Synthesis and conformation of fluorinated β-peptidic compounds

Article abstract of DOI:10.1002/chem.201200313

Experimental and theoretical data indicate that, for α-fluoroamides, the F-C-C(O)-N(H) moiety adopts an antiperiplanar conformation. In addition, a gauche conformation is favoured between the vicinal C-F and C-N(CO) bonds in N-β-fluoroethylamides. This study details the synthesis of a series of fluorinated β-peptides (1-8) designed to use these stereoelectronic effects to control the conformation of β-peptide bonds. X-ray crystal structures of these compounds revealed the expected conformations: with fluorine β to a nitrogen adopting a gauche conformation, and fluorine α to a C=O group adopting an antiperiplanar conformation. Thus, the strategic placement of fluorine can control the conformation of a β-peptide bond, with the possibility of directing the secondary structures of β-peptides. Copyright

Full text of DOI:10.1002/chem.201200313

FULL PAPER
DOI: 10.1002/chem.201200313
Synthesis and Conformation of Fluorinated b-Peptidic Compounds
Victoria Peddie,[a, b] Raymond J. Butcher,[c] Ward T. Robinson,[b] Matthew C. J. Wilce,[d]
Daouda A. K. Traore,[d] and Andrew D. Abell*[a]
Abstract: Experimental and theoretical
data indicate that, for a-fluoroamides,
8) designed to use these stereoelec-
tronic effects to control the conforma-
tion of b-peptide bonds. X-ray crystal
structures of these compounds revealed
the expected conformations: with fluo-
rine b to a nitrogen adopting a gauche
conformation, and fluorine a to a C=O
group adopting an antiperiplanar con-
formation. Thus, the strategic place-
ment of fluorine can control the con-
formation of a b-peptide bond, with
the possibility of directing the secon-
dary structures of b-peptides.
À À
À
the F C C(O) N(H) moiety adopts
an antiperiplanar conformation. In ad-
dition, a gauche conformation is fav-
À
À
oured between the vicinal C F and C
N(CO) bonds in N-b-fluoroethyla-
mides. This study details the synthesis
of a series of fluorinated b-peptides (1–
Keywords: amino acids · conforma-
tion analysis · organofluorine · pep-
tides · X-ray diffraction
Introduction
preference for the antiperiplanar conformation outweighs
the benefits associated with complete helix formation, such
as hydrogen-bonding and side-chain interactions; the result
is a “bend” in the backbone. Thus, the introduction of
a single fluorine into the backbone of a peptide can influ-
ence the secondary structure of peptides, in this case either
to stabilise or disrupt a 314-helix. The thermodynamic ad-
vantage of forming a helix overcomes the conformational
effect of the fluorine in b-peptides containing greater than
thirteen residues. This results in the fluorine being 908 to the
carbonyl oxygen, and helix formation occurring over the
entire length of the peptide.[3]
In addition, Raines and co-workers have reported hyper-
stable analogues of collagen in which natural 4(R)-hydroxy-
proline residues are replaced with 4(R)-fluoro-l-proline
(Flp).[4] The enhanced stability imparted by Flp is attributed
to the gauche effect between the amide nitrogen and the flu-
orine, which dictates the pyrrolidine ring pucker and pre-or-
ganises the three main-chain torsion angles to facilitate
triple helix formation.[5] This effect has been observed in
a number of other structures that contain two vicinal elec-
tronegative substituents. For example, OꢀHagan and col-
leagues have shown that the fluorine–amide gauche effect in
N-b-fluoroethylamides is especially strong.[6] A theoretical
analysis of N-b-fluoroethylamides revealed an energy differ-
ence of approximately 1.8 kcalmolÀ1 between the antiperi-
It has recently been reported that b-peptides, which differ
only in the absolute configuration of a centrally located a-
fluoro-b-homoalanine unit, adopt different secondary struc-
tures.[1] In particular, when the b-heptapeptide containing
(2R,3S)-a-fluoro-b-homoalanine adopts an extended 314-
helix the analogous peptide containing (2S,3S)-a-fluoro-b-
homoalanine does not. In this case the peptide assumes
a structure with two quasi-helical termini separated by a cen-
tral turn with a ten-membered hydrogen-bonded ring. The
À À
difference in the two structures was attributed to the F C
C(O) N(H) moiety in both peptides adopting an energeti-
À
cally favourable antiperiplanar conformation between the
[2]
À
C F and C=O bonds. This conformation is compatible,
and in fact stabilises, the helical conformation observed for
the former peptide. However, a helical structure for the
latter peptide is incompatible with an antiperiplanar confor-
À
mation between the C F and C=O bonds. This energetic
[a] Dr. V. Peddie, Prof. A. D. Abell
School of Chemistry and Physics, The University of Adelaide
Adelaide, SA 5005 (Australia)
Fax : (+61)8-8303-4380
E-mail: andrew.abell@adelaide.edu.au
À
À
planar and gauche conformations of the C N and C F
bonds.
