university of groningen novel asymmetric copper …(-)-sparteine together with n-butyllithium (5 eq)...

University of Groningen

Novel asymmetric copper-catalysed transformationsBos, Pieter Harm

IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.

Document VersionPublisher's PDF, also known as Version of record

Publication date:2012

Link to publication in University of Groningen/UMCG research database

Citation for published version (APA):Bos, P. H. (2012). Novel asymmetric copper-catalysed transformations. Groningen: s.n.

CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).

Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.

Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.

Download date: 28-05-2020

https://www.rug.nl/research/portal/en/publications/novel-asymmetric-coppercatalysed-transformations(67ccce1e-4eb9-4771-a68b-8fc5295f1742).html

https://www.rug.nl/research/portal/en/publications/novel-asymmetric-coppercatalysed-transformations(67ccce1e-4eb9-4771-a68b-8fc5295f1742).html

Chapter 6 Copper-Catalyzed Asymmetric Ring Opening of Oxabicyclic Alkenes with Organolithium Reagents

In this chapter a highly efficient method is reported for the asymmetric ring opening of oxabicyclic alkenes with organolithium reagents. Using a chiral copper/ phosphoramidite complex together with a Lewis acid (BF3·OEt2), full selectivity for the anti isomer, yields up to 96% and excellent enantioselectivities up to 98% ee were obtained for the ring opened products.

* Parts of this chapter have been published: Bos, P. H.; Rudolph, A.; Pérez, M.; Fañanás-Mastral, M.; Harutyunyan, S. R.; Feringa, B. L. Chem. Commun. 2012, 48, 1748.

152

Chapter6-Final-nocode.docx

Chapter 6

6.1 Introduction

The desymmetrization of meso compounds is an efficient method for the synthesis of chiral compounds bearing multiple stereocenters.1-3 This process is especially valuable as multiple stereocenters can be introduced simultaneously with high stereocontrol. In the past decade, a variety of methods were developed for the transition-metal catalyzed ring opening of meso heterobicyclic alkenes using various nucleophiles generating the ring-opened products in high yield and with excellent enantiomeric excess.4, 5

6.1.1 Stoichiometric ring opening of oxabicyclic alkenes

In 1971, Caple et al. reported the stoichiometric ring opening of oxabicyclic alkene 1a with organolithium reagents giving full selectivity for the syn product (Scheme 1).6 This syn configuration is the result of an initial exo attack of the nucleophile and the racemic ring-opened products were obtained in good yields. Addition of a few drops of BF3·Et2O to a solution of rac-syn-2 in diethyl ether at room temperature gave quantitative dehydration to naphthalene 3.

Scheme 1 Addition of organolithium reagents to oxabicyclic alkene 1a.6

Also the ring opening of oxabicyclic substrate 4 with organolithium reagents (3 eq) afforded the syn products exclusively (Scheme 2).7 If phenyllithium was used instead of n-butyllithium or methyllithium, 5-9 equivalents were necessary in order to obtain the product in a satisfactory yield.

O

R1

OH

R1

OH

OH

R2

R2Li 3-9 eq

diethyl ether, rt

rac-560-80% yield

rac-4

Scheme 2 Regio- and stereospecific synthesis of substituted cyclohexenediols.7

153


Copper-Catalyzed Asymmetric Ring Opening of Oxabicyclic Alkenes with Organolithium Reagents

In the same year, the group of Lautens et al. studied the ring opening of oxabicyclic compounds (i.e. oxabicyclo[3.2.1]octenes) using stoichiometric amounts of organocuprate and organolithium reagents.8-11 This methodology was applied in the racemic total synthesis of the C21-C27 fragment of rifamycin S (Scheme 3).11

O

OHHO

OH

4 steps HO

O O

OMe

OR

rac-8R = TBDMS

21

27

2721

6 rac-765% yield

MeLi, TMEDA

diethyl ether, 45 oC

Scheme 3 Synthesis of the C21-C27 segment of rifamycin S.11

6.1.2 Palladium and Rhodium-catalyzed asymmetric ring opening

The use of transition-metal catalysis has allowed for the development of methods applying softer organometallic reagents. In general, most asymmetric ring opening procedures with carbon nucleophiles give the syn product as a result of exo attack of the nucleophile to the oxabicyclic alkene.4 In particular the enantioselective palladium-catalyzed ring opening of oxabicyclic alkenes with diorganozinc reagents, developed by Lautens et al., proceeds with high selectivity for the syn diastereomers and is a highly valuable transformation for the synthesis of multifunctional building blocks (Scheme 4).12, 13 Using a catalyst prepared from PdCl2(CH3CN)2 and bis(diphenylphosphino)ferrocene (dppf) in dichloromethane at room temperature a variety of diorganozinc reagents induce ring opening to give the syn diastereomer 2 exclusively and in good yield. When chiral ligands (Tol-Binap or t-Bu-POX14) were employed, syn-2 could be obtained in good yield with excellent enantiomeric excess (up to 96% ee).

Scheme 4 Palladium-catalyzed ring opening of oxabicyclic alkenes with diorganozinc reagents.12

154


Chapter 6

Next to the asymmetric ring opening of oxabicyclic alkene 1a, enantioselective palladium-catalyzed methods have also been developed for the ring opening of [2.2.1] and [3.2.1] oxabicyclic alkenes and azabenzonorbornadienes using slightly modified procedures.13, 15 Furthermore, the palladium-catalyzed asymmetric ring opening was also applied for the synthesis of the C1-C10 and the C17-C23 fragments in the total synthesis of the polyether antibiotic ionomycin 12 (Scheme 5).16

Scheme 5 Total synthesis of ionomycin via asymmetric ring opening of [3.2.1] oxabicycle 9.16

Using a catalytic system based on rhodium, heteroatom nucleophiles could be applied in the asymmetric ring opening of oxabicyclic systems.17-19 After careful optimization of the reaction conditions, a rhodium complex with PPF-Pt-Bu2 as the chiral ligand provided the anti products selectively (Scheme 6). High isolated yields and high enantiomeric excess were obtained with both alcohols as well as primary and secondary amines as nucleophiles using a very low catalyst loading (S/C up to 10000:1). Removal of the chloride ligand, originating from [Rh(COD)Cl]2, and exchanging it with iodine, dramatically improved the efficiency of the catalyst.20, 21

O[RhI(L1)]

