Easy access to 4-nitrothiochroman S,S-dioxides via ring-enlargement from 3-nitrobenzo[b]thiophene

The (E)-2-aryl-1-[2-(methylthio)phenyl]-1-nitroethylenes 5 can easily be oxidized to the relevant sulfones 6 and effectively subjected to cyclization via an intramolecular Michael addition after metallation with lithium bis(trimethylsilyl)amide in THF. After quenching with ammonium chloride the 3-aryl-4-nitrothiochroman S,S-dioxides 2 are obtained as diastereomeric mixtures in good to excellent yields. Both yields and stereochemistry of the ring-closure step appear to be influenced by steric effects of the 3-aryl moiety. As sulfides 5 derive from an initial ring opening of 3-nitrobenzo[b]thiophene (1), the overall 1 to 2 process can be considered as an effective 5 to 6 ring enlargement of the sulfur heterocycle. A conformational ¹H NMR and molecular-mechanics investigation on the isolated diastereomeric 2 has also been accomplished.     

An expedient synthesis of 7(S)-ethyl-8(R or S)-indolizidinols based on a thiophene reductive desulfurization

Chiral hexahydrothieno[2,3-f]indolizine-4,7-dione (S)-12 and the ancillary alcohol 13 were generated from thiophene-2-carboxaldehyde and (S)-glutamic acid in three and four steps, respectively, in good overall yields and both high enantio- and diastereomeric purities. Applying a thiophene reductive desulfurization, compound 12 was readily converted into 7(S)-ethyl-8(S)-indolizidinol 9. The 8(R)-epimer of 9 was advantageously obtained using the Mitsunobu alcohol inversion or, starting from 13, by chemical separation after O-benzylation and lactam reduction. During these studies, the reduction of regioisomers of 12 and 13, namely 17 and 18, was investigated and the results obtained are also discussed.     

Diastereoselective route to (2R,5S)- and (2S,5S)-2-methyl-1,6-dioxaspiro[4.5]decane, a pheromone component of the wasp Paravespula vulgaris

A diastereoselective approach to (2R,5S)- and (2S,5S)-2-methyl-1,6-dioxaspiro[4.5]decane 1 and 1a is described. The route starts with an alkylation reaction among the cyclopentanone N,N-dimethylhydrazone 6 and the chiral iodides (R)-3 or (S)-3, derived from the enantiomers of ethyl β-hydroxybutyrate, controlling the estereocenter at C-2 of the molecules. The alkylated products 7 and 7a were easily transformed into the 1,8-O-TBS-1,8-dihydroxy-5-nonanones 9 and 9a in four steps, and a subsequent stereoselective spiroketalization, in acidic media, afforded a Z:E mixture (1:2) of compounds 1 and 1a.     

A new route to thiopyran S,S-dioxide derivatives via an overall ring-enlargement protocol from 3-nitrothiophene

(1E,3Z)-1-Aryl-4-methanesulfonyl-2-nitro-1,3-butadienes (8), derived from the initial ring-opening of 3-nitrothiophene (5), have been found to undergo a facile base-induced cyclization leading to thiopyran S,S-dioxides (9), thus furnishing a further example of effective ring-enlargement from 5- to 6-membered sulfur heterocycles. Compounds 9 are obtained as single racemic mixtures in satisfactory yields; they still contain a nitrovinylic moiety, which can be exploited for further modifications targeted to new derivatives endowed with either synthetic or pharmacological potentialities e.g., in the field of L-type Ca²⁺-channel blockers.     

Chemo- and diastereoselective control for a flexible approach to (5S,6S)-6-alkyl-5-benzyloxy-2-piperidinones

Chemo- and diastereoselective transformation of the N,O-acetals and their chain tautomers (4/5), readily derived from protected 3-hydroxyglutarimide 1a, was studied. It was uncovered that while the reaction with a combination of boron trifluoride etherate/zinc borohydride led to cyclic products (5S,6S/R)-6-alkyl-5-benzyloxy-2-piperidinones 3/2, and 6 in modest chemo- and diastereoselectivities, the reaction of 4/5 with zinc borohydride led exclusively to the formation of the ring-opening products 6 in excellent anti-diastereoselectivities. On the basis of the latter reaction, a flexible approach to (5S,6S)-6-alkyl-5-benzyloxy-2-piperidinones 3 was disclosed.     

