Stereocontrolled synthesis of the highly functionalized core structure of aurisides by ring-closing metathesis

Article abstract of DOI:10.1002/ejoc.201000331

Two approaches based on the ring-closing metathesis reaction have been explored for the synthesis of the core structure of the marine natural products, the aurisides. The second approach, accomplished in a stereocontrolled manner, used both a Brown's allylation and an Evans' aldolisation, and finally a transannular ketalization to deliver a highly functionalized auriside analogue.

Full text of DOI:10.1002/ejoc.201000331

FULL PAPER
DOI: 10.1002/ejoc.201000331
Stereocontrolled Synthesis of the Highly Functionalized Core Structure of
Aurisides by Ring-Closing Metathesis
Emmanuel Bourcet,[a] Fabienne Fache,[a] and Olivier Piva*[a]
Keywords: Natural products / Synthetic methods / Ring closing metathesis / Aurisides / Macrolides
Two approaches based on the ring-closing metathesis reac-
tion have been explored for the synthesis of the core struc-
ture of the marine natural products, the aurisides. The second
approach, accomplished in a stereocontrolled manner, used
both a Brown’s allylation and an Evans’ aldolisation, and fi-
nally a transannular ketalization to deliver a highly function-
alized auriside analogue.
Because of their complex structure, their promising bio-
logical activities and low availability from the natural
sources, total syntheses of the aurisides have been already
considered. The enantioselective synthesis of these com-
pounds was first achieved by Paterson and co-workers,
using highly stereoselective aldol reactions.[4] Intensive ef-
forts have also been made by the Kigoshi’s group,[5a] who
published the total synthesis, using (R)-pantolactone as a
chiron, based on previous work through the synthesis of
the aglycon achieved by Yamada–Kigoshi group.[5b] More
recently, Olivo and co-workers reported a convergent for-
mal synthesis of the aglycon part, as a result of intensive
researches in the aurisides area, using an indene-based thi-
azolidinethione chiral auxiliary for the construction of two
advanced fragments.[6] Interestingly, in all reported synthe-
ses the well-known Yamaguchi cyclisation[7] of a seco acid
was used to reach the 14-membered macrolactone.
Introduction
Aurisides A (1) and B (2) are two glycosidated macrolides
isolated from the sea hare Dolabella auricularia in 1996 by
Yamada and co-workers, which have shown significant
cytotoxicities against HeLaS3 cervical cancer cells lines,
with IC50 values of 0.17 and 1.2 µgmL–1, respectively.[1]
Their structures, determined by extensive NMR studies,
feature a 14-membered glycosidated macrolactone contain-
ing a six-membered hemiacetal ring, a E-trisubstituted en-
one and a brominated conjugated side chain (Figure 1).
In connection with our interest in the synthesis of biolo-
gically important natural products, we have focused our re-
searches on the use of the alkene metathesis reaction,[8–9] as
a key step, in order to form either the tetrahydropyran moi-
ety and/or the macrocyclic ring of the aurisides, which
could be an interesting alternative strategy for the construc-
tion of the 14-membered macrolactone. In this paper, we
would like to present our latest results concerning the
above-mentioned strategies, using alkene metathesis reac-
tion. In particular, a second generation approach will be
Figure 1. Structures of Aurisides A and B.
Several natural products structurally related to the illustrated by the convergent stereocontrolled synthesis of a
aurisides, such as dolastatin 19 (3), lyngbyaloside (4) or truncated aurisides analogue.
lyngbouilloside (5) have also been isolated (Figure 2),[2] and
studies have been made to synthesize these compounds.[3]
Results and Discussion
[a] Université de Lyon 1, Institut de Chimie et Biochimie
Our first retrosynthetic approach for the synthesis of the
Moléculaire et Supramoléculaire (ICBMS), UMR 5246 CNRS,
aglycon part of the aurisides 6 is outline on Scheme 1. It
was envisaged to install the bromodienic side chain at a
later stage while the trisubstituted enone would emerged
from the oxidation of the C9 allylic alcohol followed by
Bat. Raulin, 43, Bd du 11 Novembre 1918, 69622 Villeurbanne
cedex, France
E-mail: piva@univ-lyon1.fr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000331.
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Figure 2. Other 14-membered ring macrolides isolated the sea.
reconjugation of the double bond under basic condition relative configuration at C2. In each case, the methoxy
from compound 7. In turn, this double bond could derive group was placed in an axial position while the two alkyl
from a RCM reaction of an appropriate diene, which would rests on C3 and C7 adopted an equatorial position.
be rapidly obtained from C1–C9 fragment 8 (aurisides num-
bering). Moreover, it was planned to build the tetra-
hydropyran moiety using a cross-metathesis reaction be-
tween building blocks 9 and 10, directly followed by a re-
ductive ketalization process.
Scheme 2. Syntheses of oxygenated six-membered ring structures.
In order to verify our initial approach for the construc-
tion of the macrocyclic structure of the natural products,
we then used the same process for the rapid synthesis of a
nor-hydroxy C1–C9 fragment, which could be converted
into the required precursor for the key RCM reaction.
Thus, both compounds 16 and 17 were readily prepared in
a one- or five-step sequence from commercially available
Scheme 1. First retrosynthesis of the aurisides aglycon.
methyl propionate and 2,2-dimethylpropane-1,3-diol.[10]
The cross-metathesis reaction between 16 and 17 delivered
alkene 18, which was further oxidized using Dess–Martin
We have recently reported the feasibility of the cross Periodinane (DMP). After hydrogenation of the double
metathesis/ketalization process for the formation of several bond, we found that it was more convenient to install the
oxygenated six-membered ring structures.[10] As shown on first unsaturation on this linear precursor using sequential
Scheme 2, cross metathesis reaction, using 2nd generation ester hydrolysis with NaOH in THF/MeOH followed an es-
Grubbs catalyst 13,[11] of tert-butyl 2 methyl-3-oxo-4-pent- terification with allyl alcohol, under DCC activation[12]
enoate (11) with homoallylic alcohol 12, furnished the β- (Scheme 3).
keto esters 14 with moderate to good yields and with exclus-
Dioxolane was then cleaved under acidic condition with
ive (E) selectivity. Then, a hydrogenation/ketalization se- concomitant formation of the methoxytetrahydropyran 21.
quence yielded the expected heterocyclic compounds 15 as After purification by flash chromatography we observed the
a 1:1 mixture of stereoisomers. It was anticipated that under formation of the bicyclic compound 22, which results from
the conditions used, the two adducts differed only by the the substitution of the methoxy group by the primary
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Stereocontrolled Synthesis of Aurisides by Ring-Closing Metathesis
Scheme 4. Attempts of RCM of diene 24.
Scheme 3. Synthesis of compound 20.
alcohol in 21. This compound was used directly after basic
work-up and oxidized to give aldehyde 23 in 82% overall
yield. The second double bond was then introduced by a
chemoselective allylation of the aldehyde moiety using or-
ganoindium reagent.[13] Once the required diene 24 was
available, we next examined the formation of the macro-
cyclic structure by RCM. Unfortunately, all attempts failed,
despite the use of several catalysts and various conditions
tested. At 40 °C, we did not observe any conversion, when
elevated temperature conducted to decomposition of the
starting material (Scheme 4). Having the advanced interme-
diate 19 in hands, we reconsidered our strategy and found
an alternative synthesis of a truncated core structure of the
aurisides based on Yamaguchi’s macrolactonization process
(not shown).[10]
Scheme 5. Second retrosynthesis of the aurisides aglycon.
We first developed this strategy for the construction of
14-, 15- and 16-membered macrolactones (Scheme 6).[17]
To overcome the drawbacks of our first strategy, we have The required dienes 29a–d for the macrocyclisation were
now explored another route for the construction of the easily prepared from 1,7-heptanediol, 1,8-octanediol and
macrolactone core of the aurisides. Our second retrosyn- 1,9-nonanediol in a five-steps procedure. Ring closing me-
thetic approach is outline on Scheme 5. It was expected that tathesis was performed using catalytic amounts of second-
the 14-membered macrolactone could result from a RCM generation Grubbs catalyst 13, and similar yields were ob-
reaction of an appropriate triene 25, when the ketal ring tained regardless of the size of the cyclised products 30a–d,
would emerged from a subsequent transannular ketal- with still high E selectivity. Further oxidation of the allylic
ization,[14–16] after introduction of the hydroxy group at- alcohol with Dess–Martin Periodinane furnished com-
tached on C5. In turn, the required precursor 25 of the key pounds 31a–d in high yields (Table 1). Hydrogenation of the
RCM would arise from the coupling of three main frag- double bond, followed by cleavage of the silyl ether with
ments 26, 27, 28. Stereochemistry is planned to be con- concomitant transannular ketalization occurred nicely. The
trolled by the use of an enantioselective Brown’s allylation relative configuration of the methoxy group and the hydro-
for the construction of the C7 stereocentre, when a dia- gen atom attached on C3 and C7 respectively was assigned
stereoselective Evans’ aldol-type reaction would furnish the by nOe experiment performed on compound 32a.[17] This
correct configuration of C2. Concerning the 5-OH group, a relative configuration was assigned to the other adducts.
diastereoselective epoxydation directed by 3-OH could al- Compounds 32b–d (R = Me) were obtained as 1:1 mixture
low the installation of this functional group.
of inseparable stereoisomers.
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Scheme 6. Access to macrolactones 32a–d by a RCM/transannular
ketalization sequence.
Scheme 7. Synthesis of 5-hydroxymacrolactones 36a and 36b.
verted into methyl ester 41 prior to saponification, which
furnished the required acid 26, with slight epimerization on
the α position of the carbonyl group (Scheme 8).
Table 1. Formation of macrolactones 32a–d from esters 29a–d.
Entry n, R
RCM
Oxidation Hydrogenation
(% yield)[a] (% yield)[a] Ketalization (% yield)[a]
Next, the synthesis of fragment 27 started with
Brown’s[21] enantioselective allylation of known aldehyde
42, which yielded the homoallylic alcohol 43 in 78% yield.
The TBS protecting group was then removed by the use of
TBAF, and diol 44 was treated with p-anisaldehyde in the
presence of a catalytic amount of TsOH to deliver the
benzylidene ketal 45. Then, action of DIBAL allowed to
1
2
3
4
1, H
30a (86%) 31a (85%) 32a (79%)
1, Me 30b (83%) 31b (89%) 32b (78%)
2, Me 30c (76%) 31c (86%) 32c (79%)
3, Me 30d (82%) 31d (83%) 32d (75%)
[a] Isolated yields.
Then we took advantage of the allylic alcohol to intro- release selectively the primary alcohol 46, which was further
duce the 5-OH group of the natural products (Scheme 7). oxidized into aldehyde 27 using PCC in dichloromethane
Compound 30a could be diasteroselectively epoxidized by (Scheme 9).