[b] Dr. V. Peddie, Prof. W. T. Robinson
Department of Chemistry, University of Canterbury
Private Bag 4800, Christchurch (New Zealand)
More detailed fundamental structural information on the
secondary structure preferences of fluoro-substituted b-pep-
tides is required if we are to better define and understand
the influence of these fluorine stereoelectronic effects on
peptide conformation. To date detailed X-ray data on the
[c] Prof. R. J. Butcher
Department of Chemistry, Howard University
Washington DC 20059 (USA)
[d] Prof. M. C. J. Wilce, Dr. D. A. K. Traore
Department of Biochemistry and Molecular Biology
Monash University, Clayton, Victoria 3168 (Australia)
À
conformational effects associated with the C F bond in fluo-
roamide structures have been largely limited to simple
amides, or involve structures containing vicinal fluorine
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201200313.
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atoms.[2,6–7] In this study we report the synthesis and X-ray
structure of a series of monofluorinated b-amino acids and
peptides derived from them in order gain systematic insight
into the associated conformational preferences. This is the
first comprehensive study of this type and it helps pave the
way for the design of b-peptides with predictable and con-
trollable conformations. The effect of fluorine adds to our
ability to control the conformation of peptides based on nat-
ural effects.
tioned b to a nitrogen and a to a C=O group in an a-fluoro-
b-amino acid (see compound 4). This combines the interac-
tions present in both N-b-fluoroethylamides and a-fluoro-
AHCTUNGTREGaNNUN mides into the one structure. The antiperiplanar preference
of peptide-based a-fluoroamides was investigated by attach-
ing a-fluoropropionic acid to a-fluoro-b2-amino acid. The
further attachment of b-fluoroethylamine to the C terminus
resulted in compound 5, which has two amide groups, each
with two adjacent fluorine atoms, one positioned a to the
carbonyl group, and the other b to the nitrogen of the
amide. This derivative thus provides potential for a combina-
tion of both the antiperiplanar and gauche conformational
effects to define the conformation of the constituent amides.
Dipeptides incorporating a-fluoro-b-amino acids were
synthesised (see structures 6, 7, and 8). Coupling an a-
fluoro-b-amino acid unit to a second amino acid, as in 6 and
7, provides an opportunity to define the influence on a true
peptide bond. The dipeptide 8, containing two a-fluoro-b2-
homophenylalanine units, was also investigated. The termi-
nal amine in 8 is vicinal to fluorine, and the carbonyl of the
bromophenyl ester is positioned a to fluorine. The confor-
mational influence of fluorine on esters is known to be less
pronounced than the corresponding amide.[8] This structure
provides an example with a number of contributing confor-
mational influences. The bromophenyl ester was introduced
to facilitate crystallisation.
Results and Discussion
We chose to incorporate b-fluoroethylamine and a-fluoro-
propionic acid units into a variety of fluorinated and non-
fluorinated b2- and b3-amino acids in order to investigate the
influence of the fluorine conformational effects on the pep-
tide backbone conformation (Figure 1). As discussed, these
Synthesis: b-Fluoroethylamine·HCl was coupled to the b3-
amino acids, N-Boc-b3 hLeu-OH (11) and N-Boc-b3 hVal-OH
(12), in the presence of O-(7-azabenzotriazol-1-yl)-
N,N,N’,N’-tetramethyluronium
hexafluorophosphate
(HATU) and N,N-diisopropylethylamine (DIPEA) to give
1 and 2, respectively (Scheme 1).[9,10] Crystals of 1 and 2 suit-
Figure 1. Target compounds.
Scheme 1. Reagents and conditions: a) LiOH, 3:1 MeOH/H2O; b) b-fluo-
roethylamine·HCl, HATU, DIPEA, DMF.
two units have been reported to define gauche and antiperi-
planar conformational preferences in simple fluoroamides,
and as such provide a point of reference.[2,6]
Here we report the attachment of b-fluoroethylamine to
b-amino acids to examine the gauche effect in peptidic N-b-
fluoroethylamide. Both b2- and b3-amino acids (3 and 1–2,
respectively) were used to investigate whether or not the po-
sition of the amino acid side chain influences the conforma-
tion of the fluoroamide backbone. A fluorine was also posi-
able for X-ray crystallography were grown by slow evapora-
tion in ethyl acetate. The acids 11 and 12 were conveniently
prepared by hydrolysis of their corresponding methyl esters
9
[11] and 10,[11] respectively.
Derivative 3 was prepared as outlined in Scheme 2. The
key synthesis precursor (b2-amino acid 16) was prepared by
an initial diastereoselective aminomethylation of the Ti-eno-
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Fluorinated b-Peptidic Compounds
FULL PAPER
nesulfonimide (NFSI) to give 19 in 54% yield and >95%
diastereometric excess, as determined by 19F NMR spectros-
copy. The bulky oxazolidinone chiral auxiliary of 19 was
then removed on treatment with LiOOH to give the key
starting material 20. This acid was coupled with the amine
salt 22 (prepared from 21[15] as shown) in the presence of
HATU, to give 23. The methyl ester of 23 was hydrolysed,
and the resulting acid 24 coupled to b-fluoroethylamine·HCl
to give 5 in 47% yield. Recrystallisation, by slow evapora-
tion in ethyl acetate solution, gave crystals of 5 suitable for
X-ray crystallography.
