4-Aminocyclopentane-1,3-diols as platforms for diversity: Synthesis of a screening library

Article abstract of DOI:10.1039/c3md00252g

Trisubstituted cyclopentanes have a discrete shapely curvature. While the central ring of these compounds is devoid of rotatable bonds, the pseudo rotation of the cyclopentane ring leads to a desirable disruption of planarity. This is favorable for aqueous solubility and enables addressing of wide-ranging conformational space. The sp³-rich framework of 4-aminocyclopentane- 1,3-diols offers stereochemically defined attachment points for substituents and renders these fragment-like molecules good platforms for molecular diversity. By using an established N-selective polymer-assisted acylation protocol, these scaffolds with natural product-like properties were transformed into a screening library by attachment of substituents at defined positions. Here we describe the synthesis and characterization of these molecular platforms and their use as starting points for the construction of an 80-member library of 4-amidocyclopentane-1,3-diol monoethers. Five of the compounds displayed cytotoxicity in a tumor cell line assay with IC₅₀ values in the low micromolar range.

Full text of DOI:10.1039/c3md00252g

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Medicinal Chemistry Communications
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DOI: 10.1039/C3MD00252G
Stereochemically defined cyclopentanole
derivatives were utilized as sp3-rich platforms to
prepare a screening library. Interaction motifs are
displayed in a threedimensional manner to chart
underexplored areas in chemical space.

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RSCPublishing
ARTICLE
4-Aminocyclopentane-1,3-diols as Platforms for
Diversity: Synthesis of a Screening Library
Cite this: DOI: 10.1039/x0xx00000x
V. Zohrabi-Kalantari,a F. Wilde,a R. Grünert,a P. J. Bednarskia and A. Linka
Trisubstituted cyclopentanes have a discrete shapely curvature. While the central ring of these
compounds is devoid of rotatable bonds, the pseudo rotation of the cyclopentane ring leads to a
desirable disruption of planarity. This is favorable for aqueous solubility and enables to
address wide-ranging conformational space. The sp3-rich framework of 4-aminocyclopentane-
1,3-diols offers stereochemically defined attachment points for substituents and renders these
fragment-like molecules good platforms for molecular diversity. By using an established N-
selective polymer-assisted acylation protocol, these scaffolds with natural product-like
properties were transformed into a screening library by attachment of substituents in defined
positions. Here we describe the synthesis and characterization of these molecular platforms and
the use as starting points for the construction of an 80-member library of 4-
amidocyclopentane-1,3-diol monoethers. Five of the compounds displayed cytotoxicity in a
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
tumor cell line assay with IC50 values in the low micromolar range
.
compounds during the last decades as a possible reason for
stagnation of success in medicinal chemistry per se and for the
apparent non-druggability of many novel targets. It is
conceivable that many putatively undruggable proteins could be
turned into druggable targets by exploring more challenging
Introduction
Introducing diversity into defined positions of nitrogen
containing heterocycles such as quinolones, quinazolinones or
pyrroles is a dominant concept for the generation of molecular
7
1
chemical space . In order to come up with shapely molecules
diversity
.
While existing combinatorial libraries of
we selected sp3-rich cyclopentanes as the molecular platforms
for a compound collection as we recently suggested 8, 9. Thus,
biologically underrepresented but clinically relevant space
should be addressed 10. While it is expensive and laborious to
synthesize singletons for the screening in multi-step sequences,
it is straightforward to prepare eight racemic trisubstituted
cyclopentanoles, which were meant to display recognition
motifs in a spatial arrangement after appropriate modifications
biologically active compounds based on this perception have
proven the suitability of these core scaffolds, the chemical
space addressable by the continuous use of these most
2
commonly deployed heterocycles is limited . Compared to the
wealth of diversity of natural products, the coverage of
conformational space is small and the planarity associated with
aromaticity often leads to good crystallization properties and
3
thus poor water solubility of library members . According to
via N-acylation using a polymer-assisted synthesis approach 11
.
Hert et al. nearly 80% of the ring scaffolds present in natural
products are absent in commercially available screening
compounds 4, most likely due to their limited synthetic
accessibility. Moreover, a thorough analysis by Walters et al.
revealed that the percentage of sp3 carbons for molecules
published in the Journal of Medicinal Chemistry steadily
declined between 1995 and 2009 5.
Results and Discussion
Synthesis
Key components for assessing structural diversity in diversity-
oriented synthesis (DOS) were recognized by Spring et al. as
(1) appendage diversity-variation in structural moieties, around
a common core scaffold, (2) functional group diversity-
variation in the functional groups introduced into the periphery,
(3) stereochemical diversity-variation in the orientation of
potential macromolecule-interacting elements and (4) skeletal
(scaffold) diversity 12. With the intention to generate a set of
platforms for molecular diversity and subsequently ornament
From this point of view, novel slim and shapely compounds
with a high sp3 to sp2 ratio are looked-for starting points for the
6
construction of libraries suitable to address new targets . The
use of such molecules enables to fill white patches in the chart
of synthetically addressed molecular diversity that could hardly
be explored using flat heterocyclic ring systems. This seems of
considerable interest and has been explicated by Tsukamoto in
7
a well-received commentary, recently . Tsukamoto suggested
the repeated selection of easily accessible but analogous
This journal is © The Royal Society of Chemistry 2013
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Medicinal Chemistry Communications
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them with a limited set of interaction motifs inspired by these 7b (Scheme 2). Because it was envisioned to introduce aryl
principles, we designed and synthesized eight trisubstituted ether groups to yield templates 7c 7f, we prepared the
cyclopentane monoethers, each of which were obtained as corresponding cyclopentenol ethers 4b 4d via a different route
with tosyl chloride and sodium hydride
–
–
racemate (Tab.1).
by the reaction of 3
under reflux in tetrahydrofurane, following a previously
reported procedure 13. Ether 4d could have been prepared by
the same procedure as 4a but the second procedure gave
superior results. All products were purified by column
chromatography before being further reacted with meta-
chloroperoxybenzoic acid in dichloromethane to give the
oxirane precursors (5) in moderate to good yields. Since this
reaction step naturally forms diastereomers, a purification
process via column chromatography was essential. The
separated isomers were subsequently processed following a
method published by Guan et al. 14. The corresponding azides
(6) were prepared in good to high yields by the addition of
sodium azide and ammonium chloride in ethanol and water.
This method further provided reaction conditions which
ensured predomination of the desired SN2 reaction mechanism.
After the oxiranes´ ring opening, the three chirality centers
formed resulted in racemic products and this stereoscopic
arrangement was retained in the consecutive synthesis steps,
which could be confirmed by chiral HPLC and an X-ray crystal
9
structure (Fig.1) . For the synthesis of the desired templates
7a–h, a selective reduction of the introduced azido group to an
amino function was aspired, without effecting the benzylic
moiety present in 6a and 6b. This could be achieved with a
15
method reported by Moreno-Vargas et al.
using lithium
aluminum hydride as a mild reducing agent. The reaction
proceeded nearly quantitatively within three hours. In-process
control was realized by means of thin layer chromatography
and IR spectroscopy, in which the fading absorption band of the
azido group was detected.
Tab.1: Eight racemic trisubstituted cyclopentanes (template 7a
-
h) as building blocks for eighty 4-amidocyclopentane-1,3-diols
(
11 18(a j)).
–
–
The starting point for the synthesis of the eight amino templates
was achiral cyclopentadiene ( ), which was freshly prepared
1
from commercially available dicyclopentadiene by distillation,
Scheme 2: Synthesis of trisubstituted cyclopentane templates
as separated racemates with R = benzyl ( ), phenyl (
biphenyl ( ) and 1-naphthylmethyl (
NaH, BnCl, 10 h, yield: 83%; ii) synthesis of 4b
appropriate phenol or alcohol ( : phenol, : 4-phenylphenol
1-naphthylmethanol), 30 min reflux, NaH, 1 h reflux,
cyclopent-3-en-1-yl 4-methylbenzenesulfonate, 28 h reflux,
yields: 40–54%; iii) CH2Cl2, meta-chloroperoxybenzoic acid,
4 h rt, 2–17 h reflux, yields: 30–89%; iv) NaN3, NH4Cl, EtOH,
12 h reflux, yields: 67–98%; v) LiAlH4, THF, : 75–96%.
7
),
as reported 8. An oxidation reaction with peracetic acid in
a
h
,
b
c,
d
dichloromethane generated the oxirane intermediate (
directly reduced with lithium aluminum hydride to give
cyclopent-3-en-1-ol ( ), which is still achiral due to its internal
2). It was
e,
f
g
,
). i) synthesis of 4a
:
–
4d: THF,
3
b
c
d:
mirror plane (Scheme 1).
Scheme 1: Synthesis of cyclopent-3-en-1-ol (3): i) ∆T (in situ
distillation); ii) CH2Cl2, CH3CO3H, 19 h, yield: 56%; iii) Et2O,
LiAlH4, 3 h, yield: 88%.
