Published: February 22, 2011 r2011 American Chemical Society 1572 dx.doi.org/10.1021/jo101869z | J. Org. Chem. 2011, 76, 1572–1577 ARTICLE pubs.acs.org/joc Role of Carbocation’s Flexibility in Sesquiterpene Biosynthesis: Computational Study of the Formation Mechanism of Terrecyclene Jos  e E. Barquera-Lozada* and Gabriel Cuevas Instituto de Química, Universidad Nacional Aut onoma de M exico, Circuito Exterior, Ciudad Universitaria, M exico D.F. 04510, Mexico b S Supporting Information ABSTRACT: Two mechanisms have been proposed in the lit- erature to explain the formation of the skeleton of terrecyclic acid from farnesyl diphosphate. Both mechanisms satisfy the experimental data obtained using isotopic labeling, but compu- tational results at the mPW1B95/6-31þG(d,p) level of theory allow the differentiation between them. While one of the mechanisms is basically a carbocation cascade, the other one requires several steps that imply high energetic demands. Specifically, there is a [1,3] hydride shift that requires approxi- mately 100 kcal/mol making this mechanisms unlikely. The other mechanism is more plausible, and it suggests the partici- pation of two secondary carbocation as intermediates, but these were not observed as minimums on the potential energy surface analyzed; they only appear as a point near the transition state in the intrinsic reaction coordinate. Both mechanisms proposed a [1,3] hydride shift, but in the less likely mechanism, the rigidity of the intermediate that undergoes the hydride shift greatly increases the energy of the corresponding transition state. ’ INTRODUCTION Farnesyl diphosphate (FPP, Scheme 1) can be cyclized by the enzyme humulene synthetase to produce a carbocation with a ring of 11 members (1). 1 The sesquiterpene formed by the β elimination of a proton from the humulyl cation (1) is known as humulene (2). On the other hand, if cation 1 suffers an attack on the 2,3 double bond and the methyl on the formed carbocation’s C3 is deprotonated, then β-caryophyllene (3) is formed. Both compounds 2 and 3 occur widely found in nature. 2 The humulyl cation is a biogenetic precursor of an important number of sesquiterpenes that are products of later cyclizations (Scheme 1). Since cation 1 has great conformational freedom, many of its biogenetic products are complex tricyclic structures such as sterpurene (4), pentalenene (5), terrecyclic acid (6), quadrone (7), silphinene (8), and botrydial (9). 2 In 1982, terrecyclic acid (6) was isolated for the first time from the mold Aspergillus terreus; 3 a few years earlier, quadrone (7) was isolated from the same source; both have a similar structure. 4 Both compounds, in addition to having moderate antitumor activity, have a very interesting tricyclic structure, and their biogenetic origin has not been easily determined. Several groups have worked on the elucidation of their biosynthesis. To accomplish this, isotopically marked acetate and mevalonate have been added to Aspergillus terreus cultures. 5-9 Two different mechanisms have been proposed to explain the distribution of the labeled atoms. On the first one (Scheme 2), 5,6 it is suggested that the carbon atom with electronic deficiency of the humulyl cation cyclizes onto the 6,7 double bond. This forms a bicyclic cation with one ring with eight members and another one with five (10, Scheme 2). Later, the C7 carbon is attacked by the 2,3 double bond to form the C2-C7 bond (11). At the same time that C6 is transposed from C7 to C2, the hydrogen atom attached to C2 undergoes a [1,2] hydride shift to position C3 (12). Lastly, one of the C12 hydrogen atoms is eliminated so the hydrogen atom at C3 undergoes a [1,3] hydride shift to C7. Compound 13* (terrecyclene) is the hydrocarbon precursor of 6 and 7 as it has the same carbon skeleton. The second mechanism uses as starting point the mechanism proposed for the formation of silphinene (8), 10,11 which is also proposed for the formation of botrydial (9), another sesquiterpene. 12 In the mechanism for the formation of 8, it has been proposed that cation 1 cyclizes onto the 2,3 double bond to form an intermediate with fused 4- and 9-membered rings (14, Scheme 3). In the following step, C1 is transposed from C2 to C3 forming 15, which suffers the attack of the 6,7 double bond to form the C2-C6 bond (16). Cation 16 under- goes [1,3] hydride shift from C2 to C7 forming cation 17. Then, C7 is transposed from C6 to C2 to form 18. This is where the biosynthesis of 6 and 8 takes separate paths. In order to form 6 it is proposed that two more consecutive transpositions take place. First, C10 is transposed from C2 to C6 (19), and finally, C1 is transposed again from C3 to C2 (13). 13-15 In this paper, we perform DFT calculations of both mechanisms in order to Received: September 22, 2010