Catalytic asymmetric protonation of chiral calcium enolates via 1,4-addition of malonates

Article abstract of DOI:10.1021/ja102555a

Catalytic asymmetric protonation of chiral calcium enolates was performed. Chiral calcium enolates, prepared in situ from imides and malonates via 1,4-addition in the presence of catalytic amounts of Ca(OEt)₂, Ph-PyBox, and achiral phenol, were smoothly protonated to afford adducts bearing tertiary asymmetric carbons in high yields with high enantioselectivities. The adducts were readily converted to optically active 2-substituted 1,5-dicarboxylic acid derivatives.

Full text of DOI:10.1021/ja102555a

Published on Web 05/19/2010
Catalytic Asymmetric Protonation of Chiral Calcium Enolates via 1,4-Addition
of Malonates
Thomas Poisson, Yasuhiro Yamashita, and Shuj Kobayashi*
Department of Chemistry, School of Science and Graduate School of Pharmaceutical Sciences, The UniVersity of
Tokyo, The HFRE DiVision, ERATO, Japan Science and Technology Agency (JST), Hongo, Bunkyo-ku,
Tokyo 113-0033, Japan
Received March 26, 2010; E-mail: shu_kobayashi@chem.s.u-tokyo.ac.jp
Since the pioneer report of Duhamel and Plaquevent regarding
the first asymmetric protonation of lithium enolates,1 asymmetric
protonation has become a fascinating method for organic chemists
to build tertiary chiral carbon centers.2 Indeed, over the past 30
years several methods have been developed to introduce hydrogen
atoms stereoselectively. After the first stoichiometric systems were
successfully designed,2b the most challenging step was the develop-
ment of a catalytic asymmetric protonation of enolates. This
synthetic milestone was first achieved by Fehr3a and followed by
others, furnishing efficient processes, although the substrate scope
was relatively limited.3 On the other hand, all of these methods
required stoichiometric formation of enolates or surrogates such
as silicon enolates. An attractive alternative is catalytic formation
of chiral enolates in situ through addition to ketenes4 or as a result
of Michael addition of nucleophiles. This last strategy mainly
employed basic catalysis that required nucleophilic substrates with
a low pKa value, such as thiols.5,6 The addition of stronger
nucleophiles, such as radicals7a and π-nucleophiles,7b was suc-
cessfully achieved using Lewis acid catalysis. Finally, 1,4-addition
of organometallic compounds catalyzed by transition metals also
provided the desired chiral enolates, which were protonated
enantioselectively.8
with promising enantioselectivity (Table 1). A survey of ligands
showed that Ph-PyBox 3d was the most promising in terms of
enantioselectivity.11 Moreover, several reaction parameters were
examined to improve the yield and the selectivity, and it was found
that dibenzyl malonate gave the best selectivity in toluene (entry
5). Primary, secondary, and tertiary alkyl malonates gave racemic
products or had very low enantioselectivities (entries 6, 7, and 8).
Table 1. Ligand and Malonate Screeninga
Entry
Ligand
R1
Solvent
Yield (%)b
ee (%)
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3d
3d
3d
3d
Bn (2a)
Bn (2a)
Bn (2a)
Bn (2a)
Bn (2a)
Me (2b)
iPr (2c)
tBu (2d)
THF
THF
THF
THF
Toluene
Toluene
Toluene
Toluene
39
38
49
34
60
80
86
83
35
21
9
35
49
2
3
11
a The reaction of 1a (R ) Me, 0.20 mmol) with 2 (0.28 mmol) was
performed at 0 °C for 24 h in the presence of the chiral calcium catalyst
prepared from Ca(OiPr)2 (0.020 mmol, 10 mol %) and 3 (0.022 mmol,
11 mol %). b Isolated yield.
Table 2. Effect of Calcium Saltsa
During our studies on chiral alkaline earth metal catalysts, we
have found that anionic calcium9a and strontium9b complexes, as
well as neutral chiral calcium complexes,9c were suitable catalysts
to promote highly selective asymmetric 1,4-additions of malonates
or glycine derivatives. However, the potential of the catalytic chiral
enolates resulting from the additions has not been examined to date.
Herein, we describe catalytic asymmetric protonation of chiral
calcium enolates.
