Chiral Synthesis of the Key Intermediate of Diterpenoids

(-)-Methyl(4R,5SloR)-l4-methoxyPodocmpa-8,ll,l3-triene-l9-oate(I)isthekeyintermediateforsynthesesofditerpenoidssuchaskaurenoicacid(3),kaur-l6-en-l9-ol(4),monoginol(5)('),aswellasC,,-diterpenealkaloidssuchasveachine(6),garryine(7)andatisine(8)(=).TheracemicsynthesisofthisintermediatewasdonebyK.Morietar'),butthechiralsynthesishasnotbeenreported.Herewepresentthechiralsynthesisofthiskeyintermediatefrom(R)-(+)-2-methyl-2-(2'-nitrovinyl)-5-vaierolactone(2).2wassynthesizedaccordingtoliterattirmeth…     

New Synthesis of 2,2‐Bis(hydroxymethyl) methylenecyclopropane,a Key Intermediate for Antiviral Cyclopropavir

Synthesis of 2,2‐bis(hydroxymethyl)methylenecyclopropane (2) is described. Cyclopropane dicarboxylate 3 was reduced to diol 4, which was acetylated to give diacetate 5. Acetoxy‐bromo elimination afforded methylenecyclopropane 6. Debenzylation gave the title compound 2.     

Efficient One‐Step Synthesis of a Key Intermediate for the Synthesis of Azole Antifungals Using the Mitsunobu Protocol

A simple and single‐step process for coupling (2R,1S)‐1‐[2‐(2,4‐difluorophenyl)‐2‐oxiranyl]ethanol and various 1,2,4‐triazolones utilizing the Mitsunobu protocol is described. The product so formed is a key intermediate in the synthesis of azole antifungals with potent and broad‐spectrum activity against yeast and filamentous fungi.     

First Synthesis of a Series of New Natural Glucosides

Alkyl glucoside 1 and aryl glycosides 2-4 were highly stereospecifically synthesized over 4-6 steps from commercially available starting materials. The coupling reaction of the acetobromo-α-D-glucose with the unprotective dihydroxy aglycon in the presence of silver oxide, or with aromatic aglycon in the presence of sodium hydroxide produced the key intermediate. Only β-configuration glycosides were formed in this procedure. The synthesis of all these glycosides was reported for the first time.     

Synthesis of γ-fluoro-α-amino acids by Claisen rearrangement

A series of N-protected glycine and alanine esters 4-7 of different fluorinated allylic alcohols 1 was prepared using the dicyclohexylcarbodiimide/dimethylaminopyridine method. All fluorinated esters of this type failed to react in an esterenolate Claisen rearrangement under the general conditions of the Kazmaier variant of this rearrangement. Change of the solvent from tetrahydrofuran to the less coordinating diethyl ether enabled the rearrangement of N-Boc-protected glycine esters 4a-c of 2-fluoroalken-3-ols 1a-c to form N-Boc-2-amino-4-fluoroalk-4-enecarboxylic acids 8a-c, while the rearrangement failed with N-Boc-alanine esters and all amino acid esters of 2-fluoroallylic alcohol (1e). This might be due to competing deprotonation of the position β to fluorine. Similarly to the esters 4a-c, the TFA-protected glycine esters 5a-c of 2-fluoroalken-3-ols 1a-c were rearranged. Deprotection of the Boc or the TFA group under salt-free conditions yielded the free amino acids 11a-c, which might be seen as mimics for N-alkylasparagines a group of lipoproteins.     

Synthesis of a Protected Phosphoamino Acid,Nα-tert-Butyloxycarbonyl-O-Diethylphosphoro-L-Serine

Phosphoproteins are known to play metabolic and structural roles in many biological processes. In such proteins, serine is the most commonly phosphorylated amino acid and is usually flanked by a cluster of acidic or basic residues. In our studies of the structure and reactivity of the phosphorylated segments of the caseins, we have been concerned with the development of a synthetic methodology suitable for the rapid synthesis in gram quantities of phosphopeptides.     

Facile Preparation of α‐Acyloxyacetaldehyde,a Versatile Intermediate in the Synthesis of Antiviral Nucleosides

Abstract

This report describes a novel and simple method for the preparation of a versatile intermediate, α‐acyloxyacetaldehyde and its acetals, and its application to the synthesis of 4‐acetoxy‐2‐acyloxymethyl‐1,3‐oxathiolane, an important intermediate in the synthesis of biologically active nucleosides.     

