Total Synthesis of Mucocin

Neogi, Partha; Doundoulakis, Thomas; Yazbak, Ahmad; Sinha, Santosh C.; Sinha, Subhash C.; Keinan, Ehud

doi:10.1021/ja981302s

Cited by 50 publications

(42 citation statements)

References 29 publications

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“…Synthesis began with acetalization of the dialdehyde 6 4a to afford the bis(dimethyl acetal) 9 in 99 % yield (Scheme ). The Sharpless asymmetric dihydroxylation9 of 9 gave the C 2 ‐symmetric tetraol 5 10 in almost quantitative yield.…”

Section: Methodsmentioning

confidence: 99%

Stereoselective Total Synthesis of Mucocin, an Antitumor Agent

2002

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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

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Section: Methodsmentioning

confidence: 99%

Stereoselective Total Synthesis of Mucocin, an Antitumor Agent

2002

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“…Interestingly, mucocin was found to be as active as bullatacin in inhibition of oxygen uptake by rat liver mitochondria (LC 50 18 and 9 nM/mg protein, respectively). In 1998, the group of Sinha and Keinan reported the first total synthesis of mucocin via the “naked” carbon skeleton strategy ( Scheme 68 ) [ 145 ]. All eight asymmetric centers in the key fragment 479 of the molecule were introduced by double AE reaction of 476 followed by double AD reaction of 478 .…”

Section: Reviewmentioning

confidence: 99%

Recent progress on the total synthesis of acetogenins from Annonaceae

Li¹,

Shi²,

Tang³

et al. 2008

Beilstein J. Org. Chem.

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An overview of recent progress on the total synthesis of acetogenins from Annonaceae during the past 12 years is provided. These include mono-tetrahydrofurans, adjacent bis-tetrahydrofurans, nonadjacent bis-tetrahydrofurans, tri-tetrahydrofurans, adjacent tetrahydrofuran-tetrahydropyrans, nonadjacent tetrahydrofuran-tetrahydropyrans, mono-tetrahydropyrans, and acetogenins containing only γ-lactone. This review emphasizes only the first total synthesis of molecules of contemporary interest and syntheses that have helped to correct structures. In addition, some significant results on the novel synthesis and structure-activity relationship studies of annonaceous acetogenins are also introduced.

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“…In the total synthesis of (-)-mucocin [17], the oxygen functionalities are introduced into the tetraenediol 15 by means of SAE and SAD as shown (Scheme 8.4). Subsequently, in a later stage of the synthesis, the THP and THF rings present in the intermediate 17 simultaneously arise (by acid treatment) from the double g-epoxy alcohol functionality present in the polyhydroxylated compound 16.…”

Section: Synthesis Of Substituted Thf Ringsmentioning

confidence: 99%