Convergent strategy towards the synthesis of restricted analogues of peloruside A

Article abstract of DOI:10.1002/ejoc.201201728

A rapid convergent strategy to access unsaturated analogues of peloruside A has been demonstrated. This is depicted as an original C11-C12 aldol connection between a C12-C20 ketone fragment and a C2-C11 pyran fragment bearing an aldehyde function, with high yield and a good level of diastereoselectivity. The desired unsaturated macrocycle was obtained by a late-stage ring closing metathesis reaction.

Full text of DOI:10.1002/ejoc.201201728

FULL PAPER
DOI: 10.1002/ejoc.201201728
Convergent Strategy Towards the Synthesis of Restricted Analogues of
Peloruside A
Nicolas Zimmermann,[a] Pierre Pinard,[a] Bertrand Carboni,[b] Pascal Gosselin,[c]
Catherine Gaulon-Nourry,[c] Gilles Dujardin,[c] Sylvain Collet,[a] Jacques Lebreton,*[a] and
Monique Mathé-Allainmat*[a]
Keywords: Synthetic methods / Aldol reactions / Metathesis / Natural products / Macrocycles / Lactones
A rapid convergent strategy to access unsaturated analogues
of peloruside A has been demonstrated. This is depicted as
an original C11–C12 aldol connection between a C12–C20
ketone fragment and a C2–C11 pyran fragment bearing an
aldehyde function, with high yield and a good level of dia-
stereoselectivity. The desired unsaturated macrocycle was
obtained by a late-stage ring closing metathesis reaction.
peloruside A seemed to bind to a site distinct from the
taxoid one. In fact, synergistic phenomena have been ob-
served with drug combinations relative to single-drug ad-
ministration in a tubulin assembly model,[8] and recent
binding studies carried out with labeled [3H]-peloruside A
confirmed that paclitaxel was unable to displace [3H]-pelo-
ruside A from its binding site.[6b]
Introduction
Some of the most effective anticancer medications used
over recent decades have been drugs targeting tubulin.[1] Pa-
clitaxel (Taxol®), which is a member of the taxane family,
can be considered as one of the most successful drugs in
the battle against cancer. However, difficulties in its formu-
lation owing to its high hydrophobicity and the emergence
of drug resistance have triggered an interest in the search
for new microtubule stabilizing agents, acting in the same
manner as paclitaxel.[2] In 2000, peloruside A 1 (Figure 1),
a marine sponge macrolide, was isolated by Northcote and
co-workers and characterized as a polyoxygenated 16-mem-
bered macrocycle containing a pyran ring.[3] Peloruside A
was found to arrest cells in the G2/M phase of the cell cycle
and to induce cytotoxicity at the nanomolar range in a
series of human cancer cells.[4] Like paclitaxel, peloruside A
binds to microtubules and induces apoptosis through
microtubule stabilization.[5] In the last decade, some com-
putational[6] and biological[7] studies have been published
proposing a localization of the binding site for peloruside A
on the α- or β-tubuline of the microtubules. Although
hypotheses were argued, the common conclusion was that
[a] Université de Nantes, CNRS, UMR 6230, Chimie et
Interdisciplinarité: Synthèse, Analyse, Modélisation
(CEISAM), UFR Sciences et Techniques,
2, rue de la Houssinière, BP 92208, 44322 Nantes Cedex 3,
France
Figure 1. Structure of peloruside A 1 and natural or synthetic ana-
logues 2–5.
E-mail: monique.mathe@univ-nantes.fr
jacques.lebreton@univ-nantes.fr
Homepage: http://www.sciences.univ-nantes.fr/CEISAM/
symbiose.php
To date six total syntheses of peloruside A[9] 1 and one
of peloruside B[10] 2 have been detailed in the literature. The
first, published by De Brabander confirmed the absolute
configuration of the natural (+)-peloruside A with the syn-
thesis of the (–)-enantiomer.[9a] Few analogues have been
published since 2003.[11,12] Among them, conformationally
[b] Université de Rennes, Institut des Sciences Chimiques
de Rennes UMR CNRS 6226, Campus de Beaulieu, Bât 10A,
avenue du Géneral Leclerc, 35042 Rennes, France
[c] Université du Maine, IMMM UMR CNRS 6283,
Avenue O. Messiaen, 72085 Le Mans, France
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201728.
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constrained analogues such as natural peloruside C 3[12a] or pyran constrained analogue of peloruside A was suggested
synthetic compound 4 obtained by replacement of the C11 but not carried out.
and C13 stereogenic centers with a set of olefinic Z and E
Most of the total syntheses of peloruside A or analogues
isomers[12b] [compounds (E)-4 and (Z)-4, Figure 1] have published so far install the tetrahydropyran moiety after the
been recently characterized. At the same time, a stereoselec- macrolactonization or macrocyclization step. In those syn-
tive synthesis of monocyclic peloruside A analogue 5 has theses, a C11–C12 bond formation by using an aldol reac-
allowed the importance of the pyranose ring in the bicyclic tion was proposed by the groups of Evans[9d] and Hoye[9f]
core structure of the macrocycle to be outlined (Figure 1, starting from C11 α,α-gem-dimethyl aldehyde acceptor in-
IC50 = 16.4 μm on A549 cells).[13]
troduced on a C1–C11 open chain and a methyl ketone do-
In an effort to open the route to a flexible approach nor similar to our methyl ketone C12–C20 7 (Scheme 1).
towards the synthesis of new unsaturated analogues of pelo- The pyran ring of the targeted macrocycle was formed dur-
ruside and to identify simple macrolides as anti-cancer ing the last deprotection step under acidic conditions with
agents, we proposed a convergent strategy involving a late- acceptable yield (66 or 49% yield, respectively). Our retro-
stage macrocyclization step through ring-closing olefin me- synthetic analysis of unsaturated macrolide analogue of pe-
tathesis (RCM) and an original aldolization step to create loruside is more flexible and led to two fragments being
the C11–C12 bond starting from preformed pyran carb- targeted: (1) the 2,6-disubstituted tetrahydropyran C2–C11
aldehyde 7 as depicted in Scheme 1. A similar aldol coupling fragment bearing an aldehyde functional group and an eth-
was implicit in recent work published by Teesdale-Spittle ylenic moiety for both the C11–C12 and the C1–C2 connec-
and co-workers[14] who prepared a C1–C11 dihydropyran tions; (2) the C12–C20 fragment bearing a terminal methyl
fragment with a carbaldehyde function at the C11 position. ketone and a protected C15 hydroxy group for future func-
Aldolization with a methyl ketone to construct a dihydro- tionalization to give the corresponding acrylate (Scheme 1).
Results and Discussion
The ethylenic enantiopure compound C12-C20 6 was ob-
tained by classical Wittig reaction between racemic phos-
phonium salt 13 and enantiomerically pure protected α-hy-
droxy aldehyde 11, followed by a Tsuji–Wacker oxidation
reaction[15] (Scheme 3). To access unsaturated aldehyde 11,
we applied the strategy proposed by Whei-Shan Zhou and
co-workers[16a] but starting from protected d-glyceraldehyde
9 (Scheme 2, a). Following a literature procedure, stereose-
lective allylation of aldehyde 9 with diallylzinc at room tem-
perature gave a mixture of the expected homoallylic
alcohols[16b] (dr 78:22) and both diastereomers were benzyl-
ated with 4-methoxybenzyl chloride (PMBCl) and sepa-
rated on silica gel to give pure protected homoallylic
alcohol (+)-10 in 73% yield. Oxidative cleavage of this acet-
onide with periodic acid afforded aldehyde (–)-11 in 87%
yield. To access expected ethylenic ketone 6 (Scheme 3) or
its (2R,5R) isomer we proposed to prepare phosphonium
Scheme 1. Retrosynthetic analysis for a simplified unsaturated ana-
logue of peloruside.
Scheme 2. Reagents and conditions: (i) allylBr/Zn, THF, 83% (dr 78:22); (ii) PMBCl, NaH, DMF; 73% (iii) H5IO6, EtOAc, room temp.,
16 h, 87%; (iv) LiAlH4, Et2O, reflux, 14 h, 95%; (v) TBDPSCl, nBuLi, THF, –30 °C, 2 h, 66%; (vi) NIS/PPh3, CH2Cl2, room temp., 13 h,
70%; (vii) PPh3, toluene, reflux, 14 h, 71%.
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Towards the Synthesis of Restricted Analogues of Peloruside A
Scheme 3. Reagents and conditions: (i) KHMDS, THF, –78 °C to room temp., 63%; (ii) TBAF, THF, 48 h, diastereomer separation 17
(45%) and 18 (47%); (iii) TBDPSCl, imidazole, DMF, 48 h, 91%; (iv) O2/PdCl2/CuCl, DMF/H2O, 5 d; (v) NaClO2, NaH2PO4, tBuOH/
H2O, 16 h, 82% (two steps).
salt 13 in racemic form (Scheme 2, b).[17] Starting from oxide 19 in 45% yield.[20b] Copper-mediated ring opening
commercial diethyl 2-ethylmalonate, racemic monosilylated of (–)-19 with vinyl magnesium bromide, followed by depro-
diol 12 was prepared by hydride reduction and subsequent tection of the primary alcohol, gave optically pure diol (+)-
silylation, followed by phosphonium formation in a classi- 20. A clean and efficient oxidation–cyclization reaction pro-
cal two-step manner with N-iodosuccinimide (NIS) and tri- cedure of 1,5-diol 20, by using 4-acetamido-2,2,6,6-tet-
phenylphosphane. Compound (Ϯ)-13 was thus rapidly ob- ramethylpiperidine 1-oxyl (Ac-TEMPO)[21] as the catalyst,
tained in 31% overall yield.
gave lactone 21 in quantitative yield. The latter was engaged
A Wittig reaction was then performed between racemic in reaction with the lithium enolate derived from methyl
phosphonium salt (Ϯ)-13 and pure aldehyde (–)-11 to give isobutyrate[22] and the corresponding lactol was reduced
Z-disubstituted olefins 15/16 (yield 63%) by using one with triethylsilane in the presence of BF3·Et2O to give tetra-
equivalent of potassium bis(trimethylsilyl)amide (KHMDS)
at low temperature (Scheme 3). This yield could not be opti-
mized by either addition of hexamethylphosphoramide
(HMPA) or by using sodium hexamethyldisilazane. Both
diastereomers could not be separated at this stage but were
obtained in 45 and 47% yields for (2R,5S)-17 and (2S,5S)-
isomer 18, respectively, after alcohol desilylation. A Tsuji–
Wacker oxidation reaction[15] of diene 15, obtained after sil-
ylation of pure alcohol 17,[17] afforded ketone 6 with 8% of
the terminal aldehyde coproduct which was oxidised to the
corresponding acid under Pinnick conditions[18] for easy
purification. The optically pure methyl ketone 6 was thus
obtained in 33% overall yield starting from racemic phos-
phonium salt (Ϯ)-13. To access the methyl ketone with the
trisubstituted double bond (e.g. with a methyl group in the
C16 position versus the peloruside A structure) we envis-
aged, as suggested by Zhou and Liu,[16] a simple Wittig re-
action between phosphonium 13 and a methyl ketone ob-
Scheme 4. Reagents and conditions: (i) TBSCl/imidazole, DMF,
room temp., 5 h; (ii) mCPBA, CH2Cl2, room temp., 12 h, 72% (two
steps); (iii) toluene, AcOH (0.002 equiv.), O2, Jacobsen’s catalyst
(0.2 mol-%), 0.5 h, then (؎)-19, H2O (0.55 equiv.), room temp.,
16 h, 45%; (iv) Vinyl MgBr/CuI, THF/Et2O (1:1 v/v), –40 °C, 1 h,
90%; (v) TBAF, THF, room temp., 16 h, 87%; (vi) Ac-TEMPO,
NCS, TBABr, CH2Cl2, pH buffer (8.6), room temp., 16 h, quant.;
(vii) methyl isobutyrate, lithium diisopropylamide, THF, 0 °C, then
BF3·Et2O, Et3SiH, Et2O, –78 °C, 4 h, 86% (two steps); (viii) Li-
AlH4, THF, room temp., 4 h, 87%; (ix) oxalyl chloride, DMSO,
tained by methylation (AlMe3) followed by Swern oxidation
of aldehyde (–)-11. Under conditions described by Still[19]
[tetrahydrofuran (THF)/HMPA (9:1, v/v); KHMDS] we did
not obtain the expected trisubstituted olefin.
Disubstituted enantiopure pyran C2–C11 7 was the re-
sult of a ten-step sequence starting from commercially avail-
able 5-hexen-1-ol (Scheme 4). Racemic epoxide (Ϯ)-19 was
subjected to (R,R)-Jacobsen’s chiral (salen)CoII catalyst for
hydrolytic kinetic resolution[20a] to give known (–)-(R)-ep- Et3N, CH2Cl2, –78 °C, 1 h, quant.
