Highly diastereo- and enantioselective aldol reaction of methyl α-isocyanoacetate: A cooperative catalysis approach

Article abstract of DOI:10.1021/ol103104y

The cooperative catalyst activity between a chiral transition-metal catalyst and an achiral organocatalyst has been identified as one of the critical asymmetric reaction optimization components in the highly diastereo- and enantioselective aldol reaction

Full text of DOI:10.1021/ol103104y

ORGANIC
LETTERS
2011
Vol. 13, No. 6
1306–1309
Highly Diastereo- and Enantioselective
Aldol Reaction of Methyl
r-Isocyanoacetate: A Cooperative
Catalysis Approach
Hun Young Kim and Kyungsoo Oh*
Department of Chemistry and Chemical Biology, Indiana University Purdue University
Indianapolis, Indianapolis, Indiana 46202, United States
ohk@iupui.edu
Received December 22, 2010
ABSTRACT
The cooperative catalyst activity between a chiral transition-metal catalyst and an achiral organocatalyst has been identified as one of the critical
asymmetric reaction optimization components in the highly diastereo- and enantioselective aldol reaction of methyl R-isocyanoacetate.
The field of asymmetric catalysis continues to play a
pivotal role in advancing the molecular-level understand-
ing of chemical processes. While biocatalysts skillfully
utilize multiple covalent (for metals) and noncovalent
interactions (for H-bonding) in concert for the conforma-
tional stability and well-defined chiral environment,1 the
dominant asymmetric strategies in organic synthesis have
relied on two divergent catalyses: (1) metal-centered Lewis
acid catalysis (for electrophilic activation mode)2 and (2)
small-molecule organocatalysis (for H-bonding mode and
Brønsted acid catalysis mode).3 Although the concept of
bifunctional asymmetriccatalystshasbeenwellestablished
in transition-metal catalysis4 and organocatalysis,5 respec-
tively, the recent emergence of cooperative catalysis be-
tween metals and small organic molecules has provided
alternative ways of asymmetric reaction optimizations,
where two distinctive catalysis modes are controlled by
either one or two chiral (or achiral) components of the
reaction.6 Furthermore, such a combination of multiple
catalyst systems hasopened up newavenues for developing
cooperative catalyst systems where the respective catalyst
system alone fails to deliver sufficient catalyst reactivity
and selectivity.
(1) (a) Comprehensive Biological Catalysis; Sinnott, M., Ed.; Academic
Press: London, 1998; Vols. 1-3. (b) Silverman, R. B. The Organic
Chemistry of Enzyme-Catalyzed Reactions; Academic Press: San Diego,
CA, 2000.
The recent discovery of anion-binding thiourea organo-
catalysts is beginning to gain momentum.7 The labora-
tories of Jacobsen pioneered this field in halide-binding,8
(2) Acid Catalysis in Modern Organic Synthesis; Yamamoto, H.,
Ishihara, K., Eds.; Wiley-VCH: Weinheim, 2008; Vols. 1-2.
(3) For recent reviews, see: (a) Taylor, M. S.; Jacobsen, E. N. Angew.
Chem., Int. Ed. 2006, 45, 1520. (b) Doyle, A. G.; Jacobsen, E. N. Chem.
Rev. 2007, 107, 5713. (c) Hydrogen Bonding in Organic Synthesis; Pihko,
P. M., Ed.; Wiley-VCH: Weinheim, 2009.
(4) For recent reviews, see: (a) Yamamoto, H.; Futatsugi, K. Angew.
Chem., Int. Ed. 2005, 44, 1924. (b) Kanai, M.; Kato, N.; Ichikawa, E.;
Shibasaki, M. Synlett 2005, 1491. (c) Shibasaki, M.; Matsunaga, S.
Chem. Soc. Rev. 2006, 35, 269. (d) Shibasaki, M.; Matsunaga, M.;
Kumagai, N. Synlett 2008, 1583. (e) Shibasaki, M.; Kanai, M.; Matsunaga,
S.; Kumagai, N. Acc. Chem. Res. 2009, 42, 1117.
