Enantioselective reduction of prochiral ketones by catecholborane catalysed by chiral group 13 complexes

LiGaH4, in combination with the S,O-chelate 2-hydroxy-2'-mercapto-1,1'-binaphthyl (MTBH2), forms an active catalyst for the asymmetric reduction of prochiral ketones, with catecholborane as the hydride source. Enantioface differentiation is on the basis of the steric requirements of the ketone substituents. Aryl/ n-alkyl ketones are reduced in 90-93% ee and RC(O)Me (e.g. R = iPr, cycloC6H11, tBu) in 60-72% ee. Other borane sources and alternative catalyst structures based on indium do not form enantioselective catalysts.     

Asymmetric synthesis of 3-substituted 8-hydroxy-3,4-dihydroisocoumarins from (S)-4-isopropyl-2-(2-methoxy-6-methylphenyl)oxazoline

Reaction of the laterally lithiated (S)-4-isopropyl-2-(2-methoxy-6-methylphenyl)oxazoline with p-tolualdehyde gave an inseparable mixture of the addition products in low diastereoselectivity. However, the (S,S)-product cyclized to the corresponding 3,4-dihydroisocoumarin faster than the (S,R)-product on silica gel, which allowed to be produced both enantiomers of 8-methoxy-3-(p-tolyl)-3,4-dihydroisocoumarin in moderate to good optical purity [S-enantiomer: 75% ee; R-enantiomer: 96% ee]. This procedure was applied to the short-step synthesis of optically active 3,4-dihydroisocoumarin natural products such as (R)-8-hydroxy-3-(1-tridecyl)-3,4-dihydroisocoumarin and (R)-phyllodulcin.     

Microbial deracemisation of N-(1-hydroxy-1-phenylethyl)benzamide

Microbial deracemisation of racemic N-(1-hydroxy-1-phenylethyl)benzamide to give the (R)-enantiomer is described using whole cells of Cunninghamella echinulata NRRL 1384. The deracemisation involves fast highly (S)-selective oxidation followed by slower partially (S)-selective reduction of the intermediate ketone. The yield and ee of (R)-N-(1-hydroxy-1-phenylethyl)benzamide were optimised (82%, 98% ee) by removal of a competing extracellular amidase/protease activity by using static cells at pH 5. Use of the protease inhibitor PMSF with growing cells leads to a slower deracemisation (82% ee) but a very high (98%) overall recovery of alcohol and ketone.     

Ruthenium-Lewis acid catalyzed asymmetric Diels-Alder reactions between dienes and alpha,beta-unsaturated ketones

The complex [Ru(Cp)(R,R-BIPHOP-F)(acetone)][SbF(6)], (R,R)-1 a, was used as catalyst for asymmetric Diels-Alder reactions between dienes (cyclopentadiene, methylcyclopentadiene, isoprene, 2,3-dimethylbutadiene) and alpha,beta-unsaturated ketones (methyl vinyl ketone (MVK), ethyl vinyl ketone, divinyl ketone, alpha-bromovinyl methyl ketone and alpha-chlorovinyl methyl ketone). The cycloaddition products were obtained in yields of 50-90 % and with enantioselectivities up to 96 % ee. Ethyl vinyl ketone, divinyl ketone and the halogenated vinyl ketones worked best and their reactions with acyclic dienes consistently provided products with >90 % ee. alpha-Chlorovinyl methyl ketone performed better than alpha-bromovinyl methyl ketone. The reaction also provided a [4.3.1]bicyclic ring system in 95 % ee through an intramolecular cycloaddition reaction. Crystal structure determinations of [Ru(Cp)((S,S)-BIPHOP-F)(mvk)][SbF(6)], (S,S)-1 b, and [Ru(Cp)((R,R)-Me(4)BIPHOP-F)(acrolein)][SbF(6)], (R,R)-2 b, provided the basis for a rationalization of the asymmetric induction.     

