Asymmetric synthesis and biological evaluation of natural or bioinspired cytotoxic C 2-symmetrical lipids with two terminal chiral alkynylcarbinol pharmacophores

Article abstract of DOI:10.1021/acs.joc.5b00494

Bidirectional syntheses of C₂-symmetrical lipids embedding two terminal alkynylcarbinol pharmacophores are reported. Naturally occurring chiral alkenylalkynylcarbinol units were generated using Pus procedure for enantioselective addition of terminal alkynes to aldehydes, allowing the first asymmetric synthesis of (3R,4E,16E,18R)-icosa-4,16-diene-1,19-diyne-3,18-diol, isolated from Callyspongia pseudoreticulata. Two synthetic analogues embedding the recently uncovered (S)-dialkynylcarbinol pharmacophore were secured using Carreiras procedure adapted to ynal substrates. The dramatic effect of the carbinol configuration on cytotoxicity was confirmed with submicromolar IC₅₀ values against HCT116 cells.

Full text of DOI:10.1021/acs.joc.5b00494

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pubs.acs.org/joc
Asymmetric Synthesis and Biological Evaluation of Natural or
Bioinspired Cytotoxic C2‑Symmetrical Lipids with Two Terminal
Chiral Alkynylcarbinol Pharmacophores
Dymytrii Listunov,†,‡,§,∥ Isabelle Fabing,∥ Nathalie Saffon-Merceron,⊥ Hafida Gaspard,∥
Yulian Volovenko,§ Valerie Maraval,*,†,‡ Remi Chauvin,*,†,‡ and Yves Genisson*,∥
́
́
†UPR CNRS 8241, LCC, Universite
́
de Toulouse, 205 route de Narbonne, F-31077 Toulouse, France
‡Universite
́
de Toulouse, Universite Paul Sabatier, INPT, F-31077 Toulouse, France
́
§Kiev National Taras Shevchenko University, 60 Volodymyrska Street, 01033 Kiev, Ukraine
∥UMR CNRS 5068, LSPCMIB, Universite
́
Paul Sabatier, 118 route de Narbonne, Toulouse, 31062 Cedex 9, France
⊥Institut de Chimie de Toulouse, ICT FR 2599, Universite
́
Paul Sabatier - Toulouse III, Toulouse 31062 Cedex 9, France
S
* Supporting Information
ABSTRACT: Bidirectional syntheses of C2-symmetrical lipids embedding
two terminal alkynylcarbinol pharmacophores are reported. Naturally
occurring chiral alkenylalkynylcarbinol units were generated using Pu’s
procedure for enantioselective addition of terminal alkynes to aldehydes,
allowing the first asymmetric synthesis of (3R,4E,16E,18R)-icosa-4,16-diene-
1,19-diyne-3,18-diol, isolated from Callyspongia pseudoreticulata. Two
synthetic analogues embedding the recently uncovered (S)-dialkynylcarbinol
pharmacophore were secured using Carreira’s procedure adapted to ynal
substrates. The dramatic effect of the carbinol configuration on cytotoxicity
was confirmed with submicromolar IC50 values against HCT116 cells.
INTRODUCTION
■
Certain acetylenic lipids constitute a family of natural
compounds that appear in marine sponges and combine
unusual structural features with a wide array of biological
activities.1 Apart from an exceptionally long unbranched
aliphatic skeleton, counting up to more than 40 carbon
atoms, the main characteristic of these functional lipids is the
recurrence of various chiral alkynylcarbinol units.2 Within this
family, a series of C2-symmetrical representatives constitutes a
remarkable class of inter-related compounds such as petrosynol
(1) and congeners (Figure 1).3 The two terminal alkenylalky-
nylcarbinol motifs of petrosynols are also found in the C30
backbone of other natural derivatives exhibiting either cyclized,
dehydroxylated, or reduced central cores, such as adociacety-
lenes4 (see adociacetylene B (2), Figure 1), dideoxypetrosy-
nols5 (see dideoxypetrosynol A (3), Figure 1), or duryne6 (4),
respectively (Figure 1). Such C2-symmetrical derivatives
notably display significant antitumor activities, with IC50 values
in the submicromolar range for dideoxypetrosynols,5 durynes,6
or the C46 parent fulvinol.7 In addition, the pro-apoptotic
activity of many of these natural products was demonstrated.8
Their intriguing chemical structures have prompted efforts in
synthetic chemistry during the past decade,2,9 but investigations
of the structure−activity relationships have only recently
emerged. While the presence of the terminal alkenylalkynyl-
carbinol ((3S,4E)-en-1-yn-3-ol) fragment was shown to be
essential to their cytotoxicity and pro-apoptotic behavior,10 the
Figure 1. Representative C2-symmetrical marine acetylenic lipids.
influence of the central core has not been described.2 To
delineate further pharmacological opportunities, however,
Received: March 18, 2015
Published: May 11, 2015
© 2015 American Chemical Society
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DOI: 10.1021/acs.joc.5b00494
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straightforward enantioselective routes to simplified structures
need to be developed.
Scheme 1. Synthesis of the Natural Product 3(S)-Eicos-4(E)-
en-1-yn-3-ol (8)
a
The first chemistry-driven systematic structure−activity study
of the chiral functional alkynylcarbinol fragment as a cytotoxic
pharmacophore was recently reported.11 This revealed the
remarkable influence of the absolute configuration of the
carbinol center on the antitumor activity, with the (R)-like
stereochemistry (in reference to the enantiomer of the natural
(3S,4E)-en-1-yn-3-ol pharmacophore shown in Figures 1 and
2) leading to the strongest potency. Additionally, novel
a
Reagents and conditions: (a) (i) Et2Zn, PhMe, reflux, (ii) (R)-9,
Ti(O-i-Pr)4, Et2O, rt; (b) see ref 11; (c) 1-naphthyl isocyanate,
DMAP, K2CO3, CH2Cl2, rt.
the 6,6′-positions was examined.19 Performing the asymmetric
alkynylation reaction of (E)-octadec-2-enal (10) with ligand
(R)-9 led to the expected carbinol (+)-11 in 85% yield, to be
compared with the 75% yield obtained using standard BINOL.
In view of determining the ee by chiral supercritical fluid
chromatography (SFC), the enantioenriched carbinol (+)-11
was first converted into the corresponding naphthyl carbamate
12 so as to maximize both UV detection and diastereo-
differentiation on the chiral stationary phase.11 Analytical chiral
SFC indicated an ee value of 81% for 12, comparable to what
was previously obtained with (R)-BINOL. The activated
BINOL 9 giving rise to a more efficient transformation leads
to prospects for further optimization of the Pu’s method.
A crystalline sample of the carbamate 12 proved suitable for
X-ray diffraction analysis, allowing determination of its absolute
configuration (see the Supporting Information, Figure S1).20
On the basis of a Flack parameter value of −0.08 (16), the
crystallographic data unambiguously indicates that an (S)-
configured alkenylalkynylcarbinol was generated from the
reaction with (R)-BINOL.
In the C2-symmetrical double-headed series, the bis-enal 13
required for the synthesis of 5 was prepared from commercially
available 1,12-dodecandiol through a four-step sequence
inspired from the two-step procedure described by Miyamo-
to.12b This method was modified in view of improving the ease
of purification of the bis-enal target 13. Recently, miyakosyne
A, a cytotoxic metabolite extracted from the marine sponge
Petrosia sp. and embedding two alkenylalkynylcarbinol moieties
as in 5, was also reported to be synthesized from a lipidic
dienal, the latter being efficiently obtained by a double-olefin
cross-metathesis process.21 The isolation of miyakosyne A was,
however, performed by chemoenzymatic resolution of a
mixture of isomers. In contrast, the preparation of 5 was
envisaged by direct enantioselective synthesis (Scheme 2).