The alcohol
3 was reacted with sodium hydride and benzyl
chloride to prepare the ether precursor (4a) of template 7a and
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(DIC) (Scheme 3, Tab.2). The resulting polymer bound
intermediates 9a were activated with bromoacetonitrile or
–j
using N,N′-diisopropyl-O-2,3,4,5,6-pentafluorobenzyl-isourea,
respectively. Due to the electron withdrawing cyanomethyl or
pentafluorobenzyl moiety the nucleophilic attack on the anchor
compound was facilitated and the acyl group was readily
transferred to the amino function of 7a
–h N-selectively to give
the target carboxamides 11 18 ). Neither of these activating
–
(a–j
reagents is optimal. While the O-alkyl-isourea is easier to
handle and cheaper, the reactivity of the N-acyl-N-
alkylsulfonamides bearing a cyanomethyl residue is more
pronounced 18. All products were purified by medium pressure
liquid chromatography (MPLC) on solid phase extraction (SEP)
cartridges to remove particulates from the polymeric material
because such impurities would be invisible in HPLC analyses
but severely hamper biological evaluations. The subsequent
analysis by HPLC revealed only two compounds with less than
80% purity and one compound with less than 85% purity.
Therefore, the synthesized products were consistent with the
quality standard for parallel synthetic compound libraries and
were suitable for biological evaluation at this point already. To
prevent decomposition processes of the amine group for the
time of storage, we formulated the corresponding
hydrochlorides of the final products, which usually and
presumably here as well leads to a further purification by
crystallization.
Fig.1: Assessment of the trans-substitution pattern between the
hydroxyl- and amino group: A) separation of synthesized
oxiranes leads to cis/trans isomers with only one possible side
for attack by nucleophiles; B) X-ray crystal structure of
compound 7b as hydrochloride shows trans-positioning of N1
and O2; C) chiral HPLC of compound 14c, (Chiracel® OD-H
column), Area (%) = 50.327 (Peak 1, left and white)/ 49.673
(Peak 2, right and grey), separation due to complex stability (0-
26.47 min 90:10 hexane/isopropanol-linear, in 10 min from
90:10 to 70:30-isocratically, 70:30 hexane/isopropanol).
Based on the eight racemic templates 7a–7h we synthesized a
80-member library of 4-amido substituted cyclopentane-1,3-
diol monoesters. To add potential macromolecule-interacting
elements in a rapid manner, we applied a parallel synthetic
approach using polymer-bound acylation reagents, based on
Kenner's safety-catch linker 16. Use and limitations of this
linker in the related field of carbohydrate synthesis were
recently explored by the group of Seeberger 17. While the N-
selective introduction of such diversity elements using this
approach is straightforward, the functional group diversity
achievable via this route is limited. Neither nucleophilic
functions that could attack the activated linker construct nor
functional groups that are prone to become alkylated during the
linker activation step are compatible with this approach. Here
we accepted these severe limitations in order to be able to
synthesize a library of pure test candidates in a parallel fashion
from a limited amount of valuable scaffold material. The
advantage of this concept is the known N-selectivity that avoids
formation of unwanted esters. Using this approach, complete
transformation of the templae could be achieved. By-products
with double acylation, O-acylation or unreacted starting
material were not detected in the products and the excess of
acylating reagent could easily be removed by filtration.
Classical derivatization in solution would clearly offer a much
broader array of possible functional groups in the periphery of
Scheme 3: Reaction of Kenner's safety-catch linker i) loading
by N,N′-diisopropylcarbodiimid (DIC) activated carboxylic
acids; for R1 see table 2 ii) activation with bromoacetonitrile
(R2 = CN) or N,N′-diisopropyl-O-2,3,4,5,6-pentafluorobenzyl-
isourea (R2 = pentafluorophenyl); iii) nucleophilic attack by
racemic amino templates 7a
18 ) as racemates.
–h gave target carboxamides 11–
(a–j
the final compounds if the cyclopentanolamine templates 7a–h
would be available on a larger scale. The notoriously slow
17
connection of a carboxylic acid functionality to the linker
was brought about by the use of N,N′-diisopropylcarbodiimid
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focused libraries with a higher degree of functional diversity
around the active structures can be generated expediently.
5637
µM
MCF-7
µM
DAN-G
µM
LCLC-
µM
11j >20
16.0±1.29
14.2±3.02
>20
>20
12j 20.4±3.52
15h 11.9±1.65
>20
>20
6.76±0.65
8.91±1.23
10.3a
12.8±0.36
13.0±0.57
17.5a
13.6±0.21
12.3±1.26
13.1a
15i
12.2±1.65
12.5a
16i
Chlo 6.55±3.46b
Melp 1.32±0.14b
Carb 4.34±1.70b
18.4±5.5b
3.71±1.19
29.4±9.8b
27.8±5.0b
2.65±1.02b
12.79±6.81b
14.5±7.1b
4.00±0.42
14.59±5.67
Table 3: IC50 values (µM ± SD) of antiproliferative activities of
the most potent compounds compared to established anti-tumor
drugs after a 96 h exposure; Chlo = Chlorambucil, Melp =
Melphalan, Carb = Carboplatin; Values are averages of 3–4
independent experiments, a) n = 1; b) from reference 20
.
Conclusions
Diversity-oriented synthesis strategies opposed to target
oriented programs aim to generate molecular libraries with
diversity based e.g. on sp3-rich scaffolds and stereochemical
complexity because biological macromolecules interact with
each other in three-dimensional surroundings. The resulting
Tab.2: Compilation of carboxylic acid residues used to
introduce structural and functional diversity in the 4-
amidocyclopentane-1,3-diol products.
high degree of structural and functional diversity is
a
prerequisite for cross-examination of previously ‘un-tapped’
regions of bioactive chemical space 21. The new molecular
entities of the small library of compounds presented in this
study can thus serve as tools for the investigation of unresolved
issues in various fields of molecular biology. Some of the novel
compounds were found to have potent antiproliferative
activities, demonstrating that the cyclopentane based spatial
display of interaction motifs can lead to biologically active
compounds. In addition, we performed the synthesis of the
small, hydrophilic, and fragment-like new scaffolds,
successfully. These scaffolds are devoid of rotatable bonds and
offer stereochemically defined attachment points for diverse
substituents. Thus, these platforms are suitable starting points
for the diversity-oriented construction of combinatorial libraries
of 4-amidocyclopentane-1,3-diols or for the synthesis of arrays
of other cyclopentanoid natural products with high structural
and functional diversity as could be illustrated by this study.
Biological evaluation
Compounds 11a
16d 17a
-
d
18a
,
f
,
h
-
,
j
c
,
,
12a
-j, 13a-j, 14a-c,f,g,i,j, 15b-h,j,
-
i
,
,
c,
d
,f
-
j
,
e
-
j
were investigated as antiprotozoal
drugs. None of them displayed noteworthy activity with respect
to size and lipophilicity (lipophilic efficiency LiPE19, data not
shown). Thus, 15 representative compounds 11f
,j, 12f,j, 13c,i,
14c 15h 16i 18c were tested for in vitro anti-tumor
,
h,
i,
,
i,j
,
,
,i
activity, only five of which showed marked antiproliferative
activity and are listed in Table 3. The test system consisted of
four human tumor cell lines derived from four kinds of cancer:
urinary bladder carcinoma (5637), breast adenocarcinoma
(MCF-7), pancreas carcinoma (DAN-G) and large cell lung
carcinoma (LCLC-103H). The tumor cell lines were selected
with a view to diverse tissue exposure and in-house availability.
For each cell line the half maximal growth inhibitory
concentration (IC50) was determined. The results were
compared to established anticancer drugs. Some of the
synthesized products were found to be active in single digit
micromolar range and thus even exceeded the potency of some
of the reference substances (Table 3). Compound 15i and 16i as
well as 11j and 12j are closely related stereo isomers with
activities in the same order of magnitude. Together with 15h
the former compounds share a bulky biphenyl moiety. The
replacement of the biphenyl ether with a benzyl ether in C4-
position as well as the substitution at the carboxamide
functionality with a moiety derived from the drug fenbufen
Experimental
General
Thin layer chromatography for reaction control was performed
with ALUGRAM SIL G/UV254 silica gel plates from
Macherey-Nagel (silica gel on aluminum sheets, layer thickness
0.20 mm). Melting points were recorded on a MEL-Temp
Laboratory Device. The refractive index was measured on a
Carl Zeiss Abbé refractometer at 20 °C. The yields of all
parallel synthetic approaches were calculated via conversion
rates, specifying the percentage of the product area to the total
area of all peaks. All other yields correlate to the actual product
quantity compared to the theoretical maximum. Silica gel 60,
0.05–0.1 mm, 270–140 mesh from Macherey-Nagel was used
(
15i/16i → 11j/12j) clearly results in a drop of activity. For
more precise structure-activity information a broader set of
compounds will need to be synthesized and investigated for
cytotoxicity. Because the molecules presented here were
prepared in an efficient and modular manner, analogous
compounds can be obtained easily in larger amounts and
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for column chromatography. Medium pressure liquid organic phase (red color) washed with water, dried over sodium
chromatography was done with a Büchi pump device C-681, a sulfate and evaporated in vacuo. A final vacuum distillation
Büchi UV/Vis-filter photometer at 254 nm and Merck Lobar- (160 °C, 11 mbar) gave the colorless, liquid product. Yield:
LiChroprep®-RP-18 columns (size A, B). The specified purities 83% (30.0 g); IR (cm-1): 1615, 1096, 1072, 734, 697.
were determined by the 100% method of the DAD Cyclopent-3-en-1-yl 4-methylbenzenesulfonate. To 8.0 g
chromatogram at wavelengths as indicated. Nuclear magnetic (96 mmol) cyclopent-3-en-1-ol (3) were added 100.0 ml
resonance (NMR) spectra were recorded using a Jeol Eclipse + pyridine and while cooling 22.4 g (0.11 mol) tosyl chloride The
500 (1H: 500 MHz, 13C: 126 MHz) at 25 °C with suspension turned green and after stirring for 2 h the reaction
tetramethylsilane (TMS) as internal standard, using ppm scale. mixture was stored for 12 h at 8 °C, upon which it turned red.
