A stereochemical model for merged 1,2- and 1,3-asymmetric induction in diastereoselective Mukaiyama aldol addition reactions and related processes

4322

J. Am. Chem. Soc. 1996, 118, 4322-4343

A Stereochemical Model for Merged 1,2- and 1,3-Asymmetric

Induction in Diastereoselective Mukaiyama Aldol Addition

Reactions and Related Processes

David A. Evans,* Michael J. Dart, Joseph L. Duffy, and Michael G. Yang

Contribution from the Department of Chemistry, HarVard UniVersity,

Cambridge, Massachusetts 02138

ReceiVed NoVember 20, 1995^X

Abstract: A systematic investigation of the direction and degree of stereoselectivity in aldol addition reactions is

presented involving achiral unsubstituted metal enolate and enolsilane nucleophiles and chiral aldehydes. The BF₃‚OEt₂

mediated Mukaiyama aldol reaction with R-unsubstituted, â-alkoxy aldehydes afforded good levels of 1,3-anti induction

in the absence of internal aldehyde chelation. The level of 1,3-induction was found to be primarily dependent on

the electrostatic nature of the aldehyde â-substituent. A revised model for 1,3-asymmetric induction is presented to

account for these results based primarily on minimization of internal electrostatic and steric repulsion between the

aldehyde carbonyl moiety and the â-substituents. A full conformational analysis, corroborated by semiempirical

(AM1) calculations, is presented to support the proposed model. The merged impact of R and â aldehyde substituents

was also systematically investigated, and an integrated 1,2- and 1,3-asymmetric induction model is proposed that

incorporates the salient features of the Felkin-Anh and revised 1,3-model. In accordance with this integrated model,

uniformly high levels of Felkin, 1,3-anti diastereofacial selectivity are observed in Mukaiyama aldol reactions with

anti substituted R-methyl-â-alkoxy aldehydes, which contain stereocontrol elements that are in a stereoreinforcing

relationship. In contrast, variable levels of aldehyde facial induction were observed in the corresponding reactions

with syn substituted aldehyde substrates, which contain stereocontrol elements in a non-reinforcing relationship.

The direction of aldehyde facial induction in Mukaiyama aldol additions to the syn substituted aldehydes was found

to be primarily dependent on the size of the enolsilane, with the first known examples of anti-Felkin selective

Mukaiyama aldol reactions observed under conditions known to preclude chelation for the addition of the enolsilane

of acetone. We conclude that dominant 1,2-stereoinduction will be found in those reactions proceeding with the

reactants in an antiperiplanar relationship, favored by sterically encumbered enolsilane substituents, while dominant

1,3-stereoinduction will be manifest from a synclinal transition state, preferred for less bulky enolsilane substituents.

By inspection, the synclinal transition state may be destabilized by an increase in the steric bulk of the Lewis acid,

and in accordance with this prediction the trityl perchlorate mediated enolsilane addition resulted in a dramatic

reversal of facial selectivity relative to the BF₃‚OEt₂mediated reaction. These trends were also documented in the

mechanistically related addition of allylstannanes to anti and syn disubstituted chiral aldehydes.

Introduction

and this method has also been effectively utilized in the

prediction of reaction diastereoselection.⁶Although significant

effort has been expended in the development of transition state

models that account for the influence of the proximal substituent

on carbonyl facial induction, comparable models acknowledging

the stereochemical impact of â substituents have been less well

developed.⁷Recently we reported the results from an investiga-

tion of 1,3-asymmetric induction in the methyl ketone aldol

reaction.⁸The highest levels of 1,3-stereoinduction are achieved

The formulation of models that successfully predict the

stereochemical outcome of reactions at trigonal carbon centers

has been a major preoccupation in synthesis design. One of

the focal points in this area has been concerned with the

elucidation of the control elements that dictate acyclic carbonyl

π-facial selectivity in nucleophilic addition reactions.¹

A

succession of predictive stereochemical models for carbonyl

addition have been advanced since Cram’s initial 1952 pro-

posal.^2,3Currently, the Felkin-Anh model⁴is widely invoked

to interpret the contributions of torsional, steric, and electronic

factors from the stereogenic center R to the reacting carbonyl.⁵

Heteroatom substituents positioned either R or â to the carbonyl

moiety raise the potential for transition state chelate organization,

(4) (a) Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968,

2199-2204. (b) Anh, N. T.; Eisenstein, O. NouV. J. Chem. 1977, 1, 61-

70. (c) Anh, N. T. Top. Curr. Chem. 1980, 88, 145-162. (d) Lodge, E.

P.; Heathcock, C. H. J. Am. Chem. Soc. 1987, 109, 3353-3361. (e) Lodge,

E. P.; Heathcock, C. H. J. Am. Chem. Soc. 1987, 109, 2819-2820.

(5) For relevant computational investigations: (a) Wu, Y.-D.; Houk, K.

N. J. Am. Chem. Soc. 1987, 109, 908-910. (b) Houk, K. N.; Paddon-

Row, M. N.; Rondan, N. G.; Wu, Y.-D.; Brown, F. K.; Spellmeyer, D. C.;

Metz, J. T.; Li, Y.; Loncharich, R. J. Science 1986, 231, 1108-1117. (c)

Wong, S. S.; Paddon-Row, M. N. J. Chem. Soc., Chem. Commun. 1990,

456-458. (d) Wong, S. S.; Paddon-Row, M. N. Aust. J. Chem. 1991, 44,

765-770. (e) Wu, Y.-D.; Tucker, J. A.; Houk, K. N. J. Am. Chem. Soc.

1991, 113, 5018-5027. (f) Frenking, G.; Ko¨hler, K. F.; Reetz, M. T.

Tetrahedron 1991, 43, 9005-9018.

^XAbstract published in AdVance ACS Abstracts, March 15, 1996.

(1) For general reviews of acyclic diastereoselective synthesis: (a)

Bartlett, P. A. Tetrahedron 1980, 36, 2-72. (b) McGarvey, G. J.; Kimura,

M.; Oh, T.; Williams, J. M. J. Carbohydr. Chem. 1984, 3, 125-188. (c)

No´gra´di, M. In StereoselectiVe Synthesis; VCH: New York, 1986. (d) Ager,

D. J.; East, M. B. Tetrahedron 1993, 48, 2803-2894.

(2) Cram, D. J.; Abd Elhafez, F. A. J. Am. Chem. Soc. 1952, 74, 5828-

5835.

(3) (a) Prelog, V. HelV. Chim. Acta 1953, 36, 308-319. (b) Cornforth,

J. W.; Cornforth, R. H.; Mathew, K. K. J. Chem. Soc. 1959, 112-127. (c)

Karabatsos, G. J. J. Am. Chem. Soc. 1967, 89, 1367-1371.

(6) (a) Cram, D. J.; Kopecky, K. R. J. Am. Chem. Soc. 1959, 81, 2748-

2755. (b) Eliel, E. L. In Asymmetric Synthesis; Morrison, J. D., Ed.;

Academic Press: New York, 1983; Vol. 2., Chapter 5, pp 125-155. (c)

Reetz, M. T. Angew. Chem., Int. Ed. Engl. 1984, 23, 556-569. (d) Reetz,

M. T. Acc. Chem. Res. 1993, 26, 462-468 and references cited therein.

Merged 1,2- and 1,3-Asymmetric Induction

J. Am. Chem. Soc., Vol. 118, No. 18, 1996 4323

in the BF₃‚OEt₂promoted enolsilane (Mukaiyama)⁹aldol

and B (eqs 4 and 5).¹¹Ab initio calculations by Houk have

variants (eq 1). The facial bias imparted to the carbonyl by the

aldehyde â-heteroatom substituent generally results in prefer-

ential formation of the 1,3-anti product diastereomer in these

aldol processes. A stereochemical model is presented here to

account for this preference, with observations on the contribu-

tions of electrostatic and steric effects to 1,3-asymmetric

induction.

provided support for the Felkin hypothesis and indicate that

when the R stereogenic center bears substituents of different

size but of similar electronic character, steric factors favor

nucleophilic attack on conformer A (eq 4).^5a,bThe largest

substituent (R_L) is aligned anti to the forming bond, and the

methyl group is disposed syn to the carbonyl moiety. Steric

interactions between the nucleophile and R substituents are

minimized in this transition state as the incoming nucleophile

follows a Dunitz-Bu¨rgi trajectory¹²over the proton of the R

stereocenter. Based on this model, 1,2-asymmetric induction

should increase as the steric demands of the nucleophile

increase; this prediction has been borne out experimentally.¹³

1,3-Asymmetric Induction Models. The only well-estab-

lished strategy for controlling aldehyde face selectivity Via 1,3-

induction involves internal chelation to a â-heteroatom

substituent.^6cIndeed, preferential formation of the 1,3-anti

diastereomer is consistent with reaction through transition state

C (eq 6), which involves nucleophilic attack on the less hindered

1,3-Asymmetric induction may also play an important role

in the stereochemical outcome of additions to more complex

aldehyde substrates that possess both R and â stereogenic

centers.¹⁰For example, uniformly high levels of diastereofacial

selectivity are observed in Mukaiyama aldol reactions with anti

substituted R-methyl-â-alkoxy aldehydes (eq 2). In contrast,

we have documented variable levels of aldehyde facial induction

in the corresponding reactions with syn substituted aldehyde

substrates (eq 3).¹⁰We have asserted that the diastereofacial

bias imposed on the carbonyl moiety is the result of stereocontrol

from both the R and â stereocenters, and have concluded that,

in some cases, the â-center appears to be the dominant

stereocontrol element.¹⁰The purpose of the present investiga-

tion is to present an integrated R,â-stereoinduction model for

Mukaiyama aldol reactions and related processes.

face of a conformationally locked, internally chelated intermedi-

ate. In these systems the chelating metal center (M) must

possess a minimum of two open coordination sites to simulta-

neously complex both carbonyl¹⁴and ether oxygens. NMR

spectroscopic experiments by Keck have established that the

protecting group (P) must also permit effective bidentate

complexation of the Lewis acid between the carbonyl and ether

oxygen.¹⁵

In many diastereoselective reactions with â-heteroatom-

substituted substrates, however, chelate organization is precluded

due to either the nature of the coordinating metal species or the

heteroatom protecting group. An illustrative example has been

1,2-Asymmetric Induction Model. The sense of 1,2-

asymmetric induction in many nucleophilic additions to R-meth-

yl-substituted chiral aldehydes is consistent with predictions

made by the Felkin-Anh paradigm.^4,5The major tenet of this

transition state model is the minimization of nonbonded

interactions between the nucleophile and the substituents R to

the carbonyl center. A staggered arrangement is preferred be-

tween the partially formed bond and the R substituents to

minimize torsional strain, as is illustrated in transition states A

(11) (a) Reference 4b. (b) Caramella, P.; Rondan, N. G.; Paddon-Row,

M. N.; Houk, K. N. J. Am. Chem. Soc. 1981, 103, 2438-2440. (c) Paddon-

Row, M. N.; Rondan, N. G.; Houk, K. N. J. Am. Chem. Soc. 1982, 104,

7162-7166. (d) Reference 5b.

(12) (a) Bu¨rgi, H. B.; Dunitz, J. D.; Shefter, E. J. Am. Chem. Soc. 1973,

95, 5065-5067. (b) Dunitz, J. D. X-ray Analysis and the Structure of

Organic Molecules; Cornell University Press: Ithaca, NY, 1979. (c) Bu¨rgi,

H. B.; Dunitz, J. D. Acc. Chem. Res. 1983, 16, 153-161.

(13) For representative examples: (a) Reetz, M. T. Top. Curr. Chem.

1982, 106, 1-54. (b) Yamamoto, Y.; Matsuoka, K.; Nemoto, H. J. Am.

Chem. Soc. 1988, 110, 4475-4476.

(14) For a review on Lewis acid carbonyl complexation: Shambayati,

S.; Schreiber, S. L. In ComprehensiVe Organic Synthesis: Additions to C-X

π-Bonds, Part 1; Trost, B. M., Fleming, I., Schreiber, S. L., Eds.; Pergamon

Press: New York, 1991; Chapter 10.

(7) (a) Brienne, M.-J.; Ouannes, C.; Jacques, J. Bull. Soc. Chim. Fr. 1968,

1036-1047. (b) Leitereg, T. J.; Cram, D. J. J. Am. Chem. Soc. 1968, 90,

4011-4018. (c) Leitereg, T. J.; Cram, D. J. J. Am. Chem. Soc. 1968, 90,

4019-4026. (d) Reetz, M. T.; Kesseler, K.; Jung, A. Tetrahedron Lett.

1984, 25, 729-732. (e) Nakada, M.; Urano, Y.; Kobayashi, S.; Ohno, M.

Tetrahedron Lett. 1994, 35, 741-744.

(8) Evans, D. A.; Duffy, J. D.; Dart, M. J. Tetrahedron Lett. 1994, 35,

8537-8540.

(9) (a) Mukaiyama, T.; Banno, K.; Naraska, K. J. Am. Chem. Soc. 1974,

96, 7503-7509. (b) Gennari, C. In ComprehensiVe Organic Synthesis:

Additions to C-X π-Bonds Part 2; Trost, B. M., Fleming, I., Heathcock,

C. H., Eds.; Pergamon Press: New York, 1991; Chapter 2.4.

(10) Evans, D. A.; Dart, M. J.; Duffy, J. L.; Yang, M. G.; Livingston,

A. B. J. Am. Chem. Soc. 1995, 117, 6619-6620.

(15) (a) Keck, G. E., Castellino, S. J. Am. Chem. Soc. 1986, 108, 3847-

3849. (b) Keck, G. E.; Castellino, S.; Wiley, M. R. J. Org. Chem. 1986,

51, 5478-5480. (c) Keck, G. E.; Boden, E. P.; Wiley, M. R. J. Org. Chem.

1989, 54, 896-906.

4324 J. Am. Chem. Soc., Vol. 118, No. 18, 1996

EVans et al.

Table 1.^aLewis Acid Promoted Aldol Reactions of Enolsilanes

reported by Reetz, in which a stereoselective BF₃‚OEt₂mediated

allylsilane addition resulted in preferential formation of the 1,3-

anti-substituted product (eq 7).¹⁶Due to the monodentate nature

with â-Substituted Aldehydes 1 and 2 (Eq 8)

3:4 (P ) PMB)

5:6 (P ) TBS)

(yield, %)

entry

R

(yield, %)

A

B

C

t-Bu

i-Pr

Me

89:11 (82)

92:08 (91)

91:09 (89)

84:16 (79)

80:20^b(84)

93:07 (87)

^aAll reactions were carried out with 1 equiv of BF₃‚OEt₂in CH₂Cl₂

at -78 °C. Ratios were determined by GLC analysis after silylation

(TMS-imidazole) of the unpurified reaction mixtures unless otherwise

noted. Yields are reported for the mixture of diastereomeric adducts.

^bRatio was determined by integration of the ¹H NMR spectrum of the

unpurified reaction mixture.

of the boron Lewis acid, chelation (eq 6) cannot be invoked to

rationalize the observed anti-1,3-stereoinduction. An extension

of Cram’s polar 1,3-stereoinduction model^7chas been proposed

by Reetz to account for the diastereofacial selectivity in this

system. In this model, minimization of electrostatic repulsion

in the Lewis acid coordinated aldehyde complex results in

formation of an extended intermediate that is attacked from the

less hindered carbonyl diastereoface to provide that 1,3-anti

product. Although the stereochemical outcome is consistent

with this proposal, the Cram-Reetz model fails to acknowledge

the importance of transition state torsional interactions. We

propose herein an alternate 1,3 polar induction model, based

primarily on electrostatic interactions within the aldehyde, that

incorporates the staggered conformation of R-substituents

present in the Felkin-Ahn model for 1,2-induction. The

experimental results that led to the development of the modified

1,3-stereoinduction model are detailed in the following discus-

sion.

induction can be achieved by remote substituent effects, although

the origins of stereocontrol have not been systematically

investigated.

In order to assess the contribution from electrostatic and steric

effects, other aldehyde substrates were subjected to the BF₃‚OEt₂

mediated aldol reactions (eqs 9 and 10). The facial bias of

aldehyde 7a (X ) OPMB) was examined in an attempt to

evaluate the electrostatic contribution to 1,3-stereoinduction.

This substrate incorporates â-substituents of comparable size

(OCH₂Ar vs CH₂CH₂Ar) but of different electronic character.

Enolsilane addition to this aldehyde afforded an 81:19 mixture

of products favoring the 1,3-anti diastereomer. The degree of

aldehyde facial control was also examined in the presence of

other â-heteroatom substituents. The reaction of â-OTBS

substrate 7b also preferentially afforded the 1,3-anti aldol

adduct, but with slightly diminished selectivity relative to

â-OPMB aldehyde 7a. Unexpectedly, the tendency for 1,3-

anti product formation was not observed in the reaction with

aldehyde 7c (X ) OAc), and a 43:57 ratio of diastereomers

favoring the 1,3-syn diastereomer was obtained. Finally, the

unstable â-chloroaldehyde 7d exhibited the highest level of 1,3-

stereoinduction (83:17 anti:syn).

Results and Discussion

We initiated a systematic investigation into 1,3-asymmetric

induction by subjecting â-alkoxy aldehydes 1 and 2 to addition

reactions with a series of methyl ketone derived enolsilane

nucleophiles (eq 8, Table 1). The monodentate Lewis acid

BF₃‚OEt₂was utilized to preclude the intervention of chelate

organization. These data indicate that good levels of 1,3-

stereoinduction can be achieved in BF₃‚OEt₂promoted Mu-

kaiyama aldol reactions (1 equiv of BF₃‚OEt₂, CH₂Cl₂, -78

°C),¹⁷irrespective of the nature of the â-alkoxy protecting group

(P) or the size of the enolsilane substituent (R).¹⁸This consistent

predisposition for formation of the 1,3-anti-substituted product

under nonchelate controlled conditions has been observed in

numerous related Lewis acid promoted addition reactions.¹⁹

These processes demonstrate that a useful degree of asymmetric

Table 2.^aAldehyde â-Substituent Influence on

1,3-Induction (Eq 9)

(16) (a) Reference 7d. (b) Reetz, M.; Kesseler, K. J. Chem. Soc., Chem.

Commun. 1984, 1079-1080.

(17) For related examples; see: (a) Reference 7d. (b) Roy, R.; Rey, A.

W. Synlett 1990, 448-450. (c) Paterson, I.; Smith, J. J. Org. Chem. 1992,

57, 3261-3264. (d) Paterson, I.; Smith, J. D.; Ward, R. W. Tetrahedron

1995, 51, 9413-9436. (e) Hanessian, S.; Tehim, A.; Chen, P. J. Org. Chem.

1993, 58, 7768-7781. Similar trends have been reported in Mukaiyama

aldol additions to â-thio-substituted aldehydes: (f) Annunziata, R.; Cinquini,

M.; Cozzi, F.; Cozzi, F. G.; Consolandi, E. J. Org. Chem. 1992, 57, 456-

461.

aldehyde

X

8:9 (yield, %)

7a

7b

7c

7d

OPMB

OTBS

OAc

Cl

81:19 (87)

73:27 (90)

43:57 (79)

83:17 (84)

(18) Product stereochemical assignments are described in detail in the

supporting information.

^aSee footnote a in Table 1.

(19) Allylsilane additions: (a) Reference 7d; allylstannane additions. (b)

Yamamoto, Y.; Komatsu, T.; Maruyama, K. J. Organomet. Chem. 1985,

285, 31-42. (c) Reference 15b. (d) Nakatsuka, M.; Ragan, J. A.;

Sammakia, T.; Smith, D. B.; Uehling, D. E.; Schrieber, S. L. J. Am. Chem.

Soc. 1990, 112, 5583-5601. (e) Overly, K. R.; Williams, J. M.; McGarvey,

G. J. Tetrahedron Lett. 1990, 31, 4573-4576. [2 + 2] cycloadditions: (f)

Pons, J.-M.; Pommier, A.; Lerpiniere, J.; Kocienski, P. J. Chem. Soc., Perkin

Trans. 1 1993, 1549-1551. (g) Pommier, A.; Pons, J.-M.; Kocienski, P.

J.; Wong, L. Synthesis 1994, 1294-1300. (h) Pommier, A.; Pons, J.-M.;

Kocienski, P. J. J. Org. Chem. 1995, 60, 7334-7339.

To establish the steric contribution to 1,3-stereoinduction in

the absence of a polar â-substituent, aldehyde 10 possessing

sterically differentiated â-alkyl substituents was synthesized.

This substrate displayed low π-facial selectivity (58:42 anti:

syn) in the BF₃‚OEt₂promoted enolsilane aldol reaction,

indicating that steric effects alone do not appear to strongly

influence 1,3-stereoinduction.¹⁸

Merged 1,2- and 1,3-Asymmetric Induction

J. Am. Chem. Soc., Vol. 118, No. 18, 1996 4325

Table 3.^aRelative ∆∆H (kcal/mol) of the Illustrated

Conformations

Revised 1,3-Asymmetric Induction Polar Model. The

revised 1,3-asymmetric induction model is derived from several

assumptions common to the Felkin-Anh analysis for 1,2-

asymmetric induction.^4,5First, it is assumed that torsional

effects will dictate that aldehyde transition state conformations

adopt a staggered relationship between the forming bond and

the aldehyde R-substituents. Second, it is assumed that the

principal addition product evolves from that reactant-like

transition structure wherein the â-stereogenic center is oriented

anti, rather than gauche, to the forming bond since this geometry

reduces nonbonded interactions between the aldehyde R sub-

stituents and the incoming nucleophile.²⁰

Given the preceding assumptions concerning transition state

geometry, we speculate that aldehyde face selectivity is governed

by steric and electrostatic effects in the aldehyde that originate

from interactions between the â-substituents and the carbonyl

reaction center. Accordingly, minimization of electrostatic and

steric repulsion between these substituents affords the preferred

transition structure illustrated in two different perspectives (D1

and D2) in eq 11. In the illustrated structures, the descriptor

entry

R_â

X

D

E

F

G

H

I

1

2

t-Bu

OMe

Cl

2.8 2.6

3.0 2.8

1.2

1.8

0.3

0.0

1.7 2.2

1.8 2.6

0.0

3

4

t-Bu

OAc

Me

0.0

0.1

1.0 0.6

2.2 1.2

1.3 0.7

1.3 2.1

^aRelative energies were calculated at the semiempirical (AM1) level

through a systematic conformational analysis. See ref 22.

R_âbecomes larger, and the preferred alignment of this sub-

stituent anti to C_R-CdO thus becomes more important. When

X is a polar heteroatom substituent, a destabilizing dipolar

interaction between the C-X and the CdO bonds is present in

structures F and G. Thus, by a process of elimination, we

conclude that complementary minimization of destabilizing

dipole and steric interactions favors nucleophilic addition to the

exposed face of conformer D, affording the 1,3-anti diastere-

omer. Indeed, this conformer may also be stabilized by an

attractive electrostatic interaction between the â-heteroatom

substituent and the polarized carbonyl carbon.²¹

The relative conformational energies of the illustrated alde-

hyde complexes were investigated by semiempirical calculations

(AM1).²²A constrained 90° dihedral relationship between the

carbonyl (CdO) and C_R-C_âbonds was imposed in these

conformational analyses, which orients the â-stereogenic center

perpendicular to the σ-framework of the carbonyl moiety in

accord with the assumptions outlined above. Conformational

searches were performed with full geometry optimization about

the C_R-C_âbond (and C_â-X bond where applicable), and the

relative energies (kcal/mol) are listed in Table 3. These

calculations support the proposition that conformer D minimizes

unfavorable interactions in substrates possessing the polar

â-substituents (X ) OR, halogen) (Table 3, entries 1 and 2). It

is significant that the smaller energy variations calculated for

the staggered rotamers of the model â-OAc aldehyde (Table 3,

entry 3) are consistent with the low level of asymmetric

induction noted for this substituent (cf. Table 2) relative to the

other â-heteroatom substituents. From these experimental and

supporting computational data, we conclude that the nature of

the oxygen protecting group employed in the reaction is an

important consideration for optimal 1,3-induction.

R_âdenotes the â-carbon alkyl substituent, while X represents

the polar heteroatom substituent (OR, Cl). This model, which

leads to the 1,3-anti diastereomer, clearly depicts the staggered

conformation of the R-substituents with respect to the incoming

nucleophile D1, and the favored orientation of the â-stereocenter

relative to the coordinated carbonyl moiety D2. The relevant

steric and electronic interactions that favor this specific aldehyde

rotamer in the transition state may be estimated in the confor-

mational analysis of the constrained BF₃-coordinated aldehydes.

The perspective illustrated in model D2 has been utilized to

identify the important nonbonded interactions between the

â-substituents and carbonyl moiety in this conformational

analysis (eqs 12 and 13). Steric interactions in these aldehyde

conformations are expected to be minimized when the â-alkyl

substituent (R_â) is oriented anti to the C_R-CdO bond as in

structures D and G. Therefore, conformers E and I are

destablized by the gauche R_âTCdO interaction. Structures F

and H are also expected to become increasingly destabilized as

(21) For examples of potential transition state stabilization by similar

electrostatic interactions: (a) Lewis, M. D.; Kishi, Y. Tetrahedron Lett.

1982, 23, 2343-2346. (b) Yamamoto, Y.; Nemoto, H.; Kikuchi, R.;

Komatsu, H.; Suzuki, I. J. Am. Chem. Soc. 1990, 112, 8598-8599. (c)

Roush, W. R.; Hoong, L. K.; Palmer, M. A.; Straub, J. A.; Palkowitz, A.

D. J. Org. Chem. 1990, 55, 4117-4126. (d) Roush, W. R.; Ratz, A. M.;

Jablonowski, J. A. J. Org. Chem. 1992, 57, 2047-2052.

(22) Dewar, M. J. S.; Zoebisch, E. G.; Healy, E. F.; Stewart, J. J. P. J.

Am. Chem. Soc. 1985, 107, 3902-3909. These AM1 calculations were

performed on the SPARTAN computational platform: Deppmeier, B. J.;

Dreissen, A. J.; Hehre, W. J.; Johnson, H. C.; Leonard, J. M.; Yu, J.; Lou,

L. SPARTAN SGI Version 3.1.2 GL, Wavefunction INC.: Irvine, CA.

(20) It is not suggested that only transition states which maintain this

anti orientation between the nucleophile and â-stereocenter are viable

pathways involved in these processes. It is reasonable that transition

structures possessing a gauche relationship between the â-stereogenic center

and nucleophile should also be considered, although we propose that they

contribute less to the distribution of energetically significant reaction

pathways.

4326 J. Am. Chem. Soc., Vol. 118, No. 18, 1996

EVans et al.

Conclusions. The preceding analysis provides a stereochem-

ical model for the 1,3-asymmetric induction that is in accord

with the experimental data (Table 2, X ) OPMB, OTBS, OAc,

Cl). Elevated levels of 1,3-stereoinduction for a given â

heteroatom should be observed as the steric requirements of

the â-alkyl substituent (R_â) increase, and this trend is evident

by comparing the data presented in Tables 1 and 2. This

analysis also accounts for the low selectivity observed for

aldehydes carrying sterically differentiated â substituents such

as 10. Replacement of the â-heteroatom with a methyl group

(X ) Me) greatly diminishes any polar interactions between

the â-substituents and the carbonyl moiety. As a consequence,

the energies of conformers D and G, which lead to diastereo-

meric products, may be similar. The AM1 level calculations

support this conclusion and indicate that steric effects alone do

not induce a significant carbonyl facial bias from the â-stereo-

center (Table 3, entry 4).

induction of these systems. As previously discussed, Mu-

kaiyama aldol reactions also exhibit good levels of 1,3-

stereoinduction with â-alkoxy aldehydes under non-chelate

controlled reaction conditions (eq 16).⁸The facial bias conferred

on the carbonyl moiety by the â-stereocenter is readily accom-

modated by the revised polar 1,3-stereoinduction model D. These

results suggest that there may exist stereochemical relationships

between the R and â substituents that exert either complemen-

tary or opposing influences on the facial bias of the carbonyl

moiety.

The revised 1,3-asymmetric induction model differs in a key

respect from leading predictive theories for acyclic stereocontrol

such as the Felkin-Anh^4a,band Cram-Reetz models.^7dThe

relative energies between competing transition states in the latter

stereochemical models are primarily based on interactions

between the incoming nucleophile and the carbonyl substrate.

