Synthesis of the macrolactone structure of the aurisides

Article abstract of DOI:10.1016/j.tet.2009.12.008

The core structure of the aurisides has been reached by the coupling of three subunits including as key step a cross-metathesis/hydrogenation/ketalisation sequence, the addition of a vinyl lithium derivative onto an aldehyde and finally a lactonization un

Full text of DOI:10.1016/j.tet.2009.12.008

Tetrahedron 66 (2010) 1319–1326
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of the macrolactone structure of the aurisides
,
,
,b,
Emmanuel Bourcet a b, Fabienne Fache a b, Olivier Piva a
*
a Universite´ de Lyon 1; UMR 5246 CNRS; ICBMS (Institut de Chimie et de Biochimie Mole´culaire et Supramole´culaire); Bat. Raulin; 43,
Bd du 11 novembre 1918, 69622 Villeurbanne cedex, France
b
´
Universite de Lyon, 69622 Villeurbanne cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The core structure of the aurisides has been reached by the coupling of three subunits including as key
step a cross-metathesis/hydrogenation/ketalisation sequence, the addition of a vinyl lithium derivative
onto an aldehyde and finally a lactonization under Yamaguchi’s conditions.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 4 November 2009
Received in revised form 30 November 2009
Accepted 2 December 2009
Available online 6 December 2009
OH
1. Introduction
H3CO
=
OCH3
O
A large number of macrolides isolated from marine sources
possess a 2,6-disubstituted tetrahydropyran fragment included
within a 14-membered ring lactone. Most of them exhibit cytotoxic
activities; therefore many synthetic efforts have been made to con-
firm their structures, assign the relative and absolute configuration
of the stereocenters and to obtain enough materials for further bi-
ological studies. Aurisides A-B 1–21 and dolalastin 19 32 have been
isolated from Dolabella auricularia a sea hare living in Pacific Ocean.
These compounds possess promising and significant cytotoxic ac-
tivities against a large panel of cancer cells, for example, 1 presents
Rn
O
O
1
R1
H3CO
OCH3
O
5
O
O
OH
O
O
O
O
H2N
H3CO
O
O
Br
OCH3
2
R2 =
an IC50 value of 0.17 mm against HeLaS3 cells. Unfortunately, all these
O
compounds are produced in very small amounts, which could justify
the development of new strategies for their synthesis and those of
structural analogues. To date, two total syntheses of 1 have been
reported, respectively, by Paterson et al.3 and Kigoshi et al.,4 while
the synthesis of the aglycon structure has been recently devised by
Olivo and Tello-Aburto5 In all cases, a Yamaguchi et al. lactonization6
of an hydroxy acid was used to obtain the macrolide structure, while
the tetrahydropyran subunit was prepared by different strategies
including as key step enantioselective aldolisation, functionalization
of a dithiane prepared from (S)-pantolactone, or Meinwald con-
densation between the enolate of t-butyl acetate with a fully
substituted valerolactone (Fig. 1).
R3
O
O
OH
OH
H3CO
OCH3
O
O
OCH3
3
R3 =
Br
O
O
Figure 1.
aurisides A for which a metathesis reaction could be implicated in
the formation of the tetrahydropyran heterocycle.7,8 We first ex-
amined the synthesis of oxygenated six-membered ring structures
according to a strategy depicted on Scheme 1. It was anticipated
that such heterocycles could result from a tandem hydrogenation/
2. Results and discussion
As part of our interest for the synthesis of marine natural
products, we have investigated the synthesis of analogues of
ketalization of b-keto esters, readily prepared via a cross-metath-
esis between t-butyl 2-methyl-3-oxo-4-pentenoate 6 and an ap-
propriate homoallylic alcohol 7 (Scheme 2). According to previous
results in this field,3,4 the thermodynamic conditions used, should
* Corresponding author. Tel./fax: þ33 4 72 44 8136.
E-mail address: piva@univ-lyon1.fr (O. Piva).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.12.008

1320
E. Bourcet et al. / Tetrahedron 66 (2010) 1319–1326
Table 1
OH
R
3
7
7 (R)
9a
Products 10a
O
R
O
OMe
O
t-Bu-O
O
t-Bu-O
O
7a (C7H15
)
9a (82%)
10a (74%)
10b (86%)
t-Bu-O
O
C7H15
OMe
N
N
O
O
OH
Mes
Ph
Mes
Cl
Cl
+
Ru
PPh
O
t-Bu-O
R
7b (H)
9b (61%)
9c (81%)
9d (78%)
3
t-Bu-O
O
O
6
7
8
OMe
Scheme 1.
7c (i-Pr)
10c (71%)
10d (73%)
O
O
OH
t-Bu-O
O
1) LDA, THF, -78°C
2) acrolein, -78°C
OMe
O
O
O
4
5 (87%)
7d (c-Hex)
t-Bu-O
O
Dess-Martin
periodinane
O
O
O
OMe
CH2Cl2, 0°C -> rt
O
O
6 (92%)
10e (37%)
11e (42%)
t-Bu-O
O
Ph
Ph
OMe
O
Scheme 2.
7e (Ph)
9e (80%)
lead selectively to the formation of the more stabilized compound
for which the alkyl rests on centers 3 and 7 are cis while the
methoxy group placed in an axial position is stabilized by an
anomeric effect (Scheme 3).9
( )3
t-Bu-O
a
Isolated yields.
a competitive hydrogenolysis of the benzylic alcohol.13 With the
tertiary allylic alcohol 7f, the cross-metathesis gave the 1,2-di-
substituted alkene in a similar yield (Scheme 4). However, the re-
ductive ketalisation revealed problematic and instead of the
expected THP structure, the methoxy derivative 12f, resulting
probably from the trap by the solvent of the highly stabilized
benzylic carbocation, was formed.
O
O
t-Bu-O
O
O
8 (2.5%)
CH2Cl2, reflux
t-Bu-O
6
+
OH
HO
(E)-9
R
R
7
O
O
OH
Ph
Ph
6 (1 equiv.)
H2(1 atm.)
t-Bu-O
Pd/C
TsOH (cat.)
MeOH, rt, 2h
8 (2.5 mol.%)
CH2Cl2, reflux
Ph
O
R
HO
(0.1 équiv.)
OMe
O
Ph
9f (78%)
t-Bu-O
AcOEt, rt, 1h
7f
10
Scheme 3.
H2(1 atm.)
Pd/C
(0.1 équiv.)
Ester 6 was readily prepared by condensation of t-butyl
propionate 4 with acrolein 5,10 followed by oxidation of the
corresponding alcohol into the corresponding ketone with Dess–
Martin periodinane11 or under palladium catalyzed aerobic
conditions.12 The cross-metathesis of 6 was first tested with
alcohol 7a (R¼C7H15). When heated under reflux in the presence
of a catalytic amount of Grubbs type II catalyst 8, a 1:1 solution of
6 and 7a in methylene chloride delivered the cross adduct 9a as
a single E isomerdattributed by NMR thanks to the coupling
constant between the two olefinic protons (J¼15.5 Hz)dand in
81% yield (Scheme 3). Compound 9a was further reduced by
hydrogenation in methanol and placed under acidic conditions.
By this way, ester 10a was isolated as a 1:1 mixture of two
diastereomers, which differs only by the relative configuration on
O
O
OMe
TsOH (cat.)
MeOH, rt, 2h
t-Bu-O
Ph
Ph
AcOEt, rt, 1h
12f (51%)
Scheme 4.
Having in hand a straightforward method to 2-methoxyte-
trahydropyrans 10, we decided to apply it to the synthesis of
a truncated core structure of the aurisides depicted in colour on
Scheme 5. The strategy required the synthesis of the three building
blocks A, B, C.
The tetrahydropyran could result from the method described
above. Functionalization by addition of a vinyl lithium derivative
onto an aldehyde14 could deliver the precursor of the 14-membered
ring, which could be achieved according to a macrolactonisation
under Yamaguchi’s conditions. While cleavage of t-butyl esters
required usually acidic conditions,15 which are not compatible with
the presence of a ketal group, we turned to a methyl ester, which
could be more easily deprotected under basic conditions. Con-
densation of methyl propionate 13 with acrolein delivered the
the
a carbon atom. This short access to 2-methoxytetrahy-
dropyrans was generalized to other homoallylic alcohols 7b–e
and results are summarized in Table 1. For all these alcohols, the
overall sequence took place and furnished the expected adducts
in convenient yields.
In the case of 7e, the hydrogenation gave the THP structure
along with another compound identified as 11e, which results from

E. Bourcet et al. / Tetrahedron 66 (2010) 1319–1326
1321
R
double bond, the ketal group of compound 22 was removed by
acidic treatment in methanol. The primary hydroxy group of the 2-
methoxytetrahydropyran thus obtained was directly oxidized un-
der Parrikh–Doering conditions17 delivering 23 as a 1:1 mixture of
epimers.