The Zn-acetylide generated upon treatment of TIPS-
acetylene (7) with Et2Zn in refluxing toluene was reacted
with the bis-electrophile 13 in the presence of the chiral Lewis
acidic complex preformed from Ti(O-i-Pr)4 and (S)-BINOL in
Et2O (Scheme 2). The double adduct of expected structure
(R,R)-14 was isolated in 60% yield. Treatment with TBAF
finally delivered the targeted compound 5, which was thus
obtained in a 54% overall yield from the bis-enal 13, with
analytical data in agreement with those previously reported for
(R,R)-5.12 In order to determine the exact stereochemical
composition of the isolated stereoenriched sample of 5, a
Figure 2. Marine compound 5 and related generic target structure 6.
pharmacophore variants were envisaged, and the (3S)-1,4-
diyn-3-ol dialkynylcarbinol fragment was identified as both the
most active and the most synthetically accessible. These
findings originated from the implementation of reliable
methods for the preparation of enantioenriched alkynylcarbinol
fragments through enantiocontrolled addition of terminal
alkynes (so-called “asymmetric alkynylation”) onto enals or
ynals. The extension of this methodology to the preparation of
C2-symmetrical derivatives and the evaluation of their
antitumor activity are reported thereafter.
RESULTS AND DISCUSSION
■
The simple C2-symmetrical C20 product 5, isolated from
Callyspongia pseudoreticulata, was selected as a basis for the
study of related generic bis-dehydro representatives of type 6
(Figure 2).12 Originally isolated as the (3S,18S) stereo-
isomer,12a both enantiomers of 5 were also recently extracted
from Callyspongia sp.12b These enantiomers were prepared
through enzymatic kinetic resolution, and a series of related
compounds, including racemic analogues with different chain
lengths, were also reported for comparative cell viability studies.
The natural product 5 itself was first targeted. Taking
advantage of the ideal C2-symmetry of the molecule, a double-
elongation approach was envisaged to rapidly assemble the
functionalized C20 backbone in a stereocontrolled fashion.
Efficient methods to prepare alkenylalkynylcarbinol fragments
by asymmetric alkynylation of enals have appeared only
recently.13 Trost developed a prophenol/Me2Zn-based proce-
dure14 that was applied to a bidirectional enantioselective
synthesis of adociacetylene B.15 The Ti(O-i-Pr)4/BINOL-
catalyzed procedure reported by Pu for the asymmetric
alkynylation of aldehydes by in situ generated Zn-acetylide16
was here selected for the elaboration of the key 4(E)-en-1-yn-3-
ol moieties using TIPS-acetylene (7) as nucleophile.
Before exploring Pu’s method with a bis-electrophile en route
to 5, the reaction was first probed in the preparation of the
naturally occurring lipidic monocarbinol 3(S)-eicos-4(E)-en-1-
yn-3-ol (8) (Scheme 1).17 In view of generating a more Lewis
acidic Ti complex, the use of an activated BINOL ligand 918
bearing two highly electron-withdrawing triflone substituents in
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DOI: 10.1021/acs.joc.5b00494
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exact bis-dehydro analogue 6b of the natural C20 bis-alkenyl-
alkynylcarbinol 5 was secured in three steps and 48% overall
yield from the diol 18 by means of double bromination,
addition of lithium TMS-acetylide and desilylation (Scheme 3).
Scheme 2. Synthesis of Enantioenriched Double-Headed C2-
Symmetrical Natural Product 5
a
Scheme 3. Synthesis of the Diyne 17b Envisaged as a
a
Precursor of 6b
a
Reagents and conditions: (a) HBr, H2O, 48 h, 100 °C; (b) TMS-
acetylene, HMPA, n-BuLi, THF, −78 °C to rt; (c) K2CO3, THF−
MeOH (1:1), rt.
Treatment of the diynes 17a,b with Zn(OTf)2/Et3N in the
presence of (−)-N-methylephedrine (NME) as a chiral inducer
in CH2Cl2, followed by addition of the ynal 21, led to the bis-
alkynylated products (R,R)-22a,b in 85% yield (Scheme 4).
a
Reagents and conditions: (a) (i) Et2Zn, PhMe, reflux, (ii) 7, (S)-
Scheme 4. Synthesis of the Dehydro Analogues 6a,b of the
Natural Product 5
BINOL, Ti(O-i-Pr)4, Et2O, rt; (b) TBAF, THF, rt; (c) 1-naphthyl
isocyanate, DMAP, K2CO3, CH2Cl2, rt.
a
statistical mixture of all three stereoisomers (d/l/meso) of 14
was also prepared by addition of the lithium TIPS-acetylide
onto the bis-enal 13. The stereoisomeric mixture of alcohols
was converted into the corresponding mixture of bis-naphthyl
carbamates 15, which proved inseparable by chiral HPLC or
SFC. However, the d/l/meso statistical mixture (0.25:0.25:0.5)
of the desilylated bis-carbamate 16 could be resolved by means
of SFC (analysis on a Chiralpak IA-3 μm column eluted with
SC CO2/MeOH). A similar SFC analysis of the stereoenriched
mixture of 16 obtained by the Pu’s method with (S)-BINOL as
a chiral inducer indicated that the major (R,R) enantiomer was
formed in 94% ee, along with an equimolar amount of the meso
stereoisomer ((R,R)/(S,S)/meso = 48.7:1.4:49.9).
a
Reagents and conditions: (a) (−)-NME, Zn(OTf)2, Et3N, CH2Cl2,
rt; (b) K2CO3, THF−MeOH (1:1), rt; (c) 1-naphthyl isocyanate,
DMAP, K2CO3, CH2Cl2, rt.
For comparison, an ee of ca. 80% was previously observed for
the asymmetric addition of TIPS-acetylene 7 onto the C18
monoenal 10 under similar conditions.11 Although the
conditions are not strictly the same (regarding the structure
of the enal and the operating stoichiometry), one might assume
a comparable asymmetric induction in the course of the first
alkynylation of the bis-enal 13 toward the (R)-configured
monoadduct and deduce that the second alkynylation should
thus occur in a much higher diastereoisomeric excess from the
minor (S)-configured monoadduct (deSR = 70%) than from its
enantiomer (deRR = 8%, see the Supporting Information,
Scheme S1). A considerable mismatch effect by a factor of ca.
10 (eeR/deRR = 10) between (S)-BINOL and the (R)-
monoadduct intermediate could therefore be suggested.
Both enantiomers of the dehydro variants 6 of the natural
product 5 embedding two dialkynylcarbinol pharmacophore
moieties were then targeted. Considering the paucity of
reported methodologies for asymmetric alkynylation of ynals,
the recently adapted Carreira’s protocol22 for the enantiose-
lective preparation of simple lipidic dialkynylcarbinols11 was
envisaged from bis-terminal diyne substrates. The 1,9-
decadiyne (17a) was selected as a commercially available
precursor of the truncated C16 double-headed target 6a. The
diyne bis-nucleophile 17b required for the elaboration of the
The diols were then desilylated to afford (S,S)-6a,b, the
targeted dehydro analogues of 5. In order to determine the
stereoselectivity of the double-Carreira-type procedure, the bis-
carbinols (R,R)-22a,b were converted into the corresponding 1-
naphthyl carbamates (R,R)-23a,b. The (S,S) isomers of 22a,b
were also prepared in the same way using (+)-NME as a chiral
inducer, thus leading to (R,R)-6a,b after desilylation.
Conditions for the analytical resolution of a statistical d/l/
meso stereoisomeric mixture of 23a,b by chiral SFC (Chiralpak
AD-H 5 μm or IC-3 column, respectively, eluted with a SC
CO2/MeOH gradient) were first determined. Chiral analysis of
an enantioenriched sample of (S,S)-23a prepared from (S,S)-
22a indicated a 78% ee for the dl isomers and a dl/meso ratio of
62:38. Likewise, a 76% ee and a dl/meso ratio of 77:23 for
(R,R)-22b were indicated by chiral SFC analysis of the
corresponding stereoenriched bis-carbamate (R,R)-23b. On
the basis of previous studies, the (R,R) absolute configuration
was assigned to the major enantiomer formed in the presence
of (−)-NME.21
A crystalline sample of (S,S)-6b was found suitable for X-ray
diffraction analysis, allowing confirmation of the C2-sym-
metrical structure (Figure 3; for detailed crystallographic data,
see the Supporting Information, Table S1).23
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Scheme 5. Sequential Synthesis and Derivatization of the
a
Meso Isomer of 6b
Figure 3. Molecular view of the X-ray crystal structure of the bis-
dialkynylcarbinol 6b (Scheme 4), with thermal ellipsoids drawn at the
50% probability level. For clarity, hydrogen atoms (excepted on
asymmetric center and oxygen atom) are omitted.23
As in the case of 14, the relatively high proportion of the
meso stereoisomer of 22a,b reveals a lowest stereoinduction in
the course of the formation of the second carbinol center
compared to that of the first alkynylation. The decrease of the
meso/dl ratio vs the increase of the distance between the two
terminal reacting centers (dl/meso 62:38 for 22a vs dl/meso
84:16 for 22b) is consistent with such a mismatch effect. For a
given chain length (n = 8), the dl/meso ratio obtained for 22b
(84:16) is, however, higher than that previously observed for
the formation of 14 (50:50, Scheme 2), these two products
being obtained following two strategies of opposite electro-/
nucleophilic polarity (the aldehyde functions are indeed located
either at both ends of the lipidic chain of 13 for the synthesis of
14 or on the acetylenic unit of 21 for the synthesis of 22b).
