Synthesis of optically active 2-alkoxy-2H-pyran-3(6H)-ones. Their use as dienophiles in Diels-Alder cycloadditions

Article abstract of DOI:10.1021/jo0106896

Optically active 2-alkoxy-2H-pyran-3(6H)-ones (4a-d) were synthesized in one step by the tin(IV) chloride-promoted glycosylation and rearrangement of the 2-acetoxy-3,4-di-O-acetyl-D-xylal (3) prepared from D-xylose (1). The absolute configuration of the new stereocenter at C-2 was determined by chemical transformation of the dihydropyranones 4a and 4b into the known alkyl pentopyranosides (7a and 7b, respectively). Also, from ¹H NMR experiments using a chiral ytterbium shift reagent, the enantiomeric excesses for 4a (> 86%) and 4b (>77%) were established. Enantiomerically pure 4c and 4d were obtained by reaction of 3 with chiral 2-octanol (R and S, respectively). Dihydropyranones 4a-d were employed as dienophiles in Diels-Alder cycloadditions with 2,3-dimethylbutadiene and butadiene. Under thermal conditions, only moderate yields (～50%) of cycloadducts 9a-c and 10a were respectively obtained with good diastereofacial selectivity (> 80%). Optimized Lewis acid promoted cycloadditions led to 9a-d and 10a,c in higher yields (～80%) and with higher diastereoselectivities (> 94%). The major products were formed by approach of the dienes from the less hindered face of the dihydropyranones, and the minor products (such as 11a) were formed by addition from the opposite side. Furthermore, cycloadduct 9a was stable in an alkaline solution, whereas 11a underwent epimerization under the same conditions.

Full text of DOI:10.1021/jo0106896

J . Org. Chem. 2001, 66, 8859-8866
8859
Syn th esis of Op tica lly Active 2-Alk oxy-2H-p yr a n -3(6H)-on es.
Th eir Use a s Dien op h iles in Diels-Ald er Cycloa d d ition s
Christian A. Iriarte Capaccio and Oscar Varela*
CIHIDECAR-CONICET, Departamento de Quı´mica Orga´nica, Facultad de Ciencias Exactas y Naturales,
Universidad de Buenos Aires, Ciudad Universitaria, Pabello´n 2, 1428, Buenos Aires, Argentina
varela@qo.fcen.uba.ar
Received J uly 9, 2001
Optically active 2-alkoxy-2H-pyran-3(6H)-ones (4a -d ) were synthesized in one step by the tin(IV)
chloride-promoted glycosylation and rearrangement of the 2-acetoxy-3,4-di-O-acetyl-D-xylal (3)
prepared from D-xylose (1). The absolute configuration of the new stereocenter at C-2 was determined
by chemical transformation of the dihydropyranones 4a and 4b into the known alkyl pentopyra-
1
nosides (7a and 7b, respectively). Also, from H NMR experiments using a chiral ytterbium shift
reagent, the enantiomeric excesses for 4a (>86%) and 4b (>77%) were established. Enantiomerically
pure 4c and 4d were obtained by reaction of 3 with chiral 2-octanol (R and S, respectively).
Dihydropyranones 4a -d were employed as dienophiles in Diels-Alder cycloadditions with 2,3-
dimethylbutadiene and butadiene. Under thermal conditions, only moderate yields (∼50%) of
cycloadducts 9a -c and 10a were respectively obtained with good diastereofacial selectivity (>80%).
Optimized Lewis acid promoted cycloadditions led to 9a -d and 10a ,c in higher yields (∼80%) and
with higher diastereoselectivities (>94%). The major products were formed by approach of the dienes
from the less hindered face of the dihydropyranones, and the minor products (such as 11a ) were
formed by addition from the opposite side. Furthermore, cycloadduct 9a was stable in an alkaline
solution, whereas 11a underwent epimerization under the same conditions.
