A concise synthesis of a very late antigen-4 antagonist trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxyamide)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid via reductive etherification

This contribution describes a concise synthesis to ethyl trans-[(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylate (2b) as a key intermediate of very late antigen-4 (VLA-4) antagonist trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxyamide)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid (1). The synthesis employs a reductive etherification as a key reaction using (2S,4S)-1-benzyloxycarbonyl-4-methoxypyrrolidine-2-carboxyaldehyde (12) and trans-4-triethylsilyloxycyclohexanecarboxilic acid ethyl ester (13b). This synthesis provides 2b in 6 steps with 38% overall yield from commercially available starting material.     

Solution-phase synthesis of a combinatorial library of 3-[4-(coumarin-3-yl)-1,3-thiazol-2-ylcarbamoyl]propanoic acid amides

The parallel solution-phase synthesis of a new combinatorial library of 3-[4-(R1-coumarin-3-yl)-1,3-thiazol-2-ylcarbamoyl]propanoic acid amides 9 has been developed. The synthesis involves two steps: 1) the synthesis of core building blocks - 3- [4-(coumarin-3-yl)-1,3-thiazol-2-ylcarbamoyl]propanoic acids, 6 - by the reaction of 3-(omega-bromacetyl)coumarins 1 with 3-amino(thioxo)methylcarbamoylpropanoic acid (5); 2) the synthesis of the corresponding 3-[4-(coumarin-3-yl)-1,3-thiazol-2-yl- carbamoyl]propanoic acids amides 9 using 1,1'-carbonyldimidazole as a coupling reagent. The advantages of the method compared to existing ones are discussed.     

An improved synthesis of a novel α1A partial agonist including a new two-step synthesis of 4-fluoropyrazole

This Letter outlines a new two-step process for the synthesis of 4-fluoropyrazole and its application in an improved synthesis of 4-fluoro-1-[5-fluoro-1-(1H-imidazol-2-yl)-indan-4-ylmethyl]-1H-pyrazole. The original synthesis of 4-fluoro-1-[5-fluoro-1-(1H-imidazol-2-yl)-indan-4-ylmethyl]-1H-pyrazole is also described.     

Synthetic studies of carbapenem and penem antibiotics. II. Synthesis of 3-acetyl-2-azetidinones by (2 + 2) cycloaddition of diketene and Schiff bases.

It was found that (2 + 2) cycloaddition reaction of diketene with Schiff bases was effectively promoted by imidazole as a catalyst to afford 3-acetyl-2-azetidinone derivatives 4. As an application of this new method, a practical asymmetric synthesis of 4 and its conversion into (3S,4S)-4-carboxy-1-(di-p-anisylmethyl)-3-[(R)-1-hydroxyethyl]-2- azetidinone, which is a key intermediate for the synthesis of carbapenem and penem antibiotics, were accomplished.     

Formal synthesis of the ACE inhibitor benazepril x HCl via an asymmetric aza-Michael reaction

A formal enantioselective synthesis of benazepril.HCl (4), an anti- hypertensive drug, is reported. Our synthesis employed an asymmetric aza-Michael addition of L-homophenylalanine ethyl ester (LHPE, 1) to 4-(2-nitrophenyl)-4-oxo- but-2-enoic acid methyl ester (6) as the key step to prepare (2S,3'S)-2-(2-oxo-2,3,4,5- tetrahydro-1H-benzo[b]azepin-3-ylamino)-4-phenylbutyric acid ethyl ester (8), which is the key intermediate leading to benazepril x HCl (4).     

(1S)-1-[(4R)-2,2-dimethyl-1,3-dioxolan+-4-yl][-2-hydroxyethylamm onium benzoate, a versatile building block for chiral 2-aminoalkanols: concise synthesis and application to nelfinavir, a potent HIV-protease inhibitor

A concise synthesis of a versatile chiral C4 building block for 2-aminoalkanols, (1S)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-hydroxyethylammo nium benzoate (1a), was described. 1 (1a and its enantiomer 1b) acted as four stereoisomers of optically active 2-amino-1,3,4-butanetriol. The versatility of 1 was demonstrated by its application to the practical synthesis of nelfinavir (2), a potent HIV-protease inhibitor, as well as by the stereospecific synthesis of three diastereomers of 2.     

Synthesis and application of precursors of hetero-anthracenes : 2-halo- and 2,2′-dihalodiphenylmethanes and methine substituted derivatives

In the diphenylmethane series, the synthesis of 2,2′ - diiododiphenylmethane (4g) and the improved synthesis of 2,2′ - dibromodiphenylmethane (4e) are reported. The triphenylmethane derivatives, 2-bromo-, 2-iodo-, 2,2′-dichloro-, 2,2′-dibromo- and 2,2′-diiodotriphenylmethane (4f, 4h, 4i, 4j and 4k, respectively) have been prepared. Via an entirely different approach, 1-(2-bromophenyl)- and 1 - (2 - chlorophenyl) - 1 - phenyl - 2,2 - dimethylpropane (4m and 4l) were obtained as derivatives of t-butyldiphenylmethane. Examples are given for the application of the new compounds in the synthesis of 9,10 - dihydro - 9 - heteroanthracenes (1, 2 and 3) via the formation of the corresponding organometallic derivatives.     

