A stereodivergent approach to (-)-α-kainic acid and (+)-α-allokainic acid utilizing the complementarity of alkyne and allene cyclizations

Article abstract of DOI:10.1021/ja993069j

A formal synthesis of (+)-α-allokainic acid and a total synthesis of (-)-α-kainic acid were carried out using a short, efficient, and highly stereoselective approach. From an alkyne precursor, a nickel-catalyzed cyclization and a palladium-catalyzed rearrangement were utilized in the synthesis of (+)-α-allokainic acid. From an allene precursor, a nickel-catalyzed cyclization was utilized in the synthesis of (-)-α-kainic acid. The allene cyclization used in the latter sequence was the first example of a metal-catalyzed cyclization of this type.

Full text of DOI:10.1021/ja993069j

J. Am. Chem. Soc. 1999, 121, 11139-11143
11139
A Stereodivergent Approach to (-)-R-Kainic Acid and
(+)-R-Allokainic Acid Utilizing the Complementarity of Alkyne and
Allene Cyclizations
Maxim V. Chevliakov and John Montgomery*
Contribution from the Department of Chemistry, Wayne State UniVersity, Detroit, Michigan 48202-3489
ReceiVed August 23, 1999
Abstract: A formal synthesis of (+)-R-allokainic acid and a total synthesis of (-)-R-kainic acid were carried
out using a short, efficient, and highly stereoselective approach. From an alkyne precursor, a nickel-catalyzed
cyclization and a palladium-catalyzed rearrangement were utilized in the synthesis of (+)-R-allokainic acid.
From an allene precursor, a nickel-catalyzed cyclization was utilized in the synthesis of (-)-R-kainic acid.
The allene cyclization used in the latter sequence was the first example of a metal-catalyzed cyclization of this
type.
Introduction
Excitatory amino acids have been widely studied due to their
role in the mediation of synaptic excitation.1 L-Glutamic acid
is the major excitatory neurotransmitter in the mammalian
central nervous system, and its signals are mediated through a
combination of receptors. The recognition of L-glutamic acid
by several receptor classes has been attributed to its flexibility
in adopting numorous low-energy conformations. The kainic
acid class of neuroexcitatory amino acid receptor was originally
characterized by its selective interaction with a marine natural
product R-kainic acid.2 Kainic acid (1) is the simplest member
of a family of related natural products that include the C-4
epimer R-allokainic acid (2)2 and more structurally complex
members such as domoic acid,3 acromelic acid A,4 and related
structures (eq 1). The neuroexcitatory properties of R-kainic acid
and its selective recognition by the kainic acid receptor are
derived from its ability to function as a conformationally
restricted analogue of L-glutamate. Studies of the interaction of
kainic acid with the kainic acid receptor have played an
important role in characterization of the kainic acid receptor5
and elucidation of the requirements for kainic acid receptor
agonist activity.1 Those studies demonstrated that the C-4
isopropenyl substituent is the principal site at which structural
variation is allowed without compromising neuroexcitatory
activity.
The importance of these natural products in pharmacological
investigations has attracted the attention of a number of synthetic
groups.6 Numerous approaches to kainic acid and allokainic acid
have been reported, including ene reactions,7 Claisen rearrange-
ments,8 free-radical cyclizations,9 azomethine ylide cycloaddi-
tions,10 Pauson Khand cyclizations,11 iminium ion cyclizations,12
(6) For excellent reviews, see: (a) Parsons, A. F. Tetrahedron, 1996,
52, 4149. (b) Williams, R. M. Synthesis of Optically ActiVe R-Amino Acids;
Pergamon Press: Oxford, 1989; p 306. (c) Hashimoto, K.; Shirahama, H.
J. Synth. Org. Chem. Jpn. 1989, 47, 212. (d) Hashimoto, K.; Shirahama,
H. Trends Org. Chem. 1991, 2, 1.
(7) Oppolzer, W.; Thirring, K. J. Am. Chem. Soc. 1982, 104, 4978.
(8) (a) Cooper, J.; Knight, D. W.; Gallagher, P. T. J. Chem. Soc., Chem.
Commun. 1987, 1220. (b) Cooper, J.; Knight, D. W.; Gallagher, P. T. J.
Chem. Soc., Perkin Trans. 1 1992, 553.
