Optical amines

It has been shown that [NP(0C6H4C02H-4)2] forms a predominantly one-handed helical conformation in solution, when complexed to the optical amine (R)-l-phenylethylamine. Spectroscopic and solution properties of phos-phazene copolymers with phenoxy and optically active binaphthoxy side groups have been investigated. ... 

Bloembergen N t965 Noniinear Optics (New York Ben]amin)... 

Acetophenone similarly gives an oxime, CHjCCgHjlCtNOH, of m.p. 59° owing to its lower m.p. and its greater solubility in most liquids, it is not as suitable as the phenylhydrazone for characterising the ketone. Its chief use is for the preparation of 1-phenyl-ethylamine, CHjCCgHslCHNHj, which can be readily obtained by the reduction of the oxime or by the Leuckart reaction (p. 223), and which can then be resolved by d-tartaric acid and /-malic acid into optically active forms. The optically active amine is frequently used in turn for the resolution of racemic acids. 

Triflates of phenols are carbonylated to form aromatic esters by using PhjP[328]. The reaction is 500 times faster if dppp is used[329]. This reaction is a good preparative method for benzoates from phenols and naphthoates (473) from naphthols. Carbonylation of the bis-triflate of axially chiral 1,1 -binaphthyl-2,2 -diol (474) using dppp was claimed to give the monocarboxy-late 475(330]. However, the optically pure dicarboxylate 476 is obtained under similar conditions[331]. The use of 4.4 equiv. of a hindered amine (ethyldiisopropylamine) is crucial for the dicarbonylation. The use of more or less than 4.4 equiv. of the amine gives the monoester 475. 

The carbonyiation of o-diiodobenzene with a primary amine affords the phthalimide 501 [355,356]. Carbonyiation of iodobenzene in the presence of (9-diaminobenzene (502) and DBU or 2,6-lutidine affords 2-phenylbenzimida-zole (503)[357, The carbonyiation of aryl iodides in the presence of pentaflnor-oaniline affords 2-arylbenzoxazoles directly, 2-Arylbenzoxazole is prepared indirectly by the carbonyiation of (9-aminophenol[358j. The optically active aryl or alkenyl oxazolinc 505 is prepared by the carbonyiation of the aryl or enol triflates in the presence of the opticaly active amino alcohol 504, followed by treatment with thionyl chloride[359]. 

Phosphorus is m the same group of the periodic table as nitrogen and tricoordi nate phosphorus compounds (phosphines) like amines are trigonal pyramidal Phos phmes however undergo pyramidal inversion much more slowly than amines and a number of optically active phosphines have been prepared... 

Isolates from Indian tobacco Q obelia inflata L.), as a cmde mixture of bases, have been recognized as expectorants. The same (or similar) fractions were also used both in the treatment of asthma and as emetics. The principal alkaloid in T. inflata is lobeline (49), an optically active tertiary amine which, unusual among alkaloids, is reported to readily undergo mutarotation, a process normally associated with sugars. Interestingly, it appears that the aryl-bearing side chains in (49) are derived from phenylalanine (25, R = H) (40). 

Secondary amines having one oi two chiral groups attached to the nitrogen atom are prepared from boronic esters by their conversion into alkyldichlotobotanes, followed by treatment with organic azides (518). The second chiral group can be derived from an optically active azide. 

When additional substituents ate bonded to other ahcycHc carbons, geometric isomers result. Table 2 fists primary (1°), secondary (2°), and tertiary (3°) amine derivatives of cyclohexane and includes CAS Registry Numbers for cis and trans isomers of the 2-, 3-, and 4-methylcyclohexylamines in addition to identification of the isomer mixtures usually sold commercially. For the 1,2- and 1,3-isomers, the racemic mixture of optical isomers is specified ultimate identification by CAS Registry Number is fisted for the (+) and (—) enantiomers of /n t-2-methylcyclohexylamine. The 1,4-isomer has a plane of symmetry and hence no chiral centers and no stereoisomers. The methylcyclohexylamine geometric isomers have different physical properties and are interconvertible by dehydrogenation—hydrogenation through the imine. 

