Synthesis of the Acyclic Carbon Skeleton of Filipin III

Article abstract of DOI:10.1021/acs.joc.6b01166

The synthesis of the carbon skeleton of filipin III, a polyenic macrolactone possessing 11 stereogenic centers, was achieved using a convergent strategy with the longest linear sequence of 19 steps starting from hexanal. Construction of the polyene was re

Full text of DOI:10.1021/acs.joc.6b01166

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Article
Synthesis of the Acyclic Carbon Skeleton of Filipin III
Elodie Brun, Veronique Bellosta, and Janine Cossy
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01166 • Publication Date (Web): 09 Aug 2016
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Synthesis of the Acyclic Carbon Skeleton of Filipin III
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Elodie BRUN, Véronique BELLOSTA and Janine COSSY*
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Laboratoire de Chimie Organique, Institute of Chemistry, Biology and Innovation (CBI), CNRS, ESPCI Paris, PSL
Research University, 10 rue Vauquelin, 75231 Paris Cedex 05, France
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janine.cossy@espci.fr
Abstract
The synthesis of the carbon skeleton of filipin III, a polyenic macrolactone possessing 11
stereogenic centers, has been achieved using a convergent strategy with a longest linear sequence
of 19 steps starting from hexanal. The construction of the polyene has been realized by using two
successive Heck couplings as the key steps. The control of the stereogenic centers of the polyol
fragment has been performed by utilizing an Evans aldolization, a 1,3-syn aldolization, enantio-
and diastereoselective allylations, an hemiacetalization/oxa-Michael sequence and a 1,3-syn
reduction. The polyol and polyenic fragments have been coupled using a 1,5-anti diastereoselective
aldolization followed by a 1,3-anti reduction.
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INTRODUCTION
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Filipins were isolated from the cell culture filtrates of Streptomyces filipensis which were
collected in the Philippine Islands.1 A mixture of at least eight compounds was found in these
filtrates and four fractions were separated: filipin I (4%), filipin II (25%), filipin III (53%) and
filipin IV (18%).2 The structure of the major compound, filipin III, was determined by degradation
studies3 and its relative and absolute stereochemistry was determined by synthesis.4 Filipin III is a
polyenic macrocycle which possesses antibiotic properties5 but this product is too toxic to have
therapeutic applications. However, filipin III has been widely used as a histochemical stain for
cholesterol to study its distribution and to quantify it in cell membranes.6 This strong interaction
between cholesterol and filipin III has been used clinically in the study and the diagnosis of the
Type C Niemann-Pick disease.7 Moreover, filipin III was shown to prevent the pathological
accumulation of the membrane-bound prion protein, whose expression is a key event in the
pathogenesis of transmissible spongiform encephalopathies.8
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The synthesis of the C1-C15 polyol fragment of filipin III has been published by Kiyooka
et al.9 and the synthesis of the C1-C10 fragment of the enantiomer of filipin III has been realized
by Brückner and Walleser10 but it is worth noting that only one total synthesis of filipin III has
been reported to date by Rychnovsky et al.11 This synthesis is convergent and has been achieved
from a polyol fragment A and a polyenic fragment B which have been coupled by using at first a
Yamaguchi esterification and then an intramolecular Horner-Wadsworth-Emmons (HWE) reaction
to construct the macrocycle (Scheme 1).
Scheme 1. Synthesis of filipin III by Rychnovsky et al.
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In the context of our program concerning the synthesis of natural products12 and the study
of their biological mechanism of action, we became interested in the synthesis of filipin III, to
access several analogues in order to modulate its biological activity. Here, we would like to report
our efforts toward the synthesis of the carbon skeleton of filipin III.
From a retrosynthetic analysis, we planned to access filipin III from two fragments: a polyol
fragment C and a polyenic fragment D. The assembly of the two fragments would be achieved by
using a diastereoselective aldolization to form the C14-C15 bond and the final step would be a
macrolactonization to form the C1-O29 bond (Scheme 2).
Scheme 2. Retrosynthesis
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RESULTS AND DISCUSSION
Synthesis of the C15-C28 fragment (fragment D)
The C15-C28 fragment of filipin III is a conjugated pentaenic aldehyde possessing a 1,2-
anti-diol unit. The aldehyde function would allow the formation of the C14-C15 bond by
performing an aldol condensation.
Our retrosynthesic analysis of the polyenic fragment is based on a method developed by
Burke and co-workers to synthesize polyenes using successive chemoselective palladium-
catalyzed cross-couplings involving alkenyl boronic esters derived from N-methyliminodiacetic
acid (MIDA),13 which was recently extended by our group to more complex polyenes and applied
to the synthesis of the polyenic fragment of mirabaline.14 Based on this strategy, two Heck
couplings were envisaged to build up the polyenic fragment, one to form the C19-C20 bond and
the second one to form the C23-C24 bond (Scheme 3). By planning these two Heck couplings, the
conjugated iodo-triene F and iodo-diene 2 have to be synthesized and then respectively coupled
with the conjugated dienic ester 1 and the allylic 1,2-diol H.
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Scheme 3. Retrosynthesis of the C15-C28 fragment
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The synthesis of the α,β-unsaturated 1,2-diol H was realized in four steps starting from the
commercially available (R)-isobutyl lactate 3 (Scheme 4). After protection of the alcohol (TESCl,
imidazole, DMF) and reduction of the ester (DIBAL-H, Et2O, –78 °C), lactate 3 was transformed
to aldehyde 415 (92%) which was then treated with vinylmagnesium bromide (THF, –60 °C to rt)
to furnish a mixture of the two diastereomeric alcohols 5 and 5’ in 94% yield, in a ratio of 80:20 in
favor of the anti-isomer 5 which corresponds to the expected Felkin-Anh adduct. These two
diastereomers were separated by column chromatography on silica gel to afford the pure desired
1,2-anti-diol 5. As planned in our retrosynthesis, a Yamaguchi macrolactonization is envisioned to
access filipin III and a selective deprotection of the hydroxyl present at C27 is thus required.
