The studies on chemoselective promiscuous activity of hydrolases on acylals transformations

Article abstract of DOI:10.1016/j.bioorg.2019.02.050

Chemoselective, mild and convenient protocol for the hydrolysis of the synthetically relevant acylals via promiscuous enzyme-catalyzed hydrolysis has been developed. It has been shown that promiscuous activity of the used hydrolases dominates their native activity related with carboxylic esters hydrolysis. The main advantage of the present methodology is that it can be conducted under neutral conditions at room temperature. Moreover, complete deprotection of acylals takes place within 10–20 min. Developed protocol can be used with compounds having a variety of hydrolytic labile groups since the cleavage is proceeded under neutral conditions and occurs exclusively on acylal moiety. Further this protocol was extended by the tandem Passerini multicomponent reaction leading to the α-acetoxy amides using acylals as the surrogates of the carbonyl components to P-MCR.

Full text of DOI:10.1016/j.bioorg.2019.02.050

BioorganicChemistryxxx(xxxx)xxx–xxx
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Bioorganic Chemistry
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The studies on chemoselective promiscuous activity of hydrolases on acylals
transformations
Dominik Koszelewski⁎, Ryszard Ostaszewski
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
A R T I C L E I N F O
A B S T R A C T
Keywords:
Chemoselective, mild and convenient protocol for the hydrolysis of the synthetically relevant acylals via pro-
miscuous enzyme-catalyzed hydrolysis has been developed. It has been shown that promiscuous activity of the
used hydrolases dominates their native activity related with carboxylic esters hydrolysis. The main advantage of
the present methodology is that it can be conducted under neutral conditions at room temperature. Moreover,
complete deprotection of acylals takes place within 10–20 min. Developed protocol can be used with compounds
having a variety of hydrolytic labile groups since the cleavage is proceeded under neutral conditions and occurs
exclusively on acylal moiety. Further this protocol was extended by the tandem Passerini multicomponent re-
action leading to the α-acetoxy amides using acylals as the surrogates of the carbonyl components to P-MCR.
Acylals
Deprotection
Biotransformation
Promiscuity
Chemoselectivity
1. Introduction
additions [12]. Promiscuous activities are generally considerably less
efficient than the primary functions of an enzyme [13]. Whereas most
Recently, biocatalytic transformations have attracted significant
attention due to their high selectivity and mild reaction conditions [1].
Moreover, a new frontier, refereed as a biocatalytic promiscuity, has
largely extended the application of enzymes in organic synthesis [2].
Enzyme promiscuity is the ability of enzymes to catalyze alternative
reactions that differ from their natural physiological activity [3]. En-
zyme promiscuity started as being perceived as “associated with un-
wanted side effects, poor catalytic properties and errors in biological func-
tion” [4]. Nowadays, this marvel is increasingly being refereed as a
phenomenon which dramatically enhance application of biocatalysis in
organic synthesis. Furthermore, enzyme promiscuity provides en-
vironmentally sustainable protocols for organic synthesis. Hult and
Berglund classified enzyme promiscuity into three major classes: con-
dition, substrate and catalytic promiscuity [2d]. First two promiscuities
of enzymes have been already communicated more than 100 years ago
by Bourquelot and Bridel, who used a crude preparation of biocatalyst
to obtain alkyl glucoside in dry alcohol [5]. If not all, several enzymes
are promiscuous in nature. Among them, hydrolases (EC 3.1.1.x) un-
doubtedly play an important role due to their high stability, wide
sources and broad range of substrates [6]. Several elegant examples
regarding the significance of enzymatic promiscuity have been re-
ported, such as multikomponent Ugi, Hantzsch or Mannich reactions
[7], Canizzaro disproportionation [8], Henry reactions [9], Morita-
Baylis-Hillman reaction [10], aldol condensation [11], or Michael
enzymes exhibit kcat/KM values in the order of 105–108 M−1 s−1 for
their native substrates, the magnitude of promiscuous activities varies
over more orders of magnitude. Although, the kcat/KM values for the
promiscuous substrates are very low, the rate accelerations and cata-
lytic proficiencies can be very high [14].
In our efforts to explore the application of this new area of enzyme
promiscuity, we became interested in the selective deprotection of
functional groups what is of great interest to organic chemists in the
aspect of total synthesis of complex organic compounds both in aca-
demia and industry [15]. Recently, 1,1-diacetates (acylals) received
increasing attention, since there are stable, easy to prepare and can be
used as an alternative to acetals for the chemoselective protection of
aldehydes in the presence of a ketone or other functional groups [16].
