Nickel and palladium catalysis in the stereoselective synthesis of functionalized pyrrolidines: Enantioselective formal synthesis of (+)-α- allokainic acid

Article abstract of DOI:10.1002/(SICI)1521-3773(19981204)37:22<3144::AID-ANIE3144>3.0.CO;2-Y

Neuroexcitatory natural products are accessible from 1 via the intermediate 2, which is obtained by Ni-catalyzed cyclization, transposition of the protecting group, and Pd-catalyzed reduction with allylic transposition. This stepwise formation of stereocenters allows a highly direct and stereoselective synthesis of the excitatory amino acid (+)-α- allokainic acid, which displays an all-trans arrangement of the substituents about the pyrrolidine ring. TBS = tert-butyldimethylsilyl.

Full text of DOI:10.1002/(SICI)1521-3773(19981204)37:22<3144::AID-ANIE3144>3.0.CO;2-Y

COMMUNICATIONS
8
1
CH
H, 2-adamantanol CH), 0.45 (s, 4H, 2-adamantanol CH), 0.24 (d, 8H, J ˆ
2.5 Hz, 2-adamantanol CH
), 0.10 (d, 8H, J ˆ 12.5 Hz, 2-adamantanol
), 0.06 (d, 8H, J ˆ 12.5 Hz, 2-adamantanol CH ), � 0.10 (s, 4H,
1996, 35, 1084 ± 1086. g) T. N. Parac, D. L. Caulder, K. N. Raymond, J.
Am. Chem. Soc. 1998, 120, 8003 ± 8004, and references therein.
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Ogura, Nature 1995, 378, 469 ± 471; b) A closely related complex: P. J.
Stang, B. Olenyuk, D. C. Muddiman, R. D. Smith, Organometallics
1997, 119, 3094 ± 3096.
2
2
2
1
3
2
-adamantanol CH), � 0.43 (s, 8H, 2-adamantanol CH
2
); C NMR
(
125 MHz, D
2
O): d ˆ 170.1 (Cq), 153.4 (CH), 145.2 (Cq), 126.0 (CH),
7
4.0 (2-adamantanol CH), 47.8 (CH
2
), 37.2 (2-adamantanol CH
2
), 36.1 (2-
II
adamantanol CH
2
), 31.0 (2-adamantanol CH
2
), 27.3 (2-adamantanol CH),
[14] Guest-templated synthesis of a stable Pt derivative of 1: F. Ibukuro,
2
6.8 (2-adamantanol CH).
T. Kusukawa, M. Fujita, J. Am. Chem. Soc. 1998, 120, 8561 ± 8562.
[15] o-Carborane ± azacrown ether (1:1) complex has been reported: P. D.
Godfrey, W. J. Grigsby, P. J. Nichols, C. L. Raston, J. Am. Chem. Soc.
1997, 119, 9283 ± 9284.
1
1
8
2
´ (6)
4
: H NMR (500 MHz, D
2
O): d ˆ 9.29 (d, J ˆ 6.6 Hz, 24H, Py Ha),
.65 (d, J ˆ 6.6 Hz, 24H, Py Hb), 4.09 (s, 12H, trimethoxybenzene CH),
1
3
.98 (s, 24H, -NCH
O): d ˆ 169.9 (Cq), 160.6 (trimethoxybenzene Cq), 153.3 (CH) 145.9
Cq), 126.2 (CH), 92.0 (trimethoxybenzene CH), 54.5 (CH O) 47.8
2 2 3
CH N-), 2.43 (br s, 36H, CH O); C NMR (125 MHz,
[
16] R. J. Blanch, M. W. Williams, G. D. Fallon, M. G. Gardiner, R.
Kaddour, C. L. Raston, Angew. Chem. 1997, 109, 520 ± 522; Angew.
Chem. Int. Ed. Engl. 1997, 36, 504 ± 505.
D
2
(
(
3
2 2
-NCH CH N-).