The a-fluoro-b2-amino acid derivative 21 was also used to
prepare 6 (Scheme 4). Hydrolysis of the methyl ester of 21,
with LiOH, gave the free acid 25 and this was coupled to H-
Scheme 2. Reagents and conditions: a) TiCl4, Et3N, DCM, À208C, then
MeOCH2NHCbz (14), TiCl4, DCM, 08C, (42%); b) LiOH, H2O2, 4:1
THF/H2O, 0 8C to room temperature (62%); c) b-fluoroethylamine·HCl,
HATU, DIPEA, DMF (69%).
late of 13[12] with benzyl N-(methoxymethyl)carbamate
(14)[13] to give 15 in 42% yield (>95% de as determined by
1H NMR spectroscopy).[14] Removal of the oxazolidinone
auxiliary on treatment with LiOOH (formed in situ) gave 16
in 62% yield. This acid was then coupled to b-fluoroethyla-
mine·HCl, in the presence of HATU, to give 3 in 69% yield.
Crystals of 3 were grown by recrystallisation from petroleum
ether/ethyl acetate.
The trifluorinated analogue 5 was prepared as shown in
Scheme 3. The acid chloride of propionic acid 17 was treated
with (4R)-4-benzyl-2-oxazolidinone to give the oxazolidi-
none 18 in 78% yield. This was deprotonated with LDA and
the corresponding enolate was treated with N-fluorobenze-
Scheme 4. Reagents and conditions: a) LiOH, 3:1 MeOH/H2O (100%);
b) TFA-(S)-b3 hLeu methyl ester, HATU, DIPEA, DMF, (72%);
c) LiOH, 3:1 MeOH/H2O (100%); d) EDCI, DMAP, p-bromophenol,
DCM (77%).
b3-hLeu-OMe,[11] in the presence of HATU, to give 26 in
72% yield. The methyl ester of 26 was hydrolysed, and the
resulting acid 27 was re-esterified with p-bromophenol to
give 6 in 70% yield. This material was crystallised from
ethyl acetate to give crystals suitable for X-ray crystallo-
graphic analysis.
Derivative 7 was prepared from a-fluoro-b3-amino acid
4[15] (Scheme 5). Ester hydrolysis of the a-fluoro-b3-amino
methyl ester 4 gave the acid 28 in 92% yield. HATU-medi-
ated coupling of this acid to H-b3-hLeu-OMe[11] then gave
the dipeptide 7 in 76% yield. This dipeptide was recrystal-
lised by slow evaporation in dichloromethane to give crys-
tals suitable for X-ray crystallography.
The dipeptide 8, consisting of two a-fluoro-b2-amino
acids, was prepared (Scheme 6). HATU mediated coupling
of 22 with 25 (prepared as shown in Schemes 3 and 4, re-
spectively) gave 29. The methyl ester of 29 was hydrolysed
on treatment with LiOH to give 30 and this was esterified
Scheme 3. Reagents and conditions: a) (4R)-benzyl-2-oxazolidinone, piv-
aloyl chloride, EtN3, DMAP, THF, À78 to 08C (78%); b) LDA, NFSI,
THF, À78 to 08C (54%); c) LiOOH, 4:1 THF/H2O, 0 8C to room temper-
ature (58%); d) TFA, DCM (100%); e) 22, HATU, DIPEA, DMF,
(35%); f) LiOH, 3:1 MeOH/H2O (99%); g) b-fluoroethylamine·HCl,
HATU, DIPEA, DMF (47%).
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A. D. Abell et al.
Scheme 5. Reagents and conditions: a) LiOH, 3:1 MeOH/H2O (92%);
b) H-b3 hLeu-OMe, HATU, DIPEA, DMF (76%).
Figure 2. X-ray crystal structure of 5. The disorder is shown by hollow
and dashed bonds.
structure of 8 was obtained with disorder in the bromophen-
yl ring, with two different possible positions of its ring.
À À À
Torsion angles of the F C C N(H) moiety: The crystal
À À À
structures of 1–4 and 6–8 all reveal the F C C N moiety in
À
À
the expected gauche conformation for the C F and C N
bonds as shown by the torsion angles in Table 1 and Table 2.
À
The X-ray structure of 5 reveals disorder in the terminal F
À À
C C N(H) moiety, without a preference for a particular
conformation. Although literature indicates that the gauche
À À À
conformation for the F C C N(H) moiety is favoured over
the anti conformation by 1.8 kcalmolÀ1,[6a] this small energy
difference can be overcome by the crystal packing of 5 to
Scheme 6. Reagents and conditions: a) HATU, DIPEA, DMF, (79%);
b) LiOH, 3:1 MeOH/H2O (100%): c) EDCI, DMAP, p-bromophenol,
DCM (43%).
