Asymmetric Synthesis of Substituted Azetidine Type α- and β-Amino Acids

Abstract

A s y m m e t r i c S y n t h e s i s o f S u b s t i t u t e d A z e t i d i n e A m i n o A c i d sAbstract: A versatile asymmetric synthesis of 3-substituted azetidine-2-carboxylic acids and 2-substituted azetidine-3-carboxylic acids via 1,3-amino alcohols with excellent stereoselectivities (de ≥ 96%, ee ≥ 96%) is reported. The high asymmetric inductions were achieved employing the SAMP/RAMP-hydrazone methodology. A phenyl moiety was used as a synthetic equivalent of the carboxylic acid function. In addition, the amino acids prepared were tested as organocatalysts in an asymmetric aldol reaction.The plant growth inhibitor (S)-azetidine-2-carboxylic acid [L-aze, (S)-1] was the first known example for the occurrence of the uncommon azetidine motif in natural products. 1 Since then only a few additional natural products containing this amino acid or substituted analogues have been isolated, such as the antifungal and antibiotic polyoxins, 2 the phytosiderophores nicotianamine and mugineic acid, 3 medicanine, 4 and substituted azetidine-2,4-dicarboxylic acids. 5 Although quite rarely found in nature, derivatives of 1 are of significant importance as active pharmaceutical ingredients, as for example the non-opioid analgesic agent ABT-594 [(R)-2] 6 and the thrombin inhibitor melagatran (3) 7 ( Figure 1). Ligands derived from Laze have also been successfully employed in asymmetric catalysis. 8 Figure 1 L-aze and examples of pharmaceutically important azetidine derivativesDespite these promising applications of azetidine-2-carboxylic acid, limited progress has been made for the preparation of substituted analogues. Only a few general routes to non-racemic substituted azetidine-2-amino acids have been described so far. Very recently Lubell et al. reported the preparation of a 3-allyl substituted L-aze derivative from L-aspartic acid and the transformation of the allyl moiety into different heteroatom containing side chains. 9 Hanessian et al. used Oppolzer's sultam methodology for the preparation of 3-substituted L-aze analogues. 10 Couty et al. converted 2-cyano azetidines derived from ephedrine, norephedrine and phenylglycinol into the corresponding enantiopure 3-phenyl substituted amino acids. 11 Apart from these general approaches only some specific examples of substituted non-racemic azetidine carboxylic acids have been prepared. 3,12 We now wish to describe an efficient asymmetric synthesis of 3-substituted azetidine-2-carboxylic acids and 2-substituted azetidine-3-carboxylic acids employing the SAMP/RAMP-hydrazone methodology 13,14 and extending our recently reported asymmetric synthesis of enantiopure substituted azetidines. 15 Our synthetic approach comprises the synthesis of 1,3-amino alcohols by a-hydroxymethylation/1,2-addition of aldehyde SAMP/ RAMP-hydrazones with subsequent N-N bond cleavage. Afterwards the 1,3-amino alcohols are cyclized to the corresponding azetidines. A phenyl substituent serves as a synthetic equivalent of the carboxylic acid function, easily obtained by oxidative cleavage.The asy...

Asymmetric Synthesis of New Chiral β-Amino Acid Derivatives by Mannich-type Reactions of Chiral N-Sulfinyl Imidates with N-Tosyl Aldimines

“…N -Tosylazetidines 8b are reported compounds in the literature and thus allowed a comparison of the optical rotations ([α] D ( R , R )- trans - 8b +235.6 ( c 0.2, CHCl 3 ) vs +238.5 ( c 1.0, CHCl 3 , ee >99%) in Lit., [α] D ( S , S )- trans - 8b −232.9 ( c 0.3, CHCl 3 ) vs −228.5 ( c 1.0, CHCl 3 , ee = 97%) in Lit. ) confirming the assigned absolute stereochemistry of the N -tosylated 2-arylazetidines 8 and compounds anti - 3 - 6 . Also, the ( R , R )-enantiomer of alcohol ( S , S )- syn - 7b is a known compound in the literature, and thus allowed a comparison of the optical rotations ([α] D ( S , S )- syn - 7b −24.3 ( c 0.4, MeOH) vs ( R , R )- syn - 7b +25.4 and +26.1 ( c 1.0, MeOH) in Lit.…”

“…Reduction of esters 6 with LiAlH 4 in THF for 2.5 h afforded γ-sulfonylamino alcohols 7 in good yields (63−87%) . In a next step these alcohols 7 were cyclized under Mitsunobu conditions to the corresponding N -tosylazetidines 8 in high yields (74−94%) with high enantiomeric excess (>98% ee) …”

Recent Developments in the Synthesis of β‐Amino Acids

“…Indeed, the N-benzoylaziridine ring can undergo ring opening at either C-2 or C-3 with concomitant expansion. Following this protocol, a-substituted a-hydroxy b-amino acids were obtained in racemic form (Scheme 7.97 Other research groups that have reported aziridine opening in the synthesis of bamino acids are those of Beresford [151], Mordini [152], Davis [153], Enders [154], Yamauchi [155], Wu [156], Matthews [157] and Crousse [158].…”

General Entry to Asymmetric One-Pot [N + 2 + n] Cyclization for the Synthesis of Three- to Seven-Membered Azacycloalkanes

“…Azacyclic β-amino acid derivatives are not only potential intermediates for azacyclic bioactive compounds, such as azirinomycin ( 1 ), piperazine surrogate 2 , β-proline ( 3 ), , antipsychotic nemonapride ( 4 ), substance P antagonist CP-99,994 ( 5 ), and croomine ( 6 ), but also interesting building blocks for artificial peptides , (Figure ). We recently reported the asymmetric total synthesis of (−)-kopsinine based on one-pot [ N + 2 + 3] cyclization strategy (Scheme , n = 3), that is, chiral diether-controlled asymmetric conjugate addition of lithium N- benzyltrimethylsilylamide ( 7a : R′ = Me) to indolepropenoate ( 8c : R = N -Boc-indol-3-yl) , followed by C,N-dual alkylation with 1-chloro-3-iodopropane ( 9a : n = 3, X 1 = Cl, X 2 = I). , Herein, we describe an extension of this methodology to realize general entry to enantio- and diastereoselective one-pot [ N + 2 + n ] cyclization for azacyclic β-amino acid derivatives (Scheme , n = 0–4).…”