Studies toward the Synthesis of Colletotrichamide A: Construction of the C19–C30 Segment of the Molecule

Abstract

A synthesis of the C19–C30 segment of the neuroprotective natural product colletotrichamide A has been achieved by performing a Sonogashira coupling of two advanced intermediate fragments: a vinyl iodide and an alkyne. A Maruoka–Keck allylation, an Evans syn-aldol reaction, and Takai olefinations served as the key steps in the synthesis of the vinyl iodide intermediate, whereas glycosidation and Ohira–Bestmann reactions were used as the pivotal steps for accessing the advanced alkyne intermediate.

Key words:

colletotrichamide A - neurodegenerative disease - Maruoka–Keck allylation - Evans syn-aldol reaction - glycosidation - Sonogashira reaction

Publication History

Received: 14 June 2024

Accepted after revision: 23 July 2024

Accepted Manuscript online:
25 July 2024

Article published online:
22 August 2024

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• 26 (5R,6S)-5-[(2S,3S,4E,8R)-2-[(4-Methoxybenzyl)oxy]-3-meth­yl-8-({(2R,3S,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-[(benzyloxy)methyl]tetrahydro-2H-pyran-2-yl}oxy)non-4-en-6-yn-1-yl]-2,2,3,3,6,10,10-heptamethyl-9,9-diphenyl-4,8-dioxa-3,9-disilaundecane (28) Pd(PPh₃)₄ (231 mg, 0.20 mmol) and CuI (152 mg, 0.80 mmol) were added to a solution of vinyl iodide 9 (300 mg, 0.40 mmol), alkyne 10 (271 mg, 0.46 mmol), and Et₃N (86 μL, 0.60 mmol) in anhyd THF (10 mL) under argon at rt, and the mixture was stirred at rt for 5 h. The reaction was then quenched with sat. aq of NH₄Cl (15 mL) and the mixture was extracted with EtOAc (3 × 20 mL). The combined organic extracts were washed with brine (10 mL), dried (Na₂SO₄), and concentrated in vacuo. The residue was purified by gel column chromatography [silica gel (100–200 mesh), 10% EtOAc–hexane] to give a white solid; yield: 415 mg (87%); R_f = 0.5 (silica gel, 20% EtOAc–hexane); [α]_D ²⁵ –5.9 (c 1.2, CHCl₃). IR (neat): 3065, 3031, 2955, 2928, 1612, 1587, 1513, 1438, 1249, 1105, 1066, 824, 738 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.72–7.68 (m, 1 H), 7.65–7.60 (m, 4 H), 7.56–7.50 (m, 1 H), 7.49–7.45 (m, 2 H), 7.42–7.31 (m, 9 H), 7.29–7.25 (m, 10 H), 7.24–7.22 (m, 2 H), 7.21–7.17 (m, 3 H), 6.86–6.80 (m, 2 H), 6.20 (dd, J = 16.0, 7.1 Hz, 1 H), 5.47 (d, J = 16.0 Hz, 1 H), 4.99 (d, J = 12.4 Hz, 1 H), 4.88 (q, J = 7.7 Hz, 2 H), 4.72 (q, J = 6.3 Hz, 1 H), 4.67–4.43 (m, 6 H), 4.38 (s, 2 H), 4.22 (t, J = 6.1 Hz, 1 H), 3.93–3.84 (m, 2 H), 3.80–3.77 (m, 2 H), 3.75 (s, 3 H), 3.61 (dd, J = 10.0, 7.5 Hz, 1 H), 3.53 (dd, J = 9.3, 2.7 Hz, 1 H), 3.50–3.40 (m, 3 H), 2.48 (t, J = 7.7 Hz, 1 H), 2.34 (t, J = 7.5 Hz, 1 H), 1.95–1.89 (m, 1 H), 1.70–1.67 (m, 1 H), 1.49 (d, J = 6.6 Hz, 3 H), 1.04 (s, 9 H), 0.93 (dd, J = 6.7, 2.2 Hz, 3 H), 0.88 (d, J = 6.4 Hz, 3 H), 0.83 (s, 9 H), 0.00 (s, 3 H), –0.02 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 159.1, 147.8, 138.9, 138.6, 138.5, 138.3, 135.6, 135.4, 135.3, 135.2, 133.9, 133.8, 131.8, 131.0, 130.3, 129.7, 129.3, 128.5, 128.4, 128.4, 128.3, 128.2, 128.1, 128.0, 127.7, 127.6, 127.4, 127.3, 113.8, 108.9, 99.0, 87.7, 84.2, 82.6, 78.8, 76.2, 75.2, 74.9, 74.1, 74.0, 73.6, 71.5, 71.3, 70.5, 69.7, 66.0, 65.1, 55.3, 41.1, 39.6, 34.0, 27.0, 26.0, 22.3, 19.3, 18.1, 13.6, 12.3, –4.0, –4.2. MS (ESI): m/z = 1268 [M + NH₄]⁺. HRMS (ESI): m/z [M + NH₄]⁺ calcd for : 1268.7042; found: 1268.7081