Highly enantioselective sequential hydrogenation of ethyl 2-oxo-4-arylbut-3-enoate to ethyl 2-hydroxy-4-arylbutyrate

The hydrogenation of (E)-ethyl 2-oxo-4-arylbut-3-enoate with [NH2Me2](+)[{RuCl [(S)-SunPhos]}2(mu-Cl3)] gave ethyl 2-hydroxy-4-arylbutyrate with 94-96% ee. Further investigation has proved that the hydrogenation proceeded via a sequential hydrogenation of CO and CC bonds, which is sensitive to the reaction temperature. Hydrolysis of ethyl 2-hydroxy-4-phenylbutyrate (ee 93%) provided the 2-hydroxy-4-phenylbutyric acid with 81% yield at 99% ee after a single recrystallization from 1,2-dichloroethylene.     

Synthesis of 3, 4, 4a, 5, 6, 7, 8, 8a α-Octahydro-4a β, 8α-Dimethyl-2(1H)-Naphthalenones from the Wieland-Miescher Ketone

Conversion of the Wieland-Miescher ketone to a bicyclic dienophile capable of providing the AB rings of the picrasane skeleton of the guassinoids required the introduction of a C-8α methyl group in a 2-decalone. Among the routes explored, the conversion of the Wieland-Miescher ketone to a 4,4a,5,6,7,8-hexahydro-4aβ-methyl-8-methylene-2(3H)-napthalenone and subsequent reduction to a 3,4,4a,5,6,7,8,8aα-octahydro-4aβ,8α-dimethyl-2(1H)-napthalenone proved most useful.     

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.     

De novo asymmetric synthesis of fridamycin E

A de novo asymmetric synthesis of (R)- and (S)-fridamycin E has been achieved. The entirely linear route required only nine steps from commercially available starting materials (16% overall yield). Key transformations included a Claisen rearrangement, a Sharpless dihydroxylation and a cobalt-catalyzed epoxide carbonylation to give a β-lactone intermediate. Antibacterial activities were determined for both enantiomers using two strains of E. coli, with the natural (R)-enantiomer showing significant inhibition against a Gram-(+)-like imp strain (MIC = 8 μM).     

Enantioselective diene Cyclization/Hydrosilylation catalyzed by optically active palladium bisoxazoline and pyridine-oxazoline complexes

A 1:1 mixture of (N-N)Pd(Me)Cl ?N-N = (S,S)-4,4'-dibenzyl-4,5,4', 5'-tetrahydro-2,2'-bisoxazoline (S,S-4a) and NaBAr(4) ?Ar = 3, 5-C(6)H(3)(CF(3))(2) (5 mol %) catalyzed the asymmetric cyclization/hydrosilylation of dimethyl diallylmalonate (2) and triethylsilane at -30 degrees C for 48 h to form an 8.1:1 mixture of the silylated carbocycle (S,S)-trans-1, 1-dicarbomethoxy-4-methyl-3-?(triethylsilyl)methylcyclop ent ane (S, S-3) (95% de, 72% ee) and dimethyl 3,4-dimethylcyclopentane-1, 1-dicarboxylate (S,S-6) in 64% combined yield. In comparison, a 1:1 mixture of the palladium pyridine-oxazoline complex (N-N)Pd(Me)Cl ?N-N = (R)-(+)-4-isopropyl-2-(2-pyridinyl)-2-oxazoline (R-5b) and NaBAr(4) (5 mol %) catalyzed the asymmetric cyclization/hydrosilylation of 2 and triethylsilane at -32 degrees C for 24 h to form carbocycle S,S-3 in 82% yield (>95% de, 87% ee) as the exclusive product. Asymmetric diene cyclization catalyzed by complex R-5b was compatible with a range of functional groups and produced carbocycles with up to 91% ee. The procedure also tolerated substitution at a terminal olefinic position and at the allylic position of the diene.     