In tr od u ction
cosylation of 2-acyloxy-hex-1-enitols in the presence of a
Lewis acid. This procedure gave ready and large-scale
accessibility to the 6-substituted sugar enones, which
could be otherwise obtained via multistep procedures.1,9
We report here a convenient preparation of optically
active 2-alkoxy-2H-pyran-3(6H)-ones via tin(IV) chloride-
promoted rearrangement of 2-acetoxy-3,4-di-O-acetyl-D-
xylal.
The synthetic usefulness of these dihydropyranones
would be considerably enlarged if they could be employed
as dienophiles in Diels-Alder reactions. Structurally
similar pyranoid enones such as levoglucosenone,10 isolevo-
glucosenone,11 2-alkoxy-2H-pyran-5(6H)-ones,12 and enolo-
ne esters13 underwent [4+2] cycloaddition of dienes to
give a variety of configurationally well-defined carbocyclic
derivatives. We have now examined the Diels-Alder
reactions of the dihydropyranone dienophiles, under
thermal conditions and Lewis acid catalysis, and the level
of stereocontrol was determined.
Carbohydrate-derived sugar enones have been em-
ployed for the synthesis of a variety of asymmetric
molecules, and they constitute versatile building blocks
for the construction of natural products.1 Due to the
highly stereoselective nature of addition reactions to the
enone system of these sugar derivatives, we have em-
ployed them for the enantioselective synthesis of natural
products,2 in particular diamino tetradeoxy sugars found
in antibiotics,3 and for the preparation of modified
glycosides.4 Lichtenthaler and co-workers have described
convenient procedures for the synthesis of 4-acyloxy-6-
acyloxymethyl dihydropyranones5 (enolone esters) and
their use as six-carbon synthons of non-carbohydrate
natural products such as (-)-palythazine6 and (-)-
bissetone.7 We have also reported8 a straightforward
synthesis of 6-acyloxymethyl dihydropyranones by gly-
(1) (a) Fraser-Reid, B. Acc. Chem. Res. 1996, 29, 57. (b) Fraser-Reid,
B. Acc. Chem. Res. 1985, 18, 347. (c) Fraser-Reid, B. Acc. Chem. Res.
1975, 8, 192. (d) Holder, N. L. Chem. Rev. 1982, 82, 287.
(2) (a) Di Nardo, C.; Varela, O. J . Org. Chem. 1999, 64, 6119. (b)
Varela, O. Pure Appl. Chem. 1997, 69, 621. (c) Di Nardo, C.; J eroncic,
L. O.; Lederkremer, R. M.; Varela, O. J . Org. Chem. 1996, 61, 4007.
(3) (a) Iriarte Capaccio, C. A.; Varela, O. Tetrahedron: Asymmetry
2000, 11, 4945. (b) Zunszain, P. A.; Varela, O. Tetrahedron: Asymmetry
1998, 9, 1269.
(8) De Fina, G. M.; Varela, O.; Lederkremer, R. M. Synthesis 1988,
891.
(9) (a) Holder, N. L.; Fraser-Reid, B. Can. J . Chem. 1973, 51, 3357.
(b) Umezawa, S.; Tsuchiya, T.; Okazaki, Y. Bull. Chem. Soc. J pn. 1971,
44, 3494.
(10) (a) Bhate´, P.; Horton, D. Carbohydr. Res. 1983, 122, 189. (b)
Shafizadeh, F.; Essig, M. G.; Ward, D. D. Carbohydr. Res. 1983,
114, 71. (c) Ward, D. D.; Shafizadeh, F. Carbohydr. Res. 1981, 95,
155.
(4) Varela, O.; De Fina, G. M.; Lederkremer, R. M. Carbohydr. Res.
1993, 246, 371.
(5) (a) Lichtenthaler, F. W. Modern Synthetic Methods; Scheffold,
R., Ed.; VCH : Weinheim/New York, 1992; Vol. 6, p 273. (b) Licht-
enthaler, F. W. Natural Products Chemistry; Atta-ur-Rahman, Ed.;
Springer: New York, 1986; p 227. (c) Lichtenthaler, F. W. Pure Appl.
