Hydrolytic Kinetic Resolution of Epoxides Catalyzed by Chromium(III)‐endo,endo‐2,5‐diaminonorbornane‐salen [Cr(III)‐DIANANE‐salen] Complexes. Improved Activity,Low Catalyst Loading

The hydrolytic kinetic resolution (HKR) of terminal epoxides, using chiral chromium(III )‐salen catalysts based on DIANANE (endo,endo‐2,5‐diaminonorbornane), was studied. A broad substrate scope was found for the chromium(III )‐DIANANE catalysts, and very low loadings (down to 0.05 mol %) were needed to achieve high enantiomeric purities of both the remaining epoxides and the product diols (up to >99 % ee). Besides monosubstituted epoxides, 2‐methyl‐2‐n‐pentyloxirane, which is an example for 2,2‐disubstituted epoxides, could be ring‐opened in an asymmetric fashion with water in the presence of an electronically tuned chromium(III )‐DIANANE complex.     

Enantioselective Synthesis of Chiral β‐Aryloxy Alcohols by Ruthenium‐Catalyzed Ketone Hydrogenation via Dynamic Kinetic Resolution (DKR)

A highly efficient enantioselective synthesis of chiral β‐aryloxy alcohols by the {RuCl₂[(S)‐SDP][(R,R)‐DPEN]} [(S_a,R,R)‐ 1a ; SDP=7,7′‐bis(diarylphosphino)‐1,1′‐spirobiindane; DPEN=trans‐1,2‐diphenylethylenediamine] complex‐catalyzed asymmetric hydrogenation of racemic α‐aryloxydialkyl ketones via dynamic kinetic resolution (DKR) has been developed. Enantioselectivities of up to 99% ee with good to high cis/anti‐selectivities (up to>99:1) were achieved.     

Studies of the Deracemization of (±)‐2‐Hydroxy‐1‐tetralone by Trichosporon cutaneum

The diastereo‐ and enantioselective bioreduction of (±)‐2‐hydroxy‐1‐tetralone ( 6 ) to the corresponding enantiopure (1S,2R)‐cis‐1,2‐dihydroxy‐1,2,3,4‐tetrahydronaphthalene ( 1 ) (83 % isolated yield, >99 % ee), mediated by resting cells of the yeast Trichosporon cutaneum CCT 1903 through dynamic kinetic resolution is reported. Deracemization of (±)‐ 6 was observed in kinetic studies on the biotransformation of the enantiomers (R)‐ 6 and (S)‐ 6 .     

Ruthenium‐Catalyzed Asymmetric Hydrogenation of β‐Keto‐ enamines: An Efficient Approach to Chiral γ‐Amino Alcohols

A highly efficient and enantioselective hydrogenation of unprotected β‐ketoenamines catalyzed with ruthenium(II) dichloro{(S)‐(−)‐2,2′‐bis[di(3,5‐xylyl)phosphino]‐1,1′‐binaphthyl}[(2S)‐(+)‐1,1‐bis(4‐methoxyphenyl)‐3‐methyl‐1,2‐butanediamine] {Ru[(S)‐xylbinap][(S)‐daipen]Cl₂} has been successfully developed. This methodology provides a straightforward access to free γ‐secondary amino alcohols, which are key building blocks for a variety of pharmaceuticals and natural products, with high yields (>99%) and excellent enantioselectivities (up to 99% ee) in all cases.     

Palladium(II) Complexes of C2‐Bridged Chiral Diphosphines: Application to Enantioselective Carbonyl‐Ene Reactions

