Catalytic asymmetric synthesis of α-amino phosphonates using enantioselective carbon-carbon bond-forming reactions

Article abstract of DOI:10.1021/ja048791i

We have developed highly enantioselelctive reactions of silicon enolates with N-acyl-α-iminophosphonates leading to optically active α-amino phophonates. A copper (II)-diamine complex was shown to be effective in this reaction, and high levels of yield an

Full text of DOI:10.1021/ja048791i

Published on Web 05/07/2004
Catalytic Asymmetric Synthesis of r-Amino Phosphonates Using
Enantioselective Carbon-Carbon Bond-Forming Reactions
Shuj Kobayashi,* Hiroshi Kiyohara, Yoshitaka Nakamura, and Ryosuke Matsubara
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received March 8, 2004; E-mail: skobayas@mol.f.u-tokyo.ac.jp
Table 1. Cu(II)-3-Catalyzed Reactions of
N-Acyl-R-iminophosphonate 1 with Silicon Enolate 2a
R-Amino phosphonates are key compounds as analogues of
R-amino acids in medicinal chemistry and pharmaceutical sciences.1
Despite the importance of optically active R-amino phosphonates,
methods to synthesize them are limited.2 Scho¨llkopf et al.2a and
Steglich et al.2b reported highly diastereoselective synthetic methods,
respectively, where the use of stoichiometric amounts of chiral
auxiliaries were needed. Shibasaki et al.2c,d reported the first catalytic
asymmetric hydrophosphonylation of imines using lanthanide-
potassium-BINOL heterobimetallic complexes. In this communica-
tion, we describe an alternative approach to R-amino phosphonates
via enantioselective carbon-carbon bond-forming reactions: ad-
dition of silicon enolates to N-acyl R-iminophosphonates catalyzed
by a chiral copper(II) complex. The synthesis of biologically
important, optically active â-carboxyl-R-aminophosphonic acid
derivatives is also described.
N-Acyl-R-iminophosphonate 1 (Troc ) 2,2,2-trichloro-ethoxy-
carbonyl) was prepared by a modified Steglich method,2b in which
a polymer-supported amine was used instead of the Hu¨nig base.3
We then conducted the reaction of 1 with a silicon enolate (2a)
derived from acetophenone in the presence of a copper(II) complex
derived from Cu(OTf)2 and diamine 3. The reaction proceeded
smoothly to afford the desired adduct 4a in high yield, albeit with
moderate enantioselectivity. We have previously used the same
copper complex for the activation of R-imino esters, and high yields
and enantioselectivity were obtained.4 Compared with R-imino
esters, N-acyl-R-iminophosphonates have stronger Lewis basicity,2c
and thus, coordination of 1 to the Cu catalyst is presumed to be
stronger. Therefore, release of the Cu catalyst from the product
was assumed to be slow, thus allowing the background reaction to
take place in the absence of a catalyst serving to reduce overall
enantioselectivity (Vide infra).
To address this issue, we screened several proton sources
expected to release the catalyst from the product; we found that
hexafluoroisopropyl alcohol (HFIP) was suitable for our purpose.5
When one equivalent of HFIP was added to the reaction system,
the reaction of 1 with 2a also proceeded smoothly to afford the
desired product 4a in high yield with slight improvement of
enantioselectivity (Table 1, entry 2). Moreover, it was found that
the selectivity was further improved when the substrates, 1 and
2a, were slowly added to a solution of the catalyst over 8 h (entries
3-6). Conducting the reaction in the presence of HFIP (2 equiv)
and MS 3A (50 mg/mmol), addition of substrates to the catalyst
solution, over 8 h, gave the best result (86% yield, 91% ee).6
Interestingly, the same levels of yield and enantioselection were
obtained when the substrates were added to the catalyst over 48 h
without HFIP (entry 7).
entry
additive
yield (%)
ee (%)
1a
-
78
87
81
78
82
86
82
49
65
89
93
92
91
93
2a
HFIP (1.0 equiv)
HFIP (1.0 equiv)
HFIP (1.0 equiv)
HFIP (2.0 equiv)
HFIP (2.0 equiv), MS 3A (50 g/mol)
MS 3A (50 g/mol)
3b
4b,c
5b,c
6b,c
7d
a 1 was slowly added over 0.5 h. b 1 was slowly added over 8 h. c 2a
was slowly added over 8 h. d 1 and 2a were slowly added over 48 h
simultaneously. CH2Cl2/toluene (2:4.5) was used as a solvent system.
