Enantioselective alkylation and protonation of prochiral enolates in the asymmetric synthesis of β-amino acids

Achiral 1-benzoyl-3-methylperhydropyrimidin-4-one (1) was deemed a useful, potential precursor for the enantioselective synthesis of α-substituted β-amino acids. Pyrimidinone 1 was prepared from inexpensive β-aminopropanoic acid in 62% overall yield. Prochiral enolate derivative 1 -Li was alkylated in good yield and moderate enantioselectivity in the presence of chiral amines (S)-8, (S,S)-9, (S,S)-10, or (−)-sparteine. The enantioselectivity of the alkylation process is highest in toluene as the solvent and in the presence of lithium bromide as additive. The racemic alkylated derivatives 2 and 3 were readily metallated with LDA to give prochiral enolates 2-Li and 3-Li, that were reprotonated with novel chiral phenolic acids (S)-11, (S,S)-12, (S)-13, and (S,S)-14 in moderate enantioselectivity in the case of 2-Li and good enantioselectivity in the case of 3-Li. The acid (6N HCl) hydrolysis of enantioenriched 2 and 3 proceeded in good yield and without racemization to afford α-alkyl-β-amino acids 4 and 5, respectively.     

New pinene-derived pyridines as bidentate chiral ligands

A synthesis of new bidentate pyridines 8a-d, 9, and 10 has been developed, starting from triflate 14, readily available from β-pinene 11. A copper complex of the pyridine-oxazoline ligands 8a has been found to catalyze asymmetric allylic oxidation of cyclic olefins 36a-c with good conversion rates and acceptable enantioselectivity (≤67% ee). The imidazolium salt 10 has been identified as a precursor of the corresponding N,N′-unsymmetrical N-heterocyclic carbene ligand, whose complex with palladium catalyzed the intramolecular amide enolate α-arylation leading to oxindole 45 in excellent yield but with low enantioselectivity.     

Synthesis of model ring systems related to C10-C18 analogues of the mycalamides/theopederins

Conjugate addition to d-galactose-derived pyranones 8 and 10, with in situ enolate alkylation, or protonation, provides pyranones 11-13 or 16-19. These are related to the C10-C18 fragment of the mycalamides and provide a short entry to C10, C11, C14 and C15 stereocentres. This approach is relevant to introduction of the side-chain and analogues thereof, and allows for variable C14 functionality. Two side-chain analogues, both C14 monomethylated diastereomers, the C14 unsubstituted system and the natural product-related C14 dimethyl functionality are prepared, and C13 epimeric functionality introduced.     

Origin of stereochemistry in Meyers enolate alkylations. Importance of major enolate structure and population in tetrahydrofuran

It was found that in tetrahydrofuran solution, predominance (99.2%) of the highly stabilized Meyers enolate (1,5-dimethylpyrrolidin-2-one lithium enolate (1)) isomer with intramolecular Li-π_CC coordination from the endo-face (Ct-endo) may be responsible for exceedingly high endo-selectivity in Meyers enolate alkylation.     

Chiral diaminophosphine ligands with stable C(aryl)N(amine) axial chirality derived from prolinol

New type chiral ligands 3, which have a chiral carbon center and stable C(aryl)-N(amine) axial chirality, were prepared from chiral prolinol-derived aminophosphine oxide 4. Pd-catalyzed asymmetric allylic alkylation of 1,3-diphenyl-2-propenyl acetate (6) with a dimethyl malonate-BSA-LiOAc system was successfully carried out in the presence of 3d resulting in a good yield with good enantioselectivity (up to 95% ee).     

Macrocyclic vs acyclic derivatives of chiral bis(oxazolines); ligand distortion and enantioselectivity of Pd(II) complexes in catalytic allylic alkylation

Pd(II) complexes of acyclic (1,2;4,5) and macrocyclic (3,6-10) derivatives of 1,5-bis(oxazolines), are tested in the enantioselective allylic alkylation of racemic 1,3-diphenyl-3-acetoxyprop-2-ene (14) by dimethylmalonate anion to allyl malonate derivative 15. Conformation in solution of representative allyl Pd(II) complexes 12 and 13 is studied by 2D NMR and CD spectroscopy. 2D NMR data reveal loss of C₂ symmetry of the ligands in Pd(II)allyl-bis(oxazoline) complexes. CD spectra indicate distortion of the bidentate ligand in the complex and a conformationally forced larger twist between two chromophores in the macrocyclic complex. Only moderate variation of enantioselectivity with the length and ring size of the ligand is observed, and a rationale offered.     

