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

Publikationsverlauf

Eingereicht: 21. Februar 2025

Angenommen nach Revision: 19. März 2025

Accepted Manuscript online:
21. März 2025

Artikel online veröffentlicht:
29. April 2025

• References and Notes

• 1 Yang J, Zhao H.-W, He J, Zhang C.-P. Catalysts 2018; 8: 23
• 2 Berteina-Raboin S. Catalysts 2019; 9: 925
• 3 Ping Y, Li Y, Zhu J, Kong W. Angew. Chem. Int. Ed. 2019; 58: 1562
• 4 Beletskaya IP, Cheprakov AV. Chem. Rev. 2000; 100: 3009
• 5 Singh R, Vince R. Chem. Rev. 2012; 112: 4642
• 6 Saranya PV, Neetha M, Aneeja T, Anilkumar G. RSC Adv. 2021; 11: 7146
• 7 Ye N, Chen H, Wold EA, Shi P.-Y, Zhou J. ACS Infect. Dis. 2016; 2: 382
• 8 Panda SS, Girgis AS, Aziz MN, Bekheit MS. Molecules 2023; 28: 618
• 9 Palomo JM. RSC Adv. 2014; 4: 32658
• 10 Behrendt R, White P, Offer J. J. Pept. Sci. 2016; 22: 4
• 11 Lindman J, Gopalan G, Palo-Nieto C, Brandt P, Gising J, Larhed M. ACS Omega 2022; 7: 32525
• 12 Olofsson K, Larhed M, Hallberg A. J. Org. Chem. 1998; 63: 5076
• 13 Wetzel A, Bergman J, Brandt P, Larhed M, Brånalt J. Org. Lett. 2017; 19: 1602
• 14 Roy T, Brandt P, Wetzel A, Bergman J, Brånalt J, Sävmarker J, Larhed M. Org. Lett. 2017; 19: 2738
• 15 Freeman NS, Gilon C. Synlett 2009; 2097
• 16 Larhed M, Moberg C, Hallberg A. Acc. Chem. Res. 2002; 35: 717
• 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.