2-Amino-1,2,3,6-tetrahydro-6-oxocyclopenta[c]fluorene-2-carboxylic acid (FlAib), a completely rigidified, fluoren-9-one-based α-amino acid

Article abstract of DOI:10.1002/hlca.201200490

The synthesis, optical resolution, determination of absolute configuration and conformational preference, and spectroscopic characteristics of terminally protected (blocked) derivatives and short peptides of 2-amino-1,2,3,6- tetrahydro-6-oxocyclopenta[c]f

Full text of DOI:10.1002/hlca.201200490

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2-Amino-1,2,3,6-tetrahydro-6-oxocyclopenta[c]fluorene-2-carboxylic Acid
(FlAib), a Completely Rigidified, Fluoren-9-one-Based a-Amino Acid
by Karen Wright*a) and Antonio Blanco Alvareza)
a) ILV UMR 8180, University of Versailles, FR-78035 Versailles
(e-mail: wright@chimie.uvsq.fr)
and
Marco Crismab), Antonio Toffolettib), Fernando Formaggiob), and Claudio Toniolo*b)
b) Institute of Biomolecular Chemistry, Padova Unit, CNR, Department of Chemistry, University of
Padova, IT-35131 Padova
(e-mail: claudio.toniolo@unipd.it)
Dedicated to Prof. Dieter Seebach on the occasion of his 75th birthday
The synthesis, optical resolution, determination of absolute configuration and conformational
preference, and spectroscopic characteristics of terminally protected (blocked) derivatives and short
peptides of 2-amino-1,2,3,6-tetrahydro-6-oxocyclopenta[c]fluorene-2-carboxylic acid (FlAib), a novel,
rigid, chiral, cyclized Ca,a-disubstituted glycine are described.
Introduction. – Cia ! Cia-cyclized, Ca,a-disubstituted glycines [1] are members of a
class of sterically restricted a-amino acids that promote formation of b-turns [2] and
310-/a-helical structures [3] when incorporated into peptides. In particular, 2-amino-
indane-2-carboxylic acid (Aic; Fig. 1) has been used as a Phe-constrained analog for the
synthesis of biologically active peptides with limited conformational flexibility [4]. We
have previously synthesized a-amino acids containing the Aic motif for use as a
fluorescence marker (antAib) [5] or as a photoaffinity label (BpAib) [6].
Fig. 1. Chemical structures of the Aic, antAib, BpAib, Bpa, Fla, and FlAib a-amino acid residues
Photoreactive a-amino acids with a benzophenone side chain, such as the widely
exploited 4-benzoylphenylalanine (Bpa), have been employed as photoprobes for the
ꢀ 2012 Verlag Helvetica Chimica Acta AG, Zꢁrich

Helvetica Chimica Acta – Vol. 95 (2012)
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covalent modification of enzymes and receptors in protein-mapping studies [7].
However, results of photocross-linking experiments need to take into account the
marked flexibility of the Bpa side chain, which allows reaction with the amino acid side
chain of a residue up to 10-ꢂ distant [8]. To counteract this effect, Chorev and co-
workers have prepared the more constrained, fluorenone-based Fla residue, and
demonstrated its ability to behave as a photoactive cross-linker when introduced into a
parathyroid hormone analog [9]. The increased restrictions characterizing the chemical
structure of 2-amino-1,2,3,6-tetrahydro-6-oxocyclopenta[c]fluorene-2-carboxylic acid
(FlAib), described in this article, which belongs to the above mentioned cyclized Ca,a
-
disubstituted glycine class of a-amino acids, completely locks the side-chain fluoren-9-
one CO group into a fixed position and orientation relative to the peptide main chain.
The photophysical properties of fluoren-9-one and its derivatives have been studied in
depth, due to their sensitivity to solvent changes, making them interesting candidates as
microenvironment reporters [10].
Results and Discussion. – A key intermediate for the formation of the dimethyl-
fluorenone core is the dimethylanthranilic acid 3 (Scheme 1). Two methods have been
described in the literature for the synthesis of 3: either by nitration and subsequent
reduction of 3,4-dimethylbenzoic acid (leading to a mixture of regioisomers) [11] or via
oxidative opening of dimethylisatin 2 [12]. We chose to pursue the second route to
avoid the potentially difficult separation of the regioisomers. Compound 3 was
obtained in 55% yield from 2,3-dimethylaniline (1), via 2, over three steps. Protection
of the amino function of 3 with trifluoroacetic anhydride ((CF3CO)2O) at room
temperature resulted in the exclusive formation of the benzoxazinone 4 in 84% yield, as
determined from its 13C-NMR spectrum which displays only one CO peak. This finding
is in contrast to that observed when anthranilic acid is treated with (CF3CO)2O under
the same conditions, where the free carboxylic acid was recovered [13]. Benzoxazinone
4 is stable to atmospheric moisture, unlike the related, non-methylated compounds
described in [14].
Scheme 1. Synthesis of Benzoxazinone 4
i) Chloral hydrate (¼2,2,2-trichloroethane-1,1-diol), Na2SO4 · 5 H2O, (NH3OH)2SO4, 1m aq. HCl;
45 – 758. ii) MeSO3H; 758. iii) 5% aq. NaOH, 35% aq. H2O2; 08. iv) (CF3CO)2O; r.t.
A first attempt to obtain the 2-amino-3,4-dimethylbenzophenone 5 from the
benzoxazinone 4 by FriedelꢀCrafts acylation of benzene gave a mixture of the desired
product in low yield accompanied by the 1,2-dihydrobenzoxazinone 61) (Scheme 2).
1
)
For related compounds, see [15].

