Cong Gui Zhao

Quinidine thiourea-catalyzed aldol reaction of unactivated ketones: Highly enantioselective synthesis of 3-alkyl-3-hydroxyindolin-2-ones

Aldol reaction is one of the most important carbon-carbon bond formation reactions1 and, therefore, many asymmetric variants of this reaction have been developed in the past.1 Since List and Barbas discovered the proline-catalyzed cross aldol reaction of ketones and aldehydes,2 many amine derivatives, mainly proline derivatives, have been developed for the asymmetric cross aldol reactions.3 Mechanistically, these catalysts activate the ketones or enolizable aldehydes through the formation of an enamine intermediate (Scheme 1, upper equation).3 The mechanism is usually a combination of both covalent and noncovalent catalyses since most of these catalysts also contain a hydrogen bonding moiety to direct the approach of the enamine acceptor. In contrast, although enol and enolate (Scheme 1, lower equation) are the active intermediates in the original aldol reactions,4 organocatalyzed enantioselective direct aldol reaction of unactivated ketones via the enolate mechanism is very difficult, because the acidity of the α-proton in these ketones is very low. To our knowledge, there has been no such report.5,6,7 Nevertheless, the enolate mechanism does have certain advantages, especially when the formation of an enamine is difficult. During our study of using activated ketone compounds as the enamine acceptors for the organocatalyzed aldol reactions,8 we envisioned such an organocatalyzed enolate-mediated aldol reaction should be possible if the enolate acceptor is sufficiently activated, because the equilibrium favors the formation of the product with such a substrate. Herein we wish to report the first enantioselective aldol reaction of unactivated ketones involving the enolate mechanism, which may be used for the high enantioselective synthesis of 3-alkyl-3-hydroxyindolin-2-ones.9

Enantioselective Synthesis of β-(3-Hydroxypyrazol-1-yl)ketones Using An Organocatalyzed Michael Addition Reaction

Beta-(3-hydroxypyrazol-1-yl) ketones have been prepared in high yields and excellent enantioselectivities (94-98% ee) via a Michael addition reaction between 2-pyrazolin-5-ones and aliphatic acyclic alpha,beta-unsaturated ketones using 9-epi-9-amino-9-deoxyquinine as the catalyst. These results account for the first example of an aza-Michael addition of the ambident 2-pyrazolin-5-one anion to a Michael acceptor.

Organocatalytic Enantioselective Synthesis of Both Diastereomers of α-Hydroxyphosphinates

Racemic alpha-acylphosphinates and formylphosphinate hydrate were used directly as the substrates in a proline derivative-catalyzed cross aldol reaction with ketones. Because of the preexisting phosphorus stereogenic center, a mixture of two diastereomers of the corresponding alpha-hydroxyphosphinates was obtained in this reaction. Good to high enantioselectivities (up to 99% ee) were obtained simultaneously for the two diastereomers in good yields. Good diastereoselectivities were also obtained when the reaction generates an additional carbon stereogenic center.

1-[3,5-Bis(trifluoro­meth­yl)phen­yl]-3-[(5-ethenyl-1-aza­bicyclo­[2.2.2]octan-2-yl)(6-methoxy­quinolin-4-yl)meth­yl]thio­urea–l-proline–methanol (1/1/1)

In the methanol solvate of the title 1:1 cocrystal, C29H28F6N4OS·C5H9NO2·CH4O, the l-proline molecule exists as a zwitterion. In the crystal, the disubstituted thiourea, l-proline and methanol molecules are linked by N—H⋯O and N—H⋯N hydrogen bonds, forming a two-dimensional array in the ab plane.

Ethyl [1-(4-bromo­phen­yl)-1-hydr­oxy-3-oxobut­yl](phen­yl)phosphinate monohydrate

In the title hydrate, C18H20BrO4P·H2O, a staggered conformation is found when the organic molecule is viewed down the central P—C bond, with the oxo and hydroxyl groups being diagonally opposite; each of the central P and C atoms has an S-configuration. The crystal structure features supramolecular double chains along the b axis mediated by Ohydroxyl–H⋯Ooxo, Owater–H⋯Ooxo, and Owater–H⋯Owater hydrogen bonds.

Bis(propan-2-yl) [(1S)-1-(4-fluoro­phen­yl)-1-hydr­oxy-2-nitro­ethyl]phospho­nate

In the title compound, C14H21FNO6P, a staggered conformation about the central P—C bond occurs, with the oxo and hydroxyl groups occupying diagonally opposite positions. The crystal structure features supramolecular chains mediated by O—H⋯O hydrogen bonds, which propagate in the a-axis direction. A C—H⋯O interaction consolidates the chains. Disorder was resolved for one of the isopropyl groups with a 0.60 (2):0.40 (2) occupancy ratio for the two components.

Bis(propan-2-yl) [(2S,3S)-2-hydr­oxy-3-nitro­butan-2-yl]phospho­nate

In the title compound, C10H22NO6P, a staggered conformation is found when the molecule is viewed down the central P—C bond, with the oxo and hydroxy groups gauche to each other. The crystal structure features supramolecular chains of helical topology propagating along the b axis, mediated by O—H⋯O hydrogen bonds.

(5-Ethenyl-1-aza­bicyclo­[2.2.2]octan-2-yl)(6-meth­oxy-3-quinol­yl)methanol methanol solvate

In the title methanol solvate, C20H24N2O2·CH4O, an L-shaped conformation is found as the two substituents at the central hydroxy group are almost orthogonal to each other [the C—C—C angle at the central sp 3-C atom is 110.12 (13)°]. The most notable feature of the crystal packing is the formation of supramolecular chains along the b direction mediated by O—H⋯N hydrogen bonds occurring between the hydroxy and quinoline N atoms; the methanol molecules are linked to these chains via O—H⋯Namine hydrogen bonds. C—H⋯O interactions also occur.