Kinetic Resolution of Secondary Amines

Preparation of optically active P-aminoesters, P-aminonitriles, and P-aminocarbox-amides are of special relevance for the synthesis of enantiomerically pure P-aminoacids compounds of special relevance in several areas of medicinal chemistry. The resolution of P-aminoesters can be carried out by acylation of the amino groups or by other biocatalytic reactions of the ester groups, such as hydrolysis, transesterification, or aminolysis. The resolution of ethyl ( )-3-aminobutyrate 

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Stirling, M., Blacker J. and Page M.I., Chemoenzymatic dynamic kinetic resolution of secondary amines. Tetrahedron Lett., 2007, 48, 1247. 

All of the examples discussed so far focus on the resolution of primary amines however, secondary amines are also important building blocks in the synthesis of biologically active compounds. The development of general, efficient methods for the production of optically pure secondary amines has remained a challenge. However, there are a few reported methods for enzyme mediated kinetic resolution of secondary amines. 

Parvulescu, A., Vos, D. D., and Jacobs, P. (2005). Efficient dynamic kinetic resolution of secondary amines with Pd on alkaline earth salts and a lipase. Chem. Commun., Issue 42, 5307-5309. 

Polymers derived from natural sources such as proteins, DNA, and polyhy-droxyalkanoates are optically pure, making the biocatalysts responsible for their synthesis highly appealing for the preparation of chiral synthetic polymers. In recent years, enzymes have been explored successfully as catalysts for the preparation of polymers from natural or synthetic monomers. Moreover, the extraordinary enantioselectivity of lipases is exploited on an industrial scale for kinetic resolutions of secondary alcohols and amines, affording chiral intermediates for the pharmaceutical and agrochemical industry. It is therefore not surprising that more recent research has focused on the use of lipases for synthesis of chiral polymers from racemic monomers. 

Dynamic kinetic resolutions of secondary alcohols and amines have been achieved by the combination of biocatalysts with metal catalysts.12 For example, a metal catalyst was used to racemize the substrate, phenylethanol, and a lipase was used for the enantioselective esterification as shown in Figure 12. The yield was improved from 50% in kinetic resolution without racemization of the substrate to 100% with metal catalyzed racemization. 

In the late 1990s, several research groups worked on the development of chiral DMAP analogs. The works of Fu [23], Vedejs [24], and Fuji [25] led to the synthesis of powerful catalysts and the development of enantioselective organocatalytic reactions such as Steghch rearrangements, kinetic resolutions of secondary alcohols, kinetic resolution of amines, and so on (Scheme 1.8). 

Scheme 23.33. Kinetic resolution of secondary alcohols via oxidation with O2 mediated hy a Pd(It) catalyst bearing a bidentate amine ligand.

Miscellaneous Oxidation Reactions. The kinetic resolution of secondary alcohols is achieved by a palladium-catalyzed enan-tioselective oxidation using Pd[(—)-sparteine]Br2/(—(-sparteine or Pd(CH3CN)2(Br)2/chiral diamine sparteine mimic under an oxygen atmosphere. The chiral amine-dibromide complexes are observed to oxidize secondary alcohols more rapidly than the dichloride complexes (eq 7). This has been attributed to a greater counterion distortion from ideal square planar geometry, which could lower the energy barrier to 8-hydride elimination. 

Recently, a similar reaction has been shown to affect the kinetic resolution of racemic secondary amines (Scheme 6) [15]. In this example, A7-oxyl radical (20) was utilized as the mediator. The rest of the reaction conditions remained the... 

The procedure constitutes the first known example of a chemoenzymatic dynamic kinetic resolution of a secondary amine. The operational simplicity of the procedure is exemplified by the mild conditions, air-stable reagents and low catalyst loading. 

