Ethynylogation approach in pharmacophore design: from alkynyl-to butadiynyl-carbinols vs antitumoral cytotoxicity

Article abstract of DOI:10.1016/j.tet.2016.09.001

Ethynylogation of a chiral lipidic dialkynylcarbinol (DAC), identified as a lead for cytotoxicity against HCT116 cancer cells, is shown to typify the butadiynyl-alkynylcarbinol (BAC) unit as a new pharmacophore. The enantiomers of the internal BAC have been synthesized with 72–75% yield and 85% ee through the use of a modified Carreira reaction shown here for the first time to be compatible with butadiyne and ynal substrates. One enantiomer of the internal BAC could be characterized by X-ray crystallography. In this particular case, the ‘DAC to BAC’ ethynylogation results in a slight enhancement of the eutomer potency with a preserved vanishing eudismic ratio (IC₅₀values from 102±14 nM to 42±12 nM for the (+) enantiomers).

Full text of DOI:10.1016/j.tet.2016.09.001

Tetrahedron 72 (2016) 6697e6704
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Ethynylogation approach in pharmacophore design: from alkynyl-to
butadiynyl-carbinols vs antitumoral cytotoxicity
,b,
Dymytrii Listunov a c, Nathalie Saffon-Merceron b, Etienne Joly d, Isabelle Fabing c,
c
,
a
,
b
,
a,b,
*
*
*
ꢀ
ꢀ
Yves Genisson , Valerie Maraval
, Remi Chauvin
a CNRS, LCC (Laboratoire de Chimie de Coordination), 205 route de Narbonne, BP 44099, 31077 Toulouse Cedex 4, France
Universite de Toulouse, UPS, ICT-FR 2599, 31062 Toulouse Cedex 9, France
b
ꢀ
c
ꢀ
ꢀ
UMR CNRS 5068, LSPCMIB, Universite de Toulouse, Universite Paul Sabatier, 118 Route de Narbonne, 31062 Toulouse Cedex 9, France
d UMR CNRS 5089, IPBS (Institut de Pharmacologie et de Biologie Structurale), 205 Route de Narbonne, 31077 Toulouse Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 July 2016
Received in revised form 30 August 2016
Accepted 2 September 2016
Available online 4 September 2016
Ethynylogation of a chiral lipidic dialkynylcarbinol (DAC), identified as a lead for cytotoxicity against
HCT116 cancer cells, is shown to typify the butadiynyl-alkynylcarbinol (BAC) unit as a new pharmaco-
phore. The enantiomers of the internal BAC have been synthesized with 72e75% yield and 85% ee
through the use of a modified Carreira reaction shown here for the first time to be compatible with
butadiyne and ynal substrates. One enantiomer of the internal BAC could be characterized by X-ray
crystallography. In this particular case, the ‘DAC to BAC’ ethynylogation results in a slight enhancement of
the eutomer potency with a preserved vanishing eudismic ratio (IC50 values from 102ꢀ14 nM to
42ꢀ12 nM for the (þ) enantiomers).
Keywords:
Alkyne
Asymmetric synthesis
Antitumor agent
Cytotoxicity
Ó 2016 Elsevier Ltd. All rights reserved.
Dialkynylcarbinol
1,3-Diyne
Ethynylogation
Lipidic alkynylcarbinol
1. Introduction
bond by insertion of any divalent motif will have much more than
a simple elongation effect, and in particular modify the «chemical
Owing to a unique tradeoff between availability and reactivity,
the C^C triple bond has long been widely exploited in organic
synthesis,1 but in spite of benchmark examples,2 it has been more
sporadically envisaged as pharmacophoric component in drug de-
sign. Addressing this point, a systematic approach is first formally
proposed, and then tentatively illustrated on a particular example
of bio-active molecules containing pre-existing triple bonds.
Current options in medicinal chemistry for the optimization of
a chemical structure from a lead candidate consist in tailoring the
assumed pharmacophoric unit, or decorating its periphery, by ei-
ther isomerization, analogation, reduction/oxidation, CeH fluori-
nation, CH2-homologation (chain length variation), and general
CeH substitution. Although the limit between the pharmacophore
warhead and its ancillary environment can be somewhat arbitrary,
the bond between them is analytically essential. Expanding this
bulkiness» of the link and the relative orientations of the two
moieties. With respect to the latter two criteria, the most neutral
motif is certainly a C2 unit, i.e., a eC^Ce acetylenic motif if the
bond is a single bond.3aec In this formal context, the proposed
‘ethynylogation’ approach3deg has been put to test on a recently
disclosed anti-tumor lead compound 1 for which the limits be-
tween the functional core, assumed to be the pharmacophore, and
the periphery can be unambiguously delineated (Fig. 1).
The lead structure 1 derives from a family of natural acetylenic
lipids occurring as secondary metabolites of marine sponges.
