Four new ginkgolic acids from Ginkgo biloba

Four new compounds, 2-hydroxy-6-(12′-hydroxyheptadec-13′(E)-en-1-yl)benzoic acid (1), 2-hydroxy-6-(13′-hydroxyheptadec-11′(E)-en-1-yl)benzoic acid (2), 2-hydroxy-6-(10′-hydroxypentadec-11′(E)-en-1-yl)benzoic acid (3), and 2-hydroxy-6-(11′-hydroxypentadec-9′(E)-en-1-yl)benzoic acid (4) were isolated from the leaves of Ginkgo biloba and the structures of new ginkgolic acids were deduced on the basis of spectroscopic methods and chemical means. Compounds 1 and 2, and 3 and 4 examined as an inseparable mixture of hydroxyl and double bond positional isomers, were ultimately defined by total synthesis. Compounds 1–4 showed moderate lipid droplets accumulation inhibitory activity on mouse pre-adipocyte cell line, MC3T3-G2/PA6.     

Synthesis and stereochemistry of ceramide B, (2S,3R,4E,6R)-N-(30-hydroxytriacontanoyl)-6-hydroxy-4-sphingenine, a new ceramide in human epidermis

(2S,3R,4E,6R)-N-(30-Hydroxytriacontanoyl)-6-hydroxy-4-sphingenine (1) and its (6S)-isomer (1′) were synthesized by starting from pentadecan-15-olide, the enantiomers of 1-pentadecyn-3-ol, and (S)-Garner's aldehyde. Comparison of the ¹H NMR spectra of the tetraacetyl derivatives of 1 and 1′ with that of ceramide B, a new protein-bound ceramide in human stratum corneum, revealed it to be (2S,3R,4E,6R)-1.     

Acid-catalyzed rearrangement of α-hydroxytrialkylsilanes

Cationic rearrangement of several α-hydroxysilanes is described. Treatment of both (1R,1′R,2′S)-α-hydroxycyclopropylsilane syn-9 and (1S,1′R,2′S)-anti-9 under aqueous H₂SO₄ underwent rearrangement via a common α-silyl cation intermediate A to give a mixture of the ring-opened (R)-vinylsilane 13, the tandem [1,2]-CC bond migration product (1R,2S,1′R)-14, and its 1′S isomer 15. On the other hand, the acidic treatment of (R,E)-α-hydroxyalkenylsilane 8 or (R,Z)-8 was each accompanied with partial racemization to give an enantiomeric isomer of allylic alcohol 23 via a preferential syn-facial S_N2′ reaction, respectively. Both α-hydroxyalkynylsilane 6 and α-hydroxyalkylsilane 12 were inert to the acidic conditions; however, treatment of (R)-α-mesyloxyalkynylsilane 26 under aqueous H₂SO₄ gave a mixture of the optically active rearranged allene 27, α,β-unsaturated ketone 28, and (S)-α-hydroxyalkynylsilane 6 with partial racemization. Comparisons of the reactivities of these α-hydroxysilanes under acidic conditions are also disclosed.     

Different recognitions of (E)- and (Z)-1,1′-binaphthyl ketoximes using lipase-catalyzed reactions

Lipase-catalyzed hydrolysis of (E)-2-[α-(acetoxyimino)benzyl]-1,1′-binaphthyl [(±)-1a] and (Z)-2-[α-(acetoxyimino)benzyl]-1,1′-binaphthyl [(±)-1b] yielded optically active (E)-2-[α-(hydroxyimino)benzyl]-1,1′-binaphthyl [(S)-2a] and (Z)-2-[α-(hydroxyimino)benzyl]-1,1′-binaphthyl [(R)-2b], respectively, with high enantiomeric excess. Selectivity for the opposite enantiomer of the axial binaphthyl skeleton was shown by (Z)-isomer 1b against (E)-isomer 1a.     