(9) (a) Hanessian, S.; Ninkovic, S. J. Org. Chem. 1996, 61, 5418. (b)
Hatakeyama, S.; Sugawara, K.; Takano, S. J. Chem. Soc., Chem. Commun.
1993, 125. (c) Cossy, J.; Cases, M.; Pardo, D. G. Tetrahedron 1999, 55,
6153.
(10) (a) Monn, J. A.; Valli, M. J. J. Org. Chem. 1994, 59, 2773. (b)
Kraus, G. A.; Nagy, J. O. Tetrahedron 1985, 41, 3537. (c) DeShong, P.;
Kell, D. A. Tetrahedron Lett. 1986, 27, 3979. (d) Takano, S.; Iwabuchi,
Y.; Ogawasara, K. J. Chem. Soc., Chem. Commun. 1988, 1204.
(11) (a) Yoo, S.; Lee, S. H. J. Org. Chem. 1994, 59, 6968. (b) Takano,
S.; Inomata, K.; Ogasawara, K. J. Chem. Soc., Chem. Commun. 1992, 169.
(12) (a) Mooiweer, H. H.; Hiemstra, H.; Speckamp, W. N. Tetrahedron
1991, 47, 3451. (b) Agami, C.; Cases, M.; Couty, F. J. Org. Chem. 1994,
59, 7937.
(1) (a) Monaghan, D. T.; Bridges, R. J.; Cotman, C. W. Annu. ReV.
Pharmacol. Toxicol. 1989, 29, 365. (b) Moloney, M. G. Nat. Prod. Rep.
1998, 206. (c) Chamberlin, R.; Bridges, R. In Drug Design For Neuro-
science; Kozikowski, A. P., Ed.; Raven Press: Ltd.: New York, 1993; pp
231-259. (d) McGeer, E. G.; Olney, J. W.; McGeer, P. L. Kainic Acid as
a Tool in Neurobiology; Raven Press: New York, 1978.
(2) (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.
(3) (a) Takemoto, T.; Daigo, K. Chem. Pharm. Bull. 1958, 6, 578. (b)
Daigo, K. J. Pharm. Soc. Jpn. 1959, 79, 350.
(4) (a) Konno, K.; Shirahama, H.; Matsumoto, T. Tetrahedron Lett. 1983,
24, 939. (b) Konno, K.; Hashimoto, K.; Ohfune, Y.; Shirahama, H.;
Matsumoto, T. J. Am. Chem. Soc. 1988, 110, 4807.
(5) Wacker, D. A.; Lovering, F. E.; Bridges, R. J.; Willis, C.; Bartlett,
R.; Chamberlin, A. R. Synlett 1997, 503.
10.1021/ja993069j CCC: $18.00 © 1999 American Chemical Society
Published on Web 11/17/1999

11140 J. Am. Chem. Soc., Vol. 121, No. 48, 1999
Scheme 1. Formal Synthesis of (+)-R-allokainic Acida
CheVliakoV and Montgomery
a Conditions: (a) Triphosgene, THF, 65 °C, 4 h; (b) 1.1 equiv of KHMDS, THF, 0 °C, 30 min; then 3 equiv of 5 in THF; 40 °C, 24 h, 49 %
(2 steps); (c) NaBH4, EtOH, 0-25 °C, 3 h, 91 %; (d) 1.5 equiv of (COCl)2, 3 equiv of DMSO, 4 equiv of Et3N, CH2Cl2, -78 °C; (e) 1.5 equiv of
7, 3 equiv of DMAP, CH2Cl2, -20 to 25 °C, 1.5 h, 81 % (two steps); (f) 3 equiv of Me3Al, 10 mol % Ni(COD)2, THF, 0 °C, 40 min, 73 % (97:3
diastereoisomeric ratio); (g) HF‚Pyr, THF, 0-25 °C, 24 h, 86 %; then 3 equiv of methylchloroformate, pyridine, CH2Cl2, 0 - 25 °C, 3 h, 83 %;
(h) 10 mol % Pd2(dba)3, 40 mol % PBu3, Et3N (1.5 equiv), HCO2H (1.5 equiv), THF, 65 °C, 74%, (95:5 diastereomeric ratio); (i) 3 equiv of
MeOMgBr, 25 °C, 3 h, 54 %
intramolecular Michael additions,13 hetero-Diels-Alder cyclo-
additions,14 and cobalt-mediated cyclizations15 as the key ring-
closing and stereochemistry-determining steps. However, few
approaches allowed the highly stereoselective construction of
the pyrrolidine core, and none provided a highly selective
stereodivergent entry to both the kainic acid and allokainic acid
stereochemical relationships without extensive protecting group
manipulations. Furthermore, the flexibility to readily modify
the C-4 position is not allowed by most routes. Therefore, we
set out to develop a stereodivergent strategy that would allow
the preparation of both R-kainic acid and R-allokainic acid as
well as provide a versatile route to new analogues of this natural
