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). 

Alotaketal A

 

Alotaketal A

Organic Letters 2012, 14, 5492-5494

M. Xuan, I. Paterson, S. M. Dalby *

The retrosyntheses of Alotaketal A begins with a sequence of double oxidation of two alcohols (a primary and the other secondary) and then selective reduction of the aldehyde in presence of the ketone by using sodium triacetoxyborohydride.  This is a bold final step!  Compound 16 has the sensitive ketal group which is formed by internal cyclization and protection of compound 15.  The allylic alcohol in 15 is formed by the nucleophilic attack of lithiated 6 on lactone 14.  Lactone 14 is formed by an intermolecular HWE reaction of phosphonate 13, which comes by the coupling of acid chloride of 12 with alcohol 11.  Here, the Yamaguchi reagent (trichlorobenzoyl chloride) was used to activate the acid.  Compound 11 was prepared by the selective Johnson-Lemieux oxidation of the less-hindered alkene bond of compound 10.  Compound 10 was derived by an interesting allylic oxidation and then selective reduction procedure.  The allylic alcohol 9 gets oxidized to the ketone (at the unsaturated carbon) with simultaneous dehydration to give an a,b-unsaturated ketone (not drawn).  This is then stereoselectively reduced to the allylic alcohol 10 by using the bulky L-selectride.  The protected TBS ether in 9 came from by the reduction (and then protection) of ketone 8.  This a-hydroxyketone was prepared by Rubbotom oxidation of ketone 7 (7 was first converted to its TMS enol ether and then oxidized by using mCPBA).  Compound 7 was prepared from (R)-carvone by first chlorinating the allylic carbon (Ca(OCl)₂), then hydrolyzing it to the alcohol and then protecting it as TIPS-ether.

The intermediate 6 has the allylic iodide group, which came from the corresponding ester 5.  Ester 5 was treated with TMSCH₂MgCl which gave the double addition of the “CH₂-“ group on the ester.  It also produced a tertiary alcohol which eliminated.  Ester 5 came from a Nagao aldol reaction of chiral auxially 3 with aldehyde 2.  Aldehyde 2 is simply the oxidized form of geraniol – but it was produced in a rather round-about way.  Geraniol was first chlorinated and then reduced by LAH.  The allyl group was then oxidized to the aldehyde by MnO₂.