Demethoxycarbonylation and oxidation of 13(S/R)-hydroxy-chlorophyll a to 13-demethoxycarbonyl-13-oxo-chlorophyll a and Mg-purpurin-18 phytyl ester

The conversion of 13²(S/R)-hydroxy-chlorophyll (Chl) a to 13²-demethoxycarbonyl-13²-oxo-Chl a in a yield of 40%, utilizing a simple pyrolysis technique, is described. About 10% of the phytyl ester of Mg-purpurin-18 was formed as a side product. The completely assigned ¹H and ¹³C NMR spectra are presented for 13²-demethoxycarbonyl-13²-oxo-Chl a and a likely mechanism for its formation is proposed. A slight extension of this mechanism also explains the formation of the Mg-purpurin-18 side product. The proposed mechanism has several features comparable with those previously suggested for the allomerization of 13²(R/S)-Chl a. Attempts to apply the same pyrolysis method to prepare 13²-demethoxycarbonyl-13²-oxo-Chl b from 13²(S/R)-hydroxy-Chl b were unsuccessful.     

The enolate anions of chlorophylls a and b as ambident nucleophiles in oxidations with (−)- or (+)-(10-camphorsulfonyl)oxaziridine. Synthesis of 13(S/R)-hydroxychlorophylls a and b

The enolate anions of chlorophylls (Chl) are ambident nucleophiles that are of considerable organic chemical interest in relation to the theory of electron delocalization (aromaticity) and charge-transfer in large conjugated π-systems, as well as for their chemical reactivity. Under deaerated conditions, the (−)- and (+)-enantiomers of (10-camphorsulfonyl)oxaziridine (CSOAI) are effective oxidants for the enolate anions of Chl a and Chl b, when 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) serves as a base. In this study, the use of these sterically hindered reagents to hydroxylate Chl a and Chl b is described for the first time. The total yield of 13²(S/R)-HO-Chl a was 71 and 90% for the oxidations of Chl a with (−)-CSOAI and (+)-CSOAI, respectively. Chl b, however, behaved clearly differently from Chl a. The total yield of 13²(S/R)-HO-Chl b was 40% in the oxidation with (−)-CSOAI and 60% in the reaction with (+)-CSOAI. A competing side-reaction, which resulted in the 15²-methyl, 17³-phytyl ester of Mg-15¹(S/R)-unstable rhodin, was found to lower the yields of the desired main products. The formation of the side-products was largely avoided and the yield of 13²(S/R)-HO-Chl b was improved by increasing the volume of hexane and using phosphate buffer in the first step of the work-up. With (−)-CSOAI, a 94% diastereomeric excess (de) was achieved for 13²(R)-HO-Chl a, whereas the de for 13²(R)-HO-Chl b was 66%. With (+)-CSOAI, the de was 10% for 13²(R)-HO-Chl a and 8% for 13²(R)-HO-Chl b. The results were interpreted in terms of a nucleophilic reaction mechanism, kinetically controlled by steric hindrance, originating on the one hand in the 17-propionate phytyl ester side-chain, protruding over the isocyclic ring E of the Chl enolate ion, and on the other hand in the bulky camphorsulfonyl unit of CSOAI. Possible reasons for the different results from the Chl b oxidations as compared with those of the Chl a oxidations are discussed. Comparison of the differences in the NMR δ_C-values between 13²(S)- and 13²(R)-HO-Chl a as well as those between 13²(S)- and 13²(R)-HO-Chl b, indicated that the change of stereochemical configuration at C-13² induces only slight differences in the δ_C-values. Of special interest are the δ_C-values of C-13², which are at ca. 91 ppm for the a- and b-series diastereomers. This carbon is deshielded by ca. 25 ppm relative to the C-13² of 13²(R)-Chl a (δ_C=65.5). Owing to this, ¹³C NMR spectroscopy is a good method to distinguish the 13²-hydroxylated chlorophylls from the intact, naturally occurring chlorophylls.     

