(-) Laulimalide

Paterson, Ian, Chris De Savi, and Matthew Tudge. 2001. Total Synthesis of the

Microtubule-Stabilizing Agent (-) Laulimalide. Organic Letters 3 (20):

3149-3152. http://pubs.acs.org/isubscribe/journals/orlef7/3/i20/pdf/o101050u.pdf

Reviewed by Matt Boehm

Laulimalide is also known as fijianolide B. It was isolated from the Pacific sponges Hyatella sp., Spongia mycofijiensis, and the Okinawan sponge Fasciospongia rimosa. Laulimalide is an anticancer agent. It works within the cell cycle by initiating mitotic arrest, micronuclei formation, and apoptosis. Laulimalide has been shown to inhibit the proliferation of numerous cancer cell lines and appears to have the same microtubule-stabilizing mechanism action as the anticancer drug Taxol. In fact laulimalide was found to be superior to Taxol in its ability to circumvent P-glycoprotein mediated drug resistance and in stimulating tubulin polymerization. It is believed that laulimalide will be able to provide therapeutic utility against multi-drug resistant cancers.

Retrosynthesis

The synthesis of the laulimalide was completed in 27 steps and resulted in a 2.9% yield. To start the synthesis, compound 6 is created by a Jacobsen’s Diels-Alder reaction between compound 8 and compound 9. This reaction involves the use of a chromium(III) Lewis acid catalyst, which has two chirality centers. This allows for the production of 95% enantiopurity and gave compound 6 one chirality center. This produces a 6 membered ring and through a series of steps the methoxy group is removed and the alcohol under goes a Swern oxidation to remove the H, and produce the aldehyde of 6. Compound 7 is created from a diol. Compounds 6 and 7 then undergo a aldol coupling reaction between carbon 21 and carbon 22 that produces H₂O and compound 5. 5 then reacts with 4 in a aldol coupling reaction between carbon 14 of 4 and carbon 15 of 5. This reaction produces a mixture of enantiomers. Then through a complicated series of steps that include the transormation of a carbonyl group on Carbon 13 into a carbon-carbon double bond to produce compound 3. Compound 3 then undergoes a Sharpless asymmetric epoxidation reaction to produce the final product laulimalide.

The asymmetric epoxidation reaction was a critical step. Laulimalide contains an epoxide between the 16^th and 17^th carbon. The Sharpless asymmetric epoxidation allows for the controled introduction of the epoxide onto the unsaturated diol 3. The Sharpless epoxidation also allows for high enantiopurity, which is needed to make laulimalide. In the synthesis the Sharpless epoxidation is a very important step, which allows for the proper synthesis of laulimalide.

This review of laulimalide was put together by Matt Boehm