Conformational regulation of substituted azepanes through selective monofluorination

Article abstract of DOI:10.1039/c3ob40391b

Substituted azepanes are common bioactive epitopes with flexible ring structures. The conformational effects of monofluorination in model azepane rings were investigated by ¹H NMR spectroscopy and computational modelling. A single fluorine atom, installed diastereoselectively, was found to bias the azepane ring to one major conformation for one diastereomer. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ob40391b

Organic &
Biomolecular Chemistry
View Article Online
View Journal | View Issue
COMMUNICATION
Conformational regulation of substituted azepanes
through selective monofluorination†
Alpesh Ramanlal Patel,a Graham Ball,b Luke Hunterb and Fei Liu*a
Cite this: Org. Biomol. Chem., 2013, 11,
3781
Received 22nd February 2013,
Accepted 23rd April 2013
DOI: 10.1039/c3ob40391b
www.rsc.org/obc
Substituted azepanes are common bioactive epitopes with introduction of fluorine into these systems may offer attractive
flexible ring structures. The conformational effects of monofluori- benefits through entropy control. Previous work has elucidated
nation in model azepane rings were investigated by 1H NMR spec- the conformational effects of incorporating fluorine atoms
troscopy and computational modelling. A single fluorine atom, into four-,13 five-,14 six-15 and eight-13membered nitrogen het-
installed diastereoselectively, was found to bias the azepane ring erocycles, but the effect of fluorine substitution in highly flexi-
to one major conformation for one diastereomer.
ble, heterocyclic seven-membered ring systems is unknown.
In order to address this knowledge gap we recently reported
methods for the stereospecific fluorination of substituted aze-
panes,16a and here we report the conformational effects of
monofluorination in model azepanes 1–3 (Fig. 1). Azepane 1
bears two substituents, a C-3 azido group and a C-4 benzyloxy
group, while azepanes 2 and 3 also feature a diastereospecific
fluorine substitution at the C-6 position.
Ligand–receptor interactions frequently require conformation-
al changes in both entities.1 Such a conformational “induced-
fit” confers specificity in molecular recognition that selects for
a particular reaction or binding outcome.2 Understanding con-
formational synergy is critical to the rational discovery of
chemical function in structure-based drug design or molecular
assembly; however, the details of conformational dynamics in
most ligand–receptor interactions are not well understood.3,4
Recent examples illustrate the principle of entropy control,
where conformational tuning of ligands or receptors regulates
binding specificity and affinity.5–9 Methods for controlled con-
formational manipulation of ligands are needed for the
rational design and discovery of bioactive epitopes,3 and one
such method is selective fluorination. The C–F bond is known
to present profound conformational effects,10 and has been
shown to moderate binding specificity and affinity in a variety
of ligand–receptor systems including protease inhibition,
GABA receptor ligands, antivirals, insect pheromones, and
antimalarials.11
In azepane 1, multiple factors exist to give rise to its
complex conformational properties. For example, the mutually
trans benzyloxy and azido groups might be expected to prefer a
In this context of entropy control, conformational tuning of
substituted azepanes represents a challenging case study due
to the flexibility of such ring systems. Substituted azepanes are
common moieties in bioactive natural products, DNA binders,
helix inducers, and iminosugar mimics as glycosidase inhibi-
tors.12 Their conformational regulation is key to the potency
and specificity of their bioactivity, suggesting that the
aDepartment of Chemistry and Biomolecular Sciences, Macquarie University, Sydney
NSW 2109, Australia. E-mail: fei.liu@mq.edu.au
bSchool of Chemistry, The University of New South Wales, Sydney NSW 2052,
Fig. 1 The conformations of azepanes 1–3 are expected to be influenced by:
(a) a diequatorial preference of the benzyloxy/azido groups; (b) the azido
gauche effect; and (c) the fluorine gauche effect (e.g. azepane 3).