(E)-Iodoalkene 25 was prepared from 3-butyn-1-ol according
a two-step procedure initially described by Marshall and Eidam18
After transmetallation with t-BuLi at ꢀ95 ꢁC, the vinyl lithium de-
rivative was regioselectively added to the aldehyde group of 23
(Scheme 7).
O
O
cross-
metathesis
Yamaguchi's
macrocyclisation
OR
O
O
O
Addition of a vinyl lithium
derivative onto an aldehyde
/ oxidation
Br
I
a,b
O
R'O
TBSO
HO
25
O
OR
O
H
I
A
B
OR"
O
OMe
OMe
O
OMe
OMe
c
d
C
O
OH
O
OH
Scheme 5.
TBSO
HO
26
27
O
OH
O
a
O
3
7
O
O
OMe
OH
O
OMe
14 (62%)
f,g
13
e
O
O
OH
O
O
HO
OH OH
OH OTBS
OTBS
b
c
28
29
OHC
Scheme 7. Reagents and conditions: (a) Cp2ZrCl2, AlMe3, H2O, CH2Cl2, 0ꢁ to rt, 2.5 h,
then I2, Et2O, ꢀ20 ꢁC to rt, 2 h, 72%. (b) TBS-OTf, 2,6-lutidine, CH2Cl2, ꢀ78 ꢁC, quanti-
tatif. (c) t-BuLi, Et2O, ꢀ95 ꢁC, 1 h, then 23, Et2O, ꢀ95 ꢁC to ꢀ78 ꢁC, 2.5 h, 72%. (d) TBAF,
THF, 0 ꢁC to rt, 3 h, 66%. (e) NaOH (2 N), THF/MeOH (2/1), 45 ꢁC, 12 h. (f) 2,4,6-tri-
chlorobenzoyl chloride, Et3N, PhMe, rt, 2 h, then DMAP, PhMe, reflux, 3 h, 28% (two
steps). (g) Dess–martin periodinane, CH2Cl2, 0 ꢁC to rt, 3 h, 62%.
15
16
OH OTBS
O
O
d
e,f
The TBS ether 26 was conventionally deprotected by action of
TBAF while the methyl ester group was cleaved under basic condi-
tions. The resulting dihydroxyacid 28 was submitted to Yamaguchi’s
macrolactonization conditions under highly diluted conditions de-
livering the expected 14-membered ring. Without further purifica-
tion, the allylic alcohol was oxidized into enone 29, which possess
the core structure of the aurisides. NOE experiments carried out on
the macrolactone showed a strong correlation between the methoxy
group fixed on carbon 3 and the proton attached on carbon 7 and
confirmed by this way the relative configuration around the tetra-
hydropyran ring. Interestingly, 29 was isolated as a single di-
17
19
O
OH
O
O
g
14
19
+
O
20
O
astereomer showing that epimerization of center
2 occurred
O
O
O
probably during the ketalization step. Unfortunately, attribution of
the relative configuration cannot be unambiguously assigned.
j,k
h,i
O
OMe
O
O
H
O
O
3. Conclusion
22
23
Scheme 6. Reagents and conditions: (a) LDA, THF, ꢀ78 ꢁC then acrolein, ꢀ78 ꢁC, 62%.
(b) NaH, THF, 0 ꢁC, 1 h then TBS-Cl, 0 ꢁC to rt, 4 h, 94%. (c) PCC, CH2Cl2, rt, 4 h, 92%. (d)
Allylbromide, Zn powder, THF/NH4Cl (1/1), rt, 8 h, 91%. (e) TBAF, THF, rt, 1 h, 95%. (f)
In conclusion, we have reported the synthesis of 2-methoxy-
pyranes by a sequence including a cross-metathesis/a hydrogena-
tion and a ketalisation process, starting from readily available
secondary homoallylic alcohols. This sequence was successfully
incorporated into a multistep process to reach the core structure of
aurisides.
2,2-Dimethoxypropane, CSA, CH2Cl2, rt, 10 h, 86%. (g) Grubbs type II catalyst
8
(2.5 mol %), CH2Cl2, reflux, 80%. (h) Dess–Martin periodinane, CH2Cl2, rt, 4 h, 96%. (i) H2
(1 atm), PtO2 (10 mol %), AcOEt, rt, 1 h. (j) TsOH (cat.), MeOH, 40 ꢁC, 2 h. (k) SO3.pyr,
DMSO, Et3N, rt, 90% (two steps).
corresponding
b
-aldol 14 in 62%. In parallel, 19 was obtained from
4. Experimental
4.1. General
2,2-dimethyl propan-1,3-diol by a five-step sequence in 64% overall
yield (Scheme 6).
The cross-metathesis16 between 14 and 19 furnished the 1,2-
disubstituted alkene in 80% yield. After oxidation of the alcohol into
the corresponding ketone and subsequent hydrogenation of the
1H and 13C NMR spectra were recorded on a Bruker AM 300 MHz
NMR spectrometer, which provided all necessary data for the full

1322
E. Bourcet et al. / Tetrahedron 66 (2010) 1319–1326
assignment of each compound. Chemicals shifts were reported in
parts per million. High-resolution mass spectrometry (HRMS)
analyses were conducted using a ThermoFinigan-MAT 95 XL in-
strument. IR spectra were measured on a Perkin–Elmer Spectrum
One FTIR spectrometer. TLC analyses were performed on plates
(layer thickness 0.25 mm) and were visualized with UV light,
phosphomolybdic acid or p-anisaldehyde solution. Column chro-
mixture was stirred at room temperature for 4 h. A solution of
aqueous saturated NH4Cl (20 mL) was then added. The aqueous
phase was separated, and extracted with Et2O (3ꢂ20 mL). The
combined organics extracts were washed with brine (20 mL), then
dried over magnesium sulfate, filtered and then concentrated. Pu-
rification of the residue by flash chromatography on silica gel (10%
ethyl acetate–petroleum ether) afforded allylic alcohol 7.
matography was performed on silica gel (40–63 mm) using ethyl
acetate (EtOAc) and hexanes as eluents. When appropriate, solvents
and reagents were dried by distillation over appropriate drying
agent prior to use. Diethyl ether and tetrahydrofuran were distilled
from Na/benzophenone and used fresh. Dichloromethane was
distilled from CaH2.
4.2.3.1. 1-Undecen-4-ol (7a). Data were in accord with the lit.19
4.2.3.2. 2-Methyl-5-hexen-3-ol (7c). Data were in accord with
the lit.20
4.2.3.3. 1-Cyclohexyl-3-butenol (7d). Data were in accord with
4.2. Experimental procedures
the lit.20
4.2.1. tert-Butyl 3-hydroxy-2-methyl-4-pentenoate (5). A solution of
n-butyllithium in hexanes (1.5 M, 22.0 mL, 33.0 mmol) was added
to a solution of diisopropylamine (4.64 mL, 33.00 mmol) in THF
(150 mL) at ꢀ78 ꢁC, under nitrogen atmosphere. The resulting
mixture was stirred at ꢀ78 ꢁC for 1 h. tert-Butyl propionate
(4.51 mL, 30.0 mmol) was then slowly added at ꢀ78 ꢁC, and the
mixture held at this temperature for 1 h and 30 min. Then, acrolein
(3.00 mL, 45.00 mmol) was added in one portion, and the mixture
was stirred at ꢀ78 ꢁC for 10 min. The reaction mixture was then
quenched by adding aqueous HCl solution (1 M, 40 mL) at ꢀ78 ꢁC,
and then warmed to 23 ꢁC. The aqueous phase was separated,
extracted with ether (3ꢂ50 mL). The combined organics extracts
were washed with brine (40 mL), then dried over magnesium sul-
fate and filtered before concentration in vacuum. Purification of the
residue by flash chromatography on silica gel (10% ethyl acetate–
petroleum ether) afforded compound 5 as a 1:1 mixture of di-
astereomers as a colourless oil (4.86 g, 26.1 mmol; 87% yield). 1H
4.2.3.4. 1-Phenyl-3-butenol (7e). Data were in accord with the
lit.20
4.2.3.5. 1,1-Diphenyl-3-butenol (7f). Data were in accord with
the lit.21
4.2.4. General procedure for Cross-Metathesis reaction. Nitrogen
was bubbled through
a solution of compound 6 (184 mg,
1.00 mmol) and homoallylic alcohol 7 (3.00 mmol; 3 equiv) in
dichloromethane (5 mL) during 10 min. Then, Grubbs’ second
generation catalyst 8 (21.2 mg, 25.0 mmol) was added, and the
resulting mixture was heated to reflux, and stirred for 14 h. After
cooling to room temperature, the solution was concentrated. The
residue was then purified by flash chromatography on silica gel
(AcOEt/hexanes: 20/80) to give products 9.
