Bidirectional Synthesis of 6-Acetoxy-5-hexadecanolide, the Mosquito Oviposition Pheromone of Culex quinquefasciatus, from a C2-Symmetric Building Block Using Olefin Metathesis Reactions

Article abstract of DOI:10.1021/acs.joc.7b02944

(5R,6S)-6-Acetoxy-5-hexadecanolide (MOP) is the oviposition pheromone of the mosquito Cx. quinquefasciatus, a vector of pathogens causing a variety of tropical diseases. We describe and evaluate herein three syntheses of MOP starting from mannitol-derived

Full text of DOI:10.1021/acs.joc.7b02944

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Bidirectional Synthesis of 6-Acetoxy-5-hexadecanolide, the Mosquito
Oviposition Pheromone of Culex quinquefasciatus, from a C2-
symmetric Building Block using olefin metathesis reactions
Bernd Schmidt, Monib H. Petersen, and Diana Braun
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02944 • Publication Date (Web): 02 Jan 2018
Downloaded from http://pubs.acs.org on January 2, 2018
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Bidirectional Synthesis of 6-Acetoxy-5-hexadecanolide, the Mosquito Oviposition
Pheromone of Culex quinquefasciatus, from a C -symmetric Building Block
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using Olefin Metathesis Reactions
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Bernd Schmidt,* Monib H. Petersen and Diana Braun
Universitaet Potsdam, Institut fuer Chemie, KarlꢀLiebknechtꢀStraße 24ꢀ25, Dꢀ14476 Potsdamꢀ
Golm, Germany.
eꢀmail: bernd.schmidt@uniꢀpotsdam.de
Table of contents graphic:
Abstract: (5R, 6S)ꢀ6ꢀAcetoxyꢀ5ꢀhexadecanolide (MOP) is the oviposition pheromone of the
mosquito Cx. quinquefasciatus, a vector of pathogens causing a variety of tropical diseases.
We describe and evaluate herein three syntheses of MOP starting from mannitolꢀderived (3R,
4
R)ꢀhexaꢀ1,5ꢀdieneꢀ3,4ꢀdiol. This C ꢀsymmetric building block is elaborated through
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bidirectional olefin metathesis reactions into 6ꢀepiꢀMOP, which was converted into MOP via
Mitsunobu inversion. The shortest of the three routes makes use of two sequential cross
metathesis reactions and an assisted tandem catalytic olefin reduction, induced by an inꢀsitu
conversion of a Ruꢀcarbene to a Ruꢀhydride.
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Culex quinquefasciatus is known as the southern house mosquito. The species is widely
distributed in tropical and subtropical regions all over the world and has been known as a
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vector of many pathogens. The outbreak of the Zika fever epidemic in Brazil in 2015 has
raised concerns that not only mosquitoes of the genus Aedes (in particular Ae. aegypti) might
be vectors of the Zika virus, but that transmission of the disease could also be possible
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through other even more common mosquitoes, such as Cx. quinquefasciatus. Although recent
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laboratory experiments are inconclusive in this regard, this question has stimulated a
renewed interest in the chemical ecology of Cx. quinquefasciatus mosquitoes with a view to
the development of sustainable vector control and monitoring programs based on the use of
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pheromone traps.
In the case of Culex quinquefasciatus, (5R,6S)ꢀ6ꢀacetoxyꢀ5ꢀ
hexadecanolide (1) has been identified as a pheromone that influences the site selection for
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oviposition. Traps containing this compound or a mixture of all stereoisomers can be used
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for collecting samples of gravid Cx. quinquefasciatus mosquitoes.
Shortly after the
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identification of 1 as the mosquito oviposition pheromone of Cx. quinquefasciatus in 1982
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the first stereoselective synthesis of both enantiomers was reported. This synthesis required
multiple synthetic steps, several protecting group manipulations and chromatographic
separations of diastereomers. Since then, numerous stereoselective syntheses of 1 or its
stereoisomers have been reported, which reflect the rapid progress in synthetic methodology
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since the early 1980’s.
The two most recent approaches to this target molecule use a
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chemoenzymatic and an organocatalytic
epoxidationꢀlactonization sequence. The first
example for an olefin metathesis based approach involves a sequence of cross metathesis
(CM) of a fatty acid, epoxidation and lactonization and furnishes MOP (1) along with “other
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isomers”. Two syntheses using a ring closing metathesis (RCM) were published a few years
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later.
Another synthesis of MOP that uses olefin metathesis has been published by Quinn
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and coworkers. It relies on a dual RCM/CM functionalization
of (3R,4S)ꢀ4ꢀ
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(
benzyloxy)hexaꢀ1,5ꢀdieneꢀ3ꢀol ((3R,4S)ꢀ4), a chiral diene obtained through Sharpless
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epoxidation of divinyl carbinol, Oꢀbenzylation and epoxide opening with a sulfonium ylide.
In this contribution we describe three syntheses of MOP (1) that have a bidirectional
metathesis based elaboration of a hexaꢀ1,5ꢀdieneꢀ3,4ꢀdiol derivative with Quinn’s approach in
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common, but start from the C
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ꢀsymmetric mannitol derived (3R,4R)ꢀhexaꢀ1,5ꢀdieneꢀ3,4ꢀdiol
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(3).
One advantage of this and other C ꢀsymmetric building blocks is that a
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monofunctionalization results in identical products and that enantioselective transformations
using chiral reagents or catalysts can be avoided. Not only 3, but also its enantiomer, entꢀ3, is
accessible from the chiral pool, which allows the transfer of a previously established strategy
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to the enantiomeric target structure without any modifications, if required.
