Conformational Studies of (±)‐11,12‐Didehydro‐11‐deoxycorynoline and (+)‐11,13‐Didehydro‐11‐deoxychelidonine,Hexahydrobenzo[c]phenanthridine‐Type Alkaloid Derivatives,by X‐Ray Crystal Structure and NMR Analyses

The X‐ray crystal analyses of the two 11‐deoxy‐didehydrohexahydrobenzo[c]phenanthridine‐type alkaloid derivatives 3 and 4 , derived from (±)‐corynoline ( 1 ) and (+)‐chelidonine ( 2 ), established their structures as (±)‐(5bRS,12bRS)‐5b,12b,13,14‐tetrahydro‐5b,13‐dimethyl[1,3]benzodioxolo[5,6‐c]‐1,3‐dioxolo[4,5‐i]phenanthridine ( 3 ) and (+)‐rel‐(12bR)‐7,12b,13,14‐tetrahydro‐13‐methyl[1,3]benzodioxolo[5,6‐c]‐1,3‐dioxolo[4,5‐i]phenanthridine ( 4 ). The conformations of 3 and 4 in CDCl₃ were determined on the basis of ¹H‐ and ¹³C‐NMR spectroscopy.     

One‐Pot,Asymmetric and Diastereoselective Four‐Component Synthesis of Polyfunctional (Z)‐Alkenyl Methyl Sulfones with Three Stereogenic Centers

The reaction of 1‐(trimethylsilyloxy)cyclopentene ( 9 ) with (±)‐1,3,5‐triisopropyl‐2‐(1‐(RS)‐{[(1E)‐2‐methylpenta‐1,3‐dienyl]oxy}ethyl)benzene ((±)‐ 4a ) in SO₂/CH₂Cl₂ containing (CF₃SO₂)₂NH, followed by treatment with Bu₄NF and MeI gave a 3.0 : 1 mixture of (±)‐(2RS)‐2{(1RS,2Z,4SR)‐2‐methyl‐4‐(methylsulfonyl)‐1‐[(RS)‐1‐(2,4,6‐triisopropylphenyl)ethoxy]pent‐2‐en‐1‐yl}cyclopentanone ((±)‐ 10 ) and (±)‐(2RS)‐2‐{(1RS,2Z)‐2‐methyl‐4‐[(SR)‐methylsulfonyl]‐1‐[(SR)‐1‐(2,4,6‐triisopropylphenyl)ethoxy]pent‐2‐en‐1‐yl}cyclopentanone ((±)‐ 11 ). Similarly, enantiomerically pure dienyl ether (−)‐(1S)‐ 4a reacted with 1‐(trimethylsilyloxy)cyclohexene ( 12 ) to give a 14.1 : 1 mixture of (−)‐(2S)‐2‐{(1S,2Z,4R)‐2‐methyl‐4‐(methylsulfonyl)‐1‐[(S)‐1‐(2,4,6‐triisopropylphenyl)ethoxy]pent‐2‐enyl}cyclohexanone ((−)‐ 13a ) and its diastereoisomer 14a with (1S,2R,4R) or (1R,2S,4S) configuration. Structures of (±)‐ 10 , (±)‐ 11 , and (−)‐ 13a were established by single‐crystal X‐ray crystallography. Poor diastereoselectivities were observed with the (E,E)‐2‐methylpenta‐1,3‐diene‐1‐ylethers (+)‐ 4b and (−)‐ 4c bearing ( 1 S )‐1‐phenylethyl and (1S)‐1‐(pentafluorophenyl)ethyl groups instead of the Greene's auxiliary ((1S)‐(2,4,6‐triisopropylphenyl)ethyl group). The results demonstrate that high α/β‐syn and asymmetric induction (due to the chiral auxiliary) can be obtained in the four‐component syntheses of the β‐alkoxy ketones. The method generates enantiomerically pure polyfunctional methyl sulfones bearing three chiral centers on C‐atoms and one (Z)‐alkene moiety.     

On the Scope of a Prins‐Type Cyclization of Oxonium Ions

The Prins cyclization of an aldehyde 1 with a homoallylic alcohol 2 , affording tetrahydro‐2H‐pyrans 4 via the oxonium ion 3 as central intermediate, was conceptually transferred to (alk‐3‐enyloxy)acrylates 6 , which form a related oxonium ion 7 upon treatment with acids (Scheme 1). The scope and utility of this modification of the Prins‐type cyclization of oxonium ions is discussed exemplarily by means of the syntheses of ten tetrahydro‐2H‐pyran and tetrahydrofuran derivatives, featuring diverse substitution patterns as well as different degrees of molecular complexity. These target structures include (±)‐ethyl (2RS)‐2‐[(2RS,4SR,6RS)‐ and (2SR,4RS,6SR)‐2‐tetahydro‐4‐hydroxy‐6‐methylpyran‐2‐yl]propanoate ( 23 ), (±)‐ethyl [(2RS, 3RS)‐tetrahydro‐3‐isopropenylfuran‐2‐yl]acetate ( 32 ), (±)‐ethyl (2Z)‐3‐(tetrahydro‐2,2‐dimethylfuran‐3‐yl)acrylate ( 37 ), (±)‐(3aRS,6RS, 7aRS)‐octahydro‐7a‐methylbenzofuran‐6‐yl formate ( 42 ), (±)‐ethyl (2RS,3RS,4aRS,8SR,8aRS)‐hexahydro‐2,5,5,8‐tetramethyl‐7‐oxo‐2H,5H‐pyrano[4,3‐b]pyran‐3‐carboxylate ( 48 ), and (±)‐ethyl (2RS,3RS,6SR)‐tetrahydro‐6‐(2‐methoxy‐2‐oxoethyl)‐3‐methyl‐2H‐pyran‐2‐carboxylate ( 53 ) (see Schemes 3 and 5–8). Besides the stereochemistry and mechanistic details of this versatile oxonium‐ion cyclization, the synthesis of suitable starting materials is also described.     

