Synthesis and reactions of heterocyclic methyl 2-propenoates and 2,3-epoxypropanoates with nucleophiles

Reaction of 2-(3-,4-)pyridinecarboxaldehydes 5 with carbomethoxymethylene triphenylphosphorane afforded predominantly E-methyl-3-(pyridinyl)-2-propenoates 7. Oxidation of 7a-c with m-chloroperbenzoic acid gave methyl E-3-(1-oxidopyridinyl)-2-propenoates 8a-c in high yield. The Darzen's reaction of 5a-c with methyl bromoacetate yielded a mixture of stereoisomers cis- 9a-c and methyl trans-3-(pyridinyl)-2,3-epoxy-propanoates 10a-c in a ratio of 2:1. Oxidation of cis- 9a-c and trans- 10a-c afforded the corresponding cis- 11a-c and methyl trans-3-(1-oxidopyridinyl)-2,3-epoxypropanoates 12a-c in good yield. The reaction of 11a and 12a with cyclic amines as piperidine gave the respective threo- 13 and methyl erythro-2-(1-piperidino)-3-hydroxy-3-(1-oxido-2-pyridino)propanoate 14. The sodium borohydride reduction of the N-alkoxylcarbonyl pyridinium salts of 9c and 10c afforded the corresponding N-alkoxycarbonyl-1,2-dihydropyridyl derivatives 15 and 16. A number of selected compounds ( 7a-c , 9a-c , 10a , 10c , 11a-c and 12a , 12c ) were found to be inactive in the P388 Lymphocytic screen. Compounds 9-12 did not react with the model nucleophile ethanethiol in phosphate buffer at 37°.     

Iodocyclization/base-induced hydrodeiodination reaction of 5-substituted 4-alkenols. The influence of substituent on the stereoselective pathway

The electrophilic iodocyclization reaction of (Z)- and (E)-5-n-alkylsubstituted 4-alken-1-ols followed by base-induced hydrodeiodination reaction stereoselectively gave, respectively, (Z)- and (E)-alkylidentetrahydrofurans in high yield. Completely different outcomes were observed with (Z)- and (E)-6,6-dimethylhept-4-en-1-ol: their iodocyclization furnished, respectively, threo- and erythro-2-(1-iodo-2,2-dimetylpropyl)tetrahydrofuran with high stereoselectivity. The threo isomer gave clean formation of 6-tert-butyl-3,4-dihydro-2H-pyran by base-induced ring expansion, while erythro isomer underwent a base-induced ring contraction to 1-cyclopropyl-3,3-dimethylbutan-1-one. Moreover, (Z)- and (E)-5-cyclopropylpent-4-en-1-ol underwent a 6-endo-iodocyclization to threo- and erythro-2-cyclopropyl-3-iodotetrahydro-2H-pyran, respectively, that under the same basic treatment, gave two isomeric 6-cyclopropyldihydro-2H-pyrans in a stereoselective fashion.     

Photochemische Umsetzung von optisch aktiven 2-(1′-Methylallyl)anilinen mit Methanol

Photochemical Reaction of Optically Active 2-(1′-Methylallyl)anilines with Methanol It is shown that (?)-(S)-2-(1′-methylallyl)aniline ((?)-(S)- 4 ) on irradiation in methanol yields (?)-(2S, 3R)-2, 3-dimethylindoline ((?)-trans- 8 ), (?)-(1′R, 2′R)-2-(2′-methoxy-1′-methylpropyl)aniline ((?)-erythro- 9 ) as well as racemic (1′RS, 2′SR)-2-(2′-methoxy-1′-methylpropyl) aniline ((±)-threo- 9 ) in 27.1, 36.4 and 15.7% yield, respectively (see Scheme 3). By deamination and chemical correlation with (+)-(2R, 3R)-3-phenyl-2-butanol ((+)-erythro- 13 ; see Scheme 4) it was found that (?)-erythro- 9 has the same absolute configuration and optical purity as the starting material (?)-(S)- 4 . Comparable results are obtained when (?)-(S)-N-methyl-2-(1′-methylallyl)aniline ((?)-(S)- 7 ) is irradiated in methanol, i.e. the optically active indoline (+)-trans- 10 and the methanol addition product (?)-erythro- 11 along with its racemic threo-isomer are formed (cf. Scheme 3). These findings demonstrate that the methanol addition products arise from stereospecific, methanol-induced ring opening of intermediate, chiral trans, -(→(?)-erythro-compounds) and achiral cis-spiro [2.5]octa-4,6-dien-8-imines (→(±)-threo-compounds; see Schemes 1 and 2).     

