Photo-biocatalytic One-Pot Cascades for the Enantioselective Synthesis of 1,3-Mercaptoalkanol Volatile Sulfur Compounds

Article abstract of DOI:10.1002/anie.201802135

The synthesis of enantiomerically pure 1,3-mercaptoalkanol volatile sulfur compounds through a one-pot photo-biocatalytic cascade reaction is described. Two new KRED biocatalysts with opposite enantioselectivity were discovered and proved to be efficient

Full text of DOI:10.1002/anie.201802135

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Accepted Article
Title: Photo-biocatalytic one-pot cascades for the enantioselective
synthesis of 1,3-mercaptoalkanol volatile sulfur compounds
Authors: Daniele Castagnolo, Kate Lauder, Anita Toscani, Yuyin Qi,
Jesmine Lim, Simon Charnock, and Krupa Korah
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201802135
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10.1002/anie.201802135
Angewandte Chemie International Edition
COMMUNICATION
Photo-biocatalytic one-pot cascades for the enantioselective
synthesis of 1,3-mercaptoalkanol volatile sulfur compounds
Kate Lauder,[a] Anita Toscani,[a] Yuyin Qi,[b] Jesmine Lim,[b] Simon J. Charnock,[b] Krupa Korah,[a] and
Daniele Castagnolo*[a]
Abstract: The synthesis of enantiomerically pure 1,3-
mercaptoalkanol volatile sulfur compounds via a one-pot photo-
biocatalytic cascade reaction is described. Two new KRED
biocatalysts with opposite enantioselectivity have been discovered
and proved to be efficient on a wide range of substrates. A one-pot
cascade reaction combining the
a photocatalytic thio-Michael
addition with a biocatalytic ketoreduction in aqueous medium results
in a green and sustainable approach to access enantiopure 1,3-
mercaptoalkanols in excellent ee and yields.
Volatile sulfur compounds (VSCs) constitute a wide class of
structurally different chemicals which may contribute to both
agreeable and disagreeable flavor and aroma of foods and
beverages.[1-8] Aromas involving VSCs include tropical fruit,[4]
guava,[5] onions,[6] cheddar cheese,[7] wine[1a] and beer.[8] The
majority of VSCs found in foods and beverages exist as chiral
isomers[9] and their olfactory perception may depend on their
diastereomeric and enantiomeric configuration,[10] such as for
the chiral alcohols 1-3 (Figure 1). Since the stereodifferentiation
of chiral VSCs may have a great impact on the flavor and aroma
of foods, the identification of high-yielding, cheap and
straightforward methods for their production in an
enantiomerically pure form is highly desirable. From a chemical
point of view, 20−30% of the VSCs are 1,3-mercaptoalkanols,
making them the most important sulfur compounds with aroma
activity.[4a,9,11] 1,3-Mercaptoalkanols can be obtained in
enantiomerically pure form via preparative GC resolution of the
corresponding racemic mixtures[9] or through chemical reduction
of ketones using chiral auxiliaries[12] or metal catalysts.[13]
However, these approaches suffer from limitations in terms of
atom-economy sustainability, use of non-green solvents and
catalyst recyclability. Greener biocatalytic approaches have
been developed via lipase-mediated kinetic enzymatic
resolution[14] or Baker's yeast-mediated reduction of carbonyl
precursors[15] (Figure 1). Despite being enantioselective, these
biotransformations remain unappealing at industrial level due to
low yields and poor conversions.[16] The recent advancements in
molecular biology and metagenomics have recently made a
wide number of new enzymes accessible and suitable for a large
variety of stereocontrolled organic reactions. Within this context,
this work describes the identification and the development of two
new highly selective keto-reductase (KRED) biocatalysts for the
synthesis of enantiomerically pure 1,3-mercaptoalkanols with
general structure C. In addition, a mild and efficient one-pot
cascade sequence for the direct synthesis of C from readily
available -unsaturated carbonyls A has been developed by
combining the KRED biocatalytic step with a photocatalyzed
thio-Michael reaction (Figure 1).
