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.     

A Solid State Polymer‐Coated Electrode Containing a Chiral Crown Ether Derivative for Enantioselective Detection of Phenylglycine Methyl Ester Isomer

All solid‐state enantioselective electrode (ASESE) based on a newly synthesized chiral crown ether derivative ((R)‐(?)‐(3,3′‐diphenyl‐1,1′‐binaphthyl)‐23‐crown‐6 incorporating 1,4‐dimethoxybenzene) was prepared and characterized by potentiometry. The ASESE clearly showed enantiomer discrimination for methyl esters of alanine, leucine, valine, phenylalanine, and phenylglycine, where the enantioselectivity for phenylglycine methyl ester was the highest (K_R,S=8.5±7.1%). Experimental parameters of ASESE for the analysis of (R)‐(?)‐phenylglycine methyl ester were optimized. The optimized ASESE showed a slope of 55.3±0.2 mV/dec for (R)‐(?)‐phenylglycine methyl ester in the concentration range of 1.0×10^?5–1.0×10^?2 M and the detection limit was 9.0×10^?6 M. The ASESE showed good selectivity for (R)‐(?)‐phenylglycine methyl ester against inorganic cations and various amino acid methyl esters. The concentration of (R)‐(?)‐phenylglycine methyl ester was determined in the mixture of (R)‐(?) and (S)‐(+)‐phenylglycine methyl ester, which ratios varied from 2 : 1 to 1 : 9. The lifespan of the electrode was alleged to be 30 days.     

Two methyl 3‐(1H‐pyrazol‐4‐yl)octahydropyrrolo[3,4‐c]pyrrole‐1‐carboxylates form different hydrogen‐bonded sheets

In the molecules of both methyl (1RS,3SR,3aRS,6aSR)‐1‐methyl‐3‐(3‐methyl‐1‐phenyl‐1H‐pyrazol‐4‐yl)‐4,6‐dioxo‐5‐phenyloctahydropyrrolo[3,4‐c]pyrrole‐1‐carboxylate, C₂₅H₂₄N₄O₄, (I), and methyl (1RS,3SR,3aRS,6aSR)‐5‐(4‐chlorophenyl)‐1‐methyl‐3‐(3‐methyl‐1‐phenyl‐1H‐pyrazol‐4‐yl)‐4,6‐dioxooctahydropyrrolo[3,4‐c]pyrrole‐1‐carboxylate, C₂₅H₂₃ClN₄O₄, (II), the two rings of the pyrrolopyrrole fragment are both nonplanar, with conformations close to half‐chair forms. The overall conformations of the molecules of (I) and (II) are very similar, apart from the orientation of the ester function. The molecules of (I) are linked into sheets by a combination of an N—H...π(pyrrole) hydrogen bond and three independent C—H...O hydrogen bonds. The molecules of (II) are also linked into sheets, which are generated by a combination of an N—H...N hydrogen bond and two independent C—H...O hydrogen bonds, weakly augmented by a C—H...π(arene) 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).     

Control of Diels-Alder Addition,Stereo- and Regioselectivity by Remote Substituents and Tricarbonyl(diene)iron Moieties

A stereoselective synthesis of tricarbonyl-[((1RS,2RS,4RS,5RS,6RS)-C-5,6,C-η-(5,6,7,8,-tetramethylidenbicyclo[2.2.2]octan-2-ol)]iron ( 11 ),and of its tosylate 12 and benzoate 13 is reported. The bulk of the ‘endo’-Fe(CO))³ moiety and of the ester groups in 13 renders its Diels-Alder additions to methyl propynoate ( 15 )), butynone ( 16 ), and 1-cyanovinyl acetate highly ‘para’ regioselective. The cycloadditions of diene-alcohol 11 are either ‘meta’- or ‘para’-regioselective depending on the nature of the dienophile. In the presence of BF ₃. Et ₂O, the addition of 11 to methyl vinyl ketone is highly stereo- (Alder mode) and ‘para’-regioselective, giving adduct 52 (tricarbonyl [((1 RS,4RS,8RS,9RS,10RS,12RS)-C,9,10,C-η-(12-hydroxy-9,10-dimethylidenetricyclo[6.2.2.0^2,7]dodec-2(7)-en-4 yl methyl ketone)]iron) whose structure has been established by single-crystal X-ray crystallography.     

