Regio- and enantioselective ring-opening of epoxides with HMDST: A straightforward access to 1,2-mercaptoalcohols

Article abstract of DOI:10.1055/s-2005-921922

TBAF-catalyzed reaction of a range of substituted epoxides with hexamethyldisilathiane smoothly affords a direct and simple access to β-mercaptoalcohols in a highly regio- and stereo-selective way. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-921922

LETTER
3063
Regio- and Enantioselective Ring-Opening of Epoxides with HMDST:
A Straightforward Access to 1,2-Mercaptoalcohols
A
ccess to 1,2-Mer
l
captoa
l
e
cohols ssandro Degl’Innocenti,*a Antonella Capperucci,*a Arianna Cerreti,a,b Salvatore Pollicino,b Serena Scapecchi,c
Irene Malesci,a Giulio Castagnolia
a
Dipartimento di Chimica Organica, Università di Firenze, Via della Lastruccia 13, 50019 Sesto Fiorentino, Italy
b
Dipartimento di Chimica Organica, ‘A. Mangini’, viale Risorgimento 4, 40136 Bologna, Italy
c
Dipartimento di Scienze Farmaceutiche, Università di Firenze, via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy
Fax +39(055)4573585; E-mail: alessandro.deglinnocenti@unifi.it
Received 14 September 2005
have been used, thus affording the corresponding
functionalized b-hydroxy thioethers with high regio- and
stereocontrol, under suitable catalytic conditions.
Abstract: TBAF-catalyzed reaction of a range of substituted
epoxides with hexamethyldisilathiane smoothly affords a direct and
simple access to b-mercaptoalcohols in a highly regio- and stereo-
selective way.
Nonetheless, among the reactions of sulfur nucleophiles
Key words: epoxides, thiosilane, 1,2-mercaptoalcohols, enantio- with epoxides, to the best of our knowledge there are a
selectivity, regioselectivity
few methods which allow a direct access to b-mercapto-
alcohols, which indeed represent very interesting interme-
diates in the synthesis of various biologically important
compounds. Some procedures involve reactions of H2S,13
Ring-opening of epoxides with various nucleophiles is an
important and useful synthetic transformation providing
NaBH2S3,2a and thiourea.14
an easy access to a large number of functionalized inter-
In connection with this, it is worth mentioning the ring-
mediates, useful in the synthesis of more complex organic
opening of epoxides induced by silane thiols, such as
structures.1
Ph3SiSH11 and i-Pr3SiSH (HSTIPS),15 which behave as
monoprotected H2S, but are easier to handle and afford the
desired b-hydroxy thiols in high yields.
In this context, reactions with thio nucleophiles play an
important role2 affording hydroxythio derivatives as use-
ful building blocks in organic chemistry, particularly in
the pharmaceutical and natural products field.3 In fact,
ring-opening of 1,2-oxiranes with thiols yields b-hydroxy
thioethers, which can be used in the synthesis of leuko-
trienes,4 HIV-1 protease inhibitors,3e and MMP inhibi-
tors.3d Such ring-openings are promoted either by Lewis
acids [Zn(II) halides,5 LiClO4,2d Ln(III) complexes,2b Ti(i-
In the case of Ph3SiSH, ring-opening of epoxides proved
to be not always regiospecific, the isomeric distribution
being dependent on the stoichiometric ratio of Et3N, while
the use of HSTIPS led in a regiospecific way to the corre-
sponding b-trialkylsilyloxy mercaptans; therefore a
deprotection step must be employed to access the free hy-
droxy compounds.
2j
PrO)4,2i,6 COCl2,1g BF3·OEt2,7 Sn(II) salts,8 InCl3 ] or by
Moreover, some of the methods often involve extended
reaction times, undesirable side reactions, or poor regio-
selectivity.
basic catalysts (alumina,9 quaternary ammonium
salts,2c,e,10 including TBAF, and amines11) and afford b-
hydroxy sulfides in good yields with high regiochemical
control.
During the course of our research on the evaluation of the
reactivity of bis(trimethylsilyl)sulfide (hexamethyl-
disilathiane, HMDST) as a versatile thionating agent af-
fording thiocarbonyl derivatives directly16 we wondered
whether HMDST could behave as an efficient sulfur nu-
cleophile in the ring-opening reaction of epoxides, taking
into consideration that it may be regarded as the synthetic
equivalent of H2S, but would be much easier to handle and
to measure.
Stereoselective ring-opening of chiral epoxides is often
achieved and catalytic asymmetric oxirane ring-openings
are usually obtained through the use of chiral metal com-
plexes, leading to desymmetrization of meso-epoxides
and the introduction of two contiguous stereogenic
centers.2h
Thiosilanes, a class of compounds which couple in the
same structure a powerful oxygenophile (SiR3) and a
strong nucleophile (RS group), have also been used as
nucleophiles in reactions with oxiranes in place of
thiols.4c,5,10b,11,12 Aliphatic and aromatic organothio-
silanes, including amino acid and glutathione derivatives,
Thus, treatment of 2-methyloxirane 1a with HMDST at
room temperature in the presence of a catalytic amount of
TBAF (0.2 equiv) led smoothly to uncover a simple ac-
cess to 1-mercaptopropan-2-ol 17 (2a; Scheme 1), arising
from clean regioselective attack of the thio nucleophile on
the less hindered side of the oxirane, no trace of the other
regioisomer was detected.
SYNLETT 2005, No. 20, pp 3063–3066
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Advanced online publication: 28.11.2005
DOI: 10.1055/s-2005-921922; Art ID: G29005ST
© Georg Thieme Verlag Stuttgart · New York

