1,5-asymmetric induction in boron-mediated beta-alkoxy methyl ketone aldol addition reactions

This article presents studies that illustrate beta-alkoxy methyl ketone-derived boron enolates undergo diastereoselective aldol addition to afford the 1,5-anti diol relationship. The stereochemical outcome of this reaction is documented to be general for a variety of beta-alkoxy methyl ketone analogues and aldehyde partners. The double stereodifferentiating reactions of these enolates with chiral beta-alkoxy aldehydes have also been investigated in conjunction with the possibility of controlling the absolute stereochemistry of the aldol process. With the proper selection of reaction conditions, the proximal alkoxy substituent on either the aldehyde (1,3-induction) or the enolate fragment (1,5-induction) can be employed to control facial selectivity of the aldol addition. Selection of a boron enolate ensures dominant 1,5-anti induction from the beta-alkoxy methyl ketone-derived enolate partner while negating any influence of the beta-alkoxy aldehyde substituent. Conversely, if stereochemical control from the beta-alkoxy aldehyde is desired, a Lewis acid-catalyzed enolsilane addition ensures dominant 1,3-induction from the aldehyde beta-oxygen substituent.     

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.     

1,5-Stereoinduction in boron-mediated aldol reactions of β,δ-bisalkoxy methylketones containing cyclic protecting groups

A study of the aldol reactions of boron enolates from methylketones that are protected with dimethylacetonide or di-tert-butylsilyl groups and that possess a trans or cis relationship between the chiral centers is presented. The main objective of this work was to evaluate the influence of the relative stereochemistry between the chiral centers and the steric and electronic influences of the cyclic protecting groups on the aldol reactions. The aldol adducts were obtained with moderate to high 1,5-anti stereoselectivity that was dependent on both the identity of the protecting group on the β,δ-oxygen stereocenters and the relative stereochemistry between the β and δ chiral centers. A theoretical analysis of the transition states involving these aldol reactions was performed utilizing DFT (density functional theory).     

1,5-Asymmetric induction in boron-mediated aldol reactions of beta-alkoxy methylketones

Good levels of substrate-controlled, 1,5- syn-stereoinduction are obtained in boron-mediated aldol reactions of beta-trichloromethyl-beta-alkoxy and beta-trifluoromethyl-beta-alkoxy methylketones with achiral aldehydes, independent of the nature of the beta-alkoxy protecting group (TBS or PMB). In the case of boron aldol reactions of beta-aryl-beta-alkoxy methylketones, the 1,5- anti-adducts were obtained with high levels of diastereoselectivity only with a beta-OPMB group.     

Understanding the origins of remote asymmetric induction in the boron aldol reactions of beta-alkoxy methyl ketones

We report theoretical studies into the remote 1,5-stereoinduction shown by certain types of beta-alkoxy methyl ketones in boron-mediated aldol reactions with achiral aldehydes. For a range of common alkoxy groups, our calculations are in excellent agreement with experimentally observed diastereoselectivities. In the aldol transition structures, a stabilizing hydrogen bond between the alkoxy oxygen and formyl proton leads to preferential formation of the 1,5-adduct, by minimizing steric interactions between the beta-alkyl group and one of the ligands on boron.     

The role of β-bulky substituents in aldol reactions of boron enolates of methylketones with aldehydes: experimental and theoretical studies by DFT analysis

In this work, we show the influence of the volume of the β-substituents on the levels of 1,5-stereoselectivities of aldol reactions of boron enolates generated from β-alkoxy methylketones with aldehydes. Excellent levels of 1,5-syn stereoinduction were obtained when the β-protecting group is a silicon ether. This remarkable selectivity is attributed to the volume of the β-bulky substituent of the corresponding boron enolate. We have investigated a stereochemical model using DFT analysis to rationalize the sense of 1,5-syn stereoselectivities of β-alkyl-β-alkoxy methylketones.     

