Asymmetric synthesis of cyclo-archaeol and β-glucosyl cyclo-archaeol

Article abstract of DOI:10.1039/c3ob27277j

An efficient asymmetric synthesis of cyclo-archaeol and β-glucosyl cyclo-archaeol is presented employing catalytic asymmetric conjugate addition and catalytic epoxide ring opening as the key steps. Their occurrence in deep sea hydrothermal vents has been

Full text of DOI:10.1039/c3ob27277j

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An efficient asymmetric synthesis of cyclo-archaeol and β-glucosyl cyclo-archaeol is presented, and their
occurrence in deep sea hydrothermal vents has been confirmed.

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ARTICLE TYPE
Asymmetric Synthesis of cyclo-Archaeol and -glucosyl cyclo-Archaeol
Catalina Ferrer,a Peter Fodran,a Santiago Barroso,a Robert Gibson,b Ellen C. Hopmans,b Jaap Sinninghe
Damsté,b Stefan Schouten,*b and Adriaan J. Minnaard*a
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
An efficient asymmetric synthesis of cyclo-archaeol and -glucosyl cyclo-archaeol is presented
employing catalytic asymmetric conjugate addition and catalytic epoxide ring opening as the key steps.
Their occurrence in deep sea hydrothermal vents has been confirmed by chromatographic comparison
with natural samples.
45 compounds, virtually devoid of functional groups, are
a
challenge, as is the formation of the macrocycles. In 1994,
Kakinuma et al. pioneered with the first, and up to this work
only, total synthesis of 2.10 Synthetic 2 prepared in this way was
subsequently used to study its behavior in liposome formation
50 and membrane packing.11 In their synthesis, the methyl-branched
stereocenters originated from the chiral pool (Roche Ester and
citronellol). Inspired by this elaborate but also particularly
lengthy route, we sought to develop a more efficient approach
using asymmetric catalysis in order to bring this compound
55 within reach.
10 Introduction
The domain of the Archaea forms an evolutionary line next to the
well-known domains of Bacteria and Eukarya.1 A number of
Archaea colonize unusual ecological niches and grow under
extreme conditions including high salinity, anaerobic conditions,
15 temperatures up to 110 °C or around 0 °C, strongly acidic
conditions, or extremely high pressures.2
The membrane core lipids of the Archaea are unique since they
are composed of saturated isoprenoid chains attached to glycerol
via ether linkages, unlike the conventional ester-based lipids of
20 Bacteria and Eukarya. In addition, the stereochemistry at C-2 of
the glycerol is the opposite. The most common structures include
the monomeric diphytanylglycerol diethers (e.g. archaeol (1),3
Fig 1.) and the dimeric macrocyclic dibiphytanyldiglycerol
tetraethers.2
25
Next to dimerization of archaeol to tetraethers, intramolecular
cyclisation leads to the macrocyclic diphytanylglycerol diether 2,
termed here “cyclo-archaeol” (macrocyclic archaeol), which was
isolated for the first time in 1983 by Comita and Gagosian from
Methanococcus jannashii, found in deep sea hydrothermal vents.4
30 Subsequently, 2 has been detected a number of times,5 mostly
from hydrothermal vent systems, which has led to the communis
opinio that this lipid is important for membrane integrity at high
temperature and pressure.6 This bears direct significance for
application of this type of compounds in nanotechnology and
35 biotechnology.7
Until recent years, the analysis of archaeal lipids focussed mainly
on the core lipids, e.g. without the polar head group, as the intact
polar lipids are considerably less stable and more difficult to
analyse. As the latter are, however, considered as diagnostic for
40 the occurrence of living cells, the study of intact polar lipids
containing e.g. phosphocholine or carbohydrate residues has
intensified.8
Figure 1 Archaeol 1, and cyclo-Archaeol 2
60 Upon close inspection of the 13C-NMR spectrum of natural 2, as
reported by Sprott et al.,12 with the one reported for synthetic 2,13
Since their discovery, the structure of archaeal lipids has
fascinated synthetic chemists.9 The multiple stereocenters in these
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it became obvious that the latter spectrum was considerably more 55 highly efficient and stereoselective fashion. Thus, reaction of 4
complex. Especially in the range between 34-36 ppm, were the
depicted spectrum of natural 2 shows one signal, synthetic 2
showed several, and also around 32 and 37 ppm, more signals are
observed in synthetic 2 compared to natural 2. Added to this, we
realized that synthetic 2 had not been directly compared with a
sample of natural 2, in particular by chromatographic (GC or
HPLC) means. So, although the synthetic route seemed
unambiguous, there was a clear incentive to shed light on the
with dimethylzinc using 5 mol% copper(II) triflate and
phosphoramidite L-phos as the chiral catalyst, gave 5 in 80%
yield and 98% enantiomeric excess (ee).
5
10 discrepancy between the 13C-NMR spectra of natural and
synthetic 2, as prepared by Kakinuma et al. and to compare them
in terms of chromatographic retention time.
Taken together, we embarked on the development of an
efficient synthesis of cyclo-archaeol (2), using asymmetric
15 catalysis for the introduction of the methyl substituents. The
material prepared in this way would then be compared to natural
2, isolated from a hydrothermal vent. In addition, we sought to
prepare -glucosyl-2 (compound 23 in this paper) as this type of
compound has been detected in M. jannaschii, as well as in
20 hydrothermal vents,14 but has not been prepared. Both 2 and its -
glucosyl derivative can function as reference compounds and
internal standards in the detection and quantification of these
compounds.
60
Scheme 1 Synthesis of building block 3
Subsequently, 5 was treated under the same reactions conditions,
using in this case 2.5 mol% of the enantiomer of the copper
65 catalyst. Given that protonation of the formed zinc enolate in this
reaction would result in a meso compound and therefore loss of
the chiral information, the enolate was trapped with trimethylsilyl
chloride to yield 6. Ozonolysis of 6 with reductive work-up,
followed by esterification of the crude product gave the saturated
70 isoprenoid unit 3 in 59% yield over three steps, in >99%
diastereomeric excess and >99% ee (Scheme 1). This preparation
of 3 was optimized and scaled up to batch sizes of 6 to 10 g, and
the high overall yield together with the excellent stereoselectivity
makes this procedure very suitable for the synthesis of
75 compounds containing this “saturated isoprenoid unit”.
Compounds 9 and 10 (Scheme 2), required for the coupling of
the isoprenoid units via a Julia-Kocienski olefination, were both
synthesized from 3 in a straightforward manner. For the synthesis
of the sulfone 9, the hydroxy group of 3 was first protected with a
80 tert-butyldiphenylsilyl group, giving 7 in 88% yield. The ester
group was subsequently reduced and the resulting alcohol treated
with 1-phenyl-1H-tetrazole-5-thiol in a Mitsunobu reaction.
Finally, the thioether was oxidized with mCPBA giving the
sulfone 9 in very good overall yield from 3. Aldehyde 10 was
85 obtained by oxidation of 3 with TPAP and NMO in 70% yield.
Results and Discussion
25 The synthetic approach designed for the preparation of 2 is based
on the highly stereoselective synthesis of saturated isoprenoid
building block 3. As 3 will be used fourfold, this leads together
with an efficient connection of this building block, to a dramatic
simplification of the synthesis c.q. decrease in the number of
30 steps compared to a linear synthesis. For the dimerization of 3 to
a phytanyl-type chain, we opted for a Julia-Kocienski olefination
followed by double bond reduction (Fig. 1). A non-symmetric
coupling is required here as both termini of the phytanyl chain
have a different role in the next part of the synthesis.
Contrary to the synthesis of glycerol esters, the stereoselective
preparation of the required ether linkages to glycerol has turned
out to be far from trivial. Most approaches in literature use
isopropylidene protected glycerol (solketal) as the starting
material. In order to reduce steps, we decided to use the inherent
40 reactivity and asymmetry in commercially available enantiopure
benzyl glycidol. Efficient regioselective epoxide ring opening
with the phytanyl chain alcohol, followed by etherification of the
resulting secondary hydroxyl function with the second equivalent
of the phytanyl chain would lead in a straightforward manner to
45 an advanced intermediate that upon ring closure, this time in a
pseudo-symmetric manner, would directly lead to the 36-
membered macrocyclic diether lipid (Figure 1).
