chapter 9 1 chapter 9 - textbooks.elsevier.com

Chapter 9 1

Chapter 9

1. This transformation is taken from Org. Lett., 2002, 4, 1515. formation of the enolate anion is followed by

alkylation. The model clearly suggests that the top face (A) is less sterically hindered than the bottom face (B),

which accounts for the stereochemistry of the major product.

N

O

HH

H

O

N

O

HH

H

LiO

MeI

N

O

HH

H

O

I–CH3

B

CH3–I

ALDA HMPA

2. This transformation is taken from J. Am. Chem., 2002, 124, 12416. Enolate anion formation occurs at the more

acidic site, adjacent to the aldehyde (also a benzylic site) and transannular displacement of the primary bromide

leads to the bridged structure shown. Under these conditions, the methyl ketone is converted to its enolate anion,

and an intramolecular aldol condensation, followed by dehydration, leads to the final product.

N Br

CHO

PhO2S

OMe

MeO

O

N

CHO

PhO2S

OMe

MeO

O

Bu4NBr , reflux

N SO2Ph

OMe

MeO

CHOO

N SO2Ph

OMe

MeO

OHO

N Br

CHO

PhO2S

OMe

MeO

O

N SO2Ph

OMe

MeO

O

N SO2Ph

OMe

MeO

CHOO

K2CO3 , toluene

– H2O

3. Initial reaction with base deprotonates the hydrogen adjacent to the aldehyde (it is more acidic. This anion (A)

undergoes an internal Michael addition to generate a new ring and anion B. If anion B attacks the aldehyde moiety,

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2 Organic Synthesis Solutions Manual

a four-membered ring will be formed. Although this is possible, it is a somewhat high energy process. Since tert-

butoxide is likely used in an alcohol solvent, these are equilibrium control conditions and anion B will be in

equilibrium with anion C, analogous to the equilibrium observed in Robinson annulation. Anion C can react with

the aldehyde moiety to form a six-membered ring in D (the observed product). Under equilibrium control

conditions, formation of the 6-membered ring in D via C is favored over reaction of B to give a 4-membered ring.

C

H

O

Me

Me

CHO

DH

O

Me

Me

HO H

BAH

O

Me

Me

CHO

H

O

Me

Me

CHO

H

O

Me

Me

CHO

see Tetrahedron, 1979, 35, 293.

4. This transformation is taken from J. Am. Chem. Soc., 2003, 125, 1712. The first reaction is simply an enolate

alkylation. Reaction with LDA generates the enolate anion, which reacts with iodomethane in the usual manner.

The second step is a retro-aldol condensation. conjugate addition of hydroxide and heating leads to the retro aldol

products, acetone, and the enolate anion of dimethylcyclohexanone, which gives the product upon hydrolysis.

O OMeI

O OH

OH O O O

KOH

O O

OLDA

heat hydrolysis

5. The syn and anti diastereomers for each reaction are shown. The selectivity can be explained by examining a

Zimmerman model for each reaction. Reaction with benzaldehyde generates a transition state such as A. There is a

difference in approach since the phenyl group can be up, as shown in A, or down to generate different

diastereomers. When the Ph and Me groups are anti (as in A), there is minimal steric inter-action when compared

to the opposite orientation with Ph and Me syn. For this reason, the reaction gives predominately the anti

diastereomer. Reaction with cyclohexanone, however, generates a transition state such as B, where there is no


Chapter 9 3

difference in up or down when comparing the groups adjacent to the carbonyl. Therefore, this model shows no

difference in orientation and predicts no selectivity.

Me Ph

O

Me

OH

Me Ph

O

Me

OH

Me

MeO

OLi O

Me

Me

Ph

H

A

Me

O

Me

OH

B

OLi O

Me

Me

Me

O

Me

OH synantisyn anti

see J. Org. Chem., 1980, 45, 1066.

6. (a) The (E) and (Z) enolate anions for 3-pentanone are shown.

Me

O

Me

O

(Z) (E)

(b) The re and si faces are labeled on the (Z)-enolate. The Zimmerman model for the reaction from the re face

leads to the anti diastereomer. Conversely, the Zimmerman model for reaction for the si face also leads to the anti

diastereomer, but it is the enantiomer of the first one. Each Zimmerman model is shown with the Me and Ph

groups anti to each other, which represents the lowest energy orientation. If the phenyl group is up in each of these

models, the Me phenyl interaction is much higher, making that transition state higher in energy. With the same

orientation and using only the (Z)-enolate, the anti diastereomer results. Approach from both the re and si faces

generates enantiomers. If there is nothing to bias the re or si faces, there will be no enantioselectivity.

OLi

O

Me

H

H

Ph

O

Me

H

H

OH

Ph

Me O

O Li

O

Me

HH

Ph

Ph

O

Me

OH

O

Me

H

OHH

Ph

Ph

O

Me

OH

re

from si face

si

from re face

(c) In the Zimmerman model for this reaction (A, the pinanyl ring is anti to the methyl group, leading to the anti



diastereomer. The facial approach is dictated by the absolute configuration of the aldehyde.

