Synthesis of α,β-unsaturated dioxanes, dioxolanes and dioxepanes by trans-acetalisation of dimethylacetals with meso or C 2-symmetrical 1,2-, 1,3- and 1,4-diols

Article abstract of DOI:10.1016/j.tet.2003.11.009

Several o-dibenzylic diols were prepared reacting organometallics with o-phthalaldehyde at room temperature in ether. The identity of the meso and C₂-symmetrical (D,L) isomers as well as their ratio were determined by chiral gas chromatography. The meso and C₂ (racemic) stereoisomeric diols were easily separated by flash chromatography on silica gel. A set of 18 α,β-unsaturated acetals were then prepared reacting those, as well as commercially available 1,2, 1,3 and 1,4 diols, with the corresponding methylacetals in acidic medium. A trans-acetalisation procedure adapted to the cases of fragile allylic alcohols or unfavorable 1,6 diols-derived dioxonanes based on a Dean-Stark trapping of methanol was also employed.

Full text of DOI:10.1016/j.tet.2003.11.009

Tetrahedron 60 (2004) 415–427
Synthesis of a,b-unsaturated dioxanes, dioxolanes and dioxepanes
by trans-acetalisation of dimethylacetals with meso or
C2-symmetrical 1,2-, 1,3- and 1,4-diols
a
Loıc Lemiegre, Fleur Lesetre, Jean-Claude Combret and Jacques Maddaluno
a
b
a
,
*
`
¨
a
´ ´ ´ ´
Laboratoire des Fonctions Azotees & Oxygenees Complexes de l’IRCOF, UMR 6014 CNRS, Universite de Rouen,
76821 Mont St Aignan Cedex, France
Laboratoire des Sciences et Methodes Separatives de l’IRCOF, UPRES 2659, Universite de Rouen, 76821 Mont St Aignan Cedex, France
b
´
´
´
Received 4 August 2003; revised 4 November 2003; accepted 6 November 2003
Abstract—Several o-dibenzylic diols were prepared reacting organometallics with o-phthalaldehyde at room temperature in ether. The
identity of the meso and C2-symmetrical (D,L) isomers as well as their ratio were determined by chiral gas chromatography. The meso and C2
(racemic) stereoisomeric diols were easily separated by flash chromatography on silica gel. A set of 18 a,b-unsaturated acetals were then
prepared reacting those, as well as commercially available 1,2, 1,3 and 1,4 diols, with the corresponding methylacetals in acidic medium. A
trans-acetalisation procedure adapted to the cases of fragile allylic alcohols or unfavorable 1,6 diols-derived dioxonanes based on a
Dean–Stark trapping of methanol was also employed.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
The intramolecular Diels–Alder (IMDA) cycloaddition is a
remarkably efficient tool for the convergent and stereo-
controlled synthesis of functionalized polycyclic
systems.1–3 Classically, the direct-demand version of this
reaction relies on trienes featuring an electron-rich dienic
moiety and an electron-deficient dienophile. Therefore,
research aimed at simple and versatile accesses to such
substrates remains of synthetic importance.4–6 We have
previously described a new route to a set of such trienes
taking advantage of the sensitivity of a,b-unsaturated cyclic
acetals such as dioxolanes or dioxanes to the base-induced
conjugate-elimination (Fig. 1).7,8 The final IMDA step
showed this approach could open a relatively efficient route
to medium-ring lactones. However, the yield and the
stereoselectivity of this reaction is largely depending on
the exact structure of the tether connecting the diene to the
dienophile, and therefore to the nature of the ‘embedded’
diol.
Figure 1. From diox(ol)anes to medium-ring lactones (LICKOR¼n-
BuLiþt-BuOK).
created by the IMDA. Introducing the asymmetry through
the diols was a relatively simple way of tackling this
problem, provided the chiral elements borne by the tether
after ring fission were able to secure the diastereocontrol of
the cycloaddition step. In this perspective, one could rely
either on the ring fission of chiral cyclic acetals (derived
from either non-symmetrical or C2-symmetrical diols), or
on the opening of achiral acetals (derived this time from
meso diols). The alcohol resulting from the action of an
achiral base on acetals derived from C2-symmetrical chiral
diols will necessarily be chiral while the opening of the
meso derivatives will require the use of chiral bases to
eventually escape their achiral origin (Fig. 2).
To pursue our work on this class of trienes, we thought a
detailed investigation on a general access to this sensitive
class of reagents would deserve a separate investigation. In
particular, our previous study did not address the central
problem of the control of the stereogenic centers newly
Keywords: Diols; C2-Symmetry; meso Compounds; Acetals.
*
Corresponding author. Tel.: þ33-235-522-446; fax: þ33-235-522-971;
The aim of this paper is twofold. It first gathers results
e-mail address: jmaddalu@crihan.fr
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.11.009

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L. Lemiegre et al. / Tetrahedron 60 (2004) 415–427
416
corresponding commercially available diethyl ester 5
(Scheme 1).
For the sake of an easy final deprotection, dibenzylic 1,4-
diols 8, 9 were also considered (Scheme 2). Those were
initially prepared as racemic mixtures by direct addition of
an excess of alkyl Grignard reagents to o-phthalaldehyde 7
by Weyerstahl et al.13 A stereoselective synthesis of 8b
(R¼Et) was later studied by Shibata and colleagues who
obtained disappointing results reacting diethyl zinc with 7 in
the presence of Ti(i-PrO)4 and 1S,2R-PHONE, a chiral
thiophosphoramidate.14 Simultaneously, Brown et al.
described an efficient access to chiral 8f (R¼allyl:
d.e.¼98%, e.e.$98%) adding allyldiisopinocampheyl
borane also to o-phthalaldehyde 7.15 This procedure was,
however, restricted to allyl derivatives. Very recently, van
Koten et al. have obtained high 8/9 ratios and good
enantioselectivities reacting 7 in a two-step, one-pot
procedure involving first complexation between a chiral
aminothiolate and organozincs then Grignard reagents.16
Figure 2. Opening acetal derived from C2-symmetrical or meso diols.
regarding new 1,4-diols (including a family of dibenzylic
diols prepared from o-phthalaldehyde) that are good
precursors for acetals fitting one or the other of the above
categories. It is then centered on the access to a,b-
unsaturated cyclic acetals of various sizes through adapted
trans-acetalisation processes.
2. Results and discussion
Synthesis of diols. A relatively large variety of chiral and
achiral 1,2-, 1,3- and 1,4-diols is commercially available
and was used directly in the trans-acetalisation experiments
presented in the next paragraph. In addition, a set of racemic
1,4 diols was prepared in-house by various methods. The
anti-cyclohexanedimethanol 3 was synthesized from
commercially available racemic anti-1,2-cyclohexane-
dicarboxylic acid 1 (Scheme 1) following a described
procedure.9,10 The addition of an excess of phenyllithium on
the intermediate diester 2 led to known11 dibenzhydrilic diol
4, following Seebach et al. procedure.12 Similarly, the
cyclopropylic diol 6 was readily prepared from the
Scheme 2.
We chose to resort to the convenient Weyerstahl’s
procedure12 since racemic C2-symmetrical diols were fully
sufficient to later evaluate the IMDA step. However, the
diastereoselectivities of the alkylmagnesium reagents
addition to o-phthalaldehyde, not given in the original
paper, remained to be determined. Reacting commercial or
home-made solutions of methyllithium or organo-mag-
nesium compounds with 7 in diethyl ether, either following
a direct (organometallic added to the dialdehyde) or inverse
(vice versa) procedure at room temperature led to the results
displayed in Table 1. The D,L and meso diastereomers were
conveniently identified by a single gas chromatography run
on a chiral Supelco b-Dex column, leading to the separation
of the diastereomers as well as to the 50:50 splitting of the
D,L signal (Fig. 3).
The results in Table 1 call for several comments. First, the
amount of diols 10, a side-product resulting from a single
nucleophilic addition and a reduction, seemed related to the
bulkiness of the organometallic reagent employed (entries
1–10). Obviously, this remark did not apply to nucleophiles
devoid of b-protons such as neo-pentylmagnesium bromide
or bulky such as t-butylmagnesium chloride (entries 11 and
12). Interestingly in this latter case, a lactol resulting from a
single addition and analogous to that isolated by van Koten
from organozinc reagents, was obtained in good yield in
ether (but not in THF, following a direct or an inverse
procedure). Note also that neither the solvent (diethylether
Scheme 1.

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L. Lemiegre et al. / Tetrahedron 60 (2004) 415–427
417
Table 1. Addition of organometallics to o-phthalaldehyde at room
temperature (Scheme 1)
These data provide hints on the mechanism of this reaction
(Fig. 4). The alcoholate resulting from the first addition can
be regarded either as an aldehyde undergoing an intra-
molecular Lewis acid activation (form A) or, more likely, as
a lactolate (form B). This later can probably further
aggregate with a second equivalent of the organometallic
leading
Entry
Reagent
Solvent Additiona Yield (%)b
8/9/10
1
2
3
4
5
6
7
8
MeLi
EtMgBr
Et2O
Et2O
Et2O
THF
Et2O
Et2O
THF
Et2O
Et2O
THF
Inverse
Direct
Direct
92
63
72
68
67
66
51
84
68
61
16c
83d
39:61:0
62:21:17
59:10:31
70:8:22
48:15:37
41:10:49
65:14:21
24:10:66
23:14:63
26:8:66
100:0:0
0:0:0
i-PrMgCl
i-PrMgCl
i-PrMgCl
i-PrMgBr
i-PrMgBr
i-BuMgCl
i-BuMgCl
i-BuMgBr
Direct
Inverse
Inverse
Inverse
Inverse
Inverse
Inverse
Direct
† to the expected SN2 type substitution with smaller
nucleophiles, opening the temporary 5-membered
heterocycle and yielding diols 8 and 9 (on structure B)
or to the nucleophilic addition on the aldehyde (on form
A), in ratios obviously depending on the size of R.
† to a b-hydride transfer with cumbersome reagents (such
as i-propyl or i-butyl magnesium chloride), triggering the
second aldehyde reduction and thus leading to diols 10
plus the corresponding olefin.
9
10
11
12
neo-Pent-MgBr Et2O
t-BuMgCl Et2O
Direct
a
The organometallic was added to the aldehyde solution (direct) or vice
versa (inverse).
b
c
d
Overall yield calculated for 8þ9þ10.
Only diol 8e was isolated from the crude reaction mixture.
Only lactol B (Fig. 4, R¼t-Bu) was obtained in this case.
This mechanism fits the various observations in Table 1.
Similar side-product and steric effects, such as a diastereo-
selectivity increase in favor of the D,L isomer induced by the
bulky nucleophiles, have also been underlined by van
Koten.15
Finally, benzil 11 was treated with 2 equiv. methyllithium in
ether (Scheme 3). The expected diols 12 and 13 were
obtained in 64% yield and 84% d.e. (in favor of meso 13), in
perfect agreement with the literature results, obtained in
THF.17
Scheme 3.
Figure 3. GC chromatograms of a mixture of diols D,L 8a and meso 9a on a
Supelco b-Dex chiral column.
Synthesis of cyclic acetals. We have recently reported18 that
dimethylacetal 16 can be prepared (as a E/Z mixture
<70:30) in very high yields from isoprenyl acetate 14
following the efficient method of Venturello and
colleagues19 (Scheme 4). The poor control of the double
bond configuration in 15 and 16 is meaningless here since
we have shown in similar situations that this parameter has
versus THF, entries 3 and 4), the Grignard counterion
(chloride or bromine, entries 5 and 6 or 9 and 10) nor the
order of the introduction of the reagents (direct versus
inverse, entries 3 and 5) seem to have a significant influence
neither on the yields nor on the selectivities.
Figure 4. Proposed mechanism for the addition of Grignard reagents to
o-phthalaldehyde 7.
Scheme 4.