4.2.4.1. t-Butyl 7-hydroxy-2-methyl-3-oxo-4-undecenoate (9a). Yield:
NMR (300 MHz, CDCl3):
d
1.13 (1.5H, d, J¼7.2 Hz), 1.16 (1.5H, d,
82% (268 mg, 0.82 mmol). A 1:1 Mixture of 2 diastereomers. 1H NMR
J¼7.3 Hz), 1.45 (4.5H, s), 1.46 (4.5H, s), 2.46 (0.5H, quint, J¼7.3 Hz),
2.52 (0.5H, dq, J¼4.0, 7.2 Hz), 2.83 (1H, br s, OH), 4.14 (0.5H, m), 4.35
(0.5H, m), 5.19 (0.5H, dd, J¼10.5, 1.5 Hz), 5.20 (0.5H, dd, J¼10.5,
1.5 Hz), 5.30 (0.5H, dt, J¼17.1, 1.5 Hz), 5.32 (0.5H, dt, J¼17.1, 1.5 Hz),
5.77–5.90 (1H, ddt, J¼17.1, 10.5, 6.2 Hz). 13C NMR (75 MHz, CDCl3):
(300 MHz, CDCl3):
d
0.88 (3H, t, J¼7.0 Hz), 1.25–1.29 (8H, m), 1.30 (3H, d,
J¼7.1 Hz), 1.43–1.51 (11H, m), 1.56–1.58 (3H, m), 2.27–2.48 (2H, m), 3.63
(1H, d, J¼7.1 Hz), 3.73–3.81 (1H, m), 6.29 (1H d, J¼15.1 Hz), 6.96 (1H, dt,
J¼15.1, 7.4 Hz). 13C NMR (75 MHz, CDCl3):
d 13.0, 14.2, 22.7 and 22.8, 25.7,
25.9, 28.0, 29.3, 29.4, 29.6, 29.8, 31.9, 32.0, 37.4, 37.6, 40.6, 52.1, 70.7 and
71.5, 81.8, 129.1 and 130.6, 144.9, 170.0, 195.3. IR (neat) nmax¼3445, 2929,
2857, 1732, 1693, 1628, 1456, 1369, 1252, 1154 cmꢀ1. MS (ESI): m/z¼349.1
(C19H34O4þNaþ, 88), 675.1 (2MþNaþ, 100).
d
11.5 and 13.9, 28.1, 45.4 and 45.9, 73.2 and 74.7, 81.0, 115.9, and
116.4, 137.7 and 138.3, 174.7 and 174.9. IR (neat) nmax¼3452, 3043,
2980, 2936, 1724, 1470, 1369, 1158 cmꢀ1. MS: (ESI) m/z¼209.3
(MþNaþ, 100).
4.2.4.2. t-Butyl 7-hydroxy-2-methyl-3-oxo-4-heptenoate (9b). Yield:
4.2.2. tert-Butyl 2-methyl-3-oxo-4-pentenoate (6). Dess–Martin
Periodinane (15% wt, 7.93 mL, 3.48 mmol) was added at room tem-
perature, under nitrogen atmosphere, to a solution of ester 5
(500 mg, 2.68 mmol) in dichloromethane (25 mL). The resulting
mixture was stirred at room temperature for 8 h. A 1:1 solution of
saturated aqueous NaHCO3 and Na2S2O3 (10 mL) was then added.
The aqueous phase was separated, and extracted with DCM
(3ꢂ10 mL). The combined organic extracts were washed with brine
(15 mL), then dried over magnesium sulfate, filtered and then con-
centrated. Purification of the residue by flash chromatography on
silica gel (5% ethyl acetate–petroleum ether) afforded compound 6 as
a colourless oil (455 mg, 2.47 mmol) d92% yield. 1H NMR (300 MHz,
61% (139 mg, 0.61 mmol). 1H NMR (300 MHz, CDCl3):
d 1.31 (3H,
d, J¼7.0 Hz), 1.43 (9H, s), 2.47–2.53 (2H, dq, J¼1.3, 6.3 Hz), 3.62 (1H, q,
J¼7.0 Hz), 3.76–3.79 (2H, m), 6.32 (1H, dt, J¼15.6, 1.3 Hz), 6.93 (1H, dt,
J¼15.6, 7.1 Hz). 13C NMR (75 MHz, CDCl3):
d 12.9, 27.9, 35.8, 51.9, 60.9,
81.8, 130.1, 145.1, 170.1, 195.5. IR (neat) nmax¼3449, 2980, 2934, 2879,
1732, 1690, 1624, 1456, 1369, 1251, 1155, 1047 cmꢀ1. MS: (ESI) m/z¼250.9
(C12H20O4þNaþ, 91), 478.9 (2MþNaþ, 100).
4.2.4.3. t-Butyl 2,8-dimethyl-7-hydroxy-3-oxo-4-nonenoate (9c). Yield:
1
81% (219 mg, 0.81 mmol). A 1:1 Mixture of 2 diastereomers. H NMR
(300 MHz, CDCl3):
d
0.94 (3H, d, J¼7.0 Hz), 0.95 (3H, d, J¼6.8 Hz), 1.32 (3H,
d, J¼7.1 Hz), 1.43 (9H, s), 1.64–1.78 (2H, m), 2.24–2.98 (2H, m), 3.53 (1H, dt,
J¼8.5, 4.3 Hz), 3.63 (1H, q, J¼7.1 Hz), 6.29 (0.5H dd, J¼15.7, 1.3 Hz), 6.30
(0.5H dd, J¼15.7, 1.5 Hz), 6.98 (1H, dt, J¼15.7, 7.3 Hz). 13C NMR (75 MHz,
CDCl3):
d
1.30 (3H, d, J¼7.0 Hz), 1.41 (9H, s), 3.67 (1H, q, J¼7.0 Hz, H2),
5.82 (1H, dd, J¼10.4, 1.2 Hz), 6.30 (1H, dd, J¼17.4, 1.2 Hz), 6.46 (1H,
dd, J¼17.4, 10.4 Hz). 13C NMR (75 MHz, CDCl3):
d
12.8, 28.0, 51.6, 81.9,
CDCl3): d 12.9, 13.0, 17.4, 17.8, 18.7, 18.8, 28.0, 33.5 and 33.8, 37.6, 51.8, 75.3
129.3, 134.7, 169.8, 195.8. IR (neat) nmax¼3045, 2981, 2939,1735,1701,
and 76.1, 81.7, 129.4 and 130.2, 145.9, 170.1, 195.4 and 195.5. IR
(neat) nmax¼3435, 2965, 2934, 1732, 1621, 1456, 1366, 1154 cmꢀ1. MS: (ESI)
m/z¼293.0 (C15H26O4þNaþ, 100), 563.0 (2MþNaþ, 67).
1624, 1576, 1458, 1369, 1251, 1153 cmꢀ1
.
4.2.3. General procedure for allylation of carbonyl compound. A 1 M
solution of allylmagnesium bromide in Et2O (7.50 mmol, 7.50 mL)
was added to a solution of aldehyde (5.00 mmol) in dry Et2O
(50 mL) at 0 ꢁC and under a nitrogen atmosphere. The resulting
4.2.4.4. t-Butyl 7-cyclohexyl-7-hydroxy-2-methyl-3-oxo-4-hepte-
noate (9d). Yield: 78% (242 mg, 0.78 mmol). A 1:1 Mixture of 2 di-
astereomers. 1H NMR (300 MHz, CDCl3):
d 1.00–1.28 (4H, m), 1.34

E. Bourcet et al. / Tetrahedron 66 (2010) 1319–1326
1323
(3H, d, J¼7.0 Hz), 1.45 (9H, s), 1.64–1.70 (6H, m), 1.77–1.85 (1H, m),
2.26–2.41 (1H, m), 2.44–2.52 (1H, m), 3.54 (1H, dt, J¼8.7, 4.6 Hz),
3.66 (1H, q, J¼7.0 Hz), 6.31 (1H d, J¼15.6 Hz), 7.00 (1H, dt, J¼15.6,
m). 13C NMR (75 MHz, CDCl3):
d
13.2, 18.5, 25.1, 28.1, 28.2, 45.7, 47.4,
61.7, 80.3, 99.8, 172.6. Diastereomer 2: 1H NMR (300 MHz, CDCl3):
d
1.04 (3H, d, J¼7.1 Hz), 1.45–1.48 (11H, m), 1.57 (2H, bd, J¼10.9 Hz),
1.66–1.75 (1H, m),1.94 (1H, dt, J¼12.7, 4.1 Hz), 2.78 (1H, q, J¼7.1 Hz),
3.17 (3H, s), 3.54–3.65 (2H, m). 13C NMR (75 MHz, CDCl3):
11.8,
7.5 Hz). 13C NMR (75 MHz, CDCl3):
d 12.9, 26.1, 26.2, 26.5, 27.9, 28.0,
28.4, 29.2, 37.6, 43.7, 52.2, 75.1, 81.7, 129.5, 130.3, 145.9, 170.1, 195.3,
d
195.4. IR (neat) nmax¼3419, 2978, 2926, 2852,1732,1634,1451 cmꢀ1
.