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hydropyran cis-22 in 86% yield (two steps) with no traces ide and selective O-methylation of the C13 hydroxy group
of the trans isomer. Reduction of cis-22 followed by Swern at a late stage. The preparation of acetonide 25 allowed us
oxidation gave gem-dimethyl pyran carbaldehyde 7 with the to confirm unambiguously the 1,3-anti stereochemical rela-
correct C5 and C9 configurations relative to peloruside A.
tionship in diol 24 by 13C NMR analysis (resonances for
The aldol reaction has frequently been used in strategies the isopropylidene methyl groups at δ = 25.4 and 24.8 ppm).
published in the literature to prepare peloruside fragments Acrylate 26 was obtained in 81% yield (two steps) after
to control hydroxylated stereocenters. The boron-mediated treating 25 with pH-7 buffer 2,3-dichloro-5,6-dicyano-1,4-
aldol reaction was proved to proceed with 1,5-anti induc- benzoquinone (DDQ) to cleave the C15 PMB ether. Triene
tion with a wide range of methyl ketone donors with a β- 26 underwent RCM cyclization with Grubbs’ II catalyst
OPMB alkoxy substituent.[23] In the total synthesis of pelo- (Scheme 5). The geometry for resulting E-olefin 27 was eas-
ruside A published by Hoye et al. a late-stage Paterson ily assigned by 1H NMR analysis (H2 proton δ = 5.86 ppm;
boron aldol coupling reaction was planned between an α,α- JH2-H3 = 15.9 Hz), and compound 27 was formed as a single
1
gem-dimethyl (C1–C11) linear aldehyde acceptor and a isomer. Furthermore H NMR NOESY experiments were
methylketone similar to our C12–C20 fragment 6 bearing a done on conformationally restricted intermediate 27. In
β(C15)-OPMB substituent. The hydroxy ketone was ob- apolar solvent, NOE cross-peaks were clearly observed be-
tained with essentially complete 1,5-anti stereocontrol.[9f]
tween H9–H11 and H13–H16 (see Supporting Infor-
In our convergent strategy, the first C11–C12 connection mation), which supports a (S,S) absolute configuration of
has to be made starting from enantiopure β-alkoxy ketone the C11 and C13 carbon centers in 24 and allowed us to
6 and pyran aldehyde 7 (Scheme 5). The dicyclohexylboron conclude the major 1,5-anti stereoisomer formation in the
enolate of ketone 6 was formed and added to aldehyde 7 aldol reaction step. The acetonide TBDPS-ether protective
(2 equiv., –78 °C)[23b] to give hydroxy ketone 23 in 83% groups were sequentially removed by acid hydrolysis and
yield (Scheme 5). An acceptable 1,5-anti,syn diastereoselec- tetra-n-butylammonium fluoride (TBAF) treatment to ac-
tivity (dr 7:3) was obtained, which was not as good as cess pure triol 8, an unsaturated simplified analogue of pe-
Hoye’s group.[9f] Ketone 23 was reduced in a controlled loruside (Scheme 5).
[24a]
manner with Me4NBH(OAc)3
to give pure 1,3-anti diol
Compounds 28 and 8 were tested for their in vitro inhibi-
24 in 65% yield. Some model experiments to access a tion of cell proliferation on a panel of five human tumor
monoprotected 1,3-anti diol with a samarium-catalyzed in- cell lines (Huh7, CaCo2, HCT116, PC3 and NCI) in ad-
tramolecular Tischenko[24b] reduction starting from similar dition to normal diploid skin fibroblasts as the control. Al-
hindered β-hydroxy ketone and benzaldehyde failed. To though no activity (IC50 Ͼ 25 μm) was observed with pro-
avoid protection–deprotection steps of the C11 hydroxy tected compound 28, some effect was observed with triol 8
group, we envisaged the protection of diol 24 as its aceton- on colon carcinoma (CaCo2: IC50 = 12 μm; HCT116: IC50
Scheme 5. Reagents and conditions: (i) 6, Cy2BCl, Et3N, CH2Cl2/Et2O, 0 °C, then 7, –78 °C, 3.5 h, 83% (dr 7:3); (ii) Me4NHB(OAc)3,
AcOH, CH3CN, –20 °C, 8 h, 65%; (iii) 2,2-DMP, PPTS, CH2Cl2, room temp., 14 h, 81%; (iv) DDQ, phosphate buffer pH = 7, CH2Cl2,
3.5 h, 0 °C, 80%; (v) acryloyl chloride, EtiPr2N, CH2Cl2, room temp., 4 h, 95%; (vi) Grubbs II cat., CH2Cl2, reflux, 2 h, 83%; (vii) PPTS,
acetone/H2O, reflux, 3 h, 70%; (viii) TBAF, room temp., 8 h, 92%.
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Towards the Synthesis of Restricted Analogues of Peloruside A
in oil (60 wt.-%, 0.85 g, 22.30 mmol, 1.2 equiv.) was added at 0 °C
to a dimethylformamide (DMF) solution (50 mL) of a dia-
stereomer mixture (dr 78:22) of the corresponding homoallylic
alcohols (3.20 g, 18.58 mmol, 1 equiv.) obtained by classical allyl-
ation of protected d-glyceraldehyde 9.[16b] The reaction mixture was
stirred at 0 °C for 1 h. PMBCl (3.50 g, 22.35 mmol, 1.2 equiv.) was
added at the same temperature to the reaction mixture, which was
then warmed to room temperature and left stirring for 13 h before
being quenched by saturated aqueous NH4Cl (40 mL). The aque-
ous phase was extracted with Et2O (5ϫ 25 mL). The combined
organic layers were washed with water and brine, dried with anhy-
drous MgSO4, filtered and concentrated under reduced pressure.
This residue was subjected to column chromatography on silica gel
(PE/Et2O, 95:5) to give compound (+)-10 (12.9 g, 73%) as a color-
less oil. [α]2D0 = +28.0 (c = 0.81, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 7.25 (d, J = 8.4 Hz, 2 H, Har), 6.87 (d, J = 8.7 Hz, 2
H, Har), 5.89 (ddt, J = 7.2, J = 10.2, J = 17.1 Hz, 1 H, CHCH2),
5.18–5.05 (m, 2 H, CHCH2), 4.55 and 4.25 (AB system, J =
10.8 Hz, 2 H, CH2), 4.12–3.99 (m, 2 H, CH2O and OCH), 3.86
(dd, J = 6.0, J = 7.8 Hz, 1 H, CH2O), 3.80 (s, 3 H, OCH3), 3.54
(pq, J = 6.0 Hz, 1 H, OCH), 2.48–2.27 (m, 2 H, CH2), 1.42 (s, 3
H, CH3), 1.35 (s, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ
= 159.4 (C(IV)ar), 134.4 (CH), 130.7 (C(IV)ar), 129.5 (Car), 117.6
(CH2), 113.9 (Car), 109.2 (C(IV)), 78.7 (CH), 77.4 (CH), 72.3 (CH2),
66.6 (CH2), 55.4 (OCH3), 35.8 (CH2), 26.8 (CH3), 25.5 (CH3) ppm.
MS (CI): m/z = 310 [M + NH4]+. HRMS: calcd. for C17H23O4 [M –
H]+ 291.1596; found 291.1599.
= 15 μm) and prostate carcinoma (PC3: IC50 = 15 μm),
which is encouraging for such a constrained compound
lacking five stereocenters relative to natural peloruside A.
Conclusions
We have validated a convergent strategy to construct pe-
loruside analogues starting with a pyran carbaldehyde frag-
ment. We first focussed our work on the synthesis of the
enantiopure C12–C20 fragment and proposed a rapid and
efficient diastereomeric approach to scale-up the prepara-
tion of ketone 6 and its (2R,5R)-diastereomer. Both cou-
pling reactions between C12–C20 ketone fragment 6 and
C2–C11 pyran fragment 7 have been successfully achieved.
Aldol coupling of ketone 6 with hindered pyran aldehyde
7 gave very good yields under Paterson conditions and a
metathesis macrocyclisation reaction afforded exclusively
the E-stereoisomer. A new unsaturated simplified analogue
of peloruside A 8, was then prepared in eight steps and its
cytotoxicity on selected tumor cell lines was found to be
around 10 μm. This convergent strategy opens the way to
the synthesis of a series of analogues, involving more com-
plex tri- or tetra substituted α,α-gem-dimethyl pyran frag-
ments.
(S)-2-(4-Methoxybenzyloxy)pent-4-enal [(–)-11]: H5IO6 (2.58 g,
11.30 mmol, 1.1 equiv.) was added to a solution of compound (+)-
10 (3.01 g, 10.29 mmol, 1 equiv.) in anhydrous ethyl acetate
(125 mL). The reaction mixture was stirred at room temperature
for 13 h. Excess reagent was quenched with the addition of solid
sodium thiosulfate (3.7 g) and solid potassium carbonate (3.2 g).
The reaction mixture became light brown, and was stirred at room
temperature for 1 h. Filtration through Celite, washing with
CH2Cl2 and concentration under reduced pressure gave a brown
oily residue that was subjected to column chromatography on silica
gel (PE/Et2O, 9:1 to 7:3) to furnish aldehyde (–)-11 (1.93 g, 87%)
as a beige oil (lit. reported enantiomer[25]). [α]2D0 = –30.6 (c = 1.2,
Experimental Section
General Remarks: Water-sensitive reactions were performed under
an argon atmosphere in flame-dried glassware. All solvents used
were reagent grade. Et2O and THF were freshly distilled from so-
dium/benzophenone under argon. Toluene was freshly distilled
from sodium under argon. CH2Cl2, CH3CN, methanol, triethanol-
amine (TEA), diisopropylamine and diisopropylethylamine were
freshly distilled from calcium hydride under argon. TLC was per-
formed on silica-covered aluminum sheets (Kieselgel 60F254
,
MERCK). Flash column chromatography was performed on silica
gel 60 ACC 40–63 μm (SDS-Carlo Erba). NMR spectra were re-
corded with a Bruker AC300 (300 MHz for 1H) or a Bruker 400
1
CHCl3). H NMR (300 MHz, CDCl3): δ = 9.62 (d, J = 2.1 Hz, 1
H, HC=O), 7.27 (d, J = 9.0 Hz, 2 H, Har), 6.89 (d, J = 8.7 Hz, 2
H, Har), 5.80 (ddt, J = 6.9, J = 10.2, J = 17.1 Hz, 1 H, CHCH2),
5.18–5.07 (m, 2 H, CHCH2), 4.57 and 4.27 (AB system, J =
11.4 Hz, 2 H, CH2), 3.83–3.77 (m, 1 H, OCH), 3.81 (s, 3 H, OCH3),
2.50–2.43 (m, 2 H, CH2) ppm. 13C NMR (75 MHz, CDCl3): δ =
203.3 (CO), 159.7 (C(IV)ar), 132.6 (CH), 129.8, 129.4 (C(IV)), 118.5
(CHCH2), 114.0 (Car), 82.6 (OCH), 72.3 (CH2), 55.4 (OCH3), 34.8
(CH2) ppm. MS (CI): m/z = 238 [M + NH4]+.
1
(400 MHz for H) at room temperature, and samples dissolved in
an appropriate deuterated solvent. Tetramethylsilane was used a
reference for 1H NMR spectra, deuterated solvent signal for 13C
NMR spectra (C(IV) stands for quaternary C atom), and 85% aq.
phosphoric acid for 31P NMR spectra. HPLC analyses were per-
formed with a Hewlett–Packard 1100. IR analyses were recorded
with a Bruker Vector 22 spectrometer and performed neat with
KBr pellets. Melting points were determined with a RCH (C. Rei-
chert) microscope equipped with a Koffler heating system. Specific
optical rotation values were measured at room temperature in a
100 mm cell with a Perkin–Elmer 341 Polarimeter under sodium
radiation (λ = 589 nm). Low-resolution mass spectra were per-
formed with a Thermo-Finnigan DSQII quadripolar spectrometer
in chemical ionization mode (CI) at 70 eV with NH3 gas. High-
Resolution Mass Spectrometry (HRMS) analyses were performed
at the “Centre Commun de Spectrométrie de Masse” in Lyon
(France), with a Micro-TOFOII Thermofischer Scientific for elec-
tro-spray ionization (ESI) measurements. Some products were also
analyzed with a MALDI-TOF-TOF technique with a Bruker Auto-
flex III Smartbeam in the laboratory.
(؎)-2-[(tert-Butyldiphenylsilyloxy)methyl]butan-1-ol [(؎)-12]: Li-
AlH4 (7.51 g, 198 mmol, 2.5 equiv.) was added at room temperature
under argon to a solution of diethyl ethylmalonate (15.0 g,
79.7 mmol, 1 equiv.) in anhydrous Et2O (300 mL). The reaction
mixture was heated to reflux for 14 h and then diluted with Et2O
(100 mL), quenched with water (20 mL), followed by an aqueous
solution of NaOH 10% (20 mL). Finally water (20 mL) was added
to the mixture was filtered through Celite. The filtrate was concen-
trated under reduced pressure. The resulting diol was obtained
without further purification in 95% yield as a colorless oil (lit. re-
ported compound[26]). 1H NMR (300 MHz, CDCl3): δ = 3.62–3.84
(m, 4 H, CH2OH), 2.27 (s, 2 H, OH), 1.68 (m, 1 H, CH), 1.32
(quint, J = 7.6 Hz, 2 H, CH2CH3), 1.24 (t, J = 7.6 Hz, 3 H,
CH2CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 66.37 (CH2),
43.82 (CH), 20.76 (CH2), 11.84 (CH3) ppm.
