C549 Spring 2014 R.M. WilliamsThe Aldol Condensation Reaction

The aldol condensation reaction is one of the most important and useful C-C bond-forming reactions insynthetic organic chemistry.The general reaction:

O

HR2

O

XR1

+base

X

O

R1

OH

* *R2

Aldehydes are the best electrophilic components for this reaction due to their reactivity. Typically, it isdesirable to effect the aldol condensation between two different carbonyl derivatives; such reactions are calledcrossed aldol condensations. These reactions if allowed to proceed in an uncontrolled fashion, that is, mixingthe two components together in the presence of base (or acid, for acid-catalyzed reactions) can lead to a verycomplex mixture of both the homo-dimers and the crossed aldol products. In addition, the generation of 1-2new stereogenic centers in this reaction will result in complex stereochemical mixtures as well.

O

HR2

O

HR1

+base

H

O

R1

OH

* *A B AA

H

O

R1

OH

* *BA

H

O

R2

OH

* *AB

H

O

R2

OH

* *BB

crossed aldol

R1 R2 R1 R2

Crossed aldol condensations can be effected in both a chemoselective and stereoselective manner undertwo distinct kinds of reactions conditions: (1) kinetically controlled conditions, and (2) thermodynamicallycontrolled conditions.

The kinetically-controlled aldol condensation has been developed into the most synthetically usefulcondensation reaction. Typically, the enolate (nucleophilic) partner will be generated separately underkinetically controlled conditions and then the electrophilic partner will be added. There is a huge range ofmetal counterions that have been used in the crossed aldol condensation including: Li, Na, K, Mg, Zn, B, Al, Ti,Zr and others. In general, the stereoselectivity of the aldol condensation parallels the strength and length of theM-O bond. The table below provides some useful data on the M-O bond length.

Metal M-O Bond Length Å L M-L Bond Length ÅLi 1.92~2.00 OR2 (ether, THF) 1.92~2.00Mg 2.01~2.13 Br

ClOR2

2.432.18

2.01~2.13Zn 1.92~2.16 Cl

IOR2

2.18~2.252.42

1.92~2.16Al 1.92 CR3 2.00~2.24B 1.36~1.47 CR3 1.51~1.58Ti 1.62~1.73 Cl 2.18~2.21Zr 2.15 C5H5 (Cp) 2.21

Stereochemical Diversity of the Crossed Aldol. Consider the simple crossed aldol condensation between twosimple aldehydes as shown below:

O

HR2

O

HR1

+base

H

O

R1

OH

syn

H

O

R1

OH

syn anti anti

H

O

R1

OH

H

O

R1

OH

enantiomers enantiomers

diastereomers

R2 R2 R2 R2

Two new stereogenic centers are created in this reaction and the stereochemical diversity possible forthis reaction (not including dehydration products) can be calculated by the formula 2n, where n = # ofstereogenic centers. Thus, in this case there are four possible stereoisomers (two pairs of racemicdiastereomers). The convention for drawing the syn- and anti- aldol products is shown above. Many factorscan be manipulated to control this stereochemical diversity to favor one of the four possible isomers and willbe discussed in turn below.

There exists a large body of empirical data that demonstrate that metal enolate aldol condensationsproceed through a pericyclic transition state known as the Zimmerman-Traxler transition state model(Zimmerman, H.E.; Traxler, M.D., J.Am.Chem.Soc. 1957, 79, 1920~1923).

X R2

O O

R1

M‡

The diastereoselectivity (syn- versus anti-) of the aldol condensation can be understood by examiningthe steric interactions that develop in the Zimmerman-Traxler transition state model. One of the mostimportant parameters that is subject to control by the experimentalist, is the geometry of the enolate species.Enolate geometry. The geometry of the enolate species has a profound effect on the stereochemical outcome ofthe aldol condensation. The general diastereoselection possibilities are shown below.