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L. Lemiegre et al. / Tetrahedron 60 (2004) 415–427
418
little, if any, effect on the stereocontrol of the diene resulting
from the elimination reaction.20 Also, we retained a
p-methoxybenzyl (PMB) ether substituent as an easily
removable protecting group from the perspective of possible
applications of these synthons to sugars and carbasugars
synthesis.
nine-membered acetal (dioxonane), from either com-
mercially available diols or those described above
(Tables 2 and 4).
The results in Table 2 deserve some comments. First, the
yields were in general relatively good, and in all cases the
configuration of the double bond remained unchanged. All
the acetals derived from meso diols were obtained as a
mixture of stereoisomers, the acetalic proton being oriented
cis or trans to the two syn X substituents of the heterocycle
(Fig. 5). The acetalic carbon is in this case pseudo-
asymmetric (it bears two identical substituents but one is
R and the other S) and can be defined as r or s,22 keeping in
mind that the R center has priority over the S one. The
proportions between these pseudo-diasteromers as well as
the configuration of the major one could be determined in a
few cases through NOESY experiments (Table 3).
Obviously, acetals derived from anti diols do not exhibit
this pseudo-asymmetry feature.
In Venturello’s procedure, the reacting alcohol (methanol)
is introduced as a co-solvent to THF. This can be a
drawback when it comes to heavy (or expensive) diols that,
if used in large excess, render the purification stage tedious
or the experiment exceedingly costly. We, therefore,
resorted to a trans-acetalisation procedure expected to
favor the transformation of acyclic 16 to cyclic ketals 17.
Practically, this was achieved in most cases by simply
adding 1.2–2.2 equiv. of diol to acetals 16 in the presence of
trace amounts of dry camphorsulfonic acid (CSA) and 2,2-
dimethoxypropane.21 A few alterations to this general
procedure turned out to be necessary for some diols, and
they are presented below.
Entries 7 and 8 of Table 2 show that the trans-relationship in
1,2-diols borne by five or six-membered rings is not
compatible with the dioxolane ring closure. The strain
generated by such trans ring-junctions is probably at the
Three different families of chiral (racemic) or achiral 5, 6
and 7-membered cyclic acetals (dioxolanes, dioxanes and
dioxepanes) were thus prepared, as well as one example of
Table 2. Chiral (racemic) and meso diox(ol)anes prepared from acetal 16 (Scheme 4)
Entry
Diol
Equiv.
Acetal
Compound no.
Yield (%)
100
1
1.5
17a
2
3
4
1.2
1.2
1.2
17b
17c
17d
59
70
53
5
1.2
1.5
1.5
17e
17f
17g
43
64
0
6a
7
8
9
1.7
2.2
17h
17i
0
80
10
1.3
17j
73
a
The trans-acetalisation was run on pure (E)-16 in this case.

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L. Lemiegre et al. / Tetrahedron 60 (2004) 415–427
419
Table 4. Chiral (racemic) and meso dioxepanes and dioxonane prepared
from acetal 16 (Scheme 4)
Entry
Diol
Equiv.
Acetal
No. Yield
(%)
1
2
1.5
1.3
17k
17l
61
54
Figure 5. Symmetry elements in acetals derived from meso (left) or C2-
symmetrical (right) diols.
Table 3. cis/trans Ratios in acetals 17 derived from meso diols
Entry
Acetal
cis/trans
3
4
1.3
1.2
17m
17n
0
0
1
2
3
4
17b
17k
17p
17u
77:23
50:50
80:20
66:33 (E)
50:50 (Z)
origin of this failure, as inferred from a semiempirical
(AM1) study.23
5
6
1.2
1.5
17o
17p
70
81
When it comes to dioxepanes and dioxonanes (Table 4), the
same protocol can be followed, albeit the use of dimethoxy-
propane is not recommended in entries 6, 7, 10, and 11 since
it reacts with the corresponding diols, yielding an entangled
mixture of acetals. The trans-acetalisation with the two
TADDOL-like diols (entries 3 and 4) failed, probably
because of the high stabilization of the triply-benzylic
intermediate cations. Entries 6–10 rely on dibenzylic diols
8 and 9 described above. The trans-acetalisation yields
tended to decrease with the increasing size of the benzylic
substituents. One unsymmetrical acetal (17u, entry 11) and
one dioxonane (17v, entry 12) were also prepared,
respectively, from mono-0alkylated diol 10d or from
commercially available 2,2 -biphenyldimethanol, a model
for biarylic diols featuring a chiral axis. With 10d, the
standard trans-acetalisation procedure proved efficient,
while it did not yield any identified product in the case of
biphenyldimethanol. The classical sulfuric acid catalysis
and Dean–Stark trapping at reflux of benzene24 also proved
too harsh for 16. Actually, only a few syntheses of such
acetals have been reported. Finally, a methanol/dichloro-
methane azeotropic distillation in presence of trace amounts
of acetic acid,25 afforded 17v in 51% yield. The very fragile
allylic acetals 18 and 20 were obtained following this same
procedure in 53 and 60% conversion, respectively. Actually,
18 was prepared in an attempt to access dioxepine 19 by a
ring closing metathesis (RCM). We resorted for this step to
the use of a ruthenium carbene complex (Grubb’s catalyst)26
that has previous been reported to perform RCM of other
acid sensitive substrates.25 Unfortunately, it led here to a
partial or total failure (Scheme 5). Dioxepine 19 was indeed
obtained, but in only 27% after 12 h at room temperature.
7
8
1.5
1.5
17q
17r
60
67
9
1.5
17s
50
10
11
12
1.5
1.5
2.0
17t
17u
17v
52
68
51
Its dibenzylic analogue 20 led to a complex mixture out of
which only olefin 21 could be characterized. This by-
product suggests that the RCM takes place rather between
the trisubstituted inner double bond and one of the terminal
allyl groups than between the two acetalic appendages. The
complementary cyclic mixed-acetal 22 should therefore be
obtained as well, although we did not isolate this fragile
looking compound.
The origin of this unexpected difficulty probably stems from
the strong preference for a five-membered ring closing over
a seven-membered one. A comparable competition, leading

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L. Lemiegre et al. / Tetrahedron 60 (2004) 415–427
420
diester 2 (2.00 g, 1 equiv., 9.99 mmol, prepared refluxing
commercial anti-cyclohexane-1,2-dicarboxylic acid in
methanol containing camphorsulfonic acid) in ether
(50 mL) was added to a dispersion of LAH (1.52 g,
3.6 equiv., 36.3 mmol) in ether (20 mL). After 2 h, H2O
(2 mL), NaOH 4 M (2 mL) and H2O (6 mL) were added
successively into the reaction mixture. The aqueous phase
was extracted by ether (3£15 mL), the combined organic
phases were dried (Na2SO4) and evaporated under reduce
pressure to afford 1.38 g (96%) of diol 3 as a white solid
(mp¼60 8C) pure enough to be used as such. nmax (film)/
1
cm21 3301, 2914, 2848, 1428, 1020. H NMR (300 MHz,
Scheme 5.
CDCl3) d (ppm)¼1.00 (m, 2H), 1.23 (m, 4H), 1.58 (d,
J¼13.6 Hz, 2H), 1.71 (m, 2H), 3.47 (dd, J¼6.4, 10.7 Hz,
2H), 3.57 (d, J¼10.7 Hz, 2H), 4.09 (s, 2H). 13C NMR
(75 MHz, CDCl3) d (ppm)¼26.5, 30.2, 45.2, 68.1. EIMS
(70 eV) m/z 144 (Mþz, 0.3), 126 (Mþz218, 11), 108 (8), 96
(100), 81 (67). Anal. Calcd for C8H16O2: C, 66.63%; H,
11.18%. Found: C, 66.58%; H, 11.26%.
to a similar conclusion, has been published by Harrity and
colleagues lately.25
3. Conclusion
The results presented in this paper describe a family of
dibenzylic diols prepared by double addition of alkyl-
magnesium reagents onto o-phthalaldehyde. This procedure
provided, in most cases, the D,L diastereomers as the major
products. These compounds, together with a set of home-
made or commercially available 1,2, 1,3 or 1,4 diols were
reacted with a,b-unsaturated dimethyl acetal 16. A standard
acidic trans-acetalisation procedure provided the expected
dioxolanes, dioxanes and dioxepanes in medium to good
yields. For dioxonane or allylic acetals, an azeotropic
trapping of methanol was found necessary. An attempt to
cyclize the latter allylic acetals using Grubb’s catalyst
turned out unsuccessful. Despite this final failure, 18
different cyclic acetals were prepared that are potential
substrates for the base-induced conjugated ring-fission, the
transformation of the corresponding alcoholates into
trienic substrates as well as the thermal and hyperbaric
IMDA final step. These results will be reported in a near
future.
4.1.2. 1,2-Bis(1-hydroxyethyl)benzene (8a, 9a). A solution
of o-phthalaldehyde (4.0 g, 1 equiv., 29.8 mmol) in ether
(30 mL), was added, at room temperature, to a solution of
MeLi (65 mL, 3.5 equiv., 1.6 mol L21, 104.3 mmol) in
ether (30 mL). The reaction mixture was stirred for 3 h,
before H2O (10 mL) then HCl 1 N (20 mL) were added
carefully. The pH of the aqueous phase was brought to 5
then extracted with ether (3£20 mL) and the combined
organic phases were dried (Na2SO4) and evaporated under
reduce pressure. The ratio 8a/9a/10a was found to be, in the
crude mixture, 40:60:0 according to GC. Most of the syn
isomer was selectively precipitated out of a 60:40, heptane/
AcOEt mixture. The two isomers in the residual liquor were
separated by flash chromatography (eluting with heptane/
AcOEt, 40:60). The total amount in diols (8aþ9a) was 4.5 g
(92%), the syn isomer being isolated as a white solid
(mp¼90 8C) and the anti one as a colorless oil.
n
max (film)/cm21 3354, 2974, 2928, 1448, 1372, 1068, 734.
syn Isomer 8a. 1H NMR (300 MHz, CDCl3) d (ppm)¼1.54
(d, J¼6.6 Hz, 6H), 2.53 (bs, 2H), 5.25 (q, J¼6.6 Hz, 2H),
7.32 (m, 2H), 7.50 (m, 2H). 13C NMR (75 MHz, CDCl3) d
4. Experimental
1
(ppm)¼23.7, 65.9, 125.7, 128.4, 142.4. anti Isomer 9a. H
4.1. General remarks
NMR (300 MHz, CDCl3) d (ppm)¼1.55 (d, J¼6.4 Hz, 6H),
2.16 (bs, 2H), 5.25 (q, J¼6.4 Hz, 2H), 7.29 (m, 2H), 7.47
(m, 2H). 13C NMR (75 MHz, CDCl3) d (ppm)¼24.8, 67.5,
126.5, 128.1, 142.6. EIMS (70 eV) m/z 148 (Mþz218, 32),
133 (100), 105 (58), 77 (54). Anal. Calcd for C10H14O2: C,
72.26%; H, 8.49%. Found: C, 72.14%; H, 8.85%.
1H NMR spectra were recorded at 300 MHz and 13C NMR
spectra at 75 MHz; chemical shift (d) are given in parts per
million (ppm) and the coupling constants (J) in Hertz. The
solvent was deuterochloroform or deuterobenzene. IR
spectra were recorded by transmission. Gas chromatography
analysis were performed on high resolution DB-1 or HP-
5MS columns (30 m£0.25 mm£0.25 mm). GC/MS analysis
were performed on instruments equipped with the same
columns. The chiral gas chromatography runs were
4.1.3. 1,2-Bis(1-hydroxypropyl)benzene (8b, 9b). Direct
procedure. A solution of ethylmagnesium bromide (1.8 mL,
3 M, 3.5 equiv., 5.2 mmol) in ether was added dropwise, at
room temperature, to a solution of o-phthalaldehyde (0.20 g,
1 equiv., 1.5 mmol) also in ether (3 mL). The reaction
mixture was stirred for 1 h and 30 min. Then H2O (2 mL)
and HCl 1 N (4 mL) were added carefully. The pH of the
aqueous phase was brought to 5 and extracted with ether
(3£5 mL). The resulting organic phase was dried (Na2SO4)
and evaporated under reduce pressure. The ratio 8b/9b/10b
was found to be, in the crude mixture, 62:21:17 according to
GC. A flash chromatography afforded the pure anti isomer
8b as a white solid (mp¼77 8C) The others diols were not
performed on
a
Supelco b-Dex column (15 m£
0.25 mm£0.25 mm). The mass spectra under electron
impact conditions (EI) were recorded at 70 eV ionizing
potential; methane (CH4), isobutane (t-BuH), or ammonia
(NH3) were used for chemical ionization (CI). The silica gel
used for flash chromatography was 230–400 Mesh. All
reagents were of reagent grade and were used as such or
distilled prior to use.
4.1.1. anti-Cyclohexane dimethanol (3). A solution of