(11bR,11′bR)‐4,4′‐(1,2‐Phenylene)bis[4,5‐dihydro‐3H‐dinaphtho[2,1‐c:1′,2′‐e]phosphepin] [abbreviated as (R)‐BINAPHANE], (3R,3′R,4S,4′S,11bS,11′bS)‐4,4′‐bis(1,1‐dimethylethyl)‐4,4′,5,5′‐tetrahydro‐3,3′‐bi‐3H‐dinaphtho[2,1‐c:1′,2′‐e]phosphepin [(S)‐BINAPINE], (1S,1′S,2R,2′R)‐1,1′‐bis(1,1‐dimethylethyl)‐2,2′‐biphospholane [(S,S,R,R)‐TANGPHOS] and (2R,2′R,5R,5′R)‐1,1′‐(1,2‐phenylene)bis[2,5‐bis(1‐methylethyl)phospholane] [(R,R)‐i‐Pr‐DUPHOS] are C₂‐bridged chiral diphosphines that form stable complexes with palladium(II) and platinum(II) containing a five‐membered chelate ring. The Pd(II)‐BINAPHANE catalyst displayed good to excellent enantioselectivities with ee values as high as 99.0% albeit in low yields for the carbonyl‐ene reaction between phenylglyoxal and alkenes. Its Pt(II) counterpart afforded improved yields while retaining satisfactory enantioselectivity. For the carbonyl‐ene reaction between ethyl trifluoropyruvate and alkenes, the Pd(II)‐BINAPHANE catalyst afforded both good yields and extremely high enantioselectivities with ees as high as 99.6%. A comparative study on the Pd(II) catalysts of the four C₂‐bridged chiral diphosphines revealed that Pd(II)‐BINAPHANE afforded the best enantioselectivity. The ee values derived from Pd(II)‐BINAPHANE are much higher than those derived from the other three Pd(II) catalysts. A comparison of the catalyst structures shows that the Pd(II)‐BINAPHANE catalyst is the only one that has two bulky (R)‐binaphthyl groups close to the reaction site. Hence it creates a deep chiral space that can efficiently control the reaction behavior in the carbonyl‐ene reactions resulting in excellent enantioselectivity.     

Highly Enantioselective Phase‐Transfer Catalytic α‐Alkylation of α‐tert‐Butoxycarbonyllactams: Construction of β‐Quaternary Chiral Pyrrolidine and Piperidine Systems

A new enantioselective α‐alkylation of α‐tert‐butoxycarbonyllactams for the construction of β‐quaternary chiral pyrrolidine and piperidine core systems is reported. α‐Alkylations of N‐methyl‐α‐tert‐butoxycarbonylbutyrolactam and N‐diphenylmethyl‐α‐tert‐butoxycarbonylvalerolactam under phase‐transfer catalytic conditions (solid potassium hydroxide, toluene, −40 °C) in the presence of (S,S)‐3,4,5‐trifluorophenyl‐3,3′,5,5′‐tetrahydro‐2,6‐bis(3,4,5‐trifluorophenyl)‐4,4′‐spirobi[4H‐dinaphth[2,1‐c:1′,2′‐e]azepinium] bromide [(S,S)‐NAS Br] (5 mol%) afforded the corresponding α‐alkyl‐α‐tert‐butoxycarbonyllactams in very high chemical (up to 99%) and optical yields (up to 98% ee). Our new catalytic systems provide attractive synthetic methods for pyrrolidine‐ and piperidine‐based alkaloids and chiral intermediates with β‐quaternary carbon centers.     

Engineering Polymer‐Enhanced Bimetallic Cooperative Interactions in the Hydrolytic Kinetic Resolution of Epoxides

Through systematic variations of the length of oligo(ethylene glycol)‐based linkers and the catalyst density of poly(styrene)‐supported cobalt‐salen catalysts, we have elucidated an optimal catalyst flexibility and density of polymeric Co‐salen catalysts for the hydrolytic kinetic resolution (HKR) of racemic terminal epoxides that follows a bimetallic cooperative pathway. The optimized polymeric catalyst brings the two cooperative Co‐salen units to a favorable proximity efficiently and hence displays significantly improved catalytic performance in the HKR compared with its monomeric small molecule analogue. Complex Co(5b) , representing the most active poly(styrene)‐supported HKR catalyst known so far, can effect the resolution of a variety of epoxides to reach ≥98 % ee in 6–24 h with a low cobalt loading of 0.01–0.1 mol %.     