[18]
using tBuOOH/VO(acac)2
to deliver compound 33,
Synthesis of the third fragment 47, a truncated structure
which was directly oxidized to yield the corresponding ep- of compound 28 was conveniently obtained according to a
oxy ketone 34. Regioselective epoxide opening was then known procedure.[22] Thus, having the three required frag-
achieved with sodium selenoate.[19] Subsequent TBS depro- ments in hands, we then proceeded to add compound 47 to
tection followed by in-situ formation of the tetrahydropyran aldehyde 27, after previous transmetallation with tBuLi at
subunit furnished the expected macrolides 36a and 36b. The very low temperature. Product 48 was obtained as a 1:1
two compounds, produced as a 1:1 mixture of dia- mixture of diastereomers concerning the allylic alcohol po-
stereomers, could be eventually separated chromatography, sition. The presence of the PMB allowed us to protect this
and differ by the relative position of 5-OH.[14,17]
hydroxy group by using DDQ under anhydrous condi-
Next we decided to apply our straightforward method tions.[23] The benzylidene acetal 49 was formed in 74%
for the construction of such macrolactones to the stereo- yield. Removal of the TBS protecting group by TBAF deliv-
controlled synthesis of a truncated aurisides’ analogue. Fol- ered the primary alcohol 50, which was esterified with car-
lowing the retrosynthetic approach depicted on Scheme 5, boxylic acid 26 under DCC activation to yield ester 51 in
the synthesis of carboxylic acid 26 began with the conden- good yield (Scheme 10).
sation of propionyl chloride with Superquat oxazolidinone
In order to reduce the steric congestion around the two
37.[20] The aldol reaction was achieved by reaction of 38 terminal double bonds and to facilitate the desired RCM
with acrolein to yield the expected syn compound 39 with we removed the silyl group. Treatment of compound 51
high diastereoselectivity. Allylic alcohol was then protected with TBAF required slight heating to observe full conver-
as a silyl ether in high yield. Surprisingly, cleavage of the sion and eventually yielded the allylic alcohol 52. Unfortu-
chiral auxiliary could not be achieved under the classical nately, the ring-closure and formation of the expected 14-
LiOH/H2O2 conditions, so compound 40 was first con- membered macrolactone was not observed. Even with high
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Stereocontrolled Synthesis of Aurisides by Ring-Closing Metathesis
Scheme 8. Synthesis of carboxylic acid 26.
Scheme 9. Synthesis of aldehyde 27.
Scheme 10. Synthesis of ester 51.
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E. Bourcet, F. Fache, O. Piva
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loading of different catalysts (up to 15 mol-%) no conver-
To our delight, the RCM event of this second precursor
sion of the starting material was observed at 40 °C while 56 proceeded well and delivered the expected macrocycle 57
higher temperatures caused decomposition. We assume that with an exclusive E selectivity for the new created double
a conformational bias due to the presence of the six-mem- bond, along with the formation of cyclohexenone 58. Then
bered benzylidene moiety is responsible of the failure we repeated the sequence developed previously on unfunc-
(Scheme 11).
tionalized macrolactone 30a for the introduction of 5-OH.
Thus, epoxy ketone 60 was obtained according to a dia-
stereoselective epoxidation followed directly by the oxi-
dation of the hydroxy group with DMP. Compound 60 was
subsequently reduced compound into the β-hydroxy ketone
61. Next, deprotection of the PMB ether was envisioned
by treatment with DDQ in aqueous conditions. However,
instead of the desired diol we observed the formation of the
two benzylidene acetals 62a and 62b and a third side-prod-
uct 63 which results of the overoxidation. The three com-
pounds were separated by carefully performed flash-
chromatography (Scheme 13).
Scheme 11. First attempts of RCM.
To overcome this problem, we decided to form the enone
moiety prior to the RCM event, in order to rigidify the
structure of the precursor of the cyclization. Thus, allylic
alcohol 48 was oxidized with Dess–Martin periodinane in
good yield. Further deprotection of the silyl ether furnished
primary alcohol 54, which was esterified with acid 26 as
described above. Partial epimerization of the methyl group
attached on C2 was observed, and a 7:3 ratio was deter-
1
mined by integration of signals of the H NMR spectrum.
After optimization, CSA in MeOH appeared as the most
suitable reagent to remove the TBS protecting yielding the
new RCM precursor 56 (Scheme 12).
Scheme 13. RCM and functionalization of C5.
Compounds 62a and 62b were characterized by nOe ex-
periments, which showed strong correlation between hydro-
gen atoms attached to C5, C7 and the benzylic proton.
These results prove the same relative and absolute configu-
ration of both stereocentres C5 and C7 for the two com-
pounds, meaning also that they only differ by the relative
configuration of the C2 stereocenter. At this stage, no state-
ment concerning the absolute configuration at C2 of 62a
and 62b is possible (Figure 3).
Scheme 12. Synthesis of the second precursor 56.
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Stereocontrolled Synthesis of Aurisides by Ring-Closing Metathesis
reported in ppm on scale upfield from TMS as an internal standard
and signal patterns are indicated as follows: s, singlet; d, doublet;
dd, doublet of doublet; dt, doublet of triplet; t, triplet; m, multiplet,
br, broad singlet. High resolution mass spectrometry (HRMS)
analyses were conducted using a ThermoFinigan-MAT 95 XL in-
strument. Optical rotations were measured on a digital polarimeter
using a 5 mL cell with a 1 dm path length. IR spectra were mea-
sured on a Perkin–Elmer Spectrum One FT-IR spectrometer. TLC
analyses were performed on plates (layer thickness 0.25 mm) and
were visualized with UV light, phosphomolybdic acid or p-anisal-
dehyde solution. Column chromatography was performed on silica
gel (40–63 µm) using technical grade ethyl acetate (EtOAc) and pe-
troleum ether (EP). When appropriate, solvents and reagents were
dried by distillation over appropriate drying agent prior to use. Di-
ethyl ether and tetrahydrofuran (THF) were distilled from Na/
benzophenone and used fresh. Dichloromethane was distilled from
CaH2. All the reactions were performed under an atmosphere of
nitrogen in flame or oven-dried glassware with magnetic stirring.
Figure 3. nOe experiments for compounds 62a and 62b.
Finally, the benzylidene acetal was carefully removed
under acidic media. Prolonged exposure to the CSA/MeOH
yielded methyl ether 64 from compound 62b, a well-moni-
tored reaction furnished the expected truncated auriside an-
alogue 65 as a single diastereoisomer (Scheme 14).[24]
Compound 38:[25] To a solution of chiral auxiliary 37 (1.57 g,
10.00 mmol) in dry THF (50 mL) was added at –78 °C, nBuLi
(1.5  in hexanes, 7.33 mL, 11.00 mmol). The resulting mixture was
stirred at this temperature for 1 h, and then propionyl chloride
(0.96 mL, 11.00 mmol) was added dropwise. The mixture was
warmed at room temp. and stirred for 18 h. After the addition of
saturated aqueous NH4Cl (30 mL), the aqueous phase was ex-
tracted with Et2O (3ϫ30 mL). The combined organic extracts were
washed with brine (20 mL), dried with MgSO4, and concentrated
under reduced pressure. The crude residue was purified by column
chromatography (10% EtOAc in petroleum ether) to give com-
pound 38 (2.07 g, 9.70 mmol, 97%) as a white solid. 1H NMR
(300 MHz, CDCl3): δ = 0.94 (d, J = 7.0 Hz, 3 H, CH3-CH), 1.02
(d, J = 7.0 Hz, 3 H, CH3-CH), 1.19 (t, J = 7.4 Hz, 3 H, CH3-CH2),
1.38 (s, 3 H, CH3-C), 1.51 (s, 3 H, CH3-C), 2.14 (dsept, J = 3.3,
7.0 Hz, 1 H, CH3-CH-CH3), 2.90 (dq, J = 17.5, 7.4 Hz, 1 H, CH2-
CH3), 3.01 (dq, J = 17.5, 7.4 Hz, 1 H, CH2-CH3), 4.14 [d, J =
3.3 Hz, 1 H, CH-CH-(CH3)2] ppm. 13C NMR (75 MHz, CDCl3): δ
= 8.6, 16.8, 21.2, 21.3, 28.6, 28.9, 29.4, 66.0, 82.6, 153.4, 174.3 ppm.
Scheme 14. Synthesis of a truncated auriside analogue 56.
Compound 39: To a solution of N-oxazolidinone 38 (1.57 g,
10.00 mmol) in dry CH2Cl2 (30 mL) were successively added at
0 °C, diisopropylethylamine (2.17 mL, 13.13 mmol) and nBu2BOTf
(1  in CH2Cl2, 11.25 mL, 11.25 mmol). The resulting mixture was
stirred at this temperature for 15 min and then cooled to –78 °C.
Then acrolein (0.94 mL, 14.07 mmol) was slowly added, and the
mixture stirred 1 h at –78 °C, and then 30 min at 0 °C. After the
addition water (15 mL) and MeOH (50 mL), a 2:1 solution of
MeOH/H2O2 was added at 0 °C over a period of 20 min, and the
mixture stirred for a further 20 min. Then, solvents were removed
under reduce pressure and the residue partitioned between water
(50 mL) and Et2O (50 mL). The aqueous phase was extracted with
Et2O (3ϫ30 mL). The combined organic extracts were washed
with brine (20 mL), dried with MgSO4, and concentrated under
reduce pressure. The crude residue was purified by column
chromatography (10% EtOAc in petroleum ether) to give alcohol
39 (2.17 g, 8.07 mmol, 86%) as a colourless oil. [α]2D2 = +39.3 (c =
Conclusions
While studying synthetic methods leading to natural
macrolides of the auriside type, two different routes includ-
ing alkene metathesis reaction were found. We were able
to build the macrocyclic core of the natural product in an
alternative and original way of the well established Yama-
guchi macrocyclization. The convergent stereocontrolled
synthesis of
a truncated auriside analogue was ac-
complished in 18 steps (longest linear sequence) with an
overall yield of 2.3%. This route should also offer access to
related compounds like dolastatin 19 or lyngbouillouside.
Work is in progress to apply this strategy to different targets
and will be reported in due course.
