FeCl3·6H2O-catalyzed synthesis of substituted cis-2,6-tetrahydropyrans from ζ-hydroxy allylic derivatives

Article abstract of DOI:10.1016/j.tet.2011.03.112

A highly diastereoselective iron-catalyzed synthesis of substituted cis-2,6-tetrahydropyrans from ζ-hydroxy allylic derivatives is described. The FeCl₃·6H₂O-induced epimerization of the formed 2-alkenyl 6-substituted tetrahydropyrans is the key reaction to account for the high diastereoselectivities observed.

Full text of DOI:10.1016/j.tet.2011.03.112

Tetrahedron 67 (2011) 5024e5033
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
FeCl3$6H2O-catalyzed synthesis of substituted cis-2,6-tetrahydropyrans from
z
-hydroxy allylic derivatives
*
*
ꢀ
ꢀ
ꢀ
Amandine Guerinot, Anna Serra-Muns, Charlelie Bensoussan, Sebastien Reymond , Janine Cossy
Laboratoire de Chimie Organique, ESPCI ParisTech, UMR CNRS 7084 10, Rue Vauquelin, 75231 Paris Cedex 05, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly diastereoselective iron-catalyzed synthesis of substituted cis-2,6-tetrahydropyrans from z-hy-
Received 3 February 2011
Received in revised form 21 March 2011
Accepted 29 March 2011
Available online 8 April 2011
droxy allylic derivatives is described. The FeCl3$6H2O-induced epimerization of the formed 2-alkenyl 6-
substituted tetrahydropyrans is the key reaction to account for the high diastereoselectivities observed.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Tetrahydropyran
Diastereoselectivity
Epimerization
Heterocyclization
Iron trichloride
1. Introduction
OMe
Me
Me
O
O
H
O
Substituted tetrahydropyrans (THPs) are of outstanding impor-
tance as they are ubiquitous motifs embedded in biologically rel-
evant natural products, including antitumoral agents (Fig. 1).
As a consequence, organic chemists need efficient and com-
plementary methods in order to build substituted THPs. A wide
array of methods has been developed and some extensive reviews
give an excellent overview of the different possibilities.1 Among the
existing methods to form tetrahydropyran units, the metal-
catalyzed CeO bond formation is an attractive one.1c For our part,
we focused our attention on the metal-catalyzed heterocyclization
H
O
O
O
OMe O
O
OMe
NH
O
O
O
N
O
O
N
HN
MeO
Leucascandrolide A
O
O
(+)-Neopeltolide
OMe
O
MeO
O
OMe
of
d-hydroxy alkenes A bearing an allylic leaving group. Such
reactions have been reported to deliver cis- or trans-2,6-di-
substituted THPs B depending on the conditions used (Scheme 1).
Me
H
O
Me
H
O
Palladium chemistry widely rules the field of d-hydroxy alkenes
O
H
heterocyclizations.2 Two different modes of action are mainly
exploited: the electrophilic character of Pd(II) complexes and the
O
O
H
Me
O
H
Me
ability of Pd(0) to form p-allylic complexes.
O
O
When allylic acetates, phosphonates or carbonates, such as C
(Scheme 2) are treated with a catalytic amount of Pd(0) complex,
MeO
OMe
OMe
a
p-allyl complex intermediate is produced and can be trapped
(-)-Clavosolide A
intramolecularly by a -hydroxyl group to form a CeO bond
d
according to a favored 6-exo ring-closure. In the latter process, the
configuration of the newly created stereocenter is determined by
Fig. 1. Examples of natural products incorporating THP subunits.
the one of the initial leaving group. Indeed, during the formation of
THPs D, the palladium preferentially coordinates to the less-
hindered face of the double bond opposite to the allylic leaving
* Corresponding authors. E-mail addresses: sebastien.reymond@espci.fr
(S. Reymond), janine.cossy@espci.fr (J. Cossy).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.03.112

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A. Guerinot et al. / Tetrahedron 67 (2011) 5024e5033
5025
R2
When 2,6-THPs were formed, a good diastereoselectivity was ob-
served in favor of the 2,6-cis-diastereomers (Scheme 4). From
a mechanistic point of view, the authors proposed that the Au(I)
complex activates the allylic alcohol by coordination of the oxygen
and that the reaction proceeds via a SN20 pathway.8
R2
LG
OH
R1
R1
[M] cat.
O
A
B
OH
Scheme 1.
Ph3PAuCl/AgOTf (1 mol %)
MS 4Å
OH
C6H15
C6H15
O
R2
X
R2
-50 °C, CH2Cl2
R1
O
R1
OH
Pd(0)L2
(dr = 25/1)
95%
Scheme 4.
X-
L2Pd
OH
R2
D
C
R1
X = OAc, OCO2R
For our part, we have recently shown that FeCl3$6H2O, an in-
expensive and eco-friendly catalyst, was able to induce the cycli-
OPO(OR)2, OAr...
zation of z-hydroxy allylic alcohols G and z-hydroxy allylic acetate
derivatives G0 to afford substituted cis-2,6-THPs H (Scheme 5).9
Herein, we would like to report a full account of our results.
OBn
OBn
EtO2CO
OBn
BnO
OH
O
Pd(PPh3)4 (5 mol %)
R2
R3O
OH
R2
rt, THF
71%
R1
O
R1
FeCl3 6H2O
rt, CH2Cl2
O
R4
R4
O
OH
G : R2 = H
G' : R2 = Ac
O
O
H
N
H
Scheme 5.
O
2. Results and discussion
zampanolide
2.1. Preparation of
G, G0
z-hydroxy allylic alcohols and derivatives
Scheme 2.
group thus forming a
p-allyl cation. The d-hydroxyl group then
-allyl cation on the opposite face to the palladium.3
Most of the diols G were synthesized by utilizing a cross-
metathesis reaction catalyzed by GrubbseHoveyda catalyst (GeH)
between d-acetoxy olefins 1aed and allylic acetates 2a or 2b. A
adds to the
p
Such Pd(0)-catalyzed cyclization has been applied to the dia-
stereoselective synthesis of a subunit of zampanolide (Scheme 2).4
The other strategy to form THPs exploits the electrophilic character
subsequent methanolysis of the resulting di-acetates delivered the
expected diols 3aee, which were obtained as 1/1 mixtures of the
cis- and trans-diols (Table 1). It is worth mentioning that the cross-
metathesis product of acetates 1c and 2b (Table 1, entry 4) was
partially isomerized during the purification on silica gel, affording
of Pd(II) catalysts to generate
p-complexes with double bonds, that
can undergo an intramolecular nucleophilic addition of a
d-hydroxyl
group.5 In the presence of PdCl2(CH3CN)2, diols of type E afford dia-
stereoselectively THPs F with an excellent 1,3-chirality transfer
(Scheme 3).5e The metal is first coordinated to the allylic hydroxyl
two regioisomers 3d and the e
-hydroxy alkene 3d0.10
A cross-metathesis involving acetate 1c and 2-methyl-3-buten-
2-ol, followed by a methanolysis, afforded diol 3f (Scheme 6, Eq. 1).
A cross-metathesis between unsaturated acetate 1c and methyl
vinyl ketone followed by a Luche reduction and a methanolysis of
the acetate provided diol 3g (Scheme 6, Eq. 2).
group, which directs the formation of the
samefaceofthedoublebond.Then, asyn-oxypalladationinvolvingthe
-hydroxyl group occurs and a final syn-elimination can account for
the perfect 1,3-chirality transfer.
pePd(II) complex on the
d
Both diols 3h and its (Z)-isomer 3i were prepared from the
unsaturated protected alcohol 4. The GeH-catalyzed cross-
metathesis between 4 and 2b followed by TBAF cleavage of the
silyl ether afforded diol 3h in 23% overall yield (Scheme 7). In order
to access the (Z)-isomer 3i, an ozonolysis was first performed on 4.
The resulting aldehyde was submitted to a CoreyeFuchs reaction
and after addition of mesitaldehyde, the expected alkyne was iso-
lated. The triple bond was partially reduced (H2, Pd/Lindlar),
affording (Z)-diol 3i after cleavage of the silyl ether (28% overall
yield) (Scheme 7).
HO
OH
R2
R1
O
R2
R1
PdCl2(MeCN)2
(10 mol %)
0 °C, THF
E
F
Scheme 3.
In 2008, Aponick et al. reported that a cationic gold complex,
generated from Ph3PAuCl/AgOTf, was able to catalyze the cycliza-
tion of 1,7-monoallylic diols to provide THPs in good yields.6,7
Hydroxy acetates 3jel were prepared from
hols 5a, (1S ,3R )-5b and (1S ,3S )-5b after a cross-metathesis re-
action with allylic acetate 2a (Scheme 8).
d-unsaturated alco-
*
*
*
*

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A. Guerinot et al. / Tetrahedron 67 (2011) 5024e5033
5026
Table 1
Synthesis of diols 3aee
R1
OH
G-H (5 mol %)
2a
3j-3l
R2
40 °C, CH2Cl2
HO
OH
R2
1/ G-H (5 mol %)
R1
R1
OAc
AcO
R2
40 °C, CH2Cl2
5a (R1=CO2Et, R2=H)
5b (R1=n-C5H11, R2=OH)
2/ MeONa
rt, MeOH
3a-3e
1a : R1 = i-Pr
1b : R1 = Cy
2a : R2 = Ph
Mes
AcO
Ph
AcO
OH
Ph
AcO
OH
Ph
2b : R2 = Mes
n-C5H11
OH
1c : R1 = n-C5H11
(R)-1d : R1 = Me
n-C5H11
OH
EtO2C
n-C5H11
OH
N
N
Mes
Mes
Cl
3d'
Ru
Cl
OH
rac-3l
OH
rac-3k
(40%)
O
3j
(57%)
(34%)
G-H
Scheme 8.
Entrya
Acetate 1
Acetate 2
Diol 3 (yield %)b,c
1
2
3
4
5
1a
1b
1c
1c
2a
2a
2a
2b
2b
3a (26%)
3b (33%)
3c (25%)
evaluated in order to induce the cyclization of diol 3a. The results
are reported in Table 2. No conversion was observed by using
a catalytic amount of acetic acid (Table 2, entry 1). In the presence
of PTSA$H2O, good diastereoselectivity in favor of the cis-isomer
was observed, but the reaction required 48 h (77% yield, Table 2,
entries 2 and 3). The use of CSA led to the formation of a mixture of
cis-6a and trans-6a with poor diastereoselectivity (dr¼57/43)
(Table 2, entry 4). Among the Brønsted acids tested, the best results
were obtained with TfOH as, after 3 h, tetrahydropyran 6a was
isolated in quantitative yield with a good diastereomeric ratio of
97/3 in favor of the cis-isomer (Table 2, entry 5). Several Lewis acids,
such as InCl3, TiCl4, and FeCl3$6H2O were also evaluated and this
latter was found to be the best catalyst both in term of reaction time
(2 h) and diastereoselectivity (dr¼97/3) (Table 2, entries 6e9). As
FeCl3$6H2O is inexpensive, eco-friendly, and easier to handle than
TfOH, it was selected to determine the scope and limitations of
3d (23%)þ3d0 (16%)
(1RS,7R)-3e (30%)
(R)-1d
a
See Experimental section for details.
Isolated yield of 3aee after two steps.
