4-fluoro-2,4-methanoproline

Article abstract of DOI:10.1021/ol902381w

[Chemical Equation Presented] The first fluorinated analogue of the naturally occurring 2,4-methanoproline, 4-fluoro-2,4-methanoproline, has been synthesized In five steps from commercially available methyl 2-fluoroacrylate through a photochemical cycliza

Full text of DOI:10.1021/ol902381w

ORGANIC
LETTERS
2009
Vol. 11, No. 24
5674-5676
4-Fluoro-2,4-methanoproline
Anton N. Tkachenko, Dmytro S. Radchenko, Pavel K. Mykhailiuk,* Oleksandr
O. Grygorenko, and Igor V. Komarov
Department of Chemistry, KyiV National Taras SheVchenko UniVersity, Vul.
Volodymyrska 64, 01033 KyiV, Ukraine, and Enamine Ltd., Vul. Oleksandra
MatrosoVa 23, 01103 KyiV, Ukraine
pashamk@gmx.de
Received October 15, 2009
ABSTRACT
The first fluorinated analogue of the naturally occurring 2,4-methanoproline, 4-fluoro-2,4-methanoproline, has been synthesized in five steps
from commercially available methyl 2-fluoroacrylate through a photochemical cyclization as a key step in generating a 2-azabicyclo[2.1.1]hexane
skeleton.
2,4-Methanoproline (1) is a naturally occurring nonprotei-
nogenic amino acid first isolated from the seeds of the legume
Ateleia herbert smithii Pittier, growing in Costa Rica (Figure
1).1,2 The seeds of this tree are ignored by more than 100
seed predators, and it was recently shown that derivatives
of 1 have high insect antifeedant activity.3 It is supposed
that this biological activity is caused by the conformational
rigidity of the 2-azabicyclo[2.1.1]hexane skeleton, which
leads to the reduced metabolism of 1, compared to proline.
Since the first synthesis of 2,4-methanoproline in 1980,4 a
large number of different synthetic approaches to 1 have
appeared,5 thereby indicating an intense interest in this amino
acid. For example, 1 was found to stabilize the peptide
tertiary trans-amide bonds,6 which is of great potential in
peptide design, since the cis-trans isomerization of peptide
bonds is closely related to biologically relevant processes,
primarily to folding and unfolding.7 In particular, 1 was used
instead of proline to synthesize a conformationally con-
strained analogue of thyrotropin-releasing hormone (TRH)
and to study the latter.8 Moreover, 1 was also introduced
into the oligopeptides bradykinin and angiotensin, which are
neurotransmitters playing an important role in the regulation
of blood pressure and heart function.9 Last year, 1 was
applied as a conformationally rigid building block to prepare
new potential ligands of the nicotinic acetylcholine recep-
tor.10
The substitution of fluorine for hydrogen in organic
compounds is widely used to modify their physical, chemical,
and biological characteristics.11 Surprisingly, despite the great
potential of 2,4-methanoproline (1), there are, to the best of
our knowledge, no fluorinated analogues of 1 described in
(6) (a) Montelione, G. T.; Hughes, P.; Scheraga, H. A. J. Am. Chem.
Soc. 1986, 108, 6765. (b) Talluri, S.; Montelione, G. T.; van Duyne, G.;
Piela, L.; Chardy, J.; Scheraga, H. A. J. Am. Chem. Soc. 1987, 109, 4473.
(c) Piela, L.; Ne´methy, G.; Scheraga, H. A. J. Am. Chem. Soc. 1987, 109,
4477.
(1) Bell, E. A.; Qureshi, M. Y.; Pryce, R. J.; Janzen, D. H.; Lemke, P.;
Chardy, J. J. Am. Chem. Soc. 1980, 102, 1409
(2) Recently, 1 was also found in the legume Bocoa alterna: Kite, G. C.;
Ireland, H. Phytochemistry 2002, 59, 163
.
.
(3) Stevens, C. V.; Smagghe, G.; Rammeloo, T.; De Kimpe, N. J. Agric.
Food Chem. 2005, 53, 1945.
(7) (a) Ba¨chinger, H. P.; Engel, J.; Bruckner, P.; Timpl, R. Eur.
J. Biochem. 1978, 90, 605. (b) Salahuddin, A. J. Biosci. 1984, 6, 349. (c)
Cis-trans isomerization in biochemistry; Dugave, C., Ed.; Wiley-VCH:
Weinheim, 2006.
(4) Pirrung, M. C. Tetrahedron Lett. 1980, 21, 4577.
(5) (a) Hughes, P.; Martin, M.; Clardy, J. Tetrahedron Lett. 1980, 21,
4579. (b) Hughes, P.; Clardy, J. J. Org. Chem. 1988, 53, 4793. (c) Gaoni,
Y. Org. Prep. Proced. Int. 1995, 27, 185. (d) Stevens, C.; De Kimpe, N. J.
Org. Chem. 1996, 61, 2174. (e) Rammeloo, T.; Stevens, C. V.; De Kimpe,
N. J. Org. Chem. 2002, 67, 6509. (f) Krow, G. R.; Herzon, S. B.; Lin, G.;
Qiu, F.; Sonnet, P. E. Org. Lett. 2002, 4, 3151. (g) Rammeloo, T.; Stevens,
C. V. Chem. Commun. 2002, 250. (h) Grygorenko, O. O.; Artamonov, O. S.;
Palamarchuk, G. V.; Zubatyuk, R. I.; Shishkin, O. V.; Komarov, I. V.
Tetrahedron: Asymmetry 2006, 17, 252.
(8) Mapelli, C.; Van Halbeek, H.; Stammer, C. H. Biopolymers 1990,
29, 407.
(9) Juvvadi, P.; Dooley, D. J.; Humblet, C. C.; Lu, G. H.; Lunney, E. A.;
Panek, R. L.; Skeean, R.; Marshall, G. R Int. J. Pept. Protein Res 1992,
40, 163.
(10) (a) Malpass, J. R.; Patel, A. B.; Davies, J. W.; Fulford, S. Y. J.
Org. Chem. 2003, 68, 9348. (b) Patel, A. B.; Malpass, J. R. J. Med. Chem.
2008, 51, 7005.
10.1021/ol902381w  2009 American Chemical Society
Published on Web 11/11/2009

