Access to novel bicyclic fused γ-butyrolactone using [3,3]-sigmatropic rearrangement and acid-lactonization sequence as key transformation

Article abstract of DOI:10.1016/j.tetlet.2010.04.041

In this Letter, we wish to disclose a new strategy for the construction of substituted γ-butyrolactones. The latter might not only be of potential interest in terms of biological activity and synthesis but also allow access to original heterocyclic scaffolds. According to previous study, efficient two-step sequence involving Eschenmoser-Claisen rearrangement and acid-lactonization reaction was successfully applied for the construction of original fused bicyclic γ-butyrolactones based on an 1,4-oxazine core.

Full text of DOI:10.1016/j.tetlet.2010.04.041

Tetrahedron Letters 51 (2010) 3130–3133
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Access to novel bicyclic fused
c-butyrolactone using [3,3]-sigmatropic
rearrangement and acid-lactonization sequence as key transformation
*
Elise Claveau, Erwan Noirjean, Pascal Bouyssou, Gérard Coudert, Isabelle Gillaizeau
ICOA, UMR CNRS 6005, Université d’Orléans, rue de Chatres, 45067 Orléans Cedex 2, France
a r t i c l e i n f o
a b s t r a c t
Article history:
In this Letter, we wish to disclose a new strategy for the construction of substituted c-butyrolactones. The
Received 19 March 2010
Revised 7 April 2010
Accepted 9 April 2010
Available online 18 April 2010
latter might not only be of potential interest in terms of biological activity and synthesis but also allow
access to original heterocyclic scaffolds. According to previous study, efficient two-step sequence involv-
ing Eschenmoser–Claisen rearrangement and acid-lactonization reaction was successfully applied for the
construction of original fused bicyclic
c-butyrolactones based on an 1,4-oxazine core.
Ó 2010 Elsevier Ltd. All rights reserved.
A large number of natural products containing substituted
c
-
Taking into account previous study reported in the 1,4-benzox-
azine field,7d allylic alcohols 2 or 4 were then heated in xylenes in
the presence of N,N-dimethylacetamide dimethylacetal. According
to an Eschenmoser–Claisen rearrangement, the desired [3,3]-rear-
ranged products 3 or 5 were thus isolated in fair to good yields. As
butyrolactone fragments that have been isolated exhibit a broad
range of activity against different biological targets.1 The diversity
of their biogenetic origins suggests that this structure may be one
of the key elements in their biosynthesis.2 Therefore
c-butyrolac-
tones, in general, represent remarkable lead structures and have
attracted our interest for the development of new drug precur-
sors.3 Given this interest, we now report a novel methodology for
R3
O
R3
R
the construction of original fused bicyclic c-butyrolactones based
O
N
H+
O
on an 1,4-oxazine core. According to our previous investigation
O
NMe2
R3
concerning the easy functionalization of the 1,4-oxazine moiety,4
N
R2
R2
1 O
R1
R3
we have envisaged a new synthetic route to original bicyclic c-lac-
P
P
I
II
tone I (Scheme 1). This synthetic methodology relies on a Claisen-
type [3,3]-sigmatropic rearrangement5 from the corresponding
allylic alcohols III followed by an acidic lactonization sequence.
The interest of this approach lies in the possibility from this ori-
ginal dihydro-1H-furo[2,3-b]oxazinone I6a to easily accede to vari-
ous building blocks which could be used in the construction of core
skeletons by ring opening of the lactone (Fig. 1, pathway 1) or of
the oxazine ring (via ozonolysis for example) (pathway 2). Thus
according to the literature, the newly formed b-amino alcohols6b
could then for instance be transformed into original oxazoline
intermediates6c,d which generate an additional level of diversity.
For some time, we have been engaged in the synthesis and the
functionalization of new nitrogen-containing heterocyclic deriva-
tives.4,7 We therefore devised an original synthetic approach to
compounds 3 or 5 via an Eschenmoser–Claisen rearrangement
starting from adequate allylic alcohols 2 or 4, bearing an 1,4-oxa-
zine moiety (Table 1). As previously described,4 allylic alcohols (2
or 4) were prepared in good yields under anionic conditions from
the corresponding 3,5-disubstituted or non substituted 1,4-oxa-
zines 1a or 1b, respectively.
Eschenmoser
- Claisen
O
O
[3,3]
O
OH
NMe2
N
R1
N
P
N
R2
R1
R2
OCH3
OCH3
P
III
Scheme 1. Retrosynthetic pathway for the construction of fused bicyclic
c-
butyrolactones.
R3
O
OH
R1
R4
O
u
R3
O
N
N
P
R2
R3
pathway 1
O
O
pathway 2
N
P
R2
R1
R3
HO
O
O
O
O
*R4
O
N
HN
P
R1
R1
* Corresponding author.
E-mail address: Isabelle.Gillaizeau@univ-orleans.fr (I. Gillaizeau).
Figure 1. Easy access to various building blocks.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.04.041