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L. Lemiegre et al. / Tetrahedron 60 (2004) 415–427
421
separated and a total of 0.18 g 8bþ9bþ10b was recovered
91 (100). Anal. Calcd for C14H22O2: C, 75.63%; H, 9.97%.
Found: C, 75.76%; H, 10.09%.
(63%).
Compound 8b. nmax (film)/cm21 3286, 2964, 1456, 1326,
Compound 10c. nmax (film)/cm21 3453, 3064, 2958, 1468,
1
1
972, 754. H NMR (300 MHz, CDCl3) d (ppm)¼0.95 (t,
1013, 759. H NMR (300 MHz, CDCl3) d (ppm)¼0.76 (d,
J¼7.5 Hz, 6H), 1.81 (m, 4H), 2.40 (s, 2H), 4.88 (t,
J¼5.8 Hz, 2H), 7.26 (m, 2H), 7.39 (m, 2H). 13C NMR
(75 MHz, CDCl3) d (ppm)¼11.1, 31.8, 72.9, 126.8, 128.1,
141.8. EIMS (70 eV) m/z 176 (Mþz218, 4), 165 (24), 147
(100), 129 (69), 91 (39). Anal. Calcd for C12H18O2: C,
74.19%; H, 9.34%. Found: C, 74.21%; H, 9.39%.
J¼6.8 Hz, 3H), 1.11 (d, J¼6.4 Hz, 3H), 2.11 (m, 1H), 2.49
(s, 2H), 4.53 (d, J¼8.3 Hz, 1H), 4.73 (s, 2H), 7.33 (m, 4H).
13C NMR (75 MHz, CDCl3) d (ppm)¼19.6, 20.0, 34.4, 63.4,
77.7, 127.9, 128.0, 128.5, 129.9, 138.3, 142.3. CIMS (CH4)
m/z 162 (Mþz218, 29), 161 (76), 143 (33), 119 (87), 91
(100). Anal. Calcd for C11H16O2: C, 73.30%; H, 8.95%.
Found: C, 73.25%; H, 9.49%.
Compound 9b. 1H NMR (300 MHz, CDCl3) d (ppm)¼0.89
(t, J¼7.4 Hz, 6H), 1.72 (m, 4H), 2.69 (s, 2H), 4.74 (t,
J¼6.0 Hz, 2H), 7.23 (m, 4H).
Compound 10b. 1H NMR (300 MHz, CDCl3) d (ppm)¼0.91
(t, J¼9.0 Hz, 6H), 1.69 (s, 1H), 1.82 (m, 2H), 2.62 (s, 1H),
4.60 (d, J¼12.1 Hz, 1H), 4.71 (d, J¼12.1 Hz, 1H), 4.78 (t,
J¼7.1 Hz, 1H), 7.20 (m, 4H).
4.1.5. 1,2-Bis(1-hydroxy-3-methylbutyl)benzene (8d, 9d)
and 1-(2-hydroxymethyl-phenyl)-3-methyl-butan-1-ol
(10d). Inverse procedure. A solution of o-phthalaldehyde
(2.00 g, 1 equiv., 14.9 mmol) in ether (30 mL) was added to
a solution of isobutylmagnesium chloride (30 mL, 4 equiv.,
2.0 mol L21, 60.0 mmol) in the same solvent (20 mL). After
1.5 h of reaction, a work-up and analysis as above led to a
8c/9c/10c ratio¼24:10:66. A flash chromatography (eluting
with heptane/AcOEt, 60:40) afforded 1.60 g of 10d, as a
white solid (mp¼85 8C), 750 mg of diol anti 8d, as a white
solid (mp¼79 8C) and 340 mg of diol syn 9d, also as a white
solid (mp¼51 8C) in an overall yield of 84%.
4.1.4. 1,2-Bis(1-hydroxy-2-methylpropyl)benzene (8c,
9c) and 1-(2-hydroxymethyl-phenyl)-2-methyl-propan-
1-ol (10c). These compounds were prepared as above
following either a direct or inverse procedure, in ether or
THF and with i-propylmagnesium chloride or bromide (See
Table 1).
Compound 8d/9d. nmax (film)/cm21 3317, 3061, 2952,
2867, 1462, 1054, 760. anti Isomer 8d. 1H NMR (300 MHz,
CDCl3) d (ppm)¼0.97 (d, J¼6.4 Hz, 6H), 0.99 (d,
J¼7.1 Hz, 6H), 1.51 (m, 2H), 1.78 (m, 2H), 1.84 (m, 2H),
1.96 (d, J¼3.4 Hz, 2H), 5.08 (dt, J¼3.4, 9.0 Hz, 2H), 7.27
(m, 2H), 7.44 (m, 2H). 13C NMR (75 MHz, CDCl3) d
(ppm)¼22.3, 23.9, 25.5, 48.5, 69.3, 126.4, 128.1, 142.1. syn
Direct procedure in ether with isopropylmagnesium
chloride. To a solution of o-phthalaldehyde (0.20 g,
1 equiv., 1.5 mmol) in ether (4 mL) was added, dropwise
and at room temperature, a solution of isopropylmagnesium
chloride (2.8 mL, 3.5 equiv., 2.0 M, 5.2 mmol). After 1.5 h
of reaction and the same treatment, a GC analysis of the
crude mixture led to a 8c/9c/10c ratio¼59:10:31. A flash
chromatography (eluting with heptane/AcOEt, 60:40)
afforded 23 mg of alcohol 10c, as a yellowish oil, 94 mg
of diol anti 8c, as a colorless oil and 10 mg of its syn isomer
9c, as a white solid (mp¼70 8C). Total amount of products:
1.1 mmol (72%).
1
Isomer 9d. H NMR (300 MHz, CDCl3) d (ppm)¼0.97 (d,
J¼6.4 Hz, 6H), 0.99 (d, J¼7.1 Hz, 6H), 1.46 (m, 2H), 1.83
(m, 4H), 1.95 (d, J¼3.4 Hz, 2H), 5.16 (dt, J¼3.4, 9.2 Hz,
2H), 7.30 (m, 2H), 7.48 (m, 2H). 13C NMR (75 MHz,
CDCl3) d (ppm)¼22.3, 24.0, 25.5, 48.5, 67.9, 126.2, 128.3,
142.2. CIMS (CH4) m/z 233 (MHþ218, 9), 231 (21), 215
(83), 175 (82), 159 (100), 147 (59). Anal. Calcd for
C16H26O2: C, 76.75%; H, 10.47%. Found: C, 77.21%; H,
10.57%.
Inverse procedure in THF with isopropylmagnesium
bromide. The isopropylmagnesium bromide was prepared
from 2-bromopropane (0.55 g, 3 equiv., 4.5 mmol) in THF
(3 mL) and 0.11 g of magnesium shaves (3 equiv.,
4.5 mmol) in THF (1 mL). After 1 h of stirring at room
temperature, a solution of o-phthalaldehyde (0.20 g,
1 equiv., 1.5 mmol) in THF (3 mL) was added dropwise.
The same work-up and analysis led to a 8c/9c/10c
ratio¼65:14:21 in an overall yield of 51%.
Compound 8c/9c. nmax (film)/cm21 3420, 3064, 2958, 2872,
1468, 1002, 760. anti Isomer 8c. 1H NMR (300 MHz,
CDCl3) d (ppm)¼0.79 (d, J¼6.8 Hz, 6H), 1.07 (d,
J¼6.4 Hz, 6H), 1.98 (s, 2H), 2.02 (m, 2H), 4.64 (d,
J¼7.9 Hz, 2H), 7.27 (m, 2H), 7.40 (m, 2H). 13C NMR
(75 MHz, CDCl3) d (ppm)¼19.0, 20.0, 35.4, 76.6, 127.0,
127.9, 141.5. syn Isomer 9c. 1H NMR (300 MHz, CDCl3) d
(ppm)¼0.75 (d, J¼6.8 Hz, 6H), 1.10 (d, J¼6.4 Hz, 6H),
2.10 (m, 2H), 2.15 (s, 2H), 4.61 (d, J¼8.3 Hz, 2H), 7.28 (m,
2H), 7.41 (m, 2H). 13C NMR (75 MHz, CDCl3) d
(ppm)¼19.3, 20.3, 34.5, 75.7, 127.1, 128.2, 141.6. CIMS
(CH4) m/z 205 (MHþ218, 39), 187 (15), 161 (46), 143 (55),
Compound 10d. nmax (film)/cm21 3295, 2954, 2866, 1463,
1
1041, 763. H NMR (300 MHz, CDCl3) d (ppm)¼0.97 (d,
J¼6.4 Hz, 3H), 0.98 (d, J¼6.4 Hz, 3H), 1.61 (m, 1H), 1.83
(m, 2H), 2.47 (bs, 1H), 2.53 (bs, 1H), 4.70 (dd, J¼4.5,
12.1 Hz, 1H), 4.80 (dd, J¼3.8, 12.1 Hz, 1H), 5.03 (bs, 1H),
7.3–7.5 (m, 4H). 13C NMR (75 MHz, CDCl3) d
(ppm)¼22.5, 23.8, 25.5, 46.6, 64.3, 70.0, 126.9, 128.2,
128.9, 130.2, 138.4, 143.3. CIMS (CH4) m/z 191 (10), 175
(21), 159 (MHþ236, 100), 119 (37). Anal. Calcd for
C12H18O2: C, 74.19%; H, 9.34%. Found: C, 74.24%; H,
9.52%.
4.1.6. 1,2-Bis(1-hydroxy-3,3-dimethylbutyl)benzene (8e).
Inverse procedure. The neopentylmagnesium bromide was
prepared from 1-bromo-3,3-dimethyl-butane (10.1 g,
3 equiv., 66.9 mmol) in ether (20 mL) and 1.63 g of
magnesium shaves (3 equiv., 67.1 mmol) in THF (20 mL).
After 1 h of stirring at room temperature, a solution of
o-phthalaldehyde (3.00 g, 1 equiv., 22.4 mmol) in ether
(20 mL) was added dropwise. After 2 h, the reaction was

