Studies in Macrolide Antibiotic Synthesis:  The Role of Tethered Alkoxides in Titanium Alkoxide-Mediated Regioselective Reductive Coupling Reactions

Bahadoor, Adilah; Micalizio, Glenn C.

doi:10.1021/ol0600786

Cited by 31 publications

(23 citation statements)

References 14 publications

(15 reference statements)

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“…9 While successes in this area led to the establishment of regioselective versions of known coupling reactions (i.e. alkyne + aldehyde or terminal alkyne) and defined an early foundation of our program, controlling these processes proved to be non-trivial, likely due to uncertainty regarding the nature of the reactive metallacyclic species that would participate in the transition state (i.e.…”

Section: Introductionmentioning

confidence: 99%

Reaction Design, Discovery, and Development as a Foundation to Function-Oriented Synthesis

Micalizio

Hale

2015

Acc. Chem. Res.

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CONSPECTUS Convergent C–C bond-forming reactions define the fabric of organic synthesis and, when applied in complex molecule synthesis, can have a profound impact on efficiency by decreasing the longest linear sequence of transformations required to convert simple starting materials to complex targets. Despite their well-appreciated strategic significance, campaigns in natural product synthesis typically embrace only a small suite of reactivity to achieve such bond construction (i.e. nucleophilic addition to polarized π-bonds, nucleophilic substitution, cycloaddition, and metal-catalyzed “cross-coupling”), therefore limiting the sites at which convergent coupling chemistry can be strategically employed. In our opinion, it is far too often that triumphs in the field are defined by chemical sequences that do not address the challenges associated with discovery, development and/or production of natural product-inspired agents. We speculated that advancing an area of chemical reactivity not represented in the few well-established strategies for convergent C–C bond formation may lead to powerful new retrosynthetic relationships that could simplify approaches to the syntheses of a variety of different classes of natural products. Our studies ultimately embraced the pursuit of strategies to control the course of metallacycle-mediated “cross-coupling” between substrates containing sites of simple π-unsaturation (ubiquitous functionality in organic chemistry including alkenes, alkynes, allenes, aldehydes and imines, among others). In just eight years since our initial publication in this area, we have defined over twenty stereoselective intermolecular C–C bond-forming reactions that provide access to structural motifs of relevance for the synthesis of polyketides, fatty acids, alkaloids, and terpenes, while doing so in a direct and stereoselective fashion. These achievements continue to serve as the foundation of my group’s activity in natural product and function-oriented synthesis, where our achievements in reaction development are challenged in the context of complex targets. Among our early efforts, we achieved the most concise synthesis of a benzoquinone ansamycin ever described (macbecin I), and moved beyond this achievement to explore the role of our chemistry in function-oriented synthesis targeting the discovery of natural product-inspired Hsp90 inhibitors. These later efforts have led to the discovery of a uniquely selective benzoquinone ansamycin-inspired Hsp90 inhibitor that lacks the problematic quinone present in the natural series. This achievement was made possible by a concise chemical synthesis pathway that had at its core the application of metallacycle-mediated cross-coupling chemistry.

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Section: Introductionmentioning

confidence: 99%

Reaction Design, Discovery, and Development as a Foundation to Function-Oriented Synthesis

Micalizio

Hale

2015

Acc. Chem. Res.

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“…[18] The reactions were initiated by preforming the lithium oxide using nBuLi, [19] which would undergo ligand exchange with titanium [20] to produce lithium isopropoxide, and lead to the presumed metallacyclopropene intermediate int-4. [21] If the structure of tethered alkoxide int-4 was retained during the CÀC bond formation, it would preferentially afford the metallacyclopentadiene intermediate int-6, since int-5 would encounter significant strain when forming the bridgehead alkene. [21] Although the coordination of alkoxide with titanium was expected to exhibit considerable ring strain in the bicyclic metallacyclopropene int-4,…”

Section: Methodsmentioning

confidence: 99%

“…[21] If the structure of tethered alkoxide int-4 was retained during the CÀC bond formation, it would preferentially afford the metallacyclopentadiene intermediate int-6, since int-5 would encounter significant strain when forming the bridgehead alkene. [21] Although the coordination of alkoxide with titanium was expected to exhibit considerable ring strain in the bicyclic metallacyclopropene int-4,…”

