Progress Toward a Common Intermediate for C1 Modified Enigmols Open Access

Beckett, Allison (2010)

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"Progress Toward a Common Intermediate for C1 Modified Enigmols"
By Allison Rankin Beckett
Recent discoveries recognize the sphingolipid pathway to be involved in cell proliferation,
apoptosis, and signaling. The balance of sphingoid bases and metabolites present govern these actions,
rendering the pathway an effective target for modulation via therapeutic agents. Currently compounds
modulating the sphingolipid pathway are in clinical trials, and have shown to be effective in treating
cancer and inflammatory diseases. Though very little is known about the mechanistic actions of these
agents, the successful results warrant further investigation. The Liotta group has efficiently synthesized
Enigmol, a sphingosine analogue efficacious in a number cancer cell lines and malaria, and is
continually working toward the development of novel analogues which display improved potency,
physiochemical and pharmocodynamic properties. In an attempt to modify the C1 position of Enigmol,
a synthetic strategy has been developed to produce a common intermediate from which various
substitutions can be made. The synthesis begins with a Liebeskind thioester-boronic acid coupling to
yield an enone in multi-gram quantities. Attempts to stereoselectively reduce the enone (3) have
yielded at best a 60% de of the desired syn diastereomer. Attempts to increase the diastereoselectivity
or synthesize the desired intermediate (6) are underway but have thus far been unsuccessful.

Table of Contents

Table of Contents

Introduction 1
Results and Discussion 12
Future Work 21
Conclusions 22
Experimental Details 24
References 29

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