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L. Lemiegre et al. / Tetrahedron 60 (2004) 415–427
422
quenched by 50 mL of saturated ammonium chloride; the
rest of the work-up was as above and led to a complex
mixture out of which a flash chromatography on silica gel
(eluting with cyclohexane/AcOEt, 60:40 mixture) afforded
1.00 g anti diol 8e as a colorless oil (16%). nmax (film)/cm21
3418, 2952, 2868, 1476, 1364, 1058, 734. 1H NMR
(300 MHz, CDCl3) d (ppm)¼1.04 (m, 18H), 1.61 (dd,
J¼2.6, 14.7 Hz, 2H), 1.81 (dd, J¼9.0, 14.7 Hz, 2H), 1.98 (s,
2H), 5.18 (d, J¼9.0 Hz, 2H), 7.26 (m, 2H), 7.44 (m, 2H).
13C NMR (75 MHz, CDCl3) d (ppm)¼30.7, 31.3, 52.8, 69.2,
126.7, 128.0, 142.9. CIMS (CH4) m/z 261 (MHþ218, 5),
243 (MHþ236, 11), 189 (100), 173 (21), 161 (18), 133 (28).
added 1.2–1.5 equiv. of appropriate diol in the presence of a
catalytic amount of camphorsulfonic acid (CSA) and of 2,2-
dimethoxypropane (when precised). The reaction mixture
was stirred at room temperature for 2 h and a saturated
solution of sodium bicarbonate was added. The aqueous
phase was extracted with dichloromethane and the resulting
organic solution was dried (MgSO4) and evaporated under
reduce pressure to afford the crude product. A flash
chromatography on silica gel (eluting with an AcOEt/
heptane, 30:70 mixture) afforded the pure cyclic acetals.
The E/Z ratio of the double bond remained unchanged under
these conditions.
4.1.7. 3-t-Butyl-1,3-dihydro-isobenzofuran-1-ol (B with
R5t-Bu and M5H). Inverse procedure. A solution of
o-phthalaldehyde (0.20 g, 1 equiv., 1.5 mmol) in ether
(3 mL) was added dropwise and at room temperature, to a
solution of t-butylmagnesium chloride (2.6 mL, 2 M,
3.5 equiv., 5.2 mmol) in ether. After 1.5 h of reaction, a
work-up and analysis as above led to a yellow oil that was
purified by flash chromatography on silica gel (eluting with
cyclohexane/AcOEt, 70:30 mixture). A pale yellow oil
(235 mg), identified as an unseparable mixture (75:25) of
the syn and anti diastereomers of lactol B, was recovered in
an overall yield of 83%.
4.2.1. 2-[2-Methyl-3-(p-methoxy-benzyloxy)-prop-2-
enyl]-4,5-anti-dimethyl-[1,3]dioxolane (17a). The above
procedure was applied to 500 mg (1 equiv., 1.88 mmol) of
dimethylacetal 16 (E/Z, 70:30) and 250 mg (1.5 equiv.,
2.77 mmol) of anti-butane-2,3-diol in dichloromethane
(10 mL) in presence of 0.1 mL of 2,2-dimethoxypropane.
The reaction was monitored by TLC and upon completion, a
solution of saturated NaHCO3 (3 mL) was added. After flash
chromatography, 550 mg (100%) of dioxolane 17a were
obtained as a colorless oil (E/Z, 70:30). nmax (film)/cm21
2972, 2864, 1680, 1612, 1512, 1248, 1080, 820. E isomer.
1H NMR (300 MHz, CDCl3) d (ppm)¼1.12–1.32 (m, 6H),
1.77 (s, 3H), 3.62 (m, 2H), 3.77 (s, 3H), 3.88 (s, 2H), 4.37 (s,
2H), 5.52 (d, J¼7.3 Hz, 1H), 5.69 (d, J¼7.3 Hz, 1H), 6.84
(d, J¼8.8 Hz, 2H), 7.23 (d, J¼8.8 Hz, 2H). 13C NMR
(75 MHz, CDCl3) d (ppm)¼14.5, 17.3, 17.6, 55.6, 71.7,
74.7, 78.6, 80.2, 99.5, 114.1, 124.5, 129.7, 130.5, 140.8,
syn Isomer. 1H NMR (300 MHz, CDCl3) d (ppm)¼0.89 (s,
9H), 3.00 (d, J¼8.7 Hz, 1H), 4.98 (d, J¼2.3 Hz, 1H), 6.40
(dd, J¼8.7, 2.3 Hz, 1H), 7.20 (m, 4H). 13C NMR (75 MHz,
CDCl3) d (ppm)¼26.0, 36.5, 91.5, 101.0, 123.0 -141.0
unidentified aromatic peaks together with isomer anti.
159.6.
Z d
isomer. 1H NMR (300 MHz, CDCl3)
(ppm)¼1.12–1.32 (m, 6H), 1.81 (s, 3H), 3.62 (m, 2H),
3.77 (s, 3H), 4.05 (s, 2H), 4.37 (s, 2H), 5.43 (d, J¼7.3 Hz,
1H), 5.63 (d, J¼7.3 Hz, 1H), 6.84 (d, J¼8.8 Hz, 2H), 7.23
(d, J¼8.8 Hz, 2H). 13C NMR (75 MHz, CDCl3) d
(ppm)¼17.5, 21.8, 55.6, 68.0, 71.7, 78.6, 80.2, 98.1,
114.1, 126.7, 129.7, 130.5, 141.2, 159.6. EIMS (70 eV)
m/z 292 (Mþz, 1.8), 121 (100). Anal. Calcd for C17H24O4: C,
69.84%; H, 8.27%. Found: C, 69.98%; H, 8.83%.
anti Isomer. 1H NMR (300 MHz, CDCl3) d (ppm)¼0.98 (s,
9H), 2.99 (d, J¼8.3 Hz, 1H), 4.80 (s, 1H), 6.31 (d,
J¼8.3 Hz, 1H), 7.22 (m, 4H). 13C NMR (75 MHz, CDCl3)
d (ppm)¼26.4, 35.0, 92.2, 100.0, 123.0–141.0 unidentified
aromatic peaks together with isomer syn.
4.1.8. 2,3-Diphenyl-butane-2,3-diol (12 and 13). To a
solution of 1,2-diphenyl-ethane-1,2-dione (benzil, 2.5 g,
1 equiv., 11.9 mmol) in ether (20 mL), were added 20 mL of
a solution of MeLi/LiBr (1:1) in ether at 0 8C. The reaction
mixture was then stirred at room temperature for 2 h and
30 min. Next, 20 mL of HCl (3 M) were added and the
resulting aqueous phase was extracted by ether (3£15 mL).
The combined organic solutions were dried (Na2SO4) and
evaporated under reduce pressure. The residue was
precipitated in heptane/ether (80:20) to afford 1.85 g
(64%) of a mixture of diols 12 and 13 as a white solid
(mp¼111 8C) and with a syn/anti: 92:8 ratio as determined
by NMR. nmax (film)/cm21 3508, 3058, 2982, 1598, 1445,
900. syn Isomer 12. 1H NMR (300 MHz, CDCl3) d
(ppm)¼1.58 (s, 6H), 2.27 (bs, 2H), 7.23 (m, 10H). 13C
NMR (75 MHz, CDCl3) d (ppm)¼25.5, 79.0, 127.3, 127.7,
127.8, 144.2. anti Isomer 13. 1H NMR (300 MHz, CDCl3) d
(ppm)¼1.50 (s, 6H), 2.27 (bs, 2H), 7.23 (m, 10H). EIMS
(70 eV) m/z 224 (Mþz218, 4), 206 (Mþ236, 11), 181 (73),
165 (15), 121 (100), 105 (32). Anal. Calcd for C16H18O2: C,
79.31%; H, 7.49%. Found: C, 79.13%; H, 7.61%.
4.2.2. 2-[2-Methyl-3-(p-methoxy-benzyloxy)-prop-2-
enyl]-4,5-syn-dimethyl-[1,3]dioxolane (17b). The above
procedure was applied to 2.0 g (1 equiv., 7.51 mmol) of
dimethylacetal 16 (E/Z, 70:30) and 813 mg (1.2 equiv.,
9.03 mmol) of syn-butane-2,3-diol in dichloromethane
(20 mL) in presence of 0.2 mL of 2,2-dimethoxypropane.
The reaction was monitored by TLC and upon completion, a
solution of saturated NaHCO3 (4 mL) was added. After flash
chromatography, 1.30 g (59%) of dioxolane 17b were
obtained as a colorless oil (E/Z, 70:30) as two epimers.
For the E isomer, a syn/anti ratio¼73:27 was measured.
n
max (film)/cm21 2976, 2908, 1684, 1612, 1514, 1248, 1084,
820. E anti isomer. 1H NMR (300 MHz, CDCl3) d
(ppm)¼1.17 (d, J¼6.0 Hz, 6H), 1.77 (d, J¼1.0 Hz, 3H),
3.79 (s, 3H), 3.88 (s, 2H), 4.14 (m, 2H), 4.39 (s, 2H), 5.51
(dd, J¼7.5, 1.0 Hz, 1H), 5.57 (d, J¼7.5 Hz, 1H), 6.86 (d,
J¼8.6 Hz, 2H), 7.25 (d, J¼8.6 Hz, 2H). 13C NMR (75 MHz,
CDCl3) d (ppm)¼14.6, 15.9, 55.7, 71.9, 74.9, 75.0, 98.9,
114.1, 124.4, 129.7, 130.8, 141.0, 159.5. Other isomers: 1H
NMR (300 MHz, CDCl3) d (ppm)¼1.1–1.3 (6H), 1.7–1.9
(3H), 3.79 (s, 3H), 3.8–4.0 (2H), 4.1–4.3 (2H), 4.39 (s, 2H),
5.4–5.6 (1H), 6.86 (d, J¼8.6 Hz, 2H), 7.25 (d, J¼8.6 Hz,
2H). 13C NMR (75 MHz, CDCl3) d (ppm)¼14.5–21.8,
4.2. General procedure for cyclic acetals 17
To a solution of dimethylacetal 16 in dichloromethane, were