E. Claveau et al. / Tetrahedron Letters 51 (2010) 3130–3133
3131
Table 1
Preparation of allylic alcohols 2 or 4 and Eschenmoser–Claisen rearrangement
R'
R
R'
R
O
O
N
OH
NMe2
NMe2
R
N
R
O
O
Boc
Boc
O
(i) n-BuLi
CH3C(OCH3)2N(CH3)2
xylenes, 140°C
2
3
O
(ii) R'CHO
-78°C
O
R
N
Boc
R
R'
N
N
1a (R=H)
1b
Boc R'
Boc OH
(R=H)
(R=H)
5
Entry
1
Allylic alcohols
Yields (%)
[3,3]-Rearranged productsb
Yields (%)
O
O
OH
2ab
(99)
3ad
(69)
NMe2
Ph
N
Boc
Ph
N
Ph
Ph
O
Boc
O
O
NMe2
O
OH
2bb
(85)
3bd
(56)
N
Boc
N
Boc
2
3
OCH3
H3CO
Ph
H3CO
Ph
OCH3
OH
O
O
2ca
(64)
3bd
(55)
NMe2
N
Boc
Ph
N
Ph
O
Boc
OH
O
O
2ca
(89)
3cd
(70)
4
NMe2
NMe2
Ph
Ph
Ph
N
Boc
N
Boc
Ph
Ph
Ph
Ph
O
O
HO
O
O
2da
(82)
3dd
(0)
5
6
Ph
N
Boc
N
Boc
O
O
OH
NMe2
2eb
(100)
3ed
N
Boc
N
Boc
O
(28)
Ph
Ph
Ph
Ph
O
O
OH
2fa
NMe2
3fd
7
8
(45)
(30)
N
Boc
N
Boc
O
Ph
Ph
O
Ph
O
Ph
NMe2
4c
(100)
5e
(37)
O
N
N
Boc
OH
Boc
Reagents and conditions: (a) (i) n-BuLi (1.5 equiv), HMPA (1.5 equiv), THF, ꢀ78 °C, 40 min. (ii) R0CHO (5 equiv), THF, ꢀ78 °C, 2 h. (b) (i) cf. Ref. 4d. (ii) NaBH4 (3 equiv), MeOH,
rt 10 min. (c) (i) n-BuLi (1.2 equiv), THF, ꢀ78 °C, 5 min. (ii) C4H9CHO (5 equiv), THF, ꢀ78 °C, 45 min. (d) CH3C(OCH3)2N(CH3)2 (10 equiv), xylenes, 140 °C, 45 min. (e)
CH3C(OCH3)2N(CH3)2 (10 equiv), xylenes, M.W., 140 °C, 40 min.
R'
O
O
a consequence, a novel quaternary carbon alpha to the nitrogen
atom was created. The Z configuration of the newly formed car-
bon–carbon double bond was demonstrated by NOE NMR experi-
ments.8 In all cases no traces of the E isomer could be detected.
This revealed that the rearrangement only proceeded via the steri-
cally less hindered six-membered ring transition state, where the
R0 substituent (Me, Pr) occupies the equatorial position (TS1,
Fig. 2). The rearrangement was found to be highly influenced by
the substitution on the allyl moiety. Lower yields were thus ob-
served in the case of bis-ethynyl compounds 3e and 3f (entries 5
and 6) because of decomposition process. It is noteworthy that this
Eschenmoser–Claisen rearrangement could also be performed in
O
O
Me2N
Me2N
R
R
R'
Boc
N
N
Boc
favored TS1
R
R
disfavored TS2
[3,3]
[3,3]
R'
O
O
R'
O
NMe2
NMe2
N
Boc
(E)-3
R
N
R
R
R
O
Boc
(Z)-3
Figure 2. Stereochemical model of the rearrangement.