Australia
†Electronic supplementary information (ESI) available: Synthetic procedures,
computational details and NMR spectra. See DOI: 10.1039/c3ob40391b
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem., 2013, 11, 3781–3785 | 3781

View Article Online
Communication
Organic & Biomolecular Chemistry
diequatorial over a diaxial position in a twisted chair azepane
conformation (Fig. 1a), but this would compete with the
additional preference of the azido group to align gauche to the
ring nitrogen17 (Fig. 1b). Further, the presence of three contig-
uous unsubstituted methylene groups would be expected to
amplify the conformational disorder in the system. In each of
the fluorinated targets 2 and 3, the expected preference of the
C–F bond to align gauche to the ring nitrogen (Fig. 1c) would
be an additional influence on the azepane conformation.18
Comparison of the diastereoisomers 2 and 3 would allow us to
explore whether an appropriately oriented C–F bond can suc-
cessfully reduce or eliminate the conformational disorder
inherent in substituted azepanes. A related question would be
whether the C–F bond acts in synergy or in competition with
the other conformational influences in the molecule. By
exploring these questions, we anticipated that the general prin-
ciples for entropy control in substituted azepanes might be
extrapolated.
Azepane 1 was prepared from a key Boc-protected tetra-
hydroazepine intermediate,19 which also gave rise to the fluori-
nated compounds 2 and 3 as described previously.16a The final
Boc-deprotection in trifluoroacetic acid afforded targets 1–3 as
the trifluoroacetate salt in quantitative yield in each case. The
NMR spectra of 1–3 were recorded in CDCl3 which gave well
resolved signals, and all resonances were unambiguously
assigned using appropriate two-dimensional experiments
(COSY, NOESY, HSQC, and HMBC) and by accurate simulation
of the spectra in silico.19
The coupling constants extracted from the 1H NMR spec-
trum of 1 confirm that this molecule exhibits extensive confor-
mational disorder at room temperature (Fig. 2a).20 A single set
of resonances is observed, but most of the three-bond proton–
proton coupling constants are intermediate in magnitude
(5–6 Hz), suggesting that significant conformational averaging
is occurring on the NMR timescale. Notably, this includes H-3
Fig. 2 A combined NMR/computational analysis reveals that azepanes 1 and 2
exhibit considerable conformational disorder, while azepane 3 has one domi-
nant geometry. The low-energy geometries of 1–3 are displayed in the overlay
images on the right; these overlays are anchored by three ring atoms (C-7, N+,
and C-2), and the benzyloxy and azido side chains are omitted for clarity. The
major conformer of 3 is black. See the ESI† for full details of all low-energy geo-
metries of 1–3.
and H-4 next to the benzyloxy and azido substituents, which (Fig. 2b). As described above, three conformational effects
experience a coupling of 5.4 Hz (Fig. 2a); this intermediate were expected to be in operation: the diequatorial preference
value agrees with our hypothesis that the benzyloxy/azido di- of the benzyloxy/azido groups; the azido gauche effect; and the
equatorial preference and the azido gauche effect would fluorine gauche effect (Fig. 1). It seems that each of these pre-
compete with each other, leading to conformational disorder. ferences is only partially satisfied in azepane 2. This is demon-
The western portion of the molecule also exhibits extensive strated by, respectively, a key JH3H4 value of 6.7 Hz; a key JH2bH3
conformational mobility, as is clearly demonstrated by the value of 4.1 Hz; and a key JFH7b value of 24.0 Hz (Fig. 2b), all of
intermediate magnitude of the proton–proton coupling con- which are intermediate in magnitude20 and hence suggestive
stants, and by the appearance of the methylene hydrogens, of conformational averaging.
