Serendipitous synthesis of 3-hydroxy tetrahydrofurans from tin catalyzed sulfonylation of acyclic 1,2,4-triols

Article abstract of DOI:10.1016/j.tetlet.2012.08.110

The reaction of syn-1,2,4-triols under sulfonylation conditions catalyzed by Bu₂SnO (5 mol %) results in cyclization and the formation of 3-hydroxy tetrahydrofurans (56-85%) while the anti-1,2,4-triols react to give C1-O-sulfonyl derivatives in good yields (66-83%) and the cyclization product in poor yield (5-12%). A mechanism that justifies these observations is proposed to occur via the tosylation of the primary hydroxyl followed by an intramolecular tin acetal rearrangement to a 1,3-stannylene which then undergoes a 5-exo-tet-cyclization. The difference in rates of cyclization reactivity is due to the energetically more stable tin acetals of syn-1,3-diols compared to those of anti-1,3-diols.

Full text of DOI:10.1016/j.tetlet.2012.08.110

Tetrahedron Letters 53 (2012) 5929–5932
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Tetrahedron Letters
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Serendipitous synthesis of 3-hydroxy tetrahydrofurans from tin catalyzed
sulfonylation of acyclic 1,2,4-triols
⇑
Makhosazana P. Gamedze, Rejoice B. Maseko, Fidelis Chigondo, Comfort M. Nkambule
Department of Chemistry, Tshwane University of Technology, Private Bag X680, Pretoria 0001, South Africa
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 November 2011
Revised 2 August 2012
Accepted 24 August 2012
Available online 1 September 2012
The reaction of syn-1,2,4-triols under sulfonylation conditions catalyzed by Bu2SnO (5 mol %) results in
cyclization and the formation of 3-hydroxy tetrahydrofurans (56–85%) while the anti-1,2,4-triols react
to give C1-O-sulfonyl derivatives in good yields (66–83%) and the cyclization product in poor yield (5–
12%). A mechanism that justifies these observations is proposed to occur via the tosylation of the primary
hydroxyl followed by an intramolecular tin acetal rearrangement to a 1,3-stannylene which then under-
goes a 5-exo-tet-cyclization. The difference in rates of cyclization reactivity is due to the energetically
more stable tin acetals of syn-1,3-diols compared to those of anti-1,3-diols.
Keywords:
Sulfonylation
Tin acetal
Ó 2012 Elsevier Ltd. All rights reserved.
1,2,4-Triols
1,3-Diols
Tetrahydrofurans
As part of an ongoing investigation on the characterization of
the unsaponifiable fraction of avocado oil, we are interested in
the methods of analysis and isolation of some polyhydroxylated
compounds (acetogenins) that constitute 5–40% of the oil, depend-
ing on the maturity of the fruit.1–7 These compounds have a com-
mon structural motif, where one terminus is highly oxygenated
either as a 1,2,4-triol or a 4-oxo-1,2-diol, which may have mono
acetyl protection at the C1 or C2-hydroxyl group (Fig. 1).
When the triols 11a and 12a were subjected to the sulfonyla-
tion conditions for the C1-O-tosylation, the results were quite
unexpected (Scheme 2).à While the anti-1,2,4-triol (12a) was effi-
ciently converted to the C1-O-sulfonyl derivative 14a (75%), a minor
impurity 14b was also formed in the reaction (12%); this compound
à
General method of sulfonylation: Into
a 50 mL two-neck round-bottom flask
equipped with a condenser was added compound 11a (0.05 g, 0.175 mmol), p-TsCl
(0.04 g, 0.192 mmol), Bu2SnO (2 mg, 0.0087 mmol) and Et3N (0.05 mL, 0.192 mmol)
and the mixture heated at reflux in CH2Cl2 (2 mL, 0.1 M) for 3.5 h. The reaction was
