Stereocontrolled approach to acromelic acids

Article abstract of DOI:10.1016/S0040-4039(01)00782-1

A potential stereocontrolled route to acromelic acids, neuroexitatory amino acids isolated from the mushroom Clitocybe acromelalga, has been developed by employing either concurrent Chugaev-ene reaction or retro-Diels-Alder-ene reaction and regioselective pyridinecarboxylate formation reaction as the key steps.

Full text of DOI:10.1016/S0040-4039(01)00782-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4523–4526
Stereocontrolled approach to acromelic acids
Hiroshi Nakagawa, Tsutomu Sugahara and Kunio Ogasawara*
Pharmaceutical Institute, Tohoku University, Aobayama, Sendai 980-8578, Japan
Received 22 March 2001; revised 18 April 2001; accepted 14 May 2001
Abstract—A potential stereocontrolled route to acromelic acids, neuroexitatory amino acids isolated from the mushroom
Clitocybe acromelalga, has been developed by employing either concurrent Chugaev-ene reaction or retro-Diels–Alder-ene reaction
and regioselective pyridinecarboxylate formation reaction as the key steps. © 2001 Elsevier Science Ltd. All rights reserved.
Acromelic acids, members of the kainoid amino acid
family,1 have been isolated from the poisonous mush-
room Clitocycbe acromelalga and are reported to
exhibit much more potent neuroexitatory activity2 than
(−)-kainic acid, the 4-isopropenyl analogue of acromelic
acids and the parent compound of the kainoid group,
isolated from the marine algae Digenea simplex3 (Fig.
1). Although several enantiocontrolled syntheses of
acromelic acids have been reported so far,4,5 all suffered
from difficulty in the installation of an appropriately
functionalized pyridine moiety on the C4 center of the
common pyrrolidine framework. Quite recently, we
developed an efficient diastereospecific construction of
a cis-2,3,4-trisubstituted pyrrolidine leading to (−)-
kainic acid from a chiral building block (+)-1 by
employing concurrent Chugaev-ene reaction as the key
step6 (Scheme 1).
for the construction of the pyridinecarboxylate moiety
on the C4-center by employing the same methodology
so as to develop a new entry into the synthesis of
acromelic acids. We report here a synthesis of two
trisubstituted pyrrolidines carrying a pyridinecarboxy-
late moiety on the C4 center potentially utilizable for
the synthesis of acromelic acids A, B, D and E.
OH
CO2H
ref. 6
CO2H
N
H
NHCbz
(+)-1
(–)-kainic acid
In the present study, we explored synthesis of trisubsti-
tuted pyrrolidine carrying an appropriate functionality
Scheme 1.
H
N
H
N
HO2C
O
CO2H
O
CO2H
CO2H
CO2H
CO2H
N
H
N
H
acromelic acid B
acromelic acid A
H
N
N
CO2H
HO2C
N
O
CO2H
CO2H
CO2H
CO2H
CO2H
CO2H
N
H
N
H
N
H
acromelic acid E
acromelic acid D
acromelic acid C
Figure 1.
* Corresponding author. E-mail: konol@mail.cc.tohoku.ac.jp
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00782-1

