High turnover frequency observed in catalytic enantioselective additions of enecarbamates and enamides to iminophosphonates

Article abstract of DOI:10.1021/ol062144+

In addition reactions of enecarbamates and enamides, extremely high turnover frequency of the catalyst was observed in comparison with that of silicon enolate addition reactions. This is presumably due to fast transfer of the proton that locates on the nu

Full text of DOI:10.1021/ol062144+

ORGANIC
LETTERS
2006
Vol. 8, No. 23
5333-5335
High Turnover Frequency Observed in
Catalytic Enantioselective Additions of
Enecarbamates and Enamides to
Iminophosphonates
Hiroshi Kiyohara, Ryosuke Matsubara, and Shu¯ Kobayashi*
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
skobayas@mol.f.u-tokyo.ac.jp
Received August 30, 2006
ABSTRACT
In addition reactions of enecarbamates and enamides, extremely high turnover frequency of the catalyst was observed in comparison with
that of silicon enolate addition reactions. This is presumably due to fast transfer of the proton that locates on the nucleophiles.
Catalytic asymmetric reactions provide some of the most
important methods for the synthesis of optically active
molecules. Although great efforts to develop C-C bond-
forming reactions have been made by using chiral Lewis
acids, it is still difficult and a challenging issue to achieve
high catalyst turnover compared to late transition-metal-
catalyzed reactions such as hydrogenation of olefins. The
lower catalyst turnover is mainly ascribed to product or
intermediate inhibition, instability of Lewis acids toward
moisture and oxygen, and slow rates of metal transfer steps.
In Lewis acid catalyzed addition reactions of silicon enolates
to CdO or CdN electrophiles, which are among the most
important C-C bond-forming reactions in organic synthesis,
fast silicon transfer from enolate components to newly
generated O-M or N-M (M ) metal) moieties is required,
but those steps are often slow and catalyst turnover is limited
significantly.1 Herein, we report observation of high turnover
frequency that is realized by using enamides or enecarbam-
ates as nucleophiles instead of silicon enolates.
R-Amino phosphonic acids are established as analogues
of R-amino acids in medicinal and pharmaceutical science.2
While many methods to synthesize enantiomerically enriched
R-amino acids have been developed up to now, asymmetric
synthesis of R-amino phosphonic acids has been a challeng-
ing topic due to limited synthetic schemes.3 Recently, we
reported catalytic asymmetric synthesis of R-amino phos-
phonates using enantioselective addition of silicon enolates
to iminophosphonates.4 In that report, we showed that a wide
range of R-amino phosphonic acid derivatives could be
synthesized in good yields with high enantioselectivities (in
(1) For turnover acceleration examples by Brønsted acid as an additive,
see: (a) Dosa, P. I.; Fu, G. C. J. Am. Chem. Soc. 1998, 120, 445. (b)
Takamura, M.; Hamashima, Y.; Usuda, H.; Kanai, M.; Shibasaki, M. Angew.
Chem., Int. Ed. 2000, 39, 1650. (c) Yamasaki, S.; Fujii, K.; Wada, R.; Kanai,
M.; Shibasaki, M. J. Am. Chem. Soc. 2002, 124, 6536. (d) Wadamoto, M.;
Yamamoto, H. J. Am. Chem. Soc. 2005, 127, 14556. (e) Wada, R.;
Shibuguchi, T.; Makino, S.; Oisaki, K.; Kanai, M.; Shibasaki, M. J. Am.
Chem. Soc. 2006, 128, 7687.
(2) For reviews on enantioselective R-amino acid synthesis, see: (a)
Gro¨ger, H. Chem. ReV. 2003, 103, 2795. (b) Burk, M. J. Acc. Chem. Res.
2000, 33, 363.
10.1021/ol062144+ CCC: $33.50
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general over 90% ee). On the other hand, a drawback of
this method was the inevitably slow addition of substrates
to a catalyst or addition of hexafluoroisopropyl alcohol
(HFIP) in order to obtain high selectivities. We reasoned
that low selectivity obtained without slow addition of
substrates or addition of HFIP was ascribed to strong
coordination of the intermediate to the catalyst,5 which led
to a background reaction without chiral catalyst involvement.
Our group has also recently revealed enecarbamates and
enamides to be useful nucleophiles in several reactions with
aldehydes and imines.6 The products are reactive acylimines,
which can be further converted into complicated target
molecules. We assume that the reaction of enecarbamates
occurs via an aza-ene type pathway, in which the hydrogen
