The first asymmetric synthesis of (2S,3S,4R)-3-amino-2-hydroxymethyl-4-hydroxypyrrolidine

The novel (2S,3S,4R)-3-amino-2-hydroxymethyl-4-hydroxypyrrolidine 5 has been produced in an efficient synthesis from trans-4-hydroxy-l-proline 8. The key step involves a tethered aminohydroxylation of the alkene 7 to introduce regio- and stereoselectively the amino alcohol functionality in the resulting products 6 and 13. Subsequent deprotection steps furnish the target molecule 5 as well as several differentially protected analogues.     

Stereochemical studies—XIII: Cyclic aminoalcohols and related compounds—VI synthesis of the four 2-amino-4-t-butylcyclopentanol isomers

From diethyl 3-t-butyladipate (5), via cis- and trans-4-t-butylcyclopentene-1,2-oxide (31, 32) as key compounds, the syntheses of cis-2-amino-cis-4-t-butylcyclopentanol (1), cis-2-amino-trans-4-t-butylcyclopentanol (2), trans-2-amino-cis-4-t-butylcyclopentanol (3) and trans-2-amino-trans-4-t-butylcyclopentanol (4) have been achieved. 1, 3 and 4 were also synthesized from the corresponding 2-hydroxy-4-t-butylcarboxylic acids by Curtius degradation of the hydrazides (11, 18, 19). The steric course of process leading to the above compounds is discussed.     

The first asymmetric synthesis of all four isomers of cis- and trans-3,4-dihydroxy-3,4-dihydromollugin

Asymmetric synthesis of all the four stereoisomers of cis-3,4-dihydroxy-3,4-dihydromollugins 4 and 6 and trans-3,4-dihydroxy-3,4-dihydromollugins 5 and 7 was achieved. The O-methoxymethyl mollugin derivatives were dihydroxylated to (−)- and (+)-cis-3,4-dihydroxy-3,4-dihydromollugin derivatives using both AD-mix-α and AD-mix-β. Deprotection of the MOM-ethers of cis-dihydroxy compounds resulted in the targeted stereoisomers (−)-(3R,4R)-cis-3,4-dihydroxy-3,4-dihydromollugin 4, (−)-(3R,4S)-trans-3,4-dihydroxy-3,4-dihydromollugin 5, (+)-(3S,4S)-cis-3,4-dihydroxy-3,4-dihydromollugin 6 and (+)-(3S,4R)-trans-3,4-dihydroxy-3,4-dihydromollugin 7. These routes were paved with difficulties, for example, incompatibility of the substrates with AD-mixes, the unexpected formation of trans-dihydroxy compounds and failures in deprotection protocols.     

cis-Palladium(II) complexes of derivatives of di-(2-pyridyl)methane: Study of the influence of the bridge group in the coordination mode

Palladium(II) complexes containing di-(2-pyridyl)-N-methylimine (1), di-(2-pyridyl)methanol (2) and di-(2-pyridyl)methyl-N,N-diethyldithiocarbamate (4) ligands were synthesized and characterized by ¹H and ¹³C NMR in solution, IR and X-ray single crystal diffraction. Crystal structures of cis-dichloro[di-(2-pyridyl)-N-methylimine]palladium(II) (5), cis-dichloro[di-(2-pyridyl)methanol]palladium(II) (6) and cis-dichloro[di-(2-pyridyl)methyl-N,N-diethyldithiocarbamate]palladium(II) (7) showed a bidentate coordination mode of the di-(2-pyridyl)methane derivatives 1, 2 and 4. In these complexes is observed the formation of a five-membered chelate ring with the iminic ligand 1 and six-membered chelate rings with the pyridinic ligands 2 and 4. In all complexes the palladium atom displays a distorted square planar geometry.     