Our synthetic
routes make both MOP (1) and 6ꢀepiꢀMOP (2) accessible in few steps with little or no
protecting group efforts. A third variant proceeds from the monoacetate of 3 to 6ꢀepiꢀMOP (2)
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as a one pot sequence of two CM steps, an assisted tandem catalytic hydrogenation
acid mediated lactonization.
and an
At the outset we investigated an approach to 6ꢀepiꢀMOP (2) starting from monobenzyl
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protected dienediol (3R,4R)ꢀ4, an epimer of Quinn’s starting material. Steglich
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esterification of (3R,4R)ꢀ4 with vinyl acetic acid (5) furnished the metathesis precursor 6,
which underwent RCM to 7 in good yield and selectivity in the presence of second generation
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Grubbs’ catalyst A. Installation of the side chain through cross metathesis with 1ꢀdecene
was accomplished from isolated and purified 7 using either second generation catalyst A or
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catalyst B, which has emerged as a particularly useful catalyst for CM reactions. With
either catalyst the desired product 8 was obtained in similar yields between 70% and 75%, but
B catalyzed the cross metathesis efficiently at ambient temperature and with a catalyst loading
of just 1 mol%, whereas 5 mol% of catalyst and an elevated reaction temperature of 80 °C
were required with catalyst A. The oneꢀpot transformation of 6 into 8 via successive RCM
and CM was investigated, but offered no synthetic advantage. Palladium on charcoal
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catalyzed hydrogenation of both CꢀCꢀdouble bonds with concomitant debenzylation furnished
9, which was acetylated to 6ꢀepiꢀMOP (2) in high yield. For the synthesis of the mosquito
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oviposition pheromone 1 a Mitsunobu inversion of the secondary alcohol 9 with acetic acid
was envisaged. This step turned out to be surprisingly difficult and required optimization.
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With the most common phosphine, PPh , and either diisopropylꢀ (DIAD) or diethylazo
dicarboxylate (DEAD) the reaction failed completely and unreacted starting material was
recovered. Tsunoda et al. have reported that the combination of PBu3 and the
azodicarboxylate ADDP results in a more basic adduct than the standard combinations of
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DIAD or DEAD and PPh
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We thought that the somewhat lower acidity of acetic acid,
compared with the commonly used paraꢀnitrobenzoic acid, might be the reason for the
complete failure and therefore tested the combination of ADDP and PBu , resulting in a
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synthetically useful yield of 59% of MOP (1). In the course of these investigations we noticed
that water must be rigorously removed from the acetic acid, preferably by repeated distillation
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from P O10, immediately before the reagent is used (Scheme 1).
Scheme 1. Synthesis of MOP (1) and its 6ꢀepimer 2 from protected dienediol (3R,4R)ꢀ4.
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We then investigated a protecting groupꢀfree approach to the MOPꢀ and 6ꢀepiꢀMOP precursor
9 (Scheme 2). This synthesis started with a monoꢀacylation of the C ꢀsymmetric dienediol 3
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to the monoꢀbutenoate 10, which underwent RCM to the dihydropyranone 11 with
surprisingly low conversion under the RCM conditions previously established for the
benzylprotected butenoate 6. Literature reports on the effect of unprotected hydroxy groups
on the rate and selectivity of metathesis reactions are inconsistent. In several cases a
beneficial effect of allylic hydroxy groups was documented and explained by a hydrogen
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bonding between the proximal OH group and the Ruꢀchloro ligands.
On the other hand,
attempted RCM of allyl alcohols was found to result in the formation of methyl ketones as
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byproducts and concommitant catalyst deactivation through formation of Ruꢀhydrides. In
any case, it appears to be unlikely that the low reactivity of 10 in the RCM step results from a
catalyst inhibition by coordination of the hydroxy group to the Ruꢀcentre. We did not detect
any degradation products such as the above mentioned methyl ketones or isomerization
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products, which would point at a catalyst deactivation through Ruꢀhydride formation.
A
possible explanation for the unsatisfactory rate of conversion under standard conditions might
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be that degenerate or nonꢀproductive
metathesis reactions become more favourable for
allylic alcohol 10 compared to its benzyl protected analogue 6. These nonꢀproductive
metathesis events would slow down the RCM reaction and lead to competing catalyst
deactivation. Standard optimization protocols using various amounts of catalysts A or B,
different chlorinated or aromatic solvents and initial substrate concentrations varying from
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.01 to 0.10 mol•L− were unsuccessful and furnished 11 in yields not higher than 22%.
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Addition of phenol, which is a rate enhancing additive in metathesis reactions, did not
improve the yield. A breakthrough was eventually accomplished by addition of a catalyst
solution to the RCM precursor via syringe pump in combination with phenol as a rate
accelerating additive. We reason that the continuous addition of fresh precatalyst is beneficial
for slow metathesis reactions, which are hampered by competing catalyst decomposition
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processes.
In the next step, the cross metathesis of 11 and 1ꢀdecene was investigated.
Under optimized conditions the CM product 12 was obtained in 85% yield by using five
equivalents of 1ꢀdecene and just 1 mol % of catalyst B. We also investigated a oneꢀpot RCMꢀ
CM sequence from 10 to 12 by combining the optimized conditions for RCM and CM steps.
The yield for the oneꢀpot RCMꢀCM sequence is virtually identical to the overall yield of the
two step synthesis with isolation of 11. Hydrogenation of 12 under atmospheric hydrogen
pressure and with Pd/C as catalyst furnished 9 in 81% yield (Scheme 2).
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Scheme 2. Protecting groupꢀfree synthesis of MOPꢀprecursor 9.
Eventually, we investigated whether efficiency and protecting group economy of a metathesis
based MOPꢀsynthesis could even be further improved by exploiting Ruꢀcatalyzed assisted
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tandem catalytic transformations. In the olefin metathesis field, such transformations can
be used to functionalize a CꢀCꢀdouble bond formed in the metathesis step, without isolation of
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the intermediate and by using just one precatalyst. These reactions rely on organometallic
transformations of the metathesis catalyst in situ, which are triggered by suitable additives.
