On the origins of diastereoselectivity in the conjugate additions of the antipodes of lithium N-benzyl-(N-α-methylbenzyl)amide to enantiopure cis- and trans-dioxolane containing α,β-unsaturated esters

"Matching" and "mismatching" effects in the doubly diastereoselective conjugate additions of the antipodes of lithium N-benzyl-(N-α-methylbenzyl)amide to enantiopure cis- and trans-dioxolane containing α,β-unsaturated esters have been investigated. High levels of substrate control were established first upon conjugate addition of achiral lithium N-benzyl-N-isopropylamide to both tert-butyl (S,S,E)-4,5-O-isopropylidene-4,5-dihydroxyhex-2-enoate and tert-butyl (4R,5S,E)-4,5-O-isopropylidene-4,5-dihydroxyhex-2-enoate. However, upon conjugate addition of lithium (R)-N-benzyl-(N-α-methylbenzyl)amide and lithium (S)-N-benzyl-(N-α-methylbenzyl)amide to these substrates, neither reaction pairing reinforced the apparent sense of substrate control. These reactions do not, therefore, conform to the classical doubly diastereoselective "matching" or "mismatching" pattern usually exhibited by this class of reaction. A comparison of these reactions with the previously reported doubly diastereoselective conjugate addition reactions of lithium amide reagents to analogous substrates is also discussed.     

Double asymmetric induction as a mechanistic probe: the doubly diastereoselective conjugate addition of enantiopure lithium amides to enantiopure α,β-unsaturated esters and enantiopure α,β-unsaturated hydroxamates

The doubly diastereoselective conjugate addition of the antipodes of lithium N-benzyl-N-(α-methylbenzyl)amide to a range of enantiopure α,β-unsaturated esters [derived from Corey’s 8-phenylmenthol chiral auxiliary] and enantiopure α,β-unsaturated hydroxamates [derived from our ‘chiral Weinreb amide’ auxiliary (S)-N-1-(1′-naphthyl)ethyl-O-tert-butylhydroxylamine] has been used as a mechanistic probe to determine the reactive conformations of these acceptors.     

Stereoselective conjugate additions of sulphoxide stabilised carbanions to α,β-unsaturated esters

The reaction of lithiated alkyl t-butyl sulphoxides with α,β-unsaturated esters gives conjugate addition products in good yield, with high stereoselectivity.     

Regio- and diastereoselective conjugate addition of Grignard reagents to aryl substituted α,β-unsaturated carbonyl compounds derived from Oppolzer's sultam

Asymmetric conjugate addition of Grignard reagents to aryl substituted α,β-unsaturated carbonyl compounds (1) has been achieved with great regioselectivity (>20:1) and good to excellent diastereoselectivity (de up to 98%). The nucleophilicity and stereospecific blockade of the Grignard reagents play a key role in controlling the regioselectivities and diastereoselectivities of the conjugate addition reaction.     

Synthesis of isoxazolidin-5-ones via stereocontrolled Michael additions of benzylhydroxylamine to l-serine derived α,β-unsaturated esters

The synthesis of optically active isoxazolidin-5-ones from α,β-unsaturated esters is reported. The key features of this synthetic sequence include the stereocontrolled Michael addition of benzylhydroxylamine to alkenes 7 and 8 and the intramolecular cyclization to the target compounds     

Catalytic enantioselective conjugate additions with α,β-unsaturated sulfones

We describe the development of a highly efficient catalytic asymmetric conjugate addition to α,β-unsaturated sulfones. Utilizing practical bifunctional organic catalysts and involving air- and moisture-tolerant conditions, conjugate additions of a wide range of Michael donors to α,β-unsaturated sulfones proceeded in excellent enantioselectivity/diastereoselectivity and high yield. This efficient and operationally simple new catalytic asymmetric reaction should provide a versatile approach for the asymmetric synthesis of chiral sulfones bearing all-carbon quaternary stereocenters.     