Application of tri- and tetrasubstituted alkene dipeptide mimetics to conformational studies of cyclic RGD peptides

The first application of a combination of novel ψ[(E)-CXCX]-type alkene dipeptide isosteres to conformation studies of cyclic bioactive peptides was carried out (X=H or Me). For exploration of bioactive conformations of Kessler's cyclic RGD peptides, cyclo(-Arg-Gly-Asp-d-Phe-Val-) 1 and cyclo(-Arg-Gly-Asp-d-Phe-N-MeVal-) 2, d-Phe-ψ[(E)-CXCX]-l-Val-type dipeptide isosteres were utilized having di-, tri- and tetrasubstituted alkenes containing the γ-methylated isosteres that have been reported to be potential type II′ β-turn promoters. All of the (E)-alkene pseudopeptides 3-6 exhibited higher antagonistic potency against α_vβ₃ integrin than 1, although potencies were slightly lower than 2. Detailed structural analysis using ¹H NMR spectroscopy revealed that representative type II′ β/γ backbone arrangements proposed for 1, were not observed in peptides 3-6. Rather on the basis of ¹H NMR data, the conformations of peptides 3-6 were estimated to be more analogous to those of the N-methylated peptide 2.     

Alkaline hydrolysis of N-bromoiminothianthrene derivatives

5-(N-Bromo)iminothianthrene (2) and 5-(N-bromo)iminothianthrene 10-oxide (5) and 10,10-dioxide (8) were prepared and their alkaline hydrolyses were studied. The compound 2 and cis-5-(N-bromo)iminothianthrene 10-oxide (cis-5) afforded the corresponding sulfoximine exclusively. While, unexpectedly, both trans-5-(N-bromo)iminothianthrene 10-oxide (trans-5) and 8 afforded mainly de-brominated products, trans-5-iminothianthrene 10-oxide (trans-4) and 5-iminothianthrene 10,10-dioxide (7), respectively. In these cases, 5-iminothianthrene 5,10-dioxide (6) (Z- and E-mixture) and 5-iminothianthrene 5,10,10-trioxide (9) and further de-iminated products were also formed respectively as minor products. The stereochemical considerations on the S_N reactions are described in view of the steric effect and ‘flip-flap’ motion of the thianthrene framework.     

Silicon-carbon unsaturated compounds. 73. Photolysis of cis- and trans-1,2-dimethyl-1,2-diphenyl-1,2-disilacyclohexane in the presence of tert-butyl alcohol and acetone

Irradiation of cis-1,2-dimethyl-1,2-diphenyl-1,2-disilacyclohexane (1a) in the presence of tert-butyl alcohol in hexane with a low-pressure mercury lamp bearing a Vycor filter proceeded with high stereospecificity to give cis-2,3-benzo-1-tert-butoxy-1,4-dimethyl-4-phenyl-1,4-disilacyclooct-2-ene (2a), in 33% isolated yield, together with a 15% yield of 1-[(tert-butoxy)methylphenylsilyl]-4-(methylphenylsilyl)butane (3). The photolysis of trans-1,2-dimethyl-1,2-diphenyl-1,2-disilacyclohexane (1b) with tert-butyl alcohol under the same conditions gave stereospecifically trans-2,3-benzo-1-tert-butoxy-1,4-dimethyl-4-phenyl-1,4-disilacyclooct-2-ene (2b) in 41% isolated yield, along with a 12% yield of 3. Similar photolysis of 1a and 1b with tert-butyl alcohol-d₁ produced 2a and 2b, respectively, in addition to 1-[(tert-butoxy)(monodeuteriomethyl)(phenyl)silyl]-4-(methylphenylsilyl)butane. When 1a and 1b were photolyzed with acetone in a hexane solution, cis- and trans-2,3-benzo-1-isopropoxy-1,4-dimethyl-4-phenyl-1,4-disilacyclooct-2-ene (4a and 4b) were obtained in 25% and 23% isolated yield. In both photolyses, 1-(hydroxymethylphenylsilyl)-4-(methylphenylsilyl)butane (5) was also isolated in 4% and 5% yield, respectively. The photolysis of 1a with acetone-d₆ under the same conditions gave 4a-d₆ and 5-d₁ in 18% and 4% yields.     

Prepatellamide A, a new cyclic peptide from the ascidianLissoclinum patella

A new cyclic peptide, prepatellamide A (1), along with three known cyclic peptides (2)— (4), was isolated from the ascidianLissoclinum patella. The structure of prepatellamide A was determined from one- and two-dimensional¹H and¹³C NMR spectra. The known cyclic peptides were identified as patellamides A (2), B (3) and C (4).     

