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.     

Trading N and O: asymmetric syntheses of β-hydroxy-α-amino acids via α-hydroxy-β-amino esters

Both diastereoisomers of 2-amino-3-hydroxybutanoic acid and 2-amino-3-hydroxy-3-phenylpropanoic acid have been prepared from enantiopure α-hydroxy-β-amino esters via the intermediacy of the corresponding cis- and trans-aziridines. Aminohydroxylation of two α,β-unsaturated esters produced enantiopure 2,3-anti-α-hydroxy-β-amino esters in >99:1 dr. Subsequent epimerisation at the C(2)-position via a sequential oxidation/diastereoselective reduction protocol gave the corresponding enantiopure 2,3-syn-α-hydroxy-β-amino esters in >99:1 dr. These syn- and anti-substrates were then converted into the corresponding N-Boc protected cis- and trans-aziridines, respectively, via a three step reaction sequence: (i) hydrogenolysis and in situ N-Boc protection; (ii) OH-activation; and (iii) aziridine formation. Subsequent regioselective ring-opening of the C(3)-methyl-aziridines with Cl₃CCO₂H proceeded with inversion of configuration to give the corresponding 2-amino-3-trichloroacetate esters, whereas the analogous reaction with the C(3)-phenyl-aziridines resulted in rearrangement to the corresponding oxazolidin-2-ones with retention of configuration. In each case, hydrolysis of the products from these ring-opening reactions produced the corresponding enantiopure β-hydroxy-α-amino acids as single diastereoisomers.     

Asymmetric syntheses of the N-terminal α-hydroxy-β-amino acid components of microginins 612, 646 and 680

The asymmetric syntheses of the N-terminal α-hydroxy-β-amino acid components of microginins 612, 646 and 680 are reported. Conjugate addition of lithium (R)-N-benzyl-N-(α-methylbenzyl)amide to the requisite (E)-α,β-unsaturated ester followed by in situ enolate oxidation with (?)-(camphorsulfonyl)oxaziridne (CSO) gave the corresponding anti-α-hydroxy-β-amino esters. Sequential Swern oxidation followed by diastereoselective reduction gave the corresponding syn-α-hydroxy-β-amino esters. Subsequent N-debenzylation (i.e., hydrogenolysis for microginin 612, and NaBrO₃-mediated oxidative N-debenzylation for microginins 646 and 680) followed by acid catalysed ester hydrolysis gave the corresponding syn-α-hydroxy-β-amino acids, the N-terminal components of microginins 612, 646 and 680, in good yield. An analogous strategy for elaboration of the enantiopure anti-α-hydroxy-β-amino esters facilitated the asymmetric synthesis of the corresponding C(2)-epimeric α-hydroxy-β-amino acids.     

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.     

Doubly diastereoselective conjugate addition of enantiopure lithium amides to enantiopure N-enoyl oxazolidin-2-ones: a mechanistic probe

The doubly diastereoselective conjugate addition of the antipodes of lithium N-benzyl-N-(α-methylbenzyl)amide to a range of enantiopure N-enoyl oxazolidin-2-ones has been used as a mechanistic probe to determine that the reactive conformation is the anti-s-cis form. The β-amino carbonyl products resulting from these conjugate addition reactions are useful templates for further elaboration into an α,β,α-pseudotripeptide.     

Diastereoselective syntheses of 2-amino propargyl alcohols. Chiral building blocks for enantiopure amino γ-lactones and 5-hydroxy-piperidinone derivatives

α-Dibenzylamino aldehydes, derived from the corresponding natural α-amino acids, react with metal acetylides to yield anti-amino propargyl alcohols in good yield and diastereomeric excess. syn Amino alcohols are prepared from the anti diastereoisomers and all of them are elaborated in few steps to enantiopure amino lactones and hydroxy-piperidin-2-ones.     

