Date of Award

January 2012

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

First Advisor

Alexei Novikov

Abstract

This works explores the use of rhodium-catalyzed intramolecular C-H insertion on diazosulfones and sulfonates as a tool to simplify the synthesis of organic molecules. Dirhodium-induced intramolecular C-H insertion on diazo carbonyl compounds is a relatively well-studied reaction. It occurs with an overwhelming bias for the formation of five-membered carbocycles or heterocycles, with the order of reactivity of C-H bonds being methine > methylene >> methyl. This intrinsic preference can be overridden by dissimilar factors such as substrate conformation, insertion site electronic effects and the reactivity of the dirhodium catalyst.

This study has disclosed that when diazo- sulfones and sulfonates are employed, dirhodium-induced intramolecular C-H insertion preferentially forms six-membered heterocycles. Apparently, the difference in bond lengths and bond angles around the SO2 fragment incorporated into the newly forming ring allows more distant C-H bonds to be targeted for insertion. The preference for formation of six- versus five-membered heterocyclic sulfones, however, is tenuous in nature, and is dependent on the substrate structure and the nature of the dirhodium catalyst used. Dirhodium catalysts bearing electron poor ligands shift the preference back to formation of five-membered rings, presumably due to forming more reactive carbenoid intermediates. The presence of methyl substituents on the carbon atom adjacent to the sulfone fragment also favors the formation of five-membered sulfones, likely due to the steric compression of the bond angle. Rh2(S-pttl)4 [dirhodium(II)tetrakis(N-phthaloyl-(S)-tert-leucinate)] catalyst has been identified as the current best lead to the development of chiral catalysts for this reaction. Selectivity of 3:1 (50% ee) was achieved with its use, and 20:1 (91% de) when combined with the use of a (-)-menthol-based chiral auxiliary.

The synthetic utility of these novel six-membered heterocycles has also been explored. To which end, the enantioselective synthesis of bakuchiol has been achieved in 14 linear steps by employing intramolecular C-H insertion on a diazo sulfonate to install the quaternary center in its structure. The alkylation of these substrates with active electrophiles under relatively mild conditions and with excellent yields has been attained with high diastereoselectivity. Novel methodologies have been originated to transform the obtained δ-sultones into γ-butyrolactones and δ-valerolactones using TBHP/t-BuOK and SmI2/DMPU, respectively. The conversion of carbethoxythiane-1,1-dioxides to cyclic α-sulfonyl oximes has also been demonstrated under relatively mild conditions (NaH, isoamyl nitrite, rt, 8 h). Currently, the versatility of these new transformations is being pursued in the synthesis of the natural products quebrachamine and mesembrine.

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