The vicinal F-C-C-F moiety as a tool for influencing peptide conformation

Article abstract of DOI:10.1039/b506010a

Diastereoisomers of bis(amino acid amides) of 2,3-difluorosuccinic acid have been prepared and the erythro- and threoisomers display very different conformations. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b506010a

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The vicinal F–C–C–F moiety as a tool for influencing peptide
conformation
Martin Schu¨ler, David O’Hagan* and Alexandra M. Z. Slawin
Received (in Cambridge, UK) 29th April 2005, Accepted 8th June 2005
First published as an Advance Article on the web 14th July 2005
DOI: 10.1039/b506010a
Diastereoisomers of bis(amino acid amides) of 2,3-difluorosuc-
cinic acid have been prepared and the erythro- and threo-
isomers display very different conformations.
Strategic replacement of fluorine for hydrogen has been widely
employed in the pharmaceutical industry to protect candidate
bioactives against adventitious metabolism1,2 or in the develop-
ment of mechanism-based enzyme inhibitors.3 We have been
exploring another aspect of fluorine incorporation into organic
molecules whereby the polarity of the C–F bond is used as a tool
Scheme 1 Reagents and conditions: a) NBS, HF/py, Et2O; b) AgF,
for influencing the conformation of organic compounds.4 There
are attractive prospects here, not only in the bioactives arena, but
also for the development of performance materials products.5
Recently we reported that a-fluoroamides have a preferred
stereoelectronic orientation, where the C–F bond is syn-coplanar
with the N–H bond and anti-coplanar to the amide carbonyl.6 This
is a significant effect in energy terms, with a barrier to rotation of
around 8.0 kcal mol21 when evaluated in small molecules. Seebach
has recently shown that pairs of b-amino acid derived oligopep-
tides, which differ only in which enantiomer of 2-fluoro-b-alanine
is present at the centre of the molecule, possess different secondary
structures.7 The C–F bond is argued to be a significant contributor
to these experimental observations. Thus diastereoisomers gene-
rated by the interconversion of a single C–F bond can differently
and significantly influence the conformation of larger molecules
through such stereoelectronic effects.
73%; c) O3, AcOH, H2O2, 45%; d) PheOMe, EDCI, HOBt, DMF, 83%; e)
aq. HCl–acetone, 100%.
threo-stereoisomers 2, according to the one pot procedure reported
by Olah.11 The major product is the erythro/meso-isomer,
consistent with a predominant double inversion mechanism due
to aryl participation.12 Both of the diastereoisomers of 2 could be
purified by a combination of chromatography and crystallisation.
For preparative purposes 2 was used either as the 1:1 isomeric
mixture or as the predominant erythro/meso-stereoisomer which
can conveniently be crystallised to purity. Treatment with ozone13
followed by oxidative work up generated the corresponding
difluorosuccinic acids
3 without any stereochemical loss.
Yagupolskii et al.14 have prepared erythro-difluorosuccinic acid
3a by direct treatment of L-tartaric acid with SF4 in the presence of
hydrogen fluoride, and the threo-stereoisomer 3b was prepared in a
similar manner by Hudlicky.15 Our attempts to use DAST in such
a reaction failed and thus the synthetic route depicted in Scheme 1
offers a practical route, certainly for the small scale preparation of
3a and 3b.
The lower energy gauche- versus anti-conformer for 1,2-
difluoroethane has been widely studied and the fluorine gauche-
effect is a well known phenomenon in organofluorine chemistry.8
The effect extends to erythro- and threo-stereoisomers of organic
compounds such as 2,3-difluorobutane9 and 9,10-difluorostearic
acids; compounds which differ in physical properties and display
quite distinct behaviour, as a consequence of a single stereogenic
C–F bond inversion.10 In this study the a-fluoroamide and vicinal
fluorine gauche-preferences are explored in erythro- and threo-
diastereoisomers of a series of bis(amino acid) 2,3-difluorosucci-
namides. It was anticipated that the two different diastereoisomers
would display different conformational preferences as a result of
the relative stereochemistry of the vicinal C–F bonds.
To prepare a bis(amino acid amide), (S)-phenylalanine methyl
ester and 2,3-difluorosuccinic acids 3 (1:1 diastereoisomeric mix)
were treated with EDCI/HOBt to form the bis(amino ester amides)
4 as a diastereoisomeric mixture. Interestingly, all of the three
stereoisomers of
4 (Fig. 1) could be separated by flash
chromatography. This allowed the hydrolysis of the individual
stereoisomers 4a–c under acidic conditions, to generate the
corresponding dicarboxylic acids 5a, 5b, and 5c.
