A Mild, General, Metal-Free Method for Desulfurization of Thiols and Disulfides Induced by Visible-Light

Article abstract of DOI:10.1002/cjoc.202000607

A visible-light-induced metal-free desulfurization method for thiols and disulfides has been explored. This radical desulfurization features mild conditions, robustness, and excellent functionality compatibility. It was successfully applied not only to the desulfurization of small molecules, but also to peptides.

Full text of DOI:10.1002/cjoc.202000607

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国 化 学
Cite this paper: Chin. J. Chem. 2021, 39, 1255—1258. DOI: 10.1002/cjoc.202000607
A Mild, General, Metal-Free Method for Desulfurization of Thiols
and Disulfides Induced by Visible-Light
Wenting Qiu,a Shuai Shi,a Ruining Li,a Xianfeng Lin,a Liangming Rao,b,c and Zhankui Sun*,a
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, Zhejiang
313000, China
c Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai 200031, China
Keywords
Desulfurization| Photochemistry| Radical reactions| Thiol| Visible-light
Main observation and conclusion
A visible-light-induced metal-free desulfurization method for thiols and disulfides has been explored. This radical desulfurization fea-
tures mild conditions, robustness, and excellent functionality compatibility. It was successfully applied not only to the desulfurization
of small molecules, but also to peptides.
Comprehensive Graphic Content
*E-mail: zksun@sjtu.edu.cn
View HTML Article
Supporting Information
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Qiu et al.
Concise Report
Table 1 Optimization of reaction conditions for the desulfurization of
Background and Originality Content
small moleculesa
Desulfurization reactions are of great importance, not only in
organic synthesis,[1] but also in industrial and environmental set-
tings.[2] Desulfurization reactions have a long history. Most re-
ported methods rely heavily on transition metals, for example,
Raney nickel,[3] Fe3(CO)12,[4] Co2(CO)8,[5] Mo(CO)6,[6] etc., which
suffer from problems such as catalyst instability (unstable in the
presence of air or water),[3] poor functional group tolerance,[4-5]
high metal loadings,[5-6] etc. With the development of native
chemical ligation for peptide and protein synthesis by Kent and
other groups,[7] several desulfurization methods which convert
cysteine into alanine were developed, including the Pd/Al2O3 and
Raney nickel-mediated methods reported by Dawson (Figure
1b),[3e] the TCEP (tris(2-carboxyethyl)phosphine)/VA-044/t-BuSH
methods developed by Danishefsky and Wan (Figure 1c),[8] the
photocatalytic desulfurization developed by Guo (Figure 1c),[9]
and the P-B desulfurization developed by Li (Figure 1d).[10] Re-
cently we reported a site-specific deuteration method induced by
visible-light through a desulfurization process.[11] Herein, we dis-
closed our detailed studies which resulted in a metal-free and
highly efficient desulfurization process that enabled the chemo-
selective desulfurization of small molecules and peptides.
Entry
Phosphoric reagent
Radical initiator
Yieldb
1
2
3
4
5
6
7
8
9
2.0 equiv P(OEt)3
2.0 equiv P(OEt)3
2.0 equiv P(OEt)3
1.2 equiv P(OEt)3
2.0 equiv PPh3
2.0 equiv HEPT
2.0 equiv Ph2POEt
2.0 equiv P(OEt)3
2.0 equiv P(OEt)3
2.0 equiv P(OEt)3
—
0.5 equiv DTBP
1.0 equiv DTBP
1.2 equiv DTBP
1.2 equiv DTBP
1.2 equiv DTBP
1.2 equiv DTBP
1.2 equiv DTBP
1.2 equivTBHP
1.2 equiv DCP
—
46%
89%
96%
56%
95%
92%
92%
44%
82%
N.D.
N.D.
<5%
10
11
12c
DTBP
1.2 equiv DTBP
2.0 equiv P(OEt)3
a Reactions conditions: 1a (0.75mmol), phosphoric reagent, radical initiator,
6 mL CH3CN, 25 oC, 36 W household CFL bulb irradiation on two sides, 6 h.
b Yields of isolated product. N.D. = not detected. c Without light.
We then tested this protocol with different substrates. We
found that primary thiols with various functional groups could be
tolerated under this condition and excellent yields were achieved,
such as carbamate, ester, halogen, ether, hydroxy group, acid
group, amide, ketone, etc. As for substrate 1l, the desulfurization
and subsequent ring-opening reaction occurred. Secondary thiols
also worked well (Table 2, substrates 1n—1p). Sterically hindered
tertiary thiols worked smoothly at room temperature and af-
forded the corresponding products in excellent yields (Table 2,
substrates 1q—1t). It should be noted that disulfides also proved
to be suitable substrates and delivered the products in good to
excellent yields (Table 2, substrates 1u—1z).
