Samarium diiodide mediated intramolecular cyclisation of mixed enone-enoate systems: A simple preparation of spirocyclic ethers

Article abstract of DOI:10.1016/j.tetlet.2010.12.077

Samarium(II) diiodide mediated intramolecular cyclisation of mixed enone-enoate substrates in THF/MeOH is described. Spirocyclic ethers are obtained, and the stereodefined preparation of 1-oxaspiro[4.4]nonan-7-one products is included.

Full text of DOI:10.1016/j.tetlet.2010.12.077

Tetrahedron Letters 52 (2011) 928–931
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Tetrahedron Letters
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Samarium diiodide mediated intramolecular cyclisation of mixed enone–enoate
systems: a simple preparation of spirocyclic ethers
Junxiu Meng a,b, Mark E. Light a, Jeremy D. Kilburn a, , Sally Dixon a,
⇑
⇑
a School of Chemistry, University of Southampton, Southampton SO17 1BJ, UK
b Key Laboratory of Marine Drugs, Ministry of Education of China, School of Pharmacy, Ocean University of China, Qingdao 266003, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Samarium(II) diiodide mediated intramolecular cyclisation of mixed enone–enoate substrates in THF/
MeOH is described. Spirocyclic ethers are obtained, and the stereodefined preparation of 1-oxaspi-
ro[4.4]nonan-7-one products is included.
Received 3 November 2010
Revised 3 December 2010
Accepted 17 December 2010
Available online 23 December 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Samarium(II) diiodide
Reductive cyclisation
Michael addition
Spirocycle
Chelation control
Reductive, intermolecular cyclodimerisation of
a
,b-unsaturated
Michael acceptor functionality, as a concise preparation of spirocy-
clic ethers.10,11 Simple access to 1-oxaspiro[4.5]decane 3 or 1-oxa-
spiro[5.5]undecane 4 motifs is anticipated from cyclisation of b-
substituted cyclohexenones 1 and 2, respectively. Similarly, cycli-
sation of cyclopentenone precursors 5 and 6 is envisaged, to give
1-oxaspiro[4.4]nonane 7 and 6-oxaspiro[4.5]decane 8 products
(Scheme 1).
carbonyl compounds is a well-established coupling reaction, often
electrochemically1 or metal-mediated,2 for the preparation of func-
tionalised cyclopentanols. The intramolecular variant is of particu-
lar value for application to the synthesis of polycyclic small
molecules, and several examples of controlled intramolecular
crossed-coupling of mixed enone–enoate systems have been
reported.3,4
Cyclisation substrates 1 and 2 were prepared from 1,3-cyclohex-
anedione, and substrates 5 and 6 from 1,2-cyclopentanedione, in
Samarium(II) diiodide has been commonly employed for reduc-
tive homodimerisation of a
,b-unsaturated carbonyl compounds,5–8
which may conceptually take place either via coupling of deloca-
lised ketyl radicals arising from single-electron transfer to each
of the two
gate addition of a single radical or b-organosamarium anion result-
ing from a second electron transfer to one of the ,b-unsaturated
a,b-unsaturated carbonyl moieties present, or via conju-
a
carbonyl groups. We recently reported that upon treatment of
mixed enone–enoate substrates with SmI2 in THF/MeOH, intermo-
lecular enone homodimerisation predominates in all cases but one,
in which the enone is b-alkoxy-substituted with a pendant enoate
and where exclusive intramolecular cyclisation occurred.9 Herein,
we further examine the intramolecular reductive cyclisation of a
series of cyclic enone substrates bearing remote, b-alkoxy-tethered
⇑
Corresponding authors at present address: School of Biological and Chemical
Sciences, Queen Mary, University of London, Mile End Road, London E1 4NS, UK
(J.D.K.). Tel.: +44 20 7882 3031; fax: +44 20 7882 2848 (J.D.K.); tel.: +44 23 8059
2705; fax: +44 23 8059 3781 (S.D.).
E-mail addresses: j.kilburn@qmul.ac.uk (J.D. Kilburn), sd5@soton.ac.uk
(S. Dixon).
Scheme 1.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.12.077

J. Meng et al. / Tetrahedron Letters 52 (2011) 928–931
929
each case via conversion into an enol ether bearing terminal alkene
functionality, ruthenium-catalysed oxidative cleavage12 and subse-
quent Horner–Wadsworth–Emmons olefination (Scheme 2).13
Treatment of 1a with SmI2 (5 equiv) in mixed THF/MeOH sol-
vent gave (separable) 1-oxaspiro[4.5]decan-7-ol diastereomeric
mixtures 9a and 9b in good combined yield, via clean intramolec-
ular cyclisation and enone over-reduction. Simplification of the
product mixture 9a/b by re-oxidation at C7 gave 3a (dr = 1.2:1).
