Thiol-free chemoenzymatic synthesis of β-ketosulfides

Article abstract of DOI:10.3762/bjoc.15.34

A preparation of β-ketosulfides avoiding the use of thiols is described. The combination of a multicomponent reaction and a lipase-catalysed hydrolysis has been developed in order to obtain high chemical diversity employing a single sulfur donor. This methodology for the selective synthesis of a set of β-ketosulfides is performed under mild conditions and can be set up in one-pot two-step and on a gram-scale.

Full text of DOI:10.3762/bjoc.15.34

Thiol-free chemoenzymatic synthesis of β-ketosulfides
Adrián A. Heredia‡1, Martín G. López-Vidal‡1, Marcela Kurina-Sanz2,
Fabricio R. Bisogno*1 and Alicia B. Peñéñory1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2019, 15, 378–387.
1INFIQC-CONICET, Departamento de Química Orgánica, Facultad de
Ciencias Químicas, Universidad Nacional de Córdoba. Ciudad
Universitaria, Córdoba, X5000HUA, Argentina and
2INTEQUI-CONICET, Área de Química Orgánica, Facultad de
Química, Bioquímica y Farmacia, UNSL. Chacabuco y Pedernera,
San Luis, 5700, Argentina
doi:10.3762/bjoc.15.34
Received: 31 October 2018
Accepted: 28 December 2018
Published: 11 February 2019
Associate Editor: D. Spring
Email:
Fabricio R. Bisogno* - fbisogno@fcq.unc.edu.ar
© 2019 Heredia et al.; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author ‡ Equal contributors
Keywords:
ketosulfides; lipase; multicomponent; sulfoxide; thiol-free
Abstract
A preparation of β-ketosulfides avoiding the use of thiols is described. The combination of a multicomponent reaction and a lipase-
catalysed hydrolysis has been developed in order to obtain high chemical diversity employing a single sulfur donor. This methodol-
ogy for the selective synthesis of a set of β-ketosulfides is performed under mild conditions and can be set up in one-pot two-step
and on a gram-scale.
Introduction
Throughout the years, several strategies have been developed to protocols for the synthesis of organosulfur compounds is highly
build up organic compounds bearing a sulfide moiety [1,2]. desirable [9].
Often, thiols (or the corresponding thiolate anions) are em-
ployed as nucleophilic sulfur reagents in order to react with a In particular, the β-ketosulfide motif is present in natural prod-
suitable electrophile [3,4], however, there are certain negative ucts [10,11] and synthetic compounds displaying important
aspects of thiols that need to be taken into account (i.e., foul bioactivities (Figure 1) [12-16].
smell, easy oxidation into disulfide, participation as donors in
one-electron events, reaction with olefins through ene-type Besides the well-established protocols that make use of thiols
reactions, etc) [5-8]. Hence, the development of thiol-free (Scheme 1) [17-21], other methodologies employing different
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Beilstein J. Org. Chem. 2019, 15, 378–387.
Figure 1: Selected examples of valuable β-ketosulfides. A: bioactive synthetic compounds, B: natural products.
Scheme 1: Different strategies for the preparation of β-ketosulfides.
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Beilstein J. Org. Chem. 2019, 15, 378–387.
sulfur sources such as disulfides or silylsulfides have been de- ents, we envisaged a two-step methodology starting from an
scribed, which most of them involves metals, e.g., indium [22], α-haloketone, a thiocarboxylate and an alkyl (pseudo)halide
copper [23], mercury [24], or organocatalysts [25].
(Scheme 2). Thus, once the enolester is formed, an enzyme-cat-
alysed hydrolysis and protonation of the resulting enolate would
β-Ketosulfides, in addition, play an important role as precur- render the title β-ketosulfide products. This strategy avoids the
sors in the synthesis of bioactive compounds [13,26,27], sub- use of acidic or basic conditions for the hydrolysis of the ester
strates for multicomponent reactions [28], and lately, have suc- moiety that, normally, result unsuitable for methylene active-
cessfully been applied in polymer photodecoration [29,30]. containing products as β-ketosulfides [44].
They can easily be reduced into chiral hydroxy derivatives [31]
and properly oxidised at sulfur to generate the corresponding Results and Discussion
chiral sulfoxides or sulfone derivatives [32].