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Scheme 2. Synthesis of H-FlAib-OMe 10
i) AlCl3, benzene; 0 – 908. ii) PhMgBr, THF; ꢀ 158. iii) LiOH · H2O, THF/MeOH/H2O 2 :2 :1; 708. iv)
NaNO2, 2m aq. HCl; 08 then 708. v) N-Bromosuccinimide (NBS), benzoyl peroxide, CCl4; 908. vi) Ethyl
isocyanoacetate, 18-crown-6, K2CO3, MeCN; r.t. vii) 10m aq. HCl, CH2Cl2, EtOH; r.t.
An alternative route to aminobenzophenones, proposed by Walsh [16], using the
inverse addition of a Grignard reagent to an excess of benzoxazinone at low
temperature, was studied next. Addition of PhMgBr to 4 at ꢀ 158 was successful, giving
the trifluoroacetamide 5 in 69% yield. The amide function was hydrolyzed smoothly in
the presence of LiOH to afford the free amine 7 in 94% yield. Diazotization, followed
by Pschorr cyclization under heating in aqueous dilute HCl [17], gave the 3,4-
dimethylfluoren-9-one core structure 8 in 58% yield (addition of Cu salts did not
improve this result). Bromination of the two Me groups of 8 afforded the 3,4-
bis(bromomethyl)fluoren-9-one (9). Bis(alkylation) of ethyl isocyanoacetate in
refluxing MeCN in the presence of K2CO3 and tetrabutylammonium hydrogen sulfate
(Bu4NHSO4; TBAHS) to form the cyclic disubstituted a-amino acid, as described by
Kotha and Brahmachary [18], and previously successful in our hands in similar cases,
gave only a mixture of dark colored tars, when 9 was used as electrophile. However,
alkylation under the conditions used to form the similar amino acid Fla (room
temperature and 18-crown-6 as phase-transfer agent) [9] avoided decomposition of the
fluorenone moiety. Racemic H-FlAib-OEt 10 was isolated in 53% yield after acidic
hydrolysis of the intermediate isonitrile.
Optical resolution of FlAib was attempted using H-(S)-Phe-NHcHex (NHcHex,
cyclohexylamino) as the chiral auxiliary [19] which had proved successful in the case of
the related amino acid BpAib [6]. Na-Benzoyl (Na-Bz) protection, saponification of the
ester function, and coupling with H-(S)-Phe-NHcHex in the presence of O-(7-
azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) [20]
gave dipeptide diastereomers 12a/12b (Scheme 3), which could be resolved by
crystallization and chromatography.
A single crystal of one of these Na-Bz diastereoisomers was subjected to X-ray-
diffraction analysis (see below). The two enantiomers of H-FlAib-OMe 13a/13b were
obtained from the separated diastereoisomers by acid hydrolysis of the amide

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Scheme 3. Optical Resolution of FlAib
2449
i) Bz2O, MeCN; r.t. ii) NaOH, THF/MeOH/H2O; 608. iii) H-(S)-Phe-NHcHex, HATU, EtNiPr2
(DIEA); THF; r.t. iv) 10m HCl, dioxane; 1008. v) SOCl2; MeOH; r.t. vi) Boc2O, MeCN; r.t.
functions, followed by esterification of the resulting a-amino acids in the presence of
SOCl2. Reaction of each enantiomer with tert-butyldicarbonate (Boc2O) gave the
corresponding Na-Boc-protected a-amino esters 14a/14b.
The 3D structure of Bz-(R)-FlAib-(S)-Phe-NHcHex (12b) is illustrated in Fig. 2
with atom numbering. The known (S)-configuration of the Phe residue allowed us to
unambiguously establish the configuration of FlAib as (R). Moreover, the Na-blocked
dipeptide alkylamide 12a adopts an intramolecularly H-bonded b-turn conformation
[2], clearly generated by the presence of the Ca,a-disubstituted glycine FlAib. This
finding is not surprising, because such a folded conformation is that expected for short
peptides containing at least one residue of this class of conformationally restricted a-
amino acids, either Ca,a-dimethylated (a-aminoisobutyric acid, Aib) [1][3][21] or Ca,a
cyclized, e.g., the related 1-aminocyclopentane-1-carboxylic acid, Ac5c [1][22][23].
-
The molecule is folded into a type-I b-turn [2], stabilized by an C¼O ··· HꢀN
intramolecular H-bond between the NH group of the C-terminal cyclohexylamino
moiety and the benzoyl O-atom. The NT··· O0 and HT··· O0 separations are 3.040(10)
ꢂ and 2.18 ꢂ, respectively, and the NTꢀHT··· O0 angle is 1648. The backbone torsion
angles adopted by the FlAib(1) and Phe(2) residues are: f1 ¼ ꢀ54.5(10)8, y1 ¼
ꢀ42.3(10)8, and f2 ¼ ꢀ96.9(10)8, y2 ¼ 14.0(12)8, respectively. Interestingly, the (R)-
configured FlAib residue is right-handed helical [24], i.e., its screw sense is the same as
that of Ca-trisubstituted (protein) amino acids of (S)-configuration.
The angle between normals to the average planes of the N-terminal Bz and the
FlAib fluorenone rings is 74.0(2)8, whereas that between the latter and the Phe
aromatic ring is 82.9(2)8. The cyclopentene ring which connects the Ca-atom of FlAib to
the fluorenone moiety, with puckering parameters [25] q2 ¼ 0.196(8) ꢂ and f2 ¼
197.6(19)8 (relative to the atom sequence C1AꢀC1B1ꢀC101ꢀC106ꢀ-C1B2), is close

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Fig. 2. X-Ray-diffraction structure of the Na-blocked dipeptide alkylamide Bz-(R)-FlAib-(S)-Phe-
NHcHex with atom numbering. The H-atoms and the co-crystallized AcOEt molecule are omitted for
clarity. The intramolecular C¼O ··· HꢀN H-bond is indicated by a dashed line.
to the 2T1 (twist) disposition. The cyclohexane ring of the C-terminal NHcHex moiety
adopts a chair conformation (QT ¼ 0.562(17) ꢂ, q2 ¼ 173.7(18)8, f2 undefined), with
the amino substituent in the equatorial disposition. In the packing mode the N1ꢀH
group is H-bonded to a (x – y, x – 1, z þ 1/6) symmetry equivalent of O1, thus
connecting molecules that wrap around the sixfold screw axis. The N2ꢀH group is H-
bonded, within the same asymmetric unit, to the CO O-atom of the co-crystallized
AcOEt molecule.
Finally, it is worth mentioning that the conformational preference exhibited by
FlAib in this work is strictly comparable to that already published for BpAib [6].
The electronic properties of the fluoren-9-one chromophore are of great interest
[9][10]. To spectroscopically characterize this novel amino acid, we used the model
compound Boc-(S)-FlAib-OMe. As expected for a fluoren-9-one derivative, the near-
UV absorption spectrum in CH2Cl2 solution (Fig. 3, bottom) exhibits a few, strong and
well-resolved peaks (vibrational fine structure) at 290, 302 (maximum), 322, and
335 nm, originating from different p ! p* electronic transitions [10], followed by a very
weak and broad band at ca. 375 nm. This spectral region represents an optimal window
for photoexciting peptide molecules. The electronic circular dichroism (ECD)
spectrum is also shown in Fig. 3 (top). All above mentioned near-UV transitions are

