Synthesis of stereodefined fused δ-hydroxy-γ-lactones from dealkylative cyclization of epoxy-diesters

Article abstract of DOI:10.1016/j.tetlet.2011.06.106

A dealkylative lactonization of stereodefined aryl-substituted epoxides allows the preparation of densely functionalized fused δ-hydroxy-γ- lactones having three consecutive stereochemically defined stereocenters.

Full text of DOI:10.1016/j.tetlet.2011.06.106

Tetrahedron Letters 52 (2011) 4716–4719
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of stereodefined fused d-hydroxy-
cyclization of epoxy-diesters
c-lactones from dealkylative
⇑
⇑
Leyla Pehlivan, Maïwenn Jacolot, Nicolas Coia, Nuno Monteiro, Didier Bouyssi , Geneviève Balme
ICBMS, Institut de Chimie et de Biochimie Moléculaires et Supramoléculaires (UMR 5246 du CNRS), Université Lyon 1, ESCPE Lyon. 43 Bd du 11 Novembre 1918,
69622 Villeurbanne, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A
dealkylative lactonization of stereodefined aryl-substituted epoxides allows the preparation of
Received 19 April 2011
Revised 21 June 2011
Accepted 27 June 2011
Available online 6 July 2011
densely functionalized fused d-hydroxy-
stereocenters.
c
-lactones having three consecutive stereochemically defined
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Cyclization
Epoxide
Fused d-hydroxy-c-lactone
Diastereoselectivity
Functionalized-
c
-lactones are present in the structures of a
2).9 However, to our knowledge, no preparation of such com-
pounds having a hydroxy group at the bridgehead position (2)
has been reported.
Herein, we wish to report the results obtained in the develo
pment of this dealkylative cyclization reaction allowing the stereo-
controlled preparation of densely functionalized fused d-hydroxy-
great number of natural and unnatural products that often exhibit
interesting biological activity such as fungicidal, antitumor, and
antimicrobial properties.1 They also serve as useful intermediates
for organic synthesis.2 Consequently, a variety of methods for their
synthesis have been developed.3
We have previously reported the preparation of functionalized
cyclohexanones, mediated by lithium iodide, from oxaspirohep-
tanes of general structure 1.4 During this study, we unexpectedly
found that reaction of the stereodefined epoxy-diester 1a with
excess Me3SiI (generated in situ from Me3SiCl and NaI) led
c
-lactones 2.
The aryl-substituted epoxides 1a–j used in this study as well as
the methyl analog 1l were prepared by epoxidation of the corre-
sponding stereodefined arylidene- and alkylidene-cyclopentanes
exclusively to the formation of the [3.3.0]-bicyclic
c-lactone 2a
having three consecutive stereochemically defined stereocenters
(Scheme 1). This reaction may be explained by a stereoselective
intramolecular trans addition of an ester carbonyl to the Lewis
acid-complexed epoxide followed by dealkylation of the oxonium
intermediate5 instead of the ring enlargement reaction observed
with LiI.
R
O
O
Me3SiI
CH2Cl2
R
O
LiI
CH2Cl2
O
R
Z
Z
HO
CO2Me
Z'
this work
previous work
Z'
1
1a
2
2a
Z, Z' = CO2Me, R = Ph
Z, Z' = CO2Me, CN
R = Me, Ph
Several procedures have been reported for the Lewis acid- med-
iated cyclization of epoxyesters to c-hydroxy lactones, especially
zinc chloride to epoxy t-butylesters6 and more recently tin(IV) tri-
flimidate.7 Protic acid mediated conditions (aqueous H2SO4, CSA or
PTSA) were also used for this transformation.8 On the other hand,
only few methods are described in the literature for the synthesis
Scheme 1. Rearrangement versus lactonization on oxaspiroheptanes 1.