Figure 1. Examples of natural VSCs and biocatalytic approaches for the
synthesis of VSCs
A set of mercaptoalcohols 6a-c were initially synthesized from
appropriate ketone 5 precursors (Scheme 1S),[17] and used as
model substrates for the identification of appropriate biocatalysts
among a pool of 384 KREDs, identified and isolated through a
metagenomic approach,[18,19] from Prozomix’s library.
A
qualitative
kREDy-to-go
assay
combined
with
a
spectrophotometric UV-Vis assay[20] was performed leading to
the selection of five KRED enzymes (KRED290, 296, 311, 349,
363) able to promote the ketone 5 to alcohol 6 reduction and
thus used in this work.
The phenylthio-pentan-2-one 5a was first treated with the five
o
selected KRED biocatalysts in PBS (200 mM, pH 7.0) at 37 C,
using isopropyl alcohol (IPA) as cofactor recycling agent (Table
1). The conversion of 5a into alcohol 6a and the enantiomeric
excess (ee) were determined by HPLC (entry 1). Strikingly, a
remarkable variability in both conversions and selectivity was
shown. Although KRED 290, 296 and 363 led to alcohol 6a in a
low amount and poor ee (15%, 12% and 8% respectively), the
S-enantiomer was formed as the only product. On the contrary,
biocatalysts KRED311 and 349 fully converted 5a into 6a (99%)
with excellent ee (99% and 97% respectively). Most interestingly,
KRED311 led to the formation of the R-enantiomer (R)-6a, whilst
KRED349 catalyzed the selective formation of the S-enantiomer
(S)-6a. The absolute configuration of (R)-6a and (S)-6a was
established by comparison of the D values of 6a with those
reported in the literature.[15] The scope of the reaction was then
expanded to a set of different substrates 5 (Table 1). Methyl
ketones 5b-f were treated with KRED311 and 349 and fully
converted into the corresponding alcohols 6b-f with excellent ee
(entries 2-6) and striking enantioselectivity. Similarly, ethyl-
ketones 5g-m were converted into the corresponding alcohols
6g-m with excellent ee (>99%), although a slightly lower
conversion was obtained for (R)-6g allegedly due to the steric
hindrance of the ethyl group (entry 7). As a general trend,
KRED311 leads to lower conversions (entries 10-13) than
KRED349, which in this occasion proved to be the most efficient
biocatalyst leading to (S)-alcohols with good to excellent
conversions (>80%). Again, full and opposite enantioselectivity
was observed.
[a]
[b]
Ms K. Lauder, Dr A. Toscani, Ms K. Korah, Dr D. Castagnolo*
School of Cancer and Pharmaceutical Sciences
King’s College London
150 Stamford Street, SE1 9NH, London, United Kingdom
E-mail: daniele.castagnolo@kcl.ac.uk
Dr Y. Qi, Dr J. Lim, Dr S.J. Charnock
Prozomix Limited
Station Court, Haltwhistle, Northumberland
NE49 9HN, United Kingdom.
Supporting information for this article is given via a link at the end of
the document
This article is protected by copyright. All rights reserved.

10.1002/anie.201802135
Angewandte Chemie International Edition
COMMUNICATION
enantiomers and KRED349 affording the R-enantiomers.[21]
Because of the presence of two bulky methyl substituents at C4,
the alcohols 6q-r were not obtained when KRED311-349, as
well as 290, 296 and 363, were used. Surprisingly, alcohol
dehydrogenase ADH101[22] reduced the ketones 5q-r to alcohols
6q-r with good conversion and excellent ee (99%) (entries 17-
18), affording the R-enantiomer. The selectivity of the KRED
biocatalysts on ketones 7a-b bearing a stereocentre on the
sulfur atom was also investigated (Table 2). The reduction of the
cyclic ketone 7a with NaBH4 led to the diasteroisomers 8a as a
racemate with a 90:10 syn/anti ratio (entry 1).[23] The biocatalytic
Table 1. Biocatalytic synthesis of mercaptoalkanols 6a-r
[b]
Alcoh
ol
Conv.
