Total Synthesis of (-)-Mucosin and Revision of Structure

Article abstract of DOI:10.1021/acs.joc.8b02318

The first total synthesis of (-)-mucosin (6), an unusual marine hydrindane natural product incorporating a prostaglandin-like submotif, has been achieved. As a result of the campaign, three of the four all-carbon stereocenters in the purported structure 1 have been revised. Of particular note is the excellent control over β-chirality in conjugate addition to ester (-)-22 and the facial selectivity in the subsequent protonation of an intermediate silyl ketene acetal.

Full text of DOI:10.1021/acs.joc.8b02318

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Article
Total Synthesis of (–)-Mucosin and Revision of Structure
Jens M. J. Nolsøe, Simen Antonsen, Carl Henrik Gørbitz, Trond Vidar
Hansen, Jannicke I. Nesman, Åsmund K. Røhr, and Yngve H. Stenstrøm
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02318 • Publication Date (Web): 01 Nov 2018
Downloaded from http://pubs.acs.org on November 2, 2018
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The Journal of Organic Chemistry
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Total Synthesis of (–)-Mucosin and Revision of Structure
Jens M. J. Nolsøe,*,† Simen Antonsen,† Carl H. Görbitz,‡ Trond V. Hansen,†,§ Jannicke I. Nesman,†
Åsmund K. Røhr† and Yngve H. Stenstrøm†
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†Faculty of Chemistry, Biotechnology and Food Science, Norwegian University of Life Sciences, PO box 5003, 1432 Ås,
Norway
‡Department of Chemistry, University of Oslo, PO box 1033, 0315 Oslo, Norway
§Department of Pharmaceutical Chemistry, University of Oslo, PO box 1068, 0316 Oslo, Norway
ABSTRACT: The first total synthesis of (–)-mucosin (6), an unusual marine hydrindane natural product incorporating a
prostaglandin-like submotif, has been achieved. As a result of the campaign, three of the four all-carbon stereocenters in the
purported structure 1 have been revised. Of particular note is the excellent control over -chirality in conjugate addition to ester (–)-
22 and the facial selectivity in the subsequent protonation of an intermediate silyl ketene acetal.
Arachidonic acid (3) was cited as a plausible biogenetic origin.
The elucidation relied primarily on 2D-NMR and the relative
arrangement of the four contiguous stereogenic points was
assigned on the basis of NOESY and ROESY. However,
considering that the distinguishing correlations are confined to
a crowded aliphatic region, the absence of any corroborative
coupling patterns makes the proffered structure rest on a
precarious foundation.
INTRODUCTION
With the current level of sophistication achieved in organic
analytical techniques, it is easy to make the presumption that
structural elucidation of small-molecule natural products has
been made routine. Yet, alicyclic compounds adorned with
multiple contiguous points of chirality can still pose a
challenge when only minute amounts are available. In the
absence of X-ray crystallography, the relative topology may
be inferred by various NMR experiments.1 However, the
Achilles heel is the interpretation of the available data and
whether or not it can provide a proper basis to unravel the
architecture. Consequently, in the context of structural
elucidation and total synthesis, misassignment is a looming
peril and the target may prove to be an evasive entity.2
Although, from time to time, errors are encountered,3 the
following narrative offers a particularly interesting example of
how an incorrect structure and a mechanistic switch concealed
within the synthetic sequence have conspired to mutually
reinforce the illusion of veracity.
Given the structural attributes and the paucity of material,
the isolate from R. mucosa merits further investigation.
Ultimately, any biological evaluation hinges on the availability
and identity of the analyte. For this reason, contriving a
coherent synthetic strategy is essential. However, while the
physiological activity spectrum of the compound is unknown,
it may be noted that in the marine environment, the effect
exerted by specific arachidonic acid metabolites can serve as a
chemical defence. For example, the Caribbean coral Plexaura
homomalla produces elevated levels of prostaglandin (15S)-
PGA2 (4), which acts as an emetic in predatory fish.5
In 2012, Whitby et al. communicated their total synthesis of
antipodal (+)-mucosin,6 according to the alleged configuration
(ent-1).4 The key strategic transformation depended on
zirconium induced co-cyclization to install the correct
topology. Thus, it was projected that the intramolecular
reaction of a properly functionalized triene would furnish the
complete bicyclic core, controlling the geometry at the points
of substitution through formation of a zirconacycle. Bolstered
by results from a model system, the reaction was then
implemented in the sequence proper, encompassing 14
truncated steps to achieve the target in an overall yield of 7%.
The data gathered from the prepared material was reported to
align with the natural product from R. mucosa in all except
sign of the optical rotation.4,6,7 Paradoxically, as it became
evident later on, Whitby et al. inadvertently came up with the
correct antipode rather than achieving the total synthesis of
ent-1 (Figure 2).
In 1997, following a prospection in different regions of the
Mediterranean Sea, Casapullo et al. reported on the isolation
and characterization of an unusual eicosanoid from the marine
4
―
sponge Reniera mucosa. Named pseudo-eponymously ( )-
mucosin, their analysis was performed on the corresponding
methyl ester. It concluded that the C20-compound was
structure 1, having
a cis-fused bicyclo[4.3.0]non-3-ene
scaffold with an embedded prostaglandin-like motif (Figure
1).
Figure 1. Proposed structure of (–)-mucosin, suggested origin and
an illustrative marine prostaglandin.
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Applying the developed chemistry and demonstrating a
1
2
3
4
stereodivergent protocol, the topology of the appended
positions was examined by formation of the corresponding
anti-permutant 5 (Figure 3, eq 2).9 Yet, while the intended
pattern was confirmed by X-ray crystallography, the probe did
not match mucosin.
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RESULTS AND DISCUSION
Figure 2. Preceding attempt on total synthesis of ent-1.
Early on in our synthetic campaign directed towards the
preparation of (–)-mucosin, we voiced some concerns about
the geometry at the points of fusion.8,9 Assuming that
arachidonic acid (3) is indeed the biogenetic progenitor, the
core structure found in 1 invokes a formal disrotatory ring-
closure. A survey of the known enzymes operating on this
particular polyene system singled out 5-lipoxygenase (5-LOX)
as a possible asymmetric promotor, catalysing stereospecific
peroxidation at C5 and the concomitant formation of a 6E,8Z-
diene system.10 Taking cue from previous mechanistic
discussions of 5-LOX, a tentative biosynthetic route has been
contrived (Figure 4).
A few years after the apparent endorsement of the
assignment published by Casapullo et al,4 the authors of the
present paper followed a different approach and demonstrated
irrefutably that structure 1 does not represent (–)-mucosin.8
Central to the enforced strategy was the placement of a
Michael acceptor within the bicyclo[4.3.0]non-3-ene scaffold.
Taking heed of the inherent conformational restrictions caused
by the cis-fusion, it was projected that the implied conjugate
addition would proceed with a bias for the targeted topology.
Accordingly, the initial nucleophilic attack was anticipated to
occur from the less hindered exo face, while protonation of the
supervening enolate would be subject to kinetic vs.
thermodynamic control. Guided by eclipsing interactions and
A-values, equilibrating conditions ought to dictate anti-
orientation on the disubstituted cyclopentane moiety. This
pivotal conjecture was subsequently underpinned by a crystal
structure, demonstrating how the steric effects and
thermodynamic control had singled out one diastereomer.
With the topology confirmed, it ultimately also contradicted
the assignment of (–)-mucosin,4 since none of the data from
the final compound matched the natural product (Figure 3, eq
1).8 Our findings even impinged the mechanistic rational
provided by Whitby et al. for the
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Figure 4. Hypothetical cyclization of 3 catalysed by 5R-LOX.
The key aspects to note are: (i) intramolecular activation of
C16 by the hydroperoxide to instigate a 6-exo-trig cyclization,
leading to (ii) the stereospecific formation of a trans-vinyl
epoxide at C8 and (iii) its subsequent reaction in a 5-exo-trig
cyclization with an E-alkene at C15. In detail, the activation is
a suprafacial [6+4] process,11 which instigates cyclization
via an extended π-allyl system and dictates the final geometry
Figure 3. Total syntheses of 1 and the permutant 5.
implementation of zirconium induced co-cyclization in the
preparation of 1.6 Thus, assuming that the factors governing
the stereochemical outcome of the featured cyclization had
been misconceived, we prepared a probative structure of 1.
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at the reacting termini (C8 and C16). Governed by
transannular strain in the macrocyclic transition state, the
Based on our previous efforts,8,9 we devised a flexible
strategy that evolved around the application of
1
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“chair” conformation is preferred over the “boat”
conformation, dictating the fusion geometry in the ensuing 6-
exo-trig cyclization. At the point of initiation the E-alkene at
C15 is a consequence of a gauche configuration at C16. The
following 5-exo-trig cyclization resembles a Michael addition
and is under thermodynamic control. Thus, the delineated
biosynthetic pathway (vide supra) singles out the trans-fused
scaffold and defines an anti-configuration for the two
substituents. Eventually, there is no ambiguity in terms of
selectivity and the absence of any A1,2 strain identifies
structure 6 as the favoured diastereomer.
diastereoselective conjugate addition (Scheme 1). Relying on a
known Diels- Alder protocol to furnish the asymmetric
starting point,18 the featured Michael acceptor 10 would be
obtainable from the corresponding en route -keto ester 11.
Compared with the cis-fused system, the projected conjugate
addition could not call upon the same steric factors to control
facial selectivity. Thus, instead of endo/exo differentiation, we
invoked the presence of A1,2 strain in the transition state to be
the guiding rail.
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In the execution of the outlined strategy, our total synthesis
commenced with preparation of starting material (Scheme 2).
Although an antipodal ()-ethyl -keto ester of 11 is known in
the literature,19 neither the ()- nor the (+)-methyl -keto ester
have been described before. For the purpose of having an
easily identifiable marker in 1H-NMR to gauge reactions by, it
was opted for methyl ester (+)-21. This would also allow the
current findings to be assessed relative to our previous work in
the campaign.8,9 The synthetic sequence leading to methyl -
keto ester (+)-21 was conducted in 7 steps with an overall
yield of 63%. To make proper provisions for the strategy, the
sequence was streamlined to supply gram quantities of starting
material and to minimize chromatographic purification. Thus,
subsequent to asymmetric Diels-Alder by the protocol of
Furuta et al.,18 and reduction of the resulting cycloadduct ()-
16 to diol ()-17, the remaining five steps leading to (+)-21
took advantage of extractive work-up and recrystallization.