Both the threo- and the erythro-stereoisomers, 5a and 5b
respectively, gave suitable crystals for X-ray analysis and the
resultant structures are shown in Figs. 2 and 3.{ The approximate
relative relationships of the functional groups along C2–C3 for 5a
and 5b are illustrated by the Newman projections. It is notable that
for each structure a gauche-relationship is maintained between the
vicinal fluorines (F–C–C–F angle 54u in 5a and 77.1u in 5b). Also,
the a-fluoroamide functionalities hold an approximate planar
arrangement in each case. This is distorted a little in one of the
The diastereoisomeric mixture of the erythro/meso- (3a) and
threo-isomers (3b) was prepared as illustrated in Scheme 1.
Treatment of trans-stilbene 1 with N-bromosuccinamide in
the presence of hydrogen fluoride, followed by addition of
silver fluoride, generated
a 4:1 mixture of erythro- and
School of Chemistry and Centre for Biomolecular Sciences, University of
St. Andrews, North Haugh, St. Andrews, Fife, UK KY16 9ST.
E-mail: do1@st-and.ac.uk; Fax: +44 1334 463808; Tel: +44 1334 467176
4324 | Chem. Commun., 2005, 4324–4326
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Fig. 3 X-Ray structure of 5b, which was obtained by direct hydrolysis of
4b. There were two molecules of 5b in the asymmetric unit with similar
conformations; only one is shown. The 2,3-difluorosuccinamide moiety is
very different from 5a (Fig 2). Selected bond lengths (s) and torsion angles
(u) for 5b: N3–C4 1.349(9), N3–H(3N) 0.9800(13), C4–O4 1.236(8), C5–F5
1.406(7), C5–C6 1.538(9), C7–O7 1.229(8), C7–N8 1.345(8), N(8)–H(8N)
0.9800(11); O4–C4–C5–F5 2176.1(6), N3–C4–C5–F5 4.8(8), F5–C5–C6–
F6 75.2(6), F6–C6–C7–O7 2178.0(5), F6–C6–C7–N8 3.4(8). Flack
parameter 21.6(14).
Fig. 1 Structures, optical rotation values and 19F-NMR spectra of 4a–c.
amides in 5a [N(3)–C(4)–C(5)–F(5) dihedral angle of 223.8u]. In
the crystal packing diagram the amide N(3)–H is involved in an
intermolecular hydrogen bonding interaction with the carbonyl of
another amide (not shown) which results in a small deviation from
…
the ideal anti-planar geometry and a close N(H) F interaction to
fluorine F(5). However, in the main, the anti-planar a-fluoroamide
is a feature of these structures.
The 2,3-difluorosuccinamide moiety in structure 5a has the
carbon chain in an anti-zig-zag conformation with a C–C–C–C
torsion angle of 163u, whereas in 5b this torsion angle is 78.3u.
Thus for the different diastereoisomers the main chain of the 2,3-
difluorosuccinamide moiety is contorted quite differently. In both
cases the fluorines are gauche, whereas the amides are anti to each
other in 5a but gauche in 5b. Thus the relative configuration of the
C–F bonds is influencing the overall conformation of these
bis(amides), and in a predictable manner. These solid state
conformations are also supported by solution state NMR studies.
The 19F-NMR spectra for each of the diastereoisomers of 5 are
3
3
shown in Fig. 1 and the JHH and JHF coupling constants for 4
and 5 are shown in Table 1. The threo-stereoisomers give rise to an
AA9XX9 spin system due to the magnetic non-equivalence of the
vicinal fluorines and their geminal hydrogens. The erythro-
stereoisomers 4b and 5b have truly diastereotopic fluorines and
Fig. 2 X-Ray structure of 5a, which was obtained from 4a by direct
hydrolysis. The carbon chain conformation of the 2,3-difluorosuccinamide
moiety is very different from 5b (Fig 3), but conforms to that predicted by
the fluorine gauche-effect and the a-fluoride amide effect. Selected bond
lengths (s) and torsion angles (u) for 5a: N3–C4 1.338(7), N3–H(3N)
0.9800(11), C4–O4 1.214(7), C5–F5 1.397(7), C5–C6 1.495(10), C5–H(5A)
1.0000, C7–O7 1.220(7), C7–N8 1.332(7), N(8)–H(8N) 0.9800(12); O4–
C4–C5–F5 155.4(6), N3–C4–C5–F5 223.8(8), F5–C5–C6–F6 49.0(6), F6–
C6–C7–O7 2165.6(6), F6–C6–C7–N8 212.2(8). Flack parameter
0.23(13).
