Diastereotopic group selective intramolecular cycloadditions of sulfenic acids to 1,4-dienes

Article abstract of DOI:10.1039/b314176d

The ratio of diastereomeric cis-fused perhydrobenzothiophene S-oxides formed via the intramolecular addition of a sulfenic acid to a 1,4-diene is controlled by the nature of the protecting group on a chiral alcohol in the connecting chain.

Full text of DOI:10.1039/b314176d

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Diastereotopic group selective intramolecular cycloadditions of
sulfenic acids to 1,4-dienes†
Richard S. Grainger,* Patrizia Tisselli and Jonathan W. Steed‡
Department of Chemistry, King’s College London, Strand, London, UK WC2R 2LS.
E-mail: richard.grainger@kcl.ac.uk; Fax: 44 (0)20 7848 2810; Tel: 44 (0)20 7848 1167
Received 6th November 2003, Accepted 14th November 2003
First published as an Advance Article on the web 1st December 2003
The ratio of diastereomeric cis-fused perhydrobenzothio-
phene S-oxides formed via the intramolecular addition of a
sulfenic acid to a 1,4-diene is controlled by the nature of
the protecting group on a chiral alcohol in the connecting
chain.
glycoside isolated from a Taiwanese plant, which shows oral
hypocholesterolemic activity.7 Our group selective strategy is
outlined in Scheme 2. Thermolysis of tert-butyl sulfoxide 6
should give rise to a sulfenic acid intermediate which can cyclise
onto one of the two diastereotopic alkenes in the diene moiety
via cyclic transition states TS1 or TS2 to provide cyclic
sulfoxides 7 and/or 8 respectively, which differ only in the
relative stereochemistry between the hydroxyl group and the
three newly formed stereocentres. These three stereocentres in
turn are set by the geometrical contraints of the transition state
for sulfenic acid addition by analogy with the Jones system,
with that leading to a trans ring junction also being sterically
impossible. Our intention therefore is for the hydroxyl group in
the connecting chain to act as both a stereochemical control
element – controlling the relative amount of diastereomers 7
and 8 – and a source of the requisite oxygen functionality in the
natural product.8
Employment of a group selective reaction can be a powerful
strategy for asymmetric synthesis.1 While a large body of work
has concentrated on enantioselective desymmetrisation,2 an
important class of diastereoselective transformations involves
the differentiation of diastereotopic groups through the influ-
ence of a pre-existing stereocentre covalently attached to the
substrate.3 In this communication we outline a new diastereo-
topic group selective reaction based on the intramolecular
addition of a sulfenic acid to an alkene.
The thermally induced elimination of sulfoxides to give
sulfenic acids and alkenes is an important reaction in organic
chemistry.4 Whereas the alkene is frequently the desired prod-
uct, the reverse reaction – the addition of a sulfenic acid to an
alkene to form a sulfoxide – also finds application in synthesis,
and is subject to the same concerted syn-intramolecular mech-
anism.5 Jones exploited the reversibility of this reaction in an
elegant tandem sulfoxide elimination–intramolecular sulfenic
acid addition to form cyclic sulfoxides with high levels of regio-
and diastereocontrol (Scheme 1).6 The exclusive formation of
cis-sulfoxide 3 from thermolysis of tert-butyl sulfoxide 1 is a
consequence of the geometric requirement of the transition
state A for a concerted addition, in particular the need for the
five participating atoms to achieve co-planarity. Cyclic transi-
tion states for the cyclisation of sulfenic acid 2 into the
trans-sulfoxide 4 or the thiane oxide 5 are sterically impossible.
Scheme 2 Group selective sulfenic acid addition strategy.
