Trading N and O. Part 4: Asymmetric synthesis of syn-β-substituted-α-amino acids

A total of nine enantiopure syn-β-substituted-α-amino acids have been synthesised, comprising both syn-β-hydroxy-α-amino acids and syn-β-fluoro-α-amino acids. The key step in the synthetic strategy towards these syn-β-substituted-α-amino acids involves a stereospecific rearrangement, which proceeds via the intermediacy of the corresponding aziridinium ions. The requisite enantiopure syn-α-hydroxy-β-amino esters were prepared via asymmetric aminohydroxylation of the corresponding α,β-unsaturated esters followed by epimerisation of the resultant anti-α-hydroxy-β-amino esters at the C(2)-position. Subsequent activation of the α-hydroxy moiety as a leaving group followed by displacement by the β-amino substituent gave the corresponding aziridinium species. Regioselective in situ ring-opening of the aziridinium intermediates with either water or fluoride gave the corresponding syn-β-hydroxy-α-amino ester or syn-β-fluoro-α-amino ester, respectively, and N-deprotection and ester hydrolysis afforded the target syn-β-substituted-α-amino acids as single diastereoisomers in good overall yield.     

Highly enantioselective synthesis of anti aryl β-hydroxy α-amino esters via DKR transfer hydrogenation

An efficient preparation of highly enantiomerically enriched aryl β-hydroxy α-amino esters via dynamic kinetic resolution (DKR), asymmetric transfer hydrogenation of α-amino β-keto esters is described. The anti β-hydroxyl α-amino esters were obtained both in high yields and high diasteroselectivity. The observed high anti selectivity is inconsistent with the previous results in literature. The absolute stereochemistry of the aryl β-hydroxy α-amino esters was unambiguously confirmed via chemical derivatization as well as Vibrational Circular Dichroism (VCD) techniques.     

Fluoroalkyl substituted (Z)-dehydro α-amino ester as a building block for the fluorine-containing cyclopropyl α-amino esters and dihydrooxazole

Multi-functionalized β-trifluoromethyl and β-difluoromethyl substituted (Z)-α,β-dehydro α-amino esters have been successfully prepared from N-protected fluorinated threonine ester. Applications of this new fluorine-containing building block to the synthesis of biologically important fluorinated cylcopropyl α-amino esters and dihydrooxazole ester have also been reported.     

Homochiral lithium amides for the asymmetric synthesis of β-amino acids

Secondary homochiral lithium amides derived from α-methylbenzylamine undergo highly diastereoselective conjugate additions to a range of α,β-unsaturated esters. The corresponding β-amino acids are readily liberated by successive N-debenzylation and ester hydrolysis, furnishing (R)-β-amino butyric acid, (R)-β-amino pentanoic acid, (S)-β-leucine, (R)-β-amino octanoic acid, (S)-β-phenylalanine, (S)-β-tyrosine methyl ether, (S)-β-tyrosine hydrochloride and (S)-β-(2-methoxyphenyl)-β-amino propanoic acid in high yields and high ee. The application of this procedure to the synthesis of the natural products (R)-β-DOPA and (R)-β-lysine is demonstrated. The development of a simplified one-pot reaction protocol applicable to the multi-gram scale synthesis of homochiral β-amino esters is also delineated.     

Lithium n-benzyltrimethylsilylamide (LSA): a new reagent for conjugate addition - enolate trapping reactions

Lithium N-benzyltrimethylsilyl amide (LSA) adds to crotonates in a 1,4-manner, though the reaction of ordinary lithium amides with α,β-unsaturated carbonyl compounds is accompanied with a 1,2-addition and hydrogen abstraction at the γ-position. The conjugate addition via LSA followed by enolate trapping with electrophiles produces the corresponding α-substituted β-amino esters, which are, in turn, converted into β-lactams and α-substituted α, β-unsaturated esters.     

Catalyst-free Mannich-type reaction of 1-(N-acylamino)alkyltriphenylphosphonium salts with silyl enolates

A catalyst-free reaction of 1-(N-acylamino)alkyltriphenylphosphonium tetrafluoroborates with silyl enolates was developed to prepare β-amino carbonyl compounds. The reported method is a useful approach for the preparation of N-protected β-amino esters as well as N-protected β-amino ketones. The starting 1-(N-acylamino)alkyltriphenylphosphonium tetrafluoroborates are readily available from N-protected α-amino acids. Therefore, the presented approach can be considered a new method for the α-homologation of N-protected α-amino acids to prepare β-amino acid derivatives.     

