First Total Synthesis of the Marine-Derived Anti-inflammatory Natural Product (–)-Herdmanine D through a Steglich Esterification

Abstract

An efficient and regioselective route for the first total synthesis of the antiinflammatory marine natural product (–)-herdmanine D, with an excellent overall yield of 18%, is described. A key feature of the synthetic strategy is a Steglich esterification of regioselectively constructed 6-bromo-5-methoxy-1H-indole-3-carboxylic acid with protected l-tyrosine. The formation of the l-isomer was confirmed through measurement of the optical activity. The current strategy paves the way for the construction of diverse analogues of (–)-herdmanine D for drug development.

Key words

herdmanine D - regioselectivity - total synthesis - indoles - pharmaceutical chemistry

Publication History

Received: 07 September 2021

Accepted after revision: 18 October 2021

Accepted Manuscript online:
19 October 2021

Article published online:
11 November 2021

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• 9 (–)-Herdmanine D A solution of LiOH (0.13 g, 5.0 equiv) in H₂O (2 mL) was added slowly to a stirred solution of ester 7 (0.5 g, 1.0 equiv) in MeOH (2 mL), and the mixture was stirred for 4 h at rt. When the reaction was complete (TLC), the mixture was concentrated under reduced pressure and acidified with 1 N aq HCl to pH 2. The solid that precipitated was collected by filtration on a sintered funnel, washed with ice-cold H₂O, and then dried under a high vacuum to give a light-brown solid; yield: 0.18 g (41%); mp 210–215 °C; [α]_D ²³ –20.3. ¹H NMR (400 MHz, DMSO-d ₆): δ = 12.96 (br s, 1 H, –COOH), 12.36 (br s, 1 H, –NH), 9.22 (s, 1 H), 8.76 (s, 1 H), 8.46–8.43 (d, J = 9 Hz, 2 H), 7.83 (s, 1 H), 7.65–7.63 (d, J = 6 Hz, 2 H), 7.37–7.35 (d, J = 6 Hz, 2 H). 4.02–3.94 (m, 1 H), 2.79–2.75 (m, 2 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 176.47, 164.72, 149.21, 140.54, 136.99, 132.84, 129.65, 127.44, 123.74, 120.54, 117.34, 111.51, 108.30, 106.89, 104.67, 103.70, 57.38, 36.88. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₈H₁₅BrN₂O₅: 418.0164; found: 418.0170.