Diastereoselective addition of organozinc reagents to chiral α-imino esters

Article abstract of DOI:10.1016/S0957-4166(02)00587-6

The addition of organozinc reagents to chiral α-imino esters pre-complexed with zinc bromide, occurred with complete regioselectivity at the imino carbon. The influence of the solvent, temperature and different chiral auxiliaries was studied. The best diastereoselectivities were obtained in Et₂O or CH₂Cl₂ at 0°C, using phenylglycinol methyl ether as the chiral inductor.

Full text of DOI:10.1016/S0957-4166(02)00587-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 2205–2209
Diastereoselective addition of organozinc reagents to chiral
a-imino esters
Kan Pa¨ı Chiev, Sylvain Roland* and Pierre Mangeney
Laboratoire de chimie des organoe´le´ments, UMR 7611, universite´ P. et M. Curie, 4, place Jussieu, tr 44–45, 2e`me e´t.,
75252 Paris cedex 05, France
Received 29 August 2002; accepted 24 September 2002
Abstract—The addition of organozinc reagents to chiral a-imino esters pre-complexed with zinc bromide, occurred with complete
regioselectivity at the imino carbon. The influence of the solvent, temperature and different chiral auxiliaries was studied. The best
diastereoselectivities were obtained in Et2O or CH2Cl2 at 0°C, using phenylglycinol methyl ether as the chiral inductor. © 2002
Elsevier Science Ltd. All rights reserved.
1. Introduction
through path b.2 It was demonstrated later by
Yamamoto that the less basic but more reactive allylic
boron and benzylzinc reagents react regioselectively
with 1 at the expected imino carbon (path a).3 Bertrand
et al. reported recently that radical additions of alkyl
halides to a-imino esters also proceed regioselectively at
the imino carbon.4 Diastereoselective syntheses of a-
amino acid derivatives were realized using a-imino
esters bearing a chiral auxiliary as the R1 and/or the R2
group of 1. Enantioselective and catalytic additions of
silyl enol ethers to glyoxylimines and enantioselective
ene-reactions of a-imino esters have also been reported
recently.5
The reaction of a-imino esters 1 with organometallic
reagents1 is an interesting and potentially useful reac-
tion for the synthesis of chiral, non-racemic amino
acids and related compounds such as amino alcohols.
Nevertheless, the selective formation of the car-
bonꢀcarbon bond exclusively at the imino carbon has
proved a major problem and several studies have
demonstrated that the regioselectivity of this reaction is
closely related to the nature of the organometallic
species. Indeed, a-imino esters can behave as conju-
gated heterodienes and the nucleophile may attack
three possible electrophilic centers via paths a, b, or c,
leading respectively to a-amino ester 2, the N-alkylated
derivative 3 or the a-imino ketone 4 (Scheme 1). Kagan
et al. reported that allyl- and tert-butylmagnesium
halides and organocadmium reagents exclusively attack
the imino carbon of 1 via path a, whereas simple
Grignard reagents such as ethyl-, propyl-, benzyl- and
iso-butyl magnesium halides react predominantly
Following on from our previous studies on the addition
of tert-butyl organometallics to chiral 1,2-bisimines,6
we decided to explore the same reaction on chiral
a-imino esters. Herein, we wish to report our study
concerning the influence of solvents, additives and chi-
ral auxiliaries on the regio- and diastereoselectivity of
the addition of organomagnesium and organozinc
reagents to a-imino esters.
2. Results and discussion
2.1. Influence of the metal
We started our study with the reaction of 1a with
tert-butyl organometallics (Scheme 2) first used by
Kagan and Fiaud.7 The results are presented in Table 1.
In a first attempt, we carried out the addition of
Scheme 1.
* Corresponding author. Tel.: +33 (0) 1 44275567; fax: +33 (0) 1
44277567; e-mail: sroland@ccr.jussieu.fr
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00587-6

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K. P. Chie6 et al. / Tetrahedron: Asymmetry 13 (2002) 2205–2209
Scheme 2.
