Stereoselective allylation reactions of acyclic and chiral α-amino-β-hydroxy aldehydes

Stereoselective allylation reactions of acyclic and chiral α-amino-β-hydroxy aldehydes affording chiral β-amino-α,γ-diols are described. Several Lewis acids (BF₃·OEt₂, SnCl₄, TiCl₄, ZnCl₂, and MgBr₂·OEt₂) were employed to mediate the allylation reactions. The reactions of anti-α-NHCbz-β-OTBS substrates mediated by SnCl₄ afforded syn-selective products. The same reaction conditions also gave satisfactory results for the reactions of syn-α-NHCbz-β-OTBS substrates. The mechanism involves α-chelation between the amido group and aldehyde oxygen.     

Stereoselective allylation of acyclic and chiral α-amino-β-Hydroxy aldehydes part 2: Application to the formal synthesis of the polyhydroxylated γ-amino acid (+)-Detoxinine

Stereoselective allylations of acyclic, chiral α-amino-β-hydroxy aldehydes mediated by BF₃·OEt₂ and its application to the formal synthesis of the polyhydroxylated γ-amino acid (+)-detoxinine are described. The reactions of syn-α-NHCbz-β-OTBS substrates mediated by BF₃·OEt₂ afforded syn-selective products. The same reaction conditions gave anti-selective products from syn-α-NCbzBn-β-OTBS substrates. A hydrogen-bonded transition state and Felkin-Anh model have been suggested to account for the stereochemical outcomes of the two reactions, respectively. One of the allylation products was used for the formal synthesis of the polyhydroxylated γ-amino acid (+)-detoxinine.     

Stereoselective allylation of α-hydroxy aldimines and its application to the formal synthesis of (−)-β-conhydrine

Stereoselective allylation of N-p-methoxyphenyl (PMP)-substituted α-hydroxy aldimines is described. Several Lewis acids (BF₃·OEt₂, SnCl₄, TiCl₄, ZnCl₂, and MgBr₂·OEt₂) were employed to mediate the allylation reactions. The addition of the allyl group generates a new stereocenter and affords the syn vicinal amino alcohol. Formal synthesis of (?)-β-conhydrine (1) was accomplished via syn-selective allyl addition to N-PMP-substituted α-hydroxy aldimine.     

Stereoselective cyanation of chiral α-amino aldehydes by reaction with Nagata's reagent: a route to enantiopure β-amino-α-hydroxy acids

Chiral α-dibenzylamino aldehydes react with diethylaluminum cyanide leading to anti-β-dibenzylamino-α-hydroxycyanides as the major diastereoisomers in good yields and diastereomeric excesses. Hydrolysis of the nitrile derivatives allows the synthesis of enantiopure β-amino-α-hydroxy acids.     

Asymmetric total synthesis of (+)-1-deoxy-6-epi-castanospermine

(+)-1-Deoxy-6-epi-castanospermine was asymmetrically synthesized in ten steps from α-furfuryl amine derivative 6 in 2.9% overall yield. The kinetic resolution of α-furfuryl amine derivative 6 and Sharpless AD reaction of 14 were used as key steps.     

The asymmetric synthesis of chiral cyclic α-hydroxy phosphonates and quaternary cyclic α-hydroxy phosphonates

A highly practical, catalytic enantioselective cyclic phosphite addition to aldehydes and ketones was developed. The reaction rate of the asymmetric hydrophosphonylation was significantly enhanced by the addition of silver carbonate. Particularly, significant improvement has been achieved on the asymmetric hydrophosphonylation of unactivated ketones, giving quaternary α-hydroxy phosphonates with excellent enantioselectivity (up to 99% ee).     

Total synthesis of (+)-varitriol and (+)-6′-epi-varitriol

Total synthesis of (+)-varitriol and its C6′-epimer have been achieved starting from commercially available d-(?)-ribose and o-anisic acid. The key steps involved are Corey Chaykovsky reaction, triethylamine mediated epimerization, and an olefin cross-metathesis.     