1.01; CHCl ). IR (neat): ν = 3507, 3095, 2985, 2874, 1779, 1674,
˜
3
1363, 1234, 1177 cm–1. H NMR (300 MHz, CDCl3): δ = 0.95 (d,
1
J = 7.0 Hz, 3 H, CH3-CH-CH3), 1.01 (d, J = 7.0 Hz, 3 H, CH3-
CH-CH3), 1.28 (d, J = 7.1 Hz, 3 H, CH3-CH), 1.40 (s, 3 H, CH3-
C), 1.52 (s, 3 H, CH3-C), 2.14 (dsept, J = 3.3, 7.0 Hz, 1 H, CH3-
CH-CH3), 2.93 (br. s, 1 H, OH), 3.94 (dq, J = 3.4, 7.1 Hz, 1 H,
CH-CH3), 4.19 [d, J = 3.3 Hz, 1 H, CH-CH-(CH3)2], 4.45–4.89 (m,
1 H, CH-OH), 5.21 (dt, J = 10.6, 1.5 Hz, 1 H, CH=CH2), 5.34 (dt,
J = 17.3, 1.5 Hz, 1 H, CH=CH2), 5.83 (ddd, J = 17.3, 10.6, 5.5 Hz,
Experimental Section
1
General: H and 13C NMR spectra were recorded either in CDCl3
or in C6D6 solvent on a BrukerAM 300, 500 or 75 MHz spectrome-
ter at ambiant temperature, which provided all necessary data for
full compound assignments. Chemical shifts (δ values) are given in
ppm units, coupling constant J are in Hz. The chemical shifts are
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1 H, CH=CH2) ppm. 13C NMR (75 MHz, CDCl3): δ = 12.1, 16.9,
21.3, 21.6, 28.7, 29.6, 42.5, 66.1, 72.8, 83.0, 116.3, 137.5, 153.2,
177.2 ppm. MS (ESI): m/z (%) = 292.1 (100) [M + Na+], 561.0 (26)
[2M + Na+]. HRMS (ESI): calcd. for C14H23NO4Na 292.1525 [M
+ Na+]; found 292.1526.
(neat): ν = 3411, 2961, 2931, 2852, 1711, 1460, 1254, 1083,
˜
1
837 cm–1. H NMR (300 MHz, CDCl3): δ = 0.07 (s, 3 H, CH3-Si),
0.10 (s, 3 H, CH3-Si), 0.91 [s, 9 H, (CH3)3-Si], 1.13 (d, J = 7.0 Hz,
3 H, CH3-CH), 2.57–2.67 (m, 1 H, CH-CH3), 4.36–4.40 (m, 1 H,
CH-OSi), 5.19–5.28 (m, 2 H, CH=CH2), 5.79 (ddd, J = 17.1, 10.4,
6.6 Hz, 1 H, CH=CH2) ppm. 13C NMR (75 MHz, CDCl3): δ =
–5.0, –4.2, 11.2, 18.2, 25.9, 46.3, 75.0, 116.4, 138.4, 179.9 ppm. MS
(CI): m/z (%) = 245 (100) [M + H+]. HRMS (CI): calcd. for
C12H25O3Si 245.1573 [M + H+], found 245.1573.
Compound 40: To a solution of alcohol 39 (2.00 g, 7.43 mmol) in
dry CH2Cl2 (35 mL) were successively added at room temp., imid-
azole (2.53 g, 37.13 mmol), DMAP (91 mg, 0.74 mmol) and TBS-
Cl (2.24 g, 14.85 mmol). and the resulting mixture was stirred at
this temperature for 16 h. After the addition of saturated aqueous
NH4Cl (30 mL), the aqueous phase was extracted with Et2O
(3ϫ30 mL). The combined organic extracts were washed with
brine (20 mL), dried with MgSO4, and concentrated under reduce
pressure. The crude residue was purified by column chromatog-
raphy (5% EtOAc in petroleum ether) to give compound 40 (2.79 g,
7.28 mmol, 98%) as a colourless oil. [α]2D2 = +41.8 (c = 1.00,
Compound 43: Aldehyde 42 (2.00 g, 9.24 mmol) was enantioselecti-
vely allylated to give after purification by column chromatography
(5% EtOAc in petroleum ether) compound 43 (1.89 g, 7.30 mmol
78% yield) as a colourless oil, following the procedure described
for the synthesis of its enantiomer.[20] [α]2D2 = +19.5 (c = 1.00,
CHCl ). IR (neat): ν = 3497, 3072, 2957, 2931, 2859, 1473, 1256,
˜
3
1093, 837 cm–1. 1H NMR (300 MHz, CDCl3): δ = 0.07 (s, 6 H,
CH3-Si), 0.84 (s, 3 H, CH3-C), 0.90 [s, 9 H, (CH3)3-Si], 0.91 (s, 3
H, CH3-C), 2.04–2.15 (m, 1 H, CH2-CH=CH2), 2.23–2.31 (dd, J =
5.8, 13.6 Hz, 1 H, CH2-CH=CH2), 3.48 (s, 2 H, CH2-OSi), 3.52–
3.55 (m, 1 H, CH-OH), 5.06–5.09 (m, 1 H, CH=CH2), 5.11 (ddd,
J = 17.1, 3.2, 1.7 Hz, 1 H, CH=CH2), 5.94 (ddt, J = 17.0, 10.5,
6.9 Hz, 1 H, CH=CH2) ppm. 13C NMR (75 MHz, CDCl3): δ =
–5.6, 18.2, 18.9, 22.2, 25.9, 36.7, 38.4, 73.2, 78.2, 116.4, 136.9 ppm.
CHCl ). IR (neat): ν = 3080, 2961, 2857, 1779, 1698, 1362, 1219,
˜
3
1119 cm–1. 1H NMR (300 MHz, CDCl3): δ = 0.02 (s, 3 H, CH3-
Si), 0.06 (s, 3 H, CH3-Si), 0.88 [s, 9 H, (CH3)3-Si], 0.93 (d, J =
7.0 Hz, 3 H, CH3-CH-CH3), 1.00 (d, J = 7.0 Hz, 3 H, CH3-CH-
CH3), 1.26 (d, J = 6.8 Hz, 3 H, CH3-CH), 1.35 (s, 3 H, CH3-C),
1.49 (s, 3 H, CH3-C), 2.12 (dsept, J = 3.4, 7.0 Hz, 1 H, CH3-CH-
CH3), 4.02–4.13 [m, 2 H, CH-CH3 and CH-CH-(CH3)2], 4.24 (dd,
J = 7.2, 7.9 Hz, 1 H, CH-OSi), 5.05 (ddd, J = 10.4, 1.7, 0.9 Hz, 1
H, CH=CH2), 5.13 (ddd, J = 17.4, 1.7, 0.9 Hz, 1 H, CH=CH2),
5.83 (ddd, J = 17.4, 10.4, 7.2 Hz, 1 H, CH=CH2) ppm. 13C NMR
(75 MHz, CDCl3): δ = –4.7, –4.2, 15.0, 17.1, 18.3, 21.5, 21.6, 25.9,
28.7, 29.6, 44.4, 66.2, 76.0, 82.5, 116.0, 139.8, 153.3, 175.6 ppm.
MS (ESI): m/z (%) = 406.2 (100) [M + Na+], 789.1 (24) [2M +
Na+]. HRMS (ESI): calcd. for C20H37NO4SiNa 406.2390 [M +
Na+]; found 406.2390.
Compound 44: To a solution of homoallylic alcohol 43 (4.00 g,
15.48 mmol) in THF (75 mL) was added at room temp. TBAF (1 
in THF, 17.02 mL, 17.02 mmol), and the resulting mixture was
stirred at this temperature for 1 h. The mixture was then concen-
trated under reduce pressure. The crude residue was purified by
column chromatography (35% EtOAc in petroleum ether) to give
compound 44 (1.03 g; 7.12 mmol, 92% yield) as a colourless oil.
[α]2D2 = –4.8 (c = 0.51, CHCl ). IR (neat): ν = 3350, 3073, 2958,
˜
3
2872, 1638, 1469, 1431, 1065, 912 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 0.90 (s, 3 H, CH3-C), 0.92 (s, 3 H, CH3-C), 2.02–2.13
(m, 1 H, CH2-CH=CH2), 2.33–2.42 (m, 1 H, CH2-CH=CH2), 3.48
(d, J = 10.9 Hz, 1 H, CH2-OH), 3.53 (dd, J = 2.3, 10.7 Hz, 1 H,
CH-OH), 3.55 (d, J = 10.9 Hz, 1 H, CH2-OH), 5.15–5.20 (m, 2 H,
CH=CH2), 5.44 (dddd, J = 17.9, 12.4, 8.6, 5.5 Hz, 1 H, CH=CH2)
ppm. 13C NMR (75 MHz, CDCl3): δ = 18.7, 22.7, 36.7, 38.3, 72.1,
77.9, 117.7, 136.1 ppm.
Compound 41: nBuLi (1.5  in hexanes, 12.0 mL, 18.00 mmol) was
added slowly at 0 °C to dry MeOH (30 mL) and the resulting mix-
ture was stirred at this temperature for 15 min. Then, a solution of
compound 40 (2.30 g, 6.00 mmol) in dry MeOH (5 mL) was added
slowly at 0 °C, and the mixture was warmed at room temp. and
stirred for 18 h. After the addition of saturated aqueous NH4Cl
(30 mL), the aqueous phase was extracted with EtOAc (3ϫ30 mL).
The combined organic extracts were washed with brine (20 mL),
dried with MgSO4, and concentrated under reduce pressure. The
crude residue was purified by column chromatography (5% EtOAc
in petroleum ether) to give ester 41 (1.24 g, 4.80 mmol, 80%) as a
Compound 45: To a solution of diol 44 (2.00 g, 13.87 mmol) in THF
(65 mL) were successively added at room temp. p-anisaldehyde
(3.37 mL, 27.74 mmol) and TsOH (132 mg, 0.69 mmol), and the
resulting mixture was refluxed for 10 h. After cooling to room
temp., a saturated solution of NaHCO3 (30 mL) was added and the
aqueous phase was extracted with Et2O (3ϫ30 mL). The combined
organic extracts were washed with brine (20 mL), dried with
MgSO4, and concentrated under reduce pressure. The crude residue
was purified by column chromatography (5% EtOAc in petroleum
ether) to give compound 45 (3.20 g, 12.20 mmol, 88% yield) as a
colourless oil. [α]2D2 = +13.2 (c = 1.01, CHCl ). IR (neat): ν = 3080,
˜
3
2955, 2858, 1742, 1463, 1256, 1079, 837 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 0.01 (s, 3 H, CH3-Si), 0.02 (s, 3 H, CH3-Si), 0.87 [s, 9
H, (CH3)3-Si], 1.14 (d, J = 7.0 Hz, 3 H, CH3-CH), 2.51 (dq, J =
5.5, 7.0 Hz, 1 H, CH-CH3), 3.65 [s, 3 H, CH3-OC(O)], 4.40 (dd, J
= 5.5, 6.4 Hz, 1 H, CH3-OSi), 5.10 (ddd, J = 10.4, 1.5, 1.3 Hz, 1
H, CH=CH2), 5.13 (ddd, J = 17.4, 1.5, 1.3 Hz, 1 H, CH=CH2),
5.83 (ddd, J = 17.4, 10.4, 6.4 Hz, 1 H, CH=CH2) ppm. 13C NMR
(75 MHz, CDCl3): δ = –5.0, –4.2, 11.5, 18.2, 25.8, 46.7, 51.5, 75.0,
115.6, 139.6, 174.9 ppm.
colourless oil. [α]2D2 = +87.4 (c = 1.02, CHCl ). IR (neat): ν = 3071,
˜
3
2958, 2835, 1625, 1518, 1392, 1249, 1114, 1084, 826 cm–1. 1H NMR
(300 MHz, CDCl3): δ = 0.80 (s, 3 H, CH3-C), 1.14 (s, 3 H, CH3-
C), 2.25 (ddd, J = 6.8, 6.3, 1.4 Hz, 2 H, CH2-CH=CH2), 3.54 (t, J
= 6.3 Hz, 1 H, CH-O), 3.58 (d, J = 11.2 Hz, 1 H, CH2-O), 3.70 (d,
J = 11.2 Hz, 1 H, CH2-O), 3.80 (s, 3 H, CH3-O), 5.04 (ddt, J =
10.2, 2.1, 1.1 Hz, 1 H, CH=CH2), 5.10 (ddd, J = 17.2, 3.6, 1.4 Hz,
1 H, CH=CH2), 5.43 (s, 1 H, O-C-O), 5.94 (ddt, J = 17.2, 10.2,
6.8 Hz, 1 H, CH=CH2), 6.89 (d, J = 8.7 Hz, 2 H, Ar-H), 7.43 (d,
J = 8.7 Hz, 2 H, Ar-H) ppm. 13C NMR (75 MHz, CDCl3): δ =
18.7, 21.6, 32.8, 34.1, 55.3, 78.8, 85.1, 101.6, 113.6, 116.2, 127.4,
131.4, 136.0, 159.7 ppm. MS (CI): m/z (%) = 263 (100) [MH+].
