Zirconium-Mediated Intramolecular Ester Transfer Reaction: Synthesis of α-Substituted γ-Aminobutyric Acid (GABA) Derivatives

Article abstract of DOI:10.1021/ol025709k

(matrix presented) The zirconium-mediated intramolecular ester transfer reaction of N-alkenyl carbamate derivatives proceeded to give α-substituted γ-aminobutyric acid (GABA) derivatives in good to excellent yields. Quenching experiments of the reaction mixture with iodine or O₂ indicated the presence of a cyclopropane intermediate. The resulting iodide was converted to 2-substituted pyrrolidine-3-carboxylate and/or α-alkylidene-γ-aminobutyric acid derivatives in a stereospecific manner.

Full text of DOI:10.1021/ol025709k

ORGANIC
LETTERS
2002
Vol. 4, No. 9
1499-1501
Zirconium-Mediated Intramolecular Ester
Transfer Reaction: Synthesis of
r-Substituted γ-Aminobutyric Acid
(GABA) Derivatives
Hisanaka Ito,† Katsunori Omodera, Yasushi Takigawa, and Takeo Taguchi*
School of Pharmacy, Tokyo UniVersity of Pharmacy and Life Science,
1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
taguchi@ps.toyaku.ac.jp
Received February 13, 2002
ABSTRACT
The zirconium-mediated intramolecular ester transfer reaction of N-alkenyl carbamate derivatives proceeded to give r-substituted γ-aminobutyric
acid (GABA) derivatives in good to excellent yields. Quenching experiments of the reaction mixture with iodine or O indicated the presence
2
of a cyclopropane intermediate. The resulting iodide was converted to 2-substituted pyrrolidine-3-carboxylate and/or r-alkylidene-γ-aminobutyric
acid derivatives in a stereospecific manner.
Low-valent zirconium-mediated intramolecular coupling
reaction of unsaturated functional groups has been widely
developed as a powerful tool for the construction of cyclic
compounds.1 Although many reports on intramolecular
coupling reaction of alkene, alkyne, and imine derivatives
have appeared, to the best of our knowledge, there is no
example of a zirconium-mediated intramolecular coupling
reaction between alkene and carbonyl moieties. On the other
hand, low-valent titanium-mediated intramolecular coupling
reaction of the carbon-carbon multiple bond with a carbonyl
group to afford cycloalkanol, cycloalkanone, lactone and
related compounds has been reported.2,3 Furthermore, some
catalytic approaches to the intramolecular coupling reaction
of alkene with a carbonyl group by using titanocene
derivatives were successfully achieved.4 In particular, titanium-
mediated intramolecular nucleophilic acyl substitution (INAS)
reaction of alkene with a carbonate moiety is a useful tool
for the construction of lactone derivatives.5 Contrary to such
a low-valent titanium chemistry, the use of a zirconocene
equivalent (zirconocene butene complex, “Cp2Zr”)6 in these
reactions would be difficult due to the high oxophilicity of
the zirconium atom resulting in the attack of the butene
ligand on the carbonyl group prior to the butene-alkene
ligand exchange reaction. We anticipated that both electronic
and steric features of the carbonyl moiety would affect its
reactivity toward the zirconocene equivalent, and thus
N-alkenyl-N-substituted tert-butyl carbamate (1 or 3) was
chosen as the substrate for the intramolecular coupling
reaction due to the relatively lower reactivity of this sterically
hindered carbamate than that of ketone or ester. Moreover,
the substituent on the nitrogen atom would control the
reaction pathway depending on its ability as a leaving group.
† Current address: School of Life Science, Tokyo University of Pharmacy
and Life Science.
(4) (a) Kablaoui, N. M.; Buchwald, S. L. J. Am. Chem. Soc. 1995, 117,
6785. (b) Kablaoui, N. M.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118,
3182. (c) Kablaoui, N. M.; Hicks, F. A.; Buchwald, S. L. J. Am. Chem.
Soc. 1996, 118, 5818. (d) Kablaoui, N. M.; Hicks, F. A.; Buchwald, S. L.
J. Am. Chem. Soc. 1997, 119, 4424.
(5) (a) Lee, J.; Kim, Y. G.; Bae, J. G.; Cha, J. K. J. Org. Chem. 1996,
61, 4878. (b) Okamoto, S.; Kasatkin, A.; Zubaidha, P. K.; Sato, F. J. Am.
Chem. Soc. 1996, 118, 2208. See also ref 3.
(1) Negishi, E. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 5, p 1163.
(2) For early works on titanium-mediated intramolecular coupling reaction
of a carbon-carbon multiple bond with carbonyl compounds, see: Hewlett,
D. F.; Whitby, R. J. J. Chem. Soc., Chem. Commun. 1990, 1684.
(3) For reviews, see: (a) Kulinkovich, O. G.; de Meijere, A. Chem. ReV.
2000, 100, 2789. (b) Sato, F.; Urabe, H.; Okamoto, S. Chem. ReV. 2000,
100, 2835.
(6) Negishi, E.; Cederbaum, F. E.; Takahashi, T. Tetrahedron Lett. 1986,
27, 2829.
10.1021/ol025709k CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/05/2002

