Total synthesis of (+/-)-kainic Acid with an aza-[2,3]-Wittig sigmatropic rearrangement as the key stereochemical determining step.

Article abstract of DOI:10.1021/jo030101q

A flexible route to the kainoid skeleton is exemplified by the synthesis of (+/-)-kainic acid from 3-butyn-1-ol. The route relies on the aza-[2,3]-Wittig sigmatropic rearrangement to efficiently install the relative stereochemistry between C2-C3. The C4 s

Full text of DOI:10.1021/jo030101q

Tota l Syn th esis of (()-Ka in ic Acid w ith a n Aza -[2,3]-Wittig
Sigm a tr op ic Rea r r a n gem en t a s th e Key Ster eoch em ica l
Deter m in in g Step
J ames C. Anderson* and Matthew Whiting
School of Chemistry, University of Nottingham, Nottingham, NG7 2RD, UK
j.anderson@nottingham.ac.uk
Received March 18, 2003
A flexible route to the kainoid skeleton is exemplified by the synthesis of (()-kainic acid from
3-butyn-1-ol. The route relies on the aza-[2,3]-Wittig sigmatropic rearrangement to efficiently install
the relative stereochemistry between C2-C3. The C4 stereocenter was derived from a diastereo-
controlled iodolactonization. The aza-[2,3]-Wittig rearrangement potentially allows structural
diversity at C3 and the displacement of the tosyloxy group with retention of stereochemistry allows
structural diversity at C4. The trans-C2 carboxylic acid functional group was found to be the most
important for retention of stereochemistry at C4 upon treatment with a higher order cyano cuprate
reagent.
In tr od u ction
related members of the kainic acid family. To the best of
our knowledge kainic acid itself has not been synthesized
by this route. In this paper we show the use of the aza-
[2,3]-Wittig rearrangement in deriving the initial stere-
ochemistry needed for the stereocontrolled synthesis of
an advanced tosyloxy intermediate 5 (Scheme 1) and its
conversion to (()-kainic acid.
The stereochemical determination step would be de-
rived from aza-[2,3]-Wittig rearrangement of achiral 2,
giving the desired trans stereochemistry according to our
transition state model and previous work.8 By analogy
The kainoid amino acids are a group of nonproteino-
genic pyrrolidine dicarboxylic acids of which (-)-kainic
acid (1) is the parent member. The kainoids exhibit a
wide variety of biological properties and have been used
as insecticides, anthelmintic (anti-intestinal worm) agents,
and most prominently neuroexcitatory agents. Their
potent neuroexcitatory activity, which leads to specific
neuronal death in the brain, is attributed to their action
as conformationally restricted analogues of the neu-
rotransmitter glutamic acid. The nature and stereochem-
istry of the unsaturated C4 substituent plays a crucial
role in binding and functional activation at the active
site.1 Interest in the development of these types of
molecules as neuroprotective therapeutics2 and pesti-
cides3 demands new, flexible methods for their synthesis.
There is also great interest in the synthesis of kainic acid
derivatives as some have been shown to be more potent
than the natural molecules themselves.4 There have been
numerous asymmetric5 and racemic6 syntheses of kainic
acid over the past 20 years. However, very few of these
allow the convergent synthesis of a wide range of differ-
ent kainoids through a late-stage common intermediate.
The introduction of C4 substituents by displacement of
trans-4-tosyloxy-L-prolines, with retention of stereochem-
istry, has been reported.7 This strategy was applied to
the synthesis of C4 acromelic acid congeners,4 which are
(5) (a) Oppolzer, W.; Thirring, K. J . Am. Chem. Soc. 1982, 104, 4978.
(b) Cooper, J .; Knight, D. W.; Gallagher, P. T. J . Chem. Soc., Chem.
Commun. 1987, 1220. (c) Cooper, J .; Knight, D. W.; Gallagher, P. T.
J . Chem. Soc., Perkin Trans. 1 1992, 553. (d) Baldwin, J . E.; Li, C.-S.