Zur Stereochemie der aromatischen Claisen-Umlagerung. Thermische Umlagerung von erythroiden und threoiden ortho-Dienonen

On the Stereochemistry of the Aromatic Claisen Rearrangement. Thermal Rearrangement of erythroid and threoid ortho-Dienones. Erythro- and threo-1-methyl-1-(1′-methyl-2′-propynyl)-2-oxo-1,2-dihydronaph-thalene (erythro- and threo- 6 ) as well as erythro- and threo-2,6-dimethyl-6-(1′-methyl-2′-propynyl)-cyclohexa-2,4-dien-1-one (erythro- and threo- 8 ) were obtained together with the corresponding aromatic ethers 5 and 7 by alkylation of 1-methyl-2-naphthol and 2,6-dimethyl-phenol, respectively in alcoholic potassium hydroxide solution with 1-methyl-2-propynyl p-toluenesulfonate (Scheme 2). The diastereoisomeric dienones 6 and 8 were easily separated by column chromatography on silica gel and its relative configuration at C(1) or C(6) and C(1′) deduced from the chemical shifts in their ¹H-NMR.-spectra (Table 1). Hydrogenation of 6 and 8 using Lindlar catalyst yielded the corresponding erythro- and threo-configurated (1′-methyl-2′-propenyl)-dienones 10 and 13 , respectively (Scheme 3) the thermal rearrangement of which were studied. The following results were obtained: threo- 10 rearranged in benzene at 85–105° preferentially via a chair-like (C) transition state to yield 99,5% (E)- and 0,5% (Z)-(2′-butenyl) 1-methyl-2-naphthyl ether ((E)- and (Z)- 14 ; ΔΔG (C/B) = ?4,0 kcal/mol). On the other hand, erythro- 10 when heated at 105-125° in benzene gave 84,7% (E)- and 15,3% (Z)- 14 , i.e. in this case a boat-like (B) transition state is favoured (G (C/B) = + 1,3 kcal/mol) (Scheme 5 and Table 2). The thermal rearrangement of dienones 13 led to the corresponding ethers 12 as well as p-allyl-phenols 11 . Thus, heating of threo- 13 at 20–42° in cyclohexane resulted in the formation of 2,5% of ether 12 , consisting of 98% of the (E)- and 2% of the (Z)-isomer, and 97,5% of (E)- 11 which contained, at a maximum, 0,5% of the (Z)-isomer, (Scheme 6 and Table 3). This means that both rearrangements occurred with a strong preference of the C transition state (G ( C/B , phenol) = ?3,3 kcal/mol). On the contrary, erythro- 13 when heated at 42–68° in cyclohexane yielded a 3:2 mixture of ether 12 and phenol 11 (Scheme 6). The ethereal part consisted of 88,0% of the (E)- and 12,0% of the (Z)-isomer which again shows that the B geometry predominated in the erythro transition state leading to the ether (G ( C / B )= + 1,3 kcal/mol). In the phenolic part 36–40% of the (E)-isomer and 64–60% of (Z)-isomer were found which means that in the para-Claisen rearrangement of erythro- 13 the C arrangement is only slightly favoured (ΔΔG ( C / B )= ?0,36 kcal/mol).     