A solution-phase combinatorial synthesis of selective dopamine D4 ligands

Utilizing combinatorial synthesis and a preparative LC-MS automated chromatography system we have prepared and purified a library of 4-[2-(1,2,4-oxadiazolyl)]piperidines that were designed to be novel and selective dopamine D4 ligands. In one round of synthesis we identified N-4-chlorobenzyl-4-[2-(3-(2-thienyl)-1,2, 4-oxadiazolyl)]piperidine with a Kd of 5 nM for the human D4 receptor.     

Synthesis of R-(-)-imperanene from the natural lignan hydroxymatairesinol

A convenient and high yielding method for the synthesis of R-(-)-imperanene, starting from the readily available natural lignan hydroxymatairesinol from Norway spruce, was developed. Hydroxymatairesinol was degraded in strongly basic aqueous conditions to (E)-4-(4-hydroxy-3-methoxyphenyl)-2-(4-hydroxy-3-methoxyphenylmethyl)but-3-enoic acid, which was esterified and then reduced by LiAlH(4) to afford R-(-)-imperanene. The configuration at the crucial stereocenter was preserved in the synthesis, and the obtained product was identified by optical rotation measurements and chiral HPLC analyses as the R-(-)-enantiomer (ee 86-92%).     

SuperQuat N-acyl-5,5-dimethyloxazolidin-2-ones for the asymmetric synthesis of alpha-alkyl and beta-alkyl aldehydes

The proclivity of alpha-branched N-2'-benzyl-3'-phenylpropionyl derivatives of (S)-4-benzyl-5,5-dimethyl-, (S)-4-phenyl-5,5-dimethyl-, (S)-4-isopropyl-5,5-dimethyl-, (S)-4-benzyl- and (S)-4-benzyl-5,5-diphenyl-oxazolidin-2-ones to generate directly 2-benzyl-3-phenylpropionaldehyde upon hydride reduction with DIBAL is investigated. The (S)-4-benzyl-5,5-dimethyl-derivative proved optimal for inhibition of endocyclic nucleophilic attack, giving 2-benzyl-3-phenylpropionaldehyde in good yield upon reduction. Application of this methodology for the asymmetric synthesis of chiral aldehydes via diastereoselective enolate alkylation of a range of (S)-N-acyl-4-benzyl-5,5-dimethyloxazolidin-2-ones to afford and array of alpha-substituted-N-acyl-5,5-dimethyloxazolidin- 2-ones (85-94% de) and subsequent reduction with DIBAL afforded directly non-racemic alpha-substituted aldehydes without loss of stereochemical integrity (87-94% ee). The extension of this protocol for the asymmetric synthesis of beta-substituted aldehydes is demonstrated, via the diastereoselective conjugate addition of a range of organocuprates to (S)-N-acyl-4-phenyl-5,5-dimethyloxazolidin-2-ones which proceeds with high diastereoselectivity (generally > 95% de). Reduction of the conjugate addition products with DIBAL gives non-racemic beta-substituted aldehydes in high yields and in high ee (generally > 95% ee). This methodology is exemplified by the asymmetric synthesis of (R)-3-isopropenylhept-6-enal, which has previously been used in the synthesis of (3Z,6R)-3-methyl-6-isopropenyl-3,9-decadien-1-yl acetate, a component of the sex pheromones of the California red scale.     

A convenient synthesis of immunosuppressive agent FTY720 using the petasis reaction

A convenient synthesis of immunosuppressive agent FTY720 (1) using the Petasis reaction was developed. 4-Octylbenzaldehyde (9) was converted into 1-ethenyl-4-octylbenzene (11) by two-step synthesis. Hydroboration of 11 using catecholborane and hydrolysis gave (E)-2-(4-octylphenyl)vinylboronic acid (4). The Petasis reaction of 4, dihydroxyacetone (3), and benzylamine following catalytic hydrogenation afforded FTY720 (1).     

Preparation of carbocyclic S-adenosylazamethionine accompanied by a practical synthesis of (-)-aristeromycin

For the preparation of a carbocyclic nitrogen analogue of S-adenosylmethionine (carba-AdoazaMet, 4), a practical synthesis of (-)-aristeromycin (7) has been developed using variations of literature procedures. This approach called for a stereospecific synthesis of (3aR,6aR)-2,2-dimethyl-3a,6a-dihydrocyclopenta[1,3]dioxol-4-one ((4R, 5R)-4,5-O-isopropylidene-2-cyclopentenone) (8), which was achieved by modifying reported procedures from D-(-)-ribose.     

