One-pot preparation of chiral beta-amino esters by rhodium-catalyzed three-components coupling reaction.

Article abstract of DOI:10.1248/cpb.50.307

Chiral beta-amino esters are synthesized in one-pot from three components, amines, aldehydes, and ethyl bromoacetate, under the rhodium-catalyzed Reformatsky-type reaction condition, where complete diastereoselection is achieved in the nucleophilic addition step of ethyl bromoacetate to the imines prepared in

Full text of DOI:10.1248/cpb.50.307

February 2002
Communications to the Editor
Chem. Pharm. Bull. 50(2) 307—308 (2002)
307
and aliphatic aldehydes and amines by one-pot preparation4d)
in moderate yields, probably depending on the stability of the
imines formed in situ. The representative procedure for this
addition reaction is as follows: The suspension of an alde-
hyde (1 mmol), an amine (1.03 mmol), and activated molecu-
lar sieves 3A (0.4g) in tetrahydrofuran (THF, 2 ml) are stirred
at 0 °C for 4 h under argon. To this mixture at 0 °C was added
a solution of Wilkinson’s catalyst (0.05 mmol) in THF (3 ml),
ethyl bromoacetate (1.1 mmol), and a 1.0 M hexane solution
of diethylzinc (4 mmol). After stirring for 10 min at 0 °C, the
reaction was quenched by the addition of aqueous saturated
NaHCO3.
It is noteworthy that the addition reactions without the
presence of Wilkinson’s catalyst gave the desired products in
the range of 10—20% yields with much longer reaction time
(more than 2 h). These results obviously suggested that
Wilkinson’s catalyst accelerate the reactions in terms of the
yield and reaction time. Having developed a method for the
preparation of racemic b-amino esters, in one-pot, from three
components, aldehydes, amines and ethyl bromoacetate,
under rhodium-catalyzed reaction conditions, we next fo-
cused our attention on the synthesis of optically pure b-
amino esters. Among the various chiral auxiliaries reported
in the literatures, we chose readily available (R)-phenylglyci-
nol.4b,5,7)
Following the procedure developed above, we carried out
the reaction with (R)-phenylglycinol as an amine component,
however, none of the desired product was produced. We as-
sumed that the free hydroxyl of (R)-phenylglycinol interfered
the nucleophilic attack of the intermediate rhodium enolate.6)
Thus, we attempted this reaction with the benzyl ether8) of
(R)-phenylglycinol, and were delighted to find that desired b-
amino esters were obtained as a single isomer. Table 2 pre-
sents the results of the one-pot preparation of chiral b-amino
esters. With both aromatic and aliphatic aldehydes, desired
b-amino esters were obtained in moderate to good yields
without giving any diastereoisomers. The absolute configura-
tions of the coupling products were unambiguously deter-
mined by comparison of the specific optical rotations of the
corresponding amines (A) or debenzylated compound (B) as
shown in Table 3, with those reported.9) Figure 1 with its
transition state appears to best depict our experimental obser-