[
17] In contrast, CH signal of carborane does not shift significantly
implying the inclusion geometry with electronegative BH groups
located inside and electropositive CH groups located outside. Four
guest molecules are likely to reside in tetrahedral positions around the
1
1
´ 7: H NMR (500 MHz, D
2
O): d ˆ 9.28 (br s, 24H, Py Ha), 8.72 (br s, 24H,
CH
N-), � 0.12 (s, 27H,
O): d ˆ 170.1 (Cq), 153.3 (CH) 149.0 (7 Ar
Cq), 146.3 (Cq), 126.0 (CH), 47.8 (-NCH CH N-), 33.8 (tBu Cq), 30.4 (tBu
CH ).
Py Hb), 4.8 (s, 3H, 7 Ar CH), 2.99 (s, 24H, -NCH
2
2
tBu); 13C NMR (125 MHz, D
2
2
2
II
center of the cage, directed away from the octahedrally positioned Pd
3
centers. See the X-ray structure of 1 ´ (G)
late) reported in ref.
4
(G ˆ adamantanecarboxy-
[
13]
Received: June 2, 1998 [Z11936IE]
German version: Angew. Chem. 1998, 110, 3327 ± 3329
[18] The broadening of the signals is probably due to a slow exchange on
the NMR time scale between the free and complexed host.
[
19] The assignment of the signals was confirmed by H ± H COSY, C ± H
Keywords: adamantanes ´ boron ´ clusters ´ molecular
recognition ´ palladium
COSY, NOESY, H ± C HMBC.
[
20] The 1:4 stoichiometry was estimated by the Job plot method.
21] Force-field calculation clearly shows that tri-tert-butylbenzene is
slightly larger than the portals of 1.
[
[
[
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Chem. Commun. 1995, 59 ± 60.
Nickel and Palladium Catalysis in the
Stereoselective Synthesis of Functionalized
Pyrrolidines: Enantioselective Formal
Synthesis of (‡)-a-Allokainic Acid
[
[
3] J. Kang, J. Rebek, Jr., Nature 1997, 385, 50 ± 52.
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[
[
[
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Maxim V. Chevliakov and John Montgomery*
115, 10111 ± 10116.
(
‡)-a-Allokainic acid and (� )-a-kainic acid are represen-
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van Duynhoven, D. N. Reinhoudt, Angew. Chem. 1994, 106, 2437 ±
tative members of the kainoid family of neuroexcitatory
amino acids whose biological activity has been attributed to
their action as conformationally restricted analogues of
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Huisman, D. M. Rudkevich, F. C. M. van Veggel, D. N. Reinhoudt, J.
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[1]
glutamate (Scheme 1). Extensive structure ± activity studies
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have demonstrated that the C-4 isopropenyl substituent is the
60, 1207 ± 1213.
[
[
8] C. Sheu, K. N. Houk, J. Am. Chem. Soc. 1996, 118, 8056 ± 8070.
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1
1
485 ± 1488; b) N. Branda, R. Wyler, J. Rebek, Jr. Science 1994, 263,
267 ± 1268; c) R. Meissner, X. Garcias, S. Mecozzi, J. Rebek, Jr., J.
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[
[
10] L. R. MacGillivray, J. L. Atwood, Nature 1997, 389, 469 ± 472.
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Scheme 1. Kainoid natural products.
3
476 ± 3481; b) R. H. Vreekamp, W. Verboom, D. N. Reinhoudt, J.
[
*] Prof. J. Montgomery, M. V. Chevliakov
Org. Chem. 1996, 61, 4282 ± 4288.
Department of Chemistry,
Wayne State University
[
12] Self-assembled cage compounds containing metals: a) R. W. Saal-
frank, A. Stark, K. Peters, H. G. von Schnering, Angew. Chem. 1988,
Detroit, MI 48202-3489 (USA)
Fax: (‡1)313-577-1377
1
00, 878 ± 880; Angew. Chem. Int. Ed. Engl. 1988, 27, 851 ± 853; b) P.
Baxter, J.-M. Lehn, A. DeCian, J. Fischer, Angew. Chem. 1993, 105,
2 ± 95; Angew. Chem. Int. Ed. Engl. 1993, 32, 69 ± 72; c) S. Mann, G.