Dimerization of a lattice-framework silanone into the corresponding 1,3-dioxa-2,4-disiletanes

A lattice-framework silanone, a racemate of (4R,6R)- and (4S,6S)-2,3,4,6,7,8-hexa-tert-butyl-1,5-disilatricyclo[4.2.0.0^1,4]octa-2,7-dien-5-one (4), was generated by the photoreaction of the corresponding lattice-framework disilene, a racemate of (4R,6R,4′R,6′R)- and (4S,6S,4′S,6′S)-2,3,4,6,7,8,2′,3′,4′,6′,7′,8′-dodeca-tert-butyl-[5,5′]bi{1,5-disilatricyclo[4.2.0.0^1,4]octylidene}-2,7,2′,7′-tetraene (dl-1), with mesitonitrile oxide. The silanone 4 was dimerized to produce a mixture of the corresponding dl- and meso-1,3-dioxa-2,4-disiletane derivatives 2. DFT calculations suggested that the non-selective dimerization of 4 to 2 is attributed to the irreversibility of the reaction.     

Synthesis and ring opening reactions of 2-glyco-1,4-dimethyl-3-nitro-7-oxabicyclo[2.2.1]hept-5-enes

The high-pressure asymmetric Diels-Alder reactions of d-galacto- (1a) and d-manno-3,4,5,6,7-penta-O-acetyl-1,2-dideoxy-1-nitrohept-1-enitol (1b) with 2,5-dimethylfuran (2) afforded mixtures of cycloadducts, from which the (2S,3R)-3-exo-nitro (3a and 3b), (2R,3S)-3-exo-nitro (4a and 4b), and (2R,3S)-1′,2′,3′,4′,5′-penta-O-acetyl-1′-C-(1,4-dimethyl-3-endo-nitro-7-oxabicyclo[2.2.1]hept-5-en-2-exo-yl)-d-galacto-pentitol (5b) were isolated pure. Deacetylation of these compounds led to new chiral mono-, bi-, and tricyclic ethers, being their asymmetric centers arising from the chiral inductor used in the cycloaddition reaction. A ring opening mechanism through a 1-nitro-1,3-cyclohexadiene intermediate has been proposed.     

Formal synthesis of (−)-anisomycin based on stereoselective nucleophilic substitution along with 1,2-aryl migration

The stereoselective conversion of (4R)-5-hydroxy-4-(4′-methoxyphenyl)-2(E)-pentenoate 4 into the (4S)-4-hydroxy-5-(4′-methoxyphenyl)-2(E)-pentenoate 5 using the AgNO₃/MS 4 Å/MeNO₂ system was accomplished along with complete inversion at the C₄-position, and the synthesis of the intermediate (4S)-7 for the chiral synthesis of (−)-anisomycin 6 from (4S)-7 based on osmium tetroxide-catalyzed stereoselective hydroxylation was achieved.     

Chiral cyclopentadienyl ruthenium(II) complexes with P,P-ligands derived from (1R,2R)-1,2-diaminocyclohexane: Synthesis,crystal structures and catalytic activity in Diels–Alder reactions

Chiral cyclopentadienyl ruthenium(II) complexes [CpRu(L1–L3)Cl] (5–7) have been prepared by reaction of [CpRu(PPh₃)₂Cl] with chiral P,P-ligands (1R,2R)-1,2-bis(diphenylphosphinamino)cyclohexane (L1), N,N′-[bis-(3,3′-bis-tert-butyl-5,5′-bis-methoxy-1,1′-biphenyl-2,2′-diyl)phosphite]-(1R,2R)-1,2-diaminocyclohexane (L2) and N,N′-[bis-(R)-1,1′-binaphtyl-2,2′-diyl)phosphite]-(1R,2R)-1,2-diaminocyclohexane (L3). The molecular structures of 5 and 6 have been determined by single-crystal X-ray analysis. Studies on catalytic activity of the cations derived from (5–7) by treatment with AgSbF₆, are also reported.     

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.     

Determination of the absolute configuration of the male aggregation pheromone, 2-methyl-6-(4′-methylenebicyclo[3.1.0]hexyl)hept-2-en-1-ol, of the stink bug Erysarcoris lewisi (Distant) as 2Z,6R,1′S,5′S by its synthesis

Lipase-catalyzed asymmetric acetylation of a mixture of (6R,1′S,4′S,5′R)- and (6R,1′R,4′R,5′S)-7′-norsesquisabinen-4′-ol (3) afforded a separable mixture of the recovered former and the acetate of the latter. The recovered alcohol was oxidized to (6R,1′S,5′R)-sesquisabina ketone (2), whose absolute configuration could be assigned by its CD comparison with (1R,5S)-sabina ketone (4). Conversion of (6R,1′S,5′R)-sesquisabina ketone (2) to the bioactive pheromone revealed the stereostructure of the male aggregation pheromone of the stink bug Erysarcoris lewisi (Distant) to be (2Z,6R,1′S,5′S)-2-methyl-6-(4′-methylenebicyclo[3.1.0]hexyl)hept-2-en-1-ol (sesquisabinen-1-ol, 1).     