Although intermolecular nonbonded interactions can clearly play

an important role in dictating the facial selectivity of many

carbonyl addition processes,¹³we propose that 1,3-stereoinduc-

tion is governed to a large extent by conformational effects that

occur within the aldehyde.²³This conclusion evolves from the

assumption that steric interactions between the nucleophile and

carbonyl substrate will essentially be identical during attack on

either aldehyde diastereoface for competing transition states that

orient the â-stereogenic center of the aldehyde anti to the

incoming nucleophile.²⁰If this is true, then the conformational

preferences of the constrained ground state aldehyde geometries

might also be manifest in the transition state.²⁴

For substrates bearing substituents at both the R and â

positions, we propose that the Felkin-Anh and 1,3-asymmetric

induction models may be integrated. For example, the merged

R,â-stereoinduction model J is generated by replacing H_ain

1,3-stereoinduction model D (eq 16) with a methyl group. This

affords a substrate bearing an anti relationship between R-methyl

and â-alkoxy substituents where the relative configurations of

these substituents mutually reinforce nucleophilic addition from

the indicated aldehyde diastereoface (eq 17). This analysis leads

to the conclusion that the reinforcing diastereomeric relationship

found in the indicated anti aldehyde diastereomer should

contribute to enhanced π-facial selectivity in carbonyl addition,

and as a corollary, the nonreinforcing syn aldehyde diastereo-

mers should exhibit either diminished or inverted selectivity

(Vide infra).

Merged 1,2- and 1,3-Asymmetric Induction. It is generally

accepted that the stereogenic center R to the carbonyl dictates

diastereofacial selectivity in nucleophilic additions to aldehydes

bearing multiple stereocenters (eq 14). However, in the data

to be presented, we document cases where the â-stereocenter

can exert the dominant influence on aldehyde facial selectivity

by overriding the intrinsic bias imposed by the R-stereocenter.

An integrated R,â-stereoinduction model that accounts for the

impact of both R- and â-stereocenters is proposed by incorpo-

rating the salient features of the Felkin-Anh model and the

revised 1,3-induction model presented above.

As predicted, excellent levels of diastereoselectivity are

achieved in the BF₃‚OEt₂promoted Mukaiyama aldol reactions

with anti substituted aldehydes 13 and 14 (eq 18, Table 4).²⁶

These results are readily accommodated by the merged R,â-

stereoinduction model J, which predicts preferential formation

of the Felkin/1,3-anti product diastereomer.

Excellent levels of selectivity are typically obtained in

Mukaiyama aldol reactions with simple R-methyl-substituted

chiral aldehydes (eq 15).²⁵These Lewis acid promoted additions

generally proceed with enhanced diastereoselectivity relative to

the reactions of many standard organometallic reagents. The

Felkin-Anh model A⁴has been invoked to account for the facial

For the analogous syn-substituted aldehydes, the stereocontrol

exerted individually by the R- and â-substituents directs

nucleophilic addition to opposite diastereofaces of the carbonyl

moiety. This arrangement of vicinal substituents is identified

as a nonreinforcing relationship.²⁷For example, substitution

of a methyl group for H_bin 1,3-stereoinduction model D

produces transition state K (eq 19). This structure preserves

the configuration at the â-stereocenter that is important for 1,3-

stereoinduction, but the problems inherent with anti-Felkin

(23) Frenking and Reetz have recently postulated that conformational

effects, rather than nonbonded interactions between the nucleophile and

carbonyl substrate, are responsible for a significant portion of the energy

difference between competing transition states involved in 1,2-stereoin-

duction. See ref 5f.

(24) Eurenius, K.; Houk, K. N. J. Am. Chem. Soc. 1994, 116, 9943-

9946.

(26) For related examples: (a) Paterson, I.; Cumming, J. G.; Smith, J.

D.; Ward, R. A. Tetrahedron Lett. 1994, 35, 441-444. (b) Paterson, I.;

McLeod, M. D. Tetrahedron Lett. 1995, 36, 9065-9068. (c) Ward, R. A.;

Smith, J. D.; Cumming, J. G.; Yeung, K.-S. Tetrahedron 1995, 51, 9437-

9466.

(25) Heathcock, C. H.; Flippin, L. A. J. Am. Chem. Soc. 1983, 105,

1667-1668.

Merged 1,2- and 1,3-Asymmetric Induction

J. Am. Chem. Soc., Vol. 118, No. 18, 1996 4327

Table 4.^aLewis Acid Promoted Aldol Reactions of Enolsilanes

with anti-Substituted R-Methyl-â-alkoxy Aldehydes (Eq 18)

Table 5.^aLewis Acid Promoted Aldol Reactions of Enolsilanes

with syn-Substituted R-Methyl-â-Alkoxy Aldehydes (Eq 21)

15:16 (P ) PMB)

17:18 (P ) TBS)

21:22 (P ) PMB)

23:24 (P ) TBS)

entry

R

(yield, %)

entry

R

solvent

(yield, %)

A

B

C

t-Bu

i-Pr

Me

99:01 (94)

98:02 (91)

97:03 (86)

99:01 (91)

95:05^b(93)

71:29 (85)

A

B

C

D

E

F

t-Bu

i-Pr

Me

CH₂Cl₂

toluene

CH₂Cl₂

toluene

CH₂Cl₂

toluene

96:04 (89)

88:12 (75)

56:44 (98)

32:68 (86)

17:83 (82)

06:94 (92)

96:04 (93)

94:06 (81)

87:13 (91)

75:25 (83)

58:42 (93)

40:60 (95)

^aSee footnote a in Table 1. ^bRatio was determined by integration

of the H NMR spectrum of the unpurified reaction mixture.

1

Me

^aSee footnote a in Table 1; toluene was utilized in the indicated

reactions.

addition must be overcome in this transition state. On the other

hand, any potential transition states affording the Felkin

diastereomer, such as transition structure L (eq 20), must

overcome the conformational preferences that dictate â-stereo-

control and favor formation of the 1,3-anti product.²⁸It is clear

from this simple analysis that the direction and degree of syn

aldehyde diastereofacial selectivity cannot readily be predicted

if both R and â stereocontrol elements are significant.

stereochemical trend was observed in the additions to R-un-

substituted aldehydes (Tables 1 and 2). Furthermore, a decrease

in the solvent polarity (CH₂Cl₂f toluene) consistently provides

a greater preponderance of the anti-Felkin diastereomer. The

indicated solvent effects are consistent with the fact that 1,3-

induction, which is based primarily on electrostatic interactions,

is enhanced in nonpolar media relative to 1,2-induction, whose

origins are primarily derived from nonbonded interactions in

this family of substrates. The data in Table 5 illustrate that the

interplay between 1,2- and 1,3-asymmetric induction is influ-

enced by a number of factors, and conventional stereochemical

models cannot be relied upon to accurately assess the facial

bias associated with syn R,â-disubstituted aldehydes in these

processes.

How does one explain the turnover in aldehyde diastereofacial

selectivity from a 96:04 Felkin preference to a 94:06 anti-Felkin

preference based on the size of the enolsilane component? In

the analysis of the stereochemical data for syn aldehyde 19

(Table 5), we conclude that dominant 1,2-stereoinduction will

be found in those reactions proceeding through an antiperipla-

nar transition state, while dominant 1,3-stereoinduction will be

manifest from a synclinal transition state. Furthermore, it is

proposed that the antiperiplanar transition state is favored by

sterically encumbered enolsilane substituents, while the synclinal

transition state is preferred for less bulky enolsilane substituents.

The following discussion is provided to support these statements.

The aldehyde conformations depicted in structures K and L

(eqs 19 and 20) have been incorporated into the Mukaiyama

aldol transition states illustrated in Scheme 1. The weight of

experimental evidence suggests that Mukaiyama aldol reactions

proceed through open transition states²⁹having either synclinal

or antiperiplanar geometries, with no significant preference for

either reactant orientation. By inspection, it is evident that

nonbonded interactions between the enolsilane and the aldehyde

R-substituent (Felkin Control) will be more significant within

the subset of antiperiplanar transition structures. In fact, if

electronic effects were to emerge as the dominant control

element in a given reaction, one might expect this control

element to require a synclinal reactant orientation that minimizes

the impact of 1,2-induction.

Accordingly, a wide range of stereoselectivities are observed

in the BF₃‚OEt₂promoted Mukaiyama aldol additions to syn

substituted aldehydes 19 and 20 (eq 21, Table 5). A particularly

striking feature of these reactions is the dependence of aldehyde

diastereofacial selectivity on the steric requirements of the

enolsilane alkyl substituent (R). For â-OPMB aldehyde 19, a

turnover in carbonyl facial selectivity (Felkin f anti-Felkin) is

observed upon decreasing the size of the enolsilane substituent

R (t-Bu f Me). This reVersal in aldehyde facial induction is

unprecedented and indicates that the â-stereocenter becomes

the dominant control element as the steric demands of the

enolsilane decrease. To our knowledge these are the first

examples of anti-Felkin selective Mukaiyama aldol reactions

under conditions known to preclude chelate organization. The

â-OPMB aldehyde 19 typically affords higher levels of 1,3-

control relative to TBS-protected aldehyde 20, and this same

(27) The terms stereoreinforcing and nonreinforcing are explicitly

distinguished from the related terms matched and mismatched. Stereo-

reinforcing and nonreinforcing refer to the relationship between stereocontrol

elements on the same substrate, and therefore are intramolecular relation-

ships. The terms matched and mismatched are reserved for relationships

between stereocontrol elements on different substrates in double stereo-

differentiating reactions, and are therefore intermolecular relationships.

See: Masamune, S.; Choy, W.; Peterson, J. S.; Sita, L. R. Angew. Chem.,

Int. Ed. Engl. 1985, 24, 1-30.

In the reactions with the pinacolone enolsilane (R ) t-Bu),

synclinal structures M and O are destabilized by the nonbonded

(28) Transition structure L may contribute largely to the formation of

the Felkin/1,3-syn product diastereomer, because alternative structures

generated by 120° rotations about the C_R-C_âbond are destabilized by

nonbonded steric or dipolar interactions.

(29) For early discussions of open transition states: (a) Murata, S.;

Suzuki, M.; Noyori, R. J. Am. Chem. Soc. 1980, 102, 3248-3249. (b)

Yamamoto, Y.; Yatagai, H.; Naruta, Y.; Maruyama, K. J. Am. Chem. Soc.

1980, 102, 7107-7109.

4328 J. Am. Chem. Soc., Vol. 118, No. 18, 1996

EVans et al.

Scheme 1

Support for the Model. Based on the preceding analysis,

the energies of the synclinal transition states relative to their

antiperiplanar counterparts are critically dependent on the

enolsilaneTLewis acid interaction (RTBF₃). By inspection,

the synclinal transition state may be destabilized by an increase

in either the steric bulk of the enolsilane substituent R (Me f

t-Bu) or an increase in the size of the Lewis acid. It then follows

that a more sterically encumbered Lewis acid moiety will

decrease the anti-Felkin preference exhibited by the acetone

enolsilane in addition to aldehyde 19. Indeed, utilization of

the sterically demanding Lewis acid trityl perchlorate³³to

catalyze the addition of the acetone enolsilane to aldehyde 19

resulted in the reversal of facial selectivity relative to the BF₃‚

OEt₂mediated reaction (eq 24).³⁴An 89:11 mixture of products

interaction between the coordinated Lewis acid and tert-butyl

substituent.³⁰The destabilizing interactions in these synclinal

orientations³¹may be alleviated upon reaction through an

antiperiplanar transition state such as N or P. In this subset of

transition states, 1,3-stereoinduction favors reaction through

structure N. However, a consideration of steric interactions

between the enol component and the aldehyde R-stereocenter

in structures N and P leads to the conclusion that Felkin addition

Via antiperiplanar geometry P is favored. We believe that these

steric interactions between the pinacolone enolsilane and the

aldehyde substituents are strong enough to effectively preclude

anti-Felkin addition and override the intrinsic facial bias imposed

on the carbonyl by the â-stereocenter. Therefore, we conclude

that the R-stereogenic center is the dominant control element

in reactions proceeding through antiperiplanar transition states

and addition to the Felkin aldehyde diastereoface is preferred.

As the steric demands of the enolsilane substituent R decrease

(t-Bu f Me), the BF₃TR interaction is attenuated in synclinal

geometries M and O, and these geometries may become

competitive with antiperiplanar structures.³²In the synclinal

transition states nonbonded interactions between the nucleophile

and aldehyde R-stereocenter are significantly reduced, thereby

diminishing the influence of Felkin control. This provides an

opportunity for 1,3-asymmetric induction to play a more

prominent role in dictating the sense of aldehyde facial

selectivity. Synclinal structure M possesses the conformation

at the â-stereocenter that benefits from the electrostatic effects

that govern 1,3-stereoinduction (model K, eq 19). Therefore,

we suggest that in the addition of the acetone enolsilane (R )

Me), 1,3-asymmetric induction is the dominant stereochemical

determinant and reaction through synclinal transition state M

preferentially affords the anti-Felkin diastereomer.

favoring the Felkin diastereomer was observed in the reaction

catalyzed by this large Lewis acid. We postulate that reaction

through a synclinal geometry (M or O) is now disfavored due

to the enhanced nonbonded interaction between the enolsilane

and the trityl moiety (RTCPh₃).³⁵Therefore, we conclude that

Felkin addition through an antiperiplanar transition state

analogous to P is now preferred. These data are also consistent

with Heathcock’s projection that increased steric requirements

in the carbonyl-coordinated Lewis acid provide enhanced Felkin

induction through an altered nucleophile trajectory during the

addition process.^25,36

We have also observed the above stereochemical trends in

the related additions of allystannanes to these R,â-disubstituted

aldehydes under conditions that preclude chelate organization

(eqs 25 and 26).³⁷For example, exclusive formation of the

Felkin product was obtained in the additions of either allyl-

stannane or â-methallylstannane to anti substituted aldehyde

13, regardless of the Lewis acid employed (Table 6). On the

other hand, dominant 1,3-stereoinduction selectively afforded

the anti-Felkin isomer in the analogous BF₃‚OEt₂mediated

additions to syn substituted aldehyde 19 (Table 7, entries A and

B). As in the reaction with the acetone enolsilane, the trityl

perchlorate-catalyzed process reverts the allylation of aldehyde

19 to Felkin control. These results illustrate that the integrated

(33) (a) Mukaiyama, T.; Kobayashi, S.; Murakami, M. Chem. Lett. 1984,

1759-1762. (b) Denmark, S. E.; Chen, C.-T. Tetrahedron Lett. 1994, 35,

4327-4330.

(34) The aldol product was isolated as the corresponding trimethylsilyl

ether. Control experiments indicate that catalysis in this reaction is likely

mediated by Ph₃CClO₄and not by Me₃SiClO₄. For reports addressing the

issue of catalysis by an active trialkylsily species in enolsilane addition

reactions: (a) Carreira, E. M.; Singer, R. A. Tetrahedron Lett. 1994, 35,

4323-4326. (b) Reference 33b. (c) Hollis, T. K.; Bosnich, B. J. Am. Chem.

Soc. 1995, 117, 4570-4581.

(35) (a) Heathcock, C. H.; Walker, M. A. J. Org. Chem. 1991, 56, 5747-

5750. (b) Reference 4e. (c) Heathcock, C. H. Aldrichim. Acta 1990, 23,

99-111. (d) Denmark, S. E.; Weber, E. J. HelV. Chim. Acta 1983, 66,

1655-1660.

(36) For a recent complementary study: Davis, A. P.; Plunkett, S. J. J.

Chem. Soc., Chem. Commun. 1995, 2173-2174.

(30) Heathcock, C. H.; Davidsen, S. K.; Hug, K. T.; Flippin, L. A. J.

Org. Chem. 1986, 51, 3027-3037.

(31) Synclinal transition states Q and R, which orient the enolsilane

substituent (OTMS) syn to the coordinated carbonyl (dO-BF₃), are

energetically disfavored on the basis of electrostatic considerations.

Synclinal structure S is disfavored by the indicated nonbonded interactions.

(a) Denmark, S. E.; Lee, W. J. Org. Chem. 1994, 59, 707-709. (b)

Reference 30. (c) Reference 9b.

(37) For a review of allylmetal addition reactions: (a) Yamamoto, Y.;

Asoa, N. Chem. ReV. 1993, 93, 2207-2293. For recent insight into the

transition state orientation of crotylstannane additions, see: (b) Marshall,

J. A. Chemtracts: Org. Chem. 1992, 75-98. (c) Keck, G. E.; Savin, K.

A.; Cressman, E. N. K.; Abbott, D. E. J. Org. Chem. 1994, 59, 7889-

7896.

(32) Nakamura, E.; Yamago, S.; Machii, D. Tetrahedron Lett. 1988, 29,

2207-2210.

Merged 1,2- and 1,3-Asymmetric Induction

J. Am. Chem. Soc., Vol. 118, No. 18, 1996 4329

Table 6.^aAllylstannane Addition to the anit Aldehyde (Eq 25)

interest to note that this same stereochemical trend is also

manifest in the related addition reactions of allylmetal nucleo-

philes with â-heteroatom-substituted aldehydes (eq 31, Table

10).⁴¹In the representative allylation reactions, the additions

that are mediated by BF₃‚OEt₂(entries A-C) consistently

exhibit higher 1,3-anti stereoselectivity relative to the systems

in which no external Lewis acid is required to induce reactivity

(entries D-G). We speculate that the positively charged

transition states of Lewis acid induced carbonyl addition

reactions of neutral nucleophiles are intrinsically more polar

than their pericyclic metal enolate and allylmetal counterparts.

Electrostatic effects clearly play a significant role in influencing

the stereochemical outcome of both the aldol and allylation

processes, and perhaps this stereocontrol element assumes

greater importance for those reactions proceeding through more

polar open transition states. Of the enolate based aldol reactions,

only the lithium aldol additions displayed moderate levels of

1,3-anti stereoselectivity.

entry

conditions

R

Felkin:anti-Felkin

A

B

C

BF₃‚OEt₂, toluene

Ph₃CClO₄, CH₂Cl₂

Me

H

>99:1

^aSee footnote a in Table 1.

Table 7.^aAllylstannane Addition to the syn Aldehyde (Eq 26)

Table 8.^aAldol Reactions with â-Substituted Aldehydes 1 and 2

(Eq 29)

entry

conditions

R

Felkin:anti-Felkin

A

B

C

BF₃‚OEt₂, toluene

Ph₃CClO₄, CH₂Cl₂

Me

H

20:80

13:87

62:38

^aSee footnote a in Table 1.

R,â-stereoinduction models can be applied to other reactions

which proceed through open transition states in direct analogy

to the Mukaiyama aldol reactions.

3:4 (P ) PMB)

5:6^b(P ) TBS)

entry

metal

(yield, %)

A

B

C

D

TMS/BF₃‚OEt₂

Li

TiCl_n

92:08 (91)

71:29 (99)

60:40 (98)

42:58 (82)

80:20 (84)

76:24 (91)

58:42 (88)

52:48 (79)

The cases examined thus far have all dealt with unsubstituted

nucleophiles, such as allylmetal reagents or enolsilanes derived

from methyl ketones. Based on the preceding analysis, we

predict that substitution at the vinylic center of the nucleophile

should increase steric interactions between the nucleophile and

the R stereocenter of the aldehyde (Felkin control), thus

decreasing the relative influence of 1,3-induction in determining

carbonyl diastereofacial selectivity. However, in the additions

of the vinylic OTBS substituted allystannane to aldehydes 13

and 19, the effect of the â-stereocontrol element was still

significant (eqs 27 and 28).³⁸As anticipated, the addition of

this allystannane to anti substituted aldehyde 13 resulted in

extremely high Felkin selectivity. In contrast, the corresponding

reaction with syn aldehyde 19 exhibited significantly diminished

Felkin control, due to the nonreinforcing stereochemical influ-

ence of the R- and â-substituents.³⁹

9-BBN

^aReactions were carried out in CH₂Cl₂or THF (entry B) at -78

°C. See footnote a in Table 1. ^bRatios were determined by integration

1

of the H NMR spectrum of the unpurified reaction mixtures.

1,3-Asymmetric induction might also play a critical role in

achiral methyl ketone lithium enolate aldol reactions with R,â-

disubstituted aldehydes (eqs 32 and 33).⁴²The lithium aldol

addition reactions with anti substituted aldehydes 13 and 14

(eq 32) afford the expected Felkin diastereomer with modest

levels of selectivity (Table 11). In contrast, the anti-Felkin

diastereomer is the major product in the corresponding additions

to syn substituted aldehydes 19 and 20 (eq 33, Table 12).⁴³It is

tempting to conclude that the â-heteroatom substituent is the

dominant stereocontrol element in this series of reactions;

(38) (a) Evans, D. A.; Coleman, P. J. Unpublished results, Department

of Chemistry, Harvard University. For a related investigation of 1,2- and

1,3-induction with this allylstannane: (b) Keck, G. E.; Abbott, D. E.; Wiley,

M. R. Tetrahedron Lett. 1987, 28, 139-142.

(39) For a related study of merged stereochemical induction in Mu-

kaiyama aldol reactions involving substituted enolsilanes: Evans, D. A.;

Yang, M. G.; Dart, M. J.; Duffy, J. L.; Kim, A. S. J. Am. Chem. Soc. 1995,

117, 9598-9599.

(40) (a) For a review of lithium enolates: Seebach, D. Angew. Chem.,

Int. Ed. Engl. 1988, 27, 1624-1654. (b) The chlorotitanium enolates were

generated by the standard procedure reported by us: Evans, D. A.; Rieger,

D. L.; Bilodeau, M. T.; Urp´ı, F. J. Am. Chem. Soc. 1991, 113, 1047-1049.

Boron enolates: (c) Inoue, T.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 1980,

53, 174-178. (d) Evans, D. A.; Vogel, E.; Nelson, J. V. J. Am. Chem.

Soc. 1970, 101, 6120-6123.

(41) (a) Reetz, M. T.; Jung, A. J. Am. Chem. Soc. 1983, 105, 4833-

4835. (b) Reference 19b.

Metal Enolate Nucleophiles.⁴⁰Of the methyl ketone aldol

reaction variants examined in Tables 8 and 9 (eqs 29 and 30),

the BF₃‚OEt₂promoted enolsilane additions proceed with

enhanced levels of 1,3-anti stereocontrol relative to the corre-

sponding metal enolate mediated bond constructions. It is of

(42) For a systematic investigation of lithium, titanium, and boron aldol

reactions of methyl ketone enolates with complex aldehyde substrates:

Gustin, D. J.; VanNieuwenhze, M. S.; Roush, W. R. Tetrahedron Lett. 1995,

36, 3443-3446.

(43) For related lithium aldol reactions with syn-substituted aldehydes:

Evans, D. A.; Gage, J. R. Tetrahedron Lett. 1990, 33, 6129-6132.

4330 J. Am. Chem. Soc., Vol. 118, No. 18, 1996

EVans et al.

Table 9.^aAldehyde â-Substituent Influence on 1,3-Induction (Eq 30)

8:9 (7a, X ) OPMB)

8:9 (7b, X ) OTBS)

8:9 (7d, X ) Cl)

metal

(yield, %)

TMS/BF₃‚OEt₂

Li

TiCl_n

81:19 (87)

53:47 (94)

58:42 (84)

44:56 (77)

73:27 (90)

61:39 (96)

62:38 (93)

52:48 (82)

83:17 (84)

80:20 (65)

63:37 (75)

27:73 (68)

9-BBN

^aAll reactions were carried out at -78 °C in CH₂Cl₂or THF (Li aldols). See footnote a in Table 1.

Table 10. Allylmetal Additions with â-Substituted

Aldehydes (Eq 31)

Table 12.^aAddition of Lithium Enolates to syn

Aldehydes (Eq 33)

21:22 (P ) PMB)

23:24 (P ) TBS)

entry

R

(yield, %)

A

B

C

t-Bu

i-Pr

Me

11:89 (71)

14:86 (95)

22:78 (73)

08:92 (91)

13:87 (64)

14:86 (88)

^aReactions carried out in THF at -78 °C. See footnote a, Table 1.

tional substrates. Therefore caution must be exercised when

extending stereochemical models based on reactions of simple

substrates to more complex systems.

“Chelation Control.” The principal evidence for â-heteroa-

tom chelate organized carbonyl addition in lithium mediated

aldol addition reactions has been based on product stereochem-

istry.⁴⁵The documentation that â-heteroatom electronic effects

afford the same predicted stereochemical outcome as the

chelation addition model weakens the chelation control argu-

ment. The fact that the â-OTBS substituent^46,47also affords

the 1,3-anti diastereomer (Tables 8 and 9) or anti-Felkin product

isomer (Table 12) with qualitatively similar levels of induction

as the â-OPMB substituted aldehydes further undermines

arguments for chelate organization in these reactions. Finally,

neither kinetic nor stereochemical evidence has been observed

for chelation in the reactions of lithium enolates in THF, even

with R-alkoxy aldehydes.⁴⁸We thus conclude that chelate

organization in these addition reactions is unlikely.

Table 11.^aAddition of Lithium Enolates to anti

Aldehydes (Eq 32)

15:16 (P ) PMB)

17:18 (P ) TBS)

entry

R

(yield, %)

A

B

C

t-Bu

i-Pr

Me

67:33 (64)

72:28 (94)

84:16 (78)

58:42 (89)

65:35^b(99)

63:37 (94)

^aReactions carried out in THF at -78 °C. See footnote a, Table 1.

^bRatio was determined by integration of the ¹H NMR spectrum of the

unpurified reaction mixture.

(44) (a) Evans, D. A.; Ratz, A. M.; Huff, B. E.; Sheppard, G. S. J. Am.

Chem. Soc. 1995, 117, 3348-3467. (b) Evans, D. A.; DiMare, M. J. Am.

Chem. Soc. 1986, 108, 2476-2478. (c) Fukaiyama, T.; Akasaka, K.;

Karanewsky, D. S.; Wang, C.-L. J.; Schmid, G.; Kishi, Y. J. Am. Chem.

Soc. 1979, 101, 262-263. (d) Collum, D. B.; McDonald, J. H., III; Still,

W. C. J. Am. Chem. Soc. 1980, 102, 2120-2121. (e) Patel, P. V.;

VanMiddlesworth, F.; Donauber, J.; Gannett, P.; Sih, C. J. J. Am. Chem.

Soc. 1986, 108, 4603-4614.

however, the modest levels of induction observed with the

R-unsubstituted aldehyde substrates (eq 29, Table 8) suggest

that this control element is large. Further work in this area is

warranted. It should also be noted that the propensity for anti-

Felkin selectivity in the lithium enolate aldol reactions with syn

substituted aldehydes (Table 12) is not observed in the more

complex aldol bond constructions that have been reported in

the syntheses of lonomycin A and monensin.⁴⁴As the data

reported in this manuscript illustrate, the stereogenic center

proximal to the bond construction is not always the dominant

stereochemical determinant governing carbonyl facial induction,

and the complete architecture of the substrate should be

considered. This problem can become exceedingly complex

in the stereochemical analyses of reactions involving polyfunc-

(45) Masamune, S.; Ellingboe, J. W.; Choy, W. J. Am. Chem. Soc. 1982,

104, 5526-5528.

(46) (a) Keck, G. E.; Castellino, S. Tetrahedron Lett. 1987, 28, 281-

284. (b) Kahn, S. D.; Keck, G. E.; Hehre, W. J. Tetrahedron Lett. 1987,

28 279-280. (c) Shambayati, S.; Blake, J. F.; Wierschke, S. G.; Jorgensen,

W. L.; Schreiber, S. L. J. Am. Chem. Soc. 1990, 112, 697-703.

(47) Chen, X.;l Hortelano, E. R.; Eliel, E. L.; Frye, S. V. J. Am. Chem.

Soc. 1992, 114, 1778-1784 and references cited therein. Evidence for the

possible participation of an R-TBS ether in bidentate chelate organization

is presented in this paper.

(48) (a) Das, G.; Thornton, E. R. J. Am. Chem. Soc. 1993, 115, 1302-

1312. (b) Heathcock, C. H.; Young, S. D.; Hagen, J. P.; Pirrung, M. C.;

White, C. T.; VanDerveer, D. J. Org. Chem. 1980, 45, 3846-3856.