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Therefore, to protect the hydroxyl group present at C26, an orthogonal protecting group to the TES
group, present at C27, had to be used and a SEM group was chosen to this end. After treatment of
5 with SEMCl (iPr2NEt, n-Bu4NI, CH2Cl2, rt, 16 h), the protected diol 6 was isolated in quantitative
yield (Scheme 4).
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Scheme 4. Synthesis of the 1,2-diol 6
The synthesis of the iodo-diene 214 was then achieved (Scheme 5). The synthesis started
with the hydrostannylation followed by the iodo-destannylation of alkyne 7 to produce 8 (Bu3SnH,
AIBN then I2, THF, –78 °C to rt, 72%) (Scheme 5). The obtained vinyl iodide 8 was then involved
in a Heck coupling with vinyltrimethylsilane [Pd(OAc)2, AgOAc, MeCN, 80 °C] leading to a
mixture of the desired diene 9 and the branched diene 9’ in a ratio of 80:20 (72%) which, at this
stage, could not be separated. However, after iodo-desilylation using NIS at 0 °C (MeCN, 6 h) and
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purification by column chromatography on silica gel, the two iodo-isomers were separated, and the
desired linear iodo-diene 2 was isolated in 80% yield (Scheme 5).16 With 2 and 6 in hand, the
second Heck coupling was examined. When iodo-diene 2 was treated with 1.5 equiv of diol 6, in
the presence of Pd(OAc)2 (5 mol %) and AgOAc (1.5 equiv) in MeCN for 14 h at 80 °C, using
previously described conditions,14 only 15% of the desired coupling product 10 were obtained
(Table 1, entry 1). A decrease of the temperature to 50 °C did not increase the yield in 10 (16%)
(Table 1, entry 2). On the contrary, when the reaction was performed at 50 °C, using 5 equiv of
1,2-diol 6, the yield in 10 was increased to 44% (Table 1, entry 3).17
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Table 1. Optimization of the second Heck coupling
entry
T (°C)
80 °C
50 °C
50 °C
yield (%)a
6
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1.5 equiv
1.5 equiv
5.0 equiv
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a Isolated yield
To access pentadiene E, compound 10 has to be transformed into an iodo-triene of type F.
Thus, the MIDA boronate 10 was hydrolyzed using sodium methylate (MeONa, MeOH/THF =
3:1, rt, 1 h) and the resulting boronic acid was involved in an iodo-deborylation (I2, THF, rt, 2.5 h)
to produce iodo-triene 11 which was not purified but directly involved in a Heck coupling with
the dienic ester 118 utilizing Jeffery’s conditions19 [Pd(OAc)2, K2CO3, TBAB, DMF, 50 °C, 16 h]
providing the desired conjugated pentaenic ester 12 in 57% yield over the three steps. After
reduction of the ester (DIBAL-H, –78°C), the resulting alcohol was not purified but directly
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oxidized by MnO2 to produce the desired aldehyde 13 in 54% yield over the two steps (Scheme 5).
It is worth mentioning that aldehyde 13 is prone to degradation, so it has to be synthesized and used
rapidly after its preparation. The pentaenic fragment 13 was thus synthesized in 10 steps from
(R)-isobutyl lactate 3 with a global yield of 12% (Scheme 5).
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Scheme 5. Synthesis of the pentaenic aldehyde 13
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Synthesis of the C1-C14 fragment (fragment C)
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The synthesis of the polyol fragment C was envisaged from enone I which would be
prepared from the ,-unsaturated ketone J and the β-hydroxy aldehyde K (Scheme 6). The control
of the stereogenic centers at C2 and C3’ in K would be achieved by using an Evans aldol
condensation. The C3 and C11 stereogenic centers in K and J would be introduced by using
respectively a diastereoselective and an enantioselective allylation of the corresponding aldehydes.
An aldol condensation between J and K would allow the control of the stereogenic center at C5
according to a 1,3-syn control. The stereogenic center at C9 would be introduced by using an
hemiacetalization/oxa-Michael addition sequence applied to enone I and, finally, the control of the
C7 stereogenic center would be achieved by a 1,3-syn diastereoselective reduction of the resulting
β-hydroxy ketone (Scheme 6).
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Scheme 6. Retrosynthesis of the C1-C14 fragment
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The synthesis of the C1-C5 fragment, compound 21, started with the unsaturated
oxazolidinone 15 prepared by acylation of the (S)-4-isopropyl-5,5-dimethyloxazolidin-2-one
14.20,21,22 After treatment of 15 under Evans conditions [n-Bu2BOTf (1.1 equiv), Et3N (1.4 equiv),
CH2Cl2, –78 °C],23 the enol borinate was condensed with hexanal which, after oxidative treatment
(H2O2, pH = 7 buffer), led to the aldol product 16 as a single detectable diastereomer (by 1H NMR),
in 94% yield. After protection of the hydroxyl group [MOMCl (4 equiv), iPr2NEt, CH2Cl2, rt, 18
h], the resulting MOM ether 17 was ozonolyzed and the obtained aldehyde 18 was directly treated
with allylmagnesium chloride in the presence of ZnCl224 to produce the homoallylic alcohol 19 as
a single detectable diastereomer in 73% yield (from 17).25 The homoallylic alcohol 19 was then
transformed in three steps into aldehyde 21. After cleavage of the chiral auxiliary by LiAlH4
(toluene, –30 °C to –10 °C),26 the resulting diol was directly protected (TBDPSOTf, 2,6-lutidine,
CH2Cl2) to furnish compound 20 (63% over the 2 steps) which, after ozonolysis, led to the desired
aldehyde 21 (O3, CH2Cl2, –78 °C then PPh3, 95%). The C1-C5 fragment was thus obtained from
hexanal in 7 steps for the longest linear sequence and with an overall yield of 39% (Scheme 7).