Relying on the non-commercial alkene ()-15 to provide the
featured chirality, it was easily prepared by esterification of
fumaric acid with ()-menthol. Using DIBAL-H in the
reduction of cycloadduct ()-16 allowed recovery of the chiral
auxiliary without change in optical activity.
From a general mechanistic perspective, Gerwick has
proposed epoxy allylic carbocations as conceptual
intermediates in the biogenesis of marine carbocyclic
oxylipins.12 This could in principle apply to the pathway
suggested by us and is easily implemented without affecting
the overall stereochemical arguments. However, in its present
form, it serves the intended purpose to define a plausible target
in an unequivocal manner. Also, it could open up a vista onto
a biomimetic approach.
To evaluate the forecast, we performed a series of DFT
calculations, comparing geometry optimized structures of the
trans-fused diastereomers 6 and 7, as well as of the cis-fused
diastereomers 1 and 5 (Figure 5). All the results were obtained
in ORCA 4.0,13 using the hybrid meta-functional TPSSh,14 the
def2-TZVP basis set,15 and Grimme’s D3 dispersion
correction.16 What transpired by inspecting the computations
was the significance of eclipsing interactions and their impact
on the relative energies: Ranked according to decreasing
strain, the order was found to be structure 5, 1, 7 and 6.
Furthermore, observations pertaining to the synthesis executed
by Whitby et al., suggested that H8 and H9 are anti-periplanar
in the natural product.6,17 Consequently, the gathered
information cemented structure 6 as the target molecule in
pursuit of (–)-mucosin.
Scheme 1. Retrosynthetic Analysis of Target Molecule 6
A1,2 strain = 2
A1,2 strain = 1
H
H
CO2H
CO2H
H
H
5 (0.00 kcal/mol)
1 (-0.68 kcal/mol)
A1,2 strain = 1
A1,2 strain = 0
H
H
CO2H
CO2H
H
H
7 (-2.15 kcal/mol)
6 (-5.88 kcal/mol)
Figure 5. DFT calculations comparing geometry optimized 1 with
permutants 5, 6 and 7.
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Scheme 2. Synthesis of Methyl -Keto Ester (+)-21a
ethoxy-4-oxobutylzinc bromide in THF, (Ph3P)4Pd (cat.), rt, 7 h,
64% over three steps; (i) LiOH, THF/MeOH/H2O, rt, 12h, 96%;
(j) TMSCHN2, toluene/MeOH, 1h, rt, quant.
1
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5
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9
was prepared by Pd-catalysed reductive desulfonylation of the
corresponding conjugate vinyl triflate.23 However, being
unable to obtain (–)-22 in sufficient chemical purity for the
critical reaction, it was opted for an efficient three-step
dehydration protocol. With the unsaturated motif installed, the
conjugate addition was performed using the recognised
constellation of BuMgCl with TMSCl in the presence of CuI.9
While the addition proceeded with excellent control over the
-chirality, the protonation of the intermediate silyl ketene
acetal was more fickle. Thus, in the initial experiments, the
adduct ()-23 was formed with a dr of 85:15. This necessitated
meticulous chromatographic separation of the two -epimers
in the following step. However, minor adjustments with regard
to the quenching by dropwise addition of satd. aq. NH4Cl
eventually produced ()-23 with a dr of 93:7. After reduction
to carbinol ()-24, the topology was subsequently confirmed
by derivatization to the non-epimerizable 3,5-dinitrobenzoate
()-24-DNB and performing X-ray crystallography (Figure 6).
Also, before proceeding any further, the carbinol derivative
()-24-DNB was subjected to HPLC analysis using a chiral
column and was shown to have an ee in excess of 99%.
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aReagents and conditions: (a) 1,3-butadiene, DIBAL-Cl, hexane, -
40 to -30 C, 20 h, 96%; (b) DIBAL-H, hexane/CH2Cl2, -78 C to
rt, 16 h, 89%; (c) TsCl, pyridine, 0 C, 12 h, 96%; (d) NaCN,
EtOH, , 30 h, 98%; (e) KOH, H2O, , 36 h; (f) MeOH, H2SO4
(cat.), 50 C, 12 h, 86% over two steps; (g) NaH, THF, ,16 h,
91%.
Having previously demonstrated the ability to control
topology on the cis-fused bicyclo[4.3.0]non-3-ene scaffold,8,9
Cu(I) catalysed conjugate addition was cast as a fulcrum
feature in the total synthesis of 6.20 In the preceding example,
we observed a pronounced selectivity in terms of -chirality,
favouring the less hindered face. The facial selectivity may in
part be accounted for by the formation of a transient and
NO2
O2N
reversible
metallocyclopropane
undergoing
oxidative
O
O
H
addition/reductive elimination with the ,-unsaturated
system.21 The effect is to exaggerate steric repulsion at the
more congested face and is in line with the Dewar-Chatt-
Duncanson model.22 Following this reasoning, the main
sequence of the total synthesis was put in train (Scheme 3).
Initially, the Michael acceptor ()-22
Bu
H
(- )-24-DNB
Scheme 3. Total Synthesis of (–)-Mucosin (6)a
Figure 6. Single-crystal X-ray structure obtained from (–)-24-
DNB recorded at 100K (50% probability displacement ellipsoids).
In the main synthetic route, the carbinol ()-24 was
processed into an alkyne handle over four steps.24 Then,
capitalizing on a series of telescoped reactions developed by
us,8,9 the alkyne ()-26 was subjected to sequential
hydrometallation, halogenation and Pd-catalysed cross-
coupling to furnish the complete E-alkenyl sidechain present
in the candidate structure. In principle, hydrolysis of ethyl
ester ()-27 concluded the campaign by delivering ()-6 as the
target molecule. Yet, in order to make the necessary
correlation with the compound isolated by Casapullo et al.,4
and the material synthesised by Whitby et al.,6 the final
transformation was to prepare methyl ester ()-8.
aReagents and conditions: (a) (i) NaBH4, MeOH, 0 C, 1 h, 95%;
(ii) MsCl, Et3N, CH2Cl2, 0 C to rt, 12 h, 96 %; (iii) DBU,
toluene, r.t., 5 h, 93%; (b) BuMgCl, TMSCl, CuI (cat.), –35 C, 2
h, then NH4Cl (aq), –35 C to rt, 85% with dr 93:7; (c) DIBAL-H,
hexane, 0 C to rt, 1 h, 88%; (d) MsCl, Et3N, CH2Cl2, 0 C to rt,
12 h, 98 %; (e) KCN, DMSO, 70 C, 2h, quant.; (f) DIBAL-H,
hexane, –78 C, 2 h, 91%; (g) Ohira-Bestmann reagent [dimethyl
(1-diazo-2-oxopropyl)phosphonate], K2CO3, MeOH, 0 C to rt, 6
h, quant.; (h) (i) Cp2ZrCl2, DIBAL-H, THF/hexane, 0 C, 1 h,
then (–)-25 in THF, 0 C to rt, 2 h; (ii) I2 neat, rt, 1 h; (iii) 4-
Gratifyingly, when comparing all the recordings made on
methyl ester ()-8 with the values reported in literature,4,6,7 an
excellent agreement was found. In particular, a perfect pairing
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1
was seen when the H- and 13C-NMR spectra were overlaid
with those provided by Whitby et al.6,17 Furthermore, the
optical rotation had both similar magnitude and sign as the
methyl ester isolated from R. mucosa, while opposite sign of
the synthetic material purporting to be the cis-fused ent-2.
(+)-21 to arrive at the target structure as methyl ester ()-8 in
an overall yield of 35% and in 102 mg quantities. The devised
synthetic route is therefore capable of delivering sufficient
material for comprehensive biological testing. Furthermore, in
light of the structural assignment, some mechanistic aspects of
zirconium induced co-cyclization will have to be re-evaluated.
We are currently perusing this point and investigate the
synthetic utility. To the mind of the authors, the unique aspects
of the executed campaign show forth natural product synthesis
as an enabling technology on multiple levels.
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8
[훼]2퐷0
Thus, for the methyl ester ()-8 we registered an
= ―42.9 (푐 = 0.8, hexane)
, while the published values for
mucosin methyl ester and the methyl ester of Whitby et al. had
[훼]2퐷0 = ―35.5 and +38.2 (푐 = 0.8, hexane)
been given as
respectively.4,6
,
9
The structural elucidation has revealed a subtle mechanistic
switch, which has thwarted the original conception by Whitby
et al. regarding zirconium mediated co-cyclization as a vehicle
for the preparation of cis-fused 1.6, In this sense, the present
work represents a manifest example of how total synthesis can
serve as a mechanistic probe through side-by-side comparison
of structures and outcome. As a tentative explanation for the
observed disparity between the model and real system aimed
at cis-fused 1, we invoke the steric requirements of the allyl
zirconium species (Figure 7). Thus, the difference in rate of
ligation between a terminal methylene allyl (Figure 7, eq 1)
and a terminal methine allyl functionality is postulated to
dictate the outcome of zirconium induced co-cyclization
(Figure 7, eqs 2 and 3).
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EXPERIMENTAL SECTION
General Information. All commercially available reagents and
solvents were used in the form they were supplied without any further
purification. (+)-Menthol (optical purity 96% ee by GLC) was
purchased from Sigma-Aldrich. The stated yields are based on
isolated material. The melting points are uncorrected. Thin layer
chromatography was performed on silica gel 60 F254 aluminium-
backed plates fabricated by Merck. Flash column chromatography
was performed on silica gel 60 (40-63 µm) fabricated by Merck.