Pleasingly, upon treatment of 1a with a limiting stoichiometry of
SmI2 (2 equiv), over-reduction did not take place and 3a was ob-
tained directly, in an improved yield of 78% over one step and with
an identical diastereomeric ratio of 1.2:1. The expected 1-oxaspi-
ro[4.5]decan-7-one structure was confirmed by X-ray crystallogra-
phy14 (Scheme 3).
The results of cyclisation of substrates 1a–c, 2a,b, 5a–c and
6a,b, using 2 equiv of SmI2, are presented in Table 1.
The low diastereoselectivity achieved in the cyclisation of en-
one–enoate 1a (R = OEt) was improved upon switching to the cor-
responding enone–enoate substrate 1b (R = OtBu). Product 3b was
obtained with de = 54% (Table 1, entry 2) and the relative stereo-
chemistry of the major isomer was determined by comparison of
the NMR data obtained for the crystallised diastereomer with that
obtained for the mixture. The stereochemical outcome may be
rationalised in terms of two possible Sm(III) intermediates I and
II. In intermediate I, intramolecular Sm(III) chelation of both car-
bonyl oxygen atoms is achieved via a conformation in which the
enolate and enone groups are staggered, leading to the dominant
diastereomeric product upon protonation.17 An eclipsed relation-
ship between these groups occurs in intermediate II, and the
resulting steric congestion between a
-proton H1 and the tert-butyl
Scheme 3. Preparation of 3a via a one- or two-step protocol, and the X-ray crystal
a
b
structure of 3a. Table 1, entry 1. Two diastereomeric mixtures 9a and 9b were
substituent, presumably disfavours formation of intermediate II
(Scheme 4).
isolated (9a dr = ꢀ2.5:1 and 9b dr = ꢀ2:1).15
Mixed enone–enone substrate 1c failed to undergo clean cycli-
sation and a complex mixture of products was formed. Similarly,
substrates 2a and 2b with a one-carbon extension of the b-alkoxy
tethering region did not provide access to 1-oxaspiro[5.5]undecane
products 4 as hoped and, instead, also generated complex product
mixtures on treatment with SmI2 (entries 4 and 5).
Mixed enone–enoate substrates 5a/b underwent clean and
high-yielding intramolecular cyclisation. Good diastereoinduction
(de = 80%) was observed for the ethyl enoate (5a) and cyclisation
Table 1
SmI2-mediated intramolecular cyclisationa
Entry
Substrate
R
Productb [yield%]c
drd
1
2
3
4
5
6
7
8
9
1a
1b
1c
2a
2b
5a
5b
5c
6a
6b
OEt
3a [78]
3b [84]
—
—
—
7a [78]
7b [75]
—
8a [65]
8b [69]
1.2:1
3.4:1
—
—
—
9:1
95:5
—
1:1
2.2:1
OtBu
Me
OEt
OtBu
OEt
OtBu
Me
OEt
10
OtBu
a
Reactions were conducted on 0.29–0.82 mmol scale, using 2 equiv of SmI2 in
4:1 THF/MeOH at À78 °C.16
All product mixtures were characterised by 1H, 13C NMR and IR spectroscopy,
b
and by HRMS.
c
Isolated yield.
d
Diastereomeric ratios were calculated from the 1H NMR spectrum.
of the tert-butyl enoate was even better with de = >90%, (entries
6 and 7). Unfortunately, we were not able to determine the relative
stereochemistry of the (non-crystalline) 1-oxaspiro[4.4]nonan-7-
one products 7a and 7b obtained. Intramolecular cyclisation of
bis-enone 5c did not take place (entry 8) and multiple products
were apparent, mirroring the failed reductive cyclisation of bis-en-
one 1c. Interrogation of the product mixture and further investiga-
tion of mixed enone–enone coupling were not made.
