A mild, general, and metal-free method for site-specific deuteration induced by visible light using D2O as the source of deuterium atoms

Article abstract of DOI:10.1039/c9gc04096j

A radical deuteration procedure using D₂O as the source of deuterium atoms is strongly preferred in terms of mildness, sustainability, and cost. Herein, we disclose a radical approach for site-specific, highly efficient and metal-free deuteration using D₂O under visible light conditions. This desulfurization-deuteration strategy features mild conditions, broad substrate scope, highly efficient D-incorporation, excellent functional group compatibility, sustainable energy and is hardly affected by substrate steric factors.

Full text of DOI:10.1039/c9gc04096j

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DOI: 10.1039/C9GC04096J
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A mild, general, metal-free method for site-specific deuteration
induced by visible light using D2O as source
Shuai Shi, a Ruining Li, a Liangming Rao, b, c and Zhankui Sun*a, b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
A radical deuteration procedure using D2O as the source of smoothly in mixed solvent DCM/D2O and gave the desired
deuterium atoms is strongly preferred in term of mildness, product in 91% yield with 95% D-incorporation (Table 1, entry
sustainability, and cost. Herein, we disclose a radical approach for 1). The deuteration ratio was further improved to 96% with
site-specific, highly efficient and metal-free deuteration using D2O Ph2POEt (Table 1, entry 2). The reaction also worked well in
under visible light condition. This desulfurization-deuteration EtOAc/D2O with 94% yield and 95% D-incorporation (Table 1,
strategy features mild conditions, broad substrate scope, highly entry 3). However, P(OEt)3 didn't work probably due to the
efficient D-incorporation, excellent functional group compatibility, liability to hydrolysis (Table 1, entry 4). When the reactions
sustainable energy and is hardly affected by substrate steric were carried out in CD3OD, the deuteration ratio was only 64%
factors.
(Table 1, entry 5). With other deuterated solvents, such as D6-
DMSO and CDCl3, the deuteration hardly took place (Table 1,
entry 6 and 7). The control experiments suggested that
desulfurization-deuteration didn't occur in the absence of
phosphoric reagent, DTBP, or visible light (Table 1, entry 8-10).
Deuteration as a labeling technique has long been regarded as
an important tool,
but also in drug discovery and development.
Deutetrabenazine,
FDA in 2017, has significantly stimulated the development of
synthetic methods for deuteration.
labeling approaches mainly include dehalogenative
deuteration,
hydrogen/deuterium isotope exchange.18-24 However, most
methods developed rely on the use of transition metal or have
limited substrate scope. As recently pointed out by Philippe
Renaud13, developing a radical procedure using D2O as a
source of deuterium atoms25-31 represents by far the most
appealing procedure in term of mildness (functional group
tolerance), sustainability, and cost. Herein, we disclose a
radical approach for site-specific, highly efficient and metal-
free deuteration using D2O based on the desulfurization-
deuteration strategy under very mild conditions.
Our research was initially inspired by the work of Hoffmann
and Walling32-34. We began our study by using cysteine 1a as
the model substrate and examined different conditions under
visible light at room temperature. We found that the
combination of DTBP (Di-tert-butyl peroxide) and PPh3 worked
1-10
not only in mechanism investigations,
11
the first deuterated drug approved by
Table 1. Optimization of reaction conditions for the deuterationa.
12-24
To date, reported
SH
D
O
hv
DTBP(1.2 equiv)
phosphoric reagent
12-15
16,17
deoxygenative deuteration,
and
O
O
CbzHN
CbzHN
rt
O
1a
2a
entry
phosphoric reagent
solvent
Yield
(%)b
91
96
94
N.D.
93
95
D-incorp.
(%)c
95
1
2
3
4
5
6
7
8
9d
10e
2.0 eq PPh3
2.0 eq Ph2POEt
2.0 eq Ph2POEt
2.0 eq P(OEt)3
2.0 eq Ph2POEt
2.0 eq Ph2POEt
2.0 eq Ph2POEt
—
DCM/D2O
DCM/D2O
EtOAc/D2O
DCM/D2O
CD3OD
D6-DMSO
CDCl3
DCM/D2O
DCM/D2O
DCM/D2O
96
96
—
64
N.D.
N.D.
—
—
—
91
N.D.
N.D.
N.D.
