Phase-transfer Catalyzed Alkylation Research Articles

Enantioselective synthesis of fluorinated aromatic amino acids catalyzed by SPINOL-derived chiral quaternary ammonium salts†

We report the synthesis of a new class of chiral quaternary ammonium salts featuring a rigid spirobiindane scaffold. These chiral quaternary ammonium salts were employed as catalysts in the phase-transfer catalytic asymmetric alkylation of tert‑butyl glycinate–benzophenone Schiff base with both fluorinated and non-fluorinated benzyl bromides. Under the established reaction conditions, a series of chiral fluorinated aromatic α-amino acid derivatives, some of which are key intermediates for biologically significant compounds, were obtained in high yields and enantioselectivities.

Enantioselective phase-transfer catalyzed alkylation of 1-methyl-7-methoxy-2-tetralone: an effective route to dezocine.

In order to prepare asymmetrically (R)-(+)-1-(5-bromopentyl)-1-methyl-7-methoxy-2-tetralone (3a), a key intermediate of dezocine, 17 cinchona alkaloid-derived catalysts were prepared and screened for the enantioselective alkylation of 1-methyl-7-methoxy-2-tetralone with 1,5-dibromopentane, and the best catalyst (C7) was identified. In addition, optimizations of the alkylation were carried out so that the process became practical and effective.

Synthesis of N-substituted imidazo[4,5-e]benzo[1,2-c;3,4-c’]difuroxans

N-Substituted imidazo[4,5-e]benzo[1,2-c;3,4-c’]difuroxans were synthesized by phase-transfer catalyzed alkylation of imidazo[4,5-e]benzo[1,2-c;3,4-c’]difuroxan salts with various alkylating agents. Acid hydrolysis of N-(ethoxycarbonylmethyl)imidazo[4,5-e]benzo-[1,2-c;3,4-c’]difuroxans gives the corresponding carboxylic acids. Structures of the synthesized compounds were confirmed by NMR spectroscopy, high resolution mass spectrometry, IR spectroscopy, and elemental anslysis.

A rapid and highly enantioselective C-11C bond formation of l-[11C]phenylalanine via chiral phase-transfer catalysis.

A rapid method for the synthesis of carbon-11 radiolabeled phenylalanine was developed using a chiral phase-transfer catalyst and a sub-nanomolar quantity of [11C]benzyl iodide as a radio-precursor. Based on a reported synthesis of [11C]benzyl iodide, a Schiff base precursor was evaluated for stereoselective [11C]benzylation. Extensive and interactive screening of the precursor, catalyst, base, stirring and temperature was required to achieve high stereoinduction. The result is an efficient 5-step radiolabeling method to reliably synthesize l- or d-[11C]phenylalanine with an excellent enantiomeric excess of >90% and almost quantitative radiochemical conversion of >95% (n > 5). Additionally, a phase-transfer catalyzed alkylation was utilized on the preparative scale using automated platform. The application resulted in high specific activity ranging from 85-135 GBq μmol-1 of the enantiomerically pure [11C]phenylalanine, showing that the process is robust and amenable to broad use in PET.

A comprehensive theoretical investigation of the transition states and a proposed kinetic model for the cinchoninium ion asymmetric phase-transfer catalyzed alkylation reaction

The discovered that the cinchoninium ion could promote a highly enantioselective alkylation of an indanone enolate via phase-transfer catalysis was a breakthrough in the area asymmetric organocatalysis. However, only recently the mechanism of asymmetric induction was unraveled by theoretical calculations. It was found the process takes place through cooperative catalysis with a key role of the cinchoninum hydroxyl group. In this work, we have done a more detailed investigation of the possible transition states, reporting twenty-four structures. More reliable calculations at MP2 level was applied to the most important species and we have observed that dispersion forces play a very important role to selectively stabilize the critical transition state leading to the main enantiomer. The possible partition equilibria of several species have also been considered and a kinetic model was proposed. We have found the formation of a dimer of the cinchoninium ion takes place and this behavior leads to fractional kinetic order in the catalyst concentration. The theoretical overall kinetics is in very good agreement with the experimental data, with an effective activation free energy barrier deviating by only 1.2kcalmol−1 from the experimentally observed value. This study provides a very detailed picture at molecular level for this reaction system at first time.

