Download PDF
Synlett 2017; 28(20): 2896-2900
DOI: 10.1055/s-0036-1588515
letter
© Georg Thieme Verlag Stuttgart · New York

Chemoenzymatic Formal Total Synthesis of Pancratistatin from Narciclasine-Type Compounds via Myers Transposition: Model Study for a Short Conversion of Narciclasine to Pancratistatin

Ringaile Lapinskaite
Department of Chemistry and Centre for Biotechnology, Brock University, 1812 Sir Isaac Brock Way, St. Catharines, ON L2S 3A1, Canada   Email: thudlicky@brocku.ca
,
Mukund Ghavre
Department of Chemistry and Centre for Biotechnology, Brock University, 1812 Sir Isaac Brock Way, St. Catharines, ON L2S 3A1, Canada   Email: thudlicky@brocku.ca
,
Chelsea L. Rintelmann
Department of Chemistry and Centre for Biotechnology, Brock University, 1812 Sir Isaac Brock Way, St. Catharines, ON L2S 3A1, Canada   Email: thudlicky@brocku.ca
,
Korey Bedard
Department of Chemistry and Centre for Biotechnology, Brock University, 1812 Sir Isaac Brock Way, St. Catharines, ON L2S 3A1, Canada   Email: thudlicky@brocku.ca
,
Helen E. Dela Paz
Department of Chemistry and Centre for Biotechnology, Brock University, 1812 Sir Isaac Brock Way, St. Catharines, ON L2S 3A1, Canada   Email: thudlicky@brocku.ca
,
Tomas Hudlicky*
Department of Chemistry and Centre for Biotechnology, Brock University, 1812 Sir Isaac Brock Way, St. Catharines, ON L2S 3A1, Canada   Email: thudlicky@brocku.ca
› Author AffiliationsThe authors are grateful to the following agencies for financial support of this work: Natural Sciences and Engineering Research Council of Canada (NSERC) (Idea to Innovation and Discovery Grants), Canada Research Chair Program, Canada Foundation for Innovation (CFI), TDC Research, Inc., TDC Research Foundation, the Ontario Partnership for Innovation and Commercialization (OPIC), and The Advanced Biomanufacturing Centre (Brock University).
Further Information

Publication History

Received: 06 June 2017

Accepted after revision: 30 June 2017

Publication Date:
03 August 2017 (online)

    Permissions and Reprints All articles of this category


Dedicated to Professor Victor Snieckus on the occasion of his 80th birthday and in recognition of his many contributions to the art of organic synthesis

Abstract

A formal total synthesis of pancratistatin was accomplished by conversion of advanced intermediates, used in the synthesis of narciclasine, to pancratistatin precursors via Myers’ reductive transposition as the key strategic step. The synthesis began with the whole cell fermentation of m-dibromobenzene with JM109(pDTG601a), a recombinant strain that over-expresses toluene dioxygenase, which provided the corresponding cis-dihydrodiol 16 as a single isomer with complete optical purity. The key reductive transposition of the allylic alcohol 8a to olefin 9a allowed for further installation of the C-1/C-2 trans-diol, ­required for the pancratistatin scaffold, through the introduction of a cyclic sulfate and its subsequent opening. The formal synthesis of pancratistatin was accomplished in 14 steps (12 operations) from commercially available m-dibromobenzene. Experimental and spectral data are provided for all new compounds.

Key words

narciclasine - pancratistatin - toluene dioxygenase - enzymatic dihydroxylation of arenes - reductive transposition of allylic alcohols

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/s-0036-1588515.
  • Supporting Information
 