This difference may be due to more facile intramolecular Zn-
chelation of the bis-enal 13 used in the preparation of 14, which
would alter the reactivity of its aldehyde electrophilic centers. It
is also incidentally correlated with the higher overall freedom
degree allowed by the CC bonds of the dielectrophile 13 as
compared with the CC bonds of the dinucleophile 17b.
In view of a selective synthesis of the meso stereoisomer of 6b
bearing two heterochiral alkynylcarbinol termini, a two-step
sequential route was also explored. Monoaddition of the diyne
17b onto the ynal 21 was selectively accomplished with 4 equiv
of (−)-NME and 1 equiv of electrophile only (Scheme 5). The
monoadduct (R)-24, thus secured in 85% yield, was then
converted to the 1-naphthyl carbamate (R)-25 for the
determination of the enantiomeric excess by chiral SFC
analysis. In agreement with previous studies on the adaptation
of the Carreira’s procedure for asymmetric alkynylation of
ynals, (−)-NME induced the formation of the (R) enantiomer
in 95% ee. Subsequent addition of (R)-24 onto 21 was run with
(+)-NME, affording the bis-adduct meso-22b in 70% yield. The
corresponding bis-carbamate meso-23b was then prepared,
allowing the measurement of a dl/meso ratio of 11:89 by chiral
SFC. From this ratio, a 82% de for the second alkynylation step
in favor of the (S)-configured dialkynylcarbinol fragment in
meso-22b can be inferred. Deprotection of meso-22b finally
delivered the bis-alkynylcarbinol target meso-6b.
a
Reagents and conditions: (a) (−)-NME, Zn(OTf)2, Et3N, CH2Cl2,
rt; (b) 1-naphthyl isocyanate, DMAP, K2CO3, CH2Cl2, rt; (c) 21,
(+)-NME, Zn(OTf)2, Et3N, CH2Cl2, rt; (d) K2CO3, THF−MeOH
(1:1).
carbinol center) displayed an equivalent cytotoxicity (IC50
≈
250 nM). It is noteworthy that the single-headed analogue of
(S,S)-6b was described to exhibit a higher cytotoxity with a IC50
value of 60−90 nM in the case of the optimized C12 length of
the alkyl chain.11 As reported in the single-headed series, a
dramatic influence of the enantiomeric series on cell viability
was observed,11 with (R,R)-6b being indeed almost 20 times
less cytotoxic (IC50 ≈ 4900 nM) than its enantiomer.
Consistently, the achiral stereoisomer meso-6b featuring both
(R)- and (S)-alkynylcarbinol termini displayed an intermediate
value of IC50 (470 nM). The truncated C16 representative
(S,S)-6a (IC50 ≈ 1000 nM) was also found to be four times less
efficient than (S,S)-6b, confirming the crucial importance of the
spacer length between the two pharmacophoric units.
CONCLUSION
■
In summary, the Pu and modified Carreira methods for
asymmetric alkynylation of enals and ynals were shown to be
efficient in the synthesis of C2-symmetrical doubled-headed
acetylenic lipids featuring two alkynylcarbinol pharmacophoric
units. In the monofunctional version of Pu’s method from
enals, the formation of an (S)-configured alkenylalkynylcarbinol
center using (R)-BINOL as a chiral inducer was demonstrated
by X-ray diffraction analysis. In the difunctional version,
double-induction effects were evidenced, and the method
allowed the first stereoselective double-elongation approach to
the marine compound 5. Preparation of the hitherto unknown
bis-dehydro analogues of 5 was also performed using the
previously disclosed modified Carreira’s method for ynal
substrates. Whereas a one-pot procedure directly afforded the
chiral C2-symmetrical d/l stereoisomers according to a
bidirectional strategy, a sequential two-step approach allowed
The naturally occurring acetylenic lipid 5 and the two
dehydro analogues 6a,b were then submitted to cytotoxicity
assays. For the sake of comparison with previous studies, the
human colon carcinoma HCT116 was selected as a
representative cell line.11 An IC50 value of 230 nM at 96 h
was measured for the sample of (R,R)-5. This value is
consistent with what has been previously reported for natural
or synthetic (R,R)-5 (IC50 at 48 h against TR-LE cells of 110
nM and 350 nM).12b The unnatural bis-dialkynylcarbinol (S,S)-
6b, dehydro analogue of the C20 natural product (R,R)-5 (the
opposite configuration being due to an inversion of the CIP
priority between the alkenyl and the alkynyl substituents of the
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a THF/MeOH (1:1) mixture (5 mL) containing K2CO3 (6 equiv) was
stirred at rt for 24 h. Then H2O was added, and the mixture was
extracted with Et2O. After standard treatment of the gathered organic
layers, the crude product was submitted to chromatography over SiO2
(pentane/Et2O, 8:2) to give the desilylated compound as a white
powder.
the preparation of the meso isomer. Biological evaluations
revealed that the double-headed acetylenic lipids (R,R)-5 and
(S,S)-6b display potent cytotoxicity against HCT116 cells with
IC50 values in the submicromolar range. For the non-natural
bis-dialkynylcarbinol compounds 6b, a dramatic influence of
the configuration of the asymmetric carbinol center was
observed, the eutomer corresponding to the (R)-like series
(in reference to the (3R,4E)-en-1-yn-3-ol natural alkenyl-
alkynylcarbinol pharmacophore). The present results thus open
prospects of developments in total synthesis, asymmetric
methodology, and multivalent pharmacophore design.
(3R,4E,16E,18R)-Icosa-4,16-dien-1,19-diyne-3,18-diol ((R,R)-5).
TBAF (270 μL of a 1 M solution in THF, 4 equiv) was added to
14 (41.2 mg, 0.067 mmol) in solution in THF (0.5 mL) at 0 °C and
the resulting mixture was stirred at rt for 2 h. A saturated aqueous
NH4Cl solution was added, and the mixture was extracted with Et2O.
After standard treatment of the gathered organic layers, the crude
product was submitted to chromatography over SiO2 to give 5 (18 mg,
90%) as a white powder: Rf 0.3 (pentane/Et2O, 3:2); [α]D20 − 26.4 (c
EXPERIMENTAL SECTION
1
■
2.5, CHCl3); H NMR (300 MHz, CDCl3) δ 1.01−1.54 (m, 8H),
General Experimental Details. The following solvents and
reagents were dried and freshly distilled prior to use: CH2Cl2 (from
CaH2), Et2O, THF (from sodium/benzophenone). Analytical thin-
layer chromatography (TLC) was performed with silica gel 60 F254
precoated plates. Chromatograms were observed under UV light and/
or were visualized by heating plates dipped in 10% phosphomolybdic
acid in EtOH. Column chromatography was carried out with 35−70
mm flash silica gel. NMR spectroscopic data were obtained with
instruments working at 300 or 400 MHz for 1H nuclei. Chemical shifts
(δ) are reported in ppm relative to the residual solvent peak; J values
are given in hertz. 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
device (4 cm−1 of resolution, 16 scans) equipped with a DTGS
detector. Optical rotations were measured on a JASCO P-2000
polarimeter; [α]D values are given in deg dm−1 cm−3 g−1. SFC (CO2)
chiral resolutions were run on either a Chiralpak IA-3 (4.6 × 100 mm),
Chiralpak IC-3 (4.6 × 100 mm), or Chiralpak AD-H 5 μm (4.6 × 250
mm) column.
