Asymmetric Rhodium(II)-Carbene C-H Functionalization: A Complementary Tool To Synthetic Disconnection Strategies Restricted; Files Only
Boni, Yannick (Spring 2022)
Published
Abstract
This thesis is a collection of consulting challenges and ambitious endeavors that we took on over the past four and a half years. Herein, is presented the reasoning, logic, and plans of execution of syntheses with an ultimate goal of implementing site- and stereoselective C-H bond functionalization into the logic of retrosynthetic analyses through synthetic disconnections.
Chapter #1 of the thesis is an overview of asymmetric metal carbene C-H insertion reactions in the timeline of the past decade or so. A general discussion of historical metal complexes used for carbene transformations as well as the different types of carbenes employed will also be in play in the current chapter. Finally, examples of early reports on using C-H bond functionalization as a logical tool in complex molecule assembly will also be the subject of discussion.
Chapter #2 discusses the use of chiral rhodium(II) carbenes for regio- and stereoselective distal allylic and benzylic C-H bond functionalization of allyl and benzyl silyl ethers. The efforts achieved in this chapter give an example of how certain classical reactions such as the equivalent of a vinylogous Michael addition achieved with high asymmetric induction through a direct donor/acceptor rhodium(II) carbene C-H bond functionalization. Two sources of chiral dirhodium tetracarboxylate catalysts as well as two sources of donor/acceptor carbene precursors are used in this study.
Chapter #3 demonstrates the capability of chiral dirhodium tetracarboxylate in conjunction with donor/acceptor carbenes to achieve a selective C-H bond functionalization of allyl boronic esters with high asymmetric induction. The obtained chiral allyl boron species are also capable of undergoing a second asymmetric allylation event with aldehydes to generate chiral homoallylic alcohols bearing four contiguous stereocenters.
Chapter #4 discusses a highly regio- and stereoselective catalyst-controlled donor/acceptor rhodium carbene catalyzed functionalization of unactivated C-H bonds of silyl ethers. The level of selectivity achieved by each catalyst resulted in the generation of a variety of dioxygenated adducts analogous to those that would be obtained through certain classical named reactions. A computational and data science studies in collaboration with Matt Sigman’s group at the University of Utah are also briefly discussed. This collaboration gives about the key controlling elements for the selectivity that these dirhodium tetracarboxylate catalyst are able to achieve.
Chapter #5 showcases the syntheses, reactivity, and selectivity profile of a new series of dirhodium tetracarboxylate catalysts. As variants of Paul Muller’s Rh2(NTTL)4 these C4-symmetric naphthalimido based catalysts display a slightly wider “bowl” than the phthalimido series of catalysts previously reported by Davies and Hashimoto. This new family of Rh2(NTTL)4 derivatives are able to achieve an exceptional level of selectivity in preferring the functionalization of the C4-equatotial C-H bond of arylcyclohexanes.
Table of Contents
Chapter 1: Introduction to asymmetric donor-acceptor rhodium(II)carbene C-H functionalization
1.1 Introduction………………………………………………………………………………02
1.2 General mechanism for metal-carbene C-H functionalization reactions…………………..03
1.3 Carbene precursors………………………………………………………………………..05
1.3.1 Diazo compounds………………………………………………………………………....05
1.3.2 N-sulfonyl-1,2,3-triazoles………………………………………………………………….08
1.3.3 Alkynes…………………………………………………………………………………....08
1.4 Metal catalysts for asymmetric C-H functionalizations………………………..…………..09
1.4.1 Rhodium(II) catalysts……………………………………………………………………...09
1.4.1.1 Older generation chiral rhodium(II) catalysts……………………………………………...11
1.4.1.2 Newer generation chiral rhodium(II) catalysts…………………………………………….13
1.5 Selected early reports on asymmetric intermolecular donor/acceptor rhodium(II) carbene C– H functionalization………………………………………………………………..…………..16
1.6 Conclusion………………………………………………………………………………...17
1.7 References/bibliographic notes…………………………………………………………....18
Chapter 2: Distal allylic/benzylic C-H functionalization of silyl ethers using donor-acceptor rhodium(II) carbenes
2.1 Introduction………………………………………………………………………………25
2.2 Initial strategies and failed approach………………………………………………………27
2.3 Optimization and scope…………………………………………………………………...29