E-mail: jwm@chem.wayne.edu
9
Huttner, L. Zsolnai, K. Heinze, Angew. Chem. 1996, 108, 2983 ± 2984;
Angew. Chem. Int. Ed. Engl. 1996, 35, 2808 ± 2809; d) P. Jacopozzi, E.
Dalcanale, Angew. Chem. 1997, 109, 665 ± 667; Angew. Chem. Int. Ed.
Engl. 1997, 36, 613 ± 615; e) C. M. Hartshorn, P. J. Steel, Chem.
Commun. 1997, 541 ± 542. f) T. Beissel, R. E. Powers, K. N. Raymond,
Angew. Chem. 1996, 108, 1166 ± 1168; Angew. Chem. Int. Ed. Engl.
[**] This work was supported by the National Institutes of Health. J.M.
acknowledges receipt of a National Science Foundation CAREER
Award, a Camille Dreyfus Teacher-Scholar Award, and a 3M
Pharmaceuticals New Faculty Award. M.V.C. acknowledges receipt
of a Graduate Research Assistantship Award from Wayne State
University. The authors thank H e l eÁ ne Fain for helpful suggestions.
3
144
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
1433-7851/98/3722-3144 $ 17.50+.50/0
Angew. Chem. Int. Ed. 1998, 37, No. 22

COMMUNICATIONS
principal site at which structural variation is allowed without
[
2]
compromising neuroexcitatory activity. Given the important
role of these natural products in pharmacological investiga-
tions, we set out to develop a synthetic entry to this class of
compounds that allows facile late-stage modification of the
C-4 substituent and access to both the kainic acid and
[
3]
allokainic acid configurations. Herein, we report our initial
studies in this regard with a direct and highly stereoselective
formal total synthesis of (‡)-a-allokainic acid. The strategy
involves the nickel-catalyzed cyclization of a d-serine-derived
alkynyl enone with trimethyl aluminum followed by a
palladium-catalyzed allylic carbonate reductive transposition
Scheme 3. Stereoselectivity of nickel-catalyzed alkylative cyclization.
(Scheme 2).
d-Serine methyl ester was efficiently converted to the
central cyclization substrate 4 in straightforward fashion
Scheme 2). Condensation of d-serine methyl ester with
A silyl to carbonate protecting group transposition was
carried out in 73% yield to prepare substrate 6 for a
palladium-catalyzed reduction with allylic transposition. Re-
lated systems were reported by Tsuji et al. to rearrange with
palladium catalysis via intermediate p-allyl complexes to give
the terminal alkene by hydride delivery to the more hindered
(
[
4]
triphosgene, followed by N-propargylation with iodide 1
using KHMDS afforded 2 in 49% yield over two steps.
[
5]
Chemoselective ester reduction with NaBH4, oxidation
under Swern conditions, and Wittig olefination with oxazoli-
[
6]
[9]
dinone 3 gave substrate 4 in 74% overall yield from 2.
Cyclization of 4 with MeLi/ZnCl and 10 mol% [Ni(cod) ]
allyl terminus. The stereochemistry of oxidative addition
ultimately sets the stereochemistry of the overall process,
2
2
[
7±8]
by employing conditions previously reported
afforded high
since decarboxylation and C�H bond reductive elimination
yields but moderate diastereoselectivities (ca. 3:1). Commer-
cial trimethylaluminum or dimethylzinc, however, were found
both proceed with overall retention of configuration. Treat-
ment of 6 with [Pd (dba) ]/PBu and HCO H/Et N cleanly
2
3
3
2
3
to be superior to MeLi/ZnCl in achieving the desired trans
stereochemical relationship of the C-2 and C-3 substituents.
Cyclization of 4 with commercial trimethylaluminum and
produced 7 in 74% yield with a 95:5 diastereomeric ratio in
favor of the all-trans stereochemical relationship of the three
substituents at the pyrrolidine ring, 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 b-face of 6 (Scheme 4). The formal total synthesis of (‡)-
a-allokainic acid was then completed by converting the
acyloxazolidinone unit to the corresponding methyl ester 8
2
[
Ni(cod) ] (10 mol%) in THFafforded a 73% yield of 5 with a
2
diastereomeric ratio (d.r.) of >97:3 in favor of the desired
trans isomer, and commercial dimethylzinc under identical
conditions afforded a 67% yield of 5, also with a >97:3
diastereomeric ratio. We believe that a parallel orientation of
the two reactive p components in chelated structure 9 is
responsible for the trans relationship of the two substituents in
product 5 (Scheme 3).