O

XR1 OM

XR1

base

OM

XR1

E-enolate

Z-enolate X R2

O O

R1

M

R2CHO

syn (erythro)

X R2

O O

R1

M

anti (threo)

The Zimmerman-Traxler transition state model mandates that the geometry of the pericyclic transitionstate will adopt a chair-type conformation and minimization of steric compression, both 1,2- and 1,3- will beimportant in determining the relative energies between the various transition state possibilities. In general, Z-enolates give a preference for the syn-aldol product and E-enolates show a marked preference for theformation of the corresponding anti-aldol product; this can be rationalized by examining the four possibletransition state geometries as shown below.

OM

XR1

OM

XR1

E-enolate

Z-enolate

O OM

R1

H

R2

HX

H

X R2

O O

R1

M

syn (erythro)

‡

favored

O OM

R1

H

H

R2X

H

‡

disfavored 1,3-diaxial interaction

X R2

O O

R1

M

anti (threo)

O OM

H

R1

R2

HX

H

‡

favored

O OM

H

R1

H

R2X

H

‡

disfavored 1,3-diaxial interaction

A set of kinetically-controlled aldol reactions are given below and demonstrate the relative importanceof the size of the group X on the enolate partner.

OM

XMe

OM

XMe

E-enolate

Z-enolate X Ph

O O

Me

M

syn (erythro)

X Ph

O O

Me

M

anti (threo)

k1

k2

kc

PhCHO

Enolate substituent X Z-enolates (k1/kc) E-enolates ((k2/kc)OMe - 1.5OBut - 1.0H 1 1.5Et 9 1.0i-Pr 9 1.0Ph 7 -t-Bu >50 -1-adamantyl >50 -2,4,6-(Me)3C6H2 >50 >50

It is clear from this data that, increasing the steric bulk of the enolate “X” substituent confers greaterkinetic diastereoselection from the Z-enolate relative to that for the E-enolate. It has been proposed that thereason for this may be due to a change to a boat-like transition state geometry for the extreme case where X= avery bulky group.

OO

M

t-Bu

t-But-Bu

H

HL L

Consider the extreme case below.OMgBr

t-BuR1

Z-enolatet-Bu t-Bu

O O

R1

M

syn (erythro)

t-Bu t-Bu

O O

R1

M

anti (threo)

t-BuCHO

Enolate substituent R1 ratio syn : anti JAB (Hz) syn JAB (Hz) antiMe 100:0 1.1 4.5Et 100:0 1.2 3.0n-Pr 98:2 0 2.1i-Bu 97:3 0 2.0i-Pr 29:71 - 1.1t-Bu 0:100 - 0.8

The stereochemistry of the aldol diastereomers can usually be assigned simply by a determination ofthe vicinal coupling constants as shown below.

R1

O HbHa

R2X

OH

JAB ~ 3-6 Hz

Hb

O R1Ha

R2X

OH

JAB ~ 7-9 Hz

Ph

O HbHa

MeMeO

OH

JAB ~ 4.7 Hz

Hb

O PhHa

MeMeO

OH

JAB ~ 8.6 Hz

syn anti

In extreme cases where, the steric bulk of the substituents overrides the energetics of the internally H-bonded structures shown above, and the following applies to the syn- and anti-cases, respectively:

Hb

Ph OHHa

MeO

O

JAB ~ 10.1 Hz

MeMeMe O

Ph HbHa

O

MeO

JAB ~ 4.5 Hz

MeMeMe

Hsyn anti

Enolate geometry. A great deal of experimental work has been published on the generation anddiastereoselectivity of E- and Z-enolates. Due to the trends discussed above, it is highly desirable to havegeometrically defined enolates uncontaminated with the alternate geometrical isomer to obtain the highestlevels of aldol diastereoselection. Depending on the nature of the substituents flanking the carbonyl group, thefollowing model can be useful for rationalizing the stereoselectivity of enolate formation:

