1,5-Asymmetric induction in boron-mediated aldol reactions of beta-oxygenated methyl ketones

This tutorial review describes that high levels of substrate-controlled, 1,5-stereoinduction are obtained in the boron-mediated aldol reactions of beta-oxygenated methyl ketones with achiral and chiral aldehydes. Remote induction from the boron enolates gives the 1,5-anti adducts, with the enolate pi-facial selectivity critically dependent upon the nature of the beta-alkoxy protecting group. This 1,5-anti aldol methodology has been strategically employed in the total synthesis of several natural products with remarkable pharmacological activities. At present, the origin of the high level of 1,5-anti induction obtained with the boron enolates is unclear, although a model based on hydrogen bonding between the beta-alkoxy oxygen and the formyl aldehyde hydrogen has recently been proposed.     

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.     

Substrate-controlled stereoselectivity in the Yamamoto aldol reaction

The Yamamoto aldol reaction is a vinylogous aldol reaction that relies on bulky aluminium-based Lewis acids. These activate both the aldehyde as well as become part of the enolate moiety. The report discloses the first detailed study on the substrate-controlled Yamamoto aldol reaction in which 2,3-syn and 2,3-anti disubstituted aldehydes serve as the stereodirecting elements. The "size" of the substituent in the β-position strongly determines the facial selectivity of enolate addition to the aldehyde. Large substituents favour formation of 1,3-syn diols while slim alkynyl groups preferentially lead to 1,3-anti products.     

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.     

Diastereodivergent strategies for the synthesis of homochiral aculeatins

We report concise and stereocontrolled syntheses of aculeatins (-)-A, (+)-B, (+)-D, and (+)-6-epi-D. Diastereodivergent 1,3-inductions in Mukaiyama aldol coupling contribute to reduce steps and to increase flexibility with reactants having sterically restricted proximal substituents (i.e., CH2), involving either a good anti or a moderate syn 1,3-induction, depending on the nature of protecting group (P). In addition, the 3,5-syn-diol-ketone resulting from concomitant deprotection of the beta-alkoxy (Tr = trityl) group proves to be remarkably stable whereas the 3,5-anti diastereoisomer cyclizes spontaneously to the corresponding tetrahydropyran hemiketal, thus enabling a useful and facile separation. The second part of our study is devoted to improving the yield and the diastereoselectivity of the final phenolic oxidation reaction leading to aculeatins.     

Enantioselective total synthesis of (+)-leucascandrolide A macrolactone

[reaction: see text] The enantioselective synthesis of the (+)-leucascandrolide A macrolactone has been achieved in 20 linear steps from 1,3-propanediol. The key steps in the synthesis are a reductive cleavage of bicyclic ketal 5 to establish the C15 stereogenic center and a diastereoselective aldol of the boron enolate of methyl ketone 3 to aldehyde 4 in preparation for a heteroconjugate addition for the introduction of the C3 stereocenter.     

Asymmetric induction in methyl ketone aldol additions to alpha-alkoxy and alpha,beta-bisalkoxy aldehydes: a model for acyclic stereocontrol

A systematic study of methyl ketone aldol additions under nonchelating conditions with alpha-alkoxy and alpha,beta-bisalkoxy aldehydes is described. Additions to aldehydes containing a single alpha-alkoxy stereocenter generally provide the product diastereomers in accord with the Cornforth/polar Felkin-Anh models for carbonyl addition. Vicinal asymmetric induction is sensitive to the aldehyde alpha-alkyl substituent, but is relatively insensitive to the nature of the alkoxy protecting group. Aldehyde pi-facial selectivity in additions to substrates containing an additional beta-alkoxy-substituted stereocenter exhibits a striking dependence on the relative configuration of the alpha- and beta-stereocenters. Aldehydes with the alpha- and beta-alkoxy substituents in an anti relationship in most cases exhibit good diastereoselectivity, while aldehydes with the alpha- and beta-alkoxy substituents in a syn relationship unexpectedly give product mixtures. A stereochemical model based on Cornforth-like transition-state arrangements is proposed.     