35
The synthesis started with the preparation of saturated
50 isoprenoid building block
3 (Scheme 1). The synthesis,
previously developed in our group,15 consists of a repeated
asymmetric copper-catalyzed conjugate addition of dimethylzinc
to cyclooctadienone (4) followed by oxidative ring opening, and
allows the preparation of the four possible diastereomers of 3 in a
2
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30
Scheme 3 Synthesis of the phytanyl-type chain 13
The next step in the synthesis comprised the regioselective
connection of the phytanyl-type chain 13 to two positions of the
glycerol head group.19 Ring opening of epoxides often involves
Scheme 2 Synthesis of the precursors 9 and 10
35 the use of strong Lewis acids, which in the case of glycidol
derivatives frequently leads to regioisomeric mixtures.
Alternatively, the sodium or cesium alcoholate is used as a
powerful nucleophile but this requires an excess of the alcoholate
in most cases. We decided, therefore, for a novel, different
40 approach. Based on the work of Jacobsen et al. using cobalt salen
complexes for the hydrolytic kinetic resolution of epoxides,20,21
we envisioned that the same approach would hold for epoxide
ring opening with alcohols. Indeed, Jacobsen et al. have
described the use of phenols and simple alcohols for the kinetic
45 resolution of terminal epoxides catalyzed by cobalt salen
complexes,22 though the use of these catalysts for the ring
opening of epoxides with more complex alcohols has not been
described until now.23
The Julia-Kocienski olefination between 9 and 10 was carried
out at low temperature using LiHMDS as base. Under these
conditions, olefin 11 was obtained in 84% yield as a 2:1 trans:cis
mixture. Although inconsequential since the double bond will be
reduced, the stereoselectivity of the reaction was shortly studied.
It has been described that the use of bases with different
10 counterions, for instance potassium, leads to higher selectivity for
the trans-isomer albeit with lower yield.16 Also in this case the
use of KHMDS led to the exclusive formation of the trans alkene
11, but in only 49% yield. Therefore LiHMDS remained the base
of choice. Compound 11 was reduced with DIBAL to give
15 alcohol 12 in quantitative yield.
5
The reduction of the double bond in 12 is not trivial. Transition
metals, in particular palladium and nickel, tend to isomerise
double bonds, also under hydrogenation conditions. Such an
20 isomerisation-followed-by-reduction would undoubtedly lead to
erosion of stereoselectivity, vide infra, a phenomenon that would
be extremely difficult to detect a posteriori.17 Reduction with
diimide (diazene) is one of the few alternatives, and for this
reaction a flavin-based catalyst for the controlled oxidation of
25 hydrazine to diimide was chosen.18 In the presence of hydrazine
and under an oxygen atmosphere, the double bond was reduced
effectively and alcohol 13 was obtained in 83% yield (Scheme 3).
To make the most effective use of the precious 13, we decided
50 to carry out the ring opening on commercially available
enantiopure benzyl glycidyl ether. When the reaction was carried
out in the presence of catalytic [Co(salen)OAc], the most
commonly used catalyst in the kinetic resolution of terminal
epoxides, only starting materials were recovered together with
55 varying amounts of benzyl glycerol, formed due to the presence
of trace amounts of water. However, changing the counterion of
the catalyst from acetate to tosylate24 resulted in the formation of
compound 14 in a rewarding 87% yield (Scheme 4). This reaction
proceeds with complete regioselectivity and is carried out under
60 solvent free conditions, representing a useful and alternative
method for the regioselective epoxide ring opening with
(complex) alcohols.
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Scheme 4 Catalytic ring opening of the glycidol and synthesis of 15
of 20, a very low conversion was observed. Even with
40 stoichiometric flavin, the reaction could not be brought to
completion. This is remarkable as the actual reducing agent is the
very small diimide and we have shown previously that also
sterically hindered double bonds are reduced with this method
and the method is even applicable in solid phase organic
45 synthesis.17 The best alternative in our hands turned out to be
platinum on carbon, as Pt is known to be considerably less active
in double bond isomerization compared to palladium. With
atmospheric pressure of hydrogen, 21 was obtained in 92% yield,
an additional argument that the double bond is not particularly
50 sterically hindered. Finally, subsequent removal of the benzyl
protecting group with Pd/C provided the final product 2 in 80%
yield (Scheme 6).
The 13C-NMR of 2 prepared in this way corresponds to the 13C-
NMR of natural 212 and lacks the additional signals present in the
55 spectrum reported by Kakinuma et al.13 Most probably, the
reduction of the double bond with Pd/C in that synthesis leads to
a mixture of isomers (e.g. epimers) via partial isomerization of
the double bond followed by reduction of the subsequently
formed triple substituted alkene. This hypothesis was
60 strengthened by an experiment in which a small amount of 20
was treated under the same conditions (H2, Pd/C) and provided a
13C-NMR spectrum almost identical to the reported one by
Kakinuma et al.
In order to connect the second equivalent of the phytanyl side
chain, alcohol 13 was converted into iodide 15 using
+ -
5
MeSCH=NMe2 I in 89% yield (Scheme 4), following a recently
developed procedure by Ellwood and Porter.25 Not unexpected,
alkylation of alcohol 14 with iodide 15, proved to be a
challenging reaction. After testing various reaction conditions,
best results were obtaining when a mixture of the starting
10 materials was treated with freshly ground KOH and catalytic
tetrabutylammonium bromide under solvent free conditions. This
provided in a slow reaction the desired product 16 with moderate
though reproducible yields varying from 35% to 55% (Scheme
5), comparable to literature.10
Compound 16 contains the carbon skeleton of Archaeol and
cyclo-Archaeol, and the final steps were devoted to the
functionalization of 16 in order to carry out the ring-closing
metathesis. For this, after deprotection of the silyl groups of 16,
diol 17 was oxidized with Dess-Martin periodinane giving
15
20 aldehyde 18, which was subjected to a Wittig reaction that
afforded alkene 19 in an excellent 98% yield (Scheme 5).
65
25
Scheme 6 Synthesis of cyclo-Archeol 2, the alkene in 20 has the E-
Scheme 5 Synthesis of RCM precursor 19
configuration
The ring closing metathesis of 19 was carried out using second
generation Grubbs catalyst. When this reaction was carried out in
refluxing CH2Cl2 under dilution conditions, using a catalyst
30 loading of 14%, compound 20 was obtained in 79% yield as a
single alkene isomer (Scheme 6). The geometry of the double
Synthetic 2 was used to confirm its presence in hydrothermal
vents. The sample analysed was collected from the Rainbow
70 hydrothermal vent field (RHF) located on the Mid-Atlantic
Ridge. RHF has been characterized as an ultra-mafic
hydrothermal system with fluids that are known to reach up to
1
o
360 C and contain abundant H2, CH4 and CO2.27 Samples were
bond is trans (E), as deduced from H-NMR spectroscopy. The
current protocol is somewhat more efficient than the one reported
by Kakinuma et al. using first generation Grubbs catalyst,26 in the
35 sense that the catalyst loading is halved, and 19 was obtained as a
7:1 E/Z mixture in the previous case.
Applying the same reduction protocol, with the flavin catalyst,
as in the reduction of compound 12 (Scheme 3) for the reduction
collected during a sampling campaign in 2008 using the ROV
75 Jason. The sample is composed of material from the interior of a
vent chimney collected at a depth of 2293 meters below sea level.
Analysis by GC showed that synthetic 2 and natural 2 co-eluted
(see Supporting Information). Furthermore, their mass spectra
were identical.
4
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shift values are reported in ppm with the solvent resonance as the
1
internal standard (CHCl3: δ 7.26 for H, δ 77.0 for 13C). Data are
reported as follows: chemical shifts (δ), multiplicity (s = singlet,
50 d = doublet, dd = double doublet, td = triple doublet, t = triplet, q
= quartet, br = broad, m = multiplet), coupling constants J (Hz),
and integration.
High resolution mass spectra (HRMS) were recorded on a
Thermo Scientific LTQ Orbitrap XL or on a AEI-MS-902
55 spectrometer. HPLC analysis was performed on an Alltima HP
Silica 3μ 100 mm x 2.1 mm column (Grace Davison Discovery
Sciences) with an ELS detector (ELSD).
