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.     

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).     

Organocatalytic Asymmetric Synthesis of Protected α,β‐Diamino Acids

In the presence of the readily available quinine‐derived catalyst 4d , highly diastereo‐ and enantioselective Mannich reactions of tosyl‐protected imines and α‐isothiocyanato imides proceeded to afford the protected α,β‐diamino acids, useful building blocks for natural products and biologically active compounds, in good to excellent yields.     

Access to Both Enantiomers of α‐Chloro‐β‐keto Esters with a Single Chiral Ligand: Highly Efficient Enantioselective Chlorination of Cyclic β‐Keto Esters Catalyzed by Chiral Copper(II) and Zinc(II) Complexes of a Spiro‐2,2′‐bischroman‐Based Bisoxazoline Ligand

The spiro‐2,2′‐bichroman‐based chiral bisoxazoline ligands (SPANbox) were found to be highly efficient in copper(II)‐ and zinc(II)‐catalyzed asymmetric chlorinations of cyclic β‐keto esters with N‐chlorosuccinimide (NCS) as the chlorination reagent, to give the corresponding α‐chloro‐β‐keto esters in excellent yields in 5–30 min with ee values up to 97%. The copper(II) triflate and zinc(II) triflate complexes of a single SPANbox ligand demonstrated complementary results to each other with respect to the enantioselection, affording both antipodes of the chlorinated product enantiomers with good to excellent optical purities.     

Catalytic Hydrogenation of α‐Iminophosphonates as a Method for the Synthesis of Racemic and Optically Active α‐Aminophosphonates

It was shown that the catalytic hydrogenation of α‐iminophosphonates by molecular hydrogen can serve as a convenient method for the synthesis of racemic and optically active α‐aminophosphonates. Up to 94% ee was achieved in the rhodium‐catalyzed enantioselective hydrogenation using chiral ligand (R)‐BINAP.     

Dietary trans α‐linolenic acid does not inhibit Δ5‐ and Δ6‐desaturation of linoleic acid in man

Dietary trans monoenes have been associated with an increased risk of heart disease in some studies and this has caused much concern. Trans polyenes are also present in the diet, for example, trans α‐linolenic acid is formed during the deodorisation of α‐linolenic acid‐rich oils such as rapeseed oil. One would expect the intake of trans α‐linolenic acid to be on the increase since the consumption of rapeseed oil in the western diet is increasing. There are no data on trans α‐linolenic acid consumption and its effects. We therefore carried out a comprehensive study to examine whether trans isomers of this polyunsaturated fatty acid increased the risk of coronary heart disease. Since inhibition of Δ6‐desaturase had also been linked to heart disease, the effect of trans α‐linolenic acid on the conversion of [U‐¹³C]‐labelled linoleic acid to dihomo‐γ‐linolenic and arachidonic acid was studied in 7 healthy men recruited from the staff and students of the University of Edinburgh. Thirty percent of the habitual fat was replaced using a trans ‘free’‐ or ‘high’ trans α‐linolenic acid fat. After at least 6 weeks on the experimental diets, the men received 3‐oleyl, 1,2‐[U‐¹³C]‐linoleyl glycerol (15 mg twice daily for ten days). The fatty acid composition of plasma phospholipids and the incorporation of ¹³C‐label into n‐6 fatty acids were determined at day 8, 9 and 10 and after a 6‐week washout period by gas chromatography‐combustion‐isotope ratio mass spectrometry. Trans α‐linolenic acid of plasma phospholipids increased from 0.04 ? 0.01 to 0.17 ? 0.02 and cis ? ‐linolenic acid decreased from 0.42 ? 0.07 to 0.29 ? 0.08 g/100 g of fatty acids on the high trans diet. The composition of the other plasma phospholipid fatty acids did not change. The enrichment of phosphatidyl ¹³C‐linoleic acid reached a plateau at day 10 and the average of the last 3 days did not differ between the low and high trans period. Both dihomo‐γ‐linolenic and arachidonic acid in phospholipids were enriched in ¹³C, both in absolute and relative terms (with respect to ¹³C‐linoleic acid). The enrichment was slightly and significantly higher during the high trans period (P<0.05). Our data suggest that a diet rich in trans α‐linolenic acid (0.6% of energy) does not inhibit the conversion of linoleic acid to dihomo‐γ‐linolenic and arachidonic acid in healthy middle‐aged men consuming a diet rich in linoleic acid.     

