199722821_ftp

[(q5-C,H,)Re(NO)(PPh3)]+ and analogons unsatu- rated chiral complexes (see element symbols along the fingertips) can form two diastereomeric adducts with prochiral alkenes, aldehydes, and ketones. The ratio of these diastereomers is a measure of the chiral recognition, symbolized by the hands, of the reaction partners. The rhenium complex mentioned is

depicted above the hands (Re: light gray, P: yellow, N: light blue, 0: dark blue, Ph, Cp: dark gray). The selectivity of alkene complexation can be analyzed (and predicted) by considering the sizes of the substituents a 4 on the alkene and correlating them with the steric conditions in the chiral complexes, which can be represented with three-dimensional bar graphs.

REVIEWS

Enantioselective Synthesis with Lithium/( - )-Sparteine Carbanion Pairs

Dieter Hoppe* and Thomas Hense Dedicated to Professor Dieter Seebach on the occasion of his 60th birthday

“Chiral carbanions”-that is, enantiomerically enriched lithium-carbanion pairs in which the carbanionic center carries the chiral information-were regarded until recently as “exotic species.” In the past ten years it has become clear that they can, in fact, play a meaningful role in enantioselective synthesis, since substitution for lithium occurs here stereospecifically, usually with retention of configuration. They are also more

readily and commonly accessible than was originally assumed. The trick lies in the use of lithium cations with chiral ligands, whether in the form of alkyllithium species used as bases in kinetically controlled, enantiotopically discriminating deprotonation, or in thermodynamically controlled equilibration in configurationally labile epimeric ion pairs. The lupine alkaloid (-)-sparteine has shown itself admirably suited as a

chiral bidentate ligand, and its efficiency and breadth of application are so far unsurpassed. This contribution constitutes an overview of the preparation of chiral reagents, covering primarily “umpoled” synthons such as homoenolates, 1- oxyalkanides with a broad pattern of substitution, and a-aminobenzyl anions.

Keywords: asymmetric synthesis * chiral building blocks - lithium (-)-sparteine

1. Introduction and Delineation of the Problem

In a series of reviews that also provide insight into the funda- mental contributions of his research group, D. Seebach has since 1969 popularized the concept of “reactivity umpolung.”[’l As a consequence, the synthetic chemist has acquired not only a simple tool for the rational planning of syntheses, but has also been stimulated in the search for new synthetic building blocks. A higher standard has been achieved particularly in the case of reagents for carbanionic synthons of the d’ and d3 type, which now leaves little to be desired with respect to controlling reactivity and various levels of selectivity. Seebach has repeatedly not- ed that the reactivity and selectivity of carbanionic reagents is heavily dependent on the nature of the counterion and the structure of the relevant aggregatesc2] It will become clear in what follows that it is precisely the apparent disadvantage of most d’ and d3 reagents--a lack or at least a weakening of resonance stabilization, and thus restricted accessibility-that lends new qualities to these species.

The carbanionic center of a lithium-carbanion pair in the vicinity of + M substituents seeks to achieve a pyramidal and therefore potentially chiral configuration; in this way it is able, under appropriate conditions, to act as a carrier of chiral information, thereby opening the way to new strategies for enantiose-

[*] Prof. Dr. D. Hoppe, Dr. T. Hense Organisch-chemisches Institut der Universitat Corrensstrasse 40, 11.48149 Miinster (Germany) Fax: Int. code +(251)833-9772

lective synthesis. Chiral ligands attached to the cation-here primarily the alkaloid (- )-sparteine (1) (Scheme 1)-have shown themselves to be astonishingly efficient aids.

1A Scheme 1. Conformations of (-)-sparteine (1).

1B

In nonpolar solvents lithium salts of carbanions form tight ion pairs, usually present as dimers, tetramers, and occasionally also higher aggregates.I2. 31 The lithium cation usually prefers an approximately tetrahedral coordination geometry saturated by four donor ligands. It is thus tempting to provide the cation with chiral, enantiomerically pure ligands and to hope that stereoselectivity will be introduced in reactions with achiral, prostereogenic substrates. For purposes of clarity our first “thought experiment” will involve a bidentate, C,-symmetric ligandC4. ’] and a ql-bound anion; in addition, we will consider a monomeric ion pair. The ion pair A bears an achiral alkanide residue; that means that any chiral induction must be due to the chiral cation (Scheme2). If both components of the ion pair (the cation as well as the anion) are chiral, the result is the pair of epimers B and epi-B. The consequences will be explored in more detail.

Angeu. Chem. In!. E d Engl. 1997, 36,2282-2316 0 WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1997 0570-083319713621.2283 S 17.50+ 5010 2283

REVIEWS

A B epiS

Scheme 2. Types of chiral lithium-carbanion pairs. X is, for example, OR, NR,; L is, for example, OEt,, THF; A,B are C- or heterosubstituents.

A is already in a position to “recognize” enantiotopic faces and groups in prochiral[61 reaction partners, since it will proceed through diastereomorphic transition states, which will in principle be energetically nonequivalent (Scheme 3 ) . This is apparent in complex D, comprising a combination of A and C: the previously enantiotopic faces Re and Si are now diastereotopic in the intermediate D, and the alkanide residue ACHY will be transferred at different rates to form the adducts E and epi-E. Hydrolysis leads finally to the enantiomers F and ent-F, one of which will be present in excess.[71 Scheme 4 depicts several examples from the early stages of the development of this tech- nique.

A similar problem is posed when A interacts as a chiral base with the prostereogenic substrate A-CH,-B: in this case the enantiotopic groups pro-S-H atom H, and pro-R-H atom H, must display different reactivities. Insofar as the resulting ion pairs B and epi-B are configurationally stable under the reaction conditions and substitution occurs stereospecifically (that is, with either retention or inversion), the enantiomeric relation- ship G:ent-G reflects directly the result of enantiotopic differentiation between H, and H, (Scheme 5) . Thus, the newly created stereocenter at the carbanionic C atom determines the stereochemistry of substitution.

However, with few exceptions (which will be discussed later), configurational stability of the carbanionic intermediate cannot be assumed;[’51 the ion pairs B and epi-B are subject to equili-

D. Hoppe and T. Hense

r 1

H

E epi-E

OH OH

F enf-F Scheme 3. Enantiofacial selection in a prochiral carbonyl compound on use of an ion pair containing an achiral residue.

bration. Scheme 6 summarizes the possible situations, where for simplicity only stereoretentative substitution is illustrated. Un- der the simplifying assumption that k , z k,> keDi, the ratio G : ent-G corresponds to the position of equilibrium B : epi-B. Especially fortunate circumstances obtain when one of the diastereomers B or epi-B crystallizes, so that in the reaction mixture essentially only one diastereomer arises. This special case of a dynamic kinetic resolution through crystallization is also referred to as “asymmetric transformation of the second order.”“ 61 An additional limiting case-kinetically controlled

Dieter Hoppe, born in Berlin in 1941, worked as a chemical techni- cian in Hannover before beginning his chemistry studies at the Uni- versity of Gottingen in 1965. He received his doctorate in 1970 with U. Schollkopx submitting a dissertation on metalated isonitriles and completed his habilitation there in 1977 with a topic drawn from the realm of p-lactam chemistry. From 1977 to 1978 he was a postdoctoralfellow with R. B. Woodward at Harvard University in Cambridge (Massachusettsj . After serving as a Privatdozent at the University of Gottingen he accepted a call to a C-4 professorship at the University of Kiel in 1985. Thenfolloweda call to the University of Miinster (1992), after a call he had declined to Hamburg (1991). His work was recognized in 1993 with an Otto-Bayer Award. He is a coeditor of “Synthesis.” His areas ofresearch relate to the development of stereoselective and especially enantioselective synthetic methods based on carbanion chemistry.

D. Hoppe T. Heme

Thomas Hense, born in 1964 in Oldenburg, began his studies in 1987 in Miinster, and joined the research group of D. Hoppe in 1992. He completed his dissertation in 1996 on the subject of kinetic resolution of racemates through (-)-sparteine-induced deprotonation. In f 997 he entered upon a postdoctoral appointment with J. Otera in Okayama (Japan) in the field ofenantio- selective catalysis.

2284 Angew. Chem. Int. Ed. Engi. 1997, 36, 2282-2316

REVIEWS Enantioselective Synthesis

L;Li H El H - H OH - entG

PhX(CH&CH, d H + rrC,H,Li chiral additive

EIX

kR A y0 B G Mq CH, Me,N

NMe, enantiotope- equilibration stereoselective H3C

OMe OMe differentiatinq substitution

deprotonation e x [a] = 53 : 47 (6% ee) [b] e.r. = 67 : 33 (34% ee) [c] ex. = 56 : 44 (6% ee) [el [91 [lo, 111 Scheme 6. Limiting cases in the substitution of chiral ion pairs

stereoselective substitution with dynamic kinetic resolution" 6a* ' 9 dl-occurs when the rate constants k, and k, differ

o - ~ g greatly, and kcpi much larger than these. In this limiting case o- (e.g., k, >> k, > kepi), the enantiomeric ratio G/mt-G is deter-

It should also be recalled that achiral carbanions, which in the ground state are planar and which bear three different substituents at the carbanionic center, become chiral in the course

x \

PhPh mined solely by the quotient k,/k,."71

e.r. = 93 : 7 (86% ee) [b]

[I21

e.r. z 99 : 1 (> 98% ee) [d] e.r. = 94 : 6 (88% ee)

11 31 Vbl

e.r. = 95 : 5 (90% ee)

~ 4 1

Scheme 4. Addition of complexes of n-butyllithium and chiral ligands to benzaldehyde with differentiation between enantiotopic faces. [a] e.r. = enantiomeric ratio; [b] 2.0 equivalents of ligand utilized; [c] with 9 equivalents, 86% ee was achieved; [dl With butylmdgneslum chloride.

L A

-R*-cH, -H, R R

of interacting with a cation (Scheme 7). Since exchange of the

H entH

Scheme 7. Chiral tight ion pairs and their racemization via achiral separated ion pairs.

cation between the enantiotopic faces on the "top" and "bottom" of the benzylmetal compounds H and ent-H normally occurs with exceptional ease, enantiomerically enriched ion pairs are subject to rapid racemization, as demonstrated by D. J.

However, if the cation is provided with a configura- tively uniform ligand, the result is epimeric, configurationally stable ion pairs, to which the above argument applies.

Thus, the areas of application for chiral lithium carbanions in enantioselective synthesis can be subdivided according to the effective mechanisms :

1. Enantiofacial selection with achiral carbanions bearing a chi-

2. Kinetically determined enantiotopic selection through de-

3. Thermodynamically controlled selection between epimeric

4. Kinetically controlled selection between diastereomeric ion

ral cation.

protonation by a chiral base.

ion pairs.

pairs during a substitution step.

We will also discuss and then utilize the complications that arise out of interaction with other stereocenters that may be present.

2. (-)-Sparteine-Modified Ion Pairs- Early Experiments and Disappointments

G entG The alkaloid ( -)-sparteineI' 91 (1) is extremely well-suited to the chiral modification of cations in carbanion pairs,'''] because in the only slightly more energy-rich conformation 1A (see

Scheme Deprotonation of a prochlral CH acid ACH,B by a chiral base and stereoselective substitution of the epimeric ion pairs.

2285 Angeu. Chem. Int. Ed. Engl. 1997, 36. 2282-2316

REVIEWS D. Hoppe and T. Hense

Scheme I)["] it can function as a bidentate ligand. (-)- Sparteine is available in large quantity and is obtained through the extraction of certain papilionaceous plants such as Scotch broom.["] In contrast to its d ias te reomer~[~~] ( - )-a-isosparteine (2) and (-)-p-isosparteine (3) (Scheme 8) it deviates

tempts at rearranging cyclopropyl car be no id^;['^".^] the best results achieved in each case are illustrated without comment in Scheme 10.

-. _. J~ N\ J 58%; 3% ee [27d] [a]

( - )-a-iscsparteine (-)-p-isosparteine 2 3 1. s B u L ~ / ~ , - ~ O ~ C

15%; 30% ee [27a]

WCH3 2.co2

H H

4 5 6

Scheme 8. Various sparteine diastereomers, along with starting material 6 and intermediates 4 and 5 for semisynthetic transformations.

slightly from C,-symmetry; it is true that 2 and 3 also occur naturally, but they are best obtained by isomerization of (-)- sparteine (1) via the dehydro derivatives 4 and 5.rz41 (+)- Sparteine (ent-1) has been described as a constituent of the shrub Sophorapachycarpa C. A . Mey.[251 It is most conveniently obtained in the form of the racemic lactam rac-lupanine (6) by extraction of seeds of the bitter lupine Lupinus albus, followed by racemate resolution through the salt of (-)-camphor-10-sul- fonic acid and finally by deoxygenation to give ent-1.[261 All the sparteine diastereomers can be easily recovered from alkaline suspensions as a result of their low water solubility.

Nozaki, Aratani, Toraya, and Noyori[". 271 first studied the suitability of (-)-sparteine (1) as a chiral additive in carbanion reactions in the years 1968-70 (Scheme 9). The greatest enan-

HO H HO H PhCHO + C,H,MgBr/l - L C H , + L C H ,

15% Ph Ph S

61 : 39 (22%ee)

Scheme 9. Early attempts at (-)-sparteine-mediated nucleophilic alkylation of benzaldehyde. [lo, 27a]

tiomeric excess (22 'YO ee) was achieved by addition of ethylmag- nesium bromide/l to benzaldehyde."n, 27a1 The procedure they utilized is only of historical since today efficient catalytically asymmetric methods are known for nucleophilic alkyl tran~fer.[~"*~.'*

Other early applications relate to the asymmetric lithiation of isopropylferr~cene['~~*~] and ethylben~ene,['~"' as well as at-

20

ca.l% ee

70%; [a, = +1.4 [27a]

Scheme 10. Early applications of (-)-sparteine-mediated lithiation. [a] The configuration is unknown.

Only very small enantiomeric excesses have been observed in ( -)-sparteine-mediated conjugate addition to en one^,[^'^ allyl- ation utilizing palladium catalysis,r311 methyltitanium trichlo- ride addition to alkanals,[321 and the acylation of lithiomethyl p-tolyl s~ l fox ide . [~~]

An astonishingly high chiral induction of 98% ee was achieved in the case of 7 by M. Guette, J.-P. Guette, and J. Capillon in the Reformatzky reaction of ethyl bromoacetate and benzaldehyde in the presence of ( - ) -~par te ine[~~I (Scheme 11). However, the authors themselves and others as well[35* 361 established, for unknown reasons, much lower ee values with substrates that differ only slightly.

EtO PhCHO Y Z n B r I l - 0 0 H OH

7 ; 46%; 98% ee

Scheme 11 (-)-Sparteine-catalyzed Reformatzky reaction [34a].

( -)-Sparteine-modified alkyllithium and alkylmagnesium complexes found early application in stereoselective anionic p~lymer iza t ion .~~~. 24b1 Remarkable in this context is the reaction of racemic I-phenylethyl methacrylate (rac-8) with cyclo- hexylmagnesium bromide/(l) , as well as with other Grignard complexes (Scheme 12). Under kinetic resolution, (S)-8 is large- ly transformed into isotactic poly(methacry1ate) , whereas (R)-8 remains behind.[24b1.

2286 Angew. Chem. Int. Ed. Engl. 1997, 36, 2282-2316

Enantioselective Synthesis REVIEWS

P O l Y - I ( W 1 MgBrfl 52%:

up to 92% isotactic

toluene, -78 “c

83% ee 0 CH, (W-8

Scheme 12 Anionic polymerization of a methacrylic acid ester with kinetic resolution via (-)-sparteine [24b].

Kinetic ’H NMR studies by Fraenkel et al. document relatively slow ligand exchange in dialkylmagnesium/( - )-sparteine compIexe~. [~~]

The metal complexes of (-)-sparteine and its isomers display a strong tendency toward crystallization. This has permitted corresponding X-ray crystal structure analyses of various Grig- nard an allylpalladium complex,[401 and several transition-metal salts.[411

White, Raston, et al. solved the structure of the (-)-sparteine complex with (methylphenylphosphinyl)methyllithium[421 (9), which crystallized as a dimer, and that with l-pyrid-2-yl-l- (trimethylsilyl)methyllithium[431 ( lo ) , which can be regarded as an azaallyllithium derivative. The structure of a-isocyano- diphenylmethyllithium/1/2THF (11) was characterized by Boche et al. (Scheme 13).[441 It is interesting that here lithium

9 [a1 10 11 Li-N, (cis) 221.3 (21 8.3) 206.0 206.5 Li-N, (trans) 216.2 (210.2) 202.0 210.3

Scheme 13. Li-N bond lengths [pm] in selected lithium/( -)-sparteine complexes. [a] Two different aggregates are present in the unit cell.

seeks contact with the isonitrile C atom, but not with the carbanionic center. The bond lengths between lithium and the (nonequivalent) N atoms of (-)-sparteine are quite variable: 202-216 pm and 206-221 pm. The structures of additional lithium complexes that possess stereogenic carbanionic centers are discussed in Section 3.

3. Enantioselective Syntheses with Configurationally Labile Lithium/Sparteine-Carbanion Pairs

3.1. Lithiated Ally1 Carbamates and Enantioselective Homoaldol Reactions

We established in 1985 that enantiomerically enriched secondary 2-alkenyl diisopropylcarbamates can be deprotonated with retention of configuration using buty l l i th i~m.[~~] This

formed the basis for an enantioselective variant of the homoal- do1 Not aware at the time of the previously described sparteine efforts, 0. Zschage began in 1988 a diplom a thesisr4’] with the task of deprotonating the (E)-2-butenyl carbamate 12 in the presence of (-)-sparteine instead of the ordi- narily employed achiral complexing agent N,N,N‘,N‘-tetra- methylethylenediamine (TMEDA), and subsequently investi- gating the resulting capture products with respect to possible enantiomeric excesses. We anticipated that the chiral base sec- butyllithium/( - )-sparteine would distinguish between the enantiotopic protons pro-R-H and pro-S-H in the methylene groups. In that case, one of the epimeric ion pairs (R)-13.1 or (S)-13.1 should be generated in excess, which would be dis- cernible from a corresponding enantiomeric excess in the capture product 14 (Scheme 14, Table 1).