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Scheme 7. Synthesis of the C1-C5 fragment
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Methyl ketone 26, which represents the C6-C13 fragment, was obtained in 4 steps from 1,3-
propanediol 22. The diol was first monobenzylated to produce 2327 and after a catalytic
enantioselective allylation using the conditions developed by Krische et al.,28 the homoallylic
alcohol 24 was isolated in 72% yield with an enantiomeric excess of 94%.29 After protection of the
alcohol, the resulting silyl ether 2530 was involved in a cross-metathesis with methyl vinyl ketone
[5.1 equiv, HG-II (2 mol %), CH2Cl2, 45 °C, 2 h] and the α,β-unsaturated ketone 26 was isolated
in 98% yield (Scheme 8).
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Scheme 8. Synthesis of the C6-C13 fragment
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Having methyl ketone 26 and aldehyde 21 in hand, a diastereoselective aldol condensation
has to be performed to access the C1-C13 fragment of filipin III. As the stereogenic center at C5
has to be introduced in a stereocontrolled manner, we took advantage of the preexisting hydroxyl
group present at C3 in compound 21, and the Paterson’s conditions were chosen to control the
diastereoselectivity.31
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Different dialkyl borane reagents have been tried to favor the 1,3-syn control between the
hydroxyl groups at C3 and C5 during the aldolization. When methyl ketone enol borinate was
prepared using chlorodicyclohexylborane [(2.6 equiv) in the presence of Et3N (3.0 equiv) in Et2O
at 0 °C] and condensed with aldehyde 21, two diastereomers 27 and 27’ were obtained in 50%
yield32 in a ratio of 60:40 in favor of the 1,3-syn product 27 (Scheme 9, eq 1).31 The
diastereoselectivity in favor of 27 was improved when the methyl ketone enol borinate was
prepared
with
(+)-chlorodiisopinocampheylborane [(+)-DIPCl],33 using the same reaction conditions as
previously, as the ratio of 27/27’ was improved to 90:10. After separation of the two diastereomers
by flash column chromatography on silica gel, 27 was isolated with a yield of 67% (from aldehyde
21) (Scheme 9, eq 2). We have to point out that the 1,3-syn stereoselectivity was latter verified on
compound 29 (vide infra).
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Scheme 9. Synthesis of the C1-C13 fragment
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Two stereogenic centers remained to be controlled in fragment C1-C13. At first, the
stereogenic center at C9 was introduced by using an hemiacetalization/1,4-addition sequence
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applied to the α,β-unsaturated ketone 27 in the presence of acetaldehyde, catalyzed by
Bi(NO3)3.5H2O (0.1 equiv) (CH2Cl2, rt, 15 h).34 It was not necessary to cleave the triethylsilyl
group as, under these conditions, the acetal 28 was directly obtained in 56% yield as a single
detectable diastereomer. The last stereogenic center at C7 was controlled by realizing a 1,3-syn
diastereoselective reduction of the β-hydroxyketone 28 (Et2BOMe, NaBH4, MeOH/THF = 1:4,
–78 °C to 0 °C)35 to afford the 1,3-syn diol 29 in 73% yield, again as a single detectable
diastereomer. The transformation of 29 to methyl ketone 31 was finally realized in 5 steps. After
protection of the diol (dimethoxypropane, PPTS, rt) and deprotection of the benzyl alcohol (Pd/C,
H2, MeOH, rt), compound 30 was isolated in 77% yield. After oxidation (DMP, NaHCO3), addition
of methylmagnesium bromide (Et2O, 0 °C) and oxidation (DMP, NaHCO3), the desired methyl
ketone 31 was isolated in 86% yield over the 3 steps (Scheme 10).
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Scheme 10. Synthesis of the C1-C14 methyl ketone
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It is worth noting that compound 29 was also transformed into the 1,3,5-deprotected triol
32 in order to confirm the relative stereochemistry between the hydroxyl groups present at C3, C5
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and C7 using Kishi’s 13C NMR database.36 Treatment of 29 with TBAF (THF, 0 °C) gave tetraol
32 in 74% yield and the analysis of its 13C NMR spectrum in deuterated methanol showed a
chemical shift at 70.8 ppm for C5, which is in accordance with a syn/syn relative stereochemistry
between the hydroxyl groups at C3, C5 and C7 (Scheme 11).
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Scheme 11. Determination of the relative stereochemistry of 29
Synthesis of the carbon skeleton of filipin III
Having the C1-C14 and C15-C28 fragments in hand, a 1,5-anti diastereoselective aldol
condensation had to be performed to access the carbon skeleton of filipin III and to introduce the
stereogenic center at C15.
Methyl ketone 31 was thus involved in an aldol condensation with aldehyde 13 under the
Paterson’s conditions (Cy2BCl, Et3N, Et2O, –78 °C to –20 °C, 14 h) to produce the
β-hydroxyketone 34 in 91% yield as a single detectable diastereomer resulting from a 1,5-anti
control from the acetal at C11.37 The obtained β-hydroxyketone was stereoselectively reduced
using Me4NBH(OAc)3 (10 equiv, MeCN/AcOH = 10:1, –20 °C, 14 h)38 to produce the 1,3-anti diol
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35 again as a single detectable diastereomer (80%). After a SEM-protection of the C13 and C15
hydroxyl groups (SEMCl, iPr2NEt, CH2Cl2, rt), followed by the cleavage of the silyl ethers (TBAF,
THF, rt), we were able to isolate compound 36 (79%) which corresponds to the carbon skeleton of
filipin III with all the stereogenic centers in place (Scheme 12).