ee %
Entry
SM
5a
R
R1
R2
KRED
(%)[a]
(enan.)[c]
reduction
of
7a
with
KRED311
showed
similar
290
296
311
349
363
311
349
311
349
311
349
311
349
311
349
311
349
311
349
311
349
311
349
311
349
311
349
311
349
311
349
311
349
311
349
311
349
101
311
349
101
22
15 (S)
diastereoselectivity (85:15 syn/anti ratio) and excellent
enantioselectivity, leading to syn-8a-SR isomer with 99% ee
(entry 2),[24] whilst the anti-8a diasteroisomers were formed with
33% ee. Although KRED349 showed lower diastereoselectivity
(60:40 syn/anti ratio), syn-8a-RS was formed with 83% ee (entry
3), confirming the enantiopreference of KRED349 for the S-
enantiomer. Finally, the biocatalysts ADH101 and ADH152[22]
showed good diastereo- and enantioselectivity (entry 5).
25
>99
99
7
12 (S)
99 (R)
97 (S)
8 (S)
1
CH3
Ph
H
6a
99
99
97
98
99
99
93
94
82
54
67
>99
90
92
98
97
63
80
44
50
28
86
44
66
0
99 (R)
92 (S)
99 (R)
98 (S)
99 (R)
99 (S)
>99 (R)
>99 (S)
99 (R)
99 (S)
99 (R)
99 (S)
99 (R)
99 (S)
99 (R)
99 (S)
99 (R)
99 (S)
99 (R)
99 (S)
99 (R)
99 (S)
99 (R)
99 (S)
0
2
3
5b
5c
5d
5e
5f
CH3
CH3
CH3
CH3
CH3
Et
Bn
Allyl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
6b
6c
6d
6e
6f
Table 2. KRED biocatalysed reduction of chiral ketones 7a-b
4
2F-Ph
4Me-
Ph
5
4Br-
Ph
6
7
5g
5h
5i
Ph
Bn
6g
6h
6i
8a-b
SR:RS/RR:SS %
(ee)/(ee)b
Conv. (%)a
syn/anti
8
Et
Reducing
agent/enzyme
Entry
Ketone
%
9
Et
Allyl
2F-Ph
45:45/5:5
(0)/(0)
1
2
3
4
5
6
7
8
NaBH4
KRED311
KRED349
ADH101
ADH152
NaBH4
90/10
85/15
60/40
23/76
87/13
60/40
58/42
69/31
10
11
12
13
14
15
16
5j
Et
6j
2Cl-
Ph
85:0/10:5
(99)/(33)
5k
5l
Et
6k
6l
Et
nPr
5:55/18:22
(83)/(10)
4Br-
Ph
5m
5n
5o
5p
Et
6m
6n
6o
6p
7a
20:3/36:40
(73)/(5)
Ph
Ph
Ph
Ph
Bn
98
8
95 (R)
99 (S)
37 (R)
0
72:15/6:7
(65)/(7)
71
0
Allyl
30:30/20:20
(0)/(0)
97
0
52 (R)
0
0
0
17
18
5q
5r
CH3
CH3
Ph
Bn
CH3
CH3
6q
6r
58:0/42:0
(99)/(99)
KRED311
KRED349
81
0
99 (R)
0
7b
0
0
13:56/3:27
(61)/(80)
75
99 (R)
[a]Calculated by HPLC using a Chiralpak IC column. [b]Calculated by HPLC
[a]Calculated by 1H NMR or HPLC using Chiralpak IC or IG columns.
