Search

Based on the solution structures of chiral bidentate lithium amides ((R)-3a,b) having a phenyl group on the chiral carbon, chiral bidentate amines ((R)-5a,b-8a,b and (S)-9a,b) having a bulkier group instead of a phenyl group on the chiral carbon were designed and synthesized.

The pendant E-ring moiety of the podophyllotoxin aza-analogue 1 that is a potent inhibitor of microtubule assembly was modified in order to acquire inhibitory activity of DNA topoisomerase II. The monophenolic analogue 2 did not exhibit human topoisomerase II inhibition, while the ortho-quinone 3 that was obtained by oxidation of 2 inhibited its catalytic activity (decatenation) in a dose-dependent manner and stimulated double strand DNA breaks in supercoiled circular plasmid DNA, resulting in the production of linear DNA. These results showed that the topoisomerase II inhibition of the ortho-quinone 3 is due to stabilization of the topoisomerase II-DNA covalent binary complex. On the other hand, the ortho-quinone 3 did not inhibit the relaxation process of supercoiled DNA by topoisomerase I at concentrations up to 400 microM, nor was intercalation observed in unwinding measurements of 3. Therefore, the ortho-quinone 3 was shown to be a novel nonintercalative topoisomerase II specific inhibitor that stabilizes the cleavable complex. The present results suggest that the 4'-free hydroxyl group on the E-ring and the sugar moiety on the C-ring are not a prerequisite for topoisomerase II inhibition by podophyllotoxin derivatives.

Enantioselective deprotonation of 4-tert-butylcyclohexanone was examined using 1-phenylethylamine- and 1-(1-naphthyl)ethylamine-derived chiral lithium amides having an alkyl or a fluoroalkyl substituent at the amide nitrogen. The lithium amides having a 2,2,2-trifluoroethyl group on the amide nitrogen are easily accessible in both enantiomeric forms, and were found to induce good enantioselectivity in the present reaction.

A method of the conversion of 2,6-bis(tert-butyl)-4-methoxyphenyl dihydronaphthalenecarboxylates into substituted naphthalenes and tetrahydronaphthalenes was developed. Aromatization of substituted dihydronaphthalenecarboxylates with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and subsequent treatment with ceric ammonium nitrate (CAN) gave the corresponding substituted naphthalenecarboxylic acids. Alternatively, hydrogenolysis and subsequent treatment with CAN provided a way to tetrahydronaphthalenemethanols in good yields.

^6Li- and 15N-NMR spectroscopic studies on the solution structures of a chiral tridentate lithium amide have revealed that it exists as a chelated monomer in which the lithium is tri-coordinated, as a chelated dimer in which the lithium is tetra-coordinated, or as a mixture of these two species depending upon the solvent used. It is concluded that lower Lewis acidity of the tri- and tetra-coordinated lithium compared to the di-coordinated lithium makes tridentate lithium amides inferior to dibentate lithium amides as bases in enantioselective deprotonation reaction.

Chiral chelated lithium amides ((R))-1a-g) were designed and synthesized in optically pure forms starting from (R)-phenylglycine.

A chiral key intermediate (19a) for the synthesis of (+)-thienamycin was synthesized starting from D-glucose. The enol ether 13, obtained from the ketone 11 by Horner-Wittig reaction, was transformed to the corresponding methyl ester 16 by pyridinium chlorochromate oxidation or by employing the Wacker process. The ester 16 was further converted to the β-lactam 19a, which is a useful chiral precursor to (+)-thienamycin.

Chiral lithium 2-aminoalkoxides ((1R, 2S)-4) were applied as chiral bases for the enantioselective Horner-Wadsworth-Emmons reaction between achiral phosphonates (2) and 4-tert-butylcyclohexanone (1). A chiral olefin ((R)-3b) was obtained in up to 52% enantiomeric excess (ee). It is shown that the formation of the lithium aldolate intermediate is reversible and is not responsible for the asymmetric induction.

Enantioselective alkylation at the α-position of phenylacetic acid (1) can be realized in up to 68% ee by treating the dilithiated 1 with alkyl halides in the presence of a chiral bidentate lithium amide ((R)-3).

Enantioselective and diastereoselective Darzens reaction mediated by chiral lithium amides was achieved between tert-butyl chloroacetate and aromatic aldehydes to give the corresponding trans-glycidic esters in up to 84% enantiomeric excess.