High resolution mass spectra (HRMS) were obtained after high The suspension was poured onto 160 g ice and 48.0 ml
performance liquid chromatography (HPLC) with a mass concentrated hydrochloric acid and stirred for 30 min. The
spectrometer AutoSpec M from Micromass, current loop probe resulting residue was filtered and dried under reduced pressure.
1
supply, positive ionization, flow = 10 µl/min. Infrared (IR) Yield: 89% (20.3 g); H-NMR (500 MHz, [D6]-DMSO) = δ
spectra were recorded on a Nicolet 510P FT-IR spectrometer as (ppm) 7.79 (d, 2H), 7.48 (d, 2H), 5.68 (s, 2H), 5.12 (m, 1H),
KBr blanks or as a film on a NaCl window. Elemental analysis 2.60 (dd, 2H, J = 6.2/17.2), 2.42 (s, 3H), 2.36 (d, 2H); 13C-
was determined using a CH-Analyzer according to Dr. Salzer NMR (126 MHz, [D6]-DMSO) = δ (ppm) 145.34, 134.16,
from Labormatic/Wösthoff and a CHN-Autoanalyzer 185 from 130.75, 128.26, 128.02, 82.77, 42.75, 21.01; IR (cm-1): 1355,
Hewlett-Packard.
1172, 934, 745, 679, 571; mp: 47-49 °C.
General procedure for the synthesis of cyclopentenyl ethers
13
Characterization of compounds
(procedure A)
. To a freshly dried solution of THF
21.0 mmol of the appropriate alcohol were added and then
heated to reflux for 30 min. After cooling to room temperature
2.0 equivalents sodium hydride were added while cooling. As
no more gas evolved, the mixture was heated to reflux for an
additional hour, after which 5.0 g (21.0 mmol) cyclopent-3-en-
1-yl 4-methylbenzenesulfonate were added. After 28 h,
indicated by thin layer chromatography, the solvent was
removed and dichloromethane and 2.0 mol/l sodium hydroxide
solution were added. The organic phase was washed twice with
2.0 mol/l sodium hydroxide solution and saturated sodium
hydroxide solution, then dried over sodium sulfate and
concentrated in vacuo. The resulting residue was purified by
column chromatography with hexane/ethyl acetate (7:3).
3,4-Epoxycyclopenten (2). A solution of 40 g (0.60 mol)
cyclopentadiene and 258 g sodium carbonate in 666 ml
dichloromethane was cooled. Then 112 g peracetic acid (40%)
in sodium acetate were added drop wise. The reaction mixture
was stirred at room temperature, in-process control was done by
potassium iodide starch paper. A negative test (no violet
coloring) indicated a quantitative reaction after 19 h. The
reaction mixture was reduced in vacuo, washed with
dichloromethane and residual solvent was removed by
distillation (50 °C). A final vacuum distillation (13 mbar) gave
the product as yellow oil. Yield: 56% (28.0 g); IR (cm-1): 3047,
2909, 1749, 913, 828, 813; no further analysis, but instant
reaction to form the appropriate stable product.
Cyclopent-3-enyloxy-benzene (4b) was prepared following
the general procedure A using 1.97 g (21.0 mmol) phenol, 2.0
equivalents (1.01 g) sodium hydride and 5.0 g (21.0 mmol)
cyclopent-3-en-1-yl 4-methylbenzenesulfonate. Product was
Cyclopent-3-en-1-ol (3). To an ice cooled suspension
containing 7.0 g (0.18 mol) lithium aluminum hydride in dry
ether 27.5 g (0.33 mol) 3,4-epoxycyclopentene were added
drop wise and stirred for 3 h. Then careful addition of water
inactivates the reaction mixture successively, which is dried
over sodium sulfate and washed with ether. A final vacuum
distillation (71 °C, 61 mbar) gave the product. Yield: 88%
1
obtained as oil. Yield: 54% (1.8 g); H-NMR (500 MHz, [D6]-
DMSO) = δ (ppm) 7.27 (m, 2H), 6.89 (m, 3H), 5.74 (s, 2H),
5.04 (s, 2H), 2.78 (dd, 2H, J = 6.6/16.3), 2.38 (m, 2H); 13C-
NMR (126 MHz, [D6]-DMSO) = δ (ppm) 157.22, 129.91,
128.84, 120.67, 115.57, 76.11; IR (cm-1): 1599, 1242, 753, 692;
refractive index: 1.5438.
1
(24.8 g); H-NMR (500 MHz, [D6]-DMSO) = δ (ppm) 5.64 (m,
2H), 4.56 (d, 1H), 4.34 (m, 1H), 2.48 (dd, 2H, J = 6.6/15.1 Hz),
2.14 (dd, 2H, J = 2.9/15.4 Hz); IR (cm-1): 3334, 1430, 1047,
951; refractive index: 1.4431.
4-(Cyclopent-3-enyloxy)-biphenyl
(4c)
was
prepared
following the general procedure A using 3.59 g (21.0 mmol) 4-
phenylphenol, 2.0 equivalents (1.01 g) sodium hydride and
5.0 g (21.0 mmol) cyclopent-3-en-1-yl 4-methylbenzene-
sulfonate. Product was recrystallized from methanol/ethyl
[(Cyclopent-3-en-1-yloxy)methyl]benzene (4a). In a three-
necked flask 45 ml dry toluene and 12.0 g (0.28 mol) sodium
hydride (60% suspension in oil) stirred under exclusion of
moisture influences while cooling. After extensive flushing
with nitrogen 18.0 g (0.21 mol) cyclopent-3-en-1-ol in toluene
were added over a dropping funnel during 1 h. As no more gas
evolved, a solution of 28.6 ml (0.25 mol) benzyl chloride in
toluene was added drop wise and the reaction mixture refluxed
over night, upon which the reaction mixture turned brownish.
The excess of sodium hydride was inactivated by careful
addition of methanol in toluene. The mixture was filtered, the
1
acetate to give a colorless solid. Yield: 40% (2.0 g); H-NMR
(500 MHz, [D6]-DMSO) = δ (ppm) 7.59 (m, 4H), 7.42 (m, 2H),
7.30 (m, 1H), 6.98 (m, 2H), 5.76 (s, 2H), 5.10 (m, 1H), 2.82
(dd, 2H, J = 6.6/16.3), 2.42 (d, 2H); 13C-NMR (126 MHz, [D6]-
DMSO) = δ (ppm) 156.89, 139.78, 132.27, 128.77, 128.36,
127.71, 126.58, 126.06, 115.55, 75.90; IR (cm-1): 2936, 1489,
1201, 832, 760; mp: 109-111 °C; no further analysis, but instant
reaction to form the appropriate stable product.
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Medicinal Chemistry Communications
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1-(Cyclopent-3-enyloxymethyl)-naphthalen
(4d)
was acid, quantitative reaction was indicated after 10 h. Column
prepared following the general procedure A using 3.3 g chromatography gave trans isomer in the early fractions as
(21.0 mmol) 1-naphthylmethanol, 2.0 equivalents (1.0 g) colorless solid. Yield: overall 68% (1.8 g, thereof 1.1 g trans
sodium hydride and 5.0 g (21.0 mmol) cyclopent-3-en-1-yl 4- isomer); purity: 99% (254 nm); 1H-NMR (500 MHz, [D6]-
methylbenzenesulfonate. Product was obtained as yellow oil. DMSO) = δ (ppm) 7.26 (m, 2H), 6.89 (m, 3H), 4.49 (m, 1H),
Yield: 48% (2.2 g); purity: 97% (254 nm); 1H-NMR (500 MHz, 3.59 (s, 2H), 2.62 (dd, 2H, J = 7.3/14.4), 1.74 (dd, 2H, J =
[D6]-DMSO) = δ (ppm) 8.06 (d, 1H), 7.93 (m, 1H), 7.86 (d, 6.4/14.4); 13C-NMR (126 MHz, [D6]-DMSO) = δ (ppm)
1H), 7.52 (m, 4H), 5.69 (s, 2H), 4.89 (s, 2H), 4.37 (m, 1H), 158.10, 130.09, 121.17, 115.74, 74.79, 55.74, 34.73; IR (cm-1):
2.57 (m, 2H), 2.39 (m, 2H); 13C-NMR (126 MHz, [D6]-DMSO) 1493, 1243, 1083, 837, 751; HRMS (ESI, m/z): [M+Na]+ calc.:
= δ (ppm) 134.85, 133.82, 131.80, 128.97, 128.91, 128.62, 199.0734, found: 199.0734; mp: 33-34 °C.
