Asymmetrische Synthese von L-γ-Carboxyglutaminsäure-Derivaten

Asymmetric synthesis of L -γ-carboxyglutamic acid derivatives A modified Strecker synthesis according to Patel & Worsley was used to prepare γ,γ′-di-t-butyl L (?)-N-phthaloyl-γ-carboxyglutamate with almost 100% optical purity and an overall yield of about 10% relative to di-t-butyl malonate, or 20% relative to (?)-α-methyl-benzylamine (s. Scheme).     

Poly(γ-alkyl glutamates). I

Good yields of some crystalline γ-alkyl esters of L -glutamic acid were obtained by carrying out the esterfication with a small (20–50 mole-%) excess of alcohol in aqueous hydrochloric acid or 60–80% sulfuric acid followed by neutralization with an alkaline solution. This new method made it possible to synthesize various γ-alkyl L -glutamates, including those higher than ethyl, and consequently, various poly(γ-alkyl L -glutamates) such as methyl, ethyl, n-propyl, n-butyl, isobutyl, and isoamyl. The conformation of these poly-L -glutamates in the solid state was determined by the infrared absorption method. The molecular motions of the polymers of γ-methyl, -ethyl, -n-propyl, -n-butyl, and-isoamyl L -glutamates and poly(γ-methyl-D -glutamate) in the solid state were studied by NMR, and dielectric and mechanical measurements. At temperatures up to 400°K., the NMR spectra of poly(γ-methyl D -glutamate) can be explained only by rotational motion of the side chain. Also, from NMR results, rotational motion of C?O groups in the side chain of poly(γ-methyl D -glutamate) is expected near room temperature, and such a motion was examined by dielectric measurements. Rotation of C?O groups in the side chains of polymers of γ-methyl, γ-ethyl, γ-n-propyl, γ-n-butyl, and γ-isoamyl L -glutamate was also observed near room temperature by dielectric measurements in the frequency range from 10² to 10⁶ cps. Activation energies obtained by dielectric and mechanical measurements were similar to those for the side chain motions of the corresponding esters of poly(methacrylic acid). Although it has been noted that the molecular motion of poly(γ-benzyl L -glutamate) in the solid state at room temperature may be related to the motion of its back bone, the molecular motion in these poly-L -glutamates at these temperatures can be explained only in terms of side-chain rotation.     

Chemical Synthesis,Proton NMR. Parameters,Hydrogen- and Calcium-Ion. Complexation of L-γ-Carboxyglutamyl-L-γ-carboxyglutamic Acid and D-γ-Carboxyglutamyl-L-leucine

The purpose of this communication is to describe the preparation and some properties of the first two synthetic peptides containing D - and L -γ-carboxyglutamic acid. Use was made of N-protected γ,γ′-di-t-butyl-γ-carboxyglutamic acids (D , L , and DL ) described earlier [1 a]. Preliminary ¹H-NMR. data (360 MHz) indicate a restricted rotation of the Gla side chain in the free amino acid as well as in the C-terminal Gla of Gla-Gla in H₂O solution at acid pH. The proton dissociation from Gla and Gla-Gla was studied by potentiometric titration and NMR. methods. The pH titration in the presence of Ca²⁺ ions shows that Gla-Gla has a much higher association constant for this cation than Gla. It is almost as great as that of prothrombin (pCa²⁺ = 3.2 vs. 3.5).     

A facile and improved synthesis of tubercidin and certain related pyrrolo[2,3-d]pyrimidine nucleosides by the stereospecific sodium salt glycosylation procedure

