Microbiological transformations—XII: Microbiological reduction of racemic 1-(2',2',3'-trimethyl-cyclopent-3'-en-1'-yl)propan-2-one and 1-(2',2',3'-trimethyl-cyclopent-3'-en-1'-yl)butan-2-one by rhodotorula mucilaginosa

The microbiological reduction of (±)-l-(2',2',3'-trimethylcyclopent-3'-en-l'-yl)-propan-2-one (4) and (±)-1-(2',2',3'-trimethylcyclopent-3'-en-l'-yl)-butan-2-one (5) by Rhodotorula mucilaginosa was investigated. Both enantiomers of 4 are reduced stereospecifically to corresponding alcohols; (+)-(2S, l'R)-(2',2',3'-trimethylcyclopent-3'-en-l'-yl)-propan-2-ol (6) and (-)-(2S,l'S)-(2',2',3'-trimethylcyclopent-3'-en-l'-yl)-propan-2-ol (7). p ]The substrate selectivity in the reduction of 5 was observed: R enantiomer of 5 yields stereospecifically (+)-(2S,1'R)-(2',2',3'-trimethylcyclopent-3'-en-l'-yl)-butan-2-ol (8) while S(-)5 remains unchanged.     

The addition of benzocyclobutenylidene to benzene : The facile rearrangement of spiro[benzocyclobutene-1,7'-cyclohepta-1',3',5'-triene] to 9a,10-dihydrobenz[α]azulene

Thermal decomposition of the sodium salts of benzocyclobutenone tosylhydrazone and 2-methylbenzocyclobutenone tosylhydrazone in benzene affords 9a,10-dihydrobenz[α]azulene 4 and trans-10-methyl-9a, 10-dihydrobenz[α]azulene 3, respectively. A mechanism involving initially the addition of the carbene benzocyclobutenylidene, or its 2-Me derivative, to the benzene ring is postulated. A proposed intermediate in the reaction, spiro [benzocyclobutene 1,7' cyclohepta-1',3',5'-triene] 12 has been synthesised, and shown to give rise to 4 under the reaction conditions. The rate of rearrangement of 12 → 4 has been measured, and the activation energy determined: E_a = 125.9 ± O.8 KJmol^?1 and A = 1.38 × lO¹⁴sec^?1. The mechanism for the rearrangement must involve ring opening of the benzocyclobutene moiety of 12 to give an o- xylylene intermediate which is postulated to possess considerable diradical character. At 71.8 °, this ring opening is 2.7 × 10⁶ times faster than the ring opening of the parent benzocyclobutene molecule. The decomposition of the sodium salt of 2-(7' -cyclohepta-1',3',5' trienyl)benzaldehyde tosylhydrazone has also been investigated and is shown to yield 4a,10-dihydrobenz[α]azulene, 9,10-dihydrobenz[α]azulene and 8,9-benzotricyclo [5.3.0.0^2.10]deca-3,5,8-triene. A mechanism involving intramolecular 1,3-dipolar addition of a diazo grouping to a cycloheptatriene Π-bond, followed by decomposition of the resulting pyrazoline intermediate, is proposed.     

Photochemistry of β,γ-enones-VIII: On the remarkable photostability of some β,γ.β',γ'-dienones and the 1,3-acyl shift photoreactivity of two β,γ.γ',δ'-dienones

The direct irradiation of the β,γ.β',γ'-dienones 1–5 and the β,γ.γ',δ'-dienones (E)-6a, (E)-7a and 8a at λ 300 nm has been studied. The β,γ.β,γ'-dienones 1–5 are remarkable photostable for λ ? 300 nm, even upon prolonged irradiation, in contrast to simple β,γ-enones which upon irradiation exhibit α-cleavage, γ-hydrogen abstraction, (E)-(Z) isomerization and oxetane formation. The observed photostability of the β,γ.β',γ'-dienones is rationalized in terms of a rapid radiationless decay of the excited singlet state, enhanced by CT-interaction between the carbonyl ¹(n-π*) state and the homoconjugated 1,4-diene moiety, which precludes fluorescence, photochemical reactions and intersystem crossing (ISC).The β,γ.γ',δ'-dienones (E)-(6a), (E)-7a and 8a exhibit only a 1,3-acyl shift (1,3-AS) without (E)-(Z) isomerization of the alkenyl moiety, to yield (E)-6b, (E)-7b and 8b. It is concluded that the 1,3-AS proceeds from the ¹(n-π*) state with a rate which is very large relative to the rate of ISC to the ³(n-π*) state, thus precluding any internal triplet energy transfer (1TET) from the ³(n-π*) to the ³(π-π*) state which would manifest itself by (E)-(Z) isomerization.     