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H. Nakagawa et al. / Tetrahedron Letters 42 (2001) 4523–4526
Thus, secondary carbamate 2, obtained from enantio-
pure (+)-1, was transformed into the tertiary carbamate
3, [h]3D0 −9.5 (c 0.4, CHCl3), on reaction with
cyclopentylidenethyl chloride7 under standard condi-
tions. After desilylation of 3, the resulting alcohol 4,
[h]3D1 −16.4 (c 0.8, CHCl3), was transformed into the
xanthate 5, [h]3D0 +27.1 (c 1.0, CHCl3), used as the
substrate for the key reaction (Scheme 2).
after 2 h. The difference in reaction rates between the
two substrates may be due to the initial step where the
Chugaev reaction seemed to proceed much faster than
the retro-Diels–Alder reaction. At any rate, these
results indicated that both 5 and 9 generated initially
the same cyclopentene intermediate 10 which then
underwent intramolecular ene reaction under the same
conditions to yield the single trisubstituted pyrrolidine
11. Since the product 11 is present as a mixture of
rotamers, determination of its stereochemistry was not
an easy task. However, NOESY NMR studies (500
MHz) at 60°C revealed three hydrogens on C2, C3 and
C4 centers to be placed on the same face of the
pyrrolidine ring as expected from our previous synthesis
of (−)-kainic acid mentioned above6 (Scheme 4).
On the other hand, the known primary amine8 7,
obtained from enantiopure ketodicyclopentadiene9
(KDP) (−)-6, was transformed into the tertiary carba-
mate 9, [h]2D7 −49.6 (c 0.8, CHCl3), via the secondary
carbamate 8, [h]2D7 −74.5 (c 0.9, CHCl3), under standard
conditions. Since 9 was expected to undergo retro-
Diels–Alder-ene reaction under thermolysis conditions10
to give rise to the same product as the product from the
xanthate 5 through the same intermediate, we were very
interested in the outcome of these two compounds
under thermolysis conditions (Scheme 3).
Construction of the pyridinecarboxylic acid moiety on
the C4 center was next examined using the pyrrolidine
11 thus obtained. Hydroboration–oxidation of 11
afforded the secondary alcohol 12, as a mixture of
epimers, which was oxidized to the ketone 13. Regio-
selective carbomethoxylation of 13 was accomplished
under kinetic conditions using Mander’s reagent11 to
give the b-keto ester 14 which was transformed into the
a,b-unsaturated ester 16 by sequential chemoselective
reduction using zinc borohydride12 and regioselective
dehydration via the alcohol 15. Ozonolysis of 16, fol-
lowed by treatment of the crude product 17 with
After several experiments, it was found that both 5 and
9 furnished the same product 11 in good yields on
reflux in diphenyl ether at 280°C. Namely, the xanthate
5 afforded 11, [h]3D0 −28.0 (c 0.8, CHCl3), diastereoselec-
tively, in 89% yield after 45 min, while the KDP-derived
carbamate 6 furnished the same product 11, [h]2D7 −29.1
(c 0.9, CHCl3), diastereoselectively, in 71% yield from 9
OR
OCS2Me
OTBS
O
O
O
O
iii
i
ref. 6
(+)-1
O
O
N
N
NHCbz
Cbz
Cbz
3 : R = TBS
4 : R = H
2
5
ii
Scheme 2. Reagents and conditions: (i) cyclopentylidenethyl chloride, NaH, NaI (cat.), THF (75%). (ii) TBAF, THF (95%). (iii)
CS2, NaH, MeI, THF, −30 to 0°C (98%).
O
O
ref. 8
i
ii
O
O
O
O
H2N
O
CbzHN
CbzN
(–)-6
7
8
9
Scheme 3. Reagents and conditions: (i) Cbz-Cl, K2CO3, Et2O (41% from 6). (ii) cyclopentylidenethyl chloride, NaH, NaI (cat.),
THF (71%).
5
Ph2O
reflux
H
O
NCbz
H
H
H
3
O
4
2
H
O
N
Ph2O
reflux
O
Cbz
9
11
10
Scheme 4.

H. Nakagawa et al. / Tetrahedron Letters 42 (2001) 4523–4526
4525
hydroxylamine hydrochloride13 in methanol at reflux
proceeded in the expected way to furnish the pyridine 19,
[h]2D5 −36.5 (c 0.8, CHCl3), in one step with concurrent
removal of the acetonide protection group under the
conditions. The reaction may be presumed to proceed
through a transient generation of N-hydroxy-1,4-di-
hydropyridine intermediate 18 followed by dehydration
to give 19. Conversion of 19 to the trimethyl ester 20, [h]D25
−7.4 (c 1.0, CHCl3), the potential precursor for the
synthesis of acromelic acids A and D, was carried out by
sequential glycol cleavage and Jones oxidation followed
by workup with diazomethane6 (Scheme 5).
MeO2C
X
O
OH
i
ii
iii
O
O
11
O
N
O
N
O
N
O
Cbz
Cbz
Cbz
13
12
14 : X = O
iv
15 : X = H,OH
OH
N
MeO2C
MeO2C
MeO2C
O
CHO
v
vi
O
O
O
N
O
N
O
N
O
Cbz
Cbz
Cbz
18
17
16
MeO2C
MeO2C
N
N
vii
CO2Me
CO2Me
OH
OH
N
N
Cbz
Cbz
19
20
Scheme 5. Reagents and conditions: (i) BH3-Me2S, THF, 0°C, then 30% H2O2, 3N NaOH (89%). (ii) PCC, CH2Cl2 (90%). (iii)
MeO2CCN, LiHMDS, THF, −78°C (81%). (iv) Zn(BH4)2, Et2O, 0°C. (v) Ms-Cl, Et3N, CH2Cl2, then DBU, THF, reflux (50%
from 14). (vi) O3, CH2Cl2, Me2S, then NH2OH-HCl, MeOH, reflux (61%). (vii) NaIO4, aq. THF, 0°C, then Jones oxidation, 0°C,
then CH2N2 (31%).
CO2Me
OTf
O
O
i
ii
13
N
O
N
O
Cbz
Cbz
22
21
N
CO2Me
N
CO2Me
CO2Me
iv
OH
OH
iii
N
CO2Me
N
Cbz
Cbz
23
24
Scheme 6. Reagents and conditions: (i) 2-(N,N-trifrlyimino)pyridine, KHMDS, THF, −78°C (86%). (ii) Pd (OAc)2, Et3N, Ph3P,
CO, MeOH, DMF (92%). (iii) O3, CH2Cl2, Me2S, then NH2OH-HCl, MeOH, reflux. (iv) NaIO4, aq. THF, 0°C, then Jones
oxidation, 0°C, then CH2N2 (26% for four steps).

