Ruthenium-catalyzed alkyne-propargyl alcohol addition. An asymmetric total synthesis of (+)-alpha-kainic acid.

Article abstract of DOI:10.1021/ol034241y

A novel route to the neuroexcitatory amino acid, kainic acid, is developed. The key concept derives from a ruthenium-catalyzed cycloisomerization of a tethered alkyne-propargyl alcohol to form a cyclic 2-vinyl-1-acyl compound. A single stereocenter introd

Full text of DOI:10.1021/ol034241y

ORGANIC
LETTERS
2003
Vol. 5, No. 9
1467-1470
Ruthenium-Catalyzed Alkyne−Propargyl
Alcohol Addition. An Asymmetric Total
Synthesis of (+)-r-Kainic Acid
Barry M. Trost* and Michael T. Rudd
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
bmtrost@stanford.edu
Received February 11, 2003
ABSTRACT
A novel route to the neuroexcitatory amino acid, kainic acid, is developed. The key concept derives from a ruthenium-catalyzed cycloisomerization
of a tethered alkyne−propargyl alcohol to form a cylic 2-vinyl-1-acyl compound. A single stereocenter introduced by an asymmetric reduction
of a ketone sets the stage for all the other stereocenters. A novel 1,6-addition of silyl cuprate serves to install a hydroxyl group at the diene
termines.
Kainic acid is a marine natural product isolated in 1953 that
has been shown to have selective interaction with a class of
neuroexcitatory amino acid receptors.1 Kainic acid is the
parent member of a large class of structurally related amino
acids, two of which are the C-4 epimer allokainic acid and
the more structurally complex domoic acid. The selective
stimulated the development of the total syntheses of kainic
acid.5 The biological activity of kainic acid is linked to the
trans-C2/C3/cis-C3/C4 stereochemistry, and thus, any syn-
thesis should result in efficient control of this relative
stereochemistry.
Recently, we described an unusual ruthenium-catalyzed
dimerization of propargyl alcohols6 and a related cyclo-
isomerization of alkynes and propargyl alcohol.7 We believed
that extending this methodology to include primary propargyl
alcohols would allow a conceptually new entry into the
(4) (a) Tremblay, J.-F. Chem. Eng. News 2000, Jan 3, 14. (b) Tremblay,
J.-F. Chem. Eng. News 2000, March 6, 131.
(5) For recent reviews, see: (a) Parsons, A. F. Tetrahedron 1996, 52,
4149. Maloney, M. G. Nat. Prod. Rep. 2002, 19, 597. Selected examples:
(b) Clayden, J.; Menet, C. J.; Tchabanenko, K. Tetrahedron 2002, 4727.
(c) Xia, Q.; Ganem, B. Org. Lett. 2002, 485. (d) Hirasawa, H.; Taniguchi,
T.; Ogasawara, K. Tetrahedron Lett. 2001, 7587; Nakagawa, H.; Sugahara,
T.; Ogasawara, K. Org. Lett. 2000, 3181. (e) Miyata, O.; Ozawa, Y.;
Ninomiya, I.; Naito, T. Tetrahedron 2000, 6199. (f) Campbell, A. D.;
Raynham, T. M.; Taylor, R. J. K. J. Chem. Soc., Perkin Trans. 1 2000,
3194. (g) Chevliakov, M. V.; Montgomery, J. J. Am. Chem. Soc. 1999,
11139. (h) Rubio, A.; Ezquerra, J.; Escribano, A.; Remuinan, M. J.;
Vanquero, J. J. Tetrahedron Lett. 1998, 2171. (i) Cossy, J.; Cases, M.; Pardo,
D. G. Synlett 1998, 507. (j) Bachi, M. D.; Melman, A. J. Org. Chem. 1997,
18966. (k) Hanessian, S.; Ninkovic, S. J. Org. Chem. 1996, 61, 8. (l) Yoo,
S.; Lee, S. H. J. Org. Chem. 1994, 59, 8. (m) Monn, J. A.; Valli, M. J. J.
Org. Chem. 1994, 59, 3. (n) Cooper, J.; Knight, D. W.; Gallagher, P. T. J.
Chem. Soc., Chem. Commun. 1987, 1220. (o) Oppolzer, W.; Thirring, K.
J. Am. Chem. Soc. 1982, 104, 8.
recognition by the kainic acid receptors and neuroexcitatory
functions are a result of kainic acid’s ability to act as a
conformationally restricted analogue of L-glutamate.2 Kainic
acid has become especially important in the study of
Alzheimer’s disease, epilepsy, and other neurological dis-
orders.3 Recently, a worldwide shortage4 of kainic acid has
(1) (a) Murakami, S.; Takemoto, T.; Shimizu, Z. J. Pharm. Soc. Jpn.
1953, 73, 1026. (b) Impellizzeri, G.; Mangiafico, S.; Oriente, G.; Piatelli,
M.; Sciuto, S.; Fattorusso, E.; Magno, S.; Santacroce, C.; Sica, D.
Phytochemistry 1975, 14, 1549. (c) Balansard, G.; Gayte-Sorbier, A.;
Cavalli, C. Ann. Pharm. Fr. 1982, 40, 527.
(2) ) Chevliakov, M. V.; Montgomery, J. J. Am. Chem. Soc. 1999, 121,
11139.
(6) Trost, B. M.; Rudd, M. T. J. Am. Chem. Soc. 2001, 8862.
(3) Hollmann, M.; Heinemann, S. Annu. ReV. Neurosci. 1994, 17, 31.
(7) Trost, B. M.; Rudd, M. T. J. Am. Chem. Soc. 2002, 4178
10.1021/ol034241y CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/08/2003