Mixture (1/1) of cis- and trans-diastereomers.
b
c
HO
1/ G-H (5 mol %)
n-C5H11
OH
HO
40 °C, CH2Cl2
(Eq. 1)
1c
2/ MeONa
rt, MeOH
3f
28%
HO
d
-hydroxy alkene cyclization.11
1/ G-H (4 mol %)
n-C5H11
OH
O
40 °C, CH2Cl2
(Eq. 2)
1c
2/ CeCl3 7H2O
Table 2
NaBH4, 0 °C, MeOH
3/ MeONa
Evaluation of various Brønsted and Lewis acids
3g
Ph
HO
OH
Ph
rt, MeOH
26%
i-Pr
O
i-Pr
cat. (mol %)
rt, CH2Cl2
Scheme 6.
3a
6a
Yield (dr)a,b
HO
OH
Mes
Entry
Cat. (mol %)
Time (h)
1
2
3
4
5
6
7
8
9
AcOH (10 mol %)
24
3
48
48
3
No conversion
50% (60/40)
77% (96/4)
71% (57/43)
99% (97/3)
nd (66/34)
76% (92/8)
87% (76/24)
66% (97/3)
1/ 2b, G-H (7 mol %)
i-Pr
PTSA$H2O (5 mol %)
PTSA$H2O (5 mol %)
CSA (5 mol %)
TfOH (5 mol %)
InCl3 (5 mol %)
InCl3 (5 mol %)
TiCl4 (5 mol %)
FeCl3$6H2O (5 mol %)
40 °C, CH2Cl2
TBS
O
2/ TBAF, THF
23%
i-Pr
3h
3
1/ O3, Et3N, CH2Cl2
2/ PPh3, CBr4
0 °C, CH2Cl2
48
96
2
i-Pr
OH
Mes
OH
4
a
Isolated yields.
3/ n-BuLi, Mes-CHO
4/ H2, Pd/Lindlar
quinoline
b
dr determined by 1H NMR or by GC/MS analysis.
3i
When compounds 3bei were treated with
5 mol % of
5/ TBAF, THF
FeCl3$6H2O at room temperature in CH2Cl2, the corresponding di-
substituted cis-2,6-tetrahydropyrans were isolated in good yields
and diastereoselectivities. The results are reported in Table 3.
Various alkyl groups were introduced at the C-7 position, but no
influence of these substituents on the cyclization was observed as
disubstituted cis-2,6-THPs were produced in similar yields (up to
99%) and diastereoselectivities (91/9 to 98/2) (Table 3, entries 1, 2, 4,
and 7). Diol (1RS,7R)-3e led to the optically active tetrahydropyran
(R,R)-6e with an excellent enantiomeric excess (Table 3, entry 4).
Various aryl groups were tolerated in the allylic position, and the
28% (5 steps)
Scheme 7.
2.2. Formation of disubstituted cis-2,6-THPs of type H
-hydroxy alkenes G and G0
The cyclization of the synthesized
d
was then studied. At first, a range of Brønsted and Lewis acids were

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A. Guerinot et al. / Tetrahedron 67 (2011) 5024e5033
5027
Table 3
and in similar diastereomeric ratio (95/5 and 94/6, respectively)
Preparation of disubstituted cis-2,6-THPs 6beh
(Table 3, entries 7 and 8). It is noteworthy that tetrahydropyran 6d
was also obtained from the e
-hydroxy alkene 3d0 in good yield and
Entrya
Starting material
Cyclized product
Ph
Time (dr, yield)b,c
1 h (98/2, 99%)
diastereoselectivity (Table 3, entry 9).
HO
OH
Ph
Under the cyclization conditions, allylic acetates 3jel were
converted into the corresponding THPs in quantitative yields
highlighting that an ester group as well as a free alcohol are tol-
erated under the reaction conditions (Table 4).
Cy
O
Cy
n-C5H11
n-C5H11
Me
1
3b
6b
Ph
HO
OH
Ph
Table 4
n-C5H11
O
Preparation of substituted cis-2,6-THPs 6jel
2d
2 h (97/3, 83%)
1 h (95/5, 89%)
1 h (98/2, 95%)
Entrya
Starting material
Cyclized product
Ph
Time (dr, yield)b,c
48 h (90/10, 99%)
3c
6c
AcO
OH
Ph
HO
OH
Mes
Mes
EtO2C
EtO2C
O
1d
n-C5H11
O
3
3j
6j
3d
6d
AcO
OH
Ph
Ph
Ph
Ph
Mes
HO
OH
Mes
n-C5H11
n-C5H11
O
Me
O
2
3 h (93/7, 99%)
4
OH
3k
OH
6k
(R,R)-6e
(1RS,7R)-3e
(er = 98/2)
AcO
OH
HO
OH
n-C5H11
O
n-C5H11
n-C5H11
O
n-C5H11
n-C5H11
i-Pr
3
21 h (92/8, 99%)
5d
6e
7d
8
15 min (91/9, 87%)
24 h (97/3, 82%)
1 h (95/5, 82%)
OH
6l
OH
6f
3f
3l
a
FeCl3$6H2O (5 mol %), CH2Cl2, room temperature, see Experimental section for
HO
OH
Me
details.
b
c
Isolated yields.
n-C5H11
O
dr determined by 1H NMR or by GC/MS analysis.
FeCl3$6H2O (15 mol %) was used.
d
3g
6g
Mes
HO
Mes
During the course of our studies, an evolution of the dia-
stereomeric ratio was observed with the reaction time. The initially
formed cis- and trans-THPs equilibrate leading to the most stable
cis-isomers. With these results in hand, a mechanistic pathway can
be proposed (Scheme 9). Monoallylic diols G would cyclize in
a non-diastereoselective fashion to produce a mixture of tetrahy-
dropyrans cis-H and trans-H. The latter would re-open to form
a carbocationic intermediate and the most stable cis-isomer would
be formed preferentially.
i-Pr
O
OH
3h
6h
i-Pr
OH
Mes
6h
6d
1 h (94/6, 96%)
1 h (95/5, 88%)
OH
3i
Mes
G
n-C5H11
OH
9
OH
FeCl3 6H2O
R2
3d'
a
FeCl3$6H2O (5 mol %), CH2Cl2, room temperature, see Experimental section for
R1
OH
details.
b
c
Isolated yields.
dr determined by 1H NMR or by GC/MS analysis.
2,6-cis-relationship confirmed by NOE studies.
An additional 5 mol % of FeCl3$6H2O was added after 5.5 h when the dr was 52/48.
d
e
replacement of a phenyl group by a mesityl group shortened the
reaction times (Table 3, entries 3, 4, and 7). In addition, a tertiary
allylic alcohol as well as a non-benzylic secondary alcohol were
excellent substrates, with the corresponding THPs isolated in good
yields and with good diastereomeric ratios (Table 3, entries 5 and
6). The geometry of the double bond did not affect the outcome of
the reaction as 6h was obtained from 3h or 3i in excellent yields
R1
O
R2
R1
O
R2
cis-H
trans-H
Scheme 9.

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A. Guerinot et al. / Tetrahedron 67 (2011) 5024e5033
5028
3. Conclusion
5.00 (dtd, J¼17.1, 2.0, 1.6 Hz, 1H, CH]CHcisHtrans), 4.97e4.92 (m, 1H,
CH]CHcisHtrans), 4.74 (dt, J¼7.0, 5.5 Hz, 1H, CHeO), 2.05 (s, 3H,
CH3eC]O), 2.09e2.01 (m, 2H, CH2eCH]), 1.86e1.76 (m, J¼6.8,
1.3 Hz,1H, CHeMe2),1.55e1.48 (m, 2H),1.44e1.31 (m, 2H), 0.88 (dd,
In summary, we have developed a highly chemo- and dia-
stereoselective synthesis of disubstituted cis-2,6-tetrahydropyrans
from
z
-hydroxy allylic alcohols and
z
-hydroxy allylic acetate
J¼6.8, 1.3 Hz, 6H); 13C NMR (100 MHz, CDCl3)
d: 171.0 (s), 138.5 (d),
derivatives. The use of FeCl3$6H2O as the catalyst makes the
reaction safe, inexpensive, and eco-friendly. Application of this
method for the synthesis of complex biologically active compounds
will be reported in due course.
114.7 (t), 78.3 (d), 33.6 (d), 30.5 (t), 24.8 (t), 21.1 (q),18.5 (q),17.6 (q);
MS (EI) m/z: 142 ([MꢀAc]þ, 4), 99 (20), 96 (16), 82 (44), 81 (100), 69
(32), 68 (19), 67 (27), 57 (16), 55 (55), 54 (34); HRMS (ESI): MNaþ,
found 207.1359. C11H20NaO2 requires 207.1356.
4. Experimental section
4.2.2. Acetic acid 1-pentyl-hex-5-enyl ester (1c). Pyridinium chlor-
ochromate (2.48 g, 11.3 mmol, 1.5 equiv) was added to a stirred
solution of 5-hexen-1-ol (0.91 mL, 7.5 mmol, 1.0 equiv) and CeliteÒ
(6 g) in CH2Cl2 (170 mL) at room temperature under argon. The
mixture was stirred for 2 h and an additional portion of pyridinium
chlorochromate (0.74 g, 3.4 mmol, 0.4 equiv) was added. This
mixture was stirred for 2 h was then filtered through a pad of silica.
The solvent was evaporated at atmospheric pressure. The resulting
oil was diluted in Et2O (15 mL) and the solution was cooled to
ꢀ78 ꢁC. Pentylmagnesium bromide (2 M in THF, 5.6 mL, 11.2 mmol,
1.5 equiv) was added and the solution was stirred overnight at
room temperature. Saturated ammonium chloride solution (10 mL)
was added and the aqueous phase was extracted with Et2O
(3ꢂ10 mL). The organic layer was washed with brine, dried over
MgSO4 and the solvents were evaporated at atmospheric pressure.
The obtained oil was diluted with dichloromethane (11 mL) and
pyridine (5.5 mL) and was cooled down to 0 ꢁC. 4-(Dimethylamino)
pyridine (46.3 mg, 0.37 mmol, 0.05 equiv) and acetic anhydride
(1.06 mL, 11.25 mmol, 1.5 equiv) were added. After 1.5 h at room
temperature the mixture was washed with a 10% aqueous solution
of CuSO4 (4ꢂ10 mL) and the aqueous phase was extracted with
diethyl ether (3ꢂ20 mL). The combined organic layers were washed
with brine (50 mL), dried over MgSO4, filtered, and concentrated
under reduced pressure to give 1c (1.192 g, 75%); IR (neat) 2934,
4.1. General experimental methods
Infrared (IR) spectra were recorded on a Bruker TENSOR TM 27
(IRFT), wave-numbers are indicated in cmꢀ1. NMR spectra were
recorded on a Bruker AVANCE 400.1H NMR spectrawere recorded at
400 MHz and data are reported as follows: chemical shift inparts per
million from tetramethylsilane as an internal standard with the re-
sidual solvent peak as an internal indicator (CDCl3 d: 7.26), multi-
plicity (s¼singlet, d¼doublet, t¼triplet, q¼quartet, m¼multiplet or
overlap of non-equivalent resonances), integration.13C NMR spectra
were recorded at 100 MHz and data are reported as follows:
chemical shift in ppm from tetramethylsilane with the solvent as an
internal indicator (CDCl3 d: 77.1 ppm), multiplicity with respect to
proton (deduced from DEPT experiments, s¼quaternary C, d¼CH,
t¼CH2, q¼CH3). CH2Cl2 was distilled from CaH2. THF and Et2O were
dried over Na/benzophenone prior to distillation. TLC was per-
formed on silica gel plates visualized either with a UV lamp
(254 nm), or using solutions of p-anisaldehydeesulfuric acideacetic
acid in EtOH followed by heating. Purification was performed on
silica gel (Merck-Kieselgel 60, 230e400 mesh). Mass spectra with
electronic impact (MS-EI) were recorded on a GC/MS (70 eV). HRMS
3
ꢀ
was performed at the Laboratoire de Spectrometrie de Masse SM E
de l’Universite Pierre et Marie Curie in Paris. Acetates 1b,12 (R)-1d,13
2863, 1739, 1642, 1460, 1375, 1245, 1023, 914 cmꢀ1
;
1H NMR
ꢀ
2a,14 and olefin 5a15 were prepared according to reported
(400 MHz, CDCl3)
d
: 5.78 (ddt, J¼17.1, 10.3, 6.7 Hz, 1H, CH2]CH),
procedures.