That is, as shown in Scheme 1, lactam derivative 2 would
be formed from the substrate 1 having an electron-donating
Table 1. Zirconium-Mediated Intramolecular Ester Transfer
Reactiona
Scheme 1
group, while γ-amino carboxylic acid derivative 4 would be
obtained from the substrate 3 with an electron-withdrawing
group such as a sulfonyl group. We report herein an efficient
synthetic method for the selective construction of lactam
derivatives and R-substituted γ-aminobutyric acid (GABA)
derivatives through Cp2Zr-mediated intramolecular coupling
reaction of alkene and carbamate moieties (Scheme 1).7
Preliminary results are summarized in Table 1. The
zirconium-mediated intramolecular coupling reaction of
N-benzyl carbamate derivative 1 smoothly proceeded to give
pyrrolidine derivative 2 in 75% yield through path a (entry
1). A similar reaction of 3a having an electron-withdrawing
group (p-toluenesulfonyl group) with Cp2Zr also efficiently
proceeded through path b to give the γ-amino ester derivative
4a in excellent yield (entry 2).8 The present coupling reaction
could be applied to the substrates with a disubstituted olefin
part, 3b-e, to give the products 4b-e in slightly lower yields
(entries 3, 5, 7, and 8). As shown in entries 4 and 6, toluene,
instead of THF, was a more effective solvent for the substrate
that has a hindered olefin part. The coupling reaction of
4-pentenyl carbamate 3f proceeded smoothly after migration
of zirconium to a more hindered inner site in a way to form
the five-membered ring intermediate (entry 9 and Scheme
2).9,10 One more carbon-elongated 5-hexenyl carbamate 3g
was also reacted intramolecularly after the migration of
a Compound 1 or 3 (0.5 mmol), Cp2Zr prepared from Cp2ZrCl2 (0.6
mmol) and n-butyllithium (1.2 mmol), THF, rt. b Isolated yield. c Toluene
was used as the solvent.
zirconium to give the R-propyl-γ-amino ester 4c (entry 10).
These substrates 3a-g were easily prepared by the Mit-
sunobu reaction of the corresponding alken-1-ol with N-(tert-
butoxycarbonyl)-p-toluenesulfonamide.11
To clarify the reaction mechanism and to introduce an
additional functional group into the product, we examined
the quenching of the intermediate with electrophiles. Al-
though the reaction of alkylzirconium with oxygen has been
(7) Zirconium-mediated intermolecular coupling reaction of alkyne with
chloroformate to obtain the R,â-unsaturated esters was reported. Takahashi,
T.; Xi, C.; Ura, Y.; Nakajima, K.; J. Am. Chem. Soc. 2000, 122, 3228.
(8) Typical Experimental Procedure for the Intramolecular Ester Transfer
Reaction. Under an argon atmosphere, a solution of n-butyllithium (1.48
M in hexane, 0.81 mL, 1.2 mmol) was added to a solution of zirconocene
dichloride (175 mg, 0.6 mmol) in THF (2 mL) at -78 °C, and the reaction
mixture was stirred at the same temperature for 1 h. A solution of compound
3 (0.5 mmol) in THF (2 mL) was added to the reaction mixture at -78 °C,
and the mixture was stirred at ambient temperature for 1 h. To the reaction
mixture was added 4% hydrochloric acid, and the mixture was extracted
with ethyl acetate. The organic layer was washed with saturated sodium
bicarbonate, brine, and dried over magnesium sulfate. After filtration, the
filtrate was concentrated under vacuum. The residue was purified by silica
gel column chromatography.
Scheme 2
(9) (a) Hart, D. W.; Schwartz, J. J. Am. Chem. Soc. 1974, 96, 8115. (b)
Negishi, E.; Maye, J. P.; Choueiry, D. Tetrahedron 1995, 51, 4447.
(10) In the case of titanium-mediated intramolecular reaction of 4-pen-
tenyl carbonate reported by Sato et al., a complex mixture without any
desired product was obtained. See ref 5b.
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Org. Lett., Vol. 4, No. 9, 2002