Section: Methodsmentioning

confidence: 99%

Total Synthesis of (−)‐Virginiamycin M₂

Panek

2010

Angew Chem Int Ed

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The virginiamycins are naturally occurring antibiotics produced by Streptomyces, comprised of two principle groups of compounds (types A and B; Figure 1). The realization that natural and synthetic derivatives of virginiamycins have displayed potent antibiotic activity against methicillin-, erythromycin-, and vancomycin-resistant S.aureus, [1] by inhibiting protein synthesis through synergistic binding of weak ribsome binders, has resulted in an active research area in both academia and industry. [2,3] These efforts resulted in the development of Synercid (Figure 1), a mixture of dalfopristin (type A) and quinupristin (type B), which was approved in the United States for the treatment of severe Gram-positive bacterial infections a little over a decade ago.[4] However, production of dalfopristin-like compounds by semisynthesis has been hampered by their sensitive functionalities and pH instability.[2] Herein, we report a concise and modular total synthesis of virginiamycin M 2 , a typical member of virginiamycin group A compounds originally isolated by Todd and co-workers. [5] Our strategy for the synthesis of virginiamycin M 2 is illustrated in Scheme 1, where we envisioned formation of the 23-membered macrocycle through a SmI 2 -mediated intramolecular Barbier/Reformatsky-type cyclization [6] from the acyclic framework 2. This material could be accessed by means of esterification of the homoallylic alcohol 3 and the proline intermediate 4. The (E,E)-diene subunit 3 could be obtained through an efficient pathway; by using a titaniummediated reductive alkyne-alkyne cross-coupling between the propargylic alcohol 5 and terminal alkyne 6 a, [7] which could be conveniently introduced through crotylation utilizing the organosilane (S)-7. This silane reagent has unique features as it establishes the C1 À C2 syn stereochemistry while simultaneously creating the C3 À C5 (E)-unsaturated ester subunit, thereby functioning as a vinylogous aldol reagent. [8] Construction of the terminal alkyne 6 a began with an asymmetric crotylation between (S)-7 and isobutyraldehyde to directly obtain the vinylogous-aldol product 8 as a single diastereomer with 95 % ee (Scheme 2 A).[9] The organosilane (S)-7 was obtained through an enantioselective carbene insertion catalyzed by Rh II with the ee value reaching 95 %.[10] The ester 8 was subjected to Weinrebs amidation with propargylamine in the presence of AlMe 3 to afford the amide 6 a. To achieve the C9-C13 fragment, the propargylic alcohol 5 was prepared from known aldehyde 10 (two steps from commercial 1,3-propandiol 9)[11] using the Carreira Scheme 1. Retrosynthetic analysis of virginiamycin M 2 . TBDPS = tertbutyldiphenylsilyl, TMS = trimethylsilyl.

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“…As illustrated in Scheme 36A, coupling reactions of fully protected branched alkynes with chiral aldehydes typically proceeds with low levels of regioselectivity, despite the significant difference in steric character of the alkyne substituents (Me-vs. branched alkyl). 89,93 As summarized in Scheme 36B, when the distal hydroxyl group is unprotected (a tris-homopropargylic alcohol), these coupling reactions uniformly proceed with much higher levels of regiochemical control.…”

Section: Development Of Heteroatom-directed Alkyne-aldehyde-coupling mentioning

confidence: 99%

5.34 Early Transition Metal Mediated Reductive Coupling Reactions

Micalizio¹

2014

Comprehensive Organic Synthesis II

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Studies in Macrolide Antibiotic Synthesis: The Role of Tethered Alkoxides in Titanium Alkoxide-Mediated Regioselective Reductive Coupling Reactions

Cited by 31 publications

References 14 publications

Reaction Design, Discovery, and Development as a Foundation to Function-Oriented Synthesis

Reaction Design, Discovery, and Development as a Foundation to Function-Oriented Synthesis

Total Synthesis of (−)‐Virginiamycin M₂

5.34 Early Transition Metal Mediated Reductive Coupling Reactions

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Studies in Macrolide Antibiotic Synthesis: The Role of Tethered Alkoxides in Titanium Alkoxide-Mediated Regioselective Reductive Coupling Reactions

Cited by 31 publications

References 14 publications

Reaction Design, Discovery, and Development as a Foundation to Function-Oriented Synthesis

Reaction Design, Discovery, and Development as a Foundation to Function-Oriented Synthesis

Total Synthesis of (−)‐Virginiamycin M2

5.34 Early Transition Metal Mediated Reductive Coupling Reactions

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Total Synthesis of (−)‐Virginiamycin M₂