À À À
Table 1. Torsion angles of N C C F in crystal structures with an inter-
nal fluorine.
À À À
Compound
N C C F
Torsion angle [8]
À
À
À
4
5
N C(6) C(14) F
61.5(2)
À73.7(6)
À73.9
À
À
À
N(1) C(4) C(5) F(2)
with p-bromophenol to give 8 in order to aid the formation
of single crystals suitable for X-ray crystallography.
6a[a]
6b[a]
7a[a]
7b[a]
8
N(1A) CACTHUNRTGNEUNG(11B) C(9A) F(1A)
N(1B) C
N(1A) C(6A) C
N(1B) C(6B) C
N(1) C(6) C(7) F(1)
N(2) C(16) C(17) F(2)
À
À
À
À
À
À
(11B) C(9B) F(1B)
À68.5
À
À
À
N
60.2(10)
62.3(10)
59.5(11)
53.5(13)
À
À
À
Structure studies: X-ray crystal structures of compounds 1–8
were determined in order to define the associated conforma-
tional preferences, and also to confirm the relative stereo-
chemistry.[15,16] The presence of a bromine, in compounds 6
and 8 allowed assignment of the absolute configuration of
these compounds by using the Flack parameter.
A
À
À
À
À
À
À
[a] Refers to more than one distinct molecule in the asymmetric unit.
À À À
The structures of 2, 3 and 4 were obtained without disor-
der and with a single molecule in the asymmetric unit. How-
ever, the structure obtained for compound 1 had disorder in
the amino acid side chain and three molecules in the asym-
metric unit. The structure of 5 also contained disorder, in
the N-b-fluoroethylamide group (Figure 2). The F3 fluorine
on carbon 15 occupies three different positions in the crystal
structure. The ratio for the three positions, F3A, F3B and
F3C, is 0.387(4):0.268(16):0.345(16).
Table 2. Torsion angles of N C C F in crystal structures with a terminal
fluorine.
À À À
Compound
N C C F
Torsion angle [8]
1a[a]
1b[a]
1c[a]
2
3
5
N(2A) CACTHNUTRGENNG(U 13A) CACHTUNGTRENN(UGN 14A) F(1A)
À69.9(8)
À70.1(8)
À70.3(9)
71.7(8)
À66.5(10)
À178.4(10)
À78.4(13)
58.7(17)
À
À
À
À
À
À
N(2B) CACTHNUTRGENNG(U 13B) CACHTUNGTRENN(UGN 14B) F(1B)
À
À
À
N(2C)
C
G
ACHTUNGTRENNUNG
À
À
À
N(2) C(12) C(13) F
À
À
À
N(2) C(19) C(20) F
N(2) C(14) C(15) F(3A)
N(2) C(14) C(15) F(3B)
N(2) C(14) C(15) F(3C)
À
À
À
À
À
À
À
À
À
The X-ray crystal structures of 6 and 7 each contained
two molecules in the asymmetric unit without disorder. The
[a] Refers to more than one distinct molecule in the asymmetric unit.
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Fluorinated b-Peptidic Compounds
FULL PAPER
allow the fluorine to occupy all three possible positions. The
terminal location of fluorine might be expected to result in
a greater influence due to crystal packing forces. The inter-
À À À
nal F C C N(H) moiety in 5 adopts the expected gauche
conformation with a torsion angle of À73.78. It might also
be possible that additional dipole–dipole interactions within
À
the molecule, due to the presence of the three C F bonds,
À À À
overrule the gauche effect in the terminal F C C N(H)
moiety.
À À
Torsion angles of the F C C=O moiety: The crystal struc-
tures of 4–7 all show an antiperiplanar conformation be-
À
À
tween the C F and C=O bonds, with torsion angles for F
À
À À
C C=O ranging from 172.4 to 179.78 (Table 3). The F C
À À À
Table 3. Torsion angles of F C C O in crystal structures.
À À
F C C=O
Compound
Torsion angle [8]
À
À
À
4
5
F C(14) C(15) O(3)
174.8(2)
À172.4(6)
À179.7(4)
177.6
À
À
À
F(1) C(2) C(3) O(1)
À
À
À
F(2) C(5) C(13) O(2)
F(1A) C(9A) C(8A) O(3A)
F(1B) C(9B) C(8B) O(3B)
F(1A) C
F(1B) C
F(1) C(7) C(15) O(3)
F(2) C(17) C(25) O(4)
6a[a]
6b[a]
7a[a]
7b[a]
8
À
À
À
À
À
À
179.4
À
À
À
(14A) C
N
À175.2(9)
À175.3(10)
177.3(11)
154.5(12)
À
À
À
A
(15B) O(3B)
À
À
À
À
À
À
[a] Refers to more than one distinct molecule in the asymmetric unit.
Figure 3. Literature backbone fluorinated peptidic compounds with X-ray
crystal structures.
