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The Bronsted acid-catalyzed Diels-Alder reaction was examined. Phosphoric acids were effective Bronsted acids for the Diels-Alder reaction of cyclohexadienones and activated by the internal hydrogen-bonding of the adjacent hydroxy group.

For the purpose of synthesizing daphnezomine C, model systems were examined to see if the ring-closing metathesis (RCM) reaction could be applied to prepare an 11-membered ring system bearing a tri...

A stereoselective total synthesis of scyphostatin is described. The hydrophilic moiety was stereoselectively synthesized via (i) a highly pi-facially selective Diels-Alder reaction of a spirolactone generated from L-tyrosine and (ii) a hydroxy group directed epoxidation as key reactions. The hydrophilic moiety was combined with the hydrophobic side chain in the final stage. Total synthesis was achieved by overcoming the instability of the C5-C6 epoxide ring with carefully executed mild reactions. In the course of this work, it was revealed that we had mistakenly assigned the relative stereochemistry of the C5-C6 epoxide ring of the end product in our previous model study. Revision of the stereochemical assignment in the model study is described. A diastereomer of (+)-scyphostatin epimeric at C5 and C6 (the epoxide region) was also synthesized.

In order to elucidate the nature of a novel lipase (CSL), isolated from the yeast Cryptococcus spp. S-2, in chiral recognition by comparison with that of immobilized PPL, the desymmetrization and asymmetrization of prochiral 2-phenyl-1,3-propanediol (1a), 2-benzyl-1,3-propanediol (1b), 2-methyl-2-phenyl-1,3-propanediol (1c), 2-benzyl-2-methyl-1,3-propanediol (1d), 2-ethyl-2-phenyl-1,3-propanediol (1e), and 2-benzyl-2-ethyl-1,3-propanediol (1f) by acetylation was investigated. Acetylation of 1a with excess vinyl acetate by the CSL-enzyme catalyst gave the corresponding monoacetate 2a with high enantioselectivity (80% ee) in 46% yield. Very high levels of desymmetrization were observed in the tertiary systems of 1c–f, giving the corresponding monoacetates 2c–f, respectively, in >97%. In the desymmetrization of diols 1a, 1c, 1d, and 1f, the sense of chiral differentiation of CSL was opposite to that of immobilized porcine pancreatic lipase (PPL).

The effect of temperature on enantioselectivity and desymmetrization in the acetylation of 2-phenyl-1,3-propanediol (1a), 2-benzyl-1,3-propanediol (1b), 2-methyl-2-phenyl-1,3-propanediol (1c) and 2-benzyl-2-methyl-1,3-propanediol (1d) by a novel lipase (CSL) isolated from the yeast Cryptococcus spp. S-2 was studied. Desymmetrization of 1a, 1c and 1d by CSL-catalyzed acetylation was observed in the temperature range of −20°C to 40°C, while diacetylation of 1b occurred considerably even at 0°C. The kinetic parameters of the selectivity indicated that the acetylation of 1a is an entropy controlled process whereas the reaction of 1c and 1d is mainly controlled by the enthalpy term. In the monoacetylation of the diol 1d, the preferred configuration in the enantiomeric induction by CSL was opposite to that of immobilized porcine pancreatic lipase (PPL).

The enzymatic hydrolysis of dipeptides by carboxypeptidase-Y and carboxypeptidase-A was investigated. In the enzymatic hydrolysis of the dipeptides, a good linear relationship (r = 0.997 and 0.999)...

The influence of solvent viscosity on the rate of enzymatic hydrolysis of a series of dipeptides (Z-Phe-Gly, Z-Phe-Sar, Z-Phe-Ala, Z-Phe-NMeAla, Z-Phe-Aib and Z-Phe-Pro) by carboxypeptidase Y was investigated. The effect of solvent viscosity on the enzymatic hydrolysis revealed that whereas all kcat values decreased with viscosity, those of the N-alkyl peptides decreased more than those of the N-H peptides. The kinetic behaviour implies the involvement of conformational changes of the enzyme in terms of the ‘induced-fit’ process. Copyright © 2004 John Wiley & Sons, Ltd.

The reaction between an α-pyridinium acetamide bearing an 8-phenylmenthyl group as the chiral auxiliary and β-substituted methylidenemalononitriles gave rise to trans-cyclopropanes with diastereomeric ratios of up to 98:2. For most of the reactions, the absolute stereochemistry of the major product was found to be opposite of that of the major products of the reaction of the corresponding ester series, which also utilized the 8-phenylmenthyl group.