Merged 1,2- and 1,3-Asymmetric Induction

J. Am. Chem. Soc., Vol. 118, No. 18, 1996 4331

enolsiliane (1.1 equiv) and the aldehyde (1.0 equiv) in CH₂Cl₂at -78

°C. The reaction was stirred for the indicated amount of time, quenched

at -78 °C by addition of an equivalent volume of saturated aqueous

NaHCO₃, and then warmed to ambient temperature. The mixture was

diluted with CH₂Cl₂and washed with saturated aqueous NaHCO₃. The

aqueous washing was extracted once with CH₂Cl₂. The combined

organic layers were dried over anhydrous Na₂SO₄, concentrated in

Vacuo, and purified by silica gel chromatography. Reactions carried

out in toluene were run under otherwise identical reaction conditions.

Therefore, the pertinent results of these experiments may be obtained

from the corresponding tables.

General Procedure for the Aldol Reactions of Lithium Enolates.

The lithium diisopropylamide (LDA) was generated by addition of 1.05

equiv of n-butyllithium (2.5 M solution in hexanes) to a 0.1 M solution

of diisopropylamine (1.1 equiv) in THF at -78 °C. After 10 min, 1.0

equiv of the indicated ketone was added dropwise and the resulting

solution was stirred at -78 °C for 30 min. The aldehyde (0.9 equiv

as a solution in THF) was added dropwise and the solution was stirred

at -78 °C for 2 min. The reaction was quenched at -78 °C by addition

of an equivalent volume of saturated aqueous NH₄Cl, and the mixture

was warmed to ambient temperature. The mixture was diluted with

Et₂O and washed once each with saturated aqueous NH₄Cl and brine.

The aqueous washings were extracted once with Et₂O. The combined

organic layers were dried over anhydrous MgSO₄, concentrated in

Vacuo, and purified by chromatography.

General Procedure for the Aldol Reactions of Chlorotitanium

Enolates. Titanium(IV) chloride (1.1 equiv) was added dropwise to a

0.1 M solution of 1.0 equiv of the ketone in CH₂Cl₂at -78 °C, giving

a yellow mixture. After 2 min, 1.2 equiv of diisopropylethylamine

was added dropwise and the resulting deep red solution was stirred at

-78 °C for 0.5 h. The aldehyde (0.9 equiv, as a solution in CH₂Cl₂)

was added and the solution was stirred at -78 °C for the indicated

amount of time. The reaction was quenched at -78 °C by addition of

an equivalent volume of saturated aqueous NH₄Cl and the mixture was

warmed to ambient temperature. This mixture was diluted with CH₂-

Cl₂and washed once each with H₂O and saturated aqueous NaHCO₃.

The aqueous washings were extracted once with CH₂Cl₂. The combined

organic layers were dried over anhydrous Na₂SO₄, concentrated in

Vacuo, and purified by chromatography.

General Procedure for the Aldol Reactions of 9-Borabicyclo-

[3.3.1]nonyl (9-BBN) Enolates. To a 0.1 M solution of the ketone

(1.0 equiv) in CH₂Cl₂at -78 °C was added 1.1 equiv of 9-borabicyclo-

[3.3.1]nonyl trifluoromethanesulfonate (9-BBN triflate) and 1.2 equiv

of diisopropylethylamine. The resulting solution was stirred at -78

°C for 30 min and then 0.9 equiv of the aldehyde was added (as a

solution in CH₂Cl₂). The solution is stirred at -78 °C for the indicated

amount of time (ca. 1 h) and then quenched with 1:1 (v:v) 0.05 M pH

7 phosphate buffer and diluted with 2:1 (v:v) MeOH. After warming

to 0 °C, 30% aqueous H₂O₂(1 mL/mmol of boron Lewis acid) was

added dropwise. The mixture was stirred at 0 °C for 1 h, then the

volatiles were removed at aspirator pressure. The resulting residue was

dissolved in Et₂O and washed with H₂O and brine. The aqueous

washings were extracted with an additional portion of Et₂O. The

combined organic layers were dried over anhydrous MgSO₄, concen-

trated in Vacuo, and purified by chromatography.

Conclusion

We have provided transition state models that incorporate

the stereochemical impact of both R- and â-substituents of R,â-

disubstituted aldehydes in Mukaiyama aldol addition reactions

and related processes. Merged transition state model J illustrates

the constructive relationship between R- and â-stereoinduction,

and rationalizes the highly stereoregular nature of these pro-

cesses when the R and â substituents are in the anti (stereor-

einforcing) diastereomeric relationship as in aldehydes 13 and

14. In contrast, when the aldehyde substituents are in the syn

diastereomeric relationship, integration of the Felkin-Anh and

1,3-stereoinduction models (K and L) indicates that the facial

bias conferred on the carbonyl from the R- and â-stereocenters

is nonreinforcing. In the Mukaiyama aldol addition reactions

with syn substituted aldehydes 19 and 20 we have proposed

transition state models in which dominant Felkin control is

suggested to occur through antiperiplanar reactant geometries,

whereas dominant 1,3-induction may be achieved in reactions

proceeding through synclinal transition states. Although this

open transition model may be empirical and speculative, the

stereochemical influence of many reaction parameters including

nucleophile, aldehyde, Lewis acid structure, and solvent effects

can all be rationalized. Dominant 1,3-stereoinduction is also

apparent in the reactions of lithium enolates derived from simple

methyl ketones with these aldehydes. The â-heteroatom sub-

stituent can clearly be an important stereochemical determinant

and its stereochemical influence should be considered in

nucleophilic addition reactions to complex aldehyde substrates.

Experimental Section

General Information.⁴⁹Analytical gas-liquid chromatography

(GLC) was performed on a Hewlett-Packard 5880A Series or 5990

Series gas chromatograph with a flame ionization detector and split

mode capillary injection system, using either DB-1701, DB-1, or DX-2

fused silica columns (30 M × 0.32 mm) (J&W Scientific). Hydrogen

was used as the carrier gas at the indicated pressures. For determination

of diastereomeric ratios of thermally unstable aldol adducts by GLC,

a sample of the unpurified product mixture was silylated (1-(trimeth-

ylsilyl)imidazole) or acetylated (acetic anhydride, pyridine) prior to

analysis. All experiments were carried out under a nitrogen atmosphere

in oven or flame-dried glassware. Typically, all non-organometallic

commercially obtained reagents were purified by distillation or recrys-

tallization prior to use. Dichloromethane (CH₂Cl₂), triethylamine,

diisopropylethylamine, and diisopropylamine were distilled from CaH₂

under an inert atmosphere of nitrogen. Diethyl ether (Et₂O) and

tetrahydrofuran (THF) were distilled from potassium/benzophenone

ketyl. Methanol was distilled from Mg(OMe)₂. Dimethyl sulfoxide

was distilled under reduced pressure from calcium hydride and stored

over 4 Å molecular sieves. Isobutyraldehyde was freshly distilled from

anhydrous CaSO₄prior to use. 9-Borabicyclo[3.3.1]nonyl trifluoro-

methanesulfonate^40c,d(9-BBN triflate) and freshly prepared samarium-

(II) iodide⁵⁰were prepared according to literature procedures.

General Strategy for the Stereochemical Proofs of Aldol Addition

Products Derived from â-OPMB Substituted Aldehydes: The

configuration of the newly formed hydroxyl stereogenic center of these

aldol adducts was established by determining its relationship to the

stereocenter(s) originating from the aldehyde precursor. This strategy

relied on intramolecular oxidative formation of the p-methoxyben-

zylidene acetal (PMP), which was accomplished by treatment of the

PMB ether under anhydrous conditions with 2,3-dichloro-5,6-dicy-

anobezoquinone (DDQ).⁵¹Only a single diastereomer was obtained

at the benzylidene acetal stereocenter in all cases. The relative

stereochemistry of the acetal substituents was then ascertained by

analysis of the vicinal proton coupling constants and NOE measure-

ments. Specific stereochemical proof for all compounds, as well as

full characterization of all intermediates, may be found in the supporting

information.

In the following paragraphs, the experimental details for the aldol

reactions are followed by characterization of the aldol adducts.

A

general scheme for the stereochemical proof of aldol adducts is

provided. A specific stereochemical proof for each aldol product is

contained in the accompanying supporting information. General

Procedures for the many reactions that were utilized repetitively in this

investigation are also provided.

General Procedure for the BF₃‚OEt₂Promoted Enolsilane

Addition Reactions (Mukaiyama Aldol Reactions). Boron trifluoride

etherate (1.0 equiv) was added dropwise to a 0.1 M solution of the

(49) For a general discussion of the spectrometers employed and solvent

drying procedures: Evans, D. A.; Gage, J. R.; Leighton, J. L. J. Am. Chem.

Soc. 1992, 114, 9434-9453.

(50) Girard, P.; Namy, J. K.; Kagan, H. B. J. Am. Chem. Soc. 1980,

102, 2693-2698.

(51) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982,

23, 889-892.

4332 J. Am. Chem. Soc., Vol. 118, No. 18, 1996

EVans et al.

two 100-mL portions of CH₂Cl₂. The combined organic extracts were

washed with 100 mL of H₂O and 100 mL of brine, dried over anhydrous

Na₂SO₄, and concentrated in Vacuo. Purification by MPLC (Michel-

Miller column size D, 2% EtOAc in hexane) afforded 3.13 g (83%) of

the silyl protected homoallylic alcohol as a colorless oil. To a solution

of 2.40 g (10.5 mmol) of this olefin and 15 drops of pyridine in 200

mL of CH₂Cl₂and 70 mL of CH₃OH was added ca. 4 mg of sudan III

indicator. The light red solution was cooled to -78 °C and a stream

of ozone was passed through the reaction mixture until the solution

became colorless (ca. 10 min). The solution was purged with O₂, then

7.72 mL (105 mmol) of dimethyl sulfide was added. The mixture was

warmed to ambient temperature and stirred for 8 h. The volatiles were

removed in Vacuo and the residue was dissolved in 250 mL of CH₂Cl₂

and 200 mL of saturated aqueous NaHCO₃. The layers were separated

and the organic extract was washed with 200 mL of brine. The

combined aqueous washings were extracted with 100 mL of CH₂Cl₂.

The combined organic extracts were dried over anhydrous Na₂SO₄and

concentrated in Vacuo. Purification by MPLC (Michel-Miller column

size D, 5% EtOAc in hexane) afforded 1.79 g (74%) of the aldehyde

as a colorless oil: IR (thin film) 2959, 2931, 2888, 2858, 2720, 1728,

General Strategy for the Stereochemical Proofs of Aldol Addition

Products Derived from â-OTBS Substituted Aldehydes. The

configuration of the newly formed hydroxyl stereogenic center of these

aldol adducts was also established by determining its relationship to

the stereocenter(s) originating from the aldehyde precursor. For

example, an anti selective Tischenko reduction⁵²followed by methyl-

ation of the exposed hydroxyl moiety afforded the differentially

protected triol. Selective removal of the silyl and acetate protecting

groups followed by ketalization afforded the 1,3-diol acetonide. The

relative stereochemistry of the dioxane substituents was then ascertained

1

by analysis of the H NMR spectroscopy vicinal coupling constants,

NOE measurements, and ¹³C NMR chemical shift of the acetal carbon.⁵³

1

1472, 1387, 1370, 1254, 1091, 1055, 837, 776 cm^-1; H NMR (400

MHz, CDCl₃) δ 9.78 (dd, 1 H, J ) 3.0 Hz, J ) 2.0 Hz), 4.00 (dt, 1 H,

J ) 7.2 Hz, J ) 4.5 Hz), 2.49 (ddd, 1 H, J ) 15.7 Hz, J ) 7.2 Hz, J

) 3.0 Hz), 2.39 (ddd, 1 H, J ) 15.7 Hz, J ) 4.4 Hz, J ) 2.0 Hz), 1.76

(dseptets, 1 H, J ) 6.8 Hz, J ) 4.7 Hz), 0.87 (d, 3 H, J ) 6.9 Hz),

0.85 (d, 3 H, J ) 6.9 Hz), 0.84 (s, 9 H), 0.04 (s, 3 H), 0.01 (s, 3 H);

¹³C NMR (100 MHz, CDCl₃) δ 202.4, 72.4, 47.2, 34.0, 25.7, 18.5,

18.0, 17.2, -4.6, -4.7. This aldehyde was too unstable to aquire high

resolution mass spectral data.

Enolsilane Addition to Aldehyde 1, Table 1, Entry A. The

following reagents were combined in the amounts indicated according

to the general Mukaiyama aldol procedure: boron trifluoride etherate

(12 µL, 0.10 mmol), the trimethylsilyl enol ether of pinacolone (15

µL, 0.10 mmol), and the aldehyde 1 (24 mg, 0.10 mmol). The reaction

was stirred for 15 min at -78 °C, quenched, and isolated as described

in the general procedure. Silylation and GLC analysis (DB-1701, 215

°C, 10 psi) revealed an 11:89 ratio of diastereomers 4A (t_r) 16.81

min) to 3A (t_r) 18.17 min), respectively. Purification by flash

chromatography (5% EtOAc in hexane) afforded 28 mg (82%) of a

mixture of aldol diastereomers as a colorless oil.

3-[(4-Methoxybenzyl)oxy]-4-methylpentanal (1). To a solution of

1.15 g (10.0 mmol) of 2-methyl-5-hexen-3-ol⁵⁴in 40 mL of Et₂O at 0

°C was added 4.41 g (15.6 mmol) of the p-methoxybenzyl trichloroa-

cidimidate as a solution in 5 mL of Et₂O (5 mL rinse). A catalytic

amount (∼5 drops) of triflic acid was added, and the reaction was stirred

for 1 h at 0 °C. The reaction was quenched with 40 mL of saturated

aqueous NaHCO₃. The organic layer was washed with brine, dried

(MgSO₄), and concentrated in Vacuo. Purification by MPLC (Michel-

Miller size 11 column, 5f50% EtOAc in hexane gradient) afforded

628 mg (27%) of the desired benzyl ether as a yellow oil. To a solution

of 599 mg (2.56 mmol) of the yellow oil and 4 drops of pyridine in

200 mL of CH₂Cl₂and 70 mL of CH₃OH was added ca. 1 mg of sudan

III indicator. The light red solution was cooled to -78 °C and a stream

of ozone was passed through the reaction mixture until the solution

became colorless (∼5 min). The solution was purged with O₂, then

1.88 mL (25.6 mmol) of dimethyl sulfide was added. The mixture

was warmed to ambient temperature and stirred for 7 h. The volatiles

were removed in Vacuo and the residue was diluted with 40 mL of

CH₂Cl₂and washed with saturated aqueous NaHCO₃. The layers were

separated and the organic extract was dried over anhydrous Na₂SO₄

and concentrated in Vacuo to afford 376 mg (66%) of aldehyde 1 as a

colorless oil: IR (neat) 2080, 1724, 1612, 1514, 1486, 1248, 1173,

(5R*,7R*)-7-[(4-Methoxybenzyl)oxy]-5-hydroxy-2,2,8-trimethyl-

3-nonanone (3A). Ir (thin film) 3512, 2968, 2936, 2875, 2837, 1709,

1

1613, 1514, 1470, 1390, 1255, 1030, 840, 775 cm^-1; H NMR (400

MHz, CDCl₃) δ 7.25 (d, 2 H, J ) 8.4 Hz), 6.85 (d, 2 H, J ) 8.8 Hz),

4.52 and 4.42 (AB, 2 H, J ) 10.4 Hz), 4.22 (m, 1 H), 3.78 (s, 3 H),

3.51 (m, 1 H), 2.65 (dd, 1 H, J ) 3.2 and 18 Hz), 2.56 (dd, 1 H, J )

8.4 and 18 Hz), 1.98 (m, 1 H), 1.50 (m, 2 H), 1.09 (s, 9 H), 0.92 (d,

3 H, J ) 6.8 Hz), 0.89 (d, 3 H, J ) 6.8 Hz); ¹³C NMR (100 MHz,

CDCl₃) δ 217.5, 159.2, 130.9, 129.5, 113.8, 80.6, 72.1, 64.9, 55.3, 44.3,

43.7, 36.8, 30.5, 26.3, 18.7, 17.3. Exact mass calcd for C₂₀H₃₂O₄Na:

359.2198. Found: 359.2204 (FAB, MNBA, added NaI).

1

(5S*,7R*)-7-[(4-Methoxybenzyl)oxy]-5-hydroxy-2,2,8-trimethyl-

3-nonanone (4A). IR (thin film) 3512, 2968, 2936, 2875, 2837, 1709,

1083, 1034, 821 cm^-1; H NMR (500 MHz, CDCl₃) δ 9.79 (dd, J )

1.8 Hz, J ) 2.7 Hz, 1 H, HCdO), 7.25 (m, 2 H, ArH), 6.87 (m, 2 H,

ArH), 4.51 (d, J ) 11.0 Hz, 1 H, ArCH), 4.44 (d, J ) 11.0 Hz, 1 H,

ArCH), 3.80 (s, 3 H, ArOCH₃), 3.76 (m, 1 H, PMBOCH), 2.61 (ddd,

J ) 2.7 Hz, J ) 8.3 Hz, J ) 16.3 Hz, 1 H, OdCCHH), 2.48 (ddd, J

) 1.8 Hz, J ) 3.7 Hz, J ) 16.3 Hz, 1 H, OdCCHH), 2.01 (m, 1 H,

CH(CH₃)₂), 0.94 (d, J ) 6.9 Hz, 3 H, CH(CH₃)CH₃), 0.93 (d, J ) 6.8

Hz, 3 H, CH(CH₃)CH₃); ¹³C NMR (125 MHz, CDCl₃) δ 202.0, 159.3,

130.5, 129.3, 113.8, 78.8, 71.4, 55.3, 45.0, 31.0, 18.4, 17.3. Exact

mass calcd for C₁₄H₂₀O₃: 236.1412. Found: 236.1398 (EI).

3-((tert-Butyldimethylsilyl)oxy)-4-methylpentanal (2). To a solu-

tion of 1.99 g (17.4 mmol) of 2-methyl-5-hexen-3-ol and 2.64 mL (22.6

mmol) of 2,6-lutidine in 35 mL of CH₂Cl₂at 0 °C was added 4.80 mL

of tert-butyldimethylsilyl trifluoromethanesulfonate. After 30 min, 100

mL of H₂O was added to quench and the mixture was extracted with

1

1613, 1514, 1470, 1390, 1255, 1030, 840, 775 cm^-1; H NMR (300

MHz, CDCl₃) δ 7.20 (d, 2 H, J ) 8.1 Hz), 6.82 (d, 2 H, J ) 8.4 Hz),

4.50 and 4.33 (AB, 2 H, J ) 11.1 Hz), 4.16 (m, 1 H), 3.75 (s, 3 H),

3.46 (m, 1 H), 2.65 (dd, 1 H, J ) 6.9 and 17.4 Hz), 2.48 (dd, 1 H, J

) 5.1 and 17.4 Hz), 2.03 (m, 1 H), 1.56 (m, 2 H), 1.07 (s, 9 H), 0.87

(d, 3 H, J ) 7.2 Hz), 0.85 (d, 3 H, J ) 7.2 Hz); ¹³C NMR (100 MHz,

CDCl₃) δ 215.9, 159.2, 130.4, 129.4, 113.8, 82.9, 70.6, 67.3, 55.2, 44.2,

43.6, 35.6, 29.4, 26.2, 18.3, 16.6. Exact mass calcd for C₂₀H₃₂O₄Na:

359.2198. Found: 359.2193 (FAB, MNBA, added NaI).

Enolsilane Addition to Aldehyde 1, Table 1, Entry B. The

following reagents were combined in the amounts indicated according

to the general Mukaiyama aldol procedure: boron trifluoride etherate

(37 µL, 0.30 mmol), the trimethylsilyl enol ether of 3-methyl-2-

butanone (52.2 mg, 0.330 mmol), and aldehyde 1 (71 mg, 0.30 mmol).

The reaction was stirred for 10 min at -78 °C, quenched, and isolated

as described in the general procedure, affording 88 mg (91%) of a

mixture of aldol diastereomers as a colorless oil. Silylation and GLC

analysis (DB-1, 200 °C, 10 psi) indicated an 8:92 ratio of 4B (t_r)

6.38 min) to 3B (t_r) 6.81 min), respectively.

(52) Evans, D. A.; Hoveyda, A. H. J. Am. Chem. Soc. 1990, 112, 6447-

6449.

(53) (a) Evans, D. A.; Rieger, D. L.; Gage, J. R. Tetrahedron Lett. 1990,

31, 7099-7100. (b) Rychnovsky, S. D.; Rogers, B.; Yang, G. J. Org. Chem.

1993, 58, 3511-3515.

(54) Hoffman, R. W.; Herold, T. Chem. Ber. 1981, 114, 375-383.

Merged 1,2- and 1,3-Asymmetric Induction

J. Am. Chem. Soc., Vol. 118, No. 18, 1996 4333

Lithium Enolate Addition to Aldehyde 1, Table 8, Entry B. The

following reagents were combined in the amounts indicated according

to the general procedure: butyllithium (119 µL of a 2.52 M solution,

0.300 mmol), diisopropylamine (42 µL, 0.30 mmol), 3-methyl-2-

butanone (32 µL, 0.30 mmol), and the aldehyde 1 (74.4 mg, 0.315

mmol, as a solution in 1 mL of THF). The reaction was quenched

and isolated as described in the general lithium aldol procedure,

affording 96 mg (99%) of a mixture of aldol diastereomers as a colorless

oil. Silylation and GLC analysis (DB-1, 200 °C, 10 psi) indicated a

29:71 ratio of 4B (t_r) 6.38 min) to 3B (t_r) 6.80 min), respectively.

(4R*,6R*)-6-[(4-Methoxybenzyl)oxy]-4-hydroxy-7-methyl-2-oc-

tanone (3C). IR (thin film) 3510, 2961, 2361, 1705, 1514, 1470, 1390,

1255, 1030, 840, 775 cm^-1; ¹H NMR (300 MHz, CDCl₃) δ 7.25 (d, 2

H, J ) 8.4 Hz), 6.85 (d, 2 H, J ) 8.5 Hz), 4.52 and 4.42 (AB, 2 H, J

) 10.8 Hz), 4.25 (m, 1 H), 3.77 (s, 3 H), 3.45 (m, 1 H), 2.54 (d, 2 H,

J ) 6.4 Hz), 2.12 (s, 3 H), 1.98 (m, 1 H), 1.50 (m, 2 H), 0.90 (d, 3 H,

J ) 7.8 Hz), 0.87 (d, 3 H, J ) 7.0 Hz); ¹³C NMR (100 MHz, CDCl₃)

δ 209.5, 159.2, 130.8, 129.5, 113.8, 80.6, 71.9, 64.8, 55.2, 50.5, 36.4,

30.7, 30.4, 18.7, 17.3. Exact mass calcd for C₁₇H₂₆O₄: 294.1831.

Found: 294.1821 (FAB, MNBA, added NaI).

Titanium Enolate Addition to Aldehyde 1, Table 8, Entry C. The

following reagents were combined in the amounts indicated according

to the general procedure; titanium(IV) chloride (36 µL, 0.33 mmol),

isopropyl methyl ketone (32 µL, 0.30 mmol), diisopropylethylamine

(63 µL, 0.36 mmol), and the aldehyde 1 (74.4 mg, 0.315 mmol, as a

solution in 0.5 mL of CH₂Cl₂). The reaction was allowed to proceed

10 min at -78 °C, quenched, and isolated as described in the general

titanium aldol procedure, affording 94 mg (98%) of a colorless oil.

Silylation and GLC analysis (DB-1, 200 °C, 10 psi) indicated a 40:60

ratio of 4B (t_r) 6.39 min) to 3B (t_r) 6.81 min), respectively.

Purification by flash chromatography (5% EtOAc in CH₂Cl₂) afforded

40 mg (41%) of 4B as a colorless oil (>95% diastereomerically pure

Enolsilane Addition to Aldehyde 2, Table 1, Entry A. The

following reagents were combined in the amounts indicated according

to the general Mukaiyama aldol procedure: boron trifluoride etherate

(45 µL, 0.37 mmol), the trimethylsilyl enol ether of acetone (72 mg,

0.55 mmol), and aldehyde 1 (85 mg, 0.37 mmol). The reaction was

stirred for 10 min at -78 °C, quenched, and isolated as described in

the general procedure, affording 84 mg (79%) of a mixture of aldol

diastereomers as a colorless oil. Silylation and GLC analysis (DB-

1701, 155 °C, 10 psi) indicated an 16:84 ratio of 6A (t_r) 14.80 min)

to 5A (t_r) 15.19 min), respectively. Purification by flash chroma-

tography (20% EtOAc in hexane) afforded a sample of product 5A

(g95% diastereomerically pure by ¹H NMR spectroscopy) as a colorless

oil.

1

by H NMR spectroscopy) and 23 mg (24%) of 3B as a colorless oil

1

(>95% diasteromerically pure by H NMR spectroscopy).

(5R*,7R*)-7-[(tert-Butyldimethylsilyl)oxy]-5-hydroxy-2,2,8-tri-

methyl-3-nonanone (5A). IR (thin film) 3512 (br), 2958, 2930, 2857,

9-BBN Enolate Addition to Aldehyde 1, Table 8, Entry D. The

following reagents were combined in the amounts indicated according

to the general procedure: 9-BBN triflate (745 µL of a 0.5 M solution

in hexane, 0.372 mmol), 3-methyl-2-butanone (36 µL, 0.34 mmol),

diisopropylethylamine (71 µL, 0.41 mmol), and the aldehyde 1 (80

mg, 0.34 mmol, as a solution in 0.5 mL of CH₂Cl₂). The reaction was

allowed to proceed 15 min then subjected to the standard isolation

procedure. Silylation and GLC analysis (DB-1, 200 °C, 10 psi)

indicated a 58:42 ratio of 4B (t_r) 6.57 min) to 3B (t_r) 7.01 min),

respectively. Purification by flash chromatography (30% EtOAc in

hexane) afforded 90 mg (82%) of a mixture of the two diastereomers

1

1699, 1412, 1387, 1368, 1252, 1074, 836, 775 cm^-1; H NMR (400

MHz, CDCl₃) δ 4.22 (m, 1 H), 3.77 (q, 1 H, J ) 5.3 Hz), 3.46 (d, 1

H, J ) 2.5 Hz), 2.63 (d, 2 H, J ) 6.6 Hz), 1.82 (m, 1 H), 1.46 (m, 2

H), 1.13 (s, 9 H), 0.89 (s, 9 H), 0.87 (d, 3 H, J ) 7.0 Hz), 0.86 (d, 3

H, J ) 6.9 Hz), 0.09 (s, 3 H), 0.06 (s, 3 H); ¹³C NMR (100 MHz,

CDCl₃) δ 217.1, 74.0, 64.5, 44.3, 44.1, 38.4, 33.4, 26.3, 25.9, 18.7,

18.1, 17.0, -4.5, -4.5. Exact mass calcd for C₁₈H₃₉O₃Si: 331.2668.

Found: 331.2665 (CI, NH₃atmosphere).

Enolsilane Addition to Aldehyde 2, Table 1, Entry B. The

following reagents were combined in the amounts indicated according

to the general silyl enol ether aldol procedure: boron trifluoride etherate

(96 µL, 0.78 mmol), the trimethylsilyl enol ether of 3-methyl-2-

butanone (124 mg, 0.783 mmol), and the aldehyde 2 (180 mg, 0.781

mmol). The reaction was allowed to proceed for 10 min at -78 °C,

quenched, and isolated as described in the general procedure. The

silylated or acetylated diastereomer derivatives were not adequately

resolved by GLC analysis. Therefore, diastereomeric ratios were

determined by integration of the HHOH carbinol methine signals at

4.15 and 4.25 ppm for 6B and 5B, respectively. ¹H NMR spectrum of

the unpurified reaction mixture revealed an 80:20 ratio of 5B:6B.

Purification by MPLC (Michel-Miller column size C, 2.5% EtOAc

in CH₂Cl₂) provided 150 mg (61%) of 5B as a colorless oil (>95%

diastereomerically pure by ¹H NMR spectroscopy), 30 mg (12%) of a

mixture of diastereomers, and 27 mg (11%) of 6B as a colorless oil

1

(58:42 by H NMR spectroscopy).