HRMS (CI): calcd. for C16H23O3 263.1647 [M + H+]; found
263.1647.
Compound 26: To a 2:1 solution of ester 41 (1.10 g, 4.26 mmol) in
THF/MeOH (24 mL) was added at room temp., a aqueous solution
of NaOH (2 , 4.26 mL, 8.51 mmol) and the resulting mixture was
stirred at this temperature for 8 h. The mixture was then carefully
acidified (pH3–4) using 1  HCl. The aqueous phase was then ex-
tracted with EtOAc (5ϫ10 mL). The combined organic extracts
were washed with brine (20 mL), dried with MgSO4, and concen-
trated under reduce pressure. The crude residue was purified by
column chromatography (30% EtOAc in petroleum ether) to give
compound 26 (863 mg, 3.53 mmol, 83%) as a colourless oil. IR
4082
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4075–4087

Stereocontrolled Synthesis of Aurisides by Ring-Closing Metathesis
Compound 46: To a solution of benzylidene acetal 45 (3.10 g,
11.82 mmol) in dry CH2Cl2 (60 mL) was added at 0 °C, DIBAL
(1  in heptanes, 14.18 mL, 14.18 mmol) and the resulting mixture
was stirred at this temperature for 4 h. After adding water (20 mL),
the mixture was filtered through a pad of celite. The aqueous phase
1.5 H, CH3-C), 0.82 (s, 1.5 H, CH3-C), 0.88 [s, 4.5 H, (CH3)3-Si],
0.89 [s, 4.5 H, (CH3)3-Si], 0.96 (s, 1.5 H, CH3-C), 0.97 (s, 1.5 H,
CH3-C), 1.67 (s, 1.5 H, CH3-C=), 1.68 (s, 1.5 H, CH3-C=), 2.17–
2.57 (m, 4 H, CH2-CH=CH2 and CH2-C=), 3.45 (dd, J = 3.8,
7.3 Hz, 1 H, CH-O), 3.69 (t, J = 7.0 Hz, 2 H, CH-OSi), 3.79 (s, 3
was then extracted with CH2Cl2 (3ϫ20 mL). The combined or- H, CH3-O), 4.30 (d, J = 9.2 Hz, 0.5 H, Ar-CH2-O), 4.38–4.48 (m,
ganic extracts were washed with brine (20 mL), dried with MgSO4,
and concentrated under reduce pressure. The crude residue was
purified by column chromatography (25% EtOAc in petroleum
ether) to give compound 46 (2.87 g, 10.87 mmol, 92%) as a colour-
1.5 H, CH-OH et Ar-CH2-O), 4.63 (d, J = 10.6 Hz, 0.5 H, Ar-
CH2-O), 4.65 (d, J = 10.6 Hz, 0.5 H, Ar-CH2-O), 5.07 (d, J =
10.0 Hz, 0.5 H, CH=CH2), 5.08 (d, J = 10.2 Hz, 0.5 H, CH=CH2),
5.14 (d, J = 17.1 Hz, 0.5 H, CH=CH2), 5.15 (d, J = 17.1 Hz, 0.5
H, CH=CH2), 5.26 (t, J = 10.5 Hz, 0.5 H, CH=C), 5.27 (t, J =
less oil. [α]2D2 = –10.4 (c = 1.00, CHCl ). IR (neat): ν = 3424, 3071,
˜
3
2960, 2873, 1614, 1515, 1249, 1036 cm–1. 1H NMR (300 MHz, 10.5 Hz, 0.5 H, CH=C), 5.96 (ddt, J = 17.1, 10.0, 7.5 Hz, 0.5 H,
CDCl3): δ = 0.88 (s, 3 H, CH3-C), 0.99 (s, 3 H, CH3-C), 2.29–2.48 CH=CH2), 5.97 (ddt, J = 17.1, 10.2, 7.5 Hz, 0.5 H, CH=CH2), 6.86
(m, 2 H, CH2-CH=CH2), 3.32 (d, J = 10.9 Hz, 1 H, CH2-O), 3.36 (d, J = 8.4 Hz, 2 H, Ar-H), 7.25 (d, J = 8.4 Hz, 2 H, Ar-H) ppm.
(dd, J = 4.0, 7.5 Hz, 1 H, CH-O), 3.57 (d, J = 10.9 Hz, 1 H, CH2-
O), 3.80 (s, 3 H, CH3-O), 4.41 (d, J = 10.7 Hz, 1 H, Ar-CH2-O),
4.51 (d, J = 10.7 Hz, 1 H, Ar-CH2-O), 5.07 (ddt, J = 10.0, 2.1,
1.0 Hz, 1 H, CH=CH2), 5.15 (ddd, J = 17.2, 3.4, 1.5 Hz, 1 H,
13C NMR (75 MHz, CDCl3): δ = –5.2 16.4, 17.4, 18.4, 20.6, 21.4,
26.1, 35.5, 35.8, 42.6, 42.7, 43.4, 43.5, 55.4, 62.2, 62.3, 72.7, 73.1,
73.9, 74.6, 86.9, 113.9, 116.4, 116.7, 126.1, 126.3, 129.6, 130.3,
130.4, 136.2, 136.6, 136.9, 137.2, 159.3, 159.4 ppm. MS (ESI): m/z
CH=CH2), 5.96 (ddt, J = 17.2, 10.0, 6.8 Hz, 1 H, CH=CH2), 6.87 (%) = 485.3 (100) [M + Na+]. HRMS (ESI): calcd. for C27H46O4-
(d, J = 8.8 Hz, 2 H, Ar-H), 7.25 (d, J = 8.8 Hz, 2 H, Ar-H) ppm.
13C NMR (75 MHz, CDCl3): δ = 20.5, 23.2, 35.6, 39.7, 55.3, 70.8,
73.6, 86.3, 113.9, 116.7, 129.5, 130.5, 136.8, 159.3 ppm. MS (ESI):
m/z (%) = 287.1 (100) [M + Na+]. HRMS (ESI): calcd. for
C16H24O3Na 287.1623 [M + Na+]; found 287.1623.
SiNa 485.3063 [M + Na+]; found 485.3064.
Compound 49: To a solution of alcohol 48 (1.00 g, 2.16 mmol) in
dry CH2Cl2 (20 mL), in the presence of 4 Å molecular sieves, was
added and at –20 °C, DDQ (540 mg, 2.38 mmol) and the resulting
mixture was then stirred at –10 °C for 3 h. The mixture was then
filtered off through a pad of celite and a saturated aqueous solution
of NaHCO3 (15 mL) was added to the filtrate. After separation of
the layers, the aqueous phase was extracted with CH2Cl2
(3ϫ15 mL). The combined organic extracts were washed with
brine (20 mL), dried with MgSO4, and concentrated under reduce
pressure. The crude residue was purified by column chromatog-
raphy (5% EtOAc in petroleum ether) to give compound 49
(737 mg, 1.60 mmol, 74%) as a colourless oil; mixture of 1:1 dia-
Compound 27: To a solution of alcohol 46 (2.80 g, 10.59 mmol) in
dry CH2Cl2 (50 mL) was added in one portion at room temp., PCC
(3.42 g, 15.89 mmol) and the resulting mixture was stirred at this
temperature for 4 h. The mixture was then concentrated under re-
duce pressure, and Et2O was added to the residue. After being
stirred for 15 min, this mixture was filtered off through a pad a
celite, and solvent was then removed under reduce pressure. The
crude residue was purified by column chromatography (10%
EtOAc in petroleum ether) to give compound 27 (2.67 g,
10.17 mmol, 96%) as a colourless oil. [α]2D2 = –13.0 (c = 1.00,
stereomers. IR (neat): ν = 3076, 2930, 2852, 1615, 1517, 1471, 1250,
˜
1066 cm–1. 1H NMR (300 MHz, CDCl3): δ = 0.04 (s, 3 H, CH3-
Si), 0.07 (s, 3 H, CH3-Si), 0.75 (s, 3 H, CH3-C), 0.88 [s, 9 H,
(CH3)3-Si], 1.03 (s, 3 H, CH3-C), 1.73 (s, 1.5 H, CH3-C=), 1.74 (s,
CHCl ). IR (neat): ν = 3071, 2961, 2862, 1726, 1614, 1515, 1249,
˜
3
1081, 1036 cm–1. 1H NMR (300 MHz, CDCl3): δ = 1.05 (s, 3 H,
CH3-C), 1.12 (s, 3 H, CH3-C), 2.34 (m, 2 H, CH2-CH=CH2), 3.59 1.5 H, CH3-C=), 2.18–2.33 (m, 4 H, CH2-CH=CH2 and CH2-C=),
(dd, J = 4.9, 6.6 Hz, 1 H, CH-O), 3.80 (s, 3 H, CH3-O), 4.40 (d, J
= 10.9 Hz, 1 H, Ar-CH2-O), 4.60 (d, J = 10.9 Hz, 1 H, Ar-CH2-
3.54 (t, J = 6.1 Hz, 1 H, CH-O), 3.71 (t, J = 7.0 Hz, 2 H, CH2-O),
3.77 (s, 1.5 H, CH3-O), 3.78 (s, 1.5 H, CH3-O), 4.21 (d, J = 8.8 Hz,
O), 5.08 (ddt, J = 10.2, 2.1, 1.0 Hz, 1 H, CH=CH2), 5.15 (ddd, J 1 H, CH-O), 5.01–5.13 (m, 2 H, CH=CH2), 5.31 (d, J = 8.8 Hz,
= 17.1, 3.2, 1.5 Hz, 1 H, CH=CH2), 5.90 (ddt, J = 17.1, 10.2, 0.5 H, CH=C), 5.32 (d, J = 8.8 Hz, 0.5 H, CH=C), 5.57 (s, 1 H,
7.0 Hz, 1 H, CH=CH2), 6.86 (d, J = 8.8 Hz, 2 H, Ar-H), 7.21 (d, O-CH-O), 5.86–6.01 (m, 1 H, CH=CH2), 6.86 (d, J = 8.7 Hz, 2 H,
J = 8.8 Hz, 2 H, Ar-H), 9.55 (s, 1 H, CHO) ppm. 13C NMR Ar-H), 7.38–7.44 (m, 2 H, Ar-H) ppm. 13C NMR (75 MHz,
(75 MHz, CDCl3): δ = 17.7, 19.4, 35.4, 51.0, 55.2, 73.2, 82.3, 113.7,
117.4, 129.3, 130.3, 135.6, 159.2, 205.7 ppm. MS (ESI): m/z (%) =
CDCl3): δ = –5.2, 17.4, 17.8, 18.4, 21.0, 21.7, 21.8, 26.1, 34.0, 35.3,
36.9, 43.3, 43.6, 55.3, 62.0, 62.1, 79.6, 80.0, 82.4, 86.3, 95.0, 101.4,
285.1 (54) [M + Na+]; 317.1 (100) [MNa+ + MeOH]. HRMS (ESI): 113.6, 113.7, 116.0, 116.1, 121.0, 122.9, 127.5, 127.6, 131.7, 132.2,
calcd. for C16H22O3Na 285.1467 [M + Na+]; found 285.1467.