Me

O

Li O

HH

H

A

Me

O

HO

HH

H O

Me

OH

H

(d) With the Z enolate, transition state B is formed, again with the pinanyl ring and the methyl group anti. This

leads to the syn diastereomer shown.

H

OLi O

H

H

Me

B

H

O

HOH

H

MeO

Me

OH

H

7. Both reactions are taken from Org. Lett., 2002, 4, 715. Initial reaction generates enolate anion 1, stabilized by

the SMe unit. The stereochemistry of the carbon bearing the ester unit forces the reactive primary iodide unit away,

and initial reaction is at the ester unit (see 1A), give the ketone shown via acyl substitution. Once formed, a new

enolate anion is formed (2), stabilized by the SMe unit, but the C-enolate is rather far removed from the reactive

primary iodide (see 2A). Therefore, this enolate anion reacts via O-alkylation to give A. Formation of B, requires

enolate anion 3, but a five-membered ring is present, and the stereochemistry of the carbon bearing the ester unit is

such that a different conformation predominates (as in 3). This enolate anion is stabilized by the SMe unit. In this

case, the C-enolate carbon (marked with *) is in closer proximity to the reaction primary bromide (see 3A), and C-

alkylation occurs to give B.


Chapter 9 5

N OMeO

MeO

SMe

O

I

H

H

N OMeO

MeO

SMeMeO2C

H

Br

N O– Na+

MeO

MeO

SMe

H

I

H

OMe

N

CO2Me

OMeO

MeO

SMe

I

H

H

A

S1A

N OMeO

MeO

SMe

O– Na+

I

H

H

S

N OMeO

MeO

SMe

H

O

3A

Na

2A

B

S

N O– Na+

MeO

MeO

SMeMeO2C

H

Br

N OMeO

MeO

SMeMeO2C

H

NaH , THF reflux

NaH , THF reflux

1

3

2

ester

ester

*

*

8. Enolate A is the result of thermodynamic control conditions. The protic solvent (EtOH) is an acid and will react

with the basic enolate once it is formed. This sets up an equilibrium. Initial reaction with NaOEt removes the most

acidic hydrogen (Hb) to generate B, but this is in equilibrium with the ketone since the acidic EtOH re-protonates

B. Under equilibrium conditions, Ha can be removed, giving an equilibrium of A, B and starting ketone. The

equilibrium will favor formation of the more stable enolate, A. The base, NaOEt, generates EtOH as a conjugate

base, which is the acid that re-protonates the enolate, favoring the equilibrium. Higher temperatures (reflux)

increase the rate of all processes, including the reverse reactions that are essential to the equilibrium. The 20-hour



reaction time allows sufficient time for the equilibrium to be set up and the more stable product accumulated.

OO O

HbHa Hb

Ha

- Ha - Hb

B A

Enolate B is the result of kinetic control by removal of the more acidic hydrogen, Hb. The solvent is aprotic,

and, therefore, there is no acid to re-protonate B once it is formed. The conjugate acid of LDA is the weakly acidic

diisopropylamine. This is a weak acid but reacts very slowly with B. For this reason, low temperature and short

reaction times (30 min) minimize the possibility for reaction of B with diisopropylamine and maximize formation

of B. If there is no equilibrium, A cannot form.

H—N(i-Pr)2

H—OEt

O

Hb

O

Ha

EtOH

THF

Li—N(i-Pr)2

Na—OEt

O

HbHa

O

HbHa

+ +

acidbase

conjugate baseconjugate acid

pKa about 20 pKa about 25

+ +

acidbase

conjugate baseconjugate acid

pKa about 20 pKa about 17

The acid-base reactions for both kinetic and thermodynamic control are shown. In the LDA reaction, note that

the conjugate acid is weaker than the initial acid (the ketone). Similarly, LDA is the stronger base. The

equilibrium lies to the right (toward the enolate anion). The NaOEt reaction, however, generates a conjugate acid

that is stronger than the initial acid, and the conjugate base is stronger than NaOEt. Coupled with the presence of

the acidic solvent, the equilibrium lies to the left and only a small amount of enolate is present, in equilibrium with

the starting ketone.

9. This transformation and proposed mechanism is taken from Tetrahedron, 2002, 58, 4859.


Chapter 9 7

O O CHOO

–O2CO O

OHH

–O2CO O H+

HO–

O O CHOHO

O

–O2CO O

OH

HO2CHO O

–O2CO O CHO

–O2CO O

O

H

OO O

10. In each case, the model shows attack only from one face, even if the product generates racemic products. If a

chiral, non-racemic product is expected, it is so labeled. In the case of (a) and (b), the (E)-enolate is used since it is

expected to be the major product. This is obviously an arbitrary assumption but is made to simplify the question.

