Short total synthesis of (-)-kainic acid

Article abstract of DOI:10.1021/ol5009526

A short total synthesis of (-)-kainic acid has been developed involving a novel diastereofacial differentiating Cu-catalyzed Michael addition-cyclization reaction, which provided access to a chiral pyrroline in a highly stereoselective manner. The chiral pyrroline was converted to (-)-kainic acid via the stereoselective 1,4-reduction of the pyrroline double bond in three steps.

Full text of DOI:10.1021/ol5009526

Letter
pubs.acs.org/OrgLett
Short Total Synthesis of (−)-Kainic Acid
Kentaro Oe, Yasufumi Ohfune, and Tetsuro Shinada*
Graduate School of Science, Osaka City University, Sugimoto, Sumiyoshi, Osaka 558-8585, Japan
S
* Supporting Information
ABSTRACT: A short total synthesis of (−)-kainic acid has been developed involving a novel diastereofacial differentiating Cu-
catalyzed Michael addition−cyclization reaction, which provided access to a chiral pyrroline in a highly stereoselective manner.
The chiral pyrroline was converted to (−)-kainic acid via the stereoselective 1,4-reduction of the pyrroline double bond in three
steps.
ainic acid (1), the parent member of the kainoid family,
was first isolated in 1953 from the marine alga Digenea
and more than 35 total syntheses of 1 have been reported in the
literature.5,6 Several short, efficient, and practical syntheses of 1
have been achieved.6i,7
We have recently reported an efficient total synthesis of
manzacidin B8 via the stereoselective aldol addition reaction of
an optically active isonitrile 4 bearing Oppolzer’s camphorsul-
tam chiral auxiliary9 and the aldehyde 5 bearing a quarternary
amino carbon center (Scheme 1). In this synthesis, we used a
K
simplex by Takemoto et al. (Figure 1).1 Kainoids such as 1 and
Scheme 1. Total Synthesis of Manzacidin B (8) via Cu-
Catalyzed Aldol Reaction
Figure 1. Structure of two kainoids and glutamic acid.
2 have been reported to behave as agonists toward kainate
receptors which are ionotropic glutamate receptors and exert
potent excitatory neurotoxicity in the mammalian central
nervous system.2,3 Compounds belonging in this class are
useful tools for investigation of the role of kainate receptors in
excitatory neurotransmission, as well as inducing neuro-
degeneration with the aim of exploring the pathogenesis of
excitotoxicity in neurodegenerative disorders of the central
nervous system.2−4
Structurally, the kainoid core consists of a pyrrolidine ring
with three contiguous stereogenic centers at C2, C3, and C4 as
a core skeleton. The characteristic structural features and
biological activities of kainoids have elicited significant interest
from researchers in many areas of chemistry, including organic
chemistry, natural product chemistry, chemical biology, and
pharmaceutical chemistry.5
Kainoids have inspired many synthetic investigations toward
the stereoselective synthesis of their pyrrolidine core, which
plays a crucial role in the binding affinity of these compounds
and their derivatives to the kainate receptors.2a,5 Various
original synthetic methods have consequently been developed
for construction of the pyrrolidine ring in this context and
applied to the total synthesis of kainoids. Among them, the
total synthesis of kainic acid (1) has been studied extensively,
new and mild Cu catalyst 6 to promote the key reaction, which
allowed for the stereoselective synthesis of 7 in high yield. A
scalable total synthesis of manzacidin B (8) on a 600 mg scale
was achieved by taking advantage of this Cu-catalyzed aldol
reaction.
In terms of our synthetic strategy, it was envisioned that an
efficient total synthesis of 1 could be achieved by the Cu-
catalyzed tandem Michael addition−cyclization reaction of
Received: March 31, 2014
Published: April 17, 2014
© 2014 American Chemical Society
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Letter
chiral isonitrile 9 with α,β-unsaturated ketone 10. This key
reaction would provide access to the chiral 2,3-disubstituted
pyrroline 11, bearing similar functionalities to those of 1, which
could be transformed into 1 in just a few short steps (Scheme
2).10
yield (eq 1). The relative and absolute stereochemistries were
confirmed by X-ray analysis of 16 (see Supporting Information
(SI)). In contrast, the application of the same reaction
conditions to methyl crotonate (14) resulted in no reaction
(eq 2). Crotonaldehyde (15) gave 18 in 50% yield together
with the aldol product in 23% yield (eq 3). These results
indicated that the Cu catalyzed reaction system exhibits a
unique mode of reactivity, in that (i) nucleophilic addition to β-
substituted α,β-unsaturated esters occurred at a much slower
rate than it did to β-substituted α,β-unsaturated aldehydes and
(ii) the Michael addition−cyclization reaction was preferred to
the aldol addition reaction.