Comparative studies for selective deprotection of the N-arylideneamino moiety from heterocyclic amides: kinetic and theoretical studies. Part 2

4-Benzylideneamino-1,2,4-triazine-3,5(2H,4H)-diones (2-5), 6-styryl-1,2,4-triazine-3,5(2H,4H)-dione (6), and 6-styryl-2,3-dihydro-3-thioxo-1,2,4-triazin-5(4H)-one (7) were synthesized and pyrolyzed in the gas phase. The kinetic effect of changing the substituent on the triazine ring from hydrogen to methyl, phenyl, and styryl was measured. Analyses of the pyrolyzates of 2-5 showed the elimination products to be benzonitrile and the triazine fragment, while the pyrolyzates of 6 and 7 reveal the formation of cis- and trans-cinnamonitriles. Theoretical study of the pyrolysis reactions of 2-5 using an ab initio SCF method was investigated.     

Stereoselective synthesis of (−)-diospongins A and B and their stereoisomers at C-5

Antiosteoporotic diarylheptanoids (−)-diospongins A (1) and B (2) were synthesized stereoselectively. The key steps in the synthesis include a stereospecific Pd^II-catalyzed cyclization of chiral 1,5,7-trihydroxy-2-heptenes, 6a and 6b, to form cis and trans tetrahydropyran rings and a regioselective Wacker oxidation of β-(tetrahydro-2H-pyran-2-yl)styrenes, 5a and 5b. Their C-5 epimers 3 and 4 were also synthesized.     

Template synthesis of a macrocycle with a mixed NHC/phosphine donor set

Reaction of cis-[ReCl(NHC)(CO)₄] cis-[1] (NHC = NH,NH-substituted saturated cyclic diaminocarbene) with diphosphine (2-F-C₆H₄)₂P-CH₂CH₂-P(C₆H₄-2-F)₂2 yields complex fac-[Re(NHC)(2)(CO)₃]Cl fac-[3]Cl. Deprotonation of the NH,NH-NHC ligand in fac-[3]Cl with KOtBu leads to an intramolecular nucleophilic aromatic substitution of one fluorine atom from each -P(C₆H₄-2-F) group by the NHC ring nitrogen atoms with formation of complex fac-[4]Cl bearing a facially coordinated [11]ane-P₂C^NHC ligand. Reaction of cis-[MnBr(NHC)(CO)₄] cis-[5] (NHC = NH,NH-substituted saturated cyclic diaminocarbene) with diphosphine 2 yields complex [MnBr(NHC)(2)(CO)₂] [6] without substitution of the bromo ligand and with the phosphine donors from the bidentate diphosphine occupying one cis and one trans position to the NHC donor.     

Enantioselective diethylzinc addition to aromatic and aliphatic aldehydes using (3R,5R)-dihydroxypiperidine derivatives catalyst

A series of chiral (3R,5R)-dihydroxypiperidine derivatives 3a-f were conveniently prepared from trans-4-hydroxy-l-proline and applied to the catalytic enantioselective addition of diethylzinc to benzaldehyde and heptanal. Among them, 3d was found to show the best asymmetric induction in promoting the addition of Et₂Zn to various aldehydes, providing (R)-secondary alcohols in up to 98% ee.     

Synthesis of 1,4-disilacyclohexa-2,5-dienes

Title compounds of the type 2,3,5,6-tetraphenyl-1,4-di-X-1,4-di-Y-1,4-disilacyclohexa-2,5-diene wherein X=Y=NMe₂ (4); X=NMe₂, Y=Cl (cis, trans-5); X=NMe₂, Y=Me [(trans)-6] and X=t-Bu, Y=Cl (trans-8) were synthesized from Si₂(NMe₂)₅Cl, sym-Si₂(NMe₂)₄Cl₂, sym-Si₂(NMe₂)₄Me₂, and sym-Si₂Cl₄(t-Bu)₂, respectively, in the presence of diphenylacetylene at 200 °C. Similarly the analogous title compound from the combination of 1-phenyl-1-propyne and Si₂(NMe₂)₅Cl [X=Y=NMe₂ (cis and trans-7) was synthesized. In all cases where cis/trans diastereomers could arise from two different silicon substituents (5, 6, 8) the trans isomer was the sole or dominant product. Evidence for the intermediacy of the silylene Si(NMe₂)₂ in these reactions was gained from a trapping experiment. Compound 4 upon treatment with SiCl₄, SiBr₄ or PI₃ provided the corresponding 1,1,4,4-tetrahalo derivatives 9a-c, respectively. Treatment of 4 with MeOH or PhOH gave the 1,1,4,4-tetramethoxy and tetraphenoxy analogues 9d and 9e, respectively. The tetrachloro derivative 9a upon LAH reduction led to the corresponding tetrahydro compound 10, while the reaction of 9a with H₂O gave the tetrahydroxy derivative 11. Allowing (trans)-6 to react with SiCl₄ provided a ca. 1:1 cis/trans ratio of the derivative 12 in which X=Cl, Y=Me, and possible pathways that rationalize this loss of stereochemistry are proposed. Synthesis of trans-13 in which X=t-Bu, Y=H was achieved by LAH reduction of 8. All of the title compounds except 8 experience free phenyl rotation at room temperature. At −30 °C this rotation in 8 is essentially halted. The molecular structures of 4, 8, 9c, 9e, 10 and 13 were determined by X-ray crystallography.     