We have tested this hypothesis on the readily synthesized
methyl substituted diene 11a (Scheme 3). Birch reduction of
ethyl benzoate and quenching with methyl iodide9 gave the
1,4-diene 9 in 93% yield. Ester 9 was coupled with two eq. of
the anion of tert-butyl methyl sulfoxide to provide β-keto-
sulfoxide 10.10,11 Stereoselective reduction of the ketone group
furnished alcohol 11a as a single diastereomer.10,12 § Gratify-
ingly, thermolysis of sulfoxide 11a in refluxing xylene provided
a mixture of just two perhydrobenzothiophene S-oxides 12a
and 13a, but in a 1 : 1 ratio (Table 1, entry 1). The structures of
the two sulfoxides 12a and 13a were unambiguously determined
by X-ray crystallography.¶ Both 12a and 13a crystallise in a
conformation in which the sulfoxide oxygen and bridgehead
methyl groups occupy pseudo-equatorial positions on the
thiolane ring, with the alcohol pseudo-axial in 12a and
pseudo-equatorial in 13a.†
Scheme 1 Jones’ tandem sulfoxide elimination–sulfenic acid addition.
We envisioned that this reaction would be ideal for the syn-
thesis of the highly oxygenated, cis-fused perhydrobenzothio-
phene ring system found in breynolide. Breynolide is the
aglycon hydrolysis product of breynin A, a naturally occurring
Although the 1 : 1 ratio of sulfoxides 12a and 13a was dis-
appointing, we felt this ratio might be influenced by the nature
of the substituent on oxygen. To this end, alcohol 11a was
protected under standard conditions with a variety of groups
of varying steric and electronic demands (Scheme 3).13 Results
of the thermolyses of 11b–g are presented in Table 1. In each
† Electronic supplementary information (ESI) available: Ball and stick
representations of the X-ray crystal structures of 12a and 13a. See
http://www.rsc.org/suppdata/ob/b3/b314176d/
‡ Author to whom correspondence regarding X-ray crystal structures
should be addressed.
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 5 1 – 1 5 3
151

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Table 1 Group selective cyclisation of 11 to 12 and 13
xylene), and found to give a mixture of sulfoxides 12 and 13
in an identical ratio to that derived from thermolysis of 11.
The reversible nature of the sulfoxide elimination–sulfenic
acid addition reaction means that the product sulfoxides 12
and 13 can also eliminate to reform the sulfenic acid inter-
mediate under the reaction conditions – presumably the
temperature required for elimination of a sulfenic acid from
12 or 13 is similar or less than that from tert-butyl sulfoxide
11.15
In conclusion the stereoselective synthesis of cis-fused per-
hydrobenzothiophenes related to the breynolide ring system
can be controlled by a combination of the stereoelectronic
requirements for the addition of sulfenic acids to alkenes, and
the preference of an oxygen substituent other than hydroxyl to
occupy a position on the newly formed thiolane ring cis to the
adjacent bridgehead methyl and the lone pair on sulfur. The
overall process generates four contiguous stereocentres starting
from a simple sulfoxide starting material.
Entry
R
Time/h
Yield (%)a
Ratio 12 : 13
1
2
3
4
5
6
7
H
Me
Bn
Ac
Bz
TIPS
TBDMS
3.5
3
1
4
2.5
2
41b
65
83
80
74
45
59
1 : 1c
4 : 1d
3.6 : 1d
2 : 1c
2 : 1d
4.3 : 1d
4.9 : 1c
2.5
a Combined isolated yield of 12 and 13. b 14% recovered starting
material 11a. c Ratio of separated cycloadducts. d Ratio determined by
integration in 1H NMR of combined cycloadducts.
Acknowledgements
We thank the EPSRC for funding this work (studentship to
P. T., grant reference number GR/R20465/01).
Notes and references
§ Although the relative stereochemistry between the alcohol and the
sulfoxide in 11 is unimportant in determining the ratio of diastereomers
12 : 13 (since the sulfoxide stereocentre is destroyed in the process of
elimination to the sulfenic acid intermediate), the fact that the sulfoxide
stereocentre can be used to set the alcohol stereochemistry means that
this approach can be used to access enantiomerically pure compounds
via a chiral relay starting from enantiomerically pure tert-butyl methyl
sulfoxide.
