Thiolation of symmetrical and unsymmetrical diketopiperazines

Article abstract of DOI:10.1039/c2ob06663g

The introduction of sulfur units into a variety of symmetrical and unsymmetrical diketopiperazines (DKPs) is described. We investigated different thiolation methods utilizing several bases and electrophilic sulfur reagents, leading to monomethylthio-, bis

Full text of DOI:10.1039/c2ob06663g

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Thiolation of symmetrical and unsymmetrical diketopiperazines†
Bettina M. Ruff,a Sabilla Zhong,a Martin Niegerb and Stefan Bra¨se*a
Received 1st October 2011, Accepted 28th November 2011
DOI: 10.1039/c2ob06663g
The introduction of sulfur units into a variety of sym-
metrical and unsymmetrical diketopiperazines (DKPs) is
described. We investigated different thiolation methods uti-
lizing several bases and electrophilic sulfur reagents, leading
to monomethylthio-, bis(methylthio)-, and epithio-DKPs.
Their formation proceeded diastereoselectively, facilitating
the application in total syntheses of many thiodiketopiper-
azine (TDKP) natural products. Furthermore, possible side
reactions as well as mechanistic studies and stereochemical
structural assignments of the obtained products are given.
However, there has been progress in the synthesis of complex
epi(poly)-TDKP natural products during the last few years.
Movassaghi et al. published an approach to access the dimeric
cytotoxic metabolite (+)-11,11¢-dideoxyverticillin A (1)3 and (+)-
chaetocin A (2) as well as the epipoly-TDKPs (+)-chaetocin C
(3) and (+)-12,12¢-dideoxychetracin A (4).4 Their method for the
thiolation of the DKP core is based on the postulated biosynthesis5
of gliotoxin6 which comprises the formation of acylimmonium
ions through dehydration. Following a similar approach, Sodeoka
et al. were able to synthesize (+)-chaetocin A (2), too.7 Syntheses
of the mycotoxins gliocladine C,8 epicoccin G (5), 8,8¢-epi-ent-
rostratin B (6)9 and reported progress toward the preparation of
synthetic fragments of challenging TDKPs10 can be found in the
literature as well. The epicoccins M–P (7–10) have been isolated
from Epicoccum nigrum recently.11 They possess an unusual
unsymmetrical sulfur substitution pattern which has not been
addressed in total syntheses so far.
Despite the variety and importance of TDKP natural products,
to the best of our knowledge, no general method for the
introduction of the sulfur bridge has been published to date.
Most of the examples above use techniques that seem to be
working because of the specific properties and requirements of the
individual structures. Therefore, we were looking for a versatile
procedure that allows the facile conversion of DKPs to TDKPs in
a convenient way.
Introduction
The smallest cyclic peptides built by amino acids are the so called
diketopiperazines (DKPs). In recent research, DKPs and higher
functionalized analogs – the thiodiketopiperazines (TDKPs) –
have become attractive due to their versatile biological activity
(Fig. 1).1 Nevertheless, only a few examples of total syntheses of
the large family of (T)DKP mycotoxins exist in the literature. Es-
pecially the introduction of the sulfur bridge remains a challenge.2
aKarlsruhe Institute of Technology (KIT), Institute of Organic Chemistry,
Fritz-Haber-Weg 6, D-76131, Karlsruhe, Germany. E-mail: braese@kit.edu;
Tel: (+49) 721 608-48581
bLaboratory of Inorganic Chemistry, Department of Chemistry, University
of Helsinki, P.O. Box 55, FIN-00014, Finland
Results and discussion
† Electronic supplementary information (ESI) available: Experimental and
spectral data for all new compounds. CCDC reference numbers 846902
(1{bb}), 852473 (3{aa}), 846903 (4{bb}), 852472 (3{bb}), 852474 (4{cc}
and 17) and 846901 (14). For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c2ob06663g
The starting materials for the herein reported transformations,
symmetrical and unsymmetrical DKPs 1{xy}, could be easily
synthesized from commercially available amino acids (a–e) using
Fig. 1 Examples of epi(poly)thiodiketopiperazine natural products.