O
R
O
radical-
or
CO2Me
CO2Me
R
of fused bicyclic c-lactones 3 and they generally involve the radi-
cal- or halo-cyclization of linear 4-pentenylmalonates (Scheme
CO2Me
halocyclization
reaction
3
⇑
Corresponding authors. Tel.: + 33 472 431446; fax: + 33 472 431214.
E-mail address: balme@univ-lyon1.fr (G. Balme).
Scheme 2. Strategy previously used to prepare fused bicyclic c-lactones.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.06.106

L. Pehlivan et al. / Tetrahedron Letters 52 (2011) 4716–4719
4717
Table 1
Two-step synthesis of fused d-hydroxy-
c
-lactonesa
R2
R1
O
R2
R2
R1
O
O
R1
mCPBA
Me3SiI
CO2R
CO2R or p-TsOH
CO2R
CO2R
HO
CO2R
R3
R3
R3
1
2
4
Entry
Starting alkene
Epoxidationb
Lactonizatione
Conditions A or B
Yield (%)
Epoxides (1)c (ratio)
TMSI; PTSA
Yield (%)
Lactones (2) and other products (ratio)c
Ph
Ph
O
Ph
O
O
HO
CO2R
CO2R
CO2R
CO2R
1
2
A; 81
A; 80
81; 75
87; 87
CO2R
2a
4a R = Me
4b R = Et
1a
1b
2b
MeO2C
MeO2C
MeO2C
O
O
O
3
4
A; 88
A; 88
77; 69
90; 89
O
HO
O
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
2c
4c
1c
F
F
F
O
HO
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
2d
4d
1d
Ph
Ph
O
O
Ph
O
HO
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
5
6
B; 51
61f; —
EtO2C
F3C
EtO2C
CO2Et
4e
1e
2e
(1.1:1)
(1.2:1)
F3C
F3C
O
O
O
HO
CO2Me
B; 73
59f; —
CO2Me
CO2Me
CO2Me
CO2Me
CO2Et
EtO2C
EtO2C
2f
4f
1f
(1.2:1)
(1.4:1)
MeO2C
MeO2C
MeO2C
O
O
O
HO
CO2Me
54f; —
CO2Me
CO2Me
CO2Me
CO2Me
7
B; 69
CO2Et
EtO2C
EtO2C
2g
4g
1g
(1.1:1)
(1:1)
O
O
O
O
O
O
O
O
8
9
B; 78
B; 46
(Dec.)
—; 82
O
CO2Me
HO
CO2Me
CO2Me
CO2Me
CO2Me
2h
1h
4h
O
O
O
HO
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
2i
4i
1i
(continued on next page)

4718
L. Pehlivan et al. / Tetrahedron Letters 52 (2011) 4716–4719
Table 1 (continued)
Entry
Starting alkene
Epoxidationb
Lactonizatione
Conditions A or B
Yield (%)
Epoxides (1)c (ratio)
TMSI; PTSA
Yield (%)
Lactones (2) and other products (ratio)c
MeO
MeO
MeO
O
O
10
11
B; 34
—; 61
91; —
O
HO
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
2j
4j
1j
Ph
Ph
O
Ph
Ph
CO2Me
Ph
CO2Me
O
Ph
HO
O
A; 50d
A; 83d
CO2Me
CO2Me
CO2Me
4k
1k
2k
Me
Me
O
O
O
CO2Me
Me
CO2Me
CO2Me
CO2Me
CO2Me
12
13
87 (TMSI)
50 (PTSA)g
CO2Me
5
1l
4l
CO2Me
CO2Me
Me
I
OSO2Tol
O
7
CO2Me
O
CO2Me
CO2Me
CO2Me
CO2Me
14
15
47 (TMSI)
A; 97
CO2Me
6
1m
4m
Dec. (PTSA)
a
Reactions performed on 1 mmol. Yield of the isolated product after flash chromatography.