In this context, furfural (FUR) and 5-hydroxymethylfurfural (HMF)
which are popularly referred as “sleeping-giants” have been empha-
sized as one of the top value-added aldehydes derived from a biomass
[17]. The number of potential routes for transforming the furfural and
its analogue 5-hydroxymethylfurfural into synthetically relevant che-
micals e.g. 5-acetoxymethylfurfural (AMF), 5-dihydroxy-methyl-2-fur-
anoic acid, furfuryl alcohol or levulinic acid is enormous (Fig. 1) [18].
Deprotection of the 1,1-diacetates to their parent aldehydes is also
of practical importance and several methods have been reported in the
literature for this purpose [19]. However, many of these methods have
drawbacks, such as harsh acidic conditions, high reaction temperature
⁎ Corresponding author.
E-mail address: dominik.koszelewski@icho.edu.pl (D. Koszelewski).
https://doi.org/10.1016/j.bioorg.2019.02.050
Received 22 January 2019; Received in revised form 17 February 2019; Accepted 22 February 2019
0045-2068/©2019PublishedbyElsevierInc.
Pleasecitethisarticleas:DominikKoszelewskiandRyszardOstaszewski,BioorganicChemistry,https://doi.org/10.1016/j.bioorg.2019.02.050

D. Koszelewski and R. Ostaszewski
BioorganicChemistryxxx(xxxx)xxx–xxx
Fig. 1. Synthetically relevant aldehydes and examples of chemicals derived
from furfural (FUR) and 5-hydroxymethylfurfural (HMF).
and long reaction times what makes them incompatible with chemically
unstable compounds causing their decomposition [20]. Moreover, re-
ported protocols are not chemoselective causing hydrolysis of other
chemically labile groups present in the structure of the deprotected
compounds [21]. In addition to this, the majority of the catalysts used
for deprotection, especially the metal complexes are toxic, explosive or
expensive and the products require complex purification procedures
[22]. Due to the pharmacopoeia limits of heavy metal contaminations
(below 5 ppm) reported methods cannot be used in the pharmaceutical
and cosmetic industry. Therefore, development of a catalyst system that
do not contain harmful components like transition metals, strong acids
or bases seems highly desirable. As an alternative to the commonly
employed deprotection protocols, a biocatalytic approach can be ex-
pected to be beneficial due to mild reaction conditions, thereby ful-
filling the general principles of the sustainable chemistry. Enzymes are
also important in another aspect as they often display high chemos-
electivity what allows them to control the reaction pathways, prohi-
biting side-reactions [23]. Chemoselectivity is the existence of a pre-
ferential reaction of a chemical reagent with one functional group in the
presence of the other functional groups [24]. This incredible feature
makes enzymes a powerful tool in organic chemistry and is used more
and more often in vitro studies.
Scheme 1. Synthesis of 1,1-diacetates 2a-j from the corresponding aldehydes
1a-j.
1).
The conventional deprotection of the 1,1-diacetates is achieved ei-
ther under basic or acidic conditions by using e.g. sodium hydroxide or
hydrochloric acid in organic solvents [25], the harsh reaction condi-
tions make them inappropriate for the base- or acid-sensitive com-
pounds like furfural or cinnamaldehyde. A variety of reagents for the
removal of acylals have been developed to mend this inconvenience
[26]. Recently, some action has been taken to replace organic solvents
with environmentally benign water as
a
reaction medium
[16e,16f,22a,27]. Although some of these methods have convenient
protocols with good to high yields, they still suffer at least from one of
the following disadvantages: long reaction time, require high tem-
perature, lack of selectivity [28], the use of toxic metal catalysts and
involve strongly acidic or oxidizing conditions. Therefore, replacement
of these promoters with enzymes as a non-corrosive nature, and eco-
friendly catalysts is an area of current interest and play a significant
role in the development of clean technologies [29]. In 1997, Smonou
et al. have shown only a rudimentary studies on enantioselective re-
solution of racemic 2-phenylpropionaldehyde via enzymatic hydrolysis
of the corresponding acylal, with Candida rugosa lipase in aqueous
media. Under reported conditions in a matter of hours optically active
aldehydes were achieved with moderate enantiomeric excesses and low
[30]. The obtained results can be explained by the fact that obtained
chiral aldehydes are optically labile [31]. Inspired by this early re-
ported data we have initiated detailed investigation on enzymatic
acylals deprotection.
