2362
H.-J. Pyun et al. / Tetrahedron Letters 53 (2012) 2360–2363
X.; Wang, W. Annu. Rep. Med. Chem. 2003, 38, 333; (d) Meanwell, N. A. J. Med.
Table 2
Chem. 2011, 54, 2529.
Synthesis of (1S,2S)-ethyl 1-carboxybenzylamino-2-vinylcyclopropane-1-phosphi-
nates (15) using electrophilic alkylating reagents
2. (a) Dhawanm, B.; Redmore, D. Phosphorus, Sulfur 1987, 32, 119; (b) Oleksyszyn,
J. In Aminophosphonic and Aminophosphinic Acids; Kukhar, V. P., Hudson, H. R.,
Eds.; John Wiley & Sons: Chichester, 2000; pp 537–558. Chapter 15; (c) Kam, C.
M.; Nishino, N.; Powers, J. C. Biochemistry 1979, 18, 3032; (d) Gionnousis, P. P.;
Bartlett, P. A. J. Med. Chem. 1987, 30, 1603.
3. For phosphorus containing peptide analogs as peptidase inhibotors: Bartlett, P.
A.; Marlowe, C. K.; Gionnousis, P. P.; Hanson, J. E. Cold Harb. Symp. Quant. Biol.
1987, 52, 83. see also references cited therein.
4. (a) Froestl, W.; Mickel, S. J.; von Sprecher, G.; Diel, P. J.; Hall, R. G.; Maier, L.;
Strub, D.; Melillo, V.; Baumann, P. A.; Bernasconi, R.; Gentsch, C.; Hauser, K.;
Jaekel, J.; Karlsson, G.; Klebs, K.; Maitre, L.; Marescaux, C.; Pozza, M. F.;
Schmutz, M.; Steinmann, M. W.; van Riezen, H.; Vassout, A.; Mondadori, C.;
Olpe, H.-R.; Waldmeier, P. C.; Bittiger, H. J. Med. Chem. 1995, 38, 3313; (b)
Greco, M. N.; Hawkins, M. J.; Powell, E. T.; Almond, H. R., Jr.; De Garavilla, L.;
Hall, J.; Minor, L. K.; Wang, Y.; Corcoran, T. W.; Di Cera, E.; Cantwell, A. M.;
Savvides, S. N.; Damiano, B. P.; Maryanoff, B. E. J. Med. Chem. 2007, 50, 1727; (c)
Bartlett, P. A.; Hanson, J. E.; Gionnousis, P. P. J. Org. Chem. 1990, 55, 6268; (d)
Bartlett, P. A.; Kezer, W. B.; Gionnousis, P. P. J. Am. Chem. Soc. 1984, 106, 4282.
5. Lamarre, D.; Anderson, P. C.; Bailey, M.; Beaulieu, P.; Bolger, G.; Bonneau, P.;
Bös, M.; Cameron, D. R.; Cartier, M.; Cordingley, M. G.; Faucher, A.-M.;
Goudreau, N.; Kawai, S. H.; Kukolj, G.; Lagacé, L.; LaPlante, S. R.; Narjes, H.;
Poupart, M.-A.; Rancourt, J.; Sentjens, R. E.; St George, R.; Simoneau, B.;
Steinmann, G.; Thibeault, D.; Tsantrizos, Y. S.; Weldon, S. M.; Yong, C.-L.; Llinàs-
Brunet, M. Nature 2003, 426, 186.
R
Method
Alkylating agent
Yielda
e
f
g
2,6-F2PhCH2
CH2COOEt
CH2OCH3
A
A
A
2,6-F2PhCH2Br
BrCH2COOEt
ClCH2OCH3
63
54
60
S
S
h
A
63b
CH2
CH2Cl
H3C
N
4-MePhCH2
PhCH2CH2
Me2C@CHCH2
4-MeOPhCH2
H3C
N
i
j
k
l
A
B
B
B
4-MePhCH2Br
PhCH2CH2Br
Me2C@CHCH2Br
4-MeOPhCH2Cl
44
37
50
27
a
Yields were not optimized except e. All phosphinate products were mixtures of
two diastereomers (1:1–1:2 ratio).
b
The reaction was performed with 1 equiv of tetrabutylammonium iodide.