NMR spectra were recorded on a Bruker AscendTM 400 at 400 MHz
1
for H NMR and at 100 MHz for 13C NMR. Coupling constants (J)
are reported in hertz and chemical shifts are reported in parts per
million () relative to the central residual protium solvent resonance
in 1H-NMR (CDCl3 =  7.27 ppm) and the central carbon solvent
resonance in 13C-NMR (CDCl3 =  77.00 ppm). Mass spectra were
recorded at 70 eV on Waters Prospec Q spectrometer using EI as the
method of ionization. Alternatively, HRMS-ESI spectra were
measured with a Bruker Apex 47e QTOF instrument. IR spectra
(4000-650 cm-1) were recorded on a Agilent Technologies 5500
Series FT-IR Compact spectrophotometer. UV/Vis spectra from 190-
900 nm were recorded using
a
Biochrom Libra S32PC
spectrophotometer using quartz cuvettes and the stated solvents.
Optical rotations were measured using a 1 ml cell with a 1.0 dm path
length on a Perkin Elmer 341 polarimeter using the stated solvents.
Determination of enantiomeric excess was performed by HPLC on an
Agilent Technologies 1200 Series instrument with the diode array
detector set at 206 nm and equipped with a chiral stationary phase
column (Chiralcel OD-H, 4.6 x 250 mm, particle size 5 μm, from
Daicel Chemical Ind., Ltd) applying the conditions stated. X-ray
crystallography was performed on
a
Bruker D8 Venture
diffractometer with InCoatec ImuS Microfocus radiation source and
Photon 100 CMOS detector. Data collection with Apex2,25 data
integration and cell refinement with SAINT,25 absorption correction
by SADABS,25 structure solution with SHELXT,26 structure
refinement with SHELXL.27 Molecular graphics from Mercury.28 The
crystal deposition identifier is CCDC 1865776. Theoretical
calculations were carried out using ORCA4.13 The detailed options in
the input file were “! TPSSh RIJCOSX OPT def2-TZVP def2/J Grid6
D3BJ TightSCF”. The coordinates of all final geometries are listed in
the supporting information, starting at page S46. Diastereomeric
ratios reported in this paper have not been validated by calibration,
please consult the reference Wernerova and Hudlicky for discussions
and guidelines.29
(E)-1,4-bis((1S,2R,5S)-2-isopropyl-5-methylcarbcyclohex-1-
oxy)but-2-ene ((+)-15).30 A mixture of fumaric acid (4.89 g, 42.2
mmol, 1.00 equiv.) and (+)-menthol (37.5 g, 240.5 mmol, 2.85 equiv.)
was dissolved/suspended in benzene (50 ml). To the
solution/suspension was added conc. H2SO4 (2.0 ml, 3.68 g, 37.5
mmol) and the resulting reaction mixture was heated to reflux. After
48h, the heating was discontinued and upon cooling the yellow
mixture was washed in succession with water (2 x 50 ml), aq.
saturated NaHCO3 (2 x 50 ml) and brine (50 ml). The organic phase
was dried over MgSO4, filtered and the solvent was evaporated in
vacuo. The residue was purified by column chromatography on silica
(hexane, followed by hexane/EtOAc 90:10). This afforded the title
compound as a clear, highly viscous, syrup. Yield: 15.61 g, 87%;
TLC: Rf = 0.56 (Hexane/EtOAc 4:1, visualized with UV and KMnO4-
Figure 7. A mechanistic rational for the actual results obtained by
Whitby et al. using zirconium induced co-cyclization.
CONCLUSIONS
The original assignment of ()-mucosin as structure 1 has
been soundly negated.4 Consequently, the total synthesis that
provided the topological reaffirmation relied on a flawed key
transformation.6 In the present work, the true structure of the
isolated natural product from R. mucosa has been established
as 6. Capitalizing on a biogenetic conjecture as the key
concept, which was further underpinned by comparative DFT
calculations, we have executed a 14 steps linear sequence from
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 12
[훼]20 = + 95.2
휈
temperature and stirred for 4 h. Now, the phases were separated.
Attempt to extract the aq. phase with EtOAc resulted in the formation
dip);
(c = 1.76, CHCl3); IR (film):
2951, 2928,
max
퐷
2869, 1717, 1449, 1374, 1285, 1257, 1140 cm-1; H-NMR (CDCl3,
400 MHz):  6.82 (s, 2H), 4.79 (dt, J1 = 10.9 Hz, J2 = 4.4 Hz, 2H),
2.00-2.05 (m, 2H), 1.82-1.93 (m, 2H), 1.66-1.74 (m, 4H), 1.40-1.58
(m, 4H), 0.98-1.13 (m, 4H), 0.88-0.94 (m, 14H), 0.76 (d, J = 6.9 Hz,
6H); 13C{1H}-NMR (CDCl3, 100 MHz):  164.6, 133.8, 75.3, 47.0,
40.7, 34.1, 31.4, 26.2, 23.3, 22.0, 20.7, 16.2; HRMS (EI+): Exact
mass calculated for C24H40O4 [M]+ 392.2927, found 392.2903.
1
1
2
3
4
5
6
7
8
of a gel. The gel was poured onto a sinter funnel (frit porosity P3) and
repeated washing/decantation with EtOAc (in total 1.5 L) was
performed. The combined organic phases were dried over MgSO4,
filtered and the solvent was evaporated in vacuo. The resulting syrupy
residue was purified by column chromatography on silica (hexane,
followed by hexane/EtOAc 90:10, 80:20, 50:50 and pure EtOAc).
This afforded the title compound (–)-17 as a faint off-white solid after
being azeotroped with CHCl3 at elevated temperature in vacuo (bath
temperature 55 °C, 3.8 mbar). However, the solid sublimates easily
under the said conditions. Yield: 4.84 g, 89%; TLC (hexane/EtOAc
(1R,6R)-Bis((1S,2R,5S)-2-isopropyl-5-methylcarbcyclohex-1-
oxy)cyclohex-3-ene ((+)-16).31 Diester (+)-15 (15.61 g, 39.8 mmol,
1.00 equiv.) was first azeotroped with hexane in vacuo (2 x 100 ml)
and then dissolved in dry hexane (250 ml). The solution was cooled to
-40 °C and DIBAL-Cl (25% w/w in hexane, 80.0 ml, 14.4 g, 81.6
mmol, 2.05 equiv.) was added dropwise to the stirring solution,
resulting in a deep orange/red complex. The generated Lewis acid-
base pair was stirred at -40 °C for 0.5 h. In parallel, in a separate flask
at -78 °C was added 1,3-butadiene (20 ml, 12.3 g, 0.227 mmol, 5.71
equiv.) and cooled for 0.5h. Then, the precooled diene was added
dropwise to the complex of (+)-15 via a double-tipped cannula
(cooled by dry-ice wrapped in an aluminium sheet covering the
exposed length of the cannula). The reaction was monitored by TLC
(hexane/EtOAc 80:20, visualized by UV and KMnO4-stain).
According to this the starting material (Rf = 0.56, UV active) had
been essentially consumed and a less lipophilic compound (Rf = 0.52,
not UV active) had appeared. The temperature was then allowed to
slowly equilibrate to -30 °C. As the mixture heated up, it
progressively became lighter in colour. After 2 h at -30 °C, the
mixture had become lemon coloured and turbid. The mixture was left
at the stated temperature overnight. At this stage, TLC indicated that
no starting material remained. The cooling was discontinued and the
now clear yellow reaction mixture was allowed to attain ambient
temperature. Using a double cannula, the reaction mixture was added
dropwise into dilute aq. HCl (200 ml) with agitation. Saturated aq.
Rochelle’s salt (200 ml) was added and the biphasic mixture was
stirred for 0.5 h. Then, the phases were separated and the aq. phase
was extracted with Et2O (4 x 50 ml). The combined organic phases
were washed in succession with saturated aq. NaHCO3 (200 ml) and
brine (200 ml). The organic phases were dried over MgSO4, filtered
and the solvent was evaporated in vacuo (final bath temperature 50 °C
at 3.8 mbar). This afforded the pure title compound (+)-16 based on
NMR as an opaque, highly viscous, syrup. Yield: 17.05 g, 96%; TLC
[훼]20
9
[훼]20
o
50:50, visualized by KMnO4-stain): Rf = 0.09; M.p.: 52-54 C;
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
퐷
= ― 65.7
휈max
3329, 3026, 2891,
(c = 1.48, CHCl3); IR (film):
1438, 1068, 1023 cm-1; 1H-NMR (CDCl3, 400 MHz):  5.62-5.68 (m,
2H), 3.72 (dd, J1 = 11.1 Hz, J2 = 3.0 Hz, 2H), 3.58 (dd, J1 = 11.1 Hz,
J2 = 6.5 Hz, 2H), 3.30 (s, 2H), 2.00-2.07 (m, 2H), 1.81-1.89 (m, 2H),
1.64-1.73 (m, 2H); 13C{1H}-NMR (CDCl3, 100 MHz):  126.0, 66.2,
39.7, 28.5; HRMS (EI+): Exact mass calculated for C8H14O2 [M]+ m/z
142.0994, found 142.0992.
(1R,6R)-Bis((p-toluenesulfonyloxy)methyl)cyclohex-3-ene ((–)-
18).32 Diol (–)-17 (4.50 g, 31.7 mmo, 2.00 equiv.) was dissolved in
dry pyridine (25 ml) and cooled to 0 °C. p-Toluenesulfonyl chloride
(18.1 g, 95.0 mmol) was added in portions with efficient stirring.
