石川 勇人

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.

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.

Cytotrienin A (1) is a microbial antitumor secondary metabolite, isolated from a fermentation broth of Streptomyces sp. RK95-74 from soil. It possesses a (E, E, E)-triene within a 21-membered cyclic lactam which also contains four chiral centers, common structural features of the ansamycin-class of natural products, including the mycotrienins (or ansatrienins), trienomycins, thiazinotrienomycins, and trierixin. Cytotrienin A, with its unusual aminocyclopropane carboxylic acid side chain, exhibits potent apoptosis-inducing activity on HL-60 cells, with an ED_<50> value of 7.7nM. To facilitate elucidation of its mechanism of action, the development of a method for its total synthesis and derivatization is highly desirable. The first asymmetric total synthesis of (+)-cytotrienin A has been achieved, and its absolute stereochemistry has been determined. There are several noteworthy features to this total synthesis: A practical diastereo- and enantio-selective aldol reaction using novel catalyst 10 under solvent-free conditions, highly diastereoselective construction of the three contiguous chiral centers, a deoxygenation reaction without positional or E/Z isomerization (from 22 to 23), desulfonylation using NaBH_4 (from 30 to 31), control of the absolute configuration at C_<13> by proline-mediated α-aminoxylation (from 32 to 33), and RCM for the formation of the 21-membered macrolactam (from 43 to 44).

The effects of twenty proteinogenic amino acids have been investigated in the aldol reaction of aldehyde and ketone in DMSO and aqueous DMSO (in the presence of three equivalents of water). Not only proline but also other amino acids promote the aldol reaction enantioselectively. The effect of water varies with amino acid, and water does not affect the enantioselectivity in most cases, the exceptions being Pro, Ser and His. In the case of Pro, large positive effects on diastereo- and enantioselectivities were observed in the reaction of alpha-substituted methyl ketone, while no effect was observed in that of methyl ketone.

The effects of twenty proteinogenic amino acids have been investigated in the aldol reaction of aldehyde and ketone in DMSO and aqueous DMSO (in the presence of three equivalents of water). Not only proline but also other amino acids promote the aldol reaction enantioselectively. The effect of water varies with amino acid, and water does not affect the enantioselectivity in most cases, the exceptions being Pro, Ser and His. In the case of Pro, large positive effects on diastereo- and enantioselectivities were observed in the reaction of alpha-substituted methyl ketone, while no effect was observed in that of methyl ketone.

Highly enantioselective synthesis of tetra hydropyrans was accomplished via a domino proline-mediated aldol reaction/intramolecular acetal formation from an aldehyde and inexpensive aqueous tetrahydro-2H-pyran-2,6-diol as a five-carbon unit.

(Chemical Equation Presented) A chiral diaryl prolinol silyl ether organocatalyst with an acidis used for the direct catalytic asymmetric Mannich reaction of acetaldehyde and imines. N-Benzoyl-, N-tert-butoxycarbonyl-, and N-toluene-4-sulfonylimines can be employed to produce synthetically useful β-amino aldehydes in goodyield s andwith excellent enantioselectivity (see scheme). The reaction mechanism was investigated quantum-mechanically. © 2008 Wiley-VCH Verlag GmbH &amp; Co. KGaA.

(Chemical Equation Presented) A star-studded lineup: (+)-Cytotrienin A was the target of an asymmetric total synthesis featuring an enantioselective aldol reaction, α-aminoxylation, deoxygenation, and a ring-closing metathesis to form the 21-membered macrolactam. This first total synthesis confirms the relative and absolute confguration of the molecule. © 2008 Wiley-VCH Verlag GmbH &amp; Co. KGaA.

(Chemical Equation Presented) An acetaldehyde breakthrough: The catalytic asymmetric Michael addition reaction of acetaldehyde and various nitroalkenes in the presence of a chiral diphenylprolinol silyl ether organocatalyst is described (see scheme; TMS = trimethylsilyl). The desired 1,4-addition products, α-unsubstituted γ-nitro aldehydes, were obtained in good yields with excellent enantioselectivities. © 2008 Wiley-VCH Verlag GmbH &amp; Co. KGaA.