Stereoselective Synthesis of γ-hydroxy-α-amino acids via intramolecular amidomercuration

A general method for the stereoselective conversion of homoallylic alcohols to erythro- or threo-β-hydroxy-α-amino acids is described. The key step is the stereoselective mercuric ion-initiated cyclofunctionalization of acylaminomethyl ether derivatives of the homoallylic alcohols (3 → 8). The stereochemistry of the products obtained from the cyclofunctionalization is controlled by the choice of reaction conditions. Reaction under conditions of kinetic control leads to predominant formation of cis 4,6-disubstituted tetrahydro-1,3-oxazines, while reaction under conditions which allow for equilibration of the organomercurial intermediates results in the formation of the trans stereoisomer with very high stereoselectivity. Oxidative demercuration and oxidation of the resulting alcohol produces a protected form of the title amino acids (8 → 9 → 10). Cleavage of the tetrahydrooxazine ring with hydrobromic acid then produces the amino acid products asγ-butyrolactone hydrobromides (11 and 12). This general method thus allows for stereoselective synthesis of either diastereomer of the amino acid product starting with a single homoallylic alcohol.     

Synthesis of a New Polyoxometalate Loaded Stearic Acid Nanoparticles

The stearic acid nanoparticles loaded polyoxometalate K6[γ-(CpTi)2SiW10O38][(CpTi)2SiW10] have been prepared and structurally characterized by elemental analysis, IR spectra.The particle size was estimated by transition electron microscope and zatesizer instrument. The result showed that the polyoxometalate retained the parent structure after encapsulation by stearic acid nanoparticles.     

Glycine Imine—The Elusive α-Imino Acid Intermediate in the Reductive Amination of Glyoxylic Acid

Simple unhindered aldimines tend to hydrolyze or oligomerize and are therefore spectroscopically not well characterized. Herein we report the formation and spectroscopic characterization of the simplest imino acid, namely glycine imine, by cryogenic matrix isolation IR and UV/Vis spectroscopy. Glycine imine forms after UV irradiation of 2-azidoacetic acid by N₂ extrusion in anti-(E,E)- and anti-(Z,Z)-conformation that can be photochemically interconverted. In matrix isolation pyrolysis experiments with 2-azidoacetic acid, glycine imine cannot be trapped as it further decarboxylates to aminomethylene. In aqueous solution glycine imine is hydrolyzed to hydroxy glycine and hydrated glyoxylic acid. At higher concentrations or in the presence of Fe^IISO₄ as a reducing agent glycine imine undergoes self-reduction by oxidative decarboxylation chemistry. Glycine imine may be seen as one of the key reaction intermediates connecting prebiotic amino acid and sugar formation chemistry.     

The Acetoxyfulvene Synthesis of Prostaglandins: A New,Versatile Synthesis of dl-PGF1δ, dl-PGF2α, dl-PGE1 and dl-PGE2 from a Common Intermediate

Abstract

In the Corey¹ synthesis of prostaglandins and in our recently published modifications^2,3 a synthon containing carbon atoms 14 to 20^θ is first added to a bicyclic intermediate (C-6 to C-13) and completion of the prostaglandin skeleton by addition of a second synthon containing carbon atoms 1 to 5 forms a subsequent step. In a modification^4,5 of the Corey synthesis¹ PGF_1α and PGE₁ were made by reversing the order in which these two synthons were added to the cyclopentane ring (C-6 to C-13). The major limitation of this modified route^4,5 is that it is restricted to the preparation of prostaglandins of the 1-series,^? because hydrogenolysis of the benzyl group of the intermediate ester (1) reduces the C-5, C-6 double bond to form the saturated alcohol (2), which cannot be converted into prostaglandins of the 2-series^?.     

Direct Trapping of Ketene Intermediate by Internal Nucleophile:A New Approach for the Synthesis of γ-Lactams

The application of Wolff rearrangement of the diazoketones derived from α-amino acids has been well documented.¹ It has been generally observed that if the rearrangement is performed in aqueous solution, homologated acid is the expected products, while if the reaction is run in methanol or ammonia, the corresponding homologated ester or amide will be obtained. In connection with other synthetic work, we unexpectedly observed that the Wolff rearrangement of diazoketone 1 in anhydrous methanol gave exclusively γ-lactam 3 in excellent yield.(Scheme 1) The formation of this intramolecular cyclization product was apparently due to the nucleophilic attack of the intermediate ketene 2 by the tosyl protected amino group. Although the solvent methanol can serve as nucleophile, the exclusive formation of γ-lactam indicates the intermolecular nucleophilic attack of the ketene intermediate 2 by methanol is not effective enough to compete with intramolecular nucleophilic attack by the tosyl protected amino group. This observation aroused our interest in the generality of this reaction and its potential as a novel method for the direct synthesis of γ-lactams. We report here the results of the investigation of Wolff rearrangement of several diazoketones derived from N-tosyl protected α-amino acids and β-amino acids.     

