Diastereoselective schenck ene reaction of singlet oxygen with chiral allylic alcohols; access to enantiomerically enriched 1,2,4-trioxanes

A series of antimalarial chiral 1,2,4-trioxanes (1-8) were synthesised in high enantiomeric purities. Enantioselective addition of R₂Zn reagent to 3-methyl-2-butenal catalysed by (+)-MIB or (−)-MIB yielded both the enantiomers of the chiral allylic alcohols 9-11 (90-98% ee), which were subjected to diastereoselective photooxygenation in the presence of tetraphenylporphine (TPP) to obtain (R,R)-threo- or (S,S)-threo-β-hydroperoxy alcohols (12-14). Reaction of β-hydroperoxy alcohols (12-14) with different cyclic ketones produced optically active trioxanes 1-8.     

Enantioselective synthesis of axially chiral 1-(1-naphthyl)isoquinolines and 2-(1-naphthyl)pyridines through sulfoxide ligand coupling reactions

Racemic 1-(1′-isoquinolinyl)-2-naphthalenemethanol rac-12 was prepared through a ligand coupling reaction of racemic 1-(tert-butylsulfinyl)isoquinoline rac-7 with the 1-naphthyl Grignard reagent 10. Resolution of rac-12 was achieved through chromatographic separation of the Noe-lactol derivatives 14 and 15, providing (R)-(−)-12 of >99% ee and (S)-(+)-12 of 90% ee. The ligand coupling reaction of optically enriched sulfoxide (S)-(−)-7 (62% ee) with Grignard reagent 10 furnished rac-12, with the absence of stereoinduction resulting from competing rapid racemisation of the sulfoxide 7. Reaction of optically enriched (S)-(−)-7 with 2-methoxy-1-naphthylmagnesium bromide was also accompanied by racemisation of the sulfoxide 7, and furnished optically active (+)-1-(2′-methoxy-1′-naphthyl)isoquinoline (+)-3b in low enantiomeric purity (14% ee). The absolute configuration of (+)-3b was assigned as R using circular dichroism spectroscopy, correcting an earlier assignment based on the Bijvoet method, but in the absence of heavy atoms. Optically active 2-pyridyl sulfoxides were found not to undergo racemisation analogous to the 1-isoquinolinyl sulfoxide 7, with the ligand coupling reactions of (R)-(+)- and (S)-(−)-2-[(4′-methylphenyl)sulfinyl]-3-methylpyridines, (R)-(+)-17 and (S)-(−)-17, with 2-methoxy-1-naphthylmagnesium bromide providing (−)- and (+)-2-(2′-methoxy-1′-naphthyl)-3-methylpyridines, (−)-18 and (+)-18, in 53 and 60% ee, respectively. The free energy barriers to internal rotation in 3b and 18 have been determined, and the isoquinoline (R)-(−)-12 examined as a ligand in the enantioselectively catalysed addition of diethylzinc to benzaldehyde; (R)-(−)-12 was also converted to (R)-(−)-N,N-dimethyl-1-(1′-isoquinolinyl)-2-naphthalenemethanamine (R)-(−)-19, and this examined as a ligand in the enantioselective Pd-catalysed allylic substitution of 1,3-diphenylprop-2-enyl acetate with dimethyl malonate.     

Stereodivergent total asymmetric synthesis of polyhydroxylated pyrrolidines via tandem allylic epoxidation and intramolecular cyclization reactions

Epoxidation of the allylic alcohols 10 and 11 using the VO(acac)₂/t-BuOOH system followed by an intramolecular 5-exo cyclization of the resulting δ-epoxycarbamates 12, 13, 18, and 19 has been shown to provide a general and efficient solution for the asymmetric synthesis of polyhydroxy pyrrolidines. The requisite vicinal amino alcohol functionality was enantio-/regio-selectively installed by the Os-catalyzed asymmetric aminohydroxylation reaction of the designed achiral olefin 6.     