5.01 (dm, J¼17.1 Hz, 1H, CH]CHcisHtrans), 4.95 (dm, J¼10.3 Hz, 1H,
CH]CHcisHtrans), 4.86 (quint, J¼6.2 Hz, 1H, CHeO), 2.07e2.03 (m,
2H, CH2eCH), 2.03 (s, 3H, CH3eC]O), 1.56e1.49 (m, 4H, CH2), 1.40
(m, 2H, CH2), 1.28 (m, 6H, CH2), 0.88 (t, J¼6.7 Hz, 3H, CH3); 13C NMR
4.2. Synthesis of precursors 1a, 1c, 2b, 4, (1S
*
,3R )-5b, and
*
(1S ,3S )-5b
*
*
(100 MHz, CDCl3) d: 171.0 (s), 138.6 (d), 114.9 (t), 74.4 (d), 34.2 (t),
4.2.1. 2-Methyloct-7-en-3-yl acetate (1a). To a solution of 5-hexen-
1-ol (0.91 mL, 7.5 mmol, 1.0 equiv) and CeliteÒ (6 g) in CH2Cl2
(170 mL) was added pyridinium chlorochromate (2.48 g, 11.3 mmol,
1.5 equiv). The mixture was stirred for 2 h and an additional portion
of pyridinium chlorochromate (0.74 g, 3.4 mmol, 0.4 equiv) was
added. This mixture was stirred for 2 h was then filtered through
a pad of silica. The solvent was evaporated at atmospheric pressure.
The resulting oil was diluted in diethyl ether (15 mL) and the so-
lution was cooled down to ꢀ78 ꢁC. Isopropylmagnesium bromide
(2 M in THF, 5.6 mL, 11.2 mmol, 1.5 equiv) was added and the so-
lution was stirred overnight at room temperature. Saturated NH4Cl
solution (10 mL) was added and the aqueous phase was extracted
with Et2O (3ꢂ10 mL). The organic layer was washed with brine,
dried over MgSO4 and the solvents were evaporated at atmospheric
pressure. The obtained oil was diluted in dichloromethane (11 mL)
and pyridine (5.5 mL) and cooled down to 0 ꢁC. 4-(Dimethylamino)
pyridine (46.3 mg, 0.37 mmol, 0.05 equiv) and acetic anhydride
(1.06 mL, 11.25 mmol, 1.5 equiv) were added. After 1.5 h at room
temperature the mixture was washed with a 10% aqueous solution
of CuSO4 (4ꢂ10 mL) and the aqueous phase was extracted with
diethyl ether (3ꢂ20 mL). The combined organic layers were washed
with brine (50 mL), dried over MgSO4, filtered, and concentrated
under reduced pressure to yield 1a (1.192 g, 75%); IR (neat) 2964,
33.7 (2t), 31.8 (t), 25.1 (t), 24.7 (t), 22.6 (t), 21.4 (q), 14.1 (q); MS (EI)
m/z: 170 (10), 124 (25), 110 (18), 99 (32), 96 (45), 95 (30), 83 (25), 82
(58), 81 (100), 69 (42), 68 (36), 67 (47), 55 (58), 54 (65); HRMS (ESI):
MNaþ, found 235.1665. C13H24NaO2 requires 235.1668.
4.2.3. Acetic acid 1-(2,4,6-trimethyl-phenyl)-allyl ester (2b). To
a solution of mesitaldehyde (10 mmol, 1.4 mL, 1 equiv) in THF
(100 mL) at ꢀ78 ꢁC was added a solution of vinylmagnesium bro-
mide (13 mmol, 1 M in THF, 1.3 equiv). After 1 h at ꢀ78 ꢁC, the
reaction was warmed to room temperature and stirred until com-
plete conversion. The reaction mixture was then cooled to 0 ꢁC and
acetic anhydride (1.4 mL, 15 mmol, 1.5 equiv) was added. After one
night at room temperature, the reaction mixture was quenched
with a saturated solution of ammonium chloride in water (80 mL).
The two phases were separated and the aqueous phase was
extracted with Et2O (3ꢂ50 mL). The organic layers were combined,
dried over MgSO4, filtered and the solvents were removed under
reduced pressure. The crude product was purified by flash chro-
matography on silica gel previously neutralized by Et3N (PE/Et2O:
97/3 to 9/1) to give 2b (90%); IR (neat) 2922, 1738, 1612, 1448, 1371,
1235, 1018 cmꢀ1 1H NMR (400 MHz, CDCl3)
; d: 6.83 (s, 2H, Har),
6.73e6,67 (m,1H, CHeOAc), 6.07 (ddd, J¼17.3,10.6, 4.5 Hz,1H, CH]
CH2), 5.18 (dd, J¼10.6, 2.0 Hz, 1H, CH]CHcisHtrans), 5.09 (dd, J¼17.3,
2.0 Hz, 1H, CH]CHcisHtrans), 2.39 (s, 6H, CH3eAr), 2.26 (s, 3H,
1732, 1641, 1460, 1433, 1371, 1239, 1160, 1019 cmꢀ1
;
1H NMR
(400 MHz, CDCl3)
d: 5.78 (dtd, J¼17.1, 11.9, 5.9 Hz, 1H, CH2]CH),
CH3eAr), 2.08 (s, 3H, CH3eCO); 13C NMR (100 MHz, CDCl3)
d: 170.2

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A. Guerinot et al. / Tetrahedron 67 (2011) 5024e5033
5029
(s), 137.8 (s), 137.3 (2s), 135.6 (d), 131.9 (s), 130.0 (d), 116.2 (t), 73.1
(d), 21.2 (q), 21.0 (q), 20.6 (2q); HRMS (ESI): MNaþ, found 241.1197.
C14H18NaO2 requires 241.1199.
was added, the aqueous phase was extracted with diethyl ether.
The combined organic layers were washed with brine, dried over
MgSO4, and concentrated under reduced pressure to give
(4RS,6SR)-undec-1-ene-4,6-diol (5.29 g, 94%). 2,2-Dimethox-
ypropane (34.5 mL, 280 mmol, 10 equiv) and pyridinium p-tolue-
nesulfonate (717 mg, 2.8 mmol, 0.01 equiv) were added to
a solution of the previous diol (5.2 g, 28 mmol, 1 equiv) in CH2Cl2
(150 mL). After 21 h at room temperature, saturated ammonium
chloride solution was added and the aqueous phase was extracted
with CH2Cl2. The combined organic layers were washed with brine,
dried over MgSO4, filtered and the volatiles were removed under
reduced pressure to give a mixture of cis- and trans-acetonides
(6.48 g, quant). Then, 2.6 g of the latter mixture (11.5 mmol) was
4.2.4. tert-Butyl-(1-isopropyl-hex-5-enyloxy)-dimethyl-silane
(4). Pyridinium chlorochromate (8.25 g, 37.5 mmol, 1.5 equiv) was
added to a stirred solution of 5-hexen-1-ol (3.03 mL, 25 mmol,
1.0 equiv) and CeliteÒ (20 g) in dichloromethane (550 mL) at room
temperature. After 4 h, the mixture was filtered through a pad of
silica and the solvent was distilled at atmospheric pressure. The
resulting oil was diluted in THF (125 mL) and the solution was
cooled to ꢀ78 ꢁC. Isopropylmagnesium chloride (2 M in THF,
15 mL, 30 mmol, 1.2 equiv) was added and the solution was stirred
at room temperature overnight. Saturated ammonium chloride
solution (50 mL) was added and the aqueous phase was extracted
with diethyl ether (3ꢂ40 mL). The organic layers were then
washed with brine (100 mL), dried over MgSO4 and the solvents
were removed at atmospheric pressure. The obtained oil was di-
luted in dichloromethane (250 mL) and cooled at ꢀ78 ꢁC. 2,6-
Lutidine (7.04 mL, 60 mmol, 2.4 equiv) and TBSOTf (6.89 mL,
30 mmol, 1.2 equiv) were added. After 1 h at ꢀ78 ꢁC the reaction
mixture was allowed to reach room temperature and the stirring
was continued for 1 h. Saturated sodium hydrogenocarbonate
solution was added (150 mL), the aqueous phase was extracted
with CH2Cl2 (3ꢂ100 mL), the combined organic layers were
washed with brine (100 mL), dried over MgSO4, and concentrated
under reduced pressure. The crude was purified by flash chro-
matography (PE) to give 4 (5.21 g, 81%); IR (neat) 2956, 2930,
2896, 2857, 1642, 1472, 1463, 1386, 1361, 1252, 1187, 1050,
dissolved in CH2Cl2 (640 mL) and treated with HCl (287 mL, 2 M,
0.05 equiv).15 The evolution of the reaction was carefully followed
by GC/MS. After 2 h at room temperature, the reaction was stopped
by addition of saturated NaHCO3 solution, the aqueous phase was
extracted with CH2Cl2, the combined organic layers were washed
with brine, dried over MgSO4, filtered, and concentrated under
reduced pressure. The residue was purified by flash chromatogra-
phy on silica gel (PE/EtOAc: 9/1 to 7/3) to afford diol (4S
*
,6S )-5b
*
(698 mg, 33% from (4RS,6SR)-undec-1-ene-4,6-diol) and the re-
covered cis-acetonide (793 mg). HCl (10 mL, 2 M) was added to
a solution of the latter cis-acetonide in CH2Cl2 (50 mL). After 17 h at
room temperature, saturated NaHCO3 solution was added, the
aqueous phase was extracted with EtOAc, the combined organic
layers were washed with brine, dried over MgSO4, filtered and the
volatiles were removed under reduced pressure to give (4R
(534 mg, 25% from (4RS,6SR)-undec-1-ene-4,6-diol); (4R
IR (neat) 3317, 2925, 2857, 1642, 1434, 1277, 1126, 1036 cmꢀ1
NMR (400 MHz, CDCl3) : 5.80 (m, 1H, CH2]CH), 5.11e5.15 (m, 2H,
*
,6S
*
)-5b
)-5b:
1H
*
,6S
*
1005 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
: 5.81 (m, 1H, CH]CH2),
;
5.00 (dd, J¼17.3, 1.8 Hz, 1H, CH]CHcisHtrans), 4.94 (d, J¼10.2 Hz, 1H,
CH]CHcisHtrans), 3.43 (q, J¼5.1 Hz, 1H, CHeOTBS), 2.03 (q,
J¼6.7 Hz, 2H, CH2), 1.71 (m, 1H, CH), 1.49e1.30 (m, 4H, CH2), 0.89
(s, 9H (CH3)3CeSi), 0.86 (d, J¼6.9 Hz, 3H, CH3eCH), 0.83 (d,
J¼6.9 Hz, 3H, CH3eCH), 0.04 (s, 3H, CH3eSi), 0.03 (s, 3H, CH3eSi);
d
CH2]CH), 3.99 (m, 1H, CHeOH), 3.92 (m, 1H, CHeOH), 2.55 (s, 2H,
OH), 2.27 (t, J¼7.7 Hz, 2H, CH2), 1.62 (t, J¼7.7 Hz, 2H, CH2), 1.24e1.51
(m, 8H, CH2), 0.89 (t, J¼7.1 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3)
d: 134.8 (d), 118.3 (t), 69.4 (d), 68.3 (d), 42.1 (t), 42.0 (t), 37.6 (t), 31.9
13C NMR (100 MHz, CDCl3)
d
: 139.1 (d), 114.4 (t), 76.8 (d), 34.1 (t),
(t), 25.6 (t), 22.7 (t), 14.2 (q); MS (EI) m/z: 110 (50), 101 (26), 97 (19),
32.8 (d), 32.6 (t), 26.1 (3q), 24.9 (t), 18.3 (s), 18.2 (q), 17.7 (q), ꢀ2.9
83 (73), 71 (20), 68 (24), 67 (50), 57 (29), 55 (100); HRMS (ESI):
t
(q), ꢀ4.2 (q); MS (EI) m/z: 256 ([M]þꢃ, 1), 199 ([Mꢀ Bu]þ, 20), 187
MNaþ, found 209.1514. C11H22NaO2 requires 209.1512. (4S
*
,6S
IR (neat) 3351, 2930, 2859, 1642, 1435, 1326, 1129, 1085 cmꢀ1
NMR (400 MHz, CDCl3) : 5.80 (m, 1H, CH2]CH), 5.15e5.11 (m, 2H,
*
)-5b:
;
(5), 115 (7), 81 (21), 75 (100), 59 (7).