126.66, 126.58, 126.29, 125.86, 124.54, 78.91, 68.86, 39.53; IR (1R,3s,5S)-3-Phenoxy-6-oxabicyclo[3.1.0]hexane (5d) was
(cm-1): 2909, 1104, 1088, 791, 775; HRMS (ESI, m/z): prepared following the procedure for 5c. The cis isomer came
[M+Na]+ calc.: 247.1098, found: 247.1134; refractive index: after the trans isomer and gave a yellow solid. Yield: overall
1.6012.
68% (1.8 g, thereof 0.7 g cis isomer); purity: 97% (254 nm);
General procedure for the synthesis of cyclopentanyl 1H-NMR (500 MHz, [D6]-DMSO) = δ (ppm) 7.25 (m, 2H),
oxiranes (procedure B). To an ice cold and nitrogen flushed 6.88 (m, 1H), 6.79 (m, 2H), 4.86 (m, 1H), 3.53 (s, 2H), 2.29 (d,
solution of 0.17 mol of the appropriate cyclopentenyl ether in 2H, J = 7.6 Hz), 2.01 (d, 2H, J = 15.6 Hz); 13C-NMR (126
85.0 ml dichloromethane were added drop wise 0.24 mol meta- MHz, [D6]-DMSO) = δ (ppm) 157.97, 130.01, 120.67, 115.62,
chloroperoxybenzoic acid in 350 ml dichloromethane over a 76.43, 57.61, 35.46; IR (cm-1): 1491, 1234, 1076, 840, 759;
period of 2 h. The reaction mixture was stirred for 4 h at room HRMS (ESI, m/z): [M+Na]+ calc.: 199.0734, found: 199.0745;
temperature and then refluxed, while in-process control was mp: 63-64 °C.
accomplished by thin layer chromatography. After quantitative (1R,3r,5S)-3-([1,1′-Biphenyl]-4-yloxy)-6-
reaction was indicated, the resulting residue was washed twice oxabicyclo[3.1.0]hexane (5e) was prepared following the
with 150 ml sodium sulfite solution (10%) and sodium sulfate general procedure B using 2.0 g (8.0 mmol) 4c and 2.2 g
solution (10%). The organic phase was dried over sodium (12.0 mmol) meta-chloroperoxybenzoic acid, quantitative
sulfate and concentrated under reduced pressure. The resulting reaction was indicated after 13 h. Column chromatography
mixture of diastereomers was purified by column chromato- gave trans isomer in the early fractions as colorless solid. Yield:
graphy over silica gel (5.5 × 54 cm) with hexane/ethyl acetate overall 89% (1.9 g, thereof 1.3 g trans isomer); purity: 82%
1
(7:3).
(1 ,3
(254 nm); H-NMR (500 MHz, [D6]-DMSO) = δ (ppm) 7.58
R
r
,5
S
)-3-(Benzyloxy)-6-oxabicyclo[3.1.0]hexane (5a) was (m, 4H), 7.42 (m, 2H), 7.30 (m, 1H), 6.98 (m, 2H), 4.55 (m,
prepared following the general procedure B using 30.0 g 1H), 3.61 (s, 2H), 2.67-2.63 (dd, 2H, J = 7.3/14.4), 1.79-
(0.17 mol) 4a and 43.0 g (0.24 mol) meta-chloroperoxybenzoic 1.75(dd, 2H, J = 6.2/14.2); 13C-NMR (126 MHz, [D6]-DMSO)
acid, quantitative reaction was indicated after 120 min. Column = δ (ppm) 157.11, 139.71, 132.63, 128.78, 127.74, 126.65,
chromatography gave trans isomer in the early fractions as 126.09, 115.57, 74.40, 55.13, 34.00; IR (cm-1): 1488, 1201,
colorless oil. Yield: overall 30% (10.0 g, thereof 6.0 g trans 1117, 831, 684; Analysis calc.: C, 80.93; H, 6.39, found: C,
isomer); purity: 74% (254 nm); 1H-NMR (500 MHz, [D6]- 80.67; H, 6.32; mp: 144-145 °C.
DMSO) = δ (ppm) 7.30 (m, 5H), 4.39 (s, 2H), 3.73 (m, 1H), (1R,3s,5S)-3-([1,1′-Biphenyl]-4-yloxy)-6-
3.49 (m, 2H), 2.40-2.36 (dd, 2H, J = 7.1/14.2), 1.62-1.57(dd, oxabicyclo[3.1.0]hexane (5f) was prepared following the
2H, J = 6.9/14.2); 13C-NMR (126 MHz, [D6]-DMSO) = δ procedure for 5e. The cis isomer came after the trans isomer
(ppm) 139.06, 128.74, 128.12, 127.94, 75.79, 71.32, 55.44, and gave a colorless solid. Yield: overall 89% (1.9 g, thereof
34.44; IR (cm-1): 1740, 1241, 1113, 836, 738; HRMS (ESI, 0.6 g trans isomer); purity: 80% (254 nm); 1H-NMR (500 MHz,
m/z): [M+Na]+ calc.: 213.0891, found: 213.0908; refractive [D6]-DMSO) = δ (ppm) 7.58 (m, 4H), 7.42 (m, 2H), 7.29 (m,
index: 1.5258.
1H), 6.89 (m, 2H), 4.92 (m, 1H), 3.56 (s, 2H), 2.30-2.25 (m,
(1 ,3 ,5
R
s S
)-3-(Benzyloxy)-6-oxabicyclo[3.1.0]hexane (5b) was 2H), 2.05 (d, 2H, J = 15.6 Hz)); 13C-NMR (126 MHz, [D6]-
prepared following the procedure for 5a. The cis isomer came DMSO) = δ (ppm) 157.00, 139.77, 132.09, 128.77, 127.65,
after the trans isomer and gave a colorless oil. Yield: overall 126.57, 126.04, 115.44, 76.05, 56.99, 34.86; IR (cm-1): 1491,
30% (10.0 g, thereof 4.0 g cis isomer), purity: 94% (254 nm); 1249, 1077, 833, 764; Analysis calc.: C, 80.93; H, 6.39, found:
1H-NMR (500 MHz, [D6]-DMSO) = δ (ppm) 7.30 (m, 5H), C, 80.75; H, 6.29; mp: 164-165 °C.
4.34 (s, 2H), 4.07 (m, 1H), 3.46 (m, 2H), 1.99 (s, 4H); 13C- (1
R,3r,5S)-3-(Naphthalen-1-ylmethoxy)-6-
NMR (126 MHz, [D6]-DMSO) = δ (ppm) 139.38, 128.68, oxabicyclo[3.1.0]hexane (5g) was prepared following the
127.97, 127.73, 78.64, 70.39, 57.55, 35.15; IR (cm-1): 1737, general procedure B using 2.3 g (10.0 mmol) 4d and 2.5 g
1242, 1097, 839, 737; HRMS (ESI, m/z): [M+Na]+ calc.: (14.0 mmol) meta-chloroperoxybenzoic acid, quantitative
213.0891, found: 213.0901; refractive index: 1.5360.
reaction was indicated after 17 h. Column chromatography
(1 ,3 ,5 )-3-Phenoxy-6-oxabicyclo[3.1.0]hexane (5c) was gave trans isomer in the early fractions as oil. Yield: overall
R
r S
prepared following the general procedure B using 2.5 g 75% (1.8 g, thereof 1.1 g trans isomer); purity: 89% (254 nm);
(15 mmol) 4b and 3.9 g (22 mmol) meta-chloroperoxybenzoic 1H-NMR (500 MHz, [D6]-DMSO) = δ (ppm) 8.05 (d, 1H, J =
6 | J. Name., 2012, 00, 1-3
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ARTICLE
8.3 Hz), 7.92 (m, 1H), 7.87 (d, 1H, J = 8.0 Hz), 7.54 (m, 3H), MHz, [D6]-DMSO) = δ (ppm) 7.27 (m, 2H), 6.88 (m, 3H), 5.32
7.46 (m, 1H), 4.84 (s, 2H), 3.84 (m, 1H), 3.49 (s, 2H), 2.42- (d, 1H, J = 4.8 Hz), 4.82 (m, 1H), 4.09 (m, 1H), 3.74 (m, 1H),
2.38 (dd, 2H, J = 7.1/14.0), 1.63-1.59 (dd, 2H, J = 7.1/14.0); 2.59 (m, 1H), 1.99 (m, 2H), 1.61 (m, 1H); 13C-NMR (126 MHz,
13C-NMR (126 MHz, [D6]-DMSO) = δ (ppm) 134.59, 133.80, [D6]-DMSO) = δ (ppm) 157.08, 129.45, 120.43, 115.20, 74.74,
131.79, 128.91, 128.80, 126.81, 126.73, 126.35, 125.86, 74.16, 66.29, 35.33; IR (cm-1): 3388, 2104, 755; HRMS (ESI,
124.57, 76.03, 69.84, 55.46, 34.43; IR (cm-1): 1511, 1106, 832, m/z): [M+H2O]+ calc.: 237.1113, found: 237.1116; refractive
647; HRMS (ESI, m/z): [M+Na]+ calc.: 263.1048, found: index: 1.5538.
263.1067.