Disila‐Galaxolide and Derivatives: Synthesis and Olfactory Characterization of Silicon‐Containing Derivatives of the Musk Odorant Galaxolide

A series of silicon‐containing derivatives of the polycyclic musk odorant galaxolide ( 4 a ) was synthesized, that is, disila‐galaxolide ((4RS,7SR)‐ 4 b /(4RS,7RS)‐ 4 b ), its methylene derivative rac‐ 9 , and its nor analogue rac‐ 10 . The tricyclic title compounds with their 7,8‐dihydro‐6,8‐disila‐6 H‐cyclopenta[g]isochromane skeleton were prepared in multistep syntheses by using a cobalt‐catalyzed [2+2+2] cycloaddition of the mono‐ yne H₂C?CHCH₂OCH₂C?CB(pin) (B(pin)=4,4,5,5‐tetramethyl‐1,3,2‐di‐ oxaborolan‐2‐yl) with the diynes H₂C?C[Si(CH₃)₂C?CH]₂ or H₂C‐ [Si(CH₃)₂C?CH]₂ as the key step. Employing [Cr(CO)₃(MeCN)₃] as an auxiliary, the disila‐galaxolide diastereomers (4RS,7SR)‐ 4 b and (4RS,7RS)‐ 4 b could be chromatographically separated through their tricarbonylchromium(0) complexes, followed by oxidative decomplexation. The identity of the title compounds and their precursors was established by elemental analyses and multinuclear NMR spectroscopic studies and in some cases additionally by crystal structure analyses. Compounds (4RS,7SR)‐ 4 b , (4RS,7RS)‐ 4 b , rac‐ 9 , and rac‐ 10 were characterized for their olfactory properties, including GC‐olfactory studies of the racemic compounds on a chiral stationary phase. As for the parent galaxolide stereoisomers 4 a , only one enantiomer of the silicon compounds (4RS,7SR)‐ 4 b , (4RS,7RS)‐ 4 b , rac‐ 9 , and rac‐ 10 , smelt upon enantioselective GC‐olfactometry, which according to the elution sequence is assumed to be also (4S)‐configured as in the case of the galaxolide stereoisomers. The disila‐analogues (4S,7R)‐ 4 b and (4S,7S)‐ 4 b were, however, about one order of magnitude less intense in terms of their odor threshold than their parent carbon compounds (4S,7R)‐ 4 a and (4S,7S)‐ 4 a . The introduction of a 7‐methylene group in disila‐galaxolide ( 4 b →rac‐ 9 ) improved the odor threshold by a factor of two. With the novel silicon‐containing galaxolide derivatives, the presumed hydrophobic bulk binding pocket of the corresponding musk receptor(s) could be characterized in more detail, which could be useful for the design of novel musk odorants with an improved environmental profile.     

Studies for a Diastereoselective Synthesis of the Tetracyclic Diterpenic Diol Stemarin: A Model Study for a New Preparation of the Key Intermediate and the Synthesis of (+)-18-Deoxystemarin

Methods for a stereoselective preparation of compounds of type 2b , a key intermediate of a previous synthesis of the tetracyclic diterpene stemarin ( la ), have been tested on model compounds 5a, 5c , and 8a . Thus, (±)-(1RS,6SR,8SR,11SR)-hydroxytricyclo[6.2.2.0^l,6]dodecan-9-one ( 5a ) was transformed by the Mitsunobu reaction into (±)-(1RS,6SR,8SR,11RS)-11-(benzoyloxy)tricyclot[6.2.2.0^1,6]dodecan-9-one ( 6b ; Scheme 2). The latter was also obtained from (±)-(1RS,6SR,8SR,11RS)-11-[(4)-toluenesulfonyloxy]tricyclo[6.2.2.0^1,6]dodecan-9-one ( 5c ) by the action of Et₄N (PhCOO) in acetone. Compound 6b was then converted into (±)-(1RS,6RS,8RS,9RS)-tricyclo[6.2.2.0^1,6]dodecan-9-ol ( 8b ), a model for 2b . Compound 8b was also prepared from its epimer 8a by the Mitsunobu reaction via ester 7b . The inversion of configuration of bicyclo[2.2.2]octan-2-ols or derivates was not previously described. The model studies paved the way to the diastereoselective synthesis of (+)-18-deoxystemarin ( 1b ) via 12β-hydroxy-13-methyl-9β,13β-ethano-9β-podocarpan-15-one ( 10a ) and 13-methyl-9β,13β-ethano-9β-podpcarpan-12α-ol ( 11b ).     