Schering Plough demonstrated the kinetic resolution of a secondary amine (24) via enzyme-catalyzed acylation of a pendant piperidine (Scheme 7.13) [32]. The compound 27 is a selective, non-peptide, non-sulfhydryl farnesyl protein transfer inhibitor undergoing clinical trials as a antitumor agent for the treatment of solid tumors. The racemic substrate (24) does not contain a chiral center but exists as a pair of enantiomers due to atropisomerism about the exocylic double bond. The lipase Toyobo LIP-300 (lipoprotein lipase from Ps. aeruginosa) catalyzed the isobu-tylation of the (+) enantiomer (26), with MTBE as solvent and 2,2,2-trifluoroethyl isobutyrate as acyl donor [32]. The acylation of racemic 24 yielded (+) 26 at 97% and (-) 25 at 96.3% after 24h with an E >200. The undesired enantiomer (25)... 

The [3-hydroxy amines are a class of compounds falling within the generic definition of Eq. 6A.6. When the alcohol is secondary, the possibility for kinetic resolution exists if the Ti-tartrate complex is capable of catalyzing the enantioselective oxidation of the amine to an amine oxide (or other oxidation product). The use of the standard asymmetric epoxidation complex (i.e., T2(tartrate)2) to achieve such an enantioselective oxidation was unsuccessful. However, modification of the complex so that the stoichiometry lies between Ti2 (tartrate) j and Ti2(tartrate)1 5 leads to very successful kinetic resolutions of [3-hydroxyamines. A representative example is shown in Eq. 6A.11 [141b,c]. The oxidation and kinetic resolution of more than 20 secondary [3-hydroxyamines [141,145a] provides an indication of the scope of the reaction and of some... 

To recycle a valuable amine acylation catalyst, Janda and co-workers10 attached a proline-based catalyst to a polymeric support for the enan-tioselective kinetic resolution of alcohols (entry 6). The resin-bound catalyst behaves similarly to the soluble catalyst, providing good yields of secondary alcohols and their corresponding esters with good to excellent enantioselectivities for various substrates. 

The DMAP derivative 19a was tested for kinetic resolution of a variety of mono esters of cyclic cis diols (rac-20a-i) (Scheme 12.5) [15]. Catalyst 19a afforded selectivity factors up to 12.3 and highly enantioenriched mono esters 20 with conversions of 65-73%. For this type of reaction the selectivity of the Campbell catalyst 19b was similar (selectivity factor 13.2, Scheme 12.5) [16a], The latter catalyst was identified by screening of a 31-mer library prepared from the parent N-(4-pyridyl)-a-methylproline and a variety of amines [16a], The solid-phase-bound forms of N-(4-pyridyl)-a-methylproline, as reported by Anson et al. [16b], are easily recyclable acylation catalysts affording selectivity factors up to 11.9 in the kinetic resolution of the secondary alcohol rac-20b (Scheme 12.5). In the kinetic resolution of N-acylated amino alcohols, selectivity factors up to 21 were achieved by use of the Kawabata-Fuji catalyst 19a, and up to 18.8 by use of the Campbell system 19b (Scheme 12.5) [15, 16a]. 

Figure 57 Some of the biocatalytic steps using lipase developed at BASF Lipase-catalyzed kinetic resolution of a) phenyl ethanol 18 using succinic anhydride, b) Secondary amine 120 using ethyl methoxyacetate as acyl...

TBDMSCl, DMAP, EtjN, DMF, 25°C, 12 h. These conditions were used to silylate selectively a primary over a secondary alcohol. In the silylation of carbohydrates, it was shown that these conditions inhibit silyl migration whereas the use of imidazole as base causes migration." Besides DMAP, other catalysts such as 1,1,3,3-tetramethylguanidine, l,8-diazahicyclo[5.4.0]undec-7-ene (83-99%), l,5-diazabicyclo[4.3.0]non-5-ene, and ethyldiisopropyl-amine have also been used. A chiral guanidine has been used to give modest kinetic resolution of chiral secondary alcohols with TBDMSCl and TIPSCl. ... 

Scheme 19.9 Dynamic kinetic resolution of a secondary amine based on ruthenium-catalyzed racemization and enzymatic acylation.

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