(1 ,3s,5 )-3-(Naphthalen-1-ylmethoxy)-6-
(1
S
,2
S
,4
R
)-2-Azido-4-phenoxycyclopentanol
(6d)
was
R
S
prepared following the general procedure C using 0.6 g
oxabicyclo[3.1.0]hexane (5h) was prepared following the (3.0 mmol) 5d, 0.7 g (10.0 mmol) sodium azide and 0.6 g
procedure for 5g. The cis isomer came after the trans isomer ammonium chloride. The product was obtained as yellow oil.
and gave an oil. Yield: overall 75% (1.8 g, thereof 0.7 g cis Yield: 88% (0.7 g); purity: 93% (254 nm); 1H-NMR (500 MHz,
isomer); purity: 97% (254 nm); NMR (500 MHz, [D6]-DMSO) [D6]-DMSO) = δ (ppm) 7.26 (m, 2H), 6.89 (m, 3H), 5.35 (d,
= δ (ppm) 8.05 (m, 1H), 7.92 (m, 1H), 7.85 (d, 1H, J = 8.0 Hz), 1H, J = 5.3 Hz), 4.73 (m, 1H), 3.90 (m, 2H), 2.52 (m, 1H), 2.07
7.53 (m, 4H), 4.78 (s, 2H), 4.18 (m, 1H), 3.47 (s, 2H), 2.03 (m, (m, 1H), 1.95 (m, 1H), 1.58 (m, 1H); 13C-NMR (126 MHz,
4H); 13C-NMR (126 MHz, [D6]-DMSO) = δ (ppm) 134.21, [D6]-DMSO) = δ (ppm) 157.11, 129.44, 120.40, 115.16, 74.61,
133.16, 131.15, 128.24, 127.94, 125.99, 125.68, 125.23, 73.27, 66.26, 35.12; IR (cm-1): 3397, 2105, 755; HRMS (ESI,
124.05, 78.15, 68.35, 56.93, 34.50; IR (cm-1): 1510, 1239, m/z): [M+Na]+ calc.: 242.0905, found: 242.0847; refractive
1093, 841, 775; HRMS (ESI, m/z): [M+Na]+ calc.: 263.1048, index: 1.5564.
found: 263.1076; refractive index: 1.6050.
(1R,2R,4R)-4-([1,1′-Biphenyl]-4-yloxy)-2-azidocyclopentanol
General procedure for the introduction of an azido group (6e) was prepared following the general procedure C using
14
(procedure C)
. A solution of 20.0 mmol of the appropriate 1.1 g (4.0 mmol) 5e, 0.9 g (14.0 mmol) sodium azide and 0.7 g
oxirane, 196 ml ethanol, 39.0 ml water, 4.1 g (60.0 mmol) ammonium chloride. The product was obtained as colorless
sodium azide and 3.4 g ammonium chloride were heated to solid. Yield: 98% (1.3 g); purity: 83% (254 nm); 1H-NMR (500
reflux for 12 h. After addition of water, the reaction mixture MHz, [D6]-DMSO) = δ (ppm) 7.59 (m, 4H), 7.42 (m, 2H), 7.30
was extracted several times with ether, which was then washed (m, 1H), 6.95 (m, 2H), 5.34 (d, 1H, J = 5.0 Hz), 4.88 (m, 1H),
with a saturated solution of sodium chloride, dried over soidum 4.11 (m, 1H), 3.75 (m, 1H), 2.62 (m, 1H), 2.01 (m, 2H), 1.64
sulfate and concentrated under reduced pressure. The resiude (m, 1H); 13C-NMR
was purified by column chromatography over silica gel (3.5 × 156.73, 139.72, 132.51, 128.76, 127.73, 126.62, 126.07,
33.5 cm) with hexane/ethyl acetate (7:3).
115.65, 74.74, 74.44, 66.30, 35.35; IR (cm-1): 3300, 2110, 766;
(1 ,2 ,4 )-2-Azido-4-(benzyloxy)cyclopentanol (6a) was Analysis calc.: C, 69.14; H, 5.80, found: C, 69.35; H, 5.99; mp:
prepared following the general procedure C using 4.0 g 99-100 °C.
(20.0 mmol) 5a. The product was obtained as yellow oil. Yield: (1 ,2 ,4 )-4-([1,1′-Biphenyl]-4-yloxy)-2-azidocyclopentanol
(126 MHz, [D6]-DMSO) = δ (ppm)
R
R R
S
S R
1
77% (3.6 g); purity: 83% (254 nm); H-NMR (500 MHz, [D6]- (6f) was prepared following the general procedure C using
DMSO) = δ (ppm) 7.31 (m, 5H), 5.21 (d, 1H, J = 5.8 Hz), 4.40 0.51 g (2.0 mmol) 5f, 0.4 g (6.0 mmol) sodium azide and 0.3 g
(s, 2H), 4.02 (m, 2H), 3.64 (m, 1H), 2.37 (m, 1H), 1.93 (m, ammonium chloride. The product was obtained as colorless
1H), 1.74 (m, 1H), 1.56 (m, 1H); 13C-NMR (126 MHz, [D6]- solid. Yield: 96% (0.6 g); purity: 100% (254 nm); 1H-NMR
DMSO) = δ (ppm) 139.13, 128.73, 128.10, 127.88, 75.49, (500 MHz, [D6]-DMSO) = δ (ppm) 7.59 (m, 4H), 7.43 (m, 2H),
75.27, 70.44, 67.07, 39.64; IR (cm-1): 3421, 2104, 698; 7.30 (m, 1H), 6.96 (m, 2H), 5.37 (d, 1H, J = 5.3 Hz), 4.79 (m,
refractive index: 1.5384.
1H), 3.93 (m, 2H), 2.56 (m, 1H), 2.11 (m, 1H), 1.96 (m, 1H),
(1 ,2 ,4
S
S R
)-2-Azido-4-(benzyloxy)cyclopentanol (6b) was 1.61 (m, 1H); 13C-NMR (126 MHz, [D6]-DMSO) = δ (ppm)
prepared following the general procedure C using 3.5 g 156.76, 139.72, 132.47, 128.76, 127.71, 126.62, 126.07,
(18.0 mmol) 5b, 3.7 g (50.0 mmol) sodium azide and 3.1 g 115.63, 74.61, 73.44, 66.27, 35.45; IR (cm-1): 3286, 2105, 761;
ammonium chloride. The product was obtained as yellow oil. HRMS (ESI, m/z): [M+Na]+ calc.: 318.1218, found: 318.1238;
1
Yield: 67% (2.8 g); purity: 95% (254 nm); H-NMR 500 MHz, mp: 94-95 °C.
[D6]-DMSO) = δ (ppm) 7.32 (m, 5H), 5.29 (d, 1H, J = 5.3 Hz), (1
4.40 (s, 2H), 3.93 (m, 1H), 3.86-3.76 (m, 2H), 2.32 (m, 1H), ylmethoxy)cyclopentanol (6g) was prepared following the
2.04 (m, 1H), 1.71 (m, 1H), 1.54 (m, 1H); 13C-NMR (126
general procedure using 1.0 g (4.0 mmol) 5g 0.8 g
R,2R,4R)-2-Azido-4-(naphthalen-1-
C
,
MHz, [D6]-DMSO) = δ (ppm) 139.13, 128.73, 128.10, 127.88, (12.0 mmol) sodium azide and 0.7 g ammonium chloride. The
75.49, 75.27, 70.44, 67.07, 39.64; IR (cm-1): 3408, 2104, 699; product was obtained as oil. Yield: 90% (1.1 g); purity: 94%
1
refractive index: 1.5456.
(1 ,2 ,4 )-2-Azido-4-phenoxycyclopentanol
(254 nm); H-NMR (500 MHz, [D6]-DMSO) = δ (ppm) 8.07
R
R
R
(6c)
was (m, 1H), 7.94 (m, 1H), 7.87 (d, 1H, J = 8.3 Hz), 7.54 (m, 4H),
prepared following the general procedure C using 1.1 g 5.23 (d, 1H, J = 3.7 Hz), 4.87 (m, 2H), 4.13 (m, 1H), 4.03 (m,
(6.0 mmol) 5c, 1.2 g (20.0 mmol) sodium azide and 1.0 g 1H), 3.66 (m, 1H), 2.40 (m, 1H), 1.99 (m, 1H), 1.77 (m, 1H),
ammonium chloride. The product was obtained as yellow oil. 1.61 (m, 1H); 13C-NMR (126 MHz, [D6]-DMSO) = δ (ppm)
Yield: 97% (1.3 g); purity: 100% (254 nm); 1H-NMR (500 138.18, 137.35, 135.31, 132.45, 132.24, 130.22, 129.88,
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Medicinal Chemistry Communications
Journal Name
129.42, 128.09, 80.13, 79.01, 72.58, 70.61, 39.50; IR (cm-1): (s, 2H), 3.92 (m, 1H), 3.45 (m, 1H), 2.98 (m, 1H), 2.27 (m,
3408, 2103, 776; HRMS (ESI, m/z): [M+Na]+ calc.: 306.1218, 1H), 1.87 (m, 1H), 1.55 (s, 1H), 1.45 (m, 2H); 13C-NMR (126
found: 306.1213; refractive index: 1.6010.