3064
A. Degl’Innocenti et al.
LETTER
RO
Me
Table 1 Direct Synthesis of b-Mercaptoalcohols
O
TBAF
+ (TMS)2S
THF/r.t.
Yield (%)a
65b
SH
Me
Entry Epoxide
1,2-Mercaptoalcohol
1a
2a, 3a
1
O
HO
2a: R = H (0.2 equiv TBAF)
3a: R = TMS (0.1 equiv TBAF)
Me
Me
2a
SH
SH
1a
Scheme 1
2
95c
O
HO
Such behavior discloses a potentially useful straightfor-
ward access to 1,2-mercaptoalcohols.
Ph
Ph
1b
2b
3
72d,e
O
HO
In order to evaluate the generality of such methodology, a
series of substituted epoxides was reacted under the same
conditions (Table 1).
i-PrO
i-PrOCH2
SH
1c
2c
The reactivity proved general, leading to the synthesis of
substituted 1,2-mercaptoalcohols bearing aromatic, ali-
phatic, and vinylic moieties. This reaction appears quite
interesting, in so far as it is operationally simple and re-
presents a direct access to b-hydroxy mercaptans under
very mild conditions with a catalytic amount of TBAF.
4
87
HO
O
AllO
AllOCH2
SH
1d
2d
5
40f
O
HO
Cl
ClCH2
SH
All the reactions occur with very good yields of mono-
substituted epoxides, while for 1,2-substituted oxiranes,
as already pointed out by other authors,11 the yields tend
to decrease.
1e
2e
6
80g
55h
90h
50
HO
O
CH2=CH
SH
1f
It is interesting to underline that the process is generally
highly regioselective, only one isomer being observed in
the crude. Only in the case of styrene oxide and isopropyl
glycidyl ether were the corresponding regioisomers
detected (Table 1, entries 2, 3).
2f
HO
7
8
9
SH
O
Me
Me
Me
Me
1g
2g
OH
Concerning the amount of TBAF, it must be considered
that in most cases the addition of a catalytic amount (0.2–
0.3 equiv) of the ammonium salt afforded the b-hydroxy
thiol as the sole product (Table 1, entries 1, 2, 4, 7–9),
while smaller amounts of TBAF led to the isolation of the
silyl ether.17 On the contrary, treatment of epoxides 1c, 1e,
and 1f with 0.2 equivalents of TBAF led to the isolation
of b-trimethylsilyloxy thiols as the major compounds.
Simple addition in the same flask of an additional 0.2
equivalents of TBAF smoothly afforded the desired b-
mercaptoalcohols 2c, 2e, and 2f in good yields.
O
SH
HO
1h
O
2h
O
SH
O
O
O
O
O
O
O
1i
2i
a Refers to isolated products whose spectroscopic data are consistent
with the assigned structure.
b By using 10% of TBAF 2-(trimethylsilyloxy)propane-1-thiol (3a)
was isolated in 72% yield.16,
c Yield of regioisomer isolated: 4.6%.
Due to the mildness of the experimental conditions, this
methodology can be applied also to very useful, but labile
compounds such as glycidol derivatives, which represent
important structures in different fields.3d,7,10b,18 Protected
glycidols 1c and 1d were opened in good yields and the
protective moieties were not removed under the reaction
conditions (Table 1, entries 3 and 4).
d Yield of regioisomer recovered: 2.5%.
e Silyl ether was obtained with TBAF (0.3 equiv) in 90% yield.
f Silyl ether was obtained with TBAF (0.3 equiv) in 70% yield.
g Yield of silyl ether recovered: 18%.
h Racemic.
Moreover, epichlorohydrin (1e) reacts smoothly with
HMDST (Table 1, entry 5). In this case the reaction must
be run at –15 °C, at room temperature an exothermic reac-
tion occurs leading to a complex mixture of products. The
oxirane is again regioselectively opened at the less hin-
dered carbon, and nucleophilic attack occurs exclusively
on the epoxide, the halide being preserved on the side
chain.
butadiene mono-oxide 1f leads to the clean formation of
vinyl-substituted b-hydroxy thiol 2f, together with the
corresponding silyl ether (Table 1, entry 6). No 1,4-ad-
duct is observed, the mercaptoalcohol thus obtained arises
from the regioselective attack of the nucleophile on the
less substituted carbon of the epoxide.
The D-mannitol epoxide was also reacted to afford 1,2-
mercaptoalcohol diacetonide 2i, together with unreacted
starting oxirane (Table 1, entry 9).
Contrary to that reported by others,5 it is interesting to
note that under the present conditions, ring-opening of
Synlett 2005, No. 20, 3063–3066 © Thieme Stuttgart · New York

