Theoretical study to explain how chirality is stored and evolves throughout the radical cascade rearrangement of enyne-allenes.

This article reports a theoretical study to explain how the intrinsic property of chirality is retained throughout the radical cascade rearrangement of an enantiopure chiral enyne-allene (bearing one stereogenic center) selected as a model for this family of reactions. Calculations at the MRPT2/6-31G(d)//CASSCF(10,10)/6-31G(d) level of theory were used to determine the entire reaction pathway which includes singlet state diradicals and closed-shell species. The cascade process involves three elementary steps, i.e., by chronological order: Myers-Saito cycloaromatization (M-S), intramolecular hydrogen atom transfer (HAT), and recombination of the resulting biradical. The enantiospecificity of the reaction results from a double transmission of the stereochemical information, from the original center to an axis and eventually from this axis to the final center. The first two steps lead to a transient diradical intermediate which retains the chirality via the conversion of the original static chirogenic element into a dynamic one, i.e., a center into an axis. The only available routes to the final closed-shell tetracyclic product imply rotations around two σ bonds (σ(C-C) and σ(C-N), bonds ß and α respectively). The theoretical calculations confirmed that the formation of the enantiomerically pure product proceeds via the nonracemizing rotation around the σ(C-C) pivot. They ruled out any rotation around the second σ(C-N) pivot. The high level of configurational memory in this rearrangement relies on the steric impediment to the rotation around the C-N bond in the chiral native conformation of the diradical intermediate produced from tandem M-S/1,5-HAT.

Axial-to-central chirality transfer in cyclization processes.

Substrates, bearing axial chirality, can cyclize intra- or inter-molecularly with concomitant transfer of axial-to-central chirality to produce at least one stereocenter. In order to satisfy a strict definition of axial-to-central chirality transfer, the initial axial chirality must be lost during the cyclization process. Highly functionalized enantiopure carbocycles and heterocycles were prepared using this strategy. The transformations of configurationally stable substrates take place with high regio- and stereo-selectivity. Selected examples involving allenes, biaryls, arylamides and transient axially chiral short-lived species are discussed. Special attention is focused on the mechanistic rationale of the chirality transfer.

Double transfer of chirality in organocopper-mediated bis(alkylating) cycloisomerization of enediynes.

An original synthesis of chiral benzofulvenes triggered by organocopper reagents is reported. These enantiopure products are available through a highly chemo-, regio-, diastereo-, and enantioselective bis(alkylating) cycloisomerization process. A double chirality transfer (central-to-axial-to-central) is observed.

Cooperative use of VCD and XRD for the determination of tetrahydrobenzoisoquinolines absolute configuration: a reliable proof of memory of chirality and retention of configuration in enediyne rearrangements.

The absolute configurations (AC) of azaheterocylic compounds resulting from the cascade rearrangement of enediynes involving only light atoms were unambiguously assigned by the joint use of vibrational circular dichroism (VCD) and copper radiation single crystal X-ray diffraction (XRD). These AC determinations proved that the rearrangements of enediynes proceeded with memory of chirality and retention of configuration.

Mechanistic investigation of enediyne-connected amino ester rearrangement. Theoretical rationale for the exclusive preference for 1,6- or 1,5-hydrogen atom transfer depending on the substrate. A potential route to chiral naphthoazepines.

Memory of chirality (MOC) and deuterium-labeling studies were used to demonstrate that the cascade rearrangement of enediyne-connected amino esters 1a and 1b evolved through exclusive 1,5- or 1,6-hydrogen atom transfer, subsequent to 1,3-proton shift and Saito-Myers cyclization, depending on the structure of the starting material. These results were independently confirmed by DFT theoretical calculations performed on model monoradicals. These calculations clearly demonstrate that in the alanine series, 1,5-hydrogen shift is kinetically favored over 1,6-hydrogen shift because of its greater exergonicity. In the valine series, the bulk of the substituent at the nitrogen atom has a major influence on the fate of the reaction. N-Tosylation increases the barrier to 1,5-hydrogen shift to the benefit of 1,6-hydrogen shift. The ready availability of 1,6-hydrogen atom transfer was explored as a potential route for the enantioselective synthesis of naphthoazepines.

Memory of chirality in cascade rearrangements of enediynes.

The cascade rearrangement of chiral enediynes 1c-e, involving successively 1,3-proton shift, Saito-Myers cyclization, 1,5-hydrogen atom transfer, and intramolecular coupling of the resulting biradical, proceeded at 80 °C to form tri- and tetracyclic heterocycles possessing a quaternary stereogenic center with a very high level of memory of chirality.

An efficient and recyclable hybrid nanocatalyst to promote enantioselective radical cascade rearrangements of enediynes.

Mesoporous silica grafted with a tertiary amine was used as a basic nanocatalyst to promote in confined medium the enantioselective cascade rearrangement of enediynes based on the phenomenon of memory of chirality; the multi-substrates recyclable catalytic reagent could easily be recovered by simple filtration, and reused without any decrease in activity even when changing the solvent.