A Diastereoselective Mizoroki–Heck Reaction for Synthesis of Spirooxindole-Based Nonnatural Amino Acids Using a Boc-Protected Amine Chiral Auxiliary

Abstract

Nonnatural amino acids are pivotal for expanding the functional diversity of peptides and proteins, enabling novel therapeutic opportunities. Mono-Boc-protected spirocyclization precursors have been developed as versatile intermediates for the diastereoselective synthesis of spirooxindole-based nonnatural amino acids by the Mizoroki–Heck reaction. Catalytic hydrogenation produced cyclopentyl derivatives, expanding the diversity of these amino acids. Furthermore, one spirooxindole derivative was incorporated into a tripeptide by solid-phase peptide synthesis on Rink amide resin to demonstrate its potential in peptide modification and drug development.

Key words

amino acids - diastereoselectivity - asymmetric synthesis - Mizoroki–Heck reaction - spirooxindoles - palladium catalysis

Publication History

Received: 21 February 2025

Accepted after revision: 19 March 2025

Accepted Manuscript online:
21 March 2025

Article published online:
29 April 2025

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• 17 18a-c and 18e,f; General Procedure A 5 mL microwave vial was charged with the appropriate spirooxindole 17 (1 equiv) and Pd/C (10 mol%), and 1:1 THF–EtOH (1:1) was added to produce a 0.1 M solution. Pyridine (3 equiv) was then added and the mixture was stirred under H₂ (1 atm) at r.t. for 24 h. H₂O (5 mL) was added and the mixture was extracted with EtOAc (3 × 15 mL). The organic phase was washed with brine (5 mL), dried (MgSO₄), filtered, and concentrated under reduced pressure. Methyl (1S,3R)-3-[(tert-Butoxycarbonyl)amino]-2′-oxo-1′,2′-dihydrospiro[cyclopentane-1,3′-indole]-6′-carboxylate (18a) Synthesized according to the general procedure and purified by flash chromatography (silica gel, 40% EtOAc–isohexane) as a white solid; yield: 32.0 mg (92%); [α]_D ²⁵ = 34.7 (c = 0.1, THF). ¹H NMR (400 MHz, CDCl₃): δ = 8.62 (s, 1 H), 7.77 (dd, J = 7.8, 1.3 Hz, 1 H), 7.56 (d, J = 1.3 Hz, 1 H), 7.24 (d, J = 7.8 Hz, 1 H), 5.85 (d, J = 8.9 Hz, 1 H), 4.51 (s, 1 H), 3.91 (s, 3 H), 2.39–2.19 (m, 3 H), 2.12–1.86 (m, 3 H), 1.46 (s, 9 H). ¹³C NMR (101 MHz, CDCl₃): δ = 184.1, 166.7, 155.6, 141.3, 140.4, 130.1, 125.1, 122.5, 110.5, 79.4, 53.7, 53.1, 52.4, 44.3, 36.8, 34.7, 28.6. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₉H₂₅N₂O₅: 361.1758; found: 361.1755.