L-Valinol and L-phenylalaninol-derived 2-phenylamino-2-oxazolines as chiral auxiliaries in asymmetric alkylations

Article abstract of DOI:10.1016/S0957-4166(02)00044-7

Lithium enolates of N-acyl phenyliminooxazolidine auxiliaries reacted with alkyl halides to produce the α-alkylated products with very high diastereofacial selectivity (up to >99% d.e.). The products were readily cleaved by simple alkaline hydrolysis to give homochiral carboxylic acids and could also be directly converted to aldehydes and other acid derivatives such as esters and amides.

Full text of DOI:10.1016/S0957-4166(02)00044-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 9–12
L
-Valinol and -phenylalaninol-derived
L
2
-phenylamino-2-oxazolines as chiral auxiliaries in asymmetric
alkylations
a
a,
b
c
Gue-Jae Lee, Taek Hyeon Kim, * Jae Nyoung Kim and Uk Lee
a
Faculty of Applied Chemistry, Chonnam National University, Kwangju 500-757, South Korea
b
Department of Chemistry, Chonnam National University, Kwangju 500-757, South Korea
c
Department of Chemistry, Pukyong National University, Pusan 608-737, South Korea
Received 1 January 2002; accepted 23 January 2002
Abstract—Lithium enolates of N-acyl phenyliminooxazolidine auxiliaries reacted with alkyl halides to produce the a-alkylated
products with very high diastereofacial selectivity (up to >99% d.e.). The products were readily cleaved by simple alkaline
hydrolysis to give homochiral carboxylic acids and could also be directly converted to aldehydes and other acid derivatives such
as esters and amides. © 2002 Elsevier Science Ltd. All rights reserved.
Chiral auxiliary-derived asymmetric alkylations have
been studied extensively and are now important and
general methods for asymmetric carbonꢀcarbon bond
We herein report that the use of metal enolates of new
N-acyl phenyliminooxazolidine auxiliaries results in as
high diastereoselectivity in alkylation reactions as N-
acyl oxazolidinones. The alkylation products are easily
hydrolyzed by simple alkaline hydrolysis (NaOH) with-
out using hazardous lithium hydroperoxide to suppress
1
formation. In particular, metal enolates of N-acyl oxa-
zolidinones, developed by Evans, are highly effective in
controlling facial selectivity for the preparation of
homochiral a-substituted carboxylic acid and their
6
the endocyclic cleavage and can be directly converted
2
7
derivatives. This auxiliary, however, undergoes endo-
to aldehydes as well as to other functional groups.
cyclic cleavage rather than the required exocyclic cleav-
age in removal of the auxiliary with alkaline
hydrolysis. To suppress the troublesome endocyclic
The synthesis of 2-phenylamino-2-oxazoline auxiliaries
2 was readily performed by reaction of 1,2-aminoalco-
hol with phenyl isothiocyanate to give the correspond-
ing N-(2-hydroxyethyl)thiourea, followed by cyclo-
desulfurization of the thiourea to the 2-phenylamino-2-
oxazoline by a one-pot reaction using p-toluenesulfonyl
chloride and NaOH according to our previous work
3
cleavage, hazardous lithium hydroperoxide has been
3a,3b
used in place of the hydroxide.
N-Acyl oxazolidi-
nones are not directly converted to the corresponding
aldehydes. The generation of aldehydes is possible via
two-step processes involving reduction to the alcohol
4
8
followed by oxidation or conversion to either the
(Scheme 1). The auxiliary was then acylated with
N-methoxy-N-methyl amide (Weinreb amide) or the
ester and subsequent reduction.
propionyl chloride in the presence of potassium
tert-butoxide in THF (Scheme 1). The acylation of
5
9
S
NHPh
NPh
N
O
H2N
OH
TsCl, NaOH
EtCOCl, t-BuOK
PhNCS
PhHN
HO
NH
O
N
R
O
THF
rt, 5 min
THF
rt, 30 min
THF
rt, 15 min
R
R
R
1
1
a, R = i -Pr 99%
b, R = Bn 99%
2a, 85%
2b, 90%
3
a, 85%
3b, 87%
Scheme 1.