The earliest examples combined olefin metathesis reactions and hydrogenations, which were
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initiated by applying hydrogen pressure to completed metathesis reactions at elevated
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temperatures.
This induced a conversion of the Ruꢀcarbene into a Ruꢀhydride species,
which subsequently catalyzes the hydrogenation. More recently, hydrogen surrogates were
investigated both as chemical triggers for Ruꢀhydride formation and as hydrogenation
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reagents. Examples are 2ꢀpropanol, formic acid and triethylsilane.
We investigated
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an approach to 6ꢀepiꢀMOP (2), starting from the monoacetate 13, that proceeds via two
successive cross metathesis reactions and an assisted tandem catalytic hydrogenation using
triethylsilane (Scheme 3).
Scheme 3. Synthesis of 6ꢀepiꢀMOP (2) through cross metathesisꢀhydrogenation.
First, the cross metathesis with methylꢀ3ꢀbutenoate was accomplished using only 0.5 mol% of
precatalyst B at ambient temperature. Subsequently, 1ꢀdecene was added after evaporating
excess methylbutenoate and redissolving the residue, together with a second (1.0 mol%)
portion of B. The second cross metathesis also proceeded smoothly at ambient temperature.
Exchanging the RCM solvent dichloromethane against toluene, followed by addition of
triethylsilane and heating to reflux resulted in hydrogenation of both double bonds without
addition of fresh catalyst. Acid catalyzed cyclization furnished the δꢀlactone 6ꢀepiꢀMOP (2) in
39% overall yield. Taking into account that six synthetic operations are performed in this
sequence the yield is satisfactory. Nevertheless, we were interested in identifying the limiting
factors. Our reasoning behind the design of this oneꢀpot sequence was that the above
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mentioned OHꢀdirecting and activating effect
might be a useful selectivity control element
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in this case. Thus, we expected that the double bond adjacent to the unprotected OHꢀgroup
should be the preferred site for a cross metathesis reaction, and therefore used methylꢀ3ꢀ
butenoate as the first CM partner. The second cross metathesis, with 1ꢀdecene at the position
adjacent to the acetoxy group, was expected to proceed slower. To test these hypotheses, 13
and methylꢀ3ꢀbutenoate were subjected to various cross metathesis conditions (Scheme 4).
Formation of the double cross metathesis product 16 was only observed with more than two
equivalents of the CM partner. With 1.2 equivalents only monofunctionalized products were
formed, but with virtually no regioselectivity: the isomers 14 and 15 were obtained as an
inseparable mixture in a ratio of ca. 1 : 1. We subjected this mixture to the second cross
metathesis step in the presence of a fivefold excess of 1ꢀdecene, to test whether methylꢀ3ꢀ
butenoate is cleaved off under these conditions, but we observed only the expected cross
metathesis products 17 and 18, again as an inseparable mixture in a 1 : 1 ratio.
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Scheme 4. Individual investigation of the two CM steps.
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We conclude from these observations that the lack of selectivity of the first CM step is the
main factor limiting the yield of the assisted tandem catalytic sequence, because only the
hydrogenated product of intermediate 17 will readily undergo the final acid catalyzed
cyclization to 6ꢀepiꢀMOP. Neither double cross metathesis with the first CM partner nor
undesired alkene redistribution in the second CM step lower the overall yield substantially.
Preliminary experiments to overcome the insufficient regioselectivity of the first CM step
involved testing of the presumably less reactive second generation Grubbs’ catalyst A and its
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first generation counterpart under various conditions. With both catalysts a higher catalyst
loading of 5 mol% was required to obtain 14/15 in comparable yield, but the diminished
reactivity of these catalysts did not result in an improved regioselectivity. Future
investigations in our laboratory will address this issue further.
In summary, we describe and discuss three olefin metathesis based routes to the mosquito
2
oviposition pheromone of Cx. quinquefasciatus starting from a C ꢀsymmetric mannitol
derived dienediol. Two routes rely on combinations of RCM and CM steps. In the first route
high yields can be achieved for the crucial olefin metathesis reactions under synthetically
convenient routine conditions, but multiple steps, including protecting group operations, are
required. The second route is protecting group free, but a very elaborate and time consuming
protocol needs to be followed to overcome reactivity problems in the RCM step. The third
route is the shortest and proceeds in one flask via two successive CM reactions and a tandem
hydrogenation of both double bonds. Due to the high reactivity of the less common phosphine
free catalyst B in CM reactions this route requires the lowest amount of metathesis catalysts,
no additional noble metal catalyst for the hydrogenation step and is therefore in our opinion a
showcase example for the application of assisted tandem catalytic transformations in target
molecule synthesis.
Experimental Section
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General methods. All experiments were conducted in dry reaction vessels under an
1
atmosphere of dry nitrogen. Solvents were purified by standard procedures. H NMR spectra
were obtained at 300 MHz, 500 MHz or 600 MHz in CDCl
ppm) or C D H ( = 7.16 ppm) as an internal standard. Coupling constants are given in Hz.
C NMR spectra were recorded at 75 MHz, 125 MHz or 151 MHz in CDCl or in C with
CDCl (δ = 77.1 ppm) or C = 128.1 ppm) as an internal standard. IR spectra were
recorded as ATRꢀFTIR spectra. Wavenumbers (
3 6 6 3
or in C D with CHCl (δ = 7.26
δ
6
5
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
3
6 6
D
3
6 6
D (δ
−
1
ν
) are given in cm . The peak intensities are
defined as strong (s), medium (m) or weak (w). Lowꢀ and high resolution mass spectra were
obtained by EIꢀTOF or ESIꢀTOF. Hexanes/MTBE mixtures of increasing polarity were used
for column chromatography, starting with a hexanes : MTBE ratio of 10 : 1 (v/v), which was
gradually reduced to 2 : 1 (v/v), if necessary.