P. Newman, Optical Resolution Procedures for Chemical Compounds, Vol. 1 (Amines and Related Compounds), Optical Resolution Information Center, New York, 1978 H. Nohira ia Chemical Society of Japan, eds., Kikan Kagaku Sosetsu (No. 6, Resolution of Optical Isomers), Gakkai Shuppan Senta, Tokyo, Japan, 1989, Chapt. 4, pp. 45—54. 

Because the starting materials were optically active, the products were all pure enantiomers. Later, the synthetic scheme shown in Figure 5 was developed (22,45). Resolution of the racemic mixture was accompHshed at the penultimate stage and the optically active D-threo-amine (7) was converted to florfenicol (2). This synthetic process also resulted in the synthesis of thiamphenicol shown in Figure 6 using 1,1,2,3,3,3-hexafluoropropyl diethylamine (FPA) (46). More recently an improved method of synthesis of florfenicol has been developed (17). 

Sulfonic acids are prone to reduction with iodine [7553-56-2] in the presence of triphenylphosphine [603-35-0] to produce the corresponding iodides. This type of reduction is also facile with alkyl sulfonates (16). Aromatic sulfonic acids may also be reduced electrochemicaHy to give the parent arene. However, sulfonic acids, when reduced with iodine and phosphoms [7723-14-0] produce thiols (qv). Amination of sulfonates has also been reported, in which the carbon—sulfur bond is cleaved (17). Ortho-Hthiation of sulfonic acid lithium salts has proven to be a useful technique for organic syntheses, but has Httie commercial importance. Optically active sulfonates have been used in asymmetric syntheses to selectively O-alkylate alcohols and phenols, typically on a laboratory scale. Aromatic sulfonates are cleaved, ie, desulfonated, by uv radiation to give the parent aromatic compound and a coupling product of the aromatic compound, as shown, where Ar represents an aryl group (18). 

A synthesis of optically active citroneUal uses myrcene (7), which is produced from P-piaene. Reaction of diethylamine with myrcene gives A/,A/-diethylgeranyl- and nerylamines. Treatment of the aHyUc amines with a homogeneous chiral rhodium catalyst causes isomerization and also induces asymmetry to give the chiral enamines, which can be readily hydrolyzed to (+)-citroneUal (151). 

Retention and stereoselectivity on the BSA columns can be changed by the use of additives to the aqueous mobile phase (30). Hydrophobic compounds generally are highly retained on the BSA, and a mobile-phase modifier such as 1-propanol can be added to obtain reasonable retention times. The retention and optical resolution of charged solutes such as carboxyUc acids or amines can be controlled by pH and ionic strength of the mobile phase. 

Resolution of Racemic Amines and Amino Acids. Acylases (EC3.5.1.14) are the most commonly used enzymes for the resolution of amino acids. Porcine kidney acylase (PKA) and the fungaly3.spet i//us acylase (AA) are commercially available, inexpensive, and stable. They have broad substrate specificity and hydrolyze a wide spectmm of natural and unnatural A/-acyl amino acids, with exceptionally high enantioselectivity in almost all cases. Moreover, theU enantioselectivity is exceptionally good with most substrates. A general paper on this subject has been pubUshed (106) in which the resolution of over 50 A/-acyl amino acids and analogues is described. Also reported are the stabiUties of the enzymes and the effect of different acyl groups on the rate and selectivity of enzymatic hydrolysis. Some of the substrates that are easily resolved on 10—100 g scale are presented in Figure 4 (106). Lipases are also used for the resolution of A/-acylated amino acids but the rates and optical purities are usually low (107). 

Chirazymes. These are commercially available enzymes e.g. lipases, esterases, that can be used for the preparation of a variety of optically active carboxylic acids, alcohols and amines. They can cause regio and stereospecific hydrolysis and do not require cofactors. Some can be used also for esterification or transesterification in neat organic solvents. The proteases, amidases and oxidases are obtained from bacteria or fungi, whereas esterases are from pig liver and thermophilic bacteria. For preparative work the enzymes are covalently bound to a carrier and do not therefore contaminate the reaction products. Chirazymes are available form Roche Molecular Biochemicals and are used without further purification. 

