Asymmetric synthesis of d-fagomine and its diastereoisomers

A divergent strategy for the asymmetric syntheses of d-fagomine and three of its diastereoisomers has been developed. The diastereoselective conjugate addition of an enantiopure lithium amide to an α,β-unsaturated ester was used as the key step to install the correct configuration required for the C(5)-stereogenic centre within the targets. In situ enolate oxidation generated the corresponding anti-α-hydroxy-β-amino ester, which possessed the correct configuration required for the C(4)-stereogenic centre within both d-fagomine and d-3-epi-fagomine. Subsequent epimerisation of this key anti-α-hydroxy-β-amino ester upon oxidation and diastereoselective reduction gave the corresponding syn-α-hydroxy-β-amino ester, which possessed the correct configuration required for the C(4)-stereogenic centre within both d-4-epi-fagomine and d-5-epi-fagomine. Elaboration of both α-hydroxy-β-amino esters upon reduction to the corresponding aldehydes followed by aldol reaction generated the requisite C(3)-stereogenic centres within the target compounds, then cyclisation and deprotection gave the enantiopure iminosugars in good overall yields, as single diastereoisomers (>99:1 dr).     

Asymmetric synthesis of trifluoromethylated propargylamines via 1,2-additions of trifluoromethylacetylide to N-tert-butanesulfinyl imines

An efficient method for the asymmetric synthesis of the trifluoromethylated propargylamines was described. Addition of lithium trifluoromethylacetylide, in situ prepared from lithium diisopropylamide and the 2-bromo-3,3,3-trifluoropropene, to various N-tert-butanesulfinyl imines provided a range of trifluoromethylated propargyl sulfinamides. Besides high yields and excellent diastereoselectivities, the additions featured that the diastereoselectivities could be reversed when polar or nonpolar solvent was used. Acidic cleavage of the tert-butanesulfinyl groups delivered highly optically pure trifluoromethylated propargylamines.     

Asymmetric synthesis using catalysts containing multiple stereogenic centres and a trans-1,2-diaminocyclohexane core; reversal of predominant enantioselectivity upon N-alkylation

N-Methylation of ligands containing a trans-1,2-diaminocyclohexane core and multiple stereogenic centres is shown to provide the product of the opposite configuration in significant enantiomeric excess, in the addition of diethylzinc to aldehydes. Some of the ligands were effective in an asymmetric Michael addition.     

Asymmetric syntheses of dihydroxyhomoprolines via doubly diastereoselective lithium amide conjugate addition reactions

The asymmetric syntheses of novel dihydroxyhomoprolines have been achieved using the doubly diastereoselective conjugate additions of the antipodes of lithium N-benzyl-N-(α-methylbenzyl)amide to a set of four chiral α,β-unsaturated esters (derived from d-pentoses) as one of the key steps. A full account of the diastereoselectivity observed in these conjugate additions is presented and the stereochemical outcomes of these reactions have been established unambiguously via a combination of hydrogenolytic chemical correlation and single crystal X-ray diffraction analyses. A tandem hydrogenolysis/intramolecular reductive amination reaction was then used to create the corresponding enantiopure pyrrolidines, providing access to (2′S,3′S,4′R)-dihydroxyhomoproline and (2′S,3′R,4′S)-dihydroxyhomoproline after deprotection.     

Iodine catalyzed one-pot five-component reactions for direct synthesis of densely functionalized piperidines

A simple and convenient one-pot multicomponent reaction (MCR) has been developed for the synthesis of highly functionalized piperidines catalyzed by molecular iodine. This strategy demonstrated five-component reactions of 1,3-dicarbonyl compounds, amines and aromatic aldehydes in methanol using 10 mol % of iodine at room temperature. This methodology provides an alternative approach for easy access of highly and fully substituted piperidines in moderate to good yields using three readily available starting materials. Notably, this method is mild, cheap, straight forward, applicable to broad range of substrates and environmentally friendly as compared to the existing methods. Synthetic and mechanistic studies are presented here.     