1a

nucleophile

neat, 100 oCOH

R

anti-2R = OPh, NMePh

up to 99% eeup to 94% yield

S/C up to 10000:1

FePPh2

Pt-Bu2

L1PPF-Pt-Bu2

Scheme 6 Asymmetric ring opening of 1a with heteroatom nucleophiles.20

Furthermore, rhodium catalysis also gave excellent results in the asymmetric ring opening of oxabicyclic alkenes with aryl- and alkenylboronic acids (up to 95% ee and 95% yield).22

155



6.1.3 Copper-catalyzed asymmetric ring opening

Most of the protocols described in the last paragraph for the ring opening of oxabicyclic alkenes with carbon nucleophiles give the syn product. Exceptions leading to high anti selectivity are reported using copper-based catalytic systems.5 In 2002, our group developed the copper-catalyzed asymmetric ring opening of oxabicyclic alkenes with diorganozinc reagents (Scheme 7).23 The reaction rate could be enhanced by addition of a Lewis acid (Zn(OTf)2 1 eq) to the reaction. This protocol showed a very high level of anti-selectivity and is therefore complimentary to the palladium-catalyzed syn-selective ring-opening described in section 6.1.2.

Scheme 7 Copper-catalyzed asymmetric ring opening with diorganozinc reagents.23

This high anti selectivity was also observed for a general copper-catalyzed process using non-chiral ligands and Grignard reagents.24 In 2005, Zhou et al. reported an asymmetric version of the ring opening of oxabicyclic alkenes with Grignard reagents. Using spiro phosphoramidite (Sa,S,S)-L3 as the chiral ligand, excellent anti/syn ratios and good enantioselectivity (up to 88% ee) could be obtained (Scheme 8).25, 26

Scheme 8 Copper-catalyzed asymmetric ring opening with Grignard reagents.25 The group of Alexakis27 reported the asymmetric ring opening of oxabicyclic alkenes with Grignard and aluminium reagents using SimplePhos as the chiral ligand (Scheme 9). In the case of Grignard reagents, excellent yields and diastereoselectivity were obtained together with moderate to good ee’s (up to 82% ee). The enantiomeric excess could be improved up

156


Chapter 6

to 94% ee by using trialkylaluminium reagents. Furthermore, the authors showed that substitution at the bridgehead position (Scheme 9, R1 ≠ H) lead to a decrease in enantioselectivity and the formation of unwanted side products (elimination of the alcohol group and aromatization of the naphthyl group). The formation of side products is explained by the increased Lewis-acidity of the aluminium reagents compared to Grignard and diorganozinc reagents.27

Scheme 9 Copper-catalyzed asymmetric ring opening with RMgBr or R3Al.27

6.1.4 Catalytic asymmetric ring opening using organolithium reagents

To the best of our knowledge there is only one example reported to date in which organolithium reagents are used for the asymmetric ring opening of oxabicyclic alkenes. In 1993, the group of Lautens was able to convert oxabicyclic compound 13 using 25 mol% of (-)-sparteine together with n-butyllithium (5 eq) providing the syn product selectively with moderate enantioselectivity (51% ee) and yield (61%) (Scheme 10).28 The yield could be improved to 69% with 48% ee by adding 25 eq of (-)-sparteine.

OTBDMS

On-BuLi 5 eq

(-)-sparteine 25 mol%

n-pentane, -40 oC

OTBDMSHO

13 14up to 51% ee

up to 69% yield

N

N

H

H

(-)-sparteine

Scheme 10 Asymmetric ring opening of 13 with n-BuLi catalyzed by (-)-sparteine.28

157



6.2 Goal

As described in Chapter 5, we developed the first copper-catalyzed asymmetric allylic alkylation protocol using organolithium reagents as nucleophiles.29 Based on the excellent enantio- and regioselectivities obtained, we envisioned that this novel methodology could be extended towards the asymmetric ring opening of oxabicyclic alkenes. Organolithium reagents are arguably among the most widely used organometallic reagents in chemistry and are in general cheaper than their organozinc, Grignard or organoaluminium counterparts.30, 31 Methodology in which organolithium reagents can be applied directly as the enantioselective carbon-carbon bond forming reagent are therefore highly desirable, but challenging in view of their very high reactivity.

6.3 Results and Discussion

6.3.1 Screening of ligands and conditions

The asymmetric ring opening of oxabicyclic alkenes with organolithium reagents can lead to the formation of four products, namely the desired anti product 16aa and its syn diastereomer 17aa, 1-naphthol 18a as a result of acid-catalyzed ring opening/aromatization and alkyl naphthalene 19aa as a result of elimination of water from 16aa or 17aa (see Scheme 11).

Scheme 11 Copper-catalyzed asymmetric ring opening of oxabicyclic alkenes with n-BuLi.

In our initial experiment the optimized conditions using (R,RFc)-Taniaphos-L4 as ligand for the allylic alkylation of allylic bromides were employed (Table 1, entry 1).29 Unfortunately, no ring opening of the oxabicyclic alkene occurred at -80 oC. We anticipated that higher temperatures were needed but in order to raise the temperature the solvent had to be changed to 1,2-dichloroethane in order to prevent carbene formation.32, 33 This led to 50% conversion and syn selectivity for the ring opening reaction giving racemic product due to

158


Chapter 6

the uncatalyzed reaction (Table 1, entry 2). We also switched to phosphoramidite ligands34 because they have been shown to perform very well both with organolithium reagents in the allylic alkylation29,45 as well as in the copper-catalyzed asymmetric ring opening of oxabicyclic alkenes with diorganozinc reagents developed in our group.23 Table 1 Screening of ligands and conditions with n-butyllithiuma

Fe

Me2NPh2P

(R,RFc)-L4(R,RFc)-Taniaphos

Ph2P

O

OP N O

OP N

O

OP N

O

OP N

OMe

OMe

OMe

OMe

(S,R,R)-L7

(R,R,R)-L5(S,S,S)-L6

(S,R,R)-L8 Entry L BF3·Et2O T (oC) Solvent Conversion (%) Anti:Syn eeb, c (%)

1 L4 - -80 CH2Cl2 - -:- nd 2d L5 - -30 C2H4Cl2 50 3:97 nd 3e L5 - 0 C2H4Cl2 45 16:84 nd 4e L5 - 0 t-BuOMe Fullf 3:97 nd 5d L5 yes -40 CH2Cl2 Fullg -:- nd 6 L5 yes -80 CH2Cl2 Full >99:1 97 7h L6 yes -80 CH2Cl2 76 98:2 69i 8h L7 yes -80 CH2Cl2 53 93:7 77i 9h L8 yes -80 CH2Cl2 75 >99:1 76i 10h L5 yes -80 CH2Cl2 Full >99:1 97 a Conditions: 1a (0.2 mmol), CuBr·Me2S (5 mol%), L (6 mol%), n-butyllithium (diluted with n-hexane, 1.5 eq, 0.3 M) added slowly over 2 h, solvent, temperature, 2 h reaction time. b Enantiomeric excess of the anti product 16aa. c Determined by chiral HPLC-analysis (See experimental section). d Reaction time: 16 h. e Reaction time 5 h. f Formation of side products. g Formation of 18a and 19aa (1:1). h n-butyllithium (1.1 eq), 16 h reaction time.i In this case the opposite enantiomer of 16aa is formed (1S,2R).

