Clavosolide A

Clavosolide A

Organic Letters 2012, 14, 5614

G. Peh and P. E. Floreancig*

The retrosynthesis of clavosolide A beings with the dimerization of the hydroxyl-acid unit 11 by using the classical Yamaguchi cyclization (trichlorobenzoyl chloride, DMAP, toluene, 65 °C).  Advanced intermediate 11 was produced from 10 in three steps – first stereoselective reduction of the ketone in the presence of Corey’s boraxazoline chiral catalyst established the “S” configuration on the hydroxyl; then the TIPS group was removed under acidic conditions, which was followed by oxidation of the free primary alcohol selectively (over the secondary alcohol) to the corresponding acid by using bleach.  Intermediate 10 was prepared by a glycosidation reaction of sugar 9 with the secondary alcohol obtained by the reduction of the ketone group of 8.  It is interesting to note that reduction of ketone 8 was stereoselective in favoring the formation of the equatorial hydroxyl group only.  Compound 8 was prepared from enol-ether 7 by using DDQ and lithium perchlorate.  This oxidative cyclization is an offshoot of methodology that has been developed in the author’s laboratories during the past few years.  Compound 7 was prepared by alkylation of alcohol 5 with mesylate 6, followed by ruthenium catalyzed O-acetylation of the acetylinic bond.  Alcohol 5 was prepared from a zinc-mediated coupling between mesylate 4 and aldehyde 3 using conditions developed by the Marshall group.  Acetylene-mesylated 6 was prepared by Negeshi propargylation procedure on ketone 2, which in turn was prepared cyclopropanation of chloro-alkene 1.  This cyclopropanation procedure gives trans products selectively and proceeds via a conjugate addition step followed by enolate trapping.  (See JACS, 2010, 132, 14349). EXTRA: compound 1 was prepared by reacting allyl chloride with acetyl chloride!

Thus, in this synthesis, the cyclopropanation step was performed right in the beginning and all subsequent transformations kept the ring intact.  Also interesting was the oxidative cyclization step to prepare the pyran ring (7 to 8).