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To prove the principle of a solar laser, a laser diode was directly operated by a current from a solar cell. Average laser power of 2.5 mW (5 mW standard) per a laser diode was obtained at a voltage of 2.2 V, however, the power was decreased by a cloud which shut out the sunlight. As the operation current of the laser diode is limited to 70 mA, it is necessary for avoiding the damage of the laser diode to choose a proper laod resistance of the circuit. It was found that the value of resistance 2Ω was suitable for the present system.

The chemical modification of the 4-acetylamino group on the cycloserine moiety of lactivicin (1a) was carried out. The lactivicin derivatives (1d, k--p and w) having heterocyclic acylamino groups which have been often utilized in beta-lactam antibiotics showed potent antibacterial activities. Ester prodrugs (7a--d) of lactivicin derivatives were also prepared in order to improve the bioavailability on oral administration. The pivaloyloxymethyl (POM) esters (7a and 7b) and 1-ethoxycarbonyloxyethyl (EOE) ester (7c) were found to have slightly improved protective effect in vivo compared with their parent compounds 1c and 1k.

The chemical modification of the 4-acetylamino group on the cycloserine moiety of lactivicin (1a) was carried out.The lactivicin derivatives (1d, k-p and w) having heterocyclic acylamino groups which have been often utillized in β-lactam antibiotics showed potent antibacterial activities. Ester prodrugs (7a-d) of lactivicin derivatives were also prepared in order to improve the bioavailability on oral administration. The pivaloyloxymethyl (POM) esters (7a and 7b) and 1-ethoxycarbonyloxyethyl (EOE) ester (7c) were found to have slightly improved protective effect in vivo compared with their parent compounds 1c and 1k.

A versatile intermediate (18) for optically active 5,6- cis -carbapenem antibiotics was synthesized with a highly regioselective intramolecular aldol condensation as a key step.

Earlier studies have shown that the β-D-digitoxose (2,6-dideoxy-β-D-mannopyranose) directly attached to the cardiac glycoside steroid C3 has the greatest effect on biological activity. This report describes the synthesis of eight digitoxosides (2a-9a), with widely varying cyclic and acyclic C17β-side groups, and the corresponding C3',C4'-acetonides (2b-9b). NMR analysis of conformational strain introduced by the acetonide groups is supported by crystallographic analysis of the sugars' torsion angles.

Four epimeric 17-hydroxy-16-ethylestr-4-en-3-ones (11) having potent antiandrogenic activity were prepared stereoselectively starting from 16α-ethyl-16β, 17β-diol monoacetate (2). The nuclear magnetic resonance spectra of the four epimers and other 16-substituted estranes and androstanes were investigated in order to elucidate the possibility for the assignment of the unknown configurations at the positions of 16 and 17. The data of the coupling constants (J16, 17) and the chemical shifts (13-methyl protons and 17-proton) can be used for the determination of the configuration at the positions of 16 and 17.

Some N-alkyl derivatives of sorbistin A1 (P-2563 P) (1) and butirosin A (10) were prepared by reductive alkylation with aldehyde and NaBH4 or NaBH3CN. Among them, 4'-N-propylsorbistin A1 (8b) showed antimicrobial activity against gram-positive bacteria comparable to sorbistin A1 (1) and showed broader spectrum of activity against gramnegative bacteria including some of the sorbistin A1-resistant strains (K. pneumoniae, Ps. aeruginosa) than sorbistin A1 (1). 2'-N-Propylbutirosin A (14c) showed antimicrobial activity similar to butirosin A (10) and showed weak antimicrobial activity against some of butirosin A-resistant bacteria including E. coli JR 66/W 677 which is reported to produce 3'-phosphotransferase II. It was shown that 2'-N-propylbutirosin A (14c) was hardly phosphorylated under the condition where butirosin A (10) was almost completely phosphorylated with the purified E. coli JR 66/W 677 3'-phosphotransferase II.

金沢大学大学院医学系研究科, The mixture of enol acetates (II and III) of 16-acetyl-estrone-3-methyl ether underwent hydrogenolysis under high pressure (100kg/cm^2) of hydrogen in the presence of Raney Ni to form the 16β-ethyl-17β-ol compound (X) in high yield. The mechanism of hydrogenolysis was discussed. This facile and stereoselective introduction of 16β-ethyl and 17β-hydroxy groups was applied to the synthesis of 16β-ethyl-19-nortestosterone (TSAA-291,XIX), which shows strong antiandrogenic activity.

Cardenolide diasteromeric mixtures may be analytically separated on 2.5 x 6.5 cm x 0.25 mm pre-coated silical gel 60 F-250 (EM) tlc plates (cut from 20 x 20 cm plates). Three successive developments in mixtures of CH2Cl2-EtOAc-MeOH achieve complete separation of diastereomers in less than 15 minutes, and 2--6 micrograms of sample is sufficient. This procedure facilitated the separation of several diastereomeric mixtures, including 20(R) and 20(S)-20,22-dihydrocardenolides. A single development produces separations sufficient for separating starting materials and products of common cardenolide types of reactions.

