A convenient access to γ-lactones from O-allyl-α-bromoesters using a one-pot ionic-radical-ionic sequence

Article abstract of DOI:10.1002/asia.201200212

Cognac in the jar! An efficient one-pot sequence for the preparation of γ-lactones is described. Following reduction of α-bromo ester precursors with DIBAL-H and radical cyclization of the resulting O-aluminum acetals, a preparative in-situ Oppenauer-type oxidation of the cyclic O-aluminum acetal using simple aldehydes or ketones gives access to γ-lactones in high yields. Copyright

Full text of DOI:10.1002/asia.201200212

DOI: 10.1002/asia.201200212
A Convenient Access to g-Lactones from O-Allyl-a-Bromoesters using a
One-Pot Ionic–Radical–Ionic Sequence
Romain Bꢀnꢀteau, Jacques Lebreton, and Fabrice Dꢀnꢁs*[a]
In memory of Prof. Athelstan L. J. Beckwith, a pioneer in the field of free radical chemistry
g-Lactones are of great interest in industry due to the
odorant properties of these small, volatile molecules, which
makes them attractive candidates for applications as flavor-
ings in food and fragrances in perfumes.[1] Among the differ-
ent strategies to access g-lactones, the radical cyclization of
O-allyl-a-haloesters[2] under reducing conditions seems, at
first, to be especially appealing. However, it is now well es-
tablished that this approach is not, in most cases, an efficient
process. The failure of the process is due to conformational
constraints, which result in a slow equilibrium that lies in
favor of the s-trans rotamer (Scheme 1).[3] This rotamer is
A solution to the problem encountered for the cyclization
of a-haloesters under reductive conditions was reported in
the 1980s independently by the groups of Ueno[5] and
Stork.[6] The Ueno–Stork approach[7] consists of the use of
the related a-haloacetals, which were found to cyclize very
efficiently, even at low temperatures, to give the correspond-
ing cyclic acetals. The resulting cyclic acetals have proven to
be useful precursors for the corresponding lactones, al-
though this transformation requires at least one additional
step. Moreover, both the hydrolysis and the direct oxidation
of the acetal moiety require the use of either a Brønsted or
a Lewis acid, which poses a limitation to this approach in
the case of substrates with highly acid-sensitive functionali-
ties.[8] Recently, we reported that a-bromo aluminum ace-
tals, prepared from the corresponding a-bromo esters by re-
duction with DIBAL-H, can be cyclized at low temperature
under reducing conditions, delivering g-lactols[9] and methyl-
ene-g-lactols[10] in good to high yields. The method proved
efficient with a range of substrates, including acid-sensitive
precursors such as 1 (Scheme 2).
Scheme 1. Cyclization of a-haloesters under reducing conditions.
unable to cyclize and instead undergoes hydrogen abstrac-
tion from the radical-chain carrier, leading to the uncyclized
dehalogenated product (Scheme 1). Some isolated examples
of successful cyclization of a-haloesters under reducing con-
ditions have been reported,[4] but both high temperature and
high dilution are required to facilitate the equilibrium be-
tween s-cis and s-trans conformers and to decrease the rate
for the intermolecular hydrogen atom abstraction from the
chain carrier, respectively.
Scheme 2. Radical cyclization of aluminum acetals under reducing condi-
tions.
[a] R. Bꢀnꢀteau, Prof. J. Lebreton, Dr. F. Dꢀnꢁs
Universitꢀ de Nantes
Laboratoire CEISAM, UMR 6230, UFR des Sciences et des Tech-
niques
2, rue de la Houssiniꢁre, BP 92208-44322, Nantes Cedex 3 (France)
Fax : (+33)251-12-54-02
The formation of cyclic aluminum acetals such as 3 offers
the opportunity to investigate an in situ Meerwein–Pon-
dorff–Verley reduction of ketones and aldehydes.[11] To the
best of our knowledge, the reactivity of such aluminum ace-
tals as a reducing agent has not been studied thus far.[12] As
far as the aluminum acetal is concerned, the overall process
E-mail: fabrice.denes@univ-nantes.fr
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201200212.
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Table 1. Oppenauer-type oxidation of aluminum acetals.
Entry
R1
R2
Equiv
Solvent
Time [h]
Yield [%][a]
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
Me
iPr
iPr
Ph
Me
Me
Me
Me
Me
Me
H
H
H
H
2
20
2
20
2
20
2
2
2
2
CH2Cl2
CH2Cl2
n-hexane
n-hexane
toluene
toluene
CH2Cl2
toluene
CH2Cl2
toluene
20 h
20 h
20 h
20 h
20 h
20 h
4 h
4 h
4 h
4 h
45
71
44
59
62
70
85
91
88
94
9
10
Ph
[a] GC yields determined using bicyclohexyl as an internal standard.
