Multifunctionality of the N-Trichloroacetyl Group Developed in the Synthesis of Tetrodotoxin, a Puffer Fish Toxin

Abstract

This account describes a serendipitous discovery and the development of unique reactions associated with trichloroacetamide during synthetic studies of tetrodotoxin in our laboratory. The reactions include site-selective hydroxylation using the neighboring-group participation of trichloroacetamide, guanidinylation from a trichloroacetamide, protecting-group transformation, and removal of the N-trichloroacetyl group. These studies indicate the importance of the total synthesis of densely functionalized natural products as a field for the development of new reactions. 1 Introduction 2 Improvement of the Conditions for the Overman Rearrangement to Introduce Trichloroacetamide 3 Site-Selective Hydroxylation Using the Neighboring-Group Participation of Trichloroacetamide 4 Guanidine Synthesis 5 Protecting-Group Transformation of the N-Trichloroacetyl Group 6 New Deprotection Conditions for the Removal of the N-Trichloroacetyl Group 7 Conclusion Key words protecting groups, tetrodotoxin, trichloroacetamide, neighboring-group effects, protecting-group transformations 2 Improvement of the Conditions for the Overman Rearrangement to Introduce TrichloroacetamideThe [3,3]-sigmatropic rearrangement of allylic trichloroacetimidate to allylic trichloroacetamide is known as the Overman rearrangement after his discovery in 1974. 7 We

Tetrodotoxin: History, Biology, and Synthesis

“…Bromination with Py⋅HBr 3 and subsequent exposure to potassium carbonate in methanol furnished exclusively oxazine 430 in 78 % yield (see also Ref. ). Note that alternative treatment of dibromide with DBU in DMF led to 130 and represents the standard way to synthesis of C‐8‐hydroxy compounds.…”

“…The starting material was chosen to be levoglucosenone ( 121 ), which was brominated and further subjected to the Diels–Alder reaction with isoprene to construct the cyclohexene ring. Regioselectivity of the reaction was shown to be dependent on the Lewis acid and the solvent and, with a proper choice of conditions, regioselectivity as high as 15:1 could be reached.…”

“…In contrast to the first synthesis the Overman rearrangement was performed at an earlier stage and proceeded smoothly to obtain amide 127 , with nitrogen functionality installed. Introduction of the hydroxyl group at C‐8 required three steps, including site‐selective bromination, followed by the treatment of the dibromide 128 with DBU, which led, via allylbromide 129 , to the bicyclic oxazoline 130 (62 % from 127 ). Final hydrolysis afforded alcohol 131 , which was further converted to diol 132 via hydrogen bond directed epoxidation and Lewis acid‐mediated epoxide opening.…”

“…Scheme . While synthesis of cyclohexene 127 and cyclohexenol 131 has been described in Section 5.3.1 (Scheme ), an efficient synthesis of allylalcohol 343 as well as of diol 344 is described here following essentially the synthetic strategy implemented in the preparation of 127 and …”

Tetrodotoxin: Geschichte, Biologie und Synthese

“…Als Ausgangsmaterial wurde Levoglucosenon ( 121 ) gewählt, das bromiert und in einer Diels‐Alder‐Reaktion mit Isopren zum Aufbau des Cyclohexenrings weiter umgesetzt wurde. Es stellte sich heraus, dass die Regioselektivität der Reaktion von der Lewis‐Säure und dem Lösungsmittel abhing, und unter geeigneter Wahl der Bedingungen konnte eine hohe Regioselektivität von 15:1 erreicht werden.…”