Chem. 1978, 50, 1343.
(6) J arglis, P.; Lichtenthaler, F. W. Angew. Chem., Int. Ed. Engl.
1982, 21, 141.
(11) (a) Horton, D.; Roski, J . P.; Norris, P. J . Org. Chem. 1996, 61,
3783. (b) Horton, D.; Roski, J . P. J . Chem. Soc., Chem. Commun. 1992,
759.
(12) (a) J urczak, J .; Tkacz, M. Synthesis 1979, 42. (b) Fraser-Reid,
B.; Underwood, R.; Osterhout, M.; Grossman, J . A.; Liotta, D. J . Org.
Chem. 1986, 51, 2152. (c) Primeau, J . L.; Anderson, R. C.; Fraser-Reid,
B. J . Chem. Soc., Chem. Commun. 1980, 6.
(7) Brehm, M.; Dauben, W. G.; Ko¨hler, P.; Lichtenthaler, F. W.
Angew. Chem., Int. Ed. Engl. 1987, 26, 1271.
(13) Dauben, W. G.; Kowalczyk, B. A.; Lichtenthaler, F. W. J . Org.
Chem. 1990, 55, 2391.
10.1021/jo0106896 CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/21/2001

8860 J . Org. Chem., Vol. 66, No. 26, 2001
Iriarte Capaccio and Varela
Sch em e 1a
a
Reagents and conditions: (i) 32% HBr, AcOH, 0 °C, 2 h; (ii) DBU, room temperature, 30 min; (iii) ABCHOH, SnCl4, CH2Cl2, -18 °C,
20 min.
Sch em e 2a
Resu lts a n d Discu ssion
Acetylation of D-xylose (1) with acetic anhydride-
pyridine afforded the per-O-acetyl derivative 2. Treat-
ment of 2 with 32% hydrogen bromide in acetic acid gave
the corresponding glycosyl bromide, which underwent
elimination of HBr on reaction with 1,8-diazabicyclo-
[5.4.0]undec-7-ene (DBU) to afford the 2-acyloxy glycal
derivative 3 (Scheme 1). Crude intermediates were
employed for all the steps, and compound 3 was isolated
in crystalline form in 72% yield from 1. The 1H NMR
spectrum of 3 showed small values for J 3,4, J 4,5, and J 4,5′
,
which indicated a preferred 5H4(D) conformation, in
agreement with the preferential conformation of its
2-unsubstituted analogue.14,15 Such a conformation is free
of 1,3-diaxial interactions between substituents, and the
3-acyloxy group is quasiaxially oriented, which is a factor
that provides additional conformational stability15 (allylic
effect).
Treatment of the pent-1-enitol 3 with benzyl alcohol,
in the presence of tin(IV) chloride as Lewis acid catalyst,
afforded benzyl pent-3-enopyranosid-2-ulose 4a (2-ben-
zyloxy-2H-pyran-3(6H)-one) in 85% yield. We have re-
ported8 a similar SnCl4-catalyzed rearrangement of 2-acy-
loxy-hex-1-enitols derived from hexoses to alkyl hex-3-
enopyranosid-2-uloses having an R configuration for the
anomeric center. In the case of 4a , the large negative
value for its optical rotation ([R]D -200.6) suggested a
â(S) configuration for the new stereocenter. The glyco-
sylation of 3 was also performed using methyl alcohol as
a nucleophile to afford the 2-methoxy-2H-pyran-3(6H)-
one (4b) in 77% yield. Similar to its 2-benzyloxy analogue
(4a ), the 2-ulose derivative 4b showed a large negative
optical rotation value, suggesting again a â(R in this case)
configuration at C-2.
To confirm the configuration of the new stereocenters
in compounds 4a ,b, they were converted into the known
benzyl and methyl pentopyranosides by a sequence that
consisted of the reduction of the carbonyl function fol-
lowed by dihydroxylation of the double bond (Scheme 2).
