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.     

A facile synthesis of (6S,1′S)-(+)-hernandulcin and (6S,1′R)-(+)-epihernandulcin

A facile total synthesis of (+)-hernandulcin (1) was accomplished from (−)-isopulegol in 6 steps with 15% overall yield. Epoxidation of (−)-isopulegol with m-chloroperbenzoic acid followed by opening of the epoxide 3a with prenyl Grignard afforded the tertiary alcohol 4a with correct C-6 and C-1′ stereochemistry as a major product. Oxidation of the secondary alcohol in compound 4a to the ketone 5a was accomplished in high yield by using TPAP and N-methylmorpholine N-oxide. Conversion of the ketone 5a to α,β-unsaturated ketone via organoselenium intermediate gave (+)-hernandulcin (1). This method was also successfully applied to the synthesis of (+)-epihernandulcin (2).     

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.     

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.     

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.     

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.     

Stereoselective synthesis of (2R,3S,4S)-3-hydroxy-4-methyl-2-tetradecyl-4-butanolide starting from 2,5-anhydro-d-mannitol

A novel approach to natural β-hydroxy-γ-lactone 2 from 2,5-anhydro-d-mannitol (1) is described. The key reactions in this synthesis include stereoselective methylation of aldehyde 3 with lithium dimethylcuprate, an intramolecular radical cyclization of seleno carbonate 11 and an intermolecular cross-metathesis of 3-allyl-4-hydroxy-γ-lactone 16 with 1-tridecene.     

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.     

Stereoselective synthesis of (3S,4S)-tert-butyl-N-Boc-3-ethyl-4-hydroxy-l-prolinate and (3S,4R)-tert-butyl-N-Boc-3-ethyl-4-hydroxy-l-prolinate

Diastereomers of tert-butyl-N-Boc-3-ethyl-4-hydroxy-l-prolinate 1 and 2 have been synthesized in six steps starting from readily available Boc-protected trans-4-hydroxy-l-proline. The key reactions in the synthesis are asymmetric reductions, firstly on the 4-ketoproline intermediate 6 and secondly on the 3-exocyclic olefin bond of the resulting allylic alcohol 7 or 8. Reaction conditions were optimized in order to control the stereochemistry of the three chiral centers.     

(R,R,R)-Tris(2-hydroxy-1-methylethyl)- and (S,S,S)-tris(2-hydroxy-2-methylethyl)phosphine: water-soluble chiral trialkylphosphines with C3-symmetry

The first α- and β-chiral water-soluble trialkylmonophosphines, 1 and 2, respectively, both with C₃ symmetry, were synthesised from sodium phosphide and chiral mesylates, accessible from (S)-ethyl lactate. X-ray structures of a corresponding 2:1 gold(I) complex [1₂Au(I)]OTf and of a borane complex 2·BH₃ were determined.     

Stereocontrolled conversion of some optically active (4S,5R)-dihydroisoxazoles into acyclic 3-acetamido-1,2-diols

Optically active (4S,5R)-dihydroisoxazoles 5a-c (90-91% ee) have been prepared by reaction of the epoxyketones 4a-c with hydroxylamine. Reduction of compounds 5a and 5b using lithium aluminium hydride took place exclusively from the Re face to give (1R,2S,3S)-1,3-disubstituted-3-aminopropane-1,2-diols 6a and 6b. These amino-diols were characterised by N-acetylation and the stereochemical sense of the hydride reduction was confirmed by conversion of amides 7a and 7b into α-amino acid derivatives 10a and 10b.     

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.     

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.     

Generation of allenylthioketene S,S-dioxides through [3,3] sigmatropic rearrangement of alkynyl propargyl sulfones

Thioketene S,S-dioxides 2 were successfully generated through [3,3] sigmatropic rearrangement of alkynyl propargyl sulfones 1 and the formation of 2 was confirmed by trapping experiment using cyclohexene or allyltrimethylsilane affording a [2+2] cycloadduct 5. In situ generated thioketene S,S-dioxides 2 underwent facile conversion into allenynes 3 in moderate yields, via formation and subsequent [1,2] shift of vinylidene carbenes.     

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.     

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.     

Synthesis and evaluation of 1-deoxy-8-epi-castanospermine, 1-deoxy-8-hydroxymethyl castanospermine, and (6S,7S,8R,8aR)-8-amino-octahydroindolizine-6,7-diol

A short, versatile, and enantioselective synthesis of 1-deoxy-8-epi-castanospermine (5), 1-deoxy-8-hydroxymethyl castanospermine (6), and (6S,7S,8R,8aR)-8-amino-octahydroindolizine-6,7-diol (7) is achieved from a common template 12. The key step utilized is PET provoked amine radical cyclization of 11 to 12 in excellent diastereoselectivity. The exocyclic double bond at C-8 of the template is functionalized to obtain 5-7 as exclusive diastereomers. 1-Deoxy-8-epi-castanospermine exhibited inhibition of α- and β-galactosidase and β-glucosidase. Compounds 6 and 7 were found to be weak inhibitors of β-glucosidase.     

Synthesis of (4R,8R)- and (4S,8R)-4,8-dimethyldecanal: the common aggregation pheromone of flour beetles

The synthesis of (4R,8R)- and (4S,8R)-4,8-dimethyldecanal 1 and 1a has been achieved connecting the chiral building block (R)-2-methyl-1-bromobutane 4 with (R)- and (S)-citronellol derivatives. The key intermediate 4 was obtained optically pure in five steps from methyl (S)-3-hydroxy-2-methylpropionate 2.     

Biomimetically inspired total synthesis of (12S)-12-hydroxymonocerin and (12R)-12-hydroxymonocerin

A concise asymmetric total synthesis of (12S)-12-hydroxymonocerin (1) and (12R)-12-hydroxymonocerin (2) were efficiently achieved from the known 4-bromo-2,6-dimethoxyphenol. The synthetic approach was inspired by our biomimetic synthesis of (+)-monocerin (3) and 7-O-demethylmonocerin (4). The cis-fused furobenzopyranones of 1 and 2 was efficiently constructed via an intramolecular nucleophilic trapping of a quinonemethide intermediate, which was obtained by benzylic oxidation of compound 10 using 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).     

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.