[b]Calculated by HPLC using a Chiralpak IC or IG columns.
using
a Chiralpak IC column or by GC using a β-DEX™325 column.
[c]Absolute configuration was established by comparison of theD values of 6a
with the value reported in the literature
The KRED-biocatalyzed reduction of 7b, precursor of the VSC
4-mercaptopentan-2-ol 1,[9] was also explored. The treatment of
7b with KRED311 led to 60:40 syn/anti, similarly to NaBH4
(entries 6-7). However, the biotransformation proved to be highly
enantioselective leading to 8b-SR and 8b-RR in 99% ee.
Similarly, the use of KRED349 showed good enantioselectivity
affording isomers 8b-RS and 8b-SS with 61% and 80% ee
respectively (entry 8).
Whilst the substrates 5n-p bearing bulkier substituents were
poorly converted by KRED311, with only the exception of the
benzyl derivative (S)-6o obtained in low amount but with
excellent ee (99%), KRED349 proved to be significantly more
efficient at affording alcohols 6n-p, also with excellent 95% ee
(entry 14). In all cases, opposite R/S enantioselectivity was
observed with KRED311 catalyzing the formation of S-
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10.1002/anie.201802135
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COMMUNICATION
Once the efficacy and the enantioselectivity of the
KRED311/349 biocatalysts was proven, we decided to develop a
more sustainable one-pot protocol to access mercaptoalkanols 6
directly from alkenes 4.
under visible light affording 6a in a few minutes, with full
conversion and no additives (entry 9). The latter conditions were
therefore employed in the following studies. The combination of
the visible light-catalyzed thio-Michael reaction with the
biocatalytic ketone reduction was finally investigated as a one-
pot process (Table 4). Vinyl ketones 4a-c were suspended in
Table 3. Photocatalytic thio-Michael addition
PBS at pH 7.0 and treated with thiols
5 and catalytic
[Ru(bpy)3Cl2]. The photocatalytic thio-Michael addition is
instantaneous leading to the ketone intermediate 5 in <5min.
The simultaneous addition of KRED, NAD(P)H and IPA to the
reaction mixture resulted in the reduction of
5 into the
enantiopure alcohols 6 within 24 hours with excellent yields and
ee (Table 4).
Cosolvent
5%v/v
Conv.
(%)[b]
Entry
Initiator
Additive[a]
Time
Light h
1
2
Green LED
Blue LED
Blue LED
Blue LED
Blue LED
Blue LED
Blue LED
Blue LED
Visible
Eosin Y
Hexane
DMSO
DMF
Pyridine
2 h
0
The one-pot photo-biocatalytic cascade reaction was finally
[Ru(bpy)3Cl2]
[Ru(bpy)3Cl2]
[Ru(bpy)3Cl2]
[Ru(bpy)3Cl2]
[Ru(bpy)3Cl2]
[Ru(bpy)3Cl2]
[Ru(bpy)3Cl2]
[Ru(bpy)3Cl2]
[Ru(bpy)3Cl2]
[Ru(bpy)3Cl2]
-
5 min
5 min
5 min
5 min
5 min
5 min
5 min
5 min
5 min
3 d
95
investigated via in situ NMR. Because of the complexity of the
3
-
90
1
reaction mixture, a 19F NMR was performed in place of H NMR
4
IPA
-
Aniline
Aniline
Aniline
p-Toluidine
-
85
in order to clearly monitor the cascade process without the
interferences arising from the solvent and the enzyme recycling
system.