Enantioselective addition of methyl group to aldehydes catalyzed by titanium complex of fluorous ligand

Titanium complex of fluorous axially dissymmetric ligand ((Ra^∗)-2,2′-bis[(R^∗)-perfluoro-1H-1-hydroxyoctyl]biphenyl, ((Ra^∗)-(R^∗)₂-1)) having perfluoroheptyl carbinol moieties catalyzed enantioselective addition of a methyl group to aldehydes. Dimethylzinc prepared in situ by mixing ZnCl₂ and methyl magnesium bromide without removal of magnesium salt was more reactive for addition of methyl group than dimethylzinc without magnesium salt, and gave up to 99% ee of the products. The high fluorine content of 1 enables it to be recoverable by the selective extraction with perfluorohexane.     

Synthesis and redox behavior of 1,2-dihydro-1-oxabenz[a]azulen-2-ones

Three new 1,2-dihydro-1-oxabenz[a]azulen-2-one derivatives, 1a (R¹=H, R²=Me), 1b (R¹=H, R²=Ph), and 1c (R¹=COOEt, R²=Me), have been synthesized by the reaction of 2-hydroxyazulene (2a) and its 1-ethoxycarbonyl derivative 2b with ethyl acetoacetate (3a) or ethyl benzoylacetate (3b) in the presence of aluminum chloride. To our knowledge, these are the first examples of this type of compound, although the yield of the products is low in some cases. Their electronic properties were studied in detail utilizing the analyses of 1,2-dihydro-1-oxabenz[a]azulen-2-one derivative 1a by the spectroscopic and voltammetric analyses. The analyses revealed that the fused α-pyrone system lowers both the HOMO and the LUMO energies, relative to those of parent azulene (10), but has much pronounced effect on the LUMO, consequently, leading to decrease in HOMO–LUMO gap, compared with those of 10. These results should be attracted to the development of amphoteric redox materials. Reactivity toward electrophilic reagents was also examined by bromination and Vilsmeier–Haack formylation reactions of 1a. To evaluate the scope of the reaction products we have examined Sonogashira cross-coupling reaction of the bromination products with trimethylsilylacetylene and conversion of the formylation product to dibromoolefin by the reaction with phosphorous ylide prepared with CBr₄ and Ph₃P. Effective extension of the π-electron system in the ethynyl products has been revealed by the spectroscopic analysis. These reaction products would be attracted to the application as a terminal group for electronic applications.     

Stereoselective reduction,methylation, and phenylation of the 13-carbonyl group in chlorophyll derivatives

Regioselective reduction of the 13-carbonyl group on the five-membered exo-ring of methyl pyropheophorbide-a, one of the chlorophyll-a derivatives, with sodium borohydride gave an epimeric mixture of (13¹R/S)-hydroxy-chlorins. The stereoselectivity was controlled by the steric effect of the (17S)-methoxycarbonylethyl group to afford the (13¹S)-rich secondary alcohol (25% de). The use of sterically large lithium tri(sec-butyl)borohydride as the reductant enhanced the stereoselectivity to 55% de. The regio- and stereoselective methylation and phenylation of the 13-CO of pyropheophorbide-a were observed using methyl and phenyl lithium, respectively. The major diastereomer of the tertiary alcohols obtained had the same configuration at the 13¹-stereogenic center as in the reduced product. All of the anion species (H^?, CH₃^?, and C₆H₅^?) favorably attacked the 13¹-carbon atom from the reverse side of the 17-propionate residue, that is, the less sterically crowded face of the 13-CO plane.     

Stereoselective reduction,methylation, and phenylation of the 13-carbonyl group in chlorophyll derivatives

Regioselective reduction of the 13-carbonyl group on the five-membered exo-ring of methyl pyropheophorbide-a, one of the chlorophyll-a derivatives, with sodium borohydride gave an epimeric mixture of (13¹R/S)-hydroxy-chlorins. The stereoselectivity was controlled by the steric effect of the (17S)-methoxycarbonylethyl group to afford the (13¹S)-rich secondary alcohol (25% de). The use of sterically large lithium tri(sec-butyl)borohydride as the reductant enhanced the stereoselectivity to 55% de. The regio- and stereoselective methylation and phenylation of the 13-CO of pyropheophorbide-a were observed using methyl and phenyl lithium, respectively. The major diastereomer of the tertiary alcohols obtained had the same configuration at the 13¹-stereogenic center as in the reduced product. All of the anion species (H^?, CH₃^?, and C₆H₅^?) favorably attacked the 13¹-carbon atom from the reverse side of the 17-propionate residue, that is, the less sterically crowded face of the 13-CO plane.     