136.4, 136.5, 138.0, 140.1, 159.7, 159.9 ppm. MS (ESI): m/z (%) =
483.3 (100) [M + Na+]. HRMS (ESI): calcd. for C27H44O4SiNa
483.2907 [M + Na+]; found 483.2908.
Compound 48: To a solution of iodo olefin 47 (3.88 g, 11.89 mmol)
in dry Et2O (75 mL) was slowly added at –95 °C, a solution of
tert-butyllithium in hexanes (1.5 , 15.86 mL, 23.79 mmol) and the Compound 50: To a solution of compound 49 (700 mg, 1.52 mmol)
resulting mixture was stirred at this temperature for 1 h. Then a
solution of aldehyde 27 (2.60 g, 9.91 mmol) in dry Et2O (15 mL)
was then slowly added at –95 °C, and the mixture was stirred at
–78 °C for 2.5 h. The reaction was quenched by adding saturated
aqueous solution of NH4Cl (25 mL). After separation of the layers,
the aqueous phase was extracted with Et2O (3ϫ20 mL). The com-
bined organic extracts were washed with brine (20 mL), dried with
MgSO4, and concentrated under reduce pressure. The crude residue
was purified by column chromatography (10% EtOAc in petroleum
ether) to give compound 47 (3.16 g, 6.84 mmol, 69%) as a colour-
in THF (15 mL) was added at room temp. TBAF (1  in THF,
1.82 mL, 1.82 mmol), and the resulting mixture was stirred at this
temperature for 1 h. The mixture was then concentrated under re-
duce pressure. The crude residue was purified by column
chromatography (35% EtOAc in petroleum ether) to give com-
pound 50 (500 mg, 1.44 mmol, 95% yield) as a colourless oil; mix-
ture of 1:1 diastereomers. IR (neat): ν = 3419, 3077, 2933, 2868,
˜
1699, 1625, 1516, 1243, 1047 cm–1. 1H NMR (300 MHz, CDCl3):
δ = 0.77 (s, 3 H, CH3-C), 1.04 (s, 3 H, CH3-C), 1.76 (d, J = 1.3 Hz,
1.5 H, CH3-C=), 1.78 (d, J = 1.3 Hz, 1.5 H, CH3-C=), 2.26–2.35
(m, 4 H, CH2-CH=CH2 and CH2-C=), 3.55 (t, J = 6.1 Hz, 1 H,
less oil; mixture of 1:1 diastereomers. IR (neat): ν = 3440, 3072,
˜
2954, 2857, 1614, 1510, 1254, 1088 cm–1. 1H NMR (300 MHz, CH-O), 3.71 (t, J = 6.4 Hz, 1 H, CH2-OH), 3.72 (t, J = 6.2 Hz, 1
CDCl3): δ = 0.04 (s, 3 H, CH3-Si), 0.05 (s, 3 H, CH3-Si), 0.76 (s, H, CH2-OH), 3.79 (s, 3 H, CH3-O), 4.23 (d, J = 8.7 Hz, 0.5 H,
Eur. J. Org. Chem. 2010, 4075–4087
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4083

E. Bourcet, F. Fache, O. Piva
FULL PAPER
CH-O), 4.32 (d, J = 8.9 Hz, 0.5 H, CH-O),5.02–5.12 (m, 2 H,
CH=CH2), 5.37 (d, J = 8.7 Hz, 0.5 H, CH=C), 5.38 (d, J = 8.9 Hz,
(15 wt.-% in CH2Cl2, 7.57 mL, 3.51 mmol) and the resulting mix-
ture was stirred at this temperature for 4 h. After adding a 1:1 solu-
0.5 H, CH=C), 5.57 (s, 1 H, O-CH-O), 5.88–6.01 (m, 1 H, tion of a saturated aqueous NaHCO3 Na2S2O3 (15 mL) the layers
CH=CH2), 6.87 (d, J = 8.7 Hz, 2 H, Ar-H), 7.43 (d, J = 8.7 Hz, 2 were separated. The aqueous phase was then extracted with
H, Ar-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 16.9, 17,4, 21.0, CH2Cl2 (3ϫ15 mL). The combined organic extracts were washed
21.6, 21.8, 33.9, 35.2, 36.7, 43.0, 43.2, 55.3, 60.3, 60.4, 79.5, 80.2,
82.3, 86.2, 101.5, 113.6, 113.7, 116.1, 116.2, 123.4, 123.5, 127.4,
127.6, 131.4, 132.0, 135.3, 136.3, 137.7, 150.8, 150.9 ppm. MS
with brine (20 mL), dried with MgSO4, and concentrated under
reduce pressure. The crude residue was purified by column
chromatography (5% EtOAc in petroleum ether) to give compound
(ESI): m/z (%) = 369.1 (100) [M + Na+], 715.2 (70) [2M + Na+]. 53 (1.10 g, 2.39 mmol, 88%) as a colourless oil. [α]2D2 = –13.6 (c =
HRMS (ESI): calcd. for C20H30O4Na 369.2042 [M + Na+]; found
369.2042.
1.00, CHCl ). IR (neat): ν = 3077, 2956, 2857, 1679, 1615, 1514,
˜
3
1249, 1093 cm–1. 1H NMR (300 MHz, CDCl3): δ = 0.04 (s, 6 H,
CH3-Si), 0.88 [s, 9 H, (CH3)3-Si], 1.11 (s, 3 H, CH3-C), 1.18 (s, 3
H, CH3-C), 2.09 (d, J = 1.1 Hz, 3 H, CH3-C=), 2.20–2.23 (m, 2 H,
CH2-CH=CH2), 2.33 (t, J = 6.5 Hz, 2 H, CH2-C=CH), 3.71–3.76
(m, 3 H, CH2-OSi and CH-O), 3.79 (s, 3 H, CH3-O), 4.39 (d, J =
10.6 Hz, 1 H, Ar-CH2-O), 4.55 (d, J = 10.6 Hz, 1 H, Ar-CH2-O),
5.02 (dd, J = 10.0, 1.0 Hz, 1 H, CH=CH2), 5.09 (dd, J = 17.0,
1.9 Hz, 1 H, CH=CH2), 5.91 (ddt, J = 17.0, 10.0, 7.3 Hz, 1 H,
CH=CH2), 6.36 (d, J = 1.1 Hz, 1 H, CH=C), 6.84 (d, J = 8.6 Hz,
2 H, Ar-H), 7.20 (d, J = 8.6 Hz, 2 H, Ar-H) ppm. 13C NMR
(75 MHz, CDCl3): δ = –5.3, 18.3, 19.8, 20.7, 21.3, 25.9, 36, 44.6,
52.3, 55.2, 61.3 (CH2, C1), 73.9, 83.7, 113.6, 116.6, 122.0, 129.1,
130.9, 136.5, 155.3, 159.0, 204.8 ppm. MS (CI): m/z (%) = 461 (25)
[M + H+], 121 (100) [+CH2PhOMe]. HRMS (CI): calcd. for
C27H45O4Si 461.3087 [M + H+]; found 461.3087.
Compound 51: To a solution of alcohol 50 (450 mg, 1.30 mmol),
acid 26 (381 mg, 1.56 mmol) and DMAP (48 mg, 0.39 mmol) in dry
CH2Cl2 (15 mL) was added in one portion at 0 °C, DCC (366 mg,
1.69 mmol) and the resulting mixture was slowly warmed to room
temp. and stirred for 6 h. The mixture was then concentrated under
reduce pressure, and Et2O was added to the residue. After being
stirred for 15 min, this mixture was filtered off through, and solvent
was then removed under reduce pressure. The crude residue was
purified by column chromatography (15% EtOAc in petroleum
ether) to give compound 51 (640 mg, 1.12 mmol, 86%) as a colour-
less oil; mixture of diastereomers. IR (neat): ν = 3077, 2931, 2852,
˜
1739, 1615, 1517, 1464, 1250, 1094 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 0.01 (s, 3 H, CH3-Si), 0.02 (s, 3 H, CH3-Si), 0.75 (s, 3
H, CH3-C), 0.87 [s, 9 H, (CH3)3-Si], 1.03 (s, 3 H, CH3-C), 1.13 (d,
J = 7.0 Hz, 3 H, CH3-CH) 1.74–1.78 (m, 3 H, CH3-C=), 2.25–2.52
(m, 5 H, O2C-CH-CH3, CH2-C = and CH2-CH=CH2), 3.46–3.56
(m, 1 H, CH-O), 3.79 (s, 3 H, CH3-O), 4.06–4.40 [m, 4 H, CH-OSi,
CH2-OC(O) and CH-O], 5.01–5.21 (m, 4 H, CH-CH=CH2 and
CH2-CH=CH2), 5.36 (d, J = 7.7 Hz, 1 H, CH=C), 5.56 (s, 1 H, O-
CH-O), 5.73–6.01 (m, 2 H, CH-CH=CH2 and CH2-CH=CH2),
6.87 (d, J = 8.7 Hz, 2 H, Ar-H), 7.37–7.44 (m, 2 H, Ar-H) ppm.
13C NMR (75 MHz, CDCl3): δ = –5.0, –4.2, 11.5, 11.8, 14.3, 17.1,
17.4, 18.2, 21.0, 21.6, 25.8, 33.9, 35.2, 36.9, 39.0, 39.1, 46.7, 46.8,
55.3, 62.5, 62.6, 74.9, 75.0, 79.4, 80.1, 82.2, 86.1, 95.0, 101.4, 113.6,
113.7, 115.6, 116.1, 116.2, 121.8, 123.8, 127.4, 127.6, 131.5, 132.0,
136.2, 136.3, 136.5, 139.4, 135.5, 159.8, 159.9, 174.3 ppm.
