Intramolecular ene reaction on a bicyclo[3.2.1]octane system: An alternative route to (-)-kainic acid

Article abstract of DOI:10.1016/S0040-4039(01)01558-1

The intramolecular ene reaction of the 1,6-diene on a bicyclo[3.2.1]octane framework proceeds in a highly diastereoselective manner to form a trisubstituted pyrrolidine on the pyran ring in excellent yield. Its stereochemistry has been determined unambiguously by converting it into the known compound serving as a key intermediate of (-)-kainic acid.

Full text of DOI:10.1016/S0040-4039(01)01558-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7587–7590
Intramolecular ene reaction on a bicyclo[3.2.1]octane system:
an alternative route to (−)-kainic acid
Hideaki Hirasawa, Takahiko Taniguchi and Kunio Ogasawara*
Pharmaceutical Institute, Tohoku University, Aobayama, Sendai 980-8578, Japan
Received 28 July 2001; revised 23 August 2001; accepted 24 August 2001
Abstract—The intramolecular ene reaction of the 1,6-diene on a bicyclo[3.2.1]octane framework proceeds in a highly diastereo-
selective manner to form a trisubstituted pyrrolidine on the pyran ring in excellent yield. Its stereochemistry has been determined
unambiguously by converting it into the known compound serving as a key intermediate of (−)-kainic acid. © 2001 Elsevier
Science Ltd. All rights reserved.
We have observed that a regio- and diastereoselective
ring formation occurred on a cyclopentane ring to give
the product 3 bearing a cis-2,3,4-trisubstituted pyrro-
lidine system by an intramolecular ene reaction when
the 1,6-diene 1 was heated in diphenyl ether1 (Scheme
1). In this instance, the diastereoselectivity observed is
explained by the intervention of a rigid transition state
2 that placed the ene component most appropriately on
the enophile cyclopentene for the intramolecular ene
reaction to proceed.2 We are, therefore, very interested
in the same reaction of the 1,6-diene 4 carrying the ene
component on the enophile having a half-chair six-
membered ring, which has to take a less stable half-
boat configuration 5a to initiate the intramolecular ene
reaction to give rise to the product 6 having the same
stereochemistry as the five-membered counterpart 3.
Moreover, our further interest is in the generation of a
pyrrolidine diastereomer 7 having a trans-3,4-stereo-
chemistry through an alternative transition state 5b
owing to the more flexible six-membered framework if
the intramolecular ene reaction proceeds (Scheme 2).
The intramolecular ene reaction occurred cleanly to
give a single product supporting the structure either 6
or 7 in nearly quantitative yield when the 1,6-diene 4,
prepared from enantiopure enone (+)-8 having a dioxa-
bicyclo[3.2.1]octane framework, was refluxed in
diphenyl ether under the same conditions as for 1.
However, the structure of the ene product could not be
determined at this point on the basis of its spectro-
scopic data. To determine the structure as well as to
utilize the excellent result, we examined its conversion
into N-carbobenzoxy-2-carbomethoxy-3-methylcarbo-
methoxy-4-isopropenylpyrrolidine since its cis-2,3,4 iso-
mer was prepared from the ene product 3 and used as
a key intermediate for the synthesis of a natural kainoid
amino acid, (−)-kainic acid.1,3
Prior to the structure determination of the ene product,
synthesis of the 1,6-diene 4 used in the ene reaction has
to be described. Thus, (+)-enone4 8 (>99% ee), prepared
from furfural by employing either a chemical5 or
enzymatic6 chiral induction step, was transformed into
H
N-Z
N-Z
N-Z
H
H
H
280˚C
H
H
O
O
O
O
O
O
3
2
1
Z = CO2Bn
Scheme 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)01558-1