Stereoselective construction of the 1,1,1-trifluoroisopropyl moiety by asymmetric hydrogenation of 2-(trifluoromethyl)allylic alcohols and its application to the synthesis of a trifluoromethylated amino diol

The asymmetric hydrogenation of a series of 2-(trifluoromethyl)allylic alcohols 1a-g catalyzed by a BINAP-Ru(II) diacetate complex gave the corresponding products 2a-g in high yield (>90% yield) and high diastereoselectivity (>95% de). The asymmetric hydrogenation of 2-(trifluoromethyl)allylic alcohols provided an efficient stereoselective method to construct the 1,1,1-trifluoroisopropyl moiety. Based on the asymmetric hydrogenation of the 2-(trifluoromethyl)allylic alcohol 5a prepared by the reaction of (R)-2,2-dimethyl-1,3-dioxolane-4-carboxaldehyde with 3,3,3-trifluoroisopropenyllithium, (2R,3S,4R)-4-trifluoromethyl-1-aminopentane-2,3-diol 9 was synthesized in 36% overall yield over five steps.     

Synthetic access to optically active isoflavans by using allylic substitution

A general approach to the (S)- and (R)-isoflavans was invented, and efficiency of the method was demonstrated by the synthesis of (S)-equol ((S)-3), (R)-sativan ((R)-4), and (R)-vestitol ((R)-5). The key step is the allylic substitution of (S)-6a (Ar¹=2,4-(MeO)₂C₆H₃) and (R)-6b (Ar¹=2,4-(BnO)₂C₆H₃) with copper reagents derived from CuBr·Me₂S and Ar²-MgBr (7a, Ar²=4-MeOC₆H₄; 7b, 2,4-(MeO)₂C₆H₃; 7c, 2-MOMO-4-MeOC₆H₃), furnishing anti S_N2′ products (R)-8a and (S)-8b,c with 93-97% chirality transfer in 60-75% yields. The olefinic part of the products was oxidatively cleaved and the Me and Bn groups on the Ar¹ moieties was then removed. Finally, phenol bromide 9a and phenol alcohols 9b,c underwent cyclization with K₂CO₃ and the Mitsunobu reagent to afford (S)-3 and (R)-4 and -5, respectively.     

Synthesis and structures of dinuclear iron, molybdenum and tungsten complexes derived from (PhCHCHPh)-coupled bis(cyclopentadiene)

Reductive coupling of phenylfulvene with amalgamated calcium metal followed by hydrolysis yields CpPhCHCHPhCp (1) in high yield. Refluxing ligand 1 and Fe(CO)₅ in xylene produces (PhCHCHPh)-coupled bis(cyclopentadienyl) tetracarbonyl diiron (PhCHCHPh)[(η⁵-C₅H₄)Fe(CO)₂]₂ (2) as a mixture of meso (2-meso) and racemic isomers (2-rac). The pure racemic isomers of the Mo and W analogues (3-rac and 4-rac) have been synthesized by lithiation of ligand 1 and addition of (MeCN)₃M(CO)₃ (M = Mo, W) followed by oxidation with 2 equiv. of ferrocenium tetrafluoroborate. All the new complexes have been fully characterized. The molecular structures of 1-meso, 2-meso, 2-rac, 3-rac, and 4-rac have been determined by X-ray diffraction analysis.     