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Fig. 3. Near-UV (bottom) and ECD (top) absorption spectrum of Boc-(S)-FlAib-OMe in CH2Cl2
solution (concentration 0.2 mm)
optically active, displaying negative Cotton effects at 290 and 302 nm, and positive
Cotton effects at 322, 335, and 390 nm.
The fluorescence emission spectra of Boc-(S)-FlAib-OMe in four solvents of
different polarity are shown in Fig. 4. The excitation was accomplished at 335 nm,
where a relative maximum of absorption is observed (Fig. 3). Excitation at different
wavelengths, corresponding to absorption maxima (e.g. 322 and 302 nm), did not
modify the fluorescence properties of the amino acid derivative. Interestingly, a
remarkable blue-shift is observed for the maximum emission on going from polar
(CH2Cl2, 504 nm; DMF, 498 nm) to apolar (toluene, 486 nm; cyclohexane, 485 nm)
solvents. This phenomenon, similar to that already reported for fluoren-9-one [10],
makes FlAib an effective polarity probe of local peptide/protein environments.
To further characterize the spectroscopic properties of FlAib, we recorded a time-
resolved electron paramagnetic resonance (TR-EPR) spectrum of its photoexcited
state. Fig. 5 shows the TR-EPR spectrum of a frozen benzene solution of Boc-(S)-
FlAib-OMe. As the conventional B0 field modulation was not applied, the positive
curve is due to absorption, while the negative curve is due to the emission of
microwaves. Fitting of the experimental curve allowed us to obtain the following
spectral parameters: D ¼ ꢀ106.0 mT, E ¼ 7.2 ꢁ 0.5 mT, g factor (assumed isotropic) ¼
2.0020 ꢁ 0.0005, anisotropic population rates px, ¼ 0.01, py, ¼ 0.75, pz ¼ 1.00. Overall,
this TR-EPR spectrum of the p ! p* triplet state of Boc-(S)-FlAib-OMe is quite
similar to that reported for fluoren-9-one [26].

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Fig. 4. Fluorescence spectra of Boc-(S)-FlAib-OMe in toluene and cyclohexane (left), and in DMF and
CH2Cl2 (right). lexc, 335 nm; concentration, 0.01 mm.
Fig. 5. TR-EPR Spectrum of Boc-(S)-FlAib-OMe in a frozen benzene solution (concentration, 1 mm; T,
125 K), recorded with a 0.6-ms delay after the laser pulse at 355 nm (see text for parameters; Abs.,
absorption; Em., emission).
Conclusions. – The highly constrained, racemic a-amino acid derivative H-FlAib-
OEt (10) was prepared in three steps and 19% yield from the 2-amino-3,4-
dimethylbenzophenone 7 by Pschorr cyclization, bromination of the Me groups and
bis(alkylation) of ethyl isocyanoacetate. Resolution of the FlAib amino acid was
achieved by synthesizing the Bz-FlAib-(S)-Phe-NHcHex diastereoisomers which were
separated by crystallization and chromatography. Acid hydrolysis of each diastereo-
isomer, esterification and N-(tert-butoxy)carbonylation afforded the enantiomerically
pure Boc-FlAib-OMe derivatives 14a and 14b.

Helvetica Chimica Acta – Vol. 95 (2012)
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An X-ray diffraction analysis of one diastereoisomer of Bz-FlAib-(S)-Phe-
NHcHex allowed us to assign the FlAib absolute configuration ((R)) and provided
information on the b-turn forming propensity of this completely rigidified Ca,a
-
disubstituted glycyl residue. The spectroscopic properties (UV absorption, fluores-
cence, ECD, and triplet state EPR) of FlAib were also investigated. In particular, the
emission spectrum of FlAib maintains the remarkable solvent dependence typical of
fluoren-9-one [10]. Therefore, this novel, chiral, rigidified a-amino acid is a promising
microenvironment sensor. Moreover, this fluoren-9-one-based residue might also play
a role in the emerging field of polymer light-emitting diodes where polyfluorene
molecules with a central keto defect are extensively investigated [27]. Results on
photocross-linking experiments using FlAib-containing peptides will be reported in
due course.
Experimental Part
General. Abbreviations: FlAib, 2-Amino-1,2,3,6-tetrahydro-6-oxo-cyclopenta[c]fluorene-2-carbox-
ylic acid; HATU, O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate.
Anal. TLC and prep. FC: silica gel F 254 plates and silica gel 60 (SiO2; 0.040 ꢁ 0.063 mm; Merck),
resp.; UV fluorescence detection (254 nm) or ninhydrin development. M.p.: Tottoli apparatus (Bꢀchi);
uncorrected. Optical rotations: Perkin-Elmer 341 polarimeter (1-dm cell) at r.t. UV Spectra: Perkin-
Elmer UV/Vis/NIR Lambda 19 spectrophotometer. Fluorescence spectra: Perkin Elmer model MPF-66
spectrofluorimeter. CD Spectra: Jasco model J-715 spectropolarimeter; a fused quartz cell of 10.0 mm
path length; the values expressed in terms of [q]T, the total molar ellipticity (deg ꢂ cm2 ꢂ dmolꢀ1). IR
Spectra: Nicolet iS 10 (SMART iTR diamond ATR) spectrophotometer; l in cmꢀ1. NMR Spectra: Bruker
Avance-300 spectrometer at 300.13 (1H) and 75.77 MHz (13C); d in ppm rel. to the signal of the solvent
(1H: d (residual CHCl3) ¼ 7.27 ppm; 13C: d (CDCl3) ¼ 77.23 ppm), J in Hz. MS: Waters Xevo Q-TOF.
Elemental analyses: C.N.R.S. Service of Microanalyses, Gif-sur-Yvette, France.
7,8-Dimethyl-2-(trifluoromethyl)-4H-3,1-benzooxazin-4-one (4). 2-Amino-3,4-dimethylbenzoic acid
(3; 1 g, 6.06 mmol) was added slowly in portions (over 15 min.) to (CF3CO)2O (2.4 ml). The resulting
soln. was stirred at r.t. for 1 h then cooled on an ice bath. H2O (7 ml) was added, and the resulting
precipitate was filtered and dried under vacuum. The solid was purified by CC (CH2Cl2/cyclohexane 8 :2)
to give 4 (1.34 g, 84%). White solid. M.p. 113 – 1158. Rf (CH2Cl2/cyclohexane 8 :2) 0.93. IR: 2920w, 1775s,
1771s, 1598m, 1344s, 1215s, 1144m, 1120s, 1045m, 841m, 781m, 766m, 704m. 1H-NMR (300 MHz, CDCl3):
8.01 (d, J ¼ 7.9, 1 arom. H); 7.47 (d, J ¼ 8.0, 1 arom. H); 2.52 (s, Me); 2.46 (s, Me). 13C-NMR (77 MHz,
CDCl3): 157.6 (CO); 148.0; 146.3 (q, 2J(C,F) ¼ 42.5); 142.3; 136.4; 132.4; 126.4; 116.6 (q, 1J(C,F) ¼ 281.1);
115.8 (ArC); 21.4; 13.4 (Me). ESI-MS: 298.2 ([M þ Na þ MeOH]þ). HR-ESI-MS: 244.0585 ([M þ H]þ,
C11H9F3NOþ2 ; calc. 244.0585). Anal. calc. for C11H8F3NO2 (243.18): C 54.33, H 3.32, N 5.76; found: C
54.21, H 3.31, N 5.77.
N-(6-Benzoyl-2,3-dimethylphenyl)-2,2,2-trifluoroacetamide (5) and 7,8-Dimethyl-2-phenyl-2-(tri-
fluoromethyl)-1,2-dihydro-4H-3,1-benzooxazin-4-one (6). Method A: The benzoxazinone 4 (500 mg,
1.79 mmol) was dissolved in benzene (4 ml) and the soln. was cooled on an ice bath. AlCl3 (720 mg,
5.37 mmol) was added. The mixture was heated at 908 for 3 h. The mixture was cooled on an ice bath, and
ice cold 0.5m aq. HCl was added. The mixture was extracted twice with CH2Cl2. The combined extracts
were washed with H2O and then with sat. aq. NaHCO3 soln. The org. phase was dried (MgSO4), filtered,
and concentrated under reduced pressure. The residue obtained was purified by CC (pentane/AcOEt
95 :5) to give 5 (65 mg, 16%) and 6 (162 mg, 40%).
Method B. The benzoxazinone 4 (3.5 g, 14.4 mmol) was dissolved in THF (35 ml) under Ar. The
mixture was cooled to ꢀ 158, and a 1.8m soln. of PhMgBr in Et2O (6 ml) was added dropwise over 2 h.
The resulting mixture was stirred at r.t. for 90 min, then diluted with Et2O. The mixture was cooled on an
ice bath and acidified by the dropwise addition of 2m aq. HCl. The mixture was washed with 0.5m aq. HCl