[10]
upon treatment with CH OMgBr (Scheme 2). Compound 8
3
was previously converted to (‡)-a-allokainic acid by Hanes-
sian et al.[
3c]
Scheme 2. Formal synthesis of (‡)-a-allokainic acid. a) Triphosgene, THF, 658C, 4 h; b) KHMDS (1.1 equiv), THF, 08C, 30 min; then 1 (3 equiv) in THF;
08C, 24 h, 49% (2 steps); c) NaBH , EtOH, 0 ± 258C, 3 h, 91%; d) (COCl) (1.5 equiv), DMSO (3 equiv), Et N (4 equiv), CH Cl
, � 788C; e) 3 (1.5 equiv),
DMAP (3 equiv), CH Cl Al (3 equiv), 10 mol% [Ni(cod) ], THF, 08C, 40 min., 73% (97:3 diastereoisomeric
, � 20 to 258C, 1.5 h, 81% (two steps); f) Me
ratio); g) HF ´ pyridine, THF, 0 ± 258C, 24 h, 86%; then methylchloroformate (3 equiv), pyridine, CH Cl , 0 ± 258C, 3 h, 83%; h) 10 mol% [Pd (dba) ],
0 mol% PBu , Et N (1.5 equiv), HCO
4
4
2
3
2
2
2
2
3
2
2
2
2
3
4
3
3
2
H (1.5 equiv), THF, 658C, 74%, (95:5 diastereomeric ratio); i) MeOMgBr (3 equiv), 258C, 3 h, 54%. cod ˆ
cycloocta-1,5-diene, dba ˆ 1,5-diphenylpenta-1,4-dien-3-one, DMAP ˆ 4-dimethylaminopyridine, HMDS ˆ hexamethyldisilazanide, TBS ˆ tert-butydime-
thylsilyl.
Angew. Chem. Int. Ed. 1998, 37, No. 22
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
1433-7851/98/3722-3145 $ 17.50+.50/0
3145

COMMUNICATIONS
[
[
[
1] a) S. Marukami, T. Takemoto, Z. Shimizu, J. Pharm. Soc. Jpn. 1953, 73,
026 ± 1028; b) A. F. Parsons, Tetrahedron 1996, 52, 4149 ± 4174.
2] R. Chamberlin, R. Bridges in Drug Design for Neuroscience, (Ed.:
A. P. Kozikowski), Raven, New York, 1993, pp. 231 ± 259.
3] a) For an overview of synthetic entries to kainic acid and allokainic
acid, see reference [1b]; For representative syntheses, see: b) W.
Oppolzer, K. Thirring, J. Am. Chem. Soc. 1982, 104, 4978 ± 4979; c) S.
Hanessian, S. Ninkovic, J. Org. Chem. 1996, 61, 5418 ± 5424; d) S.
Hatakeyama, K. Sugawara, S. Takano, J. Chem. Soc. Chem. Commun.
1
1993, 125 ± 127; e) C. Agami, M. Cases, F. Couty, J. Org. Chem. 1994,
59, 7937 ± 7940; f) G. A. Kraus, J. O. Nagy, Tetrahedron 1985, 41,
3537 ± 3545; g) H. H. Mooiweer, H. Hiemstra, W. N. Speckamp,
Tetrahedron 1991, 47, 3451 ± 3462; h) P. DeShong, D. A. Kell,
Tetrahedron Lett. 1986, 27, 3979 ± 3982.
[
4] M. P. Doyle, A. B. Dyatkin, M. N. Protopopova, C. I. Yang, C. S.
Miertschin, W. R. Winchester, S. H. Simonsen, V. Lynch, R. Ghosh,
Recl. Trav. Chim. Pays-Bas 1995, 114, 163 ± 170.