18.7, 25.2, 28.0, 28.2, 45.2, 47.1, 61.0, 80.2, 99.8, 173.3. MS: (ESI)
m/z¼267.0 (MþNaþ, 100), 511.0 (2 MþNaþ, 63). HRMS: (ESI): cal-
culated for C13H24O4þNa: 267.1572; found: 267.1575.
MS: (ESI) m/z¼333.1 (C18H30O4þNaþ, 91), 643.1 (2MþNaþ, 100).
4.2.4.5. t-Butyl
noate (9e). Yield: 80% (244 mg, 0.80 mmol). A 1:1 Mixture of 2
diastereomers. 1H NMR (300 MHz, CDCl3):
7-hydroxy-2-methyl-3-oxo-7-phenyl-4-hepte-
4.2.5.3. Ketal (10c). Reaction performed from 9c (210 mg,
d
1.29 (3H, d, J¼7.0 Hz),
0.78 mmol). Yield: 71%. A 1:1 Mixture of 2 diastereomers. 1H
1.42 (9H, s), 2.63–2.71 (2H, m), 3.60 (1H, q, J¼7.0 Hz), 4.85 (0.5H, t,
J¼7.1 Hz), 4.85 (0.5H, dd, J¼4.0, 7.3 Hz), 6.27 (0.5H dt, J¼15.5,
1.5 Hz), 6.28 (0.5H dt, J¼15.5, 1.5 Hz), 6.92 (1H, dt, J¼15.5, 7.4 Hz),
NMR (300 MHz, CDCl3):
d
0.84 (3H, d, J¼6.6 Hz), 0.86 (3H, d,
J¼6.6 Hz), 1.17 (3H, d, J¼7.1 Hz), 1.42–1.44 (4H, m), 1.46 (9H, s),
1.50–1.84 (3H, m), 2.46 (1H, q, J¼7.1 Hz), 3.49 (3H, s), 3.58 (1H,
7.29–7.35 (5H, m). 13C NMR (75 MHz, CDCl3):
d
12.9, 28.0, 42.3, 52.0,
ddd, J¼11.7, 6.6, 2.0 Hz). 13C NMR (75 MHz, CDCl3):
d 11.8 and
73.2, 81.8, 125.8, 128.1, 128.8, 130.7, 144.1, 146.6, 171.3, 195.4. IR
(neat) nmax¼3445, 3027, 2980, 2929, 1732, 1692, 1624, 1455, 1366,
1252, 1153, 1044 cmꢀ1. MS: (ESI) m/z¼327.0 (C18H24O4þNaþ, 100),
630.9 (2MþNaþ, 96).
13.2, 18.1 and 18.4, 18.6 and 18.7, 18.8and 18.9, 27.1 and 27.5, 27.7
and 28.0, 28.1 and 28.2, 33.1 and 33.4, 44.8 and 44.9, 47.0 and
47.3, 75.1and 75.7, 79.9 and 80.1, 100.1 and 100.2, 172.8 and 173.5.
IR (neat) nmax¼2930, 2859, 1730, 1459, 1367, 1157, 1036 cmꢀ1. MS:
(ESI) m/z¼309.1 (MþNaþ, 30), 295.1 ([MꢀMeOHþH2O]þNaþ,
100), 254.9 ([MꢀMeOH]þ, 84).
4.2.4.6. t-Butyl 7-hydroxy-2-methyl-3-oxo-7,7-diphenyl-4-hep-
tenoate (9f). Yield: 78% (297 mg, 0.78 mmol). 1H NMR (300 MHz,
CDCl3):
3.53 (1H, q, J¼7.2 Hz), 6.26 (1H, d, J¼15.8 Hz), 6.84 (1H, dt, J¼15.8,
7.2 Hz), 7.20–7.46 (10H, m). 13C NMR (75 MHz, CDCl3):
12.9, 27.9,
d
1.23 (3H, d, J¼7.2 Hz), 1.39 (9H, s), 3.22 (2H, d, J¼7.2 Hz),
4.2.5.4. Ketal (10d). Reaction performed with 9d (230 mg,
0.74 mmol). Yield: 73% (177 mg, 0.54 mmol). 1:1 Mixture of 2 di-
d
astereomers. 1H NMR (300 MHz, CDCl3):
d 0.90–1.04 (2H, m), 1.16
45.5, 51.6, 77.7, 81.6, 126.0, 127.1, 128.2, 131.8, 143.6, 146.6, 169.9,
195.3. IR (neat) nmax¼3500, 3065, 2979, 2928, 1733, 1692, 1627,
1448, 1152 cmꢀ1. MS: (ESI) m/z¼403.1 (C24H28O4þNaþ, 100), 783.1
(2 MþNaþ, 53).
(3H, d, J¼7.4 Hz), 1.42–1.44 (4H, m), 1.46 (9H, s), 1.52–1.87 (9H, m),
2.46 (1H, q, J¼7.4 Hz), 3.49 (3H, s), 3.62 (1H, ddd, J¼11.7, 6.8, 2.1 Hz).
13C NMR (75 MHz, CDCl3):
d 11.7 and 13.3,18.1 and 18.4,18.6 and 18.7,
18.9, 26.2, 26.3, 26.4, 26.5, 26.8, 27.3, 27.7, 27.8, 28.0, 28.1 and 28.2,
28.6, 28.7, 28.9, 29.0, 32.0, 43.1 and 43.3, 44.8 and 45.9, 47.0 and 47.3,
74.6 and 74.8, 79.9 and 80.2, 100.1 and 100.2, 172.9 and 173.6. IR
(neat) nmax¼2930, 2859,1730,1459,1367,1157,1036 cmꢀ1. MS: (ESI)
m/z¼349.1 (C19H34O4þNaþ, 15); 335.1 ([MꢀMeOHþH2O]þNaþ,
100), 295.0 ([MꢀMeOH]þ, 71), 646.9 (2[MꢀMeOHþH2O]þNaþ, 29).
4.2.5. General procedure for the sequence hydrogenation/ketaliza-
tion. Pd/C (10% wt, 0.1 equiv) was added to a solution of com-
pounds 9 (1 equiv) in EtOAc (0.1 M), which was deoxygenated by
bubbling through a stream of nitrogen for 10 min. The solution
was placed under Hydrogen (1 atm), and stirred for 1 h at room
temperature. After disappearance of the starting material (TLC
control), the mixture was filtered off through a pad of Celite, and
catalyst was rinsed with EtOAc. After evaporation of the solvent,
the residue was dissolved in methanol (0.1 M), and a catalytic
amount of p-toluenesulfonic acid (0.1 equiv) was added. The
resulting mixture was stirred for 2 h at room temperature, and
then partitioned between a saturated aqueous NaHCO3 solution
(5 mL) and ether (5 mL). The aqueous phase was separated, and
extracted with ether (3ꢂ10 mL). The combined organics extracts
were washed with brine (10 mL), dried over magnesium sulfate,
filtered and concentrated. Purification of the residue by flash
chromatography on silica gel (AcOEt/hexanes: 5/95) afforded ketal
10 as colourless oil.
4.2.5.5. Ketal (10e). Reaction performed from 9e (230 mg,
0.76 mmol). Yield: 37% (95 mg, 0.28 mmol). A 3:2 Mixture of 2 di-
astereomers. 1H NMR (300 MHz, CDCl3):
d
1.11 (1.2H, d, J¼7.1 Hz),
1.26 (1.8H, d, J¼7.1 Hz), 1.46 (3.6H, s), 1.48 (5.4H, s), 1.64–2.07 (6H,
m), 2.92 (0.4H, q, J¼7.1 Hz), 2.98 (0.6H, q, J¼7.1 Hz), 3.20 (1.2H, s),
3.32 (1.8H, s), 4.57 (0.6H, dd, J¼11.7, 2.3 Hz), 4.57 (0.4H, dd, J¼11.5,
2.3 Hz), 7.29–7.41 (5H, m). 13C NMR (75 MHz, CDCl3):
d 12.0 and
13.3, 19.1 and 19.3, 27.4 and 27.8, 28.1 and 28.2, 33.4 and 33.5, 45.0
and 45.2, 47.2 and 47.6, 72.8 and 73.0, 80.3, 100.8, 125.7 and 126.0,
127.2 and 127.5; 128.1 and 128.4, 143.3, 172.6 and 173.4. IR (neat)
nmax¼3063, 3024, 2975, 2942, 1727, 1453, 1367, 1219, 1154,
1031 cmꢀ1. MS: (ESI) m/z¼343.0 (MþNaþ, 100). HRMS: (ESI) cal-
culated for C19H28O4þNa: 343.1885; found: 343.1886.