Unusual Totally Selective Cyclodimerization of Epoxides: Synthesis of a Pair of Diastereoisomers of Enantiopure 2,5‐Disubstituted‐1,4‐Dioxanes with C2 Symmetry

The synthesis of the C₂‐symmetrical (2R,5R)‐ and (2S,5S)‐2,5‐bis‐[(S)‐1‐(dibenzylaminoalkyl)]‐1,4‐dioxanes 1 or 2 in enantiopure form is reported. Compounds 1 and 2 were obtained by a completely selective and unusual cyclodimerization of chiral (2R,1′S)‐ or (2S,1′S)‐2‐(1‐aminoalkyl)epoxides 3 or 4 promoted by a mixture of diisopropylamine and boron trifluoride⋅diethyl etherate complex. The structure of the obtained dioxane was established by single‐crystal X‐ray diffraction analysis. A mechanism has been proposed to explain this transformation.     

Enantioselective Biooxidation of Racemic trans‐Cyclic Vicinal Diols: One‐Pot Synthesis of Both Enantiopure (S,S)‐Cyclic Vicinal Diols and (R)‐α‐Hydroxy Ketones

Highly regio‐ and enantioselective alcohol dehydrogenases BDHA (2,3‐butanediol dehydrogenase from Bacillus subtilis BGSC1A1), CDDHPm (cyclic diol dehydrogenase from Pseudomonas medocina TA5), and CDDHRh (cyclic diol dehydrogenase from Rhodococcus sp. Moj‐3449) were discovered for the oxidation of racemic trans‐cyclic vicinal diols. Recombinant Escherichia coli expressing BDHA was engineered as an efficient whole‐cell biocatalyst for the oxidation of (±)‐1,2‐cyclopentanediol, 1,2‐cyclohexanediol, 1,2‐cycloheptane‐diol, and 1,2‐cyclooctanediol, respectively, to give the corresponding (R)‐α‐hydroxy ketones in >99% ee and (S,S)‐cyclic diols in >99% ee at 50% conversion in one pot. Escherichia coli (BDHA‐LDH) co‐expressing lactate dehydrogenase (LDH) for intracellular regeneration of NAD⁺ catalyzed the regio‐ and enantioselective oxidation of (±)‐1,2‐dihydroxy‐1,2,3,4‐tetrahydronaphthalene to produce the corresponding (R)‐α‐hydroxy ketone in >99% ee and (S,S)‐cyclic diol in 96% ee at 49% conversion. Preparative biotransformations were also demonstrated. Thus, a novel and useful method for the one‐pot synthesis of both vicinal diols and α‐hydroxy ketones in high ee was developed via highly regio‐ and enantioselective oxidations of the racemic vicinal diols.

     

Catalytic Asymmetric Alkynylation and Arylation of Aldehydes by an H8‐Binaphthyl‐Based Amino Alcohol Ligand

A novel chiral H₈‐1,1′‐binaphthyl‐based amino alcohol ligand (1R_a,2S,3R)‐ 2 has been synthesized and applied in the direct nucleophilic addition of organozincs (alkynylzinc and arylzinc prepared in situ) to aldehydes, yielding the corresponding optically active propargylic alcohols and diarylmethanols in high yields and good to excellent enantioselectivities. For the asymmetric arylation reaction, one catalyst (1R_a,2S,3R)‐ 2 can afford both enantiomers of many pharmaceutically interesting diarylmethanols by a proper combination of various arylzinc reagents and aldehydes.     

Asymmetric Ring Opening of meso‐Epoxides with Aromatic Amines Catalyzed by a New Proline‐Based N,N′‐Dioxide‐Indium Tris(triflate) Complex

The catalytic asymmetric ring opening of meso‐epoxides with aromatic amines was achieved using a new proline‐based N,N′‐dioxide‐indium tris(triflate) complex in high yields (up to 99%) with excellent enantioselectivities (up to 99% ee) under mild conditions. The coordination ability of N,N′‐dioxide 1c was investigated by X‐ray and NMR analysis. A plausible seven‐coordinate transition state model was proposed. The chiral N,N′‐dioxides surveyed were synthesized from proline through only three conventional steps. The procedure could be run on a gram‐scale without any loss of enantioselectivity. This protocol provides a highly practical and useful tool for the bulky preparation of optically pure β‐amino alcohols.     