LETTER
Access to 1,2-Mercaptoalcohols
3065
This mild and selective procedure may be usefully applied
also to chiral molecules. When enantiopure epoxides are
reacted under the same conditions, optically active b-hy-
droxy thiols were regioselectively formed (Table 2). Be-
sides glycidol derivatives (Table 2, entries 2 and 3),
pyrrolidine-substituted b-hydroxy thiol 2n was of particu-
lar interest (Table 2, entry 4) as a useful reagent for the
synthesis of 1,3-oxathiolane-derivatives, which have been
recently demonstrated as important molecules in the
pharmacological field.19
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1,2-Mercaptoalcohol Yield (%)a [a]D
20,b
Entry Epoxide
1
95c
–5820
HO
O
Ph
Ph
SH
R-(–)-1b
R-(–)-2b
2
84
–5
HO
O
O
Me
MeOCH2
SH
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S-(+)-1l
R-(–)-2l
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–9
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HO
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Bn
BnOCH2
R-(+)-1m
S-(–)-2m
4
86d
+25
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N
Cbz
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an effective synthetic equivalent of H2S, leading directly
to b-mercaptoalcohols, interesting starting materials of
more complex molecules.
The reactions occur with high regio- and stereoselectivity
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Acknowledgment
Financial support by the National Project ‘Stereoselezione in
Sintesi Organica. Metodologie ed Applicazioni’ (MURST, Roma)
is gratefully acknowledged. Ente Cassa di Risparmio di Firenze is
acknowledged for granting a 400-MHz NMR spectrometer.
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LETTER
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(17) Typical Procedure: A solution of 2-methyloxirane (1a, 100
mg, 1.72 mmol) and HMDST (470 mL, 2.24 mmol, 398 mg)
in THF (0.1 mL) was treated at r.t. with TBAF (1 M in THF;
450 mL, 0.45 mmol) under an inert atmosphere. The mixture
became bright green and after 5 min pale yellow. The
reaction was carried out for 30 min and the progress of the
reaction monitored by TLC. After addition of citric acid
(50% aq solution; 0.5 mL) the mixture was stirred for 5 min,
then diluted with Et2O. The organic phase was then washed
with citric acid (20% aq solution), extracted with Et2O, and
dried over Na2SO4. Evaporation of the solvent afforded 106
mg of 1-mercaptopropan-2-ol (2a; 65%), which was pure
enough to be used without further purification. 1H NMR
(200 MHz, CDCl3): d = 1.25 (3 H, d, J = 6.0 Hz), 1.43 (1 H,
app t, J = 8.7 Hz), 2.32 (1 H, br s), 2.44–2.56 (1 H, m), 2.60–
2.71 (1 H, m), 3.71–3.84 (1 H, m). 13C NMR (50 MHz,
CDCl3): d = 21.7, 33.2, 68.4. MS: m/z (%) = 92 (0.08), 91
(0.25), 75 (11), 45 (100).
Following the above procedure, oxirane 1a and HMDST
were treated with a solution of TBAF (225 mL, 0.22 mmol)to
give cleanly 2-(trimethylsilyloxy)propane-1-thiol (3a; 203
mg, 72% yield). 1H NMR (200 MHz, CDCl3): d = 0.14 (9 H,
s), 1.22 (3 H, d, J = 6.0 Hz), 1.46 (1 H, dd, J = 9.0 Hz, J = 8.8
Hz), 2.43–2.59 (2 H, m), 3.84 (1 H, app sextet). 13C NMR
(50 MHz, CDCl3): d = 0.2, 22.5, 33.3, 70.0. MS: m/z (%) =
164 (0.6), 149 (10), 117 (66), 91 (15), 75 (53), 73 (100).
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Synlett 2005, No. 20, 3063–3066 © Thieme Stuttgart · New York