Regio- and stereoselective cycloadditions of (1Z,4R,5R)-1-arylmethylidene-4-benzoylamino-3-oxo-5-phenylpyrazolidin-1-ium-2-ides to methyl methacrylate

[3+2] Cycloadditions of (1Z,4R^∗,5R^∗)-1-arylmethylidene-4-benzoylamino-3-oxo-5-phenylpyrazolidin-1-ium-2-ides 1a-e to methyl methacrylate gave the 1-CO₂Me regioisomers 3/3′, exclusively, in 1-67% yields. Stereocontrol was dependent on the ortho-substituents at the 1′-aryl group in dipole 1: ortho-unsubstituted dipoles 1a-c gave the major (1R^∗,3R^∗,5R^∗,6R^∗)-isomers 3a-c, whilst ortho-disubstituted dipoles gave the major (1R^∗,3S^∗,5R^∗,6R^∗)-isomers 3′d,e. The structures of cycloadducts were determined by NMR and X-ray diffraction.     

Configurational assignment of the geometric isomers of α,β-disubstituted vinyl methyl ethers from 13C nmr shift data

¹³C chemical shifts of the C atoms in the geometric isomers of some α,β-disubstituted vinyl methyl ethers have been measured. Configurational assignment is readily accomplished from the relative ¹³C chemical shift values of the β-C atoms, the signal of the Z isomer (with the β substituent in a cis position with respect of the MeO group) lying 11–15 ppm downfield from that of the E isomer. The higher chemical shifts of the β-C of the Z form are ascribed to reduced conjugation in the vinyloxy system, due to the nonplanar gauche configuration of the MeO group about the O-C(sp²) bond. Structural effects on the other ¹³C shift values are also discussed.     

Diastereoselective synthesis of (2S)-2-[(R)-1H-indol-3-yl(phenyl)methyl]-2,3-dihydro-1H-inden-1-one

Double asymmetric induction in Michael reactions has been studied. Enantioselective alkylation of a cyclic ketone (1-indanone) with α-phenyl-nor-gramine was carried out. The relative configuration of (2S^∗)-2-[(R^∗)-1H-indol-3-yl(phenyl)methyl]-2,3-dihydro-1H-inden-1-one was established by X-ray diffraction. The relative configuration of (R^∗,R^∗,S^∗)- and (S^∗,R^∗,S^∗)-2-1H-indol-3-yl(phenyl)methyl]-2,3-dihydro-1H-inden-1-ols was established by ¹H NMR studies.     

Exo- and endo-palladacycles derived from (4R)-phenyl-2-oxazolines

Two novel oxazoline-derived palladacycles bearing an endo- or exo-CN bond were prepared by direct ortho-palladation of (R)-2,4-diphenyl- or (R)-2-methyl-4-phenyl-2-oxazolines, respectively. The structures of the palladacycles' dimeric forms and corresponding mononuclear PPh₃-derivatives were confirmed by IR, ¹H, ¹³C and 2D NMR spectroscopy. An X-ray diffraction study of the μ-chloro-dimeric cyclopalladated derivative of (R)-2,4-diphenyl-2-oxazoline proved the endo structure of the palladacycle.     

Synthesis of chlorophyll-a derivatives possessing (un)substituted 13-exo-methylene moiety and their optical properties

Chlorophyll-a derivatives possessing an un/mono/disubstituted methylene moiety at the 13¹-position were prepared by (un)substituted methylation of the 13-carbonyl group and successive dehydration. Substitution of the 13¹-oxo to the methylene group slightly blue-shifted electronic absorption and emission bands in a solution and decreased chemical stability to give an oxidation product cleaved at the E-ring. Further mono/disubstitution at the methylene terminal increased wavelengths of absorption and emission maxima as well as oxidative tolerance.     