Compound 54: To a solution of compound 53 (1.10 g, 2.39 mmol)
in THF (20 mL) was added at room temp. TBAF (1  in THF,
2.87 mL, 2.87 mmol), and the resulting mixture was stirred at this
temperature for 1 h. The mixture was then concentrated under re-
duce pressure. The crude residue was purified by column
chromatography (25% EtOAc in petroleum ether) to give com-
pound 54 (687 mg, 1.98 mmol, 84% yield) as a colourless oil.
[α]2D2 = –10.1 (c = 0.87; CHCl ). IR (neat): ν = 3429, 3075, 2973,
˜
3
2868, 1699, 1614, 1514, 1248, 1036 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 1.12 (s, 3 H, CH3-C), 1.18 (s, 3 H, CH3-C), 2.09 (s, 3
H, CH3-C=), 2.24 (dd, J = 6.6, 7.0 Hz, 2 H, CH2-CH=CH2), 2.37
(t, J = 6.2 Hz, 2 H, CH2-C=CH), 3.67–3.73 (m, 3 H, CH2-OH and
CH-O), 3.79 (s, 3 H, CH3-O), 4.38 (d, J = 10.7 Hz, 1 H, Ar-CH2-
O), 4.57 (d, J = 10.7 Hz, 1 H, Ar-CH2-O), 5.03 (d, J = 10.1 Hz, 1
H, CH=CH2), 5.10 (d, J = 17.1 Hz, 1 H, CH=CH2), 5.90 (ddt, J
= 17.1, 10.1, 7.0 Hz, 1 H, CH=CH2), 6.39 (s, 1 H, CH=C), 6.85
(d, J = 8.5 Hz, 2 H, Ar-H), 7.21 (d, J = 8.5 Hz, 2 H, Ar-H) ppm.
13C NMR (75 MHz, CDCl3): δ = 19.5, 21.0, 21.2, 36.4, 44.3, 52.3,
55.3, 60.3, 73.8, 84.0, 113.7, 116.8, 122.7, 129.2, 130.8, 136.4, 154.1,
159.1, 205.2 ppm. MS (CI): m/z (%) = 347 (42) [M + H+], 121 (100)
[+CH2PhOMe]. HRMS (CI): calcd. for C21H31O4 347.2222 [M +
H+]; found 347.2222.
Compound 52: To a solution of compound 51 (500 mg, 0.87 mmol)
in THF (5 mL) was added at room temp. TBAF (1  in THF,
1.04 mL, 1.04 mmol), and the resulting mixture was stirred at this
temperature for 1 h. The mixture was then concentrated under re-
duce pressure. The crude residue was purified by column
chromatography (25% EtOAc in petroleum ether) to give com-
pound 52 (340 mg, 0.74 mmol, 85% yield) as a colourless oil; mix-
1
ture of diastereomers. H NMR (300 MHz, CDCl3): δ = 0.75 (s, 3
H, CH3-C), 1.03 (s, 3 H, CH3-C), 1.12 (d, J = 7.2 Hz, 3 H, CH3-
CH), 1.75–1.79 (m, 3 H, CH3-C=), 2.27 (dd, J = 6.6, 6.2 Hz, 2 H,
CH2-CH=CH2), 2.39 (t, J = 6.7 Hz, 2 H, CH2-C=), 2.53–2.63 (m,
1 H, O2C-CH-CH3), 3.53 (t, J = 6.1 Hz, 1 H, CH-O), 3.79 (s, 3 H,
CH3-O), 4.08–4.40 [m, 4 H, CH-O, CH2-OC(O) and CH-OH],
5.01–5.24 (m, 4 H, CH-CH=CH2 and CH2-CH=CH2), 5.36 (d, J
= 7.7 Hz, 1 H, CH=C), 5.56 (s, 1 H, O-CH-O), 5.68–6.00 (m, 2 H,
CH-CH=CH2 and CH2-CH=CH2), 6.86 (d, J = 8.7 Hz, 2 H, Ar-
H), 7.37–7.43 (m, 2 H, Ar-H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 10.9, 14.2, 17.2, 20.9, 21.6, 33.8, 35.2, 36.8, 39.0 (CH2, C7),
44.6, 55.3, 62.4, 62.8, 72.8, 73.0, 82.2, 86.1, 95.0, 101.5, 113.6,
116.0, 116.1, 116.3, 122.0, 123.8, 127.4, 127.6, 131.4, 131.9, 136.6,
136.5, 137.6, 159.7, 159.9, 175.1 ppm. MS (ESI): m/z (%) = 481.3
(100) [M + Na+]. HRMS (ESI): calcd. for C27H38O6Na 481.2566
[M + Na+]; found 481.2568.
Compound 55: To a solution of alcohol 54 (485 mg, 1.40 mmol),
acid 26 (1.68 mmol; 411 mg) and DMAP (51 mg, 0.42 mmol) in dry
CH2Cl2 (15 mL) was added in one portion at 0 °C, DCC (394 mg,
1.82 mmol) and the resulting mixture was slowly warmed to room
temp. and stirred for 6 h. The mixture was then concentrated under
reduce pressure, and Et2O was added to the residue. After being
stirred for 15 min, this mixture was filtered off through, and solvent
was then removed under reduce pressure. The crude residue was
purified by column chromatography (10% EtOAc in petroleum
ether) to give compound 55 (690 mg, 1.20 mmol, 86%) as a colour-
less oil; mixture of 7:3 diastereomers. IR (neat): ν = 3076, 2932,
˜
2857, 1739, 1679, 1614, 1515, 1464, 1250, 1079 cm–1. 1H NMR
(300 MHz, CDCl3): δ = 0.01 (s, 3 H, CH3-Si), 0.02 (s, 3 H, CH3-
Si), 0.87 [s, 9 H, (CH3)3-Si], 1.11–1.18 (m, 9 H, CH3-C and CH3-
CH), 1.93 (d, J = 1.1 Hz, 0.9 H, CH3-C=), 2.09 (d, J = 1.1 Hz, 2.1
H, CH3-C=), 2.17–2.29 (m, 2 H, CH2-CH=CH2), 2.41–2.52 (m, 2.7
Compound 53: To a solution of alcohol 48 (1.25 g, 2.70 mmol) in
dry CH2Cl2 (20 mL), was added dropwise at room temp., DMP
4084
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4075–4087

Stereocontrolled Synthesis of Aurisides by Ring-Closing Metathesis
H, O2C-CH-CH3 and CH2-C), 3.81 (q, J = 7.0 Hz, 0.3 H, O2C- 0.4 H, CH-CH=CH), 5.41 (d, J = 15.5 Hz, 0.6 H, CH-CH=CH),
CH-CH3), 3.69 (dd, J = 4.7, 7.5 Hz, 0.3 H, CH-O), 3.70 (dd, J = 5.57–5.70 (m, 1 H, CH=CH-CH2), 6.23 (s, 0.6 H, CH=C), 6.37 (s,
4.3, 7.5 Hz, 0.7 H, CH-O), 3.79 (s, 3 H, CH3-O), 4.09–4.25 [m, 2
H, CH-OSi and CH2-OC(O)], 4.31–4.39 [m, 2 H, CH2-OC(O) et
Ar-CH2-O], 4.56 (d, J = 10.7 Hz, 1 H, Ar-CH2-O), 5.02–5.25 (m,
0.4 H, CH=C), 6.91 (d, J = 8.7 Hz, 2 H, Ar-H.), 7.30 (d, J =
8.7 Hz, 2 H, Ar-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.4,
14.5, 16.6, 19.7, 24.1, 35.5, 36.7, 39.2, 47.5, 53.4, 55.3, 61.9, 62.7,
4 H, CH-CH=CH2 and CH2-CH=CH2), 5.72–5.97 (m, 2 H, CH- 72.1, 72.9, 73.1, 73.2, 81.5, 83.6, 113.7, 113.8, 122.4, 124.0, 129.2,
CH=CH2 and CH2-CH=CH2), 6.35 (d, J = 1.1 Hz, 0.7 H, CH=C),
6.40 (d, J = 1.1 Hz, 0.3 H, CH=C), 6.84 (d, J = 8.7 Hz, 2 H, Ar-
129.4, 129.6, 130.6, 132.1, 132.2, 153.6, 154.4, 159.1, 159.2, 174.2,
174.3, 203.0, 204.0 ppm. MS (CI): m/z (%) = 431 (35) [M + H+],
H), 7.19 (d, J = 8.7 Hz, 2 H, Ar-H) ppm. 13C NMR (75 MHz, 121 (100) [+CH2PhOMe]. HRMS (CI): calcd. for C25H37O6
CDCl3): δ = –5.1, –4.2, 11.7, 18.1, 19.4, 20.8, 21.1, 25.7, 36.4, 40.0, 431.2434 [M + H+]; found 431.2434.
46.7, 52.3, 55.2, 61.9, 73.9, 75.0, 83.8, 113.6, 115.6, 116.7, 122.4,
Compound 58: Compound 58 (69 mg, 0.265 mmol 32%) was iso-
129.1, 130.8, 136.4, 139.3, 153.1, 159.0, 174.1, 204.7 ppm. MS (CI):
lated from the purification of the previous reaction. 1H NMR
m/z (%) = 571 (50) [M – H+], 451 (100) [M – MeOPhCH2+], 121
(300 MHz, CDCl3): δ = 1.11 (s, 3 H, CH3-C), 1.17 (s, 3 H, CH3-
C), 2.45 (dddd, J = 19.0, 7.0, 3.4, 2.3 Hz, 1 H, CH2-CH=CH), 2.63
(ddd, J = 19.0, 4.7, 1.7 Hz, 1 H, CH2-CH=CH), 3.55 (dd, J = 7.0,
(21) [+CH2PhOMe]. HRMS (CI): calcd. for C33H53O6Si 573.3611
[M + H+]; found 573.3610.
Compound 56: To a solution of compound 55 (550 mg, 0.96 mmol)
in MeOH (10 mL), was added and at room temp., CSA (11 mg,
0.048 mmol) and the resulting mixture was stirred at this tempera-
ture for 8 h. After adding a saturated aqueous solution of NaHCO3
(5 mL) the layers were separated. The aqueous phase was then ex-
tracted with Et2O (3ϫ5 mL). The combined organic extracts were
washed with brine (10 mL), dried with MgSO4, and concentrated
under reduce pressure. The crude residue was purified by column
chromatography (20% EtOAc in petroleum ether) to give com-
pound 56 (406 mg, 0.88 mmol, 92%) as a colourless oil; mixture of
4.7 Hz, 1 H, CH-O), 3.81 (s, 3 H, CH3-O), 4.44 (d, J = 11.5 Hz, 1
H, Ar-CH2-O), 4.54 (d, J = 11.5 Hz, 1 H, Ar-CH2-O), 5.96 (dt, J =
10.0, 2.0 Hz, 1 H, CH2-CH=CH), 6.73 (ddd, J = 10.0, 4.6, 3.4 Hz, 1
H, CH=CH), 6.87 (d, J = 8.9 Hz, 2 H, Ar-H), 7.24 (d, J = 8.9 Hz,
2 H, Ar-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 18.9, 21.6, 28.6,
48.0, 55.4, 71.7, 80.7, 113.8, 128.7, 129.3, 130.5, 144.5, 159.3,
203.7 ppm.