Asymmetric syntheses of (+)-negamycin, (+)-3-epi-negamycin and sperabillin C via lithium amide conjugate addition

The chemo- and enantioselective reduction of ethyl 4-chloroacetoacetate and the diastereoselective conjugate addition of enantiopure lithium N-benzyl-N-(α-methylbenzyl)amide to an α,β-unsaturated ester have been used as the key steps in the total asymmetric syntheses of (+)-negamycin (in 13 steps and 24% overall yield), (+)-3-epi-negamycin (in 13 steps and 10% overall yield) and sperabillin C (in 17 steps and 13% overall yield) from commercially available starting materials.     

The asymmetric synthesis of (S,S)-methylphenidate hydrochloride via ring-opening of an enantiopure aziridinium intermediate with phenylmagnesium bromide

The key step in our synthetic strategy towards (S,S)-methylphenidate hydrochloride employs the ring-opening of an in situ formed aziridinium intermediate. Treatment of an α-hydroxy-β-amino ester with methanesulfonic anhydride promoted aziridinium formation and the subsequent addition of phenylmagnesium bromide resulted in stereospecific and regioselective ring-opening to give the corresponding α-phenyl-β-amino ester with overall retention of configuration. Subsequent functional group manipulation followed by N-deprotection and cyclisation generated the piperidine ring within the target compound, and transesterification gave (S,S)-methylphenidate hydrochloride, in only 8 steps from 1,5-pentanediol, in 15% overall yield. These results demonstrate the synthetic utility of enantiopure aziridinium intermediates as substrates for the generation of stereodefined C–C bonds, and crucially this methodology provides access to α-substituted-β-amino ester substrates that are not accessible via enolate alkylation chemistry. The strategy reported herein is potentially applicable to all possible stereoisomers of methylphenidate as well as differentially substituted analogues.     

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 syntheses of 3,4-syn- and 3,4-anti-3-substituted-4-aminopiperidin-2-ones: application to the asymmetric synthesis of (+)-(3S,4R)-cisapride

The conjugate addition of lithium (R)-N-benzyl-N-(α-methylbenzyl)amide to δ-(N-allylamino)-α,β-unsaturated esters, followed by N-deallylation and cyclisation of the resultant β,δ-diamino esters, gives the corresponding 4-aminopiperidin-2-ones as single diastereoisomers (>99:1 dr). Subsequent deprotonation with LiHMDS and functionalisation of the resultant lithium enolate gives 3,4-anti-3-substituted-4-aminopiperidin-2-ones in >99:1 dr. Alternatively, in situ oxidation of the intermediate lithium (Z)-β-amino enolates formed upon conjugate addition gives α-hydroxy-β,δ-diamino esters, which after N-deallylation and cyclisation gives the corresponding 3,4-syn-3-hydroxy-4-aminopiperidin-2-ones in >99:1 dr. The utility of this methodology was successfully demonstrated in a concise asymmetric synthesis of the gastroprokinetic agent (+)-(3S,4R)-cisapride {(+)-(3S,4R)-N(1)-[3′-(4″-fluorophenoxy)propyl]-3-methoxy-4-(2?-methoxy-4?-amino-5?-chlorobenzamido)piperidine} in nine steps from commercially available starting materials with an overall yield of 19%.     

Conjugate addition of lithium N-tert-butyldimethylsilyloxy-N-(α-methylbenzyl)amide: asymmetric synthesis of β-trisubstituted amino acids

Conjugate addition of the homochiral ammonia equivalent lithium N-tert-butyldimethylsilyloxy-N-(α-methylbenzyl)amide to a range of α,β-unsaturated esters gives the corresponding β-amino esters in moderate to good levels of diastereoselectivity. O-Desilylation and cyclisation furnishes homochiral isoxazolidin-5-ones in >99:1 dr after purification. Sequential alkylation of these templates proceeds to give the corresponding 3,4-anti-disubstituted and 3,4,4-trisubstituted derivatives as single diastereoisomers after purification. The first alkylation occurs with high levels of diastereoselectivity on the face of the enolate anti to the C(3)-substituent, whereas the facial selectivity of the second alkylation is governed by a chiral relay effect, which depends upon the relative steric bulk of both the C(3)- and C(4)-substituents. Subsequent hydrogenolysis promotes cleavage of both the N-α-methylbenzyl group and the N-O bond within the isoxazolidin-5-one ring in one pot to give the corresponding β^2,2,3-trisubstituted amino acids directly.     