(5R*,7R*)-7-[(4-Methoxybenzyl)oxy]-5-hydroxy-2,8-dimethyl-3-

nonanone (3B). IR (CHCl₃) 3508 (br), 3007, 2964, 2875, 1701, 1612,

1514, 1466, 1249, 1063, 1036, 907 cm^-1; ¹H NMR (400 MHz, CDCl₃)

δ 7.29 (d, J ) 9.5 Hz, 2 H, ArH), 6.88 (d, J ) 8.6 Hz, 2 H), 4.54 (d,

J ) 10.8 Hz, 1 H), 4.46 (d, J ) 10.8 Hz, 1 H), 4.28 (m, 1 H), 3.80 (s,

3 H), 3.53 (m, 1 H), 3.42 (d, J ) 3.2 Hz, 1 H), 2.58 (m, 3 H), 2.00 (m,

1 H), 1.54 (m, 2 H), 1.09 (d, J ) 6.9 Hz, 3 H), 1.08 (d, J ) 7.0 Hz,

3 H), 0.94 (d, J ) 6.9 Hz, 3 H), 0.91 (d, J ) 6.8 Hz, 3 H); ¹³C NMR

(100 MHz, CDCl₃) δ 215.8, 159.2, 130.9, 129.5, 113.8, 80.7, 72.0,

64.9, 55.3, 47.2, 41.4, 36.7, 30.5, 18.7, 18.0, 17.3. Exact mass calcd

for C₁₉H₃₀O₄Na: 345.2042. Found: 345.2061 (FAB, MNBA, added

NaI).

(5S*,7R*)-7-[(4-Methoxybenzyl)oxy]-5-hydroxy-2,8-dimethyl-3-

nonanone (4B). IR (CHCl₃) 3472 (br), 3008, 2967, 2936, 1705, 1612,

1514, 1466, 1386, 1368, 1303, 1250, 1066, 1036, 824 cm^-1; ¹H NMR

(500 MHz, CDCl₃) δ 7.26 (m, 2 H), 6.86 (m, 2 H), 4.56 (d, J ) 10.9

Hz), 4.37 (d, J ) 10.9 Hz), 4.21 (m, 1 H), 3.80 (d, J ) 1.7 Hz), 3.80

(s, 3 H), 3.52 (m, 1 H), 2.65 (dd, J ) 7.5 Hz, J ) 16.9 Hz), 2.57

(septet, J ) 6.9 Hz, 1 H), 2.49 (dd, J ) 4.8 Hz, J ) 16.9 Hz), 2.09 (m,

1 H), 1.59 (m, 2 H), 1.08 (d, J ) 6.9 Hz, 6 H), 0.92 (d, J ) 6.9 Hz,

3 H), 0.90 (d, J ) 6.9 Hz, 3 H); ¹³C NMR (125 MHz, CDCl₃) δ 214.5,

159.3, 130.4, 129.4, 113.9, 83.0, 70.6, 67.4, 55.2, 47.3, 41.4, 35.6, 29.4,

18.3, 17.9, 16.5. Exact mass calcd for C₁₉H₃₀O₄: 322.2144. Found:

322.2159 (EI).

1

(>95% diastereomerically pure by H NMR spectroscopy).

Lithium Enolate Addition to Aldehyde 2, Table 8, Entry B. The

following reagents were combined in the amounts indicated according

to the general procedure: butyllithium (334 µL, 0.835 mmol) of a 2.50

M solution in hexanes, diisopropylamine (117 µL, 0.835 mmol),

isopropyl methyl ketone (89 µL, 0.80 mmol), and the aldehyde 2 (175

1

mg, 0.759 mmol, as a solution in 0.40 mL of THF). The H NMR

spectrum of the unpurified reaction mixture revealed a 76:24 ratio of

5B:6B. Purification by MPLC (Michel-Miller column size C, 2.5%

EtOAc in CH₂Cl₂) provided 130 mg (62%) of 5B as a colorless oil

(>95% diastereomerically pure by ¹H NMR spectroscopy), 33 mg

(16%) of a mixture of diastereomers, and 28 mg (13%) of 6B as a

colorless oil (>95% diastereomerically pure by ¹H NMR spectroscopy).

Titanium Enolate Addition to Aldehyde 2, Table 8, Entry C. The

following reagents were combined in the amounts indicated according

to the general procedure: titanium(IV) chloride (80 µL, 0.73 mmol),

isopropyl methyl ketone (71 µL, 0.66 mmol), diisopropylethylamine

(138 µL, 0.794 mmol), and the aldehyde 2 (160 mg, 0.694 mmol, as a

solution in 0.30 mL of CH₂Cl₂). The reaction was allowed to proceed

30 min at -78 °C, quenched, and isolated as described in the general

titanium aldol procedure. ¹H NMR spectroscopy of the unpurified

reaction mixture revealed a 58:42 ratio of 5B:6B. Purification by

Enolsilane Addition to Aldehyde 1, Table 1, Entry C. The

following reagents were combined in the amounts indicated according

to the general Mukaiyama aldol procedure: boron trifluoride etherate

(8 µL, 68 µmol), the trimethylsilyl enol ether of acetone (11 µL, 68

µmol), and the aldehyde 1 (16 mg, 68 µmol). The reaction was stirred

for 15 min at -78 °C, quenched, and isolated as described in the general

procedure. Silylation and GLC analysis (DB-1701, 215 °C, 10 psi)

revealed a 91:9 ratio of the diastereomers 3C (t_r) 18.96 min) and 4C

(t_r) 20.75 min), respectively. Purification by flash chromatography

(5% EtOAc in hexane) afforded 18 mg (89%) of a mixture of the aldol

diastereomers as a colorless oil.

4334 J. Am. Chem. Soc., Vol. 118, No. 18, 1996

EVans et al.

MPLC (Michel-Miller column size C, 10% EtOAc in hexane) provided

184 mg (88%) of a mixture of the aldol isomers as a colorless oil.

9-BBN Enolate Addition to Aldehyde 2, Table 8, Entry D. The

following reagents were combined in the amounts indicated according

to the general 9-BBN aldol procedure: 9-BBN triflate (1.46 mL, 0.727

mmol, as a 0.5 M solution in hexanes), 3-methyl-2-butanone (71 µL,

0.66 mmol), diisopropylethylamine (138 µL, 0.794 mmol), and the

aldehyde 2 (160 mg, 0.694 mmol, as a solution in 0.30 mL of CH₂-

Cl₂). The reaction was allowed to proceed 20 min at -78 °C then

subjected to the standard isolation procedure. ¹H NMR spectroscopy

of the unpurified reaction mixture revealed a 52:48 ratio of 5B:6B.

Purification by MPLC (Michel-Miller column size C, 10% EtOAc in

hexane) provided 166 mg (79%) of a mixture of the aldol isomers as

a colorless oil.

Purification by MPLC (Michel-Miller column size C, 60-70% EtOAc

in hexane) provided 1.12 g (81%) of the title compound as a colorless

oil. IR (film) 3476 (br), 3064, 3013, 2940, 1641, 1496, 1454, 1423,

1

1390, 1001, cm^-1; H NMR (500 MHz, CDCl₃) δ 7.30-7.15 (m, 5

H), 4.04 (m, 1 H), 3.90 (br s, 1 H), 3.67 (s, 3 H), 3.18 (s, 3 H), 2.86

(m, 1 H), 3.75-2.62 (m, 3 H), 2.48 (m, 1 H), 1.89 (m, 1 H), 1.74 (m,

1 H); ¹³C NMR (125 MHz, CD₃OD) δ 173.6, 141.9, 128.3, 128.2, 125.6,

67.0, 61.1, 38.1, 31.7. Exact mass calcd for C₁₃H₂₀O₃N: 237.1365.

Found: 237.1358 (EI).

3-[(4-Methoxybenzyl)oxy]-5-phenylpentanal (7a). To a solution

of 300 mg (1.26 mmol) of the alcohol and 464 mg (1.64 mmol) of the

p-methoxybenzyl trichloroacidimidate in 6.3 mL of Et₂O at room

temperature was added 10 µL of trifluoromethanesulfonic acid. After

10 min, the reaction was diluted with 40 mL of saturated aqueous

NaHCO₃and 40 mL of Et₂O. The layers were separated and the organic

extract was washed with 30 mL of saturated aqueous NaHCO₃. The

combine aqueous washings were extracted with 40 mL of Et₂O. The

combine organic extracts were dried over anhydrous MgSO₄and

concentrated in Vacuo. Purification by MPLC (Michel-Miller column

size B, 20f40% EtOAc in hexane) provided 325 mg (72%) of the

desired benzyl ether as a colorless oil. To a solution of 600 mg (1.68

mmol) of the amide in 8 mL of THF at -78 °C was added 1.34 mL

(2.01 mmol) of a 1.5 M solution of DIBAL-H in toluene. After stirring

at -78 °C for 30 min, the solution was transferred into a 1:1 mixture

of Et₂O:1 M aqueous HCl (40 mL at 0 °C). The mixture was allowed

to warm to ambient temperature and stirred for 30 min, and then the

layers were separated. The organic extract was washed with 30 mL

of brine, dried over anhydrous MgSO₄, and concentrated in Vacuo.

Purification by MPLC (Michel-Miller column size B, 30% EtOAc in

hexane) provided 428 mg (85%) of aldehyde 7a as a colorless oil: IR

(thin film) 3061, 3026, 2934, 2836, 1723, 1612, 1586, 1513, 1454,

1302, 1248, 1034, 822, 701 cm^-1; ¹H NMR (400 MHz, CDCl₃) δ 9.79

(t, 1 H, J ) 2.2 Hz), 7.33-7.15 (m, 7 H), 6.92-6.89 (m, 2 H), 4.49 (s,

2 H), 3.98 (m, 1 H), 3.81 (s, 3 H), 2.80-2.57 (m, 4 H), 2.06-1.85 (m,

2 H); ¹³C NMR (100 MHz, CDCl₃) δ 201.3, 159.3, 141.5, 130.1, 129.8,

129.4, 128.4, 128.3, 125.9, 113.8, 73.2, 70.9, 55.2, 48.2, 36.1, 31.3.

3-((tert-Butyldimethylsilyl)oxy)-5-phenylpentanal (7b). To a solu-

tion of 803 mg (3.38 mmol) of the alcohol and 512 µL (4.40 mmol) of

2,6-lutidine in 11 mL of CH₂Cl₂at 0 °C was added 933 µL (4.06 mmol)

of tert-butyldimethylsilyl trifluoromethanesulfonate. After 30 min, 25

mL of H₂O was added to quench and the mixture was extracted with

two 25-mL portions of CH₂Cl₂. The combined organic extracts were

washed with 25 mL of H₂O and 25 mL of brine, dried over anhydrous

Na₂SO₄, and concentrated in Vacuo. Purification by MPLC (Michel-

Miller column size C, 25% EtOAc in hexane) afforded 1.15 g (96%)

of the protected amide as a colorless oil. To a solution of 781 mg

(2.22 mmol) of the Weinreb amide in 8 mL of THF at -78 °C was

added 1.34 mL (2.44 mmol) of a 1.5 M solution of DIBAL-H in toluene.

After stirring at -78 °C for 30 min, the solution was transferred into

a 1:1 mixture of Et₂O:1 M aqueous HCl (40 mL at 0 °C). The mixture

was allowed to warm to ambient temperature and the layers were

separated. The organic extract was washed with 30 mL of brine, dried

over anhydrous MgSO₄, and concentrated in Vacuo. Purification by

MPLC (Michel-Miller column size B, 10% EtOAc in hexane) provided

428 mg (85%) of aldehyde 7b as a colorless oil: ¹H NMR (400 MHz,

CDCl₃) δ 9.83 (t, 1 H, J ) 2.4 Hz), 7.33-7.26 (m, 2 H), 7.23-7.17

(m, 3 H), 4.27 (m, 1 H), 2.72-2.55 (m, 4 H), 1.91-1.85 (m, 2 H),

0.91 (s, 9 H), 0.10 (s, 3 H), 0.07 (s, 3 H); ¹³C NMR (100 MHz, CDCl₃)

δ 201.9, 141.7, 128.4, 128.3, 125.9, 67.7, 50.7, 39.5, 31.4, 25.9, 18.0,

-4.5, -4.7.

(5R*,7R*)-7-((tert-Butyldimethylsilyl)oxy)-5-hydroxy-2,8-dimethyl-

3-nonanone (5B). IR (thin film) 3510 (br), 2958, 2931, 2895, 2858,

1

1706, 1471, 1386, 1252, 1069, 836, 775 cm^-1; H NMR (400 MHz,

CDCl₃) δ 4.25 (m, 1 H), 3.75 (m, 1 H), 3.43 (br s, 1 H), 2.66-2.54

(m, 3 H), 1.82 (m, 1 H), 1.51-1.43 (m, 2 H), 1.10 (d, 6 H, J ) 7.0

Hz), 0.89 (s, 9 H), 0.87 (d, 6 H, J ) 6.9 Hz), 0.09 (s, 3 H), 0.06 (s, 3

H); ¹³C NMR (125 MHz, CDCl₃) δ 215.5, 74.2, 64.5, 47.6, 41.4, 38.3,

33.3, 25.9, 18.7, 18.1, 17.9, 17.1, -4.5, -4.5. Exact mass calcd for

C₁₇H₃₆O₃SiNa: 339.2331. Found: 339.2337 (FAB, MNBA, added

NaI).

(5S*,7R*)-7-((tert-Butyldimethylsilyl)oxy)-5-hydroxy-2,8-dimethyl-

3-nonanone (6B). IR (thin film) 3504 (br), 2959, 2931, 2872, 2858,

1

1707, 1612, 1471, 1386, 1252, 1050, 1036, 836, 775 cm^-1; H NMR

(500 MHz, CDCl₃) δ 4.15, (m, 1 H), 3.75 (m, 1 H), 3.44 (br s, 1 H),

3.63-2.54 (m, 3 H), 1.80 (dseptets, 1 H, J ) 6.9 Hz, J ) 3.9 Hz),

1.61-1.47 (m, 2 H), 1.09 (d, 6 H, J ) 7.0 Hz), 0.88 (s, 9 H), 0.88 (d,

3 H, J ) 6.8 Hz), 0.81 (d, 3 H, J ) 6.9 Hz), 0.07 (s, 3 H), 0.05 (s, 3

H); ¹³C NMR (125 MHz, CDCl₃) δ 214.9, 75.6, 66.4, 47.2, 41.4, 38.3,

32.8, 25.9, 18.0, 17.9, 17.6, 17.0, -4.3, -4.5. Exact mass calcd for

C₁₇H₃₆O₃SiNa: 339.2331. Found: 339.2337 (FAB, MNBA, added

NaI).

Enolsilane Addition to Aldehyde 2, Table 1, Entry C. The

following reagents were combined in the amounts indicated according

to the general silyl enol ether aldol procedure: boron trifluoride etherate

(107 µL, 0.87 mmol), the trimethylsilyl enol ether of pinacolone (165

mg, 0.955 mmol), and the aldehyde 2 (200 mg, 0.870 mmol). The

reaction was allowed to proceed for 10 min at -78 °C, quenched, and

isolated as described in the general procedure. Silylation and GLC

analysis (DB-1701, 170 °C, 10 psi) revealed a 93:7 ratio of 5C:6C,

respectively. Purification by MPLC (Michel-Miller column size C,

5% EtOAc in hexane) provided 232 mg (81%) of 5C as a colorless oil

(>95% diastereomerically pure by ¹H NMR spectroscopy) and 16 mg

1

(6%) of 6C as a colorless oil (>95% diastereomerically pure by H

NMR spectroscopy).

(4R*,6R*)-6-((tert-Butyldimethylsilyl)oxy)-4-hydroxy-7-methyl-

2-octanone (5C). IR (thin film) 3486 (br), 2957, 2930, 2895, 2857,

1

1712, 1472, 1386, 1361, 1078, 1051, 836, 775 cm^-1; H NMR (400

MHz, CDCl₃) δ 4.26 (m, 1 H), 3.73 (q, 1 H, J ) 5.2 Hz), 3.41 (d, 1

H, J ) 2.5 Hz), 2.57 (m, 2 H), 2.12 (s, 3 H), 1.83 (m, 1 H), 1.46 (m,

2 H), 0.88 (s, 9 H), 0.86 (d, 3 H, J ) 6.9 Hz), 0.85 (d, 3 H, J ) 6.8

Hz), 0.07 (s, 3 H), 0.04 (s, 3 H); ¹³C NMR (100 MHz, CDCl₃) δ 209.3,

74.4, 64.5, 51.0, 38.2, 33.2, 30.7, 25.9, 18.8, 18.0, 17.1, -4.5, -4.5.

Exact mass calcd for C₁₅H₃₃O₃Si: 289.2199. Found: 289.2204 (EI).

Preparation of Aldehydes 7a-7d: 3-Hydroxy-5-phenyl-N-meth-

oxy-N-methylpentanamide. Lithium diisopropylamide (LDA) was

generated by addition of 373 µL (5.82 mmol) of n-butyllithium (1.56

M solution in hexanes) to a solution of 815 µL (5.82 mmol) of

diisopropylamine in 28 mL of THF at -78 °C. After 10 min, a solution

of 600 mg (5.82 mmol) of N-acetyl-N,O-dimethylhydroxylamine in 0.75

mL of THF was added dropwise (0.25 mL THF rinse) and the resulting

solution was stirred at -78 °C for 30 min. Then 845 µL (6.98 mmol)

of isobutyraldehyde was added dropwise and the solution was stirred

at -78 °C for 10 min. The reaction was quenched at -78 °C by the

addition of saturated aqueous NH₄Cl, and the mixture was warmed to

ambient temperature. The mixture was diluted with Et₂O and washed

once each with saturated aqueous NH₄Cl and brine. The aqueous

washings were extracted once with Et₂O. The combined organic layers

were dried over anhydrous MgSO₄and concentrated in Vacuo.

3-Acetoxy-5-phenylpentanal (7c). To a solution of 989 mg (4.17

mmol) of the alcohol, 590 µL (6.25 mmol) of acetic anhydride, and

929 µL (6.67 mmol) of triethylamine in 8 mL of CH₂Cl₂at ambient

temperature was added a catalytic amount (∼5 mg) of dimethylami-

nopyridine. The solution was stirred for 4 h at ambient temperature

then diluted with 50 mL of Et₂O. This was washed with two 30-mL

portions of saturated aqueous NH₄Cl. The organic extract was dried

over Na₂SO₄and concentrated in Vacuo. Purification by MPLC

(Michel-Miller column size B, 50% EtOAc in hexane) provided 1035

mg (97%) of the desired acetate as a colorless oil. To a solution of

780 mg (2.79 mmol) of the Weinreb amide in 28 mL of THF at -78

°C was added 1.86 mL (2.79 mmol) of a 1.5 M solution of DIBAL-H

Merged 1,2- and 1,3-Asymmetric Induction

J. Am. Chem. Soc., Vol. 118, No. 18, 1996 4335

in toluene. After stirring at -78 °C for 15 min, the solution was

transferred into a 1:1 mixture of Et₂O:1 M aqueous HCl (40 mL of 0

°C). The mixture was allowed to warm to ambient temperature and

the layers were separated. The organic extract was washed with 30

mL of brine, dried over anhydrous MgSO₄, and concentrated in Vacuo

to afford 579 mg (94%) of the aldehyde 7c as a colorless oil. The ¹H

NMR spectrum of the unpurified reaction mixture shows only the

desired aldehyde: IR (film) 3027, 2933, 2859, 2735, 1737, 1603, 1496,

1454, 1374, 1240, 1047, 751, 701 cm^-1; ¹H NMR (400 MHz, CDCl₃)

δ 9.70 (dd, 1 H, J ) 2.7 Hz, J ) 1.7 Hz), 7.31-7.15 (m, 5 H), 5.33

(5S*,7S*)-5-Hydroxy-7-[(4-methoxybenzyl)oxy]-2-methyl-9-phen-

yl-3-nonanone (9a). IR (thin film) 3477 (br), 3062, 3026, 2934, 2871,

1707, 1612, 1586, 1514, 1454, 1302, 1249, 1064, 1034, 821, 751, 701

cm^-1; ¹H NMR (400 MHz, CDCl₃) δ 7.32-7.16 (m, 7 H), 6.92-6.86

(m, 2 H), 4.53 (d, 1 H, J ) 14.2 Hz), 4.42 (d, 1 H, J ) 14.2 Hz), 4.32

(m, 1 H), 3.80 (s, 3 H), 3.70 (m, 1 H), 3.66 (br s, 1 H), 2.71-2.48 (m,

5 H), 1.97-1.89 (m, 2 H), 1.83 (m, 1 H), 1.58 (m, 1 H), 1.09 (d, 6 H,

J ) 7.0 Hz); ¹³C NMR (100 MHz, CDCl₃) δ 214.8, 159.2, 142.0, 130.2,

129.5, 128.4, 128.3, 128.1, 125.8, 113.8, 78.0, 70.2, 66.6, 47.0, 41.4,

40.3, 35.2, 31.0, 17.9, 17.9. Exact mass calcd for C₂₄H₃₂O₄Na:

407.2198. Found: 407.2200 (FAB, MNBA, added NaI).

(m, 1 H), 2.74-2.59 (m, 4 H), 2.04-1.86 (m, 2 H), 2.03 (s, 3 H); ¹³

C

Enolsilane Addition to Aldehyde 7b.⁵⁶The following reagents

were combined in the amounts indicated according to the general

Mukaiyama aldol procedure: boron trifluoride etherate (32 µL, 0.26

mmol), the trimethylsilyl enol ether of 3-methyl-2-butanone (45 mg,

0.28 mmol), and aldehyde 7b (75 mg, 0.26 mmol). The reaction was

stirred for 10 min at -78 °C, quenched, and isolated as described in

the general procedure. Silylation and GLC analysis (DB-1701, 200

°C, 15 psi) indicated a 27:73 ratio of 9b (t_r) 17.68 min) to 8b (t_r)

18.04 min), respectively. Purification by MPLC (Michel-Miller

column size B, 5% EtOAc in hexane) afforded 87 mg (90%) of a

mixture of aldol diastereomers. All attempts to separate aldol adducts

8b and 9b were unsuccessful.

NMR (100 MHz, CDCl₃) δ 199.2, 170.4, 140.7, 128.4, 128.2, 125.8,

68.6, 48.0, 35.7, 31.6, 20.8.

3-Chloro-5-phenyl-N-methoxy-N-methylpentanamide. To a solu-

tion of 1.09 g (4.59 mmol) of the â-hydroxyamide in 15.3 mL of a 1:1

solution of MeCN/CCl₄at 0 °C was added 1.57 g (5.97 mmol) of

triphenylphosphine.⁵⁵The colorless solution was stirred at 0 °C for 8

h, then diluted with 40 mL of CH₂Cl₂and washed with 40 mL of H₂O.

The aqueous phase was extracted with 20 mL of CH₂Cl₂. The combined

organic extracts were washed with 40 mL of brine, dried over anhydrous

Na₂SO₄, and concentrated in Vacuo. Purification by MPLC (Michel-

Miller column size C, 25% EtOAc in hexane) provided 973 mg (83%)

of the desired â-chloroamide as a white solid and 146 mg (12%) of

the R,â-unsaturated amide as a colorless oil. Data for the â-chloroa-

mide: IR (CHCl₃) 3065, 3014, 2970, 2940, 1654, 1496, 1454, 1390,

(5R*,7S*)-7-((tert-Butyldimethylsilyl)oxy)-5-hydroxy-2-methyl-9-

phenyl-3-nonanone (8b). IR (thin film) 3505 (br), 3062, 3027, 2953,

2930, 2857, 1706, 1603, 1496, 1471, 1384, 1255, 1069, 1035, 836,

1

994 cm^-1; H NMR (400 MHz, CDCl₃) δ 7.31-7.19 (m, 5 H), 4.41

1

776, 700 cm^-1; H NMR (400 MHz, CDCl₃) δ 7.32-7.24 (m, 2 H),

(m, 1 H), 3.69 (s, 3 H), 3.20 (s, 1 H), 3.08 (m, 1 H), 2.93 (m, 1 H),

2.81-2.70 (m, 2 H), 2.15 (m, 1 H), 2.04 (m, 1 H); ¹³C NMR (100

MHz, CDCl₃) δ 170.5, 140.8, 128.5, 128.5, 126.1, 61.3, 57.7, 40.9,

39.9, 32.7, 32.0. Exact mass calcd for C₁₃H₂₉NO₂Cl: 256.1109.

Found: 256.1098 (EI).

7.21-7.16 (m, 3 H), 4.34 (m, 1 H), 4.05 (m, 1 H), 3.58 (br d, 1 H, J

) 2.3 Hz), 2.71-2.54 (m, 5 H), 1.88 (m, 2 H), 1.63 (m, 2 H), 1.11 (d,

1

6 H, J ) 6.9 Hz), 0.92 (s, 9 H), 0.10 (s, 3 H), 0.08 (s, 3 H); 13C

NMR (100 MHz, CDCl₃) δ 215.2, 142.3, 128.4, 128.3, 125.7, 69.8,

64.5, 55.3, 47.5, 42.0, 41.4, 38.9, 31.5, 31.3, 25.8, 18.0, -4.5, -4.7.

(5S*,7S*)-7-((tert-Butyldimethylsilyl)oxy)-5-hydroxy-2-methyl-9-

phenyl-3-nonanone (9b). ¹H NMR (400 MHz, CDCl₃) δ 7.32-7.25

(m, 2 H), 7.21-7.16 (m, 3 H), 4.19 (m, 1 H), 4.01 (m, 1 H), 3.47 (br

d, 1 H, J ) 2.2 Hz), 2.71-2.54 (m, 5 H), 1.85-1.65 (m, 4 H), 1.11 (d,

3 H, J ) 6.9 Hz), 0.91 (s, 9 H), 0.10 (s, 3 H), 0.09 (s, 3 H).

Enolsilane Addition to Aldehyde 7c.⁵⁶The following reagents were

combined in the amounts indicated according to the general Mukaiyama

aldol procedure: boron trifluoride etherate (34 µL, 0.28 mmol), the

trimethylsilyl enol ether of 3-methyl-2-butanone (53 mg, 0.33 mmol),

and aldehyde 7c (61 mg, 0.28 mmol). The reaction was stirred for 10

min at -78 °C, quenched, and isolated as described in the general

procedure. Analysis by analytical HPLC (Zorbax, 20% EtOAc in

hexane) indicated a 43:57 mixture of 8c:9c, respectively. Purification

by MPLC (Michel-Miller column size B, 40% EtOAc in hexane)

afforded 67 mg (79%) of a mixture of aldol diastereomers. A related

experiment afforded 125 mg of a mixture of aldol diastereomers which

was purified by MPLC (Michel-Miller column size B, 10% EtOAc

in hexane) affording 47 mg (31%) of 8c (diastereomerically pure by

¹H NMR spectroscopy), 48 mg (31%) of a mixture of isomers, and 30

mg (20%) of aldol adduct 9c (diastereomerically pure by ¹H NMR

spectroscopy).

3-Chloro-5-phenylpentanal (7d). To a solution of 256 mg (1.00

mmol) of the Weinreb amide in 5 mL of THF at -78 °C was added

800 µL (1.20 mmol) of a 1.5 M solution of DIBAL-H in toluene. After

stirring at -78 °C for 10 min, the solution was transferred into a 1:1

mixture of Et₂O:1 M aqueous HCl (40 mL at 0 °C). The mixture was

stirred for 10 min at 0 °C then the layers were separated. The organic

extract was washed with 30 mL of brine, dried over anhydrous Na₂-

SO₄, and concentrated in Vacuo to afford 195 mg (99%) of the aldehyde

7d as a light yellow oil. The aldehyde is extremely unstable and must

be used immediately: ¹H NMR (400 MHz, C₆D₆) δ 9.12 (br s, 1 H),

7.22-6.98 (m, 5 H), 3.88 (m, 1 H), 2.70-2.42 (m, 2 H), 2.29 (m, 1

H), 1.90 (m, 1 H), 1.70-1.50 (m, 2 H). This aldehyde was found to

be too unstable for further characterization.