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Helvetica Chimica Acta – Vol. 95 (2012)
then with H2O. The org. phase was dried (MgSO4), filtered, and concentrated under reduced pressure.
The residue obtained was purified by CC (pentane/AcOEt 95 :5) to give 5 (2.39 g, 69%).
Data of 5. White solid. M.p. 146 – 1488. Rf (CH2Cl2/cyclohexane 8 :2) 0.69. IR: 3205w, 3057w, 2882w,
1718s, 1647s, 1607m, 1448m, 1290m, 1206m, 1167m, 1148s, 992w, 908w, 828m, 740m, 710m. 1H-NMR
(300 MHz, CDCl3): 10.01 (s, NH); 7.78 – 7.79 (m, 2 arom. H); 7.58 – 7.63 (m, 1 arom. H); 7.44 – 7.50 (m, 2
arom. H); 7.28 (d, J ¼ 7.9, 1 arom. H); 7.18 (d, J ¼ 7.9, 1 arom. H); 2.40 (s, Me); 2.17 (s, Me). 13C-NMR
2
(77 MHz, CDCl3): 197.9 (CO); 155.7 (q, J(C,F) ¼ 38.1, OCN); 143.8; 137.6; 135.3; 133.5; 132.9; 130.7;
130.2; 129.7; 128.7; 128.3 (ArC); 116.2 (q, 1J(C,F) ¼ 294.6, CF3); 21.4; 15.6 (Me). HR-ESI-MS: 322.1060
([M þ H]þ, C17H15F3NO2þ ; calc. 322.1055). ESI-MS: 344.1 ([M þ Na]þ), 665.1 ([2 M þ Na]þ). Anal. calc.
for C17H14F3NO2 (321.30): C 63.55, H 4.39, N 4.36; found: C 63.51, H 4.44, N 4.35.
Data of 6. White solid. M.p. 130 – 1328. Rf (pentane/AcOEt 95 :5) 0.27. IR: 3266w, 2916w, 1700s,
1605s, 1509m, 1285m, 1234m, 1188m 1089w, 976m, 757m, 719m, 698m. 1H-NMR (300 MHz, CDCl3):
7.64 – 7.67 (m, 3 arom. H); 7.36 – 7.39 (m, 3 arom. H); 6.85 (d, J ¼ 8.1, 1 arom. H); 4.68 (s, NH); 2.31 (s,
Me); 2.28 (s, Me). 13C-NMR (77 MHz, CDCl3): 161.4 (CO); 145.3; 141.1; 133.9; 130.4 (ArC); 129.6 (q,
2
1JCF ¼ 279.3, CF3); 128.7; 127.4; 125.6; 124.9; 114.1 (ArC); 89.6 (q, JCF ¼ 32.7, CꢀN); 20.9; 12.6 (Me).
ESI-MS: 344.1 ([M þ Na]þ), 665.1 ([2 M þ Na]þ). HR-ESI-MS: ([M þ H]þ, C17H15F3NOþ2 ; calc.
322.1055) 322.1053. Anal. calc. for C17H14F3NO2 (321.30): C 63.55, H 4.39, N 4.36; found: C 63.58, H
4.44, N 4.33.
(2-Amino-3,4-dimethylphenyl)(phenyl)methanone (7). Compound 5 (1.118 g, 3.48 mmol) was
dissolved in THF/MeOH/H2O 20 :20 :10 ml, and LiOH · H2O (2.19 g, 52.24 mmol) was added to the
soln. The mixture was stirred at 708 for two d. Volatiles were removed under reduced pressure, and the
residue was taken up in CH2Cl2 and H2O. The phases were separated, and the aq. phase was extracted
twice with CH2Cl2. The combined org. phases were dried (MgSO4), filtered, and concentrated under
reduced pressure. The residue obtained was recrystallized from cyclohexane/Et2O to give 7 (735 mg,
94%). Yellow needles. M.p. 105 – 1078. Rf (CH2Cl2/cyclohexane 8 :2) 0.37. IR: 3467w, 3315w, 2920w,
2357w, 1585s, 1575s, 1538m, 1444w, 1406m, 1376m, 1317m, 1241m, 1173m, 1094m, 977w, 881w, 833w, 759s,
715m, 704m. 1H-NMR (300 MHz, CDCl3): 7.44 – 7.47 (m, 2 arom. H); 7.25 – 7.38 (m, 3 arom. H); 7.09 (d,
J ¼ 7.7, 1 arom. H); 6.31 (d, J ¼ 8.1, 1 arom. H); 2.17 (s, Me); 1.97 (s, Me). 13C-NMR (77 MHz, CDCl3):
199.5 (CO); 149.8; 143.2; 140.9; 132.4; 131.0; 129.3; 128.3; 121.4; 117.9; 116.3 (ArC); 21.5; 12.7 (Me).
ESI-MS: 226.2 ([M þ H]þ). HR-ESI-MS: 226.1232 ([M þ H]þ, C15H16NOþ; calc. 226.1232). Anal.calc.
for C15H15NO (225.29): C 79.97, H 6.71, N 6.22; found:C 79.91, H 6.69, N 6.23.
3,4-Dimethyl-9H-fluoren-9-one (8). Compound 7 (2.42 g, 10.75 mmol) was dissolved in 2m aq HCl
(25 ml), and the soln. was cooled on an ice bath. A soln. of NaNO2 (1.48 g, 21.5 mmol) in H2O (25 ml) was
added. The soln. was stirred at 08 for 1 h, then heated at 708 for 3 h. The mixture was allowed to cool, and
diluted with CH2Cl2 and sat. aq. NaCl soln. The phases were separated, and the aq. phase was extracted
with CH2Cl2. The combined org. phases were dried (MgSO4), filtered, and concentrated under reduced
pressure. The residue was purified by CC (CH2Cl2/cyclohexane 1:1) to give 8 (1.29 g, 58%). Yellow solid.
M.p. 114 – 1168. Rf (CH2Cl2/cyclohexane 1:1) 0.19. IR: 3064w, 2969w, 2927w, 1700s, 1606m, 1596m,
1577m, 1444w, 1304m, 1228m, 1173w, 961m, 833m, 774m, 739m, 718m. 1H-NMR (300 MHz, CDCl3):
7.65 – 7.71 (m, 2 arom. H); 7.41 – 7.49 (m, 2 arom. H); 7.24 – 7.29 (m, 1 arom. H); 7.09 (d, J ¼ 7.5, 1 arom.
H); 2.50 (s, Me); 2.36 (s, Me). 13C-NMR (77 MHz, CDCl3): 194.3 (CO); 145.8; 145.4; 142.8; 135.5; 134.7;
133.2; 133.1; 130.6; 128.5; 124.5; 123.9; 122.0 (ArC); 21.2; 16.1 (Me). ESI-MS: 231.2 ([M þ Na]þ), 439.2
([2 M þ Na]þ). HR-ESI-MS: ([M þ H]þ, C15H13Oþ; calc. 209.0958) 209.0966.
3,4-Bis(bromomethyl)-9H-fluoren-9-one (9). Compound 8 (1.292 g, 6.21 mmol) was dissolved in
CCl4 (30 ml). The mixture was placed under Ar, and NBS (2.16 g, 12.11 mmol) and benzoyl peroxide
(Bz2O2; 60 mg) were added. The mixture was heated at reflux for 2 h. The mixture was filtered through
Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by CC
(CH2Cl2/cyclohexane 1:1) to give 9 (1.43 g, 63%). Yellow solid. M.p. 178 – 1808. Rf (CH2Cl2/cyclohexane
8 :2) 0.80. IR: 3034w, 2357w, 1709s, 1695m, 1605m, 1423w, 1303m, 1197m, 1088m, 984w, 874m, 847m,
1
751m, 700m. H-NMR (300 MHz, CDCl3): 7.79 – 7.82 (m, 1 arom. H); 7.70 – 7.73 (m, 1 arom. H); 7.55 –
7.62 (m, 2 arom. H); 7.31 – 7.39 (m, 1 arom. H); 7.32 (d, J ¼ 7.5, 1 arom. H); 4.90 (s, CH2); 4.62 (s,
CH2). 13C-NMR (77 MHz, CDCl3): 192.7 (CO); 144.1; 143.8; 143.4; 135.9; 135.6; 135.0; 132.5; 132.0;

