by NOE studies (e.g. H-2 and H-4 enhanced by irradiation at H-
3). It has been demonstrated that all syn-analogues of kainic acid
can be epimerised at C-2 to give the kainoid structure.10 Thus,
a titanium-mediated metallabicyclisation approach for the
synthesis of kainic acid could commence with l-serine and
include an epimerisation step after cyclisation. The strategy has
now been implemented successfully (Scheme 2).
procedure, complete conversion into the epimeric ester 24 was
observed [TLC (SiO2: EtOAc–light petroleum, 1:2) 23, Rf 0.30;
24,14 Rf 0.31]. Saponification of 24 was accompanied by N-
deprotection giving (2)-a-kainic acid 1, which was spec-
troscopically consistent with authentic material and corre-
sponded well in terms of polarimetry {[a]D 215.2 (c 0.95,
H2O); lit.,15 215.0 (c 0.5, H2O)} and mp [mp 244–247 °C
(decomp.); lit.,15 mp 237–243 °C (decomp.)].
In conclusion, we have developed a new enantioselective
synthesis of (2)-a-kainic acid 1 which has as its cornerstone a
totally stereoselective titanium-mediated diene metallabicycli-
sation process. The total synthesis is high yielding (3.5% in
twelve steps from commercially available material). This new
route contrasts to other cyclisation–elimination approaches to
the kainoids where stereochemical control has been poor,7 and
although our procedure does require epimerisation at C-2 to
obtain the kainoid structure, it also provides a route to b-
kainoids. In addition, kainoid analogues with a range of
different substituents at C-3 and C-4 are available via this route.
From a general methodological viewpoint, the new procedure
for the stereoselective preparation of syn,syn-2,3,4-trisub-
stituted pyrrolidines is noteworthy.
CHO
CHO
OMe
i,ii
4 steps
iii–v
i,ii
BocN
BocN
BocHN
BnHN
HCl.H2N
L-Serine
O
O
(88%)
OH
OMe
OH
17
18
iii,iv
vi
16
17
16
PhO
PhO
Cl
19
PhO
vii
I
CO2Me
OMe
OMe
PhO
viii
CH2Cl
N
Bn
18
OMe
OTBDMS
OMe
OMe
N
Bn
N
N
19
Bn
CO2Me
OMe
21
20
22
ix
We are grateful to the BBSRC and Roche Discovery Welwyn
for a CASE award (A. D. C.).
CO2Me
CO2Me
CO2H
x
xi
CO2Me
N
CO2Me
CO2Me
N
CO2H
N
H
Notes and references
† All new compounds were fully characterised spectroscopically and by
HRMS/elemental analysis.
‡ During the course of our studies Sato et al. also reported the
stereoselective synthesis of a 2,3,4-trisubstituted pyrrolidine via titanium-
mediated diene metallabicyclisation [ref. 9(c)], although their system was
not suitable for elaboration to produce kainoids.
§ Initial studies were carried out with a protected alcohol as the C-2
substituent. Metallabicyclization was successful and completely stereo-
selective, but problems were encountered when trying to adjust the
oxidation state of the C-2 substituent.
CO2Me
23
24
(–)-α-Kainic acid 1
Scheme 2 Reagents and conditions: i, Ph3P+CH3Br2 KHMDS, THF,
278 °C (80%); ii, Dowex (H+) resin, aq. MeOH (93%); iii, Dess–Martin
oxidation; iv, HCl/MeOH; v, PhCHO, NaBH(OAc)3, ClCH2CH2Cl (31%
for 3 steps); vi, K2CO3, cat. NaI, MeCN, reflux (88%); vii, Ti(OPri)4,
PriMgCl (2 equiv.), Et2O, 250 °C to room temp., then I2, 0 °C [56% (78%
based on recovered 20)]; viii, ButLi (2.2 equiv.), Et2O, 280 °C, then excess
ClCO2Me, 280 °C, then excess ClCO2Me, CICH2CH2CI, reflux, 2 h
(61%); ix, Jones’ oxidation then CH2N2 (65%); x, LiHMDS (2.5 equiv.),
THF, 0 °C, then MeOH (80%); xi, NaOH/MeOH, reflux (70%).
1 S. Murakami, T. Takemoto and Z. Shimizu, J. Pharm. Soc. Jpn., 1953,
73, 1026.
2 G. Impellizzeri, S. Mangiafico, G. Oriente, M. Piatelli, S. Sciuto, E.
Fattorusso, S. Magno, S. Santacroce and D. Sica, Phytochemistry, 1975,
14, 1549.
