5088
R. Millet et al. / Tetrahedron Letters 43 (2002) 5087–5088
unsaturated bond in their structure, a determined stereo-
chemistry, and mimic Ala-Pro.
1994, 35, 4091–4092; (c) Lombart, H.-G.; Lubell, W. D. J.
Org. Chem. 1996, 61, 9437–9446; (d) Kim, H.-O.; Kahn,
M. Tetrahedron Lett. 1997, 38, 6483–6484; (e) Wang, W.;
Xiong, C.; Hruby, V. J. Tetrahedron Lett. 2001, 42,
3159–3161; (f) Dragovich, P. S.; Zhou, R.; Prins, T. J. J.
Org. Chem. 2002, 67, 741–746.
The synthesis of the 6,5-fused bicyclic skeleton (1a,b) is
outlined in Scheme 1 and represents an extension of the
previously described chemistry.4 The strategy adopted to
synthesize enantiomerically pure azabicycloalkanes 1a
and 1b uses configurationally pure enaminoesters 7
coming from a Michael addition5 on Cbz-protected
dihydroalanine 8 followed by an in situ cyclization
4. (a) Millet, R.; Rigo, B.; Houssin, R.; He´nichart, J.-P. J.
Heterocyclic Chem. 1999, 36, 1279–1284; (b) Millet, R.;
Meulon, E.;Goossens, L.;Rigo, B.;Houssin, R.;He´nichart,
J.-P. J. Heterocyclic Chem. 2000, 37, 1491–1494.
5. Capps, N. K.; Davies, G. M.; Loakes, D.; McCabe, R. W.;
Young, D. W. J. Chem. Soc., Perkin Trans. 1 1991,
3077–3086.
promoted
by
1-ethyl-3-(3%-dimethylaminopropyl)-
carbodiimide (WSC).6
6. Kopple, K. D.; Nitecki, D. E. J. Am. Chem. Soc. 1962, 84,
4457–4464.
7. Nagasaka, T.; Tsukada, A.; Hamaguchi, F. Heterocycles
1986, 24, 2015–2022.
Enantiomerically pure enaminoester 5 was obtained by
modifying a previously described7 procedure which used
L
-methyl pyroglutamate 2 as starting material. The
conversion of lactame 2 into iminoether 3 was achieved
with dimethyl sulfate and triethylamine and the following
condensation with Meldrum’s acid afforded good yield
of the enaminoester 4. The next step applied the procedure
of Nagasaka7 to break the Meldrum’s ring of compound
5. This method which used boron trifluoride etherate in
refluxing benzene with MeOH afforded no racemization
and enaminoester 5 was proved to be the Z-isomer, in
accordance with reported results.8 Cyclization into bicy-
clolactame 7 was performed in CH2Cl2 at room temper-
ature with N-benzyloxycarbonyl dehydroalanine 89 and
WSC to accelerate the cyclization of carboxylic acid 6 into
lactames 7. The diastereoisomeric mixture 7a,b was
detected by 1H NMR and HPLC10a and easily separated
by preparative HPLC10b performed by an isocratic run.
Configurational assignments of the two diastereoisomers
7a and 7b were supported by ROESY 1H NMR. A
cross-peak between H3 and H6 was detected for 7a making
it possible to distinguish the cis (7a) from the trans isomer
(7b). In addition, the NMR analysis revealed that the
former was predominant.
8. (a) It was checked by NMR ROESY and COSY that, as
other b-enaminoesters,7,8b only the Z-isomer was obtained;
(b) Ce´lerier, J.-P.; Deloisy, E.; Lhommet, G.; Maitte, P. J.
Org. Chem. 1979, 44, 3089–3089.
9. Kolar, A. J.; Olsen, R. K. Synthesis 1977, 457–459.
10. (a) HPLC were performed at flow rates of 1 mL/min, using
three different conditions: condition A, a gradient run from
100%eluentA(0.05%TFAinH2O)to100%eluentB(0.05%
TFA, 20% H2O, 80% CH3CN) over the next 30 min with
,
C18 Vydac column (4×300 mm, 5 mm, 100 A); condition B,
an isocratic run from eluent (0.1% TFA, 50% H2O, 50%
MeOH) with C18 Kromasil column (4.6×150 mm, 5 mm, 100
,
A); condition C, an isocratic run from eluent (0.1% TFA,
54% H2O, 46% MeOH) with C18 Kromasil column (4.6×150
,
mm, 5 mm, 100 A); (b) Separation of diastereoisomeric
mixture 7a,b was performed by preparative HPLC at flow
rates 20 mL/min using C18 Kromasil column (21×250 mm,
,
10 mm, 100 A) with an isocratic run from eluent (0.1% TFA,
50% H2O, 50% MeOH).
