Stereoselective Synthesis of Functionalized γ-Amino Esters: Azetidinium Salts and Epoxy Esters

Article abstract of DOI:10.1021/ol025590f

(Matrix Presented) Addition of several lithium ester enolates to chiral 1-aminoalkyl chloromethyl ketones 1 affords enantiomerically pure 3-hydroxyazetidinium salts 3 or 3-(1′-aminoalkyl)-3,4-epoxy esters 4, depending on the reaction conditions.

Full text of DOI:10.1021/ol025590f

ORGANIC
LETTERS
2002
Vol. 4, No. 8
1299-1301
Stereoselective Synthesis of
Functionalized γ-Amino Esters:
Azetidinium Salts and Epoxy Esters
Jose´ M. Concello´n,* Estela Riego, and Pablo L. Bernad
Departamento de Qu´ımica Orga´nica e Inorga´nica, Facultad de Qu´ımica,
UniVersidad de OViedo, Julia´n ClaVer´ıa 8, 33071 OViedo, Spain
jmcg@sauron.quimica.unioVi.es
Received January 21, 2002
ABSTRACT
Addition of several lithium ester enolates to chiral 1-aminoalkyl chloromethyl ketones 1 affords enantiomerically pure 3-hydroxyazetidinium
salts 3 or 3-(1′-aminoalkyl)-3,4-epoxy esters 4, depending on the reaction conditions.
γ-Amino acids represent an important class of compounds
not only due to their biological activity1 but also because
they are present in the structure of natural products with
antitumor activity.2 Likewise, azetidines appear as substruc-
tures in natural products,3 and homochiral azetidines have
been used as ligands4 and catalysts5 in asymmetric synthesis.
R-amino esters with in situ generated chloromethyllithium.
We have also described some synthetic applications of these
R-amino chloromethyl ketones, such as the preparation of
enantiopure threo aminoalkyl epoxides,6b 3-azetidinols,7
amino epihalohydrins,8 R′-amino-R,â-epoxyketones,9 and
amino aziridines, from their ketimine derivatives.10 The high
diastereoselectivity of all these reactions, and the enantio-
purity of the obtained compounds, prompted us to study new
synthetic applications of chiral 1-aminoalkyl chloromethyl
ketones 1 in the synthesis of enantiomerically pure building
blocks. Herein, we report the addition of different lithium
ester enolates to chiral 1-aminoalkyl chloromethyl ketones
1, obtaining 3-hydroxyazetidinium salts 3 or 3-(1′-amino-
alkyl)-3,4-epoxyesters 4, depending on the reaction condi-
tions, in enantiomerically pure form.
Previously, we have described the synthesis of chiral R′-
amino R-chloro ketones 16 by treatment of easily available
(1) For recent reviews, see: (a) Marczynski, T. J. Brain Res. Bull. 1998,
45, 341-379. (b) Bryans, J. S.; Wustrow, D. J. Med. Res. ReV. 1999, 19,
1149-1177.
(2) (a) Kato, Y.; Fusetani, N.; Matsunaga, S.; Hashimoto, K.; Fujita, S.;
Furuya, T. J. Am. Chem. Soc. 1986, 108, 2780-2781. (b) Petit, G. R.; Singh,
S. B.; Harald, D. L.; Lloyd-Williams, P.; Kaantoci, D.; Burkett, D. D.;
Barcokzy, J.; Hogan, F.; Wardlaw, T. R. J. Org. Chem. 1994, 59, 6287-
6295. (c) Haddad, M.; Botuha, C.; Larcheveque, M. Synlett 1999, 1118-
1120.
(3) (a) Isono, K.; Asahi, K.; Suzuki, S. J. Am. Chem. Soc. 1969, 91,
7490-7505. (b) Nomoto, K.; Mino, Y.; Ishida, T.; Yoshioka, H.; Ota, N.;
Inoue, N.; Takagi, S.; Takemoto, T. J. Chem. Soc., Chem. Commun. 1981,
338-339. (c) Kobayashi, J.; Cheng, J.; Ishibashi, M.; Wa¨lchli, M. R.;
Yamamura, S.; Ohizumi, Y. J. Chem. Soc., Perkin Trans. 1 1991, 1135-
1137.
(4) (a) Hoshino, J.; Hiraoka, J.; Hata, Y.; Sawada, S.; Yamamoto, Y. J.
Chem. Soc., Perkin Trans. 1 1995, 693-697. (b) Starmans, W. A. J.;
Walgers, R. W. A.; Thijs, L.; de Gelder, R.; Smits, J. M. M.; Zwanenburg,
B. Tetrahedron 1998, 54, 4991-5004. (c) Shi, M.; Jiang, J. K. Tetrahedron:
Asymmetry 1999, 10, 1673-1679. (d) Marinetti, A.; Hubert, P.; Geneˆt, J.
P. Eur. J. Org. Chem. 2000, 1815-1820.
The reaction of 1-aminoalkyl chloromethyl ketones 1 with
lithium enolates of different esters at -78 °C gave, after
hydrolysis at the same temperature, the corresponding
(6) (a) Barluenga, J.; Baragan˜a, B.; Alonso, A.; Concello´n, J. M. J. Chem.
Soc., Chem. Commun. 1994, 969-970. (b) Barluenga, J.; Baragan˜a, B.;
Concello´n, J. M. J. Org. Chem. 1995, 60, 6696-6699.
(7) Barluenga, J.; Baragan˜a, B.; Concello´n, J. M. J. Org. Chem. 1997,
62, 5974-5977.
(8) Barluenga, J.; Baragan˜a, B.; Concello´n, J. M. J. Org. Chem. 1999,
64, 2843-2846.
(5) (a) Rama Rao, A. V.; Gurjar, M. K.; Kaiwar, V. Tetrahedron:
Asymmetry 1992, 3, 859-862. (b) Starmans, W. A. J.; Thijs, L.; Zwanen-
burg, B. Tetrahedron 1998, 54, 629-636. (c) Wilken, J.; Erny, S.;
Wassmann, S.; Martens, J. Tetrahedron: Asymmetry 2000, 11, 2143-2158.
(9) Barluenga, J.; Baragan˜a, B.; Concello´n, J. M. J. Org. Chem. 1999,
64, 5048-5052.
(10) Concello´n, J. M.; Bernad, P. L.; Riego, E.; Garc´ıa-Granda, S.;
Force´n-Acebal, A. J. Org. Chem. 2001, 66, 2764-2768.
10.1021/ol025590f CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/23/2002

