The supertristeroids: large, chiral, molecular bowls prepared by trimerization of pentacyclic steroidal ketones

Robinson annulation of coprostanone (1) at the 2,3- and 3,4-positions gave two pentacyclic enones (7 and 10) that contain A/B-cis-fused ring junctions. Reduction of these enones gave the pentacyclic steroidal ketones 2 alpha,3beta- (8) and 2 alpha,3 alpha-(3'-oxocyclohexano)-5 beta-cholestane (9) and 4 alpha,3beta- (11) and 4 alpha,3 alpha-(3'-oxocyclohexano)-5 beta-cholestane (12). The structures of compounds 8, 9, and 11 were unambiguously established by X-ray analysis. TiCl4-promoted trimerization of compounds 8 and 11 gave the "supertristeroids" 4 and 5, respectively: large (C93) chiral, hydrocarbon clefts with C3-symmetric pockets approximately 12 A in diameter.     

Furopyridines. VII. Preparation and hydrolysis of 2-cyano and 3-cyano derivatives of furo[3,2-b]-, furo[2,3-c]- and furo[3,2-c]pyridine

This paper describes the preparation and hydrolysis of 2-cyano and 3-cyano derivatives of furo[3,2-b]-, furo[2,3-c]- and furo[3,2-c]pyridine. Treatment of furopyridines 1a , 1b and 1c with n-butyllithium in hexane-tetrahydrofuran at -70° and subsequent addition of N,N-dimethylformamide yielded 2-formyl derivatives 2a , 2b and 2c. Dehydration of the oximes 4a , 4b and 4c of 2a , 2b and 2c gave 2-cyano compounds 5a , 5b and 5c , which were hydrolyzed to give 2-carboxylic acids, 6a, 6b and 6c , respectively. Reaction of 3-bromo compounds 7a , 7b and 7c with copper(I) cyanide in N,N-dimethylformamide afforded 3-cyano derivatives 8a , 8b and 8c. Alkaline hydrolysis of 8a , 8b and 8c gave compounds formed by fission of the 1-2 bond of furopyridines 9a , 9b and 9c , while acidic hydrolysis gave the corresponding carboxamides, 10a , 10b and 10c.     

Synthetic analogues of Peganum alkaloids. III. Pentamethylenequinazolones

Monosubstituted 5-, 6-, and 8-methoxy-3,4-dihydro-2,3-pentamethylenequinazolones (1–3) have been syntehsized by the condensation of monosubstituted methoxyanthranilic acids with caprolactam. Demethylation with hydrobromic acid gave the corresponding hydroxy compounds [4–6]. When the 6- and 8-methoxy- and 6- and 8-hydroxy-3,4-dihydro-2,3-pentamethylenequinazolones (2, 3, 5, and 6) were reduced with zinc in hydrochloric acid, the corresponding quinazoline derivatives (7–10) were obtained. The melting points of the basis and their hydrochlorides are given. Some features of their UV, mass, and PMR spectra are reported.     

Synthesis and Reactions of Some New Heterocyclic Compounds Containing Cycloalka[e]thieno[2,3‐b]pyridine Moiety

Hydrolysis of ethyl 3-amino-4-aryl-cycloalka[e]thieno[2,3-b]pyridine-2-carboxylates ( 3a-d) gave the corresponding o-aminocarboxylic acids 4a-d . Heating the latter compounds ( 4a-d) with acetic anhydride furnished the oxazinone derivatives 5a-d which, in turn, underwent recyclization reaction to give the corresponding pyrimidinones 6a-d upon treatment with ammonium acetate in acetic acid. Reaction of 3-amino-4-aryl-cycloalka[e]thieno[2,3-b]pyridine-2-carboxamides ( 3f,h ) with triethyl orthoformate gave pyrimidinone derivatives 7a,b . Reaction of 3-amino-4-phenyl-cycloalka[e]thieno[2,3-b]pyridine-2-carboxamides 3e,h with aromatic aldehydes furnished tetrahydropyridothienopyrimidinones 8a-d . Chlorination of 7a,b and 6a-d by using phosphorous oxychloride produced 4-chlorocycloalka[5′,6′]pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine derivatives 9a-f which were used as key intermediates in the synthesis of several new cycloalkapyrido-thienopyrimidines 10a-f ˜ 14a-f . Moreover, some cycloalkapyridothienotriazinones 15a,b-17a,b were synthesized.     