Flash chromatography was performed using SiliCycle silica
gel type SiliaFlash P60 (230 – 400 mesh) as obtained from
60 Screening Devices or with automated column chromatography
using a Reveleris flash system purchased from Grace Davison
Discovery Sciences. TLC analysis was performed on Merck silica
gel 60/Kieselguhr F254, 0.25 mm. Compounds were visualized
using either Seebach’s reagent (a mixture of phosphomolybdic
65 acid (25 g), cerium (IV) sulfate (7.5 g), H2O (500 mL) and H2SO4
(25 mL)) or a KMnO4 stain (K2CO3 (40 g), KMnO4 (6 g), H2O
(600 mL) and 10% NaOH (5 mL)).
Scheme 7 Glycosylation of cyclo-Archeol 2
In order to determine whether also the presence of -glucosyl-
23 could be confirmed in the hydrothermal vents, this compound
was prepared from 2. Glycosylation of archaeal ether lipids has
been studied before,28 and 1 has been glycosylated with
gentiobiose.29 In order to assure stereoselective glycosylation, a
per-esterified glucosyl bromide was selected as the donor in a
Koenigs-Knorr glycosylation. As tetra-acetylglucosyl bromide
10 gave disappointing yields due to ortho-ester formation,
tetrapivaloyl glucosyl bromide was applied, together with
molsieves to catch adventitious water, tetramethyl urea, and silver
triflate as the activator.30 This led to the desired product 22 in a
rewarding 85% isolated yield. Final deprotection by methanolysis
15 gave 23 in excellent yield. The NMR spectral data of 23 are in
very good agreement with literature data.12 Synthetic 23 was used
to confirm the presence of 23 in sediment collected from the
Rainbow hydrothermal vent field. Analysis by HPLC/ESI/MSn
showed that synthetic 23 and natural 23 co-eluted with a retention
20 time of around 10.2 min and yielded identical mass spectra on
both MS1 as well as MS2 (see Supporting Information).
5
4.31 Cyclooctanone (10 g, 79 mmol) was dissolved in DMSO
(1.2 L) and IBX (89 g, 317 mmol) was added. The resulting
70 solution was heated to 70 °C and stirred for 48 h. The solution
was poured into an erlenmeyer containing a saturated solution of
NaHCO3 upon which iodosobenzoic acid precipitated. The
precipitate was filtered and washed with diethyl ether. The
water/DMSO solution was extracted with diethyl ether and the
75 collected organic layers were dried with MgSO4. The crude
product was purified by silica gel chromatography (pentane :
Conclusions
1
ether 4:1) to give 4 (6.70 g, 69% yield) as a yellow oil. H NMR
An efficient synthesis of cyclo-archaeol has been developed. Key
steps are the quadruple use of an isoprenoid building block, in
25 turn prepared by copper-catalyzed asymmetric addition of
dimethylzinc, organocatalytic carbon-carbon double bond
reduction, and application of the Jacobsen catalyst for the
regioselective ringopening of benzyl-protected glycidol. This
synthesis is considerably more efficient than the previously
30 reported route. It was discovered that the earlier reported double
bond reduction with H2 and Pd/C in the final stages of the
synthesis leads to significant epimerization of the methyl-
substituents. This could be avoided by the use of Pt/C instead.
Synthetic cyclo-archaeol 2 was used to confirm its presence in
35 samples taken from hydrothermal vents. Furthermore, -glucosyl-
cyclo-archaeol 23 was prepared for the first time and shown to
occur in hydrothermal vents.
(400 MHz, CDCl3) δ 6.41 – 6.31 (m, 4H), 2.42 – 2.36 (m, 4H),
1.77 (dt, J = 15.2, 6.7 Hz, 2H) ppm. 13C NMR (101 MHz, CDCl3)
80 δ 193.8 (CO), 141.9 (2CH), 136.2 (2CH), 27.4 (CH2), 25.2
(2CH2) ppm.
5.15 Copper(II) triflate (931 mg, 2.6 mmol) and L-phos (R,S,S)
(2.78 g, 5.1 mmol) were suspended in dry toluene (150 mL) and
stirred at room temperature for 30 min under nitrogen. The
85 resulting solution was cooled to –25 °C and dimethylzinc (129
mL, 154 mmol) was added slowly. After stirring for 5 min, 4
(6.29 g, 51.5 mmol) dissolved in 150 mL of toluene was added
via an addition funnel over 6 h. The reaction was stirred
overnight at –25 °C and then poured into a bath containing an aq.
90 solution of saturated NH4Cl and ice. The mixture was extracted
with ether and dried over MgSO4. The crude was purified by
silica gel chromatography (pentane : ether 95:5) to give 5 (5.70 g,
80% yield, ee >99%) as a colorless oil. 1H NMR (400 MHz,
CDCl3) δ 6.33 (dt, J = 12.4, 7.3 Hz, 1H), 6.03 (d, J = 12.4 Hz,
95 1H), 2.68 (dd, J = 13.9, 5.7 Hz, 1H), 2.61 – 2.40 (m, 3H), 2.11
(dd, J = 10.5, 4.5 Hz, 1H), 1.73 – 1.53 (m, 3H), 1.39 – 1.28 (m,
1H), 1.00 (d, J = 6.8 Hz, 3H) ppm. 13C NMR (101 MHz, CDCl3)
δ 204.8 (CO), 141.8 (CH), 133.6 (CH), 50.3 (CH2), 32.3 (CH2),
29.1 (CH), 28.3 (CH2), 22.1 (CH3), 21.8 (CH2) ppm. HRMS-ESI
Experimental
All reactions were performed using oven or flame-dried
40 glassware and dry solvents. Solvents were distilled prior to use:
Et2O and THF (Na/benzophenone), DCM (CaH2). All other
reagents were purchased from Sigma Aldrich, Acros, TCI
Europe, Alfa Aesar, Chempur or Fluorochem, and used without
further purification unless noted otherwise.
20
100 m/z calcd for C9H15O: 139.1117; found: 139.112 [M++H]. []D
1H- and 13C-NMR spectra were recorded on a Varian AMX400
or a Varian 400-MR (400, 100.59 MHz, respectively). Chemical
= +23.3 (c = 0.8, CHCl3). Ee determination: GC Chiraldex -TA,
45
o
30 m x 0.25 mm, N2 flow = 0.5 mL/min, Ti = 50oC, Tf = 210 C,
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rate 10 oC/min, rt 16.69 (S), 16.76 (R).
MHz, CDCl3) δ 173.7 (CO), 135.6 (4CH), 134.1 (2C), 129.4
(2CH), 127.5 (4CH), 68.8 (CH2), 51.3 (CH3), 41.6 (CH2), 37.0
(CH2), 35.6 (CH), 33.2 (CH2), 30.3 (CH), 26.9 (3CH3), 24.2
3.15 Copper(II) triflate (393 mg, 1.1 mmol) and L-phos (S,R,R)
(1.17 g, 2.2 mmol) were dissolved in dichloromethane (136 mL)
and the mixture was stirred at room temperature for 30 min under 60 (CH2), 19.7 (CH3), 19.3 (C), 16.9 (CH3) ppm. HRMS-ESI m/z
o
20
calcd for C27H41O3Si: 441.2819; found: 441.2974 [M++H]. []D
5
nitrogen. Subsequently, the solution was cooled to –25 C and
dimethylzinc (54 mL, 65 mmol) was added dropwise. After
stirring for 5 min, 5 (6.00 g, 43.4 mmol) dissolved in 136 mL of
dichloromethane was added via an addition funnel dropwise for
several hours. The resulting solution was stirred at –25 oC
= +3.9 (c = 1.06, CHCl3).