Acid-Promoted Rearrangements of N-Substituted 8-Oxa-3-azatricyclo[3.2.1.02′4] octane-6,7-dicarboxylates: Remote Substituent Effects on the Regioselectivity of the N-Acylaziridine/Dihydrooxazone Rearrangement

Preparations of dimethyl (1RS,2SR,4RS,5SR,6SR,7RS)- and dimethyl (1 RS,2SR,4RS,5SR,6RS,7SR)-8-oxa-3-azatricyclo[3;2.1.0²⁴] octane-6,7-dicarboxylate 15 and 18 , resp.) and of their N-(tert-butyloxy)carbonyl ( 14 , 17 ) and V-benzoyl ( 16 , 19 ) derivatives are described. While treatment with nucleophilic acids (HCl, HBr. A^cOH) of the exo, exo-diesters 14 and 16 gave the corresponding products 23–27 of aziridine trans -addition, the exo, endo -diesters 17 and 19 led to the corresponding amino-lactones 63 (methyl (1RS,2RS,3SR,6RS,7SR,9RS)-2-{[(tert-butyloxy)carbonyl] amino}-5-oxo-4,8-dioxatricyclo[4.2.1.0 ³⁷] nonane-9-carboxylate) and 64 (methyl (1RS,2RS,3SR,6RS,7SR,9SR)-2-(benzoylamino)-5-oxo-4,8-dioxatricyclo[4.2.1.0 ^3′7] (nonane-9-carboxylate). Under non-nucleophilic acidic conditions, the N-benzoylaziridine 16 was rearranged quantitatively into dimethyl (1RS,2SR,26SR,67SR,7SR,8SR,9SR)-4-phenyl-5,10-dioxa-3-azatricyclo[4.3.1.0^2′7] dec-3-ene-8,9-dicarboxylate( 31 ), and 19 into dimethyl (1RS,2SR,26SR,67SR,7SR,8SR,9SR)-4-phenyl-3,10-dioxa-5-azatricyclo [5.2.1.0^2′6] dec-4-ene-8,9-di-carboxylate ( 65 ). Possible mechanisms of these highly selective reactions and rearrangements are discussed.     

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).     

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 ).     

Facile access to 6‐substituted 1,4,5,7‐tetrahydropyrrolo[3,4‐b]‐pyridines via hantzsch type dimethyl 4‐aryl‐2‐formyl‐6‐methyl‐1,4‐dihydropyridine‐3,5‐dicarboxylates

Efficient assembly of 6‐substituted 4‐aryl‐5‐oxo‐1,4,5,7‐tetrahydropyrrolo[3,4‐b]pyridines (7a‐f) is described according to a Hantzsch type reaction from formyl‐ester 4 by imination, borohydride reduction and intramolecular thermal amino‐ester cyclization. The starting compound 4 was prepared in three steps from the readily available formyl derivative 1, methyl 4,4‐dimethoxy‐3‐oxobutanoate and methyl 3‐aminocrotonate.     

Total Asymmetric Synthesis of Doubly Branched Carba-hexopyranoses and Amino Derivatives Starting from the Diels-Alder Adducts of Maleic Anhydride to Furfuryl Esters