Scheme 3. Efficient preparation of g-lactones from a-bromo esters using
a one-pot process.
tone, giving g-lactone 6 in moderate yield (Table 1, entry 1).
Similar results were obtained in hexane (44%), while
a slightly higher yield (62%) was obtained in toluene
(Table 1, entries 3 and 5). The use of a larger excess of ace-
tone (20 equivalents) in dichloromethane or toluene allowed
the yields to be further increased to about 70% (Table 1, en-
tries 2 and 6). In n-hexane, the use of 20 equivalents of ace-
tone led to g-lactone 6 in 59% yield (Table 1, entry 4). Al-
dehydes proved much more reactive in this Oppenauer-type
oxidation, with the reaction being almost complete within
4 hours. Both aliphatic and aromatic aldehydes can be used
with similar efficiency. For instance, the addition of two
equivalents of isobutyraldehyde to aluminum acetal 5 led to
g-lactone 6 in high yields for the reactions carried out in di-
chloromethane or in toluene (Table 1, entries 7 and 8). Simi-
larly, the use of two equivalents of benzaldehyde also gave
a high yield of g-lactone 6 (Table 1, entries 9 and 10).
With these promising results in hands, we then turned our
attention to the preparation of a series of g-lactones from a-
halo esters using a one-pot sequence. The latter involves the
formation of an aluminum acetal by reduction with DIBAL-
H, followed by the radical cyclization under reducing condi-
tions and the Oppenauer oxidation of the resulting cyclic
aluminum acetal. The results are presented in Table 2.
would result in the oxidation of the acetal center, a Tishchen-
ko-type intermediate, via the reverse process (Oppenauer
oxidation).[13] Should this approach be successful, it would
provide a direct and efficient access to g-lactones from read-
ily accessible a-haloesters (Scheme 3).
We investigated the feasibility of this reaction using cyclic
aluminum acetal 5 as starting material for the Oppenauer
oxidation. It was obtained from the corresponding lactone 6
by reduction with 1.2 equivalents of DIBAL-H at low tem-
perature. The reduction step was monitored by thin layer
chromatography (TLC) and gas chromatography (GC) using
bicyclohexyl as an internal standard. Following complete
conversion into the cyclic aluminum acetal, a ketone or al-
dehyde was added and the reaction was allowed to warm to
room temperature. Several ketones and aldehydes were
tested in this Oppenauer-type oxidation (Scheme 4).
a-Bromoesters 7a–g were prepared from the correspond-
ing allyl alcohols using standard procedures for esterifica-
tion. The reduction of 7a–g was achieved in toluene below
À708C using 1.2 equivalents of DIBAL-H. After complete
conversion (TLC monitoring), the resulting aluminum ace-
tals were cyclized in the presence of nBu3SnH (1.2–
1.4 equiv) using Et3B/O2 as a radical initiator. The radical
cyclization was usually complete within 5 hours (TLC and
GC monitoring). Once the radical cyclization had been ach-
ieved, the aldehyde (iPrCHO or PhCHO, 2–3 equiv) was
added and the reaction mixture was allowed to warm to
room temperature (258C). Following this one-pot protocol,
7a was converted into g-lactone 8a in high yield and with
a high level of diastereoselectivity (Table 2, entry 1). Oxida-
tion leading to 8b proved to be somewhat slower, probably
as a result of the increased steric hindrance close to the re-
active aluminum acetal center. As expected from our previ-
ous work, a low level of diastereoselectivity was observed in
this case (Table 2, entry 2). Similarly, a-bromoesters 7c and
Scheme 4. Oppenauer-type oxidation of aluminum acetals.
Different solvents that were found to be compatible with
the radical cyclization of aluminum acetals[14] were also in-
vestigated. The reactions were carried out at a concentration
of 0.12 m to work at a similar concentration to that used for
the radical cyclization of aluminum acetals. The hydride ac-
ceptors were added at À708C and the reaction mixture was
then allowed to warm to room temperature. The results are
summarized in Table 1.