8.32 To a solution of 7 (7.4 g, 16.7 mmol) in THF (85 mL) at –
78 °C was added a solution of DIBAL (1 M in dichloromethane,
65 83 mL, 83.0 mmol) and the resulting mixture was stirred for 2 h
at this temperature. The reaction was quenched with aq. NH4Cl
and then diluted with Et2O and aq. 2 M HCl until a clear solution
was obtained. The product was extracted with Et2O, dried over
Na2SO4 and the solvent evaporated giving 8 (6.7 g, 16.4 mmol,
10 overnight, after which triethylamine (18 mL, 130 mmol),
chlorotrimethylsilane (27 mL, 217 mmol) and HMPA (38 mL,
217 mmol) were added. The resulting mixture was stirred for 2 h
while slowly warming to rt. The reaction was quenched with
water and extracted with Et2O. After removal of the majority of
15 the solvent, the crude was passed through a silica gel column
previously deactivated with Et3N (pentane : ether 2:1) and the
solvent was evaporated giving 6 as a yellow oil which was used
in the next step without further purification. 6 (9.74 g, 43.4
mmol) was dissolved in methanol (36 mL) and CH2Cl2 (36 mL),
20 and ozone was bubbled through the solution at –78 °C until the
solution colored green/blue. The solution was then purged with
nitrogen, after which NaBH4 (16.3 g, 430 mmol) was added
portion wise and the reaction mixture was allowed to slowly
warm to rt. After stirring overnight, the reaction was quenched
25 with 2 M aq. HCl, stirred for 2 h and then extracted with
dichloromethane. (3R,7S)-8-Hydroxy-3,7-dimethyloctanoic acid
was obtained as a colorless oil and used in the next step without
further purification. To a solution of (3R,7S)-8-hydroxy-3,7-
dimethyloctanoic acid (8.1 g, 43.4 mmol) in MeOH (80 mL) was
30 added p-toluenesulfonic acid (370 mg, 2.1 mmol). The reaction
was refluxed for 24 h. Subsequently, it was cooled to rt and
concentrated, after which aq. NaHCO3 was added and the product
was extracted with ether. The crude was purified by silica gel
chromatography (pentane:Et2O 4:1) to give 3 (5.1 g, 25.3 mmol,
1
70 98% yield) as a colorless oil. H NMR (400 MHz, CDCl3) δ 7.65
(dd, J = 7.8, 1.6 Hz, 4H), 7.43 – 7.33 (m, 6H), 3.72 – 3.59 (m,
2H), 3.50 (dd, J = 9.8, 5.7 Hz, 1H), 3.43 (dd, J = 9.8, 6.4 Hz, 1H),
1.69 – 1.48 (m, 3H), 1.44 – 1.12 (m, 7H), 1.04 (s, 9H), 0.90 (d, J
= 6.7 Hz, 3H), 0.86 (d, J = 6.6 Hz, 3H). 13C NMR (101 MHz,
75 CDCl3) δ 135.6 (4CH), 134.1 (2C), 129.4 (2CH), 127.5 (4CH),
68.9 (CH2), 61.2 (CH2), 39.9 (CH2), 37.4 (CH2), 35.7 (CH), 33.4
(CH2), 29.5 (CH), 26.9 (3CH3), 24.3 (CH2), 19.7 (CH3), 19.3 (C),
16.9 (CH3). HRMS-ESI m/z calcd for C26H40O2SiNa: 435.269;
found: 435.269 [M++Na]. []D20 = +1.3 (c = 0.92, CHCl3).
80
9.32 To a solution of 8 (6.8 g, 16.5 mmol) and 1-phenyl-1H-
tetrazole-5-thiol (5.9 g, 33 mmol) in THF (165 mL) was added
triphenylphosphine (6.5 g, 24.7 mmol) at 0 oC. Subsequently,
DIAD (5.8 mL, 30 mmol) was added dropwise and the solution
was stirred while warming up to rt overnight. Then the reaction
85 was quenched with brine, extracted with Et2O and the organic
phase dried over Na2SO4. After evaporation of the solvent, the
mixture was purified by silica gel chromatography (5% ether in
pentane) to give 5-(((3R,7S)-8-((tert-butyldiphenylsilyl)-oxy)-
3,7-dimethyloctyl)thio)-1-phenyl-1H-tetrazole (8.3 g, 14.6 mmol,
90 88% yield) as a colorless oil. This compound (8.1 g, 14.2 mmol)
was dissolved in 80 mL of dichloromethane and mCPBA (12.3 g,
71.1 mmol) was added at 0 oC. The solution was allowed to warm
up slowly to rt and stirred overnight. Subsequently, the reaction
was treated several times with aq. Na2S2O3 and the combined
95 aqueous phases were extracted with dichloromethane. The
combined organic layers were washed with aq. NaHCO3, brine,
dried over Na2SO4 and the solvent was evaporated giving 9 (8.4
1
35 59% yield) as a colorless oil. H NMR (400 MHz, CDCl3) δ 3.66
(s, 3H), 3.55 – 3.46 (m, 1H), 3.45 – 3.37 (m, 1H), 2.30 (dd, J =
14.7, 6.1 Hz, 1H), 2.11 (dd, J = 14.7, 8.1 Hz, 1H), 1.95 (dq, J =
13.2, 6.7 Hz, 1H), 1.64 – 1.57 (m, 2H), 1.44 – 1.02 (m, 6H), 0.92
(t, J = 7.1 Hz, 6H) ppm. 13C NMR (101 MHz, CDCl3) δ 173.8
40 (CO), 68.2 (CH2), 51.3 (CH3), 41.6 (CH2), 36.9 (CH2), 35.7 (CH),
33.2 (CH2), 30.3 (CH), 24.2 (CH2), 19.8 (CH3), 16.5 (CH3) ppm.
HRMS-ESI m/z calcd for C11H23O3: 203.1641; found: 203.1638
[M++H]. []D20 = – 3.3 (c = 1.2, CHCl3).
1
g, 14.2 mmol, 98% yield) as a colorless oil. H NMR (400 MHz,
CDCl3) δ 7.71 – 7.63 (m, 6H), 7.62 – 7.55 (m, 3H), 7.44 – 7.33
100 (m, 6H), 3.79 – 3.63 (m, 2H), 3.50 (dd, J = 9.8, 5.8 Hz, 1H), 3.44
(dd, J = 9.8, 6.2 Hz, 1H), 1.94 (ddd, J = 22.0, 11.0, 5.4 Hz, 1H),
1.75 (tdd, J = 13.1, 7.7, 5.3 Hz, 1H), 1.62 (tt, J = 11.5, 5.9 Hz,
2H), 1.47 – 1.08 (m, 6H), 1.05 (s, 9H), 0.93 (d, J = 6.7 Hz, 3H),
0.91 (d, J = 6.7 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 153.7
105 (C), 135.8 (4CH), 134.3 (2C), 133.3 (C), 131.6 (CH), 129.9
(2CH), 129.7 (2CH), 127.8 (4CH), 125.3 (2CH), 69.0 (CH2), 54.5
(CH2), 36.8 (CH2), 35.8 (CH), 33.4 (CH2), 32.1 (CH), 28.6 (CH2),
27.1 (3CH3), 24.3 (CH2), 19.5 (C), 19.3 (CH3), 17.1 (CH3).
HRMS-ESI m/z calcd for C33H44N4O3SSiNa: 627.2795; found:
110 627.2794 [M++Na]. []D20 = –3.13 (c = 1.0, CHCl3).