48
(3R,4R)-4-(Benzyloxy)hexa-1,5-dien-3-yl but-3-enoate (6). To a solution of (3R,4R)ꢀ4
1.230 g, 6.02 mmol) in CH Cl (60 mL) was added vinyl acetic acid 5 (624 mg, 7.25 mmol),
(
2
2
DMAP (75 mg, 0.60 mmol) and DCC (1.490 g, 7.20 mmol) at 0 °C. The mixture was warmed
to ambient temperature and stirred until TLC showed full conversion (ca 12h). The precipitate
was removed by filtration and the solution was washed with aq. HCl (1 M, 10 mL). The
organic layer was separated and the aqueous layer was extracted with CH
mL). The combined organic layers were washed with saturated aq. NaHCO
with MgSO
column chromatography on silica, using hexanes/MTBE mixtures as eluent, to furnish 6
Cl
2 2
(three times 10
3
solution, dried
4
, filtered and evaporated under reduced pressure. The residue was purified by
26
D
1
(64%, 1.049 g, 3.85 mmol): colourless liquid; [α]
+14.9 (c 0.135, CH
2 2
Cl ); H NMR (300
MHz, CDCl
3
) δ 7.41 – 7.22 (m, 5H), 6.06 – 5.67 (m, 3H), 5.48 – 5.42 (m, 1H), 5.40 – 5.15
(m, 6H), 4.68 (d, J = 12.2 Hz, 1H), 4.44 (d, J = 12.2 Hz, 1H), 3.98 – 3.87 (m, 1H), 3.15 (dt, J
1
3
= 6.9, 1.4 Hz, 2H); C NMR (75 MHz, CDCl
3
) δ 170.4, 138.1, 134.1, 132.8, 130.2, 128.3,
1737 (s), 1248 (m); MS
1
27.6, 127.5, 119.7, 118.5, 118.2, 80.8, 75.5, 70.5, 39.2; IR (ATR)
ν
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+
+
(
EI) m/z 196 (100), 273 (60, M +H); HRMS (EI) calcd for C H O [M +H] 273.1491, found
17 21 3
273.1479.
(
R)-6-((R)-1-(Benzyloxy)allyl)-3,6-dihydro-2H-pyran-2-one (7). To a solution of 6 (381
mg, 1.40 mmol) in toluene (30 mL) was added catalyst A (60 mg, 5.0 mol %) at 80 °C. The
mixture was stirred at that temperature until TLC showed full conversion of the starting
material (ca 2h). The solvent was evaporated and the residue was purified by column
chromatography on silica, using petrol ether/MTBE mixtures as eluent, to furnish 7 (91%, 310
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
26
D
1
mg, 1.27 mmol): colourless liquid; [α]
CDCl ) δ 7.38 – 7.27 (m, 5H), 5.96 – 5.77 (m, 3H), 5.45 – 5.32 (m, 2H), 5.08 – 4.97 (m, 1H),
.65 (d, J = 11.9 Hz, 1H), 4.39 (d, J = 12.0 Hz, 1H), 3.99 (dd, J = 7.9, 3.9 Hz, 1H), 3.07 –
2 2
+97.9 (c 0.05, CH Cl ); H NMR (300 MHz,
3
4
2
1
13
.99 (m, 2H); C NMR (75 MHz, CDCl ) δ 168.6, 137.9, 133.7, 128.5, 127.8, 127.7, 123.2,
3
23.0, 121.2, 81.0, 80.7, 70.7, 30.4; IR (ATR)
ν 1739 (s), 1375 (m); MS (EI) m/z 91 (100),
+
+
244 (12, M ); HRMS (EI) calcd for C15
H
16
O
3
[M ] 244.1099, found 244.1092.
(R)-6-((R,E)-1-(Benzyloxy)undec-2-en-1-yl)-3,6-dihydro-2H-pyran-2-one (8). Synthesis
from dihydropyranone 7 with catalyst B: to a solution of 7 (360 mg, 1.47 mmol) in CH Cl (3
2
2
mL) was added 1ꢀdecene (1030 mg, 7.35 mmol) and catalyst B (9.5 mg, 1.0 mol %) at
ambient temperature. The reaction mixture was stirred until TLC showed full conversion of
the starting material (ca 12h). All volatiles were evaporated and the residue was purified by
column chromatography on silica using hexanes/MTBE mixtures as eluent to furnish 8 (88%,
462 mg, 1.29 mmol). Oneꢀpot synthesis from triene 6 with catalyst A: to a solution of 6 (272
mg, 1.00 mmol) in toluene (20 mL) was added catalyst A (43 mg, 5.0 mol %) at 80 °C. The
mixture was stirred at this temperature until TLC showed full conversion of the starting
material (ca 2h). 1ꢀDecene (701 mg, 5.00 mmol) and a second portion of catalyst A (43 mg, 5
mol %) were added and the reaction mixture was stirred at 80 °C for 12 hours. All volatiles
were removed under reduced pressure and the residue was purified by column
chromatography on silica, using hexanes/MTBE mixtures as eluent, to furnish 8 (57%, 190
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2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
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5
5
5
5
5
5
5
5
6
2
6
1
mg, 0.53 mmol): colourless liquid; [α]D +37.6 (c 0.18, CH Cl ); H NMR (300 MHz,
2
2
CDCl ) δ 7.39 – 7.23 (m, 5H), 5.97 – 5.80 (m, 2H), 5.77 (dt, J = 15.5, 6.7 Hz, 1H), 5.46 (ddt,
3
J = 15.5, 8.6, 1.5 Hz, 1H), 5.05 – 4.95 (m, 1H), 4.62 (d, J = 12.0 Hz, 1H), 4.36 (d, J = 12.0
Hz, 1H), 3.94 (dd, J = 8.5, 3.9 Hz, 1H), 3.05 – 2.97 (m, 2H), 2.14 – 2.00 (m, 2H), 1.44 – 1.19
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
(
m, 12H), 0.88 (d, J = 6.7 Hz, 3H); C NMR (75 MHz, CDCl
3
) δ 168.7, 138.7, 138.2, 128.4,
1
27.7, 125.0, 123.3, 122.9, 81.0, 80.9, 70.2, 32.5, 31.9, 30.5, 29.5, 29.3, 29.2, 29.0, 22.7, 14.2;
+
IR (ATR)
ν
1744 (s), 1454 (m), 1375 (m); MS (ESI) m/z 357 (20, M ); HRMS (EI) calcd for
+
C
23
H
33
O
3
[M ] 357.2430, found 357.2410.
