Studies on the asymmetric Birch reductive alkylation to access spiroimines

Article abstract of DOI:10.1016/j.tetlet.2012.01.008

The asymmetric Birch reductive alkylation has been investigated to synthesize spiroimine analogs of the neurophycotoxin (-)-gymnodimine A 1. Two types of chiral aromatic substrates, an acyclic benzamide 2 and a benzoxazepinone 3 were studied. We found tha

Full text of DOI:10.1016/j.tetlet.2012.01.008

Tetrahedron Letters 53 (2012) 1370–1372
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Studies on the asymmetric Birch reductive alkylation to access spiroimines
⇑
⇑
Thierry Jousseaume, Pascal Retailleau, Laurent Chabaud , Catherine Guillou
Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS, 1 Avenue de la Terrasse, 91198 Gif-sur-Yvette, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The asymmetric Birch reductive alkylation has been investigated to synthesize spiroimine analogs of the
neurophycotoxin (À)-gymnodimine A 1. Two types of chiral aromatic substrates, an acyclic benzamide 2
and a benzoxazepinone 3 were studied. We found that the chiral auxiliary of benzoxazepinone could be
easily removed in a three step procedure to afford b-ketoester 14 that was converted into spiroimines 23–
24 possessing antagonist effects on nicotinic acetylcholine receptors (nAChRs).
Received 12 December 2011
Revised 3 January 2012
Accepted 4 January 2012
Available online 12 January 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric Birch reductive alkylation
Marine natural product
Quaternary center
Spiroimine
The asymmetric Birch reductive alkylation is a valuable method
for the formation of chiral cyclohexa-1,4-dienes with a stereogenic
quaternary carbon.1 The availability of benzoic acid derivatives and
the possibility to use a wide range of electrophiles bearing func-
tional groups resulted in several applications of this reaction in
the synthesis of natural products.1b,2 During the course of our
ongoing project on the synthesis of 6,6-spiroimine analogs of the
neurophycotoxin (À)-gymnodimine A 1 (Fig. 1),3 we therefore were
interested in the asymmetric Birch reductive alkylation of chiral
benzamides 2 and 3 to create the quaternary carbon of the spiro-
imine skeleton. This strategy complements the asymmetric allylic
alkylation approach recently reported by our group.3
We began our investigations with (S)-2-methoxymethylpyrroli-
dine-derived benzamide 2 and benzoxazepinone 3 which were
subjected to the Birch reduction under optimized conditions using
potassium (3 equiv) in a 10/1 mixture of liquid ammonia and THF
at À78 °C, in the presence of t-BuOH (1 equiv) (Table 1). The excess
of potassium was then quenched with piperylene followed by
addition of the electrophile bearing either an azido (entry 1) or a
protected alkoxy group (entries 2–4). When the electrophile
containing an acetate function was used, the crude mixture was di-
rectly treated with potassium carbonate in a mixture of THF/H2O to
afford the corresponding alcohols (entries 2 and 3). In these condi-
tions, chiral cyclohexadienes 4a–b and 5a–b were obtained in
excellent yields and diastereomeric ratios whatever the nature of
the aromatic amides 2 or 3 and the electrophiles.
Figure 1. Structure of (À)-gymnodimine A (1).
ods have been described to cleave the chiral amide of the Birch ad-
duct.1 The action of organometallic (MeLi)4 or reducing agents
(LiAlH4)5 were tested on substrate 4a, but led to degradation or
recovery of the starting material. Cleavage of the chiral auxiliary
under acidic conditions was then examined on azido amide 4a
(Scheme 1).6 Treatment of 4a with 6 N HCl in refluxing methanol
gave a 90/10 mixture of amide 6 and acid 7, as determined by 1H
NMR. Other acidic conditions (12 N HCl, 2 N H2SO4) or prolonged
reaction time did not improve the formation of acid 7 and led to
complete degradation. We thus decided to obtain acid 7 from iod-
olactone 8 prepared in quantitative yield by treatment of 6 with io-
dine in aqueous THF.7 Unfortunately, our attempts to fragment
iodolactone 8 in the presence of metal (Li/NH3 or Zn/EtOH) failed
to give acid 7.8
We next investigated a second strategy based on the cleavage of
the chiral auxiliary by lactonization (Scheme 2).9 This would give
spirolactone 9 that should be easily transformed into a spiroimine
analog. However, treatment of alcohol 4b with dry HCl (2 N in
Et2O) in toluene gave the enol ether 10. The same reaction con-
ducted with aqueous 2 N HCl in MeOH resulted in the degradation
of the starting material.
With compounds 4a–b and 5a–b in hand, we then turned our
attention to the cleavage of the chiral auxiliary. A number of meth-
⇑
Corresponding authors. Tel.: +33 (0) 1 69 82 30 75; fax: +33 (0) 1 69 07 72 47.
E-mail address: guillou@icsn.cnrs-gif.fr (C. Guillou).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.01.008