Studies on the syntheses of heterocyclic compounds—DCCLXII : Alternative synthesis of trans-3-(1'R*-hydroxyethyl)-4-(2',2'-dimethoxyethyl)-2-azetidinone,a synthetic intermediate of thienamycin

Synthesis of trans-3-(1'R^*-hydroxyethyl)-4-(2',2'-dimethoxyethyl)-2-azetidinone (5), an important intermediate for the synthesis of thienamycin (1), was investigated starting from the isoxazoline derivatives 3 and 9. The most effective method was catalytic hydrogenation of trans-4-t-butoxycarbonyl-3-(2,2'-dimethoxyethyl)-5-methyl-isoxazoline (9) with Adams catalyst in acetic acid, followed by trimethylsilylation of the resulting epimeric aminoesters 11A and B, cyclization with EtMgBr, and deblocking. Novel reductions of the isoxazolines with sodium borohydride and nickel chloride or with diborane followed by catalytic hydrogenation were also reported.     

2' And 3'-ketonucleosides and their arabino and xylo reduction products: Convenient access via selective protection and oxidation of ribonucleosides

A number of 2',5'- or 3',5'-diprotected ribonucleosides and 5'-protected 2'- or 3'-deoxy-β-D-erythro-pentofuranosyl nucleosides have been oxidized to the corresponding 3' or 2'-ketonucleoside derivatives using chromium trioxide/pyridine/acetic anhydride or dimethyl sulfoxide/ acetic anhydride. Reduction of the carbonyl functions with sodium borohydride gave the inverted arabino, xylo, or deoxy-threo isomers as predominant products by attack at the less hindered α-face of the sugar ring. Parallel reductions using sodium borodeuteride corroborated the epimeric ratios by demonstrating that complete oxidation of the original hydroxyl groups had occurred. The deuterium labeling also aided in making NMR spectral assignments.     

Synthesis of 2'-deoxy-1-deazawyosine: A stabile 2'-deoxyisostere of a rare trna constituent

2'-Deoxy-1-deazawyosine (3a), an isostere of the rare tRNA constituent wyosine (la) and its α-anomer have been synthesized via glycosylation of the nucleobase 5a with the halogenose 6. In contrast to the labile parent 1a, the isostere is highly stabile against hydrolysis even as 2'-deoxynuclcoside. The stability of 3a is due to the low susceptibility of the pyrrol ring to protonation. The rapid hydrolysis of wyosine (la) compared to guanosine is explained by a favoured solvatization of the molecule being freezed in the anti-conformation.     

Biphenylenes-xxxi: Condensation of benzocyclobutene-1,2-dione with aliphatic and heterocyclic 1,2-diamines and the synthesis of cis-2-cyano-3-(2'-cyanovinyl)-1,4-diaz

As possible routes to 1,4-diazabiphenylene and its 2,3-disubstituted derivatives we have studied the condensation of benzocyclobutene-1,2-dione (BBD) with various 1,2-diamines. Instead of giving the 1,4-diazabiphenylene ring system, BBD reacted with ethylenediamine, diaminomaleonitrile, 4,5-diaminopyrimidine, 2-aminopyridine, also 2,3- and 3,4-diaminopyridine to give, respectively, 2-o-carboxyphenylimidazolidinium acetate 4, 3,4-dicyano-2,5-dihydro[2,5]benzodiazocine-1,6-dione 10, 4-amino-5a,9b-dihydro-5-,9b-dihydroxybenzo [3',4']cyclobuta[1',2'-4,5]imidazo[1,2-c]pyrimidine 14, 5a,9b-dihydro-5a,9b-dihydroxybenzo[3',4']cyclobuta[1',2'-4,5] imidazo[1,2-a]pyridine 17, the 4-amino derivative 16 of the latter, and the zwitter ion 18 of 4-amino-3(2-carboxy-benzylideneamino) However, BBD reacted with 4,5-diaminobenzotriazole to give the expected 1,2,3,6,11-penta-aza-1-H-indeno [4,5-b]biphenylene 20, which, on amination followed by oxidation, gave a very low yield of cis-2-cyano-3-(2'-cyanovinyl)-1,4-diazabiphenylene 3. In model experiments, 7,8-diphenylfurazano [3,4-f]quinox-aline 28 was reduced to 2,3-diamino-5,6-diphenyl quinoxaline 29, which on oxidation, gave a mixture of cis- and trans-2-cyano-3-(2'-cyanovinyl)5,6-diphenylpyrazine, 30 and 31. The pentacyclic compounds, 1,3,6,II-tetra-aza-2-oxa-2H-indeno [4,5-b]biphenylene 23 and 1,3,5,10-tetra-aza-1-H-indeno[5,6-b] biphenylene 25, were formed from BBD and the appropriate 1,2-diamines but the 5-membered heterocyclic rings could not be cleaved by reduction and hydrolysis respectively) to give tetracyclic diamines which might have undergone oxidation to give derivatives of 1,4-diazabiphenylene. Compounds 14, 16, 20, 23, 25 and 28 are derivatives of new heterocyclic systems.     