1H
d
4.2.5. (4R
*
,6S
*
)-Undec-1-ene-4,6-diol (4R
*
,6S
*
)-5b and (4S
*
,6S
*
)-
CH2]CH), 3.94e3.82 (m, 2H, CHeOH), 2.76 (s, 2H, OH), 2.25 (m, 2H,
CH2), 1.62 (m,1H, CH2), 1.52e1.29 (m, 9H, CH2), 0.89 (t, J¼6.8 Hz, 3H,
undec-1-ene-4,6-diol (4S
*
,6S )-5b. To a solution of hexanal (3.7 mL,
*
30 mmol, 1.0 equiv) in THF (70 mL) at ꢀ78 ꢁC was added allyl-
magnesium chloride (2 M in THF, 22.5 mL, 45 mmol, 1.5 equiv).
After one night at room temperature, saturated ammonium chlo-
ride solution was added and the aqueous phase was extracted with
diethyl ether. The combined organic layers were washed with
brine, dried over MgSO4, filtered, and concentrated under pressure.
The obtained oil was diluted in tert-BuOH (60 mL) and deionised
water (60 mL). OsO4 (5.6 mL, 2.5 wt % in t-BuOH, 0.45 mmol,
0.015 equiv) and NMO (3.98 g, 33 mmol, 1.1 equiv) were added.
After 3 h at room temperature Na2SO4 (30 g) and EtOAc (100 mL)
were added, the resulting mixture was stirred for 30 min and fil-
tered through a pad of CeliteÒ. The aqueous phase was extracted
with EtOAc and the organic phases were concentrated under re-
duced pressure to yield a black oil. The latter was diluted in THF
(20 mL) and water (20 mL) and NaIO4 (17.04 g, 79.5 mmol,
2.65 equiv) was added. After 5 h at room temperature, the reaction
mixture was filtered through a CeliteÒ pad and the aqueous phase
was extracted with EtOAc. The combined organic layers were
washed with brine, dried over MgSO4, filtered, and concentrated
under reduced pressure. The residue was purified by flash chro-
matography on silica gel (Et2O) to give a yellow oil. This oil was
diluted in THF (60 mL), cooled at ꢀ78 ꢁC, and allylmagnesium
chloride (2 M in THF, 37.5 mL, 75 mmol, 2.5 equiv) was added. After
13 h at room temperature, saturated ammonium chloride solution
CH3); 13C NMR (100 MHz, CDCl3)
d: 134.5 (d), 118.4 (t), 73.1 (d), 72.1
(d), 42.7 (t), 42.5 (t), 38.2 (t), 32.0 (t), 25.2 (t), 22.8 (t), 14.2 (q); MS
(EI) m/z: 186 ([M]þꢃ, 1), 145 (18), 127 (22), 109 (84), 101 (39), 97 (32),
83 (100), 71 (27), 69 (23), 68 (28), 67 (58), 57 (30), 55 (93); HRMS
(ESI): MNaþ, found 209.1515. C11H22NaO2 requires 209.1512.
4.3. Synthesis of substrates 3ael
General procedure A for acetate methanolysis: to a solution of
acetate or diacetate (1 equiv) in MeOH (0.3 M) was added sodium
methoxide (1 M in MeOH,1.2 equiv). Themixturewas stirred at room
temperaturefor 20 h and an additional portion of sodium methoxide
(1 M in MeOH,1.2 equiv) was added. After 10 h, water was added and
the aqueous phase was extracted with EtOAc, the organic layers
were washed with brine, dried with MgSO4, filtered, and concen-
trated under reduced pressure. Purification of the residue by flash
chromatography on silica gel furnished the pure product.
4.3.1. (E)-8-Methyl-1-phenylnon-2-ene-1,7-diol (3a, mixture of dia-
stereomers). To a solution of olefin 1a (460 mg, 2.50 mmol, 1 equiv)
and acetate 2a (878 mg, 4.99 mmol, 3 equiv) in CH2Cl2 (15 mL) was
added GrubbseHoveyda catalyst (78 mg, 0.12 mmol, 0.05 equiv).
The mixture was stirred overnight at 40 ꢁC and the solvent was
removed under reduced pressure. The residue was purified by flash

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A. Guerinot et al. / Tetrahedron 67 (2011) 5024e5033
5030
chromatography on silica gel previously neutralized by Et3N to
afford the corresponding diacetate. The latter was submitted to
general procedure A to furnish diol 3a (160 mg, 26%, two steps); IR
(neat) 3369, 2932, 2870, 1682, 1450, 1384, 1286, 1201, 1070,
1376 cmꢀ1; 1H NMR (400 MHz, C6D6)
d: 6.77 (s, 2H, Har), 5.82 (dd,
J¼15.4, 4.7 Hz, 1H, CH]CH), 5.60 (m, 1H, CH]CH), 5.52 (dd, J¼4.7,
1.3 Hz,1H, CHeOH), 3.33 (m, 1H, CHeOH), 2.38 (s, 6H, CH3eAr), 2.14
(s, 3H, CH3eAr), 1.92e1.98 (m, 2H, CH2), 1.45e1.20 (m, 12H, CH2),
1026 cmꢀ1
;
1H NMR (400 MHz, C6D6)
d
: 7.35e7.30 (m, 2H, Har),
0.90 (t, J¼7.7 Hz, 3H, CH3); 13C NMR (100 MHz, C6D6)
d: 136.5 (s),
7.16e7.11 (m, 2H, Har), 7.06e7.00 (m, 1H, Har), 5.58e5.54 (m, 2H,
CH]CH), 4.95e4.92 (m, 1H, PheCHeO), 3.04e2.98 (m, 1H, CHeO),
1.90e1.80 (m, 2H), 1.45e1.12 (m, 5H), 0.79e0.74 (m, 6H); 13C NMR
136.4 (2s), 131.8 (d), 130.5 (d), 130.4 (s), 130.3 (2d), 71.4 (d), 67.6 (d),
38.0 (t), 37.4 (t), 32.3 (t), 25.8 (t), 25.7 (t), 23.1 (t), 32.6 (t), 20.8 (3q),
14.3 (q); HRMS (ESI): MNaþ, found 341.2446. C21H34NaO2 requires
341.2451. Compound 3d0: IR (neat) 3328, 2925, 2856, 1611, 1577,
(100 MHz, C6D6) d: 144.5 (s), 133.9 (d), 131.6 (d), 128.7 (2d), 127.6
(d), 126.6 (2d), 76.3 (d), 76.2 (d), 75.2 (d, C), 34.0 (d), 32.6 (t), 32.5
(t), 26.0 (t), 26.0 (t), 19.1 (q), 17.4 (q); HRMS (ESI) MNaþ, found
271.1672. C16H24NaO2 requires 271.1669.
1457, 1377, 850, 750 cmꢀ1; 1H NMR (400 MHz, C6D6)
d: 6.92 (s, 2H,
Har), 6.60 (d, J¼16.6 Hz, 1H, CH]CH), 5.76 (dd, J¼16.6, 6.6 Hz, 1H,
CH]CH), 4.22 (q, J¼6.1 Hz, 1H, CHeOH), 3.55 (m, 1H, CHeOH), 2.38
(s, 6H, CH3eAr), 2.27 (s, 3H, CH3eAr), 1.36e1.73 (m, 14H, CH2), 1.01
4.3.2. (E)-7-Cyclohexyl-hept-2-ene-1,7-diol (3b, mixture of diaster-
eomers). To a solution of 1b (248 mg, 1.11 mmol, 1 equiv) and acetate
2a (487 mg, 2.76 mmol, 2.5 equiv) in CH2Cl2 (10 mL) was added
GrubbseHoveyda catalyst (88 mg, 0.14 mmol, 0.13 equiv). The mix-
ture was stirred overnight at 40 ꢁC and the solvent was removed
under reduced pressure. The residue was purified by flash chroma-
tography on silica gel previously neutralized by Et3N to afford the
expected diacetate. The latter was submitted to general procedure A
to furnish diol 3b (105 mg, 33%, two steps); IR (neat) 3307, 2919, 2849,
(t, J¼6.9 Hz, 3H, CH3); 13C NMR (100 MHz, C6D6)
d: 138.4 (d), 136.0
(s), 135.8 (2s), 134.2 (s), 129.0 (2d), 127.5 (d), 73.1 (d), 71.5 (d), 38.1
(t), 37.9 (t), 37.7 (t), 32.4 (t), 25.9 (t), 23.1 (t), 22.1 (t), 21.6 (2q), 21.1
(q), 14.3 (q); HRMS (ESI): MNaþ, found 341.2446. C21H34NaO2 re-
quires 341.2451.
4.3.5. (E)-(1RS,7R)-1-(2,4,6-Trimethyl-phenyl)-oct-2-ene-1,7-diol
((1RS,7R)-3e, mixture of diastereomers). To a solution of (R)-hept-6-
en-2-yl acetate (R)-1d (820 mg, 5.26 mmol, 1 equiv) and 2b (2.45 g,
11.2 mmol, 2.1 equiv) in CH2Cl2 (15 mL) was added
GrubbseHoveyda catalyst (117 mg, 0.19 mmol, 0.05 equiv). The
mixture was stirred overnight at 40 ꢁC and the solvent was re-
moved under reduced pressure. The residue was purified by flash
chromatography on silica gel previously neutralized by Et3N to
afford the expected diacetate, which was treated according to
general procedure A. Purification of the residue by flash chroma-
tography on silica gel furnished diol (1RS,7R)-3e (412 mg, 30%, two
steps); IR (neat) 3353, 2965, 2923, 2859,1714,1611,1577,1447,1375,
;
2360, 1492, 1449, 1262, 1192, 1066, 1005 cmꢀ1 1H NMR (400 MHz,
C6D6)
d
: 7.39 (d, J¼7.4 Hz, 2H, Har), 7.20 (t, J¼7.4 Hz, 2H, Har), 7.09 (t,
J¼7.4 Hz, 1H, Har), 5.61e5.68 (m, 2H, CH]CH), 4.97e5.02 (m, 1H,
CHeOH), 3.06e3.14 (m, 1H, CHeOH), 1.87e1.99 (m, 2H), 0.75e1.80
(m, 17H); 13C NMR (100 MHz, C6D6)
d: 144.5 (s), 133.8 (d), 131.6 (d),
128.6 (d), 127.5 (d), 126.6 (d), 75.7 (2d), 75.1 (d), 44.1 (d), 33.9 (2t),
32.5 (2t), 29.6 (t), 28.0 (2t), 27.0 (t), 26.8 (t), 26.7 (t), 25.9 (2t); HRMS
(ESI): MNaþ, found 311.1978. C19H28NaO4 requires 311.1981.