Stereoselective synthesis of fluorine-containing analogues of anti-bacterial sanfetrinem and LK-157

The synthesis of (1′S,3R,4R)-4-acetoxy-3-(1′-trimethylsilyloxy-2′,2′,2′-trifluoroethyl)-2-azetidinone (10) precursor of modified carbapenems is described relying upon [Ru(C₆Me₆)(S,S)-(CH₂)₅NSO₂DPEN]-catalyzed asymmetric transfer hydrogenation under dynamic kinetic resolution using HCO₂H-Et₃N. This fluorine-containing precursor yielded the targeted trinems 1 and 2 via a stereoselective key step condensation with lithium (S)-6-methoxy-cyclohexenolate.     

Synthesis, structure, and catalytic activity of titanium(IV) and zirconium(IV) amides with chiral biphenyldiamine-based ligands

A new series of titanium(IV) and zirconium(IV) amides have been prepared from the reaction between M(NMe₂)₄ (M = Ti, Zr) and C₂-symmetric ligands, (R)-2,2′-bis(pyridin-2-ylmethylamino)-6,6′-dimethyl-1,1′-biphenyl (2H₂), (R)-2,2′-bis(pyrrol-2-ylmethyleneamino)-6,6′-dimethyl-1,1′-biphenyl (3H₂), (R)-2,2′-bis(diphenylphosphinoylamino)-6,6′-dimethyl-1,1′-biphenyl (4H₂), (R)-2,2′-bis(methanesulphonylamino)-6,6′-dimethyl-1,1′-biphenyl (5H₂), (R)-2,2′-bis(p-toluenesulphonylamino)-6,6′-dimethyl-1,1′-biphenyl (6H₂), and C₁-symmetric ligands, (R)-2-(diphenylthiophosphoramino)-2′-(dimethylamino)-6,6′-dimethyl-1,1′-biphenyl (7H) and (R)-2-(pyridin-2-ylamino)-2′-(dimethylamino)-6,6′-dimethyl-1,1′-biphenyl (8H), which are derived from (R)-2,2′-diamino-6,6′-dimethyl-1,1′-biphenyl. Treatment of M(NMe₂)₄ with 1 equiv. of N₄-ligand, 2H₂ or 3H₂ gives, after recrystallization from an n-hexane solution, the chiral zirconium amides (2)Zr(NMe₂)₂ (9), (3)Zr(NMe₂)₂ (11), and titanium amide (3)Ti(NMe₂)₂ (10), respectively, in good yields. Reaction of Zr(NMe₂)₄ with 1 equiv of diphenylphosphoramide 4H₂ affords the chiral zirconium amide (4)Zr(NMe₂)₂ (12) in 85% yield. Under similar reaction conditions, treatment of Ti(NMe₂)₄ with 1 equiv. of sulphonylamide ligand, 5H₂ or 6H₂ gives, after recrystallization from a toluene solution, the chiral titanium amides (5)Ti(NMe₂)₂·0.5C₇H₈ (13·0.5C₇H₈) and (6)Ti(NMe₂)₂ (15), respectively, in good yields, while reaction of Zr(NMe₂)₄ with 1 equiv. of 5H₂ or 6H₂ gives the bis-ligated complexes, (5)₂Zr (14) and (6)₂Zr (16). Treatment of M(NMe₂)₄ with 2 equiv. of diphenylthiophosphoramide ligand 7H or N₃-ligand 8H gives, after recrystallization from a benzene solution, the bis-ligated chiral zirconium amides (7)₂Zr(NMe₂)₂ (17) and (8)₂Zr(NMe₂)₂ (19), and bis-ligated chiral titanium amide (8)₂Ti(NMe₂)₂ (18), respectively, in good yields. All new compounds have been characterized by various spectroscopic techniques, and elemental analyses. The solid-state structures of complexes 10, 12, 13, and 17-19 have further been confirmed by X-ray diffraction analyses. The zirconium amides are active catalysts for the asymmetric hydroamination/cyclization of aminoalkenes, affording cyclic amines in good to excellent yields with moderate ee values, while the titanium amides are not.     