2.3.1 Optimization of the system with respect to N-Sulfonyl-1,2,3-triazoles…………………….29
2.3.2 Scope of allyl silyl ethers using N-Sulfonyl-1,2,3-triazoles as the corresponding coupling partner…………………………………………………………………………………….31
2.3.3 Optimization of the system with respect to aryldiazoacetates……………………………...33
2.3.4 Scope of allyl silyl ethers using aryldiazoacetates as the corresponding coupling partner…..35
2.3.5 Scope of C-H functionalization of distal benzyl silyl ethers using N-Sulfonyl-1,2,3-triazoles and aryldiazoacetates as the corresponding carbene precursors……………………………37
2.4 Applications………………………………………………………………………………37
2.4.1 Selective distal allylic C-H functionalization of challenging substrates with competing C–H bonds……………………………………………………………………………………...37
2.4.2 Efficient synthesis of a proline derivative (advanced intermediate to phenyl kainic acid)…..38
2.5 Conclusion………………………………………………………………………………...40
2.6 Acknowledgements………………………………………………………………………..40
2.7 Distribution of credit……………………………………………………………………...40
2.8 Experimental procedures and data………………………………………………………...41
2.8.1 General…………………………………………………………………………………....41
2.8.2 Experimental procedures and data of synthetic intermediates/products…………………..42
2.9 References/bibliographic notes………………………………………………………….164
Chapter 3: Catalyst controlled site- and stereoselective carbene C(sp3)–H functionalization of allyl boronic esters
3.1 Introduction……………………………………………………………………………..168
3.2 Initial strategies and optimizations……………………………………………………….170
3.3 Scope…………………………………………………………………………………….175
3.3.1 Scope of allyl boronic esters……………………………………………………………...175
3.3.2 Scope of aryldiazoacetates………………………………………………………………..177
3.4 Application………………………………………………………………………………178
3.4.1 C–H functionalization of chiral allyl boronic ester with concomitant allylation of benzaldehyde…………………………………………………………………………….179
3.5 Conclusion………………………………………………………………………………181
3.6 Acknowledgements……………………………………………………………………...182
3.7 Distribution of credit……………………………………………………………………182
3.8 Experimental procedures and data………………………………………………………182
3.8.1 General………………………………………………………………………………….182
3.8.2 Experiment procedures and data for synthetic intermediates/products………………….183
3.9 References/bibliographic notes………………………………………………………….264
Chapter 4: Complementing classical disconnection strategies via a regio- and stereoselective C-H functionalization of unactivated silyl ethers
4.1 Introduction……………………………………………………………………………..268
4.2 Initial strategies and optimizations……………………………………………………….270
4.3 Scope…………………………………………………………………………………….274
4.3.1 Catalyst controlled a-to-oxygen C-H functionalizations………………………………....274
4.3.2 Catalyst controlled g-to-oxygen C-H functionalizations…………………………………275
4.3.3 Catalyst controlled d-to-oxygen C-H functionalizations………………………………....276
4.3.4 Desymmetrization of linear meso-silyl ethers……………………………………………...278
4.3.5 Functionalization beyond the d-to-oxygen C–H bond…………………………………...298
4.3.6 Unexpected asymmetric functionalization of silyl protecting group……………………...299
4.4 Computational insight and reasoning for the observed catalyst-controlled site selectivity..300
4.5 Conclusion………………………………………………………………………………304
4.6 Acknowledgement……………………………………………………………………….305
4.7 Distribution of credit…………………………………………………………………….305
4.8 Experimental procedures and data……………………………………………………….306
4.8.1 General…………………………………………………………………………………..306
4.8.2 Experimental procedures and data for synthetic intermediates/products………………...307
4.9 References/bibliographic notes…………………………………………………………..442
Chapter 5: Design of chiral rhodium(II) catalysts and their application for regio- and stereoselective C-H functionalization of arylcyclohexanes
5.1 Introduction……………………………………………………………………………..449
5.2 Hypothesis, initial strategies, and failed approach…………………………………….…..452
5.3 New approach, reaction optimizations and scope…………………………………..……460
5.3.1 Scope of arylcyclohexanes……………………………………………………………….466
5.4 Conclusion………………………………………………………………………………467
5.5 Acknowledgements……………………………………………………………………....467
5.6 Distribution of credit…………………………………………………………………….467
5.7 Experiment procedures and data………………………………………………………....468
5.7.1 General…………………………………………………………………………………..468
5.7.2 Experimental procedures and data for synthetic intermediates/products………………...469
5.8 References/bibliographic notes………………………………………………………......557
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