O
P
O
P
OEt
O
P
OH
H2N
R
OEt
CbzHN
R
H2N
R
b
a
6. Pyun, H.-J.; Chaudhary, K.; Somoza, J. R.; Sheng, C.; Kim, C. U. Tetrahedron Lett.
2009, 50, 3833.
7. Sheng, X. C.; Pyun, H.-J.; Chaudhary, K.; Wang, J.; Doerffler, E.; Fleury, M.;
McMurtrie, D.; Chen, X.; Delaney, W. E.; Kim, C. U. Bioorg. Med. Chem. Lett. 2009,
19, 3453.
5a-5l
15
4a-4l
8. Crofts, P. C.; Kosolapoff, G. M. J. Am. Chem. Soc. 1953, 75, 3379.
9. Clarke, M. O.; Chen, X.; Cho, A.; Delaney, W. E.; Doerffler, E.; Fardis, M.; Ji, M.;
Mertzman, M.; Pakdaman, R.; Pyun, H.-J.; Rowe, T.; Yang, C. Y.; Sheng, X. C.;
Kim, C. U. Bioorg. Med. Chem. Lett. 2011, 21, 3568.
10. (a) Walsh, C.; Pascal, R. A., Jr.; Johnston, M.; Raines, R.; Dikshit, D.; Krantz, A.;
Honma, M. Biochemistry 1981, 20, 7509; (b) Honma, M.; Shimomura, T. Agric.
Biol. Chem. 1979, 43, 1677.
11. (a) Penrose, D.; Glick, B. R. Indian J. Exp. Biol. 1997, 35, 1; (b) Pirrung, M. C.;
McGeehan, G. M. J. Org. Chem. 1986, 51, 2103; (c) Li, K.; Du, W.; Que, N. L. S.; Liu,
H.-W. J. Am. Chem. Soc. 1996, 118, 8763.
12. (a) Ecker, J. E. Science 1995, 268, 667; (b) Burg, S. P.; Burg, E. A. Plant Physiol.
1962, 35, 24.
13. Honma, M.; Shimomura, T. Agric. Biol. Chem. 1825, 1978, 42.
14. (a) Patel, D. V.; Rielly-Gauvin, K.; Ryono, D. E. Tetrahedron Lett. 1990, 31, 5591;
(b) Minowa, N.; Fukatu, S.; Niida, T. Tetrahedron Lett. 1983, 24, 2391; (c)
Mortier, J.; Fortineau, A.-D.; Vaultier, M. Phosphorus, Sulfur Silicon 1999, 149,
221.
S
N
S
N
NH
NH
O
N
O
O
N
O
O
O
P
H
H
N
N
P
OH
R
R
OH
N
N
H
N
H
O
O
O
O
N
O
O
O
O
11a-11l
8a-8l
15. Procedure for the synthesis of the phosphinate ester 15a from the mono acid 13
using methyllithium is as follows: A solution of the monoacid 13 (415 mg,
Scheme 3. Deprotections of 15. Reagents and conditions: (a) Me2S–TFA (1:4), rt,
16 h; (b) TMSI, CH3CN, 0 °C to rt.
1.28 mmol) in toluene (8 mL) was stirred at 0 °C as (COCl)2 (29
lL, 2.56 mmol)
was added dropwise. After addition, DMF (44 L, 0.56 mmol) was added also.
l
After 2 h at 0 °C, the mixture was concentrated and evacuated for 1 h. The
resulting residue was disolved in THF (6.4 mL) and stirred at À78 °C as 1.4 M
methyllithium in diethyl ether (1.37 mL, 1.92 mmol) was addedAfter 40 min,
additional methyllithium solution (0.46 mL, 0.64 mmol) was added. After
10 min, the reaction was quenched by addition of aq NH4Cl solution at À78 °C.
After the mixture was diluted with ethyl acetate, it was washed with aq NH4Cl
solution (Â1) and brine (Â1). The resulting organic fraction was dried (MgSO4)
and concentrated. The residue was purified by flash chromatography with
hexane–ethyl acetate mixture to afford 2140 mg (52%) of the phosphinate ester
15a. 1H NMR (300 MHz, CDCl3) d 7.33 (s, 5H) 6.09 (dt, J = 9.9, 17.1 Hz, 1H), 5.65
(d, J = 23.7 Hz, 1H), 5.31 (d, J = 17.1 Hz, 1H), 5.06 (m, 3H), 4.06 (m, 2H), 2.09 (m,
1H) 1.73 (m, 1H), 1.40 (d, 3H), 1.13 (dt, J = 8.1, 26.4 Hz, 3H); 31P NMR (121.4 Hz,
CD3OD) d 53.7, 50.8. LC/MS = 324 (M++1), 346 (M++Na).