As a part of an ongoing research to elaborate environmentally sus-
tainable protocols, we wish to report a simple and efficient enzymatic
method for chemoselective deprotection of aldehydes catalyzed under
very mild reaction conditions. Additionally, we report our results on the
novel approach to the synthesis of α-acetoxy amides via chemoenzya-
matic tandem reaction in aqueous media.
2. Results
The model studies under enzymatic deprotection were performed
using benzylidene 1,1-diacetatein (2a) in phosphate buffer (50 Mm, pH
7.0) at 20 °C for 1 h. Initially, 10%v/v of acetone was used as a co-
solvent [32]. To find the most convenient biocatalyst more than 20
different commercially available hydrolases and 3 domestic prepared
liver acetone powders (Supplementary information) were screened
(Scheme 2). The progress of the reaction was followed by GC analysis.
After completion, the reaction mixture was extracted with ethyl
acetate and the crude product was purified by column chromatography
(ethyl acetate/hexanes). Among the tested biocatalysts several lead to
formation of benzaldehyde (1a) (Table 1, entries 3–16). Results are
In the model reactions corresponding 1,1-diacetates 2a-j were syn-
thesized from their parent aldehydes 1a-j using two different catalytic
systems reported in literature [21]. Application of the domestically
prepared catalyst, poly(4-vinylpyridine)-supported sulfuric acid and an
acetic acid anhydride in DCM at ambient temperature (Method A) re-
sulted in target products 2a-j with excellent yields, up to 99% (Scheme
1). In case of the aldehydes 1h-j the P4VP-H2SO4 catalyst turned out
inactive and the used substrates 1h-j were recovered. Application of a
Lewis acid BF3-OEt2 with acetic acid anhydride under solvent free
conditions at 0 °C (Method B) provided desired 1,1-diacetates 2h-j with
quantitative yields within few minutes (Supplementary data, Scheme
2

D. Koszelewski and R. Ostaszewski
BioorganicChemistryxxx(xxxx)xxx–xxx
Scheme 2. Deprotection of the 1,1-diacetate 2a to its parent aldehyde 1a.
Table 1
Enzyme catalyzed deprotection of the benzylidene 1,1-diacetatein (2a) to the
benzaldehyde (1a).a
Entry
Catalyst
Conv. [%]b
1
–
< 1
2
BSA
< 1
3
P4VP-H2SO4
7
4
Novozym 435
3
5
Candida cylindracea lipase
Candida rugosa lipase
Wheat germ lipase
Pseudomonas cepacia lipase
Pseudomonas fluorescence lipase
Hog pancreas lipase
Pig pancreas lipase
Rhizopus oryzae lipase
Aspergillus melleus acylase I
PLAP
57
6
15
Fig. 2. Time profile of conversion of 1a (–■–), butyl acetate (–●–) and benzyl
acetate (–▲–) in reaction catalyzed by BLAP. Reaction conditions: substrate
(1 mmol), acetone 10%v/v, PBS (50 mM, pH 7.4), 20 °C, 200 rpm, BLAP
(10 mg).
7
53
8
5
9
5
10
11
12
13
14
15
16
17
20
18
23
Table 2
72
Optimization of enzymatic deprotection of the benzylidene 1,1-diacetatein (2a)
> 99 (91%)
> 99 (95%)
> 99 (89%)
< 1
in PBS with various co-solvents catalyzed by BLAP.a.
BLAP
TLAP
Entry
Co-solvent
Conv. [%]b
BLAPc
1
2
3
4
5
6
7
8
9
–
73
a
Reaction conditions: 2a (1 mmol), acetone 10%v/v, PBS (50 mM, pH 7.4),
acetone 5%v/v
acetone 10%v/v
acetone 15%v/v
acetone 10%v/v
TBME
92
20 °C for 1 h, 200 rpm, enzyme (10 mg).
> 99
98
b
c
Determined by GC (Agilent VF-1701 ms). Isolated yields in brackets.
> 99c
82
Thermally deactivated catalyst.
MeCN
69
summarized in Table 1.