(R)-4-[(S)-1-(4-Methoxybenzyloxy)but-3-enyl]-2,2-dimethyl-1,3-di-
oxolane [(+)-10]: From adaptation of the literature procedure, NaH
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nBuLi (2.5 m, 14 mL, 35 mmol, 0.92 equiv.) was added at –25 °C
under argon to a solution of diol (4.01 g, 38.4 mmol, 1 equiv.) in
anhydrous THF (110 mL) and the reaction mixture was stirred at
this temperature for 1 h. tert-Butyldiphenylsilyl chloride
3.30 (dd, J = 13.5, J = 3.3 Hz, 1 H, CHCH2Ph), 2.82 (dd, J = 13.5,
J = 9.3 Hz, 1 H, CHCH2Ph), 1.92 (br. s, 1 H, OH), 1.82–1.55 (m,
2 H, CH2CH3), 0.97 (t, J = 7.5 Hz, 3 H, CH2CH3) ppm. 13C NMR
(75 MHz, CDCl3): δ = 175.9 (CO), 153.7 (CO), 135.3 (C(IV)), 129.6
(TBDPSCl; 10.55 g, 38.4 mmol, 1 equiv.) in THF (40 mL) was (Car), 129.1 (Car), 127.5 (Car), 66.3 (CH2), 63.6 (CH2OH), 55.6
added at –30 °C and the colorless solution was stirred for 2 h before
being quenched by a saturated aqueous solution of NH4Cl. The
aqueous phase was extracted with CH2Cl2 (3ϫ 50 mL), and the
combined organic layers were dried with anhydrous MgSO4, fil-
tered and concentrated under reduced pressure. The resulting crude
mixture was then subjected to column chromatography on silica
gel (PE/Et2O, 9:1 to 1:1) to give compound (؎)-12 (8.60 g, 66%)
as a colorless oil (lit. reported compound[27]). 1H NMR (300 MHz,
CDCl3): δ = 7.71–7.66 (m, 4 H, Har), 7.47–7.37 (m, 6 H, Har), 3.83–
3.61 (m, 4 H, CH2OH and CH2O), 1.75–1.62 (m, 1 H, CH), 1.37–
1.18 (m, 2 H, CH2CH3), 1.06 (s, 9 H, tBu), 0.85 (t, J = 7.5 Hz, 3
H, CH2CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 135.8 (Car),
133.3 (C(IV)ar), 130.0 (Car), 127.9 (Car), 67.3 (CH2O), 66.0
(CH2OH), 44.1 (CH), 27.0 (tBu), 20.7 (CH2), 19.3 (C(IV) tBu), 11.8
(CH3) ppm. MS (CI): m/z = 343 [M + H]+. HRMS: calcd. for
C21H31O2Si [M + H]+ 343.2093; found 343.2099.
(CHBn), 47.2 (CHCO), 38.0 (CH2Ph), 21.8 (CH2CH3), 11.8
(CH3) ppm.
4-(Dimethylamino)pyridine (DMAP; 397 mg, 3.25 mmol,
0.1 equiv.), TEA (9.05 mL, 64.9 mmol, 2 equiv.) and TBDPSCl
(10.1 mL, 38.9 mmol, 1.2 equiv.) were successively added at 0 °C to
a solution of the previous crude alcohol (9.0 g, 32.4 mmol, 1 equiv.)
in anhydrous CH2Cl2 (48 mL). This solution was stirred at room
temperature for 48 h. After dilution with CH2Cl2, the organic
phase was washed with water and brine, then dried with anhydrous
MgSO4, filtered and concentrated under reduced pressure. The re-
sulting residue was subjected to column chromatography on silica
gel (PE/Et2O, 9:1 to 1:1) to give compound (R)-4-benzyl-3-{(S)-2-
[(tert-butyldiphenylsilyloxy)methyl]butanoyl}oxazolidin-2-one
(16.9 g) in quantitative yield as a colorless oil. [α]2D0 = –2.1 (c =
0.34, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.73–7.66 (m, 4
H, Har), 7.44–7.18 (m, 11 H, Har), 4.77–4.69 (m, 1 H, CHBn), 4.20–
4.09 (m, 3 H, CHCO and CH2), 4.02 (dd, J = 9.9, J = 8.1 Hz, 1
H, CH2 OTBDPS), 3.83 (dd, J = 9 . 6 , J = 4.8 Hz, 1 H,
CH2OTBDPS), 3.38 (dd, J = 13.5, J = 3.3 Hz, 1 H, CHCH2Ph),
2.59 (dd, J = 13.5, J = 10.2 Hz, 1 H, CHCH2Ph), 1.78–1.64 (m, 1
H, CH2CH3), 1.60–1.46 (m, 1 H, CH2CH3), 1.04 (s, 9 H, tBu), 0.86
(t, J = 7.5 Hz, 3 H, CH2CH3) ppm. 13C NMR (75 MHz, CDCl3):
δ = 175.2 (CO), 153.4 (CO), 135.8 (Car), 134.9 (Car), 133.6 (Car),
133.5 (Car), 129.8, (Car) 129.5 (Car), 129.1 (Car), 127.8 (Car), 127.4
(Car), 66.1 (CH2), 65.0 (CH2), 55.6 (CHBn), 47.2 (CHCO), 38.3
(CH2Ph), 27.0 (tBu), 21.9 (CH2CH3), 19.4 (C(IV) tBu), 11.6
(CH3) ppm. MS (CI): m/z = 516 [M + H]+; 533 [M + NH4]+.
HRMS: calcd. for C31H38NO4Si [M + H]+ 516.2570; found
516.2573.
(R)-4-Benzyl-3-[(S)-2-(benzyloxymethyl)butanoyl]oxazolidin-2-one
(14): To a solution of (R)-4-benzyl-3-butyryloxazolidin-2-one[28]
(10.0 g, 40.4 mmol, 1 equiv.) in anhydrous CH2Cl2 (16 mL), a com-
mercial TiCl4 solution (1.0 m in CH2Cl2, 44.4 mL, 44.4 mmol,
1.1 equiv.) was added dropwise at 0 °C under argon. A yellowish
solid appeared in the reaction mixture, which was stirred for
30 min. Freshly distilled TEA (6.8 mL, 48.5 mmol, 1.2 equiv.) was
then added dropwise at 0 °C: the solid disappeared and a dark red
solution appeared. After 1 h stirring at the same temperature,
freshly-distilled benzyl chloromethyl ether (BOMCl; 14 mL,
101 mmol, 2.5 equiv.) was added to the reaction mixture which was
stirred for 5 h at 0 °C and warmed to room temperature. The mix-
ture was diluted with CH2Cl2, washed with saturated aqueous
NH4Cl (4ϫ), saturated aqueous NaHCO3 (3ϫ) and brine, then
dried with anhydrous MgSO4, filtered and concentrated under re-
duced pressure. The resulting brown oil was subjected to column
chromatography on silica gel (PE/EA, 95:5 to 60:40) to give a whit-
ish solid, which was recrystallized from isopropyl ether. Desired
compound 14 was obtained (9.01 g, 61%) as a single diastereomer
as white crystals, m.p. 70–71 °C (in DIPO). [α]2D0 = –39.0 [c = 0.96,
CHCl3; lit. enantiomer:[28] [α]2D2 = +40.9 (c = 0.94, CHCl3)]. 1H
NMR (300 MHz, CDCl3): δ = 7.33–7.18 (m, 10 H, Har), 4.77–4.69
(m, 1 H, CHCH2Ph), 4.55 (s, 2 H, CH2Ph), 4.21–4.10 (m, 3 H,
CHCO and CH2), 3.81 (pt, J = 9.0 Hz, 1 H, CH2OBn), 3.66 (dd,
J = 9.3, J = 5.1 Hz, 1 H, CH2OBn), 3.23 (dd, J = 13.5, J = 3.3 Hz,
1 H, CHCH2Ph), 2.70 (dd, J = 13.5, J = 9.3 Hz, 1 H, CHCH2Ph),
1.83–1.52 (m, 2 H, CH2 CH3 ), 0.94 (t, J = 7.5 Hz, 3 H,
CH2CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 175.2 (CO), 153.4
(CO), 138.4 (C(IV)ar), 135.5 (C(IV)ar), 129.6 (Car), 129.0 (Car), 128.5
(Car), 127.8 (Car), 127.4 (Car), 73.3 (OCH2Ph), 71.2 (CH2OBn),
66.0 (CH2), 55.4 (CHBn), 45.0 (CHCO), 37.9 (CH2Ph), 22.3
(CH2CH3), 11.7 (CH3) ppm.
To a solution of (R)-4-benzyl-3-{(S)-2-[(tert-butyldiphenylsilyloxy)-
methyl]butanoyl}oxazolidin-2-one (16.8 g, 32.5 mmol, 1 equiv.) in
dry Et2O (260 mL) and dry THF (260 mL), water (711 μL,
39.1 mmol, 1.2 equiv.) and a commercial LiBH4 solution (2.0 m in
THF, 21.2 mL, 42.3 mmol, 1.3 equiv.) were added dropwise. The
opaque mixture was stirred at room temperature for 5 h. The reac-
tion was quenched with saturated aqueous NH4Cl solution, and
the resulting aqueous phase was extracted with Et2O (2ϫ). The
combined organic fractions were then washed with brine, dried
with anhydrous MgSO4, filtered and concentrated under reduced
pressure. The obtained residue was subjected to column
chromatography on silica gel (PE/Et2O, 9:1 to 7:3) to give alcohol
(+)-12 (8.96 g, 80%) as a beige oil. [α]2D0 = +7.9 (c = 0.45, CHCl3).
(؎)-{2-[(tert-Butyldiphenylsilyloxy)methyl]butyl}triphenyl-
phosphonium Iodide [(؎)-13]: Triphenylphosphane (1.38 g,
5.25 mmol, 1.5 equiv.), then NIS (1.17 g, 5.23 mol, 1.5 equiv.) were
cautiously added at 0 °C under argon to a solution of alcohol (Ϯ)-
12 (1.2 g, 3.5 mmol, 1 equiv.) in anhydrous CH2Cl2 (20 mL). The
(R)-2-[(tert-Butyldiphenylsilyloxy)methyl]butan-1-ol [(+)-12]: A reaction mixture was stirred at room temperature for 13 h. After
mixture of compound 14[29a] (12.3 g, 33.3 mmol, 1 equiv.) and 10%
Pd/C (350 mg, 0.33 mmol, 0.01 equiv.) in EtOH/CH2Cl2 (4:1,
100 mL) was stirred for 20 h at room temperature under H2 (5 atm).
Filtration through Celite followed by evaporation of the filtrate
gave the corresponding pure alcohol (9.3 g) as a colorless oil in
quantitative yield. [α]2D0 = –62.3 [c = 0.82, CHCl3; lit. enantio-
mer:[29b] [α]2D5 = +71.6 (c = 0.83, CHCl3)]. 1H NMR (300 MHz,
dilution with CH2Cl2 (20 mL), the organic layer was washed with
10% aqueous Na2S2O3 (20 mL) and brine, then dried with anhy-
drous MgSO4, filtered and concentrated under reduced pressure.
The resulting residue was subjected to column chromatography on
silica gel (PE/Et2O, 99:1 to 8:2) to give (Ϯ)-tert-butyl-[2-(iodometh-
1
yl)butoxy]diphenylsilane (1.11 g, 70%) as a colorless oil. H NMR
(300 MHz, CDCl3): δ = 7.71–7.63 (m, 4 H, Har), 7.46–7.34 (m, 6
CDCl3): δ = 7.37–7.22 (m, 5 H, Har), 4.75–4.67 (m, 1 H, CHBn), H, Har), 3.63 (dd, J = 3.9, J = 10.2 Hz, 1 H, CH2OTBDPS), 3.53–
4.25–4.16 (m, 2 H, CH2), 3.92–3.84 (m, 3 H, CHCO and CH2), 3.47 (m, 2 H, CH2OTBDPS and CH2I), 3.39 (dd, J = 4.8, J =
2308
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 2303–2315

Towards the Synthesis of Restricted Analogues of Peloruside A
9.6 Hz, 1 H, CH2I), 1.42–1.25 (m, 3 H, CH and CH2CH3), 1.06 (s, temperature for 30 min. The mixture became dark red and the ini-
9 H, tBu), 0.84 (t, J = 7.5 Hz, 2 H, CH2CH3) ppm. 13C NMR tial phosphonium salt dissolved completely. A solution of aldehyde
(75 MHz, CDCl3): δ = 135.8 (Car), 133.8 (Car), 129.8 (Car), 127.8
(Car), 65.6 (CH2OTBDPS), 43.9 (CH), 27.0 (tBu), 24.1 (CH2CH3),
(–)-11 (2.15 g, 9.75 mmol, 1 equiv.) in dry THF (5 mL) was added
dropwise to the reaction mixture at –80 °C. This mixture was then
19.5 (C(IV)), 12.3 (CH2I), 11.3 (CH2CH3) ppm. MS (CI): m/z = 470 stirred at the same temperature for 1 h, before being slowly warmed
[M + NH4]+, 453 [M + H]+. HRMS: calcd. for C21H30IOSi [M +
H]+ 453.1111; found 453.1107.
to room temperature, and further stirred at this temperature for
16 h. Reaction was quenched with saturated aqueous NH4Cl
(10 mL), and the resulting aqueous phase was extracted with
CH2Cl2 (3 ϫ 20 mL). The combined organic layers were then
washed with brine, dried with anhydrous MgSO4, filtered and con-
centrated under reduced pressure. The residue was subjected to col-
umn chromatography on silica gel (PE/Et2O, 98:2 to 90:10) to give
a mixture of compounds 15 and 16 (3.25 g, 63%) as a colorless oil.
A solution of this iodo compound (4.03 g, 8.91 mmol, 1 equiv.) and
PPh3 (2.80 g, 10.69 mmol, 1.2 equiv.) in anhydrous toluene (35 mL)
was heated to reflux for 96 h. A solid appeared progressively in the
reaction mixture, which was subjected to vigorous stirring when
cooling to room temperature. After concentration under reduced
pressure, the sticky residue was triturated in anhydrous Et2O for
14 h. The liquid supernatant was then removed, and resulting hy-
groscopic beige solid (Ϯ)-13 was obtained (4.74 g, 71%) after dry-
For analysis see optically pure compound 15.
(2R,5S,Z)- (17) and (2S,5S,Z)-2-Ethyl-5-(4-methoxybenzyloxy)octa-
3,7-dien-1-ol (18): The protected mixture of 15 and 16 (2.93 g,
5.38 mmol, 1 equiv.) was dissolved in THF (90 mL). Then TBAF
(1 m in THF, 6.92 mL, 6.92 mmol, 1.29 equiv.) was added at 0 °C.
The mixture was stirred 48 h and then concentrated under reduced
pressure. The crude mixture was subjected to column chromatog-
raphy on silica gel (PE/Et2O, 99:1 to 30:70) to give expected pure
(2R,5S,Z)-2-ethyl-5-(4-methoxybenzyloxy)octa-3,7-dien-1-ol (17)
ing under vacuum with P2O5 for one week. IR (KBr): ν = 3071,
˜
3048, 2959, 2928, 2855, 1483, 1112 cm–1 1H NMR (300 MHz,
.