chlorohydrins 2, despite of the formation of a quaternary
center (Scheme 1). Compounds 2 were stable in tetrahydro-
onate enolates (Table 1, entries 1-4), the corresponding
azetidinium salts 3 were isolated, whereas epoxy esters 4
were obtained when disubstituted ester enolates were used
(Table 1, entries 5-7). Therefore, the use of bulky esters
favors epoxidation instead of azetidinium salt formation.
Although azetidinium salts 3a-c were obtained when
acetate enolate was used, we also prepared the corresponding
epoxy esters 4a-c, as shown in Scheme 2.14 To do this, the
Scheme 1. Addition of Ester Enolates to Ketones 1
Scheme 2. Synthesis of Epoxy Esters 4a-c
reaction of R-amino ketone 1 with acetate enolate at -78
°C was followed by addition of a few drops of water at the
same temperature. Then, without isolating the intermediate
chlorohydrin, the reaction mixture was treated with an excess
of sodium hydride at -40 °C. When this mixture was
allowed to warm to room temperature, the epoxy esters 4a-c
were isolated in high yield (Table 2).15
furan solution.11 But, when the solvents were completely
evaporated to dryness at room temperature, compounds 2
underwent an intramolecular heterocyclization, yielding
azetidinium salt 312 or epoxy ester 4, with high yield and
diastereoselectivity (Table 1).13 The isolation of compound
Table 2. Synthesis of Epoxy Esters 4a-c
Table 1. Addition of Ester Enolates to Ketones 1
product
R1
yield (%)a
deb
entry
product
R1
R2
R3
yield (%)a
deb
4a
4b
4c
Me
i-Bu
Bn
80
76
70
>95
>95
>95
1
2
3
4
5
6
7
3a
3b
3c
3d
4e
4f
Me
i-Bu
Bn
Me
Me
i-Bu
Me
H
H
H
Bn
Me
Me
H
H
H
H
Me
Me
87
82
80
68c
76
72
73c
>95
>95
>95
72
93
>95
95
a Isolated yield based on the starting ketone 1. b Diastereoisomeric excess
determined by 300 MHz H and 13C NMR analysis of the crude products
1
4.
4g
-(CH2)5-
a Isolated yield based on the starting ketone 1, after a 1 h reaction time.
b Diastereoisomeric excess determined by 300 MHz 1H and 13C NMR
analysis of the crude products 3 and 4. c To complete the reaction, 8 h was
required.
Azetidinium salts 3 and epoxy esters 4 were isolated in
enantiomerically pure form,16 and with total or high diaste-
reoselectivity. The degree of stereoselectivity was only
moderately affected by the size of R1 in the R-amino ketone
and the substituents in the enolate ester (see Tables 1 and
2). In the case of product 3d, two new chiral centers were
created in moderately diastereoisomeric excess (de ) 72%).
3 or 4 depends on the substitution pattern in the ester enolate.
Thus, in the case of ethyl acetate and ethyl 3-phenylpropi-
(11) Compound 2a with 20% of THF was characterized by 13C NMR:
δ 171.5, 139.2, 128.7, 127.9, 126.6, 75.9, 60.3, 55.6, 55.0, 49.5, 38.9, 13.6,
6.0.
(14) Representative procedure for the synthesis of epoxy esters 4a-
c: To a -85 °C stirred solution of lithium diisopropylamide (5.5 mL of
solution 0.3 M in THF, 1.65 mmol) was added dropwise a solution of ethyl
acetate (0.14 mL, 1.5 mmol) in dry THF (1 mL). After stirring for 10 min,
a solution of the corresponding 1-aminoalkyl chloromethyl ketone 1
(1 mmol) in dry THF (2 mL) was added dropwise at -78 °C. The reaction
mixture was stirred at the same temperature for 1 h, and then water (4
drops) was added. After stirring for 15 min at -40 °C, NaH (0.24 g, 10
mmol) was added, and the mixture was allowed to warm to room
temperature for 20 min and carefully quenched with water (10 mL). Usual
workup provided crude compound 4a-c. Flash column chromatography
over silica gel (hexane:ethyl acetate ) 15:1) afforded pure compounds
4a-c.
(12) Formation of azetidinium salts starting from halohydrins has been
also observed in similar substrates: (a) Reference 7. (b) Concello´n, J. M.;
Bernad, P. L.; Pe´rez-Andre´s, J. A. J. Org. Chem. 1997, 62, 8902-8906.
(13) Representative procedure for the enolate ester addition to
ketones 1: To a -85 °C stirred solution of lithium diisopropylamide (5.5
mL of solution 0.3 M in THF, 1.65 mmol) was added dropwise a solution
of the corresponding ester (1.5 mmol) in dry THF (1 mL). After stirring
for 15 min, a solution of 1-aminoalkyl chloromethyl ketone 1 (1 mmol) in
dry THF (2 mL) was added dropwise at -78 °C. When the reaction was
complete (see Table 1), the mixture was quenched with a saturated aqueous
solution of NH4Cl (5 mL) and extracted with diethyl ether (3 × 5 mL).
The combined organic layers were dried (Na2SO4), filtered, and concentrated
in vacuo. Crude azetidinium salts 3 was recrystallized from CH2Cl2/EtOAc
to give pure compounds 3. When epoxy esters 4 were isolated, flash column
chromatography over silica gel (hexane:triethylamine ) 50:1) provided pure
compounds 4e-g.
(15) When the aldol reaction was hydrolyzed at room temperature, a
mixture of 4 and an R,â-unsaturated lactone derived from 4 was isolated.
See: Concello´n, J. M.; Riego, E.; Bernad, P. L. Org. Lett. 2002, 4, 1303.
(16) The optical purity was determined by chiral HPLC analysis of the
R,â-unsaturated lactone derived from 4c. See ref 15.
1300
Org. Lett., Vol. 4, No. 8, 2002

