Article Cite This: J. Org. Chem. 2018, 83, 3780−3793
pubs.acs.org/joc
A Maze of Dyotropic Rearrangements and Triple Shifts: Carbocation Rearrangements Connecting Stemarene, Stemodene, Betaerdene, Aphidicolene, and Scopadulanol Young J. Hong and Dean J. Tantillo* Department of Chemistry, University of California−Davis, Davis, California 95616, United States S Supporting Information *
ABSTRACT: Results of quantum chemical investigations shed new light on the mechanisms of formation of the stemarene, stemodene, betaerdene, aphidicolene, and scopadulanol diterpenes from syn-copalyl diphosphate (syn-CPP). These terpenes are shown to be connected by a complex network of reaction pathways involving concerted but asynchronous dyotropic rearrangements and triple shift rearrangements. The interconnection of these pathways leads to multiple routes for formation of each diterpene, which could lead to different origins for some carbon atoms in a given diterpenes under different conditions.
■
INTRODUCTION Tetracyclic diterpenes are widespread in the plant kingdom and perform many essential biological roles.1 One diterpene family marked by tetracyclic core structures includes stemarene (2), stemodene (3), betaerdene (4), aphidicolene (5), and scopadulanol (6) (Scheme 1).2,3 These diterpenes are formed from geranylgeranyl diphosphate (1) via syn-copalyl diphosphate (syn-CPP), the latter of which is a progenitor of carbocations that participate in many complex cyclization/rearrangement cascades.3 Typical mechanisms proposed for the formation of these diterpenes are illustrated in Scheme 1 (paths in black). The diterpenes stemarene (2) and stemodene (3) share a common reaction pathway thought to involve three carbocationic intermediates: the isopimarenyl cation (A), tertiary cation (B), and secondary cation (C) (Scheme 1, bottom left). From cation C, the pathway branches toward stemarene (via C12 shift) and toward stemodene (via C14 shift). Analogous pathways from the pimarenyl cation (F) are proposed to lead to betaerdene (4; Scheme 1, center) and aphidicolene (5; Scheme 1, top right), diastereomers of stemarene and stemodene, respectively. The pathway from the pimarenyl cation also branches toward scopadulanol (6; Scheme 1, top). Related pathways have been described previously for the formation of kaurene, atiserene, beyerene, and trachylobane diterpenes.4,5 In 2002, Oikawa and co-workers described a carbocation reaction network for the formation of the diterpenes in Scheme 1 based on the results of density functional theory (DFT) computations using the B3LYP/6-31G(d,p) method.3 While this work shed a considerable amount of light on the complex network of carbocations involved in the formation of diterpenes © 2018 American Chemical Society
2−5, some mechanistic issues remained to be resolved. Detailed structural data on carbocation minima and transition state structures were not provided with the previous report, nor were data on intrinsic reaction coordinate (IRC) calculations. We provide this data here (for calculations with a slightly larger basis set), along with improved estimates of relative energies of carbocations (from calculations with a more reliable functional), information on conformational interconversions necessary for navigating the maze of structures toward particular products, and a discussion of the implications of the potential energy surface (PES) topography for the biosynthesis of diterpenes 1−6. In the intervening 15 years from Oikawa and co-workers’s seminal report, much has been learned about PESs for complex carbocations and their implications for biological reactivity.6−10 In light of such developments, the importance of Oikawa and coworkers’ computational results is clearer than ever, and we are now able to refine and extend their reactivity model.
■
METHODS
Calculations were performed with the GAUSSIAN0311 and GAUSSIAN0912 software suites. Geometries were optimized using the B3LYP method with the 6-31+G(d,p) basis set (see the Supporting Information for a comparison with X3LYP calculations).13 All stationary points were characterized as minima or transition state structures using frequency calculations. All reported energies included zero-point energy corrections (unscaled) from the frequency calculations. IRC calculations were used for further characterization of transition state structures.14 mPW1PW9115 single point energies also were computed, since B3LYP underestimates the relative energies of cyclic structures versus acyclic Received: January 16, 2018 Published: March 1, 2018 3780
DOI: 10.1021/acs.joc.8b00138 J. Org. Chem. 2018, 83, 3780−3793
Article
The Journal of Organic Chemistry
Scheme 1. Previously Proposed Network of Carbocation Interconversions Involved in the Formation of Diterpenes 2−6
■
isomers.8,16 The computational methods used here are well established for examining carbocation cyclization/rearrangement reactions.8,10,17−19 Structural images were created with the Ball & Stick software.20 Atom numbering throughout was based on that for the structure A. The structures with and without prime labels are equivalent in the absence of atom labeling.
RESULTS AND DISCUSSION Diphosphate departure-initiated cyclization of syn-CPP is proposed to open two carbocationic rearrangement pathways, leading to diastereomeric products. The pathway beginning with the formation of the isopimarenyl cation (A) leads to the stemarenes (2) and stemodenes (3), while the pathway 3781
DOI: 10.1021/acs.joc.8b00138 J. Org. Chem. 2018, 83, 3780−3793
Article
The Journal of Organic Chemistry
Figure 1. Conversion of isopimarenyl cation conformer A1 into E1, the cation that precedes the stemarenes (2a and 2b). Computed structures (selected distances in Å) and relative energies (in kcal/mol) of minima and transition state structures are shown (B3LYP/6-31+G(d,p)//B3LYP/6-31+G(d,p) in normal texts and mPW1PW91/6-31+G(d,p)//B3LYP/6-31+G(d,p) in brackets). The potential energy surface is drawn based on mPW1PW91/631+G(d,p)//B3LYP/6-31+G(d,p) energies.
and subsequent 9,16-cyclization en route to the stemarenes (2) (Figure 1). The 1,2-hydride shift proposed to convert A1 into a particular conformer of cation B, B1, is predicted to have a barrier
