A chiral tricyclic proline analogue obtained from camphor

Article abstract of DOI:10.1016/S0040-4039(02)02325-0

Synthesis of 3a,6a-dimethylhexahydro-1,4-methanocyclopenta[c]pyrrole-1(2H)-carboxylic acid, a new chiral constrained proline analogue is reported. The synthesis was accomplished in five steps from 8-bromocamphor, easily available in both enantiomeric forms. A key step in the synthesis is an intramolecular 'domino'-type cyclisation, initiated by a nucleophile attack at an activated C=N bond.

Full text of DOI:10.1016/S0040-4039(02)02325-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 9411–9412
A chiral tricyclic proline analogue obtained from camphor
Marian V. Gorichko, Oleksandr O. Grygorenko and Igor V. Komarov*
Department of Chemistry, Kiev Taras Shevchenko University, Vladimirskaya Street, 64, Kiev 01033, Ukraine
Received 27 August 2002; revised 26 September 2002; accepted 11 October 2002
Abstract—Synthesis of 3a,6a-dimethylhexahydro-1,4-methanocyclopenta[c]pyrrole-1(2H)-carboxylic acid, a new chiral constrained
proline analogue is reported. The synthesis was accomplished in five steps from 8-bromocamphor, easily available in both
enantiomeric forms. A key step in the synthesis is an intramolecular ‘domino’-type cyclisation, initiated by a nucleophile attack
at an activated CꢀN bond. © 2002 Published by Elsevier Science Ltd.
The last decade witnessed a growth of activity in the
area of modified peptides. They have been found to
possess many advantages in comparison to natural
biologically active peptides in terms of activity, selectiv-
ity of the biological action, and in vivo stability.1,2 One
of the conceptual approaches towards the synthesis of
modified peptides is incorporation of conformationally
restricted a-amino acid analogues into the peptide
backbone.3 Of the a-amino acid analogues used, con-
strained proline analogues have attracted most atten-
tion.4,5 This amino acid is frequently found in peptide
b-turns which play an important role in peptide recep-
tor recognition and antigen determination.6 Here we
report on the synthesis of a new chiral tricyclic proline
analogue 1 starting from the natural terpenoid, cam-
phor, available in both enantiomeric forms.
out on a large scale.7 The cyclisation could be initiated
by nucleophilic attack of the cyanide ion at the CꢀN
bond, as shown in Scheme 1a. An analogous reaction
(Scheme 1b) led to the formation of the 4-oxatricy-
clo[4.3.0.03,7]nonane skeleton.8
The success of the outlined synthetic plan depends
crucially on the proper choice of the functional group
X in compound 2. First of all, it must be an electron-
withdrawing group to increase the electrophilicity of
the carbon atom in the azomethine group, otherwise
simple nucleophilic substitution at C-8 will occur. For
example, 8-bromocamphoroxime 4 reacts with the cya-
nide ion giving compound 5—the product of nucleo-
philic substitution, not cyclisation (Scheme 2).
As the key step in the synthesis we planned to use the
intramolecular ‘domino’-type cyclisation of the 8-bro-
mocamphor derivatives 2 which contain a CꢀN bond.
8-Bromocamphor 3 itself can be obtained stereospecifi-
cally from camphor in three steps which can be carried
Scheme 2. Reagents and conditions: KCN/DMFA, reflux, 2 h.
Scheme 1.
* Corresponding author. E-mail: ik214@yahoo.com
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)02325-0