It quickly became apparent that the deprotonation here is not kineticalIy controlled, but the process is nevertheless extremely e f f i ~ i e n t . [ ~ ~ . ~ * ] In the very first experiment deprotonation with sec-butyllithium/( - )-sparteine (1) in isopentane/cyclohexane and addition of tetra(i~opropoxy)titanium[~~~ to the suspension of the organolithium intermediate, followed by 2-methyl- propanal, led to the (2)-anti-configured homoaldol adduct 17 a [R’ = CH(CH,),] with 83% ee. Because of the complete 1,3- chirality transfer[s41 during carbonyl addition, the titanated intermediate (R)-14 must have been present here with the same enantiomeric excess, corresponding to the diastereomeric excess in the (-)-sparteine complex 13.1. Nevertheless, the reaction at first proved not to be reproducible; only a nearly racemic product was subsequently isolated. In contrast to the successful experiment, crystallization failed to occur after deprotonation. Our suspicion was confirmed that dynamic kinetic racemate resolution[551 occurred in the course of crystallization; the epimeric (R)- and (S)-13.1 are in equilibrium in solution, and one diastereomer crystallizes preferentially. A certain amount of cyclohexane is required for the crystallization, however, and this had been introduced in sufficient quantity into the first experiment only due to the use of a sec-butyllithium solution in isopentane/cyclopentane with the unusually low concentration of 0.5 M. An optimized procedure, in which a defined quantity of cyclohexane was added to the hexane solution and n-butyllithium was employed as the base, resulted unambiguously in substitution products with 90-94% ee.[551

Metal exchange occurs under the refined conditions[551 with complete inversion of configuration, and the titanium intermediate (R)-14 is configurationally stable up to at least -40°C. Thus the epimeric ratio of (S)- and (R)-13.1 determines the enantiomeric ratio of the homoaldol adducts 17/ent-17. The stereoselectivity is predominantly reagent-controlled; that is, equally good results are achieved for the “mismatched pair”[16c*d* s61 with chiral aldehyde components.[57. 581

The crystalline suspension of (S)-13.1 can also be trapped with retention of optical activity using trialkyltin chloride (Scheme 15).[”] This results, with low regioselectivity and about 80% ee, in a mixture of the a-adduct (S)-20 (inversion) and the y adduct (S)-19 from an anti-S,‘ reaction. However, stannylation of the titanium intermediate (R)-14 leads with high efficiency to the (IZ,3R)-configured stannane 19, from which the tributylstannyl derivative (R)-19b is obtained with about 95% ee.

Angew Chem. Int. E d Engl. 1997, 36, 2282-2316 2287


Ti(ORr), _ _ _ _ _ _ _ _ _ _ _ _

NPr, (S)-14

crystallization

Ti(ORr), + - H2.C q l - ! !

NPr, (R)-14

NRr, 12

= OCb

1. Hg(OAc),

Scheme 14. Dynamic kinetic racemate resolution in the (-)-sparteine-induced deprotonation of 12; lithium-titanium

~ r 16 M = Ti(OPr), 18 exchange and enantioselective homoal-

+ - [ R1$Zb ] R1%

(R)-14 -7O'C H 3 C e 2Ti(ORr)a - R'I?CO CH, OCb

2. BF3-OEtz I mCPBA+ RZ 9' OM

____________________- -

(R)-15

"z0L 17 M=H'

Table 1. Various optically active homoaldol products that were prepared. ~ ~ ~ ~

17 R' R2 Yield [%] ee[%] Yield(l8)[%] Ref

a (CH,),CH H 90 90[a] 89 [481

c CH,C(CHd, H 93 84[a] 90 [481

e (CH,),C=CH-CH, H 62 92 7O[c] ~501 f H,C=CMe H I 8 W a I [bl 1511 g H,C=rPrC H 81 90 [bl 1511

b CH, H 95 SO[aI [bl [481

d CH,CCH, H 90 [bl 1491

h CH, CH, 92 82 [bl 1481

[a] Nonoptimized preparation of 13.1. [b] Not determined. [c] A different oxida- tion method was utilized; see text.

The stannanes 19 are storable homoenolate reagents that are activated by the addition of titanium tetrachloride (Scheme 16, Table 2) .[55, 5 9 , 601 All indications suggest a stereospecific tin-titanium exchange (similar to that shown by Marshall for tin-tin

to give a trichlorotitanate, and pericyclic syn-S,' addition of the latter to the aldehyde. Starting with stannane (R)-19 one obtains the enantiomerically enriched homoaldol adduct 22, whereas the antipode (S)-19 leads to ent-22. Thus, both series of enantiomers are accessible via this Lewis acid mediated variant from the same lithium intermediate (S)-13- 1. The strength of the variant lies in a smooth reaction with sterically demanding ketones.

The extension of thermodynamically controlled asymmetric lithiation with a subsequent homoaldol reaction to the diisopropylcarbamates of (E)-2-hexen-l-o1, 3-methyl-2-buteno1, or (E)-3-trimethylsilyl-2-butenol provided only modest enantiomeric excesses (41 - 76% ee ) , because optimized conditions for the crystallization had not yet been established.[481

(inversion) 4

- do1 reaction [48.51,52,55].

nBuLi I (-)-sparteine I

"30n R,Sn OCb

(S)-l9a R = Me: 48%; 82% ee

(S)-19b R = Bu: 22%; 82%' ee R,SnCI (anfi-S;) I

(S)-2Oa R = Me: 21%; 82% ee

(S)-2Ob R = BU: 58%; 82% 88 R,Sn OCb

(R)-19a R = Me: 73%; 86% ee

(R)-19b R = Bu: 80%; 95% ee

Scheme 15. Synthesis of enantiomerically enriched alkenylstannanes from the lithium complex (S)-Wl [55].

2288 Angew. Chem Int Ed. Engl. 1997,36,2282-2316


TiCI, 1 H 3 C q T i C I , I RLRsC=O

H3c-l R3Sn OCb OCb

(R)-19 L J

(R)-21

H , C p , TiCI, I H 3 C 9 TiCI, 1 RLRSC=O

(antis;) R,Sn OCb OCb

(S)-19

L OCb _] enf-22

Scheme 16. Lewis acid induced enantioselective homoaldol reaction with 3-stannyl- 1-alkenyl carbamates [55]. RS, RL: see Table 2; OCb = O,CON(iF’r),.

Table 2. Enantioselective Lewis acid catalyzed homoaldol reactions [55] _____~ _ _ _ _ _ _ ~

22 Starting R L RS Yield[%] eel%] Ref. material

22a (R)-19a enr-22a (S)-19a 22a (R)-19b 22b (R)-19b 22c (R)-19b 22d (R)-19b 22e (R)-19b

[a] See text.

(CH,),CH H 91 88 [55] (CH,),CH H 82 82 I551 (CH,),CH H 96 96 [55] (CHd3C CH3 80 74 [55] EtOCO(CH,), CH, 84 94 [55] EtOCO(CH,), CH, 91[a] 94 [SS] CzH, PhCO(CH,), 67[a1 94 [621

In collaboration with Boche et al. it proved possible to obtain an X-ray crystal structure analysis of sparteine complex 23.1 (Figure 1) . I631 This revealed the (IS)-configuration at the carbanionic center and verified our earlier assumptions regarding the structure of lithioallyl carbamates: they are monomeric even in the crystalline state, because the lithium cation is offered optimal preconditions for four-fold coordination in the a-position. The allylic system is I?’-bonded, and the electron-donating carbamoyl 0x0 group and the nitrogen atom of the tertiary diamine function as residual ligands. Firm attachment of the cation at the a-position is the key to high y-selectivity in the course of carbonyl addition. This also causes the observed tor- sional stability in most cases of the j?,y-double bondr641 and presumably contributes much to increasing the barrier to racemization in chiral lithium derivatives.

The lithiated secondary 2-alkenyl and 2,4-alkadienyl carbamates 24 and 25 (Scheme 17), readily accessible in enantiomerically enriched form, are configurationally stable below - 70 “C ;[451 to our knowledge they represent the first known examples of allyllithiurn derivatives with configurationally

Figure 1. X-Ray crystal structure analysis of ~‘-[(lS,2E)-1-(N,N-diisopropylcar- bamoyloxy)-3-trimethylsilyl-2-propen-l-yl]lithium~(-)-sparteine (23.1)[63]. A11 hydrogen atoms have been omitted, with the exception of H-l and H-2. (C Atoms gray, 0 atoms dark gray, N atoms black).

VCFL OCb

24 25

Scheme 17. Configurationally stable alkenyl carbamates 24 and 25. L, = TMEDA.

stable stereogenic, metal-bearing C atoms. As we reported in 1990, the enantiomerically enriched lithium derivative 24 can be obtained not only from the optically active carbamate, but also with sec-butyllithium/( -)-sparteine under kinetic resolution of the corresponding racemic allyl carbamate 24 (H for Li/L, in ra~-24).[~~7 601 The rich chemistry of the compound[45* 60* 651

and 25,r661 as well as their analogues, is governed by their tor- sional behavior; further discussion of this point would exceed the bounds of this review, however.

The value of the enantiomerically enriched homoaldol adducts in stereoselective synthesis extends far beyond formal hydrolysis to carbonyl compounds; numerous stereoselective transformations of the (Z)-vinyl carbamate group have been developed by P. Kocienski as well as by us.[673 Oxidative de- blocking1711 of adduct 17c or 17e (Table 1) leads to completion of the syntheses of (+)-quercus lactone A[52,481 (18c) and (+)- eldanolide (18e) .Iso1 This procedure is readily transferable to the synthesis of diverse y-lactones (Scheme 18).

3.2. Benzyllithium Compounds

Primary and secondary benzyl N,N-dialkylcarbamates are deprotonated with the same ease as the corresponding allyl esters.[”’ Whereas the lithium derivatives of chiral secondary benzyl carbamates are configurationally stable at - 70 “C, this is not true for lithiated primary benzyl carbamates, although the “Hoffmann test”[571 for the complex 27.TMEDA demonstrates

Angeu. Chem. h i t . Ed. Engl. 1997, 36, 2282-2316 2289

REVIEWS D. Hoppe and T. Heme

18c 82%ee 18e 92%ee

H 3 C q % . ..Li I 1 H+ 0H3:\ o c R HO OCb

epimer leads to a dynamic resolution. The configuration of the favored ion pair has not been established with certainty; since we have found inversion in carboxylation of a similar complex (29, CH, for l-H),[74a*b1 there are strong arguments for the ( S ) c~nfiguration."~* 761

P. Beak et al. succeeded in carrying out stereoselective lithiation of a series of benzyl systems; the results are collected along with an extensive discussion of the mechanistic aspects in a recent review.["] N-Methyl-3-phenylpropionamide (30) reacts with two equiv-

alents of butyllithium/( - )-sparteine to give the dilithium derivative 31 .1,[771 which leads with various electrophiles to amides substituted at the benzyl position with 60-94% ee (Scheme 20). Similar results were achieved when 30 was pre-

Scheme 18. Synthesis of optically active fl-methyl-y-lactones by enantioselective homoaldol reactions [SO]

increased stability at the microscopic This can also be concluded from the following series of experiments; Benzyl N,N-diisopropylcarbamate (26) was deprotonated with sec- butyllithium/( -)-sparteine in ether at ~ 78 "C, and after 4 h the epimeric mixture of ion pairs 27.1 was trapped by introduction of carbon dioxide into the homogeneous reaction mixture (Scheme 19). After esterification with diazomethane one iso-

0 sBuLi/l

PhXOKNPr, m

so!vent,-70 "C

26

\ / _____)

(5)-27-1 (R)-27-1

MeO,C H 0 Ms0,C H 0

PhAOKNPr, + PhLOKNPrz

(a-28 (W-28

Et,O (91%) 57:43 (14%ee) hexane (77%) 91 : 9 (82% ee) hexane (solid) (50%) 95 : 5 (90% ee) hexane (solution) (18%) 69 : 31 (38% ee)

Scheme 19. Investigations into the configurational stability of lithiated benzyl carbamates.

lates the mandelic acid derivatives (+)-(S)-28 and ( - ) - (R)-28 with only 14% ee in favor of (S)-28. Under identical experimental conditions but with hexane as the solvent crystallization occurred, and (+)-(S)-28 was formed with 82 % ee. In a third experiment the solution was separated from the crystalline mass, and the two were treated separately; the enantiomeric excesses amounted to 38% and 90% ee, respectively.

It is thus very probable that the lithium complexes equilibrate even at - 70 "C, and that here also the crystallization of one

Li - 31-1

EIX Yield ["A] ee [%] 3- MeSiCI 86 94 32b CH,I 84 70

1. EIX 2. HzO I

32 c 32 d 32e 32 f

Me,Sj

A N , C H 3 1. sBuLi Bu,Sc 0

a N , C H 3 2. Me,SiCI I * HSC6 HSCB H

321 (60%ee) H

32a (60% ee)

Scheme 20. Enantioselective substitution of N-alkyl-3-phenylpropionic acid amides [77]

pared first in the absence of (-)-sparteine (1) and the latter was added only subsequently. This argues in favor of equilibration between the epimers 31.1, a suspicion that has recently been verified.['*] On the other hand, racemization-free lithiodestannylation/silylation proved successful with the enantiomerically enriched stannane 32f to give silane 32a; under these reaction conditions the carbanionic intermediate was configurationally stable. It is noteworthy that reaction in this case can be carried out in THF without displacement of ( - ) ) -~par te ine . [~~~l Equally efficient are transformations of the 2-methoxyphenyl derivative; adducts of the type 32 (2-MeOC6H, for C6H5) offer the possibility of transformation into enantiomerically enriched co~marins.[~'"l

As in the case of 31.1, configurational stability at - 78 "C was demonstrated for a series of additional benzyllithium-( -)- sparteine complexes. Warming of the reaction mixture is required to cause epimerization. This opens up interesting pathways for controlling stereoselectivity, as will be demonstrated.


Enantloselective Synthesis REVIEWS

M. Schlosser and D. Limat["] discovered that N-Boc-N- methylbenzylamine (33) is smoothly deprotonated by sec-butyllithium/( - )-sparteine (Scheme 21). The resulting enantiomeric excess and the direction of chiral induction depend not only on the solvent and electrophile, but also on the length of time the

H Y S 0 sBuLV 1 d - N A 0 B u I solvent *

\ Me

33

H El 0 2.lh 1. EIX d , , K O f B u +

\ Me - I

35

34-1 + epi34-1

ent-35

Figure 2. X-Ray crystal structure analysis of z-(N-methyl-,V-piva1oylamino)- benzyllithium.( -)-sparteine (36.1)[82]. All hydrogen atoms have been omitted with the exception of the benzylic hydrogen atoms. (C atoms gray, 0 atoms dark gray, N atoms black).

37 3&1

EIX solvene 35 : en135 ee [%l

DCaCPh hexaneIa1 95.0 : 5.0 90 THF 7.5: 92.5 85

CH,, hexane 87.5: 12.5 75

hexane 91.5 : 9.5 81 THF 7.5: 92.5 85

THF 10.0: 90.0 80

co* Scheme 21 amine (33) [79]. [a] The same excess enantiomer is formed in ether.

Enantloselective lithiation and substitution of N-Boc-N-methylbenzyl-

reagent was kept before quenching it. Only after about 2 h at - 75 "C is maximum enantiomeric excess achieved; exchange of hexane for THF causes the configuration of the product to be reversed, and precipitation of a solid is observed in THF after 1 h.

Through deprotonation and subsequent carboxylation of (S)-[I 0133 with sec-butyllithium/TMEDA~sol it was established that the ion pair was configurationally labile in all the solvents employed at 75°C. The ratio of the ion pairs 34.1 and epi-34. I is therefore thermodynamically determined.[*'l Boche et al. conducted an X-ray crystal structure analysis on the N-pivaloyl derivative 36.1 and found it to possess the (IS)-configuration (Figure 2).18'] What is the cause of the solvent-dependent stereoselectivity of the substitution step? The authors suspect that in both cases an ion pair with the (S)-configuration is present, but the stereoselectivity in the substitution step is reversed under the influence of the solvent. However, all the results are also consistent with the following interpretation: The predominant ion pairs in hexane and ether solution possess a reversed configuration relative to the aggregate obtained through THF crystallization, and the substitution step follows the same configurational pathway in each case.

Beak et al. describe a (-)-sparteine-mediated lithiation of N-Boc-N-(pmethoxypheny1)benzylamine (37), followed by enantioselective alkylation or addition to carbonyl compounds and imines (Scheme 22).IS3] In a formal sense the p r o 3 H atom

- EIX 0";:"" 39

EIX 8 MeOTf 81%; 94% ee b EtOTf 78%;94%ee c AllOTf 69%; 93%- d BnOTf 73%;96%ee

Scheme 22. Enantioselective lithiation and substitution of N-Boc-N-(p- rnethoxypheny1)benzylamine (37) [83]. Ar = 4-MeO-C6H,; Tf = F,CSO,; All = CH,=CHCH,.

in 37 is substituted, and the resulting enantiomeric excesses in most cases range around 95% ee.

The configuration of the dominant intermediate 38.1 is unknown.[841 As we have previously demonstrated for a lithiated benzyl arba am ate,'^^^] it can be reversed by stannylation- delithiostannylation (Scheme 23) .Is3] It is important to note here that the intermediates complexed with ( - )-sparteine are configurationally stable. It follows that one can obtain the oppositely configured tertiary amines (S)- and (R)-41 by the same sequence of methylation, deprotonation, and alkylation, with subsequent oxidative deblo~king . [~~"]

In the case of the N-Boc-N-(3-chloropropyl)benzylamine 42a it proved possible to show with the aid of the (@-deuterium derivative 42 b that the (- )-sparteine reagent preferentially abstracts the pro-S-proton in 42 a (Scheme 24) .[8s1 Intramolecular cycloalkylation of the (S)-configured lithium derivative 42 a - 1 to pyrrolidine (S)-44a occurs very rapidly, and therefore virtually free of racemization. Alkylation with stereoretention is an astonishing The reaction is transferable with compar- able efficiency to a whole series of arylmethyl- and heteroaryl- methylamines of the type 42. N,N-Diisopropyl-2-ethylbenzamide (45) was transformed by

P. Beak et al. into the (-)-sparteine-lithium complex 46.1[s61

Angeu Chem Int Ed EngI 1997,36,2282-2316 2291

D. Hoppe and T. Hense REVIEWS

H,C . Ph

HaC Li I TMEDA 1, AllOTf Li I 1 9 4 3

p h A N , ~ c nBuLil1 ,!,,,~oc CH,OV . phAN,Bo~ nBuLiITMEDA &3oc 2 . CAN - Ph I

Ph I I I I Ar Ar k Ar Ar

38 1 37 1.nBuliI l

2. Me,SnCI

(S)-39a 90% ee (99% ee)

40-TMEDA

4 SnMe, L i l l CH H,C Li I TMEDA 1 , AllOTf

A i , & c nBuLilTMEDA, x N O B o c 2.CAN . - Ph I Ar

Ph I , A y , & c nBuLi I 1

I I Ar Ar Ar Ar

39e enf-38-1 enf40-TMEDA (W-41 97%; 90% ee 90% ee (99% ee) 98% ee

Scheme 23. Enantiodivergent synthesis of tertiary benzylamines [83a]. CAN = (NH,),Ce(NO&; Ar = p-MeOC,H,.