DMSO
75
Following examples indicated that enzymes provided from the an-
imal tissues and used as crude liver acetone powders (LAPs) from pig
(PLAP), bovine (BLAP) and turkey (TLAP) were the most efficient
biocatalyst resulted in quantitative deprotection of the acylal 2a and
very high isolated yield of the corresponding aldehyde 1a, up to 95%
(Table 1, entries 14–16). Recently, LAPs have been recognized as an
inexpensive and accessible sources of the biocatalysts for chemo- end
enantioselective transformations [33]. The control experiment without
the enzyme proved that the non-enzymatic reaction does not occur
(Table 1, entry 1). Furthermore, the denatured BLAP (denatured by
heating) or BSA (Table 1, entries 2 and 17) was used as catalyst in this
reaction and the result was similar to the control (Table 1, entry 1).
P4VP-H2SO4 used initially for an aldehyde protection turned to be in-
efficient in reverse reaction under studied conditions providing 1a with
very low conversion (Table 1, entry 3). Based on the preliminary re-
sults, BLAP was arbitrary selected and more efforts were taken to im-
prove the overall procedure. Detailed analysis of the reaction progres-
sion revealed that the reaction proceeded smoothly and is complete
within 15 min (Fig. 2).
THF
85
a
Reaction conditions: 2a (1 mmol), co-solvent 10%v/v, PBS (50 mM, pH
7.4), 20 °C for 20 min, 200 rpm, BLAP (10 mg).
b
c
Determined by GC (Agilent VF-1701 ms).
Result after 12 min. at 30 °C.
miscible THF (Table 2, entries 6 and 9).
Only, slight increase in the conversion of 2a comparable with this
for neat buffer was observed for DMSO (Table 2, entry 8). The results
indicated that the most suitable solvent for the enzymatic reaction was
at first applied acetone, which offers the highest quantitative conver-
sion to aldehyde 1a at the concentrations of 10%v/v (Table 2, entry 3).
Any variation in the concentration of this solvent resulted in the de-
crease of the reaction conversion (Table 2, entries 1 and 3). The ele-
vation of the medium temperature to 30 °C manifested in higher reac-
tion rate leading to the product 1a with quantitative conversion within
12 min (GC and TLC analysis) (Table 2, entry 5). Finally, the enzymatic
deprotection was carried on a preparative scale. Thus, 1 g (5 mmol) of
the acylal 2a was accomplished within 20 min with 92% yield of the
isolated benzaldehyde 1a (conv. > 99%).
The influence of the type of the water-miscible and immiscible co-
solvent on the lipase-catalyzed reaction was widely reported in recent
years, as it is one of the most easily altered factors in enzymatic reaction
[34]. Simultaneously, the influence of various co-solvents; methyl tert-
butyl ether (TBME), acetonitrile (MeCN), THF and DMSO on the reac-
tion of 2a with BLAP was investigated (Table 2). Deprotection of the
acylal 2a was conducted in phosphate buffer (PBS, pH 7.4) with 10 %v/
v co-solvent at 20 °C for 20 min. Although, the substrate 2a was hardly
dissolve in water, enzymatic hydrolysis does take place without co-
solvent providing product 1a with high conversion (Table 2, entry 1).
Adverse impact on the enzyme activity was noticed for acetonitrile
(Table 2, entry 7). The application of methyl tert-butyl ether improved
the enzyme activity and was similar to the result obtained for water-
Having established the preferred reaction conditions, the depro-
tection of several representative acylals 2 were also performed to de-
monstrate the versatility and uniqueness of the present protocol
(Table 3). Aromatic acylals 2b-g with various electron-withdrawing,
and donating groups located at aromatic ring (Scheme 1) were con-
verted to the parent aldehydes in an impressive conversion and high
isolated yield of the target product 1 (Table 3, entries 1–6). (Furan-2-yl)
methylene diacetate 2h and 2-thiophenecarboxaldehyde diacetate 2i
were also efficiently converted to its corresponding aldehydes 1h and 1i
without polymerization in the presence of BLAP (Table 3, entries 7 and
8). It is worthy of mention that the unsaturated acylals 2j (Table 3,
entry 9) were also proved amicable to this methodology.
