Hayato Ishikawa

High‐Yielding Synthesis of the Anti‐Influenza Neuramidase Inhibitor (−)‐Oseltamivir by Three “One‐Pot” Operations

Taking shortcuts: A remarkably short and high-yielding asymmetric total synthesis of (-)-oseltamivir takes advantage of organocatalysis and single-pot domino operations. The target, known as the drug Tamiflu, is prepared efficiently in a short time, and also its derivatives can be synthesized effectively.

Asymmetric aldol reaction of acetaldehyde and isatin derivatives for the total syntheses of ent-convolutamydine E and CPC-1 and a half fragment of madindoline A and B.

The asymmetric aldol reaction of isatin derivatives and acetaldehyde has been developed using 4-hydroxydiarylprolinol as a catalyst, affording the aldol products with high enantioselectivity, these products being key intermediates in the synthesis of 3-hydroxyindole alkaloids. Short syntheses of ent-convolutamydine E and CPC-1 and a half fragment of madindoline A and B have been accomplished.

Asymmetric Diels–Alder Reactions of α,β‐Unsaturated Aldehydes Catalyzed by a Diarylprolinol Silyl Ether Salt in the Presence of Water

The Diels–Alder reaction is a powerful synthetic method for the construction of regioand stereochemically defined cyclohexane frameworks. There are several catalytic enantioselective methods, and MacMillan and co-workers developed the first Diels–Alder reaction involving an organocatalyst, which proceeds by a LUMO-lowering activation mechanism. Since then several asymmetric Diels–Alder reactions involving organocatalysts have been reported. Our group and that of Jørgensen developed a diarylprolinol silyl ether as an effective organocatalyst in 2005, and this type of catalyst has since been employed widely in several asymmetric reactions. Recently, we found that diarylprolinol silyl ether 1 combined with CF3CO2H is an effective Diels–Alder catalyst in toluene. In contrast, water has attracted a lot of interest as a reaction medium in current organic chemistry because of its unique properties. In the Diels–Alder reaction, for instance, the reaction is accelerated “in water” (homogeneous dilute conditions) and “on water” (biphasic conditions). We reported the positive effect of water on diastereoand enantioselectivities for the asymmetric aldol reaction in the presence of water. Palomo et al. and Ma and co-workers reported the enantioselective Michael reaction catalyzed by dialkyland diphenylprolinol silyl ethers, respectively in the presence of water. Some organocatalyzed reactions are known to be affected by dissolved water, and on the basis of our interest in reactions in the presence of water, we have examined the enantioselective Diels–Alder reaction by using diarylprolinol silyl ether as an organocatalyst. Although Northrup and MacMillan and Ogilvie and co-workers reported the asymmetric Diels–Alder reaction in the presence of water, we developed a green and practical procedure that does not require an organic solvent, even for the purification step. We also observed an interesting phenomenon, namely the positive effect of water on the rate and enantioselectivity of the reaction, which is different from that of the “on water” reaction and will be described herein. First, we chose the model reaction between cinnamaldehyde and cyclopentadiene, which we had found to be promoted by a combination of 1 (Figure 1) and CF3CO2H in

Diphenylprolinol silyl ether catalysis in an asymmetric formal carbo [3 + 3] cycloaddition reaction via a domino Michael/Knoevenagel condensation.

Diphenylprolinol silyl ether was found to catalyze the formal carbo [3 + 3] cycloaddition reaction through the domino reaction via the Michael reaction, followed by Knoevenagel condensation of the alpha,beta-unsaturated aldehyde and dimethyl 3-oxopentanedioate, affording substituted cyclohexenone derivatives with excellent enantioselectivity.