Scheme 2. Synthesis of 4-Fluoro-2,4-methanoproline (2)
Figure 1. Natural nonproteinogenic amino acid 2,4-methanoproline
(1) and its fluorinated analogue 4-fluoro-2,4-methanoproline (2).
Proline numbering is shown.
the literature to date. Therefore, here we wish to report the
synthesis of the first fluorine-containing analogue of 2,4-
methanoproline (1): 4-fluoro-2,4-methanoproline (2) (Figure
1). The 4-CH position was selected for the labeling by a
fluorine atom, since this is the only substitution which retains
the nonchirality of 1.
Among known approaches to construct the 2-azabicyclo-
[2.1.1]hexane skeleton,5,12 we chose a strategy based on an
intramolecular light-induced [2 + 2] cycloaddition of the
appropriate diene (Scheme 1).
Reduction of 4 with AlH3, generated in situ from LiAlH4
and AlCl3, at -5 °C smoothly afforded alcohol 3 in 82%
yield (Scheme 2). Next, 3 was reacted with MsCl at room
temperature using diisopropylethylamine as a base to produce
mesylate 5 in 93% yield. Thereafter, alkylation of the readily
available serine derivative BzNHCH(CH2Cl)CO2Me (6)5a
with 5 was performed; however, the product 7 was obtained
in only 25% yield.15 The key step in the synthesis, the
intramolecular light-induced [2 + 2] cycloaddition of diene
7, smoothly afforded the target 2-azabicyclo[2.1.1]octane
derivative (8) in 64% yield.
Scheme 1. Retrosynthetic Approach to 2
Finally, standard acidic cleavage of the N-Boc and
COOMe groups in 8, followed by ion-exchange chromatog-
raphy on “Amberlite” resin, produced the fluorinated amino
acid 2 in 94% yield.16
Recently, Piotrowski demonstrated the high efficiency of
this reaction by synthesizing diverse potential ligands of the
nicotinic acetylcholine receptor, the yields being good almost
irrespective of the substituents in the starting dienes.13 Our
retrosynthetic approach to 2 was based on 2-fluoroallylic
alcohol (3) as a starting material (Scheme 1). Surprisingly,
although the compound 3 has already been described in the
literature,14 we found no efficient and straightforward method
for its practical preparation from commercially available
materials. Therefore, a procedure to obtain 3 directly from
commercially available methyl 2-fluoroacrylate (4) was
elaborated (Scheme 2).
In summary, we have synthesized 4-fluoro-2,4-methano-
proline (2): the first fluorinated analogue of a naturally
occurring amino acid 2,4-methanoproline (1). The synthesis
commences from commercially available methyl 2-fluoro-
acrylate (4) and involves five steps. The key synthetic step
is a photochemical intramolecular [2 + 2] cyclization of
(15) A similar transformation using allyl bromide is described in ref 5.
The corresponding product was obtained in 94% yield. However, in that