monitored by TLC and quenched with saturated NH4Cl (5 mL) and taken up in EtOAc
(50 mL). The organic layer was washed with water (15 mL) and brine (15 mL) before
drying over MgSO4. The solvent was evaporated and the crude was purified by
column chromatography using 5% EtOH/CHCl3 to give a non UV-active compound 13b
(0.04 g, 85%). tmax (Nujol): 3407, 3076, 2929, 2853, 1640, 1464, 1377, 1226, 1176,
1070, 909 cmÀ1; dH (400 MHz, CDCl3): 5.75 (1H, ddt, J = 6.8, 10, 17 Hz), 4.92 (1H, dd,
J = 3.2, 17 Hz), 4.86 (1H, dd, J = 2, 10 Hz), 4.39–4.35 (1H, m), 3.78–3.68 (1H, m), 3.60
(1H, dd, J = 4; 9.6 Hz), 2.31–2.24 (1H, m), 1.97 (2H, q, J = 6.8 Hz), 1.86 (1H, bs), 1.69–
1.24 (22H, m); dC (100 MHz, CDCl3): 139.24, 114.05, 79.25, 75.35, 72.59, 41.47, 36.19,
33.78, 29.60, 29.55, 29.47, 29.12, 28.91, 26.27.The reaction of the anti-1,2,4-triol 12a
(0.104 g, 0.363 mmol) was carried out under exactly the same conditions, but two
products were isolated after column chromatography: a UV active compound 14a
(0.12 g, 75%) and a non-UV active 14b (0.02 g, 12%).Compound 14a: tmax (Nujol):
3359, 2917, 2855, 1602, 1464, 1376, 1338, 1187, 1168, 1096, 975, 907, 835, 813, 721,
696 cmÀ1; dH (400 MHz, CDCl3): 7.73 (2H, d, J = 8 Hz), 7.25 (2H, d, J = 8 Hz), 5.74 (1H,
ddt, J = 6.8, 10, 17 Hz), 4.92 (1H, dd, J = 2, 17 Hz), 4.86 (1H, dd, J = 2, 10 Hz), 4.11–4.07
(1H, m), 3.98 (1H, dd, J = 4.4, 10 Hz), 3.89 (1H, dd, J = 7.2, 10.4 Hz), 3.81À3.78 (1H, m),
2.39 (3H, s), 2.21 (2H, bs), 1.96 (2H, q, J = 7.2 Hz), 1.60–1.19 (22H, m); dC (100 MHz,
CDCl3): 145.06, 139.25, 132.62, 129.91, 128.94, 127.98, 127.93, 114.05, 73.59, 68.91,
67.01, 38.37, 37.55, 33.78, 29.58, 29.56, 29.53, 29.47, 29.33, 29.12, 28.91, 25.57,
We hypothesized that the tin-catalyzed regioselective sulfony-
lation of diols could be useful in a discriminatory derivatization
of the 1,2,4-triol and 1,2-diol compounds within the complex ma-
trix of avocado oil.8–11 A test of the Martinelli protocol on model
1,2-diol substrates showed that the reaction was complete within
3.5 h, but in our hands we found it necessary to heat the reaction to
a gentle reflux in dichloromethane instead of carrying out the reac-
tion at room temperature where it was sluggish.10 Additionally, we
found it expedient to increase the catalytic tin oxide load from 2 to
5 mol %. The avocado 1,2,4-triols 11a and 12a, and the other triol
analogues, were prepared from commercially available (S)-malic
acid according to the method reported by Sato and co-workers as
12
shown in Scheme 1.
The diastereomeric products of the Grignard reactions (9a–c
and 10a–c) were easily separated by column chromatography,
while the 2,4-diol relative stereochemistry of the triols 11a–c
and 12a–c was confirmed by acetal protection as the 2,4-dioxol-
anes as described by Rychnovsky.13,14
21.66.Compound 14b: tmax (Nujol): 3400, 2923, 2858, 1641, 1462, 1376, 1260, 1097,
910 cmÀ1; dH (300 MHz, CDCl3): 5.78 (1H, ddt, J = 6.8, 10, 17 Hz), 5.01–4.88 (2H, m),
4.42 (1H, bs), 3.84–3.74 (2H, m), 3.64 (1H, dd, J = 4.5, 10 Hz), 2.37–2.28 (1H, m), 2.05–
1.98 (3H, m), 1.8–1.24 (22H, m); dC (75 MHz, CDCl3): 139.25, 114.05, 79.19, 75.36,
72.60, 41.43, 36.23, 33.78, 29.56, 29.11, 28.89, 26.27.
⇑
Corresponding author. Tel.: +27 12 3826382; fax: +27 12 3826286.
E-mail address: Nkambulecm@tut.ac.za (C.M. Nkambule).
Physical data for avocado triols 11a (mp 66–67 °C; Lit mp 66.5–67 °C) and 12a
(mp 82–83 °C; Lit mp 82-82.5 °C).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.110