Enolsilane Addition to Aldehyde 7a.⁵⁶The following reagents

were combined in the amounts indicated according to the general

Mukaiyama aldol procedure: boron trifluoride etherate (41 µL, 0.34

mmol), the trimethylsilyl enol ether of 3-methyl-2-butanone (58 mg,

0.37 mmol), and aldehyde 7a (100 mg, 0.335 mmol). The reaction

was stirred for 10 min at -78 °C, quenched, and isolated as described

in the general procedure. Silylation and GLC analysis (DB-1701, 250

°C, 15 psi) indicated a 19:81 ratio of the 1,3-syn adduct (t_r) 14.86

min) to the 1,3-anti isomer (t_r) 15.74 min), respectively. Purification

by MPLC (Michel-Miller column size B, 5% EtOAc in hexane)

afforded 67 mg (52%) of 8a as a colorless oil (>95% diastereomerically

pure by ¹H NMR spectroscopy), 35 mg (27%) of a mixture of

diastereomers, and 10 mg (8%) of 9a as a colorless oil (>95%

(5R*,7S*)-7-Acetoxy-5-hydroxy-2-methyl-9-phenyl-3-nonanone

(8c). IR (thin film) 3505 (br), 3065, 3028, 2971, 2934, 1736, 1712,

1

1604, 1454, 1375, 1247, 1038, 911, 734 cm^-1; H NMR (400 MHz,

CDCl₃) δ 7.30-7.24 (m, 2 H), 7.20-7.13 (m, 3 H), 5.13 (m, 1 H),

4.02 (m, 1 H), 3.37 (br d, 1 H, J ) 3.6 Hz), 2.72-2.48 (m, 5 H), 2.06

(s, 3 H), 2.01-1.81 (m, 2 H), 1.70-1.60 (m, 2 H), 1.11 (d, 3 H, J )

6.9 Hz), 1.09 (d, 3 H, J 6.9 Hz); ¹³C NMR (100 MHz, CDCl₃) δ 214.5,

171.7, 141.3, 128.4, 128.3, 125.9, 71.0, 64.0, 46.7, 41.7, 41.5, 36.5,

31.8, 21.1, 17.9, 17.9. Exact mass calcd for C₁₈H₂₇O₄: 307.1909.

Found: 307.1912 (CI).

(5S*,7S*)-7-Acetoxy-5-hydroxy-2-methyl-9-phenyl-3-nonanone (9c).

IR (thin film) 3496 (br), 3062, 3027, 2969, 2934, 2874, 1734, 1710,

1603, 1454, 1373, 1244, 1030, 701 cm^-1; ¹H NMR (400 MHz, CDCl₃)

δ 7.31-7.25 (m, 2 H), 7.21-7.15 (m, 3 H), 5.05 (m, 1 H), 4.08 (m, 1

H), 3.30 (br d, 1 H, J ) 3.4 Hz), 2.75-2.48 (m, 5 H), 2.03 (s, 3 H,

1

diastereomerically pure by H spectroscopy).

(5R*,7S*)-5-Hydroxy-7-[(4-methoxybenzyl)oxy]-2-methyl-9-phen-

yl-3-nonanone (8a). IR (thin film) 3486 (br), 3061, 3026, 2933, 2871,

1706, 1612, 1586, 1513, 1465, 1302, 1249, 1068, 1035, 822, 734, 700

cm^-1; ¹H NMR (400 MHz, CDCl₃) δ 7.32-7.24 (m, 4 H), 7.21-7.16

(m, 3 H), 6.90-6.86 (m, 2 H), 4.53 (d, 1 H, J ) 10.9 Hz), 4.46 (d, 1

H, J ) 10.9 Hz), 4.32 (m, 1 H), 3.80 (s, 3 H), 3.75 (m, 1 H), 3.44 (br

s, 1 H), 2.71-2.51 (m, 5 H), 2.01-1.82 (m, 2 H, PhCH₂CH₂), 1.76-

1.58 (m, 2 H), 1.11 (d, 3 H, J ) 6.9 Hz), 1.10 (d, 3 H, J ) 6.9 Hz);

¹³C NMR (100 MHz, CDCl₃) δ 215.5, 159.3, 142.2, 130.5, 129.6, 128.4,

128.3, 128.3, 125.8, 113.8, 75.3, 71.2, 64.9, 55.3, 47.1, 40.5, 35.8, 31.4,

18.0, 18.0. Exact mass calcd for C₂₄H₃₂O₄Na: 407.2198. Found:

407.2192 (FAB, MNBA, added NaI).

(56) Standard procedures were utilized for the metal enolate mediated

aldol addition reactions with this aldehyde substrate. The diastereomeric

ratios and isolated yields for the combined mixtures of isomers are contained

in Table 9.

(55) For a review of this transformation: Appel, R. Angew. Chem., Int.

Ed. Engl. 1975, 14, 801-811.

4336 J. Am. Chem. Soc., Vol. 118, No. 18, 1996

EVans et al.

1

CH₃CdO), 1.98-1.85 (m, 3 H), 1.64 (m, 1 H), 1.09 (d, 6 H, J ) 6.9

Hz); ¹³C NMR (100 MHz, CDCl₃) δ 215.8, 170.9, 141.4, 128.4, 128.3,

125.9, 71.3, 65.1, 46.1, 41.4, 40.7, 36.1, 31.7, 21.2, 18.0, 17.9. Exact

mass calcd for C₁₈H₂₇O₄: 307.1909. Found: 307.1908 (CI).

925 cm^-1; H NMR (400 MHz, CDCl₃) δ 9.73 (dd, 1 H, J ) 1.1 Hz,

J ) 3.0 Hz), 5.75 (dd, 1 H, J ) 10.8 Hz, J ) 17.5 Hz), 4.98 (dd, 2 H,

J ) 10.7 Hz, J ) 16.2 Hz), 2.54 (dd, 1 H, J ) 2.5 Hz, J ) 16.1 Hz),

2.09 (ddd, 1 H, J ) 3.1 Hz, J ) 10.2 Hz, J ) 16.5 Hz), 1.99 (m, 1 H),

0.99 (s, 3 H), 0.96 (s, 3 H), 0.90 (d, 3 H, J ) 6.7 Hz); ¹³C NMR (100

MHz, CDCl₃) δ 203.0, 146.9, 111.9, 47.1, 39.1, 36.4, 24.8, 22.7, 15.2.

Exact mass calcd for C₉H₁₆O: 140.1201. Found: 140.1203 (EI).

Enolsilane Addition to Aldehyde 10. The following reagents were

combined in the amounts indicated according to the general Mukaiyama

aldol procedure: the aldehyde 10 (67 mg, 0.48 mmol), the trimethylsilyl

enol ether of 2-methyl-3-pentanone (84 mg, 0.53 mmol), and BF₃‚-

OEt₂(59 µL, 0.48 mmol). After 10 min at -78 °C, the reaction was

quenched and the products isolated as described in the general

procedure, yielding 96.0 mg (88%) of the mixture of aldol diastereomers

as a clear oil. ¹H NMR spectroscopy indicated the absence of starting

materials or impurities, only the aldol products 11:12 in a 58:42 ratio,

respectively. Purification of 54 mg of a related mixture by flash

chromatography (30% Et₂O in hexane) afforded 10.5 mg of diastere-

Enolsilane Addition to Aldehyde 7d.⁵⁶The following reagents

were combined in the amounts indicated according to the general

Mukaiyama aldol procedure: boron trifluoride etherate (41 µL, 0.34

mmol), the trimethylsilyl enol ether of 3-methyl-2-butanone (58 mg,

0.37 mmol), and the freshly prepared aldehyde 7d (100 mg, 0.335

mmol). The reaction was stirred for 10 min at -78 °C, quenched, and

isolated as described in the general procedure. Silylation and GC/MS

analysis (DB-1701, 220 °C, 15 psi) indicated a 17:83 ratio of 9d (t_r)

7.38 min) to 8d (t_r) 8.70 min), respectively. Purification by MPLC

(Michel-Miller column size B, 20% EtOAc in hexane) afforded 78

mg (84%) of a mixture of an inseparable mixture of aldol diastereomers

as a colorless oil.

(5S*,7S*)-7-Chloro-5-hydroxy-2-methyl-9-phenyl-3-nonanone (8d).

IR (thin film) 3472 (br), 3062, 3027, 2969, 2933, 2874, 1706, 1603,

1

1496, 1454, 1384, 1288, 1257, 1095, 1030, 836, 750, 700 cm^-1; H

omer 11 (diastereomerically pure by H NMR spectroscopy) and 5.0

mg of diastereomer 12 (diastereomerically pure by ¹H NMR spectros-

copy).

NMR (400 MHz, CDCl₃) δ 7.32-7.26 (m, 2 H), 7.23-7.17 (m, 3 H),

4.37 (m, 1 H), 4.24 (m, 1 H), 3.31 (br d, 1 H, J ) 2.5 Hz), 2.91 (m,

1 H), 2.75 (m, 1 H), 3.69-2.51 (m, 3 H), 2.07-1.97 (m, 2 H), 1.86

(m, 2 H), 1.69 (m, 1 H), 1.11 (d, 6 H, J ) 7.0 Hz); ¹³C NMR (100

MHz, CDCl₃) δ 215.7, 141.0, 128.4, 128.4, 126.0, 64.7, 59.6, 46.5,

45.1, 41.4, 40.8, 32.7, 18.0, 17.9.

(5R*,7R*)-5-Hydroxy-7,8,8-trimethyl-9-decen-3-one (11). IR

(CHCl₃) 3556 (br), 2972, 2938, 2977, 1700, 1467, 1386, 1302, 1094,

1

1040, 1007 cm^-1; H NMR (500 MHz, CDCl₃) δ 5.78 (dd, 1 H, J )

10.9 Hz, J ) 17.5 Hz), 4.93 (dd, 2 H, J ) 10.8 Hz, J ) 15.3 Hz), 4.08

(m, 1 H), 3.03 (dd, 1 H, J ) 1.3 Hz, J ) 3.5 Hz), 2.59 (m, 3 H), 1.63

(m, 2 H), 1.11 (d, 3 H), 1.10 (d, 3 H, J ) 7.0 Hz), 0.96 (s, 3 H), 0.94

(s, 3 H), 0.87 (d, 3 H, J ) 7.1 Hz); ¹³C NMR (125 MHz, CDCl₃) δ

216.2, 147.9, 110.8, 65.5, 47.6, 41.4, 39.3, 38.6, 37.3, 24.6, 23.1, 18.0,

18.0, 13.9. Exact mass calcd for C₁₄H₂₆O₂Na: 249.1830. Found:

249.1837 (FAB, MNBA, added NaI).

(5R*,7S*)-7-Chloro-5-hydroxy-2-methyl-9-phenyl-3-nonanone (9d).

¹H NMR (400 MHz, CDCl₃) δ 7.32-7.26 (m, 2 H), 7.23-7.17 (m, 3

H), 4.24 (m, 1 H), 4.06 (m, 1 H), 3.29 (br s, 1 H), 2.91 (m, 1 H), 2.75

(m, 1 H), 2.69-2.51 (m, 3 H), 2.20-2.02 (m, 2 H), 1.85 (m, 2 H),

1.69 (m, 1 H), 1.10 (d, 6 H, J ) 6.9 Hz); ¹³C NMR (100 MHz, CDCl₃)

δ 215.7, 141.0, 128.4, 128.4, 126.0, 65.2, 59.4, 45.8, 44.6, 40.8, 39.4,

32.5, 17.9, 17.9.

(5S*,7R*)-5-Hydroxy-7,8,8-trimethyl-9-decen-3-one (12). IR

(CHCl₃) 3542 (br), 3083, 2972, 2936, 2247, 1700, 1467, 1386, 1299,

1097, 1048, 1007 cm^-1; ¹H NMR (500 MHz, CDCl₃) δ 5.73 (dd, 1 H,

J ) 10.8 Hz, J ) 17.4 Hz), 4.94 (dd, 1 H, J ) 1.4 Hz, J ) 12.2 Hz),

4.91 (dd, 1 H, J ) 1.4 Hz, J ) 17.5 Hz), 4.02 (m, 1 H), 2.67 (dd, 1 H,

J ) 2.3 Hz, J ) 17.7 Hz), 2.59 (sept, 1 H, 6.9 Hz), 2.44 (dd, 1 H, J

) 9.3 Hz, J ) 17.7 Hz), 1.55 (m, 1 H), 1.23 (m, 2 H), 1.10 (d, 6 H,

3,4,4-Trimethyl-5-hexenal (10). To a solution of 2.85 g (13.5

mmol) of 3-methyl-2-butene phenylsulfone in 100 mL of THF at -78

°C was added 9.46 mL (13.5 mmol) of a 1.43 M solution of

sec-butyllithium. After 10 min at -78 °C, (E)-crotonaldehyde (2.24

mL, 27.1 mmol) was added and the solution was warmed to 0 °C.

After 20 min at 0 °C, the reaction was quenched by the addition of 25

mL of saturated aqueous NaHCO₃. The mixture was diluted with 300

mL of ether, and the organic layer was washed with brine, dried

(MgSO₄), and concentrated in Vacuo, affording a yellow oil. Purifica-

tion by flash chromatography (30% EtOAc in hexane) afforded 3.29 g

(87%) of the pure 5-hydroxy-2-methyl-4-(phenylsulfonyl)-2,6-octadiene

J ) 6.9 Hz), 0.94 (s, 3 H), 0.92 (s, 3 H), 0.88 (d, 3 H, J ) 6.3 Hz); ¹³

C

NMR (125 MHz, CDCl₃) δ 216.3, 147.6, 111.2, 67.6, 46.0, 41.5, 39.6,

39.3, 38.7, 24.5, 23.0, 18.0, 18.0, 15.2. Exact mass calcd for C₁₄H₂₆O₂-

Na: 249.1830. Found: 249.1839 (FAB, MNBA, added NaI).

(2R,3R)-2,4-Dimethyl-3-[(4-methoxybenzyl)oxy]pentanal (13). To

a solution of titanium(IV) chloride (5.08 mL, 46.3 mmol) in 250 mL

of CH₂Cl₂at 0 °C was added 4.59 mL (15.4 mmol) of titanium(IV)

isopropoxide. After 5 min, 12.0 g (51.4 mmol) of the propionyl (4R)-

oxazolidinone (as a solution in 50 mL of CH₂Cl₂) was added, resulting

in a yellow solution with a white precipitate. After 5 min, 10.8 mL

(61.7 mmol) of diisopropylethylamine was added and the resulting deep

red enolate solution was stirred at 0 °C for 1 h. In a separate flask,

freshly distilled isobutyraldehyde (9.34 mL, 103 mmol) was added to

a solution of diethylaluminum chloride (69.0 mL of a 25.4% solution

in THF, 129 mmol) in 100 mL of CH₂Cl₂at -78 °C. After 15 min

the enolate solution was cooled to -78 °C and the aldehyde solution

was added Via cannula, rinsing with two 10-mL portions of CH₂Cl₂.

After 1.5 h the reaction was quenched at -78 °C by addition of 30

mL of saturated aqueous NH₄Cl (gas evolution). The mixture was

slowly warmed to ambient temperature with the addition of an additional

1 L of saturated aqueous NH₄Cl. After stirring 2 h at ambient

temperature the aluminum salts were dissolved by the addition of 120

mL of 3 M aqueous HCl. The aqueous layer was extracted with two

additional 50-mL portions of CH₂Cl₂. The combined organic layers

were washed with 300 mL of saturated aqueous NaHCO₃, dried (Na₂-

SO₄), and concentrated in Vacuo HPLC analysis (DuPont Zorbax, 30%

EtOAc in hexane) of the unpurified mixture indicated 10% of unreacted

propionyl oxazolidinone (t_f) 3.55 min), and a 71:29 mixture of the

2S,3S-diastereomer (t_r) 4.17 min) and the minor 2S,3R-diastereomer

(t_r) 5.00 min), respectively. Purification by flash chromatography

(15% EtOAc in hexane) afforded 1.05 g (9%) of the propionyl

oxazolidinone, 9.13 g (58%) of the 2S,3S-diastereomer as a white

crystalline solid (g97% diastereomerically pure by ¹H NMR spectros-

copy), and 4.00 g (25%) of the 2S,3R-diastereomer as a white crystalline

1

as a 3:1 mixture of diastereomers by H NMR spectroscopy. This

material was reduced according to the procedure of Inomata and co-

workers.⁵⁷Thus the allylic phenylsulfone (3.650 g, 13.0 mmol) was

dissolved in 150 mL of THF and cooled to -23 °C. To this solution

was added 32.5 mL (65.1 mmol) of a 2.0 M solution of LiBH₄. After

15 min at -23 °C, a cooled (-23 °C) solution of 914 mg (1.3 mmol)

of palladium dichloride bis(triphenylphosphine) in 65 mL was added

and the solution was stirred at -23 °C for 24 h. An additional 914

mg (1.3 mmol) of palladium dichloride bis(triphenylphosphine) was

added and the solution was stirred an additional 24 h at -23 °C. The

reaction was then quenched at -23 °C with 15 mL of MeOH, then 20

mL of saturated aqueous NH₄Cl. The mixture was warmed to ambient

temperature and diluted with 150 mL of ether. The organic layer was

washed with saturated aqueous NaHCO₃and brine, dried, and concen-

trated in Vacuo. Purification by flash chromatography afforded 1.29 g

(71%) of 5-hydroxy-2-methyl-2,6-octadiene as a colorless oil. This

material was dissolved in 10 mL of THF and added Via cannula to a

suspension of 553 mg (13.8 mmol) of KH and 4.50 g (18.4 mmol) of

18-crown-6 in 150 mL of THF at ambient temperature. The suspension

was then heated to 50 °C for 13 h, cooled to 0 °C, and quenched by

the dropwise addition of 10 mL of saturated aqueous NH₄Cl. The

mixture was diluted with 50 mL of ether, washed sequentially with

150 mL of saturated aqueous NH₄Cl, saturated aqueous NaHCO₃, and

brine, dried (MgSO₄), and concentrated in Vacuo. Purification by flash

chromatography afforded 768 mg (60%) of the aldehyde as a colorless

oil: IR (CHCl₃) 3084, 2970, 1721, 1639, 1602, 1463, 1415, 1377, 1007,

(57) Inomata, K.; Igarashi, S.; Mohri, M.; Yamamoto, T.; Kinoshita, H.;

Kotake, H. Chem. Lett. 1987, 707-710.

Merged 1,2- and 1,3-Asymmetric Induction

J. Am. Chem. Soc., Vol. 118, No. 18, 1996 4337

solid. To a solution of 8.32 g (27.3 mmol) of the anti substituted

(2S,3S)-â-hydroxyimide and 1.16 mL (27.3 mmol) of MeOH in 91 mL

of THF at 0 °C was slowly added 13.6 mL (27.3 mmol) of a 2.0 M

solution of LiBH₄in THF (gas evolution). After being stirred for 1 h

at 0 °C the reaction mixture was quenched by the addition of 125 mL

of 1.0 M aqueous sodium potassium tartrate and stirred for an additional

20 min. The mixture was then diluted with 200 mL of CH₂Cl₂and

100 mL of 1.0 M aqueous sodium potassium tartrate. The layers were

separated and the aqueous layer was extracted with two 100-mL portions

of CH₂Cl₂. The combined organic extracts were washed with 200 mL

of brine, dried over anhydrous Na₂SO₄, and concentrated in Vacuo. This

provided 8.25 g of a mixture of the chiral auxiliary and the desired

diol as a white solid. To a solution of this white solid and 5.96 g

(32.7 mmol) of the dimethylacetal of anisaldehyde in 110 mL of CH₂-

Cl₂at ambient temperature was added 5 mg (catalytic amount) of

p-toluenesulfonic acid. After 2 h the reaction was diluted with 150

mL of CH₂Cl₂and 150 mL of saturated aqueous NaHCO₃. The layers

were separated and the aqueous phase was extracted with two 100-mL

portions of CH₂Cl₂. The combined organic extracts were washed with

200 mL of brine, dried over anhydrous Na₂SO₄,a nd concentrated in

Vacuo. The white solid was purified by MPLC (Michel-Miller column

size D, 10% EtOAc in hexane) to provide 5.42 g (79%) of the

benzylidene acetal as a colorless oil. To a solution of 3.15 g (12.6

mmol) of the benzylidene acetal in 63.0 mL of CH₂Cl₂at 0 °C was

added 21.0 mL (31.5 mmol) of a 1.5 M solution of DIBAL-H in toluene.

After 1 h the solution was transferred by cannula into a rapidly stirring

mixture of 200 mL of 1:1 CH₂Cl₂:1 N aqueous HCl at 0 °C. The

mixture was stirred for 30 min at ambient temperature then the layers

were separated. The aqueous phase was extracted with two 75-mL

portions of CH₂Cl₂. The combined organic extracts were washed with

100 mL of brine, dried over anhydrous Na₂SO₄, and concentrated in

Vacuo to afford 3.15 g (99%) of the 3-benzyl alcohol as a colorless

oil. To a solution of 105 µL (1.20 mmol) of oxalyl chloride in 4.5 mL

of CH₂Cl₂at -78 °C was added 170 µL (2.4 mmol) of DMSO (gas

evolution). After 10 min, a solution of 252 mg (1.00 mmol) of the

alcohol in 0.50 mL of CH₂Cl₂was added. The cloudy white mixture

was stirred for 15 min then 697 µL (5.00 mmol) of triethylamine was

added. The reaction was stirred at -78 °C for 40 min then quenched

by the addition of 5 mL of saturated aqueous NH₄Cl. The mixture

was allowed to warm to ambient temperature then diluted with 30 mL

of CH₂Cl₂and 30 mL of saturated aqueous NH₄Cl. The layers were

separated and the aqueous phase was extracted with two 15-mL portions

of CH₂Cl₂. The combined organic extracts were washed with 30 mL

of brine, dried over anhydrous Na₂SO₄, and concentrated in Vacuo. ¹H

NMR spectroscopy of the unpurified aldehyde was very clean.

Purification by MPLC (Michel-Miller column size B, 15% EtOAc in

hexane) provided 239 mg (95%) of aldehyde 13 as a colorless oil:

[R]²_D²-44.9° (c 1.32, CHCl₃); IR (thin film) 2964, 2936, 2875, 2836,

2724, 1723, 1613, 1586, 1514, 1465, 1386, 1302, 1249, 1037, 823,

silyl-protected aldol adduct was added Via cannula, as a solution in 10

mL of THF. After 15 min at 0 °C, the reaction was quenched by the

slow addition of 50 mL of H₂O. The organic layer was extracted, and

the aqueous layer was washed with an additional 30 mL of Et₂O. The

combined organic layers were washed wtih brine, dried (MgSO₄), and

concentrated in Vacuo. Purification by flash chromatography (10%

EtOAc in hexane) afforded 10.89 g (92%) of the pure thioester as a

colorless oil. The column was flushed (33% EtOAc in CH₂Cl₂)

affording 3.74 g (87%) of the recovered oxazolidinone. To a solution

of 6.74 g (22.1 mmol) of the thioester in 240 mL of acetone at ambient

temperature was added 3.50 g (3.30 mmol) of 10% palladium on carbon.

To this well-stirred mixture was slowly added 5.30 mL (33.2 mmol)

of triethylsilane (gas evolution). After 10 min, an additional 5.30 mL

of triethylsilane was added. After 45 min the reaction mixture was

filtered through Celite and concentrated in Vacuo. The residue was

purified by flash chromatography (50% CH₂Cl₂in hexane) affording

5.19 g (96%) of the aldehyde ent-4 as a colorless liquid; [R]²_D¹+35.7°

(c 0.61, CHCl₃); IR (CHCl₃) 2959, 2858, 1719, 1472, 1389, 1258, 1038,

1

838 cm^-1; H NMR (400 MHz, CDCl₃) δ 9.78 (d, J ) 2.5 Hz, 1 H,

HCdO), 3.67 (dd, J ) 4.1 Hz, J ) 5.0 Hz, 1 H, TBSOCH), 2.53 (m,

1 H, CHCdO), 1.84 (m, 1 H, CH(CH₃)₂), 1.10 (d, J ) 7.1 Hz, 3 H,

CH(CH₃)CdO), 0.92 (d, J ) 6.8 Hz, 3 H, CH(CH₃)CH₃), 0.90 (d, J )

6.9 Hz, 3 H, CH(CH₃)CH₃), 0.89 (s, 9 H, SIC(CH₃)₃), 0.07 (s, 3 H,

SiCH₃), 0.06 (s, 3 H, SiCH₃); ¹³C NMR (100 MHz, CDCl₃) δ 205.1,

79.2, 49.9, 32.9, 25.9, 18.8, 18.2, 12.0, -4.1, -4.3. This material

proved too unstable to obtain a high resolution mass spectral analysis.

Enolsilane Addition to Aldehyde 13, Table 4, Entry A. The

following reagents were combined in the amounts indicated according

to the general enolsilane addition procedure: boron trifluoride etherate

(38 µL, 0.32 mmol), pinacolone trimethylsilyl enol ether (50 µL, 0.32

mmol), and aldehyde 13 (80 mg, 0.32 mmol). The reaction was allowed

to proceed for 15 min at -78 °C, quenched, and isolated as described

in the general procedure. Silylation and GLC analysis (DB-1701, 215

°C, 10 psi) indicated the presence of a single isomer 15A (t_r) 14.21

min). Purification by flash chromatography (10% EtOAc in hexane)

provided 105 mg (94%) of 15A as a colorless oil.

Lithium Enolate Addition to Aldehyde 13, Table 11, Entry A.

The following reagents were combined the the amounts indicated

according to the general procedure: butyllithium (28 µL of a 1.45 M

solution, 0.40 mmol), diisopropylamine (56 µL, 0.40 mmol), pinacolone

(50 µL, 0.40 mmol), and the aldehyde 13 (100 mg, 0.40 mmol, as a

solution in THF). The reaction was allowed to proceed at -78 °C for

2 min, quenched, and isolated as described in the general lithium aldol

procedure. Silylation and GLC analysis (DB-1701, 215 °C, 10 psi)

indicated a 67:33 ratio of 15A (t_r) 14.21 min) to 16A (t_r) 12.29

min), respectively. Purification by flash chromatography (10% EtOAc

in hexane) provided 90 mg (64%) of a mixture of aldol diastereomers

as a colorless oil.

(5R,6S,7R)-7-[(4-Methoxybenzyl)oxy]-5-hydroxy-2,2,6,8-tetram-

1

756 cm^-1; H NMR (500 MHz, CDCl₃) δ 9.78 (d, 1 H, J ) 2.2 Hz),

ethyl-3-nonanone (15A). [R]²³-12.3° (c 1.5, CH₂Cl₂); IR (CH₂-

D

1

Cl₂) 3508 (br), 2968, 1700, 1614, 1515, 1465, 1249, 1035 cm^-1; H

7.26-7.23 (m, 2 H), 6.89-6.86 (m, 2 H), 4.50 (AB, 2 H, J_AB) 10.8

Hz, ∆ν ) 20.4 Hz, CH₂Ar), 3.80 (s, 3 H), 3.40 (t, 1 H, J ) 5.6 Hz),

2.67 (ddd, 1 H, J ) 7.3 Hz, J ) 5.6 Hz, J ) 2.2 Hz), 1.94 (octet, 1 H,

J ) 6.8 Hz), 1.11 (d, 3 H, J ) 7.0 Hz), 0.99 (d, 3 H, J ) 6.7 Hz), 0.94

(d, 3 H); ¹³C NMR (125 MHz, CDCl₃) δ 204.6, 159.3, 130.5, 129.2,

113.8, 85.7, 73.8, 55.2, 48.9, 30.9, 19.5, 17.8, 11.4. Exact mass calcd

for C₁₅H₂₂O₃Na: 273.1467. Found 273.1452 (FAB, MNBA, added

NaI).

NMR (400 MHz, CDCl₃) δ 7.25 (d, 2 H, J ) 8.7 Hz), 6.83 (d, 2 H, J

) 8.4 Hz), 4.57 and 4.53 (AB, 2 H, J ) 11.1 Hz), 4.47 (m, 1 H), 3.77

(s, 3 H), 3.50 (d, 2 H, J ) 1.2 Hz), 3.22 (t, 1 H, J ) 6.0 Hz), 2.67 (dd,

1 H, J ) 7.5 Hz, J ) 17.4 Hz), 2.55 (dd, 1 H, J ) 5.1 Hz, J ) 17.4

Hz), 1.99 (m, 1 H), 1.70 (m, 1 H), 1.11 (s, 9 H), 1.00 (d, 3 H, J ) 6.6

Hz), 0.96 (d, 3 H, J ) 6.6 Hz), 0.95 (d, 3 H, J ) 6.9 Hz); ¹³C NMR

(400 MHz, CDCl₃) δ 216.5, 159.3, 129.4, 113.9, 88.7, 75.8, 66.5, 55.3,

44.4, 41.3, 39.3, 30.8, 26.4, 20.3, 17.7, 11.1. Exact mass calcd for

C₂₁H₃₄O₄Na: 373.2355. Found: 373.2352 (FAB, MNBA, added NaI).

