Asymmetric synthesis of (−)-(R)-sitagliptin

The asymmetric synthesis of (?)-(R)-sitagliptin was achieved in seven steps from commercially available starting materials using the highly diastereoselective conjugate additions of either lithium (R)-N-benzyl-N-(α-methylbenzyl)amide or lithium (R)-N-benzyl-N-(α-methyl-p-methoxybenzyl)amide to tert-butyl 4-(2′,4′,5′-trifluorophenyl)but-2-enoate to install the correct stereochemistry. Subsequent sequential acid-catalysed hydrolysis of the resultant β-amino esters, HOBt/EDC mediated coupling with the triazolopyrazine fragment, and hydrogenolysis gave (?)-(R)-sitagliptin in 43% and 42% overall yields, respectively.     

Concise,efficient and highly selective asymmetric synthesis of (+)-(3S,4R)-cisapride

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} from commercially available starting materials has been developed. The key step of this synthesis employs the diastereoselective conjugate addition of lithium (R)-N-benzyl-N-(α-methylbenzyl)amide to tert-butyl 5-[N-3′-(4″-fluorophenoxy)propyl-N-allylamino]pent-2-enoate and in situ enolate oxidation with (?)-camphorsulfonyloxaziridine to set the (3S,4R)-configuration found within the piperidine ring of the product. This synthesis proceeds in 9 steps from commercially available 1-(4′-fluorophenoxy)-3-bromopropane with an overall yield of 19%.     

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.     

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.     

Asymmetric syntheses of (−)-isoretronecanol and (−)-trachelantamidine

Short and concise total asymmetric syntheses of (−)-isoretronecanol and (−)-trachelantamidine are reported. Oxidative cleavage of tert-butyl (S,S,S,Z)-7-[N-benzyl-N-(α-methylbenzyl)amino]cyclohept-3-ene-1-carboxylate, followed by hydrogenolysis promoted in situ cyclisation/reduction, which provided rapid access to the bicyclic core within (−)-isoretronecanol. Analogous treatment of the C(1)-epimer gave (−)-trachelantamidine. Overall, the syntheses of (−)-isoretronecanol and (−)-trachelantamidine were completed in eight and seven steps and 20 and 9.5% yield, respectively, from commercially available starting materials.     

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 N,O,O,O-tetra-acetyl d-lyxo-phytosphingosine,jaspine B (pachastrissamine) and its C(2)-epimer

The highly diastereoselective conjugate addition of lithium (S)-N-benzyl-N-(α-methylbenzyl)amide to a γ-silyloxy-α,β-unsaturated ester and in situ enolate oxidation with (+)-(camphorsulfonyl)oxaziridine has been used as the key step in the asymmetric synthesis of N,O,O,O-tetra-acetyl d-lyxo-phytosphingosine, jaspine B (pachastrissamine) and its C(2)-epimer.     

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%.     

Solution phase structures of enantiopure and racemic lithium N-benzyl-N-(α-methylbenzyl)amide in THF: low temperature 6Li and 15N NMR spectroscopic studies

The antipodes of lithium N-benzyl-N-(α-methylbenzyl)amide are highly efficient enantiopure ammonia equivalents for the asymmetric synthesis of β-amino acid derivatives via conjugate addition to α,β-unsaturated esters. ⁶Li and ¹⁵N NMR spectroscopic studies of doubly labelled ⁶lithium (S)-¹⁵N-benzyl-¹⁵N-(α-methylbenzyl)amide in THF at low temperature reveal the presence of lithium amide dimers as the only observable species. Either a monomeric or dimeric lithium amide reactive species can be accommodated within the transition state mnemonic for this class of conjugate addition reaction. This enantiopure lithium amide offers unique opportunities over achiral (e.g., lithium dibenzylamide) and C₂-symmetric (e.g., lithium bis-N,N-α-methylbenzylamide) counterparts for further mechanistic study owing to the ready distinction of the various dimers formed.     

Asymmetric syntheses of dihydroxyhomoprolines via doubly diastereoselective lithium amide conjugate addition reactions

The asymmetric syntheses of novel dihydroxyhomoprolines have been achieved using the doubly diastereoselective conjugate additions of the antipodes of lithium N-benzyl-N-(α-methylbenzyl)amide to a set of four chiral α,β-unsaturated esters (derived from d-pentoses) as one of the key steps. A full account of the diastereoselectivity observed in these conjugate additions is presented and the stereochemical outcomes of these reactions have been established unambiguously via a combination of hydrogenolytic chemical correlation and single crystal X-ray diffraction analyses. A tandem hydrogenolysis/intramolecular reductive amination reaction was then used to create the corresponding enantiopure pyrrolidines, providing access to (2′S,3′S,4′R)-dihydroxyhomoproline and (2′S,3′R,4′S)-dihydroxyhomoproline after deprotection.     

Asymmetric synthesis of homochiral Baylis–Hillman products employing (R)-N-methyl-N-α-methylbenzyl amide

The conjugate addition of (R)-N-methyl-N-α-methylbenzyl amide to tert-butyl cinnamate followed by an asymmetric aldol reaction and subsequent N-oxidation/Cope elimination affords β-substituted homochiral Baylis–Hillman products in good yield.     

