Asymmetric Total Synthesis of Vindoline

Kato, Daisuke; Sasaki, Yukichi; Boger, Dale L.

doi:10.1021/ja910695e

Cited by 133 publications

(56 citation statements)

References 47 publications

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“…As a result of these developments, several series of key analogs have been prepared recently, systematically exploring and defining the impact individual structural features and substituents have on tubulin binding affinity and tumor cell growth inhibition. 8 Complementary to the studies that probed the vindoline C4 acetate, 9 C5 ethyl substituent, 10 C6–C7 double bond, 11 and the vindoline core structure itself, 12 herein we detail a systematic study of the C20′ ethyl substituent found in the upper catharanthine-derived subunit. In preceding studies, we have shown that whereas replacement of the C20′-OH with extended C20′ ureas led to remarkably potent analogs as much as 100-fold more active than vinblastine (IC 50 as low as 50–75 pM), 13 C16′ methyl ester modification, 14 C10′ or C12′ indole substitution, 15 or alteration of the C20′ ethyl group appear much less forgiving with respect to the substituent presence, nature, and size.…”

mentioning

confidence: 93%

Key analogs of a uniquely potent synthetic vinblastine that contain modifications of the C20′ ethyl substituent

Allemann

Cross

Brütsch

et al. 2017

Bioorganic & Medicinal Chemistry Letters

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A key series of vinblastine analogs 7–13, which contain modifications to the C20′ ethyl group, was prepared with use of two distinct synthetic approaches that provide modifications of the C20′ side chain containing linear and cyclized alkyl groups or added functionalized substituents. Their examination revealed the unique nature of the improved properties of the synthetic vinblastine 6, offers insights into the origins of its increased tubulin binding affinity and 10-fold improved cell growth inhibition potency, and served to probe a small hydrophobic pocket anchoring the binding of vinblastine with tubulin. Especially noteworthy were the trends observed with substitution of the terminal carbon of the ethyl group that, with the exception of 9 (R = F vs H, equipotent), led to remarkably substantial reductions in activity (>10-fold): R = F (equipotent with H) > N3, CN (10-fold) > Me (50 fold) > Et (100-fold) > OH (inactive). This is in sharp contrast to the maintained (7) or enhanced activity (6) observed with its incorporation into a cyclic C20′/C15′-fused six-membered ring.

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mentioning

confidence: 93%

Key analogs of a uniquely potent synthetic vinblastine that contain modifications of the C20′ ethyl substituent

Allemann

Cross

Brütsch

et al. 2017

Bioorganic & Medicinal Chemistry Letters

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“…55,56 Cycloaddition of 8 proceeded cleanly, providing predominantly 9 in superb conversions, and only small amounts (0−13%) of a second diastereomer were occasionally isolated. The dienophile linking tether of 8 was reduced in length by one carbon relative to the earlier work, which not only permitted effective control of facial selectivity of the initiating Diels–Alder reaction but also allowed the reaction to be conducted under milder conditions than previously observed.…”

Section: Applications In the Total Synthesis Of Natural Productsmentioning

confidence: 99%

“…Together, the asymmetric [4 + 2]/[3 + 2] cycloaddition reaction cascade along with two approaches to ring expansion provided two distinct, concise asymmetric total syntheses of (−)-vindoline ( 1 ). 55,56 …”

Section: Applications In the Total Synthesis Of Natural Productsmentioning

confidence: 99%

Tandem Intramolecular Diels–Alder/1,3-Dipolar Cycloaddition Cascade of 1,3,4-Oxadiazoles: Initial Scope and Applications

Sears

Boger

2016

Acc. Chem. Res.