(1 ,2 ,4 )-2-Azido-4-(naphthalen-1-
MHz, [D6]-DMSO) = δ (ppm) 139.48, 128.71, 128.02, 127.76,
78.34, 76.41, 70.31, 58.64, 39.08; IR (cm-1): 3390, 2887, 1617,
S
S
R
ylmethoxy)cyclopentanol (6h) was prepared following the 1359, 1063, 749, 698; mp: 88-89 °C.
general procedure using 0.7 g (3.0 mmol) 5h 0.6 g (1 ,2 ,4 )-4-(Benzyloxy)-2-hydroxycyclopentanaminium
C
,
S S R
(8.0 mmol) sodium azide and 0.5 g ammonium chloride. The chloride (7b hydrochloride). 7b was dissolved in ether and
product was obtained as oil. Yield: 87% (0.7 g); purity: 89% cooled, then HCl gas was initiated, upon what immediately a
1
1
(254 nm); H-NMR (500 MHz, [D6]-DMSO) = δ (ppm) 8.08 colorless solid precipitated. Yield: 81% (0.8 g); H-NMR (500
(m, 1H), 7.94 (m, 1H), 7.87 (d, 1H, J = 8.3 Hz), 7.54 (m, 4H), MHz, [D6]-DMSO) = δ (ppm) 8.20 (bs, 3H), 7.32 (m, 5H), 5.36
5.28 (d, 1H, J = 5.3 Hz), 4.87 (m, 2H), 4.05 (m, 1H), 3.81 (m, (d, 1H, J = 5.0 Hz), 4.41 (s, 2H), 3.97 (m, 2H), 3.26 (m, 1H),
2H), 2.35 (m, 1H), 2.08 (m, 1H), 1.74 (m, 1H), 1.56 (m, 1H); 2.36 (m, 1H), 2.06 (m, 1H), 1.81 (m, 1H), 1.56 (m, 1H); 13C-
13C-NMR (126 MHz, [D6]-DMSO) = δ (ppm) 134.64, 133.80, NMR (126 MHz, [D6]-DMSO) = δ (ppm) 139.06, 128.79,
131.78, 128.91, 128.71, 126.73, 126.70, 126.34, 125.88, 128.08, 127.94, 75.32, 73.46, 70.37, 57.05, 34.90; IR (cm-1):
124.57, 75.76, 75.27, 68.96, 67.13, 39.64; IR (cm-1): 3415, 3325, 2891, 1510, 1068, 735; Analysis calc.: C, 59.14; H, 7.44;
2103, 776; HRMS (ESI, m/z): [2M+Na]+ calc.: 589.2539, N, 5.75; Cl, 14.55, found: C, 59.20; H, 7.57; N, 5.90; Cl, 14.52;
found: 589.2548; refractive index: 1.5999.
mp: 194-195 °C.
,2 ,4 )-2-Amino-4-phenoxycyclopentanol
. To a solution of 16.9 mmol lithium prepared following the general procedure D using 0.4 g
General procedure for the reduction of azido to amino (1
group (procedure D)
R
R
R
(7c)
was
15
aluminum hydride in freshly over sodium/benzophenone dried (10.7 mmol) lithium aluminum hydride and 0.6 g (2.7 mmol)
THF was added drop wise 4.3 ml of the appropriate azido 6c. Product was obtained as colorless solid; Yield: calc. as
compound in 20.0 ml THF under nitrogen atmosphere. After hydrochloride; purity: 100% (254 nm); 1H-NMR (500 MHz,
complete addition the reaction was stirred for 2 h at room [D6]-DMSO) = δ (ppm) 7.27 (m, 2H), 6.86 (m, 3H), 4.74 (m,
temperature, then diethyl ether and a solution of sodium sulfate 2H), 3.73 (m, 1H), 2.89 (m, 1H), 2.41 (m, 1H), 1.97 (m, 1H),
was added until no more hydrogen was formed. The aqueous 1.88 (m, 1H), 1.52 (bs, 2H), 1.38 (m, 1H); 13C-NMR (126
phase was cleared from the resulting residue and extracted MHz, [D6]-DMSO) = δ (ppm) 157.47, 129.36, 120.07, 115.11,
several times with diethyl ether. The organic phases were 77.70, 74.63, 58.61, 38.99; IR (cm-1): 3400, 2927, 1600, 1489,
combined, dried over sodium sulfate and concentrated under 1239, 1074, 755, 694; Analysis calc.: C, 68.37; H, 7.82; N,
reduced pressure.
7.25, found: C, 67.99; H, 7.66; N, 7.55; mp: 104-106 °C.
,2 ,4 )-2-Hydroxy-4-phenoxycyclopentanaminium
(1 ,2 ,4 )-2-Amino-4-(benzyloxy)cyclopentanol (7a) was (1R R R
R
R
R
prepared following the general procedure D using 1.0 g chloride (7c hydrochloride). 7c was dissolved in ether and
(4.3 mmol) 6a. Product was obtained as colorless solid; Yield: cooled, then HCl gas was initiated, upon what immediately a
1
1
calc. as hydrochloride; purity: 96% (254 nm); H-NMR (500 colorless solid precipitated. Yield: 85% (0.5 g); H-NMR (500
MHz, [D6]-DMSO) = δ (ppm) 7.30 (m, 5H), 4.63 (bs, 1H), 4.38 MHz, [D6]-DMSO) = δ (ppm) 8.32 (bs, 3H), 7.28 (m, 2H), 6.89
(s, 2H), 3.96 (m, 1H), 3.66 (m, 1H), 2.78 (m, 1H), 2.19 (m, (m, 3H), 5.48 (d, 1H, J = 4.6 Hz), 4.83 (m, 1H), 4.22 (m, 1H),
1H), 1.92 (m, 1H), 1.66 (m, 1H), 1.51 (bs, 1H), 1.31 (m, 1H); 3.20 (m, 1H), 2.64 (m, 1H), 2.07 (m, 1H), 1.95 (m, 1H), 1.71
13C-NMR (126 MHz, [D6]-DMSO) = δ (ppm) 139.44, 128.73, (m, 1H); 13C-NMR (126 MHz, [D6]-DMSO) = δ (ppm) 156.98,
128.02, 127.78, 78.59, 76.99, 70.42, 59.34; IR (cm-1): 3392, 129.45, 120.55, 115.21, 73.45, 72.51, 56.24, 38.73, 34.70; IR
2887, 1617, 1467, 1067, 749, 699; mp: 114-115 °C.
(1 ,2 ,4 )-4-(Benzyloxy)-2-hydroxycyclopentanaminium
chloride (7a hydrochloride). 7a was dissolved in ether and prepared following the general procedure D using 0.3 g
cooled, then HCl gas was initiated, upon what immediately a (7.2 mmol) lithium aluminum hydride and 0.4 g (1.8 mmol) 6d
(cm-1): 3336, 3010, 1675, 1495, 1242, 751; mp: 185-186 °C.
R
R
R
(1S,2S,4R)-2-Amino-4-phenoxycyclopentanol (7d) was
.
1
colorless solid precipitated. Yield: 86% (0.9 g); H-NMR (500 Product was obtained as colorless solid; Yield: calc. as
MHz, [D6]-DMSO) = δ (ppm) 8.31 (bs, 3H), 7.31 (m, 5H), 5.38 hydrochloride; purity: 91% (254 nm); 1H-NMR (500 MHz,
(s, 1H), 4.41 (s, 2H), 4.14 (m, 1H), 4.02 (m, 1H), 3.11 (m, 1H), [D6]-DMSO) = δ (ppm) 7.25 (m, 2H), 6.86 (m, 3H), 4.76 (bs,
2.41 (m, 1H), 2.03 (m, 1H), 1.74 (m, 1H), 1.64 (m, 1H); 13C- 1H), 4.71 (m, 1H), 3.56 (m, 1H), 3.08 (m, 1H), 2.51 (m, 1H),
NMR (126 MHz, [D6]-DMSO) = δ (ppm) 138.40, 128.13, 1.92 (m, 1H), 1.70 (m, 1H), 1.56 (bs, 2H), 1.52 (m, 1H); 13C-
127.50, 127.30, 75.27, 72.57, 69.95, 56.44, 38.60, 34.86; IR NMR (126 MHz, [D6]-DMSO) = δ (ppm) 158.16, 130.00,
(cm-1): 3339, 3029, 1505, 1066, 735; Analysis calc.: C, 59.14; 120.67, 115.74, 78.16, 75.04, 58.64, 39.30; IR (cm-1): 3200,
H, 7.44; N, 5.75; Cl, 14.55, found: C, 59.16; H, 7.14; N, 5.88; 2927, 1600, 1489, 1242, 1091, 755, 693; mp: 81-82 °C.
Cl, 14.39; mp: 156-157 °C.
