Dynamic kinetic resolution chemoenzymatic of tertiary alcohols

• Grant number: 19/15230-8
• Support Opportunities: Regular Research Grants
• Start date: January 01, 2021
• End date: December 31, 2022
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Organic Chemistry
• Principal Investigator: Humberto Márcio Santos Milagre
• Grantee: Humberto Márcio Santos Milagre
• Host Institution: Instituto de Química (IQ). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil

Abstract

The enantioselective synthesis of tertiary alcohols and their derivatives has attracted many efforts and is still a challenge for synthetic organic chemist. Currently, there is no report in the literature of a standard methodology for the synthesis of these compounds. Among the methods developed to obtain enantiomerically pure compounds, the resolution of racemates (chemical or enzymatic) stands out for being one of the methods most used by the fine chemical and pharmaceutical industries. The resolution of secondary alcohols is a very well-established methodology, but the resolution of tertiary alcohols is a nascent area, mainly the enzymatic kinetic resolution. The chemoenzymatic dynamic kinetic resolution (DKR) of tertiary alcohols is still a very nascent area and that requires efforts for its development. This project aims at the development of a chemoenzymatic DKR methodology for the preparation of enantiomerically pure benzylic cyclic tertiary alcohols using the following system: a hydrolases-class enzyme (lipase or esterase) and a heterogeneous vanadium catalyst. In this catalytic system, the enzyme will be responsible for the enantioselective step and the vanadium catalyst for the racemization step. Due to the success of lipase CAL-A in performing the kinetic resolution of cyclic benzyl alcohols, we chose to select this enzyme and these substrates as the starting point for the development of this work. Vanadyl sulfate was selected as racemization agent because of its compatibility with lipases and the experience of our research group chemoenzymatic DKR of secondary alcohols. The model substrate for this reaction will be the benzyl cyclic alcohol 1-methyl-1,2,3,4-tetrahydronaphthalen-1-ol, and thereafter, the scope of the reaction will be evaluated for a number of variants of this compound. The main challenge in this project is to obtain an efficient DKR methodology by combining the enantioselective (enzymatic) catalytic step with a catalyst for the racemization so that both are highly active and selective under the same reaction conditions. The importance of this project is based on the fact that, to date, there is only one chemoenzymatic RCD methodology, from a single example of tertiary alcohol, reported in the literature, with moderate results, which is a current and necessary challenge in the area of knowledge in which this project is inserted. (AU)

Scientific publications

(4)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

NETO, LAERTE GANEO; MILAGRE, CINTIA DUARTE FREITAS; MILAGRE, HUMBERTO MARCIO SANTOS. Enantioselective transesterification of a propargyl tertiary alcohol by Candida antarctica lipase A: A reaction medium engineering approach. RESULTS IN CHEMISTRY, v. 5, p. 6-pg., 2023-05-24. (19/15230-8)

MORAES, MARAYLLA I.; IGLESIAS, CESAR; TEIXEIRA, IRIS S.; MILAGRE, HUMBERTO M. S.; GIORDANO, SONIA RODRIGUEZ; MILAGRE, CINTIA D. F.. Biotransformations of nitriles mediated by in vivo nitrile hydratase of Rhodococcus erythropolis ATCC 4277 heterologously expressed in E. coli. RESULTS IN CHEMISTRY, v. 5, p. 7-pg., 2023-01-03. (14/50249-8, 19/15230-8, 14/50926-0)

TEIXEIRA, IRIS S.; FARIAS, ANDRE B.; HORTA, BRUNO A. C.; MILAGRE, HUMBERTO M. S.; DE SOUZA, RODRIGO O. M. A.; BORNSCHEUER, UWE T.; MILAGRE, CINTIA D. F.. omputer Modeling Explains the Structural Reasons for the Difference in Reactivity of Amine Transaminases Regarding Prochiral Methylketone. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 23, n. 2, JAN 2022. (14/50249-8, 19/15230-8, 14/50926-0)

LAIZA A. DE ALMEIDA; LAERTE GANÉO NETO; CINTIA D. F. MILAGRE; HUMBERTO M. S. MILAGRE. Enzymatic Kinetic Resolution of Tertiary Benzyl Bicyclic Alcohols: Studies of the Reaction Conditions for a More Efficient Protocol. Journal of the Brazilian Chemical Society, v. 35, n. 8, 2024-04-05. (19/15230-8)