1
11. Compound 7a: H NMR (DMSO-d6, 300 MHz): l 1.85–
2.01 (m, 1H), 2.17–2.24 (m, 1H), 2.42–2.54 (m, 1H),
2.68–2.82 (m, 2H), 3.10–3.18 (m, 1H), 3.57 (s, 3H), 3.58 (s,
3H), 4.09–4.16 (m, 1H), 4.62 (dd, 1H, J=9.5 Hz, J%=2.0
Hz), 4.96 (s, 2H), 7.20–7.31 (m, 5H), 7.61 (d, 1H, J=8.2
Hz); MS (ESI) m/z 403 [M+H]+, 425 [M+Na]+, 441 [M+K]+;
HPLC (condition A) tR 19.9 min, (condition B) tR 17.4 min.
The azabicycloalkanes11 1a,b were finally obtained via
hydrolysis of diesters 7a,b with LiOH in dioxane/H2O
followed by neutralization and regioselective decarboxy-
lation of the 8-carboxylic function with 2N HCl. The
reaction was monitored by HPLC: after 4 h, a single
isomer 1a or 1b was formed, indicating that no epimer-
ization occurred at C-3 or C-6 of the indolizine ring.
1
Compound 7b: H NMR (DMSO-d6, 300 MHz): l 1.89–
2.01 (m, 1H), 2.17–2.24 (m, 1H), 2.42–2.54 (m, 1H),
2.68–2.82 (m, 2H), 3.05–3.18 (m, 1H), 3.57 (s, 3H), 3.58 (s,
3H), 4.19–4.27 (m, 1H), 4.55 (dd, 1H, J=9.2 Hz, J%=3.7
Hz), 4.96 (s, 2H), 7.21–7.28 (m, 5H), 7.58 (d, 1H, J=8.2
Hz); MS (ESI) m/z 403 [M+H]+, 425 [M+Na]+, 441 [M+K]+;
HPLC (condition A) tR 19.9 min, (condition B) tR 16.3 min.
In conclusion, we described a convenient and efficient
method to prepare a stereochemically pure 6,5-bicyclic
lactam peptidomimetic that can be incorporated as a
building unit into the drug design peptidic block.
1
Compound 1a: H NMR (DMSO-d6, 300 MHz): l 1.80–
2.00 (m, 1H), 2.05–2.20 (m, 2H), 2.27–2.35 (m, 1H),
2.38–2.44 (m, 1H), 2.75–2.95 (m, 1H), 4.10–4.20 (m, 1H),
4.42–4.45(m, 1H), 4.60–4.65(m, 1H), 4.97(s, 2H), 7.23–7.34
(m, 5H), 7.64 (d, 1H, J=8.3 Hz); MS (ESI) m/z 331 [M+H]+,
353 [M+Na]+, 369 [M+K]+; HPLC (condition A) tR 12.0
min, (condition C) tR 13.7 min.
References
1. Hanessian, S.; McNaughton-Smith, G.; Lombart, H.-G.;
Lubell, W. D. Tetrahedron Lett. 1997, 38, 12789–12854.
2. (a) Millet, R.; Goossens, L.; Goossens, J.-F.; Chavatte, P.;
Bertrand-Caumont, K.; Houssin, R.; He´nichart, J.-P. J.
Pept. Sci. 2001, 6, 323–330; (b) Millet, R.; Goossens, L.;
Bertrand-Caumont, K.; Goossens, J.-F.; Houssin, R.;
He´nichart, J.-P. J. Pharm. Pharmacol. 2001, 53, 929–934.
3. (a) Lombart, H.-G.; Lubell, W. D. J. Org. Chem. 1994, 59,
6147–6149; (b) Mueller, R.; Revesz, L. Tetrahedron Lett.
1
Compound 1b: H NMR (DMSO-d6, 300 MHz): l 1.80–
2.00 (m, 1H), 2.05–2.20 (m, 2H), 2.27–2.35 (m, 1H),
2.38–2.44 (m, 1H), 2.75–2.95 (m, 1H), 4.10–4.20 (m, 1H),
4.42–4.45(m, 1H), 4.60–4.65(m, 1H), 4.97(s, 2H), 7.23–7.34
(m, 5H), 7.61 (d, 1H, J=8.3 Hz); MS (ESI) m/z 331 [M+H]+,
353 [M+Na]+, 369 [M+K]+; HPLC (condition A) tR 12.0
min, (condition C) tR 12.9 min.