Increasing the temperature even further did not lead to a higher conversion or selectivity (Table 1, entry 3). Switching solvents from 1,2-dichloroethane to methyl tert-butyl ether led to the isolation of mainly the syn isomer (17aa) together with a considerable amount of

159



side products (Table 1, entry 4). We then added a Lewis acid (BF3·Et2O, 1.1 eq) to the reaction mixture to activate the substrate and performed the reaction at -40 oC overnight (Table 1, entry 5). In this case full conversion was reached, but the formation of a 1:1 mixture of 1-naphthol 18a, originating from Lewis acid-catalyzed ring opening, and n-butylnaphthalene 19aa, originating from addition of the n-butyl group followed by an elimination process, was observed (Table 1, entry 5). Upon lowering the temperature to -80 oC in dichloromethane full conversion was obtained after 2 h, after which the reaction had to be stopped to prevent side reactions. Using phosphoramidite ligand (R,R,R)-L5 exclusive formation of the anti diastereomer (1R,2S)-16aa was observed with excellent enantioselectivity (97% ee, Table 1, entry 6). The same anti selectivity was observed in the synthesis of the racemates under the same conditions, but using triphenylphosphine (10 mol%) as the ligand. The use of other phosphoramidite ligands did not improve the enantioselectivity obtained with ligand (R,R,R)-L5 although excellent anti:syn ratios were achieved in all cases (Table 1, entries 7-9). The amount of organolithium reagent could be lowered to 1.1 eq without affecting the regio- and enantioselectivity (Table 1, entry 10). In this case the reaction mixture was stirred overnight to ensure full conversion while undesired side reactions were prevented.

6.3.2 Copper-catalyzed ring opening with organolithium reagents

After optimization of the reaction conditions, as indicated in Table 1, entry 10, the use of several commercial available organolithium reagents was examined for the copper-catalyzed asymmetric ring opening of oxabicyclic alkenes 1a and 1b (Table 2). In all cases full conversion was obtained after stirring overnight at -80 oC using only a slight excess of organolithium reagent (1.1 eq) and the anti product was formed exclusively. Table 2 Cu-catalyzed asymmetric ring opening of 1a and 1b with organolithium reagents.a

Entry Substrate RLi Anti:Syn Product Yield 16b (%) ee 16c (%)

1 1a n-BuLi (15a) >99:1 16aa 84 97 2 1b n-BuLi (15a) >99:1 16ba 82 95 3 1a EtLi (15b) >99:1 16ab 80 98 4 1b EtLi (15b) >99:1 16bb 71 97 5 1a n-HexLi (15c) >99:1 16ac 81 97 6 1b n-HexLi (15c) >99:1 16bc 82 93 7 1a i-BuLi (15d) >99:1 16ad 86 97 8 1b i-BuLi (15d) >99:1 16bd 96 93 9 1a TMSCH2Li (15e) >99:1 16ae 65d 42 a Conditions: 1 (0.2 mmol), CuBr·Me2S (5 mol%), (R,R,R)-L5 (6 mol%), BF3·Et2O (1.1 eq), n-butyllithium (diluted with n-hexane, 1.1 eq, 0.3 M) added slowly over 2 h, CH2Cl2, -80 oC, full conversion after 16 h. b Isolated yield. c Enantiomeric excess determined by chiral HPLC-analysis (See experimental section). d Conversion: ~70%.

160


Chapter 6

The asymmetric ring opening of 1b using n-butyllithium gave a slightly lower enantiomeric excess than 1a (Tabel 2, entry 2). Both ethyllithium as well as n-hexyllithium gave excellent enantioselectivities and isolated yields (Table 2, entry 3-6). Furthermore, the use of the more bulky reagent i-butyllithium also resulted in an excellent yield and enantioselectivity for the desired products 3ad and 3bd (Table 2, entries 7-8). The use of a trimethylsilyl-substituted organolithium reagent led to a decrease in reactivity and enantioselectivity. Full conversion was not obtained after 16 h and the enantiomeric excess dropped to 42% (Table 2, entry 9) and in combination with substrate 1b very low conversions were obtained.

6.3.3 System limitations

The limitations of this catalytic system under different conditions (A and B) and the major products obtained are shown in Table 3. Table 3 Limitations of the catalytic system.a

Entry Substrate RLi Conditions Aa Conditions Bb

1 1a MeLi (15f) - 1a 2 1b MeLi (15f) - 1b 3 1a PhLi(15g) - Side products 4 1a s-BuLi (15h) - Side products 5 1c n-BuLi (15a) 19ca 18c 6 1d n-BuLi (15a) Mixture of 1d, 16da and 19da Mixture of 1d, 16da and 19da 7 1e n-BuLi (15a) 19fa - 8 1f n-BuLi (15a) 19fa Mixture of 1f and 19fa 9 1g n-BuLi (15a) - 19ga a Conditions A: 1 (0.2 mmol), CuBr·Me2S (5 mol%), (R,R,R)-L5 (6 mol%), BF3·Et2O (1.1 eq), RLi (diluted with n-hexane, 1.5 eq, 0.3 M) added slowly over 2 h, CH2Cl2, -80 oC, reaction time 2 h. b Conditions B: 1 (0.2 mmol), CuBr·Me2S (5 mol%), (R,R,R)-L5 (6 mol%), BF3·Et2O (1.1 eq), RLi (diluted with n-hexane, 1.1 eq, 0.3 M) added slowly over 2 h, CH2Cl2, -80 oC, reaction time 16 h.