C=O torsion angle for the a-fluoroester in 8 was 154.58.
This slight deviation from the antiperiplanar conformation
might be due to steric clash, between the phenyl rings of the
bromophenyl ester and the phenylalanine side chain, over-
coming the conformational preference. It is also important
155.4(6)8, with distortion from the ideal antiperiplanar con-
formation being attributed to crystal packing interactions. In
À
À
to note that the conformational preference for the C F
bond to be antiperiplanar to the C=O bond, a conformation
the crystal packing diagram the N H group of the amide is
involved in an intermolecular hydrogen bond with the car-
bonyl of another amide and this results in a small deviation
from the ideal antiplanar geometry. Both the syn and anti
isomers adopt the preferred gauche conformation between
the two fluorine atoms, and in the anti isomer (32) both flu-
orine atoms align antiperiplanar to the amide carbonyls. To
accommodate these conformational preferences the two dia-
stereoisomers adopt very different backbone conformations;
the syn isomer adopts an anti-zig-zag conformation, whereas
the anti isomer has a bend in the carbon backbone.
À
in which the C F dipole opposes the carbonyl dipole, is less
pronounced for an a-fluoroester than an a-fluoroamide.[8]
This is due to a reduced dipole moment for the ester car-
bonyl group. The energy difference between the trans and
cis conformers for an ester is reported to be approximately
3–3.5 kcalmolÀ1 lower than for the corresponding amides.[8]
Thus, the weaker antiperiplanar conformational preference
of the a-fluoroester in 8 is likely overcome by steric effects
and crystal packing. The a-fluoroamide moiety in 8 exhibit-
À
ed a classic antiperiplanar conformation between the C F
Hunter et al. reported the stereoselective synthesis of syn
and anti diastereoisomers of an a,b-difluoro-g-amino acid,
which were then incorporated into short peptides 33 and 34
(Figure 3).[7e] X-ray crystal structures of these peptides re-
vealed different backbone conformations, within accordance
À À
and C=O bonds, with a torsion angle for F C C=O of
177.38.
There are other reports of X-ray crystal structures of
backbone fluorinated peptidic compounds (Figure 3).
OꢀHagan has reported the synthesis and X-ray structures of
the peptides 31 and 32 that contain 2,3-diflurorosuccinic
acid cores.[7a,b] Here different conformations were observed
for the syn and anti vicinal fluorine stereochemistries. For
the syn isomer (31) one a-fluoroamide group deviates from
À
with the known conformational effects of fluorine: the a-C
F bond aligns antiparallel to the adjacent amide carbonyl,
À
À
the b-C F bond is gauche to the vicinal g-C N bond, and
the two vicinal fluorine atoms are gauche to each other. To
maintain these conformations the diastereoisomers must
adopt very different structures; the syn isomer forms an ex-
tended zig-zag structure, whereas the anti isomer has a bend
in the carbon backbone.
À
the expected antiperiplanar arrangement between the C F
and C=O bond to a similar extent to that seen for com-
À À À
pound 8. The F C C O torsion angle was observed to be
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A. D. Abell et al.
The X-ray crystal structure of the Boc-b-dipeptide methyl
ester containing an a-fluoro-b3 homoalanine unit (35) re-
veals an antiperiplanar arrangement of the F and carbonyl
synthesised to investigate how the associated stereoelec-
tronic effects might influence the conformation of b-peptide
bonds through the strategic placement of fluorine. X-ray
crystal structures were obtained for eight compounds, with
structures 1–4 and 6–8 all exhibiting the expected gauche
À À
atom with a torsion angle of 173.38. In addition, the F C
À
C N torsion angle was observed to be À59.58, as for
a gauche conformation.[1c] This compound is very similar to
7 as both contain a syn-a-fluoro-b3-amino acid attached to
a b-amino acid, and both exhibit the expected conforma-
tions based on the conformational preferences seen in fluo-
roamide groups.
conformation between the vicinal C F and C N bonds, and
structures 4–7 showing an antiperiplanar conformation for
À
À
À À
À
the F C C(O) N(H) moiety.
The reduced dipole moment for an ester carbonyl group,
compared to an amide, results in a decreased preference for
À
The crystal structures of a-fluoro-b-amino acids 36, 37
and 38 have also been reported, with only 36 exhibiting the
a C F bond to be antiperiplanar to the C=O bond. This was
apparent for the C-terminal ester of the a-fluoroester 8 ex-
À
expected gauche conformation between the fluorine and
hibiting a torsion angle of 154.58 between the C F and C=O
bonds.