Asymmetric total synthesis of spongistatins 1 and 2

The total synthesis of spongistatin 1 (1) and spongistatin 2 (2) has been achieved through an advanced-stage intermediate. The synthesis is highlighted by a highly convergent assembly of the four key fragments (the C1-C15 AB fragment 2, the C16-C28 CD fragment 3, the C29-C43 EF fragment 4, and the C44-C51 side chain 5) at a very advanced stage of the synthesis with minimal functional group interconversion. The CD fragment 3 functions as the central building block to which the other fragments are attached. The synthesis of the AB and CD spiroketal fragments is accomplished through the addition of a metalated gamma-pyrone to a beta-alkoxy aldehyde followed by spiroketalization. The EF subunit was assembled with high diastereoselectivity relying on asymmetric aldol reactions of chlorotitanium enolates of N-propionyl oxazolidinethiones and a double diastereoselective boron aldol to join the E and F fragments. Wittig coupling of the CD and EF fragments followed by a diastereoselective aldol reaction between the CDEF ketone and an AB aldehyde set the stage for attachment of the C44-C51 side chains and final macrolactonization and deprotection.     

Addition of kinetic boron enolates generated from β-alkoxy methyl ketones to aldehydes. Density functional theory calculations on the transition structures

Herein we report that good to excellent levels of 1,5-anti stereoinduction are obtained in boron enolate aldol reactions of 1,2-syn β-alkoxy methyl ketones with achiral aldehydes, when the β-alkoxy protecting group is part of a benzylidene acetal. We have also investigated the effects of the ligands on boron, the α-, β-, and γ-substituents and the β-alkoxy protecting group on the boron enolates, using density functional theory (B3LYP) and Møller-Plesset perturbation theory (MP2) calculations.     

Chiral boron enolate aldol additions to chiral aldehydes

We have examined the double-diastereodifferentiating aldol addition reactions of chiral enolborinate 1a with chiral aldehydes leading to the corresponding aldol adducts with excellent levels of 1,5-anti diastereoselection.     

Studies toward the total synthesis of sorangiolides and their analogues. A convergent stereoselective synthesis of the macrocyclic lactone precursors

Stereoselective synthesis of the fully protected 18-membered macrocyclic lactones as the immediate precursors of the natural products, sorangiolides A and B, is described. The key steps used in the synthesis include the sp3-hybridized carbon-carbon Fu cross coupling, the stereoselective Evans' aldol reaction with 1,5-anti induction, the 1,3-diastereoselective syn reduction of a beta-hydroxyketone intermediate, and Mukaiyama macrolactonization reactions.     

The influence of a beta-electron withdrawing substituent in aldol reactions of methylketone boron enolates

We wish to describe here that good levels of substrate-based, 1,5-syn-stereocontrol could be achieved in the boron-mediated aldol reactions of beta-trichloromethyl methylketones with achiral aldehydes, independent of the nature of the beta-alkoxy protecting group.     

The boron-mediated ketone-ketone aldol reaction

The first examples of the directed, boron-mediated aldol reaction between different ketones are presented. Transformation of a variety of ketones to their corresponding boron enolates with Chx₂BCl/Et₃N, followed by reaction with acceptor ketones in diethyl ether, and oxidation of the resultant boron aldolate (H₂O₂, MeOH/pH 7 buffer), provided the aldol addition products. The reaction was most facile when cyclic ketones were used, with the highest yields obtained for the reaction of boron enolates with cyclohexanone as the acceptor.     

Stereoselective aldol condensations via alkenyloxy dialkoxyboranes : mechanistic and stereochemical details

A detailed investigation of the enolization of ketones with ethylenechloroboronate ( ECB ) in the presence of a tertiary amine and the subsequent aldol condensations of these boron enolates was conducted. The enolization with ECB- DPEA system was found to be regioselective except for the case of butanone. The stereochemistry of the enolates derived from ethyl ketones was defined as Z on the basis of ¹H-NMR comparison to the Z enolates obtained by a stereodefined route. A mechanistic model for the enolization is proposed to explain the enolization selectivity. E enolates were found to be more reactive than the Z enolates. The product aldol stereochemistry ( syn ) was correlated to the enolate geometry via a chairlike transition state ( Z enolates ) or via a boatlike transition state ( E enolates ).     