R1R2

O

L2NLi, THF

N H

O

LiL

L

R1

R2H

E‡

N H

O

LiL

L

R1

HR2

Z‡

OLi

R2

R1H

OLi

HR1

R2

E-enolate Z-enolateR1 R2 Base E : Z enolate ratioOMe Me LDA 95:5OMe Et LDA 91:9OMe Ph LDA 29:71OMe t-Bu LDA 97:3O-t-Bu Me LDA 95:5O-t-Bu Et LDA 95:5S-t-Bu Me LDA 90:10NEt2 Me LDA <3:97N(CH2)4 Me LDA <3:97N(i-Pr)2 Me LDA 19:81

Evans has rationalized the high Z-stereoselection for amide enolate formation based on ground stateallylic strain which disfavors conformer B (see: Evans, D.A., Top. Stereochem., 1982, 13, 1-115):

OLi

MeNR2

HOLi

HNR2

Me

E-enolateZ-enolate

HMeO N R

RH

LDA, THF

MeHO N R

RH

A B

LDA, THF

Influence of the metal. The kinetic diastereoselection of the group I and II metal enolates is strongly influencedby the enolate substituents, principally “X”. In addition to the steric interaction between R2 and X, which raisesthe heat of formation of the Zimmerman-Traxler transition state structure B relative to that for A , variablemetal-ligand effects R2 / L, can also have a profound influence on the relative heats of formation of thetransition structures. For the Zimmerman-Traxler chair transition state structures A and B, it can be reasonableto assume that the R2 / X and R2 / L effects will be cooperative, but will be antagonistic for boat transitionstate structures. Further, the magnitude of the R2 / L steric interaction should be inversely proportional to boththe metal-ligand and metal-oxygen bond lengths.

OM

R1

XH

OM

HXR1

E-enolateZ-enolate

OMO

X

R1

H

R2

L

LO

MO

X

R1

R2

H

L

L

A BBoron enolates. Due to the short B-O and B-C bond lengths relative to that for the group I and II metals, thetransition state A should be greatly favored over that for B due to the exacerbation of the R2 / X and R2 / Leffects. Excellent kinetic diastereoselection for syn-aldol products has thus been realized through the agency ofboron enolates. The table below shows the effect of the metal counterion in kinetic aldol reactions withbenzaldehyde.

Enolate Metal (M) Syn- : Anti ratioOM

MeMe Me

MeLiMgBRB(n-Bu)2

>98:2>97:3>97:3

OMMe

LiB(n-Bu)2

88:12>97:3

� LiB(n-Bu)2

88:12>97:3

� LiB(n-Bu)2

60:405:95

� LiAl(Et)2B(C5H9)C6H13

48:5250:504:96

The most popular and convenient method to prepare boron enolates is via reaction of the carbonylderivative with a dialkylboron triflate as shown below (ref., see: Evans, D.A., Topics in Stereochemistry, 1982,13, 1-115). The initial reaction product is a boron aldolate that must be decomposed either by oxidation withhydrogen peroxide or other suitable oxidant or, alternatively, these can be treated with NaOMe in MeOH if thesubstrate can withstand mild base treatment.

�

X L temp. oC enolate Z:E syn:anti yield (%)Et n-Bu -78 >97:3 >97:3 77i-Bu n-Bu -78 >99:1 >97:3 82t-Bu n-Bu 35 >99:1 >97:3 65c-C6H11 9-BBN -78Æ 0 >99:1 >97:3 79Ph n-Bu 25 >99:1 >97:3 82

Several examples of boron enolate aldol condensation reactions are shown below.

MeO2C CHO

Me Me Me OB-9BBN

R

40:1MeO2C

Me Me

OH

Me

O

OTBSHF, NaIO4 O

Me

Me

O

HOMe

O

from: Masamune, S., Aldrichimica Acta, 1982, 15, 47~63 Prelog-Djerassi lactonic acid

CBzNO

O

PhPh

MeO H

O

PhPh

O

OCBzNCBzN

O

OBBu2

PhPh

HOO

NPh

Ph OMe

O

N

OO

Ph

PhH H

HOO

NPh

Ph OMe

O

N

OO

Ph

Ph

H H

CBz CBz CBz CBz

+CH2Cl2 /0 °C

n-Bu2BOTf, NEt3

(4%)(61%)

+

(~15:1)

CH2Cl2 /-78 °C

from: Williams, R.M.; Im, M-N.; Cao, J., J.Am.Chem.Soc., 1991, 113, 6976-6981.

