Photochemical desulfurization of thiols and disulfides

Article abstract of DOI:10.1016/S0957-4166(99)00265-7

A visible light-induced desulfurization process for thiols and disulfides using triethylphosphite and triethylborane is reported. The reaction can be effected on a range of organic molecules having either primary, secondary or tertiary thiol groups and disulfides without the need of protecting groups. Thus, after treating L-cystine 7, L-cystine dimethylester 8, thioctic amide 9 and glutathione disulfide 10, first with tributylphosphine, later with triethylborane/triethylphosphite under irradiation in a one-pot reaction, the corresponding desulfurized compounds L-Ala, L-Ala, 1-octanamide and γ-L-Glu-L-Ala-Gly, respectively, are prepared in high yields with retention of configuration.

Full text of DOI:10.1016/S0957-4166(99)00265-7

Pergamon
Tetrahedron: Asymmetry 10 (1999) 2643–2646
Photochemical desulfurization of thiols and disulfides †
Javier Cuesta,a Gemma Arsequell,b Gregorio Valencia b,∗ and Asensio González a,∗
aLaboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, 08028 Barcelona, Spain
bUnit for Glycoconjugate Chemistry, C.S.I.C., Jordi Girona 18-26, 08034 Barcelona, Spain
Received 11 June 1999; accepted 24 June 1999
Abstract
A visible light-induced desulfurization process for thiols and disulfides using triethylphosphite and triethyl-
borane is reported. The reaction can be effected on a range of organic molecules having either primary, secondary
or tertiary thiol groups and disulfides without the need of protecting groups. Thus, after treating L-cystine 7,
L-cystine dimethylester 8, thioctic amide 9 and glutathione disulfide 10, first with tributylphosphine, later with
triethylborane/triethylphosphite under irradiation in a one-pot reaction, the corresponding desulfurized compounds
L-Ala, L-Ala, 1-octanamide and γ-L-Glu-L-Ala-Gly, respectively, are prepared in high yields with retention of
configuration. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
Reactions promoted by visible light are advantageous in many ways because of mild reaction condi-
tions, cleaner reaction products and energy savings. Several reactions of synthetic importance have been
satisfactorily performed under visible light irradiation.1 We have recently accomplished the reductive
desulfurization of L-cysteine derivatives, and an L-cysteine containing peptide, but no attempts were
made to investigate other structural possibilities of the substrates.2
To broaden the scope of the reaction, we have first studied some aliphatic primary, secondary and
tertiary thiol-containing organic molecules. Second, with the aim of developing new mild chemical
tools for the study of the role of disulfide bridges in stabilizing and maintaining the biologically active
conformations of complex peptides and proteins we have extended this photochemical desulfurization
method to L-cystine and glutathione disulfide, simple models of such macromolecules.
∗
†
Corresponding authors.
Dedicated with affection to Professor Albert H. Soloway in his retirement.
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00265-7

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2. Results and discussion
A series of commercially available primary, secondary and tertiary thiols have been tested for desulfur-
ization in the presence of triethylphosphite and triethylborane under light irradiation (see Table 1). The
primary thiol group of captopril 1, inhibitor of angiotensin converting enzymes, was removed in good
yield (83%). However, a lower yield was obtained with 3-mercapto-1,2-propanediol 2 (47%). In the
latter, side reactions of triethylboron with the hydroxyl groups of the substrate could give diethylborane
ethers3 or boron chelates,4 competing with the reductive elimination of the thiol. Moderate yields were
obtained for the removal of secondary thiol groups, for N-(mercaptopropionyl)glycine 3 (71%), and
mercaptosuccinic acid 4 (65%). In addition, the tertiary thiol group of 8-mercaptomenthone 6 was
eliminated in a satisfactory 78% yield, although lower than that observed with D-penicillamine 5 (95%).2
Initial attempts to remove the disulfide function of L-cystine under the same conditions failed.
Due to the polar character of this substance the procedure had to be adapted to conditions using
aqueous solvent. Previous reduction of L-cystine 7 with tributylphosphine in 1-propanol/water at room
temperature according to Rüegg and Rudinger’s procedure,5 followed by light irradiation in the presence
of triethylborane/triethylphosphite in a one-pot reaction, afforded L-alanine (90%) with retention of
configuration (Scheme 1).
Scheme 1. Reagents: (i) PBu3/CH3CH2CH2OH/NaHCO3/H2O; (ii) BEt3; (iii) P(EtO)3/hν
In an analogous way, L-cystine dimethylester 8 furnished the desulfurized compound with concomitant
hydrolysis of the ester under the mild basic reaction conditions (88%), and thioctic amide 9 afforded 1-
octanamide in 86% yield. A blank reaction in the presence of triethylborane/tributylphosphine, but in the
absence of triethylphosphite, showed only partial conversion of L-cystine to L-alanine (33%), tributyl-
phosphine acting as a reducing and desulfurizing agent. Remarkably, the above reaction conditions were
successfully applied to glutathione disulfide 10, which was converted to the tripeptide, γ-L-Glu-L-Ala-
Gly in 85% yield (Scheme 2).6
Scheme 2. Reagents: (i) PBu3/CH3CH2CH2OH/NaHCO3/H2O; (ii) BEt3; (iii) P(EtO)3/hν
In conclusion, we have demonstrated that this visible light induced desulfurization of thiols can
be effected on a number of organic substrates regardless of their substitution pattern, effected by the
combination of triethylphosphite and triethylborane. Moreover, reductive elimination of sulfur from
disulfides is also possible using tributylphosphine as a previous reducing agent of the disulfide, even
in the presence of water in a one-pot process. Studies aimed at the application of this process in peptide
chemistry are currently underway in our laboratories.