on the nitrogen atoms of enecarbamates and enamides plays
an important role for reaction acceleration and stereoselective
outcome. Based on these findings and the fact that addition
of HFIP accelerated dissociation of the catalyst from the
intermediate, we assumed that the use of enecarbamates and
enamides could solve the catalyst-trapping problems in the
reactions of iminophosphonates.
Table 2. Substrate Scope
entry
R1
Ph (2a)
R2
Cbz 5.0
Bz 1.5
x
product yield (%) ee (%)
1
2
4a
4a
4b
4c
4c
4d
4e
4f
77
81
77
78
72
77
66
83
89
85
93
87
86
94
89
86
Ph (2b)
3
4
5a
6
4-MeC6H4 (2c)
4-ClC6H4 (2d)
4-ClC6H4 (2e)
Cbz 5.0
Cbz 5.0
Bz
2.0
4-MeOC6H4 (2f) Cbz 5.0
7
8a
â-Nap (2g)
3-MeC6H4 (2h)
Cbz 5.0
Bz 1.5
a 1.5 equiv of enamide was employed.
First, we conducted the reaction of iminophosphonate 1
with enecarbamate 2a in the presence of Cu(OTf)2 and chiral
diamine 3a6a,7 in dichloromethane at 0 °C. To our delight,
the product 4a was obtained with high enantioselectivity even
when the iminophosphonate 4a was added to the catalyst
over 30 min (Table 1, entry 1).
enolate 5 when 1 was added over 48 h (entry 5). From these
results, it was approximately estimated that turnover fre-
quency (TOF) of the reaction of 2a with 1 was ca. 1000
times higher than that of the reaction of 5 with 1. In the
reaction using 5, the use of HFIP (1 equiv) was not so
effective (entries 6-8). In addition, it is remarkable that the
reaction of 2a with 1 in the absence of the catalyst completes
at 0 °C in 1.5 min to afford the product 4a in 86% yield.
Encouraged by this remarkably high TOF thus observed
in the presence of 10 mol % of catalyst, we then tried to
decrease the catalyst loading. As ligand 3b was found to be
superior to 3a for enantioselectivity, the following investiga-
tions were conducted using 3b. When 5 mol % of the catalyst
was employed in the reaction of 2a with 1, the desired
product 4a was obtained in 77% yield with 89% ee (Table
2, entry 1). The advantage of using enecarbamate 2a instead
Table 1. Comparison of Enecarbamate vs Silicon Enolate
entry
nucleophile
addition time (h)
yield (%)
ee (%)
(3) For examples of carbon-phosphorus bond-forming reactions, see:
(a) Sasai, H.; Arai, S.; Tahara, Y.; Shibasaki, M. J. Org. Chem. 1995, 60,
6656. (b) Gro¨ger, H.; Saida, Y.; Arai, S.; Martens, J.; Sasai, H.; Shibasaki,
M. Tetrahedron Lett. 1996, 37, 9291. (c) Gro¨ger, H.; Saida, Y.; Sasai, H.;
Yamaguchi, K.; Martens, J.; Shibasaki, M. J. Am. Chem. Soc. 1998, 120,
3089. (d) Schlemminger, I.; Saida, Y.; Gro¨ger, H.; Maison, W.; Durot, N.;
Sasai, H.; Shibasaki, M.; Martens, J. J. Org. Chem. 2000, 65, 4818. (e)
Joly, G. D.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 4102. (f)
Akiyama, T.; Morita, H.; Itoh, J.; Fuchibe, K. Org. Lett. 2005, 7, 2583. (g)
Pettersen, D.; Marcolini, M.; Bernardi, L.; Fini, F.; Herrera, R. P.; Sgarzani,
V.; Ricci, A. J. Org. Chem. 2006, 71, 6269. For examples of enamide
hydrogenation, see: (h) Scho¨llkopf, U.; Hoppe, I.; Thiele, A. Liebigs Ann.
Chem. 1985, 555. (i) Schmidt, U.; Oehme, G.; Krause, H. W. Synth.
Commun. 1996, 26, 777. (j) Schmidt, U.; Krause, H. W.; Oehme, G.;
Michalik, M.; Fischer, C. Chirality 1998, 10, 564. (k) Burk, M. J.; Stammers,
T. A.; Straub, J. A. Org. Lett. 1999, 1, 387. For examples of carbon-
carbon bond-forming reactions, see: (l) Sawamura, M.; Ito, Y.; Hayashi,
T. Tetrahedron Lett. 1989, 30, 2247. (m) Kuwano, R.; Nishio, R.; Ito, Y.
Org. Lett. 1999, 1, 837. For examples of carbon-nitrogen bond-forming
reactions to give quaternary carbon centers, see: (n) Bernardi, L.; Zhuand,
W.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 5772. (o) Kim, S. M.;
Kim, H. R.; Kim, D. Y. Org. Lett. 2005, 7, 2309. See also: (p) Kitamura,
M.; Tokunaga, M.; Pham, T.; Lubell, W. D.; Noyori, R. Tetrahedron Lett.
1995, 36, 5769.
1
2
3
4
2a
2a
5
5
5
5
5
5
0.5
0.05
0.5
8.0
48.0
0.5
86
72
78
81
79
87
84
81
89
89
49
73
90
65
86
89
5
6a
7a
8a
4.0
8.0
a HFIP (1.0 equiv) was employed.
It is noted that much lower enantioselectivity was obtained
when silicon enolate 5 was employed instead of 2a under
the same reaction conditions (entry 3). Furthermore, no
erosion of enantioselectivity was observed when the imino-
phosphonate 1 was added over just 3 min (entry 2). The same
level of the enantioselectivity was observed using silicon
5334
Org. Lett., Vol. 8, No. 23, 2006

