Synlett 2023; 34(14): 1694-1698
DOI: 10.1055/a-1932-9717
letter
Published as part of the Special Section 13th EuCheMS Organic Division Young Investigator Workshop

A Consecutive Ring-Expansion Strategy towards the Macrocyclic Core of the Solomonamide Natural Products

Zhongzhen Yang
,
Christopher R. B. Swanson
,
William P. Unsworth  ∗
The authors would like to thank the University of York for the provision of an Eleanor Dodson Fellowship (to W.P.U.) and the China Scholarship Council for a funding the PhD studentship of Z.Y.
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Abstract

A synthetic strategy based on the application of three consecutive ring-expansion reactions has been used in the synthesis of analogues of the macrocyclic core of the solomonamide natural products. Starting from a simple, readily available tetrahydrocarbazole, oxidative ring expansion is followed by two further 3- and 4-atom ring-expansion reactions, enabling the insertion of amino acid and hydroxy acid derived linear fragments into 15- to 17-membered-ring-enlarged macrocyclic products.

Key words

macrocycles - medium-sized rings - ring expansion - natural product analogues - lactams - lactones - solomonamides

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/a-1932-9717.
  • Supporting Information


Publication History

Received: 21 July 2022

Accepted after revision: 29 August 2022

Accepted Manuscript online:
29 August 2022

Article published online:
30 September 2022

© 2022. Thieme. All rights reserved

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  • References and Notes

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  • 18 In the cases of products 28 and 33 (both prepared from enantiopure proteinogenic amino acids), the enantiopurity of the products was not measured in this study, but epimerisation is considered to be unlikely based on our previous studies (ref. 14), in which such epimerisation was not observed in related systems.
  • 19 Representative Procedure for SuRE Method A (Synthesis of 28) 3,4,5,6-Tetrahydro-1H-(1)-benzazonin-2,7-dione 8 (406.4 mg, 2.00 mmol), DMAP (24.4 mg, 0.200 mmol), and pyridine (0.970 mL, 12.0 mmol) in dry DCM (10 mL) under an argon atmosphere were stirred at RT for 30 min. Next, a solution of acid chloride (6.0 mmol, 3.0 equiv., prepared from Cbz-proline using the procedure described in the Supporting Information) in dry DCM (10 mL) was added, and the resulting mixture was heated at reflux (50 °C) for 18 h. The solvent was then concentrated in vacuo, loaded onto a short silica plug and eluted with ethyl acetate, to remove majority of excess carboxylic acid and pyridine residues, and concentrated in vacuo. This material was redissolved in MeOH (20 mL) and placed under an argon atmosphere. Palladium on carbon (200 mg, 10% Pd on carbon) was added, and the reaction vessel was backfilled with hydrogen (via balloon) several times, then stirred at RT under a slight positive pressure of hydrogen (balloon) for 1 h. The reaction was then purged with argon, filtered through Celite, washed with methanol, and the solvent was removed in vacuo. Purification by flash column chromatography (SiO2, ethyl acetate) afforded the title compound as a colorless oil (414 mg, 69% over 2 steps from 8) which exists as a 5:1 mixture of rotamers in solution in CDCl3; [α]D 23 –312.13 (c = 1.0, CHCl3); Rf = 0.23 (ethyl acetate). IR (neat) νmax = 3252, 2948, 2242, 1691, 1672, 1602, 1505, 1442, 1299, 1238, 910, 756, 725, 644, 580 cm–1. 1H NMR (400 MHz, CDCl3): δ = 9.43 (s, 1 H, NH, major rotamer), 9.34 (s, 1 H, NH, minor rotamer), 7.77–7.73 (m, 1 H, PhCH, major rotamer), 7.42–7.28 (m, 2 H, PhCH, both rotamers), 7.20–7.14 (m, 1 H, PhCH, minor rotamer), 7.07 (td, J = 7.6, 1.0 Hz, 1 H, PhCH, major rotamer), 4.31–4.20 (m, 1 H, NCHCO, both rotamers), 3.78 (dt, J = 10.1, 7.0 Hz, 1 H, NCH2, major rotamer), 3.60 (ddd, J = 11.5, 7.3, 4.3 Hz, 1 H, NCH2, minor rotamer), 3.55–3.44 (m, 1 H, NCH2, both rotamers), 3.07–2.78 (m, 2 H, CH2, both rotamers), 2.68–2.49 (m, 1 H, CH2, major rotamer), 2.36–2.01 (m, 4 H, CH2, both rotamers), 2.02–1.61 (m, 5 H, CH2, both rotamers). 13C NMR (100 MHz, CDCl3) for the major rotamer only: δ = 207.2 (CO), 173.4 (CO), 172.8 (CO), 134.8 (PhC), 133.0 (PhC), 131.4 (PhCH), 126.9 (PhCH), 124.5 (PhCH), 124.1 (PhCH), 62.6 (COCHN), 47.0 (CH2), 41.8 (CH2), 35.1 (CH2), 28.4 (CH2), 25.3 (CH2), 22.6 (CH2), 22.1 (CH2). Diagnostic 13C NMR resonances for the minor rotamer: δ = 204.8 (CO), 172.6 (CO), 172.3 (CO), 135.9 (PhC), 133.6 (PhC), 127.9 (PhCH), 126.0 (PhCH), 125.5 (PhCH), 61.4 (COCHN), 38.5 (CH2), 31.9 (CH2), 31.6 (CH2), 23.6 (CH2), 23.0 (CH2), 21.2 (CH2). HRMS (ESI): m/z calcd for C17H20N2NaO3: 323.1366; found [MNa]+: 323.1362 (1.3 ppm error). For spectroscopic data and procedures for all novel compounds prepared in this manuscript, see the Supporting Information.