Enantiomerically pure chiral amines

Hydroamination reactions involving alkynes and enantiomerically pure chiral amines can produce novel chiral amine moieties after single pot reduction of the Schiffbase intermediate 82 (Scheme 11.27) [123]. Unfortunately, partial racemiza tion ofthe amine stereocenter was observed with many titanium based hydroamina tion catalysts, even in the absence of an alkyne substrate. No racemization was observed when the sterically hindered Cp 2TiMe2 or the constrained geometry catalyst Me2Si(C5Me4)(tBuN)Ti(NMe2)2 was used in the catalytic reaction. Also, the addition of pyridine suppressed the racemization mostly. 

Give an overview of the different biocatalytic methods that can be used to prepare enantiomerically pure chiral amines. 

Chiral amines can react with so-called Mannich donors such as ketones or aldehydes. The resulting chiral enamines wiU then attack a Mannich acceptor, usually a prochiral aldimine, thereby introducing one or two chiral centers in the Mannich product. This usually is a P-aminoaldehyde or P-aminoketone, optionally substituted at the a-position. Inspired by their work on proline-catalyzed asymmetric aldol reactions [1], the List group envisioned that the related Mannich reactions might also be carried out with a catalytic amount of an enantiomerically pure chiral amine. This led in 2000 to the first direct catalytic asymmetric organocatalyzed Mannich reaction, catalyzed by L-proline (1, Scheme 5.1) [2],... 

Truppo, M., Rozzell, (., and Turner, N. (2010) Efficient production of enantiomerically pure chiral amines at concentrations of 50 g/1 using aminotransferases. Org. Process Res. Dev., 14, 234-237. 

Heteroaromatics such as 10 are inexpensive compared to enantiomerically-pure cyclic amines such as 11. Yong-Gui Zhou of the Dalian Institute of Chemical Physics reports (J. Am. Chem. Soc. 125 10536, 2003) the development of a chiral Ir catalyst that effects hydrogenation... 

Enantiomerically pure homoallylic amines are very important chiral building blocks for the synthesis of natural products. However, enantioselective methods for homoallylamine are quite undeveloped. In 1995, Itsuno and co-workers reported the first example of enantioselective allylation of an imine (Scheme 7) [13]. The reaction of N-trimethylsilylbenzaldimine 19 with a chiral allylboron reagent 20 in ether at -78 °C afforded the corresponding homoallylamine 22 in 73% ee. 

Catalytic hydrogenation of PGA-homoallylamines simultaneously reduced the double bond and removed the chiral auxiliary in one step. Some typical examples of enantiomerically pure (R)-aminobutanes 12 obtained are shown in Scheme 25.6. The nonoptimized yields varied between 49% and 88% with ee values of 94% to >98%. The high enantiomeric excesses of these chiral amines are in agreement with the equally high diastereoselectivity of the allylation reaction and lack of racemization of the phenylglycine amide moiety in any of the steps. Enantiomerically pure chiral (f )-a-propylpiperonylamine 12c is an important building block of the human leukocyte elastase inhibitor L-694,458 (13).28... 

One possibility to separate the enantiomers of rac- 1-phenylethanamine is to form diastereomeric salts with an enantiomerically pure chiral acid, e.g. (R,R) tartaric acid or (S)-2-hydroxysuccinic acid. These can be separated from each other by recrystallisation as a consequence of their different solubilities. Note, however, that the separation process is not complete at this stage since the amines are now present as salts. The separated salts must be treated with a strong base, e.g. aqueous sodium hydroxide, to convert them back to the free amines which can then be extracted into an organic solvent. After drying the extract distillation of the solvent leaves the pure amine. 

The asymmetric synthesis of enantiomerically pure primary amines has received considerable attention in recent years due to applications of the chiral amines, either as chiral auxiliaries for the synthesis of optically active molecules [33] or as a deri-vatizing agent for the resolution of racemic carboxylic acids [34], Hydroboration -amination is also a convenient synthetic route to epimerically clean amine derivatives in a simple one-stage reaction. Interestingly, rrans-2-phenylcyclopentylamine (cypenamine), which is an antidepressant [35], can be obtained as a pure isomer in good yields by the hydroboration of 1-methylcyclopentene [7,10,36] (Scheme 13). 

Enantiomerically pure secondary amines can be readily prepared from a-chiral organodichloroboranes and azides [63] (Scheme 22). 

One of the most effective ways of preparing enantiomerically pure secondary amines is the addition of organometallic reagents to chiral sul fmimines, which are prepared by the condensation of an aldehyde (or ketone) with a sulfinamide. The preparation of /-butyl sulfinamide had been problematic, but the synthesis (and supplies) now seems to be more reliable. 

An ideal method for testing a wide variety of substructures was developed through the condensation of enantiomerically pure chiral primary amines with 2-(2-bromoethyl)benzaldehyde (11) as shown in Scheme 5.14 [19,21]. 

Enantiomerically pure homoallylic amines are very important chiral building blocks for the synthesis of pharmacologically important molecules and natural products. The enantioselective synthesis of these compounds initially involved the chiral auxiUary-based asymmetric allylation of imines [41a, 4lb, 41c], and it is just recently that a few enantioselective variants have been reported. Although still in the regime of stoichiometric asymmetric synthesis, the first methods described below merit discussion for their synthetic utility and for establishing the groundwork for future development. 