¶ Crystal data for 12a: C9H15O2.50S, M = 195.27, colourless prism,
0.80 × 0.25 × 0.20 mm3, triclinic, space group P-1 (No. 2), a = 7.1304(3),
b = 10.9979(4), c = 13.4699(6) Å, α = 109.079(2), β = 92.0540(10),
γ = 100.681(2)Њ, V = 975.68(7) Å3, Z = 4, Dc = 1.329 g cmϪ3, F000 = 420,
Nonius KappaCCD diffractometer, MoKα radiation, λ = 0.71073 Å,
T = 120(2)K, 2θmax = 54.9Њ, 3808 reflections collected, 2637 unique
(Rint = 0.0534). Final GooF = 1.047, R1 = 0.0347, wR2 = 0.0832,
R indices based on 2203 reflections with I > 2σ(I ) (refinement on F 2),
239 parameters, 0 restraints. Lp and absorption corrections applied, µ =
0.298 mmϪ1. CCDC reference number 218530. See http://www.rsc.org/
suppdata/ob/b3/b314176d/ for crystallographic data in.cif or other
electronic format.
Crystal data for 13a: C9 H14 O2 S, M = 186.26, 0.20 × 0.15 ×
0.10 mm3, monoclinic, space group P21/n (No. 14), a = 7.5780(3),
b = 9.7836(4), c = 12.0885(5) Å, β = 92.028(2)Њ, V = 895.68(6) Å3, Z = 4,
Dc = 1.381 g cmϪ3, F000 = 400, Nonius KappaCCD diffractometer,
MoKα radiation, λ = 0.71073 Å, T = 120(2)K, 2θmax = 54.9Њ, 2782
reflections collected, 1640 unique (Rint = 0.0388). Final GooF = 1.069,
R1 = 0.0361, wR2 = 0.0779, R indices based on 1265 reflections with
I > 2σ(I ) (refinement on F 2), 115 parameters, 0 restraints. Lp and
absorption corrections applied, µ = 0.317 mmϪ1. CCDC reference
number 218529. See http://www.rsc.org/suppdata/ob/b3/b314176d/ for
crystallographic data in.cif or other electronic format.
Scheme 3 Reagents and conditions: (i) Na, NH3, THF, t-BuOH then
piperylene, MeI, 93%; (ii) t-BuS(O)Me, LDA, THF, Ϫ78 ЊC, 76%;
(iii) DIBAL-H, THF, Ϫ78 ЊC, 96% (> 95% de); (iv) xylene, reflux; (v) b:
NaH, MeI, THF, 66%; c: NaH, BnBr, THF, 74%; d: Ac2O, cat. DMAP,
65 ЊC, 80%; e: BuLi, BzCl, THF, Ϫ78 ЊC, 54%; f: TIPSOTf, 2,6-lutidine,
CH2Cl2, 56%; g: TBDMSCl, imidazole, DMF, 49%.
case the stereochemistry of the major and minor products was
determined by comparison with alcohols 12a and 13a of known
configuration, either by O-alkylation of 12a and 13a (in the
case of R = Me and Bn), or deprotection of 12d–g and 13d–g
(TBAF in the case of silyl protecting groups, basic hydrolysis in
the case of ester protecting groups) to yield 12a and 13a.
In all cases the reaction gave rise to a major isomer 12b–g
with the bridgehead methyl and adjacent substituted oxygen cis
to one another. However, the diastereomeric ratio is apparently
not simply a reflection of the relative size of the group attached
to oxygen.14 Alkyl substituents gave rise to similar levels of
selectivity (entries 2 and 3). Lower and identical selectivity
is observed in the case of ester groups (entries 4 and 5). The
best selectivity is seen in the case of a silyl ether (entries
6 and 7), with the TBDMS group proving optimum in terms
of diastereomeric ratio, product stability, and ease of separ-
ation.
1 (a) M. Maier, in Organic Synthesis Highlights II, ed. H. Waldmann,
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2167.
2 M. C. Willis, J. Chem. Soc., Perkin. Trans. 1, 1999, 1765.
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groups: (a) S. F. Martin, S. K. Davidsen and T. A. Puckette, J. Org.
Chem., 1987, 52, 1962; (b) S. F. Martin and C. L. Campbell, J. Org.
