Stereoselective formation of N-acyliminium ion via chiral N,O-acetal TMS ether and its application to the synthesis of β-amino acids

Article abstract of DOI:10.1021/ol035289e

(Matrix Presented) The highly stereoselective synthesis of β-amino acids via the chiral 4-phenyloxazolidinone-controlled linear N-acyliminium ion reaction has been achieved by employing chiral N,O-acetal TMS ethers. In addition, the mechanism of the excel

Full text of DOI:10.1021/ol035289e

ORGANIC
LETTERS
2003
Vol. 5, No. 20
3635-3638
Stereoselective Formation of
N-Acyliminium Ion via Chiral N,O-Acetal
TMS Ether and Its Application to the
Synthesis of
â-Amino Acids
Dong-Yun Shin,† Jae-Kyung Jung,‡ Seung-Yong Seo,† Yong-Sil Lee,†
Seung-Mann Paek,† Young Keun Chung,§ Dong Mok Shin,§ and Young-Ger Suh*,†
College of Pharmacy, Seoul National UniVersity, Seoul 151-742, Korea,
College of Pharmacy, Chungbuk National UniVersity, Cheongju 361-763, Korea, and
Department of Chemistry, College of Natural Sciences, Seoul National UniVersity,
Seoul 151-742, Korea
ygsuh@snu.ac.kr
Received July 12, 2003
ABSTRACT
The highly stereoselective synthesis of
â-amino acids via the chiral 4-phenyloxazolidinone-controlled linear N-acyliminium ion reaction has
been achieved by employing chiral N,O-acetal TMS ethers. In addition, the mechanism of the excellent stereochemical outcome has been
elucidated. The oxazolidinone auxiliary plays a dual role in stereocontrol: the E/Z geometry control of the N-acyliminium ion induced by an
initial stereoselective amide reduction, leading to the chiral N,O-acetal TMS ether, and face control of the nucleophile attack in the N-acyliminium
ion reaction.
The development of new synthetic methods for the asym-
metric synthesis of â-amino acids1 is of considerable current
interest, because â-amino acids possess unique biological
activities as well as a wide range of synthetic utilities, as
key components of antibiotics, peptides, and other bioactive
materials.2 For this purpose, a number of reactions of imine
species with ester enolates or ketenes have been developed.3,4
Recently, we have reported a novel N-acyliminium ion
precursor of N,O-acetal TMS ethers, as well as their efficient
preparation.5 In particular, N,O-acetal TMS ethers turned out
to be one of the most general and practical precursors, since
they are superior to other N-acyliminium ion precursors in
terms of their convenient preparation, functional group
compatibility, substituent diversity, and facile conversion to
the corresponding N-acyliminium ion. Moreover, their suc-
(3) For recent reports about the asymmetric synthesis of â-amino acids
utilizing imine species, see: (a) Murahashi, S.; Imada, Y.; Kawakami, T.;
Harada, K.; Yonemushi, Y.; Tomita, N. J. Am. Chem. Soc. 2002, 124, 2888.
(b) Moglioni, A. G.; Muray, E.; Castillo, J. A.; Alvarez-Larena, A.;
Moltrasio, G. Y.; Branchadell, V.; Ortuno, R. M. J. Org. Chem. 2002, 67,
2402. (c) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002,
35, 984. (d) Kobayashi, S.; Matsubara, R.; Kitagawa, H. Org. Lett. 2002,
4, 143. (e) Kise, N.; Uena, N. Org. Lett. 1999, 1, 1803. (f) Muller, R.;
Goesmann, H.; Waldmann, H. Angew. Chem., Int. Ed. 1999, 37, 184 and
related references are therein.
(4) For excellent reviews on the chemistry of N-acyliminium ions and
related intermediates, see: (a) Speckamp, W. N.; Moolenaar, M. J.
Tetrahedron 2000, 56, 3817-3856. (b) Hiernstra, H.; Speckamp, W. N. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon
Press: Oxford, 1991; Vol. 2, pp 1047-1082.
(5) (a) Suh, Y.-G.; Kim, S.-H.; Jung, J.-K.; Shin, D.-Y. Tetrahedron Lett.
2002, 43, 3165 (b) Suh, Y.-G.; Shin, D.-Y.; Jung, J.-K.; Kim, S.-H. Chem.
Commun. 2002, 1064.
† College of Pharmacy, Seoul National University.
‡ Chungbuk National University.
§ Department of Chemistry, Seoul National University.
(1) For a review, see: Juaristi, E., Ed., EnantioselectiVe Synthesis of
â-Amino Acids. Wiley-VCH: New York, 1997.
(2) For reviews, see: (a) Drey, C. N. C. In Chemistry and Biochemistry
of the Amino Acids; Barrett, G. C., Ed.; Chapman and Hall: London, 1985;
pp 25-54; (b) Bewley, C. A.; Faulkner, D. J. Angew. Chem., Int. Ed. 1998,
37, 2162.
10.1021/ol035289e CCC: $25.00
© 2003 American Chemical Society
Published on Web 09/11/2003

