Synthesis of the Otteliones A and B: Use of a Cyclopropyl Group as Both a Steric Shield and a Vinyl Equivalent

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Derrick L. J. Clive*, Dazhan Liu

Chemistry Department, University of Alberta, Edmonton, AB T6G 2G2, Canada

A total synthesis of two related systems: otteliones A and B, which are stereochemically-related as cis- and trans-5,6-fused bicycles, respectively.

These two compounds are potent anticancer agents against various cancer cell lines with in vitro GI-50 values in the nanomolar to picomolar range.

In previous syntheses, ottelione A was first synthesized and ottelione B was then prepared by epimerization of C3a of ottelione A to afford the material in variable yields. The current synthesis served to prepare these two natural products independently from a common precursor. Key features of this synthesis are the use of the chiral cyclopropane 3, as a stereo-bias group to install other functionalities, and regioselective RCM reaction of tetraene 4 to give the requisite core structure of both natural products.

First, cyclopropane 3 was prepared using the carbohydrate route starting from methyl 2,3-O-isopropylidene-D-ribofuranosides to give 6 via a known procedure. The chiral acetonide group in 6 led to stereoselective introduction of cyclopropane by sulfonium reagent and DBU. Following deprotection of diol, dimesylation/hydrogenation/hydrogenolysis sequence was achieved to give the desired 3.

Routine chemical operations in Scheme 3 then led to alpha,beta-unsaturated aldehyde 17. The key features in this sequence included introduction of CH2-Ar group opposite to the cyclopropane ring, and SmI2-mediated demasking of cyclopropane to give required vinyl group at C1. Thus, the cyclopropane moiety had served as both stereochemical anchor for subsequent functionalizations and precursor to the vinyl group.

Next, 17 was subjected to a series of routine reactions to tetraene 4 as a mixture of isomers epimeric at C4 alcohol. It should be noted that 1,4-addition of diene occurred anti to the vinyl group at C1 and reprotonation of the resulting enolate at C3a occurred on the opposite face to substituent at C3. Then, the key RCM reaction was conducted using Grubbs' generation I catalyst regioselective and efficiently to give the core bicycle 20 in consistently excellent yield. More routine operations ensued and 1 was completed upon deprotection of TBS group on the aryl ring with TBAF.

As for completion of 2, triene 18 was epimerized at C3a with DBU to give the desired trans- isomer (>10:1 trans-:cis-). Aldehyde 22 was then subjected to a practically identical series of reactions as Scheme 4 above to give the desired 2.