High-pressure Diels-Alder approach to natural kainic acid

Article abstract of DOI:10.1021/ol062419l

The first Diels-Alder based synthesis of (-)-kainic acid is described. Danishefsky's diene and a vinylogous malonate derived from 4-hydroxyproline combine under high pressure to afford a key bicyclic intermediate with virtually no loss of enantiopurity. This adduct can be converted into the natural product with complete stereocontrol.

Full text of DOI:10.1021/ol062419l

ORGANIC
LETTERS
2006
Vol. 8, No. 24
5665-5668
High-Pressure Diels
Natural Kainic Acid
−Alder Approach to
Sushil K. Pandey, Arturo Orellana, Andrew E. Greene, and
Jean-Francois Poisson*
¸
Chimie Recherche (LEDSS), UniVersite´ Joseph Fourier, 38041 Grenoble, France
jean-francois.poisson@ujf-grenoble.fr
Received October 2, 2006
ABSTRACT
The first Diels−Alder based synthesis of (−)-kainic acid is described. Danishefsky’s diene and a vinylogous malonate derived from 4-hydroxyproline
combine under high pressure to afford a key bicyclic intermediate with virtually no loss of enantiopurity. This adduct can be converted into
the natural product with complete stereocontrol.
(-)-Kainic acid (Figure 1), the parent member of the class
of marine natural products called kainoids, was first isolated
discontinuance of its commercial extraction from the above
alga3 created concern as to future supply, but this halt in
production proved to be only temporary.4 The supply concern
did, however, serve to focus the attention of synthetic
chemists on this deceptively simple natural product. A large
number of approaches thus resulted and new syntheses
continue to appear.5
We recently published a preparation of (-)-kainic acid
from trans-4-hydroxy-L-proline, which was based on a
regioselective alkylation of a keto derivative and an unusual
cuprate-mediated tosylate substitution with retention of
configuration.5h This represented, surprisingly, the first use
of 4-hydroxyproline in an approach to kainic acid and led
us to consider whether other efficient syntheses might also
be possible from this inexpensive starting material. An
unprecedented6 approach based on a Diels-Alder reaction
Figure 1. (-)-Kainic acid.
in 1953 from Digenea simplex.1 Originally used in anthel-
mintic and insecticide preparations, it has more recently
found application in the study of serious neuronal disorders,
such as Alzheimer’s disease and epilepsy.2-5a,b In 1999, the
(4) Producers Strive to Bring Kainic Acid Back on the Market. Chem.
Eng. News 2000, 78 (10), 31.
(1) (a) Murakami, S.; Takemoto, T.; Shimizu, Z. J. Pharm. Soc. Jpn.
1953, 73, 1026-1028. (-)-Kainic acid has also been isolated from
Centrocerus claVulatum [(b) Impellizzeri, G.; Mangiafico, G.; Oriente, G.;
Piattelli, M.; Sciuto, S.; Fattorusso, E.; Magno, S.; Santacroce, C.; Sica, D.
Phytochemistry 1975, 14, 1549-1557] and from Alsidum helmithocorton
[(c) Balansard, G.; Pellegrini, M.; Cavalli, C.; Timon-David, P. Ann. Pharm.
Fr. 1983, 41, 77-86].
(2) Since the beginning of 2006, over 300 papers have been published
on the use of kainic acid for the study of various neuronal disorders.
(3) Shortage of Kainic Acid Hampers Neuroscience Research. Chem.
Eng. News 2000, 78 (1), 14-15.
(5) For syntheses prior to 2002, see: (a) Parsons, A. F. Tetrahedron
1996, 52, 4149-4174. (b) Moloney, M. G. Nat. Prod. Rep. 2002, 19, 597-
616 and references cited therein. For more recent syntheses, see: (c) Trost,
B. M.; Rudd, M. T. Org. Lett. 2003, 5, 1467-1470. (d) Martinez, M. M.;
Hoppe, D. Org. Lett. 2004, 6, 3743-3746. (e) Scott, M. E.; Lautens, M.