Entry
Ca(OR2)2
x
Solvent
t, °C
Yield (%)b
ee (%)c
1
2
3
4
Ca(OiPr)2
Ca(OiPr)2
Ca(OiPr)2
Ca(OEt)2
Ca(OEt)2
Ca(OMe)2
Ca(OEt)2
Ca(OEt)2
Ca(OEt)2
0
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
CPME
0
0
60
86
33
86
41
85
63
75
90
49
74
84
83
91
83
92
94
95
10
10
10
10
10
10
10
10
-20
0
5
-20
0
-20
-20
-20
6
7d
8d e
CPME
CPME
,
9d e f
,
,
Scheme 1. Catalytic Asymmetric Protonation of Chiral Calcium
Enolates
a The reaction of 1a (R ) Me, 0.20 mmol) with 2a (0.28 mmol) was
performed for 24 h in the presence of the chiral calcium catalyst
prepared from Ca(OR2)2 (0.020 mmol, 10 mol %), 3d (0.022 mmol, 11
mol %), and phenol 4 (x mol %), unless otherwise noted. b Isolated
yield. c Determined by HPLC analysis using a chiral column. d 2a was
slowly added over 10 h. e The reaction was conducted for 48 h. f EtOH
(200 mol %) was added as an additive.
To further improve the enantioselectivity, we carefully examined
calcium salts, which were previously found to be crucial for chiral
induction (Table 2).9c Interestingly, it was found that the use of 10
mol % of phenol 4 with Ca(OiPr)2 showed a significant increase in
the selectivity from 49% enantiomeric excess (ee) to 74% ee at 0
°C (entries 1 and 2). This promising selectivity was further improved
to 84% ee at -20 °C despite a decrease in the yield to 33% (entry
3). A survey of calcium alkoxides showed that Ca(OEt)2 was the
best salt and that the selectivity reached 91% ee at -20 °C (entry
5). Moreover, the use of cyclopentyl methyl ether (CPME) as the
Our approach was based on catalytic formation of a calcium
enolate via 1,4-addition of malonate to a Michael acceptor bearing
an achiral template,10 which can coordinate to the calcium center
to rigidify the enolate and control its geometry. Initially, we selected
the addition of malonate 2 to imide 1a (R ) Me) as models and
screened several types of ligands with Ca(OiPr)2 as catalysts
(Scheme 1). We were pleased to find that pyridinebisoxazoline
(PyBox) 3a-d gave the desired product 5a in acceptable yields
9
7890 J. AM. CHEM. SOC. 2010, 132, 7890–7892
10.1021/ja102555a  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Substrate Scopea
solvent combined with the slow addition of malonate12 provided
5a with high selectivity in acceptable yields (entry 7). A simple
extension of the reaction time to 48 h gave the product in good
yield with excellent selectivity (entry 8). Finally, ethanol was found
to be an effective additive for obtaining a high yield and high
enantioselectivity. The yield was increased to 90%, and the
enantioselectivity reached 95% ee (entry 9).11
With this new and efficient process in hand, the scope of the
reaction was surveyed. Access to both enantiomers was found to
be possible with the same level of enantioselectivity (entry 2).
Interestingly, the catalyst loading could be decreased to 5 mol %
without significant loss of reactivity and selectivity (entry 1). 1,4-
Adducts containing allylic derivatives gave excellent results with
high selectivity up to 96% ee (entries 3-6). Alkynyl derivatives
5f-5h were obtained in good yields with excellent selectivity
(entries 7-9). The gram scale (2 mmol) reaction was possible
without any loss of reactivity and enantioselectivity (entry 7). It is
noted that, according to previous methods, access to these products
required the use of diastereoselective alkylation using chiral
auxiliaries.13 On the other hand, despite several attempts, the aryl
substitution of the Michael acceptor gave only moderate selectivity,
albeit with good reactivity (R ) Ph, entry 10).
Entry
R
5
Yield (%)b
ee (%)c
1
Me (1a)
Me (1a)
Allyl (1b)
Prenyl (1c)
5a
5a
5b
5c
5d
5e
5f
5g
5h
5i
90 (88)j
72
86
85
96
95 (92)j
94
96
93
95
2d
3
4e f
,
5
cis-CH2CHdCHCl (1d)
Cinnamyl (1e)
CH2sCtCsPh (1f)
CH2sCtCsCH2OBn (1g)
CH2sCtCsBu (1h)
Ph (1i)
6f,g
7h
8
85
94
88 (93)k
77
94 (93)k
93
9
91
72
94
48
10i
a The reaction of 1 (0.20 mmol) with 2a (0.28 mmol) was performed
in CPME at -20 °C for 48 h in the presence of the chiral calcium
catalyst prepared from Ca(OEt)2 (0.020 mmol, 10 mol %), 3d (0.022
mmol, 11 mol %), phenol 4 (0.020 mmol, 10 mol %), and EtOH (0.40
mmol, 200 mol %), unless otherwise noted. 2a was slowly added over
10 h. b Isolated yield. c Determined by HPLC analysis using a chiral
column. d The reaction was conducted for 24 h with (R,R)-3d. e 0.06 M.
f The reaction was conducted for 72 h. g Mixed solvent (CPME/THF )
2/1) was used. h Mixed solvent (CPME/toluene
) 4/1) was used.
i Mixed solvent (toluene/DCM ) 4/1) at 0.06 M for 24 h. j The reaction
was carried out in the presence of 5 mol % of the catalyst. k 2 mmol
scale.