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.     

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.     

Double asymmetric induction as a mechanistic probe: the doubly diastereoselective conjugate addition of enantiopure lithium amides to enantiopure α,β-unsaturated esters and enantiopure α,β-unsaturated hydroxamates

The doubly diastereoselective conjugate addition of the antipodes of lithium N-benzyl-N-(α-methylbenzyl)amide to a range of enantiopure α,β-unsaturated esters [derived from Corey’s 8-phenylmenthol chiral auxiliary] and enantiopure α,β-unsaturated hydroxamates [derived from our ‘chiral Weinreb amide’ auxiliary (S)-N-1-(1′-naphthyl)ethyl-O-tert-butylhydroxylamine] has been used as a mechanistic probe to determine the reactive conformations of these acceptors.     

Non-enzymatic diastereoselective asymmetric desymmetrization of 2-benzylserinols giving optically active 4-benzyl-4-hydroxymethyl-2-oxazolidinones: asymmetric syntheses of α-(hydroxymethyl)phenylalanine,N-Boc-α-methylphenylalanine,cericlamine and BIRT-377

A reaction of (S)-2-benzyl-2-(α-methylbenzyl)amino-1,3-propanediol (S)-4a and 2-chloroethyl chloroformate, and the subsequent addition of DBU gave (4R,αS)-4-benzyl-4-hydroxymethyl-3-(α-methylbenzyl)-2-oxazolidinone (4R)-5a (92% de) via a diastereoselective asymmetric desymmetrization process. Debenzylation of (4R)-5a using trifluoromethanesulfonic acid and anisole in MeNO₂ gave (R)-4-benzyl-4-hydroxymethyl-2-oxazolidinone (R)-15a, which was converted into (R)-(α-hydroxymethyl)phenylalanine (7) in two steps. N-Boc-α-methylphenylalanine (8), cericlami0ne (9) and BIRT-377 (10) were also synthesized using these asymmetric desymmetrization and debenzylation.     

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.     

Studies on two different diastereoselective reaction pathways from a serinol derivative to 4-hydroxymethyl-2-oxazolidinones using 2-chloroethyl chloroformate and N,N′-disuccinimidyl carbonate

Two reaction pathways and their diastereoselectivity-determining steps of the asymmetric desymmetrization of (R)-2-(α-methylbenzyl)amino-1,3-propanediol 1 with 2-chloroethyl chloroformate (CCF) and with N,N′-disuccinimidyl carbonate giving (4S,αR)-4-hydroxymethyl-3-α-methylbenzyl-2-oxazolidinones (4S)-3 and its (4R,αR)-diastereomer (4R)-3 were investigated. The reaction of serinol 1 and CCF to give the corresponding carbonates was not a diastereoselectivity-determining step. The carbonates gave (R)-5-(α-methylbenzyl)amino-1,3-dioxan-2-one 4 after addition of DBU, and an intramolecular acyl transfer of 4 was found to be a diastereoselectivity-determining step to give (4S)-3. Conversely, the reaction of serinol 1 and N,N′-disuccinimidyl carbonate afforded directly the opposite diastereomer (4R)-3 but not via the intermediate 4. Thus, their diastereoselectivities depended on the acylating reagent.     

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.     

Convenient preparation of chiral phase-transfer catalysts with conformationally fixed biphenyl core for catalytic asymmetric synthesis of α-alkyl- and α,α-dialkyl-α-amino acids: application to the short asymmetric synthesis of BIRT-377

Chiral phase-transfer catalysts (S)-1a, (S)-1b, and (S)-2 with conformationally fixed biphenyl cores were conveniently prepared from the known, easily available (S)-6,6′-dimethylbiphenyl-2,2′-diol 3 and (S)-4,5,6,4′,5′,6′-hexamethoxybiphenyl-2,2′-dicarboxylic acid 14, respectively, in five steps. The catalysts, (S)-1a and (S)-1b are readily applicable to asymmetric alkylation of N-(diphenylmethylene)glycine tert-butyl ester with excellent enantioselectivity. In particular, catalyst (S)-1b was found to exhibit the unique temperature effect on the enantioselectivity, and asymmetric alkylation of glycine derivatives at room temperature gave higher enantiomeric excess than that at 0 °C. In addition, the catalyst (S)-2 exhibited the high catalytic performance (0.01-1 mol %) in the asymmetric alkylation of N-(diphenylmethylene)glycine tert-butyl ester and N-(p-chlorophenylmethylene)alanine tert-butyl ester compared to the existing chiral phase-transfer catalysts, thereby allowing to realize a general and useful procedure for highly practical enantioselective synthesis of structurally diverse natural and unnatural α-alkyl-α-amino acids as well as α,α-dialkyl-α-amino acids. This approach is successfully applied to the short asymmetric synthesis of cell adhesion BIRT-377.     

A practical synthesis of protected β-homolysine

Protected β-homolysine of high enantiomeric purity (ee>99.5%) is prepared utilizing the stereoselective conjugate addition of lithiated (S)-(α-methylbenzyl)benzylamide to (E)-7-(tosyloxy)hept-2-enoic acid tert-butyl ester, followed by subsequent ammonia substitution, Boc protection and removal of the auxiliary.