Synthesis and reactions of heterocyclic 2,3-epoxypropionitriles with pyrrolidine

The Darzen's reaction of 2-(3-)pyridinecarboxaldehydes 5 with chloroacetonitrile yielded a mixture of stereoisomers cis- 6 and trans-3-(pyridinyl)-2,3-epoxypropionitriles 7 in a ratio of approximately 1:1. Oxidation of cis- 6 and trans- 7 afforded the corresponding cis- 8 and trans-3-(1-oxidopyridinyl)-2,3-epoxypropionitriles 9 in good yield. The reaction of 8a and 9a with pyrrolidine at 25° gave the respective threo- 10 and erthyro-2-(1-pyrrolidino)-3-hydroxy-3-(1-oxido-2-pyridinyl)propionitrile ( 11 ). A number of selected compounds ( 7-9a-b ) were found to be inactive in the P388 Lymphocyctic screen.     

Rh(I)-katalysierte Umlagerungen von 3,4-Diacycloxy-1,5-hexadiinen; synthese von (E)-4-acyloxymethyliden-2-cyclopenten-1-onen

Rh(I)-Catalysed Rearrangements of 3,4-Diacyloxy-1,5-hexadiynes; Synthesis of (E)-4-Acyloxymethyliden-2-cyclopenten-1-ones The 3,4-diacyloxy-1,5-hexadiynes 3, 6 and 8 which were synthesized according to a known, slightly modified procedure react with [Rh(CO)₂Cl]₂ at 100° in chloroform with formation of the (E)-4-acyloxymethyliden-2-cyclopenten-1-ones 4, 7 and 9 (Schemes 2, 3 and 4), respectively. DL - and meso- 3 as well as trans- and cis- 8 , give the same (E)-isomers 4 and 9 , respectively. 3,4-Diacetoxy-3, 4-dimethyl-1, 6-diphenyl-1,5-hexadiyne ( 10 ) produces with the same catalyst 2,6-diacetoxy-3, 4-dimethyl-1,6-diphenylfulvene ( 11 ) (Scheme 5). A mechanism for the formation of the cyclopentenones is proposed in Scheme 6.     

Synthesis and Stereoisomerization of 2-(1-Alkoxyimino-2,2,2-trifluoroethyl)-5-trimethylsilylfurans

2-(1-Alkoxyimino-2,2,2-trifluoroethyl)-5-trimethylsilylfurans were synthesized by the condensation of 2-(trifluoroacetyl)-5-trimethylsilylfuran with alkoxyamines. According to ¹H and ¹⁹F NMR spectroscopic data, the alkoxyimino group in the E-isomers descreens the H-3 and H-4 protons of the furan ring more strongly than in the Z-isomers, shifting their signals downfield. The fluorine atoms of the α-trifluoromethyl group in the Z-isomer are characterized by a downfield shift in relation to the E-isomer. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 834–838, June, 2005.     

Nucleophilic Vinylic Substitutions of (E)- and (Z)-Ethyl 3-Aryl-3-chloro-2-cyanopropenoates with Primary and Secondary Amines

Some new (Z)-ethyl 3-amino-3-aryl-2-cyanopropenoates have been prepared in good yields by reacting (E)- and (Z)-ethyl 3-aryl-3-chloro-2-cyanopropenoates with primary and secondary amines. The (Z)-isomers were exclusively formed.although the starting material consisted of a mixture of (E)- and (Z)-isomers (≈ 1:1)     

Simultaneous determination of enantiomeric purity and erythro/threo relationship in chiral 1,2-aminoalcohols by NMR using (R)-(+)-t-butylphenylphosphinothioic acid

The rapid simultaneous determination of enantiomeric purity and erythro/threo relationship for a series of chiral 1,2-aminoalcohols is reported. Complexation with 1 equivalent (R)-(+)-t-butylphenylphosphinothioic acid results in a preferred conformation of the aminoalcohol which in turn causes the interproton dihedral angle to assume either large (threo) or small (erythro) J values. Measurement of the resulting vicinal coupling constant allows easy and rapid assignment of erythro versus threo.     

