Thermal/hyperbaric heterocycloaddition of 1,4-dialkoxy-1,3-dienes: The de novo (E,Z) way to sugars

Article abstract of DOI:10.1021/jo0204193

1-(Z)-Alkoxy-4-(E)-methoxybutadiene derivatives have been reacted with ethylgyoxylate and diethyl ketomalonate under thermal or hyperbaric conditions. They provide, with a total regioselectivity and fair to total endoselectivities, the expected dihydropyranic cycloadducts. Three of those pseudoglycals have been converted in a few classical steps (deprotection, reduction, and dihydroxylation) into (racemic) allose, mannose, and gullose derivatives. The order of these three steps has a direct influence on the efficiency of the transformation and determines the stereochemistry of the final sugar.

Full text of DOI:10.1021/jo0204193

Th er m a l/Hyp er ba r ic Heter ocycloa d d ition of
1,4-Dia lk oxy-1,3-d ien es: Th e d e n ovo (E,Z) Wa y to Su ga r s
Carole Bataille,† Gautier Be´gin,† Anne Guillam,† Lo¨ıc Lemie`gre,† Caroline Lys,†
J acques Maddaluno,*,† and Lo¨ıc Toupet‡
Laboratoire des Fonctions Azote´es et Oxyge´ne´es Complexes, UMR 6014 CNRS, IRCOF,
Universite´ de Rouen, 76821-Mont St. Aignan Cedex, France, and Groupe de Matie`re Condense´e et
Mate´riaux-UMR 6626 CNRS, Universite´ de Rennes I, 35042-Rennes Cedex, France
jmaddalu@crihan.fr
Received J une 19, 2002
1-(Z)-Alkoxy-4-(E)-methoxybutadiene derivatives have been reacted with ethylgyoxylate and diethyl
ketomalonate under thermal or hyperbaric conditions. They provide, with a total regioselectivity
and fair to total endoselectivities, the expected dihydropyranic cycloadducts. Three of those pseudo-
glycals have been converted in a few classical steps (deprotection, reduction, and dihydroxylation)
into (racemic) allose, mannose, and gullose derivatives. The order of these three steps has a direct
influence on the efficiency of the transformation and determines the stereochemistry of the final
sugar.
In tr od u ction
diene also adds to glyoxylates, while providing a complex
mixture of [2+2] adducts. Interestingly, one of the
simplest routes to these heterocycles, viz. the addition
of 1,4-dialkoxydienes on glyoxylates (Scheme 1), has been
relatively neglected.2b,c,h,j,6 Early reports about the poor
reactivity of these types of dienes (assigned to the
competing polarizations induced by the 1,4-disubstitution
pattern)2c and the relative paucity of simple synthetic
routes to 1,4-difunctionalized dienes are probably re-
sponsible for this partial void in the literature.
We have previously described a one-step stereoselective
access to (1Z,3E)-1,4-dialkoxydienes 2,7 from R,â-unsat-
urated acetals such as 1.8 Despite their (1Z,3E) config-
uration, the [4+2] cycloadditions involving these dienes
turned out to be chemically efficient and highly regio-
The biological potential of rare and modified saccha-
rides, carba and pseudosugars, disaccharide mimics, ...
explains the renewed interest of the organic chemist’s
community into new routes to highly functionalized
tetrahydropyran skeletons, in particular asymmetric
(catalytic) ones.1 The so-called de novo approach of sugars
sometimes offers an interesting short-cut toward these
targets and can thus favorably compare to the classical
methods of glycochemistry. In particular, the convergent
[4+2] cycloaddition strategies, under their direct (diene
+ heterodienophile)2 or inverse (heterodiene + dieno-
phile)3 demand versions, have been widely explored and
both have led to convincing results. The very convergent
approach proposed by Danishefsky and colleagues,4 which
relies on 1,4-dialkoxy-2-silyloxy dienes, is especially
worth underlining since it takes double advantage of the
silyloxy moiety that acts both as a convenient hydroxy
precursor and as a polarizing group increasing the
reactivity of the diene. By contrast, Scheeren et al.5 have
shown that the gem-disubstituted 1,1,4-trimethoxybuta-
(3) See inter alia: (a) Schmidt, R. R.; Maier, M. Tetrahedron Lett.
1985, 26, 2065. (b) Tietze, L. F.; Schneider, C.; Montenbruck, A. Angew.
Chem., Int. Ed. Engl. 1994, 33, 980. (c) Dondoni, A.; Kniezo, L.;
Martinkova, M. J . Chem. Soc., Chem. Commun. 1994, 1963. (d)
Dujardin, G.; Rossignol, S.; Brown, E. Tetrahedron Lett. 1996, 37, 4007.
(e) Dujardin, G.; Martel, A.; Brown, E. Tetrahedron Lett. 1998, 39,
8647. (f) Dujardin, G.; Leconte, S.; Coutable, L.; Brown, E. Tetrahedron
Lett. 2001, 42, 8849.
(4) (a) Danishefsky, S. J .; Maring, C. J . J . Am. Chem. Soc. 1985,
107, 7761. (b) Danishefsky, S. J .; Barbachyn, M. R. J . Am. Chem. Soc.
1985, 107, 7762. (c) Danishefsky, S. J .; Hungate, R.; Shulte, G. J . Am.
Chem. Soc. 1988, 110, 7434.
(5) Van Balen, H. C. J . G; Broekhuis, A. A.; Scheeren, J . W.; Nivard,
R. J . F. Recl. Trav. Chim. Pays-Bas 1979, 98, 36.
(6) (a) Schmidt, R. R.; Angerbauer, R. Angew. Chem., Int. Ed. Engl.
1977, 16, 783. (b) David, S.; Eustache, J . J . Chem. Soc., Perkin Trans.
1 1979, 2230. See also in relation: (c) Schmidt, R. R.; Wagner, A.
Tetrahedron Lett. 1983, 24, 4661.
(7) (a) Maddaluno, J .; Gaonac’h, O.; Le Gallic, Y.; Duhamel, L.
Tetrahedron Lett. 1995, 36, 8591. (b) Guillam, A.; Maddaluno, J .;
Duhamel, L. J . Chem. Soc., Chem. Commun. 1996, 1295. (c) Guillam,
A.; Toupet, L.; Maddaluno, J . J . Org. Chem. 1998, 63, 5110. (d)
Guillam, A.; Toupet, L.; Maddaluno, J . J . Org. Chem. 1999, 64, 9348-
9357.
† Universite´ de Rouen.
‡ Universite´ de Rennes I.
(1) Very convincing recent exemples: (a) Dosseter, A. G.; J amison,
T. F.; J acobsen, E. N. Angew. Chem., Int. Ed. 1999, 38, 2398-2400.
(b) Yao, S.; Roberson, M.; Reichel, F.; Hazell, R. G.; J ørgensen, K. A.
J . Org. Chem. 1999, 64, 6677-6687. (c) Gruner, S. A. W.; Locardi, E.;
Lohof, E.; Kessler, H. Chem. Rev. 2002, 102, 491. (d) Lillelund, V. H.;
J ensen, H. H.; Liang, X.; Bols, M. Chem. Rev. 2002, 102, 515.
(2) See inter alia: (a) Banaszek, A. Bull. Acad. Pol. Sci. Ser. Sci.
Chim. 1974, 22, 1045. (b) Angerbauer, R.; Schmidt, R. R. Carbohydr.
Res. 1981, 89, 193. (c) Schmidt, R. R. Acc. Chem. Res. 1986, 19, 250.
(d) Danishefsky, S. J .; DeNinno, M. P. Angew. Chem., Int. Ed. Engl.
1987, 26, 15. (e) Bauer, T.; Kozak, J .; Chapuis, C.; J urczak, J . J . Chem.
Soc., Chem. Commun. 1990, 1178. (f) Terada, M.; Mikami, K.; Nakai,
T. Tetrahedron Lett. 1991, 32, 935. (g) Lubineau, A.; Auge´, J .; Queneau,
Y. Synthesis 1994, 741. (h) Danishefsky, S. J .; Bilodeau, M. T. Angew.
Chem., Int. Ed. Engl. 1996, 35, 1380. (i) Kleindl, P. J .; Donaldson, W.
A. J . Org. Chem. 1997, 62, 4176. (j) Seeberger, P. H.; Bilodeau, M. T.;
Danishefsky, S. J . Aldrichim. Acta 1997, 30, 75.
(8) These acetals were easily prepared from either 1-acetoxyisoprene
(for 1a ,b) or 1-acetoxybutadiene (for 1c,d ) following the very convenient
procedure described in: Deagostino, A.; Balma Tivola, P.; Prandi, C.;
Venturello, P. Synlett 1999, 11, 1841.