A simple synthesis of tubercidin ( 1 ), 7-deazaguanosine ( 2 ) and 2′-deoxy-7-deazaguanosine ( 14 ) has been accomplished using the sodium salt glycosylation procedure. Reaction of the sodium salt of 4-chloro- and 2-amino-4-chloro-pyrrolo[2,3-d]pyrimidine, 3 and 4 , respectively, with 1-chloro-2,3-0-isopropylidene-5-0-(t-butyl)dimethylsilyl-α-D-ribofuranose ( 5 ) gave the corresponding protected nucleosides 6n and 7 with β-anomeric configuration. Deprotection of 6 provided 8 , which on heating with methanolic ammonia gave tubercidin ( 1 ) in excellent yield. Functional group transformation of 7 , followed by deisopropylidenation gave 2-aminotubercidin ( 10 ) and 2-amino-7-β-D-ribofuranosylpyrrolo[2,3-d]pyrimidine-4(3H)-thione ( 11 ). Treatment of 7 with 1N sodium methoxide followed by exposure to aqueous trifluoroacetic acid, and ether cleavage furnished 7-deazaguanosine ( 2 ). 2′-Deoxy-7-deazaguanosine ( 14 ) and 2′-deoxy-7-deaza-6-thioguano-sine ( 18 ) were also prepared by using similar sequence of reactions employing 4 and 1-chloro-2-deoxy-3,5-di-O-p-toluoyl-α-D-erythro-pentofuranose ( 15 ).     

Synthesis of the penta-glutamyl derivative of N-[4-[N-[3-(2,4-diamino-1,6-dihydro-6-oxo-5-pyrimidinyl)-propyl]amino]benzoyl]-L-glutamic acid (5-DACTHF). An acyclic analogue of tetrahydrofolic acid

The penta-glutamyl derivative of N-[4-[N-[3-(2,4-diamino-1,6-dihydro-6-oxo-5-pyrimidinyl)propyl]amino]-benzoyl)-L-glutamic acid (1, 5-DACTHF, 543U76) was synthesized by a convergent route. L-γ-Glutamyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-L-glutamic acid heptakis t-butyl ester ( 20 ) was prepared in ten steps from L-glutamic acid di-t-butyl ester and N-(benzyloxycarbonyl)-L-glutamic acid α-t-butyl ester. 4-[N-[3-(2,4-Diamino-1,6-dihydro-6-oxo-5-pyrimidinyl)propyl]trifluoroacetamido]benzoic acid ( 6 ), which was synthesized from pyrimidinylpropionaldehyde 3 in three steps, was condensed with 20 , followed by deprotection to provide N-[4-[N-[3-(2,4-diamino-1,6-dihydro-6-oxo-5-pyrimidinyl)propyl]amino]benzoyl]-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-L-glutamic acid ( 2 ). Hexaglutamate 2 is a potent inhibitor of glycinamide ribonucleotide transformylase.     

The Enantioselective Synthesis of 3-Methoxy-1, 3, 5 (10)-estratrien-11, 17-dione by a Thermal Intramolecular Cycloaddition Reaction. Preliminary communication

The enantiomerically pure (+)-3-methoxy-1, 3, 5 (10)-estratrien-11, 17-dione 11 (with trans-anti-trans configuration) was synthesized in a highly stereocontrolled fashion from (±)-t-butyl 4-methoxy-1-benzocyclobutene carboxylate (8) and the (+)-carboxylic acid 6 , obtained from 4 in two steps, followed by one crystallization of the (+)-ephedrine salt. The key step 10→11 (Scheme 2) involves a thermal intramolecular cycloaddition reaction.     

Total synthesis of 2-(β-D-ribofuranosyl)thiazole-4-carboxamide (Tiazofurin) and of precursors of ribo-C-nucleosides

(1R,2S,4R)-2-Cyano-7-oxabicyclo[2.2.1]hept-5-en-2-yl (1S′)-camphanate ( 5 ) was transformed into (?)-methyl 2,5-anhydro-3,4,6-O-tris[(tert-butyl)dimethylsilyl]-D -allonate ( 2 ), (+)-1,3-diphenyl-2-{2′,3′,5′-O-tris[(tert-butyl)dimethylsilyl]-β-D -ribofuranosyl}imidazolidine ( 3 ), and the benzamide 20 of 1-amino-2,5-anhydro-1-deoxy-3,4,6-O-tris-[((tert-butyl)dimethylsily)]-D -allitol. Compound 2 was converted efficiently into optically active tiazofurin ( 1 ).     

