Ring-closing metathesis in the synthesis of fused sultones

Article abstract of DOI:10.1016/j.tetlet.2014.01.074

Synthesis of seven-membered sultones fused with different carbo- and heterocycles have been developed using ring closing metathesis as the key operation. The required substrates have been easily synthesized from their commercially available corresponding

Full text of DOI:10.1016/j.tetlet.2014.01.074

Tetrahedron Letters 55 (2014) 1577–1580
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Ring-closing metathesis in the synthesis of fused sultones
⇑
Shovan Mondal , Sudarshan Debnath
Department of Chemistry, Visva-Bharati University, Santiniketan 731235, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthesis of seven-membered sultones fused with different carbo- and heterocycles have been developed
using ring closing metathesis as the key operation. The required substrates have been easily synthesized
from their commercially available corresponding phenols.
Received 12 December 2013
Revised 16 January 2014
Accepted 19 January 2014
Available online 27 January 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Ring closing metathesis
Grubbs’ II catalyst
Claisen rearrangement
Vinyl sulfonates
Sultones
Sultones, the internal esters of hydroxyl sulfonic acids, are syn-
thetically very useful heterocycles in organic synthesis since they
can be manipulated in a flexible fashion.1 Many natural products
have been synthesized using sultones as the key intermediates.
For example, Metz et al. developed the total synthesis of 1,
10-seco-eudesmanolides ivangulin,2 eriolanin, and eriolangin3–5
using the sultone chemistry. Metz and co-workers also demon-
strated the application of the sultone route in the total synthesis
of pamamycin-607.6 By applying the sultone chemistry, Metz
et al. were also able to synthesize the monomeric subunits, methyl
nonactate, of naturally occurring macrotetrolides.7–9 A further syn-
thetic application employing a sultone as a key intermediate in an
enantioselective synthesis of the unusual sesquiterpenoid
alcohol (À)-myltaylenol has been described by Winterfeldt and
co-workers.10,11 Recently, Novikov and co-workers developed12
the enantioselective synthesis of bakuchiol by the desulfonation of
d-sultone as the key step. Cossy and co-workers also described the
racemic synthesis of the originally-proposed structure of marine
natural product, mycothiazole (5) via an unsaturated sultone inter-
mediate (3), generated by ring-closing metathesis of compound 1
(Scheme 1).13–15 Besides their synthetic application, sultone
scaffolds are in great demand in medicinal chemistry research.16
Biological studies on sultones are mainly concerned with their
toxicological, skin sensitization, and antiviral activities.17–23
coupling reactions (CSIC reaction)24 or sulfonation of olefins with
dioxane-sulfur trioxide. Recently, many powerful methodologies
have been developed for the synthesis of the sultones, such as
intramolecular Diels–Alder reactions,25 Pd-catalyzed intramolecu-
lar coupling reactions,26 Rh-catalyzed C–H insertion,27 etc.
Ring-closing metathesis (RCM) is a very well known method for
the construction of small to large ring size carbo- and heterocycles.
The olefin metathesis reaction of sulfur-containing alkenes and
dienes is
a challenging area in synthetic organic chemistry
research.28 A few numbers of sultones have also been synthesized
by ring-closing metathesis. For example, Metz and co-workers
reported the preparation of a series of normal (five-, six- and
seven-membered), medium (eight- and nine-membered), and
large (15-membered) ring size sultones by ring closing metathesis
(RCM).29,30 In our continuous effort on sultone chemistry,1a,26a we
now want to make an investigation on the synthesis of carbo- or
heterocycle fused sultones using the RCM reaction. Here we report
our results.
For the synthesis of sultones, the ortho-allylphenol derivatives
1a–g, which are the common starting materials, were prepared
according to the standard literature procedures31 via Claisen rear-
rangement of their corresponding aryl allyl ether derivatives. The
required precursors 2a–g for the synthesis of seven-membered
fused sultams, were prepared in 81–95% yields by the sulfonylation
of 1a–g with 2-chloroethylsulfonyl chloride. In a dichloromethane
solution of the ortho-allylphenol derivatives 1a–g, triethyl amine
was added and stirred for 15 min at room temperature. Then the
dropwise addition of 2-chloroethylsulfonyl chloride to the reaction
mixture at 0 °C and stirring for 1 h at the same temperature gave
the vinyl sulfonates 2a–g in excellent yields (Table 1).
The earlier literatures for sultone synthesis involved either
carbanion-mediated sulfonate intermolecular or intramolecular
⇑
Corresponding author. Tel.: +91 9830318498.
E-mail addresses: shovan.mondal@visva-bharati.ac.in, shovanku@gmail.com
(S. Mondal).
http://dx.doi.org/10.1016/j.tetlet.2014.01.074
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