(5S,6S,7R)-7-[(4-Methoxybenzyl)oxy]-5-hydroxy-2,2,6,8-tetra-

methyl-3-nonanone (16A). [R]²³_D-40.9° (c 0.75, CH₂Cl₂); IR (CH₂-

(2R,3R)-2,4-Dimethyl-3-((tert-butyldimethylsilyl)oxy)pentanal (14).

To a solution of 7.36 g (24.1 mmol) of the â-hydroxyimide used in

the preparation of 13 in 100 mL of THF at 0 °C was added 3.37 mL

(28.9 mmol) of 2,6-lutidine and 6.09 mL (26.5 mmol) of tert-

butyldimethylsilyl trifluoromethanesulfonate. After 15 min at 0 °C the

reaction was quenched by the addition of 5 mL of MeOH. After an

additional 5 min the reaction was washed with 100 mL of pH 4 aqueous

NaHSO₄and 100 mL of saturated aqueous NaHCO₃. The organic layer

was dried (Na₂SO₄) and concentrated in Vacuo yielding 10.11 g (100%)

of the pure material as a white crystalline solid, which was carried on

without purification. To a solution of 3.21 mL (43.4 mmol) of

ethanethiol in 120 mL of THF at -78 °C was added 13.5 mL (33.7

mmol) of a 2.5 M solution of butyllithium in hexanes. After 10 min

the solution was warmed to 0 °C, and 10.11 g (24.09 mmol) of the

1

Cl₂) 3508 (br), 2969, 1693, 1613, 1514, 1466 cm^-1; H NMR (400

MHz, CDCl₃) δ 7.24 (m, 2 H), 6.85 (m, 2 H), 4.51 and 4.45 (AB, 2 H,

J ) 10.4 Hz), 4.22 (m, 1 H), 3.77 (s, 3 H), 3.11 (t, 1 H, J ) 5.6 Hz),

2.79 (dd, 1 H, J ) 2.4 Hz, J ) 17.6 Hz), 2.54 (dd, 1 H, J ) 9.6 Hz,

J ) 17.6 Hz), 1.95 (m, 1 H), 1.87 (m, 1 H), 1.06 (s, 9 H), 0.98 (d, 3

H, J ) 6.8 Hz), 0.95 (d, 3 H, J ) 6.8 Hz), 0.92 (d, 3 H, J ) 7.2 Hz);

¹³C NMR (400 MHz, CDCl₃) δ 217.8, 159.1, 130.9, 129.1, 113.7, 87.6,

74.6, 68.8, 55.3, 44.4, 40.6, 40.3, 31.1, 26.2, 20.4, 17.8, 13.4. Exact

mass calcd for C₂₁H₃₄O₄Na: 373.2355. Found: 373.2361 (FAB,

MNBA, added NaI).

4338 J. Am. Chem. Soc., Vol. 118, No. 18, 1996

EVans et al.

Enolsilane Addition to Aldehyde 13, Table 4, Entry B. The

following reagents were combined in the amounts indicated according

to the general silyl enol ether aldol procedure: boron trifluoride etherate

(37 µL, 0.30 mmol), the enol ether (52.2 mg, 0.330 mmol), and the

aldehyde 13 (75 mg, 0.30 mmol). The reaction was allowed to proceed

for 30 min at -78 °C, quenched, and isolated as described in the general

Mukaiyama aldol procedure, affording 96 mg (95%) of a colorless oil.

in the general lithium aldol procedure, affording 96 mg (78%) of a

colorless oil. Silylation and GLC analysis (DB-1701, 215 °C, 10 psi)

indicated a 16:84 ratio of 16C (t_r) 11.39 min) and 15C (t_r) 12.54

min), respectively.

(4R,5S,6R)-6-[(4-Methoxybenzyl)oxy]-4-hydroxy-5,7-dimethyl-2-

octanone (15C). [R]²³-6.9° (c 1, CH₂Cl₂); IR (CH₂Cl₂) 3482 (br),

D

2966, 2964, 2361, 1710, 1613, 1514, 1464 cm^-1; ¹H NMR (300 MHz,

CDCl₃) δ 7.27-7.24 (m, 2 H), 6.86-6.84 (m, 2 H), 4.58 and 4.51

(AB, 2 H, J ) 10.2 Hz), 4.46 (m, 1 H), 3.77 (s, 3 H), 3.43 (s, 1 H),

3.19 (t, 1 H, J ) 5.4 Hz), 2.68 (dd, 1 H, J ) 8.7 Hz, J ) 16.5 Hz),

2.39 (dd, 1 H, J ) 4.2 Hz, J ) 16.5 Hz), 2.15 (s, 3 H), 2.00 (m, 1 H),

1.69 (m, 1 H), 0.98 (m, 9 H); ¹³C NMR (400 MHz, CDCl₃) δ 208.8,

159.2, 130.5, 129.4, 113.8, 89.2, 75.7, 66.6, 55.2, 48.4, 38.5, 30.8, 30.7,

20.1, 18.0, 11.4. Exact mass calcd for C₁₈H₂₈O₄Na: 331.1885.

Found: 331.1874 (FAB, MNBA, added Na).

1

The H NMR spectrum of the unpurified reaction mixture indicated

no unreacted starting material, and the pure major diastereomer.

Silylation and GLC analysis (DB-1, 190 °C, 10 psi) indicated a 2:98

ratio of the 5S-diastereomer 16B (t_r) 9.64 min) and the 5R-

diastereomer 15B (t_r) 10.82 min), respectively. Purification of a

related 31:69 mixture of 16B:15B by flash chromatography (8% EtOAc,

32% CH₂Cl₂in hexane) afforded 99 mg (60%) of the 15B as a colorless

oil (>95% diastereomerically pure by ¹H NMR spectroscopy), and 58

mg (31%) of 16B as a colorless oil (>95% diastereomerically pure by

¹H NMR spectroscopy).

Lithium Enolate Addition to Aldehyde 13, Table 11, Entry B.

The following reagents were combined in the amounts indicated

according to the general procedure: methyllithium (210 µL of a 1.43

M solution, 0.300 mmol), diisopropylamine (42 µL, 0.30 mmol),

isopropyl methyl ketone (32 µL, 0.30 mmol), and the aldehyde 13 (79

mg, 0.32 mmol, as a solution in 1 mL of THF). The reaction was

allowed to proceed at -78 °C for 10 min, quenched, and isolated as

described in the general lithium aldol procedure, affording 95 mg (94%)

of a colorless oil. Silylation and GLC analysis (DB-1, 190 °C, 10 psi)

indicated a 28:72 ratio of 16B (t_r) 9.64 min) and 15B (t_r) 10.82

min), respectively.

(5R,6S,7R)-7-[(4-Methoxybenzyl)oxy]-5-hydroxy-2,6,8-trimethyl-

3-nonanone (15B). [R]²³_D1.7° (c 0.72, CHCl₃); IR (CHCl₃) 3476 (br),

2971, 1704, 1613, 1466, 1385, 1302, 1250, 1174, 1036 cm^-1; ¹H NMR

(500 MHz, CDCl₃) δ 7.27 (d, J ) 8.4 Hz, 2 H), 6.86 (d, J ) 8.7 Hz,

2 H), 4.59 (d, J ) 10.4 Hz, 1 H), 4.55 (d, J ) 10.4 Hz, 1 H), 4.50 (m,

1 H), 3.79 (s, 3 H), 3.46 (d, J ) 1.5 Hz, 1 H), 3.21 (t, J ) 5.8 Hz, 1

H), 2.69 (dd, J ) 8.3 Hz, J ) 17.0 Hz, 1 H), 2.60 (sept, J ) 7.0 Hz,

1 H), 2.49 (dd, J ) 4.7 Hz, J ) 17.0 Hz, 1 H), 2.02 (m, 1 H), 1.72 (m,

1 H), 1.09 (d, J ) 7.0 Hz, 6 H), 1.01 (d, J ) 6.9 Hz, 3 H), 0.99 (d, J

) 6.5 Hz, 3 H), 0.98 (d, J ) 6.9 Hz, 3 H); ¹³C NMR (125 MHz, CDCl₃)

δ 214.8, 159.3, 130.7, 129.4, 113.9, 89.0, 75.7, 66.6, 55.3, 45.1, 41.4

38.7, 30.8, 20.2, 18.1, 17.9, 17.9, 11.3. Exact mass calcd for

C₂₀H₃₂O₄: 336.2300. Found: 336.2310 (EI).

Enolsilane Addition to Aldehyde 14, Table 4, Entry A. The

following reagents were combined in the amounts indicated according

to the general procedure: boron trifluoride etherate (48 µL, 0.39 mmol),

pinacolone trimethylsilyl enol ether (93 µL, 0.43 mmol), and the

aldehyde 14 (96 mg, 0.39 mmol). The reaction was allowed to proceed

for 30 min at -78 °C, quenched, and isolated as described in the general

procedure. Acetylation and GLC analysis (DB-1701, 180 °C, 10 psi)

revealed the presence of a single aldol diastereomer (t_r) 14.03 min).

Purification by MPLC (Michel-Miller column size B, 10% EtOAc in

hexane) provided 123 mg (91%) of 17A (>99% pure by GLC analysis)

as a colorless oil.

Lithium Enolate Addition to Aldehyde 14, Table 11, Entry A.

The following reagents were combined in the amounts indicated

according to the general procedure: butyllithium (284 µL of a 2.52 M

solution in hexanes, 0.716 mmol), diisopropylamine (105 µL, 0.722

mmol), pinacolone (85 µL, 0.682 mmol), and the aldehyde 14 (150

mg, 0.614 mmol, as a solution in THF). The reaction was allowed to

proceed at -78 °C for 2 min, quenched, and isolated as described in

the general lithium aldol procedure. Silylation and GLC analysis (DB-

1701, 180 °C, 10 psi) indicated a 58:42 ratio of 17A:18A. Purification

by MPLC (Michel-Miller column size C, 5f10% EtOAc in hexane)

1

afforded 92 mg (44%) of 17A (diastereomerically pure by H NMR

spectroscopy), 64 mg (30%) of a mixture of diastereomers, and 32 mg

(15%) of 18A (diastereomerically pure by ¹H NMR spectroscopy), all

as colorless oils.

(5R,6S,7R)-7-((tert-Butyldimethylsilyl)oxy)-5-hydroxy-2,2,6,8-tet-

ramethyl-3-nonanone (17A). [R]²²_D-1.1° (c 2.10, CH₂Cl₂); IR (film)

3507 (br), 2960, 2858, 1704, 1474, 1387, 1368, 1255, 1052, 836, 774

cm^-1; ¹H NMR (400 MHz, CDCl₃) δ 4.51 (br t, 1 H, J ) 6.4 Hz), 3.52

(d, 1 H, J ) 1.0 Hz), 3.47 (dd, 1 H, J ) 5.8 Hz, J ) 4.3 Hz), 2.64 (dq,

2 H, J ) 17.8 Hz, J ) 7.1 Hz), 1.94 (octet, 1 H, J ) 6.8 Hz), 1.68 (m,

1 H), 1.12 (s, 9 H), 0.96 (d, 3 H, J ) 6.9 Hz), 0.93 (d, 3 H, J ) 6.8

Hz), 0.91 (d, 3 H, J ) 6.4 Hz), 0.89 (s, 9 H), 0.11 (s, 3 H), 0.08 (s, 3

H); ¹³C NMR (100 MHz, CDCl₃) δ 215.9, 82.4, 66.7, 44.3, 41.4, 38.2,

31.8, 26.3, 26.2, 19.7, 18.5, 18.4, 11.6, -3.7, -3.8. Exact mass calcd

for C₁₉H₄₁O₃: 345.2825. Found: 345.2836 (CI, NH₃atmosphere).

(5S,6S,7R)-7-((tert-Butyldimethylsilyl)oxy)-5-hydroxy-2,2,6,8-tet-

(5S,6S,7R)-7-[(4-Methoxybenzyl)oxy]-5-hydroxy-2,6,8-trimethyl-

3-nonanone (16B). [R]²³_D-41.5° (c 1.16, CHCl₃); IR (CHCl₃) 3489

(br), 3011, 2969, 2935, 1710, 1613, 1514, 1466, 1364, 1249, 1036 cm^-1

;

¹H NMR (500 MHz, CDCl₃) δ 7.26 (d, J ) 8.6 Hz, 2 H), 6.87 (d, J )

8.6 Hz, 2 H), 4.54 (d, J ) 10.6 Hz, 1 H), 4.50 (d, J ) 10.6 Hz, 1 H),

4.23 (m, 1 H), 3.80 (s, 3 H), 3.54 (d, J ) 2.3 Hz, 1 H), 3.14 (dd, J )

5.0 Hz, J ) 6.4 Hz, 1 H), 2.69 (dd, J ) 2.5 Hz, J ) 16.9 Hz, 1 H),

2.56 (m, 2 H), 1.93 (m, 2 H), 1.07 (d, J ) 6.9 Hz, 3 H), 1.06 (d, J )

6.9 Hz, 3 H), 1.02 (d, J ) 6.9 Hz, 3 H), 0.96 (d, J ) 6.8 Hz, 3 H),

0.91 (d, J ) 7.1 Hz, 3 H); ¹³C NMR (125 MHz, CDCl₃) δ 215.9, 159.2,

130.8, 129.2, 113.8, 87.9, 74.6, 69.3, 55.2, 44.0, 41.5, 40.8, 31.2, 20.5,

18.0, 17.9, 17.5, 13.7. Exact mass calcd for C₂₀H₃₂O₄Na: 359.2198.

Found: 359.2202 (FAB, MNBA, added NaI).

ramethyl-3-nonanone (18A). [R]²²-44.6° (c 2.80, CH₂Cl₂); IR

D

(film) 3456 (br), 2959, 2931, 2856, 1697, 1472, 1387, 1388, 1367,

Enolsilane Addition to Aldehyde 13, Table 4, Entry C. The

following reagents were combined in the amounts indicated according

to the general procedure: boron trifluoride etherate (20 µL, 0.12 mmol),

acetone trimethylsilyl enol ether (16 µL, 0.12 mmol), and the aldehyde

22 (30 mg, 0.12 mmol). The reaction was allowed to proceed for 15

min at -78 °C, quenched, and isolated as described in the general

procedure. Silylation and GLC analysis (DB-1701, 215 °C, 10 psi)

indicated a 3:97 ratio of anti-Felkin isomer 16C (t_r) 10.23 min) to

the Felkin diastereomer 15C (t_r) 11.28 min), respectively. Purification

by flash chromatography (10% EtOAc in hexane) provided 31 mg

(86%) of 15C as a colorless oil.

Lithium Enolate Addition of Aldehyde 13, Table 11, Entry C.

The following reagents were combined in the amounts indicated

according to the general lithium aldol procedure: butyllithium (280

µL of a 1.45 M solution, 0.400 mmol), diisopropylamine (56 µL, 0.40

mmol), acetone (30 µL, 0.40 mmol), and the aldehyde 13 (100 mg,

0.400 mmol, as a solution in 1 mL of THF). The reaction was allowed

to proceed at -78 °C for 5 min, quenched, and isolated as described

1252, 1052, 836, 774 cm^-1; ¹H NMR (400 MHz, CDCl₃) δ 4.14 (br t,

1 H, J ) 8.1 Hz), 3.51 (t, 1 H, J ) 4.8 Hz), 3.44 (br s, 1 H), 2.75 (dd,

1 H, J ) 17.7 Hz, J ) 2.3 Hz), 2.54 (dd, 1 H, J ) 17.7 Hz, J ) 9.3

Hz), 1.90-1.77 (m, 2 H), 1.14 (s, 9 H), 0.91 (s, 9 H), 0.91 (d, 3 H, J

) 6.4 Hz), 0.88 (d, 3 H, J ) 6.8 Hz), 0.87 (d, 3 H, J ) 7.1 Hz), 0.07

(s, 3 H), 0.06 (s, 3 H); ¹³C NMR (100 MHz, CDCl₃) δ 21.4, 79.5,

68.8, 44.4, 42.1, 40.5, 31.9, 26.4, 26.2, 20.2, 18.3, 18.2, 13.3, -3.9,

-4.1. Exact mass calcd for C₁₉H₄₁O₃: 345.2825. Found: 345.2814

(CI, NH₃

atmosphere).

Enolsilane Addition to Aldehyde 14, Table 4, Entry B. The

following reagents were combined in the amounts indicated according

to the general Mukaiyama aldol procedure: boron trifluoride etherate

(37 µL, 0.30 mmol), isopropyl methyl ketone trimethylsilyl enol ether

(52 mg, 0.33 mmol), and the aldehyde 14 (73 mg, 0.30 mmol). The

reaction was allowed to proceed for 50 min at -78 °C, quenched, and

isolated as described in the general procedure, affording 92 mg (93%)

1

of a colorless oil. The H NMR spectrum of the unpurified reaction

mixture (400 MHz, CDCl₃) indicated the two products 17B and 18B

Merged 1,2- and 1,3-Asymmetric Induction

J. Am. Chem. Soc., Vol. 118, No. 18, 1996 4339

1

in a 95:5 ratio, respectively (determined by integration of the carbinol

protons at 4.54 (17B) and 4.12 ppm (18B). Purification of 101 mg of

a related 47:53 mixture of 17B:18B respectively by flash chromatog-

raphy (2.5% EtOAc, 22.5% CH₂Cl₂in hexane) afforded 23 mg of 17B

as a colorless oil (g96% diastereomerically pure by ¹H NMR

spectroscopy).

2958, 2858, 1713, 1473, 1387, 1361, 1255, 1050, 837, 775 cm^-1; H

NMR (400 MHz, CDCl₃) δ 4.55 (m, 1 H, CHOH), 3.48-3.43 (m, 2

H), 2.70 (A of ABX, 1 H, J_AB) 16.5 Hz, J_AX) 8.4 Hz), 2.40 (B of

ABX, 1 H, J_AB) 16.5 Hz, J_BX) 4.6 Hz), 2.18 (s, 3 H), 1.95 (octet,

1 H, J ) 6.7 Hz), 1.66 (m, 1 H), 0.96 (d, 3 H, J ) 7.2 Hz), 0.94 (d,

3 H, J ) 6.9 Hz), 0.93 (d, 3 H, J ) 6.8 Hz), 0.90 (s, 9 H), 0.12 (s, 3

H), 0.09 (s, 3 H); ¹³C NMR (100 MHz, CDCl₃) δ 208.4, 83.0, 66.9,

48.7, 38.2, 32.1, 30.9, 26.2, 19.6, 19.0, 18.4, 12.0, -3.7, -3.8. Exact

mass calcd for C₁₆H₃₅O₃Si: 303.2355. Found: 303.2352 (CI, NH₃

atmosphere).

Lithium Enolate Addition to Aldehyde 14, Table 11, Entry B.

The following reagents were combined in the amounts indicated

according to the general lithium aldol procedure: butyllithium (119

µL of a 2.52 M solution, 0.300 mmol), diisopropylamine (42 µL, 0.30

mmol), isopropyl methyl ketone (32.1 µL, 0.300 mmol), and the

aldehyde 14 (77 mg, 0.32 mmol, as a solution in 1 mL of THF). The

reaction was allowed to proceed at -78 °C for 2 min, quenched, and

isolated as described in the lithium aldol procedure, affording 98.3 mg

(4S,5S,6R)-6-((tert-Butyldimethylsilyl)oxy)-4-hydroxy-5,7-dimethyl-

2-octanone (18C). [R]²³-17.2° (c 1.25, CH₂Cl₂); IR (film) 3507

D

(br), 2958, 2930, 2858, 1713, 1472, 1388, 1361, 1253, 1053, 836, 773

cm^-1; H NMR (400 MHz, CDCl₃) δ 4.08 (m, 1 H), 3.52 (br s, 1 H),

1

(99%) of a mixture of aldol diastereomers as a colorless oil. The H

3.47 (t, 1 H, J ) 4.9 Hz), 2.66 (A of ABX, 1 H, J_AB) 16.2 Hz, J_AX

) 2.7 Hz), 2.47 (B of ABX, 1 H, J_AB) 16.2 Hz, J_BX) 9.6 Hz), 2.19

(s, 3 H), 1.86-1.74 (m, 2 H), 0.92 (d, 3 H, J ) 6.8 Hz), 0.92 (s, 9 H),

0.88 (d, 3 H, J ) 6.8 Hz), 0.85 (d, 3 H, J ) 7.1 Hz), 0.09 (s, 3 H),

0.08 (s, 3 H); ¹³C NMR (100 MHz, CDCl₃) δ 209.6, 80.7, 68.7, 47.9,

41.6, 32.7, 30.8, 26.1, 19.6, 18.3, 18.0, 14.6, -4.0, -4.2. Exact mass

calcd for C₁₆H₃₅O₃Si: 303.2355. Found: 303.2355 (CI, NH₃atmo-

sphere).

NMR spectrum of the unpurified reaction mixture (400 MHz, CDCl₃)

indicated a 65:35 ratio of 17B:18B.

(5R,6S,7R)-7-((tert-Butyldimethylsilyl)oxy)-5-hydroxy-2,6,8-tri-

methyl-3-nonanone (17B). [R]²³5.2° (c 1.42, CHCl₃); IR (CHCl₃)

D

3463 (br), 2963, 2932, 1705, 1467, 1386, 1256, 1049, 1015, 838 cm^-1

;

¹H NMR (400 MHz, CDCl₃) δ 4.55 (m, 1 H), 3.48 (m, 2 H), 2.71 (dd,

J ) 7.6 Hz, J ) 17.1 Hz, 1 H), 2.62 (sept, J ) 6.9 Hz, 1 H), 2.51 (dd,

J ) 5.3 Hz, J ) 17.1 Hz, 1 H), 1.95 (m, 1 H), 1.69 (m, 1 H), 1.11 (d,

J ) 7.0 Hz, 6 H), 0.97 (d, J ) 6.9 Hz, 3 H), 0.96 (d, J ) 7.1 Hz, 3 H),

0.93 (d, J ) 6.9 Hz, 3 H), 0.91 (s, 9 H), 0.13 (s, 3 H), 0.10 (s, 3 H);

¹³C NMR (100 MHz, CDCl₃) δ 214.4, 82.7, 66.8, 45.2, 41.4, 38.3,

32.0, 26.2, 19.7, 18.7, 18.4, 18.2, 17.9, 11.8, -3.8, -3.8. Exact mass

calcd for C₁₈H₃₈O₃SiNa: 353.2488. Found: 353.2462 (FAB, MNBA,

added NaI).

(2S,3R)-2,4-Dimethyl-3-[(4-methoxybenzyl)oxy]pentanal (19). Di-

n-butylboryl trifluoromethanesulfonate (18.0 g, 16.6 mL, 65.8 mmol)

was added to a solution of 13.93 g (59.80 mmol) of (S)-3-(1-oxo-1-

propyl)-4-(phenylmethyl)-1,3-oxazolidin-2-one in 120 mL of CH₂Cl₂

at such a rate to maintain the internal temperature below +3 °C

(thermocouple thermometer). Triethylamine (7.20 g, 10.0 mL, 71.8

mmol) was then added dropwise (internal temperature below +4 °C).

The resulting yellow solution was cooled to -78 °C and 6.5 mL (5.2

g, 72 mmol) of freshly distilled isobutyraldehyde was added slowly

(internal temperature below -70 °C). After 20 min, the solution was

warmed to 0 °C and stirred at that temperature for 1 h. The reaction

was quenched by addition of 60 mL of pH ) 7 aqueous phosphate

buffer solution and 180 mL of MeOH (internal temperature below +10

°C, bath temperature ) -10 °C). A solution of 120 mL of MeOH

and 60 mL of 30% aqueous H₂O₂was added carefully (internal

temperature below +10 °C) and the resulting solution was stirred at 0

°C for 1 h. The volatiles were removed at aspirator pressure and the

residue was extracted with three 200-mL portions of Et₂O. The

combined organic extracts were washed with 200 mL of saturated

aqueous NaHCO₃and 200 mL of brine. The organic solution was dried

over anhydrous MgSO₄and purified by flash chromatography (40%

EtOAc in hexane) to give 18.03 g (99%) of the syn aldol adduct as a

white solid. To a solution of 9.05 g (29.6 mmol) of this aldol adduct

and 1.27 mL (29.6 mmol) of MeOH in 118 mL of THF at 0 °C was

slowly added 14.8 mL (29.6 mmol) of a 2.0 M solution of LiBH₄in

THF (gas evolution). After the mixture was stirred 45 min at 0 °C the

reaction was quenched by the addition of 150 mL of 1.0 M aqueous

sodium potassium tartrate and stirred for an additional 10 min. The

mixture was then diluted with 300 mL of CH₂Cl₂and 150 mL of 1.0

M aqueous sodium potassium tartrate. The layers were separated and

the aqueous layer was extracted with two 100-mL portions of CH₂Cl₂.

The combined organic extracts were washed with 300 mL of brine,

dried over anhydrous Na₂SO₄, and concentrated in Vacuo. This

provided 9.10 g of a mixture of the chiral auxiliary and the desired

diol as a white solid. To a solution of this white solid and 6.14 g

(32.6 mmol) of the dimethylacetal of anisaldehyde in 120 mL of CH₂-

Cl₂at ambient temperature was added 5 mg (catalytic amount) of

p-toluenesulfonic acid. After 3 h the reaction was diluted with 100

mL of CH₂Cl₂and 200 mL of saturated aqueous NaHCO₃. The layers

were separated and the aqueous phase was extracted with two 100-mL

portions of CH₂Cl₂. The combined organic extracts were washed with

200 mL of brine, dried over anhydrous Na₂SO₄, and concentrated in

Vacuo. The oily white solid was triturated in 40 mL of hexane at 0 °C

for 15 min. The white solid was collected on a Bu¨chner funnel and

washed with 40 mL of cold hexane. This afforded 4.90 g (93%) of

the recovered oxazolidinone. The filtrate was concentrated and then

purified by MPLC (Michel-Miller column size D, 5f10% EtOAc in

hexane gradient) to provide 6.87 g (93%) of the benzylidene acetal as

a white solid. To a solution of 986 mg (3.94 mmol) of the acetal in

19.7 mL of CH₂Cl₂at 0 °C was added 6.56 mL (9.85 mmol) of a 1.5

(5S,6S,7R)-((tert-butyldimethylsilyl)oxy)-5-hydroxy-2,6,8-trimethyl-

3-nonanone (18B). [R]²³_D-27.5° (c 1.23, CHCl₃); IR (CHCl₃) 3501

1

(br), 2961, 2932, 1702, 1468, 1386, 1256, 1212, 1051, 838 cm^-1; H

NMR (400 MHz, CDCl₃) δ 4.13 (m, 1 H), 3.49 (m, 2 H), 2.72 (dd, J

) 2.4 Hz, J ) 16.9 Hz, 1 H), 2.64 (sept, J ) 6.9 Hz, 1 H), 2.51 (dd,

J ) 9.4 Hz, J ) 16.9 Hz, 1 H), 1.83 (m, 2 H), 1.11 (d, J ) 6.9 Hz, 6

H), 0.93 (d, J ) 6.2 Hz, 3 H), 0.92 (s, 9 H), 0.89 (d, J ) 7.3 Hz, 3 H),

0.87 (d, J ) 7.6 Hz, 3 H, CHCH₃), 0.09 (s, 3 H), 0.08 (s, 3 H); ¹³C

NMR (100 MHz, CDCl₃) δ 215.7, 80.1, 69.3, 44.4, 41.9, 41.4, 32.3,

26.1, 19.9, 18.3, 18.1, 18.1, 18.0, 13.9, -3.9, -4.1. Exact mass calcd

for C₁₈H₃₈O₃SiNa: 353.2488. Found: 353.2471 (FAB, MNBA, added

NaI).

