Coupling biocatalysis and click chemistry: One-pot two-step convergent synthesis of enantioenriched 1,2,3-triazole-derived diols

Article abstract of DOI:10.1039/c3cc38674k

A fully convergent one-pot two-step synthesis of different chiral 1,2,3-triazole-derived diols in high yields and excellent enantio- and diastereoselectivities has been achieved under very mild conditions in aqueous medium by combining a single alcohol dehydrogenase (ADH) with a Cu-catalysed 'click' reaction. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3cc38674k

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Coupling biocatalysis and click chemistry: one-pot
two-step convergent synthesis of enantioenriched
1,2,3-triazole-derived diols†
Cite this: DOI: 10.1039/c3cc38674k
Received 3rd December 2012,
Accepted 7th February 2013
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An´ıbal Cuetos, Fabricio R. Bisogno,z Ivan Lavandera* and Vicente Gotor*
DOI: 10.1039/c3cc38674k
www.rsc.org/chemcomm
A fully convergent one-pot two-step synthesis of different chiral triazole-containing structures are versatile ligands in coordination
1,2,3-triazole-derived diols in high yields and excellent enantio- and chemistry,13b and some related complexes have displayed antitumor
diastereoselectivities has been achieved under very mild conditions activities.13c In this sense, the copper(I)-catalysed version of the
in aqueous medium by combining a single alcohol dehydrogenase Huisgen cycloaddition in water between an alkyne and an azido
(ADH) with a Cu-catalysed ‘click’ reaction.
compound to form them, is perhaps the most outstanding example
of the so-called ‘click’ chemistry.14 A Cu(I) salt must be added into
Nowadays, the selective synthesis of enantioenriched derivatives for the reaction medium, but in the last few years, the in situ formation
fine chemicals must go in hand with the design of sustainable of this species by reduction of Cu(II) salts with e.g. ascorbate has been
processes.1 Hence, final targets must be obtained with excellent mostly employed. Albeit more scarcely studied, comproportionation
purities, but minimising the use of harmful solvents, reagents and of a Cu(II) salt with Cu(0) is gaining more relevance due to availability
also purification steps involved in a synthetic pathway.2 In this sense, and economic issues.15 Noteworthily, there are few examples in
the employment of water as reaction medium,3 recyclable catalysts4 which biocatalysis and click chemistry have been combined in one-
and the design of one-pot multi-step sequential or concurrent pot procedures, although both protocols can be perfectly compatible.
synthesis5 are highly desired. In the last few years enzymes have In this sense, the kinetic resolution of aromatic epoxides by
been elegantly employed together with organo- or metal-catalyst(s), halohydrin dehalogenase (Hhe)-catalysed azidolysis has been
achieving (chemoenzymatic) one-pot multi-step synthesis of reported, affording the corresponding b-azido alcohols that
interesting compounds.6 Besides lipase-based dynamic processes,7,8 subsequently reacted with alkynes to achieve chiral 1,2,3-triazole
most of the examples deal with the concurrent use of oxidoreductases alcohols.16 Yields of these processes could be increased by
with organo-9 or metal-10 catalysts. For instance, alcohol dehydro- introducing the bioreduction of an a-halo ketone as a first step.17
genases,11 responsible for the stereoselective reduction of carbonylic
Herein, we envisaged a one-pot two-step fully convergent
compounds, have been successfully combined with proline-9a or strategy in which, starting from two achiral compounds, a pair
Zn-catalysed10b aldol reactions to obtain enantioenriched 1,3-diols, of suitable chiral precursors could be stereoselectively formed
and with Pd-based catalysts for Wacker–Tsuji,10a Heck,10c,j Suzuki,10d,f,i and then assembled by a ‘click’ reaction, giving rise to a single
or Suzuki–Miyaura10h reactions. In these examples, the non-enzymatic compound bearing two chiral centres (Scheme 1).
transformation occurred first to afford the non-isolated (di)ketone
which further underwent ADH-catalysed reduction.
The synthesis of the enantioenriched 1,2,3-triazole-derived diols
was performed by the concurrent stereoselective bioreduction of an
1,2,3-Triazoles are very important pharmacophores that can exert a-azido- and an alkynyl ketone, followed by cycloaddition catalysed
multiple biological activities,12 e.g., hydroxylated derivatives have
been described as potent b-adrenergic receptor blockers.13a Besides,
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Dpto. de Quımica Organica e Inorganica, Instituto Universitario de Biotecnologıa de
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Asturias, Universidad de Oviedo. c/Julian Claverıa 8, 33006, Oviedo, Spain.
E-mail: lavanderaivan@uniovi.es, vgs@uniovi.es; Fax: +34 985 103448;
Tel: +34 985 103452
† Electronic supplementary information (ESI) available: Experimental proce-
dures, analytics and copies of 1H- and 13C-NMR spectra of the novel compounds.
See DOI: 10.1039/c3cc38674k
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‡ Current address: INFIQC-CONICET, Dpto. de Quımica Organica, Facultad de
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Scheme 1 One-pot two-step fully convergent strategy combining stereo-
Ciencias Quımicas, Universidad Nacional de Cordoba, Ciudad Universitaria,
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selective enzymatic and metal-catalysed transformations.
CP 5000, Cordoba, Argentina.
