Nucleophilic additions to N-glycosylnitrones part IV Asymmetric synthesis of N-hydroxy-α-aminophosphonic and α-aminophosphonic acids

The addition of phosphite anions and of tris(trimethylsilyl) phosphite (P(OSiMe₃)₃) to N-glycosyl-C-arylnitrones was examined. While these nitrones proved inert towards the phosphite anions, they reacted with P(OSiMe₃)₃ under catalysis by Lewis acids. Thus, P(OSiMe₃)₃ reacted with the crystalline (Z)-N-glycosylnitrones 2 and 8 to give the optically active N-hydroxy-α-aminophosphonic acids 4 and 10 , respectively, and hence the α-aminophosphonic acids 5 and 11 in yields up to 92% and with an enantiomeric excess (e.e.) up to 97% (Scheme 1). The absolute configuration of the phosphonates depend upon the nature and – in one case – upon the quantity of the catalyst (Figure). Upon catalysis by HCIO₄ or Zn(OTF)₂, p(OSiMe₃)₃ added to 2 to give, in both cases, the (+)-(R)-phenylphosphaglycine 5 (optical purity 79–84 and 90–93%, resp.). The optical purity (o.p.) was hardly influenced by the amount of these catalysts (0.02-;1 equiv.). However, catalysis by ZnCl₂ gave, with trace quantities of the catalyst, (–)-(S)- 5 (o.p. 79%), while an equimolar amount of ZnCl₂ yielded (+)-(R)- 5 (o.p. 82%). The HClO₄-catalyzed addition of P(OSiMe₃)₃ to the nitrone 14 (Scheme 2) led to (+)-(R)-N-hydroxyphosphavaline 15 (78%) and hence to (–)-(R)-phosphavaline 16 (71% from 14 e.e. 95%). Under conditions leading from the nitrones 2 , 8 , 14 , and 20 (Schemes 1 and 2) predominantly to (R)-α-aminophosphonic acids, the addition of P(OSiMe₃)₃ to nitrone 18 , possessing a benzyloxy substituent as an additional potential ligand for the catalyst, gave (S)-phosphaserine 19 . The addition of P(OSiMe₃)₃ to the nitrone 20 , catalyzed by Zn(OTf)₂, led to (+)-(R)-N-hydroxyphosphamehionine 21 (71%, e.e. 77%) and hence to (–)-(R)-phosphamethionine 22 (77% from 20 , e.e. 79%). Catalysis by trace quantities of ZnCl₂ gave (+)-(S)- 22 (85%, e.e. 61%). The enantiomerically pure aminophosphonic acids 5 , 11 , and 16 were obtained by recrystalliztion. The e.e. of the N-hydroxyaminosphosphonic acids 10 , 15 , and 21 and the aminophosphonic acids 5 , 11 , 16 , and 22 were determined by the HPLC analysis of the dimethyl N-naphthoyl-α-aminophosphonats 7 , 13 , 17 , and 23 , on a chiral stationary phase.     

A convenient route to α-amido-β-lactams

Dedicated to Professor John C. Sheehan on the occasion of his sixty-fifth birthday. A method for the synthesis of α-amido-β-lactams without the intermediacy of an α-amino-β-lactam is described. The appropriate β-keto ester is used for preparing a vinylamino β-lactam via a “Dane salt” by a previously reported method. Oxidation with ruthenium tetroxide and periodic acid of this product leads directly to the desired “V”, or “G” or analogous α-amido side chain.     

A new synthetic route to α-alkylacrylic esters and α-alkylacrylonitriles

α-Alkylacrylic esters and α-alkylacrylonitriles have been synthesized by cracking their cyclopentadiene adducts. The latter were derived by treatment of the lithium enolates of cyclopentadiene-blocked acrylates or acrylonitriles with alkyl halides.     

Synthesis of chiral α-amino acids

A novel method for the synthesis of chiral α-amino acids has been developed where the acid functionality was constructed by oxidizing a hydroxymethyl group introduced by Evans’ method in the α-position of an appropriate acid substrate and the amino part came from the amide of the original carboxyl group following a modified Hofmann rearrangement reaction.     

Asymmetric reduction of azirines; a new route to chiral aziridines

The first enantioselective reduction of aromatic 2H-azirines yields aziridines in up to 70% ee, using the aminoalcohol-[RuCl2(p-cymene)]2 catalyzed asymmetric transfer hydrogenation reaction.     