CDCl3): δ = 7.71–7.63 (m, 4 H, Har), 7.46–7.34 (m, 6 H, Har), 3.63
(dd, J = 3.9, J = 10.2 Hz, 1 H, CH2O), 3.53–3.47 (m, 2 H, CH2O
and CH2P), 3.39 (dd, J = 4.8, J = 9.6 Hz, 1 H, CH2P), 1.42–1.25
(m, 3 H, CH and CH2CH3), 1.06 (s, 9 H, tBu), 0.84 (t, J = 7.5 Hz,
3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 135.0 (Car), 134.9
(Car), 134.8 (Car), 134.4 (Car), 133.2 (Car), 133.0 (Car), 132.9 (Car),
132.5 (C(IV)ar), 132.2 (C(IV)ar), 131.5 (Car), 130.2 (Car), 130.1 (Car),
129.5 (Car), 128.1 (Car), 128.0 (Car), 127.4 (Car), 127.0 (Car), 118.3
(C(IV)ar), 117.2 (C(IV)ar), 64.6 and 64.5 (CH2O), 37.4 (CH), 26.5
(tBu), 24.2 + 23.9 + 23.2 (CH2), 18.8 (C(IV) tBu), 10.6 (CH3) ppm.
31P{1H} NMR (121 MHz, CDCl3): δ = 23.1 ppm. MS (CI): m/z =
587 [M – I]+; 263 [Ph3PH]+.
(0.70 g, 45%). [α]2D0 = –1.5 (c = 1.0, CHCl ). IR (KBr): ν = 3438,
˜
3
2959, 2931, 2872, 1612, 1514, 1248, 1037 cm–1
.
1H NMR
(300 MHz, CDCl3): δ = 7.28–7.25 (m, 2 H, Har), 6.88–6.85 (m, 2
H, Har), 5.84 (ddt, J = 6.8, J = 10.0, J = 17.1 Hz, 1 H, CHCH2),
5.60 (dd, J = 2.0, J = 9.1 Hz, 1 H, CHCH), 5.34 (t, J = 11.1 Hz, 1
H, CHCH), 5.07 (m, 2 H, CHCH2), 4.51 and 4.37 (AB system, J
= 11.3 Hz, 2 H, CH2Ar), 4.19 (m, 1 H, CH), 3.58 (dd, J = 5.3, J
= 10.6 Hz, 1 H, CH2OH), 3.39 (dd, J = 8.1, J = 10.6 Hz, 1 H,
CH2OH), 2.50–2.38 (m, 2 H, CH and CH2), 2.35–2.24 (m, 1 H,
CH2), 1.51–1.39 (m, 1 H, CH2CH3), 1.28–1.12 (m, 1 H, CH2CH3),
0.85 (t, J = 7.4 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3):
δ = 159.4 (C(IV)ar), 135.1 (CH), 134.8 (CH), 133.9 (CH), 131.0 (C(IV)
ar), 129.6 (Car), 117.4 (CH2), 114.1 (Car), 74.4 (CH–O), 70.0
(CH2Ar), 66.4 (CH2OH), 55.6 (OCH3), 43.0 (CH), 40.1 (CH2), 24.7
(CH2), 12.1 (CH3) ppm. HRMS: calcd. for C18H26O3Na [M + Na+]
313.1774; found 313.1778.
(S)-{2-[(tert-Butyldiphenylsilyloxy)methyl]butyl}triphenyl-
phosphonium Iodide [(–)-13]: Triphenylphosphane (10.22 g,
39.0 mmol, 1.5 equiv.), then N-iodosuccinimide (8.77 g, 39.0 mmol,
1.5 equiv.) were cautiously added at 0 °C under argon to a solution
of alcohol (+)-12 (8.9 g, 26.0 mmol, 1 equiv.) in anhydrous CH2Cl2
(105 mL). The reaction mixture was stirred at room temperature
for 16 h. After dilution with CH2Cl2, the organic phase was washed
with 10% aqueous Na2S2O3 solution (2ϫ) and brine, then dried
with anhydrous MgSO4, filtered and concentrated under reduced
pressure. The resulting beige solid was subjected to column
chromatography on silica gel (PE/Et2O, 98:2 to 8:2) to give (+)-
tert-butyl[2-(iodomethyl)butoxy]diphenylsilane (10.7 g, 92%) as a
colorless oil. [α]2D0 = +3.7 (c = 0.57, CHCl3). MS (CI): m/z = 453
[M + H]+; 470 [M + NH4]+.
(2S,5S,Z)-2-Ethyl-5-(4-methoxybenzyloxy)octa-3,7-dien-1-ol, Dia-
stereomer 18: Compound 18 was obtained pure in 47 % yield
(0.73 g). [α]2D0 = –15.2 (c = 1.0, CHCl ). IR (KBr): ν = 3438, 2959,
˜
3
2931, 2872, 1613, 1514, 1248, 1037 cm–1 1H NMR (300 MHz,
.
CDCl3): δ = 7.16–7.13 (m, 2 H, Har), 6.78–6.75 (m, 2 H, Har), 5.74
(ddt, J = 6.9, J = 10.0, J = 17.2 Hz, 1 H, CHCH2), 5.47 (dd, J =
1.3, J = 11.0 Hz, 1 H, CHCH), 5.26 (t, J = 11.0 Hz, 1 H, CHCH),
5.02–4.95 (m, 2 H, CHCH2), 4.43 and 4.19 (AB system, J =
11.4 Hz, 2 H, CH2Ar), 4.13–4.06 (m, 1 H, CH–O), 3.70 (s, 3 H,
OCH3), 3.43 (dd, J = 5.4, J = 10.6 Hz, 1 H, CH2OH), 3.25 (dd, J
= 8.1, J = 10.6 Hz, 1 H, CH2OH), 2.45–2.30 (m, 2 H, CH and
CH2), 2.25–2.10 (m, 1 H, CH2), 1.45–1.32 (m, 1 H, CH2CH3), 1.22–
1.09 (m, 1 H, CH2CH3), 0.83 (t, J = 7.5 Hz, 3 H, CH3) ppm. 13C
This iodo compound (10.7 g, 23.7 mmol, 1 equiv.) and PPh3
(7.44 g, 28.4 mmol, 1.2 equiv.) in anhydrous toluene (85 mL) were
heated to reflux for 96 h. A solid appeared progressively in the reac-
tion mixture, which was subjected to vigorous stirring when cooling
to room temperature. After concentration under reduced pressure,
the sticky residue was triturated in anhydrous Et2O for 16 h. The
liquid supernatant was then removed, and the resulting hygroscopic
yellowish solid (–)-13 was obtained (11.8 g, 85%) after drying un-
der vacuum with P2O5 for several hours, m.p. 53–55 °C (not NMR (75 MHz, CDCl3): δ = 159.4 (C(IV)ar), 135.1 (CH), 134.1
recryst.). [α]2D0 = –3.4 (c = 0.86, CHCl3). 31P{1H} NMR (121 MHz,
CDCl3): δ = 23.1 ppm. HRMS: calcd. for C39H44OPSi [M – I]+
587.2899; found 587.2899.
(CH), 129.4 (Car), 114.7 (CH2), 114.1 (Car), 74.3 (CH), 70.0
(CH2Ar), 66.3 (CH2OH), 55.6 (OCH3), 43.0 (CH), 40.8 (CH2), 24.9
(CH2), 12.1 (CH3) ppm. MS (CI): m/z = 308 [M + NH4+]; 273 [M –
H2O + H+]; 138 [C8H10O2+].
tert-Butyl [(2R,5S,Z)-2-Ethyl-5-(4-methoxybenzyloxy)octa-3,7-dien-
yloxy]diphenylsilane (15) and tert-Butyl [(2S,5S,Z)-2-Ethyl-5-(4-
methoxybenzyloxy)octa-3,7-dienyloxy]diphenylsilane (16): Phos-
phonium salt (Ϯ)-13 (8.0 g, 11.19 mmol, 1.15 equiv.) was intro-
duced in dry THF (30 mL) under argon. A commercial KHMDS
solution (0.5 m in THF, 19.5 mL, 9.75 mmol, 1 equiv.) was added
dropwise to this slurry at 0 °C, which was then stirred at room
[(2R,5S,Z)-2-Ethyl-5-(4-methoxybenzyloxy)octa-3,7-dienyloxy]-
(tert-butyl)diphenylsilane (15): Imidazole (0.35 g, 5.14 mmol,
2 equiv.) and TBDPSCl (1.07 g, 3.89 mmol, 1.5 equiv.) were suc-
cessively added to a solution of alcohol 17 (0.76 mg, 2.62 mmol,
1 equiv.) in DMF (12 mL). The reaction mixture was stirred at
room temperature for 48 h, before being quenched with saturated
Eur. J. Org. Chem. 2013, 2303–2315
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2309

J. Lebreton, M. Mathé-Allainmat et al.
FULL PAPER
aqueous NH4Cl (10 mL). The aqueous phase was extracted with
Et2O (3ϫ 8 mL), and the combined organic layers were washed
with water and brine, dried with anhydrous MgSO4, filtered and
concentrated under reduced pressure. The resulting residue was
subjected to column chromatography on silica gel (PE/Et2O, 99:1
to 90:10) to give compound 15 (1.26 g, 91%) as a colorless oil.
J = 15.3 Hz, 1 H, CH2COCH3), 2.15 (s, 3 H, CH2COCH3), 1.76–
1.61 (m, 1 H, CH2CH3), 1.34–1.16 (m, 1 H, CH2COCH3), 1.05 (s,
9 H, tBu), 0.82 (t, J = 7.5 Hz, 3 H, CH2CH3) ppm. 13C NMR
(75 MHz, CDCl3): δ = 206.4 (CO), 159.3 (C(IV)ar), 135.8 (Car),
135.6 (CHCH), 134.0 (C(IV)ar), 130.9 (Car), 129.8 (C(IV)ar), 129.7
(CHCH), 129.3 (Car), 127.8 (Car), 113.9 (Car), 71.7 (CHOPMB),
70.3 (CH2Ar), 67.3 (CH2OSi), 55.4 (OCH3), 49.9 (CH2COCH3),
1
[α]2D0 = –50.2 (c = 0.56, CHCl3). H NMR (300 MHz, CDCl3): δ =
7.69–7.63 (m, 4 H, Har), 7.42–7.31 (m, 6 H, Har), 7.14–7.08 (m, 2 42.3 (CHCH2OSi), 31.3 (CH2COCH3), 27.1 (tBu), 24.72
H, Har), 6.82–6.76 (m, 2 H, Har), 5.84 (ddt, J = 6.9, J = 10.2, J =
(CH2CH3), 19.5 (C(IV)), 11.7 (CH2CH3) ppm. MS (CI): m/z = 562
17.1 Hz, 1 H, CHCH2), 5.45 (dd, J = 8.7, J = 11.1 Hz, 1 H, [M + NH4]+. HRMS (ESI): calcd. for C34H44O4SiNa [M + Na]+
CHCH), 5.40 (dd, J = 7.8, J = 11.1 Hz, 1 H, CHCH), 5.11–4.99 567.2907; found 567.2910.
(m, 2 H, CHCH2), 4.50 and 4.21 (AB system, J = 11.4 Hz, 2 H
CH2Ar), 4.09–4.00 (m, 1 H, CH–O), 3.77 (s, 3 H, OCH3), 3.57 (dd,
J = 5.4, J = 9.9 Hz, 2 H, CH2–OSi), 2.50–2.32 (m, 2 H, CH and
CH2), 2.29–2.18 (m, 1 H, CH2), 1.79–1.63 (m, 1 H, CH2CH3), 1.34–
1.18 (m, 1 H, CH2CH3), 1.05 (s, 9 H, tBu), 0.83 (t, J = 7.5 Hz, 3
H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 159.1 (C(IV)ar),
135.8, 135.1 and 135.0 (2ϫ CH), 133.9 (C(IV)ar), 131.9 (CH), 131.1
(C(IV)ar), 129.8, 129.2, 127.8, 116.8 (CH2), 113.8, 74.5 (CH), 69.7
(CH2), 67.2 (CH2), 55.4 (OCH3), 42.1 (CH), 40.6 (CH2), 27.0 (C(IV)
tBu), 24.7 (CH2), 19.5 (tBu), 11.9 (CH3) ppm. MS (CI): m/z = 546
[M + NH4]+. HRMS: calcd. for C34H45O3Si [M + H]+ 529.3138;
found 529.3138.
(؎)-tert-Butyldimethyl[4-(oxiran-2-yl)butoxy]silane [(؎)-19]: Com-
mercial 5-hexen-1-ol (3.70 g, 37 mmol, 1 equiv.) was dissolved in
DMF (38 mL) and tert-butyldimethylsilyl (TBSCl; 6.15 g,
40.7 mmol, 1.1 equiv.) with imidazole (2.77 g, 40.7 mmol,
1.1 equiv.) were added to the mixture. After 5 h stirring at room
temperature the reaction was quenched with water (40 mL), and
the aqueous phase was extracted with Et2O (6ϫ 20 mL). The com-
bined organic layers were washed with brine (30 mL), dried with
MgSO4, filtered and concentrated under reduced pressure. tert-
Butyl(hex-5-enyloxy)dimethylsilane was obtained without further
purification as a colorless oil. 1H NMR (300 MHz, CDCl3): δ =
5.85–5.75 (m, 1 H, CH2CHCH2), 4.98–4.92 (m, 2 H, CH2CHCH2),
3.61 (t, J = 6.0 Hz, 2 H, CH2OTBS), 2.05 (q, J = 6.0 Hz, 2 H,
CH2CH2OTBS), 1.55–1.47 (m, 4 H, CH2CH2), 0.89 (s, 9 H, tBu),
0.05 (s, 6 H, 2ϫ CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 136.9
(CH2CHCH2), 112.3 (CH2CHCH2), 61.1 (CH2OTBS), 31.5
(CH2CH2), 30.3 (CHCH2CH2), 23.9 (tBu), 20.3 (CH2CH2OTBS),
16.3 (C(IV) tBu), –5.3 (2ϫ CH3) ppm.