Scheme 3.
tert-butylmagnesium chloride at −78°C to a solution of
1a in THF. Surprisingly, this reaction led to very poor
regioselectivity since the N-alkylated adduct 3a was
obtained in 55% yield, with only 45% of the expected
products 2a and 2a% (entry 1). However, the same
reaction at 20°C gave a 91:09 ratio of 2/3a (entry 2).8
As previously reported by Yamamoto for the addition
of benzyl organometallic reagents to imino esters, the
zinc reagent seemed to be more appropriate in terms of
regioselectivity. Indeed, the addition of tert-butylzinc
bromide in THF led to the exclusive formation of
2a/2a% (entry 3). Nevertheless, the best diastereoselectiv-
ity, in THF, was obtained with tert-BuMgCl (83:17)
when a 71:29 ratio of the two diastereomers was
obtained with the zinc reagent (entry 3). The ‘mis-
matched’ analog of 1a, synthesized from (S)-(−)-1-
phenylethylamine and (−)-menthyl glyoxylate gave a
d.r. of 53:47 in the addition of tert-BuMgCl. Finally,
the use of Et2O as the solvent gave the best d.r. (80:20)
with the zinc reagent (entry 5). The diastereoselectivity
was slightly lower in hexane (entry 4). The regioselectiv-
ity was complete for the reactions using tert-BuZnBr in
hexane or ether.
Thus, we carried out the addition of 1.1 equiv. of ZnBr2
(1 M in Et2O) to a solution of 1a in Et2O at 20°C. The
zinc complex immediately precipitated during the addi-
tion. After stirring for 0.5 h, tert-BuZnBr was added
dropwise and the mixture stirred for 1 h. The result of
this experiment (Scheme 3) confirmed the importance of
this complexation since the diastereomeric ratio
increased from 80:20 without Lewis acid to 91:9 in the
presence of ZnBr2. This first result was encouraging.
Nevertheless, all our attempts to increase the
diastereoselectivity, by changing the solvent (THF, hex-
ane), the zinc salt (ZnCl2) or the temperature (from −20
to +35°C) were unsuccessful. The best diastereoselectiv-
ity was obtained by performing the reaction at room
temperature in Et2O.
2.3. Influence of the chiral ester
The same reactions were carried out with imino esters
1b and 1c, derived respectively from ethyl- or isopropyl
glyoxylate and (R)-(+)-1-phenylethylamine, to estimate
the influence of the (−)-menthyl group on the
diastereoselectivity (Scheme 4). These two substrates
each gave a lower diastereoselectivity (close to 40%),
showing the importance of the chiral ester group in 1a.9
2.2. Influence of zinc salts
In order to increase the diasteroselectivity of the addi-
tion, we studied the influence of zinc salts as additives.
We anticipated that complexation of the imino ester
with a Lewis acid, prior to the addition of the organo-
zinc reagent, should enhance the diastereoselectivity by
forming a rigid cyclic precursor and also by displacing
the possible equilibrium between the s-cis and s-trans
forms of the imino ester in favor of the s-cis-form
(Scheme 3).
Scheme 4.
Table 1. Addition of tert-BuMX on imino ester 1a
Entry
MX
T (°C)
Yield (%)
Solvent
2/3ab
2a/2a%b
1
2
3
4
5
MgCl
MgCl
ZnBr
ZnBr
ZnBr
−78“20
99a
THF
THF
THF
Hexane
Et2O
45:55
91:09
100:0
100:0
100:0
75:25
83:17
71:29
76:24
80:20
20
20
20
20
68 (98a)
52 (80a)
55 (88a)
64 (91a)
Typical procedure: To a solution of 1a (1 mmol) in the appropriate solvent (15 ml) was added dropwise a solution of tert-BuMgCl (2 M in Et2O;
1.5 equiv.) or tert-BuZnBr (0.5 M in THF; 1.5 equiv.). The mixture was stirred for 1 h at 20°C. The reaction was hydrolyzed with aqueous NH4Cl
satd (5 ml), extracted with ether, dried over MgSO4 and concentrated. The crude was purified by silica gel chromatography (pentane/Et2O, 95:5).
a Crude yield.
b Ratio determined by 1H NMR (400 MHz). Compound 3a was not separable from the minor diastereoisomer by chromatography on silica gel.