10.1021/jo0204193 CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/23/2002
8054
J . Org. Chem. 2002, 67, 8054-8062

Heterocycloaddition of 1,4-Dialkoxy-1,3-dienes
TABLE 1. Heter ocyloa d d ition of 2 w ith Eth ylglyoxyla te in Tolu en e u n d er Va r iou s Con d ition s
entry
diene
R
Y
T °C
P (kbar)
t (h)
adduct
yielda (%)
endo/exob
1
2
3
4
5
2a
2b
2b
2b
2c
Ph
Me
Me
Me
Me
H
80
80
20
50
50
1 × 10-3
1 × 10-3
12
12
12
12
12
48
48
24
4a
4b
4b
4b
4c
73
58
58
69
40
85:15
75:25
91:9
>99:1
>99:1
PMB
PMB
PMB
PMB
a
b
Calculated on the mixture or endo + exo isomers with respect to (1Z,3E) dienes 2. Based on the NMR integrations for the adducts
derived from the (1Z,3E) dienes 2.
SCHEME 1. Dir ect Dem a n d d e n ovo Access to
Su ga r s
Cycloa d d ition s a n d Selectivities. Three dienes 2
were then reacted with commercial ethyl glyoxylate un-
der thermal or hyperbaric conditions (eq 2). This hetero-
dienophile is available as a 50% solution in toluene and
was first depolymerized by refluxing the solution for 1
h. The results gathered in Table 1 are relative to adducts
4 obtained from the major (>90%) (1Z,3E) isomers of
dienes 2. All adducts 4 obtained show that the regiose-
lectivity is totally controlled by the E-borne alkoxy group,
as previously observed in classical Diels-Alder cycloaddi-
tions,7c probably because of the better conjugation of this
substituent with the π-system of the diene. Entries 1 and
2 indicate that a simple thermal activation (80 °C) leads,
in good yields for both 2a and 2b, to the expected
heteroadducts but with relatively low diastereoselectivi-
ties (de ) 50 to 70%). Resorting to high pressure (entry
3) increases the selectivity,9 as expected in favor of the
endo isomer 4b (de > 80%). Finally, a slight warming of
the pressurized medium improves both the yield and/or
the selectivity, entries 4 and 5 exhibiting a total endo
preference under the 12 kbar/50 °C conditions for dienes
2b,c. The adducts stemming from the (1E,3E) dienes 2
have been separated but their endo/exo ratio was found
insignificant (ca. 50:50 for 4b as obtained under 12 kbar
at 50 °C). The full regio- and endoselectivities obtained
with the (1Z,3E) dienes 2 demonstrate the superiority,
in a strategy relying on a heterocycloaddition key step,
of these isomers over the (1E,3E) ones.2c
and endoselective, providing, for instance, cyclohexene
3 as a single (racemic) isomer in good yield under thermal
activation (eq 1).7c We now present the extension of this
reaction to the heterocycloaddition of these dienes with
activated carbonyl species, under both thermal and
hyperbaric conditions.
The regio- and endoselectivities reported above have
been determined by high-field NMR analysis. The deter-
mination of the regioselectivity of this reaction was first
carried out on 4a . The close values of the chemical shifts
for the acetalic proton H1 and that for H4 made the
assignment of the signals difficult. We thus compared our
data to that described in the literature for related
dihydropyranes10 (Table 2). The presence of a phenoxy
group at the anomeric center is indeed known to shift
the corresponding H1 at low field. This is not observed
for 4a isomers, indicating that the methoxy moiety
occupies the anomeric position. This same orientation
was easily checked for 4b,c, the chemical shifts for the
acetalic proton H1 and that for H4 being very different
Resu lts a n d Discu ssion
As described previously,7 the treatment of R,â-unsatur-
ated acetals 1a by 2.5 equiv of n-BuLi at -45 °C in THF
triggers a deprotonation-conjugated elimination se-
quence leading, in an almost quantitative step, to diene
2a (eq 1). This reaction also applies to acetals 1b,c, in
which the phenyl group is replaced by a cleavable
p-methoxybenzyl (PMB) one, using a lesser quantity of
a stronger base (1.2 equiv of t-BuLi). The yields remain
in the 90-95% range. Acetal 1d could also be deproto-
nated using 1.6 equiv of KHMDS in THF at room
temperature in 78% yield. As previously described for
2a ,7c these compounds were obtained mainly under their
(1Z,3E) configuration (1Z,3E/1E,3E ) 90:10 for 2b and
100:0 for 2c,d ) and were pure enough to be used as such.
These relatively fragile enol ethers are otherwise difficult
to chromatograph.
(9) J enner, G. Tetrahedron 1997, 53, 2669.
(10) (a) Brakta, M.; Lhoste, P.; Sinou, D. J . Org. Chem. 1989, 54,
1890. (b) Brescia, M. R.; Shimshock, Y. C.; DeShong, P. J . Org. Chem.
1997, 62, 1257.
J . Org. Chem, Vol. 67, No. 23, 2002 8055

Bataille et al.
TABLE 2. Com p a r ison of th e Ch em ica l Sh ifts of
Dih yd r op yr a n es 4a ,b w ith Liter a tu r e Da ta
F IGURE 1. ORTEP representation of heterocycloadduct 4b.
indicate that the anomeric H1 proton is pseudoequatorial,
in both 4a and 4b. This suggests that the methoxy and
the phenoxy/PMBO groups adopt pseudoaxial orienta-
tions, while the ester moiety is either in an axial (endo
isomers) or an equatorial (exo isomers) position (Scheme
2, left). The J 4-5 values measured are also consistent with
pseudoequatorial/equatorial and pseudoequatorial/axial
situations in 4a and 4b.
SCHEME 2. Con for m a tion a l Equ ilibr ia for
Dih yd r op yr a n s 4
These structural hypotheses have been supported by
a single-crystal X-ray analysis on 4b(endo) that shows
the all-axial orientation of the methoxy, PMBO, and
COOEt appendages (Figure 1). Upon thermal treatment,
these all-axial adducts tend to epimerize. This has been
checked on 4a (endo) (80 °C, 12 h, neat), which partially
converts (70%) into its isomer 5 in which the anomeric
methoxy remains axial but both the phenoxy and ethyl
carboxylate groups have swapped to an equatorial ori-
entation (eq 3).
this time. This regiodirection is expected from the
polarization of diene 2a , as deduced from our previous
observations on classical Diels-Alder cycloadditions.7c
While the anti relationship between the methoxy and
4-alkoxy groups is secured by the (1Z,3E) configuration
of 2 the determination of the syn/anti relationship
between the methoxy and the ester apendages, i.e. the
endo/exo selectivity, on the basis of the simple NMR data
is not straightforward. Two half-chair conformations have
to be considered for the both the endo and the exo isomers
(Scheme 2). In the 4a ,b (endo) cases, the conformation
on the left puts all substituents in an axial position,
which of course gives rise to unfavorable 1,3-diaxial
interactions between the methoxy and ester groups.
Twisting to the other threshold half-chair (to the right)
puts all the substituents in an equatorial arrangement,
which, in turn, is unfavorable to the anomeric methoxy
and generates a A1,2 allylic strain11 between the methyl
and the phenoxy/PMBO groups. A comparable reasoning
can be applied to the exo-adducts 4a ,b (Scheme 2,
middle). This equilibrated situation could result in a
balanced mixture between both conformers.12 In the case
discussed here, we have measured13 the critical coupling
constants in 4. The comparison between J 1-2 and values
from the literature6a,14 in similar situations tends to
The case of adduct 4c(endo) deserves separate com-
ments since the absence of a vinylic methyl group in this
compound affects its conformation in solution (Scheme
2). The disappearance of the A1,2 allylic strain displaces
the balance on the all-equatorial side (Scheme 2, bottom
right) at the expense of the anomeric effect. The coupling
constants are in agreement with the endo-adduct sub-
stituents relationships.
A cycloaddition between 2a and the highly activated
diethyl ketomalonate has also been performed in reflux-
ing toluene (eq 4). Following this slow reaction by TLC
(11) J ohnson, F. Chem. Rev. 1968, 68, 375-412.
(12) See for instance ref 8a and: Achmatowicz, O.; Bukowski, P.
Rocz. Chem. 1973, 47, 99.
(13) The precise measurement of these coupling constants requires
a simultaneous homodecoupling on the allylic methyl group.
(14) Ferrier, R. J .; Prasad, N.; Sankey, G. H. J . Chem. Soc. 1969,
587.
8056 J . Org. Chem., Vol. 67, No. 23, 2002

Heterocycloaddition of 1,4-Dialkoxy-1,3-dienes
SCHEME 3. F r om Dih yd r op yr a n s to Su ga r s
and GC showed that the (1E,3E) isomer converted,
relatively rapidly and quasiquantitatively, into the cor-
responding syn-adduct 6, while its (1Z,3E) analogue was
sluggish and decomposed progressively during the pro-
longed warming. Finally a 58:42 mixture of 6(syn),
derived from (1E,3E) 2a , and 6(anti), derived from the
(1Z,3E) 2a isomer, is recovered in a mediocre 18% total
yield. The same result was obtained under 12 kbar, in
dichloromethane, and at room temperature.