W H

CI

BuLdl Ha Ldl toluene, -78 “C &BOC ____t

CI

42 (S)434 42-44 a H:=H

b H = D

( 9 4 4 72%; 96% ee

Scheme 24. Synthesis of (S)-N-Boc-2-phenylpyrrolidine by intramolecular substitution [85].

and then alkylated. All experimental indications are that the rare case of dynamic kinetic resolution (Scheme 6) has been realized.[871 The epimers (R)- and (S)-46.1 are in equilibrium, and one [presumably (S)-46.1] reacts preferentially. In the process, substitutions with alkyl halides and alkyl tosylates take opposite courses (Scheme 25). No such strong dependence on the leaving had previously been observed for alkylating agents.

I (R) 46.1 45 (S)-46.1 , 1 1

47 enf-47

Scheme 25. Enantioselective lithiation and substitution of 2-alkyl-N,N-diisopropyl- benzamides [86.87].

The (-)-sparteine complex of the dilithium salt of 2-ethyl-N- pivaloylaniline (49.1) is configurationally stable at - 78 “C. On- ly after equilibration between the epimers 49.1 and epi-49.1, which occurs upon raising the temperature, does electrophilic substitution lead to good enantiomeric excessesr881 (Scheme 26).

The two diastereomeric complexes 49.1 and epi-49.1 are present before equilibration in roughly equal amounts. Their re-

0

48

49-1 epi-49 -1

50 83:17 to 955 en150

Scheme 26. Enantioselective lithiation and substitution of 2-ethyl-N-pivaloylaniline [88]. El = alkyl, Me,Si, and others.

activities toward electrophiles differ; from subsequent experiments a difference AGGi+49.1 - AG&.l = 3.4 kJmol-’ was established for trimethylsilylation at - 78 oC.[88b1 This can be exploited as follows (Scheme 27): If one adds to this mixture only half an equivalent of trimethylsilyl chloride, primarily 49.1 is trapped, with formation of the (R)-configured silane 50a. Excess ally1 bromide transforms the residual epi-49.1 into the oppositely configured product ent-50b.

The configurational lability of lithiated intermediates at higher temperature permits recycling of the less reactive epimer into the other (“diastereomeric recycling”[88b1) through a warming and cooling sequence (“warm and cool protocol”[88b1) as a means of increasing the enantiomeric excess. As a result of warming to - 25 “C, a 49.1 : epi-49.1 ratio of 92: 8 is established, which is then frozen by cooling the reaction mixture to - 78 “C. A trapping experiment with excess trimethylsilyl chloride produces the enantiomers 50a and ent-50a in a ratio of 92:s (84% ee). However, if the electrophile is added in two portions of 0.45 equivalents each, with warming to -25 “C in between, the result is 50a with a 98 % ee (e.r. = 99: 1).

2292 Angen. Chem. Int. Ed. Engl. 19!37,36,2282-2316

Enantioselective Synthesis

1. 0.5 equiv Piv, ,Li

Piv,NOLi Lill N l i / l MesSiCI W C H , + &CH,? 2. AllBr

\ \

49-1 epiQ9 4

Piv, ,H

50a ent-5Ob

39%; 52% ee 32%; 44% ee

Piv, /Li Piv,N,Li N Ldl

P C H , \ + ~ C H 3 \

I epiQ9.1 + - 2 5 % 49.1

1 + Me,SiCI i 50a ent-50a

Scheme 27. Differing reactivities of the diastereomeric ion pairs 49.1 and epi-49.1: “diastereomeric recycling.”[88b]

a-Monosubstituted benzyllithium compounds thus assume an intermediate position with respect to their configurational stability, and in favorable cases their behavior can be prear- ranged by the selected reaction temperature. Configurational lability permits efficient dynamic kinetic resolution at higher temperature, whereas freezing the equilibrium between the epimers opens the possibility of thermodynamically governed reaction control.

V. Snieckus et al. established a high enantiomeric excess by deprotonation of the 2-ethylphenyl carbamate 51 with subsequent silylation (Scheme 28) .[901 The configuration of the dominant products 53 and intermediates 52.1, as well as the extent of the configurational stability, are so far unknown.

2 equiv dkNEt2 sBuLil1 ,Pr20,-78 OCC

x 51

a X=OMe b X = SiMe,

53

a X = OMe; 50%; 92% ee b X = SiMe,; 58%; 69% ee

Scheme 28. Enantioselective lithiation and substitution of 2-ethylphenyi N,N-di- ethylcarbamates [90].

REVIEWS

3.3. Chiral Lithium Indenides

The epimeric ( - )-sparteine complexes of I-lithioindenyl N,N-dii~opropylcarbamate[~’] (55a. 1 and epi-55a. 1) rapidly equilibrate at temperatures around 0 “C, and produce upon silylation the optically active silane ( +)-56a’921 with only 16% ee (Scheme 29). In a similar way, one obtains from the 2- methylindenyl derivative 54b via the corresponding indenides

\ NPr, -

54 =OCb

a : R = H

SiMe,

R

b: R = CH,

O Y O

\ OCb

I NPr, 56

55.1 + epi65.1

a: 80%; 16% ee b: 97%; 6% ee C: 63%; 51% ee with tj-a-isosparteine (2)

Scheme 29. Lithiation and silylation of indenyl carbamates 191. 961

55b.l and epi-55b.1 the silane ( +)-56b‘92] with only 6 % ee. ‘H NMR spectra in [DJtoluene could be obtained from both of the indenide complexes 55a. 1 and 55b 1 (Figures 3 and 4), and

_ - I

7.6 7.0 6.4

-6

Figure 3. Excerpt from a ‘H NMR spectrum (300 M H r ) of [l-(~~”.N-diisopropyl- carbamoyloxyj-lH-inden-l-yl)lithium.( - j-sparteine (55a- I and epi-SSa 1) in [D,]toluene at -15°C: [91]. The 5pectrum indlcales the presence of tuo diastereomers in the ratio 60:40; these interconvert only slowly. if at ali.

these verify the presence in each case of two diastcreomers in a ratio of roughly 60:40.[91 -941 This in turn indicates an energy difference AG,,, of 0.9 kJ inol- ’.

Semiempirical calculations (MOPAC, PM3)[951 predict for the ground state energies of the complexes 55b.2 and epi-55b.2,

Angrw. Chrm. Int. Ed. Engl. 1997, 36. 2282-2316 2293


vided by the I-butyl derivative 57b, although here the regioselectivity is reversed even sooner to the benefit of the y-adduct (S)-60h.

I I I 7.5 7.0 6.5

-6

Figure 4. Excerpt from a ‘HNMR spectrum (300 MHz) of[l-(NJ-diisopropylcar- bamoyloxy)-2-methyl-lH-inden-l-yl]lithium~( -)-sparteine (55b. 1 and epi-55b. 1) in [DJtoluene at ~ 10 “C[91]. The sharp signals of the “cyclopentadienyl protons” H-3 and H-3’ (in the diastereomers) are A 6 ~ 0 . 1 apart.

which bear the C,-symmetric (-)-a-isosparteine as ligand, a higher difference of 2.5 kJmol- I , and the silylation experiment in fact led to (+)-56b with 51 YO ee.[961

To our great surprise, the ion pairs 58.1 derived from l-alkyl- 3H-indenes 57 proved to be the most efficient representatives (Scheme30).[971 As I. Hoppe observed as early as 1990, the

1 a nBuLi, EbO, 1

57 k a: R = CH, b: R =n-C,H,

4 A (IS)-58.1

crystallization

li

q+ 6 El

El

(1 R)S8.1 K3-59 ( R P O

Scheme 30. Lithiation, dynamic kinetic resolution of (1 S)-58.1 by crystallization and enantioselective substitution of I-alkyl-3H-indenes [97].

1 -methyl derivative 57a is rapidly deprotonated by n-butyllithium/( - )-sparteine in ether, and a yellow solid crystallizes upon warming the reaction mixture. After addition of an acid chloride or an the 1 -substitution product (R)-59 is usually isolated with an enantiomeric purity greater than 95% ee. Only with bulky carbonyl compounds such as 2,2- dimethylpropanal or acetone does a 3-substitution product of the type (S)-60 predominate (Table 3). Similar results are pro-

Table 3 . Lithiation and stereoselective substitution of I-alkyl-3H-indenes [97].

Starting EIX Products [a] El 59:60 Yield[%] material

57 a 57 a 57 a 57 a 57 a 57 a 57 b 57 b

Me0,CI MeCOCl PhCOCl PhCHO tBuCHO MeCOMe PhCOCl PhCHO

(R)-59a (R)-59 b (R)-59c (R)-59 d [bl (R)-59e[b] (R)-59f + (S)-60f (R)-59g (R)-59h[b] + (S)-60h[b,c]

MeOCO MeCO PhCO PhCHOH tHuCHOH Me,COH PhCO PhCHOH

>91:3 64 >91:3 63 >91:3 14 >91:3 67

<3:97 55 31169 36

>95:5 79 35:65 52

[a] Unless indicated otherwise. the enantiomeric excess is greater than 95 % ee. [b] Epimers with respect to the 1’-stereocenter. [c] The ee value could not be determined.

These results are best interpreted with an assumption of equi- librating dissolved ion pairs (1s)- and (1R)-58.1, from which one epimer crystallizes and reacts stereoselectively as a solid at low temperature with the carbonyl compound added as electrophile. It was long unknown which configuration applied to the crystallizing ion pair. An X-ray structural analysisr971 was ultimately successful for the dominant complex 58b. 1 (Fig- ure 5) . This established a (1s)-configuration along with y3-c0- ordination for the indenide to the lithium cation. The C1 -Li and C3-Li distances of 243.2 and 233.4 pm are unusually long.

Figure 5. X-Ray crystal structure analysis of q3-[(1S)-l-butylindenyl]lithium.(-)- sparteine 58b’l[47]. All hydrogen atoms have been omitted.

Carbonyl addition thus proceeds with retention. Apparently the attacking carbonyl group reversibly displaces one coordination site of the ally1 anion with the formation of intermediates 61 or 62, which react further by transfer of the carbonyl compound with allylic inversion to give adducts 63 or 64 (Scheme 31).[991 Route A should be favored because of the weaker C1-Li interaction. Only when the C-C bonding step leading to 63 is heavily burdened sterically should route B with formation of the y-adduct 60 gain the upper hand.

The (-)-sparteine complexes 58.1 are quite labile. Addition of THF causes one coordination site of the indenide and also

2294 Angew. Chem. Int. Ed. Engl. 1997,36,2282-2316

Enantioselective Synthesis REWEWS

66 EIX

an intermediate, which can be trapped with various electrophiles to give products with high enantiomeric enrichments. Conclu- @$ - [ q o L i /I- (Wd9 sive control experiments prove the configurational stability of 67.1 under the selected reaction conditions. The configuration of 67.1 was derived under the assumption that transformations with alkylating and silylating agents proceed as anti-E reactions, and hydroxyalkylations with ketones as syn-E reactions.[’041

X R ’ R’

route^ R 61 63

k --.) (S)-60

Ph nBuLll toluene. - -78 O C -4.’ Ph

R 62 64

R

1 0 0 Scheme 31. Formation of the b- and y-adducts 59 and 60.

67.1

sparteine on lithium to be displaced; (1S)-58a- 1 is transformed into the ql-(THF), complex rac-65, which has also been characterized by crystal structure analysis (Scheme 32, Fig- ure 6) .I9’, “’] Reaction of the latter with benzaldehyde produces the completely racemic y-adduct me-60a. Quite generally, the regioselectivity of substitution is strongly influenced by the ligands on lithium, since in the complex 58-TMEDA there is a considerable tendency toward y-substitution.“’”

C,H, Table 4. Enantioselective deprotonation and substitution of 66. HO LiflHF),

Major product Yield[%] ee [“lo]

68 a 74 92

D L i , , + EN H,COTf H,CI 68a 73 95 H,C=CHCH,Br 68 b 12 Y4

en1-68e[b] 49 YO

CH3 CH3 CH3

(lS)-58a.l rac-65 raC-608 PhCH,Br 6 8 C 70 96 68dIaI 46 96

Scheme 32. Formation of the complex ruc-65 and its addition to benzaldehyde. Me,SnCI (CH,),C=O enr-68 f [c] 77 98

Figure 6. X-Ray crystal structure analysis of rac-(3-methylinden-l-yl)lithium. (3THF) (ruc-65) [97]. All hydrogen atoms with the exception of those on C-l and C-2 have been omitted.

_ _ _ _ _ _ _ _ _ _ _ _ _

[a] Together with 24% of the psilane 69d (94% ee) [b] Together wlth 24% of the 7-stannane enr-69e. [c] El = 1-hydroxycyclohexyl.

In order to gain access to the opposite series of enantiomers, the authors again utilized the sequence of stannylation of 67-1 followed by lithium-tin exchange,[”51 which led to ent-68 (Scheme 34). This lithiostannylation was carried out in the pres-

1. nBuLl1

N Me3Sn N Ph+YSnMe3 N

Ar’ ‘Boc Ar’ ‘Boc Ar’ ‘Boc

66

I 1 . nBuLi/l 2. AllylBr I

ent68e ent69e 49%; 90% ee 24%; 90% ee

1. nBuLl 1 2. AllylBr

Ph N Ph Ar’ ’Boc

68 e n t a b 72%; 94% ee 60%; 74% ee 77%; 80% ee

from enf68e from ent69e

Ar /“Boc

3.4 Lithiated Cinnamylamides

As P. Beak and G . A. Weisenburger recently one of the enantiotopic methylene protons in (E)-N-(p-methoxy- pheny1)cinnamylamide (66) is released with outstanding differentiation by n-but)..llithiuml(-))-sparteine (Scheme 337 4). The q3-allyllithium compoundr103J 67.1 has been formulated as

Scheme 34. Configurational inversion through stannylation and lithiodestannyla tion [102].

Angew Chem h i Ed Engl 1997, 36, 2282-2316

2295


ence of (- )-sparteine, because uncomplexed 67 is configurationally labile.

The high y-selectivity and enantioxlectivity of the methylation remains intact in corresponding transformations of the cyclohexylallyl derivative 70 as well, although the result is the oppositely configured products 71 and 72, with (Z) - and (E)- double bonds['061 (Scheme 35). Since the enamides of the corresponding aldehydes are subject to hydrolysis, these experiments demonstrate an additional route to enantiomerically enriched homoenolate equivalents.

1. nBuLi/l, toluene 2. CH,I

N Ar' 'Boc

70

71 43%; 84% ee 72 27%; 92% w Scheme 35. Lithiation and methylation of the cyclohexyl derivative 70 [102]. Ar = 4-MeOC6H,.

4. Configurationally Stable Chiral Ion Pairs through Deprotonation of Achiral and Racemic Precursors

4.1. Preparations of Non-Resonance-Stabilized 1-Hydroxyalkyllithium Derivatives

Enantiomerically enriched 1-(a1koxymethoxy)alkyllithium derivatives of the type 74 were recognized to be configurationally stable by W. C. Still and C. Streekumar in 1980; the compounds fail to racemize below - 40 "C in ethereal solvent~.["~* They were prepared by lithium-tin exchange starting from the precursor 73. Transmetalation is accomplished, as is the subsequent methylation to 75, with stereoretention (Scheme 36).[107,109,1101

73 ,CH3 Li-0 CH3

R R 0 /\OMe

74 75

Scheme 36. Preparation of enantiomerically enriched 1 -oxyalkyllithium derivatives by lithiodestannylation [107].

The tin derivative 73 was obtained through a laborious racemate resolution by way of diastereomeric esters, although simpler pathways are now known, most of which involve asymmetric reduction of acylstannanes." 'I

In contrast to the above-described lithiodestannylation, reductive cleavage of chiral monothioacetals 76 is not suitable for stereoselective carbanion generation (Scheme 37) ,[I ''I because

- naphthalene 76

I- 1

R I T O j + Li+ NaphthLR' OR' -naphthalene )FL Li

R2

77 + ent-77 78

Scheme 37. Preparation of racemic a-oxyalkyllithium derivatives by reductive desnlfenylation.

it proceeds via a configurationally labile radical intermediate 77 due to the single-electron transition involved. This reaction thus leads to the racemic products 78.['13]

Formation via deprotonation is ruled out by the extraordinarily low CH-acidity of dialkyl ethers. The situation is more favorable for esters because of the possibility of efficient complexation of the lithium reagent[114] and the associated increase in kinetic acidity, as well as dipole stabilization of the ion pair, although a competitive nucleophilic attack is a potential threat. Thus, only lithiomethyl derivatives of a tert-butyl methyl ether"' 51 (79) and sterically blocked benzoic acid esters (80" 16]

and 81" "I) could be obtained (Scheme 38); persistent homo- logues with primary alkyl chains cannot be generated in this

79 80 R = iPr

81 R = fBu

Scheme 38. I-Oxymethyllithium derivatives accessible by deprotonation [I 15,116a, 1171.

As expected, the methyl N,N-diisopropylcarbamate" 19] 82 is easily deprotonated by sec-butyllithiumlTMEDA in diethyl ether or pentane as solvent (Scheme 39); addition of the lithium intermediate 83.TMEDA to aldehydes and ketones to give diol derivatives of type 84 is straightforward.['201

This reaction is applicable to the ethyl carbamate, although "the faithful servants" that one called upon in the case of the

83 84 Scheme 39. Preparation and carhonyl addition of I-(N,N-diisopropylcarbamoyl- oxy)methyllithinrn (83) [120b].

2296 Angew. Chem. Inf . Ed. Engl. 1997,36,2282-2316


bulky carbamoyl group proved hard to dismiss; subsequent hy- drolytic cleavage of N,N-dialkylcarbamates of saturated alcohols cause considerable difficulties, and only reductive methods with large excesses of diisobutylaluminum hydride[”’] under drastic conditions have so far led to success.

A general solution to the problem was achieved with IJ-oxazolidine-3-carboxylic esters of the types 89[1221 and 90[1231 (Scheme 40) .[’ 221 2,2,4,4-Tetrasubstitution accomplishes extremely efficient shielding of the carbonyl group, but incorpora-

0 MeSO H clco(occ13) 3 ,N-H - H O X

85 R’ = CH, 06 2R’ = (CHJ,

07 R’ = CH, 00 2R‘ = (CH,),

2

Scheme 40. General synthesis of 1,3-oxazolidine-3-carboxylic acid esters.