Design of a stabilized short helical peptide and its application to catalytic enantioselective epoxidation of (E)-chalcone

Stabilized short helical heptapeptides containing a combination of an α-aminoisobutyric acid as a helical promoter and l/d-serine derivatives to produce cross-linked units were synthesized. The cyclic peptide R₃,₇R-2, which had d-serine derivatives at its 3rd and 7th positions, formed a stable right-handed (P) α-helix in solution and the crystalline state. Furthermore, its N-terminal free helical peptide catalyzed the enantioselective epoxidation of (E)-chalcone to afford the epoxide in a high yield and moderate enantioselectivity.     

Synthesis and structure of highly substituted pyrazole ligands and their complexes with platinum(II) and palladium(II) metal ions

Reaction of 3-methoxycarbonyl-2-methyl- or 3-dimethoxyphosphoryl-2-methyl-substituted 4-oxo-4H-chromones 1 with N-methylhydrazine resulted in the formation of isomeric, highly substituted pyrazoles 4 (major products) and 5 (minor products). Intramolecular transesterification of 4 and 5 under basic conditions led, respectively, to tricyclic derivatives 7 and 8. The structures of pyrazoles 4a (dimethyl 2-methyl-4-oxo-4H-chromen-3-yl-phosphonate) and 4b (methyl 4-oxo-2-methyl-4H-chromene-3-carboxylate) were confirmed by X-ray crystallography. Pyrazoles 4a and 4b were used as ligands (L) in the formation of ML₂Cl₂ complexes with platinum(II) or palladium(II) metal ions (M). Potassium tetrachloroplatinate(II), used as the metal ion reagent, gave both trans-[Pt(4a)₂Cl₂] and cis-[Pt(4a)₂Cl₂], complexes with ligand 4a, and only cis-[Pt(4b)₂Cl₂] isomer with ligand 4b. Palladium complexes were obtained by the reaction of bis(benzonitrile)dichloropalladium(II) with the test ligands. trans-[Pd(4a)₂Cl₂] and trans-[Pd(4b)₂Cl₂] were the exclusive products of these reactions. The structures of all the complexes were confirmed by IR, ¹H NMR and FAB MS spectral analysis, elemental analysis and Kurnakov tests.     

Solid-phase synthesis of backbone-cyclized β-helical peptides

This paper describes the synthesis and purification of two 22-residue cyclic peptides, cyclo{[(l-Val-d-Val)₄-(l-Val-d-Pro-Gly)]₂-} 3 and cyclo{[(d-Leu-l-Leu)₄-(d-Leu-l-Pro-Gly)]₂-} 4, that were designed to fold into double-stranded antiparallel β-helical structures. Due to intramolecular hydrogen bonding and the conformational constraints imposed by the two reverse-turn segments (d-Pro-Gly and l-Pro-Gly, respectively), the linear precursors to 3 and 4 (lin-3 and lin-4) were expected to adopt preorganized conformations that would bring the N and C termini close together and thereby favor ring closure. Precursors lin-3 and lin-4 were constructed by stepwise Boc solid-phase peptide synthesis using the commercially available alkanesulfonamide ‘safety-catch’ linker and cyclized head-to-tail via the method of cleavage-by-cyclization. The crude cyclic peptides were highly hydrophobic and contained minor impurities that could not be removed solely by reversed-phase HPLC (RP-HPLC); however, two-step purification—first by RP-HPLC with i-PrOH/water gradients, followed by gel-permeation chromatography (GPC) on Sephadex LH-20 with CHCl₃/MeOH—afforded both peptides in pure form (≥95% by ¹H NMR) and in acceptable yield (23%). Subsequent ¹H NMR experiments supported the expected structures of 3 and 4. The successful formation of the 66-membered rings of 3 and 4 is consistent with the notion of conformational preorganization in the linear precursors; furthermore, the protocols for synthesis and purification described should prove useful for preparing additional cyclic β-helical peptides, including longer peptides and peptides having polar residues.     