4.3.3. (E)-1-Phenyl-dodec-2-ene-1,7-diol (3c, mixture of diaster-
eomers). To a solution of 1c (848 mg, 4.0 mmol,1 equiv) and acetate
2a (2.1 g, 12 mmol, 3 equiv) in CH2Cl2 (15 mL) was added
GrubbseHoveyda catalyst (125 mg, 0.2 mmol, 0.05 equiv). The
mixture was stirred overnight at 40 ꢁC and the solvent was re-
moved under reduced pressure. The residue was purified by flash
chromatography on silica gel previously neutralized by Et3N to
afford the expected diacetate. The latter was submitted to general
procedure A to furnish diol 3c (280 mg, 25%, two steps); IR (neat)
1302,1261,1203,1177,1085,1036 cmꢀ1; 1H NMR (400 MHz, C6D6)
d:
6.86 (s, 2H, Har), 5.90 (dd, J¼15.4, 5.0 Hz, 1H, CH]CH), 5.73e5.66
(m, 2H, CH]CH, CHeOH), 3.60 (m, 1H, CHeOH), 2.49 (s, 6H,
CH3eAr), 2.24 (s, 3H, CH3eAr), 2.03 (m, 2H, CH2), 1.47e1.31 (m, 4H,
CH2), 1.04 (d, J¼6.8 Hz, 3H, CH3eCH); 13C NMR (100 MHz, C6D6)
d:
136.5 (2s), 131.7 (d), 130.5 (d), 130.3 (2d), 128.6 (2s), 71.2 (d), 67.5
(d), 39.1 (t), 32.6 (t), 25.7 (t), 23.7 (q), 21.0 (2q), 20.9 (q); HRMS
(ESI): MNaþ, found 285.1817. C17H26NaO2 requires 285.1825.
3338, 2928, 2857, 1453, 1276 cmꢀ1; 1H NMR (400 MHz, C6D6)
d
: 7.51
4.3.6. (E)-2-Methyl-tridec-3-ene-2,8-diol (3f, mixture of diaster-
eoisomers). To a solution of 1c (200 mg, 0.94 mmol, 1 equiv) and 2-
(m, 2H, Har), 7.30 (m, 2H, Har), 7.20 (m, 1H, Har), 5.77 (m, 2H, CH]
CH), 5.15 (m, 1H, CHeOH), 3.46 (m, 1H, CHeOH), 2.45 (br s, 1H, OH),
2.06e2.04 (m, 2H, CH2), 1.59e1.32 (m, 12H, CH2), 1.02 (t, J¼7.2 Hz,
methyl-3-buten-2-ol (302
mL, 2.82 mmol, 3 equiv) in CH2Cl2
(5.5 mL) was added GrubbseHoveyda catalyst (29 mg, 0.05 mmol,
0.05 equiv). The mixture was stirred overnight at 40 ꢁC and the
solvent was removed under reduced pressure. The residue was
purified by flash chromatography on silica gel previously neutra-
lized by Et3N to afford the expected diacetate, which was treated
according to general procedure A. Purification of the residue by
flash chromatography on silica gel furnished diol 3f (60 mg, 28%,
3H, CH3); 13C NMR (100 MHz, C6D6)
d: 144.5 (s), 133.8 (d), 131.5 (d),
128.6 (2d), 127.4 (d), 126.6 (2d), 75.1 (d), 71.5 (d), 38.0 (t), 37.3 (t),
32.5 (t), 25.8 (t), 25.5 (t), 23.1 (t), 32.5 (t), 14.3 (q); HRMS (ESI):
MNaþ, found 299.1977. C18H28NaO2 requires 299.1981.
4.3.4. (E)-1-(2,4,6-Trimethyl-phenyl)-dodec-2-ene-1,7-diol (3d, mix-
ture of diastereomers) and (E)-1-(2,4,6-trimethyl-phenyl)-dodec-1-
ene-3,7-diol (3d0, mixture of diastereomers). To a solution of 1c
(637 mg, 3.0 mmol, 1.0 equiv) and 2b (1.965 g, 9.0 mmol, 3.0 equiv)
in CH2Cl2 (18 mL) was added GrubbseHoveyda catalyst (94 mg,
0.15 mmol, 0.05 equiv). After 8 h at 40 ꢁC another portion of
GrubbseHoveyda catalyst (47 mg, 0.07 mmol, 0.03 equiv) was
added. After 4 h at 40 ꢁC, silica was added to the reaction mixture
and the volatiles were removed under reduced pressure. The resi-
due was purified by flash chromatography on silica gel (PE/Et2O 9/
1) to give the expected diacetate (201 mg, 17%) and a mixture of the
two regioisomeric acetates (371 mg, 31%). General procedure A was
applied to the pure fraction giving rise to diol 3d (124 mg, 13%, two
steps). The same procedure was applied to the regioisomeric mix-
ture of the two acetates and a flash chromatography on silica gel
allowed to separate 3d (98 mg, 10% from 1c) from 3d0 (153 mg, 16%
from 1c); compound 3d: IR (neat) 3309, 2921, 2855, 1610, 1456,
two steps); IR (neat) 3334, 2924, 2856, 1670, 1458, 1374, 1148 cmꢀ1
1H NMR (400 MHz, C6D6)
: 5.76e5.65 (m, 2H, CH]CH), 3.50 (m,
;
d
1H, CHeOH), 2.11e2.08 (m, 2H, CH2),1.33 (s, 3H, CH3eC),1.32 (s, 3H,
CH3eC), 1.60e1.20 (m, 12H, CH2), 1.02e0.95 (m, 3H, CH3); 13C NMR
(100 MHz, C6D6) d: 139.1 (d),126.7 (d), 71.5 (d), 70.2 (s), 38.1 (t), 37.4
(t), 32.6 (t,) 32.3 (t), 30.2 (2q), 25.9 (t), 25.8 (t), 23.1 (t), 14.3 (q);
HRMS (ESI): MNaþ, found 251.1979. C14H28NaO2 requires 251.1981.
4.3.7. (E)-Tridec-3-ene-2,8-diol (3g, mixture of diastereoisomers). To
a solution of 1c (1.02 g, 4.8 mmol, 1.0 equiv) and 3-buten-2-one
(973
mL, 12 mmol, 2.5 equiv) in CH2Cl2 (14 mL) was added
GrubbseHoveyda catalyst (40 mg, 0.06 mmol, 1.3 mol %). After 16 h
at 40 ꢁC, an additional portion of GrubbseHoveyda catalyst
(1.3 mol %) was added. After 8 h at 40 ꢁC, a third portion of
GrubbseHoveyda catalyst (1.3 mol %) was added. After 12 h at 40 ꢁC,
silica was added to the reaction mixture and the volatiles were

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A. Guerinot et al. / Tetrahedron 67 (2011) 5024e5033
5031
removed under reduced pressure. The residue was purified by flash
chromatography on silica gel (PE/EtOAc: 9/1 to 8/2) to give acetic
acid (E)-7-oxo-1-pentyl-oct-5-enyl ester (515 mg, 42%); IR (neat)
with a saturated Na2CO3 solution (100 mL) and with brine (100 mL),
dried over MgSO4, filtered, and concentrated under reduced pres-
sure to yield 6-methyl-5-(tert-butyldimethyl-silyloxy)-heptan-
aldehyde as an oil. PPh3 (6.66 g, 25.4 mmol, 4.0 equiv) was added to
a solution of CBr4 (4.25 g, 12.7 mmol, 2.0 equiv) in CH2Cl2 (47 mL) at
2933, 2861, 1734, 1676,1628, 1372, 1244, 1022 cmꢀ1 1H NMR
;
(400 MHz, CDCl3)
d
: 6.76 (dt, J¼15.9, 6.8 Hz, 1H, CH]CH), 6.06 (d,
J¼15.9 Hz,1H, CH]CH), 4.87 (m,1H, CHeOAc), 2.24 (s, 3H, CH3eCO),
0
ꢁC. After 30 min, the previously obtained oil was added to the
2.24e2.21 (m, 2H, CH2), 2.04(s, 3H, CH3eCO),1.56e1.47 (m, 6H, CH2),
solution and after 2 h at 0 ꢁC pentane (150 mL) was added to the
reaction mixture and a solid appeared. The mixture was filtered
through a pad of silica, the solvents were removed under reduced
pressure to deliver the crude gem-dibromo olefin as an oil (1.9 g,
72% crude yield from 4). This oil was diluted in THF (5 mL), cooled to
ꢀ78 ꢁC and n-BuLi (2 M in hexanes, 5.0 mL, 10.0 mmol) was added
dropwise. The reaction mixture was allowed to warm to ꢀ25 ꢁC and
was stirred at this temperature for 1 h. Then, mesitaldehyde
(4.6 mL, 31 mmol) was added. After 1.5 h at room temperature,
saturated NH4Cl solution was added (5 mL), the aqueous phase was
extracted with Et2O (3ꢂ5 mL), the combined organic layers were
dried over MgSO4, filtered and the volatiles were removed under
reduced pressure. The residue was filtered through a pad of silica
1.27 (m, 6H, CH2), 0.87 (m, 3H, CH3); 13C NMR (100 MHz, CDCl3)
d:
198.8 (s), 171.1 (s), 147.8 (d), 131.7 (d), 74.0 (d), 34.3 (t), 33.8 (t), 32.4
(t), 31.8 (t), 27.1 (q), 25.1 (t), 24.0 (t), 22.7 (t), 21.4 (q), 14.1 (q); HRMS
(ESI): MNaþ, found 277.1771. C15H26NaO3 requires 277.1774.
CeCl3$7H2O (1.46 g, 3.93 mmol, 2.0 equiv) was added to a solu-
tion of the previously prepared enone (500 mg, 1.97 mmol,
1.0 equiv) in methanol (28 mL). After 10 min at room temperature,
the reaction mixture was cooled down to 0 ꢁC and NaBH4 (90 mg,
2.36 mmol, 1.2 equiv) was slowly added. The reaction mixture was
stirred at 0 ꢁC for 15 min and then 4 h at room temperature. Sat-
urated ammonium chloride aqueous solution (10 mL), saturated
aqueous solution of potassium sodium tartrate (10 mL), and EtOAc
(20 mL) were added. The mixture was filtered, the organic phase
was washed with brine (20 mL), dried over MgSO4, filtered and the
volatiles were removed under reduced pressure to give the corre-
sponding alcohol (405 mg, 80%). General procedure A was then
applied to the latter to give 3g (265 mg, 81%, 34% from 1c); IR (neat)
gel (PE/EtOAc: 9/1) to give a crude oil (1.89 g). Quinoline (293 mL,
2.48 mmol, 1.0 equiv) and Pd Lindlar 5% (74 mg, 0.035 mmol,
0.014 equiv) were added to a solution of 1 g of the previously
obtained crude oil in EtOAc (31 mL) under H2 atmosphere. After
1.25 h at room temperature the reaction mixture was filtered
through a pad of silica and the solvents were removed under re-
duced pressure. The residue was filtered on silica gel (PE/EtOAc: 9/
1) to give a crude oil (982 mg). TBAF (1 M in THF, 2.4 mL, 2.4 mmol,
2.0 equiv) was added to a solution of 490 mg of the previously
obtained oil in THF (4 mL). After 15 h at room temperature, an
additional portion of TBAF (1 M in THF, 2.4 mL, 2.4 mmol, 2.0 equiv)
was added and the reaction was stirred overnight. Saturated
NaHCO3 solution was added (3 mL) to the reaction mixture, the
aqueous phase was extracted with diethyl ether (3ꢂ3 mL),
the combined organic layers were washed with brine (4 mL) and
the solvents were removed under reduced pressure. The residue
was purified by flash chromatography on silica gel (PE/EtOAc: 8/2 to
7/3) to give 3i (140 mg, 28% from 4); IR (neat) 3319, 2919, 2870,
3340, 2929, 2858, 1276, 1064 cmꢀ1 1H NMR (400 MHz, C6D6)
; d:
5.66 (m, 2H, CH]CH), 4.28 (qd, J¼6.1, 6.1 Hz, 1H, CHeOH), 3.56 (m,
1H, CHeOH), 2.50e1.90 (m, 2H, OH), 2.09 (m, 2H, CH2), 1.65e1.38
(m, 12H, CH2), 1.33 (d, J¼6.1 Hz, 3H, CH3eCHOH), 1.02 (t, J¼7.0 Hz,
3H, CH3); 13C NMR (100 MHz, C6D6)
d: 135.4 (d), 130.0 (d), 71.5 (d),
71.5 (d), 68.6 (d), 38.0 (t), 38.0 (t), 37.3 (t), 37.3 (t), 32.5 (t), 32.5 (t),
32.4 (t), 25.7 (t), 5.7 (t), 23.8 (t), 23.1 (t), 25.8 (q), 14.3 (q); HRMS
(ESI): MNaþ, found 237.1822. C13H26NaO2 requires 237.1825.