In a first set of experiments, a series of commercially available
hydrolases were screened in aqueous buffer containing 5% v/v
Multicomponent reactions (MCRs), in which three or more of an organic cosolvent towards a β-thioalkyl-substituted
reagents react giving rise to generally complex molecules in enolester as model substrate 1a (Table 1). As enol acetates,
one-pot, have arisen as a powerful tool to connect fragments in (e.g., vinyl acetate, isopropenyl acetate), are outstanding acyl
a simple manner, avoiding cost and time-consuming isolation of donors in lipase-catalysed reactions [45], it is expected that the
intermediates and creating chemical diversity with high atom desired lipase-catalysed hydrolysis shall be controlled by the
economy [33-36].
steric demand of substituents at the enoyl moiety. On the other
hand, cosolvent and buffer composition are two factors that may
In the last two decades, enzymes have found a privileged place influence both, substrate solubility and enzyme activity. Hence,
in organic chemistry by virtue of its inherent selectivity and two different buffer solutions (KPi 50 mM pH 7.5 and Tris·HCl
eco-friendly reaction conditions. Such properties, among other, 50 mM pH 7.5) containing 5% v/v of an (miscible or inmis-
make them catalysts of choice for multiple kilo- and even ton- cible) organic cosolvent, were tested towards a set of commer-
scale industrial processes [37,38].
cially available lipases. In this line, a remarkable hydrolytic ac-
tivity (89–99% conversion) was found for Candida antarctica
The combination of MCRs and enzymatic catalysis offers a lipase B (CAL-B, Novozym® 435) in all tested conditions
myriad of new possibilities by taking advantage of the robust- (Table 1, entry 2). For porcine pancreas lipase (PPL), a differ-
ness and bond forming power of MCRs and the mildness and ent scenario was found, since conversion was strongly influ-
selectivity displayed by biocatalysts [39,40]. Such a combina- enced by buffer composition and, to a lesser extent, the cosol-
tion has been scarcely exploited as compared to strategies com- vent nature. For instance, when toluene was tested as cosolvent,
prising transition metal catalysis and biocatalysis [41] or, in a conversions varied from 40% (in KPi) to 9% in (Tris·HCl), and
lesser extent, organocatalysis and enzymes [42].
for DMSO conversions range from 90% (in KPi) to 20%
(Tris·HCl, Table 1, entry 4). Candida rugosa lipase (CRL, entry
In this context, a versatile and robust synthesis of β-ketosul- 5) and immobilised Burkholderia cepacia lipase (PSL-IM,
fides avoiding the use of thiols under benign conditions is Table 1, entry 3) displayed lower activities (3–26% and
highly desirable. Based on our previously developed MCR [43] 6–32% conversion, respectively). Meanwhile, Candida antarc-
for the synthesis of enol esters with sulfur-containing substitu- tica lipase A (CAL-A, Table 1, entry 1), immobilised Ther-
Scheme 2: Thiol-free chemoenzymatic synthesis of β-ketosulfides.
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Beilstein J. Org. Chem. 2019, 15, 378–387.
Table 1: Screening of hydrolases and conditions towards a model substrate.a
entry hydrolase
MeCN 5%
Tris·HCl
DMSO 5%
Tris·HCl
toluene 5%
MTBE 5%
Tris·HCl
KPi
KPi
Tris·HCl
KPi
KPi
1
2
3
4
5
6
7
8
CAL-A
<1
93
7
<1
89
14
26
3
<1
3
>99
32
90
19
2
1
97
16
9
1
97
16
41
7
2
>99
10
25
20
5
1
CAL-B
90 (99)b
93
13
29
26
4
PSL-IM
PPL
6
24
26
1
20
3
CRL
7
Lypozyme TL-IM
Lypozyme RM
–
<1
2
<1
<1
<1
2
2
2
5
2
3
2
2
<1
<1
<1
<1
<1
<1
<1
aReaction conditions: 3 mg of 1a (30 mM) and 3 mg of enzyme, cosolvent 5% v/v, final volume 500 μL, 12 h; conversion was determined by GC-FID
% relative area; b1.25 mg of 1a (final conc. 12 mM) and 2 mg of enzyme.
momyces lanuginosa (Lypozyme TL IM, Table 1, entry 6) and
Rhizomucor miehei lipase (Lypozyme RM, Table 1, entry 7)
showed marginal or no activity in the tested conditions.
In general, no clear correlation could be drawn by considering
the cosolvent logP (or water miscibility) and buffer nature with
the lipase activity towards the model substrate 1a.
Once the best conditions were set, the model reaction was
monitored as a function of time (Figure 2). As can be seen, the
biohydrolysis of 1a reaches around 80% conversion at 2 h and
is complete after 8 h.