Doubly diastereoselective conjugate additions of the antipodes of lithium N-benzyl-N-(α-methylbenzyl)amide to enantiopure ε-O-protected α,β-unsaturated esters derived from d-ribose

Enantiopure ε-O-silyloxy- and ε-O-benzyloxy-α,β-unsaturated esters derived from d-ribose, each containing a cis-dioxolane unit, display excellent (⩾95:5 dr) levels of diastereofacial directing ability upon conjugate addition of achiral lithium N-benzyl-N-isopropylamide. In contrast to the corresponding enantiopure ε-O-silyloxy-α,β-unsaturated ester derived from l-tartaric acid, which contains a trans-dioxolane unit, the conjugate additions of the antipodes of lithium N-benzyl-N-(α-methylbenzyl)amide to its cis-configured counterpart result in doubly diastereoselective ‘matched’ and ‘mismatched’ reaction pairings in which the inherent reagent control serves to augment or oppose, respectively, the established substrate diastereocontrol.     

Asymmetric synthesis of (−)-(1R,7aS)-absouline

The most efficient and concise asymmetric synthesis of (?)-(1R,7aS)-absouline to date, which was accomplished in eight steps and 20% overall yield from commercially available starting materials, is described. The doubly diastereoselective conjugate addition of lithium (S)-N-benzyl-N-(α-methylbenzyl)-amide to an enantiopure α,β-unsaturated ester derived from l-proline was employed as the key step. Subsequent hydrogenolytic N-debenzylation and acid-promoted cyclisation of the resultant β-amino ester produced the 1-aminopyrrolizidin-3-one scaffold, then reduction with DIBAL-H was followed by DCC-mediated coupling with (E)-p-methoxycinnamic acid to complete the synthesis of (?)-(1R,7aS)-absouline.     

Rhodium-catalyzed asymmetric hydrogenation through dynamic kinetic resolution: asymmetric synthesis of anti-β-hydroxy-α-amino acid esters

Rhodium-catalyzed asymmetric hydrogenation of α-amino-β-keto ester hydrochlorides through dynamic kinetic resolution is described. The hydrogenation proceeds with the catalyst derived from a Rh complex and a chiral ferrocenylphosphine under hydrogen in the presence of sodium acetate in acetic acid to afford anti-β-hydroxy-α-amino acid esters with 58–83% ee in a diastereomeric ratio of 92:8–97:3.     

Asymmetric synthesis of α-mercapto-β-amino acid derivatives: application to the synthesis of polysubstituted thiomorpholines

Tandem conjugate addition of homochiral lithium N-benzyl-N-(α-methyl-p-methoxybenzyl)amide to tert-butyl cinnamate and enolate trapping with TsS^tBu proceeds with high diastereoselectivity to give a homochiral anti-α-tert-butylthio-β-amino ester. Stepwise deprotection gives the corresponding free α-tert-butylthio-β-amino acid without epimerisation. Tandem conjugate addition of homochiral lithium N-allyl-N-(α-methylbenzyl)amide to tert-butyl cinnamate and enolate trapping with TsS^tBu followed by conversion of the S-tert-butyl group to a disulphide, and reduction with Lalancette’s reagent generates polysubstituted thiomorpholine derivatives.     

Asymmetric synthesis of α,α-difluoro-β-amino phosphonic acids using sulfinimines

Addition of diethyl lithiodifluoromethylphosphonate to enantiopure sulfinimines afforded the corresponding N-sulfinyl α,α-difluoro-β-amino phosphonates with good diastereoselectivity. A two-step deprotection involving treatment of diastereomerically pure N-sulfinyl α,α-difluoro-β-amino phosphonates with trifluoroacetic acid in EtOH followed by refluxing with 10 N HCl afforded enantiopure α,α-difluoro-β-amino phosphonic acids.     

