Enders’ SAMP‐Hydrazone as Traceless Auxiliary in the Asymmetric 1,4‐Addition of Cuprates to Enones

Conjugate additions of Gilman cyanocuprates to (S)‐N‐amino‐2‐(methoxymethyl)pyrrolidine (SAMP)‐hydrazones 4 , 5 derived from cyclic and acyclic α,β‐unsaturated ketones were investigated. A protocol utilizing copper(II) sulfate/ammonium chloride was evolved, which allowed cleavage of SAMP (S)‐ 1 under the hydrolysis and work‐up conditions, followed by recovery of the auxiliary with ethylenediaminetetraacetic acid (EDTA). The enantioselectivity of cuprate additions was dominated for cyclic SAMP‐hydrazones 4 by the cuprate alkyl substituent and the ring size, in the case of acyclic arylidene SAMP‐hydrazones 5 , however, by the nature of the aryl substituent. Electron‐donating substituents gave poor enantiomeric excesses, whereas electron‐withdrawing groups provided excellent ee values of 98–99%. The configuration of the new stereocenter was determined to be (R). Moreover, a reaction sequence was developed which integrates a tandem 1,4‐addition/methylation and traceless hydrolytic cleavage of the auxiliary (S)‐ 1 in a one‐pot reaction, resulting in enantiomerically pure methyl ketones 11 – 13 , each of them with>99% ee.     

Production of (R)‐3′‐fluorophenylethan‐1‐ol by Trichothecium roseum isolate in a laboratory scale bioreactor

BACKGROUND: Enantiomerically pure, fluorinated compounds play an important role in medicinal chemistry. Trichothecium roseum strains were isolated for the production of (R)‐3′‐fluorophenylethan‐1‐ol. Biocatalytic production of optically active (R)‐3′‐fluorophenylethan‐1‐ol was achieved by asymmetric reduction of 3′‐fluoroacetophenone in a batch culture of Trichothecium roseum using ram horn peptone (RHP). The reaction conditions (pH, temperature and agitation) required to improve the conversion of 3′‐fluoroacetophenone and enantiomeric excess (ee) of (R)‐3′‐fluorophenylethan‐1‐ol were studied. RESULTS: The gram scale production of (R)‐3′‐fluorophenylethan‐1‐ol by the most effective biocatalyst, Trichothecium roseum EBK‐11 using RHP was carried out in a fermenter with 1 L working volume. The results showed that the yield with >99% ee of (R)‐3′‐fluorophenylethan‐1‐ol reached 77%. The concentration of (R)‐3′‐fluorophenylethan‐1‐ol at the end of 62 h fermentation was 2.70 g L^?1. CONCLUSION: An important chiral intermediate for the pharmaceutical industry using T. roseum EBK‐11 in submerged culture containing RHP from waste material was produced up to gram scale with excellent ee (99%). In this work, T. roseum fungus was used for the first time as a biocatalyst for efficient production of a chiral alcohol. Copyright © 2009 Society of Chemical Industry     

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.     

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.     

Asymmetric Sulfoxidation of Thioethers with Hydrogen Peroxide in Water Mediated by Platinum Chiral Catalyst

Easy stereoselective oxidation of prochiral aryl alkyl sulfides 2 to the corresponding sulfoxides can be achieved in water‐surfactant medium with inexpensive hydrogen peroxide mediated by the chiral platinum diphosphine complex {[(R)‐BINAP]Pt(μ‐OH)}₂(BF₄)₂ ( 1 ). Remarkable key features of general interest are (i) easy isolation of the products from catalyst by simple diethyl ether/water‐surfactant two phase separation, (ii) catalyst loading as low as 1% mol, (iii) good yields, sulfoxide 3 to sulfone 4 ratio up to 200 : 1 and enantioselectivities up to 88%, (iv) mild experimental conditions.     

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 Efficient and Enantioselective Iridium‐Catalyzed Asymmetric Hydrogenation of N‐Arylimines

A catalytic method employing the cationic iridium‐(S_c,R_p)‐DuanPhos [(1R,1′R,2S,2′S)‐2,2′‐di‐tert‐butyl‐2,2′,3,3′‐tetrahydro‐1H,1′H‐1,1′‐biisophosphindole] complex and BARF {tetrakis[3,5‐bis(trifluoromethyl)phenyl]borate} counterion effectively catalyzes the enantioselective hydrogenation of acyclic N‐arylimines with high turnover numbers (up to 10,000 TON) and excellent enantioselectivities (up to 98% ee), achieving the practical synthesis of chiral secondary amines.     