We then conducted some mechanistic investigations to clarify
the reaction pathway.11 For the real catalyst, the existence of a
mixed Ca alkoxy aryloxide is plausible as well as the existence of
phenol in the presence of Ca(OEt)2. A survey of phenols revealed
that the phenol moiety might be involved in the deprotonation step,
supported by a relationship between the acidity of the corresponding
phenol and the basicity of the aryloxide. This information also
suggested that the protonation step is the rate-determining step.
However, all our attempts to characterize the mixed calcium salt
were unsuccessful. Therefore, the sole function of phenol as a proton
source cannot be denied at this stage. Finally, labeling experiments
confirmed the reaction pathway and excluded a protonation through
an internal proton return14 by ethanol coordinated to the calcium
center. With all these experimental observations, a mechanism
involving the existence of a monomeric mixed calcium salt
complexed with the PyBox ligand has been proposed.11
tion with high selectivity requires excellent chiral environments.
Further investigations to extend these powerful chiral calcium
enolates to the introduction of other functionalities and to apply
this strategy in multistep synthesis are now ongoing.
Acknowledgment. This work was partially supported by a
Grant-in-Aid for Science Research from JSPS and the Global COE
Program, The University of Tokyo, MEXT, Japan. T.P. thanks the
JSPS Postdoctoral Fellowship for Foreign Researchers.
Supporting Information Available: Experimental procedure, mecha-
nistic studies, and characterization of the products. This material is
available free of charge via the Internet at http://pubs.acs.org.
References
(1) (a) Duhamel, L.; Plaquevent, J.-C. Tetrahedron Lett. 1977, 18, 2285. (b)
Duhamel, L.; Plaquevent, J.-C. J. Am. Chem. Soc. 1978, 100, 7415.
(2) For reviews on enantioselective protonation, see: (a) Yanagisawa, A.;
Yamamoto, H. In ComprehensiVe Asymmetric Catalysis Vol. III; Jacobsen,
E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Heidelberg, 1999; pp
1295-1306. (b) Duhamel, L.; Duhamel, P.; Plaquevent, J.-C. Tetrahedron:
Asymmetry 2004, 15, 3653. (c) Mohr, J. T.; Hong, A. Y.; Stoltz, B. M.
Nat. Chem. 2009, 1, 359.
(3) Selected examples of catalytic asymmetric protonation: (a) Fehr, C.; Stempf,
I.; Galindo, J. Angew. Chem., Int. Ed. 1993, 32, 1044. (b) Vedejs, E.;
Kruger, A. W. J. Org. Chem. 1998, 63, 2792. (c) Yamashita, Y.; Emura,
Y.; Odashima, K.; Koga, K. Tetrahedron Lett. 2000, 41, 209. (d) Ishihara,
K.; Nakamura, S.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1996,
118, 12854. (e) Sugiura, M.; Nakai, T. Angew. Chem., Int. Ed. 1997, 36,
2366. (f) Yanagisawa, A.; Touge, T.; Arai, T. Angew. Chem., Int. Ed. 2005,
44, 1546. (g) Poisson, T.; Dalla, V.; Marsais, F.; Dupas, G.; Oudeyer, S.;
Levacher, V. Angew. Chem., Int. Ed. 2007, 46, 7090. (h) Cheon, C. H.;
Yamamoto, H. J. Am. Chem. Soc. 2008, 130, 9246.
Finally, the synthetic potential of the protonated adduct was
demonstrated. The adduct 5a was readily converted to 6, 7, 8, and
9 in high yields without losing optical purity. These transformations
also led us to determine the absolute configuration of 5a (R) by
analogy with the literature data (Scheme 2).11
Scheme 2. Synthetically Useful Transformations of the Productsa
(4) (a) Pracejus, H. Justus Liebigs Ann. Chem. 1960, 634, 9. (b) Pracejus, H.;
Ma¨tje, H. J. Prakt. Chem. 1964, 24, 195. (c) Hodous, B. L.; Ruble, J. C.;
Fu, G. C. J. Am. Chem. Soc. 1999, 121, 2637. (d) Hodous, B. L.; Fu, G. C.