Maintaining the cooling, the reaction mixture was stirred overnight,
whereupon it was poured into dilute aq. HCl (5%, 200 ml). EtOAc
(200 ml) was added to the heterogeneous mixture to dissolve
precipitated material. The phases were separated and the aq. phase
was extracted with EtOAc (5 x 50 ml). The combined org. extracts
were dried over MgSO4, filtered and the solvent was evaporated in
vacuo. This afforded the title compound (–)-18 as a white sugary
solid, which was used without any further purification. Yield: 13.63 g,
96%; TLC: Rf = 0.18 (hexane/EtOAc 80:20, visualized by UV and
[훼]20 = ― 40.0
KMnO4-stain); M.p.: 107-109 °C;
(c = 1.40, CHCl3);
퐷
3031, 2908, 2852, 1600, 1359, 1171, 1093 cm-1; 1H-
휈
IR (film):
max
NMR (CDCl3, 400 MHz):  7.76 (d, J = 8.3 Hz, 4H), 7.36 (d, J = 8.3
Hz, 4H), 5.48-5.55 (m, 2H), 3.90-3.98 (m, 4H), 2.46 (s, 6H), 1.98-
2.01 (m, 4H), 1.82-1.87 (m, 2H); 13C{1H}-NMR (CDCl3, 100 MHz):
 144.9; 132.7, 129.9, 127.8, 124.6, 71.2, 33.0, 25.4, 21.6; HRMS
(EI+): Exact mass calculated for C22H26O6S2 [M]+ m/z 450.1171, found
450.1188.
(hexane/EtOAc 80:20, visualized by KMnO4-stain): Rf = 0.47;
퐷
(1S,6S)-Bis(cyanomethyl)cyclohex-3-ene ((–)-19).32 Ditosylate (–
)-18 (13.6 g, 30.2 mmol, 2.00 equiv.) was dissolved in abs. EtOH
(120 ml) and sodium cyanide (4.97 g, 101 mmol, 3.35 equiv.) was
added. The resulting reaction mixture was heated to reflux and
maintained at that temperature for 48 h. Then, the mixture was cooled
to ambient temperature, decanted and the solvent was evaporated in
vacuo. The residue was suspended/dissolved in CH2Cl2 (150 ml) and
water (150 ml) was added. The resulting biphasic mixture was stirred
for 0.5 h and then the phases were separated. The aq. phase was
extracted with CH2Cl2 (3 x 50 ml), whereupon the combined organic
phases were dried over Na2SO4, filtered and the solvent was removed
in vacuo. This afforded a tanned solid, which upon analysis was
shown to be the title compound (–)-19 with some minute impurities
and was subsequently used as is without further purification. Yield:
4.74 g, 98%; TLC (hexane/EtOAc 80:20, visualized by KMnO4-
= + 29.0
휈max
2952, 2922, 2869,
(c = 2.07, CHCl3); IR (film):
1728, 1456, 1386, 1368, 1298, 1234, 1175 cm-1; 1H-NMR (CDCl3,
400 MHz):  5.65-5.72 (m, 2H), 4.67 (dt, J1 = 10.9 Hz, J2 = 4.34 Hz,
2H), 2.83-2.90 (m, 2H), 2.40-2.45 (m, 2H), 2.12-2.20 (m, 2H), 1.98-
2.04 (m, 2H), 1.84-1.92 (m, 2H), 1.64-1.69 (m, 4H), 1.45-1.56 (m,
2H), 1.36-1.44 (m, 2H), 0.98-1.10 (m, 4H), 0.88-0.91 (m, 14H), 0.74
(d, J = 6.92 Hz, 6H); 13C{1H}-NMR (CDCl3, 100 MHz):  174.5,
125.0, 74.3, 47.0, 41.2, 40.7, 34.3, 31.4, 27.9, 25.9, 23.1, 22.0, 20.8,
15.9; HRMS (EI+): Exact mass calculated for C28H46O4 [M]+ m/z
446.3396, found 446.3388.
(1R,6R)-Bis(hydroxymethyl)cyclohex-3-ene ((–)-17).31 Diester
(+)-16 (17.05 g, 38.2 mmol, 2.00 equiv.) was dissolved in dry CH2Cl2
(100 ml) and cooled to -78 °C. DIBAL-H (1M in hexane, 195.0 ml,
195.0 mmol, 5.10 equiv.) was added via a double tipped cannula in a
dropwise manner. After 2 h at the stated temperature, the reaction
mixture was taken to ambient temperature and was stirred overnight.
By TLC (hexane/EtOAc 80:20, visualized by KMnO4-stain), the
starting material (Rf = 0.47) had been consumed and two, more polar,
components were visible (Rf = 0.16 and Rf = 0.00). The more
lipophilic component was associated with (+)-menthol. TLC
(hexane/EtOAc 50:50, visualized by KMnO4-dip) revealed the
relative mobility of the two components. Thus, the component
associated with (+)-menthol had moved to Rf = 0.62, while the less
polar component had moved to Rf = 0.09. The mixture was then
cooled to 0 °C and treated with MeOH (10 ml). Then, saturated aq.
Rochelle’s salt (100 ml) was added, the mixture was diluted with
CH2Cl2 (200 ml), whereupon the mixture was taken to ambient
[훼]20 = ―95.6
o
stain): Rf = 0.09; M.p.: 86-89 C;
(c = 1.40, CHCl3);
퐷
IR (film): max 3031, 2914, 2841, 2248, 1661, 1421, 1333, 1169 cm-1;
1H-NMR (CDCl3, 400 MHz):  5.63-5.69 (m, 2H), 2.42-2.53 (m, 4H),
2.23-2.35 (m, 2H), 2.01-2.15 (m, 4H); 13C{1H}-NMR (CDCl3, 100
MHz):  124.4, 117.6, 32.6, 28.3, 21.0; HRMS (EI+): Exact mass
calculated for C10H12N2 [M]+ m/z 160.1000 found 160.1004.
휈
(1S,6S)-Bis((carbmethoxy)methyl)cyclohex-3-ene ((–)-20).
(i) Dicyanide (–)-19 (4.74 g, 29.6 mmol) was dissolved in aq. KOH
(33% w/v, 100 ml) and heated to reflux. Relying on olfactory, heating
was terminated once the odour of ammonia was undetectable. The
cooled basic solution was washed with CH2Cl2 (50 ml) and carefully
acidified with conc. HCl to effectuate precipitation (pH = 1). To the
resulting heterogeneous mixture was added EtOAc (100 ml) and the
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The Journal of Organic Chemistry
biphasic mixture was stirred for 0.5 h. The phases were separated and
manner. The reaction mixture was stirred for 10 min at the stated
temperature, whereupon the cooling was discontinued. At this point a
white precipitate had formed. The mixture was stirred at ambient
temperature overnight, which resulted in a turbid yellow mixture.
According to TLC (hexane/EtOAc 80:20, visualized by KMnO4-
stain), the starting material (Rf = 0.11) and the desired mesylate are
indistinguishable from each other. The mixture was treated with brine
(50 ml) and the volatiles were removed in vacuo. The aq. residue was
extracted with EtOAc (4 x 40 ml) and the combined organic extracts
were dried over Na2SO4, filtered and the solvent was evaporated in
vacuo. This afforded a syrupy orange/red crude, which, according to
1H-NMR (CDCl3), corresponded to a diastereomeric mixture of the
desired mesylate pre-(–)-22b. Nominal yield: 2.996 g, 96%; TLC
(hexane/EtOAc 80:20, visualized by KMnO4-stain): 0.11.
the aq. phase was extracted with EtOAc (6 x 50 ml). Then, the
combined organic phases were dried over Na2SO4, filtered and the
solvent evaporated in vacuo. This afforded the crude diacid pre-20 as
a slightly off-white solid, which was used directly without any further
purification. Yield: 5.36 g, 91%; TLC (EtOAc, visualized by KMnO4-
stain): Rf = 0.14.
1
2
3
4
5
6
7
8
(ii) Diacid pre-20 (5.36 g, 27.0 mmol) was dissolved/suspended in
MeOH (200 ml) and con. H2SO4 (0.5 ml) was added dropwise. The
°
resulting reaction mixture was heated to 50 C overnight, whereupon
it was cooled to ambient temperature and aq. satd. K2CO3 (20 ml) was
added. The solvent was concentrated in vacuo and the residue was
treated with a mixture of aq. satd. NaHCO3/water (50:50, 100 ml).
The aq. phase was subsequently extracted with Et2O (4 x 50 ml), the
combined organic extracts were dried over MgSO4, filtered and the
solvent was evaporated in vacuo. This afforded a faint yellow liquid,
which upon NMR analysis was shown to be the pure title compound
(–)-20. Yield: 5.81 g, 95%; TLC (hexane/EtOAc 80:20, visualized by
[훼]2퐷0 = ―47.2
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(iii) Mesylate pre-(–)-22b (2.996 g, 10.9 mmol, 1.00 equiv.) was
dissolved in dry toluene (50 ml) and DBU (4.99 g, 4.9 ml, 32.7 mmol,
3.00 equiv.) was added in a dropwise manner at ambient temperature.
The reaction mixture was stirred at the stated temperature and
followed on TLC (hexane/EtOAc 80:20, visualized by UV and
KMnO4-stain). According to this, the starting material (Rf = 0.11) had
been all but completely consumed after 1h and a more lipophilic spot
(Rf = 0.54) was observed. At this stage, the mixture had taken on a
biphasic character noticeable by a small amount of orange/brown oil
settling at the bottom of the flask. The mixture was allowed to stir 4h
at the stated temperature. Then, mixture was treated with dilute aq.
HCl (2M, 25 ml) and Et2O (25 ml), The phases were separated and
the aq. phase was extracted with Et2O (3 x 20 ml). The combined
organic phases were dried over MgSO4, filtered and the solvent was
evaporated in vacuo. The residue was purified by column
chromatography on silica (hexane, followed by hexane/Et2O 75:25).
This afforded the pure title (–)-22 compound as a clear liquid (NB! It
was noted that, the liquid has a high vapour pressure and is prone to
co-evaporate at 10-20 mbar). Yield: 1.797 g, 84% over 3 steps; TLC
(hexane/EtOAc 80:20, visualized by UV and KMnO4-stain): Rf =
[훼]20
KMnO4-stain) Rf = 0.40;
(c = 1.40, CHCl3); IR
(film): 3028, 2978, 2908, 2846, 1729, 1436, 1269, 1159 cm-1; 1H-
NMR (CDCl3, 400 MHz):  5.52-5.68 (m, 2H), 3.59 (s, 6H), 2.35-
2.49 (m, 2H), 2.24-2.34 (m, 2H), 2.13-2.23 (m, 2H), 1.99-2.12 (m,
2H), 1.73-1.93 (m, 2H); 13C{1H}-NMR (CDCl3, 100 MHz):  173.3,
124.8, 51.5, 38.2, 33.5, 28.3; HRMS (EI+): Exact mass calculated for
C12H18O4 [M]+ m/z 226.1205 found 226.1193.