Chiral Aldehydes and Achiral Enolates. For aldehydes that bear an adjacent stereogenic center, the bias forthe face-selective addition to the carbonyl group can be predicted using the Felkin-Anh transition state model.Superimposed on the conformational bias dictated by the relative steric bulk of RM and RL are p*-s* stabilizinginteractions and a-substituents with the lowest lying s* orbital are thus considered the “large” (RL)substituent. Thus, a-halo and a-alkoxy groups will dominate and be assigned the largest effective size for thistransition state model.

Destabilizing interaction

‡

disfavored

favored

Nu:

‡

Felkin

Anti-Felkin

Nu:

Nu:

Nu:

RL

C RH RM

O

CRRMHO

RL

RL ORM

R

R

RM

OHRL

RL OHRM

R

Nu

Nu

The a-alkoxy aldehydes present a particularly useful and common instance and these additionreactions are further complicated by the possibility of chelation control in the presence of strongly chelatingmetals.

OR

C HH R

O

CHRHO

OR

R2 OOR

H

Destabilizing interaction

‡Nu:

‡

Felkin

Anti-Felkin

Nu:

Nu:

Nu:

R2

OH

ORX

O

R1syn

R2

OH

ORX

O

R1

anti

CH OOR

H

R2

M

Nu:

CH OOR

H

R2

M

Nu:chelation control

‡

‡

A striking example of chelation control is shown below:

MeC7H15

OMEM

O C4H9M

THF, -78oC MeC7H15

OMEM

OHn-Bu

MeC7H15

OMEM

OHn-Bu

metal

LiMg

ratio

70:30<1:100

As can be seen from the example below, under non-chelating conditions using lithium as the enolatemetal, excellent Felkin-Anh diastereoselectivity can be observed for the case where R =H but when a secondmodestly sterically demanding substituent enters the picture, the diastereoselectivity is compromised.

OOH

O

MeMe

OLiRt-Bu

OO

OH

MeMe

t-Bu

O

R OO

OH

MeMe

t-Bu

O

R+

R = H, >95, <1R = Me, 85:15

C549 Spring 2003R.M. Williams

Asymmetric Aldol Condensations

Chiral Enolate + Chiral Aldehyde Aldol Reactions

Double diastereodifferentiation. Utilizing a chiral, non-racemic (that is, optically active or preferably,optically pure) chiral auxiliary that we shall designate Xc, there are a limited number of permutations wherethis moiety can be placed on the enolate component. There are accordingly basically three types of chiralenolate derivatives as generalized below:

XcR2

OM

R1Xc

OM

R1R2

OMXc

R3CHOXc R3

O OH

R2

* *

R1 R3

O OH

Xc

* *R3CHO

R3CHOR1 R3

O OH

R2

* *

R1R2

NMXc R3CHO

R1 R3

N OH

R2

* *

Xc

A

B

C

In the first two subsets, the Xc group is part of the enolate framework. In the first subset, the Xc groupcan be later carved off of the molecular skeleton after doing it’s job in chirality transfer in the aldolizationreaction. In the second subset, the Xc moiety becomes part of the molecular structure and by definition, will beof limited structural utility. In the third subset, either a chiral metal center or a chiral metalated enamine can beemployed and later removed.

In addition, the aldehyde component may also contain a stereogenic center(s) and this will influence thecreation of new stereogenic centers in the aldol reaction in either a cooperative (“matched”) or antagonistic(“mismatched”) mode. The “matched” or “mismatched” partnering of the chiral aldehyde and chiral enolate isreferred to as double diastereodifferentiation.Consider the general situations shown below for the aldol condensation between an optically pure enolate andan optically pure aldehyde:

EtMeO

Me

EtO

HMe

+S R

Et Et

MeMeMe

OHOEt Et

MeMeMe

OHO

S,R,S,R S,S,R,RSYN

Et Et

MeMeMe

OHOEt Et

MeMeMe

OHO

ANTIS,R,R,R S,S,S,R

opticallypure

opticallypure

SYN

ANTI

k1k2

k3k4

There are four optically pure diastereomers possible from this reaction: a pair of optically pure,diastereomeric syn-aldol products and a pair of optically pure, diastereomeric anti-aldol products. Therelative product distribution for a kinetically controlled reaction of this type, will be a manifestation of themagnitude of the four separate rate constants k1 : k2 : k3 : k4.