Analogous structures could be generated using the (Z)-enolate, but the product would be the diastereomer with the

opposite stereochemistry (syn rather than anti or anti rather than syn). For (c)-(e), the stereochemistry of the

enolate is fixed, as is the absolute configuration of the reactants.

To achieve consonance in (c), the aldehyde must approach from the face shown. Similarly in (d), this aldehyde

approaches the enolate from the opposite face in order to achieve consonance. The two chiral, non-racemic

reactants in (e) require the facial approach shown to achieve consonance.

(a)

OLi

O

MeO

Ph

H H

iPrOOH

MeO

Ph

H H

iPr (b)

OLi

O

NaO

Ph

H H

PhOOH

HO

Ph

H H

Ph

(c)

OLi

O

Me

H H

H PhMe

OOH

Me

H H

H PhMe (d)

OLi

O

Me

HH

O

O

HOHO

Me

HH

OO

H



(e)

OLi

O

Me

HH

O

O

H

HOTMS

OHO

Me

HH

OO

H

HOTMS

11. This reaction is taken from a synthesis in J. Am. Chem. Soc., 2002, 124, 4257. Initial reaction with NaNTMS2

generates the planar enolate anion. The model (note the enolate carbons A and B, and the enolate oxygen C in the

model) clearly shows that one face (marked inner) is sterically hindered. As the enolate anion approaches

iodomethane, reaction should occur at the face marked outer, leading to the product shown with good selectivity.

The hindrance comes from the enantiopure Evan's auxiliary with the benzyl group, and somewhat from the

OTBDPS group. This model assumes that the major product is the E-enolate anion. Clearly, if the Z-enolate

predominates, or if there is a mixture, the model will change.

MeI

N

OTBDPS

Et

O

O

Ph

O

AC

B

N

OTBDPS

Et

O

O

Ph

O

Me

MeI

C

AN

OTBDPS

Et

O–Li+

O

Ph

O

B

1. NaN(SiMe3)2

2. MeI

outer

inner

12. When this nitrile reacts with hexamethyldisilazide, the anion is formed. Two resonance forms are drawn to

show that although the original nitrile is a mixture of epimers, the enolate anion has a planar nature in one

resonance contributor. When this reacts with the alkyl halide, approach can be form path A or path B. The bridge

bearing the carbamate unit effectively blocks path B, so delivery form path A leads to the final alkylation product

with the stereochemistry shown.


Chapter 9 9

N

NOMe

CO2MeNC

TsH

(MeO)2CH(CH)9I

KN(SiMe3)2

N

NOMe

CO2MeCN

TsH

(MeO)2CH(CH2)9

N

NOMe

CO2MeNC

TsH

A

B

N

NOMe

CO2Me

TsH

CN

see J. Org. Chem., 1999, 64, 587

13. Thiophenol reacts with potassium carbonate to generate the thiophenoxide anion, a nucleophile. Conjugate

addition as shown leads to an enolate anion, which adds to the end of the other conjugated ketone across the ring.

This forms the 6-membered ring and generates a new enolate. This sequence therefore involves two Michael

addition reactions. Methanol reacts with the enolate anion and delivers the proton from the less sterically hindered

face of the molecule to give the final product with the stereochemistry shown.

O

O

H

HO

O

Me

O

O

Me

PhS

O

OMePhS

MeH H

H

PhS

O

O

Me

PhS O

O

Me

PhS

HMeOH

see Tetrahedron, 2000, 41, 4805

This selectivity is induced by minimizing steric hindrance with the R group on the aldehyde and the N-methyl

group, as shown in the following figure.



OO

Li

N

O

Me

N

Me

O

R

H

O

H

R

>

14. (a) The purpose of the first reaction with benzaldehyde is to block one carbon in order to direct formation of

the bicyclic ring system.

O

OAc

Me

Me

O

OAc

Me

Me

Ph

I

O

OTs

Me

Me

Ph

II

O

Me

Me

Ph

III IV

O

Me

Me

see Tetrahedron Lett., 1973, 4687.

(b) In reaction B, two enolate anions will be formed, 1 and 2. Enolate anion 1 will generate V, which is identical

to IV. The other anion (2) will generate VI.

O

Me

Me

O

OAc

Me

Me

O

OAc

Me

Me

VI

O

Me

Me

V 1 2

The first route (a) is superior in that it uses a benzylidene protecting group to block one carbon, allowing only

one enolate to form and, therefore, only one bicyclic ketone. In reaction B, both enolate anions form and two

bicyclic ketones are generated. Since VI is probably less sterically hindered in the transition state forming it than

that for V, VI will probably be the major product of B, whereas IV (V) will be the major product of A.