product class.16
produced by a cyclization of compound 4 utilizing nickel
cyclization methodology previously developed in our labora-
tory.17
With this plan in mind, D-serine methyl ester was efficiently
converted to cyclization substrate 8 in straightforward fashion
(Scheme 1). Condensation of D-serine methyl ester with
triphosgene18 followed by N-propargylation with iodide 5 using
KHMDS afforded 6 in 49% yield over two steps. Chemo-
selective ester reduction with NaBH4,19 oxidation under Swern
conditions, and Wittig olefination with oxazolidinone 720 gave
substrate 8 in 74% overall yield from 6.21
Cyclization of 8 with MeLi/ZnCl2 and 10 mol % Ni(COD)2
employing conditions previously reported afforded high yields
but moderate diastereoselectivities (ca. 3:1). Commercial tri-
methylaluminum or dimethylzinc, however, were found to be
superior to MeLi/ZnCl2 in achieving the desired trans stereo-
chemical relationship of the C-2 and C-3 substituents. Cycliza-
tion of 8 with commercial trimethylaluminum and Ni(COD)2
(10 mol %) in THF afforded a 73% yield of 9 with a
diastereomeric ratio >97:3 in favor of the desired trans
stereochemistry, and commercial dimethylzinc under identical
conditions afforded a 67% yield of 9, also with a >97:3
diastereomeric ratio.
Results and Discussion
Our initial strategy focused on the preparation of compound
3 as a late-stage common intermediate for the preparation of
both kainic acid and allokainic acid (eq 2). We envisioned that
With compound 9 in hand, we were first attracted to the
palladium-catalyzed procedure reported by Tsuji for the desired
reduction with allylic transposition.22 A silyl to carbonate
protecting group transposition was carried out in 73% yield to
prepare substrate 10 for the palladium-catalyzed reduction.
a formal SN2′ displacement of an allylic alcohol derivative at
C-4 with a hydride donor would directly produce the desired
C-4 isopropenyl unit. Reduction from the â-face of 3 would
afford the trans stereochemistry of allokainic acid, whereas
reduction from the R-face of 3 would afford the cis stereo-
chemistry of kainic acid. Common intermediate 3 could be
(17) (a) Montgomery, J.; Savchenko, A. V. J. Am. Chem. Soc. 1996,
118, 2099. (b) Montgomery, J.; Oblinger, E.; Savchenko, A. V. J. Am. Chem.
Soc. 1997, 119, 4911. (c) Montgomery, J.; Chevliakov, M. V.; Brielmann,
H. L. Tetrahedron 1997, 53, 16449.
(18) Doyle, M. P.; Dyatkin, A. B.; Protopopova, M. N.; Yang, C. I.;
Miertschin, C. S.; Winchester, W. R.; Simonsen, S. H.; Lynch, V.; Ghosh,
R. Recl. TraV. Chim. Pays-Bas 1995, 114, 163.
(19) Sibi, M. P.; Rutherford, D.; Sharma, R. J. Chem. Soc., Perkin. Trans
1 1994, 1675.
(13) Barco, A.; Benetti, S.; Spalluto, G. J. Org. Chem. 1992, 57, 6279.
(14) Takano, S.; Sugihara, T.; Satoh, S.; Ogasawara, K. J. Am. Chem.
Soc. 1988, 110, 6467.
(15) (a) Baldwin, J. E.; Li, C.-S. J. Chem. Soc., Chem. Commun. 1987,
166. (b) Baldwin, J. E.; Moloney, M. G.; Parsons, A. F. Tetrahedron 1990,
46, 7263.
(16) For a preliminary account of a portion of this work, see: Chevliakov,
M. V., Montgomery, J. Angew. Chem. 1998, 110, 3346; Angew. Chem.,
Int. Ed. 1998, 37, 3144.
(20) Reagent 7 was prepared in a fashion analogous to the reported
procedure for a phenylalanine-derived reagent: Evans, D. A.; Black, W.
