8406
M. J. O’Donnell et al. / Tetrahedron Letters 44 (2003) 8403–8406
(4×0.5 min). Fmoc-Cl (516 mg, 10 equiv.) was dissolved
in NMP (2 mL), added to the resin, and acylation was
started by addition of DIEA (680 mL, 20 equiv.). Reaction
mixture was rotated for 24 h at 25°C. The resin was
washed with NMP, THF, and CH2Cl2 (4×0.5 min each).
1-[[(9H-Fluoren-9-ylmethoxy)carbonyl]amino]cyclo pro-
panecarboxylic acid (10a). Using 1-bromo-2-chloroethane
1
(166 mL, 10 equiv.) in the alkylation step. H NMR
(CD3OD+CDCl3, 3:1 mixture of two rotamers) l 0.94–
1.04 (m, 0.5H), 1.08–1.22 (m, 1.5H), 1.34–1.44 (m, 0.5H),
1.44–1.58 (m, 1.5H), 4.26 (t, J=6.9 Hz, 1H), 4.37 (d,
J=6.6 Hz, 1.5H), 4.46 (d, J=6.0 Hz, 0.5H), 7.26–7.48
(m, 4H), 7.69 (d, J=7.5 Hz, 2H), 7.81 (d, J=7.5 Hz, 2H);
13C NMR (CD3OD+CDCl3, mixture of two rotamers) l
17.9, 34.8, 48.3, 67.8, 120.8, 126.1, 128.0, 128.6, 142.4,
145.1, 159.1, 176.7.
Cleavage and purification. The resin was cleaved with
TFA–Et3SiH (95:5, 1×2 h, 1×30 min). Filtrates were
collected, combined with TFA–CH2Cl2 washes (1:3, 2×2
min) of the resin, and evaporated. Crude products were
purified over silica gel with CHCl3–THF–HOAc (92:8:1).
6-Chloro-2-[[(9H-fluoren-9-ylmethoxy)carbonyl] amino]-
hexanoic acid (4c). Using 1-bromo-4-chlorobutane (230
mL, 10 equiv.) in the alkylation step. 1H NMR (CD3OD)
l 1.48–1.66 (m, 2H), 1.66–2.00 (m, 4H), 3.61 (t, J=6.6
Hz, 2H), 4.14–4.24 (m, 1H), 4.27 (t, J=6.6 Hz, 1H), 4.40
(d, J=6.6 Hz, 2H), 7.30–7.48 (m, 4H), 7.64–7.76 (m, 2H),
7.84 (d, J=7.2 Hz, 2H); 13C NMR (CD3OD) l 24.3, 32.0,
33.2, 45.4, 48.6, 55.2, 67.9, 120.9, 126.2, 128.1, 128.7,
142.6, 145.2, 145.4, 158.7, 175.9.
Acknowledgements
We gratefully acknowledge the financial support of Lilly
Research Laboratories and NIH (GM 28193).
References
6-Cyano-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-
hexanoic acid (6c). Using 1-bromo-4-chlorobutane (230
mL, 10 equiv.) in the alkylation step. 1H NMR (CD3OD)
l 1.50–1.65 (m, 2H), 1.65–1.85 (m, 3H), 1.85–2.00 (m,
1H), 2.49 (t, J=6.9 Hz, 2H), 4.15–4.25 (m, 1H), 4.27 (t,
J=7.5 Hz, 1H), 4.41 (d, J=7.5 Hz, 2H), 7.30–7.52 (m,
4H), 7.62–7.78 (m, 2H), 7.84 (d, J=7.5 Hz, 2H); 13C NMR
(CD3OD) l 17.2, 26.0, 26.1, 31.9, 48.8, 55.1, 67.9, 120.9,
121.0, 126.3, 128.2, 128.8, 142.6, 145.2, 145.3, 158.7,
175.7.
1. For lead references, see: Asymmetric Synthesis of Novel
Sterically Constrained Amino Acids; Symposium-in-Print,
Hruby, V. J.; Soloshonok, V. A., Eds. Tetrahedron 2001,
57, 6329–6650.
2. Scott, W. L.; O’Donnell, M. J.; Delgado, F.; Alsina, J. J.
Org. Chem. 2002, 67, 2960–2969.
