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 S(N)1-like, S(N)2-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.
This study describes a new convenient method for the photocatalytic generation of glycosyl fluorides using sulfur(VI) hexafluoride as an inexpensive and safe fluorinating agent and 4,4′dimethoxybenzophenone as a readily available organic photocatalyst. This mild method was employed to generate 16 different glycosyl fluorides, including the substrates with acid and base labile functionalities, in yields of 43%−97%, and it was applied in continuous flow to accomplish fluorination on an 7.7 g scale and 93% yield.
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 ββ′-enones and substituted ββ′-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 controling 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.
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.
This article describes studies on
the regioselective acetal protection
of monosaccharide-based diols using chiral phosphoric acids (CPAs)
and their immobilized polymeric variants, (R)-Ad-TRIP-PS
and (S)-SPINOL-PS, as the catalysts. These catalyst-controlled
regioselective acetalizations were found to proceed with high regioselectivities
(up to >25:1 rr) on various d-glucose-, d-galactose-, d-mannose-, and l-fucose-derived 1,2-diols and could
be carried out in a regiodivergent fashion depending on the choice
of chiral catalyst. The polymeric catalysts were conveniently recycled
and reused multiple times for gram-scale functionalizations with catalytic
loadings as low as 0.1 mol %, and their performance was often found
to be superior to the performance of their monomeric variants. These
regioselective CPA-catalyzed acetalizations were successfully combined
with common hydroxyl group functionalizations as single-pot telescoped
procedures to produce 32 regioisomerically pure differentially protected
mono- and disaccharide derivatives. To further demonstrate the utility
of the polymeric catalysts, the same batch of (R)-Ad-TRIP-PS
catalyst was recycled and reused to accomplish single-pot gram-scale
syntheses of 6 differentially protected d-glucose derivatives.
The subsequent exploration of the reaction mechanism using NMR studies
of deuterated and nondeuterated substrates revealed that low-temperature
acetalizations happen via a syn-addition mechanism
and that the reaction regioselectivity exhibits strong dependence
on the temperature. The computational studies indicate a complex temperature-dependent
interplay of two reaction mechanisms, one involving an anomeric phosphate
intermediate and another via concerted asynchronous formation of an
acetal, that results in syn-addition products. The
computational models also explain the steric factors responsible for
the observed C2 selectivities and are consistent with experimentally
observed selectivity trends.
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