Among these natural products, functional representatives embed-
ding an alkenyl-alkynylcarbinol (AAC) fragment in their structure
were first found to display numerous biological activities (antibi-
otic, antiviral, cytotoxic, enzyme inhibition, .).4 More recently,
a rational approach consisting in a systematic four-parameter
structural variation from the naturally occurring C20 lipidic AAC
(S)-(þ)-2,4aeb,4d led to the discovery of a bio-inspired artificial
pharmacophore, namely the terminal dialkynylcarbinol (DAC) unit
of the C17 lipid 1 exhibiting a cytotoxicity against HCT116 tumor
* Corresponding authors. E-mail addresses: genisson@chimie.ups-tlse.fr
ꢀ
(Y. Genisson), valerie.maraval@lcc-toulouse.fr (V. Maraval), chauvin@lcc-toulouse.fr
cells 100 times higher than 2 (IC50¼90 nM vs 10
m
M; Fig. 1).5 The
(R. Chauvin).
http://dx.doi.org/10.1016/j.tet.2016.09.001
0040-4020/Ó 2016 Elsevier Ltd. All rights reserved.

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D. Listunov et al. / Tetrahedron 72 (2016) 6697e6704
Fig. 1. Proposed ethynylogation approach for the design of the artificial BAC targets, and related natural products.
lead (þ)-1 differs from the reference product (þ)-2, not only by the
level of the internal unsaturation (C^C instead of C]C), but also by
the absolute configuration of the carbinol asymmetric center and
by the length of the alkyl chain, these characteristics being in-
dependently optimal in (S)-(þ)-1.5a Further standard modulations
around the AAC and DAC motifs, like oxidation or substitution of
the DAC center and E/Z isomerization or cyclomethylenation of
the AAC double bond, led to lower cytotoxic activity.5b Insertion of
an ethynyl unit at either ends of the DAC core, i.e., in the terminal
spCeH or in the internal spCeC12H25 bonds, was thus envisaged
according to the above-proposed ethynylogation approach, de-
ethynyl terminus. Notably, H2-saturation of the vinyl end of the
most active enantiomer of a panaxytriol derivative was reported to
induce a significant drop in cytotoxicity,14 and the same effect was
observed upon H2-saturation of the ethynyl end of 1.5a These results
are in the same line as the enhancement of cytotoxicity upon in-
creasing the degree of unsaturation from AAC to DAC, and a similar
effect was expected upon increasing the extent of unsaturation
from DAC to BAC.
2. Results and discussion
fining the butadiynyl-alkynylcarbinol (BAC) targets
respectively.
3 and 4,
Synthesis of racemic samples of the BACs 3 and 4 was first ac-
complished by using a Cadiot-Chodkiewicz coupling to assemble
the butadiynyl fragment from a non-functional bromoalkyne and
a terminal DAC precursor, itself prepared by nucleophilic addition
of a metal acetylide onto an aldehyde.
The synthesis of (rac)-3 started with the addition of tetra-
decynyllithium to trimethylsilylpropynal 6a giving the silylated
DAC 7a, followed by K2CO3-promoted desilylation leading to the
Related natural products containing 1,3-butadiynylcarbinol
motifs are the falcarinol 5a (also known as panaxynol)6 and pan-
axytriol 5b,7 found in dietary plants (carrots, celery, parsnip, gin-
seng) and used in traditional Asian medicines (Panax ginseng, P.
quinquefolium, P. notoginseng).8 The antiproliferative properties of
falcarinol 5a towards various cancer cell-lines were also in-
vestigated in a systematic manner,9 and an apoptotic cell division
terminal DAC 7b, with 55% yield over two steps (Scheme 1).5b
A
Cadiot-Chodkiewicz coupling of 7b with the bromoalkyne 8,15
prepared by bromination of triisopropylsilylacetylene with NBS in
the presence of AgNO3,16 afforded the silylated BAC 9 in 87% yield.17
Desilylation of 9 with TBAF at ꢁ30 ꢂC afforded (rac)-3 with 48%
yield.
inhibition pathway, associated with a proteolytic cleavage of PKCd,
a caspase-3 activation and a degradation of PARP, were evidenced
on the HL60 cell-line.10 Racemic falcarinol-like probes were also
recently shown to act as irreversible inhibitors of ALDH2.11 After
a first report in 1999 on the synthesis of the two enantiomers of
falcarinol from (D)-gluconolactone and (D)-xylose,12 their asym-
metric synthesis through a BINOL/Ti(OiPr)4-mediated asymmetric
addition of an alkynylzinc reactant to an aldehyde substrate was
recently described.13
A similar method was used for the synthesis of (rac)-4, in which
the butadiynyl fragment lies in the internal position. The silylated
carbinol 10 was thus obtained in two steps and 40% yield from the
silylated propynal 6b (Scheme 2): the intermediate DAC 11 was first
obtained by addition of ethynylmagnesium bromide to 6b,18 and
the butadiynyl fragment of 10 was then formed by a Cadiot-
The (S)-4 target is an isomer of the lipidic bishomologue of (S)-
falcarinol 5a, where the vinyl end of 5a is dehydrogenated to an

D. Listunov et al. / Tetrahedron 72 (2016) 6697e6704
6699
Scheme 1. Synthesis of the racemic BAC (rac)-3.
Scheme 2. Attempt at synthesis and synthesis of the racemic BAC (rac)-4.