Enantioselective α‐Alkylation of Benzylideneamino tert‐Butyl Malonates by Phase‐Transfer Catalysis

A new enantioselective synthetic method for the synthesis of α,α‐dialkylmalonates with a quaternary carbon center was developed via α‐alkylation of prochiral malonates by phase‐transfer catalysis (PTC). Asymmetric α‐alkylation of benzylideneamino tert‐butyl α‐methylmalonates under phase‐transfer catalytic conditions in the presence of (S,S)‐3,4,5‐trifluorophenyl‐NAS bromide afforded the corresponding α,α‐dialkylmalonates in high yields (up to 97%) with excellent enantioselectivities (up to 98% ee). The products were then selectively hydrolyzed to chiral malonic monoacids under basic, acidic, or catalytic hydrogenation conditions.

     

Heterocycles as Nonclassical Bioisosteres of α‐Amino Acids

Bioisosterism of α‐amino acids is often accomplished by replacing the α‐carboxylate with one of the many known carboxylic acid bioisosteres. However, bioisosterism of the whole α‐amino acid moiety is accomplished with heterocyclic bioisosteres that often display an acidic function. In this Minireview, we summarized the reported heterocycles as nonclassical bioisosteres of α‐amino acids, which include quinoxaline‐2,4(1H)‐dione, quinoxaline‐2,3(1H)‐dione and quinolin‐2(1H)‐one, azagrevellin and azepine‐derived structures. The binding mode of the crystalized bioisosteres were compared with those of the crystalized α‐amino acids that bind in the same domain, and where no data on the crystal structure were available, the displacement studies of known orthosteric ligands were used. The reported bioisosteres share the following essential structural features for mimicking α‐amino acids: an aromatic ring system joined to a lactam ring system with an acidic feature next to the lactam carbonyl, where this acidic feature together with the lactam carbonyl can mimic the α‐carboxylate, and the lactam nitrogen together with the aromatic ring system can mimic the α‐ammonium. The majority of these heterocycles can be prepared from three common corresponding starting materials: the corresponding anilines, isatins or anthranilic esters. The data collected here show the potential of this class of bioisosteres in the design of glutamate receptor ligands and beyond.     

Multi‐Enzymatic Synthesis of Optically Pure β‐Hydroxy α‐Amino Acids

A novel enzymatic production system of optically pure β‐hydroxy α‐amino acids was developed. Two enzymes were used for the system: an N‐succinyl L ‐amino acid β‐hydroxylase (SadA) belonging to the iron(II)/α‐ketoglutarate‐dependent dioxygenase superfamily and an N‐succinyl L ‐amino acid desuccinylase (LasA). The genes encoding the two enzymes are part of a gene set responsible for the biosynthesis of peptidyl compounds found in the Burkholderia ambifaria AMMD genome. SadA stereoselectively hydroxylated several N‐succinyl aliphatic L ‐amino acids and produced N‐succinyl β‐hydroxy L ‐amino acids, such as N‐succinyl‐L ‐β‐hydroxyvaline, N‐succinyl‐L ‐threonine, (2S,3R)‐N‐succinyl‐L ‐β‐hydroxyisoleucine, and N‐succinyl‐L ‐threo‐β‐hydroxyleucine. LasA catalyzed the desuccinylation of various N‐succinyl‐L ‐amino acids. Surprisingly, LasA is the first amide bond‐forming enzyme belonging to the amidohydrolase superfamily, and has succinylation activity towards the amino group of L ‐leucine. By combining SadA and LasA in a preparative scale production using N‐succinyl‐L ‐leucine as substrate, 2.3 mmol of L ‐threo‐β‐hydroxyleucine were successfully produced with 93% conversion and over 99% of diastereomeric excess. Consequently, the new production system described in this study has advantages in optical purity and reaction efficiency for application in the mass production of several β‐hydroxy α‐amino acids.

     

Asymmetric Aza‐Morita–Baylis–Hillman‐Type Reactions: The Highly Enantioselective Reaction between Unmodified α,β‐ Unsaturated Aldehydes and N‐Acylimines by Organo‐co‐catalysis

The highly enantioselective organo‐co‐catalytic aza‐Morita–Baylis–Hillman (MBH)‐type reaction between N‐carbamate‐protected imines and α,β‐unsaturated aldehydes has been developed. The organic co‐catalytic system of proline and 1,4‐diazabicyclo[2.2.2]octane (DABCO) enables the asymmetric synthesis of the corresponding N‐Boc‐ and N‐Cbz‐protected β‐amino‐α‐alkylidene‐aldehydes in good to high yields and up to 99% ee. In the case of aza‐MBH‐type addition of enals to phenylprop‐2‐ene‐1‐imines, the co‐catalytic reaction exhibits excellent 1,2‐selectivity. The organo‐co‐catalytic aza‐MBH‐type reaction can also be performed by the direct highly enantioselective addition of α,β‐unsaturated aldehydes to bench‐stable N‐carbamate‐protected α‐amidosulfones to give the corresponding β‐amino‐α‐alkylidene‐aldehydes with up to 99% ee. The organo‐co‐catalytic aza‐MBH‐type reaction is also an expeditious entry to nearly enantiomerically pure β‐amino‐α‐alkylidene‐amino acids and β‐amino‐α‐alkylidene‐lactams (99% ee). The mechanism and stereochemistry of the chiral amine and DABCO co‐catalyzed aza‐MBH‐type reaction are also discussed.     