3

D. Koszelewski and R. Ostaszewski
BioorganicChemistryxxx(xxxx)xxx–xxx
Table 3
Table 4
Enzymatic deprotection of the various acylals 2 in PBS/acetone catalysed by
Enzymatic deprotection of various acylals 2 in PBS/acetone catalysed by BLAP.a
BLAP.a
Entry
Entry
Acylal 2
Conv.(%)b
Aldehyde 1
Yield (%)d
Acylal 2
Conv.(%)b
Aldehyde 1
Yield (%)c
1
2
3
4
5
6
2k
2l
79 (95)c
81 (> 99)c
92 (> 99)c
75 (93)c
> 99
1k
1l
84
85
91
81
85
83
1
2
3
4
5
6
7
8
9
2b
2c
2d
2e
2f
> 99
> 99
> 99
> 99
> 99
> 99
> 99
> 99
> 99
1b
1c
1d
1e
1f
89
92
87
95
97
91
87
85
94
2m
2n
2o
2p
1m
1n
1o
1p
> 99
2g
2h
2i
1g
1h
1i
a
Reaction conditions: 2 (1 mmol), co-solvent 10%v/v, PBS (50 mM, pH 7.4),
20 °C for 20 min, 200 rpm, BLAP (10 mg).
b
c
d
2j
1j
Determined by GC (Agilent VF-1701 ms) or TLC.
Result after 30 min at 20 °C.
a
Reaction conditions: 2 (1 mmol), co-solvent 10%v/v, PBS (50 mM, pH 7.4),
Yield of isolated product.
20 °C for 20 min, 200 rpm, BLAP (10 mg).
b
c
Determined by GC (Agilent VF-1701 ms) or TLC.
enzyme chemoselectivity, the 1,1-diacetates obtained from the aliphatic
or heterocyclic aldehydes possessing hydrolytically labile functional
groups 2o and 2p were converted to their parent aldehydes 1o and 1p
without affecting those sensitive moieties in short time with full con-
version and high yields (Table 4, entries 5 and 6). 4-Oxobutyl benzoate
1o and 5-acetoxymethyl-2-furaldehyde 1p are the progenitors for the
furano-epothilone D and halichondrins, which exhibit anti-cancer ac-
tivity [37] as well as a ranitidine also known as Zantac, a drug com-
monly used in treatment of peptic ulcer disease, gastroesophageal re-
flux disease, and the Zollinger–Ellison syndrome [38].
Yield of isolated product.
Parallel, under the same reaction conditions used for deprotection of
the acylals two different acetates were subjected to enzymatic hydro-
lysis with BLAP. As can be seen on Fig. 2 conversion of butyl acetate
after 20 min did not exceed 8% and for benzyl acetate was negligible,
less than 1%. Obtained results revealed that promiscuous activity of
used biocatalyst in acylals transformation is noticeably higher than the
expected one related with a carboxylic esters hydrolysis [35].
Encouraged by these results we were wondering if the deprotection
may occur selectively in the presence of other label functional groups
existing in the same molecule (Scheme 3).
In addition, the 1,1-diacetates were additionally recognized as an
important starting materials for Diels-Alder reactions [39], moreover
they can be converted into the other useful functional groups by the
reaction with appropriate nucleophiles [40] or used as the carbonyl
surrogates for asymmetric synthesis [41]. Recently, we have shown that
vinyl acetate provides components for the promiscuous enzyme-pro-
moted Passerini reaction (P-MCR) and the Knoevenagel condensation
[42]. As a consequence we extend our studies to verify if the acylals 2
can be used as the substrates for P-MCR providing both carbonyl
components, aldehyde and carboxylic acid (Scheme 4). It is well re-
cognized that multicomponent reaction can be carried on under aqu-
eous conditions [43].
A series of the various O-acetyl 1,1-diacetates 2 k-p were obtained
with the yields up to 99% from their parent aldehydes according to the
general Method B with BF3-OEt2 as a catalyst (Supplementary in-
formation). Although the salicylaldehyde is a simple molecule, its O-
acetylated homologous are important and versatile precursors for a
variety of useful compounds, particularly for the complex heterocyclic
systems which exhibit desirable biological activity [36]. Due to this fact
several acylals provided from the 2-acetoxybenzaldehyde 2k and its
three analogues 2l-n were tested under developed enzymatic conditions
(Table 4, entries 1–4).