Chodkiewicz coupling of 11 with the bromoalkyne 12,17 the latter
being prepared by AgNO3-promoted bromination of 1-tetradecyne
with NBS.16,19 However, proto-desilylation of 10 using TBAF or silver
fluoride failed to produce the BAC target 4.
evidenced that the activity is much higher for the racemic BAC
(rac)-4 containing the butadiynyl fragment at the internal position,
with an IC50 of ca. 120 nM, comparable to that of the parent DAC in
the scalemic series (S)-1 (90 nM) (Table 1).
The access to 4 was thus envisaged through another strategy,
relying on the addition of ethynylmagnesium bromide to the
butadiynal 13 (Scheme 2). The synthesis of 13 required first the use
of a Cadiot-Chodkiewicz coupling between the bromoalkyne 12
and propargyl alcohol, giving the butadiynol 14 with 73% yield.20
After oxidation of 14 to 13, the final addition afforded the tar-
geted racemic BAC (rac)-4 with 45% yield.
The cytotoxicity of racemic mixtures of the regioisomeric BACs 3
and 4 was first evaluated on the human colon carcinoma HCT116
cancer cell-line previously used to assess the biological activity of
alkynylcarbinol pharmacophores.5 MTT cell viability assays
Asymmetric synthesis of the enantiomers of 4 was undertaken
through the ‘modified Carreira method’ that proved efficient for the
enantioselective preparation of DACs.5 Instead of TIPS, a TMS pro-
tecting group of the terminal triple bond was selected for its pos-
sible removal under neutral conditions (using silver nitrate),21 and
two possible retrosynthetic disconnections were considered
(Scheme 3). The disconnection 1, requiring the use of a Carreira
reaction of the diynal 13 with trimethylsilylacetylene, failed to
produce the silylated BAC 15, likely because of the instability of 13
under these conditions. The disconnection 2, involving the a priori
more stable trimethylsilylpropynal 6a was then addressed.22

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D. Listunov et al. / Tetrahedron 72 (2016) 6697e6704
63% yields, respectively,19 and an enantiomeric excess of 85%, as
determined by chiral supercritical fluid chromatography (SFC) us-
ing an IA-3 column (default value: depending on the experiment,
an ee up to 89% has been measured). The BAC products were found
remarkably stable, a sample of (þ)-4 remaining unchanged after
storage over several months at ꢁ20 ꢂC, either in solution or in the
dry state. It can also be stored for a few weeks at room temperature
in the solid state without degradation (and without a loss of bi-
ological activity against HCT116 cells).
Single crystals of the levo product obtained by slow evaporation
of a dichloromethane solution proved suitable for X-ray diffraction
analysis, which confirmed the chemical structure of (ꢁ)-4
(Fig. 2).25,26 Because the compound contains no heavy atom and the
Table 1
Evaluation of the cytotoxicity against HCT116 cancer cells of the DAC 1 and the BACs
3 and 4. Cells were seeded in 96-well plates and treated with concentrations ranging
from 5 nM to 10
MTT test (SD)
m
M; after 72 h, the number of live cells was evaluated by standard
Derivative
IC50 [nM]
102 (ꢀ14)a,b
10,000
(S)-(þ)-1
(rac)-3
(rac)-4
120
(S)-(þ)-4
42 (ꢀ12)a
1500
(R)-(ꢁ)-4
a
The given statistical errors were calculated from six different MTT tests per-
formed in strictly identical conditions.
b
The IC50 value of 90 nM earlier reported for (S)-(þ)-1 (see ref. 5a) is within the
given margin of error.
X-ray diffraction analysis was performed using Mo-Ka radiation,
the absolute configuration of the carbinol center cannot be reliably
ascertained. Nevertheless, the (R) configuration is represented on
the basis of the general rules of asymmetric induction for the
Carreira method: having used (þ)-NME as chiral auxiliary, a (S)
configuration can be predicted for (ꢁ)-15, and thus a (R) configu-
ration for (ꢁ)-4.
The lipidic butadiyne nucleophile 16 was prepared in two steps
and 68% yield from the bromoalkyne 12 and 2-methylbut-3-yn-2-
ol, via the diynol 17, through a Cadiot-Chodkiewicz coupling and
a retro-Favorskii reaction using procedures previously described for
other substrates.15 The asymmetric addition of the 1,3-diyne 16 to
the ynal 6a under the modified Carreira conditions afforded the
TMS-protected BACs (þ)-15 and (ꢁ)-15 with 72% and 75% yields,
respectively.23 It is noteworthy that this is the first example of
application of the Carreira reaction, which is known to be highly
substrate-dependent,24 to butadiyne and ynal substrates. Proto-
desilylation of (þ)-15 and (ꢁ)-15 was first attempted with the
K2CO3eMeOH combination, but these basic conditions proved in-
efficient, giving only polymerization products instead. Under neu-
tral conditions, however, treatment of (þ)-15 and (ꢁ)-15 with
AgNO3 led to the ultimate BAC targets (þ)-4 and (ꢁ)-4 with 58% and
The cytotoxicity of the scalemic BACs was evaluated towards the
HCT116 cell-line, and compared with that of the reference DAC (S)-
(þ)-1 exhibiting an IC50 of 90 nM.5a In Table 1 are listed the IC50
values measured for the racemic samples of the BACs 3 and 4, and
for the enantio-enriched samples of (S)-(þ)-4 and (R)-(ꢁ)-4. As
mentioned above, the internal BAC ethynylogue (rac)-4 is two order
of magnitude more active than the external regioisomer (rac)-3.