Ring Enlargement and Sulfur‐Transfer Processes in SiO2‐Catalyzed Reactions of Thiocarbonyl Compounds with Optically Active Oxiranes

The reactions of 1,3‐dioxolane‐2‐thione ( 3 ) with (S)‐2‐methyloxirane ((S)‐ 1 ) and with (R)‐2‐phenyloxirane ((R)‐ 2 ) in the presence of SiO₂ in anhydrous dichloroalkanes led to the optically active spirocyclic 1,3‐oxathiolanes 8 with Me at C(7) and 9 with Ph at C(8), respectively (Schemes 2 and 3). The analogous reaction of 1,3‐dimethylimidazolidine‐2‐thione ( 4a ) with (R)‐ 2 yielded stereoselectively (S)‐2‐phenylthiirane ((S)‐ 10 ) in 83% yield and 97% ee together with 1,3‐dimethylimidazolidin‐2‐one ( 11a ). In the cases of 3‐phenyloxazolidine‐2‐thione ( 4b ) and 3‐phenylthiazolidine‐2‐thione ( 4c ), the reaction with (RS)‐ 2 yielded the racemic thiirane (RS)‐ 10 , and the corresponding carbonyl compounds 11b and 11c (Scheme 4 and Table 1). The analogous reaction of 4a with 1,2‐epoxycyclohexane (= 7‐oxabicyclo[4.1.0]heptane; 7 ) afforded thiirane 12 and the corresponding carbonyl compound 11a (Scheme 5). On the other hand, the BF₃‐catalyzed reaction of imidazolidine‐2‐thione ( 5 ) with (RS)‐ 2 yielded the imidazolidine‐2‐thione derivative 13 almost quantitatively (Scheme 6). In a refluxing xylene solution, 1,3‐diacetylimidazolidine‐2‐thione ( 6 ) and (RS)‐ 2 reacted to give two imidazolidine‐2‐thione derivatives, 13 and 14 (Scheme 7). The structures of 13 and 14 were established by X‐ray crystallography (Fig.).     

Preparation and structural analysis of (±)‐cis‐ethyl 2‐sulfanylidenedecahydro‐1,6‐naphthyridine‐6‐carboxylate and (±)‐trans‐ethyl 2‐oxooctahydro‐1H‐pyrrolo[3,2‐c]pyridine‐5‐carboxylate

Bicycle ring closure on a mixture of (4aS,8aR)‐ and (4aR,8aS)‐ethyl 2‐oxodecahydro‐1,6‐naphthyridine‐6‐carboxylate, followed by conversion of the separated cis and trans isomers to the corresponding thioamide derivatives, gave (4aSR,8aRS)‐ethyl 2‐sulfanylidenedecahydro‐1,6‐naphthyridine‐6‐carboxylate, C₁₁H₁₈N₂O₂S. Structural analysis of this thioamide revealed a structure with two crystallographically independent conformers per asymmetric unit (Z′ = 2). The reciprocal bicycle ring closure on (3aRS,7aRS)‐ethyl 2‐oxooctahydro‐1H‐pyrrolo[3,2‐c]pyridine‐5‐carboxylate, C₁₀H₁₆N₂O₃, was also accomplished in good overall yield. Here the five‐membered ring is disordered over two positions, so that both enantiomers are represented in the asymmetric unit. The compounds act as key intermediates towards the synthesis of potential new polycyclic medicinal chemical structures.     

The Diels-Alder Reactivity of 2,2′-Ethylidenebis[3,5-dimethylfuran] and Exploratory Chemistry of the Mono-adducts

In the presence of Me₃Al, 1-cyanovinyl acetate added to 2,2′-ethylidenebis[3,5-dimethylfuran] ( 1 ) to give a 20:10:1:1 mixture of mono-adducts 4,5,6 , and 7 resulting from the same regiocontrol (‘para’ orienting effect of the 5-methyl substituent in 1 ). The additions of a second equiv. of dienophile to 4–7 were very slow reactions. The major mono-adducts 4 (solid) and 5 (liquid) have 2-exo-carbonitrile groups. The molecular structure of 4 (1RS,1′RS,2SR,4SR)-2-exo-cyano-4-[1-(3,5-dimethylfuran-2-yl)ethyl-7-oxabicyclo[2.2.1]hept-5-en-2-endo-yl acetate) was determined by X-ray single-crystal radiocrystallography. Mono-adducts 4 and 5 were saponified into the corresponding 7-oxanorbornenones 8 and 9 which were converted with high stereoselectivity into (1RS,1′SR,4RS,5RS,6RS)-4-[1-(3,5-dimethyl furan-2-yl)ethyl]-6-exo-methoxy-1,5-endo-dimethyl-7-oxabicyclo [2.2.1]heptan-2-one dimethyl acetal ( 12 ) and its (1′RS-stereoisomer 12a , respectively. Acetal hydrolysis of 12a followed by treatment with (t-Bu)Me₂SiOSO₂CF₃ led to silylation and pinacol rearrangement with the formation of (1RS,1′RS,5RS,6RS)-4-[(tert-butyl)dimethy lsilyloxy]-1-(3,5-dimethylfuran-2-yl)ethyl]-5-methoxy-6-methyl-3-methylidene- 2-oxabicyclo[2.2.1]heptane ( 16 ). In the presence of Me₃Al, dimethyl acetylenedicarboxylate added to 12 giving a major adduct 19 which was hydroborated and oxidized into (1RS,1′RS,2″RS,3″RS,4SR,4″RS,5 SR,6SR)-dimethyl 5-exo-hydroxy-4,6-endo-dimethyl-1-[1-(3-exo,5,5-trimeth oxy-2-endo,4-dimethyl-7-oxabicyclo[2.2.1]hept-2-yl)ethyl]-7-oxabicyclo [2.2.1]hept-2-ene-2,3-dicarboxylate ( 20 ). Acetylation of alcohol 20 followed by C?C bond cleavage afforded (1′RS,1″SR,2RS,2′″SR,3RS, 3″SR,4RS,4″SR,5RS)-dimethyl {3-acetoxy-2,3,4,5-tetrahydro-2,4-dimethyl-5-[1-(3-exo,5,5-trimethoxy ?2-endo,4-dimethyl-7-oxabicyclo[2.2.1]hept-1-yl)-ethyl]furan-2,5-diyl} bis[glyoxylate] ( 24 ).     