Since the reactions with disubstituted ester enolates take place
with high or total diastereoselectivity (Table 1, entries 5-7),
the lower de observed in this product could be due to the
stereogenic center formed from the ester enolate.
Azetidinium salts 3 can be precursors of azetidines via a
hydrogenolysis process. In this way, compound 3a was
monodebenzylated by treatment with formic acid in the
presence of palladium in refluxing methanol, to afford the
azetidine 5a in quantitative yield (Scheme 3).17
protons.18 Therefore, addition of ester enolate to ketone 1
took place under nonchelation control, in agreement with
the previously reported aldol addition to dibenzylated amino
aldehydes19 and reduction and addition of organometallic
compounds to amino ketones.6b,7
In conclusion, we have developed new synthetic applica-
tions of chiral 1-aminoalkyl chloromethyl ketones 1 by
reaction with ester enolates, affording different enantiopure
γ-amino esters, such as azetidinium salts and epoxy esters,
with high yield and diastereoselectivity. This method is
simple, and the starting materials are readily available.
Scheme 3. Hydrogenolysis of the Azetidinium Salt 3a
Acknowledgment. We thank III Plan Regional de In-
vestigacio´n del Principado de Asturias (PB-EXP01-11) and
the Ministerio de Ciencia y Tecnolog´ıa (BQU2001-3807) for
financial support. J.M.C. thanks Carmen Ferna´ndez-Flo´rez
for her time. E.R. thanks the Ministerio de Ciencia y
Tecnolog´ıa for a predoctoral fellowship.
Configurational assignments of the condensation products
were made by NOESY experiment with azetidine 5a. As
shown in Figure 1, NOE effects were observed between the
Supporting Information Available: Spectroscopic data
for all new compounds 3, 4, and 5a, 13C NMR spectra of
2a, 3, 4, and 5a, and NOESY 1H NMR spectrum of 5a. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL025590F
(17) Representative procedure for the synthesis of 5a: A solution of
3a (0.3 g) in 5% formic acid-methanol (30 mL) containing palladium black
catalyst (0.3 g) was stirred at reflux temperature overnight. Then, the reaction
mixture was filtered through a pad of Celite and evaporated to dryness.
The residue was dissolved in CH2Cl2 and washed with saturated K2CO3.
The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo
to provide compound 5a.
Figure 1. NOE effects observed in azetidine 5a.
(18) The relative configuration of the chiral center formed from the
enolate in the major diastereoisomer 3d was determined by an NOESY
experiment on a 3d derivative. See ref 15.
(19) Reetz, M. T.; Drewes, M. W.; Schmitz, A. Angew. Chem., Int. Ed.
Engl. 1987, 26, 1141-1143.
H-2 proton at the heterocycle and R-hydrogens at the
carbonyl position, showing the cis relationship of these
Org. Lett., Vol. 4, No. 8, 2002
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