Rh(I)-catalyzed formal [6 + 2] cycloaddition of 4-allenals with alkynes or alkenes in a tether

Rh(I)-catalyzed formal [6 + 2] cycloaddition of allenal 6 having an alkyne or alkene in a tether proceeded smoothly, giving 5-8- and 6-8-fused bicyclic ketone derivatives 7 in good to excellent yields. It was also found that cyclization of enantiomerically enriched (S)-6a (94% ee) gave cyclic ketone derivative (S)-7a in high yield with reasonable chirality transfer (86% ee). This result indicates that this cyclization proceeds through stereoselective formation of rhodacycle H' followed by insertion of a multiple bond.     

A catalytic asymmetric synthesis of chiral glycidic acid derivatives through chiral dioxirane-mediated catalytic asymmetric epoxidation of cinnamic acid derivatives

A novel and practical asymmetric synthesis of chiral glycidic acid derivatives involving methyl (2R,3S)-3-(4-methoxyphenyl)glycidate ((2R,3S)-2a), a key intermediate for diltiazem hydrochloride (1), was developed. Treatment of methyl (E)-4-methoxycinnamate ((E)-3a) with chiral dioxirane, generated in situ from a catalytic amount (5 mol %) of an 11-membered C(2)-symmetric binaphthyl ketone (R)-7a, provided (2R,3S)-2a in 92% yield and 80% ee. Other cinnamic acid esters and amides were epoxidized by the use of the same procedure to give the corresponding chiral glycidic acid derivatives with up to 95% yield and 92% ee. Higher enantioselectivities in the asymmetric epoxidation of (E)-cinnamates than that of (E)-stilbene derivatives were observed and were proposed to be attributed to a dipole-dipole repulsion between oxygen atoms of an ester group in the cinnamates and those of the lactone moieties in the binaphthyl dioxirane.     

(+)-(1S,7aS)-1-羟基-7a-甲基-茚满-4-烯-5-酮的合成及其烷基化反应研究

以2-甲基-2-(3-丁酮)环戊烷-1,3-二酮为原料,经环合和还原反应合成了手性(+)-(1S,7aS)-1-羟基-7a-甲基-茚满-4-烯-5-酮(3);3在其羟基未进行保护情况下与不同芳香侧链进行α,β-不饱和酮的α-位烷基化反应,制备了5个3的衍生物,其结构经1H NMR确证。     

Enantioselective synthesis of imperanene, a platelet aggregation inhibitor

Both enantiomers of imperanene, a platelet aggregation inhibitor, have been synthesized in 82-90% ee. The key step of establishing the chiral center was achieved through stereoselective alkylation with benzyl chloromethyl ether using Enders' RAMP/SAMP chiral auxiliary method. The natural product was determined to be the (S)-enantiomer through comparison of optical rotation data. Reaction: see text.     

An investigation into the allylic imidate rearrangement of trichloroacetimidates catalysed by cobalt oxazoline palladacycles

Dimeric palladacycles, di-mu-X-bis[{eta(5)-(S)-((p)R)-2-[2'-(4'-methylethyl)oxazolinyl]cyclopentadienyl,1-C,3'-N}(eta(4)-tetraphenylcyclobutadiene)cobalt]dipalladium (COP-X), containing bridging groups X=OAc, Cl, Br, I, O(2)CCF(3), p-O(2)CC(6)H(4)F, were synthesised and compared as catalysts for the asymmetric allylic imidate rearrangement of (E)-Cl(3)CC(=NH)OCH(2)CH=CHR with R=nPr. The enantiomeric excess of the product (S)-Cl(3)CC(=O)NHCHRCH=CH(2) was essentially invariant of X (93-96%) and the yield increased in the sequence I相似文献   

Synthesis of 4,4a,5,6,7,8-hexahydro-5-hydroxy-4a-methyl-2(3H)-naphthalenone

Summary New preparative methods were developed for the synthesis of 4,4a,5,6,7,8~hexahydro-5-hydroxy-4a-methyl-2(3H)-naphtalenone (II) from 3,4,8,8a-tetrahydro-8a-methyl-1,6(2H,7H)-naphthalenedione (I).     