Stereoselective synthesis of syn-α-methyl-β-hydroxy esters

Boron enolates of an ethyl ketone structurally related to erythrulose react with achiral aldehydes in a highly stereoselective fashion to yield 1,2-syn/1,3-syn stereoisomers. Oxidative cleavage of the aldol adducts yields enantiopure O-formylated syn-α-methyl-β-hydroxy esters, easily cleaved to the corresponding hydroxyl-free compounds. The aforementioned ketone behaves therefore as a chiral propionate enolate equivalent.     

Stereoselective palladium-catalyzed α-arylation of 3-aryl-1-indanones: an asymmetric synthesis of (+)-pauciflorol F

Highly stereoselective, palladium-catalyzed α-arylation reactions of 3-aryl-1-indanones with aryl bromides are described. The use of sodium tert-butoxide as a base in this process is required to elevate the efficiencies and stereoselectivities of these reactions. The new methodology was successfully applied to a highly efficient route for the asymmetric synthesis of (+)-pauciflorol F.     

Total synthesis of (+)-balanitol and of (+)-selin-4-(15)-ene-1β,11-diol

(+)-Balanitol (1) and (+)-selin-4-(15)-ene-1β,11-dio1 (2), two recently-isolated naturally occurring eudesmanoid bicyclic sesquiterpene alcohols, have been synthesized stereoselectively by a route involving a [2 +2] photocycloaddition of a cyclobutene and a suitably structured 2-cyclohexenone. The structure and stereochemistry of the compounds are thereby corroborated.     

Diastereoselective α-alkylation of β-hydroxy sulfoxides and its application to the synthesis of (+)- and (3)-disparlure

α-Alkylation of the dianions of β-hydroxy sulfoxides proceeds with high 1, 2-asymmetric induction to give threo-α-alkyl-β-hydroxy sulfoxides. The utility of the present reaction was demonstrated in the asymmetric synthesis of (+)- and (3)-cis-7, 8-epoxy-2-methyloctadecanes (disparlure).     

Stereoselective palladium-catalyzed functionalization of homoallylic alcohols: a convenient synthesis of di- and trisubstituted isoxazolidines and β-amino-δ-hydroxy esters

Enantiopure, Boc-protected alkoxyamines 12 and 13, derived from the readily available homoallylic alcohols 4 via a reaction that involves either inversion or retention of configuration, undergo a diastereoselective Pd-catalyzed ring-closing carbonylative amidation to produce isoxazolidines 16/17 (≤50:1 diastereoisomer ratio (d.r.)) that can be readily converted into the N-Boc-protected esters of β-amino-δ-hydroxy acids and their γ-substituted homologues 37. The key carbonylative cyclization proceeds through an unusual syn addition of the palladium and the nitrogen nucleophile across the C=C bond (19→21), as revealed by the reaction of 15, which afforded isoxazolidine 18 with high diastereoselectivity.     

Stereoselective synthesis of α-aryl-2-benzofuranmethanamines and α-aryl-1H-indole-2-methanamines through palladium-mediated annulation of chiral α-arylpropargylamines

The title compounds, valuable chiral synthons for the synthesis of biologically active compounds, have been prepared in good yield and with high stereoselectivity through palladium-catalyzed heteroannulation of 2-iodophenol or 2-iodo-N-mesylaniline with enantiomerically pure or enriched α-arylpropargylamines.     

Total synthesis of natural (−)- and unnatural (+)-Melearoride A

This communication details the first total synthesis of the 13-membered macrolide, (?)-Melearoride A, as well as unnatural (+)-Melearoride A. The synthesis features a concise 13 step synthesis (11 steps longest linear sequence) that offers flexible stereo-control and multiple opportunities for unnatural analog synthesis to delve into antifungal SAR. The route features a cuprate addition, an Evans asymmetric alkylation, and a ring-closing metathesis (RCM) to close the 13-membered macrocyclic core.     

A versatile reagent for synthesis of α-hydroxy aldehydes and ketones —methylthiomethyl p-tolyl sulfone

Methylthiomethyl p-tolyl sulfone (1) can be utilised for synthesizing α-hydroxy ketones as well as α-hydroxy aldehydes, the hydroxyl group of which is protected with acetyl, tetrahydropyranyl, or methoxymethyl group.