Ti-mediated addition of diethylzinc to benzaldehyde. The effect of chiral additives

In the presence of a chiral tridentate bissulfonamide, the titanium-mediated addition of diethylzinc to benzaldehyde gave alkylated products ranging from the (R)-enantiomer, formed with an e.e. of 26%, to the (S)-enantiomer, formed in 72% e.e. The enantioselectivity was also affected by the presence of additional chiral mono- and bidentate ligands, with the reactions proceeding via complexes containing the chiral sulfonamide and the additive. The addition of (1R,2R)-1,2-diphenyl-1,2-ethanediamine and (1S,2S)-1,2-diphenyl-1,2-ethanediamine gave the (S)-product with e.e. of 49% and the (R)-product with 16% e.e., respectively, whereas without additives the (R)-product was obtained in 26% e.e. In the presence of (1R,2R)-1,2-diphenyl-1,2-ethanediamine only (i.e. without the chiral sulfonamide), the (S)-product formed with a 3% e.e.     

The catalytic asymmetric addition of alkyl- and aryl-zinc reagents to an isoxazole aldehyde

Nucleophilic addition of alkyl- and aryl-zinc reagents to a C(4) functionalized isoxazolyl aldehyde proceeded effectively with high enantioselectivity (85-94% ee). The amino alcohol catalyst (S)-2-piperidinyl-1,1,2-triphenyl ethanol (10) afforded the (R)-product 2b, as established by X-ray crystallography.     

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.     

Regioselective synthesis of trifluoromethyl group containing allylic amines by palladium-catalyzed allylic amination and sequential isomerization

The palladium-catalyzed regioselective allylic amination of the α-trifluoromethyl group-substituted allyl acetate has been accomplished using Pd(OAc)₂/DPPE and [Pd(π-allyl)(cod)]BF₄/DPPF as catalysts. The selective formation of the γ-product was attained in the presence of Pd(OAc)₂/DPPE, while the α-product was obtained using [Pd(π-allyl)(cod)]BF₄/DPPF. We also succeeded in the regioselective synthesis of the enantiomerically enriched aminated product from chiral allyl acetate using Pd(OAc)₂/DPPE and [Pd(π-allyl)(cod)]BF₄/(S)-BINAP. Furthermore, we found that kinetic resolution had occurred during the isomerization step from the γ-type product to the α-type product by the [Pd(π-allyl)(cod)]BF₄/(S)-BINAP catalyst.     

Assymetric synthesis of (2S,3R)- and (2S,3S)-[2-C;3-H] glutamic acid

We have developed a synthetic route for (2S,3R)- and (2S,3S)-[2-¹³C;3-²H] glutamic acids with high enantioselectivity. The key reactions in this synthesis are the asymmetric reduction of the 2,3-didehydroornithine derivative using the (S,S)-Et-DuPHOS-Rh catalyst and the oxidation of the δ-position by ruthenium catalysis.     

Extremely high regio- and stereoselective C-C bond formation of substituted γ-hydroxylactams: synthesis of macronecines based on their structural duality

With a view to develop a new synthetic entry for the necine bases, treatment of functionalized γ-hydroxylactams was found to undergo quite high regio- and diastereoselective carbon-carbon bond formation reactions, affording the corresponding structurally dualistic alkylated lactams in satisfactory yields. The reaction was further applied to the practical and efficient synthesis of (±)-macronecine [(1S^∗,2R^∗,7aR^∗)-1-hydroxymethyl-2-hydroxypyrrolizidine] and (±)-2-epi-macronecine [(1S^∗,2S^∗,7aR^∗)-1-hydroxymethyl-2-hydroxypyrrolizidine].     

Stereochemical control in microbial reduction. Part 31: Reduction of alkyl 2-oxo-4-arylbutyrates by baker's yeast under selected reaction conditions

Treatment of baker's yeast with phenacyl chloride in an aqueous–organic solvent has been proven to be an effective method of inhibiting the enzymes that afford (S)-enantiomers of α-hydroxy esters in the reduction of α-keto esters. The procedure is effective for the whole-cell system to produce the (R)-product with high chemical yield and high enantiomeric excess.     