1578
S. Mondal, S. Debnath / Tetrahedron Letters 55 (2014) 1577–1580
OH
N
O
S
O
N
H
5
(originally proposed structure of mycothiazole)
5 steps
OH
N
O
O
O
S
S
OMe
OMe
(i) n-BuLi, THF, -78 ο
N
4
S
1
C
60%
(ii) ICH2MgCl, -78 ο
MeO
C
Grubbs' 2nd
70%
OMe
OMe
generation catalyst,
OMe
C6H6, 70 ο
C
O
I
O
O
O
S
LiHMDS,
O
O
S
THF/HMPA, -78 οC
76%
N
N
S
S
2
3
Scheme 1. Synthesis of mycothiazole via sultone intermediate.
Table 1
Synthesis of vinyl sulfonates 2a–g
Cl
Cl
S
O2
OH
Et3N, CH2Cl2, 0 οC, 1 h
O
Ar
S
Ar
O
O
1a-g
2a-g
Entry
1
Substrate
Molecular structure of substrate
Sulfonate
Yield (%)
92
OH
1a
2a
OH
2
3
1b
1c
2b
2c
90
95
HO
O
O
OH
Me
4
5
6
1d
1e
1f
2d
2e
2f
88
85
85
Me
OH
Me
Me
OH
Me

S. Mondal, S. Debnath / Tetrahedron Letters 55 (2014) 1577–1580
1579
Table 1 (continued)
Entry
Substrate
Molecular structure of substrate
Sulfonate
Yield (%)
OH
7
1g
2g
81
Cl
Grubbs’ catalyst in dichloromethane at room temperature. But no
conversion was shown in TLC. After that we performed the same
reaction in dichloromethane at a refluxing condition for 24 h and
it also showed no evolution in TLC. Then we tried the above men-
tioned reaction with 10 mol % 1st generation Grubbs’ catalyst in
toluene at 80 °C for 12 h but still no cyclized product was obtained.
We then went for Grubbs’ 2nd generation catalyst. When the com-
pound 2a was subjected with 3 mol % Grubbs’ 2nd generation cat-
alyst in toluene and heated for 12 h at 80 °C, the cyclized product,
that is, the sultone 3a,32 was obtained in 78% yield (Scheme 2).
After getting satisfactory results, we treated the other sultone
precursors 2b–g with the optimized reaction conditions, that is,
O
3 mol% Grubbs' 2nd
generation catalyst ,
toluene, 80 οC, 12 h
S
O
O
O
S
O
O
78%
3a
2a
Scheme 2. Synthesis of sultone 3a.
Now to reach the final goal that is, the synthesis of sultones by
RCM, we started our experiment with the compound 2a. At first,
the compound 2a was treated with the 5 mol % 1st generation
Table 2
Summarized results of sultones
Entry
Sultone Precursor
Time (h)
Sultone
Yield (%)
O
S
O
O
O
S
1
12
78
O
O
3a
2a
O
O
O
S
O
S
O
O
2
3
12
15
80
2b
3b
O
O
S
O
O
S
O
O
71
O
O
O
O
3c
2c
O
O
O
O
S
S
O
O
Me
Me
4
12
79
Me
Me
3d
2d
O
O
O
S
O
S
O
O
5
12
75
Me
Me
Me
Me
3e
2e
(continued on next page)

