Phosphine-assisted rearrangement of 4,5-dihydroxy-1,2-dithianes to 4-hydroxy-3-mercaptotetrahydrothiophenes

Article abstract of DOI:10.3987/com-02-9603

Treatment of 4,5-dihydroxy-1,2-dithianes with trialkylphosphines and triphenylphosphine under neutral and moderately basic conditions led to the efficient and stereospecific production of 4-hydroxy-3-mercaptotetrahydrothiophenes. The reaction is projected

Full text of DOI:10.3987/com-02-9603

HETEROCYCLES, Vol. 60, No. 1, 2003
47
HETEROCYCLES, Vol. 60, No. 1, 2003, pp. 47 - 56
Received, 16th August, 2002, Accepted, 28th October, 2002, Published online, 28th October, 2002
PHOSPHINE-ASSISTED REARRANGEMENT OF 4,5-DIHYDROXY-
1,2-DITHIANES TO 4-HYDROXY-3-
MERCAPTOTETRAHYDROTHIOPHENES
Sang Hyup Lee and Harold Kohn*
Division of Medicinal Chemistry and Natural Products,
School of Pharmacy, University of North Carolina,
Chapel Hill, NC 27599-7360, USA
Abstract-Treatment of 4,5-dihydroxy-1,2-dithianes with trialkylphosphines
and triphenylphosphine under neutral and moderately basic conditions led to
the
efficient
and
stereospecific
production
of
4-hydroxy-3-
mercaptotetrahydrothiophenes. The reaction is projected to proceed through
three successive intramolecular rearrangements.
Tetrahydrothiophenes (thiolanes) are heterocycles of interest1 and recently 3,4-disubstituted
tetrahydrothiophenes (1)2-4 have gained importance for the construction of novel nucleosides and
glycosides.2 Few synthetic methodologies exist for the preparation of 1.2-4 In this paper, we report an
efficient phosphine (3)-mediated procedure for the conversion of 4,5-dihydroxy-1,2-dithianes5 (2) to 4-
hydroxy-3-mercaptotetrahydrothiophenes (4) that proceeds with stereospecificity.
S
S S
S
R3P (3)
X
Y
HO
SH
HO
OH
1
4
2
X, Y= OH, NH2, SH
RESULTS AND DISCUSSION
Our starting cyclic disulfides were cis-4,5-dihydroxy-1,2-dithiane (DTEox, 5)6 and trans-4,5-dihydroxy-
1,2-dithiane (DTTox, 6)7 and we employed the three phosphines, triethylphosphine (7), tris(2-
carboxyethyl)phosphine hydrochloride8 (TCEP, 8), and triphenylphosphine (9). Dithiane (6a) is
commercially available while 56 and 6b5,7 were prepared by oxidation of dithioerythritol (DTE, 10) and L-
dithiothreitol (L-DTT, 11b), in basic methanol, respectively (Scheme 1).

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HETEROCYCLES, Vol. 60, No. 1, 2003
S S
R3P
HO
OH
OH
7
8
R = CH2CH3
5
R = CH2CH2CO2H HCl
S S
9
R =
HO
6
a (R,R + S,S)
b (R,R)
Scheme 1. Phosphine-mediated Transformations
disulfide
cleavage
10 meso-DTE
11b (R,R)-threo-L-DTT
S S
R3P
HS
SH
O2, KOH
HO
OH
HO
OH
S
rearrangement
5 cis-DTEox
10 meso-DTE
11b (R,R)-threo-L-DTT
6a (R,R + S,S)-trans-DL-DTTox
6b (R,R)-trans-L-DTTox
HO
SH
12 (R,S + S,R)-trans
13a (S,S + R,R)-cis
13b (S,S)-cis
The reactions of 4,5-dihydroxy-1,2-dithianes (5 and 6) with phosphines (7-9) were pH-dependent (Table
1). Under mildly acidic conditions, TCEP (8) efficiently reduced 5 (Table 1, Entries a,b) and 6b (Table 1,
Entries h-j) to the corresponding dithiols (10) and (11b), respectively, at room temperature. These
findings mirrored the earlier report of Whitesides and coworkers.8 Correspondingly, when the reactions
with 5, 6a and 6b were conducted under neutral or moderately basic conditions (Table 1, Entries c-g,k,l)
we did not obtain the corresponding dithiols, but rather, we observed the efficient production of 4-hy-
droxy-3-mercaptotetrahydrothiophenes (12, 13a and 13b), respectively. For 5 and 6a, we obtained
racemic 12 and 13a, respectively, while for 6b, we isolated the stereospecific product (13b). Air
oxidation of 13a gave a 1.1:1 diastereomeric mixture of disulfide (14) (NMR spectral analysis). We
found that the reaction rate for Et3P (7) was comparable to TCEP (8) (< 0.2 h) but that the Ph3P (9)
transformation was significantly slower (~ 24 h) (Table 1, Entries c,d,e). This finding was consistent with
the nucleophilicity of alkyl- and aryl- phosphines9-11 and likely reflects, in part, the rate of the disulfide
cleavage reaction.