The Horner-Wadsworth-Emmons reaction of diphenylphosphonoacetamides [(PhO) 2 P(O)CH 2 CONRR'] ( 2a : R, R' = CH 2 Ph; 2b : R = CH 2 Ph, R' = H; 2c : R = Me, R' = OMe) was examined. The reaction of ...

The cyclopropanation of (−)-8-phenylmenthyl (E)-3-aryl-2-phosphonoacrylates E-3a–d with dimethyloxosulfonium methylide and diazomethane affords the corresponding trans cyclopropane derivatives as the major diastereomers with high diastereoselectivity. On the other hand, the cyclopropanation of (−)-8-phenylmenthyl (Z)-3-aryl-2-phosphonoacrylates Z-3a–d and (−)-menthyl derivative 4 gives mixtures of cis and trans cyclopropane derivatives with low diastereoselectivity. The high diastereoselectivity in the cyclopropanation of (E)-acrylates E-3a–d can be rationalized by considering the π–π interaction between the phenyl ring of the chiral auxiliary and the acrylate moiety in the s-cis conformer. The low selectivity in the cyclopropanation of (Z)-acrylates (Z-3a–d and 4) can be attributed to a low-lying conformer with the acrylate moiety twisted out of conjugation.

The synthesis of 2,5-disubstituted tetrahydropyrans bearing a hydrophobic moiety at the C5 position from (E)- and (Z)-7-hydroxy-6-substituted 2,3-unsaturated esters by way of intramolecular nucleop...

The cyclopropanation of (−)-8-phenylmenthyl (E)-3-aryl-2-phosphonoacrylates with dimethyloxosulfonium methylide and diazomethane afforded the corresponding trans cyclopropane derivatives with high diastereoselectivity as the major diastereomer. The high selectivity is understandable in terms of the π–π interaction between the phenyl ring of the chiral auxiliary and the acrylate moiety.

The reaction of various mono-substituted methylidenemalononitriles with (−)-8-phenylmenthyl α-pyridiniumacetate in the presence of base afforded the corresponding dicyanocyclopropane compounds with exclusive trans -selectivity and good diastereoselectivity (up to 86:14). The stereochemistry of the major products were determined to be of 1 R configuration by X-ray structural analysis of the crystalline trans -2,2-dicyano-3-(4-pyridyl)cyclopropanecarboxylate. The geometric and diastereofacial selectivities were rationalized assuming anti -periplanar approach in the open-chain model, followed by epimerization and then cyclization to give the cyclopropane compounds.

Catalysts, oligo-L-leucine, for the Julia-Colonna asymmetric epoxidation of chalcone with defined degrees of polymerization were prepared by a stepwise elongation method. The yield and enantioselectivity in the epoxidation increased with the degree of polymerization of the catalyst. The presence of an unprotected amine moiety at the N-terminus proved to be essential for high asymmetric induction. The IR characteristic absorption bands (the amide I region) of the catalysts suggested that helical structure in the catalyst is related to asymmetric induction.

rac-Hippospongic acid A of the reported structure 1 and the revised structure 2 were synthesized. The synthetic strategy of these compounds consists of homologation of (2E,6E,10E)-geranylgeraniol and (2E,6E)-farnesol, respectively, Wadsworth–Emmons reaction, and cyclization to form the tetrahydropyran ring bearing an α-methylene group on the carboxylic moiety. Spectral comparisons of the synthetic compounds 1, 2 and the natural product suggested that hippospongic acid A bears the structure of 2.

Rhopaloic acid A (+)-1 and the related compounds (–)-ent-1 and (±)-rac-1 have been stereoselectively synthesized. The synthetic strategy consists of successive homologation of (2E,6E)-farnesol 7 and cyclization to form a tetrahydropyran ring, together with final introduction of an α-methylene group on the carboxylic moiety. The cyclization is carried out by intramolecular hetero-Michael addition leading to 2,5-disubstituted tetrahydropyrans. The stereochemistry can be rationalized by invoking a model of a chair-like transition state. The asymmetric synthesis is achieved by way of the Evans’ asymmetric alkylation procedure using (S)- or (R)-4-benzyloxazolidin-2-one as the chiral auxiliary. In the event, the configuration of natural rhopaloic acid A (+)-1 could be assigned as 2R,5S by comparison of the specific rotations of synthetic compounds with that of the natural product.