The catalytic activity of new chiral salen complexes immobilized on MCM-41 in the asymmetric hydrolysis of epoxides to diols

The synthesis of MCM-41 type mesoporous material has been performed by the solvent evaporation method. The chiral salen Co(III)(OAc) complexes are immobilized on a siliceous MCM-41 through the multi-step anchoring and applied as catalysts in the hydrolytic kinetic resolution of racemic epoxides to diols. The incorporation of salen complexes onto the mesoporous material is demonstrated by UV–Vis spectroscopy, and tested with the catalytic hydrolysis reaction. The chiral salen Co(III) complexes catalyze the hydrolysis of epichlorohydine, 1,2-epoxyhexane, epoxystyrene and epoxycyclohexane under very mild conditions. This reaction can proceed in acetonitrile and THF solvents.     

A New Class of 3′‐Sulfonyl BINAPHOS Ligands: Modulation of Activity and Selectivity in Asymmetric Palladium‐Catalysed Hydrophosphorylation of Styrene

Palladium‐catalysed monophosphorylation of (R)‐2,2′‐bisperfluoroalkanesulfonates of BINOL (R^F=CF₃ or C₄F₉) by a diaryl phosphinate [Ar₂P(O)H] followed by phosphine oxide reduction (Cl₃SiH) then lithium diisopropylamide‐mediated anionic thia‐Fries rearrangement furnishes enantiomerically‐pure (R)‐2′‐diarylphosphino‐2′‐hydroxy‐3′‐perfluoralkanesulfonyl‐1,1′‐binaphthalenes [(R)‐ 8ab and (R)‐ 8g–j ], which can be further diversified by Grignard reagent (RMgX)‐mediated CF₃‐displacement [→(R)‐ 8c–f ]. Coupling of (R)‐ 8a–j with (S)‐1,1′‐binaphthalene‐2,2′‐dioxychlorophosphine (S)‐ 9 generates 3′‐sulfonyl BINAPHOS ligands (R,S)‐ 10a–j in good yields (43–82%). These new ligands are of utlility in the asymmetric hydrophosphonylation of styrene ( 1 ) by 4,4,5,5‐tetramethyl‐1,3,2‐dioxaphospholane 2‐oxide ( 2 ), for which a combination of the chiral ligands with either [Pd(Cp)(allyl)] or [Pd(allyl)(MeCN)₂]⁺/NaCH(CO₂Me)₂ proves to be a convenient and active pre‐catalyst system. A combination of an electron‐rich phosphine moiety and an electron‐deficient 3′‐sulfone moiety provides the best enantioselectivity to date for this process, affording the branched 2‐phenethenephosphonate, (−)‐iso‐ 3 , in up to 74% ee with ligand (R,S)‐ 10i , where Ar=p‐anisyl and the 3′‐SO₂R group is triflone.     

Sulfonated N‐Heterocyclic Carbenes for Pd‐Catalyzed Sonogashira and Suzuki–Miyaura Coupling in Aqueous Solvents

The reactions of the N,N′‐diarylimidazolium and N,N′‐diarylimidazolinium salts with chlorosulfonic acid result in the formation of the respective disulfonated N‐heterocyclic carbene (NHC) precursors in reasonable yields (46–77%). Water‐soluble palladium catalyst complexes, in situ obtained from the respective sulfonated imidazolinium salt, sodium tetrachloropalladate (Na₂PdCl₄) and potassium hydroxide (KOH) in water, were successfully applied in the copper‐free Sonogashira coupling reaction in isopropyl alcohol/water mixtures using 0.2 mol% catalyst loading. The preformed (disulfonatedNHC)PdCl(cinnamyl) complex was used in aqueous Suzuki–Miyaura reactions at 0.1 mol% catalyst loading. The coupling protocol reported here is very useful for Sonogashira reactions of N‐ and S‐heterocyclic aryl bromides and chlorides with aryl‐ and alkylacetylenes.     

