Intramolecular Aldol Ring Closures of Cysteine Derivatives Leading to Densely Functionalised Pyroglutamates

Hadia Almahli; Niamh C. Jimenez; Mark G. Moloney

doi:10.1055/s-0037-1611829

Synlett, Table of Contents

Synlett 2019; 30(10): 1237-1240
DOI: 10.1055/s-0037-1611829

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Intramolecular Aldol Ring Closures of Cysteine Derivatives Leading to Densely Functionalised Pyroglutamates

Hadia Almahli

,

Niamh C. Jimenez

,

Mark G. Moloney*

The Department of Chemistry, Chemistry Research Laboratory, The University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK Email: mark.moloney@chem.ox.ac.uk

› Author Affiliations

Abstract

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Abstract

The synthesis of densely functionalised pyroglutamates derived from cysteine by an aldol cyclisation strategy has been achieved.

Key words

aldol reaction - cyclization - heterocycles - pyroglutamate - lactams

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References

References
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13 Method for aldol cyclisation: To a solution of N-acylated thiazolidine (1.0 equiv) in methanol was added sodium methoxide (1.05 equiv) and the resulting mixture was stirred at r.t. for 15–24 h. Subsequently, the mixture was partitioned between Et₂O and 1 M HCl. The Et₂O layer was washed with brine, dried (MgSO₄), filtered and concentrated in vacuo to furnish the crude pyroglutamates. Methyl (3R,7R,7aR) and (3R,7S,7aR)-3-(tert-butyl)-7-hydroxy-7-methyl-5-oxodihydro-1H,3H-pyrrolo[1,2-c]thiazole-7a(5H)-carboxylate (7a and 8a). Yellow oil. IR: 2958, 1739, 1688, 1616, 1366, 1260, 1108, 1022 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ (major) = 5.11 (s, 1 H, H-3), 3.80 (s, 3 H, CO₂Me), 3.62 (d, J = 12.1 Hz, 1 H, H-1), 3.55 (d, J = 12.1 Hz, 1 H, H-1), 3.04 (d, J = 16.3 Hz, 1 H, H-6), 2.45 (d, J = 16.3 Hz, 1 H, H-6), 1.27 (s, 3 H, H-9), 0.93 (s, 9 H, t-Bu); δ (minor) = 5.07 (s, 1 H, H-3), 3.82 (s, 3 H, CO₂Me), 3.69 (d, J = 12.9 Hz, 1 H, H-1), 3.27 (d, J = 12.9 Hz, 1 H, H-1), 3.23 (d, J = 15.7 Hz, 1 H, H-6), 2.42 (d, J = 15.6 Hz, 1 H, H-6), 1.51 (s, 3 H, H-9), 0.93 (s, 9 H, t-Bu). ¹³C NMR (500 MHz, CDCl₃): δ (major) = 175.3 (C-5), 172.0 (CO₂Me), 85.0 (C-7a), 79.6 (C-7), 73.1 (C-3), 53.1 (CO₂Me), 47.2 (C-6), 38.3 (C-10), 33.4 (C-1), 26.4 (t-Bu), 21.8 (C-9); δ (minor) = 173.6 (C-5), 172.4 (CO₂Me), 84.2 (C-7a), 78.7 (C-7), 72.2 (C-3), 53.0 (CO₂Me), 46.7 (C-6), 38.3 (C-10), 33.8 (C-1), 26.4 (t-Bu), 24.04 (C-9). HRMS (ESI⁺): m/z [M + H⁺] calcd for C₁₃H₂₂NO₄S⁺: 288.12641; found 288.12650. Methyl (3R,7S,7aR)-3-(tert-butyl)-7-hydroxy-6-methyl-5-oxo-7-((phenylthio)methyl)-hexahydropyrrolo[1,2-c]thiazole-7a(5H)-carboxylate (11b). Yield: 0.19 g (76%); yellow oil; [α]_d ²³ –19.8 (c 1.0 in CHCl₃). IR: 3358, 2930, 2854, 1713, 1583 cm^–1. ¹H (500 MHz, CDCl₃): δ = 7.19–7.23 (m, 5 H, ArH), 5.11 (s, 1 H, C(3)H), 3.79 (s, 3 H, OCH₃), 3.75 (d, J = 16.2 Hz, 1 H, C(1)H_AH_B), 3.65 (d, J = 16.2 Hz, 1 H, C(1)H_AH_B), 3.22 (d, J = 16.2 Hz, 1 H, CH_AH_B), 3.10 (q, J = 7.2 Hz, 1 H, C(6)H), 3.07 (d, J = 16.2 Hz, 1 H, CH_AH_B), 1.07 (d, 3 H, CH₃), 0.93 (s, 9 H, t-Bu). ¹³C (126 MHz, CDCl₃): δ = 176.7 (C(O)), 172.1 (CO₂Me), 126.8–129.4 (C(Ar)), 83.50 (C(7a)), 83.31 (C(3)), 72.85 (C(7)), 53.43 (OMe), 51.46 (OMe), 46.49 (C(6)), 41.11 (CH₂), 38.40 (C(3)), 34.32 (C(CH₃)₃), 26.64 (C(CH₃)₃), 14.41 (CH₃). HRMS (ESI): m/z [M⁺] calcd for C₂₀H₂₈NO₄S₂: 410.14543; found: 410.14539.
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