9412
M. V. Gorichko et al. / Tetrahedron Letters 43 (2002) 9411–9412
Scheme 3. Reagents and conditions: (a) aqueous NaNO2/H2SO4, 1 h; (b) (CH3)2C(OH)CN/KOH/ethanol, reflux, 1 h; (c)
H2/PdꢁC/MeOH, 60°C, 2 days; (d) conc. aq. HCl, reflux, 1.5 days.
References
1. Gante, J. Angew. Chem., Int. Ed. Engl. 1994, 33, 1699–
1720.
2. Giannis, A.; Kolter, T. Angew. Chem., Int. Ed. Engl.
1993, 32, 1244–1267.
3. Mendel, D.; Ellman, J.; Schultz, P. G. J. Am. Chem.
Scheme 4. Reagents and conditions: Zn/RCOOH, 60°C, 2.5 h.
Soc. 1993, 115, 4359–4360.
4. Avenoza, A.; Cativiela, C.; Busto, J. H.; Ferna´ndez-
Recio, M. A.; Peregrina, J. M.; Rodr´ıguez, F. Tetra-
hedron 2001, 57, 545–548.
5. Avenoza, A.; Cativiela, C.; Busto, J. H.; Peregrina, J.
M. Tetrahedron Lett. 1995, 36, 7123–7126.
6. Wilmot, C. M.; Thornton, J. M. J. Mol. Biol. 1988,
203, 221–232.
7. Eck, C. R.; Mills, R. W.; Money, T. J. Chem. Soc.,
Chem. Commun. 1973, 911–912.
8. Komarov, I. V.; Gorichko, M. V.; Kornilov, M. Y.
Scheme 5. Reagents and conditions: (a) 10% aq. KOH, reflux,
2 h; (b) 10% aq. HCl, heating, 15 min.
Tetrahedron: Asymmetry 1997, 8, 435–445.
9. For 1, 1H NMR (400 MHz, DMSO-d6, l) (for hydro-
chloride): 10.33 (br. s, 1H), 9.16 (br. s, 1H), 3.21 (m,
1H), 2.90 (m, 1H), 2.20 (m, 1H), 2.05 (m, 2H), 1.78 (m,
1H), 1.59 (d, J=13.2 Hz, 1H), 1.43 (m, 1H), 1.33 (m,
1H), 0.93 (s, 6H).
Another important feature of the group X should be its
ease of removal. We found that the nitro group meets
these requirements. Nitroimine 6 is easily available from
the oxime 4. The carbon atom of the C=N bond in 6
is electrophilic enough for the compound to undergo the
desired cyclisation to yield 7. Subsequent Pd-catalysed
hydrogenolysis of the nitro group and hydrolysis of the
nitrile accomplishes the synthesis of 19(Scheme 3).
10. For 7, 1H NMR (400 MHz, DMSO-d6, l): 3.95 (d,
J=11.4 Hz, 1H, 5-CH2), 3.68 (d, J=11.4 Hz, 1H, 5-
CH2), 2.12 (m, 1H), 2.03 (m, 1H), 1.55–1.78 (m, 4H),
1.37 (m, 1H), 1.08 (s, 3H), 0.95 (s, 3H). IR (KBr,
cm−1): 1530 (NꢁNO2, NꢁO as), 2240 (CꢂN).
11. For 10, The product is a mixture of isomers; 1H NMR
(400 MHz, DMSO-d6, l) (for major): 9.29 (d, J=9.6
Hz, 1H, NH), 8.09 (d, J=9.6 Hz, 1H, CHO), 2.97 (d,
J=9.6 Hz, 1H, 5-CH2), 2.73 (d, J=9.6 Hz, 1H, 5-
CH2), 2.47 (m, 1H), 1.94 (s, 1H), 1.64–1.75 (m, 2H),
1.49 (m, 1H), 1.30 (m, 1H) 1.15–1.22 (m, 4H), 0.86 (s,
3H).
We also explored the possibility of reducing the nitro
group in 7 without cleavage of the NꢁN bond. The
reduction could be performed by Zn in acetic or formic
acid yielding the acylated derivatives 9 or 1011 (Scheme
4).
1
The latter compound dissolves in dilute aqueous potas-
sium hydroxide, most likely because of reversible depro-
tonation; addition of hydrochloric acid regenerates the
starting material. Heating results in hydrolysis in both
alkaline and acidic media to yield 1112 and 12,13 respec-
tively (Scheme 5).
12. For 11, H NMR (400 MHz, DMSO-d6, l): 7.01 (br. s,
1H, CONH2), 6.82 (br. s, 1H, CONH2), 3.44 (br. s,
2H, NꢁNH2), 2.97 (d, J=9.6 Hz, 5-CH2), 2.33 (d, J=
9.6 Hz, 5-CH2), 1.86 (m, 2H), 1.76 (m, 1H), 1.65 (m,
1H), 1.31 (d, J=12.4 Hz, 1H), 1.17 (m, 2H), 0.88 (s,
3H), 0.75 (s, 3H).
1
13. For 12, H NMR (400 MHz, DMSO-d6, l): 3.74 (br. s,
2H, NH2), 2.90 (d, J=9.6 Hz, 1H, 5-CH2), 2.34
(m, 2H), 1.86 (m, 1H), 1.66–1.73 (m, 2H), 1.56 (m,
1H), 1.41 (m, 1H), 1.26 (m, 1H), 1.04 (s, 3H), 0.77 (s,
3H).
Acknowledgements
Financial support from Du Pont de Nemours Interna-
tional S.A. is gratefully acknowledged.