A. Córdova et al.
Compounds 2d and 2d’: HPLC (Daicel Chiralpak AD, iso-hexanes/
iPrOH=90:10, flow rate 0.5 mLminÀ1, l=254 nm): 2d major isomer:
tR =84.18 min; minor isomer: tR =71.50 min; 2d’ major isomer: tR =
54.90 min; minor isomer: tR =51.60 min; [a]2D5 =À32.0 (c=1.4, CHCl3);
1H NMR (400 MHz, CDCl3): d=1.07 (dd, J=6.8 Hz, 6H), 1.62–1.74 (m,
2H), 1.87–1.93 (m, 4H), 1.96–2.03 (m, 4H), 2.39–2.44 (m, 2H), 2.92–2.97
(m, 2H), 3.65 (s, 3H; OMe), 3.66 (s, 3H; OMe), 4.78 (d, J=4.1 Hz, 2H),
6.45 (d, J=9.0 Hz, 4H), 6.66 (d, J=8.9 Hz, 4H), 7.53 (d, J=8.8 Hz, 4H),
8.13 ppm (d, J=8.8 Hz, 4H); 13C NMR (100 MHz, CDCl3) d=26.9, 32.9,
34.9, 35.2, 38.9, 41.1, 52.8, 55.8, 58.8, 114.9, 115.8, 123.8, 128.7, 140.9,
147.2, 150.1, 152.8, 210.9 ppm.
DMFwere removed under reduced pressure. The crude product was ob-
tained as a yellowish solid. 1H NMR (400 MHz, CDCl3) of the crude
Cbz–alanine–tetrazole: d=1.59 (d, J=6.9 Hz, 3H), 5.07 (m, 2H), 5.22
(m, 1H), 6.19 (brs, 1H), 7.28 ppm (m, 5H). The Cbz–alanine–tetrazole
(825 mg) was dissolved in MeOH (10 mL) and a catalytic amount of Pd/
C was added. After 17 h, the catalyst was filtered off by using celite and
the solvent was removed under reduced pressure to quantitatively give
alanine–tetrazole 9 as a white solid. 1H NMR (400 MHz, [D6]DMSO):
d=1.41 (d, J=6.8 Hz, 3H), 4.51 ppm (m, 1H); 13C NMR (100 MHz,
[D6]DMSO): d=20.2, 44.4, 161.0 ppm.
Compound 2e: HPLC (Daicel Chiralpak AS, iso-hexanes/iPrOH=94:6,
flow rate 0.5 mLminÀ1, l=254 nm): major isomer: tR =31.10 min; minor
isomer: tR =42.80 min; [a]2D5 =À71.0 (c=1.0, CHCl3); 1H NMR
(400 MHz, CDCl3) d=1.19–1.26 (m, 6H), 2.23 (s, 3H; CH3) 3.04 (m,
1H), 3.67 (s, 3H; OMe), 4.10–4.20 (m, 2H), 4.32 (m, 1H), 6.65 (d, J=
8.9 Hz, 2H), 6.76 ppm (d, J=8.9 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d=12.1, 14.1, 28.4, 49.1, 55.5, 59.4, 114.7, 115.7, 140.5, 140.7, 153.0, 172.7,
209.2 ppm.
Acknowledgements
We gratefully acknowledge the Swedish National Research Council, the
Lars Hierta Foundation, the Carl Trygger Foundation, and the Wenner–
Gren Foundation for financial support.
Compound 2 f: HPLC (Daicel Chiralpak AS, iso-hexanes/iPrOH=97:3,
flow rate 0.5 mLminÀ1, l=254 nm): major isomer: tR =33.20 min; minor
isomer: tR =29.39 min; [a]D25 =À2.3 (c=1.0, CHCl3); 1H NMR (400 MHz,
CDCl3) d=1.10 (d, J=7.0 Hz, 3H; CH3), 2.16 (s, 3H; CH3) 2.99–3.06 (m,
1H), 3.67 (s, 3H; OMe), 4.77 (d, J=5.1 Hz, 1H), 6.41 (d, J=8.8 Hz, 1H),
6.67 (d, J=8.8 Hz, 2H), 7.52 (d, J=8.8, 2H), 8.18 ppm (d, J=8.7, 2H);
13C NMR (100 MHz, CDCl3) d=11.2, 29.5, 52.7, 55.8, 59.4, 115.0, 115.2,
124.1, 128.2, 140.4, 147.4, 128.2, 140.4, 147.4, 149.6, 153.0, 209.9 ppm.