Helvetica Chimica Acta – Vol. 95 (2012)
2455
129.8; 125.0; 125.0; 124.7 (ArC); 29.3; 25.9 (CH2). ESI-MS: 389 ([M þ Na]þ), 754.8 ([2 M þ Na]þ). HR-
ESI-MS: 364.9182 ([M þ H]þ, C15H11Br2Oþ; calc. 364.9177).
Ethyl 2-Amino-1,2,3,6-tetrahydro-6-oxocyclopenta[c]fluorene-2-carboxylate (10). Compound 9
(1.22 g, 3.34 mmol) was dissolved in MeCN (150 ml). The mixture was placed under Ar, and 18-
crown-6 (87 mg, 0.33 mmol) and K2CO3 (4.61 g, 33.4 mmol) were added. Ethyl isocyanoacetate (0.37 ml,
3.34 mmol) was added, and the mixture was stirred at r.t. for 24h. The mixture was filtered through Celite,
and the filtrate was concentrated under reduced pressure. The residue obtained was taken up in CH2Cl2
(30 ml) and EtOH (30 ml), and the mixture was cooled on an ice bath. Conc. aq. HCl (36% w/v, 1.3 ml)
was added, and the mixture was stirred at 08 for 1 h, then at r.t. for 3 h. The mixture was diluted with
CH2Cl2 and extracted four times with 0.5m aq. HCl. The pH of the extracts was adjusted to 7 by addition
of NaHCO3. This mixture was extracted three times with CH2Cl2. The combined org. extracts were dried
(MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by CC (CH2Cl2/
MeOH 95 :5) to give 10 (546 mg, 53%). Yellow solid. M.p. 143 – 1458. Rf (CH2Cl2/MeOH 95 :5) 0.45. IR:
3349w, 3288w, 3057w, 2980w, 2897w, 2357w, 1718s, 1700s, 1597s, 1471m, 1429m, 1364m, 1299m, 1220s,
1166m, 1102w, 1025m, 973m; 888m, 868m, 775s, 744s, 726m. 1H-NMR (300 MHz, CDCl3): 7.48 – 7.51 (m, 1
arom. H); 7.37 (d, J ¼ 7.5, 1 arom. H); 7.23 – 7.33 (m, 2 arom. H); 7.10 – 7.15 (m, 1 arom. H); 6.98 (d, J ¼ 7.5,
1 arom. H); 4.13 (q, J ¼ 7.1, CH2); 3.53 (d, J ¼ 16.1, 1 H of CH2); 3.40 (d, J ¼ 16.9, 1 H of CH2); 3.04 (d, J ¼
16.4, 1 H of CH2); 2.77 (d, J ¼ 16.9, 1 H of CH2); 1.19 (t, J ¼ 7.1, Me ) . 13C-NMR (77 MHz, CDCl3): 193.8
(CO); 176.3 (CO); 149.7; 144.49; 140.75; 135.34; 134.9; 134.7; 133.7; 128.9; 125.0; 124.5; 123.6; 122.4
(ArC); 65.4 (C); 61.9 (OCH2); 46.0; 44.6 (CH2); 14.4 (Me). ESI-MS: 308.2 ([M þ H]þ), 330.2 ([M þ
Na]þ), 637.2 ([2 M þ Na]þ); 944.6 ([3 M þ Na]þ). HR-ESI-MS: 308.1289 ([M þ H]þ, C19H18NOþ3 ; calc.
308.1287).
2-(Benzoylamino)-1,2,3,6-tetrahydro-6-oxocyclopenta[c]fluorene-2-carboxylic Acid (11). Com-
pound 10 (546 mg, 1.78 mmol) was dissolved in MeCN (30 ml). Bz2O (1 g, 4.45 mmol) was added, and
the mixture was stirred at r.t. for 18 h. The mixture was concentrated under reduced pressure. The residue
was taken up in CH2Cl2, and washed twice with 2m aq. NaOH soln. and then with sat. aq. NaCl soln. The
combined org. extracts were dried (MgSO4), filtered, and concentrated under reduced pressure. The
residue was purified by CC (CH2Cl2/iPrOH 98 :2). The residue obtained was dissolved in THF/MeOH/
H2O 5 :2 :1, and NaOH (170 mg, 4.27 mmol) was added. The mixture was heated at 608 for 1 h. The
mixture was allowed to cool, diluted with H2O, and volatiles were removed under reduced pressure. The
resulting soln. was cooled on an ice bath and acidified by addition of 2m aq. HCl. The mixture was
extracted three times with AcOEt. The combined org. extracts were dried (MgSO4), filtered, and
concentrated under reduced pressure. The residue was purified by CC (CH2Cl2/MeOH 90 :10) to give 11
(540 mg, 79%). Yellow solid. M.p. 102 – 1058. Rf (CH2Cl2/MeOH 90 :10) 0.29. IR: 3338w, 3254w, 3049w,
2923w, 2581w, 2349w, 1734m, 1707s, 1696s, 1648m, 1599m, 1576m, 1525m, 1486m, 1429m, 1294m, 1221m,
1170m, 969w, 881w, 769m, 727s, 693m. 1H-NMR (300 MHz, CDCl3): 7.84 – 7.88 (m, 2 arom. H); 7.41 – 7.56
(m, 7 arom. H); 7.26 – 7.31 (m, 1 arom. H); 7.16 (d, J ¼ 7.5, 1 arom. H); 3.91 (d, J ¼ 16.9, 1 H of CH2);
3.65 – 3.77 (m, CH2); 3.52 (d, J ¼ 17.5, 1 H of CH2). 13C-NMR (77 MHz, CDCl3): 196.1 (CO); 177.2 (CO);
177.6 (CO); 152.0; 146.2; 142.1; 137.4; 136.9; 136.6; 136.1; 135.2; 133.6; 130.8; 130.3; 129.4; 126.5; 125.8;
125.0; 124.6 (ArC); 68.5 (C); 45.0; 43.5 (CH2). HR-ESI-MS: 384.1232 ([M þ H]þ, C24H18NO4þ ; calc.
384.1236).
Bz-(S)-FlAib-Phe-NHcHex (¼(2S)-2-(Benzoylamino)-N-(N-cyclohexylphenylalanyl)-1,2,3,6-tetra-
hydro-6-oxocyclopenta[c]fluorene-2-carboxamide; 12a) and Bz-(R)-FlAib-Phe-NHChex (¼(2R)-2-
(Benzoylamino)-N-(N-cyclohexylphenylalanyl)-1,2,3,6-tetrahydro-6-oxocyclopenta[c]fluorene-2-carbox-
amide; 12b). Compound 11 (502 mg, 1.31 mmol) was dissolved in THF (4 ml). The soln. was cooled on an
ice bath, and l-phenylalanine cyclohexylamide (444 mg, 1.57 mmol) was added. HATU (597 mg,
1.57 mmol) and DIEA (0.8 ml) were added, and the mixture was stirred at r.t. for 5 d. The mixture was
concentrated under reduced pressure. The residue was taken up in CH2Cl2, and washed twice with 0.5m
aq. HCl, then with H2O and finally with sat. aq. NaHCO3 soln. The org. phase was dried (MgSO4),
filtered, and concentrated under reduced pressure. The residue obtained was recrystallized from AcOEt/
cyclohexane to give 12b (237 mg) as yellow needles. The mother liquor was concentrated under reduced
pressure, and the residue was purified by CC (AcOEt/cyclohexane 1:1) to give 12a (269 mg, 34%) and
12b (45 mg; total recovered, 269 mg, 35%).