4.2.5.1. Ketal (10a). Reaction performed from 9a (250 mg,
4.2.5.6. t-Butyl2-methyl-3-oxo-7-phenylheptanoate(11e). Reaction
performed from 9e (230 mg, 0.76 mmol). Yield: 42% (93 mg,
0.77 mmol). Yield: 74% (194 mg, 0.57 mmol). 1H NMR (300 MHz,
CDCl3):
d
0.88 (3H, t, J¼6.6 Hz), 1.04 (1.5H, d, J¼7.4 Hz), 1.14 (1.5H, d,
0.32 mmol). 1H NMR (300 MHz, CDCl3):
d
1.27 (3H, d, J¼7.1 Hz), 1.44
(9H, s), 1.62–1.64 (4H, m), 2.46–2.64 (4H, m), 3.37 (1H, q, J¼7.1 Hz),
7.15–7.32 (5H, m). 13C NMR (75 MHz, CDCl3):
12.8, 23.3, 28.0, 31.0,
J¼7.0 Hz), 1.23–1.36 (12H, m), 1.43–1.46 (11H, m), 1.58–1.91 (4H, m),
2.81 (0.5H, q, J¼7.4 Hz), 2.86 (0.5H, q, J¼7.0 Hz), 3.16 (1.5H, s), 3.26
d
(1.5H, s), 3.42–3.50 (1H, m). 13C NMR (75 MHz, CDCl3):
d
11.6, 13.3,
35.8, 41.2, 53.9, 81.7, 125.8, 128.4, 142.2, 169.8, 206.2.
14.2, 18.6 and 18.9, 22.8 and 25.5, 27.6 and 28.0, 28.1 and 28.2, 29.4,
29.5, 29.7, 29.8, 29.9, 30.7 and 31.0, 36.4 and 36.5, 44.7 and 45.9,
47.0 and 47.3, 70.6and 70.7, 79.8 and 80.1, 100.1, and 100.2, 172.8
and 173.5. IR (neat) nmax¼2930, 2859, 1730, 1459, 1367, 1157,
1036 cmꢀ1. MS: (ESI) m/z¼365.1 (MþNaþ, 100). HRMS: (ESI) cal-
culated for C20H38O4þNa 365.2668; found: 365.2667.
4.2.5.7. t-Butyl 7-methoxy-2-methyl-3-oxo-7,7-diphenyl hepta-
noate (12f). Reaction performed from 9f (290 mg, 0.76 mmol).
Yield: 51% (154 mg, 0.39 mmol). 1H NMR (300 MHz, CDCl3):
d 1.23
(3H, d, J¼7.2 Hz), 1.38–1.52 (11H, m), 2.24–2.30 (2H, m), 2.37–2.58
(2H, m), 3.06 (3H, s), 3.34 (1H, q, J¼7.2 Hz), 7.17–7.34 (10H, m). 13C
NMR (75 MHz, CDCl3):
d 12.8, 17.3, 28.0, 34.4, 41.3, 50.2, 53.9, 81.8,
4.2.5.2. Ketal (10b). Reaction performed from 9b (130 mg,
0.57 mmol). Yield: 86% (120 mg, 0.48 mmol). Diastereomer 1: 1H
82.3, 126.7, 127.0, 128.0, 169.9, 206.2. IR (neat) nmax¼3060, 3021,
2978, 2938, 2846, 1736, 1714, 1493, 1448, 1368, 1155, 1076,
700 cmꢀ1. MS: (ESI) m/z¼419.0 (MþNaþ, 100). HRMS: (ESI) Calcu-
lated for C25H32O4þNa: 419.2198; found: 419.2200.
NMR (300 MHz, CDCl3):
d
1.13 (3H, d, J¼7.1 Hz), 1.42–1.44 (11H, m),
1.50–1.78 (4H, m), 2.84 (1H, q, J¼7.1 Hz), 3.27 (3H, s), 3.54–3.60 (2H,

1324
E. Bourcet et al. / Tetrahedron 66 (2010) 1319–1326
4.2.6. Synthesis of the core structure of the aurisides. 4.2.6.1. Methyl
3-hydroxy-2-methyl-4-pentenoate (14). Ester 14 was prepared
according the procedure described for 5. Starting from methyl pro-
pionate (2.89 mL, 30.00 mmol) and acrolein (3.00 mL, 45.00 mmol),
ester 14 (2,68 g, 18.60 mmol) was isolated as a 1:1 mixture of
diastereomers in 62% yield. Data are in accord with the lit.22
5.15–5.20 (2H, m), 5.44 (1H, ddt, J¼17.3, 9.2, 7.1 Hz). 13C NMR
(75 MHz, CDCl3):
d 18.8, 22.9, 36.8, 38.3, 72.3, 78.0, 118.2, 136.0. IR
(neat) nmax¼3367, 3077, 2962, 2874, 1641, 1473, 1429, 1065, 1040,
912 cmꢀ1
.
4.2.6.6. 4-Allyl-2,2,5,5-tetramethyl-1,3-dioxane(19)26. Dimethoxy-
propane (9.03 mL, 72.81 mmol) and CSA (169 mg, 0.73 mmol) were
successively added at rt, under a nitrogen atmosphere, to a solution
of diol 18 (2.10 g, 14.56 mmol) in dry CH2Cl2 (70 mL). The resulting
mixture was stirred at rt for 18 h. The reaction mixture was then
quenched with a saturated aqueous solution of NaHCO3 (30 mL).
The aqueous phase was separated, extracted with CH2Cl2 (3ꢂ
30 mL). The combined organics extracts were washed with brine
(30 mL), then dried over magnesium sulfate, filtered and then
concentrated. Purification of the residue by flash chromatography
on silica gel (AcOEt/hexanes: 5/95) afforded compound 19 (2.31 g,
12.52 mmol) as a colourless oil. Yield¼86%. 1H NMR (300 MHz,
4.2.6.2. 3-(tert-Butyl dimethyl silanyloxy)-2,2-dimethyl propan-1-ol
(15)23. NaH (60% in oil, 1.60 g, 40.00 mmol) was added at 0 ꢁC in
small portions to
a solution of 2,2-dimethyl-1,3-propanediol
(4.16 g, 40.00 mmol) in THF (200 mL) under a nitrogen atmosphere.
The resulting mixture was stirred at this temperature for 1 h. A
solution of TBDMS-Cl (6.02 g, 40.00 mmol) in THF (20 mL) was
added at 0 ꢁC, and the mixture was allowed to warm to rt and
stirred at this temperature for 4 h. The reaction mixture was then
quenched by adding water (75 mL). The aqueous phase was sepa-
rated, extracted with ether (3ꢂ50 mL). The combined organics
extracts were washed with brine (70 mL), dried over magnesium
sulfate filtered and then concentrated under vacuum. Purification
of the residue by flash chromatography on silica (AcOEt/hexanes: 5/
95) afforded compound 15 (8.21 g, 37.60 mmol) as a colourless oil.
Yield: 94% yield. Data are in accord with the lit.23
CDCl3):
d 0.74 (3H, s), 1.03 (3H, s), 1.41 (6H, s), 2.02–2.22 (2H, m),
3.27 (1H, d, J¼11.4 Hz), 3.58 (1H, dd, J¼3.0, 9.2 Hz), 3.61 (1H, d,
J¼11.4 Hz), 4.99–5.11 (2H, m), 5.44 (1H, ddt, J¼17.3, 10.0, 7.4 Hz). 13C
NMR (75 MHz, CDCl3):
d 18.2, 18.9, 21.9, 29.7, 32.9 34.0, 72.1, 77.3,
98.7, 115.8, 136.3. IR (neat) nmax¼3077, 2989, 2959, 2859, 1642,
1466, 1378, 1264, 1197, 1105, 907 cmꢀ1
.