The Diels-Alder adducts of maleic anhydride to furfuryl esters were reduced into 7-oxabicyclo[2.2.1]hept-5-ene-1,2-exo,3-exo-trimethanol (±)- 15 and enantiomerically pure (−)- 15 (Scheme 1). The tripivalate of (±)- 15 was converted into (1RS,2RS,3RS,4RS,5SR,6SR)-1,5,6-tris(hydroxymethyl)cyclohexane-1,2,3,4-tetrol ((±)- 23 ; Scheme 2). Reaction of BBr₃ with the triacetate (±)- 30 of (±)- 15 gave (1RS,2RS,5RS,6RS)-5-bromo-6-hydroxycyclohex-3-ene-1,2,3-trimethyl triacetate ((±)- 31 ) at −78°, and (1RS,2RS,5SR,8SR)-2-endo-hydroxy-6-oxabicylo[3.2.1]oct-3-ene-5,8-dimethyl diacetate ((±)- 32 ) at 0° (Scheme 3). Single-crystal X-ray diffraction of (1RS,2RS,5SR,8SR)-2-acetoxy-6-oxabicyclo[3.2.1]oct-3-ene-5,8-dimethyl diacetate ((±)- 33 ) was carried out. Displacement of bromide (+)- 31 (derived from (−)- 15 ) with azide anion gave (+)- 38 which was transformed into (+)-(1R,2R,5S,6S)-5-amino-6-hydroxycyclohex-3-ene-1,2,3-trimethanol ((+)- 40 ) (Scheme 4). Reaction of (±)- 31 with BBr₃ at 0°, followed by azide disubstitution led to (1RS,2RS,5SR,6SR)-5-amino-3-(aminomethyl)-6-hydroxycyclohex-3-ene-1,2-dimethanol ((±)- 45 ). Dihydroxylation of (±)- 38 and further transformations gave (1RS,2RS,3SR,4RS,5SR,6RS)-5-amino-1,4,6-trihydroxycyclohexane-1,2,3-trimethanol ((±)- 49 ) and (1RS,2RS,3SR,4RS,5SR,6RS)-2,3-dihydroxy-7-oxabicyclo[4.1.0]heptane-2,3,4-trimethanol ((±)- 55 ) (Schemes 5 and 6). Expoxidation of the 4-nitrobenzoate (±)- 61 of (±)- 38 allowed the preparation of (1RS,2RS,3SR,4RS,5RS)-5-amino-1,4-dihydroxycyclohexane-1,2,3-trimethanol ((±)- 65 ) and of (1RS,2RS,3SR,4RS,5SR,6RS)-5-amino-4-hydroxy-7-oxabicyclo[4.1.0]heptane-1,2,3-trimethanol ((±)- 67 ) (Scheme 7). The new unprotected polyols and aminopolyols were tested for their inhibitory activity toward commercially available glycohydrolases. At 1 mM concentration, 34, 30, and 31% inhibition of β-galactosidase from bovine liver was observed for (+)- 40 , (±)- 65 , and (±)- 67 , respectively.     

Cyclization of a cysteine conjugate of N-(3,5-Dichlorophenyl)succinimide

N-(3,5-Dichlorophenyl)-2-cysteinylsuccinimide methyl ester hydrochloride ( 5 ) was prepared from N-(3,5-dichlorophenyl)maleimide ( 3 ) and cysteinyl methyl ester hydrochloride. Attempted neutralization of the cysteine conjugate salt with triethylamine resulted in spontaneous cyclization of 5 to form the more stable 2-(N-3,5-dichlorophenylcarbamoylmethyl)-5-carbomethoxy-1,4-thiazine- 3-one ( 6 ). Similar results might be expected in vivo should these metabolites of succinimides be formed.     

Three New Sesquiterpenoids from Echinops ritro L.

From the whole plants of E. ritro L., the three new sesquiterpenoids (3α,4α,6α)‐3,13‐dihydroxyguaia‐7(11),10(14)‐dieno‐12,6‐lactone ( 1 ), (3α,4α,6α,11β)‐3‐hydroxyguai‐1(10)‐eno‐12,6‐lactone ( 2 ), and (11α)‐11,13‐dihydroarglanilic acid methyl ester (=(4β,6α,11α)‐4,6‐dihydroxy‐1‐oxoeudesm‐2‐en‐12‐oic acid methyl ester; 3 ), together with eight known sesquiterpenoids, were isolated. Their structures were elucidated through analysis of spectroscopic data including extensive 2D‐NMR.     

