Vinblastine total synthesis

Ishikawa H, Colby DA, Boger DL (2008) Direct coupling of catharanthine and vindoline to provide vinblastine total synthesis of (+)- and enr-(-)vinblastine. J Am Chem Soc 130 420 21... 

In a versatile stereocontrolled total synthesis of (+)-vinblastine, Fukuyama used a base-promoted macrocyclization of the N-nosylate and the terminal epoxide moiety present in 88 as one of the key steps, giving the 11-membered-ring product 89 in 82% yield (Scheme 8.23) [42],... 

The two alkaloids vinblastine and vincristine found in Catharanthus roseus have been recent targets of total synthesis because of their potency in cancer chemotherapy. The reduced tree diagram for the Fukuyama plan to vincristine is shown in Figure 4.66. There are three points of convergence, four branches leading to the target product and four tiers of reaction yields. 

Yokoshima, S., Ueda, T., Kobayashi, S. et al. (2002) StereocontroUed Total Synthesis of (-Pi-Vinblastine. Journal of the American Chemical Society, 124,2137-2139. 

A total synthesis of (+ )-vinblastine widely used in cancer chemotherapy, has been reported. It includes the synthesis of (-)-vindoline. 1,3-Dipolar cycloaddition of a nitrile oxide has played an important role in the preparation of the indoloazacycloundecane moiety, whose coupling with (-)-vindoline occurs with the desired stereochemistry, leading to an intermediate readily transformed to the target (+ )-vinblastine (492). 

The structural modification of natural products is useful in several ways. The known pharmacology of bisindole alkaloids is enriched by the diversity of chemical structures that are made available by structure modification and total synthesis. These molecules have served as biochemical probes in several areas of biology, especially in those of microtubule assembly and drug resistance. The most elusive prize, however, has remained the discovery of new compounds with clinical activity. In recent years several compounds have been evaluated in clinical trials, but vinblastine and vincristine remain the only bisindole alkaloids approved for the treatment of cancer in the United States. These compounds are joined by vindesine in Europe, and at least two new derivatives are the subject of ongoing clinical trials. Considering the breadth of chemical research in this area, the overall yield as measured by new compounds with clinical activity has been relatively low, but this observation is not unique in history of analog development in cancer research. Nevertheless, the search continues, and this chapter details the chemical endeavors to discover a new bisindole alkaloid with clinical activity. 

The tubulin-binding properties of (-)-rhazinilam were discovered through screening of a number of Malaysian plant extracts [60]. Natural (-)-rhazinilam induces tubulin spiralization, inhibiting tubulin assembly in the same way as vinblastine-like alkaloids, and protects microtubules from cold disassembly such as with paclitaxel [67]. This effect has never been observed with other microtubule poisons. For this reason, and despite the in vivo inactivity of (-)-rhazinilam [67], a number of analogues have been prepared by semi-synthesis and total synthesis (see Sections 3.1.3. and 3.2.3.) in order to improve the pharmacological properties of this molecule. 

A total synthesis of vinblastine has not as yet been achieved. Methods of preparation involve making initial crude extracts from the periwinkle plant, followed by extraction at selected pH into organic solvents, and final separation of the complex mixture of alkaloids by column chromatography. Several methods have been devised since Noble, Beer, and Cutts1 first reported the isolation of vinblastine as the sulfate salt. A few are briefly described here. 

Buchi has presented an interim report " on progress towards the total synthesis of vinblastine. The general strategy involves the condensation of vindoline (174)... 

Yokoshima S, Ueda T, Kobayashi S, Sato A, Kuboyama T, Tokuyama H, Fukuyama T (2002) Stereocontrolled total synthesis of (+)-vinblastine. J Am Chem Soe 124 2137-2139... 

Since vinblastine is a dimeric alkaloid, consists of vindoline moiety and carbomethoxyvelbanamine part, schemes for the total synthesis of both are required followed by joining the two monomeric units to produce the dimeric alkaloid. 

Fukuyama, T, Vinblastine in Classics in Total Synthesis II More Targets, Strategies, Methods, ed. Nicolaou, K. C. and Snyder, S. A., Wiley-VCH Verlag GmbH Co. KGaA, Weinheim, 2003, p. 505. 

Scheme 5 Total synthesis of vinblastine (117) by Boger and structure of anhydrovinblastine (126).

Scheme 14. Final stages and completion of the total synthesis of (+)-vinblastine (1).

Kutney, J. P., T. Hibino, E. Jahngen, T. Okutani, A. H. Rat-cliffe, a. M. Treasurywala, and S. Wunderly, Total synthesis of indole and dihydroindole alkaloids. IX. Studies on the synthesis of bisindole alkaloids in the vinblastine-vincristine... 

A stereocontrolled total synthesis of (+)-vinblastine (329), a prominent alkaloid used in cancer chemotherapy, was reported by the Fukuyama/ Tokuyama team and features an INOC reaction for the preparation of a key reaction intermediate utilized in their synthesis (2010CR101). Thus, the oxidation of oxime 323 with sodium hypochlorite generated the expected nitrile oxide 324 which imderwent a subsequent 1,3-dipolar cycloaddition to produce isoxazoline 325 as a single isomer (Scheme 59). The INOC proceeded via a six-membered chairlike transition state (i.e., 324) to furnish 325 with the desired stereochemistry. After reductive cleavage of the N—O bond in isoxazoftne 325 with zinc dust in acetic acid, a... 

Scheme 13.56. A path showing the formation of the piece of (+)-vinblastine representing the catharanthine -like fragment needed for the total synthesis. After Yokoshima, S. Ueda, T. Kobayashi, S. Sato, A. Kuboyama, T. Tokuyama, H. Fukuyama,T. Pure Appl. Chem., 2003, 75,29. OTBDPS = f-butyldiphenylsilyl ether OTMS = trimethylsilyl ether OTHP = tetrahy-dropyranyl acetal OTES = trie thy Isilyl ether OTs = toluenesulfonate ester.

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