kanoid family of amino acids wherein the diversity of alkyne
chemistry allows easy access to the required substrate. We
report herein our successful realization of an asymmetric total
synthesis of kainic acid.
Scheme 1 depicts our retrosynthetic strategy. We planned
to introduce the isopropylidene fragment through an olefi-
nation of the ketone. This disconnection also enables easy
rane16) gave the product in high yield and ee. The optimum
reduction method was then found to be the LAH/(R)-
BINOL17/MeOH system developed by Noyori18 which gave
the product in high yield (90%) and excellent ee (96%)
(Scheme 2). The major enantiomer, which is in agreement
Scheme 2. Synthesis of Cycloisomerization Substratea
Scheme 1. Retrosynthetic Analysis
n
a Key: (a) TBSOCH2CtCH( 2), BuLi, -78 to -40 °C; (b)
TEMPO/NaOCl/DCM/KBr/NaHCO3; (c) LAH, (R)-BINOL, MeOH,
THF, -100 °C; (d) TsNHCH2CtCCH3(5), Ph3P, DIAD, THF, rt.
access to domoic acid as well, through use of a different
olefination reagent. We envisioned hydroxyl-directed hy-
drogenation would set the required relative stereochemistry
present in the natural product. Introduction of a hydroxyl
group or an oxygen equivalent would immediately follow
the ruthenium-catalyzed cycloisomerization of the diyne
substrate A.
The most rapid entry into diyne precursors A would be
the addition of an alkyne fragment to an imine. While this
can be done to give racemic product,9 all attempts to carry
out the reaction asymmetrically resulted in either no reaction
or very low ee. The new copper-catalyzed methods developed
by Li10 and Knochel11 show promise but cannot be applied
directly to the desired system. A Mitsunobu reaction could
also be used to produce the diyne from the corresponding
propargyl alcohol. However, the required propargyl alcohol
could not be accessed in a high level of enantioselectivity
using established methods of direct addition.12
with the model proposed by Noyori, leads ultimately to the
unnatural enantiomer of kainic acid. Of course, the natural
enantiomer is equally readily accessible simply by switching
the chirality of the BINOL. This reduction is in fact simple
to carry out utilizing a filtered, standardized solution of
LAH.19 It is important to conduct the reaction at -100 °C,
as raising the temperature to the more convenient -78 °C
resulted in lower ee (93%). Also, the reaction mixture must
become milky white following addition of LAH, BINOL,
and MeOH. If a clear solution with fine particulates results,
the yield (∼50%) and ee (83%) are dramatically affected.
The Mitsunobu reaction was then carried out using the easily
available tosylamine 5, triphenylphosphine, and diisoprop-
ylazadicarboxylate in THF (Scheme 2) to give the diyne 6
in high yield (85%) with nearly perfect chirality transfer.
To carry out the [CpRu(CH3CN)3]PF6-catalyzed20 cycliza-
tion, a free propargyl alcohol is preferred; however, the
catalyst can deprotect unhindered TBS groups in aqueous
acetone. This observation allows 6 to be used directly in the
cycloisomerization (eq 1). The formation of 7 is rationalized
An alternative approach starts with the alkyne 4 derived
in two steps and 98% from the commercially available
aldehyde 1. The key to the high yield in the addition of the
alkynyllithium was raising the temperature to -40 °C. The
most convenient oxidation method involves the two-phase
TEMPO/bleach oxidation13 which only requires 1% of the
commercially available TEMPO reagent.
Although the asymmetric reduction of alkynyl ketones is
a well-developed reaction, none of the standard reduction
methods (Noyori ruthenium catalyst,14 CBS,15 Alpine-Bo-
(8) Trost, B. M. Science 1991, 254, 1471. Trost, B. M. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 259.
(9) Wada, M.; Sakurai, Y.; Akiba, K. Y. Tetrahedron Lett. 1984, 1083.
The reaction between lithiated protected progargyl alcohol and the imine
derived from benzyloxyacetaldehyde and 1-amino-2-butyne in the presence
of BF3‚OEt2 gave the expected product in ∼60% yield, which could be
subsequently protected.
(10) Wei, C.; Li, C. J. J. Am. Chem. Soc. 2002, 124, 5638.
(11) Koradin, C.; Polborn, K.; Knochel, P. Angew. Chem., Int. Ed. Engl.
2002, 41, 2535.
through the mechanism depicted in Scheme 3, cycle A. To
maximize yields, the reaction is carried out in aqueous
(14) Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem.
Soc. 1997, 119, 8738. The ee was good (90%), but the conversion was low
for 4 and related substrates.
(12) The method developed by Carreira only gave a moderate level of
enatioselectivity (∼60%) in the applicable case. (a) Frantz, D. E.; Fassler,
R.; Carreira, E. M. J. Am. Chem. Soc. 2002, 122, 1806. (b) Anand, N. K.;
Carreira, E. M. J. Am. Chem. Soc. 2001, 123, 9687. Other methods also
resulted in low yields or poor ee.
(13) For a general review, see: de Nooy, A. E. J.; Besemer, A. C.; van
Bekkum, H. Synthesis 1996, 1153.
(15) (a) Helal, C. J.; Magriotis, P. A.; Corey, E. J. J. Am. Chem. Soc.
1996, 118, 10938. (b) Parker, K. A.; Ledeboer, M. W. J. Org. Chem. 1996,
61, 3214. The ee here was 67%.
(16) Midland, M. M.; McDowell, D. C.; Hatch, R. L.; Tramontano, A.
J. Am. Chem. Soc. 1980, 102, 7. The ee here was 86%.
(17) The ligand can be recovered and reused through precipitation and/
or column chromatography.
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Org. Lett., Vol. 5, No. 9, 2003