Anionic versus photochemical diastereoselective deconjugation of diacetone d-glucose α,β-unsaturated esters

Deconjugation of diacetone d-glucose α,β-unsaturated esters has been conducted by deprotonation using NaHMDS with HMPA as co-solvent followed by stereoselective protonation at low temperature. High selectivities (>95%) were obtained with α-methyl linear compounds.     

Highly enantioselective Cu(I)-Tol-BINAP-catalyzed asymmetric conjugate addition of Grignard reagents to α,β-unsaturated esters

The copper-catalyzed conjugate addition (CA) of organometallic reagents to α,β-unsaturated carbonyl compounds is one of the most versatile synthetic methods for the construction of C-C bonds. Interestingly, the application of Grignard reagents, which are among the most widely used of organometallic compounds, in asymmetric conjugate addition (CA) reactions has received less attention. Therefore, our group and others have been exploring better catalytic systems to effect the asymmetric 1,4-conjugate addition of Grignard reagents to α,β-unsaturated esters. It is only in the past decade that significant breakthroughs have been made in this field. In our studies, we found that CuI-Tol-BINAP could catalyze the asymmetric conjugate addition (CA) reactions of Grignard reagents, including the addition of MeMgBr to α,β-unsaturated esters to afford the β-methylated esters in good yields with excellent regio- and enantioselectivities. Both enantiomers of the products could be obtained by either using the enantiomers of the chiral Tol-BINAP or by using the geometrical isomer of the starting material. This method is also suitable for other Michael acceptors. In this article, we describe the development of the asymmetric Cu(I)-Tol-BINAP catalyzed 1,4-conjugate addition of Grignard reagents to α,β-unsaturated esters and applications of this chemistry. This method provides a convenient method to synthesize β-alkyl esters with high enantioselectivity or diastereoselectivity using CuI and the inexpensive chiral ligand, Tol-BINAP.     

Copper-catalyzed conjugate additions of alkylboranes to imidazolyl α,β-unsaturated ketones: formal reductive conjugate addition of terminal alkenes

Conjugate addition of alkylboron compounds (alkyl-9-BBN) to imidazol-2-yl α,β-unsaturated ketones proceeded in the presence of a catalytic amount (10 mol %) of CuCl, 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene (IMes), and t-BuOK. The alkylboranes are available through alkene hydroboration, and thus the overall process represents a reductive conjugate addition of alkenes to enone derivatives. A variety of functional groups are tolerated in both the alkenes and the α,β-unsaturated ketones. The 2-acylimidazole moiety can easily be converted into the corresponding carboxylic acid, ester, and amide derivatives.     

Cobalt-catalyzed conjugate addition of silylacetylenes to α,β-unsaturated ketones

Catalytic addition of silylacetylenes to α,β-unsaturated ketones proceeded in the presence of a cobalt complex coordinated with a bisphosphine ligand to give high yields of β-alkynylketones.     

Addition of esters of nitroacetic acid to α,β-unsaturated ketones

Summary The addition reaction of esters of nitroacetic acid to, -unsaturated ketones was studied, and new esters of ketonitroacids were prepared.     

Conjugate addition of lithium N-phenyl-N-(α-methylbenzyl)amide: application to the asymmetric synthesis of (R)-(-)-angustureine

The conjugate addition of lithium (R)-N-phenyl-N-(α-methylbenzyl)amide to a range of α,β-unsaturated 4-methoxyphenyl esters proceeds with excellent levels of diastereoselectivity to give the corresponding β-amino esters in good yield and as single diastereoisomers (>99:1 dr). The synthetic utility of this methodology has been demonstrated via the short and concise asymmetric synthesis of the tetrahydroquinoline alkaloid (R)-(-)-angustureine in six steps and 32% overall yield from commercially available oct-2-enoic acid.     

