Stereoselective ortho-ester Claisen

The enantioselective total synthesis of the 13-membered macrolide fungal metabolite (+)-brefeldin A was accomplished using a triple chirality transfer process and intramolecular nitrile oxide cycloaddition in the laboratory of D. Kim. To set the correct stereochemistry at C9, the stereoselective ortho ester Claisen rearrangement was applied on a chiral allylic alcohol precursor. The rearrangement was catalyzed by phenol and it took place at 125 °C in triethyl orthoacetate to give 84% isolated yield of the desired diester. 

Ortho ester rearrangement of allylic alkynyl alcohols. The allylic alkynyl alcohols (1) and (4) undergo stereoselective ortho ester Claisen rearrangement when refluxed with triethyl orthoacetate (propionic acid catalysis). In both cases... 

The Johnson Claisen rearrangement,31 also called the ortho ester Claisen rearrangement, involves the reaction of an allylic alcohol with an ortho ester, often triethyl orthoacetate, in the presence of a carboxylic acid such as propionic acid, usually at temperatures between 120 and 140 JC (Scheme 3).1 The intermediate kctcnc acetal rearranges stereoselectively. 

For the stereoselective synthesis of (5 )-2-[D3]methyl-2-methylbutanol via the ortho ester Claisen rearrangement see ref 376. 

Tadano K, Idogaki Y, Yamada H, Suami T (1987) Ortho Ester Claisen Rearrangements of Three 2-C-(Hydroxymethyl)methylene Derivatives of Hexofuranose Stereoselective Introduction of a Quaternary Center on C-3 of D-ribo-, L-lyxo-, and D-arabino-Hexofuranoses. J Org Chem 52 1201... 

Stereoselective Claisen-type [3,3] sigmatropic rearrangements of propynyl vinyl ethers, which are intermediates in the reaction of propynyl alcohols with aldehydes or ortho esters leading to a-allenic aldehydes or esters, have been reported15,16. 

The installation of the butyrolactone substituent at C3 started with the addition of the lithiated form of the ortho ester 121 to 120. The y-butyrolactone core was installed after stereoselective reduction of the ketone moiety and exposure to TsOH in methanol. Claisen rearrangement afforded 122 which resisted attempts to undergo iodocyclization, but afforded tetracylic 123 after selenolactonization followed by Keck allylation and a-methylation. The total synthesis of (—)-tuberostemonine (4) was concluded after 25 steps and in 1.7% overall yield from 113 after isomerization of the allyl group and cross-metathesis with ethylene promoted by ruthenium catalyst 117 to provide the terminal vinyl group which was stereoselectively hydrogenated. 

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