Boron Enolate Aldol Research Articles

Diastereoselectivity in the boron aldol reaction of α-alkoxy and α,β-bis-alkoxy methyl ketones.

In this work, using DFT calculations, we investigated the 1,4 and 1,5 asymmetric induction in boron enolate aldol reactions of α-alkoxy and α,β-bisalkoxy methyl ketones. We evaluated the steric influence of alkyl substituents at the α position and the stereoelectronic influence of the oxygen protecting groups at the α and β positions. Theoretical calculations revealed the origins of the 1,4 asymmetric induction in terms of the nature of the β-substituent. The synergistic effect between the α,β-syn and α,β-anti-bisalkoxy stereocenters was elucidated. In the presence of the β-alkoxy center, the reaction proceeds through the Goodman-Paton 1,5-stereoinduction model, experiencing a minor influence of the α-alkoxy center.

ChemInform Abstract: Boron Enolate Chemistry Toward the Syntheses of Polyketide Stereotetrads

AbstractReview: [40 refs.

Boron Enolate Chemistry toward the Syntheses of Polyketide Stereotetrads

In 1976 Mukaiyama published a paper that was to make a major impact on the development of the aldol reaction in the future. Mild enolate formation by treatment of a ketone with dibutylboron triflate in the presence of a tertiary amine generates a relatively stable boron enolate, which can subsequently react with an aldehyde to give the cross-aldol product in good yields. This reaction has become a reliable tool for the practicing synthetic chemist. Nearly 10000 polyketides are known, and of these about 600 contain the tripropionate unit with a stereotetrad, four contiguous stereocenters with alternating methyl and hydroxyl substituents in the main chain. The versatility of the boron enolate aldol reaction is showcased with selected applications in the synthesis of these structural motifs.

ChemInform Abstract: Developing a Force Field for the Transition State of the Aldol Reaction of Enolborinates: Evaluation of the Use of Fixed Point Charges.

Abstract A method for assigning atom-centred point charges, within the constraints of the MacroModel implementation of the MM2 force field, is described. The method has been applied to obtain charges with sensible magnitudes for the transition structures of boron enolate aldol reactions. The effect of these new charges on the aldol force field model is discussed, and it is concluded that atom-centred point charges do not help in the analysis of this transition state, and a more flexible system for the treatment of electrostatics is essential.

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.

Total Synthesis of (±)‐Decursivine

AbstractThe first preparation of the antimalarial natural product decursivine is described. A Diels–Alder/Plieninger indolization protocol allows convenient preparation of the indole 15 which, in turn is a suitable substrate for a boron–enolate aldol reaction with piperonal (16). The resulting adduct 14 is transformed efficiently to the natural product. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

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.

Natural Product‐Guided Synthesis of a Spiroacetal Collection Reveals Modulators of Tubulin Cytoskeleton Integrity

AbstractThe spiro[5.5]ketal moiety forms the underlying structural skeleton of numerous biologically active natural products. Since simplified but characteristic spiroketals derived from the parent natural products retain biological activity, the spiro[5.5]ketal unit can be regarded as a biologically prevalidated framework for the development of natural product‐derived compound collections. We report an enantioselective synthesis of spiro[5.5]ketals on solid support. The reaction sequence employs asymmetric boron enolate aldol reactions with the enolate bound to the polymer or in solution as the key enantiodifferentiating step. It proceeds in up to 12 steps on solid support, makes the desired spiroketals available in high overall yields and with high stereoselectivities and is amenable to structural variation of the products. The small spiroketal collection synthesized contains phosphatase inhibitors and compounds that modulate the formation of the tubulin cytoskeleton in human cancer cells without directly targeting microtubules. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

A Study of the Paterson Boron Aldol Reaction as Used in the Large-Scale Total Synthesis of the Anticancer Marine Natural Product (+)-Discodermolide

This note discusses an optimisation study of a key reagent-controlled enantioselective boron enolate aldol reaction forming the C6−C7 bond and the C7 hydroxyl-bearing stereocenter in (+)-discodermolide. Conditions were found which increased the yield, decreased the excess of enolate necessary, and increased product stability with respect to the published procedure.

Large-Scale Synthesis of the Anti-Cancer Marine Natural Product (+)-Discodermolide. Part 5: Linkage of Fragments C1-6 and C7-24 and Finale

The finale of the large-scale preparation of 60 g of the highly complex marine natural product, (+)-discodermolide (1), using a hybridized Novartis−Smith−Paterson synthetic route is presented. This contribution, which is the concluding part of a five-part series, highlights a reagent-controlled stereoselective boron enolate aldol reaction between 2 and 3 forming the C7 hydroxyl-bearing stereocenter, selective reduction of 4a to generate the 1,3-anti-diol 5, and a global deprotection and concomitant lactonization leading to (+)-discodermolide (1). A novel procedure for converting the minor epimeric aldol adduct 4b into discodermolide using a five-step sequence is also described. This large-scale synthesis of discodermolide involved 39 steps (26 steps in the longest linear sequence) and several chromatographic purifications and delivered sufficient material for early-stage human clinical trials.