(Chemical Presented) Aza-ene reaction: Diphenylprolinol silyl ether was found to be an effective organocatalyst for the formal aza [3+3] cycloaddition reaction of a,b-unsaturated aldehydes and enecarbamates (see scheme). The reaction proceeds through an asymmetric catalytic ene reaction, isomerization, hydrolysis, and cyclization to afford piperidine derivatives in good yields and excellent enantioselectivities. © 2008 Wiley-VCH Verlag GmbH &amp; Co. KGaA.

(Chemical Equation Presented) No over-reacting: A diarylprolinol was found to be an effective organocatalyst of the direct, enantioselective aldol reaction of acetaldehyde, affording β-hydroxy α-unsubstituted aldehydes in good yield with excellent enantioselectivity (see scheme). In the proposed transition state the aldehyde reacts on the more hindered face of the intermediate enamine as a consequence of the hydrogen bond between the aldehyde and the OH group of the organocatalyst. © 2008 Wiley-VCH Verlag GmbH &amp; Co. KGaA.

A direct coupling of catharanthine with vindoline to provide vinblastine is detailed along with key mechanistic and labeling studies. Following an Fe (III)-promoted coupling reaction initiated by generation of a presumed catharanthine amine radical cation that undergoes a subsequent oxidative fragmentation and diasteroselective coupling with vindoline, addition of the resulting reaction mixture to an Fe(III)-NaBH4/air solution leads to oxidation of the C15'-C21' double bond reduction of the intermediate iminium ion directly providing vinblastine (43%) and leurosidine (23%), its naturally occuring C21' alcohol isomer. The yield of coupled products, which exclusively possess the natural C16' stereochemistry approaches or exeeds 80%, and the combined yield of the isomeric C21' alcohols is 66%.

A catalytic enantioselective direct conjugate addition of nitroalkanes to alpha,beta-unsaturated aldehydes using diphenylprolinol silyl ether as an organocatalyst has been developed. Using this methodology as a key step, short syntheses of therapeutically useful compounds have also been accomplished.

A concise synthesis of (-)- and ent-(+)-4-desacetoxy-5desethylvindoline (2), a key analogue of vindoline, is disclosed enlisting an intramolecular tandem [4+2]/[3+2] cycloaddition cascade of 1,3,4-oxadiazole (5) to assemble the pentacyclic skeleton of 2 in a single step that forms three new rings, four C-C bonds, and sets all five key stereocenters. The subsequent efforts on the elaboration of 6 to 2 revealed two subtle features key to our recent total syntheses of vindoline, vindorosine, and related natural products based on this strategy.

Treatment of indole alkaloids with hypervalent iodine in the presence of ethylene glycol provides 2,3-ethylene glycol bridged adducts that could be converted into the original indoles under mild reductive conditions. This procedure, which involves masking of the reactivity of the indole nucleus at the beta-position, was utilized for the modification of the benzene ring of the indoline derivative and was applied to the preparation of potent opioid receptor agonists with the Corynanthe skeleton.

A concise 11-step total synthesis of (-)- and ent-(+)-vindoline (3) is detailed based on a unique tandem intramolecular [4+2]/[3+2] cycloaddition cascade of a 1,3,4-oxadiazole inspired by the natural product structure, in which three rings and four C-C bonds are formed central to the characteristic pentacyclic ring system setting all six stereocenters and introducing essentially all the functionality found in the natural product in a single step. As key elements of the scope and stereochemical features of the reaction were defined, a series of related natural products of increasing complexity were also prepared by total synthesis including both enantiomers of vindorosine (4), minovine (31), 4-desacetoxy-6,7-dihydrovindorosine (32), and 4-desacetoxyvindorosine (48) as well as N-methylaspidospermidine (52). Subsequent extensions of the approach provided both enantiomers of dihydrovindoline (47), 4-desacetoxyvindoline (49), 4-desacetoxy-6,7-dihydrovindoline (50) and 4-desacetoxy-5-desethylvindoline (51).

Full details of a systematic exploration of the intramolecular [4 + 2]/[3 + 2] cycloaddition cascade of 1,3,4-oxadiazoles are disclosed in which the scope and utility of the reaction are defined. © 2006 American Chemical Society.