7.32 3 (4.0 g, 19.7 mmol) was dissolved in DMF (33 mL) and
45 1H-imidazole
(2.7
g,
39.5
mmol)
and
tert-
butylchlorodiphenylsilane (7.7 ml, 30 mmol) were added. The
resulting solution was stirred for 16 h at rt, after which TLC
showed complete conversion. The solution was diluted with
water and extracted with ether. The mixture was purified by silica
50 gel chromatography (5% ether in pentane) to give 7 (7.7 g, 17.5
1
mmol, 88% yield) as a colorless oil. H NMR (400 MHz, CDCl3)
δ 7.81 – 7.57 (m, 4H), 7.44 – 7.35 (m, 6H), 3.66 (s, 3H), 3.50 (dd,
J = 9.8, 5.7 Hz, 1H), 3.43 (dd, J = 9.8, 6.3 Hz, 1H), 2.29 (dd, J =
14.7, 5.9 Hz, 1H), 2.09 (dd, J = 14.7, 8.2 Hz, 1H), 1.93 (dt, J =
55 13.4, 6.8 Hz, 1H), 1.63 (dt, J = 12.7, 6.5, 1H), 1.45 – 1.10 (m,
6H), 1.05 (s, 9H), 0.91 (d, J = 6.7 Hz, 6H) ppm. 13C NMR (101
10. 3 (3.0 g, 14.8 mmol) was dissolved in 148 mL of
dichloromethane and NMO (2.6 g, 22.2 mmol) and TPAP (26.1
6
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mg, 0.74 mmol) were added. The resulting black solution was
stirred overnight. Then the solvent was evaporated and the crude
reaction mixture was passed through a silica gel column using a
135.5, 134.0, 132.7, 129.3, 127.4, 126.8, 68.8, 61.1, 47.0, 39.9,
39.9, 37.7, 37.2 – 36.4, 35.6, 34.7, 33.4, 33.3, 33.1, 31.6, 30.3,
29.4, 29.3, 26.8, 24.7 – 24.1, 21.3, 21.0, 20.2, 19.5, 19.5, 19.4,
mixture of pentane:ether 2:1. The solvent was evaporated and 10 60 19.2, 18.7, 16.9. HRMS-ESI m/z calcd for C36H58O2SiNa:
1
20
573.410; found: 573.410 [M++Na]. []D = +2.12 (c = 0.9,
5
(2.1 g, 10.5 mmol, 70% yield) was obtained as a colorless oil. H
NMR (400 MHz, CDCl3) δ 9.59 (d, J = 2.0 Hz, 1H), 3.64 (s, 3H),
2.35 – 2.22 (m, 2H), 2.11 (dd, J = 14.8, 7.9 Hz, 1H), 1.99 – 1.88
(m, 1H), 1.72 – 1.62 (m, 1H), 1.41 – 1.15 (m, 5H), 1.07 (d, J =
7.0 Hz, 3H), 0.91 (d, J = 6.7 Hz, 3H). 13C NMR (101 MHz,
10 CDCl3) δ 205.2 (CHO), 173.7 (CO), 51.5 (CH3), 46.4 (CH), 41.7
(CH2), 36.7 (CH2), 30.7 (CH2), 30.3 (CH), 24.4 (CH2), 19.8
(CH3), 13.5 (CH3). HRMS-ESI m/z calcd for C11H21O3: 201.149;
found: 201.148 [M++H]. []D20 = +21.25 (c = 1.6, CHCl3).
CHCl3).
13. 12 (2.6 g, 4.7 mmol) was dissolved in 23 mL of EtOH at rt
and stirred vigorously. An atmosphere of oxygen was applied
65 (balloon, 1 atm) and, via a syringe pump, a solution of L-flav (3.2
g, 7.0 mmol) in EtOH (15 mL) was added slowly together with,
via a second syringe, hydrazine hydrate (2.9 mL, 94 mmol) over a
period of 10 h. The reaction mixture was stirred at rt for another 2
h and progress of the reaction was followed by 1H NMR (samples
11. LiHMDS (1 M in THF, 9.9 mL, 9.9 mmol) was added 70 were washed with water and extracted with CH2Cl2). CH2Cl2 was
15 dropwise to a solution of 9 (6.0 g, 9.9 mmol) in THF (25 mL) at –
78 °C resulting in a yellow solution. The mixture was stirred for
30 min, and subsequently 10 (2.2 g, 10.9 mmol) dissolved in 25
mL of THF was added via canula and the resulting solution was
added, and subsequently the mixture was washed with water.
After drying with Na2SO4, the solvent was evaporated to yield the
crude product which was purified by column chromatography
(pentane:Et2O 5:1) to give 13 (2.2 g, 3.9 mmol, 83% yield) as a
stirred overnight while slowly warming to rt. The reaction was 75 colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.67 (dd, J = 7.8, 1.6
20 quenched with water and extracted with ether. The crude was
purified by silica gel chromatography using 2% Et2O in pentane.
11 (4.8 g, 8.3 mmol, 84% yield as a 2:1 mixture of Z and E
alkenes) was obtained as a colorless oil. 1H NMR (400 MHz,
Hz, 4H), 7.45 – 7.34 (m, 6H), 3.74 – 3.62 (m, 2H), 3.52 (dd, J =
9.8, 5.7 Hz, 1H), 3.44 (dd, J = 9.8, 6.4 Hz, 1H), 1.70 – 1.51 (m,
3H), 1.45 – 1.12 (m, 18H), 1.10 – 1.02 (m, 3H), 1.06 (s, 9H), 0.93
(d, J = 6.7 Hz, 3H), 0.90 (d, J = 6.6 Hz, 3H), 0.85 (d, J = 6.6 Hz,
CDCl3) δ 7.68 (dd, J = 7.8, 1.6 Hz, 4H), 7.46 – 7.34 (m, 6H), 5.37 80 3H), 0.84 (d, J = 6.6 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ
25 – 5.10 (m, 2H), 3.66 (s, 3H), 3.52 (dd, J = 9.8, 5.7 Hz, 1H), 3.44
(dd, J = 9.8, 6.4 Hz, 1H), 2.30 (dd, J = 14.7, 6.0 Hz, 1H), 2.10
(dd, J = 14.7, 8.1 Hz, 1H), 2.07 – 1.89 (m, 3H), 1.88 – 1.75 (m,
1H), 1.69 – 1.61 (m, 1H), 1.48 – 1.13 (m, 13H), 1.06 (s, 9H), 0.97
135.6 (4CH), 134.1 (2C), 129.4 (2CH), 127.5 (4CH), 68.9 (CH2),
61.2 (CH2), 40.0 (CH2), 37.5 (CH2), 37.4 (2CH2), 37.3 (CH2),
37.3 (CH2), 35.7 (CH), 33.5 (CH2), 32.8 (CH), 32.8 (CH), 29.5
(CH), 26.9 (3CH3), 24.5 (CH2), 24.4 (CH2), 24.4 (CH2), 19.8
– 0.90 (m, 9H), 0.86 (d, J = 6.6 Hz, 3H, E alkene), 0.83 (d, J = 85 (CH3), 19.75 (CH3), 19.7 (CH3), 19.3 (C), 17.0 (CH3). HRMS-
30 6.6 Hz, 3H, Z alkene). 13C NMR (101 MHz, CDCl3) δ 173.7
(CO), 137.5 (CH, E alkene), 136.9 (CH, Z alkene), 135.6 (CH),
134.1 (C), 129.4 (CH), 127.5 (CH), 127.1 (CH, Z alkene), 127.0
(CH, E alkene), 68.9 (CH2), 51.3 (CH3), 41.7 (CH2), 39.9 (CH2),
37.6 (CH2, Z alkene), 37.2 (CH2, E alkene), 36.9 (CH2, Z alkene),
35 36.9 (CH2, E alkene), 36.8 (CH2), 36.7 (CH2), 35.7 (CH), 34.8
(CH2, Z alkene), 33.4 (CH2, E alkene), 33.2 (CH), 31.6 (CH),
30.3 (CH), 26.9 (CH3), 24.8 (CH2, Z alkene), 24.6 (CH2, E
alkene), 24.5 (CH2, Z alkene), 24.4 (CH2, E alkene), 21.3 (CH3, Z
alkene), 21.1 (CH3, E alkene), 19.7 (CH3), 19.5 (CH3), 19.3 (C),
40 16.9 (CH3). HRMS-ESI m/z calcd for C37H58O3SiNa: 601.405;
found: 601.405 [M++Na]. []D20 = +2.1 (c = 1.1, CHCl3).
ESI m/z calcd for C36H60O2SiNa: 575.425; found: 575.425
[M++Na]. []D20 = –0.70 (c = 1.0, CHCl3).
