Enantioselective syntheses of α-phenylalkanamines via intermediate addition of Grignard reagents to chiral hydrazones derived from (R)-(−)-2-aminobutan-1-ol

The hydrazine (R)-(−)-28 was obtained in four steps from 2-aminobutan-1-ol (R)-(−)-11, and reacted with benzaldehyde to give the hydrazone (R)-(−)-29. Nucleophilic addition of various alkyl Grignard reagents to the latter yielded the corresponding trisubstituted hydrazines (R,R)-30a–g in 70–89% yields and having d.e.s=100% (¹H and ¹³C NMR). Catalytic hydrogenolysis of these hydrazines afforded the corresponding (R)-(+)-α-phenylalkanamines (R)-(+)-31a–g having e.e.s=90–92% (chiral GPC).     

Synthesis of versatile chiral intermediates by enantioselective conjugate addition of alkenyl Grignard reagents to enamides deriving from (R)-(−)- or (S)-(+)-2-aminobutan-1-ol

Conjugate addition of but-3-enylmagnesium bromide to the chiral crotonamide (R)-(+)- and (S)-(−)-3, followed by hydrolysis and oxidation, afforded enantiopure (R)-(+)- and (S)-(−)-3-methyladipic acids 8, respectively. Conjugate addition of vinylmagnesium chloride to the chiral crotonamide and cinnamamides (R)-(+)-3–5, followed by hydrolysis, gave the alkenoic acids (S)-12–14, respectively. Iodolactonization of the latter led to the 5-iodomethyllactones (+)-15–17, which were reduced by means of n-Bu₃SnH into the trans-disubstituted 5-methyllactones (+)-19–21, respectively. Treatment of the iodomethyllactone (+)-16 with LiMe₂Cu or n-Bu₂CuLi furnished the trans-5-alkyl-4-phenyllactones (−)-22 or (+)-23.     

Diastereoselective LiAlH4 reduction of chiral ketone hydrazones derived from (R)-(–)-2-aminobutan-1-ol

Various chiral N,N-dialkylhydrazines were prepared in four to five steps from (R)-(–)-2-aminobutan-1-ol 6. They reacted with various prochiral ketones, thus giving the corresponding hydrazones. Reduction of the latter by means of LiAlH₄ afforded N,N,N′-trisubstituted hydrazines whose d.e.s were in the range 43–100%. Interestingly, LiAlH₄ reduction of the four N-trifluoroethylhydrazones 34 and 38–40 yielded the hydrazines 46 and 48–50, respectively, and with d.e.s=100% by ¹H and ¹³C NMR.     

Highly enantioselective Cu(I)-Tol-BINAP-catalyzed asymmetric conjugate addition of Grignard reagents to α,β-unsaturated esters

The copper-catalyzed conjugate addition (CA) of organometallic reagents to α,β-unsaturated carbonyl compounds is one of the most versatile synthetic methods for the construction of C-C bonds. Interestingly, the application of Grignard reagents, which are among the most widely used of organometallic compounds, in asymmetric conjugate addition (CA) reactions has received less attention. Therefore, our group and others have been exploring better catalytic systems to effect the asymmetric 1,4-conjugate addition of Grignard reagents to α,β-unsaturated esters. It is only in the past decade that significant breakthroughs have been made in this field. In our studies, we found that CuI-Tol-BINAP could catalyze the asymmetric conjugate addition (CA) reactions of Grignard reagents, including the addition of MeMgBr to α,β-unsaturated esters to afford the β-methylated esters in good yields with excellent regio- and enantioselectivities. Both enantiomers of the products could be obtained by either using the enantiomers of the chiral Tol-BINAP or by using the geometrical isomer of the starting material. This method is also suitable for other Michael acceptors. In this article, we describe the development of the asymmetric Cu(I)-Tol-BINAP catalyzed 1,4-conjugate addition of Grignard reagents to α,β-unsaturated esters and applications of this chemistry. This method provides a convenient method to synthesize β-alkyl esters with high enantioselectivity or diastereoselectivity using CuI and the inexpensive chiral ligand, Tol-BINAP.     

Totally stereocontrolled synthesis of α,β-diamino acids by addition of Grignard reagents to nitrones derived from l-serine

The asymmetric synthesis of protected (2R,3S)- and (2R,3R)-3-substituted 2,3-α-amino acids is reported. The key step in the synthesis of these compounds is the diastereoselective addition of Grignard reagents to α-amino nitrones derived from l-serine. Total stereocontrol of the addition step is achieved by changing the protecting groups in the starting material. The predominant selectivity in each case can be reasonably interpreted in terms of steric effects of the substituents.     