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Helvetica Chimica Acta – Vol. 95 (2012)
25
Data of 12a. Yellow solid. M.p. 139 – 1418. Rf (AcOEt/cyclohexane 6 :4) 0.51. [a] ¼ þ170 (c ¼ 1.0,
589
CH2Cl2). IR: 3304w, 3060w, 2923w, 2851w, 2364w, 1706m, 1640s, 1520s, 1486s, 1447m, 1294m, 1221m,
1
971m, 885m, 737s, 693s. H-NMR (300 MHz, CDCl3): 8.01 (s, 1 arom. H); 7.85 – 7.88 (m, 2 arom. H);
7.47 – 7.52 (m, 1 arom. H); 7.32 – 7.41 (m, 4 arom. H); 7.08 – 7.18 (m, 7 arom. H, NH); 6.92 (d, J ¼ 7.5, 1
arom. H); 6.80 (d, J ¼ 7.5, 1 arom. H); 6.63 (d, J ¼ 8.3, NH); 6.53 (d, J ¼ 8.1, NH); 4.73 (dd, J ¼ 7.3, 15.4,
HꢀC(a)(Phe)); 3.81 (d, J ¼ 18.1, 1 H of CH2); 3.67 – 3.71 (m, HꢀC); 3.23 – 3.40 (m, CH2); 3.15 – 3.19 (m,
CH2(b)(Phe)); 1.57 – 1.75 (m, 3 CH2); 1.06 – 1.18 (m, 2 CH2). 13C-NMR (77 MHz, CDCl3): 194.3 (CO);
172.0; 169.7; 168.4 (CO); 149.9; 144.1; 140.4; 137.2; 134.9; 134.8; 134.1; 133.7; 133.1; 132.8; 129.6; 129.3;
128.9; 128.9; 127.8; 127.2; 125.3; 124.6; 123.8; 122.7 (ArC); 68.3 (C); 54.6 (C); 48.9 (CH); 42.9; 42.4; 37.9;
33.2; 33.0; 25.9; 25.3 (CH2). HR-ESI-MS: 612.2866 ([M þ H]þ, C39H38N3O4þ ; calc. 612.2862).
25
Data of 12b. Yellow solid. M.p. 125 – 1288. Rf (AcOEt/cyclohexane 6 :4) 0.41. [a] ¼ ꢀ75 (c ¼ 1.0,
589
CH2Cl2). IR: 3311w, 3057w, 2927w, 2844w, 2364w, 1700m, 1638s, 1522s, 1486s, 1447m, 1293m, 1229m,
972m, 893m, 736s, 694s. 1H-NMR (300 MHz, CDCl3): 7.77 – 7.83 (m, 3 arom. H); 7.49 – 7.54 (m, 1 arom.
H); 7.37 – 7.43 (m, 3 arom. H); 7.25 – 7.30 (m, 1 arom. H); 7.08 – 7.21 (m, 8 arom. H, NH); 6.92 (d, J ¼ 7.5, 1
arom. H); 6.75 (d, J ¼ 7.5, NH); 6.64 (d, J ¼ 7.5, NH); 4.71 (dd, J ¼ 6.5, 13.7, HꢀC(a)(Phe)); 3.88 (d, J ¼
17.1, 1 H of CH2); 3.68 (m, HꢀC); 3.45 (d, J ¼ 16.9, 1 H of CH2); 3.35 (d, J ¼ 17.7, 1 H of CH2); 3.25 (d, J ¼
17.7, 1 H of CH2); 3.15 (m, CH2(b)(Phe)); 1.74 (m, 5 H of CH2); 1.18 (m, 5 H of CH2). 13C-NMR
(77 MHz, CDCl3): 194.1 (CO); 172.2; 169.7; 168.5 (CO); 148.3; 144.1; 140.7; 137.0; 135.2; 134.9; 134.7;
133.9; 133.1; 132.7; 129.5; 129.2; 128.9; 128.9; 127.7; 127.3; 124.9; 124.4; 123.7; 122.9 (ArC); 68.0 (C); 54.7
(C); 48.8 (CH); 43.8; 41.5; 37.8; 33.2; 33.0; 25.9; 25.3 (CH2). HR-ESI-MS: 612.2869 ([M þ H]þ,
C39H38N3Oþ4 ; calc. 612.2862).
Methyl (2S)-2-Amino-1,2,3,6-tetrahydro-6-oxocyclopenta[c]fluorene-2-carboxylate (13a). Com-
pound 12a (125 mg, 0.20mmol) was dissolved in a mixture of dioxane (5 ml) and conc. aq. HCl (36%
(w/v), 5 ml) and heated at 1108 for 42 h. The mixture was allowed to cool, and concentrated under
reduced pressure. Toluene was added to the residue, and the mixture was concentrated again. The residue
was taken up in MeOH (7 ml), and the mixture was cooled on an ice bath. SOCl2 (0.2 ml) was added