€
(5) (a) Berkessel, A.; Groger, H. Asymmetric Organocatalysis;from
Biomimetic Concepts to Applications in Asymmetric Synthesis; Wiley-
VCH: Weinheim, 2005. (b) Enantioselective Organocatalysis; Dalko, P. I.,
Ed.; Wiley-VCH: Weinheim, 2007.
(6) For recent reviews, see: (a) Paull, D. H.; Abraham, C. J.; Scerba,
M. T.; Alden-Danforth, E.; Lectka, T. Acc. Chem. Res. 2008, 41, 655. (b)
Shao, Z.; Zhang, H. Chem. Soc. Rev. 2009, 38, 2745. (c) Rueping, M.;
Koenigs, R. M.; Atodiresei, I. Chem.;Eur. J. 2010, 16, 9350.
(7) For a recent review, see: Zhang, Z. G.; Schreiner, P. R. Chem. Soc.
Rev. 2009, 38, 1187.
r
10.1021/ol103104y
Published on Web 02/11/2011
2011 American Chemical Society

cyanide-binding,9 and sulfonate-binding chiral thiourea
organocatalysts.10 The oxyanion-binding thiourea orga-
nocatalysts were explored by the laboratories of Schreiner
in alcohol funtionalization strategies.11 Most recently, the
laboratories of Seidel disclosed the carboxylate-binding
chiral thiourea organocatalyst systems for the kinetic
resolution of various amine derivatives.12 Given the facile
synthetic variation of thiourea structures, it is of interest to
exam if achiral thiourea derivatives exhibit the cooperative
catalysis with chiral transition metal complexes.
The idea of cooperative catalysis was explored in the
context of direct catalytic asymmetric aldol reaction of
R-isocyanoacetates. In the paradigm of transition-metal-
catalyzed reactions of isocyanides, the ability of a metal ion
to form a complex I with isocyano functionality dictates
the chemical pathways of such complexes (Scheme 1).13
Accordingly, the aldol reactions of R-isocyanoacetates are
catalyzed by a number of metal complexes. While the
highly diastereo- and enantioselective aldol reaction of
methyl R-isocyanoacetate was demonstrated by Ito and
Hayashi using chiral Au(I)- and Ag(I)-ferrocenylphos-
phine complexes,14 the development of metal-catalyzed
asymmetric aldol reactions of R-isocyanoacetates remains
a significant challenge.15 Given the strong complexing
ability of isocyanides to metals, the low level of stereo-
induction in oxazolines III likely stems from the fact
that enolates derived from the linear metal-isocyanide
Scheme 1. Transition-Metal-Catalyzed Direct Aldol Reaction
of R-Isocyanoacetate
complex I are far removed from the chiral pocket. In
addition, a recent organocatalytic approach employing
methyl R,R-arylisocyanoacetate by Gong et al. has resulted
in modest diastereo- and enantioselectivities (2-6:1 dr’s
with 70-89% ee’s) in the presence of cupreine-derived
organocatalysts,16a while the related asymmetric aldol
reactions of R-isothiocyanato esters and imides have been
successful using chiral thiourea organocatalysts.16b-e
Scheme 2. Cooperative Catalysis of Lewis Acid and Thiourea
for Aldol Reaction of R-Isocyanoacetates
(8) (a) Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126,
10558. (b) Taylor, M. S.; Tokunaga, N.; Jacobsen, E. N. Angew. Chem.,
Int. Ed. 2005, 44, 6700. (c) Raheem, I. T.; Thiara, P. S.; Peterson, E. A.;
Jacobsen, E. N. J. Am. Chem. Soc. 2007, 129, 13404. (d) Reisman, S. E.;
Doyle, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2008, 130, 7198. (e)
Peterson, E. A.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2009, 48, 6328.
(f) Klausen, R. S.; Jacobsen, E. N. Org. Lett. 2009, 11, 887. (g) Knowles,
R. R.; Lin, S.; Jacobsen, E. N. J. Am. Chem. Soc. 2010, 132, 5030. (h)
Veitch, G. E.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2010, 49, 7332.
(9) (a) Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120,
4901. (b) Sigman, M. S.; Vachal, P.; Jacobsen, E. N. Angew. Chem., Int.