(1R,6S,9S)-9-Carbmethoxy-8-oxybicyclo[4.3.0]non-3-ene ((+)-
21). Diester (–)-20 (5.81 g, 25.7 mmol) was dissolved in dry THF
°
(100 ml) and cooled to 0 C, whereupon NaH (60% dispersion in
mineral oil, 2.10 g, 51.9 mmol) was washed free of the mineral oil
(hexane 3 x 25 ml) and added in portions. After the addition was
complete, the reaction mixture was heated to reflux. After 16h, the
heating was discontinued and aq. satd. NH4Cl (20 ml) was added. The
mixture was diluted with brine (80 ml), the phases were separated and
the aq. phase was extracted with Et2O (4 x 30 ml). The combined
organic phases were dried over Na2SO4, filtered and the solvent was
evaporated in vacuo. This afforded a faint yellow, viscous, liquid,
which was shown to be the pure title compound (+)-21 containing 6%
of the 9-epimer by 1H-NMR. Yield: 4.56 g, 91%: TLC
[훼]20
0.56;
(film):
= -248.8 (c = 0.8, CHCl3); UV (44.9 mM in CHCl3): IR
3021, 2939, 2892, 2834, 1718, 1432, 1234, 1117, 1105
퐷
휈
max
cm-1; H-NMR (400 MHz, CDCl3): 6.85-6.87 (m, 1H), 5.69-5.76
(m, 2H), 3.72 (s, 3H), 2.70-2.77 (m, 1H), 2.48-2.55 (m, 1H), 2.36-
2.45 (m, 1H), 2.20-2.27 (m, 1H), 1.89-2.10 (m, 3H), 1.76-1.88 (m,
1H); 13C{ H}-NMR (100 MHz, CDCl3): 165.7, 144.8, 139.2, 127.4,
127.3, 51.1, 45.7, 44.3, 37.0, 30.7, 30.4; HRMS (EI+): Exact mass
calculated for C11H14O2 [M]+ m/z 178.0994, found 178.0998.
1
δ
(hexane/EtOAc 80:20, visualized by KMnO4-stain): Rf = 0.32;
퐷
1
δ
= + 12.1
휈max
3021, 2951, 2904,
(c = 1.40, CHCl3); IR (film):
2834, 1755, 1724, 1436, 1321, 1269, 1234, 1125, 1047 cm-1; 1H-NMR
(CDCl3, 400 MHz):  5.65-5.80 (m, 2H), 3.70 (s, 3H), 2.84-2.99 (m,
1H), 2.50-2.66 (m, 1H), 2.35-2.49 (m, 2H), 2.23-2.35 (m, 1H), 1.83-
2.10 (m, 4H); 13C{1H}-NMR (CDCl3, 100 MHz):  209.7, 169.2,
126.5, 126.1, 61.6, 52.3, 44.8, 42.5, 36.1, 31.2, 30.3; HRMS (EI+):
Exact mass calculated for C11H14O3 [M]+ m/z 194.0943 found
194.0931.
(1R,6S,8S,9R)-8-Butyl-9-carbmethoxybicyclo[4.3.0]non-3-ene
((–)-23). Michael acceptor (–)-22 (0.774 g, 4.34 mmol, 1.00 equiv.)
°
was dissolved in dry THF (40 ml), degassed thrice and cooled to -35
C. To the solution was added in succession CuI (0.082 g, 0.43 mmol,
0.10 equiv.) and TMSCl (1.181 g, 1.38 ml, 10.1 mmol, 2.50 equiv).
The resulting heterogeneous mixture was powerfully stirred for 5 min,
whereupon BuMgCl (2.0 M in THF, 6.53 ml, 13.0 mmol, 3.00 equiv.)
was added in a manual dropwise manner during 1.5h. After the first
few drops, the reaction mixture became homogeneous and the colour
cycled between clear and yellow for each successive addition. As the
reaction progressed, the yellow colour became more persistent, taking
a full minute or more to revert to a turbid grey. After the addition was
complete, TLC (hexane/EtOAc 80:20, visualized by UV and KMnO4-
stain) revealed that the starting material (Rf = 0.58) had been
consumed (NB! Prior to elution, the TLC plate was briefly fanned
with a heat gun to decompose the presumed transient silyl ketene
acetal formed during the reaction). While still in the cold, the reaction
mixture was treated with saturated aq. NH4Cl (10 ml) and taken to
ambient temperature. Then water (40 ml) was added, the phases were
separated and the aqueous phase was extracted with EtOAc (4 x 25
ml). The combined organic phases were dried over MgSO4, filtered
and the solvent was evaporated in vacuo. The residue was purified by
column chromatography on silica (hexane, followed by
hexane/EtOAc 95:5) to afford the title compound (–)-23 as clear
(1R,6S)-9-Carbmethoxybicyclo[4.3.0]non-3,8-diene ((–)-22).
(i) Keto ester 9 (2.333 g, 12.0 mmol, 1.00 equiv.) was dissolved in
°
MeOH (50 ml) and the solution was cooled to 0 C. To the stirring
mixture was added NaBH4 (0.682 g, 18.0 mmol, 1.50 equiv.) in one
go. The progress of the reaction was monitored by TLC
(hexane/EtOAc 80:20, visualized by KMnO4-stain). According to this,
the starting material (Rf = 0.32) had been completely converted to a
more polar compound (Rf = 0.11) after 1 h. The reaction mixture was
treated dropwise with dilute aq. HCl (5 M, 25 ml) in the cold,
whereupon it was concentrated in vacuo. The residue was diluted with
brine (50 ml) and extracted with EtOAc (4 x 50 ml). The combined
organic extracts were dried over Na2SO4, filtered and the solvent was
evaporated in vacuo. This afforded a faint yellow oil as crude, which,
according to 1H-NMR (CDCl3), corresponded to a diastereomeric
β
mixture of the desired -hydroxy ester pre-(–)-22a. Nominal yield:
2.228 g, 95%; TLC (hexane/EtOAc 80:20, visualized by KMnO4-
stain): 0.11.
β
(ii) -Hydroxy ester pre-(–)-22a (2.228 g, 11.4 mmol, 1.00 equiv.)
1
was dissolved in dry CH2Cl2 (50 ml). Then, Et3N (3.461 g, 4.8 ml,
34.2 mmol, 3.00 equiv.) was added dropwise at ambient temperature.
liquid. By H-NMR (CDCl3), the isolated material contained approx.
α
5% of the -epimere. Yield: 0.785 g, 85%; Rf = 0.64 (hexane/EtOAc
°
[훼]20
After 5 min, the slightly tanned mixture was cooled to 0 C and MsCl
80:20, visualized by UV and KMnO4-stain);
= –55.5 (c = 0.8,
퐷
(2.612 g, 1.76 ml, 22.8 mmol, 2.00 equiv.) was added in a dropwise
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The Journal of Organic Chemistry
Page 8 of 12
휈max
δ
CHCl3); IR (film):
3027, 2933, 2863, 1730, 1438, 1234, 1158
CDCl3): 5.53-5.82 (m, 2H), 4.25-4.33 (m, 1H), 4.18-4.24 (m, 1H),
3.01 (s, 3H), 2.29-2.41 (m, 1H), 2.18-2.29 (m, 1H), 1.71-1.92 (m,
3H), 1.49-1.70 (m, 3H), 1.38-1.49 (m, 2H), -1.19-1.38 (m, 6H), 0.90
-1
1
δ
1
2
3
4
5
6
7
8
cm ; H-NMR (400 MHz, CDCl3): 5.62-5.69 (m, 2H), 3.69 (s, 3H),
2.19-2.30 (m, 3H), 2.01-2.06 (m, 1H), 1.77-1.89 (m, 2H), 1.68-1.76
(m, 1H), 1.52-1.67 (m, 3H), 1.41-1.50 (m, 1H), 1.21-1.37 (m, 5H),
0.88 (t, J = 6.92 Hz, 3H); 13C{ H}-NMR (100 MHz, CDCl3): 176.5,
127.0, 126.0, 57.2, 51.5, 46.3, 41.5, 40.3, 37.1, 36.7, 32.1, 30.9, 30.2,
22.7, 14.0; HRMS (EI+): Exact mass calculated for C15H24O2 [M]+ m/z
236.1776, found 236.1770.
(1R,6S,8S,9R)-8-Butyl-9-(hydroxymethyl)bicyclo[4.3.0]non-3-
ene ((–)-24). Ester (–)-23 (0.587 g, 2.48 mmol, 1.00 equiv.) was
(t, J = 6.82 Hz, 3H); 13C{1H}-NMR (100 MHz, CDCl3): 127.1,
126.5, 72.3, 51.3, 45.3; 40.0, 39.8, 37.2, 36.9, 36.6, 32.0, 31.3, 30.4,
22.8, 14.1; HRMS (ESI+): Exact mass calculated for C15H26O3SNa [M
+ Na]+ m/z 309.1495, found 309.1495.
