CHEMICAL STRUCTURE 



isoeuphol reaction should be difficult to reverse chemically, but 

 this would not preclude the feasibility of the analogous reaction 

 in an enzymatic system. In the event that isoeuphol is also the 

 precursor of lanosterol (IX to XII, Figure 4), a single 1,3 methyl 

 shift (from Cs to C13) would establish the methyl group at C13 in 

 the /5 configuration which is typical of lanosterol and of all the 

 natural steroids except euphol.* 



It is perhaps significant that in the pentacyclic triterpenes, 

 the only naturally occurring products which are branched at both 

 the 8 and 14 positions, the configurations of the methyl sub- 

 stituents are without exception /3 and a, respectively, as they are 

 in isoeuphol. It is therefore reasonable to expect that the same 

 configuration will be assumed by the first tetracyclic transition 

 state or intermediate (VI, Figure 3). The subsequent course of 

 the reactions will be governed by the stereochemical nature of the 

 end products, the fi configuration at C13 in lanosterol resulting 

 from a single 1,3 shift of the j3 methyl at Cg, whereas the forma- 

 tion of euphol is more readily explained by two consecutive 1,2 

 methyl shifts. 



For the further biochemical exploration of steroid biogene- 

 sis it will be crucial to ascertain whether cyclization is initiated 

 by an oxidative attack on squalene, as Ruzicka suggests (20), or 

 whether the hydroxyl group at carbon atom 3 is introduced 

 after the tetracyclic ring system has been completed. The 

 chemical behavior of squalene, i.e., the acid-catalyzed formation 

 of tetracyclo-squalene (Figure 5), merely shows that, as expected, 



* Recent evidence obtained by Dr. Tchen in this laboratory suggests 

 that squalene is converted to lanosterol without formation of stabilized inter- 

 mediates. In the presence of D2O, squalene cyclizes to lanosterol without in- 

 corporating deuterium. This result eliminates any reaction mechanism in- 

 volving an irreversible attachment of protons to the carbon skeleton, e.g., 

 reactions VI to X in Figure 4, and thus rules out isoeuphol as an intermediate 

 in lanosterol formation. On the other hand, the experimental results ob- 

 tained with DoO can be rationalized by assuming intramolecular hydride 

 shifts from d; to C20 and from C13 to Cn accompanied by methyl shifts, events 

 which would yield lanosterol from the carbonium ion VI (Figure 4) without 

 uptake of hydrogen from an external source. 



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