Asymmetric syntheses of methyl N-Boc-2-deoxy-2-amino-l-erythroside,methyl N-Boc-2-deoxy-2-amino-d-threoside and methyl N-Boc-2,3-dideoxy-3-amino-l-arabinopyranoside

The asymmetric syntheses of methyl N-Boc-2-deoxy-2-amino-l-erythroside and methyl N-Boc-2-deoxy-2-amino-d-threoside have been achieved from sorbic acid, in six and eight steps, and in 35 and 13% overall yield, respectively. Diastereoselective aminohydroxylation of tert-butyl sorbate gives access to two diastereoisomeric α-hydroxy-β-amino-γ,δ-unsaturated esters. Reduction of the ester functionality and ozonolysis of the double bond gives the corresponding aldehyde, which exists exclusively in the ring-closed (furanose) form. An alternative synthesis of methyl N-Boc-2-deoxy-2-amino-l-erythroside was also developed, reliant on aminohydroxylation of an α,β-unsaturated ester bearing an acetal functionality at the γ-position, and this synthesis proceeded in five steps and 54% overall yield from acrolein diethyl acetal. This approach was extended to permit the synthesis of methyl N-Boc-2,3-dideoxy-3-amino-l-arabinopyranoside in six steps and 58% overall yield from ethyl 3,3-diethoxypropanote.     

Asymmetric syntheses of the methyl glycosides of 2-deoxy-2-aminohexoses: d-allosamine, d-mannosamine, d-idosamine and d-talosamine

A range of the methyl glycosides of 2-deoxy-2-aminohexoses, comprising d-allosamine, d-mannosamine, d-idosamine and d-talosamine, were prepared from the corresponding d-aldopentoses via a seven step synthetic sequence. The doubly diastereoselective conjugate addition of the requisite antipode of lithium N-benzyl-N-(α-methylbenzyl)amide and in situ enolate oxidation with the requisite antipode of camphorsulfonyloxaziridine (CSO) was used as the key, stereodefining step. Sequential reduction of the resultant α-hydroxy-β-amino esters and oxidative cleavage of the C(1)–C(2) diol unit furnished the corresponding α-amino aldehydes. Subsequent N- and O-deprotection gave the target compounds (as mixtures of anomers) in good yield and high diastereoisomeric purity.     

Regioselective addition of 1,3-dicarbonyl dianion to N-sulfonyl aldimines: an expedient route to N-sulfonyl piperidines and N-sulfonyl azetidines

A simple route for the synthesis of δ-amino-β-keto esters and δ-amino-β-diketones is reported. This involves regioselective addition of 1,3-dianions derived from ethyl acetoacetate and acetyl acetone to N-sulfonyl aldimines. The δ-amino-β-keto ester derivatives were further converted into the corresponding N-sulfonyl piperidines and N-sulfonyl azetidines.     

Stereoselective synthesis of cis-2,6-disubstituted piperidines from 1,2-cyclic sulfamidates

Diastereoselective synthesis of cis-2,6-disubstituted piperidines from 1,2-cyclic sulfamidates is described. Regioselective ring-opening reactions of 1,2-cyclic sulfamidates derived from L-phenylalanine, alanine, valine, norvaline with the ketal protected acetylide with a phenyl substituent proceed smoothly to form the N-sulfamate intermediates which on acidic hydrolysis give alkynylated amines with the ketal group intact. Hydrogenation of the alkynylated amines, debenzylation, ketal deprotection, subsequent cyclization (of aminoketones) and stereoselective hydrogenation of the cyclic iminium ion intermediates afford the corresponding cis-2,6-disubstituted piperidines in high diastereoselectivity (98%?≥?d.e.) with good chemical yields (68–86%). The present approach provides a novel route for the stereoselective synthesis of cis-2,6-disubstituted piperidines.     

A three-step total synthesis of goniothalesdiol A using a one-pot Sharpless epoxidation/regioselective epoxide ring-opening

Using a one-pot Sharpless asymmetric epoxidation/regioselective epoxide ring-opening as a key step, the protecting-group-free total synthesis of goniothalesdiol A was accomplished in only three steps starting from commercially available trans-cinnamaldehyde in 55.1% overall yield. In 6 previously reported total syntheses, 6–11 steps were required.     

Intramolecular 1,3-dipolar cycloaddition of N-alkenyl nitrones en route to glycosyl piperidines

Stereoselective intramolecular 1,3-dipolar cycloaddition of homochiral N-(alkenylglycosyl)nitrones, prepared by allylation of C-(glycosyl)nitrones and subsequent oxidation, is described. The previously described 2-aza-Cope rearrangement was not observed for these substrates, but evidences of E/Z isomerism during the cycloaddition were obtained. The obtained cycloadducts can serve as key precursors of imino disaccharide analogues. This is exemplified by a short route to a protected 2-furanosyl-4-hydroxy-6-phenyl piperidine.     