3 G. Balansard, M. Pellegrini, C. Cavalli and P. Timon-David, Ann.
Pharm. Fr., 1983, 41, 77.
4 A. F. Parsons, Tetrahedron, 1996, 52, 4149.
Thus, l-serine was converted into the (S)-Garner aldehyde 16
using our improved procedure.11 Wittig methylenation and acid
hydrolysis gave the Boc protected vinylglycinol 1711,12 which
underwent Dess–Martin oxidation to a very unstable aldehyde
which was immediately subjected to N-Boc deprotection–acetal
formation to give an amino acetal which was then reductively
aminated with benzaldehyde to give 18 in 31% yield over three
steps. The ee of this amine was shown to be 93% by comparison
with racemic material using HPLC on a chiral column
[Chiralpak AS, 1:99 PriOH–hexane, Rt 324 s (vs. 287 s)]. This
is the first preparation of an acetal-protected vinylglycinal, a
compound that could be useful in other synthetic applications.
Alkylation with allyl chloride 19 then gave the cyclisation
precursor 20 in 88% yield.§ Allyl chloride 19 was prepared by
Horner–Wadsworth–Emmons elaboration of 2-phenoxyacetone
with methyl diethyl phosphonoacetate (94%, E:Z = 2:1)
followed by chromatographic separation, reduction of the
resulting a,b-unsaturated ester (DIBAL-H) and chlorination
(TsCl, DMAP).
5 A. F. Parsons and R. J. K. Taylor, J .Chem. Soc., Perkin Trans. 1, 1994,
1945.
6 A. J. Bird, R. J. K. Taylor and X. Wei, Synlett, 1995, 1237.
7 S.-E. Yoo, S.-H. Lee, K.-Y. Yi and N. Jeong, Tetrahedron Lett., 1990,
31, 6877; M.-P. Bertrand, S. Gastaldi and R. Nourguier, Tetrahedron
Lett., 1996, 37, 1229; O. Miyata, Y. Ozawa, I. Ninomiya and T. Naito,
Synlett, 1997, 275; see also M. D. Bachi and A. Melman, J. Org. Chem.,
1997, 62, 1896.
8 A. D. Campbell, T. M. Raynham and R. J. K. Taylor, unpublished
results.
9 (a) K. Harado, H. Urabe and F. Sato, Tetrahedron Lett., 1995, 36, 3203;
(b) Y. Takayama, Y. Gao and F. Sato, Angew. Chem., Int. Ed. Engl.,
1997, 36, 851; (c) Y. Takayama, S. Okamoto and F. Sato, Tetrahedron
Lett., 1997, 38, 8351.
TiII-mediated cyclisation–iodination of 20 gave the syn,syn-
pyrrolidine 21 as the only cyclised product in 56% yield (78%
based on recovered diene 20). Lithium–halogen exchange and
quenching with excess methyl chloroformate gave 22 in 61%
overall yield. Jones’ oxidation cleaved the acetal and oxidised
the aldehyde produced to the corresponding acid which was
treated with CH2N2 to give ester 23. Compound 23 is a
protected derivative of the so-called b-kainic acid: the titanium
methodology provides a very convenient stereoselective route
to these compounds which are reported to have interesting anti-
convulsant properties.13
10 (a) S. Takano, Y. Iwabuchi and K. Ogasawara, J. Chem. Soc., Chem.
Commun., 1988, 1204; (b) A. Rubio, J. Esquerra, A. Escribano, M. J.
Remuiñán and J. J. Vaquero, Tetrahedron Lett., 1998, 39, 2171.
11 A. D. Campbell, T. M. Raynham and R. J. K. Taylor, Synthesis, 1998,
1707; see also A. McKillop, R. J. K. Taylor, R. J. Watson and
N. J. Lewis, Synthesis, 1994, 31 and references cited therein.
12 Z.-Y. Wei and E. Knaus, Synthesis, 1994, 1463.
13 J. F. Collins, A. J. Dixon, G. Badman, G. De Sarro, A. G. Chapman,
G. P. Hart and B. S. Meldrum, Neurosci. Lett., 1984, 51, 371.
14 S. Takano, K. Inomata and K. Ogasawara, J. Chem. Soc., Chem.
Commun., 1992, 169.
15 W. Oppolzer and K. Thirring, J. Am. Chem. Soc., 1982, 104, 4978.
Epimerisation at C-2 was successfully achieved using
LiHMDS (2.5 equiv.) and quenching with MeOH.10b Using this
Communication 8/09598A
246
Chem. Commun., 1999, 245–246