Controlling cis/trans-selectivity in intramolecular Diels–Alder reactions of benzo-tethered, ester linked 1,3,9-decatrienes

Abstract

Predictions from DFT (B3LYP/6-31 G(d))-computed stereoisomer product distributions for intramolecular Diels-Alder (IMDA) reactions have been successfully replicated in the laboratory. Benzo-tethered hexadienyl acrylates generally undergo moderately trans-selective IMDA reactions which, as suggested by DFT calculation, arise from two opposing transition structure (TS) features: stabilising secondary orbital interactions, which are stronger in the cis-TSs, and stabilising pi-conjugative interactions between the benzo moiety and the 1,3-diene component - which are stronger in trans-TSs. Substrates carrying a removable substituent (i.e. Br or TMS) at C3 of the diene or C12 of the aromatic ring are predicted to undergo highly cis-selective thermal IMDA reactions by steric destabilisation of the trans-TS. A substrate carrying a two atom tether between C3 and C12 is predicted to undergo a highly trans-selective intramolecular cycloaddition by destabilisation of the cis-TS. These calculations are borne out experimentally.

Experimental and Computational Studies into an ATPH‐Promoted exo‐Selective IMDA Reaction: A Short Total Synthesis of Δ9‐THC

“…These markedly different dihedral angles between the aromatic ring and the C3C4 double bond in the cis ‐ and trans ‐IMDA TSs of 10 suggest that placement of a large group at either C3 or C12 should disfavor the trans ‐TS relative to the cis ‐TS. Both DFT calculations and experimental findings confirmed this expectation: both Br and trimethylsilyl (TMS) substituents at C3 or C12 led to very high cis ‐IMDA selectivities (>95 % cis ) (Scheme ) 16…”

“…Recently, we explored the cis / trans selectivity in IMDA reactions of a series of hexadienyl acrylates 15. 16 Interestingly, we observed that, whereas the IMDA reaction of the cognate system possessing the ethylene tether (CH 2 CH 2 OC(=O)) displays strong cis stereoselectivity, the IMDA reactions of the benzo‐tethered systems exhibit moderate trans selectivity, for example, cis / trans =26:74 (Scheme ) 15…”

“…Recently, we explored the cis/trans selectivity in IMDA reactions of a series of hexadienyl acrylates. [15,16] Interestingly, we observed that, whereas the IMDA reaction of the cognate system possessing the ethylene tether (ÀCH 2 CH 2 OC(=O)À) displays strong cis stereoselectivity, the IMDA reactions of the benzo-tethered systems exhibit moderate trans selectivity, for example, cis/trans = 26:74 (Scheme 3). [15] Our DFT calculations traced the origin of the preference for the trans isomer to conjugation effects between the diene and the aromatic ring of the tether, as reflected in the magnitude of the dihedral angle q between the diene and the aromatic ring in the cis-and trans-IMDA TSs for 10.…”

“…Both DFT calculations and experimental findings confirmed this expectation: both Br and trimethylsilyl (TMS) substituents at C3 or C12 led to very high cis-IMDA selectivities (> 95 % cis) (Scheme 3). [16] On the basis of these findings, it was expected that the 3-OMe substituent in 8 a should likewise favor formation of the cis-IMDA product. The predicted and observed selectivity, stereorandom (gas phase; calculations) or moderately cis selectivity (toluene; calculation and experiment), is smaller than might be expected ( Table 1, Entry 3; Table 2, Entry 1).…”

On the Effect of Tether Composition on cis/trans Selectivity in Intramolecular Diels–Alder Reactions

“…This goal remains elusive, notwithstanding recent significant progress towards delineating the various factors controlling IMDA stereochemistry. [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] In this paper, we explore, using density functional theory, the origin of cis/trans selectivity in IMDAs of 1,3,8nonatrienes, 1-9, possessing tethers that are three atoms long (Scheme 1). Given the experimental fact that IMDAs generally give kinetically controlled product distributions, the key to understanding cis/trans selectivity in these reac-Abstract: Intramolecular Diels-Alder (IMDA) transition structures (TSs) and energies have been computed at the B3LYP/6-31+G(d) and CBS-QB3 levels of theory for a series of 1,3,8nonatrienes, H 2 C=CH À CH=CH À CH 2 À X À Z À CH=CH 2 [ À X À Z À = À CH 2 À CH 2 À (1); À O À C(=O) À (2); À CH 2 À C(=O) À (3); À O À CH 2 À (4); À NH À C(=O) À (5); ÀSÀC(=O)À (6); ÀOÀC(=S)À (7); ÀNHÀC(=S)À (8); ÀSÀC(=S)À (9)].…”