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Table 1 Synthesis of monomethylthio- (2{xy}), bis(methylthio)- (3{xy}) and epithio- (4{xy}) DKPs from symmetrical and unsymmetrical DKPs 1{xy}
Isolated yield (%)
Entry
Starting material
Conditionsa
2{xy}
3{xy}
4{xy}
1
2
3
4
5
6
7
8
1{aa}
1{aa}
1{aa}
1{bb}
1{bb}
1{bb}
1{cc}
1{cc}
1{dd}
1{dd}
1{ee}
1{ee}
1{ab}
1{ab}
1{ab}
A
B
C
A
B
C
B
C
B
C
B
C
A
B
C
17
52
traces
50
50
30
32
23
42
9
41
10
11
12
13
14
15
31
traces
traces
16/epi-16 (see Scheme 3)
21
16
a A: NaHMDS, THF, -78 ◦C, 1 h; then MeSO2SMe (12), THF, -78 ◦C to r.t., 2 h; B: NaHMDS, S8, THF, r.t.; then 1{xy}; then NaHMDS, r.t., 30 min;
then NaBH4, THF/MeOH (1 : 1), 0 ◦C to r.t., 45 min; then MeI, r.t., 15 h; C: NaHMDS, S8, THF, r.t.; then 1{xy}; then NaHMDS, r.t., 30 min; then
NaBH4, THF/MeOH (1 : 1), 0 ◦C to r.t., 45 min; then KI3, r.t., 10 min.
our previously published one-pot procedure.12 The figure in Table 1
derivatives 13 and rac-3{aa} are present in the reaction mixture
gives an overview of the amino acid monomers as well as a general
structure of the possible starting materials 1{xy} and products
2–4{xy} described in this article. In our first experiments, we
deprotonated cyclo-proline-proline 1{aa} with LDA as a base.
This led to the formation of dianion 11 (Scheme 1) as proved by
a quench with D2O followed by work-up and NMR as well as
mass spectroscopy experiments. Addition of electrophilic sulfur
reagent 12 did not furnish desired bis(methylthio) product 3{aa}
(Scheme 2).
We only observed formation of dimeric product 14 whose
structure could be unequivocally proven by X-ray crystallography
(Fig. 2).‡ The surprisingly long C–C bond (161 pm) between the
two DKP rings is noteworthy. Schmidt et al. already postulated
this structure as a side product in their thiolation experiments13
which we were now able to confirm. We postulate that dimerization
occurs as shown in Scheme 1. Dianion 11 subsequently reacts with
12 in a substitution reaction. Thus, mono- and bis(methylthio)-
at the same time. Monoanion 13 can attack derivative rac-
3{aa} due to the now positively charged a-carbon atom. This
C-C-bond formation furnishes observed DKP dimer 14 as one
diastereoisomer in a racemic mixture.
In the further course of our work we varied base (LDA,
KHMDS, NaHMDS, LiHMDS, LDEA, LDA + n-BuLi, LDA
+ DMPU), solvent, temperature and sulfur reagent (Me-SS-Me,
Me-SO2S-Me (12), PMB-SS-PMB, tolyl-SO2S-PMB, tolyl-SO2S-
butyl, Ph-SO2S-Ph, tetramethylthiuram disulfide) to introduce one
or more thio units to the DKP core.
With both DKP 1{aa} and DKP 1{bb}, we were able to
obtain monomethylthio derivatives 2{aa} and 2{bb} (Scheme 2,
Table 1, Entry 1,4) using NaHMDS as a base and S-methyl
methanesulfonothioate (12) as the electrophilic sulfur reagent.
This method depicts the first approach toward natural products
bearing only one thiomethyl substituent, e.g. epicoccins M–P (7–
10).
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Scheme 1 Proposed mechanism for deprotonation of DKP 1{aa} with
base, followed by thiolation with S-methyl methanesulfonothioate (12) and
formation of dimeric compound 14.
Fig. 2 Crystal structure of dimeric compound 14. One of the crystallo-
graphic independent molecules is shown. The dotted line shows the long
C–C bond between the two DKP rings.
Scheme 2 Synthesis of thiolated derivatives 2–4{aa} and 14 of cy-
clo-proline-proline 1{aa}. Reagents and conditions: (a) LDA, THF, -78
◦C, 3 h; then MeSO2SMe, THF, -78 ◦C to r.t., 71%; (b) NaHMDS, S8, THF,
r.t.; then 1{aa}; then NaHMDS, r.t., 30 min; then NaBH4, THF/MeOH
(1 : 1), 0 ◦C to r.t., 45 min; then KI3, r.t., 10 min, traces; (c) NaHMDS,
S8, THF, r.t.; then 1{aa}; then NaHMDS, r.t., 30 min; then NaBH4,
THF/MeOH (1 : 1), 0 ◦C to r.t., 45 min; then MeI, r.t., 15 h, 52%; (d)
NaHMDS, THF, -78 ◦C, 1 h; then MeSO2SMe, THF, -78 ◦C to r.t., 2 h,
17%.
