Total Synthesis of (±)-Maoecrystal V

Total Synthesis of (±)-Maoecrystal V

Feng Peng and Samuel J. Danishefsky

DOI: http://dx.doi.org/10.1021/ja309905j

Yet another interesting synthesis of Maoecrystal V was just reported from Danishefsky and Peng. Besides the completed total synthesis a first attempt is also featured in this article which might have been successful when the crucial Diels Alder reaction would have given them the correct stereoisomer. After straightforward preparation of precursor A Diels Alder reaction furnished B instead of C. This outcome puts paid to the whole strategy because there is no handle on the C2-bridge with which the required functionalities could be introduced.

Scheme 1

scheme_1_17022013

With this result in hand the group started a study which then turned out be the starting point of their revised synthesis. In the first step readily accessible precursors 1 and 2 where joined together in moderate yield. Global reduction with DIBAL-H and selective oxidation of the allylic alcohol gave 4 which was acylated with D and converted to TBS enol ether 5. Under almost identical conditions as for the synthesis of B this time Diels Alder product 6 was obtained after TBAF mediated desilylation and base induced desulfinylation. Epoxidation of the unsaturated lactone double bond was followed by MgI2 facilitated opening of the epoxide with formation of the corresponding a-iodo alcohol. Dehalogenation was accomplished with Bu3SnH to give 7.

 Scheme 2

scheme_2_17022013

Next the cyclohexadiene ring was functionalized. Stereoselective epoxidation with mCPBA and subsequent opening under acid catalysis furnished tetrahydrofurane 9. Acetylation of the alcohol and reduction of the ketone yielded an inseparable mixture of diastereomers which proved to be inconsequential because the alcohol will be transformed into a sp2 center during the synthesis.[1] MOM-protection and deacetylation gave homoallylic alcohol which could be epoxidated again to epoxide 12. Oxidation and acetic anhydride assisted opening of the epoxide was followed by conjugate addition of phenyl thiol and reduction of the ketone to give thioether 14. Desulfination with Raney-Ni and elimination of the alcohol furnished at last enol ether 15. Though the functionalization of the cyclohexadiene ring seems to be pretty steppy the transformations could be executed in overall acceptable yield.

Scheme 3

scheme_3_17022013

To the end of the synthesis mainly the remaining methyl groups have to be introduced. Therefore again an epoxidation was used to functionalize the enol ether double bond. Note the overall inversion of the stereogenic center comparing 14 and 16. Under Lewis acidic conditions the epoxide was opened to ketone 16 in a Rubottom-type oxidation. Then a rather cool approach for the introduction of a gem-dimethyl group was utilized. First the ketone was transformed to an exomethylene group in the presence of Lombardo’s reagent. A Simmons-Smith cyclopropanation converts the double bond into the spiro-cyclopropane 17 which was opened under hydrogenolytic conditions after deprotection and adjustment of the oxidation states of the appendant alcohols. Chemoselective methylenation of the less hindered ketone was accomplished again in the presence of Lombardo’s reagent and followed by acid catalyzed migration of the double bond. Saegusa oxidation, epoxidation with TFDO and Lewis acid assisted opening of the ketone produced Maoecrystal V.[2]

Scheme 4

scheme_4_17022013

[1] Though the following purification steps were of course be affected.

[2] I know that this piece of work is not a pretty recent one anymore but I really wanted to cover this nice synthesis. I am really busy these days. Hopefully this changes within the next weeks because there are a lot of nice papers out. I hope you guys are still enjoying my posts and thanks for still visiting my blog…

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2 Responses

  1. Reblogged this on medchemhot.

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