Ed. 2000, 39, 1279. (c) Vachal, P.; Jacobsen, E. N. Org. Lett. 2000, 2, 867.
(d) Su, J. T.; Vachal, P.; Jacobsen, E. N. Adv. Synth. Catal. 2001, 343,
197. (e) Zuend, S. J.; Coughlin, M. P.; Lalonde, M. P.; Jacobsen, E. N.
Nature 2009, 461, 968. (f) Zuend, S. J.; Jacobsen, E. N. J. Am. Chem. Soc.
2009, 131, 15358.
(10) Xu, A.; Zuend, S. J.; Woll, M. G.; Jacobsen, E. N. Science 2010,
327, 986.
(11) (a) Kotke, M.; Schreiner, P. R. Tetrahedron 2006, 62, 434. (b)
Kleiner, C. M.; Schreiner, P. R. Chem. Commun. 2006, 4315. (c) Kotke,
M.; Schreiner, P. R. Synthesis 2007, 779. (d) Weil, T.; Kotke, M.; Kleiner,
C. M.; Schreiner, P. R. Org. Lett. 2008, 10, 1513.
(12) (a) De, C. K.; Klauber, E. G.; Seidel, D. J. Am. Chem. Soc. 2009,
131, 17060. (b) Klauber, E. G.; De, C. K.; Shar, T. K.; Seidel, D. J. Am.
Chem. Soc. 2010, 132, 13624.
(13) For a recent review, see: Gulevich, A. V.; Zhdanko, A. G.; Orru,
R. V. A.; Nenajdenko, V. G. Chem. Rev. 2010, 110, 5235.
(14) For Au(I) catalysis, see: (a) Ito, Y.; Sawamura, M.; Hayashi, T.
J. Am. Chem. Soc. 1986, 108, 6405. For a Ag(I) catalysis, see: (b)
Hayashi, T.; Uozumi, Y.; Yamazaki, A. Tetrahedron Lett. 1991, 32,
2799. For a comprehensive review, see: ref 13.
Motivated by the historical evidence of strong H-bonding
to carbon in isocyanides,17 our initial experiments were
directed to the establishment of anion-binding inter-
actions IV between thiourea and methyl R-isocyanoacetate
(Scheme 2). We envisioned that the thiourea-assisted en-
olates would be capable of coordinating to a chiral metal
center in a more organized fashion V. From our prelimin-
ary spectroscopic investigation, the proposed anion-binding
interaction between the carbon atom of isocyanides and
N-H of thioureas was evident, where the downfield shift
of thiourea proton in 1H NMR as well as the lower N-H
stretching frequency in IR were interpreted as that
H-bonded complexes IV were being formed.18
Next, we focused on examining the cooperative catalysis
that utilizes the anion-binding interactions of thioureas
under chiral transition-metal catalysis for the aldol reac-
tion of methyl R-isocyanoacetate (Table 1). The coopera-
tive catalyst effect was clearly evident in the stereoselec-
tivity of reactions employing the chiral Cu (I) complexes
derived from brucine amino diol L1 and copper(I) salts
(entries 1-3).19 While the use of copper(I) acetate elimi-
nated use of an external base since acetate played a role of
€
€
(15) (a) Nesper, R.; Pregosin, P. S.; Puntener, K.; Worle, M. Helv.
Chim. Acta 1993, 76, 2239. (b) Gorla, F.; Togni, A.; Venanzi, L. M.;
Albinati, A.; Lianza, F. Organometallics 1994, 13, 1607. (c) Longmire,
J. M.; Zhang, X.; Shang, M. Organometallics 1998, 17, 4374. (d)
Motoyama, Y.; Kawakami, H.; Shimozono, K.; Aoki, K.; Nishiyama,
H. Organometallics 2002, 21, 3408. (e) Gosiewska, S.; Huisin’t Vald, M.;
de Pater, J. J. M.; Bruijnincx, P. C. A.; Lutz, M.; Spek, A. L.; van Koten,
G.; Klein Gebbink, R. J. M. Tetrahedron: Asymmetry 2006, 17, 674. (f)
