Published: March 10, 2011 r2011 American Chemical Society 2494 dx.doi.org/10.1021/jo102280n | J. Org. Chem. 2011, 76, 2494–2501 ARTICLE pubs.acs.org/joc Protecting-Group-Free Synthesis of Chokols Carmen P  erez Morales, Julieta Catal  an, Victoriano Domingo, Jos  e A. Gonz  alez Delgado, Jos  e A. Dobado, M. Mar Herrador, Jos  e F. Quílez del Moral,* and Alejandro F. Barrero* Department of Organic Chemistry, University of Granada, Avda. Fuentenueva, 18071 Granada, Spain b S Supporting Information ’ INTRODUCTION A number of terpenoid compounds of different origin share a common structural motif consisting of a cyclopentanic unit with contiguous asymmetric centers (Figure 1). 1 These structures include sesquiterpenes in the form of chokols. Chokols are 2,6- cyclofarnesanes isolated from the stroma of the timothy-grass Phleum pratense infected by the endophytic fungus Epichloe typhina and have been reported to have antifungal properties. They have thus attracted significant interest over the years, and in fact the enantioselective synthesis of chokols A, C, and G has already been achieved. 2 Although cyclopentanes are common structural motifs in natural compounds, the synthesis of these structures is often lengthy and tedious, especially when these blocks are highly functionalized, although noteworthy synthetic efforts have been recently published. 3 Within this context, we believe that structure 1, which contains suitable functionalities to lead to further synthetic steps, may well serve as a versatile building block for the stereoselective synthesis of these kinds of compounds. Consequently we embarked on a project aimed at developing an expedient, practical route to 1 4 and its application to the synthesis of bioactive chokols. ’ RESULTS AND DISCUSSION Bearing in mind the concept of step economy, 5 our approach to this cyclopentanic structure involved as a single step a Ti(III)- mediated, 6 stereocontrolled cyclization of the 1,2-monoepoxy derivative of commercially available enantiopure (À)-linalool (2). Taking into account the Lewis acid character of titanocene- (III) and its reported ability to exert a template effect during pinacol couplings 7 and in the regioselective opening of 2,3-epoxy alcohols, 8 we anticipated that this effect might play a determining role in the stereochemical outcome of the key 5-exo-trig cyclization, 9 in which the cyclic complex A is proposed to be involved (Scheme 1). Since two stereogenic centers are formed in the cyclization of I to II, apart from the desired cyclopentanic core 1, three other distereomers may be well created. To evaluate the feasibility of our approach, theoretical studies 10 through DFT methods (UM05/Ahlrichs-pVDZ) 11 were undertaken to provide the crucial reaction and activation energies of the key cyclization process leading from the acyclic radicals IaÀd to the cyclopentane radicals IIaÀd. 12 These studies are summarized in Figure 2, which also sets out the relative energies of the four possible cyclic radicals IIaÀd. In summary, these calculations showed that the process involving intermediate Ia, which should finally lead to compound 1, presents the most favorable thermodynamic and kinetic data in support of our hypothesis. Encouraged by the computational results, we went on to address the experimental studies that should corroborate the applicability of our synthetic proposal. We started by subjecting the commercially available (À)-linalool 2 to Sharpless experi- mental conditions to epoxidize chemoselectively the terminal double bond, 13 thus giving a diastereomeric mixture of mono- epoxides 3 in a molecular ratio close to unity. We then allowed this mixture to react with a 0.3 equiv of Cp 2 TiCl 2 , an excess of Mn, and a collidine/TMSCl mixture as regenerator. 6 In this way, we found six products, that is, 1 and 4À8, (Table 1, entry 1), with the cis-tetrahydrofuran 6 14 and the desired cyclopentane 1 obtained as major products. These compounds were isolated with the help of the semi/preparative HLPC, and their structure and stereochemistry unequivocally assigned by mass and ex- haustive NMR spectroscopy, including bidimensional NOE- DIFF experiments. Noteworthy here is the fact that under these experimental conditions, where the excess of TMSCl precludes the formation of the cyclic Ti(IV) complex A Received: November 16, 2010 ABSTRACT: As a result of a combined theoretical and experi- mental study, we describe a two-step protocol for the prepara- tion of an optically pure, multifunctional, cyclopentanic core shared by a number of natural products. This process is based on a hitherto unreported Ti(III)-mediated diastereoselective cycli- zation in which the hydroxy-directed template effect played by the Ti(III) species was found to be crucial for the stereoselective outcome of the reaction. The viability of this concept was confirmed with the first protecting-group free synthesis of three enantiopure chokols, namely, chokols K, E, and B.