An investigation into the mechanism of the imidazolidinone catalyzed cascade reaction

The cascade reaction of α,β-unsaturated butyric aldehydes with 2-methyl furan and chlorinated quinone catalyzed by a (2S,5S)-5-benzyl-2-tert-butyl-3-methylimidazolidin-4-one·TFA was investigated by using density functional theory (DFT) calculations at the PCM(EtOAc)/B3LYP/6-311++G(d,p)//B3LYP/6-31G(d) level to (a) confirm the detailed reaction mechanism and key factors controlling the enantioselectivity; and (b) check the models of the iminium ion formation and hydrolysis process that were carried out in another reaction. Two favorable reaction channels, corresponding to the enantioselectivity of the (2R,3S)-product and (2S,3S)-product, have been characterized. The enantioselectivity is controlled by the steps involved in the formation of the C–C bond and the C–Cl bond in the iminium catalysis and the enamine catalysis, respectively. The calculated results explain the reaction mechanism and the enantioselectivity, which are in agreement with experimental observations, and may be helpful for understanding the reaction mechanism of similar cascade reactions.     

Insights into the spontaneous emergence of enantioselectivity in an asymmetric Mannich reaction carried out without external catalyst

ESI-MS, chiral HPLC, time-resolved ¹H NMR and optical rotation measurements were performed to gain insights into the nature of spontaneous mirror symmetry breaking in the catalyst-free Mannich reaction of PMP protected α-iminoethylglyoxylate with hydroxyacetone. Spontaneous temporary generation of enantiomeric excesses of up to 7.4% in the major syn diastereomer is reproducibly observed in aqueous phosphate buffers, starting from achiral conditions. The syn-product ee values for both enantiomers [(2S,3S) and (2R,3R)], although not with stochastic distribution, have been observed with no clear preference for either enantiomer.     

An improved synthesis of deuterated Schöllkopf’s bis-lactim ether and its use for the asymmetric synthesis of (R)-[α-2H]-phenylalanine methyl esters

Treatment of (S)-3-isopropyl-2,5-dimethoxy-3,6-dihydropyrazine with trifluoroacetic acid in MeOD results in regioselective deuteration at its C₆-position affording its corresponding (S)-[6-²H₂]-isotopomer in excellent yield with no loss of stereochemical integrity at its C₃-stereocentre. The lithium aza-enolate of this deuterated chiral template has been alkylated with a range of substituted benzyl bromides to afford (3S,6R)-[6-²H]-3-isopropyl-6-benzyl-bis-lactim ethers that were hydrolysed to afford their corresponding (R)-[α-²H]-phenylalanine methyl esters as hydrochloride salts in good yield.     

Asymmetric enamide hydrogenation in the synthesis of N-acetylcolchinol: a key intermediate for ZD6126

A synthesis of N-acetylcolchinol, a key intermediate in the synthesis of ZD6126, was developed. The enantiodifferentiating step required the catalytic asymmetric hydrogenation of an enamide. After screening a range of metal and ligand combinations it was found that (S,S)-ⁱPr-FerroTANE Ru(methallyl)₂ and [(S,S)-^tBuFerroTANE Rh(COD)]BF₄ gave both high enantioselectivity (>90% ee) and high catalyst utility (molar S/C = 1000).     

(4R,5S)-1,5-Dimethyl-4-phenylimidazolidin-2-one as a chiral auxiliary for the diastereoselective alkylation of a new iminic glycine derivative: practical asymmetric synthesis of α-amino acids

The lithium enolate of enantiomerically pure N-[bis(methylthio)methylene] glycinate 11 derived from (4R,5S)-1,5-dimethyl-4-phenylimidazolidin-2-one reacts with alkyl halides giving the alkylated derivatives 12 with a high degree of control of the diastereoselectivity. These alkylated systems are easily hydrolyzed to the corresponding α-amino acids, the chiral auxiliary being recovered.     

Synthesis of the bifunctional BINOL ligands and their applications in the asymmetric additions to carbonyl compounds