A concise 11-step total synthesis of (-)- and ent-(+)-vindoline (3) is detailed based on a unique tandem intramolecular [4 + 2]/[3 + 2] cycloaddition cascade of a 1,3,4-oxadiazole inspired by the natural product structure, in which three rings and four C-C bonds are formed central to the characteristic pentacyclic ring system setting all six stereocenters and introducing essentially all the functionality found in the natural product in a single step. As key elements of the scope and stereochemical features of the reaction were defined, a series of related natural products of increasing complexity were prepared by total synthesis including both enantiomers of minovine (4), 4-desacetoxy-6,7-dihydrovindorosine (5), 4-desacetoxyvindorosine (6), and vindorosine (7) as well as /V-methylaspidospermidine (11). Subsequent extensions of the approach provided both enantiomers of 6,7-dihydrovindoline (8), 4-desacetoxyvindoline (9), and 4-desacetoxy-6,7-dihydrovindoline (10). © 2006 American Chemical Society.

Mitragynine is an indole alkaloid isolated from the Thai medicinal plant Mitragyna speciosa that is reported to have opioid agonistic properties. The 9-demethyl analogue of mitragynine, 9-hydroxycorynantheidine, is synthesized from mitragynine. 9-Hydroxycorynantheidine inhibited electrically stimulated guinea-pig ileum contraction, but its maximum inhibition was weaker than that of mitragynine and its effect was antagonized by naloxone, suggesting that 9-hydroxycorynantheidine possesses partial agonist properties on opioid receptors. Receptor binding assays revealed that 9-hydroxycorynantheidine has high affinity for p-opioid receptors. In an assay of the guinea-pig ileum, naloxone shifted the concentration-response curves for [D-Ala(2), N-MePhe(4), Gly-ol(5)]-enkephalin (DAMGO), (5 alpha,7 alpha,8 beta)-(+)-N-Methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-benzeneacetamide (U69593) and 9-hydroxycorynantheidine to the right in a competitive manner. The pA(2) values of naloxone against 9-hydroxycorynantheidine and DAMGO were very similar, but not that against U69593. As indicated by the two assay systems, the opioid effect of 9-hydroxycorynantheidine is selective for the p-opioid receptor. 9-Hydroxycorynantheidine shifted the concentration-response curve for DAMGO slightly to the right. Pretreatment with the mu-opioid selective and irreversible antagonist beta-funaltorexamine hydrochloride (beta-FNA) shifted the concentration-response curve for DAMGO to the right without affecting the maximum response. On the other hand, beta-FNA did not affect the curve for 9-hydroxycorynantheidine, but decreased the maximum response because of the lack of spare receptors. These studies suggest that 9-hydroxycorynantheidine has partial agonist properties on mu-opioid receptors in the guinea-pig ileum. (c) 2005 Elsevier Inc. All rights reserved.

(Chemical Equation Presented) From tandem to pentacycle: The intramolecular tandem [4+2]/[3+2] cycloaddicycloaddition cascade of 1,3,4-oxadiazole (Z)-1 to give the pentacyclic skeleton 2 of (-)- and ent-(+)-vindorosine introduces all the requisite substituents and functionality in a single step by which three new rings and four C-C bonds form and all six key stereocenters are installed. © 2006 Wiley-VCH Verlag GmbH &amp; Co. KGaA.

7-Hydroxymitragynine is a potent opioid analgesic alkaloid isolated from the Thai medicinal herb Mitragyna speciosa, In the present study, we investigated the opioid receptor subtype responsible for the analgesic effect of this compound, [it addition. we tested whether development of tolerance, cross-tolerance to morphine and naloxone- induced withdrawal signs were observed in chronically 7-hydroxymitragynine-treated mice. Subcutaneous (s.c.) administration of 7-hydroxymitragynine produced a potent antinociceptive effect mainly through activation of mu-opioid receptors. Tolerance to the antinociceptive effect of 7-hydroxymitragynine developed as occurs to morphine, Cross-tolerance to morphine was evident in mice rendered tolerant to 7-hydroxymitragynine and vice versa. Naloxone-induced withdrawal signs were elicited equally in mice chronically treated with 7-hydroxymitragynine or morphine. 7-Hydroxymitragynine exhibited a potent antinociceptive effect based on activation of mu-opioid receptors and its morphine-like pharmacological character, but 7-hydroxymitragynine is structurally different from morphine. These interesting characters of 7-hydroxymitragynine promote further investigation of it as a novel lead compound for opioid studies, (c) 2005 Elsevier Inc. All rights reserved.

graph Two exceptionally concise total syntheses of (-)- and ent-(+)-vindoline are detailed enlisting a diastereoselective tandem [4 + 2]/[3 + 2] cycloaddition of a 1,3,4-oxadiazole. The unique reaction cascade assembles the fully functionalized pentacyclic ring system of vindoline in a single step that forms four C-C bonds and three rings while introducing all requisite functionality and setting all six stereocenters within the central ring including three contiguous and four total quaternary centers.