vations, where the zinc enolates6) attack from the sterically
b
One-Pot Preparation of Chiral -Amino
Esters by Rhodium-Catalyzed Three-
Components Coupling Reaction
Toshio HONDA,* Hitoshi WAKABAYASHI, and
Kazuo KANAI
Faculty of Pharmaceutical Sciences, Hoshi University, 2–4–41
Ebara, Shinagawa-ku, Tokyo 142–8501, Japan.
Received October 30, 2001; accepted December 5, 2001
Chiral b-amino esters are synthesized in one-pot from three
components, amines, aldehydes, and ethyl bromoacetate, under
the rhodium-catalyzed Reformatsky-type reaction condition,
where complete diastereoselection is achieved in the nucleophilic
addition step of ethyl bromoacetate to the imines prepared in
situ.
Key words chiral b-amino ester; Reformatsky reaction; rhodium-cat-
alyzed coupling reaction; Wilkinson’s catalyst; diethylzinc
b-Amino acids or b-amino esters are recognized to be
pharmacologically important compounds,1) since those com-
pounds play key roles in medicinal chemistry, such as precur-
sors of medicinally important b-lactam antibiotics, and as
constituents of biologically active unnatural peptides.2) More-
over, some cyclic b-amino acids are reported to exhibit re-
markable antifungal activities.3) Therefore, development of a
new and operationally simple methodology for the prepara-
tion of b-amino acids or their ester derivatives in optically
pure forms, is highly desirable in this field of chemistry.
Based on these considerations, numerous methods for the
synthesis of b-amino acids (esters) have been investigated
to date.4) Among the various methodologies developed, a
straightforward manner for obtaining b-amino acids (esters)
seems to be the addition of the Reformatsky reagents5) to
aldimines.
We recently disclosed a novel rhodium-catalyzed Refor-
matsky-type reaction in which b-hydroxy esters are produced
under very mild reaction conditions.6)
To extend the usefulness of this type of reaction in the syn-
thesis of biologically active compounds, we investigated the
further application of this methodology to the preparation of
optically active b-amino esters, and herein we report our suc-
cessful results.
Table 1. One-Pot Preparation of Racemic b-Amino Esters
Although the difficulties were initially encountered for ob-
taining the desired products by addition of ethyl bromo-
acetate to imines under the various reaction conditions at-
tempted, probably due to the instabilities of the imines, we
found fortunately that ethyl bromoacetate could be intro-
duced to the imines, prepared in situ, in the presence of
Wilkinson’s catalyst and diethylzinc giving b-amino esters by
one-pot procedure in reasonable yields. As shown in Table 1,
the desired b-amino esters were obtained from both aromatic
Entry
1
R1
R2
Ph
Ph
Product
Yield (%)
56
4
2
3
5
6
56
45
Ph
Ph
4
5
7
8
51
54
6
9
57
Chart 1. Rhodium-Catalyzed Reformatsky Reaction with Carbonyl Com-
pounds
To whom correspondence should be addressed. e-mail: honda@hoshi.ac.jp
© 2002 Pharmaceutical Society of Japan