4.3.8. (E)-8-Methyl-1-(2,4,6-trimethyl-phenyl)-non-2-ene-1,7-diol
(3h, mixture of diastereomers). To a solution of 2b (655 mg,
3.0 mmol, 3.0 equiv) and 4 (256 mg, 1.0 mmol, 1.0 equiv) in CH2Cl2
(6 mL) was added GrubbseHoveyda catalyst (42 mg, 0.07 mmol,
0.07 equiv). After 12 h at 40 ꢁC the reaction mixture was filtered
through a pad of CeliteÒ and the volatiles were removed under
reduced pressure to give an oil. To a solution of the residue in THF
(3.5 mL) was added TBAF (1 M in THF, 2 mL, 2 mmol, 2.0 equiv).
After one night at room temperature, an additional portion of TBAF
(1 M in THF, 2 mL, 2 mmol, 2.0 equiv) was added. After one night,
saturated aqueous solution of sodium hydrogen carbonate was
added (4 mL), the aqueous phase was extracted with EtOAc
(3ꢂ5 mL), the organic phases were washed with brine (10 mL),
dried over MgSO4 and the volatiles were removed under reduced
pressure to obtain an oil. General procedure A was applied to the
latter oil to deliver 3h (68 mg, 23% overall yield); IR (neat) 3338,
1612, 1578, 1459, 1378, 1038 cmꢀ1; 1H NMR (400 MHz, C6D6)
d: 6.83
(s, 2H, Har), 6.10 (m, 1H, CH]CH), 5.95 (m, 1H, CHeOH), 5.49 (m, 1H,
CH]CH), 3.17 (m, 1H, CHeOH), 2.52 (s, 3H, CH3eAr), 2.51 (s, 3H,
CH3eAr), 2.36e1.97 (m, 2H, CH2), 2.23 (m, 3H, CH3eAr), 1.54e1.27
(m, 5H, CH2, CH), 0.95e0.90 (m, 6H, CH3eCH); 13C NMR (100 MHz,
C6D6) d: 137.5 (s), 137.5 (s), 136.6 (s), 136.5 (s), 136.4 (s), 136.4 (s),
133.0 (d), 132.9 (d), 131.4 (d), 131.1 (d), 130.3 (2d), 76.5 (d), 76.2 (d),
67.7 (d), 67.5 (d), 34.1 (d), 34.0 (d), 33.9 (d), 33.4 (t), 28.3 (t), 28.0 (t),
26.5 (t), 26.3 (t), 21.0 (2q), 20.8 (q), 19.1 (q), 19.0 (q), 17.3 (q); HRMS
(ESI): MNaþ, found 313.2134. C19H30NaO2 requires 313.2138.
4.3.10. (E)-8-Acetoxy-2-hydroxy-8-phenyl-oct-6-enoic acid ethyl
ester (3j, mixture of diastereoisomers). To a solution of acetate 2a
(1.58 g, 9.0 mmol, 3 equiv) and 2-hydroxy-hept-6-enoic acid ethyl
ester 5a16 (516 mg, 3.0 mmol, 1 equiv) in CH2Cl2 (15 mL) was added
GrubbseHoveyda catalyst (56 mg, 0.09 mmol, 3 mol %). The re-
action mixture was stirred for 36 h at 40 ꢁC and an additional
portion of GrubbseHoveyda catalyst (56 mg, 0.09 mmol, 3 mol %)
was added. After 24 h at 40 ꢁC, the solvent was removed under
reduced pressure and the crude was purified by flash chromato-
graphy on silica gel (PE/Et2O: 9/1 to 5/5) to furnish 3j as a mixture of
two diastereomers (545 mg, 57%); IR (neat) 3489, 2929, 1730, 1495,
2919, 1610, 1447, 1275 cmꢀ1; 1H NMR (400 MHz, C6D6)
d: 6.86 (br s,
2H, Har), 5.92 (m, 1H), 5.70 (m, 1H), 5.68 (m, 1H), 3.17 (m, 1H), 2.48
(s, 6H), 2.24 (s, 3H), 2.04 (m, 2H), 1.32e1.59 (m, 5H), 0.94e0.89 (m,
6H); 13C NMR (100 MHz, C6D6)
d: 136.5 (2s), 136.4 (s), 131.7 (d),
130.5 (d), 130.2 (2d), 128.7 (s), 76.1 (d), 71.2 (d), 34.0 (d), 33.8 (t),
32.6 (t), 26.0 (t), 20.8 (3q), 19.0 (q), 17.2 (q); HRMS (ESI): MNaþ,
found 313.2136. C19H30NaO2 requires 313.2138.
4.3.9. (Z)-8-Methyl-1-(2,4,6-trimethyl-phenyl)-non-2-ene-1,7-diol
(3i, mixture of diastereomers). Ozone was bubbled into a solution of
4 (1.63 g, 6.35 mmol, 1.0 equiv) in CH2Cl2 (160 mL) at ꢀ78 ꢁC. When
the solution turned blue, argon was bubbled and then NEt3
(1.78 mL, 12.7 mmol, 2.0 equiv) was added. The reaction mixture
was stirred at ꢀ78 ꢁC for 10 min and then was allowed to reach
room temperature. Pentane (100 mL) and a 10% aqueous solution of
H3PO4 (25 mL) were added. The aqueous phase was extracted with
Et2O (3ꢂ20 mL), and the combined organic layers were washed
1454, 1370, 1231, 1099, 1020 cmꢀ1 1H NMR (400 MHz, C6D6)
; d:
7.38e7.32 (m, 2H, Har), 7.18e7.12 (m, 2H, Har), 7.10e7.03 (m, 1H,
Har), 6.47e6.43 (m, 1H, CHeOAc), 5.70e5.62 (m, 2H, CH]CH),
4.03e3.98 (m, 1H, CHeOH), 3.92e3.79 (m, 2H, CH2eO), 2.75 (m, 1H,
OH), 1.88e1.80 (m, 2H, CH2), 1.71e1.64 (m, 0.5H, CH2), 1.68 (s, 3H,
CH3eCO), 1.55e1.39 (m, 3.5H, CH2), 0.93e0.82 (m, 3H, CH3eCH2);
13C NMR (100 MHz, C6D6)
d: 175.3 (s), 169.3 (s C8), 140.5 (s), 134.1

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A. Guerinot et al. / Tetrahedron 67 (2011) 5024e5033
5032
(d), 129.5 (d), 128.7 (2d), 128.3 (d), 128.0 (d), 127.4 (d), 76.3 (d), 70.4
(d), 61.3 (t), 34.2 (t), 32.1 (t), 24.5 (t), 20.8 (q), 14.1 (q); HRMS (ESI):
MNaþ, found 343.1513. C18H24NaO5 requires 343.1516.
4.4.2. cis-2-Cylohexyl-6-((E)-styryl)-tetrahydropyran (6b). Prepared
from 3b according to general procedure B (99%); IR (neat) 2919,
2849, 1726, 1599, 1494, 1448, 1283, 1072, 1039 cmꢀ1 1H NMR
;
(400 MHz, CDCl3)
d
: 7.38 (dapp, J¼7.4 Hz, 2H, Har), 7.29 (tapp
,
4.3.11. Acetic acid (E)-(5S
*
,7S
*
)-5,7-dihydroxy-1-phenyl-dodec-2-
,6S )-5b (281 mg, 1.5 mmol,
J¼7.4 Hz, 2H, Har), 7.20 (tapp, J¼7.4 Hz, 1H, Har), 6.58 (d, J¼16.4 Hz,
1H, ]CHePh), 6.23 (dd, J¼16.4, 5.5 Hz, 1H, ]CHe), 3.96 (m, 1H,
CHeO), 3.12 (m,1H, CHeO),1.01e2.01 (m,17H); 13C NMR (100 MHz,
enyl ester (3k). To a solution of (4S
*
*
1.0 equiv) and acetate 2a (798 mg, 4.5 mmol, 3.0 equiv) in CH2Cl2
(9 mL) was added GrubbseHoveyda catalyst (30 mg, 0.048 mmol,
3.2 mol %). After 24 h at 40 ꢁC, another portion of GeH catalyst
(15 mg, 0.024 mmol, 1.6 mol %) was added. After 24 h at 40 ꢁC, the
volatiles were removed under reduced pressure and the residue
was purified by flash chromatography on silica gel (PE/EtOAc: 8/2 to
6/4) to give 3k (202 mg, 40%); IR (neat) 3407, 2930, 2858, 1736,
CDCl3) d: 137.4 (s), 131.6 (d), 129.3 (d), 128.6 (2d), 127.4 (d), 126.6
(2d), 82.5 (d), 78.3 (d), 42.4 (d), 32.3 (t), 29.5 (t), 28.9 (t), 28.1 (t),
26.9 (t), 26.5 (t), 26.4 (t), 24.0 (t); MS (EI) m/z: 270 ([M]þꢃ, 4), 130
(21), 129 (33), 128 (30), 122 (66), 115 (38), 104 (21), 91 (52), 81 (33),
79 (21), 77 (21), 67 (41), 55 (100); HRMS (ESI): MNaþ, found
293.1880. C19H26NaO requires 293.1876.
1454, 1259 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
: 7.46 (d, J¼7.7 Hz, 2H,
Har), 7.26 (m, 2H, Har), 7.18 (t, J¼7.7 Hz, 1H, Har), 6.55 (m, 1H,
CHeOAc), 5.90 (m, 1H, CH]CH), 5.81 (dd, J¼14.9, 6.5 Hz, 1H, CH]
CH), 3.99e3.88 (m, 2H, CHeOH), 2.22 (m, 2H, CH2), 1.79 (s, 3H,
CH3eCO), 1.55e1.33 (m, 10H, CH2), 1.02 (t, J¼6.7 Hz, 3H, CH3); 13C
4.4.3. cis-2-Pentyl-6-((E)-styryl)-tetrahydropyran (6c). Prepared from
3c according to general procedure B (83%); IR (neat) 2927, 2856, 1711,
1600, 1494, 1449, 1310, 1195, 1072, 104 cmꢀ1 1H NMR (400 MHz,
;
CDCl3) d: 7.39 (m, 2H, Har), 7.30 (m, 2H, Har), 7.21 (m, 1H, Har), 6.58 (d,
NMR (100 MHz, CDCl3) d: 169.6 (s), 140.3 (s), 131.8 (d), 131.0 (d),
J¼16.6 Hz, 1H, CH]CH), 6.25 (dd, J¼16.6, 6.0 Hz, 1H, CH]CH), 3.99
(ddapp, J¼11.2, 6.0 Hz, 1H, CHeO), 3.39 (m, 1H, CHeO), 1.85e1.78 (m,
1H, CH2),1.65e1.20 (m, 13H, CH2), 0.91 (t, J¼6.7 Hz, 3H, CH3); 13C NMR
128.8 (d), 128.2 (2d), 127.4 (2d), 76.6 (d), 69.2 (t), 68.5(t), 42.6 (t),
37.9 (t), 32.3 (t), 25.9 (t), 23.1 (t), 40.9 (t), 20.8 (q), 14.3 (q); HRMS
(ESI): MNaþ, found 357.2034. C20H30NaO4 requires 357.2036.
