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. 2008 Sep 24;130(38):12630-1.
doi: 10.1021/ja805651g. Epub 2008 Aug 29.

A stereoselective synthesis of (+)-gonyautoxin 3

John V Mulcahy  1 , J Du Bois
Affiliations

A stereoselective synthesis of (+)-gonyautoxin 3

John V Mulcahy et al. J Am Chem Soc. .

Abstract

An asymmetric synthesis of the paralytic shellfish poison (PSP), (+)-gonyautoxin 3, is described. A unique, Rh-catalyzed amination reaction provides rapid access to the heteratom-rich, tricyclic core of the toxin, which is common to more than 30 related natural products. The completed route should facilitate the preparation of other naturally occurring PSPs and designed analogues thereof.

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Figures

Figure 1
Figure 1
Pyrrole oxidation highlights synthetic approach to GTX 3.
Scheme 1a
Scheme 1a
a Conditions: (a) pyrrole-1-carboxylic acid, DCC, Et3N, CH2Cl2, 65%; (b) tBuPh2SiCl, imidazole, DMF, 97%; (c) iBu2AlH, CH2Cl2, -90 °C; (d) allylamine, BF3•OEt2, CH2Cl2, 56% (2 steps, >20:1 trans/cis); (e) Pd(PPh3)4, 1,3-dimethylbarbituric acid, CH2Cl2; then Na2CO3, TcesN=(SMe)Cl, 94%; (f) EtOSO2CF3, 2,4,6-tri-tert-butylpyrimidine, CH2Cl2, 47 °C, 78%; (g) NH3, NH4OAc, MeOH, 60 °C, 82%; (h) CCl3C(O)Cl, iPr2NEt, CH2Cl2, -20 °C, 87%; (i) 5 mol% Rh2(esp)2, PhI(OAc)2, MgO, CH2Cl2, 42 °C, 61%; (j) Et3SiH, BF3 • OEt2, CH2Cl2, 81%; (k) nBu4NF, THF; (l) Cl3CC(O)NCO, CH2Cl2, -20 °C; then MeOH, 76% (2 steps); (m) 2 mol% OsO4, NMO, THF/H2O, 81%; (n) PhC(O)CN, DMAP, CH2Cl2/MeCN, -78 °C, 67%; (o) Dess-Martin periodinane, CH2Cl2, 79%; (p) H2, Pd/C, CF3CO2H, MeOH; then NH3, MeOH, 83%; (q) DMF•SO3, 2,6-di-tert-butyl-4-methylpyridine, NMP, 71%.
Figure 2
Figure 2
Epimerization at C11 occurs upon standing.
See this image and copyright information in PMC

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