As above, and for both 6(syn) and 6(anti), the A1,2 strain
arising between the phenoxy and vinylic methyl groups
(eq 5) explains the preference for an axial PhO and
the acetalic precursor 1a following Gassman’s condi-
tions.16 The heterocycloaddition is actually much more
efficient when performed with 7. The reaction takes place
at room temperature in diethyl ether and the correspond-
ing dihydropyrane 8 is obtained this time in 94% yield
(eq 6).
equatorial MeO in 6(syn), as well as the diaxial PhO and
MeO in 6(anti). Comparable results have been reported
in the literature.2b,15 The equatorial anomeric methoxy
group in 6(syn) can be epimerized almost quantitatively
into its diaxial (anti) isomer after a mild Lewis acid
treatment. After 24 h at room temperature in a ZnCl2
presaturated chloroform solution, 95% epimerization was
observed (eq 5). These NMR results were confirmed on
5(anti) by single-crystal X-ray diffraction. The corre-
sponding ORTEP (Figure 2) clearly shows the axial
orientation of the two allylic substituents.
F u n ction a liza tion of Ad d u cts. The validity of this
[4+2] strategy for the de novo approach of carbohydrates
was then dependent on the efficiency of the following
functionalization steps. Basically, the conversion of di-
hydropyranes 4 in the corresponding sugars required
three operations, viz. a deprotection, a dihydroxylation,
and a reduction step (Scheme 3). Because it was likely
to have an impact on the stereochemistry of the final
sugar, the order of these transformations had to be
studied in detail.
We have first examined the reduction/dihydroxylation/
deprotection sequence on the model adduct 4a (endo). This
compound was reacted with LAH in diethyl ether,
providing the corresponding alcohol 9 in 82% yield (eq
7). Unfortunately, all further attempts to dihydroxylate
this dihydropyrane resorting to classical catalytic or
stoichiometric osmium tetroxide methods17 turned out to
be in vain.
Interestingly, this sequence worked, albeit poorly, in
the case of 5, the anomer of 4a (endo). The LAH reduction
was quantitative (99%) while the OsO4 dihydroxylation
in pyridine provided the mannose skeleton 10 diastereo-
F IGUR E 2. ORTEP representation of heterocycloadduct 6
(anti).
(16) Gassman, P. G.; Burns, S. J .; Pfister, K. B. J . Org. Chem. 1993,
58, 1449.
(17) Stoichiometric: ref 6a. Catalytic: (a) Ray, M.; Matteson, D. S.
Tetrahedron Lett. 1980, 21, 449. (b) Cha, J . K.; Christ, W. J .; Kishi, Y.
Tetrahedron 1984, 40, 2247. (c) Burdisso, M.; Gandolfi, R. Tetrahedron
Lett. 1991, 32, 2634. (d) Carless, H. A. J .; Busia, K.; Dove, Y.; Malik,
S. S. J . Chem. Soc., Perkin Trans. 1 1993, 2505.
Finally, it was tempting to probe the reactivity of this
same dienophile with the allylic diene 7,7c prepared from
(15) Achmatowicz, O.; Grynkiewicz, G.; Szechner, B. Tetrahedron
1976, 32, 1051.
J . Org. Chem, Vol. 67, No. 23, 2002 8057

Bataille et al.
To avoid this structural feature and elude from the
possible chelation of the osmium nucleus by the two
alcohols borne by 13, we decided to evaluate the depro-
tection/dihydroxylation/reduction sequence on compounds
12b,c, obtained as above from 4b,c. Their dihydroxyla-
tion by 1.1 equiv of OsO4 in pyridine at room temperature
afforded the expected triols 14 in high yields this time.
A total R-diastereoselectivity was also observed, probably
due to the anchimeric assistance of the allylic 4-hydroxyl
group oriented along the R-face (eq 10). Unfortunately,
we have been unable to turn this stoichiometric dihy-
droxylation into its catalytic version. The following steps
have then been restricted to 14c, a natural sugar precur-
sor. A preliminary silylation of the three hydroxyl groups
has been performed before the reduction.19 The interme-
diate tris(tert-butyldimethylsilyl) ether was not isolated
and directly engaged in the LAH reduction step that
provided alcohol 15 in a low (nonoptimized) 20% yield
for the two steps. The NMR characteristics indicated 15
to be a protected form of (D,L)-allose, thus confirming the
dihydroxylation selectivity.
selectively but in very low yield (27%, eq 7). This same
sequence became efficient (65% for the two steps) when
applied to the small amounts of epimer 4a (exo) available
and led to triol 11, a gulose derivative (eq 8). These two
results suggest that the dihydroxylation step requires the
methoxy and CH2OH groups to be anti one to the other.
The final conversion of 11 into the corresponding sugar
was not attempted in this case since the deprotection of
the phenoxy group was expected to require conditions too
harsh to be compatible with this delicate substrate.
The dihydroxylation/deprotection/reduction sequence
has finally been investigated on adduct 4c. The same
dihydroxylation conditions as above provide diol 16 in
good yield and total diastereoselectivity but along the
â-face this time (eq 11). This underlines the importance
We thus next considered the deprotection/reduction/
dihydroxylation sequence applied to substrates 4b,c
bearing an easy to remove PMB protecting group (eq 9).
This latter was indeed cleanly cleaved under the action
of dichlorodicyanoquinone (DDQ) in a methylene chloride/
water mixture at room temperature.18 The reduction was
still performed with LAH and provided efficiently the
diols 13. However, these proved inert toward OsO4 in
pyridine or mixtures of t-BuOH and pyridine, up to 50
°C, even using stoichiometric quantities of osmium
tetroxide. Note that, in this case again, the methoxy and
CH2OH appendages are in a syn relationship.
of the allylic hydroxyl group in the orientation of the
8058 J . Org. Chem., Vol. 67, No. 23, 2002

Heterocycloaddition of 1,4-Dialkoxy-1,3-dienes
product 1b. Flash chromatography on silica gel (eluent: ethyl
acetate/heptane 30:70) afforded 13.02 g (48.9 mmol, 86%) of
1b E/Z:70/30 as a colorless oil.
dihydroxylation of such substrates. The following steps
rely on classical carbohydrate chemistry. The diol in
protected ethyl mannuronate 16 was transformed into
its acetonide 17 by 2,2-dimethoxypropane in catalytic
acidic conditions and the PMB group removed by DDQ.
The alcohol 18 was then reduced by LAH in ether,
affording diol 19, a protected form of (D,L)-mannose, as
checked by comparison to literature data, in good yield.
The overall yield for the conversion of 4c into 19 is about
42% in 4 steps.
IR νmax (film)1 2934, 1612, 820 cm-1. E isomer: 1H NMR
(300 MHz, CDCl3) δ (ppm) 1.75 (3H, d, J ) 1.1 Hz), 3.32 (6H,
s), 3.79 (3H, s), 3.90 (2H, s), 4.40 (2H, s), 5.08 (1H, d, J ) 6.4
Hz), 5.55 (1H, dq, J ) 1.1, 6.4 Hz), 6.87 (2H, dd, J ) 1.9, 8.7
Hz), 7.26 (2H, dd, J ) 1.9, 8.7 Hz). 13C NMR (75 MHz, CDCl3)
δ (ppm) 14.9, 52.7, 55.7, 71.9, 75.0, 100.4, 114.2, 124.1, 129.7,
130.7, 139.0, 159.6. Z isomer 1H NMR (300 MHz, CDCl3) δ
(ppm) 1.84 (3H, d, J ) 1.1 Hz), 3.27 (6H, s), 3.79 (3H, s), 4.04
(2H, s), 4.40 (2H, s), 5.02 (1H, d, J ) 6.4 Hz), 5.44 (1H, dq, J
) 1.1, 6.4 Hz), 6.87 (2H, dd, J ) 1.9, 8.7 Hz), 7.26 (2H, dd, J
) 1.9, 8.7 Hz). δC (75 MHz) 21.6, 52.7, 55.7, 68.7, 72.0, 99.8,
114.3, 126.1, 129.7, 130.7, 139.3, 159.6. EIMS (70 eV) m/z 266
(M+., 0.3), 234 (M+ - MeOH, 0.7), 121 (100). Anal. Calcd for
Con clu d in g Rem a r k s
The results presented here show that (1Z,3E)-1,4-
dialkoxydienes are efficient partners in hetero-Diels-
Alder reactions with simple heterodienophiles such as
ethyl glyoxylate, giving a totally regio- and endocontrolled
access to the corresponding dihydropyranes. These char-
acteristics seem to be closely related to the polarization
induced by the configuration of the diene, the (1E,3E)
isomers leading to poorly controlled cycloadditions. We
then investigated the transformation of such adducts into
carbohydrates. Four of the six possible different permu-
tation sequences of the deprotection/reduction/dihydroxy-
lation steps to be performed have been considered. Three
have provided a diastereoselective access to various
derivatives of three different (racemic) natural sugars
(gulose, allose, and mannose). In conclusion, the use of
(1Z,3E)-1,4-dialkoxydienes allows the interest in de novo
strategies in the synthesis of rare or modified sugars
(such as those based on branched diene 2b that have not
been exploited yet) to be restored. Further developments
will be presented in due time.
C
15H22O4: C, 67.65; H, 8.33. Found: C, 67.56; H, 8.34.