High 1,5-anti stereoinduction in boron-mediated aldol reactions of methyl ketones

[reaction: see text] We report herein a very efficient and synthetically useful 1,4-anti-1,5-anti boron-mediated aldol reaction of a chiral alpha-methyl-beta-alkoxy methyl ketone with achiral aldehydes.     

A tandem non-aldol aldol Mukaiyama aldol reaction

[reaction: see text] A new one-pot tandem aldol process is described in which a secondary epoxy silyl ether is converted into the 1,5-bis-silyloxy-3-alkanone in good yield. Thus, treatment of the epoxy silyl ether 8 with TBSOTf and base affords the silyl enol ether 9 via non-aldol aldol rearrangement and addition of benzaldehyde and TBSOTf gives the ketone 10 with 4:1 syn selectivity. The diastereoselectivity changes to an anti preference for most aldehydes. This anti selectivity overwhelms the normal Felkin-Ahn preference; namely, the 1,5-anti isomer predominates even when it is anti-Felkin-Ahn.     

The Mukaiyama Aldol Reaction: 40 Years of Continuous Development

A directed cross‐aldol reaction of silyl enol ethers with carbonyl compounds, such as aldehydes and ketones, promoted by a Lewis acid, a reaction which is now widely known as the Mukaiyama aldol reaction. It was first reported in 1973, and this year marks the 40th anniversary. The directed cross‐aldol reactions mediated by boron enolates and tin(II) enolates also emerged from the Mukaiyama laboratory. These directed cross‐aldol reactions have become invaluable tools for the construction of stereochemically complex molecules from two carbonyl compounds. This Minireview provides a succinct historical overview of their discoveries and the early stages of their development.     

Asymmetric aldol reactions using chiral CF3-Oxazolidines (Fox) as chiral auxiliary

The aldol reactions of amide enolates derived from a trifluoromethylated oxazolidine (Fox) chiral auxiliary occur in good yields with a moderate anti diastereoselectivity (Li and Na enolates) to a high syn diastereoselectivity (boron enolate). After removal, the Fox chiral auxiliary is very conveniently and efficiently recovered in basic conditions.     

Enantioselective aldol condensations via boron enolates. A steric model for asymmetric induction.

Chiral boron enolates have been shown to be effective in stereoregulated aldol condensations. A transition state model is proposed for chirality transfer.     

Reversibility in the boron-mediated ketone-ketone aldol reaction

The boron-mediated ketone-ketone aldol reaction is demonstrated, through 1H NMR studies, to be reversible, in contrast to the strictly irreversible aldol reactions of boron enolates with aldehydes.     

Aldol addition of lithium and boron enolates of 1,3-dioxan-5-ones to aldehydes. A new entry into monosaccharide derivatives

Methods allowing control of stereoselectivity in aldol reactions of enolates derived from 1,3-dioxan-5-ones (4) are described. Boron enolates, generated in situ, react with benzaldehyde to give the corresponding anti aldol selectively (the anti:syn ratio of up to 96:4) and in high yield. Lithium enolates give high anti selectivity only with aldehydes branched at the alpha-position. Enantioselective deprotonation of C(S) symmetrical dioxanones (e.g., 4b) can be accomplished efficiently, with enantiomeric excess of up to 90%, with chiral lithium amide bases of general structure PhCH(Me)N(Li)R (9, 10) if the R group is sufficiently bulky (e.g, R = adamantyl) or is fluorinated (e.g., R = CH2CF3). Dioxanone boron and lithium enolates react readily with glyceraldehyde derivatives (19), yielding protected ketohexoses (20 and 21).