The compared cytotoxicity of the (S) and (R) enantiomers of 4,
isolated in 85% ee, once again evidenced the dramatic influence of
the absolute configuration of the carbinol center.5 The much higher
Scheme 3. Retrosynthesis and synthesis of the two enantiomers of the BAC 4. The depicted absolute configurations correspond to those predicted by the Noyori’s asymmetric
induction model admitted for the Carreira’s method.

D. Listunov et al. / Tetrahedron 72 (2016) 6697e6704
6701
Fig. 2. Molecular view of the BAC 4 from X-ray diffraction analysis of a single crystal of the levo enantiomer (ꢁ)-4.24 Thermal ellipsoids represent 50% probability. H atoms are
omitted for clarity (except for that on asymmetric carbon C3 and on O1 atom) (see SD).
potency of the (S) enantiomer with respect to the (R) counterpart is
consistent with the systematic trend observed in the DAC series.5a
The cytotoxicity of (S)-(þ)-4, with an IC50 value of 40 nM, is slightly
higher than that of the reference DAC (S)-(þ)-1. The IC50 value of
(þ)-1 and (þ)-4 being in the same range, for the sake of compari-
son, the uncertainties were calculated from six different MTT tests:
the respective statistical errors of ꢀ14 nM and ꢀ12 nM show that
the tests exhibit a reliable level of reproducibility, and confirm that
the BAC (þ)-4 is definitely more active than the DAC (þ)-1. The
significance of the ethynylogation effect is also supported by
pointing out that the enantiomeric enrichment of the sample of
(þ)-4 is lower (85% ee) than that of (þ)-1 (91% ee).5a Furthermore,
the cytotoxicity enhancement from (þ)-1 to (þ)-4 cannot be simply
assigned to an effect of the two-carbon increase of the chain length:
it has indeed been previously shown that elongation or truncation
of the lipidic chain of (þ)-1 results in higher IC50 values.5b
available. Analytical thin-layer chromatography (TLC) was per-
formed with silica gel 60 F254 pre-coated plates. TLC-plates were
observed under UV light and/or revealed with a 10% phosphomo-
lybdic acid ethanolic solution. Column chromatographies were
ꢁ
carried out with silica gel 60 A, 70e230 mesh. NMR spectroscopic
data were obtained with instruments working at 300 or 400 MHz
for 1H nuclei. The following instruments were used: 1H and 13C
NMR: Bruker Avance 300 or Avance 400 spectrometers. High-
resolution mass spectra (HRMS) were performed by Desorption
Chemical Ionization with methane gas (DCI (CH4)) using a TOF mass
analyzer. IR analyses were run on an ATR PerkineElmer Spectrum
100 FT-IR spectrometer. Optical rotations were measured on a Jasco
P-2000 polarimeter. Chiral SFC: Acquity UPC2 System by Waters
and SFC PIC Lab Analytic by Pic Solution with column Chiralpak IA-3
(4.6ꢃ100 mm). Chemical shifts (
residual solvent peak; J values are given in Hz. [
in deg dmꢁ1cmꢁ3gꢁ1
d
) are given in ppm relative to the
a
]D values are given
.
3. Conclusion
4.2. Experimental procedures and characterizations
The observed slight enhancement of cytotoxicity upon internal
ethynylogation of the DAC (þ)-1 to the BAC (þ)-4 is a factual result,
yielding the most active cytotoxic compound against HCT116 can-
cer cells at disposal to date in the lipidic alkynylcarbinols series. The
results also provide a preliminary support to the relevance of the
proposed ethynylogation approach, which has however to be ap-
praised with other molecules before being possibly considered as
generally useful in pharmacophore design. In passing, the enan-
tioselective synthesis of (þ)-4 and (ꢁ)-4 illustrates further and
extend the scope of the modified Carreira procedure for asym-
metric addition of terminal alkynes to ynals. The vanishing eudis-
mic ratio of the BAC 4 (<40/1500) surpasses the trend established
in the AAC and DAC series.5 The triple bond inserted between the
DAC pharmacophore and its lipidic periphery defines a BAC
chemical functionality which can be in turn considered as a phar-
macophore by itself, while repelling the limit with the lipidic chain
by two CeC bonds. In principle, ethynylogation of the new phar-
macophore limit might be applied again, and so sequentially until
facing the stability limit of such bio-inspired polyynes. On the other
hand, considering the lipidic BAC (þ)-4 as a new lead molecule for
cytotoxicity, further optimization would consist in a systematic
variation of the lipidic chain length, which was shown to be of
paramount importance in the DAC series.5a Comparative biological
evaluation of DACs and BACs against other cancer cell-lines, beyond
HCT116, is also planned. Results in these directions will be com-
municated in due course.
4.2.1. Nonadeca-1,3,6-triyn-5-ol (3). To a solution of 9 (50 mg,
0.117 mmol) in THF (2 mL) containing one drop of water, at ꢁ30 ꢂC,
was added 1M TBAF solution in THF (350 mL, 0.349 mmol, 3 equiv).
