Practical Synthesis of Enantiomerically Pure β²‐Amino Acids via Proline‐Catalyzed Diastereoselective Aminomethylation of Aldehydes.

Abstract

Practical Synthesis of Enantiomerically Pure β 2 -Amino Acids via Proline-Catalyzed Diastereoselective Aminomethylation of Aldehydes. -A concise and versatile route for the synthesis of title compounds such as (VI) features a diastereoselective Mannich reaction to give the amino alcohols (III) as the key step. Diastereomeric ratios of the crude products in the Mannich reaction are in the range of 83:17 to 90:10 after NaBH4 treatment the major isomers are enriched via column chromatography or crystallization. The method can be used for the introduction of orthogonally protected side chains such as in (VIc) or (VId). -(CHI, Y.; ENGLISH, E. P.; POMERANTZ, W. C.; HORNE, W. S.; JOYCE, L. A.; ALEXANDER, L. R.; FLEMING, W. S.; HOPKINS, E. A.; GELLMAN*, S. H.; J. Am. Chem. Soc. 129 (2007) 18, 6050-6055; Dep. Chem., Univ. Wis., Madison, WI 53706, USA; Eng.) -Kieslich 37-181

Bisubstrate Inhibitors of Nicotinamide N-Methyltransferase (NNMT) with Enhanced Activity

“…37,38 In an analogous fashion, aldehydes 22 and 23, both containing tert-butyl ester moieties, were prepared by ring opening of succinic or glutaric anhydride with tert-butyl alcohol to obtain mono-esters 18 and 19. 39,40 The carboxylic acid functionalities were reduced to alcohols 20 and 21 and then oxidized using PDC to yield aldehydes 22 and 23.…”

“…High-resolution mass spectrometry (HRMS) analysis was performed using a Q-TOF instrument. Compounds 1, 24 2, 31 3, 34 7, 34 8, 36 9, 37 10, 43 12, 38 14, 38 16, 44 18, 40 19, 40 20, 45 21, 46 22, 47 23, 40 24, 41 25, 41 26, 48 27, 41 and 28 48 were prepared as previously described and had NMR spectra and mass spectra consistent with the assigned structures. Purity was confirmed to be ≥95% by analytical reversedphase HPLC using a Phenomenex Kinetex C18 column (5 μm, 250 × 4.6 mm 2 ) eluted with a water−acetonitrile gradient moving from 0 to 100% CH 3 CN (0.1% TFA) in 30 min.…”

“…Following the procedure described for compound 33, coupling 4-oxo-Ntritylbutanamide 16 (62 mg, 0.18 mmol) and compound 30 (68 mg, 0.15 mmol) afforded compound 39 as a white powder (63 mg, 54% yield). 1 (40). Following the procedure described for compound 33, coupling 5-oxo-N-tritylpentanamide 17 (64 mg, 0.18 mmol) and compound 30 (68 mg, 0.15 mmol) afforded compound 40 as a white powder (67 mg, 53% yield).…”

Enantioselective Synthesis of ?-amino acids: A Review

“…They are also used in the treatment of many diseases and health issues.Therefore, enantioselective β-amino acids have potential therapeutic values and are a great challenge for chiral synthesis.Therefore, β-amino acids with various substitution patterns are now available. Each approach has itsown advantages and limitations while more than 80 numbers of different approaches have been discussed here but the organo-Rh based and heterogeneous catalyzed approach is found to be more effective ( Scheme 1,2,4,11,12,13,28,29) and (Scheme 8,9,33,34,35,36,37,45,54,63). Other approaches can also be considered to synthesize enantioselective amino acids ( Scheme 11,13,15,40,45,50,61,62,68,70,74).…”

“…The β-amino aldehydes were reduced to the corresponding alcohols by reaction with Proline derivative. For the synthesis of β²-amino acids, the amino alcohol was recrystallized as hydrochloride salt to increase the yield, the protecting groups removed by hydrogenation followed by BOC-protection, and the alcohol oxidized to the corresponding carboxylic acid [53,54]. High yields up to 98% were obtained by Córdova et al by using LiBr (Scheme 38b).…”