Finally, reductive cyclisation of cyclopentenone substrates 6a/b
also took place in good yield, yielding spirocyclic ketones 8a/b (en-
tries 9 and 10). Once again an improved (moderate) diastereoselec-
tivity was observed when R = OtBu (8b, de = 37%) in comparison
with non-diastereoselective formation of 8a (R = OEt). Structural
Scheme 2. Reagents and conditions: (a) 3-buten-1-ol (n = 1) or 4-penten-1-ol
(n = 2), catalytic p-TsOH, toluene,
D, 5–14 h, Dean–Stark conditions (n = 1, 88%;
n = 2, 82%); (b) RuCl3, NaIO4, CH3CN/H2O (6:1), rt, 3–4 h (n = 1, 27%; n = 2, 51%); (c)
(EtO)2P(O)CH2C(O)R, NaH, THF, rt, 3–4 h (1a, 62%), (1b, 33%), (1c, 56%), (2a, 63%),
(2b, 82%), (5a, 27%), (5b, 40%), (5c, 41%), (6a, 45%), (6b, 63%).

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J. Meng et al. / Tetrahedron Letters 52 (2011) 928–931
as a straightforward means for the preparation of spirocyclic ethers
from simple starting materials. High-yielding syntheses of both the
1- and 6-oxaspiro[4.5]decane core scaffolds (3 and 8, respectively)
have been achieved with moderate diastereoinduction, and we
have also developed a route to 1-oxaspiro[4.4]nonane products,
7, which proceeds with excellent stereocontrol. A reversal of dia-
stereoselectivity in the respective formation of 3 and 8 is observed,
which precludes speculation of the relative stereochemistry in 7.
Application of this method towards the synthesis of naturally
occurring and pharmacologically active compounds, which feature
an embedded 1-oxaspiro[4.4]nonane motif,18 is of potential value.
Acknowledgements
This work was supported by the Chinese Government
Scholarship Programme 2007–2009 (J.M.) and by the University
of Southampton.
Supplementary data
Supplementary data (Spectroscopic characterisation of com-
pounds 1b,c, 2a,b, 5a–c and 6a,b) associated with this article can
be found, in the online version, at doi:10.1016/j.tetlet.2010.12.077.
References and notes
1. Nielsen, M. F.; Utley, J. H. P. In Organic Electrochemistry; Lund, H., Hammerich,
O., Eds.; Marcel Dekker: New York, 2001; pp 795–882.
2. (a) Banik, B. K. Eur. J. Org. Chem. 2002, 2431–2444; (b) Bowers, K. W.; Giese, R.
W.; Grimshaw, J.; House, H. O.; Kolodny, N. H.; Kronberg, K.; Roe, D. K. J. Am.
Chem. Soc. 1970, 92, 2783–2799; (c) House, H. O.; Giese, R. W.; Kronberg, K.;
Kaplan, J. P.; Simeone, J. F. J. Am. Chem. Soc. 1970, 92, 2800–2810; (d) Kumar, A.;
Kumar, S.; Kapoor, K. K. Aust. J. Chem. 2007, 60, 621–623; (e) Shi, D. Q.; Dou, G.
L.; Li, Z. Y.; Shi, C. L.; Li, X. Y.; Jiang, H.; Ni, S. N.; Ji, S. J. Synthesis 2007, 1797–
1806; (f) Takaki, K.; Beppu, F.; Tanaka, S.; Tsubaki, Y.; Jintoku, T.; Fujiwara, Y. J.
Chem. Soc., Chem. Commun. 1990, 516–517; (g) Zhou, L. H.; Shi, D. Q.; Gao, Y.;
Shen, W. B.; Dai, G. Y.; Chen, W. X. Tetrahedron Lett. 1997, 38, 2729–2732.
3. For electrochemically-mediated examples, see: (a) Handy, S. T.; Omune, D.
Tetrahedron 2007, 63, 1366–1371; (b) Manchanayakage, R.; Omune, D.; Hayes,
C.; Handy, S. T. Tetrahedron 2007, 63, 9691–9698.
Scheme 4. SmI2-mediated cyclisation of 1b and the X-ray crystal structure of the
major diastereoisomer of 3b.14
verification of 8a and identification of the major diastereomer of
8b were made by X-ray diffraction and NMR studies, and the
reversal of selectivity in comparison with formation of 3b is
notable (Figure 1). In 1-oxaspiro[4.5]decane 3b, the spiro-atom
and
a-stereogenic centre are of the same configuration, whilst in
6-oxaspiro[4.5]decane 8b they are of opposite configuration. We
are not able to account for this observation using simple models
of possible intermediates.
In conclusion, we have investigated the SmI2-mediated intra-
molecular reductive cyclisation of mixed enone–enoate systems,
4. For cyclisation of mixed enone–enoates under strongly reducing conditions (Li/
NH3), see: (a) Wasnaire, P.; Wiaux, M.; Touillaux, R.; Marko, I. E. Tetrahedron
Lett. 2006, 47, 985–989; and under Bu3SnH/AIBN/
D conditions, see: (b)
Enholm, E. J.; Kinter, K. S. J. Org. Chem. 1995, 60, 4850–4855.