HETEROCYCLES, Vol. 60, No. 1, 2003
49
Table 1. Reaction of 5, 6a and 6b with Phosphine Reagents (7-9)
R3Pa
Base
(equiv.)
-
Reaction
time (h)
6
Product
(% yield)b
10 (70)
Entry
Compound
(2 equiv.)
a
5
5
8
8
b
pyridine
(10)
0.2
10 (65)
c
K2CO3
(10)
-
0.2
12 (45)
5
8
d
e
f
0.2
24
0.2
48
6
12 (79)
12 (45)
5
7
9
7
9
8
8
-
-
-
-
5
13a (51)
13a (68)
11b (80)
11b (70)
6a
6a
6b
6b
g
h
i
pyridine
(2)
0.5
j
pyridine
(8)
0.2
11b (55)
6b
8
k
l
pH 7.0c
0.2
0.2
13b (66)
13b (73)
6b
6b
7
8
K2CO3
(10)
aTwo equiv. of R3P was used. bIsolated yield. cBuffered methanolic solution
(0.5 M bis-Tris·HCl).
S
S
S
S
S
O2
+
HO
OH
14 (meso)
S
S
HO
OH
S
S
HO
SH
13a (dl)
14 (dl)
We documented the identity of 4-hydroxy-3-mercaptotetrahydrothiophenes (12) and (13). Characteristic
signals in the 1H and 13C NMR spectra12,13 in related structures permitted the identity of the C(3) and C(4)
methine hydrogen and carbon signals, respectively. Furthermore, we were able to assign the relative
orientation of the C(3) and C(4) substituents by inspection of the 13C and 1H NMR resonances for these
signals. We observed that in the 13C NMR, the C(3) and C(4) signals for cis-tetrahydrothiophene (13a)
appeared upfield (0.5-4.8 ppm) compared to the trans-isomer (12) while the corresponding 1H NMR
signals for the methine hydrogens appeared downfield (0.03-0.2 ppm). This inverse relationship of 13C
and 1H NMR signals is diagnostic of a γ-effect14,15 and has been observed in structurally related
systems.16 Our assignment for the cis-adduct (13a) was bolstered by the NOESY spectrum where we
observed a strong interaction for the C(3)Hα and C(4)Hα methine hydrogens, a strong interaction for

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HETEROCYCLES, Vol. 60, No. 1, 2003
C(4)Hα and C(5)Hα, and a weak interaction for C(4)Hα and C(5) Hβ. We ran the corresponding NOESY
spectrum on the trans-tetrahydrothiophene (12) but overlapping signals did not permit structural
assignment. The 13C NMR data for 12 and 13a documented the stereospecific conversion of dithiane (2)
to tetrahydrothiophene (4). For each reaction we observed a unique set of four signals in the 13C NMR
spectrum. Racemization at either C(3) or C(4) would have led to diastereomeric mixtures and the
observation of a pair of four signals in the 13C NMR spectrum.
Why are dithiols (10, 11) produced from dithianes (5, 6) under acidic conditions while the ring-contracted
tetrahydrothiophenes (12, 13) are the sole adducts under neutral and moderately basic conditions? We
suggest that both reactions proceed by initial phosphine-assisted disulfide cleavage8,9,17-19 (Scheme 2 for
5). Under acidic conditions, the ring-cleaved product (15) is hydrolyzed to give dithiol (10) and
phosphine oxide. Under neutral and basic conditions, rearrangement of 15 to 16 competes with solvolysis.
Subsequent cyclization of 16 leads to thiirane (17) and the release of the corresponding phosphine oxide.
Intramolecular nucleophilic substitution at the methylene site in thiirane (17) by the terminal thiol gives
the stable tetrahydrothiophene (12). We have evidence for the overall pathway depicted in Scheme 2.
We monitored the conversion of 6a to 13a in CD3OD-CDCl3-D2O using 1H and 13C NMR spectrometry
(data not shown). We observed the appearance of diagnostic signals in the 1H NMR (δ 2.23 (dd), 2.51
(dd)) and the 13C NMR (δ 24.0, 31.5) in the early stages of the reaction that have been tentatively
assigned to 17 and which disappeared with time. These signals are similar to those reported for 18.20
Scheme 2. Proposed Pathway for Phosphine-mediated Disulfide Transformations
HS
SH
HO
OH
10
+
H2O
R3P O
-
disulfide
cleavage
S S
S
+
R3P
2
S PR3
3
HO
OH
HO
OH
15
rearrangement
SH
5
S
SH
S
S
H
HO
HO
SH
O-PR3
HO
12
16
17
+
R3P O