Now consider this same reaction with an optically pure aldehyde and a racemic enolate component. Inthis case, there are a possible total of eight optically pure diastereomers (see the imaginary TLC depicting thenumber of potentially separable diastereomers). In this system, there are now eight competing transition statesall with their own separate rate constants: k1 : k2 : k3 : k4 : k1’ : k2’: k3’: k4’. As compared to the situation above,this is obviously a much more complex condensation reaction.

EtMeO

Me

EtO

HMe

+S

Et Et

MeMeMe

OHOEt Et

MeMeMe

OHO

S,R,S,R S,S,R,RSYN

Et Et

MeMeMe

OHOEt Et

MeMeMe

OHO

ANTIS,R,R,R S,S,S,R

opticallypure

racemic

SYN

ANTI

k1k2

k3k4

S

Et Et

MeMeMe

OHO

S,R,S,SSYN

S

R

S

k2'

S R

Et Et

MeMeMe

OHO

S,S,R,SSYN

S

k1'

S

S R

Et Et

MeMeMe

OHO

ANTIS,R,R,S

S

k3'

S

S

Et Et

MeMeMe

OHO

S,S,S,SANTI

S

R

S

k4'

R,S

"TLC"

Finally, consider the same condensation with both a racemic (but still chiral) aldehyde and racemicenolate component. In this case, there a total of 16 stereoisomers possible as 8 pairs of racemic diastereomers.Note that the “TLC” is identical to that above. The same eight diastereomers are created in this reaction, buteach along with it’s mirror image (enantiomer).

EtMeO

Me

EtO

HMe

+

Et Et

MeMeMe

OHOEt Et

MeMeMe

OHO

S,R,S,R S,S,R,RSYN

Et Et

MeMeMe

OHOEt Et

MeMeMe

OHO

ANTIS,R,R,R S,S,S,R

racemic racemic

SYN

ANTI

k1k2

k3 k4

S

Et Et

MeMeMe

OHO

S,R,S,SSYN

S

R

S

k2'

S R

Et Et

MeMeMe

OHO

S,S,R,SSYN

S

k1'

S

S R

Et Et

MeMeMe

OHO

ANTIS,R,R,S

S

k3'

S

S

Et Et

MeMeMe

OHO

S,S,S,SANTI

S

R

S

k4'

R,S

"TLC"

Et Et

MeMeMe

OHO

R,R,S,RSYN

R

Et Et

MeMeMe

OHO

R,R,S,SSYN

R

R

SEt Et

MeMeMe

OHO

R,S,R,SSYN

R S

Et Et

MeMeMe

OHO

R,S,R,RSYN

R R

R,S

Et Et

MeMeMe

OHO

ANTIR,R,R,R

R R

Et Et

MeMeMe

OHO

ANTIS,R,R,S

R S

Et Et

MeMeMe

OHO

R,S,S,R

R R

Et Et

MeMeMe

OHO

S,S,S,SANTI

R S

ANTI

For a kinetically-controlled aldol condensation of the type illustrated above, the product distributionwill be a reflection of the relative magnitudes of the DDG‡’s for the competing transition states. In all of thesecases, the ground state energies for the reactants are all identical for each product manifold and the ground

state energies for the products, although not necessarily identical, will likely be very similar. For example, if welook at the first case, where the condensation was between an optically pure aldehyde and an optically pureenolate, there are four competing transition states a shown below (corresponding to k1 : k2 : k3 : k4). Theproduct distribution will be governed by the relative magnitude in energy difference between these transitionstates.