Scheme 4. Palladium-catalyzed reductive transposition.
[5] M. P. Sibi, D. Rutherford, R. Sharma, J. Chem. Soc. Perkin Trans 1
1
994, 1675 ± 1678.
[
6] Reagent 3 was prepared in a fashion analogous to the reported
procedure for a phenylalanine-derived reagent: D. A. Evans, W. C.
Black, J. Am. Chem. Soc. 1993, 115, 4497 ± 4513.
The above strategy should provide simple variation of the
C-4 substituent of allokainic acid simply by selection of a
more complex organoaluminum or organozinc reagent. In
addition, the introduction of chirality in sequential operations
provides the opportunity for modification of the above
strategy to allow preparation of the epimeric series of
kainoids typified by kainic acid itself through a late-stage
[
7] a) J. Montgomery, A. V. Savchenko, J. Am. Chem. Soc. 1996, 118,
2
099 ± 2100; b) J. Montgomery, E. Oblinger, A. V. Savchenko, J. Am.
Chem. Soc. 1997, 119, 4911 ± 4920; c) application of the [Ni(cod) ]/
2
organozinc-mediated cyclization in the preparation of hetereocycles
has been described: J. Montgomery, M. V. Chevliakov, H. L. Briel-
mann, Tetrahedron 1997, 53, 16449 ± 16462; d) J. Montgomery; J. Seo;
H. M. P. Chui, Tetrahedron Lett. 1996, 37, 6839 ± 6842.
8] For leading references to other classes of transition metal catalyzed
carbocyclizations, see: I. Ojima, M. Tzamarioudaki, Z. Li, R. J.
Donovan, Chem. Rev. 1996, 96, 635 ± 662.
9] a) T. Mandai, S. Suzuki, T. Murakami, M. Fujita, M. Kawada, J. Tsuji,
Tetrahedron Lett. 1992, 33, 2987 ± 2990; b) J. Tsuji, I. Shimizu, I.
Minami, Chem. Lett. 1984, 1017 ± 1020; c) J. Tsuji, I. Minami, I.
Shimizu, Synthesis 1986, 623 ± 627.
[
11]
common intermediate.
[
[
Experimental Section
5
: Trimethylaluminum (2.0m in hexanes, 1.44 mmol) was added dropwise to
a solution of [Ni(cod) ] (13.2 mg, 0.05 mmol) in THF (1.5 mL) at 08C. After
min, the mixture was transferred to a solution of 4 (210 mg, 0.48 mmol) at
8C in THF (3 mL) by cannula, and stirring was continued for 40 min at
8C. The reaction was quenched with NH Cl/NH OH pH 8 buffer,
, filtered, and
concentrated. Flash chromatography (EtOAc/hexanes 1/1) afforded 5
2
[
10] D. A. Evans, M. M. Morrissey, R. L. Dorow, J. Am. Chem. Soc. 1985,
07, 4346 ± 4348.
11] For a conceptually related strategy involving intramolecular proto-
desilylations, see reference [3d].
5
0
0
1
[
4
4
extracted with EtOAc (four times), dried over MgSO
4
2
5
(
(
160 mg, 0.35 mmol, 73%) in a 97:3 diastereomeric ratio: [a]
D
ˆ � 90.9
c ˆ 0.5 in CHCl ): d ˆ 4.64 (dd, J ˆ 4.5,
3
); 1H NMR (500 MHz, CDCl
3
3
4
2
3
7
.5 Hz, 1H), 4.41 ± 4.48 (m, 2H), 4.01 ± 4.09 (m, 4H), 3.73 (dt, J ˆ 8.0,
.5 Hz, 1H), 3.59 (d, J ˆ 15 Hz, 1H), 3.36 (d, J ˆ 16 Hz, 1H), 2.91 ± 3.02 (m,
H), 1.68 (s, 3H), 1.58 (s, 3H), 1.55 (s, 3H), 0.89 (s, 9H), 0.06 (s, 3H), 0.05 (s,
H); 1 C NMR (125 MHz, CDCl
3
Acrylate-Assisted Arene ± Chromium Bond
3
): d ˆ 173.0, 161.1, 154.0, 132.8, 130.2,
5.4, 70.5, 65.1, 64.8, 60.5, 48.5, 44.2, 41.1, 25.9, 24.85, 24.81, 18.3, 16.3, � 5.3,
Cleavage: Generation of a [Cr(CO) ] Fragment
2
�
5.4; IR (film): nÄ ˆ 2928, 1772, 1695, 1396, 1311; HRMS: m/z: calcd. for
under Mild Conditions*
‡
C
18
H
27
N
2
O
6
Si 395.1639, found 395.1642 [M � C(CH
3
)
3
].