InBr3-catalyzed Friedel-Crafts addition of indoles to chiral aromatic epoxides: a facile route to enantiopure indolyl derivatives

Aromatic optically active epoxides can be opened in a regioselective and clean way with indoles in the presence of catalytic amount of InBr3 (1 mol %). The reaction takes place with a SN2 pathway affording the 2-aryl-2-(3'-indolyl)ethan-1-ols with excellent enantioselectivity (ee up to 99%).     

Diastereoselective addition of diethyl difluoromethylphosphonate to enantiopure sulfinimines: synthesis of α,α-difluoro-β-aminophosphonates, phosphonic acids, and phosphonamidic acids

Addition of diethyl lithiodifluoromethylphosphonate to enantiomerically pure aromatic, heteroaromatic, and aliphatic aldehyde-derived sulfinimines afforded N-sulfinyl α,α-difluoro-β-aminophosphonates with generally good enantioselectivity and in high yield. The reaction with acetophenone-derived sulfinimine resulted in the formation of the addition product with high diastereoselectivity and in only moderate yield. A two-step deprotection involving treatment of diastereomerically pure N-sulfinyl α,α-difluoro-β-aminophosphonates with trifluoroacetic acid in EtOH followed by refluxing with 10 N HCl provided enantiopure α,α-difluoro-β-aminophosphonates and α,α-difluoro-β-aminophosphonic acids. The N-Cbz derivative of (R)-2-amino-1,1-difluoro-2-phenylethylphosphonate was a convenient starting point for the preparation of corresponding difluorophosphonate monoester, difluorophosphonic acid, and difluorophosphonamidic acid. At 21 °C difluorophosphonamidic acid was stable in aqueous solution at pH above 5.     

Determination of the enantiomeric excess of α-hydroxy acids

This work describes a convenient and accurate method for optical purity determination of α-hydroxy acids. Their derivatization with commercially available valine methyl ester affords diastereoisomers easily separable by HPLC using achiral C₁₈ columns.     

Amine-induced rearrangements of 2-bromo-1-(1H-indol-3-yl)-2-methyl-1-propanones: A new route to α-substituted indole-3-acetamides, β-substituted tryptamines, α-substituted indole-3-acetic acids and indole β-aminoketones

The reaction of 2-bromo-1-(1H-indol-3-yl)-2-methyl-1-propanone ( 1 ) and 2-bromo-1-(1-methyl-1H-indol-3-yl)-2-methyl-1-propanone ( 2 ) with primary amines proceeds in good yields to produce rearranged amides by a proposed pseudo-Favorskii mechanism. These amides in turn can either be reduced to produce β-substituted tryptamines or hydrolyzed to produce substituted indole-3-acetic acids. When the reaction is carried out using bulky primary or secondary amines, β-aminoketones are produced by elimination of hydrogen bromide followed by Michael addition. When hindered secondary amines or tertiary amines are used, elimination to the α,β-unsaturated ketones occurs.     

Catalytic enantioselective conjugate addition of dialkyl zinc reagents to α,β-unsaturated ketones mediated by new phosphite ligands containing binaphthalene/1,2-diphenylethane moieties: a practical synthesis of (R)-(−)-muscone

New diastereoisomeric phosphites based on either (R)- or (S)-2,2′-dihydroxy-1,1′-binaphthyl (BINOL) and having the chiral alcoholic moiety derived from the monobenzyl ether of (R,R)-1,2-diphenylethane-1,2-diol have been prepared and used as chiral ligands in the enantioselective copper-catalyzed 1,4-addition of diethylzinc to chalcone and 2-cyclohexen-1-one (enantiomeric excesses up to 48%). With the (aR,R,R) ligand dimethylzinc adds enantioselectively to (E)-cyclopentadecen-2-en-1-one to give (R)-(−)-muscone (68% yield, 78% ee). This provides an efficient access to a valuable ingredient of the perfume industry. However, with the (aS,R,R) ligand, (S)-(+)-muscone is obtained with longer reaction times (37% yield and 10% ee) with a very high double diastereoselection effect being observed.     

An efficient and convenient transformation of α-haloketones to α-hydroxyketones using cesium formate

A new safe and convenient transformation has been developed. In the presence of cesium formate in dry MeOH solution, α-haloketones underwent direct conversion reaction to afford α-hydroxyketone in excellent yields. Furthermore, this methodology can be extended and applied in 2-chloro-N-(1,3-diphenyl-1H-pyrazol-5-yl)acetamide, 2-chloro-N-(2,6-dimethylphen-yl)acetamide, 1-(bromomethylsulfonyl)benzene, and N-(bromomethyl)phthalimide to give the corresponding products in moderate to excellent yields.     