Direct catalytic asymmetric aldol reaction of hydroxyketones: asymmetric Zn catalysis with a Et(2)Zn/linked-BINOL complex

Full details of our newly developed catalyses with asymmetric zinc complexes as mimics of class II zinc-containing aldolase are described. A Et(2)Zn/(S,S)-linked-BINOL complex was developed and successfully applied to direct catalytic asymmetric aldol reactions of hydroxyketones. A Et(2)Zn/(S,S)-linked-BINOL 1 = 2/1 system was initially developed, which efficiently promoted the direct aldol reaction of 2-hydroxy-2'-methoxyacetophenone (7d). Using 1 mol % of (S,S)-linked-BINOL 1 and 2 mol % of Et(2)Zn, we obtained 1,2-dihydroxyketones syn-selectively in high yield (up to 95%), good diastereomeric ratio (up to 97/3), and excellent enantiomeric excess (up to 99%). Mechanistic investigation of Et(2)Zn/(S,S)-linked-BINOL 1, including X-ray analysis, NMR analysis, cold spray ionization mass spectrometry (CSI-MS) analysis, and kinetic studies, provided new insight into the active oligomeric Zn/(S,S)-linked-BINOL 1/ketone 7d active species. On the basis of mechanistic investigations, a modified second generation Et(2)Zn/(S,S)-linked-BINOL 1 = 4/1 with molecular sieves 3A (MS 3A) system was developed as a much more effective catalyst system for the direct aldol reaction. As little as 0.1 mol % of (S,S)-linked-BINOL 1 and 0.4 mol % of Et(2)Zn promoted the direct aldol reaction smoothly, using only 1.1 equiv of 7d as a donor (substrate/ligand = 1000). This is the most efficient, in terms of catalyst loading, asymmetric catalyst for the direct catalytic asymmetric aldol reaction. Moreover, the Et(2)Zn/(S,S)-linked-BINOL 1 = 4/1 system was effective in the direct catalytic asymmetric aldol reaction of 2-hydroxy-2'-methoxypropiophenone (12), which afforded a chiral tetrasubstituted carbon center (tert-alcohol) in good yield (up to 97%) and ee (up to 97%), albeit in modest syn-selectivity. Newly developed (S,S)-sulfur-linked-BINOL 2 was also effective in the direct aldol reaction of 12. The Et(2)Zn/(S,S)-sulfur-linked-BINOL 2 = 4/1 system gave aldol adducts anti-selectively in good ee (up to 93%). Transformations of the aldol adducts into synthetically versatile intermediates were also described.     

Syntheses of (S)-(+)-trihexyphenidyl hydrochloride and (S)-(+)-procyclidine hydrochloride, two anticholinergics, using (S)-(-)-3-cyclohexyl-3-hydroxy-3-phenylpropanoic acid as chiral synthon

The absolute configuration of the more active (-)-enantiomer of the anticholinergic trihexyphenidyl hydrochloride has been established as (R) by syntheses of (S)-(+)-procyclidine hydrochloride, whose absolute configuration has been established previously, and (S)-(+)-trihexyphenidyl hydrochloride from the same chiral building block, viz. (S)-(-)-cyclohexyl-3-hydroxy-3-phenylpropanoic acid. Both enantiomers of this chiral synthon were prepared by optical resolution of the corresponding racemate, employing (R)- and (S)-1-phenylethylamine, respectively, as resolving agents.     

Asymmetric synthesis of Wieland-Miescher and Hajos-Parrish ketones catalyzed by an amino-acid-derived chiral primary amine

This paper describes a simple chiral primary amine-catalyzed highly efficient and practical protocol for the synthesis of both Wieland-Miescher ketone and Hajos-Parrish ketone as well as their analogues. The reaction can be conducted in gram scale with 1% mol catalyst loading producing high enantioselectivity (up to 96% ee) and excellent yields (up to 98%). This procedure represents one of the most efficient methods for the synthesis of these versatile chiral building blocks.     

