Homologation of α-amino acids to β-amino acids using Boc₂O

Abstract

The use of Boc 2 O as a coupling agent in the homologation of N-urethane protected-α-amino acid to its β-homomers by the Arndt-Eistert method is described. The homologation gives good yields without racemization. The use of Boc 2 O as a coupling agent not only allows the easy scale up of the process but also it is cost effective. CO urethane); 1 H NMR (δ, CDCl 3 ): 0.9 (3H, J = 7.5, t), 0.93 (3H, J = 7.1, d), 1.32 (11H, m), 1.5 (1H, m), 4.24 (1H, m), 5.3 (1H, s) and 5.42 (1H, J = 8.3, d).Boc-D-isoleucyldiazomethane (II g). 1.55 g (5 mmol) of I g, after the reaction gave 1.18 g (92.5%) of II g; mp 85-86 ЊC; Anal. Calc. for C 12 H 21 N 3 O 3 (255.28): C, 56.45; H, 8.28; N, 16.45; Found C, 56.32; H, 8.30; N,16.50%; IR ν max. cm Ϫ1 2107 (CHN 2 ), 1700 (CO urethane); 1 H NMR (δ, CDCl 3 ): 0.9 (3H, J = 7.5, t), 0.93 (3H, J = 7.1, d), 1.3 (11H, m), 1.55 (1H, m), 4.24 (1H, m), 5.35 (1H, s) and 5.45 (1H, J = 8.3, d).

Structure–Activity Studies of N‐Butyl‐1‐deoxynojirimycin (NB‐DNJ) Analogues: Discovery of Potent and Selective Aminocyclopentitol Inhibitors of GBA1 and GBA2

“…For the synthesis of 3,5‐dideoxy analogue 13 (Method A in Scheme ), we applied a synthetic method developed in our group . β‐Amino acid 7 was prepared from amino acid derivative 6 via Arndt–Eistert homologation and was then converted into Weinreb amide 8 . Because the direct alkylation of 8 was slow and low yielding, we removed the Boc protecting group to obtain the free amine, which was then subjected to reductive alkylation to yield 9 .…”

“…For the synthesis of 3,5-dideoxya nalogue 13 (Method Ai n Scheme 2), we applied as ynthetic method developed in our group. [32] b-Amino acid 7 wasp reparedf rom amino acid derivative 6 via Arndt-Eistert homologation [33,34] and was then converted into Weinreb amide 8.B ecause the directalkylation of 8 was slow and low yielding, we removed the Boc protecting group to obtain the free amine, which was then subjected to reductivea lkylation to yield 9.B oc protection then furnished intermediate 10.Y none 11 was obtained upon treatment of 10 with ethynylmagnesium bromide. After removalo ft he N-Boc protecting group of 11 and subsequent treatment with K 2 CO 3 , ar apid ring closure occurred to yield key intermediate enaminone 12.At wo-step, one-flask reduction (sodium borohydride, followed by hydrogenolysis) of 12 completed the synthesis of the desired analogue 13.T he configuration of the 3-OH group was confirmed by comparing the NMR spectra of 13 with a sample derived from the commercially available pipecolic acid derivative 14 (Method Bi nS cheme 2).…”

Enantioselective Synthesis of 3,4-Dihydro-1,2-oxazepin-5(2H)-ones and 2,3-Dihydropyridin-4(1H)-ones from β-Substituted β-Hydroxyaminoaldehydes

“…In the case of the Arndt–Eistert homologation, the handling of explosive diazomethane reagent is required. 45 − 47 …”

Preparation of Enantiopure β-Amino Acids by Homologation of α-Amino Acids

“…Application of the dicyclohexylcarbodiimide (DCC) method is possible, though laborious separation of the side product dicyclohexylurea has been reported with this method. 6 Further activation methods have been reported and might be useful in special cases, for example, activation with tert-butyl pyrocarbonate (Boc 2 O) 7 or toluenesulfonyl chloride 8 or utilization of the pentafluorophenylesters. The activated amino acid is used as acylating agent for diazomethane, which is conveniently prepared as an ethereal solution starting with, for example, N-methyl-N-nitrosotoluenesulfonamide.…”