C1-symmetric oxazolinyl sulfoximines as ligands in copper-catalyzed asymmetric mukaiyama aldol reactions

Article abstract of DOI:10.1021/ol703065x

Aryl-bridged C¹-symmetric oxazolinyl sulfoximines are applicable in copper-catalyzed asymmetric Mukaiyama aldol reactions with methyl pyruvate. The resulting a-hydroxy esters have been obtained with up to 94% ee in good yields. They contain a quaternary stereogenic center and represent valuable precursors for biologically active molecules.

Full text of DOI:10.1021/ol703065x

ORGANIC
LETTERS
2008
Vol. 10, No. 5
917-920
C1-Symmetric Oxazolinyl Sulfoximines
as Ligands in Copper-Catalyzed
Asymmetric Mukaiyama Aldol Reactions
Jo1rg Sedelmeier, Tim Hammerer, and Carsten Bolm*
Institute of Organic Chemistry, RWTH Aachen UniVersity, Landoltweg 1,
D-52056 Aachen, Germany
carsten.bolm@oc.rwth-aachen.de
Received December 20, 2007
ABSTRACT
Aryl-bridged C1-symmetric oxazolinyl sulfoximines are applicable in copper-catalyzed asymmetric Mukaiyama aldol reactions with methyl
pyruvate. The resulting -hydroxy esters have been obtained with up to 94% ee in good yields. They contain a quaternary stereogenic center
r
and represent valuable precursors for biologically active molecules.
The enantioselective metal-catalyzed Mukaiyama aldol reac-
tion has become an important synthetic tool for C-C bond
formations.1 It allows the preparation of enantiomerically
enriched alcohols, which often represent useful building
blocks for biologically active molecules.2 Most catalytic
systems have been applied in additions of enol silanes to
aldehydes, resulting in secondary alcohols. However, for
reactions involving pyruvates as electrophiles, the number
of efficient systems is rather limited.3 Recently, we reported
that copper complexes with C1-symmetric amino sulfox-
imines are efficient catalysts for asymmetric Mukaiyama and
vinylogous Mukaiyama-type aldol reactions.4 Inspired by
these results, we decided to test the applicability of newly
designed oxazolinyl sulfoximines 4 in such transformations.
Sulfoximines of this type can be prepared in a two-step
synthesis using readily accessible, commercially available
starting materials.5 Following the reaction sequence depicted
in Scheme 1, sulfoximines 4a-j were prepared in overall
yields of 65-78%.6
For the optimization of the Mukaiyama-type aldol reaction,
the solvent, temperature, metal source, and catalyst structure
were varied. In the coupling reaction between ketoester 5
and enol silyl ether 6a to give 7a, toluene proved superior
to DCE, DCM, 1,4-dioxane, Et2O, THF, and EtOH. This
variation also revealed that use of a weakly coordinating
(3) (a) Evans, D. A.; MacMillan, D. W. C.; Campos, K. R. J. Am. Chem.
Soc. 1997, 119, 10859. (b) Evans, D. A.; Kozlowski, M. C.; Burgey, C. S.;
MacMillan, D. W. C. J. Am. Chem. Soc. 1997, 119, 7843. (c) Evans, D.
A.; Burgey, C. S.; Kozlowski, M. C.; Tregay, S. W. J. Am. Chem. Soc.
1999, 121, 686. (d) Du, D.-M.; Lu, S.-F.; Fang, T.; Xu, J. J. Org. Chem.
2005, 70, 3712. (e) Christensen, C.; Juhl, K.; Hazell, R. G.; Jørgensen, K.
A. J. Org. Chem. 2002, 67, 4875. (f) Christensen, C.; Juhl, K.; Jørgensen
K. A. Chem. Commun. 2001, 2222.
(4) (a) Langner, M.; Bolm, C. Angew. Chem., Int. Ed. 2004, 43, 5984.
(b) Langner, M.; Re´my, P.; Bolm, C. Chem.sEur. J. 2005, 11, 6254. (c)
Re´my, P.; Langner, M.; Bolm, C. Org. Lett. 2006, 6, 1209.
(5) (a) Fusco, R.; Tericoni, F. Chim. Ind. (Milan) 1965, 47, 61. (b)
Johnson, C. R.; Schroeck, C. W. J. Am. Chem. Soc. 1973, 95, 7418. For an
improved protocol, see: (c) Brandt, J.; Gais, H.-J. Tetrahedron: Asymmetry
1997, 6, 909.
(1) For reviews, see: (a) Bach, T. Angew. Chem., Int. Ed. Engl. 1994,
33, 417. (b) Hollis, T. K.; Bosnich, B. J. Am. Chem. Soc. 1995, 117, 4570.
(c) Gro¨ger, H.; Vogl, E. M.; Shibasaki, M. Chem.sEur. J. 1998, 4, 1137.
(d) Nelson, S. G. Tetrahedron: Asymmetry 1998, 9, 357. (e) Palomo, C.;
Oiarbide, M.; Garc´ıa, J. M. Chem.sEur. J. 2002, 8, 36. (f) Carreira, E. M.
In ComprehensiVe Asymmetric Catalysis;Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: Berlin, 1999; Vol. 1, p 997.
(2) (a) Schwartz, A.; Van Wart, H. E. Prog. Med. Chem. 1992, 29, 271.
(b) Babine, R. E.; Bender, S. L. Chem. ReV. 1997, 97, 1359. (c) Coppola,
G. M.; Schuster, H. F. R-Hydroxy Acids in EnantioselectiVe Synthesis;
VCH: Weinheim, Germany, 1997. (d) Davidson, A. H.; Drummond, A.
H.; Galloway, W. A.; Whittaker, M. Chem. Ind. 1997, 258. (e) Levy, D.
E.; Lapierre, F.; Liang, W.; Ye, W.; Lange, C. W.; Li, X.; Grobelny, D.;
Casabonne, M.; Tyrell, D.; Holme, K.; Nadzan, A.; Galardy, R. E. J. Med.
Chem. 1998, 41, 199 and references therein.
(6) (a) For the oxazoline formation used here, see: Bolm, C.; Weickhardt,
K.; Zehnder, K.; Ranff, T. Chem. Ber. 1991, 124, 1173. (b) For the Cu-
catalyzed N-arylation of the sulfoximines applied here, see: Sedelmeier,
J.; Bolm, C. J. Org. Chem. 2005, 70, 6904.
10.1021/ol703065x CCC: $40.75
© 2008 American Chemical Society
Published on Web 01/29/2008

