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Enantioselective Total Synthesis of (+)- KB343.

Record Type:	Language materials, manuscript : Monograph/item
Title/Author:	Enantioselective Total Synthesis of (+)- KB343./
Author:	Bi, Cheng.
Description:	1 online resource (264 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 85-09, Section: B.
Contained By:	Dissertations Abstracts International85-09B.
Subject:	Chemistry. -
Online resource:	click for full text (PQDT)
ISBN:	9798381750843

Enantioselective Total Synthesis of (+)- KB343.
Bi, Cheng.

Enantioselective Total Synthesis of (+)- KB343. - 1 online resource (264 pages)

Source: Dissertations Abstracts International, Volume: 85-09, Section: B.

Thesis (Ph.D.)--The Scripps Research Institute, 2023.

Includes bibliographical references

[Introduction] Guanidine-containing (guanidinium) natural products are a fascinating group of synthetic targets that show a wide spectrum of biological activities and present unique challenges. We (Baran Lab) initiated a synthetic campaign toward a large family of cyclic guanidine-containing natural products about two decades ago. Over the years, we completed multiple total syntheses including Palau'amine. Recently, a new marine-derived toxin named KB343 was isolated and characterized which immediately drew out attention for its unusually highly functional group density. As an extension of our long-lasting interest in guanidinium natural products, we set out to pursue KB343 as a synthetic target hoping to discover novel and useful chemical tools along the way.[Chapter 1] The synthetic challenge of KB343 was analyzed for the first time. An ambitiously simplifying disconnection was brought up featuring a double-cyclization cascade. The linear intermediate prior to the cascade can be constructed in a modular way that further broke down the target to three non-chiral and easily accessible building blocks. The three building blocks have been successfully synthesized unfortunately the following C-C bond formation was met with failure. A model substrate was synthesized to test our key cyclization step and the formation of desired product could not be detected under a variety of conditions.[Chapter 2] The structure of KB343 was scrutinized again but from a different angle. The difficulty to handle 2-aminoimidazole derivatives compelled us to focus on C-N bond formations. Taking inspiration from "two phase" synthesis, we designed a new route where almost the entire carbon framework was bought in and a series of functionalization (mostly relying on olefin reactivity) was carefully choreographed to install required C-N bonds. The synthesis of the properly functionalized carbon framework was streamlined and an extensive research of allylic oxidation and olefin diamination reactions was conducted and ultimately helped us understand the reactivity of our decalin core/extended enone better. An unexpected result was discovered and was utilized to push forward our synthesis. Two major problems were met in the very late stage of our synthesis and could not be solved or circumvented regardless of our efforts.[Chapter 3] After we had repeatedly run into compatibility issues when we were dealing with highly functionalized intermediates in the previous route, we came to the realization that maximizing convergency might be the way to minimize the numbers of chemical operations done on late-stage intermediates. In the third generation of retrosynthesis, the first disconnection was applied to one of the hindered a-tertiary C-N bonds unraveling the complex ring system to a highly substituted six-member ring onto which all the functional groups can be introduced via a carefully designed sequence of orthogonal transformations. The parent six-member ring can then be brought back to commercially available 1,3-cyclohexanedione. Serious problems emerged when we tried to install a C-N bond at the a position of a carbonyl group, several detours were taken but all led to unsatisfactory results which eventually made us abandon the third route.[Chapter 4] The philosophy of convergency originated from the third generation of retrosynthesis was kept but a better execution plan was proposed to avoid the undesired reactivity we encountered before. The simplifying power of hidden symmetry was exploited to achieve convergency and ultimately materialized as two dearomative cyclizations of phenol. Two building blocks with similar size converged via a cross-coupling reaction, one of which was derived from commercially available benzyl alcohol and the other one of which was synthesized by three sequential functionalizations of 1,3,4-tribromoimidazole. Post the cross-coupling step, a series of unusual yet effective maneuvers were applied to realized difficult bond formations and invert unfavored selectivity. Our endeavor in the fourth generation of route culminated in the successful completion of total synthesis of KB343 whose structure was unequivocally confirmed by X-ray crystallography.[Chapter 5] In order to unambiguously assign the absolute configuration of KB343, we desired an enantioselective route in addition to the previously established racemic route. The original plan to render the methyl conjugate addition asymmetric was unsuccessful and some ideas involving concession steps to intercept the same intermediate were investigated which eventually paved way to the asymmetric Diels-Alder cycloaddition technique. A de novo synthesis of intermediate X was designed and executed. After carrying the enantio-enriched material through the same steps in the racemic route, we were able to assign the absolute configuration of KB343 as (+).