Pd-catalyzed asymmetric synthesis of allylic tert-butyl sulfones and sulfides: Kinetic resolution of the allylic substrate by a chiral Pd-complex

The acyclic and cyclic allylic tert-butyl sulfones 3, ent-3, 11a, 11b and 15a–c of 89–98% ee were synthesized in 40–92% yield by a Pd-catalyzed reaction of the respective allylic acetates and carbonates rac-1a, rac-1b, rac-10a, rac-10b and rac-14a–c with LiO₂St-Bu in the presence of the chiral ligands 2a, ent-2b and 12. Formation of the n-butyl sulfones 13a and 13b of 95% ee was observed. Reactions of rac-1a and 1b/ent-1b with LiO₂St-Bu in the presence of 2a and ent-2b, respectively, in THF under heterogeneous conditions were accompanied by a kinetic resolution of the allylic substrates. The faster reacting allylic substrate and the preferentially formed sulfone had the same absolute configuration. The allylic tert-butyl sulfide 17 of 92% ee was obtained in 63% yield by the Pd-catalyzed reaction of rac-1b with Me₃SiSt-Bu in the presence of ent-2b.     

Synthesis, crystal structure analysis, and pharmacological characterization of desmethoxy-sila-venlafaxine, a derivative of the serotonin/noradrenaline reuptake inhibitor sila-venlafaxine

rac-Desmethoxy-sila-venlafaxine (rac-3) is a derivative of the noradrenaline-selective serotonin/noradrenaline reuptake inhibitor rac-sila-venlafaxine (rac-1b), a silicon analogue of the serotonin-selective serotonin/noradrenaline reuptake inhibitor rac-venlafaxine (rac-1a) (rac-1a, rac-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexan-1-ol; rac-1b, rac-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]-1-silacyclohexan-1-ol). The synthesis and crystal structure analyses of rac-3 and rac-3 · HCl are reported, and the pharmacological properties of rac-1a, rac-1b, rac-2 (a sila-venlafaxine derivative with a silacyclopentanol skeleton instead of a silacyclohexanol framework), and rac-3 are compared (comparison of the pharmacological selectivity profiles with respect to serotonin, noradrenaline, and dopamine reuptake inhibition).     

Palladium-catalyzed asymmetric tandem allylic substitution using chiral 2-(phosphinophenyl)pyridine ligand

Palladium-catalyzed asymmetric tandem allylic substitution of (Z)-1,4-diacyloxy- and (Z)-1,4-bis(alkoxycarbonyloxy)-2-butene (2a-c) using 2-(phosphinophenyl)pyridine 1 as chiral ligand provided optically active six-membered 2-vinyl-1,4-diheterocyclic compounds with good to high enantioselectivity. For example, the reactions with catechol, 2-(benzylamino)phenol, or 1,2-bis(benzylamino)ethane as a nucleophile gave 2-vinyl-1,4-benzodioxane (71% ee), 4-benzyl-2-vinyl-1,4-benzoxazine (86% ee), and 1,4-dibenzyl-2-vinylpiperazine (86% ee), respectively.     

Aziridine-derived iminophosphine ligands in palladium-catalyzed allylic substitution

New iminophosphines have been synthesized from (R,R)-1-amino-2-diphenylphosphino cyclohexane (R.R)-1 in good to excellent yields. The catalysts obtained from iminophosphines 3a-g and [Pd(C₃H₅)Cl]₂ promote the enantioselective allylic substitution of 1,3-diphenyl-2-propenyl acetate (6) with diethyl malonate with good enantioselectivity. The air-stable complex PdCl₂[κ²-P,N-(R,R)-2-Ph₂PC₆H₁₀NCHPh] (4) has been prepared and structurally characterized by X-ray crystallography.     

Malonate-type bis(oxazoline) ligands with sp hybridized bridge carbon: synthesis and application in Friedel-Crafts alkylation and allylic alkylation

A series of simple and new C₂-symmetric diphenylmethylidene malonate-type bis(oxazoline) ligands were synthesized and applied to the Friedel-Crafts reaction and allylic alkylation. The Cu(II) complex of ligand 4b bearing the benzyl group afforded good to excellent enantioselectivity for the F-C adducts (up to >99% ee) between indole and alkylidene malonate, and the palladium complex of ligand 4c bearing the phenyl group afforded excellent enantioselectivity (up to 94% ee) for the allylic alkylation product.     

