From Prof. Wei-Dong Z. Li's group at Lanzhou University, and Nankai University, P.R. China
A recent report in Org Lett ASAP highlights a synthetic study conducted toward a formal synthesis of cephalotaxine (CET) showcasing a new tactic used in the closure of the B-ring. Cephalotaxine and its naturally occurring ester derivatives (harringtonine and homo- harringtonine) possess antitumor therapeutic potentials.
Although, the tactic employed in closing the B-ring is novel, the synthetic interest in the CET-type structure is hardly new. Because of its antitumor property and its unique spirocyclic alkaloid core structure, it has attracted numerous attention from synthetic chemists in the past.
Several strategic approaches have been explored in the formation of the B-ring and this article could also be treated as a summary of these past strategems. The past approches include:
1) Lewis acid or protic acid mediated Friedel-Crafts-type cyclization as employed by the Kuehne, Royer, Sha, and Mori groups.
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2) Pd(0)-catalyzed Heck-type coupling of an unsaturated spirocyclic aryl halide precursor as exemplified by the Tietze, Ikeda, Suga-Yoshida, and Hayes groups.
(9) (a) Tietze, L. F.; Shirok, H. Angew. Chem., Int. Ed. 1997, 36, 1124. (b) Tietze, L. F.; Shirok, H. J. Am. Chem. Soc. 1999, 121, 10264.
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3) radical cyclization approaches as used by the Semmelheck and Taniguchi groups.
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The current synthesis commenced with synthesis of cyclization substrate 4a and 4b and also 8a and 8b.
It should be noted that both 4a and 8a (where the R groups are the methylenedioxy group) did not cyclize to give any desired product, whereas the dimethoxy derivatives 4b and 8b cyclized smoothly. This stereoelectronic effect of methylenedioxy group on the aryl system, which precludes the acid-promoted Friedel-Craft cyclization, was first noticed by Sha and co-workers.
The current acid-catalyzed cyclization strategy was also tested with other spirocyclic systems 10-13. Here, again, the stereoelectronic of methylenedioxy group precluded the cyclization even under forcing conditions, while dimethoxy derivatives underwent smooth cyclization (compare 10b and 11b).
A similar skeletal rearragement was also previously observed by Dolby and co-workers where the Dolby-Weinreb enamine alkylation product 15 underwent a facile reorganization through a proposed pathway as shown in the scheme. At the end, 14a was the sole isolable product. Upon acid treatment, 14a easily converted to 14b. The alpha-ethoxy carbonyl group in the cyclopentanone ring and the methylenedioxy substituent on the aryl ring of 15 may have influenced this facile isomerization process.
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