15. A synthetic sequence is shown for each transformation. In (a) the alkene is converted to a ketone via

hydroboration and oxidation. Alkylation under thermodynamic control conditions gives the target. In (b), the

ketone is similarly produced, but alkylation under kinetic control conditions gives the other regioisomer relative to


Chapter 9 11

(a). In (c), oxymercuration-demercuration (Sec. 2.10.B) of the alkene is followed by a Chugaev elimination

sequence (see Sec. 2.9.C.iv) to give the exocyclic methylene compound. Hydroboration and oxidation with PCC

provides the aldehyde, and alkylation under kinetic control (mild) conditions gives the target.

(a)

Me

OH

Me

O

Me

O

Pha b

(a) 1. 9-BBN 2. NaOH , H2O2 (b) CrO3 (c) NaOEt , EtOH , BnBr

c

(b)

Me

OH

Me

O

Me

O

Ph

a b

(a) 1. 9-BBN 2. NaOH , H2O2 (b) CrO3 (c) LDA , THF , –78°C , BnBr

c

(c)

OH OHCHO CHO

Pha b c d e

(a) i. Hg(OAc)2 , H2O ii. NaBH4 (b) i. CS2 ii. MeI iii. 200°C (c) 9-BBN ; H2O2, NaOH(d) PCC (e) i. LDA , THF , –78°C ii. BnBr

16. Reaction (h) could give cyclohexanone if the product shown decarboxylates under the reaction conditions.

(a)

EtO2C CN

Ph

see Synth. Commun., 1997, 27, 533

(b)

OSiPh2t-Bu

HOJ. Am. Chem. Soc., 2002, 124, 11102

(c)

O

O

CO2H

Tetrahedron, 2002, 58, 4917

(d)

H

Me

Me

Me

O O

CO2MeAngew. Chem. Int. Ed., 2003, 42, 549

(e)

MeO

O

CO2Me

Chem. Eur. J., 2004, 10, 1042

(f)

O

O

CO2Et




(g)

OSiMe2t-Bu

O

J. Org. Chem., 2003, 68, 6096

(h)

NHPf

O

MeO2C

Pf = 9-phenyl-9-fluorenylJ. Org. Chem., 2003, 68, 109

(i)

Ph C N

OEt

(j)

Cl

OH

CO2Et

see Synthesis, 2000, 561

(k)

O

HOPh

(l)

N

O

H

OTBDPS

J. Org. Chem., 2003, 68, 7219

(m)

O

J. Am. Chem. Soc., 2003, 125, 1843

(n)

N

Et

CNBn

CN

see Chem. Commun., 1996, 1479

(o)

MeO2C

CO2Me

MeO2C

CO2Me

see Synthesis, 1996, 71

(p)

N

H OH

O OH

Eur. J. Org. Chem., 2002, 3315

(q)

CHO

J. Am. Chem. Soc., 2003, 125, 1567

(r)

HO

O

OMeO

O

O

see J. Am. Chem. Soc., 1996, 118, 5304

(s)

Ph Ph

OH

Me

O

see Tetrahedron, 1999, 55, 8739

(t)

OH

Me

H

Me

O

see J. Am. Chem. Soc., 1999, 121, 5467

(u)

O

TBSO

BnOO


(v)

OO

Me

see J. Am. Chem. Soc., 1996, 118, 7513

(w)

O

N

OO

O

Ph

HO

see J. Am. Chem. Soc., 1999, 121, 5653

(x)

N(CH2)4

O

CH(OMe)2

see J. Org. Chem., 1999, 64, 3778


Chapter 9 13

(y)

O

O

CO2HC11H23

Angew. Chem. Int. Ed., 2004, 43, 313 (z)

N

N

Me

Ph

CO2Me

OH

J. Org. Chem., 2003, 68, 6279 (aa)

O

O

O

OC3H7

OH

J. Am. Chem. Soc., 2002, 124, 7061

(ab)

CO2Me

OHPh

see J. Org. Chem., 1997, 62, 1521 (ac)

Pht-Bu

via Haller-Bauersee Tetrahedron, 2000, 56, 1399 (ad)

O

O

O

O

H

HO

J. Org. Chem., 2002, 67, 5461

(ae)

PhCO2Et

NHBn

see Chem. Lett., 1999, 591 (af)

OEur. J. Org. Chem., 2004, 1953 (ag)

O

O

O

O

OAcO

J. Org. Chem., 2003, 68, 7768

17. In each case a complete synthesis is provided. In virtually all cases there are alternative, synthetic routes.

(a) All reactions in this sequence are taken from Angew. Chem. Int. Ed., 2003, 42, 3406. Enolate alkylation of the

initial ketone (9.3.A) was followed by oxidative cleave to the aldehyde, via the diol (3.7.C). A Grignard reaction

(8.4.C.i) generated the alcohol, and oxidation with pyridinium chlorochromate (3.2.B.ii) gave the ketone. An

intramolecular aldol condensation (9.4.A.ii) gave the final product, where dehydration occurred from the initially

formed aldol product.