Synthesis of optically active 2-fluoroalk-1-en-3-yl esters and chirality transfer in their Claisen-type rearrangements

A series of enantioenriched long chain 2-fluoroalk-1-en-3-ols 1 has been prepared by lipase-catalyzed resolution of the racemic compounds synthesized from terminal alkenes. The lipase of Candida antarctica was shown to be the most efficient one in terms of enantioselectivity. Transesterification of the fluorinated allylic alcohols 1 was superior over the hydrolysis in a phosphate buffer of the corresponding acetates 2. Lipase-catalyzed acetylation of allylic alcohols 1 in organic medium gave (S)-(−)-3-acetoxy-2-fluoroalk-1-enes of chain lengths C₁₀, C₁₆ and C₁₈ with 68-89% yield and 92-96% ee, while the remaining (R)-(+)-2-fluoroalk-1-en-3-ols were isolated with 54-96% yield and 72-86% ee. The absolute configuration was assigned by comparison of measured and calculated CD-spectra, and unambiguously by ¹H and ¹⁹F NMR spectroscopy using a modified Mosher's method. From the optically active fluorinated allylic alcohols 1 corresponding esters 2 such as propionates, 3,3,3-trifluoropropionates and Boc-glycinates were synthesized. These compounds were rearranged to 2-substituted 4-fluoroalk-4-enecarboxylic acids 3 applying modified conditions of the [3,3]-sigmatropic Ireland-Claisen rearrangement. While a complete chirality transfer from C-3 of the allylic esters to C-2 of the carboxylic acids or 2-amino acids, respectively, occurred in rearrangements of the propionates and Boc-glycinates, racemic 2-(trifluoromethyl)alk-4-enecarboxylic acids were formed from the allylic trifluoropropionates. The configurational lability of the latter products is caused by the strongly acidic proton in α-position to the trifluoromethyl and the carboxyl groups under the basic rearrangement conditions.     

Synthesis of C2-symmetric chiral crown ethers by lipase-catalyzed reactions

Kinetic resolution of a racemic mixture of C₂-symmetric 18-crown-6 diols (rac-1a) and 15-crown-5 diol (rac-1c) was achieved by lipase-catalyzed acetylation. The enantiomeric excess of the chiral crown diols (95% ee and 82% ee) was determined by ¹H NMR spectroscopy, using (R)-(+)-1-(1-naphthyl)ethylammonium hydrochloride as a shift reagent. The C₂-symmetric chiral 15-crown-5 diol (>95% ee) was also obtained by kinetic resolution of the racemic diacetate (rac-2c) using lipase-catalyzed solvolysis.     

Convenient synthesis of antisepsis agent TAK-242 by novel optical resolution through diastereomeric N-acylated sulfonamide derivative

A convenient synthesis method of antisepsis agent TAK-242 ((R)-1) through diastereomeric resolution was developed. By condensation of racemate rac-1 with chiral acid (S)-O-acetylmanderic acid (6a), the desired diastereomer 5a was isolated with 98% de in 39% yield by simple crystallization. Deacylation of 5a with aq NaOH followed by recrystallization provided (R)-1 with 99% ee in 20% yield from rac-1.     

Macrocyclic vs acyclic derivatives of chiral bis(oxazolines); ligand distortion and enantioselectivity of Pd(II) complexes in catalytic allylic alkylation

Pd(II) complexes of acyclic (1,2;4,5) and macrocyclic (3,6-10) derivatives of 1,5-bis(oxazolines), are tested in the enantioselective allylic alkylation of racemic 1,3-diphenyl-3-acetoxyprop-2-ene (14) by dimethylmalonate anion to allyl malonate derivative 15. Conformation in solution of representative allyl Pd(II) complexes 12 and 13 is studied by 2D NMR and CD spectroscopy. 2D NMR data reveal loss of C₂ symmetry of the ligands in Pd(II)allyl-bis(oxazoline) complexes. CD spectra indicate distortion of the bidentate ligand in the complex and a conformationally forced larger twist between two chromophores in the macrocyclic complex. Only moderate variation of enantioselectivity with the length and ring size of the ligand is observed, and a rationale offered.     