[1] C. Mannich, W. Krçsche, Arch. Pharm. 1912, 250, 647.
[2] For excellent reviews, see: a) E. F. Kleinmann in Comprehensive Or-
ganic Synthesis, Vol. 2 (Eds.: B. M. Trost, I. Flemming), Pergamon
Press, New York, 1991, Chapter 4.1; b) M. Arend, N. Westerman,
N. Risch, Angew. Chem. 1998, 110, 1096; Angew. Chem. Int. Ed.
1998, 37, 1044; c) S. Denmark, O. J.-C. Nicaise in Comprehensive
Asymmetric Catalysis, Vol. 2 (Eds.: E. N. Jacobsen, A. Pfaltz, H. Ya-
momoto), Springer, Berlin, 1999, p. 93; d) M. Tramontini, L. An-
giolini, Tetrahedron 1990, 46, 1791; e) H. Hellmann, G. Optiz, a-
Aminoalkylierung, VCH, Weinheim, 1960, p. 1; f) For examples,
see: Enantioselective Synthesis of b-Amino Acids (Ed.: E. Juaristi),
Wiley-VCH, Weinheim, 1997; for a review of multicomponent re-
actions, see: D. J. Ramón, M. Yus, Angew. Chem. 2005, 117, 1628;
Angew. Chem. Int. Ed. 2005, 44, 1602.
[3] a) R. Kober, K. Papadopoulos, W. Miltz, D. Enders, W. Steglich, H.
Reuter, H. Puff, Tetrahedron 1985, 41, 1693; b) D. Enders, S. Ober-
bçrsch, J. Adam, Synlett 2000, 644; c) D. Seebach, M. Hoffmann,
Eur. J. Org. Chem. 1998, 1337; d) Y. Aoyagi, R. P. Jain, R. M. Wil-
liams, J. Am. Chem. Soc. 2001, 123, 3472, and references therein;
e) U. Schçllkopf in Topics in Current Chemistry, Vol. 109 (Ed.: F. L.
Boschke), Springer, Berlin, 1983, pp. 45–85; f) D. A. Evans, F.
Urpi, T. C. Somers, J. S. Clark, M. T. Bilodeau, J. Am. Chem. Soc.
1990, 112, 8215; g) C. Palomo, M. Oiarbide, A. Landa, M. C. Gon-
zales-Rego, J. M. Garcia, A. Gonzales, J. M. Odriozola, M. Martin-
Pastor, A. Linden, J. Am. Chem. Soc. 2002, 124, 8637, and referen-
ces therein.
Compound 2g: HPLC (Daicel Chiralpak AD, iso-hexanes/iPrOH=97:3,
flow rate 0.5 mLminÀ1, l=254 nm): major isomer: tR =32.95 min; minor
isomer: tR =37.41 min; [a]2D5 =À15.8 (c=1.0, CHCl3); 1H NMR
(400 MHz, CDCl3): d=1.23 (t, J=7.1 Hz, 3H), 1.44 (s, 3H; CH3), 1.44 (s,
3H; CH3), 1.49 (s, 3H; CH3), 3.72 (s, 3H; OMe), 4.01 (d, J=16.6 Hz,
1H), 4.14 (m, 2H), 4.29 (dd, J=16.4, 1.5 Hz, 1H), 4.58 (d, J=2.0 Hz,
1H), 4.73 (m, 1H), 6.72–6.77 ppm (m, 4H); 13C NMR (100 MHz, CDCl3):
d=14.4, 23.5, 24.5, 55.8, 59.1, 61.7, 67.0, 67.3, 101.1, 114.9, 117.2, 141.1,
153.8, 171.5, 206.5 ppm.
Synthesis of alanine–tetrazole (9): NH4HCO3 (0.89 g, 1.26 equiv) was
added to a solution of Boc2O (2.5 g, 1.3 equiv; Boc=1,1-dimethylethoxy-
carbonyl) and Cbz–Ala (2.0 g; Cbz=phenylmethoxycarbonyl) in MeCN
(14 mL) and pyridine (Py, 2.2 mL, 3 equiv), and the reaction mixture was
stirred overnight at RT. The solvents were removed by evaporation and
the residue was dissolved in EtOAc and washed with water (215 mL).
