Concise enantioselective synthesis of non-proteinogenic α-aminoacids via an organocatalytic Mannich-type reaction

Abstract

A bifunctional tertiary amine-squaramide catalyzed enantioselective Mannich-type addition of available allomaltol to N-protected aldimines was developed. The resulted adducts were readily transformed to nonproteinogenic α-amino acids and their derivatives not...

Asymmetric Synthesis of Functionalized α-Amino Acid Derivatives via the γ-Pyrone Carbaldimine-Based Organocatalytic Mannich Reaction

“…5 Herein, we report the first chemical synthesis of this compound. 1 H and 13 C NMR spectra of our product and the natural compound are similar. The anti location of the amide and methyl groups in the γ-lactone ring was confirmed by 1 H− 1 H COSY, 1 H− 13 C HSQC, and 1 H− 1 H NOESY experiments (see the Supporting Information).…”

“…Viscous oil (74.5 mg, 85% yield); R f = 0.51 (EtOAc); [α] D 25 = +70.82 (c = 1.0, CH 2 Cl 2 , 95% ee); 1 H NMR (300 MHz, CDCl 3 ) δ 7.45−7.35 (m, 5H), 6.74−6.71 (d, J = 8.7 Hz, 0.10H), 6.68−6.65 (d, J = 8.8 Hz, 1.94H), 6.55−6.53 (d, J = 8.7 Hz, 0.14H), 6.48−6.45 (d, J = 8.8 Hz, 1.91H), 6.14 (s, 0.05H), 6.12 (s, 0.95H), 5.34−5.30 (d,J = 11.3 Hz,1H),J = 11.3 Hz,1H), 4.78−4.76 (d, J = 6.1 Hz, 0.93H, syn), 4.67−4.64 (d, J = 8.7 Hz, 0.07H, anti), 3.71 (s, 3H), 3.62−3.54 (m, 2H), 2.94 (brs, 2H), 2.22 (s, 0.18H), 2.19 (s, 2.82H), 1.83−1.74 (m, 1H), 1.49−1.38 (m, 3H), 1.23−1.16 (m, 1H), 0.89− 0.85 (t, J = 6.2 Hz, 3H); 13 C{ 1 H} NMR (75 MHz, CDCl 3 ) δ 175.7, 164.1, 159.1, 153.3, 143.4, 140.3, 137.2, 128.8, 128.7, 128.5, 116.1, 115.0, 73.8, 63.3, 55.8, 55.1, 44.2, 28.6, 20.7, 19.7, 14.4…”

“…Viscous oil (74.7 mg, 80% yield); R f = 0.57 (EtOAc); [α] D 25 = +74.11 (c = 1.0, CH 2 Cl 2 , >99% ee); 1 H NMR (300 MHz, CDCl 3 ) δ 7.46−7.35 (m, 5H), 6.74−6.71 (m, 0.24H), 6.69−6.64 (m, 1.75H), 6.55−6.52 (m, 0.24H), 6.49−6.44 (m, 1.76H), 6.14 (s, 0.13H), 6.11 (s, 0.87H), J = 11.3 Hz,0.84H),0.28H),J = 11.3 Hz,0.85H), 4.78−4.76 (d, J = 6.1 Hz, 0.87H, syn), 4.67− 4.64 (d, J = 8.8 Hz, 0.13H, anti), 3.72 (s, 0.38H), 3.71 (s, 2.60H), 3.64−3.54 (m, 2H), 3.10 (brs, 2H), 2.19 (s, 2.52H), 2.18 (s, 0.45H), 1.82−1.71 (m, 1H), 1.49−1.22 (m, 8H), 0.88−0.84 (t, J = 6.7 Hz, 3H); 13 C{ 1 H} NMR (75 MHz, CDCl 3 ) δ 175.7, 164.1, 159.2, 153.2, 143.4, 140.3, 137.2, 129.3, 128.7, 128.6, 128.5, 116.0, 114.9, 114.9, 73.7, 64.5, 63.3, 55.7, 55.0, 44.4, 42.0, 32.1, 27.2, 26.4, 22.6, 19.7, 14.1; HPLC data dr (syn/anti) 93/7, >99% ee [Chiralpak AS-H, 90/ 10 n-hexane/i-PrOH, flow rate of 1.0 mL min −1 , λ of 220 nm, t major (syn) of 27.2 min, t major (anti) of 43.1 min, t minor (anti) of 44.0 min, t minor (syn) of 47.9 min]; HRMS (ESI) m/z [M + H] + calcd for C 28 H 36 NO 5 466.2588, found 466.2596. 175.6, 164.1, 159.1, 153.3, 143.5, 140.3, 137.2, 128.8, 128.7, 128.5, 116.1, 114.9, 73.8, 63.3, 55.8, 55.0, 44.5, 31.9, 29.6, 27.6, 26.4, 22.7, 19.7, 14.2; HPLC data dr (syn/anti) 96/4, 98% ee [Chiralpak AS-H, 90/10 nhexane/i-PrOH, flow rate of 1.0 mL min −1 , λ of 220 nm, t major (syn) of 24.3 min, t minor (anti) of 31.5 min, t major (anti) of 38.4 min, t minor (syn) of 41.6 min]; HRMS (ESI) m/z [M + H] + calcd for C 29 H 38 NO 5 480.2744, found 480.2747.…”

Total synthesis of (S)-forphenicinol via asymmetric organocatalysis

“…Recently, we identified this compound as perspective nucleophile in enantioselective syntheses of α-amino acids via asymmetric catalytic Mannich reaction. 25 At first, we screened tertiary chiral amines I–XIV , in particular compounds bearing squaramide group, alkaloids and their derivatives (Fig. 2), as potential catalysts in the reaction of N -Boc-imine 6a with allomaltol 8 in DCM at ambient temperature.…”

Enantioselective organocatalytic strategies to access noncanonical α-amino acids

“…, Strecker, aza-Henry, and Ugi). 25 The carboxylate functionality is unveiled through synthetic manipulations of the catalytic products. Since the reactions invariably employ N -substituted imines, AA derivatives carrying a substituent at their amino group are obtained.…”