New chiral bidentate ligands containing thiazolyl and pyridyl donors for copper-catalyzed asymmetric allylic oxidation of cyclohexene

Chiral bidentate ligands 1-3, which contain a combination of thiazolyl and pyridyl donors units, were prepared. The syntheses are facile and being based on Kröhnke condensation of a pinene derivative to form the pyridine ring. Modification at the 8-position of the tetrahydroquinoline ring can be carried out by alkylation reaction with 2a and 3a but not 1a. The structure of a copper(II) perchlorate complex of 1a was characterized with X-ray crystallography, which reveals the binding of the pyridyl-thiazole as a N-N donors at the copper center. The copper(I) thiazolyl-pyridine complexes prepared in situ are active catalysts in the enantioselective allylic oxidation of cyclohexene using tert-butyl perbenzoate as the oxidant. The isolated yields of the allylic benzoate were up to 98%, and enantioselectivity was up to 62% e.e.     

New pinene-derived pyridines as bidentate chiral ligands

A synthesis of new bidentate pyridines 8a-d, 9, and 10 has been developed, starting from triflate 14, readily available from β-pinene 11. A copper complex of the pyridine-oxazoline ligands 8a has been found to catalyze asymmetric allylic oxidation of cyclic olefins 36a-c with good conversion rates and acceptable enantioselectivity (≤67% ee). The imidazolium salt 10 has been identified as a precursor of the corresponding N,N′-unsymmetrical N-heterocyclic carbene ligand, whose complex with palladium catalyzed the intramolecular amide enolate α-arylation leading to oxindole 45 in excellent yield but with low enantioselectivity.     

Palladium(0) catalyzed enantioselective rearrangement of O-allylic thiocarbamates to S-allylic thiocarbamates: asymmetric synthesis of allylic thiols

The Pd(0) catalyzed rearrangement of the O-allylic thiocarbamates rac-2a, rac-2b and rac-4 in the presence of the chiral bisphosphane 5 proceeded quantitatively and gave the S-allylic thiocarbamates 6a, 6b and 7, respectively, with 91, 92 and 97% ee, respectively, in high yields. Saponification of the S-allylic thiocarbamate 7 furnished the allylic thiol 9 with 97% ee.     

Synthesis of l-cyclopentenyl nucleosides using ring-closing metathesis and palladium-mediated allylic alkylation methodologies

The enantiomeric synthesis of l-cyclopentenyl nucleosides is described. The key intermediate (+)-cyclopentenyl alcohol (8) was prepared from methyl-α-d-galactopyranoside 1 using a ring closing metathesis reaction. Transformation of the allylic alcohol 8 into the allylic acetate (9) or carbonate (10), allows their coupling with purine and pyrimidine bases under Pd(0)-catalyzed Tsuji-Trost allylic alkylation's to yield 12a-c. The Pd catalyzed reaction was found to require the use of AlEt₃.     

Facile syntheses, structural characterizations, and isomerization of disiloxane-1,3-diols

In the hydrolysis reaction of dichlorosilanes having an intramolecular coordinating atom, dcisiloxane-1,3-diols, [(OH){o-(CH₃)₂NCH₂-C₆H₄}RSi]₂O(R=CH₂CH (1), C₆H₅ (2), o-(CH₃)₂NCH₂C₆H₄ (3), Me (4)), were obtained in high yields. The results of the crystal structure analyses of meso-2, rac-2a, rac-2b and 3 are reported. They showed strong intramolecular hydrogen bondings between the hydroxy group and the nitrogen atom. We have also found that the diastereomeric isomerization of meso-2 to rac-2 in CDCl₃ solvent containing moisture occurred to result in the 55:45 equilibrium mixtures of the isomers and vice versa.