The mixture was stirred for 30e45 min, and quenched with a sat-
urated aqueous solution of NH4Cl. After extraction with Et2O, the
combined organic layers were dried with Na2SO4 and concentrated
under reduced pressure. The residue was purified by silica gel
chromatography (pentane/Et2O 10:1) to give 3 as an oil (15 mg,
48%). 1H NMR (400 MHz, CDCl3):
d
0.89 (t, J¼6.70 Hz, 3 H), 1.21e1.41
(m, 18 H), 1.53 (pseudo-quint, J¼7.17 Hz, 2 H), 2.16 (d, J¼7.86 Hz,
1 H), 2.23 (td, J¼5.10, 2.50 Hz, 2 H, overlap with the signal at
2.24 ppm), 2.24 (d, J¼1.20 Hz, 1 H, overlap with the signal at
2.23 ppm), 5.14 (dtd, J¼7.86, 2.50, 1.20 Hz, 1 H); 13C{1H} NMR
(101 MHz, CDCl3):
d 14.1, 18.7, 22.7, 28.2, 28.9, 29.1, 29.3, 29.5, 29.6,
29.6, 29.7, 31.9, 52.6, 67.2, 68.2, 69.3, 73.2, 76.0, 87.0; IR (neat):
n
¼3274, 2918, 2870, 2848, 2316, 2290, 2256, 2223, 1739, 1490, 1465,
1428, 1405,1376,1346,1330, 1305, 1291, 1156, 1117, 1083, 1049,1031,
1005, 995, 890, 813, 789, 755, 721, 697, 663, 641, 601, 582,
560 cmꢁ1; HRMS-DCI (CH4): m/z [MþH]þ calcd for C19H29O:
273.2218, found: 273.2238.
4.2.2. Racemic nonadeca-1,4,6-triyn-3-ol (4). To a solution of the
aldehyde 13 (20 mg, 0.081 mmol) in THF (5 mL) under stirring at
0
ꢂC was added dropwise ethynylmagnesium bromide (162
mL,
0.081 mmol). The reaction mixture was stirred for 1 h at 0 ꢂC and
1 h at room temperature before treatment with a saturated aqueous
NH4Cl solution. After extractions with E2O (3ꢃ1 mL), the combined
organic layers were washed with brine, dried over Na2SO4, and
concentrated to dryness under reduced pressure. The residue was
purified by silica gel chromatography (Rf¼0.2, pentane/Et2O 20:1)
to give 4 as a colorless oil (10 mg, 45%). 1H NMR (300 MHz, CDCl3):
4. Experimental section
4.1. General experimental details
The following solvents and reagents were dried and freshly
distilled prior to use: CH2Cl2 (from CaH2), Et2O, THF (from sodium/
benzophenone). All the reagents were used as commercially
d
0.89 (t, J¼6.53 Hz, 3 H), 1.23e1.45 (m, 18 H), 1.54 (pseudo-quin,
J¼7.10 Hz, 2 H), 2.29 (t, J¼6.91 Hz, 2 H), 2.59 (d, J¼2.05 Hz, 1 H), 5.16

6702
D. Listunov et al. / Tetrahedron 72 (2016) 6697e6704
(br s, 1 H); 13C{1H} NMR (101 MHz, CDCl3):
d
14.1, 19.3, 22.7, 28.0,
then added dropwise, and the resulting mixture was stirred at 0 ꢂC
28.8, 29.1, 29.3, 29.5, 29.6 (3C), 31.9, 52.4, 64.0, 70.2, 71.1, 73.2, 80.0,
83.4; IR (neat):
for 4 h (TLC monitoring). The mixture was treated with a saturated
aqueous NH4Cl solution (5 mL) and the aqueous layer was extracted
with diethyl ether (3ꢃ1 mL). The combined organic layers were
dried with Na2SO4 and concentrated under reduced pressure. The
residue was purified by silica gel chromatography (pentane/Et2O
25:1) to give 10 as a clear yellow oil (104 mg, 57%). 1H NMR
n
¼3313, 3289, 3230, 2955, 2922, 2847, 2257, 2123,
1719, 1498, 1464, 1422, 1371, 1290, 1276, 1230, 1220, 1127, 1023, 990,
970, 881, 724, 711, 699, 666, 649, 565, 558 cmꢁ1; HRMS-DCI (CH4):
m/z [MþH]þ calcd for C19H29O: 273.2218, found: 273.2221. Chiral
SFC analysis: Chiralpak IA 3
m
m (4.6ꢃ100 mm), SC CO2þ15% MeOH
(gradient), 4 mL/min, 40 ꢂC, 130 bar, UV 240 nm, tR 3.93 (R), 4.08 (S)
(400 MHz, CDCl3):
d
0.88 (t, J¼6.70 Hz, 3 H), 1.09 (s, 21 H), 1.21e1.45
min.