reported as a useful method for the conversion of the
carbon-zirconium bond to a hydroxyl group,12 no oxygen-
ated product was detected by treating the reaction mixture
with O2 before the aqueous workup. On the other hand,
iodination was accomplished by the addition of iodine to
the reaction mixture. The iodide 5c and 5d derived from (E)-
isomer 3c and (Z)-isomer 3d were obtained as single
stereoisomers, respectively (Scheme 3). These compounds
Scheme 4. Proposed Reaction Mechanism
Scheme 3
the chiral center bearing the iodine atom in the product 5d
was inverted, if the intermediate B was trapped with iodine.
Presumably, the bicyclic intermediate B easily converted to
the cyclopropane intermediate C due to the facile cleavage
of the bridgehead carbon-nitrogen bond by attacking the
nucleophilic carbon center bearing the zirconium atom.
Similar cyclopropane formation reaction has been reported
in the titanium-mediated inter- or intramolecular coupling
reaction of alkene with an ester group, in which an
alkyltitanium intermediate cyclized intramolecularly to form
cyclopropanol derivatives.3 We also reported zirconium-
mediated cyclopropanation by the attack of an alkylzirconium
species on the oxocarbenium ion.14 Subsequently, this
intermediate C reacts with iodine via inversion of the
stereocenter to afford the iodide 5d (Scheme 4).15 The
participation of the cyclopropane intermediate C in this
reaction is possibly supported not only by the stereochemical
outcome of the iodide 5d but also by the result of the
quenching reaction with oxygen, instead of iodine, (vide
supra) indicating that there is no zirconium-carbon bond in
the intermediate.
could be converted stereospecifically to the pyrrolidine
derivatives 6c and 6d, respectively, upon treatment with
potassium carbonate and to the R,â-unsaturated esters 7c and
7d, respectively, by reaction with DBU. The stereochemistry
of 5c was determined on the basis of the stereochemistries
of the pyrrolidine derivative 6c and R,â-unsaturated ester
7c formed via SN2 and E2 mechanisms, respectively.
Likewise, the stereochemistries of 6d and 7d were the basis
for the structure determination of 5d. Our proposed reaction
mechanism is shown in Scheme 4. The ligand exchange
reaction of the zirconocene equivalent with the carbon-
carbon double bond in the substrate 3d gave zirconacyclo-
propane intermediate A, which then coupled with the
carbonyl moiety intramolecularly to form a bicyclic inter-
mediate B. It is known that the iodination of an alkylzirco-
nium intermediate proceeds with complete retention of
configuration.13 However, the observed stereochemistry of
In conclusion, we have developed a useful preparative
method for R-substituted γ-aminobutyric acid derivatives via
a zirconium-mediated intramolecular ester transfer reaction
of N-alkenyl-N-tosyl carbamates. 2-Substituted pyrrolidine-
3-carboxylic acid derivative 6 and R,â-unsaturated carboxy-
late 7 could be obtained in a stereospecific manner through
the iodination of the intermediate followed by treatment with
base.
Supporting Information Available: Typical experimen-
tal procedure and spectral and analytical data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL025709K
(11) Henry J. R.; Marcin, L. R.; McIntosh, M. C.; Scola, P. M.; Harris,
G. D., Jr.; Weinreb, S. M. Tetrahedron Lett. 1989, 30, 5709.
(12) Blackburn, T. F.; Labinger, J. A.; Schwartz, J. Tetrahedron Lett.
1975, 3041.
(13) Hart, D. W.; Blackburn, T. F.; Schwartz, J. J. Am. Chem. Soc. 1975,
97, 679. See also ref 8a.
(14) (a) Ito, H.; Kuroi, H.; Ding, H.; Taguchi, T. J. Am. Chem. Soc.
1998, 120, 6623. (b) Ito, H.; Sato, A.; Kusanagi, T.; Taguchi, T. Tetrahedron
Lett. 1999, 40, 3397.
(15) DePuy, C. H.; Breitbeil, F. W.; DeBruin, K. R. J. Am. Chem. Soc.
1966, 88, 3347.
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