OMe

O

OMe

O

OMe

O CHOOMe

O

OMe

O OH

OMe

OO

a b c

d e

(a) 1. LDA , THF/HMPA , –78°C 2. allyl bromide (b) OsO4 , NaIO4 , aq dioxane(c) i-BuMgCl , ether , –78°C (d) PCC , CH2Cl2 (e) NaOH , aq EtOH , reflux

(b) All reagents are taken from the cited reference. Initial formation of the enolate anion and quenching with

dimethyl carbonate gives the keto-ester. Reaction with bromine gives the dibromide, allowing a Favorskii

rearrangement to occur upon treatment with NaOMe in methanol, giving the final target.

O

Et

O

Et

CO2Me

O

Et

CO2MeBr

Br

MeO2C

MeO2C

Et

see J. Am. Chem. Soc., 2000, 122, 8665

a

b

c

(a) NaH , (MeO)2CO , PhH (b) Br2 , ether (c) NaOMe , MeOH

(c) All reagents are taken from J. Org. Chem., 2004, 69, 6433. Base-induced hydrolysis of the benzoate ester

(2.5.C) liberated the alcohol, and catalytic hydrogenation of the C=C unit (4.8) was followed by PCC oxidation

(3.2.B.ii) to the aldehyde. Wittig olefination (8.8.A.i) with an aldehyde-containing ylid was followed by reduction

with sodium borohydride (4.4.A) to the allylic alcohol. Bromination with carbon tetrabromide/triphenylphosphine

(2.8.A) was followed by cyclization via the ester enolate anion (9.3.A). In this case, direct displacement of the

allylic bromide would give an 8-membered ring, whereas SN2' displacement (2.6.A.iii) gave the 5-membered ring,

with concomitant formation of the alkene unit. A final ozonolysis (3.7.B), with a reductive workup using

triphenylphosphine, gave the final target.


Chapter 9 15

EtO2C

OBz

EtO2C

O

H

EtO2C

Br

EtO2C

OH

EtO2C

EtO2C

CHO

EtO2C

OH

O

EtO2C

EtO2C

OH

a b c

d e f

g h

(a) NaOEt , EtOH , rt (b) H2 , PtO2 , EtOH (c) PCC , NaOAc , CH2Cl2(d) Ph3P=C(Me)CHO , toluene , reflux (e) NaBH4 , etOH (f) CBr4 , PPh3 , CH2Cl2(g) LHMDS , THF , rt (h) O3; PPh3

(d)

O O

CO2Et

O

CO2Et

MeCHO O

CO2EtMe

HO

O

CO2EtMeO

CO2Et

Mea

b

c

de (a) LDA; ClCH2CO2Et (b) NaOEt , EtOH ; Me

(c) NaH ; 1-bromo-3-butene(d) O3 ; Me2S (e) t-BuOK , t-BuOH , heat ; H2O

(e) All reagents and steps are taken from J. Am. Chem. Soc., 2002, 124, 12078. Sharpless asymmetric

dihydroxylation (3.5.B.ii) and protection of the resulting diol as the acetonide (7.3.A.iii), allowed formation of the

ester enolate anion (9.2), which was condensed with the propargyl aldehyde to give the alcohol (9.4.B). Protection

of the alcohol as the triisopropylsilyl derivative (7.3.A.i) allowed saponification of the ester, and conversion to the

acid chloride with oxalyl chloride , and quenching with ammonia led to the amide.



EtCO2Me

OO Ph

Et OTIPSH

O

OMe

EtCO2Me

OH

OH

OO Ph

Et OTIPSH

O

OH

OO

EtH O

OMe

OO Ph

Et OTIPSH

O

NH2

OO Ph

Et OHH

O

OMea b c

d e f

(a) 1% (DHQ)2PHAL , 05% K2OsO4•2 H2O , 3 eq K2Fe(CN)6 , 3 eq K2CO3 , MeSO2NH2 , aq t-BuOH , 0°C(b) MeC(OMe)3 , TsOH , CH2Cl2 (c) 1. 2 eq LDA , 2 eq TBSOTf , THF2. phenylpropargyl aldehyde , MgBr•OEt2(d) TIPSOTf , 2,6-lutidine , CH2Cl2 (e) 3N LiOH–t-BuOH , 110°C (f) 1. (COCl)s2 , NEt3 , cat DMF 2. liq NH3

(f) All steps in this sequence are taken from Org. Lett., 2002, 4, 501. This is a convergent synthesis (10.3.C)

Reductive alkylation of the amine with the protected aldehyde shown (4.5.A) generates the N-substituted

derivative. Protection of the hydroxyl unit as the TBDMS derivative (7.3.A.i) was followed by cleavage of the

pivaloyl protecting group (7.3.A.ii). A specialized oxidation was used to give the aldehyde (see Bull. Chem. Soc.