Org. Lett. 2005, 7, 3045-3047. (f) Anderson, J. C.; O’Loughlin, J. M. A.;
Tornos, J. A. Org. Biomol. Chem. 2005, 3, 2741-2749. (g) Hodgson, D.
M.; Hachisu, S.; Andrews, M. D. Org. Lett. 2005, 7, 815-817. (h) Poisson,
J. F.; Orellana, A.; Greene, A. E. J. Org. Chem. 2005, 70, 10860-10863.
(6) See, however: Ohfune, Y.; Tomita, M. J. Am. Chem. Soc. 1982,
104, 3511-3513.
10.1021/ol062419l CCC: $33.50
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Published on Web 11/02/2006

seemed particularly attractive for it had the potential to set
in a straightforward manner the C2-C3-C4 relationship.
The Diels-Alder reaction of a dehydroproline I with an
electron-rich diene II (e.g., Danishefsky’s or Rawal’s) might
lead to enone III (Figure 2). This product could then, in
amples in which the trisubstituted olefin is incorporated in
a five-membered ring: none without activation, only a few
with formyl activation,8 and fewer yet with carboxy, car-
balkoxy,9 or keto activation.10 These limited examples,
furthermore, require in general heating and/or Lewis acid
catalysis, conditions most likely inappropriate in the present
context due to facile racemization of chiral (Vinylogous)
malonate deriVatiVes.
Triflate 411 was prepared to serve as a direct precursor of
dehydroproline derivatives I (Scheme 1). trans-4-Hydroxy-
Scheme 1. Synthesis of Dehydroprolines
Figure 2. Overview of the projected approach to (-)-kainic acid.
principle, rapidly be converted into kainic acid through a
sequence that would include conjugate addition of a methyl
group and enolate trapping to produce IV, followed by
oxidative cleavage, double bond formation, and hydrolysis.
It was obvious that success of the plan would primarily
hinge on whether the unactivated disubstituted (R ) H) or
activated trisubstituted (R ) CHO, CO2H, CO2Me) olefin I
could be made to react satisfactorily with diene II. It was
feared, however, and with some foundation, that the disub-
stituted olefin, even if reactive, would not undergo cycload-
dition regioselectively as desired and, moreover, that an
activated trisubstituted olefin would prove nevertheless
resistant under normal conditions. The literature contains
relatively few examples of trisubstituted olefins as reactive
Diels-Alder partners,7-10 and particularly scarce are ex-
L-proline was converted in 93% yield into the N-Boc methyl
ester derivative 3, which was smoothly oxidized to the
corresponding ketone11 in 85% yield with PCC in the
presence of molecular sieves. This procedure was found to
be considerably more efficient and reliable than the others
tested (TPAP/NMO, Swern, and Dess-Martin). Triflate 4
was then obtained regioselectively and in high yield from
this ketone with NaHMDS-PhNTf2.
Reduction of 4 with triethylsilane in the presence of Pd-
(PPh3)4 led to 3,4-dehydroproline 5 in 85% yield. Unfortu-
nately, however, none of many Diels-Alder reactions
attempted with 5 and various diene partners (electron rich
and electron poor) was found to be even marginally produc-
tive, including those heated in a sealed tube or subjected to
high pressure. Since an acceptable means of converting
triflate 4 into the corresponding acrolein derivative could
not be found,12 attention was directed toward the preparation
of diester 7. Pleasingly, Pd-catalyzed methoxycarbonylation
of 4 afforded the desired acrylate derivative 7 in 60% yield
(7) Six-membered ring dienophiles: (a) Danishefsky, S.; Kitahara, T.;
Yan, C. F.; Morris, J. J. Am. Chem. Soc. 1979, 101, 6996-7000. (b)
Jankowski, C. K.; LeClair, G.; Be´langer, J. M. R.; Pare´, J. R. J.;
VanCalsteren, M.-R. Can. J. Chem. 2001, 79, 1906-1909. (c) Boger, D.