(1S,2S,4R)-2-Hydroxy-4-phenoxycyclopentanaminium
(1 ,2 ,4 )-2-Amino-4-(benzyloxy)cyclopentanol (7b) was chloride (7d hydrochloride). 7d was dissolved in ether and
S
S R
prepared following the general procedure D using 1.0 g cooled, then HCl gas was initiated, upon what immediately a
1
(4.3 mmol) 6b. Product was obtained as colorless solid; Yield: colorless solid precipitated. Yield: 84% (0.4 g); H-NMR (500
1
calc. as hydrochloride; purity: 97% (254 nm); H-NMR (500 MHz, [D6]-DMSO) = δ (ppm) 8.35 (bs, 3H), 7.28 (m, 2H), 6.91
MHz, [D6]-DMSO) = δ (ppm) 7.30 (m, 5H), 5.67 (bs, 1H), 4.37 (m, 3H), 4.97 (m, 1H), 4.81 (m, 1H), 4.08 (m, 1H), 3.35 (m,
8 | J. Name., 2012, 00, 1-3
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1H), 2.58 (m, 1H), 2.11 (m, 1H), 2.04 (m, 1H), 1.62 (m, 1H); 124.55, 76.07, 73.25, 69.14, 57.03, 39.27; IR (cm-1): 3325,
13C-NMR (126 MHz, [D6]-DMSO) = δ (ppm) 158.10, 130.01, 2931, 1508, 1064, 772; Analysis calc.: C, 65.41; H, 6.86; N,
120.71, 115.72, 77.96, 74.95, 58.30, 39.10; IR (cm-1): 3312, 4.77; Cl, 12.07, found: C, 65.68; H, 6.55; N, 5.16; Cl, 12.09;
2913, 1488, 1242, 754; Analysis calc.: C, 57.52; H, 7.02; N, mp: 182-184 °C.
6.10, found: C, 57.59; H, 6.85; N, 6.17; mp: 199-201 °C.
(1 ,2 ,4 )-4-([1,1′-Biphenyl]-4-yloxy)-2-
(1
S,2S,4R)-2-Amino-4-(naphthalen-1-
R
R R
ylmethoxy)cyclopentanol (7h) was prepared following the
aminocyclopentanol (7e) was prepared following the general general procedure D using 0.6 g (6.9 mmol) lithium aluminum
procedure D using 0.3 g (7.2 mmol) lithium aluminum hydride hydride and 0.5 g (1.8 mmol) 6h. Product was obtained as
1
and 0.6 g (2.0 mmol) 6e. Product was obtained as colorless colorless solid; Yield: 96% (0.4 g); purity: 96% (254 nm); H-
solid; Yield: 78% (0.4 g); purity: 100% (254 nm); 1H-NMR NMR (500 MHz, [D6]-DMSO) = δ (ppm) 8.07 (d, 1H, J = 8.2
(500 MHz, [D6]-DMSO) = δ (ppm) 7.59 (m, 4H), 7.42 (m, 2H), Hz), 7.94 (m, 1H), 7.86 (d, 1H, J = 8.2 Hz), 7.54 (m, 3H), 7.46
7.30 (m, 1H), 6.94 (m, 2H), 4.80 (m, 2H), 3.75 (m, 1H), 2.90 (m, 1H), 4.83 (s, 2H), 4.68 (bs, 1H), 4.04 (m, 1H), 3.46 (m,
(m, 1H), 2.45 (m, 1H), 2.01 (m, 1H), 1.91 (m, 1H), 1.58 (bs, 1H), 3.00 (m, 1H), 2.32 (m, 1H), 1.92 (m, 1H), 1.55-1.45 (m,
2H), 1.41 (m, 1H); 13C-NMR (126 MHz, [D6]-DMSO) = δ 3H); 13C-NMR (126 MHz, [D6]-DMSO) = δ (ppm) 134.95,
(ppm) 157.80, 140.45, 132.81, 129.40, 128.31, 127.21, 126.69, 133.80, 131.82, 128.89, 128.59, 126.65, 126.61, 126.30,
116.23, 78.35, 75.59, 59.27; IR (cm-1): 3345, 2939, 1606, 1488, 125.88, 124.59, 78.38, 76.73, 68.89, 58.70, 39.13; IR (cm-1):
1244, 1071, 829, 761, 688; Analysis calc.: C, 75.81; H, 7.11; N, 3346, 2890, 1617, 1331, 1105, 794, 768; Analysis calc.: C,
5.20, found: C, 75.85; H, 6.88; N, 5.31; mp: 163-164 °C.
(1 ,2 ,4 )-4-([1,1′-Biphenyl]-4-yloxy)-2-
74.68; H, 7.44; N, 5.44, found: C, 74.32; H, 7.28; N, 5.32; mp:
74-75 °C.
S
S R
aminocyclopentanol (7f) was prepared following the general
procedure D using 0.2 g (5.3 mmol) lithium aluminum hydride
and 0.4 g (1.4 mmol) 6f. Product was obtained as colorless
solid; Yield: 75% (0.3 g); purity: 99% (254 nm); 1H-NMR (500
MHz, [D6]-DMSO) = δ (ppm) 7.57 (m, 4H), 7.42 (m, 2H), 7.30
(m, 1H), 6.94 (m, 2H), 4.77 (m, 2H), 3.57 (m, 1H), 3.08 (m,
1H), 2.53 (m, 1H), 1.95 (m, 1H), 1.74 (m, 1H), 1.58 (bs, 2H),
1.52 (m, 1H); 13C-NMR (126 MHz, [D6]-DMSO) = δ (ppm)
157.21, 139.81, 132.09, 128.75, 127.64, 126.55, 126.03,
115.56, 77.63, 74.75, 58.06; IR (cm-1): 3400, 2925, 1608, 1487,
1244, 762, 695; Analysis calc.: C, 75.81; H, 7.11; N, 5.20,
found: C, 75.76; H, 6.83; N, 5.44; mp: 144-145 °C.
Preparation of polymer-bound acylation reagents based on
Kenner´s safety-catch linker
Coupling of carboxylic acids to the linker (resin 1). 1.0 g
(1.2 mmol) of 4-sulfamoylbenzamidomethyl functionalized
cross-linked polystyrene resin (prepared from very high load
aminomethylated polystyrene, purchased from Novabiochem,
Switzerland, batch number A20540) was dispersed in 12.5 ml
THF, DMF or DCM, depending on the solubility of the
appropriate carboxylic acid. To the suspension 290 µl DIPEA
and 7.5 mg DMAP (dissolved in as less as possible DCM) were
added and the reaction mixture was shaken for 5 h at room
temperature. Meanwhile 4.6 mmol of the appropriate
carboxylic acid was dissolved in as little as possible THF, DMF
or DCM, depending on its solubility. To the solution 387 µl
(2.3 mmol) DIC were added and the reaction mixture was
shaken for 5 h at room temperature. When using THF or DCM
the precipitating N,N'-diisopropylurea was filtered off. The
solution of activated carboxylic acid was then poured into the
resin suspension and shaken for at least 10 h at room
temperature. Finally, the resin was filtered of, washed three
times with DMF, DCM and MeOH and dried under reduced
pressure.
Activation of the acylsulfamoyl functionality by means of
alkylation with bromoacetonitrile (resin 2). 150 mg (ca.
0.2 mmol) of the appropriate 4-(N-acylsulfamoyl)-benzamide
resin 1 was suspended in 1.5 ml dry NMP, then 128 µl DIPEA
and 240 µl bromoacetonitrile were added and the reaction
mixture was shaken for 10 h at room temperature. The resulting
resin was filtered, washed five times with DMSO and three
times with THF and the subsequent reaction was immediately
performed.
(1R,2R,4R)-2-Amino-4-(naphthalen-1-
ylmethoxy)cyclopentanol (7g) was prepared following the
general procedure D using 0.3 g (8.3 mmol) lithium aluminum
hydride and 0.6 g (2.1 mmol) 6g. Product was obtained as
colorless solid; Yield: calc. as hydrochloride; purity: 98%
(254 nm); 1H-NMR (500 MHz, [D6]-DMSO) = δ (ppm) 8.07 (d,
1H, J = 8.0 Hz), 7.93 (d, 1H, J = 9.1 Hz), 7.86 (d, 1H, J = 8.2
Hz), 7.52 (m, 3H), 7.45 (m, 1H), 4.83 (s, 2H), 4.64 (bs, 1H),
4.07 (m, 1H), 3.66 (m, 1H), 2.80 (m, 1H), 2.24 (m, 1H), 1.97
(m, 1H), 1.70 (m, 1H), 1.46 (bs, 1H), 1.36 (m, 1H); 13C-NMR
(126 MHz, [D6]-DMSO) = δ (ppm) 134.93, 133.80, 131.80,
128.90, 128.61, 126.66, 126.63, 126.31, 125.89, 124.57, 78.62,
77.30, 68.98, 59.35, 49.17; IR (cm-1): 3346, 2900, 1617, 1100,
796, 770; mp: 88-89 °C.