Compound 60: To a solution of compound 57 (190 mg, 0.441 mmol)
in dry CH2Cl2 (10 mL), in the presence of 4 Å molecular sieves,
was added and at 0 °C, VO(acac)2 (11.8 mg, 0.044 mmol) and the
resulting mixture was then stirred at 0 °C for 15 min. Then
tBuOOH (5.5  in decane, 0.12 mL, 0.662 mmol) was slowly added
to the solution at 0 °C, and the resulting mixture was stirred at this
temperature for 4 h. The mixture was then filtered through a short
pad of celite, a solution of saturated aqueous NaHCO3 (5 mL) was
added. After separation of the layers, the aqueous phase was ex-
tracted with CH2Cl2 (3ϫ5 mL). The combined organic extracts
were washed with brine (10 mL), dried with MgSO4, and concen-
trated under reduce pressure. The crude residue was then directly
oxidized with Dess Martin periodinane (repeated procedure of
compound 53). The crude product was purified by column
chromatography (20% EtOAc in petroleum ether) to give com-
pound 60 (114 mg, 0.256 mmol, 67% for the two steps) as a colour-
less oil; mixture of 3:2 diastereomers. 1H NMR (300 MHz, CDCl3):
δ = 1.08 (s, 3 H, CH3-C), 1.24 (s, 3 H, CH3-C), 1.28 (d, J = 7.0 Hz,
1.8 H, CH3-CH), 1.34 (d, J = 7.0 Hz, 1.2 H, CH3-CH), 1.75–1.91
(m, 2 H, CH2-CH-O), 2.09 (d, J = 0.9 Hz, 1.8 H, CH3-C=), 2.17
(s, 1.2 H, CH3-C=), 2.40–2.63 (m, 3 H, CH2-C = and CH2-CH-O),
3.17–3.19 [m, 1 H, (O)C-CH-O], 3.56 (q, J = 7.0 Hz, 0.4 H, CH-
CH3), 3.57 (q, J = 7.0 Hz, 0.6 H, CH-CH3), 3.74–3.82 (m, 4 H,
CH-OPMB et CH3-O), 4.18–4.41 [m, 2 H, CH2-OC(O)], 4.51 (d, J
= 11.5 Hz, 1.2 H, Ar-CH2-O), 4.64 (d, J = 11.5 Hz, 0.8 H, Ar-CH2-
O), 6.42 (s, 0.6 H, CH=C), 6.46 (s, 0.4 H, CH=C), 6.90 (d, J =
8.5 Hz, 2 H, Ar-H), 7.30 (d, J = 8.5 Hz, 2 H, Ar-H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 12.3, 12.8, 17.2, 18.3, 23.7, 35.2, 39.1,
40.3, 46.0, 53, 55.4, 57.0, 58.4, 58.8, 59.6, 62.2, 72.7, 74.5, 80.9,
81.0, 113.9, 114.0, 120.5, 123.3, 129.5, 129.6, 130.0, 130.1, 154.9,
159.4, 159.5, 169.5, 170.0, 201.6, 202.8 ppm. MS (CI): m/z (%) =
445 (100) [M + H+], 121 (46) [+CH2PhOMe], 427 (32) [M – H20].
HRMS (CI): calcd. for C25H33O7 445.2226 [M + H+]; found
445.2225.
3:2 diastereomers. IR (neat): ν = 3501, 3071, 2937, 1731, 1679,
˜
1615, 1515, 1248, 1032 cm–1. 1H NMR (300 MHz, CDCl3): δ =
1.11–1.17 (m, 9 H, CH3-C and CH3-CH), 1.93 (d, J = 1.3 Hz, 1.2
H, CH3-C=), 2.08 (d, J = 1.1 Hz, 1.8 H, CH3-C=), 2.24 (dd, J =
7.4, 7.8 Hz, 2 H, CH2-CH=CH2), 2.45 (t, J = 6.7 Hz, 1.2 H, CH2-
C=CH), 2.53–2.64 (m, 0.8 H, CH2-C=CH), 2.73–2.90 (m, 1 H, CH-
CH3), 3.69 (dd, J = 4.7, 7.2 Hz, 1 H, CH-O), 3.79 (s, 3 H, CH3-
O), 4.23 [t, J = 6.7 Hz, 2 H, CH2-OC(O)], 4.35–4.40 (m, 2 H, CH-
OH et Ar-CH2-O), 4.56 (d, J = 10.7 Hz, 1 H, Ar-CH2-O), 5.03 (d,
J = 10.0 Hz, 1 H, CH2-CH=CH2), 5.10 (d, J = 16.4 Hz, 1 H, CH2-
CH=CH2), 5.18 (d, J = 10.5 Hz, 0.4 H, CH-CH=CH2), 5.20 (dd,
J = 10.5, 1.5 Hz, 0.6 H, CH-CH=CH2), 5.30 (dd, J = 15.6, 1.5 Hz,
0.6 H, CH-CH=CH2), 5.31 (dd, J = 15.6, 1.5 Hz, 0.4 H, CH-
CH=CH2), 5.75–5.97 (m, 2 H, CH2-CH=CH2 and CH-CH=CH2),
6.35 (d, J = 1.1 Hz, 0.6 H, CH=C), 6.42 (s, 0.4 H, CH=C), 6.84
(d, J = 8.6 Hz, 2 H, Ar-H), 7.19 (d, J = 8.6 Hz, 2 H, Ar-H) ppm.
13C NMR (75 MHz, CDCl3): δ = 11.1, 11.2, 19.3, 20.8, 20.9, 21.0,
36.3, 39.9, 44.7, 51.1, 51.2, 55.1, 62.0, 63.1, 72.9, 73.0, 73.6, 73.9,
83.6, 83.7, 113.6, 116.0, 116.1, 116.6, 116.7, 122.6, 123.1, 129.1,
130.7, 136.3, 137.6, 152.8, 153.9, 159.0, 174.8, 175.0, 204.4,
204.8 ppm. MS (CI): m/z (%) = 459 (16) [M + H+], 121 (100)
[+CH2PhOMe], 337 (39) [M – MeOPhCH2+], 457 (25) [M – H+].
HRMS (CI): calcd. for C27H39O6 459.2747 [M + H+]; found
459.2747.
Compound 57: To a solution of diene 56 (380 mg, 0.829 mmol) in
dry CH2Cl2 (160 mL) was added in one portion Grubbs catalyst
13 (17.6 mg, 0.027 mmol). Nitrogen was then bubbled through the
solution for 15 min, and the mixture was refluxed for 1 h. After
cooling at room temp., the mixture was concentrated under reduce
pressure. The crude residue was purified by column chromatog-
raphy (25% EtOAc in petroleum ether) to give compound 57
(239 mg, 0.555 mmol, 67%) as a colourless oil; mixture of 3:2 dia-
1
stereomers. H NMR (CDCl3): δ = 1.08–1.27 (m, 9 H, CH3-C and Compound 61: To a solution of (PhSe)2 (140 mg, 0.450 mmol) in
CH3-CH), 1.93 (d, J = 1.3 Hz, 1.2 H, CH3-C=), 2.08 (d, J = 1.1 Hz, EtOH (2 mL) was added at 0 °C NaBH4 (26 mg, 0.675 mmol), and
1.8 H, CH3-C=), 2.18–2.65 (m, 5 H, CH2-CH=CH2, CH2-C=CH,
the resulting mixture was stirred at 0 °C for 10 min. Then a solution
CH-CH3), 3.51–3.62 (m, 1 H, CH-O), 3.81 (s, 1.2 H, CH3-O), 3.82 of epoxyketone 60 (100 mg, 0.225 mmol) in EtOH (1 mL) was
(s, 1.8 H, CH3-O), 3.96–4.26 [m, 2 H, CH-OH and CH2-OC(O)],
4.37–4.65 [m, 3 H, CH2-OC(O) et Ar-CH2-O], 5.38 (d, J = 15.2 Hz,
slowly added to the solution at 0 °C, and the mixture was stirred
at this temperature for 15 min. A solution of saturated aqueous
Eur. J. Org. Chem. 2010, 4075–4087
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4085

E. Bourcet, F. Fache, O. Piva
FULL PAPER
NH4Cl (3 mL) was then added. The aqueous phase was separated,
and extracted with EtOAc (4ϫ4 mL). The combined organics ex-
tracts were washed with brine (5 mL), then dried with magnesium
sulfate, and concentrated under reduce pressure. The crude residue
was purified by column chromatography (35% EtOAc in petroleum
ether) to give compound 61 (87 mg, 0.196 mmol, 87%) as a colour-
less oil; mixture of 1.2:1 diastereomers. 1H NMR (300 MHz,
CDCl3): δ = 1.09 (s, 1.35 H, CH3-C), 1.14 (s, 1.65 H, CH3-C), 1.22
(s, 1.65 H, CH3-C), 1.25 (s, 1.35 H, CH3-C), 1.29 (d, J = 7.1 Hz,
1.35 H, CH3-CH), 1.30 (d, J = 7.1 Hz, 1.65 H, CH3-CH), 1.49–
1.79 (m, 3 H, CH2-CH-O and -OH), 2.11 (s, 1.35 H, CH3-C=), 2.17
(s, 1.65 H, CH3-C=), 2.44–2.65 [m, 2.55 H, (O)C-CH2-CH and
CH2-C=], 2.89 [dd, J = 17.9, 4.5 Hz, 0.45 H, (O)C-CH2-CH], 3.49
(q, J = 7.1 Hz, 0.45 H, CH-CH3), 3.50 (q, J = 7.1 Hz, 0.55 H, CH-
CH3), 3.58 (dd, J = 8.1, 2.4 Hz, 0.55 H, CH-OPMB), 3.68 (dd, J
= 9.8, 1.7 Hz, 0.45 H, CH-OPMB), 3.81 (s, 1.35 H, CH3-O), 3.82
(s, 1.65 H, CH3-O), 3.94–4.18 [m, 1.45 H, CH-OH and CH2-
OC(O)], 4.25 [ddd, J = 11.7, 8.1, 3.6 Hz, 0.45 H, CH2-OC(O)], 4.51
[ddd, J = 10.4, 6.0, 3.0 Hz, 0.55 H, CH2-OC(O)], 4.58–4.74 [m, 2.55
H, CH2-OC(O) and Ar-CH2-O], 6.30 (s, 0.45 H, CH=C), 6.42 (d,
J = 1.0 Hz, 0.55 H, CH=C), 6.90 (d, J = 8.6 Hz, 2 H, Ar-H), 7.30
(d, J = 8.6 Hz, 2 H, Ar-H) ppm. 13C NMR (75 MHz, CDCl3): δ =
12.3, 12.6, 18.0, 18.5, 24.0, 24.4, 39.6, 39.9, 40.2, 47.4, 49.4, 52.6,
53.3, 53.8, 54.1,55.3, 55.4, 61.9, 62.1, 66.0, 66.7, 74.4, 75.1, 81.7,
81.9, 114.0, 114.1, 122.1, 122.8, 129.5, 129.7, 130.1, 130.4, 155.1,
155.3, 159.5, 170.0, 170.1, 202.5, 203.0, 205.8, 205.9 ppm. MS (CI):
m/z (%) = 121 (100) [+CH2PhOMe], 429 (18) [MH+ – H2O], 446
(8) [M – H+]. HRMS (CI): calcd. for C25H35O7 447.2383 [M + H+];
found 447.2383.