(
R)-6-((R)-1-Hydroxyundecyl)tetrahydro-2H-pyran-2-one (9). Synthesis from benzyl
protected diene 8: To a solution of 8 (142 mg, 0.40 mmol) in THF (5 mL) was added Pd/C
10 wtꢀ%, 0.8 mg) and the solution was saturated with hydrogen. The reaction mixture was
(
kept under an atmosphere of hydrogen (1 bar) and stirred vigorously until TLC showed full
conversion of the starting material (ca 36 h). All volatiles were removed under reduced
pressure and the residue was purified by column chromatography on silica using
hexanes/MTBE mixtures as eluent to furnish 9 (97%, 105 mg, 0.39 mmol). Synthesis from
unprotected diene 12: following the procedure given above for the debenzylationꢀ
hydrogenation of 8, compound 12 (405 mg, 1.52 mmol) was hydrogenated using Pd/C (10 wtꢀ
%
, 14 mg) as a catalyst to furnish 9 (81%, 332 mg, 1.23 mmol): colourless solid, mp 71 – 72
26
D
1
°C; [α]
2 2 3
−8.0 (c 0.295, CH Cl ); H NMR (300 MHz, CDCl ) δ 4.16 (dt, J =10.8, 3.7 Hz,
1
H), 3.59 ꢀ 3.48 (m, 1H), 2.72 – 2.33 (m, 3H), 1.96 – 1.66 (m, 4H), 1.53 – 1.48 (m, 2H), 1.23
13
(
16H), 0.84 (t, J = 6.3 Hz, 3H); C NMR (75 MHz, CDCl ) δ 171.6, 83.3, 73.3, 32.7, 31.9,
3
2
1
2
9.7, 29.7, 29.7, 29.6, 29.6, 29.3, 25.5, 24.2, 22.7, 18.5, 14.1; IR (ATR) 3422 (m), 1750 (s),
+
+
261 (m); MS (ESI) m/z 271 (100, M +H); HRMS (ESI) calcd for C16
30 3
H O Na [M+Na]
29
93.2093, found 293.2096. All analytical data match those previously reported for 9.
(R)-1-((R)-6-Oxotetrahydro-2H-pyran-2-yl)undecyl acetate (6-epi-MOP, 2). To a solution
of 9 (30 mg, 0.11 mmol) in CH Cl (2 mL) was added acetic anhydride (34 mg, 0.33 mmol)
2
2
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and DMAP (40 mg, 0.33 mmol). The reaction mixture was stirred at ambient temperature
until TLC showed full conversion of the starting material (ca 4 h). It was diluted with CH Cl2
2
(
10 mL) and washed with a saturated aq. solution of NaHCO
separated and the aqueous layer was extracted three times with CH
The combined organic layers were washed with water and brine and then dried with MgSO
3
. The organic layer was
2
Cl (three times 5 mL).
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4
.
All volatiles were evaporated under reduced pressure and the residue was purified by column
chromatography on silica, using hexanes/ethyl acetate mixtures as eluent to afford 2 (90%, 31
2
6
1
mg, 0.10 mmol): colourless oil; [α]
4.96 (ddd, J = 8.2, 5.6, 3.6 Hz, 1H), 4.34 (dt, J = 11.5, 3.3 Hz, 1H), 2.59 (dddd, J = 17.7, 6.2,
.4, 1.5 Hz, 1H), 2.44 (ddd, J = 17.8, 9.4, 7.2 Hz, 1H), 2.08 (s, 3H), 1.96 – 1.90 (m, 1H), 1.83
m, 2H), 1.71 – 1.64 (m, 2H), 1.61 – 1.54 (m, 1H), 1.31 – 1.19 (m, 16H), 0.86 (t, J = 7.0 Hz,
D
2 2 3
+12.1 (c 0.20, CH Cl ); H NMR (600 MHz, CDCl ) δ
4
(
1
3
3
2
H); C NMR (151 MHz, CDCl ) δ 171.0, 170.7, 79.8, 73.9, 31.9, 30.0, 29.7, 29.6, 29.6,
3
9.5, 29.4, 29.4, 25.4, 24.2, 22.7, 21.0, 18.4, 14.2; IR (ATR)
ν
1733 (s), 1227 (s); MS (ESI)
+
+
m/z 196 (100), 313 (33, M +H); HRMS (ESI) calcd for C18
H
33
O
4
[M+H] 313.2379, found
29
34
3
13.2386. All analytical data match those previously reported for 2 and entꢀ2.
(S)-1-((R)-6-Oxotetrahydro-2H-pyran-2-yl)undecyl
acetate
(MOP,
1).
