J. Am. Chem. Soc. 1997, 119, 7595-7596
7595
Nucleophilic r-Addition to Alkynoates. A Synthesis
of Dehydroamino Acids
Table 1. Ra -Addition of Nitrogen Nucleophiles to Conjugated
Alkynoates
Barry M. Trost* and Gregory R. Dake
Department of Chemistry, Stanford UniVersity
Stanford, California 94305
ReceiVed April 18, 1997
The design of ligands for biological systems to provide
increased understanding of function at a molecular level and to
open avenues for therapeutic agents has placed increased
emphasis on the availability of unusual amino acids and their
derivatives.1 Dehydroamino acids constitute one such class as
2
well as serve as precursors to the saturated amino acids.
Increasing the availability of such amino acid derivatives
becomes an important goal. The postulation that the phosphine-
3
induced isomerization of alkynoates to 2,4-dienoates and
addition of pronucleophiles to the 4-position4 of these substrates
suggested the possibility of a new and unprecedented reactivity
pattern for alkynoatessnucleophilic addition at the R-position
as shown in eq 1 as a new source of dehydroamino acids. In
this communication, we record our initial studies that validate
this new pattern of reactivity.
,5
a
3 3
All reactions were run in PhCH at 105 °C with 10 mol % Ph P,
5
0 mol % HOAc, and 50 mol % NaOAc.
singlets at δ 6.66 and 5.97. Other substrates that cannot undergo
isomerization to allenes and 2,4-dienoates and thereby should
participate in this reaction are the arylpropiolates. Indeed, ethyl
phenylpropiolate (eq 2 and Table 1, entry 2) participated equally
A critical issue to consider in the realization of this new
paradigm is the ability of the nucleophile to undergo simple
conjugate addition in preference to the R-attack since phosphines
7
well to give a single geometric and regio-isomer 3, which is
6
could also serve as general base catalysts for Michael additions.
8
also a known compound. The regioselectivity is unambigously
Ethyl propiolate should be particularly prone to undergo such
Michael additions. Given that the proposed route of eq 1
requires both general acid and base catalysis, a 1:1 sodium
acetate-acetic acid buffer was employed. Heating a 1:1 mixture
of ethyl propiolate and phthalimide at 105 °C in toluene with
established spectroscopically. For both adducts 1 and 3, the
regioselectivity was further verified by catalytic hydrogenation
9
a
9b
to the phthalimide derivatives of alanine and phenylalanine,
respectively.
Sulfonamides also serve as pronucleophiles with the arylpro-
piolates. Under identical conditions as above, ethyl phenylpro-
piolate and p-toluenesulfonamide gave the R-adduct 410 (eq 3
1
0 mol % triphenylphosphine, 50 mol % acetic acid, and 50
mol % sodium acetate gave a 1:1 adduct in 95% yield (eq 2
and Table 1, entry 1).
and Table 1, entry 3). The illustration of the ease of removal
1
1
of a (p-(nitrophenyl)sulfonyl group led us to examine its
(
4) Trost, B. M.; Li, C.-J. J. Am. Chem. Soc. 1994, 116, 3167. Trost, B.
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995, 645.
5) Rafel, S.; Leahy, J. W. J. Org. Chem. 1997, 62, 1521. Nozaki, K.;
1
(
Sato, N.; Ikeda, K.; Takaya, H. J. Org. Chem. 1996, 61, 4516. Zhang, C.;
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J. Org. Chem. 1993, 58, 299. Roth, F.; Gygax, P.; Frater, G. Tetrahedron
Lett. 1992, 32, 1045. Amri, H.; Rambaud, M.; Villicras, J. Tetrahedron
Lett. 1989, 30, 7381. Imayawa, T.; Uemura, K.; Nagai, Z.; Kawanisi, M.
Synth. Commun. 1984, 14, 1267. Miyakoshi, T. Saito, S. Nippon Kagaku
Kaishi 1980, 44. Morita, K.; Suzuki, Z.; Hirose, H. Bull Chem. Soc. Jpn.
1968, 41, 2815.
1
The H NMR spectrum immediately reveals that the structure
7
of the adduct must be the R-addition product 1 and not the
conjugate addition one 2 since the olefinic signals were two
(
1) For reviews, see: North, M. Contemp. Org. Synth. 1995, 2, 269.
Duthaler, R. O. Tetrahedron 1994, 50, 1539. O’Donnell, M. J. Tetrahedron
988, 44, 5253. Ohfune, Y. Acc. Chem. Res. 1992, 25, 360. Williams, R.
M. Synthesis of Optically ActiVe R-Amino Acids; Pergamon Press: Oxford,
989.
2) Schmidt, U.; Lieberknecht, A.; Wild, J. Synthesis 1988, 159. Noyori,
1
(6) Inanaga, J.; Baba, Y.; Hanamoto, T. Chem. Lett. 1993, 241.
(7) This compound has been satisfactorily characterized.
(8) Barluenga, J.; Ferrero, M.; Palacios, F. J. Chem. Soc., Perkin Trans.
1 1990, 2193. Also, see: Easton, C. J.; Hutton, C. A.; Roselt, P. D.; Tiekink,
E. R. T. Tetrahedron 1994, 50, 7327; Aust. J. Chem. 1991, 44, 687.
(9) (a) Julia, S.; Ginebreda, A.; Guixer, J. Chem. Commun. 1978, 742.
Wada, M.; Sano, T.; Mitsunobu, O. Bull. Chem. Soc. Jpn. 1973, 46, 2833.
(10) Yonezawa, Y.; Shin, C. G.; Ono, Y.; Yoshimura, J. Bull. Chem.
Soc. Jpn. 1980, 53, 2905.
1
(
R. Asymmetric Catalysis in Organic Synthesis; Wiley-Interscience: New
York, 1994; pp 16-28. Inoguchi, K.; Sakuraba, S.; Achiwa, K. Synlett 1992,
1
69. Ojima, I., Ed. Catalytic Asymmetric Synthesis; VCH Publishers:
Weinheim, 1993; Chapter 2.
(
3) Trost, B. M.; Kazmaier, U. J. Am. Chem. Soc. 1992, 114, 7933. Guo,
C.; Lu, X. J. Chem. Soc., Perkin Trans. 1 1993, 1921. Rychnovsky, S. D.;
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(11) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995, 36,
6373.
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