Synthesized phosphinate analogs were tested for the inhibition
of the HCV NS3 protease. Acyclic phosphinate analog 8a was found
to have an IC50 of 6 nM, whereas the IC50’s of 6 and 7 were found to
be 3 and 0.9 nM, respectively. The weaker inhibition of the phosph-
inate compared to its phosphonate analog at the enzyme level is
probably due to the loss of H-bonding interaction.9 In a cell-based
assay, 8a exhibited an EC50 of 69 nM, which is also somewhat
weaker than the EC50’s of 6 (4 nM) and 7 (18 nM). The properties
and SAR of phosphinate analogs as HCV NS3 protease inhibitors
have been described elsewhere.9,25
In summary, conversion of the phosphonate of 3 to the corre-
sponding phosphinate group was accomplished by using either
nucleophilic organometallic agents or electrophilic alkylating
agents. Reaction of the phosphonomonochloridate 14 with nucleo-
philic organometallic reagents provided 15a–15d in moderate
yields. Alternatively, the chloridate 11 was efficiently reduced to
16 with a mild reducing agent, LiAlH(Ot-Bu)3. Phosphonous ester
16 was subsequently alkylated with alkyl halides to afford the cor-
responding phosphinate analogs of (+)-(1R,2S)-1-amino-2-vinylcy-
clopropanecarboxylic acid. Deprotection of the Cbz group was
efficient and did not affect the vinyl-cyclopropane moiety.
16. (a) Thottathil, J. K.; Przybyla, C. A.; Moniot, J. L. Tetrahedron Lett. 1984, 25, 4737;
(b) Allen, M. C.; Fuhrer, W.; Tuck, B.; Wade, R.; Wood, J. M. J. Med. Chem. 1989,
32, 1652; (c) Malachowski, W. P.; Coward, J. K. J. Org. Chem. 1994, 59, 7625.
17. Engel, R.; Chakraborty, S. Synth. Commun. 1988, 18, 665.
18. (a) Lynch, E. R. J. Chem. Soc. 1962, 3729; (b) Wetzel, R. B.; Kenyon, G. L. J. Am.
Chem. Soc. 1972, 94, 1774; (c) Wetzel, R. B.; Kenyon, G. L. J. Org. Chem. 1974, 39,
1531; (d) Cabioch, J. L.; Denis, J. M. J. Organomet. Chem. 1989, 377, 227; (e)
Dallemer, F.; Collin, J.; Kagan, H. B. Appl. Organomet. Chem. 1995, 9, 431; (f)
Nycz, J.; Rachon, J. Phosphorus, Sulfur Silicon Relat. Elem. 2000, 161, 39; (g) Zhao,
Y.; Jiang, N.; Wang, J. Tetrahedron Lett. 2003, 44, 8339; (h) Guillen, F.; Rivard,
M.; Toffano, M.; Legros, J.-Y.; Daran, J.-C.; Fiaud, J.-C. Tetrahedron 2002, 58,
5895; (i) Dallemer, F.; Collin, J.; Kagan, H. B. Appl. Organomet. Chem. 1995, 9,
431.
19. Procedure for the synthesis of the phosphonous ester 16 from the mono acid 13 is
as follows: A solution of (COCl)2 (29 mL, 332.4 mmol) in acetonitrile (150 mL)
was stirred at rt as 1.04 mL of DMF was added dropwise. After addition, a
solution of the monoacid 10 (21.533 g, 66.19 mmol) in acetonitrile (100 mL)
was added over 40 min. The solution was stirred at rt for additional 40 min and
concentrated and dried in high vacuum for 1 h to yield the dark-brown, crude
chloridate 14. The residue was dissolved in THF (150 mL) and stirred at IPA-dry
ice bath as 1.0 M LiAlH(O-t-Bu)3 in THF (200 mL, 200 mmol) was added over
References and notes
1. (a) Moreira, L.; Barreiro, E. J. Curr. Med. Chem. 2005, 12, 23; (b) Wermuth, C. G.;
Ciapetti, P.; Giethlen, B.; Bazzini, P. Compr. Med. Chem. II 2006, 2, 649; (c) Chen,