H-7a and H-7b, as an apparent triplet ( J = 5.9 Hz) rather than
Computational analysis of 2 identified several azepane ring
two doublet of doublets. A computational analysis19 identified geometries that may possibly contribute to the observed NMR
seven clusters of distinctly different azepane ring confor- characteristics.19 In order to identify the major geometries, the
mations within 3 kcal mol−1 of the global minimum (Fig. 2a, energy of each geometry candidate was subjected to DFT calcu-
overlay image of the possible conformers of 1). Overall, lations at several different levels of theory, but it was not possi-
azepane 1 is found to be a highly flexible and disordered mole- ble to reliably rank the geometries because of the
cule, and as such, is an excellent but challenging starting uncertainties inherent to the calculations and the side chain
point for the production of conformationally biased fluori- rotations that tended to obscure the native preferences of the
nated analogues.
azepane ring itself.19 Given the limited reliability of the com-
For the 6S-fluorinated azepane 2, an initial qualitative putational methods alone, it was therefore necessary to
J-based analysis suggested that this molecule still exhibits con- perform J-based conformational analysis to assist in ranking
siderable conformational disorder at room temperature the candidate geometries. Spin–spin coupling constants were
3782 | Org. Biomol. Chem., 2013, 11, 3781–3785
This journal is © The Royal Society of Chemistry 2013

View Article Online
Organic & Biomolecular Chemistry
Communication
calculated for each geometry using the program Gaussian09,19 reinforced, whereas if the fluorine acts in competition with
and the calculated J values were compared with the experi- existing groups (i.e. azepane 2), such a loss of synergy results
mental values. As expected, no individual geometry of 2 in reduced conformational bias.22 This finding has wider sig-
matched the experimental J values perfectly, but a reasonably nificance for future efforts to optimise host–guest interactions
good agreement between calculated and experimental J values involving flexible heterocyclic ligands.
was obtained when three candidate geometries were selected
and a weighted average was created in the ratio of 39 : 31 : 30
(Fig. 2b, overlay image of the probable major geometries of 2).
Acknowledgements
This population ratio corresponds to relative energies of 0.00,
0.12 and 0.13 kcal mol−1, which are too close to one another
The authors thank Prof. Peter Karuso and Dr Douglas Lawes
to have been reliably predicted by energy calculations alone. for NMR assistance.
The three lowest-energy geometries thus identified all satisfy
two of the three conformational preferences described in
Fig. 1. Overall, introducing a single fluorine atom into azepane
Notes and references
2 does not reduce the conformational disorder enough to
achieve one dominant ring geometry in solution.
1 S. Llabrés, J. Juárez, F. Forti, R. Pouplana and F. J. Luque,
Recognition of ligands by macromolecular targets, in
Physico-Chemical and Computational Approaches to Drug Dis-
covery, The Royal Society of Chemistry, 2012, ch. 1.
2 Y. Savir and T. Tlusty, PLoS ONE, 2007, 2, e468.
3 C. E. Chang, W. Chen and M. K. Gilson, Proc. Natl. Acad.
Sci. U. S. A., 2007, 104, 1534–1539.
Our attention was next turned to azepane 3 (Fig. 2c), in
which the diastereospecific fluorination gives the R configur-
ation at C-6. A qualitative J-based analysis20 of the 1H NMR
spectrum of 3 reveals that, in contrast to azepanes 1 and 2, a
single geometry of 3 seems to strongly dominate in solution.
The benzyloxy/azido diequatorial preference is reasonably
clearly satisfied, as demonstrated by a JH3H4 value of 7.3 Hz;
the azido gauche effect is reasonably clearly satisfied, as
demonstrated by a JH2aH3 value of 2.8 Hz; and the fluorine
gauche effect is clearly satisfied, as demonstrated by a key JFH7a
value of 30.7 Hz (Fig. 2).
In order to acquire theoretical confirmation of the pre-
dicted ring geometry of 3, a computational sequence was per-
formed similar to that already described for 2. A ring geometry
of 3 consistent with the above description was readily identi-
fied amongst the low-energy candidates from a conformational
analysis followed by DFT optimisation (Fig. 2c), and the calcu-
lated coupling constants for this geometry matched the experi-
mental values reasonably well.19 In addition, a second closely
4 L. Skjaerven, N. Reuter and A. Martinez, Future Med. Chem.,
2011, 3, 2079–2100.