Scheme 2. Synthetic Strategy for the Short Synthesis of
Kainic Acid (1)
We next investigated the key reaction described in our
synthetic strategy and prepared the Michael reaction acceptor
10 on a large scale (18 g) from sorbic acid (19) in five steps
(Scheme 4). Sorbic acid (19) was converted to epoxide 21 via
Scheme 4. Synthesis of the Michael Addition Reaction
Acceptor 10
The use of a Michael addition−cyclization reaction for the
synthesis of substituted pyrrolines was first reported by Ito et
al.10,11 Grigg et al. later employed a Ag(I) catalyst to promote
this transformation.12 Although several catalytic asymmetric
versions of this process have been developed and reported in
the literature,13 these have not been developed to the extent
that would allow us to overcome the challenges associated with
our current synthetic goal. For example, the applicability of
these methods to chiral isonitriles has not yet been examined.
Reports pertaining to the use of Michael reaction acceptors
such as β-alkyl substituted α,β-unsaturated enone 10 for the
synthesis of pyrrolidine are rare, likely because of their poor
reactivities. Enone 10 has two possible electrophilic sites, and
very little work has been conducted with regard to examining
the regioselectivity (i.e., aldol reaction vs the Michael addition
reaction) of this reaction toward substrates of this nature.10−13
To assess the reactivity of 9 toward Michael acceptors, we
conducted a series of model reactions using dimethyl maleate
(13) (Scheme 3), methyl crotonate (14), and crotonaldehyde
(15). Dimethyl maleate (13) reacted smoothly with 9 in the
presence of Cu catalyst 6 and triethylamine to give 16 in 77%
tert-butyl ester 20 in three steps. The reductive ring-opening
reaction of 21 gave deconjugated ester 22 in 74% yield which
was oxidized with PDC to give an inseparable 3:2 mixture of
conjugated ketone 10 and ester 23.
The use of this mixture in the next key reaction potentially
gave rise to three possible products, including two aldol
products from 10 and 23, and a pyrroline product from ester
23. It was envisaged, however, that the desired reaction to
provide 11 would be a major reaction pathway of the three
possibilities listed above because of the characteristic reactivity
displayed in the model study in Scheme 3. Furthermore, it was
envisaged that the addition reaction of the chiral isonitrile 9 to
ketone 10 would be slower than the addition reaction of 9 to
the less sterically hindered aldehyde 15.
Scheme 3. Michael Addition Cyclization Reaction with 9
The mixture of 10 and 23 was subjected to the key reaction
with 9 in the presence of triethylamine and the Cu catalyst 6
(Scheme 5; see also Table SI-1). Disappointingly, the reaction
only afforded a trace amount of 11 (entry 1). Use of the
stronger bases 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and
1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) led to a slight
improvement in the yield (entries 2 and 3). After extensive
experimentation, it was established that the reaction performed
most effectively when it was conducted in the presence of the
Cu catalyst 6 without any base.14 When 1 equiv of the mixture
10 and 23 was employed under these conditions, compound 11
was obtained in 24% yield (entry 4). The product yield was
improved to 54% using 2 equiv of the regioisomeric mixture
(entry 5). Although the reaction conditions that are currently
used as a standard protocol gave 11 in 54% yield, the synthetic
process could be scaled-up to the 4 g scale without any
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a
more stable 3,4-trans-product 33 was always isolated as the
major product (Table SI-2).15 To overcome this issue, we
adopted a challenging approach of using the carboxylic acid
moiety as a directing group for the proton donor.16 Of the
various reduction conditions tested (Table SI-3),17 the
stereoselective process was achieved by treatment with L-
Selectride (6 equiv) in THF followed by acidification with 1 N
HCl.18 This process was also found to be amenable to scale up
and was conducted on a gram scale. After the esterification
reaction, cis-35 was obtained in 77% yield in a highly
stereoselective manner (1:25). The application of the same
reaction conditions to methyl ester 31 gave trans-33 as the
major product (3:1). These results indicated that the carboxylic
acid moiety played an important role in the reaction as a
directing group. We also found that the nature of the
protonation reagent and the presence of water had a significant
impact on the selectivity of the reaction (i.e., 1 N HCl (33:35 =
1:25), AcOH (33:35 = 4:1), H2O (33:35 = 1:2.4); see also
Table SI-4). Based on these results, we have proposed a
reaction mechanism for the trasformation, which is depicted in
Scheme 7. The chelation of a water molecule to the carboxylate
would contribute to the protonation on the upper face to give
cis-34.