Enolsilane Addition to Aldehyde 14, Table 4, Entry C. The

following reagents were combined in the amounts indicated according

to the general enolsilane addition procedure: boron trifluoride etherate

(61 µL, 0.50 mmol), acetone trimethylsilyl enol ether (98 mg, 0.75

mmol), and the aldehyde 14 (122 mg, 0.500 mmol). The reaction was

allowed to proceed for 10 min at -78 °C, quenched, and isolated as

described in the general procedure. Silylation and GLC analysis (DB-

1701, 145 °C, 15 psi) revealed a 29:71 ratio of anti-Felkin isomer 18C

(t_r) 16.91 min) and the Felkin diastereomer 17C (t_r) 17.24 min),

respectively. Purification by MPLC (Michel-Miller column size B,

5% EtOAc in hexane) provided 85 mg (56%) of 17C (>95%

diastereomerically pure by ¹H NMR spectroscopy), 13 mg (10%) of a

mixture of isomers, and 28 mg (19%) of 18C (>95% diastereomerically

1

pure by H NMR spectroscopy).

Lithium Enolate Addition to Aldehyde 14, Table 11, Entry C.

The following reagents were combined in the amounts indicated

according to the general lithium aldol procedure: butyllithium (139

µL of a 2.52 M solution, 0.350 mmol), diisopropylamine (51 µL, 0.37

mmol), acetone (24 µL, 0.33 mmol), and the aldehyde 14 (73 mg, 0.30

mmol, as a solution in 1 mL of THF). The reaction was allowed to

proceed at -78 °C for 5 min, quenched, and isolated as described in

the lithium aldol procedure. Silylation and GLC analysis (DB-1701,

180 °C, 10 psi) revealed a 37:63 ratio of anti-Felkin isomer 18C (t_r)

17.14 min) and the Felkin diastereomer 17C (t_r) 17.49 min),

respectively. Purification by MPLC (Michel-Miller column size B,

5% EtOAc in hexane) provided 44 mg (48%) of 17C (g95%

diastereomerically pure by ¹H NMR spectroscopy), 18 mg (20%) of a

mixture of diastereomers, and 24 mg (26%) of 18C (g95% diastereo-

1

merically pure by H NMR spectroscopy) as colorless oils.

(4R,5S,6R)-6-((tert-Butyldimethylsilyl)oxy)-4-hydroxy-5,7-dimethyl-

2-octanone (17C). [R]²³_D-2.4° (c 1.79, CH₂Cl₂); IR (film) 3500 (br),

4340 J. Am. Chem. Soc., Vol. 118, No. 18, 1996

EVans et al.

M solution of DIBAL-H in toluene. After 45 min the solution was

transferred by cannula into a rapidly stirring mixture of 120 mL of 1:1

CH₂Cl₂:1 N aqueous HCl at 0 °C. The mixture was stirred for 30 min

at ambient temperature then the layers were separated. The aqueous

phase was extracted with two 30-mL portions of CH₂Cl₂. The combined

organic extracts were washed with 60 mL of brine, dried over anhydrous

Na₂SO₄, and concentrated in Vacuo to afford 978 mg (98%) of the

3-benzyloxy alcohol as a colorless oil. To a solution of 166 µL (1.90

mmol) of oxalyl chloride in 7.4 mL of CH₂Cl₂at -78 °C was added

270 µL (3.80 mmol) of DMSO (gas evolution). After 10 min, a solution

of 400 mg (1.59 mmol) of the alcohol in 0.50 mL of CH₂Cl₂was added

forming a cloudy white mixture. This was stirred for 15 min then 1105

µL (9.50 mmol) of triethylamine was added. The reaction was stirred

at -78 °C for 45 min then quenched by the addition of 10 mL of

saturated aqueous NH₄Cl. The mixture was allowed to warm to ambient

temperature then diluted with 30 mL of CH₂Cl₂and 30 mL of saturated

aqueous NH₄Cl. The layers were separated and the aqueous phase was

extracted with two 15-mL portions of CH₂Cl₂. The combined organic

extracts were washed with 30 mL of brine, dried over anhydrous Na₂-

SO₄, and concentrated in Vacuo. ¹H NMR spectroscopy of the

unpurified aldehyde was very clean. Purification by MPLC (Michel-

Miller column size B, 15% EtOAc in hexane) provided 358 mg (90%)

of the aldehyde 19 as a colorless oil: [R]²³_D+56.0° (c 0.58, CH₂Cl₂);

IR (thin film) 2962, 2874, 2837, 2715, 1723, 1613, 1586, 1514, 1466,

1385, 1302, 1249, 1174, 1036, 823 cm^-1; ¹H NMR (500 MHz, CDCl₃)

δ 9.79 (d, 1 H, J ) 1.0 Hz), 7.26-7.21 (m, 2 H), 6.87-6.83 (m, 2 H),

4.41 (s, 2 H), 3.80 (s, 3 H), 3.58 (dd, 1 H, J ) 7.5 Hz, J ) 3.5 Hz),

2.60 (ddd, 1 H, J ) 7.0 Hz, J ) 3.5 Hz, J ) 1.0 Hz), 1.90 (octet, 1 H,

J ) 7.0 Hz), 1.16 (d, 3 H, J ) 7.1 Hz), 1.03 (d, 3 H, J ) 6.7 Hz,

(CH₃)₂CH), 0.94 (d, 3 H, J ) 6.8 Hz); ¹³C NMR (125 MHz, CDCl₃)

δ 204.7, 159.2, 130.4, 129.2, 113.7, 83.3, 73.5, 55.2, 49.2, 31.2, 19.6,

18.9, 8.1. Exact mass calcd for C₁₅H₂₂O₃Na: 273.1467. Found

273.1454 (FAB, MNBA, added NaI).

(400 MHz, CDCl₃) δ 9.79 (d, J ) 0.8 Hz, 1 H), 3.89 (dd, J ) 5.5 Hz,

J ) 3.9 Hz, 1 H), 2.50 (dqd, J ) 7.0 Hz, J ) 3.9 Hz, J ) 0.7 Hz, 1

H), 1.81 (m, 1 H), 1.09 (d, J ) 7.0 Hz, 3 H), 0.92 (d, J ) 6.9 Hz, 3

H), 0.89 (d, J ) 6.8 Hz, 3 H), 0.89 (s, 9 H), 0.08 (s, 3 H), 0.01 (s, 3

H); ¹³C NMR (100 MHz, CDCl₃) δ 204.8, 76.2, 50.4, 32.1, 25.8, 19.6,

18.2, 18.1, 8.4, -4.2, -4.4. This material was too unstable to acquire

a high resolution mass spectral analysis.

Enolsilane Addition to Aldehyde 19, Table 5, Entry A. The

following reagents were combined in the amounts indicated according

to the general procedure: boron trifluoride etherate (100 µL, 0.800

mmol), pinacolone trimethylsilyl enol ether (130 µL, 0.800 mmol), and

the aldehyde 19 (200 mg, 0.800 mmol). The reaction was allowed to

proceed for 15 min at -78 °C, quenched, and isolated as described in

the general procedure. Acylation and GLC analysis (DB-1701, 210

°C, 15 psi) indicated a 4:96 ratio of anti-Felkin isomer 22A (t_r) 21.42

min) and the Felkin diastereomer 21A (t_r) 22.90 min), respectively.

Purification by flash chromatography (10% EtOAc in hexane) provided

250 mg (89%) of the aldol adduct 21A as a colorless oil.

Lithium Enolate Addition to Aldehyde 19, Table 12, Entry A.

The following reagents were combined in the amounts indicated

according to the general procedure: butyllithium (300 µL of a 1.47 M

solution, 0.440 mmol), diisopropylamine (60 µL, 0.44 mmol), pina-

colone (55 µL, 0.44 mmol), and the aldehyde 19 (100 mg, 0.44 mmol,

as a solution in 0.2 mL of THF). The reaction was allowed to proceed

at -78 °C for 2 min, quenched, and isolated as described in the general

lithium aldol procedure. Silylation and GLC analysis (DB-1701, 210

°C, 15 psi) indicated a 11:89 ratio of 21A:22A. Purification by flash

chromatography (10% EtOAc in hexane) provided 140 mg (71%) of a

mixture of aldol adducts as a colorless oil.

(5S,6R,7R)-7-[(4-Methoxybenzyl)oxy]-5-hydroxy-2,2,6,8-tetram-

ethyl-3-octanone (21A). [R]²³-45° (c 1.5, CH₂Cl₂); IR (CH₂Cl₂)

D

1

3508 (br), 2969, 1696, 1514, 1264, 1065, 1034 cm^-1; H NMR (300

MHz, CDCl₃) δ 7.25 (m, 2 H), 6.83 (m, 2 H), 4.58 and 4.46 (AB, 2 H,

J ) 12.9 Hz), 4.15 (m, 1 H), 3.77 (s, 3 H), 3.29 (dd, 1 H, J ) 5.4 Hz,

J ) 7.5 Hz), 3.24 (d, 1 H, J ) 2.4 Hz, OH), 2.63 (m, 2 H), 1.98 (m,

1 H), 1.75 (m, 1 H), 1.10 (s, 9 H), 0.97 (m, 9 H); ¹³C NMR (400 MHz,

CDCl₃) δ 216.7, 160.2, 159.2, 131.1, 129.1, 113.9, 87.0, 73.8, 70.4,

55.3, 44.4, 41.2, 39.6, 30.9, 26.3, 19.8, 18.5, 8.6. Exact mass calcd

for C₂₁H₃₄O₄Na: 373.2355. Found: 373.2364 (FAB, MNBA, added

NaI).

(2S,3R)-2,4-Dimethyl-3-(tert-butylsilyloxy)pentanal (20). To a

suspension of 12.5 g (128 mmol) of N,O-dimethylhydroxylamine

hydrochloride in 66 mL of THF at 0 °C was added 65 mL (130 mmol)

of a 2.0 M solution of trimethylsilane in toluene (gas evolution). The

resulting solution was stirred at ambient temperature for 30 min and

then cooled to -15 °C. A solution of 13.1 g (42.9 mmol) of the

â-hydroxy imide used in the synthesis of aldehyde 19 (Vide supra) in

66 mL of THF was added by cannula and the resulting mixture was

stirred at 0 °C for 2.5 h. This solution was transferred by cannula to

a well-stirred mixture of 330 mL of CH₂Cl₂and 665 mL of 0.5 N

aqueous HCl. After the mixture was stirred at 0 °C for 1 h, the organic

phase was separated. The aqueous phase was extracted with three 200-

mL portions of CH₂Cl₂. The combined organic extracts were dried

over anhydrous MgSO₄and purified by flash chromatography (80%

Et₂O in hexane) to give 7.17 g (88%) of the N-methoxy-N-methyl amide

as a white solid. To a solution of 7.10 g (37.6 mmol) of the â-hydroxy

amide in 38 mL of CH₂Cl₂at ambient temperature were added 5.0 mL

(4.60 g, 43.0 mmol) of 2,6-lutidine and 9.0 mL (10.0 g, 39.0 mmol) of

tert-butyldimethylsilyl trifluoromethanesulfonate. After 15 min, 75 mL

of H₂O was added to quench and the mixture was extracted with 75

mL of Et₂O. The organic extract was washed with 40 mL of H₂O and

40 mL of brine. The combined aqueous washings were extracted with

40 mL of Et₂O. The combined organic extracts were dried over

anhydrous MgSO₄and purified by flash chromatography (10% EtOAc

in hexane, then 25% EtOAc in hexane) to give 11.28 g (99%) of the

silyl ether as a colorless oil. A solution of diisobutylaluminum hydride

in toluene (1.0 M, 33.3 mL, 33.3 mmol) was added to a solution of

5.05 g (16.6 mmol) of the N-methoxy-N-methyl amide in 166 mL of

THF at 0 °C. After 30 min, 24 mL of EtOAc was added carefully to

quench the excess hydride followed by 33 mL of H₂O. This solution

was diluted with 300 mL of Et₂O and 150 mL of H₂O. Enough 1 N

aqueous HCl (200 mL) was added to dissolve the aluminum salts and

the phases were separated. The aqueous phase was extracted with two

100-mL portions of Et₂O. The combined organic extracts were washed

with 200 mL of saturated aqueous NaHCO₃and 200 mL of brine, dried

over anhydrous MgSO₄, and concentrated in Vacuo. Purification by

MPLC (Michel-Miller column size B, CH₂Cl₂) provided 3.50 g (86%)

of the aldehyde 20 as a colorless oil: [R]²⁰_D+60.8° (c 0.365, CHCl₃);

IR (neat) 2960, 1730, 1250, 1100, 1050, 1030, 835, 770 cm^-1; ¹H NMR

(5R,6R,7R)-7-[(4-Methoxybenzyl)oxy]-5-hydroxy-2,2,6,8-tetra-

methyl-3-octanone (22A). [R]²³_D+20.5° (c 1.75, CH₂Cl₂); IR (CH₂-

1

Cl₂) 3508 (br), 2969, 1696, 1514, 1264, 1065, 1034 cm^-1; H NMR

(300 MHz, CDCl₃) δ 7.25 (d, 2 H, J ) 8.4 Hz), 6.83 (d, 2 H, J ) 8.7

Hz), 4.59 and 4.54 (AB, 2 H, J ) 11.1 Hz), 3.91 (m, 1 H), 3.77 (s, 3

H), 3.53 (d, 1 H, J ) 3.5 Hz), 3.49 (dd, 1 H, J ) 1.9 Hz, J ) 8.8 Hz),

2.80 (dd, 1 H, J ) 2.1 Hz, J ) 18 Hz), 2.49 (dd, 1 H, J ) 9.3 Hz, J

) 18 Hz), 1.73 (m, 2 H), 1.11 (s, 9 H), 1.02 (d, 3 H, J ) 6.6 Hz), 0.83

(m, 6 H); ¹³C NMR (400 MHz, CDCl₃) δ 218.3, 158.9, 131.5, 129.1,

113.6, 83.6, 74.2, 69.5, 55.2, 44.5, 41.2, 40.1, 31.2, 26.3, 20.1, 19.5,

9.9. Exact mass calcd for C₂₁H₃₄O₄Na: 373.2355. Found: 373.2357

(FAB, MNBA, added NaI).

Enolsilane Addition to Aldehyde 19, Table 5, Entry C. The

following reagents were combined in the amounts indicated according

to the general procedure: boron trifluoride etherate (50 µL, 0.41 mmol),

isopropyl methyl ketone trimethylsilyl enol ether (71 mg, 0.45 mmol),

and the aldehyde ent-19 (102 mg, 0.407 mmol). The reaction was

allowed to proceed for 30 min at -78 °C, quenched, and isolated as

described in the general Mukaiyama aldol procedure, affording 126

mg (98%) of a colorless oil. The ¹H NMR spectrum of the unpurified

reaction mixture indicated no unreacted starting material, and the two

products in an 55:45 ratio. Silylation and GLC analysis (DB-1, 200

°C, 10 psi) indicated an 56:44 ratio of the 5R-diastereomer ent-21C (t_r

) 7.85 min) and the 5S-diastereomer ent-22C (t_r) 8.06 min),

respectively.

Lithium Enolate Addition to Aldehyde 19, Table 12, Entry B.

The following reagents were combined in the amounts indicated

according to the general procedure: butyllithium (124 µL of a 2.41 M

solution, 0.300 mmol), diisopropylamine (42 µL, 0.30 mmol), isopropyl

methyl ketone (32 µL, 0.30 mmol), and the aldehyde ent-19 (79 mg,

0.32 mmol, as a solution in 1 mL of THF). The reaction was allowed

to proceed at -78 °C for 10 min, quenched, and isolated as described

Merged 1,2- and 1,3-Asymmetric Induction

J. Am. Chem. Soc., Vol. 118, No. 18, 1996 4341

in general lithium aldol procedure, affording 96 mg (95%) of a the

mixture of diastereomeric products as a colorless oil. Silylation and

GLC analysis (DB-1, 200 °C, 10 psi) indicated a 14:86 ratio of ent-

21C:ent-22C, respectively.

J ) 9.3 Hz, J ) 17.4 Hz), 2.14 (s, 3 H), 1.86 (m, 1 H), 1.73 (m, 1 H),

1.02 (d, 3 H, J ) 6.6 Hz), 0.86 (d, 3 H, J ) 7.2 Hz), 0.83 (d, 3 H, J

) 7.5 Hz); ¹³C NMR (400 MHz, CDCl₃) δ 210.4, 160, 131.2, 129.2,

113.7, 83.8, 74.1, 69.5, 55.2, 48.0, 40.1, 30.9, 30.8, 19.9, 19.6, 10.1.

Exact mass calcd for C₁₈H₂₈O₄: 308.1988. Found: 308.2001 (EI).

Enolsilane Addition to Aldehyde 20, Table 5, Entry A. The

following reagents were combined in the amounts indicated according

to the general procedure: boron trifluoride etherate (49 µL, 0.40 mmol),

pinacolone trimethylsilyl enol ether (95 µL, 0.44 mmol), and the

aldehyde 20 (98 mg, 0.40 mmol). The reaction was allowed to proceed

for 30 min at -78 °C, quenched, and isolated as described in the general

procedure. Silylation and GLC analysis (DB-1701, 180 °C, 10 psi)

indicated a 4:96 ratio of anti-Felkin isomer 24A (t_r) 9.95 min) and

the Felkin diastereomer 23A (t_r) 10.34 min), respectively. Purification

by MPLC (Michel-Miller column size B, 5% EtOAc in hexane)

provided 128 mg (93%) of the Felkin adduct 23A (>99% pure by GLC

analysis) as a colorless oil.

(5R,6S,7S)-7-[(4-Methoxybenzyl)oxy]-5-hydroxy-2,6,8-trimethyl-

3-nonanone (ent-21C). [R]²³_D49.5° (c 0.55, CHCl₃); IR (CHCl₃) 3708

(br), 2972, 1702, 1613, 1514, 1466, 1386, 1302, 1249, 1036 cm^-1; ¹H

NMR (500 MHz, CDCl₃) δ 7.28 (m, 2 H), 6.87 (m, 2 H), 4.60 (d, J )

10.6 Hz, 1 H), 4.49 (d, J ) 10.6 Hz, 1 H), 4.20 (m, 1 H), 3.80 (s, 3 H),

3.32 (dd, J ) 4.3 Hz, J ) 6.4 Hz, 1 H), 3.23 (d, J ) 1.9 Hz, 1 H), 2.68

(dd, J ) 8.5 Hz, J ) 17.2 Hz, 1 H), 2.59 (sept, J ) 6.9 Hz, 1 H), 2.55

(dd, J ) 3.9 Hz, J ) 17.2 Hz, 1 H), 2.01 (m, 1 H), 1.74 (m, 1 H), 1.09

(d, J ) 6.9 Hz, 6 H), 1.01 (d, J ) 6.8 Hz, 3 H), 0.98 (d, J ) 7.1 Hz,

3 H), 0.96 (d, J ) 6.9 Hz, 3 H); ¹³C NMR (125 MHz, CDCl₃) δ 215.2,

159.2, 130.8, 129.2, 113.8, 87.3, 73.9, 70.4, 55.3, 44.9, 41.5, 39.4, 30.9,

19.8, 18.6, 18.0, 18.0, 8.3. Exact mass calcd for C₂₀H₃₂O₄Na:

359.2198. Found: 359.2186 (FAB, MNBA, added NaI).

(5S,6S,7S)-7-[(4-Methoxybenzyl)oxy]-5-hydroxy-2,6,8-trimethyl-

Lithium Enolate Addition to Aldehyde 20, Table 12, Entry A.

The following reagents were combined in the amounts indicated

according to the general procedure: butyllithium (292 µL of a 1.60 M

solution, 0.467 mmol), diisopropylamine (69 µL, 0.49 mmol), pina-

colone (56 µL, 0.44 mmol), and the aldehyde 20 (98 mg, 0.40 mmol,

as a solution in THF). The reaction was allowed to proceed at -78

°C for 2 min, quenched, and isolated as described in the general lithium

aldol procedure. Silylation and GLC analysis (DB-1701, 180 °C, 10

psi) indicated a 8:92 ratio of anti-Felkin isomer 24A (t_r) 9.95 min)

and the Felkin diastereomer 23A (t_r) 10.34 min), respectively.

Purification by MPLC (Michel-Miller column size B, 5% EtOAc in

hexane) provided 119 mg (86%) of the Felkin adduct 23A (>99% pure

by GLC analysis) as a colorless oil and 7 mg (5%) of the minor

diastereomer 24A as a colorless oil.

3-nonanone (ent-22C). [R]²³-20.0° (c 1.25, CHCl₃); IR (CHCl₃)

D

3620 (br), 3015, 2975, 1699, 1612, 1514, 1466, 1386, 1248, 1036 cm^-1

;

¹H NMR (500 MHz, CDCl₃) δ 7.28 (d, J ) 8.6 Hz, 2 H), 6.87 (d, J )

8.6 Hz, 2 H), 4.59 (m, 2 H), 3.96 (m, 1 H), 3.80 (s, 3 H), 3.50 (m, 2

H), 2.79 (dd, J ) 2.4 Hz, J ) 17.6 Hz, 1 H), 2.60 (sept, J ) 7.0 Hz,

1 H), 2.52 (dd, J ) 9.3 Hz, J ) 17.6 Hz, 1 H), 1.87 (m, 1 H), 1.77 (m,

1 H), 1.11 (d, J ) 7.0 Hz, 3 H), 1.10 (d, J ) 6.9 Hz, 3 H), 1.05 (d, J

) 6.6 Hz, 3 H), 0.87 (d, J ) 6.8 Hz, 3 H), 0.85 (d, J ) 7.0 Hz, 3 H);

¹³C NMR (100 MHz, CDCl₃) δ 216.7, 159.0, 131.4, 129.1, 113.7, 83.7,

74.2, 69.6, 55.2, 44.6, 41.5, 40.2, 31.1, 20.0, 19.6, 18.1, 18.0, 10.0.

Exact mass calcd for C₂₀H₃₂O₄: 336.2300. Found: 336.2305 (EI).

Enolsilane Addition to Aldehyde 19, Table 5, Entry E. The

following reagents were combined in the amounts indicated according

to the general procedure: boron trifluoride etherate (24 µL, 0.20 mmol),

acetone trimethylsilyl enol ether (33 µL, 0.20 mmol), and the aldehyde

19 (50 mg, 0.20 mmol). The reaction was allowed to proceed for 15

min at -78 °C, quenched, and isolated as described in the general

procedure. Silation and GLC analysis (DB-1701, 210 °C, 10 psi)

indicated a 83:17 ratio of anti-Felkin isomer 22E (t_r) 15.27 min) and

the Felkin diastereomer 21E (t_r) 15.03 min), respectively. Purification

by flash column (10% EtOAc in hexane) provided 50 mg (82%) of a

mixture of aldol adducts as a colorless oil.

(5S,6R,7R)-7-((tert-Butyldimethylsilyl)oxy)-6-hydroxy-2,2,6,8-tet-

ramethyl-3-nonone (23A). [R]²¹_D+21.7° (c 0.46, CHCl₃); IR (CHCl₃)

3562 (br), 2959, 2932, 2858, 1693, 1472, 1387, 1366, 1257, 1100, 1067,

1005, 837 cm^-1; ¹H NMR (500 MHz, CDCl₃) δ 4.05 (m, 1 H), 3.55 (t,

J ) 4.2 Hz, 1 H), 3.05 (d, J ) 2.8 Hz, 1 H), 2.73 (dd, J ) 2.8 Hz, J

) 17.9 Hz, 1 H), 2.59 (dd, J ) 9.1 Hz, J ) 17.8 Hz, 1 H), 1.86 (m,

1 H), 1.65 (m, 1 H), 1.15 (s, 9 H), 0.95 (d, J ) 7.0 Hz, 3 H), 0.92 (s,

J ) 6.7 Hz, 3 H), 0.91 (s, 9 H), 0.87 (d, J ) 6.8 Hz, 3 H), 0.07 (s, 6

H); ¹³C NMR (100 MHz, CDCl₃) δ 217.6, 78.4, 69.5, 44.4, 41.5, 40.8,

32.2, 26.3, 26.1, 19.6, 18.4, 18.1, 10.4, -3.6, -3.9. Exact mass calcd

for C₁₉H₄₁O₃Si: 345.2848. Found: 345.2825 (CI, NH₃atmosphere).

(5R,6R,7R)-7-((tert-Butyldimethylsilyl)oxy)-6-hydroxy-2,2,6,8-tet-

ramethyl-3-nonone (24A). [R]²²_D+30.5° (c 0.75, CH₂Cl₂); IR (CHCl₃)

Lithium Enolate Addition to Aldehyde 19, Table 12, Entry C.

The following reagents were combined in the amounts indicated

according to the general procedure: butyllithium (1.3 mL of a 1.6 M

solution, 0.2.0 mmol), diisopropylamine (290 µL, 2.1 mmol), acetone

(150 µL, 0.2.0 mmol), and the aldehyde 19 (100 mg, 0.40 mmol, as a

solution in 1 mL of THF). The reaction was allowed to proceed at

-78 °C for 30 min, quenched, and isolated as described in the general

lithium aldol procedure, affording 90 mg (73%) of a the mixture of

diastereomeric products as a colorless oil. Silylation and GLC analysis

(DB-1701, 215 °C, 10 psi) indicated a 22:78 ratio of 21E (t_r) 9.11

min) and 22E, (t_r) 9.24 min) respectively.

(4S,5R,6R)-6-[(4-Methoxybenzyl)oxy]-4-hydroxy-5,7-dimethyl-2-

octanone (21E). [R]²³_D-49° (c 0.2, CH₂Cl₂); IR (CHCl₃) 3708 (br),

2963, 1709, 1514, 1274 cm^-1; ¹H NMR (300 MHz, CDCl₃) δ 7.25 (d,

2 H, J ) 8.4 Hz, ArH), 6.85 (d, 2 H, J ) 8.7 Hz, ArH), 4.59 and 4.45

(AB, 2 H, J ) 10.8 Hz, ArCH₂), 4.18 (m, 1 H, HOCH), 3.77 (s, 3 H,

ArOCH₃), 3.28 (dd, 1 H, J ) 4.2 Hz, J ) 6.6 Hz, PMBOCH), 3.18 (d,

1 H, J ) 1.8 Hz, OH), 2.65 (dd, 1 H, J ) 8.7 Hz, J ) 17.1 Hz,

OdCCHH), 2.45 (dd, 1 H, J ) 3.6 Hz, J ) 17.1 Hz, OdCCHH), 2.13

(s, 3 H, OdCCH₃), 2.13 (m, 1 H, PMBOCHCH(CH₃)₂), 1.69 (m, 1 H,

HOCHCHCHOPMB), 1.09 (d, 3 H, J ) 6.6 Hz, HOCHCHCH₃), 0.94

(d, 3 H, J ) 4.2 Hz, PMBOCHCH(CH₃)CH₃), 0.91 (d, 3 H, J ) 3.9

Hz, PMBOCHCH(CH₃)CH₃); ¹³C NMR (400 MHz, CDCl₃) δ 209.3,

159.2, 130.6, 129.3, 113.9, 87.5, 73.9, 70.5, 55.3, 48.4, 39.3, 30.9, 19.7,

18.7, 8.0. Exact mass calcd for C₁₈H₂₈O₄Na: 331.1885. Found:

331.1888 (FAB, MNBA, added NaI).

1

3524 (br), 2960, 2931, 1694, 1473, 1386, 1366, 1077, 838 cm^-1; H

NMR (400 MHz, CDCl₃) δ 3.88-3.33 (m, 1 H), 3.78 (dd, J ) 1.8 Hz,

J ) 6.7 Hz, 1 H), 3.46 (d, J ) 3.0 Hz, 1 H), 2.74 (dd, J ) 2.3 Hz, J

) 17.6 Hz, 1 H), 2.52 (dd, J ) 9.2 Hz, J ) 17.7 Hz, 1 H), 1.71 (m,

2 H), 1.15 (s, 9 H), 0.93 (d, J ) 6.8 Hz, 3 H), 0.89 (s, 9 H), 0.86 (d,

J ) 6.8 Hz, 3 H), 0.78 (d, J ) 7.0 Hz, 3 H), 0.10 (s, 3 H), 0.07 (s, 3

H); ¹³C NMR (100 MHz, CDCl₃) δ 218.0, 76.3, 69.2, 44.5, 41.2, 40.7,

32.3, 26.3, 26.2, 19.9, 19.6, 18.5, 10.7, -3.9, -4.0. Exact mass calcd

for C₁₉H₄₀O₃SiNa: 367.2644. Found: 367.2657 (FAB, MNBA, added

NaI).

