Total Syntheses of the Tetracyclic Cyclopiane Diterpenes Conidiogenone, Conidiogenol, and Conidiogenone B

Si-Hua Hou, Yong-Qiang Tu, Shuang-Hu Wang, Chao-Chao Xi, Fu-Min Zhang, Shao-Hua Wang, Yan-Tao Li, and Lin Liu, Angew. Chem. Int. Ed. 2016, 55, 4456 –4460

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• Since 2002, a series of novel tetracyclic diterpenes of thecyclopiane class with some biologically important propertieshave been isolated and characterized, both from fermentationbroths and marine-derived entophytic fungi of the Penicilliumgenus.

• Conidiogenone (1) and conidiogenol (2) exhibit potent conidiation-inducing activity (20 ng of 1 or 2 per milliliter of medium is enough for the total induction of conidiogenesis in the fermentation ofPenicillium cyclopium).

• Conidiogenone (1) (0.64 mg) was isolated from a 300 L fermentation broth of Penicillium cyclopium.

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Semipinacol Rearrangement

Classical Pinacol Rearrangement

Original Definition of Semipinacol Rearrangement

The term “semipinacol” was first coined by Tiffeneau in 1923to describe a special type of pinacol rearrangement in which thetertiary secondary 1,2-diol undergoes an unusual 1,2-migrationtoward the secondary center, rather than the tertiary one.

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General Description of the Semipinacol Rearrangement

Mechanistically, all such processes share a common reactive species in which an electrophilic carbon center, including but not limited to carbocations,is vicinal to an oxygen-containing carbon and can drive the 1,2-migration of a C-C or C-H bond to terminate the process, generating a carbonyl group.

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Type I Rearrangement

Refers to the rearrangement of 2-heterosubstituted alcohols and their derivatives. In this reaction, good leaving groups such as OMs, OTs, Cl, Br, I, N2, SR, and SeR are usually attached to the electrophilic carbon center.

Tsuchihashi’s Total Synthesis of Protomycinolide IV

Suzuki, K.;Tomooka, K.; Katayama, E.; Matsumoto, T.; Tsuchihashi, G. J. Am. Chem. Soc. 1986, 108, 5221.

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Refers to rearrangements of allylic alcohols and their derivatives. The electrophilic carbon center is a carbocation that can be generated by the addition of an electrophile to a C=C bond. In contrast, oxocarbeniums, thiocarbeniums, and iminiums mainly undergo intramolecular ones. The latter case is now widely known as the Prins-pinacol rearrangement.

Type II Rearrangement

Tu’s Synthetic Studies toward Colchicine

Wang,A.X.;Song,Z.L.;Gao,S.H.;Jiang,Y.J.;Yuan,D.Y.;Tu, Y. Q.; Li, N. Z. Chin. J. Org. Chem. 2007, 27, 1171.

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Overman’s Stereocontrolled Construction of Either Stereoisomer of 12-Oxatricyclo-[6.3.1.0]-dodecanes

Prins-pinacol rearrangement.

Overman, L. E.; Velthuisen, E. J. Org. Lett. 2004, 6, 3853.

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Type III Rearrangement

Refers to rearrangements of epoxides. Investigations in this field have focused largely on the rearrangement of 2,3-epoxy alcohols and their derivatives. In this case, the electrophilic carbon center corresponds to either carbon of theoxirane, and the migration is driven by acid-promoted epoxide ring-opening.

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Tu’s Formal Total Synthesis of Cephalotaxine

Zhao, Y. M.; Gu, P. M.; Zhang, H. J.; Zhang, Q. W.; Fan, C. A.;Tu, Y. Q.; Zhang, F. M. J. Org. Chem. 2009, 74, 3211.

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Type IV Rearrangement

Refers to rearrangements of tertiary α-hydroxy ketones and imines. This reaction is also known as the “acyloin rearrangement” or “α-ketol rearrangement”

McWhorter’s Synthesis of 8-Desbromohinckdentine A

Liu, Y. H.; McWhorter, W. W., Jr. J. Am. Chem. Soc. 2003,125, 4240.

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Summary

• total synthesis ofthe cyclopiane class tetracyclic diterpene conidiogenone B (3) in 24 steps

• Intramolecular [2+2] cyclization, a regioselective and diastereoselective cycloenlargement semipinacol-type rearrangement, and subsequent aldol cyclization.