Tert-leucine

The Jacobsen group has also shown that the recycling of the resin-bounded catalyst can be successfully performed [152,154]. Moreover, they have developed an efficient method for the hydrolysis of the aminonitrile into the corresponding amino acid. This method was apphed for the commercial production of optically active K-amino acids at Rhodia ChiRex (e.g. tert-leucine) the catalyst was immobihsed on a resin support (4 mol %, 10 cycles) and the intermediate hydrocyanation adduct was trapped by simply replacing TFAA with HCOOH/AC2O, for example. Highly crystalhne formamide derivatives were thus obtained in excellent yields (97-98% per cycle) with very high enantioselectivities (92-93% per cycle) [158]. 

Prasad RS, Anderson CE, Richards CJ, Overman LE (2005) Synthesis of tert-leucine-derived cobalt oxazoline palladacycles. Reversal of palladation diastereoselectivlty and application to the asymmetric rearrangement of N-aryl trifluoroacetimidates. Organometallics 24 77-81... 

Figure 4.18 Enzyme membrane reactor synthesis of L-tert-leucine from trimethylpyruvic acid in an continuously operated enzyme membrane reactor with ultrafiltration followed by a crystallization step...

Diastereoselective Slrecker reactions based on (R)-phenylglycine amide as chiral auxiliary are reported. The Strecker reaction is accompanied by an In situ crystallization-induced asymmetric transformation, whereby one diastereomer selecliveiy precipitates and can be isolated in 76-33% yield and dr > gsti. The diastereomeilcaily pure a-amino nitrtie obtained from pivaidehyde (R, = t-Bu, Rj = H) was converted in three steps to (S)-tert-leucine in 73% yieid and >98% ee. 

In summary, (R)-phenylglycine amide 1 is an excellent chiral auxiliary in the asymmetric Strecker reaction with pivaldehyde or 3,4-dimethoxyphenylacetone. Nearly diastereomerically pure amino nitriles can be obtained via a crystallization-induced asymmetric transformation in water or water/methanol. This practical one-pot asymmetric Strecker synthesis of (R,S)-3 in water leads to the straightforward synthesis of (S)-tert-leucine 7. Because (S)-phenylglycine amide is also available, this can be used if the other enantiomer of a target molecule is required. More examples are currently under investigation to extend the scope of this procedure. ... 

P35 Pivaldehyde and 3,4-dimethoxyphenylacetone were used as starting materials, which lead, respectively, to enantiomerically enriched tert-leucine and a-methyl-dopa, two important nonproteogenic a-amino acids for pharmaceutical applications. In addition, tert-leucine has considerable utility as a chiral building block.(From Boesten et ah, 2001)... 

R)-Phenylglycine amide I is an excellent chiral auxiliary in the asymmetric Strecker reaction of pivaldehyde 2. In water at 70 °C, the (R,S)-3 product was isolated in 93% yield and dr > 99/1. Work is underway to convert (R,S)-3 to (S)-tert-leucine and thereby complete the asymmetric Strecker reaction. 

Finally in this sechon, a novel approach has been developed for the enzyme-catalyzed synthesis of D-tert-leucine 55 from the corresponding racemate (Scheme... 

In contrast, amino acid dehydrogenases comprise a well-known class of enzymes with industrial apphcations. An illustrative example is the Evonik (formerly Degussa) process for the synthesis of (S)-tert-leucine by reductive amination of trimethyl pyruvic acid (Scheme 6.12) [27]. The NADH cofactor is regenerated by coupling the reductive amination with FDH-catalyzed reduction of formate, which is added as the ammonium salt. 

Scheme 6.12 Synthesis of (S)-tert-leucine by enzymatic reductive amination.

For the calculations, we used a simplified model system in which all subshtuents were replaced by methyl groups (Scheme 3.4). Experimentally, the methyl subsh-tuted catalyst and methanol as nucleophile are active, but the enantiomeric excesses obtained fall below those obtained with the tert-leucine amide-derived catalyst in combinahon with allyl alcohol (Scheme 3.3). 

Scheme 6.44 Reaction sequence for the synthesis of enantiopure (/ )-tert-leucine hydrochloride starting from the pivalaldimine Strecker adduct obtained under catalysis with polymer-bound thiourea 41.

The Jacobsen group independently focussed on the development of primary amine-functionalized thiourea derivatives and published, in 2006, the thioureas 100-103 incorporating the established tert-leucine (amide) motif (Figure 6.14) and the diaminocyclohexane or diphenylethylenediamine chiral backbone, respectively (Figure 6.31) [262]. The catalyst screening was carried out in the asymmetric Michael addition [149-152] of 2-phenylpropionaldehyde, an a,a-disubstituted aldehyde, to 1-nitrohex-l-ene (at 20mol% loading, DCM, rt, variable equiv. of H2O)... 

L-tert-leucine trimethylpyruvate leucine dehydrogenase + formate dehydroenase... 

Recently, a lipase-catalysed kinetic resolution has been developed to produce L-tert-leucine via a lactone of its A-benzoyl derivative. There is also reputed to be another bioroute to L-terMeucine using transaminase technology. 

Some of the products formed are functional ingredients in their own right, such as high fmctose syraps, cefuroxime etc. Others are intermediates that can be either freely traded, such as acrylamide as a pre-polymer and 6-APA and p-hydroxyphenylglycine as precursors of semi-synthetic antibiotics. Alternatively some intermediates tend to be used in-house by the company producing them such as fS)-2-chloropropanoate and L-tert-leucine. 

Reactions possible that are not possible using chemistry. HFCS, cefuroxime, L-tert-leucine, (S)-2-chloropropanoic acid. If -decalactone... 

In addition, the /erf-butyl esters of valine and tert-leucine are excellent chiral auxiliaries in asymmetric alkylation of their imines. These chiral auxiliaries are preferentially used in the alkylation of cyclic ketones (73 to >99% ee)17 and /i-oxo esters (44 to >99% ee)18,, 9 and the absolute configuration of the products can be safely predicted. 

Valine and tert-leucine derived cyclohexanone imines were hydrolyzed with 5% aqueous citric acid in an ice bath under vigorous stirring for 25 minutesi-17. From the acidic layer 67% of the chiral auxiliary was recovered3. Aldimines13. acyclic ketimines10, and cyclic polymer-... 

A series of chiral amines derived from amino acids has been used the best optical yields have been obtained with phenylalanine derivatives (128) (R1 = CH2C6H5) and tert-leucine tert-butyl ester (129) 146>. 

Synthesis of (S)-Benzyl-L-tert-Leucine Butyl Ester... 

The amino acid (S)-tert-leucine (48) has been shown to be an important intermediate for a wide variety of pharmaceutically active molecules in the areas of antitumor, anti-inflammatory, and antiviral activity [42]. A number of routes to (S)-tert-leucine (48) have been developed, in particular the aqueous-based process from Degussa using asymmetric reductive animation of the prochiral keto acid with dehydrogenase and factor recycling [43, 44]. An industrial alternative was... 

Scheme 7.19 The synthesis of homochiral L-(S)-tert-leucine via a lipase-catalyzed dynamic resolution process.

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