Enolsilane Addition to Aldehyde 20, Table 5, Entry C. The

following reagents were combined in the amounts indicated according

to the general Mukaiyama aldol procedure: boron trifluoride etherate

(39 µL, 0.32 mmol), the enolsilane (56 mg, 0.35 mmol), and the

aldehyde ent-20 (78 mg, 0.32 mmol). The reaction was allowed to

proceed for 3 h at -78 °C, quenched, and isolated as described in the

general procedure, affording 96.0 mg (91%) of a colorless oil. The

¹H NMR spectrum of the unpurified reaction mixture indicated the two

products in an 82:18 ratio. Silylation and GLC analysis (DB-1, 160

°C, 3.5 psi) revealed a 13:87 ratio of the 5S-diastereomer ent-24C (t_r

) 21.27 min) and the 5R-diastereomer ent-23C (t_r) 21.47 min),

respectively.

(4R,5R,6R)-6-[(4-Methoxybenzyl)oxy]-4-hydroxy-5,7-dimethyl-2-

octanone (22E). [R]²³_D+14° (c 1.75, CH₂Cl₂); IR (CHCl₃) 3516 (br),

2962, 1708, 1613, 1514, 1466, 1278 cm^-1; ¹H NMR (300 MHz, CDCl₃)

δ 7.25 (d, 2 H, J ) 7.9 Hz), 6.85 (d, 2 H, J ) 8.6 Hz), 4.56 (s, 2 H),

3.95 (m, 1 H), 3.78 (s, 3 H), 3.47 (dd, 1 H, J ) 2.1 Hz, J ) 8.4 Hz),

3.29 (s, 1 H), 2.73 (dd, 1 H, J ) 2.7 Hz, J ) 17.4 Hz), 2.46 (dd, 1 H,

Lithium Enolate Addition to Aldehyde 20, Table 12, Entry B.

The following reagents were combined in the amounts indicated

according to the general procedure: butyllithium (200 µL of a 2.51 M

solution, 0.500 mmol), diisopropylamine (70 µL, 0.50 mmol), isopropyl

methyl ketone (54 µL, 0.50 mmol), and the aldehyde ent-20 (122 mg,

0.500 mmol, as a solution in 1 mL of THF). The reaction was allowed

4342 J. Am. Chem. Soc., Vol. 118, No. 18, 1996

EVans et al.

to proceed at -78 °C for 10 min, quenched, and isolated as described

in the general lithium aldol procedure, affording 148 mg (89%) of a

colorless oil. Acylation and GLC analysis (DB-1701, 200 °C, 10 psi)

revealed a 87:13 ratio of the the 5S-diastereomer ent-24C (t_r) 7.68

min) and the 5R-diastereomer ent-23C (t_r) 8.05 min), respectively.

Purification by flash chromatography (10% EtOAc in hexane) afforded

98 mg (59%) of the 5S-diastereomer ent-24C as a colorless oil (>95%

(4R,5R,6R)-6-((tert-Butyldimethylsilyl)oxy)-4-hydroxy-5,7-dimethyl-

2-octanone (24E). [R]²³+23.4° (c 3.05, CH₂Cl₂); IR (film) 3473

D

(br), 2954, 2858, 1711, 1473, 1386, 1360, 1253, 1064, 837, 773 cm^-1

;

¹H NMR (400 MHz, CDCl₃0 δ 3.93 (m, 1 H), 3.72 (dd, 1 H, J ) 6.1

Hz, J ) 2.1 Hz), 3.56 (d, 1 H, J ) 3.0 Hz), 2.68 (dd, 1 H, J ) 16.9

Hz, J ) 2.6 Hz), 2.46 (dd, 1 H, J ) 16.9 Hz, J ) 9.2 Hz), 2.19 (s, 3

H), 1.78 (octet, 1 H, J ) 6.7 Hz), 1.68 (m, 1 H), 0.93 (d, 3 H, J ) 6.8

Hz), 0.89 (s, 9 H), 0.88 (d, 3 H, J ) 7.0 Hz), 0.78 (d, 3 H, J ) 7.0

Hz), 0.10 (s, 3 H), 0.07 (s, 3 H); ¹³C NMR (100 MHz, CDCl₃) δ 210.1,

77.4, 69.5, 48.4, 41.4, 31.8, 30.9, 26.1, 20.1, 19.6, 18.4, 11.4, -4.1,

-4.1. Exact mass calcd for C₁₆H₃₅O₃Si: 303.2355. Found: 303.2361

(CI, NH₃atmosphere).

1

diastereomerically pure by H NMR spectroscopy) and 9 mg (5%) of

the 5R-diastereomer ent-23C as a colorless oil (>95% diastereomeri-

1

cally pure by H NMR spectroscopy).

(5R,6S,7S)-7-((tert-Butyldimethylsilyl)oxy)-5-hydroxy-2,6,8-tri-

methyl-3-nonanone (ent-23C). [R]²¹-28.8° (c 0.56, CHCl₃); IR

D

â-Methallylstannane Addition to Aldehyde 13, Table 6, Entry

A. The following reagents were combined in the amounts indicated

according to the general allylstannane addition procedure using toluene

as the solvent: boron trifluoride etherate (10 µL, 0.077 mmol),

methallyltri-n-butylstannane (14 mg, 0.046 mmol), and the aldehyde

13 (10 mg, 0.052 mmol). The reaction was allowed to proceed for 13

min at -78 °C, quenched and isolated as described in the general

procedure. Silylation and GLC analysis (DB-1701, 190 °C, 15 psi)

indicated a 99:1 ratio of the 4R-diasteromer 25A (t_r) 18.12 min) and

the 4S-diasteromer (t_r) 17.35 min), respectively. Purification by silica

gel chromatography afforded 12 mg (86% yield) of the product 25A

as a colorless oil.

(CHCl₃) 3468 (br), 2960, 2860, 1670, 1472, 1406, 1386, 1363, 1254,

1

1123, 1074, 1026, 1006, 838 cm^-1; H NMR (400 MHz, CDCl₃) δ

3.90 (m, 1 H), 3.77 (dd, J ) 1.8 Hz, J ) 6.4 Hz, 1 H), 3.51 (d, J ) 2.0

Hz, 1 H), 2.72 (dd, J ) 2.5 Hz, J ) 17.3 Hz, 1 H), 2.63 (sept, J ) 6.9

Hz, 1 H), 2.50 (dd, J ) 9.1 Hz, J ) 17.3 Hz, 1 H), 1.77 (m, 1 H), 1.68

(m, 1 H), 1.11 (d, J ) 6.9 Hz, 6 H), 0.94 (d, J ) 6.8 Hz, 3 H), 0.90

(s, 9 H), 0.89 (d, J ) 6.9 Hz, 3 H), 0.79 (d, J ) 7.0 Hz, 3 H), 0.10 (s,

3 H), 0.07 (s, 3 H); ¹³C NMR (100 MHz, CDCl₃) δ 216.3, 76.7, 69.3,

44.9, 41.5, 41.1, 32.1, 26.1, 19.8, 19.7, 18.4, 18.1, 17.9, 11.0, -4.0,

-4.1. Exact mass calcd for C₁₈H₃₉O₃Si: 331.2668. Found: 331.2684

(CI, NH₃atmosphere).

(5S,6S,7S)-7-((tert-Butyldimethylsilyl)oxy)-5-hydroxy-2,6,8-tri-

(4R,5S,6R)-6-[(4-Methoxybenzyl)oxy]-4-hydroxy-2,5,7-trimethyl-

methyl-3-nonanone (ent-24C). [R]²¹+27.2° (c 0.42, CHCl₃); IR

D

1-octene (25A). [R]²³-17.3° (c 0.56, CH₂Cl₂); IR (CH₂Cl₂) 3495

D

(CHCl₃) 3536 (br), 2960, 2854, 1700, 1472, 1405, 1386, 1362, 1257,

1125, 1110, 1051, 838 cm^-1; ¹H NMR (400 MHz, CDCl₃) δ 4.08 (m,

1 H), 3.56 (t, J ) 4.2 Hz, 1 H), 2.98 (s, 1 H), 2.70-2.58 (m, 3 H),

1.86 (m, 1 H), 1.64 (m, 1 H), 1.12 (d, J ) 7.0 Hz, 6 H), 0.96 (d, J )

7.0 Hz, 3 H), 0.92 (d, J ) 6.8 Hz, 3 H), 0.92 (s, 9 H), 0.88 (d, J ) 6.8

Hz, 3 H), 0.08 (s, 3 H), 0.07 (s, 3 H); ¹³C NMR (100 MHz, CDCl₃) δ

216.0, 78.4, 69.6, 45.1, 40.6, 32.3, 26.1, 19.5, 18.4, 18.1, 18.1, 18.0,

10.2, -3.6, -4.0. Exact mass calcd for C₁₈H₃₉O₃Si: 331.2668.

Found: 331.2671 (CI, NH₃atmosphere).

(br), 2963, 1613, 1514, 1463, 1301, 1249, 1173, 1037 cm^-1; ¹H NMR

(250 MHz, CDCl₃) δ 7.04 (dd, 4 H, J ) 101 Hz, 8.7 Hz, ArH), 4.77

(d, 2 H, J ) 9.8 Hz, CH₂Ar), 4.55 9dd, 2 H, J ) 11.7 Hz, 10.4 Hz,

CdCH₂), 4.15 (t, 1 H, J ) 6.38 Hz, CHOH), 3.77 (s, 3 H, CH₃OAr),

3.15 (dd, 1 H, J ) 7.23 Hz, 4.16 Hz, CHOPMB), 3.09 (s, OH), 2.28

(ddd, 2 H, J ) 63.4 Hz, 16.3 Hz, 7.8 Hz, CH₂CHOH), 1.97 (m, 1 H,

CH₃CHCHOH), 1.76 (s, 3 H, CH₃CdC), 1.70 (1H, (CH₃)₂CH), 1.02

(d, 6 H, J ) 8.8 Hz, (CH₃)₂CH), 0.91 (d, 3 H, J ) 6.8 Hz,

CH₃CHCHOH); ¹³C NMR (400 MHz, CDCl₃) δ 159.1, 143.4, 130.8,

129.6, 114.2, 112.8, 90.8, 76.1, 68.2, 55.6, 43.6, 38.0, 31.4, 22.8, 20.3,

19.0, 11.6. Exact mass calcd for C₁₉H₃₀O₃: 306.4454. Found:

306.21950 (EI).

Enolsilane Addition to Aldehyde 20, Table 5, Entry E. The

following reagents were combined in the amounts indicated according

to the general procedure: boron trifluoride etherate (71 µL, 0.50 mmol),

acetone trimethylsilyl enol ether (98 mg, 0.75 mmol), and the aldehyde

20 (122 mg, 0.500 mmol). The reaction was allowed to proceed for

15 min at -78 °C, quenched, and isolated as described in the general

procedure. Acetylation and GLC analysis (DB-1701, 180 °C, 10 psi)

indicated a 42:58 ratio of anti-Felkin isomer 23E (t_r) 10.00 min) and

the Felkin diastereomer 24E (t_r) 10.58 min), respectively. Purification

by MPLC (Michel-Miller column size B, 8% EtOAc in hexane)

provided 34 mg (28%) of the anti-Felkin adduct 24E (>95% diaste-

reomerically pure by ¹H NMR spectroscopy), 21 mg (19%) of a mixture

of isomers, and 56 mg (46%) of the Felkin adduct 23E (>95%

Allylstannane Addition to Aldehyde 13, Table 6, Entry B. The

following reagents were combined in the amounts indicated according

to the general enolsilane procedure, except the nucleophile is allyl-

stannane: boron trifluoride etherate (30 µL, 0.25 mmol), allyltributyl-

stannane (72 µL, 0.25 mmol), and the aldehyde rac-13 (56 mg, 0.23

mmol). The reaction was allowed to proceed for 30 min at -78 °C,

quenched, and isolated as described in the general procedure. GLC

analysis (DB-1, 200 °C, 10 psi) indicated the presence of a single

diastereomer 25B (t_r) 7.25 min). Purification by flash column (20%

EtOAc in hexane) provided 62.3 mg (95%) of the Felkin isomer 25B

1

diastereomerically pure by H NMR spectroscopy).

1

(>95% diastereomerically pure by H NMR spectroscopy).

Lithium Enolate Addition to Aldehyde 20, Table 12, Entry C.

The following reagents were combined in the amounts indicated

according to the general procedure: butyllithium (146 µL of a 1.6 M

solution, 0.23 mmol), diisopropylamine (34 µL, 0.24 mmol), acetone

(16 µL, 0.22 mmol), and the aldehyde 19 (49 mg, 0.20 mmol, as a

solution in 1 mL of THF). The reaction was allowed to proceed at

-78 °C for 2 min, quenched, and isolated as described in the general

lithium aldol procedure. Acylation and GLC analysis (DB-1701, 180

°C, 10 psi) indicated a 86:14 ratio of 23E:24E, respectively. Purifica-

tion by MPLC (Michel-Miller size B, 5% EtOAc in hexane) afforded

43 mg (70%) of 24E (g95% diastereomerically pure by ¹H NMR

spectroscopy) and 11 mg (18%) of a mixture of diastereomers.

Allylstannane Addition to Aldehyde 13, Table 6, Entry C. To a

suspension of 48 mg (0.14 mmol) of Ph₃CClO₄in 0.5 mL of CH₂Cl₂

at -78 °C was added a solution of 32 mg (0.13 mmol) of aldehyde 13

in 0.25 mL of CH₂Cl₂, rinsing with 0.5 mL CH₂Cl₂. After 5 min at

-78 °C, this solution was transferred Via cannula to a solution of 110

µL (0.38 mmol) of allyltributylstannane in 0.75 mL of CH₂Cl₂at -78

°C. After 10 min at -78 °C, the reaction was quenched by addition

of 1 mL of Et₃N, then 5 mL of saturated aqueous NH₄Cl. The mixture

was diluted with 20 mL of Et₂O and washed with saturated aqueous

NH₄Cl, saturated aqueous NaHCO₃, and brine, dried (MgSO₄), and

concentrated in Vacuo affording 157.8 mg of a clear oil. GLC analysis

(DB-1, 200 °C, 10 psi) indicated the presence of a single diastereomer

(t_r) 10.72 min). Purification by flash chromatography (5% EtOAc,

45% CH₂Cl₂in hexane) afforded 23.4 mg (64%) of 25B (g95%

(4S,5R,6R)-6-((tert-Butyldimethylsilyl)oxy)-4-hydroxy-5,7-dimethyl-

2-octanone (23E). [R]²³-26.7° (c 1.05, CH₂Cl₂); IR (film) 3466

D

1

diastereomerically pure by H NMR spectroscopy) as a colorless oil.

(br), 2958, 2930, 2857, 1713, 1472, 1387, 1361, 1253, 1046, 836, 773

cm^-1; ¹H NMR (400 MHz, CDCl₃) δ 4.08 (m, 1 H), 3.54 (t, 1 H, J )

4.2 Hz), 2.83 (br d, 1 H, J ) 3.0 Hz), 2.60 (m, 2 H), 2.18 (s, 3 H),

1.84 (dseptets, 1 H, J ) 6.9 Hz), 1.61 (m, 1 H), 0.93 (d, 3 H, J ) 7.0

Hz), 0.90 (s, 9 H), 0.89 (d, 3 H, J ) 7.0 Hz), 0.86 (d, 3 H, J ) 7.0

Hz), 0.06 (s, 3 H), 0.06 (s, 3 H); ¹³C NMR (100 MHz, CDCl₃) δ 209.7,

78.5, 69.6, 48.5, 40.5, 32.4, 30.8, 20.1, 19.4, 18.4, 18.2, 10.0, -3.6,

-4.0. Exact mass calcd for C₁₆H₃₅O₃Si: 303.2355. Found: 303.2343

(CI, NH₃atmosphere).

(4R,5S,6R)-6-[(4-Methoxybenzyl)oxy]-4-hydroxy-5,7-dimethyl-1-

octene (25B). IR (CHCl₃) 3466 (br), 3007, 2964, 2875, 1613, 1514,

1

1465, 1303, 1250, 1174, 1081, 1036, 920, 826 cm^-1; H NMR (400

MHz, CDCl₃) δ 7.26 (m, 2 H), 6.86 (m, 2 H), 5.79 (m, 1 H), 5.10 (dd,

J ) 1.4 Hz, J ) 15.4 Hz, 1 H), 5.05 (dd, J ) 0.8 Hz, J ) 10.2 Hz, 1

H), 4.55 (quartet, J ) 10.3 Hz, 2 H), 4.03 (t, J ) 7.6 Hz, 1 H), 3.79

(s, 3 H), 3.35 (s, 1 H), 3.14 (dd, J ) 3.5 Hz, J ) 7.8 Hz, 1 H), 2.31

(m, 1 H), 2.10 (m, 1 H), 1.99 (m, 1 H), 1.79 (m, 1 H), 1.05 (d, J ) 7.1

Merged 1,2- and 1,3-Asymmetric Induction

J. Am. Chem. Soc., Vol. 118, No. 18, 1996 4343

Hz, 3 H), 1.04 (d, J ) 6.6 Hz, 3 H), 0.90 (d, J ) 6.8 Hz, 3 H); ¹³C

NMR (100 MHz, CDCl₃) δ 159.2, 135.5, 130.4, 129.3, 116.8, 113.8,

91.0, 69.9, 55.2, 39.2, 37.2, 31.1, 19.8, 19.1, 11.4. Exact mass calcd

for C₁₈H₃₂NO₃: 310.2382. Found: 310.2389 (CI, NH₃atmosphere).

â-Methallylstannane Addition to Aldehyde 19, Table 7, Entry

A. The following reagents were combined in the amounts indicated

according to the general procedure for the BF₃‚OEt₂mediated addition

reactions using only toluene as the solvent: boron trifluoride etherate

(20 µL, 0.16 mmol), the methallyltri-n-butylstannane (34 mg, 0.10

mmol), and the aldehyde 19 (23 mg, 0.094 mmol). The reaction was

allowed to proceed for 11 min at -78 °C, quenched, and isolated as

described in the general procedure. Silylation and GLC analysis of

the unpurified mixture (DB-1701, 180 °C, 15 psi) indicated a 80:20

ratio of the 4R-diasteromer 26A (t_r) 26.93 min) and the 4S-

diastereomer (t_r) 26.33 min) respectively. Purification by silica gel

chromatography provided 13.4 mg (86% yield) of a mixture of

diastereomeric products as a colorless oil.

-78 °C was added a solution of 26 mg (0.11 mmol) of aldehyde 19 in

0.25 mL of CH₂Cl₂, rinsing with 0.25 mL of CH₂Cl₂. After 5 min at

-78 °C, this solution was transferred Via cannula to a solution of 91.5

µL (0.31 mmol) of allyltributylstannane in 0.75 mL CH₂Cl₂at -78

°C. After 30 min at -78 °C, the reaction was quenched by the addition

of 1 mL of Et₃N, followed by 3 mL of saturated aqueous NH₄Cl. The

mixture was diluted with 25 mL of Et₂O and washed with saturated

aqueous NH₄Cl, saturated aqueous NaHCO₃, and brine, dried (MgSO₄),

and concentrated in Vacuo, to give 144 mg of a colorless oil. GLC

analysis (DB-1, 200 °C, 10 psi) indicated a 38:62 mixture of the anti-

Felkin adduct 26B (t_r) 6.99 min) and the Felkin diastereomer (t_r)

7.49 min), respectively. Purification by flash chromatography (35%

Et₂O in hexane) afforded 7 mg (23%) of the anti-Felkin diastereomer

1

26B (g95% diastereomerically pure by H NMR spectroscopy) and

10 mg (34%) of the Felkin diastereomer (g95% diastereomerically pure

1

by H NMR spectroscopy) as colorless oils.

(4S,5S,6S)-6-[(4-Methoxybenzyl)oxy]-4-hydroxy-5,7-dimethyl-1-

(4R,5R,6R)-6-[(4-Methoxybenzyl)oxy]-4-hydroxy-2,5,7-trimethyl-

octene (26B). [R]²³+32° (c 1.42, CHCl₃); IR (CHCl₃) 3467 (br),

1-octene (26A). [R]²³-35.5° (c 0.35 CH₂Cl₂); IR (CH₂Cl₂) 3474

D

3008, 2962, 2874, 1612, 1514, 1466, 1302, 1249, 1174, 1036 cm^-1

;

(br), 2959, 2361, 1646, 1612, 1514, 1457, 1381, 1301, 1247, 1172 cm^-1

;

¹H NMR (400 MHz, CDCl₃) δ 7.28 (d, J ) 8.6 Hz, 2 H), 6.87 (d, J )

8.6 Hz, 2H), 5.85 (m, 1H), 5.16 (d, J ) 5.1 Hz, 2 H), 4.60 (d, J ) 10.9

Hz, 1 H), 4.56 (d, J ) 10.9 Hz, 1 H), 3.80 (s, 3 H), 3.61 (m, 1 H), 3.45

(dd, J ) 2.3 Hz, J ) 8.1 Hz), 2.42 (m, 2 H), 2.13 (m, 1 H), 1.92

(octet, J ) 7.8 Hz, 1 H), 1.05 (d, J ) 6.6 Hz, 3 H), 0.91 (d, J ) 7.0

Hz, 3 H), 0.89 (d, J ) 6.8 Hz, 3 H); ¹³C NMR (100 MHz, CDCl₃) δ

159.0, 135.1, 131.2, 129.2, 118.2, 113.7, 84.7, 73.7, 72.4, 55.3, 39.9,

39.8, 30.8, 19.9, 19.9, 10.9. Exact mass calcd for C₁₈H₃₂NO₃:

310.2382. Found: 310.2390 (CI, NH₃atmosphere).

¹H NMR (300 MHz, CDCl₃) δ 7.07 (dd, 4 H, J ) 127 Hz, 8.6 Hz),

4.84 (d, 2 H, J ) 27.9 Hz), 4.57 (s, 2 H, J ) 17.2 Hz, 10.5 Hz), 3.78

(s, 3 H), 3.60 (m, 1 H), 3.47 (dd, 1 H, J ) 8.4 Hz, 2.3 Hz), 2.35 (d, 1

H, J ) 13.9 Hz), 2.00 (dd, 2 H, J ) 13.5 Hz, 10.1 Hz), 2.86 (m, 1 H),

1.73 (s, 3 H), 1.70 (m, 1 H), 1.03 (d, 3 H, J ) 6.6 Hz), 0.87 (d, 6 H,

J ) 6.9 Hz, 4.5 Hz); ¹³C NMR (100 MHz, CDCl₃) δ 159.3, 131.8,

129.6, 129.5, 114.0, 84.9, 74.4, 70.4, 55.6, 44.5, 40.9, 31.4, 30.0, 22.6,

20.3, 20.0, 10.7. Exact mass calcd for C₁₉H₃₀O₃: 306.4454. Found:

306.21950 (EI).

(4S,5R,6R)-6-[(4-Methoxybenzyl)oxy]-4-hydroxy-2,5,7-trimethyl-

1-octene. [R]²³_D-3.2° (c 0.26 CH₂Cl₂); IR (CH₂Cl₂) 3486 (br), 3072,

2960, 1644, 1612, 1586, 1513, 1463, 1382, 1301, 1248, 1173, 1083,

(4R,5S,6S)-6-[(4-Methoxybenzyl)oxy]-4-hydroxy-5,7-dimethyl-1-

octene. [R]²³+48° (c 0.34, CHCl₃); IR (CHCl₃) 3450 (br), 2977,

D

1613, 1514, 1465, 1384, 1302, 1250, 1174, 1111, 1034, 910 cm^-1; ¹H

NMR (400 MHz, CDCl₃) δ 7.29 (d, J ) 8.6 Hz, 2 H), 6.87 (d, J ) 8.6

Hz, 2 H), 5.82 (m, 1 H), 5.11 (m, 2 H), 4.62 (d, J ) 10.4 Hz, 1 H),

4.49 (d, J ) 10.4 Hz, 1 H), 3.83 (m, 1 H), 3.80 (s, 3 H), 3.27 (dd, J

) 3.5 Hz, J ) 7.4 Hz, 1 H), 2.93 (s, 1 H), 2.29 (m, 1 H), 2.22 (m, 1

H), 2.01 (octet, J ) 6.9 Hz, 1 H), 1.77 (m, 1 H), 1.04 (d, J ) 6.7 Hz,

3 H), 0.95 (d, J ) 7.0 Hz, 3 H), 0.94 (d, J ) 6.8 Hz, 3 H); ¹³C NMR

(100 MHz, CDCl₃) δ 159.2, 135.4, 130.4, 129.4, 117.2, 113.9, 89.3,

74.6, 74.0, 55.3, 39.7, 38.3, 31.0, 19.6, 19.1, 6.8. Exact mass calcd

for C₁₈H₃₂NO₃: 310.2382. Found: 310.2379 (CI, NH₃atmosophere).

1

1036 cm^-1; H NMR (300 MHz, CDCl₃) δ 7.05 (ddd, 4 H, J ) 125

Hz, 6.6 Hz, 2.1 Hz), 4.77 (dd, 2 H, J ) 18.7 Hz, 0.7 Hz), 4.54 (dd, 2

H, J ) 17.2 Hz, 10.5 Hz), 3.90 (t, 1 H), 3.77 (s, 3 H), 3.24 (dd, 1 H,

J ) 7.1 Hz, 1.9 Hz), 2.71 (s, 1 H), 2.21 (m, 2 H), 2.07 (m, 1 H), 1.73

(s, 3 H), 1.01 (d, 3 H, J ) 6.7 Hz), 0.91 (dd, 6 H, J ) 5.6 Hz, 6.9 Hz);

¹³C NMR (100 MHz, CDCl₃) δ 143.3, 130.8, 129.6, 125.8, 114.2, 113.2,

89.2, 74.3, 72.7, 55.6, 43.9, 39.0, 31.3, 22.8, 19.9, 19.3, 7.5. Exact

mass calcd for C₁₉H₃₀O₃: 306.4454. Found: 306.21950 (EI).

Allylstannane Addition to Aldehyde ent-19, Table 7, Entry B.

The following reagents were combined in the amounts indicated

according to the general Mukaiyama aldol procedure using toluene as

solvent: boron trifluoride etherate (13 µL, 0.11 mmol), allyltri-n-

butylstannane (33 µL, 0.11 mmol), and the aldehyde ent-19 (24 mg,

0.098 mmol). The reaction was allowed to proceed for 10 min at -78

°C, quenched, and isolated as described in the general procedure. GLC

analysis (DB-1, 200 °C, 10 psi) indicated a 87:13 ratio of the anti-

Felkin isomer ent-26B (t_r) 7.00 min) and the Felkin isomer (t_r)

7.46 min), respectively. Purification by flash chromatography (20%

EtOAc in hexane) provided 25 mg (86%) of an 86:14 mixture of aldol

diastereomers free of impurities by ¹H NMR spectroscopy. Purification

of 285 mg of a related 75:25 mixture of anti-Felkin and Felkin

diastereomers respectively (35% Et₂O in hexane) provided 50 mg (41%)

Acknowledgment. We gratefully acknowledge the NIH, the

NSF, Merck, and Pfizer for research support. The NIH BRS

Shared Instrumentation Grant Program (1-S10-RR04870) and

the NSF (CHE88-14019) are acknowledged for providing NMR

facilities.

Supporting Information Available: Experimental proce-

dures for compounds indicated in the text and structure proofs

of all reaction products (25 pages). This material is contained

in many libraries on microfiche, immediately follows this article

in the microfilm version of the journal, can be ordered from

the ACS, and can be downloaded from the Internet; see any

current masthead page for ordering information and Internet

access instructions.

1

of the anti-Felkin isomer 26B (>95% diastereomerically pure by H

NMR spectroscopy), 31 mg (25%) of a mixture of isomers, and 11 mg

1

(9%) of the Felkin diasteromer (>95% diastereomerically pure by H

NMR spectroscopy).

Allylstannane Addition to Aldehyde 19, Table 7, Entry C. To a

solution of 40 mg (0.12 mmol) of Ph₃CClO₄in 0.5 mL of CH₂Cl₂at

JA953901U

Article Doi

A stereochemical model for merged 1,2- and 1,3-asymmetric induction in diastereoselective Mukaiyama aldol addition reactions and related processes

DOI: 10.1021/ja953901u

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Article abstract of DOI:10.1021/ja953901u

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