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An Accessible Continuous Flow Procedure for the Enantioselective Desymmetrization of a Key Precursor of Bioactive Myo‐Inositol Derivatives

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Evelin A. Manoel
Evelin A. Manoel
Evelin A. Manoel
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Marcela Vasconcelos at Instituto Federal de Educação, Ciência e Tecnologia do Rio de Janeiro (IFRJ)
Marcela Vasconcelos
Denise M. G. Freire
Denise M. G. Freire
Denise M. G. Freire
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Alessandro B. C. Simas at Federal University of Rio de Janeiro
Alessandro B. C. Simas
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Abstract and Figures

We report herein continuous flow conditions for the TL‐IM lipase‐catalyzed enantioselective desymmetrization of 4,6‐di‐O‐benzyl‐myo‐inositol, a relevant precursor of bioactive myo‐inositol derivatives to the D‐1‐O‐acetyl derivative. This study represents the first example of enantioselective desymmetrization of an inositol under continuous flow conditions. Given the roles of myo‐inositol derivatives in cell biology research and medicine, practical, sustainable, and efficient preparative procedures for chiral inositols are highly desirable. Upon testing substrate solutions in vinyl acetate/hexanes at various ratios and passing them through a packed‐bed lipase reactor, a home‐made assembly, we identified optimal conditions. Reactions conducted in a 1.0:1.5 vinyl acetate/hexanes mixture at 45 °C achieved conversions of 97–95% with residence times of 2.6–1.6 min, respectively. Notably, reactions in a more hydrophobic solvent system (1.0:2.5 vinyl acetate/hexanes) also showed high conversions (95%) at a 1.6‐min residence time, highlighting the benefits of increased solvent hydrophobicity. Productivity assessments and reuse experiments confirmed the robustness of the biocatalyst under flow conditions, contrasting with a significant decline in performance under batch conditions.
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Research Article
doi.org/10.1002/slct.202405535
www.chemistryselect.org
An Accessible Continuous Flow Procedure for the
Enantioselective Desymmetrization of a Key Precursor of
Bioactive Myo-Inositol Derivatives
Evelin A. Manoel,*[a,b]Marcela G. Vasconcelos,[c]Denise M. G. Freire,[b]
and Alessandro B. C. Simas*[c]
We report herein continuous ow conditions for the TL-IM
lipase-catalyzed enantioselective desymmetrization of ,-di-
O-benzyl-myo-inositol, a relevant precursor of bioactive myo-
inositol derivatives to the D--O-acetyl derivative. This study
represents the rst example of enantioselective desymmetriza-
tion of an inositol under continuous ow conditions. Given the
roles of myo-inositol derivatives in cell biology research and
medicine, practical, sustainable, and ecient preparative pro-
cedures for chiral inositols are highly desirable. Upon testing
substrate solutions in vinyl acetate/hexanes at various ratios and
passing them through a packed-bed lipase reactor, a home-
made assembly, we identied optimal conditions. Reactions
conducted in a .:. vinyl acetate/hexanes mixture at  °C
achieved conversions of –% with residence times of .–
. min, respectively. Notably, reactions in a more hydrophobic
solvent system (.:. vinyl acetate/hexanes) also showed high
conversions (%) at a .-min residence time, highlighting the
benets of increased solvent hydrophobicity. Productivity assess-
ments and reuse experiments conrmed the robustness of the
biocatalyst under ow conditions, contrasting with a signicant
decline in performance under batch conditions.
1. Introduction
Myo-inositol and its derivatives continue to garner attention
due to their wide-ranging biological activities, spanning cellular
signaling to therapeutic and nutritional applications.[–]These
interests have driven advancements in synthetic methodolo-
gies for inositols,[–]with notable progress reported in recent
years.[–]The sustainable production of myo-inositol itself
has also become a research focus.[,]Controlling stereochem-
istry in natural and synthetic compounds remains a signicant
challenge in organic chemistry. Enantioselective synthesis—the
controlled production of compounds with specic absolute
congurations—is vital for pharmaceuticals, both clinically and
for regulatory purposes.[,]The FDA’s  guidance under-
scored the preference for single enantiomer drugs over race-
mates during registration.[]Despite % of marketed pharma-
ceuticals being chiral, % are administered as racemates.[,]
[a] E. A. Manoel
Universidade Federal do Rio de Janeiro (UFRJ), Departamento de
Biotecnologia Farmacêutica, Faculdade de Farmácia, Centro de Ciências da
Saúde (CCS), Avenida Carlos Chagas Filho, 373. Centro de Ciências da Saúde,
Bloco K, Cidade Universitária CEP: 21941-902, Rio de Janeiro, Rio de Janeiro,
Brazil
E-mail: biorecados@yahoo.com.br
[b] E. A. Manoel, D. M. G. Freire
UFRJ, Departamento de Bioquímica, IQ, Bloco A, Cidade Universitária, Rio de
Janeiro, Rio de Janeiro 21941-909, Brazil
[c] M. G. Vasconcelos, A. B. C. Simas
UFRJ, Instituto de Pesquisas de Produtos Naturais Walter Mors (IPPN), CCS,
Bloco H, Cidade Universitária, Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
E-mail: abcsimas@ippn.ufrj.br
Desymmetrization of prochiral compounds is a powerful
tool for synthesizing chiral molecules, involving selective mod-
ications to remove symmetry elements.[,]Most reported
syntheses of inositols utilize the abundant cyclitol myo-inositol
as the starting material, as it features six oxygenated methinic
stereocenters on its carbocyclic backbone, all present in a single
diastereomeric form. Achiral meso precursors, such as myo-
inositol and its regioselectively protected derivatives, are ideal
candidates for enantioselective desymmetrization, as demon-
strated in several studies.[–]Lipases, known for their cat-
alytic prociency in desymmetrizations, oer attractive alter-
natives to classical resolution methods due to their potential
for higher yields (up to %) and operational practicality.[–]
However, their application to chiral inositol synthesis remains
underexplored.[–]
Compared to traditional resolution methods that rely on sep-
arations, lipase-catalyzed desymmetrization oers greater appeal
due to its ability to achieve maximum yields of up to %.
Despite its advantages and practicality, the application of lipases
to kinetic resolutions remains more limited than one might
expect.[–]
While lipase-catalyzed reactions have demonstrated success
in batch reactors, they often face challenges, including pro-
longed reaction times and high catalyst loads. These limitations,
however, can be eectively addressed through the use of con-
tinuous ow systems. Literature indicates that continuous ow
setups improve productivity and signicantly reduce reaction
times. Their advantages over batch reactors include superior pro-
cess control, increased eciency, and enhancements in product
quality, purity, and yield.[,,–]Among the available continu-
ous ow reactor congurations, packed-bed reactors (PBRs) are
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