1,1'ꢀ
(Azodicarbonyl)dipiperidine (ADDP, 70 mg, 0.185 mmol) and PBu
3
(70 ꢀL, 0.185 mmol)
were dissolved in dry and degassed THF (1.0 mL) at 0 °C and stirred for 0.5 h at this
temperature. A solution of 9 (25 mg, 0.093 mmol) in THF (0.5 mL), followed by acetic acid
(
dried by repeated distillation from P O immediately before use, 20 mg, 0.560 mmol) were
2 5
added and the reaction mixture was allowed to warm to ambient temperature. After 4 hours,
the mixture was quenched by addition of a saturated aq. solution of NaHCO and the organic
layer was separated. The aqueous layer was extracted with ethyl acetate (three times 5 mL)
and the combined organic layers were dried with MgSO . All volatiles were removed under
3
4
reduced pressure and the residue was purified by column chromatography on silica, using
hexanes/ethyl acetate mixtures as eluent, to furnish 1 (59%, 17 mg, 0.054 mmol): colourless
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
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4
4
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5
5
5
5
5
5
6
2
6
1
oil; [α]
D
−32.9 (c 0.175, CH
Cl
2 2
); H NMR (500 MHz, CDCl
3
) δ 4.95 (ddd, J = 7.9, 5.7, 3.6
Hz, 1H), 4.33 (dt, J = 11.5, 3.3 Hz, 1H), 2.61 – 2.54 (m, 1H), 2.46 – 2.38 (m, 1H), 2.06 (s,
3
–
7
ν
H), 1.95 – 1.88 (m, 1H), 1.86 – 1.77 (m, 2H), 1.69 – 1.61 (m, 2H), 1.61 – 1.54 (m, 1H), 1.34
13
1.22 (m, 16H), 0.84 (t, J = 6.9 Hz, 3H); C NMR (126 MHz, CDCl
3
) δ 170.9, 170.7, 79.8,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3.9, 31.9, 29.9, 29.6, 29.6, 29.5, 29.5, 29.4, 29.3, 25.3, 24.1, 22.7, 21.0, 18.4, 14.1; IR (ATR)
+
1734 (s), 1227 (s); MS (ESI) m/z 196 (100), 313 (12, M +H); HRMS (ESI) calcd for
+
C
18
H
33
O
4
[M+H] 313.2379, found 313.2371. All analytical data match those previously
29,34
reported for 1.
3R,4R)-4-Hydroxyhexa-1,5-dien-3-yl but-3-enoate (10). To a solution of 3 (230 mg, 2.00
mmol) in CH Cl (20 mL) was added vinyl acetic acid (5, 208 mg, 2.40 mmol), DMAP (25
(
2
2
mg, 0.20 mmol) and DCC (495 mg, 2.40 mmol) at 0 °C. The ice bath was removed and the
mixture was stirred at ambient temperature until TLC showed full conversion (~12h). The
resulting precipitate was filtered off and the solution was washed with aq. HCl (1 M). The
organic layer was separated and the aqueous layer was extracted with dichloromethane (three
times 10 mL). The combined organic layers were washed with saturated NaHCO solution,
3
dried with MgSO and evaporated under reduced pressure. The residue was purified by
4
column chromatography on silica, using hexanes/MTBE mixtures as eluent, to furnish 10
2
D
6
1
(
73%, 265 mg, 1.46 mmol): yellowish liquid; [α]
+38.8 (c 0.385, CH
2 2
Cl ); H NMR (500
MHz, CDCl
3
) δ 5.93 – 5.72 (3H), 5.32 – 5.09 (7H), 4.15 (dd, J= 5.7, 5.6 Hz, 1H), 3.08 (d, J =
1
3
6
1
.9 Hz, 2H), 2.74 (s, 1H); C NMR (75 MHz, CDCl ) δ 170.7, 135.9, 132.6, 130.0, 119.2,
3
18.9, 117.4, 77.1, 73.7, 39.2; IR (ATR)
ν
3451 (m), 1722 (s), 1250 (m); MS (ESI) m/z 98
+
+
(
100), 183 (8, M +H); HRMS (ESI) calcd for C10
H
15
O
3
[M +H] 183.1021, found 183.1029.
(
R)-6-((R)-1-Hydroxyallyl)-3,6-dihydro-2H-pyran-2-one (11). Without pseudoꢀhigh
dilution conditions: butenoate 10 (91 mg, 0.50 mmol) was dissolved in CH
2
Cl (10 mL) and
2
heated to 40 °C. Catalyst A (22 mg, 5 mol %) was added to the refluxing solution and the
mixture was stirred at this temperature for three hours. After cooling to ambient temperature
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all volatiles were removed in vacuo and the residue was purified by chromatography on silica,
using hexanes/MTBE mixtures as eluent, to furnish 11 (22%, 17 mg, 0.11 mmol). With
pseudoꢀhighꢀdilution conditions in the presence of phenol: to a refluxing solution of 10 (91
mg, 0.50 mmol) and phenol (24 mg, 0.25 mmol) in CH
2 2
Cl (10 mL) was added a solution of
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
at 0.05 mL•min−1).
Cl
2
catalyst A via syringe pump (22 mg, 5 mol %, dissolved in 2.0 mL CH
2
After completed addition the mixture was heated for 1 h at 40 °C. After cooling to ambient
temperature, all volatiles were removed in vacuo and the residue was purified by column
chromatography on silica, using hexanes/MTBE mixtures as eluent, to furnish 11 (69%, 52
26
1
mg, 0.35 mmol): brownish oil; [α]
D
2 2 6 6
+78.3 (c 0.255, CH Cl ); H NMR (600 MHz, C D ) δ
5.94 (ddd, J = 16.9, 10.5, 6.2 Hz, 1H), 5.56 (dm, J = 10.1, Hz, 1H), 5.43 (dt, J = 17.2, 1.5 Hz,
1H), 5.37 (dtd, J = 10.1, 3.6, 1.6 Hz, 1H), 5.20 (dd, J = 10.5, 1.4 Hz, 1H), 4.69 ꢀ 4.66 (m, 1H),
4.16 (ddt, J = 6.0, 4.8, 1.2 Hz, 1H), 3.70 (s(br), 1H), 2.84 (ddt, J = 21.7, 3.1, 2.7 Hz, 1H), 2.67
1
3
3
(dtd, J = 21.7, 3.6, 1.7 Hz, 1H); C NMR (75 MHz, CDCl ) δ 168.7, 135.1, 123.5, 122.9,
119.1, 82.2, 74.9, 30.3; IR (ATR)
ν
3417 (m), 1718 (s); MS (ESI) m/z 98 (100), 155 (1,
+
+
M +H); HRMS (ESI) calcd for C H O [M +H] 155.0708, found 155.0705.