Synthesis of 3,4‐Fused γ‐Lactone‐γ‐Lactam Bicyclic Moieties as Multifunctional Synthons for Bioactive Molecules

A short approach for the synthesis of 3,4‐fused γ‐lactone‐γ‐lactam bicyclic systems ( 1 ) in diastereomeric mixtures from chiral D ‐alanine methyl ester hydrochloride is described. The key step towards lactonisation is the reduction of the carbonyl ketone of the 5R‐configured 3,5‐dimethylpyrrolidine‐2,4‐dione diastereomers ( 8 ) via sodium borohydride in the presence of hydrochloric acid. With the presence of ethyl acetyl functionality at C3‐position, ester hydrolysis of 8 occurred concomitantly with keto reduction leading to lactonisation and eventually affording the anticipated (3S,4S,5R), (3R,4R,5R), (3R,4S,5R) and (3S,4R,5R) bicyclic moieties. The formation of the fused systems was confirmed by mass spectroscopy (MS) and nuclear magnetic resonance (NMR) analyses.     

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.     

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.     

Secoiridoid Constituents from the Fruits of Ligustrum lucidum

Four new secoiridiod glucosides, p‐hydroxyphenethyl 7‐β‐D ‐glucosideelenolic acid ester ( 1 ), 6′‐elenolylnicotiflorine ( 2 ), 6′′′‐acetylnicotiflorine ( 3 ), and oleoside 7‐ethyl 11‐methyl ester ( 4 ), as well as six known glucosides, nuezhenide ( 5 ), Gl‐3 ( 6 ), nicotiflorine ( 7 ), isonuezhenide ( 8 ), neonuezhenide ( 9 ), and oleoside 11‐methyl ester ( 10 ) were isolated from the fruits of Ligustrum lucidum. Their structures were elucidated by spectroscopic methods. Compound 4 was an artifact produced during extraction.     

Face Selectivity of the Diels-Alder Reaction of Hexadienone Moieties Grafted onto the Bicyclo[2.2.2]octene Skeleton and Perturbed by a Remote Tricarbonylbutadieneiron Group

Selective oxidations of bis(tricarbonyliron) complexes of methyl (3,7,8-trimethylidenebicyclo[2.2.2]oct-5-en-2-ylidene)methyl ketones 15 – 17 afforded selectively the tricarbonyl {(1RS,4SR,7SR,8RS)-C,7,8,C-η-[methyl (3,7,8-trimethylidenebicyclo[2.2.2]oct-5-en-(2Z)-2-ylidene)methyl ketone]}iron ( 12 ), the corresponding (2E)-derivative 13 and the tricarbonyl{(1RS,2RS,3SR,4SR)-C,2,3,C-η-[methyl (3,7,8-trimethylidenebicyclo[2.2.2]oct-5-en-(2Z)-2-ylidene)methyl ketone]}iron ( 18 ). The stereoselectivity of the Diels-Alder reactions of the uncomplexed (Z)- and (E)-hexadienone 12 and 13 , respectively, was established. The face of the diene syn with respect to the C(5), C(6) etheno bridge was preferred for the cycloadditions of N-phenyltriazolinedione (NPTAD). In contrast, the reactions of dimethyl acetylenedicarboxylate (DMAD) and methyl propynoate showed a slight preference for addtion to the face of the hexadienones anti with respect to the etheno bridges of 12 and 13 . The crystal structure of the adduct 25 resulting from the cycloaddition of NPTAD to 12 is reported.     

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.     

β-Carbolines derived from β-methyltryptophan and a stereoselective synthesis of (2RS,3SR)-β-methyltryptophan methyl ester

The methyl ester of isomer A of β-methyltryptophan (2SR,3RS; 2A ) was stereoselectively prepared by an efficient modified method through the reaction of a-methyl-N-(1-Methylethyl)-1H-indole-3-methanamine ( 3 ) with methyl nitroacetate to give the desired nitro compound as a mixture of two racemates 5A , and 5B. During the recrystallization process epimerization occurred and only racemate 5A crystallized out. Catalytic hydrogenation of 5A in the presence of acid stereoselectively yielded the desired amino acid ester 2A. Pictet-Spengler condensation of 2A with aldehydes under aprotic conditions followed by dehydrogenation gave excellent yields of β-carbolines 7a-i , (R = methyl, ethyl, acetyl, phenyl, pyridine-2-yl, furan-2-yl, quinoline-2-yl, styryl, phenethyl). Also β-carbolines 7a,b,i were synthesized by the Pictet-Spengler condensation of (3-meth-yltryptophan under acidic aqueous conditions followed by esterification and dehydrogenation.