Stereoselective synthesis of fluorinated β-aminoacids from ethyl trans-N-benzyl-3-trifluoromethylaziridine-2-carboxylate

trans-N-Benzyl-3-trifluoromethyl-2-ethoxycarbonylaziridine 2a, easily obtainable in enantiopure forms by CAL-catalysed enzymatic resolution, allowed the regio- and stereoselective synthesis of chiral fluorinated anti-α-functionalised-β-aminoacids, such as trifluoroisoserinates or trifluoro-β-alanine, and trans-3-halo- or 3-hydroxy-β-lactams. Starting from the enantiomerically pure methyl analogue of the title compound, 2c, pure enantiomers of trifluoroisoserine can be obtained in high overall chemical yield. Absolute configurations of optically active β-aminoacids were determined by chemical correlation.     

Asymmetric synthesis of 4-amino-γ-butyrolactones via lithium amide conjugate addition

Upon treatment with homochiral lithium (R)-N-benzyl-N-(α-methylbenzyl)amide, γ-benzyloxy but-2-enoates undergo competitive conjugate addition and γ-deprotonation, while γ-tert-butyldimethylsilyloxy but-2-enoates undergo exclusive conjugate addition. Treatment of γ-benzyloxy or γ-tert-butyldimethylsilyloxy but-2-enamides with lithium (R)-N-benzyl-N-(α-methylbenzyl)amide furnishes exclusively the γ-benzyloxy- or γ-tert-butyldimethylsilyloxy-β-amino amide products of conjugate addition in high de. The γ-tert-butyldimethylsilyloxy-β-amino butanoate products of conjugate addition readily undergo O-desilylation and concomitant cyclisation to furnish 4-[N-benzyl-N-(α-methylbenzyl)amino]-γ-butyrolactone, which may be stereoselectively functionalised via deprotonation and alkylation to give the corresponding trans-3-alkyl-4-amino-γ-butyrolactones. Alternatively, stereoselective alkylation of γ-benzyloxy- or γ-tert-butyldimethylsilyloxy-β-amino butanoates and butanamides through enolate formation and alkylation following a tandem (via the (Z)-lithium enolate) or stepwise (via the (E)-lithium enolate) protocol gives a range of separable syn- and anti-α-alkyl-β-amino esters and amides. O-Silyl deprotection of the syn- and anti-α-alkyl-β-amino butanoates with TBAF and concomitant cyclisation provide trans-3-alkyl-4-amino-γ-butyrolactones, consistent with epimerisation to the thermodynamically favoured trans-lactone occurring upon deprotection.     

Stereospecific total synthesis of (−)-8-epi-hyperaspine

Condensation of protected δ-hydroxy-β-amino ester 7 with a β-keto ester provides vinylogous urethane 8, which is cyclized under the action of t-BuOK followed by decarboxylation to afford enone 12. Hydrogenation of 12 or its N,O-diprotected derivative 13 gives 2,6-cis-disubstituted piperdines. Using these intermediates, (−)-8-epi-hyperaspine is synthesized.     

Stereoselective synthesis of β-hydroxy-α-amino acids β-substituted with non-aromatic heterocycles

We have stereoselectively synthesised β-hydroxy-α-amino acids β-substituted with non-aromatic heterocycles by means of a condensation reaction between enantiomerically pure heterocyclic aldehydes and the (R)-(+)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine (Schöllkopf’s reagent) as a chiral auxiliary. The stereocontrolled addition gave mixtures of diastereoisomers whose steric configurations were assigned on the basis of spectroscopic data and X-ray analysis. Upon controlled hydrolysis, the adducts were transformed into the corresponding methyl esters of β-hydroxy-β-heterocyclic substituted α-amino acids.