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Scheme 12. Construction of the carbon skeleton of filipin III
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Unfortunately, if the primary alcohol at C1 was selectively oxidized to the corresponding
aldehyde, using TEMPO in the presence of a catalytic amount of [bis(acetoxy)-iodo]benzene
(BAIB),39 it was not possible to oxidize this aldehyde to the corresponding acid which would have
allowed the formation of the macrolactone. Even under the mild Pinnick-Lindgren oxidation
conditions (NaClO2, NaH2PO4, 2-methylbut-2-ene), which proved to be efficient in several
syntheses of polyenic natural products,40 the aldehyde was transformed to a complex mixture due
to the degradation of the polyenic moiety under these oxidative conditions. In addition, the direct
selective oxidation of the primary alcohol to the corresponding acid using Epp and Widlanski
conditions [TEMPO, PhI(OAc)2, MeCN/H2O = 1:1],41 conditions which were also used in several
total syntheses,42 led to the decomposition of compound 36, and we were never able to obtain the
desired carboxylic acid.
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CONCLUSION
The strategy which has been envisioned to construct the macrocyclic core of filipin III, even
if reported to be successful in the syntheses of several polyenic natural products,40,42 proved to be
inefficient in our case, probably due to the instability of the polyenic moiety during the last steps.
Due to our previous failures in the synthesis of wortmannilactone (concomitantly realized to the
synthesis of filipin III),43 we would like to stress on avoiding the use of an
oxidation/macrolactonization sequence at the last crucial step to access polyenic macrolactones.
One advice would be to favor a Horner-Wadsworth-Emmons reaction to construct one of the olefin
of the polyene and to access the macrocycle, a strategy which was used by Rychnovsky et al. for
the synthesis of filipin III11 as well as in our final successful attempt to access
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wortmannilactone.12b,43 A cross-coupling reaction would be another alternative to install the
sensitive polyene moiety in one of the latest step of the synthesis.
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EXPERIMENTAL SECTION
General experimental methods: All reactions were carried out under anhydrous conditions, using
flame-dried glassware and under an argon atmosphere. CH2Cl2, Et3N and iPr2NEt were distilled
from CaH2; Et2O and THF were distilled from Na/benzophenone. Other reagents were obtained
from commercial suppliers and used as received. TLC was performed on silica gel plates with UV
and p-anisaldehyde or KMnO4 stain visualization. Flash chromatography was performed on silica
gel (230-400 mesh). Optical rotations were measured using a polarimeter with a 1 dm path length.
Infrared (IR) spectra were recorded on an ATR plate, wave numbers are indicated in cm-1. 1H NMR
spectra were recorded at 400 MHz in CDCl3, acetone-d6, C6D6, or CD3OD and data are reported
as follows: chemical shift in ppm from tetramethylsilane or residual solvent signals (CHCl3: 7.26
ppm, acetone-d5: 2.05 ppm, C6D5H: 7.16 ppm, MeOD-d3: 3.31 ppm) as an internal standard,
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, quint = quintuplet, hept = heptuplet, m
= multiplet or overlap of non equivalent resonances, br = broad), coupling constant in Hz,
integration. 13C NMR spectra were recorded at 100 MHz in CDCl3, acetone-d6, C6D6, or CD3OD
and data are reported as follows: chemical shift in ppm from tetramethylsilane with the solvent as
an internal indicator (CDCl3: 77.16 ppm, acetone-d6: 29.84 and 206.26 ppm, C6D6: 128.06 ppm,
MeOD-d4: 49.00 ppm). Mass spectra were realized with a gas chromatograph-mass spectrometer
by electronic impact. High resolution mass spectra (HRMS) were performed with an orbitrap mass
analyzer by electrospray ionization.
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(1):18
To
a
solution
of
3
4
(E)-Ethyl
2-methylpenta-2,4-dienoate
5
6
7
8
(carboethoxyethylidene)triphenylphosphorane (2 g, 5.5 mmol, 1.0 equiv) in dry CH2Cl2 (16 mL)
was added acrolein (0.37 mL, 5.5 mmol, 1.0 equiv) dropwise. The mixture was stirred at rt for 1 h
and then heated at 38 °C for 3.5 h. The solution was cooled to rt, concentrated under vacuum and
then pentane was added (20 mL). The suspension was filtered over Celite® and the filtrate was
concentrated under vacuum. Purification of the crude material by flash column chromatography on
silica gel (pentane/Et2O = 98:2) afforded the dienic ester 1 (517 mg, 3.69 mmol, 67%) as a colorless
oil. The spectral data are in agreement with those reported in the literature.18 IR: ν 3091, 2982,
2933, 1705, 1633, 1596, 1446, 1421, 1392, 1367, 1341, 1244, 1195, 1176, 1100, 1034, 1008, 990,
9
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1
928 cm-1; H NMR (CDCl3, 400 MHz): δ 7.17 (br d, J = 11.4 Hz, 1H), 6.66 (ddd, J = 16.8 Hz,
J = 11.3 Hz, J = 10.1 Hz, 1H), 5.57 (br d, J = 16.8 Hz, 1H), 5.45 (br d, J = 10.0 Hz, 1H), 4.22 (q,
J = 7.1 Hz, 2H), 1.96 (br d, J = 1.3 Hz, 3H), 1.31 (t, J = 7.1 Hz, 3H); 13C NMR (CDCl3, 100 MHz):
δ 168.5, 138.4, 132.4, 128.3, 124.2, 60.8, 14.4, 12.8; MS (EI) m/z: 140 (M+., 25), 112 (36), 111
[(M-Et)+, 23], 97 (16), 96 (11), 95 [(M-EtO)+, 57], 69 (15), 67 (100), 66 (31), 65 (36), 56 (12), 55
(13).