5 C. Diehl, O. Engström, T. Delaine, M. Håkansson,
S. Genheden, K. Modig, H. Leffler, U. Ryde, U. J. Nilsson
and M. Akke, J. Am. Chem. Soc., 2010, 132, 14577–14589.
6 C. Cabezas, M. Varela, I. Pena, S. Mata, J. C. Lopez and
J. L. Alonso, Chem. Commun., 2012, 48, 5934–5936.
7 G. R. Stockwell and J. M. Thornton, J. Mol. Biol., 2006, 356,
928–944.
8 N. Sturm, J. Desaphy, R. J. Quinn, D. Rognan and
E. Kellenberger, J. Chem. Inf. Model., 2012, 52, 2410–2421.
9 C. S. Leung, S. S. F. Leung, J. Tirado-Rives and
W. L. Jorgensen, J. Med. Chem., 2012, 55, 4489–4500.
related conformer of 3 was identified which, when included as 10 (a) L. Hunter, Beilstein J. Org. Chem., 2010, 6, 38;
the minor component of an 82 : 18 weighted average mixture, (b) D. O’Hagan, Chem. Soc. Rev., 2008, 37, 308–319.
provided a still closer match with the experimental J values. 11 (a) I. Yamamoto, M. J. T. Jordan, N. Gavande,
This population ratio corresponds to relative energies of 0.00
and 0.77 kcal mol−1. The two low-energy geometries of 3 thus
identified (Fig. 2c) differ only in a slight twist about the C3–C4
dihedral angle, with the lowest-energy geometry better satisfy-
ing the benzyloxy/azido diequatorial preference, and the next
higher-energy geometry better satisfying the azido gauche
effect.19 Overall, introducing the fluorine atom into azepane 3,
with the R configuration at C-6, is found to greatly reduce the
conformational disorder relative to the non-fluorinated parent
structure 1, to the extent that a single geometry strongly domi-
nates in solution.
In conclusion, this study has demonstrated that a single
C–F bond, installed diastereospecifically, can significantly
regulate the conformations of substituted azepane deriva-
tives.21 The extent of conformational biasing is found to
depend on both the fluorine stereochemistry and that of the
other groups present: if the fluorine acts in synergy with the
other groups (i.e. azepane 3) a single ring conformation can be
M. R. Doddareddy, M. Chebib and L. Hunter, Chem.
Commun., 2012, 48, 829–831; (b) P. W. Chia, M. R. Livesey,
A. M. Slawin, T. van Mourik, D. J. Wyllie and D. O’Hagan,
Chem.–Eur. J., 2012, 18, 8813–8819; (c) L. Hunter, Chim.
Oggi, 2012, 30, 20; (d) M. Winkler and D. O’Hagan, Mol.
Med. Med. Chem., 2012, 6, 299–331; (e) I. Yamamoto,
G. P. Deniau, N. Gavande, M. Chebib, G. A. Johnston and
D. O’Hagan, Chem. Commun., 2011, 47, 7956–7958;
(f) N. H. Campbell, D. L. Smith, A. P. Reszka, S. Neidle and
D. O’Hagan, Org. Biomol. Chem., 2011, 9, 1328–1331;
(g) D. O’Hagan, Future Med. Chem., 2011, 3, 189–195;
(h) C. Bucher, C. Sparr, W. B. Schweizer and R. Gilmour,
Chem.–Eur. J., 2009, 15, 7637–7647; (i) J. J. Barchi,
R. G. Karki, M. C. Nicklaus, M. A. Siddiqui, C. George,
I. A. Mikhailopulo and V. E. Marquez, J. Am. Chem. Soc.,
2008, 130, 9048–9057; ( j) G. Deniau, A. M. Slawin, T. Lebl,
F. Chorki, J. P. Issberner, T. van Mourik, J. M. Heygate,
J. J. Lambert, L. A. Etherington, K. T. Sillar and
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem., 2013, 11, 3781–3785 | 3783

View Article Online
Communication
Organic & Biomolecular Chemistry
D. O’Hagan, ChemBioChem, 2007, 8, 2265–2274;
(k) M. D. Clift, H. Ji, G. P. Deniau, D. O’Hagan and
R. B. Silverman, Biochemistry, 2007, 46, 13819–13828;
(l) A. G. A. Myers, J. K. J. Barbay and B. B. Zhong, J. Am.