According to these literature data we set up an experiment with the
benzylidene 1,1-diacetatein (2a) and 1.0 equiv. of an 1-(iso-
cyanomethyl)-4-methoxybenzene (4) in neat buffer what resulted after
24 h in the α-acetoxy amides 5 with 32% yield. The acetone was ex-
cluded from the reaction medium as a co-solvent, due to its competitive
character towards the aldehyde in P-MCR [44]. The moderate yield of
the conducted reaction can be justified by the fact that isocyanides have
low stability and undergo spontaneous hydrolysis in an aqueous
The obtained results reveal that enzyme catalyzed deprotection
generally results in high yields with acylals 2k-l and 2n including those
carrying hindered O-acetylated groups (Table 4, entries 1, 2 and 4). It is
noteworthy that deprotection of an aryl aldehyde diacetates occurs
selectively without cleavage of the phenolic acetate function (Table 4,
entries 1–4). The formation of the products 3 was not observed (Scheme
3). With the advantages of the mild reaction conditions and tremendous
Scheme 4. Chemoenzymatic tandem synthesis of the α-acetoxy amides 5 from
1,1-diacetate 2a.
Scheme 3. Chemoselective deprotection of the O-acetyl 1,1-diacetates 2a.
4

D. Koszelewski and R. Ostaszewski
BioorganicChemistryxxx(xxxx)xxx–xxx
solution [45,46]. Nevertheless, the target α-acetoxy amide 5 was pro-
vided with substantially higher yield than analogously obtained under
similar reaction conditions in classical three component P-MCR (32% vs
19%) [43]. It is important to notice that again the promiscuous activity
of enzymes in acylals 2 deprotection is predominant and the product 6
which arises from the enzymatic hydrolysis [47] of α-acetoxy amide 5
was not observed under studied reaction conditions (Scheme 4).
Aldrich. Column chromatographies were performed on Merck silica gel
60/230–400 mesh. Enzymatic reactions were performed in a vortex
(Heidolph Promax 1020) equipped with incubator (Heidolph Inkubator
1000). To prove the ability of the established protocol each reaction
was repeated at least three times.
4.2. Preparation of crude liver powders (LAPs)
3. Conclusions
Freshly purchased liver (200 g) is homogenized twice in a cold
(−20 °C) acetone using the kitchen stand blender (24 000 rpm)
equipped with a glass jar. The mass obtained after filtration was further
homogenized twice in a cold (−20 °C) DCM and filtrated. The residue
obtained was dried under the vacuum at room temperature for 2 h.
Light brown powder (50 g) was stored in a refrigerator before used.
In conclusion, we have developed a practical and efficient protocol
for the selective enzyme catalyzed hydrolysis of the acylals in the
presence of the ester groups leading to the parent aldehydes in an
aqueous media. The hydrolysis reaction catalyzed by hydrolases occurs
quantitatively in neutral pH at room temperature within minutes. This
interesting and predominantly promiscuous role of an enzyme activity
in the acylals hydrolysis dominates the native activity of BLAP hydro-
lase. This is the first example showing the dominant role of pro-
miscuous enzymes activity over the native one. After a careful opti-
mization of the reaction condition, target products were obtained with
the yields up to 97% and with excellent chemoselectivity. It is im-
portant to note that all described enzymatic transformations were cat-
alyzed by the catalyst prepared from animal tissues, easy accessible
from the local butcher store. The advantage of the present protocol is
the simplicity in operation, low cost of used catalysts, high yields and
chemoselectivity in respect to the functional groups. Moreover, devel-
oped protocol is compatible with the sensitive functionalities such as
OMe, Bz, OAc, and double bonds which upon deprotection of the acy-
lals remain untouched. Simple experimental procedure is important
with regard to the economic and sustainable consideration and allows
us to believe that elaborated method may represent a valuable alter-
native to the existing reagents reported in the literature. In addition this
protocol can be applied for compounds possessing synthetically re-
levant protecting groups like carboxybenzyl group (Cbz) or tert-butox-
ycarbonyl (Boc) which remain unaffected under enzymatic transfor-
mation [29a,29c,48].
4.3. Preparation of acylals 2a-g. General Method A
P4VP-H2SO4 was prepared according to the literature procedure
[48,49]. Catalyst (20 mg) was added to a stirred solution of an aldehyde
(1 mmol) and acetic anhydride (3 mmol) in dry DCM at room tem-
perature. The progress of the reaction was monitored by thin-layer
chromatography (TLC). After completion, the mixture was diluted with
dichloromethane and filtered to remove the catalyst. The organic so-
lution was washed with an aqueous solution of NaHCO3 and dried over
anhydrous sodium sulfate. Solvent was removed under reduced pres-
sure, and the crude product was purified by the crystallization from
ethyl ether/hexane. Benzylidene 1,1-diacetatein (2a): white crystals,
99% yield (206 mg, 0.99 mmol); 1H NMR (400 MHz, CDCl3) δ 7.68 (s,
1H), 7.59–7.47 (m, 2H), 7.41 (dd, J = 4.0, 2.6 Hz, 3H), 2.12 (s, 6H); 13
C
NMR (100 MHz, CDCl3) δ 168.75, 135.51, 129.74, 128.59, 126.67,
89.73, 20.84. The 1H and 13C NMR data were in accordance with those
reported in the literature [50].