This condition even worked for sp2-hybridized compounds,
albeit with lower yields. At elevated temperature, thiols bearing
aromatic rings such as benzothiazole, pyridine and quinoline
worked successfully with moderate yields, as shown in Table 3.
To further demonstrate the feasibility of this protocol, we
scaled up the reactions for substrates 1g and 1t (Scheme 1). Both
products could be obtained in high yields on gram-scale.
Scheme 1 Scale-up reactions of 1g and 1t on gram scale
Figure 1 Examples of desulfurization reactions.
Results and Discussion
We began our study by using cysteine 1a as the model sub-
strate and examined different conditions under visible-light at
room temperature. We found that the combination of DTBP
(di-tert-butyl peroxide) and P(OEt)3 worked smoothly in CH3CN
and gave the product in 96% yield (Table 1, entry 3). The reactions
also worked well in different solvents, such as DCM, DMF, toluene,
EtOAc, acetone and methanol (see Supporting Information). Be-
sides, PPh3, HEPT (hexaethyl-phosphoroustriamid) or Ph2POEt
could also provide the desired product with excellent yields (Table
1, entries 5—7). However, replacing DTBP with TBHP (tert-butyl
hydroperoxide) and DCP (dicumyl peroxide) led to diminished
yields (Table 1, entries 8—9). The control experiments suggested
that desulfurization hardly took place in the absence of DTBP,
P(OEt)3 or visible-light (Table 1, entries 10—12).
Encouraged by the above-mentioned results, we then turned
our attention to the reactions of peptides. We examined gluta-
thione (GSH) as the model substrate with water-soluble phos-
phine and DTBP under visible-light irradiation in water. When the
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Desulfurization of Thiols and Disulfides Induced by Visible-Light
Chin. J. Chem.
Table 2 Substrate scope for the desulfurization of small moleculesa,b
reaction was done at 80 mmol/L concentration, 2 equivalents of
DTBP and TPPTS (triphenylphosphine-3,3',3''-trisulfonic acid tris-
odium salt) were sufficient for the full conversion of glutathione
within 6 h (Table 4, entry 1). However, with 1 mmol/L concen-
tration, 30 equivalents of DTBP and TPPTS were needed for the
full conversion (Table 4, entry 3). The reaction could also be car-
ried out in phosphate buffer (Table 4, entry 4), with tert-butyl
mercaptan (TBM) (Table 4, entry 5) and guanidine hydrochloride
(Gn·HCl) (Table 4, entry 6). TCEP (tris(2-carboxyethyl)phosphine)
could also provide the desired product with excellent yield (Table
4, entry 7).
Table 4 Optimization of reaction conditions for the desulfurization of
glutathionea,b
GSH
(mmol/L)
Phosphoric
reagent
Entry
DTBP
Additive Solvent Yieldb/%
1
2
3
4
5
80
1
1
1
1
2 equiv TPPTS
2 equiv TPPTS
30 equiv TPPTS 30 equiv
30 equiv TPPTS 30 equiv
2 equiv
2 equiv
—
—
—
—
H2O
H2O
H2O
PB
>95
<5
>95
>95
>95
30 equiv TPPTS 30 equiv 30 eq TBM
PB
PB,
Gn·HCl
PB
6
1
30 equiv TPPTS 30 equiv 30 eq TBM
>95
7
8
1
1
30 equiv TCEP
30 equiv
—
—
>95
N.D.
30 equiv Ph2POEt 30 equiv
PB
a Reaction conditions: 3a (mmol/L), phosphoric reagent, DTBP, 25 oC, 36 W
1
household CFL bulb irradiation on two sides, 6 h. b Yield by H NMR analy-
sis. PB = phosphate buffer (pH = 7.0, 200 mmol/L), TBM = tert-butyl mer-
captan, N.D. = not detected.
With the optimized conditions in hand, we next investigated
longer peptide substrates with different amino acid residues, and
all corresponding desulfurization peptides were obtained in good
yields. Peptides with either mono- or multi-cysteine residues
worked well. Remarkably, this protocol could also remove the thiol
group of cysteine in the presence of phosphorylated serine (Table
5, substrates 3c, 3h) and methionine (Table 5, substrate 3g).
