Highly stereoselective addition of Grignard reagents to C- cyclopropylnitrone via the bisected s-trans conformation. An efficient synthesis of PEDC, a potent NMDA receptor antagonist having a cyclopropane structure

Article abstract of DOI:10.1016/S0040-4039(00)00823-6

An efficient synthesis of PEDC (1), a potent NMDA receptor antagonist of a cyclopropane structure, was achieved. The highly stereoselective addition reaction of MeMgBr to C-cyclopropylnitrone 2, via its bisected s-trans conformation which can be predicted from the stereo-electronic effects, was developed as the key step. The s-trans conformation predominant in C- cyclopropynitrone 2 was suggested by NOE experiments. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00823-6

Tetrahedron Letters 41 (2000) 5373±5377
Highly stereoselective addition of Grignard reagents to
C-cyclopropylnitrone via the bisected s-trans conformation.
An ecient synthesis of PEDC, a potent NMDA receptor
antagonist having a cyclopropane structure
Yuji Kazuta, Satoshi Shuto* and Akira Matsuda
Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku,
Sapporo 060-0812, Japan
Received 27 April 2000; revised 17 May 2000; accepted 19 May 2000
Abstract
An ecient synthesis of PEDC (1), a potent NMDA receptor antagonist of a cyclopropane structure,
was achieved. The highly stereoselective addition reaction of MeMgBr to C-cyclopropylnitrone 2, via its
bisected s-trans conformation which can be predicted from the stereo-electronic e€ects, was developed as
the key step. The s-trans conformation predominant in C-cyclopropynitrone 2 was suggested by NOE
experiments. # 2000 Elsevier Science Ltd. All rights reserved.
Stereoselective preparation of biologically important cyclopropane derivatives is of great interest.1
It is known that a,b-unsaturated cyclopropanes, such as cyclopropylalkenes, -carbaldehydes and
-ketones, preferentially exist in bisected s-trans or s-cis conformation, due to the characteristic
stereo-electronic e€ects of the cyclopropane ring, as shown in Fig. 1a.1a We previously showed
that nucleophilic attacks of organometallic reagents to the carbonyls adjacent to a cyclopropane
occur highly stereoselectively via the bisected conformations.2,3 In this report, we describe stereo-
selective addition of Grignard reagent to a C-cyclopropylnitrone via its bisected s-trans con-
formation.
In recent years, we have been working to develop novel ecient antagonists of the NMDA (N-
methyl-d-aspartic acid) receptor, which are expected to be new therapeutic agents for epilepsy,
stroke, or ischemia. During our studies, we found 1-phenyl-2-[(S)-1-aminoethyl]-N,N-diethyl-
cyclopropanecarboxamide (1) is a new class of potent non-competitive NMDA receptor antag-
onists.4 We needed an alternative synthetic method of the large scale preparation of 1 for further
biological evaluation.5
* Corresponding author. Fax: +81-11-706-4980; e-mail: shu@pharm.hokudai.ac.jp
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00823-6

5374
Figure 1.
The chelation controlled addition of organometallic reagents to nitrones has been studied
extensively, because of its usefulness in the preparation of a variety of asymmetric amines.6 We
planned to develop stereoselective addition to aldonitrones adjacent to a cyclopropane via a non-
chelation controlled pathway. We hypothesized that C-cyclopropylnitrones should preferentially
exist in the bisected conformation, due to the stereoelectronic interaction between the imino
moiety and the cyclopropane ring, as in the cyclopropylcarbonyls and the cyclopropylalkenes;
the s-trans conformer would predominate, due to the steric repulsion of the alkyl substituent at
the nitrogen of the nitrone for the cyclopropane ring in the s-cis conformation, as shown in Fig. 1b.
If this is indeed the case, the stereoselective nucleophilic addition to C-cyclopropylnitrones from
the least hindered face should occur as in the case of the cyclopropylcarbonyls described above.
Thus, we investigated whether the nucleophilic addition of Grignard reagent to the cyclopropyl-
nitrone 2 gives the desired 10S-product 3, as shown in Scheme 1. Subsequent deprotection would
give the target NMDA receptor antagonist 1.
Scheme 1.
Treatment of the asymmetric cyclopropylcarbaldehyde 5,2 which was prepared from (^)-epi-
chlorohydrin (4), with N-benzylhydroxyamine hydrochloride in CH2Cl2 gave quantitatively the
N-benzyl-C-cyclopropylnitrone 2 (Scheme 2).
We wanted to determine whether the bisected s-trans conformation would predominate in
compound 2 as we had expected, since none of studies on the conformation of C-cyclopropyl-
nitrones have been reported. Thus, NOE experiments of 2 in CDCl3 were performed. When the
H-10 was irradiated, very strong NOEs were observed at the H-3 of the cyclopropane (16.5%),
which was in the position trans to the adjacent 1-phenyl group, and at the benzyl methylene
proton (20.0%), as shown in Fig. 2. This NOE study suggests that the molecule would be rigidly
restricted in the bisected s-trans conformation. As far as we know, this is the ®rst result demon-
strating that nitrones adjacent to cyclopropane ring prefer the bisected conformation.6