[17]
À À À
amine nitrogen (F C C N torsion angle of À53.08). The
À À À
F C C N torsion angle in 37 is À75.78, a slight deviation
Thus, the conformational effects associated with fluoroa-
mides can be used to control the conformation of peptide
bonds in small fluorinated b-peptides. These studies are im-
portant to future efforts to exploit the biological properties
of these structures, as conformation is implicitly linked to
biological function.[18] This complements other approaches
for controlling and influencing the conformation of peptides
and peptidomimetics.[19]
from the gauche conformation, and À171.98 in 38; this corre-
sponds to an antiperiplanar arrangement between the fluo-
rine and nitrogen. In all three structures, the a-fluoroester
functionalities do not adopt the expected antiperiplanar ar-
À
À À À
rangement between the C F and C=O bonds. The F C C
O torsion angles were À2.88 and À11.98 for compounds 36
and 37, respectively, showing synperiplanar arrangements,
and 127.48 for compound 38, an anticlinal conformation.
These observations contrast with those obtained for the a-
fluoro-b-amino acid 4, which exhibits all the expected con-
formational preferences. The deviations from the expected
conformations for 36–38 could be attributed to p stacking
between the phenyl rings in the structures, and to the steric
clash between the bulky groups in the molecules distorting
the conformations.
Experimental Section
Synthesis: Detailed synthetic procedures for all compounds and charac-
terisation data can be found in the Supporting Information.
X-ray diffraction analysis: Table 4 and Table 5 contain selected crystallo-
graphic data for compounds 1–8. X-ray crystallographic data for 1–5, 7
and 8 were collected on a Bruker APEXII diffractometer employing
The results in this study and
comparison made with other lit-
erature reports shed further
light on the backbone confor-
mations of fluorinated peptidic
compounds. The results also
demonstrate that these confor-
mations persist in the solid
state as defined in X-ray crystal
Table 4. Crystal data for compounds 1–4.
1
2
3
4
formula
Mr
C14H27FN2O3
290.38
C13H25FN2O3
276.35
98(2)
monoclinic
C2
21.349(5)
5.0311(8)
15.514(3)
90
109.19(2)
90
1573.7(5)
4
1.166
0.090
C20H23FN2O3
358.40
133(2)
orthorhombic
P2(1)2(1)2(1)
4.9335(19)
10.106(7)
37.26(2)
90
C16H22FNO4
311.35
135(2)
orthorhombic
P2(1)2(1)2(1)
5.2431(2)
9.1728(3)
33.9923(13)
90
temperature [K]
crystal system
space group
a [ꢂ]
b [ꢂ]
c [ꢂ]
133(2)
monoclinic
C2
23.647(19)
15.056(12)
14.321(12)
90
À À
À
structures; the F C C(O)
N(H) moiety adopts an antiper-
a [8]
iplanar
conformation,
and
b [8]
90
90
90
90
90
a gauche conformation is exhib-
g [8]
90
4955(7)
12
1.168
0.089
À
ited between the vicinal C F
V [ꢂ3]
Z
1857.6(18)
4
1.282
1634.82(10)
4
1.265
À
and C N(CO) bonds. However,
1calcd [gcmÀ3
]
these conformational preferen-
ces can be overridden by inter-
actions in the crystal structure,
such as crystal packing, steric
m [mmÀ1
]
0.093
0.098
crystal size [mm]
q range
total reflns
1.30ꢃ0.25ꢃ0.12
1.62 to 24.71
11783
0.80ꢃ0.78ꢃ0.02
2.78 to 25.24
9940
0.75ꢃ0.25ꢃ0.08
2.19 to 24.99
3164
0.50ꢃ0.35ꢃ0.25
1.20 to 30.21
38535
interactions
bonding.
and
hydrogen
independent reflns
4389
[Rint =0.0867]
0.7456 and 0.4084 1 and 0.658196
647
1.015
0.1125
0.3941
1584
[Rint =0.2118]
1894
2805
[Rint =0.0840]
1 and 0.018256
235
1.009
0.0741
[Rint =0.0393]
0.7460 and 0.6377
203
1.210
0.0372
max. and min. transmission
parameters
177
goodness-of-fit on F2
0.931
0.0628
0.1775
Conclusion
R(F)
G
wR(F2) (all data)
0.2204
0.1127
largest diff. peak and hole
0.688 and À0.615 0.294 and À0.324 0.325 and À0.348 0.352 and À0.196
A series of fluorinated b-pep-
tides (1–8) were designed and
[eꢂÀ3
]
&
6
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Chem. Eur. J. 0000, 00, 0 – 0
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These are not the final page numbers!

Fluorinated b-Peptidic Compounds
FULL PAPER
Table 5. Crystal data for compounds 5–8.
[2] J. W. Banks, A. S. Batsanov,
J. A. K. Howard, D. OꢀHagan,
H. S. Rzepa, S. Martin-Santama-
ria, J. Chem. Soc. Perkin Trans. 2
1999, 2409.
