Christian T. Goralski

Asymmetric addition of diethylzinc to aldehydes catalyzed by β-amino alcohols derived from limonene oxide

A series of β-amino alcohols, conveniently prepared from limonene oxide, were evaluated as catalysts for the enantioselective addition of dialkylzinc to benzaldehyde. These limonene-based amino alcohols are of particular interest because they are easily synthesized in both enantiomeric forms. Ethylation of benzaldehyde using diethylzinc and catalyzed by limonene derived amino alcohols proceeded with enantioselection of up to 87% ee. This is an unusually high level of induction for amino alcohols possessing a trans relationship between the amino and alcohol functionalities. Both enantiomers of 1-phenyl-1-propanol can be synthesized with equal control since both enantiomers of the chiral catalyst are readily available. When (1S,2S,4R)-limonene amino alcohols are used as chiral catalysts, (R)-1-phenyl-1-propanol is obtained as the major product. A plausible mechanism is proposed to explain the facial selectivity determining the asymmetric induction observed in these reactions.

A facile and efficient method for the kinetic separation of commercially available cis- and trans-limonene epoxide

Abstract cis- and trans-Diastereomers of (R)-(+)-limonene oxide can be purified by simple kinetic separation of the commercially available (1:1) diastereomeric mixture of limonene oxides. Nucleophilic amines, such as pyrrolidine and piperidine, selectively open the epoxide ring of the trans-isomer, leaving the cis-limonene oxide largely unreacted. The unreacted cis-(R)-limonene oxide is recovered in up to 88% yield. On the other hand, less nucleophilic amines, such as triazole or pyrazole, selectively catalyze hydrolysis of the cis-limonene oxide to 1,2-limonene diol leaving the trans-limonene oxide largely unreacted. The unreacted trans-limonene oxide is recovered in up to 80% of the theoretical yield by a simple workup procedure. The cis- and trans-diastereomers of (R)-(+)-limonene oxide thus isolated were found to be >98% pure by both GC and NMR analyses. Thus, depending on the choice of amine, either cis- or trans-limonene oxide may be obtained in high diastereomeric purity by this simple and environmentally friendly method.

A simple and convenient synthesis of β-amino alcohol chiral auxiliaries based on limonene oxide

Abstract A series of chiral β-amino alcohols was prepared by the reaction of secondary amines with a 1:1 mixture of cis - and trans -limonene oxide in the presence of water as a catalyst. The β-amino alcohol obtained was derived from the trans -limonene oxide, and the unreacted cis -limonene oxide was recovered from the reaction mixture. The β-amino alcohols are useful chiral auxiliaries for the addition of diethylzinc to benzaldehyde.

Lithium aminoborohydrides 16. Synthesis and reactions of monomeric and dimeric aminoboranes.

Aminoboranes are synthesized in situ from the reaction of the corresponding lithium aminoborohydrides (LABs) with methyl iodide, trimethylsilylchloride (TMS-Cl), or benzyl chloride under ambient conditions. In hexanes, the reaction using methyl iodide produces aminoborane and methane, whereas in tetrahydro-furan (THF) this reaction produces amine-boranes (R1R2HN:BH3) as the major product. The reaction of iPr-LAB with TMS-Cl or benzyl chloride yields exclusively diisopropylaminoborane [BH2-N(iPr)2] in THF as well as in hexanes at 25 degrees C. Diisopropylaminoborane and dicyclohexylaminoborane exist as monomers due to the steric requirement of the alkyl group. All other aminoboranes studied are not sterically hindered enough to be monomers in solution, but instead exist as a mixture of monomers and dimers. The dimers are four-membered rings formed through boron-nitrogen coordination. In general aminoboranes are not hydroborating reagents. However, monomeric aminoboranes, such as BH2-N(iPr)2, can reduce nitriles in the presence of catalytic amounts of LiBH4. This BH2-N(iPr)2/LiBH4 reducing system also re-duces ketones, aldehydes, and esters. Diisopropylaminoborane, synthesized from iPr-LAB, can be converted into boronic acids by a palladium-catalyzed reaction with aryl bromides. Aminoboranes derived from heterocyclic amines, such as pyrrole, pyrazole, and imidazole, can be prepared by the direct reaction of borane/tetrahydrofuran (BH3:THF) with these heterocyclic amines. It has been reported that pyrazole-derived aminoborane forms a six-membered dimer through boron-nitrogen coordination, where as, pyrrolylborane forms a dimer through boron-hydrogen coordination. Pyrrolylborane monohydroborates both alkenes and alkynes at ambient temperatures. Hydroboration of styrene with pyrrolylborane followed by hydrolysis gives the corresponding boronic acid, 2-phenylethylboronic acid, in 40% yield. Similarly phenylacetylene is mono-hydroborated by pyrrolylborane, to give E-2-phenylethenylboronic acid in 50% yield.