Novel cyclophanes (9a, b) having eight carboxyl groups on the aromatic rings were designed and synthesized. Macrocyclization of 7a and 7b with 6 was carried out under a high dilution condition to give the corresponding 8a and 8b in 23% and 28% yields, respectively.

A water-soluble cyclophane (9) having eight carboxyl groups that are attached to the aromatic rings via a spacer (-CH2SCH2-) was designed and synthesized. By 1H NMR spectral analysis, it is shown that 9 forms inclusion complexes in particular geometries with cationic, anionic, and neutral aromatic guests in D2O at pD 7.9.

Novel bicyclic chiral crown ethers having an α,α'-p-xylenedioxy unit were synthesized. Crown dithiol 1 with a p-xylenedioxy bridge-structure performed intra-complex thiolysis with α-amino acid p-nitrophenyl ester HBr salts much faster than the corresponding dithiol 3 without the bridge-structure. A 1 H-NMR study suggested that the increased rate of intra-complex thiolysis is due to increased stability of the intermediary complex during the reaction

Enantioselective dihydroxylation of E-stilbene afforded (1S, 2S)-1, 2-diphenyl-1, 2-ethanediol in 70% ee by employing a stoichiometric amount of osmium tetroxide-chiral amine 5, prepared from N-methylephedrine and 2-bromopyridine.

Aerobic oxidative coupling of naphthols catalyzed by a copper-amine complex was found to proceed without solvent in high efficacy. The present reaction was applied to a practical synthesis of 1, 1'-binaphthalene-2, 2'-diol on multi-gram scale.

The rates of transacylation were studied between thiol-bearing chiral crown ethers (1-10) and α-amino acid p-nitrophenyl ester salts. Enantioselectivities, kD/kL ratios, of 6.5 for valine ester salt, 8.7 for phenylalanine ester salt, and 7.7 for valine ester salt were achieved by 1, 5, and 8, respectively. Saturation phenomena of rate acceleration depending on crown concentration were observed and analysis of these data revealed that the chiral recognition occurs in the step of liberation of p-nitrophenol by intra-complex thiolysis, not in the complex-forming step. A possible mechanism for the enantioselectivity is proposed on the basis of the kinetic data.

The Michael reaction of diethyl malonate with chiral α, β-unsaturated aldimines (4), prepared from crotonaldehyde and optically active α-amino acid tert-butyl esters (3), was found to give the corresponding β-substituted aldehydes (5) in reasonably high optical yields after hydrolysis. A proposed stereochemical mechanism of the reaction is presented.

A new stereoselective synthesis of methyl α-L-amicetoside (11), methyl α-L-mycaminoside (14) and methyl α-L-oleandroside (17) starting from L-alanine is described. It is shown that methyl 2, 3, 6-trideoxy-α-L-hex-2-enopyranosid-4-ulose (8) is readily accessible from L-alanine in optically pure state and is a potential intermediate for the synthesis of various kinds of 6-deoxy-L-hexoses.

Total synthesis of (-)-β-bourbonene (3) was achieved by employing the (2+2) photocycloaddition reaction of (S)-γ-pivaloyloxymethyl-β-methyl-γ-butenolide (5e) with cyclopentenone ethyleneacetal (15). The major photoadduct (16) was readily converted to the cis, anti, cis-tricyclo[5.3.0.02, 6]decane system (22) in 70% yield. Further transformation provided the optically pure title compound (3).

A novel method for the asymmetric synthesis of both enantiomers of 2, 3-disubstituted-butanolides (8) was devised using a readily available (S)-4-hydroxymethyl-4-butanolide 4-derivative (6) as a chiral source in the asymmetric induction and as the carbon framework of 8. Application of this method to the asymmetric total synthesis of podorhizon (23) and deoxypodorhizon (4) is described.