Parallel synthesis of homochiral β-amino acids

The parallel asymmetric synthesis of an array of 30 β-amino acids of high enantiomeric purity using the conjugate addition of homochiral lithium N-benzyl-N-(α-methylbenzyl)amide as the key step is accomplished. The experimental simplicity and highly practical nature of the protocol is demonstrated by the efficient parallel conversion of 15 α,β-unsaturated esters to both enantiomeric series of the corresponding β-amino acids in high overall yields and selectivities with minimal purification involved in each step of the reaction protocol.     

A solventless protocol for the Michael addition of aromatic amides to α,β-unsaturated esters promoted by microwave irradiation

A very simple and efficient solvent-free method for the preparation of N-benzoylated β-amino esters (protected β-amino acids) via the microwave-assisted Michael addition of aromatic amides to α,β-unsaturated esters in the presence of Cs₂CO₃ and tetrabutylammonium bromide (TBAB) is described. The advantages of this method are efficiency, high yields and short reaction times.     

Enantioselective gem-chlorofluorination of active methylene compounds using a chiral spiro oxazoline ligand

Highly enantioselective gem-chlorofluorination of active methylene compounds was carried out by using a copper(II) complex of a chiral spiro pyridyl monooxazoline ligand. This reaction yielded α-chloro-α-fluoro-β-keto esters and α-chloro-α-fluoro-β-keto phosphonates with up to 92% ee. The resulting dihalo β-keto ester was converted into various α-fluoro-α-heteroatom-substituted carbonyl compounds via nucleophilic substitution without loss of optical purity. A fully protected β-amino acid with a gem-chlorofluoromethylene function was also synthesized.     

Solution-phase synthesis of novel seven-membered cyclic dipeptides containing α- and β-amino acids

A convenient synthetic procedure for the preparation of seven-membered cyclic α,β-dipeptides is described. Following coupling of N-protected α-amino acids with N-substituted β-amino acid tert-butyl esters, that affords linear α,β-dipeptides, the protecting groups at the terminal functionalities were removed and the open-chain dipeptides were cyclized with phenylphosphonic dichloride, PhP(O)Cl₂, to give the desired cyclic α,β-dipeptides in good yields. NMR studies, X-ray diffraction analysis, and DFT calculations provided evidence for the conformation adopted by these cyclic dipeptides in solution, in the solid-state, and in the gas phase.     

Regio- and diastereoselective Reformatsky reaction of chiral fluoroalkyl α,β-unsaturated N-tert-butanesulfinyl ketimines: Efficient asymmetric synthesis of β-fluoroalkyl β-vinyl β-amino esters

Highly regio- and diastereoselective Reformatsky reaction of stable, chiral fluoroalkyl α,β-unsaturated N-tert-butanesulfinyl ketimines was developed, which provided an efficient method for the asymmetric synthesis of structurally diverse β-tetrasubstituted β-fluoroalkyl β-vinyl β-amino esters in good yields and with excellent diastereoselectivities (dr up to 96:4).     

Trading N and O. Part 2: Exploiting aziridinium intermediates for the synthesis of β-hydroxy-α-amino acids

The β-hydroxy-α-amino acids (S,S)-allo-threonine, (S,S)-β-hydroxyleucine and a range of aryl substituted (S,S)-β-hydroxyphenylalanines were prepared from the corresponding enantiopure anti-α-hydroxy-β-amino esters via a rearrangement protocol, which proceeds via the intermediacy of the corresponding aziridinium ions. The starting anti-α-hydroxy-β-amino esters were prepared in >99:1 dr using our diastereoselective aminohydroxylation procedure, whereby conjugate addition of lithium (R)-N-benzyl-N-(α-methylbenzyl)amide to an α,β-unsaturated ester is followed by oxidation of the resultant enolate with (−)-camphorsulfonyloxaziridine. Subsequent activation of the hydroxyl group within the anti-α-hydroxy-β-amino esters promoted aziridinium ion formation [which proceeds with inversion of configuration at C(2)], and regioselective ring-opening of the intermediate aziridinium ions with H₂O [which proceeds with inversion of configuration at C(3)] gave the corresponding anti-β-hydroxy-α-amino esters as single diastereoisomers (>99:1 dr). Deprotection of these substrates via sequential hydrogenolysis and ester hydrolysis gave the corresponding β-hydroxy-α-amino acids in good yield and high diastereoisomeric and enantiomeric purity.     

