Takahiro Tokuyasu

Electrophilic Reactivities of α,β-Unsaturated Iminium Ions†

for amine-catalyzed additions of nucleophiles to cinnamaldehyde (1). The cycle is initiated by the condensation of the catalyst 2with the aldehyde 1 to produce the reactive iminium ion intermediate 3, which is attacked by the nucleophile in the second step. In the final step, the product is released, and the catalyst is regenerated. Despite numerous applications of the iminium ion catalysis in organic syntheses, mechanistic data, which are needed to systematically optimize known processes and explore the scope and limitations, are rare. During the preparation of this manuscript, Platts, Tomkinson et al. reported kinetic and theoretical investigations of the iminium ion catalyzed Diels–Alder reaction of cinnamaldehyde with cyclopentadiene, using 2-(trifluoromethyl)pyrrolidine as the catalyst. By studying the first two steps of the organocatalytic cycle separately, they concluded that the cycloaddition step is rate-determining under the specific reaction conditions used. The key step in Scheme 1, as in related organocatalytic cycles employing iminium catalysis, is the reaction of an iminium ion with a nucleophile. Because reactions of carbocations and Michael acceptors with C, N, O, and P nucleophiles have previously been reported to follow Equation (1), where electrophiles are characterized by one

Electrophilicities of benzaldehyde-derived iminium ions: quantification of the electrophilic activation of aldehydes by iminium formation.

Rate constants for the reactions of benzaldehyde-derived iminium ions with C-nucleophiles (enamines, silylated ketene acetals, and enol ethers) have been determined photometrically in CH3CN solution and used to determine the electrophilicity parameters E of the cations defined by the correlation log k(20°C) = s(N)(E + N) (Mayr, H.; et al. J. Am. Chem. Soc. 2001, 123, 9500-9512). With electrophilicity parameters from E = -10.69 (Ar = p-MeOC6H4) to E = -8.34 (Ar = p-CF3), the iminium ions Ar-CH═NMe2(+) have almost the same reactivities as analogously substituted arylidenemalononitriles Ar-CH═C(CN)2 and are 10 orders of magnitude more reactive than the corresponding aldehydes. The rate constants for the reactions of iminium ions with amines and water in acetonitrile are 10(3)-10(5) times faster than predicted by the quoted correlation, which is explained by the transition states which already experience the anomeric stabilization of the resulting N,N- and O,N-acetals.

Nucleophilic Reactivities of Imide and Amide Anions

The kinetics of the reactions of amide and imide anions 2a-o with benzhydrylium ions 1a-i and structurally related quinone methides 1j-q have been studied by UV-vis spectroscopy in DMSO and acetonitrile solution. The second-order rate constants (log k(2)) correlated linearly with the electrophilicity parameters E of 1a-q according to the correlation log k(2) = s(N + E) (Angew. Chem., Int. Ed. Engl. 1994, 33, 938-957), allowing us to determine the nucleophilicity parameters N and the nucleophile-specific parameters s for these nucleophiles. The reactivities of all sulfonamide and diacylimide anions are found in a relatively small range (15 < N < 22). Comparison with structurally related carbanions revealed that amide and imide anions are less reactive than carbanions of the same pK(aH). These effects can be attributed to the absence of resonance stabilization of one of the lone pairs in the amide or imide anions. As amide and imide anions are exclusively attacked at nitrogen by benzhydrylium ions, Kornblums interpretation of the ambident reactivity of amide anions has to be revised.

Synthesis of novel macrocyclic peroxides by bis(sym-collidine)iodine (I) hexafluorophosphate-mediated cyclization of unsaturated hydroperoxides and unsaturated alcohols

Bis(sym-collidine)iodine (I) hexafluorophosphate-mediated cyclization of unsaturated hydroperoxides, prepared by a variety of different methods, afforded the corresponding 10- to 20-membered macrocyclic peroxides having two or three peroxide units located within one ring in moderate yields. By analogy, cyclization of unsaturated alcohols having one or two peroxide bond in the chain afforded the corresponding cyclic ethers. The efficiency of the latter reactions were found to be a function of the structure of the alcohols.

Yingzhaosu A analogues: synthesis by the ozonolysis of unsaturated hydroperoxides, structural analysis and determination of anti-malarial activity

Abstract Ozone-mediated cyclization of a series of unsaturated hydroperoxides 7, prepared from dienes 2, afforded the corresponding yingzhaosu A analogues 9 in moderate to high yield. X-Ray crystallographic analysis of two yingzhaosu A analogues, endo-9f and 13, showed that the 2,3-dioxabicyclo[3.3.1]nonane system adopts a chair–boat arrangement. Subsequent treatment of endoperoxides 9 with Ag2O/MeI afforded the expected methyldioxy-substituted cyclic peroxides 14, several of which showed notable anti-malarial activity against P. falciparum in vitro.

The synthesis and crystal structure analysis of novel macrocyclic peroxides

Abstract Bis(syn-collidine)iodine(I) hexafluorophosphate-mediated cyclization of unsaturated hydroperoxides afforded the corresponding 11- to 16-membered macrocyclic peroxides having three peroxide units located within one ring. The crystal structures of three novel macrocyclic triperoxides were unambiguously determined by X-ray analysis.

Synthesis and anti-malarial activity of yingzhaosu A analogues from unsaturated hydroperoxy acetals

Abstract Ozonolysis of a vinyl ether 2 , prepared from dihydrocarvone 1 (a 1:4 mixture of cis - and trans -isomer), in methanol gave two isomeric unsaturated hydroperoxy acetals cis - and trans - 3 . Iodonium ion- or ozone-mediated cyclizations of the hydroperoxide cis - 3 gave the corresponding yingzhaosu A analogues 4 and 6 in moderate yields. The peroxide 8 , obtained by the Ag 2 O-mediated methylation of 6 , showed notable anti-malarial activity in vitro (IC 50 =1.0×10 −7 M).