Gosiewska, S.; Herreras, S. M.; Lutz, M.; Spek, A. L.; Havenith,
R. W. A.; van Klink, G. P. M.; van Koten, G.; Klein Gebbink,
R. J. M. Organometallics 2008, 27, 2549.
(16) (a) Xue, M.-X.; Guo, C.; Gong, L.-Z. Synlett 2009, 2191. (b) Li,
L.; Klauber, E. G.; Seidel, D. J. Am. Chem. Soc. 2008, 130, 12248. (c) Shi,
Z.; Yu, P.; Chua, P. J.; Zhong, G. Adv. Synth. Catal. 2009, 351, 2797. (d)
Jiang, X.; Zhang, G.; Fu, D.; Cao, Y.; Shen, F.; Wang, R. Org. Lett.
2010, 12, 1544. (e) Vecchione, M. K.; Li, L.; Seidel, D. Chem. Commun.
2010, 4604.
(17) (a) Schleyer, P. V. R.; Allerhand, A. J. Am. Chem. Soc. 1962, 84,
1322. (b) Ferstandig, L. L. J. Am. Chem. Soc. 1962, 84, 1323.
(18) See the Supporting Information for more details.
Org. Lett., Vol. 13, No. 6, 2011
1307

was superior in reactions using other cobalt(II) metals
(entries 6-7). During our previous copper(I)-catalyzed
asymmetric investigation, we observed the beneficial effect
of DBU in the chiral copper catalysts derived from copper(I)
iodide.19a Our speculation at that time was that a tight ion
pair might be formed between the protonated DBU and
iodide ions. Since halide ions are capable of H-bonding to
thiourea, wefurtherexaminedotherbasesinthecobalt(II)-
catalyzed reactions (entries 8-13). The effect of amidine
base, DBU, was detrimental to the outcomes of CoF2- and
CoCl2-catalyzed reactions (entries 8-9); however, the
beneficial effect of DBU was evident in the CoI2-catalyzed
reaction, providing chiral oxazoline 3a in 75% ee with 15:1
dr (entry 10). The use of related amidine base, DBN, was
slightly less efficient (entry 11), but delivered improved
results compared to other bases (entries 7 and 12-13).22 A
further fine-tuning of reaction conditions was accom-
plished by employing a mixed solvent of THF/1,4-dioxane
(4:1) to increase the solubility of chiral cobalt catalysts.
With this final experimental modification, the exclusive
formation of trans-(4R,5S)-3a was possible with 97% ee
(entry 14). The importance of thiourea 4a in the current
catalytic system was further demonstrated in the structure-
enantioselectivity studies (entries 15-17). Urea 4b and
thiourea 4c rendered cooperative catalyst systems with
enhanced diastereoselectivies, but they induced poor en-
antioselectivities (entry 15-16), whereas the unsymmetric
thiourea 4d restored the highly selective cooperative cata-
lyst activity (entry 17). These results strongly suggest
the cooperative role of thiourea and chiral Lewis acid in
the enantioselectivity-determining transition state. Finally,
we conducted a series of control experiments to establish
the cooperative catalyst activity between the four catalyst
components (entries 18-21).