Oxetane from A-nor-steroides: 2-alpha, 5-oxido-A-nor-5-alpha-cholestane, 2-beta, 5-oxido-A-nor-5-beta-cholestane and 2-alpha-ethyl-2-beta,2'-oxido-A-nor-5-alpha-cholestane

Treatment of 2β-tosyloxy-A-nor-5α-cholestane-5-ol ( 2 ) with t-butoxide in t-butanol gave 2α, 5-epoxy-A-nor-5α-cholestane ( 3 ) in quantitative yield. When A-nor-5β-cholestane-2α, 5-diol ( 4 ) was treated with tosyl chloride in pyridine 2β-chloro-A-nor-5β-cholestane-5-ol ( 7 ) and 2α-tosyloxy-A-nor-5β-cholestane-5-ol ( 8 ) were obtained. Whereas the chloride 7 was resistant to t-butoxide the tosylate 8 was transformed into an 1 : 1 mixture of 2α, 5-epoxy-5β-cholestane ( 10 ) and 2ξ-t-butoxy-A-nor-5β-cholestane-5-ol ( 11 ). In 2α-tosyloxy-A-nor-5α-cholestane-5-ol ( 12 ) substitution occurred as the only reaction. Both oxetanes 3 and 10 isomerize after heating above 50° and in polar or protic solvents to form A-nor-Δ³⁽⁵⁾-cholestene-2α-ol ( 6 ) and -2β-ol ( 14 ) respectively. Also, 2, 5-diols are encountered. 2α-Ethyl-2β, 2′-epoxy-A-nor-5α-cholestane ( 23 ) was synthesized starting from A-nor-5α-cholestane-2-one ( 17 ). The intermediates were the ester 16 , the diol 18 , the hydroxy-tosylate 19 and the chlorhydrin 20 . The spirocyclic oxetane 23 was reduced by LiAlH₄ in dioxane (not in ether). By chromatography on silica gel 23 was isomerized to the homoallylic alcohol 21 and transformed into 2-methylene-A-nor-5α-cholestane ( 24 ) by fragmentation. The IR. and NMR. spectra of the new oxetanes were compared with those of a series of known oxetanes.     

A new domino reaction based on [4+2]-cycloadditions of pyrido[1,2-a]pyrazines with azadienophiles

The reaction of pyrido[1,2-a]pyrazines 1 with nitroso compounds 2 provides pyridyl substituted 1,2,4-triazinones 4 via a domino reaction which involves a cycloaddition and a ring transformation reaction. The intermediate and regioselective formed oxadiazines 4′ were trapped by complexation yielding the (CO)₄Mo-complex 5. Derivatives of diazene such as N-phenyltriazolindione 6a , phthalazinedione 6b or esters of azodicarboxylic acid 6c-6f reacted with 1 to give different derivatives of 1,2,4-triazine 7a-f . The use of oxygen gave oxadiazinones 8 .     

Syntheses of Diamino-dideoxylyxose Derivatives using Acylnitroso Dienophiles

N-Acylnitroso derivatives 6 which were prepared by in-situ oxidation of the corresponding hydroxamic acids 5 reacted instantaneously and in high yields with dihydropyridine 4 . The Diels-Alder adducts 8 were formed regiospecifically with the acylnitroso dienophiles 6a–c , whereas the dienophiles 6d–f gave mixtures of both regioisomers 7 and 8 . These and some other results [2] were best explained by the FMO theory. The Diels-Alder adducts 7 and 8 gave the corresponding ‘anti’-cis-glycols when reacted with OsO₄/N-methylmorpholine N-oxide. Hydrogenolysis of the N–O bond followed by peracetylation led to the expected aminolyxose derivatives 14 and 16 . A similar sequence, using 4 and the hydroxamic-acid derivative 18 of (+)-D-mandelic acid led, with a poor asymmetric induction, to a mixture of the expected optically active aminolyxose compounds 19A / 19B .     

Synthesis of novel acyclonucleosides. Reactions of 1-(2-oxopropyl)pyridazin-6-ones

Multi-substituted-1-(1-bromo-2-oxopropyl)pyridazin-6-ones 3, 4 , multi-substituted-1-(1,1-dibromo-2-oxopropyl)pyridazin-6-ones 7, 8 , and multi-substituted-1-(3-bromo-2-oxopropyl)pyridazin-6-ones 5, 6 were synthesized from the corresponding 1-(2-oxopropyl)pyridazin-6-ones 1, 2 by the selective bromination in acidic or neutral medium. And treatment of 1,1-dibromo-2-oxopropyl derivatives 7, 8 with aqueous potassium carbonate gave the corresponding pyridazin-6-ones 9, 10 by the dealkylation. Reaction of 1 with methanolic potassium cyanide afforded only the corresponding 4-methoxy derivative 11 , whereas reaction of 2 with methanolic potassium cyanide gave 4-methoxy derivative 12 and 2-cyano-2-hydroxypropyl derivative 13 . Reaction of 1 and 2 with hydroxylamine in methanol afforded the corresponding syn-2-hydroxyiminopropyl derivatives 14 and 15 .     