*
Corresponding author. E-mail: thkim@chonnam.ac.kr
0
957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00044-7

1
0
G.-J. Lee et al. / Tetrahedron: Asymmetry 13 (2002) 9–12
2
-phenylamino-2-oxazoline might afford the regioiso-
meric N-endo- and N-exo-acylated products. The
obtained acyl derivative 3 was a regiocontrolled N-endo
product which was confirmed by X-ray crystallographic
1
0
analysis of the alkylation product 4e (Fig. 1).
Formation of the lithium enolate at −78°C using LiH-
MDS occurred within 1 h in THF and then subsequent
addition of the alkyl halide led to the formation of
a-alkylated product with excellent diastereoselectivity
1
1
(
Table 1). The purified products 4 were identified by
1
13
H, C NMR and MS analyses. The diastereomeric
ratios were determined by HPLC. The absolute
configurations of the alkylated products 4 were
assigned by comparison of the [h]D value reported in
Scheme 2.
the literature after removal of auxiliary. As the results
in Table 1 reveal, allyl bromide and benzyl bromides
reacted with these enolates to give the respective alkyl-
ated products with excellent yields (runs 2–3 and 5–6).
On the other hand, although a somewhat lower yield
was observed with ethyl iodide, the diastereoselectivity
was found to be virtually complete (runs 1 and 4). To
enhance the reactivity to ethyl iodide the use of HMPA
(
5 V%) as cosolvent in NaHMDS was found to result in
lower diastereoselectivity of 67:33 in HPLC.
The alkylation product can be converted to a variety of
derivatives (Scheme 2). Treatment with NaOH yielded
12
the a-alkylated carboxylic acid. Conversion to the
14
chiral amide via simple substitution using benzyl-
amine also proceeded cleanly in the presence of two
15
drops of acetic acid. Formation of the methyl ester
was also possible by treatment with sodium methoxide.
Most significantly, direct conversion to aldehydes using
Figure 1. X-Ray structure of 4e. Thermal ellipsoids are drawn
at the 30% probability level. Selected bond lengths (A
angles (°): N(1)ꢀC(10) 1.408(6), N(2)ꢀC(10) 1.252(6);
N(2)ꢀC(10)ꢀO(1) 125.1(5), N(2)ꢀC(10)ꢀN(1) 126.4(5),
O(1)ꢀC(10)ꢀN(1) 108.4(4).
,
) and
i-Bu AlH (DIBAL-H) was achievable. In all cases,
2
recovery of deacylated auxiliary was performed
successfully.
Table 1. Diastereoselective alkylations of N-acyl-2-phenyliminooxazolidines 3
Li
NPh O
N
NPh O
N
PhN
O
O
LiHMDS
THF
R'-X
O
O
N
o
-
78 C, 1 h
R'
R
R
R
3
4
Run
Substrate
R
R%
Producta
Yield (%)b
D.e.c,d
1
2
3
4
5
6
3a
3a
3a
3b
3b
3b
i-Pr
i-Pr
i-Pr
PhCH2
PhCH2
PhCH2
Et
4a
4b
4c
4d
4e
4f
55
82
88
53
80
81
98 (98:2)
Allyl
PhCH2
Et
Allyl
PhCH2
\99 (95:5)
\99 (97:3)
\99 (100:0)
\99 (98:2)
\99 (95:5)
a
The configuration was verified by correlation to authentic samples after removal of the auxiliary.
Isolated yields after purification.
Determined by HPLC (Spherisorb ODS column) after purification.
Parenthesis is the ratios of the unpurified diastereomeric mixture.
b
c
d

G.-J. Lee et al. / Tetrahedron: Asymmetry 13 (2002) 9–12
11
In summary, N-acyl 2-phenyliminooxazolidines have
been shown to perform highly diastereoselective alkyla-
tions similarly to the corresponding oxazolidinones
when using LiHMDS. The products are easily isolated
and can be converted directly to aldehydes as well as
various other functional groups. Clean removal of the
auxiliary with aqueous base is also possible without
using hydroperoxide.