Chem. Soc., 2001, 123, 7207–7219; (m) A. P. Khrimian,
J. E. Oliver, R. M. Waters, S. Panicker, J. M. Nicholson and
J. A. Klun, Tetrahedron: Asymmetry, 1996, 7, 37–40;
(n) P. Van Roey, J. M. Salerno, C. K. Chu and R. F. Schinazi,
Proc. Natl. Acad. Sci. U. S. A., 1989, 86, 3929–3933.
Chem. Soc., 2005, 127, 225–235; (u) H. Li, Y. Bleriot,
J.-M. Mallet, E. Rodriguez-Garcia, P. Vogel, Y. Zhang and
P. Sinay, Tetrahedron: Asymmetry, 2005, 16, 313–319;
(v) K. Martinez-Mayorga, J. L. Medina-Franco, S. Mari,
F. J. Canada, E. Rodriguez-Garcia, P. Vogel, H. Li, Y. Bleriot,
P. Sinay and J. Jimenez-Barbero, Eur. J. Org. Chem., 2004,
4119–4129; (w) H. Li, Y. Bleriot, J.-M. Mallet, Y. Zhang,
E. Rodriguez-Garcia, P. Vogel, S. Mari, J. Jimenez-Barbero
and
P.
Sinay,
Heterocycles,
2004,
64,
65–74;
12 For recent and representative examples see: (a) P.-L. Yeh,
C.-K. Tai, T.-L. Shih, H.-L. Hsiao and B.-C. Wang, J. Mol.
Struct., 2012, 1018, 64–71; (b) S. Goumain, H. Taghzouti,
C. Portella, J.-B. Behr and R. Plantier-Royon, Tetrahedron
Lett., 2012, 53, 4440–4443; (c) J. Perez-Castells,
M. Fontanella, A. Arda, F. J. Canada, M. Sollogoub,
Y. Bleriot and J. Jimenez-Barbero, New J. Chem., 2012, 36,
1008–1013; (d) L. J. Parker, H. Watanabe, K. Tsuganezawa,
Y. Tomabechi, N. Handa, M. Shirouzu, H. Yuki, T. Honma,
N. Ogawa, T. Nagano, S. Yokoyama and A. Tanaka, Acta
Crystallogr., Sect. F: Struct. Biol. Cryst. Commun., 2012, 68,
860–866; (e) D. Nunez-Villanueva, L. Infantes, M. T. Garcia-
(x) D. D. Dhavale, S. D. Markad, N. S. Karanjule and
J. PrakashaReddy, J. Org. Chem., 2004, 69, 4760–4766;
(y) C. B. Breitenlechner, T. Wegge, L. Berillon, K. Graul,
K. Marzenell, W.-G. Friebe, U. Thomas, R. Schumacher,
R. Huber, R. A. Engh and B. Masjost, J. Med. Chem., 2004,
47, 1375–1390; (z) S. Barluenga, K. B. Simonsen,
E. S. Littlefield, B. K. Ayida, D. Vourloumis, G. C. Winters,
M. Takahashi, S. Shandrick, Q. Zhao, Q. Han and
T. Hermann, Bioorg. Med. Chem. Lett., 2004, 14, 713–718;
(aa) M. Y. Le, L. Poitout, J.-C. Depezay, I. Dosbaa,
S. Geoffroy and M.-J. Foglietti, Bioorg. Med. Chem., 1997, 5,
519–533.