5375
Scheme 2.
Figure 2.
Based on the results on this conformational analysis, we next investigated addition reactions of
MeMgBr on the C-cyclopropylnitrone 2, since Grignard reagents are known to add to nitrones
eciently.7 The results are summarized in Table 1. The reaction was ®rst carried out with 5 equiv.
of the Grignard reagent in THF at ^78ꢀC for 2 h to give the addition products, in which the
desired 10-S product 3 was produced with high stereoselectivity (R:S=5:95), although the yield
was unsatisfactory (45%, entry 1). The stereochemistry was con®rmed by the conversion of 3 into
the ®nal product PEDC (1), as described below. The reactions at relatively higher temperatures
increased the yield somewhat, but the stereoselectivity decreased (entries 2 and 3). When the
reaction was carried out at ^78ꢀC for 8 h with Et2O:THF (2:1)8 as the solvent, it gave the addition
products in 83% yield with high stereoselectivity (entry 5, R:S=6:94), whereas in a similar reaction
in THF alone (entry 4), the yield was only moderate. We next investigated the e€ect of additives
on the reaction with 3 equiv. of MeMgBr in Et2O:THF (entries 7±11). Addition of HMPA,
ZnBr2, or TMSCl (entries 7±9) did not improve the yield or the stereoselectivity compared to the
reaction without an additive (entry 6). The best result was observed when the reaction was per-
formed with MgBr2 as an additive7a,b (entry 10, 81%, R:S=2:98). A similar reaction with 2
equiv. of MeMgBr lowered both the yield and stereoselectivity (entry 11).
Thus, a highly stereoselective addition to the nitrone 2 has been developed. The facial selectivity
of the addition of the Grignard reagents can be explained as an attack occurring from the least
hindered face (si-face) on to the imino carbon of 2, in the bisected s-trans conformation IV0, to
give the desired 10S-product 3 highly stereoselectively, as shown in Fig. 3. This study suggests that

5376
Table 1
The addition reactions of MeBgBr to C-cyclopropylnitorone 2
the reaction pathway of the nucleophilic addition to a cyclopropylnitrone probably occurs via the
predominant bisected conformation, which can be predicted from stereoelectronic e€ects. In the
course of the nucleophilic addition, the electrons of the cyclopropane ring, which can be char-
acterized as a strong p-donor,1a interact with the antibonding orbital of the incipient bond
between the nucleophile and the imino carbon of the nitrone 2. The nucleophilic addition can be
facilitated by this interaction, which is maximal when the nitrone is in the bisected conformation.
As a result, the reaction should proceed highly stereoselectively.
Figure 3.
The N-benzyl groups of the 10S-products 3 was readily removed by hydrogenation with Pd±C
in MeOH to give the targets 1 in 98% yield.
In summary, we have developed an ecient method for preparing the potent NMDA receptor
antagonist PEDC (1), and we have demonstrated that the highly stereoselective addition of
Grignard reagent to C-cyclopropylnitrones would occur via its bisected s-trans conformation.

5377
References
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10-position are limited, which prevents further structure±activity relationship studies.
6. The X-ray crystallographic structure of the nitrone 2 also demonstrated that it exists in the bisected s-trans
conformation in the solid state.
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8. Compound 2 was insoluble in Et2O.