Synthesis of (4R,8R)- and (4S,8R)-4,8-dimethyldecanal: the common aggregation pheromone of flour beetles

The synthesis of (4R,8R)- and (4S,8R)-4,8-dimethyldecanal 1 and 1a has been achieved connecting the chiral building block (R)-2-methyl-1-bromobutane 4 with (R)- and (S)-citronellol derivatives. The key intermediate 4 was obtained optically pure in five steps from methyl (S)-3-hydroxy-2-methylpropionate 2.     

Synthesis of the two enantiomers of the sex pheromone of Diabrotica Undecimpunct at a Howardi and of chiral precursors of other pheromones starting from enantiomerically pure methyl hydrogen (R)-3-methylglutarate

Readily available methyl hydrogen (R)-3-methylglutarate(2) is a useful chiral building block for the synthesis of several biologically active compounds. Enantiomerically pure (R)-2 has been employed to synthesize stereospecifically each of the two enantiomers, 1a and 1b, of 10-methyl-2-tridecanone, the sex pheromone of the southern corn rootworm, Diabrotica undecimpunctata howardi Barber. Compound (R)-2 has been also used to prepare 99% optically pure (R)-3-methyl-1-pentanol (6) and enantiomerically pure (R)-5-methyl-i-tricosyne (7). These compounds are useful building blocks suitable for the further elaboration to other chiral insect pheromones.     

Stereoselective synthesis of (R)-(+)-1-methoxyspirobrassinin, (2R,3R)-(−)-1-methoxyspirobrassinol methyl ether and their enantiomers or diastereoisomers

Stereoselective synthesis of cruciferous indole phytoalexin (R)-(+)-1-methoxyspirobrassinin and its unnatural (S)-(−)-enantiomer was achieved by spirocyclization of 1-methoxybrassinin in the presence of (+)- and (−)-menthol and subsequent oxidation of the obtained menthyl ethers. Methanolysis of menthyl ethers in the presence of TFA afforded (2R,3R)-(−)-1-methoxyspirobrassinol methyl ether as well its unnatural (2S,3S)-, (2R,3S)-, and (2S,3R)-isomers.     

The chemistry and 13C NMR assignments of oxaline,a novel alkaloid from penicillium oxalicum

Oxaline is the main alkaloid of several strains of Penicillium oxalicum. Structural studies on oxaline (1a) and the assignment of its ¹³C NMR spectrum are described.     

Rhodium(I) catalysis of cycloprop[a]acenaphthylene isomerizations

Cycloprop [a] acenaphthylene was found to rearrange to phenalene in the presence of rhodium dicarbonyl chloride dimer. Deuterium labeling of this molecule at C(7) (both exo and endo), at C(8), at C(7) (exo) and C(8) and at C(7) (exo), C(8), and C(8') indicated that the C(7) (exo) deuterium was migrating stereospecifically. Furthermore, all of the isotopic label present in the cycloprop[a]acenaphthylene was found statistically distributed over positions 1, 3, 4, 6, 7, and 9 of the phenalene product. Control experiments established the need of the catalyst, the inability to achieve rearrangement of the exo-7-methyl derivative, and the susceptibility of a monodeuterated phenalene for extensive isotopic scrambling in its own right when exposed to rhodium(I). These results have been interpreted on the basis of oxidative addition by rhodium(I) into the central bond of cycloprop[a]acenaphthylene from above the “flap”, followed by shifting of the C(7) (exo) hydrogen (or deuterium) to give a η³-allylrhodim-(III) complex. The experimental data further support a mechanism involving subsequent rearrangement of this intermediate around the periphery of the phenalene ring. This process which is otherwise degenerate is thought to be facilitated by the special electronic features of the phenalenyl system.     