Recently, we found that mitragynine, a major constituent of Mitragyna speciosa, has an opioid agonistic activity, but its weak potency could not explain the opium-like effect of this plant. In the present study, bioassay-guided fractionation of the crude extract of the leaves of M. speciosa was carried out to search for potent opioid agonists other than mitragynine. Opioid agonistic activities were evaluated using twitch contraction induced by electrical stimulation in guinea-pig ileum. The crude extract of M. speciosa inhibited the twitch contraction in a concentration-dependent manner. The inhibition was reversed by naloxone. The opioid effect was detected only in the crude base fraction, which was followed by the isolation of five indole alkaloids. Among these alkaloids, 7-hydroxymitragynine showed the most potent opioid effect on the electrically-stimulated contraction (pD(2) = 8.38 +/- 0.12). The potency, calculated using pD(2) values, was 30- and 17-fold higher than that of mitragynine and morphine, respectively. Antagonism of naloxone on concentration-response curves for 7-hydroxymitragynine confirmed its opioid effect. These results suggest that the opioid effect of M. speciosa is mostly based on the activity of 7-hydroxymitragynine.

[GRAPHICS] Efficient and unusually concise total syntheses of both enantiomers of the Aspidosperma alkaloids 4-desacetoxy-6,7-dihydrovindorosine (12) and minovine (1) are detailed. A tandem intramolecular Diels-Alder/1,3-dipolar cycloaddition reaction of the 1,3,4-oxadiazole 8, in which three new rings, four new C-C bonds, and five stereocenters are formed, is a key step in the sequence. The availability of optically active material permitted an assessment of the enantiomeric integrity of minovine and the source of its reported unusual optical rotation.

The m-chloroperbenzoic acid oxidation of a Corynanthe-type indole alkaloid, mitragynine (1), in the presence of trifluoroacetic acid produced unusual dimeric compounds (3 and 4), both of which had a linkage between the C-7 and C-12' positions in the indole part of the starting material.

A new yohimbine-type indole alkaloid (1) was isolated from the stem bark of Mitragyna africanus (WILLD.) collected in Nigeria, along with known seven Corynanthe-type oxindole alkaloids, two secoiridoids, three lignans, and a quinovic acid derivative. Their structures were elucidated by spectroscopic analyses.

A new yohimbine-type indole alkaloid (1) was isolated from the stem bark of Mitragyna africanus (WILLD.) collected in Nigeria, along with known seven Corynanthe-type oxindole alkaloids, two secoiridoids, three lignans, and a quinovic acid derivative. Their structures were elucidated by spectroscopic analyses. © 2004 Pharmaceutical Society of Japan.

Mitragynine is an indole alkaloid isolated from the Thai medicinal plant Mitragyna speciosa. We previously reported the morphine-like action of mitragynine and its related compounds in the in vitro assays. In the present study, we investigated the opioid effects of 7-hydroxymitragynine, which is isolated as its novel constituent, on contraction of isolated ileum, binding of the specific ligands to opioid receptors and nociceptive stimuli in mice. In guinea-pig ileum, 7-hydroxymitragynine inhibited electrically contraction through the opioid receptors. Receptor-binding assays revealed that 7-hydroxymitragynine has a higher affinity for mu-opioid receptors relative to the other opioid receptors. Administration of 7-hydroxymitragynine (2.5-10 mg/kg, s.c.) induced dose-dependent antinociceptive effects in tail-flick and hot-plate tests in mice. Its effect was more potent than that of morphine in both tests. When orally administered, 7-hydroxymitragynine (5-10 mg/kg) showed potent antinociceptive activities in tail-flick and hot-plate tests. In contrast, only weak antinociception was observed in the case of oral administration of morphine at a dose of 20 mg/kg. It was found that 7-hydroxymitragynine is a novel opioid agonist that is structurally different from the other opioid agonists, and has potent analgesic activity when orally administered. (C) 2003 Elsevier Inc. All rights reserved.

