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

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.

Isolation, Synthesis, and Semisynthesis of Amaryllidaceae Constituents from Narcissus and Galanthus sp.: De Novo Total Synthesis of 2-epi-Narciclasine

“…A total synthesis of 2- epi -narciclasine was accomplished from 1,3-dibromobenzene via enzymatic dihydroxylation to diol 20 , which was converted in five steps to the allylic alcohol 23 [acetonide protection, nitroso Diels–Alder reaction, Suzuki coupling, Mo­(CO) 6 and Luche reductions] (Scheme ). Details of these transformations were recently published [up to the allylic alcohol 23 ] . The allylic alcohol 23 was deprotected with 2 M HCl, and the resulting triol 24 was reprotected as triacetate 25 .…”

“…The combined organic extract was washed with H2O (1×10 mL) and brine (1×10 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting crude mixture was purified by silica gel column (EtOAc:hexanes 1:5 to 1:4) and afforded an inseparable mixture of 10 and 11 16 (1:6, 10 mg), which was characterized by 1 H NMR and COSY data. Rf = 0.70 [DCM:MeOH (19:1)], the mixture of 10 and 11 was used directly in the next step.…”

The role of biocatalysis in the asymmetric synthesis of alkaloids – an update

“…The allylic alcohol 123 that is a central intermediate in this sequence also proved useful in a formal total synthesis of (+)-pancratistatin (101) that uses 1,3-chirality transfer by Myers' reductive transposition as a key step ( Scheme 16b ). 76 While this transposition could be accomplished in satisfactory yield (68–79%), trans -dihydroxylation of the resulting olefin 127 by literature-known methods was unsuccessful. The authors, therefore, chose to establish the required (1 R ,2 S )-stereochemistry (isocarbostyril numbering) through cis -dihydroxylation followed by preparation and ring-opening of a cyclic sulfate.…”

A Review on Recent Syntheses of Amaryllidaceae Alkaloids and Isocarbostyrils (Time period mid-2016 to 2017)

“…When this compound was then subjected to Zn/AcOH reduction of the nitro group at 100 °C, (+)-pancratistatin 241 was produced in an improved yield of 68% (Scheme 39). published an improved synthesis of (+)-pancratistatin 241 starting from the relatively advanced intermediate 242 [42] which the group had synthesized earlier [43]. Luche reduction of enone 242 afforded the allylic alcohol 243 (75%).…”