The Oppenauer-type oxidation of cyclic aluminum acetal
5 was first attempted with acetone as an acceptor for the hy-
dride transfer. The oxidation took place at room tempera-
ture in dichloromethane using only two equivalents of ace-
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One-Pot Synthesis of g-Lactones
Table 2. Synthesis of g-lactones using the reduction–cyclization sequence,
followed by in-situ Oppenauer oxidation.
one-pot approach involving the cyclization of 7a via an alu-
minum acetal intermediate led to 8a in approximately 90%
yield, the reduced compound 9 was obtained as the sole
product when nBu3SnH/AIBN was introduced at once to
a 0.1 m refluxing solution of 7a in toluene (Scheme 5, meth-
od A). Still, the reduced compound 9 was obtained exclu-
sively for the reaction carried out at an initial concentration
in tin hydride of 10 mm (Scheme 5, method B). Finally, even
at high dilution (10 mm) and using a slow addition of the tin
hydride (over 6 h), compound 9 was the major product
(Scheme 5, method C), with the expected lactone 8a being
isolated in only 45% yield.[15]
Entry Substrate[a]
Product
Yield[b] d.r.[c]
1
91%[e]
>95:5
2
3
88%[d,e] 50:50
83%[d,e] 55:45
4
90%[d,e] 50:50
80%[f]
85%[f]
62%[d]
>95:5
>95:5
>95:5
Scheme 5. Cyclization of a-bromoester 7a under classical tin-hydride
conditions.
5
6
7
To illustrate the efficiency of the one-pot approach, the
sequence was applied to the total synthesis of (À)-trans-
cognac lactone (Scheme 6). Felluga and co-workers recently
reported the synthesis of trans-cognac lactone using non-re-
ducing conditions, that is, the atom-transfer method. The
radical cyclization was achieved in moderate yield (60%)
using a CuCl/bipyridine-promoted cyclization of a trichloroa-
cetate derivative at 1458C in acetonitrile. Dehalogenation of
the resulting chlorinated g-lactone was achieved with
nBu3SnH and gave cognac lactone in high yield (88%) but
with only relatively moderate levels of diastereoselectivity
(74% de).[16]
The required optically enriched allylic alcohol 10 was
readily obtained from commercially available (E)-1-octen-3-
ol, using a two-steps sequence involving a Sharpless asym-
metric epoxidation,[17] followed by ring opening of the epox-
ide with TiIII.[18] The a-bromo ester precursor 11 was pre-
pared using standard conditions for esterification, and then
[a] All reactions were carried out with a-bromo esters (2 mmol) in tolu-
ene (see the Supporting Information for details), using DIBAL-H
(1.2 equiv) at À708C, then nBu3SnH (1.2–1.4 equiv), and Et3B (0.3–
1.1 equiv), unless otherwise stated. [b] Yields of isolated products.
[c] Diastereomeric ratio (d.r.) determined by GC or 1H NMR spectro-
scopic analysis. [d] g-Lactones were isolated as mixture of diastereoiso-
mers. [e] Oxidation carried out with PhCHO (3 equiv). [f] Oxidation car-
ried out with iPrCHO (3 equiv).
7d, presenting a substituent at the a-position of the ester
functionality, could be cyclized into 8c and 8d, respectively,
in good to high yields (Table 2, entries 3 and 4). g-Lactone
8d was obtained as a mixture of two diastereoisomers, with
no diastereomeric control of the newly formed stereogenic
center (Table 2, entry 4). Interestingly, this one-pot process
allowed the cyclization of 7e–g into the corresponding g-lac-
tones 8e–g presenting a hydroxy group protected with an
acid-sensitive protecting group, which included benzyloxy-
methyl (BOM), tert-butyldimethylsilyl (TBS), or even tri-
phenylmethyl (Tr), thus demonstrating the mildness of the
method (Table 2, entries 5–7).
For the sake of comparison, we attempted the radical cyc-
lization of 7a under “classical” conditions. The reactions
were carried out in refluxing toluene to accelerate the equi-
librium between the s-trans and s-cis conformers. While the
Scheme 6. A straightforward approach to (À)-trans-cognac lactone.
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Fabrice Dꢀnꢁs et al.
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introduced to the one-pot sequence to give (À)-trans-cognac
lactone 12 in 89% yield and with high levels of diastereose-
lectivity (d.r.>95:5) and enantiomeric purity (94% ee).[19]
In conclusion, we have developed a straightforward access
to g-lactones from easily accessible precursors. This one-pot
sequence allowed the desired g-lactones to be obtained in
good to high yields. This approach appears quite general
and efficient, and competes favorably with the direct cycliza-
tion of a-halo esters under tin-hydride conditions, which re-
quire both high dilutions and/or slow addition techniques, as
well as high temperatures, for only moderate efficiency. This
very simple approach tolerates substitution at the different
positions of the starting a-bromo ester derivatives with
a high flexibility. Both aliphatic and aromatic aldehydes
proved highly reactive as oxidants for this unprecedented
preparative Oppenauer-type oxidation of an O-aluminum
acetal center. The result is a large variety of aldehydes to
choose from in order to facilitate the purification of the de-
sired products. The efficiency of the methodology was illus-
trated by a straightforward synthesis of optically enriched
(À)-trans-cognac lactone (four steps from commercially
available allyl alcohol, 94% ee).