6.90 (d, J = 8.7 Hz, 2 H, Ar-H), 7.42 (d, J = 8.7 Hz, 2 H, Ar-H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 13.6, 16.6, 17.3, 23.9, 31.4,
39.3, 48.8, 51.3, 51.4, 55.5, 63.0, 73.6, 81.4, 101.9, 113.8, 123.4,
127.6, 130.9, 152.2, 160.6, 170.2, 203.0, 204.4 ppm.
Compound 63: Compound 63 (8 mg, 0.018 mmol, 20%) was iso-
lated from the purification of the previous reaction; mixture of 7:3
diastereomers. 1H NMR (300 MHz, CDCl3): δ = 1.14–1.26 (m, 6.9
H, CH3-C and CH3-CH), 1.28 (d, J = 7.0 Hz, 2.1 H, CH3-CH),
1.47–1.61 (m, 2 H, CH-CH2-CH), 2.15 (s, 2.1 H, CH3-C=), 2.23 (s,
0.9 H, CH3-C=), 2.42–2.76 (m, 2 H, CH2-CH2), 2.82–3.13 [m, 2 H,
CH2-C(O)], 3.39 (q, J = 7.1 Hz, 0.3 H, CH-CH3), 3.76 (q, J =
7.0 Hz, 0.7 H, CH-CH3), 3.88 (s, 3 H, CH3-O), 3.93–4.01 (m, 1 H,
CH-OH), 4.14 (td, J = 4.0, 11.4 Hz, 0.7 H, CH2-O), 4.31–4.54 (m,
0.6 H, CH2-O), 4.61 (dt, J = 11.4, 2.1 Hz, 0.7 H, CH2-O), 5.39 (d,
J = 10.4 Hz, 0.7 H, CH-O), 5.47 (d, J = 10.7 Hz, 0.3 H, CH-O),
5.96 (s, 0.3 H, CH=C), 6.45 (s, 0.7 H, CH=C), 6.95 (d, J = 9.0 Hz,
2 H, Ar-H), 8.01 (d, J = 9.0 Hz, 1.4 H, Ar-H), 8.01 (d, J = 8.9 Hz,
0.6 H, Ar-H) ppm. MS (ESI): m/z (%) = 483.2 (100) [M + Na+],
942.9 (50) [2M + Na+]. HRMS (ESI): calcd. for C25H32O8Na
483.1995 [M + Na+]; found 483,1995.
Compound 64: To a solution of compound 62b (5.0 mg, 11.25 µmol)
in MeOH (1 mL) was added at room temp. CSA (0.1 mg,
0.56 µmol), and the resulting mixture was then stirred at this tem-
perature for 3 h. The reaction was then quenched by adding a solu-
tion of NaHCO3 (1 mL) and Et2O (1 mL) was also added. After
separation of the layers, the aqueous phase was extracted with Et2O
(3ϫ1 mL). The combined organic extracts were washed with brine
(2 mL), dried with MgSO4, and concentrated under reduce pres-
sure. The crude residue was purified by column chromatography
(15% EtOAc in petroleum ether) to give compound 64 (6.52 µmol;
2.1 mg, 58%) as a colourless oil. 1H NMR (500 MHz, CDCl3): δ
= 1.05–1.15 (m, 4 H, CH3-C and CH-CH2-CH), 1.33 (s, 3 H, CH3-
C), 1.35 (d, J = 7.3 Hz, 3 H, CH3-CH), 1.97–2.05 (m, 4 H, CH3-C
= and CH-CH2-CH), 2.26 (td, J = 14.4, 3.9 Hz, 1 H, CH2-CH2),
2.67 (ddd, J = 14.4, 10.5, 4.6 Hz, 1 H, CH2-CH2), 3.15 (q, J =
7.3 Hz, 1 H, CH-CH3), 3.32 (s, 3 H, CH3-O), 3.69 (ddd, J = 5.5,
3.6, 2.1 Hz, 1 H, CH-OMe), 3.82 (dd, J = 12.9, 2.0 Hz, 1 H, CH-
O), 4.11 (td, J = 10.7, 3.6 Hz, 1 H, CH2-O), 4.52 (dt, J = 11.1,
4.6 Hz, 1 H, CH2-O), 4.94 (d, J = 5.5 Hz, 1 H, CH-CH=C), 6.33
(s, 1 H, C-CH=C) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.7,
18.2, 20.1, 22.7, 27.7, 39.6, 44.9, 50.1, 55.3, 61.2, 69.1, 77.2, 96.6,
126.0, 148.3, 156.3, 175.0, 203.6 ppm. MS (ESI): m/z (%) = 345.2
(100) [M + Na+], 291.1 (86) [MH+ – MeOH]+. HRMS (ESI): calcd.
for C18H26O5Na 345.1678 [M + Na+]; found 345.1679.
Compound 62a: To a solution of alcohol 61 (40 mg, 0.090 mmol) in
CH2Cl2/H2O (4.5:1 mL) was added and at room temp., DDQ
(540 mg, 2.38 mmol) and the resulting mixture was then stirred at
this temperature for 3 h. The reaction was then quenched by adding
a solution of NaHCO3 (3 mL). After separation of the layers, the
aqueous phase was extracted with CH2Cl2 (3ϫ5 mL). The com-
bined organic extracts were washed with brine (5 mL), dried with
MgSO4, and concentrated under reduce pressure. The crude residue
was purified by column chromatography (25% EtOAc in petroleum
ether) to give compound 62a (15 mg, 0.034 mmol, 38%) as a
colourless oil. 1H NMR (500 MHz, CDCl3): δ = 1.10 (s, 3 H, CH3-
C), 1.22–1.23 (m, 4 H, CH-CH2-CH and CH3-C), 1.25 (d, J =
7.4 Hz, 3 H, CH3-CH), 1.56–1.62 (m, 1 H, CH-CH2-CH), 2.10 (s,
3 H, CH3-C=), 2.29 (dd, J = 12.1, 2.6 Hz, 1 H, CH2-CH2), 2.35–
2.57 [m, 2 H, CH2-C(O)], 3.19 (dd, J = 12.1, 5.3 Hz, 1 H, CH2-
CH2), 3.60 (dd, J = 8.3, 5.9 Hz, 1 H, C-CH-O), 3.83 (s, 3 H, CH3-
O), 4.07–4.21 (m, 3 H, CH-CH3, CH2-CH-O and CH2-O), 4.43 (td,
J = 11.5, 3.0 Hz, 1 H, CH2-O), 5.41 (s, 1 H, O-CH-O), 6.76 (s, 1
H, CH=C), 6.92 (d, J = 8.9 Hz, 2 H, Ar-H), 7.47 (d, J = 8.9 Hz, 2
H, Ar-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 13.1, 17.7, 22.1,
22.7, 29.7, 40.4, 46.8, 51.1, 53.6, 55.6, 62.1, 73.8, 82.1, 102.3, 114.0,
125.6, 128.0, 131.4, 152.7, 160.4, 171.1, 203.3, 207.2 ppm. MS
(ESI): m/z (%) = 467.2 (100) [M + Na+]; 429 (23) [2M + Na+].
HRMS (ESI): calcd. for C25H32O7Na 467.2046 [M + Na+]; found
467.2046.
Compound 65: The same procedure as for compound 62b, was ap-
plied to compound 62a (12.0 mg, 26.99 µmol) with stirring for
1.5 h. The crude product was purified by column chromatography
(25% EtOAc in petroleum ether) to give compound 65 (6.2 mg,
18.36 µmol, 64%) as a colourless oil. 1H NMR (500 MHz, CDCl3):
δ = 1.03–1.08 (m, 4 H, CH3-C and CH-CH2-CH), 1.10 (d, J =
7.4 Hz, 3 H, CH3-CH), 1.50 (s, 3 H, CH3-C), 1.76–1.87 (m, 2 H,
C-CH2-CH and CH-CH2-CH), 2.03 (d, J = 1.1 Hz, 3 H, CH3-C=),
2.10–2.15 (m, 1 H, C-CH2-CH), 2.21 (td, J = 12.9, 2.4 Hz, 1 H,
CH2-CH2), 2.49 (dt, J = 12.9, 4.0 Hz, 1 H, CH2-CH2), 2.98 (q, J
= 7.4 Hz, 1 H, CH-CH3), 3.28 (s, 3 H, CH3-O), 3.67 (dd, J = 12.2,
Compound 62b: Compound 62b (8 mg, 0.018 mmol, 20%) was iso-
lated from the purification of the previous reaction. 1H NMR
(500 MHz, CDCl3): δ = 1.16 (s, 3 H, CH3-C), 1.25 (s, 3 H, CH3- 1.9 Hz, 1 H, CH-O), 3.78 (ddd, J = 11.2, 4.3, 3.0 Hz, 1 H, CH2-
C), 1.35 (d, J = 7.1 Hz, 3 H, CH3-CH), 1.43–1.50 (m, 2 H, CH-
CH2-CH), 1.99 (d, J = 1.0 Hz, 3 H, CH3-C=), 2.46–2.55 [m, 3 H,
O), 4.04–4.08 (m, 1 H, CH-OH), 4.90 (ddd, J = 13.4, 11.2, 2.3 Hz,
1 H, CH2-O), 6.46 (s, 1 H, CH=C) ppm. 13C NMR (75 MHz,
CH2-C(O) and CH2-CH2], 3.10 (dd, J = 11.7, 3.8 Hz, 1 H, CH2- CDCl3): δ = 12.1, 18.7, 21.4, 24.0, 32.3, 32.4, 40.8, 43.8, 47.3, 49.9,
CH2), 3.76 (q, J = 7.1 Hz, 1 H, CH-CH3), 3.83 (s, 3 H, CH3-O), 60.2, 64.0, 72.9, 102.4, 127.1, 148.4, 173.5, 203.6 ppm. MS (ESI):
3.98 (dd, J = 9.8, 3.4 Hz, 1 H, C-CH-O), 4.16–4.41 (m, 3 H, CH2- m/z (%) = 363.2 (100) [M + Na+]. HRMS (ESI): calcd. for
CH-O and CH2-O), 5.64 (s, 1 H, O-CH-O), 6.33 (s, 1 H, CH=C),
C18H26O5Na 363.1784 [M + Na+]; found 363.1784.
4086
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Eur. J. Org. Chem. 2010, 4075–4087

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Received: March 10, 2010
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Published Online: June 2, 2010
Eur. J. Org. Chem. 2010, 4075–4087
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4087