Efficient one-step syntheses of the bifunctional BINOL and H₈BINOL ligands (S)-6 and (S)-8 have been developed from the reaction of BINOL and H₈BINOL with morpholinomethanol, respectively. The X-ray analyses of these compounds have revealed their structural similarity and difference. The bifunctional H₈BINOL (S)-8 is found to be highly enantioselective for the reaction of diphenylzinc with many aliphatic and aromatic aldehydes and especially is the most enantioselective catalyst for linear aliphatic aldehydes. Unlike other catalysts developed for the diphenylzinc addition which often require the addition of a significant amount of diethylzinc with cooling (or heating) the reaction mixture in order to achieve high enantioselectivity, using (S)-8 needs no additive and gives excellent results at room temperature. (S)-8 in combination with diethylzinc and Ti(OⁱPr)₄ can catalyze the highly enantioselective phenylacetylene addition to aromatic aldehydes. It can also promote the phenylacetylene addition to acetophenone at room temperature though the enantioselectivity is not very high yet. Without using Ti(OⁱPr)₄ and a Lewis base additive, (S)-8 in combination with diethylzinc can catalyze the reaction of methyl propiolate with an aldehyde to form the highly functional γ-hydroxy-α,β-acetylenic esters except that the enantioselectivity is low at this stage. The bifunctional BINOL ligand (S)-6 in combination with Me₂AlCl is found to be a highly enantioselective catalyst for the addition of TMSCN to both aromatic and aliphatic aldehydes.     

Dual activation in a homolytic coupling reaction promoted by an enantioselective dinuclear vanadium(IV) catalyst

A new concept of dual activation catalysis in homolytic coupling reaction of 2-naphthol derivatives is described. The dinuclear vanadium(IV) catalyst (R,S,S)-1a promotes the oxidative coupling reaction of 2-naphthol derivatives with high reactivity and enantioselectivity. This dual activation mechanism is supported by the fact that the reaction rate of oxidative coupling of 2-naphthol promoted by the (R,S,S)-1a is 48 times faster than that of the mononuclear complex (S)-3 and a lower catalyst loading of (R,S,S)-1a shows higher catalyst efficiency both in enantioselectivity and chemical yield.     

Synthesis of (R)- and (S)-4-hydroxyisophorone by ruthenium-catalyzed asymmetric transfer hydrogenation of ketoisophorone

The first synthesis of (R)- and (S)-4-hydroxyisophorone by catalytic transfer hydrogenation of ketoisophorone is reported. Ruthenium catalysts containing commercially available chiral amino alcohols afforded 4-hydroxyisophorone in up to 97% selectivity and 97% ee. (R)- or (S)-4-Hydroxyisophorones with >99% ee were isolated by crystallization. The catalyst precursors [RuCl₂((S,R)-ADPE)(η⁶-p-cymene)] ((S,R)-ADPE=(1S,2R)-amino-1,2-diphenylethanol-N) and (R_Ru)-[RuCl((S,R)-ADPE⁻¹)(η⁶-p-cymene)] (ADPE⁻¹=amino-1,2-diphenylethanolato-N,O) were isolated for the first time and the X-ray crystal structure of the latter determined.     

Enantioselective synthesis of β-amino acids. Part 10: Preparation of novel α,α- and β,β-disubstituted β-amino acids from (S)-asparagine

Perhydropyrimidinone (S)-1 is alkylated with very high diastereoselectivity to give trans products (2S,5R)-3, (2S,5R)–4 and (2S,5R)-5. Dialkylation of (S)-1 also proceeds with complete stereoselectivity to afford adducts (2S,5R)-6, (2S,5S)-6, (2S,5R)-7 and (2S,5S)-7. Hydrolysis (6N HCl, 100°C) of monoalkylated derivative (2S,5R)-3 gives enantiopure α-substituted β-amino acid (R)-8. Hydrolysis of dialkylated adducts 6 and 7 affords enantiopure α,α-disubstituted β-amino acids (R)- or (S)-9 and (R)- or (S)-10. Related iminoester (2S,6S)-2 is alkylated with complete diastereoselectivity to give products (2S,6S)-11–13 whose hydrolysis under relatively mild conditions (2N CF₃CO₂H, CH₃OH, 100°C) affords enantiopure N-benzoylated β,β-disubstituted β-amino acid esters (S)-14–16, with intact double bonds in the olefinic substituents.     

PTC and organic bases–LiCl assisted alkylation of imidazolidinone–glycine iminic derivatives for the asymmetric synthesis of α-amino acids

Iminic derivatives of (4R,5S)-1,5-dimethyl-4-phenylimidazolidin-2-one and glycine 4 have been highly diastereoselectively alkylated with activated alkyl halides or electrophilic olefins either under PTC conditions or in the presence of the strong organic bases DBU or BEMP at −20°C in the presence of LiCl. Hydrolysis of the alkylated imino imides gave (S)-α-amino acids with recovery of the imidazolidinone chiral auxiliary.     