7588
H. Hirasawa et al. / Tetrahedron Letters 42 (2001) 7587–7590
N-Z
N-Z
O
H
H
O
H
O
O
OTBS
OTBS
6
5a
N-Z
H
280˚C
O
diphenyl ether
O
OTBS
N-Z
N-Z
O
H
4
H
O
O
O
H
OTBS
OTBS
7
5b
Z = CO2Bn
Scheme 2.
the endo-mesylate 10 via endo-alcohol 9. The 1,2-
reduction7 of 8 proceeded diastereoselectively from the
convex-face of the molecule to give 8 owing to its
biased framework. Reaction of 10 with sodium azide in
DMF proceeded in a competitive SN2 and SN2% path-
way to furnish a readily separable mixture of two
regioisomeric exo-azides, 11: [h]3D0 +273.0 (c 0.7,
CHCl3), and 12: [h]2D9 −236.5 (c 1.0, CHCl3), in a ratio
of 1:1.2 after silylation of some desilylated products in
the same flask. Fortunately, after separation the unde-
sired isomer 11 furnished an equilibrium mixture of 11
and 12 in a ratio of 1:2.4 on reflux in toluene for 6 h
CHCl3), which furnished the substrate 1,6-diene 4, [h]D29
−82.6 (c 1.0, CHCl3), by N-alkylation with prenyl chlo-
ride under standard conditions. As mentioned, 4 fur-
nished a single intramolecular ene product, [h]2D5 +25.5
(c 0.5, CHCl3), in 98% yield on refluxed in diphenyl
ether for 30 min in the presence of sodium hydrogen
carbonate (Scheme 3).
The structure of the ene product was eventually deter-
mined as 6 having a cis-2,3,4 pyrrolidine structure, but
not as 7 having a trans-2,3,4 stereochemistry by the
following transformation. Thus, the ene product confir-
med later as 6 was first desilylated to give primary
alcohol 14, [h]2D5 +6.6 (c 0.6, CHCl3), which was further
transformed into iodide 16, [h]2D5 +50.8 (c 0.5, CHCl3),
via mesylate 15. Refluxing 16 with zinc in methanol
containing acetic acid induced reductive ring-opening to
give vinyl-hemiacetal 17 as an epimeric mixture, which
presumably through
a
[3,3]-sigmatropic pathway.8
Total yield of 12 from the mixture was attainable up to
93% after repetition of the rearrangement sequence
three times. Reduction of azide 12 with lithium alu-
minum hydride, followed by N-carbobenzoxylation
afforded secondary carbamate 13, [h]3D0 −89.8 (c 0.9,
O
O
O
OR
Ref.5,6
i
iii
CHO
TBSO
O
TBSO
ii
O
O
furfural
9: R= H
10: R= Ms
(+)-8
N3
N3
O
NHZ
O
O
+
v
v
i
ZN
O
TBSO
TBSO
O
O
TBSO
O
12
11
TBSO
O
13
4
iv
Z = CO2Bn
Scheme 3. Reagents and conditions: (i) NaBH4, CeCl3–7H2O, MeOH, −78°C (98%); (ii) MsCl, Et3N, CH2Cl2; (iii) NaN3, DMF,
80°C then TBS–Cl, imidazole (1:1.2 mixture, 89%, two steps); (iv) toluene, reflux, 6 h (1:2.4 mixture, 93%); (v) LiAlH4, Et2O, 0°C
then Cl–CO2Bn(Cl-Z), K2CO3, 0°C (98%, two steps); (vi) prenyl–Cl, NaH, DMF, 0°C (83%).