5930
M. P. Gamedze et al. / Tetrahedron Letters 53 (2012) 5929–5932
OH OH
OH OH
OH OH
OH
OH
OH
10
12
10
3
2
1
O
OH
O
OH
OAc
OAc
4
10
5
4
5
Figure 1. Some highly oxygenated components of avocado oil.
OH OH
11a-c
OH
O
O
OH
OH
O
O
R
R
R
R
O
OH
9a-c
O
O
(c)
(a)
(b)
OH
O
HO
H
O
OH OH
OH
6
7
12a-c
10a-c
8a-c
Reagents: (a) 15% overall yield over 5 steps; (b) RMgBr (
), Et2O, rt, 24 h, 67%; (c) 80% AcOH (aq), rt, 24 h, 64-99%
Scheme 1. Synthesis of substrate 1,2,4-triols.
O
OH OH
OH OH
OH
+
OTs
OH
10
10
10
13a 0%
13b 85%
11a
p-TsCl, Et3N, Bu2SnO (5 mol%)
CH2Cl2, reflux, 3.5 h
O
OH OH
OH OH
OH
OTs
OH
+
10
14b
10
10
12a
14a
12%
75%
Scheme 2. Sulfonylation of syn- and anti-1,2,4-triols.
was identified and characterized as 3-hydroxy tetrahydrofuran. The
reaction of the syn-1,2,4-triol was even more surprising since the
reaction exclusively, and efficiently, produced only the 3-hydroxy
tetrahydrofuran 13b (85%). Similar results were observed for other
1,2,4-triols (11b, 11c, 12b, and 12c) as shown in Table 1.
While the formation of the tetrahydrofurans from 1,2,4-triols
was unexpected under these conditions, what was more intriguing
to us was the apparent stereo dependence of the cyclization reac-
tion. Why should one diastereomer favour cyclization, while the
other favored tosylation? We thus turned our attention to the
mechanistic possibilities that could explain these observations
and made the following four postulations: Firstly, the chelation
and derivatization of the 1,2-diol is the fastest reaction in both dia-
stereomers since it is generally accepted that the formation of five-
membered rings is kinetically more favored than the formation of
six-membered rings.15 Thus C1-O-tosylation should be favored
over C4-O-tosylation. Secondly, the formation of the THF must
arise from the internal displacement of the tosylate by the C4-hy-
droxyl group in a 5-exo-tet cyclization. Thirdly, the cyclization
reaction is still under the mediation of tin chelation to enhance
the nucleophilicity of the C4-hydroxyl group since no additional
(strong) base was added;16,17 this type of double activation of poly-
ols by stannylene acetals has precedence in the work of the Simas
and Grindley groups.18,19 Lastly, we postulated that the better sta-
bility of formation of the six-membered chelate for the syn-1,3-diol
is responsible for the faster reaction of the intermediate (I) versus
intermediate (II) which experiences larger 1,3-diaxial steric repul-
sive interactions (Fig. 2). The reactive transition states are more
likely the boat conformations (Ia) and (IIa).
Indeed the approximately 7:1 ratio of THFs from the syn and
anti triols (13b/14b; 15b/16b; and 17b/18b) corresponds closely
to that predicted by molecular modeling: ab initio (HF/3-212G)