4.2.6.3. 3-(tert-Butyl dimethyl silanyloxy)-2,2-dimethyl propion-
aldehyde (16)23. PCC (12.14 g, 56.32 mmol) was added in one por-
tion to a solution of alcohol 15 (8.20 g, 37.54 mmol) in CH2Cl2
(150 mL) at rt and under a nitrogen atmosphere. The resulting
mixture was stirred at rt for 4 h. The solvent was removed under
vacuum, and the residue was dissolved in Et2O. The mixture was
stirred at rt for 15 min., and filtered through a pad of Celite. Evap-
oration of Et2O afforded compound 16 (7.47 g, 34.54 mmol) as
a colourless oil. Yield: 92%. This compound was used in the next
4.2.6.7. Methyl 3-hydroxy-2-methyl-6-(4-(2,2,5,5-tetramethyl)-
dioxolanyl)-4-hexenoate (20). Nitrogen was bubbled through a so-
lution of compound 19 (1.29 g, 7.00 mmol) and ester 14 (2.02 g,
14.00 mmol) in DCM (35 mL) for 10 min. After addition of Grubbs’
second generation catalyst 8 (149 mg, 175 mmol), the resulting
mixture was heated to reflux, and stirred for 14 h. After cooling to
room temperature, DCM was evaporated. Purification of the residue
by flash chromatography on silica gel (AcOEt/hexanes: 25/75)
afforded a colourless oil identified as compound 18 (1.68 g, 5.60
mmol) as an inseparable mixture of stereoisomers. Yield: 80%. 1H
step without further purification. 1H NMR (300 MHz, CDCl3):
d 0.03
(6H, s), 0.84 (9H, s), 1.01 (6H, s), 3.56 (2H, s), 9.54 (1H, s). 13C NMR
(75 MHz, CDCl3):
d
ꢀ3.5, 18.3, 18.6, 25.8, 48.2, 68.4, 206.3. IR (neat)
NMR (300 MHz, CDCl3): d 0.74 (3H, s), 1.02 (3H, s), 1.11–1.17 (3H, m),
nmax¼2957, 2931, 2858, 1733, 1473, 1258, 1104, 838 cmꢀ1
.
1.38 (3H, s), 1.39 (3H, s), 2.00–2.20 (2H, m), 2.47–2.66 (1H, m), 3.27
(1H, d, J¼11.5 Hz), 3.53–3.57 (1H, m), 3.60 (1H, d, J¼11.5 Hz), 3.71
(1.5H, s), 3.72 (1.5H, s), 4.13–4.20 (0.5H, m), 4.31–4.38 (0.5H, m),
5.42–5.46 (1H, m), 5.67–5.83 (1H, m). 13C NMR (75 MHz, CDCl3):
4.2.6.4. 1-(tert-Butyldimethylsilanyloxy)-2,2-dimethyl-5-hexen-3-ol
(17)24. Zinc powder (3.38 g, 51.65 mmol) and allylbromide
(4.49 mL, 51.65 mmol) were successively added at 0 ꢁC to a solution
of aldehyde 16 (7.45 g, 34.43 mmol) in a 1:1 mixture of THF and
saturated aqueous solution of NH4Cl (175 mL). The resulting mix-
ture was stirred at rt for 6 h. The reaction mixture was then
quenched by adding water (50 mL), and Et2O was also added
(50 mL). The aqueous phase was separated, extracted with ether
(3ꢂ50 mL). The combined organics extracts were washed with
brine (50 mL), then dried over magnesium sulfate, filtered and then
concentrated. Purification of the residue by flash chromatography
on silica gel (AcOEt/hexanes: 5/95) afforded compound 17 (8.10 g,
31.33 mmol) as a colourless oil. Yield: 91% yield. 1H NMR (300 MHz,
d
11.4, 11.6, 14.1, 14.2, 18.2, 18.9, 19.0, 21.9, 29.7, 32.3, 32.4, 32.5, 32.9,
33.0, 44.9, 45.0, 45.6, 51.9, 72.1, 73.0, 73.4, 74.7, 75.1, 76.9, 77.1, 77.2,
77.4, 98.7, 98.8, 130.4, 130.6, 130.7, 130.8, 131.3, 131.5, 131.6, 131.7,
175.7, 175.8, 176.1, 176.2. IR (neat) nmax¼3445, 2995, 2953, 2868,
1733, 1462, 1374, 1102 cmꢀ1. MS: (ESI) m/z¼323.1 (MþNaþ, 100).
HRMS (CI): Calculated for [C16H29O5þHþ]: 301.2005; found:
301.2007.
4.2.6.8. Methyl 2-methyl-3-oxo-6-(4-(2,2,5,5-tetramethyl)-dioxol-
anyl)-4-hexenoate (21). Dess Martin Periodinane (15% wt, 14.84 mL,
7.14 mmol) was added at room temperature, under nitrogen atmo-
sphere, to a solution of compound 20 (1.65 g, 5.49 mmol) in
dichloromethane (50 mL). The resulting mixture was stirred at room
temperature for 8 h. A 1:1 solution of saturated aqueous NaHCO3 and
Na2S2O3 (10 mL) was then added. The aqueous phase was separated,
and extracted with dichloromethane (3ꢂ10 mL). The combined or-
ganics extracts were washed with brine (15 mL), then dried over
magnesium sulfate, filtered and then concentrated. Purification of
the residue by flash chromatography on silica gel (AcOEt/hexanes: 5/
95) afforded compound 21 (1.57 g, 5.27 mmol) as a mixture of di-
CDCl3):
d 0.03 (6H, s), 0.84 (3H, s), 0.90 (9H, s), 0.91 (3H,s), 2.04–
2.14 (1H, m), 2.23–2.31 (1H, m), 3.48 (2H, s), 3.54 (1H, dd, J¼2.6,
10.4 Hz), 5.06–5.14 (2H, m), 5.94 (1H, ddt, J¼16.6, 9.8, 7.4 Hz). 13C
NMR (75 MHz, CDCl3):
d
ꢀ5.6, 18.2, 18.9, 22.2, 25.9, 36.7, 38.4, 73.2,
78.2, 116.4, 136.9. IR (neat) nmax¼3497, 3072, 2957, 2931, 2859,1473,
1256, 1093, 837 cmꢀ1
.
4.2.6.5. 2,2-Dimethyl-5-hexen-1,3-diol (18)25. TBAF (1 M in THF,
17.02 mL, 17.02 mmol) was added at 0 ꢁC to a solution of homo-
allylic alcohol 17 (4.00 g, 15.48 mmol) in THF (75 mL). The resulting
mixture was stirred at rt for 1 h. THF was then evaporated, and the
residue was purified by flash chromatography on silica gel (AcOEt/
hexanes: 40/60) ether to give compound 18 (2.12 g, 14.70 mmol) as
astereomers. Yield: 96%. 1H NMR (300 MHz, CDCl3):
d 0.75 (3H, s),
1.04 (3H, s), 1.37 (1.5H, d, J¼7.2 Hz), 1.39–1.41 (7.5H, m), 2.20–2.37
(2H, m), 3.29 (1H, d, J¼11.5 Hz), 3.60–3.68 (2H, m), 3.71 (3H, s), 3.73–
3.76 (1H, m), 6.24 (0.5H, dt, J¼15.7, 1.5 Hz), 6.25 (0.5H, dt, J¼15.7,
a colourless oil. Yield: 95% yield. 1H NMR (300 MHz, CDCl3):
(3H, s), 0.92 (3H, s), 2.02–2.13 (1H, m), 2.34–2.41 (3H, m), 3.48 (1H,
d, J¼10.7 Hz), 3.53 (1H, dd, J¼2.1, 10.6 Hz), 3.55 (1H, d, J¼10.7 Hz),
d
0.91
1.4 Hz), 6.96 (1H, dt, J¼15.7, 6.9 Hz). 13C NMR (75 MHz, CDCl3):
d 13.1,
13.2, 18.2, 18.9, 21.8, 29.6, 32.7, 32.8, 32.9, 50.6, 50.7, 52.4, 71.9, 76.2,
76.3, 98.9, 129.2, 129.3, 146.8, 146.9, 171.2, 194.8, 194. IR (neat)

E. Bourcet et al. / Tetrahedron 66 (2010) 1319–1326
1325
nmax¼2989, 2956, 2852, 1747, 1703, 1627, 1457, 1377, 1253, 1196,
1100 cmꢀ1. MS: (CI) m/z¼299.0 (MþHþ, 100). HRMS (CI): Calculated
for [C16H27O5þHþ]: 299.1858; found: 299.1861.
stirred for 2.5 h. The mixture was then cooled to ꢀ20 ꢁC and a so-
lution of I2 (6.14 g, 24.00 mmol) in dry Et2O (60 mL) was dropwise
added. The reaction mixture was allowed to warm to rt and was
stirred for 2 h. The reaction was quenched by careful addition of
water. The resulting biphasic mixture was filtered through CeliteÒ.