Keywords: aluminum acetals · cognac lactone · Oppenauer
oxidation · radical cyclization · g-lactone
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Experimental Section
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Diisobutylaluminum hydride (DIBAL-H, 2 mL, 1.2m in toluene,
2.4 mmol) was added dropwise to a solution of a-bromoester 7a (0.566 g,
2.0 mmol) and bicyclohexyl (0.333 g, 2.0 mmol, used as an internal stan-
dard for GC monitoring) in toluene (16 mL) under argon atmosphere at
À788C. After complete disappearance of the starting material (TLC
monitoring), Et3B (0.6 mL, 1m in hexanes, 0.6 mmol) and nBu3SnH
(0.65 mL, 2.4 mmol) were simultaneously added dropwise at À788C. Sub-
sequently, air (0.3 mL) was introduced via a syringe above the solution,
and the mixture was kept at À708C. After 2 h, Et3B (0.4 mL, 1m in hex-
anes, 0.4 mmol), nBu3SnH (0.16 mL, 0.6 mmol), and air (1 mL) were
added to the solution, and the reaction mixture was stirred at À708C
until complete disappearance of the allyl alcohol (TLC monitoring, vanil-
lin revelation, and GC monitoring with a sample quenched with 0.5m
HCl, extracted with Et2O, washed with aqueous NaHCO3, and filtered
over silica-KF). Benzaldehyde (0.61 mL, 6 mmol) was added at once and
the cooling bath was removed. The reaction mixture was stirred at room
temperature (258C) for ca. 4 h (GC monitoring) and then quenched with
0.5m HCl (17 mL). Next, Et2O was added and the organic phase was col-
lected. The aqueous phase was extracted four times with Et2O. The re-
sulting organic phase was washed with an aqueous NaHCO3, dried over
MgSO4, filtered, and concentrated in vacuo. The residue was purified by
flash chromatography (first with petroleum ether/Et2O 80:20, then with
CH2Cl2 to remove benzyl alcohol). g-Lactol 8a (372 mg, 91%) was ob-
tained as a colorless oil.
[7] For a review, see: X. J. Salom-Roig, F. Dꢀnꢁs, P. Renaud, Synthesis
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Acknowledgements
This work was supported by the ANR (grant ANR-10-JCJC-0712). The
authors thank Julie Hꢀmez (CEISAM) for MS measurements, Isabelle
Louvet and Marie-Josephe Bertrand (CEISAM) for chiral HPLC analy-
sis, Nathali Henriques and F. Albrieux (Centre Commun de Spectromꢀ-
trie de Masse, Universitꢀ Claude Bernard Lyon 1, France) for HRMS
measurements. F.D. warmly thanks Prof. Alexandre Alexakis for sharing
ideas and for helpful discussions, as well as Anjum Dadabhoy and Chris-
topher Dobe for careful proofreading of the manuscript.
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Commun. 1990, 843–844; R. Fu, J.-L. Ye, X.-J. Dai, Y.-P. Ruan, P.-
Q. Huang, J. Org. Chem. 2010, 75, 4230–4243.
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One-Pot Synthesis of g-Lactones
[19] A similar approach to trans-(+)-cognac lactone using a Ueno–Stork
been reported: G. Sabitha, M. Bhikshapathi, J. S. Yadav, Synth.
Commun. 2007, 37, 559–567.
cyclization followed by hydrolysis and subsequent oxidation has
Received: March 6, 2012
Published online: && &&, 0000
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Domino Reactions
Romain Bꢀnꢀteau, Jacques Lebreton,
Fabrice Dꢀnꢁs*
&&&& — &&&&
A Convenient Access to g-Lactones
from O-Allyl-a-Bromoesters using
a One-Pot Ionic–Radical–Ionic
Sequence
Cognac in the jar! An efficient one-
pot sequence for the preparation of g-
lactones is described. Following reduc-
tion of a-bromo ester precursors with
DIBAL-H and radical cyclization of
the resulting O-aluminum acetals,
a preparative in-situ Oppenauer-type
oxidation of the cyclic O-aluminum
acetal using simple aldehydes or
ketones gives access to g-lactones in
high yields.
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ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 0000, 00, 0 – 0
ÝÝ These are not the final page numbers!