(1R,6S,8S,9R)-8-Butyl-9-(cyanomethyl)bicyclo[4.3.0]non-3-ene
(pre-(–)-25b). Mesylate pre-(–)-25a (0.490 g, 1.71 mmol, 1.00 equiv.)
was dissolved in dry DMSO (30 ml), solid KCN (0.659 g, 10.3 mmol,
6.00 equiv.) was added in one go and the resulting faint yellow,
δ
1
δ
°
dissolved in dry CH2Cl2 (40 ml) and the solution was cooled to -78
9
°
homogenous, mixture was heated to 70 C. After stirring overnight, a
C. After 10 min, DIBAL-H (1 M in hexane, 9.93 ml, 9.93 mmol, 4.00
equiv.) was added in a dropwise manner. When the addition was
complete, the reaction mixture was stirred at the stated temperature
and the progression was monitored by TLC (hexane/EtOAc 80:20,
visualized by KMnO4-stain). According to this, the starting material
(Rf = 0.68) had been consumed after 3h and a new, less lipophilic
compound (Rf = 0.34) had been formed. While still in the cold, the
mixture was treated with a saturated aq. solution of Rochelle’s salt
(50 ml) and allowed to attain ambient temperature. The mixture was
diluted with CH2Cl2 (80 ml) and stirred overnight. The phases were
separated, the aq. phase was extracted with CH2Cl2 (2 x 40 ml) and
the combined organic phases were washed with brine (40 ml). The
combined organic phases were dried over MgSO4, filtered and the
solvent was evaporated in vacuo. The residue was purified by column
chromatography on silica (hexane, followed by hexane/EtOAc 90:10
and 80:20). This afforded the title compound (–)-24 as a viscous
colourless liquid/syrup. Yield: 0.457 g, 88%; TLC (hexane/EtOAc
[훼]20
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
yellow homogeneous mixture had been obtained and the heating was
discontinued. Upon equilibration to ambient temperature, water (5 ml)
was added in a dropwise manner, resulting in a decolourization, and
the mixture was poured into water/EtOAc (50:50, 50 ml). The phases
were separated and the aq. phase was extracted with EtOAc (4 x 25
ml). The combined organic phases were washed with brine, dried over
MgSO4, filtered and the solvent was evaporated in vacuo. The residue
was purified by column chromatography on silica (hexane, followed
by hexane/Et2O 75:25). This afforded the title compound pre-(–)-25b
as a clear liquid. Yield: 0.370 g, quant.; TLC (hexane/EtOAc 80:20,
[훼]2퐷0 = ― 52.9
visualized by KMnO4-stain): Rf = 0.58;
(c = 0.80,
휈
CHCl3); IR (film):
3017, 2955, 2924, 2830, 2238, 1636, 1456,
max
-1
1
δ
1428 cm ; H-NMR (400 MHz, CDCl3): 5.59-5.78 (m, 2H), 2.40-
2.53 (m, 2H), 2.30-2.40 (m, 1H), 2.19-2.30 (m, 1H), 1.70-1.87 (m,
3H), 1.54-1.69 (m, 2H), 1.43-1.54 (m, 2H), 1.19-1.42 (m, 7H); 0.91 (t,
, J = 6.94 Hz, 3H); 13C{ H}-NMR (100 MHz, CDCl3): 127.3, 126.1,
119.0, 48.0, 46.9, 42.8, 39.8, 36.6, 36.0, 32.2, 30.5, 30.4, 22.9, 20.3,
14.1; HRMS (EI+): Exact mass calculated for C15H23N [M]+ m/z
217.1830, found 217.1834.
(1R,6S,8S,9R)-8-Butyl-9-(formylmethyl)bicyclo[4.3.0]non-3-ene
((–)-25). Nitrile pre-(–)-25b (0.370 g, 1.71 mmol, 1.00 equiv.) was
1
δ
90:10, visualized by KMnO4-stain): Rf = 0.18;
= –65.3 (c = 0.8,
퐷
휈
CHCl3); IR (film):
3336, 3017, 2958, 2916, 2877, 1456, 1428,
max
-1
1
δ
1047 cm ; H-NMR (400 MHz, CDCl3): 5.64-5.71 (m, 2H), 3.65-
3.73 (m, 2H), 2.30-2.36 (m, 1H), 2.16-2.28 (m, 1H), 1.69-1.90 (m,
3H), 1.53-1.65 (m, 2H), 1.18-1.51 (m, 10H), 0.89 (t, J = 6.76 Hz, 3H);
o
13
1
δ
dissolved in dry hexane (25 ml) and cooled to -78 C. After 10 min,
C{ H}-NMR (100 MHz, CDCl3): 127.2, 126.9, 65.8, 54.7, 45.0,
40.1, 39.8, 37.2, 37.1, 32.1, 31.8, 30.6, 22.9, 14.1; HRMS (EI+): Exact
mass calculated for C14H24O [M]+ m/z 208.1827, found 208.1822.
(1R,6S,8S,9S)-8-Butyl-9-(hydroxymethyl)bicyclo[4.3.0]non-3-ene
[훼]20
the resulting solution was treated with DIBAL-H (1.0 M in hexane,
2.57 ml, 2.57 mmol, 1.50 equiv.) in a dropwise manner. The reaction
was monitored by TLC (hexane/EtOAc 80:20, visualized by KMnO4-
stain). As only one spot was discernible (Rf = 0.57), which could not
be unequivocally ascribed to starting material or product, more
DIBAL-H (1.0 M in hexane, 2.57 ml, 2.57 mmol, 1.50 equiv.) was
added after 1 h. Finally, more DIBAL-H (1.0 M in hexane, 2.57 ml,
2.57 mmol, 1.50 equiv.) was added after a further 0.5 h. Then, after a
total of 2 h, the reaction mixture was treated with a saturated aq.
solution of Rochelle’s salt (40 ml) and taken to ambient temperature.
The mixture was diluted with hexane (40 ml) and stirred for 1 h. Then
the phases were separated and the aq. phase was extracted with
hexane (2 x 40 ml). The combined organic phases were washed with
brine (20 ml), dried over Na2SO4, filtered and the solvent was
evaporated in vacuo. The residue was purified by column
chromatography on silica (hexane, followed by hexane/Et2O 75:25).
This afforded the title compound (–)-25 as a slightly opaque oil.
Yield: 0.340 g, 91%; TLC (hexane/EtOAc 4:1, visualized by KMnO4-
(epi-(–)-24). Viscous colourless liquid/syrup. Rf = 0.19;
= –51.8
퐷
휈
(c = 0.9, CHCl3); IR (film): max 3383, 3021, 2962, 2928, 2869, 1467,
1436, 1023 cm ; H-NMR (400 MHz, CDCl3): 5.51-5.83 (m, 2H),
3.56-3.79 (m, 2H), 2.22-2.38 (m, 1H), 2.14-2.22 (m, 2H), 2.01-2.13
(m, 2H), 1.57-1.88 (m, 3H), 1.42-1.56 (m, 3H), 1.17-1.39 (m, 7H),
0.90 (t, J = 6.82 Hz, 3H); 13C{ H}-NMR (100 MHz, CDCl3): 127.9,
127.4, 60.4, 46.9, 45.6, 41.3, 37.9, 36.1, 34.0, 31.8, 31.3, 28.6, 22.9,
14.1; HRMS (EI+): Exact mass calculated for C14H24O [M]+ m/z
208.1827, found 208.1845.
-1
1
δ
1
δ
(1R,6S,8S,9R)-8-Butyl-9-
((methylsulfonyloxy)methyl)bicyclo[4.3.0]non-3-ene (pre-(–)-25a).
Carbinol (–)-24 (0.365 g, 1.75 mmol, 1.00 equiv.) was dissolved in
dry CH2Cl2 (15 ml) and Et3N (0.355 g, 0.49 mL, 3.50 mmol, 2.00
equiv.) was added to the solution at ambient temperature. After 10
°
min, the mixture was cooled to 0 C and MsCl (0.602 g, 0.41 ml, 5.26
[훼]20 = ― 57.6
휈
stain): Rf = 0.57;
(c = 0.8, CHCl3); IR (film):
퐷
max
mmol, 3.00 mmol) was added dropwise. After an additional 10 min,
the reaction mixture was brought to ambient temperature and the
progress was monitored by TLC (hexane/EtOAc 80:20, visualized by
UV and KMnO4-stain). According to this, traces of starting material
(Rf = 0.29) were left after 8h and a new, more lipophilic, compound
(Rf = 0.34) had been formed. The reaction was left overnight and was
then deemed complete. Brine (20 ml) was added in a dropwise
manner, followed by a mixture of brine and EtOAc (50:50, 80 ml).
The phases were separated and the aq. phase was extracted with
EtOAc (4 x 30 ml). The combined organic phases were dried over
MgSO4, filtered and the solvent was evaporated in vacuo. The residue
was purified by column chromatography on silica (hexane, followed
by hexane/EtOAc 80:20). This afforded the title compound pre-(–)-
3017, 2963, 2922, 2834, 2717, 1724, 1460, 1438 cm-1; 1H-NMR (400
δ
MHz, CDCl3): 9.81 (t, J = 2.66 Hz, 1H), 5.53-5.80 (m, 2H), 2.40-
2.57 (m, 2H), 2.10-2.31 (m, 2H), 1.71-1.88 (m, 2H), 1.52-1.71 (m,
4H), 1.38-152 (m, 2H), 1.12-1.38 (m, 6H), 0.89 (t, J = 6.94 Hz, 3H);
13
1
δ
C{ H}-NMR (100 MHz, CDCl3): 203.1, 127.3, 126.5, 48.5, 48.0,
46.8, 43.5, 39.9, 36.6, 36.0, 32.4, 31.0, 30.6, 22.8, 14.1; HRMS (EI+):
Exact mass calculated for C15H24O [M]+ m/z 220.1827, found
220.1829.
(1R,6S,8S,9R)-8-Butyl-9-(prop-2-yn-1-yl)bicyclo[4.3.0]non-3-
ene ((–)-26). Aldehyde (–)-25 (0.340 g, 1.54 mmol, 1.00 equiv.) was
dissolved in MeOH (15 ml) and cooled to 0 oC. Ohira-Bestmann
reagent (0.593 g, 3.09 mmol, 2.00 equiv.) in MeOH (5 ml) was added
in one go to afford a colourless homogeneous mixture. Then, K2CO3
(0.533 g, 3.86 mmol, 2.50 equiv.) was added in one go, which
resulted in a phosphorescent yellow, heterogeneous, mixture. The
cooling was discontinued and the reaction mixture was stirred at
25a as
(hexane/EtOAc 80:20, visualized by UV and KMnO4-stain): Rf =
[훼]2퐷0 = ―46.5
휈max
3025, 2963,
a clear, syrupy, liquid. Yield: 0.493 g, 98%; TLC
0.34;
(c = 0.8, CHCl3); IR (film):
2924, 2869, 1467, 1444, 1350, 1175 cm-1; 1H-NMR (400 MHz,
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The Journal of Organic Chemistry
ambient temperature. According to TLC (hexane/EtOAc 80:20,
31.9, 31.6, 30.7, 24.8, 22.9, 14.2, 14.1; HRMS (ESI+): Exact mass
calculated for C22H36O2Na [M + Na]+ m/z 355.2607, found 355.2608.