K. P. Chie6 et al. / Tetrahedron: Asymmetry 13 (2002) 2205–2209
2207
of the reaction significantly (entry 4). Diastereomeric
ratio of >95:5 was also obtained in THF at 0°C (entry
6) and comparable results were observed in toluene
(entry 7). This study showed that the conditions did not
have a marked influence on this reaction although small
variations were observed in the yields and diastereo-
selectivities.
2.4. Influence of the chiral amine
High levels of diastereoselectivity are often obtained in
the addition of organometallic compounds to chiral
imines which have a heteroatom in the chiral auxiliary
group attached to nitrogen, owing to the formation of
rigid chelated intermediates.10 Our focus, after obtain-
ing the preliminary results described above, was to test
the addition of tert-BuZnBr to 1d, which has a chelat-
ing methoxy group (Scheme 5). Compound 1d was
synthesized as previously described7 from (R)-phenyl-
glycinol methyl ether11 and ethyl glyoxylate. The results
are presented in Table 2. First of all, comparison of the
diastereoselectivities obtained with the similar imino
esters 1b and 1d (Scheme 4 and Table 2, entry 2),
clearly demonstrated the importance of the chelating
methoxy group in 1d since the d.r. significantly
increased from 70:30 to 93:7. Performing the addition
of t-BuZnBr at 0°C after complexation with ZnBr2 at
room temperature, gave the best yield of isolated
product (68%, entry 3) with d.r. of >95:5. The use of
two equivalents of ZnBr2 did not change the outcome
The reaction was extended to other organozinc reagents
using the same procedure (Scheme 6). The results are
presented in Table 3. The reaction of benzylzinc bro-
mide with 1d for 1 h at 20°C, afforded in 58% isolated
yield, the expected adduct 2e with a d.r. of 93:7 (entry
2). The reactivity and the stereoselectivity in this case
were similar to those obtained with tert-butylzinc bro-
mide. The addition was slower using secondary zinc
reagents such as cyclohexylzinc bromide (cHexZnBr) or
sec-butylzinc bromide. Indeed, after 1 h at rt the cyclo-
hexyl adduct 2f was isolated in only 25% yield with a
d.r. of 80:20 (entry 3). About 50% of 1d was recovered
at the end of the reaction. The use of CH2Cl2 as the
solvent with a longer reaction time (5 h) gave a com-
plete conversion and 2f was then isolated in 58% yield
with a better d.r. of 89:11 (entry 4). The same proce-
dure was applied to the addition of sec-BuZnBr to give
2g as a mixture of four diastereomers in a 50:40:5:5
ratio (entry 6).12
Scheme 5.
Scheme 6.
Table 2. Addition of tert-BuZnBr to 1d
Table 3. Addition of RZnBr to 1d
Entry
Additive
–
Conditions
Yield (%)
41 (83a)
58 (82a)
d.r.b
70:30
93:7
Entry
R
Conditionsa
Yield (%)
d.r.c
1
2
Et2O,
+20°C
Et2O,
+20°C
Et2O, 0°C
Et2O,
+20°C
THF,
+20°C
THF, 0°C
PhCH3,
+20°C
1
2
3
4
5
6
tert-Bu
Bn
cHex
cHex
sec-Bu
sec-Bu
Et2O, 1 h
Et2O, 1 h
Et2O, 1 h
68 (86b)
62 (91b)
25 (72b)
96:4
93:7 (90:10d)
80:20 (87:13d)
89:11 (88:12d)
41:41:10:8
50:40:5:5
ZnBr2
CH2Cl2, 5 h 58 (93b)
3
4
ZnBr2
2(ZnBr2)
68 (86a)
96:4
Et2O, 5 h
40 (68b)
64 (82a)
94:6 (96:4c)
CH2Cl2, 5 h 50 (72b)
5
ZnBr2
52 (80a)
95:5
a The mixture was stirred for the indicated time at 20°C after addition
of the zinc reagent dropwise at 0°C. The crudes were purified by
silica gel chromatography (pentane/Et2O, 9:1).
b Crude yields.
6
7
ZnBr2
ZnBr2
58 (83a)
97:3
68 (84a)
94:6 (95:5c)
c Ratio determined by 1H NMR spectroscopy (400 MHz) Ha (CH
6 -
R).