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423
15.9, 52.7–55.7, 71.9, 68.1–74.9, 75.0, 98.1–98.9, 114.1,
124–128, 129.7, 130.8, 139–141, 159.5. EIMS (70 eV) m/z
292 (Mþz, 1), 219 (2), 155 (23), 121 (100). Anal. Calcd for
C17H24O4: C, 69.84%; H, 8.27%. Found: C, 69.73%; H,
8.54%.
4.2.5. 2-[3-(4-Methoxy-benzyloxy)-2-methyl-propenyl]-
4,5-syn-dimethyl-4,5-diphenyl-[1,3]dioxolane (17e). The
above procedure was applied to 1.0 g (1 equiv., 3.76 mmol)
of dimethylacetal 16 (E/Z, 70:30) and 1.2 g (1.3 equiv.,
4.96 mmol)of
syn-1,2-diphenyl-1,2-dimethylethane-1,2-
diol in dichloromethane (20 mL). The reaction was
monitored by TLC and upon completion, a solution of
saturated NaHCO3 (4 mL) was added. After flash chroma-
tography, 720 mg (43%) of dioxolane 17e were obtained as
a colorless oil (E/Z, 70:30) and as a single (undetermined)
epimer. nmax (film)/cm21 3058, 2994, 2922, 2854, 1612,
1514, 1248, 1072, 820, 698. E isomer. 1H NMR (300 MHz,
CDCl3) d (ppm)¼1.81 (s, 6H), 1.94 (d, J¼1.1 Hz, 3H), 3.82
(s, 3H), 4.04 (s, 2H), 4.51 (s, 2H), 6.04 (d, J¼7.2 Hz, 1H),
6.24 (d, J¼7.2 Hz, 1H), 6.91 (d, J¼8.7 Hz, 2H), 7.00 (m,
10H), 7.32 (d, J¼8.7 Hz, 2H). 13C NMR (75 MHz, CDCl3)
d (ppm)¼15.0, 22.9, 55.7, 71.9, 74.9, 87.8, 97.1, 114.2,
123.9, 126.4, 126.8, 127.5, 129.8, 130.8, 141.6, 143.8,
159.6. Z isomer. 1H NMR (300 MHz, CDCl3) d (ppm)¼1.74
(s, 6H), 1.99 (d, J¼1.1 Hz, 3H), 3.80 (s, 3H), 4.22 (s, 2H),
4.47 (s, 2H), 5.94 (d, J¼6.8 Hz, 1H), 6.13 (d, J¼6.8 Hz,
1H), 6.91 (d, J¼8.7 Hz, 2H), 7.00 (m, 10H), 7.32 (d,
J¼8.7 Hz, 2H). 13C NMR (75 MHz, CDCl3) d (ppm)¼22.0,
22.9, 55.7, 68.4, 71.7, 87.8, 96.4, 114.2, 125.9, 126.4, 126.8,
127.5, 129.8, 130.8, 141.6, 143.8, 159.6.
4.2.3. 2-[2-Methyl-3-(p-methoxy-benzyloxy)-prop-2-
enyl]-4,5-anti-diphenyl-[1,3]dioxolane (17c). The above
procedure was applied to 1.0 g (1 equiv., 3.75 mmol) of
dimethylacetal 16 (E/Z, 70:30) and 965 mg (1.2 equiv.,
4.50 mmol) of anti-1,2-diphenylethane-1,2-diol in dichloro-
methane (10 mL) in presence of 0.1 mL of 2,2-dimethoxy-
propane. The reaction was monitored by TLC and upon
completion, a solution of saturated NaHCO3 (4 mL) was
added. After flash chromatography, 1.11 g (70%) of
dioxolane 17c were obtained as a colorless oil (E/Z,
70:30). nmax (film)/cm21 3032, 2918, 1684, 1612, 1512,
1
1248, 1068, 820. E isomer. H NMR (300 MHz, CDCl3) d
(ppm)¼1.95 (s, 3H), 3.82 (s, 3H), 4.04 (s, 2H), 4.52 (s, 2H),
4.87 (s, 2H), 5.92 (d, J¼7.2 Hz, 1H), 6.27 (d, J¼7.2 Hz,
1H), 6.95 (d, J¼8.7 Hz, 2H), 7.34 (m, 12H). 13C NMR
(75 MHz, CDCl3) d (ppm)¼14.9, 55.7, 72.1, 74.8, 85.3,
87.2, 101.5, 114.3, 123.7, 126.8, 127.4, 128.6, 128.96,
129.04, 129.8, 130.8, 137.3, 138.9, 141.4, 159.7. Z isomer.
1H NMR (300 MHz, CDCl3) d (ppm)¼1.99 (s, 3H), 3.82 (s,
3H), 4.24 (s, 2H), 4.52 (s, 2H), 4.81 (d, J¼7.5 Hz, 1H), 4.86
(d, J¼7.5 Hz, 1H), 5.81 (d, J¼7.2 Hz, 1H), 6.20 (d,
J¼7.2 Hz, 1H), 6.95 (d, J¼8.7 Hz, 2H), 7.34 (m, 12H).
13C NMR (75 MHz, CDCl3) d (ppm)¼22.1, 55.7, 68.5, 71.9,
85.3, 87.2, 100.7, 114.3, 126.2, 126.8, 127.4, 128.6, 128.96,
129.04, 129.9, 130.8, 137.3, 138.9, 141.6, 159.7. CIMS
(i-BuH) m/z 417 (MHþ, 9), 197 (12), 121 (100). Anal. Calcd
for C27H28O4: C, 77.86%; H, 6.78%. Found: C, 77.92%; H,
6.94%.
4.2.6. 2-[3-(4-Methoxy-benzyloxy)-2-methyl-propenyl]-
tetrahydro-cyclopenta[1,3]dioxolane (17f). The above
procedure was applied to 1.0 g (1 equiv., 3.76 mmol) of
pure
E dimethylacetal 16 and 575 mg (1.5 equiv.,
5.63 mmol) of syn-1,2-cyclopentanediol in dichloro-
methane (15 mL) in the presence of 0.1 mL of 2,2-
dimethoxypropane. The reaction was monitored by TLC
and upon completion, a solution of saturated NaHCO3
(4 mL) was added. After flash chromatography, 730 mg
(64%) of dioxolane 17f were obtained as a colorless oil.
Two epimers were detected (88:12) but only the major
isomer could be isolated. nmax (film)/cm21 2926, 1686,
1612, 1514, 1248, 1040, 820. 1H NMR (300 MHz, CDCl3) d
(ppm)¼1.39 (m, 2H), 1.56 (m, 1H), 1.76 (m, 1H), 1.77 (s,
3H), 1.93 (dd, J¼6.0, 13.6 Hz, 2H), 3.79 (s, 3H), 3.90 (s,
2H), 4.39 (s, 2H), 4.53 (d, J¼4.5 Hz, 2H), 5.41 (d,
J¼7.1 Hz, 1H), 5.54 (d, J¼7.1 Hz, 1H), 6.86 (d,
J¼8.7 Hz, 2H), 7.24 (d, J¼8.7 Hz, 2H). 13C NMR
(75 MHz, CDCl3) d (ppm)¼14.8, 22.7, 33.5, 55.7, 72.0,
74.9, 82.0, 99.6, 114.2, 122.8, 129.7, 130.8, 141.6, 159.7.
CIMS (i-BuH) m/z 305 (MHþ, 15), 203 (3), 121 (100).
4.2.4. 2-[2-Methyl-3-(p-methoxy-benzyloxy)-prop-2-
enyl]-4,5-syn-diphenyl-[1,3]dioxolane (17d). The above
procedure was applied to 2.0 g (1 equiv., 7.51 mmol) of
dimethylacetal 16 (E/Z, 70:30) and 1.93 g (1.2 equiv.,
9.01 mmol) of syn-1,2-diphenylethane-1,2-diol in dichloro-
methane (20 mL) in presence of 0.2 mL of 2,2-dimethoxy-
propane. The reaction was monitored by TLC and upon
completion, a solution of saturated NaHCO3 (4 mL) was
added. After flash chromatography, 1.65 g (53%) of
dioxolane 17d were obtained as a colorless oil (E/Z,
70:30) as two epimers (90:10). Only the major isomer
could be isolated. nmax (film)/cm21 3030, 2914, 1686, 1612,
1512, 1248, 1066, 820. E isomer. 1H NMR (300 MHz,
CDCl3) d (ppm)¼1.92 (s, 3H), 3.82 (s, 3H), 4.04 (s, 2H),
4.52 (s, 2H), 5.37 (s, 2H), 6.01 (s, 2H), 6.93 (d, J¼8.6 Hz,
2H), 7.05 (m, 10H), 7.35 (d, J¼8.6 Hz, 2H). 13C NMR
(75 MHz, CDCl3) d (ppm)¼15.0, 55.7, 72.1, 74.8, 82.8,
100.4, 114.3, 122.6, 127.4, 127.8, 128.0, 130.1, 130.7,
137.6, 142.4, 159.7. Z isomer. 1H NMR (300 MHz,
CDCl3) d (ppm)¼2.00 (s, 3H), 3.81 (s, 3H), 4.21 (s,
2H), 4.48 (s, 2H), 5.47 (s, 2H), 5.92 (s, 2H), 6.93 (d,
J¼8.6 Hz, 2H), 7.05 (m, 10H), 7.35 (d, J¼8.6 Hz, 2H).
13C NMR (75 MHz, CDCl3) d (ppm)¼22.0, 55.7, 67.5,
71.9, 81.7, 99.6, 114.3, 124.6, 127.2, 127.8, 128.1,
129.8, 130.7, 137.6, 142.4, 159.7. CIMS (NH3) m/z 434
(MþNHþ4 , 16), 238 (47), 121 (100). Anal. Calcd for
C27H28O4: C, 77.86%; H, 6.78%. Found: C, 77.78%; H,
7.04%.
4.2.7. 2-[2-Methyl-3-(p-methoxy-benzyloxy)-prop-2-
enyl]-[1,3]dioxane (17i). The above procedure was applied
to 500 mg (1 equiv., 1.88 mmol) of dimethylacetal 16 (E/Z,
70:30) and 0.30 mL (2.2 equiv., 4.15 mmol) of propanediol
in dichloromethane (10 mL) in presence of 0.1 mL of 2,2-
dimethoxypropane. The reaction was monitored by TLC
and upon completion, a solution of saturated NaHCO3
(3 mL) was added. After flash chromatography, 420 mg
(80%) of dioxolane 17i were obtained as a colorless oil (E/Z,
70:30). nmax (film)/cm21 2958, 2850, 1666, 1612, 1514,
1
1248, 1092, 820. E isomer. H NMR (300 MHz, CDCl3) d
(ppm)¼1.35 (d, J¼13.6 Hz, 1H), 1.76 (s, 3H), 2.14 (m, 1H),
3.79 (s, 3H), 3.85 (m, 4H), 4.13 (dd, J¼4.9, 11.3 Hz, 2H),
4.37 (s, 2H), 5.24 (d, J¼6.4 Hz, 1H), 5.55 (d, J¼6.4 Hz,
1H), 6.85 (d, J¼8.7 Hz, 2H), 7.24 (d, J¼8.7 Hz, 2H). 13C

