Total Synthesis of Lignans by C sp3 —H Arylation Reactions

The aforementioned method, though elegant, cannot be adapted to the synthesis of head-to-tail homodimerization-or heterodimerization-derived cyclobutane lignans, such as piperarborenine B (157) [58a] and D (158) [58b], both of which were isolated from the stems of the creeping shrub Piper arborescens and exhibit in vitro cytotoxicity against P-388, HT-29, and A-549 cancer cell fines (IC5 4pg/ml) [58b], They are assumed to arise from the head-to-tail heterodimerization of piplartine-type monomers, with cis-trans-cis and trans-trans-trans stereochemistry, respectively. However, a biomimetic [2+2] photocycloaddition fashion is certainly problematic since homodimerization and head-to-head dimerization and E/Z isomerization would 

SCHEME 10 J2 Biomimetic synthesis of magnosalin via photoinduced electron transfer. 

SCHEME 10.33 Total synthesis of piperarborenines B and D enabled by double cyclobutane C—H arylations. 

SCHEME 10.34 Total synthesis of pipercyclobutanamide A enabled by sequential sp C—H arylation and olefination. 

As shown in Schane 10.35a, this distinct synthesis began with the scalable preparation of benzocyclobntenol silyl ether 178 from 6-bromopiperonal (177) throngh epoxida-tion, cyclization, and silylation procedure [69]. The subsequent thermal cycloaddition of 179, via an o-quinodi-methane intermediate 180, with fumarate-derived amide 181 afforded C—H functionalization precursor 182 albeit in moderate yield and diastereoselectivity. As expected, when this amide is subjected to stoichiometric Pd(OAc)j in hot CHjCN, the Pd complex 183 was formed in 53% yield. However, upon the exposure of this intermediate with C7 —H activation to excess of 3,4,5-trimethoxyiodobenzene (163) under the usual arylation condition, p-lactam 184 was obtained exclusively in 75% yield, instead of the expected 

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