J. Cuesta et al. / Tetrahedron: Asymmetry 10 (1999) 2643–2646
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Table 1
Desulfurization with triethylboron/triethylphosphite/hν7

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J. Cuesta et al. / Tetrahedron: Asymmetry 10 (1999) 2643–2646
Acknowledgements
Support for this research was provided by DGICYT (Spain) through Grant PB97-0877.
References
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3. Taba, K. M.; Köster, R.; Dahlhoff, V. Synthesis 1984, 399–401.
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7. Typical experiment: L-cystine 7 (0.6 g, 2.5 mmol) was treated with 4 ml of 10% NaHCO3, 6 ml of water and 10 ml of
1-propanol followed by 1.3 ml (5 mmol) of tributylphosphine under an argon atmosphere for 1 h at room temperature.
A 1 M solution of triethylborane in tetrahydrofuran (3.5 ml, 3.5 mmol) was added and stirred under argon for 3 min.
Triethylphosphite (2.6 ml, 15 mmol) was added and the resulting mixture was irradiated with a 300 W visible light bulb
located about 20 cm from the flask for 36 h in an open system (Dimroth refrigerant). The solution became transparent.
The organic solvent was evaporated under reduced pressure. 6 M HCl (6 ml) was added, the mixture stirred for 1 h and
extracted with CH2Cl2 (3×2 ml). After evaporation of the acidic fraction under high vacuum, the residue was column
chromatographed on silylated silica gel [Evans, M. B.; Dale, A. D.; Little, C. J. Chromatographia 1980, 13, 5–10] to give
L-alanine hydrochloride (0.56 g, 90% yield). Selected spectral data: 13C NMR (D2O, 50 MHz) δ 175.0 (C_O), 51.2 (CH),
17.8 (CH3). L-Ala·HCl: [α]D22=+14.3 (c 10, 6N HCl), lit.: [α]D20=+14.5 (c 10, 6N HCl). Glutathione disulfide 10 treated
with tributylphosphine in 1-propanol/0.5 M NaHCO3/water for 1 h followed by triethylborane for 2 min and irradiated in
the presence of triethylphosphite for 14 h was converted into γ-L-Glu-L-Ala-Gly. The reaction was checked by RP-HPLC
and MALDI-TOF-MS, [M+H]=276.10. 13C NMR (D2O, 50 MHz) δ 177.2, 175.5, 173.6, 172.0, 53.9 (CH), 51.5 (CH),
42.8 (CH2), 32.6 (CH2), 27.2 (CH2), 18.6 (CH3). Captopril 1 was converted into 1-(1-oxo-2-methylpropyl)-L-proline: 13
C
NMR (CDCl3, 50 MHz) δ 178.8, 173.1, 59.9 (CH), 47.5 (CH2), 32.5 (CH), 27.6 (CH2), 24.9 (CH2), 19.0 (CH3), 18.6
(CH3). [α]D20=−121 (c 1, ethyl acetate). M.p. 117–119°C.