A new class of substituted aryl bis(oxazoline) ligands for highly enantioselective copper-catalyzed asymmetric aldol addition of dienolsilane to pyruvate and glyoxylate esters

Article abstract of DOI:10.1021/ol048179w

(Chemical Equation Presented) A new class of bis(oxazoline) ligands are introduced that feature o-alkoxyaryl substituents and provide the highest enantioselectivities yet reported for the copper-catalyzed asymmetric dienosilane aldol addition to pyruvate and glyoxylate esters. Enantioselectivities up to 98% ee (before recrystallization) and isolated yields up to 91% were observed. Additionally, chloride counterions were found to be superior to triflate for this reaction.

Full text of DOI:10.1021/ol048179w

ORGANIC
LETTERS
2004
Vol. 6, No. 22
4097-4099
A New Class of Substituted Aryl
Bis(oxazoline) Ligands for Highly
Enantioselective Copper-Catalyzed
Asymmetric Aldol Addition of
Dienolsilane to Pyruvate and Glyoxylate
Esters
Julie Cong-Dung Le and Brian L. Pagenkopf*
The Department of Chemistry and Biochemistry, UniVersity of Texas at Austin,
Austin, Texas 78712
pagenkopf@mail.utexas.edu
Received September 8, 2004
ABSTRACT
A new class of bis(oxazoline) ligands are introduced that feature o-alkoxyaryl substituents and provide the highest enantioselectivities yet
reported for the copper-catalyzed asymmetric dienosilane aldol addition to pyruvate and glyoxylate esters. Enantioselectivities up to 98% ee
(before recrystallization) and isolated yields up to 91% were observed. Additionally, chloride counterions were found to be superior to triflate
for this reaction.
In recent years, the notoriously difficult challenge of execut-
ing catalytic, asymmetric nucleophilic additions on prochiral
ketone substrates to afford enantiomerically pure tertiary
alcohols has inspired a number of ingenious synthetic
strategies.1 In pioneering investigations, Evans described the
use of C2 symmetric bis(oxazoline) ligands (Figure 1, A)
for the Lewis acid catalyzed aldol addition of trimethylsilyl
ketene S,O-acetals to methyl pyruvate.2 Recently, we became
particularly interested in accessing highly optically enriched
tertiary alcohols such as 3 (Scheme 1); however, broadly
(1) For recent examples of nonaldol approaches, see: Li, H.; Walsh, P.
J. J. Am. Chem. Soc. 2004, 126, 6538-6539. (b) Wada, R.; Oisaki, K.;
Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2004, 126, 8910-8911. (c)
Tian, S.-K.; Hong, R.; Deng, L. J. Am. Chem. Soc. 2003, 125, 9900-9901.
(d) Jeon, S.-J.; Walsh, P. J. J. Am. Chem. Soc. 2003, 125, 9544-9545. (e)
Garcia, C.; LaRochelle, L. K.; Walsh, P. J. J. Am. Chem. Soc. 2002, 124,
10970-10971. (f) Tian, S.-K.; Deng, L. J. Am. Chem. Soc. 2001, 123,
6195-6196. (g) Waltz, K. M.; Gavenonis, J.; Walsh, P. J. Angew. Chem.,
Int. Ed. 2002, 41, 3697-3699. (h) Tietze, L. F.; Volkel, L.; Wulff, C.;
Weigand, B.; Bittner, C.; McGrath, P.; Johnson, K.; Schafer, M. Chem.
Eur. J. 2001, 7, 1304-1308. (i) Dosa, P. I.; Fu, G. C. J. Am. Chem. Soc.
1998, 120, 445-446.
Figure 1.