1.95−2.15 (m, 2H), 2.55 (d, J 2.2 Hz, 1H), 4.82 (ddd, J 1.1, 2.2, 6.2
Hz, 1H), 5.59 (ddt, J 1.5, 6.1, 15.3 Hz, 1H), 5.90 ppm (dtd, J 1.2, 6.8,
15.0 Hz, 1H); 13C{1H} NMR (75 MHz, CDCl3) δ 28.8, 29.1, 29.4,
29.5, 31.9, 62.7, 74.0, 83.4, 128.4, 134.5 ppm; IR (neat) ν 3271, 3030,
2919, 2849, 2223, 2111, 2049, 1671, 1466, 1430, 1397, 1263, 1190,
1136, 1085, 1038, 1009, 968, 962, 923, 900, 889, 843, 809, 719, 676,
665, 656, 589, 572, 557, 549 cm−1; MS-DCI (NH3) m/z 320 (100, [M
+ NH4]+). A 94% ee and 50:50 dl/meso ratio was estimated for (R,R)-5
from the chiral SFC analysis of the corresponding bis-1-naphthylcar-
bamate (R,R)-16 (vide infra).
(3S,14S)-Hexadeca-1,4,12,15-tetrayne-3,14-diol ((S,S)-6a). Com-
pound (S,S)-6a was obtained from (R,R)-22a as a viscous oil (75 mg,
80%) according to general procedure D: Rf 0.3 (pentane/Et2O, 1:1);
[α]D20 + 14 (c 0.7, CHCl3); 1H NMR (400 MHz, CDCl3) δ 1.32−1.46
(m, 4H), 1.46−1.61 (m, 4H), 2.23 (td, J 2.1, 7.0 Hz, 4H), 2.54 (m,
4H), 5.10 ppm (dt, J 2.2, 4.6 Hz, 2H); 13C{1H} NMR (100 MHz,
CDCl3) δ 18.5, 27.9, 28.1, 52.1, 72.2, 81.5, 85.8 ppm; IR (neat) ν
3267, 2945, 2842, 2298, 2216, 2122, 1485, 1455, 1416, 1332, 1322,
1318, 1294, 1119, 1008, 956, 934, 799, 758, 722, 685, 661, 578, 495
cm−1; HRMS-DCI (CH4) m/z [M − H2O]+ calcd for C16H17O
225.1279, found 225.1284.
General Procedures. General Procedure A: Preparation of the
1-Naphthyl Carbamates. 1-Naphthyl isocyanate (1.5 equiv/hydroxyl
group), DMAP (0.1 equiv), and alcohol (1 equiv) were taken into an
anhydrous CH2Cl2/pentane (1:1) mixture (1 mL). The reaction
mixture was stirred at rt overnight. The solvent was evaporated off, and
the crude product was purified by chromatography over SiO2
(pentane/Et2O, 8:2) to give the expected 1-naphthyl carbamate.
General Procedure B: Preparation of the Stereoisomeric Mixtures
of Bis-dialkynyldiols. n-Butyllithium (1.6 M solution in hexanes, 2.2
equiv) was added to a solution of diyne (1 equiv) in anhydrous THF
(10 mL) at −78 °C under Ar atmosphere, and the reaction mixture
was stirred at this temperature for 30 min. A solution of 3-
(trimethylsilyl)propiolaldehyde (21) (2.2 equiv) in THF (1 mL)
was then added, and the reaction mixture was stirred for 4 h at −78
°C. After addition of an NH4Cl saturated aqueous solution, the
reaction mixture was partitioned between brine and Et2O and the
aqueous phase extracted with Et2O. After standard treatment of the
gathered organic layers, the crude product was purified by
chromatography over SiO2 (pentane/Et2O, 8:2) to give stereoisomeric
mixtures of compounds (70−90% yield) as colorless oils. These
stereoisomeric mixtures gave analytical data identical to that of their
(R,R), (S,S), or meso stereoisomers, except for their optical rotation.
General Procedure C: Enantioselective Synthesis of Bis-
dialkynylcarbinols. A flask was charged with Zn(OTf)2 (8 equiv)
and (+)- or (−)-N-methylephedrine (8 equiv) and purged with dry
argon for 15 min. To the flask were added anhydrous CH2Cl2 (15 mL)
and triethylamine (8 equiv). The resulting mixture was vigorously
stirred for 2 h at rt. Then the diyne (1 equiv, in solution in anhydrous
CH2Cl2) was added in one portion. After another 1 h of stirring, the 3-
(trimethylsilyl)propiolaldehyde (21) (4 equiv) was added, and then
the mixture was stirred at rt overnight. A saturated aqueous NH4Cl
solution was added, and the mixture was extracted with CH2Cl2. After
standard treatment of the gathered organic layers, the crude product
was submitted to chromatography over SiO2 (pentane/Et2O, 8:2) to
give the desired compound.
(3R,14R)-Hexadeca-1,4,12,15-tetrayne-3,14-diol ((R,R)-6a). Com-
pound (R,R)-6a was obtained from (S,S)-22a as a viscous oil (70 mg,
75%) according to general procedure D. (R,R)-6a gave analytical data
20
identical to that of its enantiomer except for its optical rotation. [α]D
−12 (c 0.7, CHCl3).
(3S,18S)-Icosa-1,4,16,19-tetrayne-3,18-diol ((S,S)-6b). Compound
(S,S)-6b was obtained from (R,R)-22b as a white powder (60 mg,
75%) according to general procedure D: Rf 0.35 (pentane/Et2O, 8:2);
mp 54 °C; [α]D20 − 5.0 (c 6.9, CHCl3); 1H NMR (300 MHz, CDCl3)
δ 1.10−1.42 (m, 12H), 1.42−1.63 (m, 4H), 2.20 (td, J 2.1, 7.1 Hz,
4H), 2.53 (d, J 2.3 Hz, 2H), 2.58 (d, J 7.0 Hz, 2H), 2.09 (dd, J 2.0, 4.8
Hz, 2H); 13C{1H} NMR (75 MHz, CDCl3) δ 18.7 (2C), 28.3 (2C),
28.8 (2C), 29.1 (2C), 29.4 (2C), 52.2 (2C), 72.3 (2C), 77.1 (2C),
81.6 (2C), 86.1 (2C) ppm; IR (neat) ν 3274, 2922, 2848, 2292, 2226,
2118, 1497, 1461, 1426, 1352, 1332, 1314, 1284, 1139, 1011, 976, 930,
797, 752, 724, 692, 659, 576, 499 cm−1; HRMS-DCI (CH4) m/z [M +
H]+ calcd for C20H27O2 299.2011, found 299.2017. Selected crystal
data for 6b: C20H26O2, M = 298.41, monoclinic, space group P 21, a =
4.5889(2) Å, b = 46.758(2) Å, c = 8.8264(5) Å, V = 1829.68(15) Å3, Z
= 4, 12767 reflections collected (6915 independent, Rint = 0.0312), R
[I > 2σ(I)] = 0.1027, wR2 [all data] = 0.2845, largest difference peak
and hole = 0.390 and −0.407 e Å−3.
(3R,18R)-Icosa-1,4,16,19-tetrayne-3,18-diol ((R,R)-6b). Compound
(R,R)-6b was obtained as white powder (75 mg, 70%) from (S,S)-22b
according to general procedure D. Compound (R,R)-6b gave
analytical data identical to that of its enantiomer except for its optical
20
rotation. [α]D + 5.8 (c 7.1, CHCl3).