When DKP 1{ab} was treated with NaHMDS followed by the
addition of S-methyl methanesulfonothioate (12) (Table 1, Entry
13), we isolated dehydro-DKP 16 and its epimer epi-16 in a 2 : 1
ratio in overall 87% yield. A proposed mechanism for its formation
is shown in Scheme 3.
Scheme 3 Formation of dehydro-DKP 16 and epi-16. Reagents and
conditions: (a) NaHMDS, THF, -78 ◦C, 3 h; then MeSO2SMe, THF,
-78 ◦C to r.t., 87%.
Initially, the anion of monomethyl derivative 15 is built through
deprotonation followed by addition of a methylthio unit. In the
presence of an excess of base, this group can be eliminated.
Reprotonation occurs in a 2 : 1 favor of one side of the molecule
to give the unsaturated species 16 and epi-16. The dehydro-DKP
structural motif can be found in several natural products, e.g.
spirotryprostatin B14 and drimentin B.15 After optimization, the
described one-step elimination reaction could be used for their
total syntheses. It would be an improvement to the non-selective
or multi-step procedures that can be found in the literature.16
During the course of our work,12a,17 Nicolaou et al. came up
with their method using molecular sulfur and NaHMDS9 based
on the pioneering sulfenylation work by Schmidt et al.13 The latter
were the first ones to deprotonate a diketopiperazine followed by
addition of molecular sulfur to obtain epithio-DKPs. By changing
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the non-practicable use of sodium in liquid ammonia to NaHMDS
as a base, we, as well as the group of Nicolaou, were able to improve
Schmidt’s method. We found that applying these revised reaction
conditions to our substrates yielded all monomethylthio- (2{xy}),
bis(methylthio)- (3{xy}) and epithio- (4{xy}) DKPs depending
on the various reaction conditions. The results comparing the
different methods with a range of different DKPs 1{xy} are
summarized in Table 1.
We were able to synthesize a variety of thiolated DKPs which
were all obtained as single diastereoisomers. Upscaling (2 g scale)
the reaction of DKP 1{aa} to give TDKP 3{aa} still gave a
comparable yield of 39%.
Both sulfur electrophiles were found to attack the molecule from
the same side, as all symmetrical bis(methylthio)-DKPs (3{xy})
only showed one signal in both 1H and 13C NMR for the two methyl
groups. Stereochemistry of the thiolated species was assigned using
NOE correlations (Fig. 4) as well as X-ray crystallography. The
structure of 3{aa} was found to be racemic in its crystal (Fig. 3).
Fig. 4 NOE correlations (arrows) for compounds 2{aa}, 2{bb}, 3{bb}
and 3{cc} and crystal structure of compound 3{bb}.
Fig. 3 Crystal structure of bis(methylthio)-DKP 3{aa}. The relative R,R
configuration is shown.
Since the molecule showed optical rotation, no complete
racemization had occurred, but the formation of one enantiomer
was favored. Apparently, partial racemization occurs during
deprotonation as the starting material 1{aa} is an enantiomerically
pure compound. The shape of the molecule, as seen in the crystal
structure of 1{aa},12b has presumably no strongly favored side
for an electrophilic attack. This observation is in accordance
to the proposed mechanism – comprising a dianion – for the
formation of dimer 14 (Scheme 1). The structures of 2{bb},
3{bb}, 3{cc}, 4{bb}, 4{cc}, 3{ab} and 4{ab} could be assigned
as enantiomerically pure. The 4aS,14aS configuration of 2{bb}
and 3{bb} cannot be changed during the reaction. Due to the
NOE correlations between these protons and the protons of the
methylthio group, the stereogenic center at position 13a (and
6a for 3{bb}) has to have R configuration. Furthermore, we
were able to confirm the structure of compound 3{bb} by X-
ray crystallography (Fig. 4). Since the 2R configuration in 3{cc}
cannot be altered, a 5aR,10aR structure must be on hand here.