[(1E,3E)-4-Iodobuta-1,3-dien-1-yl]boronic acid MIDA ester (2):14 To a solution of vinyl
trimethylsilane 9 used as a 80:20 mixture with 9’ (500 mg, 1.78 mmol, 1.0 equiv) in anhydrous
MeCN (17.8 mL) cooled to 0 °C was added NIS (800 mg, 3.56 mmol, 2.0 equiv). The mixture was
stirred at 0 °C in the absence of light for 6 h, and then quenched by the addition of a saturated
aqueous solution of Na2S2O3 (20 mL). EtOAc (20 mL) was added, the layers were separated and
the aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic layers were dried
over Na2SO4, filtered and concentrated under vacuum. The crude material was purified by flash
column chromatography on silica gel (Et2O/acetone = 8:2 to 7:3) to afford the iododiene 2 (476
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mg, 1.42 mmol, 80%) as a yellow viscous foam. The spectral data are in agreement with those
5
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reported in the literature.14 IR: ν 3007, 2958, 1753, 1698, 1616, 1458, 1336, 1285, 1247, 1154,
7
8
9
1
1119, 1083, 1023, 997, 954, 890, 872, 835 cm-1; H NMR (acetone-d6, 400 MHz): δ 7.15 (ddd,
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J = 14.4, J = 10.4 and J = 0.8 Hz, 1H), 6.67 (br d, J = 14.4 Hz, 1H), 6.53 (dd, J = 17.4 and J = 10.5
Hz, 1H), 5.77 (d, J = 17.4 Hz, 1H), 4.23 (dAB syst, J = 16.8 Hz, 2H), 4.05 (dAB syst, J = 16.8 Hz, 2H),
3.02 (s, 3H); 13C NMR (acetone-d6, 100 MHz): δ 169.0 (2C), 148.3, 142.5, 82.1, 62.2 (2C), 47.4,
C-B not visible.44
Synthesis of 4:
(R)-Isobutyl 2-(triethylsilyloxy)propanoate (3’):15 To a solution of (R)-isobutyl lactate 3 (7.1 g,
48.6 mmol, 1.0 equiv) in DMF (50 mL) were added imidazole (3.9 g, 57.3 mmol, 1.2 equiv) and
TESCl (8.5 mL, 50 mmol, 1.1 equiv). The mixture was stirred at rt for 4.5 h and then quenched by
addition of H2O (20 mL). Et2O (50 mL) was added, the layers were separated and the aqueous layer
was extracted with Et2O (4 × 50 mL). The combined organic layers were washed with brine (2 ×
10 mL), dried over MgSO4, filtered and concentrated under vacuum. The crude material was
purified by flash column chromatography on silica gel (petroleum ether/Et2O = 95:5) to afford the
silyl ether 3’ (12.62 g, 48.5 mmol, quant) as a colorless oil. The spectral data are in agreement with
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those reported in the literature.15 [α]D + 25.3 (c 0.04, CHCl3); IR: ν 2956, 2877, 1756, 1459,
1141, 1002 cm-1; 1H NMR (CDCl3, 400 MHz): δ 4.32 (q, J = 6.7 Hz, 1H), 3.92 (ddAB syst, J = 10.6
and J = 6.8 Hz, 1H), 3.87 (ddAB syst, J = 10.6 and J = 6.7 Hz, 1H), 1.95 (hept, J = 6.7 Hz, 1H), 1.40
(d, J = 6.7 Hz, 3H), 0.98-0.90 (m, 15H), 0.62 (q, J = 8.0 Hz, 6H); 13C NMR (CDCl3, 100 MHz) : δ
174.2, 70.8, 68.1, 27.8, 21.6, 19.09, 19.07, 6.7 (3C), 4.6 (3C); MS (EI) m/z: 231 [(M-Et)+, 3], 203
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[(M-iBu)+, 11], 176 (14), 175 (100), 159 (40), 147 (22), 131 (TESO+, 21), 119 (28), 115 (TES+,
25), 103 (62), 87 (25), 75 (27), 59 (22), 58 (11), 57 (iBu+, 27).
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(R)-2-(Triethylsilyloxy)propanal (4):15 To a solution of previously synthesized ester 3’ (2.6 g, 10
mmol, 1.0 equiv) in dry Et2O (40 mL), cooled to –78 °C, was added dropwise a solution of DIBAL-
H (15 mL, 1M in hexanes, 15 mmol, 1.5 equiv) over a period of 20 min. The mixture was stirred
for 3 h at –78 °C, then quenched by the addition of H2O (20 mL), and warmed to rt. The gel formed
was dissolved by the addition of an aqueous solution of HCl (10% in weight). The layers were
separated and the aqueous layer was extracted with Et2O(3 × 30 mL). The combined organic layers
were washed with brine (20 mL), dried over MgSO4, filtered and concentrated under vacuum. The
crude material was purified by flash column chromatography on silica gel (petroleum ether/Et2O =
95:5) to afford aldehyde 4 (1.74 g, 9.2 mmol, 92%) as a colorless oil. The spectral data are in
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agreement with those reported in the literature.15 [α]D 20 + 10 (c 1.56, CHCl3) {for ent-4 [α]D
−
lit
1
11.5 (c 1.55 , CHCl3)}15b IR: ν 2956, 2878, 1739, 1459, 1375, 1239, 1135, 1096, 1006 cm-1; H
NMR (CDCl3, 400 MHz): δ 9.62 (d, J = 1.4 Hz, 1H), 4.08 (qd, J = 6.8 and J = 1.4 Hz, 1H), 1.29
(d, J = 6.8 Hz, 3H), 0.97 (t, J = 7.9 Hz, 9H), 0.64 (q, J = 7.9 Hz, 6H); 13C NMR (CDCl3, 100 MHz):
δ 204.3, 73.5, 18.6, 6.7 (3C), 4.7 (3C); MS (EI) m/z: 159 [(M-CHO)+, 98], 131 (100), 115 (49), 103
(29), 87 (75), 75 (25), 59 (41).