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Conspectus A summary of the development and initial studies on the scope of a powerful tandem intramolecular [4 + 2]/[3 + 2] cycloaddition cascade of 1,3,4-oxadiazoles is detailed and provides the foundation for its subsequent use in organic synthesis. Implemented with substrates in which both the initiating dienophile and subsequent dipolarophile are tethered to the 1,3,4-oxadiazoles, the studies expanded the scope of oxadiazoles that participate in the reaction cascade, permitted the use of differentiated dienophiles and dipolarophiles, extended their use to unsymmetrical dienophiles and dipolarophiles, provided exclusive control of the cycloaddition regioselectivities, and imposed exquisite control on the cycloaddition stereochemistry. As key reactivity and stereochemical features of the reactions were being defined, the cascade cycloaddition reaction was implemented in the total synthesis of a series of alkaloids including (−)-vindoline, (−)-vindorosine, the closely related natural products (+)-4-desacetoxyvindoline and (+)-4-desacetoxyvindorosine, natural minovine, (+)-N-methylaspidospermidine, (+)-spegazzinine, (−)-aspidospermine, and a number of key analogues. Most recently it was used in the divergent total syntheses of (+)-fendleridine, (−)-kopsinine, (−)-kopsifoline D, and (−)-deoxoapodine, in which four different strategic bonds in four different classes of the hexacyclic alkaloids were formed from a common cascade cycloaddition intermediate. A large number of vindoline analogues were prepared by variations on the cascade cycloaddition reaction for single step incorporation into analogues of vinblastine. These structural changes to vindoline permitted both systematic alterations to the peripheral substituents as well as deep-seated changes to the core structure and embedded functionality of vinblastine not previously accessible. Although explored initially for accessing vindoline and vinblastine, the use of the cycloaddition cascade in the total synthesis of an impressive range of additional natural products illustrate the power of the methodology. Alternative tethering strategies for the cascade cycloaddition reaction, combined intramolecular and intermolecular variants of either the initiating Diels–Alder reaction or the subsequent carbonyl ylide 1,3-dipolar cycloaddition, an expanded examination of the tethered dipolarophile scope, and applications to additional natural product classes represent attractive areas for future work.

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“…Recently, we reported concise total syntheses of vindoline 6 enlisting two variations on a tandem intramolecular [4+2]/[3+2] cycloaddition cascade of 1,3,4-oxadiazoles 7 that form the fused pentacyclic core of the natural product in one step and as a single diastereomer. The development of a single flask Fe(III)-promoted coupling with catharanthine 8 and subsequent in situ Fe(III)/NaBH 4 air oxidation 9 provided the basis for a 12-step total synthesis of vinblastine and related natural products.…”

mentioning

confidence: 99%

“…It was anticipated that the requisite macrocycles could be accessed by ring closing metathesis (RCM) of diene 7 , although several alternative approaches can be envisioned, and 7 would be derived from the oxadiazole 8 available from our prior studies. 6 …”

mentioning

confidence: 99%

Transannular Diels–Alder/1,3-Dipolar Cycloaddition Cascade of 1,3,4-Oxadiazoles: Total Synthesis of a Unique Set of Vinblastine Analogues

et al. 2013

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A powerful tandem [4+2]/[3+2] cycloaddition cascade of 1,3,4-oxadiazoles initiated by a transannular [4+2] cycloaddition is detailed. An impressive four rings, four carbon-carbon bonds, and six stereocenters are set on each site of the newly formed central six-membered ring in a cascade thermal reaction that proceeds at temperatures as low as 80 °C. The resulting cycloadducts provide the basis for the synthesis of unique analogues of vinblastine containing metabolically benign deep-seated cyclic modifications at the C3/C4 centers of the vindoline-derived subunit of the natural product.

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Asymmetric Total Synthesis of Vindoline

Cited by 133 publications

References 47 publications

Key analogs of a uniquely potent synthetic vinblastine that contain modifications of the C20′ ethyl substituent

Key analogs of a uniquely potent synthetic vinblastine that contain modifications of the C20′ ethyl substituent

Tandem Intramolecular Diels–Alder/1,3-Dipolar Cycloaddition Cascade of 1,3,4-Oxadiazoles: Initial Scope and Applications

Transannular Diels–Alder/1,3-Dipolar Cycloaddition Cascade of 1,3,4-Oxadiazoles: Total Synthesis of a Unique Set of Vinblastine Analogues

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