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42016-AC1
Intramolecular Reactions Employing a Ketal Tether: Total Synthesis of Fusidilactone C
Aim I. Total Synthesis of Fusidilactone C.
(A) We communicated our approach toward the 2-oxadecalinic spiroketal frame of fusidilactone C via a chiral cyclic ketal-tethered intramolecular Diels-Alder cycloaddition. Over the course of the last 12 months, we managed to reach the stage of assembling the entire oxoadamantane core of fusidilactone C from endo-II cycloadducts that actually contains all the relevant carbons. We have a series of problems in correcting the wrong stereocenter but we are still exerting our efforts, although it is not likely that we will finish this natural product target before the end of the grant period.
(B) In addition, recently we have completed an enantioselective total synthesis of (+)-aigialospirol featuring a cyclic ketal tethered ring-closing metathesis strategy and an unexpected stereoselective epimerization of a benzylic hydroxy group. This 15-step synthetic sequence from (S)-glycidol represents a proof of concept that cyclic ketal tethered RCM can be competitive with the classical spiroketal synthesis. We have just submitted this work to Angew. Chem. entitled "A Concise Total Synthesis of (+)-Aigialospirol via a Cyclic Ketal-Tethered Ring-Closing Metathesis."
Aim II. Development of Ketal Tethered Intramolecular Reactions: IMDA and RCM.
(A) We have completed our development ofa ketal- and aminal-tethered RCM strategy that conceptually represents a very different or an unconventional approach toward the synthesis of spiroketals and spiroaminals.
(B) This work led us to embark on a new total synthesis effort toward spirastrellolide. Specifically to date, our ketal-tethered RCM strategy was applied successfully to the synthesis of simple insect pheromone and the C11-epi-C22-C23 fragment in spirastrellolide A. We have now completed a concise synthesis C1-10 pyranyl unit that differed from the existing syntheses of comparable fragment in spirastrellolide A, and we are in the process of completing the southern half of this complex natural product target.
(C) In our efforts to continue developing methodologies, we uncovered evidences for an anomeric control on the stereoselectivity of a remote center are described here. This study suggests a reversed concept for stereoselective constructions of spiroketals: Cyclic ketals, with a stereochemically predetermined ketal center, can be employed as a chiral template that upon subjecting to various reactivities may direct stereochemical outcome away from the pending spirocenter under the conformational influence exerted by the anomeric effect.
(D) Finally, we recently uncovered a stereoselective halo-etherification of chiral enamides, leading to the synthesis of halogenated cyclic ethers, which are prevalent among natural products. While this work provides a stereoselective entry to chiral secondary halides, these halo-etherifications also provide mechanistic insight to the chemistry of chiral enamides. Applications of this new synthetic method are current underway. We have just submitted this work to The Organic Lett. entitled "A Stereoselective Intramolecular Halo-Etherification of Chiral Enamides in the Synthesis of Halogenated Cyclic Ethers."