E-4-(4-Meth oxyben zyloxy)bu t-2-en a l Dim eth yl Aceta l
(1c). This compound was prepared as above deprotonating
p-methoxybenzylic alcohol (8.15 g, 59.0 mmol) by KH (7.50 g,
65.5 mmol) and reacting the alcoholate with E-4-bromobut-2-
enal dimethyl acetal (11.50 g, 59.0 mmol). 1c (12.20 g) was
thus obtained (48.4 mmol, 82%) as a pale yellow oil and as a
pure E isomer.
IR νmax (film) 2934, 2834, 1690, 1514, 820 cm-1 1H NMR
.
(300 MHz, CDCl3) δ (ppm) 3.32 (6H, s), 3.79 (3H, s), 4.02 (2H,
d, J ) 5.3 Hz), 4.44 (2H, s), 4.79 (1H, d, J ) 4.8 Hz), 5.70 (1H,
ddt, J ) 1.5, 4.8, 15.8 Hz), 5.95 (1H, ddt, J ) 0.8, 5.3, 15.7
Hz), 6.87 (2H, d, J ) 8.5 Hz), 7.26 (2H, d, J ) 8.5 Hz). 13C
NMR (75 MHz, CDCl3) δ (ppm) 53.1, 55.6, 69.7, 72.3, 102.9,
114.2, 129.1, 129.7, 130.6, 131.8, 159.6.
E-4-Ben zyloxybu t-2-en a l Dim eth yl Aceta l (1d ). This
compound was prepared as above deprotonating benzylic
alcohol (2.53 g, 23.4 mmol) by NaH (1.44 g, 60.0 mmol) and
reacting the alcoholate with E-4-bromobut-2-enal dimethyl
acetal (4.07 g, 20.9 mmol). 1c (3.80 g) was thus obtained (17.1
mmol, 82%) as a colorless oil and as a pure E isomer.
1
IR νmax (film) 2934, 2830, 1454, 1128, 1052 cm-1. H NMR
(200 MHz, CDCl3) δ (ppm) 3.30 (6H, s), 4.05 (2H, d, J ) 5.7
Hz), 4.55 (2H, s), 4.80 (1H, d, J ) 5.2 Hz), 5.45 (1H, dd, J )
5.2, 16.8 Hz), 5.95 (1H, dd, J ) 5.7, 16.8 Hz), 7.35 (s, 5H). 13C
NMR (50 MHz, CDCl3) δ (ppm) 52.6, 69.4, 72.1, 102.3, 126.8,
127.6, 128.3, 128.6, 131.0, 141.2. EIMS (70 eV) m/z 221 (M -
H, 32), 205 (19), 190 (99), 173 (100), 91 (60).
Exp er im en ta l Section
Gen er a l Asp ects. 1H NMR spectra were recorded at 200
or 300 MHz and 13C NMR spectra at 50 or 75 MHz; chemical
shift (δ) are given in parts per million (ppm) and the coupling
constants (J ) in hertz. The solvent was deuteriochloroform or
deuteriobenzene. IR spectra were recorded by transmission.
Gas chromatography analyses were performed on a high-
resolution DB-1 type column (30 m × 0.25 mm i.d., 0.25 µm
coating). GC/MS analyses were performed on an instrument
equipped with the same column. The mass spectra under
electron impact conditions (EI) were recorded at 70 eV ionizing
potential; methane (CH4), isobutane (t-BuH), and ammonia
(NH3) were used for chemical ionization (CI). The silica gel
used for flash chromatography was 230-400 mesh. All re-
agents were of reagent grade and were used as such or distilled
prior to use.
4-(4-Meth oxyben zyloxy)-3-m eth ylbu t-2-en a l Dim eth yl
Aceta l (1b). A solution of p-methoxybenzyl alcohol (7.95 g,
57.4 mmol) in THF (30 mL) was added to a dispersion of KH
(2.52 g, 63.1 mmol) in THF (70 mL). After dihydrogen bubbling
ended, a solution of 4-bromo-3-methylbut-2-enal dimethyl
acetal E/Z:70/30 (12,0 g, 57.4 mmol) in THF (50 mL) was added
at 0 °C. The reaction mixture was stirred for 30 min at room
temperature, then water was poured slowly after returning
to 0 °C. The aqueous phase was extracted with ethyl acetate
(3 × 50 mL) and the resulting organic solution was dried
(MgSO4) and concentrated under vacuum to give the crude
1Z,3E-1-(4-Meth oxyben zyloxy)-3-m eth yl-4-m eth oxybu ta-
1,3-d ien e (2b). This diene has been prepared from acetal 1b
in 93% yield following a procedure similar to that described
for 2a in ref 7c (method A) and was recovered as a colorless
oil and as a mixture of (1Z,3E) and (1E,3E) isomers (90:10).
Crude spectral data: IR νmax (film) 2930, 2830, 1614, 1514,
1426, 820 cm-1 1H NMR (200 MHz, CDCl3) for (1Z,3E)
.
isomer: δ (ppm) 1.57 (3H, s), 3.57 (3H, s), 3.78 (3H, s), 4.70
(2H, s), 5.82 (1H, s), 6.00 (1H, d, J ) 13.1 Hz), 6.48 (1H, d, J
) 13.1 Hz), 6.87 (2H, d, J ) 8.6 Hz), 7.25 (2H, d, J ) 8.6
Hz).13C NMR (75 MHz, CDCl3) for (1Z,3E) isomer: δ (ppm)
14.5, 55.6, 56.7, 73.8, 101.7, 110.4, 114.2, 129.5, 130.0, 140.5,
147.4, 159.8.
1Z,3E-1-(4-Meth oxyben zyloxy)-4-m eth oxybu ta -1,3-d i-
en e (2c). This diene has been prepared from acetal 1c in 91%
yield following a procedure similar to that described for 2a in
ref 7c (method A) and was recovered as a colorless oil and as
a single (1Z,3E) isomer. Crude spectral data: 1H NMR (200
MHz, CDCl3) δ (ppm) 3.56 (3H, s), 3.79 (3H, s), 4.74 (2H, s),
4.96 (1H, dd, J ) 6.2, 10.9 Hz), 5.79 (1H, dd, J ) 10.9, 12.8
Hz), 5.89 (1H, d, J ) 6.2 Hz), 6.54 (2H, d, J ) 12.8 Hz), 6.88
(2H, d, J ) 8.6 Hz), 7.26 (2H, d, J ) 8.6 Hz).
1Z,3E-1-Ben zyloxy-4-m eth oxybu ta -1,3-d ien e (2d ). This
diene has been prepared from acetal 1d in 78% yield following
a procedure similar to that described for 2a in ref 7c (method
A) and was recovered as a yellowish oil and as a single (1Z,3E)
isomer. Crude spectral data: IR νmax (film) 2934, 2830, 1612,
1454, 734 cm-1. 1H NMR (200 MHz, CDCl3) δ (ppm) 3.31 (3H,
(18) Achmatowicz, O.; Maurin, J . K.; Szechner, B. J . Carbohydr.
Chem. 1998, 17, 249.
(19) Mignet, N.; Chaix, C.; Rayner, B.; Imbach, J .-L. Carbohydr. Res.
1997, 303, 17.
(20) Khan, S. H.; J ain, R. K.; Matta, K. L. Carbohydr. Res. 1990,
207, 57.
J . Org. Chem, Vol. 67, No. 23, 2002 8059

Bataille et al.
s), 4.82 (2H, s), 4.98 (1H, dd, J ) 6.2, 11.0 Hz), 5.78 (1H, dd,
J ) 11.0, 12.8 Hz), 5.89 (1H, d, J ) 6.2 Hz), 6.55 (1H, d, J )
12.8 Hz), 7.33 (5H, s).13C NMR (50 MHz, CDCl3) δ (ppm) 55.9,
72.1, 98.7, 103.7, 127.3, 127.8, 128.4, 138.1, 142.2, 148.7. EIMS
(70 eV) m/z 190 (M+, 100), 159 (80).
6-Met h oxy-3-(4-m et h oxyb en zyloxy)-3,6-d ih yd r o-2H -
p yr a n -2-ca r boxylic Acid Eth yl Ester (4c). The same pro-
cedure as above applied to a mixture of ethyl glyoxylate (50%
in toluene, 8.1 mL, 35.0 mmol) and diene 2c (1.88 g, 8.6 mmol,
100% ZE isomer) led to pure 4c endo (1.11 g, 3.45 mmol, 40%)
as a yellowish oil.
6-Meth oxy-4-m eth yl-3-p h en oxy-3,6-d ih yd r o-2H-p yr a n -
2-ca r boxylic Acid Eth yl ester s (4a a n d 5). A commercial
solution of ethyl glyoxylate (50% in toluene, d ) 1.03, 2.57 g
of glyoxylate, 29.9 mmol) was refluxed for 1 h then kept at 40
°C under argon before adding freshly prepared diene 2a (800
mg, 4.2 mmol, 1E,3E/1Z,3E ) 8:92) and 100 mg of hydro-
quinone. The medium was then warmed to 80 °C and the
reaction followed by GC. After 12 h, 2a was consumed. The
solvents were then evaporated and the residual oily mixture
directly flash chromatographed on silica gel (eluent: petroleum
ether/ethyl acetate 80:20). Two oily adducts were separated
(85:15, 822 mg total, 73% yield with respect to the (1Z,3E) 2a )
which correspond to the endo and exo isomers of the hetero-
cycloadducts 4a .