5. For examples of enone homodimerisation, see: (a) Cabrera, A.; Le Lagadec, R.;
Sharma, P.; Arias, J. L.; Toscano, R. A.; Velasco, L.; Gavino, R.; Alvarez, C.;
Salmon, M. J. Chem. Soc., Perkin Trans. 1 1998, 3609–3617; (b) Cabrera, A.;
Rosas, N.; Sharma, P.; Le Lagadec, R.; Velasco, L.; Salmon, M. Synth. Commun.
1998, 28, 1103–1108; (c) Howells, D. M.; Barker, S. M.; Watson, F. C.; Light, M.
E.; Hursthouse, M. B.; Kilburn, J. D. Org. Lett. 2004, 6, 1943–1945; (d) Zhou, L.
H.; Zhang, Y. M. Synth. Commun. 2000, 30, 597–607.
6. For homodimerisation of enoates, see: Inanaga, J.; Handa, Y.; Tabuchi, T.;
Otsubo, K.; Yamaguchi, M.; Hanamoto, T. Tetrahedron Lett. 1991, 32, 6557–
6558.
7. For examples of intramolecular reductive coupling of bisenones, see: (a) Handy,
S. T.; Omune, D. Org. Lett. 2005, 7, 1553–1555; (b) Sono, M.; Mizutani, T.;
Nozaki, M.; Takaoka, S.; Tori, M. Heterocycles 2008, 76, 851–860.
8. For examples of intramolecular reductive coupling of bisenoates, see: (a)
Shinohara, I.; Okue, M.; Yamada, Y.; Nagaoka, H. Tetrahedron Lett. 2003, 44,
4649–4652; (b) Williams, D. B. G.; Caddy, J.; Blann, K.; Grove, J. J. C.; Holzapfel,
C. W. Synthesis 2009, 2009–2014.
9. Powell, J. R.; Dixon, S.; Light, M. E.; Kilburn, J. D. Tetrahedron Lett. 2009, 50,
3564–3567.
10. For a recent review of strategies for spiro-ether synthesis, and their importance
as pharmaceutically active compounds, see: Rosenberg, S.; Leino, R. Synthesis
2009, 2651–2673. and references therein.
11. For a similar radical anionic cyclisation of b-alkoxy linked olefinic enones, see:
Bischof, E. W.; Mattay, J. Tetrahedron Lett. 1990, 31, 7137–7140.
12. Yang, D.; Zhang, C. J. Org. Chem. 2001, 66, 4814–4818.
13. Spectroscopic characterisation of compounds 1b,c, 2a,b, 5a–c and 6a,b are
provided as Supplementary data. Compound 1a has been reported by us
previously, see Ref. 9.
14. Crystallographic data (excluding structure factors) for structures 3a, 3b, 8a and
8b in this Letter have been deposited with the Cambridge Crystallographic
Data Centre as supplementary publication nos. CCDC 788095–788098. Copies
of the data can be obtained, free of charge, on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK, [fax: +44-(0)1223-336033 or e-mail:
deposit@ccdc.cam.ac.uk]. Data were collected on a Bruker Nonius KappaCCD
Figure 1. X-ray crystal structures of (a) 8a and (b) the major diastereoisomer of
8b.14

J. Meng et al. / Tetrahedron Letters 52 (2011) 928–931
931
with a Mo rotating anode generator; standard procedures were followed. All
hydrogen atoms were identified from the difference map and then positioned
geometrically and refined using a riding model. Crystal data for 3a: M = 240.29,
16. Typical procedure: MeOH (5.3 mL) was added to
a
stirring solution
of SmI2 in dry THF (0.1 M, 16.4 mL) and the resultant dark-blue mixture
was cooled to À78 °C. A solution of the mixed enone–enoate substrate 1a
(196 mg, 0.82 mmol) in dry THF (4.6 mL) was then added dropwise over a
period of 3 min, and the mixture was stirred at À78 °C for a further 1.5 h.