10.1021/ol048179w CCC: $27.50
© 2004 American Chemical Society
Published on Web 09/30/2004

Table 1. Ligand Screening and Reaction Optimizationa
Scheme 1
% ee (% yield)/counterion
substrate-tolerant catalysts for aldol additions of dienolsilanes
to pyruvate esters have remained elusive.
entry
ligand
T (°C)
OTf
Cl
1
2
3
4
5
6
7
8
9
A
B
-78
-78
-78
-78
-78
-78
-40
-20
0
74 (77)b
11 (70)b
76 (78)
91 (31)
40 (35)
90 (81)
86 (80)
20 (75)
44 (78)
90 (78)
94 (81)
92 (85)
The state-of-the-art in this area provides aldol product 3a
in a modest 74% ee using the commercially available tert-
butyl box ligand A (and 17% ee with ligand B).3 While many
structurally diverse bis(oxazoline) architectures have been
introduced in recent years,4-6 there exists a paucity of
reported variations in aryl substituents (i.e., C) of bis-
(oxazoline)s.7 In this regard, the electronic and steric tuning
of aryl rings in chiral ligands is a cornerstone of reaction
optimization, and given the gearing and high rotational
barriers imposed by ortho substituents we chose to focus on
their influence. However, at the onset of these investigations
it became immediately obvious that a lack of suitable aryl
glycinol precursors had thwarted advancements in this area.
We addressed this deficiency by preparing a family of
o-alkoxy-substituted aryl glycinols 48 and converting four
of these to their corresponding bis(oxazoline)s (Scheme 2).9,10
6a
6b
6c
6d
6a
6a
6a
39 (80)
11 (75)
a Reactions were done in THF (0.25 M), with 1.1 equiv of dienolsilane
relative to methyl pyruvate. Isolated yields. Enantiomeric excess was
determined by chiral HPLC. b These values are similar to those reported in
ref 3.
(up to 98% ee) observed to date in the addition of a
dienolsilane to pyruvate and glyoxylate esters.
The key results from reaction optimization are summarized
in Table 1. Our ideas about ligand design were supported
by the substantially better asymmetric induction observed
with aryl-substituted ligand 6a (76% ee, entry 3) than the
parent ligand B (11% ee, entry 2). The selectivity was further
improved to 90% ee by replacing the triflate counterion with
chloride.11,12 Other changes to the ligand, such as decreasing
the size of the aryl substituent at C(5) (entries 4 and 5) or
increasing the sterics of the alkoxy protecting group (entry
6) resulted in decreased selectivity. The optimized conditions
consist of running the reaction at -20 °C (compare entries
7-9) in THF with preformed catalysts.13
Scheme 2
(7) To the best of our knowledge, there is only a single instance of a
highly enantioselective (Diels-Alder) reaction catalyzed by a substituted
aryl (R-1-naphthyl) bis(oxazoline). Crosignani, S.; Desimoni, G.; Faita, G.;
Righetti, P. P. Tetrahedron 1998, 54, 15721-15730.
(8) Le, J. C-D.; Pagenkopf, B. L. J. Org. Chem. 2004, 69, 4177-4180.
(9) (a) Evans, D. A.; Peterson, G. S.; Johnson, J. S.; Barnes, D. M.;
Campos, K. R.; Woerpel, K. A. J. Org. Chem. 1998, 63, 4541-4544. (b)
Denmark, S. E.; Stavenger, R. A.; Faucher, A.-M.; Edwards, J. P. J. Org.
Chem. 1997, 62, 3375-3389.
Herein, we reveal that copper(II) complexes of bis(oxazoline)
ligands 6 provide the highest levels of asymmetric induction
(10) Selection of the o-alkoxy substituent was made with the expectation
(and realization) that a second ligand architecture 7, which can be described
as a novel bis(oxazoline) salen hybrid, is obtained essentially gratis by simple
deprotection. Catalytic asymmetric reactions with tetradentate ligands 7,
which we call “oxalens,” will be reported elsewhere.
(2) (a) Evans, D. A.; Kozlowski, M. C.; Burgey, C. S.; MacMillan, D.
W. C. J. Am. Chem. Soc. 1997, 119, 7893-7894. (b) Evans, D. A.;
MacMillan, D. W. C.; Campos, K. R. J. Am. Chem. Soc. 1997, 119, 10859-
10860. (c) Evans, D. A.; Burgey, C. S.; Kozlowski, M. C.; Tregay, S. W.
