As a model for the squalene cyclization the interaction between a methyl cation or a methyl radical and two double bonds has been studied using the CNDO/Z and INDO method. I n both cases bond formation between the CH,-group and one double bond is facilitated by a second one, but not in a concerted way.One of the most interesting and exciting reactions in terpene biosynthesis is the cyclization of squalene oxide (1) to lanosterol [l] [Z]. A somewhat simpler example of this kind of cyclization, that of 1 to damaradienol(2), is shown below. 1 2When squalene'oxide is converted to lanosterol, a product is formed with no less than seven asymmetric centers. This reaction is of particular interest to organic chemists since only one product is formed in the biosynthesis instead of a mixture of isomers. Besides this high stereospecifity of the reaction it is found that no isotopic Present adress: 1) exchange occurs when the biosynthesis from squalene is carried out in a medium containing H,O1* and D,O [3].Although these facts indicate a concerted process [l-41, a stepwise mechanism would explain the situation just as well if the conformation of squalene were similar to that shown above: namely a helical arrangement of the double bonds. A stepwise mechanism in such an arrangement should work like a zipper, one bond being formed after another.Besides the carbonium ion mechanism indicated in (I), a radical mechanism has been postulated for the ring closure of squalene [5]. Although this mechanism seems to be of less importance for the biochemical process it is still very interesting, since studies on model reactions [IS] also show a high stereospecificity.We discuss here the two possibilities, concerted or stepwise ring closure for both the cationic and radical process, with the aid of molecular orbital calculations. The calculations should also provide us with some indirect information concerning the role of the enzyme i.e. at what distance the reaction between a positive center and one double bond is facilitated by a second. Our efforts are perforce limited to model calculations, and we cannot estimate the entropy factors involved. The methods used are CNDO/Z and INDO [6]. d3-4 PI 2.8 2.4 2.0 1.6 1.2 1.2 1.6 2.0 2.4 Fig. la HELVETICA CHIMICA ACTA -Vol. 57, Fasc. 3 (1974) -Nr. 91 825 dJA1 2.8 2.L 2.0 1.6 1.2 I * 1.2 1.6 2.0 2.4 2.8 A d,-*Fig. l b Figure 1. Potential surfacefor model I . I n a a methyl cation and in b a methyl radical interacts with two double bonds. The path of minimum energy (. -. . -.) and for a concerted mechanism(-----1 is indicated I Our first hypothesis for the geometry of the transition state is, that the positive or radical center and double bonds interact as shown in eq. (1). Molecular models show that such a chair-like arrangement of olefinic and CH, groups is practically strainfree. A reasonable model for MO-calculations is obtained if we exclude both CH,-groups and the CH,-substituents in squalene. A p-orbital centered on a terminal CH,-group which interacts with the double bonds in a helical arr...