Aza analogues of lactivicin (1), a recently discovered novel antibiotic, were prepared by an application of our earlier convenient synthesis of 1 and its derivatives. A 1-unsubstituted pyrazolidinone derivative bearing 2-aminothiazol-4-yl-(Z)-methoxyiminoacetyl group exhibited in vitro antibacterial activity.

The Serini reaction of 16α-alkyl (or phenyl)-1β,17β-dihydroxysteroid monoacetates 5 and 10 gave stereospecifically 16β-substituted steroids 6 and 111 in good yields. This rearrangement was shown to proceed through 1,2 hydride shift. It was found that under the same reaction conditions, 16α-vinyl-16β,17β-diol 17-acetate 5c rearranged into Z -16-ethylidene compound 24 via 1,4 hydride shift.

The improved method for synthesizing gonanes having the allyl group at C-13 was examined. Potassium salt of 2-ethoxycarbonylmethylcyclopentane-1, 3-dione (I) was choosen as a starting material and the ethoxycarbonylmethyl group was converted into the allyl group after the steroid skeleton was formed.

dl-17α-Ethynyl-17β-hydroxy-13β-allylgon-4-en-3-one (XXIV) was synthesized via 17β, 2'-epoxy pentaene (X). The double bonds at C-14 and -8 of X was hydrogenated sequentially by conventional methods. 17β, 2'-Epoxy triene (XIII) was treated with p-toluenesulfonic acid in acetic anhydride to give 13β-allylgonane (XIV) as a major product. Birch reduction of the tetrahydropyranyl ether (XIX) followed by acid treatment yielded the 4-en-3-one compound (XXI), which was oxidized with chromium trioxidepyridine complex to the 17-ketone (XXII). The enol ether (XXIII) was treated with lithium acetylide in ethylenediamine, and then with acid to yield XXIV. The progestational activity of XXIV is as potent as norgestrel.

Four epimeric 17-hydroxy-16-ethylestr-4-en-3-ones (11) having potent antiandrogenic activity were prepared stereoselectively starting from 16α-ethyl-16β, 17β-diol monoacetate (2). The nuclear magnetic resonance spectra of the four epimers and other 16-substituted estranes and androstanes were investigated in order to elucidate the possibility for the assignment of the unknown configurations at the positions of 16 and 17. The data of the coupling constants (J16, 17) and the chemical shifts (13-methyl protons and 17-proton) can be used for the determination of the configuration at the positions of 16 and 17.

Some N-alkyl derivatives of sorbistin A1 (P-2563 P) (1) and butirosin A (10) were prepared by reductive alkylation with aldehyde and NaBH4 or NaBH3CN. Among them, 4'-N-propylsorbistin A1 (8b) showed antimicrobial activity against gram-positive bacteria comparable to sorbistin A1 (1) and showed broader spectrum of activity against gramnegative bacteria including some of the sorbistin A1-resistant strains (K. pneumoniae, Ps. aeruginosa) than sorbistin A1 (1). 2'-N-Propylbutirosin A (14c) showed antimicrobial activity similar to butirosin A (10) and showed weak antimicrobial activity against some of butirosin A-resistant bacteria including E. coli JR 66/W 677 which is reported to produce 3'-phosphotransferase II. It was shown that 2'-N-propylbutirosin A (14c) was hardly phosphorylated under the condition where butirosin A (10) was almost completely phosphorylated with the purified E. coli JR 66/W 677 3'-phosphotransferase II.

The mixture of enol acetates (II and III) of 16-acetyl-estrone-3-methyl ether underwent hydrogenolysis under high pressure (100kg/cm2) of hydrogen in the presence of Raney Ni to form the 16β-ethyl-17β-ol compound (X) in high yield. The mechanism of hydrogenolysis was discussed. This facile and stereoselective introduction of 16β-ethyl and 17β-hydroxy groups was applied to the synthesis of 16β-ethyl-19-nortestosterone (TSAA-291, XIX), which shows strong antiandrogenic activity.

Five cardioactive steroid genins 1a to 5a of widely varying C17 beta-side groups were converted by modified Koenigs-Knorr reactions into the corresponding beta-D-glucosides 1c to 5c and beta-D-galactosides 1e to 5e. The genins included digitoxigenin (3 beta, 14-dihydroxy-5 beta, 14 beta-card-20-(22)-enolide, 1a); (20R)-20, 22-dihydrodigitoxigenin (3 beta, 14-dihydroxy-5 beta, 14 beta, 20R-cardanolde, 2a); 3 beta, 14-dihydroxy-22-methylene-5 beta, 14 beta, 20S-cardanolide (3a); methyl 3 beta, 14-dihydroxy-5 beta, 14 beta-pregn-20(E)-ene-21-carboxylate (4a); and methyl 3 beta, 14-dihydroxy-21-methylene-5 beta, 14 beta-pregnane-21-carboxylate (5a).