Synthesis of (4R,15R,16R,21S)- and (4R,15S,16S,21S)-rollicosin

A convergent synthesis of (4R,15R,16R,21S)-rollicosin (1) and (4R,15S,16S,21S)-rollicosin (2) was accomplished. Hydroxy lactone 6a and/or 6b were synthesized from 4-pentyn-1-ol, and α,β-unsaturated lactone 7 was synthesized from γ-lactone 8 and 5-hexen-1-ol. Inhibitory activity of these compounds was examined with bovine heart mitochondrial complex I.     

Synthesis of (2S,3R)- and (2S,3S)-[3-H1]-proline via highly stereoselective hydrolysis of a silyl enol ether

A straightforward synthesis of (2S)-[3,3-²H₂]-proline 1c and (2S,3R)- and (2S,3S)-[3-²H₁]-proline, 1b and 1a, respectively, has been devised. The key step of the route to the latter compounds involves highly stereoselective hydrolysis of the silyl enol ethers 3 and 3a, respectively, with protonation (deuteriation) from the re-face of the silyl enol ether.     

Mononuclear ruthenium(II) complexes bearing the (S,S)-Pr-pybox ligand

The complexes trans-[RuCl₂(L){(S,S)-ⁱPr-pybox}] ((S,S)-ⁱPr-pybox = 2,6-bis[4′-(S)-isopropyloxazolin-2′-yl]pyridine, L = PMe₃ (1), P(OMe)₃ (2), PPh₂(CH₂CHCH₂) (3), CNBn (5), CNCy (6) and MeCN (7)) have been synthesized by substitution of ethylene on the precursor trans-[RuCl₂(η²-C₂H₄){(S,S)-ⁱPr-pybox}]. This complex also reacts with cyclooctadiene (cod) or norbornadiene (nbd) and NaPF₆, in refluxing methanol, giving the coordination compounds [RuCl(η⁴-cod){(S,S)-ⁱPr-pybox}][PF₆] (8) and [RuCl(η⁴-nbd){(S,S)-ⁱPr-pybox}][PF₆] (9). The structures of complexes [RuCl(CO)(PPh₃)(H-pybox)][BF₄] (H-pybox = 2,6-bis(dihydrooxazolin-2′-yl)pyridine) (4), 6 and 8, have been resolved by X-ray diffraction methods. The catalytic activity of the new complexes in transfer hydrogenation of acetophenone has also been examined.     

S-Transalkylation/ring closing metathesis as a route to azathiamacrocycles incorporating 2,2′-bipyridine subunits

A new route to cyclophanes 6a,b incorporating 2,2′-bipyridine subunits has been elaborated using as the key steps (1) S-transalkylation of 6,6′-bis(methylsulfanyl)-2,2′-bipyridines 2a,b with ethyl bromoacetate resulting in the formation of 6,6′-bis[(ethoxycarbonyl)methylsulfanyl]-2,2′-bipyridines 3a,b and (2) ring-closing metathesis of the corresponding alkenyl ethers 5a,b.     

Stereoselective synthesis of (2S,3S,7S)-3,7-dimethylpentadec-2-yl acetate and propionate, the sex pheromones of pine sawflies

The stereoselective synthesis of (2S,3S,7S)-3,7-dimethylpentadec-2-yl acetate (2) and propionate (3) was accomplished by utilizing the cheap and easily available chiron (R)-4-methyl-δ-valerolactone (4). The key steps were chelation-controlled addition of Gilmann reagent to chiral β-alkoxy aldehyde 12 and the Cu(I)-catalyzed coupling of Grignard reagent with bromoester 5 in the presence of NMP.     