Synthesis of 3-aminoaspartic acid derivatives from glycine precursors

3-Aminoaspartic acid derivatives 3 have been synthesized via stereoselective alkylation of α-acetyloxyglycine Schiff base 2 with the enolate of glycine anion equivalent 1 as a carbon nucleophile in the presence of Pd(OAc)₂ and BINAP at room temperature. High chemical yields and moderate stereoselectivities were observed. The enantiomeric excess of the dl diastereomer can be increased to 95% after a single recrystallization from isopropanol and hexanes.     

Thermodynamic equilibration of dihydropyridone enolates: application to the total synthesis of (+/−)-epiuleine

Following 1,4-reduction of 2-substituted dihydropyridones (1), the requisite ‘kinetic’ enolate can be isomerized upon warming to allow the isolation of the thermodynamic enolate as its vinyl triflate (3). This enolate interconversion is dependent on the dihydropyridone C-2 substituent and can be interpreted in terms of conformational analysis. This novel scaffold (3) opens another avenue for the strategic deployment of dihydropyridones into both natural product synthesis and drug discovery. To this end, this method is highlighted by its use as a key step in a total synthesis of (+/−) epiuleine (14).     

A stereoselective aldol reaction via diisopinocampheyl boron-enolate in preparation of chromane carboxylate with quaternary carbon

A highly stereoselective aldol reaction was observed on chromane carboxylate ester 1 via the corresponding diisopinocampheyl boron-enolate using commercially available (−)-DIP-Cl reagent. The aldol product 2c was obtained in 89% yield with 48 dr and 92% ee. Further studies indicate that stereoselective formation of the enolate and proper chiral ligand on boron are responsible for the exceptional diastereo- and enantioselectivity in the aldol reaction.     

Asymmetric addition of diethylzinc to aromatic aldehydes by chiral ferrocene-based catalysts

A series of chiral C₁- and C₂-symmetric ferrocenyl Schiff bases (1a-c), ferrocenyl aminoalcohols (2a), ferrocenylphosphinamides (2b-c), 1,1′-ferrocenyl-diol (3), and 1,1′-ferrocenyl-disulfonamide (4) were prepared and employed as base catalysts or as ligand for titanium(IV) complexes in the asymmetric addition of diethylzinc to aromatic aldehydes. High enantioselectivity up to almost 100% ee was achieved for the alkylation of benzaldehyde and p-methoxybenzaldehyde with 1 or 3. In contrast, however, the β-aminoalcohol (2a) and phosphinamides (2b and c) that are ubiquitous classes of base catalysts for this reaction proved inefficient in our hands, regardless of the types of substrates or reaction conditions. Comparative studies show that there exist various reaction parameters governing not only chemical yields but also optical yields. These include steric and electronic environment of the substrate, the solvent, the reaction temperature, and the nature of the ferrocene moieties.     

Nitroalkylation and nitroalkenylation reactions of γ-lactone enolates. A facile ring switch from polysubstituted γ-lactones to polysubstituted γ-lactams

Michael addition of lithium enolates of γ-butyrolactone 1 and α-methyl-γ-butyrolactone 1′ to (E)-1-nitropropene 2, (E)-β-nitrostyrene 3 and (E)-2-nitro-1-phenylpropene 4 is described. Reactions of the lithium enolate of 1′ with 2 and 4 occurred with high diasteroselectivity (80 and 92% d.e., respectively). Reactions of the zinc enolate of 1′ with two β-nitroenamines and two methylthio-substituted 1-amino-2-nitro-1,3-dienes were also examined. Catalytic reduction of the nitroalkylated and nitroalkenylated products allowed the achievement of functionalized γ-lactams and/or cyclic hydroxamic acids.     