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L. Lemiegre et al. / Tetrahedron 60 (2004) 415–427
424
NMR (75 MHz, CDCl3) d (ppm)¼15.0, 26.1, 55.7, 67.4,
71.8, 74.8, 98.9, 114.1, 124.7, 129.7, 130.8, 139.4, 159.5. Z
isomer. 1H NMR (300 MHz, CDCl3) d (ppm)¼1.35 (d,
J¼13.6 Hz, 1H), 1.81 (s, 3H), 2.14 (m, 1H), 3.79 (s, 3H),
3.85 (m, 4H), 4.04 (dd, J¼4.9, 11.7 Hz, 2H), 4.39 (s, 2H),
5.14 (d, J¼6.4 Hz, 1H), 5.45 (d, J¼6.4 Hz, 1H), 6.85 (d,
J¼8.7 Hz, 2H), 7.24 (d, J¼8.7 Hz, 2H). 13C NMR (75 MHz,
CDCl3) d (ppm)¼20.3, 26.1, 55.7, 67.4, 72.9, 74.8, 98.2,
114.8, 126.7, 129.7, 130.8, 139.4, 159.5. CIMS (i-BuH) m/z
279 (MHþz, 25), 121 (100). HRMS Calcd for C16H22O4:
279.1596. Found: 279.1596.
3.98 (s, 2H), 4.29 (s, 1H), 4.30 (s, 1H), 5.25 (d, J¼7.2 Hz,
0.5H), 5.27 (d, J¼7.2 Hz, 0.5H), 5.46 (d, J¼7.2 Hz, 1H),
6.77 (d, J¼8.5 Hz, 2H), 7.17 (d, J¼8.5 Hz, 2H). 13C NMR
(75 MHz, CDCl3) d (ppm)¼21.3, 24.7, 27.2, 27.4, 40.0,
40.2, 55.6, 67.9, 68.5, 71.8, 71.9, 97.7, 97.3, 114.1, 127.2,
129.7, 130.8, 138.1, 159.6. EIMS (70 eV) m/z 347.2 (MHþ,
15), 220 (45), 156 (56), 137 (100), 121 (85). Anal. Calcd for
C21H30O4: C, 72.80; H, 8.73%. Found: C, 72.58%; H,
8.64%.
4.2.10. 3-[3-(4-Methoxy-benzyloxy)-2-methyl-propenyl]-
hexahydro-benzo[e]-[1,3]dioxepane (17l). The above pro-
cedure was applied to 709 mg (1 equiv., 2.67 mmol) of
dimethylacetal 16 E/Z, 70:30 were used with 500 mg
(1.3 equiv., 3.47 mmol) of anti-1,2-cyclohexane dimethanol
in dichloromethane (10 mL) in presence of 0.1 mL of 2,2-
dimethoxypropane. The reaction was monitored by TLC
and upon completion, a solution of saturated NaHCO3
(3 mL) was added. After flash chromatography, 500 mg
(54%) of dioxepane 17l (E/Z, 70:30) were recovered as a
colorless oil. nmax (film)/cm21 2924, 2854, 1612, 1514,
4.2.8. 2-[2-Methyl-3-(p-methoxy-benzyloxy)-prop-2-
enyl]-3,5-syn-dimethyl-[1,3]dioxane (17j). The above
procedure was applied to 2.0 g (1 equiv., 7.52 mmol) of
dimethylacetal 16 (E/Z, 70:30) and 1.08 mL (1.3 equiv.,
9.85 mmol) of pentane-1,3-diol (mixture of isomers) in
dichloromethane (30 mL) in presence of 0.1 mL of 2,2-
dimethoxypropane. The reaction was monitored by TLC
and upon completion, a solution of saturated NaHCO3
(5 mL) was added. After flash chromatography, 441 mg of
syn-E-17j, 144 mg of syn-Z-17j and 1.09 g as a mixture of
isomers. A total of 1.67 g (73%) dioxanes was recovered.
1
1248, 1032, 820. E isomer. H NMR (300 MHz, CDCl3) d
(ppm)¼0.86 (m, 2H), 1.25 (m, 4H), 1.62 (m, 2H), 1.74 (s,
3H), 1.78 (m, 2H), 3.2–3.7 (m, 4H), 3.78 (s, 3H), 3.86 (s,
2H), 4.39 (s, 2H), 5.42 (d, J¼6.4 Hz, 1H), 5.61 (d, J¼
6.4 Hz, 1H), 6.86 (d, J¼8.3 Hz, 2H), 7.24 (d, J¼8.3 Hz,
2H). 13C NMR (75 MHz, CDCl3) d (ppm)¼15.7, 26.6, 28.9,
29.2, 46.6, 55.6, 67.6, 71.8, 75.0, 97.7, 114.1, 125.1, 129.7,
130.8, 137.8, 159.5. Z isomer. 1H NMR (300 MHz, CDCl3)
d (ppm)¼0.86 (m, 2H), 1.25 (m, 4H), 1.62 (m, 2H), 1.80 (s,
3H), 1.78 (m, 2H), 3.2–3.7 (m, 4H), 3.78 (s, 3H), 4.05 (s,
2H), 4.39 (s, 2H), 5.42 (d, J¼6.4 Hz, 1H), 5.52 (d, J¼
6.4 Hz, 1H), 6.86 (d, J¼8.3 Hz, 2H), 7.24 (d, J¼8.3 Hz,
2H). 13C NMR (75 MHz, CDCl3) d (ppm)¼21.6, 26.6, 28.9,
29.2, 46.6, 55.6, 68.5, 71.8, 72.9, 97.0, 114.1, 127.3, 129.4,
130.8, 138.1, 159.5. EIMS (70 eV) m/z 347.2 (MHþ, 7), 210
(50), 155 (47), 122 (100). HRMS Calcd for C21H31O4
(MHþ) 347.2222. Found: 347.2216.
n
max (film)/cm21 2932, 2854, 1612, 1514, 1248, 1036, 820.
1
E isomer. H NMR (300 MHz, CDCl3) d (ppm)¼1.26 (m,
7H), 1.53 (dt, J¼12.3, 2.3 Hz, 1H), 1.76 (s, 3H), 3.79 (m,
5H), 3.89 (s, 2H), 4.38 (s, 2H), 5.26 (d, J¼6.4 Hz, 1H), 5.60
(d, J¼6.4 Hz, 1H), 6.85 (d, J¼8.3 Hz, 2H), 7.24 (d,
J¼8.3 Hz, 2H). 13C NMR (75 MHz, CDCl3) d (ppm)¼
14.9, 22.1, 40.7, 55.7, 71.9, 72.8, 75.1, 98.1, 114.1, 124.8,
1
129.7, 130.9, 139.2, 159.5. Z isomer. H NMR (300 MHz,
CDCl3) d (ppm)¼1.22 (m, 7H), 1.49 (dt, J¼2.3, 13.2 Hz,
1H), 1.81 (s, 3H), 3.71 (m, 2H), 3.80 (s, 3H), 4.05 (s, 2H),
4.39 (s, 2H), 5.18 (d, J¼6.8 Hz, 1H), 5.51 (d, J¼6.8 Hz,
1H), 6.87 (d, J¼8.7 Hz, 2H), 7.26 (d, J¼8.7 Hz, 2H). 13C
NMR (75 MHz, CDCl3) d (ppm)¼21.6, 22.0, 40.5, 55.7,
68.7, 71.5, 72.8, 97.3, 114.1, 126.7, 129.8, 130.9, 139.3,
159.5. CIMS (NH3) m/z 324 (MþNHþ4 , 100), 307 (MHþ,
90), 238 (10), 121 (72). Anal. Calcd for C18H26O4: C,
70.56%; H, 8.55%. Found: C, 70.59%; H, 8.66%.
4.2.11. 3-[3-(4-Methoxy-benzyloxy)-2-methyl-propenyl]-
benzo[e]-[1,3]dioxepane (17o). The above procedure was
applied to 3.0 g (1 equiv., 11.3 mmol) of dimethylacetal 16
(E/Z, 70:30) and 2.34 g (1.5 equiv., 16.9 mmol) of
(2-hydroxymethyl-phenyl)-methanol in dichloromethane
(30 mL) in presence of 0.2 mL of 2,2-dimethoxypropane.
The reaction was monitored by TLC and upon completion, a
solution of saturated NaHCO3 (5 mL) was added. After flash
chromatography, 2.66 g (70%) of dioxepane 17o (E/Z,
70:30) as a colorless oil. nmax (film)/cm21 2954, 2852, 1612,
1512, 1248, 1088, 1032, 820. E isomer. 1H NMR (300 MHz,
CDCl3) d (ppm)¼1.76 (d, J¼0.8 Hz, 3H), 3.73 (s, 3H), 3.85
(s, 2H), 4.34 (s, 2H), 4.86 (s, 4H), 5.55 (d, J¼6.0 Hz, 1H),
5.65 (dd, J¼6.0, 1.1 Hz, 1H), 6.80 (d, J¼8.7 Hz, 2H), 7.1–
7.3 (m, 6H). 13C NMR (75 MHz, CDCl3) d (ppm)¼15.0,
55.7, 71.1, 71.9, 74.9, 103.5, 114.2, 124.5, 127.6,127.7,
4.2.9. 3-[3-(4-Methoxy-benzyloxy)-2-methyl-propenyl]-
hexahydro-benzo[e]-[1,3]dioxepane (17k). The above
procedure was applied to 2.0 g (1 equiv., 7.52 mmol) of
dimethylacetal 16 (E/Z, 70:30) and 1.63 g (1.5 equiv.,
11.3 mmol) of syn-1,2-cyclohexane dimethanol in dichloro-
methane (15 mL) in presence of 0.1 mL of 2,2-dimethoxy-
propane. The reaction was monitored by TLC and upon
completion, a solution of saturated NaHCO3 (3 mL) was
added. After flash chromatography, 1.60 g (61%) of
dioxepane 17k (E/Z, 70:30) were recovered as a colorless
oil and as a mixture of two epimers (50:50). nmax (film)/
cm21 2926, 2856, 1612, 1512, 1248, 1144, 820. E isomer
(syn, anti). 1H NMR (300 MHz, CDCl3) d (ppm)¼1.36 (m,
4H), 1.65 (m, 6H), 1.66 (s, 3H), 3.4–3.8 (m, 4H), 3.68 (s,
3H), 3.79 (s, 2H), 4.30 (s, 1H), 4.32 (s, 1H), 5.31 (d,
J¼6.4 Hz, 0.5H), 5.33 (d, J¼6.4 Hz, 0.5H), 5.54 (d, J¼
6.4 Hz, 1H), 6.77 (d, J¼8.5 Hz, 2H), 7.17 (d, J¼8.5 Hz,
2H). 13C NMR (75 MHz, CDCl3) d (ppm)¼14.7, 24.7, 27.2,
27.4, 40.0, 40.2, 55.6, 67.9, 71.8, 71.9, 75.0, 97.9, 98.3,
114.1, 125.0, 129.7, 130.8, 137.8, 159.6. Z isomer (syn,
anti). 1H NMR (300 MHz, CDCl3) d (ppm)¼1.36 (m, 4H),
1.65 (m, 6H), 1.73 (s, 3H), 3.4–3.8 (m, 4H), 3.68 (s, 3H),
1
129.8, 130.8, 139.3, 159.6. Z isomer. H NMR (300 MHz,
CDCl3) d (ppm)¼1.77 (s, 3H), 3.73 (s, 3H), 4.05 (s, 2H),
4.37 (s, 2H), 4.75 (d, J¼13.9 Hz, 2H), 4.82 (d, J¼13.9 Hz,
2H), 5.49 (d, J¼6.4 Hz, 1H), 5.55 (d, J¼6.4 Hz, 1H), 6.80
(d, J¼8.7 Hz, 2H), 7.1–7.3 (m, 6H). 13C NMR (75 MHz,
CDCl3) d (ppm)¼21.7, 55.7, 68.8, 71.2, 71.9, 103.1, 114.2,
126.6, 127.6, 127.7, 129.8, 130.8, 139.1, 159.6. CIMS
(i-BuH) m/z 341 (MHþ, 100), 259 (15), 121 (98). Anal.