J . Chem. Soc., Chem. Commun. 1987, 166. (e) Baldwin, J . E.; Moloney,
M. G.; Parsons, A. F. Tetrahedron 1990, 46, 7263. (f) Takano, S.;
Iwabuchi, Y.; Ogasawara, K. J . Chem. Soc., Chem. Commun. 1988,
1204. (g) Takano, S.; Sugihara, T.; Satoh, S.; Ogasawara, K. J . Am.
Chem. Soc. 1988, 110, 6467. (h) J eong, N.; Yoo, S.-E.; Lee, S. J .; Lee,
S. H.; Chung, Y. K. Tetrahedron Lett. 1991, 32, 2137. (i) Yoo, S.-E.;
Lee, S.-H.; J eong, N.; Cho, I. Tetrahedron Lett. 1993, 34, 3435. (j) Yoo,
S.-E.; Lee, S.-H. J . Org. Chem. 1994, 59, 6968. (k) Takano, S.; Inomata,
K.; Ogasawara, K. J . Chem. Soc., Chem. Commun. 1992, 169. (l) Barco,
A.; Benetti, S.; Pollini, G. P.; Spalluto, G.; Zanirato, V. J . Chem. Soc.,
Chem. Commun. 1991, 390. (m) Hatakeyama, S.; Sugawara, K.;
Takano, S. J . Chem. Soc., Chem. Commun. 1993, 125. (n) Hanessian,
S.; Ninkovic, S. J . Org. Chem. 1996, 61, 5418. (o) Nakada, Y.; Sugahara,
T.; Ogasawara, K. Tetrahedron Lett. 1997, 38, 857. (p) Bachi, M. D.;
Melman, A. J . Org. Chem. 1997, 62, 1896. (q) Miyata, O.; Ozawa, Y.;
Ninomiya, I.; Naito, T. Synlett 1997, 275. (r) Rubio, A.; Ezquerra, J .;
Escribano, A.; Remuin˜a´n, M. J .; Vaquero, J . J . Tetrahedron Lett. 1998,
39, 2171. (s) Cossy, J .; Cases, M.; Pardo, D. G. Tetrahedron 1999, 55,
6153. (t) Campbell, A. D.; Raynham, T. M.; Taylor, R. J . K. Chem.
Commun. 1999, 245. (u) Kakagawa, H.; Sugahara, T.; Ogasawara, K.
Org. Lett. 2000, 2, 3181. (v) Campbell, A. D.; Raynham, T. M.; Taylor,
R. J . K. J . Chem. Soc., Perkin Trans. 1 2000, 3194. (w) Miyata, O.;
Ozawa, Y.; Ninomiya, I.; Naito, T. Tetrahedron 2000, 56, 6199. (x) Xia,
Q.; Ganem, B. Org. Lett. 2001, 3, 485. (y) Clayden, J .; Menet, C. J .;
Tchabanenko, K. Tetrahedron 2002, 58, 4727.
(1) (a) Husinec, S.; Porter, A. E. A.; Roberts, J . S.; Strachan, C. H.
J . Chem. Soc., Perkin Trans.
1 1984, 2517. (b) Hansen, J . J .;
Krogsgaard-Larsen, P. Med. Res. Rev. 1990, 10, 55. (c) Hashimoto, K.;
Horikawa, M.; Ishida, M.; Shinozaki, H.; Shirakama, H. Bioorg. Med.
Chem. Lett. 1992, 2, 743. (d) Horikawa, M.; Shirakama, H. Synlett
1996, 95.
(2) Hansen, J . J .; Krogsgaard-Larsen, P. Med. Res. Rev. 1990, 10,
55.
(3) Maeda, M.; Kodama, T.; Saito, M.; Tanaka, T.; Yoshizumi, H.;
Nomoto, K.; Fujita, T. Pestic. Biochem. Physiol. 1987, 28, 85.
(4) Hashimoto, K.; Shirahama, H. Tetrahedron Lett. 1991, 32, 2625.
(6) (a) Monn, J . A.; Valli, M. J . J . Org. Chem. 1994, 59, 2773. (b)
Yoo, S.-E.; Lee, S.-H.; Yo, K.-Y.; J eong, N. Tetrahedron Lett. 1990, 31,
6877. (c) Clayden, J .; Tchabanenko, K. Chem. Commun. 2000, 317.
