40
G. Vo-Thanh et al.
LETTER
(13) Huwe, C. M.; Kiehl, O; C; Blechert, S Synlett 1996, 65.
NaHCO3 followed by filtration. Imidate 25 was not
stored, but directly put in solution in a 1/7 (v/v) mixture of
THF and 0.3 N aqueous HCl. Stirring for 24 h at room
temperature under an argon atmosphere led almost quan-
titatively to aminoester hydrochloride 26. This disubsti-
tuted aminoester proved much more resistant to acidic
hydrolysis than its monosubstituted analogue bearing no
substituent next to the carbonyl function.2 Final conver-
sion to the aminoacid was finally achieved by treatment
with 20% aqueous HCl at reflux for 1 h. The crude amino
acid hydrochloride thus obtained was purified by ion-ex-
change chromatography and reprecipitated as its hydro-
chloride salt 27. Compound 27 (2R, 5S) was obtained in
> 95% de (NMR analysis) and in 75% yield from dihydro-
pyridone 24. The racemic R*R* amino acid hydrochloride
was similarly obtained from N-deprotected R*R* dihy-
dropyridone.
(14) (a) Ugi, I.; Lohberger, S.; Karl, R. in Comprehensive Organic
Synthesis, B. M. Trost and I. Fleming Eds, Pergamon Press
1991, vol. 2, p. 1083. (b) Most recent review: Dömling, A.;
Ugi, I. Angew. Chem. Int. Ed. Engl. 2000, 39, 3168.
(15) Baussanne, I.; Chiaroni, A.; Husson, H.-P.; Riche, C.; Royer,
J. Tetrahedron Lett. 1994, 35, 3931.
(16) Dudot, B.; Micouin, L.; Baussanne, I.; Royer, J. Synthesis
1999, 688.
(17) All compounds in this series were fully characterized by
spectroscopy (1H and 13C NMR, IR), and by combustion
analysis or HRMS in the case of 23, 24 and 27. Selected data:
(3R,6S)-N-[(2,4-dimethoxyphenyl)methyl]-3,6-dibenzyl-
3,6-dihydro-2-pyridone 23: 1H NMR (250 MHz, toluene d8)
d 7.46 (d, J = 8.2 Hz, 1H); 7.16-6.87 (m, 10H); 6.31 (m, 2H);
5.64 (d, J = 14.8 Hz, 1 H); 5.25 (dd, J = 10.3, 3.9 Hz, 1H);
5.18 (dd, J = 10.3, 3.9 Hz, 1H); 4.33 (d, J = 14.8 Hz, 1 H);
3.91 (m, 1H); 3.37 (s, 3H); 3.32 (s, 3H); 3.14 (m, 1H); 2.92
and 2.33 (two dd, ABX system, JAB = 12.8 Hz, JAX = 3.9 Hz,
J
BX = 8.7 Hz, (1+1)H); 2.63 and 1.85 (two dd, ABX system,
JAB = 13.0 Hz, JAX = 3.3 Hz, JBX = 8.6 Hz, (1+1)H). 13C NMR:
d 170.2; 160.1; 158.4; 138.6; 136.5; 130.7; 129.8; 129.5;
128.1; 128.0; 126.5; 126.2; 125.7; 124.9; 117.5;104.3; 98.2;
57.7; 55.24; 55.2; 43.7; 40.5; 39.8; 39.4. HRMS (EI): calc for
C28H29NO3 [M+]427.2153, found 427.2147.
Acknowledgement
We thank the Aventis-Pharma Company for financial support (to V.
B. and G. V.-T.) and Dr J.-F. Peyronel and Dr F. Clerc for very fruit-
ful discussions.
(3R*,6R*)-N-[(2,4-dimethoxyphenyl)methyl]-3,6-
dibenzyl-3,6-dihydro-2-pyridone: 1H NMR (250 MHz,
toluene d8) d 7.2-6.8 (m, 11 H), 6.34 (d, J = 2.3 Hz, 1H), 6.30
(dd, J = 8.3, 2.3 Hz, 1H), 5.63 (d, J = 14.8 Hz, 1H), 5.38 (dd,
J = 10.1, 2.1 Hz, 1H), 5.23 (ddd, J = 10.0, 4.5, 2.4 Hz, 1H);
4.32 (d, J = 14.8 Hz, 1H), 3.88 (m, 1H), 3.38 (s, 3H), 3.30 (s,
3H), 3.18 and 3.08 (two dd, ABX system, JAB = 13.2 Hz,
References and Notes
(1) Most recent review about olefin metathesis catalyzed by new
Grubbs’ ruthenium or Schrock’s molybdenum catalysts:
Fürstner, A. Angew. Chem. Int. Ed. Engl. 2000, 39, 3012.