In this sequence, there was a remarkable diastereose-
lectivity in the reduction of 4a to 5a , probably due to the
stereocontrol exerted by the anomeric center vicinal to
the carbonyl group.3,4,16 The following osmylation17 of 5a
occurred also by diastereoselective addition of osmium
a
Reagents and conditions: (i) NaBH4, CeCl3‚7 H2O, MeOH, 0
°C, 20 min; (ii) OsO4, NMO, tert-butyl alcohol-H2O, room tem-
perature, 16 h. b Diastereomeric ratios: 40:1 for 5a :6a and 6:1 for
7a :8a .
tetroxide to the double bond from the side of the ring
opposite to the allylic hydroxyl group, in agreement with
Kishi’s rule of osmylation of allylic alcohols.18 The NMR
spectra of the major glycoside (7a ) isolated from 4a were
consistent with a â-arabinopyranoside structure,19,20 and
the largely negative optical rotation ([R]D -184.0) led to
the conclusion that it belonged to the D-series. However,
such a value, compared with that of the pure benzyl â-D-
arabinopyranoside19 ([R]D -217.0), indicated that 7a was
a partially racemic product. The enantiomeric excess (ee)
for 7a (ee > 84%) was estimated on the basis of these
data. An analogous sequence applied to dihydropyranone
4b led to partially racemic methyl â-D-arabinopyranoside
(7b) as the main product, and an ee > 75% was calculated
from the optical rotation.21
The foregoing syntheses confirmed that the enantiomer
in excess in 4a and 4b had the same â configuration (S
and R, respectively). To establish the enantiomeric
composition directly from partially racemic 4a and 4b,
NMR experiments were conducted using a chiral lan-
thanide shift reagent.22,23 Thus, with ytterbium tris[3-
(18) Cha, J . K.; Christ, W. J .; Kishi, Y. Tetrahedron 1984, 40, 2247.
(19) Kawasaki, M.; Matsuda, F.; Terashima, S. Tetrahedron 1988,
44, 5695.
(20) Bock, K.; Pedersen, C. Adv. Carbohydr. Chem. Biochem. 1983,
41, 27.
(14) Rico, M.; Santoro, J . J . Magn. Reson. 1976, 8, 49.
(15) Chalmers, A. A.; Hall, R. H. J . Chem. Soc., Perkin Trans. 2
1974, 728.
(16) Lichtenthaler, F. W.; Nishiyama, S.; Ko¨hler, P.; Lindner, H. J .
Carbohydr. Res. 1985, 136, 13.
(17) J arosz, S. Carbohydr. Res. 1992, 224, 73.
(21) (a) Breitmaier, E.; Voelter, W.; J ung, G.; Ta¨nzer, C. Chem. Ber.
1971, 104, 1147. (b) Mizutani, K.; Kasai, R.; Tanaka, O. Carbohydr.
Res. 1980, 87, 19.

Cycloadditions to Optically Active 2-Alkoxy-2H-pyran-3(6H)-ones
J . Org. Chem., Vol. 66, No. 26, 2001 8861
Sch em e 3
Sch em e 4
(heptafluoropropylhydroxymethylene)-(+)-camphorate],
the H-2 resonance of 4a split into two broad singlets; from
the integral of these signals, the enantiomeric excess in
favor of the (2S) isomer (ee > 86%) was calculated.
Similarly, a satisfactory split of the methyl signal was
observed upon addition of the ytterbium compound to 4b,
and an ee > 77% was established for 4b. These ee values
were in good agreement with those previously estimated
from the optical rotation of 7a and 7b.