The structure of the corresponding epidithio-DKP, 4{cc}, could
be proven by crystal structure analysis (Fig. 5). The structure co-
crystallized in a 2 : 1 ratio together with the epitrithio-DKP 17,
Fig. 5 Structures and crystal structures of epidithio-DKP 4{cc} and
epitrithio-DKP 17.
which is another interesting natural product motif.18 With this
example, we were able to show that the presented method tolerates
protected hydroxyl functional groups without epimerization. The
unsymmetrical thiolated species 3{ab} and 4{ab} were obtained
as single diastereomers confirming that thiolation had occurred in
an enantioselective procedure. This supports the applicability of
the selective thiolation procedure for unsymmetrical DKPs such
as 1{ab}.
Fig. 6 shows a Least Square Fit of the crystal structures of DKP
1{bb} and epithio-DKP 4{bb}. Almost no change in the geometry
of starting material and product has occurred during the thiolation
reaction. The rigid scaffold of the pentacyclic DKP 1{bb} might
be the reason why only one thiolated stereoisomer is formed. Due
to the curved shape of 1{bb}, the attack of the sulfur from the
convex side of the molecule is strongly favored. The substitution
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enantioselective total syntheses. In these cases, the introduction
of the sulfur occurs under retention of the configuration at the
a-carbon atom of the DKP ring as proved with various examples.
When we treated the complex DKP 23 with NaHMDS and
molecular sulfur, we observed the formation of monomethylthio-
DKP 24 (Scheme 5).
Fig. 6 Least Square Fit of the crystal structures of DKP 1{bb} and
epithio-DKP 4{bb}.
of the hydrogen atoms under retention of the configuration implies
the occurrence of free anions since a concerted mechanism would
lead to inversion at the a-carbon atoms.
The obtained enantiomeric purity of thiolated species 4{bb} in
comparison to racemically built structure 3{aa} shows that the
method reported is suitable for the stereoselective synthesis of
complex thiolated molecules. DKP 1{bb} represents the scaffold
of dethio-rostratin 18 (Scheme 4). The presented method should
therefore be applicable for the enantioselective total synthesis of
rostratins B–D (19–21).19
Scheme 5 Formation and thiolation of DKP 23. (a) MeOPCl2, NEt3,
1,3-dimethylimidazolium dimethylphosphate, toluene, 30 ◦C, overnight;
then MW, 145 ◦C, 1 h, 32%; (b) NaHMDS, S8, THF, r.t.; then 23; then
NaHMDS, r.t., 30 min; then NaBH4, THF/MeOH (1 : 1), 0 ◦C to r.t., 45
min; then MeI, r.t., 15 h, 23%.
DKP 23 was obtained through dimerization of amino acid 22,
which was prepared in 4 steps according to the literature.20 Its
thiolation result proves the compatibility of the presented method
with pyrroloindole units which can be found in many natural
products.21 It can furthermore be seen as another example for the
selective preparation of monomethylthio-DKPs.
Conclusions
We were able to synthesize a range of different thiodiketopiper-
azines (TDKPs) from diketopiperazines (DKPs), which them-
selves were accessible in one step from commercially available
amino acids. The thiolation reactions proceeded with high di-
astereoselectivity (stereochemistry and structural properties were
confirmed by NOESY experiments and/or X-Ray crystallogra-
phy) and could be carried out on both milligram and gram scales.
The substitution pattern of the products obtained depended on
the applied reaction conditions, which consisted of treatment with
a base and an electrophilic sulfur reagent, such as sulfonothioates
or S8. Hereby, various TDKPs bearing one or two methylthio
substituents as well as disulfide bridges could be obtained. The
herein proposed mechanism for thiolation – implying the forma-
tion of a dianion – was supported by deuteration experiments and
determination of the stereochemistry of the products obtained.
Furthermore, the formation of a dimeric DKP with a notable
structure was observed. We were also able to obtain a dehydro-
DKP in a single step procedure, which is another structural motif
found in several natural products. In conclusion, we proved that
Scheme 4 Enantioselective synthesis of epidithio-DKP 4{bb} and its
potential application to the total synthesis of rostratins B–D (19–21). (a)
NaHMDS, S8, THF, r.t.; then 1{bb}; then NaHMDS, r.t., 30 min; then
NaBH4, THF/MeOH (1 : 1), 0 ◦C to r.t., 45 min; then KI3, r.t., 10 min.