New chiral 1,4-aminoalcohols derived from (+)-camphor and (−)-fenchone for the enantioselective addition of diethylzinc to aldehyde

Various optically active 1,4-aminoalcohols were synthesized from (+)-camphor and (−)-fenchone. The aminoalcohols 5 or 6-mediated enantioselective addition reactions of diethylzinc to benzaldehyde resulted in the formation of the optically active secondary alcohol in good yield. When the catalyst derived from (+)-camphor was used, the (S)-alcohol was obtained in high ee, while the (R)-alcohol was obtained in the reaction with the catalyst derived from (−)-fenchone.     

Regio- and diastereoselective conjugate addition of Grignard reagents to aryl substituted α,β-unsaturated carbonyl compounds derived from Oppolzer's sultam

Asymmetric conjugate addition of Grignard reagents to aryl substituted α,β-unsaturated carbonyl compounds (1) has been achieved with great regioselectivity (>20:1) and good to excellent diastereoselectivity (de up to 98%). The nucleophilicity and stereospecific blockade of the Grignard reagents play a key role in controlling the regioselectivities and diastereoselectivities of the conjugate addition reaction.     

Cerium(III) chloride promoted addition of organometallic reagents to (−)-menthone—preparation of chiral neomenthyl derivatives

The activation of (−)-menthone with anhydrous CeCl₃ led to high yielding additions of different organometallic reagents. Products of exclusively equatorial-addition of the reagents were obtained; only PhMgBr yielded additionally ca. 5% of the axial-addition product.     

Access to chiral α-bromo and α-H-substituted tertiary allylic alcohols via copper(I) catalyzed 1,2-addition of Grignard reagents to enones

The catalytic asymmetric synthesis of tertiary alcohols by the addition of organometallic reagents to ketones is of central importance in organic chemistry. The resulting quaternary stereocentres are difficult to prepare selectively by other means despite their widespread occurrence in natural products and pharmaceuticals. Here we report on a new methodology which allows access to both α-bromo-substituted and α-H-substituted allylic tertiary alcohols with excellent yields, and enantioselectivities of up to 98% using the copper(I)-catalysed 1,2-addition of Grignard reagents to enones. As an example, the methodology is applied in the synthesis of a chiral dihydrofuran.     

Synthesis of new homochiral 2,3-dialkylpiperazines derived from (R)-(−)-phenylglycinol

The synthesis of four new 2,3-dialkylpiperazines in yields of 70–99% using (R)-(−)-phenylglycinol as a chiral inductor is described. The synthesis involved reduction of the oxazino–oxazine type derivatives obtained by condensation of glyoxal and phenylglycinol to give hydroxyethylenediamine precursors which were further condensed with glyoxal, butanedione and 1-phenyl-1,2-propanedione and then reduced to provide the corresponding piperazines. The stereochemical outcome is determined by the configuration of the bisoxazolidine precursors, which is in turn dictated by steric effects exerted by the substituents on the five membered ring. The structures of five derivatives were established by X-ray analysis.     

Diastereoselective nucleophilic addition to chiral open-chain α-ketoacetals: Synthesis of (R)- and (S)-mevalolactone

Highly stereoselective addition of Grignard reagents to chiral open-chain α,-ketoacetals ($\text{3a}$,$\text{3b}$) has been attained. Application of the reaction to syntheses of the key intermediates ($\text{6}$,$\text{8}$) for (R)- and (S)-mevalolactone is also described.     

Stereoselective addition of Grignard reagents to (2-methyl-5-tert-butyl)phenyl 1-thio-β-D-ribopentodialdo-1,4-furanoside derivative

Addition of a wide range of Grignard reagents to acetone protected (2-methyl-5-tert-butyl)phenyl 1-thio-β-D-ribopentodialdo-1,4-furanoside 3b produced useful 5(R)C-substituted products with moderate to good yields, and moderate to perfect stereoselectivities, with no need of additives. n.O.e. Analysis of 3b showed that 1-S-aryl group could contribute to the stereoselectivity of addition reaction. The stereochemistry of 4 representative 5-C-substituted ribofuranoside products was further confirmed by NMR study of corresponding Mosher esters, by chemical derivatization, or by single crystal study.     

A diastereo- and enantioselective Michael addition of chiral amide enolates to α, β-unsaturated esters a stereoelective synthesis of (+)-dehydroiridodiol and (−)-isodehydroiridodiol

(+)-Dehydroiridodiol and (−)-isodehydroiridodiol were synthesized stereoselectively using the diastereo- and enantioselective Michael addition of chiral amide enolates to α, β-unsaturated esters.     