Table 2. Cu(II)-3-Catalyzed Reactions of 1 with Various Kinds of
Silicon Enolates 2
yield ee
yield ee
entryb enolate product (%) (%)
entryb enolate product (%) (%)
1
2
3
4
5
6
2a
2b
2c
2d
2e
2f
4a
4b
4c
4d
4e
4f
86 91
82 85
71 91
86 86
80 89
82 76
7
8
9
10
11
12c
2g
2h
2i
2j
2k
2l
4g
4h
4i
4j
4k
4l
83 92
79 92
84 87
88 94
70 89
69 90
a 50 g/mol. b 1 and 2 were slowly added over 8 h. c In the absence of
HFIP, 1 and 2l were slowly added over 48 h. CH2Cl2/toluene (2:4.5) was
used as a solvent system, and catalyst (15 mol %) was used.
ee) in all cases (entries 1-11). On the other hand, in the reaction
with silicon enolate 2l derived from the thioester, it was found that
decomposition of 2l in the presence of HFIP decreased the yield
of the desired product. We then decided to use the slow addition
of the substrates to the catalyst without HFIP. The enantioselectivity
increased as the addition time was prolonged, and when the
Having determined the optimal conditions (Table 1, entry 6),
other silicon enolates were examined, the results are summarized
in Table 2. Silicon enolates derived from various aromatic and
aliphatic ketones worked well to afford the corresponding adducts
in high yields (70-88%) with high enantioselectivities (76-94%
9
6558
J. AM. CHEM. SOC. 2004, 126, 6558-6559
10.1021/ja048791i CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1. Proposed Catalytic Cycle
Scheme 3. Synthesis of 12
In summary, we have developed a highly enantioselelctive
reaction of silicon enolates with N-acyl-R-iminophosphonates
leading to nonracemic R-amino phosphonates. A copper (II)
complex was shown to be effective catalysts for this reaction, giving
high yields and selectivities. It is noteworthy that this reaction opens
a new pathway to various biologically important, nonracemic
R-amino phosphonate derivatives. Studies into substrate variation,
allowing access to libraries of R-amino phosphonates, and the
application of this catalytic procedure to other reactions of N-acyl-
R-iminophosphonates are currently underway in our laboratory.
Acknowledgment. This work was partially supported by
CREST, SORT, and ERATO, Japan Science Technology Corpora-
tion (JST), and a Grant-in-Aid for Scientific Research from Japan
Society of the Promotion of Sciences (JSPS). R.M. thanks the JSPS
fellowship for Japanese Junior Scientists.
Scheme 2. Synthesis of 8g and 8j
Supporting Information Available: Experimental section (PDF).
This material is available free of charge via the Internet at http://
pubs.acs.org.
References
(1) Kafarski, P.; Lejczak, B. In Aminophosphonic and Aminophosphinic Acids;
Kukhar, V. P., Hudson, H. R., Eds.; John Wiley and Sons: 2000; Chapter
12, p 407.
(2) (a) Scho¨llkopf, U.; Schu¨tze, R. Liebigs Ann. Chem. 1987, 45. (b) Schrader,
T.; Kober, R.; Steglich, W. Synthesis 1986, 372. (c) Sasai, H.; Arai, S.;
Tahara, Y.; Shibasaki, M. J. Org. Chem. 1995, 60, 6656. (d) Schlem-
minger, I.; Saida, Y.; Gro¨ger, H.; Maison, W.; Durot, N.; Sasai, H.;
Shibasaki, M.; Martens, J. J. Org. Chem. 2000, 65, 4818. (e) Sawamura,
M.; Ito, Y.; Hayashi, T. Tetrahedron Lett. 1989, 30, 2247. For review, (f)
Kukhar, V. P. In Aminophosphonic and Aminophosphinic Acids; Kukhar,
V. P., Hudson, H. R., Eds.; John Wiley and Sons: 2000; Chapter 5, p
127. (g) Dhawan, B.; Redmore, D. Phosphorus Sulfur 1987, 32, 119. (h)
Kukhar, V. P.; Soloshonok, V. A.; Solodenko, V. A. Phosphorus, Sulfur,
Silicon 1994, 92, 239. (i) Gro¨ger, H.; Hammer, B. Chem. Eur. J. 2000, 6,
943. Recent examples using reduction: (j) Burk, M. J.; Stammers, T. A.;
Straub, J. A. Org. Lett. 1999, 1, 387. (k) Schmidt, U.; Krause, H. W.;
Oehme, G.; Michalik, M.; Fischer, C. Chirality 1998, 10, 564. (l) Kitamura,
M.; Tokunaga, M.; Pham, T.; Lubell, W. D.; Noyori, R. Tetrahedron Lett.
