Hiroaki Gotoh

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.

New Insights into the Mechanism and an Expanded Scope of the Fe(III)-Mediated Vinblastine Coupling Reaction

A definition of the scope of aromatic substrates that participate with catharanthine in an Fe(III)-mediated coupling reaction, an examination of the key structural features of catharanthine required for participation in the reaction, and the development of a generalized indole functionalization reaction that bears little structural relationship to catharanthine itself are detailed. In addition to providing insights into the mechanism of the Fe(III)-mediated coupling reaction of catharanthine with vindoline suggesting the reaction conducted in acidic aqueous buffer may be radical mediated, the studies provide new opportunities for the preparation of previously inaccessible vinblastine analogs and define powerful new methodology for the synthesis of indole-containing natural and unnatural products.

A Theoretical and Experimental Study of the Effects of Silyl Substituents in Enantioselective Reactions Catalyzed by Diphenylprolinol Silyl Ether

The effect of silyl substituents in diphenylprolinol silyl ether catalysts was investigated. Mechanistically, reactions catalyzed by diphenylprolinol silyl ether can be categorized into three types: two that involve an iminium ion intermediate, such as for the Michael-type reaction (type A) and the cycloaddition reaction (type B), and one that proceeds via an enamine intermediate (type C). In the Michael-type reaction via iminium ions (type A), excellent enantioselectivity is realized when the catalyst with a bulky silyl moiety is employed, in which efficient shielding of a diastereotopic face of the iminium ion is directed by the bulky silyl moiety. In the cycloaddition reaction of iminium ions (type B) and reactions via enamines (type C), excellent enantioselectivity is obtained even when the silyl group is less bulky and, in this case, too much bulk reduces the reaction rate. In other cases, the yield increases when diphenylprolinol silyl ethers with bulky substituents are employed, presumably by suppressing side reactions between the nucleophilic catalyst and the reagent. The conformational behaviors of the iminium and enamine species have been determined by theoretical calculations. These data explain the effect of the bulkiness of the silyl substituent on the enantioselectivity and reactivity of the catalysts.

Organocatalytic, Enantioselective Intramolecular [6 + 2] Cycloaddition Reaction for the Formation of Tricyclopentanoids and Insight on Its Mechanism from a Computational Study

Diphenylprolinol silyl ether was found to be an effective organocatalyst for promoting the asymmetric, catalytic, intramolecular [6 + 2] cycloaddition reactions of fulvenes substituted at the exocyclic 6-position with a δ-formylalkyl group to afford synthetically useful linear triquinane derivatives in good yields and excellent enantioselectivities. The cis-fused triquinane derivatives were obtained exclusively; the trans-fused isomers were not detected among the reaction products. The intramolecular [6 + 2] cycloaddition occurs between the fulvene functionality (6π) and the enamine double bond (2π) generated from the formyl group in the substrates and the diphenylprolinol silyl ether. The absolute configuration of the reaction products was determined by vibrational circular dichroism. The reaction mechanism was investigated using molecular orbital calculations, B3LYP and MP2 geometry optimizations, and subsequent single-point energy evaluations on model reaction sequences. These calculations revealed the following: (i) The intermolecular [6 + 2] cycloaddition of a fulvene and an enamine double bond proceeds in a stepwise mechanism via a zwitterionic intermediate. (ii) On the other hand, the intramolecular [6 + 2] cycloaddition leading to the cis-fused triquinane skeleton proceeds in a concerted mechanism via a highly asynchronous transition state. (iii) The fulvene functionality and the enamine double bond adopt the gauche-syn conformation during the C-C bond formation processes in the [6 + 2] cycloaddition. (iv) The energy profiles calculated for the intramolecular reaction explain the observed exclusive formation of the cis-fused triquinane derivatives in the [6 + 2] cycloaddition reactions. The reasons for the enantioselectivity seen in these [6 + 2] cycloaddition reactions are also discussed.

Two Reaction Mechanisms via Iminium Ion Intermediates: The Different Reactivities of Diphenylprolinol Silyl Ether and Trifluoromethyl‐Substituted Diarylprolinol Silyl Ether

The reactions of α,β-unsaturated aldehydes with cyclopentadiene in the presence of diarylprolinol silyl ethers as catalyst proceed via iminium cations as intermediates, and can be divided into two types; one involving a Michael-type reaction (type A) and one involving a cycloaddition (type B). Diphenylprolinol silyl ethers and trifluoromethyl-substituted diarylprolinol silyl ethers, which are widely used proline-type organocatalysts, have been investigated in this study. As the LUMO of the iminium ion derived from trifluoromethyl-substituted diarylprolinol silyl ether is lower in energy than that derived from diphenylprolinol silyl ether, as supported by ab initio calculations, the trifluoromethyl-substituted catalyst is more reactive in a type B reaction. The iminium ion from an α,β-unsaturated aldehyde is generated more quickly with diphenylprolinol silyl ether than with the trifluoromethyl-substituted diarylprolinol silyl ether. When the generation of the iminium ion is the rate-determining step, the diphenylprolinol silyl ether catalyst is the more reactive. Because acid accelerates the generation of iminium ions and reduces the generation of anionic nucleophiles in the Michael-type reaction (type A), it is necessary to select the appropriate acid for specific reactions. In general, diphenylprolinol silyl ether is a superior catalyst for type A reactions, whereas the trifluoromethyl-substituted diarylprolinol silyl ether catalyst is preferred for type B reactions.

Scavenging and characterization of short-lived radicals using a novel stable nitroxide radical with a characteristic UV-vis absorption spectrum.

A stable tert-butyl(10-phenyl-9-anthryl)nitroxide (BPAN) radical was newly synthesized and used for the capture/characterization of reactive radicals. Adducts obtained from the reactions of BPAN with in situ generated reactive radicals showed excellent stability, assuring complete isolation and purification. The structures of the adducts were established by LC-MS and NMR analyses.

Trapping chlorine radicals via substituting nitro radicals in the gas phase

Although chlorine radicals are strong atmospheric oxidants, their direct spectroscopic detection in the environment (gas phase) using conventional analytical techniques has not been reported. Herein, chlorine radicals (Cl˙), generated by the YAG laser photolysis (λ = 355 nm) of Cl2 in the gas phase, were captured by using 2,2-diphenyl-1-picrylhydrazyl (DPPH˙). The product was identified as DPPH, wherein NO2 was substituted by Cl˙ at the ortho-carbon on the picryl aromatic ring, and was characterized using ion attachment ionization-quadrupole mass spectrometry. This reaction mechanism is a rare example of the detection and characterization of radical species, where radical spin densities on trapping reagents and frontier orbital interactions play important roles.

6.5 C–C Bond Formation: Aldol Reaction with Non-Proline Derivatives

The aldol reaction is one of the most important carbon–carbon bond-forming reactions in organic synthesis. Since the discovery of intra- and intermolecular aldol reactions catalyzed by proline, organocatalyst-mediated aldol reactions have been developed extensively. Currently, asymmetric organocatalytic aldol reactions can be classified into four major categories, differentiated by their reaction mechanisms: (1) enamine mechanisms; (2) ion-pair mechanisms; (3) chiral enolate mechanisms; and (4) electron acceptor activation by Bronsted acids. In this chapter, the authors describe these four types of aldol reactions; herein, the authors limit their discussion to reactions catalyzed by nonproline derivatives, whereas in the previous chapter, aldol reactions catalyzed by proline and proline derivatives are reviewed.