Synthesis of the C1-C21 (C1'-C21') fragment of the dimeric polyketide natural product SCH 351448

[structure: see text] A convergent, stereoselective assembly of the C1-C21 (C1'-C21') fragment of SCH 351448, a 28-membered bis-lactone natural product, has been developed. A highly efficient approach to this fragment assembles 75% of the carbon skeleton and all the stereochemical elements present in the natural product. In addition, an interesting boron ligand effect on the diastereoselectivity of a key aldol reaction with methyl ketone-derived enolborinates is reported.     

Stereoselective Aldol Reactions with α-Unsubstituted Chiral Enolates

The aldol reaction is among the most important methods of forming carbon-carbon bonds. The addition of an enolate to an aldehyde leads to the formation of at least one chiral center. In the case of α-substituted enolates it has to a large extent been possible to control the product stereochemistry, while the aldol reaction of α-unsubstituted chiral enolates was for many years a “problem child” for synthetic chemists because of its insufficient stereoselectivity. Progress in this area has only been made in the last few years using either new chiral auxiliaries or alternatives to the aldol reaction.     

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.     

Asymmetric aldol reactions using (S,S)-(+)-pseudoephedrine-based amides: stereoselective synthesis of alpha-methyl-beta-hydroxy acids, esters, ketones, and 1,3-Syn and 1,3-anti diols

A very efficient method for performing stereoselective aldol reactions is reported. The reaction of (S, S)-(+)-pseudoephedrine-derived propionamide enolates with several aldehydes yielded exclusively one of the four possible diastereomers in good yields, although transmetalation of the firstly generated lithium enolate with a zirconium(II) salt, prior to the addition of the aldehyde, is necessary in order to achieve high syn selectivity. The so-formed syn-alpha-methyl-beta-hydroxy amides were transformed into other valuable chiral nonracemic synthons such as alpha-methyl-beta-hydroxyacids, esters, and ketones. Finally, a stereocontrolled reduction procedure starting from the so-obtained alpha-methyl-beta-hydroxy ketones has been developed allowing the synthesis of either 1,3-syn- or 1,3-anti-alpha-methyl-1,3-diols in almost enantiopure form by choosing the appropriate reaction conditions.     

Lewis base catalyzed aldol additions of chiral trichlorosilyl enolates and silyl enol ethers

[structures: see text] The consequences of double diastereodifferentiation in chiral Lewis base catalyzed aldol additions using chiral enoxysilanes derived from lactate, 3-hydroxyisobutyrate, and 3-hydroxybutyrate have been investigated. Trichlorosilyl enolates derived from the chiral methyl and ethyl ketones were subjected to aldolization in the presence of phosphoramides, and the intrinsic selectivity of these enolates and the external stereoinduction from chiral catalyst were studied. In the reactions with the lactate derived enolate, the strong internal stereoinduction dominated the stereochemical outcome of the aldol addition. For the 3-hydroxyisobutyrate- and 3-hydroxybutyrate derived enolates, the catalyst-controlled diastereoselectivities were observed, and the resident stereogenic centers exerted marginal influence. The corresponding trimethylsilyl enol ethers were employed in SiCl4/bisphosphoramide catalyzed aldol additions, and the effect of double diastereodifferentiation was also investigated. The overall diastereoselection of the process was again controlled by the strong external influence of the catalyst.     

Studies on the synthesis of bafilomycin A(1): stereochemical aspects of the fragment assembly aldol reaction for construction of the C(13)-C25) segment

Highly stereoselective syntheses of aldols 8a-c corresponding to the C(13)-C(25) segment of bafilomycin A(1) were developed by routes involving fragment assembly aldol reactions of chiral aldehyde 6a and the chiral methyl ketones 7. A remote chelation effect plays a critical role in determining the stereoselectivity of the key aldol coupling of 6a and the lithium enolate of 7b. The protecting group for C(23)-OH of the chiral aldehyde fragment also influences the selectivity of the lithium enolate aldol reaction. In contrast, the aldol reaction of 6a and the chlorotitanium enolates of 7a,c were much less sensitive to the nature of the C(15)-hydroxyl protecting group. Studies of the reactions of chiral aldehydes with Takai's (gamma-methoxyallyl)chromium reagent 40 are also described. The stereoselectivity of these reactions is also highly dependent on the protecting groups and stereochemistry of the chiral aldehyde substrates.     