Solution-phase parallel synthesis of S-DABO analogues

A simple and straightforward methodology for the parallel, solution-phase synthesis of a new series of S-DABO derivatives 1 and 2, bearing aromatic substituents at the C2 and C6 positions, has been developed. Starting from potassium ethyl malonates 3, thiouracil intermediates 5 were prepared through parallel synthesis and isolated as pure products by simple extraction with ethyl acetate. Selective S-benzylation of 5 was achieved in few minutes under microwave irradiation to give the title compounds 1, which were oxidized in parallel to the corresponding sulfones 2. Some of the new compounds 1 showed potent inhibitory activity against HIV-1 RT.     

Straightforward synthesis of (R,R/S,S)-2-[2-(2-aryl)-1-phenyl-ethyl]-morpholines: a new class of inhibitors of the norepinephrine transporter

Diastereoselective synthesis of (R,R/S,S)-2-[2-(2-aryl)-1-phenyl-ethyl]-morpholines 6 has been achieved through the preparation of key E-enol-triflate 4 and its further coupling with benzylzinc reagents and final hydrogenation.     

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.     

Asymmetric synthesis of (R)- and (S)-2-trifluoromethylepinephrine

An asymmetric synthesis of (R)- and (S)-2-trifluoromethylepinephrine (1R and 1S) is presented. Trifluoromethylation involves nucleophilic aromatic substitution of halobenzene 4 most likely via a copper mediated CF₃ anion equivalent generated in situ. The asymmetric step involves conversion of 3,4-dimethoxy-2-trifluoromethylbenzaldehyde (5) to silyl cyanohydrin (6R and 6S) using a chiral salen catalyst in the presence of titanium. 1R and 1S are potential alternatives to currently used vasoconstrictors in local anesthetic formulations.     

Reactions of P4S10 and pyPS2Cl with N,N′-diphenylurea and N,N′-diphenylthiourea

The reaction of P₄S₁₀ (1) with N,N′-diphenylurea (PhNH)₂CO (2) results in new heterocyclic compounds: the pyridinium salt of 1,3-diphenyl-2-sulfido-2-thioxo-1,3-diaza-2λ⁵-phosphetidine (3) (with a P–N–C–N cycle) and the pyridinium salt of 1,4-diphenyl-2,5-disulfido-2,5-dithioxo-1,4-dithiadiaza-2λ⁵,5λ⁵-diphosphinane (4), containing the (P–S–N)₂ cycle and the cyclic thiophosphates [pyH]₂[P₂S₈] (5), [pyH]₂[P₂S₇] (6) and [pyH]₃[P₃S₉] (7). A similar reaction, but carried out with N,N′-diphenylthiourea (PhNH)₂CS (8), leads to the formation of 4 and 6. pyPS₂Cl (9), used as an alternative starting material, also yields compounds 3, 4, 5, and further [pyH][PS₂Cl₂] (10) and S₈ after reaction with 2. Compound 3 reacts with Pd(CH₃COO)₂, with the formation of the complex [Pd(Ph₂N₂COPS₂)₂] (11). The crystal structures of 3 and 7 were determined by single-crystal X-ray diffraction.     

A route to fluorocontaining N,S-heterocycles via octafluoro-2,3-epoxybutane

The reaction of octafluoro-2,3-epoxybutane 1 with 2-aminothiophenol gave three kinds of novel fluorocontaining N,S-heterocyclic compounds depending on the solvent nature: 2,3-bis(trifluoromethyl)-3,4-dihydro-2H-1,4-benzothiazin-2-ol 2, 2-trifluoromethyl-2-[1-(2-aminophenylthio)-2,2,2-trifluoroethyl]-1,3-benzothiazolidine 6 and 5a,11a-bis(trifluoromethyl)-5a,6,11a,12-tetrahydro-5,11-dithia-6,12-diazanaphthacene 5. Use of the toluene, dioxane, tetrahydrofuran, acetonitrile and dimethoxyethane gave the unexpected dihydrobenzothiazine 2 (RS,SR > RR,SS) in good to moderate yields. In dimethylsulfoxide and N,N-dimethylacetamide, unusual cyclization occurred resulting in benzothiazolidine 6 (RS,SR/RR,SS ∼ 1:1) in moderate yields. Formation of minor 1,1,1,3,4,4,4-heptafluoro-3-(2-aminophenylthio)-2,2-dihydroxybutane 4 which was converted into bis(benzothiazine) 5 was observed in all solvents tested with the exception of toluene and dioxane. The molecular structure of the RS,SR-diastereomer of dihydrobenzothiazine 2, bis(benzothiazine) 5 and the RS,SR-diastereomer of benzothiazolidine 6 has been established by X-ray crystallography.     