308
Vol. 50, No. 2
Table 2. One-Pot Preparation of Chiral b-Amino Esters
Entry
R1
R2
Product ([a]D in CHCl3)
Yield (%)
Fig. 1. Plausible Transition State
1
2
3
4
5
Ph
Isopropyl
Propyl
Propyl
Cyclohexyl Et
Et
Et
Et
Me
10 (Ϫ3.4)
11 (Ϫ50.7)
12 (Ϫ48.3)
13 (Ϫ52.8)
14 (Ϫ34.6)
78
70
85
76
62
Acids,” ed. by Juaristi E., Wiley-VCH, Inc., New York, 1996, pp. 1—
43 and references cited therein.
2) a) Appela D. H., Christianson L. A., Karle I. L., Powel D. R., Gellman
S. H., J. Am. Chem. Soc., 118, 13071—13072 (1996); b) Seebach D.,
Overhand M., Kühnle F. N. M., Martinoni B., Oberer L., Hommel U.,
Widmer H., Helv. Chim. Acta, 79, 913—941 (1996).
3) a) Iwamoto T., Tsuji E., Ezaki M., Fujie A., Hashimoto S., Okuhara
M., Kohsaka M., Imanaka H., Kawabata K., Inamoto Y., Sakane K., J.
Antibiot., 43, 1—7 (1990); b) Kawabata K., Inamoto Y., Sakane K.,
Iwamoto T., Hashimoto S., ibid., 43, 513—518 (1990); c) Ohki H.,
Inamoto Y., Kawabata K., Kamimura T., Sakane K., ibid., 44, 546—
549 (1991).
Table 3. Removal of the Chiral Auxiliary
4) a) Wu M.-J., Pridgen L. N., Synlett, 1990, 636—637; b) Mokhallalati
M. K., Wu M.-J., Pridgen L. N., Tetrahedron Lett., 34, 47—50 (1993);
c) Davis S. G., Ichihara O., Tetrahedron: Asymmetry, 2, 183—186
(1991); d) Kobayashi S., Araki M., Yasuda M., Tetrahedron Lett., 36,
5773—5776 (1995); e) Cimarelli C., Palmieri G., J. Org. Chem., 61,
5557—5563 (1996).
5) a) Andrés C., González A., Pedrosa R., Párez-Encabo A., Tetrahedron
Lett., 33, 2895—2898 (1992); b) Katritzky A. R., Hong Q., Yang Z., J.
Org. Chem., 60, 3405—3408 (1995); c) Adrian J. C., Jr., Barkin J. L.,
Hassib L., Tetrahedron Lett., 40, 2457—2460 (1999); d) Mecozzi T.,
Petrini M., ibid., 41, 2709—2712 (2000); e) For a review; see, Cole D.
C., Tetrahedron, 50, 9517—9582 (1994) and references cited therein.
6) Kanai K., Wakabayashi H., Honda T., Org. Lett., 2, 2549—2551
(2000).
Entry Substrate
R1
R2 Product ([a]D in CHCl3) Yield (%)
1
2
10
11
Ph
Et
15A (ϩ12.9)
16A (ϩ21.8)
16B (Ϫ24.2)
17A (ϩ12.3)
17B (Ϫ46.1)
18A (ϩ12.7a))
19B (Ϫ31.7)
58
46
28
39
59
54
40
isopropyl Et
3
12
propyl
propyl
Et
4
5
13
14
Me
cyclohexyl Et
a) This value is for the N-Boc derivative, derived from 18A with (Boc)2O.
less hindered re face of the imines. The observed stereoselec-
tivity was similar to those of previously reported.4b)
Further cleavage of the chiral auxiliary was best achieved
by hydrogenolysis in the presence of Pearlman’s catalyst
under 4 atms of hydrogen in acetic acid or subsequent lead
tetraacetate treatment of the debenzylation products.
Thus, we developed an efficient one-pot preparation of
chiral b-amino esters via three components coupling by ap-
plying the rhodium-catalyzed Reformatsky-type reaction.
Since both enantiomeric forms of the chiral auxiliaries em-
ployed here are readily accessible, both enantiomers of the b-
amino esters can be obtained with a same operation. Support
was provided by a Grant-in-Aid from the Ministry of Educa-
tion, Culture, Sports, Science and Technology of Japan.
7) Higashiyama K., Inoue H., Takahashi H., Tetrahedron Lett., 33, 235—
238 (1992).
8) The reductive cleavage of the methyl ether of (R)-phenylglycinol, after
the coupling reaction, did not give satisfactory result.
9) The reported specific optical rotations of 15A are [a]D ϩ21.1
(CHCl3),10) and ϩ4.5 (EtOH).11) Also 19B and the N-Boc derivative
17A exhibited [a]D Ϫ37.2 (CHCl3),12) and [a]D ϩ20.9 (CHCl3),12) re-
spectively. Although 16 and 18 are unknown compound, its stereo-
chemistry can tentatively be assigned to be the same as other products
based on the reaction mechanism. We assumed that the coupling prod-
ucts seem to be optically pure, since the chiral auxiliary obtained by
hydrolysis of the imines prior to the coupling reaction was optically
pure, and its removal by catalytic hydrogenolysis, after coupling reac-
tion, usually did not take place any racemization.
10) Mokhallalati M. K., Pridgen L. N., Synth. Commun., 23, 2055—2064
(1993).
11) Graf E., Boeddeker H., Liebigs Ann. Chem., 613, 111—119 (1959).
12) Alcón M., Canas M., Poch M., Moyano A., Pericàs M. A., Riera A.,
Tetrahedron Lett., 35, 1589—1592 (1994).
References and Notes
1) Boge T. C., Georg G. I., “Enantioselective Synthesis of b-Amino