Scheme 5. Synthesis of Chiral Pyrroline 11
a
4.25 g scale.
discernible loss in selectivity. During the course of this study,
we found that the ratio of 10 and 23 was always maintained at
3:2. This consistency in the ratio was attributed to the
occurrence of a rapid olefin isomerization process between 10
and 23, which allowed for the α,β-unsaturated ketone 10 to be
effectively recovered and recycled.
Scheme 7. Total Synthesis of Kainic Acid (1) via
Stereoselective Reduction of Pyrrolines
To develop a deeper understanding of the reaction
mechanism, we employed isocyanoacetate 26 as a substrate
for the reaction. In contrast to the reaction of 9 with a mixture
of 10 and 23, the reaction of 26 with the same mixture gave
aldol adduct 27 as the major product (Scheme 6, eq 4). Grigg
Scheme 6. Comparable Experiments
et al. reported the facile Ag-catalyzed Michael addition−
cyclization reaction of methyl isocyanoacetate with methyl
acrylate (29) to provide the corresponding pyrroline
derivative.12 With this in mind, the same Ag catalyst was
used for the reaction of 9 and 29, where it facilitated the self-
cyclization of 9 to give oxazole 30 (eq 5). These results
indicated that the combination of the sultam auxiliary with the
Cu catalyst 6 was critical to the success of the key reaction.
We then investigated the stereoselective reduction of the
CC double bond of the pyrrolidine 11 to allow for the
introduction of 3,4-cis stereogenic centers. The sultam auxiliary
of 11 was initially removed because the sultam had an adverse
impact on the downstream transformations. Treatment of 11
with sodium methoxide followed by the protection with Boc2O
gave 31. Although a variety of different reaction conditions
were evaluated for the reduction of 31, the thermodynamically
Ketone 35 has been reported to readily epimerize to more
stable trans-33 under the basic reaction conditions.19 Fukuyama
et al. recently reported a mild olefination reaction using the
Nozaki reagent; it occurred without any epimerization.20 Our
application of the same conditions to 35 afforded 36 in 74%
yield. Subsequent deprotection of 36 completed the total
synthesis of (−)-kainic acid (1). Our analytical data for the
synthetic kainic acid (1) were found to be identical in all
respects with those reported in the literature for the authentic
material.7a
In summary, we have developed an efficient nine step
procedure for the total synthesis of (−)-kainic acid. The total
synthesis was conducted on a 300 mg scale in 16.8% overall
yield from the chiral isonitrile 9. The application of this
synthetic strategy to the synthesis of a range of other kainoid
analogues is currently being investigated in our laboratory, as
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Letter
well as the use of these compounds in chemical biology21 as
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ASSOCIATED CONTENT
* Supporting Information
Detailed experimental procedures, spectroscopic data, copies of
1H and 13C NMR spectra, and X-ray structure of 16. This
material is available free of charge via the Internet http://pubs.
acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: shinada@sci.osaka-cu.ac.jp.
Notes
The authors declare no competing financial interest.
(14) See SI.
ACKNOWLEDGMENTS
■
(15) Pd/C, H2; Pd(OH)2/C, H2; Rh/Al2O3, H2; L-Selectride; and
CoCl2−6H2O, NaBH4 were tested. See SI.
This work was financially supported by the Yamada Science
Foundation (Scientific Research of Innovative Areas, Chemical
Biology of Natural Products), the Ministry of Education,
Culture, Sports, Science and Technology (MEXT) (No.
23102009), and the Japan Society for the Promotion of
Science (KAKENHI) (Nos. 23228001, 25282233).
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127. (d) Thompson, H. W.; Wong, J. K. J. Org. Chem. 1985, 50, 4270−
4276.
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