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G. Chambournier, V. Dragan and D. J. Hart, Tetrahedron, 1999, 55,
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Carreño, M. P. González, M. Ribagorda and K. N. Houk, J. Org.
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Y. Yamamoto, K. Fujii and Y. Ito, J. Am. Chem. Soc., 1995, 117,
The origin of the selectivity presented in Table 1 has yet to be
determined, but we believe it represents a thermodynamic
rather than kinetic preference. A number of separated sulf-
oxides 12 and 13 (R = H, Me, Ac, Bz, TBDMS) have been
independently resubjected to the reaction conditions (refluxing
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 5 1 – 1 5 3
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9608; (k) D. P. Curran, S. J. Geib and C.-H. Lin, Tetrahedron:
Asymmetry, 1994, 5, 199; (l ) D. P. Curran, C.-H. Lin, N. DeMello
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T. Kolly-Kovac, O. Equey and P. Renaud, Chem. Eur. J., 2003, 9,
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Org. Lett., 2002, 4, 3959; (o) T. Ishikawa, K. Shimizu, H. Ishii,
S. Ikeda and S. Saito, J. Org. Chem., 2001, 66, 3834; (p) K. Ohmori,
Y. Hachisu, T. Suzuki and K. Suzuki, Tetrahedron Lett., 2002, 43,
1031; (q) Y.-i. Fukuda, H. Sasaki, M. Shindo and K. Shishido,
Tetrahedron Lett., 2002, 43, 2047; (r) P. A. Evans, J. Cui and
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4 J. W. Cubbage, Y. Guo, R. D. McCulla and W. S. Jenks, J. Org.
Chem., 2001, 66, 8722 and references therein.
5 S. Braverman, in The Chemistry of Sulfenic Acids and their
Derivatives, ed. S. Patai, Wiley, New York, 1990, p. 311.
6 (a) D. N. Jones, D. R. Hill, D. A. Lewton and C. Sheppard, J. Chem.
Soc., Perkin Trans. 1, 1977, 1574; (b) D. N. Jones, in Perspectives in
the Organic Chemistry of Sulfur, ed. B. Zwanenburg and A. J. H.
Klunder, Elsevier, New York, 1987, p. 189.
7 For a review on synthetic strategies towards the total synthesis of
breynolide see: A. B. Smith and J. R. Empfield, Chem. Pharm. Bull.,
1999, 47, 1671.
8 For other examples where the stereochemical control element is
designed also to ultimately reside in the target compound see refs
3a,d,e, f, j.
9 A. G. Schultz and L. O. Lockwood, J. Org. Chem., 2000, 65, 6354.
10 Reviews on the preparation and application of β-ketosulfoxides:
(a) M. Carmen Carreño, Chem. Rev., 1995, 95, 1717; (b) G. Solladié
and M. Carmen Carreño, in Organosulfur Chemistry, Synthetic
Aspects, ed. P. Page, Academic Press, New York, 1995, p. 1.
11 All chiral compounds used in this study are racemic.
12 (a) I. Fernandez, J. M. Llera, F. Zorrilla and F. Alcudia,
Tetrahedron, 1989, 45, 2703; (b) F. Alcudia, I. Fernandez, J. M. Llera
and F. Zorrilla, An. Quim., 1988, 84, 333.
13 Yields for the preparation of 11b–g have not been optimised.
14 The selectivity observed can be contrasted with the conformational
energies (A-values) for OX [X = H, CH3, Ac, Bz, Ts, TMS, t-Bu],
which show little variation with the nature of X : E. L. Eliel, S. H.
Wilen and L. N. Mander, Stereochemistry of Organic Compounds,
Wiley, New York, 1994, p. 695.
15 For an example of lowering the temperature of sulfoxide elimination
through structural variation see: H. Adams, J. C. Anderson, R. Bell,
D. N. Jones, M. R. Peel and N. C. O. Tomkinson, J. Chem. Soc.,
Perkin. Trans. 1, 1998, 3967.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 5 1 – 1 5 3
153