Racemization in the use of N-(9-(9-phenylfluorenyl))serine-derived cyclic sulfamidates in the synthesis of delta-keto alpha-amino carboxylates and prolines

[reaction: see text]Ring opening of enantiopure N-(9-(9-phenylfluorenyl)serine-derived cyclic sulfamidates with beta-keto esters, beta-keto ketones, and dimethyl malonate gave a variety of gamma-substituted amino acid analogues in racemic form. Investigation of the mechanism for racemization revealed that beta-elimination occurred to form a dehydroalanine intermediate that underwent subsequent Michael addition.     

A 2,3-butanedione protected chiral glycine equivalent--a new building block for the stereoselective synthesis of enantiopure N-protected alpha-amino acids

A new chiral glycine equivalent 7 has been synthesised from glycidol using a chiral memory protocol, and its use in the synthesis of N-Z protected alpha-amino acids was demonstrated in a series of diasteroselective lithium enolate alkylation reactions and subsequent acid hydrolyses.     

A beta-lactone route to chiral gamma-substituted alpha-amino acids: application to the concise synthesis of (S)-alpha-azidobutyro lactone and a natural amino acid

[reaction: see text] Beta-lactones are useful synthetic intermediates allowing access to a number of functional arrays. In this report, enantiomerically pure 4-trichloromethyl-2-oxetanone is shown to be a versatile amino acid synthon leading to a variety of gamma-substituted alpha-amino acid precursors. The utility of this methodology was demonstrated by the concise synthesis of a protected homoserine equivalent, alpha-azidobutyro lactone, and a naturally occurring alpha-amino acid from the seeds of Blighia unijugata.     

A new method for the synthesis of chiral beta-branched alpha-amino acids

A new method for the synthesis of chiral beta-branched alpha-amino acids based on a copper-mediated directed allylic substitution reaction with Grignard reagents is reported. This is the first case in which a delta-stereogenic center is controlling the diastereoselectivity of an o-DPPB-directed allylic substitution. Depending on the alkene geometry of the starting material either diastereomer, anti or syn, is accessible with good levels of acyclic stereocontrol.     

Practical and convenient enzymatic synthesis of enantiopure alpha-amino acids and amides

Catalyzed by the nitrile hydratase and the amidease in Rhodococcus sp. AJ270 cells under very mild conditions, a number of alpha-aryl- and alpha-alkyl-substituted DL-glycine nitriles 1 rapidly underwent a highly enantioselective hydrolysis to afford D-(-)-alpha-amino acid amides 2 and L-(+)-alpha-amino acids 3 in high yields with excellent enantiomeric excesses in most cases. The overall enantioselectivity of the biotransformations of nitriles originated from the combined effects of a high L-enantioselective amidase and a low enantioselective nitrile hydratase. The influence of the substrates on both reaction efficiency and enantioselectivity was also discussed in terms of steric and electronic effects. Coupled with chemical hydrolysis of D-(-)-alpha-phenylglycine amide, biotransformation of DL-phenylglycine nitrile was applied in practical scale to produce both D- and L-phenylglycines in high optical purity.     

A new chiral catalyst for the enantioselective Strecker synthesis of alpha-amino acids

[reaction: see text] The chiral ammonium salt 3 is demonstrated to be an effective catalyst for the highly enantioselective Strecker reaction of N-allylbenzaldimines with hydrogen cyanide in CH2Cl2 solution.     

Practical synthesis of fluorous oxazolidinone chiral auxiliaries from alpha-amino acids

[reaction: see text] A series of new fluorous-supported oxazolidinone chiral auxiliaries has been prepared using a versatile and general five-step pathway, starting from readily available chiral alpha-amino acids. The key feature of this synthesis is the efficient generation of a suitably active perfluoroalkyllithium species. By use of this protocol, the auxiliaries can be obtained in high enantiomeric purity and on multigram scales from L-phenylalanine and L-valine with overall yields as high as 55%. The new methodology also incorporates fluorous solid-phase extraction on the large scale, allowing bulk quantities (up to 25 g) of fluorous compounds to be purified from the crude reaction mixture.     