Synthesis of tricyclic isoindoles and thiazolo[3,2-c][1,3]benzoxazines

The thermolysis of (3R,9bS)-5-oxo-2,3,5,9b-tetrahydrothiazolo[2,3-a]isoindole-3-carboxylic acids in Ac₂O led to novel 3-methylene-2,5-dioxo-3H,9bH-oxazolo[2,3-a]isoindoles and chiral (9bS)-5-oxo-2,3,5,9b-tetrahydrothiazolo[2,3-a]isoindoles were obtained on FVP. Starting from l-cysteine methyl ester (3R,10bR)-5-oxo-2,3-dihydro-10bH-[1.3]thiazolo[3,2-c][1,3]benzoxazines were obtained as single stereoisomers. The thermolysis of (3R,10bR)-5-oxo-2,3-dihydro-10bH-[1.3]thiazolo[3,2-c][1,3]benzoxazine-3-carboxylic acid in Ac₂O gave 5-acetyl-2-phenyl-2,3-dihydrothiazole. The structures of methyl (3R,9bS)-5-oxo-2,3,5,9b-tetrahydrothiazolo[2,3-a]isoindole-3-carboxylate 1a and methyl (2R,4R)-N-chlorocarbonyl-2-(2-hydroxyphenyl)thiazolidine-4-carboxylate 9 were determined by X-ray crystallography.     

Synthesis of 7-substituted chlorophyll-a derivatives as chlorophyll-b analogs with specific visible absorption bands

Methyl 3-substituted 13¹-deoxo-pyropheophorbides-a possessing the 7-methyl group were transformed into the corresponding 13¹-deoxo-pyropheophorbides-b bearing the 7-formyl group via the regioselective mono-dehydration of cis-7,8-diols to 7-hydroxymethyl-chlorins under mild acidic conditions. The exclusive production of the 7¹-hydroxy-chlorins without detection of the 8¹-hydroxy-chlorins in the reaction mixture did not depend on the 3-substituents. The regioselectivity was regulated by the 13-functional groups, and the ratio of the 8¹-OH over 7¹-OH products enhanced with an increase of the group electronegativity. Methyl mesopyropheophorbide-b (7-formyl-13¹-oxo-chlorin) was efficiently obtained by modifying methyl mesopyropheophorbide-a, one of the chlorophyll-a derivatives, through the protection of the 13¹-oxo moiety and the aforementioned mono-dehydration. The effects of the 7-substituents on the visible absorption spectra in a solution were comparable to those of naturally occurring, photosynthetically active chlorophylls-a/b and bacteriochlorophylls-c/e bearing the 7-methyl/formyl groups.     

Synthetic studies on homophymine A: stereoselective synthesis of (2R,3R,4R,6R)-3-hydroxy-2,4,6-trimethyloctanoic acid

An efficient and highly stereocontrolled synthesis of (2R,3R,4R,6R)-3-hydroxy-2,4,6-trimethyloctanoic acid, the β-hydroxy acid unit that acylates the N-terminus of homophymine A, has been devised starting from iodoethane and (S,S)-pseudoephedrine propionamide in 9 steps and 36% average overall yield. Comparison of the ¹H and ¹³C NMR and optical rotation data of the resulting β-hydroxy acid with the natural fragment unambiguously verifies the configurational assignment as (2R,3R,4R,6R).     

Isoeichlerianic acid from Aglaia silvestris and revision of the stereochemistry of foveolin B

A new series of 20,24-epoxy (tetrahydrofuryl) type dammarane triterpenoids were established. So far two series were described, based on the stereochemistries of the tetrahydrofurane ring linked to the D ring of the triterpenoid skeleton. Eichlerianic acid was characterised by the absolute configuration (20S,24S) and shoreic acid by (20S,24R). Foveolins A and B were correlated with these compounds and published also as (20S,24S) and (20S,24R), respectively. ¹³C NMR analysis of a further stereoisomer of the acids isolated from Aglaia silvestris allowed the conclusion that the new isoeichlerianic acid, its methyl ester and the known foveolin B belonged to the new stereochemical series (20R,24S).