The asymmetric bromolactonization of (S)-N-(α, β-unsaturated) acylproline ((S)-17a) prepared from the α, β-unsaturated acid (10a) was found to occur stereoselectively to give the bromolactone (18a) in which one diastereomer (18Aa) was predominant. Debromination of 18a followed by acidic hydrolysis, afforded the (R)-α-hydroxy acid ((R)-12a) in 92% optical purity. Reaction of (R)-12a with methylithium gave the (R)-α-hydroxy ketone ((R)-9a), a model compound of the optically active anthracyclinone AB ring system, in good yield. When the reaction scheme established by the model study was applied to 10b, c, which possess the AB and ABCD ring systems of anthracyclinones (2), (R)-α-hydroxy acid methyl esters ((R)-21b, c) could be prepared in 97% and 87% optical yields, respectively. Alkaline hydrolysis of optically pure (R)-21b, c independently prepared from the pure debrominated lactones (19Ab, c) gave (R)-12b, c. Although the reaction of tetracyclic (R)-12c with methyllithium did not proceed in the expected manner, bicyclic (R)-12b was successfully converted to optically pure (R)-9b, which has previously been utilized as a starting material for the synthesis of optically active natural and unnatural 2.

The rates of transacylation were studied between crown ethers (1, 2, 3) having sulfhydryl groups at the end of side arms of different lengths and α-, β-, γ-, and e-amino acid p-nitrophenyl ester salts (4, 6, 7, 8). It was shown that regioselectivity of the reaction can be successfully correlated with the distance of the catalytic site from the polyether ring. It was also shown that introduction of ether oxygen in the side arm can be used to keep the side arm sticking up from the polyether ring in the complex.

Novel isomerizations of isostegane (6) into the three other possible isomers, namely, isopicrostegane (7), picrostegane (8), and stegane (9) are described. All the possible enantiomers were synthesized.

Reaction of (S) (-)-α-tosyloxy acid ((S)(-)-3) with methyl- or n-butyllithium was found to afford (R)(+)-vicinal (vic)-diol ((R)(+)-4) in an excellent yield with almost full inversion. On the other hand, when (S)(-)-α-hydroxy acid ester ((S)(-)-5) was allowed to react with methyl- or n-butyllithium, (S)(-)-vic-diol ((S)(-)-4) was obtained in an excellent yield with full retention. Since (S)(-)-3 and (S)(-)-5 are both derivable from L-phenylalanine (L-1), it has become possible to obtain an enantiomeric pair of vic-diols from L-1. Plausible formation mechanism for (R)(+)-4 from (S)(-)-3 was proposed. The utility of optically active vic-diols in natural product synthesis was also visualized by preparing the novel synthetic intermediate for epoxyterpene synthesis ((S)(-)-6) from (S)(-)-4a.

The 1, 4-addition of Grignard reagents to the chiral α, β-unsaturated aldimines (3d, e), prepared from α, β-unsaturated aldehydes (1) and optically active tert-leucine tert-butyl ester (2d), afforded, after hydrolysis, optically active β-substituted aldehydes (4) in 91-98% enantiomeric excess. The present method has advantages in giving aldehydes (4) in high enantiomeric purities, allowing easy preparation of the aldimines as well as easy recovery of optically active tert-leucine tert-butyl ester (2d) without any racemization for reuse, and exhibiting general utility. The possible mechanism of the reaction, by which the absolute configuration of the aldehydes (4) is unequivocally predictable, is proposed.

With an aim to further explore the utility of L-α-amino acids (I) in the synthesis of optically active compounds, the reaction of optically active α-tosyloxy acids and their derivatives (III) readily obtainable from I, with several types of organocopper reagents were studied. Although there still remain some ambiguity in the formation of unusual reaction products such as the β-keto ester (dl-6) and the vicinal diol ((R)(+)-13) and in lower yields for the substitution products, it has become evident that when optically active α-tosyloxy acids prepared from L-phenylalanine, L-alanine, and L-leucine, respectively, are treated with lithium dialkyl- or diarylcuprates, the substitution reactions can proceed with almost full inversion to give corresponding optically active α-alkyl or α-aryl acids in max. 63% yield.

It has become apparent that deaminative bromination of 3, 5-dichloro-L-tyrosine (L-4) to the corresponding α-bromo acid ((-)-5) occurs with retention of configuration, and that amination of this bromo acid to the starting amino acid (L-4) occurs also with retention of configuration. The unusual stereochemical course in this amination step was found to be due to the strong neighboring aryl group participation as a phenoxide form.

Novel water-soluble cyclophanes (2a, 2b) which act as hosts having hydrophobic cavities were made by connecting two naphthylphenylmethane units and two tetramethylene bridges via four nitrogens. 1H NMR spectral studies have shown that in water these cyclophanes form inclusion complexes with aliphatic as well as aromatic guests.