Design of N-spiro C2-symmetric chiral quaternary ammonium bromides as novel chiral phase-transfer catalysts: synthesis and application to practical asymmetric synthesis of alpha-amino acids

A series of C(2)-symmetric chiral quaternary ammonium bromides 10 and 11 have been designed as a new, purely synthetic chiral phase-transfer catalyst, and readily prepared from commercially available optically pure 1,1'-bi-2-naphthol as a basic chiral unit. The details of the synthetic procedures of each requisite chiral binaphthyl subunit have been disclosed, and the structures of the assembled N-spiro chiral quaternary ammonium bromides 11a and 11f were unequivocally determined by single-crystal X-ray diffraction analysis. The reactivity and selectivity of these chiral ammonium bromides as chiral phase-transfer catalysts have been evaluated in the asymmetric alkylation of the benzophenone Schiff base of glycine ester 7 under mild liquid-liquid phase-transfer conditions, and the optimization of the reaction variables (solvent, base, and temperature) has also been conducted. Further, the scope and limitations of this asymmetric alkylation have been thoroughly investigated with a variety of alkyl halides, in which the advantage of the unique N-spiro structure of 11 and dramatic effect of the steric as well as the electronic properties of the aromatic substituents on the 3,3'-position of one binaphthyl moiety have been particularly emphasized. Finally, the potential synthetic utility of the present method for the practical asymmetric synthesis of structurally diverse natural and unnatural alpha-amino acids has been demonstrated by its successful application to the facile asymmetric syntheses of (S)-N-acetylindoline-2-carboxylate, a key intermediate in the synthesis of the ACE inhibitor, and l-Dopa (l-3,4-dihydroxyphenylalanine) ester and its analogue.     

Improved and efficient synthesis of chiral N,P-ligands via cyclic sulfamidates for asymmetric addition of butyllithium to benzaldehyde

A robust and scaleable route to chiral 1-isopropylamino-2-(diphenylphosphino)ethanes is described via the ring-opening of chiral, cyclic sulfamidates with potassium diphenylphosphide (KPPh(2)). The novel protocol offers a robust access to gram quantities of chiral amino phosphinoethanes in high yields. The Li-amides of the chiral aminophosphines were evaluated as chiral ligands in the asymmetric addition of n-butyllithium (BuLi) to benzaldehyde, yielding 1-phenylpentanol up to 98% ee.     

Dynamic kinetic resolution in the stereoselective synthesis of 4,5-diaryl cyclic sulfamidates by using chiral rhodium-catalyzed asymmetric transfer hydrogenation

The dynamic kinetic resolution of 4,5-diaryl cyclic sulfamidate imines was achieved via asymmetric transfer hydrogenation using a HCO(2)H/Et(3)N mixture as the hydrogen source and chiral Rh catalysts (R,R)- or (S,S)-RhCl(TsDPEN)Cp* affording the corresponding cyclic sulfamidates in good yields with up to >20 : 1 dr and up to >99% ee.     

Reactivity of cyclic sulfamidates towards lithium acetylides: synthesis of alkynylated amines

A synthetically useful level of reactivity of cyclic sulfamidates toward acetylides is described. Ring-opening reactions of a structurally diverse set of 1,2- and 1,3-cyclic sulfamidates with a range of lithium acetylides from aliphatic, cyclic, aromatic, heteroaromatic, and functionalized alkynes proceed smoothly in a regioselective manner to give the corresponding N-sulfate intermediates. Hydrolysis of these intermediates under acidic conditions furnishes the alkynylated amines in yields ranging from 29% to 98%. The scope of the acetylenic substitution reaction with the structural variations in both the cyclic sulfamidates and alkynes is briefly examined.     

Improved synthesis of proline-derived Ni(II) complexes of glycine: versatile chiral equivalents of nucleophilic glycine for general asymmetric synthesis of alpha-amino acids

A synthetically practical and operationally convenient method for preparing (S)-2-[N-(N'-benzylprolyl)amino]benzophenone (BPBP) and hitherto unknown (S)-2-[N-(N'-benzylprolyl)amino]-4-methylbenzophenone (4-Me-BPBP), (S)-2-[N-(N'-benzylprolyl)amino]-5-nitrobenzophenone (5-NO(2)-BPBP), and their corresponding Ni(II) complexes with glycine [GlyNi(II)BPBP], a widely used chiral equivalent of nucleophilic glycine, and new analogues [GlyNi(II)-4-Me-BPBP] and [GlyNi(II)-5- NO(2)-BPBP] is described. The key step of the method is the synthetically efficient amid bond formation between the corresponding o-aminobenzophenones, featuring significant steric shielding and low nucleophilicity of the amino functionality as well as sterically constrained (S)-N-benzylproline (BP).     

Development of a recyclable fluorous chiral phase-transfer catalyst: application to the catalytic asymmetric synthesis of alpha-amino acids

[structure: see text] A recyclable fluorous chiral phase-transfer catalyst was synthesized and successfully applied for the catalytic asymmetric synthesis of both natural and unnatural alpha-amino acids. The reaction involves alkylation of a glycine derivative followed by extractive recovery of the chiral phase-transfer catalyst using fluorous solvent.     

