Synthesis of the Tricyclic Core of Colchicine via a Dienyne Tandem Ring-Closing Metathesis Reaction

Link: Org Lett ASAP

François-Didier Boyer and Issam Hanna*

Unité de Chimie Biologique, AgroParisTech, INRA, F-78026 Versailles, and Laboratoire de Synthèse Organique associé au CNRS, Ecole Polytechnique, F-91128 Palaiseau, France

This paper presented a very neat use of RCM and quite clever strategy to construct the 7,7-fused core of colchicine. For the first time, the 7,7-fused bicyclic system could be accessed very quickly in a single step. This main strategy is summarized in the retrosynthetic analysis below.

Therefore, substrate 4 was needed for the RCM step and it was constructed according to the following scheme.

The key reactions were formylation of 6 mediated by SnCl4 to give 7 and the synthesis of propargylic alcohol 14 which was achieved in three steps from 5, using the Ohira-Bestman reagent in the last step.

Next, sequential RCM reactions were performed on 14 using Grubbs' second generation catalyst (15) after the protection of the OH group with TMS. The reaction proved to be very efficient, providing the desired 16 in 74% yield from 14.

This intermediate 16 was further elaborated as shown in Scheme 4 via oxidative rearrangement. Compound 18 could be obtained in high yield. However, going along a more well-known route of previous total syntheses of colchicine, intermediate 19 could be obtained in modest yield, along with 20, from 17. This latter route effectively constituted a formal synthesis of colchicine. The final completion of this molecule by a novel sequence is currently under investigation.

Overall, the double RCM (enyne RCM and RCM) in constructing the 7,7-core of colchicine presented in this paper is quite ingenius.

A Concise Synthesis of Butylcycloheptylprodigiosin

Link: Org Lett ASAP

Jonathan T. Reeves*

Department of Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Old Ridgebury Road, P.O. Box 368, Ridgefield, Connecticut 06877

A total synthesis in racemic form of butylcycloheptylprodigiosin in a very short sequence by a single author.

The key reaction was installation of the 2-formyl pyrrole ring in 4 based on previously reported method as shown below.

The synthesis started with enone 6. A sequence of 1,4-addition to 6 and trapping with oxazole 7 led to 5. Treatment of 5 based on previous method afforded 4 in good yield.

The rate of cyclization of enone type B in Figure 3 was tested. Dehydration of 5 led to 6:1 mixture of E-8 and Z-8 which could be separated by chromatography. E-8 was found to convert to 4 faster than Z-8 probably because of torsional strain of the enone in Z-8 which prevented optimal conjugation and thus rendering C-2 of oxazole ring less reactive towards hydrolysis in with base.

The total synthesis was completed according to the following sequence. Installation of triflate group, for Suzuki-Miyaura cross-coupling, was pretty cool. The conversion of 3 to 1 followed the Furstner protocol of the total synthesis of the same molecule accomplished previously.

The current total synthesis was accomplished in 5 steps from 6, which compared favorably with Furstner's 16 linear steps from 1,4-cyclononadien-3-one.

Novel Formal Synthesis of Cephalotaxine via a Facile Friedel-Crafts Cyclization

Link: http://pubs.acs.org/cgi-bin/abstract.cgi/orlef7/asap/abs/ol070024b.html

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.

(4) Kuehne, M. E.; Bornmann, W. G.; Parsons, W. H.; Spitzer, T. D.; Blount, J. F.; Zubieta, J. J. Org. Chem. 1988, 53, 3439.
(5) Planas, L.; Perard-Viret, J.; Royer, J. J. Org. Chem. 2004, 69, 3087.
(6) Sha, C. K.; Young, J. J.; Yeh, C. P.; Chang, S. C.; Wang, S. L. J. Org. Chem. 1991, 56, 2694.
(7) Isono, N.; Mori, M. J. Org. Chem. 1995, 60, 115.

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.
(10) (a) Ikeda, M.; Hirose, K.; El Bialy, S. A. A.; Sato, T.; Yakura, T.; Bayomi, S. M. M. Chem. Pharm. Bull. 1998, 46, 1084. (b) Ikeda, M.; El Bialy, S. A. A.; Hirose, K.; Kotake, M.; Sato, T.; Bayomi, S. M. M.; Shehata, I. A.; Abdelal, A. M.; Gad, L. M.; Yakura, T. Chem. Pharm. Bull. 1999, 47, 983.
(11) Suga, S.; Watanabe, M.; Yoshida, J. I. J. Am. Chem. Soc. 2002, 124, 14824.
(12) Worden, S. M.; Mapitse, R.; Hayes, C. J. Tetrahedron Lett. 2002, 43, 6011.

3) radical cyclization approaches as used by the Semmelheck and Taniguchi groups.

(13) Semmelhack, M. F.; Chong, B. P.; Stauffer, R. D.; Rogerson, T. D.; Chong, A.; Jones, L. D. J. Am. Chem. Soc. 1975, 97, 2507.
(14) Taniguchi, T.; Ishita, A.; Uchiyama, M.; Tamura, O.; Muraoka, O.; Tanabe, G.; Ishibashi, H. J. Org. Chem. 2005, 70, 1922.

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).

Upon standing in mild acidic conditions, compound 9b could undergo skeletal rearrangement to give isomers 9b' and 14, where 9b' is more stable than 9b.

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.

(24) Dolby, L. J.; Nelson, S. J.; Senkovich, D. J. Org. Chem. 1972, 37, 3691.