Convenient preparation of chiral phase-transfer catalysts with conformationally fixed biphenyl core for catalytic asymmetric synthesis of α-alkyl- and α,α-dialkyl-α-amino acids: application to the short asymmetric synthesis of BIRT-377

Chiral phase-transfer catalysts (S)-1a, (S)-1b, and (S)-2 with conformationally fixed biphenyl cores were conveniently prepared from the known, easily available (S)-6,6′-dimethylbiphenyl-2,2′-diol 3 and (S)-4,5,6,4′,5′,6′-hexamethoxybiphenyl-2,2′-dicarboxylic acid 14, respectively, in five steps. The catalysts, (S)-1a and (S)-1b are readily applicable to asymmetric alkylation of N-(diphenylmethylene)glycine tert-butyl ester with excellent enantioselectivity. In particular, catalyst (S)-1b was found to exhibit the unique temperature effect on the enantioselectivity, and asymmetric alkylation of glycine derivatives at room temperature gave higher enantiomeric excess than that at 0 °C. In addition, the catalyst (S)-2 exhibited the high catalytic performance (0.01-1 mol %) in the asymmetric alkylation of N-(diphenylmethylene)glycine tert-butyl ester and N-(p-chlorophenylmethylene)alanine tert-butyl ester compared to the existing chiral phase-transfer catalysts, thereby allowing to realize a general and useful procedure for highly practical enantioselective synthesis of structurally diverse natural and unnatural α-alkyl-α-amino acids as well as α,α-dialkyl-α-amino acids. This approach is successfully applied to the short asymmetric synthesis of cell adhesion BIRT-377.     

Highly efficient ortho-fluoro-dimeric cinchona-derived phase-transfer catalysts

A series of cinchona alkaloid-derived dimeric quaternary ammonium salts were prepared as chiral phase-transfer catalysts by the introduction of various functional groups on the phenyl ligand. Among them, the 2-F-substituted derivative 21 showed the highest enantioselectivity in the alkylation of the glycine anion equivalent 1 (97 to >99% ee).     

Origin of enantioselectivity with heterobidentate sulfide-tertiary amine (sp) ligands in palladium-catalyzed allylic substitution

A series of new chiral heterobidentate sulfide-tertiary amine (sp³) ligands 3a-c, 6 were readily prepared from cheap and easily available (R)-cysteine and l-(+)-methionine. A Pd-catalyzed asymmetric allylic alkylation of 1,3-diphenyl-2-propenyl acetate with dimethyl malonate was used as a model reaction to examine the catalytic efficiencies of these aziridine sulfide ligands, and ligand 3b afforded the enantioselectivity of up to 91% ee. The origin of enantioselectivity for heterobidentate sulfide-tertiary amine (sp³) ligands was first rationalized based on X-ray crystallographic data, and NMR spectroscopic data for relevant intermediate palladium allylic complexes. Our results demonstrated that the sulfur atom was a better π-allyl acceptor than the nitrogen atom for heterobidentate sulfide-tertiary amine (sp³) ligands, and the steric as well electronic properties of the palladium allylic complexes were crucial for the enantioselectivity.     

Highly enantioselective alkylation of glycine methyl and ethyl ester derivatives under phase-transfer conditions: its synthetic advantage

Phase-transfer alkylation of the benzophenone Schiff base of glycine methyl or ethyl ester (2) was found to be catalyzed by 3,4,5-F₃-C₆H₂-NAS-Br [(S,S)-1] with high efficiency and excellent enantioselectivity. This procedure allows facile derivatization of the resulting alkylation products to other synthetically useful chiral building blocks.     

An efficient asymmetric synthesis of Fmoc-l-cyclopentylglycine via diastereoselective alkylation of glycine enolate equivalent

Stereoselective alkylation of the enolate derived from benzyl (2R,3S)-(−)-6-oxo-2,3-diphenyl-4-morpholinecarboxylate (1) with cyclopentyl iodide afforded anti-α-monosubstituted product, benzyl (2R,3S,5S)-(−)-6-oxo-2,3-diphenyl-5-cyclopentyl-4-morpholinecarboxylate (3) in 60% yield. Catalytic hydrogenolysis over PdCl₂ cleaved the auxiliary ring system to give l-cyclopentylglycine (4) in 84% yield. Subsequent protection of the α-amino function with Fmoc-OSu gave Fmoc-l-cyclopentylglycine (5) in high yield.     