14. To a roundbottom flask containing 13 (488 mg, 0.88
mmol)
without
any
solvent,
was
added
(S)-2-
90 ((benzyloxy)methyl)oxirane (0.25 mL, 1.63 mmol) and
[Co(salen)OTs] (35 mg, 0.04 mmol). An atmosphere of dry
oxygen was applied (balloon, 1 atm). The mixture was left to stir
for 16 h and then purified by silica gel chromatography
(hexane:Et2O 4:1). 14 (533 mg, 0.80 mmol, 85% yield) was
1
95 obtained as a colorless oil. H NMR (400 MHz, CDCl3) δ 7.69 –
7.65 (m, 4H), 7.45 – 7.27 (m, 11H), 4.57 (s, 2H), 3.98 (br s, 1H),
3.59 – 3.40 (m, 8H), 2.47 (br d, J = 3.1 Hz, 1H), 1.70 – 1.47 (m,
4H), 1.46 – 1.14 (m, 20H), 1.06 (s, 9H), 0.92 (d, J = 6.7 Hz, 3H),
0.88 (d, J = 6.6 Hz, 3H), 0.85 (d, J = 5.9 Hz, 3H), 0.83 (d, J = 6.0
12. To a solution of 11 (4.8 g, 8.3 mmol) in 42 mL of THF at –
78 °C was added a solution of DIBAL (1 M in dichloromethane,
42 mL, 42 mmol) and the resulting mixture was stirred for 2 h at 100 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 138.0 (C), 135.6 (CH),
45 this temperature. The reaction was quenched with aq. NH4Cl and
then diluted with Et2O and aq. HCl until a clear solution was
obtained. The mixture was extracted with Et2O, dried over
Na2SO4 and the solvent evaporated. 12 (4.5 g, 8.2 mmol, 99%
134.1 (C), 129.4 (CH), 128.4 (CH), 127.7 (CH), 127.7 (CH),
127.5 (CH), 73.4 (CH2), 71.8 (CH2), 71.4 (CH2), 70.0 (CH2), 69.5
(CH), 68.9 (CH2), 37.5 (CH2), 37.4 (CH2), 37.4 (CH2), 36.6
(CH2), 35.7 (CH), 33.5 (CH2), 32.8 (CH), 32.8 (CH), 29.9 (CH),
yield as a 2:1 mixture of Z and E alkenes) was obtained as a 105 26.9 (CH3), 24.5 (CH2), 24.4 (CH2), 24.4 (CH2), 19.8 (CH3), 19.7
50 colorless oil without any further purification. 1H NMR (400
MHz, CDCl3) δ 7.67 (dd, J = 7.7, 1.5 Hz, 4H), 7.45 – 7.35 (m,
6H), 5.45 – 5.11 (m, 2H), 3.67 (br s, 2H), 3.51 (dd, J = 9.8, 5.7
Hz, 1H), 3.44 (dd, J = 9.7, 6.5 Hz, 1H), 2.63 (br s, 1H), 2.40 (br s,
1H), 2.33 – 1.94 (m, 2H), 1.88 – 1.75 (m, 1H), 1.67 – 1.52 (m,
55 3H), 1.46 – 1.11 (m, 14H), 1.06 (s, 9H), 0.98 – 0.86 (m, 9H), 0.83
(d, J = 6.7 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 137.5, 136.9,
(CH3), 19.3 (C), 17.0 (CH3). HRMS-ESI m/z calcd for
20
C46H72O4SiNa: 739.509; found: 739.509 [M++Na]. []D = –0.3
(c = 1.2, CHCl3).
15. To a solution of 13 (498 mg, 0.90 mmol) in toluene (5 mL)
110 at
85
oC
was
added
N,N-dimethyl-N-
(methylsulfanylmethylene)ammonium iodide (313 mg, 1.35
mmol) and imidazole (30 mg, 0.45 mmol). The mixture was
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o
stirred at 85 C for 16 h and subsequently cooled to rt and the
solvent evaporated. The crude mixture was purified by silica gel
dichloromethane, 1.2 mL, 0.56 mmol). The reaction mixture was
stirred at room temperature for 1 h and then saturated aqueous
Na2S2O3 was slowly added. The aqueous layer was extracted with
chromatography using 2% of Et2O in pentane to give 15 (500 mg,
0.75 mmol, 85% yield) as a colorless oil. H NMR (400 MHz, 60 CH2Cl2, and the combined organic phases were washed with
1
5
CDCl3) δ 7.68 – 7.63 (m, 4H), 7.43 – 7.33 (m, 6H), 3.50 (dd, J =
9.8, 5.7 Hz, 1H), 3.42 (dd, J = 9.8, 6.4 Hz, 1H), 3.27 – 3.20 (m,
1H), 3.15 (ddd, J = 9.5, 8.2, 7.3 Hz, 1H), 1.93 – 1.80 (m, 1H),
1.69 – 1.57 (m, 2H), 1.57 – 1.48 (m, 1H), 1.46 – 1.02 (m, 20H),
saturated aqueous NaHCO3 and brine. After evaporation of the
solvent, the residue was purified by silica gel chromatography
(pentane:Et2O 10:1) to give 18 (131 mg, 0.17 mmol, 76% yield).
1H NMR (400 MHz, CDCl3) δ 9.61 (d, J = 2.0 Hz, 2H), 7.36 –
1.04 (s, 9H), 0.91 (d, J = 6.7 Hz, 3H), 0.86 (d, J = 6.6 Hz, 3H), 65 7.26 (m, 5H), 4.55 (s, 2H), 3.68 – 3.39 (m, 9H), 2.34 (qd, J = 6.8,
10 0.84 (d, J = 6.8 Hz, 3H), 0.83 (d, J = 6.7 Hz, 3H). 13C NMR (101
MHz, CDCl3) δ 135.6 (CH), 134.1 (C), 129.4 (CH), 127.5 (CH),
68.9 (CH2), 40.9 (CH2), 37.4 (CH2), 37.3 (CH2), 37.2 (CH2), 36.6
(CH2), 35.7 (CH), 33.9 (CH), 33.5 (CH2), 32.8 (CH), 26.9 (CH3),
2.0 Hz, 2H), 1.77 – 1.45 (m, 7H), 1.45 – 0.99 (m, 39H), 1.09 (d, J
= 7.0 Hz, 6H), 0.88 – 0.82 (m, 18H). 13C NMR (101 MHz,
CDCl3) δ 205.3, 138.4, 128.3, 127.5, 127.5, 77.94, 73.3, 70.9,
70.3, 69.9, 68.9, 46.3, 37.52, 37.4, 37.3, 37.1, 37.0, 36.6, 32.8,
24.5 (CH2), 24.4 (CH2), 24.2 (CH2), 19.8 (CH3), 19.3 (C), 18.8 70 32.6, 30.9, 29.9, 29.8, 24.4, 24.4, 24.4, 19.7, 19.6, 13.3. HRMS-
15 (CH3), 17.0 (CH3), 5.4 (CH2). HRMS-ESI m/z calcd for
ESI m/z calcd for C50H90O5Na: 793.668; found: 793.667
[M++Na]. []D20 = +12.8 (c = 1.3, CHCl3).
20
C36H60OISi: 663.345; found: 663.346 [M++H]. []D = –6.32 (c
= 1.1, CHCl3).
