New Advances in Asymmetric Cyclopropanation and Drug Discoveries Using Dirhodium(II) Tetracarboxylates Restricted; Files Only

Abstract

Dirhodium(II) tetracarboxylate paddle-wheel complexes are robust catalysts that can achieve highly enantioselective intermolecular cyclopropanations for the reactions of donor-acceptor carbenes. The work performed by the Davies Group demonstrated that in the presence of these Rh(II) complexes, highly enantioselective, highly diastereoselective, and high-yielding reactions using a donor-acceptor carbene precursor and an electron-rich alkene could be achieved⁵. However, the new catalysts that were developed in the lab lack a complete cyclopropanation dataset, and it is not exactly clear how the catalysts would behave for a wide range of donor-acceptor carbenes. The first part of the thesis explores a series of screening reactions involving various dirhodium (II) catalysts, aryldiazoacetate (carbene precursor), and electron-rich alkene (trap). Also, the previous kinetic studies heavily focused on substituted phenyl group as the donor for aryldiazoacetate (carbene derivative). It was hypothesized that using a more electron-donating group as the donor would make the reaction faster while maintaining the robustness of the reaction (high e.e, d.r. and yield). The latter part of the thesis, therefore, expands to the kinetic studies of aryldiazoacetates with methoxy naphthalene as the donor group. The new substrates could potentially boost turnover numbers due to the methoxy-naphthalene motif, a more electron-rich and extended π-system, aiming to achieve and exceed the turnover numbers for this type of reaction using the new substrates. The product structure has high similarity to naproxen, implicating pharmaceutical relevance.

Table of Contents

Table of Contents

1.) Introduction……………………………………………………………..……………………..1

1.1) Carbenes/Carbenoids & Davies Group Catalyst Development .… ………………………….1

1.2) Asymmetric Cyclopropanation with Dirhodium(II) Tetracarboxylate Catalysts and its Kinetic Aspects…....………………………………………………………………………………4

2.) First Advance: Asymmetric Cyclopropanation using Rh2(TPPTTL)4 Catalysts Derivatives…...……………………………………………………………………………………5

3.) Second Advance: Kinetic Studies via Cyclopropanation of Methyl 2-Diazo-2-(6-methoxynaphthalen-2-yl)acetate ………………………………….……………..………………11

4.) Conclusions…………………………………………………………………………………..16

5.) Experimental………..…………………….…………………………………………………..16

5.1) Supporting Information for Asymmetric Cyclopropanation Screening using Rh2(S-TPPTTL)4.…………………… .…………………… .…………………… .……………………16

5.1.1) General Procedure for Asymmetric Cyclopropanation with Rh2(TPPTTL)4 Derivatives.……………....………...……... .…………………… .…………………… .………16

5.1.2) Compound Characterization.…………………… .………………… .………………...…17

5.1.3) HPLC Traces.…………………… .…………………… .………………… .……………25

5.2) Kinetic Studies on Asymmetric Cyclopropanation.…………………… .……………….…44

5.2.1) General Procedure for Catalyst Screening……………………………………………..…45

5.2.2) Preparation of Stock Solution for Low Catalyst Loading & General Procedure for Kinetic Cyclopropanation……………………………………………………………………………...…45

5.2.3) React IR Protocols………………………………………………………………….…..…48

5.2.4) Experimental Methods for Diazo Synthesis of Scheme 1………………………….…..…49

5.2.5) NMR Spectra……………………………………………………………………….…..…50

5.2.6) SFC Traces for Determination of Enantioselectivity (Catalyst Screening) ………………52

6.) References……………………………………………..………………………………….…..60

About this Honors Thesis

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School	Emory College
Department	Chemistry
Degree	B.S.
Submission	Honors Thesis
Language	English
Research Field	Chemistry, Organic
Keyword	Dirhodium(II) Tetracarboxylates Asymmetric Cyclopropanation Donor-Acceptor Carbene
Committee Chair / Thesis Advisor	Huw M.L. Davies, Emory University
Committee Members	Brian Dyer, Emory University Frank McDonald, Emory University

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