(7) Thottathil, J . K.; Moniot, J . L. Tetrahedron Lett. 1986, 27, 151.
10.1021/jo030101q CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/27/2003
6160
J . Org. Chem. 2003, 68, 6160-6163

Total Synthesis of (()-Kainic Acid
SCHEME 1. Syn th etic P la n
tert-butyldimethylsilyl group is normally stable to metal
hydride reagents, it is cleaved by DIBAL at room tem-
perature.12 We did investigate the use of the bulky
triisopropylsilyl group,13 and although this withstood the
harsh hydroalumination conditions, it proved problematic
in the protodesilylation of the aza-[2,3]-Wittig product 2
later on in the synthesis. We decided to use the tert-butyl
ether as a protecting group as it is robust, cheaply
attached with use of isobutene, and removed under a
variety of mild conditions.14 Protection of 6 as its t-Bu
ether15 followed by deprotonation of the terminal alkyne
and quenching with chlorodimethylphenylsilane gave
fully protected 7 in 82% yield over two steps (Scheme 2).
Regio- and stereospecific hydroalumination of the alkyne,
treatment with MeLi to form the ate complex, and
quenching with paraformaldehyde16 gave the allylic
alcohol, which was readily converted to bromide 8 in 75%
yield over two steps. The rearrangement precursor was
then completed by coupling 8 with the potassium anion
of N-Bocglycine N,N-dimethylamide to give 9 in 91%
yield. The aza-[2,3]-Wittig rearrangement was induced
by using LDA (1.4 equiv) at -78 °C with warming to 0
°C for 2 h to give the pivotal unnatural amino acid
SCHEME 2a
1
derivative 3 (P ) t-Bu) in 78% yield. The crude H NMR
revealed only one rearranged product although a small
amount (0.6%) of the minor diastereoisomer was isolated
after column chromatography. We were confident at this
stage that the sense of diastereoselection would be
identical with simpler analogues which had been proved
by single-crystal X-ray crystallography and was therefore
assigned anti as drawn (Scheme 2).8,11 This assignment
was later verified by conversion to (()-kainic acid (1).
Protodesilylation was achieved by a slight alteration
of conditions previously reported by us and required an
optimum 1.5 equiv of water in the first step of a two-
step process that furnished silanol 10 and alkene 11 as
a 1:2 mixture in the crude material. Direct treatment
with excess TBAF gave 11 in 59% overall yield. This
protodesilylation reaction is still under investigation.17
Iodolactonization with I2 in DME/H2O gave a 7:1 mixture
of 4 (P ) t-Bu):12 in 74% and 11% isolated yields,
respectively (Scheme 3). The major diastereoisomer was
predicted to be 4 based upon the work of Yoshida and
was verified by comparison of selected one-dimensional
nOe data. Vicinal protons with a trans relationship
around the lactone ring gave a nOe enhancement of <3%,
whereas those with a cis relationship gave enhancements
of >9%.18 Deprotection of the amine substituent followed
by base-induced ring opening of the lactone gave the
proline skeleton 13 after 5-exo-tet cyclization in 86%
yield.
a
Reagents: (i) isobutene, amberlyst 15; (ii) n-BuLi, PhMe2SiCl;
(iii) DIBAL; MeLi, (HCHO)n; (iv) PPh3, Br2, Et3N; (v) KH,
BocNHCH2CONMe2; (vi) LDA.
to the work of Yoshida et.al.9 on the iodolactonization of
R- and R,â-substituted γ,δ-unsaturated amides, 1,3-
stereochemical transfer would ensure the formation of
the C4-oxygen stereocenter in 4. Base-promoted rear-
rangement according to the methodology of Ohfune et
al.10 would provide the proline skeleton of kainic acid.
We have used this strategy before in the synthesis of the
nonproteinogenic amino acid (()-(2S,3R,4R)-4-hyroxy-3-
methylproline, which possesses a similar carbon core to
kainic acid.11 The present synthesis requires further
manipulation to tosyloxy derivative 5 to give the late-
stage intermediate required for the synthesis of kainic
acid via retentive displacement with an isopropenyl
nucleophile.