Enantiopure erythro- and threo-1-aryl-1-[2-pyrrolidyl]-methanols: synthesis from l-proline

Enantiopure (1R,2S)-erythro- and (1S,2S)-threo-isomers of four new aryl-pyrrolidyl alcohols 5aH, 5aMe, 5bH and 5bMe have been obtained in five steps from (−)-(S)-proline and fully characterized. The oxidation of alcohol 8 into aldehyde 9 was the most difficult step and racemization occurs during Swern oxidation but this difficulty can be overcome by using SO₃/pyridine as oxidant. Diastereomer I of the protected amino alcohol 10a crystallized and was shown to be the (1R,2S)-erythro-isomer (e-10a-I) using X-ray crystallography. Therefore the (1R,2S)-erythro structure was assigned to all compounds obtained from e-10a-I, and, as a consequence, the (1S,2S)-threo structure was assigned to diastereomers II.     

Synthesis of D-Erythro- and D-Threo-Sphingosine Derivatives From L-Serine

The protected serine aldehyde 10 was converted to the crystalline N-Boc-protected sphingosines 6 – 9 by a three-step reaction sequence. Compound 10 was transformed with high diastereoselectivity (95%) either to the erythro- or threo-alkynols, 17 and 18 , respectively. The erythro-isomer 17 is formed by the addition to 10 of lithium pentadecyne 16 in THF/HMPT at ?78°, whereas the corresponding threo-isomer 18 is produced in the presence of ZnBr² in Et₂O. Deprotection of the acetal moiety afforded 1,3-diols 19 and 20 . These diols were selectively reduced with Red-Al to the (E)-sphingosines 6 and 8 , or the (Z)-isomers 7 and 9 by partial hydrogenation over Lindlar's catalyst. Cleavage of the N-Boc group and further transformation to ceramides were readily achieved as demonstarted by the conversion of 6 to N-octadecanoyl-D -erythro-sphingosine 5 .     

Convenient Entry to α‐Amino‐β‐hydroxy‐γ‐methyl Carboxylic Acids. Diastereoselective Formation and Directed Homogeneous Hydrogenation of 3‐(3‐Aryl‐1‐hydroxy‐2‐methylprop‐2‐enyl)‐1,4‐benzodiazepin‐2‐ones

Aldol reaction of 7‐chloro‐1,3‐dihydro‐1‐methyl‐5‐phenyl‐2H‐1,4‐benzodiazepin‐2‐one ( 1 ) with 4‐substituted α‐methylcinnamaldehydes 2 – 5 afforded a mixture of threo‐ and erythro‐3‐(3‐aryl‐1‐hydroxy‐2‐methylprop‐2‐enyl)‐7‐chloro‐1,3‐dihydro‐1‐methyl‐5‐phenyl‐2H‐1,4‐benzodiazepin‐2‐ones 6 – 13 . The chromatographically separated threo diastereoisomers 6, 8, 10 , and 12 and erythro diastereoisomers 7, 9, 11 , and 13 were submitted to ‘directed' homogeneous hydrogenation catalyzed by [Rh^I(cod)(diphos‐4)]ClO₄ (cod=cycloocta‐1,5‐diene, diphos‐4=butane‐1,4‐diylbis[diphenylphosphine]. From the erythro‐racemates 9, 11 , and 13 , the erythro,erythro/erythro,threo‐diastereoisomer mixtures 16 / 17, 20 / 21 , and 24 / 25 were obtained in ratios of 20 : 80 to 28 : 72 (HPLC), which were separated by chromatography. From the threo racemates 8, 10 , and 12 , the threo,threo/threo,erythro‐diastereoisomer mixtures were obtained in a ratio of ca. 25 : 75 (¹H‐NMR). The relative configurations were assigned by means of ¹H‐NMR data and X‐ray crystal‐structure determination of 21 . Hydrolysis of 21 afforded the diastereoisomerically pure N‐(benzyloxy)carbonyl derivative 27 of α‐amino‐β‐hydroxy‐γ‐methylpentanoic acid 26 , representative of the novel group of polysubstituted α‐amino‐β‐hydroxycarboxylic acids.     