Jpn., 1977, 50, 2773), and this was followed by oxidation of the aldehyde to the carboxylic acid (3.2.G.ii), and

esterification with the diazo compound (13.9.C). Treatment of the ester with LDA generated the ester enolate,

which reacted with the acid chloride fragment to give the ketone product (9.4.B). The acid chloride fragment was

prepared from the phosphonate ester shown by alkylation and then a Horner-Wadsworth-Emmons olefination

(8.8.A.iii). Saponification of the ester to the carboxylic acid was followed by reaction with thionyl chloride to give

the acid chloride.

NH

O

HO

H

N N NO

O

N

i-PrMgBr

NO

O

H

CO2Me

SiMe2t-Bu

OHC

OPiv

NO

O

H

CHO

SiMe2t-Bu

NO

HO

H

OPiv

NaClO2

P(O )(OEt) 2

CO2Et

P(O)(OEt)2

CO2Et

SiMe 3

CO Cl

SiMe3

Bu

N aH

Me3SiCH2I

NaH

BuCH O

NO

O

H

CO2H

SiMe 2t-Bu

CO2Et

SiMe 3

Bu

NO

O

H

SiMe2t-Bu

MeO2C

O

BuSiMe 3

NO

O

H

OH

SiMe2t-Bu

TMSCH N2

NaBH(OAc)3 , AcOH

1. t-BuMe2SiOTf

2. KOH

1. LDA

2.

1. KOH 2. SOCl2

(g) All reactions and reagents in this sequence are taken from J. Am. Chem. Soc., 2002, 124, 8584. The lactone


Chapter 9 17

was treated with LDA (9.2.B) and the enolate anion trapped with TMSCl (9.4.C). Alkylation of the enolate anion

was facilitated with the Lewis acid. Next, formation of the enolate anion with LDA and trapping with PhSeCl to

form the selenide, allowed oxidation to the selenoxide and syn elimination (2.9.C.vi) to give the conjugated lactone.

Dibal reduction of the lactone gave the alcohol-aldehyde (4.6.C) and Wittig reaction (8.8.A.i) gave the diene unit.

Conversion of the primary alcohol to its tosylate allowed the SN2 reaction (2.6.A.i) with the amine to give the

target.

O

O

O

OBnOBnO

HOBnO

TsO

O

OBnO

BnO

NHBn

OBnO

HO

Ha b c de

f

(a) 1. LDA ; TMSCl2. BnOCH2Cl , ZnCl2 (b) 1. LDA , PhSecl , –78°C 2. H2O2 , AcOH/CH2Cl2(c) Dibal, THF , –78°C (d) Ph3P=CH2 (salt free) (e) TsCl , Py , –20°C (f) BnNH2 , MeCN , heat

(h) All reagents in this sequence are taken from Org. Lett. 2002, 4, 1023. A Lewis acid catalyzed alcohol

condensation (9.4.A.i) was followed by protection of the alcohol as the dimethyl-t-butylsilyl ether (7.3.A.i).

Catalytic hydrogenation removed the O-benzyl protecting group (7.3.A.i), allowing a diastereoselective Dibal

reduction of the ketone (4.6.C) to the alcohol shown. Swern oxidation to the aldehyde (3.2.C.i) and Wittig

olefination (8.8.A.i) gave the conjugated ester. Reduction of the ester to the alcohol with Dibal (4.6.C) was

followed by bromination with carbon tetrabromide and triphenylphosphine (2.8.A) to give the final target.

OBn O

OHC

OH OSiMe2t-Bu

OH OH OSiMe2t-Bu

OHC

O

CH2-

OSiMe2t-BuOH

Ph3P CO2Et

O OHOBn

CH2Cl2

EtO2C

OH OSiMe2t-Bu

t-BuMe2SiOTf 2m6-lutidine

OH OSiMe2t-BuOH

Br OH OSiMe2t-Bu

CH2Cl2

O OSiMe2t-BuOBn

1. Sn(OTf)2 , NEt3

2.

–78°C

H2 , Pd/C EtOH Dibal , –78°C

(COCl)2 , DMSO –60°C

Dibal , –78°C

CBr4 , PPh3

2,6-lutidine , MeCN



(i) All reagents are taken from the cited reference. Initial enolate alkylation occurs from the less sterically

hindered endo- face (see problem 2). Deprotection of the acetal gives the aldehyde and NaBH4 selectively reduces

the more reactive aldehyde in preference to the somewhat hindered ketone. Conversion of the alcohol to a tosylate

allows an intramolecular enolate alkylation that generates the new ring, with the appropriate stereochemistry of the

methyl group dictated by the angle of approach of the enolate to the tosyl group on the exo- face of the molecule.

Hydroboration with 9-BBN gives the alcohol with high regioselectivity for the less sterically hindered site away

form the bridgehead methyl group. Oxidation with PCC allows a Grignard reaction to occur form the less hindered

exo- face to give the product shown.