Boranes in synthesis. 2. Asymmetric synthesis of β-amino alcohols. A facile conversion of 2-amino acetophenones to the corresponding β-amino alcohols in high enantiomeric purity

The asymmetric reduction of 2-amino acetophenones with Ipc2BH or Ipc2BCl at −78°C, yields the corresponding β-amino alcohols in good to excellent yields. Although only modest (12–45% ee) enantiomeric excesses were obtained with Ipc2BH, 75–99% enantiomeric excesses were obtained when Ipc2BCl was used as the asymmetric reducing agent.

Aminoborohydrides. 9. Selective reductions of aldehydes, ketones, esters, and epoxides in the presence of a nitrile using Lithium N,N-dialkylaminoborohydrides

Abstract A series of competitive reductions of several functional groups was carried out in the presence of aromatic and aliphatic nitriles using Lithium N,N-dimethylaminoborohydride (LiMe 2 NBH 3 ) or Lithium Pyrrolidinoborohydride (LiPyrrBH 3 ) as the reducing agents. Both LiMe 2 NBH 3 and LiPyrrBH 3 cleanly and quantitatively reduced aldehydes, ketones, esters, and epoxides in the presence of the nitriles to give the corresponding reduction products in yields ranging from 85 to 98%. In no case was the nitrile reduced: no products arising from the reduction of nitriles were detected by GC analysis. Two difunctional nitriles were also reduced to give complete reduction of the more active functional group with no reduction of the nitrile.

Boranes in synthesis — VII. Synthesis of 2-dialkylamino-6,6-dimethylbicyclo[3.1.1]heptan-3-ols from (R)-(+)-nopinone. Chiral auxiliaries for the addition of diethylzinc to aromatic aldehydes

Abstract The reaction of (1 R ,5 S )-(+)-nopinone with secondary amines in cyclohexane with the azeoptropic removal of water afforded excellent yields of the correspondin enamines. Hydroboration of these enamines with BMS followed by methanolysis and oxidation with basic hydrogen peroxide gave the corresponding (1 R ,2 S ,3 S ,5 R )-2-dialkylamino-6,6-dimethylbicyclo[3.1.1]heptan-3-ols. These amino alcohols, in spite of their trans geometry, served as chiral auxiliaries for the addition of diethylzinc to aromatic aldehydes to give nearly quantitative yields of the corresponding ( R )-1-aryl-1-propanols with 52 to 80% ee.

A CONVENIENT SYNTHESIS OF METHYL (Z)-1-CARBAMOYL-2-ETHENYLCYCLOPROPANECARBOXYLATE AND (Z)-1-CARBAMOYL-2-ETHENYLCYCLOPROPANECARBOXYLIC ACID

Abstract A simple method for the preparation of the title compounds via the reaction of dimethyl 2-ethenylcyclopropane-1,1-dicarboxylate with 6M ammonia in methanol is described.

High-performance liquid chromatographic separation of β-amino alcohols II. Separation of trans-2-(dialkylamino)cyclohexanols on an amylose-based chiral stationary phase

Direct enantiomeric separations of racemic mixtures of trans-2-(dialkylamino)cyclohexanols were achieved with a variety of alcohol-modified pentane mobile phases and a Chiralpak AD chiral stationary phase. The effects of the aliphatic component and the alcohol modifier in the mobile phase were studied independently. A variety of alcohol modifiers were investigated that introduced steric factors or affected hydrogen bonding. Ring-size effects of the substituents were noted.

Aminoborohydrides. 5. Reduction of alkylcyclohexanones to the corresponding alcohols with unique steric selectivity

Abstract Lithium aminoborohydrides (LAB), obtained by the reaction of n-butyllithium with amineboranes, are powerful reducing agents for a wide range of functional groups including the carbonyl group of alkylcyclohexanones. Reduction of 2-methylcyclohexanone with LAB reagents shows superior formation of the axial alcohol as compared to sodium borohydride (NaBH4). Reduction of 3- and 4-methylcyclohexanones shows formation of the equatorial alcohol in proportions similar to that obtained with NaBH4. Reduction of 4-tert-butylcyclohexanone leads predominantly to the corresponding cyclohexanol containing an equatorial alcohol group. Unlike NaBH4, LAB reagents are soluble in ether solvents allowing for homogeneous reductions.