E 09 R’ = CH, 90 2R‘ = (CH,),

tion of an aminoketal group also ensures the presence of an acid-labile potential cleavage site. The acid chlorides 87 and 88 required for introduction of an activating 0-protective group are obtained by of 2-amino-2-methyl- propanol with acetone or cyclohexanone to give the distillable oxazolidines 85 and 86, followed by chlorocarbonylation with diphosgene.[’22. The carbamates 89 and 90, generally obtained by the acylation of alcohols with acid chlorides 87 and 88, are present as E/Z mixtures, which in the time frame of ‘H NMR spectroscopy interconvert only slowly. The consequence is a doubling of the signals when ‘H NMR spectra are recorded without special precautions.[’251 Spectroscopic evalua- tion is less hampered for Cby-esters of the type 89 than for the originally utilized spirocyclic Cbx-esters 90.

The 2,2,4,4-tetramethyl-1,3-oxazolidinyl group corresponds approximately in terms of spatial demand to a di-(tert-butyl- amino) group, so it is hardly surprising that secondary alkyl esters 91 (R and El = alkyl) usually are not attacked even by lithium aluminum hydride[’261 in boiling THE Stirring in methanol containing methanesulfonic acid releases the N-@-hy- droxyalkylurethane) 92 from the N,O-acetonide 91. Thereafter, the hydroxy group plays an active role in base- or acid-catalyzed deblocking to alcohol 93 (Scheme 41).

91

92 93 94

Scheme 41. Stepwise cleavage of the 1,3-oxazolidine-3-carbonyl residue.

4.2. ( - )-Sparteine-Induced Deprotonation of Achiral Alkyl Carbamates

The deprotonation of “ordinary” achiral primary alkyl carbamates of types 89 or 90 with see-butyllithium/( -)-sparteine in diethyl ether or hydrocarbons proceeds with a reIiable preference for the pro-S-proton to give the lithium derivatives 95.1 or 96.1, which can be substituted with various electrophiles under stereoretention to give 97 or 98, respectively (Scheme 42, Table 5 ) . The resulting enantiomeric enrichment is normally

09 Cb= Cby 90 Cb = Cbx

95 Cb= Cby 96 Cb= Cbx

97 Cb= Cby 90 Cb = Cbx

Scheme 42. Enantioselective deprotonation and substitution of “oxazolidine carbamates” 89 and 90.

Table 5. Selected examples of the ( - )-sparteme-mediated lithsation and substitution of alkyl carbamates.

Product R El EIX Yield[%] Config.[a] Ref

98aa CH, C0,Me CO,[b] 75 R [123,130] 98ab CH, Me,% Me,SnCI 76 S [123,130]

97ad CH, H,C=CHCH, AllBr 60 R(42) [130]

97ae CH, PhC=O PhCOCl 38

97ac CH, PhCHOH PhCHO 76 R 11301

97aa CH, C0,Me MeOCOCl 73 R ~1301 R ~ 3 0 1

97af CH, Me,Si Me,SiCI 86 S (1 301 97ag CH, Me,% Me,SnCI 72 S [1301 97ah CH, Me,Pb Me,PbBr 61 S(93) 11301 97ba (CH,),CH CO,Me[b] CO, 52 R [123,130] 97bg (CH,),CH Me,Sn Me,SnCI 62 S [123,130] 97ci H,C(CH,), CH, CH,I 87 S [123,130] 97ca H,C(CH,), C0,Me co, 79 R [123,130] 97da PhCH,CH, C0,Me co, 88 R [1311 97ek FcCH,[e] Ph,P Ph,PCI 70 S 11321 97fi H,C(CH,),, CH, CH,I 60[d] S(98) [122,130] 979i If1 CH3 CH,I 64 S ( 1 9 2 ) [130]

[a] The enantiomeric excess is greater than 95% ee. Deviations are indicated in parentheses. [b] Subsequent methylation of the carboxylic acid with diazomethane. [c] Mixture of epimers [d] Use of 3 equivalents of sec-butyllithium/l. [el Fc = ferroceny!. I f I W,C),C=CH-(CHdz.

Rngew Chem. in?. Ed. Engf. 1997, 36, 2282-2316 2297


more than 95% ee. Suitable reaction partners include methyl iodide, CO,, alkyl chloroformates, aldehydes, ketones, carboxylic acid chlorides and esters, and trialkylsilyl and trialkyltin chlorides. Partial racemization is observed in reactions with benzylic and allylic halides, which speaks for the involvement here of single-electron transfer in the substitution step, which is favored by resonance stabilization of the benzylic or allylic radical. Primary alkyl iodides can be caused to react[’281 by the addition of HMPTA-substitutes such as 1,3- dimethyltetrahydro-2( 1H)-pyrimidinone (DMPU) . [1291 It is especially noteworthy that acylation occurs without racemization. This points to weak kinetic basicity of the lithium compounds 95 and 96, which presumably has its origin in the severe steric burden of the lithium cation, that in turn hinders “docking” at the ketone on the carbonyl group and thus activation of the neighboring CH-bond.

Methylation product 97fi led, with 98 % eerl”] after deblocking and acetylation, to (S)-( + )-Ztridecylacetate 99, a pheromone of the fruit fly Drosophila muelleri,[’ 331 whereas (S)-( -)-sulca- to1 (100),1’34a1 a pheromone of the beetle Gnathotricus sulca- t ~ s , [ ’ ~ ~ ~ ] (92% ee) was obtained from 97gi (Scheme 43).11301

0

n

U I

Scheme 45. General synthetic strategy.

displacement of (-)-sparteine by Lewis-basic substituents in the substrate; opposite stereochemical preferences in chiral substrates through the formation of “mismatched pairs.”[56]

First, however, we discuss insights gained to date into the mechanistic pathway of (-)-sparteine-mediated deprotonation.

4.3. On the Mechanism of Kinetically Controlled Carbarnate Deprotonation

A series of simple experiments[’ 361 with the deuterium-labeled substrate [l D197a supports the validity of the previously described interpretation (Scheme 46):“ 371 Through double application of the sequence (- )-sparteine-induced deprotonation

99 100

Scheme 43. Synthetic insect pheromones *[I221 and 100[130].

Unlike in the case of the lithium ion pairs of resonance-stabilized a-carbamoyloxyalkanides (see Section 3.1), substitution reactions of the saturated analogues 95.1 and 96.1 always occur with retention of configuration. Thus, the synthetic ester 97aa is identical with a sample prepared from (R)-lactic a ~ i d . 1 ” ~ ~ (R)- 97aa was also obtained via the detour of stannylation of 101.1 to (S)-97ag and destannylation with n-butyllithiumlTMEDA by way of the sparteine-free complex 101 .TMEDA (Scheme 44).“ 231

SBULil

YLflMEDA

- H3cY.C0fle

H,C,SnMe, TMEDA_H,C

Me,SnCI OCby OCby 97ag 101-TMEDA

1. co2 1. CO, 12. CH,N,

2. CH,N2

OCby

97aa

H3C) - sBuLill H,C,.Lin J OCby OCby

97a 101.1

Scheme 44. Stereochemical correlation of the metal derivatives with (R)-lactic acid [123].

Since according to all previous experience[’09* ’ 351 the lithiodestannylation step is always accompanied by retention, stannylation must also have taken this configurative course.

Thus, the process permits a broad range of electrophilic substitution reactions of pro-S-protons in alkanols; the lithiated carbamates 95.1 or 96.1 correspond to the chiral synthon I (Scheme 45).

Irregularities can arise if the starting material contains heterosubstituents. The following causes will be discussed in Sections 4.1 -4.6: 1,2- and 1,3-elimination of nucleofugic leaving groups;

1. SBULill 1. sBuLi/l ’2 - 2.MeOD ‘2 2. Me,SiCI

Cbfl CH, CbyO CH,

97a [1 Dl978 >99% D 97af

sBuLil I TMEDA

n SM+ 2 CbyO CH,

.Me,SiCl

97at ent-lola-TMEDA [lD}lOl8-TMEDA enf-[l D]97a? >96% ee; 98.7% D

Scheme 46. Determination of the kinetic isotope effect k,lk, in the deprotonation of an alkyl carbamate [136].

and deuterolysis of the organolithium intermediate it was possible to isolate the a-deuterioethyl carbamate [l D197a with a 1-D,-content higher than 99 YO. An attempt at renewed deprotonation with sec-butyllithium/( - )-sparteine (1) and subsequent trapping with chlorotrimethylsilane failed; the anticipated silane 97af was detectable at most in trace amounts. Deprotona- tion of [1D]97a with the achiral base pair sec-butyllithiuml TMEDA, on the other hand, is not subject to any stereochemical restriction: the ratio of rates according to which reaction pathways A and B proceed is determined exclusively by the kinetic isotope effect k,/k,. The reaction produced, after silylation, the silane ent-IlD197af with greater than 96% ee and a ‘H content of less than 1.3%.[’381 From this one can calculate a k,/k, ratio of > 70.[1391

The following conclusions can be drawn from these results: 1) Lithiated alkyl carbamates are completely stable configurationally in the form of TMEDA or (-)-sparteine complexes under the reaction conditions. 2) The deprotonation step is kinetically controlled, and this step determines the stereochemical course. 3) A pro-S-proton is abstracted with high selectivity

2298 Angew. Chem. Inl. Ed. Engl. 1997,36, 2282-2316


configurationally stable

89

+ sBuLi/ 1

Scheme 47. Diastereomorphic transition states in the (-)-sparteine-mediated deprotonation of ethyl carbamate 97a with sec-butyllithium

under the influence of (-)-sparteine, and the incoming electrophile occupies its topochemical position. 4) The observed kinetic isotope effect k,/k, of at least 70 points to the interven- tion of a quantum-mechanical tunneling I4O1 Power- ful H/D tunneling effects are observed when the reactants and products are separated by high, very “thin” potential barriers. This applies to proton transfer when the base and the resulting carbanion have similar basicities, and when the reacting centers are heavily shielded sterically. To our knowledge, the largest H/D kinetic isotope effect for a deprotonation reaction (kH/ k , = 24.3) was determined in the deprotonation of 2-nitro- propane with 2,4,6-trimethylpyridine.“40b‘

Additional experimental facts are also important if one wish- es to propose a solid mechanistic model: 1) Without addition of a bidentate ligand such as TMEDA or (-)-sparteine ( l ) , deprotonation of “simple” alkyl carbamates is excluded. 2) A reactive alkyl carbamate like 89 or 90 added to an equimolar mixture of sec-butyllithium, (-)-sparteine ( l ) , and the (not deprotonate- able) isopropyl carbamate iprOCby at - 78 “C is also not attacked.[’41] This means that prior to the deprotonation step a complex consisting of alkyllithium, the bidentate ligand, and the carbamate forms virtually irreversibly. Beak et al.r’4z1 verified by NMR spectroscopy the presence in ethereal solution of an unsymmetrical complex of the composition [(RLi),(Et,O); l ) , which is, however, under the conditions applicable here for the kinetics of the deprotonation step of no significance.

Proton transfer in the aggregate 102.1 is turned in this way into an intramolecular process with differentiation between diastereotopic protons (Scheme 47). Abstraction of the pro-S-H from conformation A occurs roughly 50 times more rapidly than that of the pro-R-H from conformation B, which leads to the minor diastereomer epi-103.1. From this result a free energy difference AC* of about 6.3 kJmol-’ is calculated.

The limits of the deprotonation of very weak CH acids have nearly been reached; it is apparent here that the combination sec-alkyllithium/( -)-sparteine was a fortunate choice, and with

respect to the basicity and steric demands of base and ligand an optimum has almost surely been reached: Deprotonation of nonactivated alkyl carbamates does not occur with use of n- or tert-butyllithium/( -)-sparteine (1) or sec-butyllithium/( -)a- isosparteine (2) .[1311

J. Haller and E.-U. Wiirthwein simulated the energy minima for transition states along the diastereomorphic reaction pathways A and B with the aid of semiempirical calculations (MOPAC, PM3) .I9’] For this process, sec-butyllithium was re- placed by the achiral is~propylli thium,[’~~~ and lithium parame- ters from A n d e r ~ ‘ ~ ’ ~ ] were utilized. In both transition structures 104.1A and 104.1B (Figure 7) the reaction center inserts into a “niche” that is left free by a “wing” of the ligand (-)-sparteine.

Figure 7. Models of the calculated diastereomorphic transition states (MOPAC, PM3) in the intramolecular removal of thepro-S-proton (left) and thepro-R-proton (right) in carbamate 97a by isopropyllithium/( -)-sparteine[l41]. In the case of sparteine (top of both illustrations) all hydrogen atoms have been omitted except for those at the bridgeheads; the same applies to the 2,2,4,4-tetrarnethyloxazolidin-3- carbonyl residue (bottom left). The view into the reaction center [the “triangle” consisting of the lithium cation (violet), C-1 of the substrate (left), the proton to be transferred (white), and C-2 of the base (right)] has been held constant. In both transition states, the bulky base (bottom right) extends into the niche left free by the cis-annelated outer six-membered ring of the sparteine. The pro-Stransition state (left) corresponds to the experimentally observed stereochemical course; here the methyl group (bottom left) extends forward. In the pro-R-transition state (right) it points downward; here the distance to the isopropyl group of the base IS smaller, and therefore the steric interaction greater.

Angen. Chem. h i . Ed. Engl. 1997, 36, 2282-2316 2299


The structures differ from each other in that the urethane alkyl group in structure 104.1A extends into the free space, whereas that in 104'1B collides with the isopropyl group. The calculated energy difference AAG* of 0.8 kJmol-' is much too small in comparison to the experimental value of 26.3 kJmol-'; we suspect that the calculation method selected for the exact solution of this complex problem is, like other semiempirical methods, inadequate for the task, which is complicated further by the appearance of tunneling

Better agreement between experimental and calculated results is obtained when diastereotopic differentiation is established through a neighboring stereogenic center in the substrate:['451 (R)-2-Phenyl- propyl ~ a r b a m a t e t ' ~ ~ ] 105 leads after deprotonation and methoxycar- bonylation to the diastereomeric esters 108 and 109 in a ratio of 95: 5 (Scheme 48); that is, the pro-S-proton is removed roughly 20 times more rapidly than the pro-R-proton. However, in (l-tetrahydronaph- thy1)methyl carbamate 110, which has an equivalent configuration,['461 a reverse preference for 113:114 is registered with a ratio of 13:87.r'471

Figure 8. Models of the calculated diastereomorphic transition states (MOPAC, PM3) for removal of the pro-R-proton in a complex consisting of methyllithium/ethylenediamine and (S)-1 -phenylethyl formate (left) or (R)-1-phenylethyl formate (right)[l45]. In the transition state a triangle is formed consisting of the now pentacoordinated lithium cation (violet), the (also pentacoordinated) carbon atom of the base, and the C-H acid, on the basis of which the attacked proton wanders. The calculated energy difference AAHin favor of the ul-proton (left) relative to the lk-process (right) amounts to 2.9 kJmol-'. In the most favorable conformations in each case the plane of the phenyl residue is parallel to the C-H bond at the stereogenic center in order to avoid 1,3-allyl strain. In the favorable ul-transition state (left) the C1 -C2 bond can assume a completely eclipsed conformation at the expense of an interaction between an ortho-H atom and the remaining I-H atom, whereas that conformation in the Ik-transition state apparently represents a poor compro- mise. The two experiments are possible only by computer, since in a reaction flask the system would discover that removal of an N-H proton and subsequent attack of lithium amide on the formyl group would be the favored reaction pathway.

Figure 9. Models of the calculated diastereomorphic transition states (MOPAC, PM3) for removal of the pro-R-proton in a complex consisting of methyllithium/ethyIenediamine and @)-(left) or (S)-(1,2,3,4-tetrahydronaphth-l -yl)methyl formate (right)[145J. In this case calculations (AAK = 2.9 kJmol-') and experiment (AG = = 2.9 kJmol-') show the Ik-transition state (left) to be the more favorable. Since the phenyl residue and the attached alkyl group are constrained in a plane by the ring, the conformational energies are reversed relative to the txJ-(l,l')-C-C bond. In the ul-transition state (right) the interaction of the C-2-methylene group of the tetrahydronaphthyl residue with the reaction center la apparently stronger than that of the Ik-transition state (left).

Although the PM3 c a I c ~ 1 a t i o n s ~ ~ ~ ~ are carried out with simplified substrates (formyl in place of oxazolidinecarbonyl) and

105 110

106-TMEDA 107;TMEDA 111-TMEDA 112-TMEDA

1. co, 1. co, I 2.CH2N, I 108 955 109 113 m a 7 314

Scheme 48. Diastereotope-differentiating deprotonation of chiral alkyl carbamates [145].

reagents (MeLi for sec-BuLi and ethylenediamine for TMEDA), they correctly reflect the observed trend (Figures 8, 9).11481

Calculated energy differences A(AH2 - AH:) correspond well with the experimentally determined values A(AG2 - AG: in parentheses): 2.5 (5.0) kJmol-I for the system 105 and -2.5 (- 2.5) kJmol-' for 110.

It is apparent that significant differences in the energies of diasteromorphic reaction pathways for a kinetic racemate resolution under the influence of the chiral base pair sec-butyllithium/( -)-sparteine are susceptible to exploitation.1145* 1491 The enantiomer that reacts most rapidly is the one in which the pro-S preference of substrate matches that of the reagent, namely (R)-105 and (S)-l10.c145. 1491

4.4. Deprotonation of Heterosubstituted Alkyl Carbamates

As described in the preceding section, the formation of a complex consisting of alkyl carbamate, sec-butyllithium, and ( - )-sparteine is essential for achieving highly stereoselective deprotonation. If the alkyl group bears a strong donor substituent, this may displace the sparteine.

Thus, deprotonation of the 3-(N,N-dimethylamino)propyl carbamate 117a, followed by reaction with various electrophiles, leads to the nearly racemic product 118a (Scheme 49) .[150. 15'] The bulkier N,N-dibenzylamino group on

2300 Angew. Chem. In(. Ed. Engl. 1997, 36, 2282-2316


1. sBuL/l 2. co, 3. CH,N,

RiR2Nq0cby R’R‘N-OCby - 117 118 a , M e

R’ R2 Yield [%] ee [%I

a CH, CH, 92bl CIO

b CH, PhCH, 70 80 c PhCH, PhCH, 94 97

Scheme 49 ( - )-Sparteine-induced deprotonation of 3-(dialkylamino)alkyl carbamates [152]. [a] CH, instead of C0,Me.

the other hand does not interfere, and the product 118c of electrophilic substitution is obtained with the customary enantiomeric enrichment of greater than 95 % ee.[1501 In this respect the (N-benzyl-N-methylamino) group in 117b (80 YO ee) occupies an intermediate position.[”’]

The 3-, 4-, and 5-~arbamoyloxy,[’~~~ 4-methoxy or 5-silyl- OX^,[^^^^^ and 2-dibenzylamino groupsr’ 541 do not disrupt the enantioselectivity of deprotonation in the presence of ( -)- sparteine (Scheme 50, Table 6).

1 . sBuLiI1 2. ED(

y - Y o c b y Y 4 0 C b y - El 119

1-20

Scheme 50 Enantioselective deprotonation and substitution of o-heterosubstituted alkyl carhamates.