2.0 eq Ph2POEt
2.0 eq Ph2POEt
aStandard conditions: 1a (0.75 mmol), DTBP (0.90 mmol), phosphoric reagent
(0.90 mmol), solvent (6 ml), 36 W household CFL bulb irradiation on two sides,
10 h. bYield of the isolated product. cDeuterium incorporation was determined
by 1H NMR spectroscopy. dWithout DTBP. eWithout visible light. N.D. = not
detected. DCM = dichloromethane. DTBP = di-tert-butyl peroxide.
a. Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of
Pharmacy, Shanghai Jiao Tong University, No. 800 Dongchuan Rd., Shanghai
200240, China
b. Huzhou Research and Industrialization Center for Technology, Chinese Academy
of Sciences, 1366 Hongfeng Road, Huzhou 313000, China
c. Shanghai Institute of nutrition and health, Chinese academy of sciences
Electronic Supplementary Information (ESI) available: [details of any The generality and robustness of this method was challenged
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
with different substrates. Various functional groups could be
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tolerated under this mild condition and all tested compounds
gave excellent deuteration, such as carbamate (79% - 97%
yield, 96% - 99% D-incorporation, Table 2, substrate 1a, 1b, 1d,
1D, 1E), ester (79% - 97% yield, 94% - 99% D-incorporation,
Table 2, substrate 1a, 1b, 1c, 1i, 1j, 1n, 1s, 1w, 1x, 1y, 1B, 1D,
View Article Online
DOI: 10.1039/C9GC04096J
O
O
SH
SH
O
O
O
SH
N
O
O
O
Si
HS
O
O
O
SH
O
O
N
O
O
HS
HS
HS
e
e
e
1E), aromatic ring (73%
- 91% yield, 88% - 95% D-
1i
1k
: 94%, 99%
91%, 99%d
1j
: 95% , 93%
1l
: 73% , 95%
: 90% , 96%
incorporation, Table 2, substrate 1e, 1f, 1g, 1l), benzyl group
(92% - 93% yield, 95% - 98% D-incorporation, Table 2,
substrate 1c, 1d), ether (81% - 95% yield, 93% - 94% D-
incorporation, Table 2, substrate 1e, 1k, 1F), ketone (95%
yield, 97% D-incorporation, Table 2, substrate 1z), alkene (97%
yield, 90% D-incorporation, Table 2, substrate 1u), free
hydroxy group (90% - 92% yield, 91% - 94% D-incorporation,
Table 2, substrate 1q, 1v), free acid group (85% - 97% yield,
91% - 96% D-incorporation, Table 2, substrate 1h, 1o, 1r, 1G),
free amino group (>95 yield, 98% - 99% D-incorporation, Table
2, substrate 1H, 1I), sodium sulfonate (75% yield, 96% D-
incorporation, Table 2, substrate 1p), sugar moiety (96% yield,
96% D-incorporation, Table 2, substrate 1s), etc. As for
substrate 1r, the desulfurization and subsequent ring-opening
reaction occurred and the deuteration happened at the β
position of the alkene (97% yield, 94% D-incorporation), thus
suggesting a radical process. Secondary thiols worked well
(90% - 97% yield, 94% - 99% D-incorporation, Table 2,
substrate 1s - 1x). The high efficiency of this radical protocol
was hardly affected by steric factors. Even strongly hindered
tertiary thiols worked smoothly at room temperature and
afforded the corresponding products in excellent yields (89% -
95%) and excellent D-incorporation (89% - 97%) (Table 2,
substrate 1y, 1z, 1A). This mild and metal-free condition was
especially useful for the deuteration of drugs. In this context
we tested Captopril (1m), Mesna (1p), 3-Azetidinethiol (1t),
and Thiocholesterol (1u), and all of these commercial drugs
were highly efficiently deuterated (75% - 97% yield, 90% - 96%
D-incorporation).
O
HS
SH
O
O
O
N
SH
SH
HO
OH
O
NaO3S
O
O
O
O
SH
SH
f
e
e
1p
: 75%, 96%
1m
1n
1o
: 95% , 95%
: 91%, 92%
93%, 92%d
: 92% , 98%
O
O
HS
OH
SH
HO
HO
D
e
1q
1r
: 97%, 94%
: 92% , 91%
O
HS
O
O
O
O
H
N
O
O
N
O
H
H
S
HS
SH
O
g
1u
: 97%, 90%
1s
1t
: 96%, 96%
: 94%, 94%
93%, 94%d
O
SH
SH
O
BnOOC
OH
COOBn
SH
e
e
1v
: 90% , 94%
1x
1w
: 95% , 99%
: 96%, 97%
95%, 97%d
SH
HS
O
O
O
HN
SH
O
e
1y
: 89% , 95%
1z
1A
: 95%, 97%
: 90%, 89%
O
O
H
S
S
OBn
BnO
N
S
BnO
S
N
OBn
H
It should be noted that disulfides also worked well with good
to excellent yields under this mild condition (81% - 92% yield,
94% - 99% D-incorporation, Table 2, substrate 1B - 1G), and
different functionalities could be tolerated.