Me

O

CH(OMe)2

Me

O

CH(OMe)2

MeMe

O

CHO

MeMe

O

OH

Me

MeO

HO Me

Me

O

OTs

MeMe

O

MeMe

O

Me

HO

MeO

Me

O

see J. Org. Chem., 1996, 61, 4967

a b c d

e f gh

(a) LDA ; MeI (b) 2N aq HCl (c) NaBH4 (d) TsCl , NEt3 (e) LDA (f) 9-BBN ; H2O2 , NaOH(g) PCC (h) CH2=C(Me)MgBr , CeCl3

(j) All reagents in this sequence are taken from Eur. J. Org. Chem., 2004, 209. A simple aldol condensation

(9.4.A) leads to the aldol product, and benzylic oxidation with manganese dioxide (3.2.F.iii gives the product.

O

O

OH

CHO

Me

OMe

OMe

O

O

OH

Me

OMe

OMe

OH O O

O

OH

Me

OMe

OMe

O O

ab

(a) acetone , NaOH (b) MnO2

(k) The initial reaction is a Baylis-Hillman to give the conjugated ester. The alcohol is protected and reaction with

dimethylsulfoxonium methylid (see Sec. 8.8.B.i) leads to the cyclopropyl derivative. A kinetically controlled

mixed Claisen condensation (Sec. 9.4.B.i) follows to give the ketone, and deprotection with tetrabutylammonium

fluoride completes the synthesis.


Chapter 9 19

PhCHO

Ph

OEt

OH O

Ph

OEt

OTBSO Ph

Ph

OTBSO

CO2Et

Ph

OEt

OTBSO

Ph

Ph

OH O

CO2Et

a b c

(a) CH2=CHCO2Et , DABCO , 0°C (b) TBSCl , imidazole (c) Me2SO=CH2(d) PhCH2CO2Et/LDA/THF/–78°C (e) TBAF, THF

d e

(l) Step b relies on conversion of bromobenzene to phenyllithium and then conversion to the higher-order cuprate

(see Sec. 8.7.B), which reacts with the acid chloride to form a ketone. Subsequent enolate alkylations are

straightforward. The ethyl group was inserted prior to the benzyl group because the second alkylation is often more

difficult than the first due to steric hindrance. Benzyl bromide is a more potent electrophile than ethyl iodide and

should give better yields in the second alkylation.

BrO O O O

Cl

O O

O O

Ph

O O

Ph

a b c d

e(a) Br2 , FeBr3 (b) 1. Li° 2. CuCN 3. (c) NaH ; EtI (d) NaH ; BnBr

(e) LDA ; EtI

(m) All reagents are taken from J. Org. Chem., 2004, 69, 4626. Hydroboration provided the alcohol (5.4.A), and

PCC oxidation generated the aldehyde (3.2.B.ii). Horner-Wadsworth-Emmons olefination (8.8.A.iii) gave the

conjugated ester, which was catalytically hydrogenated (4.8.B). Reduction to the aldehyde with

diisobutylaluminum hydride (4.6.C) gave the aldehyde, and a boron-mediated aldol condensation (9.4.D) gave the

final product.

OBn

OBn

EtO2C

OBn

OH

OBn

OHC

OBn

OHC

OBz

O

OBn

EtO2C

OBnOH

OBz

O

a b c

d e f

(a) BH3•THF; H2O2 , NaOH (b) PCC (c) (EtO)2P(O)CH2CO2Et , NaH , THF (d) H2 , cat PtO2 , EtOAc (e) Dibal , toluene , –78°C (f) X , c-hex2BCl , Me2NEt , ether , then add aldehyde

= X



(n) The cuprate addition-alkylation in step e is discussed in Section 8.7.A.vi. The internal aldol condensation in

step d (Sec. 9.4.A.ii) assumes elimination of water during the acid workup. In fact, heating may be necessary to

induce elimination.

O OHMe

Me

CHOO

O O

Ph

Eta bc

d e

(a) MeMgBr ; H3O+ (b) POCl3 , pyridine (c) O3 ; Me2S (d) NaOEt , EtOH , reflux ; H3O+ (e) Ph2CuLi ; EtI

(o) All reagents are taken from the cited paper. Enolate formation under phase transfer conditions was followed by

alkylation. Reduction with NaBH4 gave the hydroxy ester, which was saponified to the carboxylic acid. The

alcohol was activated by conversion to the sulfonate ester, facilitating formation of the b-lactone. Olefination with

the Petasis reagent (see Sec. 8.8.D) gave the final product.

CO2Et

O

O

CO2Et

O

CO2Et

OH

CO2H

OHO

O

see J. Org. Chem., 1999, 64, 7074

a b c d

e(a) NaOH , Bu4NHSO4 , 5-iodo-1-pentene (b) NaBH4 , EtOH (c) KOH , aq. MeOH(d) PhSO2Cl , pyridine (e) Cp2TiMe2 , PhMe , 80°C

(p) An important item to note in this sequence is that alkylation of dithiane anions is sluggish. Secondly, and

probably most importantly, the conjugate addition of the dithiane anion to ethyl acrylate may not give good yields.