Asymmetric Darzens condensation of benzaldehyde and various ketones has been investigated. The condensation of acetophenone, propiophenone and symmetric ketones with (–)-8-phenylmenthyl halogenoacetates 3a,b afforded the corresponding glycidic esters cis-12, cis-13 and 15–19 in 77–96% de, respectively, as the major products. Aza-Darzens condensation between N-benzylideneaniline and 3a occurred to give the trans-aziridine 21 as the major isomer in >85% de. The stereochemistry of the major diastereoisomers of cis-12 and 18 was confirmed by their conversion into the known optically active diols 22 and 24. The configuration of the major product of cis-12 was determined to be 2R,3R and that of 18 to be 2R. The geometric and disastereofacial selectivities were understandable in terms of the open-chain or non-chelated antiperiplanar transition state model in the initial aldol-type reaction.

(-)-Loliolide (1) showing an inhibitory activity for lettuce seed germination was isolated from leaves of Equisetum arvense. It is rare that this active compound occurred from the family Equisetaceae.

Adamantane derivatives were constructed by the one-pot reaction of ethyl 2,4-dioxocyclohexanecarboxylate with 2-phenylethyl 2-(acetoxymethyl)acrylate or 2-(acetoxymethyl)-1-phenyl-2-propen-1-one via domino Michael reactions and a Dieckmann condensation or an aldol-type reaction (four-bond formation). This is the first one-pot construction of adamantane derivatives from cyclohexanone derivatives not involving enamines.

A series of neutral (8−10), monomethylated (12−14), and dimethylated (17) 10-S-3 sulfuranes, derivatives of tetraazathiapentalenes fused with pyrimidine and/or pyridine ring, were prepared. These molecules are planar, and bond energies of the hypervalent N−S−N bond were evaluated by the temperature dependent restricted rotation of the pyrimidine ring caused by cleavage of one of the S−N bonds. The bond length is longer, and the energy is lower for the S−N bond fused with more electron-withdrawing heterocycles.

The essentially complete (>99%) asymmetric Diels-Alder reactions were achieved between 3-(8-phenylmenthyloxycarbonyl)coumarin ( 1c ) and 1,3-butadienes ( 2a–c ) in high chemical yields.

The mechanism we propose for the cyclopentane annulation is the following one. The allylic reagent (5D) attacks the siloxypyrylium salts (2a,b) at the C2 position, giving the intermediate carbocation (B) which is stabilized by the trimethylsilyl and the methyl group. Attack by the emerging enolate at C 3 , forms the five-membered ring compound (8a,b). Generally, electrophiles attack allylic silanes anti to the silyl group. Since there is undoubtedly interaction with the silicon in the transition state, the stereochemistry of the bridged intermediate (B) should be trans geometry due to stereoelectronic effect and allylic 1,3-strain. In the reaction of 2a, the favored pathway is cyclization. However, competition between cyclization and desilylation was observed in 2b due to steric hindrance between the two methyl groups at the step of cyclization

The reactions of allylstannanes with 4-siloxy-1-benzopyrylium salts gave the corresponding allylated derivatives more smoothly than allylsilanes. Similar reactions with 3-trimethylsilyl-1-butene afforded unexpected five-membered ring adducts in 87% and 37% yields, respectively.

Some 5H,7H-dibenzo[b,g][1,5]dithiocin oxides (4–8) and their related compounds 9–13 were prepared and the assignment of the most favorable conformation was carried out on the basis of the characteristic 1H NMR spectral data. Only a single conformer (BC: boatchair form) exists for 4,5, and 8–13, while two conformers (BC and TB: twist-boat form) are apparent for 6 and 7. Oxidation and methylation of 4 gave exclusively a single geometrical isomer (8 and 13, respectively). These results are interpreted as a sterically preferential attack of electrophiles on the BC conformer of the starting material. A 1,5-oxygen shift of 4 occurred smoothly to give 6 in the presence of trifluoroacetic acid in CDCl3 solution. The mechanistic investigation is described briefly. Differences in chemical behavior between dibenzodithiocin 12-oxide 4 and dibenzothiazocine 12-oxide 2 are also discussed on the basis of the conformational features.