(3S,4R)-4-(Triethylsilyloxy)pent-1-en-3-ol (5): To a solution of vinylmagnesium bromide (10.8
mL, 1M in THF, 10.8 mmol, 1.2 equiv) in dry THF (15 mL), cooled to –60 °C, was cannulated a
solution of aldehyde 4 (1.7 g, 9.0 mmol, 1.0 equiv) in dry THF (10 mL). The mixture was stirred
at –60 °C for 30 min, then warmed to rt and stirred for 3 h. The reaction mixture was quenched by
the addition of a saturated aqueous solution of NH4Cl (20 mL) and H2O (20 mL). Et2O (30 mL)
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was added, the layers were separated and the aqueous layer was extracted with Et2O (3 × 50 mL).
The combined organic layers were washed with brine (20 mL), dried over MgSO4, filtered and
concentrated under vacuum. The crude material was purified by flash column chromatography on
silica gel (petroleum ether/EtOAc = 98:2) to afford the alcohols 5 and 5’ as a mixture of
diastereomers in a 80:20 ratio (1.84 g, 8.5 mmol, 94%) as a colorless oil. The spectral data are in
agreement with those reported in the literature.15a Separation of the two diastereomers by flash
column chromatography on silica gel (CH2Cl2) afforded pure 5. [α]D 20 – 21.7 (c 1.02, CHCl3); IR:
ν 3462, 3080, 2956, 2912, 2878, 1459, 1416, 1379, 1239, 1130, 1093, 1005, 972, 933 cm-1;
1H NMR (CDCl3, 400 MHz): δ 5.82 (ddd, J = 17.3, J = 10.5 and J = 6.1 Hz, 1H), 5.30 (dtapp, J =
17.3 and J = 1.6 Hz, 1H), 5.19 (dtapp, J = 10.5 and J = 1.5 Hz, 1H), 4.05 (m, 1H), 3.86 (qd, J = 6.3
and J = 3.6 Hz, 1H), 2.36 (br d, J = 4.0 Hz, 1H, OH), 1.09 (d, J = 6.3 Hz, 3H), 0.97 (t, J = 7.9 Hz,
9H), 0.62 (q, J = 7.9 Hz, 6H); 13C NMR (CDCl3, 100 MHz): δ 136.6, 116.5, 76.7, 71.1, 17.5, 6.9
(3C), 4.9 (3C); MS (EI) m/z: 198 [(M-H2O)+., 1], 187 [(M-Et)+, 32], 159 (30), 131 (26), 115 (51),
103 (100), 87 (54), 75 (77), 59 (24).
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(3S,4R)-4-(Triethylsilyloxy)-3-[(trimethylsilylethoxy)methyloxy]pent-1-ene (6): To a solution
of alcohol 5 (1.25 g, 5.77 mmol, 1.0 equiv) in dry CH2Cl2 (24 mL) were added iPr2NEt (2.4 mL,
14.5 mmol, 2.5 equiv), n-Bu4NI (1.07 g, 2.9 mmol, 0.5 equiv) and SEMCl (1.53 mL, 8.64 mmol,
1.5 equiv). The mixture was stirred at rt for 16 h and then quenched by the addition of H2O (30
mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (3 × 45 mL). The
combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated
under vacuum. The crude material was purified by flash column chromatography on silica gel
(petroleum ether/Et2O = 99:1) to afford the acetal 6 (2.0 g, 5.77 mmol, quant) as a colorless oil.
[α]D 20 + 51.4 (c 1.04, CHCl3); IR: ν 3079, 2955, 2878, 1684, 1459, 1416, 1377, 1249, 1107, 1031,
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1010, 925, 860 cm-1; 1H NMR (CDCl3, 400 MHz): δ 5.73 (ddd, J = 16.8, J = 11.1 and J = 7.5 Hz,
1H), 5.26-5.19 (m, 2H), 4.69 (dAB syst, J = 6.8 Hz, 1H), 4.64 (dAB syst, J = 6.8 Hz, 1H), 3.87-3.78 (m,
2H), 3.74-3.50 (m, 2H), 1.15 (d, J = 6.1 Hz, 3H), 0.94 (t, J = 7.9 Hz, 9H), 0.98-0.88 (m, 2H), 0.58
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(q, J = 7.9 Hz, 6H), 0.01 (s, 9H); C NMR (CDCl3, 100 MHz): δ 135.8, 118.7, 92.4, 81.7, 70.8,
65.2, 20.0, 18.2, 7.0 (3C), 5.1 (3C), -1.3 (3C); MS (EI) m/z: 309 (1), 287 (1), 273 [(M-TMS)+, 1],
259 (10), 215 (8), 199 (20), 175 (10), 159 (67), 147 (10), 131 (40), 115 (63), 103 (32), 87 (35), 73
(100), 59 (17); HRMS (ESI): Calculated for C17H38O3Si2Na [M + Na]+: 369.2252, found: 369.2251.