Reactions of 2-(α-Haloalkyl)thiiranes with nucleophilic reagents: V. Reactions of 2-(α-Chloroalkyl)thiiranes with organolithium compounds

2-(α-Haloalkyl)thiiranes reacted with methyl-, butyl-, and phenyllithium to give the corresponding allyl sulfides. The reactions of diastereoisomeric erythro- and threo-2-(1-chloroethyl)thiiranes with phenyllithium were stereospecific, and they afforded (E)- and (Z)-1-phenylsulfanylbut-2-enes, respectively. 3-Chloromethyl-2,2-dimethylthiirane and phenyllithium gave rise to a mixture of 3-methyl-3-phenylsulfanylbut-1-ene and 3-methyl-1-phenylsulfanylbut-2-ene. The reactions of 2-chloromethylthiiranes with phenyllithium and methyllithium in the presence of a catalytic amount of copper(I) iodide (10 mol %) led to the formation of substituted thiiranes as the major products. Mechanisms of the observed transformations are discussed.     

Syntheis of 2-aryloxy- and 2-arylalkoxy-1-(2-piperidyl)ethanols

The preparation and separation of diastereomeric pairs of a series of 2-aryloxy- and 2-arylalkoxy-1-(2-piperidyl)ethanols is reported. The erythro aminoalcohols were converted into threo isomers by thionyl chloride treatment of their N-acetyl derivatives and alkaline hydrolysis.     

Studies on the Stereochemistry of 2-(Nitromethylidene)-Heterocycles

The ¹H-NMR spectra of 2-(nitromethylidene)pyrrolidine ( 7 ), 1-methyl-2-(nitromethylidene)imidazolidind ( 10 ) and 3-(nitromethylidene)tetrahydrothiazine ( 11 ) in CDCl₃ and (CD₃)₂SO indicate that these compounds have the intramolecularly H-bonded structures (Z)- 7 , (E)- 10 and (Z)- 11 while the N-methyl derivative 8 of 7 is (E)-configurated in both solvents. 1-Benzylamino-1-(methyltio)-2-nitroehtylene ( 13 ), an acylic model, has the H-bonded configuration (E)- 13 in CDCl₃ and in (CD₃)₂SO. 2-(Nitromethylidene)thiazolidine ( 3 ) has the (E)-configuration in CDCl₃ but exists in (CD₃)₂SO as a mixture of (Z)- and (E)-isomers with the former predominating. Both species are detected to varying proportions in a mixture of the two solvents. ¹⁵N-NMR spectroscopy of 3 ruled out unambiguously the nitronic acid structure 6 and the nitromethyleimine structure 5 . The N-methyl derivative 4 of 3 is (Z)-configurated in (CD₃)₂SO. Comparison of the olefinic proton shifts of (Z)- 3 and (Z)- 4 with those of analogues and also of 1,1-bis(methylti)-2-nitroethylene ( 12 ) shows decreased conjugation of the lone pair of electrons of the ring N-atom in (Z)- 3 and (Z)- 4 . This is also supported by ¹³C-NMR studies. Plausible explanations for the phenomenon are offered by postulating that the ring N-atoms are pyramidal in (Z)- 3 and (Z)- 4 and planar in other cases or, alternatively, that the conjugated nitroenamine system gets twisted due to steric interaction between the NO₂-group and the ring S-atom. Single-crystal X-ray studies of 3 and 8 show that the former exists in the (Z)-configuration and the latter in (E)-configuration; the ring N-atom in the former has slightly more pyramidal character than in the latter.     

