This work describes the first example of using chiral catalysts to control site-selectivity for the glycosylations of complex polyols such as 6-deoxyerythronolide B and oleandomycin-derived macrolactones. The regiodivergent introduction of sugars at the C3, C5, and C11 positions of macrolactones was achieved by selecting appropriate chiral acids as catalysts or through introduction of stoichiometric boronic acid-based additives. BINOL-based chiral phosphoric acids (CPAs) were used to catalyze highly selective glycosylations at the C5 positions of macrolactones (up to 99:1 rr), whereas the use of SPINOL-based CPAs resulted in selectivity switch and glycosylation of the C3 alcohol (up to 91:9 rr). Additionally, the C11 position of macrolactones was selectively functionalized through traceless protection of the C3/C5 diol with boronic acids prior to glycosylation. Investigation of the reaction mechanism for the CPA-controlled glycosylations revealed the involvement of covalently linked anomeric phosphates rather than oxocarbenium ion pairs as the reactive intermediates.

This work describes chiral phosphoric acid (CPA)-catalyzed desymmetrizative glycosylation of meso-diol derived from 2-deoxystreptamine. The chirality of CPA dictates the outcome of the glycosylation reactions, and the use of enantiomeric CPAs results in either C4-glycosylated (67 : 33 d.r.) or C6-glycosylated (86 : 14 d.r.) 2-deoxystreptamines. These glycosylated products can be converted to aminoglycosides, and the application of this strategy to the synthesis of protected iso-neamine and iso-kanamycin B with inverted connection at the C4 and C6 positions is described.

The expedient and scalable approach to cardiotonic steroids carrying oxygenation at the C11- and C19-positions has been developed and applied to the total asymmetric synthesis of steroids 19-hydroxysarmentogenin and trewianin aglycone as well as to the assembly of the panogenin core. This new approach features enantioselective organocatalytic oxidation of an aldehyde, diastereoselective Cu(OTf)2-catalyzed Michael reaction/tandem aldol cyclizations, and one-pot reduction/transposition reactions allowing a rapid (7 linear steps) assembly of a functionalized cardenolide skeleton. The ability to quickly set this steroidal core with preinstalled functional handles and diversity elements eliminates the need for difficult downstream functionalizations and substantially improves the accessibility to the entire class of cardenolides and their derivatives for biological evaluation.

A new scalable enantioselective approach to functionalized oxygenated steroids is described. This strategy is based on chiral bis(oxazoline) copper(II) complex-catalyzed enantioselective and diastereoselective Michael reactions of cyclic ketoesters and enones to install vicinal quaternary and tertiary stereocenters. In addition, the utility of copper(II) salts as highly active catalysts for the Michael reactions of traditionally unreactive β,β′-enones and substituted β,β′-ketoesters that results in unprecedented Michael adducts containing vicinal all-carbon quaternary centers is also demonstrated. The Michael adducts subsequently undergo base-promoted diastereoselective aldol cascade reactions resulting in the natural or unnatural steroid skeletons. The experimental and computational studies suggest that the torsional strain effects arising from the presence of the Δ5-unsaturation are key controlling elements for the formation of the natural cardenolide scaffold. The described method enables expedient generation of polycyclic molecules including modified steroidal scaffolds as well as challenging-to-synthesize Hajos–Parrish and Wieland–Miescher ketones.

A direct single-step hydrogenation of BINOL-based chiral phosphoric acids, N-triflyl phosphoramides, and disulfonimides to the corresponding H8-BINOL Brønsted acids in excellent yields and chemoselectivities is described. In addition, the conditions for the single-step oxidation of H8-BINOL-based Brønsted acids into the corresponding BINOL-based acids have been identified and employed to accomplish these interconversions in 41–81% yield.

A thiophosphoramide-based co-catalyst was found to significantly accelerate copper(II) trifluoromethanesulfonate-catalyzed arylation of potassium carboxylates with diaryliodonium salts. This effect could be attributed to counterion activation of diaryliodonium salts or organocopper intermediates by thiophosphoramides. Inclusion of thiophosphoramides permits achieving significantly milder reaction conditions and expands the scope of solvents and diaryliodonium counterions that could be used for the arylation of carboxylate nucleophiles.

An enantioselective synthesis of potent eukaryotic translation elongation inhibitor lactimidomycin has been accomplished in 21 linear steps. This synthesis features a Zn(II)-mediated Horner–Wadsworth–Emmons reaction that could be executed on a large scale to provide the highly strained 12-membered lactimidomycin macrolactone.

Catalytic enantioselective and diastereoselective spiroketalizations with BINOL-derived chiral phosphoric acids are reported. The chiral catalyst can override the inherent preference for the formation of thermodynamic spiroketals, and highly selective formation of nonthermodynamic spiroketals could be achieved under the reaction conditions.

Selective metalation of sulfonylphosphonates results in sufficiently stable carbanions that undergo chemoselective Julia–Kocienski condensation with various aldehydes to provide (E)-allylic phosphonates in good yields and selectivities. The subsequent Horner–Wadsworth–Emmons condensation with aldehydes is used to synthesize various unsymmetrical trans-dienes, trienes, and tetraenes. This methodology is utilized for the concise synthesis of a naturally occurring fluorescent probe for membrane properties, β-parinaric acid.

Mechanistic and computational studies were conducted to elucidate the mechanism and the origins of enantiocontrol for asymmetric chiral phosphoric acid-catalyzed spiroketalization reactions. These studies were designed to differentiate between the SN1-like, SN2-like, and covalent phosphate intermediate-based mechanisms. The chiral phosphoric acid-catalyzed spiroketalization of deuterium-labeled cyclic enol ethers revealed a highly diastereoselective syn-selective protonation/nucleophile addition, thus ruling out long-lived oxocarbenium intermediates. Hammett analysis of the reaction kinetics revealed positive charge accumulation in the transition state (ρ = −2.9). A new computational reaction exploration method along with dynamics simulations supported an asynchronous concerted mechanism with a relatively short-lived polar transition state (average lifetime = 519 ± 240 fs), which is consistent with the observed inverse secondary kinetic isotope effect of 0.85. On the basis of these studies, a transition state model explaining the observed stereochemical outcome has been proposed. This model predicts the enantioselective formation of the observed enantiomer of the product with 92% ee, which matches the experimentally observed value.

A thiophosphoramide-based co-catalyst was found to significantly accelerate copper(II) trifluoromethanesulfonate-catalyzed arylation of potassium carboxylates with diaryliodonium salts. This effect could be attributed to counterion activation of diaryliodonium salts or organocopper intermediates by thiophosphoramides. Inclusion of thiophosphoramides permits achieving significantly milder reaction conditions and expands the scope of solvents and diaryliodonium counterions that could be used for the arylation of carboxylate nucleophiles.