(m, 18 H), 1.54 (pseudo-quintet, J¼7.00 Hz, 2 H), 2.25e2.35 (m, 3 H),
5.16 (d, J¼7.00 Hz, 1 H); 13C{1H} NMR (101 MHz, CDCl3):
d 11.1, 14.1,
4.2.3. (þ)-Nonadeca-1,4,6-triyn-3-ol ((þ)-4). To
a
solution of
18.5, 19.3, 22.7, 28.1, 28.8, 29.1, 29.3, 29.5, 29.6 (3C), 31.9, 53.0, 64.2,
(þ)-15 (57 mg, 0.166 mmol) in acetone (3 mL) was added AgNO3
(2.8 mg, 0.016 mmol, 0.1 equiv) and one drop of water. The mixture
was stirred for 4 h (followed by TLC), and then quenched with
a saturated aqueous NaCl solution. The aqueous layer was extracted
with CH2Cl2, and the combined organic layers were dried over
MgSO4 and concentrated to dryness under reduced pressure. The
residue was purified by silica gel chromatography (pentane/Et2O
15:1) to give (þ)-4 as a white solid (26 mg, 58%). The analytical data
69.5, 71.9, 82.9, 86.7, 102.9; IR (neat):
n
¼3390, 2923, 2855, 2725,
2257, 2232, 2178, 1709, 1624, 1462, 1383, 1367, 1291, 1262, 1228,
1101, 1037, 1017, 996, 919, 882, 805, 717, 676, 611, 579, 566,
559 cmꢁ1; HRMS-DCI (CH4) m/z [MþH]þ calcd for C28H49OSi:
229.3553, found: 229.3565.
4.2.7. Heptadeca-2,4-diyn-1-ol (14). To a stirred solution of prop-
argyl alcohol (23 mg, 0.42 mmol), ethylamine (0.15 mL of 70% w/w
solution in water) and 1-bromo-1-tetradecyne 12 (100 mg,
0.366 mmol) in MeOH (5 mL), was added freshly prepared CuCl
(1 mg, 0.01 mmol). After the reaction mixture turned to a yellowish
green color, hydroxylamine hydrochloride (7 mg, 0.1 mmol) was
added, inducing an immediate change of the color which became
yellow. The reaction was monitored by TLC (pentane/Et2O 10:1) and
reached completion after 20 h. Then, the mixture was filtered
through a short pad of CeliteÒ, and the filtrate was concentrated to
dryness under reduced pressure. The residue was dissolved in
EtOAc, washed with water and saturated brine. The organic layer
was dried over Na2SO4 and concentrated under reduced pressure.
The residue was purified by silica gel (pentane/Et2O 10:1) to give 14
as a white solid 76 mg (73%). The obtained physical data were in
agreement with literature.20
for (þ)-4 are identical to those of the racemate 4 excepted the
20
optical rotation [
a
]
D
þ7.5 (c¼2.24, CHCl3). Chiral SFC analysis:
Chiralpak IA 3
m
m (4.6ꢃ100 mm), SC CO2þ15% MeOH (gradient),
4 mL/min, 40 ꢂC, 130 bar, UV 240 nm, tR 3.93 (R), 4.08 (S) min.
4.2.4. (ꢁ)-Nonadeca-1,4,6-triyn-3-ol ((ꢁ)-4). The BAC (ꢁ)-4 was
prepared from (ꢁ)-15 using the procedure described for the (þ)-4
enantiomer. It was obtained as a white solid (32 mg, 63%). Ana-
lytical data for (ꢁ)-4 are identical to those of the racemate 4
excepted the optical rotation. [
a
]
20 ꢁ8.8 (c¼2.84, CHCl3). Chiral SFC
D
analysis: Chiralpak IA 3
m
m (4.6ꢃ100 mm), SC CO2þ15% MeOH
(gradient), 4 mL/min, 40 ꢂC, 130 bar, UV 240 nm, tR 3.93 (R), 4.08 (S)
min.
4.2.5. 1-[tris(Propan-2-yl)silyl]nonadeca-1,3,6-triyn-5-ol (9). CuCl
(1.75 mg, 0.0176 mmol) was added to a n-propylamine solution
(0.55 mL, 30% v/v in water) at 0 ꢂC. After stirring for 5 min, hy-
droxylamine hydrochloride (0.7 mg, 0.0102 mmol) was added, in-
ducing the disappearance of the blue color of the mixture. A
solution of the terminal alkyne 7b (100 mg, 0.4032 mmol) in THF
(0.1 mL) was then added, and the mixture stirred at 0 ꢂC for 15 min.
Finally, a solution of the bromoalkyne 8 (125 mg, 0.4757 mmol) in
THF (0.1 mL) was added dropwise, and the mixture stirred at 0 ꢂC
for 4 h (TLC monitoring). The reaction was quenched with a satu-
rated aqueous NH4Cl solution (5 mL). The aqueous layer was
extracted with diethylether (3ꢃ1 mL). The combined organic layers
were dried with Na2SO4 and concentrated under reduced pressure.