HETEROCYCLES, Vol. 60, No. 1, 2003
51
S
20
+
(HOCH2CH2S)2
S
S
19
18
+
Ph3P
HOCH2CH2SH
21
The proposed pathway of 5 with phosphines to 17 and the conversion of 17 to 12 gains support from
previous studies. First, Grayson21 and Overman10 have reported that treatment of 2-hydroxyethyl
disulfide (19) with triphenylphosphine gave thiirane (20) and 2-mercaptoethanol (21). We have repeated
this reaction with 7 (1.3 equiv) under the conditions employed in our study and observed the rapid
production (< 0.2 h) of 20 and 21 (NMR spectral analysis, data not shown).22 Second, Sanchez showed
that heating 6a with concentrated aqueous HCl led to a moderate yield (32%) of 13a.4 Attempts to
convert 5 to 12 were unsuccessful and gave 22.4 Sanchez proposed that 13a formation proceeded through
intermediate (23).23
S
SH
S
S
S
H
S
HO
22
23
CONCLUSIONS
In summary, we report a mild and efficient procedure for the stereospecific rearrangement of 4,5-
dihydroxy-1,2-dithianes (2) to 4-hydroxy-3-mercaptotetrahydrothiophenes (4). We attribute the ease of
this transformation to the phosphine (3), which initiates disulfide cleavage and assists in the removal of
the C(3) hydroxyl group permitting tetrahydrothiophene formation. Stereospecific conversion of 2 to 4 is
projected to proceed through three successive intramolecular rearrangements. The importance of this
novel transformation is underscored by recent reports for the introduction of nucleic bases at the C(2) site
in 3,4-dihydroxytetrahydrothiophenes.2
EXPERIMENTAL
1H and 13C NMR spectra were recorded on Varian VXR-300 and Bruker DRX-500 MHz spectrometer.
MS spectral data were obtained by Dr. Mehdi Moini at the University of Texas at Austin. The low-
resolution MS spectral studies were run on a Finnegan TSQ-70 triple quadrupole mass spectrometer, and
the high-resolution MS spectral studies were conducted on a Micromass ZAB-E mass spectrometer. FT-
IR spectra were run on a Mattson Galaxy Series FT-IR 5000 spectrophotometer. Melting points were
determined in open capillary tubes using a Thomas-Hoover melting point apparatus and are uncorrected.
Microanalyses were provided by Atlantic Microlab, Inc. (Norcross, GA).
cis-4,5-Dihydroxy-1,2-dithiane (DTEox, 5). 6 To a stirred solution of 10 (Aldrich Co., 500 mg, 3.24
mmol) in MeOH (150 mL) was added KOH (381 mg, 6.8 mmol) at rt and then O2 was bubbled through