Reagents and conditions: Condition A: 4, MCPBA (3 equiv), in CH2Cl2 (0.1 M), rt. Condition B: 4, MCPBA (3 equiv) in a buffered two phase system 0.2 M Na2CO3–CH2Cl2
b
(2:1 v/v).
c
Diastereomeric ratio determined by 1H NMR.
Reaction performed at reflux temperature.
Lactonization with Me3SiI: 1, Me3SiCl (1.5 equiv), NaI (1.5 equiv) in CH2Cl2, 15 h, rt; lactonization with PTSA: 1, PTSA (0.2 equiv) in CH2Cl2, 15 h, rt.
For 1i–k, Me3SiCl (3 equiv), NaI (3 equiv).
One equivalent of p-TSOH was used.
d
e
f
g
acid (MCPBA) in CH2Cl2 to afford the corresponding oxiranes in
good yields. For the preparation of the acid-sensitive aryl epoxides
4h–j possessing electron-donating groups, the reaction was per-
formed with the same oxidant, but in a buffered two phase system
0.2 M Na2CO3–CH2Cl2 (2:1 v/v).12 Finally, treatment of substituted
methylenecyclopentanes 4e–g with MCPBA gave a mixture of the
epimeric epoxides at the ethyl ester position in varying diastereo-
meric ratio (Table 1).
We first studied the reaction of aryl-epoxides with neutral and
electron-withdrawing groups on the aryl moiety with Me3SiI
formed in situ from 1.5 equiv of Me3SiCl and 1.5 equiv of NaI in
CH2Cl2. As shown in Table 1, reaction of aryl-epoxides 1a–d was
found to be very clean and complete conversion was observed after
15 h at room temperature to give the corresponding fused d-hydro-
xy-c-lactones 2a–d isolated in a single isomeric form, the trans
relationship between the aryl group and the created hydroxy being
totally controlled (entries 1–4). The structure of these fused lac-
tones was unequivocally assigned by the X-ray crystallographic
analysis of 2a (Fig. 1).13 In the case of the aryl-epoxide substrates
1e–g, the reaction conducted on the mixture of epimers needs
the use of 3 equiv of Me3SiI to go to completion and led to the cor-
responding lactones 2e–g with no appreciable change in the dia-
stereomeric ratio (entries 5–7). Reaction on the difunctionalized
Figure 1. X-ray representation of 2a.
epoxy-ester 1k led to the expected d-hydroxy-c-lactone 2k in very
good yields (entry 11).
4a–j and 4l.10 To study the generality of this dealkylative cycliza-
tion reaction, methylenecyclopentane 4m and the more substi-
tuted unsaturated substrate 4k were also epoxidized.11 Thus
compounds 4a–d, k–m were treated with m-chloroperoxybenzoic
When the reaction was conducted on epoxide 1h bearing a 3,
4-(methylenedioxy)phenyl group, the dealkylative lactonization
reaction was unsuccessful. Indeed, only a degradation of the start-
ing material was observed, even when the reaction was conducted

L. Pehlivan et al. / Tetrahedron Letters 52 (2011) 4716–4719
4719
5627–5630; (c) Wheatley, J. R.; Bichard, C. J. F.; Mantell, S. J.; Son, J. C.; Hughes,
D. J.; Fleet, G. W. J.; Brown, D. J. Chem. Soc., Chem. Commun. 1993, 1065–1067;
(d) Gasey, M.; Manoge, A. C.; Murphy, P. J. Tetrahedron Lett. 1992, 33, 965–968;
(e) Delhaye, L.; Merschaert, A.; Diker, K.; Houpis, I. N. Synthesis 2006, 1437–
1443.
at low temperature, which seems to be due to the instability of this
most electron-rich aryl-epoxide under the reaction conditions.14
We also decided to test protic acids as catalysts instead of Me3-
SiI and we found that simple treatment of the aryl epoxides 1a–d
with 0.2 equiv of p-toluenesulfonic acid (PTSA) in CH2Cl2 at room
temperature has similar effect on this dealkylative lactonization
(Table 1, entries 1–4). Under these acidic conditions, the reaction
failed to occur with the methylenedioxy derivative 1h. However,
aryl-epoxides 1i–j with electron-donating group such as the 4-
methoxy or 4-methyl moieties proceeded efficiently to give the
corresponding lactones 2i–j in rather good yields.