A facile direct nucleophilic synthesis of O-(2-[18F]fluoroethyl)-l-tyrosine ([18F]FET) without HPLC purification

Due to favourable in vivo characteristics, its high specificity and the longer half-life of ¹⁸F (109.8 min) allowing for remote-site delivery, O-(2-[¹⁸F]fluoroethyl)-l-tyrosine ([¹⁸F]FET) has gained increased importance for molecular imaging of cerebral tumors. Consequently, the development of simple and efficient production strategies for [¹⁸F]FET could be an important step to further improve the cost-effective availability of [¹⁸F]FET in the clinical environment. In the present study [¹⁸F]FET was synthesized via direct nucleophilic synthesis using an earlier developed chiral precursor, the Ni^II complex of an alkylated (S)-tyrosine Schiff base, Ni-(S)-BPB-(S)-Tyr-OCH₂CH₂OTs. The purification method has been developed via solid phase extraction thereby omitting cumbersome HPLC purification. The suggested SPE purification using combination of reverse phase and strong cation exchange cartridges provided [¹⁸F]FET in high chemical, radiochemical and enantiomeric purity and 35 % radiochemical yield (decay-corrected, 45 min synthesis time). The method was successfully automated using a commercially available synthesis module, Scintomics Hotbox^one. Based on the current results, the proposed production route appears to be well suited for transfer into an automated cassette-type radiosynthesizers without using HPLC.     

Asymmetric synthesis and retroracemisation of amino acids via copper(II) complexes with schiff bases between chiral 1-(N,N-dimethylaminomethyl)-2-formylcymantrene and dipeptides

1-(N,N-Dimethylaminomethyl)-2-formylcymantrene (AFCMT) has been resolved into enantiomers through an intermediate formation of diastereomeric complexes with (S)-Ala-(S)-Ala, (S)-Ala-Gly and Gly-(S)-Ala. By the X-ray anomalous dispersion method the absolute configuration of its enantiomers has been determined: (-)₄₃₆ AFCMT-(S), (+)₄₃₆ AFCMT-(R).Alkylation of enantiomeric complexes (R)-and (S)-AFCMT-(GlyGly) Cu(II) with acetaldehyde gives, respectively, (R)-and (S)-Thr with an asymmetric yield of 92–98% and (R)- and (S)-allo-Thr with an asymmetric yield of 95–100%, only the N-terminal glycine being alkylated.The AFCMT enantiomers were also employed for retroracemisation of (R,S)-Ala-(R,S)-Nva; in this case an excess of (S)-Ala and (R)-Nva is obtained for (S)-AFCMT. (R)- and (S)-AFCMT are not liable to racemisation in the course of the threonine synthesis and retroracemisation of depeptides and can be repeatedly employed for these transformations.     

Ruthenium-catalyzed reduction of racemic tricarbonyl(η-aryl ketone)chromium complexes using transfer hydrogenation: A simple alternative to the resolution of planar chiral organometallics

Racemic planar chiral (η⁶-aryl ketone)Cr(CO)₃ complexes (aryl ketone = 1-indanone, 1-tetralone, 4-chromanone and thiochroman-4-one) were prepared by refluxing the aryl ketone with Cr(CO)₆ in a 10:1 mixture of dibutyl ether and THF. The reductions of the organometallic ketones by transfer hydrogenation in 2-propanol containing KOH and the catalyst precursor, generated from [RuCl₂(η⁶-benzene)]₂ and (−)-ephedrine, resulted in optically active syn-(R,S)-(η⁶-aryl alcohol)Cr(CO)₃ and (R)-(η⁶-aryl ketone)Cr(CO)₃ compounds in 31-97% ee. Reduction of racemic (η⁶-thiochroman-4-one)Cr(CO)₃ with the catalyst precursor generated from (+)-norephedrine, instead of (−)-ephedrine, inverted the configuration of the products obtained. Syn-(S,R)-(η⁶-thiochroman-4-ol)Cr(CO)₃ and (S)-(η⁶-thiochroman-4-one)-Cr(CO)₃ were isolated in 49% and >95% ee, respectively. The free aryl ketones were reduced using the same conditions as their respective chromium complexes, giving aryl alcohols in high ee (>95%). Reactions of non-rigid acetophenone, propriophenone and their tricarbonylchromium complexes resulted in moderate to low ee.