(3R,18S)-Icosa-1,4,16,19-tetrayne-3,18-diol (meso-6b). Com-
pound meso-6b was obtained as a white powder (50 mg, 70%) from
meso-22b according to general procedure D: Rf 0.35 (pentane/Et2O,
1
8:2); H NMR (400 MHz, CDCl3) δ 1.28 (s, 8H), 1.37 (s, 4H), 1.52
(ddt, J 6.5, 7.5, 8.8 Hz, 4H), 2.18 (d, J 7.4 Hz, 2H), 2.23 (td, J 2.1, 7.1
Hz, 4H), 2.55 (d, J 2.3 Hz, 2H), 5.10 (dq, J 2.2, 7.5 Hz, 2H); 13C{1H}
NMR (101 MHz, CDCl3) δ 18.8 (2C), 28.4 (2C), 28.9 (2C), 29.2
General Procedure D: Deprotection of the Silylated Bis-
dialkynylcarbinols. A solution of the silylated precursor (1 equiv) in
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(2C), 29.5 (2C), 52.4 (2C), 72.4 (2C), 77.1 (2C), 81.6 (2C), 86.3
(2C). IR (neat) ν 3271, 2926, 2842, 2293, 2224, 2119, 1494, 1465,
1428, 1351, 1335, 1312, 1281, 1135, 1013, 971, 929, 795, 754, 728,
694, 657, 578, 497 cm−1; HRMS-DCI (CH4) m/z [M + H]+ calcd for
C20H27O2 299.2011, found 299.2015.
washed with DCM (20 mL). The filtrate was concentrated in vacuo.
Purification by flash chromatography (PE/Et2O 8:2) gave 13 (395 mg,
80%) as a clear oil. The physical data and NMR spectra were in
agreement to a previously described in literature.12b
[(3R,18R)-3,18-dihydroxy-20-[tris(propan-2-yl)silyl]icosa-4,16-
dien-1,19-diyn-1-yl]tris(propan-2-yl)silane ((R,R)-14). A mixture of
(triisopropylsilyl)acetylene (7) (360 μL, 1.6 mmol, 8 equiv) and Et2Zn
(1.45 mL of a 1.1 M solution in toluene, 8 equiv) was held at reflux
under N2 atmosphere for 1 h before being cooled to rt. Then (S)-
BINOL (45 mg, 0.8 equiv) and Ti(O-i-Pr)4 (118 μL, 2 equiv) in
solution in anhydrous Et2O (2 mL) were added. After the mixture was
stirred at rt for 1 h, bis-enal 13 (50 mg, 0.2 mmol) in solution in
anhydrous Et2O (1 mL) was added, and the reaction was allowed to
stand with stirring at rt overnight. A saturated aqueous NH4Cl solution
was added to the mixture, which was then extracted with Et2O. After
standard treatment of the collected organic layers the crude product
was submitted to chromatography over SiO2 (petroleum ether/Et2O,
8:2) to give 14 as a colorless oil (74 mg, 60%): Rf 0.3 (petroleum
ether/Et2O, 8:2); [α]D20 − 28.0 (c 6.8, CHCl3); 1H NMR (300 MHz,
CDCl3) δ 1.08 (s, 42H), 1.18−1.47 (m, 16H), 1.83 (s, 2H), 2.06 (q, J
6 Hz, 4H), 4.84 (d, J 6 Hz, 2H), 5.60 (ddt, J 1.4, 5.8, 15.3 Hz, 2H),
5.94 ppm (dtd, J 1.3, 6.8, 15.1 Hz, 2H); 13C{1H} NMR (75 MHz,
CDCl3) δ 11.3 (6C), 18.7 (12C), 29.1 (2C), 29.2 (2C), 29.6 (2C),
29.7 (2C), 32.1 (2C), 63.5 (2C), 87 (2C), 107.1 (2C), 129.1 (2C),
134.3 (2C) ppm; IR (neat) ν 3600, 3314, 2924, 2893, 2864, 2757,
2724, 2247, 2170, 1728, 1668, 1462, 1383, 1366, 1302, 1244, 1088,
1074, 1017, 996, 965, 907, 882, 812, 733, 674, 659, 619, 578, 550
cm−1; HRMS-DCI (CH4) m/z [M + H]+ calcd for C38H71O2Si2
615.4966, found 615.4993.
(3S,4E)-1-[Tri(propan-2-yl)silyl]icos-4-en-1-yn-3-ol ((S)-11). A mix-
ture of (triisopropylsilyl)acetylene (7) (137 mg, 168 μL, 4 equiv) and
Et2Zn (0.68 mL of a 1.1 M solution in toluene, 4 equiv) was held at
reflux under N2 atmosphere for 1 h before being cooled to rt. Then
(R)-9 (41 mg, 0.4 equiv) and Ti(O-i-Pr)4 (53 mg, 1 equiv) in solution
in anhydrous Et2O (2 mL) were added. After the mixture was stirred at
rt for 1 h, 10 (50 mg, 0.19 mmol) was added in solution in anhydrous
Et2O (1 mL), and the reaction was stirred at rt overnight. A saturated
aqueous NH4Cl solution was added to the mixture before extraction
with Et2O. After standard treatment of the collected organic layers, the
crude product was submitted to chromatography over SiO2
(petroleum ether/Et2O, 20:1) to give (S)-11 (70 mg, 85%) as a
colorless oil. The physical data and NMR spectra are in accord with
those previously described in the literature.11 A 81% ee was estimated
for (S)-11 on the basis of the chiral SFC analysis of the corresponding
1-naphthyl carbamate (S)-12 (vide infra).
(3S,4E)-1-[Tris(propan-2-yl)silyl]icos-4-en-1-yn-3-yl N-(Naphtha-
len-1-yl)carbamate ((S)-12). Compound (S)-12 (25 mg, 60%) was
obtained as a yellow viscous solid from (S)-11 according to general
procedure A. The physical data and NMR spectra are in accord with
those previously described in the literature.11 Chiral SFC analysis:
Chiralpak AD-H 5 μm (4.6 × 250 mm), SC CO2 + 10% MeOH, 4
mL/min, 35 °C, 110 bar, UV 220 nm, tR (R) 7.5 min, tR (S) 4.7 min
(see the Supporting Information).
(2E,14E)-Hexadeca-2,14-dienedial (13). To a solution of 1,12-
dodecanedial12b (1 g, 5 mmol, 1 equiv) in toluene (80 mL) was added
ethyl (triphenylphosphoranylidene)acetate (4.18 g, 12 mmol, 2.4
equiv), and the reaction mixture was heated to reflux for 6 h. The
reaction mixture was cooled to rt, and toluene was evaporated under
reduced pressure. The residue was cooled to 0 °C diluted with Et2O
and the mixture filtered through a sintered glass funnel to remove the
triphenylphosphinoxide. The organic layer was evaporated under
reduced pressure to afford the crude product as a mixture of (E,E)/
(E,Z)-isomers (9:1), which was purified by column chromatography
(pentane/EtOAc, 9:1) to give 1,16-diethyl (2E,14E)-hexadeca-2,14-
dienedioate (1.02 g, 60%) as a colorless liquid. The physical data and
NMR spectra were in agreement with the literature.24
The bis-ester 1,16-diethyl (2E,14E)-hexadeca-2,14-dienedioate (1 g,
2.96 mmol, 1.0 equiv) was dissolved in Et2O (50 mL) and cooled to
−78 °C. DIBAL-H (1 M solution in toluene) (14.8 mL, 14.8 mmol, 5
equiv) was added dropwise, and the reaction mixture was stirred at
−78 °C for 4 h, before warming to rt, and further stirred for 1 h. The
solution was cooled to 0 °C, quenched by the addition of a saturated
solution of NH4Cl (10 mL), and warmed to rt with vigorous stirring
over 1 h, producing a white precipitate. The precipitate was filtered
through a pad of Celite and washed with Et2O (100 mL). The filtrate
was then dried (MgSO4) and concentrated in vacuo. Purification was
carried out by flash column chromatography (Et2O/PE, 2:1) to deliver
product (2E,14E)-hexadeca-2,14-diene-1,16-diol (600 mg, 80%) as a
white powder. The physical data and NMR spectra were in agreement
with the literature.25
(2E,14E)-16-Hydroxyhexadeca-2,14-dienal and (2E,14E)-hexade-
ca-2,14-dienedial 13. To a solution of (2E,14E)-hexadeca-2,14-diene-
1,16-diol (1 g, 3.94 mmol) in DCM (50 mL) at 0 °C was added MnO2
(2.27 g, 25.5 mmol) in one portion and the reaction mixture was
stirred at rt until complete consumption of the starting diol (TLC
monitoring, ca. 3−4 h). The MnO2 was filtered off and the solvent was
evaporated. Purification by flash chromatography (PE/Et2O, 8:2) gave
(2E,14E)-hexadeca-2,14-dienedial (13) (198 mg, 20% yield) and
mono-oxidized compound (2E,14E)-16-hydroxyhexadeca-2,14-dienal-
(690 mg, 70%). To a solution of the latter (500 mg, 1.98 mmol) in
DCM (50 mL) at 0 °C was added PCC (1.28 g, 5.95 mmol, 3 equiv)
in one portion, followed by silica (6 g) and the mixture was stirred at rt
until complete consumption of the starting material (TLC monitoring
3−4 h). The precipitate was filtered through a pad of Celite and
(4E,16E)-18-{[(Naphthalen-1-yl)carbamoyl]oxy}-1,20-bis[tris-
(propan-2-yl)silyl]icosa-4,16-dien-1,19-diyn-3-yl N-(naphthalen-1-
yl)carbamate ((R,R)-15). Compound (R,R)-15 (20 mg, 65%) was
obtained as a yellow sticky solid from (R,R)-14 according to general
procedure A: Rf 0.5 (petroleum ether/Et2O, 8:2); 1H NMR (300
MHz, CDCl3) δ 1.10 (s, 21H), 1.35 (m, 8H), 2.00−2.17 (m, 2H), 5.65
(dd, J 6.2, 15.1 Hz, 1H), 5.91−6.04 (m, 1H), 6.13 (dt, J 6.8,14.3 Hz,
1H), 6.98 (s, 1H), 7.38−7.59 (m, 3H), 7.67 (d, J 8.2 Hz, 1H), 7.75−
8.06 ppm (m, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 11.3, 18.8,
28.9, 29.3, 29.6, 29.8, 32.1, 66.2, 77.2, 88.8, 103.2, 120.6, 125.2, 125.3,
126.0, 126.1, 126.4, 128.9, 132.5, 134.2, 137.2, 153.3 ppm; IR (neat) ν
3336, 3227, 3053, 2925, 2863, 2177, 1842, 1709, 1647, 1598, 1580,
1534, 1495, 1463, 1403, 1382, 1366, 1346, 1258, 1206, 1176, 1100,
1067, 1027, 997, 964, 919, 882, 829, 790, 769, 730, 678, 566, 558, 529
cm−1; HRMS-DCI (CH4) m/z [M]+ calcd for C60H84N2O4Si2
952.5987, found 952.5970.