Regioselective synthesis of heterocyclic scaffold by aryl radical cyclization

Regioselective synthesis of a number of coumarin‐annulated pentacyclic heterocycles have been achieved by tri‐n‐butyltin hydride‐mediated aryl radical cyclization. The products are formed as a mixture of cis‐ and trans‐ forms which were successfully separated by careful silica gel flash chromatography.     

Saturated heterocycles. 254 . synthesis and stereochemistry of saturated or partially saturated pyridazino-[6,1-b]- and phthalazino[1,2-b]quinazolinones

By the reaction of anthranilic hydrazide 1 with cis-2-(p-methylbenzoyl)-1-cyclohexanecarboxylic acid 2a or diendo-3-(p-methylbenzoyl)bicyclo[2.2.1]heptane-2-carboxylic acid 2b , fused tetra- and pentacyclic ring systems 3a, b were prepared, trans-2-Amino-1-cyclohexanecar-bohydrazide 4b was reacted with 3-(p-chlorobenzoyl)propionic acid 5 to yield the pyridazino[6,1-b]quinazolinone 6 . From the reaction of cis-2-amino-1-cyclohexanecarbohydrazide 4a with 2a , three isomeric partially saturated 8H-phthalazino[1,2-b]quinazolin-8-ones 7a-c were formed. The reaction of diexo-2-aminobicyclo[2.2.1]heptane-3-carbohydrazide 4c and 2a furnished the pentacyclic derivatives 8 and 9 containing a 3-aryl-4,5-dihydropyridazine or 3-arylhexahydropyridazine ring C with cis annelated C/D rings. The formation of 8 and 9 involving different ring systems can be rationalized by two reaction pathways: (i) in the bislactam 9 the carboxyl group acylates the hydrazide, while (ii) in 8 it forms a pyridazine ring with the cyclic amino group by cyclocondensation. The structures of the products were elucidated by ¹H and ¹³C nmr methods, including DEPT, DNOE and 2D-HSC measurements.     

Paterno-Buchi photocyclization of 2-siloxyfurans and carbonyl compounds. Notable substituent and carbonyl (Aldehyde vs ketone and singlet- vs triplet-excited state) effects on the regioselectivity (Double-bond selection) in the formation of bicyclic exo-oxetanes

Paterno-Buchi coupling, photochemical [2 + 2] cycloaddition, of carbonyl compounds 2a-f with 2-siloxyfurans 1a-d has been investigated in detail. The stereoselective formations of exo-oxetanes 3 and 4 were observed in high yields. The regioselectivity (double-bond selection, 3 vs 4) was found to be largely dependent upon the carbonyls, the substituents at the furan ring, and the excited state of the carbonyls (singlet vs triplet). The photoreaction of aldehydes 2a-c gave bicyclic exo-oxetanes 3 and 4 at regio-random, independent upon their excited states and the substituents at furan ring. However, the photoreaction of the triplet state of ketones 2d-f was found to give regioselectively exo-oxetanes 4, except for the 4-methyl-2-siloxyfurane 1d case. The singlet-excited state of acetone 2f gave both oxetanes 3 and 4 at regio-random. For the singlet-state photochemistry, the approach direction of the electrophilic oxygen of the excited carbonyls to the furan ring is proposed to be an important factor for the exo-stereoselection. The Griesbeck model can rationalize the regio- and exo-selective formation of oxetanes in the triplet-state photoreaction.     

