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B. Andes Hess Jr.

Hess

Research

Computational and Physical Organic Chemistry
Recent advances in computer technology have allowed many problems of interest to the organic chemist to be studied computationally. Described below is an application of computational chemistry to the study of the reaction mechanism of the recently studied biochemical transformation of squalene oxide to lanosterol.

Mechanism of the Conversion of Squalene to Lanosterol, the Precursor to All Steroids
It was suggested over 50 years ago that in animals the acyclic triterpene squalene is converted enzymatically to lanosterol, a systems containing four rings. What appears to be a very simple reaction on the surface has been described as one of the most complex reactions in biological systems. The formation of the tetracycle is thought to first involve epoxidation of one of the double bonds of squalene followed by protonation that leads to a cascade of reactions in which the four rings are formed:

Originally this cascade of reactions was proposed to proceed through discrete carbocationic intermediates with the stepwise formation of the first three rings (each giving rise to a tertiary carbocation). Although in the steroids these rings are all six-membered, in order to produce a carbocation from the formation of the third ring, a five-membered ring must form. It was thought that this five-membered ring then underwent an anti-Markovnikov ring expansion to give the six-membered ring followed by formation of the fourth ring, a cyclopentane ring. We have recently shown that the formation of these last to rings might very well involve a concerted ring expansion of the five-membered ring with the formation of the fourth ring by studying a model system as shown.

The middle structure represents the transition structure for this concerted ring expansion and ring formation.

Recently we have turned our attention to whether the formation of the first three rings (6,6,5) in the cyclization of squalene is a concerted reaction or might involve discrete carbocation intermediates. It turns out that this problem initially reduces to one of studying the possible conformations of the individual carbocations that might be intermediates. This was done using model systems. In all cases it was found that the conformation that would lead to ring cyclization does not exist on as a minimum on the potential surface, rather collapsing to the cyclic structure. This is strongly suggestive that the formation of the at least the first three rings is concerted, and to test this we have undertaken calculations on model systems which involve the potential for a double cyclization. These cyclizations are studied by first finding an initial transition structure and then subjecting it to the intrinsic reaction coordinate calculations which follow the pathway downhill to product. Preliminary results obtained for the related cyclization of squalene to the hopanoids indeed confirms our conjecture of a concerted reaction. Along the pathway shown in Figure 2, no intermediates were located, though it was found that the first ring is almost completely formed prior to the formation of the second ring.


Figure 1. Concerted ring-closure of rings A and B of squalene.