mol % led to reduced product yields and lower enantio-
selectivities.
Scheme 1
Next, the effect of ligand structure in the reaction depicted
in Scheme 2 was investigated. Again, the catalytic conversion
Scheme 2
solvent was crucial for achieving high enantioselectivities.
Strongly coordinating solvents such as ethanol hampered the
reaction. Table 1 summarizes the results. Furthermore, the
of 5 and 6a to give 7a served as a test reaction. From the
behavior of the two diastereomeric oxazolinyl sulfoximine
(S,S)-4a and (S,R)-4a, it was concluded that the former was
superior with respect to yield and enantioselectivity (Table
2, entries 1 and 2). Thus, the subsequent ligand screening
focused on the use of homochiral oxazolinyl sulfoximine
derivatives.
Table 1. Solvent Effect on the Mukaiyama Aldol Reaction
between Ketoester 5 and Enol Silyl Ether 6a to give 7aa
yieldb
(%)b
eec
(%)
entry
solvent
Et2O
1
2
3
4
5
6
7
67
40
17
37
47
23
5
THF
49
DCM
83
DCE
85
1,4-dioxane
EtOH
toluene
69
trace
84
Table 2. Influence of Ligand Structure in the Mukaiyama
Aldol Reaction between Ketoester 5 and Enol Silyl Ether 6a to
give 7aa
67
a Reaction conditions: 5 (0.25 mmol), 6a (0.30 mmol), CF3CH2OH (0.30
mmol), Cu(OTf)2 (0.025 mmol), (S,S)-oxazolinyl sulfoximine 4a (0.026
mmol), solvent (1.5 mL) at rt for 14 h. b Yield after column chromatography.
c The enantiomer ratios were determined by HPLC using a chiral stationary
phase (Chiracel ODH). The (R)-configured product 7a was formed in
preference.
yieldc
(%)
eed
(%)
entry
sulfoximineb
1
2
3
4
5
6g
7
8
9
(S,S)-4a
(S,R)-4ae
(S)-4b
(S,S)-4c
(S,1R,2S)-4df
(S,1R,2S)-4df
(S,S)-4e
(S,S)-4f
95
92
68
74
94
94
56
79
46
51
33
71
84
23
9
57
91
94
46
66
21
16
32
11
effect of 2,2,2-trifluorethanol was investigated. As observed
in previous studies,5,7 the reaction rate increased immensely
in the presence of this additive. The enantioselectivity
remained unaffected by 2,2,2-trifluorethanol.
Further studies focused on the variation of the copper
source and catalyst loading. Among various copper salts,
including Cu(ClO4)2, Cu(OAc)2, CuCl2, Cu(OTf), and
Cu(OAc), copper(ΙΙ) triflate was the most efficient salt
concerning yield and ee. Copper(Ι) salts did not catalyze the
reaction at all. Lowering the catalyst loading from 10 to 5
(S,S)-4g
(S,S)-4h
(S,S)-4i
10
11
12
(S,S)-4j
a Reaction conditions: 5 (0.25 mmol), 6a (0.30 mmol), CF3CH2OH (0.30
mmol), Cu(OTf)2 (0.025 mmol), sulfoximine 4 (0.026 mmol), toluene (1.5
mL), rt, 20 h. b All sulfoximidoyl units have (S)-configuration at sulfur.
c Yield after column chromatography. d The enantiomer ratios were deter-
mined by HPLC using a chiral stationary phase (Chiracel ODH). The (R)-
configured product 7a was preferentially formed. e Oxazolinyl moiety
derived from (R)-configured tert-leucinol. f Oxazolinyl moiety derived from
L-(-)-norephedrine. g Performed at -20 °C.
(7) (a) Evans, D. A.; Johnson, D. S. Org. Lett. 1999, 1, 595. (b) Evans,
D. A.; Willis, M. C.; Johnston, J. N. Org. Lett. 1999, 1, 865. (c) Evans, D.
A.; Rovis, T.; Kozlowski, M. C.; Tedrow, J. S. J. Am. Chem. Soc. 1999,
121, 1994.
918
Org. Lett., Vol. 10, No. 5, 2008

