Key Chiral Intermediates Research Articles

A novel total synthesis of kinsenoside and goodyeroside A relying on the efficient reaction of the chiral 2(5H)-furanones

A new total synthesis of the bioactive compounds, kinsenoside (1) and goodyeroside A (2), has been accomplished from readily available starting materials. The chiral 2(5H)-furanone 5a and its enantiomer 5b were employed as the key chiral intermediates to construct the chiral glycosides 8a and 8b with the appropriate stereochemistry. The spectral data of the target compounds and their acetylated derivatives 1a and 2b are identical with those of the natural and corresponding acetylated products.

Total synthesis of the quinone epoxide dimer (+)-torreyanic acid: application of a biomimetic oxidation/electrocyclization/Diels-Alder dimerization cascade.

An asymmetric synthesis of the quinone epoxide dimer (+)-torreyanic acid (48) has been accomplished employing [4 + 2] dimerization of diastereomeric 2H-pyran monomers. Synthesis of the related monomeric natural product (+)-ambuic acid (2) has also been achieved which establishes the biosynthetic relationship between these two natural products. A tartrate-mediated nucleophilic epoxidation involving hydroxyl group direction facilitated the asymmetric synthesis of a key chiral quinone monoepoxide intermediate. Thermolysis experiments have also been conducted on a model dimer based on the torreyanic acid core structure and facile retro Diels-Alder reaction processes and equilibration of diastereomeric 2H-pyrans have been observed. Theoretical calculations of Diels-Alder transition states have been performed to evaluate alternative transition states for Diels-Alder dimerization of 2H-pyran quinone epoxide monomers and provide insight into the stereocontrol elements for these reactions.

Highly convergent stereoselective synthesis of chiral key intermediates in the synthesis of Palinavir from imines derived from l-glyceraldehyde

Imines derived from O-protected ( S)-glyceraldehyde are valuable intermediates in the synthesis of different kinds of amino acids. We have developed a highly convergent and stereoselective method to obtain (2 S,3 S)- N- tert-butoxycarbonyl-1-phenyl-3,4-epoxy-2-butylamine and (2 S,4 R)- N- tert-butoxycarbonyl-4-hydroxypipecolic acid tert-butylamide, which are key intermediates in the synthesis of Palinavir, that consist in the treatment of the appropriate imine with benzylmagnesium bromide and Danishefsky's diene, respectively, and subsequent transformation of the obtained adducts into the desired compounds. The reaction of N-benzylimine derived from ( S)-2,3-di- O-benzylglyceraldehyde with benzylmagnesium bromide is completely diastereoselective at low temperature. Hetero Diels–Alder reaction of imine derived from ( S)-2,3-di- O-benzylglyceraldehyde and ( R)- N-α-methylbenzylamine is completely diastereoselective at low temperature in the presence of ZnI 2.

Two key chiral intermediates in a new 4-hydroxyisoleucine synthesis.

We present the crystal and molecular structure of two key compounds of a new synthesis strategy for isomers of natural (2S,3R, 4S)-4-hydroxyisoleucines, 2,3,5,6,7, 8-hexahydro-3-(1-hydroxy-1-methyl-2-oxopropyl)-6,8-methano-7,7, 8a-trimethyl-5H-1,4-benzoxazin-2-one, C(16)H(23)NO(4), and 2,3,5,6,7, 8-hexahydro-3-(1-methyl-2-oxopropyl)-6,8-methano-7,7, 8a-trimethyl-5H-1,4-benzoxazin-2-one, C(16)H(23)NO(3). A new optically pure chiral oxazinone auxiliary derived from (1R,2R, 5R)-2-hydroxypinan-3-one was used.

Biocatalytic Production of Chiral Pharmaceutical Intermediates

Biocatalytic production of several key chiral intermediates in the synthesis of anti-inflammatory, anti-viral and anti-leukaemic agents is described. These include (i) a nucleoside oxidase from Stenotrophomonas maltophilia to oxidise unnatural purine nucleosides, (ii) a serine-type protease from an alkalophilic Bacillus sp. to resolve racemic N-substituted lactams, and (iii) a co-immobilised uridine phosphorylase and purine nucleoside phosphorylase preparation from recombinant E. coli strains that catalyse base transfer reactions.

Access to enantiopure ribosyl-diazepanone core of liposidomycins

A convergent synthesis of the ribosyl-diazepanone core of liposidomycins, new nucleoside antibiotics, has been carried out via enantiomerically pure epoxide and α-ribosyl aminoacid, chiral key intermediates obtained from L-ascorbic acid and D-ribose, respectively.

Metal salts induced improved α-hydroxylation of ketones for the preparation of the key chiral intermediate of azole antifungals

The first example demonstrating the influence of metal salts for an improved synthesis of 2′,4′-difluoro-( R)-2-hydroxypropiophenone, ( 2) a key intermediate for the preparation of azole antifungals such as Sch 42427 ( 1) in excellent enantiomeric excess and high chemical yield via the use of camphorsulfonyloxaziridines is described.