A series of 10-S-3 type sulfuranes, tetraazathiapentalenes (10a-i, 11a-f, 12, and 17) fused with pyrimidine ring and/or pyridine ring, were prepared by oxidation of the corresponding thioureas. The restricted internal rotation of the pyrimidine ring was observed by temperature dependent 1H NMR spectrum which gave the kinetic parameters of ΔG298_??_=16.6kcal/mol, ΔH=15.9kcal/mol, and ΔS_??_=-2.4 eu at 25°C for the rotational barrier in 10a. The substituent effect to the kinetic data can be reasonably explained in terms of electronic balance of the N-S-N hypervalent bond or the different degree of contribution of resonance canonical structures. Comparison of the rotational barrier of 10a with that of model compounds (18 and 24) suggests that hypervalent N-S-N stabilization in 10a is more than 6kcal/mol. Methylation of these 10-S-3 type sulfuranes (10a, 10d, and 11a) was investigated to clarify the electronic effect in these molecules. The crystal structure of the neutral symmetric sulfurane 10a reveals to be a planar molecule in which the sulfur atom was found to be in the same plane of the two pyrimidine rings. The S-N bond lengths 1.948(3) and 1.938(3) A are longer than the sum of the covalent bond radii, consistent with a bond order less than unity. The crystal structures of the dicationic symmetric sulfurane 17 and the unsymmetrical sulfurane 11a also show to be planar molecules. The S-N distances in 11a were different each other due to the electronic imbalance between the apical ligands. Semi-empirical calculation (AM 1) of these systems (10a and 17) indicate the expected electronic features of the hypervalent molecules (10-S-3 sulfuranes) and the small contribution of π-overlapping in the N-S-N bonds.

A series of neutral (8−10), monomethylated (12−14), and dimethylated (17) 10-S-3 sulfuranes, derivatives of tetraazathiapentalenes fused with pyrimidine and/or pyridine ring, were prepared. These molecules are planar, and bond energies of the hypervalent N−S−N bond were evaluated by the temperature dependent restricted rotation of the pyrimidine ring caused by cleavage of one of the S−N bonds. The bond length is longer, and the energy is lower for the S−N bond fused with more electron-withdrawing heterocycles.

The Darzens condensation of symmetric and unsymmetric ketones with (–)-8-phenylmenthyl α-chloroacetate diastereoselectively affords glycidic esters in 77–94% de; the stereochemistry [(2R,3R) configuration] of the product is understandable in terms of π–π interaction in the open transition state model.

The stereoselective synthesis of rac- and ent-rhopaloic acid A 1 has been accomplished, via successive homologation of (2E,6E)-farnesol 2 and cyclization to form a tetrahydropyran ring, together with final introduction of an α-methylene group; the asymmetric synthesis was achieved via an Evans’ asymmetric alkylation using (S)-4-benzyloxazolidin-2-one as a chiral auxiliary; the synthetic rhopaloic acid A, with a predicted absolute configuration of (2S,5R), had a specific rotation of opposite sign to that of the natural product, and therefore the configuration of natural rhopaloic acid A should be assigned as (2R,5S).

Asymmetric Darzens condensation of benzaldehyde and various ketones has been investigated. The condensation of acetophenone, propiophenone and symmetric ketones with (–)-8-phenylmenthyl halogenoacetates 3a,b afforded the corresponding glycidic esters cis-12, cis-13 and 15–19 in 77–96% de, respectively, as the major products. Aza-Darzens condensation between N-benzylideneaniline and 3a occurred to give the trans-aziridine 21 as the major isomer in >85% de. The stereochemistry of the major diastereoisomers of cis-12 and 18 was confirmed by their conversion into the known optically active diols 22 and 24. The configuration of the major product of cis-12 was determined to be 2R,3R and that of 18 to be 2R. The geometric and disastereofacial selectivities were understandable in terms of the open-chain or non-chelated antiperiplanar transition state model in the initial aldol-type reaction.

Rhopaloic acid A (+)-1 and the related compounds (–)-ent-1 and (±)-rac-1 have been stereoselectively synthesized. The synthetic strategy consists of successive homologation of (2E,6E)-farnesol 7 and cyclization to form a tetrahydropyran ring, together with final introduction of an α-methylene group on the carboxylic moiety. The cyclization is carried out by intramolecular hetero-Michael addition leading to 2,5-disubstituted tetrahydropyrans. The stereochemistry can be rationalized by invoking a model of a chair-like transition state. The asymmetric synthesis is achieved by way of the Evans’ asymmetric alkylation procedure using (S)- or (R)-4-benzyloxazolidin-2-one as the chiral auxiliary. In the event, the configuration of natural rhopaloic acid A (+)-1 could be assigned as 2R,5S by comparison of the specific rotations of synthetic compounds with that of the natural product.