O
O
e
1B
: 81% , 95%
1C
: 84%, 99%
CbzHN
O
NHCbz
CbzHN
O
NHCbz
O
S
S
O
S
S
Table 2. Substrates scope for desulfurization-deuteration reactions. a, b, c
O
O
O
O
1D
1E
: 83%, 98%
85%, 98%d
:
79%, 99%
hv
DTBP
Ph2POEt
SH
R
or
R D
DCM/D2O(V:V = 2:1)
S S R
1
R
O
O
O
2
S
S
OH
O
O
Si
Si O
O
HO
SH
O
O
S
S
SH
H
HS
O
O
N
O
O
e
SH
e
1F
CbzHN
: 90% , 94%
CbzHN
1G
: 92% , 96%
O
O
O
1a
D-incorporation
HS
: 92%e, 95%
1d
1c
: 96% yield, 96%
: 93%, 98%
94%, 98%d
1b
: 97% , 97%
97% , 96%d
Glu-Cys-Gly ( ) (>95% yield, 98%g D-incorporation)
1H
Cys-Glu-Gly-Pro-Glu-Val-Asp-Val-Asn-Leu-Pro-Lys ( )(>95% yield, 99%g D-incorporation)
1I
HS
HS
Ala-Arg-Gly-Asn-Glu-Ser-Ser-Cys-Met-Asp-Thr-Pro-Thr-Glu-Gly-Cys ( )(>95% yield, 97%g D-incorporation)
1J
O
SH
HO
aReaction conditions: For thiols: substrate (0.75 mmol), DTBP (0.90 mmol),
Ph2POEt (1.50 mmol), DCM/D2O (2:1, v/v, 6 mL). For disulfides: substrate
(0.375 mmol), DTBP (0.90 mmol), Ph2POEt (1.50 mmol), DCM/D2O (2:1, v/v,
6 mL). For peptides: cysteinyl peptide (1 mM), TPPTS (30 mM), DTBP (30
mM), TBM (30 mM), D2O (2 mL). 36 W household CFL bulb irradiation on
O
Cl
1g
1h: 85%e, 91%
: 89%, 90%
1e
:81%, 93%
1f
: 91%, 88%
c
two sides, 25 oC, 6 h. bYields refer to isolated yields. D-incorporation was
based on 1H NMR. Reactions were carried out in EtOAc/D2O (2:1, v/v, 6
e
f
mL). Yields by 1H NMR analysis. Reaction was carried out in CD3OD/D2O
2 | J. Name., 2012, 00, 1-3
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(2:1, v/v, 6 mL). gD-incorporation was assessed by mass spectrometry. TBM
= 2-methylpropane-2-thiol.
reliable and powerful approach for site-specific and highly
efficient deuteration.
View Article Online
DOI: 10.1039/C9GC04096J
Furthermore, we tested a few substrates in EtOAc/D2O. The
reactions also worked well and excellent results were obtained
(Table 2, 1b (97%, 96%), 1d (94%, 98%), 1i (91%, 99%), 1m
(93%, 92%), 1t (93%, 94%), 1w (95%, 97%), 1D (85%, 98%)).
Thus, EtOAc/D2O could also be the solvent of choice.
Conflicts of interest
There are no conflicts to declare.
The rich functional group tolerances prompted us to try even
challenging substrates. We tested this strategy on glutathione
first (Table 2, substrate 1H). When water-soluble phosphoric
reagent such as TPPTS (Triphenylphosphine-3, 3', 3''-trisulfonic
acid trisodium salt) was employed instead of Ph2POEt, this
radical deuteration strategy worked smoothly in D2O and
provided the desired product with excellent result (> 95%
yield, 98% D-incorporation). When longer peptides such as 1I
and 1J were used, the reactions also worked well and different
functional groups in the peptides didn't affect the deuteration
efficiency at all ( > 95% yield, 97% - 99% D-incorporation, Table
2, substrate 1I, 1J).
Notes and references
1
2
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hv
DTBP
Ph2POEt
H
H
O
N
O
N
SH
D
DCM/D2O(V:V = 2:1)
O
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1d
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7.5 mmol, 1.5846 g
Fig 1. Scale-up reaction of 1d on gram scale
87% yield, 95% D-incorporation
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To gain insight into the mechanism of this reaction, we
performed radical-inhibition experiment by the addition of
2,2,6,6-tetramethyl-1-piperidyloxy
(TEMPO)
and
EPR
experiment using 5,5-dimethyl-1-pyrroline N-oxide (DMPO) as
an EPR spin trap to the model reaction (see the Supporting
Information for details). Both experiments suggested the
possibility of a radical process. Hence, we propose a plausible
mechanism described in Figure 2.
PPh2OEt
t-BuOO-t-Bu
PPh2OEt
complex
hv
t-BuO
t-BuOD
R
S PPh2OEt
D2
O
PPh2OEt
S
R
R
SH
R
S
R
SD
R
S
R
SD
R
R
D
SPPh2OEt
Fig 2. Plausible reaction mechanism of the desulfurization-deuteration reaction
Conclusions
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We have developed
a mild, general and metal-free
desulfurization-deuteration method induced by visible light
using D2O as the source of deuterium atoms. This radical
approach features green conditions, robustness, and excellent
functionality compatibility. It worked smoothly with primary,
secondary and tertiary thiols, thus providing a simple yet
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