Table 5 Substrate scope for the desulfurization of peptidesa
a Reaction conditions: For thiols: substrate (0.75 mmol), DTBP (0.90 mmol),
P(OEt)3 (1.50 mmol), CH3CN (6 mL), 25 oC, 36 W household CFL bulb irradi-
ation on two sides, 6 h. For disulfides: substrate (0.375 mmol), DTBP (0.90
Peptide substrates
Conversionb/%
Cys-Gly-Arg-Ala-Ser-Ser-His-Ser-Ser-Gln-Thr-Gln-Gly-Gly- > 95
Gly-NH2 (3b)
Cys-Gly-Arg-Ala-Ser-{pSer}-His-Ser-Ser-Gln-Thr-Gln-Gly-
Gly-Gly-NH2 (3c)
b
mmol), P(OEt)3 (1.50 mmol). Unless otherwise noted, yields refer to
> 95
isolated yields. c Yields analyzed by 1H NMR.
Cys-Glu-Gly-Pro-Glu-Val-Asp-Val-Asn-Leu-Pro-Lys (3d)
Cys-Glu-Leu-Phe-Lys-Phe-Leu-Asp-Gly-Lys-Leu-Leu-Asp-
Ile-Asn-Lys-Asp(3e)
> 95
> 95
Table 3 Desulfurization of sp2-hybridized organosulfur compoundsa,b
Cys-Glu-Leu-Asn-Asp-Pro-Asn-Lys-Ala-Glu-Asp-Pro-Lys-
Lys-Phe-Thr (3f)
Ala-Arg-Gly-Asn-Glu-Ser-Ser-Cys-Met-Asp-Thr-Pro-Thr-
Glu-Gly-Cys (3g)
> 95
> 95
Cys-Glu-Leu-Leu-Pro-Asn-{pSer}-Gly-His-Gly-Pro-Asp-Gly- > 95
Glu-Val (3h)
Cys-Glu-Leu-Leu-Pro-Asn-Ser-Gly-His-Gly-Pro-Asp-Gly-
79
Glu-Val (3i)
Glu-Ser-Glu-Lys-Ser-Lys-Ala-Glu-Asn-Arg-Ala-Gln-Cys (3j)
> 95
a Reaction conditions: For thiols: substrate (0.75 mmol), DTBP (0.90 mmol),
a
Desulfurization conditions: Cysteinyl peptide (1 mmol/L), TPPTS (30
mmol/L), DTBP (30 mmol/L), TBM (30 mmol/L), PB, 36 W household CFL
bulb irradiation on two sides, 25 oC, 6 h. PB = phosphate buffer, 200
mmol/L, pH = 7.0. b Conversion was determined by LC-MS.
o
PPh3 (1.50 mmol), anisole (6 mL), 130 C, 36 W household CFL bulb irradi-
ation on two sides, 6 h. b Yields refer to isolated yields. c Reaction under 50
oC in CH3CN.
Chin. J. Chem. 2021, 39, 1255—1258
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Qiu et al.
Concise Report
Based on our understanding, we proposed a possible mecha‐
nism which was depicted in Scheme 2.
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Scheme 2 Proposed mechanism of the desulfurization reaction
P(OEt)3
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hv
t-BuOO-t-Bu
t-BuO
SH
t-BuOH
R
S P(OEt)3
R
S
R
R
SH
R
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H
S=P(OEt)3
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We have developed a general and metal‐free desulfurization
method induced by visible‐light. This method works not only for
small molecules, but also for peptides. It features mild conditions,
robustness, and excellent functionality compatibility, which
makes it a reliable tool for organic chemists and medicinal chem‐
ists.
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Experimental
General procedure for the desulfurization reactions: To a 25
mL round‐bottom flask equipped with a stir bar was added the
substrate (0.75 mmol, 1.0 equiv.) and P(OEt)3 (249.2 mg, 1.50
mmol, 2.0 equiv.). CH3CN was added (6 mL, 8 mol/L concentration)
followed by the addition of DTBP (131.6 mg, 0.90 mmol, 1.2
equiv.). The flask was capped and the reaction was stirred and
irradiated using two 36 W household CFL bulbs (6 cm away, to
keep the reaction at room temperature) at room temperature for
6 h. When the reaction was complete, the solvent was removed
under vacuum. The product was obtained by column chromatog‐
raphy on silica with petroleum ether/ethyl acetate mixture as the
eluent.
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Supporting Information
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.202000607.
Acknowledgement
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We thank Shanghai Jiao Tong University and the National
“1000‐Youth Talents Plan” for financial support.
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Manuscript received: October 29, 2021
Manuscript revised: January 15, 2021
Manuscript accepted: January 17, 2021
Accepted manuscript online: January 21, 2021
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Chin. J. Chem. 2021, 39, 1255—1258