Asymmetric synthesis of cyclic β-amino acids and cyclic amines via sequential diastereoselective conjugate addition and ring closing metathesis

Diastereoselective conjugate addition of lithium (S)-N-allyl-N-α-methylbenzylamide to a range of α,β-unsaturated esters followed by ring closing metathesis is used to afford efficiently a range of substituted cyclic β-amino esters in high d.e. Alternatively, conjugate addition to α,β-unsaturated Weinreb amides, functional group conversion and ring closing metathesis affords cyclic amines in high d.e. The further application of this methodology to the synthesis of a range of carbocyclic β-amino esters via conjugate addition, enolate alkylation and ring closing metathesis is also described. Application of this methodology affords, after deprotection, (S)-homoproline, (S)-homopipecolic acid, (S)-coniine and (1S,2S)-trans-pentacin.     

Asymmetric synthesis of β-fluoroaryl-β-amino acids

The conjugate addition of lithium (R)-N-benzyl-N-(α-methylbenzyl)amide to a range of β-fluoroaryl-α,β-unsaturated esters gave the corresponding β-amino esters with high diastereoselectivity and in good isolated yields. Sequential treatment of the resultant β-fluoroaryl-β-amino esters under optimised hydrogenolysis conditions, followed by ester hydrolysis with 2.0 M aq HCl, provided access to a range of β-fluoroaryl-β-amino acids in good yield.     

Diastereoselective synthesis of trans-trifluoromethyl-β-lactams and α-alkyl-β-trifluoromethyl-β-amino esters

The diastereoselective synthesis of β-lactams was examined from N-tosyl-1-chloro-2,2,2-trifluoroethylamine 3 and various nonactivated aliphatic acid chlorides in the presence of a Brønsted base. The mild reaction conditions allowed to get trifluoromethyl-β-lactams in good yields with high trans-diastereo selectivity. In addition, we also demonstrated that ring-opening of β-lactams easily provided α-alkyl-β-trifluoromethyl-β-amino esters.     

Nanocrystalline copper(II) oxide catalyzed aza-Michael reaction and insertion of α-diazo compounds into N-H bonds of amines

Nanocrystalline copper(II) oxide efficiently catalyzed the conjugate addition of aliphatic amines to α,β-unsaturated compounds to produce β-amino compounds with excellent yields under mild reaction conditions. Similarly, Glycine esters are obtained in good yields by the insertion of α-diazoacetate into N-H bonds of amines. The catalyst is used for three cycles with minimal loss of activity.     

Microwave-assisted Michael addition of sulfonamides to α,β-unsaturated esters: A rapid entry to protected β-amino acid synthesis

An efficient, clean and very simple procedure for the synthesis of protected β-amino acids is described. Michael addition of sulfonamides to α,β-unsaturated esters in the presence of K₂CO₃ and tetrabutylammonium bromide (TBAB) under microwave irradiation affords the title compounds in good to high yields and short reaction times. This new method affords protected β-amino acids in high yields and short reaction times.     

Preparation of sugar derived β,β′-dihydroxy α,α-disubstituted α-amino acids

A novel strategy for the preparation of β,β′-dihydroxy α,α-disubstituted α-amino acids bearing a sugar moiety has been developed. The procedure is based on two Henry reactions: the first Henry reaction involves a sugar aldehyde and nitroethanol to furnish a sugar derived α-hydroxymethyl α-nitroalkanol while the second Henry reaction is between this nitro sugar and formaldehyde. This sequence provided the expected epimers of sugar derived α,α-dihydroxymethyl α -nitroalkanols, from which the corresponding β,β′-dibenzyloxy α-N-benzyloxycarbonylamino esters were easily obtained. All rights reserved.     

Unusual reaction of β-hydroxy α-diazo carbonyl compounds with TsNHNCHCOCl/Et3N

The reaction of β-hydroxy α-diazo carbonyl compounds with TsNHNCHCOCl/Et₃N gave β-(p-tolylsulfonyl) α,β-unsaturated carbonyl compounds or β-(p-tolylsulfonyl) α-diazo esters. The reaction mechanism is discussed.     

Stereoselective Mannich-type reaction of chlorotitanium α-phenylseleno esters enolates with aromatic aldimines

The stereoselective Mannich-type reaction of α-phenylseleno chlorotitanium enolates with aromatic aldimines is described. The corresponding α-phenylseleno-β-amino esters were obtained in good yields and with moderate to good diastereoselectivity. A rationale for the predominant syn selectivity based on a chelated cyclic transition state is suggested. The obtained compounds are useful synthetic tools and direct precursors of new α-phenylseleno-β-lactams.