Synthesis and characterization of polyrotaxanes comprising α‐cyclodextrins and poly(ε‐caprolactone) end‐capped with poly(butyl methacrylate)s

Biodegradable polyrotaxane‐based triblock copolymers were synthesized via the bulk atom transfer radical polymerization (ATRP) of n‐butyl methacrylate (BMA) initiated with polypseudo‐rotaxanes (PPRs) built from a distal 2‐bromoisobutyryl end‐capped poly(ε‐caprolactone) (Br‐PCL‐Br) with α‐cyclodextrins (α‐CDs) in the presence of Cu(I)Br/N,N,N′,N″,N″‐pentamethyldiethylenetriamine at 45 ºC. The structure was characterized in detail by means of ¹H NMR, gel permeation chromatography, wide‐angle X‐ray diffraction, DSC and TGA. When the feed molar ratio of BMA to Br‐PCL‐Br was changed from 128 to 300, the degree of polymerization of PBMA blocks attached to two ends of the PPRs was in the range 382 ? 803. Although about a tenth of the added α‐CDs were still threaded onto the PCL chain after the ATRP process, the movable α‐CDs made a marked contribution to the mechanical strength enhancement, blood anticoagulation activity and protein adsorption repellency of the resulting copolymers. Meanwhile, they could also protect the copolymers from the attack of H₂O and Lipase AK Amano molecules, exhibiting a lower mass loss as evidenced in hydrolytic and enzymatic degradation experiments. © 2013 Society of Chemical Industry     

Highly Enantioselective Michael Addition of Cyclic 1,3‐Dicarbonyl Compounds to β,γ‐Unsaturated α‐Keto Esters

A highly enantioselective Michael addition of cyclic 1,3‐dicarbonyl compounds to β,γ‐unsaturated α‐keto esters catalyzed by amino acid‐derived thiourea‐tertiary‐amine catalysts is presented. Using 5 mol% of a novel tyrosine‐derived thiourea catalyst, a series of chiral coumarin derivatives were obtained in excellent yields (up to 99%) and with up to 96% ee under very mild conditions within a short reaction time.     

Highly Enantioselective Allylation of Aromatic α‐Keto Phosphonates Catalyzed by Chiral N,N′‐Dioxide‐Indium(III) Complexes

The ramipril derivative N,N′‐dioxide 3g ‐indium(III) complex was found to be an efficient catalyst for the allylation of the aromatic α‐keto phosphonates. The corresponding α‐hydroxy phosphonates were obtained with high yields (up to 98 %) and high enantioselectivities (up to 91 % ee). A bifunctional catalyst system was described with an N‐oxide as Lewis base activating tetraallyltin and indium as Lewis acid activating aromatic α‐keto phosphonates. A possible catalytic cycle has been proposed to explain the mechanism of the reaction.     

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.     

Preparation and characterization of chitosan/α‐zirconium phosphate nanocomposite films

Nano‐fillers play an important role in the final structure and properties of nanocomposites. The objective of the work presented here was to prepare nanocomposite films of chitosan/α‐zirconium phosphate using a casting process, with α‐zirconium phosphate (α‐ZrP) as nano‐filler and chitosan as matrix. The effects of α‐ZrP on the structure and properties of the nanocomposites were investigated. X‐ray diffraction patterns showed that α‐ZrP crystals were intercalated by n‐butylamine. The results from scanning electron microscopy and transmission electron microscopy indicated that α‐ZrP could be uniformly dispersed in the chitosan matrix when α‐ZrP loading in the composites was less than 2 wt%. A strong interaction between α‐ZrP and chitosan formed during the film‐forming process. Tensile testing showed that the tensile strength and elongation at break of nanocomposite films achieved maximum values of 61.6 MPa and 58.1%, respectively, when α‐ZrP loading was 2 wt%. The parameter B calculated from tensile yield stress according to the Pukanszky model was used to estimate the interfacial interaction between the chitosan matrix and α‐ZrP. Films with a loading of 2 wt% α‐ZrP had the highest B value (3.2), indicating the strongest interfacial interaction. The moisture uptake of the nanocomposites was reduced with addition of α‐ZrP. It can be concluded that α‐ZrP as nano‐filler in a chitosan matrix can enhance the mechanical properties of nanocomposites due to the strong interactions between α‐ZrP and chitosan. Copyright © 2010 Society of Chemical Industry     

N‐Heterocyclic Carbene‐Mediated Organocatalytic Transfer of Tin onto Aldehydes: New Access to α‐Silyloxyalkylstannanes and γ‐Silyloxyallylstannanes

A new, highly efficient and mild N‐heterocyclic carbene (NHC)‐mediated organocatalytic procedure for the transfer of tin from tributyl(trimethylsilyl)stannane (Bu₃SnSiMe₃) onto aldehydes for the preparation of α‐silyloxyalkylstannanes and γ‐silyloxyallylstannanes has been developed.     