1
IR: νmax (film) 2934, 1732, 1612, 1510, 834 cm-1. H NMR
(300 MHz, CDCl3) δ (ppm) 1.24 (3H, t, J ) 7.1 Hz), 3.41 (3H,
s), 3.73 (3H, s), 4.14 (2H, m), 4.27 (1H, t, J ) 3.9 Hz), 4.30
(1H, t, J ) 4.9 Hz), 4.47 (2H, s), 4.96 (1H1, s), 5.80 (1H, d, J )
10.6 Hz), 6.01 (1H, dd, J ) 3.39, 10.6 Hz), 6.80 (2H, d, J ) 8.6
Hz), 7.19 (2H, d, J ) 8.6 Hz). 13C NMR (75 MHz, CDCl3) δ
(ppm) 14.2, 55.4, 56.0, 61.5, 68.7, 71.1, 74.2, 96.5, 114.0, 128.1,
128.4, 129.7, 130.1, 159.6, 170.0. CIMS (CH4) m/z 291 (M+H
- MeOH, 3), 185 (6), 154 (7), 121 (100).
6-Meth oxy-4-m eth yl-3-p h en oxy-3,6-d ih yd r op yr a n -2,2-
d ica r boxylic Acid Dieth yl Ester (6). Th er m a l p r oced u r e:
Diene 2a (500 mg, 2.6 mmol, 1Z,3E/1E,3E ) 92:8) and diethyl
ketomalonate (2.29 g, 13.2 mmol, 5.0 equiv) were dissolved in
10 mL of toluene containing 200 mg of hydroquinone and the
solution was warmed to 110 °C under argon. The evolution of
the medium was followed by TLC, GC, and NMR. After 12 h
the 1E,3E isomer of diene 2a was consumed while new
compounds appeared progressively. The reaction was stopped
after 7 days despite some 1Z,3E diene remaining in the
medium. The solvent was evaporated and the oily residue
directly flash chromatographed on silica gel (eluent: petroleum
ether/ethyl acetate 80:20). A colorless oil was thus recovered,
consisting of the two isomers 6 syn and 6 anti (163 mg, yield
18%) in a 58:42 ratio. After 3 days at -20 °C, the anti isomer
crystallized spontaneously out of the mixture and was sepa-
rated, rinsed with ether, and recrystallized in a petroleum
ether/ethyl acetate mixture (70:30). A white solid (85 mg) was
thus obtained. The supernatant consisted mainly in 6 syn,
contaminated with small amounts of 6 anti. The colorless oily
6 syn was then dissolved in a saturated solution of ZnCl2 in
CHCl3 (2 mL) and left for 24 h at room temperature. An almost
total isomerization into 6 anti occurred (final ratio 95:5).
Hyp er ba r ic p r oced u r e: Diene 2a (500 mg, 2.6 mmol,
1Z,3E/1E,3E ) 92:8) and diethyl ketomalonate (2.29 g, 13.2
mmol, 5.0 equiv) were dissolved in 5 mL of CH2Cl2 containing
200 mg of hydroquinone. The solution was compressed to 13
kbar at room temperature and left for 7 days. A 56:44 mixture
of 6 syn and 6 anti was obtained and the overall conversion
was about 20% (based on NMR integrations).
Endo isomer: IR νmax (film) 1742, 1594, 1494, 1449, 1374,
1
1222 cm-1. H NMR (200 MHz, CDCl3) δ (ppm) 1.24 (3H, t, J
) 6.9 Hz), 1.90 (3H, s), 3.45 (3H, s), 4.12, 4.23 (2H, 2dqAB, J )
6.9, 10.7 Hz), 4.53 (1H, d, J ) 2.1 Hz), 4.99 (1H, d, J ) 2.1
Hz), 5.02 (1H, d, J ) 2.7 Hz), 5.69 (1H, J ) 2.7 Hz), 6.75-
7.20 (5H, m). 13C NMR (50 MHz, CDCl3) δ (ppm) 13.6, 20.1,
55.8, 61.1, 70.5, 71.8, 95.7, 115.8, 121.6, 123.3, 129.5, 134.0,
157.5, 170.0. EIMS (70 eV) m/z 292 (M+•, 5), 261 (5), 199 (28),
187 (82), 167 (44), 125 (100).
Exo isomer: IR νmax (film) 1768, 1600, 1499, 1449, 1374,
1
1232 cm-1. H NMR (200 MHz, CDCl3) δ (ppm) 0.92 (3H, t, J
) 6.9 Hz), 1.83 (3H, s), 3.97 (3H, s), 3.76, 4.01 (2H, 2dqAB, J )
6.9, 10.6 Hz), 4.74, 4.75 (2H, 2dAB, J ) 2.5 Hz), 5.11 (1H, dm,
J ) 3.3 Hz), 5.71 (1H, dm, J ) 3.3 Hz), 6.75-7.20 (5H, m). 13
C
NMR (50 MHz, CDCl3) δ (ppm) 13.4, 20.1, 55.8, 60.9, 69.9, 72.1,
95.6, 116.3, 121.6, 123.9, 129.1, 134.3, 158.8, 168.0. EIMS (70
eV) m/z 292 (M+•, 2), 264 (3), 219 (11), 187 (92), 94 (100).
Anal. Calcd (on the mixture of isomers) for C16H20O5: C,
65.45; H, 7.03. Found: C, 65.75; H, 6.85.
Warming up neat 4a under argon at 80 °C for 12 h led to a
mixture of 4a and its R-anomer 5 (30:70). Colorless oil. Crude
spectral data: 1H NMR (200 MHz, CDCl3) δ (ppm) 1.03 (3H,
t, J ) 6.9 Hz), 1.77 (3H, s), 3.43 (3H, s), 4.02, 4.13 (2H, 2dqAB
,
J ) 6.9, 10.7 Hz), 4.53 (1H, d, J ) 8.1 Hz), 5.01 (2H, m), 5.58
(1H, dm, J ) 2.9 Hz), 6.75-7.20 (5H, m). 13C NMR (75 MHz,
CDCl3) δ (ppm) 13.6, 18.3, 55.4, 61.2, 69.8, 71.8, 95.7, 115.4,
121.5, 122.3, 129.7, 137.7, 158.4, 169.6.
1
6 syn: IR νmax (film) 1740, 1427, 1235, 1221 cm-1. H NMR
(200 MHz, CDCl3) δ (ppm) 0.95, 1.25 (6H, 2t, J ) 7.0 Hz), 1.83
(3H, s), 3.55 (3H, s), 3.85-4.35 (4H, m), 5.18 (1H, quint, J )
1.2 Hz), 5.29 (1H, s), 5.53 (1H, quint, J ) 1.2 Hz), 6.80-7.40
(5H, m). 13C NMR (50 MHz, CDCl3) δ (ppm) 13.5, 20.8, 56.3,
61.6, 72.0, 82.6, 96.2, 116.0, 121.7, 122.0, 129.2, 133.9, 158.5,
167.8. EIMS (70 eV) m/z 364 (M+•, 5), 271 (14), 239 (17), 224
(43), 197 (100), 125 (94).
6-Meth oxy-4-m eth yl-3-(4-m eth oxyben zyloxy)-3,6-d ih y-
d r o-2H-p yr a n -2-ca r boxylic Acid Eth yl Ester (4b). A com-
mercial solution of ethyl glyoxylate (50% in toluene, 7.7
mL, 33.0 mmol) was refluxed for 1 h then cooled to room
temperature under argon before adding freshly prepared diene
2b (1.93 g, 8.3 mmol, 1E,3E/1Z,3E ) 10:90) and trace
amounts of hydroquinone. The resulting mixture was placed
under 12 kbar of pressure at 50 °C for 48 h. After release of
the pressure and evaporation of the solvents, the resulting oily
mixture was flash chromatographed on silica gel (eluent:
heptane/ethyl acetate 70:30). Adduct 4b endo is thus recovered
as white solid (1.72 g, 5.1 mmol, 69% yield with respect to
(1Z,3E) 2b). In a separate fraction, a 50:50 mixture of the endo
and exo isomers of cycloadducts deriving from the heterocy-
cloaddition of glyoxylate on the (1E,3E) isomer of 2b was also
recovered (280 mg, 0.8 mmol, 98% yield, with respect to
(1E,3E) 2b).
6 anti: IR νmax (film) ) 1740, 1427, 1235, 1221 cm-1 1H
.