Mitragynine (1) is a major alkaloidal component in the Thai traditional medicinal herb, Mitragyna speciosa Korth., and has been proven to exhibit analgesic activity mediated by opioid receptors. By utilizing this natural product as a lead compound, synthesis of some derivatives, evaluations of structure-activity relationship, and surveys of intrinsic activities and potencies on opioid receptors were studied, as follows. Initially, a variety of mitragynine derivatives were prepared, which included the modification of the substituent at C9 and of the indole nucleus. During this study, we found unusual dimerization reactions of indole alkaloid at C7, when phenyliodine (III) bis (trifluoroacetate) (PIFA) or Pb(OAc)_4, was used. This finding led us to develop a concise total synthesis of meso- and rac- chimonanthines (25 and 26). An indole alkaloid, mitragynaline, was first isolated from the young leaves of Malaysian Mitragyna speciosa Korth. and its chemical structure was proposed in 1991. In the present study, we concluded the structure of mitragynaline to be formula 28 by exhaustive NMR analysis at low temperature, by partial synthesis from mitragynine (1), and finally by X-ray analysis. Opioid agonistic activities of mitragynine-related compounds were evaluated by their ability to inhibit the electrically-induced twitch contraction with guinea-pig ileum preparation. Their affinities for μ,δ, and κ-receptors were determined in a receptor-binding assay. As the result, the essential structural moieties in the Corynanthe type indole alkaloids for inducing the opioid agonistic activity were clarified. It was found that the methoxy group on the indole ring at the C9 position is essential structural function for opioid agonistic activity. Interestingly, with altering the functional group at the C9 position, i.e., OMe→OH→H, of mitragynine, the activities of compounds dramatically shifted from that of full agonists through partial agonists to that of antagonists on opioid receptors. Mitragynaline (28) was found to exhibit a potent antagonist for opioid receptors. The oxidative derivatives of mitragynine, i.e., 7-hydroxymitragynine (5) and mitragynine pseudoindoxyl (19), were found as opioid agonists with higher potency than morphine in experiment with guinea pig ileum. In addition, 5 induced a potent analgesic activity in the tail flick test in mice. Especially, this compound showed remarkable antinociceptive activity at oral administration in mice. In conclusion, we could find a promising lead-molecule for the development of new type of analgesics, which were structurally different from morphine.

Hypervalent iodine(III)-induced dimerization of indole derivatives, mitragynine, tetrahydrocarbazole, and N-b-carbomethoxytryptamine, was investigated. By applying this procedure, the concise total synthesis of rac- and meso-chimonanthines was accomplished. (C) 2002 Elsevier Science Ltd. All rights reserved.

Lead tetraacetate oxidation of a Corynanthe-type indole alkaloid, mitragynine, produced mainly 7-acetoxyindolenine derivative (2) together with a dimeric compound (4) as a minor product. The novel structure having a bridge between the C-11' and C-7 positions in the respective indolenine parts and its formation mechanism were studied.

Mitragynine (1) is a major alkaloidal component in the Thai traditional medicinal herb, Mitragyna speciosa, and has been proven to exhibit analgesic activity mediated by opioid receptors. By utilizing this natural product as a lead compound, synthesis of some derivatives, evaluations of the structure-activity relationship, and surveys of the intrinsic activities and potencies on opioid receptors were performed with guinea pig ileum. The affinities of some compounds for mu-, delta-, and kappa-receptors were determined in a receptor binding assay. The essential structural moieties in the Corynanthe type indole alkaloids for inducing the opioid agonistic activity were also clarified. The oxidative derivatives of mitragynine, i.e., mitragynine pseudoindoxyl (2) and 7-hydroxymitragynine (12), were found as opioid agonists with higher potency than morphine in the experiment with guinea pig ileum. In addition, 2 induced an analgesic activity in the tail flick test in mice.

The structure of mitragynaline, an indole alkaloid isolated from Malaysian Mitragyna speciosa, was revised as formula 3 by analysis of the NMR spectra measured at low temperature and by chemical transformation with DDQ oxidation from the known alkaloid mitragynine (5). (C) 2001 Elsevier Science Ltd. All rights reserved.