Ring-expansion of methyl 2-bromomethyl-5-oxiranylpent-2-enoate (7) with various acids was studied; treatment with Lewis acids (TiBr4, MgBr2 and ZnBr2) afforded the tetrahydrofuran derivative 4-Br as a major product, while reaction with silver salt (AgNO3/KPF6), which is known to have a high halide affinity, gave preferentially the tetrahydropyran 3-ONO2 derivatives as the major products.

rac-Hippospongic acid A of the reported structure 1 and the revised structure 2 were synthesized. The synthetic strategy of these compounds consists of homologation of (2E,6E,10E)-geranylgeraniol and (2E,6E)-farnesol, respectively, Wadsworth–Emmons reaction, and cyclization to form the tetrahydropyran ring bearing an α-methylene group on the carboxylic moiety. Spectral comparisons of the synthetic compounds 1, 2 and the natural product suggested that hippospongic acid A bears the structure of 2.

Length-defined organic solvent soluble oligo-L-leucines containing an Aib residue were prepared by stepwise elongation and fragment condensation methods, and were used as catalysts in the Julia–Colonna asymmetric epoxidation reaction. The yield and enantioselectivity rose by increasing the number of amino acid units in the catalyst. The enantioselectivity was very sensitive to the reaction solvent. The IR characteristic bands (the amide I region) in CH2Cl2 indicated the soluble catalysts to be of helical structure in solution.

The synthesis of 2,5-disubstituted tetrahydropyrans bearing a hydrophobic moiety at the C5 position from (E)- and (Z)-7-hydroxy-6-substituted 2,3-unsaturated esters by way of intramolecular nucleop...

The cyclopropanation of (−)-8-phenylmenthyl (E)-3-aryl-2-phosphonoacrylates with dimethyloxosulfonium methylide and diazomethane afforded the corresponding trans cyclopropane derivatives with high diastereoselectivity as the major diastereomer. The high selectivity is understandable in terms of the π–π interaction between the phenyl ring of the chiral auxiliary and the acrylate moiety.

The [5+2]cycloaddition reaction of 2-substituted-3-oxidopyrylium betaine with dialkyl fumarates was found to proceed with stereoselectivity up to 15.5 : 1. The stereoselectivity became higher as either the 2-substituent of the 3-oxidopyrylium or the alkoxy group of the fumarate became larger. The stereoselectivity could be rationalized by considering these steric effects.

Various 3-sulfonyl-1,2,4-triazole-1-carboxamides (5a–h) were synthesized and their hydrophobicities were evaluated from their retention time in reversed-phase HPLC chromatography. Although the compounds have rather complex structures, a good linear relationship was observed between log k′ of these compounds derived from the retention time of HPLC and log PH for water–hexadecane partition coefficients of related alcohols. In regards with the rotation about the O2S–C(ester part) single bond, the preference for a gauche conformer relative to the anti form was revealed by both X-ray structural analysis of 5a and calculations at the AM1 level. In this conformation, substituents are arrayed to have the largest separation between the hydrophilic and hydrophobic parts. This can be rationalized as the primary reason for the good linearity.

The cyclopropanation of (−)-8-phenylmenthyl (E)-3-aryl-2-phosphonoacrylates E-3a–d with dimethyloxosulfonium methylide and diazomethane affords the corresponding trans cyclopropane derivatives as the major diastereomers with high diastereoselectivity. On the other hand, the cyclopropanation of (−)-8-phenylmenthyl (Z)-3-aryl-2-phosphonoacrylates Z-3a–d and (−)-menthyl derivative 4 gives mixtures of cis and trans cyclopropane derivatives with low diastereoselectivity. The high diastereoselectivity in the cyclopropanation of (E)-acrylates E-3a–d can be rationalized by considering the π–π interaction between the phenyl ring of the chiral auxiliary and the acrylate moiety in the s-cis conformer. The low selectivity in the cyclopropanation of (Z)-acrylates (Z-3a–d and 4) can be attributed to a low-lying conformer with the acrylate moiety twisted out of conjugation.

With the purpose of developing a method of preparing Z-alpha,beta-unsaturated amides, the Peterson reaction of the (triphenylsilyl)acetamide Ph(3)SiCH(2)COX (1, X = NBn(2); 3, X = NMe(2)) with various aldehydes was examined. The reaction of aromatic aldehydes gave selectivities up to >97:3. It was found that the selectivity was a function of the electronic nature of the aromatic ring and higher Z selectivity was attained with electron-rich aldehydes. With aliphatic aldehydes selectivities up to 92:8 were achieved, and unlike with analogous phosphorus reagents, less sterically hindered aldehydes gave higher Z selectivity. Also, 3, which has a smaller amide group than 1, tended to give rise to higher selectivity. A comparison with the reaction of trimethylsilyl analogues revealed the significance of the phenyl substituents on the silyl group.