(4E,16E)-18-{[(Naphthalen-1-yl)carbamoyl]oxy}icosa-4,16-dien-
1,19-diyn-3-yl N-(Naphthalen-1-yl) Carbamate ((R,R)-16). Com-
pound (R,R)-16 (15 mg, 60%) was obtained from (R,R)-5 as yellow
sticky solid according to general procedure A: Rf 0.3 (pentane/Et2O,
1
3:1); H NMR (300 MHz, CDCl3) δ 1.21−1.32 (m, 8H), 1.42−1.49
(m, 2H), 2.12 (q, J 7.1 Hz, 1H), 2.66 (d, J 2.2 Hz, 1H), 5.66 (dd, J 6.8,
15.0 Hz, 1H), 5.97 (ddd, J 1.1, 2.2, 6.3 Hz,1H), 6.12 (dd, J 6.8, 15.3
Hz, 1H), 7.03 (s, 1H), 7.49−7.55 (m, 3H), 7.69 (d, J 8.2 Hz, 1H),
7.94−7.89 ppm (m, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 28.6,
29.2, 29.4, 29.5, 29.7, 32.0, 65.4, 75.1, 77.2, 80.0, 120.3, 124.5, 125.1,
125.8, 126.0, 126.3, 128.8, 132.2, 134.1, 137.5, 152.9 ppm; IR (neat) ν
3297, 3051, 2924, 2852, 2124, 1712, 1629, 1598, 1578, 1536, 1496,
1465, 1437, 1402, 1373, 1346, 1256, 1207, 1176, 1100, 1068, 1026,
1000, 964, 874, 791, 769, 731, 665, 639, 571, 489 cm−1; HRMS-DCI
(CH4) m/z [M-H]+ calcd for C42H45N2O4 641.3379, found 641.3400.
Chiral SFC analysis: Chiralpak IA-3 (4.6 × 100 mm), SC CO2 + 25%
MeOH, 2.7 mL/min, 40 °C, 130 bar, UV 220 nm, tR 14.99 (R,R),
17.13 (meso) and 18.71 (S,S) min (see the Supporting Information).
Tetradeca-1, 13-diyne (17b). To a solution of 20 (2.0 g, 5.99
mmol) in a mixture of THF/MeOH (1:1) (100 mL) at 0 °C was
added K2CO3 (4.95 g, 35.9 mmol, 6 equiv) in one portion. The
reaction mixture was stirred at rt overnight, then diluted with a
saturated aqueous NH4Cl solution (200 mL) and extracted with Et2O.
The combined organic layers were washed with brine and dried with
Na2SO4. The crude product was recrystallized from ethanol to give
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diyne 17b (910 mg, 80%) as a white powder. The physical data and
NMR spectra were in agreement with the literature.26
1,10-Dibromodecane (19). Compound 19 was obtained (5.0 g,
80%) by reaction of diol 18 with HBr at 100 °C according to a
previously described procedure.27
with Zn(OTf)2 (920 mg, 2.53 mmol, 8 equiv) and (+)-N-
methylephedrine (453 mg, 2.53 mmol, 8 equiv) and purged with
dry argon for 15 min. To the flask were added anhydrous CH2Cl2 (10
mL) and triethylamine (256 mg, 2.53 mmol, 8 equiv). The resulting
mixture was vigorously stirred for 2 h at rt. Then alkyne (R)-24 (100
mg, 0.36 mmol, 1 equiv, solution in dried CH2Cl2) was introduced by
syringe in one portion. After another 1 h of stirring the 3-
(trimethylsilyl)propiolaldehyde (21) (160 mg, 1.24 mmol, 4 equiv)
was added and the mixture was stirred at rt overnight. A saturated
aqueous NH4Cl solution was added, and the mixture was extracted
with CH2Cl2. After standard treatment of the collected organic layers,
the crude product was submitted to chromatography over SiO2
(pentane/Et2O, 8:2) to give a colorless oil meso-22b (100 mg,
1,14-Bis(trimethylsilyl)tetradeca-1, 13-diyne (20). Trimethylsilyla-
cetylene (6.56 g, 0.0668 mol, 4.0 equiv) was dissolved in THF (100
mL) and cooled to −78 °C. To this solution was added dropwise n-
BuLi (27 mL of 2.5 M solution in hexanes, 0.0668 mol, 4.0 equiv). The
reaction mixture was stirred at −78 °C for 30 min and then warmed to
0 °C for 50 min. The anion obtained was transferred by cannula to a
solution of dibromide 19 (5 g, 0.0167 mol, 1.0 equiv) in THF (50 mL)
at rt. Freshly distilled HMPA (48 g, 0.267 mol, 16.0 equiv) was then
added, and the brown reaction mixture was stirred at rt for 12 h before
being quenched with 3 N HCl. The aqueous layer was extracted with
Et2O, and the organic layer was separated and washed sequentially
with saturated NaHCO3 and brine. Then the combined organic layers
were dried over MgSO4 and concentrated. The crude product was
purified by flash chromatography on SiO2 (pentane) to give 20 (4.2 g,
75%). The physical data and NMR spectra are in accordance with the
literature.27
1
70%): Rf 0.35 (pentane/Et2O, 8:2); H NMR (300 MHz, CDCl3) δ
0.19 (s, 18H), 1.18−1.42 (m, 12H), 1.45−1.61 (m, 4H), 2.15 (d, J 7.2
Hz, 2H), 2.22 (td, J 2.1, 7.2 Hz, 4H), 5.09 (dt, J 2.0, 7.2 Hz, 2H);
13C{1H} NMR (101 MHz, CDCl3) δ −0.1 (6C), 18.9 (2C), 28.4
(2C), 29.0 (2C), 29.2 (2C), 29.6 (2C), 52.9 (2C), 77.4 (2C), 86.0
(2C), 89.0 (2C), 102.7 (2C). IR (neat) ν 3520, 3006, 2925, 2860,
2652, 2289, 2229, 2175, 1953, 1709, 1624, 1460, 1425, 1410, 1363,
1320, 1298, 1253, 1146, 1024, 959, 841, 750, 732, 708, 660, 641, 611,
599, 569, 509 cm−1; HRMS-ES m/z [M + Na]+ calcd for
C26H42O2Si2Na 465.2621, found 465.2617. A 89:11 meso/dl ratio
was estimated for meso-22b on the basis of the chiral SFC analysis of
the corresponding bis-1-naphthyl carbamate meso-23b (vide infra).