Table 6. Enantioselectibe deprotonation and substitution of achiral w-heterosubstituted alkyl carbamates 119. TBDMS = ierf-butyldimethylsilyl, MEM = methoxy- ethoxymethyl.

Starting material

119a 119b 119c 119d 119e 119f 119g

Product n Y E K Yield[%]

120a 1 120b 2 l20c 2 120d 2 l2Oe 2 120f 3 12og 0

OCby Me1 83 OCby Me1 92 OMe Me,SnCI 70 OTBDMS CO,[a] 77 OMEM CO,[a] 69 OCby Me,SiCA 70 NBn, CO,[a] 56

ee [YO]

> 91 97 99

> 95 62 96

> 95

Ref.

[153a] [153a] [153a] [153a] 11551 [153b] [is41

[a] Isolated as the methyl ester after treatment with diazomethane

Compound 120g is a protected derivative of D-isoserine.[1541 Carboxylation of lithiated 1,3-dicarbamates leads in two steps to essentially enantiomerically pure y-lactones, as illustrated in an exemplary way by the synthesis of D-pantolactone (124) (Scheme 51).[153a,

1,3-Dicarbamates like 122.1 (Scheme 52) bear potential leaving groups that are activated by Lewis acids. In fact, we observed upon treatment with chlorotrimethylsilane the formation of the cyclopropyl carbamate 125 with 1,3-elimination of the lithium carbamate salt.[136. 15’] In the process the (S) - enantiomer 125 results with greater than 95% ee, as could be demonstrated by transformation into the carboxylic acid ester 126 and crystalline ketone 127 via the configurationally stable“ intermediate lithium cyclopropanide. Investigations with the deuterium labeled, enantiomerically enriched starting material (S)-[lD]121 proved without question that ring closure

cb@&ocby SBULdl c Cb@&OCby

121 A w

122-1

123 U

124

80%; 95% ee Scheme 51. Synthesis of (R)-pantolactone [153a].

Cb@*ocby - - Cb@&Ldl

Li H OCby

122-1A 122-1 B

tEuMe$iiTf or BF3- OEt, I I ;;r or

4 ”‘.H

I OCby

125

1. sEuLirrMEDA 2. CIC0,Me

4 " -OCby H

ent-125

1. sBuLirrMEDA 2. CICO,Me I

4 “‘-CO,Me OCby

126

4 ““OCby C0,Me

ent-126

&CH3

OCby NEn,

127

Scheme 52. Stereochemistry of the 1,3-elimination of a 1,3-dicarbamate [157,160].

here occurs stereospecifically, with retention at C-I as well as inversion at C-3, hence out of conformation 122.1a.[’361 To our great surprise, stronger Lewis acids like tert-butyldimethylsilyl triflate or boron trifluoride caused formation of the opposite enantiomerically enriched cyclopropane, ent-125 ( > 95 YO ee and 74% ee); stereoinversion at both reactive centers was veri-

Despite many possible complications, the carbamate group is distinguished by its unsurpassed directing effects. The following “acid test” (Scheme 53) underscores this assertion: Carbamate

fied.[’ 60 - 1631

1. sBuLdl 2. PhCOCl

OCby OCby

0 ‘Ph

128 129 85%; >95% ee Scheme 53. Competing acidic positions in (-)-sparteine-induced lithiation [165]

Angew. Chem. Int. Ed. Engl. 1991,36,2282-2316 2301


128 bears three extraordinarily easily activable protons in H,, H,, and HB.;[1641 nevertheless, under the usual conditions of ( - )-sparteine-induced deprotonation, exclusively the pro& proton HA is released.f1651

4.4.1. Competition with Stereogenic Centers in the Substrate; Kinetic Resolution

Provided that a good donor substituent is attached to a stereogenic C atom in the y- or &position, it can ensure a significant amount of chirai induction in the deprotonation step. It is useful when this chelate effect is subordinate in the competition with (- )-sparteine (1). In favorable cases-as with 1,3-dicarbamate 130a-lithiation can then be directed preferentially in either of the two directions.[1661 Application of the sparteine variant with subsequent methylation led to the (S,S)-2,4- pentanediol derivative 132a with high selectivity, whereas in the presence of TMEDA the meso-compound epi-132a dominated (Scheme 54).[’661 We suspect that a bicyclic chelate complex of

131 V 131-1

+ CH,I I + CH,I 1 Cb@&OCby

- - - - - - cb@ +OCby CH, CH, CH, CH,

132 [a] a n = 1; 56%; 945 [b] b n = 2; 51%; >98:2

epi-132 a n = 1; 44%; 98:2 [c] b n = 2; 60%; 12:88

Scheme 54. (-)-Sparteine- vs. substrate-directed diastereoselective lithiation of 1,3- and 1,Cdicarbamates [166]. [a] Conducted with the carbamate residue Cbx. [b] Ratio 132:epi-132 [ = (S,S):(S,R)]. [c] Ratio epi-132:132 [ = (S,R):(S,S)l.

the type 131[1671 forms, and the more favorable exo-position of the stationary methyl group determines the transition In the homologous (S)-2-methyl-l,4-butanediyl dicarbamate 130b, reagent- and substrate-controlled deprotonations take the identical stereochemical course, and lead with differing efficiency to the (S,S)-diol derivative 132b.

An effective substrate-inherent chiral induction can also be exploited with the acetonide of the (S)-3,4-dihydroxybutyl carbamate 133.[16’] Deprotonation in diethyl ether (without any other additive) and reaction of the resulting ion pairs 134 and

epi-134 with trimethyltin chloride produces mainly the (1 S,3S)- diastereomer 135 (Scheme 55, Table 7). From this one can conclude that there is highly selective formation of the anti-annelated tricyclic chelate complex 134.f16831701 In the presence of ( -)-sparteine (1) the tendency toward release of the p r o 4 pro-

0 q O C b y

PO - 133 HsHR

1

134 epi-134

o-n(ocby OCby

El El

- epi-135

OH -0Cby

Me0 H OMe

1 1 136 K

Scheme 55. Diastereoselective lithiation of the chiral acetonide 133 [169]

Table7. Deprotonation of the acetonide 133 and reaction with various electrophiles 11691.

Additive L Products E m Yield[%] 135:epi-135

Et,O 135a Me,SnCI 63 98:2 TMEDA 135a Me,SnCI 71 15: 35 1 135a Me,SnCI 61 >99:1 ent-1 135a Me,SnCI 15 28:12

Et,O 135 b MeOCO(0Me) 35 98:2 Et,O 135c 69 96:4 HCOOEt

Et,O 135b Me1 10 >95:5

Et,O 135e iPrCOCl 57 >95:5 Et,O 135f Ph,CO 16 >95:5 Et,O 135g [a1 39 >95:5 Et,O 135 h [bl 51 >95:5 Et,O 135 i [CI 62 >95:5

[a] (E)-Crotonyl chloride. [b] (S)-2-(N,N-Dibenzyl)alanine benzyl ester. [c] 6- Valerolactone .

ton is further increased, because in this case epi-135a is no longer identifiable in the reaction mixture. The 2,2-dimethyl-substituted 1,3-dioxolane ring is only a weak ligand for lithium, for in the deprotonation step, as with sparteine, it is displaced by TMEDA. As Table 7 indicates, diastereoselectivity decreases


REVIEWS Enantioselective Synthesis

under these conditions and is reversed by means of (+)- sparteine (ent-1)" 'I with its preference for the pro-R-proton. In other words, in the presence of a bidentate complexing ligand, intramolecular complexation is not involved, and the normal deprotonation pathway applies. Conformational rigidity in the form of the acetonide is essential for achieving high substrate- controlled stereoselectivity, for the 3,4-dimethoxy derivative 136 reacts unselectively under the above-described condi- t i0ns.[ '~~1

As Table 7 shows, the ion pair 134 reacts smoothly with a wide variety of electrophiles, and acylation also poses no problems. For this reason the substrate constitutes a valuable synthetic equivalent to the (S)-I ,3,4-trihydroxybutanide (K) .I' The method should be generalizable to the transfer of longer chains and more highly functionalized analogues.

How might one now gain entrance to the epimeric series epi-135 without the need for the awkwardly available (+)- sparteine? This is easy so long as a deuteration of the product can be tolerated (Scheme 56).[65e1 Acetonide 133 is lithiated and

137 R,bi 138

IElX

NB", C b $ y OCby

139

El

Scheme 57. Substrate-directed regio- and diastereoselective deprotonation of dicarbamate 137 [173b].

Table 8. Substrate-directed deprotonation and substitution of the dicarbamate 137 [173b].

1. sBuLfib0 2.MeOD qocby sBuLi/ *

- 0 0 HSHR LO D H TMEDA

[l DIepi-134-TMEDA [l Dlepi-135

El = Me,%: 45%; d.r. = 98:2

Scheme 56. Reversal of diastereoselectiv~ty through deuteration of 133 [65e].

deuterated under substrate control. Because of the large kinetic H/D isotopic effect (see Section 4.2), TMEDA-assisted lithiation leads from (S) - [ 101133 to the diastereomerically pure ion pair [IDIepi-lM, which is configurationally stable and can be substituted to give [ID]epi-135 under stereoretention.

High substrate-controlled diastereoselectivities are also achievable if the substituent capable of chelating is not itself on a stereogenic center, but rather adjacent to one. Upon deprotonation according to either the TMEDA or the (-)-sparteine variant, followed by reaction with electrophiles, dicarbamate 137 of (S)-2-(dibenzylamino)-1,4-butanediol,['73a~ derived from (S)-asparaginic acid, leads to mixtures of regio- and diastereomers." 73b1 However, if the transformation is carried out in diethyl ether (without addition of a diamine), the pure 1-substitution product 139 results (Scheme 57, Table 8). The breadth of the applicable electrophiles and the high reactivity are noteworthy. We therefore conclude that formation of the chelate complex 138 is kinetically controlled;[' 74, the cause of the highly stereoselective course of the reaction is thought to be the strong tendency of the 2-dibenzylamino and 4-carbamoyloxy groups to occupy an equatorial position in the developing six-membered ring.

Product [a] El ElX Yield ["A] ~~

139a 139b 139c 139d 139e 139f 139g 139 h 139i 139k[e] 1391[e]

D Me CO,Me[b] Me,COH iPr,COH

[cl Me$ Me& PhS PPh,

EtC=O

DOMe Me1 coz Me,C=O 1Pr,C=O EtCOCl [dl MeJiCI Me,SnCI PhSSPh Ph,PCl

95 93 92 85 75 80 71 73 75 73 56

[a] In no case could a second diastereomer be verified by 'H NMR, so the diastereomeric ratio was at least 97:3. [b] After esterification with diazomethane. [c] (E)-MeCH=CH-C=O. [d] (E)-MeCH=CHCOCI. [el Ref. [175].

The 4-methyl ether 142 shows very similar selectivity,['73b. 1 7 7 1 whereas the 4-0-TBDMS ether 143 is unreac- tive," "I which also supports the important role played by the complexing substituent in the 4-position.

If the 1-pro-S-position of substrate 137 is blocked, whether by an alkyl group or deuterium,['78* ' 791 the (-)-sparteine-mediated deprotonation "at the other end" takes its usual course, with the abstraction ofpro-S-H-4 (Scheme 58). Obviously the l-posi-

H HR NBn* 1. sBuWl E' NB".

R k R H

h O C b y 2.EIX ,,-OCby CbYQ

139a R = D 139b R=CH,

140 R = D; El = CH,; 86%; d.r. >95:5

141 R = CH,; El = C0,Me; 90X; d.r. z 955

142 R=CH, 143 R=SiMqiBu

144 R=Me 145 R=CPh,

Scheme 58. Lithiation of 2-amino-1,4-butanediol derivatives in the 4-position [173b,177].

Angew Chem. Inl. Ed. Engl. 1997,36, 2282-2316 2303


tion can also be blocked in a classical way after introduction of a nonactivating protective group such as methyl or trityl at 0-1 (144 and 145, Scheme 5 8 ) , leading to regio- and stereoselective deprotonation at C-4.[1771

In the corresponding 2-amino-1,s-pentanediol derivative 146, made from (S)-glutamic acid, internally assisted deprotonation is apparently retarded due to the unfavorable ring size of the resulting lithium chelate complex (Scheme 59) . [I 73b1 Thus, in

146

1. sBuLd1. EbO. 1. sBuLi. EbO 2. co,

-54s -1 -Hs

yB"2 YBn,

cb@-Ocby Cbfl-OCby

C02Me C02Me

61%; d.r. w 97:3 80%; d.r. w 97:3 147 148

Scheme 59. Regio- and diastereoselective substitution of the 2-amino-1,S-pentanediol derivative 146 [173b].

the presence of (-)-sparteine, proton 5-H, is abstracted almost exclusively, whereas in the absence of a diamine a slower deprotonation at C-1 is initiated; the intermediate lithium compounds produce, after trapping with carbon dioxide and U-methylation, the regioisomeric esters 147 and 148.

Therefore, the procedures described offer extremely facile access to equivalents for the stereoisomerically pure carbanionic synthons L through 0 (Scheme 60).

rtrH2 r?Y Ho*HOH $ 2 -

8

n = l L n = 2 M

n = l N n = 2 0

Scheme 60. Carbanionic synthons accessible from 2-amino-1,w-alkanediols [173b].

(S)-2-(N,N-Dibenzylamino)alkyl carbamates, accessible in a small number of steps from the natural amino acids,['801 display marked ul-induction[6a1 in TMEDA-assisted deprotonation" 541

(L, = TMEDA). Therefore, the pro-R-proton is preferentially abstracted, and one obtains after reaction, irrespective of the electrophile, an excess of the diastereomer 152 (Scheme 61, Table 9). The (S)-alaninol derivative 149a constitutes an excep-

sBuLi/L, 14' 1 EbO,-78 "C

i" yBn2

R i &OCby

El

1 52

7 OK NRz L,,L'-o L

151

iEiX y".

R 7 0 C b Y El

153

Table 9. Substrate- and reagent-directed deprotonation of 2-(dibenzylamino)alkyl carbamates 149.

Scheme 61. Deprotonation of (S)-2-(N,N-dibenzylamino)alkyl carbamates. For R, see Table 9.

tion. One presumes that proton abstraction takes place in the antiperiplanar conformation, and in the normal case the pro-R- H is more accessible (Figure As described above, we have so far found no indication that the dibenzyiamino group interacts as a complexing ligand.[18']

In the presence of (-)-sparteine (L, = 1) as complexing partner, the situation of a "mismatched pair" arises due to its preference for the p r o - S - p r ~ t o n . [ ~ ~ ~ Strong substrate-directed stereoselection is directed toward the pro-R-H, and thus retards

Starting L, = TMEDA L, = 1 material R EIX Products Yield[%] 152: 153 Yield[%] 152:153 Ref.

149a CH3 CH31 152aa, 153aa 82 37: 63 56 <3:97 [183] 149a CH3 Bu3SnC1 152ab, 153ab 49 36: 64 59 <3:97 [183] 149a CH3 CO,Me[a] 152ac, 153ac 76 31:69 48 <3:97 [183]

[I831 [I831

149 b H,CCH, CH,I 152ba, 153ba 72 88:12 PI

[I831 149b H,CCH, Bu,SnCI 152bb, 153bb 70 89:11 [bl 149b H,CCH, PhCOCl 152bd, 153bd 74 88: 12 PI ent-149 b H,CCH, CO,Me[a] enr-152bq ent-153bc - - 57 >97:3 [183]

[I831 11541

149c BnzN(CHd3 CIC0,Me 1 5 2 q 153cc 78 84:16 [CI (CH,),CHCH, CO,Me[al 152dc, 153dc 56 >95:5 [bl

152ec, 153ec - 43 11:89 [184] 149d 149e C6H5CH2 CU,Me[a] 149e C,H&Hz PhCOOMe 152ed, 153ed 74 92:8 65 ruc-149f c-C,H,CH, CO,Me[a] ent-l52fc, enf-153fc 89 83: 17 [dl Id1 [I851

- - -

- -

- 7:93 [184]

[a] Isolated after esterification with diazomethane; CO, was used as electrophile. [b] No deprotonation. [c] Not carried out. [d] See text.


Enantloselective Synthesis REVIEWS

v. P formation of the diastereomeric ion

Bn,N+OyNR, pair 151, which in the presence of large residues R may be completely excluded.

5 i . HSHR 0 */I

Bu Also with the (S)-prolinol deriva- Figure l o Favored confor- tive 154 there is a strong preference deprotonatlOn of (S)-2-(N,N- for abstraction of the pro-R-proton, dibenzy1arnino)alkyl carba- which leads via the ion pair 155 to mates. the diastereomerically pure substitu-

tion products 156 (Scheme 62).1'541 Quite surprisingly, when deprotonation is carried out in ether solution in the presence of ( - ) -~par te ine[ '~~I or entirely without the addition of a diamine, the very same diastereomer re- s u l t ~ . [ ' ~ ~ ~ This observation permits only one conclusion: Here the less shielded amino function intervenes in the deprotonation step in an intra- or intermolecular way.

mation for substrate-directed

(N%OCby - sBuLi

in H,c~,

154

155 156

a El = CH,; 72%; d.r. > 95:5 b El = BuSn; 71%; d.r. > 95:5 c El = (CH3),CHOH 33%; d.r. > 95:5

Scheme 62. Diastereoselective deprotonation of the prolinol carbamate 154 11541.

In the ( -1-sparteine-induced deprotonation of (R)-2-(diben- zy1amino)alkyl carbamates enr-149, both the substrate- and the reagent-controlled preferences point to the pro-S-proton. As a consequence, the reaction is rapid and stereoselectivity virtually complete (compare with enr-149b in Table 9) (Scheme 63).[183. lE4] The sharply differing reactivities of the

ent-15Ob-1 ent-152bc

El = CO,; 65%; d.r. > 95:5

Scheme 63. Highly diastereoselective deprotonation and substitution of the (R)-2- (N,N-dibenzy1arnino)butyl carbamate enr-149b [lS3].

two enantiomers with respect to sec-butyllithium/( -)-sparteine can be exploited for efficient kinetic racemate resolution. As with all kinetic racemate resolutions with carbamates, at least one equivalent of alkyllithium is required; apparently this is irreversibly bound in a precomplex even with the less reactive enantiomer. From the racemic P-cyclopropylalaninol derivative

ruc-149f it was possible in this way to acquire the ester ent-152fc (>95% ee) and recover (S)-carbamate (S) -149f (Scheme 64).['28, 1851 The advantage relative to classical or en- zymatic racemate resolution lies in the possibility of accomplish- ing a highly diastereoselective C-C coupling in addition.

qoc.. + <ocby

I ; q G OCby OCby

1 i q OCby GOCbY

H S H R HSHR

enf-14% 14s

1.5 equiv sBuL/ 1 ; EbO, - 78 "C

Lit 1 LV 1

ent-l5Of-1 151f.1

1 . CO,, 2. CH,N,

C02Me C0,Me en?-1 52fc 153fc 40%; > 95% ee 6%

~ GOCby 42%; 80% ee

Scheme 64. Kinetic resolution of the carbarnate rat-149f Il29.1851

As was demonstrated with 3-(piperidine-2-yl)ethyl carbamate ruc-156, the method can also prove valuable when differentiation between the enantiomers is less efficient.['861 One obtains after methylation the epimeric (2S)-alkyl carbamates 157 (>95% ee) and 158 (89% ee), which after deblocking lead to the alkaloids ( +)-~edridine['~'l (159) and (+ )-allosedridine (160) (Scheme 65). The sequence possesses the character of a

r c OCby

rjn rac-156

158 49% (89% ee)

Scheme 65. Synthesis of (+)-sedridine and (+)-allosedridine [1X6]

(yOH I

Q ,",i\oH CH3

H 160

highly enantioselective substitution on a racemic starting material, which simplifies racemate resolution of the starting material by turning it into a separation of product diastereomers.

