Highly Convergent Three Component Benzyne Coupling:  The Total Synthesis of ent-Clavilactone B

Abstract

The first total synthesis of (+)-clavilactone B, a potent antifungal agent and novel tyrosine kinase inhibitor, is described. The absolute configuration of clavilactones has been unambiguously established by using Sharpless asymmetric epoxidation to generate the enantiomerically pure substrate. The strategy highlights the use of a powerful and convergent three-component benzyne coupling with a methylallyl Grignard and a chiral epoxy-aldehyde to generate two C-C bonds and install the carbon skeleton of clavilactone. Oxidative lactonization, ten-membered ring construction by ring closing metathesis, and oxidation gave clavilactone B.

Asymmetric synthesis of quaternary aryl amino acid derivatives via a three-component aryne coupling reaction

“…We are particularly interested in the use of arynes in multicomponent coupling reactions, in which the resultant aryl carbanion following nucleophilic attack is allowed to react with a further electrophile, providing ortho -disubstituted, functionalized aromatic products in a one-pot procedure [7–9]. In particular, we have focused on the addition of carbon-based nucleophiles in such systems (Scheme 1) and have applied this methodology to the syntheses of natural products ent-clavilactone B and dehydroaltenuene B [10–11]. …”

Synthesis of Natural Products Containing Medium‐Size Carbocycles by Ring‐Closing Alkene Metathesis

“…As expected, RCM proved to be difficult and had to be performed under special conditions: the catalyst [Ru]-II (40 mol%) was slowly added, along with tetrafluoro-1,4-BQ (to prevent olefin isomerization), and the formed ethylene was removed during the reaction. Under these conditions, the RCM product 390 was obtained in a satisfactory yield (65%) and converted to ent-clavilactone B [103].…”

Large‐Ring Carbocycles

“…e«i-Clavilactone B, a unique compound with antifungal and antibacterial properties, was synthesized by Barrett and co-workers using olefin metathesis as a key step in their strategy. 168 Extensive optimization led to the slow addition of 40 mol % of 4 to diene 385 in the presence of 80 mol % tetrafluorobenzoquinone in toluene to afford the desired 10-membered ring 386 in 65% yield. The authors noted that the reaction proceeded smoothly without affecting the strained epoxide ring.…”