3132
E. Claveau et al. / Tetrahedron Letters 51 (2010) 3130–3133
Table 2
Preparation of syn c-butyrolactones 6 via acidic cyclization sequence
R'
O
R'
R
O
O
TFA, DCM
rt
O
NMe2
N
Boc
R
N
Boc
R
R
O
3
6
Entry
1
[3,3]-Rearranged compounds
c
-Butyrolactones
Yields (%)
O
O
O
NMe2
O
Ph
N
Boc
6a
(70)
Ph
N
Boc
Ph
O
Ph
3a
3a
O
O
NMe2
O
O
O
N
Boc
N
Boc
6b
(45)
2
H3CO
MeO
Ph
OCH3
OMe
3b
3b
O
N
O
O
O
O
NMe2
6c
(52)
Ph
N
Boc
3
4
Ph
Ph
O
Boc
3c
3c
O
O
NMe2
O
N
Boc
N
Boc
O
6e
(20)
Ph
Ph
Ph
Ph
3e
3e
Reagents and conditions: (a) TFA (6 equiv), DCM, rt 10 min.
Yields are comparable with primary or secondary allylic alcohol.
+
H
Unfortunately, no rearrangement occurred starting from tertiary
allylic alcohol (compound 2d, entry 5) even by performing the
reaction under microwave activation. It should be pointed out that
one of the attractive features of our approach lies in its inherent
versatility since a wide range of aldehydes (R0CHO) could be used
in the first step. According to our previous methodology,4 diversity
onto R groups at C-3 and C-5 position of 1 can also be easily
envisaged.
+
O
O
O
O
O
O
+
N
CF3COOH
Ph
N
Boc
N
Ph
N
Boc
Ph
N
Boc
N
Ph
Ph
Ph
O
H2O
O
O
Ph
N
Boc
Ph
Given these results, our intent, therefore, was turned to synthe-
size original c-butyrolactones from alkylidene 3 (Table 2). In this
context, rearranged-compounds 3a, 3b, 3c, and 3e were submitted
Scheme 2. Proposed mechanism for acid-catalyzed formation of
syn.
c-butyrolactone
for short time to acidic conditions and afforded spontaneously in
good yields fused bicyclic c
-butyrolactones 6-syn.10
This outcome is consistent with the reaction mechanism
outlined in Scheme 2. Under acidic conditions, we anticipated the
formation of an oxonium ion which could undergo a nucleophilic
attack and afford an unstable iminium species which was subse-
quently hydrolyzed during workup.
It is noteworthy that with a longer acidic treatment at 0 °C, re-
moval of the Boc group occurred which afforded the original imine
7 isolated in good yields (Scheme 3).
O
N
Boc
6a
O
N
O
O
CF3COOH
O
O
CH2Cl2
0°C, 4h
(82%)
Ph
Ph
Ph
Ph
7
Scheme 3.
To sum up, we have developed a new and easy method that pro-
fair yield from compound 4 which bears the allylic alcohol function
at the C-3 position onto the oxazine ring (entry 7). In this case, best
yield was obtained under microwave activation.9 Under classical
heating, 5 was recovered in only 26% yield.
vides a useful tool for the synthesis of fused bicyclic c-butyrolac-
tones employing an efficient tandem Eschenmoser–Claisen
rearrangement and acid-lactonization sequence. In addition, it is
worth noting that the presence of different functional groups in

E. Claveau et al. / Tetrahedron Letters 51 (2010) 3130–3133
3133
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further structural modifications and suitable as intermediates for
various heterocyclic scaffolds. Access to various lactams, oxazo-
lines, and also to chiral c-butyrolactones could be easily envisaged.
A chiral N-substituted quaternary carbon center was also success-
fully created. Further studies and their applications to natural
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Experiments designed to explore the potentiality offered by this
original heterocyclic scaffold will be described in due course.
Acknowledgments
We are grateful to the CNRS and the Region Centre for their
financial support.
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Supplementary data
Supplementary data (experimental procedures and full spectro-
scopic data for all new compounds. Decomposition products were
formed for longer reaction time at room temperature) associated
with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2010.04.041.
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