(+)-Cystothiazole G: isolation and structural elucidation

Palladium-catalyzed cyclization-methoxycarbonylation of (2R,3S)-3-methylpent-4-yne-1,2-diol (6) derived from (2R,3S)-epoxybutanoate 5 followed by methylation gave the tetrahydro-2-furylidene acetate (−)-7, which was converted to the left-half aldehyde (+)-3. A Wittig reaction between (+)-3 and the phosphoranylide derived from the bithiazole-type phosphonium iodide 4 using lithium bis(trimethylsilyl)amide afforded the (+)-cystothiazole G (2), whose spectral data were identical with those of the natural product (+)-2. Thus, the stereochemistry of cystothiazole G (2) was proved to be (4R,5S,6(E)).     

Synthetic access to optically active isoflavans by using allylic substitution

A general approach to the (S)- and (R)-isoflavans was invented, and efficiency of the method was demonstrated by the synthesis of (S)-equol ((S)-3), (R)-sativan ((R)-4), and (R)-vestitol ((R)-5). The key step is the allylic substitution of (S)-6a (Ar¹=2,4-(MeO)₂C₆H₃) and (R)-6b (Ar¹=2,4-(BnO)₂C₆H₃) with copper reagents derived from CuBr·Me₂S and Ar²-MgBr (7a, Ar²=4-MeOC₆H₄; 7b, 2,4-(MeO)₂C₆H₃; 7c, 2-MOMO-4-MeOC₆H₃), furnishing anti S_N2′ products (R)-8a and (S)-8b,c with 93-97% chirality transfer in 60-75% yields. The olefinic part of the products was oxidatively cleaved and the Me and Bn groups on the Ar¹ moieties was then removed. Finally, phenol bromide 9a and phenol alcohols 9b,c underwent cyclization with K₂CO₃ and the Mitsunobu reagent to afford (S)-3 and (R)-4 and -5, respectively.     

Total syntheses of the strobilurins G, M, and N

The key reactions in the general synthesis of strobilurins are the highly (Z)-selective Wittig reaction of an (E)-cinnamaldehyde with the phosphorus ylide 8 derived from (1,1-dibromoethyl)triphenylphosphonium bromide, followed by bromine-iodine exchange and Pd-Cu co-catalyzed Stille cross-coupling of the resulting alkenyl iodide with methyl (Z)-2-tributylstannyl-3-methoxyacrylate (7). The synthetic strobilurins G, M, and N were identical with the corresponding natural compounds. In addition, the (2′ S)-configuration of strobilurin G (1) was unambiguously established by oxidative degradation of the synthetic intermediate (S)-9 to (R)-2,3-dihydroxyisovaleric acid.     

Nitroalkylation and nitroalkenylation reactions of γ-lactone enolates. A facile ring switch from polysubstituted γ-lactones to polysubstituted γ-lactams

Michael addition of lithium enolates of γ-butyrolactone 1 and α-methyl-γ-butyrolactone 1′ to (E)-1-nitropropene 2, (E)-β-nitrostyrene 3 and (E)-2-nitro-1-phenylpropene 4 is described. Reactions of the lithium enolate of 1′ with 2 and 4 occurred with high diasteroselectivity (80 and 92% d.e., respectively). Reactions of the zinc enolate of 1′ with two β-nitroenamines and two methylthio-substituted 1-amino-2-nitro-1,3-dienes were also examined. Catalytic reduction of the nitroalkylated and nitroalkenylated products allowed the achievement of functionalized γ-lactams and/or cyclic hydroxamic acids.     

Endoplasmic reticulum (ER) stress protecting compounds from the mushroom Mycoleptodonoides aitchisonii

Two novel compounds, 3-(hydroxymethyl)-4-methylfuran-2(5H)-one (1) and (3R,4S,1′R)-3-(1′-hydroxyethyl)-4-methyldihydrofuran-2(3H)-one (2), were isolated along with two known ones (3 and 4) from an edible mushroom Mycoleptodonoides aitchisonii. The structures of 1-4 were determined by the interpretation of spectroscopic data. Compounds 1-4 showed protective activity against endoplasmic reticulum (ER) stress-dependent cell death.     