Scheme 3. Mechanistic Rationale for Cycloisomerization and Formation of Side Product
acetone; however, if a larger percentage of water is utilized
to give the desired product 9 in 87% yield over two steps
(Scheme 4).
side product 8, resulting from addition of a molecule of water
to the substrate (Scheme 3, cycle B), becomes a larger
component of the reaction mixture.21 This mechanistic
proposal differs from the one proposed in the tertiary and
secondary propargyl alcohol examples.7 The isolation of
products similar to 8, along with other data, led us to propose
that a different mechanism operates with primary propargyl
alcohol substrates. While the addition of malonic acid is not
required, an increase in yield from 75% to 80% occurred
upon its addition.
Scheme 4. Setting the Relative Stereochemistrya
Attempts to introduce a hydroxyl group at the γ position
of 7 with hydroboration-oxidation led to either decompo-
sition or various products resulting from 1,6 or 1,2 reduc-
tion depending on conditions. Protecting the ketone as a
cyclic acetal alleviated this problem but was less desirable
as added steps were required. If a hydroxyl group cannot be
introduced directly, an oxygen equivalent could be used in
its place. Silicon can be used as a stable oxygen surrogate
that can be oxidized at the appropriate time. Owing to the
conjugated nature of 7, it is feasible to introduce the silicon
moiety through a 1,6 addition of silicon. While much work
has been done on the 1,4-addition of silyl cuprates,22 the
1,6-addition is unknown. When the standard phenyldimeth-
ylsilyl cuprate was added to 7, no reaction occurred at -78
°C; however, when the temperature was raised to 0 °C, 1,6-
addition took place smoothly to yield 8 as a mixture of
R-diastereomers (in a 2.8:1 ratio). The olefin could be easily
isomerized into conjugation with DBU in refluxing benzene
a Key: (a) Li[Si(Me)2Ph], CuCN, THF, -78 to 0 °C; (b) DBU,
PhH, reflux; (c) Pd/C, rt, 1:1 formic acid/MeOH; (b) 20%
[Ir(cod)Py(PCy3)]PF6, 2000 psi H2, 1 equiv of B(O-iPr)3 24 h.
The relative stereochemistry was then set by a directed
hydrogenation of the R,â-unsaturated alkene. Various func-
tional groups are known to direct reduction including methyl
ethers; however, with the benzyl ether moiety in 9 intact,
no reaction occurred with Crabtree’s catalyst23 [Ir(cod)Py-
(PCy3)]PF6. Removal of the benzyl group to reveal the more
powerfully directing free hydroxyl group was then carried
out with 1:1 formic acid/methanol and Pd/C. Use of other
Pd sources or direct hydrogen pressure led to either no
reaction or over-reduction of the double bond as well. Even
with the strong directing effects of the free hydroxyl group,
high pressure and extended reaction times were required to
maximize the yield of 11 (Scheme 4). We found that addition
of triisopropyl borate increased turnover to give an isolated
yield of 11 of 65%, 95% based on recovered 10.
(18) (a) Noyori, R.; Tomino, I.; Yamada, M.; Nishizawa, M. J. Am. Chem.
Soc. 1984, 106, 6717. (b) Noyori, R.; Tomino, I.; Tanimoto, Y.; Nishizawa,
M. J. Am. Chem. Soc. 1984, 106, 6709.
(19) Refer to the Experimental Section (Supporting Information) for
details.
(20) The catalyst is readily available through an improved procedure:
Trost, B. M.; Older, C. M. Organometallics 2002, 21, 2544.
(21) Changes in the temperature, concentration, and substrate (ring size
formed or alkyl group on the alkyne) can also alter the ratio of these type
of products.
After the initial step of the Peterson olefination,24 it was
envisioned that the elimination and the oxidation of the
(22) (a) Fleming, I.; Winter, S. B. D. J. Chem. Soc., Perkin Trans. 1
1998, 2687. (b) Fleming, I.; Roberts, R. S.; Smith, S. C. J. Chem. Soc.,
Perkin Trans. 1 1998, 1209.
(23) (a) Crabtree, R. H.; Davis, M. W. Organometallics 1983, 2, 681.
(b) Crabtree, R. H.; Davis, M. W. J. Org. Chem. 1986, 51, 2655.
Org. Lett., Vol. 5, No. 9, 2003
1469