E. Peter Kündig,* Mikhail Kondratenko, and
Patrick Romanens
7
[
(
: Tributylphosphane (6.1 mg, 0.03 mmol) was added to a solution of
Pd (dba) ] (6.4 mg, 0.007 mmol) in THF (0.3 mL) at 08C. Formic acid
4.83 mg, 0.1 mmol) and triethylamine (10.6 mg, 0.1 mmol) were added
2
3
neat, followed by carbonate 6 (25 mg, 0.06 mmol) in THF (0.3 mL), and the
reaction mixture was refluxed (bath temperature 80 ± 858C) for 3 h. The
mixture was filtered through florisil, and the solvent was removed. Flash
chromatography (EtOAc/hexanes 1/1) afforded 7 (15 mg, 0.05 mmol, 74%)
Ligand exchange is a key reaction in stoichiometric and
catalytic applications of transition metal compounds. It is
instrumental in the coordination of a substrate and, following
metal-mediated reactions, in the release of the product.
Therefore the rate of these processes often determines the
efficiency of the overall transformation. Acceleration of
ligand exchange and the increase in selectivity that results
2
5
1
in a 95:5 diastereomeric ratio: [a]
D
ˆ � 22.4 (c ˆ 1.45 in CHCl
): d ˆ 4.87 (br. s,1H), 4.85 (t, J ˆ 1.5 Hz, 1H), 4.45 ± 4.49
m, 2H), 4.02 (s, 2H), 3.74 (m, 1H), 3.47 (dd, J ˆ 8.5, 11.0 Hz, 1H), 3.38 (dd,
3
); H NMR
(
500 MHz, CDCl
3
(
J ˆ 9.5, 11.5 Hz, 1H), 3.20 (dd, J ˆ 17.0, 4.0 Hz, 1H), 2.75 (m, 2H), 2.25 (dq,
1
3
J ˆ 9.5, 4.0 Hz, 1H), 1.70 (s, 3H), 1.54 (s, 6H); C NMR (125 MHz, CDCl
3
):
d ˆ 172.4, 160.7, 154.0, 141.6, 114.7, 75.3, 68.0, 64.8, 60.6, 54.9, 48.6, 42.9,
38.2, 24.7, 24.6, 18.2; IR (film): nÄ ˆ 1774, 1696, 1381, 1308; HRMS (EI): m/z:
[*] Prof. Dr. E. P. Kündig, Dr. M. Kondratenko, P. Romanens
D e partement de Chimie Organique, Universit e de Gen eÁ ve
‡
calcd for C16
H
22
N
2
O
5
322.1529, found 322.1535 [M ].
3
0 Quai Ernest Ansermet, CH-1211 Gen eÁ ve 4 (Switzerland)
Received: June 22, 1998 [Z12026IE]
German version: Angew. Chem. 1998, 110, 3346 ± 3348
Fax: (‡41)22-328-7396
E-mail: peter.kundig@chiorg.unige.ch.
[
**] We thank the Swiss National Science Foundation for support of this
work (SNSF grants 20-045291.95 and 20-52478.97) and Dr. Allan
Cunningham Jr., Ciba Specialty Chemicals for valuable discussions.
Keywords: cyclizations ´ neurotoxins ´ nickel ´ palladium ´
pyrrolidines
3
146
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1433-7851/98/3722-3146 $ 17.50+.50/0
Angew. Chem. Int. Ed. 1998, 37, No. 22