Allysine ethylene acetal

The stereoselective total synthesis of (+)-epiquinamide 301 has been achieved starting from the amino acid L-allysine ethylene acetal, which was converted into piperidine 298 by standard protocols. Allylation of 297 via an. V-acyliminium ion gave 298, which underwent RCM to provide 299 and the quinolizidine 300, with the wrong stereochemistry at the C-l stereocenter. This was corrected by mesylation of the alcohol, followed by Sn2 reaction with sodium azide to give 301, which, upon saponification of the methyl ester and decarboxylation through the Barton procedure followed by reduction and N-acylation, gave the desired natural product (Scheme 66) <20050L4005>. 

Replacing T. intermedins with E. coli as a source for PheDH, 197 kg of (S)-allysine ethylene acetal product was produced in three batches with an average yield of 91% mol/mol and the e.e. was > 98%. 

In a third-generation process, heat-dried methanol-grown P. pastoris expressing endogenous FDH and recombinant Thermoactinomyces PheDH were used to produce 15 kg (S)-allysine ethylene acetal with a yield of 97% mol/mol and> 98% e.e. Both 5-(l,3-dioxolan-2-yl)-2-oxopentanoic acid and lithium-6,6-dimethoxy-2-oxohexanoate served as substrates for the enzymatic reductive amination. 

J. J. Venit, L. J. Szarka, and R. N. Patel, Synthesis of allysine ethylene acetal using phenylalanine dehydrogenase from Thermoactinomyces intermedius, Enzyme Microb. Technol. 2000b, 26, 348-358. 

S)-2-Amino-5-(l,3-dioxolan-2-yl)-pentanoic acid [allysine ethylene acetal (4)] is one of three building blocks used for an alternative synthesis of omapatrilat, a vasopeptidase inhibitor [13,14], It has previously been prepared in an eight-step synthesis from 3,4-dihydro-2H-pyran [23],... 

A Rumbero, JC Martin, MA Lumbreras, P Liras, C Esmahan. Chemical synthesis of allysine ethylene acetal and conversion in situ into l-piperidine-6-carboxylic acid key intermediate of the a-aminoadipic acid for (3-lactam antibiotics biosynthesis Bioorg Med Chem 3 1237 -1240, 1995. 

Allysine ethylene acetal is synthesized from the corresponding keto acid by reductive amination using phenylalanine dehydrogenase (PDH) from Thermoacti-nomyces intermedius ATCC 33205 combined with FDH from C. boidinii SC13822 for the regeneration of NADH (Fig. 39). 

With heat-dried cells of T. intermedius as PDH source and heat-dried C. boidinii as FDH source, reaction yields of 84% and ee >98% were achieved. As a major drawback of this system the production of T. intermedius could not be scaled up. To solve this problem heat-dried E. coli containing T. intermedius PDH and heat-dried C. boidinii as source of FDH were used. In this procedure, recovery was not a problem and 197 kg allysine ethylene acetal were synthesized in three batches with an average yield of 91% and ee >8%. In a third approach, recombinant Thermo-actinomyces PDH as well as heat-dried methanol-grown Pichia pastoris expressing endogenous FDH were used to produce 15 kg allysine ethylene acetal with a yield of 97% and ee >98%. This process allowed both enzymes to be produced during a... 

S)-2-amino-5-(1, 3-dioxolan-2-yl) pentanoic acid (allysine ethylene acetal)... 

Fig. 39 Conversion of 5-(l,3-dioxolan-2-yl)-2-oxo-pentanoid acid to allysine ethylene acetal by reductive amination using phenylalanine dehydrogenase (PDH) and formate dehydrogenase (FDH) for cofactor recycling...

Figure 15.3-4. Synthesis of allysine ethylene acetal with PheDH/FDH,58).

PheDH from Thermoactinomyces intermedius ATCC 33 205 was utilized recently to synthesize allysine ethylene acetal [(S)-2-amino-5-(l,3-dioxolan-2-yl)-pentanoic acid (2)] from the corresponding keto acid with regeneration of NAD+ cofactor by FDH/ formate[58 (Fig. 15.3-4) the specific activity towards the keto acid was 16% compared to the standard substrate phenylpyruvate. 

Altogether, more than 200 kg of allysine ethylene acetal have been produced. 

Preparation of Allysine Ethylene Acetal by Reductive Amination Using... 

Enzymatic Synthesis of At lysine Ethylene Acetal. (S)-2-Amino-5-(l,3-dioxolan-2-yl)-pentanoic acid (5 )-allysine ethylene acetal (7) (Fig. 3A) is one of three building blocks used in an alternative synthesis of Omapatrilat (1). It previously had been prepared via an eight-step chemical synthesis from 3,4-dihydro [2H] pyran (16). An alternate synthesis of (7) was demonstrated by reductive amination of ketoacid acetal (8) using phenylalanine dehydrogenase (PDH) from Thermoactinomyces intermedins (17). The reaction required ammonia and NADH NAD produced during the reaction was recycled to NADH by the oxidation of formate to CO using formate dehydrogenase (FDH). 

Fig. 3. (A) Enzymatic synthesis of chiral synthon for Omapatrilat (1) Reductive amination of keto acid acetal (8) to (S)-allysine ethylene acetal (Z) by phenylalanine dehydrogenase. Regeneration of NADH was carried out using formate dehydrogenase. (B) Enzymatic synthesis of chiral synthon for Omapatrilat (1) Conversion of disulfide (U) to thiazepine (9) by S-lysine a-aminotransferase.

The only other application of hydroformylation applied to the synthesis of a pharmaceutical intermediate on a commercial scale has recently been reported. The synthesis of (S)-allysine ethylene acetal, an intermediate in the manufacmre of angiotensin I-converting enzyme (ACE) and neutral endopeptidase (NEP) inhibitors, was reported by researchers at Dr. Reddy s and Chirotech using a combination of... 

Fig. 3 Synthesis of (5)-allysine ethylene acetal by rhodium-catalyzed asymmetric hydroformylation H2/CO...

Vanlev enzymatic synthesis of allysine ethylene acetal. 

VANLEV ENZYMATIC SYNTHESIS OF ALLYSINE ETHYLENE ACETAL... 

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