Practical Total Syntheses of Acromelic Acids A and B

Abstract

Practical total syntheses of acromelic acids A (1) and B (2), which have potent neuro-excitatory activity, were accomplished in 13 (36% total yield) and 17 steps (6.9% total yield), respectively, from 2,6-dichloropyridine (8). Regioselective transformation of symmetric 8 provided nitroalkenes 15 and 16. The pyrrolidine ring was efficiently constructed by Ni-catalyzed asymmetric conjugate addition followed by intramolecular reductive amination.

Chemistry of α-Oxoesters: A Powerful Tool for the Synthesis of Heterocycles

“…62 The synthesis of N-benzyloxy-α-methylene-L-pyroglutamic acid 48 was reported via PTSA-catalyzed cyclization of Nbenzyloxy derivative 47, which was prepared by allylation of the glyoxalate oxime using t-butyl ester-substituted allylzinc reagent 46 in THF at −78°C for 0.5 h, followed by hydrolysis of tbutyl ester moieties with TFA in DCM (Scheme 15). 63 The synthesis of pyrrolidine moiety of acromelic acid 55 was reported by Ouchi et al 64 via conjugate addition of nitroalkene 49 with α-ketoester 50 using 5 mol % Ni(OAc) 2 −diamine catalyst II in DME at −10°C within 48 h, to give 51 in 88% yield, followed by reduction of nitro group with H 2 in the presence of Raney Ni in MeOH at 75°C, leading to ketimine 52 by in situ cyclocondensation of amine with ketone moiety, which underwent in situ reduction to the corresponding pyrrolidine structure 53. Hydrogenolysis of diphenylmethyl (Dpm) moiety followed by esterification using SOCl 2 and MeOH at room temperature for 20 h afforded pyrrolidine 54 in 63% yield, for three steps (Scheme 16).…”

Practical Total Syntheses of Acromelic Acids A and B

“…In contrast, we planned to use methoxy picolinic acid ester as a pyridone precursor to improve the efficiency of the syntheses, even though the reaction of a pyridine substrate might be challenging, since such heterocyclic compounds tend to affect key catalytic and stereoselective reactions. As a part of our research program on kainoid chemistry, [40][41][42][43] we herein describe the details of practical and scaleable total syntheses of acromelic acids A (1) and B (2).…”

“…As shown in Table 1, as the size of the ester group at the γ-position of the nucleophile was increased, higher diastereoselectivity was observed, probably because epimerization at the α-position of the keto group was minimized. Although the excellent results were obtained when bulky t-Bu and diphen ylmethyl (Dpm) esters 7c and d 43) were used, we selected the Dpm ester for selective deprotection in the advanced stage.…”

“…The next task was inversion of the stereochemistry at the C-2 position. Since t-BuOK-promoted inversion gave the excellent results in our previous synthesis of MFPA, [40][41][42][43] the same condition was applied to N-Cbz-protected 23. However, treatment with t-BuOK resulted in marked decomposition of the substrate (vide infra).…”

“…To address this issue, we examined the reaction of α-ketoester 7a. 40,43) The Ni-catalyzed reaction between 16 and 7a produced the desired product 28 quantitatively with excellent stereoselectivity (dr=20 : 1, 91% ee). Subsequent hydrogenation with Raney Ni also proceeded smoothly, but a 1 : 2 mixture of 29a and b were isolated after protection with a Cbz group at the secondary amine.…”