J. Am. Chem. Soc. 1999, 121, 686-699.
(3) van Lingen, H. L.; van de Mortel J. K. W.; Kekking, K. F. W.; van
Delft, F. L.; Songinke, T.; Rutjes, F. P. J. T. Eur. J. Org. Chem. 2003,
317-324. Our results were similar; see Table 1, entries 1 and 2.
(4) Fritschi, H.; Leutenegger, U.; Pfaltz, A. Angew. Chem., Int. Ed. Engl.
1986, 25, 1005-1006.
(5) (a) Pfaltz, A. Acc. Chem. Res. 1993, 23, 339-345. (b) Jørgensen, K.
A.; Johannsen, M.; Yao, S.; Audrain, H.; Thorhauge, J. Acc. Chem. Res.
1999, 32, 605-613. (c) Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000,
33, 325-335.
(6) (a) Ghosh, A. K.; Mathivanan P.; Cappiello, J. Tetrahedron:
Asymmetry 1998, 9, 1-45. (b) Rechavi, D.; Lemaire, M. Chem. ReV. 2002,
102, 3467-3494. (c) Desimoni, G.; Faita, G.; Quadrelli, P. Chem. ReV.
2003, 103, 3119-3154. (d) McManus, H. A.; Guiry, P. J. Chem. ReV. 2004,
104, 4151-4202.
(11) Reaction with A‚CuCl2 gave 3a in 92% ee, but only 31% yield.
This catalyst system was inactiVe with all the substrates listed in Table 2
except for 1a.
(12) (a) Evans, D. A.; Murry, J. A.; von Matt, P.; Norcross, R. D.; Miller,
S. D. Angew. Chem., Int. Ed. Engl. 1995, 34, 798-800. (b) O’Mahony, D.
J. R.; Belanger, D. B.; Livinghouse, T. Synlett 1998, 443-445. (c) For a
review, see: Fagnou, K.; Lautens, M. Angew. Chem., Int. Ed. 2002, 41,
26-47.
4098
Org. Lett., Vol. 6, No. 22, 2004

91 and 91% ee, respectively). Entry n demonstrates compat-
ibility with thiophene containing substrates as well.
Table 2. Aldol Reaction with Dienolsilane 2a
In summary, a new class of bis(oxazoline) ligands has been
introduced that features o-alkoxyaryl substituents. These
ligands provide the highest enantioselectivities yet reported
for the copper-catalyzed asymmetric dienolsilane aldol
additions to pyruvate and glyoxylate esters: enantioselec-
tivities up to 98% ee (before recystallization) and isolated
yields up to 91%. Bis(oxazoline) ligands have been success-
fully employed in many contemporary catalytic asymmetric
processes,4-6 including: aldol,14 aziridination,15 carbonyl-
ene,16 Diels-Alder,17 hetero-Diels-Alder,18 cyclopropana-
tion,19 and Michael20 reactions. The ability of the new ligands
6 (and 7) to positively impact these and other enantioselective
transformations will be reported in due course.
entry
R1
R2
% yieldb
% eec,d
94
94
92
79
96 (>99)
93
94
98
84
80 (>99)
96
91
a
b
c
d
ee
f
g
h
i
j
k
l
m
n
Me
Me
Me
Me
Me
Et
Bn
t-Bu
Me
Et
Et
Et
Et
Et
81
75
72
70
91
82
75
90
74
77
85
75
81
78
C6H5
4-MeOC6H4
4-MeC6H4
4-IC6H4
4-CF3C6H4
4-NO2C6H4
n- C6H13
Acknowledgment. J.C.-D.L. is grateful to the Gates
Millennium Scholars foundation for a graduate fellowship.
We thank the Robert A. Welch Foundation, donors of the
American Chemical Society Petroleum Research Fund, and
the Texas Advanced Research Program for financial support.
We thank Vincent Lynch for determination of the X-ray
structures.