M. P. Gamedze et al. / Tetrahedron Letters 53 (2012) 5929–5932
5931
Table 1
Tin catalyzed sulfonylation reaction of 1,2,4-triols
OH OH
O
OH
Entry
Substrate
OTs
R
R
OH OH
OH
OH
1
15a
16a
17a
18a
0%
15b
82%
12%
56%
5%
11b
OH OH
2
3
4
66%
16b
17b
18b
12b
OH OH
OH
OH
0%
3
11c
OH OH
83%
3
12c
H
H
Bu
Sn
Bu
Bu
Bu
R
O
Cl
O
Bu
Sn
R
O
Sn
O
Bu
O
O
OH
Sn Bu
OTs
=
THF
THF
Bu
O
OTs
OTs
R
R
TsO
(Ia)
(I)
R
R
Bu
Sn
Bu
Bu
Bu
O
Cl
H
O
Sn
H
Bu
O
OH O Sn Bu
OTs
Bu
O
=
O
Sn
O
OTs
Bu
R
R
OTs
TsO
(II)
(IIa)
Figure 2. Rationale for the observed stereo differentiation in reactivity.
optimization DDG = 1.15 kcal/mol; DFT (B3LYP/LACVP//HF/3-
212G) DDG = 1.43 kcal/mol.§
reaction was left to proceed for 24 h, the combined yield of the THFs
(20b + 21b) was 70%, but still 21a persisted at 20%.
We then applied this derivatization method to the mixed dia-
stereomers of phenyl-1,2-4-triols (19) to synthesize the known
THFs 20b and 21b.20,21 Indeed we observed diastereoselectivity
in the reaction whereby after 3.5 h the syn-triol was converted to
THF compound 20b, while the anti-triol formed the sulfonyl deriv-
ative 21a in excellent yields of 84% and 83%, ‘respectively’
(Scheme 3); the THF 21b was formed in only 9% yield.– When the
In summary, we have observed that the tin-catalyzed regiose-
lective sulfonylation of 1,2-diols leads to the cyclization of syn-
1,2,4-triols to form 3-hydroxy tetrahydrofurans, while anti-1,2,4-
triols are efficiently and regioselectively tosylated. While we are
continuing our investigation of the scope of this method as a trun-
cated route for the synthesis of functionalized THFs, we are also in-
trigued by the possibility that the method may be used to
distinguish between mixed diastereomers of 1,2,4-triols since the
anti-triols preferentially give sulfonylation, while the syn-triols
exclusively give cylization products.22 The results of these investi-
gations will be reported shortly.
§
We acknowledge the assistance of Professor Richard Johnson at the University of
New Hampshire (USA) for the molecular modeling results.
–
The characterization of compounds 20b and 21b (Supplementary Data) showed
that they were identical to those previously reported.20,21

5932
M. P. Gamedze et al. / Tetrahedron Letters 53 (2012) 5929–5932
OH OH
O
O
OH OH
p-TsCl, Et3N, Bu2SnO (5 mol %)
CH2Cl2, reflux, 3.5 h
OH
+
+
OH
OH
OTs
Ph
Ph
Ph
Ph
19
20b 84%
21b 9%
21a 83%
Scheme 3. Diastereoselective derivatization of phenyl-1,2,4-triols.
6. Mostert, M. E.; Botha, B. M.; Du Plessis, L. M.; Duodu, K. G. J. Sci. Food Agric.
2007, 87, 2880–2885.
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We acknowledge the institutional and financial support of the
Tshwane University of Technology and the financial support from
the National Research Foundation (NRF-South Africa) for a Human
and Institutional Capacity Development Programmes grant (IRDP
GUN 62464) to CMN; MPG, and FC were supported by Grant-holder
linked NRF student bursaries for this study.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.08.
110.
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