(100 MHz, CDCl3) d: 137.2 (s), 131.2 (d), 129.6 (d), 128.5 (2d), 127.3 (d),
126.4 (2d), 78.2 (d), 78.0 (d), 36.6 (t), 32.0 (t), 31.9 (t), 31.3 (t), 23.7 (t),
25.3 (t), 22.7 (t), 14.1 (q); MS (EI) m/z: 258 ([M]þꢃ, 54), 161 (11), 133
(64), 131 (65), 130 (75), 129 (45), 128 (42), 115 (54), 110 (34), 105 (75),
104 (100), 103 (25), 91 (87), 84 (22), 81 (27), 77 (23), 69 (29), 55 (67);
HRMS (ESI): MNaþ, found 281.1880. C18H26NaO requires 281.1876.
4.3.12. Acetic acid (E)-(5R
*
,7S
*
)-5,7-dihydroxy-1-phenyl-dodec-2-
,6S )-5b (500 mg, 2.7 mmol,
enyl ester (3l). To a solution of (4R
*
*
1.0 equiv) and acetate 2a (1.3 g, 7.4 mmol, 3.0 equiv) in CH2Cl2
(18 mL) was added GrubbseHoveyda catalyst (30 mg, 0.048 mmol,
1.8 mol %). After 24 h at 40 ꢁC, another portion of GeH catalyst
(30 mg, 0.048 mmol, 1.8 mol %) was added. After 24 h at 40 ꢁC,
another portion of GeH catalyst (30 mg, 0.048 mmol,1.8 mol %) was
added. After 24 h at 40 ꢁC, the volatiles were removed under
reduced pressure and the residue was purified by flash chroma-
tography on silica gel (PE/EtOAc: 8/2 to 6/4) to give 3l (235 mg,
4.4.4. cis-2-Pentyl-6-[(E)-2-(2,4,6-trimethyl-phenyl)-vinyl]-tetrahy-
dropyran (6d). Prepared according to general procedure B from 3d
(89%) or from 3d0 (88%); IR (neat) 2926, 2856, 1612, 1456, 1195,
1078, 1044, 850 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d: 6.87 (br s, 2H,
Har), 6.53 (d, J¼16.0 Hz, 1H, CH]CH), 5.74 (dd, J¼16.0, 5.6 Hz, 1H,
CH]CH), 4.01 (dddd, J¼11.3, 5.6, 2.3,1.5 Hz,1H, CHeO), 3.39 (m,1H,
CHeO), 2.30 (s, 6H, CH3eAr), 2.28 (s, 3H, CH3eAr),1.92e1.88 (m,1H,
CH2), 1.76e1.73 (m, 1H, CH2), 1.66e1.23 (m, 12H, CH2), 0.92
26%); IR (neat) 3390, 2930, 2857, 1736, 1452, 1371, 1234 cmꢀ1
NMR (400 MHz, CDCl3)
;
1H
d
: 7.46 (d, J¼7.7 Hz, 2H, Har), 7.26 (m, 2H,
Har), 7.17 (t, J¼7.7 Hz, 1H, Har), 6.55 (m, 1H, CHeOAc), 5.93 (m, 1H,
CH]CH), 5.81 (dd, J¼15.0, 6.6 Hz, 1H, CH]CH), 3.80e3.73 (m, 2H,
CHeOH), 2.16 (m, 2H, CH2), 1.78 (s, 3H, CH3eCO),1.47e1.35 (m, 10H,
(t, J¼7.0 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3)
d: 136.2 (2s), 135.9
(d), 135.8 (s), 133.8 (s), 128.5 (2d), 126.8 (d), 78.7 (d), 77.9 (d), 36.6
(t), 31.3 (t), 25.3 (t), 22.7 (t), 32.4 (t), 32.0 (t), 23þ.8 (t), 20.9 (3q), 14.1
(q); MS (EI) m/z: 300 ([M]þꢃ, 34), 282 ([MꢀH2O] ꢃ, 50), 211 (26), 173
(29), 171 (21), 170 (60), 169 (26), 159 (45), 157 (76), 146 (49), 142
(24), 133 (100), 132 (35), 129 (21); HRMS (ESI): MNaþ, found
323.2341. C21H32NaO requires 323.2345.
CH2), 1.01 (t, J¼6.8 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3)
d: 169.2
(s), 140.0 (s), 131.6 (d), 130.3 (d), 128.5 (2d), 127.9 (d), 127.1 (2d), 76.2
(d), 72.6 (d), 71.9 (d), 42.6 (t), 41.2 (t), 38.3 (t), 32.0 (t), 25.1 (t), 22.8
(t), 20.6 (q), 14.0 (q); HRMS (ESI): MNaþ, found 357.2033.
C20H30NaO4 requires 357.2036.
4.4. Synthesis of tetrahydropyrans
4.4.5. cis-(2R,6R)-2-Methyl-6-((E)-styryl)-tetrahydropyran ((R,R)-6e).
Prepared from (1RS,7R)-3e according to general procedure B (95%);
General procedure B for iron-catalyzed cyclizations: to a solu-
tion of substrate 3ael in CH2Cl2 (0.1 M) at room temperature was
added FeCl3$6H2O (5 mol %). After the required time (see Tables for
details), the resulting mixture was directly filtered through a pad of
silica gel (CH2Cl2) and the volatiles were removed under reduced
pressure to yield the corresponding cyclized product without any
further purification.
20
[
a
]
þ2.8 (c 1.15, CHCl3); chiral SFC: Chiralcel AD-H column, CO2
D
100 bar, 1% i-PrOH, 5 mL/min, 254 nm, tR(S,S) 2.23 min, tR(R,R)
2.62 min; IR (neat) 2926, 2843, 1727, 1440, 1085 cmꢀ1 1H NMR
(400 MHz, CDCl3)
;
d: 6.88 (br s, 2H, Har), 6.54 (d, J¼16.2 Hz, 1H, CH]
CH), 5.76 (dd, J¼16.2, 6.4 Hz, 1H, CH]CH), 4.05 (m, 1H, CHeO), 3.59
(dqd, J¼11.0, 6.1, 1.9 Hz, 1H, CHeO), 2.32 (s, 6H, CH3eAr), 2.29 (s, 3H,
CH3eAr), 1.94e1.88 (m, 1H, CH2), 1.77e1.30 (m, 5H, CH2), 1.27 (d,
J¼6.1 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3)
d: 136.3 (d), 136.1 (2s),
4.4.1. cis-2-Isopropyl-6-((E)-styryl)-tetrahydropyran (6a). Prepared
from 3a according to general procedure B (66%); IR (neat) 3026,
2936, 2872, 2361, 2341, 1715, 1600, 1578, 1495, 1470, 1449, 1377,
136.0 (s),133.8 (s),128.6 (2d),127.2 (d), 79.0 (d), 74.0 (d), 33.2 (t), 32.2
(t), 23.9 (t), 22.4 (q), 21.1 (2q), 21.0 (q); MS (EI) m/z: 244 ([M]þꢃ, 45),
226 ([MꢀH2O]þꢃ, 49), 170 (41), 159 (51), 157 (93), 146 (53), 142 (30),
141 (24), 133 (100), 132 (79), 131 (48), 129 (39), 128 (38), 115 (35), 91
(25), 55 (47); HRMS (ESI): MNaþ, found 267.1720. C17H24NaO requires
267.1719.
1336, 1302, 1203, 1188, 1147, 1106, 1076, 1044 cmꢀ1 1H NMR
;
(400 MHz, CDCl3) d: 7.41e7.37 (m, 2H, Har), 7.33e7.27 (m, 2H, Har),
7.24e7.18 (m, 1H, Har), 6.60 (dd, J¼16.0, 1.2 Hz, 1H), 6.25 (dd, J¼16.0,
5.4 Hz, 1H), 4.01e3.95 (m, 1H, CHeO), 3.10 (ddd, J¼11.0, 5.5, 1.8 Hz,
1H, CHeO), 1.96e1.89 (m, 1H), 1.80e1.17 (m, 6H), 1.00 (d, J¼6.8 Hz,
3H), 0.93 (d, J¼6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d: 137.3 (s),
4.4.6. cis-2-(2-Methyl-propenyl)-6-pentyl-tetrahydropyran
(6f). Prepared from 3f according to general procedure B (87%); IR
(neat) 2930, 2857, 1739, 1677, 1440, 1376, 1076, 1046 cmꢀ1; 1H NMR
131.5 (d),129.2 (d),128.5 (2d),127.3 (d),126.5 (2d), 83.0 (d), 78.1 (d),
33.4 (d), 32.2 (t), 27.7 (t), 23.8 (t), 19.0 (q), 18.5 (q); HRMS (ESI):
MNaþ, found: 253.1566. C16H22NaO requires 253.1563.
(400 MHz, CDCl3)
d
: 5.18 (dm, J¼7.8 Hz, 1H, CH]C), 3.99 (ddd,

ꢀ
A. Guerinot et al. / Tetrahedron 67 (2011) 5024e5033
5033
J¼11.2, 7.8, 2.0 Hz,1H, CHeO), 3.29 (m,1H, CHeO),1.86e1.78 (m,1H,
CH2), 1.70 (d, J¼1.2 Hz, 3H, CH3eC), 1.67 (d, J¼1.2 Hz, 3H, CH3eC),
1.59e1.09 (m, 13H, CH2), 0.87 (t, J¼7.5 Hz, 3H, CH3); 13C NMR
3.88 (m, 1H, CHeOH), 3.40 (m, 1H, CHeO), 2.10 (m, 1H, CH2), 1.95
(m,1H, CH2),1.64e1.19 (m, 10H, CH2), 0.89 (t, J¼6.7 Hz, 3H, CH3); 13
C
NMR (100 MHz, CDCl3) d: 136.8 (s), 130.3 (d), 129.7 (d), 128.5 (2d),
(100 MHz, CDCl3)
d
: 135.3 (s), 126.8 (d), 77.8 (d), 74.9 (d), 36.6 (t),
127.6 (d), 126.5 (2d), 75.9 (d), 75.8 (d), 68.3 (d), 41.4 (t), 40.9 (t), 36.0
(t), 31.9 (t), 25.3 (t), 22.6 (t), 14.1 (q); MS (EI) m/z: 274 ([M]þꢃ, 22),
133 (47), 131 (28), 130 (21), 129 (23), 115 (26), 105 (42), 104 (100), 91
(32), 55 (28); HRMS (ESI): MNaþ, found 297.1829. C18H26NaO2 re-
quires 297.1825.