3. Scott, W. L.; Alsina, J.; O’Donnell, M. J. J. Comb. Chem.
2003, 5, 684–692.
4. For selected reports of solution-phase synthesis and use
of v-halo-a-amino acid derivatives, see footnote 11 in
Ref. 2.
5. For recent reviews concerning the solution-phase synthe-
sis of cyclic amino acid derivatives, see: (a) Cativiela, C.;
D´ıaz-de-Villegas, M. D. Tetrahedron: Asymmetry 2000,
11, 645–732. (b) Park, K.-H.; Kurth, M. J. Tetrahedron
2002, 58, 8629–8659.
Alternative synthetic procedure for proline derivatives
Intramolecular cyclization of the resin-bound alkylated
products. The resin-bound amine 3 (200 mmol) was washed
with NMP (4×0.5 min). 10% DIEA in NMP (4 mL) was
added to the resin and the reaction mixture was rotated
for 24 h at 25°C. The resin was washed with NMP and
CH2Cl2 (4×0.5 min each).
6. For examples of applications of organic-soluble, nonionic
phosphazine bases BEMP and BTPP from earlier studies,
see Refs. 2 and 3.
7. For reports on the solid-phase synthesis of proline deriva-
tives, see footnote 4 in Ref. 3.
8. For the solution-phase synthesis of similar derivatives
using this methodology, see: O’Donnell, M. J.; Bruder,
W. A.; Eckrich, T. M.; Shullenberger, D. F.; Staten, G. S.
Synthesis 1984, 127–128.
9. For the solid-phase preparation of analogs of 10c under
similar conditions, see: Bhandari, A.; Jones, D. G.;
Schullek, J. R.; Vo, K.; Schunk, C. A.; Tamanaha, L. L.;
Chen, D.; Yuan, Z.; Needels, M. C.; Gallop, M. A.
Bioorg. Med. Chem. Lett. 1998, 8, 2303–2308.
10. Colman, R. F. In Protein Function, 2nd Ed.; Creighton,
T. E., Ed.; IRL Press: Oxford, UK, 1997; pp. 155–183.
11. (a) McNamara, L. M. A.; Andrews, M. J. I.; Mitzel, F.;
Siligardi, G.; Tabor, A. B. J. Org. Chem. 2001, 66,
4585–4594; (b) Blackwell, H. E.; Sadowsky, J. D.;
Howard, R. J.; Sampson, J. N.; Chao, J. A.; Steinmetz,
W. E.; O’Leary, D. J.; Grubbs, R. H. J. Org. Chem. 2001,
66, 5291–5302.
1-(9H-Fluoren-9-ylmethyl) hydrogen 1,2-piperidine dicar-
boxylate (8c). Using 1-bromo-4-chlorobutane (230 mL, 10
1
equiv.) in the alkylation step. H NMR (CD3OD, 3:2
mixture of two rotamers) l 1.24–1.54 (m, 2H), 1.54–1.82
(m, 3H), 2.16–2.36 (m, 1H), 2.94–3.20 (m, 1H), 3.88–4.10
(m, 1H), 4.22–4.36 (m, 1H), 4.36–4.52 (m, 2H), 4.68 (d,
J=5.1 Hz, 0.4 H), 4.83 (d, J=5.1 Hz, 0.6 H), 7.28–7.50
(m, 4H), 7.56–7.72 (m, 2H), 7.84 (m, 2H); 13C NMR
(CD3OD, mixture of two rotamers) l 21.7, 25.7, 25.8,
27.8, 42.8. 43.0, 48.6, 55.6, 55.8, 68.8, 120.9, 126.1, 128.2,
128.8, 142.6, 145.2, 145.2, 145.3, 145.4, 157.8, 158.1,
174.6.
Alternative synthetic procedure for spiro derivatives
Intramolecular cyclization by Ca-alkylation of the resin-
bound alkylated products. Resin 2 (200 mmol) was washed
with NMP (2×0.5 min). Spiro formation was carried out
in a glass vessel by adding BTPP (612 mL, 10 equiv.) in
NMP (2 mL) to the resin. Reaction mixture was heated
at 85°C for 24 h with occasional stirring. Resin was
washed with NMP and CH2Cl2 (4×0.5 min each).
12. Equipment and general procedures for parallel manual
solid-phase organic synthesis are described in Refs. 2 and
3.