C. J. Am. Chem. Soc. 1993, 115, 4497.
(21) For the reason for utilizing an acyloxazolidinone rather than a simple
enoate, see: Seo, J.; Fain, H.; Blanc, J. B.; Montgomery, J. J. Org. Chem.
1999, 64, in press.

(-)-R-Kainic Acid and (+)-R-Allokainic Acid
J. Am. Chem. Soc., Vol. 121, No. 48, 1999 11141
Scheme 2. Total Synthesis of (-)-R-Kainic Acida
a Conditions: (a) KHMDS, propargyl bromide, THF, 0 to 25 °C, 73 %; (b) NaBH4, EtOH, 0-25 °C, 82 %; (c) paraformaldehyde, CuI, HN(iPr)2,
dioxane, 100 °C, 76 %; (d) (i) (COCl)2, DMSO, Et3N, CH2Cl2, -78 °C, (ii) reagent 7, DMAP, CH2Cl2, -20 to 25 °C, 62%, 2 steps; (e) MeLi/
ZnCl2, Ni(COD)2 (10 mol %), Ti(O-iPr)4, 57 % (98:2 diastereomeric ratio); (f) (i) MeOMgBr, 25 °C, 60 %, (ii) MeONa, 25 °C, 73 %; (g) (i) CrO3,
H2SO4, 0 °C; (ii) NaOH/H2O/MeOH, reflux; (iii) ion exchange chromatography (40% from 18)
Related systems were reported by Tsuji to rearrange with
palladium catalysis via intermediate π-allyl complexes to give
the terminal alkene by hydride delivery to the more hindered
allyl terminus. The stereochemistry of oxidative addition
ultimately sets the stereochemistry of the overall process, since
decarboxylation and C-H bond reductive elimination both
proceed with overall retention of stereochemistry. We initially
anticipated that oxidative addition might occur from the R-face,
opposite the adjacent C-3 side chain, to afford the stereochem-
istry observed in R-kainic acid. However, treatment of 10 with
Pd2(dba)3/PBu3 and HCO2H/Et3N cleanly produced 11 in 74%
yield with a 95:5 diastereomeric ratio in favor of the all-trans
stereochemical relationship of the three pyrrolidine substituents,
as seen in allokainic acid. This result is consistent with exo-
selective oxidative addition, syn to the adjacent side chain, to
ultimately deliver hydride to the â-face of 10a (eq 3). Alternate
Whereas endo-selective hydride addition to 10 would afford
the R-kainic stereochemistry, the conformational bias toward
exo-selective hydride addition would likely be difficult to reverse
with any hydride delivery agent. Choice of acyclic protecting
groups in place of the internal oxazolidinone would remove the
conformational biases associated with the [3.3.0] bicycle;
however, such a strategy would destroy the divergent nature of
the synthetic plan and potentially compromise the high stereo-
selectivity of the nickel-catalyzed cyclization. Therefore, a
simple reversal of chemical steps was instead considered for
completing the synthesis of R-kainic acid. Rather than cycliza-
tion of an alkyne followed by double bond isomerization as
described in the synthesis of R-allokainic acid, we anticipated
that isomerization of an alkyne to an allene followed by
cyclization should result in the identical introduction of a C-4
isopropenyl unit.24 Furthermore, our prior studies on cyclizations
of bis-enones demonstrated a preference for formation of cis-
fused products via an eclipsed conformation of the two reactive
π-components when two sp2-hybridized units were involved (eq
4).17b,25 A similar transition structure for an allene/alkene
cyclization would directly afford the R-kainic acid stereochem-
istry.
With this plan in mind, oxazolidinone 13 was N-propargylated
with propargyl bromide followed by one-carbon homologation
with formaldehyde, diisopropylamine, and copper bromide to
afford allene 15 (Scheme 2). This novel method for allene
introduction, initially described by Crabbe´, was proposed to
involve an acetylide Mannich condensation/sigmatropic rear-
rangement sequence.26 Swern oxidation followed by Wittig
olefination with oxazolidinone 720 afforded cyclization substrate
16. Treatment of 16 with MeLi/ZnCl2 in the presence of
conformation 10b with a more accessible concave (R) face is
destabilized by severe A1,3 strain associated with the exocyclic
double bond. The formal synthesis of (+)-R-allokainic acid was
then completed by converting the acyloxazolidinone unit to the
corresponding methyl ester 12 upon treatment with CH3OMgBr
(Scheme 1).23 Compound 12 was previously converted to (+)-
R-allokainic acid (2) by Hanessian.9a
(23) Evans, D. A.; Morrissey, M. M.; Dorow, R. L. J. Am. Chem. Soc.