Resu lts a n d Discu ssion
The synthesis of the aza-[2,3]-Wittig precursor began
with commercially available 3-butyne-1-ol (6, Scheme 2).
The hydroxyl function would ultimately become the C3
carboxyl group in 1, but it needed protecting throughout
most of the synthesis. We required a robust protecting
group that would withstand the high concentration of
DIBAL required for hydroalumination to 8. Although the
(12) Corey, E. J .; J ones, G. B. J . Org. Chem. 1986, 51, 5291.
(13) Bennett, F.; Knight, D. W.; Fenton, G. J . Chem. Soc., Perkin
Trans. 1 1991, 1543.
(14) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 2nd ed.; J ohn Wiley & Sons: New York, 1991.
(15) Alexakis, A.; Gardette, M.; Colin, S. Tetrahedron Lett. 1988,
29, 2951. We thank A. Alexakis for the suggestion that we consider
this protecting group for our synthesis.
(16) Metz, P.; Linz, C. Tetrahedron Lett. 1994, 50, 3951.
(17) (a) Anderson, J . C.; Flaherty, A. J . Chem. Soc., Perkin Trans.
1 2000, 3025. (b) Anderson, J . C.; Anguille, S.; Bailey, R. Chem.
Commun. 2002, 2018.
(18) See the Supporting Information for details of irradiations and
enhancements. The stereochemical assignment was also verified by
the completion of the synthesis.
(8) (a) Anderson, J . C.; Siddons, D. C.; Smith, S. C.; Swarbrick, M.
E. J . Org. Chem. 1996, 61, 4820. (b) Anderson, J . C.; Flaherty, A.;
Swarbrick, M. E. J . Org. Chem. 2000, 65, 9152 and references therein.
(9) Tamaru, Y.; Mizutani, M.; Furukawa, Y.; Kawamura, S.; Yoshi-
da, Z.; Yanagi, K.; Minobe, M. J . Am. Chem. Soc. 1984, 106, 1079.
(10) (a) Ohfune, Y.; Kurokawa, N. Tetrahedron Lett. 1985, 26, 5307.
(b) Ohfune, Y.; Hori, K.; Sakaitani, M. Tetrahedron Lett. 1986, 27, 6079.
(11) Anderson, J . C.; Flaherty, A. J . Chem. Soc., Perkin Trans. 1
2001, 267.
J . Org. Chem, Vol. 68, No. 16, 2003 6161

Anderson and Whiting
SCHEME 3a
reagent at -78 °C followed by warming to room temper-
ature for 2 h to give a 56% yield of the desired product.
Retention of stereochemistry was verified by one-
dimensional nOe experiments.18 In an attempt to increase
the yield and probe which functional groups were re-
sponsible for retention of stereochemistry in this step,
the cuprate reaction was conducted on protected ana-
logues of 16. Treatment of fully protected tosylate 14
under identical substitution conditions gave only insepa-
rable mixtures of unidentified products. Subjection of 15
to identical reaction conditions gave isopropenyl-substi-
tuted compound 17 in 38% isolated yield along with an
inseparable mixture of other unidentifiable products (eq
1). Retention of stereochemistry was again verified by
one-dimensional nOe enhancements.18 Treatment of 14
with NaOH gave the carboxylic acid derivative in 98%
yield, which upon treatment with our optimized substitu-
tion conditions gave isopropenyl product 18 in 55% yield
(eq 2). Retention of stereochemistry at C3 was verified
by removal of the t-Bu protecting group to give 16.
a
Reagents: (i) t-BuOK, 18-crown-6, H2O; (ii) TBAF; (iii) I2;
(iv) TFA; KOH.