If the DKP scaffold of the starting material is bearing small and
non-rigid substituents as in the case of 1{aa}, no enantioselectivity
can be observed. Due to that fact, the thiolated species 2{aa},
3{dd} and 4{dd} were presumably obtained as scalemic mixtures
of the two possible cis-configurated enantiomers, too. Never-
theless, with all DKPs, diastereoselectivity is obtained as both
sulfur atoms attack each molecule from the same side. As most
of the TDKP natural products have fully substituted structures
anyway (see Fig. 1), the method reported could be used for their
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the selection of the used thiolation methods is applicable to nu-
merous DKPs, as exemplified by a variety of symmetrical, unsym-
metrical and unsubstituted as well as functionalized DKPs, which
can be mono- to heptacyclic. Because we were able to mono-,
bis- and epithiolate DKPs bearing very different structural,
electronic, stereochemical and steric properties, we anticipate
transferring these results to the thiolation of other DKPs leading
to highly biologically active natural products. Investigations
toward the total synthesis of potent TDKPs are currently carried
out in our group.
4{cc} and 17: yellow, C74H74CL6N6O12S6.31 (2.69C24H24N2O4S2–0.31
C24H24N2O4S3–2CHCl3), M = 1654.39 (formula weight of the asymmetric
unit), crystal size 0.36 ¥ 0.12 ¥ 0.06 mm, monoclinic, space group P21 (no.
◦
˚
˚
˚
4): a = 11.4283(1) A, b = 17.1077(2) A, c = 19.3984(2) A, b = 92.773(1) ,
3
-3
˚
V = 3788.18(7) A , Z = 2, r(calc) = 1.450 Mg m , F(000) = 1718, m = 0.466
mm-1, 51084 reflections (2qmax = 55◦), 17215 unique [Rint = 0.042], 924
parameters, 220 restraint, R1 (I > 2s(I)) = 0.076, wR2 (all data) = 0.186,
GOF = 1.03, largest diff. peak and hole 1.816 (in solvent CHCl3)/-1.324 e
-3
˚
A .
14: yellow, C22H30N4O4S2–1/8H2O, M = 480.88, crystal size 0.40 ¥ 0.20 ¥
¯
˚
˚
0.10 mm, triclinic, space group P1 (no. 2): a = 9.648(1) A, b = 14.822(2) A,
◦
◦
◦
˚
c = 16.441(3) A, a = 104.68(1) , b = 103.17(1) , g = 91.75(1) , V = 2204.8(6)
3
-3
-1
˚
A , Z = 4, r(calc) = 1.449 Mg m , F(000) = 1021, m = 0.281 mm , 15993
reflections (2qmax = 50◦), 7743 unique [Rint = 0.048], 591 parameters, 3
restraint, R1 (I > 2s(I)) = 0.058, wR2 (all data) = 0.146, GOF = 1.01,
Acknowledgements
-3
˚
largest diff. peak and hole 0.503/-0.399 e A .
CCDC reference numbers 846902 (1{bb}), 852473 (3{aa}), 846903
(4{bb}), 852472 (3{bb}), 852474 (4{cc} and 17) and 846901 (14).
For crystallographic data in CIF or other electronic format see DOI:
10.1039/c2ob06663g
We thank the Deutsche Forschungsgemeinschaft (DFG BR
1750/17-1) and the Fonds der Chemischen Industrie (fellowship
to B. M. Ruff) for financial support.
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Notes and references
‡ Crystal structure determinations. The single-crystal X-ray diffraction
study was carried out on a Bruker-Nonius Kappa-CCD diffractometer
or a Bruker-Nonius APEXII diffractometer at 123(2) K using Mo-Ka
22
˚
radiation (l = 0.71073 A). Direct Methods (SHELXS-97) were used
for structure solution and refinement was carried out using SHELXL-
9722 (full-matrix least-squares on F2). Hydrogen atoms were localized by
difference electron density determination and refined using a riding model
(H(O) free). A semi-empirical absorption correction was applied for 4{bb}.
Due to the bad quality of the data caused by the size and shape of the
crystal for 3{bb} general ISOR restrains were applied. In 4{cc} and 17 the
two solvent molecules are disordered. Two of the three crystallographic
independent molecules are ordered showing the structure 4{cc}. The third
molecule is disordered showing the structure of 4{cc} and 17 in the ratio
0.69 : 0.31.
The absolute structure of 1{bb} could neither be determined reliably by
refinement of Flack’s x-parameter (x = -3(3)),23 nor by using Bayesian
statistics on Bijvoet differences (y = 0.3(14)).24 The enantiomer has been
assigned by reference to an unchanging chiral center in the synthetic
procedure. The absolute structure of 3{bb}, 4{bb} and (4{cc} and 17)
could be determined (x = 0.07(6), y = 0.05(3) (4{bb}), x = 0.0(2), y =
0.03(1) (3{bb}), x = 0.03(7), y = 0.047(13) ({4{cc} and 17)).