Nucleophilic addition of organocerium reagents to α‐alkoxy hydrazones: A new type of elimination reaction to α‐hydroxynitriles

We studied the nucleophilic addition of organocerium reagents to α‐alkoxy hydrazones. The results depend upon the organocerium reagents, the nature of protection for the hydroxy group, and the solvents used. Contrary to Grignard reagents, organocerium reagents derived from Grignard reagents effectively add to α‐alkoxy hydrazones. In addition, a new type of elimination reaction of α‐alkoxy hydrazones to the corresponding nitriles by methyl chloroformate was found. This methodology is an efficient and potentially practical synthetic route to β‐hydroxy amines. © 2000 John Wiley & Sons, Inc. Heteroatom Chem 11:65–72, 2000     

Transformations of N-heteroarylformamidines into derivatives of β-heteroarylamino-α,β-dehydro-α-amino acids, β-heteroarylamino-α-amino acids,and dipeptides

Transformations of N'-heteroaryl-N,N-dimethylformamidines 1 as a general method for the preparation of β-heteroarylamino-α,β-dehydro-α-amino acids, β-heteroarylamino-α-amino acid derivatives 5–9 , and dipeptides 10 , are described.     

Reduction of α,β-unsaturated nitroalkenes with borane and borohydrides. A convenient route to 3-nitro-, 3-hydroxylamino-, and 3-amino-2h-1-benzopyran derivatives

The borohydride catalyzed borane reduction of 3-nitrochromenes provided a facile route to a variety of 3-hydroxylamino- 5 and 3-amino-2H-1-benzopyranes 6. Reduction with methoxyborohydride species, on the other hand, provided 3-nitrochromans 2,4.     

Asymmetric addition of a nitrogen nucleophile to an enoate in the presence of a chiral phase‐transfer catalyst: A novel approach toward enantiomerically enriched protected β‐amino acids

A proof of concept for the asymmetric organocatalytic aza‐Michael addition reaction of nitrogen nucleophiles with simple and readily available alkyl enoates as acceptor molecules in the presence of a chiral phase‐transfer catalyst has been demonstrated. The desired enantiomerically enriched β‐amino acid derivatives were obtained in up to 86% yield and with enantioselectivities of up to 37% ee. © 2012 Wiley Periodicals, Inc. Heteroatom Chem 23:202–209, 2012; View this article online at wileyonlinelibrary.com . DOI 10.1002/hc.21004     

The addition reaction of α-azido ethers and α-azido thioethers to phenylacetylene

Several v-triazoles were synthesized by 1,3-dipolar cycloaddition of certain α-azido ethers and α-azidothioethers to phenylacetylene. In most of the cases the reaction led to the formation of the two isomeric v-triazoles. Structural assignments for the products obtained were made on the basis of NMR data and chemical reactions. Characteristic differences between the NMR spectra of the isomers have been noted.     

1,3-Dipolar Addition of Methyl α-Diazoacetoacetate to Enamines： A New Synthetic Route to 5-Amino-4,5-dihydrofurans

The reaction of methyl α-diazoacetoacetate with enamines catalyzed by dirhodium and copper complexes underwent formal 1,3-dipolar addition to give 5-amino-4,5-dihydrofurans in moderate yields. The reaction was suggested to proceed via a nucleophilic addition of enamines to rnetal-carbenes and a subsequent intramolecular cyclization of the resulting zwitterionic intermediates.     

Direct Catalytic Asymmetric Aldol Reaction of α‐Alkoxyamides to α‐Fluorinated Ketones

α‐Oxygen‐functionalized amides found particular utility as enolate surrogates for direct aldol couplings with α‐fluorinated ketones in a catalytic manner. Because of the likely involvement of open transition states, both syn‐ and anti‐aldol adducts can be accessed with high enantioselectivity by judicious choice of the chiral ligands. A broad variety of alkoxy substituents on the amides and aryl and fluoroalkyl groups on the ketone were tolerated, and the corresponding substrates delivered a range of enantioenriched fluorinated 1,2‐dihydroxycarboxylic acid derivatives with divergent diastereoselectivity depending on the ligand used. The amide moiety of the aldol adduct was transformed into a variety of functional groups without protection of the tertiary alcohol, showcasing the synthetic utility of the present asymmetric aldol process.