Copolymerization of ethylene/α‐olefins over (2‐MeInd)2ZrCl2/MAO and (2‐BzInd)2ZrCl2/MAO systems

Ethylene homopolymerization and ethylene/α‐olefin copolymerization were carried out using unbridged and 2‐alkyl substituted bis(indenyl)zirconium dichloride complexes such as (2‐MeInd)₂ZrCl₂ and (2‐BzInd)₂ZrCl₂. Various concentrations of 1‐hexene, 1‐dodecene, and 1‐octadecene were used in order to find the effect of chain length of α‐olefins on the copolymerization behavior. In ethylene homopolymerization, catalytic activity increased at higher polymerization temperature, and (2‐MeInd)₂ZrCl₂ showed higher activity than (2‐BzInd)₂ZrCl₂. The increase of catalytic activity with addition of comonomer (the synergistic effect) was not observed except in the case of ethylene/1‐hexene copolymerization at 40°C. The monomer reactivity ratios of ethylene increased with the decrease of polymerization temperature, while those of α‐olefin showed the reverse trend. The two catalysts showed similar copolymerization reactivity ratios. (2‐MeInd)₂ZrCl₂ produced the copolymer with higher M_w than (2‐BzInd)₂ZrCl₂. The melting temperature and the crystallinity decreased drastically with the increase of the α‐olefin content but T_m as a function of weight fraction of the α‐olefins showed similar decreasing behavior. © 2000 John Wiley & Sons, Inc. J Appl Polym Sci 75: 928–937, 2000     

Quasi‐alternating polyesteramides from ε‐caprolactone and α‐amino acids

Glycine‐ɛ‐caprolactone‐based and α‐alanine‐ɛ‐caprolactone‐based polyesteramides with a strong tendency to form alternating sequences (degree of randomness = 1.64 and 1.31) were synthesized by melt polycondensation of intermediate hydroxy‐ and ethyl ester‐terminated amides. These intermediates were synthesized by the reaction of equimolar amounts of ɛ‐caprolactone and glycine or L‐α‐alanine ethyl esters in mild conditions. The structure and microstructure of these polyesteramides are discussed on the basis of an in‐depth nuclear magnetic resonance study. Both polyesteramides are semi‐crystalline, but the glycine‐based one presents the highest melting enthalpy. This polyesteramide also exhibits higher Young's modulus and stress at break than its α‐ and β‐alanine counterparts. © 2016 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016 , 133, 44220.     

Chemical Synthesis of the Epimeric (23R)‐ and (23S)‐Fluoro Derivatives of Bile Acids via Horner–Wadsworth–Emmons Reaction

A method for the synthesis of two (23R)‐ and (23S)‐epimeric pairs of 23‐fluoro‐3α,7α,12α‐trihydroxy‐5β‐cholan‐24‐oic acid and 23‐fluoro‐3α,7α‐dihydroxy‐5β‐cholan‐24‐oic acid is described. The key intermediates, 23,24‐dinor‐22‐aldehyde peracetates were prepared from cholic and chenodeoxycholic acids via the 24‐nor‐22‐ene, 24‐nor‐22ξ,23‐epoxy, and 23,24‐dinor‐22‐aldehyde derivatives. The Horner–Wadsworth–Emmons reaction of the 23,24‐dinor‐22‐aldehydes using triethyl 2‐fluoro‐2‐phosphonoacetate in the presence of LiCl and 1,8‐diazabicyclo[5,4,0]undec‐7‐ene (DBU), and subsequent hydrogenation of the resulting 23ξ‐fluoro‐22‐ene ethyl esters, followed by hydrolysis, gave a mixture of the epimeric (23R)‐ and (23S)‐fluorinated bile acids which were resolved efficiently by preparative RP‐HPLC. The stereochemical configuration of the fluorine atom at C‐23 in the newly synthesized compounds was confirmed directly by the X‐ray crystallographic data. The ¹H and ¹³C NMR spectral differences between the (23R)‐ and (23S)‐epimers were also discussed.     

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.