(E)-(2-Iodovinyl)boronic acid MIDA ester (8):14 To a suspension of alkyne 7 (2.5 g, 13.8 mmol,
1.0 equiv) in dry THF (60 mL) were added AIBN (227 mg, 1.38 mmol, 0.1 equiv) and Bu3SnH
(5.6 mL, 20.8 mmol, 1.5 equiv). The mixture was heated at reflux for 16 h and then AIBN (227
mg, 1.38 mmol, 0.1 equiv) and Bu3SnH (5.6 mL, 20.8 mmol, 1.5 equiv) were added again. After 8
h of reflux, the solution was cooled to –78 °C and a solution of I2 (7.0 g, 27.6 mmol, 2.0 equiv) in
dry THF (40 mL) was added dropwise over 1 h. The mixture was stirred at –78 °C, progressively
warmed to rt overnight, and then quenched by the addition of a saturated aqueous solution of
Na2S2O3 (40 mL). EtOAc (50 mL) was added, the layers were separated and the aqueous layer was
extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine, dried
over MgSO4, filtered and concentrated under vacuum. The resulting solid was suspended in Et2O,
filtered, washed with additional Et2O to give the vinyl iodide 8 (3.07 g, 9.9 mmol, 72%) as a white
solid. The spectral data are in agreement with those reported in the literature.14 mp: 163-165 °C
(lit.:14 145 °C); IR: ν 3005, 2961, 1745, 1708, 1569, 1451, 1336, 1283, 1184, 1154, 1104, 1077,
1022, 1005, 965, 952, 893 cm-1; 1H NMR (acetone-d6, 400 MHz): δ 6.91 (d, J = 15.6 Hz, 1H), 6.82
(d, J = 15.6 Hz, 1H), 4.27 (dAB syst, J = 16.9 Hz, 2H), 4.11 (dAB syst, J = 16.9 Hz, 2H), 3.08 (s, 3H);
13C NMR (acetone-d6, 100 MHz): δ 168.6 (2C), 90.2, 62.6 (2C), 47.6, C-B not visible.44
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[(1E,3E)-4-(Trimethylsilyl)buta-1,3-dien-1-yl]boronic acid MIDA ester (9):14 To a solution of
vinyl iodide 8 (1.0 g, 3.24 mmol, 1.0 equiv) in anhydrous MeCN (22 mL) in a vial, were added
AgOAc (810 mg, 4.85 mmol, 1.5 equiv), Pd(OAc)2 (36 mg, 0.16 mmol, 0.05 equiv) and
vinyltrimethylsilane (0.71 mL, 4.82 mmol, 1.5 equiv). The vial was sealed and the mixture was
heated at 80 °C for 14 h. The mixture was then cooled to rt, transferred into a flask containing
Celite® using acetone and concentrated under vacuum to give a grey powder. Purification of the
crude material by flash column chromatography on silica gel (solid loading, Et2O/acetone = 10:0
to 8:2) afforded the desired diene 9 as an unseparable mixture with the branched isomer 9’ in a 8:2
ratio (660 mg, 2.35 mmol, 72%) and as a beige solid. The spectral data are in agreement with those
reported in the literature.14 mp: 205-207 °C (lit.:14 210 °C); IR (mixture of isomers): ν 3016, 2956,
2899, 1753, 1624, 1572, 1462, 1333, 1294, 1246, 1175, 1155, 1118, 1083, 1000, 966, 952, 851
cm-1; 1H NMR (acetone-d6, 400 MHz, major isomer): δ 6.66-6.52 (m, 2H), 5.92 (d, J = 17.9 Hz,
1H), 5.74 (d, J = 17.0 Hz, 1H), 4.22 (dAB syst, J = 16.8 Hz, 2H), 4.04 (dAB syst, J = 16.8 Hz, 2H), 3.01
(s, 3H), 0.08 (s, 9H); 13C NMR (acetone-d6, 100 MHz, major isomer): δ 169.0 (2C), 147.3, 145.9,
135.1, 62.3 (2C), 47.4, -1.3 (3C), C-B not visible.44
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{(1E,3E,5E,7S,8R)-8-(Triethylsilyloxy)-7-{[2-(trimethylsilyl)ethoxy]methoxy}nona-1,3,5-
trien-1-yl}boronic acid MIDA ester (10): To a solution of vinyl iodide 2 (330 mg, 0.98 mmol,
1.0 equiv) in anhydrous MeCN (11.2 mL) in a vial, were added the protected allylic alcohol 6 (1.70
g, 4.9 mmol, 5.0 equiv), AgOAc (246 mg, 1.48 mmol, 1.5 equiv), and Pd(OAc)2 (11 mg, 0.05
mmol, 0.05 equiv). The vial was sealed and the mixture was heated at 50 °C for 14 h. The mixture
was then cooled to rt, diluted with acetone, transferred into a flask containing Celite® and
concentrated under vacuum to give a grey powder. Purification of the crude material by flash
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column chromatography on silica gel (solid loading, Et2O/acetone = 10:0 to 8:2) afforded the
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desired triene 10 contamined with traces of another unidentified isomer (95% purity, 238 mg, 0.43
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mmol, 44%) as a yellow oil. [α]D + 78.9 (c 1.0, acetone); IR: ν 2956, 2879, 1769, 1623, 1586,
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1461, 1379, 1340, 1299, 1250, 1196, 1110, 1028, 990, 959, 863, 838 cm-1; 1H NMR (acetone-d6,
400 MHz): δ 6.62 (br dd, J = 17.3 and J = 9.4 Hz, 1H), 6.40-6.25 (m, 3H), 5.74 (m, 1H), 5.73 (d,
J = 17.4 Hz, 1H), 4.64 (br s, 2H), 4.21 (dAB syst, J = 16.9 Hz, 2H), 4.03 (ddAB syst, J = 16.9 and J =
1.4 Hz, 2H), 3.94-3.87 (m, 2H), 3.73 (td, J = 9.5 and J = 7.4 Hz, 1H), 3.57 (td, J = 9.1 and J = 7.4
Hz, 1H), 2.99 (s, 3H), 1.13 (d, J = 6.0 Hz, 3H), 0.96 (t, J = 8.0 Hz, 9H), 0.98-0.89 (m, 2H), 0.61
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(q, J = 8.0 Hz, 6H), 0.03 (s, 9H); C NMR (acetone-d6, 100 MHz): δ 169.0 (2C), 143.2, 135.8,
134.6, 133.7, 132.8, 92.8, 81.4, 71.6, 65.4, 62.3 (2C), 47.3, 20.5, 18.5, 7.2 (3C), 5.5 (3C),
-1.3 (3C), C-B not visible;44 HRMS (ESI): Calculated for C26H48BNO7Si2Na [M + Na]+: 576.2955,
found: 576.2952.