dropwise. The mixture was left to stir at r.t. for 6 d. The mixture was concentrated under reduced
pressure. Toluene was added to the residue, and the mixture was concentrated again. The residue was
taken up in AcOEt and washed with a sat. aq. soln. of NaHCO3. The org. phase was dried (MgSO4),
filtered, and concentrated under reduced pressure. The residue was purified by CC (CH2Cl2/MeOH
25
95 :5) to give 13a (36 mg, 61%). Yellow oil. Rf (CH2Cl2/MeOH 95 :5) 0.31. [a] ¼ þ16 (c ¼ 0.28,
589
MeOH). IR: 3372w, 2954w, 2923w, 2844w, 2353w, 1730m, 1704s, 1588s, 1429m, 1387m, 1293w, 1199m,
1047m, 971m, 869m, 770m, 735s, 674m. 1H-NMR (300 MHz, CDCl3): 7.62 (d, J ¼ 7.3, 1 arom. H); 7.49 (d,
J ¼ 7.3, 1 arom. H); 7.35 – 7.45 (m, 2 arom. H); 7.22 – 7.27 (m, 1 arom. H); 7.10 (d, J ¼ 7.5, 1 arom. H); 3.80
(s, MeO); 3.65 (d, J ¼ 16.4, 1 H of CH2); 3.52 (d, J ¼ 16.7, 1 H of CH2); 3.14 (d, J ¼ 16.4, 1 H of CH2); 2.91
(d, J ¼ 16.7, 1 H of CH2). 13C-NMR (77 MHz, CDCl3): 193.5 (CO); 176.4 (CO); 149.3; 144.1; 140.4; 134.9;
134.6; 134.4; 133.4; 128.7; 124.7; 124.2; 123.4; 122.1 (ArC); 65.1 (C); 52.7 (Me); 45.7; 44.3 (CH2). HR-
ESI-MS: 294.1130 ([M þ H]þ, C18H16NO3þ ; calc. 294.1130).
Methyl (2R)-2-Amino-1,2,3,6-tetrahydro-6-oxocyclopenta[c]fluorene-2-carboxylate (13b). Com-
pound 12b (125 mg, 0.20 mmol) was treated in the same way as described above to give 13b (43 mg,
25
72%). [a] ¼ ꢀ17 (c ¼ 0.33, MeOH). HR-ESI-MS: 294.1131 ([M þ H]þ, C18H16NO3þ ; calc. 294.1130).
589
Methyl (2S)-2-[(tert-Butoxycarbonyl)amino]-1,2,3,6-tetrahydro-6-oxocyclopenta[c]fluorene-2-car-
boxylate (14a). Compound 13a (39 mg, 0.13 mmol) was dissolved in MeCN (3 ml), and Boc2O (40 mg,
0.18 mmol) was added. The mixture was stirred at r.t. for 7 d. The mixture was concentrated under
reduced pressure. The residue was purified by CC (AcOEt/cyclohexane 3 :7) to give 14a (41 mg, 80%).
25
Yellow foam. Rf (AcOEt/cyclohexane 4 :6) 0.51. [a] ¼ þ59 (c ¼ 0.23, CH2Cl2). IR: 3315m, 2977w,
589
2927m, 2844w, 2361w, 1734s, 1700s, 1675s, 1525s, 1429m, 1366m, 1290m, 1225m, 1160s, 1048m, 1019m,
968m, 836m, 736s, 677m. 1H-NMR (300 MHz, CDCl3): 7.65 (d, J ¼ 7.2, 1 arom. H); 7.52 (d, J ¼ 7.4, 1 arom.
H); 7.40 – 7.47 (m, 2 arom. H); 7.30 (d, J ¼ 7.3, 1 arom. H); 7.11 (d, J ¼ 7.4, 1 arom. H); 5.30 (s, NH); 3.80 –
3.84 (m, Me, 1 H of CH2); 3.49 – 3.61 (m, CH2); 3.27 (d, J ¼ 17.4, 1 H of CH2); 1.44 (s, 3 Me). 13C-NMR
(77 MHz, CDCl3): 193.5 (CO); 173.7 (CO); 155.0 (CO); 148.5; 144.0; 140.3; 134.7; 134.5; 133.6; 128.8;
124.5; 124.3; 123.5; 122.3 (ArC); 80.7 (C); 65.9 (C); 52.9 (Me); 43.8; 41.9 (CH2); 28.2 (Me). HR-ESI-
MS: 394.1653 ([M þ H]þ, C23H24NO5þ ; calc. 394.1654).