Next, a series of diversely substituted β-thioalkyl enol esters
Figure 2: Time-course plot for the CAL-B catalysed hydrolysis of 1a.
was submitted to CAL-B-catalysed hydrolysis under the chosen
conditions, as summarised in Table 2.
accepted as substrate (Table 2, entry 18). The same results were
As can be seen in Table 2, substrates containing diversely obtained when an ester moiety was pending at α-position (1s,
substituted aryl moieties at the α-position of the enol ester, Table 2, entry 19).
underwent smooth conversion (typically 94–99% except for
p-nitrophenyl derivative 1f, for which more enzyme was needed Substitution on the sulfur atom was also screened, and small
to reach 96%, Table 2, entry 6), regardless the electronic nature substituents [such as methyl- (1a), 2-hydroxyethyl- (1g), allyl-
of the substituents (see Table 2, entries 1–6) [46]. For aliphatic (1h)] rendered excellent conversions (98–99%, Table 2, entries
substituents at the α-position, a methyl group was perfectly 1, 7, and 8, respectively). For a bulkier linear S-substituent
accepted (Table 2, entries 22–24). Longer unbranched hydro- (butyl), 1k, the conversion dropped to 62% (Table 2, entry 11)
carbon was tolerated, although moderate conversion was and for S-Bn derivative 1i, a slower reaction took place,
achieved, even with higher lipase loading (Table 2, entry 12, reaching 41% conversion under standard conditions and an im-
1l). For the latter, it must be considered the additional bulky proved 94% conversion when the catalyst loading was risen to
o-iodobenzyl substituent attached to the sulfur. The bulky 50% (Table 2, entry 9). The S-(o-iodobenzyl) derivative 1j
alicyclic adamantyl α-substituent (compound 1r), was not (Table 2, entry 10) rendered a fair 19% conversion, considering
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Beilstein J. Org. Chem. 2019, 15, 378–387.
Table 2: Lipase-catalysed hydrolysis–protonation sequence over a series of β-thioalkyl enol esters.a
entry
1
substrate
product
conv. %b
>99
1a
1b
2a
2b
2
3
>99
>99
1c
2c
4
5
6
94
>99
1d
1e
2d
2e
40 (96)c
1f
1g
1h
2f
2g
2h
7
8
>99
98
9
41 (94)d
1i
2i
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Beilstein J. Org. Chem. 2019, 15, 378–387.
Table 2: Lipase-catalysed hydrolysis–protonation sequence over a series of β-thioalkyl enol esters.a (continued)
10
19
1j
2j
11
12
13
62
1k
1l
2k
2l
31 (61)c
52 (95)c (65)e
1m
2m
14
–
n.r.
1n
15
16
17
–
–
–
n.r.
n.r.
n.r.
1o
1p
1q
18
19
–
–
n.r.
n.r.
1r
1s
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Beilstein J. Org. Chem. 2019, 15, 378–387.
Table 2: Lipase-catalysed hydrolysis–protonation sequence over a series of β-thioalkyl enol esters.a (continued)
20
21
–
–
n.r.
n.r.
1t
1u
22
23
24
>99
>99
>99
1v
2v
1w
2w
1x
2x
aReaction conditions: Substrate 1a–x (12 mM) and 2 mg of CAL-B (Novozym® 435), final volume 500 μL, Tris·HCl buffer (50 mM pH 7.5), cosolvent
DMSO 5% v/v, 30 °C, 24 h, 250 rpm; bGC–FID % relative area; c4 mg of enzyme; d3 mg of enzyme; e48 h reaction time; n.r.: no reaction.
the high steric demand of α- and ß-substituents. For even scale, as shown in Scheme 3, and isolated the products in good
bulkier S-(bromobenzodioxole)methyl derivative 1t (Table 2, yields.