Synthesis of poly(methylphenylsiloxane) rich in syndiotacticity by Rh‐catalysed stereoselective cross‐dehydrocoupling polymerization of optically active 1,3‐dimethyl‐1,3‐diphenyldisiloxane derivatives

Cross‐dehydrocoupling reactions of (R)‐methyl(1‐naphthyl)phenylsilane (>99%ee) with (S)‐methyl(1‐naphthyl)phenylsilanol (>99% ee) proceeded with 82–99% retention of configuration of chiral silicon centres in the presence of various Rh‐catalysts. Cross‐dehydrocoupling polymerization of 1,3‐dimethyl‐1,3‐diphenyl‐1,3‐disiloxanediol with 1,3‐dihydro‐1,3‐dimethyl‐1,3‐diphenyl‐1,3‐disiloxane gave poly(methylphenylsiloxane) of moderate molecular weight in toluene at 60 °C in the presence of [RhCl(cod)]₂ (5.0 mol%) and triethylamine (1.0 equivalent). Assignment of the triad signals of the resulting polymer was made by ¹H NMR spectroscopy of the methyl proton (I = 0.04, H = 0.09 and S = 0.14 ppm) and ¹³C NMR spectroscopy of the ipso carbon of the phenyl group (S = 136.7, H = 136.9, and I = 137.1 ppm). Although the reaction of optically pure (S,S)‐1,3‐dimethyl‐1,3‐diphenyl‐1,3‐disiloxanediol with 1,3‐dihydro‐1,3‐dimethyl‐1,3‐diphenyl‐1,3‐disiloxane [(S,S):(S,R):(R,R)] = 84:16:0] gave a poly(methylphenylsiloxane) of rather low molecular weight, its triad tacticity was found to be rich in syndiotacticity (S:H:I = 60:32:8) by ¹³C NMR spectroscopy. © 2001 Society of Chemical Industry     

Synthesis and Highly Stereoselective Hydrogenation of the Statin Precursor Ethyl (5S)‐5,6‐Isopropylidenedioxy‐3‐oxohexanoate

A search for the large‐scale preparation of (5S)‐5,6‐(isopropylidenedioxy)‐3‐oxohexanoates ( 2 ) – a key intermediate in the synthesis of pharmacologially important statins – starting from (S)‐malic acid is described. The synthesis of the required initial compound methyl (3S)‐3,4‐(isopropylidenedioxy)butanoate ( 1 ) by Moriwake’s reduction of dimethyl (S)‐malate ( 3 ) has been improved. Direct 2‐C chain elongation of ester 1 using the lithium enolate of tert‐butyl acetate has been shown to be successful at a 3‐ to 5‐fold excess of the enolate. Unfortunately, the product, tert‐butyl (5S)‐5,6‐(isopropylidenedioxy)‐3‐oxohexanoate ( 2a ) is unstable during distillation. Ethyl (5S)‐5,6‐(isopropylidenedioxy)‐3‐oxohexanoate ( 2b ) was prepared alternatively on a multigram scale from (3S)‐3,4‐(isopropylidenedioxy)butanoic acid ( 7 ) by activation with N,N′‐carbonyldiimidazole and subsequent reaction with Mg(OOCCH₂COOEt)₂. A convenient pathway for the in situ preparation of the latter is also described. Ethyl ester ( 2b ) can be advantageously purified by distillation. The stereochemistry of the catalytic hydrogenation of β‐keto ester ( 2b ) to ethyl (5S)‐5,6‐(isopropylidenedioxy)‐3‐hydrohyhexanoate (syn‐ 6 and anti‐ 6 ) has been studied using a number of homogeneous achiral and chiral Rh(I) and Ru(II) complexes with phosphine ligands. A comparison of Rh(I) and Ru(II) catalysts with (S)‐ and (R)‐BINAP as chiral ligands revealed opposite activity in dependence on the polarity of the solvent. No influence of the chiral backbone of substrate 2b on the enantioselectivity was noted. A ratio of syn‐ 6 /anti‐ 6 =2.3 was observed with an achiral (Ph₃P)₃RuCl₂ catalyst. Ru[(R)‐Tol‐BINAP]Cl₂ neutralized with one equivalent of AcONa afforded the most efficient catalytic system for the production of optically pure syn‐(5S)‐5,6‐isopropylidenedioxy‐3‐hydroxyhexanoate (syn‐ 6 ) at a preparative substrate/catalyst ratio of 1000:1.     