An alternative is to acylate the 2-ethyl dithiane anion with propanoyl chloride, reduce the ketone to an alcohol,

convert it to a bromide and then displace the bromide with the lithium enolate of ethyl acetate. This is lengthier and

has some potential problems. The shorter route shown should be tried first.

S SS S S S

CO2Et

S S

CHOCHO

Oa b c d

(a) n-BuLi ; EtI (b) n-BuLi ; ethyl acrylate (c) DIBAL-H , -78°C (d) HgCl2 , aq THF , BF3

18. In each case one possible synthesis is shown. For convenience, the Aldrich Chemical company catalog was

used as the source of starting materials. Clearly, other sources of organic chemicals are available, and other

syntheses are possible based on other starting materials.


Chapter 9 21

(a)

CN OH

C3H7Br

C3H7

OHOHC

OHC

C3H7

CN

(a) BrCH=PPh3 (b) 1. Mg , THF 2. butanal 3. H3O+ (c) 1. TsCl , pyridine 2. KCN , DMF

a b c

Butanal is available as butyraldehyde from Aldrich, $18.60/L.

(b)

O

OMe

OH OMe

CO2H

OMe O

CO2H

OMe O

CO2H

OMe

OH

O

OMe

a b c d

(a) NaH ; MeI (b) AlCl3 , phthalic anhydride (c) Zn(Hg) , HCl (d) PPA

Phenol is available from Aldrich, $23.10/500g.

(c)

Me

OH

Ph

Me

O

Ph

Me

OH

Ph

Me

O

Ph

Me

O

Me

CHO

Ph

Me

O

Ph

Me

Me

OH a

b c

d ef

(a) PCC (b) PhCH2CH2MgBr ; H3O+ (c) CrO3 (d) Ph3P=CH2 (e) MCPBA (f) Me2S=CH2

2-Methyl-1-pentanol is available from Aldrich, $59.00/L.

(d)

O OO

OO O O

a b c

(a) NaOEt , methyl vinyl ketone ; H3O+ (b) CeBH4 (c) NaOEt , methyl vinyl ketone ; H3O+

Cyclohexanone is available from Aldrich, $19.70/L.



(e)

O

OO

O OPhS

O

PhS

OPhS

O

O

O

O

a b c d

(a) LDA ; n-PrI (b) LDA ; PhSCl (c) NBS , h ; KOH , EtOH (d) 3-furyllithium ; H2O

Cyclopentanone is available from Aldrich, $27.80/500 mL.

(f)

Me

OPh

OH

O

Ph

OR

O O

Ph

SS

PhS

S

O

PhS

S

O Me

OPh

OR

O

Ph

SS

Br

O

PhS

S

MeO

O

O

Ph

ORO

O

Ph

SS

O

Ph

O Me

OH

a b c

d

ef g

(a) 2-lithio-2-phenyl-1,3-dithiane (b) LDA ; 1,2-dibromo-2-propene (c) aq BF3 (d) LDA ; H3O+ , heat (e) Me2CuLi (f) ethylene glycol , H+ (g) 1. HgCl2 , BF3 ,aq THF 2. NaBH4 3. H3O+

Cyclopentenone is available from Aldrich, $390.30/100g.

(g) The last step (g) is a Grob fragmentation, described in Section 2.9.E. The hydrolysis step that converts the

ketal to the ketone may induce hydrolysis of the tosylate, but this should be controllable. It may be necessary to

protect the phenolic OH during the Friedel-Crafts sequences (see Sec. 12.4).

Phenol is available from Aldrich, $23.10/500g.


Chapter 9 23

OH

O

OH

O O

OH O

HO2C

OTs

OH

O O

OH

OH

HO2C

OR

OH

O O

OTsO

OH

OTs

OH

O

OH

OH

O O

O

OH

a b c d

e

f g h i

(a) AlCl3 , phthalic anhydride (b) Zn(Hg) , HCl (c) PPA (d) ethylene glycol , H+

(e) excess H2 , Rh (f) 1. POCl3 , pyridine 2. HgCl2 , H2O ; NaBH4 (g) TsCl , pyridine(h) 1. aq H+ 2. NaBH4 (i) NaH

(h) The Collins oxidation is discussed in Section 3.2.B.i, and the Wolff-Kishner reduction (step d) is discussed in

Section 4.10.A. Conjugate addition of organocuprates is discussed in Chapter 8. trans-2-Pentenal is available from

Aldrich, $67.00/25g.

n-C7H15

O

n-C7H15 H

O

H

O OH

n-C7H15

O

n-C7H15

O

n-C7H15 n-C7H15

a b c d

(a) n-C8H17MgBr ; H2O (b) Collins oxidation (c) Et2CuLi (d) N2H4 , KOH


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