Lopez, R. Gonzalez-Muniz and M. Martin-Martinez, J. Org. 13 N. E. Gooseman, D. O’Hagan, A. M. Slawin, A. M. Teale,
Chem., 2012, 77, 9833–9839; (f) J. Sardinha, A. P. Rauter,
M. Sollogoub and Y. Bleriot, Carbohydr. Chem.: Proven
D. J. Tozer and R. J. Young, Chem. Commun., 2006, 3190–
3192.
Synth. Methods, 2012, 1, 129–135; (g) E. Wojaczynska, 14 (a) L. E. Combettes, P. Clausen-Thue, M. A. King, B. Odell,
I. Turowska-Tyrk and J. Skarzewski, Tetrahedron, 2012, 68,
7848–7854; (h) J. Deschamp, M. Mondon, S. Nakagawa,
A. Kato, D. S. Alonzi, T. D. Butters, Y. Zhang, M. Sollogoub
and Y. Bleriot, Bioorg. Med. Chem., 2012, 20, 641–649;
(i) E. Cini, G. Bifulco, G. Menchi, M. Rodriquez and
M. Taddei, Eur. J. Org. Chem., 2012, 2133–2141;
( j) T.-L. Shih, M.-T. Liang, K.-D. Wu and C.-H. Lin, Carbo-
hydr. Res., 2011, 346, 183–190; (k) S. D. Orwig, Y. L. Tan,
N. P. Grimster, Z. Yu, E. T. Powers, J. W. Kelly and
R. L. Lieberman, Biochemistry, 2011, 50, 10647–10657;
(l) D. Nunez-Villanueva, M. A. Bonache, L. Infantes,
M. T. Garcia-Lopez, M. Martin-Martinez and R. Gonzalez-
Muniz, J. Org. Chem., 2011, 76, 6592–6603; (m) B. Luo,
A. L. Thompson, V. Gouverneur and T. D. W. Claridge,
Chem.–Eur. J., 2012, 18, 13133–13141; (b) D. D. Staas,
K. L. Savage, V. L. Sherman, H. L. Shimp, T. A. Lyle,
L. O. Tran, C. M. Wiscount, D. R. McMasters,
P. E. J. Sanderson, P. D. Williams, B. J. Lucas, J. A. Krueger,
S. D. Lewis, R. B. White, S. Yu, B. K. Wong, C. J. Kochansky,
M. R. Anari, Y. Yan and J. P. Vacca, Bioorg. Med. Chem.,
2006, 14, 6900–6916; (c) L. E. Combettes, P. Clausen-Thue,
M. A. King, B. Odell, A. L. Thompson, V. Gouverneur and
T. D. W. Claridge, Chem.–Eur. J., 2012, 18, 13133–13141;
(d) J. A. Hodges and R. T. Raines, J. Am. Chem. Soc., 2003,
125, 9262–9263; (e) J. T. Gerig and R. S. McLeod, J. Am.
Chem. Soc., 1973, 95, 5725–5729.
F. Marcelo, J. Desire, Y. Zhang, M. Sollogoub, A. Kato, 15 (a) R. Surmont, G. Verniest, A. De Groot, J. W. Thuring and
I. Adachi, F. J. Canada, J. Jimenez-Barbero and Y. Bleriot,
J. Carbohydr. Chem., 2011, 30, 641–654; (n) F. Marcelo,
Y. He, S. A. Yuzwa, L. Nieto, J. Jimenez-Barbero,
M. Sollogoub, D. J. Vocadlo, G. D. Davies and Y. Bleriot,
N. De Kimpe, Adv. Synth. Catal., 2010, 352, 2751–2756;
(b) S. Singh, C.-M. Martinez, S. Calvet-Vitale, A. K. Prasad,
T. Prangé, P. I. Dalko and H. Dhimane, Synlett, 2012, 2421–
2425.
