Total Synthesis of (S)-(-)-Curvularin: A Ring-Closing-Metathesis-Based Construction of the Macrocyclic Framework

Abstract

A convergent, flexible, and efficient approach to the synthesis of curvularin is described. Key step is the high-yielding macrocyclic ring formation by ring-closing metathesis (RCM) using the Grubbs second-generation catalyst.

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“…Since the first isolation of 1 , by Musgrave7 in 1956, it was an interesting target molecule in total synthesis, starting in 1967 with work by Baker, Bycroft, and Roberts 8. In these efforts, the 12‐membered lactone was formed by Friedel–Crafts acylation,8–13 by esterification with oxazoles as masked activated carboxylates,14,15 by ring‐closing metathesis,16–18 or by aryne acyl‐alkylation 19. In contrast, the only synthetic route to the α,β‐unsaturated series was reported in 2013 by Fürstner20 and co‐workers, with ( S )‐10,11‐dehydrocurvularin ( 2 ) being made by an alkyne ring‐closing metathesis.…”

“…The strategy for the formation of the β,γ‐unsaturated ketone by ring‐closing metathesis is related to the synthesis of ( S )‐curvularin by Mohapatra 18. By starting from arylacetic acid 22 , the protected alcohol 25 was prepared in high yield by reduction with lithium aluminum hydride and protection with PMBCl.…”

“…The solvent was removed in vacuo. The protected alcohol 25 was obtained as a yellow oil (10.41 g, 22.9 mmol, quant., ref 18. 81 %).…”

“…1,3‐Bis(benzyloxy)‐5‐{2‐[(4‐methoxybenzyl)oxy]ethyl}benzene (25): 18,21 A suspension of sodium hydride (95 %, 1.10 g, 45.8 mmol, 2.0 equiv.) in dry DMF (50 mL) was cooled to 0 °C.…”

“…2,4‐Bis(benzyloxy)‐6‐{2‐[(4‐methoxybenzyl)oxy]ethyl}benzaldehyde: 18 Phosphoryl chloride (1.03 mL, 11.0 mmol, 5.0 equiv.) was added at room temperature to a solution of protected phenyl ethanol 25 (1.00 g, 2.20 mmol, 1.0 equiv.)…”