work a 20-fold excess of allyl bromide was used.
(16) Spectral and analytical data for the key compounds: Methyl
2-benzoyl-4-fluoro-2-azabicyclo[2.1.1]hexane-1-carboxylate (8): colorless
oil; 1H NMR (500 MHz, CDCl3, Me4Si) δ 2.34 (2 H, br s, 2 × CHH), 2.44
(2 H, br s, 2 × CHH), 3.61 (2 H, s, NCH2), 3.81 (3 H, s, CH3), 7.43 (2 H,
3
3
t, JH-H ) 7.5 Hz, Ph), 7.51 (1 H, t, JH-H ) 7.5 Hz, Ph), 7.73 (2 H,
d,3JH-H ) 7.0 Hz, Ph); 13C NMR (125 MHz, CDCl3, Me4Si) δ 47.0 (d,
(11) (a) O’Hagan, D.; Rzepa, H. S. Chem. Commun. 1997, 645. (b)
Modern fluoroorganic chemistry; Kirsch, P., Ed.; Wiley-VCH: Weinheim,
2004.
2JC-F ) 10.1 Hz, 2 × CH2), 52.6 (s, OCH3), 53.9 (d, JC-F ) 27.7 Hz,
2
NCH2), 60.4 (d, 3JC-F ) 22.6 Hz, CCO2CH3), 87.8 (d, 1JC-F ) 265.4 Hz,
CF), 127.1 (s, CH, Ph), 128.6 (s, CH, Ph), 132.1 (s, CH, Ph), 133.2 (s,
(12) Some representative examples: (a) Lescop, C.; Me´vellec, L.; Huet,
F. J. Org. Chem. 2001, 66, 4187. (b) Krow, G. R.; Lin, G.; Herzon, S. B.;
Thomas, A. M.; Moore, K. P.; Huang, Q.; Carroll, P. J. J. Org. Chem.
2003, 68, 7562. (c) Jenkins, C. L.; Lin, G.; Duo, J.; Rapolu, D.; Guzei,
I. A.; Raines, R. T.; Krow, G. R. J. Org. Chem. 2006, 71, 1754. (d)
Esslinger, S.; Koch, H. P.; Kavanaugh, M. P.; Philips, D. P.; Chamberlin,
A. R.; Thompson, C. M.; Bridges, R. J. Bioorg. Med. Chem. Lett. 1998, 8,
tert-C, Ph), 167.7 (d, JC-F ) 11.3 Hz, NCOPh), 173.5 (s, CO2CH3); 19F
4
NMR (470 MHz, CDCl3, CFCl3) δ -173.1 (s, F); MS m/z (CI) 264 (M +
1, 100). 4-Fluoro-2-azabicyclo[2.1.1]hexane-1-carboxylic Acid (2): white
solid; mp > 220 °C; 1H NMR (500 MHz, CDCl3, Me4Si) δ 2.34 (2 H, d, J
) 5.5 Hz, 2 × CHH), 2.58 (2 H, br s, 2 × CHH), 3.50 (2 H, s, NCH2); 13
C
2
NMR (125 MHz, CDCl3, Me4Si) δ 44.5 (d, JC-F ) 20.1 Hz, 2 × CH2),
3101
.
46.4 (d, 2JC-F ) 30.2 Hz, NCH2), 62.3 (d, 4JC-F ) 17.6 Hz, NCH2C), 87.8
1
4
(13) Piotrowski, D. W. Synlett 1999, 7, 1091.
(d, JC-F ) 264.2 Hz, CF), 170.4 (d, JC-F ) 8.8 Hz, COOH); 19F NMR
(470 MHz, CDCl3, CFCl3) δ -170.4 (s, F). Anal. Calcd for C6H8FNO2: C,
49.66; H, 5.56; N, 9.65. Found: C, 49.78; H, 5.42; N, 9.83.
(14) (a) Laue, K. W.; Haufe, G. Synthesis 1998, 1453. (b) Nagakura, I.;
Savary, D. N.-H.; Schlosser, M. HelV. Chim. Acta 1980, 63, 1257.
Org. Lett., Vol. 11, No. 24, 2009
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diene 7 to obtain the 2-azabicyclo[2.1.1]hexane skeleton (8).
During the synthesis, an easy and efficient one-step procedure
to prepare a valuable building block, 2-fluoroallylic alcohol
(3), from 4 was elaborated.
Supporting Information Available: Experimental pre-
cedures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. This work was supported by Enamine
Ltd. of Kyiv, Ukraine.
OL902381W
5676
Org. Lett., Vol. 11, No. 24, 2009