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L. Lemiegre et al. / Tetrahedron 60 (2004) 415–427
425
Calcd for C21H24O4: C, 74.09%; H, 7.11%. Found: C,
74.15%; H, 7.25%.
dimethylacetal 16 (E/Z, 70:30) and 1.64 g (1.5 equiv.,
8.45 mmol) of anti-diol 8b in dichloromethane (15 mL) in
presence of 0.1 mL of 2,2dimethoxypropane. The reaction
was monitored by TLC and upon completion, a solution of
saturated NaHCO3 (4 mL) was added. After flash chroma-
tography, 1.50 g (67%) of dioxepane 17r (E/Z, 70:30) were
recovered as a colorless oil. nmax (film)/cm21 2930, 2874,
4.2.12. 3-[3-(4-Methoxy-benzyloxy)-2-methyl-propenyl]-
1,5-syn-dimethyl-benzo[e]-[1,3]dioxepane (17p). The
above procedure was applied to 1.41 g (1 equiv.,
5.30 mmol) of dimethylacetal 16 (E/Z, 70:30) and 1.32 g
(1.5 equiv., 7.95 mmol) of syn-diol 9a in dichloromethane
(20 mL). The reaction was monitored by TLC and upon
completion, a solution of saturated NaHCO3 (4 mL) was
added. After flash chromatography, 1.54 g (81%) of
dioxepane 17p (E/Z, 70:30) were obtained as a colorless
oil and as a mixture of two epimers (syn/anti: 80:20). nmax
(film)/cm21 2978, 2854, 1612, 1512, 1246, 1094, 818. E
1
1612, 1514, 1248, 1070, 1036, 820. E isomer. H NMR
(300 MHz, CDCl3) d (ppm)¼1.04 (t, J¼6.0 Hz, 3H), 1.07 (t,
J¼5.7 Hz, 3H), 1.79 (s, 3H), 1.93 (m, 2H), 2.13 (m, 2H),
3.80 (s, 3H), 3.91 (s, 2H), 4.41 (s, 2H), 4.90 (dd, J¼3.8,
8.3 Hz, 1H), 5.07 (dd, J¼4.5, 8.6 Hz, 1H), 5.64 (d, J¼
6.0 Hz, 1H), 5.74 (d, J¼6.0 Hz, 1H), 6.87 (d, J¼8.6 Hz,
2H), 7.1–7.3 (m, 6H). 13C NMR (75 MHz, CDCl3) d
(ppm)¼10.6, 11.0, 15.1, 26.3, 28.4, 55.1, 71.8, 73.7, 75.1,
81.5, 97.6, 114.3, 125.3, 126.5, 127.4, 129.7, 130.8, 138.7,
140.3, 142.0, 159.5. Z isomer. 1H NMR (300 MHz, CDCl3)
d (ppm)¼1.04 (t, J¼6.0 Hz, 3H), 1.07 (t, J¼5.7 Hz, 3H),
1.85 (s, 3H), 1.93 (m, 2H), 2.13 (m, 2H), 3.80 (s, 3H), 3.96
(d, J¼12.2 Hz, 1H), 4.10 (d, J¼12.2 Hz, 1H), 4.38 (s, 2H),
4.79 (dd, J¼3.7, 8.3 Hz, 1H), 5.06 (m, 1H), 5.59 (d,
J¼6.0 Hz, 1H), 5.74 (d, J¼6.0 Hz, 1H), 6.87 (d, J¼8.6 Hz,
2H), 7.1–7.3 (m, 6H). 13C NMR (75 MHz, CDCl3) d
(ppm)¼10.6, 11.0, 21.1, 26.3, 28.4, 55.1, 68.8, 71.8, 73.7,
81.5, 95.5, 114.3, 125.3, 126.5, 127.4, 129.7, 130.8, 138.7,
140.3, 142.0, 159.5. EIMS (70 eV) m/z 396.2 (Mþz, 1), 205
(7), 177 (55), 159 (100), 121 (62). Anal. Calcd for
C25H32O4: C, 75.73; H, 8.13%. Found: C, 75.86%; H, 8.11%.
1
(anti) isomer. H NMR (300 MHz, CDCl3) d (ppm)¼1.69
(d, J¼6.4 Hz, 6H), 1.80 (s, 3H), 3.79 (s, 3H), 3.88 (s, 2H),
4.37 (s, 2H), 5.20 (q, J¼6.4 Hz, 1H), 5.60 (d, J¼6.0 Hz,
1H), 5.84 (d, J¼6.0 Hz, 1H), 6.85 (d, J¼8.7 Hz, 2H), 7.1–
7.3 (m, 6H). 13C NMR (75 MHz, CDCl3) d (ppm)¼15.0,
19.8, 55.7, 71.9, 75.2, 75.4, 105.2, 114.1, 125.4, 126.5,
128.0, 129.8, 130.9, 137.5, 142.5, 159.5. Z (anti) isomer. 1H
NMR (300 MHz, CDCl3) d (ppm)¼1.65 (d, J¼6.4 Hz, 6H),
1.80 (s, 3H), 3.80 (s, 3H), 4.10 (s, 2H), 4.37 (s, 2H), 5.08 (q,
J¼6.4 Hz, 1H), 5.51 (d, J¼6.0 Hz, 1H), 5.78 (d, J¼6.0 Hz,
1H), 6.85 (d, J¼8.7 Hz, 2H), 7.1–7.3 (m, 6H). 13C NMR
(75 MHz, CDCl3) d (ppm)¼19.8, 21.6, 55.7, 68.8, 71.9,
75.2, 104.4, 114.2, 125.4, 126.5, 128.0, 129.8, 130.9, 137.5,
142.5, 159.5. EIMS (70 eV) m/z 368.2 (Mþz, 1), 232 (8), 220
(12), 177 (70), 132 (100), 121 (55). Anal. Calcd for
C23H28O4: C, 74.97%; H, 7.66%. Found: C, 74.63%; H,
7.84%.
4.2.15. 3-[3-(4-Methoxy-benzyloxy)-2-methyl-propenyl]-
1,5-anti-diisopropyl-benzo[e]-[1,3]dioxepane (17s). The
above procedure was applied to 1.50 g (1 equiv.,
5.63 mmol) of dimethylacetal 16 (E/Z, 70:30) and 1.90 g
(1.5 equiv., 8.56 mmol) of anti-diol 8c in dichloromethane
(15 mL) in presence of 0.1 mL of 2,2dimethoxypropane.
The reaction was monitored by TLC and upon completion, a
solution of saturated NaHCO3 (5 mL) was added. After flash
chromatography, 1.20 g (50%) of dioxepane 17s (E/Z,
70:30) were recovered as a colorless oil. nmax (film)/cm21
2960, 2872, 1612, 1514, 1248, 1076, 1034, 822. E isomer.
1H NMR (300 MHz, CDCl3) d (ppm)¼0.88 (m, 6H), 1.03
(d, J¼6.8 Hz, 3H), 1.11 (d, J¼6.8 Hz, 3H), 1.80 (s, 3H),
2.4–2.6 (m, 2H), 3.80 (s, 3H), 3.92 (s, 2H), 4.42 (s, 2H),
4.81 (d, J¼3.0 Hz, 1H), 4.91 (d, J¼4.5 Hz, 1H), 5.56 (d,
J¼6.0 Hz, 1H), 5.74 (d, J¼6.0 Hz, 1H), 6.87 (d, J¼8.7 Hz,
2H), 7.2–7.3 (m, 6H). 13C NMR (75 MHz, CDCl3) d
(ppm)¼15.2, 16.4, 16.9, 20.6, 21.2, 29.7, 31.5, 55.7, 71.9,
75.2, 76.6, 83.9, 98.1, 114.2, 125.3, 126.9, 127.0, 129.7,
130.8, 138.6, 140.9, 141.9, 159.5. Z isomer. 1H NMR
(300 MHz, CDCl3) d (ppm)¼0.88 (m, 6H), 1.03 (d,
J¼6.8 Hz, 3H), 1.11 (d, J¼6.8 Hz, 3H), 1.85 (s, 3H), 2.4–
2.6 (m, 2H), 3.80 (s, 3H), 4.06 (d, J¼12.8 Hz, 1H), 4.13 (d,
J¼12.8 Hz, 1H), 4.39 (s, 2H), 4.71 (d, J¼3.4 Hz, 1H), 4.89
(m, 1H), 5.51 (d, J¼6.4 Hz, 1H), 5.60 (d, J¼6.4 Hz, 1H),
6.87 (d, J¼8.7 Hz, 2H), 7.2–7.3 (m, 6H). 13C NMR
(75 MHz, CDCl3) d (ppm)¼16.6, 17.2, 19.4, 20.0, 21.6,
29.5, 31.8, 55.7, 68.8, 71.9, 76.6, 84.4, 97.1, 114.2, 125.3,
126.9, 127.0, 129.7, 130.8, 138.6, 140.9, 141.9, 159.5. Anal.
Calcd for C27H36O4: C, 76.38; H, 8.55%. Found: C, 76.44%;
H, 8.85%.
4.2.13. 3-[3-(4-Methoxy-benzyloxy)-2-methyl-propenyl]-
1,5-anti-dimethyl-benzo[e]-[1,3]dioxepane (17q). The
above procedure was applied to 1.20 g (1 equiv.,
4.51 mmol) of dimethylacetal 16 (E/Z, 70:30) and 1.10 g
(1.5 equiv., 6.63 mmol) of anti-diol 8a in dichloromethane
(20 mL). The reaction was monitored by TLC and upon
completion, a solution of saturated NaHCO3 (4 mL) was
added. After flash chromatography, 1.00 g (60%) of
dioxepane 17q (E/Z, 70:30) was obtained as a colorless
oil. nmax (film)/cm21 2978, 2934, 1612, 1512, 1248, 1104,
1
1034, 820, 754. E isomer. H NMR (300 MHz, CDCl3) d
(ppm)¼1.55 (m, 6H), 1.73 (s, 3H), 3.73 (s, 3H), 3.85 (s, 2H),
4.34 (s, 2H), 5.07, 5.26 (2q, J¼6.8 Hz, 2H), 5.57 (d,
J¼6.0 Hz, 1H), 5.67 (d, J¼6.0 Hz, 1H), 6.81 (d, J¼8.7 Hz,
2H), 7.1–7.2 (m, 6H). 13C NMR (75 MHz, CDCl3) d
(ppm)¼15.0, 20.3, 22.1, 55.7, 68.2, 71.9, 75.1, 76.3, 97.4,
114.2, 124.9, 126.1, 126.3, 127.5, 127.6, 129.7, 130.8,
1
139.3, 141.2, 143.1, 159.6. Z isomer. H NMR (300 MHz,
CDCl3) d (ppm)¼1.78 (s, 3H), 3.73 (s, 3H), 4.05 (s, 2H),
4.34 (s, 2H), 4.95, 5.10 (2q, J¼6.8 Hz, 2H), 5.56 (d,
J¼6.0 Hz, 1H), 5.67 (d, J¼6.0 Hz, 1H), 6.80 (d, J¼8.7 Hz,
2H), 7.1–7.3 (m, 6H). 13C NMR (75 MHz, CDCl3) d
(ppm)¼25.0, 55.7, 67.3, 72.9, 73.6, 76.2, 96.4, 114.2, 125.4,
126.1, 126.3, 127.5, 127.6, 129.7, 130.8, 139.3, 140.6,
142.6, 159.6. EIMS (70 eV) m/z 368.2 (Mþz, 1), 220 (10),
177 (57), 131 (100), 121 (57). Anal. Calcd for C23H28O4: C,
74.97%; H, 7.66%. Found: C, 74.48%; H, 7.93%.
4.2.14. 3-[3-(4-Methoxy-benzyloxy)-2-methyl-propenyl]-
1,5-anti-diethyl-benzo[e]-[1,3]dioxepane (17r). The above
procedure was applied to 1.50 g (1 equiv., 5.63 mmol) of
4.2.16. 3-[3-(4-Methoxy-benzyloxy)-2-methyl-propenyl]-
1,5-anti-diisobutyl-benzo[e]-[1,3]dioxepane (17t). The