L.; Patel, M. Tetrahedron Lett. 1986, 27, 683-686. (d) Grieco, P. A.; Lis,
R.; Zelle, R. E.; Finn, J. J. Am. Chem. Soc. 1986, 108, 5908-5919. (e)
O’Connor, P. D.; Mander, L. N.; McLachlan, M. M. W. Org. Lett. 2004,
6, 703-706. Acyclic dienophiles: (f) Paczkowski, R.; Maichle-Mossmer,
C.; Maier, M. E. Org. Lett. 2000, 2, 3967-3969.
(8) Five-membered carbocycles with cyclopentadiene: (a) Ishihara, K.;
Yamamoto, H. J. Am. Chem. Soc. 1994, 116, 1561-1562. (b) Ishihara, K.;
Kurihara, H.; Matsumoto, M.; Yamamoto, H. J. Am. Chem. Soc. 1998, 120,
6920-6930. (c) Ryu, D. H.; Lee, T. W.; Corey, E. J. J. Am. Chem. Soc.
2002, 124, 9992-9993. (d) Sprott, K. T.; Corey, E. J. Org. Lett. 2003, 5,
2465-2467. (e) Davies, H. M. L.; Dai, X. J. Am. Chem. Soc. 2004, 126,
2692-2693. With Rawal’s diene: (f) Huang, Y.; Iwama, T.; Rawal, V. H.
J. Am. Chem. Soc. 2000, 122, 7843-7844. Furanoside-type dienophiles:
(g) Rehnberg, N.; Sundin, A.; Magnusson, G. J. Org. Chem. 1990, 55,
5477-5483. (h) Ponten, F.; Magnusson, G. J. Org. Chem. 1997, 62, 7978-
7983. Indole dienophiles: (i) Chataigner, I.; Hess, E.; Toupet, L.; Piettre,
S. R. Org. Lett. 2001, 3, 515-518. (j) Chretien, A.; Chataigner, I.; L’Helias,
N.; Piettre, S. R. J. Org. Chem. 2003, 68, 7990-8002.
(10) (a) Reddy, T. J.; Rawal, V. H. Org. Lett. 2000, 2, 2711-2712. (b)
Jung, M. E.; Davidov, P. Angew. Chem., Int. Ed. Engl. 2002, 41, 4125-
4128. (c) Jung, M. E.; Ho, D.; Chu, H. V. Org. Lett. 2005, 7, 1649-1651.
(11) (a) Oba, M.; Terauchi, T.; Miyakawa, A.; Kamo, H.; Nishiyama,
K. Tetrahedron Lett. 1998, 39, 1595-1598. (b) Honda, T.; Takahashi, R.;
Namiki, H. J. Org. Chem. 2005, 70, 499-504.
(9) (a) Strunz, G. M.; Bethell, R.; Dumas, M. T.; Boyonoski, N. Can. J.
Chem. 1997, 75, 742-753. (b) Martin, C.; Mailliet, P.; Maddaluno, J. J.
Org. Chem. 2001, 66, 3797-3805. (c) Pichon, N.; Harrison-Marchand, A.;
Mailliet, P.; Maddaluno, J. J. Org. Chem. 2004, 69, 7220-7227.
(12) Surprisingly, no aldehyde was obtained on treatment of triflate 4
with Pd(0) and tributyltin hydride in DMF under carbon monoxide (only
the reduced product 5 was formed). Other approaches to the conjugated
aldehyde were low yielding and/or too long.