161



Organolithium reagents commercially available as solutions in ethereal solvents (i.e. methyllithium and phenyllithium) were not effective under the optimized conditions and no conversion was observed in both cases (Table 3, entries 1-3). This can be rationalized by a possible interaction of the ethereal solvent with the Lewis acid. The use of sec-butyllithium, which is more reactive and a stronger base, led to the isolation of a mixture of indefinable side products (Table 3, entry 4). The reaction of oxabicyclic alkene 1c using 1.5 eq of organolithium reagent and a reaction time of 2 h (conditions A) gave the elimination product 19ca as the major product (Table 3, entry 5). When a longer reaction time with 1.1 eq of n-BuLi was employed, it was discovered that the substrate does not dissolve properly under these conditions. Upon work up the ring opened product 18c was isolated. Substrate 1d gave a mixture of desired product, starting material and elimination product under both reaction conditions examined (Table 3, entry 6). Furthermore, substrates 1e and 1f, bearing electron donating groups were not compatible under the reaction conditions, leading to elimination of the alcohol group and aromatization of the naphthyl group. Even in the absence of Lewis acid mainly elimination product was isolated. Furthermore, the use of different Lewis acids, such as: ZnOTf2 and mixtures of BF3·Et2O and TMSCl,35 did not improve the outcome of the reaction. This substrate incompatibility has also been observed in the copper-catalyzed asymmetric ring opening of oxabicyclic alkenes with organoaluminium and Grignard reagents.25, 27 Bridgehead substituted substrate 1g showed quantitative conversion to elimination product 19ga. To further examine the limitations of the catalytic system, the copper-catalyzed ring opening of [3.2.1] oxabicycle 13 and [2.2.1] oxabicycle 27 was studied. Oxabicyclic alkene 13 was synthesized from 3-pentanone in 4 steps (Scheme 12).

Scheme 12 Synthesis of [3.2.1] oxabicycle 13.

Chlorination in the α-position of 3-pentanone 20 afforded 21 in 76% yield after distillation under reduced pressure. Subsequent 1,3-dipolar cycloaddition to furan constructed the oxabicyclic system. The ketone moiety was reduced with sodium borohydride in good yield

162


Chapter 6

and the resulting alcohol 6 was protected using potassium hydride and TBDMSCl to give the desired [3.2.1] oxabicycle 13 in 26% yield over 4 steps. Oxabicyclic alkene 27 was synthesized from furan in 3 steps (Scheme 13). A solvent free reaction of furan with maleic anhydride afforded 25 in 88% yield. Subsequent reduction with lithium aluminium hydride led to the isolation of diol 26 in 61% yield. Methylation of the alcohol groups with potassium hydride and methyl iodide provided the [2.2.1] oxabicycle 27 in 42% yield overall.

Scheme 13 Synthesis of [2.2.1] oxabicycle 27.

Both oxabicyclic substrates 13 and 27 were studied using the optimized conditions for the copper-catalyzed asymmetric ring opening with organolithium reagents (Table 3, conditions B) and to our disappointment, no reaction took place. Addition of extra Lewis acid (up to 3.1 eq) did not give any ring opened product under these conditions and only starting material was isolated.

6.4 Conclusion and Future Prospects

In conclusion, we have developed a highly regio-, enantio- and anti-selective procedure for the copper-catalyzed asymmetric ring opening of oxabicyclic alkenes for the first time using organolithium reagents. The use of BF3·Et2O proved to be necessary for the activation of the oxabicyclic alkene. A possibility for further study is the copper-catalyzed asymmetric ring opening of azabicyclic alkenes (Scheme 14).

Scheme 14 Copper-catalyzed asymmetric ring opening of azabicyclic alkenes with RLi.

Azabicyclic alkenes are considered less reactive and have been successfully used in the racemic copper-catalyzed ring opening with Grignard reagents.5 Depending on the protecting group on the nitrogen atom different anti:syn ratios were found. Furthermore, using Grignard reagents, addition of ligands, such as Binap or PPh3, resulted in inhibition of the reaction. For these reasons, more reactive organolithium reagents together with a Lewis acid might lead to asymmetric ring opening and isolation of the desired products.

163



6.5 Experimental Section

General

Chromatography: Merck silica gel type 9385 230-400 mesh, TLC: Merck silica gel 60, 0.25 mm. Components were visualized by UV and staining with cerium/molybdenum or potassium permanganate. Progress and conversion of the reaction were determined by GC-MS (GC, HP6890: MS HP5973) with an HP1 or HP5 column (Agilent Technologies, Palo Alto, CA). Mass spectra were recorded on an AEI-MS-902 mass spectrometer (EI+) or a LTQ Orbitrap XL (ESI+). 1H- and 13C-NMR were recorded on a Varian AMX400 (400 and 100.59 MHz, respectively) or a Varian VXR300 (300 and 75 MHz, respectively) using CDCl3 as solvent. Chemical shift values are reported in ppm with the solvent resonance as

the internal standard (CHCl3: 7.26 for 1H, 77.0 for 13C). Data are reported as follows: chemical shifts, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constants (Hz), and integration. Optical rotations were measured on a Schmidt + Haensch polarimeter (Polartronic MH8) with a 10 cm cell (c given in g/100 mL). Enantiomeric excesses were determined by HPLC analysis using a Shimadzu LC-10ADVP HPLC equipped with a Shimadzu SPD-M10AVP diode array detector. All reactions were carried out under a nitrogen atmosphere using oven dried glassware and using standard Schlenk techniques. Dichloromethane was dried and distilled over calcium hydride; 1,2-dichloroethane was dried over molecular sieves (3Å). CuBr·SMe2 was purchased from Aldrich, and used without further purification. Organolithium reagents 15 were purchased from Acros: n-BuLi (15a) (1.6 M in hexane), i-BuLi (15d) (1.6 M in hexane), TMSCH2Li (15e) (0.8 M in hexane), MeLi (15f) (1.6 M in diethyl ether) or Aldrich: EtLi (15b) (0.5 M in benzene/cyclohexane 9:1), n-HexLi (15c) (2.3 M in n-hexane), PhLi (15g) (1.8 M in dibutyl ether). Ligand L4 was purchased from Aldrich. Phosphoramidite ligands L5, L736 and L6, L737 were prepared as reported in the literature. Racemic products were synthesized by reaction of the oxabicyclic alkenes 1 with the corresponding organolithium reagent 15 at -80°C in dichloromethane in the presence of CuI (10 mol%) and PPh3 (20 mol%).