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).     

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.     

Unexpected ambidoselectivity in crossed-aldol reactions of α-oxy aldehyde trichlorosilyl enolates

The ambido-, stereo- and enantioselectivity of the phosphoramide-promoted aldol reactions of α-oxy aldehyde trichlorosilyl enolates with benzaldehyde has been investigated. Analysis of the products from α-tert-butyldimethylsilyloxy α-deuterioacetaldehyde trichlorosilyl enolate confirmed that this 1,2-bis-silyloxyethene derivative reacted as a tert-butyldimethylsilyl enolate rather than trichlorosilyl enolate in the aldol reaction with very high ambidoselectivity. The phosphoramide-coordinated trichlorosilyl group acted as an organizing center for the aldol reaction. From the aldol process, excellent anti-diastereoselectivity could be achieved. The enantioselectivity remained moderate to low for both anti- and syn-diastereomer with a wide range of phosphoramide catalysts. α-Triisopropylsilyloxy, phenoxy and benzyloxy acetaldehyde trichlorosilyl enolates also reacted in a similar fashion with benzaldehyde to give aldol products with varying degrees of selectivities.     

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.     

Double stereodifferentiation in the "acetate-type" aldol reaction with garner's aldehyde. Stereocontrolled synthesis of polyhydroxylated gamma-amino carbonyl compounds

[reaction: see text] The aldol reaction of acetamide enolates with protected chiral alpha-amino-beta-hydroxy aldehyde 1 (Garner's aldehyde) has been performed in a stereocontrolled way under double stereodifferentiation conditions using pseudoephedrine as the additional chiral information source attached to the enolate reagent. In addition, the obtained adduct has been transformed into other valuable chiral building blocks such as gamma-amino-beta,delta-dihydroxy acids, esters, and ketones.     

Mechanism of the double aldol reaction: the first spectroscopic characterization of a carbon-bound boron enolate derived from carboxylic esters

The novel doubly borylated enolate is identified as an intermediate of the double aldol reaction of acetate esters. As a precursor to the formation of the doubly borylated enolate, carbon-bound boron enolates of carboxylic esters are spectroscopically characterized for the first time. When 2,6-diisopropylphenyl acetate (10d) is treated with c-Hex(2)BOTf (1.3 equiv) and triethylamine (1.5 equiv) in CDCl(3), the corresponding mono-enolate is formed as a mixture of oxygen- (11d) and carbon-bound (12d) forms in 71% and 20% yields, respectively. The structures of these enolates have been unambiguously determined by NMR spectroscopy. Investigation of the enolization of a series of substituted aryl acetates shows that the steric factor of the acetate affects the degree of the mono-enolate (as a mixture of oxygen- and carbon-bound enolates) and the doubly borylated enolate formation. Studies also revealed that oxygen- and carbon-bound boron enolates exist as equilibrium mixtures and that a proton transfer process occurs between oxygen- and carbon-bound enolates. The doubly borylated enolate formation is general for a variety of carbonyl compounds. Besides acetate esters, carbonyl containing compounds, such as acetic acid, dimethylacetamide, methoxyacetone, and 3-acetyl-2-oxazolidinone, also produce the doubly borylated enolates when treated with c-Hex(2)BOTf (2.5 equiv) and triethylamine (3.0 equiv). A plausible pathway of the double aldol reaction involving a carbon-bound boron enolate as a key intermediate is proposed.     

The Impact of the Mukaiyama Aldol Reaction in Total Synthesis

Four decades since Mukaiyama’s first reports on the successful application of silicon and boron enolates in directed aldol reactions, the ability of this highly controlled carbon–carbon bond‐forming method to simultaneously define stereochemistry, introduce complexity, and construct the carbon skeleton with a characteristic 1,3‐oxygenation pattern has made it a powerful tool for natural product synthesis. This Minireview highlights a number of representative total syntheses that demonstrate the impact of the Mukaiyama aldol reaction and discusses the underlying mechanistic rationale that determines the stereochemical outcomes.