8
11
3
(
R)-6-((R,E)-1-Hydroxyundec-2-en-1-yl)-3,6-dihydro-2H-pyran-2-one (12). Synthesis from
dihydropyranone 11: compound 11 (78 mg, 0.50 mmol) and 1ꢀdecene (351 mg, 2.50 mmol)
were dissolved in CH Cl (1.0 mL) and precatalyst B (3.0 mg, 1.0 mol %) was added. The
2
2
reaction mixture was stirred at ambient temperature until TLC showed full conversion of the
starting material (ca 12h). All volatiles were evaporated in vacuo and the residue was purified
by column chromatography on silica using hexanes/MTBE mixtures as eluent to furnish 12
(
85%, 114 mg, 0.43 mmol). Oneꢀpot synthesis from triene 10: compound 10 (91 mg, 0.50
mmol) and phenol (24 mg, 0.25 mmol) were dissolved in CH Cl (10 mL). The solution was
heated to 40 °C and and a solution of precatalyst A (22 mg, 5 mol %) in CH Cl (2.0 mL) was
2
2
2
2
−
1
slowly added via syringe pump (0.05 mL•min ). After completed addition the mixture was
heated at 40 °C for 1 h, cooled to ambient temperature and evaporated. The residue was
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5
5
6
redissolved in CH Cl (1.0 mL) and 1ꢀdecene (351 mg, 2.50 mmol) and precatalyst B (3.0 mg,
2
2
1.0 mol %) were added. The solution was stirred for 24 h at ambient temperature. All volatiles
were removed in vacuo and the residue was purified by column chromatography on silica
using hexanes/MTBE mixtures as eluent to furnish 12 (59%, 79 mg, 0.29 mmol): colourless
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
26
D
1
liquid; [α]
2 2 3
+60.1 (c 0.295, CH Cl ); H NMR (500 MHz, CDCl ) δ 5.94 (dddd, J = 10.2,
3
.3, 3.3, 1.5 Hz, 1H), 5.90 (dddd, J = 10.2, 2.6, 1.5, 1.5 Hz, 1H), 5.84 (dt, J = 15.3, 6.9 Hz,
H), 5.55 (ddt, J = 15.4, 7.5, 1.4 Hz, 1H), 4.91 – 4.87 (m, 1H), 4.21 (dd, J = 7.5, 5.0 Hz, 1H),
1
3.15 – 3.08 (m, 2H), 2.24 (s, 1H), 2.14 – 2.04 (m, 2H), 1.42 – 1.34 (m, 2H), 1.33 – 1.23 (m,
1
3
10H), 0.91 (t, J = 6.1 Hz, 3H); C NMR (126 MHz, CDCl
3
) δ 168.6, 136.9, 126.6, 123.2,
1
1
23.2, 82.5, 75.0, 32.4, 31.9, 30.3, 29.5, 29.3, 29.2, 29.0, 22.7, 14.2; IR (ATR) 3423 (w),
ν
+
728 (s); HRMS (ESI) calcd for C H O [M +H] 267.1960, found 267.1992.
16
27
3
Synthesis of 6-epi-MOP (2) from 13 via double CM and tandem hydrogenation.
Compound 13 (156 mg, 1.00 mmol) and methylꢀ3ꢀbutenoate (120 mg, 1.20 mmol) were
2 2
dissolved in CH Cl (2.0 mL). Precatalyst B (3.27 mg, 0.5 mol %) was added and the solution
was stirred at ambient temperature for 12 h. After this a second portion of precatalyst B (6.54
mg, 1.0 mol %) and 1ꢀdecene (701 mg, 5.00 mmol) were added and the solution was stirred
for 16 h at ambient temperature. The volatile compounds were removed in vacuo and the
3
residue was redissolved in toluene (5.0 mL). Et SiH (928 mg, 8.00 mmol) was added and the
solution was stirred at 110 °C for 24 h. The mixture was cooled to 60 °C and pꢀTSA (5 mg)
was added. After stirring for 12h at 60 °C the solution was quenched by addition of a satd. aq.
solution of NaHCO . The aqueous layer was extracted with ethyl acetate (three times 10 mL)
3
4
and the combined organic layers were dried with MgSO . All volatiles were removed under
reduced pressure and the residue was purified by column chromatography on silica, using
hexanes/ethyl acetate mixtures as eluent, to furnish 2 (39%, 122 mg 0.39 mmol).
Methyl (5R,6R,E)-6-acetoxy-5-hydroxyocta-3,7-dienoate (14) and methyl (5R,6R,E)-5-
acetoxy-6-hydroxyocta-3,7-dienoate (15). Compound 13 (78 mg, 0.50 mmol) and methylꢀ3ꢀ
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butenoate (60 mg, 0.60 mmol) were dissolved in CH Cl (1.0 mL). Precatalyst B (3.27 mg,
2
2
1.0 mol%) was added and the solution was stirred at ambient temperature for 12 h. The
volatiles were then evaporated in vacuo and the residue was purified by column
chromatography on silica using hexanes/MTBE mixtures as eluent to furnish 14 and 15 (73%,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
8
5 mg, 0.37 mmol) as an inseparable 1 : 1 mixture: brownish liquid; H NMR (500 MHz,
CDCl ) δ 5.95 – 5.75 (m, 2H), 5.65 – 5.56 (m, 1H), 5.39 – 5.20 (m, 3H), 4.21 (m, 1H), 3.68
3
13
(
s, 3H), 3.10 (dm, J = 7.2 Hz, 2H), 2.11 (s, 3H); C NMR (126 MHz, CDCl ) δ 172.8, 172.7,
3
171.3, 171.3, 137.1, 133.8, 132.9, 129.7, 128.5, 126.6, 120.2, 118.3, 78.0, 77.3, 74.8, 74.2,
53.1, 53.6, 38.5, 38.5, 22.2, 22.2; IR (ATR) ν 3421 (w), 1732 (s); HRMS (ESI) calcd for
+
C
11
H
16
O
5
Na [M +Na] 251.0895, found 251.0900.