The residue was purified by silica gel chromatography (pentane/
Et2O 15:1) to give 9 as a pale yellow oil (150 mg, 87%). 1H NMR
4.2.8. Heptadeca-2,4-diynal (13). To a solution of 14 (50 mg,
0.201 mmol) in dichloromethane (5 mL) under stirring at 0 ꢂC was
added MnO2 (336 mg, 4 mmol, 20 equiv) in one portion. The
resulting mixture was stirred at this temperature for 1 h, and at rt
for 2 h before being filtered through a pad of CeliteÒ. The filtrate
was concentrated under reduced pressure to give 13 as a pale
yellow oil (60%, 29 mg). 1H NMR (300 MHz, CDCl3):
d 0.89 (t,
J¼7.20 Hz, 3 H), 1.18e1.47 (m, 18 H), 1.59 (quin, J¼8.20 Hz, 2 H), 2.40
(t, J¼7.04 Hz, 2 H), 9.20 (s, 1 H); 13C{1H} NMR (75 MHz, CDCl3):
d
14.1, 19.8, 22.7, 27.7, 28.8, 29.0, 29.3, 29.4, 29.6 (2C), 29.7, 31.9, 63.7,
72.4, 80.7, 93.2, 176.1; IR (neat):
n
¼2922, 2852, 2733, 2477, 2230,
2131, 1727, 1660, 1551, 1464, 1423, 1380, 1260, 1237, 1075, 1021, 947,
910, 856, 803, 771, 722, 697, 580, 567, 556 cmꢁ1;HRMS-DCI (CH4) m/
z [MþH]þ calcd for C17H27O: 247.2062, found: 247.2074.
(300 MHz, CDCl3):
d
0.89 (t, J¼6.40 Hz, 3 H), 1.09 (s, 21 H), 1.22e1.45
(m, 18 H), 1.46e1.57 (m, 2 H), 2.16 (d, J¼7.68 Hz, 1 H), 2.23 (td,
J¼7.10, 2.18 Hz, 2 H), 5.16 (dt, J¼7.68, 2.05 Hz, 1 H); 13C{1H} NMR
(75 MHz, CDCl3): 11.2,14.1,18.5,18.7, 22.7, 28.2, 28.9, 29.1, 29.4, 29.5,
29.6 (2C), 29.7, 31.9, 52.8, 69.3, 73.3, 76.2, 86.2, 86.8, 88.6. IR (neat):
4.2.9. 2-Methyl-3,5-octadecadiyn-2-ol
(17).27 CuCl
(6
mg,
0.064 mmol), was added to a solution of n-propylamine (2 mL of
30% v/v in water) at 0 ꢂC. After stirring for 5 min, hydroxylamine
hydrochloride (2.6 mg, 0.038 mmol) was added, inducing the dis-
appearance of the blue color of the solution. 2-Methyl-3-butyn-2-ol
n
¼3369, 2923, 2854, 2727, 2209, 2154, 2106, 1715, 1650, 1615, 1463,
1379, 1367, 1292, 1242, 1071, 1016, 996, 919, 882, 721, 678, 663, 618,
602, 595 cmꢁ1; HRMS-DCI (CH4) m/z [MþH]þ calcd for C28H49OSi:
229.3553, found: 229.3560.
(166 mL, 145 mg, 1.72 mmol) was then added and the mixture was
stirred at 0 ꢂC for 15 min. A solution of the bromoalkyne 12
(554 mg, 2.03 mmol) in THF (0.1 mL) was then added dropwise, and
the resulting mixture was stirred at 0 ꢂC for 4 h (TLC monitoring).
The mixture was treated with a saturated aqueous NH4Cl solution
(5 mL) and the aqueous layer was extracted with diethyl ether
(3ꢃ1 mL). The combined organic layers were dried with Na2SO4
and concentrated under reduced pressure. The residue was purified
by silica gel chromatography (pentane/Et2O 10:1) to give 17 as
a colorless oil 390 mg (82%). Rf¼0.3, pentane/Et2O¼10:1. 1H NMR
4.2.6. 1-[tris(Propan-2-yl)silyl]nonadeca-1,4,6-triyn-3-ol (10). CuCl
(1.85 mg, 0.0186 mmol), was added to a solution of n-propylamine
(0.58 mL of 30% v/v in water) at 0 ꢂC. After stirring for 5 min, hy-
droxylamine hydrochloride (0.8 mg, 0.0108 mmol) was added, in-
ducing the disappearance of the blue color of the mixture. A
solution of the terminal alkyne 11 (100 mg, 0.4255 mmol) in THF
(0.1 mL) was added under stirring at 0 ꢂC for 15 min. A solution of
the bromoalkyne 12 (137 mg, 0.5028 mmol) in THF (0.1 mL) was
(300 MHz, CDCl3):
d
0.88 (t, J¼6.4 Hz, 3H), 1.20e1.45 (m, 18H),
1.47e1.60 (m, 10H), 1.89 (s, 1H), 2.27 (t, J¼7.0 Hz, 1H); 13C{1H} NMR

D. Listunov et al. / Tetrahedron 72 (2016) 6697e6704
6703
(75 MHz, CDCl3):
(2C), 32.0, 64.5, 65.5, 67.4, 80.0, 81.6. IR (neat):
d
14.1, 19.3, 22.7, 28.3, 28.9, 29.2, 29.7 (3C), 31.2
reference drug (þ)-1 (IC50 around 100 nM). Plates were then placed
n
¼3361, 2981, 2922,
in a CO2 tissue culture incubator for 72 h before the MTT test was
2853, 2252, 1713, 1465, 1423, 1363, 1328, 1261, 1153, 956, 895, 795,
performed. This was done by adding 10
(12 M, 5 mg/ml in PBS, Sigma) to each well and incubating the
plate for 90 min at 37 ꢂC. 100
mL of MTT stock solution
721, 597, 553, 464 cmꢁ1; HRMS-DCI (CH4) m/z [MþH]þ calcd for
m
C
19H33O:277.2531, found: 277.2531.
mL isopropanol, 0.1 M HCl were then
added to each well, and the plates were returned to 37 ꢂC for 90 min
before reading the OD at 570 nM.