5
6
7
8
formula
Mr
C15H17F3N2O2
314.31
C28H36BrFN2O5
579.50
100(2)
orthorhombic
P2(1)2(1)2(1)
10.178(2)
20.341(4)
27.274(6)
90
90
90
5647(2)
8
1.363
C23H35FN2O5
438.53
125(2)
triclinic
P1
5.1493(6)
10.3220 (12)
22.863(3)
96.333(5)
92.157(8)
90.063(9)
1206.8
C31H33BrF2N2O5
631.50
125(2)
orthorhombic
P2(1)2(1)2
10.5501(6)
53.765(3)
5.1663(3)
90
temperature [K]
crystal system
space group
a [ꢂ]
b [ꢂ]
c [ꢂ]
135(2)
monoclinic
P2(1)
10.946(3)
5.1174(12)
14.488(4)
90
[3] R. I. Mathad, B. Jaun, O. Flçgel,
J. Gardiner, M. Lçweneck,
J. D. C. Codꢄe, P. H. Seeberger,
D. Seebach, M. K. Edmonds,
F. H. M. Graichen, A. D. Abell,
Helv. Chim. Acta 2007, 90, 2251.
[4] a) S. K. Holmgren, K. M. Taylor,
L. E. Bretscher, R. T. Raines,
Nature 1998, 392, 666; b) S. K.
Holmgren, L. E. Bretscher, K. M.
Taylor, R. T. Raines, Chem. Biol.
1999, 6, 63; c) C. L. Jenkins, R. T.
Raines, Nat. Prod. Rep. 2002, 19,
49; d) R. T. Raines, Protein Sci.
2006, 15, 1219.
a [8]
b [8]
108.611(15)
90
769.1(3)
2
1.366
0.115
90
90
g [8]
V [ꢂ3]
Z
2930.5(3)
4
1.431
2
1calcd [gcmÀ3
]
1.207
0.089
0.51ꢃ0.09ꢃ0.01
0.90 to 23.25
18132
3478
[Rint =0.0954]
0.7456 and 0.5909 0.7460 and 0.2715
571
m [mmÀ1
]
1.501
1.458
crystal size [mm]
q range
total reflns
0.57ꢃ0.10ꢃ0.03
2.97 to 25.00
8096
0.10ꢃ0.01ꢃ0.01
1.96 to 26.66
25419
9090
[Rint =0.1054]
0.78ꢃ0.07ꢃ0.05
0.76 to 25.10
36999
5186
[Rint =0.1282]
[5] a) E. S. Eberhardt, N. Panasik,
R. T. Raines, J. Am. Chem. Soc.
independent reflns
1506
[Rint =0.0835]
1996,
118,
12261;
b) L. E.
max. and min. transmission
parameters
0.7452 and 0.5710 n/a[a]
221
0.929
0.0564
0.1567
Bretscher, C. L. Jenkins, K. M.
Taylor, M. L. DeRider, R. T.
Raines, J. Am. Chem. Soc. 2001,
123, 777.
323
369
goodness-of-fit on F2
1.077
0.069
0.1884
1.110
0.0936
0.2589
1.169
0.1101,
0.2912
R(F)ACHTUNGTRENNUNG(I>2s(I))
wR(F2) (all data)
[6] a) D. O’Hagan, C. Bilton, J. A. K.
Howard, L. Knight, D. J. Tozer, J.
Chem. Soc. Perkin Trans. 2 2000,
largest diff. peak and hole
0.349 and À0.281 0.927 and À0.799 0.801 and À0.443 0.759 and À1.889
[eꢂÀ3
]
[a] Not available.
605;
b) C. R. S.
Briggs,
D.
OꢀHagan, J. A. K. Howard, D. S.
Yufit, J. Fluorine Chem. 2003,
119, 9.
MoKa radiation (l=0.71073 ꢂ) with a graphite monochromator and CCD
detector at the temperatures indicated in Tables 4 and 5.[20] Cell refine-
ment and data reduction were undertaken with SAINT[20] and
SADABS[21] for multiscan absorption correction. The structures were
solved by direct methods by using SHELXS97,[22] and refined by full-
matrix least squares calculations on F2 by using SHELXL97.[22]
[7] a) M. Schꢅler, D. O’Hagan, A. M. Z. Slawin, Chem. Commun. 2005,
4324; b) D. O’Hagan, H. S. Rzepa, M. Schꢅler, A. M. Z. Slawin,
Beilstein J. Org. Chem. 2006, 2, 19; c) L. Hunter, D. OꢀHagan, Org.
Biomol. Chem. 2008, 6, 2843; d) L. Hunter, Beilstein J. Org. Chem.
2010, 6, 38; e) L. Hunter, K. A. Jolliffe, M. J. T. Jordan, P. Jensen,
R. B. Macquart, Chem. Eur. J. 2011, 17, 2340.
[8] a) B. J. van der Veken, S. Truyen, W. A. Herrebout, G. Watkins, J.
Mol. Struct. 1993, 293, 55; b) D. OꢀHagan, Chem. Soc. Rev. 2008, 37,
308.
X-ray crystallographic data for 6 was collected on the MX2 beamline
(l=0.77345 ꢂ) at the Australian Synchrotron, Victoria, Australia, at
100 K by using Blu-Ice software.[23] Cell refinement and data reduction
were undertaken with XDS.[24] The structure was determined by direct
methods by using SHELXS97, and refined by full-matrix least squares
calculations on F2 by using SHELXL97.