Asymmetric syntheses of α-amino acids via double chiral induction in alkylation of the ketimine derived from 2-hydroxypinan-3-one and menthyl glycinate

Asymmetric syntheses of (S)-α-amino acids in 28--98% optical yields via doublechiral induction in alkylations of ketimine 1 derived from (+)-2-hydroxypinan-3-one and (-)-men-thyl glycinate which is a chiral match pair have been studied. The factors controlling the diastereoselec-tivities in alkylation reactions of the ketimine, the properties of alkylating agents and various alkylationconditions are examined.     

Chiral β- and γ-aminoalcohols derived from (+)-camphor and (−)-fenchone as catalysts for the enantioselective addition of diethylzinc to benzaldehyde

The addition of Me₃SiCN and LiCH₂CN to (+)-camphor and (−)-fenchone, respectively, followed by reduction leads to chiral β- and γ-aminoalcohols. The enantioselectivities realized using these aminoalcohols as ligands in the addition of Et₂Zn to benzaldehyde were lower than those obtained using the corresponding δ-aminoalcohols.     

Enantioselective addition of diethylzinc to aldehydes catalyzed by a new chiral β-amino alcohol derived from d-mannitol

A new chiral β-dialkylamino alcohol 1 prepared from d-mannitol has been used as a highly effective chiral catalyst for the enantioselective addition of diethylzinc to unhindered aliphatic aldehydes to afford the product alcohols in up to 94% ee.     

Design of chiral bis-phosphoric acid catalyst derived from (R)-3,3'-di(2-hydroxy-3-arylphenyl)binaphthol: catalytic enantioselective Diels-Alder reaction of α,β-unsaturated aldehydes with amidodienes

Chiral bis-phosphoric acid 1 was designed to identify a new class of structural features in chiral Br?nsted acid catalysts. X-ray diffraction analysis revealed the single atropisomer 1, bearing S axial chirality at 3,3'-biaryl substituents on (R)-binaphthyl and intramolecular hydrogen bonding between the two phosphoric acid moieties. The newly designed bis-phosphoric acid 1 was evaluated in the Diels-Alder reaction of α,β-unsaturated aldehydes 4 with 1-N-acylamino-1,3-butadienes 3. After systematic variation of the catalyst substituents, as well as the N-acyl substituents of 1,3-butadiene, the use of an N-Cbz amidodiene 3a in the presence of bis-phosphoric acid 1e with a 2,4,6-tri-isopropylphenyl group was found to be optimal to yield the 1S,6R enantiomeric product 5aa in a Diels-Alder reaction of acrolein (4a). Application of this method to substituted substrates was found to be an efficient approach to the enantioselective synthesis of 3- and 3,6-substituted cyclic formylcarbamates 5. The specific character as well as the utility of 1e was further established by comparing its enantioselectivity, absolute stereochemistry, and catalytic efficiency with those of mono-phosphoric acid 2.     

Copper-catalyzed enantioselective 1,4-conjugate addition of dialkylzinc reagents to α,β- and α,β,γ,δ-unsaturated ketones

An enantioselective Cu(II)-catalyzed conjugate addition of dialkylzinc reagents to α,β- or α,β,γ,δ-unsaturated ketones with chiral cyclohexane-based amidophosphine ligands was developed. With 2 mol% of Cu(OAc)₂·H₂O/L5, the conjugate addition of diethylzinc to α,β-unsaturated ketones was achieved in good-to-excellent yields (up to 98%) and high enantioselectivities (up to 92% ee). This catalytic system was shown to be efficient for the 1,4-conjugate addition of Et₂Zn to (2E,4E)-1,5-diphenylpenta-2,4-dien-1-one with 85% yield and 90% ee. Moreover, with 1 mol% of Cu(OTf)₂/L11, the conjugate addition of α,β,γ,δ-unsaturated ketones was accomplished with 1,4-regioselectivity, good yields (79–86%) and excellent enantioselectivities (up to 97% ee).     

Enantioselective total and formal syntheses of paroxetine (PAXIL) via phosphine-catalyzed enone α-arylation using arylbismuth(V) reagents: a regiochemical complement to Heck arylation

Exposure of dihydropyridinone 1 to the arylbismuth(V) reagent (p-F-Ph)₃BiCl₂ in the presence of substoichiometric quantities of tributylphosphine (10 mol %) results in aryl transfer to the transiently generated (β-phosphonio)enolate to provide the α-arylated enone 2. This transformation, which represents a regiochemical complement to the Mizoroki-Heck arylation, is used strategically in concise formal and enantioselective total syntheses of the blockbuster antidepressant (−)-paroxetine (PAXIL).