Lanthanum-pyBOX complexes as catalysts for the enantioselective conjugate addition of malonate esters to β,γ-unsaturated α-ketimino esters

Abstract

In this paper, we report the application of chiral complexes of La(III) with pyBOX ligands as Lewis acid catalysts in the conjugate addition of malonic esters to N-tosyl imines derived from β,γ-unsaturated α-keto esters to give the corresponding chiral α,β-dehydroamino esters. pyBOX complexes with La(III), Yb(III), Sc(III), and In(III) triflates were assessed in this reaction but only La(III) showed good activity and enantioselectivity, while Yb(III) provided the expected product with low yield and stereoselectivity, and the Sc(III) and In(III) complexes were completely inactive. The complex of La(OTf)₃ with the diphenyl-pyBOX ligand prepared in situ provided the best results and allowed obtaining chiral α,β-dehydroamino esters 3 with excellent yields, E:Z diastereomeric ratios (29:71–99:1) and high enantiomeric excesses (20–95%). The reaction could be applied to imines having a substituted aromatic ring or a heterocycle attached to the double bond, although the presence of electron-withdrawing groups on the aromatic ring was detrimental for stereoselectivity. The reaction products were obtained with the S configuration at the stereogenic center and the Z configuration at the enamine double bond as determined by NOESY experiments and X-ray analysis. Based on the experimental results a stereochemical model involving a nine-coordinate La(III) species has been proposed.     

Chiral ferrocenyl phosphine-phosphoramidite ligands for Cu-catalyzed asymmetric conjugate reduction of α,β-unsaturated esters

Unsymmetrical hybrid chiral ferrocenyl phosphine-phosphoramidite ligands have been applied for the first time in the Cu-catalyzed asymmetric 1,4-reduction of β-aryl substituted α,β-unsaturated esters. The results show that the ligand bearing (S_c)-central, (R_p)-planar, and (R_a)-axial chiralities gave the best performance. The present catalytic system proved to be highly substrate-dependent, catalyzing the conjugate reduction of α,β-unsaturated esters in moderate to excellent enantioselectivities.     

Solution phase structures of enantiopure and racemic lithium N-benzyl-N-(α-methylbenzyl)amide in THF: low temperature 6Li and 15N NMR spectroscopic studies

The antipodes of lithium N-benzyl-N-(α-methylbenzyl)amide are highly efficient enantiopure ammonia equivalents for the asymmetric synthesis of β-amino acid derivatives via conjugate addition to α,β-unsaturated esters. ⁶Li and ¹⁵N NMR spectroscopic studies of doubly labelled ⁶lithium (S)-¹⁵N-benzyl-¹⁵N-(α-methylbenzyl)amide in THF at low temperature reveal the presence of lithium amide dimers as the only observable species. Either a monomeric or dimeric lithium amide reactive species can be accommodated within the transition state mnemonic for this class of conjugate addition reaction. This enantiopure lithium amide offers unique opportunities over achiral (e.g., lithium dibenzylamide) and C₂-symmetric (e.g., lithium bis-N,N-α-methylbenzylamide) counterparts for further mechanistic study owing to the ready distinction of the various dimers formed.     

Preparation of chiral secondary boronic esters via copper-catalyzed enantioselective conjugate reduction of β-boronyl-β-alkyl α,β-unsaturated esters

A new methodology involving the copper(I)-catalyzed enantioselective conjugate reduction of β-boronyl-β-alkyl enoates was developed. Various chiral secondary boronate derivatives can be accessed in excellent yields and good to high levels of enantioselectivity through this efficient copper-catalyzed process using polymethylhydrosiloxane (PMHS) as hydride source.     

Synthesis of β-carbolines from aldehydes and ketones via the α-siloxy α,β-unsaturated esters

We report an efficient method for the synthesis of β-carbolines from α-siloxy α,β-unsaturated esters, which are accessible from a variety of aldehydes and ketones.     

Selective reduction of α,β-unsaturated esters in the presence of olefins

Several α,β-unsaturated esters containing also isolated olefins or other functionalities subject to saturation were selectively reduced to the corresponding saturated esters by magnesium in methanol.