Synthesis and spectroelectrochemistry of dithieno(3,2‐b:2′,3′‐d)pyrrole derivatives

New π‐conjugated polymers containing dithieno(3,2‐b:2′,3′‐d)pyrrole (DTP) were successfully synthesized via electropolymerization. The effect of structural differences on the electrochemical and optoelectronic properties of the 4‐[4H‐dithieno(3,2‐b:2′,3′‐d)pyrrol‐4‐yl]aniline (DTP–aryl–NH₂), 10‐[4H‐dithiyeno(3,2‐b:2′,3′‐d)pirol‐4‐il]dekan‐1‐amine (DTP–alkyl–NH₂), and 1,10‐bis[4H‐dithieno(3,2‐b:2′,3′‐d)pyrrol‐4‐yl] decane (DTP–alkyl–DTP) were investigated. The corresponding polymers were characterized by cyclic voltammetry, NMR (¹H‐NMR and ¹³C‐NMR), and ultraviolet–visible spectroscopy. Changes in the electronic nature of the functional groups led to variations in the electrochemical properties of the π‐conjugated systems. The electroactive polymer films revealed redox couples and exhibited electrochromic behavior. The replacement of the DTP–alkyl–DTP unit with DTP–aryl–NH₂ and DTP–alkyl–NH₂ resulted in a lower oxidation potential. Both the poly(10‐(4H‐Dithiyeno[3,2‐b:2′,3′‐d]pirol‐4‐il)dekan‐1‐amin) (poly(DTP–alkyl–NH₂)) and poly(1,10‐bis(4H‐dithieno[3,2‐b:2′,3′‐d]pyrrol‐4‐yl) decane) (poly(DTP–alkyl–DTP)) films showed multicolor electrochromism and also fast switching times (<1 s) in the visible and near infrared regions. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40701.     

Approaches to the Preparation of Enantiomerically Pure (2R,2′R)‐(+)‐threo‐Methylphenidate Hydrochloride

Various approaches to the preparation of enantiomerically pure (2R,2′R)‐(+)‐threo‐methylphenidate hydrochloride ( 1 ) are reviewed. These approaches include synthesis using enantiomerically pure precursors obtained by resolution, classical and enzyme‐based resolution approaches, enantioselective synthesis approaches, and approaches based on enantioselective synthesis of (2S,2′R)‐erythro‐methylphenidate followed by epimerization at the 2‐position. 1 Introduction 2 Methods for the Enhancement of Enantiomeric Purity of 1 3 Approaches Using Enantiomerically Pure Precursors Obtained by Resolution 4 Classical Resolution Approaches 4.1 Resolution of Amide and Acid Derivatives 4.2 Resolution of (±)‐threo‐Methylphenidate 5 Enzyme‐Based Resolution Approaches 6 Enantioselective Synthesis Approaches 7 Approaches Based on Enantioselective Synthesis of (2S,2′R)‐erythro‐Methylphenidate and Epimerization 8 Conclusions     

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.     

MOP‐Type Binaphthyl Phosphite and Diamidophosphite Ligands and Their Application in Catalytic Asymmetric Transformations

Monodentate phosphite and diamidophosphite ligands have been developed based on O‐methyl‐BINOL. These chiral ligands are easy to prepare from readily accessible phosphorylating reagents – (S_a or R_a)‐2‐chlorodinaphtho[2,1‐d:1′,2′‐f][1,3,2]dioxaphosphepine and (2R,5S)‐2‐chloro‐3‐phenyl‐1,3‐diaza‐2‐phosphabicyclo[3.3.0]octane. The new ligands have demonstrated excellent enantioselectivity in the palladium‐catalysed allylic substitution reactions of (E)‐1,3‐diphenylallyl acetate with sodium p‐toluenesulfinate (up to 99 % ee), pyrrolidine (up to 97 % ee), dipropylamine (up to 95 % ee) and dimethyl malonate (up to 99 % ee). In the palladium‐catalysed deracemization of ethyl (E)‐1,3‐diphenylallyl carbonate, up to 96 % enantioselectivity has been achieved. The diamidophosphite ligands have exhibited very good enantioselectivity in the Rh‐catalysed asymmetric hydrogenation of dimethyl itaconate (up to 90 % ee).     