ChemInform Abstract: Asymmetric Radical Cyclization Leading to β‐Lactams: Stereoselective Synthesis of Chiral Key Intermediates for Carbapenem Antibiotics PS‐5 and Thienamycin.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Asymmetric radical cyclization leading to β-lactams: Stereoselective synthesis of chiral key intermediates for carbapenem antibiotics PS-5 and thienamycin

A stereoselective synthesis of β-lactams by 4- exo-trig radical cyclizations of N-[2,2-bis(phenylthio)ethenyl]-α-bromo amides bearing a chiral inductor on the nitrogen atom has been examined. Bromide 8, upon treatment with Bu 3SnH in the presence of AIBN in boiling benzene, gave a mixture of (4 S)-2-azetidinone 12a and its (4 R)-isomer 12b in a ratio of 71:29 and 69% combined yield. Similar treatment of α-bromobutanamide 11 with Bu 3SnH afforded trans-(4 S)-2-azetidinone 17a as the major product along with its (4 R)-isomer 17b (70:30, 77% combined yield). Compound 17a was converted into 24, a chiral key intermediate in the synthesis of (+)-PS-5 (25). The cyclization of bromide 28 bearing an additional stereogenic center [( S)-oxygen functionality] at the side chain proceeded with much higher (4 S)-stereoselectivity to give azetidinone 29a as the major product together with its (4 R)-isomer 29b in a ratio of 78:22 and 40% combined yield. Compound 29a was converted, via an inversion of the oxygen functionality, into 37, a chiral key intermediate in the synthesis of (+)-thienamycin (38). A possible explanation for the observed diastereoselectivity in radical cyclizations is presented.

Preparations of antifungal Sch 42427/SM 9164: Preparative chromatographic resolution, and total asymmetric synthesis via enzymatic preparation of chiral α-hydroxy arylketones

Efficient approaches towards the preparation of chiral azole antifungals Sch 42427/SM 9164 ( 1) via large scale chromatographic separation of its enantiomers, or via enzymatic syntheses of key chiral intermediates α-hydroxy arylketones 5 in excellent enantiomeric excesses ( ees) are described.

ChemInform Abstract: Stereoselective Amination of Chiral Enolates: Synthesis of Chiral Key Intermediates for β‐Lactam Antibiotics.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Stereoselective syntheses of D-ribo- and L-lyxo-phytosphingosine

D-ribo-Phytosphingosine has been synthesized from D-galactose via the key intermediate 5, itself prepared by stereoselective prop-2-ynylation with prop-2-ynyl bromide and zinc, and L-lyxo-phytosphingosine has been synthesized from D-xylose via the key intermediate 18, itself prepared by a CBr4–Ph3P–Zn Wittig reaction and debromination. These key chiral intermediates, 5 and 18, have potential as intermediates for the synthesis of other phytosphigosine derivatives.

Stereoselective amination of chiral enolates: Synthesis of chiral key intermediates for β-lactam antibiotics

Stereoselective enolate trapping of lithium ( 1S, 2R, 4R)- 10-dicyclohexylsulfamoylisobornyl-2-cyano-3-phenylpropanoate with O-(diphenylphosphinyl) hydroxylamine followed by appropriate reduction, hydrolysis, and cyclisation processes allows the asymmetric synthesis of ( S)-3-amino-3-benzyl-2-azetidinone.

Synthesis of (R,S)-10-methyloctadecanoic acid (tuberculostearic acid) and key chiral 2-methyl branched intermediates

Tuberculostearic acid, (R)-10-methyloctadecanoic acid, is a characteristic component of pathogenic mycobacteria and related organisms. Sensitive detection of this acid in infected material allows rapid detection of mycobacterial disease. A novel, convergent synthesis of tuberculostearic acid and key chiral intermediates is described in this communication, to provide a reference compound. Racemic and (R)- and (S)-1-iodo-2-methyldecanes were synthesised from 1-octanal and 1-carboethoxyethylidenetriphenylphosphorane as initial starting materials. 1-Hydroxyoct-7-yne was made from 1,6-hexanediol by two alternative methods and coupled with the above racemic iodide. Hydrogenation and oxidation of the resulting (R,S)-10-methyloctadec-7-yn-1-ol gave racemic tuberculostearic acid.

A practical synthesis of ( R)- and ( S)-( E)-4-hydroxyalk-2-enals, cytotoxic products of the microsomal lipid peroxidation

The chemical synthesis of some ( S)- and ( R)-( E)-4-hydroxyalk-2-enals, important products of lipid peroxidation (LPO), has been carried out via enantiomerically pure 2-benzoyloxyaldehydes, chiral key intermediates obtained from two diastereomeric diepoxides deriving from D-mannitol. These aldehydes were transformed into the final compounds by Wittig condensation with (formylmethylene)triphenylphosphorane and regeneration of the hydroxy group.

Microbial reduction of 1-(4-fluorophenyl)-4-[4-(5-fluoro-2-pyrimidinyl)-1- piperazinyl]butan-1-one.