Stereoselective synthesis of norephedrine and norpseudoephedrine by using asymmetric transfer hydrogenation accompanied by dynamic kinetic resolution

Each of the enantiomers of both norephedrine and norpseudoephedrine were stereoselectively prepared from the common, prochiral cyclic sulfamidate imine of racemic 1-hydroxy-1-phenyl-propan-2-one by employing asymmetric transfer hydrogenation (ATH) catalyzed by the well-defined chiral Rh-complexes, (S,S)- or (R,R)-Cp*RhCl(TsDPEN), and HCO(2)H/Et(3)N as the hydrogen source. The ATH processes are carried out under mild conditions (rt, 15 min) and are accompanied by dynamic kinetic resolution.     

Hydrogenation versus transfer hydrogenation of ketones: two established ruthenium systems catalyze both

The established standard ketone hydrogenation (abbreviated HY herein) precatalyst [Ru(Cl)(2)((S)-tolbinap)[(S,S)-dpen]] ((S),(S,S)-1) has turned out also to be a precatalyst for ketone transfer hydrogenation (abbreviated TRHY herein) as tested on the substrate acetophenone (3) in iPrOH under standard conditions (45 degrees C, 45 bar H(2) or Ar at atmospheric pressure). HY works at a substrate catalyst ratio (s:c) of up to 10(6) and TRHY at s:c<10(4). Both produce (R)-1-phenylethan-1-ol ((R)-4), but the ee in HY are much higher (78-83 %) than in TRHY (4-62 %). In both modes, iPrOK is needed to generate the active catalysts, and the more there is (1-4500 equiv), the faster the catalytic reactions. The ee is about constant in HY and diminishes in TRHY as more iPrOK is added. The ketone TRHY precatalyst [Ru(Cl)(2)((S,S)-cyP(2)(NH)(2))] ((S,S)-2), established at s:c=200, has also turned out to be a ketone HY precatalyst at up to s:c=10(6), again as tested on 3 in iPrOH under standard conditions. The enantioselectivity is opposite in the two modes and only high in TRHY: with (S,S)-2, one obtains (R)-4 in up to 98 % ee in TRHY as reported and (S)-4 in 20-25 % ee in HY. iPrOK is again required to generate the active catalysts in both modes, and again, the more there is, the faster the catalytic reactions. The ee in TRHY are only high when 0.5-1 equivalents iPrOK are used and diminish when more is added, while the (low) ee is again about constant in HY as more iPrOK is added (0-4500 equiv). The new [Ru(H)(Cl)((S,S)-cyP(2)(NH)(2))] isomers (S,S)-9 A and (S,S)-9 B (mixture, exact structures unknown) are also precatalysts for the TRHY and HY of 3 under the same conditions, and (R)-4 is again produced in TRHY and (S)-4 in HY, but the lower ee shows that in TRHY (S,S)-9 A/(S,S)-9 B do not lead to the same catalysts as (S,S)-2. In contrast, the ee are in accord with (S,S)-9 A/(S,S)-9 B leading to the same catalysts as (S,S)-2 in HY. The kinetic rate law for the HY of 3 in iPrOH and in benzene using (S,S)-9 A/(S,S)-9 B/iPrOK or (S,S)-9 A/(S,S)-9 B/tBuOK is consistent with a fast, reversible addition of 3 to a five-coordinate amidohydride (S,S)-11 to give an (S,S)-11-substrate complex, in competition with the rate-determining addition of H(2) to (S,S)-11 to give a dihydride [Ru(H)(2)((S,S)-cyP(2)(NH)(2))] (S,S)-10, which in turn reacts rapidly with 3 to generate (S)-4 and (S,S)-11. The established achiral ketone TRHY precatalyst [Ru(Cl)(2)(ethP(2)(NH)(2))] (12) has turned out to be also a powerful precatalyst for the HY of 3 in iPrOH at s:c=10(6) and of some other substrates. Response to the presence of iPrOK is as before, except that 12 already functions well without it at up to s:c=10(6).