A first biogenetic-type asymmetric synthesis of natural (+)-maritidine from L-tyrosine is described. Phenolic oxidative coupline of monophenol (10b) with thallium (III) trifluoroacetate afforded the corresponding spiro dienone (11b) in 66.5% yield. Asymmetric cyclization of dienone (14) was found to occur highly selectively to give one diastereomer (15) preferentially. Removal of the carboxamide group in 15 was effected by reductive decyanization of the intermediate amino nitrile (18) by sodium in liquid ammonia to (+)-epimaritidine (19), which was epimerized to the objective (+)-maritidine by the known method.

Stereoselective synthesis of several D-pentose derivatives from L-glutamic acid without resolution step was performed. Isolation of all possible isomers of methyl 2, 3-anhydro-5-O-benzyl-D-pentofuranosides and their reactions leading to deoxy, amino, and thio derivatives were discussed on the stereochemical ground. Examples in which methoxy group at C1 exhibits more steric hindrance in the reactions than the benzyloxymethyl group at C4 are presented.

Metalation and alkylation of the chiral imines prepared from cyclohexanone and methoxy amines (2b, 4c, 6d, and 7d) derived from D-camphor derivatives provided, after hydrolysis, optically active 2-alkylcyclohexanones (9) in high enantiomeric purities of up to 99.5%.

Synthese des derives cis- et trans- a partir de [benzodioxole-1,3yl-5methyl]-4 perhydro furannone-2. Le burserane naturel est le compose trans

A chiral carbapenam ring system ((3R, 5R)-(+)-19 and -20) having the desired absolute configuration at C-5 was synthesized starting from (S)-aspartic acid, and the latter product was further transformed to a chiral carbapenem derivative ((5S, 2'R)-(+)-21) having an (R)-cysteine moiety as a side chain.

A series of quaternary ammonium cyclophanes, 2b∼e and 4a∼d, having well-defined hydrophobic cavities rationally designed with diphenylmethane and naphthylphenylmethane units, respectively, were synthesized and fully characterized. A systematic study on the molecular recognition and discrimination properties of these hosts in neutral water was carried out. Whereas host 2 having diphenylmethane units formed inclusion complexes selectively with aromatic guests, host 4 having naphthylphenylmethane units were proved to form inclusion complexes with bulky aliphatic guests that were not complexed by host 2.

A biogenetic-type asymmetric synthesis of optically active galanthamine ((+)-4 and (-)-4) is described. Norbelladine derivative (10), having C2 symmetry in the aromatic moiety of C6-C1-N part, was prepared from L-tyrosine, and was converted to narwedinetype enone (11) by oxidation and highly specific asymmetric cyclization. Phosphorylation of phenolic hydroxyl group followed by sodium borohydride reduction afforded 14 having galanthamine skeleton. N-Methylation followed by removal of the methoxycarbonyl and phosphate moieties afforded (+)-galanthamine ((+)-4). Formal total synthesis of (-)-galanthamine ((-)-4) from L-tyrosine via enantiomeric interconversion of narwedine derivative (12) is also described.

Novel water-soluble bis-cyclophanes (3a-c) with quaternary ammonium nitrigens, composed of two untis of QCP44 (2) connected by appropriate bridges, were synthesized as hosts having two discrete hydrophobic cavities to bind two guest molecules simultaneously or a single guest molecule via double recognition in neutral water. Glutaryl, terephthaloyl and isophthaloyl groups were used as spacers to bridge the two cyclophane units. THe bridge formation was carried out using 5 as an intermediate, in which three of the four nitrogens of CP44 (1) were protected. The details of the synthesis and characterization of duplex hosts (3a-c) as well as of the reference compounds (9-11) are described.

Atropine (VI), littorine (VII), apoatropine (IX), and related compounds have been synthesized by a one-step deamination reaction from dl-phenylalanine 3α-tropanyl ester (V). The amino ester (V) was obtained by coupling tropine with N-phthalyl-dl-phenylalanyl chloride (III) followed by hydrazinolysis with an equimolar amount of hydrazine hydrate.