cessful synthetic application to the amidoalkylation of acyclic
systems enabled us to introduce a variety of chiral auxiliaries
at the nitrogen atom for the asymmetric version.
Scheme 1a
As part of our ongoing studies, we herewith report a novel
asymmetric synthetic route to â-amino acids via the stereo-
selective formation of N-acyliminium ions, using 4-phenyl-
oxazolidinone as both a chiral auxiliary and as an amine
source. In addition, the important dual role of the chiral
oxazolidinone in the outstanding stereochemical outcome of
this method is described.
For the asymmetric induction (2 f 3) at the newly formed
stereogenic center in the N-acyliminium ion species, two
important stereocontrolling factors were considered, as shown
in Figure 1. The first factor is the E/Z geometry control of
a Reagents and conditions: (a) DIBAL-H, CH2Cl2, -78 °C; then,
pyridine, TMSOTf, 93%. (b) BF3-OEt2, CH2dC(OTBS)OEt or
CH2dCHCH2TMS or CHdC(OTMS)Ph, CH2Cl2, -78 to -30 °C;
94, 85, and 89%, respectively.
considered to be one of the most suitable precursors for an
N-acyliminium ion bearing a chiral auxiliary from the
viewpoints of high reactivity and generality.
Preparation of the chiral N,O-acetal TMS ethers 9 from
the chiral acyloxazolidinones was carried out by analogy with
the procedure of Scheme 1, as shown in Table 1. The amide
Table 1.
Figure 1.
CdN+ (e.g., 2), and the second factor is the face control of
nucleophile attack in the iminium ion. The E/Z geometry
control is expected to be dependent on the energy difference
of the two geometric isomers, although they are highly
influenced by substituents.4,6 The face selectivity of the
nucleophilic attack is expected to be directed by the chiral
auxiliary. Considering these points, we chose the easily
cleavable 4-phenyl-oxazolidinone as a chiral auxiliary, in
which both the alkoxycarbonyl protecting group of the amine
and the nucleophilic face-controlling phenyl group are fixed
by the ring system.
Our studies began with an examination of oxazolidinone
in the acyclic N-acyliminium ion, because the exocyclic
N-acyliminium ions of oxazolidinone from other precursors
are known to have serious limitations such as poor reactivity
and/or poor stereoselectivity in adopting various nucleo-
philes.7
As shown in Scheme 1, N-propionyl-oxazolidinone 5 was
reduced to the aminal aluminum alkoxide, which was trapped
in situ with TMSOTf/pyridine to afford the N,O-acetal TMS
ether 6.5 Subsequent amidoalkylation of the TMS ether was
performed by reaction with ketene acetal, allylsilane, and
silyl enol ether as nucleophiles under the established con-
ditions to afford the corresponding alkylation products
(7a-c) in high yields. Thus, N,O-acetal TMS ether was
yield
entry
8
R
N,O-TMS ether (9)a (%)b
drc
1
2
3
4
5
6
7
8a CH3
8b CH2CH3
9a
9b
9c
9d
9e
9f
92 >98:2
93 >98:2
87 >98:2
89 >98:2
90 >98:2
8c CH2(CH2)2CH3
8d CH2Ph
8e CH2CH2CHdCH2
8f CH2(CH2)7CH3
8g CH2CH2Ph
81
83
89:11
93:7
9g
a All of the N,O-acetal TMS ethers 9 were sufficiently stable for storage
at room temperature. b Isolated yields. c Determined by 1H NMR spectra
of the diastereomeric mixture 9 or the isolation yield of each isomer by
flash column chromatography.
precursors possessing various alkyl substituents were pre-
pared by n-BuLi treatment of (R)-(-)-4-phenyl-oxazolidi-
none, followed by the addition of the corresponding acyl
chlorides in THF at -78 °C.8 Reduction of the acylamides
8 with DIBAL-H, followed by in situ trapping of the resulting
aluminum alkoxide with TMSOTf, gave the corresponding
N,O-acetal TMS ethers 9 in high yields as well as in high
diastereoselectivities. The absolute configurations of the
newly generated stereogenic centers in the major stereoiso-
mers of 9a-g were confirmed by the X-ray crystallographic
analysis of 14a, the major product of 13 (Figure 2, vide
infra).9 The two diastereomers of 9f and 9g, shown in entries
6 and 7, respectively, were readily separable by a simple
column chromatography step.
(6) (a) Yamamoto, Y.; Nakada, T.; Nemoto, H. J. Am. Chem. Soc. 1992,
114, 121. (b) Al-Talib, M.; Zaki, M.; Hehl, S.; Stumpf, R.; Fischer, H.;
Jochims, J. C. Synthesis 1996, 1115.
(7) Marcantoni, E.; Mecozzi, T.; Petrini, M. J. Org. Chem. 2002, 67,
2989. We are very thankful to Professor M. Petrini for his kind and helpful
discussion on this topic.
(8) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis, 3rd ed.; Wiley-Interscience: New York, 1999.
(9) For details, see Supporting Information.
3636
Org. Lett., Vol. 5, No. 20, 2003