An Unusual (R)‐Selective Epoxide Hydrolase with High Activity for Facile Preparation of Enantiopure Glycidyl Ethers

A novel epoxide hydrolase (BMEH) with unusual (R)‐enantioselectivity and very high activity was cloned from Bacillus megaterium ECU1001. Highest enantioselectivities (E>200) were achieved in the bioresolution of ortho‐substituted phenyl glycidyl ethers and para‐nitrostyrene oxide. Worthy of note is that the substrate structure remarkably affected the enantioselectivities of the enzyme, as a reversed (S)‐enantiopreference was unexpectedly observed for the ortho‐nitrophenyl glycidyl ether. As a proof‐of‐concept, five enantiopure epoxides (>99% ee) were obtained in high yields, and a gram‐scale preparation of (S)‐ortho‐methylphenyl glycidyl ether was then successfully performed within a few hours, indicating that BMEH is an attractive biocatalyst for the efficient preparation of optically active epoxides.     

Chemoenzymatic Preparation of Enantiopure Homoadamantyl β‐Amino Acid and β‐Lactam Derivatives

Racemic cis‐10‐azatetracyclo[7.2.0.1^2,6.1^4,8]tridecan‐11‐one was prepared from homoadamant‐4‐ene by chlorosulfonyl isocyanate addition. The transformation of the β‐lactam to the corresponding β‐amino ester followed by Candida antarctica lipase A‐catalyzed enantioselective (E>>200) N‐acylation with 2,2,2‐trifluoroethyl butanoate afforded methyl (1R,4R,5S,8S)‐5‐aminotricyclo[4.3.1.1^3,8]undecane‐4‐carboxylate and the (1S,4S,5R,8R)‐butanamide with>99% ee at 50% conversion. Alternatively, transformation of the β‐lactam to the corresponding N‐hydroxymethyl‐β‐lactam and the following Pseudomonas cepacia (currently Burkholderia cepacia) lipase‐catalyzed enantioseletive O‐acylation provided the (1S,4S,6R,9R)‐alcohol (ee=87%) and the corresponding (1R,4R,6S,9S)‐butanoate (ee>99%). In the latter method, competition for the enzyme between the (1R,4R,6S,9S)‐butanoate, 2,2,2‐trifluoroethyl butanoate and the hydrolysis product, butanoic acid, tended to stop the reaction at about 45% conversion and finally gave racemization in the (1S,4S,6R,9R)‐alcohol with time.     

Iron salen‐catalysed oxidative coupling of phenol derivatives: formaldehyde‐free access to amphiphilic polymers

The oxidative coupling of 4‐tert‐butylphenol ( 1 ), 2,6‐di‐tert‐butyl‐p‐cresol ( 11 ) and 4‐cyanophenol ( 10 ) in the presence of iron salen catalysts (salen = N,N′‐bis(salicylidine)ethylenediamine) and the influence of amine additives on the conversion of 1 were investigated. Furthermore, the activity of the iron complexes was correlated with the substituents at the 5,5′‐positions of the salen ligands. Mechanistically conclusions based on dimer formation in the reaction between 10 and 11 are presented. In the second part of the study the obtained hydrophobic poly(4‐tert‐butylphenol) was modified with Jeffamine^® M‐600, M‐1000 or M‐2070 to give amphiphilic copolymers (18a–c). The amphiphilic copolymers were characterized via size‐exclusion chromatography and dynamic light scattering. The concentration dependence of the cloud point appearance in water of amphiphilic copolymer 18c was analysed via turbidity measurements. © 2016 Society of Chemical Industry     

Highly Active Polymer‐Supported (Salen)Al Catalysts for the Enantioselective Addition of Cyanide to α,β‐Unsaturated Imides

In this contribution, we describe polymer‐supported (R,R)‐(salen)AlCl complexes that were immobilized on poly(norbornene)s and display excellent activities and enantioselectivies as catalysts for the 1,4‐conjugate addition of cyanide to α,β‐unsaturated imides. These supported catalysts could be recycled up to 5 times without compromising catalyst activities or selectivities. Furthermore, the catalyst loadings could be reduced from 10–15 mol%, the common catalyst loadings for non‐supported (salen)Al catalysts, to 5 mol%, a decrease of metal content by 50–66%, without lowering product yields or enantioselectivities. Kinetic studies indicated that the polymer‐supported catalysts are significantly more active than their corresponding unsupported analogues, which makes this catalyst system key to a successful implementation of this catalytic transformation into the fine chemical and pharmaceutical industries.