Application of asymmetric alkylation of malonic diester with phase-transfer catalysis: synthesis of LFA-1 antagonist BIRT-377

An efficient asymmetric synthesis of LFA-1 antagonist BIRT-377 using enantioselective phase-transfer catalytic alkylation has been developed. The alkylation of α-monosubstituted tert-butyl methyl malonate was catalyzed by a quaternary ammonium salt derived from a cinchona alkaloid to obtain the product with a quaternary stereogenic carbon in high yield and with high enantioselectivity. The chiral α,α-disubstituted product thus obtained was transformed into BIRT-377 through alternating chemoselective deprotection of the two ester groups followed by Curtius rearrangement.

Asymmetric synthesis and evaluation of α-quaternary chiral lactam derivatives as novel anticancer agents

Asymmetric synthesis of α-quaternary chiral lactam derivatives as novel anticancer agents and evaluation of their cytotoxic potentials and spectrums are reported. Among the developed lactam derivatives, the most active new compounds (S)-4m and (S)-4n synthesized via asymmetric phase-transfer catalytic alkylation in very high optical yields (98% ee) show promising in vitro anticancer activities with low micromolar IC50 values against colon, uterus, lung, and breast human cancer cells.

ChemInform Abstract: Enantioselective Phase‐Transfer Catalytic α‐Alkylation of 2‐Methylbenzyl tert‐Butyl Malonates.

A new asymmetric synthetic method to prepare α,α-dialkylmalonates for the construction of a quaternary carbon center via phase-transfer catalytic (PTC) alkylation has been developed. Enantioselective α-alkylation of 2-methylbenzyl tert-butyl α-methylmalonates under phase-transfer catalytic conditions in the presence of (S,S)-3,4,5-trifluorophenyl-NAS bromide (10) afforded the corresponding α,α-dialkylmalonates in high chemical (up to 99%) and optical yields (up to 91% ee), which were selectively hydrolyzed to malonic monoacids under alkali basic conditions for conversion to versatile chiral intermediates.

Enantioselective phase-transfer catalytic α-alkylation of 2-methylbenzyl tert-butyl malonates

A new asymmetric synthetic method to prepare α,α-dialkylmalonates for the construction of a quaternary carbon center via phase-transfer catalytic (PTC) alkylation has been developed. Enantioselective α-alkylation of 2-methylbenzyl 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 chemical (up to 99%) and optical yields (up to 91% ee), which were selectively hydrolyzed to malonic monoacids under alkali basic conditions for conversion to versatile chiral intermediates.

Stereoselective synthesis of cyclic amino acidsvia asymmetric phase-transfer catalytic alkylation

An asymmetric synthesis of cyclic amino acids having piperidine and azepane core structures was realized starting from readily available glycine and alanine esters by combination of phase-transfer catalyzed asymmetric alkylation and subsequent reductive amination.

Highly enantioselective synthesis of 5-phenyl-2-alkylprolines using phase-transfer catalytic alkylation

An efficient enantioselective synthetic method for the synthesis of (2R)-5-phenyl-2-alkylproline tert-butyl esters was reported. The phase-transfer catalytic alkylation of tert-butyl-5-phenyl-3,4-dihydro-2H-pyrrole-2-carboxylate in the presence of chiral quaternary ammonium catalysts gave the corresponding alkylated products (up to 97% ee). The following diastereoselective reductions afforded chiral 5-phenyl-2-alkylprolines which can be applied to asymmetric synthesis as organocatalysts or synthesis of biologically active proline based compounds, such as chiral α-alkylated analogues of (+)-RP66803, as potential CCK antagonists.

One-Pot Enantioselective Synthesis of Tryptophan Derivatives via Phase-Transfer Catalytic Alkylation of Glycine Using a Cinchona-Derived Catalyst

Tryptophans are building blocks for many natural products. This paper describes the enantiospecific synthesis of ring-A substituted tryptophan derivatives from commercially available gramines using chiral phase-transfer conditions. This one-pot reaction avoids protecting/deprotecting the indolylic nitrogen of gramine by choosing a chemoselective quaternization reagent, 4-(trifluoro-methoxy)benzyl bromide, to produce an electrophilic salt intermediate, which is subsequently alkylated in good yield with high enantiomeric excess.

BOTPPI, a new Wittig salt for the synthesis of 12-(S)-hydroxy-eicosatetraenoic acid [12-(S)-HETE

An efficient route to (Z)-(8-benzyloxy-8-oxooct-3-en-1-yl)triphenylphosphonium iodide, or BOTPPI, is disclosed, complete with full experimental details, NMR spectra, and HRMS data. BOTPPI serves as a surrogate for (Z)-(8-methoxy-8-oxooct-3-en-1-yl)triphenylphosphonium iodide, or MOTPPI, a Wittig salt previously used in two 12-HETE syntheses. BOTPPI has the advantage over MOTPPI of being derived from a sequence for which every intermediate is UV-active and amenable to large-scale chromatographic purification. A formal asymmetric total synthesis of 12-(S)-HETE is also reported, involving a stereoselective phase-transfer catalyzed (PTC) alkylation in its key step.