Brine (10 mL) was added before stirring for 10 min. EtOAc (20 mL) was
added to the stirring solution and, after 10 min, the organic phase was
separated. This process was repeated (3 Â 20 mL EtOAc in total) and the
combined organic extracts were washed with brine (2 Â 20 mL) and dried
over MgSO4 before concentration in vacuo. Purification by flash column
chromatography (SiO2 eluted with 5:1 EtOAc/petrol) gave 3a as a colourless
oil (153 mg, 78%).
monoclinic, a = 9.9593(4), b = 14.7898(6), c = 8.5672(3) Å,
b = 97.961(2)°,
= 90.00°, U = 1249.75(8) Å3, T = 120(2) K, space group P2(1)/
c, Z = 4, 12,964 reflections measured, 2839 unique reflections (Rint = 0.0390).
The final R1 values were 0.0666 (I > 2 (I)). The final wR(F2) values were 0.1250
(I > 2 (I)). The final R1 values were 0.0915 (all data). The final wR(F2) values
were 0.1391 (all data). Crystal data for 3b: M = 268.34, monoclinic,
a = 12.2040(5), b = 10.1894(5), c = 11.8973(6) Å, = 90.00°, b = 93.572(3)°,
= 90.00°, U = 1476.57(12) Å3, T = 120(2) K, space group P2(1)/c, Z = 4, 18,502
reflections measured, 3383 unique reflections (Rint = 0.0637). The final R1
values were 0.0663 (I > 2 (I)). The final wR(F2) values were 0.1739 (I > 2 (I)).
a = 90.00°,
c
r
r
a
c
r
r
17. We have previously reported the same ring-junction stereochemical
preference for Sm(II)-mediated, intramolecular 5-exo-trig homodimerisation
of an acyclic bis-enone substrate, see Ref. 9.
The final R1 values were 0.0955 (all data). The final wR(F2) values were 0.1925
(all data). Crystal data for 8a: M = 240.29, orthorhombic, a = 5.5701(2),
b = 6.8642(3),
c = 32.4529(12) Å,
a
= 90.00°,
b = 90.00°,
c
= 90.00°,
18. (a) Barone, G.; Michela, M. M.; Lanzetta, R.; Mangoni, L.; Parrilli, M.
Phytochemistry 1993, 33, 431–436; (b) Shen, X.; Krasnoff, S. B.; Lu, S.-W.;
Dunbar, C. D.; O’Neal, J.; Turgeon, B. G.; Yoder, O. C.; Gibson, D. M.; Hamann, M.
T. J. Nat. Prod. 1999, 62, 895–897; (c) Lee, S.-M.; Chun, H.-K.; Lee, C.-H.; Min, B.-
S.; Lee, E.-S.; Kho, Y.-H. Chem. Pharm. Bull. 2002, 50, 1245–1249; (d) Moodley,
N.; Mulholland, D. A.; Crouch, N. R. J. Nat. Prod. 2004, 67, 918–920; (e) Evidente,
A.; Andolfi, A.; Cimmino, A.; Vurro, M.; Fracchiolla, M.; Charudattan, R.; Motta,
A. Phytochemistry 2006, 67, 2281–2287; (f) Phuwapraisirisan, P.; Sawang, K.;
Siripong, P.; Tip-pyang, S. Tetrahedron Lett. 2007, 48, 5193–5195; (g) Nishida,
Y.; Eto, M.; Mikashita, H.; Ikeda, T.; Yamaguchi, K.; Yoshimitsu, H.; Nohara, T.;
Ono, M. Chem. Pharm. Bull. 2008, 56, 1022–1025.
U = 1240.81(8) Å3, T = 120(2) K, space group P2(1)2(1)2(1), Z = 4, 14,074
reflections measured, 1697 unique reflections (Rint = 0.0829). The final R1
values were 0.0518 (I > 2r(I)). The final wR(F2) values were 0.1213 (I > 2r(I)).
The final R1 values were 0.0788 (all data). The final wR(F2) values were 0.1346
(all data). Crystal data for 8b: M = 268.34, monoclinic, a = 5.7514(3),
b = 6.7956(5),
c = 38.179(2) Å,
a
= 90.00°,
b = 91.547(2)°,
c = 90.00°,
U = 1491.67(16) Å3, T = 120(2) K, space group P2(1)/c, Z = 4, 10,479 reflections
measured, 3367 unique reflections (Rint = 0.0567). The final R1 values were
0.0821 (I > 2r(I)). The final wR(F2) values were 0.1622 (I > 2r(I)). The final R1
values were 0.1189 (all data). The final wR(F2) values were 0.1849 (all data).
15. Approximate diastereomeric ratios are based upon measurement of the peak
height and integral of resonances of paired diastereomeric carbons in the 13C
NMR spectrum (400 MHz, CDCl3).