Tin(IV) triflimidate-catalyzed cyclization of epoxy esters to functionalized δ-hydroxy-γ-lactones

Article abstract of DOI:10.1016/j.tetlet.2009.03.055

In the presence of 5 mol % of tin(IV) triflimidate, a cyclization reaction of epoxyesters to δ-hydroxy-γ-lactones proceeding in 46-98% yields without additives, ligands, or co-catalysts was observed. The cyclization to five-membered rings is greatly favor

Full text of DOI:10.1016/j.tetlet.2009.03.055

Tetrahedron Letters 50 (2009) 2536–2539
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Tin(IV) triflimidate-catalyzed cyclization of epoxy esters
to functionalized d-hydroxy-c-lactones
*
Sylvain Antoniotti, Elisabet Duñach
Laboratoire de Chimie des Molécules Bioactives et Arômes UMR 6001, Université de Nice—Sophia Antipolis, CNRS, Institut de Chimie de Nice,
28 Avenue de Valrose, F-06108 Nice, France
a r t i c l e i n f o
a b s t r a c t
Article history:
In the presence of 5 mol % of tin(IV) triflimidate, a cyclization reaction of epoxyesters to d-hydroxy-c-lac-
Received 6 February 2009
Revised 9 March 2009
Accepted 10 March 2009
Available online 14 March 2009
tones proceeding in 46–98% yields without additives, ligands, or co-catalysts was observed. The cycliza-
tion to five-membered rings is greatly favored compared to the possible six-membered rings formation
and is probably under the control of a Thorpe–Ingold type effect.
Ó 2009 Elsevier Ltd. All rights reserved.
Metal-based catalytic reactions involving functionalized com-
pounds have provided the organic chemist with a wide collection
of efficient, selective, atom-economical, and creative methods to
form new bonds and molecules.1–3 Among these methodologies,
cycloisomerization of functionalized substrates has been devel-
oped, based on ring-closure processes involving the metal-based
electrophilic activation of unsaturated compounds (alkynes, al-
lenes, alkenes, as well as carbonyl compounds) to allow the attack
of a remote nucleophile (e.g., alcohols, amides, sulfonamides, thi-
ols, carboxylic acids, active methylene, and electrons-rich are-
nes).4–13 In many instances, the creation of new functionalities
on the product results in new opportunities of reaction within
the same molecule in cascade reactions of high synthetic effi-
ciency.14–17
We have developed cycloisomerization reactions based on the
electrophilic activation of electron-rich olefins by metallic triflates
and triflimidates in intramolecular hydroalkoxylation,18,19 hydro-
carboxylation,20 hydro-thiolation,21 hydrooxyamination,22 and
1,6-dienes cycloisomerization.23 We have been lately interested
in using strong Lewis acids such as Sn(NTf2)4 as catalyst to activate
triple bonds and allow the nucleophilic addition of a remote epox-
ide function. The challenging metal triflimidate activation of a tri-
ple bond was recently reported by Nakamura with In(NTf2)3, which
was able to catalyze a cyclization reaction through the addition of
the active methylene of a b-ketoester to a terminal alkyne (Conia-
ene reaction).24 In our case however, we also had to bypass the in-
nate propensity of epoxides to isomerize into carbonyl compounds.
Recent reactions on similar substrates were described, for example,
in AuI-catalyzed tandem epoxide ring-opening/hydroalkoxylation
reactions of epoxy alkynes25,26 and in AuI- and AuIII-catalyzed syn-
thesis of functionalized furans,27–29 acylindenes,30 spiropyranon-
es,31 and divinylketones32 from epoxy propargyl derivatives.
When epoxypropargyl ester 1a was heated at 80 °C in nitro-
methane in the presence of 5 mol % Sn(NTf2)4ꢀ6DMSO,33 the start-
ing material was totally consumed in favor of the formation of the
corresponding d-hydroxy-c-lactone 2a in 70% yield as a 3/1 mix-
ture of 2 diastereomers, leaving unchanged the propargyl side
chain (Scheme 1). As a side product, the isopropylketone 3a result-
ing from the epoxide isomerization was formed in 30% yield.
In a previous work of Baltas and co-workers, a cyclization reac-
tion of
c,d-epoxy-b-hydroxyesters promoted by excess ZnCl2 was
described to lead to mixtures of
c- and d-lactone derivatives, with
a selectivity strongly influenced by the presence of a hydroxyl
group at carbon atom b.34 In these reactions, tert-butyl esters, lead-
ing to the release of the stable tert-butyl cation, were used and
4 equiv of Lewis acid were needed to overcome the intrinsically
weak nucleophilicity of the ester function. In particular, while
compounds with free alcohol at C-b were cyclized to d-lactone
derivatives with more than 95% selectivity, the protection of the
hydroxyl group by TBDMS or TBDPS resulted in a spectacular
inversion of the selectivity in favor of the
c-lactone derivatives.
Conversely, Ti(III)-catalyzed radical cyclizations of epoxy alkenes
proceed selectively by ring-closure with attack of the most substi-
tuted carbon atom.35 In our case with 1a and in the presence of
5 mol % of tin(IV) catalyst, the cyclization proceeded exclusively
to d-hydroxy-
tack of one ester group.
The d-hydroxy- -lactone motif is the core structure of bioactive
natural products such as ( )-muricatacin and has been the focus of
c-lactone 2a through the 5-exo-tet nucleophilic at-
c
Sn(NTf2)4
(5 mol%)
O
O
EtOOC
EtOOC
EtOOC
EtOOC
+
O
OH
CH3NO2
80 °C
O
EtOOC
2a, 70%, dr 3/1
Scheme 1.
3a, 30%
1a
* Corresponding author.
E-mail address: dunach@unice.fr (E. Duñach).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.055

