Spongipyran Synthetic Studies. Total Synthesis of (+)-Spongistatin 2

Overview

Journal Tetrahedron

Specialty Chemistry

Date 2010 Feb 18

PMID 20161196

Citations 10

Authors

Amos B Smith

Qiyan Lin

Victoria A Doughty

Linghang Zhuang

Mark D McBriar

Jeffrey K Kerns

Armen M Boldi

Noriaki Murase

William H Moser

Christopher S Brook

Clay S Bennett

Kiyoshi Nakayama

Masao Sobukawa

Robert E Lee Trout

Affiliations

Soon will be listed here.

Abstract

Evolution of a convergent synthetic strategy to access (+)-spongistatin 2 (2), a potent cytotoxic marine macrolide, is described. Highlights of the synthesis include: development of a multicomponent dithiane-mediated linchpin union tactic, devised and implemented specifically for construction of the spongistatin AB and CD spiro ring systems; application of a Ca(II) ion controlled acid promoted equilibration to set the thermodynamically less stable axial-equitorial stereogenicity in the CD spiroketal; use of sulfone addition/Julia methylenation sequences to unite the AB and CD fragments and introduce the C(44)-C(51) side chain; and fragment union and final elaboration to (+)-spongistatin 2 (2) exploiting Wittig olefination to unite the advanced ABCD and EF fragments, followed by regioselective Yamaguchi macrolactonization and global deprotection. Correction of the CD spiro ring stereogenicity was subsequently achieved via acid equilibration in the presence of Ca(II) ion to furnish (+)-spongistatin 2 (2). The synthesis proceeded with a longest linear sequence of 41 steps.

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References

Sikorski W, Reich H . The regioselectivity of addition of organolithium reagents to enones and enals: the role of HMPA. J Am Chem Soc. 2001; 123(27):6527-35. DOI: 10.1021/ja010053w. View

Smith 3rd A, Minbiole K, Verhoest P, Schelhaas M . Total synthesis of (+)-phorboxazole A exploiting the Petasis-Ferrier rearrangement. J Am Chem Soc. 2001; 123(44):10942-53. DOI: 10.1021/ja011604l. View

Smith Iii A, Lin Q, Doughty V, Zhuang L, McBriar M, Kerns J . The Spongistatins: Architecturally Complex Natural Products-Part Two: Synthesis of the C(29-51) Subunit, Fragment Assembly, and Final Elaboration to (+)-Spongistatin 2 Financial support was provided by the National Institutes of Health (National.... Angew Chem Int Ed Engl. 2001; 40(1):196-199. View

Smith 3rd A, Doughty V, Sfouggatakis C, Bennett C, Koyanagi J, Takeuchi M . Spongistatin synthetic studies. An efficient, second-generation construction of an advanced ABCD intermediate. Org Lett. 2002; 4(5):783-6. DOI: 10.1021/ol017273z. View

Smith 3rd A, Zhu W, Shirakami S, Sfouggatakis C, Doughty V, Bennett C . Total synthesis of (+)-spongistatin 1. An effective second-generation construction of an advanced EF Wittig salt, fragment union, and final elaboration. Org Lett. 2003; 5(5):761-4. DOI: 10.1021/ol034037a. View

Kobayashi M, Aoki S, Sakai H, Kihara N, Sasaki T, Kitagawa I . Altohyrtins B and C and 5-desacetylaltohyrtin A, potent cytotoxic macrolide congeners of altohyrtin A, from the Okinawan marine sponge Hyrtios altum. Chem Pharm Bull (Tokyo). 1993; 41(5):989-91. DOI: 10.1248/cpb.41.989. View

Heathcock C, McLaughlin M, Medina J, Hubbs J, Wallace G, Scott R . Multigram synthesis of the C29-C51 subunit and completion of the total synthesis of altohyrtin C (spongistatin 2). J Am Chem Soc. 2003; 125(42):12844-9. DOI: 10.1021/ja030317+. View