phenyldimethylsilyl group could be carried out simulta-
neously. This in fact was possible using the Woerpel
modification of the Tamao-Fleming oxidation.25 The stan-
dard Tamao-Fleming conditions require strong acids to
oxidize phenyldimethylsilyl groups, which were expected to
be incompatible with the olefin present in the molecule. The
addition of (trimethylsilylmethyl)lithium proceeded smoothy
to give 12, which could be directly converted to 13 using
the Woerpel KH/tBuOOH/TBAF conditions.
Scheme 5. Adjusting the Oxidation Levela
However, some amount of a protodesilyated product was
also isolated under these conditions, and modifications to
minimize this undesired product resulted in lower yields of
13. Higher yields were obtained if the elimination was carried
out with HF/acetonitrile first, followed by the Woerpel
oxidation to diol 13 without any prior purification (Scheme
5). Both primary alcohols were then oxidized simultaneously
with the Jones reagent26 to give a quantitative yield of the
diacid. The tosyl group was then removed in a known step27
with Li/NH3 to give kainic acid in 80% yield over two steps.
In conclusion, we have successfully carried out the
stereoselective synthesis of the unnatural enantiomer of kainic
acid in 14 linear steps. Since the initially introduced
stereogenic center dictates all the remaining ones, this route
provides equal access to the natural enantiomer by simply
switching the chirality of the BINOL in the enantioselective
reduction of ketone 4. The ring structure was formed through
a novel ruthenium-catalyzed cycloisomerization and was
functionalized through an unprecedented 1,6-addition of a
a Key: (a) (trimethylsilylmethyl)lithium, THF, -78 °C; (b) HF/
t
CH3CN, rt; (c) KH, BuOOH, TBAF, DMF, 65 °C; (d) 8 N Jones
reagent, acetone, rt, 1.5 h; (e) Li/NH3, THF, -78 °C.
silyl cuprate. The relative stereochemistry was set by directed
hydrogenation, and the endgame was carried out expedi-
tiously through the use of two different types of silicon-
carbon reactivity.
Acknowledgment. We thank the National Science Insti-
tutes of Health, General Medical Science (GM 13598), and
the National Science Foundation for their generous support
of our programs. Mass spectra were provided by the Mass
Spectrometry Regional Center of the University of Californias
San Francisco supported by the NIH Division of Research
Resources.
Supporting Information Available: Experimetal proce-
dures for the preparation of new compounds as characteriza-
tion data are included. This material is available free of
charge via the Internet at http://pubs.acs.org.
(24) Johnson, C. R.; Tait, B. D. J. Org. Chem. 1987, 52, 281. For a
recent review, see: van Staden, L. F.; Gravestock, D.; Ager, D. J. Chem.
Soc ReV. 2002, 31, 195.
(25) Smitrovich, J. H.; Woerpel, K. A. J. Org. Chem. 1996, 61, 6044.
(26) See the Experimental Section (Supporting Information) for prepara-
tion.
(27) Yoo, S.; Lee, S. H J. Org. Chem. 1994, 59, 6968.
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