Optically active amines

The chlorides 73a and 73b on reacting with dimethylamine in benzene afforded the amidates 92 and 93 respectively with complete diastereoselectivity. [58] The diastero-meric amides 94-96 were prepared in a similar manner by reacting 73a with chiral primary amines (optically active or racemic) and the isolated amides were applied for quantification of enantiomeric excesses of the amines of interest (Scheme 27) [55], A similar reaction with 1,2-diaminoethane gave bisphosphoramide 98 [59],... 

Isoamyl nitrite/sodium acetate Acetoxy compounds from amines Optically active compounds... 

Perchloric acid Alcohols from tert. amines Optically active compds. 

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. 

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. 

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). 

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. 

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). 

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. 

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). 

Reductive alkylation with chiral substrates may afford new chiral centers. The reaction has been of interest for the preparation of optically active amino acids where the chirality of the amine function is induced in the prochiral carbonyl moiety 34,35). The degree of induced asymmetry is influenced by substrate, solvent, and temperature 26,27,28,29,48,51,65). Asymmetry also has been obtained by reduction of prochiral imines, using a chiral catalyst 44). Prediction of the major configurational isomer arising from a reductive alkylation can be made usually by the assumption that amine formation comes via an imine, not the hydroxyamino addition compound, and that the catalyst approaches the least hindered side (57). 

The disclosure, in 1982, that cationic, enantiopure BINAP-Rh(i) complexes can induce highly enantioselective isomerizations of allylic amines in THF or acetone, at or below room temperature, to afford optically active enamines in >95 % yield and >95 % ee, thus constituted a major breakthrough.67-68 This important discovery emerged from an impressive collaborative effort between chemists representing Osaka University, the Takasago Corporation, the Institute for Molecular Science at Okazaki, Japan, and Nagoya University. BINAP, 2,2 -bis(diphenylphosphino)-l,l -binaphthyl (Scheme 7), is a fully arylated, chiral diphosphine which was introduced in... 

Since these adducts undergo reductive desulfuration with Raney nickel, optically active aryl methyl sulfoxides are versatile reagents for the conversion of imines to optically active amines. 

The procedure is modified for the reaction of preformed cyanohydrins with chiral amines39. I11 a further variation, Schiff bases of aliphatic aldehydes with optically active 1-arylalkyl-amines are transformed with liquid hydrogen cyanide to the corresponding a-aminonitrilcs, which, after acid hydrolysis, give the /V-aryUilkylamino acids. Hydrogenation then yields the a-amino acids40 41. 

In Ugi four-component reactions (for mechanism, see Section 1.4.4.1.) all four components may potentially serve as the stereodifferentiating tool65. However, neither the isocyanide component nor the carboxylic acid have pronounced effects on the overall stereodiscrimination60 66. As a consequence, the factors influencing the stereochemical course of Ugi reactions arc similar to those in Strecker syntheses. The use of chiral aldehydes is commonly found in substrate-controlled syntheses whereas the asymmetric synthesis of new enantiomerically pure compounds via Ugi s method is restricted to the application of optically active amines as the chiral auxiliary group. 

Several methods for asymmetric C —C bond formation have been developed based on the 1,4-addition of chiral nonracemic azaenolates derived from optically active imines or enamines. These methods are closely related to the Enders and Schollkopf procedures. A notable advantage of all these methods is the ready removal of the auxiliary group. Two types of auxiliaries were generally used to prepare the Michael donor chiral ketones, such as camphor or 2-hydroxy-3-pinanone chiral amines, in particular 1-phenylethanamine, and amino alcohol and amino acid derivatives. 

A very interesting approach to optically active sulphoxides, based on a kinetic resolution in a Pummerer-type reaction with optically active a-phenylbutyric acid chloride 269 in the presence of /V,A -dimethyIaniline, was reported by Juge and Kagan332 (equation 149). In contrast to the asymmetric reductions discussed above, this procedure afforded the recovered sulphoxides in optical yields up to 70%. Chiral a, /1-unsaturated sulphoxides 270 were prepared via a kinetic resolution elaborated by Marchese and coworkers333. They found that elimination of HX from racemic /i-halogenosulphoxides 271 in the presence of chiral tertiary amines takes place in an asymmetric way leading to both sulphoxides 270 and 271, which are optically active (optical yields up to 20%) with opposite configurations at sulphur (equation 150). 

Partial photochemical decomposition of racemic alkyl aryl sulphoxides in the presence of chiral amines as sensitizers gave non-decomposed sulphoxides in optically active form with optical purity of about 3%339. The report340 on the use of cholesteric liquid crystalline reaction media to change the enantiomeric composition of racemic sulphoxides at high temperatures could not be reproduced341. 

Reaction of benzylideneaniline with optically active methyl p-tolyl sulphoxide 449 in the presence of lithium diethylamide produces the corresponding jS-anilinosulphoxide 450 with 100% asymmetric induction. Its reductive desulphurization with Raney nickel leads to the enantiomerically pure amine 451524 (equation 270). When the same optically active... 

The procedure herein presented allows the preparation of the same optically active amine in approximately 70% yield by the use of a... 

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