Detailed examinations on nitrous acid deaminations of L-phenylalanine ethyl ester (Ib) and its p-nitro (Ia) and p-methoxy (Ic) derivatives in 1 N sulfuric acid, acetic acid, and trifluoroacetic acid have shown that the reactions are highly dependent both on the solvent employed and on the substituent attached to the aromatic ring. Results may be rationalized by evaluating the changes in nucleophilicities of both the solvent and the aryl group. We clearly demonstrated that aryl groups exhibit strong neighboring group participation in deamination in trifluoroacetic acid.

Changes in the stereochemical course of 1, 2-asymmetric induction in the reduction of N-substituted 2-aminopropiophenones with sodium borohydride were examined. It was concluded that substitution for the two hydrogens of the amino group by two bulky groups is important for the synthesis of threo-isomer, while at least one of the two hydrogensof the amino group must be left attached for the synthesis of erythro-isomer. This stereochemical outcome was considered to be attributable to the steric phenomena.

Detailed examinations on nitrous acid deamination of (R)-α-methylphenylalanine methyl ester (I) in acctic acid have shown that elimination (68%), substitution (21%), hydrogen migration (8%), and phenyl migration (3%) products were obtained. The stereochemical courses of these products were also clarified. Substitution reactions giving α-hydroxy ester (VIII) and α-acetoxy ester (IX) proceeded with net retention, while migration reactions proceeded with net inversion at their migration termini, as shown in Table I. Nitrous acid deamination of (R)-α-methylphenylalanine (II) in acetic acid was also examined as shown in Table II.

Effects of neighboring functional groups on 1, 2-asymmetric induction in sodium borohydride reduction were examined with eight kinds of ketones (I-VIII) having functional groups, such as -NH2HCl, -OH, and-OCH3, at a-and/or β-positions to the carbonylgroup. It was recognized that the stereochemical course of the reduction was highlydependent on the position of these functional groups, i. e. erythro-rich products were obtained in reduction of ketones having a functional group at a-position to the carbonyl group, while threo-rich products were obtained in reduction of ketones having a functional group at β-position to the carbonyl group. A six-membered empirical model (XXXVII) was proposed for predicting the stereochemical course in the reduction of ketones having a functional group at β-position to the carbonyl group.Determinations of the relative configurations of the diastereomers (X, XI, XII, XIV, XV, and XVI) were also performed.

Detailed examinations were made of nitrous acid deaminations of L-valine and its benzyl ester in acetic acid. These showed that while the substitution product is the only detectable compound in the deamination of L-valine, various migration and elimination products are obtained along with the substitution product in the deamination of L-valine benzyl ester.

A facile reduction of optically active α-amino acid esters and their hydrochlorides took place with sodium borohydride in ethanol or aqueous ethanol to give the corresponding optically active α-aminoalcohols in fair yields. The reaction conditions were investigated.

Mixed carbonic-carboxylic acid anhydrides prepared from N-acylated a-amino acids and ethyl chloroformate in tetrahvdrofuran were reduced to the corresponding N-acylated a-amino aldehydes with palladium-charcoal under hydrogen bubbling. The optimum conditions found for N-acetyl-L-alanine were applied to the conversion of several kinds of N-acylated x-amino acids to their corresponding aldehydes, as shown in Table II. It was found that considerable racemization occurred under the present reduction conditions.Oxidation of some N-acylated β-amino alcohols with dimethylsulfoxide in the presence of dicyclohexylcarbodiimide and phosphoric acid was also studied.

The absolute configuration of mercaptosuccinic acid was unequivocally determined by its chemical correlation with glyceraldehyde via (-) N-acetyl-4-allomercapto-L-proline thiol-lactone ((-) XI), as shown in Chart 2 and Chart 3. It becomes clear that mercaptosuccinic acid, with a positive rotation in water, belongs to the R-series. Our results show that Fredga's proposal, based on the method of quasi-racemate formation, is correct.This method of configurational correlation is unique since chemical correlation was performed without replacing the C-S bond with the C-O bond.

Stereoselective synthesis of l-norephedrine hydrochloride (XI) was investigated starting from D-phenylalanine (D-I), by making use of the comparable configuration at the α-carbon in D-I with the asymmetric center bearing the amino group in XI. The synthetic route is shown in Chart 2.

Chiral thienamycin intermediate (12) having the correct absolute configuration was synthesized from D-glucose.