Table 1 NMR derived coupling constants (J) for compounds 4 and 5
Compound
3JHF
3JHH
3JFF
2JHF
threo-4a
erythro-4b
threo-4c
threo-5a
erythro-5b
threo-5c
30.5
23.0
30.9
31.8
24.1
31.1
1.3
1.3
1.4
1.0
1.3
1.5
12.0
12.0
12.3
12.0
12.3
10.0
46.1
48.0
45.6
44.9
47.4
45.6
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therefore show first order spectra. In a similar manner to the
3
Karplus relationship for JHH coupling constants, the magnitude
Notes and references
{ Crystal data for pseudopeptide 5a: M 5 486.87; orthorhombic, space
group P2(1)2(1)2(1); a 5 4.9826(19), b 5 22.066(10), c 5 24.319(9) s;
3
of the JHF coupling constants have an angular dependence,
V 5 2673.7(18) s3; T 5 173(2) K; Z 5 4; m 5 (Mo-Ka) 1.709 mm21
;
although these values are quite sensitive to the nature of the other
substituents.16 On the other hand the 3JFF coupling constants are
not reliable indicators of vicinal relationships.17
reflections: total 5 35848, unique 4760 (Rint 0.1355); R1 5 0.1260,
wR2 5 0.3296 for 4760 observed data [I . 2s(I)]. CCDC 271257.
Crystal data for pseudopeptide 5b: M 5 448.42; monoclinic, space group
P2(1); a 5 11.121(2), b 5 6.1323(10), c 5 30.671(6) s; b 5 90.179(6)u;
The large 3JHF (y30 Hz) and small 3JHH (1.0–1.5 Hz) coupling
constant values for the threo-a/c isomers can be contrasted with the
smaller 3JHF (y23 Hz) coupling constants for the difluoro-erythro-
V 5 2091.8(7) s3; T 5 93(2) K; Z 5 4; m 5 (Mo-Ka) 0.115 mm21
;
reflections: total 5 13463, unique 6970 (Rint 0.0887); R1 5 0.0825,
wR2 5 0.1525 for 4011 observed data [I . 2s(I)]. CCDC 271258. See http://
dx.doi.org/10.1039/b506010a for crystallographic data in CIF or other
electronic format.
3
b isomers. In the threo-a/c isomers the larger JHF coupling
constants indicate that both C–F bonds have a vicinal C–H bond
anti to each other, as found in the solid state structure of 5a, and
they also conserve a fluorine gauche-relationship (see Newman
projections, Figs 2 and 3). The smaller 3JHF coupling constants of
the erythro-series are consistent with a solution conformation
where the vicinal fluorines are predominantly gauche with respect
to each other. Concurrently, the small 3JHH coupling constants in
each series indicate a vicinal gauche-H–H relationship in each case
(see Newman projections in Figs 2 and 3). Hence it can be
concluded that for each diastereoisomeric series the vicinal
fluorines prefer a gauche-relationship, which influences the relative
orientation of the peripheral amides. We note that the threo-
diastereoisomers (4a and 4c) had very different optical rotation
[a]D values ranging from 258.0u to +19.4u (Fig 1).
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A series of amino acids, including (S)-alanine, (S)-valine
and (S)-leucine, were then coupled as their methyl esters to
erythro/meso-difluorosuccinic acid 3a, prepared from the purified
meso-difluorodiphenylethane 2a by means of ozonolysis. This
generated the erythro-stereoisomers 6, 7 and 8 respectively, in
enantiomerically pure form. The NMR coupling constants of all
these compounds resemble closely those values for the erythro-
compounds 4b and 5b, and thus similar solution state conforma-
tions of the difluorosuccinamide moiety can be assumed.
In summary, the bis((S)amino acid ester) amides of 2,3-
difluorosuccinic acid, 4a–c, have been prepared in diastereomeri-
cally pure form. The solid state conformations of the hydrolysed
bis(acids) 5a and 5b suggest that the a-fluoro amides adopt an
approximately anti-planar arrangement and solution state NMR
data of 4 and 5 indicate that the vicinal fluorines adopt a gauche-
conformation within the difluorosuccinamide moiety, and that the
amide groups are orientated differently for the two diastereoiso-
meric series. Such behaviour of the C–F bond should be useful in
the design of peptide mimetics and in influencing the conformation
of bioactive molecules.
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4326 | Chem. Commun., 2005, 4324–4326
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