Formation of 3,4-dimethyl-2-pyrones from allene carboxylates and 2-silyloxydienes via 3-carboethoxyethylidene cyclobutanols

The 3-carboethoxyethylidene cyclobutanols 4 are prepared in two steps via [2+2] cycloaddition of the 2-silyloxydienes 1 and the allene carboxylate 2 followed by acidic hydrolysis. Treatment of these cyclobutanols 4 with various bases affords good yields of the substituted 3,4-dimethyl-2-pyrones 6. The proposed mechanism involves ring opening of the metal alkoxide 7 to give the carbanion 8, which undergoes proton transfer to give the more stable carbanion 9 and double bond isomerization to give the enolate 10, which then forms the pyrone ring 6 via attack on the ester via 11.     

Malonate-type bis(oxazoline) ligands with sp hybridized bridge carbon: synthesis and application in Friedel-Crafts alkylation and allylic alkylation

A series of simple and new C₂-symmetric diphenylmethylidene malonate-type bis(oxazoline) ligands were synthesized and applied to the Friedel-Crafts reaction and allylic alkylation. The Cu(II) complex of ligand 4b bearing the benzyl group afforded good to excellent enantioselectivity for the F-C adducts (up to >99% ee) between indole and alkylidene malonate, and the palladium complex of ligand 4c bearing the phenyl group afforded excellent enantioselectivity (up to 94% ee) for the allylic alkylation product.     

Enantioselective Diels-Alder reactions of α-fluorinated α,β-unsaturated carbonyl compounds : Part 5. Chemical consequences of fluorine substitution

α-Fluoro-α,β-unsaturated carbonyl compounds, compared with the corresponding non-fluorinated parent compounds, are less reactive in Diels-Alder reactions with normal 1,3-dienes. The cycloadducts of such dienophiles with 2,3-dimethylbutadiene (1) or o-quinodimethane (6) exhibit low stability whereas the corresponding cycloaddducts formed with cyclopentadiene (7) are stable compounds. While the cycloadditions of oct-1-en-3-one (2e) or benzyl acrylate (10b) with 7 are endo-selective, the corresponding reactions with 2-fluorooct-1-en-3-one (2a) or benzyl 2-fluoroacrylate (10a) are exo-selective. Applying Lewis acids as mediators, the reactions with non-fluorinated dienophiles become even more endo-selective, while the corresponding reactions with the fluorinated analogues become more exo-selective. Using enantiopure Lewis acidic metal complexes such as titanium TADDOLates, low enantioselectivity is observed in reactions of 7 with 2e or 10b. Moderate enantioselectivity (max. 43% enantiomeric excesses (ee)) is found in the corresponding cycloadditions of 7 with 2a, whereas 10a shows practically no enantioselectivity. The more efficient chiral induction in reactions with the fluorinated dienophile 2a might be caused by a chelate-like complexation of the carbonyl compound involving the fluorine substituent.     

Dendritic BINOL ligands for asymmetric catalysis: effect of the linking positions and generations of the dendritic wedges on catalyst properties

Three types of new chiral BINOL ligands (2, 3 and 4) bearing dendritic wedges have been synthesized through coupling reaction between 3-hydroxymethyl-2,2′-bis(methoxymethyl)-1,1′-binaphthol (7), 6,6′-dihydroxymethyl-2,2′-bis(methoxymethyl)-1,1′-binaphthol (12), 6-hydroxymethyl-2,2′-bis(methoxymethyl)-1,1′-binaphthol (15) and Fréchet-type polyether dendritic benzyl bromide, followed by deprotection of methoxymethyl groups by ⁱPrOH/HCl, respectively. These new ligands obtained were assessed in enantioselective Lewis acid-catalyzed addition of diethylzinc to benzaldehyde. Compared to the enantioselectivity observed with dendrimer 1 bearing the dendritic wedges at 3,3′-positions of the binaphthyl backbone, higher enantioselectivity for all these ligands was observed. Difference in the effect of linking positions and generations on enantioselectivity and/or activity for all three kinds of dendritic ligand-derived catalysts was observed. Among these dendritic ligands, (R)-3/Ti(IV) catalyst with the dendritic wedges at 6,6′-positions of BINOL gave the highest enantioselectivity (up to 87% ee).