Among various micro-organisms screened for the stereoselective reduction of 4-chloro-1-(4-fluorophenyl)butan-1-one (1), Hansenula polymorpha [American Type Culture Collection (A.T.C.C.) 26012 and 86014], Nocardia salmonicolor [Squibb Culture (S.C.) 6370], Arthobacter simplex (A.T.C.C. 6949), Mycobacterium vaccae (A.T.C.C. 29678), Candida boidinii (A.T.C.C. 13821) and Saccharomyces cerevisiae (A.T.C.C. 13792) reduced compound 1 to the corresponding (R)-(+)-alcohol (2). In contrast, Lactobacillus kefir (A.T.C.C. 35411), Pullularia pullulans (A.T.C.C. 16623), Trigonopsis variabilis (A.T.C.C. 10679) and Cunninghamella echinulata (A.T.C.C. 26269) reduced compound 1 to the (S)-(-)-alcohol (2). When 1-(4-fluorophenyl)-4-(1-piperazinyl)butan-1-one (3) was used as substrate for the reduction, only Nocardia globerula (A.T.C.C. 12505) and Saccharomyces cerevisiae (A.T.C.C. 13792) converted compound 3 into the corresponding (R)-(+)-alcohol (4). Organisms which reduced compound 1 were inactive for the reduction of compound 3. 1-(4-Fluorophenyl)-4-[4-(5-fluoro-2- pyrimidinyl)butan-1-one (5) was reduced to the corresponding (R)-(+)-alcohol (6) by Mortierella ramanniana (A.T.C.C. 38191) and to the (S)-(-)-alcohol (6) by Pullularia pullulans (A.T.C.C. 16623). (R)-(+)-compound 2 and compound 4 are key chiral intermediates in the total chemical synthesis of (R)-(+)-compound 6, an effective antipsychotic agent under development at Bristol-Myers Squibb. A single-stage (fermentation/biotransformation) process and two-stage (fermentation and subsequent biotransformation by cell suspensions) process were developed for the stereoselective reduction of compound 5 to (R)-(+)-compound 6 by Mortierella ramanniana (A.T.C.C. 38191). In both processes, the reaction yield of 98% and the optical purity of 99.4% were obtained for (R)-(+)-compound 6. The enzyme which catalysed the reduction of compound 5 to (R)-(+)-compound 6 was purified to homogeneity. The purified protein consisted of a single polypeptide of 29 kDa.

Asymmetric synthesis of β-amino-γ-hydroxysulfoxides

Optically pure [4-(3′-oxazoline)]methyl methyl- and p-tolylsulfoxides ( 5R, 5S, 6R and 6S) were prepared from the enolate of the 3-oxazoline 4 and the corresponding o.p. diacetone-D-glucofuranosyl methanesulfinate and menthyl p-toluenesulfinate. The highly diastereoselective reduction of these substrates was successfully achieved using DIBAL/ZnCl 2 at −78°C. In this way, four o.p. N-cyclohexyl-β-amino-γ-hydroxysulfoxides, chiral key intermediates in the asymmetric synthesis of various biologically active molecules, were obtained.

Preparation of key intermediates for the asymmetric synthesis of oxygenated elemanoids

In connection with search for chiral key intermediates useful for the synthesis of elemanoids, (3R,4S)-3-acetoxymethyl- and 3-tert-butyldimethylsiloxymethyl-4-isopropenyl-3-vinylcyclohexanone, (12a, R = Ac and TBDMS) and (1S,4S,5R)-4-isopropenyl-1-methoxy-5-vinyl-7-oxabicyclo[3.2.1]octane (24, R = Me) have been synthesised in good overall yields from (1R,5S)nopinone 5via(1R,5S)-4-hydroxymethyl-6,6-dimethylbicyclo[3.1.1]hept-3-en-2-one, 17a, (1R,4R,5S)-4-acetoxymethyl-6,6-dimethyl-4-vinylbicyclo[3.1.1]heptan-2-one 20, and its cyclobutanering opened product, (4S,5R)-1-acetoxy-5-acetoxymethyl-4-isopropenyl-5-vinylcyclohex-1-ene 21. The enantiomer of 17a, (1S,5R)-17b, was prepared from (1R,5S)-5 as the common starting material. The above compounds, (3R,4S)-12a as well as 24, are useful for the asymmetric synthesis of (5S,10R)-elemanoid with oxygen functions at the C–8 and C-14 positions, while the compounds (3S,4R)-12b, enantiomers of 12a which could be derived from 17b according to a sequence of reactions for the preparation of 12a from 17a are useful for the synthesis of (5R,10S)-oxygenated elemanoid.

Asymmetrization of 2-substituted glycerols: syntheses of R-etomoxir and R-palmoxirate

Formal syntheses of R-etomoxir and R-palmoxirate are described utilizing 6a and 6b as key chiral intermediates.

A stereoselective approach to 1β-methylcarbapenem antibiotic starting from ( [formula omitted])-(−)-3-hydroxybutyric acid ester

The chiral key intermediate of 1 β-methylcarbapenem antibiotic is synthesized via (2 R ,3 R ,4 S ,5 R )-3-amino-2,5-dimethyl-5-pentanolide-4-carboxylic acid, which is prepared in a stereoselective manner from ( R )-(−)-3-hydroxybutyrate.