(4S,7R,Z)-7-[(tert-Butyldiphenylsilyloxy)methyl]-4-(4-methoxy-
benzyloxy)non-5-en-2-one (6): CuCl (0.25 g, 2.49 mmol, 1.1 equiv.)
and PdCl2 (0.08 g, 0.46 mmol, 0.2 equiv.) were added to a solution
of compound 15 (1.18 g, 2.23 mmol, 1 equiv.) in a DMF/H2O sol-
vent mixture (7:1, 32 mL). Because of substrate solubility problems
in this solvent mixture, Et2O (1.0 mL) was regularly added to the
reaction mixture when stirring. The black slurry was vigorously
stirred at room temperature and in contact with oxygen (bubbling)
for 5 days. It was then diluted with 1 n aqueous HCl (50 mL), and
the resulting aqueous phase was extracted with Et2O (5ϫ 20 mL).
The combined organic layers were washed with brine, dried with
anhydrous MgSO4, filtered and concentrated under reduced pres-
sure. 1H NMR spectroscopic data of the resulting residue indicated
formation of the expected ketone along with 8% of the correspond-
ing aldehyde. TLC analysis of this green oil showed no separation
between both formed carbonylated compounds. As a result, the
crude product (1.22 g, quantitative yield) was directly subjected to
an aldehyde-oxidation-based purification step.
To a solution of tert-butyl(hex-5-enyloxy)dimethylsilane (8.00 g,
37 mmol, 1 equiv.) in CH2Cl2 (150 mL) meta-chloroperoxybenzoic
acid (mCPBA) in water (70%, 11.05 g, 44.4 mmol, 1.2 equiv.) was
added. The mixture was stirred for 14 h at room temperature. Satu-
rated aqueous solution of Na2S2O3 (30 mL) followed by aqueous
solution of NaOH 10% were added to the mixture (20 mL). The
aqueous phase was extracted with CH2Cl2 (3ϫ 100 mL). The com-
bined organic layers were then washed with brine (50 mL), dried
with MgSO4, filtered and concentrated under reduced pressure. The
crude mixture was subjected to column chromatography on silica
gel (PE/Et2O, 99:1 to 90:10) to give racemic epoxide (Ϯ)-19 (6.09 g,
72%) as a colorless oil. For analytical description see optically pure
(–)-19.
The crude mixture (8 mol-% aldehyde) was dissolved in tBuOH
(3.8 mL) and 2-methyl-2-butene (0.9 mL). An aqueous solution
(1.5 mL) of NaClO2 (147 mg, 1.62 mmol) and NaH2PO4·H2O
(174 mg, 1.30 mmol) was then added dropwise to the reaction mix-
ture, which was stirred at room temperature for 16 h. The volatile
solvents (tBuOH and isoamylene) were then removed under re-
duced pressure, and saturated aqueous NaHCO3 solution (10 mL)
was added to the oily residue. The resulting aqueous phase was
extracted with CH2Cl2 (3ϫ 15 mL), and the combined organic lay-
ers were washed with brine, dried with anhydrous MgSO4, filtered
and concentrated under reduced pressure. The residue was sub-
jected to column chromatography on silica gel (PE/Et2O, 95:5 to
7:3) to give methyl-ketone 6 (990 mg, 82% over two steps) as a
(R)-tert-Butyldimethyl[4-(oxiran-2-yl)butoxy]silane [(–)-19]: Ja-
cobsen (R,R)-CoII-Salen (0.12 g, 0.19 mmol) was placed in toluene
(4 mL) and acetic acid (125 μL) was added. The mixture was stirred
for 30 min under an air atmosphere. Toluene was eliminated by
evaporation under reduced pressure and racemic epoxide (Ϯ)-19
(23.45 g, 101 mmol) was added to the complex. Water (930 μL,
52 mmol, 0.51 equiv.) was added and the reaction was stirred 16 h
at room temperature. The crude mixture was subjected to column
chromatography on silica gel (PE/Et2O, 99:1 to 90:10) to give enan-
tiomerically pure epoxide (–)-19 (10.5 g, 45%) as a clear yellow
liquid (lit. reported compound[20b]). [α]2D0 = –1.5 (c = 1.0, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 3.61 (t, J = 6.0 Hz, 2 H,
CH2OTBS), 2.95–2.87 (m, 1 H, CHCH2CH2), 2.74 (t, J = 3.0 Hz,
1 H, OCH2CH), 2.46 (t, J = 3.0 Hz, 1 H, OCH2CH), 1.60–1.40 (m,
6 H, CH2CH2CH2), 0.89 (s, 9 H, tBu), 0.05 (s, 6 H, 2ϫ CH3) ppm.
13C NMR (75 MHz, CDCl3 ): δ = 60.9 (CH2 OTBS), 50.3
(CHCH2CH2), 45.0 (OCH2CH), 30.5 (CH2CH2OTBS), 30.2
(CH2CH2CH), 23.9 (tBu), 20.3 (CH2CH2CH), 16.3 (C(IV) tBu),
–5.3 (2ϫ CH3) ppm. MS (CI): m/z = 231 [M + H]+.
colorless oil. [α]2D0 = –26.7 (c = 1.2, CHCl ). IR (KBr): ν = 3070,
˜
3
2999, 2958, 2857, 1718, 1514, 1248, 1272 cm–1
.
1H NMR
(300 MHz, CDCl3): δ = 7.69–7.63 (m, 4 H, Har), 7.42–7.31 (m, 6
H, Har), 7.10–7.04 (m, 2 H, Har), 6.81–6.75 (, 2 H, Har), 5.47 (dd,
J = 9.3, J = 11.1 Hz, 1 H, CHCH), 5.40 (dd, J = 8.7, J = 11.1 Hz,
1 H, CHCH), 4.56 (m, 1 H, CHOPMB), 4.48 and 4.19 (AB system,
J = 11.1 Hz, 2 H, CH2Ar), 3.77 (s, 3 H, OCH3), 3.59 (dd, J = 5.7,
J = 10.2 Hz, 2 H, CH2OSi), 2.78 (dd, J = 9.0, J = 15.3 Hz, 1 H,
(R)-Oct-7-ene-1,5-diol [(+)-20]: To a solution of CuI (0.48 g,
CH2COCH3), 2.61–2.48 (m, 1 H, CHCH2OSi), 2.39 (dd, J = 3.9, 2.50 mmol, 0.22 equiv.) in dry Et2O (70 mL) under argon at –30 °C,
2310 Eur. J. Org. Chem. 2013, 2303–2315
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Towards the Synthesis of Restricted Analogues of Peloruside A
commercially available vinylmagnesium bromide (25.1 mL,
25.1 mmol, 2.2 equiv., 1 m in THF) was added dropwise and the
mixture stirred for 1 h at the same temperature. The solution of
epoxide (–)-19 (2.63 g, 11.44 mmol) in Et2O (40 mL) was added
slowly to the mixture through a cannula. After 3 h at –30 °C the
reaction was carefully quenched with saturated aqueous solution
of ammonium chloride. The aqueous layer was extracted with
CH2Cl2, and the combined organic layers were dried with MgSO4,
filtered and solvent was eliminated under reduced pressure. The
mixture was subjected to column chromatography on silica gel (PE/
Methyl (–)-2-[(2S,6R)-6-Allyl-tetrahydro-2H-pyran-2-yl]-2-methyl-
propanoate [(–)-22]: To a solution of diisopropylamine (2.86 mL,
20.3 mmol, 2.9 equiv.) in THF (25 mL) at 0 °C was added slowly
n-butyllithium (2.5 n in hexane, 20.3 mmol, 2.9 equiv.). After
15 min the solution was cooled to –78 °C and methylisobutyrate
(2.3 mL, 20.3 mmol, 2.9 equiv.) was added dropwise. The mixture
was then stirred for 40 min at –78 °C, warmed up to 0 °C and a
solution of (–)-21 (1.0 g, 7 mmol) in THF (10 mL) was added with
a cannula. After 1 h at the same temperature the solution was
quenched with the addition of an aqueous solution of HCl (1 n,
Et2O, 99:1 to 90:10) to give (R)-8-(tert-butyldimethylsilyloxy)oct-1- 30 mL). The aqueous layers were extracted with Et2O (3ϫ 100 mL)
en-4-ol (2.25 g, 76%) as a colorless oil. (lit. enantiomer reported
and the combined organic layers were washed with brine, dried
with MgSO4, filtered, and concentrated under reduced pressure.
The crude mixture was quickly subjected to column chromatog-
raphy on silica gel (PE/Et2O, 80:20) to furnish a colorless oil. This
residue was then dissolved in CH2Cl2 (25 mL) and the solution was
compound[30]). [α]2D0 = +4.6 (c = 1.0, CHCl3) [lit. (–)-enantiomer:
[α]2D0 = –4.8 (c = 0.46, CHCl3)]. H NMR (300 MHz, CDCl3): δ =
1
5.90–5.76 (m, 1 H, CHCH2), 5.16–5.11 (m, 2 H, CHCH2), 3.66–
3.60 (m, 1 H, CHOH), 3.62 (t, J = 6.1 Hz, 2 H, CH2OTBS), 2.35–
2.26 (m, 1 H, CH2CHCH2), 2.19–2.09 (m, 1 H, CH2CHCH2), 1.62– cooled to –78 °C, before addition of triethylsilane (2.2 mL,
1.35 (m, 6 H, CH2CH2CH2), 0.90 (s, 9 H, tBu), 0.05 (s, 6 H, 14 mmol) followed by BF3·Et2O (1.0 g, 7 mmol). The mixture was
2CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 135.0 (CH2CH), then stirred 4 h at –78 °C, warmed up to 0 °C and quenched with
118.2 (CH2 CH), 70.8 (CHOH), 62.3 (CH2 OTBS), 42.1
a saturated aqueous ammonium chloride solution (50 mL). The
(CH2CHCH2), 36.7 (CH2CH2CHOH), 32.9 (CH2CH2OTBDPS), aqueous layer was extracted with CH2Cl2 (3ϫ 100 mL) and the
22.1 (CH2), 18.5 (C(IV) tBu), –5.1 (2CH3) ppm. MS (CI): m/z = 259
combined organic layers were dried with MgSO4, filtered and con-
centrated under reduced pressure. The crude mixture was subjected
to column chromatography on silica gel (PE/Et2O, 90:10) to afford
tetrahydropyran (–)-22 (1.36 g, 86% over two steps) as a colorless
[M + H]+.
This monoprotected diol (300 mg, 1.16 mmol, 1 equiv.) was dis-
solved in THF (6 mL), then TBAF (1 m in THF, 2.20 mL,
2.20 mmol, 1.9 equiv.) was added at 0 °C. The mixture was stirred
16 h at room temperature and the reaction was quenched with
water (5 mL). The aqueous phase was extracted with CH2Cl2 (3ϫ
15 mL), and the combined organic layers were dried with MgSO4,
filtered and concentrated under reduced pressure. The crude mix-
ture was subjected to column chromatography on silica gel
(CH2Cl2/MeOH, 99:1 to 90:10) to give 1,5-diol (+)-20 (139 mg,
oil. [α]2D0 = –12.7 (c = 1.0, CHCl3). H NMR (300 MHz, CDCl3):
1
δ = 5.87–5.73 (m, 1 H, CH2CH), 5.04–4.95 (m, 2 H, CH2CH), 3.65
(s, 3 H, OMe), 3.49 [d, J = 1.1, J = 11.3 Hz, 1 H, OCHC(Me)2],
3.35–3.27 (m, 1 H, OCHCH2), 2.25–2.05 (m, 2 H, CH2CHCH2),
1.87–1.80 (m, 1 H, CH2), 1.55–1.11 (m, 5 H, CH2CH2CH2), 1.17 (s,
3 H, CH3), 1.10 (s, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ
= 177.7 (CO), 135.6 (CH2CH), 116.0 (CH2CH), 82.3 [OCHC-
(Me)2], 77.8 (OCHCH2), 51.8 (OCH3), 46.9 [C(Me)2], 40.9
(CH2CHCH2), 31.3 (CH2CH–O), 25.3 (CH2), 23.8 [CH2CH(O)-
CH2CH], 21.1 (CH3), 20.6 (CH3) ppm. MS (CI): m/z = 227 [M +
H]+. HRMS: calcd. for C13H22O3Na [M + Na+] 249.1461; found
249.1471.