Lithiated a-amino nitriles derived from an enantiomerically pure secondary amine have been used to achieve the asymmetric synthesis of trfl 5-dibenzylbutyrolactones (scheme 10) [58]. Enantiomeric excesses of greater than 96% were obtained after removing the chiral auxiliary. When aromatic aldehydes were used as electrophiles the benzylic alcohols were obtained as a mixture of the two epimers with a diastereomeric excess of 60-75%. Addition of a chiral sulfoxide, prepared using a modified Sharpless oxidation, to butenolide has also been utilised as part of an expeditious synthesis of podophyllotoxin (scheme 11) [59]. 

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. 

The interest in asymmetric synthesis that began at the end of the 1970s did not ignore the dihydroxylation reaction. The stoichiometric osmylation had always been more reliable than the catalytic version, and it was clear that this should be the appropriate starting point. Criegee had shown that amines, pyridine in particular, accelerated the rate of the stoichiometric dihydroxylation, so it was understandable that the first attempt at nonenzymatic asymmetric dihydroxylation was to utilize a chiral, enantiomerically pure pyridine and determine if this induced asymmetry in the diol. This principle was verified by Sharpless (Scheme 7).20 The pyridine 25, derived from menthol, induced ee s of 3-18% in the dihydroxylation of /rcms-stilbene (23). Nonetheless, the ee s were too low and clearly had to be improved. 

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. 

For a chiral molybdenum-based catalyst available in situ from commercial components, see (a) Aeilts SL, Cefalo DR, Bonitatebus PJ, Houser JH, Hoveyda AH, Schrock RR (2001) Angew Chem Int Ed 40 1452 (b) For the first enantiomerically pure solid-sup-ported Mo catalyst, see Hultzsch KC, Jernelius JA, Hoveyda AH, Schrock RR (2002) Angew Chem Int Ed 41 589 (c) For a chiral Mo catalyst, allowing RCM to small- and medium-ring cyclic amines, see Dolman SJ, Sattely ES, Hoveyda AH, Schrock RR (2002) J Am Chem Soc 124 6991 (d) For a novel adamantyl imido-molybdenum complex with advanced selectivity profiles, see Tsang WCP, Jernelius JA, Cortez GA, Weatherhead GS, Schrock RR, Hoveyda AH (2003) J Am Chem Soc 125 2591... 

In recent years, a great variety of primary chiral amines have been obtained in enantiomerically pure form through this methodology. A representative example is the KR of some 2-phenylcycloalkanamines that has been performed by means of aminolysis reactions catalyzed by lipases (Scheme 7.17) [34]. Kazlauskas rule has been followed in all cases. The size of the cycle and the stereochemistry of the chiral centers of the amines had a strong influence on both the enantiomeric ratio and the reaction rate of these aminolysis processes. CALB showed excellent enantioselec-tivities toward frans-2-phenylcyclohexanamine in a variety of reaction conditions ( >150), but the reaction was markedly slower and occurred with very poor enantioselectivity with the cis-isomer, whereas Candida antarctica lipase A (GALA) was the best catalyst for the acylation of cis-2-phenylcyclohexanamine ( = 34) and frans-2-phenylcyclopropanamine ( =7). Resolution of both cis- and frans-2-phenyl-cyclopentanamine was efficiently catalyzed by CALB obtaining all stereoisomers with high enantiomeric excess. 

One of the potentially most useful aspects of the imine anions is that they can be prepared from enantiomerically pure amines. When imines derived from chiral amines are alkylated, the new carbon-carbon bond is formed with a bias for one of the two possible stereochemical configurations. Hydrolysis of the imine then leads to enantiomerically enriched ketone. Table 1.4 lists some examples that have been reported.118... 

Clerici and Porta reported that phenyl, acetyl and methyl radicals add to the Ca atom of the iminium ion, PhN+Me=CHMe, formed in situ by the titanium-catalyzed condensation of /V-methylanilinc with acetaldehyde to give PhNMeCHMePh, PhNMeCHMeAc, and PhNMeCHMe2 in 80% overall yield.83 Recently, Miyabe and co-workers studied the addition of various alkyl radicals to imine derivatives. Alkyl radicals generated from alkyl iodide and triethylborane were added to imine derivatives such as oxime ethers, hydrazones, and nitrones in an aqueous medium.84 The reaction also proceeds on solid support.85 A-sulfonylimines are also effective under such reaction conditions.86 Indium is also effective as the mediator (Eq. 11.49).87 A tandem radical addition-cyclization reaction of oxime ether and hydrazone was also developed (Eq. 11.50).88 Li and co-workers reported the synthesis of a-amino acid derivatives and amines via the addition of simple alkyl halides to imines and enamides mediated by zinc in water (Eq. 11.51).89 The zinc-mediated radical reaction of the hydrazone bearing a chiral camphorsultam provided the corresponding alkylated products with good diastereoselectivities that can be converted into enantiomerically pure a-amino acids (Eq. 11.52).90... 

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