(2) Garro-Hélion, F.; Guibé, F. Chem. Commun. 1996, 641.
(3) Sauriat-Dorizon, H.; Guibé, F. Tetrahedron Lett. 1998, 39,
6711.
(4) For a recent review dealing with application of RCM to the
synthesis of nitrogen-containing heterocycles and
peptidomimetics, see Phillips, A. J.; Abell, A. D. Aldrichimica
Acta 1999 3, 32.
J
AX = 4.0 Hz, JBX = 8.0 Hz, (1+1) H), 2.70 and 2.55 (two dd,
ABX system, JAB = 13.0 Hz, JAX = 7.1 Hz, JBX = 3.5 Hz, (1+1)
H), 2.40 (m, 1H).
(3R,6S)-3,6-dibenzyl-3,6-dihydro-2-pyridone 24 and its
(3R*,6R*) diastereoisomer: see reference 3.
(3R,6S)-3,6-dibenzyl-2-ethoxy-3,6-dihydropyridine 25: 1H
NMR (250 MHz, CD2Cl2): d 7.4-6.9 (m, 10H); 5.65 (ddd,
J = 10.2, 1.5, 1.0 Hz, 1H); 5.5 (dd, J = 10.2, 3.9 Hz, 1H); 4.2-
3.95 (m, 3H); 3.0 (m, 1H); 2.8 (dd, J = 13.2 Hz, 3.9 Hz, 1H);
2.9-2.47 (m, 2H); 2.07 (dd, J = 12.8, 7.3 Hz); 1.3 (t, J = 7.7
Hz, 3H).
(5) The RCM reactions were run in Schlenk tubes under argon
atmosphere and in degassed solvents. All new compounds
described in this communication have been characterized by
NMR spectroscopy and GC/MS.
(Z)-(2R,5S)-2-benzyl-5-amino-6-phenyl-3-hexenoic acid,
hydrochloride salt 27: [a]20D = - 69.3 (c 0.07, D2O); 1H NMR
(200 MHz, D2O): d 7.2-6.9 (m, 10H); 5.55 (t, J = 11.5 Hz,
1H); 5.30 (t, J = 10.6 Hz, 1H); 4.0 (broad q, 1H); 3.22 (broad
q, 1H); 2.55 and 2.15 (two dd, ABX system, JAB = ca 13.5 Hz,
JAX = ca 6.5 Hz, JBX = ca 8.5 Hz, (1+1)H); 2.53 and 2.05 (two
dd, ABX system, JAB = ca 13.5 Hz, JAX = ca 7.0 Hz, JBX = ca
7.5 Hz, (1+1)H). 13C NMR (D2O): d 177.0, 134.9, 133.1,
129.6, 129.1, 128.9, 128.5, 127.4, 126.6, 49.8, 46.4, 37.4,
38.5; Anal. Calcd for C19H22NO2Cl. 2.2 H2O: C: 61.47, H:
7.16, N: 3.77. Found: C: 61.47, H: 7.05, N: 3.76.
(6) Piscopio, A. D.; Miller, J. F.; Koch, K. Tetrahedron Lett.
1997, 38, 7143; Piscopio, A. D.; Miller, J. F.; Koch, K.
Tetrahedron Lett. 1998, 39, 2667.
(7) Miller, S. J.; Kim, S.-H.; Chen, Z.-R.; Grubbs, R. H. J. Am.
Chem. Soc. 1995, 117, 2108.
(8) For a recent review on the synthesis of medium-sized rings by
the RCM reaction, see: Maier, M. E. Angew. Chem. Int. Ed.
Engl. 2000, 39, 2073.
(9) Beal, L. M.; Moeller, K. D. Tetrahedron Lett. 1998, 39, 4639.
(10) Groossmith, C. E.; Senia, F.; Wagner, J. Synlett 1999, 1660.
(11) Goldring, W. P. D.; Hodder, A. S.; Weiler, L. Tetrahedron
Lett. 1998, 39, 4955.
(12) See for instance: Fink, B. E.; Kym, P. R.; Katzenellenbogen,
J. A. J. Am. Chem. Soc. 1998, 63, 2133 (ten-membered ring);
Fürstner, A.; Thiel, O. R.; Ackermann, L.; Schanz, H.-J.;
Nolan, S. P. J. Org. Chem. 2000, 65, 2204 (eighteen-
membered ring).
(18) Boeckman, R. K. Jr; Weidner, C. H.; Perni, R. B.; Napier, J.
S. J. Am. Chem. Soc. 1989, 111, 8036.
Article Identifier:
1437-2096,E;2001,0,01,0037,0040,ftx,en;G21200ST.pdf
Synlett 2001, No. 1, 37–40 ISSN 0936-5214 © Thieme Stuttgart · New York