Rational design of mimetic peptides based on promiscuous aldo-ketoreductase enzyme as asymmetric catalysts in aldol and Michael reactions

The asymmetric aldol and Michael reactions, as the most prominent carbon-carbon bond formation reactions, are the central study issues in the field of asymmetric synthesis. In this study, promiscuous aldo-ketoreductase (AKR) used to catalyze aldol reaction. between aromatic aldehydes and ketones. Go...

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Main Author:	Bayat, Saadi
Format:	Thesis
Language:	English
Published:	2014
Subjects:	Chemistry Chemistry Catalysis
Online Access:	http://psasir.upm.edu.my/id/eprint/55659/1/FS%202014%2032RR.pdf
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spelling	my-upm-ir.556592017-06-06T01:53:11Z Rational design of mimetic peptides based on promiscuous aldo-ketoreductase enzyme as asymmetric catalysts in aldol and Michael reactions 2014-03 Bayat, Saadi The asymmetric aldol and Michael reactions, as the most prominent carbon-carbon bond formation reactions, are the central study issues in the field of asymmetric synthesis. In this study, promiscuous aldo-ketoreductase (AKR) used to catalyze aldol reaction. between aromatic aldehydes and ketones. Good yield (up to 75%),moderate enantioselectivity (60%), and high diastereoselectivity (dr) up to 93/7 (anti/syn) were obtained. Several mimetic peptides from AKR’s active site were designed and synthesized as asymmetric catalysts in the aldol and Michael reactions. Mimetic peptides PE16aa (1), PH16aa (2), 16aa (3), 8aa (4), 8aa-z (5), 5aa (6), 3aa (7), Fmoc-KLH-R (8), K(z)LH-R (9), PYE (10), PEY (11), PHE (12), PEH (13),LFV (14) 4a and 4b were successfully synthesized using manually solid phase peptide synthesis protocol. Then, all of these mimetic peptides were employed to catalyze aldol reactions and peptides 2, 4, 4a, 4b, 10, 11, 12, and 13 were selected to catalyze Michael reactions. In the aldol and Michael reactions, peptide 4 exhibited the best results (up to 97% yield, up to 99.9% ee and dr up to 99/1). Peptide 1 produced a good yield (88%), moderate enantioselectivity (68%), and excellent diastereoselectivity (dr = 99/1). Peptide 2 afforded the desired anti aldol product in 95% yield, 86% ee and 95/5 dr. Peptide 3 exhibited moderate yield (67%) but poor enantioselectivity (39% ee). Peptide 5 showed good catalytic activity and produced high yield (89%) and enantioselectivity (86%). Pentapeptide 6 catalyzed aldol reaction in high diastereo-and enantioselectivity (dr = 99/1 and 90% ee). PHE showed the best reactivity and selectivity amongst four tripeptides (PYE, PEY, PEH, PHE) up to 94% ee and up to 95/5 dr. Peptide 2 afforded corresponding Michael reaction up to 89% yield, 44% ee, and 99/1 dr. Peptide 4 generated desired Michael product up to 95% yield, 84% ee and 95/5 dr. Mechanism study demonstrated that enamine intermediate and hydrogen-bonding interaction are very important for obtaining high enantiomeric excess. The reusability of peptide 4 as the best catalyst was also conducted for 10 times. Peptide 4 is able to hydrolysis esters in a good to excellent yields of up to 99.7 %. All mimetic peptides exhibited to be active in terms of reactivity and selectivity in c-c bond forming reactions. Chemistry Chemistry, Organic Catalysis 2014-03 Thesis http://psasir.upm.edu.my/id/eprint/55659/ http://psasir.upm.edu.my/id/eprint/55659/1/FS%202014%2032RR.pdf application/pdf en public phd doctoral Universiti Putra Malaysia Chemistry Chemistry, Organic Catalysis
institution	Universiti Putra Malaysia
collection	PSAS Institutional Repository
language	English
topic	Chemistry Chemistry Catalysis
spellingShingle	Chemistry Chemistry Catalysis Bayat, Saadi Rational design of mimetic peptides based on promiscuous aldo-ketoreductase enzyme as asymmetric catalysts in aldol and Michael reactions
