Synthesis of Oxetane- and Azetidine-Containing Spirocycles Related to the 2,5-Diketopiperazine Framework

This article is dedicated to Professor Steven V. Ley CBE FRS on the occasion of his 70^th birthday

Abstract

A simple two-step sequence is used to efficiently make novel spirocyclic analogues of the diketopiperazine nucleus. Conjugate addition of chiral α-amino esters to nitroalkenes, generated from oxetan-3-one or N-Boc-azetidin-3-one, followed by nitro group reduction provides, after spontaneous cyclization, the spirocycles in good overall yields. These rigid scaffolds can be functionalized by selective N-alkylations as well as by carbonyl reduction to the corresponding piperazines.

Key words

oxetanes - diketopiperazines - spirocycles - peptidomimetics - piperazines

• References and Notes

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• 15 General Procedure for Nitro Reduction and Cyclization to 12 The substrate (1 equiv) and Raney Ni (1.0 mL, slurry in H₂O) in MeOH (10 mL/mmol) were stirred at r.t. under an atmosphere of H₂ (balloon) for 16 h. The reaction mixture was filtered through a plug of Celite^®, eluting with EtOAc. The eluent was concentrated under reduced pressure, and the crude product was purified by column chromatography. Using this method, (S)-10 (325 mg, 1.32 mmol) gave, after column chromatography (0–10% MeOH in EtOAc), (S)-12a (197 mg, 81%) as white solid. R_f  = 0.31 (10% MeOH in EtOAc); mp 153–158 °C; [α]_D ²⁵ –118.1 (c 0.10, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ = 6.36 (1H, br s, NHCO), 4.62 (2H, s, OCH₂), 4.50 (1H, d, J = 7.1 Hz, OCHH), 4.45 (1H, d, J = 7.1 Hz, OCHH), 3.65 (1H, dd, J = 11.5, 4.6 Hz, NHCHH), 3.51–3.40 (2H, m, NHCHH, CHi-Pr), 2.50–2.34 (1H, m, CHMe₂), 1.80 (1H, br s, NH), 0.99 (3H, d, J = 7.3 Hz, CH₃), 0.91 (3H, d, J = 6.8 Hz, CH₃) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 170.4 (C), 81.5 (CH₂), 79.3 (CH₂), 59.3 (CH), 54.7 (C), 48.4 (CH₂), 29.5 (CH), 18.5 (CH₃), 15.6 (CH₃) ppm. IR (film): 3253, 2965, 2869, 1649, 1321, 980 cm^–1. MS (ES⁺): m/z = 185 [M + H]⁺, 207 [M + Na]⁺. HRMS (ES⁺): m/z calcd for C₉H₁₇N₂O₂ [M + H]⁺: 185.1285; found: 185.1284.
• 16 CCDC 1430502 (12j) and 1430503 (12a) contain the supplementary crystallographic data. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk.