Despite a sizable body of literature demonstrating the
biological activity of N-sulfonyl-R-amino acid derivatives,4
there are no examples of asymmetric hydrogenation of
N-sulfonyl-R-dehydroamino acid derivatives in the literature.5
Additionally, hydrogenation of tetrasubstituted variants of
amide- or carbamate-protected R-dehydroamino acid deriva-
tives are less common as a result of the decreased reactivity
caused by steric hindrance and have, in all cases, employed
Rh catalysts.6 The Me or Et ester derivative is almost
exclusively used rather than the acid,7 so we began our
investigation by screening Rh catalysts for the hydrogenation
of the Me ester of carboxylic acid 1 and found it to be quite
unreactive. This led us to evaluate the hydrogenation of acid
1 with a Ru catalyst.2 The use of Ru catalysts for the
hydrogenation of R-dehydroamino acids has been known for
some time;8,9 however, to the best of our knowledge, there
are no reported examples of tetrasubstituted substrates.10
Ru catalysts were found to have good reactivity for the
hydrogenation of 1,11 and screening experiments identified
the Josiphos ligand (R)-(S)-Ph2P-F-C-P(tBu)2 A (Figure 1)
as the most enantioselective, giving 97% ee of desired (R)-2
after optimization.2 To investigate the generality of this Ru-
mediated asymmetric hydrogenation reaction, we synthesized
Figure 1. Phosphine ligand structures.
a variety of N-sulfonyl-R-dehydroamino acids, 3a-i (Table
1). Compounds 3a-i were all prepared by MSA-catalyzed
condensation of an R-ketoacid with a sulfonamide in toluene
with Dean-Stark removal of water.12,13 No attempt was made
to optimize the yields of 3a-i. These compounds were taken
to high purity by chromatography, recrystallization, or both.
Table 1. Synthesis of N-Sulfonyl-R-dehydroamino Acids 3a-i
(1) Shoop, W. L.; Xiong, Y.; Wiltsie, J.; Woods, A.; Guo, J.; Pivnichny,
J. V.; Felcetto, T.; Michael, B. F.; Bansal, A.; Cummings, R. T.;
Cunningham, B. R.; Friedlander, A. M.; Douglas, C. M.; Patel, S. B.;
Wisniewski, D.; Scapin, G.; Salowe, S. P.; Zaller, D. M.; Chapman, K. T.;
Scolnick, E. M.; Schmatz, D. M.; Bartizal, K.; MacCoss, M.; Hermes, J.
D. Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 7958-7963.
entry
no.
R1
-(CH2)5-
-(CH2)5-
R2
R3
yield (%)
(2) Full details of these experiments are reported in an upcoming
publication.
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
3g
3h
3i
4-Me-C6H4-SO2-
4-F-C6H4-SO2-
4-Me-C6H4-SO2-
4-OMe-C6H4-SO2-
4-F-C6H4-SO2-
C6H5-CH2-SO2-
C6H5-(CH2)3-SO2-
4-Me-C6H4-SO2-
4-Me-C6H4-SO2-
86
62
54
15
62
51
67
59
57
(3) Burk, M. J.; Gross, M. F.; Martinez, J. P. J. Am. Chem. Soc. 1995,
117, 9375-9376.
Me
Me
Me
Me
Me
Me
H
Me
Me
Me
Me
Me
iPr
(4) For example, see: (a) Kottirsch, G.; Zerwes, H.-G.; Cook, N. S.;
Tapparelli, C. Bioorg. Med. Chem. Lett. 1997, 7, 727. (b) O’Brien, P. M.;
Ortwine, D. F.; Pavlovsky, A. G.; Picard, J. A.; Sliskovic, D. R.; Roth, B.
D.; Dyer, R. D.; Johnson, L. L.; Man, C. F.; Hallak, H. J. Med. Chem.
2000, 43, 156. (c) Pikul, S.; Ohler, N. E.; Ciszewski, G.; Laufersweiler, M.
C.; Almstead, N. G.; De, B.; Natchus, M. G.; L. C., H.; Janusz, M. J.;
Peng, S. X.; Branch, T. M.; King, S. L.; Taiwo, Y. O.; G. E., M. J. Med.
Chem. 2001, 44, 2499. (d) Dankwardt, S. M.; Abbot, S. C.; Broka, C. A.;
Martin, R. L.; Chan, C. S.; Springman, E. B.; Van Wart, H. E.; Walker, K.
A. M. Bioorg. Med. Chem. Lett. 2002, 12, 1233.
H
(5) Recently, Ito has reported the asymmetric hydrogenation of an
N-sulfonylated indole with a Rh catalyst. Kuwano, R.; Kaneda, K.; Ito, T.;
Sato, K.; Kurokawa, T.; Ito, Y. Org. Lett. 2004, 6, 2213-2215.
(6) For example, see: (a) Sawamura, M.; Kuwano, R.; Ito, Y. J. Am.
Chem. Soc. 1995, 117, 9602. (b) Pye, P. J.; Rossen, K.; Reamer, R. A.;
Tsou, N. N.; Volante, R. P.; Reider, P. J. J. Am. Chem. Soc. 1997, 119,
6207. (c) Kuwano, R.; Okuda, S.; Ito, Y. J. Org. Chem. 1998, 63, 3499.
(d) Yamanoi, Y.; Imamoto, T. J. Org. Chem. 1999, 64, 2988-2989 (e)
Blaser, H.-U.; Spindler, F.; Studer, M. Appl. Catal., A 2001, 221, 119-
143. (f) Sheih, W.-C.; Xue, S.; Reel, N.; Wu, R.; Fitt, J.; Repic, O.
Tetrahedron: Asymmetry 2001, 12, 2421. (g) Liu, D.; Li, W.; Zhang, X.
Org. Lett. 2002, 4, 4471 (h) Ohashi, A.; Kikuchi, S.-i.; Yasutake, M.;
Imamoto, T. Eur. J. Org. Chem. 2002, 2535. (i) Lennon, I. C.; Moran, P.
H. Curr. Opin. Drug DiscoVery DeV. 2003, 6, 855-875. (j) Blaser, H. U.;
Malan, C.; Pugin, B.; Spindler, F.; Steiner, H.; Studer, M. AdV. Synth. Catal.
2003, 345, 103. (k) Tang, W.; Zhang, X. Chem. ReV. 2003, 103, 3029.
(7) Asymmetric hydrogenation of tetrasubstituted amide-protected R-ami-
no acids with Rh catalysts is known: (a) Takahashi, H.; Achiwa, K. Chem.
Lett. 1989, 2, 305. (b) Nagel, U.; Kinzel, E. Chem. Ber. 1986, 119, 3326.
(8) Ikariya, T.; Ishii, Y.; Kawano, H.; Arai, T.; Saburi, M.; Yoshikawa,
S.; Akutagawa, S. J. Chem. Soc., Chem. Commun. 1985, 922.
(9) Kawano, H.; Ikariya, T.; Ishii, Y.; Saburi, M.; Yoshikawa, S.; Uchida,
Y.; Kumobayashi, H. J. Chem. Soc., Perkin Trans. 1 1989, 1571.
(10) A Ru catalyst has been used to hydrogenate a tetrasubstituted
enamide; see: Dupau, P.; Bruneau, C.; Dixneuf, P. H. AdV. Synth. Catal.
2001, 343, 331-334.
Using conditions similar to those that proved optimal for
the reduction of 1 (90 psig H2, 0.5 equiv NEt3, 25 °C, 1 mol
% catalyst, EtOH solvent),14 we found that the Josiphos
ligand Ph2P-F-C-P(tBu)2 A worked well for substrates 3a
and 3b (Table 2), which are structurally analogous to 1. The
Ts-valine substrate 3c, however, gave unsuitably low enan-
tioselectivity (49% ee) with the Josiphos ligand A. Catalyst
screening identified the bis-thiophene atropisomeric ligand
TMBTP B,15 which gave very high enantioselectivity (96-
97% ee) for 3c and worked well for the other valine
substrates 3d-g as well. Both ligands A and B showed only
modest stereoselectivity for trisubstituted substrate 3h (A
gave 67% ee, and B gave 70% ee16). Zhang’s (S,S,S,S)-Me-
f-Ketalphos C17 gave useful enantioselectivity for the trisub-
stituted variants, reducing 3h in 91% ee. The bulky i-Pr group
in the dehydro-leucine substrate 3i significantly reduced
(12) Yonezawa, Y.; Shin, C.; Ono, Y.; Yoshimura, J. Bull. Chem. Soc.
Jpn. 1980, 53, 2905.
(13) A small amount of high-boiling diethylene glycol diethyl ether was
employed to keep the polar materials in solution during the reaction.
(11) Ru catalyst solutions were prepared by mixing [(cymene)RuCl2]2
+ phosphine ligand in 3:1 EtOH/1,2-dichloroethane at 50 °C for g1 h.
See Supporting Information for complete details.
3406
Org. Lett., Vol. 7, No. 16, 2005