Influence of the heterocyclic side ring on orientation during nitrations of 1,2-alkylenedioxy-annelated benzenes and their mononitro derivatives

Nitration of 1,2-alkylenedioxybenzenes 1 furnished the respective nitro derivatives 3 and 4 in the relative ratios: 4a:3a /100:trace, 4b:3b /98:2.4, 4c:3c /86:14, 4e:3e /91:9 and 4f:3f /99:1.3. Nitration of 4 gave 5a:6a:8a /0:0:100, 5b:6b:8b /7.7:3.2:89, 5c:6c:8c /23:12:65, 5d:6d:8d /14:74:12, 5e:6e:8e /27:18:55 and 5f:6f:8f /23:7.0:70. Nitration of the isomeric 3 afforded the dinitro products 5, 6 and 7 in the following relative ratios: 5a:6a:7a /92:8:0, 5b:6b:7b /80:20:0, 5c:6c:7c /69:20:1 1, 5d:6d:7d /45:19:36, 5e:6e:7e /37:57:5.9 and 5f:6f:7f /64:36:0. Nitration of 3-nitro-1,2-dimethoxybenzene ( 9 ) furnished: 10:11 /63:37. Orientation as a function of the heterocyclic ring-size is discussed.     

para-Bridged symmetrical pillar[5]arenes: their Lewis acid catalyzed synthesis and host-guest property

Condensation of 1,4-dimethoxybenzene (DMB) with paraformaldehyde in the presence of BF3.O(C2H5)2 gave novel para-bridged pentacyclic pillar DMB (DMpillar[5]arene). Moreover, para-bridged pentacyclic hydroquinone (pillar[5]arene) was prepared. Pillar[5]arene formed 1:1 host-guest complexes with dialkyl viologen and alkyl pyridinium derivatives. However, pillar[5]arene did not form complexes with the diadamantyl viologen derivative since a bulky adamantyl group was unable to thread the cavity of pillar[5]arene.     

Synthesis of heierocyclic compounds from 2-phenyl-1, 2,3-triazole-4-formylhydrazine

2-Phenyl-1, 2, 3-triazole-4-formylhydrazine (2) was prepared by hydrazinolysis of the corresponding ester 1. Reaction of 2 with CS2/KOH gave the oxadiazole derivatives (3) which via, Mannich reaction with different dialkyl amines furnished 3-N, N-dialkyl derivatives (4a-c). Also, condensation of 2 with appropriate aromatic acid in POCl3 yielded oxadiazole derivatives (5a-c), or with aldehydes and ketones afforded hydrazones (6a-c). Cyclization of (6a-c) with acetic anhydride gave the desired dihydroxadiazole derivatives (7a-c). On the other hand, reaction of dithiocarbazate (8) with hydrazine hydrate gave the corresponding triazole derivative (9) which on treatment with carboxylic acids in refluxing POCl3 yielded s-triazole[3,4-b]-1, 3, 4-thiadiazole derivatives (10a-b). The structures of all the above compounds were confirmed by means of IR, 1H NMR, MS and elemental analysis.     

Synthesis of new 3<Emphasis Type="Italic">H</Emphasis>-pyrrole derivatives from 3-aryl-2-oxa-7-azaspiro[4.4]nona-3,6,8-trienes

8-Amino-3-aryl-1-imino-4-methyl-6-(morpholin-4-yl)-2-oxa-7-azaspiro[4.4]nona-3,6,8-triene-9-carbonitriles reacted with acetic anhydride to give different products, depending on the solvent. The reaction in tetrahydrofuran gave the corresponding N-acyl derivatives at the imino group, whereas in pyridine 5-amino-2-morpholin-4-yl-3-(1-aryl-1-oxopropan-2-yl)-3H-pyrrole-3,4-dicarbonitriles were formed as a result of opening of the furan ring.     

Model compounds for (6-4) photolyases: a comparative flavin induced cleavage study of oxetanes and thietanes

Thietanes were used in the past as mimics for an unstable oxetane intermediate formed during the repair of mutagenic (6-4) lesions. The thietane derivatives were found to be not repaired, raising the question of how well thietanes are cleaved by single electron donation compared to oxetanes. We have prepared two flavin-containing oxetane and thietane model compounds for the (6-4) photolyase catalyzed repair process and we show that both are efficiently cleaved by a reduced and deprotonated flavin. Thietanes are therefore excellent models. The lack of their repair can be attributed to lack of binding.     

