Total Synthesis of Cryptotrione

Abstract

The total synthesis of cryptotrione (1) was enabled by substrate-controlled diastereoselective construction of the bicyclo[3.1.0]hexene framework through platinum-catalyzed enyne cycloisomerization and Lewis acid induced polyene cyclization to construct the abietane-type tricyclic diterpene skeleton. The stereogenic tertiary carbon center in the side chain was installed in a diastereodivergent manner by conjugate addition reactions.

Pivotal Reactions in the Creation of the Polycyclic Skeleton of Cryptotrione

“…To construct the abietane-type skeleton of cryptotrione (1), a Lewis acid induced polyene cyclization of polyene 184 to yield the trans-decalin product 185 was explored. 1 As shown in Table 3, after optimization of the Lewis acid, solvent, and temperature, Bi(OTf) 3 -induced polycyclization was indeed found to be able to convert polyene 184 into the abietane-type product 185 as a single diastereomer, after further cyclization of partially cyclized intermediates 186.…”

“…Recently, we reported the total synthesis of cryptotrione (1), 1 a novel C 35 -terpene isolated from the bark of Cryptomeria japonica by the Kuo group. 2 Interestingly, cryptotrione (1) exhibits anticancer activity against human oral epidermoid carcinoma KB cells with an IC 50 value of 6.44 ± 2.23 m, being only slightly weaker than that of the clinically used anticancer drug, etoposide (VP-16, IC 50 ≈ 2.0 m).…”

“…2 Interestingly, cryptotrione (1) exhibits anticancer activity against human oral epidermoid carcinoma KB cells with an IC 50 value of 6.44 ± 2.23 m, being only slightly weaker than that of the clinically used anticancer drug, etoposide (VP-16, IC 50 ≈ 2.0 m). As shown in Scheme 1, we achieved the first total synthesis of cryptotrione (1) from commercially available homoveratric acid (7) in a diastereoselective and diastereodivergent manner. The key reactions to formulate the polycyclic skeleton of cryptotrione include: (I) transition-metal-catalyzed enyne cycloisomerization to form the bicyclo[3.1.0]hexene skeleton (the EF ring species), (II) polyene cyclization to form the abietane-type tricyclic diterpene skeleton (the AB ring species), and (III) quinone methide formation (the CD ring species).…”

Total Synthesis of Cryptotrione

“…The structure of 7'-epi-cryptotrione (25) was unambiguously confirmed using X-ray crystallographic analysis. [24] In summary, we achieved the first total synthesis of cryptotrione (1) from commercially available homoveratric acid (11) in a diastereoselective and diastereodivergent manner. This synthetic protocol features with a novel platinum(IV) chloride catalyzed diastereoselective cycloisomerization of 1,5-enynes to construct the bicyclo[3.1.0]hexane core, a Lewis acid induced diastereoselective polyene cyclization, and a stereo divergent conjugate addition to construct the tertiary carbon center of the side chain with full stereocontrol.…”

“…Desilylation of 13 e followed by hydrogenation yielded alcohol 14 in 75 % yield (Scheme 2) and Xray crystallographic analysis showed the bicyclo[3.1.0]hexane skeleton to have the same relative configuration as in natural cryptotrione (1). [24] Oxidation of 14 with Dess-Martin periodinane furnished the corresponding ketone, which then under- went monoalkylation with geranyl bromide using one equivalent of LDA in a mixed solvent (THF:DMPU 10:1) to afford a diastereomeric mixture of monoalkylated polyene ketones 15 in 72 % yield (84 % brsm) together with 15 % yield of the dialkylated by-product. The mixture of ketones 15 was inseparable by column chromatography and, since it also proved unstable and prone to decomposition.…”