164


Chapter 6

General procedure for the synthesis of oxabicyclic alkenes 1a-1g

Br

Br

OR4

R3

R1

R1 n-BuLi 1.05 eq

toluene -78 oC - rt

5 eq R1

R1

O

R3

R4

R2

R2

R2

R2

1a-1g The 1,2-dibromosubstituted benzene (40 mmol) was dissolved in toluene (80 mL, 0.5 M) and furan (0.2 mol, 5 eq) was added. The reaction mixture was cooled to -78 oC and n-butyllithium (1.05 eq, 42 mmol, 26,25 mL, 1.6 M solution in n-hexane) was added dropwise. The reaction mixture was stirred at -78 oC for 2 h and then allowed to warm up to room temperature overnight. The reaction mixture was poured into water. The organic layer was separated and the aqueous layer was extracted with diethyl ether (3x75 mL). The combined organic layer was dried with Na2SO4, filtered and concentrated in vacuo. The crude product were purified by column chromatography (n-pentane:diethyl ether, 15:1-10:1) to give oxabicyclic alkenes 1a-1g. Oxabicyclic alkene 1b (R1 = H, R2 = Me, R3 and R4 = H) was synthesized according to the literature procedure.38 meso-(3aR,4S,7R,7aS)-3a,4,7,7a-Tetrahydro-4,7-epoxyisobenzofuran-1,3-dione (25)

Maleic anhydride (4.95 g, 50 mmol) was suspended in furan (20 mL, 275 mmol, 5.5 eq) and stirred at room temperature overnight. The crude product was diluted in dichloromethane and the solvent was evaporated. The product was washed with cold diethyl ether and n-pentane and the product was isolated as a white solid (7.28 g, 44 mmol, 88% yield). The spectroscopic data matched those reported in literature.39

meso-(1R,2R,3S,4S)-7-Oxabicyclo[2.2.1]hept-5-ene-2,3-diyldimethanol (26)

A solution of exo-3a,4,7,7a-tetrahydro-4,7-epoxyisobenzofuran-1,3-dione (25) (4.0 g, 24.1 mmol) in dry tetrahydrofuran (30 mL) was added dropwise to a suspension of LiAlH4 (1.37 g, 36.1 mmol, 1.5 eq) in dry tetrahydrofuran (50 mL) over an hour at 0 oC. The reaction mixture was allowed to warm up slowly to room temperature and was stirred for 48 h.

Excess LiAlH4 was quenched by dropwise addition of a saturated aqueous sodium sulfate solution while maintaining the temperature between 0-5 oC. Addition was continued until all the inorganic salts were precipitated as white granular solids. Anhydrous MgSO4 was added to the reaction mixture. After filtration, the residue was thoroughly washed with dichloromethane. The combined filtrate was concentrated in vacuo and the crude product

165



was purified by column chromatography on silica (n-pentane:diethyl ether, 1:1 to pure diethyl ether) to afford 26 as a colorless viscous oil. The spectroscopic data matched those reported in literature.40 meso-(1R,2R,3S,4S)-2,3-Bis(methoxymethyl)-7-oxabicyclo[2.2.1]hept-5-ene (27)

To a suspension of potassium hydride (3.6 g, 17.9 mmol, 2.8 eq) in 10 mL of tetrahydrofuran at 0°C was added slowly a solution of 26 (1.0 g, 6.4 mmol) in tetrahydrofuran (10 mL). After addition and stirring at -78 °C for 10 min methyl iodide (1.2 ml, 19.2 mmol, 3 eq) was added dropwise. The mixture was allowed to stir overnight while slowly

warming to room temperature. The resulting white suspension was quenched by the addition of methanol (2 mL), aqueous NH4Cl and water. The aqueous layer was extracted with Et2O (3x) and the organic layers were dried with Na2SO4, filtered and the solvent evaporated to give 27 (920 mg, 5.0 mmol, 78 % yield) as a pale yellow oil. The spectroscopic data matched those reported in literature.41 2-Chloropentan-3-one (21)

A solution of pentan-3-one (85 ml, 0.8 mol) in carbon tetrachloride (200 ml) was heated to 45 °C and then, sulfuryl dichloride (71.4 ml, 0.88 mol, 1.1 eq) was added dropwise to the reaction mixture over 2h. The resulting reaction mixture was stirred for 3 h at 45 °C. The carbon tetrachloride was removed

by distillation under atmospheric pressure at 85 °C. The residue was purified by distillation under reduced pressure to give, after a forerun of pentan-3one, 21 (73 g, 0.605 mol, 76 % yield) as a pale yellow liquid. The spectroscopic data matched those reported in literature.42 meso-(1R,2S,4S,5S)2,4-Dimethyl-8-oxabicyclo[3.2.1]oct-6-en-3-one (22)

To a vigorously stirred mixture of 2-chloropentan-3-one 21 (15 g, 124 mmol), furan (36.4 ml, 500 mmol) and water (125 ml) was added triethylamine (19.1 ml, 137 mmol) dropwise over 20 min at room temperature. The reaction mixture turned bright pink and later turned yellow. The reaction mixture was stirred overnight at room temperature, quenched with 50 mL of an aqueous NH4Cl solution and extracted with dichloromethane (3x). The organic layer was dried with Na2SO4, filtered

and the solvent evaporated. Crude 1H-NMR showed almost full conversion and the crude product was dry-loaded onto silicagel and purified by column chromatography (n-pentane:diethyl ether, 10:1-8:1) to give pure 22 (7.3 g, 48.0 mmol, 39 % yield) as a white crystalline solid. The spectroscopic data matched those reported in literature.43

Cl

O

O

O

22

166


Chapter 6

meso-(1R,2R,3r,4S,5S)-2,4-Dimethyl-8-oxabicyclo[3.2.1]oct-6-en-3-ol (6) To a stirred solution of meso-2,4-dimethyl-8-oxabicyclo[3.2.1]oct-6-en-3-one 22 (2.0 g, 13.14 mmol) in methanol (20 ml) was added sodium borohydride (1.0 g, 26.3 mmol, 2 eq) portionwise at 0 °C. The reaction mixture was stirred for 2 h at this temperature and quenched with an aqueous NH4Cl solution. Methanol was evaporated in vacuo and the aqueous layer was extracted with dichloromethane (3 x 20 mL). The

organic layers were washed with brine, dried and the solvent evaporated to afford 6 as a white crystalline solid (1.8 g, 11.8 mmol, 90% yield). The spectroscopic data matched those reported in literature.43 meso-tert-Butyl(((1R,2S,3s,4R,5S)-2,4-dimethyl-8-oxabicyclo[3.2.1]oct-6-en-3-yl)oxy) dimethylsilane (13)

