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DOI: 10.1055/a-2564-4920
A Diastereoselective Mizoroki–Heck Reaction for Synthesis of Spirooxindole-Based Nonnatural Amino Acids Using a Boc-Protected Amine Chiral Auxiliary
We thank Uppsala University and the Kjell and Märta Beijer Foundation for their support.

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 catalysisSupporting Information
- Supporting information for this article is available online at https://doi.org/10.1055/a-2564-4920.
- Supporting Information
Publication History
Received: 21 February 2025
Accepted after revision: 19 March 2025
Accepted Manuscript online:
21 March 2025
Article published online:
29 April 2025
© 2025. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by/4.0/)
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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.