Synthesis of certain alkenyl purines and purine analogs

Synthesis of alkenyl derivatives of certain purines and purine analogs is described. Direct alkylation of the sodium salt of 6-chloropurine (1) either with 1-bromo-2-pentene or 4-bromo-2-methyl-2-butene in N,N-dimethylformamide furnished N-7, 4a and N-9, 3a , 3b alkenyl derivatives. Similar alkylation of 2-amino-6-chloropurine (2) provided the corresponding N-7, 4c-4e and N-9, 3c-3e alkenyl derivatives. Acid hydrolysis of these chloro derivatives 3a-3e, 4a,c-e furnished the corresponding alkenyl hypoxan-thines 6a, 6b and 7a or alkenyl guanines 6c-6e and 7c-7e. Treatment of 3a-3d with thiourea in absolute ethanol provided the corresponding 6-thio derivatives 5a-5d. Alkylation of the sodium salt of either purine-6-carboxamide (8) or 1,2,4-triazole-3-carboxamide (10) gave mainly one isomer 9a, 9b and 11a, 11b. The direct alkylation of pyrrolo[2,3-d]pyrimidin-4(3H)-one (12) gave N-3 alkenyl derivatives 13a, 13b , and the N-7 alkenyl derivatives 16a, 16b have been prepared starting from the 4-chloro derivative 14 . Synthesis of 2-amino-7-(2-penten-1-yl)pyrrolo[2,3-d]pyrimidin-4(3H)-one (19a) has been accomplished starting from 2-amino-4-methoxypyrrolo[2,3-d]pyrimidine (17) . These alkenyl derivatives were found to be devoid of anti-HCMV activity in vitro.     

Synthesis of carpachromene and related isopentenylated derivatives of apigenin

Acacetin (4) on reaction with prenyl bromide in the presence of methanolic sodium methoxide yielded 6,8-di-C-prenyl-(5) and 6-C-prenyl-(10) derivatives. The former (5) formed the corresponding bisdihydropyrano derivative (8). Monomethyl derivative of 10 (12) gave monodihydropyrano derivative (13). DDQ reaction of 10 followed by methylation afforded di-O-methyl carpachromene (2); whereas that of 5 gave a mixture of 21 and 22.

Nuclear prenylation of apigenin (3) in a similar way gave 6,8-di-C-C-prenyl-(16), its 7-0-prenyl-(15) and 6-C-prenyl-(18) derivatives. DDQ reaction of 18 provided natural carpachromene.¹ The structure of the isopentylated apigenin isolated by Dreyer et al.² needs further consideration.     

Furopyridines. XXVIII. Reactions of 3-bromo derivatives of furo[2,3-b]-, -[3,2-b]-, -[2,3-c]- and -[3,2-c]pyridine and their N-oxides

Bromination of 3-bromofuro[2,3-b]- 1a , -[3,2-b]- 1b and - [3,2-c]pyridine 1d afforded the 2,3-dibromo derivatives 2a, 2b and 2d , while the -[2,3-c]- compound 1c did not give the dibromo derivative. Nitration of 1a-d gave the 2-nitro-3-bromo compounds 3a-d . The N-oxides 4a-d of 1a-d were submitted to the cyanation with trimethylsilyl cyanide to yield the corresponding α-cyanopyridine compound 6a-d . Chlorination of 4a and 4d with phosphorus oxychloride gave mainly the chloropyridine derivatives 7a, 7′a and 7d , while 4b and 4c gave mainly the chlorofuran derivatives 7′b and 7′c accompanying formation of the chloropyridine derivatives 7b, 7′b and 7c . Acetoxylation of 4a and 4b with acetic anhydride yielded the acetoxypyridine compounds 8a, 8′a and 8b , while 4c and 4d gave the acetoxypyridine 8′c, 8′d and 8′d , pyridone 8c and 8d , acetoxyfuran 8′c and dibromo compound 9c and 9′c.     

Synthesis of (±) lupinifoun, di-o-methyl xanthohumol and isoxanthohumol and related compounds

Nuclear prenylation of naringenin (7) with 2-methylbut-3-en-2-ol in the presence of boron trifluoride etherate gives a mixture of 6-C-prenyl-(11), 8-C-prenyl-(15) and 6,8-di-C-prenyl-(8) derivatives. On formic acid cyclisation, 11 yielded two monodihydropyrans (12 and 13), but 15 afforded only one viz 16; similarly 8 formed the bisdihydropyran 10. Methylation of 8-C-prenyl naringenin (15) with Me₂SO₄ resulted in the formation of di-O-methyl derivatives of xanthohumol (22) and isoxanthohumol (23).

Cyclodehydrogenation of 6,8-di-C-prenyl-naringenin (8) with DDQ gave a mono-C-prenyl-2,2-dimethylpyran (1) corresponding to (±) lupinifolin. The angular isomer (2) was also formed. The structure of natural flemichin-B therefore needs further consideration. Similarly, cyclodehydrogenation of 6-C-(11)- and 8-C-prenyl-(15) naringenins afforded the corresponding linear (24) and angular (25) derivatives which have been characterized by conversion into known chalcones 26 and 27 by O-methylation.