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Secondary Carbocations in the Biosynthesis of Pupukeanane Sesquiterpenes Christina H. McCulley, and Dean J Tantillo J. Phys. Chem. A, Just Accepted Manuscript • DOI: 10.1021/acs.jpca.8b07961 • Publication Date (Web): 13 Sep 2018 Downloaded from http://pubs.acs.org on September 15, 2018
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The Journal of Physical Chemistry
Secondary Carbocations in the Biosynthesis of Pupukeanane Sesquiterpenes Christina H. McCulley and Dean J. Tantillo* Department of Chemistry, University of California–Davis, Davis, CA 95616, USA *
[email protected] ABSTRACT The results of quantum chemical calculations on putative biosynthetic carbocation cyclization/rearrangements leading to pupukeanane and related sesquiterpenes indicate that a secondary carbocation proposed as an intermediate is not a minimum on the potential energy surface and instead resides in a region of the potential energy surface associated with a plateau containing multiple exit channels. INTRODUCTION
The formal s-bond frameworks of carbocations tend towards greater delocalization than
those of carbanions, carbon-centered radicals and alkanes.1-4 As a result, barriers for rearrangement reactions that involve the breaking of bonds involved in delocalized arrays (e.g., engaged in strong hyperconjugation4) can have very low barriers, and transition state structures (TSSs) for such rearrangements are frequently lacking in s-delocalization. For example, many secondary carbocations proposed as intermediates in cyclization/rearrangement reactions involved in the biosynthesis of terpene natural products have been shown not to be minima on potential energy surfaces (PESs), at least in the absence of enzymatic chaperons, occurring instead at other points on reaction coordinates, sometimes near TSSs (Figure 1).5,6 Our ongoing studies on the scope and generality of this concept led us to examine the reactions shown in Scheme 1. It was proposed that cation 2, formed from cyclization of cation 1, could undergo a
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1,2-alkyl shift to form either cation 3 or cation 4. Cation 3 would be a biosynthetic precursor to neopupukeanane sesquiterpenes, while cation 4 would be a direct precursor to pupukeanane sesquiterpenes and an indirect precursor to abeopupukeanane sesquiterpenes (via cation 5).7 Based on previous experience, we suspected that one or both of secondary cations 3 and 4 might not be PES minima and set out to test this hypothesis using density functional theory (DFT) calculations.
frequently proposed
A R1 R2
transition structure for concerted asynchronous dyotropic rearrangement; classical 2° carbocation
B
E
H
3°
R3 R4
R2 H 2°
frequently found R2 H
R1 R4 2°
R3
B
A
B
R1 R4
R2
R3
R3
three classical minima
H
3°
R1 R4
R1 R2
H
3°
R3 R4
R2 R3
H
3°
R1 R4
two classical minima (often engaged in strong hyperconjugative delocalization)
A: transition state structure stabilization
B: minimum destabilization
Figure 1. Comparison between reaction coordinate for a stepwise carbocation rearrangement (left), which is often assumed, and a concerted rearrangement involving multiple asynchronous events (right), which is often observed. In the specific example shown, a reaction that might be formulated as two 1,2-shifts (of R1 and then R3) separated by a minimum (intermediate on the PES) is instead found to be a concerted process where the two 1,2-shifts occur sequentially but without an intervening minimum; instead the transition state structure for the concerted rearrangement (here a dyotropic rearrangement26) resembles the secondary cation formed after the first 1,2-shift.
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The Journal of Physical Chemistry
Scheme 1. Carbocations involved in proposed mechanisms for formation of pupukeanane and related sesquiterpene natural products. Newly formed s-bonds in each structure are bolded and colored blue.
α-amorphene + H+
a
neopupukeanane skeleton 2° cation
3 protonated amorphene
1,2-alkyl (a) shift a cation-π cyclization
2
b
1
1,2-alkyl (b) shift
d
b
pupukeanane skeleton
1,2-alkyl (c) shift
2° cation c
4
1,2-alkyl (d) shift
abeopupukeanane skeleton
d
c
5
dyotropic rearrangement
6
METHODS Computations were performed at the B3LYP/6-31+G(d,p),8-10 B3LYP-D3/6-31+G(d,p)11 and mPW1PW91/6-31+G(d,p)12-13 levels of theory, using Gaussian09.14 Identities of all stationary points (minima or transition state structures) were confirmed by frequency analysis and intrinsic reaction coordinate (IRC) calculations were performed on all transition state structures to confirm connectivity to products.15,16 All energies shown are free energies at room temperature, except for those in the IRC plots, which are electronic energies. Three-dimensional molecular images were generated with CylView.17
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RESULTS AND DISCUSSION
Secondary cation 3 is predicted to be a minimum at all levels used and is formed from
cation 2 via a TSS that is similar in structure and energy to 2 (Figure 2). The formal secondary carbocation center in cation 3 benefits from hyperconjugation from two adjacent C–C bonds (1.59 and 1.70 Å; see Figure 2). Hyperconjugation with the 1.70 Å C–C bond has entered the realm of bridging (C–C–C angle