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HETEROCYCLES, Vol. 60, No. 1, 2003
the solution (2.5 d). The reaction solution was evaporated to one-fourth of its volume and H2O (100 mL)
was added. The mixture was extracted with EtOAc (2 X 150 mL). The combined organic layers were
washed with H2O (100 mL), dried (MgSO4), and concentrated to one-tenth of its volume leading to
formation of a precipitate. The solid was collected and washed with Et2O to give 5 without further
purification: yield, 320 mg (65%); mp 129-131 oC (lit.,6 mp 132 oC); Rf 0.42 (2:1 EtOAc/hexanes); IR
(KBr) 3404, 3314, 2896, 1399, 1269, 1212, 1047, 916, 743, 591 cm-1; 1H NMR (CD3OD, -20 oC) δ 2.52
(dd, 1 H, J = 12.5, 3.5 Hz), 3.02 (dd, 1 H, J = 13.8, 4.5 Hz), 3.20 (app t, 1 H, J = 11.8 Hz), 3.28-3.37 (m,
1 H), 3.66 (br d, 1 H, J = 11.0 Hz), 4.10 (s, 1 H); 13C NMR (CD3OD, -20 oC) δ 32.4, 42.4, 67.3, 70.8, the
1H and 13C NMR spectral data were in agreement with the COSY and HMQC spectra.
(4R,5R)-trans-4,5-Dihydroxy-1,2-dithiane (L-DTTox, 6b).7 Employing the preceding procedure and
using 11b (Aldrich Co., 500 mg, 3.24 mmol), MeOH (60 mL), and KOH (381 mg, 6.8 mmol) gave 6b
without further purification: yield, 315 mg (64%); mp 113-115 oC (lit.,7 mp 113-115 oC); Rf 0.47 (2:1
EtOAc/hexanes); IR (KBr) 3368, 2903, 1403, 1278, 1177, 1031, 874, 738, 581, 540 cm-1; 1H NMR
(CD3OD, -60 oC) δ 2.91 (dd, 2 H, J = 13.5, 10.5 Hz), 3.04 (dd, 2 H, J = 13.5, 3.0 Hz), 3.45-3.52 (m, 2 H);
13C NMR (CD3OD, -60 oC) δ 42.1, 75.7, the 1H and 13C NMR spectral data were in agreement with the
COSY and HMQC spectra.
General Procedure for Disulfide Cleavage to Dithiols. To a stirred solution of 4,5-dihydroxy-1,2-
dithiane (5, 6b) (20 mg, 0.13 mmol) in the appropriate solvent mixture either in the absence or presence
of a base was added the phosphine reagent (0.26 mmol) at rt. Stirring was continued for 10 min - 6 h.
After the reaction was completed H2O (20 mL) was added and the mixture was extracted with EtOAc (2 х
20 mL). The combined organic layers were washed with H2O (20 mL), dried (MgSO4), and concentrated
in vacuo. The crude product was purified by PTLC using EtOAc/hexanes (1:2) as the eluent.
Dithioerythritol (DTE, 10).5
(A) Using TCEP: Using 5 (20 mg, 0.13 mmol), MeOH-CHCl3-H2O (5:2:5, v/v, 3.6 mL), and 8 (75 mg,
0.26 mmol) and the general procedure gave 10 as a white solid (6 h) without further purification: yield, 14
mg (70%); mp 79-81 oC (lit.,5 mp 83 oC).
(B)
Using TCEP and pyridine: Using 5 (20 mg, 0.13 mmol), MeOH-CHCl3-H2O (5:2:5, v/v, 3.6 mL),
8 (75 mg, 0.26 mmol), and pyridine (105 µL, 1.3 mmol) and the general procedure gave 10 as a white
solid (0.2 h): yield, 13 mg (65%).
L-Dithiothreitol (L-DTT, 11b).5
(A)
Using TCEP: Using 6b (20 mg, 0.13 mmol), MeOH-CHCl3-H2O (5:2:5, v/v, 3.6 mL), and 8 (75
mg, 0.26 mmol) and the general procedure gave 11b as a white solid (6 h) without further purification:
yield, 16 mg (80%) mp 44-47 oC (lit.,5 mp 48-50 oC).