Carbohydrates as chiral templates: asymmetric ugi-synthesis of alpha-amino acids using galactosylamines as the chiral matrices

In the presence of Lewis acid catalysts O-acetyl- (1) and O-pivaloyl- (2) protected β-D-galactopyranosylamines react with aldehydes, isocyanides and carboxylic acids in Ugi-four-component-condensations to give the corresponding N-galactosyl-amino acid amide derivatives 3,5 in almost quantitative yields. Zinc chloride is the most effective Lewis acid catalyst. At 0°C or even at room temperature the (2R,β-D)-diastereomers of the amino acid derivatives 3,5 are formed with high diastereoselectivity. If the sterically more demanding O-pivaloyl galactosylamine 2 is used at -78°C to -25°C the stereoselectivity often exeeds 20:1 favouring the (2R,β-D) diastereomers 5. After one recrystallisation pure (R)-amino acid derivatives 5 are obtained in yields of 80–95%. In addition to the high yields and stereoselectivity the amino acid synthesis discribed here has the further advantage that it neither requires organometallic reagents and intermediates nor exclusion of oxygen and moisture. Two step acid hydrolysis of the N-galactosylamino acid amide derivatives 5 delivers the enantiomerically pure (R)-amino-acids 8 in high yields.     

Versatile synthons for optically pure alpha-amino aldehydes and alpha-amino acids: (+)- and (-)-4,5-dialkoxy-2-oxazolidinones

Both enantiomers of trans-5-benzyloxy-4-methoxy- (BMOx) and trans-4,5-dimethoxy-2-oxazolidinones (DMOx), which are readily accessible from simple 2-oxazolone heterocycles, represent good candidates for a new class of chiral synthons for use in the preparation of optically pure alpha-amino aldehydes and alpha-amino acids, respectively.     

Application of serine- and threonine-derived cyclic sulfamidates for the preparation of S-linked glycosyl amino acids in solution- and solid-phase peptide synthesis

Cyclic sulfamidates were synthesized in 60% yield from L-serine and allo-L-threonine, respectively. These sulfamidates reacted with a variety of unprotected 1-thio sugars in aqueous bicarbonate buffer (pH 8) to afford the corresponding S-linked serine- and threonine-glycosyl amino acids with good diastereoselectivity (> or =97%) after hydrolysis of the N-sulfates. The serine-derived sulfamidate was incorporated into a simple dipeptide to generate a reactive dipeptide substrate that underwent chemoselective ligation with a 1-thio sugar to afford an S-linked glycopeptide. This sulfamidate was also incorporated into a peptide on a solid support in conjunction with solid-phase peptide synthesis. Chemoselective ligation of a 1-thio sugar with the cyclic sulfamidate was achieved on the solid support, followed by removal of the N-sulfate. Finally, the peptide chain of the resulting support-bound S-linked glycopeptide was extended using standard peptide synthesis procedures.     

Serine as chiral educt for the practical synthesis of enantiopure N-protected beta-hydroxyvaline

N-tert-Butyloxycarbonyl- and N-benzenesulfonyl-beta-hydroxyvalines 1a and 1b were, respectively, synthesized in enantiomerically pure form by a two-step protocol from their enantiomeric N-protected serine methyl esters 2a and 2b. The addition of CH(3)MgBr to 2a and 2b provided diols 3a and 3b, respectively as major products in 83% and 81% yields. Selective oxidation of diols 3a and 3b was performed using a TEMPO, NaClO(2), NaOCl cocktail in 96% and 93% respective yields. This two-step process effectively furnished multigram amounts of enantiopure N-Boc-beta-hydroxyvaline 1a.     

Synthesis of all nineteen appropriately protected chiral alpha-hydroxy acid equivalents of the alpha-amino acids for Boc solid-phase depsi-peptide synthesis

[reaction: see text] The preparation of depsi-peptides, amide-to-ester-substituted peptides used to probe the role of hydrogen bonding in protein folding energetics, is accomplished by replacing specific l-alpha-amino acid residues by their alpha-hydroxy acid counterparts in a solid-phase synthesis employing a t-Boc strategy. Herein we describe the efficient stereoselective synthesis of all 19 appropriately protected alpha-hydroxy acid equivalents of the l-alpha-amino acids, employing commercially available materials, expanding the number of available alpha-hydroxy acids from 9 to 19.