1{bb}: colorless, C18H26N2O2, M = 302.41, crystal size 0.24 ¥ 0.06 ¥ 0.02
˚
mm, orthorhombic, space group P212121 (no. 19): a = 6.430(1) A, b =
3
˚
˚
˚
11.207(2) A, c = 21.269(3) A, V = 1532.7(4) A , Z = 4, r(calc) = 1.311 Mg
m-3, F(000) = 656, m = 0.085 mm-1, 15375 reflections (2qmax = 50◦), 2697
unique [Rint = 0.141], 199 parameters, R1 (I > 2s(I)) = 0.078, wR2 (all
-3
˚
data) = 0.148, GOF = 1.04, largest diff. peak and hole 0.249/-0.280 e A .
3{aa}: colorless, C12H18N2O2S2, M = 286.40, crystal size 0.32 ¥ 0.04 ¥
˚
0.04 mm, monoclinic, space group P21/c (no.◦14): a = 17.1844(13) A, b =
3
˚
˚
˚
7.3729(5) A, c = 10.8107(8) A, b = 105.732(3) , V = 1318.39(17) A , Z =
4, r(calc) = 1.443 Mg m-3, F(000) = 608, m = 0.400 mm-1, 6338 reflections
(2qmax = 55◦), 2966 unique [Rint = 0.032], 165 parameters, R1 (I > 2s(I)) =
0.048, wR2 (all data) = 0.105, GOF = 1.14, largest diff. peak and hole
-3
˚
0.394/-0.288 e A .
3{bb}: yellow, C20H30N2O2S2, M = 394.58, crystal size 0.15 ¥ 0.02 ¥ 0.02
˚
17 U. Gross, M. Nieger and S. Bra¨se, Chem.–Eur. J., 2010, 16, 11624.
18 E. Iwasa, Y. Hamashima and M. Sodeoka, Isr. J. Chem., 2011, 51, 420.
19 R. X. Tan, P. R. Jensen, P. G. Williams and W. Fenical, J. Nat. Prod.,
2004, 67, 1374.
mm, triclinic, space group P1 (no. 1): a = 9.1262(9) A, b = 9.6454(10)
◦
◦
◦
˚
˚
A, c = 11.5103(9) A, a = 91.426(5) , b = 101.320(6) , g = 91.777(5) , V =
3
-3
-1
˚
992.52(16) A , Z = 2, r(calc) = 1.320 Mg m , F(000) = 424, m = 0.286 mm ,
5890 reflections (2qmax = 50◦), 4287 unique [Rint = 0.060], 473 parameters,
315 restraint, R1 (I > 2s(I)) = 0.101, wR2 (all data) = 0.226, GOF = 1.17,
20 J. Xiao, F. Xu, Y. Lu and T. Loh, Org. Lett., 2010, 12, 1220–1223.
-3
´
˚
21 P. Ruiz-Sanchis, S. A. Savina, F. Albericio and M. Alvarez, Chem.–Eur.
largest diff. peak and hole 0.665/-0.447 e A .
J., 2011, 17, 1388.
4{bb}: yellow, C18H24N2O2S2, M = 364.51, crystal size 0.30 ¥ 0.20 ¥ 0.05
˚
22 G. M. Sheldrick, Acta Crystallogr., Sect. A: Found. Crystallogr., 2007,
mm, orthorhombic, space group P212121 (no. 19): a = 6.4416(6) A, b =
3
˚
˚
˚
64, 112.
10.8045(5) A, c = 24.6270(20) A, V = 1714.0(2) A , Z = 4, r(calc) = 1.413
Mg m-3, F(000) = 776, m = 0.324 mm-1, 12711 reflections (2qmax = 55◦),
3924 unique [Rint = 0.035], 217 parameters, R1 (I > 2s(I)) = 0.035, wR2
(all data) = 0.075, GOF = 1.07, largest diff. peak and hole 0.253/-0.199 e
23 H. D. Flack, Acta Crystallogr., Sect. A: Found. Crystallogr., 1983, 39,
876.
24 R. W. W. Hooft, L. H. Straver and A. L. Spek, J. Appl. Crystallogr.,
-3
˚
2008, 41, 96.
A .
940 | Org. Biomol. Chem., 2012, 10, 935–940
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The Royal Society of Chemistry 2012
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