c
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Table 1 Stereoselectivities in selected bioreductions of alkynones 1a–b and a-
azido ketones 1c–g employing ADHs (t = 24 h)a
Ketoneb E. coli/ADH-A E. coli/ADH-T E. coli/TesADH LBADH LKADH
1a
96 (S)
98 (R)
>99 (R)
>99 (R)
99 (R)
>99 (R)
>99 (R)
96 (S)
90 (R)
>99 (R)
—
99 (R)
>99 (R)
—
76 (S)
96 (R)
—
—
—
—
—
64 (R) —
>99 (S) 99 (S)
>99 (S) 98 (S)
1bc
1cc
1dc
1ec
1fc
1gc
Scheme 2 Chemoenzymatic protocol to synthesise enantioenriched 1,2,3-tri-
—
—
azole-derived diols.
99 (S) 99 (S)
>99 (S)
—
—
—
by Cu(I) in situ formed via comproportionation of Cu(II) and Cu(0)
(Scheme 2).
a
For experimental details, see ESI. b In all cases where an ee value appears,
the conversion was quantitative. For incomplete reactions, see c and ee in
Tables S1 and S2 in ESI. c Change in Cahn–Ingold–Prelog (CIP) priority.
Several practical issues were considered in advance: (a) both
ketones should be quantitatively reduced so, after the cycloaddition
step, only diols must be formed, avoiding hydroxy ketones or
diketones that would make the purification more complex;
(b) alkynyl ketones may decompose in aqueous media,18 so the
bioreduction step must also be quick and clean; (c) the selectivity of
the ADH-catalysed process must be high to avoid the formation of
diastereoisomers at the end of the sequence; (d) the cycloaddition
step must take place in the presence of the enzyme and the
hydroalcoholic medium without the loss of the performance; and
(e) it would be highly desirable that the Cu(0)-precatalyst source
could be easily recycled with no stirring impairment.
In a first set of experiments, we studied the influence of different
alkynones (1a–b) and a-azido ketones (1c–g) bearing aliphatic or
aromatic (phenyl or 2-naphthyl) groups with e.g. nitro or hydroxy
moieties on ADH-catalysed reduction using Prelog ADHs over-
expressed in E. coli (ADH-A from Rhodococcus ruber,19 ADH-T from
Thermoanaerobium sp.,20 and TesADH from Thermoanaerobacter
ethanolicus21) or commercially available anti-Prelog enzymes (LBADH
from Lactobacillus brevis22 or LKADH from Lactobacillus kefir23). In
ADH-catalysed bioreductions, TrisꢀHCl buffer is usually a suitable
medium, but it was observed that alkynones were not stable, so we
turned to phosphate buffer (50 mM) pH 7.5 at 30 1C and 250 rpm, in
which these derivatives remained stable for longer periods. Under
these conditions, the reduction of all ketones was tested using ADHs
(Table 1), showing in some cases quantitative conversions (c) and
excellent stereoselectivities (ee).
we envisaged a system that could be simple, economic and environ-
mentally friendly to obtain Cu(I) via comproportionation using a Cu
wire with a catalytic amount of CuSO4. Thus, a copper wire was
rolled on a magnetic bar (see ESI†), allowing at the same time
stirring, easy recovery and its reuse along several cycles. Different
solvent mixtures were tried (H2O:tBuOH 1 : 1 v vꢁ1; H2O:iPrOH
1:1 v vꢁ1; H2O:iPrOH 95 : 5 v vꢁ1) at 60 1C for 24 h, obtaining in all
cases the triazole diols with quantitative conversions, but since the
enzymatic step took place with iPrOH (5% v vꢁ1),24 we chose the last
setting to perform the sequential chemoenzymatic transformation.
Microwave heating was also tried, but due to the formation of
by-products, e.g. 1,5-regioisomers,25 this methodology was not
further investigated. After four cycles, the Cu wire got passivated,
but it could be recovered by simple washing with HCl 2 N for 5 min.
In the final stage, the one-pot fully convergent chemoenzymatic
approach was achieved furnishing the 1,2,3-triazole-derived diols
in good overall yields and excellent selectivities (Fig. 1). After
performing the bioreduction in phosphate buffer at 30 1C with
2-propanol for 24 h, the copper wire and CuSO4 were added into the
reaction mixture, and it was heated up at 60 1C for 24 h. While with
alkynone 1b syn-3 diols were obtained, in the case of substrate 1a,
Especially ADH-A as a Prelog representative enzyme and LBADH
as an anti-Prelog counterpart rendered quantitative conversions and
excellent ee with several substrates. Furthermore, they were able
to accept both alkynones and a-azido ketones, being excellent
candidates to achieve the desired one-pot process. In a second stage,
simultaneous bioreduction of a 1 :1 mixture of alkynone–azido
derivatives was tried to study if any interference could exist, either
between reactants or with the ADH. Pleasingly, both substrates were
perfectly reduced with the same values of stereoselectivity and no
cross-inhibition was detected.
Later, the Cu-catalysed ‘click’ reaction was studied to find out
suitable conditions. In this regard, the source of Cu(I) was firstly
studied using racemic alcohols, rac-2a and rac-2c, as model substrates
to afford a mixture of syn- and anti-3ac diols. CuSO4–ascorbic acid in
a H2O:tBuOH 1 : 1 v/vꢁ1 mixture was tried at room temperature
for 24 h, but the conversion was not complete. At this point,
Fig. 1 Examples of 1,2,3-triazole-derived diols synthesised using the chemoenzymatic
approach. ee values correspond to the major diastereoisomer obtained. Isolated yields
(69–85%) are relative to the diastereoisomeric mixture of the final diols.
c
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since the enzyme recognised the ethynyl group as the ‘big’ moiety,26
anti-3 diols were synthesised.
¨
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tions has been developed. Hence, starting from two prochiral
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Chem. Commun.