HETEROCYCLES, Vol. 60, No. 1, 2003
53
(B)
Using TCEP and pyridine (2 equiv): Using 6b (20 mg, 0.13 mmol), MeOH-CHCl3-H2O (5:2:5,
v/v, 3.6 mL), 8 (75 mg, 0.26 mmol), and pyridine (21 µL, 0.26 mmol) and the general procedure gave 11b
as a white solid (0.5 h): yield, 14 mg (70%).
(C)
Using TCEP and pyridine (8 equiv): Using 6b (20 mg, 0.13 mmol), MeOH-CHCl3-H2O (5:2:5,
v/v, 3.6 mL), 8 (75 mg, 0.26 mmol), and pyridine (84 µL, 1.04 mmol) and the general procedure gave 11b
as a white solid (0.2 h): yield, 11 mg (55%).
General Procedure for 4-Hydroxy-3-mercaptotetrahydrothiophenes. To a stirred solution of 4,5-
dihydroxy-1,2-dithiane (5, 6a, 6b) (20 mg, 0.13 mmol) in the appropriate solvent mixture either in the
absence or presence of a base was added the phosphine reagent (0.26 mmol) at rt. Stirring was continued
for 10 min- 2 d. After the reaction was completed CH3CN (2 mL) and H2O (20 mL) was added and the
mixture was extracted with EtOAc (2 X 20 mL). The combined organic layers were washed with H2O (20
mL), dried (MgSO4), and concentrated in vacuo (2 h). The crude product was purified by PTLC using
EtOAc/hexanes (1:2) as the eluent.
trans-4-Hydroxy-3-mercaptotetrahydrothiophene (12).
(A)
Using Et3P: Using 5 (20 mg, 0.13 mmol), MeOH-CHCl3-H2O (5:5:1, v/v, 2.2 mL), and 7 (39 µL,
0.26 mmol) and the general procedure gave 12 as a viscous liquid (0.2 h): yield, 14 mg (79%); Rf 0.49
(1:2 EtOAc/hexanes); IR (neat) 3384, 2930, 2537, 1434, 1269, 1063, 1014 cm-1; 1H NMR (CDCl3) δ 1.82
(d, 1 H, J = 8.7 Hz), 2.30 (br s, 1 H), 2.76-2.84 (m, 2 H), 3.21-3.38 (m, 3 H), 4.18 (q, 1 H, J = 5.2 Hz);
13C NMR (CDCl3) δ 35.2, 36.1, 47.2, 80.7, the 1H and 13C NMR data were in agreement with the COSY,
HMQC, and DEPT spectra; MS (+CI) m/z 137 [M+1]+; Mr (+CI) 137.00905 [M+1]+ (calcd for C4H9OS2
137.00948). Anal. Calcd for C4H8OS2·0.2 CH3CN: C, 36.59; H, 6.00. Found: C, 36.69; H, 5.66.
(B)
0.26 mmol) and the general procedure gave 12 as a viscous liquid (24 h): yield, 8 mg (45%).
(C) Using TCEP: Using 5 (20 mg, 0.13 mmol), MeOH-CHCl3-H2O (5:2:5, v/v, 3.6 mL), 8 (Fluka, 75
Using Ph3P: Using 5 (20 mg, 0.13 mmol), MeOH-CHCl3-H2O (3:6:1, v/v, 3.0 mL), and 9 (68 mg,
mg, 0.26 mmol), and K2CO3 (180 mg, 1.3 mmol) and the general procedure gave 12 as a viscous liquid
(0.2 h): yield, 8 mg (45%).
cis-4-Hydroxy-3-mercaptotetrahydrothiophene (13a).4
(A)
Using Et3P: Using 6a (Aldrich Co., 20 mg, 0.13 mmol), MeOH-CHCl3-H2O (5:5:1, v/v, 2.2 mL),
and 7 (39 µL, 0.26 mmol) and the general procedure gave 13a as a viscous liquid (0.2 h): yield, 9 mg
(51%); Rf 0.49 (1:2 EtOAc/hexanes); IR (neat) 3422, 2932, 2545, 1436, 1263, 1160, 1030 cm-1; 1H NMR
(CDCl3) δ 1.86 (d, 1 H, J = 8.7 Hz), 2.45 (br s, 1 H), 2.84 (t, 1 H, J = 10.4 Hz), 2.92 (dd, 1 H, J = 11.4,
3.0 Hz), 3.09 (dd, 1 H, J = 11.4, 4.8 Hz), 3.18 (dd, 1 H, J = 10.4, 6.6 Hz), 3.25-3.38 (m, 1 H), 4.30-4.38
(m, 1 H); 13C NMR (CDCl3) δ 35.5, 36.1, 46.8, 76.0, the 1H and 13C NMR data were in agreement with