J. Am. Chem. Soc., 2009, 131, 5390–5392; (o) H. Li, 16 (a) A. R. Patel and F. Liu, Tetrahedron, 2013, 69, 744–752.
F. Marcelo, C. Bello, P. Vogel, T. D. Butters, A. P. Rauter,
Y. Zhang, M. Sollogoub and Y. Bleriot, Bioorg. Med. Chem.,
2009, 17, 5598–5604; (p) H. Li, T. Liu, Y. Zhang, S. Favre,
C. Bello, P. Vogel, T. D. Butters, N. G. Oikonomakos,
For another example of azepane fluorination, see:
(b) M. Mondon, N. Fontelle, J. Desire, F. Lecornue,
J. Guillard, J. Marrot and Y. Bleriot, Org. Lett., 2012, 14,
870–873.
J. Marrot and Y. Bleriot, ChemBioChem, 2008, 9, 253–260; 17 A gauche preference of 1–3 kcal mol−1 is observed in
(q) T.-L. Shih, R.-Y. Yang, S.-T. Li, C.-F. Chiang and
C.-H. Lin, J. Org. Chem., 2007, 72, 4258–4261; (r) H. Li,
C. Schuetz, S. Favre, Y. Zhang, P. Vogel, P. Sinay and
uncharged molecules containing the N–C–C–N3 motif; see:
L.-S. Sonntag, S. Schweizer, C. Ochsenfeld and
H. Wennemers, J. Am. Chem. Soc., 2006, 128, 14697–14703.
Y. Bleriot, Org. Biomol. Chem., 2006, 4, 1653–1662; 18 A gauche preference of 5.7 kcal mol−1 is observed in
(s) Y. Bleriot, M. I. Simone, M. R. Wormald, R. A. Dwek,
D. J. Watkin and G. W. J. Fleet, Tetrahedron: Asymmetry,
2006, 17, 2276–2286; (t) P. Wipf and S. R. Spencer, J. Am.
FCH2CH2NH3+; see: C. R. Briggs, M. J. Allen, D. O’Hagan,
D. J. Tozer, A. M. Z. Slawin, A. E. Goeta and
J. A. K. Howard, Org. Biomol. Chem., 2004, 2, 732–740.
3784 | Org. Biomol. Chem., 2013, 11, 3781–3785
This journal is © The Royal Society of Chemistry 2013

View Article Online
Organic & Biomolecular Chemistry
Communication
19 See ESI.†
(c) P. Tähtinen, A. Bagno, K. D. Klika and K. Pihlaja, J. Am.
Chem. Soc., 2003, 125, 4609–4618.
20 Three-bond H–H and H–F coupling constants obey Karplus
relationships with the corresponding H–C–C–H and H–C– 21 For comparison, analogues of 2 and 3 in which the fluorine
3
C–F dihedral angles: “typical” JHH values are 1–3 Hz for
gauche alignments and 6–9 Hz for anti alignments; see:
(a) A. M. Ihrig and S. L. Smith, J. Am. Chem. Soc., 1970, 92,
759–763. “Typical” 3JHF values are 5–15 Hz for gauche align-
ments and 25–35 Hz for anti alignments; see:
substituents were replaced with hydroxyl groups were also
examined. The similarities and differences observed
between these two polar substituents are presented in pre-
liminary form in the ESI,† and will be described more fully
in a forthcoming publication.
(b) C. Thibaudeau, J. Plavec and J. Chattopadhyaya, J. Org. 22 For examples of conformational synergy/competition in
Chem., 1998, 63, 4967–4984. For an example of confor-
fluorinated peptides, see: R. I. Mathad, F. Gessier and
mational analysis by NMR and DFT methods, see:
D. Seebach, Helv. Chim. Acta, 2005, 88, 266–280.
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem., 2013, 11, 3781–3785 | 3785