T. Jousseaume et al. / Tetrahedron Letters 53 (2012) 1370–1372
1371
Table 1
Asymmetric Birch reductive alkylation of benzamides 2 and 3
Scheme 3. Hydrolysis of benzoxazepinones 5a and 5b.
Entry
Substrate
Electrophile (R)
Product (R)
Yielda (%)
d.r.b
1
2
3
4
2
2
3
3
N3
4a (N3)
91
97/3
97/3
94/6
94/6
OAc
OAc
OBn
4b (OH)c
5a (OH)c
5b (OBn)
80d
91d
85
a
b
c
Isolated yield.
Determined by HPLC.
The hydroxyl group was obtained after treatment with K2CO3 in THF/H2O.
Yield after deprotection.
d
Scheme 1. Chiral auxiliary cleavage of benzamide 4a by iodolactonization.
The observed difficulties to remove the prolinol derivative of
benzamides 4a–b led us to examine benzoxazepinones 5a–b
(Scheme 3). Hydrolysis of the enol ethers 5a and 5b under acidic
conditions results in the formation of amide 11 which is in equilib-
rium with ester 12. Treatment of 5a by para-toluene sulfonic acid
in a mixture of toluene/water gave ketal 13 in 31% yield,10 which
Scheme 4. Elaboration of b-ketoester 14 into spiroimines 23–24.
structure and absolute configuration of 13 were confirmed by X-
ray analysis.11 Again, the formation of ketal 13 highlights the pro-
pensity of the alcohol to react onto the cyclic ketone to form a
fused bicycle instead of a spirocycle, as already observed in the re-
lated cyclization of alcohol 4b (Scheme 2).
To avoid the formation of ketal 13, we carried out the hydrolysis
on benzoxazepinone 5b (d.r. = 94/6) bearing the benzyloxy group
(Scheme 3). The enol ether of 5b was subjected to 6 N HCl in
Scheme 2. Attempt to cleave chiral auxiliary of 4b with HCl.

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T. Jousseaume et al. / Tetrahedron Letters 53 (2012) 1370–1372
key lactone intermediate 19 was finally obtained by treating 29
with DBU. Although the AAA is a shorter route to the common lac-
tone 19, it only allows the formation of 6,6-spiroimines. In con-
trast, the Birch reaction tolerates electrophiles with longer alkyl
chain and could be used for the synthesis of the 6,7-spiroimines
contained in spirolides and pinnatoxins.19
In conclusion, we have demonstrated that the asymmetric Birch
reductive alkylation is a valuable strategy to create the quaternary
carbon of spiroimine analogs of the neurotoxin gymnodimine A 1.
Although the acyclic amides 4a–b could not be converted into an
appropriate substrate for the synthesis of spiroimines, we have
shown that the chiral auxiliary of cyclic amide 5b bearing a pro-
tected alcohol could be easily removed in a three step sequence
to afford the b-ketoester 14 in good enantiomeric ratio. b-Ketoester
14 was a suitable intermediate to access spiroimine analogs 23–24
possessing a biological activity.3 In addition, our study highlights
the difficulties to remove the chiral auxiliary after the asymmetric
Birch reductive alkylation of benzamide derivatives. Thus, when
planning this reaction, particularly with benzamides bearing an
ortho-alkoxy group, the benzoxazepinones (i.e., 3) or related acy-
clic 2-(methoxymethoxymethyl)pyrrolidine benzamides2 should
be considered as a starting material to easily remove the chiral
auxiliary.
Acknowledgments
Scheme 5. Enantioselective synthesis of lactone 19 by AAA.
The authors thank the CNRS and ICSN for financial support, Pro-
fessor J.-Y. Lallemand for his interest in this work. We thank Pro-
fessor Y. Landais, Dr. V. Desvergnes (ISM, University of Bordeaux)
and Dr. J. Molgó (NBCM, Gif-sur-Yvette) for fruitful discussions.
We also thank Elvina Barre for technical assistance with preparing
starting materials.
refluxing methanol and the resulting ammonium 12 transformed
into a methyl carbamate. Methanolysis in presence of cesium car-
bonate afforded the methyl ester 14. Interestingly, this three step
sequence gave b-ketoester 14 in a 65% yield (e.r. = 92/8),12 without
the need for temporary protection of the cyclic ketone.13
With a reliable synthesis of b-ketoester 14 in hand, we then
turned to its transformation into the bioactive spiroimine analogs
23–24 possessing an antagonist effect on nAChRs (Scheme 4).3
Chemoselective hydrogenation of the double bond of 14 with
Crabtree’s catalyst gave the saturated ketone 15 in almost quanti-
tave yield.14 The benzyloxy ether of 15 was oxidized in the pres-
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