A structural study of (1RS,2SR,3RS,4SR,5RS)‐2,4‐dibenzoyl‐1,3,5‐triphenylcyclohexan‐1‐ol chloroform hemisolvate and (1RS,2SR,3RS,4SR,5RS)‐2,4‐dibenzoyl‐1‐phenyl‐3,5‐bis(2‐methoxyphenyl)cyclohexan‐1‐ol

(1RS,2SR,3RS,4SR,5RS)‐2,4‐Dibenzoyl‐1,3,5‐triphenylcyclohexan‐1‐ol or (4‐hydroxy‐2,4,6‐triphenylcyclohexane‐1,3‐diyl)bis(phenylmethanone), C₃₈H₃₂O₃, (1), is formed as a by‐product in the NaOH‐catalyzed synthesis of 1,3,5‐triphenylpentane‐1,5‐dione from acetophenone and benzaldehyde. Single crystals of the chloroform hemisolvate, C₃₈H₃₂O₃·0.5CHCl₃, were grown from chloroform. The structure has triclinic (P) symmetry. One diastereomer [as a pair of (1RS,2SR,3RS,4SR,5RS)‐enantiomers] of (1) has been found in the crystal structure and confirmed by NMR studies. The dichoromethane hemisolvate has been reported previously [Zhang et al. (2007). Acta Cryst. E 63 , o4652]. (1RS,2SR,3RS,4SR,5RS)‐2,4‐Dibenzoyl‐3,5‐bis(2‐methoxyphenyl)‐1‐phenylcyclohexan‐1‐ol or [4‐hydroxy‐2,6‐bis(2‐methoxyphenyl)‐4‐phenylcyclohexane‐1,3‐diyl]bis(phenylmethanone), C₄₀H₃₆O₅, (2), is also formed as a by‐product, under the same conditions, from acetophenone and 2‐methoxybenzaldehyde. Crystals of (2) have been grown from chloroform. The structure has orthorhombic (Pca2₁) symmetry. A diastereomer of (2) possesses the same configuration as (1). In both structures, the cyclohexane ring adopts a chair conformation with all bulky groups (benzoyl, phenyl and 2‐methoxyphenyl) in equatorial positions. The molecules of (1) and (2) both display one intramolecular O—H...O hydrogen bond.     

A concise and versatile route to tetrahydro‐1‐benzazepines carrying [a]‐fused heterocyclic units: synthetic sequence and spectroscopic characterization,and the molecular and supramolecular structures of one intermediate and two products

A concise, efficient and versatile route from simple starting materials to tricyclic tetrahydro‐1‐benzazepines carrying [a]‐fused heterocyclic units is reported. Thus, the easily accessible methyl 2‐[(2‐allyl‐4‐chlorophenyl)amino]acetate, (I), was converted, via (2RS,4SR)‐7‐chloro‐2,3,4,5‐tetrahydro‐1,4‐epoxy‐1‐benzo[b]azepine‐2‐carboxylate, (II), to the key intermediate methyl (2RS,4SR)‐7‐chloro‐4‐hydroxy‐2,3,4,5‐tetrahydro‐1H‐benzo[b]azepine‐2‐carboxylate, (III). Chloroacetylation of (III) provided the two regioisomers methyl (2RS,4SR)‐7‐chloro‐1‐(2‐chloroacetyl)‐4‐hydroxy‐2,3,4,5‐tetrahydro‐1H‐benzo[b]azepine‐2‐carboxylate, (IVa), and methyl (2RS,4SR)‐7‐chloro‐4‐(2‐chloroacetoxy)‐2,3,4,5‐tetrahydro‐1H‐benzo[b]azepine‐2‐carboxylate, C₁₄H₁₅Cl₂NO₄, (IVb), as the major and minor products, respectively, and further reaction of (IVa) with aminoethanol gave the tricyclic target compound (4aRS,6SR)‐9‐chloro‐6‐hydroxy‐3‐(2‐hydroxyethyl)‐2,3,4a,5,6,7‐hexahydrobenzo[f]pyrazino[1,2‐a]azepine‐1,4‐dione, C₁₅H₁₇ClN₂O₄, (V). Reaction of ester (III) with hydrazine hydrate gave the corresponding carbohydrazide (VI), which, with trimethoxymethane, gave a second tricyclic target product, (4aRS,6SR)‐9‐chloro‐6‐hydroxy‐4a,5,6,7‐tetrahydrobenzo[f][1,2,4]triazino[4,5‐a]azepin‐4(3H)‐one, C₁₂H₁₂ClN₃O₂, (VII). Full spectroscopic characterization (IR, ¹H and ¹³C NMR, and mass spectrometry) is reported for each of compounds (I)–(III), (IVa), (IVb) and (V)–(VII), along with the molecular and supramolecular structures of (IVb), (V) and (VII). In each of (IVb), (V) and (VII), the azepine ring adopts a chair conformation and the six‐membered heterocyclic rings in (V) and (VII) adopt approximate boat forms. The molecules in (IVb), (V) and (VII) are linked, in each case, into complex hydrogen‐bonded sheets, but these sheets all contain a different range of hydrogen‐bond types: N—H…O, C—H…O, C—H…N and C—H…π(arene) in (IVb), multiple C—H…O hydrogen bonds in (V), and N—H…N, O—H…O, C—H…N, C—H…O and C—H…π(arene) in (VII).     

