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

Dedicated to Professor Victor Snieckus on the occasion of his 80^th 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

• References and Notes


For biological activity, see:
• 1a Van Goietsenoven G. Mathieu V. Lefranc F. Kornienko A. Evidente A. Kiss R. Med. Res. Rev. 2013; 33: 439
• 1b Van Goietsenoven G. Andolfi A. Lallemand B. Cimmino A. Lamoral-Theys D. Gras T. Abou-Donia A. Dubois J. Lefranc F. Mathieu V. Kornienko A. Kiss R. Evidente A. J. Nat. Prod. 2010; 73: 1223
• 1c Evidente A. Kireev AS. Jenkins AR. Romero AE. Steelant WF. A. Van Slambrouck S. Kornienko A. Planta Med. 2009; 75: 501
• 1d Stafford GI. Pedersen ME. van Staden J. Jäger AK. J. Ethnopharmacol. 2008; 119: 513
• 1e Ingrassia L. Lefranc F. Mathieu V. Darro F. Kiss R. Translational Oncology 2008; 1: 1
• 2 Pettit GR. Gaddamidi V. Cragg GM. J. Nat. Prod. 1984; 47: 1018
• 3 Lubbe A. Gude H. Verpoorte R. Choi YH. Phytochemistry 2013; 88: 43

For reviews on synthesis, see:
• 4a Ghavre M. Froese J. Pour M. Hudlicky T. Angew. Chem. Int. Ed. 2016; 55: 5642
• 4b Jin Z. Nat. Prod. Rep. 2009; 26: 363
• 4c Kornienko A. Evidente A. Chem. Rev. 2008; 108: 1982
• 4d Manpadi M. Kornienko A. Org. Prep. Proced. Int. 2008; 40: 107
• 4e Chapleur Y. Chrétien F. Ibn Ahmed S. Khaldi M. Curr. Org. Synth. 2006; 3: 341
• 4f Rinner U. Hudlicky T. Synlett 2005; 365
• 4g Hoshino O. In The Alkaloids: Cordell G. A. Vol 51. Academic Press; New York: 1998: 323-424
• 4h Bridges A. Chemtracts: Org. Chem. 1996; 9: 101
• 4i Martin SF. In The Alkaloids . Vol. 30. Brossi A., Academic Press; New York: 1987: 251-376
• 4j Yingjie L. Zeyang D. Chong T. Hongliang Y. Yubin J. Chin. J. Org. Chem. 2015; 35: 1009

For previous syntheses of pancratistatin, see:
• 5a Danishefsky S. Lee JY. J. Am. Chem. Soc. 1989; 111: 4829
• 5b Tian X. Hudlicky T. Kēnigsberger K. J. Am. Chem. Soc. 1995; 117: 3643
• 5c Trost BM. Pulley SR. J. Am. Chem. Soc. 1995; 117: 10143
• 5d Doyle TJ. Hendrix M. VanDerveer D. Javanmard S. Haseltine J. Tetrahedron 1997; 53: 11153
• 5e Magnus P. Sebhat IK. J. Am. Chem. Soc. 1998; 120: 5341
• 5f Magnus P. Sebhat IK. Tetrahedron 1998; 54: 15509
• 5g Rigby JH. Maharoof US. M. Mateo ME. J. Am. Chem. Soc. 2000; 122: 6624
• 5h Pettit GR. Melody N. Herald DL. J. Org. Chem. 2001; 66: 2583
• 5i Kim S. Ko H. Kim E. Kim D. Org. Lett. 2002; 4: 1343
• 5j Ko H. Kim E. Park JE. Kim D. Kim S. J. Org. Chem. 2004; 69: 112
• 5k Li M. Wu A. Zhou P. Tetrahedron Lett. 2006; 47: 3707
• 5l Dam JH. Madsen R. Eur. J. Org. Chem. 2009; 27: 4666
• 5m Jung Y.-G. Kang H.-U. Cho H.-K. Cho C.-G. Org. Lett. 2011; 13: 5890
• 5n Cagide-Fagin F. Nieto-Garcia O. Lago-Santome H. Alonso R. J. Org. Chem. 2012; 77: 11377
• 5o Akai S. Kojima M. Yamauchi S. Kohji T. Nakamura Y. Sato K. Asian J. Org. Chem. 2013; 2: 299
• 5p Cho H.-K. Lim H.-Y. Cho C.-G. Org. Lett. 2013; 15: 5806
• 5q Potter TJ. Ellman JA. Org. Lett. 2017; 19: 2985
• 6 Gonzalez D. Martinot T. Hudlicky T. Tetrahedron Lett. 1999; 40: 3077
• 7 Hudlicky T. Rinner U. Gonzalez D. Akgun H. Schilling S. Siengalewicz P. Martinot TA. Pettit GR. J. Org. Chem. 2002; 67: 8726

For Commercial sources of narciclasine, see:
• 8a http://www.molbase.com/en/cas-29477-83-6.html?p6=336.
• 8b https://www.medchemexpress.com/Narciclasine.html?gclid=CMnaoNWtjdACFQMpaQodqW8N8w.
• 8c McNulty J. Thorat A. Vurgun N. Nair JJ. Makaji E. Crankshaw DJ. Holloway AC. Pandey S. J. Nat. Prod. 2011; 74: 106
• 9 Myers AG. Zheng B. Tetrahedron Lett. 1996; 37: 4841
• 10 Banwell MG. Bissett B. Cowden CJ. Hockless DC R. Holman JW. Read RW. Wu AW. J. Chem. Soc., Chem. Commun. 1995; 2551
• 11a Movassaghi M. Piizzi G. Siegel DS. Piersanti G. Angew. Chem. Int. Ed. 2006; 45: 5859
• 11b Movassaghi M. Ahmad OK. J. Org. Chem. 2007; 72: 1838
• 11c Movassaghi M. Ahmad OK. Angew. Chem. Int. Ed. 2008; 47: 8909
• 11d For the synthesis of IP-NBSH, see: Willwacher J. Ahmad OK. Movassaghi M. Org. Synth. 2012; 89: 230
• 12 Revu O. Zepeda-Velazquez C. Nielsen AJ. McNulty J. Yolken RH. Jones-Brando L. ChemistrySelect 2016; 1: 5895
• 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: R_f 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: R_f 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: R_f 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