entry 20) no conversion was detected at 24 h. Similar results
were obtained with the S-propyl-3-phthalimido derivative 1u As depicted in Scheme 3, α-chloroacetophenone (1.0 g,
(Table 2, entry 21) and the dimeric substrate bis-enol acetate 1p 6.47 mmol) was reacted with 1.1 equiv of potassium thio-
(Table 2, entry 16), suggesting that o-iodobenzyl substituent is acetate, 1.1 equiv of allyl bromide and 2 equiv of K2CO3 in
approaching the upper limit of steric congestion. Additional 5 mL of DMSO. After 24 h, 45 mL of buffer (Tris·HCl 50 mM
β-substitution could be tolerated in the tetralone-derived sub- pH 7.5) were added. Then, KH2PO4 was added in order to reach
strate, 1m, affording 52 and 65% conversion at 24 and 48 h, re- pH ≈7.5, followed by 200 mg of CAL-B. It is worth noting that
spectively. Accordingly, 95% conversion at 24 h was achieved this amount represents a ≈8 fold decrease of used enzyme as
by a twofold increase of lipase loading (Table 2, entry 13). On compared to the corresponding small scale reaction (Table 2,
the contrary, no conversion was detected for the α,β-diphenyl entry 8). After 24 h, we were delighted to find that no enolester
enol acetate substrate 1q (Table 2, entry 17).
was detected by TLC monitoring, and after extraction and silica
gel column chromatography (petroleum ether/EtOAc 9:1) a
In order to test the chemoselectivity of the enzymatic hydroly- 68% isolated yield was obtained for the S-allyl-β-ketosulfide
sis, we turned our attention to the acyl moiety of the enol ester. 2h.
Hence, only acetate was easily accepted while ethyl thiocar-
bonate 1n (Table 2, entry 14) and benzoate enol esters 1o The obtained β-ketosulfides can be chemoselectively converted
(Table 2, entry 15), were recovered unaltered. These results into the corresponding sulfoxide/sulfone derivative [47,48]. It is
pave the way for developments of orthogonal deprotection well known that β-ketosulfoxides and β-ketosulfones are valu-
protocols in the future.
able moieties occurring in bioactive molecules, such as the
immunosuppresor oxisurane [49], quinolone vasodilator flose-
Once the enzymatic hydrolysis and the MCR reaction were op- quinan [50], and potential drugs for the treatment of diabetes
timised, we investigated the robustness of this protocol for the [51]. As such, employing simple transformations, compound 2a
one-pot two-step preparation of different β-ketosulfide was conveniently oxidised in moderate to good isolated yields
departing from the corresponding α-haloacetophenone at higher (45% ketosulfoxide 3; 70% ketosulfone 4, Scheme 4).
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Beilstein J. Org. Chem. 2019, 15, 378–387.
Scheme 3: One-pot two-step preparation of phenacylalkylsulfides. aReaction conditions: i. α-haloketone (0.25 mmol), potassium thioacetate
(1.1 equiv), alkyl halide (1.1 equiv) and K2CO3 (2.0 equiv) in 500 µL of DMSO, 5 h at room temperature; ii. 100 mg of CAL-B (Novozyme 435) and
9.5 mL of Tris·HCl buffer (50 mM pH 7.5), 30 °C, 24 h, 250 rpm. bReaction performed using 1.0 g of α-chloroacetophenone, potassium thioacetate
(1.1 equiv), alkyl halide (1.1 equiv) and K2CO3 (2.0 equiv) in 5 mL of DMSO, 200 mg of CAL-B and 45 mL of Tris-HCl buffer (50 mM pH 7.5), 24 h at
room temperature one-pot two-step preparation of the phenacyl allyl sulfide 2h. cIsolated yield.
Scheme 4: Selective oxidation of the β-ketosulfide 2a.
Conclusion
Acknowledgements
In this work we have shown the development of a versatile CONICET, FONCyT and SeCyT-UNC are acknowledged for
chemoenzymatic methodology for the efficient preparation of research funding. AAH and MGL-V thankfully acknowledge
β-ketosulfides avoiding the use of thiols. Candida antarctica CONICET for postdoctoral and predoctoral fellowships, respec-
lipase B resulted active in the presence of any tested cosolvent, tively. We are deeply indebted with Prof. Vicente Gotor-
regardless the buffer composition. Alternatively, PPL can be Santamaría for the generous donation of lipase samples.
employed in the presence of DMSO as cosolvent and KPi buffer
ORCID® iDs
Adrián A. Heredia - https://orcid.org/0000-0002-2242-8855
with good results. The steric congestion of the substrates
resulted the main factor affecting the lipase activity, being the
Martín G. López-Vidal - https://orcid.org/0000-0003-1748-3697
electronic nature of the substituents EDG/EWG, less important.
Marcela Kurina-Sanz - https://orcid.org/0000-0001-9839-6573
The combination of the MCR and the lipase-catalysed hydroly-
Fabricio R. Bisogno - https://orcid.org/0000-0002-9153-1274
sis can be carried out a in one-pot two-step fashion and afford
the desired products in high isolated yield and high selectivity.
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