A Maze of Dyotropic Rearrangements and Triple Shifts: Carbocation

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A Maze of Dyotropic Rearrangements and Triple Shifts: Carbocation Rearrangements Connecting Stemarene, Stemodene, Betaerdene, Aphidicolene and Scopadulanol Young J Hong, and Dean J Tantillo J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00138 • Publication Date (Web): 01 Mar 2018 Downloaded from http://pubs.acs.org on March 2, 2018

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The Journal of Organic Chemistry

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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, CA 95616 USA

Abstract Results of quantum chemical investigations shed new light on the mechanisms of formation of the stemarene, stemodene, betaerdene, aphidicolene and scopadulanol diterpenes from syncopalyl 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 interconnectedness 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.

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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 (synCPP), 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


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Scheme 1. Previously proposed network of carbocation interconversions involved in the formation of diterpenes 2-6. 12

1 18

13

OPP

4

OH

2

6

15

20

12

19

14

8

10 17

15 16

12

13 14

9

- OPP-

H

H H

9

11(16)

13

- H+

14

7

16

13 14

9

C-to-H': 1,3-hydride shift

14 9

E

H-to-C': 1,3-hydride shift

E'

E-to-C: alkyl (C15) shift

12

11 15 16 9

8

H H

C'-to-E': alkyl (C15) shift

putative secondary carbocation

13 14

8

H H

C'


- H+ alkyl (C12) shift concerted alkyl (C12)shift / alkyl (C14) shift

17

H

16

alkyl (C14) shift

D (D')

13

H+

15

9 8

H

-

17

12 11

15 (12) 14

12

H

H 13

H

8

H

8

cation-alkene cyclization

12(15) 13

9

11

13 14

16

H (H')

12 16

8

H

concerted cation-alkene cyclization/ alkyl (C14) shift

11(16) 16(11)

J-to-E': concerted alkyl (C12) shift/ 1,3-hydride shift/ alkyl (C15) shift

17 13 14

16

H

B

9

15 15

8

H

alkyl (C12) shift

J (J')

12 11

aphidicolenes

12 11 15

H

E-to-J': concerted alkyl (C12) shift/ 1,3-hydride shift/ alkyl (C15) shift

∆13,12-5a/∆13,17-5b

alkyl (C14) shift

17

H

betaerdenes


H H

H 15(12) 13

8

∆13,14-4a/∆13,17-4b

- H+

I (I')

H

H

15(12)

8

H

14

9

17

H

14

16(11)

H

15 12

11(16) 16(11)

concerted alkyl (C14)shift / alkyl (C12) shift

13

H

H

cation-alkene cyclization

12(15)

17 16

1,2-hydride shift

12

9


A

alkyl (C16) shift

12(15) 13

G

F

8 5


H

H

13 14

9

13 14

concerted alkyl (C16) shift/ +H2O/- H+

H

17 15

12

K

8

- OPP-

12

16

9

8

H

syn-copalyl diphosphate (syn-CPP)

15

1,2hydride shift


H H

6

H

OPP

1

14

9

H

scopadulanol

3

15

8

geranylgeranyl diphosphate (GGPP)

16

16

+ H2O/- H+

H

13

13 14

H

C

14


H H

∆13,14-2a/∆13,17-2b

stemarenes

17

H

H

dyotropic rearrangement triple shift

H

∆13,12-3a/∆13,17-3b

stemodenes

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


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amount of light on the complex network of carbocations involved in the formation of diterpenes 2-5, some mechanistic issues remained to be resolved. Detailed structural data on carbocation minima and transition state structures was not provided with the previous report, nor was 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 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 co-workers’ 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 Supporting Information for comparison with X3LYP calculations).13 All stationary points were characterized as minima or transition state structures using frequency calculations. All reported energies include 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 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 Ball&Stick.20 Atom numbering throughout is based on that for the structure A. The structures with and without prime labels are equivalent in the absence of atom labeling.


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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 formation of the isopimarenyl cation (A) leads to the stemarenes (2) and stemodenes (3), while the pathway beginning with formation of the pimarenyl cation (F) leads to the betaerdenes (4), aphidicolenes (5) and scopadulanol (6) (Scheme 1). Herein we describe in detail the results of quantum chemical calculations that reveal not only energetics and structural details for both pathways, but also routes by which these two pathways can interconnect.

Pathway to stemarenes. Carbocation A1 is a conformer of the isopimarenyl cation that is productive for hydride shift 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

A Maze of Dyotropic Rearrangements and Triple Shifts: Carbocation

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