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2024

Mode of access: World Wide Web

ISBN: 9798381750843Subjects--Topical Terms:

593913
Chemistry.
Subjects--Index Terms:

GuanidiniumIndex Terms--Genre/Form:

554714
Electronic books.

Enantioselective Total Synthesis of (+)- KB343.
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504 $a Includes bibliographical references
520 $a [Introduction] Guanidine-containing (guanidinium) natural products are a fascinating group of synthetic targets that show a wide spectrum of biological activities and present unique challenges. We (Baran Lab) initiated a synthetic campaign toward a large family of cyclic guanidine-containing natural products about two decades ago. Over the years, we completed multiple total syntheses including Palau'amine. Recently, a new marine-derived toxin named KB343 was isolated and characterized which immediately drew out attention for its unusually highly functional group density. As an extension of our long-lasting interest in guanidinium natural products, we set out to pursue KB343 as a synthetic target hoping to discover novel and useful chemical tools along the way.[Chapter 1] The synthetic challenge of KB343 was analyzed for the first time. An ambitiously simplifying disconnection was brought up featuring a double-cyclization cascade. The linear intermediate prior to the cascade can be constructed in a modular way that further broke down the target to three non-chiral and easily accessible building blocks. The three building blocks have been successfully synthesized unfortunately the following C-C bond formation was met with failure. A model substrate was synthesized to test our key cyclization step and the formation of desired product could not be detected under a variety of conditions.[Chapter 2] The structure of KB343 was scrutinized again but from a different angle. The difficulty to handle 2-aminoimidazole derivatives compelled us to focus on C-N bond formations. Taking inspiration from "two phase" synthesis, we designed a new route where almost the entire carbon framework was bought in and a series of functionalization (mostly relying on olefin reactivity) was carefully choreographed to install required C-N bonds. The synthesis of the properly functionalized carbon framework was streamlined and an extensive research of allylic oxidation and olefin diamination reactions was conducted and ultimately helped us understand the reactivity of our decalin core/extended enone better. An unexpected result was discovered and was utilized to push forward our synthesis. Two major problems were met in the very late stage of our synthesis and could not be solved or circumvented regardless of our efforts.[Chapter 3] After we had repeatedly run into compatibility issues when we were dealing with highly functionalized intermediates in the previous route, we came to the realization that maximizing convergency might be the way to minimize the numbers of chemical operations done on late-stage intermediates. In the third generation of retrosynthesis, the first disconnection was applied to one of the hindered a-tertiary C-N bonds unraveling the complex ring system to a highly substituted six-member ring onto which all the functional groups can be introduced via a carefully designed sequence of orthogonal transformations. The parent six-member ring can then be brought back to commercially available 1,3-cyclohexanedione. Serious problems emerged when we tried to install a C-N bond at the a position of a carbonyl group, several detours were taken but all led to unsatisfactory results which eventually made us abandon the third route.[Chapter 4] The philosophy of convergency originated from the third generation of retrosynthesis was kept but a better execution plan was proposed to avoid the undesired reactivity we encountered before. The simplifying power of hidden symmetry was exploited to achieve convergency and ultimately materialized as two dearomative cyclizations of phenol. Two building blocks with similar size converged via a cross-coupling reaction, one of which was derived from commercially available benzyl alcohol and the other one of which was synthesized by three sequential functionalizations of 1,3,4-tribromoimidazole. Post the cross-coupling step, a series of unusual yet effective maneuvers were applied to realized difficult bond formations and invert unfavored selectivity. Our endeavor in the fourth generation of route culminated in the successful completion of total synthesis of KB343 whose structure was unequivocally confirmed by X-ray crystallography.[Chapter 5] In order to unambiguously assign the absolute configuration of KB343, we desired an enantioselective route in addition to the previously established racemic route. The original plan to render the methyl conjugate addition asymmetric was unsuccessful and some ideas involving concession steps to intercept the same intermediate were investigated which eventually paved way to the asymmetric Diels-Alder cycloaddition technique. A de novo synthesis of intermediate X was designed and executed. After carrying the enantio-enriched material through the same steps in the racemic route, we were able to assign the absolute configuration of KB343 as (+).
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538 $a Mode of access: World Wide Web
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650 4 $a Molecular chemistry. $3 1179636
650 4 $a Organic chemistry. $3 1148722
653 $a Guanidinium
653 $a Biological activities
653 $a Chemical tools
653 $a Orthogonal transformations
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