Studies of nucleosides and nucleotides—LXXIV: Purine cyclonucleosides—34 a new method for the synthesis of 2'-substituted 2'-deoxyadenosines

8,2'-O-Cycloadenosine was protected at 3' and 5'-OHs with acetyl groups and cleaved using liq. H₂S. Subsequent dethiolation and mesylation gave 2'-O-mesyl-3',5'-di-O-acetyl-arabinosyladenine (6). When 6 or its deacetylated parent compound (7) was heated with sodium azide in DMF, 3'-azido-3'-deoxyxylofuranosyladenine (9) was the only product. The cyclonucleoside was then protected with tetrahydropyranyl groups and subjected to a similar series of reactions as above to give 2'-O-mesyl-3',5'-di-O-tetrahydropyranylarabinosyladenine (14). The compound 14 was heated with sodium azide after which acidic deprotection afforded 2'-azido-2'-deoxyadenosine (16). Hydrogenation of 16 gave 2'-amino-2'-deoxyadenosine (18). 2'-Chloro-2'-deoxyadenosine (19) was also obtained by treatment of 14 with lithium chloride and subsequent deprotection. UV, IR and NMR spectral data of these compounds are described.     

Flavonoids—38: Reaction of 2'-hydroxychalcone dibromides and -α-bromochalcones with azide ion

The reaction of 2'-hydroxychalcone dibromides 1 or α-bromo-2'-hydroxychalcones 15 with sodium azide resulted in a mixture of α-azido-2'-hydroxychalcones 2, 3-aryl-5-(2-hydroxy-pheny)isoxazoles 3, flavones 4, aurones 5 and 4-aryl-5-(2-hydroxybenzoyl)-1,2,3-triazoles 6. The product ratio was strongly influenced by the character of the substituent at position C-4. Similar results were obtained with 2'-benzyloxy-4-nitrochalcone dibromide (10) and 2'-benzyloxy-α-bromo-4-mtrochalcone (17). The mechanism of the transformation of chalcone dibromides into the products via an α-bromochalcone intermediate is discussed.     

Heterocyclic N-glycosyl derivatives—XIX : Glycal nucleosides. their relationship with 2',3'-unsaturated nucleosides and their utilization in the synthesis of 1',3'-two base nucleosides

The acid catalized reaction of tri-0-acetyl-D-glucal with benzotriazole or 6-methylthiopurine in acetonitrile gave a mixture of 1',2'- and 2',3'-unsaturated nucleosides, the former predominating. The relationship between these unsaturated nucleosides is studied and an allylic carbonium ion is proposed as an intermediate for these isomerizations. The acid catalized reaction of 1',2'-unsaturated nucleosides with more benzotriazole or 6-methylthiopurine gave 1',3'-two base nucleosides. The conformation and anomeric configuration of the N-glycosyl compounds obtained were assigned by NMR spectroscopy.     

Photochemistry of 5-aryl-2(3H)-furanones. : A new route to the synthesis of chromones

The photochemistry of 5-phenyl-, 5-(2',5'-dimethoxyphenyl)-, 5-(2'-acetoxy-5'-methoxyphenyl)- and 5- (2',5'-diacetoxyphenyl)- 2(3H)-furanone (1a-d) has been investigated. Compound 1a yields phenyl vinyl ketone as expected. Similarly, 1b affords the corresponding aryl vinyl ketone but, in this case, photodimerization also occurs. Irradiation of the two o-acetoxyaryl furanones 1c and 1d gives rise to the formation of chromones as the main products. This interesting result can be accounted for in terms of a photochemical opening of the lactonic ring followed by radical addition to the acetoxy group.     