Anxeu Chem lnr €0. Erin/ 1997, 36, 2282-2316 2305


An interesting stereochemical problem is presented by meso- dicarbamate 161 (Scheme 66).['53b3 1881 The compound bears two enantiotopic side groups, each with two diastereotopic protons. The chiral base sec-butyllithium/( -)-sparteine abstracts that pro-S-proton whose removal is supported by the substrate- inherent preference, namely R-H,.['891 The [lR,I(lR),2S]-configured lithium intermediate 162.1 arises in excess together with the [IS,l(lR),2R]-diastereomer and leads to the substitution products 164 with high stereoselectivity.

L/ 1 sBuLdl + q O C b y r! ($

OCby toluene,-78 "C

OCby OCby -

H C H HSHR Ld 1

161 162-1 163-1

1 EIX : EIX v

sBuLdl Q+R EbO. -78 O C

Hs - mu A0

'*..Ln EIX ('***El

mu A0 mu L O

Q 168

170 169.1

170 a EIX = MeOS0,OMe; 88%; 94% ee b EIX = CO,; 55%; 88% ee c EIX = Ph,CO; 75%: 90% ee d EIX = Bu,SnCI; 83%; 96% ee

Scheme 67. (-)-Sparteine-controlled deprotonation of N-Boc-pyrrolidine 11931

(Scheme 68) As expected, reagent-induced chiral induction dominates, as has also been shown to be the case with the 2-phenylpyrrolidine derivative 173.[' 51

H \\ X H H

164 165 :g 12 2 RuClJNalO, a EIX Q COJCH,N,; 57%;

d.r. = 982; > 95% ee

d.r. = 955; > 95% ee b EIX = CH& 65%;

Scheme 66 Desymmetrization of a meso-1,Cdrcarbamate [153b].

Carboxylic acid ester 164a was transformed with 5~ hy- drochloric acid into the tetrahydrofuran derivative 166, which was oxidized to the lactone acid ester 167.1'90] At this stage the expected configuration was verified by an X-ray crystal structure All in all, desymmetrization of the meso-substrate was associated with highly diastereoselective C-C bond formation.

4.5. Enantioselective Lithiation of N-Boc-Pyrrolidines

As Beak et al. were able to show as early as 1984 that N-(tevt- butoxycarbony1)pyrrolidines and -piperidines are easily deprotonated to the corresponding racemic dipole-stabilized lithium- carbanion pairs.['921 Application of sec-butyllithium/( -)- sparteine to N-Boc-pyrrolidine leads through enantiotopic differentiation, after removal of the pro-S-2-H atom, to the configurationally stable intermediate 169.1, which can be substituted with retention by various electrophiles (Scheme 67) .I' 931

The (R)-diphenylprolinol derivative 170c can be enriched to 99.3 % ee by recrystallization and provides a valuable ligand for enantioselective ketone reduction according to Corey-It- ~ u n o . ~ ' ~ ~ ] Tin compound 170d is the starting material for the synthesis of enantiomerically enriched 2-lithio-N-methylpyrro- lidines developed by R. E. G a ~ l e y . [ ' ~ ~ ] Double lithiation/ methylation offers easy access to the (S,S)-2,5-dimethylpyrro- lidine derivative 171; a possibility has also been worked out for separation of the roughly 10% content of meso-compound 172

Boc

17Oa Boc

171 >99%ee 172 90 10

I

BOC BOC BOC

173 174 175 93 7

Scheme 68. Reagent-directed deprotonation of chiral 2-substituted N-Boc-pyrrolidines [SS].

From a mechanistic standpoint there are many parallels to the deprotonation of 0-alkyl carbamates (Sections 4.1 -4.3);['961 kinetic and deuteration studies suggest rapid formation of a precomplex of the reaction partner^.['^**'^'^ M. E. Kopach and A. I. Meyers were able to show with a conformationally biased pyrrolidine that both the deprotonation and substitution steps proceed with retention.['981 In a paper that is well worth read- ing, about two dozen ligands-mainly chiral diamines-were investigated to see to what extent they could replace (-)- sparteine (l), or even lead conveniently into the other series of enantiomers." The most effective among them have been collected in Scheme 69.

Essential, sufficiently high configurational stability of the lithiated intermediates seems to be limited to pyrrolidines like 168.[2001 The greater configurational lability of the corresponding piperidines can be compensated for to some extent through a rapid, intramolecular subsequent reaction. Thus, Y. S. Park and P. Beak obtained the l-azabicyclo[3.l.0]hexane 182 with 55 % ee after deprotonation of N-Boc-4-tosylpiperidine (179) in the presence of (-)-sparteine by the addition of chlorotrimethylsilane; the configuration is still unknown (Scheme 70).Iz011 In this case, rapid 1,3-substitution of the enantiomerically enriched intermediate 180.1 preserves most of the chiral information.



1. sBuLiR' Q 2. Me3SiCI Q'***SiMe3 QSiMe, I EbO, -78 "C

I BOC Boc BOC

168 17Oe ent-17Oe

(3- sparteine (1) 87%(96%ee) 98 2

63%(72%ee) 86 : 14

'OH I

CH3 177

Scheme 69. Testing of various bidentate ligands in reagent-controlled deprotonation of N-Boc-pyrrolidine [199].

BOC

179 180-1 1. sBuLi 2.M+SiC;

I SiMe, Boc B W

181 182 77%; 55% ee

Scheme 70. Enantioselective deprotonation and intramolecular alkylation of an N-Boc-piperidine [201]. Ts = 4-MeC6H,SO,.

4.6. Enantiotopically Differentiating Lithiation at Other Prochiral Groups; Planar- and Axial-Chiral Intermediates

In the preceding sections, chirality was in most cases introduced through differentiation by the chiral base between enantiotopic protons of a methylene group. This means that configurational stability of the lithiated intermediate under the reaction conditions as well as a subsequent stereoselective substitution are necessary prerequisites. A few other cases in which no stereogenic carbanionic C atom is formed will now be discussed.

Hodgson et al. investigated a rearrangement of meso-epoxides induced by chiral Treatment of exo-norbornene epoxide (183) with sec-butyllithium/( -)-sparteine in pentane permitted the isolation of (-)-nortri~yclanol[ '~~~ in 73 % yield and 52% ee (Scheme 71).[202b1 The base differentiates between the (R)- and (S)-sites on the oxirane unit during proton abstraction, and the carbenoid stabilizes immediately through open-

165

73%; 52% ee J

184-1 H L

183

H 186

187

86%; 84% ee Scheme 71. (-)-Sparteine-induced rearrangement of meso-epouides via 1 8 4 1

ing of the epoxide ring and insertion into the y-endo-CH bond. cis-Epoxides of medium-sized cycloalkanes undergo similar reactions with transannular CH-insertion.[202a1

An interesting vinylogous nucleophilic ring opening of meso- oxabicyclic system 188 by n-butyllithium/( - )-sparteine was discovered by M. Lautens et al. (Scheme 72).I2O3l The best results [60% yield of (-)-189 with 52% eel were obtained with five equivalents of butyllithium and 15 mol% (-)-sparteine at -40°C in pentanelhexane.

OH 188

H6 .

(-)-US9 (+)-189 76 : 24

Scheme 72. Nucleophilic ring opening ofmeso-oxabicyclic compound 188. R = Bu.

Both methyl groups in the dimethylphosphane derivatives 190- 192 (Scheme 73) are enantiotopic, and the attached hydrogen atoms are acidified. During deprotonation to 191.1- 193.1 the phosphorus atom becomes a stereogenic center. First experiments in deprotonation of dimethylphenylphosphine oxide (190a, R = C,H,) with n-butyllithium/( -)-sparteine were described in very brief form by Raston, White, et al.,[421 with an observed diastereomeric ratio in the range of 60: 40.

Better results were obtained by D. A. Evans et al. with aryldimethylphosphine sulfides 190b and the borane complex

ee values of 74-94% were achieved in the capture products with benzophenone (194b and 194c).

Oxidative coupling of the lithium derivative 193.1 with cop- per@) pivalate to give the bis(phosph0nium) complexes 195 and 196 is associated with an enhancement of the enantiomeric ratio to 98:2 (96% ee) (Scheme 73), because the greatest part of the epimer (PR)-193.1 (present to the extent of about 12%) is removed as the meso-diastereomer (R,S)-196. Deblocking of the

Angew. Chem. Int. Ed. Engl. 1997,36,2282-2316 2307


19oax=o 19ObX=S 1 9 0 ~ X = BH,

CH, B e 6 g,,,, 193.1

Ar ... ; j jj..*CH3 H,C' LsiJ .Ar

Me 'Me

(R, R)-197

191.1 x = o 192.1 X= S 193.1 X = BH,

€BH,BBH, Cu(O,CtRu), Ar-..& &CH,

H3C w Ar 67%

(S,S)-195

96% ee 88

Are..;. ij.;.CH, H 3 C v p U Ar

(S,S)-l98

Ar = D tnlvl

Good enantiomeric enrichments have also been achieved through enantioselective deprotonation of other ferrocene deriva-

194a X =0, R = Ph tives : (diphenylphosphany1)ferrocene (2Ola) x = s (79%. 79% ee) with lithium (R,R)-bis(1-phenylethyl)amide,

55 % ee,[2081 and (dimethylaminomethyl)- ferrocene (201b) with (R ,R) -N,N,N' ,N-

194c X = BH, (84%, 87% ee) 104b.c: R = * tolyl

tetramethyl-I ,2-~yclohexanediamine/n- bu- t y l l i t h i ~ m , [ ~ ~ ~ ~ 80% ee (Scheme 74).

A breakthrough was achieved by V. Snieckus et al.,[2071 when they subjected

+ Ar$@ &.CH3 N,N-diisopropylferrocene carboxamide

(202) to deprotonation with n-butyl- + (R,S)-l% lithium/( -)-sparteine in diethyl ether : 12 (Scheme 75). The expected products 203

were isolated with a host of electrophiles in 62-96% yield and 81-99% ee.

Related stereochemical problems are posed by monosubstituted arenetricarbonylchromium complexes; in this case chiral bases other than alkyllithium/ (-)-sparteine prove to be most useful.

€SH,BBH,

H,C w Ar

I - . .. - Scheme 76 collects examples from the research groups of Kiindig,[2101 Uernura,l2l Simpkins,[212s 2131 and S c h m a l ~ . [ ~ * ~ ]

Scheme 73. Enantioselective, (-)-sparteine-induced deprotonation of aryldimethylphosphane derivatives [204].

borane complex (S,S)-195 with diethylamine leads to the free Axial chirality can also be created through enantiotopically diphosphane (S,S)-198. Just as in the case of the bis(phos- discriminating deprotonation. The first examples, with 22'-di- phiny1)-substituted silane (R,R)-197, C,-symmetric diphos- methyl-1,l'-binaphthyl and 2,2',6,6'-tetramethyl-l,l'-biphenyl phanes obtained in this way represent valuable potential ligands for enantioselective catalyst systems.

Based on the seminal work by I. Ugi and H. B. Kagan,[20s1

catalyst ligands. When one succeeds in using an enantiomerically pure base to distinguish between the enantiotopic sites of the achirai monosubstituted ferrocene 199 (Scheme 74), racemiza-

ferrocenes are extraordinarily versatile chiral auxiliaries and &(A L[Ezoc a N 4 &A 2.EIX

202 203

X X X

199 200 ent-200

El a Me,Si; 96%; 98% ee b PkCOH; 91 %; 99% ee c PhS; 90%; 93% ee d I; 85%; 96% ee

Scheme 75. Lithiation and substitution of monosubstituted ferrocenes with enantiotopic differentiation.

Scheme 74. (-)-Sparteine-induced ortho-lithiation of a ferrocene derivative 12071. bases:

sBuLd Li Li & y'h MqNhNMe2 PhyNvPh PhyNyPh

Ph Ph

tion of the enantiomerically enriched planar-chiral intermediates 200 and ent-200 remains possible only through a proton transfer reaction or dissociation- recombination of the fer- rOcene ; that is, configurational stability can be presup- posed.1zo6] plexes [2 10-21 2,2141.

Scheme 76. Enantioselective deprotonation of arenetricarbonylchromium com-

2308 Angen Chem Int. Ed Engl. 1997, 36, 2282-2316


from Raston et al., are unfortunately not well documented with respect to quantitative results and configurational assign- rnent.I2l5] P. Beak and D. P. Curran recently described a (-)- sparteine-induced deprotonation and methylation of the 1- naphthoic acid amide 204 with 50% ee (Scheme 77).['16] The yield at - 78 "C amounted to only 53 YO, and from that one can conclude that the chiral base apparently accomplishes a kinetic racemate resolution between conformers that are interconverted only very slowly at - 78 0C.[2171 & H

- 1

/ / /

(R)-204 (S) -204

1. sBuLi11

2. CH,I EGO. -78 'C I

03""' / / (3y"' (W-205 6) -205

30%. e.r. = 75 : 25 (50% ee)

R = CH,(CH,),

Scheme 77 Induction o f axial chirality through (-)-sparteine-induced deprotonation [216]

5. Sparteine-Induced Carbolithiation

So far we have discussed only the most popular route to "carbanion generation", the deprotonation of CH-acidic precursors. The addition of organolithium to C=C double bonds (carbolithiation)[21 *I is an attractive alternative, because it yields an additional C-C bond "gratis" (Scheme 78). This reac-

206 207.1 208 poly-208

Scheme 78. Sparteine-induced asymmetric polymerization.

tion represents the first step in anionic polymerization;[2181 its use in organic synthesis depends upon retarding (relative to the first step) addition of the intermediate 208 to another molecule of alkene 206. This can be accomplished, for example, by con- ducting carbolithiation with a 5-alkenyllithium derivative in an intramolecular way according to W. F. Bailey,~Z'9~2z01 or in a case where the adduct 208 is specially stabilized.

As a benefit, control is extended over two or even three (if the residue R3 is chiral) stereogenic centers in the product. I. Marek,

J.-F. Normant, and co-workers succeeded in carrying out an enantioselective (-)-sparteine-controlled addition of alkyllithium to cinnamyl alcoholates and cinnamylamines (Scheme 79) .[2z1] Reaction of the (E)-alcoholate (E)-209 with

OLi

nButiIl hexane . 1 Li P 3 - f

\

(€)-209 2104 Li

epirnerization I f

R S..' CH,] pb Ph OH lLi, OH

H*,k f

213 ti 21 2

63%; 82% ee 82%; 80% ee 211-1

Scheme 79. Enantio- and diastereoselective carbolithiation of lithium (E)-3- phenyl-2-propen-I-olate [221]

butyllithium/( - )-sparteine provides good insight into the course of the reaction. In a syn-addition, typical for carbometa- lation,[2221 butyllithium/( -)-sparteine [presumably bonded in a precomplex to the alcoholate (E)-2091 attacks the C=C double bond from the Si-face. The resulting five-membered ring chelate complex 210.1 bears phenyl and butyl residues in cis-orienta- tion, hence the configurationally labile benzyllithium derivative epimerizes with formation of the more stable trans-substituted chelate 211- 1. Protonation produces the (S)-configured alcohol 212 with 80% ee, whereas methylation with inversion[2231 leads to the doubly branched (S,S)-alkanol213. Locking the intermediate into the chelate and the formation of reactive, presumably h e x a m e r i ~ [ ~ ~ ~ I lithium alcoholate clusters with diminished reactivity protects adducts 210.1 and 211.1 from polymerization. Quite remarkably, 5 mol YO of (-)-sparteine is sufficient to produce enantioselective reaction."' s]

Enantiofacial differentiation on the part of the ( -)-sparteine reagent at C-2 of the double bond in the conformationally restricted complex determines the stereochemical course of the reaction, since a configurationally stable stereocenter is created at C-2. Consequently, the (Z)-alcoholate (2)-209 leads to the opposite series of enantiomers.[2z1a1 Similarly successful additions have 'been realized with (E)-cinnamylamines and -acetals.[zz bl

Kiindig et al. have recently reported on enantioselective carbolithiation of the arenetricarbonylchromium complex 214 from 4,4-dimethyl-2-phenyl-l,3-oxazolidine (Scheme 80) Here the (-)-sparteine reagent attacks one of the enantiotopic sites preferentially from the "upper side," and treatment of the carbanionic intermediaterzz7] with propargyl bromide leads to a 5,6-trans-disubstituted cyclohexadiene 215. Greater enantiomeric excesses (65-93% ee) with somewhat lower yields (51 -67 YO) were achieved on using (S,S)-1,2-dimethoxy-1,2- diphenylethane (216) in place of ( -))-~parteine.[~'~]

Angebr. Chem. Int. Ed. EnxI. 1997, 36, 2282-2316 2309


sBuLil1

1. sBuWl

2. PhMe,SiCI Et20, - 78 'C

c Ph OCby

SiMe,Ph

222 221

q-P Me0 OMe

48%; d.r. > 98:2; >95% ee Scheme 82. Stereohomogeneous cyclopentyl carbamates through cyclocarbolithia- tion [231]

R a C,H, 72% %%ee

C CH, 70% 47%ee d CH3(CHJ365% 36% ee

b CH,=CH, 87% 3 4 % ~

have turned out in all the relevant studies to be especially configurationally labile. Experimental results from Reich et al. point to the fact that the formation of solvent-separated ion pairs tends to increase the barrier to inversion rather than lower it.[232b1 Nevertheless, we thought it might be possible that incor- poration into a rigid chelate complex might lead to an increase in configurational stability. Alky1r2331 and vinyl N,N-dimethyl- monothiocarbarnates[2341 are distinguished by high kinetic acidity. B. Kaiser thus investigated the ( - )-sparteine-induced deprotonation of S-alkyl thiocarbamates of the type 224;[235* 2 3 6 1

the reactions with S-butyl esters (Scheme 83) will be discussed as

21 6

Scheme 80. Diastereo- and enantioselective reaction of the tricarbonylchromium arene complex 214 [226]. HMPA = hexamethylphosphoramide.