Dimethyl (3E,5R,6R,7E)-5-acetoxy-6-hydroxydeca-3,7-dienedioate (16). Compound 13
78 mg, 0.50 mmol) and methylꢀ3ꢀbutenoate (250 mg, 2.50 mmol) were dissolved in CH Cl
(
2
2
(1.0 mL). Precatalyst B (3.27 mg, 1.0 mol%) was added and the solution was stirred at
ambient temperature for 12 h. The volatiles were then evaporated in vacuo and the residue
was purified by column chromatography on silica using hexanes/ethyl acetate mixtures as
26
eluent to furnish 16 (60%, 90 mg, 0.30 mmol): brownish liquid; [α]D +6.2 (c 0.260,
1
CH
2
Cl
2
); H NMR (300 MHz, CDCl
3
) δ 5.94 – 5.80 (m, 2H), 5.64 – 5.51 (m, 2H), 5.22 (dd, J
=
6.4, 6.1 Hz, 1H), 4.19 (dd, J = 5.7, 5.5 Hz, 1H), 3.66 (s, 6H), 3.08 (d, J = 6.9 Hz, 4H), 2.32
13
3
(s, 3H); C NMR (75 MHz, CDCl ) δ 171.8, 171.6, 170.2, 132.0, 128.7, 127.4, 125.4, 76.3,
73.1, 52.0, 51.9, 37.5, 21.1; IR (ATR)
ν 3522 (w), 1730 (s), 1232 (s); HRMS (ESI) calcd for
+
C H O Na [M +Na] 323.1107, found 323.1082.
14
20
7
Methyl (3E,5R,6R,7E)-6-acetoxy-5-hydroxyhexadeca-3,7-dienoate (17) and methyl
3E,5R,6R,7E)-5-acetoxy-6-hydroxyhexadeca-3,7-dienoate (18). A mixture of isomers 14
and 15 (114 mg, 0.50 mmol) and 1ꢀdecene (350 mg, 2.50 mmol) were dissolved in CH Cl
(
2
2
(2.5 mL). Precatalyst B (3.27 mg, 1.0 mol%) was added and the solution was stirred at
ambient temperature for 3 h. All volatiles were evaporated in vacuo and the residue was
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5
5
5
5
5
5
5
5
6
purified by column chromatography on silica using hexanes/ethyl acetate mixtures as eluent
to furnish 16 and 17 (73%, 125 mg, 0.37 mmol) as an inseparable 1 : 1 mixture: brownish
1
liquid; H NMR (500 MHz, CDCl
3
) δ 5.93 – 5.80 (m, 1H), 5.84 – 5.69 (m, 1H), 5.63 – 5.53
(m, 1H), 5.46 – 5.35 (m, 1H), 5.24 – 5.10 (m, 1H), 4.20 – 4.05 (m, 1H), 3.68 (s, 3H), 3.09 (d,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
J = 7.1 Hz, 2H), 2.09 (s, 3H, isomer 1), 2.08 (s, 3H, isomer 2), 2.07 – 1.98 (m, 2H), 1.68 (s,
1
3
1
1
H), 1.30 – 1.21 (m, 14H), 0.87 (t, J = 6.9 Hz, 3H); C NMR (126 MHz, CDCl ) δ 172.5,
3
72.5, 171.2, 171.2, 138.3, 135.9, 135.9, 133.0, 129.8, 129.8, 128.5, 128.5, 127.9, 127.9,
126.0, 125.1, 77.5, 77.5, 74.7, 73.8, 52.9, 52.9, 38.4, 38.4, 33.3, 33.2, 32.8, 32.8, 30.4, 30.3,
30.2, 30.1, 30.0, 23.6, 22.1, 15.0; IR (ATR) 3451 (w), 1720 (s); HRMS (ESI) calcd for
+
C
19
H
32
O
5
Na [M +Na] 363.2147, found 363.2120.
Acknowledgments
We thank Evonik Oxeno for generous donations of solvents and Umicore (Hanau, Germany)
for generous donations of catalysts. This work was generously supported by the Deutsche
Forschungsgemeinschaft (DFGꢀgrant Schm1095/6ꢀ2).
Supporting Information Available statement
1
13
Copies of H and C NMR spectra for all compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
References and Footnotes
(1)
Arensburger, P.; Megy, K.; Waterhouse, R. M.; Abrudan, J.; Amedeo, P.;
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Costas, J.; Eisenstadt, E.; Feschotte, C.; FraserꢀLiggett, C.; Guigo, R.; Haas, B.; Hammond,
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M. C.; Roberston, H. M.; Severson, D. W.; Shumway, M.; Stanke, M.; Strausberg, R. L.; Sun,
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(
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(
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(
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
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9
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(
Asymmetry 2014, 25, 610ꢀ616.
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Asymmetry 2005, 16, 1305ꢀ1307.
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(
(
(
36) Prasad, K. R.; Anbarasan, P. Tetrahedron: Asymmetry 2007, 18, 2479ꢀ2483.
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(
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