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HETEROCYCLES, Vol. 60, No. 1, 2003
the COSY, HMQC, and DEPT spectra; MS (+CI) m/z 137 [M+1]+; Mr (+CI) 137.01017 [M+1]+ (calcd for
C4H9OS2 137.00948). Anal. Calcd for C4H8OS2·1.75 CH3CN: C, 43.29; H, 6.42. Found: C, 43.35; H,
6.32.
(B) Using Ph3P: Using 6a (20 mg, 0.13 mmol), MeOH-CHCl3-H2O (3:6:1, v/v, 3.0 mL), and 9 (68 mg,
0.26 mmol) and the general procedure gave 13a as a viscous liquid (48 h): yield, 12 mg (68%).
(S,S)-cis-4-Hydroxy-3-mercaptotetrahydrothiophene (13b). Using 6b (20 mg, 0.13 mmol), MeOH-
CHCl3-H2O (5:2:5, v/v, 3.6 mL), 8 (75 mg, 0.26 mmol), and K2CO3 (180 mg, 1.3 mmol) and the general
procedure gave 13b as a viscous liquid (0.2 h): yield, 13 mg (73%); [α]D25 = -125o (c = 0.1, CHCl3); IR
(neat) 3409, 2926, 2857, 2549, 1437, 1385, 1268, 1198, 1159, 1021 cm-1; 1H NMR (CDCl3) δ 1.85 (d, 1
H, J = 8.7 Hz), 2.34 (d, 1 H, J = 5.4 Hz), 2.84 (dd, 1 H, J = 10.8, 9.3 Hz), 2.92 (dd, 1 H, J = 11.4, 3.0 Hz),
3.09 (dd, 1 H, J = 11.4, 4.8 Hz), 3.18 (dd, 1 H, J = 10.8, 6.6 Hz), 3.28-3.39 (m, 1 H), 4.30-4.37 (m, 1 H);
13C NMR (CDCl3) δ 35.6, 36.1, 46.8, 76.1; MS (+CI) m/z 137 [M+1]+; Mr (+CI) 137.009175 [M+1]+
(calcd for C4H9OS2 137.00948). Anal. Calcd for C4H8OS2·0.05 EtOAc: C, 35.87; H, 6.02. Found: C,
36.00; H, 6.02.
Bis(4-hydroxytetrahydrothiophenyl) 3,3’disulfide (14). To a stirred solution of 4,5-dihydroxy-1,2-
dithiane (6a, 20 mg, 0.13 mmol) in MeOH-CHCl3-H2O (3:6:1, v/v, 3.0 mL) was added 9 (68 mg, 0.26
mmol) at rt and then stirring was continued (2 d) followed by bubbling O2 through the solution (6 d). H2O
(20 mL) was added to the reaction and the mixture was extracted with EtOAc (2 X 20 mL). The combined
organic layers were washed with H2O (20 mL), dried (MgSO4), and concentrated in vacuo. The crude
product was purified by PTLC using EtOAc/hexanes (1:2) as the eluent to give 14 as a mixture of
diastereomers (1.1:1, 13C NMR spectral analysis): yield, 8 mg (42%); mp 75-85 oC; Rf 0.23 (1:2
EtOAc/hexanes); IR (KBr) 3414, 2931, 1436, 1320, 1153, 1024, 916 cm-1; 1H NMR (CDCl3) δ 2.37 (br s,
2 H), 2.85-3.16 (m, 8 H), 3.38-3.48 (m, 2 H), 4.55-4.63 (m, 2 H), 13C NMR (CDCl3) δ 31.6, 31.7, 37.3,
37.4, 60.0, 60.1, 74.3, 74.4; MS (+CI) m/z 393 [M+1]+; Mr (+CI) 270.99643 [M+1]+ (calcd for
C8H15O2S4 270.99549). Anal. Calcd for C4H14O2S4·0.15 EtOAc: C, 36.41; H, 5.41. Found: C, 36.69; H,
5.33.
ACKNOWLEDGEMENTS
This investigation was supported, in part, by NIH grant CA29756.
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Attempts to extend this transformation for the preparation of other heterocycles were unsuccessful.
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acid, and N,N'-di-Cbz-cystamine.
23.
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