87%) as a colorless oil. [α]2D0 = +7.4 (c = 0.5, CHCl ). IR (KBr): ν
˜
3
= 3346, 3075, 2934, 2863, 1825, 1255, 913, 736 cm–1. 1H NMR
(300 MHz, CDCl3): δ = 5.90–5.81 (m, 1 H, CHCH2), 5.17–5.12 (m,
2 H, CHCH2), 6.69–6.64 (m, 1 H, CHOH), 3.67 (t, J = 6.1 Hz, 2
H, CH2OH), 2.35–2.29 (m, 1 H, CH2CHCH2), 2.20–2.10 (m, 1 H,
CH2CHCH2), 1.60–1.30 (m, 6 H, CH2CH2CH2) ppm. 13C NMR (–)-2-[(2S,6R)-6-Allyl-tetrahydro-2H-pyran-2-yl]-2-methylpropanal
(75 MHz, C6D6): δ = 134.7 (CH2CH), 118.2 (CH2CH), 70.5 (7): To a solution of ester (–)-22 (480 mg, 2.12 mmol, 1 equiv.) in
( C H O H ) , 6 2 . 8 ( C H 2 O H ) , 4 2 . 0 ( C H 2 C H C H 2 ) , 3 6 . 4 THF (20 mL) was added LiAlH4 (85 mg, 2.25 mmol) at –5 °C. The
(CH2CH2CHOH), 32.6 (CH2CH2OH), 22.2 (CH2) ppm. MS (CI): mixture was then stirred 4 h at room temperature. The solution was
m/z = 145 [M + H]+.
quenched with water (2.2 mL) followed by an aqueous solution of
NaOH (1 n, 2.2 mL) and a second addition of water (2.2 mL). The
mixture was stirred vigorously for 30 min and then filtered. The
liquid phase was then evaporated under reduced pressure to furnish
(R)-6-Allyl-tetrahydropyran-2-one [(–)-21]: To a solution of diol (+)-
20 (1.16 g, 8.04 mmol, 1 equiv.) in CH2Cl2 (40 mL), a buffer solu-
tion (NaHCO3 (0.5 m)/K2CO3 (0.05 m), 40 mL), Ac-TEMPO
(0.17 g, 0.82 mmol, 0.1 equiv.) and tetra-n-butylammonium brom-
ide (TBABr; 0.26 g, 0.80 mmol, 0.1 equiv.) were added and this
mixture was vigorously stirred at room temperature. Then N-chlo-
rosuccinimide (NCS; 3.22 g, 24.1 mmol, 3 equiv.) was added, and
the reaction was stirred for 16 h at the same temperature. The layers
were separated and the aqueous phase was extracted with CH2Cl2
(3ϫ 40 mL), dried with MgSO4, filtered and concentrated under
reduced pressure. The crude mixture was subjected to column
chromatography on silica gel (PE/Et2O, 99:1 to 40:60) to give vola-
tile lactone (–)-21 (1.35 g, with 20% of Et2O) as a yellow liquid.
[α]2D0 = –4.1 (c = 1.0, CHCl3), lit.[31] [α]2D0 = –8.1 (c = 1.0, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 5.90–5.75 (m, 1 H, CH2CH),
5.19–5.11 (m, 2 H, CH2CH), 4.39–4.29 (m, 1 H, CHOCO), 2.60–
2.25 (m, 4 H, 2CH2) 2.0–1.6 (m, 4 H, CH2CH2CHOCO) ppm. 13C
the corresponding alcohol (365 mg, 87%) as a colorless oil. [α]2D0
=
+17.3 (c = 1.0, CHCl ). IR (KBr): ν = 3445, 3075, 2993, 1642,
˜
3
2857, 1087, 1050, 913 cm–1. 1H NMR (400 MHz, CDCl3): δ = 5.87–
5.73 (m, 1 H, CH2CH), 5.10–5.04 (m, 2 H, CH2CH), 3.44 (s, 2 H,
CH2OH), 3.42–3.34 (m, 1 H, OCHCH2), 3.23 [dd, J = 1.9, J =
11.1 Hz, 1 H, OCHC(Me)2], 2.23–2.18 (m, 2 H, CH2CHCH2),
1.90–1.84 (m, 1 H, CH2), 1.60–1.19 (m, 5 H, CH2CH2CH2), 0.91
(s, 3 H, CH3), 0.85 (s, 3 H, CH3) ppm. 13C NMR (100 MHz,
CDCl3): δ = 135.0 (CH2CH), 117.3 (CH2CH), 87.3 [OCHC(Me)2],
77.9 (OCHCH2), 73.4 (CH2OH), 41.1 (CH2CHCH2), 38.0
[C(Me)2], 31.3 (CH2CHO), 25.6 (CH2), 23.7 [CH2CH(O)CH2CH],
22.9, (CH3) 19.2 (CH3) ppm. MS (CI): m/z = 198 [M + H]+.
To a solution of oxalyl chloride (60 mg, 0.48 mmol) in CH2Cl2
(2 mL) at –78 °C was added dropwise a solution of DMSO (70 mg,
NMR (75 MHz, CDCl3): δ = 170.8 (CO), 132.6 (CH2CH), 118.6 0.96 mmol) in CH2Cl2 (2 mL). The reaction was stirred 30 min at
(CH2CH), 79.8 (CHOCO), 40.0 (CH2CHCH2), 29.5 (CH2CO), the same temperature. A solution of the previous alcohol (80 mg,
27.2 (CH2), 18.4 (CH2CH2CHOCO) ppm. MS (CI): m/z = 158 [M 0.41 mmol) in CH2Cl2 (2 mL) was added slowly through a cannula
+ NH4]+.
and the mixture was stirred for 30 min. Then Et3N (0.32 mL,
Eur. J. Org. Chem. 2013, 2303–2315
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2311

J. Lebreton, M. Mathé-Allainmat et al.
FULL PAPER
2.3 mmol) was added slowly and the reaction was stirred for 1 h at
–78 °C, then warmed to 0 °C and stirred for 1 h. The reaction was
quenched with water (5 mL) and diluted with Et2O (5 mL). The
organic layer was separated and the aqueous layer was extracted
with Et2O (3ϫ 25 mL). The organic layers were combined, washed
with saturated NaCl aqueous solution (20 mL), dried with MgSO4,
filtered and concentrated under reduced pressure. The crude mix-
ture was subjected to column chromatography (PE/Et2O, 85:15) to
), 133.9 (2C(IV)), 130.8 (C(IV)), 129.8 (Car), 129.6 (Car), 127.9 (Car),
127.8 (Car), 117.4 (CH=CH2, anti isomer), 117.1 (CH=CH2, syn
isomer), 113.8 (Car), 85.8 {[OCHC(Me)2], syn isomer}, 85.6
{[OCHC(Me)2], anti isomer}, 78.3 (CH2CHCH2CH–O, anti iso-
mer), 77.9 (C6 pyran, syn isomer), 75.2 (CHOH, syn isomer), 74.7
(CHOH, anti isomer), 71.8 (CHOPMB, anti isomer), 71.7
(CHOPMB, syn isomer), 70.4 (CH2Ar, anti isomer), 70.3 (CH2Ar,
syn i so me r) , 6 7. 3 (CH2 OTB DP S) , 5 5. 4 ( OC H3 ), 50.3
(CH2CHOPMB, anti isomer), 49.6 (CH2CHOPMB, syn isomer),
47.2 (CH2CHOH, anti isomer), 46.7 (CH2CHOH, syn isomer), 42.2
(CHEt), 41.2 (CH2CHCH2, syn isomer), 41.1 (CH2CHCH2, anti
isomer), 40.5 [C(Me)2, syn isomer], 40.1 [C(Me)2, anti isomer], 31.3
furnish aldehyde 8 in quantitative yield as a yellow liquid. [α]2D0
=
–18.6 (c = 1.0, CHCl ). IR (KBr): ν = 3076, 2936, 2858, 2711, 1726,
˜
3
1643, 1269, 1196, 1090, 912 cm–1. H NMR (400 MHz, CDCl3): δ
1
= 9.59 (s, 1 H, CHO), 5.85–5.73 (m, 1 H, CH2CH), 5.05–4.98 (m,
2 H, CH2CH), 3.40 [dd, J = 1.6, J = 11.2 Hz, 1 H, OCHC(Me)2], (O–CHCH2CH2, anti isomer), 31.2 (O–CHCH2CH2, syn isomer),
3.35–3.27 (m, 1 H, OCHCH2), 2.25–2.09 (m, 2 H, CH2CHCH2), 27.1 (C tBu, two isomers), 25.3 (CH2CH3, syn isomer), 25.2
1.90–1.85 (m, 1 H, CH2), 1.65–1.15 (m, 5 H, CH2CH2CH2), 1.05
(s, 3 H, CH3), 1.02 (s, 3 H, CH3) ppm. 13C NMR (100 MHz,
CDCl3): δ = 206.10 (CHO), 135.5 (CH2CH), 116.6, (CH2CH) 82.0
[OCHC(Me)2], 78.1 (OCHCH2), 49.9 [C(Me)2], 41.1 (CH2CHCH2),
(CH2CH3, anti isomer), 24.7 (CH2CH2CH2), 23.9 (CH2CH2CH2,
syn isomer), 23.8 (CH2CH2CH2, anti isomer), 21.3 (CH3), 21.2
(CH3 ), 19.5 (C( I V ) tBu), 16.04 (CH3 , one isomer), 11.8
(CH2CH3) ppm. HRMS: calcd. for C46H64O6SiNa [M + Na+]
31.1 (CH2CH–O), 25.4 (CH2), 23.8, [CH2CH(O)CH2CH] 19.5 763.4364; found 763.4362. HPLC (C18, MeOH/H2O = 95:5 v/v):
(CH3), 17.1 (CH3) ppm. MS (CI): m/z = 214 [M + NH4]+; 197 [M
+ H]+. HRMS: calcd. for C12H20O2Na [M + Na+] 219.1356; found
219.1354.
tR = 21.76 (70%, anti isomer), 23.69 min (30%, syn isomer).
(3S,5S,7S,10R,Z)-2-[(2S,6R)-6-Allyl-tetrahydro-2H-pyran-2-yl]-10-
[(tert-butyldiphenylsilyloxy)methyl]-7-(4-methoxybenzyloxy)-2-
methyldodec-8-ene-3,5-diol (24): Acetic acid (3.5 mL) was added to
a solution of both aldol 24 and its diastereomer (dr 7:3; 150 mg,
0.20 mmol, 1 equiv.) in dry CH3CN (3.5 mL) under argon. The
mixture was stirred 2 min at –20 °C before fast addition of
Me4NHB(OAc)3 (220 mg, 0.84 mmol, 4.1 equiv.). The resulting
mixture was then stirred for 8 h under argon at the same tempera-
ture. The reaction was quenched with addition of saturated aque-
ous NaHCO3 solution (10 mL) and the aqueous phase was ex-
tracted with CH2Cl2 (3ϫ 20 mL). The combined organic layers
were washed with brine, dried with anhydrous MgSO4, filtered and
concentrated under reduced pressure. The crude mixture was then
subjected to column chromatography on silica gel (PE/Et2O, 98:2
to 50:50) to give pure anti-1,3-diol 24 (97 mg, 65%) as a colorless
(3S,7S,10R,Z)-2-[(2S,6R)-6-allyl-tetrahydro-2H-pyran-2-yl]-10-
[(tert-butyldiphenylsilyloxy)methyl]-3-hydroxy-7-(4-methoxybenz-
yloxy)-2-methyldodec-8-en-5-one (23): Methyl ketone 6 (300 mg,
0.55 mmol, 1 equiv.) was dissolved in anhydrous CH2Cl2/Et2O
(2.5 mL:1.5 mL), and aldehyde 7 (216 mg, 1.10 mmol, 2 equiv.) was
dissolved in anhydrous Et2O (1.5 mL), both under argon. Both sub-
strate solutions were stirred for 30 min in the presence of 1–3 CaH
pellets. The solution of 6 was transferred by cannula into a flame-
dried flask. A commercial (c-Hex)2BCl hexanes solution (1.0 m,
1.55 mL, 1.55 mmol, 3 equiv.) was added dropwise to the ketone
solution at 0 °C, followed by freshly distilled Et3N (210 μL,
1.54 mmol, 3 equiv.). The solution was then stirred for 1.5 h at 0 °C
before the addition of the solution of 7 by a cannula at –85 °C. The
mixture was then stirred 3.5 h at –78 °C and the reaction mixture
was poured onto NaHCO3 solution (5 %, 5 mL). The aqueous
phase was extracted with CH2Cl2 (3ϫ 15 mL) and the combined
organic layers were washed with brine, dried with anhydrous
MgSO4, filtered and concentrated under reduced pressure. The
crude mixture was then subjected to column chromatography on
silica gel (PE/Et2O, 99:1 to 90:10) to give a mixture of 1,5-anti-23
and 1,5-syn-23 with a dr of 7:3 in favor of anti-23 (160 mg, 83%)
as a colorless oil. 1H NMR (400 MHz, CDCl3): (two isomers): δ =
7.68–7.66 (m, 4 H, Har), 7.38–7.35 (m, 6 H, Har), 7.09 (d, J =
8.6 Hz, 2 H, Har), 6.78 (d, J = 8.6 Hz, 2 H, Har), 5.84–5.73 (m, 1
H, CH2CH), 5.50–5.39 (m, 2 H, CHCH), 5.08–5.00 (m, 2 H,
CH2CH), 4.66–4.59 (m, 1 H, CHOPMB), 4.31 (d, J = 10.9 Hz, 1
H, CH2OPMB), 4.10–4.01 (m, 2 H, CHOH and CH2OPMB), 3.88
(d, J = 5.1 Hz,1 H, OH), 3.78 (s, 3 H, OCH3), 3.60–3.57 (m, 2 H,
CH2OTBDPS), 3.39–3.27 (m, 1 H, CH2CHCH2CHO), 3.22 [dd, J
= 1.4, J = 11.4 Hz, 1 H, CH(Me)2], 2.91–2.83 [m, 1 H, O–
CHCH2C(O)], 2.60–2.41 [m, 4 H, O–CHCH2C(O) and CHCH2O
and C(O)CH2CH(OH)], 2.21–2.16 (m, 2 H, CH2CHCH2), 1.91–
1.84 (m, 1 H, CH2), 1.74–1.64 (m, 1 H, CH2CH3), 1.55–1.22 (m, 6
H, CH2CH3 and CH2CH2CH2), 1.06 (s, 9 H, tBu), 0.89 (s, 0.9 H,
CH3 syn isomer), 0.86 (s, 2.1 H, CH3 anti isomer), 0.85 (s, 2.1 H,
CH3 anti isomer), 0.84 (t, J = 7.5 Hz, 3 H, CH2CH3), 0.70 (s, 0.9
H, CH3 syn isomer) ppm. 13C NMR (100 MHz, CDCl3): δ = 209.6
(CO, syn isomer), 208.7 (CO, anti isomer), 159.2 (Car), 135.8 (Car),
135.6 (CH=CH, syn isomer), 135.5 (CH=CH, anti isomer), 135.1
oil. [α]2D0 = –58.5 (c = 1.0, CHCl3). H NMR (400 MHz, C6D6): δ
1
= 7.82–7.78 (m, 4 H, Har), 7.26–7.22 (m, 8 H, Har), 6.77–6.74 (m,
2 H, Har), 5.82–5.68 (m, 1 H, CH2CH), 5.55–5.37 (m, 2 H, CHCH),
5,08–4.98 (m, 2 H, CH2CH), 4.59–4.48 (m, 2 H, CHOPMB and
CHOH), 4.51 and 4.14 (AB system, J = 11.1 Hz, 2 H, CH2Ar),
4.16–4.12 (m, 2 H, CHOH), 3.92 (d, J = 5.5 Hz, 1 H, OH), 3.71–
3.60 (m, 2 H, CH2OTBDPS), 3.12–3.06 [m, 1 H, C(Me)2CH–O],
3.03–2.95 (m, 1 H, CH2CHCH2CH–O), 2.65–2.53 (m, 1 H, CHEt),
2.25–2.13 (m, 1 H, PMBO–CHCH2), 2.00–1.80 (m, 2 H,
CH2CHCH2), 1.85–1.80 (m, 1 H, PMBO–CHCH2), 1.70–1.65 [m,
2 H, CH(OH)CH2CH(OH)], 1.20–0.85 (m, 8 H, CH2CH2CH2 and
CH2CH3), 1.18 (s, 9 H, tBu), 0.93 (s, 3 H, CH3), 0.89 (s, 3 H, CH3),
0.89 (t, J = 7.3 Hz, 3 H, CH2CH3) ppm. 13C NMR (100 MHz,
C6D6): δ = 159.7 (C(IV)ar), 135.2 (CH2CH), 134.9 (CHCH), 134.1
(C(IV)ar), 132.6 (CHCH), 131.2 (C(IV)ar), 130.2 (Car), 130.1 (Car),
129.6 (Car), 128.2 (Car), 128.1 (Car), 117.2 (CH2CH), 114.2 (Car),
85.9 [C(Me)2CH–O], 78.1 (CH2CHCH2CH–O), 76.0 (CHOPMB),
74.9 (CHOH), 70.3 (CH2Ar), 68.8 [C(Me)2CHOH], 67.7 (CH2-
OSiTBDPS), 54.8 (OCH3), 44.2 (PMBOCHCH2), 42.3 (CHEt),
41.1 (CH2CHCH2), 40.2 [C(Me)2], 39.8 [CH(OH)CH2CH(OH)],
31.3 (CH2CH–O), 27.2 (C tBu), 25.2 (CH2CH2CH2), 25.0
(CH2CH3), 23.9 (CH2CH2CH2), 21.6 (CH3), 21.5 21.6 (CH3), 19.6
(C(IV) tBu), 11.9 (CH2CH3) ppm. MS (CI): m/z = 744 [M + H]+.