of silicon enolate 5 was obvious since the product 4a was
obtained with lower enantioselectivity in the case of using
silicon enolate 5. After minor changes of the nitrogen
protecting group, we have found that the reaction of enamide
2b with 1 proceeded smoothly to afford 4a with acceptable
ee (85% ee) in the presence of 1.5 mol % of the catalyst
(Table 2, entry 2). We evaluated other aromatic ketone-
derived enecarbamates and enamides, and high yields and
high enantioselectivities were obtained (Table 2).
In summary, we have achieved high turnover frequency
in the reactions of enamides or enecarbamates with imino-
phosphonates. A copper complex prepared from Cu(OTf)2
and chiral diamine 3b efficiently catalyzed nucleophilic
addition of enecarbamates or enamides to iminophosphonates
to provide the acylimine products in high yields with high
enantioselectivities. In this reaction, remarkably high turnover
frequency was observed, and we ascribed it to fast proton
transfer leading to quick dissociation of the catalyst from
the adducts. There are several issues to be addressed to attain
really high catalyst turnover in chiral Lewis acid catalysis.
This report has solved one of the most difficult issues, and
it should be noted that this is the first example to demonstrate
that proton transfer is much faster than silicon transfer in
enolate-addition reactions. Further investigations to apply this
new concept to other reactions as well as to elucidate a
precise reaction mechanism are now in progress.
We assume the catalytic cycle of this reaction is as shown
in Scheme 1. The catalyst-coordinated iminophosphonate 6
Scheme 1. Assumed Catalytic Cycle and Rationalization of
Observed High TOF
Acknowledgment. This work was partially supported by
a Grant-in-Aid for Scientific Research from the Japan Society
of the Promotion of Sciences (JSPS). H.K. thanks the JSPS
fellowship for Japanese Junior Scientists.
Supporting Information Available: Experimental pro-
cedures and spectral data for synthesized compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL062144+
(4) Kobayashi, S.; Kiyohara, H.; Nakamura, Y.; Matsubara, R. J. Am.
Chem. Soc. 2004, 126, 6558.
(5) For examples of the use of HFIP for turnover acceleration, see: (a)
Kitajima, H.; Ito, K.; Katsuki, T. Tetrahedron 1997, 53, 17015. (b) Evans,
D. A.; Willis, M. C.; Johnston, J. N. Org. Lett. 1999, 1, 865. (c) Evans, D.
A.; Johnson, D. S. Org. Lett. 1999, 1, 595. (d) Evans, D. A.; Scheidt, K.
A.; Johnston, J. N.; Wills, M. C. J. Am. Chem. Soc. 2001, 123, 4480. (e)
Takita, R.; Ohshima, T.; Shibasaki, M. Tetrahedron Lett. 2002, 43, 4661.
(f) Majima, K.; Takita, R.; Okada, A.; Ohshima, T.; Shibasaki, M. J. Am.
Chem. Soc. 2003, 125, 15837.
(6) (a) Matsubara, R.; Nakamura, Y.; Kobayashi, S. Angew. Chem., Int.
Ed. 2004, 43, 1679. (b) Matsubara, R.; Nakamura, Y.; Kobayashi, S. Angew.
Chem., Int. Ed. 2004, 43, 3258. (c) Matsubara, R.; Vital, P.; Nakamura,
Y.; Kiyohara, H.; Kobayashi, S. Tetrahedron 2004, 60, 9769. (d) Fossey,
J. S.; Matsubara, R.; Vital, P.; Kobayashi, S. Org. Biomol. Chem. 2005, 3,
2910. (e) Matsubara, R.; Kawai, N.; Kobayashi, S. Angew. Chem., Int. Ed.
2006, 45, 3814. After our reports, other groups also used enecarbamates as
nucleophiles. See, for example: (f) Terada, M.; Machioka, K.; Sorimachi,
K. Angew. Chem., Int. Ed. 2006, 45, 2254.
is attacked by nucleophile 2a (X ) NCbz, M ) H) to
generate zwitterionic species 7. Efficient chiral induction
occurs at this stage. Conversion of 7 to 9 occurs via M+
transfer, and we assume 8 as a possible precursor of 9.
Proton, which is supposed to transfer more readily than
silicon cation, accelerates dissociation of the catalyst from
the product, leading to high turnover frequency (TOF).
(7) (a) Kobayashi, S.; Matsubara, R.; Kitagawa, H. Org. Lett. 2002, 4,
143. (b) Kobayashi, S.; Matsubara, R.; Nakamura, Y.; Kitagawa, H.; Sugiura,
M. J. Am. Chem. Soc. 2003, 125, 2507.
Org. Lett., Vol. 8, No. 23, 2006
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