The scope of the catalytic asymmetric aldol reaction of
methyl R-isocyanoacetate was evaluated under the opti-
mized cooperative catalysis conditions (Scheme 3). The
reaction was applicable to a range of aromatic, heteroaro-
matic, and aliphatic aldehydes. In general, excellent dia-
stereo- and enantioselectivities (>20:1 dr, 90-98% ee’s)
were obtained at ambient temperature within 18 h. Less
satisfactory enantioselectivities were found in the reactions
of 2-thiophenecarboxaldehyde (trans-3e, 84% ee) and
pivaldehyde (trans-3i, 74% ee), while high diastereoselec-
tivities were maintained (>20:1 dr). The limitation of the
current cooperative catalysis lies in ortho- and meta-sub-
stituted benzaldeydes, where low levels of enantioselectiv-
ity were obtained in the range of 20-50% ee but with
excellent diastereoselectivities (>20:1 dr). Our current
efforts are directed to bring improvements with these
substrates.23
Table 1. Cooperative Catalysis in Asymmetric Aldol Reaction.a
entry
metal
base
thiourea drb yieldc (%) eed (%)
1
CuOAc
CuOAc
7:1
80
85
72
50
50
50
88
30
90
50
74
55
60
70
40
50
58
40
84
10
67
2
26
40
8
2
4a
4a
-
4:1
3
CuOTf NEt3
4:1
4
CoCl2
CoCl2
CoF2
CoI2
CoF2
CoCl2
CoI2
CoI2
CoI2
CoI2
CoI2
CoI2
CoI2
CoI2
NEt3
NEt3
NEt3
NEt3
DBU
DBU
DBU
DBN
DMAP
DABCO
DBU
DBU
DBU
DBU
DBU
DBU
5:1
5
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4b
4c
4d
5:1
70
30
2
6
10:1
12:1
10:1
6:1
7
8
50
25
75
65
22
5
9
10
11
12
13
14e
15e
16e
17e
18e
19e
20e
21e
15:1
11:1
6:1
10:1
17:1
10:1
10:1
15:1
10:1
14:1
5:1
97
5
10
86
10
12
12
15
CoI2
f
4a
4a
f
f
5:1
a Reaction with 1 (0.5 mmol) and 2 (0.5 mmol) in THF (0.16 M).
b Determined by crude 1H NMR. c Combined isolated yields of 3 after
column chromatography. d Determined by chiral HPLC analysis
(absolute configuration was determined by HPLC comparison with
authentic samples). e Reaction in a mixture of THF/1,4-dioxane (4:1).
f Use of 10 mol % of L1 without metal.
base, the potential anion-binding property of acetate
to thiourea was reasoned for the low enantioselectivity
(entry 2). Thus, we employed an alternative approach to
chiral Lewis acid formation using a catalytic amount of NEt3.
Among other copper salts screened,20 only marginal im-
provement of enantioselectivity was observed with CuOTf
(entry 3). Next, we opted for screening other metal salts
that possess similar ionic radii and coordination numbers
as those of copper(I) metal. To our delight, the more
pronounced cooperative catalyst effect was observed upon
using cobalt(II) salts (entries 4-7).21 In particular, the use
of cobalt(II) chloride improved the enantioselectivity up to
70% ee (entry 5), while the observed diastereoselectivity
(22) Presently, we do not know the cause for the dramatic effect of
amidine bases on enantioselectivity, but our M/L1 catalyst systems
provide trends: metal chlorides and bromides seem to tolerate tertiary
amine bases (i.e., Et3N, i-Pr2NEt), but metal iodides require amidine
bases (i.e., DBU); see: (a) Ref 19. A cooperative role of amidine bases
in the asymmetric Co(II) catalysis has been recently reported; see: (b)
Kalow, J. A.; Doyle, A. G. J. Am. Chem. Soc. 2010, 132, 3268.
(23) Use of other metal salts and modified thiourea derivatives is
currently under investigation.
(19) (a) Kim, H. Y.; Shih, H.-J.; Knabe, W. E.; Oh, K. Angew. Chem.,
Int. Ed. 2009, 48, 7420. (b) Kim, H. Y.; Oh, K. Org. Lett. 2009, 11, 5682.
(c) Kim, H. Y.; Kim, S.; Oh, K. Angew. Chem., Int. Ed. 2010, 49, 4476.
(20) Use of other copper salts (CuF, CuCl, CuBr, CuI, Cu(CH3CN)4-
PF6, CuCl2) resulted in catalysts with low enantioselectivities.
(21) Typical ionic radius for Cu(I) with a coordination number of 4 is
˚
˚
0.60 A, whereas that of Co(II) is around 0.56 A; see: Handbook of
Chemistry and Physics, 87th ed.; CRC: Boca Raton, FL, 2006; pp 12-11.
1308
Org. Lett., Vol. 13, No. 6, 2011

Scheme 3. Scope of the Catalytic Asymmetric Aldol Reaction.a
Figure 1. Proposed stereomodel for cooperative catalysis.
proposed as the reactive species; however, use of tert-butyl
R-isocyanoacetate resulted in markedly reduced reactivity
and enantioselectivity,27 implying the necessity of enolate
coordination to the cobalt metal center. Furthermore, our
preliminary studies into the potential role of the C21-OH
and C22-OH in our ligand L revealed that both alcohol
moieties are critical for the cooperative catalysis. Thus,
upon using the modified ligands L2-4 (having either the
nitrogen atom or the C21-OH/C22-OH group protected),
products with significantly lower enantioselectivities were
observed.28 These results suggest the possibilty of a sec-
ondary H-bond interaction between the enolate and the
C22-OH of chiral metal complexes.
