The stereoselective access to stereotriads as important polyketide building blocks is reported on the basis of the Krische-type hydrogen-mediated syn-crotylation. The products were obtained with an extremely high diastereoselectivity (dr >99:1), and the newly formed syn stereocenters were controlled solely by the chiral catalyst. The stereochemistry was assigned by crystallography and HPLC for both product manifolds. This extension of the burgeoning transfer hydrogen methodology gives divergent asymmetric access to anti,syn and syn,syn polyketide stereotriads from the same α-chiral starting material and avoids potentially epimerizable aldehyde intermediates.
The asymmetric total synthesis of the polyketide benzannulated spiroketal natural product, (-)-peniphenone A, is reported. The key reaction in the synthesis involved sp-sp Negishi cross-coupling between a chiral organozinc species and an aryl bromide to construct the challenging α-chiral β-aryl carbonyl motif present in the natural product. Access to the spiroketal possessing the correct stereochemistry was facilitated by an unusual thermodynamic resolution at C10. The synthesis was achieved in 14 steps (longest linear sequence) from commercially available 2,4-dihydroxybenzaldehyde in 6% overall yield. Investigations into a parallel approach required extension of Krische's enantioselective hydrogen-mediated C-C coupling to α-substituted alcohols and oxetane ring-opening with an aryllithium for assembly of the polyketide domain. These studies provide a useful foundation for further work toward the natural product family, members of which demonstrate significant activity against M. tuberculosis and offer continuing inspiration for the development of efficient new chemical methods.
A family of nonsymmetrical Mitsunobu reagents possessing both dialkyl amide and ester substituents was developed. These new reagents were readily prepared in a single pot from inexpensive, commercially available materials by using a scalable and environmentally friendly procedure. They were shown to exhibit activity parallel to that of diethyl azodicarboxylate/diisopropyl azodicarboxylate in a wide variety of Mitsunobu reactions. Importantly, the acyl hydrazine reaction byproducts were readily separable from the crude mixture by standard aqueous workup. In addition, the discovery of effective nonsymmetrical Mitsunobu reagents offers new directions for the ongoing development of this important reaction.
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