R. L.; Sanganee, H. J.; Smith, A. D. Tetrahedron: Asym-
metry 2000, 11, 3475; (b) Oppolzer, W.; Darcel, C.;
Rochet, P.; Rosset, S.; DeBrabander, J. Helv. Chim. Acta
1997, 80, 1319; (c) Myers, A. G.; Yang, B. H.; Chen, H.;
Gleason, J. L. J. Am. Chem. Soc. 1994, 116, 9361.
8. Kim, T. H.; Lee, N.; Lee, G.-J.; Kim, J. N. Tetrahedron
2001, 57, 7137.
9. Procedure for synthesis of 3. To a stirred solution of
potassium tert-butoxide (0.16 g, 1.43 mmol) and 2 (1.19
mmol) in anhydrous THF (15 mL) under nitrogen at
room temperature, propionyl chloride (1.13 mL, 1.55
mmol) was added dropwise. The solution was allowed to
stir for 15 min, then was quenched with water (30 mL)
and extracted with ether. The combined extracts were
dried over magnesium sulfate, filtered, and concentrated.
Purification by flash chromatography (hexane/EtOAc,
Acknowledgements
This work was supported by the grant No. (2001-1-
1
2300-004-1) from the Basic Research Program of the
Korea Science and Engineering Foundation.
8
:2, R =0.6) afforded the desired compounds 3 in good
f
yields.
References
10. Crystal data for 4e: C H N O : M=348.43, monoclinic,
22
24
2
2
a=13.137(5), b=7.546(3), c=9.835(4) A
,
, i=100.40(4),
3
1
2
3
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Asymmetric Synthesis; Wiley: New York, 1995; (b) Gaw-
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U=958.9(7) A
,
, T=298(2) K, space group P21, Z=2,
−
3
D
=1.207 g cm , F(000)=372, v(Mo–Ka)=0.078
mm , crystal size 0.3×0.4×0.6 mm, 2356 reflections col-
lected, 2356 unique (Rint=0.0000), which were used in all
calcd
−
1
calculations. Final
R indices [I>2|(I)]: R =0.0711,
1
1
4.
wR =0.1074, R indices (all data) R =0.1510, wR =
2
1
2
. (a) Evans, D. A. Aldrichim. Acta 1982, 15, 23; (b) Evans,
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scans. The structure was solved using direct methods
techniques (SHELXS-86, Sheldrick, G. M. Acta Crystal-
logr. 1990, A46, 467) and refined using full-matrix least-
2
1
997, 30, 3.
squares based on F (SHELXL-97-2, Sheldrick, G. M.
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G.; Sanganee, H. J.; Szolcsanyi, P. Tetrahedron 1999, 55,
University of G o¨ ttingen, Germany, 1997). (Note that two
independent molecules which have the same configura-
tion are contained in the unit cell of the crystal of 4e.)
The absolute configuration could not be determined.
Further details of the structural investigations of 4e are
available on request from the Cambridge Crystallo-
graphic Data Centre, 12 Union Road, Cambridge, CB2
1EZ, UK (Deposit number CCDC 171612).
3
337.
. (a) Evans, D. A.; Weber, A. E. J. Am. Chem. Soc. 1986,
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4
1
11. Procedure for alkylation of 3b. To a dry round-bottomed
flask under nitrogen was added 3b (0.1 g, 0.32 mmol) in
anhydrous THF (4 mL). The solution was cooled to
−78°C. A solution of lithium bis(trimethylsilylamide)
(LiHMDS) in THF (1.0 M, 0.39 mL 120 mol%) was
added dropwise, and the solution was allowed to stir for
1 h. The mixture was treated with allyl bromide (0.03 mL,
120 mol%). After stirring for 30 min at −78°C and 1 h at
0°C, the reaction mixture was quenched with saturated
ammonium chloride (4 mL) and water (20 mL), extracted
with ether. The combined extracts were dried over mag-
nesium sulfate, filtered, and concentrated. HPLC analysis
of the crude product revealed the isomer ratios. Purifica-
tion by flash chromatography (hexane/EtOAc, 8:2)
afforded the major diastereomer 4e. Yield 80%; mp 92–
(
5
hedron Lett. 1997, 38, 6577; (e) Schinzer, D.; Bauer, A.;
Schieber, J. Chem. Eur. J. 1999, 5, 2492.