4.4. Preparation of acylals 2 h-p. General Method B
Acetic acid anhydride (2 mmol) and BF3-OEt2 (2 drops) were cooled
down to 0 °C. Aldehyde (1 mmol) was added slowly with stirring, and
the mixture was stirred at room temperature for 30 min. The product
mixture was poured into a 10% aqueous solution of NaOAc (20 mL) and
stirred rapidly for 10 min. The product was extracted with ethyl ether
(3 × 15 mL), the extracts were combined, and washed with aqueous
NaHCO3 followed by water. After drying over anhydrous sodium sulfate
the crude product was concentrated under vacuum and isolated by
recrystallization from ethyl ether/hexane or silica gel chromatography
(ethyl acetate/hexane). (Furan-2-yl)methylene diacetate (2 h): white
crystals, 98% yield (194 mg, 0.98 mmol); 1H NMR (400 MHz, CDCl3) δ
7.70 (s, 1H), 7.44 (dd, J = 1.8, 0.8 Hz, 1H), 6.52 (dd, J = 3.3, 0.5 Hz,
1H), 6.38 (dd, J = 3.3, 1.8 Hz, 1H), 2.12 (s, 6H); 13C NMR (100 MHz,
CDCl3) δ 168.36, 147.93, 143.62, 110.35, 109.67, 83.49, 20.64. 1H and
13C NMR data were in accordance with those reported in the literature
[50].
In order to expand this protocol toward synthesis of peptidomi-
metics, additional experiments were performed. Developed protocol
was extended by the multicomponent reaction providing target α-
acetoxy amides under one-pot one step procedure. These experiments
revealed that acylals can be used as the surrogates of the carbonyl
components and carboxylic acids for the multicomponent reactions
leading to the pharmaceutically relevant peptidomimetic molecules.
This cascade process is characterized by very high atom economy and
can be enlarged for the synthesis of biologically active compounds.
Conducted experiments showed the advantage of an enzyme catalysed
reaction conducted in water over classical chemical methods fulfilling
the requirements of green chemistry.
4. Materials and methods
4.1. General methods
4.5. General deprotection protocol
All the chemicals were obtained from commercial sources and the
solvents were of an analytical grade. 1H- and 13C NMR spectra were
recorded in CDCl3 solution. Chemical shifts are expressed in parts per
million using TMS as an internal standard. The conversion of amine was
measured by gas chromatography using PerkinElmer Gas
Chromatograph Clarus 680that was equipped with a coating DB-
1701 ms 0.25 column (30 m × 0.25 mm). TLC analyses were done on
Kieselgel 60 F254 aluminum sheets. Lipases from hog pancreas,
Pseudomonas cepacia, Pseudomonas fluorescens, Candida rugosa, Candida
cylindracea, wheat germ, Rhizopus oryzae, and acylase I from Aspergillus
melleus were purchased from Sigma-Aldrich. Immobilized lipase from
Candida antarctica B (Novozyme 435) was purchased from Novo
Nordisk. Bovine serum albumin (BSA) was purchased from Sigma-
A solution of diacetate 2 (1 mmol) and BLAP (10 mg) in phosphate
buffer (50 mM, pH 7.4) was stirred in a vortex (200 rpm) at 20 °C for for
an appropriate time as required to complete the reaction. After com-
plete conversion, as indicated by GC or TLC, the reaction mixture was
extracted with ethyl acetate (3 × 15 mL). The combined organic layers
were dried over anhydrous sodium sulfate and concentrated in vacuum
to give the corresponding aldehyde 1.
4.6. General GC methods for conversion determination
GC program parameters; injector 250 °C; flow 1 mL/min;
5

D. Koszelewski and R. Ostaszewski
BioorganicChemistryxxx(xxxx)xxx–xxx
temperature program 70 °C; 140 °C/rate 10 °C per min./hold 3 min;
250 °C/rate 10 °C per min./hold 3 min.
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We gratefully acknowledge the financial support from the Polish
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Appendix A. Supplementary material
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.bioorg.2019.02.050.
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