5
DMSO
DMF
99
6
99
7
IPA
99
8
DMSO
DMSO
DMSO
DMSO
>99
>99
>99
52
Table 4. One-pot photo-biocatalytic cascade
9
10
11
Visible
p-Toluidine
-
[c]
-
[a]50mol% of additive were used. [b]Determined by 1H NMR. [c]In the dark
Mercaptoketones 5 were initially synthesized from 4 with
Borax under basic conditions (pH 9)[17] which are incompatible
with the biocatalytic reaction conditions (pH 7). Thus, we
explored an alternative photocatalytic thiol-ene approach[25] to
access ketones
5
in neutral aqueous medium. The
photocatalytic Michael addition of thiophenol to vinyl ketone 4a
in phosphate buffer solution (PBS) at pH 7.0 was first
investigated (Table 3). The use of green LED light in the
presence of Eosin Y[26] proved to be ineffective (entry 1) and no
ketone 5a was obtained after 2h. On the contrary, when 4a was
reacted with PhSH under blue LED light using 0.3mol% of
[Ru(bpy)3Cl2] as initiator and no additives, the thioketone 5a was
formed in few minutes. Excellent conversion (95%) was obtained
when DMSO was used as cosolvent (entry 2) and was therefore
preferred over DMF and IPA (entries 3-4). Additives like aniline
or p-toluidine (50mol%) also proved to be beneficial, leading to
5a with >99% conversion within 5 minutes (entries 5-8).
Surprisingly, the photocatalytic formation of 5a also proceeded
a
Conv.
%
ee %
Yieldsb
(%)
Entry
Cmpd
R
R1
KRED
a
(enant.)
1
2
3
4
5
6
7
8
9
6a
6a
6b
6b
6c
6d
6g
6g
6h
6i
CH3
CH3
CH3
CH3
CH3
CH3
Et
Et
Et
Et
Ph
Ph
Ph
Bn
311
349
311
349
311
311
311
349
311
311
349
99
99
99
99
99
98
97 (48h)
95
98
99
>99 (R)
>99 (S)
99 (R)
97 (S)
>99 (R)
99 (R)
>99 (R)
>99 (S)
99 (R)
99 (R)
95 (S)
73
71
66
54
43
68
45
60
40
49
38
Bn
Allyl
2F-Ph
Ph
Ph
Bn
10
11
Allyl
Ph
6n
98
[a]Calculated by HPLC using a CHIRALPAK IC column. [a]Isolated yields.
Compounds were purified by flash chromatography
Figure 2. a) In situ 19F NMR stacked spectra of the photo-biocatalytic cascade reaction; b) kinetic profile of the reaction showing the disappearance of the 2-
fluorothiophenol ( ), the formation and subsequent disappearance of the ketone 5d ( ) in correspondence to the appearance of 6d ( ).
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10.1002/anie.201802135
Angewandte Chemie International Edition
COMMUNICATION
[1] a) M.I. Kinzurik, M.Herbst-Johnstone, R.C. Gardner, B. J. Fedrizzi, J. Agric.
Food Chem. 2015, 63, 8017−8024; b) M. H. Boelens, L. van Gemert, Perfum.
Flavor. 1993, 18, 29; c) M. Mestres, O. Busto, J.J. Guasch, Chromatogr. A
2000, 881, 569−581. d) J.A. Maga, CRC Crit. Rev. Food Sci. 1976, 7,
147−192.
The alkene 4a was treated with 2F-phenylthiol and
KRED311 under the conditions reported in Table 4 and the
formation of ketone 5d and alcohol 6d was monitored at 37 C.
o
At t0 the 19F NMR shows the presence of the 2-fluorothiophenol
(Figure 2). As soon as 4a and the photoinitiator are added, the
photocatalyzed reaction takes place and the ketone 5d is formed
within 3 minutes. The KRED311 was added, together with the
NADH and IPA, just after the photoinitiator. At t=9 minutes, the
formation of the alcohol 6d can be observed. From the kinetic
profile shown in Figure 2, it is clear that the in situ-generated
ketone 5d (-110.04 ppm) is almost fully converted (90% ca.) to
the respective alcohol 6d (-110.70 ppm) after 3 hours. Finally,
after 5 h the ketone 5d is reduced to 6d with 97% conversion.
