Total synthesis of (-)-virginiamycin M2 and chiral organosilane based sequential transformations to access polycyclic scaffolds
MetadataShow full item record
Research projects have involved the development of enantioenriched crotylsilane reagents and their application in natural product synthesis. These novel crotylsilanes were generated through Rh(II) or Cu(l) catalyzed asymmetric carbenoid Si-H insertion. Jacobsen's Crsymmetric copper(!) diimine complexes were applied to carbenoid Si-H insertions with o.-diazovinylacetates, which resulted in the formation of crotylsilanes bearing C-centered chirality with high enantioenrichment. A comparison of chiral Cu(l) and Rh(II) catalysis was also detailed in this study. The generated organosilane products were then utilized in a Lewis acid-promoted crotylation with aldehydes and imines to provide stereochemically well-defined homoallylic ethers and carbamates. In some cases, [3 + 2] annulation products were formed tlu-ough a [1.2]-silyl rearrangement pathway. (-)-Virginiamycin M2 belongs to a class of naturally occurring antibiotics known as virginiamycins. Derivatives of virginiamycins displayed potent antibiotic activity against methicillin-, erythromycin-, and vancomyc in-resistant S. aureus. The unique chemical structure of (-)-virginiamycin M2 and its potential bioactivity motivated us to initiate a study towards its total synthesis. Notable features of our synthetic strategy included the application of the novel crotylsilane to address stereochemical features of the syn vinylogous aldol product; the use of an alkoxide-directed reductive coupling to assemble the (E,E)-diene; and a Sml2-promoted Barbier-type macrocyclization to construct the 23-membered macrocycle. A sequential transformation involving an asymmetric crotylation followed by metal carbenoid reactions has been developed to access novel bicylic and tri cyclic chemotypes. By subsequent pairing of installed functi onal groups using Heck cyclization or [2 + 2] photo-cycloaddition, the syntheses of tetracycles, pentacycles, and condensed polycycles were achieved with high stereochemical and skeletal variation. Densely functionalized chiral allylsilanes were accessed through organosilane based alkyne-alkene reductive coupling of readily available propm·gyl si lanes. The chemodivergent reactivity of the generated allylsilanes was controlled with ease to deliver a broad range of novel carbocycles through the intramolecular allylation, [3 + 2] annulations. and a Sakurai-like homodimerization.
Thesis (Ph.D.)--Boston UniversityPLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at firstname.lastname@example.org. Thank you.