5666
Org. Lett., Vol. 8, No. 24, 2006

Scheme 2. Diels-Alder Reactions
Table 1. Diels-Alder Reactions of Diester 7 with Electron-Rich Dienes
entry
dienea
solvent
activation method
time (h)
conversion (%)b
yield of 8 (%)c
eed
1
2
3
Danishefsky
Rawal
Rawal
toluene
toluene
toluene
115 °C
120 °C
Et2AlCN, CuOTf, or
AlBr3/AlMe3
15 kbar
82
6
24
57
100
0
22
24
10
<10, 40e
4
5
6
Rawal
Danishefskyf
Danishefskyg
CH2Cl2
CH2Cl2
CH2Cl2
52
82
72
100
96
100
27
79
80
54
2
90
15 kbar
15 kbar
a Danishefsky’s diene: (4-methoxy-2-trimethylsilyloxybutadiene); Rawal’s diene: (4-dimethylamino-2-tert-butyldimethylsilyloxybutadiene). b Based on
unreacted diester (1H NMR of crude product). c Isolated yield. d By HPLC: Chiralcel OD-H, isopropanol:hexane ) 20:80, 0.5 mL/min. tR of minor enantiomer
) 18.13 min; tR of major enantiomer ) 24.44 min. e Yield of purified cycloadducts. f Contains a small amount of triethylamine. g Distilled from trichlorophenol.
and with an enantiomeric excess of 94%. As anticipated,
however, racemization of this compound occurred quite
readily: after 10 days at 20 °C, the ee was only 20%.
Fortunately, it was discovered that hydroxycarbonylation
could be accomplished in yet higher yield and that the
resultant acid-ester 6, which was obtained pure (94% ee) by
simple base-acid extraction, was significantly less prone than
the diester to racemization. It was more effective, therefore,
to prepare the diester 7 via the acid-ester 6 (diazomethane,
just prior to use).
Initial Diels-Alder results with diester 7 were not at all
encouraging (Scheme 2 and Table 1). Reaction with Dan-
ishefsky’s diene, incomplete after 82 h at 115 °C, provided
after elimination enone 8 in only 22% yield, and worse, with
an enantiomeric excess of just 24% (entry 1). In an attempt
to improve both the yield and the enantiomeric excess,
Rawal’s diene, known to be substantially more reactive than
Danishefsky’s,13 was tested. Indeed, after just 6 h at 120 °C,
the diester was completely consumed; however, the combined
yield of the purified diastereomeric cycloadducts (NMe2
epimers) was only 40%, their conversion to enone 8
problematic, and the enantiomeric excess of 8 extremely low
(entry 2). The use of Lewis acids at ambient temperature,
furthermore, failed to improve the situation (entry 3). These
initial results confirmed the expected low reactivity and the
facile racemization of diester 7 and suggested that another
reaction parameter should be examined: pressure. It was
hoped that high pressure14 might allow the reaction to
proceed at room temperature, and thereby limit the degree
of attendant racemization.
Diester 7 indeed underwent cycloaddition with the Rawal
diene at 20 °C under 15 kbar to yield after dimethylamine
elimination enone 8, still in modest yield, but now with a
much improved 54% ee (entry 4). Even better were the
results obtained with Danishefsky’s diene: a complete, totally
face-selective reaction was achieved at 20 °C under 15 kbar
to provide a ca. 3:1 mixture of cycloadducts (OMe epimers).
This mixture on treatment with aqueous KHSO4 was partially
(major diastereomer) converted into enone 8; the recovered
material (methoxy ketone from minor diastereomer) could
also be transformed into the enone by reaction with DBU in
toluene. While the enone was found to be essentially racemic
with simply distilled Danishefsky diene (which contained
residual triethylamine, entry 5), strikingly, when triethy-
lamine-free diene (by distillation from trichlorophenol) was
used, a 90% ee was produced (80% yield, entry 6). Thus,
the enantiopurity of the highly racemization-prone Vinylogous
malonate could be transferred to the cycloadduct Virtually
undiminished through the use of high pressure.