description	The asymmetric aldol and Michael reactions, as the most prominent carbon-carbon bond formation reactions, are the central study issues in the field of asymmetric synthesis. In this study, promiscuous aldo-ketoreductase (AKR) used to catalyze aldol reaction. between aromatic aldehydes and ketones. Good yield (up to 75%),moderate enantioselectivity (60%), and high diastereoselectivity (dr) up to 93/7 (anti/syn) were obtained. Several mimetic peptides from AKR’s active site were designed and synthesized as asymmetric catalysts in the aldol and Michael reactions. Mimetic peptides PE16aa (1), PH16aa (2), 16aa (3), 8aa (4), 8aa-z (5), 5aa (6), 3aa (7), Fmoc-KLH-R (8), K(z)LH-R (9), PYE (10), PEY (11), PHE (12), PEH (13),LFV (14) 4a and 4b were successfully synthesized using manually solid phase peptide synthesis protocol. Then, all of these mimetic peptides were employed to catalyze aldol reactions and peptides 2, 4, 4a, 4b, 10, 11, 12, and 13 were selected to catalyze Michael reactions. In the aldol and Michael reactions, peptide 4 exhibited the best results (up to 97% yield, up to 99.9% ee and dr up to 99/1). Peptide 1 produced a good yield (88%), moderate enantioselectivity (68%), and excellent diastereoselectivity (dr = 99/1). Peptide 2 afforded the desired anti aldol product in 95% yield, 86% ee and 95/5 dr. Peptide 3 exhibited moderate yield (67%) but poor enantioselectivity (39% ee). Peptide 5 showed good catalytic activity and produced high yield (89%) and enantioselectivity (86%). Pentapeptide 6 catalyzed aldol reaction in high diastereo-and enantioselectivity (dr = 99/1 and 90% ee). PHE showed the best reactivity and selectivity amongst four tripeptides (PYE, PEY, PEH, PHE) up to 94% ee and up to 95/5 dr. Peptide 2 afforded corresponding Michael reaction up to 89% yield, 44% ee, and 99/1 dr. Peptide 4 generated desired Michael product up to 95% yield, 84% ee and 95/5 dr. Mechanism study demonstrated that enamine intermediate and hydrogen-bonding interaction are very important for obtaining high enantiomeric excess. The reusability of peptide 4 as the best catalyst was also conducted for 10 times. Peptide 4 is able to hydrolysis esters in a good to excellent yields of up to 99.7 %. All mimetic peptides exhibited to be active in terms of reactivity and selectivity in c-c bond forming reactions.
format	Thesis
qualification_name	Doctor of Philosophy (PhD.)
qualification_level	Doctorate
author	Bayat, Saadi
author_facet	Bayat, Saadi
author_sort	Bayat, Saadi
title	Rational design of mimetic peptides based on promiscuous aldo-ketoreductase enzyme as asymmetric catalysts in aldol and Michael reactions
title_short	Rational design of mimetic peptides based on promiscuous aldo-ketoreductase enzyme as asymmetric catalysts in aldol and Michael reactions
title_full	Rational design of mimetic peptides based on promiscuous aldo-ketoreductase enzyme as asymmetric catalysts in aldol and Michael reactions
title_fullStr	Rational design of mimetic peptides based on promiscuous aldo-ketoreductase enzyme as asymmetric catalysts in aldol and Michael reactions
title_full_unstemmed	Rational design of mimetic peptides based on promiscuous aldo-ketoreductase enzyme as asymmetric catalysts in aldol and Michael reactions
title_sort	rational design of mimetic peptides based on promiscuous aldo-ketoreductase enzyme as asymmetric catalysts in aldol and michael reactions
granting_institution	Universiti Putra Malaysia
publishDate	2014
url	http://psasir.upm.edu.my/id/eprint/55659/1/FS%202014%2032RR.pdf
_version_	1747812107645091840

Rational design of mimetic peptides based on promiscuous aldo-ketoreductase enzyme as asymmetric catalysts in aldol and Michael reactions

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