19.26 To a solution of methyltriphenyl-phosphonium bromide
(271 mg, 0.76 mmol) in 4 mL of THF was added KHMDS (0.5 M
16. To a mixture of 14 (275 mg, 0.38 mmol), 15 (280 mg, 0.42
mmol) and tetra-n-butylammonium bromide (71 mg, 0.19 mmol) 75 in toluene, 1.4 mL, 0.71 mmol) under an atmosphere of nitrogen
20 was added freshly ground potassium hydroxide (65 mg, 1.15
mmol). The reaction was stirred for 48 h at 42 °C. Then it was
quenched with water, extracted with Et2O and the residue purified
at rt and stirred for 1 h. Then a solution of 18 (130 mg, 0.17
mmol) in 4 mL of THF was added and the reaction was stirred at
room temperature for 1 h. Subsequently, the reaction was
quenched with an aqueous solution of NH4Cl and extracted with
by silica gel chromatography using 2% of Et2O in pentane to give
1
16 (263 mg, 0.21 mmol, 55% yield) as a colorless oil. H NMR 80 Et2O. The residue was purified by silica gel chromatography
25 (400 MHz, CDCl3) δ 7.65 (dd, J = 7.8, 1.6 Hz, 8H), 7.43 – 7.28
(m, 16H), 4.54 (s, 2H), 3.65 – 3.38 (m, 13H), 1.68 – 1.01 (m,
48H), 1.04 (s, 9H), 0.90 (d, J = 6.7 Hz, 6H), 0.85 (d, J = 6.6 Hz,
6H), 0.83 (d, J = 4.8 Hz, 6H), 0.81 (d, J = 4.8 Hz, 6H). 13C NMR
(pentane:Et2O 95:5) and 19 (114 mg, 0.15 mmol, 87% yield) was
obtained as a colorless oil. H NMR (400 MHz, CDCl3) δ 7.36 –
7.26 (m, 5H), 5.69 (ddd, J = 17.6, 10.3, 7.5 Hz, 2H), 4.98 – 4.92
(m, 2H), 4.90 (d, J = 10.3 Hz, 2H), 4.55 (s, 2H), 3.66 – 3.42 (m,
1
(101 MHz, CDCl3) δ 138.4 (C), 135.6 (CH), 134.1 (C), 129.4 85 9H), 2.14 – 2.07 (m, 2H), 1.67 – 1.46 (m, 4H), 1.42 – 1.01 (m,
30 (CH), 128.3 (CH), 127.5 (CH), 127.5 (CH), 127.5 (CH), 77.9
(CH), 73.3 (CH2), 70.8 (CH2), 70.3 (CH2), 70.0 (CH2), 68.9
(CH2), 68.9 (CH2), 37.5 – 37.4 (CH2), 37.1 (CH2), 36.6 (CH2),
35.7 (CH), 33.5 (CH2), 32.8 (CH), 32.8 (CH), 29.9 (CH), 29.8
42H), 0.98 (d, J = 6.7 Hz, 6H), 0.86 (d, J = 6.6, 6H), 0.84 (d, J =
6.5 Hz, 12H). 13C NMR (101 MHz, CDCl3) δ 145.0 (CH), 138.4
(C), 128.3 (CH), 127.5 (CH), 127.5 (CH), 112.2 (CH2), 77.9
(CH), 73.3 (CH2), 70.8 (CH2), 70.3 (CH2), 69.9 (CH2), 68.9
(CH), 26.9 (CH3), 24.5 (CH2), 24.4 (CH2), 19.8 – 19.7(CH3), 19.3 90 (CH2), 37.7 (CH), 37.5 (CH2), 37.5 (CH2), 37.4 (CH2), 37.1
35 (C), 17.0 (CH3). HRMS-ESI m/z calcd for C82H130O5Si2Na:
(CH2), 37.0 (CH2), 36.6 (CH2), 32.8 (CH), 32.7 (CH), 29.9 (CH),
29.8 (CH), 24.6 (CH2), 24.5 (CH2), 24.4 (CH2), 20.2 (CH3), 19.8
(CH3), 19.7 (CH3), 19.7 (CH3). HRMS-ESI m/z calcd for
20
1273.935; found: 1273.938 [M++Na]. []D = –0.83 (c = 0.9,
CHCl3).
20
17.13 TBAF (1.0 M in THF, 0.96 mL, 0.96 mmol) was added
C52H94O3Na: 789.710; found: 789.710 [M++Na]. []D = +7.02
to a solution of 16 (300 mg, 0.24 mmol) in 1.5 mL of THF and 95 (c = 1.0, CHCl3).
40 the solution was stirred overnight at rt. Subsequently, the reaction
was quenched with aq. NH4Cl and extracted with Et2O. The
residue was purified by silica gel chromatography (pentane:Et2O
2:1) to give 17 (172 mg, 0.22 mmol, 92% yield) as a colorless oil.
20.26 To a solution of 19 (50 mg, 0.07 mmol) in 32 mL of
CH2Cl2 was added Grubbs 2nd generation catalyst (5.4 mg, 0.01
mmol) and the mixture was refluxed for 48 h. Subsequently the
solvent was evaporated and the residue purified by silica gel
1H NMR (400 MHz, CDCl3) δ 7.35 – 7.26 (m, 5H), 4.55 (s, 2H), 100 chromatography with 7% of Et2O in pentane to give 20 (40 mg,
1
45 3.67 – 3.36 (m, 13H), 1.69 – 0.98 (m, 48H), 0.92 (d, J = 6.7 Hz,
6H), 0.86 (d, J = 6.5 Hz, 6H), 0.84 (d, J = 3.2 Hz, 6H), 0.83 (d, J
= 3.2 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 138.4 (C), 128.28
(CH), 127.6 (CH), 127.5 (CH), 77.9 (CH), 73.3 (CH2), 70.8
0.05 mmol, 78% yield as a single isomer) as a colorless oil. H
NMR (400 MHz, CDCl3) δ 7.38 – 7.27 (m, 5H), 5.11 (dd, J = 5.1,
2.5 Hz, 2H), 4.55 (s, 2H), 3.67 – 3.44 (m, 9H), 2.01 (br s, 2H),
1.64 – 1.53 (m, 4H), 1.43 – 0.98 (m, 42H), 0.94 (d, J = 6.7 Hz,
(CH2), 70.3 (CH2), 69.9 (CH2), 68.9 (CH2), 68.4 (CH2), 37.5 – 105 6H), 0.87 (d, J = 6.5 Hz, 6H), 0.84 (d, J = 6.5 Hz, 6H), 0.83 (d, J
50 37.3 (CH2), 37.1 (CH2), 36.6 (CH2), 35.8 (CH), 33.5 (CH2), 32.8
(CH), 32.7 (CH), 29.9 (CH), 29.8 (CH), 24.4 (CH2), 24.4 (CH2),
24.4 (CH2), 19.8 – 19.7(CH3), 16.6 (CH3). HRMS-ESI m/z calcd
= 6.5 Hz, 6H). 13C NMR (101 MHz, CDCl3, due to overlapping
signals the reported number of signals does not correspond to the
expected number) δ 138.4 (C), 134.9 (CH), 128.3 (CH), 127.5
(CH), 127.5 (CH), 77.9 (CH), 73.3 (CH2), 71.4 (CH2), 70.3
110 (CH2), 69.7 (CH2), 68.6 (CH2), 37.8 (CH2), 37.5 – 37.2 (CH2),
37.0 (CH2), 36.6 (CH2), 32.8 (CH), 32.8 (CH), 29.7 (CH), 29.7
(CH), 29.6 (CH), 25.0 (CH2), 24.5 (CH2), 21.8 (CH3), 19.8 (CH3),
20
for C50H94O5Na: 797.699; found: 797.698 [M++Na]. []D = –
3.34 (c = 0.9, CHCl3).
55
18.26 To a solution of 17 (170 mg, 0.22 mmol) in CH2Cl2 (2.5
mL) was added Dess-Martin periodinane (15 wt% in
8
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19.8 (CH3). HRMS-ESI m/z calcd for C50H91O3: 739.696; found:
739.696 [M++H]. []D20 = +6.4 (c = 0.6, CHCl3).
38.7 (C), 38.7 (C), 37.4 (CH2), 37.4 (CH2), 37.3 (CH2), 37.3
(CH2), 37.3 (CH2), 37.2 (CH2), 37.2 (CH2), 37.1 (CH2), 37.1
(CH2), 37.1 (CH2), 37.0 (CH2), 36.6 (CH2), 34.1 (CH2), 34.1
60 (CH2), 33.0 (CH), 32.8 (CH), 32.8 (CH), 32.7 (CH), 32.6 (CH),
30.3 (CH), 29.8 (CH), 29.7 (CH2), 27.1 (CH3), 27.1 (CH3), 27.1
(CH3), 27.0 (CH3), 24.4 (CH2), 24.2 (CH2), 24.2 (CH2), 20.2
(CH3), 20.1 (CH3), 20.1 (CH3), 20.0 (CH3), 19.9 (CH3), 19.9
(CH3), 19.8 (CH3), 19.8 (CH3). HRMS-ESI m/z calcd for
21. 20 (38 mg, 0.05 mmol) was dissolved in 3 mL of a 2:1
mixture of MeOH:CH2Cl2 and Pt on charcoal (10 wt%, 10 mg,
0.01 mmol) was added. The mixture was stirred under a hydrogen
atmosphere (1 atm, balloon) for 16 h. The suspension was filtered
over silica, the solvent evaporated, and the residue was purified
by silica gel chromatography using 5% Et2O in pentane to give
5
20
65 C69H128O12: 1171.928; found: 1171.915 [M++Na]. [α]D = + 4.0
1
21 (34 mg, 0.04 mmol, 92% yield) as a colorless oil. H NMR
(c = 0.5, CHCl3).