With the key enone in hand, the removal of the angular
methoxycarbonyl group was next addressed. While rhodium-
mediated decarbonylation of a formyl derivative would have
been expected to proceed with retention of configuration,15
the stereochemical outcome of demethoxycarbonylation of
8 was expected to reflect product stability. AM1 calculations,
encouragingly, indicated the desired cis-fused product to be
ca. 6.5 kcal/mol more stable than the trans.16 Saponification
of 8, followed by a single recrystallization of the crude
(15) (a) Walborsky, H. M.; Allen, L. E. J. Am. Chem. Soc. 1971, 93,
5465-5468. (b) Andrews, M. A.; Gould, G. L.; Klaeren, S. A. J. Org.
Chem. 1989, 54, 5257-5264. (c) O’Connor, J. M.; Ma, J. J. Org. Chem.
1992, 57, 5075-5077.
(16) See: Clayden, J.; Menet, C. J.; Tchabanenko, K. Tetrahedron 2002,
58, 4727-4733.
(13) Kozmin, S. A.; Green, M. T.; Rawal, V. H. J. Org. Chem. 1999,
64, 8045-8047.
(14) For a review, see: High Pressure Chemistry, van Eldik, R., Kla¨rner,
F-G., Eds.; Wiley: Weinheim, 2002.
Org. Lett., Vol. 8, No. 24, 2006
5667

product, conveniently provided in 80% yield the enantiopure
(>99% ee) diacid 9, which was monodecarboxylated in hot
pyridine and then esterified with diazomethane to give the
deconjugated enone 10 in 83% yield (two steps, Scheme 3).
Scheme 4. Final Steps of the Synthesis
Scheme 3. Decarbomethoxylation of 8
Saponification of 14 and then removal of the Boc group
with TFA afforded kainic acid in 75% yield after recrystal-
lization. The synthetically derived material (mp 241-243
°C, [R]20 -14.3 (c 0.16, H2O)) was spectroscopically and
D
chromatographically indistinguishable from an authentic
sample of the natural product (mp 241-243 °C, [R]20D -13.9
(c 0.16, H2O)).
Transformation of 10 into the conjugated enone was next
effected with DBU in dichloromethane, which produced a
single isomer. Gratifyingly, the relative stereochemistry in
this isomer, determined by NOE experiments on the dihydro
N-tosyl derivative, was the expected cis.
Conjugate addition of a methyl group to enone 11 through
the use of a higher-order cyanocuprate in the presence of
trimethylsilyl chloride afforded the trimethylsilyl enol ether
derivative 12, which was subjected to ozonolysis to give,
following treatment with dimethyl sulfide and diazomethane,
aldehyde 1317 in 70% overall yield (Scheme 4). Conversion
of this aldehyde into the desired olefin 14 was next achieved
in 60% yield through palladium-catalyzed triethylsilane
reduction of the enol triflate, formed with KHMDS and
Comins triflimide.18 This approach was found to be far
superior to others examined, such as dehydration of the
corresponding alcohol and selenoxide elimination.19
In summary, enantiopure (-)-kainic acid has been pre-
pared from 4-hydroxyproline in nearly 10% overall yield.
High-pressure activation in the crucial Diels-Alder reaction
of the chiral vinylogous malonate 7 with Danishefsky’s diene
was found to provide a unique solution to the connected
problems of reactivity and enantioretention and should prove
useful for related transformations.
Acknowledgment. We thank Professor P. Dumy (UJF)
for his interest in our work. Financial support from the CNRS
and the Universite´ Joseph Fourier (UMR 5616, FR 2607)
and a Chateaubriand fellowship (to A.O.) from the French
Ministry are gratefully acknowledged.
Supporting Information Available: Complete experi-
mental procedures and spectral data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(17) For an alternative preparation of this aldehyde (for the synthesis of
(-)-domoic acid), see ref 6.
(18) Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299-
6302.
(19) Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem. 1976, 41,
1485-1486.
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