E

Rx

DDG‡'s

DG's

k1

k4k3k2

A specific example of a doubly diastereodifferentiating aldol condensation can be found in the keyaldol condensation in the Kishi total syntheses of lasalocid A:

HMe

Me

HOCO2Bn

OO

Me

OEt

H

Me

MeOHMe

O

Me 1. LDA, Et2O, -78oC

2. ZnCl23. (add aldehyde)

+ O

Me

OEt

H

Me

MeOHMe

OZnCl

Me

O

Me

OEt

H

Me MeOH

Me

O

Me

OH

MeCO2BnHO

Me

H2, Pd-C

MeOH O

Me

OEt

H

Me MeOH

Me

O

Me

OH

MeCO2HHO

Me

lasalocid A

Kishi, et al., J.Am.Chem.Soc., 1978, 100, 2933~2935.

67%

40:10:7:3 ratio

Although the initial report on this synthesis from the Kishi laboratory indicated that the aldehydecomponent was an optically active compound with the (presumed) natural stereochemistry, subsequentstudies by Ireland and co-workers, demonstrated that this component was essentially racemic. (Ireland, R.E.,et al., J.Am.Chem.Soc., 1980, 102, 6178~6180). Although the stereochemistry of the three minor aldoldiastereomers in the Kishi aldol condensation have not been elucidated, this reaction could have thereforegiven rise to a total of eight optically pure diastereomers, yet only four were detected experimentally. This is apowerful example of double diastereodifferentiation.

Another example of double diastereodifferentiation in an aldol condensation reaction was reported byWilliams and co-workers in the total synthesis of bicyclomycin as shown below. In the initial Communication,aldol condensation between the racemic bicyclo[4.2.2] bridgehead carbanion with the racemic aldehyde at lowtemperature gave a single, racemic diastereomer with the natural stereochemistry. It was found that it wasextremely important to quench the aldol condensation below -80 oC or a thermodynamic mixture of the twoaldol products shown was observed, such as when the reaction was allowed to warm to room temperaturebefore quenching.

O

HN NH

HO

OH

HO

HMe

O

O OH

d,l-bicyclomycin

O

pMBN NpMBO

O OHH

racemic

1. 2 eq. n-BuLi

THF, -100oC

O

pMBN NpMBO

O OLiLi

O

O

MeCHO

Me

Me

racemic

O

pMBN NpMB

OHHMe

O

O OHO

OMe

Me

42% (95% based on recovered SM)single, racemic diastereomer

O

pMBN NpMB

OHHMe

O

O OHO

OMe

MeO

pMBN NpMB

OHHMe

O

O OHO

OMe

MeO

pMBN NpMB

OHHMe

O

O OHO

OMe

Me

S

S

S

R

R

R

S

S

not observed

1. TFAA, DMAP

2. CAN

from: Williams, R.M.; Armstrong, R.A.; Dung, J-S., J.Am.Chem.Soc., 1984, 106, 5748~5750

2.

3. quench < -80oC

The thermodynamic equilibration presumably occurred via a reversible retro-aldol / re-aldol process.

O

pMBN NpMBO

O OLiLi

O

O

MeCHO

Me

Me O

pMBN NpMB

OHHMe

O

O OH

O

OMe

Me

S

S

2.

3. warm to 25oC

O

pMBN NpMB

OHHMe

O

O OH

O

OMe

Me

S

R+

~ 1: 1 ratio observed

O

pMBN NpMB

OLiHMe

O

O OLi

O

OMe

Me

retro-aldol

aldol

O

O

MeCHO

Me

Me

O

pMBN NpMBO

O OLiLi+

equilibration via:

The above result clearly illustrates that the “matched” partners: the (S)-aldehyde with the (SR) enolateand the (R)-aldehyde with the (RS) enolate have equal rate constants (kSR/S = k RS/R) and that the othermismatched partners, the (R)-aldehyde with the (SR) enolate and the (S)-aldehyde with the (RS) enolate, haveactivation energies higher than that for the “matched” partners. Superimposed on each pair of matched andmismatched interactions are the two sets of facial selectivities that gives rise to either the (R)- or (S)-stereochemistry at the newly created stereogenic center. This is just a more detailed way of articulating theconcept of double diastereodifferentiation.

