Total synthesis of (-)-(α)-kainic acid via a diastereoselective intramolecular [3 + 2] cycloaddition reaction of an aryl cyclopropyl ketone with an alkyne

Article abstract of DOI:10.1021/ol3008414

An enantioselective synthesis of (-)-(α)-kainic acid in 15 steps with an overall yield of 24% is reported. The pyrrolidine kainoid precursor with the required C2/C3 trans stereochemistry was prepared with complete diastereoselectivity via an unprecedented SmI₂-catalyzed intramolecular [3 + 2] cycloaddition reaction of an aryl cyclopropyl ketone and an alkyne. Double bond isomerization was then employed to set the remaining stereochemistry at the C4 position en route to (-)-(α)-kainic acid.

Full text of DOI:10.1021/ol3008414

ORGANIC
LETTERS
2012
Vol. 14, No. 10
2540–2543
Total Synthesis of (ꢀ)-(r)-Kainic Acid
via a Diastereoselective Intramolecular
[3 þ 2] Cycloaddition Reaction of an
Aryl Cyclopropyl Ketone with an Alkyne
Zhi Luo, Bing Zhou,* and Yuanchao Li*
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Road Zu
Chong Zhi, Zhangjiang Hi-Tech Park, Shanghai 201203, P.R. China
zhoubing2012@hotmail.com; ycli@mail.shcnc.ac.cn
Received April 3, 2012
ABSTRACT
An enantioselective synthesis of (ꢀ)-(R)-kainic acid in 15 steps with an overall yield of 24% is reported. The pyrrolidine kainoid precursor with the
required C2/C3 trans stereochemistry was prepared with complete diastereoselectivity via an unprecedented SmI2-catalyzed intramolecular [3 þ 2]
cycloaddition reaction of an aryl cyclopropyl ketone and an alkyne. Double bond isomerization was then employed to set the remaining
stereochemistry at the C4 position en route to (ꢀ)-(R)-kainic acid.
Kainoids are an important class of natural nonprotein-
ogenic amino acids which have a common characteristic
structure consisting of a pyrrolidine nucleus with two
carboxylic groups. They also display potent anthelmintic
properties1 and neurotransmitting activities2 in the mam-
malian central nervous system. In particular, (ꢀ)-R-kainic
acid (1) (Figure 1), the parent member of the kainoid
family,3 isolated in 1953 from the Japanese marine alga
Digenea simplex,4 has been widely used as a tool in
neuropharmacology5 for simulating central nervous sys-
tem (CNS) disorders, such as epilepsy,6 Alzheimer’s dis-
ease, and Huntington’s chorea.7 Due to its importance in
neuroscience, a limited supply from natural resources,8
and the synthetic challenge posed by a highly functiona-
lized trisubstituted pyrrolidine ring with three contiguous
chiral centers, the synthesis of (ꢀ)-R-kainic acid has re-
ceived considerable attention, and several total syntheses
and synthetic approaches9 have been reported. Herein, we
describe an efficient synthetic route to 1, featuring an
(1) Nitta, I.; Watase, H.; Tomiie, Y. Nature (London) 1958, 181, 761.
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Hoo, K. H.; Tizzano, J. P.; Pullar, I. A.; Farrell, L. N.; Bleakman, D.
J. Med. Chem. 1996, 39, 3617.
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M. G. Nat. Prod. Rep. 1999, 16, 485. (c) Maloney, M. G. Nat. Prod. Rep.
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Figure 1
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Tool in Neurogiology; Raven: New York, 1978.
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r
10.1021/ol3008414
Published on Web 05/03/2012
2012 American Chemical Society

intramolecular [3 þ 2] cycloaddition reaction of an aryl
cyclopropyl ketone with an alkyne for the stereoselective
construction of the functionalized pyrrolidine ring.
utilized “donorꢀacceptor” cyclopropanes,10 or methylene
cyclopropanes.11 Moreover, cyclopropyl ketyl radicals
have most commonly been exploited for their propensity
to undergo reductive fragmentations12 and have not been
examined as intermediates in [3 þ 2] cycloaddition reac-
tions except for a few intermolecular examples catalyzed
by Ni0 complexes13 and particularly scarce intramolecular
examples catalyzed by Ru(bpy)3 with visible light.14
Scheme 1. Synthetic Strategy for (ꢀ)-R-Kainic Acid (1)
Scheme 2. Synthesis of Precursor 4
Our synthetic strategy is outlined in Scheme 1. We
planned to introduce the isopropylidene fragment through
an olefination of the ketone 2. This disconnection would
also enable easy access to domoic acid as well, through use
of a different olefination reagent. Ketone intermediate 2
could be formed by oxidative cleavage of the bicyclic
compound 3 which could beobtained by anintramolecular
radical [3 þ 2] cycloaddition of aryl cyclopropyl ketones 4,
installing the cis C3ꢀC4 side chains of kainic acid, with the
trans C2ꢀC3 relationship induced by a bulky TBS ether.
The cyclization substrate 4 could be derived from commer-
cially available D-serine methyl ester hydrochloride 5.
It was obvious that success of the plan would primarily
hinge on whether the intramolecular radical [3 þ 2]
cycloaddition of aryl cyclopropyl ketones 4 could proceed
satisfactorily with good diasteroselectivity. It was feared,
however, and with some foundation, that most [3 þ 2]
cycloadditions of cyclopropanes reported to date have
D-Serine methyl ester hydrochloride 5 was converted in
87% yield into N-tosyl methyl ester derivative 6,15 which
was reduced with DIBAL-H to the corresponding alde-
hyde. A Wittig olefination16 provided the enone 7 in 94%
yield (two steps from 6) (Scheme 2). Cyclopropanation of 7
with Me3SOI followed by N-alkylation with 1-bromo-2-
butyne delivered the key precursor 4 as a 1.2:1 mixture of
diastereomers in 79% yield over two steps.
With the precursor 4 in hand, we then investigated the
key annulation reaction (Table 1). We began our investi-
gation by opening cyclopropanes with [Ni(cod)2] and a
variety of Lewis acids (entries 1ꢀ4).13 Unfortunately, we
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Org. Lett., Vol. 14, No. 10, 2012
2541