The Synthesis of trans‐Perhydroindolic Acids and their Application in Asymmetric Domino Reactions of Aldehyde Esters with β,γ‐Unsaturated α‐Keto Esters

(2S,3aR,7aS)‐Perhydroindolic acid, the key intermediate in the synthesis of trandolapril, and its trans‐isomers, were readily prepared. These proline‐like molecules are unique in that they contain a rigid bicyclic structure, with two hydrogen atoms trans to each other at the bridgehead carbon atoms. These molecules were used successfully as chiral organocatalysts in asymmetric domino Michael addition/cyclization reactions of aldehyde esters with β,γ‐unsaturated α‐keto esters. They proved to have excellent catalytic behavior, allowing for the synthesis of multi‐substituted, enantiomerically enriched hemiacetal esters. Under optimal conditions (using 10 mol% catalyst loading), a series of β,γ‐unsaturated α‐keto esters was examined with up to 99% de, ee and yield, respectively. Additionally, the enantiomerically enriched hemiacetal esters could be readily transformed into their corresponding bioactive pyrano[2,3‐b]pyrans (possessing a multi‐substituted bicyclic backbone).     

Third‐Generation Amino Acid Furanoside‐Based Ligands from d‐Mannose for the Asymmetric Transfer Hydrogenation of Ketones: Catalysts with an Exceptionally Wide Substrate Scope

A modular ligand library of α‐amino acid hydroxyamides and thioamides was prepared from 10 different N‐tert‐butyloxycarbonyl‐protected α‐amino acids and three different amino alcohols derived from 2,3‐O‐isopropylidene‐α‐d ‐mannofuranoside. The ligand library was evaluated in the half‐sandwich ruthenium‐ and rhodium‐catalyzed asymmetric transfer hydrogenation of a wide array of ketone substrates, including simple as well as sterically demanding aryl alkyl ketones, aryl fluoroalkyl ketones, heteroaromatic alkyl ketones, aliphatic, conjugated and propargylic ketones. Under the optimized reaction conditions, secondary alcohols were obtained in high yields and in enantioselectivities up to >99%. The choice of ligand/catalyst allowed for the generation of both enantiomers of the secondary alcohols, where the ruthenium‐hydroxyamide and the rhodium‐thioamide catalysts act complementarily towards each other. The catalytic systems were also evaluated in the tandem isomerization/asymmetric transfer hydrogenation of racemic allylic alcohols to yield enantiomerically enriched saturated secondary alcohols in up to 98% ee. Furthermore, the catalytic tandem α‐alkylation/asymmetric transfer hydrogenation of acetophenones and 3‐acetylpyridine with primary alcohols as alkylating and reducing agents was studied. Secondary alcohols containing an elongated alkyl chain were obtained in up to 92% ee.

     

Axially Chiral Phosphine‐Oxazoline Ligands in Silver(I)‐ Catalyzed Asymmetric Mannich Reaction of Aldimines with Trimethylsiloxyfuran

A new asymmetric catalytic system for the Mannich reaction of aldimines with trimethylsiloxyfuran is described. The combination of an axially chiral phosphine‐oxazoline ligand (S)‐2‐[(R)‐2′‐(diphenylphosphino)‐1,1′‐binaphthyl‐2‐yl]‐4‐phenyl‐4,5‐dihydrooxazole with silver acetate and 2,2,2‐trifluoroacetic acid is a very effective catalytic system in the asymmetric Mannich reaction of various aldimines with trimethylsiloxyfuran in dichloromethane at −78 °C, affording the corresponding adducts in up to 99% yield, 99:1 (dr) and 99% ee (major diastereoisomer) under mild conditions.     

N,N′‐Dioxide‐Magnesium Ditriflate Complex‐Catalyzed Asymmetric α‐Hydroxylation of β‐Keto Esters and β‐Keto Amides

The highly catalytic asymmetric α‐hydroxylation of 1‐tetralone‐derived β‐keto esters and β‐keto amides using tert‐butyl hydroperoxide (TBHP) as the oxidant was realized by a chiral N,N′‐dioxide‐magnesium ditriflate [Mg(OTf)₂] complex. A series of corresponding chiral α‐hydroxy dicarbonyl compounds was obtained in excellent yields (up to 99%) with excellent enantioselectivities (up to 98% ee). The products were easily transformed into useful building blocks and the precursor of daunomycin was achieved in an asymmetric catalytic way for the first time.     

tert‐Butyl Sulfoxides: Key Precursors for Palladium‐Catalyzed Arylation of Sulfenate Salts

The present report describes an efficient and clean generation of sulfenate salts (R¹SO⁻) by pyrolysis of readily available tert‐butyl sulfoxides to give sulfenic acids (R¹SOH) and traceless isobutene, followed by hydrogen abstraction with a weak inorganic base (K₃PO₄). The relevance of this process was exemplified through an in situ palladium‐catalyzed cross‐coupling reaction with aryl halides/triflates leading to aryl sulfoxides. The operationally simple C S bond‐forming protocol developed uses Pd(dba)₂ as catalyst and Xantphos as ligand in toluene or a toluene/H₂O mixture. Further extensions include the use of di‐tert‐butyl sulfoxide as an equivalent for sulfur monoxide dianion (SO²⁻) and the development of diastereoselective versions in the [2.2]paracyclophane and biaryl series.