H. Hirasawa et al. / Tetrahedron Letters 42 (2001) 7587–7590
7589
Z
Z
N
N
Z
iv
O
i
v
N
O
H
H
O
H
X
HO
O
TBSO
O
17
14:X=OH
15:X=OMs
16:X=I
ii
6
iii
O
viii
vii
vi
OH
O
OH
CO2Me
CO2Me
N
Z
N
Z
N
Z
O
20
19
18
CO2H
CO2H
CHO
CO2Me
CO2Me
CO2Me
22
Z = CO2Bn
Ref.1,3
ix
N
H
N
Z
N
Z
(–)-kainic acid 23
21
Scheme 4. Reagents and conditions: (i) TBAF, THF (97%); (ii) Ms–Cl, Et3N, CH2Cl2; (iii) LiI, THF, reflux (98%, two steps); (iv)
Zn, AcOH–MeOH (1:10), reflux (90%); (v) TPAP–NMO, CH2Cl2–MeCN (4:1) (83%); (vi) NaOMe (2 equiv.), MeOH, rt (75%,
recovery 15%); (vii) ButO2H, VO(acac)2, benzene, 40°C (78%); (viii) PhSH, NaH, THF, then aq. NaIO4, 0°C (79%); (ix)
NaClO2–NH2SO3H, 50% aq. dioxane, then CH2N2, MeOH (63%).
was oxidized to give the single d-lactone 18, [h]2D8 +35.6
(c 0.5, CHCl3). On being stirred with two equivalents of
sodium methoxide in methanol, 18 underwent solvolysis
reaction to give a 5:1 equilibrium mixture of methyl
ester 19, [h]2D8 +38.8 (c 0.3, CHCl3), and starting lactone
18 which were separated in yields of 75 and 15%.
1. At the same time, an alternative route to (−)-kainic
acid 23 was established since it has been prepared in
two steps1,3 from the diester 22 (Scheme 4).
In conclusion, we have found the intramolecular ene
reaction of the 1,6-diene on a bicyclo[3.2.1]octane
framework proceeds in a highly diastereoselective man-
ner to form a single trisubstituted pyrrolidine on the
pyran ring in excellent yield. Its stereochemistry has
been determined unambiguously by converting it into
the known compound serving as a key intermediate of
(−)-kainic acid.
To discriminate two double bonds in the molecule, the
ester 19 was treated with tert-butyl hydroperoxide in
benzene in the presence of vanadyl acetylacetonate9 at
40°C to give rise to glycidol 20, [h]2D7 +44.0 (c 0.3,
CHCl3), as a single product without affection of the
isopropenyl functionality. Having discriminated the two
double bonds in the molecule, the epoxy functionality
of 20 was cleaved with thiophenol in THF in the
presence of sodium hydride to give 1,2-diol which,
without separation, was immediately cleaved in the
same flask with aqueous sodium periodate to furnish
aldehyde 21, [h]2D7 +25.8 (c 0.2, CHCl3). Treatment of 21
with sodium chlorite-sulfamic acid10 in aqueous diox-
ane allowed smooth oxidation of the formyl functional-
ity to give dimethyl ester 22, [h]2D8 +22.1 (c 0.2, CHCl3),
after esterification with diazomethane, which was iden-
tical in all respects with an authentic dimethyl ester1 22,
[h]2D5 +21.6 (c 0.2, CHCl3), thus, proving the structure of
the starting 6. This also concluded that the stereochem-
ical course of the ene reaction of 4 is consistent with
transition state 5a as in the five-membered counterpart
Acknowledgements
This work was supported by grants from the Ministry
of Education, Science, Sports and Culture, Japan.
References
1. Nakagawa, H.; Sugahara, T.; Ogasawara, K. Org. Lett.
1990, 2, 3181. See also: Nakagawa, H.; Sugahara, T.;
Ogasawara, K. Tetrahedron Lett. 2001, 42, 0000.
2. For a pertinent review, see: Oppolzer, W.; Snieckus, V.
Angew. Chem., Int. Ed. Engl. 1978, 17, 476.

7590
H. Hirasawa et al. / Tetrahedron Letters 42 (2001) 7587–7590
3. Takano, S.; Iwabuchi, Y.; Ogasawara, K. J. Chem. Soc.,
42, 3360; (h) Conduritols: Kadota, K.; Takeuchi, M.;
Taniguchi, T.; Ogasawara, K. Org. Lett. 2001, 3, 1769.
5. Takeuchi, M.; Taniguchi, T.; Ogasawara, K. Synthesis
1999, 341.
6. Taniguchi, T.; Takeuchi, M.; Kadota, K.; ElAzab, A.
S.; Ogasawara, K. Synthesis 2000, 1325.
7. Gemal, A. L.; Luche, J.-L. J. Am. Chem. Soc. 1981, 103,
5454.
8. (a) Gagneux, A.; Winstein, S.; Young, W. G. J. Am.
Chem. Soc. 1960, 82, 5956; (b) VanderWerf, C. A.;
Heasley, V. L. J. Org. Chem. 1966, 31, 3534.
9. Sharpless, K. B.; Michaelson, R. C. J. Am. Chem. Soc.
1973, 95, 6136.
Chem. Commun. 1988, 1204.
4. (a) Aldohexoses: Takeuchi, M.; Taniguchi, T.;
Ogasawara, K. Chirality 2000, 12, 338; (b) (+)-Noviose:
Takeuchi, M.; Taniguchi, T.; Ogasawara, K. Tetra-
hedron Lett. 2000, 41, 2609; (c) C28-C34 segment of
FK-506: Takeuchi, M.; Taniguchi, T.; Ogasawara, K.
Tetrahedron: Asymmetry 2000, 11, 1601; (d) Calabar
bean alkaloids: ElAzab, A. S.; Taniguchi, T.;
Ogasawara, K. Org. Lett. 2000, 2, 2757; (e) Calabar
bean alkaloids: ElAzab, A. S.; Taniguchi, T.;
Ogasawara, K. Org. Lett. 2000, 2, 2757; (f) (+)-
Febrifugine: Taniguchi, T.; Ogasawara, K. Org. Lett.
2000, 2, 3193; (g) Pseudomonic acid key segment:
Taniguchi, T.; Ogasawara, K. Tetrahedron Lett. 2001,
10. Lindgren, B. O.; Nilsson, T. Acta Chem. Scand. 1973,
27, 888.