Typical procedure: To a solution of 1d (1 mmol.; 235 mg) in the
appropriate solvent (10 ml) was added dropwise at 20°C, a solution
of ZnBr2 1 M in Et2O (1.1 ml). The mixture was stirred for 30 min.
at 20°C. The zinc reagent (0.5 M in THF, 1.5 equiv.) was added
dropwise at the appropriate temperature (0 or 20°C). After the
addition, the mixture was stirred for 1 h at 20°C. The reaction was
hydrolyzed with NH4Cl satd (5 ml), extracted with ether, dried on
MgSO4 and concentrated. The crude was purified by silica gel chro-
matography (pentane/Et2O, 9:1).
d Ratio determined after purification. The two diastereomers are
separable on silica gel.
The absolute configuration at the a-carbon of 2d (bear-
ing the tert-butyl group) was determined by chemical
correlation. Hydrogenolysis of 2d in EtOH, in the
presence of catalytic Pd/C led to ethyl 2-amino-3,3-
dimethyl butanoate 4 in quantitative yield (Scheme 7).
The R absolute configuration was assigned to this
compound after establishment of its specific rotation
value ([h]2D5=−40.7 (c 0.52, CHCl3)) and comparison
with the values reported in the literature.13
a Crude yields.
b Ratio determined by 1H NMR spectroscopy (400 MHz) Ha (CH
6 -
tert-Bu).
c Ratio determined on the purified compound.

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K. P. Chie6 et al. / Tetrahedron: Asymmetry 13 (2002) 2205–2209
methyl ether as the chiral auxiliary. This method allows
the synthesis of various functionalized amino esters and
this could be of interest for the preparation of the
corresponding amino acids or amino alcohols such as
tert-butylglycinol. The a-amino esters 2 are also poten-
tial ligands for asymmetric catalysis.
Scheme 7.
References
The stereochemical outcome of this reaction can be
rationalized by two possible chelate models presented in
Scheme 8, both of which lead to the (R)-adduct. In
chelate A, ZnBr2 is associated to the nitrogen atom of
the imine and to two oxygens (from the methoxy group
and the ester) forming two rigid five-membered rings
and the zinc reagent adds to the less hindered re face.
In chelate B, ZnBr2 may form only one five-membered
ring but, the delivery of the nucleophile could be
assisted by the oxygen of the methoxy group, leading to
preferential attack from the re face also.10a The increase
in diastereoselectivity when using phenylglycinol deriva-
tives instead of 1-phenylethylamine can be explained by
comparing the chelate models and the model proposed
by Yamamoto in the second case. Indeed, it is easily
seen that in chelate A, the phenyl group of the chiral
auxiliary is closer to the prochiral center to be attacked
(the carbon of the imino group) than in Yamamoto’s
model. In chelate B, the major conformation of the
imino ester could be similar to the one described by
Yamamoto (same position of the phenyl group) but
chelation of the methoxy group to the organozinc
reagent should lead to almost exclusive delivery of the
nucleophile from the re face.
1. For reviews on the addition of organometallics to CN
double bonds, see: (a) Enders, D.; Reinhold, U. Tetra-
hedron: Asymmetry 1997, 8, 1895–1946; (b) Bloch, R.
Chem. Rev. 1998, 98, 1407–1438.
2. (a) Fiaud, J.-C.; Kagan, H. B. Tetrahedron Lett. 1970,
1813–1816; (b) Fiaud, J.-C.; Kagan, H. B. Tetrahedron
Lett. 1971, 1019–1022.
3. (a) Yamamoto, Y; Nishii, S.; Mruyama, K.; Komatsu,
T.; Ito, W. J. Am. Chem. Soc. 1986, 108, 7778–7786; (b)
Yamamoto, Y; Ito, W. Tetrahedron 1988, 44, 5415–5423.
4. (a) Bertrand, M. P.; Feray, L.; Nouguier, R.; Stella, L.
Synlett 1998, 780–782; (b) Bertrand, M. P.; Coantic, S.;
Feray, L.; Nouguier, R.; Perfetti, P. Tetrahedron 2000,
56, 3951–3961; (c) See also: Miyabe, H.; Ushiro, C.;
Ueda, M.; Yamakawa, K.; Naito, T. J. Org. Chem. 2000,
65, 176–185 for similar reactions with glyoxylic oxime
ethers.