O

pMBN NpMBO

O OHHO

O

MeCHO

Me

Me

RSS+

O

pMBN NpMB

OHHMe

O

O OHO

OMe

Me

S

S

kSR/S

O

NNOHH

R

O OpMB

pMB S O

O

MeCHO

Me

MeR+

O

NNOHR

O OpMB

pMB SO

OMe

Me

MeHHOR

R

kRS/R

racemate kSR/S = kRS/R

kSR/S = kRS/R >> kSR/R; kRS/S

RS

Finally, the asymmetric aldol reaction was carried out with racemic enolate and optically active (~83%ee) aldehyde as shown below.

O

pMBN NpMBO

O OHH

racemic

1. 2 eq. n-BuLi

THF, -100oC

O

pMBN NpMBO

O OLiLi

O

O

MeCHO

Me

Me O

pMBN NpMB

OHHMe

O

O OHO

OMe

Mesingle, optically active diastereomer

S

S

2.

3. quench < -80oC

(83% ee)

49%

~80%ee

The asymmetric synthesis of the aldehyde component was achieved via Sharpless asymmetricepoxidation technology as shown below. The final conversion of the phenyl sulfide derivative to the aldehydeis an illustration of the Pummerer rearrangement.

O

O

MeCHO

Me

Me

MeHO

t-BuOOH, CH2Cl2

Ti(O-t-Bu)4, (+)-DET MeHO O PhSH, H2O

NaOH, diox.

HO

HO

MeSPh Me Me

MeO OMe

CSA

O

O

MeMe

Me

SPhm-CPBA

CH2Cl2

O

O

MeMe

Me

SPhO

*1. Ac2O, NaOAc

2. K2CO3, MeOH10% overall ~83% ee

* = Pummerer rearrangement

from: Dung, J-S-; Armstrong, R.A.; Anderson, O.P.; Williams, R.M., J.Org.Chem., 1983, 48, 3592~3594

*Sharpless asymmetric epoxidation

MeOH

OMe

O

HOS SN2

SN2

S* Note degenerative Payne rearrangement

Chiral Amide Enolates: The Evans Chiral Auxiliaries. A very powerful method for effectingdiastereoselective and asymmetric aldol condensation reactions has been developed by Dave Evans and co-workers over the past 15-20 years. The methodology utilizes chiral, non-racemic amide oxazolidinones in avery effective way. Two chiral oxazolidinones have become very popular as shown below; one is derived fromL-valinol and the other, from (-)-ephedrine. These can be utilized as either boron enolates or other metalatedamide enolates to provide excellent diastereoselective, asymmetric aldol condensations. For the aldol reaction,the boron enolates have proven to give the best selectivities via the correponding Z-enolates as shown below.

N Me

O

OMe

Me

O

1. (n-Bu)2BOTf, R3N

2. RCHON

O

OMe

Me

O

RMe

OHLiOH, LiOOH

HO

O

RMe

OH+ NH

O

MeMe

O

N Me

O

OMe

O

1. (n-Bu)2BOTf, R3N

2. RCHON

O

OMe

O

RMe

OHLiOH, LiOOH

HO

O

RMe

OH+

Ph Ph NHO

Me

O

Ph

syn-selectivities >99:1

XcMe

OB(n-Bu)2Z-boron enolate

A specific case of the extraordinarily high diastereoselectivities that have been realized with thismethodology is illustrated below (see Evans, D.A., Aldrichimica Acta, 1982, 15, 23~32).

Me Me

OH

MeXc

O

Me Me

OH

MeXc

O

(2S, 3R) (2R, 3S)

HMe Me

O

XcMe

OB(n-Bu)2+

-78oC, CH2Cl2

substrate (2S, 3R) : (2R, 3S) Yield

N Me

O

OMe

O

Ph

N Me

O

OMe

Me

O

N Me

O

O

O

36 : 64 -

>400:1

<1:500

73%

86%