In summary, we have developed a cooperative catalyst
system for the highly diastereo- and enantioselective cata-
lytic aldol reaction of methyl R-isocyanoacetate. The key
to our successful stereocontrol probably lies in the strong
anion-binding interaction between isocyanides and thiour-
eas, which potentially disturbs the intrinsic metal-isocya-
nide complexation. Additional studies to broaden this
asymmetric approach are currently underway.
a Isolated yield of trans-3 with dr values from crude 1H NMR and ee
values from chiral HPLC analysis.
To understand the observed stereochemical outcome of
reactions, we monitored the asymmetric aldol reactions at
frequent intervals for the possible formation of cis-oxazo-
lines. The observed diastereoselectivities were consistently
high for trans-oxazolines (>20:1 dr) throughout the entire
reaction period regardless of reaction conversions. Since
the epimerization might be a facile process under the
reaction conditions,24 we also subjected a diastereomeric
mixture of oxazolines (2.2:1 = trans/cis) to our optimized
asymmetric reaction conditions, and found that there was
a minimal change in the diastereomeric ratio of oxazolines
(2.4:1 = trans/cis) after 8 h at ambient temperature, a clear
indication that the experimentally observed diasteroselec-
tivities are primarily derived from the action of catalyti-
cally active species.
A stereomodel for the cooperative catalysis, which is
consistent with the observed stereoselectivities, is proposed
in Figure 1. This transition-state model is consistent with
our previous proposals for monometallic Cu(I)/L1 cata-
lysts,19 where a si-face attack of enolates to aldehydes occurs
through a chairlike conformation. While the nature of co-
operative catalysis waits further studies,25 the blue Co(II)-
L1 complexes support a possible involvement of tetra-
hedral cobalt complexes.26 The (Z)-enolate configuration is
Acknowledgment. This research was supported by IU-
PUI. The Bruker 500 MHz NMR was purchased via an
NSF-MRI award (CHE-0619254).
Supporting Information Available. Experimental pro-
cedures and spectral data for all compounds. This mate-
rial is available free of charge via the Internet at http://
pubs.acs.org.
(26) Tetrahedral Co(II) complexes are known to be blue, and octa-
hedral Co(II) complexes are usually pink; see:(a) Norwood, V. M., III;
Morse, K. W. Inorg. Chem. 1987, 26, 284. (b) Romerosa, A.; Saraiba-
Bello, C.; Serrano-Ruiz, M.; Caneschi, A.; McKee, V.; Peruzzini, M.;
Sorace, L.; Zanobini, F. J. Chem. Soc., Dalton Trans. 2003, 3233.
(27) Oxazolines were isolated in <10% yields after 48 h (>20:1 dr
and 5% ee).
(28) Use of modified ligand L2 (C22-OAc) gave anti-3a in 70% yield
with 18:1 dr and 38% ee. Use of L3 (C21/C22-OAc) was not successful,
but L4 (N19-Bn,Br-) provided racemic anti-3a in 71% yield and 10:1 dr.
(24) cis-Oxazolines were epimerized to trans-oxazolines with Et3N in
refluxing benzene, see: ref 14a. For the epimerization of cis-2-substituted
oxazolines using Et3N, see: Evans, D. A.; Janey, J. M.; Magomedov, N.;
Tedrow, J. S. Angew. Chem., Int. Ed. 2001, 40, 1884.
(25) The anion-binding of thioureas to isocyanides under our co-
operative catalysis could not be confirmed by NMR or IR due to the
line-broadening caused by the multifunctional nature of our chiral metal
complexes. However, our control experiments (Table 1, entries 14-17)
clearly indicate the cooperative role of thiourea derivatives on
enantioselectivity.
Org. Lett., Vol. 13, No. 6, 2011
1309