Oxidative and Enantioselective Cross-Coupling of Aldehydes and Nitromethane Catalyzed by Diphenylprolinol Silyl Ether

Activation of the C H bond and transformation of this bond into a new C C bond is one of the fundamental transformations in organic chemistry. 2] Recently, great progress has been achieved in the field of the activation of unreactive C H bonds, in which organometallic reagents play a central role. Moreover, it is one of the great synthetic challenges not only to transform the unreactive C H bond into a new C C bond but also to control the absolute configuration of the newly generated stereogenic center. There are many methods for the transformation of a C H bond at the a position of an aldehyde that involve an enolate as a reactive intermediate [Eq. (1)]. On the other hand, the substitution of a proton at the b-carbon atom of the aldehyde with a functional group in a one-pot operation—this oper-

Dimerization of indole derivatives with hypervalent iodines(III): a new entry for the concise total synthesis of rac- and meso -chimonanthines

Abstract Hypervalent iodine(III)-induced dimerization of indole derivatives, mitragynine, tetrahydrocarbazole, and Nb-carbomethoxytryptamine, was investigated. By applying this procedure, the concise total synthesis of rac- and meso-chimonanthines was accomplished.

Enantio- and diastereoselective synthesis of piperidines by coupling of four components in a "one-pot" sequence involving diphenylprolinol silyl ether mediated Michael reaction.

An efficient, asymmetric, four-component, one-pot synthesis of highly substituted piperidines with excellent diastereo- and enantioselectivity was established through the diphenylprolinol silyl ether mediated Michael reaction of aldehyde and nitroalkene, followed by the domino aza-Henry reaction/hemiaminalization reaction and a Lewis acid mediated allylation or cyanation reaction. All carbons of the piperidine ring are substituted with different groups, and its five contiguous stereocenters are completely controlled in both relative and absolute senses.

Polymeric Ethyl Glyoxylate in an Asymmetric Aldol Reaction Catalyzed by Diarylprolinol

Diarylprolinol was found to be an effective organocatalyst of the direct, enantioselective aldol reaction of commercially available polymeric ethyl glyoxylate, affording gamma-ethoxycarbonyl-beta-hydroxy aldehydes, versatile synthetic intermediates, in good yield with excellent enantioselectivity.

Asymmetric, catalytic, and direct self-aldol reaction of acetaldehyde catalyzed by diarylprolinol.

An asymmetric, catalytic, and direct self-aldol reaction of acetaldehyde was catalyzed by diarylprolinol in NMP, affording the trimer acetal, which was generated by the reaction of the self-aldol product with another acetaldehyde molecule in a moderate yield with good enantioselectivity. Acetal is the synthetic equivalent of the self-aldol product, which can be converted into other synthetically useful compounds in one pot without compromising the enantioselectivity.

One‐Pot Synthesis of (−)‐Oseltamivir and Mechanistic Insights into the Organocatalyzed Michael Reaction

The one-pot sequential synthesis of (-)-oseltamivir has been achieved without evaporation or solvent exchange in 36% yield over seven reactions. The key step was the asymmetric Michael reaction of pentan-3-yloxyacetaldehyde with (Z)-N-2-nitroethenylacetamide, catalyzed by a diphenylprolinol silyl ether. The use of a bulky O-silyl-substituted diphenylprolinol catalyst, chlorobenzene as a solvent, and HCO2 H as an acid additive, were key to produce the first Michael adduct in both excellent yield and excellent diastereo- and enantioselectivity. Investigation into the effect of acid demonstrated that an acid additive accelerates not only the E-Z isomerization of the enamines derived from pentan-3-yloxyacetaldehyde with diphenylprolinol silyl ether, but also ring opening of the cyclobutane intermediate and the addition reaction of the enamine to (Z)-N-2-nitroethenylacetamide. The transition-state model for the Michael reaction of pentan-3-yloxyacetaldehyde with (Z)-N-2-nitroethenylacetamide was proposed by consideration of the absolute configuration of the major and minor isomers of the Michael product with the results of the Michael reaction of pentan-3-yloxyacetaldehyde with phenylmaleimide and naphthoquinone.