1985, 107, 4346.
(22) (a) Mandai, T.; Suzuki S.; Murakami, T.; Fujita, M.; Kawada, M.;
Tsuji, J. Tetrahedron Lett. 1992, 33, 2987. (b) Tsuji, J.; Shimizu, I.; Minami,
I. Chem. Lett. 1984, 1017. (c) Tsuji, J.; Minami, I.; Shimizu, I. Synthesis
1986, 623.
(24) For a nice discussion of thermodynamic considerations of insertions
of alkynes and allenes into metal-nitrogen bonds, see: Arredondo, V. M.;
McDonald, F. E.; Marks, T. J. Organometallics 1999, 18, 1949.
(25) Savchenko, A. V.; Montgomery, J. J. Org. Chem. 1996, 61, 1562.

11142 J. Am. Chem. Soc., Vol. 121, No. 48, 1999
CheVliakoV and Montgomery
Scheme 3
Ni(COD)2 and Ti(Oi-pr)4 directly afforded compound 17 in 57%
yield with a diastereomeric ratio of 97:3 in favor of the R-kainic
acid stereochemistry. Deprotection was accomplished most
efficiently with a two-step procedure in which the counterion
was varied. Cleavage of the acyl linkage to the external
oxazolidinone was accomplished with MeOMgBr,23 then the
internal oxazolidone was converted to the methylcarbamate with
NaOMe in methanol to generate compound 18. Jones oxidation
followed by hydrolysis with KOH and ion exchange chroma-
tions have been reported,30 including extensive work from
Brummond31 on Pauson Khand cyclizations involving a number
of transition metals and from Sato32 on titanium-mediated
stoichiometric reductive cyclizations. Interestingly, the methods
reported by Brummond and Sato likely involve metallacycles
analogous to structure 23 (Scheme 3), and the models advanced
by these authors for predicting the regiochemistry of allene
cyclizations are completely consistent with our observations.
In contrast, metal-catalyzed cyclizations of ω-haloallenes ex-
tensively studied by Negishi typically occur at the internal allene
carbon in an exo- or endocyclization,33 although some excep-
tions have been noted in related reaction classes.34
1
tography afforded (-)-R-kainic acid (1) that displayed H and
13C NMR data, optical rotation data, and melting point identical
with that previously reported.
The strategy of utilizing an alkyne cyclization/alkene isomer-
ization sequence in the preparation of allokainic acid and an
alkyne isomerization/allene cyclization sequence in the prepara-
tion of kainic acid effectively leads to a stereodivergent route
to these two epimeric natural products. Significantly, the same
general reaction, the nickel-catalyzed cyclization of a doubly
unsaturated substrate in the presence of dimethylzinc, could be
utilized in both approaches. We believe that the same mecha-
nism is likely operative in both instances (Scheme 3). Initial
oxidative cyclization of nickel(0) complexes 19 and 22 would
afford metallacycles 20 and 23.27 Transmetalation of dimeth-
ylzinc would afford nickel alkenyl species 21 and 24. Carbon-
carbon bond reductive elimination would then afford products
9 and 17 upon hydrolysis of the crude reaction mixtures. The
stereodivergent nature of the parallel sequences is allowed since
the allene cyclization directly introduces the C-4 stereocenter,
whereas the alkyne cyclization defers introduction of that
stereocenter until a later step.
An eclipsed orientation of the two reactive π-components in
nickel(0) complexes 25 or 26 should give rise to the lowest
activation barriers in the oxidative rearrangement to metalla-
cycles 20 and 23 (eq 5).35 Hence, formation of the reactive
To our knowledge, this represents the first example of a metal-
catalyzed allene/alkene cyclization of this type. Rhodium-
catalyzed intramolecular [5+2] cycloadditions involving allenes
and vinylcyclopropanes were reported by Wender,28 and a
ruthenium-catalyzed intermolecular cycloisomerization involving
an electron-deficient alkene and an allene to produce 1,3-dienes
was recently reported by Trost.29 Several allene/alkyne cycliza-
conformers 25 and 26 could explain the stereoselectivities
observed in the nickel-catalyzed reactions of alkynes and allenes.