A chalcone showing positional disorder,two related diarylcyclohexenones showing enantiomeric disorder and a related hydroxyterphenyl,all derived from simple carbonyl precursors

Four compounds are reported, all of which lie along a versatile reaction pathway which leads from simple carbonyl compounds to terphenyls. (2E)‐1‐(2,4‐Dichlorophenyl)‐3‐ [4‐(prop‐1‐en‐2‐yl)phenyl]prop‐2‐en‐1‐one, C₁₈H₁₄Cl₂O, (I), prepared from 4‐(prop‐1‐en‐2‐yl)benzaldehyde and 2,4‐dichloroacetophenone, exhibits disorder over two sets of atomic sites having occupancies of 0.664 (6) and 0.336 (6). The related chalcone (2E)‐3‐(4‐chlorophenyl)‐1‐(4‐fluorophenyl)prop‐2‐en‐1‐one reacts with acetone to produce (5RS)‐3‐(4‐chlorophenyl)‐5‐[4‐(propan‐2‐yl)phenyl]cyclohex‐2‐en‐1‐one, C₂₁H₂₁ClO, (II), which exhibits enantiomeric disorder with occupancies at the reference site of 0.662 (4) and 0.338 (4) for the (5R) and (5S) forms; the same chalcone reacts with methyl 3‐oxobutanoate to give methyl (1RS,6SR)‐4‐(4‐chlorophenyl)‐6‐[4‐(propan‐2‐yl)phenyl]‐2‐oxocyclohex‐3‐ene‐1‐carboxylate, C₂₃H₂₃ClO₃, (III), where the reference site contains both (1R,6S) and (1S,6R) forms with occupancies of 0.923 (3) and 0.077 (3), respectively. Oxidation, using 2,3‐dichloro‐5,6‐dicyano‐1,4‐benzoquinone, of ethyl (1RS,6SR)‐6‐(4‐bromophenyl)‐4‐(4‐fluorophenyl)‐2‐oxocyclohex‐3‐ene‐1‐carboxylate, prepared in a similar manner to (II) and (III), produces ethyl 4′′‐bromo‐4‐fluoro‐5′‐hydroxy‐1,1′:3′,1′′‐terphenyl‐4′‐carboxylate, C₂₁H₁₆BrFO₃, (IV), which crystallizes with Z′ = 2 in the space group P. There are no significant intermolecular interactions in the structures of compounds (I) and (II), but for the major disorder component of compound (III), the molecules are linked into sheets by a combination of C—H...O and C—H...π(arene) hydrogen bonds. The two independent molecules of compound (IV) form two different centrosymmetric dimers, one built from inversion‐related pairs of C—H...O hydrogen bonds and the other from inversion‐related pairs of C—H...π(arene) hydrogen bonds. Comparisons are made with related compounds.     

Six polycyclic pyrimidoazepine derivatives: syntheses,molecular structures and supramolecular assembly

A versatile synthetic method has been developed for the formation of variously substituted polycyclic pyrimidoazepine derivatives, formed by nucleophilic substitution reactions on the corresponding chloro‐substituted compounds; the reactions can be promoted either by conventional heating in basic solutions or by microwave heating in solvent‐free systems. Thus, (6RS)‐6,11‐dimethyl‐3,5,6,11‐tetrahydro‐4H‐benzo[b]pyrimido[5,4‐f]azepin‐4‐one, C₁₄H₁₅N₃O, (I), was isolated from a solution containing (6RS)‐4‐chloro‐8‐hydroxy‐6,11‐dimethyl‐6,11‐dihydro‐5H‐benzo[b]pyrimido[5,4‐f]azepine and benzene‐1,2‐diamine; (6RS)‐4‐butoxy‐6,11‐dimethyl‐6,11‐dihydro‐5H‐benzo[b]pyrimido[5,4‐f]azepin‐8‐ol, C₁₈H₂₃N₃O₂, (II), was formed by reaction of the corresponding 6‐chloro compound with butanol, and (RS)‐4‐dimethylamino‐6,11‐dimethyl‐6,11‐dihydro‐5H‐benzo[b]pyrimido[5,4‐f]azepin‐8‐ol, C₁₆H₂₀N₄O, (III), was formed by reaction of the chloro analogue with alkaline dimethylformamide. (6RS)‐N‐Benzyl‐8‐methoxy‐6,11‐dimethyl‐6,11‐dihydro‐5H‐benzo[b]pyrimido[5,4‐f]azepin‐4‐amine, C₂₂H₂₄N₄O, (IV), (6RS)‐N‐benzyl‐6‐methyl‐1,2,6,7‐tetrahydropyrimido[5′,4′:6,7]azepino[3,2,1‐hi]indol‐8‐amine, C₂₂H₂₂N₄, (V), and (7RS)‐N‐benzyl‐7‐methyl‐2,3,7,8‐tetrahydro‐1H‐pyrimido[5′,4′:6,7]azepino[3,2,1‐ij]quinolin‐9‐amine, C₂₃H₂₄N₄, (VI), were all formed by reaction of the corresponding chloro compounds with benzylamine under microwave irradiation. In each of compounds (I)–(IV) and (VI), the azepine ring adopts a conformation close to the boat form, with the C‐methyl group in a quasi‐equatorial site, whereas the corresponding ring in (V) adopts a conformation intermediate between the twist‐boat and twist‐chair forms, with the C‐methyl group in a quasi‐axial site. No two of the structures of (I)–(VI) exhibit the same range of intermolecular hydrogen bonds: different types of sheet are formed in each of (I), (II), (V) and (VI), and different types of chain in each of (III) and (IV).     

