Stereocontrol of the Intramolecular Diels−Alder Reaction by Internal Hydrogen Bonding

Abstract

A novel approach for exo/endo stereocontrol of intramolecular Diels−Alder reactions is described. Substrates carrying a hydroxymethyl group attached to the diene and an ester group attached to the dienophile participate in hydrogen bonding in the transition state. This non-covalent interaction causes either a significant enhancement or diminution in the observed kinetic endo/exo product ratio. Thus, the parent pentadienyl maleate 12 undergoes intramolecular Diels−Alder reaction to give an approx. 5:1 mixture of transand cis-fused bicyclic cycloadducts, whereas the C2-hydro-

Allylic Stereocontrol of the Intramolecular Diels–Alder Reaction

“…Fumarate 1 f underwent cycloaddition with virtually complete unlike ‐selectivity and high cis ‐selectivity, the latter feature being in stark contrast to previous findings with pentadienyl fumarates, which generally furnish mildly trans ‐selective IMDA reactions 4. 7, 10, 31, 32…”

“…In recent times, transition structures (TSs) for certain IMDA reactions have been located by using density functional theory (DFT). With reference to these TS geometries, cis/trans and π‐facial selectivities of IMDA reactions have been discussed in detail 4–10. This approach promises to greatly simplify the prediction of IMDA stereoselectivities.…”

“…To shed light upon stereoselectivities, these reactions are examined computationally by using the hybrid B3 LYP functional together with the 6–31G(d) basis set. It is generally accepted that B3 LYP/6–31G(d) models give reliable geometries of TSs and activation energies for pericyclic reactions 4–10. 18…”

Synthesis of the stereogenic triad of the halicyclamine A core

“…The reaction worked well using the conditions described by Sherburn et al .,7 affording only one diastereoisomer of the bicyclic alcohol 9 (Scheme 3). A reductive amination with benzylamine in the presence of sodium triacetoxyborohydride afforded the corresponding amine 10 (Scheme 4), the stereochemistry of which was confirmed by NMR experiments ( vide infra ).…”

“…The central concept for the synthesis was to install the three stereocenters at once using a diastereoselective intramolecular Diels-Alder reaction, taking advantage of an internal hydrogen bonding effect that was reported earlier on other substrates 7. We envisioned that a Suzuki-Miyaura cross-coupling reaction between a potassium alkenyltrifluoroborate and a 2-bromoallylic alcohol would lead to the diene, while a Wittig-Horner reaction would be utilized to construct the dienophile.…”