The water was re-extracted with EtOAc and the combined volume of
EtOAc was dried over MgSO4, filtered, and concentrated. The crude
product was weakly UV active and had an Rf value of 0.42 (MeOH/DCM
1:9). 1H NMR (400 MHz, CDCl3) of the crude Cbz–alanine–amide: d=
1.41 (d, J=7.1 Hz, 3H), 4.29 (m, 1H), 5.17 (m, 2H), 5.39 (brs, 1H), 6.11
(brs, 1H), 7.27 ppm (m, 5H).
[4] a) S. Kobayashi, H. Ishitani, Chem. Rev. 1999, 99, 1069; b) A. Córdo-
va, Acc. Chem. Res. 2004, 37, 102.
Next, POCl3 (0.55 mL, 1.2 equiv in DCM (5 mL)) was added dropwise to
a solution of Cbz–alanine–amide (1.1 g) in Py (10 mL) at À108C, and the
resulting mixture was stirred for 3 h. When the starting material was ob-
served as “depleted” by TLC analysis (MeOH/DCM 1:9), the mixture
was poured onto ice (ca. 30 g). The organic phase was separated and the
pyridine was removed by repeated washing with a hot, concentrated
CuSO4 solution. The organic phase was then predried with brine and
later dried over MgSO4. Filtration and concentration afforded the crude
product as an oil. Rf =0.51 (MeOH/DCM 1:9); 1H NMR (400 MHz,
CDCl3) of the crude Cbz–alanine–nitrile: d=1.41 (d, J=6.8 Hz, 3H),
4.65 (m, 1H), 5.17 (m, 2H), 5.39 (brs, 1H), 7.28 ppm (m, 5H).
[5] a) H. Ishitani, M. Ueno, S. Kobayashi, J. Am. Chem. Soc. 1997, 119,
7153; b) S. Kobayashi, T. Hamada, K. Manabe, J. Am. Chem. Soc.
2002, 124, 5640; c) H. Ishitani, M. Ueno, S. Kobayashi, Org. Lett.
2002, 4, 143; d) H. Ishitani, S. Ueno, S. Kobayashi, J. Am. Chem.
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Chem. Soc. 1997, 119, 7153.
[7] a) E. Hagiwara, A. Fujii, M. Sodeoka, J. Am. Chem. Soc. 1998, 120,
2474; b) A. Fujii, E. Hagiwara, M. Sodeoka, J. Am. Chem. Soc.
1999, 121, 545; c) Y. Hamashima, K. Yagi, H. Tamas, M. Sodeoka, J.
Am. Chem. Soc. 2002, 124, 14530; d) Y. Hamashima, M. Hotta, M.
Sodeoka, J. Am. Chem. Soc. 2002, 124, 11240; e) D. Ferraris, B.
Young, T. Dudding, T. Lectka, J. Am. Chem. Soc. 1998, 120, 4548;
f) D. Ferraris, B. Young, C. Cox, W. J. Drury III, T. Dudding, T.
Lectka, J. Org. Chem. 1998, 63, 6090; g) D. Ferraris, B. Young, C.
Cox, T. Dudding, W. J. Drury III, L. Ryzhkov, T. Taggi, T. Lectka, J.
Am. Chem. Soc. 2002, 124, 67; See also this excellent report:
h) W. S. Josephsohn, M. L. Snapper, A. H. Hoveyda, J. Am. Chem.
Soc. 2004, 126, 3734.
NaN3 (300 mg, 1.1 equiv) and NH4Cl (256 mg, 1.15 equiv) were simulta-
neously added to a solution of crude Cbz–alanine–nitrile (850 mg) in
DMF(13 mL). The reaction mixture was heated to 90–95 8C and kept at
this temperature (3 h) until the TLC (HOAc/EtOAc 1:99) spot at Rf =
0.63 did not increase in strength. The reaction mixture was poured onto
ice (30 g), acidified to a pH close to 2 with 2m HCl, and then extracted
with CHCl3 (320 mL). The organic phase was washed with water
(20 mL), then predried with brine (20 mL), and finally dried over MgSO4
before filtration and removal of the solvent by evaporation. Traces of
[8] S. Yamasaki, T. Iida, M. Shibasaki, Tetrahedron Lett. 1999, 40, 307.
7028
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Chem. Eur. J. 2005, 11, 7024 – 7029