J. Am. Chem. Soc. 2002, 124, 10006. (e) Wiskur, S. L.; Fu, G. C. J. Am.
Chem. Soc. 2005, 127, 6176.
a (a) H2, Pd/C, rt; (b) 6 M HCl, 110 °C 5 h; (c) toluene 120 °C, 5 h; (d)
MeONa (cat.), MeOH -20 °C, 30 min.
(5) Pracejus, H.; Wilcke, F.-W.; Hanemann, K. J. Prakt. Chem. 1977, 319,
219.
(6) Selected examples using thiol as nucleophile: (a) Leow, D.; Lin, S.;
Chittimalla, S. K.; Fu, X.; Tan, C.-H. Angew. Chem., Int. Ed. 2008, 47,
5641. (b) Emori, E.; Arai, T.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc.
1998, 120, 4043. Quite recently, a paper dealing with the asymmetric 1,4-
addition of cyanide has appeared : (c) Morita, M.; Drouin, L.; Motoki, R.;
Kimura, Y.; Fujimori, I.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2009,
131, 3858.
(7) (a) Sibi, M. P.; Sausker, J. B. J. Am. Chem. Soc. 2002, 124, 984. (b) Sibi,
M. P.; Patil, K. Angew. Chem., Int. Ed. 2004, 43, 1235. (c) Sibi, M. P.;
Coulomb, J.; Stanley, L. M. Angew. Chem., Int. Ed. 2008, 47, 9913.
(8) Selected examples: (a) Navarre, L.; Darses, S.; Genet, J.-P. Angew. Chem.,
Int. Ed. 2004, 43, 719. (b) Nishimura, T.; Hirabayashi, S.; Yasuhara, Y.;
Hayashi, T. J. Am. Chem. Soc. 2006, 128, 2556. (c) Navarre, L.; Martinez,
R.; Genet, J.-P.; Darses, S. J. Am. Chem. Soc. 2008, 130, 6159. (d) Frost,
In conclusion, catalytic asymmetric protonation of chiral calcium
enolates was performed. Chiral calcium enolates were prepared in
situ from imides 1 and malonates 2 via 1,4-addition in the presence
of catalytic amounts of Ca(OEt)2, Ph-PyBox 3d, and achiral phenol
4 and were smoothly protonated to afford the adducts 5 bearing
tertiary asymmetric carbons in high yields with high enantioselec-
tivity. It should be noted that the hydrogen atom represents the
smallest element in the periodic table and its asymmetric introduc-
9
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C O M M U N I C A T I O N S
C. G.; Penrose, S. D.; Lambshead, K.; Raithby, P. R.; Warren, J. E.; Gleave,
R. Org. Lett. 2007, 9, 2119. (e) Sibi, M. P.; Tatamidani, H.; Patil, K. Org.
Lett. 2005, 7, 2571.
Sodeoka, M. Org. Lett. 2004, 6, 1861. (f) Murarka, S.; Deb, I.; Zhang, C.;
Seidel, D. J. Am. Chem. Soc. 2009, 131, 13226. See also ref 7a.
(11) See Supporting Information for details.
(12) The slow addition of malonate was found to be essential for reproducibility
of the reaction, probably to prevent oligomerization of the catalyst.
(13) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982, 104,
1737.
(9) (a) Tsubogo, T.; Saito, S.; Seki, K.; Yamashita, Y.; Kobayashi, S. J. Am.
Chem. Soc. 2008, 130, 13321. (b) Agostinho, M.; Kobayashi, S. J. Am.
Chem. Soc. 2008, 130, 2430. (c) Tsubogo, T.; Yamashita, Y.; Kobayashi,
S. Angew. Chem., Int. Ed. 2009, 48, 9117.
(10) Selected references using oxazolidinones as achiral templates in asymmetric
synthesis: (a) Narasaka, K.; Inoue, M.; Okada, N. Chem. Lett. 1986, 1109.
(b) Kanemasa, S.; Kanai, T. J. Am. Chem. Soc. 2000, 122, 10710. (c) Evans,
D. A.; Scheidt, K. A.; Johnston, J. N.; Willis, M. C. J. Am. Chem. Soc.
2001, 123, 4480. (d) Hird, A. W.; Hoveyda, A. H. Angew. Chem., Int. Ed.
2003, 42, 1276. (e) Hamashima, Y.; Somei, H.; Shimura, Y.; Tamura, T.;
(14) Selected references: (a) Gerlach, U.; Hu¨nig, S. Angew. Chem., Int. Ed. 1987,
26, 1283. (b) Vedejs, E.; Lee, N. J. Am. Chem. Soc. 1991, 113, 5483. (c)
Vedejs, E.; Lee, N. J. Am. Chem. Soc. 1995, 117, 891. (d) Yasukata, T.;
Koga, K. Tetrahedron: Asymmetry 1993, 4, 35.
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