The aqueous phase was separated, and the organic phase was with
a saturated aqueous solution of Na2S2O3 and brine, then dried over
magnesium sulfate, filtered and then concentrated. Purification of
the residue by flash chromatography on silica gel (AcOEt/hexanes:
20/80) afforded compound 24 (3.05 g, 14.40 mmol) as a light yellow
4.2.6.9. Methyl 2-methyl-3-oxo-6-(4-(2,2,5,5-tetramethyl)-diox-
olanyl)-hexanoate (22). Platinum oxide (36 mg, 0.13 mmol) was
added to a solution of enone 21 (800 mg, 2.68 mmol) in EtOAc
(25 mL). The solution was placed under Hydrogen (1 atm) and
stirred for 1 h at rt. The mixture was filtered off through a pad of
CeliteÒ, and catalyst was rinsed with EtOAc (10 mL). EtOAc was
removed by concentration. Purification of the residue by flash
chromatography on silica gel (AcOEt/hexanes: 20/80) furnished
compound 21 (693 mg, 2.31 mmol) as a 1:1 mixture of di-
astereomers and as a colourless oil. Yield: 86%. 1H NMR (300 MHz,
oil. Yield: 72%. 1H NMR (300 MHz, CDCl3):
d
1.87 (3H, d, J¼0.9 Hz),
2.48 (2H, td, J¼6.3, 0.9 Hz), 3.72 (2H, t, J¼6.3 Hz), 6.02 (1H, d,
J¼0.9 Hz). 13C NMR (75 MHz, CDCl3):
d 23.9, 42.4, 60.1, 76.9,144.6. IR
(neat) nmax¼3350, 3055, 2933, 2879, 1432, 1375, 1273, 1047 cmꢀ1
.
CDCl3):
d
0.70 (3H, s), 0.98 (3H, s), 1.34 (3H, d, J¼7.2 Hz), 1.39 (3H, s),
1.40 (3H, s), 1.51–1.84 (4H, m), 2.45–2.67 (2H, m), 3.26 (1H, d,
J¼11.4 Hz), 3.46 (1H, dd, J¼1.7, 10.0 Hz), 3.53 (1H, q, J¼7.2 Hz), 3.59
(1H, d, J¼11.4 Hz), 3.72 (1.5H, s), 3.73 (1.5H, s). 13C NMR (75 MHz,
4.2.6.12. (E)-tert-Butyl (4-iodo-3-methyl-but-3-enyloxy)-dimethyl-
silane (25)18. 2,6-Lutidine (2.00 mL, 17.20 mmol) and TBSOTf
(3.62 mL, 15.78 mmol) were successively added at ꢀ78 ꢁC, under
CDCl3):
d
12.9, 18.2, 19.0, 20.7, 21.9, 28.4, 28.5, 29.8, 32.9, 41.2, 41.3,
nitrogen atmosphere, to a solution of alcohol 24 (3.04 g,
52.5, 52.7, 52.8, 72.2, 77.3, 77.4, 98.7, 171.2, 205.9. IR (neat)
nmax¼2989, 2954, 2868, 1747, 1716, 1454, 1378, 1262, 1200,
1111 cmꢀ1. MS (CI) m/z¼301 (MHþ, 58), 243 ([MꢀC3H6O]þHþ, 100),
283 ([MꢀH2O]þHþ, 44). HRMS (CI): Calculated for [C16H29O5þHþ]:
301.2015; found 301.2007.
14.34 mmol) in dry CH2Cl2 (70 mL). The resulting mixture was
stirred at ꢀ78 ꢁC for 4 h. The reaction mixture was then quenched
with a saturated aqueous solution of NH4Cl (15 mL). The aqueous
phase was separated, extracted with CH2Cl2 (3ꢂ15 mL). The com-
bined organics extracts were washed with brine (15 mL), then dried
over magnesium sulfate, filtered and then concentrated. Purifica-
tion of the residue by flash chromatography on silica gel (AcOEt/
hexanes: 5/95) afforded compound 25 (4.68 g, 14.34 mmol) as
a colourless oil. Quantitative yield. 1H NMR (300 MHz, CDCl3):
4.2.6.10. Methyl 2-(2-methoxy-6-(1-formyl-1-methyl)ethyl-tetra-
hydropyranyl)-propionate (23). TsOH (43 mg, 0.23 mmol) was
added at rt to a solution of compound 22 (680 mg, 2.26 mmol) in
MeOH (20 mL). The resulting mixture was warmed to 40 ꢁC and
stirred for 2 h. After cooling to rt, the reaction mixture was then
quenched with a saturated aqueous solution of NaHCO3 (10 mL)
and Et2O (10 mL) was also added. The aqueous phase was sepa-
rated, extracted with Et2O (3ꢂ10 mL). The combined organics ex-
tracts were washed with brine (15 mL), then dried over magnesium
sulfate, filtered and concentrated.
d
0.04 (6H, s), 0.88 (9H, s), 1.85 (3H, d, J¼1.1 Hz), 2.41 (2H, td, J¼6.6,
1.1 Hz), 3.68 (2H, t, J¼6.6 Hz), 5.93 (1H, q, J¼1.1 Hz). 13C NMR
(75 MHz, CDCl3):
d
ꢀ5.2, 18.0, 24.4, 26.0, 42.7, 61.5, 76.5, 145.3. IR
(neat) nmax¼3058, 2958, 2857, 1472, 1256, 1104, 835, 775 cmꢀ1
.
4.2.6.13. Methyl 2-(2-methoxy-6-(1-(5-(tert-butyldimethyl sila-
nyloxy)-3-methyl-2-penten-1-ol)-1-methyl)ethyl-tetrahydropyr-
anyl)-propionate (26). A solution of tert-butyllithium in hexanes
(1.5 M, 1.37 mL, 2.06 mmol) was slowly added to a solution of
compound 25 (335 mg, 1.03 mmol) in dry Et2O (10 mL) at ꢀ95 ꢁC,
under nitrogen atmosphere. The resulting mixture was stirred at
ꢀ95 ꢁC for 1 h. A solution of ester 23 (280 mg,1.03 mmol) in dry Et2O
(2 mL) was then slowlyadded at ꢀ95 ꢁC, and the mixturewas stirred
at ꢀ78 ꢁC for 2.5 h. The reaction mixture was then quenched by
adding saturated aqueous solution of NH4Cl (10 mL) at ꢀ78 ꢁC, and
then warmed to 23 ꢁC. The aqueous phase was separated, extracted
with ether (3ꢂ10 mL). The combined organics extracts were washed
with brine (15 mL), then dried over magnesium sulfate, filtered and
then concentrated. Purification of the residue by flash chromatog-
raphy on silica gel (AcOEt/hexanes: 10/90) afforded compound 26
(349 mg, 0.74 mmol) as a mixture of stereoisomers as a colourless
To a solution of the above crude residue in dry DMSO (20 mL)
were added Et3N (3.18 mL, 22.60 mmol) and sulfurtrioxide pyridine
complex (1.08 g, 6.78 mmol), under a nitrogen atmosphere. The
resulting mixture was stirred for 4 h. The reaction mixture was then
quenched by addition of a saturated aqueous solution of NaHCO3
(10 mL) followed by the addition of AcOEt (10 mL). The aqueous
phase was separated, extracted with AcOEt (3ꢂ10 mL). The com-
bined organics extracts were washed with water and brine (15 mL),
then dried over magnesium sulfate, filtered and concentrated. Pu-
rification of the residue by flash chromatography on silica gel
(AcOEt/hexanes: 10/90) afforded compound 23 (519 mg,
1.90 mmol) as a colourless oil and as a 2:1 mixture of di-
astereomers. Yield: 84%. 1H NMR (300 MHz, CDCl3):
d 1.01–1.08
(9H, m), 1.49–1.87 (6H, m), 2.94 (0.66H, q, J¼7.4 Hz), 2.99 (0.33H, q,
J¼7.2 Hz), 3.17 (2H, s), 3.25 (1H, s), 3.65 (2H, s), 3.68 (1H, s), 3.69–
3.71 (1H, m), 9.59 (0.66H, s), 9.62 (0.33H, s). 13C NMR (75 MHz,
oil. Yield: 72%.1H NMR (300 MHz, CDCl3):
d 0.03–0.05 (6H, m), 0.68–
0.72 (3H, m), 0.87–0.89 (9H, m),1.09–1.28 (6H, m),1.50–1.99 (9H, m),
2.17–2.35 (2H, m), 2.64–2.73 (0.66H, m), 2.98–3.06 (0.33H, m), 3.28
(0.5H, s), 3.46–3.49 (2.5H, m), 3.64–3.72 (5.66H, m), 3.94 (0.33H, dd,
J¼11.7, 2.0 Hz), 4.22–4.39 (1H, m), 4.91 (0.17H, d, J¼8.3 Hz), 4.93
(0.33H, d, J¼8.3 Hz), 5.10 (0.17H, d, J¼9.4 Hz), 5.16 (0.33H, d,
J¼9.4 Hz). IR (neat) nmax¼2952, 2857, 1739, 1455, 1358, 1207,
CDCl3):
d 11.5, 13.1, 16.7, 16.8, 18.2, 18.3, 18.9, 19.0, 24.2, 27.5, 28.2,
43.4, 44.7, 47.3, 47.6, 49.2, 49.5, 51.5, 51.7, 74.6, 75.0, 100.2, 100.3,
173.3, 174.4, 205.8, 206.2. IR (neat) nmax¼2953, 2874, 1738, 1627,
1463, 1351, 1212, 1037 cmꢀ1. MS (ESI): m/z¼295.1 (MþNaþ, 44),
240.9 ([MꢀCH3OH]þHþ, 100), 263.1 ([MꢀCH3OH]þNaþ, 45). HRMS
(ESI): Calculated C14H24O5Na: 295.1521; found: 295.1520.