An efficient synthesis of a potent PPARpan agonist

An efficient synthesis of 2-{4-[({4-{[4-(4-methoxyphenyl)piperazin-1-yl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)thio]phenoxy}-2-methylpropanoic acid (1), a potent PPARpan agonist, is described. The seven-step synthesis, which afforded 1 in 30% overall yield, includes a highly regioselective carbon-sulfur bond formation via coupling of a bishydroxymethylthiazole (3) with 4-hydroxythiophenol, displacement of the remaining alcohol through a three-step telescoped sequence involving an efficient cleavage of an aryl mesylate, and an efficient and practical method of introducing an isobutyric acid fragment.     

Synthesis of 2s, 4s, 5s -dihydroxypipecolic acid and bulgecinine [2s,4s,5r-4-hydroxy-5- (hydroxymethyl)proline] from d-glucuronolactone,a strategy for the synthesis of 2s,4s-4-hydroxy-α-amino acids

The efficient synthesis of 4S,5S-2-(N-benzyloxycarbonyl)amino-5,6-dihydroxyhex-2-en-4-olide (4) from D-glucuronolactone is described, the potential of (4) as a divergent intermediate for the synthesis of 2S,4S-4-hydroxy-α-amino acids is illustrated by the conversion of (4) to 2S,4S,5S-dihydroxypipecolic acid and bulgecinine [2S,4S,5R-4-Hydroxy-5-(hydroxymethyl)-proline].     

Synthesis of （2R,4R）—2—N—tert—Butyloxycarbonyl Amino—4,5—epoxido—valeric Acid Methyl Ester

The stereoselective synthesis of (2R,4R)-2-N-tert-butyloxycarbonyl amino-4,5-epoxido-valeric acid methyl ester 8,which is the key intermediate for the synthesis of (2′S,2R)-3-trans-nitrocyclopropyl-alanine,was first accomplished.     

A Stereoselective Synthesis of Pear Ester Via Arsenic Ylide

The paper describes a four-step synthesis of ethyl (2E, 4Z)-2, 4-decadienoate (pear ester) from propargyl alcohol with a 50% total yield. It also gives the synthesis of ethyl (2E, 4E)-2, 4-decadienoate. In both cases arsenic ylides were used to give the satisfactory results.     

Rhodium-catalyzed asymmetric 1,4-addition of organoboron reagents to 5,6-dihydro-2(1H)-pyridinones. Asymmetric synthesis of 4-aryl-2-piperidinones

Catalytic asymmetric synthesis of 4-aryl-2-piperidinones was realized for the first time by asymmetric 1,4-addition of arylboron reagents to 5,6-dihydro-2(1H)-pyridinones in the presence of a chiral bisphosphine-rhodium catalyst. In the reaction introducing 4-fluorophenyl group, the use of 4-fluorophenylboroxine and 1 equiv (to boron) of water at 40 degrees C gave the highest yield of the arylation product with high enantioselectivity (98% ee). The (R)-4-(4-fluorophenyl)-2-piperidinone obtained here is a key intermediate for the synthesis of (-)-Paroxetine.     

Rearrangement of 4-(1-haloalkyl)- and 4-(2-haloalkyl)-2-azetidinones into methyl omega-alkylaminopentenoates via transient aziridines and azetidines

The synthesis of 4-(1-haloalkyl)-2-azetidinones and 4-(2-haloalkyl)-2-azetidinones was investigated with use of the Staudinger reaction between in situ generated ketenes and alpha-haloimines or beta-haloimines. This new class of functionalized 2-azetidinones was further evaluated for its potential use as intermediates in the synthesis of highly functionalized compounds. The reaction of 4-(1-haloalkyl)-2-azetidinones and 4-(2-haloalkyl)-2-azetidinones with sodium methoxide in methanol yielded ring-opened products, i.e., methyl 2-alkoxy-4-(alkylamino)pentenoate and methyl 5-(alkylamino)pentenoate, respectively. Further attention was paid in detail to the reaction mechanism involved in this peculiar transformation. It was proven that these reactions proceeded via intermediate aziridines or azetidines.     

Total synthesis of (-)-21-isopentenylpaxilline

[structure: see text] The total synthesis of (-)-21-isopentenylpaxilline (1) has been achieved. Key elements of the synthesis include the stereocontrolled construction of the advanced eastern hemisphere (-)-5, a highly efficient union of the eastern and western fragments (-)-5 and 4, respectively, exploiting our 2-substituted indole synthesis, and a new protocol for the construction of ring C.     

4-(2-R-Aryl)-1,2,3-chalcogenadiazoles in the synthesis of fused heterocycles

The review generalizes and systemizes published data on the synthesis and chemical transformations of 4-(2-R-aryl)-1,2,3-thia- and -selenadiazoles. Powerful synthetic potential of 4-(2-R-aryl)-1,2,3-chalcogenadiazoles ensures their use in the synthesis of various heterocyclic compounds, such as 1-benzofurans, indoles, 1-benzothiophenes, 1-benzoselenophenes, and their more complex derivatives.