Scheme 2a
a Reagents and conditions: (a) LiOH-H2O, THF/H2O (1/1),
99%. (b) Li, liquid NH3, THF/t-BuOH; then, CbzCl, Na2CO3, 82%.
Figure 2. ORTEP drawing of the X-ray structure of N,O-acetal
TMS ether 14a. Other hydrogens have been omitted for clarity.
protected â-amino acid 12,11 which was identical in all
aspects. The stereochemical outcome can be understood by
the preferred formation of the (Z)-isomer of the N-acylimin-
ium ion,12 which was contrary to our initial assumption (vide
infra).
The efficient and highly diastereoselective conversion of
other N,O-acetal TMS ethers to the corresponding esters is
summarized in Table 3. All of the N,O-acetal TMS ethers
To establish the optimal reaction conditions for the
asymmetric alkylation, the conversion of 9b to 10b was
initially examined under various reaction conditions as shown
in Table 2. The yield and stereoselectivity were not influ-
Table 2.
Table 3.
Lewis acid
(equiv)
temp
(°C)
yield
(%)a
entry
solvent
drb
c
1
2
3
4
5
6
7
8
9
BF3‚OEt2 (0.2)
BF3‚OEt2 (0.5)
BF3‚OEt2 (1.0)
BF3‚OEt2 (2.0)
BF3‚OEt2 (1.0)
BF3‚OEt2 (1.0)
BF3‚OEt2 (1.0)
BF3‚OEt2 (1.0)
BF3‚OEt2 (1.0)
BF3‚OEt2 (1.0)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
PhCH3
CH3CN
-78 f 0
-78 f 0
-78 f 0
-78 f 0
-78
0
-23
-41
-78 f 0
-10
35
91
95
92
yield
(%)b
96:4
95:5
95:5
entry
9
10
drc
1
2
3
4
5
6
7
9a
9b
9c
9d
9e
9f
10a
10b
10c
10d
10e
10f
99
98
87
47
96
70
74
95:5
96:4
92:8
96:4
93:7
91:9
96:4
91
95
89
89
26
89:11
93:7
96:4
91:9
67:33
9g
10g
10
a Only the major component of the two diastereomers was used for the
alkylation reaction. b Isolated yields. c Determined by 1H NMR spectra for
all compounds and HPLC measurement for 10a and 10b; both experiments
showed the same results
a Isolated yields. b Determined by both 1H NMR spectra and HPLC
measurement of the diastereomeric mixture. c Not determined.
enced by the amount of Lewis acid. However, they were
very sensitive to the reaction temperature and the solvent.
These results imply that the temperature and polarity of the
solvent significantly affect the selective formation of the (E)-
or (Z)-geometry of the N-acyliminium ion.
To determine the stereochemistry of the newly generated
stereogenic center, the ester 10b was hydrolyzed to the acid
11, and then the 4-phenyloxazolidinone auxiliary was cleaved
under reductive conditions with Li/NH3 (Scheme 2).10 Cbz
protection of the resulting amino acid gave the known
possessing various alkyl substituents gave excellent yields
and diastereoselectivities. The stereochemistry of the newly
formed stereogenic center was determined by analogy with
10b. The byproduct (especially in entry 4) was mainly the
enamine, which resulted from elimination rather than ketene
(11) Palomo, C.; Oiarbide M.; Condepcion Gonzalez-Rego, M.; Sharma,
A. K.; Garcia, J. M.; Gonzalez, A.; Landa, C.; Linden, A. Angew. Chem.,
Int. Ed. 2000, 39, 1063.
(12) Formation of N-acyliminium ion was partly confirmed by the
observation of the change of 1H NMR spectrum at -40 °C after an addition
of BF3‚OEt2 to the N,O-acetal TMS ether in CD2Cl2 in the absence of the
nucleophiles. We thank the referees for their valuable advice on the
mechanistic aspects.
(10) (a) Ojima, I.; Pei, Y. Tetrahedron Lett. 1990, 31, 977 (b) Lucet,
D.; Sabelle, S.; Kostelitz, O.; Gall, T. L.; Mioskowski, C. Eur. J. Org.
Chem. 1999, 2583.
Org. Lett., Vol. 5, No. 20, 2003
3637

