An invocation for computational evaluation of isomerization transforms: cationic skeletal reorganizations as a case study

Abstract

This review article describes how cationic rearrangement reactions can be used in natural product total synthesis as a case study for the many productive ways by which isomerization reactions are enabling for synthesis.

Computational Investigation of Multifaceted Cationic Rearrangement and Stereo- and Regioselectivity in the Formation of Dysideanone’s Analogues

“…22 The presence of carbocationic centers at the fused positions in 6 and 7 has reduced their relative energy difference than in original cis-and trans-decalins by 2.4 kcal/mol (ΔG L S ; Scheme S1). From 7, a facile (Δ ‡ G L S = 2.1 kcal/mol) [1,2]-H migration furnishes a relatively stable isomer 8, where the carbocation has moved to the juxtaposed fused center C 10 (Figure 2). Undoubtedly, alternative [1,2]-H migrations from the adjacent −CH 2 center provided unstable intermediates involving secondary carbocations, thereby disfavoring any γ-arylated route.…”

“…From 7, a facile (Δ ‡ G L S = 2.1 kcal/mol) [1,2]-H migration furnishes a relatively stable isomer 8, where the carbocation has moved to the juxtaposed fused center C 10 (Figure 2). Undoubtedly, alternative [1,2]-H migrations from the adjacent −CH 2 center provided unstable intermediates involving secondary carbocations, thereby disfavoring any γ-arylated route. From 8, following minor conformational rearrangement, C−C bond coupling at the γ′position affords intermediate 10.…”

“…Energy profiles of these unfavorable routes are collected in Figures S1−S4. In search of an alternative pathway for γ-arylated product 19 formation, we explored the possibility of synchronous [1,2]-Me and [1,2]-H migrations from 5, similar to the dyotropic rearrangement proposed by Tantillo 8 in the case of abietadiene synthesis. Unfortunately, we are unable to characterize this single-step transition state even after numerous attempts; however, the potential energy scan shows a barrier greater than 40 kcal/mol (Figure S13).…”

“…Now, if we compare the γand γ′arylation routes, interestingly, then the activation barriers leading to γ-arylated products are the same for both the carbinols (1/1 Me ; 9.6/9.6 kcal/mol). However, the preference for γ′-arylation in 1 is an outcome of combined factors, which includes facile [1,2]-H migration from 7 (2.1 kcal/mol), less steric crowding during C−C coupling (Δ ‡ G L S = 5.8 kcal/mol), and a relatively facile dearomatization route 24 (Δ ‡ G L S = 3.0 kcal/mol; Figure 4). 25 In fact, it is the C−C coupling step (8 Me → 10 Me ) that contributes substantially toward the high barrier for γ′arylation in 1 Me (Figure 4 and Figure S5).…”

“…Therefore, the laboratory synthesis of terpenoids is essential and of utmost necessity to drive further advancement of terpene chemistry. Generally, the synthesis involves a process of multiple events, such as cation migration, alkyl or hydride shifts, cyclizations, fragmentations, protonations, deprotonations, etc., which can lead to the formation of terpenoid skeletons with diverse structures and stereochemistry. Therefore, paramount challenges are encountered in unfolding the structural and stereochemical complexities while building up such polycyclic hydrocarbon cores. , …”