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Development of Novel Methods and Applications in Total Synthesis of Natural Products
Sirasani, Gopal
Sirasani, Gopal
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2012
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Chemistry
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http://dx.doi.org/10.34944/dspace/2383
Abstract
The olefin cross metathesis reaction has been sequenced with four common organic transformations in a one-pot manner to rapidly access useful building blocks. Those reactions are: (1) phosphorus-based olefination (e.g., Wittig and Horner- Wadsworth-Emmons); (2) hydride reduction; (3) Evans propionate aldol reaction; and (4) Brown allyl- and Roush crotylboration. The products of these reactions include stereodefined 2,4-dienoates, trans allylic alcohols, syn-propionate aldols and chiral non- racemic homoallylic alcohols, respectively, which can be carried further in the context of chemical synthesis. Two approaches toward the total synthesis of cytotoxic polyketide natural product (+)-crocacin C have been accomplished. The first-generation approach used a Crimmins aldol reaction and reagent-controlled double asymmetric crotylboration (Brown and Roush) reaction, which was not selective. The first-generation approach was replaced altogether with a second that afforded (+)-crocacin C in 10 steps from commercially available Evans' chiral propionimide (5% overall yield). The key reactions in the second-generation approach included an Evans dipropionamide aldol reaction, 1,3-anti reduction and a vinylogous Horner-Wadsworth- Emmons olefination. No protecting groups were utilized in the total synthesis of (+)- crocacin C. A novel method to access the ABCE tetracyclic framework of the Strychnos alkaloids has been developed. Five different strategies were utilized toward this goal, out of which the first four were unsuccessful. The fifth-generation strategy featured a novel sequential one-pot bis-cyclization method. Specifically, the AgOTf-mediated spirocyclization of an appropriately functionalized indole 3-carbinamide afforded a stable spiroindolenine intermediate; subsequent addition of DBU to the reaction mixture effected an unprecedented intramolecular aza-Baylis-Hillman reaction, delivering tetracyclic product in 70% isolated yield. The bis-cyclization was showcased in concise racemic total syntheses of akuammicine and strychnine in six and thirteen operations, respectively. Key steps include (1) the vinylogous Mannich reaction; (2) our sequential one-pot spirocyclization/intramolecular aza-Baylis-Hillman reaction; and (3) a Heck cyclization. The synthesis of strychnine proceeded via the Wieland-Gumlich aldehyde. We have also utilized our method to prepare other biologically active Strychnos alkaloids (-)- akuammicine, (-)-leuconicines A and B, (-)-norfluorocurarine, (-)-dehydrotubifoline, (-)- dihydroakuammicine, (-)-tubifoline and (-)-valparicine in a concise, asymmetric manner.
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