To a stirred suspension of potassium hydride (546 mg, 2.72 mmol, 1.4 eq) in dry tetrahydrofuran (4 mL) at 0 °C was added slowly a solution of 6 (300 mg, 1,945 mmol) in dry tetrahydrofuran (4 mL). After addition and stirring at -78 °C for 10 min, tert-butylchlorodimethylsilane (340 mg, 2.14 mmol, 1.1 eq) dissolved in 2 mL of dry tetrahydrofuran was added dropwise. The reaction mixture was stirred overnight while

slowly warming to room temperature and subsequently quenched by pouring into a aqueous saturated NH4Cl solution, extracted with diethyl ether (3 x 5 mL), dried with Na2SO4, filtered and the solvent evaporated in vacuo. The crude product was purified by column chromatography on silica (n-pentane:diethyl ether, 100:0-15:1) to give 13 (497 mg, 1.85 mmol, 95 % yield) as a colorless oil that solidified upon standing. The spectroscopic data matched those reported in literature.43

General procedure for the copper-catalyzed ring opening of oxabicyclic alkenes 1 with organolithium reagents 15

A Schlenk tube equipped with septum and stirring bar was charged with CuBr·SMe2 (0.01 mmol, 2.06 mg, 5 mol%) and phosphoramidite ligand (R,R,R)-L5 (0.012 mmol, 6.48 mg, 6 mol%). Dry dichloromethane (2 mL) was added and the solution was stirred under nitrogen at room temperature for 15 min. Then, oxabicyclic alkene 1 (0.2 mmol) was added and the resulting solution was cooled to -80 °C. To the cooled mixture, BF3·OEt2 (28 μL, 0.22 mmol, 1.1 eq) was added with a microsyringe. In a separate Schlenk vessel, the corresponding organolithium reagent 2 (0.22 mmol, 1.1 eq) was diluted with dry n-hexane

(combined volume of 1 mL) under nitrogen and added dropwise to the reaction mixture over 2 h using a syringe pump. Once the addition was complete, the mixture was stirred overnight at -80°C. The reaction was quenched with a saturated aqueous NH4Cl solution (2

OH

O

6

OTBDMS

O

13

167



mL) and the mixture was warmed up to room temperature, diluted with diethyl ether and the layers were separated. The aqueous layer was extracted with diethyl ether (3 x 5 mL) and the combined organic layers were dried with anhydrous Na2SO4, filtered and the solvent was evaporated in vacuo. The crude product was purified by flash chromatography on silica gel using a gradient of n-pentane/diethyl ether (15:1 – 9:1) as the eluent. (+)-(1R,2S)-2-Butyl-1,2-dihydronaphthalen-1-ol (16aa)

Isolated as a white solid. [84% yield, >99:1 anti:syn, 97% ee]. The spectroscopic data matched those reported in literature.23 [α]D

20 = +230.0 (c = 1.0, CHCl3), [lit.23 (-)-(1S,2R)-16aa (92%

ee): [α]D20 = -233.0 (c = 0.94, CHCl3)]. Enantiomeric excess

was determined by chiral HPLC analysis, Chiralcel OD-H column, 0.5 mL/min, n-heptane/i-PrOH 98:2, 40 °C, 254 nm, retention times (min.): 23.1 (minor) and 26.5 (major). (+)-2-Butyl-5,8-dimethyl-1,2-dihydronaphthalen-1-ol (16ba)

Isolated as a pale yellow oil. [82% yield, >99:1 anti:syn, 95%

ee]. 1H NMR: (400 MHz, CDCl3) 7.00 (q, J = 7.7 Hz, 2H), 6.71 (d, J = 9.9 Hz, 1H), 6.11 (dd, J = 9.8, 5.9 Hz, 1H), 4.76 (s, 1H), 2.63 (dd, J = 13.8, 6.7 Hz, 1H), 2.40 (s, 3H), 2.33 (s, 3H), 1.70 (bs, 1H), 1.43 – 1.10 (m, 6H), 0.87 (t, J = 7.1 Hz, 3H). 13C

NMR: (100 MHz, CDCl3) 134.3, 132.7, 131.5, 130.4, 130.0, 129.9, 129.4, 122.6, 68.1, 42.1, 31.6, 29.9, 22.8, 18.9, 18.2,

14.0. [α]D20 = +357.0 (c = 1.0, CHCl3). HRMS (ESI+, m/z): calcd for C16H23O [M+H]+:

231.17434; found: 231.17329. Enantiomeric excess was determined by chiral HPLC analysis, Chiralcel OD-H column, 0.5 mL/min, n-heptane/i-PrOH 99:1, 40 °C, 254 nm, retention times (min): 24.3 (minor) and 27.1 (major). In accordance with the results obtained in the other ring opening reactions, the absolute configuration of this compound is assumed to be (1R, 2S), analogous to the other products. (+)-(1R,2S)-2-Ethyl-1,2-dihydronaphthalen-1-ol (16ab)

Isolated as a white solid [80% yield, >99:1 anti:syn, 98% ee]. The spectroscopic data matched those reported in literature.23, 44 [α]D

20 = +245.0 (c = 1.0, CHCl3). Enantiomeric excess was determined by chiral HPLC analysis, Chiralcel OD-H column, 0.5 mL/min, n-heptane/i-PrOH 99:1, 40 °C, 254 nm, retention times (min.): 44.9

(minor) and 51.9 (major).

OH

16ba

168


Chapter 6

(+)-(1R,2S)-2-Ethyl-5,8-dimethyl-1,2-dihydronaphthalen-1-ol (16bb) Isolated as a pale yellow oil. [71% yield, >99:1 anti:syn, 97% ee]. The spectroscopic data matched those reported in literature.23 [α]D

20 = +250.6 (c = 0.53, CHCl3), [lit.

23 (-)-(1S,2R)-16bb (99% ee): [α]D20 = -

256.16 (c = 2.66, CHCl3)]. Enantiomeric excess was determined by chiral HPLC analysis, Chiralpak AD column, 1.0 mL/min, n-heptane/i-PrOH 99:1, 40 °C, 254 nm, retention times (min.): 14.2 (minor) and 15.8 (major).