NMR (200 MHz, CDCl3) δ (ppm) 0.72, 1.25 (6H, 2t, J ) 7.0
Hz), 1.89 (3H, s), 3.49 (3H, s), 3.85-4.35 (4H, m), 5.20 (1H,
m, J ) 2.9 Hz), 5.25 (1H, s), 5.64 (1H, m, J ) 2.9 Hz), 6.80-
7.40 (5H, m). 13C NMR (50 MHz, CDCl3) δ (ppm) 13.8, 20.8,
54.6, 61.9, 73.3, 82.6, 95.9, 116.2, 121.7, 123.7, 129.6, 136.0,
158.8, 164.5, 166.3. EIMS (70 eV) m/z. 364 (M+•, 4), 271 (14),
239 (16), 197 (100), 125 (96).
Anal. Calcd (on the mixture of syn and anti isomers) for
C
19H24O7: C, 62.63; H, 6.59. Found: C, 62.33; H, 6.64.
4b endo isomer: IR νmax (film) 2934, 1732, 1612, 1514, 822
6-Meth oxy-4-p h en oxym eth yl-3,6-d ih yd r op yr a n -2,2-d i-
1
cm-1. H NMR (300 MHz, CDCl3) δ (ppm) 1.30 (3H, t, J ) 7.2
ca r boxylic Acid Dieth yl Ester (8). Diene 7 (70 mg, 0.37
mmol) was prepared from acetal 1a following a procedure
similar to that described for 2a in ref 7c (method C). It was
then dissolved in 2 mL of THF containing diethyl ketomalonate
(64 mg, 0.37 mmol, 1 equiv) and 10 mg of hydroquinone and
left under argon and at room temperature for 3 days, following
the evolution of the medium by TLC. After evaporation of the
solvent, the oily mixture was chromatographed on silica gel
Hz), 1.81 (3H, s), 3.45 (3H, s), 3.79 (3H, s), 4.16 (3H, m), 4.47
(1H, d, J ) 2.6 Hz), 4.47, 4.50 (2H, 2dAB, J ) 10.9 Hz), 4.54
(1H, d, J ) 10.9 Hz), 4.96 (1H, s), 5.59 (1H, s), 6.86 (2H, d, J
) 8.7 Hz), 7.26 (2H, d, J ) 8.7 Hz). 13C NMR (75 MHz, CDCl3)
δ (ppm) 14.4, 20.6, 56.0, 56.2, 61.6, 71.8, 71.9, 73.3, 96.5, 114.2,
123.4, 130.1, 130.3, 135.8, 159.8, 170.8. EIMS (70 eV) m/z 305
(M+•, 49), 185 (30), 167 (16.5), 137 (26), 121 (100).
8060 J . Org. Chem., Vol. 67, No. 23, 2002

Heterocycloaddition of 1,4-Dialkoxy-1,3-dienes
(eluent: petroleum ether/ethyl acetate 70:30), providing 8 as
Hz), 3.78 (1H,dd, J ) 7.2, 11.0 Hz), 3.87 (1H, d, J ) 3.9 Hz),
4.30 (1H, t, J ) 6.0 Hz), 4.35 (1H, s), 4.91 (1H, d, J ) 3.9 Hz),
6.92 (3H, m), 7.25 (2H, m). 13C NMR (125 MHz, CDCl3) δ (ppm)
21.9, 56.5, 62.3, 68.0, 69.0, 73.9, 79.3, 101.0, 115.7, 121.9, 130.0,
159.2. CIMS (t-BuH, 200 eV) m/z 285 (M + 1, 12), 253 (100),
235 (29), 217 (8).
a colorless oil (126 mg, 0.35 mmol, 94%).
1
IR: νmax (film) 1746, 1598, 1496, 1456, 1368, 1242 cm-1. H
NMR (200 MHz, CDCl3) δ (ppm) 1.26 (6H, t, J ) 6.8 Hz), 2.40
(1H, d, J ) 16.8 Hz), 2.87 (1H, d, J ) 16.8 Hz), 3.45 (3H, s),
4.00-4.40 (4H, m), 4.52 (2H, s), 5.16 (1H, s), 5.78 (1H, s), 6.80-
7.40 (5H, m). 13C NMR (50 MHz, CDCl3) δ (ppm) 13.6, 13.8,
28.9, 56.0, 61.6, 61.9, 69.6, 96.2, 114.5, 119.6, 120.9, 129.3,
134.1, 158.1, 168.0. EIMS (70 eV) m/z 364 (M+•, 4), 332 (59),
259 (58), 224 (43), 197 (100). Anal. Calcd for C19H24O7: C,
62.63; H, 6.59. Found: C, 62.98; H, 6.48.
(6-Meth oxy-4-m eth yl-3-ph en oxy-3,6-dih ydr o-2H-pyr an -
2-yl)m eth a n ol (9). To a solution of ester 4a (endo or exo
isomer, 276 mg, 1.0 mmol) in 4 mL of anhydrous ether was
added 5 mL of a LAH (76 mg, 2.0 mmol) solution of the same
solvent at 0 °C under argon. The mixture was left 1.5 h at
room temperature and then quenched by 2 mL of a saturated
solution of Na2SO4. The medium was filtered on a Celite pad,
then washed with ethyl acetate. After drying (MgSO4) and
evaporation of all solvents, the crude product was obtained as
a colorless oil (248 mg, 1.0 mmol, 99%) that was used as such
in the next step.
Endo isomer: IR νmax (film) 3444, 3062, 2922, 1682, 1596,
1234, 754 cm-1. 1H NMR (200 MHz, CDCl3) δ (ppm) 1.74 (3H,
s), 3.48 (3H, s), 3.68 (1H, dd, J ) 4.4, 12.0 Hz), 3.75 (1H, m),
3.82 (1H, dd, J ) 2.3, 12.0 Hz), 3.96 (1H, m), 4.87 (s, 1H), 5.52
(1H, m), 6.96 (3H, m), 7.32 (2H, m). EIMS (70 eV) m/z 250
(M+, 8), 218 (65), 187 (61), 157 (54), 124 (100).
Exo isomer: IR νmax (film) 3474, 2930, 1596, 1492, 1226,
1056, 754 cm-1. 1H NMR (200 MHz, CDCl3) δ (ppm) 1.77 (3H,
s), 3.49 (3H, s), 3.72 (1H, dd, J ) 5.4, 11.5 Hz), 3.85 (1H, dd,
J ) 6.5, 11.5 Hz), 4.22 (1H, ddd, J ) 2.5, 5.4, 6.5 Hz), 4.42
(1H, d, J ) 2.5 Hz), 4.99 (1H, m), 5.70 (1H, m), 7.01 (3H, m),
7.22 (2H, m). EIMS (70 eV) m/z 250 (M+, 8), 218 (65), 187 (61),
157 (54), 124 (100). 13C NMR (50 MHz, CDCl3) δ (ppm) 20.6,
55.4, 61.7, 71.1, 71.9, 95.4, 116.0, 121.5, 124.0, 129.6, 135.3,
159.3. EIMS (70 eV) m/z 250 (M+, 3), 218 (7), 187 (5), 157 (4),
125 (16), 95 (100).
3-Hyd r oxy-6-m eth oxy-4-m eth yl-3,6-d ih yd r o-2H-p yr a n -
2-ca r boxylic Acid Eth yl Ester (12b). Dihydropyrane 4b (96
mg, 0.30 mmol, mixture of 3 isomers 86:7:7) was dissolved in
5 mL of a dichloromethane/water/buffer (pH 7.0) mixture (15:
1:1). The solid dichlorodicyanoquinone (DDQ, 10 mg, 0.48
mmol, 1.6 equiv) was then introduced and the mixture stirred
for 2 h at room temperature. The organic layer was separated
and the aqueous one extracted with dichloromethane (4 × 10
mL). The organic layers were gathered, dried (MgSO4), and
evaporated under reduced pressure. The oily residue was then
flash chromatographed on silica gel (eluent:heptane/AcOEt 40:
60) providing 12b as a yellowish oil (40 mg, 0.19 mmol, 63%).
The major isomer was separated from the other two, which
are the endo and exo adducts derived from (1E,3E)-2b.
IR: νmax (film) 3436, 2920, 1732, 1446, 1384, 1210, 1142,
1034, 968 cm-1. 1H NMR (300 MHz, CDCl3) δ (ppm) 1.31 (3H,
t, J ) 7.3 Hz), 1.88 (3H, s), 2.48 (1H, d, J ) 6.6 Hz), 3.47 (3H,
s), 4.20-4.27 (2H + 1H, m), 5.01 (1H, s), 5.50 (1H, s). 13C NMR
(75 MHz, CDCl3) δ (ppm) 14.3, 19.6, 55.9, 61.7, 66.4, 75.7, 97.5,
122.6, 138.6, 170.7. CIMS (t-BuH, 200 eV) m/z 199 (M+H -
H2O, 5) 185 (M+H - MeOH, 100), 167 (36), 145 (15), 113 (19).
3-Hyd r oxy-6-m eth oxy-3,6-d ih yd r o-2H-p yr a n -2-ca r box-
ylic Acid Eth yl Ester (12c). The same procedure as above
applied to 4c (603 mg, 2.1 mmol) in 34 mL of the same solvent
mixture to which was added DDQ (760 mg, 3.3 mmol, 1.6
equiv) led to 12c (310 mg, 1.5 mmol, 73%) as a pale yellow oil.