5. (a) Kobayashi, S.; Ishitani, H. Chem. Rev. 1999, 99,
1069–1094; (b) Ferraris, D.; Youg, B.; Cox, C.; Dudding,
T.; Drury, W. J.; Ryzhkov, L.; Taggi, A. E.; Lectka, T. J.
Am. Chem. Soc. 2002, 124, 67–77; (c) Drury, W. J.;
Ferraris, D.; Cox, C.; Youg, B.; Lectka, T. J. Am. Chem.
Soc. 1998, 120, 11006–11007.
6. (a) Roland, S.; Mangeney, P.; Alexakis, A. Synthesis
1999, 228–230; (b) Roland, S.; Mangeney, P. Eur. J. Org.
Chem. 2000, 611–616; (c) Alexakis, A.; Tomassini, A.;
Chouillet, C.; Roland, S.; Mangeney, P.; Bernardinelli,
G. Angew. Chem., Int. Ed. 2000, 39, 4093–4095.
7. Compound 1a was prepared at 20°C from (−)-menthyl
glyoxylate (1 mmol) and (R)-(+)-1-phenylethylamine (1
mmol) in CH2Cl2 (5 ml) in the presence of MgSO4.
Stirring for 1 h, filtration and concentration afforded the
crude imino ester quantitatively, which was used without
further purification. Compounds 1b–d were obtained by
the same procedure.
In conclusion, we have developed a totally regioselec-
tive addition of organozinc reagents to a-imino esters
pre-complexed with zinc bromide. High levels of
diastereoselectivity were obtained using phenylglycinol
8. Kagan and Fiaud in 1971 (see Ref. 2b) reported a
complete regioselectivity in this reaction.
9. Good stereoselectivities were obtained by Yamamoto
with R2=(−)-8-phenylmenthyl (see Ref. 3b).
10. (a) Spero, D. M.; Kapadia, S. R. J. Org. Chem. 1997, 62,
5537–5541; (b) Yamada, T.; Suzuki, H.; Mukaiyama, T.
Chem. Lett. 1987, 2, 293–296.
11. (R)-Phenylglycinol was prepared by LiAlH4 reduction of
phenylglycine in refluxing THF. The methyl ether was
synthesized according to: Hiroi, K.; Sato, S. Chem.
Pharm. Bull. 1985, 33, 2331–2338. A modified representa-
tive procedure for this preparation is outlined as follows:
To a solution of (R)-phenylglycinol (5 mmol) in CH2Cl2
(20 ml), were added benzaldehyde (560 ml, 5.5 mmol) and
MgSO4. The mixture was stirred for 2 h at 20°C, filtered
through a pad of Celite and concentrated under vacuum
at 20°C. The crude iminoalcohol was dissolved in dry
THF (10 ml) and NaH (50% w/w dispersion in mineral
Scheme 8.

K. P. Chie6 et al. / Tetrahedron: Asymmetry 13 (2002) 2205–2209
2209
oil, 720 mg, 15 mmol) was added in portions. The
suspension was stirred for 15 min at 20°C. The alkyl
halide (7.5 mmol) was then added and the mixture heated
at 40°C for 2 h. After cooling to 20°C, HCl 3N (10 ml)
was slowly added followed by Et2O (10 ml). The mixture
was stirred vigorously for 3 h. The aqueous layer was
separated and the organic layer was extracted with HCl
1N (2×10 ml). The combined aqueous layers were washed
with pentane (3×10 ml) and solid NaOH was added
slowly until pH 10. The aqueous layer was extracted with
Et2O (3×15 ml). The combined extracts were dried over
K2CO3, filtered and concentrated at 20°C to give the
aminoether in 85% yield. This procedure is applicable to
hindered aminoalcohols such as norephedrine.
12. We supposed that in this case, the syn/anti selectivity was
very low. This implied that the stereoselectivity must be
9:1 at the a-carbon.
13. Jaeger, D. A.; Broadhurst, M. D.; Cram, D. J. J. Am.
Chem. Soc. 1979, 101, 717–732. (+)-(S)-Ethyl 2-amino-
3,3-dimethyl butanoate [h]2D5=+47.8 (c 1, CHCl3).