Origins of Endo Selectivity in Diels–Alder Reactions of Cyclic Allene Dienophiles

Abstract

Strained cyclic allenes, first discovered in 1966 by Wittig and co‐workers, have recently emerged as valuable synthetic building blocks. Previous experimental investigations, and computations reported here, demonstrate that the Diels–Alder reactions of furans and pyrroles with 1,2‐cyclohexadiene and oxa‐ and azaheterocyclic analogs proceed with endo selectivity. This endo selectivity gives the adduct with the allylic saturated carbon of the cyclic allene endo to the diene carbons. The selectivity is very general and useful in synthetic applications. Our computational study establishes the origins of this endo selectivity. We analyze the helical frontier molecular orbitals of strained cyclic allenes and show how secondary orbital and electrostatic effects influence stereoselectivity. The LUMO of carbon‐3 of the allene (C‐3 is not involved in primary orbital interactions) interacts in a stabilizing fashion with the HOMO of the diene in such a way that the carbon of the cyclic allene attached to C‐1 favors the endo position in the transition state. The furan LUMO, allene HOMO interaction reinforces this preference. These mechanistic studies are expected to prompt the further use of long‐avoided strained cyclic allenes in chemical synthesis.

Quantification of the Helicality of Helical Molecular Orbitals

“…Given the interest in helical MOs as a means to understand related properties and the range of molecular systems in which these MOs appear, − it is problematic that the assessment of helical MOs relies on visual inspection alone. It is thus altogether binary; if an MO is shaped like a coil, we may deem it to be helical.…”

Leveraging Fleeting Strained Intermediates to Access Complex Scaffolds

“…In a collaboration with the Houk group at UCLA, a distortion-interaction analysis demonstrated that interaction energies, related to electron-factors, likely govern regioselectivity . With regard to diastereoselectivity, reactions proceed with endo selectivity with respect to the unreactive cyclic allene double bond. , Given the synthetic utility of this methodology and the ability to understand the regiochemical and stereochemical outcomes, we expect this methodology will see increased usage in chemical synthesis. For example, Schreiber and co-workers have recently harnessed heterocyclic allene chemistry for the synthesis of DNA-encoded libraries …”

Trifluoroethanol as a Unique Additive for the Chemoselective Electrooxidation of Enamines to Access Unsymmetrically Substituted NH‐Pyrroles

“…In this regard, the activation strain model as proposed by Bickelhaupt and co-workers provides an in-depth understanding of the observed chemoselectivity. [19] Thea ctivation energy (DE °)c orresponding to cyclization transition states is bifurcated into distortion energy (DE dist ), which provides an energetic cost of geometric deformation and interaction energy (DE int ), which is responsible for stabilizing electronic interactions between reactants and additives in the transition state.Asshown in Figure 4, DE int is found to be stabilizing in TS FT-GT (cyclization TS of product 4a in the presence of TFE additive, DDE int = À16.3 kcal mol À1 )a sc ompared to that in TS BT-CT (DDE int = 0.0 kcal mol À1 ), presumably due to stronger H-bonding and CÀH•••p interactions (Figure S6). However, steric encumbrance from TFE leads to ag reater degree of geometrical distortion, which is evident from the significantly higher DE dist in TS FT-GT (DDE dist = 18.3 kcal mol À1 )w ith respect to TS BT-CT (DDE dist = 0.0 kcal mol À1 ), signifying that the reaction is selective due to lower extent of ring strain in TS BT-CT than in TS FT-GT .Asimilar trend was observed for the unassisted and HFIP-assisted pathways (Figure 4a nd…”