1099 cmꢀ1
.
MS: (ESI) m/z¼495.2 (MþNaþ, 75), 481.2
([MꢀCH3OHþH2O]þNaþ,100), 463.2 ([MꢀCH3OH]þNaþ, 84). HRMS
4.2.6.11. (E)-4-Iodo-3-methyl-but-3-en-1-ol (24)18. AlMe3 (2 M
in toluene, 31 mL, 62.00 mmol) was added dropwise at ꢀ20 ꢁC,
under nitrogen atmosphere, to a solution of Cp2ZrCl2 (1.46 g,
5.00 mmol) in dry CH2Cl2 (100 mL). After 10 min, water (0.58 mL,
3.20 mmol) was added dropwise. After an additional 10 min, 3-
butyn-1-ol (1.51 mL, 20.00 mmol) (pretreated with AlMe3 (2 M in
toluene, 3 mL, 6.00 mmol) in dry CH2Cl2 (20 mL) at 0 ꢁC) was slowly
added. The reaction mixture was allowed to warm to rt and was
(ESI): Calculated for C25H48O6SiNa: 495.3118; found: 495.3114.
4.2.6.14. Methyl 2-(2-methoxy-6-(1-(3-methyl-2-penten-1,5-diol)-
1-methyl)ethyl-tetrahydropyranyl)-propionate(27). TBAF (1 M in THF,
0.84 mL, 0.84 mmol) was added at 0 ꢁC to a solution of compound
26 (330 mg, 0.70 mmol) in THF (5 mL). The resulting mixture was
stirred at rt for 1 h. THF was then evaporated, and the residue was
purified by flash chromatography on silica gel (AcOEt/hexanes: 40/

1326
E. Bourcet et al. / Tetrahedron 66 (2010) 1319–1326
60) ether to give compound 27 (165 mg, 0.46 mmol) as a colourless
(1H, ddd, J¼11.1, 4.3, 3.2 Hz), 4.86 (1H, ddd, J¼12.5, 11.1, 2.4 Hz), 6.48
(1H, s). 13C NMR (75 MHz, CDCl3):
12.4, 19.0, 21.9, 24.2, 25.6, 27.5,
oil and as a 1:1 mixture of diastereomers. Yield: 66%. 1H NMR
d
(300 MHz, CDCl3):
d
0.68 (1.5H, s), 0.78 (1.5H, s), 0.87 (1.5H, s), 0.96
30.1, 40.7, 44.3, 47.6, 50.7, 60.5, 78.8, 100.9, 127.7, 148.1, 174.3, 204.4.
MS (ESI): m/z¼347.2 (MþNaþ, 100), 292.9 ([MꢀMeOH] Hþ, 76).
HRMS (ESI): Calculated for C18H28O5Na: 347.1834; found: 347.1834.
(1.5H, s), 1.09 (1.5H, q, J¼7.3 Hz), 1.11 (1.5H, q, J¼7.2 Hz), 1.56–1.74
(9H, m), 2.31 (2H, t, J¼6.4 Hz), 3.00 (0.5H, q, J¼7.3 Hz), 3.01 (0.5H, q,
J¼7.2 Hz), 3.25 (1.5H, s), 3.29 (1.5H, s), 3.57–3.73 (6H, m), 4.34 (0.5H,
d, J¼9.2 Hz), 4.40 (0.5H, d, J¼9.2 Hz), 5.36 (0.5H, d, J¼10.4 Hz), 5.40
(0.5H, d, J¼10.5 Hz). 13C NMR (75 MHz, CDCl3):
d 11.3 and 11.5, 13.0
Acknowledgements
and 14.5, 16.8, 18.3 and 18.5, 20.1, 21.4, 21.8, 24.3 and 24.4, 27.6 and
27.9, 40.6 and 40.7, 43.0 and 43.1, 43.6 and 43.9, 47.4 and 47.8, 51.8
and 51.9, 60.3, 75.4 and 75.7, 78.4 and 80.8, 100.8 and 100.9, 126.6
and 126.9, 135.5 and 135.6, 174.1 and 174.2. IR (neat) nmax¼3391,
2978, 2862, 1732, 1435, 1068, 873 cmꢀ1. HRMS (ESI): Calculated for
C19H34O6Na: 381.2253; found: 381.2252.
`
E.B. thanks the French ‘Ministere de la Recherche et de l’En-
´
´
seignement Superieur’ for a Ph-D grant. We thank Universite de
Lyon and CNRS for financial support.
References and notes
4.2.6.15. Hydroxymacrolactone (28). Aqueous NaOH (2 M,
0.78 mL) was added at rt to a solution of ester 27 (75 mg, 0.21 mmol)
in THF (4.8 mL) and MeOH (2.4 mL). The resulting mixture was
warmed to 45 ꢁC, and stirred for 12 h. After cooling to rt, aqueous HCl
(1 M) was added to reach acidic pH (3–4), and the EtOAc (10 mL) was
added. The aqueous phase was separated, extracted with EtOAc
(5ꢂ10 mL). The combined organics extracts were washed with brine
(10 mL), then dried over magnesium sulfate, filtered and
concentrated.
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To a solution of the above crude seco acid in toluene (0.5 mL)
was added successively at rt, under nitrogen atmosphere, Et3N
(0.15 mL, 1.05 mmol) and 2,4,6-trichlorobenzoyl chloride (39 mL,
0.25 mmol). The resulting mixture was stirred at rt for 2 h, then
diluted in toluene (20 mL) to give a solution of mixed anhydride,
which was added over a period of 1 h to a solution of DMAP
(153 mg, 1.26 mmol) in hot (80 ꢁC) toluene (3 mL). The resulting
mixture was then refluxed for an additional 2 h, cooled to rt and
washed with brine (10 mL). The aqueous phase was separated,
extracted with EtOAc (2ꢂ5 mL). The combined organics extracts
were then dried over magnesium sulfate, filtered and then con-
centrated. Purification of the residue by flash chromatography on
silica gel (AcOEt/hexanes: 25/75) afforded compound 28 (19 mg,
0.059 mmol) as a 1:1 mixture of diastereomers and as a colourless
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oil. Yield: 28% (for two steps). 1H NMR (300 MHz, CDCl3):
d 0.97–
1.25 (9H, s), 1.50–1.87 (9H, m), 1.97–2.23 (1H, m), 2.45–2.67 (1H, m),
2.88 (0.66H, q, J¼7.4 Hz), 2.91 (0.33H, q, J¼7.4 Hz), 3.14 (2H, s), 3.16
(1H, s), 3.23–3.28 (1H, m), 3.77–3.88 (1H, m), 4.14 (0.66H, d,
J¼9.8 Hz), 4.23 (0.33H, d, J¼9.8 Hz), 4.67 (0.66H, ddd, J¼11.3, 7.3,
3.8 Hz), 4.67 (0.33H, dt, J¼12.8, 2.8 Hz), 5.33 (0.66H, d, J¼9.8 Hz),
5.48 (0.33H, d, J¼9.8 Hz).
4.2.6.15.1. Ketomacrolactone (29). Reaction of compound 28
(15 mg, 0.046 mmol) with Dess–Martin Periodinane (15% wt,
0.12 mL, 0.060 mmol) in CH2Cl2 (2 mL) gave 29 (9.2 mg, 0.028 mmol)
in 62% yield. 1H NMR (300 MHz, CDCl3):
d 1.01 (3H, s), 1.08 (3H, d,
J¼7.1 Hz), 1.45 (3H, s), 1.52–1.65 (5H, m), 1.78–1.88 (1H, m), 2.04 (3H,
d, J¼1.1 Hz), 2.21 (1H, dt, J¼13.1, 2.4 Hz), 2.60 (1H, dt, J¼4.3, 13.1 Hz),
2.99 (1H, q, J¼7.1 Hz), 3.23 (3H, s), 3.32 (1H, dd, J¼11.7, 1.9 Hz), 3.80