(+)-2-Hexyl-1,2-dihydronaphthalen-1-ol (16ac)

Isolated as a white solid. [81% yield, >99:1 anti:syn, 97%

ee]. 1H NMR: (400 MHz, CDCl3) 7.36 (dd, J = 7.2, 0.8 Hz, 1H), 7.25 (dqd, J = 14.4, 7.4, 1.5 Hz, 2H), 7.11 (dd, J = 7.2, 1.2 Hz, 1H), 6.49 (d, J = 9.7 Hz, 1H), 6.02 (dd, J = 9.6, 4.8 Hz, 1H), 4.52 (s, 1H), 2.70 – 2.45 (m, 1H), 1.79 (d, J = 5.2 Hz, 1H), 1.48 – 1.34 (m, 2H), 1.34 – 1.19 (m,

8H), 0.87 (t, J = 6.8 Hz, 3H). 13C NMR: (100 MHz, CDCl3) 135.7, 132.3, 131.1, 128.5, 127.8, 127.6, 126.4, 125.8, 72.4, 42.5, 31.7, 31.6, 29.4, 27.0, 22.6, 14.0. [α]D

20 = +311.1 (c = 1.0, CHCl3). HRMS (ESI+, m/z): calcd for C16H22ONa [M+Na]+: 253.15798; found: 253.15647. Enantiomeric excess was determined by chiral HPLC analysis, Chiralcel OD-H column, 0.5 mL/min, n-heptane/i-PrOH 99:1, 40 °C, 254 nm, retention times (min): 33.0 (minor) and 39.9 (major). In accordance with the results obtained in the other ring opening reactions, the absolute configuration of this compound is assumed to be (1R, 2S), analogous to the other products. (+)-2-Hexyl-5,8-dimethyl-1,2-dihydronaphthalen-1-ol (16bc)

Isolated as a pale yellow oil. [82% yield, >99:1 anti:syn,

93% ee]. 1H NMR: (400 MHz, CDCl3) 7.00 (q, J = 7.7 Hz, 2H), 6.71 (d, J = 9.9 Hz, 1H), 6.10 (dd, J = 9.8, 5.9 Hz, 1H), 4.76 (s, 1H), 2.63 (dd, J = 13.3, 6.5 Hz, 1H), 2.40 (s, 3H), 2.33 (s, 3H), 1.72 (s, 1H), 1.48 – 1.32 (m, 2H), 1.32 – 1.12 (m, 8H), 0.87 (t, J = 6.7 Hz, 3H). 13C

NMR: (100 MHz, CDCl3) 134.3, 132.7, 131.5, 130.4, 130.0, 129.9, 129.4, 122.5, 68.1, 42.1, 31.8, 31.7, 29.4, 27.6, 22.6, 18.9, 18.2, 14.0. [α]D

20 = +272.8 (c = 1.0, CHCl3). HRMS (ESI+, m/z): calcd for C18H27O [M+H]+: 259.20564; found: 259.20575. Enantiomeric excess was determined by chiral HPLC analysis, Chiralcel OD-H column, 0.5 mL/min, n-heptane/i-PrOH 99:1, 40 °C, 254 nm, retention times (min): 20.7 (minor) and 23.6 (major).

OH16bb

169



In accordance with the results obtained in the other ring opening reactions, the absolute configuration of this compound is assumed to be (1R, 2S), analogous to the other products. (+)-(1R,2S)-2-isoButyl-1,2-dihydronaphthalen-1-ol (16ad)

Isolated as a white solid. [86% yield, >99:1 anti:syn, 97% ee]. The spectroscopic data matched those reported in literature.27 [α]D

20 = +270.6 (c = 1.0, CHCl3), [lit.

27 (-)-(1S,2R)-16ad (94% ee): [α]D20 =

-345.9 (c = 0.66, CHCl3)]. Enantiomeric excess was determined by chiral HPLC analysis, Chiralcel OD-H column, n-heptane/i-

PrOH 98:2, 40 °C, 254 nm, retention times (min.): 22.2 (minor) and 25.7 (major). (+)-2-isoButyl-5,8-dimethyl-1,2-dihydronaphthalen-1-ol (16bd)

Isolated as a pale yellow oil. [96% yield, >99:1 anti:syn, 93% ee]. 1H NMR: (400 MHz, CDCl3) 7.00 (q, J = 7.7 Hz, 2H), 6.71 (d, J = 9.9 Hz, 1H), 6.09 (dd, J = 9.8, 6.0 Hz, 1H), 4.72 (s, 1H), 2.74 (dd, J = 14.6, 6.9 Hz, 1H), 2.39 (s, 3H), 2.33 (s, 3H), 1.86 – 1.60 (m, 2H), 1.15 – 1.00 (m, 2H), 0.94 (d, J = 6.6 Hz, 3H), 0.89 (d, J =

6.6 Hz, 3H). 13C NMR: (100 MHz, CDCl3) 134.3, 132.6, 131.5, 130.4, 130.0, 129.9, 129.4, 122.6, 68.3, 40.8, 39.8, 25.8, 23.2,

22.3, 18.9, 18.2. [α]D20 = +345.0 (c = 1.0, CHCl3). HRMS (ESI+, m/z): calcd for C16H23O

[M+H]+: 231.17434; found: 231.17421. Enantiomeric excess was determined by chiral HPLC analysis, Chiralcel OD-H column, 0.5 mL/min, n-heptane/i-PrOH 99.5:0.5, 40 °C, 254 nm, retention times (min): 40.2 (major) and 43.1 (minor). In accordance with the results obtained in the other ring opening reactions, the absolute configuration of this compound is assumed to be (1R, 2S), analogous to the other products. (+)-2-((Trimethylsilyl)methyl)-1,2-dihydronaphthalen-1-ol (16ae)

Isolated as a white solid. [56% yield, >99:1 anti:syn, 42% ee]. 1H

NMR: (400 MHz, CDCl3) 7.34 (d, J = 7.4 Hz, 1H), 7.26 (dt, J = 16.5, 7.3 Hz, 2H), 7.12 (d, J = 7.3 Hz, 1H), 6.45 (d, J = 9.6 Hz, 1H), 6.02 (dd, J = 9.6, 5.1 Hz, 1H), 4.43 (s, 1H), 2.68 (td, J = 9.8, 5.0 Hz, 1H), 1.79 (s, 1H), 0.69 (dd, J = 14.4, 5.1 Hz, 1H), 0.50

(dd, J = 14.4, 10.3 Hz, 1H), 0.05 (s, 9H). 13C NMR: (100 MHz, CDCl3) 135.3, 132.7, 132.2, 128.6, 128.3, 127.6, 126.5, 125.0, 75.1, 38.9, 19.2, -0.6. [α]D

20 = +84.7 (c = 1.0, CHCl3). HRMS (ESI+, m/z): calcd for C14H21OSi [M+H]+: 233.13562; found: 233.13466. Enantiomeric excess was determined by chiral HPLC analysis, Chiralcel OD-H column, 0.5 mL/min, n-heptane/i-PrOH 98:2, 40 °C, 261 nm, retention times (min): 18.0 (minor) and 18.9 (major).

