Stereoselective Total Synthesis of Mucocin, an Antitumor Agent

Abstract

Mucocin (1) is a representative annonaceous acetogenin [1] having a tetrahydropyran (THP) and a tetrahydrofuran (THF) ring. [2] This novel type of acetogenin is known to show remarkable inhibitory activities against A-549 (lung cancer) and PACA-2 (pancreatic cancer) solid tumor lines with a potency of more than 10 000 times that of adriamycin. The powerful antitumor activity and the unique structure of 1 have consequently stimulated synthetic efforts, [3] and quite recently three research groups (including ours) have succeeded in its total synthesis.[4] Recently, we developed a highly efficient method for the synthesis of tetrahydropyrans and oxepanes based on a SmI 2 -induced [5] reductive cyclization of b-alkoxy acrylate containing a formyl group.[6] We thus planned the total synthesis of 1 to demonstrate the utility of the method and now describe here an efficient total synthesis of 1 based on the SmI 2 -induced reductive cyclization as a key step.Our synthetic strategy directed toward 1 was based on a convergent process which involves a Pd-catalyzed crosscoupling reaction of the THP/THF segment 2 and a vinyl iodide 3 as illustrated in Scheme 1. The THP ring in the central core 2 could be constructed by the SmI 2 -induced reductive cyclization, whereas the trans-THF ring should be synthesized by oxidative cyclization [7] of a homoallyl alcohol. This retrosynthetic approach can revert 2 back to the b-alkoxy acrylate 4 having two formyl groups, and then to a tetraol 5. Therefore, dialdehyde 6 with the requisite carbon backbone was selected as the starting material. In this scenario, whether the C-12 formyl group in the reductive cyclization of 4 could be retained or not and the development of an efficient method for desymmetrization of C 2 -symmetric 5 were problems to be solved. On the other hand, the g-lactone 3 should be synthesized by aldol condensation of chiral ester 7 and aldehyde 8. [8] Synthesis began with acetalization of the dialdehyde 6[4a] to afford the bis(dimethyl acetal) 9 in 99 % yield (Scheme 2). The Sharpless asymmetric dihydroxylation [9] of 9 gave the C 2 -symmetric tetraol 5 [10] in almost quantitative yield. To achieve efficient desymmetrization 5 was transformed into a bisTHF derivative 10 by treatment with CSA in methanol at À5 8C. Formation of THP derivatives was observed when the acetalization was conducted at RT. Benzylidenation of 10 followed by reduction with DIBAH gave a monobenzyl ether COMMUNICATIONS

The relationship between the molecular structure of natural acetogenins and their inhibitory activities which affect DNA polymerase, DNA topoisomerase and human cancer cell growth

“…however, research on the inhibition of acetogenins against pol and topo activities is limited, probably due to the small quantities of natural products. Since the total synthesis of bioactive acetogenins, such as compound 5, is possible (17)(18)(19)(20)(21)(22)(23)(24)(25), these compounds should be provided and studied in pharmaceutical research throughout the world. compound 5 directly inhibited animal pol and human topo activities (table ii), but did not bind to dna.…”

“…1) was achieved (17)(18)(19)(20)(21)(22)(23)(24)(25). Since mclaughlin et al and mata et al reported that some acetogenins have cytotoxicity against human cancer cell lines (4-7), the purpose of this review is to investigate the biochemical action of the compounds against dna metabolic enzymes such as pols and topos, and to use the compound as an antineoplastic agent.…”

SmI2‐induced cyclizations and their applications in natural product synthesis

“…14). 47 Treatment of dialdehyde 103 with SmI 2 at –5 °C afforded THP 104 in 87% yield. Interestingly, the other aldehyde group in 103 survives the reducing conditions.…”

Recent progress on the total synthesis of acetogenins from Annonaceae

“…In 2002, the group of Takahashi and Nakata reported the total synthesis of 475 based on the SmI 2 -induced reductive cyclization as a key step ( Scheme 71 ) [ 150 ]. The THP ring in the central core 494 was constructed from 493 by the SmI 2 -induced reductive cyclization, whereas the trans -THF ring was synthesized by oxidative cyclization of a homoallylic alcohol.…”