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Perylenequinone natural products: total synthesis of hypocrellin A.

ABSTRACT: An efficient and stereoselective total synthesis of the perylenequinone natural product hypocrellin A (1) is described. The key features include a potentially biomimetic 1,8-diketone aldol cyclization to set the centrochiral C7,C7'-stereochemistry, bis(trifluoroacetoxy)iodobenzene mediated oxygenation, a palladium-catalyzed decarboxylation, and an enantioselective catalytic oxidative 2-naphthol coupling to establish the biaryl axial chirality. The helical stereochemistry is formed from an axial chiral intermediate and is then utilized in a dynamic stereochemical transfer to dictate the stereochemistry of the C7,C7'-seven membered ring formed during the aldol cyclization.

SUBMITTER: O'Brien EM

PROVIDER: S-EPMC2798931 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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Perylenequinone natural products: total synthesis of hypocrellin A.

O'Brien Erin M EM Morgan Barbara J BJ Mulrooney Carol A CA Carroll Patrick J PJ Kozlowski Marisa C MC

The Journal of organic chemistry 20100101 1

An efficient and stereoselective total synthesis of the perylenequinone natural product hypocrellin A (1) is described. The key features include a potentially biomimetic 1,8-diketone aldol cyclization to set the centrochiral C7,C7'-stereochemistry, bis(trifluoroacetoxy)iodobenzene mediated oxygenation, a palladium-catalyzed decarboxylation, and an enantioselective catalytic oxidative 2-naphthol coupling to establish the biaryl axial chirality. The helical stereochemistry is formed from an axial ...[more]

PMID: 19894741

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Project description:Full details of the development of a direct coupling of catharanthine with vindoline to provide vinblastine are described along with key mechanistic and labeling studies. Following an Fe(III)-promoted coupling reaction initiated by generation of a presumed catharanthine radical cation that undergoes a subsequent oxidative fragmentation and diastereoselective coupling with vindoline, addition of the resulting reaction mixture to an Fe(III)-NaBH(4)/air solution leads to oxidation of the C15'-C20' double bond and reduction of the intermediate iminium ion directly providing vinblastine (40-43%) and leurosidine (20-23%), its naturally occurring C20' alcohol isomer. The yield of coupled products, which exclusively possess the natural C16' stereochemistry, approaches or exceeds 80% and the combined yield of the isomeric C20' alcohols is >60%. Preliminary studies of Fe(III)-NaBH(4)/air oxidation reaction illustrate a generalizable trisubstituted olefin scope, identify alternatives to O(2) trap at the oxidized carbon, provide a unique entry into C20' functionalized vinblastines, and afford initial insights into the observed C20' diastereoselectivity. The first disclosure of the use of exo-catharanthine proceeding through Delta(19',20')-anhydrovinblastine in such coupling reactions is also detailed with identical stereochemical consequences. Incorporating either a catharanthine N-methyl group or a vindoline N-formyl group precludes Fe(III)-promoted coupling, whereas the removal of the potentially key C16 methoxy group of vindoline does not adversely impact the coupling efficiency. Extension of these studies provided a total synthesis of vincristine (2) via N-desmethylvinblastine (36, also a natural product), 16-desmethoxyvinblastine (44) and 4-desacetoxy-16-desmethoxyvinblastine (47) both of which we can now suggest are likely natural products produced by C. roseus, desacetylvinblastine (62) and 4-desacetoxyvinblastine (59), as well as a series of key analogues bearing systematic modifications in the vindoline subunit. Their biological evaluation provided additional insights into the key functionality within the vindoline subunit contributing to the activity and sets the foundation on which further, more deep-seated changes in the structures of 1 and 2 will be explored in future studies.

Dataset Information

Perylenequinone natural products: total synthesis of hypocrellin A.

Publications

Perylenequinone natural products: total synthesis of hypocrellin A.

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