Et
Et
Et
Et
i-Pr
E-PhCHdCH
2-benzothiophene
91
81 (92)
a Reactions were done in THF (0.25 M) with 1.1 equiv of dienolsilane
relative to substrate. b Isolated yield. c Enantiomeric excess was determined
by chiral HPLC. d Value in parentheses: ee after single recrystallization.
e X-ray data included in the Supporting Information.
Supporting Information Available: General experimen-
tal procedures, characterization of all new compounds, and
X-ray structure data for 3e and 6a (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
Encouraged by the enhanced selectivity, we set out to
explore reaction scope. The catalyst system was undeterred
by ethyl or benzyl pyruvate esters (Table 2, entries b and
c), but increasing the size of the ester substituent to a tert-
butyl resulted in a drop to 79% ee (entry d). Next, we
examined the reaction with aryl glyoxylates, and with
electronically neutral or electron rich arenes excellent enan-
tioselectivities were observed, ranging from 93 to 98% ee
(entries e-i). The ee of the parent ethyl phenylglyoxylate
(entry e) could be fortified to >99% ee by a single
recrystallization. Activation of the ketone by electron
withdrawing groups on the arene (entries i and j) resulted in
a faster aldol reaction, but the rate increase was mitigated
by a decrease in enantioselectivity (84 and 80% ee, respec-
tively). Reactions with branched and unbranched alkyl
glyoxylates (entries k and l), as well as R,â-unsaturated
glyoxylates (entry m) afforded good enantioselectivities (96,
OL048179W
(14) Evans, D. A.; Murry, J. A.; Kozlowski, M. C. J. Am. Chem. Soc.
1996, 118, 5814-5815.
(15) (a) Evans, D. A.; Faul, M. M.; Bilodeau, M. T.; Anderson, B. A.;
Barnes, D. M. J. Am. Chem. Soc. 1993, 115, 5328-5329. (b) Li, Z.; Quan,
R. W.; Jacobsen, E. N. J. Am. Chem. Soc. 1995, 117, 5889-5890.
(16) Evans, D. A.; Burgey, C. S.; Paras, N. A.; Vojkovsky, T.; Tregray,
S. W. J. Am. Chem. Soc. 1998, 120, 5824-5825.
(17) (a) Carona, D.; Lamata, M. P.; Oro, L. A. Coord. Chem. ReV. 2000,
200, 717-772. (b) Rovis, T.; Evans, D. A. Prog. Inorg. Chem. 2001, 50,
1-150. (c) Fraile, J. M.; Garcia, J. I.; Harmer, M. A.; Hereerias, C. I.;
Mayroral, J. A. J. Mol. Chem. A-Chem. 2001, 165, 211-218.
(18) (a) Evans, D. A.; Johnson, J. S.; Olhava, E. J. J. Am. Chem. Soc.
2000, 122, 1635-1649. (b) Jørgensen, K. A. Angew. Chem., Int. Ed. 2000,
39, 3558-3588. (c) Ghosh, A. K.; Shirai, M. Tetrahedron Lett. 2001, 42,
6231-6233.
(19) (a) Lowenthal, R. E.; Abiko, A.; Masamune, S. Tetrahedron Lett.
1990, 31, 6005-6008. (b) Evans, D. A.; Woerpel, K. A.; Hinman, M. M.;
Faul, M. M. J. Am. Chem. Soc. 1991, 113, 726-729.
(20) For recent representative examples, see: (a) Evans, D. A.; Scheidt,
K. A.; Johnston, J. N.; Willis, M. C. J. Am. Chem. Soc. 2001, 123, 4480-
4491. (b) Desimoni, G.; Faita, G.; Filippone, S.; Mella, M.; Zampori, M.
G.; Zema, M. Tetrahedron 2001, 57, 10203-10212.
(13) With the in situ formed catalyst, conversion decreased by 15% and
enantioselectivity dropped by 25-30%. Enantioselectivity dropped by 25%
in CH2Cl2.
Org. Lett., Vol. 6, No. 22, 2004
4099