4.2.10. (þ)-1-(Trimethylsilyl)nonadeca-1,4,6-triyn-3-ol ((þ)-15). A
flask was charged with Zn(OTf)2 (664 mg, 1.83 mmol, 4 equiv),
(ꢁ)-N-methylephedrine (328 mg, 1.83 mmol, 4 equiv) was purged
with argon for 15 min. Anhydrous CH2Cl2 (10 mL) and triethylamine
Acknowledgements
(248 mL, 1.83 mmol, 4 equiv) were then added, and the resulting
mixture was vigorously stirred for 2 h at rt. Then, a solution of the
diyne 16 (400 mg,1.83 mmol, 4 equiv) in CH2Cl2 (0.5 mL) was added
The ‘Institut de Chimie de Toulouse’ (ICT) is acknowledged for
SFC facilities. The chromatographic analysis were recorded on an
UPC2 apparatus which is part of the Integrated Screening Platform
of Toulouse (PICT, IBiSA). The work was performed within the
framework of the ‘Groupement Franco-Ukrainien en Chimie
in one portion. After stirring 1 h, the aldehyde 6a (68
mL,
0.4575 mmol, 1 equiv) was added and the mixture was stirred
overnight at rt. A saturated aqueous NH4Cl solution was added and
the aqueous layer was extracted with CH2Cl2. The combined or-
ganic layers were washed with brine, dried with MgSO4 and con-
centrated under reduced pressure. The residue was purified by
ꢀ
Moleculaire’ (GDRI) funded by the ‘Centre National de la Recherche
Scientifique’ (CNRS, France). The authors are grateful to the ukrai-
nian manager of the GDRI, Prof. Zoia Voitenko, Taras Chevtchenko
National University in Kiev. D. L. thanks the French Embassy in Kiev
for financial support. R. C. is indebted to the CNRS for half of
a teaching sabbatical in 2015e2016.
silica gel chromatography (pentane/Et2O 15:1) to give (þ)-15 as
20
a clear oil 114 mg (72%). [
a
]
D
þ8.3 (c¼7.5, CHCl3); 1H NMR
(300 MHz, CDCl3):
d
0.19 (s, 9H), 0.89 (t, J¼6.27 Hz, 3H), 1.20e1.45
(m, 20H), 1.54 (quin, J¼6.98 Hz, 2H), 2.23e2.35 (m, 3H), 5.14 (d,
J¼7.68 Hz, 1H); 13C{1H} NMR (75 MHz, CDCl3):
d
ꢁ0.4, 14.1, 19.3,
Supplementary data
22.7, 28.0, 28.8, 29.0, 29.3, 29.4, 29.6, 29.6, 29.6, 31.9, 52.9, 64.2,
Supplementary (Experimental details, procedures and charac-
terizations for new compounds, NMR spectra, chiral SFC chro-
matograms, crystallographic data, MTT tests for biological
evaluations.) data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2016.09.001.
69.7, 71.6, 83.1, 90.2, 100.7; IR (neat):
n
¼3357, 2955, 2923, 2853,
2669, 2257, 2179, 1710, 1622, 1465, 1424, 1409, 1376, 1292, 1250,
1228, 1115, 1036, 1010, 929, 898, 841, 760, 719, 700, 649, 623, 610,
563 cmꢁ1
;
HRMS-DCI (CH4) m/z [MþH]þ calcd for
C
22H37OSi:345.2614, found: 345.2610. A 89% ee was deduced from
the value measured for (þ)-4 by chiral SFC analysis.
References and notes
4.2.11. (ꢁ)-1-(Trimethylsilyl)nonadeca-1,4,6-triyn-3-ol ((ꢁ)-15). It
was obtained from the diyne 16 and the aldehyde 6a as a colorless
oil (120 mg, 75%) using (þ)-N-methylephedrine according to the
procedure described for the (þ)-15 enantiomer. The obtained an-
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alytical data for (ꢁ)-15 were identical to those described for the
20
(þ)-15 enantiomer, excepted for the optical rotation. [
a
]
ꢁ8.15
D
(c¼6.75, CHCl3). A 85% ee was deduced from the one measured by
chiral SFC analysis of (L)-4.
4.2.12. Hexadeca-1,3-diyne (16).27 To solution of 17 (300 mg,
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for 1 h. After complete consumption of the starting material (TLC
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J¼7.0, 1.2 Hz, 2H). 13C{1H} NMR (75 MHz, CDCl3):
d 14.2, 19.2, 22.8,
28.2, 29.0, 29.2, 29.5, 29.6, 29.8 (3C), 32.1, 64.5, 64.9, 68.7, 78.5. IR
(neat):
n
¼3312, 2922, 2852, 2298, 2226, 1465, 1425, 1377, 1323,
1208, 721, 608 cmꢁ1
.
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D. Listunov et al. / Tetrahedron 72 (2016) 6697e6704
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