Montamine, a unique dimeric indole alkaloid, from the seeds of Centaurea montana (Asteraceae), and its in vitro cytotoxic activity against the CaCo2 colon cancer cells

Reversed-phase HPLC analysis of the methanol extract of the seeds of Centaurea montana afforded a flavanone, montanoside (4), six epoxylignans, berchemol (7), berchemol 4′-O-β-d-glucoside (5), pinoresinol (10), pinoresinol 4-O-β-d-glucoside (8), pinoresinol 4,4′-di-O-β-d-glucoside (6), pinoresinol 4-O-apiose-(1→2)-β-d-glucoside (9), two quinic acid derivatives, trans-3-O-p-coumaroylquinic acid (1), cis-3-O-p-coumaroylquinic acid (2), and eight indole alkaloids, tryptamine (3), N-(4-hydroxycinnamoyl)-5-hydroxytryptamine (11), cis-N-(4-hydroxycinnamoyl)-5-hydroxytryptamine (12), centcyamine (16), cis-centcyamine (17), moschamine (13), cis-moschamine (14) and a dimeric indole alkaloid, montamine (15). While the structures of two new compounds, montanoside (4) and montamine (15), were established unequivocally by UV, IR, MS and a series of 1D and 2D NMR analyses, all known compounds were identified by comparison of their spectroscopic data with literature data. The antioxidant properties of these compounds were assessed by the DPPH assay, and their toxicity towards brine shrimps and cytotoxicity against CaCo-2 colon cancer cells were evaluated by the brine shrimp lethality and the MTT cytotoxicity assays, respectively. The novel dimer, montamine (15), showed significant in vitro anticolon cancer activity (IC₅₀=43.9 μM) while that of the monomer, moschamine (13), was of a moderate level (IC₅₀=81.0 μM).     

Circular dichroism—LI : Circular dichroism of derivatives of hop constituents containing a five-membered ring

The conformation of the cyclopentenones 5 to 8 is determined from their CD-spectra. The site of enolization and the conformation of cis- and trans-isohumulone (1 and 2) is determined with the help of the CD-spectra, the direction of enolization for the humulinic acids 3 and 4 is tentatively determined by the same method.     

Novel regiochemistry in the aqueous singlet oxygen ene reactions of carboxylic acid salts: a comparison of substrate structure

The singlet oxygen (¹Δ_g) photooxidations of angelic acid salt (1), tiglic acid salt (2), 2,3-dimethyl-2-butenoic acid salt (3), 3-ethoxycarbonyl-5,6-dihydro-2-methyl-4H-pyrane acid salt (4), cis-3-hexenoic acid salt (5), and trans-3-hexenoic acid salt (6) were conducted in deuterated water. The major and minor ene allylic hydroperoxide products were quantified and indicate that the allylic hydrogen geminal to the carboxylate group is preferentially abstracted in 1-4, whereas the allylic hydrogen α to the carboxylate is slightly favored for 5 and 6. We have attributed the observed regiochemistry in 1-4 to stabilizing hydrogen bonding interactions between the solvent and the perepoxide, which leads to the major ene product.     

Chemo enzymatic synthesis of Rengyol and Isorengyol

Cyanohydrins 2 of O-protected 4-hydroxycyclohexanones 1 are excellent starting compounds for the synthesis of Isorengyol (I) and Rengyol (II). The cyano group of the O-benzyl derivative 2d is first converted into the corresponding aldehyde 4, which via Wittig olefination led to the vinyl compound 6. Hydroboration of the trans-derivative (trans-6) leads, after debenzylation, to Isorengyol, whereas hydroboration and debenzylation of the cis-isomer (cis-6) gives Rengyol. With hydroxynitrile lyases (HNLs) as catalysts the stereoselective preparation of cis- as well as trans-cyanohydrin 2d is possible, which enables the selective preparation of Isorengyol or Rengyol, respectively. The trans-configuration of Isorengyol and the cis-configuration of Rengyol were secured by X-ray crystal structure analysis.