Increasing the steric bulk of the substituents at the sulfur
atom [by changing methyl to iso-butyl or xylenyl (Table 2,
entries 8 vs 9 and 4 vs 12, respectively)] led to a decrease
in yield and enantioselectivity. For further ligand optimiza-
tion, the methyl phenyl combination at the sulfonimidoyl
moiety was kept constant and the oxazolinyl substituents
were varied.
Use of sulfoximine 4b having no stereogenic center at the
heterocycle led to 7a with poor ee in moderate yield (Table
2, entry 3). The testing of other oxazolinyl sulfoximine
derivatives revealed that the substitution pattern at the
oxazoline ring was of major importance, and finally,
compound 4d derived from L-(-)-norephedrine and (S)-
configured methyl phenyl sulfoximine was identified as the
best ligand yielding 7a with 91% ee in 94% yield (Table 2,
entry 5). Lowering the reaction temperature to -20 °C
increased the enantioselectivity to remarkable 94% ee without
affecting the yield (Table 2, entry 6). Consequently, the
optimal conditions for the catalytic reaction between methyl
pyruvate (5) and silyl enol ether 6 (1.2 equiv) involved the
use of 10.5 mol % of (S,S)-oxazolyl sulfoximine 4a, 10.0
mol % of Cu(OTf)2, and 1.2 equiv of 2,2,2-trifluorethanol,
and the reaction had to be performed in a temperature range
of 0 to -20 °C (Scheme 2).
general, catalyses with methyl pyruvate (5) and enol silyl
ethers derived from acetophenones proceeded smoothly,
whereas other pyruvate esters and donor substrates with
aliphatic R1 groups did not react at all. Enol silyl ethers
bearing aryl groups with electron-donating substituents were
good substrates. If the presence of electron-withdrawing
groups reduced electron density of the enol silyl ether (Table
3, entries 6, 10, and 13), the reaction temperature had to be
increased to room temperature to obtain acceptable yields.
Silyl enol ethers with sterically more demanding groups
resulted in somewhat lower enantioselectivities and reduced
yields. Nevertheless, 90% ee was still achieved in conver-
sions of ortho-substituted compounds 6g and 6h (Table 3,
entries 9 and 10).
In a vinylogous Mukaiyama aldol reaction 2-(trimethyl-
silyloxy)furan (8) underwent facile reaction with pyruvate
5 to afford anti-aldol adduct 9 in high yield with excellent
diastereoselectivity, albeit with low ee (Table 3, entry 12).
This transformation is particularly interesting since it pro-
vides a highly functionalized γ-lactone which represents a
versatile precursor for natural product synthesis.8
In order to further demonstrate the synthetic value of the
newly developed Mukaiyama aldol catalyst system, conver-
sions of 7 into tetronic and malic acid derivatives were
established (Scheme 3). Tetronic acids and their metabolites
In order to evaluate the substrate scope of the asymmetric
Mukaiyama aldol reaction, the applicability of various silyl
enol ethers and pyruvate esters was examined. To our delight,
several substrate combinations reacted well, affording prod-
ucts with enantioselectivities in the 80-90% ee range (Table
3). The highest enantiomeric excesses (94%) were achieved
in reactions with enol silyl ethers 6a, 6b, and 6e derived
from aryl methyl ketones (Table 3, entries 2, 3, and 7). In
Scheme 3
Table 3. Substrate Scope of the Mukaiyama Aldol Reaction
between Ketoester 5 and Enol Silyl Ethers 6 to give 7a
temp
(°C)
yieldb
(%)
dec
(%)
eed
(%)
entry
product
1
2
3
4
5
6
7
8
9
10
11
12
13
14
7a
7a
7b
7c
7c
7d
7e
7f
7g
7h
7h
7i
rt
-20
-20
rt
0
rt
-20
-20
-20
rt
0
rt
94
85
89
70
67
58
98
74
81
21
17
65
46
95
91
94
94
90
82
86
94
85
are common in nature,9 and optically active derivatives are
of immense interest due to their versatile pharmacological
applications.10 Tetronic acid derivative 12, for example, can
be used in the treatment and prevention of diseases modulated
by a â-secretase inhibitor, such as Alzheimer’s disease,11 or
can be applied for the inhibition of the HIV protease
enzyme.12
90
90
88
20
98
72/40e
90
7j
9
rt
-20
22f
a Reaction conditions: 5 (0.25 mmol), 6 (0.30 mmol), CF3CH2OH (0.30
mmol), Cu(OTf)2 (0.025 mmol), sulfoximine 4d (0.026 mmol), toluene (1.5
mL), 16 h. b After column chromatography. c Diastereomer ratio was
determined by 1H NMR. d The enantiomer ratios were determined by HPLC
using a chiral stationary phase (Chiracel ODH, OBH, ADH, OJ). The (R)-
configured product 7 was preferentially formed. The absolute configurations
of the products were assigned in analogy to 7a. e The relative configuration
has not been determined. f Absolute and relative configurations have been
determined by comparison with literature data (see ref 3c).
(8) (a) Casiraghi, G.; Rassu, G. Synthesis 1995, 607. (b) Kong, K.; Romo,
D. Org. Lett. 2006, 8, 2909. (c) Cameron, J. S.; Abbanat, D.; Bernan, V.
S.; Maiese, W. M.; Greenstein, M.; Jompa, J.; Tahir, A.; Ireland, C. M. J.
Nat. Prod. 2000, 63, 142. (d) Li, R.-T.; Han, Q.-B.; Zheng, Y.-T.; Wang,
R.-R.; Yang, L.-M.; Lu, Y.; Sang, S.-Q.; Zheng, Q.-T.; Zhao, Q.-S.; Sun,
H.-D. Chem. Commun. 2005, 23, 2936.
(9) Haynes, L. J.; Plimmer, J. R. Q. ReV. Chem. Soc. 1960, 14, 292.
Org. Lett., Vol. 10, No. 5, 2008
919