A New Approach to the Synthesis of Long-Chain Polypropionates Based on the Diels-Alder Monoadditions of 2,2′-Ethylidenebis[3,5-dimethylfuran]

Acidic condensation of 2,4-dimethylfuran with acetaldehyde provided 2,2′-ethylidenebis[3,5-dimethylfuran] ( 7 ) which added 1 equiv. of methyl bromopropynoate to give a major adduct 8 . Regio- and stereoselective hydroboration of the latter 7-oxanorbornadiene derivative followed by alcohol protection and methanolysis of its β-bromoacrylate moiety gave (1RS,2RS,4RS,5SR,6SR,1′RS)-methyl 4-[1′-(3″,5″-dimethylfuran-2″-yl)ethyl]-3,3-dimethoxy-6-exo-[(2-methoxy)ethoxy]-1,5-endo-dimethyl-7-oxabicyclo[2.2.1]heptane-2-endo-carboxylate ( 24 ) (Schemes 2 and 3). Reduction of 24 with LiAlH₄, followed by H₂O and MeOH elimination gave the 3-methyl-idene-7-oxanorbornan-2-one derivative 26 which underwent 7-oxa ring opening through a S_N2′ type of reaction with Me₂CuLi (Scheme 4). Stereoselective hydrogenation and ketone reduction provided (1RS, 2SR,3RS,4RS,5RS,6RS,1′SR)-1- [1″-(3 ″,5″-dimethylfuran-2″-yl)]-c-3-ethyl-c-5-[(2-methoxyethoxy)m e-c-ethyl-c-c-5-(2-methoxyethoxy)methoxy]-t-4,t-6-dimethyl-cyclohexane-r-1,c-2-diol ( 32 ), the oxidative cleavage of which with Pb(OAc)₄ generated a 6-oxo-aldehyde 33 (Schemes 4 and 5). Chemoselective protection of 33 and chemo- and stereoselective reductions generated (2RS,3RS,4SR,5SR,6SR,7RS)-7-(3′,5″-dimethylfuran-2′-yl)-2-ethyl-6-hydroxy-4-[(2-methoxyethoxy)methoxy]-3,5-dimethyloct-1-yl pivaloate ( 36 ) and its 4-hydroxy 6-epimer 40 (12 and 13 steps, resp., from adduct 8 ; Scheme 5). Oxidation of the furan ring of 36 led to a (2RS,3SR,4RS,5SR,6RS,7RS)-7-ethyl-3,5,8-trihydroxy-2,4,6-trimethyl-octanoic acid derivative 44 , a polypropionate fragment with six contiguous stereogenic centres (Scheme 6).     

Three closely‐related cyclohexanols (C35H27X2N3O3; X = F,Cl or Br): similar molecular structures but different crystal structures

Three highly‐substituted cyclohexanol derivatives have been prepared from 2‐acetylpyridine and 4‐halogenobenzaldehydes under mild conditions. (1RS,2SR,3SR,4RS,5RS)‐3,5‐Bis(4‐fluorophenyl)‐2,4‐bis(pyridine‐2‐carbonyl)‐1‐(pyridin‐2‐yl)cyclohexanol, C₃₅H₂₇F₂N₃O₃, (I), (1RS,2SR,3SR,4RS,5RS)‐3,5‐bis(4‐chlorophenyl)‐2,4‐bis(pyridine‐2‐carbonyl)‐1‐(pyridin‐2‐yl)cyclohexanol acetone 0.951‐solvate, C₃₅H₂₇Cl₂N₃O₃·0.951C₃H₆O, (II), and (1RS,2SR,3SR,4RS,5RS)‐3,5‐bis(4‐bromophenyl)‐2,4‐bis(pyridine‐2‐carbonyl)‐1‐(pyridin‐2‐yl)cyclohexanol, C₃₅H₂₇Br₂N₃O₃, (III), all crystallize in different space groups, viz. Pbca, Fdd2 and P, respectively. In compound (II), the acetone molecule is disordered over two sets of atomic sites having occupancies of 0.690 (13) and 0.261 (13). Each of the cyclohexanol molecules contains an intramolecular O—H...N hydrogen bond and their overall molecular conformations are fairly similar. The molecules of (I) are linked by two independent C—H...O hydrogen bonds to form a C(5)C(10)[R₂²(15)] chain of rings, and those of (III) are linked by a combination of C—H...O and C—H...N hydrogen bonds, forming a chain of alternating R₂²(16) and R₂²(18) rings. The cyclohexanol molecules in (II) are linked by a single C—H...N hydrogen bond to form simple C(4) chains and these chains are linked by a π–π stacking interaction to form sheets, to which the disordered acetone molecules are weakly linked via a number of C—H...O contacts.     

Stereoselective Synthesis of 5a-Ethyl-1,2,3,3a,4,5,5a,6,9a,9b-decahydro- 1,3,4-trihydroxy-3a-(hydroxymethyl)-7H-benz[e]inden-7-one Derivatives