Helvetica Chimica Acta – Vol. 95 (2012)
2457
Methyl (2R)-2-[(tert-Butoxycarbonyl)amino]-6-oxo-1,2,3,6-tetrahydrocyclopenta[c]fluorene-2-car-
boxylate (14b). Compound 13b (54 mg, 0.18 mmol) was treated in the same way as described above to
25
give 14b (53 mg, 75%). [a] ¼ ꢀ56 (c ¼ 0.21, CH2Cl2). HR-ESI-MS: 394.1652 ([M þ H]þ, C23H24NO5þ ;
589
calc. 394.1654).
EPR Measurements. An EPR quartz tube (4 mm o.d.) containing a 1 mm soln. of Boc-(S)-FlAib-
OMe was connected to a vacuum line and sealed, after several ꢃfreeze-pump-thawꢄ cycles, to avoid any O2
presence. Time-resolved EPR spectra (TR-EPR) were acquired with a cw Bruker ER200D X-band
spectrometer, equipped with a temp.-control unit working with liquid N2. The sample was photoexcited
inside the microwave cavity of the spectrometer by using short UV pulses produced by the 3rd harmonic
of a Quantel Brilliant Nd:YAG laser (l, 355 nm, 5-ns duration, 50-Hz repetition rate). Data were then
acquired according to published procedures [28].
X-Ray Diffraction. Crystals, in the shape of thin needles, were grown from an AcOEt/cyclohexane
mixture by slow evaporation. A crystal, ca. 0.30 ꢂ 0.05 ꢂ 0.05 mm3 in size, was glued on the tip of a glass
fiber and coated with paratone. X-Ray diffraction data were collected at 1808 K with an Agilent
Technologies Gemini E four-circle kappa diffractometer equipped with a 92-mm EOS CCD detector,
using graphite monochromated CuKa radiation (l 1.54178 ꢂ). Data collection and reduction were
performed with the CrysAlisPro software (version 1.171.33.52; Agilent Technologies). A semi-empirical
absorption correction, based on the multi-scan technique using spherical harmonics, implemented in the
SCALE3 ABSPACK scaling algorithm, was applied.
The structure was solved by direct methods of the SIR 2002 program [29]. The asymmetric unit is
composed of one peptide molecule and one co-crystallized AcOEt molecule. The choice of the space
group P61, rather than its enantiomorph P63, was based on the known (S)-configuration of the Phe
residue used in racemization-free procedures for the synthesis of the N-acylated dipeptide alkylamide.
Refinement was carried out by full-matrix least-squares procedures on F2, using all data, by application
of the SHELXL-97 program [30]. All aromatic rings were constrained to the idealized geometry.
Restraints were applied to the anisotropic displacement parameters of all atoms, to approach isotropic
behavior. The H-atoms were calculated at idealized positions and refined using a riding model. Relevant
crystallographic data are compiled in the Table. Overall, a number of crystallographic parameters suffer
from the far from optimal crystal size and quality. We are confident, however, that the basic
conformational features of the molecule, as discussed in this work, are unambiguously established.
CCDC-887940 contains the supplementary crystallographic data for this paper. These data can be
obtained from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Table. Crystal Data and Structure Refinement for Bz-(R)-FlAib-(S)-Phe-NH-cHex Ethyl Acetate Solvate
Identification code
Empirical formula
Formula weight
Temp.
Wavelength
Crystal system
Space group
mc166f
C43H45N3O6
699.82
180(2) K
1.54178 ꢂ
Hexagonal
P61
F(000)
Crystal size
q Range for data collection 3.57 to 61.368
Index ranges
2232
0.30 ꢂ 0.05 ꢂ 0.05 mm3
ꢀ 13 ꢃ h ꢃ 17, ꢀ 19 ꢃ k ꢃ 18,
ꢀ 25 ꢃ l ꢃ 16
Reflections collected
Independent reflections
11121
4543 (Rint ¼ 0.0806)
Unit cell dimensions a 17.1665(10) ꢂ Completeness to q ¼ 61.368
99.0%
b 17.1665(10) ꢂ Absorption correction
Semi-empirical from equivalents
c
22.3956(10) ꢂ Max. and min. transmission 1.00000 and 0.53482
a 908
b 908
g 1208
Refinement method
Data/restraints/parameters
Full-matrix least-squares on F2
4543/313/414
Goodness-of-fit on F2
1.329
Volume
Z
Density (calculated)
5715.5(5) ꢂ3 Final R indices (I > 2s(I))
6
R1 ¼ 0.1078, wR2 ¼ 0.3118
R indices (all data)
R1 ¼ 0.1330, wR2 ¼ 0.3303
1.220 Mg/m3 Absolute structure parameter ꢀ 0.1(8)
Absorption coefficient 0.655 mmꢀ1
Largest diff. peak and hole
0.678 and ꢀ 0.409 e ꢂꢀ3

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Helvetica Chimica Acta – Vol. 95 (2012)
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Received August 21, 2012