The reaction of the unfunctionalized epoxy-ester derivative 1m
and the methyl analog 1l takes a different course when these com-
pounds were treated according to the standard procedures de-
scribed above. Thus reaction of 1l and 1m with Me3SiI did not
give any desired cyclization product but led to the ring opened
products 5 and 6, respectively, in good yields. Under TsOH cataly-
sis, only decomposition of the starting material was observed for
unfunctionalized epoxide 1m while reaction of the methyl substi-
tuted epoxide 1l needed the presence of equimolar amounts of acid
3. For some recent reviews on the synthesis of c-lactones see: (a) Gil, S.; Parra, M.;
Rodriguez, P.; Segura, J. Mini-Rev. Org. Chem. 2009, 6, 345–358; (b) Seitz, M.;
Reiser, O. Curr. Opin. Chem. Biol. 2005, 9, 285–292.
4. Bouyssi, D.; Cavicchioli, M.; Large, S.; Monteiro, N.; Balme, G. Synlett 2000, 749–
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7. Antoniotti, S.; Duñach, E. Tetrahedron Lett. 2009, 50, 2536–2539.
8. (a) Kende, A. S.; Toder, B. H. J. Org. Chem. 1982, 47, 163–167; (b) Mohr, P.;
Rösslein, L.; Tamm, C. Tetrahedron Lett. 1989, 30, 2513–2516; (c) Concellon, J.
M.; Riego, E.; Bernad, P. L. Org. Lett. 2002, 4, 1303–1305; (d) Wang, J.-X.; Zhang,
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Enomoto, M.; Kuwahara, S. Biosci. Biotechnol. Biochem. 2010, 74, 152–157.
9. Radical cyclization: (a) Baciocchi, E.; Paolobelli, A. B.; Ruzziconi, R. Tetrahedron
1992, 48, 4617–4622; (b) Powel, L. H.; Docherty, P. H.; Hulcoop, D. G.;
Kemmitt, P. D.; Burton, J. W. Chem. Commun. 2008, 2559–2561; (c) Davies, J. J.;
Krulle, T. M.; Burton, J. W. Org. Lett 2010, 12, 2738–2741; Iodocyclization:
(a) Curran, D. P.; Chang, C.-T. J. Org. Chem. 1989, 54, 3140–3157; (b) Kitagawa,
O.; Inoue, T.; Hirano, K.; Taguchi, T. J. Org. Chem. 1993, 58, 3106–3112;
(c) Inoue, T.; Kitagawa, O.; Oda, Y.; Taguchi, T. J. Org. Chem. 1996, 61, 8256–
8263.
10. All unsaturated substrates used in this study were obtained according to
procedures previously reported by our group: for the preparation of
stereodefined arylidene- and alkylidene-cyclopentanes 4a–d, 4h–j, and 4l,
see: Montel, S.; Bouyssi, D.; Balme, G. Adv. Synth. Catal. 2010, 352, 2315–2320;
For the synthesis of substituted methylenecyclopentanes 4e–g, see: Coia, N.;
Bouyssi, D.; Balme, G. Eur. J. Org. Chem. 2007, 3158–3165.
11. For the synthesis of methylenecyclopentane 4m, see: Bouyssi, D.; Monteiro, N.;
Balme, G. Tetrahedron Lett. 1999, 40, 1297–1300; For the synthesis of 4k see:
Fournet, G.; Balme, G.; Gore, J. Tetrahedron 1991, 47, 6293–6304.