Syntheses of the Enantiomers of γ-Cyclogeranic Acid, γ-Cyclocitral,and γ-Damascone: Enantioselective protonation of enolates

(R)-and (S)-γ-cyclogeranic acid ((R)-and (S)- 9 , resp.) were obtained by resolution of the racemate, and their absolute configurations determined by chemical correlation. The γ-acids (R)-and (S)- 9 were converted into (R)-and (S)-methyl γ-cyclogeranate ((R)-and (S)- 6 , resp.), and (R)-and (S)-γ-damascone ((R)-and (S)- 5 , resp.). A more direct entry to (R)-and (S)- 9 consisted in the enantioselective protonation of a thiol ester enolate with (?)- or (γ)-N-isopropylephedrine((?)- or (γ)- 20 ) and subsequent hydrolysis of the (R)-and (S)-S-phenyl γ-thiocyclogeranate ((R)- and (S)- 24 , resp.; 97% ee). The esters (R)- and (S)- 24 were also used as precursors of (R)- and (S)-γ-damascone ((R)- and (S)- 5 , resp.). Alternatively, (S)- 5 (75% ee) was obtained by enantioselective protonation of ketone enolate 29 with (?)-N-isopropylephedrine ((?)- 20 ). Organoleptic evaluation demonstrated that the (S)-enantiomers of methyl γ-cyclogeranate and γ-damascone are markedly superior to their (R)-enantiomers.     

Crystal and molecular structure of the levorotatory (1R,2S)-ephedrinium (S)-t-butylsulfinylacetate: a definitive proof of the absolute configuration of enantiomeric t-butyl methyl sulfoxides

The levorotatory enantiomer of t-butylsulfinylacetic acid 3 was obtained in the reaction of the α-carbanion of (+)-t-butyl methyl sulfoxide 1 with carbon dioxide. The same enantiopure form of the acid 3 was isolated from its diastereomerically pure levorotatory salt 5 with (−)-(1R,2S)-ephedrine. The structure of this salt was determined by X-ray analysis and the absolute configuration (S) at sulfur was ascribed to the t-butylsulfinylacetate anion. Consequently, the absolute configuration (S) was assigned to the acid (−)-3 and its precursor (+)-t-butyl methyl sulfoxide 1.     

Stereoselective synthesis of pinane-based β- and γ-amino acids via conjugate addition of lithium amides and nitromethane

Michael addition of dibenzylamine to (?)- and (+)-tert-butyl myrtenate, (?)-2 and (+)-2, derived from (?)- and (+)-myrtenal, furnished monoterpene-based β-amino acid derivatives in highly stereospecific reactions. The resultant amino esters (?)-3 and (+)-3 were transformed to unsubstituted, mono- and disubstituted and Fmoc-protected amino acids (?)-6-11 and (+)-6-11, which are promising building blocks for the synthesis of β-peptides and 1,3-heterocycles. The microwave-assisted conjugate addition of nitromethane to α,β-unsaturated esters (?)-12 and (+)-12 likewise resulted in nitro esters (?)-13 and (+)-13 in highly stereospecific reactions. Compounds (?)-13 and (+)-13 were successfully transformed into γ-amino acids (?)-16 and (+)-16 in two steps.     

Copper(II) tetrafluoroborate as a novel and highly efficient catalyst for N-tert-butoxycarbonylation of amines under solvent-free conditions at room temperature

Commercially available copper(II) tetrafluoroborate hydrate was found to be a highly efficient catalyst for chemoselective N-tert-butoxycarbonylation of amines with di-tert-butyl dicarbonate under solvent-free conditions and at room temperature. Various aromatic amines were protected as their N-tert-butyl carbamates in high yields and in short times. No competitive side reactions such as isocyanate, urea, and N,N-di-t-Boc formation was observed. Chemoselective N-tert-butoxycarbonylation was achieved with substrates bearing OH and SH groups. Chiral α-amino acid esters afforded the corresponding N-t-Boc derivatives in excellent yields.     

