Deceptive Complexity in Formation of Cleistantha-8,12-diene

Abstract

A barley diterpene synthase (HvKSL4) was found to produce (14S)-cleistantha-8,12-diene (1). Formation of the nearly planar cyclohexa-1,4-diene configuration leaves the ring poised for aromatization, but necessitates a deceptively complicated series of rearrangements steered through a complex energetic landscape, as elucidated here through quantum chemical calculations and labeling studies.

Cyclopropylcarbinyl-to-Homoallyl Carbocation Equilibria Influence the Stereospecificity in the Nucleophilic Substitution of Cyclopropylcarbinols

“…36 Moreover, the conclusion that BCB structures are TSs on the PES in the Marek system is replicated by other DFT methods (Supporting Information Figure S14). These methods also agree on the large energetic difference between BCB and CPC structures in 2a, which is consistent with studies of other substituted cyclopropylcarbinyl cations 22,31 (including when the BCB structures are minima on the PES). 14,17,18 Thus, even if the curvature of the ωB97X-D potential energy surface is not fully accurate (although, as shown above, it reproduces MP2 results favorably for C 4 H 7 + ) or if the presence of a counter anion influences the PES as to make BCB structures shallow minima instead of TSs, they would still be unlikely participants in the reactions of those cations.…”

“…The base cyclopropylcarbinyl/bicyclobutonium cation (C 4 H 7 + ) system has been heavily studied since Roberts’ 1951 report that cyclobutyl and cyclopropylcarbinyl electrophiles solvolyze readily to form the same mixture of cyclobutyl, cyclopropylcarbinyl, and homoallyl products, hinting at a common intermediate . CPC/BCB cations have since been proposed as intermediates in a variety of organic reactions/rearrangements − and terpene biosynthetic pathways. − An array of spectroscopic, NMR, and computational techniques have been used to probe the C 4 H 7 + system, − which is now understood as an equilibrating mixture of triply degenerate σπ-bisected cyclopropylcarbinyl I and non-classical bicyclobutonium II cations (Figure B). These are similar in energy and interconvert stereospecifically through low-energy transition structures (TSs) on a flat potential energy surface (PES).…”

Substituent Effects on the Equilibria between Cyclopropylcarbinyl, Bicyclobutonium, Homoallyl, and Cyclobutyl Cations

“…Similarly, if CPC XXI is initially formed, the cations will spontaneously rearrange to the highly stable HA XXII and get trapped, forming homoallyl products XXVIII (as shown in Figure B, top) or butadienes (not shown) upon elimination. Indeed, the tendency for EDGs to promote CPC XIX and HA XXII as deep minima is consistent with fewer reported cases of highly alkylated BCB minima in comparison to reported CPC and HA structures. ,− ,,,,,, …”

“…Indeed, the tendency for EDGs to promote CPC XIX and HA XXII as deep minima is consistent with fewer reported cases of highly alkylated BCB minima in comparison to reported CPC and HA structures. 7,[18][19][20]31,34,35,39,59,60 For EWGs, neutral substituents, and electron-deficient aromatics, most of the PES is accessible as the minima are shallower, with several minima and TSs relatively close in energy. For instance, we predict that CPC XIX is the lowest- Overall, due to the shallowness of these PESs, we expect that the identity of the electrophile that initially generates the cation, in addition to solvation and nonstatistical dynamic effects during the generation and capture of the intermediates, 68 will impact the final product distributions upon nucleophilic attack, making these cases harder to predict (Figure S13).…”

“…Cyclopropylcarbinyl (CPC) and bicyclobutonium (BCB) cations (C 4 H 7 + ) have been of great scientific interest since Roberts’ 1951 report that cyclobutyl and cyclopropylcarbinyl electrophiles solvolyze quickly to the same mixture of cyclobutyl, cyclopropylcarbinyl, and homoallyl products, hinting at a common, stabilized intermediate . After many years of scientific debate, the C 4 H 7 + intermediates are now understood as a mixture of triply degenerate σπ-bisected cyclopropylcarbinyl (CPC) I and nonclassical bicyclobutonium (BCB) II cations (Figure A), − the latter being the more stable structure (by 1.8 kcal/mol from MP2 calculations). − Solvolysis experiments of substituted cyclobutyl or cyclopropylcarbinyl electrophiles provide complex product mixtures in which the major component seems difficult to predict, even for simple substitution patterns (Figure B). − Nevertheless, over the years multiple synthetic approaches have reported CPC/BCB and cyclobutyl (CB) cations as intermediates toward cyclopropylcarbinyl, − cyclobutyl, , and homoallyl (HA) products. ,, Such cations have also been proposed as intermediates in the biosynthesis of various terpenes, using Density Functional Theory (DFT) calculations as support. − …”