The synthesis and evaluation of a solution phase indexed combinatorial library of non-natural polyenes for reversal of P-glycoprotein mediated multidrug resistance.

A combinatorial library of polyenes, based on (-)-stipiamide, has been constructed and evaluated for the discovery of new multidrug resistance reversal agents. A palladium coupling was used to react each individual vinyl iodide with a mixture of the seven acetylenes at near 1:1 stoichiometry. The coupling was also used to react each individual acetylene with the mixture of six vinyl iodides to create 13 pools indexed in two dimensions for a total of 42 compounds. Individual compounds were detected at equimolar concentration. The vinyl iodides, made initially using a crotylborane addition to generate the anti1,2-hydroxylmethyl products, were now made using a more efficient norephedrine propionate boron enolate aldol reaction. The indexed approach, ideally suited for cellular assays that involve membrane-bound targets, allowed for the rapid identification of reversal agents using assays with drug-resistant human breast cancer MCF7-adrR cells. Intersections of potent pools identified new compounds with promising activity. Aryl dimension pools showed R = ph and naphthyl as the most potent. The acetylene dimension had R' = phenylalaninol and alaninol as the most potent. Isolated individual compounds, both active and nonpotent, were assayed to confirm the library results. The most potent new compound was 4ek (R = naphthyl, R' = phenylaninol) at 1.45 microM. Other nonnatural individual naphthyl-amide compounds showed potent MDR reversal including the morpholino-amide 4ej (1.69 microM). Synergistic activities attributed to the two ends of the molecule were also identified. Direct interaction with Pgp was established by ATPase and photoaffinity displacement assays. The results indicate that both ends of the polyene reversal agent are involved in Pgp interaction and can be further modified for increased potency.

Transformations of chiral (.eta.6-arene)chromium complexes in organic synthesis: aldol reactions of (ortho-substituted acetophenone)chromium complexes

The aldol reaction of (o-alkoxyacetophenone)chromium complexes with boron enolates gave predominantly one diastereomeric product as a result of attack at the re-face of the aldehydes. The selectivity of the aldol reactions was remarkably dependent on the ortho substituents of the acetophenone complexes and the ligands on the chromium metal. In the case of the o-methoxy substituent, high diastereoselectivity in the boron enolate aldol condensation was achieved.

Studies in macrolide synthesis: A stereocontrolled synthesis of a (9 S)-macrolide intermediate for oleandomycin using chiral boron reagents.

The (9 S)-macrolide 1 (P = TBS) was prepared in 14 steps (5% yield) with 63% overall ds starting from the ethyl ketone ( S)- 2. The C 1–C 7 and C 8–C 13 segments, 3 and 4, were obtained via boron enolate aldol reactions mediated by (+)- and (−)-(Ipc) 2BOTf, respectively.

Developing a force field for the transition state of the aldol reaction of enolborinates: Evaluation of the use of fixed point charges.

A method for assigning atom-centred point charges, within the constraints of the MacroModel implementation of the MM2 force field, is described. The method has been applied to obtain charges with sensible magnitudes for the transition structures of boron enolate aldol reactions. The effect of these new charges on the aldol force field model is discussed, and it is concluded that atom-centred point charges do not help in the analysis of this transition state, and a more flexible system for the treatment of electrostatics is essential.

Origins of stereoselectivity in chiral boron enolate aldol reactions: A computational study using transition state modellings

A molecular mechanics model of the boron enolate aldol transition state is used to analyse the stereoselectivity of various synthetically interesting reactions. The model reproduces the sense and degree of stereoselectivity for several examples in Scheme 1, including reactions involving chiral ketones, as in 1 (substrate control) and chiral ligands on boron, as in 2 (reagent control). The origins of the stereoselectivity in the aldol reactions of Z enol diisopinocampheyl borinates are analysed in detail. It is concluded that the relative orientation of the ligands with respect to the chair transition structure core, as well as the relative orientation and restrained rotation of one ligand relative to the other, are important for determining the reaction selectivity. For chiral ketone cases, a general model 59 can be devised by inspection of the preferred transition structures viewed as the Newman projections ( 31, 38 and 44). This model has the hydrogen on the stereogenic centre of the enol borinate directed towards the boron ligand ( i.e. the dihedral angle CCC*H is in the range 133–173°), the large group opposite to the incoming aldehyde, and the small group pointing towards the forming CC bond of the chair transition structure. As shown by the work described here, our force field model of the boron aldol transition state is useful in understanding the origins of the stereoselectivity over a wide range of substrates. The aldol force field model, therefore, may also have predictive value in new situations.

Total synthesis of the esterase inhibitor (±)-ebelactone a using an aldol-claisen strategy

The β-lactone (±)-ebelactone A has been prepared in 12 steps from diethylketone (9% overall yield) using a series of three boron enolate aldol reactions coupled with the Ireland ester enolate Claisen rearrangement, 10 → 11.