Sesquiterpenoids from Costus Root Oil (Saussurea lappa CLARKE)

Apart from the well-known constituents (+)-β-selinene ( 2 ), (?)-β-elemene ( 4 ), (+)-β-costol ( 7 ), (?)-caryophyllene ( 17 ), and (?)-elemol ( 19 ) the following sesquiterpenoids have been isolated for the first time from costus root oil (Saussurea lappa CLARKE ): (?)-α-selinene ( 1 ), (+)-selina-4, 11-diene ( 3 ), (?)-α-trans-bergamotene ( 5 ), (?)-α-costol ( 6 ), (+)-γ-costol ( 8 ), (?)-elema-1,3,11 (13)-trien-12-ol ( 9 ), (?)-α-costal ( 11 ), (+)-γ-costal ( 12 ), (+)-γ-costal ( 13 ), (?)-elema-1,3,11 (13)-trien-12-al (elemenal, 14 ), (?)-(E)-trans-bergamota-2, 12-dien-14-al ( 15 ), (?)-ar-curcumene ( 16 ), and (?)-caryophyllene oxide ( 18 ). Compounds 6 , 8 , 9 , and 13 are new sesquiterpenoids. IR. and NMR. spectra of 12 sesquiterpenoids are reproduced.     

Enantioselective Synthesis of 3- Azabicyclo[4.3.0]nonane Alkaloids

The stereospecific synthesis of the monoterpene alkaloids (?)-α-skytanthine ((?)- 2 ), (?)-N -demethyle-δ-sky-tanthine((?)- 7 ), and (+)-epidihydrotecomanine (+)- 4 was achieved from a common intermediate 22 , which in turn was obtained from (1R,4S,1′S)-2-(1′-phenylethyl)-2-azabicyclo[2.2.1]hept-5-ene (10) ,via a ketene aza-Claisen rearrangement. The piperidine derivative (+)- 31 , formally the aza-analogue of (+)-isoiridomyrmecin, was also obtained from the same intermediate 22 .     

Amino-derivatives of usninic acid

Products from the reaction of usninic acid and 4-(3-aminopropyl)-2,6-di-t-butylphenol, 4-(2-aminoethyl)-2,6-di-t-butylphenol, antipyrine, N,N-diethylaminoethylamine, p-chloroaniline, and p-bromoaniline in addition to the quaternary ammonium salt (E)-2-(1-(6-acetyl-7,9-dihydroxy-8,9b-dimethyl-1,3-dioxo-1,9b-dihydrodibenzo[b,d]furan-2(3H)-ylidene)ethylamino)-N,N-diethyl-N-methylethaneammonium iodide were obtained.     

Synthesis of glucose phosphate derivatives by the phosphite triester method

Synthesis of sugar phosphate derivatives by means of phosphite triester method is described. Seven glucose phosphotriester derivatives have been prepared, i.e. dimethyl, methyl n-propyl, and methyl isopropyl (1, 2:5, 6-di-O-isopropylidene-α-D-glucofuranose-3-) phosphate (5, 7 and 8); methyl bis-(1, 2:5, 6-di-O-isopropylidene-α-D-glucofuranose-3-) phosphate (6); methyl bis-(1, 2, 3, 4-tetra-O-acetyl-β-D-glucopyranose-6-) phosphate (9); methyl bis-(1, 2-O-isopropylidene-3,5-O-benzylidene-α-D-glucofuranose-6-) phosphate (10); and methyl (1, 2, 5, 6-di-O-iso-propylidene-α-D-glucofuranose-3-) (1, 2, 3, 4-tetra-O-acetyl-β-D-glucopyranose-6-) [phosphate (11). The results of the displacement of second chlorine atom of the reagent by different alcohols showed that methanol, n-propanol, isopropanol and as well as the glucose derivatives reacted normally to give the expected phosphite esters which yield the expected phosphate products after oxidation, but not the t-butanol. Removal of methyl group from a phosphotriester linkage can be easily achieved by the action of t-butyl amine and thus, t-butyl ammonium bis-(1, 2:5, 6-di-O-isopropylidene-α-D-glucofuranose-3-) phosphate t-butyl amine salt (12) has been obtained from its parent phosphotriester in nearly quantitative yield. The mass spectra data of di-O-isopropylideneglucose phosphate reveals that the cleavage of these compounds follows a general pattern and can be used for their characterization.     