S. Antoniotti, E. Duñach / Tetrahedron Letters 50 (2009) 2536–2539
2537
recent research.36–39 We thus examined the behavior of epoxyest-
ers 1a–j, displaying various substitution patterns, in the presence
of 5 mol % of tin(IV) triflimidate (Table 1). Taking into account
the lack of reactivity of the alkyne moiety, we engaged compound
1b in the reaction (entry 2). However, in the absence of the side
chain, the cyclization was not observed and ketone 3b was quanti-
tatively formed through epoxide isomerization. Product 3b was
also obtained in 100% yield when the reaction was performed in
toluene or acetonitrile (entries 3 and 4). The reaction of entry 2
was repeated in the presence of 10 mol % of 1-hexyne as ligand
Table 1
Reaction of
c,d-epoxyesters 1a–j catalyzed by tin(IV) triflimidate (5 mol %)
Entrya
Substrate
Solvent/T/time
Products, yieldsb
O
O
EtOOC
EtOOC
EtOOC
EtOOC
1c
CH3NO2/80 °C/6 h
2a, 70%
+
3a, 30%
OH
O
dr=1/3
EtOOC
O
1a
O
EtOOC
EtOOC
EtOOC
EtOOC
2
3
4
CH3NO2/80 °C/2 h
Toluene/80 °C/2 h
CH3CN/80 °C/2 h
1b
O
3b, 100%
O
O
OH
O
O
EtOOC
EtOOC
+
EtOOC
EtOOC
OH
O
O
5
6
CH3NO2/80 °C/24 h
1c
2c', 28%
2c, 72%
Mixture of 4 diastereomers of 2c and 4 diasteromers of 2c'
O
EtOOC
EtOOC
EtOOC
EtOOC
EtOOC
EtOOC
+
CH3NO2/80 °C/3 h
3d
O
3d'
1d
Complexe mixture of products including 3d and 3d'
O
EtOOC
EtOOC
O
O
2e, 65%
7
8
CH3NO2/80 °C/7 h
O
O
dr 3/2
OH
1e
EtOOC
O
EtOOC
OH
Ph
EtOOC
Ph
2f, 46%
Ph
CH3NO2/80 °C/4.5 h
3f, 54%
+
dr=n.d.
COOEt
O
EtOOC
1f
EtOOC
O
O
EtOOC
EtOOC
O
O
2g, 85%
9
10
11
CH3NO2/60 °C/3 h
CH3NO2/80 °C/7 h
CH3NO2/60 °C/5 h
CH3NO2/60 °C/7 h
OH
EtOOC
dr=2/1
1g
O
EtOOC
EtOOC
O
2h, 98%
dr=1/1
OH
O
EtOOC
1h
1i
O
EtOOC
NC
2i, 45%
EtOOC
NC
3i, 55%
3j, 27%
+
O
O
1 diastereoisomer
OH
NC
O
EtOOC
O
O
Ph
OH
2j, 73%
O
12
EtOOC
+
1 diastereoisomer
Ph
Ph
1j
a
Reactions were performed in 1 mL of anhydrous and degassed solvent on 0.5 mmol of substrate in the presence of 0.025 mmol Sn(NTf2)4ꢀ6DMSO prepared following a
procedure previously described.33
b
Isolated yields.
Taken from Scheme 1.
c