Vogel P . Synthesis of a C(29)-C(51) subunit of spongistatin 1 (Altohyrtin A) starting from (R)-3-benzyloxy-2-methylpropan-1-ol. J Org Chem. 2000; 65(11):3346-56. DOI: 10.1021/jo991642b. View

Micalizio G, Pinchuk A, Roush W . Synthesis of the C(29)-C(45) bis-pyran subunit (E-F) of spongistatin 1 (Altohyrtin A). J Org Chem. 2000; 65(25):8730-6. DOI: 10.1021/jo001236o. View

10.

Smith 3rd A, Lin Q, Pettit G, Chapuis J, Schmidt J . Synthesis and in vitro cancer cell growth inhibitory activity of monocyclic model compounds containing spongistatin triene side-chains. Bioorg Med Chem Lett. 1999; 8(6):567-8. DOI: 10.1016/s0960-894x(98)00050-x. View

11.

Hayes C, Heathcock C . A Method for Constructing the C18-C28 Dispiroacetal Moiety of Altohyrtin A. J Org Chem. 1997; 62(9):2678-2679. DOI: 10.1021/jo9701703. View

12.

Smith 3rd A, Pitram S, Boldi A, Gaunt M, Sfouggatakis C, Moser W . Multicomponent linchpin couplings. Reaction of dithiane anions with terminal epoxides, epichlorohydrin, and vinyl epoxides: efficient, rapid, and stereocontrolled assembly of advanced fragments for complex molecule synthesis. J Am Chem Soc. 2003; 125(47):14435-45. DOI: 10.1021/ja0376238. View

13.

Brown H, Bhat K . Chiral synthesis via organoboranes. 7. Diastereoselective and enantioselective synthesis of erythro- and threo-.beta.-methylhomoallyl alcohols via enantiomeric (Z)- and (E)-crotylboranes. J Am Chem Soc. 2011; 108(19):5919-23. DOI: 10.1021/ja00279a042. View

14.

Zuev D, Paquette L . A modular approach to marine macrolide construction. 3. Enantioselective synthesis of the C1-C28 sector of spongistatin 1 (altohyrtin A). Org Lett. 2000; 2(5):679-82. DOI: 10.1021/ol0000049. View

15.

Crimmins M, Katz J . Synthesis of the C16-C28 spiroketal subunit of spongistatin 1 (altohyrtin A): the pyrone approach. Org Lett. 2000; 2(7):957-60. DOI: 10.1021/ol005605e. View

16.

Bai R, Taylor G, Cichacz Z, Herald C, Kepler J, Pettit G . The spongistatins, potently cytotoxic inhibitors of tubulin polymerization, bind in a distinct region of the vinca domain. Biochemistry. 1995; 34(30):9714-21. DOI: 10.1021/bi00030a009. View

17.

Smith 3rd A, Kim W, Wuest W . Ortho-TMS benzaldehyde: an effective linchpin for type II anion relay chemistry (ARC). Angew Chem Int Ed Engl. 2008; 47(37):7082-6. PMC: 2756143. DOI: 10.1002/anie.200802301. View

18.

Pettit R, McAllister S, Pettit G, Herald C, Johnson J, Cichacz Z . A broad-spectrum antifungal from the marine sponge Hyrtios erecta. Int J Antimicrob Agents. 1997; 9(3):147-52. DOI: 10.1016/s0924-8579(97)00044-7. View

19.

Crimmins M, Katz J, Washburn D, Allwein S, McAtee L . Asymmetric total synthesis of spongistatins 1 and 2. J Am Chem Soc. 2002; 124(20):5661-3. DOI: 10.1021/ja0262683. View

20.

Wallace G, Scott R, Heathcock C . Synthesis of the C29-C44 portion of spongistatin 1 (altohyrtin A). J Org Chem. 2000; 65(13):4145-52. DOI: 10.1021/jo0002801. View