Aziridination of the uracil 5,6-olefinic bond of 3-N-3′,5′-Di-O-tribenzoyl-5-vinyl-2′-deoxyuridine

Oxidation of N-aminophthalimide with lead tetra-acetate at -50° gives N-acetoxyaminophthalimide ( 3 ) which selectively aziridinates the 5,6-double bond present in 3-N-3′,5′-di-O-tribenzoyl-5-vinyl-2′-deoxyuridine ( 1a ) to yield 2-[1′-(2′-deoxy-β-D-ribofuranosyl)]-7-(1-phthalimido)-4-N-3′,5′-di-O-tribenzoyl-6-vinyl-2,4,7-triazabicyclo[4.1.0]heptan-3,5-dione ( 5 ).     

Synthesis of(+)-(2S, 6S)-trans-α-Irone and of(-)-(2S, 6S)-trans-γ-Irone

A 3:1 mixture of (+)-(2S, 6S)-trans-α-irone ((+)-1) and (?)-(2S, 6S)-trans-γ-irone (?)-2) has been synthesized with ca. 70% e. e. by the ene reaction of (?)-(S)-3 and but-3-yn-2-one.     

Total synthesis of natural cis-3-hydroxy-l-proline from d-glucose

Synthesis of cis-3-hydroxy-l-proline from d-glucose is reported. The methodology involves conversion of d-glucose into N-benzyloxycarbonyl-γ-alkenyl amine which on 5-endo-trig-aminomercuration gave the pyrrolidine ring skeleton with sugar appendage in 25% yield. Alternatively, N-benzyloxycarbonyl-γ-alkenyl amine on hydroboration-oxidation, mesylation and intramolecular S_N2 cyclisation afforded pyrrolidine ring compound in high yield. Hydrolysis of 1,2-acetonide functionality, NaIO₄ cleavage followed by oxidation of an aldehyde into acid and hydrogenolysis afforded cis-3-hydroxy-l-proline in overall 29% yield from d-glucose.     

Über die absolute Konfiguration der Visnagane

(+)-cis-Khellactone methyl ether ( 4 ) and (?)-trans-khellactone methyl ether ( 6 ) had earlier been assigned the absolute configurations 3′-S; 4′-S and 3′-S; 4′-R, respectively, on the basis of the FREUDENBERG , rule. Both compounds together with their defunctionalised derivatives (?)- 7 and (+)- 8 (=(+)-lomatin), obtained from a mixture of (+)-visnadin ( 1 ) and (+)-samidin ( 2 ), were investigated by the HOREAU method. A conformational analytical study showed that the optical yield should rise in the order 4 < 6 < 7 , 8. This order was found and the α-phenylbutyric acid liberated was always dextrorotatory. The centre 3′ of the khellactones and their derivatives must be R-chiral and not S. Treatment of (?)- 6 with pyridinium perbromide gave (?)-trans-3-bromokhellactone methyl ether ( 11 ) as orthorhombic crystals. The X-ray crystal structure determination was made using the anomalous scattering of the Mo-K α radiation by Br. The result, — centre 3′ R-chiral (fig. g) — showed that the HOREAU method was correct.     

Concise,efficient and highly selective asymmetric synthesis of (+)-(3S,4R)-cisapride

A concise asymmetric synthesis of the gastroprokinetic agent (+)-(3S,4R)-cisapride {(+)-(3S,4R)-N(1)-[3′-(4″-fluorophenoxy)propyl]-3-methoxy-4-(2″′-methoxy-4″′-amino-5″′-chlorobenzamido)piperidine} from commercially available starting materials has been developed. The key step of this synthesis employs the diastereoselective conjugate addition of lithium (R)-N-benzyl-N-(α-methylbenzyl)amide to tert-butyl 5-[N-3′-(4″-fluorophenoxy)propyl-N-allylamino]pent-2-enoate and in situ enolate oxidation with (?)-camphorsulfonyloxaziridine to set the (3S,4R)-configuration found within the piperidine ring of the product. This synthesis proceeds in 9 steps from commercially available 1-(4′-fluorophenoxy)-3-bromopropane with an overall yield of 19%.