Homochiral Diels-Alder cyclodimerization of (±)-6-ethenyl-7-oxabicyclo[2.2.1]hept-5-en-2-endo-ol ( 1 ) followed by oxidation gives (1RS,4RS,4aSR,4bSR,5RS,8RS,8aRS)-8a-ethenyl-1,3,4,4a,4b,5,6,8,8a,9-decahydro-1,4:5,8-diepoxyphenanthrene-2,7-dione ( 18 ). Selective hydrogenation followed by epoxidation produced (1RS,4RS,4aRS,5aRS,6aRS,7RS,10RS,10aSR,10bRS)-6a-ethyl-1,4,5a,6,6a,7,9,10,10a,10b-decahydro-1,4:7,10-diepoxyphenanthro[8a,9-b]oxirene-3,8-dione ( 21 ), which was solvolyzed (Me₃SiOSO₂CF₃, Piv₂O) with concomitant pinacol rearrangement involving an acyl-group migration to give a 6-oxo-7-oxabicyclo[2.2.1]hept-2-yl cation intermediate, which finally generated (1RS,3SR,3aRS,4SR,5aRS,6RS,9RS,9aSR,9bSR)-5a-ethyl-1,4,5,5a,6,7,8,9,9a,9b-decahydro-7,10-dioxo-3H-6,9-epoxy-1,3a-ethanonaphtho[1,2-c]furan-3,4-diyl bis(2,2-dimethylpropanoate) ( 24 ). Photo-reductive 7-oxa bridge opening of 24 , followed by water elimination and silylation, provided (1RS,3SR,3aRS,4SR,5aSR,9aSR,9bSR)-7-{[(tert-butyl)dimethylsilyl]oxy}-5a-ethyl-1,4,5,5a,9a,9b-hexahydro-10-oxo-3H-1,3-ethanonaphtho[1,2-c]furan-3,4-diyl bis(2,2-dimethylpropanoate) ( 34 ). Reduction of 34 with NaBH₄ in MeOH followed by desilylation and alcohol protection produced (1RS,3RS,3aRS,4SR,5aSR,9aSR,9bSR)-5a-ethyl-2,3,3a,4,5,5a,6,7,9a,9b-decahydro-1,3-bis(methoxymethoxy)-3a-[(methoxymethoxy)methyl]-7-oxo-1H-benz[e]inden-4-yl 2,2-dimethylpropanoate ( 5 ), a polyoxy-substituted decahydro-1H-benz[e]indene derivative with cis-transoid-trans junction for the two cyclohexane and the cyclopentane rings bearing an angular 3a-(oxymethyl) substituent.     

A tetrabromo‐1,4‐ethanonaphthalene and related dibromo‐1,4‐ethenonaphthalene

(1RS,3RS,4RS,10SR)‐2,2,3,10‐Tetrabromo‐1,2,3,4‐tetrahydro‐1,4‐ethanonaphthalene, C₁₂H₁₀Br₄, (I), is the first structure to be reported with four Br atoms bound to a 1,4‐ethanonaphthalene framework and also the first which possesses three Br atoms in exo positions. Interactions between the Br atoms [three short intramolecular Br...Br distances of 3.1094 (4), 3.2669 (4) and 3.4415 (5) Å] have little effect on the C—C bond lengths but lead to significant twisting of the cage structure compared with the parent hydrocarbon, which is expected to be fully eclipsed at the two saturated C₂H₄ bridge positions. Chemically related (1SR,4RS)‐2,3‐dibromo‐1,4‐ethenonaphthalene, C₁₂H₈Br₂, (II), obtained by double dehydrobromination of (I), represents the first structure of any halogen‐substituted benzobarrelene. This cis‐dibromide shows little evidence of steric congestion at the double bond [Br...Br = 3.5276 (8) Å] as a consequence of the large C—C—Br angles [average C=C—Br angle = 126.15 (10)°].     

Two New Steroidal Saponins from the Processed Polygonatum kingianum

Two new spirostanol saponins, kingianoside I ( 1 ) and kingianoside K ( 2 ), corresponding to (3β,23S,25R)‐23‐hydroxy‐12‐oxospirost‐5‐en‐3‐yl 4‐O‐β‐D ‐glucopyranosyl‐β‐D ‐galactopyranoside ( 1 ) and (3β,25R)‐7‐oxospirost‐5‐en‐3‐yl α‐L ‐arabinofuranosyl‐(1→4)‐[6‐deoxy‐α‐L ‐mannopyranosyl‐(1→2)]‐β‐D ‐glucopyranoside ( 2 ), along with 13 known compounds, daucosterol, (25R)‐kingianoside G, (25RS)‐kingianoside A, pratioside D₁, (25RS)‐pratioside D₁, (25S)‐kingianoside C, kingianoside C, ginsenoside Rb₁, saponins Tb and Pb, dioscin, gracillin, and saponin Pa, were isolated from the processed rhizomes of Polygonatum kingianum. The structures of the new compounds were elucidated by detailed spectroscopic analyses, including 1D‐ and 2D‐NMR techniques, and chemical methods. Compound 2 contains a novel unusual spirostanol saponin aglycone. Ginsenoside Rb₁ and saponin Tb were isolated for the first time from the genus Polygonatum. The 13 known compounds were detected for the first time in the processed Polygonatum kingianum.     

Four differently substituted 2‐aryl‐2,3,4,5‐tetrahydro‐1H‐1,4‐epoxy‐1‐benzazepines: hydrogen‐bonded structures in one,two and three dimensions

In (2RS,4SR)‐7‐chloro‐2‐exo‐(2‐chloro‐6‐fluorophenyl)‐2,3,4,5‐tetrahydro‐1H‐1,4‐epoxy‐1‐benzazepine, C₁₆H₁₂Cl₂FNO, (I), molecules are linked into chains by a single C—H...π(arene) hydrogen bond. (2RS,4SR)‐2‐exo‐(2‐Chloro‐6‐fluorophenyl)‐2,3,4,5‐tetrahydro‐1H‐1,4‐epoxy‐1‐benzazepine, C₁₆H₁₃ClFNO, (II), is isomorphous with compound (I) but not strictly isostructural with it, as the hydrogen‐bonded chains in (II) are linked into sheets by an aromatic π–π stacking interaction. The molecules of (2RS,4SR)‐7‐methyl‐2‐exo‐(4‐methylphenyl)‐2,3,4,5‐tetrahydro‐1H‐1,4‐epoxy‐1‐benzazepine, C₁₈H₁₉NO, (III), are linked into sheets by a combination of C—H...N and C—H...π(arene) hydrogen bonds. (2S,4R)‐2‐exo‐(2‐Chlorophenyl)‐2,3,4,5‐tetrahydro‐1H‐1,4‐epoxy‐1‐benzazepine, C₁₆H₁₄ClNO, (IV), crystallizes as a single enantiomer and the molecules are linked into a three‐dimensional framework structure by a combination of one C—H...O hydrogen bond and three C—H...π(arene) hydrogen bonds.     