[9] E. Valeur, M. Bradley, Chem. Soc. Rev. 2009, 38, 606.
[10] See the Supporting Information for full details of the experimental
procedures.
All H atoms bound to carbon were constrained to their expected geome-
[11] D. Seebach, M. Overhand, F. N. M. Kꢅhnle, B. Martinoni, L.
Oberer, U. Hommel, H. Widmer, Helv. Chim. Acta 1996, 79, 913.
[12] M. K. Edmonds, F. H. M. Graichen, J. Gardiner, A. D. Abell, Org.
Lett. 2008, 10, 885.
[13] C. J. Barnett, T. M. Wilson, D. A. Evans, T. C. Somers, Tetrahedron
Lett. 1997, 38, 735.
À
tries (C H 0.98, 0.99, 1.00 ꢂ). Methyl H atoms were refined with Uiso
=
1.5Ueq(C); all other H atoms were refined with Uiso =1.2U
eqA
gen atoms on nitrogens in compound 6 were located from the difference
maps and modelled with isotropic displacement parameters. A riding
atom model was used for the remaining hydrogen atoms.
[14] T. Hintermann, D. Seebach, Helv. Chim. Acta 1998, 81, 2093.
[15] V. Peddie, M. Pietsch, K. M. Bromfield, R. N. Pike, P. J. Duggan,
A. D. Abell, Synthesis 2010, 1845.
[16] CCDC 771854–771859 and CCDC 774553 contain(s) the supplemen-
tary crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif
Acknowledgements
A.D.A. acknowledges financial support from the Australian Research
Council (ARC). V.P. thanks the Tertiary Education Commission of New
Zealand for funding. We also thank Dr. Graeme Gainsford and Dr. Mat-
thew Polson (X-ray Crystallography), and Dr. Marie Squire (NMR spec-
troscopy and MS).
[17] a) P. C. Andrews, V. Bhaskar, K. M. Bromfield, A. M. Dodd, P. J.
Duggan, S. A. M. Duggan, T. D. McCarthy, Synlett 2004, 791; b) P. J.
Duggan, M. Johnston, T. L. March, J. Org. Chem. 2010, 75, 7365.
[18] D. Seebach, J. Gardiner, Acc. Chem. Res. 2008, 41, 1366.
[19] a) M.-O. Ebert, J. Gardiner, S. Ballet, A. D. Abell, D. Seebach, Helv.
Chim. Acta 2009, 92, 2643; b) A. D. Abell, M. A. Jones, J. M. Coxon,
J. D. Morton, S. G. Aitken, S. B. McNabb, H. Y.-Y. Lee, J. M. Mehrt-
ens, N. A. Alexander, B. G. Stuart, A. T. Neffe, R. Bickerstaffe,
Angew. Chem. 2009, 121, 1483; Angew. Chem. Int. Ed. 2009, 48,
1455; c) J. Gardiner, K. H. Anderson, A. Downard, A. D. Abell, J.
[1] a) F. Gessier, C. Noti, M. Rueping, D. Seebach, Helv. Chim. Acta
2003, 86, 1862; b) R. I. Mathad, C. Gessier, D. Seebach, B. Jaun,
Helv. Chim. Acta 2005, 88, 266; c) B. Jaun, D. Seebach, R. I.
Mathad, Helv. Chim. Acta 2011, 94, 355.
Chem. Eur. J. 2012, 00, 0 – 0
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A. D. Abell et al.
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1 1997, 2475; g) A. D. Abell, J. M. Taylor, J. Org. Chem. 1993, 58,
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[22] G. M. Sheldrick, SHELX97 Programs for Crystal Structure Analysis,
University of Gçttingen, Germany, 1998.
[23] T. M. McPhillips, S. E. McPhillips, H. J. Chiu, A. E. Cohen, A. M.
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[20] Bruker (1995), APEX2 and SAINT. Area detector control and data
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[21] G. M. Sheldrick, SADABS. Program for Emperical Absorption Cor-
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1996.
Received: January 29, 2012
Published online: && &&, 0000
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Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Fluorinated b-Peptidic Compounds
FULL PAPER
Making moves: X-ray crystal structures
were obtained for a series of a-fluoro-
b-amino acids and small fluorinated b-
peptides (see picture for an example).
When fluorine was positioned a to
Peptides
V. Peddie, R. J. Butcher,
W. T. Robinson, M. C. J. Wilce,
D. A. K. Traore,
À À
a carbonyl group, the F C C=O
A. D. Abell* ................... &&&& — &&&&
moiety was found to adopt an antiperi-
planar conformation; but when fluo-
rine was positioned b to an amide
Synthesis and Conformation of Fluori-
nated b-Peptidic Compounds
À
nitrogen, a conformation in which C F
À
and C N(CO) bonds are gauche was
favoured.
Chem. Eur. J. 2012, 00, 0 – 0
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