Orientational investigations with a-styryl-N,N-diisopropyl carbamate (217) reveal a pathway to enantiomerically enriched secondary benzyl alcohols (Scheme 81) .[228] Attack by alkyllithium/( -)-sparteine leads-albeit with reduced enantiofacial selectivity-to the configurationally stable adducts 218.1, which are carboxylated with inversion174b1 and protonated with retention of configuration.L2 291

217

1 EiX a R=nBu;73%;32%ae b R = iPr; 80%; 45% ee C R = fBu; 77%; 25% ee

M~O,C*'*

'R

219 220 Scheme 81. Enantioselective carbolithiation of or-styryl carbamate 217 [228].

(R)-226

Intramolecular carbolithiations of (E)-alkenyllithium compounds proceed rapidly, as documented by numerous studies by Bailey et al., by 5-exo-trig-ring closure.[219. 2301 However, this pathway has so far been used only to synthesize racemic or achiral cyclopentane derivatives. The gap has been closed by a highly stereoselective carbolithiation developed by us, which also assures control over the configuration of the attacking C- nucleophile; it produces in the case of the substituted cyclopentane 222, for example, three consecutive, uniformly configured stereogenic centers (Scheme 82) .[2311

a El = SiMq; 92%; 63 : 37 (46% M) b €1 = C0,Me; 91%; 63.5 : 36.5 (47% W )

Scheme 83. (- )-Sparteine-mediated deprotonation of S-alkyl thiocarbamates [235].

an example of the results of this study. Deprotonation of 224a with sec-butyllithium/( -)-sparteine in diethyl ether and trapping of the carbanionic intermediate with chlorotrimethylsilane led to the silane (+)-(S)-226a with 46% ee. A nearly identical result was recorded in carboxylation and esterification to (-)- (S)-226b.I2 61

Is the cause here insufficient configurational stability of the diastereomeric intermediates (R)-225.1 and (S)-225.1, which enter into equilibrium under the reaction conditions, or inadequate enantiotopic differentiation in the deprotonation step? As demonstrated by the following series of experiments with the

6. Ion Pairs from a-Thiocarbanions

In contrast to a-alkoxyalkyllithium derivatives, a-thio-substituted a l k y l l i t h i ~ m [ ~ ~ ~ ~ and benzyllithium corn pound^^^^^^ 223- 1

2310 Angeu,. Chem Int. Ed. Engl. 1997, 36, 2282-2316


deuterated substrate ruc-[D]224, in this case both factors are responsible (Scheme 84) .[2351 During deprotonation with sec- butyllithium/TMEDA (a) and capture of the intermediate ion

me[D]224 rao(D1226a 93%, w 99% D

Why do S- and 0-lithioalkyl derivatives behave so different- ly? Presumably the relatively long C( = 0)-S and C-S bonds (about 180 pm compared to 140 pm for C - 0 ) establish a less compact transition state for deprotonation, coupled with diminished enantiotopic differentiation. Moreover, the mechanisms of enantiomer interconversion differ. Evidence is increasing that rotation of the attached C-S bond from the antiperiplanar to the synperiplanar conformation is the rate-determining step in the enantiomer interconversion, whereas for a-hydroxyalkyllithium derivatives inversion at the carbanionic center appears to be the slowest step (Scheme 85) .[2401

1. 0.5 equiv sBuLil1

2. Me,SiCl m~[D]224 (S>[Dl226~1 + ra~IDJ224

34% ee Scheme 84 Reactions with deuterium-labeled thiocarbamates

Scheme 85 The rate-determrning step in enantiomer interconversion of z-heterosubstituted alkyllithium compounds.

pair rac-[D]225 to give the silane ruc-[D]226a, all the deuterium remains in the molecule; that is, the kinetic H/D isotope effect is on the order of about 100. In the next experiment (b), ruc- [Dl224 was treated with one equivalent of the chiral base system see-butyllithium/( -)-sparteine, and silylation was initiated; the result was a greater than 99% deuterated product (S)-[D]226a in 93% yield and 34% ee.[2371 If there were a great preference for one of the enantiotopic protons pro-S-H or pro-R-H, one of the enantiomers would have been preferentially deprotonated, thus introducing a kinetic resolution like that observed with the corresponding 0-alkyl carbarnates (Section 4.2). However, the substrate was nearly completely deprotonated; nevertheless, an overproportional amount of enantiomerically enriched product was isolated. From this it can be concluded that the diastereomeric ion pairs (1 R)- and (1 S)-[D]225.1 equilibrate under the reaction conditions. Experiment (c) solidifies this conclusion; it differs from experiment (b) only in a reduced amount of base (0.5 equivalents). Again the product was (S)-[D]224a with 34% ee, and the recovered unchanged substrate 101224 took the form of a racemate. There was thus no kinetic resolution, and the product ratio was determined thermodynamically at the stage of the ion pairs.

Also for the (-)-sparteine complex of the dilithium compound derived from N-methyl-3-phenylthiopropionamide, which represents a valuable homoenolate reagent, Takei et al. found evidence of configurational lability in THF at - 78 "C, as well as similarly low enantiomeric enrichment in the aldehyde ad duct^.^^^''

For an efficient utilization of chiral a-thiocarbanions, conditions and ligands must be found that lead to the largest possible energy difference between the diastereomeric lithium complexes. Corresponding investigations with (similarly configurationally labile) lithium-I-(phenylseleny1)alkanides carried out by R. W. Hoffmann et al. show through an NMR study that this is not a simple

It can be concluded from the work of R. W. Hoffmann et al. on racemic I-(arylse1enyl)alkyllithium derivatives that bulky arylthio residues increase the barrier to enantiomer interconver- ion.^^^^' An increased crowding of groups at the carbanionic center should for the same reason lead to increased configurational stability. Indeed, the lithium compound (S)- 225a.TMEDA prepared from (S)-224a (46% ee) with sec- butyllithium in diethyl ether proved to be configurationally stable at - 78 "C, because after standing for 2.5 h, deuterolysis produces the capture product (S)-[D]226a with 44% ee (Scheme 86).[2351

This is, to the best of our knowledge, the first enantiomerically enriched a-thioalkyllithium derivative. The world record with respect to configurational stability is held by benzyllithium derivative (S)-227 (99% ee).[2423 2431 No racemization could be demonstrated after standing for 24 h at -78 "C, and even 10 min of warming the reaction mixture to 0 "C caused less than 1 YO racemization.

EbO, - 70 'C Cbys

(5)-224a 46%-

227 Scheme 86. Configurationally stable z-thioalkyllithium derivatives [235,241.242].

A n p w Chrm. fn t . Ed Engl. 1997, 36, 2282-2316 231 3


7. Summary and Prospects

The interaction between a lithium ion bearing chiral ligands and a developing or previously formed carbanion forces the latter into a specific configuration, whether through a preferred diastereomorphic transition state in the course of deprotonation or because of the establishment of a state of equilibrium. In combination with a stereoselective substitution step, this provides a new and effective strategy for enantioselective synthesis. The synthetic value of the process is increased by the fact that the carbanionic reagents are obtained by simple deprotonation of the corresponding CH acids. The examples discussed above were discovered through intuition, whereby spontaneous crystallization of one of the diastereomers occasionally played a crucial role in increasing efficiency. One goal is to understand the interaction between chiral ligand, cation, and substrate or carbanion better, as well as to quantify it through quantum-mechanical calculations in order ultimately to succeed in predicting favorable ligand -carbanion combinations. We are closer to this goal with respect to estimating the relative energies of diastereomeric ion pairs than for diastereomorphic transition states.

The results described from our own research group have been achieved over the past eight years by capable and enthusiastic co-workers. Their names are included in the bibliography. Special thanks are due to Prof. Dr. E.-U. Wurthwein, who convinced me ( D . H . ) of the value of quantum-mechanical computational methods for the solution of our problems, introduced several co-workers to the application of these methods, and stood at our side with unseyish advice and assistance. A . Deiters and Dipl.-Chem I: Heinl gave valuable support with the presentation of the manuscript and the graphics. The work was supported for many years by the Deutsche Forschungsgemeinschaft, the Fonds der Chemischen Industrie, the Stiftung Volkswagenwerk, and Bayer AG.

Received: March 5 , 1997 [A2151E] German version. Angen. Chem. 1997, 109, 2376-2410

Translated by Dr. W E Russey, Huntingdon, PA (USA)

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[68] Metalate rearrangements and related reactions: a) P. Kocienski, N. J. Dixon, Synlett 1989, 52; b) A. Pimm, P. Kocienski, S. D. A. Street, ibid. 1992, 886; c) P. Kocienski, C . Barber, Pure Appl. Chem. 1990, 62, 1933; d) [49a]; e) D. Madec, S Pujol, V. Henryon, J. P. Ferezou, Synletr 1995. 435.

I691 Epoxjdation and furanosde synthesis: a) D. Hoppe, .I. LiiBmann, P. G. Jones, D. Schmidt, G. M. Sheldrick, Tetrahedron Lett. 1986. 27. 3591; b) J. LiiRmann, D. Hoppe, P. G. Jones, C. Fittschen, G. M. Sheldrick, ihid. 1986, 31,3595; c) ;[58] d) G. Tarara, D. Hoppe, Svnrhesis 1989,89; e) [SO]; 3-acylte- trahydrofurans: f ) D. Hoppe, T. Kramer, C Freire Erdbriigger, E. Egert, Tetrahedron Lett. 1989,30, 1233; synthesis of dipeptide isosteres: g) R. Han- ko, K. Rabe, R. Dally, D. Hoppe, Angew. Chem. 1991. 103. 1725; Angew. Chem. Int. Ed. Engl. 1991,30,1690; h) F. Rehders. D. Hoppe. Synthesis 1992, 859; i) F. Rehders, D. Hoppe, ihid. 1992, 865.

[70] Applications in the synthesis ofcomplex natural products: Dehydroavermect- in BI,: a) J. P FCrezou, M. Julia, R. Khourzom, Y. Li, A. Pancrazi, P Robert, Synlerr 1991, 611; Desepoxy-Rosaramycin: b) ref.[49b], c) P. Le Menez. I . Berque, V. Fargeas, J. Ardisson, A. Pancrazi, S.vnlerr 1994.998; d) Le Mtnez. N. Firmo, V. Fargeas, J. Ardisson, A. Pancrazi, hid. 1994, 995; jaspamide: e) P. Ashworth, B. Broadbelt, P. Jankowski, A. Pimm. P. Kocienski, Syn- thesi.s 1995, 199; herboxidiene A: f) N. D. Smith, P. J. Kocienski, S. D. A. Street, ibid. 1996, 652; rue-tylosine: g) P. Le Menez, V. Fargeas, I . Berque, J. Poisson, J. Ardisson, J:Y. Lallemand. A. Pancrazi. J Org. Chem. 1995, 60, 3592.

[71] D. Hoppe, A. Bronneke, Tetrahedron Lett. 1983. 24, 1687. [72] D. Hoppe, A. Bronneke, Synthesis 1982, 1045. [73] R. W. Hoffmann, T. Riihl, J. Harbach, Liebigs Ann. Chem. 1992,725. [74] a) A. Carstens, D. Hoppe, Terrahedron 1994, 50, 6097; b) C Derwing, D.

Hoppe, Synthesi.? 1996,149; c) E Hammerschmidt. A. Hanninger, Chem. Ber. 1995, 128, 1069.

[75] Information on the stereochemical course of electrophilic substitution of chiral benzyllithium compounds is still quite fragmentary. Only in the case of (I-lithio-1-phenylethy1)-NNdiisopropyl carbamate [74a.b] and 2,4,6-triiso- propyl benzoate,[74c) which are accessible in enantiomerically enriched fom with known configuration through deprotonation of optically active precursors, do there exist firm correlations between the configurations of starting materials and products. The trend toward stereoinversion in reactions with alkyl and acyl halides, carbon dioxide, carbon disulfide, and silyl and stannyl chlorides is strong. Protonation with alcohols and carboxylic acids, hydrox- yalkylation with aliphatic aldehydes, and acylation with esters occur with retention; in these cases one can assume a preassociation of the reagent at the cation. The experimental basis is too small for solid generalization, moreover, a strong dependence on individual factors is to be anticipated.

[76] Zhang and Gawley carried out similar experiments in THF and isolated racemic products. This once again verities that (-)-sparteine is easily displaced from the lithium cation by THF: P. Zhang, R E Gawley, J Org. Chem. 1993.58. 3223.

[77] a) P. Beak, H. Du, J Am. Chem. Sac. 1993, 115,2516; bj G. P. Lutz, H. Du, D. J. Gallagher. P. Beak, J Org. Chem. 1996, 61, 4542

1781 D. J. Gallagher, H. Du, S . A. Long, P. Beak, J Am. Chem. Soc. 1996, 118, 11391.

[79] M. Schlosser, D. Limat, J Am. Chem. SOC. 1995, 117, 12342. [801 As we have already established in related cases [I36, 2351, deprotonation is

subject to an unusually large kinetic H/D isotope effect. [XI] Synthesis of (R)-phenylsarcosine: N. Voyer, J. Roby, Tetrahedron Lett. 1995,

36, 6627 [821 G. Boche, M. Marsch, J. Harbach, K. Harms, B Ledig. F Schubert. J. C. W.

Lohrenz, H. Ahlbrecht. Chem. Ber. 1993, 126, 1887. [83] a) Y. S. Park, M. L. Boys, P. Beak, J Am. Chem. Soc. 1996. 118,3757; other

applications and examples: b) Y S . Park, P. Beak, J Org. Chem 1997, 62, 1574.

I841 We refrain here from provjding an interpretation m depth. If the individual lithiation and substitution steps are subject to the same stereochemical course as was proven to be the case for the lithium derivatives of secondary benzyl carbamates [75], 38- 1 must possess the (R)-configuration [83b].

[85] S. Wu, S. Lee, P. Beak, J Am. Chem. SOC. 1996, 118. 715.

Angew. Chem Int Ed. Engl 1997,36, 2282-2316 2313

REVIEWS D. Hoppe and T. H e n s

[86] S. Thayumanavan, S. Lee, C. Liao, P. Beak, L Am. Chem. SOC. 1994, 116,

[87] The configuration at the benzylic center is unknown. [SS] a) A. Basu, P. Beak, L An?. Chem. Soc. 1996, 118, 1575; b) A. Basu, D. J.

Gallagher, P. Beak, L Org. Chem. 1996, 61, 5718. [89] Configurational assignment is based on the assumption of stereoinversion in

the course of silylation. [90] V. Snieckus, lecture on December 16, 1996, in Miinster. [91] S. Retzow, dissertation, Universitat Kiel, 1993. [92] The absolute configuration of the predominant stereoisomer is unknown. 1931 For 55a.llepI-55a.1, a free energy of epimerization AGG, of about

67 kJmol- was estimated from the coalescence temperature, whereas for the pair 55b. llepr-55b. 1 a value of > 78 kJ mol- results in the same way.

[94] An additional problem will be touched upon only briefly: Since (-)-sparteine is not C,-symmetric, a stereogenic center is also created at the tetrahedrally coordinated lithium cation. In this way four diastereomers compete. All experimental indications are consistent with the view that epimerization at lithium is much more rapid than that a t the carbanionic C atom.

I951 a) J. J. P. Stewart, L Comp. Chem. 1989, 10, 209; b) E. Anders, R. Koch, P. Freunscht, ibid. 1993, 14, 1301.

[96] T. Heinl, Diplomarbeit, Universitat Miinster, 1996. [97] I. Hoppe, M. Marsch, K. Harms, G. Boche, D. Hoppe, Angew. Chem. 1995,

107,2328; Angew. Chem. h i . Ed. Engl. 1995,34,2158 [98] The addition of tetra(isoprop0xy)titanium leads to increases in the yield and

product purity of the resulting carbinols, but does not change either the enantio- or the diastereoselectivity. From this we conclude that metal exchange does not arise in the carbanionic intermediate. Rather, we suspect that the lithium alcoholate is bound as a titanate, and hence possible subsequent and retroreactions are prevented.

I991 In a general sense, and with the same consequences with respect to regioselectivity, intermediates can be formulated in which the carbonyl oxygen atom has displaced one coordination site of (-)-sparteine.

[lo01 A lithium-sparteine contact has also been demonstrated by NMR spectroscopy in diethyl ether solution, whereas in THF solution no such evidence was discovered; S. Gessler, Diplomarbeit, Universitat Marburg, 1996.

9755.

[loll I. Hoppe, unpublished. [lo21 G. A. Weisenburger, P. Beak, J Am. Chem. Sac. 1996, 118, 12218. 11031 The authors suggest a $structure 67.1 and not a q‘-z-lithio ion pair [102].

Presumably the marked y-selectivity of the substitution reaction serves as an argument. We were able to show that related ~i-c-lithioallyl ion pairs (for which the I-chelate structure was established) display a strong tendency toward y-alkylation [46a, 64, 6SdI.

I1041 Only the (S)-configuration of 68d was rigorously proven 11021. [lo51 The authors claim that the provisional assignments of absolute configuration

for the stannanes ent-68e and ent-69e are based on analogies to our results [102]. On this basis we come to the reverse conclusion (68e and 69e), but then encounter contradictions with respect to the configurational assignment of the alkylation products 68b and enr-68b.

[lo61 The high enantioselectivity is only useful in a preparative sense if the (E)- and (2)-enamides 71 and 72 are separated and they do not interconvert during workup and separation.

[lo71 W.C. Still, C. Sreekumar, J Am. Chem. SOC. 1980, 102, 1201. See also ref. [lOS].

[I081 J. S. Sawyer, A. Kucerovy, T. L. Macdonald, G. J. McGarvey, L Am. Chem. SOC. 1988,110, 842.

[lo91 J. S. Carey, T. S. Coulter, D. J. Hallett, R. J. Maguire, A. H. McNeill, S. J. Stanway, A. Teerawutgulrag, E. J. Thomas, Pure Appl. Chem. 1996,68, 707.

[110] As demonstrated by many examples, sp3-hybridized (thus non-resonance- stabilized) alkyllithium derivatives react with retention of configuration, apart from a few very special exceptions.

[1111 a) P. C.-M. Chang, J. M. Chong, J Org. Chem. 1988, 53, 5584; b) J. A. Marshall, W. Y. Gung, Terrahedron 1989, 45, 1043; c) Ref. [135].

[112] a) T. Cohen, M.-T. Lin,J. Am. Chem. SOC. 1984,106, 1130; b) C. G. Screttas, M. Micha-Screttas, L Org. Chem. 1978, 43, 1064.