HRMS: calcd. for C29H38O4Na [M + Na]+ 765.4521; found
765.4514. HPLC (C18, MeOH/H2O = 95:5 v/v): tR = 19.76 (98.5%,
1,5-anti), 24.12 min (1.5%, minor product).
(CH=CH2, syn isomer), 131.0 (CH=CH, anti isomer), 130.9 [(2R,5S,Z)-[6-((4R,6R)-6-{[(2S,6R)-6-Allyl-tetrahydro-2H-pyran-2-
(CH=CH, syn isomer), 135.0 (CH=CH2, anti isomer), 134.0 (C(IV) yl]methyl}-2,2,5,5-tetramethyl-1,3-dioxan-4-yl)-2-ethyl-5-(4-meth-
2312
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 2303–2315

Towards the Synthesis of Restricted Analogues of Peloruside A
oxybenzyloxy)hex-3-enyloxy](tert-butyl)diphenylsilane (25): At
room temperature under argon, 2,2-dimethoxypropane (2,2-DMP;
166 mg, 1.59 mmol, 10 equiv.) followed by pyridinium p-toluene-
sulfonate (PPTS; 40 mg, 0.159 mmol, 1 equiv.) were added to diol
24 (118 mg, 0.159 mmol, 1 equiv.) dissolved in dry CH2Cl2. The
resulting mixture was then stirred for 14 h at the same temperature.
After this time the solvent was evaporated and the crude mixture
was subjected to column chromatography on silica gel (PE/Et2O,
98:2 to 80:20) to give pure diastereomer 25 (101 mg, 81%) as a
H, CH(OH)CH2 and CH2(CH–O–acetonide)2 and CH2CH3], 1.50–
1.00 [m, 8 H, CH2(CH–O–acetonide)2 and CH2 CH3 and
CH2CH2CH2], 1.40 (s, 3 H, CH3), 1.37 (s, 3 H, CH3), 1.21 (s, 9 H,
tBu), 0.87 (s, 3 H, CH3), 0.84 (s, 3 H, CH3), 0.80 (t, J = 7.5 Hz, 3
H, CH2CH3) ppm. 13C NMR (100 MHz, C6D6): δ = 136.2 (Car),
135.9 (CH2CH), 135.8 (CHCH), 134.0 (C(IV)ar), 133.6 (CHCH),
130.0 (Car), 116.6 (CH2CH), 100.7 (C(IV) acetonide), 80.0 [C(Me)2-
CH–O], 77.8 (CH2CHCH2CH–O), 68.6 (CHOH), 67.8 [C(Me)2-
CH–O–acetonide] 67.2 (CH2OTBDPS), 67.0 (CH–O–acetonide),
43.8 [CH(OH)CH2], 42.7 (CHEt), 41.7 (CH2CHCH2), 40.4 (C(IV)
1
colorless oil. [α]2D0 = –44.4 (c = 1.0, C HCl3). H NMR (400 MHz,
C6D6): δ = 7.82–7.79 (m, 4 H, Har), 7.30–7.28 (m, 2 H, Har), 7.26– acetonide), 34.1 [CH2(CH–O–acetonide)2], 31.5 (CH2CH2CH2),
7.21 (m, 6 H, Har), 6.83–6.81 (m, 2 H, Har), 5.97–5.87 (m, 1 H, 27.2 (tBu), 25.2 (CH3), 25.1 (CH2CH2CH2), 24.8 (CH2CH3), 24.4
CH2=CH), 5.59 (dd, J = 9.4, J = 11.0 Hz, 1 H, CHCH), 5.45 (t, J
= 11.0 Hz, 1 H, CHCH), 5.05–5.00 (m, 2 H, CH2=CH), 4.57 and
(CH3), 24.3 (CH2CH2CH2), 19.5 (C(IV) tBu), 17.8 (CH3), 17.1
(CH3), 12.0 (CH2CH3) ppm. HRMS: calcd. for C41H62O5SiNa [M
4.24 (AB system, J = 11.4 Hz, 2 H, CH2OPMB), 4.44–4.38 (m, 1 + Na+] 685.4259; found 685.4282.
H, CHOPMB), 4.32 [dd, J = 4.0, J = 6.2 Hz, 1 H, C(Me)2CH–O–
To a solution of the previous alcohol (67 mg, 0.1 mmol, 1 equiv.)
acetonide], 4.28–4.24 (m, 1 H, CH–O–acetonide), 3.74–3.65 (m, 2
H, CH2OTBDPS), 3.45 [dd, J = 1.5, J = 11.0 Hz, 1 H, C(Me)2CH–
O], 3.26–3.19 (m, 1 H, CH2CHCH2CH–O), 2.70–2.61 (m, 1 H,
CHEt) 2.35–2.28 [m, 2 H, CH2 (CH–O–acetonide)2 and
CH2CHCH2], 2.19–2.13 (m, 1 H, CH2CHCH2), 1.90–1.72 [m, 4 H,
CH2CH3 and CH2(CH–O–acetonide)2 and CH2CHOPMB], 1.51
(s, 3 H, CH3), 1.48 (s, 3 H, CH3), 1.40–1.10 (m, 7 H, CH2CH2CH2
and CH2CHOPMB), 0.94 (s, 3 H, CH3), 0.91 (s, 3 H, CH3), 0.86
(t, J = 7.5 Hz, 3 H, CH2CH3) ppm. 13C NMR (100 MHz, C6D6):
δ = 159.6 (C(IV)ar), 136.1 (Car), 135.8 (CH2CH), 134.6 (CHCH),
134.2 (C(IV)ar), 133.0 (CHCH), 131.8 (C(IV)ar), 130.1 (Car), 129.6
(Car), 128.7 (C(IV)ar), 128.3 (Car), 116.4 (CH2CH), 114.1 (Car), 100.5
(C(IV) acetonide), 80.3 [C(Me)2CH–O], 77.8 (CH2CHCH2CH–O),
71.5 (CHOPMB), 70.0 (CH2Ar), 68.6 [C(Me)2CH–O–acetonide],
67.6 (CH2OTBDPS), 64.7 (CH–O–acetonide), 54.8 (OCH3), 43.3
(CH2CHOPMB), 42.3 (CHEt), 41.7 (CH2CHCH2), 40.5 [C(Me)2],
33.8 [CH2(CH–O–acetonide)2], 31.6 (CH2CH2CH2), 27.2 (C(IV)
tBu), 25.4 (CH3), 25.3 (CH2CH2CH2), 25.0 (CH2CH3), 24.8 (CH3),
24.4 (CH2CH2CH2), 19.6 (C(IV) tBu), 18.0 (CH3), 17.3 (CH3), 12.0
(CH2CH3) ppm. MS (CI): m/z = 783 [M + H]+. HRMS: calcd. for
C49H70O6SiNa [M + Na+] 805.4834; found 805.4845.
and Hünig’s base (70 μL, 0.4 mmol, 4 equiv.) in CH2Cl2 (1 mL) at
0 °C under argon atmosphere was added acryloyl chloride (16 μL,
0.2 mol, 2 equiv.). The mixture was stirred for 4 h at room tempera-
ture and quenched with a saturated aqueous solution of ammo-
nium chloride (2 mL). The aqueous layer was extracted with
CH2Cl2 (3ϫ 10 mL) and the combined organic layers were washed
with brine, dried with anhydrous MgSO4, filtered and concentrated
under reduced pressure. The resulting residue was subjected to col-
umn chromatography on silica gel (PE/Et2O, 99:1 to 90:10) to af-
ford expected acrylate 26 (68 mg, 95%). [α]2D0 = –25.1 (c = 1.25,
1
CHCl3). H NMR (300 MHz, C6D6): δ = 7.84–7.79 (m, 4 H, Har),
7.30–7.22 (m, 6 H, Har), 6.28 (dd, J = 1.6, J = 17.2 Hz, 1 H,
CH2CHCO), 6.14–6.10 [m, 1 H, CHO(CO)], 6.00–5.85 (m, 2 H,
2ϫ CH2CH), 5.61 (dd, J = 1.6, J = 9.2 Hz, 1 H, CHCH), 5.45 (t,
J = 10.4 Hz, 1 H, CHCH), 5.24 (dd, J = 1.6, J = 10.4 Hz, 1 H,
CH2CHCO), 5.06–5.02 (m, 2 H, CH2CH), 4.26 [dd, J = 6.4, J =
10.4 Hz, 1 H, C(Me)2CH–O–acetonide], 4.05–3.98 (m, 1 H, CH–
O–acetonide), 3.76 (dd, J = 4.8, J = 9.8 Hz, 1 H, CH2OTBDPS),
3.69 (dd, J = 5.6, J = 9.8 Hz, 1 H, CH2OTBDPS), 3.42 [dd, J =
1.6, J = 11.2 Hz, 1 H, C(Me)2CH–O], 3.26–3.20 (m, 1 H,
CH2CHCH2CH–O), 2.95–2.86 (m, 1 H, CHEt), 2.35–2.28 (m, 1 H,
CH2CHCH2), 2.24–2.13 [m, 2 H, m, 1 H, CH2CHCH2 and
CH2(CH–O–acetonide)2], 1.90–1.66 [m, 4 H, CH2(CH–O–aceton-
ide)2 and CH2CHOCO and CH2CH3], 1.47 (s, 3 H, CH3), 1.43 (s,
3 H, CH3), 1.41–1.05 (m, 7 H, CH2CH2CH2 and CH2CH3), 1.19
(s, 9 H, tBu), 0.89 (s, 3 H, CH3), 0.88 (s, 3 H, CH3), 0.84 (t, J =
7.5 Hz, 3 H, CH2CH3) ppm. 13C NMR (75 MHz, C6D6): δ = 165.0
(CO), 136.3 (CHCH), 136.2 Car, 135.8 (CH2CH), 134.4 (Car), 129.9
(CH2CHCO), 129.8 Car, 129.6 (CHCH), 129.4 (CH2CHCO), 116.5
(CH2CHCH2), 100.6 (C(IV) acetonide), 80.2 [C(Me)2CH–O], 77.8
(CH2CHCH2CH–O), 68.5 [CHO(CO)], 68.3 [C(Me)2CH–O–acet-
onide], 67.2 (CH2OTBDPS), 64.8 (CH–O–acetonide), 42.5
[CH2(CH–O–acetonide)2], 42.2 (CHEt), 41.7 (CH2CHCH2), 40.4
(C(IV)), 34.0 [CH2(CH–O–acetonide)2], 31.6 (CH2CH2CH2), 27.2
(tBu), 25.3 (CH2CH3), 25.2 (CH2CH2CH2), 24.8 (CH3), 24.7
(CH3), 24.3 (CH2CH2CH2), 19.7 (C(IV)), 17.9 (CH3), 17.2 (CH3),
11.9 (CH2CH3) ppm. HRMS: calcd. for C44H64O6SiNa [M + Na+]
739.4370; found 739.4359.