IR: νmax (film) 3436, 2920, 1732, 1446, 1384, 1210, 1142,
1034, 968 cm-1. 1H NMR (300 MHz, CDCl3) δ (ppm) 1.27 (3H,
t, J ) 6.2 Hz), 2.62 (1H, br d, J ) 4.1 Hz), 3.44 (3H, s), 4.11
(1H, d, J ) 7.9 Hz), 4.21 (2H, m), 4.42 (1H, m), 5.05 (1H, dd,
J ) 1.5, 3.4 Hz), 5.72 (1H, dt, J ) 1.9, 10.2 Hz), 5.99 (1H, ddd,
J ) 1.5, 3.0, 10.2 Hz). 13C NMR (75 MHz, CDCl3) δ (ppm) 14.4,
56.0, 62.0, 63.6, 76.3, 97.7, 128.0, 131.3, 170.6. EIMS (70 eV)
m/z 184 (M - H2O, 11), 167 (13), 149 (36), 111 (81), 97 (100).
2-Hyd r oxym eth yl-6-m eth oxy-4-m eth yl-3,6-d ih yd r o-2H-
p yr a n -3-ol (13b). A solution of ester 12b (120 mg, 0.55 mmol)
in 4 mL of dry ether was added, under argon, to a suspension
of LiAlH4 (50 mg, 1.30 mmol, 2.2 equiv) in 5 mL of cool (0 °C)
ether in 15 min. After 2 h of stirring at room temperature,
the suspension was hydrolyzed successively with 0.1 mL of
water, 0.1 mL of a 4.0 M solution of NaOH, and 0.3 mL of
water. The resulting solid was filtered on a Celite pad and
washed with ethyl acetate. The organic phases are dried
(Na2SO4) then evaporated under reduced pressure. Diol 13b
was obtained as a pale yellow oil (85 mg, 0.49 mmol, 89%) that
did not need further purification.
6-Hyd r oxym et h yl-2-m et h oxy-4-m et h yl-5-p h en oxyt et -
r a h yd r op yr a n -3,4-d iol (10). The same experimental proce-
dure as above applied to ester 5 led to a colorless oily alcohol
that was not isolated. This compound (295 mg, 1.3 mmol) was
dissolved in 13 mL of pyridine and added to a solution of
osmium tetroxide (387 mg, 1.5 mmol, 1.2 equiv) in 2 mL of
pyridine. The mixture stirred for 2 h at room temperature
before quenching with 3 mL of saturated solution of NaHSO3,
then 5 mL of water. Pyridine was evaporated under reduced
pressure before ethyl acetate (20 mL) was added. The organic
layers were separated, dried (MgSO4), then evaporated to
afford an oily residue that was flash chromatographed on silica
gel (eluent: chloroform/methanol 19:1). The triol 10 was
obtained as a yellowish oil (264 mg, 0.93 mmol, 80%).
1
IR: νmax (film) 3386, 2922, 1448, 1364, 1048 cm-1. H NMR
1
IR: νmax (film) 3382, 2928, 1596, 1494, 1044, 756 cm-1. H
(300 MHz, CDCl3) δ (ppm) 1.79 (3H, s), 2.22 (1H, br s), 2.57
(1H, br s), 3.42 (3H, s), 3.70-3.76 (2H + 1H, m), 3.90 (1H, s),
4.94 (1H, m), 5.44 (1H, m). 13C NMR (75 MHz, CDCl3) δ (ppm)
19.5, 55.8, 64.0, 66.9, 78.3, 97.4, 123.0, 139.7. EIMS (70 eV)
m/z 173 (M - H, 1), 143 (5), 125 (8), 114 (61), 83 (100).
2-Hyd r oxym eth yl-6-m eth oxy-3,6-d ih yd r o-2H-p yr a n -3-
ol (13c). The same procedure as above applied to 12c (140
mg, 0.7 mmol) in 4 mL of dry ether added to LAH (60 mg,
1.57 mmol, 2.2 equiv) led to diol 13c (96 mg, 0.60 mmol, 87%).
IR: νmax (film) 3382, 2934, 1654, 1392, 1064, 812 cm-1.1H
NMR (300 MHz, CDCl3) δ (ppm) 1.95 (1H, br s), 2.29 (1H, br
s), 3.43 (3H, s), 3.67 (1H, dt, J ) 1.5, 6.1 Hz), 3.79 (2H, m),
4.14 (1H, br s), 5.01 (1H, d, J ) 1.9 Hz), 5.73 (1H, dt, J ) 1.5,
10.6 Hz), 5.98 (1H, ddd, J ) 1.6, 3.0, 10.6 Hz). 13C NMR (75
MHz, CDCl3) δ (ppm) 55.7, 63.5, 63.7, 78.6, 97.7, 128.1, 133.0.
CIMS (CH4) m/z 143 (M+H - H2O, 24), 129 (M+H - MeOH,
82), 111 (56), 100 (21), 81 (40).
NMR (200 MHz, CDCl3) δ (ppm) 1.37 (3H, s), 3.30 (3H, s), 3.49
(1H, d, J ) 12.9 Hz), 3.66 (3H,m), 4.50 (1H, d, J ) 8.7 Hz),
4.70 (1H, s), 6.68 (1H, t, J ) 6.4 Hz), 7.03 (2H, d, J ) 8.1 Hz),
7.23 (2H, m), 7.22 (2H, m). CIMS (t-BuH, 200 eV) m/z 284 (M+,
12), 253 (32), 235 (8), 173 (100).
6-Hyd r oxym et h yl-2-m et h oxy-4-m et h yl-5-p h en oxyt et -
r a h yd r op yr a n -3,4-d iol (11). Dihydropyran 9 exo (6.5 mg,
0.03 mmol) was dissolved in 1 mL of an acetone/water/tert-
butyl alcohol (2:5:1) mixture and added to a solution of OsO4
(42 mg, 0.16 mmol, 5 equiv) in 2 mL of an ether/pyridine (1:1)
mixture. After the mixture had stirred for 24 h at room
temperature, 10 mg of solid NaHSO3 was added and the
solution was saturated in NaCl. The mixture was extracted
with ethyl acetate (3 × 5 mL). The organic layers were dried
(MgSO4) and evaporated under reduced pressure then chro-
matographed under the same conditions as above. The triol
11 was obtained as a colorless oil (2 mg, 0.01 mmol, 27%).
1H NMR (200 MHz, CDCl3) δ (ppm) 1.23 (3H, s), 1.60 (2H,
br m), 3.45 (1H, s), 3.50 (3H, s), 3.64 (1H, dd, J ) 4.8, 11.0
3,4,5-Tr ih ydr oxy-6-m eth oxy-4-m eth yltetr ah ydr opyr an -
2-ca r boxylic Acid Eth yl Ester (14b). The experimental
J . Org. Chem, Vol. 67, No. 23, 2002 8061

Bataille et al.
1
procedure described above for 10 was applied to dihydropyrane
12b (27 mg, 0.12 mmol) in 4 mL of pyridine added to an
osmium tetroxide (35 mg, 0.14 mmol, 1.2 equiv) solution in
0.5 mL of pyridine. After 2 h at room temperature, the reaction
was quenched with NaHSO3 (1 mL of saturated solution) then
water (2 mL). After flash chromatography on silica gel (elu-
ent: CH2Cl2/MeOH 9:1), 14b was recovered as a colorless oil
(18 mg, 0.07 mmol, 60%).
IR: νmax (film) 3446, 2922, 1742, 1514, 1248, 822 cm-1. H
NMR (300 MHz, CDCl3) δ (ppm) 1.23 (3H, t, J ) 7.2 Hz), 2.39
(2H, br s), 3.43 (3H, s), 3.46 (1H, m), 3.73 (3H, s), 3.85 (1H,
dd, J ) 3.0, 7.1 Hz), 4.15 (3H, m), 4.27 (1H, d, J ) 7.5 Hz),
4.44, 4.50 (2H, 2dAB, J ) 11.0 Hz), 4.58 (1H, d, J ) 6.0 Hz),
6.79 (2H, d, J ) 8.7 Hz), 7.16 (2H, d, J ) 8.7 Hz). 13C NMR
(75 MHz, CDCl3) δ (ppm) 14.5, 55.7, 57.8, 61.9, 66.8, 71.2, 72.5,
72.8, 76.8, 102.9, 114.4, 130.0, 159.8, 169.8.
