bisacylhydrazine family of commercial insecticides4 and was
used to control gene expression in systems based on
engineered ecdysone receptors.5 The generation of a small
library3e allowed the identification of 1a (Scheme 1),
the oxazoline scaffold10 and the numerous methods of
preparation.11 We envisioned that 2a could be directly
synthesized from 1a by the use of a deoxofluorinating agent
such as DAST.12 The cyclodehydration of ꢀ-hydroxyamide
to 4,5-unsubstituted oxazolines is known;11c nevertheless this
reagent was never applied to ketone counterparts. Gratify-
ingly the treatment of 1a with an excess of DAST at low
temperature promoted smoothly the desired cyclization
affording 2a in very good isolated yields (Scheme 2).
Scheme 1
.
Design of a Conformationally Restricted Analogue
Based on X-ray Structure of 1aa
Scheme 2. DAST-Mediated Cyclization of 1a
a X-ray structure from ref 3c.
synthetically derived from 1-aminocyclohexyl-1-carboxylic
acid, displaying micromolar range affinity close to that of
the commercial product Tebufenozide.6
The cyclization is proposed to follow two SN1 pathways
involving prior activation of the carbonyl by DAST to allow
intramolecular attack of the amide oxygen.13 Subsequent
formation of the stabilized benzylic R-oxycarbenium ion,
which is trapped by a fluoride, provides the desired fluo-
rooxazoline.
The biological evaluation of 2a was performed on an
ecdysone reporter gene assay.14 It displayed a high potency
similar to that of 1a (EC30(2a) ) 1.21 µM; EC30(1a) ) 1.33
µM). Oxazoline 2a represents therefore a potential new class
of nonsteroidal ecdysone agonists based on a conformation
analogue of 1a.
The X-ray structure of 1a displays a folded shape that
particularly attracted our attention and was used as a starting
point for our design. This conformation is induced to
minimize steric clashes with the cyclohexyl substituent and
is further stabilized by an additional carbonyl-carbonyl
attractive interaction, recently thoroughly studied by Raines
et al. and named n-π* interaction.7,8 We assumed that this
conformation was responsible for the biological activity, and
conformationally restricted analogue oxazoline 2a was
designed to assess this hypothesis. Indeed 2a mimics the
X-ray structure of 1a while displaying a similar electronic
distribution. The (sp3)C-F bond is of particular importance,
replacing the pyramidalized and elongated ketone of 1a due
to n-π* delocalization.
Encouraged by these results we embarked on investigating
the scope of the DAST-mediated cyclization process (Table
1). The substrates acylaminoketones 1b-j were readily
available in 2-3 steps from commercially available building
Surprisingly oxazolines bearing a heteroatom at C5 are
scarcely found in the literature9 despite the importance of
(10) For examples of naturally occuring oxazoline, see: (a) Portmann,
C.; Blom, J. F.; Gademann, K.; Jttner, F. J. Nat. Prod. 2008, 71, 1193. (b)
Wipf, P.; Fritch, P. C.; Geib, S. J.; Sefler, A. M. J. Am. Chem. Soc. 2009,
131, 16758. For a review on insecticidal oxazolines, see: Stevenson, T. M.;
Amoo, V. E.; Chiang, G. C.; Keskeny, E.; Long, J. K.; Crouse, B. A.;
Sharpe, P.; Hillegass, K.; Jones, L.; Yatsko, C. Synthesis and Chemistry of
Agrochemicals VI; ACS Symposium Series 800; American Chemical
Society: Washington, DC, 2001; pp 188-198. For a review on recent
applications of oxazoline-containing ligands, see: Hargaden, G. C.; Guiry,
P. J. Chem. ReV. 2009, 109, 2505.
(4) Dhadialla, T. S.; Ross, R. Modern Crop Protection Compounds;
Wiley-VCH: Weinheim, 2003; pp 773-797.
(5) (a) Laudet, V.; Gronemeyer, H. The Nuclear Receptor Facts Book;
Academic Press: San Diego, CA, 2002; pp 181-191. (b) Dhadialla, T. S.;
Carlson, G. R.; Le, D. P. Annu. ReV. Entomol. 1998, 43, 545.
(6) see the Supporting Information.
(7) (a) Choudhary, A.; Gandla, D.; Krow, G. R.; Raines, R. T. J. Am.
Chem. Soc. 2009, 131, 7244. (b) Jakobsche, H. E.; Choudhary, A.; Miller,
S. J.; Raines, R. T. J. Am. Chem. Soc. 2010, 132, 6651
.
(8) The criteria for n-π* delocalization are fulfilled (see ref 7a): the
distance between the oxygen of the amide and the carbon of the carbonyl
is 2.62 Å which is less than the sum of their van der Waals radii (rS + rC
< 3.50 Å). The angle O-CdO is 104.9°, and the carbonyl presents a slight
pyramidalization.
(11) For recent exemples, see: (a) Fan, L.; Lobkovsky, E.; Ganem, B.
Org. Lett. 2007, 9, 2015. (b) Schwekendiek, K.; Glorius, F. Synthesis 2006,
2996. (c) Phillips, A. J.; Uto, Y.; Wipf, P.; Reno, M. J.; Williams, D. R.
Org. Lett. 2000, 2, 1165.
(12) Middleton, W. J. J. Org. Chem. 1975, 40, 574.
(9) (a) Hassner, A.; Burke, S. S.; Cheng-fan, I, J. J. Am. Chem. Soc.
1975, 97, 4692. (b) Morwick, T.; Hrapchak, M.; DeTuri, M.; campbell, S.
Org. Lett. 2002, 4, 2665.
(13) The n-π* delocalization increases the negative charge on the ketone
oxygen, which possibly becomes more prone to react with DAST.
(14) See Supporting Information.
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