5
. (a) Evans, D. A.; Bender, S. L.; Morris, J. J. Am. Chem.
Soc. 1988, 110, 2506; (b) Block, M. H.; Cane, D. E. J.
Org. Chem. 1988, 53, 4923; (c) Jones, T. K.; Mills, S. G.;
Reamer, R. A.; Askin, D.; Desmond, R.; Volante, R. P.;
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R. K.; Rupprecht, K. M.; Armistead, D. M.; Boger, J.;
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J. M.; Witzel, B. E. Tetrahedron Lett. 1998, 39, 229; (e)
Smith, A. B., III; Lodise, S. A. Org. Lett. 1999, 1, 1249.
. For an endocyclic hydrolysis of a modified oxazolidinone
without using lithium hydroperoxide, see: (a) Davies, S.
G.; Sanganee, H. J. Tetrahedron: Asymmetry 1995, 6, 671;
2
0
1
6
7
93°C; [h] =+94.8 (c=3.4, CHCl ); H NMR (CDCl3,
D 3
300 MHz) l 7.34–6.96 (m, 10H), 5.96–5.83 (m, 1H),
5.16–5.04 (m, 2H), 4.82–4.77 (m, 1H), 4.31 (m, 1H),
4.15–4.13 (m, 2H), 3.22 (dd, 1H, J=13.2, 3.3 Hz), 2.80
(dd, 1H, J=13.2, 9.6 Hz), 2.72–2.62 (m, 1H), 2.30–2.17
(
b) Gibson, C. L.; Gillon, K.; Cook, S. Tetrahedron Lett.
1
998, 39, 6733; (c) Bull, S. D.; Davies, S. G.; Jones, S.;
13
Sanganee, H. J. J. Chem. Soc., Perkin Trans. 1 1999, 387.
. For a direct stereoselective synthesis of a-substituted
aldehydes, see: (a) Bull, S. D.; Davies, S. G.; Nicholson,
(m, 1H), 1.22 (d, 3H, J=6.9 Hz); C NMR (CDCl , 75
3
MHz) l 176.3, 145.8, 145.6, 136.1, 136.0, 129.6, 128.8,
128.7, 127.1, 123.5, 122.8, 116.8, 67.7, 56.2, 37.9, 37.8,

1
2
G.-J. Lee et al. / Tetrahedron: Asymmetry 13 (2002) 9–12
7.0, 16.3; HRMS calcd for C H N O : 348.1838. son of the measured optical rotation ([h] =−23.6
2
0
3
22
24
2
2
D
20
13
Found 348.1841; anal. calcd for C H N O : C, 75.83;
(c=0.8, CHCl )] with the published values ([h] =−23.1
22
24
2
2
3
D
H, 6.94; N, 8.04. Found: C, 75.36; H, 6.86; N,
.93%.
2. In the case of acid the auxiliary was recovered by extrac-
tion of the reaction mixture with CH Cl . The chiral acid
(c=1, CHCl )].
13. Tyrrell, E.; Tsang, M. W. H.; Skinner, G. A.; Fawcett, J.
Tetrahedron 1996, 52, 9841.
14. Davies, S. G.; Dixon, D. J. Synlett 1998, 963.
15. For related N-acyl phenyliminooxazolidines previously
used for conversion to amides, see: Ganboa, I.; Palomo,
C. Bull. Soc. Chim. Fr. 1982, 2, 167.
3
7
1
2
2
was almost quantitatively isolated by extraction with
EtOAc after acidification to pH 2. The absolute configu-
ration and enantiomeric purity were assigned by compari-