Organocatalyzed Asymmetric Aldol Reaction of α-Keto Amides with A Tripeptide Catalyst

Abstract

An organocatalyzed asymmetric aldol reaction of α-keto amides was developed. An N-terminal 4-trans-siloxyproline-based tripeptide with an l-tert-leucine unit adjacent to the 4-trans-siloxyproline residue was used to catalyze the reaction between various α-keto amides and acetone, to produce the corresponding aldol adducts with up to 99% yield and 91% ee.

Key words

aldol reaction - asymmetric catalysis - peptide catalysis - organocatalysis - keto amides - hydroxy amides

Publication History

Received: 28 December 2020

Accepted after revision: 02 February 2021

Accepted Manuscript online:
02 February 2021

Article published online:
12 February 2021

• References and Notes

• 1a Schneider CH, Kasper MF, De Weck AL, Rolli H, Angst BD. Allergy 1987; 42: 597
• 1b Matumoto N, Momose I, Umekita M, Kinoshita N, Chino M, Iinuma H, Sawa T, Hamada M, Takeuchi T. J. Antibiot. 1998; 51: 1087
• 1c Lu S.-H, Yamagata T, Atuki K, Sun L, Smith CP, Yoshimura N, Chancellor MB, De Groat WC. Brain Res. 2002; 946: 72
• 1d Schäcke H, Schottelius A, Döcke W.-D, Strehlke P, Jaroch S, Schmees N, Rewinkel H, Hennekes H, Asadullah K. Proc. Natl. Acad. Sci. U.S.A. 2004; 101: 227
• 1e Oku N, Krishnamoorthy R, Benson AG, Ferguson RL, Lipton MA, Phillips LR, Gustafson KR, McMahon JB. J. Org. Chem. 2005; 70: 6842
• 1f Cantarini M, Fuhr R, Morris T. Pharmacol. 2006; 77: 171
• 1g Xie W, Ding D, Zi W, Li G, Ma D. Angew. Chem. Int. Ed. 2008; 47: 2844
• 1h Lu Z, Van Wagoner RM, Harper MK, Baker HL, Hooper JN. A, Bewley CA, Ireland CM. J. Nat. Prod. 2011; 74: 185

For selected reviews, see:
• 2a Brandão P, Burke AJ. Tetrahedron 2018; 74: 4927
• 2b Yu B, Xing H, Yu D.-Q, Liu H.-M. Beilstein J. Org. Chem. 2016; 12: 1000
• 2c Kumar A, Chimni SS. RSC Adv. 2012; 2: 9748

For reactions using α-keto amides as substrates, see:
• 3a Di Sanza R, Nguyen TL. N, Iqbal N, Argent SP, Lewis W, Lam HW. Chem. Sci. 2020; 11: 2401
• 3b Xia A.-B, Pan G.-J, Wu C, Liu X.-L, Zhang X.-L, Li Z.-B, Du X.-H, Xu D.-Q. Adv. Synth. Catal. 2016; 358: 3155
• 3c Ishida N, Nečas D, Masuda Y, Murakami M. Angew. Chem. Int. Ed. 2015; 127: 7526
• 3d Hatano M, Nishimura T. Angew. Chem. Int. Ed. 2015; 54: 10949
• 3e Wang L, Ni Q, Blümel M, Shu T, Raabe G, Enders D. Chem. Eur. J. 2015; 21: 8033
• 3f Joie C, Deckers K, Raabe G, Ender D. Synthesis 2014; 46: 1539
• 3g Joie C, Deckers K, Enders D. Synthesis 2014; 49: 799
• 3h Goudedranche S, Pierrot D, Constantieux T, Bonne D, Rodriguez J. Chem. Commun. 2014; 50: 15605
• 3i Shirai T, Ito H, Yamamoto Y. Angew. Chem. Int. Ed. 2014; 53: 2658
• 3j Raimondi W, del Mar Sanchez Duque M, Goudedranche S, Quintard A, Constantieux T, Bugaut X, Bonne D, Rodriguez J. Synthesis 2013; 1659
• 3k Yin L, Kanai M, Shibasaki M. Angew. Chem. Int. Ed. 2011; 50: 7620

For reactions using β,γ-unsaturated α-keto amides as substrates, see:
• 4a Guo Y.-J, Guo X, Kong D.-Z, Lu H.-J, Liu L.-T, Hua Y.-Z, Wang M.-C. J. Org. Chem. 2020; 85: 4195
• 4b Yang X.-C, Liu M.-M, Mathey F, Yang H, Hua Y.-Z, Wang M.-C. J. Org. Chem. 2019; 84: 7762
• 4c Liu M.-M, Yang X.-C, Hua Y.-Z, Chang J.-B, Wang M.-C. Org. Lett. 2019; 21: 2111
• 4d Yao Q, Yu H, Zhang H, Dong S, Chang F, Lin L, Liu X, Feng X. Chem. Commun. 2018; 54: 3375
• 4e Lefranc A, Guénée L, Contal SG, Alexakis A. Synlett 2014; 25: 2947
• 4f Evans DA, Olhava EJ, Johnson JS, Janey JM. Angew. Chem. Int. Ed. 1998; 37: 3372
• 5a Luo W, Zhao J, Ji J, Lin L, Liu X, Mei H, Feng X. Chem. Commun. 2015; 51: 10042
• 5b Xu H, Wolf C. Angew. Chem. Int. Ed. 2011; 50: 12249
• 6a Kon K, Kohari Y, Murata M. Tetrahedron Lett. 2019; 60: 415
• 6b Kon K, Kohari Y, Murata M. Heterocycles 2019; 99: 841
• 6c Kon K, Takai H, Kohari Y, Murata M. Catalysts 2019; 9: 514
• 7 List B, Lerner RA, Barbas CF. III. J. Am. Chem. Soc. 2000; 122: 2395
• 8 Aldol Products 4a–h; General Procedure A mixture of 1d (20 μmol, 10.7 mg), MeOH (0.1 mL), and acetone (3; 2 mmol, 0.15 mL) was stirred at –40 °C for 10 min. The appropriate α-keto amide 2 (0.1 mmol) was added, and the mixture was stirred at –40 °C for 5 d then concentrated under reduced pressure. The aldol product was purified by column chromatography (silica gel, hexane–EtOAc). The enantiomeric excess of the aldol adduct was determined by chiral HPLC. 2-Hydroxy-N-methyl-4-oxo-2-phenylpentanamide (4a) White solid, 20.8 mg (94%, 91% ee); mp 71–73 °C; [α]_D ²³ +169.4 (c = 0.13, CHCl₃). HPLC [Daicel CHIRALPAK AD-H, hexane–i-PrOH (90:10), 1.0 mL/min, 254 nm, 35 °C]: t _R (minor) = 10.9 min; t _R (major) = 12.3 min. ¹H NMR (600 MHz, CDCl₃): δ = 7.59–7.57 (m, 2 H), 7.37–7.32 (m, 2 H), 7.28 (tt, J = 7.3, 1.5 Hz, 1 H), 6.78 (br s, 1 H), 5.34 (s, 1 H), 3.67 (d, J = 17.6 Hz, 1 H), 2.79 (d, J = 17.6 Hz, 1 H), 2.76 (d, J = 5.0 Hz, 3 H), 2.24 (s, 3 H). ¹³C NMR (150 MHz, CDCl₃): δ = 212.2, 174.1, 141.3, 128.4, 127.8, 124.4, 78.2, 50.8, 31.3, 26.1. HRMS (EI): m/z [M⁺] calcd for C₁₂H₁₅NO₃: 221.1052; found: 221.1029.