OH16bd

170


Chapter 6

In accordance with the results obtained in the other ring opening reactions, the absolute configuration of this compound is assumed to be (1R, 2S), analogous to the other products.

6.6 References

(1) Ward, R. S. Chem. Soc. Rev. 1990, 19, 1. (2) Magnuson, S. R. Tetrahedron 1995, 51, 2167. (3) Willis, M. C. J. Chem. Soc., Perkin Trans. 1 1999, 1765. (4) Lautens, M.; Fagnou, K.; Hiebert, S. Acc. Chem. Res. 2003, 36, 48. (5) Gómez Arrayás, R.; Cabrera, S.; Carretero, J. C. Synthesis 2006, 1205. (6) Caple, R.; Chen, G. M. -S.; Nelson, J. D. J. Org. Chem. 1971, 36, 2874. (7) Arjona, O.; Fernandez de la Pradilla, R.; Garcia, E.; Martin-Domenech, A.; Plumet, J.

Tetrahedron Lett. 1989, 30, 6437. (8) Lautens, M.; Di Felice, C.; Huboux, A. Tetrahedron Lett. 1989, 30, 6817. (9) Lautens, M.; Smith, A. C.; Abd-El-Aziz, A. S.; Huboux, A. H. Tetrahedron Lett. 1990, 31,

3253. (10) Lautens, M.; Abd-El-Aziz, A. S.; Lough, A. J. Org. Chem. 1990, 55, 5305. (11) Lautens, M.; Belter, R. K. Tetrahedron Lett. 1992, 33, 2617. (12) Lautens, M.; Renaud, J. -L.; Hiebert, S. J. Am. Chem. Soc. 2000, 122, 1804. (13) Lautens, M.; Hiebert, S.; Renaud, J. -L. Org. Lett. 2000, 2, 1971. (14) Von Matt, P.; Pfaltz, A. Angew. Chem. Int. Ed. Engl. 1993, 32, 566. (15) Lautens, M.; Hiebert, S.; Renaud, J. -L. J. Am. Chem. Soc. 2001, 123, 6834. (16) Lautens, M.; Colucci, J. T.; Hiebert, S.; Smith, N. D.; Bouchain, G. Org. Lett. 2002, 4, 1879. (17) Lautens, M.; Fagnou, K.; Rovis, T. J. Am. Chem. Soc. 2000, 122, 5650. (18) Lautens, M.; Fagnou, K.; Taylor, M. Org. Lett. 2000, 2, 1677. (19) Lautens, M.; Fagnou, K.; Taylor, M.; Rovis, T. J. Organomet. Chem. 2001, 624, 259. (20) Lautens, M.; Fagnou, K. J. Am. Chem. Soc. 2001, 123, 7170. (21) Lautens, M.; Fagnou, K. Tetrahedron 2001, 57, 5067. (22) Lautens, M.; Dockendorff, C.; Fagnou, K.; Malicki, A. Org. Lett. 2002, 4, 1311. (23) Bertozzi, F.; Pineschi, M.; Macchia, F.; Arnold, L. A.; Minnaard, A. J.; Feringa, B. L. Org. Lett.

2002, 4, 2703. (24) Gómez Arrayás, R.; Cabrera, S.; Carretero, J. C. Org. Lett. 2003, 5, 1333. (25) Zhang, W.; Wang, L. -X.; Shi, W. -J.; Zhou, Q. -L. J. Org. Chem. 2005, 70, 3734. (26) Zhang, W.; Zhu, S. -F.; Qiao, X. -C.; Zhou, Q. -L. Chem. Asian J. 2008, 3, 2105. (27) Millet, R.; Gremaud, L.; Bernardez, T.; Palais, L.; Alexakis, A. Synthesis 2009, 2101. (28) Lautens, M.; Gajda, C.; Chiu, P. J. Chem. Soc., Chem. Commun. 1993, 1193. (29) Pérez, M.; Fañanás-Mastral, M.; Bos, P. H.; Rudolph, A.; Harutyunyan, S. R.; Feringa, B. L.

Nature Chem. 2011, 3, 377. (30) Nájera, C.; Yus, M. Curr. Org. Chem. 2003, 7, 867. (31) Rappoport, Z.; Marek, I. Eds. The Chemistry of Organolithium Compounds; Wiley-VCH:

Weinheim, Germany, 2003. (32) Closs, G. L.; Closs, L. E. J. Am. Chem. Soc. 1960, 82, 5723.

171



(33) Closs, G. L. J. Am. Chem. Soc. 1962, 84, 809. (34) Teichert, J. F.; Feringa, B. L. Angew. Chem. Int. Ed. 2010, 49, 2486. (35) Myers, E. L.; Butts, C. P.; Aggarwal, V. K. Chem. Commun. 2006, 4434. (36) Feringa, B. L.; Pineschi, M.; Arnold, L. A.; Imbos, R.; de Vries, A. H. M. Angew. Chem. Int.

Ed. Engl. 1997, 36, 2620. (37) Tissot-Croset, K.; Polet, D.; Gille, S.; Hawner, C.; Alexakis, A. Synthesis 2004, 2586. (38) Jung, K. Y.; Koreeda, M. J. Org. Chem. 1989, 54, 5667. (39) Chola, J.; Masesane, I. B. Tetrahedron Lett. 2008, 49, 5680. (40) Das, J.; Vu, T.; Harris, D. N.; Ogletree, M. L. J. Med. Chem. 1988, 31, 930. (41) Millward, D. B.; Sammis, G.; Waymouth, R. M. J. Org. Chem. 2000, 65, 3902. (42) Föhlisch, B.; Gehrlach, E.; Stezowski, J. J.; Kollat, P.; Martin, E.; Gottstein, W. Chem. Ber.

1986, 119, 1661. (43) Candy, M.; Audran, G.; Bienaymé, H.; Bressy, C.; Pons, J. -M. Org. Lett. 2009, 11, 4950. (44) Bertozzi, F.; Crotti, P.; Del Moro, F.; Feringa, B. L.; Macchia, F.; Pineschi, M. Chem. Commun. 2001, 2606. (45) Fañanás-Mastral, M.; Pérez, M.; Bos, P. H.; Rudolph, A.; Harutyunyan, S. R.; Feringa, B. L.

Angew. Chem. Int. Ed. 2012, DOI: 10.1002/anie.201107840.

172


Chapter 6

university of groningen novel asymmetric copper …(-)-sparteine together with n-butyllithium (5 eq)...

Documents