Polybrominated diphenyl ethers from Dysidea herbacea,Dysidea chlorea and Phyllospongia foliascens

The marine sponges Dysidea herbacea, D. chlorea and Phyllospongia foliascens were differentiated with difficulty in the field. D. herbacea contained 2-(2',4'-dibromophenoxy)-3,4,5-tribromophenol (1), 2-(2',4'-dibromophenoxy)-4,5,6-tribromophenol (2) and 2-(2',4'-dibromophenoxy)-3,5-dibromophenol (6). D. chlorea contained only 2-(2',4'-dibromophenoxy)-4,6-dibromophenol(3), a compound previously reported as a metabolite of D. herbacea. Phyllospongia foliascens contained 2-(3',5'-dibromo-2'-methoxy-phenoxy)-3,5-dibromoanisole (7) and a 1:2 mixture of 2-(3',5'-dibromo-2'-hydroxyphenoxy)-3,5,6-tribromophenol (8) and 2-(3',5'-dibromo-2'-hydroxyphenoxy)-3,4,5,6-tetrabromophenol (9).     

Homonucleoside phosphonic acid-I: Ageneral synthesis of isosteric phosphonate analogs of nucleoside 3'-phosphates

A general synthetic route to 3'-deoxy-3'-dihydroxyphosphinylmethyl ribonucleosides 3 the isosteric phosphonate analogs of nucleoside 3'-phosphates, is described. This involved alkylation of 1,2;5,6-di-O-isopropylidene-α-D-ribo-hexofuranose-3-ulose 7) with tetraethyl methylenediphosphonate 6, followed by stereoselective catalytic reduction and cleavage of C₆ to generate 3-deoxy-3-diethoxyphosphinylmethyl-1,2-O-isopropylidene-α-D 12a. Benzoylation followed by acetolysis then generated the key crystalline intermediate 1,2-di-O-acetyl-5-O-benzoyl-3-deoxy-3-diethoxyphosphinylmethyl-β-D-ribofuranose 13, This compound, or the related glycosyl chloride, was condensed with several purine and pyrimidine bases and all protecting groups were removed by mild alkaline treatment via a series of intramolecular cyclizations and hydrolysis. In this manner the phosphonate analogs of nucleoside 3'-phosphates derived from adenine, 6-dimethylaminopurine, uracil, thymine, and cytosine were prepared.     

v-Triazolines. part XXI. Spiro[bicyclo[2.2.1]hept-2-ene[54']1',2'.s'-triazole]derivatives from cyclopentadiene and 5-amino-4-methylene-v-triazolines

1R^*, 4R^*, 5S^*, 5'S^*-5'-Amino-1'-(4-nitrophenyl)-4',5'-dihydrospiro[bicyclo [2.2. 1]hept-2-ene[5.4]-1',2',3'-triazoles]$\text{2}$ have been obtained both by ?4 +2]-cycloaddition of cyclopentadiene to amino-methylene-1-(4-nitrophenyl)-4,5-dihydro-v-triazoles $\text{1}$ and by [3+2]-cycloaddition of 4-nitrophenylazide to 5-aminomethylene-2-norborenes $\text{4}$. The configuration has been fully established by X-ray crystallographic analysis. The course of the cycloaddition and the thermal behaviour of $\text{2}$ are discussed.     

Reactions of β-substituted amines-IV: Kinetics and stereochemistry of the thermal to (r) 3-chloro-1-ethylpiperidine,and the stereo-chemical course of their reactions with nucleophiles

The rate of the thermal rearrangement of (S) 2 chloromethyl-1-ethylpyrrolidine [(S)-1a] to (R)-3-chloro-1-ethylpiperidine [(R) 2a] has been examined at three temperatures in benzene by PMR and polarimetry. The rearrangement was shown to be completely stereospecific and to obey a simple first order rate law. The calculated E_a ΔH3 and ΔS3 were 22 ± 2 $\text{kcal}\text{mole}$ (25°), 21 ± 2.5 $\text{kcal}\text{mole}$ (25°) and - 10 ± 2 e.u. (0°K) respectively. The effect of solvents having differing dielectric constants was also studied. A transition state 9'a and an ion pair intermediate 3a are suggested for the rearrangement. The stereochemical course of the reactions of (S)-1a, (R)-2a and (S)-2a with hydroxide and methoxide ions have been shown to be 100% stereospecific with an uncertainty of about 1%. The absolute configurations of all optically active reactants and products [(S)- and (R)-4a, (S)-4b (R)- and (S)-5a, (R)-5b, (S,S')-6a, (S,R')-7a and (R,R')-8a] were established by chemical correlations with known compounds or by ORD and chemical inference. The ring opening of both the primary and secondary aziridinium ion positions of 1-azonia-1-ethylbicyclo [3.1.0]hexane [(S)-3a] by nucleophiles proceeds entirely by S_N2 processes. The conversion of (R)-1-ethyl-3-hydroxypiperidine [(R)-5a] to (S)-2a. HCl with thionyl chloride in chloroform proceeds by inversion with 4.8% racemization, whereas the thermal rearrangement of (S)-1a to (R)-2a occurs with complete retention of absolute configuration.     

