Chemoenzymatic Synthesis of Advanced Intermediates for Formal Total Syntheses of Tetrodotoxin

Abstract

Advanced intermediates for the syntheses of tetrodotoxin reported by the groups of Fukuyama, Alonso, and Sato were prepared. Key steps include the toluene dioxygenase mediated dihydroxylation of either iodobenzene or benzyl acetate. The resulting diene diols were transformed into Fukuyama's intermediate in six steps, into Alonso's intermediate in nine steps, and into Sato's intermediate in ten steps.

Chemoenzymatic Synthesis of (−)-Ribisins A and B from Dibenzo[b,d]furan

“…The chemoenzymatic syntheses of natural products, from cisdihydrodiol metabolites, have generally been restricted to those obtained from monocyclic arene substrates. [6][7][8][10][11][12][13][14][15][16][17][18][19] cis-Dihydrodiols of acridine and dictamnine, obtained by BPDO-catalyzed cis-dihydroxylation, were among the few examples of tricyclic arenes utilized in the chemoenzymatic synthesis of secondary metabolites. 20 Following on from the innovative use of a monocyclic arene cis-dihydrodiol of bromobenzene in chemoenzymatic syntheses, 6,7 this study has demonstrated that a tricyclic cis-dihydrodiol, formed by TDO-catalyzed cis-dihydroxylation of dibenzofuran, 27 can also be used as a precursor for the asymmetric synthesis of the chiral dibenzofuran derivatives, ribisins A and B.…”

“…(3aR,4S,5S,10cR)-4-Methoxy-5-((4-methoxybenzyl)oxy)-2,2dimethyl-3a, 4,5,10c-tetrahydrobenzo[b] [1,3]dioxolo [4,5e]benzofuran (13). To a solution of alcohol 11 (16 mg, 0.040 mmol) in dry THF (4 mL) was added sodium hydride (5 mg), under an argon atmosphere, followed by the addition of methyl iodide (12 µL).…”

“…Biotransformations of monocyclic aromatic compounds are routinely utilized, to produce enantiopure cis-dihydrodiol metabolites for application in the chemoenzymatic synthesis of natural products. 6,7,[10][11][12][13][14][15][16][17][18][19] Conversely, cis-dihydrodiol metabolites, from polycyclic arenes or heteroarenes, are rarely used in chemoenzymatic synthesis. 20 Thus, although the isolation and stereochemical assignment of cis-dihydrodiols from tricyclic aromatic substrates was reported, using naphthalene dioxygenase (NDO) 21 or biphenyl dioxygenase (BPDO) [20][21][22][23] as biocatalysts, few examples of their employment as chiral synthons have been documented.…”

“…13 C-NMR (100 MHz, CDCl3):  155.9, 151.9, 126 4,. 125.3, 123.4, 120.2, 113.0, 111.8, 111.0, 71.8, 69.5, 64.0, 29.7, 28.21, 26.3; IR νmax/cm -1 3454, 2988, 2935, 1958, 1630, 1245.…”

“…Water (2 mL) and CH2Cl2 (5 mL) were added to the stirring mixture, the organic phase separated, and the remaining aqueous phase extracted with CH2Cl2 (5 mL). The combined organic extract was dried (MgSO4), concentrated, and the residue obtained was purified by flash column chromatography (50% EtOAc in hexane) to afford ribisin A (2.9 mg, 63%), a pale-yellow solid; Rf = 0.20 (60% EtOAc in hexane); [α]D -16.0 (c 0.2, MeOH); HRMS (ES) calcd for C26H24O10Na (2M + Na) + 519.1267 found 519.1259; 1 H-NMR (600 MHz, CDCl3):  7.93 (dm, J = 7.6 Hz, 1H), 7.56 (dm, J = 8.1 Hz, 1H), 7.36 (dt, J = 7.4, 1.4 Hz, 1H), 7.32 (dt, J = 7.6, 1.0 Hz, 1H), 4.93 (d, J = 7.6 Hz, 1H), 3.97 (d, J = 9.9 Hz, 1H), 3.92 (dd, J = 9.9, 7.6 Hz, 1H), 3.66 (s, OMe);13 C-NMR (150 MHz, CDCl3):  91.3, 169.4, 157.6, 127.2, 126.0, 124.3, 122.9, 116.1, 112.8, 87.2, 78.9, 70.4, 60.8.…”