New Methodology for the Synthesis of α,α-difluoroketones

A new methodology is described for the synthesis of α,α-difluorinated ketones by the addition of organolithium reagents to α,α-difluoro-N-methoxy-N-methyl amides (Weinreb amides).     

Synthesis of α,α-dideutero-β-amino esters

A straight forward entry to α,α-dideutero-β-amino esters starting from the corresponding imines and deuterated acetonitrile has been developed involving a two-step process.     

STUDY ON THE SYNTHESIS OF TETRACYCLIC DITERPENOID 7 Preparation of the Key Intermediate 5 for the Synthesis of Grandiflorenic Acid and its Analogues

The key intermediate 5 for synthesis of the contragestationallyactive diterpenoid grandiflorenic acid(1)and its analogues 2 and 3 wasprepared and an acetyl transposition reaction occurred in the SeO_2 oxida-tion of 8.     

Construction of the Skeleton of Phthalascidin, Mechanism of the Formation of the Key Tricyclic Lactam Intermediate

Phthalascidin is a structurally simplified version of Et-743, which is a potent anti-tumor marine natural product isolated from Ecteinascidia turbinata. Its antiproliferative activity is greater than that of the agents taxol, camptothecin, adriamycin, mitomycin C, cisplatin, bleomycin, and etoposide by 1-3 orders of magnitude. An elegant synthesis of Et-743 and phthalascidin has been reported by E. J. Corey and co-workers1,2. As part of our continuing program, we have also engaged in dev…     

Synthesis ofα-substitutedα-amino acids by the alkylation of 5-oxazolinone derivatives

Methods have been developed for the alkylation of 5-oxazolinone derivatives in DMF in the presence of K₂CO₃, KOH, or diisopropylethylamine and a phase transfer catalyst as well as for the preparation of-methyl-phenylalanine,-methylalanine,-methylalanine, and the methyl ester of N-benzoyl--methylalanine. Increasing the initial concentration of the starting 5-oxazolinone in the reaction mixture leads to a sharp drop in the yield of reaction products due to side condensation reactions. The reaction of 2-phenyl-4-benzyl-5- oxazolinone with ethyl iodide gave a dimer namely, 3-(benzoylamino)-3,5-dibenzylpyrrolidine-2,4-dione.Latvian Institute of Organic Chemistry, LV-1006 Riga. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 829–833, June, 1994. Original article submitted January 21, 1994.     

Synthesis of difluorinated pseudopeptides using chiral α,α-difluoro-β-amino acids in the Ugi reaction

2,2-Difluoro-3-(2-hydroxy-1 R-phenylethylamino)-3 S-phenylpropionic acid 3, obtained by a Reformatsky-type reaction of ethyl bromodifluoroacetate with (4R)-2,4-diphenyloxazolidine, was used as a classical carboxylic acid in the Ugi reaction to prepare various difluorinated pseudopeptides 5a-n. Compounds 5 were then deprotected by hydrogenolysis to furnish difluorinated pseudopeptides 6.     

Terminalic Acid, a New Tannin from the Fruit of Terminalia chebula

AsatheraPeuticherbusedintraditionalChinesemedicine,TerminaliachebulaisconventionallygrowninGuangdong,Guangxi,andtheYunnanprovinceofChina.Itsripefruitisefficaciouslycurativewhenusedintreatingdiarrheaandhoarsenessofthethroatandcanalsobeusedasanastringenttobringabouthemostasisortoremovesomepathogenic"internalheat"ortoxicelementsfromwithinhumanphysique'.SeveralstudiesonhydroIysabletanninswithchebuloylgrouphavebeenreportedsofar2.AspartofaprogramforasystematicstudyofTchebula,wehavesuccessfullyis…     

Construction of the Skeleton of Phthalascidin,Mechanism of the Formation o the Key Tricyclic Lactam Intermediate

The mechanism of the formation of a key tricyclic lactam intermediate 3 was studied. It was found that the E-form compound 3 was transformed from the Z-form compound 4. The formation of 4 was a kinetically controlled process while the formation of 3 was a thermodynamically favorable one. A possible mechanism was given in this paper.