The preparation of 5,5-disubstituted (R)-tetronic acid
derivative 12 started from 2-hydroxyester 7a. The deoxy-
genation step from 7a to methyl ester 10 proceeded smoothly,
but traces of the corresponding acid were formed as
byproduct. In order to obtain a quantitative yield of 10, the
reaction mixture was evaporated to dryness and the resulting
oil was dissolved in MeOH/HCl. After 2 h at 50 °C, all acid
was converted into ester 10, which could then be isolated
with 94% ee in 99% yield.13 Subsequent acylation with acetic
anhydride/pyridine and DMAP led to the corresponding
2-acetoxycarboxylate 11 in 90% yield. Finally, tetronic acid
derivative (R)-12 was obtained in excellent yield (94%) by
cyclization of (R)-11 using LiN(SiMe3)2 (2.2 equiv) in THF
at -78 °C.14 As expected, no racemization occurred during
the described reaction sequence providing 12.
stereogenic quaternary center and two different ester moi-
eties, was obtained in 95% yield by Baeyer-Villiger
oxidation of 7a using m-CPBA and TFA in DCM at room
temperature (Scheme 3).
In summary, we have described the synthesis of novel C1-
symmetric aryl-bridged oxazolinyl sulfoximines and dem-
onstrated their applicability as ligands in copper-catalyzed
enantioselective Mukaiyama-type aldol reactions. Various
R-hydroxy esters with quaternary stereogenic centers have
been obtained in good yields with enantioselectivities of up
to 94% ee. Furthermore, we have shown that the newly
developed catalytic system can be used for the synthesis of
synthetically and pharmacologically interesting compounds,
such as γ-lactone 9, tetronic acid derivative 12, and the malic
acid ester derivative 13.
Malic acid derivatives represent valuable building blocks
for peptides15 and are potential precursors for natural product
synthesis. Citramalic acid derivative (R)-13, containing a
Acknowledgment. This work was supported by the
Fonds der Chemischen Industrie and the Deutsche Fors-
chungsgemeinschaft (DFG) within the “Graduiertenkolleg”
(GRK) 440 “Methods in Asymmetric Synthesis”.
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Supporting Information Available: Experimental pro-
cedures and full characterization (1H and 13C NMR data and
spectra, MS, IR, and CHN analyses) for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL703065X
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Org. Lett., Vol. 10, No. 5, 2008