12. Ishikawa, K.; Charles, H. C.; Griffin, G. W. Tetrahedron Lett. 1977, 427–430.
13. Crystallographic data for compound 5a have been deposited with the
Cambridge Crystallographic Data Centre, No CCDC 819990. Copies of the data
can be obtained, free of charge, on application to CCDC (e-mail:
deposit@ccdc.cam.ac.uk).
to go to completion. Under these conditions the linear a-tosyloxy
ketone 7 was obtained. These three linear substrates were believed
to result from attack by halide ions or p-TsOH on the primary or
secondary epoxy carbon followed by a cyclopentane ring opening
reaction.15 A reductive dehalogenation of the resulting
a-iodoke-
tone in the presence of iodide ions could be envisaged for the
formation of linear adduct 5.16
The difference of reactivity (intra- vs inter-molecular nucleo-
philic attack of epoxide) between the aryl substituted epoxides
1a–k and epoxides 1l–m may be attributed to stabilizing effects of
the aryl substituent on the development of a partial positive charge
at the benzylic position.
In conclusion, we have shown that stereochemically defined
14. The instability of such electron-rich aryl epoxides has previously been reported
see: Aldous, D. J.; Batsanov, A. S.; Yufit, D. S.; Dalençon, A. J.; Dutton, W. M.;
Steel, P. G. Org. Biomol. Chem. 2006, 4, 2912–2927.
15. Wawrzenczyk, C.; Grabarczyk, M.; Bialonska, A.; Ciunik, Z. Tetrahedron 2003,
59, 6595–6601.
densely functionalized fused d-hydroxy-c-lactones could be pre-
pared via dealkylative cyclization reaction.17 The synthetic utility
of this reaction for the preparation of oxygenated furofuran lignans
will be explored in a subsequent work.18
16. Erian, A. W.; Sherif, S. M.; Gaber, H. M. Molecules 2003, 8, 793–865; Olah, G. A.;
Arvanaghi, M.; Vankar, Y. D. J. Org. Chem. 1980, 45, 3531–3532.
17. Typical synthetic procedure for fused d-hydroxy-
c-lactones: cyclization of 1a to 2a.
Acknowledgment
A
mixture of sodium iodide (1.5 mmol, 223.5 mg) and TMSCl (1.5 mmol,
162 mg) in dry CH2Cl2 was stirred for 5 min under Argon atmosphere, after
which time epoxy ester 1a (1 mmol, 294 mg) was added and the resulting
mixture was stirred at room temperature for 16 h. The mixture was then
diluted with CH2Cl2 and washed with water. The crude product was purified by
column chromatography (silica gel, cyclohexane/ethylacetate 4:1) affording 2a
as a white solid (mp 116–120 °C, 223.5 mg, 81% yield, one diastereomer).
We thank Dr. E. Jeanneau (Centre de Diffractométrie Henri
Longchambon, Université Lyon 1) for the X-ray crystallographic
analysis.
1H NMR (300 MHz, CDCl3)
d in ppm: 1.51–1.73 (m, 3H); 1.80–1.88
References and notes
(m, 1H); 2.33–2.41 (m, 1H); 2.51–2.61 (m, 1H); 2.88 (s, 1H, OH) 3.88 (s, 3H,
COOCH3); 5.63 (s, 1H, H6); 7.36–7.40 (m, 5H, Ar). NMR 13C (CDCl3, 75 MHz): d
in ppm: 174.1 (COOCH3), 168.8 (CO), 135.2, 128.9, 128.8, 125.4 (CH Ar), 90.3
(C–OH), 85.4 (C–COOMe), 66.7 (C–HAr), 53.8 (OCH3), 37.6, 33.4, 24.2 (CH2).
HRMS (CI): [MH]+ found 277.1076, calculated for C15H17O5 = 277.1075.
18. See Jacolot, M.; Pehlivan, L.; Bouyssi, D.; Monteiro, N.; Balme, G. next paper.
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