A new type of 5, 6-cis-carbapenems (racemic) having a sulfonyl group in the C-6 side-chain were synthesized by employing the synthetic methodology reported in our previous papers, and an alternative stereocontrolled synthesis of these 5, 6-cis-carbapenems was achieved starting from 8-oxo-7-azabicyclo [4.2.0] oct-3-ene (14) via an intramolecular aldol condensation as the key step. Chiral 5, 6-cis-carbapenems were also synthesized from (1S, 6R) -8-oxo-7-azabicyclo [4.2.0] oct-3-ene (29), which was derived from cis-1, 2, 5, 6-tetrahydrophthalic anhydride. The carbapenems thus obtained proved to be highly stable to the mouse kidney homogenate, and most of them showed good antibacterial activity as well as potent β-lactamase inhibitory activity.

Lactivicin, a new type of antibiotic having β-lactam-like activity, and its derivatives were synthesized starting from 4-benzyloxycarbonylamino-3-isoxazolidinones and 2-oxoglutaric acid.

Aza analogues of lactivicin (1), a recently discovered novel antibiotic, were prepared by an application of our earlier convenient synthesis of 1 and its derivatives. A 1-unsubstituted pyrazolidinone derivative bearing 2-aminothiazol-4-yl-(Z)-methoxyiminoacetyl group exhibited in vitro antibacterial activity.

Synthese des composes du titre substitues en 3 par [(amino-2 thiazolyl-4)-2' methoxyimino-2' (ou carboxymethoxyimino-2' ou (carboxy-1'' methyl-1'' ethoxyimino)-2') acetamido]

By applying the synthetic process reported in our previous paper, we synthesized new carbapenems having various (substituted) thio and alkoxy groups at the C(3) position and 1-hydroxy-1-methylethyl and analogous groups at the C(6) position with cis- and trans-stereochemistry; the in vitro antibacterial and beta-lactamase inhibitory activities of these new carbapenems were examined. Compared to C-19393 H2, some of these compounds (e.g., 11A-a-3 approximately 5) showed improved in vitro antibacterial activity especially against Pseudomonas aeruginosa; they showed a strong beta-lactamase inhibitory activity as well. Two noteworthy effects of substituent variation at the C(6) position on the activities were observed: 1) the trans-configuration caused a definite loss; and 2) introduction of 1-hydroxycyclobutyl and 1-hydroxy-1-methylpropyl groups in place of the 1-hydroxy-1-methylethyl group caused a diminution. The carbapenem (13A-a-2) with an alkoxy group at the C(3) position had a marked decrease in activity compared to the corresponding thio-substituted carbapenem (11A-a-12).

The Na+,k+-adenosine triphosphatase-inhibiting activity of digitalis genins and their analogs is a function of side-group carbonyl (C = O) oxygen position. For each 2.2 angstroms that this oxygen is displaced from its position in digitoxigenin, activity drops by one order of magnitude. This quantitative relation resolves previously proposed models which have attempted to describe the molecular basis of genin activity. A multidisciplinary (crystallographic, conformational energy, synthetic, biological) approach to structure-activity relations is described.

A new type of 5, 6-cis-carbapenems (racemic) having a sulfonyl group in the C-6 side-chain were synthesized by employing the synthetic methodology reported in our previous papers, and an alternative stereocontrolled synthesis of these 5, 6-cis-carbapenems was achieved starting from 8-oxo-7-azabicyclo [4.2.0] oct-3-ene (14) via an intramolecular aldol condensation as the key step. Chiral 5, 6-cis-carbapenems were also synthesized from (1S, 6R) -8-oxo-7-azabicyclo [4.2.0] oct-3-ene (29), which was derived from cis-1, 2, 5, 6-tetrahydrophthalic anhydride. The carbapenems thus obtained proved to be highly stable to the mouse kidney homogenate, and most of them showed good antibacterial activity as well as potent β-lactamase inhibitory activity.

Lactivicin, a new type of antibiotic having β-lactam-like activity, and its derivatives were synthesized starting from 4-benzyloxycarbonylamino-3-isoxazolidinones and 2-oxoglutaric acid.

The synthesis of 6,7-cis-7-(1-hydroxy-1-methylethyl)-3-oxa-1-azabicyclo[4.2.0]octan-8-ones (3a, b), key intermediates for the preparation of the 5,6-cis-carbapenem antibiotic C-19393 H2{sodium (5R, 6R)-3-[(E)-(2-acetamidoethenyl)-(R)-sulphinyl]-6-(1-hydroxy-1-methylethyl)-7-oxo-1-azabicyclo-[3.2.0]hept-2-ene-2-carboxylate}(1a) and its derivatives, was investigated. Sulphenylation of the 3-oxa-1-azabicyclo[4.2.0]octan-8-ones (2a, b), followed by the aldol reaction with acetone, gave the 7-(1-hydroxy-1-methylethyl)-7-sulphenyl derivatives (7a—e). Reductive desulphurization of compounds (7a—e) with an organotin hydride (tri-n-butyltin hydride or triphenyltin hydride) in the presence of a radical initiator gave rise to stereoselective formation of the cis-azetidinones (3a, b). A total synthesis of (±)-C-19393 H2(1a) and its derivatives having other substituents at the C (3) position, (1b—e), starting from (3a, b)via a carbene insertion reaction, is also described.

The title compound was synthesized using various methods of protecting the C-13 allyl group from reducing agents.