(2S,5R,Z)-1-((4R,6S)-6-{2-[(2S,6R)-6-Allyl-tetrahydro-2H-pyran-
2-yl]propan-2-yl}-2,2-dimethyl-1,3-dioxan-4-yl)-5-[(tert-butyldi-
phenylsilyloxy)methyl]hept-3-en-2-ylacrylate (26): To a cold solu-
tion of acetonide 25 (205 mg, 0.262 mmol, 1 equiv.) in CH2Cl2
(2.4 mL) and phosphate buffer (pH = 7.0, 1.2 mL) was added DDQ
(71 mg, 0.313 mmol, 1.2 equiv.). The reaction mixture was stirred
for 2.5 h at 0 °C before a second addition of DDQ (30 mg,
0.132 mmol, 0.5 equiv.) and the mixture was stirred for a further
1 h. The reaction was diluted with CH2Cl2 (3 mL) quenched with
saturated aqueous NaHCO3 solution (3 mL), and diluted with
water. The layers were separated and the aqueous layer extracted
with CH2Cl2 (3ϫ 5 mL). The combined organic layers were dried
with anhydrous MgSO4, filtered and concentrated under reduced
pressure. The resulting residue was subjected to column chromatog-
raphy on silica gel (PE/Et2O, 99:1 to 70:30) to give the expected
C15 hydroxy compound (139 mg, 80%) as a colorless liquid. [α]2D0
1
= –25.0 (c = 1.0, CHCl3). H NMR (400 MHz, C6D6): δ = 7.89–
7.80 (m, 4 H, Har), 7.27–7.24 (m, 6 H, Har), 5.98–5.85 (m, 1 H, (1S,7S,9S,11R,13R,E)-7-{(R,Z)-3-[(tert-Butyldiphenylsilyloxy)meth-
CH2CH), 5.83–5.76 (m, 1 H, CHCH), 5.21 (t, J = 10.5 Hz, 1 H, yl]pent-1-enyl}-9,11-dimethyl-1,3-dioxan-12,12-dimethyl-6,17-di-
CHCH), 5.09–5.02 (m, 2 H, CH2CH), 4.80–4.74 (m, 1 H, CHOH), oxabicyclo[11.3.1]heptadec-3-en-5-one (27): Acrylate 26 (31 mg,
4.24 [dd, J = 6.4, J = 10.3 Hz, 1 H, C(Me)2CH–O–acetonide], 4.08–
3 . 9 9 (m , 1 H, CH– O – a ce t o ni d e) , 3 . 6 6 –3 . 5 4 ( m , 2 H ,
CH2OTBDPS), 3.42 [dd, J = 1.2, J = 10.8 Hz, 1 H, C(Me)2CH–
O], 3.25–3.18 (m, 2 H, OH and CH2CHCH2CH–O), 2.80–2.72 (m,
0.043 mmol, 1 equiv.) was dissolved in degassed CH2Cl2 (35 mL).
Grubbs II catalyst (10 mg) was quickly added and argon was
bubbled through the solution for 10 min before heating to reflux.
After 2 h, the temperature was lowered to room temperature and
1 H, CHEt), 2.36–2.24 (m, 1 H, CH2CHCH2), 2.20–2.11 (m, 1 H, air was bubbled through the solution to destroy excess catalyst. The
CH2CHCH2), 2.07–1.97 [m, 1 H, CH(OH)CH2], 1.78–1.61 [m, 3 solvent was evaporated and the resulting residue was subjected to
Eur. J. Org. Chem. 2013, 2303–2315
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2313

J. Lebreton, M. Mathé-Allainmat et al.
FULL PAPER
column chromatography on silica gel (pentane/Et2O, 99:1 to 90:10)
1 equiv.) was dissolved in THF (6 mL), then freshly opened TBAF
reagent (1 m in THF, 0.06 mL) was added and the reaction mixture
was stirred for 24 h. To drive the reaction to completion a second
to afford macrocycle 27 (25 mg, 83%) as a colorless oil. [α]2D0 = –8
1
(c = 0.55, CHCl3). H NMR (400 MHz, C6D6): δ = 7.84–7.80 (m,
4 H, Har), 7.32–7.25 (m, 6 H, Har), 7.19–7.12 (m, 1 H, CHCH), portion of TBAF (1 m in THF, 0.06 mL) was added and after 8 h
6.36–6.32 [m, 1 H, CHO(CO)], 5.86 (d, J = 15.9 Hz, 1 H, the solvent was evaporated under reduced pressure. The resulting
COCHCH), 5.73 (dd, J = 2.1, J = 8.9 Hz, 1 H, CHCH), 5.33 (dt, residue was subjected to column chromatography on silica gel
J = 1, J = 8.9 Hz, 1 H, CHCH), 4.24–4.18 (m, 1 H, CH–O–aceton- (Et2O then Et2O/MeOH, 9:1) to give triol 8 (7 mg, 92%) as color-
1
ide), 3.69 [m, dd, J = 5.3, J = 5.8 Hz, 1 H, C(Me)2CH–O–aceton-
less oil. [α]2D0 = –8 (c = 0.1, CHCl3). H NMR (500 MHz, C6D6): δ
ide], 3.64 (d, J = 5.7 Hz, 2 H, CH2OTBDPS), 2.79–2.66 (m, 3 H, = 7.2 [m, 1 H, (CO)CHCH], 6.09 [dtd, J = 0.97, J = 7.08, J =
CHEt and 2ϫ CH–O pyran), 2.34–2.27 [m, 1 H, CH2CHO(CO)],
2.22–2.15 [m, 1 H, CH2–(O–acetonide)2], 1.97–1.87 [m, 2 H,
8.18 Hz, 1 H, CHOC(O)], 5.8 (ddd, J = 0.69, J = 8.2, J = 11.29 Hz,
1 H, CHCH), 5.67 [d, J = 16.25 Hz, 2 H, C(O)CHCH], 5.21 (dd,
CH2CHO(CO) and CHCHCH2], 1.75–1.69 (m, 1 H, CHCHCH2), J = 1.08, J = 11.67 Hz, 1 H, CHCH), 4.52 [m, 1 H, CH(OH)], 3.62
1.60–1.51 [m 3 H, CH2–(O–acetonide)2 and CH2CH3], 1.38 (s, 3 H, (m, 1 H, CH2OH), 3.53 [t, J = 10.88 Hz, 1 H, 1 H, CH(OH)], 3.39
CH3), 1.36 (s, 3 H, CH3), 1.36–0.85 (m, 6 H, CH2CH2CH2), 1.07 (m, 1 H, CH2OH), 3.07 (d, J = 9.9 Hz, 1 H, OH), 2.95 (dd, J =
(s, 3 H, CH3), 0.87 (s, 3 H, CH3), 0.76 (t, J = 7.4 Hz, 3 H,
2.32, J = 10.36 Hz, 1 H, CH–O pyran), 2.85 (m, 1 H, CHEt), 2.78
CH2CH3) ppm. 13C NMR (100 MHz, C6D6): δ = 165.0 (CO), 147.4 (m, 1 H, OH), 2.60 (tt, J = 2.13, J = 11 Hz, 1 H, CH–O pyran),
(Car), 136.2 (Car), 135.1 [CHCHCO(CO)], 134.4 (C(IV)), 129.9 (Car), 2.12 [ddd, J = 4.19, J = 7.66, J = 14.72 Hz, 1 H, CH2CHOC(O)],
129.1 [CHCHCO(CO)], 128.7 (COCHCH), 124.3 (COCHCH), 1.96 [ddd, J = 1.6, J = 4.11, J = 14.75 Hz, 1 H, CH2CHOC(O)],
100.6 (C(IV)), 82.2 (CH–O pyran), 78.0 (CH–O pyran), 72.8
[C(Me)2CH–O–acetonide), 68.3 [CHO(CO)], 67.3 (CH2OTBDPS),
64.0 (CH–O–acetonide), 42.61 (CHEt), 41.46 [CH2CHO(CO)],
40.44 (C(IV)), 38.4 [CH2(CH–O–acetonide)2], 38.1 (CHCHCH2),
1.75–1.60 {m, 2 H, CH2[CH(OH)CMe2 and C(O)CHCHCH2]},
1.5–0.89 [m, 7 H, CH2CH2CH2 and C(O)CHCHCH2], 1.10 (s, 3
H, CH3), 0.81 (t, J = 7.43 Hz, 3 H, CH2CH3), 0.63 (s, 3 H,
CH3) ppm. 13C NMR (125 MHz, C6D6): δ = 165.28 (CO), 148.86
32.2 (CH2CH2CH2), 27.2 (tBu), 25.4 (CH2CH2CH2), 24.7 (CH3), [C(O)CHCH], 136.07 (CHCH), 129.69 (CHCH), 123.37 [C(O)-
24.6 (CH2CH2CH2), 24.5 (CH3), 24.1 (CH2CH3), 21.8 (CH3), 19.6 CHCH], 84.84 (CH–O pyran), 82.09 (CH–O pyran), 79.17
(C(IV)), 14.9 (CH3), 11.9 (CH2CH3) ppm. HRMS: calcd. for
[CH(OH)], 69.71 [CHOC(O)], 66.82 (CH2OH), 66.22 [CH(OH)],
43.81 (CHEt), 42.72 [CH2CHOC(O)], 40.83 (CH2), 40.71 (C(IV)),
37.19 (CHCHCH2), 31.45 (CH2CH2CH2), 25.71 (CH2CH2CH2),
24.75 (CH2CH3), 24.02 (CH2CH2CH2), 23.36 (CH3), 20.82 (CH3),
11.99 (CH2CH3) ppm. MS (CI): m/z = 411.19 [M + H]+. HRMS:
calcd. for C23H38O6Na [M + Na+] 433.2561; found 433.2569.
C42H60O6SiNa [M + Na+] 711.4057; found 711.4060.
(1R,7S,9S,11R,13S,E)-7-{(R,Z)-3-[(tert-Butyldiphenylsilyloxy)meth-
yl]pent-1-enyl}-9,11-dihydroxy-12,12-dimethyl-6,17-dioxabicyclo-
[11.3.1]heptadec-3-en-5-one (28): Acetonide-protected macrocycle
27 (7 mg, 0.011 mmol, 1 equiv.) was dissolved in acetone/H2O (9:1,
3 mL), and PPTS was added (2 mg, 0.008 mmol, 0.74 equiv.). The
resulting reaction mixture was gently heated to reflux for 1 h but
the reaction was not complete. Acetone/H2O (9:1 1 mL) was added
and the mixture was heated for 2 h until completion of the reaction
and then cooled to room temperature and diluted with buffer solu-
tion (pH = 7.0, 5 mL). It was then extracted with CH2Cl2 (3ϫ
5 mL) and the organic layers were dried with MgSO4, and concen-
trated under reduced pressure. The resulting residue was subjected
to column chromatography on silica gel (pentane/Et2O, 95:5 to 1:1)
to give compound 28 (5 mg, 70%) as a colorless oil. [α]2D0 = –47.8
Supporting Information (see footnote on the first page of this arti-
cle): 1H NMR and 13C NMR spectra for all key intermediates and
final products as well as the NOESY spectrum and geometry opti-
mization for 27.
Acknowledgments
The authors are grateful to V. Silvestre and J. Graton working in
the laboratory for NMR and modelisation supports and to R.
Le Guével (ImPACcell-SFR BIOSIT, Rennes, France) for bio-
logical evaluations. This work was supported by grants from
CNRS – Région Bretagne-Pays de Loire and financial contri-
butions from the Cancéropôle Grand-Ouest, the Ligue contre le
cancer and Institut National du Cancer (INCa).
1
(c = 0.35, CHCl3). H NMR (500 MHz, C6D6): δ = 7.87–7.82 (m,
4 H, Har), 7.35–7.10 [m, 7 H, Har and (CO)CHCH], 6.33–6.27 [m,
1 H, CHO(CO)], 5.97 (dd, J = 9.4, J = 10.9 Hz, 1 H, CHCH), 5.75
[d, J = 15.8 Hz, 1 H, (CO)CHCH], 5.39 (t, J = 10.9 Hz, 1 H,
CHCH), 4.55 (m, 1 H, CHOH), 3.75–3.65 (m, 2 H, CH2CH3),
3.59–3.56 (m, 1 H, CHOH), 2.95 [dd, J = 3.0, J = 9.4 Hz, 1 H,
C(Me)2CH–O], 2.87–2.79 (m, 2 H, CHEt and OH), 2.62–2.55 (m,
1 H, CH–O pyran), 2.39–2.30 [m, 1 H, CH2CHO(CO)], 1.97–1.90
[m, 1 H, CH2CHO(CO)], 1.78–1.46 (m, 6 H, 3ϫ CH2), 1.22 (s, 9
H, tBu), 1.24–0.9 (m, 6 H, 2ϫ CH2 and CH2CH3), 1.09 (s, 3 H,
CH3), 0.84 (t, J = 7.4 Hz, 3 H, CH2CH3), 0.65 (s, 3 H, CH3) ppm.
13C NMR (125 MHz, C6D6): δ = 164.8 (CO), 148.0 (COCHCH),
136.2 (Car), 136.2 (Car), 135.7 (CHCH), 129.9 (Car), 129.7 (Car),
128.7 (CHCH), 124.7 [C(O)CHCH], 84.3 (CH–O pyran), 81.6
(CH–O pyran), 78.0 [CH(OH)], 67.3 (CH2OTBDPS), 66.7
[CH(OH)], 43.1 [CH2OC(O)], 42.7 (CHEt), 40.8 (C(IV)), 40.7
[CH2CH(OH)CMe2], 37.5 (CHCHCH2), 31.5 (CH2CH2CH2), 27.2
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7103–7106.
Received: December 21, 2012
Published Online: March 5, 2013
Eur. J. Org. Chem. 2013, 2303–2315
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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