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L. Lemiegre et al. / Tetrahedron 60 (2004) 415–427
426
above procedure was applied to 500 mg (1 equiv.,
1.88 mmol) of dimethylacetal 16 (E/Z, 70:30) and 700 mg
(1.5 equiv., 2.80 mmol)of anti-diol 8d in dichloromethane
(5 mL). The reaction was monitored by TLC and upon
completion, a solution of saturated NaHCO3 (2 mL) was
added. After flash chromatography (heptane/AcOEt, 80/20
as eluent), 446 mg (52%) of dioxepane 17t (E/Z, 70:30)
were recovered as a colorless oil. nmax (film)/cm21 2954,
2867, 1612, 1513, 1247, 1084, 820, 750. E isomer. 1H NMR
(300 MHz, CDCl3) d (ppm)¼1.00 (m, 12H), 1.7–2.0 (m,
6H), 1.77 (s, 3H), 3.80 (s, 3H), 3.91 (s, 2H), 4.41 (s, 2H),
5.09 (dd, J¼3.6, 10.2 Hz, 1H), 5.23 (m, 1H), 5.64 (d,
J¼6.3 Hz, 1H), 5.73 (d, J¼6.3 Hz, 1H), 6.87 (d, J¼6.8 Hz,
2H), 7.24 (m, 6H). 13C NMR (75 MHz, CDCl3) d
(ppm)¼15.0, 22.2, 22.4, 24.2, 24.7, 42.8, 45.1, 55.7, 71.0,
71.9, 75.1, 78.4, 97.2, 114.2, 125.5, 126.3, 126.4, 127.5,
129.6, 130.8, 138.5, 140.4, 142.9, 159.5. Z isomer. 1H NMR
(300 MHz, CDCl3) d (ppm)¼1.00 (m, 12H), 1.7–2.0 (m,
6H), 3.80 (s, 3H), 4.00, 4.11 (2d, J¼16.7 Hz, 2H), 4.38 (s,
2H), 5.01 (dd, J¼3.6, 10.2 Hz, 1H), 5.23 (m, 1H), 5.60 (d,
J¼6.3 Hz, 1H), 5.73 (d, J¼6.3 Hz, 1H), 6.87 (d, J¼6.8 Hz,
2H), 7.24 (m, 6H). 13C NMR (75 MHz, CDCl3) d
(ppm)¼21.6, 22.2, 22.4, 24.2, 24.7, 42.8, 45.1, 55.7, 68.8,
71.0, 71.9, 78.4, 96.2, 114.2, 125.5, 126.3, 126.4, 127.5,
129.6, 130.8, 138.8, 140.4, 142.9, 159.5. EIMS (70 eV) m/z
452.3 (Mþz, 1), 231 (100), 215 (80), 121 (55). Anal. Calcd
for C29H40O4: C, 76.95; H, 8.91%. Found: C, 76.55%; H,
8.96%.
aqueous phase was extracted with dichloromethane
(2£10 mL). The resulting organic phase was dried
(MgSO4) and evaporated under reduce pressure. A flash
chromatography on silica gel (eluting with heptane/AcOEt,
70:30) afforded 399 mg (51%) of dioxonane 17v. nmax
(film)/cm21 3060, 2932, 1674, 1612, 1514, 1248, 1076, 822,
760. E isomer. 1H NMR (300 MHz, CDCl3) d (ppm)¼1.63
(s, 3H), 3.79 (s, 3H), 3.86 (s, 2H), 4.05 (d, J¼12.3 Hz, 1H),
4.29 (d, J¼10.9 Hz, 1H), 4.39 (s, 2H), 4.53 (d, J¼10.9 Hz,
1H), 4.74 (d, J¼12.3 Hz, 1H), 5.01 (d, J¼6.4 Hz, 1H), 5.63
(d, J¼6.4 Hz, 1H), 6.86 (d, J¼8.7 Hz, 2H), 7.15–7.45 (m,
9H). 13C NMR (75 MHz, CDCl3) d (ppm)¼14.9, 55.7, 65.7,
72.0, 74.1, 75.1, 101.4, 114.2, 126.6, 128.4, 128.8, 128.9,
129.0, 129.7, 130.1, 130.2, 130.6, 131.0, 130.8, 135.6,
136.9, 137.0, 141.8, 142.0, 159.7. Z isomer. 1H NMR
(300 MHz, CDCl3) d (ppm)¼1.80 (s, 3H), 3.79 (s, 3H), 3.94
(d, J¼12.4 Hz, 1H), 4.04 (s, 2H), 4.27 (d, J¼10.9 Hz, 1H),
4.39 (s, 2H), 4.51 (d, J¼10.9 Hz, 1H), 4.66 (d, J¼12.4 Hz,
1H), 5.01 (d, J¼6.4 Hz, 1H), 5.53 (d, J¼6.4 Hz, 1H), 6.86
(d, J¼8.7 Hz, 2H), 7.15–7.45 (m, 9H). 13C NMR (75 MHz,
CDCl3) d (ppm)¼21.7, 55.7, 65.6, 69.0, 72.0, 73.9, 100.7,
114.2, 126.6, 128.4, 128.8, 128.9, 129.0, 129.7, 130.1,
130.2, 130.6, 131.0, 130.8, 135.6, 136.9, 137.0, 141.8,
142.0, 159.7. CIMS (i-BuH) m/z 417 (MHþ, 6), 335 (4), 197
(24), 121 (100).
4.2.19. 1,1-Diallyloxy-3-methyl-4-(p-methoxy-benzyl-
oxy)-but-2-ene (18). A solution of dimethylacetal 16
(500 mg, 1 equiv., 1.88 mmol) in dichloromethane
(25 mL) and allylic alcohol (1.09 g,10 equiv., 18.8 mmol)
were put in a flask equipped with a heavy-solvent designed
Dean–Stark device. The reaction mixture was refluxed in
presence of acetic acid (0.05 mL). After 12 h, NaHCO3
(4 mL) was added and the aqueous phase extracted with
dichloromethane (2£10 mL). The resulting organic phase
was dried (MgSO4) and evaporated under reduce pressure.
A flash chromatography on silica gel (eluting with heptane/
AcOEt, 70:30) afforded 320 mg (53%) of diallylacetal 18 as
4.2.17. 5-Isobutyl-3-[3-(4-methoxy-benzyloxy)-2-methyl-
propenyl]-benzo[e]-[1,3]dioxepane (17u). The above pro-
cedure was applied to 1.00 g (1 equiv., 3.76 mmol) of
dimethylacetal 16 (E/Z, 70:30) and 1.1 g (1.5 equiv.,
5.67 mmol) of anti-diol 10d in dichloromethane (15 mL).
The reaction was monitored by TLC and upon completion, a
solution of saturated NaHCO3 (4 mL) was added. After flash
chromatography (heptane/AcOEt, 75:25 as eluent), 1.01 g
(68%) of dioxepane 17u (E/Z, 70:30) were obtained as a
yellowish oil, each stereoisomer being a mixture of two
epimers (E: 33:66, Z, 50:50). nmax (film)/cm21 2953, 2865,
1611, 1512, 1247, 1086, 820, 747. Major isomer syn or anti
E. 1H NMR (300 MHz, CDCl3) d (ppm)¼1.00 (m, 6H), 1.81
(s, 3H), 1.7–2.1 (m, 3H), 3.79 (s, 3H), 3.90 (s, 2H), 4.39 (s,
2H), 4.8–5.1 (m, 3H), 5.74 (s, 2H), 6.86 (d, J¼8.7 Hz, 2H),
1
a colorless oil. E isomer. H NMR (300 MHz, CDCl3) d
(ppm) 1.75 (s, 3H), 3.79 (s, 3H), 3.89 (s, 2H), 4.06 (m, 4H),
4.39 (s, 2H), 5.24 (m, 5H), 5.60 (d, J¼6.8 Hz, 1H), 6.87 (d,
J¼8.7 Hz, 2H), 7.25 (d, J¼8.7 Hz, 2H). Z isomer. 1H NMR
(300 MHz, CDCl3) d (ppm) 1.82 (s, 3H), 3.79 (s, 3H), 4.06
(m, 4H), 4.39 (s, 2H), 5.24 (m, 5H), 5.49 (d, J¼6.8 Hz, 1H),
6.87 (d, J¼8.7 Hz, 2H), 7.25 (d, J¼8.7 Hz, 2H).
7.1–7.4 (m, 6H). 13C NMR (75 MHz, CDCl3)
d
(ppm)¼15.0, 22.0, 24.6, 42.5, 55.7, 71.1, 71.9, 73.7, 75.0,
104.0, 114.2, 125.5, 127.7, 128.1, 128.7, 129.71, 129.74,
130.7, 138.0, 139.3, 143.7, 159.5. Other isomers. H NMR
4.2.20. 2-[3-(4-Methoxy-benzyloxy)-2-methyl-propenyl]-
4,7-dihydro-[1,3]dioxepine (19). Diallyl acetal 18
(207 mg, 1 equiv., 0.651 mmol) was dissolved in 10 mL
dichloromethane containing 60 mg Grubbs catalyst
(0.1 equiv., 0.073 mmol) under argon and at room tempera-
ture. After 2 h, a second load of 50 mg (0.09 equiv.,
0.061 mmol) catalyst was added. The reaction mixture
was stirred overnight then evaporated under reduce
pressure. A flash chromatography on silica gel (eluting
with heptane/AcOEt, 70:30) afforded 52 mg (27%) of
dioxepine 19 as a colorless oil. E isomer. 1H NMR
(300 MHz, CDCl3) d (ppm) 1.77 (s, 3H), 3.79 (s, 3H),
3.89 (s, 2H), 4.20 (d, J¼15.1 Hz, 2H), 4.44 (m, 4H), 5.50 (d,
J¼6.0 Hz, 1H), 5.70 (d, J¼6.0 Hz, 1H), 5.73 (s, 2H), 6.86
(d, J¼8.7 Hz, 2H), 7.25 (d, J¼8.7 Hz, 2H). 13C NMR
(75 MHz, CDCl3) d (ppm) 14.9, 55.7, 65.2, 72.0, 74.9,
100.1, 114.2, 124.2, 129.7, 130.4, 130.7, 139.1, 159.6. Z
1
(300 MHz, CDCl3) d (ppm)¼0.98 (m, 6H), 1.7–2.1 (m,
6H), 3.79 (s, 3H), 4.09 (s, 2H), 4.42 (s, 2H), 4.8–5.1 (m,
3H), 5.56–5.78 (m, 2H), 6.86 (d, J¼8.7 Hz, 2H), 7.1–7.4
(m, 6H). EIMS (70 eV) m/z 397.2 (MHþ, 1), 260 (8), 220
(25), 175 (77), 119 (100). Anal. Calcd for C25H32O4: C,
75.73; H, 8.13%. Found: C, 75.52%; H, 8.51%.
4.2.18. 2-[3-(4-Methoxy-benzyloxy)-2-methyl-propenyl]-
dibenzo[e,g]-[1,3]dioxonane (17v). A solution of dimethyl-
acetal 16 (500 mg, 1 equiv., 1.88 mmol) in dichloromethane
(25 mL) and (20-hydroxymethyl-biphenyl-2-yl)-methanol
(806 mg, 2 equiv., 3.76 mmol) were put in a flask equipped
with a heavy-solvent designed Dean–Stark device. The
mixture was refluxed in presence of 0.05 mL acetic acid.
After 24 h, 4 mL saturated NaHCO3 were added and the

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427
1
5. Yakelis, N. A.; Roush, W. R. Org. Lett. 2001, 3, 957–960.
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isomer. H NMR (300 MHz, CDCl3) d (ppm) 1.83 (s, 3H),
3.79 (s, 3H), 4.07 (s, 2H), 4.20 (d, J¼15.1 Hz, 2H), 4.44 (m,
4H), 5.44 (d, J¼6.0 Hz, 1H), 5.6 (d, J¼6.0 Hz, 1H), 5.73 (s,
2H), 6.86 (d, J¼8.7 Hz, 2H), 7.25 (d, J¼8.7 Hz, 2H). 13C
NMR (75 MHz, CDCl3) d (ppm) 21.6, 55.7, 65.2, 68.7, 72.0,
99.5, 114.2, 126.4, 129.8, 130.3, 130.7, 139.3, 159.6.
7. Deagostino, A. M.; Maddaluno, J.; Prandi, C.; Venturello, P.
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4.2.21. 1,1-Bis-[10-phenyl-prop-20-en-10-yloxy]-3-methyl-
4-(p-methoxy-benzyloxy)-but-2-ene (20). A solution of
dimethylacetal 16 (500 mg, 1 equiv., 1.88 mmol) in
dichloromethane (25 mL) and 1-phenyl-prop-2-en-1-ol
(1.01 g, 4 equiv., 7.52 mmol) were put in a flask equipped
with a heavy-solvent designed Dean–Stark device. The
reaction mixture was refluxed in presence of acetic acid
(0.05 mL). After 30 h, NaHCO3 (4 mL) was added and the
aqueous phase extracted with dichloromethane (2£10 mL).
The resulting organic phase was dried (MgSO4) and
evaporated under reduce pressure. A flash chromatography
on silica gel (eluting with heptane/AcOEt, 70:30) afforded
509 mg (60%) of acetal 20 as an inseparable mixture of
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12. Ito, Y.; Ariza, X.; Beck, A. K.; Bohac, A.; Ganter, C.; Gawley,
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1
diastereoisomers. Mixture of isomers: H NMR (300 MHz,
CDCl3) d (ppm) 1.5 (s, 3H), 3.79 (s, 5H), 4.9–5.7 (m, 10H),
5.95 (m, 2H), 6.86 (d, J¼8.3 Hz, 2H), 7.1–7.4 (m, 12H).
16. Kleijn, H.; Jastrzebski, J. T. B. H.; Boersma, J.; van Koten, G.
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¨
17. Clausen, C.; Wartchow, R.; Butenschon, H. Eur. J. Org.
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´
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18. Bataille, C.; Begin, G.; Guillam, A.; Lemiegre, L.; Lys, C.;
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Acknowledgements
`
L.L. thanks the Ministere de la Recherche et de la
19. Deagostino, A.; Balma Tivola, P.; Prandi, C.; Venturello, P.
Synlett 1999, 11, 1841–1843.
Technologie for a PhD grant (2000–2002). Dr. Jean-Erick
Ancel (Archemis) is acknowledged for samples of 1-acet-
oxyisoprene. F.L. was a summer-student from the Ecole
Superieure de Chimie Organique et Minerale (ESCOM,
Cergy-Pontoise, France). The high-resolution mass spectra
were performed by Mr. Albert Marcual (IRCOF, Mont St
Aignan, France) or Richard Stevens (Department of
Chemistry, UCLA, Los Angeles, USA). We thank Professor
A. P. Evans (University of Delaware) for discussing the
metathesis topic.
20. Guillam, A.; Toupet, L.; Maddaluno, J. J. Org. Chem. 1998,
63, 5110–5122.
`
21. Lemiegre, L.; Regnier, T.; Combret, J.-C.; Maddaluno, J.
´
´
Tetrahedron Lett. 2003, 44, 373–377.
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Organic Compounds; Wiley: New York, 1994.
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J. P. J. J. Am. Chem. Soc. 1985, 107, 3902–3909, A full
optimization on dioxolanes derived from propanal and cis or
trans cyclopentanediols, that are fair models for 17f and 17g,
indicates the latter to be less stable by more than 28 kcal/mol.
24. Uno, T.; Ku, J.; Prudent, J. R.; Huang, A.; Schultz, P. G. J. Am.
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