Enantioselective synthesis of axially chiral 1-(1-naphthyl)isoquinolines and 2-(1-naphthyl)pyridines through sulfoxide ligand coupling reactions

Racemic 1-(1′-isoquinolinyl)-2-naphthalenemethanol rac-12 was prepared through a ligand coupling reaction of racemic 1-(tert-butylsulfinyl)isoquinoline rac-7 with the 1-naphthyl Grignard reagent 10. Resolution of rac-12 was achieved through chromatographic separation of the Noe-lactol derivatives 14 and 15, providing (R)-(−)-12 of >99% ee and (S)-(+)-12 of 90% ee. The ligand coupling reaction of optically enriched sulfoxide (S)-(−)-7 (62% ee) with Grignard reagent 10 furnished rac-12, with the absence of stereoinduction resulting from competing rapid racemisation of the sulfoxide 7. Reaction of optically enriched (S)-(−)-7 with 2-methoxy-1-naphthylmagnesium bromide was also accompanied by racemisation of the sulfoxide 7, and furnished optically active (+)-1-(2′-methoxy-1′-naphthyl)isoquinoline (+)-3b in low enantiomeric purity (14% ee). The absolute configuration of (+)-3b was assigned as R using circular dichroism spectroscopy, correcting an earlier assignment based on the Bijvoet method, but in the absence of heavy atoms. Optically active 2-pyridyl sulfoxides were found not to undergo racemisation analogous to the 1-isoquinolinyl sulfoxide 7, with the ligand coupling reactions of (R)-(+)- and (S)-(−)-2-[(4′-methylphenyl)sulfinyl]-3-methylpyridines, (R)-(+)-17 and (S)-(−)-17, with 2-methoxy-1-naphthylmagnesium bromide providing (−)- and (+)-2-(2′-methoxy-1′-naphthyl)-3-methylpyridines, (−)-18 and (+)-18, in 53 and 60% ee, respectively. The free energy barriers to internal rotation in 3b and 18 have been determined, and the isoquinoline (R)-(−)-12 examined as a ligand in the enantioselectively catalysed addition of diethylzinc to benzaldehyde; (R)-(−)-12 was also converted to (R)-(−)-N,N-dimethyl-1-(1′-isoquinolinyl)-2-naphthalenemethanamine (R)-(−)-19, and this examined as a ligand in the enantioselective Pd-catalysed allylic substitution of 1,3-diphenylprop-2-enyl acetate with dimethyl malonate.     

Synthesis and characterization of polybinaphthalene incorporating chiral (R) or (S)-1,1′-binaphthalene and oxadiazole units by Heck reaction

Chiral conjugated polymers P-1 and P-2 were synthesized by the polymerization of (R)-3,3′-diiodo-2,2′-bisbutoxy-1,1′-binaphthalene ((R)-M-1) and (S)-3,3′-diiodo-2,2′-bisbutoxy-1,1′-binaphthalene ((S)-M-1) with 2,5-bis(4-vinylphenyl)-1,3,4-oxadiazole (M-2) under Pd-catalyzed Heck coupling reaction, respectively. Both monomers and polymers were analysed by NMR, MS, FT-IR, UV, DSC-TG, fluorescent spectroscopy, GPC and CD spectra. The chiral conjugated polymers exhibit strong Cotton effect in their circular dichroism (CD) spectra indicating a high rigidity of polymer backbone. CD spectra of polymers P-1 and P-2 are almost identical and have opposite signs for their position. These polymers have strong blue fluorescence.     

Asymmetric Friedel-Crafts alkylation of activated benzenes with methyl (E)-2-oxo-4-aryl-3-butenoates catalyzed by [Pybox/Sc(OTf)3]

The asymmetric Friedel-Crafts reaction between methyl (E)-2-oxo-4-aryl-3-butenoates (1a-c) and activated benzenes (2a-d) has been efficiently catalyzed by the Sc^III triflate complex of (4′S,5′S)-2,6-bis[4′-(triisopropylsilyl) oxymethyl-5′-phenyl-1′,3′-oxazolin-2′-yl]pyridine (pybox 3). The 4,4-diaryl-2-oxo-butyric acid methyl esters (4) are usually formed in good yields and the enantioselectivity is up to 99% ee. The sense of the stereoinduction can be rationalized with the same octahedral complex (10) between 1, pybox 3 and Sc triflate already proposed for other reactions involving pyruvates, and catalyzed by the same complex.