According to the in situ NMR experiment, the reaction is
completed after 12 h. As it can be seen from the 19F stacked
spectra, at t=2h, the formation of two broad peaks (-109.71 and -
110.07 ppm) was observed. The signals were attributed to the
intermolecular H-bonds of 6d with the phosphate salts. To
confirm this hypothesis, the reaction was stopped after 16 h and
6d was extracted in EtOAc. The 19F NMR of the crude extract in
CDCl3 showed only the peak of the alcohol 6d, together with
traces of the remaining excess of ketone 5d. Alcohol 6d was
then re-suspended in phosphate buffer and stirred for 6 hours,
before being analysed by 19F NMR. Again, the formation of two
broad peaks was observed confirming our assumption. The
reason for the reappearance of the signal at -108.28 ppm of the
2F-thiophenol is yet not clear, although possible issues with the
suspension of the compounds, as well as the stirring, could have
contributed to its appearance. However, it is evident that the
remaining 2-fluorothiophenol fully reacts with 4a (added in slight
excess) affording 5d, which is in turn converted into the alcohol
6d.
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In conclusion, an efficient, mild and highly enantioselective
one-pot photo-biocatalytic cascade protocol to access 1,3-
mercaptoalkanols from -unsaturated ketones has been
developed. Two new KRED biocatalysts able to reduce the
ketones 5 with opposite enantioselectivity and excellent ee have
been identified. Both biocatalysts proved to be efficient on a
wide range of ketone substrates including the chiral precursors
7a-b. In addition, a photocatalytic synthesis of ketones 5 was
developed and combined in a one-pot cascade with the KRED
biocatalytic reaction, allowing the manufacturing of enantiopure
1,3-mercaptoalkanols 6 in a greener and more sustainable
fashion. The single enantiomer derivatives 6 are currently being
investigated for their olfactory and flavour properties.
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4985-4988.
Experimental Section
Experimental details, procedures and copies of spectra are
reported in the Supporting Information.
[17] See Supporting Information for details on the synthesis of racemic 6a-c
(Scheme 1S) for kREADy-to-go assay.
[18] Details on the identification, isolation, cloning and purification of the
KREDs are reported in the Supporting Information.
Acknowledgements
[19] J. Handelsman, Microbiol. Mol. Biol. Rev. 2004, 669-685.
This work was supported by BBSRC (iCASE Studentship to KL)
as well as EPSRC. AT acknowledges Maplethorpe Research
Fellowship. Johnson Matthey is gratefully acknowledged for
providing in kind ADH101 and ADH152. KL is thankful to CMST
COST Action CM1303 Systems Biocatalysis for conference
funding. We gratefully acknowledge the EPSRC UK National
Mass Spectrometry Facility for providing the mass spectrometry
data. Dr Richard Parsons at KCL is gratefully acknowledged for
helpful discussion.
[20] kReady-to-go and UV-Vis assays are described in the Suppoting
Information.
[21] The absolute configuration was determined by comparison of the D value
observed for 6n with 6a as well as the opposite elution time observed for
phenyl derivatives 6n-p in chiral HPLC analysis (Chiralpak IC).
[22] ADH101 and ADH152 were provided in kind by Johnson Matthey
[23] R. Tanikaga, A. Morita, Tetrahedron Lett. 1998, 39, 635-638.
Keywords:
ketoreductase,
photocatalysis,
biocatalysis,
[24] Configuration established by comparison with the previously observed R-
selectivity of KRED311
mercaptoalkanols, volatile sulfur compounds
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Kate Lauder,[a] Anita Toscani,[a] Yuyin
Qi,[b]
Jesmine
Lim,[b]
Simon
J.
Charnock,[b] Krupa Korah,[a] and Daniele
Castagnolo*[a]
Page No. – Page No.
Photo-biocatalytic one-pot cascades
for the enantioselective synthesis of
1,3-mercaptoalkanol volatile sulfur
compounds
Text for Table of Contents
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