addition. We have also investigated the mechanistic basis
for the excellent stereochemical outcome of this transforma-
tion.
Scheme 3a
At the outset, we assumed that the selectivity for the (E)-
or (Z)- geometry of the N-acyliminium ion would be
determined by the energy difference of the two isomeric
forms. Thus, we carried out a semiempirical calculation on
the (E)- and (Z)-isomers generated from 9b. However, the
energy difference of the two isomers was unexpectedly only
0.005 kcal/mol,13 which was not at all sufficient to support
our assumption. After intensively investigating the stereo-
controlling factors, we realized that the stereochemistry of
the OTMS-attached carbon could crucially influence the
stereoselectiVe formation of the corresponding N-acyliminium
ion.
To certify our rationale, we performed amidoalkylations
of the diastereomers 14a and 14b, which were prepared from
the amide 13 by the same procedure employed for 9. We
chose 4,5-diphenyloxazolidinone as the most suitable chiral
auxiliary for our purpose, because the two diastereomers of
the TMS ethers 14 had a relatively low diastereomeric ratio
(dr ) 89:11) and were easily separable for the next step
(Scheme 3). To our surprise, the newly formed stereogenic
center of each major product possessed the exactly opposite
stereochemistry. This result implies that the stereochemistry
of the OTMS-bearing carbon controls the E/Z geometry of
the N-acyliminium ion. Furthermore, the selective formation
of (E)- or (Z)- geometry of N-acyliminium ion is essential
for the desired asymmetric induction by the chiral auxiliary-
controlled selective amidoalkylation.
To the best of our knowledge, no mechanistic studies on
the diastereoselective alkylation using a chiral precursor of
the N-acyliminium ion species have been carried out, due to
the difficulty of preparing suitable chiral acyclic precursors.
Obviously, this unique N,O-acetal TMS ether enabled us to
develop this conceptually new mechanistic rationale for the
outstanding stereoselectivity of our transformation as well
as the new stereoselective synthesis of â-amino acids.
In conclusion, we have developed a highly stereoselective
synthetic route to â-amino acids via diastereoselective
amidoalkylation, which was induced by stereoselective
formation of the N-acyliminium ion from the chiral N,O-
acetal TMS ether. The chirality of the oxazolidinone auxiliary
turned out to play a dual role for both the stereoselective
reduction of the amide by DIBAL-H, leading to the chiral
a Yields of 14a and 14b were 89 and 56%, respectively. In the
case of 14b, a substantial amount of the enamine was formed.
N,O-acetal TMS ether and the stereoselective alkylation of
the N-acyliminium ion. Currently, intensive studies on the
detailed mechanism and generality of this new transforma-
tion, based on our observations, and its wide range of
synthetic applications are in progress. Updated results will
be reported in due course.
Acknowledgment. This work was supported by the Korea
Research Foundation Grant (KRF-2002-070-C-00058).
Supporting Information Available: Representative ex-
perimental procedures for the synthesis of compounds 9a,
10a, 11, and 12, spectral data for all new compounds in
Schemes 1-3 and Tables 1-3, and the X-ray crystal-
lographic file (in CIF format) for 14a. This material is
available free of charge via the Internet at http://pubs.acs.org.
(13) Calculation was carried out with SYBYL 6.6 (Tripos) on a Silicon
Graphics O2 workstation.
OL035289E
3638
Org. Lett., Vol. 5, No. 20, 2003