Highly Enantioselective Total Synthesis of (+)-Isonitramine

A new efficient enantioselective synthetic method of (+)-isonitramine is reported. (+)-Isonitramine was obtained in 12 steps (98% ee and 43% overall yield) from δ-valerolactam via enantioselective phase-transfer catalytic alkylation, Dieckman condensation, and diastereoselective reduction as key steps.

Asymmetric Alkylation of Malonic Diester Under Phase-Transfer Conditions

An enantioselective phase-transfer catalytic alkylation of α-monosubstituted malonic diester has been developed. The alkylation of α-monosubstituted tert-butyl methyl malonate in the presence of N-(9-anthracenylmethyl)cinchoninium chloride afforded α,α-disubstituted products in high yields and with high enantioselectivities. Moreover, a successful gram-scale (10 mmol) experiment using the cinchona catalyst indicates the potential for practical applications of this methodology. To demonstrate the utility of this method, product with a quaternary chiral carbon was converted to both (R)- and (S)-α,α-dialkylated amino acids through alternative chemoselective transformation of the two ester groups.

Highly Enantioselective Synthesis of α,α-Dialkylmalonates by Phase-Transfer Catalytic Desymmetrization

A novel enantioselective synthetic method for the construction of a quaternary carbon center from malonates via phase-transfer catalytic (PTC) alkylation has been developed. The asymmetric α-alkylation of diphenylmethyl tert-butyl α-alkylmalonates with alkylating agents under phase-transfer catalysis conditions (aq 50% KOH, toluene, 0 °C) in the presence of (S,S)-3,4,5-trifluorophenyl-NAS bromide (8) as PTC catalyst afforded the corresponding α,α-dialkylmalonates in high chemical (up to 99%) and optical yields (up to 97% ee) which could be readily converted to versatile chiral intermediates. Notably, the direct double α-alkylations of diphenylmethyl tert-butyl malonate also provided the corresponding α,α-dialkylmalonates without loss of enantioselectivity. The synthetic potential of this method has been demonstrated by the preparation of α,α-dialkylamino acid and oxindole systems.

New synthetic route to N-tocopherol derivatives: synthesis of pyrrolopyridinol analogue of α-tocopherol from pyridoxine

A new synthetic route to pyrrolopyridinol antioxidants from easily accessible pyridoxine was developed which includes phase-transfer catalytic alkylation and intramolecular Cu(I)-catalyzed amination as key steps.

Synthesis of (−)-Paroxetine via Enantioselective Phase-Transfer Catalytic Monoalkylation of Malonamide Ester

A new enantioselective synthetic method of (-)-paroxetine is reported. (-)-Paroxetine could be obtained in 15 steps (95% ee and 9.1% overall yield) from N,N-bis(p-methoxyphenyl)malonamide tert-butyl ester via the enantioselective phase-transfer catalytic alkylation and the diastereoselective Michael addition as the key steps.

Solid-phase synthesis of α-alkylserines via phase-transfer catalytic alkylation of polymer-supported 2-phenyl-2-oxazoline-4-carboxylate

Described is the development of a new solid-phase synthetic method for α-alkylserines in which phase-transfer catalytic alkylation of polymer-supported 2-phenyl-2-oxazoline-4-carboxylate ( 12) is the key step. The easy preparation of the polymer-supported substrate 12, the high chemical yield (up to 93%), and the mild cleavage conditions could make this method very practical for the synthesis of α-alkylserines.

Highly Enantioselective Synthesis of (S)-α-Alkyl-α,β-diaminopropionic Acids via Asymmetric Phase-Transfer Catalytic Alkylation of 2-Phenyl-2-imidazoline-4-carboxylic Acidtert-Butyl Esters

An efficient enantioselective synthetic method for (S)-alpha-alkyl-alpha,beta-diaminopropionic acid is reported. The asymmetric phase-transfer catalytic alkylation of N(1)-Boc-2-phenyl-2-imidazoline-4-carboxylic acid tert -butyl ester in the presence of chiral quaternary ammonium catalyst gave the corresponding alkylated products (93-98% ee) which could be transformed to enantioenriched alpha-alkyl-alpha,beta-diaminopropionic acids.