32.0 (t), 31.9 (t), 31.2 (t), 25.3 (t), 23.8 (t), 22.6 (t), 25.8 (q), 18.4 (q),
14.1 (q); MS (EI) m/z: 210 ([M]þꢃ, 12), 195 ([MꢀMe]þ, 41), 177
([MꢀMeꢀH2O]þ, 1), 85 (100), 82 (31), 69 (32), 55 (34); HRMS (ESI):
MNaþ, found 233.1876. C14H26NaO requires 233.1876.
4.4.7. cis-2-Pentyl-6-((E)-propenyl)-tetrahydropyran (6g). Prepared
from 3g according to general procedure B (82%); IR (neat) 2929,
4.4.11. (2R
(6l). Prepared from 3l according to general procedure B (99%); IR
(neat) 3407, 3026, 2928, 2858, 1494, 1450, 1057 cmꢀ1 1H NMR
(400 MHz, CDCl3) : 7.38 (m, 2H, Har), 7.30 (m, 2H, Har), 7.24e7.20
*
,4R
*
,6R
*
)2-Pentyl-6-((E)-styryl)-tetrahydro-pyran-4-ol
2857, 1720, 1454, 1439, 1377, 1197, 1077, 1040 cmꢀ1
;
1H NMR
;
(400 MHz, CDCl3)
d
: 5.66 (dqd, J¼15.1, 6.0, 1.2 Hz, 1H, CH]CH), 5.50
d
(ddq, J¼15.1, 6.0, 1.6 Hz, 1H, CH]CH), 3.74 (m, 1H, CHeO), 3.29 (m,
1H, CHeO), 1.84e1.80 (m, 1H, CH2), 1.67 (dm, J¼6.0 Hz, 3H,
CH3eCH), 1.60e1.10 (m, 13H, CH2), 0.87 (t, J¼5.2 Hz, 3H, CH3); 13C
(m, 1H, Har), 6.60 (d, J¼15.9 Hz, 1H, CH]CH), 6.22 (dd, J¼15.9,
6.0 Hz,1H, CH]CH), 3.47 (m, 1H, CHeO), 4.30 (m, 1H, CHeOH), 3.85
(m, 1H, CHeO), 1.80e1.31 (m, 12H, CH2), 0.89 (t, J¼6.7 Hz, 3H, CH3);
NMR (100 MHz, CDCl3)
d
: 133.0 (d), 126.4 (d), 78.3 (d), 78.0 (d), 36.8
13C NMR (100 MHz, CDCl3)
d: 137.0 (s), 130.7 (d), 130.2 (d), 128.6
(t), 32.2 (t), 31.9 (t), 31.4 (t), 25.4 (t), 23.8 (t), 22.8 (t), 18.0 (q), 14.2
(q); MS (EI) m/z: 196 ([M]þꢃ, 10), 181 ([MꢀMe]þ, 6), 153
([MꢀC3H7]þ, 21), 125 (21), 110 (17), 97 (15), 71 (100); HRMS (ESI):
MNaþ, found 219.1721. C13H24NaO requires 219.1719.
(2d),127.6 (d),126.6 (2d), 72.2 (d), 71.8 (d), 64.8 (d), 39.0 (t), 38.5 (t),
36.4 (t), 32.0 (t), 25.3 (t), 22.7 (t), 14.2 (q); MS (EI) m/z: 274 ([M]þ
,
ꢃ
16), 133 (50), 131 (30), 130 (21), 129 (23), 115 (25), 105 (45), 104
(100), 91 (29), 55 (29); HRMS (ESI): MNaþ, found 297.1831.
C18H26NaO2 requires 297.1825.
4.4.8. cis-2-Isopropyl-6-[(E)-2-(2,4,6-trimethyl-phenyl)-vinyl]-tetra-
hydropyran (6h). Prepared according to general procedure B from
3h (82%) or from 3i (96%); IR (neat) 2933, 2857, 1612, 1439,
Acknowledgements
1078 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d: 6.87 (br s, 2H, Har), 6.54 (d,
The CNRS (grant to A.G.) and the commission at per a Uni-
versitats I Recerca del Departament d’Innovacio’ Universitats I
Empresa de la Generalitat de Catalunya (grant to A.S.-M.) are
gratefully acknowledged.
J¼16.3 Hz, 1H, CH]CH), 5.74 (dd, J¼16.3, 6.0 Hz, 1H, CH]CH), 3.99
(m, 1H, CHeO), 3.10 (m, 1H, CHeO), 2.30 (s, 6H, CH3eAr), 2.28 (s,
3H, CH3eAr), 1.95e1.92 (m, 1H, CH2), 1.66e1.44 (m, 4H, CH2, CH),
1.37e1.10 (m, 2H, CH2), 1.00 (d, J¼6.9 Hz, 3H, CH3eCH), 0.94 (d,
J¼6.9 Hz, 3H, CH3eCH); 13C NMR (100 MHz, CDCl3)
d: 136.5 (d),
136.0 (2s), 135.9 (s), 134.1 (s), 128.6 (2d), 126.5 (d), 82.9 (d), 78.5 (d),
33.5 (d), 32.6 (t), 28.0 (t), 24.0 (t), 21.1 (q), 21.0 (2q), 19.0 (q), 18.6
(q); MS (EI) m/z: 272 ([M]þꢃ, 27), 254 ([MꢀH2O]þꢃ, 26), 211 (22), 170
(34), 157 (56), 133 (100), 115 (17), 55 (34); HRMS (ESI): MHþ, found
273.2211. C19H29O requires 273.2213.
References and notes
1. (a) Clarke, P. A.; Santos, S. Eur. J. Org. Chem. 2006, 2045; (b) Boivin, T. L. B.
Tetrahedron 1987, 43, 3309; (c) Larrosa, I.; Romea, P.; Urpi, F. Tetrahedron 2008,
64, 2683.
2. Muzart, J. Tetrahedron 2005, 61, 5955.
3. For reviews on stereoselective allylic alkylations, see: (a) Trost, B. M.; Van
Vranken, D. L. Chem. Rev. 1996, 96, 395; (b) Trost, B. M. Acc. Chem. Res. 1996, 29,
355; (c) Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921.
4. Hansen, E. C.; Lee, D. Tetrahedron Lett. 2004, 45, 7151.
5. (a) Miyazawa, M.; Hirose, Y.; Narantsetseg, M.; Yokoyama, H.; Yamagushi, S.;
Hirai, Y. Tetrahedron Lett. 2004, 45, 2883; (b) Uenishi, J.; Ohmi, M. Angew. Chem.,
Int. Ed. 2005, 44, 2756; (c) Uenishi, J.; Ohmi, M.; Ueda, A. Tetrahedron: Asym-
metry 2005, 16, 1299; (d) Uenishi, J.; Vikhe, Y. S.; Kawai, N. Chem.dAsian J. 2008,
3, 473; (e) Kawai, N.; Lagrange, J.-M.; Ohmi, M.; Uenishi, J. J. Org. Chem. 2006, 71,
4530; (f) Kawai, N.; Lagrange, J.-M.; Uenishi, J. Eur. J. Org. Chem. 2007, 2808.
6. (a) Aponick, A.; Li, C.-Y.; Biannic, B. Org. Lett. 2008, 10, 669; (b) Aponick, A.;
Biannic, B. Org. Lett. 2011, 13, 1330.
4.4.9. cis-6-((E)-Styryl)-tetrahydropyran-2-carboxylic acid ethyl es-
ter (6j). Prepared from 3j according to general procedure B (99%);
IR (neat) 2937, 2858, 1751, 1599, 1495, 1448, 1383, 1296, 1191, 1157,
1100, 1040 cmꢀ1 1H NMR (400 MHz, CDCl3)
; d: 7.39 (m, 2H, Har),
7.30 (m, 2H, Har), 7.21 (m, 1H, Har), 6.58 (d, J¼16.6 Hz, 1H, CH]CH),
6.25 (dd, J¼16.6, 6.0 Hz,1H, CH]CH), 3.99 (ddapp, J¼11.2, 6.0 Hz,1H,
CHeO), 3.39 (m, 1H, CHeO), 1.85e1.78 (m, 1H, CH2), 1.65e1.20 (m,
7H, CH2), 0.91 (t, J¼6.7 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3)
d:
171.5 (s), 136.9 (s), 130.7 (d), 129.9 (d), 128.6 (2d), 127.7 (d), 126.6
(2d), 78.8 (d), 76.9 (d), 61.1 (t), 31.3 (t), 28.6 (t), 23.4 (t), 14.4 (q); MS
(EI) m/z: 260 ([M]þꢃ, 19), 187 ([MꢀCO2Et]þ, 80), 186 (21), 169 (31),
168 (15), 158 (18), 146 (11), 143 (38), 141 (23), 131 (50), 130 (29), 129
(53), 128 (81), 127 (27), 117 (31), 115 (64), 114 (22), 110 (16), 105 (19),
104 (51),103 (24), 101 (26), 91 (100), 78 (16), 73 (36), 55 (44); HRMS
(ESI): MNaþ, found 283.1303. C16H20NaO3 requires 283.1305.
7. For another gold-catalyzed formation of tetrahydropyrans, see: Jung, H. H.;
Floreancig, P. E. Org. Lett. 2006, 8, 1949.
8. In a tandem Ru-catalyzed cross-metathesis/intramolecular SN20 reaction be-
tween allylbromide and b,d-dihydroxyolefins, the diastereoselective synthesis
of 4-hydroxy-2,6-cis-tetrahydropyrans was described. However, the SN20 pro-
cess was reported to be thermally mediated and not metallo-catalyzed. See:
Lee, K.; Kim, H.; Hong, J. Org. Lett. 2009, 11, 5202.
ꢀ
9. Guerinot, A.; Serra-Muns, A.; Gnamm, C.; Bensoussan, C.; Reymond, S.; Cossy, J.
Org. Lett. 2010, 12, 1808.
ꢀ
10. Serra-Muns, A.; Guerinot, A.; Reymond, S.; Cossy, J. Chem. Commun. 2010, 4178.
11. We have to point out that in the cyclization of other substrates, such as ami-
noacetates giving rise to piperidines, TfOH gave lower yields than FeCl3$6H2O.
12. Hon, Y.-S.; Liu, Y.-W.; Hsieh, C.-H. Tetrahedron 2004, 60, 4837.
13. Prepared from the commercially available (R)-propylene oxide. See: Lin, W.;
Zercher, C. K. J. Org. Chem. 2007, 72, 4390.
4.4.10. (2R
(6k). Prepared from 3k according to general procedure B (99%); IR
(neat) 3373, 2929, 2856, 1600, 1449, 1275, 1138 cmꢀ1 1H NMR
(400 MHz, CDCl3) : 7.38 (m, 2H, Har), 7.30 (m, 2H, Har), 7.24e7.20
*
,4S
*
,6R
*
)-2-Pentyl-6-((E)-styryl)-tetrahydropyran-4-ol
;
d
14. Marion, N.; Gealageas, R.; Nolan, S. P. Org. Lett. 2007, 9, 2653.
(m, 1H, Har), 6.60 (d, J¼15.9 Hz, 1H, CH]CH), 6.23 (dd, J¼15.9,
15. Macritchie, J. A.; Silcock, J. A.; Willis, C. L. Tetrahedron: Asymmetry 1997, 8, 3895.
€
6.0 Hz, 1H, CH]CH), 3.99 (dddd, J¼11.1, 6,0, 1.6, 1.6 Hz, 1H, CHeO),
16. Bode, S. E.; Muller, M.; Wolberg, M. Org. Lett. 2002, 4, 619.