It should be noted that the distal π-system of the allene in
(30) Hicks, F. A.; Kablaoui, N. M.; Buchwald, S. L. J. Am. Chem. Soc.
1996, 118, 9450.
(31) (a) Brummond, K. M.; Wan, H.; Kent, J. L. J. Org. Chem. 1998,
63, 6535. (b) Brummond, K. M.; Lu, J. J. Am. Chem. Soc. 1999, 121, 5087.
(c) Kent, J. L.; Wan, H.; Brummond, K. M. Tetrahedron Lett. 1995, 36,
2407.
(32) (a) Urabe, H.; Takeda, T.; Hideura, D.; Sato, F. J. Am. Chem. Soc.
1997, 119, 11295. (b) Urabe, H.; Sato, F. Tetrahedron Lett. 1998, 39, 7329.
(33) (a) Ma, S.; Negishi, E. J. Org. Chem. 1994, 59, 4730. (b) Ma, S.;
Negishi, E. J. Am. Chem. Soc. 1995, 117, 6345.
(34) Doi, T.; Yanagisawa, A.; Nakanishi, S.; Yamamoto, K.; Takahashi,
T. J. Org. Chem. 1996, 61, 2602.
(26) (a) Crabbe´, P.; Fillion, H.; Andre´, D.; Luche, J. J. Chem. Soc., Chem.
Commun. 1979, 859. (b) Searles, S.; Li, Y.; Nassim, B.; Lopes, M.-T. R.;
Tran, P. T.; Crabbe´, P. J. Chem. Soc., Perkin Trans I 1984, 747. (c) Crabbe´,
P.; Nassim, B.; Lopes, M.-T. R. Organic Syntheses; Wiley: New York,
1990; Collect. Vol. VII, p 276.
(27) For a related mechanistic proposal, see: Ikeda, S.; Kondo, K.; Sato,
Y. J. Org. Chem. 1996, 61, 8248.
(28) (a) Wender, P. A.; Glorius, F.; Husfeld, C. O.; Langkopf, E.; Love,
J. A. J. Am. Chem. Soc. 1999, 121, 5348. (b) Wender, P. A.; Fuji, M.;
Husfeld, C. O.; Love, J. A. Org. Lett. 1999, 1, 137.
(35) For an excellent discussion of the geometric relationship of nickel
metallacycles and nickel bis-olefin complexes, see: McKinney, R. J.; Thorn,
D. L.; Hoffman, R.; Stockis, A. J. Am. Chem. Soc. 1981, 103, 2595.
(29) Trost, B. M.; Pinkerton, A. B. J. Am. Chem. Soc. 1999, 121, 4068.

(-)-R-Kainic Acid and (+)-R-Allokainic Acid
J. Am. Chem. Soc., Vol. 121, No. 48, 1999 11143
conformation 26 is orthogonal to the unsaturated acyloxazoli-
dinone carbon/carbon double bond, thus precluding formation
of a chelated complex that would lead to cyclization onto the
central allene carbon. An analysis of molecular models suggests
that formation of a chelated complex involving the distal
π-system would require bond rotations that would introduce
significant nonbonded interactions.
work will be devoted to further investigating nickel-catalyzed
cyclizations of allenes and to the preparation of more structurally
complex natural and unnatural members of the kainic acid class.
Acknowledgment. The authors thank the National Institutes
of Health for support of this research. J.M. acknowledges receipt
of a Camille Dreyfus Teacher Scholar Award and a National
Science Foundation CAREER Award. Professor Stephen Han-
nesian is kindly thanked for helpful suggestions and for
providing spectra of (-)-R-kainic acid (1) and related precursors
for comparison.
Conclusions
An efficient stereodivergent entry to both (-)-R-kainic acid
(1) and (+)-R-allokainic acid (2) was developed. The strategy
is highlighted by the stereochemical complementarity of an
alkyne cyclization/alkene isomerization sequence to produce
allokainic acid and an alkyne isomerization/allene cyclization
sequence to produce kainic acid. Both routes were highly
diastereoselective. Whereas related alkyne cyclizations have
previously been extensively investigated,17 this report describes
the first example of an allene cyclization of this type. Future
Supporting Information Available: Full experimental
details, 1H NMR spectra of all compounds, and additional
correlations with known compounds to confirm stereochemical
assignments (PDF). This material is available free of charge
via the Internet at http://pubs.acs.org.
JA993069J