Chloro(η6‐p‐cymene)(phosphoramidite)ruthenium(II), a 16‐Electron Fragment Stabilized by an η2‐Aryl–Metal Interaction,and Its Use in Asymmetric Cyclopropanation

Chloride abstraction from the half‐sandwich complexes [RuCl₂(η⁶‐p‐cymene)(P*‐κP)] ( 2a : P* = (S_a,R,R)‐ 1a = (1S_a)‐[1,1′‐binaphthalene]‐2,2′‐diyl bis[(1R)‐1‐phenylethyl)]phosphoramidite; 2b : P* = (S_a,R,R)‐ 1b = (1S_a)‐[1,1′‐binaphthalene]‐2,2′‐diyl bis[(1R)‐(1‐(1‐naphthalen‐1‐yl)ethyl]phosphoramidite) with (Et₃O)[PF₆] or Tl[PF₆] gives the cationic, 18‐electron complexes dichloro(η⁶‐p‐cymene){(1S_a)‐[1,1′‐binaphthalene]‐2,2′‐diyl {(1R)‐1‐[(1,2‐η)‐phenyl]ethyl}[(1R)‐1‐phenylethyl]phosphoramidite‐κP}ruthenium(II) hexafluorophosphate ( 3a ) and [Ru(S)]‐dichloro(η⁶‐p‐cymene){(1S_a)‐[1,1′‐binaphthalene]‐2,2′‐diyl {(1R)‐1‐[(1,2‐η)‐naphthalen‐1‐yl]ethyl}[(1R)‐1‐(naphthalen‐1‐yl)ethyl]phosphoramidite‐κP)ruthenium(II) hexafluorophosphate ( 3b ), which feature the η²‐coordination of one aryl substituent of the phosphoramidite ligand, as indicated by ¹H‐, ¹³C‐, and ³¹P‐NMR spectroscopy and confirmed by an X‐ray study of 3b . Additionally, the dissociation of p‐cymene from 2a and 3a gives dichloro{(1S_a)‐[1,1′‐binaphthalene]‐2,2′‐diyl [(1R)‐(1‐(η⁶‐phenyl)ethyl][(1R)‐1‐phenylethyl]phosphoramidite‐κP)ruthenium(II) ( 4a ) and di‐μ‐chlorobis{(1S_a)‐[1,1′‐binaphthalene]‐2,2′‐diyl [(1R)‐1‐(η⁶‐phenyl)ethyl][(1R)‐1‐phenylethyl]phosphoramidite‐κP}diruthenium(II) bis(hexafluorophosphate) ( 5a ), respectively, in which one phenyl group of the N‐substituents is η⁶‐coordinated to the Ru‐center. Complexes 3a and 3b catalyze the asymmetric cyclopropanation of α‐methylstyrene with ethyl diazoacetate with up to 86 and 87% ee for the cis‐ and the trans‐isomers, respectively.     

The influence of sulfur substituents on the molecular geometry and packing of thio derivatives of N‐methylphenobarbital

The room‐temperature crystal structures of four new thio derivatives of N‐methylphenobarbital [systematic name: 5‐ethyl‐1‐methyl‐5‐phenylpyrimidine‐2,4,6(1H,3H,5H)‐trione], C₁₃H₁₄N₂O₃, are compared with the structure of the parent compound. The sulfur substituents in N‐methyl‐2‐thiophenobarbital [5‐ethyl‐1‐methyl‐5‐phenyl‐2‐thioxo‐1,2‐dihydropyrimidine‐4,6(3H,5H)‐dione], C₁₃H₁₄N₂O₂S, N‐methyl‐4‐thiophenobarbital [5‐ethyl‐1‐methyl‐5‐phenyl‐4‐thioxo‐3,4‐dihydropyrimidine‐2,6(1H,5H)‐dione], C₁₃H₁₄N₂O₂S, and N‐methyl‐2,4,6‐trithiophenobarbital [5‐ethyl‐1‐methyl‐5‐phenylpyrimidine‐2,4,6(1H,3H,5H)‐trithione], C₁₃H₁₄N₂S₃, preserve the heterocyclic ring puckering observed for N‐methylphenobarbital (a half‐chair conformation), whereas in N‐methyl‐2,4‐dithiophenobarbital [5‐ethyl‐1‐methyl‐5‐phenyl‐2,4‐dithioxo‐1,2,3,4‐tetrahydropyrimidine‐6(5H)‐one], C₁₃H₁₄N₂OS₂, significant flattening of the ring was detected. The number and positions of the sulfur substituents influence the packing and hydrogen‐bonding patterns of the derivatives. In the cases of the 2‐thio, 4‐thio and 2,4,6‐trithio derivatives, there is a preference for the formation of a ring motif of the R₂²(8) type, which is also a characteristic of N‐methylphenobarbital, whereas a C(6) chain forms in the 2,4‐dithio derivative. The preferences for hydrogen‐bond formation, which follow the sequence of acceptor position 4 > 2 > 6, confirm the differences in the nucleophilic properties of the C atoms of the heterocyclic ring and are consistent with the course of N‐methylphenobarbital thionation reactions.