(2E,4E,6E,8E,10E,12S,13R)-Ethyl
2-methyl-13-(triethylsilyloxy)-12-{[2-(trimethylsilyl)
ethoxy]-methoxy}tetradeca-2,4,6,8,10-pentaenoate (12): To a solution of triene 10 (160 mg,
0.29 mmol, 1.0 equiv) in a mixture of THF (2.1 mL) and MeOH (0.7 mL) was added MeONa (78
mg, 1.44 mmol, 5.0 equiv). The mixture was stirred at rt in the dark for 1 h and then a solution of
I2 (220 mg, 0.87 mmol, 3.0 equiv) in dry THF (2.1 mL) was added. The mixture was stirred at rt
in the dark for 2.5 h and then a pH 7 buffer (5 mL) was added. The mixture was diluted with Et2O
(5 mL), the layers were separated and the organic layer was washed with a saturated aqueous
solution of Na2S2O3 (5 mL). The aqueous layer was then extracted with Et2O (3 × 5 mL). The
combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated
under vacuum to afford the iodotriene 11, which was not purified but directly involved in the next
step.
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To the unpurified iodotriene 11 were added K2CO3 (80 mg, 0.58 mmol, 2.0 equiv), Pd(OAc)2 (3.3
mg, 0.015 mmol, 0.05 equiv) and n-Bu4Br (93 mg, 0.29 mmol, 1.0 equiv). The mixture was
degassed under vacuum and refiled with argon, three times. The ester 1 (61 mg, 0.435 mmol, 1.5
equiv) and DMF (3 mL) were then added and the mixture was stirred in the dark and heated at
50 °C for 16 h, and then cooled to rt. Et2O (5 mL) was added followed by a saturated aqueous
solution of NaCl (5 mL). The layers were separated and the aqueous layer was then extracted with
Et2O (3 × 5 mL). The combined organic layers were washed with H2O, dried over MgSO4, filtered
and concentrated under vacuum. Purification of the crude material by flash column
chromatography on silica gel (pentane/Et2O = 95:5) afforded the pentaenic ester 12 (89 mg, 0.166
mmol, 57%) as a bright yellow oil. [α]D 20 + 112.6 (c 1.0, CHCl3); IR: ν 3022, 2954, 2877, 1702,
1620, 1577, 1458, 1415, 1367, 1241, 1219, 1162, 1140, 1101, 1028, 1003, 937, 920, 860, 836
cm-1; 1H NMR (C6D6, 400 MHz): δ 7.51 (dq, J = 11.0 and J = 1.4 Hz, 1H), 6.42-6.08 (m, 7H), 5.85
(dd, J = 15.3 and J = 7.9 Hz, 1H), 4.85 (dAB syst, J = 6.8 Hz, 1H), 4.72 (dAB syst, J = 6.8 Hz, 1H),
4.14 (br dd, J = 7.9 and J = 4.8 Hz, 1H), 4.10 (q, J = 7.1 Hz, 2H), 4.01 (qd, J = 6.2 and J = 4.6 Hz,
1H), 3.86 (m, 1H), 3.61 (m, 1H), 1.98 (d, J = 1.3 Hz, 3H), 1.30 (d, J = 6.2 Hz, 3H), 1.07 (t, J = 8.0
Hz, 9H), 1.08-0.98 (m, 2H), 1.03 (t, J = 7.1 Hz, 3H), 0.68 (q, J = 8.2 Hz, 6H), 0.03 (s, 9H);
13C NMR (C6D6, 100 MHz): δ 167.9, 139.5, 138.3, 136.3, 134.6, 134.4, 133.3, 132.9, 128.5 (2C),
127.7, 92.6, 81.2, 71.4, 65.3, 60.5, 20.7, 18.3, 14.4, 13.1, 7.2 (3C), 5.5 (3C), -1.3 (3C); HRMS
(ESI): Calculated for C29H52O5Si2Na [M + Na]+: 559.3246, found: 559.3238.
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(2E,4E,6E,8E,10E,12S,13R)-2-Methyl-13-(triethylsilyloxy)-12-{[2-(trimethylsilyl)ethoxy]
methoxy}tetradeca-2,4,6,8,10-pentaenal (13): To a solution of ester 12 (69 mg, 128 µmol, 1.0
equiv) in dry CH2Cl2 (2.4 mL) cooled to –78 °C was added DIBAL-H (0.39 mL, 1 M in toluene,
0.39 mmol, 3.0 equiv) dropwise. The mixture was stirred at –78 °C in the dark for 20 min, then
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