[6-C]-(2S,4S)-5-Chloroleucine: synthesis and incubation studies with cultures of the cyanobacterium, Lyngbya majuscula

[6-¹³C]-(2S,4S)-5-Chloroleucine 12 was prepared in six steps and 26% overall yield from protected l-glutamic acid using ¹³CH₃I as the source of isotopic label. On feeding 12 to cultures of L. majuscula no incorporation of isotopic label into the trichlorinated marine natural product barbamide was detected. The synthesis of a novel dichloroleucine derivative 16 is also described.     

Unexpected Ti-catalyzed formal intramolecular [4+4] cycloaddition of 1,1′-bi[(S,S)-6-(trimethylsilyl)cyclohepta-2,4-dien-1-yl]

Reductive disilylation (Li+Me₃SiCl−THF) of 1,3,5-cycloheptatriene led to 1,1′-bi[(S^∗,S^∗)-6-(trimethylsilyl)cyclohepta-2,4-dien-1-yl] (2). In the presence of TiCl₄ in dichloromethane, 2 gave rise to a spherical molecule 5 resulting from an intramolecular formal [4+4] supra-supra cycloaddition.     

Enantioselective protonation of prochiral enolates in the asymmetric synthesis of (S)-naproxen

Racemic methyl, iso-propyl, and tert-butyl ester derivatives of naproxen were treated with achiral LDA base to give the corresponding prochiral enolates 2-Li, 3-Li, and 4-Li. Protonation of these enolates with novel chiral proton sources (S)-10 and (S,S)-11, containing the α-phenylethylamino group, proceeded in a highly enantioselective manner. Saponification of enantioenriched ester derivatives 2-4 afforded naproxen, (S)-1, with no loss of enantiopurity.     

Enantioselective synthesis of (1S,2S)-1,2-di-tert-butyl and (1R,2R)-1,2-di-(1-adamantyl)ethylenediamines

An enantioselective synthesis of sterically congested 1,2-di-tert-butyl and 1,2-di-(1-adamantyl)ethylenediamines has been developed. Thus, diastereomerically pure trans-1-apocamphanecarbonyl-4,5-dimethoxy-2-imidazolidinones 6 and 7 were successfully prepared by optical resolution of (±)-trans-4,5-dimethoxy-2-imidazolidinone using apocamphanecarbonyl chloride (MAC-Cl) followed by stereospecific and stepwise substitution of the dimethoxyl groups using tert-butyl or 1-adamantyl cuprates to provide (4S,5S)-4,5-di-tert-butyl and (4R,5R)-4,5-di-(1-adamantyl)-2-imidazolidinones 12 and 15, respectively. Furthermore, N-acetyl 4,5-di-tert-butyl and 4,5-di-(1-adamantyl)-2-imidazolidinones 16a,b were enantioselectively deacetylated using a catalytic oxazaborolidine system to provide enantiopure 1-p-tolylsulfonyl-4,5-di-tert-butyl-2-imidazolidinones 12 and 19 and 1-p-tolylsulfonyl-4,5-di-(1-adamantyl)-2-imidazolidinones 18 and 20, respectively. Finally, N-p-tolylsulfonyl-2-imidazolidinones 12 and 15 were treated with 30 equiv of Ba(OH)₂·8H₂O to achieve ring cleavage and to provide (1S,2S)-1,2-di-tert-butylethylenediamine 3 and (1R,2R)-1,2-di-(1-adamantyl)ethylenediamine 4.