observed no evidence of ring opening for 4. We then
screened visible light photocatalyzed [3 þ 2] cycloadditions
by formation of anion radicals (entry 5).14 However,
visible light photocatalysis failed to promote the desired
cycloaddition. We speculated that weak visible light photo-
catalysis might not activate the cyclopropyl ketone toward a
one-electron reduction or could not stabilize the ketyl radical
intermediate. In an attempt to increase the reduction poten-
tial of the reagent, we turned to using SmI217 as a one-electron
reducing agent. To our delight, substrate 4 indeed underwent
cycloaddition with SmI2 and HMPA to afford products 8a
and 8b in 50% yield with a ratio of 4:1 (entry 6). More
importantly, complete C2/C3 trans stereochemistry was ob-
served in this annulation reaction. A higher yield (81%) and
excellent diastereoselectivity (8a:8b = 12:1) were obtained
when the reaction proceeded in the absence of HMPA
(entry 7). Remarkably, the stereoselectivity of this cycliza-
tion was substrate-controlled and formed the desired iso-
mer at the C-3 center. The two diastereomers of compound
4 showed almost the same reactivity for this annulation
reaction. Attempts to perform the reaction at lower tem-
perature resulted in a decrease in yield (entry 8). The
mechanism we envision for the [3 þ 2] cycloaddition
reaction involves initial formation of the ketyl radical A,
followed by rapid cleavage of the cyclopropyl ring (Scheme 3).
Sequential radical cyclizations might then give rise to cyclized
ketyl radical D, with the trans C2ꢀC3 relationship induced by
the bulky TBS ether. Loss of an electron would produce 8a
and 8b as the products of the formal intramolecular [3 þ 2]
cycloaddition of 4. The relative configuration of 8a and 8b was
confirmed by NOE experiment.
Scheme 3. Proposed Mechanism for the [3 þ 2] Cycloaddition
Reaction of Aryl Cyclopropyl Ketone 4
Scheme 4. Synthesis of (ꢀ)-Kainic Acid 1
with DBU isomerized the double bond to afford the expected
bicyclic enone 3 in 95% yield (Scheme 4). Ozone oxidation of
the bicyclic enone 3, followed by oxidative cleavage of the
resulting diketone group with basic hydrogen peroxide in a
biphasic medium (2 M aqueous NaOHꢀH2O2 in dioxane,
10 min, 0 °C), and subsequent protection of the resulting
carboxylic group provided the key intermediate 2in 78% yield
over three steps. Treatment of methylketone 2 with Tebbe’s
reagent18 gave the olefin 9 in 72% yield. No epimerization
occurred in the buildup of the propenyl group. One-pot de-
protection and Jones oxidation of the TBS ether provided the
corresponding carboxylic acid.19 Ester hydrolysis followed by
tosyl deprotection using Birch conditions afforded (ꢀ)-kainic
acid 1([R]20D ꢀ14.5 (c0.11, H2O), natural (ꢀ)-(R)-kainic acid
[R]23D ꢀ14.6 (c 0.9, H2O)) in 83% yield over three steps.
In summary, we have successfully synthesized (ꢀ)-(R)-
kainic acid in enantiopure form in 15 linear steps from
inexpensive D-serine methyl ester hydrochloride, using
Table 1. Screening the Intramolecular [3 þ 2] Cycloaddition
Reaction of Aryl Cyclopropyl Ketone 4
yield
(%)c
entry
conditions
8a:8bd
1a
2a
3a
4a
[Ni(cod)2], Me2AlOTf, THF, 50 °C
[Ni(cod)2], Me2AlCl, THF, 50 °C
[Ni(cod)2], Me3Al, THF, 50 °C
[Ni(cod)2], Ti(O-t-Bu)4,
tBuOK, PhMe, 90 °C
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
5b
6
Ru(bpy)3Cl2, La(OTf)3,
ꢀ
ꢀ
TMEDA, MeCN, rt
SmI2 (2.5 equiv), HMPA (2.5 equiv),
THF, rt
50
4:1
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7
8
SmI2 (2.5 equiv), THF, rt
SmI2 (2.5 equiv), THF, 0 °C
81
13
12:1
14:1
a The reactionwasperformed with0.1equivof[Ni(cod)2] and 1 equiv of
Lewis acid. b Subjected to irradiation with a 23 W compact fluorescent bulb.
c Isolated yields of 8a and 8b. d Determined by 1H NMR prior to workup.
With the key intermediates 8a and 8b in hand, removal of
the aryl ketone was next addressed. Treatment of 8a and 8b
2542
Org. Lett., Vol. 14, No. 10, 2012

an intramolecular [3 þ 2] cycloaddition reaction of an aryl
cyclopropyl ketone with an alkyne. To the best of our
knowledge, this is the first example of a SmI2 catalyzed
[3 þ 2] cycloaddition reaction of an aryl cyclopropyl ketone
with an alkyne with excellent diastereoselectivity.
Acknowledgment. This work was supported by Na-
tional Science & Technology Major Project “Key New
Drug Creation and Manufacturing Program”, China
(Number: 2009ZX09102-026).
Supporting Information Available. Experimental pro-
cedures and compound characterization. This material
is available free of charge via the Internet at http://pubs.
acs.org.
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The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 10, 2012
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