     

3‐Heterocycle‐Phenyl N‐Alkylcarbamates as FAAH Inhibitors: Design,Synthesis and 3D‐QSAR Studies

Carbamates are a well‐established class of fatty acid amide hydrolase (FAAH) inhibitors. Here we describe the synthesis of meta‐substituted phenolic N‐alkyl/aryl carbamates and their in vitro FAAH inhibitory activities. The most potent compound, 3‐(oxazol‐2yl)phenyl cyclohexylcarbamate ( 2 a ), inhibited FAAH with a sub‐nanomolar IC₅₀ value (IC₅₀=0.74 nM ). Additionally, we developed and validated three‐dimensional quantitative structure–activity relationships (QSAR) models of FAAH inhibition combining the newly disclosed carbamates with our previously published inhibitors to give a total set of 99 compounds. Prior to 3D‐QSAR modeling, the degree of correlation between FAAH inhibition and in silico reactivity was also established. Both 3D‐QSAR methods used, CoMSIA and GRID/GOLPE, produced statistically significant models with coefficient of correlation for external prediction (R²_PRED) values of 0.732 and 0.760, respectively. These models could be of high value in further FAAH inhibitor design.     

Enantioselective Protonation by Aza‐Michael Reaction between Pyrazoles and α‐Substituted Vinyl Ketones

An enantioselective protonation by means of chiral scandium complex‐catalyzed aza‐Michael reaction was realized. A series of α‐aryl‐substituted vinyl ketones reacted with pyrazoles smoothly, affording the corresponding enantiomerically enriched pyrazole derivatives with excellent results (up to 99% yield, 94% ee). Water and hydrogen chloride were found to accelerate the protonation process.

     

Bioreduction of α‐Acetoxymethyl Enones: Proposal for an SN2′ Mechanism Catalyzed by Enereductase

(Z)‐3‐Acetoxymethyl‐4‐R‐3‐buten‐2‐ones (R=aryl, alkyl) and (Z)‐3‐methyl‐4‐R‐3‐buten‐2‐ones (R=aryl) were synthesized and submitted to reduction by the yeast Saccharomyces cerevisiae producing the (R)‐ and (S)‐4‐R‐3‐methybutan‐2‐ones, respectively. This stereochemistry control strategy was applied in the syntheses of (R)‐ and (S)‐Tropional® with moderate to high enantiomeric excesses. Other (Z)‐3‐acyloxymethyl‐4‐phenyl‐3‐buten‐2‐ones showed similar behavior to the (Z)‐3‐acetoxymethyl counterpart, and the acylated Morita–Baylis–Hillman adduct 1‐acetoxy‐2‐methylene‐1‐phenylbutan‐3‐one produced a mixture of products, with and without the acetoxy group, via three different reaction pathways. In addition to experiments employing whole cells, those in which isolated enereductases were used suggested that the main pathway through which the loss of the acetoxy group occurs during the biocatalytic cascade is an S_N2′‐type reaction, rather than formal hydrogen addition followed by acetic acid elimination. Finally, related ethyl enones were reduced enantioselectively by the yeast Candida albicans, producing both (R)‐ and (S)‐reduction products, depending on the presence of the acetoxy group in the starting material.

     

Synthesis of Methylene‐Bridge Polyarenes through Palladium‐Catalyzed Activation of Benzylic Carbon‐Hydrogen Bond

In the presence of palladium(II) acetate [Pd(OAc)₂] and an N‐heterocyclic carbene (NHC) ligand, fluorene derivatives can be generated in good to excellent yields from 2‐halo‐2′‐methylbiaryls through the benzylic C H bond activation (14 examples; 81–97% yields). The scope and limitations of this protocol have been examined. A wide range of functional groups, such as alkyl, alkoxy, ester, nitrile, and others, is able to tolerate the reaction conditions herein. The cyclization of an isotope‐labelled biphenyl gave the corresponding product with a primary kinetic isotope effect (k_H/k_D=4.8:1), which indicates that the rate‐determining step of this reaction is the activation of the benzylic C H bond. Moreover, indenofluorenes were also accessed in excellent results from terphenyls (3 examples; 91–92% yields). The cascade reaction of 2,6‐dichloro‐2′‐methylbiphenyl with diphenylacetylene produced 8,9‐diphenyl‐4H‐cyclopenta[def]phenanthrene in 60% yield through the activation of an aryl and a benzylic C H bond.