(–)-Mucosin ((–)-6). Ethyl ester (–)-27 (0.160 g, 0.48 mmol, 1.00
equiv.) was dissolved in THF (4.0 ml), whereupon MeOH (4.0 ml)
and water (2.0 ml) was added. To the stirring solution at ambient
visualized with KMnO4-stain), the starting material (Rf = 0.57) had
been consumed after 6 h and a new more lipophilic compound (Rf =
0.71) had been formed. To decompose the excess of Ohira-Bestmann
reagent, acetone (10 ml) was added, followed by aq. saturated
NaHCO3 (40 ml). The mixture was partitioned with pentane (30 ml)
and the aq. phase was extracted with pentane (3 x 30 ml). The
combined organic phases were dried over Na2SO4, filtered and the
solvent was evaporated in vacuo (reduced pressure at 150 mbar, bath
1
2
3
4
5
6
7
8
⋅
temperature was added LiOH H2O (0.707 g, 16.8 mmol, 35.0 equiv.)
and the resulting reaction mixture was stirred overnight. At this point,
analysis by TLC (hexane/EtOAc 80:20, visualized by KMnO4-stain)
indicated that the starting material (Rf = 0.61) had been consumed and
that a new polar component had been formed (Rf = 0.14). The mixture
was diluted with Et2O (25 ml) and the pH was adjusted to approx. 2
with dilute aq. HCl. The phases were separated and the aq. phase was
extracted with EtOAc (4 x 20 ml), whereupon the combined organic
phases were dried over MgSO4, filtered and the solvent was
evaporated in vacuo. The residue was purified by column
chromatography on silica (hexane, followed by hexane/EtOAc 60:40).
This afforded the title compound 6 as a clear oil. Yield: 0.140 g, 96%;
TLC (hexane/EtOAc 80:20, visualized by KMnO4-stain): Rf = 0.14;
temperature at
0
oC). The residue was purified by column
chromatography on silica (pentane, followed by pentane/Et2O 90:10).
This afforded the title compound (–)-26 as a colourless oil. Yield:
0.430 g, quant.; TLC (hexane/EtOAc 80:20, visualized by KMnO4-
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
[훼]20 = ― 51.5
휈
stain): Rf = 0.71;
(c = 0.8, hexane); IR (film):
퐷
max
3308, 3021, 2951, 2916, 2828, 1456, 1428 cm-1; 1H-NMR (400 MHz,
δ
CDCl3): 5.57-5.84 (m, 2H), 2.29-2.45 (m, 3H), 2.18-2.27 (m, 1H),
1.91 (t, J = 2.68 Hz, 1H), 1.70-1.88 (m, 3H), 1.39-1.65 (m, 4H), 1.16-
1.39 (m, 7H), 0.90 (t, J = 6.99 Hz, 3H); 13C{1H}-NMR (100 MHz,
[훼]2퐷0 = ― 46.3
[훼]20 = ― 45.2
(c = 1.0, hexane);
퐷
δ
(c = 0.8, CHCl3);
CDCl3): 127.2, 126.9, 83.4, 68.8, 50.3, 46.5, 42.2, 39.9, 36.9, 36.4,
32.4, 31.0, 30.6, 22.9, 21.4, 14.1; HRMS (EI+): Exact mass calculated
UV (26.3 mM, CHCl3): max 245 nm (1.220 AU), 275 nm (0.970 AU);
λ
for C16H24 [M]+ m/z 216.1878, found 216.1874.
IR (film): max 3027, 2963, 2924, 2869, 1713, 1444, 1296, 1245 cm-1;
휈
1
(1R,6S,8S,9R)-8-Butyl-9-((E)-6-(carbethoxy)hex-2-en-1-
yl)bicyclo[4.3.0]non-3-ene ((–)-27).
(i) Cp2ZrCl2 (0.892 g, 3.05 mmol, 2.00 equiv.) was dissolved in dry
THF (15 ml) and the resulting homogeneous solution was cooled to 0
δ
H-NMR (400 MHz, CDCl3): 11.45 (brs, 1H), 5.60-5.73 (m, 2H),
5.43-5.54 (m, 1H), 5.33-5.43 (m, 1H), 2.32-2.41 (m, 2H), 2.09-2.32
(m, 4H) 2.02-2.09 (m, 2H), 1.66-1.81 (m, 4H), 1.47-1.66 (m, 3H),
1.05-47 (m, 9H), 0.89 (t, J = 6.88 Hz, 3H); 13C{1H}-NMR (100 MHz,
°
C and protected from light. DIBAL-H (3.05 ml, 3.05 mmol, 2.00
equiv.) was added in a dropwise manner to obtain a heterogeneous
δ
CDCl3): 180.0, 130.5, 129.6, 127.3, 127.1, 52.2, 47.2, 42.3, 40.1,
37.0, 36.74, 36.67, 33.3, 32.4, 31.8, 31.6, 30.7, 24.4, 22.9, 14.1;
HRMS (ESI+): Exact mass calculated for C20H32O2Na [M + Na]+ m/z
327.2295, found 327.2294.
°
mixture with a slightly yellow hue. After 1 h at 0 C, the mixture had
taken on an eggshell colour. Then, alkyne (–)-26 (0. 330 g, 1.53
mmol, 1.00 equiv.) was dissolved in dry THF (10 ml) and added in a
dropwise manner to the preformed reagent. Upon heating to ambient
temperature, the reaction mixture became homogeneous within 10
min to yield a translucent watered-down orange appearance. The
resulting mixture was stirred for 2 h.
(1R,6S,8S,9R)-8-Butyl-9-((E)-6-(carbmethoxy)hex-2-en-1-yl)-
bicyclo[4.3.0]non-3-ene ((–)-8). Acid (–)-8 (0.130 g, 0.43 mmol, 1.00
equiv.) was dissolved in MeOH (8.0 ml), whereupon toluene (12.0
ml) was added. To the stirring solution at ambient temperature was
added trimethylsilyldiazomethane (2.0 M in hexane, 0.43 ml, 0.85
mmol, 2.00 equiv.) in a dropwise manner. During the addition,
instantaneous decolourization of the added reagent was noticed,
accompanied by evolution of gas. At the end, a faint yellow colour
persisted. The resulting reaction mixture was stirred at the stated
temperature and the progress was monitored by TLC (hexane/EtOAc
80:20, visualized by KMnO4-stain). According to this, the starting
material (Rf = 0.14) had been completely consumed after 0.5 h and a
more lipophilic material (Rf = 0.60) had appeared. The reaction
mixture was treated with dilute aq. HCl (1.0 M, 20 ml), followed by
addition of brine (20 ml) and pentane (20 ml). The mixture was stirred
for 0.25 h, whereupon the phases were separated and the aq. phase
was extracted with pentane (3 x 25 ml). The combined organic phases
were dried over MgSO4, filtered and the solvent was evaporated in
vacuo. The residue was purified by column chromatography on silica
(hexane, followed by hexane/EtOAc 95:5) to afforded the pure title
compound as a faintly yellow oil. Yield: 0.135 g, quant.; TLC
[훼]20
°
(ii) The above mixture was cooled to 0 C and iodine (0.581 g, 2.29
mmol, 1.50 equiv.) was added in one go to afford a deep purple
medium. The reaction mixture was then allowed to attain ambient
temperature and was stirred for 1 h, while maintaining protection
from light. At the end, the colour had turned a light reddish purple.
(iii) To above mixture at ambient temperature was added 4-ethoxy-
4-oxobutylzinc bromide (0.5 M in THF, 6.1 ml, 3.05 mmol, 2.00
equiv.) in a dropwise manner. When approx. 1/6 of the volume had
been added, the mixture had attained a faint yellow colour, which
persisted during the rest of the addition. Then, Pd(PPh3)4 (0.088 g,
0.075 mmol, 0.05 equiv.) was added, which after a few min resulted
in a reddish orange mixture. The reaction was monitored by TLC
(hexane/EtOAc 80:20, visualized by KMnO4-stain). According to this,
the starting alkyne (Rf = 0.77) had been consumed within 1 h and a
slightly more polar compound had appeared (Rf = 0.67). The reaction
was left for 6 h at the stated conditions to ensure completion. The
reaction mixture was then treated with dilute aq. HCl (1 M, 40 ml).
The phases were separated and the aq. phase was extracted with Et2O
(4 x 40 ml). The combined organic phases were dried over MgSO4,
filtered and the solvent was evaporated in vacuo. The residue was
purified by column chromatography on silica (hexane, followed by
hexane/EtOAc 95:5) to afford the title compound (–)-27 as a clear oil
(NB! Traces of co-eluting ethyl butanoate, originating from the zinc
(hexane/EtOAc 80:20, visualized by KMnO4-stain): Rf = 0.60;
퐷
= ― 42.9
λ
(c = 0.8, hexane); UV (25.1 mM, hexane):
219 nm
max
휈
(3.504 AU), 272 nm (1.070); IR (film): max 3021, 2958, 2921, 2864,
1743, 1436, 1366, 1249, 1210, 1171 cm-1; 1H-NMR (400 MHz,
δ
CDCl3): 5.60-5.74 (m, 2H), 5.31-5.53 (m, 2H), 3.67 (s, 3H), 2.29-
2.34 (m, 2H), 2.14-2.29 (m, 2H), 2.08-2.14 (m, 2H), 2.00-2.07 (m,
2H), 1.65-1.80 (m, 4H), 1.46-1.65 (m, 3H), 1.24-1.46 (m, 5H), 1.07-
1.24 (m, 4H), 0.89 (t J = 6.92 Hz, 3H); 13C{1H}-NMR (100 MHz,
o
reagent, was removed by prolonged heating at 55 C and reduced
pressure set at 10 mbar. However, loss of some product was
encountered due to high vapour pressure). Yield: 0.327 g, 64%; TLC
[훼]20
δ
CDCl3): 174.1, 130.3, 129.8, 127.2, 127.1, 52.2, 51.4, 47.2, 42.3,
40.1, 36.9, 36.72, 36.65, 33.4, 32.4, 31.9, 31.6, 30.7, 24.7, 22.9, 14.1;
Exact mass calculated for C21H34O2Na [M + Na]+ m/z 341.2451,
found 341.2451.