Synthese de la cyclo-5'-8 desoxy-5' adenosine: stereochimie et mecanisme de la cyclisation d'un derive de l'iodo-5' adenosine par le zinc

N,N'-Dibenzoyl 2', 3'-O-isopropylidene 5'-deoxy 5'-iodo adenosine can efficiently transformed into the corresponding 5',8-cyclo-7,8-dihydronucleoside by zinc in pyridine. Only one diastereoisomer is obtained. By spin decoupling and NOE techniques at 250 MHz, the R-configuration at C-8 was established. This compound showed typical dihedral angles of about 90° for the vicinal protons H-1', H-2' and H-3', H-4'. Using adenosine derivatives stereospecifically labelled at C-5', it was demonstrated that the cyclisation occurs with racemisation at that position.     

5'-Substituted 2,2'-anhydrouridines

3',5'-Di-O-acetyl-2'-halogenouridines (1a, 1c and 1d) can be partially deacetylated at C-5' by transesterification with methanol-HCl, providing the 3'-O-acetyl derivatives 2a–2c. These can be converted into the 5'-O-mesyl derivatives 3a–3c, and latter into the 5'-chloro compounds 3d-3f. All 5'-substituted 2'-halogeno compounds give the corresponding 2,2'-anhydrouridine derivatives 4a–4c on treatment with NaOMe. Structures were proved by IR and ¹H-NMR.     

A novel synthesis of 2'-hydroxy-1',3'-xylyl crown ethers

Six novel 2' - hydroxy - 1',3' - xylyl crown ethers (8a–e and 13)¹ have been synthesized utilizing the allyl group to protect the OH function during the cyclization reaction. The macrocycles 6a-e were formed in yields of 26 to 52%, by intermolecular reaction of 4 - chloro - 2,6 - bis(bromomethyl) - 1 - (2 - propenyloxy)benzene (5) with polyethylene glycols; 6a was also obtained by an intramolecular cyclization reaction of monotosylate 14.A 30-membered ring with a 2' - hydroxy - 1',3' - xylyl sub-unit was obtained in 87% yield by reaction of ditosylate 9 with bis [2 - (o - hydroxyphenoxy)ethyl]ether (11) in the presence of cesium fluoride. The synthesis of crown ethers with a 2' - hydroxy - 1',3' - xylyl sub-unit (1c–e, H for CH₃) by demethylation of the corresponding 2'-methoxy crown ethers 1c–e with lithium iodide were unsuccessful; it would appear that the demethylation reaction is restricted to 15- and 18-membered rings. One of the 2' - hydroxy - 1',3' - xylyl crown ethers 8d forms a crystalline 1:1-complex with water.     

Further applications of endocyclic enamine-enone annulations : The total syntheses of rac-Sceletium alkaloid A4 and 3'-demethoxy sceletium alkaloid A4

The total synthesis of rac-sceletium alkaloid A₄1a and of its 3'-demethoxy analogue 1b via the annulation of endocyclic enamines 4a–b is presented. The Michael acceptor 5a is a useful synthon for the two-step synthesis of 2,3-disubstituted pyridines from Δ²-pyrrolines.     

1H-NMR-spektroskopische konformationsanalyse von halogenierten thymidinabkömmlingen: I. konformation von thymidin, 3',5'-didesoxy-3'-chlor-5'-fluor-thymidin und 3', 5'-didesoxy-3',5'-difluor-thymidin

An improved method is given for determining the conformation of furanoid nucleosides by ¹H-NMR-spectra analysis using halogen-substituted thymidines as examples. The state of the three equilibria - ring-puckering, rotation about the C₄-C₅- bond and about the glycosidic bond - are influenced by the halogen substituents. Compared with thymidine the 3'-chlorine substituent shifts the furanose conformation to conformers, where the 3'-chlorine substituent is equatorial. The 5'-fluorine substituent increases the contribution of the G-G-rotamer and the ratio of syn-conformation. The relationships between the conformers in the pseudo-rotatory cycle and the population of the C_4'-C_5' rotamers are discussed.