(1R,2R,4R)-2-Hydroxy-4-(naphthalen-1-
ylmethoxy)cyclopentanaminium chloride (7g hydro-
chloride). 7g was dissolved in ether and cooled, then HCl gas
was initiated, upon what immediately a colorless solid
precipitated. Yield: 80% (0.5 g); 1H-NMR (500 MHz, [D6]-
DMSO) = δ (ppm) 8.23 (bs, 3H), 8.07 (d, 1H, J = 8.3 Hz), 7.95
(m, 1H), 7.88 (d, 1H, J = 8.0 Hz), 7.55 (m, 3H), 7.47 (m, 1H),
5.36 (d, 1H, J = 4.6 Hz), 4.88 (m, 2H), 4.13 (m, 2H), 3.13 (m,
1H), 2.45 (m, 1H), 2.07 (m, 1H), 1.77 (m, 1H), 1.65 (m, 1H);
13C-NMR (126 MHz, [D6]-DMSO) = δ (ppm) 134.53, 133.81,
131.78, 128.94, 128.78, 126.79, 126.73, 126.37, 125.87,
Activation of the acylsulfamoyl functionality by means of
alkylation with
benzyl-isourea (resin 3). 150 mg (ca. 0.2 mmol) of the
appropriate 4-(N-acylsulfamoyl)-benzamide resin was
N,N′-diisopropyl-O-2,3,4,5,6-pentafluoro-
1
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J. Name., 2012, 00, 1-3 | 9

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DOI: 10.1039/C3MD00252G
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Medicinal Chemistry Communications
ARTICLE
Journal Name
suspended in 1.5 ml dry NMP, then 128 µl DIPEA and 1.1 g
(3.4 mmol) of N,N′-diisopropyl-O-2,3,4,5,6-pentafluorobenzyl- hydroxycyclopentyl]-2,2-diphenylacetamide
N
-[(1R,2R,4S)-4-(1,1′-Biphenyl-4-yloxy)-2-
(15i)
was
isourea were added and the reaction mixture was shaken for prepared following the general procedure E using appropriate
24 h at 50 °C. The resulting resin was filtered, washed five resin 2 and 20.0 µmol 7e. Yield: 96%; purity: 97% (254 nm);
times with DMSO and three times with THF and the 1H-NMR (500 MHz, [D6]-DMSO) = δ (ppm) 8.33 (d, 1H, J =
subsequent reaction was immediately performed.
General transfer procedure of the acyl functionality to the
amino template for the preparation of target carboxamide
7.1 Hz), 7.56 (m, 4H), 7.42 (m, 2H), 7.32-7.19 (m, 11H), 6.93
(m, 2H), 4.99 (d, 1H, J = 4.8 Hz), 4.97 (s, 1H), 4.85 (m, 1H),
4.07 (m, 1H), 3.89 (m, 1H), 2.59 (m, 1H), 2.03 (m, 1H), 1.97
(procedure E). 150 mg of the appropriate activated resin 2 or 3 (m, 1H), 1.52 (m, 1H); HRMS (ESI, m/z): [M+Na]+ calc.:
was suspended in 3.0 ml THF and 20.0 µmol of the appropriate 486.2045, found: 486.2062.
amino template (dissolved in as less as possible THF) was
N
-[(1S,2S,4S)-4-(1,1′-Biphenyl-4-yloxy)-2-
added to shake the reaction mixture for 12 to 24 h at room hydroxycyclopentyl]-2,2-diphenylacetamide
(16i)
was
temperature. In-process control was done by thin layer prepared following the general procedure E using appropriate
chromatography. After quantitative acylation of the amine, the resin 2 and 20.0 µmol 7f. Yield: 95%; purity: 97% (254 nm);
resin was filtered and washed several times with THF, which 1H-NMR (500 MHz, [D6]-DMSO) = δ (ppm) 8.37 (d, 1H, J =
was previously distilled over KOH. The solvent was evaporated 7.3 Hz), 7.57 (m, 4H), 7.42 (m, 2H), 7.30 (m, 9H), 7.22 (m,
under reduced pressure and the residue further dried in high 2H), 6.95 (m, 2H), 4.99 (d, 1H, J = 5.0 Hz), 4.93 (s, 1H), 4.79
vacuum. Finally, the residue was dissolved in MeOH/H2O and (m, 1H), 4.02 (m, 1H), 3.90 (m, 1H), 2.53 (m, 1H), 2.09 (m,
purified by medium pressure column chromatography.
1H), 1.79 (m, 1H), 1.60 (m, 1H); HRMS (ESI, m/z): [M+Na]+
calc.: 486.2045, found: 486.2067.
Antiproliferative compounds
Crystallographic data for compound 7b. Crystallographic data
(excluding structure factors) have been deposited with the
prepared Cambridge Crystallographic Data Centre as supplementary
N
-[(1
R
,2
R
,4
S
)-4-(Benzyloxy)-2-hydroxycyclopentyl]-4-(1,1′-
(11j) was
biphenyl-4-yl)-4-0xobutanamide
following the general procedure E using appropriate resin 2 publication no. CCDC 766218. Copies of the data can be obtained,
and 20.0 µmol 7a. Yield: 93%; purity: 95% (254 nm); 1H-NMR free of charge, on application to CCDC, 12 Union Road, Cambridge
(500 MHz, [D6]-DMSO) = δ (ppm) 8.05 (d, 2H, J = 8.5 Hz), CB2 1EZ, UK, (fax: +44-(0)1223-336033 or e-mail:
7.90 (d, 1H, J = 7.6 Hz), 7.83 (d, 2H, J = 8.5 Hz), 7.74 (m, 2H), deposit@ccdc.cam.ac.uk). Mono-crystals were measured using a
7.51 (m, 2H), 7.43 (m, 1H), 7.33 (m, 4H), 7.27 (m, 1H), 4.84 Rigaku-AFC7F diffractometer with Cu-Kα irradiation (α
(m, 1H), 4.41 (s, 2H), 4.00 (m, 1H), 3.94 (m, 1H), 3.75 (m, 1,5418 Å).
=
1H), 3.26 (m, 2H), 2.50 (m, 2H), 2.34 (m, 1H), 1.93 (m, 1H),
1.74 (m, 1H), 1.43 (m, 1H); HRMS (ESI, m/z): [M+Na]+ calc.:
466.1994, found: 466.1972.
Cytotoxicity assay. The antiproliferative activity of the tested
compounds was determined by screening against four human
tumor cell lines as previously described.12 The cell lines were
suspended in RPMI 1640 medium containing 10% fetal calf
serum (FCS) and added to each well of the 96 well microplate
(1000 cells per well). After 24 h incubation, five serial dilutions
of the test compound in DMSO were added to the cultures at a
1000-fold dilution. A 1000-fold dilution of just DMSO served
as the untreated control. The microtiter plates were then
incubated for 96 h at 37 °C in 5% CO2 atmosphere. Medium
was removed and the cells were fixed with 1% glutaraldehyde.
Cell staining was done with crystal violet (0.2‰ in water) for
30 min. After the dye was removed, the plates were washed to
remove non-bound dye, 70% ethanol/water mixture was added
to redissolve the cell-bound dye, and the optical density was
measured at = 570 nm with an Anthos 2010 plate reader. The
N
-[(1
S
,2
S
,4
S
)-4-(Benzyloxy)-2-hydroxycyclopentyl]-4-(1,1′-
(12j) was prepared
biphenyl-4-yl)-4-oxobutanamide
following the general procedure E using appropriate resin 2
and 20.0 µmol 7b. Yield: 89%; purity: 96% (254 nm); 1H-NMR
(500 MHz, [D6]-DMSO) = δ (ppm) 8.05 (d, 2H, J = 8.5 Hz),
7.88 (d, 1H, J = 7.1 Hz), 7.83 (d, 2H, J = 6.6 Hz), 7.75 (m, 2H),
7.51 (m, 2H), 7.43 (m, 1H), 7.32 (m, 4H), 7.26 (m, 1H), 4.85
(m, 1H), 4.40 (s, 2H), 3.93 (m, 2H), 3.79 (m, 1H), 3.26 (m,
2H), 2.50 (m, 2H), 2.28 (m, 1H), 1.99 (m, 1H), 1.61 (m, 1H),
1.51 (m, 1H); HRMS (ESI, m/z): [M+Na]+ calc.: 466.1994,
found: 466.2001.
N
-[(1
R
,2
R
,4
S
)-4-(1,1′-Biphenyl-4-yloxy)-2-
-Indol-3-yl)butanamide
hydroxycyclopentyl]-2-(1
H
(15h)
was prepared following the general procedure E using
half maximal inhibitory concentrations (IC50) were estimated
appropriate resin 2 and 20.0 µmol 7e. Yield: 93%; purity: 96%
(254 nm); H-NMR (500 MHz, [D6]-DMSO) = δ (ppm) 10.72
20
1
by linear regression of the log dose to the T/C ratio
.
(s, 1H), 7.84 (d, 1H, J = 7.1 Hz), 7.56 (m, 4H), 7.48 (d, 1H, J =
7.8 Hz), 7.42 (m, 2H), 7.30 (m, 2H), 7.08 (m, 1H), 7.04 (m,
1H), 6.94 (m, 3H), 4.98 (d, 1H, J = 4.4 Hz), 4.85 (m, 1H), 4.04
(m, 1H), 3.87 (m, 1H), 2.66 (t, 2H, J = 7.4 Hz), 2.58 (m, 1H),
2.15 (t, 2H, J = 7.4 Hz), 2.02 (m, 1H), 1.96 (m, 1H), 1.86 (m,
2H), 1.53 (m, 1H); HRMS (ESI, m/z): [M+Na]+ calc.:
477.2154, found: 477.2125.
Notes and references
Institute of Pharmacy, Ernst-Moritz-Arndt-University, Friedrich-
a
Ludwig-Jahn-Str. 17, 17487 Greifswald, Germany.
Electronic Supplementary Information (ESI) available: synthesis and
characterization data of inactive products. See DOI: 10.1039/b000000x/
10 | J. Name., 2012, 00, 1-3
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