The Total Synthesis of a Conformationally Constrained Organophosphorus Analog of Acetycholine

We propose the total synthesis of a conformationally constrained organophosphorus analog of acetylcholine (5, Scheme 5). This compound will contain two crural centers, one being the phosphorus atom and the other being the pyrrolidine ring carbon beta to the phosphorus atom. The chiral beta carbon is conformationally constrained because it is part of the pyrrolidine ring. Studies with such a compound should allow us to make substantial progress towards the clarification of the stereospecificity of AChE inhibition by OP compounds and eventually help us understand more about the structure of the AChE active site. The synthesis begins with Cbz-L-proline methyl ester (1) which is commercially available. Reduction of the methyl ester with sodium borohydride in the presence of CaCl2 will yield Cbz-L-prolinol (2). Phosphorylation of the primary alcohol will yield a pair of diastereomers (3,.). After separation by flash chromatography, each diastereomer will be subjected to hydrogenolysis, to cleave the Cbz-protecting group, followed by methylation of the amine with methyl iodide. By repetition of this process with Cbz-D-proline methyl ester, we should be able to access all four stereoisomers

Synthesis of 3‐Oxaterpenoids and Its Application in the Total Synthesis of (±)‐Moluccanic Acid Methyl Ester

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/94262/1/ange_201205981_sm_miscellaneous_information.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/94262/2/10771_ftp.pd

Total synthesis of (-)-spinosyn A.

A concise, stereoselective total synthesis of (-)-spinosyn A is described. Spinosyn A is a member of a family of polyketide natural products possessing extraordinary insecticidal activity. Dr. Herbert A. Kirst has proposed that the biosynthesis of spinosyn may involve a transannular Diels-Alder reaction and a transannular Michael cyclization of a macrocyclic pentaene. Based on Kirst's proposal, a biomimetic approach to spinosyn A was developed, in which two key issues have been successfully addressed: control of the diastereoselectivity in the Diels-Alder reaction and development of methodology to accomplish the Michael cyclization. A steric directing group strategy has been successfully utilized to control the diastereoselectivity of the Diels-Alder reaction. It was discovered that a C(6)-Br steric directing group and an additional C(8)-silyloxy substituent were required for diastereocontrol in the intramolecular Diels-Alder reaction of an appropriately substituted pentaene precursor. However, the C(6)-Br group alone was sufficient for diastereocontrol in the transannular Diels-Alder reaction of a macrocyclic pentaene. In order to accomplish the Michael ring closure, the vinylogous intramolecular Morita-Baylis-Hillman reaction was developed. The scope and utility of this reaction was explored for the synthesis of substituted cyclopentenes and cyclohexenes by trialkylphosphine-catalyzed cyclizations of deactivated 1,5-hexadienes and 1,6-heptadienes. It was found that trimethylphosphine is the best catalyst for this reaction, while the optimal solvent is tert-amyl alcohol. In general, the cyclizations of 1,5-hexadienes are faster, more efficient, and require lower phosphine catalyst loading than the 1,6-heptadienes. A concise synthesis of the spinosyn A tricyclic nucleus was then developed by a route featuring a one-pot tandem intramolecular Diels-Alder and intramolecular vinylogous Morita-Baylis-Hillman cyclization sequence. This cyclization sequence was subsequently applied in a transannular manifold to a formal total synthesis of spinosyn A. Finally, a transannular Diels-Alder and Morita-Baylis-Hillman cyclization sequence, followed by a highly diastereoselective glycosidation sequence, has been successfully applied to a total synthesis of (-)-spinosyn A.Ph.D.Organic chemistryPure SciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/124133/2/3121998.pd