1,5-anti stereocontrol in the boron-mediated aldol reactions of beta-alkoxy methyl ketones: the role of the formyl hydrogen bond.

The boron-mediated aldol reactions of certain types of beta-alkoxy methyl ketone show remarkably high levels of stereoinduction with achiral aldehydes, leading preferentially to 1,5-anti related stereocenters. Given the low levels of asymmetric induction usually observed in acetate aldol reactions, this is of great synthetic utility and has been used successfully in the total synthesis of a number of polyketide natural products. We have investigated the effects of the alkoxy protecting group (OMe, OPMB, PMP acetal, tetrahydropyran, and OTBS) present in the boron enolate on the level and sense of remote 1,5-stereoinduction, using density functional theory calculations (B3LYP/6-31G**). Our predictions of diastereoselectivity from comparison of the competing aldol transition structures are in excellent qualitative and quantitative agreement with experimentally reported values. We conclude that the boron aldol reactions of unsubstituted boron enolates proceed via boat-shaped transition structures in which a stabilizing formyl hydrogen bond exists between the alkoxy oxygen and the aldehyde proton. It is this interaction that leads to preferential formation of the 1,5-anti adduct, by minimizing steric interactions between the beta-alkyl group and one of the ligands on boron. In the case of silyl ethers, the preference for this internal hydrogen bond is not observed due to the size of the protecting group and the electron-poor oxygen atom that donates electron density into the adjacent silicon atom. We show that this stereochemical model is also applicable in rationalizing the 1,4-syn stereoselectivity of boron aldol reactions involving certain alpha-chiral methyl ketones. These detailed results may be summarized as a conformational diagram that can be used to predict the sense of stereoinduction.

[1]  Ian Paterson,et al.  Recent developments in asymmetric aldol methodology , 1994 .

[2]  I. Paterson,et al.  A fully stereocontrolled total synthesis of (+)-leucascandrolide A , 2003 .

[3]  Ian Paterson,et al.  Stereocontrolled total synthesis of (+)-leucascandrolide A. , 2003, Angewandte Chemie.

[4]  J. Goodman,et al.  Gas phase versus solution chemistry: On the reversal of regiochemistry of methylation of sp2- and sp3-nitrogens , 2001 .

[5]  M. Frisch,et al.  Ab Initio Calculation of Vibrational Absorption and Circular Dichroism Spectra Using Density Functional Force Fields , 1994 .

[6]  J. Goodman,et al.  Understanding the origins of remote asymmetric induction in the boron aldol reactions of beta-alkoxy methyl ketones. , 2006, Organic letters.

[7]  K. Narasaka,et al.  Stereoselective reduction of β hydroxyketones to 1,3-diols highly selective 1,3-asymmetric induction via boron chelates , 1984 .

[8]  J. Goodman,et al.  Enantio- and diastereoselective aldol reactions of achiral ethyl and methyl ketones with aldehydes: the use of enol diisopinocampheylborinates , 1990 .

[9]  Y. Kai,et al.  Synthesis and molecular structure of [7]circulene , 1988 .

[10]  A. Saksena,et al.  Recent studies on veratrum alkaloids: a new reaction of sodium triacetoxyborohydride [NaBH(OAc)3] , 1983 .

[11]  A. Becke,et al.  Density-functional exchange-energy approximation with correct asymptotic behavior. , 1988, Physical review. A, General physics.

[12]  S. Kozmin.  Efficient stereochemical relay en route to leucascandrolide A. , 2001, Organic letters.

[13]  Wang,et al.  Cofactor-Bound Cross-Linked Enzyme Crystals (CLEC) of Alcohol Dehydrogenase. , 2000, Angewandte Chemie.

[14]  B. Honig,et al.  Accurate First Principles Calculation of Molecular Charge Distributions and Solvation Energies from Ab Initio Quantum Mechanics and Continuum Dielectric Theory , 1994 .

[15]  J. Petersen,et al.  Double Asymmetric Synthesis and a New Strategy for Stereochemical Control in Organic Synthesis , 1985 .

[16]  R. Herzog,et al.  Zur Kenntnis der Seidenbeschwerung , 1926 .

[17]  Erick M Carreira,et al.  Total synthesis of leucascandrolide A. , 2002, Angewandte Chemie.

[18]  J. Panek,et al.  Studies directed toward the total synthesis of discodermolide: asymmetric synthesis of the C1-C14 fragment. , 2002, Organic letters.

[19]  E. T. Silva,et al.  Reaction of 1,3-dimethyl-5-acetyl-barbituric acid (DAB) with primary amines. Access to intermediates for selectively protected spermidines , 2003 .

[20]  Jonathan M. Goodman,et al.  TRANSITION-STATE MODELING OF THE ALDOL REACTION OF BORON ENOLATES - A FORCE-FIELD APPROACH , 1990 .

[21]  W. E. Mcewen,et al.  Metal ion effects in Wittig reactions. A general hypothesis for the mechanism of the Wittig reaction , 1990 .

[22]  E. Carreira,et al.  Leucascandrolide a: synthesis and related studies. , 2003, The Journal of organic chemistry.

[23]  D. Durand,et al.  Controlled formation of highly ordered cubic and hexagonal mesoporous nanocrystalline yttria-zirconia and ceria-zirconia thin films exhibiting high thermal stability. , 2003, Angewandte Chemie.

[24]  R. Hance,et al.  ESR study of iron carbonyl radical anions , 1981 .

[25]  B. Honig,et al.  New Model for Calculation of Solvation Free Energies: Correction of Self-Consistent Reaction Field Continuum Dielectric Theory for Short-Range Hydrogen-Bonding Effects , 1996 .