1580
S. Mondal, S. Debnath / Tetrahedron Letters 55 (2014) 1577–1580
Table 2 (continued)
Entry
Sultone Precursor
O
Time (h)
Sultone
Yield (%)
O
O
S
O
S
O
O
6
24
73
Me
Me
3f
2f
O
O
O
O
S
S
O
O
7
15
70
Cl
Cl
2g
3g
12. Bequette, J. P.; Jungong, C. S.; Novikov, A. V. Tetrahedron Lett. 2009, 50, 6963.
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3 mol % Grubbs’ 2nd generation in toluene at 80 °C for 12–24 h and
obtained the sultones 3b–g in 70–80% yields. All the results for the
synthesis of sultones are summarized in Table 2.
In conclusion, we have successfully demonstrated the synthesis
of a series of seven-membered sultones fused with different het-
ero- or carbocycles via ring-closing metathesis (RCM) reaction in
70–80% yields. Our next endevour, which is to study the biological
activities of the newly synthesized sultones is underway and will
be published in due course.
18. Castro, S. D.; García-Aparicio, C.; Andrei, G.; Snoeck, R.; Balzarini, J.; Camarasa,
M. J.; Velázquez, S. J. Med. Chem. 2009, 52, 1582.
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Velázquez, S.; Camarasa, M. J. J. Med. Chem. 2008, 51, 5823.
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J.; Camarasa, M. J. J. Med. Chem. 2004, 47, 3418.
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Acknowledgments
DST, Government of India, is gratefully acknowledged for giving
a research grant to S.M. through INSPIRE Faculty Award (No. IFA12/
CH/56) and S.D. is thankful to the DST, for providing a junior
research fellowship under the same project.
23. Castro, S. D.; Lobatón, E.; Pérez-Pérez, M. J.; San-Félix, A.; Cordeiro, A.; Andrei,
G.; Snoeck, R.; Clercq, E. D.; Balzarini, J.; Camarasa, M. J.; Velázquez, S. J. Med.
Chem. 2005, 48, 1158.
Supplementary data
24. Postel, D.; Nhien, A. N. V.; Marco, J. L. Eur. J. Org. Chem. 2003, 19, 3713.
25. Plietker, B.; Seng, D.; Fröhlich, R.; Metz, P. Tetrahedron 2000, 56, 873.
26. (a) Majumdar, K. C.; Mondal, S.; Ghosh, D. Tetrahedron Lett. 2009, 50, 4781; (b)
Majumdar, K. C.; Chattopadhyay, B.; Sinha, B. Synthesis 2008, 23, 3857.
27. Wolckenhauer, S. A.; Devlin, A. S.; Du Bois, J. Org. Lett. 2007, 9, 4363.
28. Samojłowicz, C.; Grela, K. Arkivoc 2011, iv, 71.
Supplementary data (1H and 13C NMR spectra of all new
compounds) associated with this article can be found, in the online
version, at http://dx.doi.org/10.1016/j.tetlet.2014.01.074.
29. Karsch, S.; Schwab, P.; Metz, P. Synlett 2002, 2019.
References and notes
30. Karsch, S.; Freitag, D.; Schwab, P.; Metz, P. Synthesis 2004, 10, 1696.
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(b) Majumdar, K. C.; Ray, K.; Debnath, P.; Maji, P. K.; Kundu, N. Tetrahedron Lett.
2008, 49, 5597.
1. For recent reviews on sultone chemistry, see: (a) Mondal, S. Chem. Rev. 2012,
112, 5339; (b) Metz, P. J. Prakt. Chem. 1998, 340, 1.
2. Metz, P.; Stölting, J.; Läge, M.; Krebs, B. Angew. Chem., Int. Ed. Engl. 1994, 33,
2195.
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4. Merten, J.; Fröhlich, R.; Metz, P. Angew. Chem., Int. Ed. 2004, 43, 5991.
5. Merten, J.; Hennig, A.; Schwab, P.; Fröhlich, R.; Tokalov, S. V.; Gutzeit, H. O.;
Metz, P. Eur. J. Org. Chem. 2006, 5, 1144.
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7. Metz, P.; Meiners, U.; Cramer, E.; Fröhlich, R.; Wibbeling, B. Chem. Commun.
1996, 431.
8. Meiners, U.; Cramer, E.; Fröhlich, R.; Wibbeling, B.; Metz, P. Eur. J. Org. Chem.
1998, 10, 2073.
9. Metz, P.; Meiners, U.; Seng, D.; Plietker, B. Phosphorus, Sulfur Silicon 1997, 120–
121, 345.
10. Doye, S.; Hotopp, T.; Winterfeldt, E. J. Chem. Soc., Chem. Commun. 1997, 16,
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32. Preparation of sultone 3a: Nitrogen gas was bubbled through a solution of
compound 2a (100 mg, 0.36 mmol) in distilled toluene (5 mL) for 10 min.
Another solution of 2nd generation Grubbs’ catalyst (9 mg, 3 mol %) in distilled
toluene (5 mL) was also degassed by nitrogen for 10 min. Then the catalyst
solution was drop-wise added to the compound solution and heated for 1 h at
80 °C under nitrogen atmosphere. The crude product was purified by silica gel
column chromatography (10% ethyl acetate/pet. ether) to afford the compound
3a (70 mg, 78%) as a white solid. mp 148–151 °C; IR (KBr,cmÀ1
) mmax: 2341,
1348, 1161; 1H NMR (CDCl3, 400 MHz): d = 8.02 (1H, d, J = 8.4 Hz), 7.92 (1H, d,
J = 8.4 Hz), 7.87 (1H, d, J = 8.8 Hz), 7.61 (1H, td, J = 6.8, 1.2 Hz), 7.55 (1H, td,
J = 8.0, 0.8 Hz), 7.50 (1H, d, J = 9.2 Hz), 6.78–6.72 (1H, m), 6.40 (1H, d,
J = 11.2 Hz), 4.15 (2H, dd, J = 6.4, 0.8 Hz); 13C NMR (CDCl3, 100 MHz):
d = 146.3, 138.4, 132.7, 131.1, 129.9, 129.2, 128.4, 127.9, 127.6, 126.5, 122.9,
121.6, 24.3; ESI-MS: m/z: 247 (M++H); Anal. Calcd for C13H10O3S: C, 63.40; H,
4.09. Found: C, 63.51; H, 4.01.