If very pure amine is desired the product described above is dissolved with 1.04 parts of crystalline oxalic acid in eight parts of hot water. After clarification with Norite, the filtered solution on cooling deposits crystals of the acid oxalate. About 5 g. of the salt remains in each 100 cc. of the mother liquor most of this can be obtained by evaporation and further crystallization. The amine is liberated from the pure oxalate with potassium hydroxide, distilled with steam, and purified as described above. When a known amount of amine is desired in water solution (as for optical resolution) a weighed amount of the (anhydrous) oxalate is decomposed and the amine is distilled quantitatively with steam. 

Although unsynunetrically substituted amines are chiral, the configuration is not stable because of rapid inversion at nitrogen. The activation energy for pyramidal inversion at phosphorus is much higher than at nitrogen, and many optically active phosphines have been prepared. The barrier to inversion is usually in the range of 30-3S kcal/mol so that enantiomerically pure phosphines are stable at room temperature but racemize by inversion at elevated tempeiatuies. Asymmetrically substituted tetracoordinate phosphorus compounds such as phosphonium salts and phosphine oxides are also chiral. Scheme 2.1 includes some examples of chiral phosphorus compounds. 

An asymmetric synthesis has used the reduction of imonium salts to optically active tertiary amines with lithium aluminum alkoxy hydrides derived from optically active alcohols (538,539). 

Compounds analogous to the cobaltammines may be similarly obtained using chelating amines such as ethythenediamine or bipyridyl, and these too have played an important role in stereochemical studies. Thus ct5-[Co(cn)2(NH3)Cl] was resolved into d(+) and /(—) optical i.so-mers by Werner in 1911 thereby demonstrating. to all but the most determined doubters, its octahedral stereochemistry. More recently, the absolute configuration of one of the optical isomers of [Co(en)3] was determined (.sec Panel on p, 1125),... 

The configuration of the amine was retained, except in the case of amino acid derivatives, which racemized at the stage of the pyridinium salt product. Control experiments showed that, while the starting amino acid was configurationally stable under the reaction conditions, the pyridinium salt readily underwent deuterium exchange at the rz-position in D2O. In another early example, optically active amino alcohol 73 and amino acetate 74 provided chiral 1,4-dihydronicotinamide precursors 75 and 76, respectively, upon reaction with Zincke salt 8 (Scheme 8.4.24). The 1,4-dihydro forms of 75 and 76 were used in studies on the asymmetric reduction of rz,>S-unsaturated iminium salts. 

Denniatk and co-wotkets teporied tlie brst example in 1990 [16], using substrates 1, s7ntliesized Grom adiital allylic alcohols and tead dy ava dable optically active amine auxdiaries. Substrates 1 were tlien employed in coppet-niediaied allylic substitution reactions, as shown in Sdienie 8.4. 

Replacement of the ketone by an amide leads to Increased potency. Hydrolysis of nitrile, 133 (obtained by alkylation of diphenylacetonitrile with the morpholine analog of the chloro-amine used in the original preparation of methadone), affords acid, 134. Conversion to the acid chloride followed by reaction with pyrrolidine affords racemoramide (135) Separation of the (+) isomer by optical resolution gives dextromoramide, an analgesic an order of magnitude more potent than methadone. 

The synthesis starts by condensation of readily available optically active (R)-(+)-alpha-methylbenzylamine with 4-phenyl-2-butanone to form an imine which is itself reduced by hy-drogenolysis (Raney nickel) to give a 9 1 mixture of the (R,R)-amine and the (R,S)-amine (4). 

Up to this point no evidence was forthcoming that any oneoffthe fenchenes prepared was pure, as the optical rotation of nearly every specimen was different. Wallach i has, however, more recently prepared fenchene by treating fenchyl-amine with nitrous acid. The resulting terpenes were separated by fractional distillation into two main portions, one of which had the following characters —... 

---