Synthesis of highly functionalized piperidines by one-pot multicomponent reaction using tetrabutylammonium tribromide (TBATB)

Tetrabutylammonium tribromide (TBATB) has been found to be an efficient catalyst for the one-pot synthesis of highly substituted piperidines through a combination of 1,3-dicarbonyl compounds, aromatic aldehydes, and various amines in ethanol at room temperature. Atom economy, good yields, environmentally benign, and mild reaction conditions are some of the important features of this protocol.     

Bis-Lewis acids-catalyzed highly diastereoselective one-pot reductive dehydroxylation of chiral N,O-acetals

A one-pot and highly diastereoselective method for the reductive dehydroxylation of three classes of heterocyclic N,O-acetals with general structure 4 is reported. The method features a ‘two in one’ concept, namely, by synergetic action of two complementary Lewis acids (BF·OEt₂ and TiCl₄), the bicyclic or tricyclic oxazololactams 5 were formed in situ and reductively cleaved to give the corresponding lactams 6 in a high-yielding and highly diastereoselective manner.     

N-Methylative aziridine ring opening and asymmetric synthesis of MeBmt

Asymmetric synthesis of MeBmt, an unusual amino acid constituent of cyclosporine A, was achieved from aziridine-(2R)-carboxaldehyde through the highly stereoselective addition of (E)-crotylboronate and the subsequent N-methylative aziridine ring opening as key steps.     

Asymmetric synthesis of Sedum alkaloids via lithium amide conjugate addition

Conjugate addition of lithium (R)-N-allyl-N-(α-methylbenzyl)amide or lithium (R)-N-but-3-enyl-N-(α-methylbenzyl)amide to an alkyl hexa-2,4-dienoate or alkyl hepta-2,6-dienoate, followed by ring-closing metathesis of the olefin functionalities within the resultant β-amino ester, generates a range of diastereoisomerically pure azacycles in good yield. These homochiral templates are readily transformed to a range of piperidine alkaloids of the Sedum family, and the corresponding five-, seven- and eight-membered ring homologues.     

Asymmetric synthesis of 2-chloroaziridines via a diastereoselective nucleophilic dichloromethylation and N-alkylation in one pot

A diastereoselective nucleophilic dichloromethylation between the N-tert-butanesulfinyl imines and dichloromethyllithium was developed. A series of 2-chloroaziridines with excellent yields and dr values were obtained via this nucleophilic addition and N-alkylation in one pot. On the basis of X-ray crystallography experiment, the predicting model for this diastereoselective transformation was provided.     

Asymmetric synthesis of furofurans

Furofurans are one of the largest sub-types of classical lignans which have been found to possess a broad range of important biological activities. Tremendous efforts have been directed to develop synthetic methodologies for the synthesis of furofurans, especially in a stereoselective manner, due to their interesting bioactivities associated with the structural and stereochemical complexity. This article summarizes the reports on asymmetric synthesis of furofurans disclosed during the period of 2004–2017.     

Asymmetric synthesis of 3-butylphthalide using isomannide and isosorbide as chiral auxiliaries

A new approach for asymmetric syntheses of (S) and (R)-3-n-butylphthalide (NBP) is presented.The diastereoselective addition of dibutylzinic to aromatic aldehyde 10 or 11 generated from isomannide-or isosorbide-derived chiral auxiliary afforded S-NBP or R-NBP in high optical yields.     

Asymmetric synthesis of SMS-Phos series’ precursor and a naphthalene analogue

An efficient and high-yielding (up to 57% overall yield) asymmetric route to enantiopure P-stereogenic 1,2-bis[(o-hydroxyaryl)(phenyl)phosphino-P-borane]ethanes wherein aryl = phenyl and naphthyl, is presented. The occurring P-stereomutation is confirmed through X-ray crystal structure analysis of key intermediates.     

Asymmetric synthesis of 3,3-disubstituted isoindolinones

An anionic chiral auxiliary-mediated asymmetric alkylation of carbamate 2 affords 3,3-disubstituted isoindolinones 3 in moderate to high de. The chiral auxiliary can be removed and recovered under mild conditions, and the resulting enantiopure lactams further elaborated.