SCHEME 4a
Whether the hydroxyl group was protected, when in
the presence of the carboxylic acid function, was immate-
rial to the yield and selectivity of the reaction. Participa-
tion of the C2 acid group was one of the possible scenarios
suggested for lithium diphenylcuprate retentive displace-
ment of trans-4-tosyloxy-L-proline.7 From our limited
study it would appear that the ester function, as well as
the carboxylic acid function, can assist this retentive
displacement reaction. The carboxylic acid function gives
a higher yield. Although none of the intermediate lactone
was isolated, we invoke participation of the C2 carboxyl
group in the substitution reaction.
a
Reagents: (i) BCN, 98%; (ii) CH2N2, 98%; (iii) Ts-Imid, MeOTf,
Me-Imid, 83%; (iv) TFA, 96%; (v) 0.5
[CH2dC(CH3)]2CuCNLi2, 56%.
M NaOH, 98%; (vi)
Completion of the synthesis required orthogonal pro-
tecting group manipulation to obtain the alkylation
precursor 5. Reaction of 13 with BCN19 in THF/H2O
(Scheme 4) gave the Cbz-protected amine (98%), which
was then esterified with CH2N2 (98%). Tosylation of the
C3 hydroxyl with TsCl gave disappointing yields; how-
ever, use of 1-(toluenesulfonyl)-3-methylimidazolium tri-
flate20 gave the desired tosylate 14 in 83% yield. Removal
of the long-serving tert-butyl protecting group with TFA
gave 15 (96%), which was saponified with NaOH (98%)
to give our key intermediate 5 in 75% overall yield from
13.
Completion of the synthesis involved oxidation with
J ones’ reagent, followed by removal of the Cbz protecting
group with aqueous NaOH and purification by ion
exchange chromatography, which gave (()-kainic acid (1)
in 73% yield from the substitution product 16 (eq 3). The
We initially attempted the substitution reaction of 5
with a lower order Gilman type diisopropenyl cuprate by
analogy to the work of Shirahama.4 Even after prolonged
reaction periods at room temperature no product forma-
tion was observed, only degradation of the starting
material. We had more success with a higher order
diisopropenyl cyano cuprate, generated from CuCN and
2-lithiopropene. This reaction was very sensitive to
reaction conditions and care had to be taken to rigorously
dry the CuCN and perform the reaction under a positive
pressure of argon. Optimum reaction conditions involved
treatment of 5 with 5 equiv of the higher order cuprate
1
synthetic material displayed identical H NMR data to
1
an authentic sample and gave a homogeneous H NMR
spectrum when co-mixed.
We have achieved a novel total synthesis of (()-kainic
acid in 18 steps starting from 3-butyne-1-ol. The silicon-
assisted aza-[2,3]-Wittig sigmatropic rearrangement was
key in defining the C2-C3 relative stereochemistry with
the final C4 stereocenter being derived from a diastereo-
(19) Henklein, P.; Heyne, H.-U.; Halatsch, W.-R.; Niedrich, H.
Synthesis 1987, 2, 166.
(20) O’Connel, J .; Rapoport, H. J . Org. Chem. 1992, 57, 4775.
6162 J . Org. Chem., Vol. 68, No. 16, 2003

Total Synthesis of (()-Kainic Acid
controlled iodolactonization We believe that this route
could be useful for synthesizing other kainoid analogues.
The aza-[2,3]-Wittig rearrangement offers the opportu-
nity of structural diversity at C3, which, coupled with
the retentive displacement of the C4 tosyloxy substituent
with different nucleophiles, opens up many opportunities
for uncharted structural diversity in this class of thera-
peutic compounds. Work is currently underway to control
absolute stereochemistry in the aza-[2,3]-Wittig sigma-
tropic rearrangement, which will lead to the synthesis
of enantiomerically pure kainic acid derivatives.
thank the University of Nottingham and AstraZeneca
for funding, Dr. Gair Ford for helpful discussions, Mr.
T. Hollingworth and Mr. D. Hooper of the University of
Nottingham and the EPSRC National Mass Spectrom-
etry Service Centre for providing mass spectra, and Mr.
T. J . Spencer for micro analytical data.
Su p p or tin g In for m a tion Ava ila ble: Syntheses and spec-
troscopic data of all compounds, including selected 1H NMR
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
Ack n ow led gm en t. This work is part of the Ph.D.
Thesis of M.W., University of Nottingham, 2003. We
J O030101Q
J . Org. Chem, Vol. 68, No. 16, 2003 6163