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H. Nakagawa et al. / Tetrahedron Letters 42 (2001) 4523–4526
The isomeric pyridinecarboxylate 24, the potential pre-
cursor for the synthesis of acromelic acid B and E, was
also prepared from the same key intermediate 11. Thus,
the ketone 13, generated from 11, was first transformed
into the enol triflate 21, regioselectively, using Comins’
reagent14 under kinetic conditions. Palladium-mediated
carbomethoxylation15 of 21 proceeded smoothly to
afford the a,b-unsaturated ester 22 isomeric to the ester
16 above. Under the same conditions above involving
ozonolysis and condensation with hydroxylamine
hydrochloride, 22 furnished the pyridinecarboxylate 23
with concurrent removal of the acetonide protecting
group as for the regioisomer 19. Conversion of 23 to
the trimethyl ester 24, [h]2D5 −28.0 (c 0.8, CHCl3), was
also carried out in the same way as for the regioisomer
20 above involving periodate cleavage and Jones oxida-
tion (Scheme 6).
24, 939; (b) Konno, K.; Hashimoto, K.; Ohfune, Y.;
Shirahama, H.; Matsumoto, T. J. Am. Chem. Soc. 1988,
110, 4807; acromelic acids C, D, E: (c) Fushiya, S.; Satou,
S.; Kera, Y.; Nozoe, S. Heterocycles 1992, 34, 1277; (d)
Fushiya, S.; Satou, S.; Kanazawa, T.; Kusano, G.;
Nozoe, S. Tetrahedron Lett. 1990, 31, 3901.
2. Shinozaki, H.; Ishida, M.; Okamoto, T. Brain Res. 1986,
399, 395.
3. Takemoto, T. Jikken Kagaku Koza 1958, 23, 2081.
4. Synthesis: acromelic acid A: (a) Ref. 1a; (b) Ref. 1b; (c)
Takano, S.; Iwabuchi, Y.; Ogasawara, K. J. Am. Chem.
Soc. 1987, 109, 5523; (d) Baldwin, J. E.; Li, C.-S. J.
Chem. Soc., Chem. Commun. 1988, 261; acromelic acid B:
(e) Ref. 1a; (f) Ref. 1b; (g) Takano, S.; Tomita, S.;
Iwabuchi, Y.; Ogasawara, K. Heterocycles 1989, 29,
1473; (h) Horikawa, M.; Hashimoto, K.; Shirahama, H.
Tetrahedron Lett. 1993, 34, 331; acromelic acid E: (i) Ref.
4h.
5. For pertinent reviews for the synthesis of the kainoid
amino acids, see: (a) Hashimoto, K.; Shirahama, H.
Trends Org. Chem. 1991, 2, 1; (b) Parsons, A. F. Tetra-
hedron 1996, 52, 4149.
6. Nakagawa, H.; Sugahara, T.; Ogasawara, K. Org. Lett.
2000, 2, 3181.
7. Prepared from cyclopentanone in three steps.
8. Tanaka, K.; Ogasawara, K. Synthesis 1996, 219.
9. Sugahara, T.; Kuroyanagi, Y.; Ogasawara, K. Synthesis
1996, 1101.
10. Ogasawara, K. J. Syn. Org. Chem. Jpn. 1996, 54, 29.
11. Mander, L. N.; Sethi, S. P. Tetrahedron Lett. 1983, 24,
5425.
Unfortunately, epimerization of the C2 center of two
trisubstituted pyrrolidines, 20 and 24, carrying a
pyridinecarboxylate on the C4 center to the natural
configuration has not been successful so far despite
considerable examination as both triesters were fragile
under basic conditions.4c,4g An alternative synthesis of
acromelic acids on the basis of the present results is in
progress.
Acknowledgements
The authors thank the Ministry of Education, Science,
Sports and Culture, Japan, for financial support.
12. Oishi, T.; Nakata, T. Acc. Chem. Res. 1984, 17, 338.
13. Chumakov, Y. I.; Sherstyuk, V. P. Tetrahedron Lett.
1965, 129.
14. Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33,
6299.
References
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1. Isolation: acromelic acids A and B: (a) Konno, K.;
Shirahama, H.; Matsumoto, T. Tetrahedron Lett. 1983,
.