2538
S. Antoniotti, E. Duñach / Tetrahedron Letters 50 (2009) 2536–2539
but again, ketone 3b was obtained quantitatively (not shown).
With substrate 1c, compared to substrate 1a, the only change of
methyl group for a hydrogen atom on the oxirane significantly al-
tered the regioselectivity of the reaction yielding a 7/3 mixture of
In terms of mechanism, we hypothesize that, following the for-
mation of the starting complex A, the reaction could start with an
ester group attacking the epoxide on the opposite side at the less
substituted position to form intermediate B (Scheme 2). Intermedi-
ate B would further dealkylate to yield C, in a process similar to the
dealkylative lactonization recently described in TfOH-mediated
reactions, and maybe favored by the involvement of a water mol-
ecule.42 Protonolysis of the tin alcoholate would then lead to 2
and the recovery of the catalyst. The putative seven-membered
ring chelate A allows to explain why a less strained five-membered
ring-closure with the attack of the less substituted oxirane atom is
observed while Lewis acid epoxide ring-opening usually proceeds
through the attack of the most substituted carbon atom, where
more stable carbocations could be formed.
diastereoisomers of c
- and d-lactones 2c and 2c0 almost quantita-
tively (entry 5). The decrease in steric hindrance at carbon atom
d in that particular case probably allowed the nucleophilic attack
of one ester group, disfavored in the case of 1a. Substrate 1d did
not cyclize under our conditions (entry 6) and the isomerization
of the epoxide to both possible carbonyl compounds 3d and 3d0 oc-
curred, within a complex mixture of unidentified products. In that
case, the lower substitution of the oxirane ring and the absence of
substituent at carbon atom
a resulted in a decrease in the overall
efficiency of the reaction. Taking into account the results of entries
2–4,6, it appeared more plausible that rather than a coordination of
the electron-rich alkyne moiety to the metal during the cyclization,
In summary, we have described a novel tin(IV) triflimidate-cat-
alyzed (5 mol %) cyclization reaction involving the ring-opening of
the presence of a quaternary carbon atom at position
a
, putting the
epoxides by readily available ethyl ester groups to d-hydroxy-c-
substrate into a more favorable conformation for cyclization in a
lactones in 46–98% yields.43 We suggest that the reaction is under
the control of steric hindrance and conformation through a
Thorpe–Ingold type effect.
Thorpe–Ingold type effect,40 could explain our results. Thus, sub-
strate 1e, with a methyl substituent at carbon atom
to d-hydroxy- -lactone 2e in 65% yield as a 3/2 mixture of diaste-
reoisomers (entry 7).
a, cyclized
c
Acknowledgments
The case of compound 1f offered another example of competi-
tion cyclization/isomerization with the formation of the d-hydro-
This work was supported by the CNRS, the University of Nice—
Sophia Antipolis, and the CP2D program of the French National Re-
search Agency (ANR CASAL).
xy-
ketone 3f formed in 53% yield (entry 8). Compound 1g bearing a
prenyl side chain selectively cyclized to d-hydroxy- -lactone 2g
c-lactone 2f in a moderate 46% yield, the main product being
c
in 85% yield (dr = 2/1, entry 9). During the process, the question
of whether or not 2g could then cyclize again through a Sn(IV)-cat-
alyzed intramolecular hydroalkoxylation18 was of concern, but no
eight-membered product was observed. The best result was
undoubtedly obtained with substrate 1h bearing a methyl group
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O
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O
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C
O
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+
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H2O
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-
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HOEt
+ H+
[Sn]
O
Scheme 2.

S. Antoniotti, E. Duñach / Tetrahedron Letters 50 (2009) 2536–2539
2539
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flash chromatography over silica gel (eluent: petroleum ether/diethyl ether,
100/0 to 95/5) yielding 2a as a colorless oil (89 mg, 70% yield, 1:3 mixture of 2
diastereomers). 1H NMR (200 MHz, CDCl3, 20 °C): d ppm 4.42–4.36 (m, 1H);
4.22–4.14 (m, 2H); 2.86–2.78 (m, 2H); 2.65–2.30 (m, 2H); 2.06–1.97 (m, 1H);
1.37–1.11 (m, 9H). 13C NMR (50 MHz, CDCl3, 20 °C):
d ppm, major
41. We previously observed a similar stereoselectivity in the cyclization of 1,6-
dienes with substrates bearing only one ester group: see Ref. 23.
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43. Representative procedure: Cyclization of 1a to 2a. To a solution of 1a (0.5 mmol,
141 mg) in degassed anhydrous nitromethane (1 mL), Sn(NTf2)4ꢀ6DMSO
(0.025 mmol, 43 mg) was added and the mixture was stirred at 80 °C under
a nitrogen atmosphere. After completion, the reaction mixture was purified by
diastereomer: 172.7 (C@O); 169.1 (C@O); 84.4 (CH); 84.3 (CH); 71.9 (˜C—);
71.6 (˜C—); 62.7 (CH2); 55.5 (˜C—); 32.1 (CH2); 26.8 (CH3); 24.0 (CH2); 23.8
(CH3); 14.0 (CH3). MS (EI, 70 eV): major diastereomer 254(0) [M+Å], 236(1),
209(3), 197(11), 180(3), 163(14), 151(30), 139(13), 123(26), 111(35), 105(39),
93(63), 79(41), 58(100). Minor diastereomer 254(1) [MÅ], 236(2), 207(2),
197(21), 179(2), 163(15), 151(50), 139(15), 123(29), 111(34), 105(44), 93(99),
79(52), 58(100). HRMS (m/z): [MNa]+ calculated for C13H18O5Na, 277.10464;
found 277.10446.