[113] For elegant synthetic applications based on diastereoselective “capture” of the lithium cation as well as thermodynamically controlled equilibrations, see a) S. D. Rychnovsky, D. E. Mickus, Tetrahedron Lert. 1989,30,3011; b) S. D. Rychnovsky, J Org. Chem. 1989,54,4982.

[114] N. G. Rondan, K. N. Houk, P. Beak, W. J. Zajdel, J. Chandrasekhar, P. von R. Schleyer, J Org. Chem. 1981, 46, 4108.

[115] E. J. Corey, T. M. Eckrich, Terruhedron Letr. 1983, 24, 3165. [116] a) P. Beak, B. G. McKinnie, J. Am. Chem. Sac. 1977, 99, 5213; b) P. Beak,

[117] R. Schlecker, D. Seebach, W. Lubosch, Helv. Chim. Acra 1978,61, 512. [118] The 2-(dimethylaminoethyl) ester of type 80 constitutes an exception, activa-

tion through the chelating dialkylamino group here certainly plays a significant role; cf. [116b].

[119] First application of N,N-dialkylcarbamoyl groups in the activation of alcohols: D. Hoppe, R. Hanko, A. Bronneke, Angew. Chem. 1980, 92, 637; Angew. Chem. Inr. Ed. Engl. 1980, 19, 625.

L. G. Carter, J Org. Chem. 1981, 46, 2363.

[1201 a) P. Tebben, dissertation, Universitat Kiel, 1991; b) T. Raffel, Diplomarbeit,

[I211 T. Nakai, personal communication, 1996. [122] F. Hintze, D. Hoppe, Synfhesis 1992, 1216. [I231 D. Hoppe, F. Hintze, P. Tebben, Angew. Chem. 1990, 102, 1457; Angew.

Chem. Inr. Ed. Engl. 1990, 29, 1422. [1241 P. Mickon, A. Rassat, Bull. Soc Chim Fr. 1971, 3561; see also Ref. [122]. [12S] Coalescence is achieved in CDCl, by warming to about 70°C; J. Haller,

Diplomarbeit, Universitat Kiel, 1992. [1261 If there are additional hydroxy groups in the vicinity of the carbamoyloxy

group, reductive ester cleavage with lithium aluminum hydride occurs readily. Apparently these bring the metal hydride into place.

1127) a) J. Tanaka, J Chem. Soc. Perkin Truns. 2 1989,1009; b) K. S. Rein, Terrahe- dronLrtr. 1991,32.194l;c)Gawley,L Org. Chem. 1989,54,175;d) J. J. Eisch, Res. Chem. Inrermed. 1996, 22, 145.

UniversitPt Kiel, 1990.

[128] T. Hense, dissertation, Universitat Miinster, 1996. [I291 a) D. Seebach, R. Henning, T. Mukhopadhyay, Chem. Ber. 1982, f15, 1705;

11291 T. Hense, Dissertation, Universitat Miinster, 1996. [130] F. Hintze, Dissertation, Universitat Kiel, 1993. [131] K. Behrens, dissertation, UniversitPt Miinster, 1997. [132] I. Hoppe, unpublished (1991). [I331 R. H. Bartelt, A. M. Schaner, C. L. Jackson, L Chem. Ecol. 1989, 15, 399. [1341 a) K. Mori. Terrahedron 1975.31,3011; b) J. H. Borden, E. Stokkink, Can. L

[135] Y. Yamamoto, Chemrractst Org. Chem. 1991, 4, 255 [136] D. Hoppe, M. Paetow. F. Hintze, Angew. Chem. 1993, 105, 430; Angew.

Chem. inr. Ed. Engl. 1993, 32, 394. [I371 We wish to thank Professor D. 0. Collum for stimulating us to carry out this

investigation through a comment at the Gordon Conference in Newport (1992).

[I381 Starting from (S)-configured I-deuterocarbamates of the type 97 one is able to enter the series of enantiomeric products enr-97. However, these suffer the blemish of being deuterated. We are aware of no precedent in which a kinetic isotope effect has been similarly utilized for the synthesis of highly enantiomerically enriched products.

[139] A high, though not quantified, kinetic HID isotope effect was observed in the deprotonation of S-ethyl thiobenzoates; D. B. Reitz, P. Beak, R. F. Farney, L. S. Helmick, L Am. Chem. SOC. 1978,100, 5428.

[140] a) Review. “Isotope Effects in Hydrogen Atom Transfer Reactions,” E. S. Lewis in Isotopes in Organic Chemistry, Vol. 2 (Eds. E. Buncel, C C. Lee), Elsevier, Amsterdam 1976, p. 127; b) E. S. Lewis, L. H. Funderburg, J. Am. Chem. SOC. 1967,89,2322.

b) T. Mukhopadhyay, D. Seebach, Helv. Chim. Aefa 1982,65, 385.

Zool. 1973, 51. 469.

[I411 J. Haller, dissertation, Universitat Miinster, 1995. [142] D. J. Gallagher, S. T. Kerrick, P. Beak, 1 Am. Chem. Sac. 1992, 114, 5872. [143] In this way the useless stereogenic center in the base is avoided. It follows from

studies by Beak that this exchange has virtually no influence on the stereoselectivity [142].

[I441 We believe that despite the small calculated energy difference the calculated structures portray the decisive distinction. It is very likely that the “true” transition states are more compact than the calculated ones. For the ground state of the lithium-sparteine-methylindenide complex 58a-1: Li-N distances measured in the crystal structure (209.5 pm and 214.1 pm) are notice- ably shorter than the calculated distances (225.2 pm und 226.4 pm). T. Heinl, Diplomarbeit, Universitat Miinster, 1996.

[145] J. Haller, T. Hense, D. Hoppe, Liebigs Ann. Chem. 1996, 489. (1461 These investigations were carried out with racemic mixtures, for greater clar-

[147] T. Hense, Diplomarbeit, Universitat Miinster, 1993. (1481 Those with little practice in stereochemistry are asked to forgive us for the

confusion we may have perpetrated. For reasons of clarity we have held constant the configurational arrangement at the reaction center in the calculations, and instead varied the configuration at the stationary center. This is legitimate, since all such transformations that obey the relative topicity Ik (like) [6a]-irrespective whether R,Re, S,Si or R*,Re*-must overcome the same energy barrier. The same applies in principle to the ul (unlike) series.

ity, one enantiomer has been singled out.

[I491 J. Haller, T. Hense, D. Hoppe, Synlerr 1993, 726. [l SO] P. Sommerfeld, D. Hoppe, Synlerr 1992, 764. [lSl] The great tendency toward complexation for y-Me,N groups in organolithi-

um compounds is well known: G. W. Klumpp, M. Vos, F. J. J. de Kanter, C. Slob, H. Krabbendam, A. L. Spek, J. Am Chem. SOC. 1985, 107,8292.

[I 521 Because of the unfavorable solubility characteristics of the intermediate carboxylic acid, methyl iodide was used as trapping reagent. The observed enantiomeric excesses are independent of the electrophile [ISO].

[153] a) M. Paetow, H. Ahrens, D. Hoppe, Tetrahedron Lett. 1992,33, 5323; b) H. Ahrens, dissertation, Universitat Miinster, 1994.

[I541 J. Schwerdtfeger, D. Hoppe, Angew. Chem. 1992, 104, 1547, Angew. Chem. Inr. Ed. Engl. 1992, 31, 1505.

[155] S. Kleinfeld, Diplomarbeit, Universitat Miinster, 1996. [156] D-Pantolactone (124) is produced by BASE The key step here is a sophisticat-

ed racemate resolution on a technical scale.



[157] M Paetow. M. Kotthaus, M. Grehl, R. Frohlich, D. Hoppe, Synlett 1994, 1034.

11 581 I t is unclear whether Me,SiC1 or LiCl formed in the process functions as Lewis acid.

[I591 Cyclopropyl anions possess a very high barrier to inversion: H. M. Wal- borsky, C. Hamdouchi, J . Am. Chem. Soc. 1993, 115,6406 and earlier papers by these authors.

[160] M. Kotthaus, dissertation, Universitat Miinster, 1996. [161] This represents the only case in which stereoinversion of a lithiated alkyl

carbamate was observed during the reaction. [162] The stereochemistry at the nucleophilic center during 1,3-eliminations was

accorded little attention until recently: a) B. Beruben, I. Marek, J.-F. Nor- mant, N. Platzer, Tetrahedron Lett. 1993,34,7575; b) J. Org. Chem. 1995,60, 2488; c) J.-F. Normant, Chemtracrs. Org. Chem. 1994, 7, 59; d) A. Krief, M. Hobe, Tetrahedron Lett. 1992,33,6529; e) A. Krief, M. Hobe, W. Dumont, E. Badaoui, E. Guittet, G. Evard, ibid. 1992, 33, 3381; f) N. Isono, M. Mori, J. .Org. Chem. 1996, 61, 7867.

[163] Similar findings are obtained with 2-monosubstituted 1,3-dicarbamates ofthe type 121 [160]. Because of the complicated stereochemical relationships (the CH,OCbv groups are enantiotopic, their protons diastereotopic), a presentation will be dispensed with in this context.

[164] Reviews ofdirectea lithiation: a) P. Beak, A I Meyers, Arc. Chem. Res. 1986, IY, 356, b) D D. Clark, A. Jahangir, Organic Reactions 1995, 47, 1; c) V. Snieckus, Chenr. Rev. 1990, 90, 879.

[165] a) C. Boie, dissertation, Universitdt Munster, 1996; b) C. Boie, D. Hoppe, Synthesis 1997, 176.

[166] H Ahrens, M Paetow, D. Hoppe, Tetrahedron Lett. 1992,33, 5327. [167] We do not know the precise structure of bis-chelate complexes like 131. It is

also possible that the more effectively donating carbonyl group of the y- or 3-carbamoyloxy residue binds, but then a seven- or eight-membered ring would need to form. We can also only speculate about the fourth ligand L; Et,O or Me,NCHICH,NMe, (TMEDA) bound in monodentate fashion are possible candidates.

[I681 Irrespective of the fact that the deprotonation step is kinetically directed, the energetically more favorable bicyclic chelate complex is formed in excess.

[169] H. Helmke. D. Hoppe, Synlert 1995, 978. [170] Based on MOPAC calculations [65e], there is an energy difference of

4.6 kJ mol- ’ between the simplified complexes 134 and epi-134 (Me,NC=O for Cby. L = Me,O).

[171] For the preparation of (+)-sparteine from rac-lupinane, which is obtained from the seeds of Lupinus alha, see ref. [26a].

[172] Another elegant route for diastereoselective generation of protected 1,3-dihy- droxyalkanides was developed by S . E. Rychnovsky: a) [113b]; b) T. I. Richardson, S. D. Rychnovsky, J . Org. Chem. 1996,61,4219; review: c) S. D. Rychnovsky. Chern. Rev. 1995, 95, 2021.

[173] a) W. Guarnieri. Diplomarbeit, Universitat Kiel, 1992; b) W. Guarnieri, M. Grehl, D Hoppe, .4ngew. Chem. 1994,106,1815; Angew. Chem. Int. Ed. Engl. 1994.33. 1734; c) P. Gmeiner. A. Kirtner, Synrhesis 1995, 83.

[174] The energy difference in the ground state between the complexes (1S)-138 and (1 R)-138 is apparently smaller than the relevant free energies of activation, because the addition of lithium bromide initiates an epimerization that leads to a 1 :2 mixture [175]. Nevertheless, the possibility that a further LiBr-containing aggregate enters into competition cannot be ruled out [175].

[175] M. Sendzik, Diplomarbeit, Universitat Kiel, 1995. [176] We do not know the structure of 138; our suggestion offers one plausible

interpretation of the experimental findings. In particular, it remains unclear in what way the 4-OCby group is bound to the lithium cation, and whether an additional ligand L (here Et,O) is acquired.

[177] M. Sendzik, dissertation, Universitat Miinster, 1997. 11781 This experiment proves that there is a kinetically determined deprotonation. [179] As demonstrated here, the high H/D kinetic isotope effect permits a very

general utilization of deuterium as protective group in the deprotonation of alkyl cdrbamates.

[180] Preparation of 2-(dibenzy1amino)alkanols: a) L. Velluz, D. Amiard, R. Heymes, BUN Sor. Chim. Fr. 1954. 1012; 6 ) M. T. Reetz, M. W. Dtewes, A. Schmidt, Angeu. Chem. 1987,99,1186; Angew. Chem. Int. Ed. Engl. 1987,26, 1141: c) ref. [173cl.

[181] The following problem has been avoided in Figure 10: With the exception of two energetically unfavorable conformational arrangements, the pyramidal dibenzylamino group contributes to varying degree to the shielding of the front and rear faces. It is quite conceivable that the influence of the “small” methyl group is overcompensated in this way.

[182] For experiments with N-(diphenylmethylene) derivatives see ref. [165] [183] S Kolczewski, dissertation, Universitat Miinster 1995. 11841 B. Weber, D. Hoppe, unpublished. [185] T. Hense. D. Hoppe, Synthesis 1997, in press. [186] P. Sommerfeld. dissertation, Universitat Miinster, 1995. I1871 Enanrioselective total syntheses of (+ )-sedridine: a) S. Murahashi, Y. Imada,

M. Kohno. T. Kawakami, Synfett 1993,395; b) C Louis, C. Hootel&, Tetrahe- dron- AJymmerry 1995, 6, 2149, c) B. J. Littler, T. Gallagher, I. K. Boddy, P. D. Riordan, Synlett 1997, 22.

REVlEWS

[188] J. van Bebber, D. Hoppe, unpublished. 11891 No indications of participation by the 3-OCby-group were detected. 11901 P. H. J. Carlsen, T. Katsuki, V. S . Martin, K. B. Sharp1ess.J. Org. Chem. 1981,

[I911 R. Frohlich, M. Grehl, personal communication (1994). [192] P. Beak, W. J. Zajdel, J . Am. Chem. SOC. 1984,106, 1010. [193] a) S. T. Kerrick, P. Beak, J. Am. Chem. Soc. 1991, 113,9708; b) P. Beak, S T.

Kerrick, S. Wu, J. Chu, ibid. 1994, fl6, 3231. [194] a) E. J. Corey, R. K. Bakshi, S. Shibata, J Am. Chem. Soc. 1987,109,5551;

b) E. J. Corey, R. K. Bakshi, S. Shibata, C. P. Chen, K. K. Singh. (bid. 1987, 109,7925; c) review: S . Wallbaum, J. Martens, Tetrahedron Asymmetry 1992, 3, 1475.

[I951 a) R. E. Gawley, Q. Zhang, J . Am. Chem. SOC. 1993, 115, 7515; b) T. R. Elworthy, A. I. Meyers, Tetrahedron 1994, 50, 6089; c) K. E Gawley, Q. Zhang, J. Org. Chein. 1995, 60, 5763; d) R. E. Gawley, Q. Zhang, S. Cam- pagna, J . Am. Chem. Soc. 1995, I f 7,11817: e) I. Coldham. R. Hufton, D. J. Snowden, ibid. 1996, 118, 5322.

46,3936

[196] For a detailed discussion, see a very recent review by Beak: ref. [I71 [197] D. J Gallagher, P. Beak, J . Org. Chem. 1995, 60, 7092. [I981 M. E. Kopach, A. I. Meyers, J Urg. Chem. 1996,61, 6764. 11991 D. J. Gallagher, S. Wu, N. A. Nikolic, P. Beak, J Org. Chrm. 199560, 8148. [200] In orientational experiments with N-Boc-piperidine we obtained nearly

[20l] Y S. Park, P. Beak , Tetrahedron 1996, 52, 12333. [202] a) D. M. Hodgson, G. P. Lee, Chem. Commun. 1996,1015; b) D M. Hodg-

son, R. Wisedale, Tetrahedron ’ Asymmetry 1996, 7, 1275: c) D. M. Hodgson, G. P. Lee, [bid. 1997, 2303.

[203] M. Lautens, C. Gajda, P. Chiu, J. Chem. SOC. Chem. Conzmun. 1993, 1193. 12041 R. A. Muci, K. R. Campos, D. A. Evans, J . Am. Chem. So<.. 1995,117,9075. 12051 Brief reviews: a) A. Togni, Angew. Chem. 1996,108,1581 : Angew. Chem. Int.

Ed. Engl. 1996,35, 1475; b) S. Borman, Chem. Eng. News 1996, 74 (30), 38. [206] With respect to relevant experiments with isopropylferrocene (199,

X = CHMe,) by Nozaki et a]. see Section 2 and refs. [27c,d] [207] a) M. Tsukazaki, M. Tinkl, A. Roglans, B. J. Chapell. N. J. Taylor, V.

Snieckus, J. Am. Chem. SOC. 1996, 116.685; b) an application. H. Jendralla, E. Paulus, Synlett 1997,471

racemic products; I. Hoppe, unpublished (1990).

[208] D. Price, N. S. Simpkins, Tetrahedron Let/ . 1995, 36, 6135. [209] Y. Nishibayashi, Y Arikawa, K. Ohe, S. Uemura, J. Org. Chem. 1996, 61,

[210] E. P. Kiindig, A. Quattropani, Tetrahedron Lett. 1994, 35, 3497. I2111 M. Uemura, Y Hayashi, Y. Hayashi, Tetrahedron: Asymmetry 1994,5, 1427. [212] D. A. Price, N. S. Simpkins, A. M. MacLeod, A. P. Watt, J. Org Chem. 1994,

[213] J. Aube, Chemtracrs: Urg. Chem. 1994, 7,413. [214] H -G. Schmalz, K. Schellhaus, Tetrahedron Lett. 1995, 36. 5515. [215] L. M. Engelhardt, W.-P. Leung, C. L. Kaston, G. Salem, P. Twiss, A. H.

[216] S. Thayumanavan, P. Beak, D. P. Curran. Tetrahedron Lett. 1996, 37, 2899. [217] A very effective approach to ( - )-sparteine-assisted synthesis of enantiomeri-

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[225] To our knowledge, this discovery constitutes the first example of a catalytic enantioselective lithiation induced by (-)-sparteine.

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published [226]. The propargyl residue enters from the side complexed by chromium; thus a bonding interaction between the metal and the alkynyl residue is very probable.

I2281 J. G. Peters, Diplomarbeit, Universitat Miinster, 1996. 12291 Stereochemistry of the electrophilic substitution of lithiated secondary benzyl

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D. Hoppe and T. Heme REVIEWS

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[237] We do not know how to account for the marked deviation of the ee value (34%) from that obtained with the undeuterated substrate (46% ee). Is it likely that equilibrium between the diastereomers would be upset by a thermo- dynamic isotope effect on the order of magnitude of AAG = 0.4 kJmol-I?

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No. 24; Angew. Chem. Intl. Ed. Engl. 1997, 36, No. 24.

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