1
IR: νmax (film) 3451, 2979, 2934, 1739, 1045 cm-1. H NMR
4-Me t h o x y -7-(4-m e t h o x y b e n zy lo x y )-2,2-d im e t h y l-
tetr ah ydr o[1,3]dioxolo[4,5-c]pyr an -6-car boxylic Acid Eth -
yl Ester (17). Diol 16 (85 mg, 0.24 mmol) prepared above was
(300 MHz, CDCl3) δ (ppm) 1.27 (3H, t, J ) 7.1 Hz), 1.37 (3H,
s), 2.38 (2H, br s), 3.08 (1H, br s), 3.19 (1H, d, J ) 7.5 Hz),
3.51 (3H, s), 3.55 (1H, br d, J ) 9.8 Hz), 4.09 (1H, d, J ) 9.8
Hz), 4.21 (1H, dq, J ) 1.9, 7.1 Hz), 4.26 (1H, dq, J ) 1.9, 7.1
Hz), 4.43 (1H, d, J ) 7.9 Hz). 13C NMR (75 MHz, CDCl3) δ
(ppm) 14.5, 22.7, 57.7, 62.3, 72.8, 73.5, 73.8, 74.4, 102.8, 170.9.
EIMS (70 eV) m/z 232 (M - 18, 1), 219 (M - 31, 1), 200 (3),
172 (1), 117 (30), 104 (39), 87 (100). CIMS (CH4) m/z 251 (MH+,
17), 219 (M+H - MeOH, 95), 201 (100), 183 (31), 155 (14), 127
(11).
dissolved in
a mixture of dry acetone (6 mL) and 2,2-
dimethoxypropane (2 mL) to which was added a catalytic
amount of dry camphorsulfonic acid. The mixture was stirred
overnight at room temperature under argon. The solvents were
then evaporated under reduced pressure and the oily residue
directly flash chromatographed on silica gel (eluent: heptane/
ethyl acetate 60:40) to provide 17 (65 mg, 0.18 mmol, 75%) as
a pale yellow oil.
3,4,5-Tr ih ydr oxy-6-m eth oxytetr ah ydr opyr an -2-car box-
ylic Acid Eth yl Ester (14c). The experimental procedure
described above was applied to dihydropyrane 12c (50 mg, 0.25
mmol) in 4 mL of pyridine added to an osmium tetroxide (70
mg, 0.28 mmol, 1.1 equiv) solution in 0.5 mL of pyridine. After
2 h at room tempeature, the reaction was quenched with
NaHSO3 (1 mL of saturated solution) then water (2 mL). After
flash chromatography on silica gel (eluent: CH2Cl2/MeOH 9:1),
14c was recovered as a colorless oil (60 mg, 0.25 mmol, 100%).
IR: νmax (film) 3066, 2936, 1744, 1514, 1250, 1094, 822 cm-1
.
1H NMR (300 MHz, CDCl3) δ (ppm) 1.26 (3H, t, J ) 7.5 Hz),
1.28 (3H, s), 1.46 (3H, s), 3.36 (3H, s), 3.73 (3H, s), 4.00 (1H,
dd, J ) 2.9, 6.0 Hz), 4.17 (3H, m), 4.29 (1H, d, J ) 9.0 Hz),
4.34 (1H, dd, J ) 3.0, 5.9 Hz), 4.45 (1H, d, J ) 3.0 Hz), 4.53
(2H, s), 6.79 (2H, d, J ) 8.7 Hz), 7.20 (2H, d, J ) 8.7 Hz). 13C
NMR (75 MHz, CDCl3) δ (ppm) 14.5, 25.4, 27.2, 55.7, 56.9, 61.8,
71.4, 72.1, 72.51, 72.53, 76.1, 101.3, 111.0, 114.1, 130.1, 130.3,
159.8, 171.0. EIMS (70 eV) m/z 364 (M + H - 15, 2), 186 (5),
121 (100).
1
IR: νmax (film) 3418, 2930, 1736, 1084, 734 cm-1. H NMR
(300 MHz, CDCl3) δ (ppm) 1.26 (3H, t, J ) 7.1 Hz), 2.78 (3H,
br s), 3.47 (1H, dd, J ) 3.4, 7.1 Hz), 3.49 (3H, s), 3.86 (1H, dd,
J ) 3.0, 9.0 Hz), 4.16-4.26 (1H + 2H, m), 4.56 (1H, d, J ) 6.8
Hz). 13C NMR (75 MHz, CDCl3) δ (ppm) 14.4, 57.8, 62.2, 69.5,
69.7, 71.0, 73.5, 102.4, 170.8. EIMS (70 eV) m/z 218 (M - 18,
1), 205 (M - 31, 2), 186 (4), 158 (3), 117 (47), 104 (84), 89 (93),
71 (100). CIMS m/z 237 (MH+, 1), 205 (M + H - MeOH, 18),
187 (100), 169 (55), 159 (9).
[3,4,5-Tr is(ter t-bu tyldim eth ylsilan yloxy)-6-m eth oxytet-
r a h yd r op yr a n -2-yl]m eth a n ol (15). To a solution of triol 14c
(60 mg, 0.25 mmol) and imidazole (170 mg, 2.5 mmol, 10 equiv)
in pyridine (2 mL) was added, at room temperature and under
argon, tert-butyldimethylsilyl chloride (634 mg, 4.3 mmol, 17
equiv). After 48 h at room temperature, the reaction was
quenched with water (0.5 mL). The yellow oily residue thus
obtained was directly reduced by LAH (20 mg, 0.5 mmol, 2
equiv) in ether as described above for 13b. After chromatog-
raphy (eluent: heptane/AcOEt 95:5), 15 was obtained as a
colorless oil (22 mg, 0.05 mmol, 20% for the 2 steps).
7-H yd r oxy-4-m e t h oxy-2,2-d im e t h ylt e t r a h yd r o[1,3]-
d ioxolo[4,5-c]p yr a n -6-ca r boxylic Acid Eth yl Ester (18).
The procedure described above for 12b and applied to ester
17 (65 mg, 0.16 mmol) and DDQ (55 mg, 0.24 mmol, 1.5 equiv)
provided alcohol 18 after the same purification procedure
described for 12b (36 mg, 0.13 mmol, yield 81%) as a colorless
oil.
1
IR: νmax (film) 3468, 2986, 2934, 1744, 1094 cm-1. H NMR
(300 MHz, CDCl3) δ (ppm) 1.26 (3H, t, J ) 7.2 Hz), 1.31 (3H,
s), 1.47 (3H, s), 1.60 (1H, br s), 2.79 (1H, d, J ) 6.0 Hz), 3.41
(3H, s), 4.14 (1H, dd, J ) 2.6, 7.2 Hz), 4.19-4.27 (3H, m), 4.50
(1H, d, J ) 3.3, 7.2 Hz), 4.55 (1H, d, J ) 2.7 Hz). 13C NMR (75
MHz, CDCl3) δ (ppm) 14.5, 25.3, 26.9, 56.8, 62.1, 66.0, 72.2,
73.2, 75.9, 100.5, 111.1, 171.9. EIMS (70 eV) m/z, 261 (M +
H- 15, 28), 229 (16), 85 (100).
Ack n ow led gm en t. A.G. and L.L. thank the Minis-
te`re de la Recherche et de la Technologie for Ph.D.
grants. G.B. and C.L. were summer students from the
Ecole Supe´rieure de Chimie Organique et Mine´rale
(ESCOM, Cergy-Pontoise). Dr. Jean-Erick Ancel (Rhoˆne-
Poulenc Industrialisation) is acknowledged for generous
samples of 1-acetoxyisoprene. The high-pressure devices
used in this work have been purchased thanks to
FIACIR and CPER joint grants of the Conseil Re´gional
de Haute-Normandie and the DRRT to J .M.
IR: νmax (film) 3447, 2928, 2855, 1471, 1250, 1090, 836 cm-1
.
1H NMR (300 MHz, C6D6) δ (ppm) 0.27 (15H, s), 0.35 (3H, s),
1.11 (18H, s), 1.13 (9H, s), 2.20 (1H, br s), 3.34 (3H, s), 3.51
(1H, d, J ) 6.0 Hz), 3.63 (1H, d, J ) 8.7 Hz), 3.90 (3H, m),
4.11 (1H, s), 4.71 (1H, d, J ) 7.1 Hz). 13C NMR (75 MHz,
CDCl3) δ (ppm) 19.8, 26.6, 39.8, 57.6, 63.6, 69.5, 73.8, 74.6,
75.3, 102.0.
4,5-Dih yd r oxy-6-m eth oxy-3-(4-m eth oxyben zyloxy)tet-
r a h yd r op yr a n -2-ca r boxylic Acid Eth yl Ester (16). The
experimental procedure described above for 10 was applied
to dihydropyrane 4c (87 mg, 0.27 mmol) in 4 mL of pyridine
added to an osmium tetroxide (76 mg, 0.30 mmol, 1.1 equiv)
solution in 0.4 mL of pyridine. After 2 h at room temperature,
the reaction was quenched with NaHSO3 (1 mL of saturated
solution) then water (1.5 mL). After flash chromatography on
silica gel (eluent: CH2Cl2/MeOH 9:1), 16 was recovered as a
colorless oil (86 mg, 0.24 mmol, 89%).
Su p p or tin g In for m a tion Ava ila ble: Copies of the 1H
NMR and/or 13C spectra for compounds 1c-d , 2b-d , 4b,c, 5,
9, 10, 11, 12b,c, 13b,c, 14b,c, and 15-18. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O0204193
8062 J . Org. Chem., Vol. 67, No. 23, 2002