10 (400 MHz, CDCl3) δ 7.41 – 7.27 (m, 5H), 4.55 (s, 2H), 3.72 –
3.42 (m, 9H), 1.64 – 0.99 (m, 54H), 0.88 – 0.84 (m, 24H). 13C
NMR (101 MHz, CDCl3, due to overlapping signals the reported
number of signals does not correspond to the expected number) δ
138.4 (C), 128.3 (CH), 127.6 (CH), 127.5 (CH), 77.9 (CH), 73.3
15 (CH2), 71.1 (CH2), 70.3 (CH2), 69.8 (CH2), 68.7 (CH2), 37.4
(CH2), 37.3 – 37.1 (CH2), 37.0 (CH2), 36.6 (CH2), 34.1 (CH2),
33.0 (CH), 32.8 (CH), 32.6 (CH), 29.9 (CH), 29.7 (CH), 24.4
(CH2), 24.2 (CH2), 20.1 (CH3), 20.0 (CH3), 19.9 (CH3), 19.8
(CH3). HRMS-ESI m/z calcd for C50H91O3: 763.694; found:
20 763.694 [M++Na]. []D20 = +2.4 (c = 0.8, CHCl3).
23. 22 (10 mg, 0.012 mmol) and sodium methoxide (14 mg,
0.36 mmol) were dissolved in methanol (0.5 mL). The reaction
was stirred until complete consumption of the starting material
70 (24 h, TLC in pentane-ether 8:2). Then, amberlite (H+ form) was
added to the reaction and the mixture stirred for an additional 3
min. The solution was then filtered, washing the solid several
times with methanol. The solvent was removed under reduced
pressure and the crude purified by column chromatography (from
75 pentane-ethyl acetate 5:5 to ethyl acetate-methanol 95:5), giving
1
6.4 mg (0.010 mmol, 90% yield) of the product. H NMR (400
2.26 21 (28 mg, 0.04 mmol) was dissolved in 2 mL of EtOAc
and Pd on charcoal (10 wt% Degussa type, 8 mg, 0.01 mmol) was
added. The mixture was stirred under a hydrogen atmosphere (1
atm, balloon) for 16 h followed by filtration over silica and
25 evaporation of the solvent. The residue was purified by silica gel
chromatography (pentane:Et2O 5:1) to give 2 (21 mg, 0.03 mmol,
MHz, CDCl3-CD3OD 9:1) δ 4.21 (d, J = 7.3 Hz, 1H), 3.87 (d, J =
6.6 Hz, 1H), 3.79 (dd, J = 11.1, 8.6 Hz, 1H), 3.68 (dd, J = 12.5,
4.8 Hz, 1H), 3.61 – 3.50 (m, 4H), 3.49 – 3.39 (m, 4H), 3.39 –
80 3.26 (m, 6H), 3.26 – 3.17 (m, 2H), 1.61 – 1.40 (m, 4H), 1.39 –
1.08 (m, 36H), 1.08 – 0.91 (m, 12H), 0.86 – 0.68 (m, 24H). 13C
NMR (101 MHz, CDCl3-CD3OD 9:1) δ 103.2 (CH), 77.6 (CH),
76.0 (CH), 75.8 (CH), 73.3 (CH), 70.1 (CH2), 69.9 (CH), 69.9
(CH2), 69.0 (CH2), 68.3 (CH2), 61.6 (CH2), 37.2 (CH2), 37.1
85 (CH2), 37.1 (CH2), 37.1 (CH2), 37.1 (CH2), 37.0 (CH2), 36.9
(CH2), 36.9 (CH2), 36.9 (CH2), 36.6 (CH2), 36.3 (CH2), 33.9
(CH2), 33.8 (CH2), 32.8 (CH), 32.6 (CH), 32.6 (CH), 32.4 (CH),
32.4 (CH), 29.6 (CH), 29.5 (CH), 24.2 (CH2), 24.0 (CH2), 23.9
(CH2), 19.9 (CH3), 19.9 (CH3), 19.8 (CH3), 19.7 (CH3), 19.6
90 (CH3), 19.6 (CH3), 19.5 (CH3), 19.5 (CH3). CD3OD was added to
the NMR sample in CDCl3 in order to improve its resolution.
HRMS-ESI m/z calcd for C49H96O8: 835.691; found: 835.689
[M++Na]. [α]D20 = –6.9 (c = 0.26, MeOH).
1
80% yield) as a colorless oil. H NMR (400 MHz, CDCl3) δ 3.79
– 3.30 (m, 9H), 2.08 (br s, 1H), 1.66 – 0.92 (m, 52H), 0.82 (d, J =
6.2 Hz, 6H), 0.81 (d, J = 6.5 Hz, 6H), 0.78 (d, J = 6.5 Hz, 12H).
30 13C NMR (101 MHz, CDCl3, due to overlapping signals the
reported number of signals does not correspond to the expected
number, in addition small signals of residual solvent are present)
δ 78.4 (CH), 71.2 (CH2), 70.0 (CH2), 68.5 (CH2), 63.0 (CH2),
37.3 – 37.1 (CH2), 37.0 (CH2), 36.5 (CH2), 34.1 (CH2), 33.0
35 (CH), 32.7 (CH), 32.6 (CH), 29.7 (CH), 29.7 (CH), 29.7 (CH),
24.4 (CH2), 24.2 (CH2), 20.1 (CH3), 20.0 (CH3), 19.9 (CH3), 19.8
(CH3), 19.8 (CH3). HRMS-CI m/z calcd for C50H91O3: 673.647;
found: 673.647 [M++Na]. []D20 = +6.5 (c = 0.8, CHCl3).
Acknowledgments
22. 2 (15 mg, 0.02 mmol) was dissolved in 1 mL of a 1:1
40 mixture of toluene and dichloromethane. Subsequently, 4 Å
molecular sieves (14 mg), tetrapivaloyl bromoglucose (40 mg,
0.07 mmol), tetramethylurea (11 μL, 0.09 mmol) and silver
triflate (18 mg, 0.07 mmol) were added at 0 ºC. The resulting
reaction was stirred and allowed to reach slowly rt. Progress of
45 the reaction was followed by TLC (pentane-ether 5:5 and
pentane-ether 8:2) until completion and subsequently the mixture
was filtered and purified by column chromatography, to give 22
95 C. F. thanks the Ministerio de Educación for a postdoctoral grant
from the “Programa Nacional de Movilidad de Recursos
Humanos del Plan Nacional de I+D+i 2008-2011”. S. B. thanks
the Generalitat Valenciana for a postdoctoral grant (VALi+D
program). The Zernike Institute for Advanced Materials is
100 acknowledged for financial support (P. F.). R. G was supported
by a grant from the Darwin Center for Biogeology to J. S. S. D.
1
(22.6 mg, 0.02 mmol, 85%). H NMR (400 MHz, CDCl3) δ 5.30
Notes and references
(t, J = 9.4 Hz, 1H), 5.10 (t, J = 9.7 Hz, 1H), 5.02 (t, J = 7.1 Hz,
50 1H), 4.56 (d, J = 7.9 Hz, 1H), 4.20 (d, J = 11.7 Hz, 1H), 4.06 (dd,
J = 12.1, 5.8 Hz, 1H), 3.81 (dd, J = 12.4, 7.3 Hz, 1H), 3.70 (dd, J
= 8.8, 5.6 Hz, 1H), 3.63 – 3.51 (m, 4H), 3.51 – 3.30 (m, 4H), 1.47
– 0.93 (m, 88H), 0.93 – 0.72 (m, 24H). 13C NMR (101 MHz,
CDCl3) δ 178.0 (C), 177.2 (C), 176.4 (C), 176.4 (C), 101.0 (CH),
55 77.7 (CH), 72.3 (CH), 72.2 (CH), 71.2 (CH), 71.0 (CH2), 69.9
(CH2), 69.6 (CH2), 68.7 (CH2), 68.1 (CH), 62.0 (CH2), 38.8 (C),
a Stratingh Institute for Chemistry, University of Groningen, Nijenborgh
7, 9747 AG Groningen, The Netherlands. +31 50 3634235;
105 A.J.Minnaard@rug.nl
b NIOZ Royal Netherlands Institute for Sea Research, Department of
Marine Organic Biogeochemistry, P.O. Box 59, 1790 AB Den Burg, The
Netherlands. Stefan.Schouten@nioz.nl
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† Electronic Supplementary Information (ESI) available: [1H- and 13C-
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