(hexane/EtOAc 80:20, visualized by KMnO4-stain): Rf = 0.61;
퐷
= ― 43.3
λmax
252 nm
(c = 0.8, CHCl3); UV (24.1 mM, CHCl3);
휈max
(1.349 AU); IR (film):
3021, 2963, 2921, 2864, 1736, 1439,
(1R,6S,8S,9R)-8-Butyl-9-((3,5-
-1
1
δ
1374, 1292, 1175 cm ; H-NMR (400 MHz, CDCl3): 5.60-5.73 (m,
2H), 5.32-5.52 (m, 2H), 4.13 (q, J = 7.15 Hz, 2H), 2.15-2.33 (m, 4H),
2.07-2.15 (m, 2H), 1.99-2.07 (m, 2H), 1.64-1.80 (m, 4H), 1.46-1.64
dinitrobenzoyl)oxymethyl)bicyclo[4.3.0]non-3-ene ((–)-24-DNB).
Carbinol (–)-24 (0.036 g, 0.17 mmol) in dry CH2Cl2 (10 ml) and Et3N
(0.070 g, 0.096 ml, 0.69 mmol, 4.00 equiv.) was added to the solution
(m, 3H), 1.30-1.46 (m, 3H), 1.07-1.30 (m, 9H), 0.89 (t, J = 6.88 Hz,
°
at ambient temperature. After 10 min, the mixture was cooled to 0 C
1
3H); 13C{ H}-NMR (100 MHz, CDCl3): 173.7, 130.2, 129.9, 127.2,
δ
and 3,5-dinitrobenzoyl chloride l (0.080 g, 0.35 mmol, 2.00 equiv.)
was added in one portion. The reaction mixture was allowed to reach
127.1, 60.1, 52.2, 47.2, 42.3, 40.1, 36.9, 36.71, 36.65, 33.7, 32.4,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 12
ambient temperature overnight. Water (20 ml) was added to the
(5) Gerhart, D. Prostaglandin A2: An Agent of Chemical Defense
reaction mixture and diluted with CH2Cl2 (20 ml). The phases were
separated and the aq. phase was extracted with CH2Cl2 (3 x 20 ml).
The combined organic phases were washed with brine (30 ml), dried
over MgSO4, filtered and concentrated in vacuo. The residue was
purified by column chromatography on silica (hexane/EtOAc, 95:5) to
afford the title compound (–)-24-DNB as white, tiny, fern-like
needles. Yield: 0.061 g, 88%; M.p.: 64-65 °C; TLC (hexane/EtOAc
[훼]20 = ―28.1
in the Caribbean Gorgonian Plexaura homomalla. J. Mar. Ecol.
Progr. Ser. 1984, 19, 181−187.
(6) Henderson, A. R.; Stec, J.; Owen, D. R.; Whitby, R. J. The First
1
2
3
4
5
6
7
8
―
Total Synthesis of (+)-Mucosin. Chem. Commun. 2012, 48, 3409
3411.
(7) According to communication rendered in the supporting
information accompanying Ref. 6, a resonance at δ 30.7 had been
omitted in Ref. 4, while an additional signal at δ 36.3 was observed.
The data were subsequently revised and this fact is not touched upon
in the main paper.
(8) Gallantree-Smith, H. C.; Antonsen, S. G.; Görbitz, C. H.;
Hansen, T. V.; Nolsøe, J. M. J.; Stenstrøm, Y. H. Total Synthesis
Based on the Originally Claimed Structure of Mucosin. Org. Biomol.
80:20, visualized by KMnO4-stain): Rf = 0.52;
(c =
퐷
λ
1.0, CHCl3); UV (26.8 mM, CHCl3):
nm (1.968 AU), 381 nm (1,252); IR (film):
2925, 2858, 1734, 1633, 1544, 1465, 1342, 1275, 1169, 1074 cm-1;
260 nm (1.984 AU), 295
max
휈
3104, 3020, 2956,
max
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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42
43
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45
46
47
48
49
50
51
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53
54
55
56
57
58
59
60
1
δ
H-NMR (400 MHz, CDCl3): 9.24 (t, J = 2.12 Hz, 1H), 9.16 (d, J =
2.12 Hz, 2H), 5.62-5.75 (m, 2H), 4.49-4.57 (m, 1H), 4.42-4.49 (m,
1H), 2.31-2.42 (m, 1H), 2.22-2.31 (m, 1H), 1.89-2.01 (m, 1H), 1.75-
1.89 (m, 2H), 1.61-1.89 (m, 3H), 1.42-1.55 (m, 2H), 1.24-1.42 (m,
―
Chem. 2016, 14, 8433 8437.
(9) Antonsen, S. G.; Gallantree-Smith, H. C.; Görbitz, C. H.;
Hansen, T. V.; Stenstrøm, Y. H.; Nolsøe, J. M. J. Stereopermutation
on the Putative Structure of the Marine Natural Product Mucosin.
13
1
δ
6H), 0.84-0.94 (m, 3H); C{ H}-NMR (100 MHz, CDCl3): 162.6,
148.7, 134.1, 129.3, 127.3, 126.4, 122.3, 70.2, 51.1, 45.9, 40.6, 40.1,
37.2, 37.0, 32.0, 31.6, 30.6, 22.9, 14.1; HRMS (ESI+): Exact mass
calculated for C21H26N2O6Na [M + Na]+ m/z 425.1683, found
425.1684. The enantiomeric excess was determined by chiral-phase
HPLC analysis (Chiralcel OD-H, hexanes/iPrOH, 95:5, 1 mL/min,
―
Molecules 2017, 22, 1720 1737.
(10) (a) Hada, T.; Swift, L. L.; Brash, A. R. Discovery of 5R-
Lipoxygenase Activity in Oocytes of the Surf Clam, Spisula
―
solidissima. Biochim. Biophys. Acta 1997, 1346, 109 119. (b) Jiang,
Z. D.; Ketchum, S. O.; Gerwick, W. H. 5-Lipoxygenase-derived
Oxylipins from the Red Alga Rhodymenia pertusa. Phytochemistry
>
206 nm): tR(major) = 17.42 min and tR(minor) = 19.20, ee: 99%.
Supporting Information
―
2000, 53,129 133. (c) Newcomer, M. E.; Brash, A. R. The
1H- and 13C-NMR spectra of all compounds listed in the
experimental section ((–)-6 to (–)-27). HRMS (ESI+), IR and
UV/vis spectra of (–)-6, (–)-8, (–)-24-DNB and (–)-27.
Chromatograms from HPLC analysis to determine enantiomeric
excess and X-ray crystallographic data recorded for single-crystal
of (–)-24-DNB.
Structural Basis for Specificity in Lipoxygenase Catalysis. Protein
―
Sci. 2015, 24, 298 309.
(11) (a) Woodward, R. B.; Hoffman, R. Selection Rules for
―
Sigmatropic Reactions. J. Am. Chem. Soc., 1965, 87, 395 397. (b)
Hoffman, R.; Woodward, R. B. The Conservation of Orbital
―
Symmetry. Acc. Chem. Res. 1968, 1, 17 22. (c) Woodward, R. B.;
Hoffman R. The Conservation of Orbital Symmetry. Angew. Chem.
―
AUTHOR INFORMATION
Int. Ed. 1969, 8, 781 932.
(12) (a) Gerwick, W. H. Carbocyclic Oxylipins of Marine Origin
Corresponding Author
―
Chem. Rev., 1993, 93, 1807 1823. (b) Gerwick, W. H. Epoxy
*jens.mj.nolsoe@nmbu.no
Allylic Carbocations as Conceptual Intermediates in the Biogenesis of
―
Diverse Marine Oxylipins. Lipids, 1996, 31, 1215 1231. (c)
Author Contributions
Gerwick, W. H.; Singh, I. P. Structural Diversity of Marine Oxylipins.
In Lipid Biotechnology; Kuo, T. M., Gardner, H. W., Eds., Marcel
J.M.J.N. is the main contributor of this work.
Notes
The authors declare no competing financial interest.
―
Dekker: New York, 2002; pp 249 275.
(13) Neese, F. Software update: The ORCA Program System,
Version 4.0. Wiley Interdiscip. Rev.: Comput. Mol. Sci. 2018, 8,
e1327.
(14) Tao, J.; Perdew, J. P.; Staroverov, V. N.; Scuseria, G. E.
Climbing the Density Functional Ladder: Nonempirical Meta–
Generalized Gradient Approximation Designed for Molecules and
ACKNOWLEDGMENT
The authors are much indebted to Dag Ekeberg for the
performance of mass spectrometric analysis. A research grant to
J.M.J.N. and a postdoctoral scholarship for S.A. from the
Department of Chemistry, the Norwegian University of Life
Sciences, as well as funding from the Research Council of
Norway for a research scholarship to J.M.J.N. and grants to
Y.H.S. (NFR 209335 and NFR 244351) are gratefully
acknowledged.
―
Solids. Phys. Rev. Lett. 2003, 91, 146401 146404.
(15) Weigend, F.; Ahlrichs, R. Balanced Basis Sets of Split
Valence, Triple Zeta Valence and Quadruple Zeta Valence Quality for
H to Rn: Design and Assessment of Accuracy. Phys. Chem. Chem.
―
Phys. 2005, 7, 3297 3305.
(16) Grimme, S.; Antony, J.; Ehrlich, S.; Krieg, H. A Consistent
and Accurate Ab Initio Parametrization of Density Functional
Dispersion Correction (DFT-D) for the 94 Elements H-Pu. J. Chem.
Phys. 2010, 132, 154104.
(17) Henderson, A. R.; Stec, J.; Owen, D. R.; Whitby, R. J.
Supporting Information. The First Total Synthesis of (+)-Mucosin.
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