14-{[(Naphthalen-1-yl)carbamoyl]oxy}-1,16-bis(trimethylsilyl)-
hexadeca-1,4,12,15-tetrayn-3-yl N-(Naphthalen-1-yl) Carbamate
((S,S)-23a). Compound (S,S)-23a was obtained from 22a as a yellow
semisolid (30 mg, 65%) according to general procedure A: Rf 0.4
(petroleum ether/Et2O, 8:2); 1H NMR (404 MHz, CDCl3) δ 0.23 (s,
18H), 1.40−1.50 (m, 4H), 1.52−1.60 (m, 4H), 2.28 (td, J 2.1, 6.8 Hz,
4H), 6.20 (td, J 2.1, 1.3 Hz, 2H), 7.10 (s, 2H), 7.44−7.59 (m, 6H),
7.65−7.75 (m, 2H), 7.83−7.96 ppm (m, 6H); 13C{1H} NMR (101
MHz, CDCl3) δ − 0.3 (6C), 18.7 (2C), 27.9 (2C), 28.2 (2C), 55.1
(2C), 74.5 (2C), 86.8 (2C), 90.4 (2C), 98.9 (2C), 120.3, 125.2, 125.9,
126.0, 126.3, 128.8, 132.0, 134.0, 152.4 (2C) ppm; IR (neat) ν 3328,
3053, 2935, 2859, 2308, 2243, 2186, 1931, 1714, 1629, 1598, 1579,
1537, 1496, 1463, 1437, 1403, 1372, 1346, 1308, 1291, 1250, 1204,
1175, 1155, 1098, 1067, 1029, 996, 953, 909, 843, 791, 760, 731, 702,
657, 641, 629, 608, 563, 548 cm−1; HRMS-DCI (CH4) m/z [M + H]+
calcd for C44H48N2O4Si2 724.3153, found 724.3181. Chiral SFC
analysis: Chiralpak AD-H 5 μm (4.6 × 250 mm), SC CO2 + 20%
MeOH, 4 mL/min, 35 °C, 110 bar, UV 220 nm, tR 7.22 (S,S), 9.02
(meso) and 10.5 (R,R) min (see the Supporting Information).
18-{[(Naphthalen-1-yl)carbamoyl]oxy}-1,20-bis(trimethylsilyl)-
icosa-1,4,16,19-tetrayn-3-yl N-(Naphthalen-1-yl) Carbamate ((R,R)-
23b). Compound (R,R)-23b was obtained from 22b as a yellow waxy
solid (25 mg, 50%) according to general procedure A: Rf 0.4
(petroleum ether/Et2O, 8:2); 1H NMR (300 MHz, CDCl3) δ 0.24 (s,
18H), 1.23−1.44 (m, 12H), 1.44-1.60 (m, 4H), 2.25 (td, J 7.1, 2.1 Hz,
4H), 6.19 (t, J 2.1 Hz, 2H), 7.07 (s, 2H), 7.41-7.57 (m, 6H), 7.62−
7.74 (m, 2H), 7.80−8.00 ppm (m, 6H); 13C{1H} NMR (75 MHz,
CDCl3) δ − 0.2, 19.0, 28.3, 29.0, 29.2, 29.6, 55.3, 74.5, 87.2, 90.6, 99.1,
120.4, 125.4, 125.9, 126.2, 126.5, 128.9, 132.2, 134.2, 152.5 ppm; IR
(neat) ν 3301, 3060, 2958, 2928, 2855, 2242, 2186, 1943, 1732, 1699,
1659, 1630, 1599, 1551, 1504, 1465, 1435, 1405, 1393, 1374, 1346,
1304, 1275, 1246, 1198, 1177, 1164, 1119, 1101, 1067, 1027, 996, 954,
932, 902, 843, 792, 770, 732, 712, 701, 650, 590, 561 cm−1; HRMS-
DCI (CH4) m/z [M-Si(CH3)3]+ calcd for C45H47N2O4Si: 707.3305,
found 707.3307. Chiral SFC analysis: Chiralpak IC 3 μm (4.6 × 100
mm), SC CO2 + 20% MeOH, 2.5 mL/min, 35 °C, 130 bar, UV 220
nm, tR 9.45 (S,S), 9.68 (meso) and 9.89 (R,R) min (see the Supporting
Information).
[(3S,14S)-3,14-Dihydroxy-16-(trimethylsilyl)hexadeca-1,4,12,15-
tetrayn-1-yl]trimethylsilane ((S,S)-22a). Compound (S,S)-22a was
obtained from 17a and 21 as a colorless oil (358 mg, 90%) according
to general procedure C using (+)-N-methylephedrine: Rf 0.3
20
1
(pentane/Et2O, 8:2); [α]D − 1.75 (c 2.3, CHCl3); H NMR (300
MHz, CDCl3) δ 0.19 (s, 18H), 1.40−1.47 (m, 4H), 1.51−1.60 (m,
4H), 2.17 (d, J 6 Hz, 2H), 2.26 (td, J 2.1, 7 Hz, 4H), 5.12 ppm (dt, J
2.1, 7.3 Hz, 2H); 13C{1H} NMR (75 MHz, CDCl3) δ −0.17 (6C),
18.7 (2C), 28.1 (2C), 28.3 (2C), 52.8 (2C), 77.6 (2C), 85.6 (2C),
88.9 (2C), 102.7 (2C) ppm; IR (neat) ν 3328, 3276, 2931, 2852, 2682,
2351, 2292, 2226, 2120, 1630, 1498, 1461, 1426, 1359, 1305, 1293,
1207, 1139, 1018, 933, 796, 692, 667, 604, 540, 518, 462 cm−1;
HRMS-DCI (CH4) m/z [M + H]+ calcd for C22H34O2Si2 386.2097,
found 386.2080. A 78% ee and a 62:38 dl/meso ratio was estimated for
(S,S)-22a from the chiral SFC analysis of the corresponding bis-1-
naphthylcarbamate (S,S)-23a (vide infra).
[(3R,14R)-3,14-Dihydroxy-16-(trimethylsilyl)hexadeca-1,4,12,15-
tetrayn-1-yl]trimethylsilane ((R,R)-22a). The compound (R,R)-22a
was obtained from 17a and 21 as a colorless oil (273 mg, 85%)
according to general procedure C using (−)-N-methylephedrine.
Compound 22a gave analytical data identical to that of its enantiomer
20
except for optical rotation. [α]D + 1.68 (c 2.6, CHCl3).
[(3R,18R)-3,18-Dihydroxy-20-(trimethylsilyl)icosa-1,4,16,19-tet-
rayn-1-yl]trimethylsilane ((R,R)-22b). Compound (R,R)-22b was
obtained from 17b and 21 as a colorless oil (197 mg, 85%) according
to general procedure C using (−)-N-methylephedrine. Rf 0.3
20
1
(pentane/Et2O, 8:2); [α]D + 1.76 (c 1.8, CHCl3); H NMR (300
MHz, CDCl3) δ 0.18 (s, 18H), 1.44−1.18 (m, 12H), 1.60−1.44 (m,
4H), 2.21 (td, J 7.1, 2.1 Hz, 4H), 2.29 (d, J 7.2 Hz, 2H), 5.09 ppm (dt,
J 7.1, 2.1 Hz, 2H); 13C{1H} NMR (75 MHz, CDCl3) δ − 0.2 (6C),
18.9 (2C), 28.4 (2C), 28.9 (2C), 29.2 (2C), 29.5 (2C), 52.9 (2C),
77.4 (2C), 85.9 (2C), 88.9 (2C), 102.7 (2C) ppm; IR (neat) ν 3516,
3000, 2928, 2855, 2654, 2291, 2232, 2177, 1950, 1707, 1627, 1463,
1429, 1408, 1369, 1328, 1295, 1249, 1141, 1029, 962, 839, 759, 737,
700, 668, 647, 617, 593, 573, 506 cm−1; HRMS-DCI (CH4) m/z [M +
H]+ calcd for C26H42O2Si2 442.2721, found 442.2723. A 76% ee and
77:23 dl/meso ratio was estimated for (R,R)-22b from the chiral SFC
analysis of the corresponding naphthyl carbamate (R,R)-23b (vide
infra).