1989, 30, 2247. After submitting this manuscript, Jacobsen et al. have
reported catalytic enantioselective hydrophosphonylation of imines: (m)
Joly, G. D.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 4102.
(3) 1 is unstable and must be prepared in situ and used immediately. Cf.
Kobayashi, S.; Kitagawa, H.; Matsubara, R. J. Comb. Chem. 2001, 3,
401.
substrates were added over 48 h to the catalyst, the enantioselectivity
was improved to be 90%.
Scheme 1 shows the proposed catalytic cycle. The copper(II)-
diamine complex is assumed to activate 1 to attack silicon enolates
via a bidentate coordination mode (5) to form intermediate 6. The
key for completion of the catalytic cycle is the release of the catalyst
from 6, and it is assumed that this process would be slow due to
the high basicity of 1. When HFIP was added, intermediate 6 reacted
with HFIP to form the product 4 along with regeneration of the Cu
catalyst; the adduct 7 was not observed at all. On the other hand,
in the absence of HFIP, when the substrates 1 and 2 were slowly
added to the catalyst, silicon transfer process from 6 to 7 occurred
slowly to release the catalyst from 6. In the experiments, N-silylated
adduct 7 was obtained as a major product. In addition, it is
noteworthy that, in the absence of any copper complex when 1
and 2 were combined over 1 min even at -78 °C, the reaction
proceeded rapidly to give 4a. Considering these results, the slow
addition of the substrates to the catalyst is preferable for the
asymmetric induction.
The products obtained in this reaction are â-carboxyl-R-amino-
phosphonic esters, phosphorus analogues of aspartic acid,7 which
have potentially interesting bioactivity. γ-Keto-R-amino acid
derivatives 9 (FCE28833) and 10 (m-NBA) are kynurenine 3-hy-
droxylase inhibitors.8 We prepared their phosphorus analogues 8g
and 8j from 4g and 4j, respectively (see Scheme 2).9 On the other
hand, the adduct 4a was transformed into R-aminophosphonate 12,
an intermediate for the synthesis of inhibitors of endothelin-
converting enzymes (see Scheme 3).10 It is noted that these
biologically interesting compounds can be readily prepared using
this catalytic asymmetric reaction.
(4) Kobayashi, S.; Matsubara, R.; Nakamura, Y.; Kitagawa, H.; Sugiura, M.
J. Am. Chem. Soc. 2003, 125, 2507.
(5) For examples where HFIP was used in catalytic asymmetric reactions,
see: (a) Kitajima, H.; Ito, K.; Katsuki, T. Tetrahedron 1997, 53, 17015.
(b) Evans, D. A.; Scheidt, K. A.; Johnston, J. N.; Wills, M. C. J. Am.
Chem. Soc. 2001, 123, 4480.
(6) Experimental details are shown in the Supporting Information.
(7) (a) Vasella, A.; Voeffray, R. HelV. Chim. Acta 1982, 65, 1953. (b)
Monique, D.; Jose, B. M.; Andre, C. Biochem. Soc. Trans. 1988, 16, 611.
(8) (a) Pellicciari, R.; Natalini, B.; Constantino, G.; Mahmoud, R. M.; Mattoli,
L.; Sadeghpour, B. M.; Moroni, F.; Chiarugi, A.; Carpenedo, R. J. Med.
Chem. 1994, 37, 647. (b) Carpenedo, R.; Chiarugi, A.; Russi, P.; Lombardi,
G.; Carla, V.; Pellicciari, R.; Mattoli, L.; Moroni, F. Neuroscience 1994,
61, 237. (c) Speciale, C.; Cini, M.; Wu, H.-Q.; Salvati, P.; Schwarcz, R.;
Molinari, A.; Calabresi, M.; Varasi, M. AdV. Exp. Med. Biol. 1996, 410,
407.
(9) Preliminary biological tests have shown that 8g and 8j have low activity
for inhibition of kynureninase and kynurenine 3-hydroxylase. We thank
Dr. Kuniaki Saito (Gifu University) for measurements of the biological
activity of 8g and 8j.
(10) Ishikawa, K.; Fukami, T.; Hayama, T.; Matsuyama, K.; Noguchi, K.; Yano,
M. European Patent EP0623625A1, 1994.
JA048791I
9
J. AM. CHEM. SOC. VOL. 126, NO. 21, 2004 6559