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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.

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 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 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.

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.

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.

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 construction of a highly functionalized adamantane core of plukenetione-type polycyclic polyprenylated acylphloroglucinols (PPAPs) is described. The method features the construction of the bicyclo[3.3.1]nonane core (3) by successive Michael reactions and the construction of the adamantane core of plukenetione-type PPAPs by acid-catalyzed cyclization of a bicyclo[3.3.1]nonane precursor (2).

A monogalactosyl monoacylglycerol 1 and two digalactosyl monoacylglycerols 2 and 3 were isolated from a cultured marine dinoflagellate Heterocapsa circularisquama along with known (2S)-1-O-6,9,12,15-octadecatetraenoyl-3-O-beta-D-galactopyranosyl]-sn-glycerol (4). On the basis of spectral analysis, the glycolipid 1 was characterised as (2S)-1-O-3,6,9,12,15-octadecapentaenoyl-3-O-beta-D-galactopyranosyl]-sn-glycerol. The glycolipids 2 and 3 were characterised as (2S)-1-O-3,6,9,12,15-octadecapentaenoyl-3-O-[alpha-D-galactopyranosyl-(1''' --> 6'')-O-beta-D-galactopyranosyl]-sn-glycerol and (2S)-1-O-6,9,12,15-octadecatetraenoyl-3-O-[alpha-D-galactopyranosyl-(1''' --> 6'')-O-beta-D-galactopyranosyl]-sn-glycerol, respectively. The isolated monoacylglycerols 1-4 showed cytolytic activity towards heart and gill cells of oyster.

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.

Symmetrical 10-S-3 sulfuranes ( 1a - c ) fused with two pyrimidine rings and their unsymmetrically substituted ones ( 1d , e ) were synthesized by oxidation of the corresponding thioureas. Substituent effect on the kinetic data of the restricted rotation was explained in terms of the balance of electron-withdrawing ability of the ligand in the NSN hypervalent bond.

A method for the practical construction of poly-functionalized bicyclo[3.3.1]nonenones by successive Michael reactions of cyclohexenones with acrylates using K2CO3 and TBAB (n-Bu4N+ Br-) was developed. The construction could be carried out in both stepwise and one-pot reactions with similar tendencies in regioselectivity. The alpha-regioselectivity in the intramolecular Michael reaction agreed with that stereoelectronically expected in intermolecular reactions based upon consideration of the HOMO orbital profile of the enolate I, the precursor to ring-closure, although the reaction site was trisubstituted and prone to steric hindrance in most of the examples presented. For the acetoxymethylacrylates substituted at either the alpha or gamma position, steric hindrance of the substituents (R2 and R3) served as a controlling factor to induce high regiocontrol. Facial selection in the protonation of enolate II, formed upon ring-closure, was also affected by these substituents. In both the intramolecular Michael reaction and the protonation of enolate II, the ammonium counter cation played an important role.

Cinchonidine catalyzed the cyclopropanation reaction between chloromethyl ketones and β-substituted methylidenemalononitriles to give trans-cyclopropanes with enantioselectivity up to 82% ee. Experimental evidence suggests that cinchonidine functions as a chiral Bronsted base catalyst in the reaction and hydrogen bonding is essential for inducing high enantioselectivity.

A 6-alkyl-4,5-epoxy-6-hydroxy-2-cyclohexen-1-one derivative, a model compound for the hydrophilic moiety of scyphostatin, was stereoselectively synthesized from the Diels–Alder adduct. The key steps were the reductive cleavage of the 4,5-epoxide ring of the epoxidated adduct, the 1,3-carbonyl transposition of the 3-carbonyl group to the C1 position by a Wharton reaction and stereoselective bromination to provide a trans bromohydrin derivative, a precursor to the desired compound. Desilylation of the bromohydrin derivative with TBAF directly gave the target compound.

Construction of the bicyclo[3.3.1]nonenone core was achieved by stepwise annulation of 2-cyclohexenone derivatives and acrylates via successive Michael reactions. The process could also be effected by a one-pot procedure.

The Diels-Alder reaction of spirolactones with cyclopentadiene afforded the adduct with high pi-facial selectivity; a hydrophilic analogue of scyphostatin was synthesized from the Diels-Alder adduct.

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.

Ab initio MO calculations were performed on the cyclopropanation reaction of methylidenemalononitriles with the ylide generated from α-pyridiniumacetates. The calculations indicated that the rate-determining step was the final cyclopropane forming step for the gas phase reaction, whereas solvent effect approximations implied that it was the initial Michael addition leading to the cis intermediate for reaction in water. It was also revealed that the plausible [3+2] cycloaddition reaction to give bicyclic products is more likely to be a stepwise and not an asynchronous concerted process in DFT calculations at the B3LYP/6-31G(d) level of theory.