[(3S,18S)-3,18-Dihydroxy-20-(trimethylsilyl)icosa-1,4,16,19-tet-
rayn-1-yl]trimethylsilane ((S,S)-22b). Compound (S,S)-22b was
obtained as a colorless oil (190 mg, 80%) according to general
procedure C using (+)-N-methylephedrine. (S,S)-22b gave analytical
data identical to that of its enantiomer except for optical rotation.
18-{[(Naphthalen-1-yl)carbamoyl]oxy}-1,20-bis(trimethylsilyl)-
icosa-1,4,16,19-tetrayn-3-yl N-(Naphthalen-1-yl) Carbamate
(meso-23b). Compound meso-23b was obtained as a yellow waxy
solid (25 mg, 50%) according to general procedure A: Rf 0.4
(petroleum ether/Et2O, 8:2); 1H NMR (400 MHz, CDCl3) δ 0.22 (s,
18H), 1.25 (s, 8H), 1.36 (m, 4H), 1.48−1.60 (m, 4H), 2.25 (td, J 2.1,
7.1 Hz, 4H), 6.19 (br.s, 2H), 7.08 (s, 2H), 7.52 (s, 6H), 7.68 (d, J 8.5
20
[α]D −1.6 (c 1.3, CHCl3). A 87% ee and 90:10 dl/meso ratio was
estimated for (S,S)-22b from the chiral SFC analysis of the
corresponding bis-1-naphthylcarbamate (S,S)-23b (vide infra).
[(3R,18S)-3,18-Dihydroxy-20-(trimethylsilyl)icosa-1,4,16,19-tet-
rayn-1-yl]trimethylsilane (meso-22b). A 25 mL flask was charged
5392
DOI: 10.1021/acs.joc.5b00494
J. Org. Chem. 2015, 80, 5386−5394

The Journal of Organic Chemistry
Featured Article
Hz, 2H), 7.83−7.96 (m, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ −
0.2 (6C), 19.0 (2C), 28.3 (2C), 29.0 (2C), 29.2 (2C), 29.6 (2C), 55.3
(2C), 74.5 (2C), 87.2 (2C), 90.6 (2C), 99.1 (2C), 120.4, 125.4, 125.9,
126.2, 126.5, 128.9, 132.2, 134.2, 152.5 (2C); IR (neat) ν 3306, 3058,
2956, 2926, 2858, 2244, 2183, 1946, 1731, 1695, 1655, 1631, 1594,
1550, 1508, 1469, 1431, 1408, 1391, 1376, 1341, 1308, 1271, 1242,
1195, 1172, 1161, 1113, 1109, 1061, 1022, 998, 951, 936, 901, 845,
796, 771, 731, 711, 705, 656, 594, 563 cm−1; HRMS-ES m/z [M +
Na]+ calcd for C48H56N2O4NaSi2: 803.3676, found 803.3683. Chiral
SFC analysis: Chiralpak IC-3 (4.6 × 100 mm), SC CO2 + 20% MeOH,
2.5 mL/min, 35 °C, 130 bar, UV 220 nm, tR 9.45 (S,S), 9.68 (meso)
and 9.89 (R,R) min (see the Supporting Information).
Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b00494.
AUTHOR INFORMATION
■
Corresponding Authors
*Fax: (+33)5 61 55 30 03. E-mail: valerie.maraval@lcc-
toulouse.fr.
*Fax: (+33)5 61 55 30 03. E-mail: chauvin@lcc-toulouse.fr.
*Fax: (+33)5 61 55 60 11. E-mail: genisson@chimie.ups-tlse.fr.
Notes
(3R)-1-(Trimethylsilyl)heptadeca-1,4,16-triyn-3-ol ((R)-24). A 25
mL flask was charged with Zn(OTf)2 (765 mg, 2.104 mmol, 4 equiv)
and (−)-N-methylephedrine (377 mg, 2.104 mmol, 4 equiv) and
purged with dry argon for 15 min. To the flask were added anhydrous
CH2Cl2 (15 mL) and triethylamine (212 mg, 2.104 mmol, 4 equiv).
The resulting mixture was vigorously stirred for 2 h at rt. Then the bis-
alkyne 17b (100 mg, 0.526 mmol, 1 equiv, solution in anhydrous
CH2Cl2) was introduced by syringe in one portion. After another 1 h
of stirring, the 3-(trimethylsilyl)propiolaldehyde (21) (66 mg, 0.526
mmol, 1 equiv) was added, and then the mixture was stirred at rt
overnight. A saturated aqueous NH4Cl solution was added, and the
mixture was extracted with CH2Cl2 (3 × 10 mL). After standard
treatment of the gathered organic layers, the crude product was
submitted to chromatography over SiO2 (pentane/Et2O, 9:1) to give
compound (R)-24 (85%, 140 mg): Rf 0.35 (pentane/Et2O, 9:1);
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
D.L. was supported by the French Embassy in Kiev, Ukraine,
and the investigations were performed within the framework of
́
the “Groupement Franco-Ukrainien en Chimie Moleculaire”
(GDRI) funded by the “Centre National de la Recherche
Scientifique” (CNRS). The French Embassy in Kiev and the
CNRS are thus acknowledged. R.C. is also indebted to the
CNRS for half of a teaching sabbatical in 2014−2015. The
“Institut de Chimie de Toulouse” (ICT) and the “Plateforme
Integ
for SFC facilities. We are thankful to the “Institut des
Technologies Avancees en sciences du Vivant” (ITAV) for
́ ́
ree de Criblage Toulousaine” (PICT) are acknowledged
[α]D20 − 3.2 (c 5.8, CHCl3); H NMR (300 MHz, CDCl3) δ 0.18 (s,
1
́
9H), 1.17−1.44 (m, 12H), 1.51 (pseudo q, J 8.4 Hz, 4H), 1.94 (t, J 2.6
Hz, 1H), 2.09−2.27 (m, 4H), 2.38 (d, J 7.1 Hz, 1H), 5.09 ppm (dt, J
7.1, 2.1 Hz, 1H); 13C{1H} NMR (75 MHz, CDCl3) δ − 0.2, 18.5, 18.8,
28.4, 28.6, 28.8, 28.9, 29.2, 29.5 (2C), 52.8, 68.2, 77.2, 77.4, 84.8, 85.8,
88.8, 102.7 ppm; IR (neat) ν 3310, 2927, 2855, 2290, 2232, 2177,
2117, 1464, 1431, 1370, 1328, 1295, 1249, 1141, 1030, 961, 841, 760,
721, 700, 622, 574, 559 cm−1; HRMS-DCI (CH4) m/z [M + H]+ calcd
for C20H33OSi 317.2301, found 317.2310. A 95% ee was estimated for
(R)-24 from chiral SFC analysis of the corresponding 1-naphthyl
carbamate (R)-25 (vide infra).
biological evaluations.
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ASSOCIATED CONTENT
■
S
* Supporting Information
[Stereoisomeric ratio calculation for compound 14. H and
1
13C{1H} NMR spectra for (R,R)-5, (S,S)-6a, (S,S)-6b, meso-6b,
(R,R)-14, (R,R)-15, (R,R)-16, (R,R)-22a, (R,R)-22b, meso-22b,
(S,S)-23a, (R,R)-23b, meso-23b, (R)-24, and (R)-25. Crystallo-
graphic data and CIF for compounds 12 and 6b. SFC chiral
chromatograms for (S)-12, a stereoisomeric mixture of 16,
(R,R)-16, a stereoisomeric mixture of 23a, (S,S)-23a, a
stereoisomeric mixture of 23b, (R,R)-23b, (S,S)-23b, meso-
23b, an enantiomeric mixture of 25, and (R)-25. The
5393
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The Journal of Organic Chemistry
Featured Article
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