Synthese von threo-cis/threo-trans- und erythro-cis/erythro-trans-Dihydropalustrin. 17. Mitteilung über Schachtelhalmalkaloide

Synthesis of threo-cis/threo-trans- and erythro-cis/erythro-trans-dihydropalustrin The first synthesis of a threefold protected spermidine, namely ³-benzyloxycarbonyl-N¹-phthaloyl-N²-tosylspermidin ( 9 ) is presented. Each of the protecting groups can be removed selectively. After hydrazinolysis the resulting N³-benzyloxy-carbonyl-N²-tosylspermidine ( 10 ) has been condensed with methyl (2 E)-cis-7,8-epoxy-2-decenoate to the threo-cis/trans piperidines 17 , and with methyl (2 E)-trans-7,8-epoxy-2-decenoate to the erythro-cis/trans piperidines 17 , respectively. After catalytic removal of the Z group, the resulting aminoesters 13 and 18 , in a melt with imidazole, underwent ring closure to the 13-membered lactames 14 and 19 , respectively. reductive deprotection of the N-tosyl group with sodium/ammonia led to the stereoisomeric palustrines 15 and 20 , respectively.     

A Note on Stereochemical Observations of the Deprotonation of Ethyl 2-Alkenoates

Deprotonation of ethyl (E)-2-alkenoates 1 , 3 and 4 yields after protonation the double bond migrated (3 Z)-isomers 5 , 7 and 9 as major products. In contrast, deprotonation and reprotonation of ethyl (Z)-2-pentenoate ( 2 ) gives the (3 E)-isomer 6 exclusively. These findings are explained by reaction paths starting from different ester conformations.     

Synthesis of (-) or (+) -threo-3-(3,4-dihydroxyphenyl) serine and (-) or (+) -erythro-3-(3,4-dihydroxyphenyl)-serine]

The known synthesis of DL -3-(3,4-dihydroxyphenyl)-serine (DOPS) has been modified so that the diastereomeric threo and erythro forms could be separated. These were resolved into their antipodes, whose chemical, physical, and spectrochemical properties are discussed.     

Preference for Syn Ene Additions of 1O2 to Trisubstituted,Acyclic Olefins

Dye-sensitized photooxygenations of 3 pairs of (E)/(Z) trisubstituted olefins were studied in order to establish the partitioning between the 3 possible ene additions. The (E)-isomers underwent only the 2 ene additions (>95%) involving H-atom abstractions at the same, disubstituted side of the olefins, termed syn ene additions, with almost equal ease. The (Z)-isomers underwent mainly (85-90%) the syn ene additions, with the ones leading to the tertiary hydroperoxides distinctly favoured, and some (10-15%)ene additions at the monosubstituted side of the olefin, termed anti ene addition.     

Fluoroimines from the reaction of fluoro amino acids or fluoroketo acids with the aldehyde or amine form of vitamin B6: 2—Stereochemical aspects of their formation from β-fluoroaspartates or β-fluorooxaloacetate,using 19F NMR

The fluorine NMR spectra of systems initially containing 0.05–0.1 M of pyridoxal 5′-phosphate and erythro-β-fluoroaspartate (or threo-β-fluoroaspartate) in D₂O solution were examined over the pD range 1–12. The formation of the aldimine Schiff base gave only one stereoisomer, whcih was trapped with sodium borohydride. Reactions of pyriodoxamine 5′-phosphate and fluorooxaloacetate were examined under the same conditions. A mixture of two products was given, identified as two ketimine Schiff bases (E and Z isomers) with well characterized fluorine chemical shifts and ²J(DF) values. This mixture, trapped with sodium borohydride, gives the two reduced erythro and threo aldimines. The configurations and conformations of all reaction products were determined using the ³J(HF) values and their correlation with the fluorine chemical shift. The role of the 3-phenolate oxygen of the pyridine ring, of the conjugate acid of the iminium nitrogen and of the carboxylate oxygen in ionic or hydrogen bond interactions in the determination of the stereochemistry is discussed.