(2S,6S)-2,4,6-Tris(phenylmethyl)piperazine was prepared in 11 steps and 53% overall yield from S-phenylalanine. Key steps in the synthesis involved reductive amination to introduce an ethoxycarbonylmethyl group on to the secondary nitrogen of the product and selective alkylation to introduce a benzyl group with complete diastereoselectivity.

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.

The reaction between β-substituted methylidenemalononitriles and the ylide from (-)-8-phenylmenthyl α-pyridiniumacetate, which affords activated cyclopropanes bearing two cyano groups and one carboxylic ester group, was examined. The trans isomer was obtained in up to 91:9 diastereoselectivity under optimized solvent conditions for the t-butyl substituted substrate. The selectivity increased to 96:4 upon using 4-methoxypyridine in the place of pyridine, whereas selectivities were generally lower for N,N-diethylnicotinamide. The major 4-pyridyl substituted cyclopropane was determined to be trans-1R by X-Ray structural analysis.

Selectivity of alkylation of and that of deuteration of methyl groups attached to the pyrimidine ring of tetraazathiapentalenes are discussed.

In order to construct the tetrahydropyran ring of rhopaloic acid A and hippospongic acid A, the ring-expansion of methyl 2-bromomethyl-6,7-epoxyhept-2-enoate with various acids was studied; treatment of the bromo oxirane with Lewis acids (TiBr 4 , MgBr 2 and ZnBr 2 ) afforded a tetrahydrofuran derivative as the major product, while reaction of the oxirane with silver salt (AgNO 3 /KPF 6 ) gave a tetrahydropyran derivative as the major product.

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 Julia-Colonna asymmetric epoxidation reaction of substituted benzalacetophenone afforded the corresponding epoxide with high yield and high enantioselectivity, catalyzed by the specified length of poly-L-leucine (chain length n > 15). Poly-L-leucine catalysts have been prepared by the polymerization reaction of L-leucine-NCA with initiators (BnONa, n-BuNH 2 , H 2 O) and characterized by the MALDI-TOF Mass and IR analysis.

The hydrophobic side chain of scyphostatin was synthesized by a convergent synthetic pathway. The key reactions were the enzymatic asymmetric acetylation of a meso-diol, construction of the C12′–C13′ trisubstituted E-olefin moiety by Negishi coupling, and construction of the (2′E,4′E ,E,6′E)-triene moiety by Horner–Wadsworth–Emmons olefination.

An analogue of the hydrophilic moiety of scyphostatin was synthesized via π-facial selective Diels-Alder reaction of a 2,5-cyclohexadien-1-one bearing a spirolactone with cyclopentadiene.

The Diels-Alder reactions of cross-conjugated ketones bearing an oxa-spiro-ring with some simple sterically undemanding dienes (cyclopentadiene, 2,3-cyclohexadiene, 2,3-dimethyl-1,3-butadiene) afforded the adduct with high π-facial selectivity under mild conditions. The π-facial selectivity can be explained in terms of Cieplak model.

The selective monochlorination of 5-[2-(N-silyl-amino)vinyl] isothia- zoles (1a,b) and their related compounds (1c,d, 2a-g, 3a-c, and 4a,b) with N-chlorosuccinimide is described. Chlorination of (1a,b) occurred at vinyl carbon to give (5a,b) and the geometry was determined to be Z-isomer according to spectral data. It is noteworthy that (1d) smoothly occurred bond switch at room temperature but (5)d did not ring-trans- form under the same conditions

Methylation of the title compounds (10-S-3 sulfurane: 1-3) took place exclusively on the nitrogen at 3(4)-position and selectively on the nitrogen bound to the more electron-withdrawing heterocycle. The acti- vation energy of the hindered rotation in 5 was lower for the pyrimidine ring (ΔGc = 20.2 kcal mol −1 ) bound to the methylated nitrogen than the other one (4Gc = 22.9 kcal mol −1 )

In the presence of 1,4-diazabicyclo[2.2.2]octane, 5-amino-3-methylisothiazole (4a) in acetonitrile condensed with N-methyl-p-chlorobenzimidoyl chloride (5a) to afford two kinds of compounds along with several minor products. One of the two was 1 : 1 condensed product (6a) and the other was 2 : 1 condensed product (7a). The latter compound was obtained in higher yield when an excess 4a was treated with 5a. On the other hand, in the absence of the additional base, 2 : 3 condensed compound (8a) was isolated as a major product besides 6a and 7a. 8a was obtained by treatment of 7a with 2 equiv. of imidoyl chloride in 21% yield. Reaction of 5-amino-3-phenylisothiazole (4b) with imidoyl chloride (5a,b) furnished the analogous products

A new simple methodology is described for the preparation of oxasteroidal skeletons containing a lactone ring via cycloaddition of 2-t-butyldimethylsiloxypyrylium triflate (2a,b) with syloxydienes.