  • References and Notes

  • 2 Pettit GR. Gaddamidi V. Cragg GM. J. Nat. Prod. 1984; 47: 1018
    CrossrefPubMedSearch in Google Scholar
  • 3 Lubbe A. Gude H. Verpoorte R. Choi YH. Phytochemistry 2013; 88: 43
    CrossrefPubMedSearch in Google Scholar
  • 6 Gonzalez D. Martinot T. Hudlicky T. Tetrahedron Lett. 1999; 40: 3077
    CrossrefSearch in Google Scholar
  • 7 Hudlicky T. Rinner U. Gonzalez D. Akgun H. Schilling S. Siengalewicz P. Martinot TA. Pettit GR. J. Org. Chem. 2002; 67: 8726
    CrossrefPubMedSearch in Google Scholar
  • 9 Myers AG. Zheng B. Tetrahedron Lett. 1996; 37: 4841
    CrossrefSearch in Google Scholar
  • 10 Banwell MG. Bissett B. Cowden CJ. Hockless DC R. Holman JW. Read RW. Wu AW. J. Chem. Soc., Chem. Commun. 1995; 2551
  • 12 Revu O. Zepeda-Velazquez C. Nielsen AJ. McNulty J. Yolken RH. Jones-Brando L. ChemistrySelect 2016; 1: 5895
    CrossrefSearch in Google Scholar
  • 13 Experimental Procedures for 8a, 9a, and 18a. Methyl {(3aS,4R,7R,7aR)-7-Hydroxy-7′-methoxy-2,2-dimethyl-3a,4,7,7a-tetrahydro(5,5′-bibenzo[d][1,3]dioxol)-4-yl}carbamate (8a; see ref 7): The solution of enone 7a (50 mg, 0.13 mmol) in MeOH (0.5 mL) was degassed with a stream of argon for 15 min. After addition of cerium (III) chloride heptahydrate (71 mg, 0.19 mmol) the reaction mixture was stirred for 20 min, then cooled to 0 °C and sodium borohydride (6 mg, 0.14 mmol) was added in 2 portions. The reaction mixture was allowed to warm slowly to r.t. and stirred for 3 h. The reaction mixture was diluted with EtOAc (5 mL) and the grey precipitate was filtered through a plug of Celite. After concentration under reduced pressure the product was purified by preparative TLC (hexanes–EtOAc, 1:1) to furnish 8a as a white foamy oil (48 mg, 96%). Compound 8a: Rf 0.2 (hexanes–EtOAc, 1:1); [α]D 24 –61.6 (c = 0.8, CHCl3) {lit. [α]D 25 –14.4 (c = 0.8, CHCl3)}. 1H NMR (600 MHz, CDCl3): δ = 6.57 (m, 2 H), 6.08 (s, 1 H), 5.96 (s, 2 H), 4.67 (dd, J = 10.6, 6.3 Hz, 3 H), 4.55 (s, 1 H), 4.41 (d, J = 10.2 Hz, 1 H), 3.89 (s, 3 H), 3.68 (s, 3 H), 2.77 (d, J = 10.3 Hz, 1 H), 1.34 (s, 3 H), 1.30 (s, 3 H). 13C NMR (150 MHz, CDCl3): δ = 156.6, 149.3, 143.7, 137.3, 135.4, 133.7, 130.8, 109.4, 105.7, 101.8, 100.1, 75.3, 66.7, 56.8, 52.6, 51.1, 29.8, 26.3, 24.8. Methyl {(3aS,4R,5R,7aR)-7′-Methoxy-2,2-dimethyl-3a,4,5,7a-tetrahydro(5,5′-bibenzo[d][1,3]dioxol)-4-yl}carbamate (9a; see ref. 14): Allylic alcohol 8a (629 mg, 1.60 mmol), triphenylphosphine (839 mg, 3.20 mmol), 2-nitro-N′-(propan-2-ylidene)benzenesulfonohydrazide (IP-NBSH; 823 mg, 3.20 mmol) was charged into Schlenk flask and kept under high vacuum for 1 h, then dissolved in THF (6 mL). Reaction mixture was cooled to 0 °C and di-tert-butyl azadicarboxylate (DBAD; 737 mg, 3.20 mmol) solution in THF (3 mL) was added dropwise. The reaction mixture was allowed to warm slowly to r.t. and stirred for 8 h. The reaction mixture was cooled to 0 °C and the mixture of 2,2,2-trifluoroethanol (3 mL) and H2O (3 mL) was added dropwise and stirred for 16 h whereupon it was evaporated and submitted to two consecutive chromatographical columns [10 wt% deactivated silica gel, hexanes–EtOAc (1:1), then CH2Cl2–MeOH, 100:1]. The product was obtained as a white foamy glassy oil (345 mg, 64%). Compound 9a: Rf 0.1 (hexanes–EtOAc, 1:1); [α]D 24 +14.3 (c = 0.9, CHCl3). IR (neat): 3331, 2984, 2936, 1705, 1607, 1524, 1475, 1071, 1048 cm–1. 1H NMR (600 MHz, CDCl3): δ = 6.36 (s, 1 H), 6.34 (s, 1 H), 5.90–6.01 (m, 4 H), 4.68 (m, 1 H), 4.62 (m, 1 H), 4.42 (m, 1 H), 3.87 (s, 3 H), 3.56 (s, 4 H (methyl group plus NH)), 3.38 (s, 1 H), 1.54 (s, 3 H), 1.41 (s, 3 H). 13C NMR (150 MHz, CDCl3): δ = 156.6, 149.0, 143.7, 136.3, 135.6, 134.3, 123.7, 109.8, 107.5, 102.3, 101.6, 76.0, 72.6, 57.3, 56.7, 52.1, 45.8, 28.4, 26.1. Methyl {(3aS,4R,5R,6S,7S,7aR)-6,7-Dihydroxy-7′-methoxy-2,2-dimethyl-3a,4,5,6,7,7a-hexahydro-(5,5′-bibenzo[d][1,3]dioxol)-4-yl}carbamate (18a): Olefin 9a (1.35 g, 3.579 mmol) was dissolved in 20 mL of acetone and 5 mL of H2O. Then OsO4 (250 mg, 0.9834 mmol) and N-methylmorpholine-N-oxide (NMO, 419 mg, 3.579 mmol) were added. The reaction mixture was stirred at r.t. for 4 d, then quenched with sat. NaHSO3 solution (20 mL). The reaction mixture was filtered through a plug of Celite, filtrate was concentrated, the residue was adsorbed on 10 wt% deactivated silica, and subjected to purification by column chromatography (hexanes–EtOAc, 1:2). Diol 18a was isolated as a white foamy oil (785 mg, 53%) Compound 18a: Rf 0.1 (hexanes–EtOAc = 1:2); [α]D 25 –55.4 (c = 0.5, CHCl3). 1H NMR (600 MHz, CDCl3): δ = 6.44 (s, 2 H), 5.96 (s, 2 H), 4.60 (s, 1 H), 4.26–4.45 (m, 2 H), 4.19 (s, 1 H), 3.81–4.04 (m, 5 H), 3.54 (s, 3 H), 2.92 (s, 1 H), 2.65 (s, 1 H), 1.82 (s, 1 H), 1.60 (s, 3 H), 1.39 (s, 3 H). 13C NMR (150 MHz, CDCl3): δ = 156.7, 149.4, 144.0, 134.8, 132.1, 109.4, 102.5, 101.7, 77.6, 76.6, 72.7, 69.5, 56.7, 55.1, 52.3, 48.3, 29.9, 28.1, 26.0. Anal. Calcd for C19H25NO9: C, 55.47; H, 6.13. Found: C, 54.80; H, 6.44.
  • 14 Shukla KH. DeShong P. Heterocycles 2012; 86: 1055
    CrossrefSearch in Google Scholar