Enantiomerically pure dihydropyranones were pre-
pared by the tin(IV) chloride-promoted glycosylation of
3 with a chiral alcohol ((R)-2-octanol). The introduction
of an additional stereocenter of defined configuration led
1
to the diastereomeric products 4c and 4e. The H NMR
spectrum of the crude reaction mixture showed charac-
teristic signals for each diastereoisomer, and from the
average integral of such signals, a diastereomeric excess
(de) > 80% was determined for 4c. The mixture was
subjected to chromatographic purification to afford pure
4c (de > 97%). The glycosylation of 3 was also conducted
with (S)-(+)-2-octanol to give 4d and 4f. The NMR spectra
of purified 4d (de > 96%) exactly overlapped those of 4e,
as expected for enantiomeric compounds. This fact pro-
vides additional support to all the structural assign-
ments.
anomeric center.26 Furthermore, molecular mechanics
calculations for the â isomer of 2-methoxy-4,6-disubsti-
tuted dihydropyranones showed that the conformer with
an axial methoxy group (E0) was preferred by -27 kJ /
mol over its equatorial (0E) counterpart.13 The same
conformational preference has been found in the solid
state.27
As far as we know, this is the first report on the
synthesis of optically active pure 2,6-dihydropyran-3-
ones. Previous preparations of 4b in racemic form have
been described.28
As compounds 4a -d possess in their structures a
carbonyl group conjugated with a double bond, we have
explored their reactivity as dienophiles in Diels-Alder
cycloadditions. Reaction of 4a -d with common acyclic
dienes would lead to two cycloadducts, if isomerization
is excluded. However, the chiral center at C-2 of pyra-
nones is expected to induce asymmetry, to afford a major
diastereoisomer. Such facial selectivities have been re-
ported for cyclic enones.10-13 With these considerations
in mind, we have examined the Diels-Alder reactions
of 4a -d toward butadienes to determine the level of
stereocontrol attainable. The reactions were performed
under thermal and Lewis acid catalyzed conditions
(Scheme 4); selected experiments are shown in Table 1.
The thermal Diels-Alder reactions were conducted
with an excess of diene during long periods (3-4 days).
In any case, a main cycloadduct was obtained in moder-
ate yield (45-51%) and starting material was recovered.
Higher concentrations of diene, higher temperatures, or
longer reactions times did not improve the yield of
cycloadducts and, in most cases, increased the extent of
polymerization of the diene. The high total material
recovery (>85%), even after extending heating, indicated
that dihydropyranones 4a -c and the corresponding
adducts are quite stable toward heating. The main
The selectivity for the â isomer in the formation of
4a -d can be explained by taking into account the steric
course of the glycosylation of 3. Assuming that 3 reacts
5
in the preferred H4 conformation, the quasiaxial allylic
acetoxy group can be readily eliminated by coordination
with the Lewis acid. Simultaneous migration of the
double bond (Ferrier’s rearrangement24) generates a
cation at C-1 that can be stabilized by participation of
the oxygen-ring lone pair (Scheme 3). The quasiaxially
oriented alkoxy group at C-4 should induce the attack of
the alcohol from the opposite face to give the 2-enopyra-
noside having the â anomeric configuration. This inter-
mediate undergoes a second Ferrier’s rearrangement
affording the dihydropyranones 4a -d .
1
The H NMR spectra of 4a -d showed magnitudes for
homoallylic couplings (J 4,6 and J 4,6′) that were consistent
with a preferential E0 conformation for such compounds.
This assignment was confirmed by the characteristic
long-range coupling between H-2 and H-4 (0.7 Hz) similar
to that observed for levoglucosenone, in which the pyra-
none is constrained to the E0 conformation because of the
five-membered fused ring.25 The E0 conformation for
4a -d is stabilized by the anomeric effect, which is
probably intensified by the carbonyl function next to the
(22) McCreary, M. D.; Lewis, D. W.; Wernick, D. L.; Whitesides, G.
M. J . Am. Chem. Soc. 1974, 96, 1038.
(23) Mayo, B. C. Chem. Soc. Rev. 1973, 249.
(26) Bernasconi, C.; Cottier, L.; Descotes, G.; Grenier, M. F.; Metres,
F. Nouv. J . Chim. 1978, 2, 79.
(27) Lichtenthaler, F. W.; Ro¨nninger, S.; Lindner, H. J .; Immel, S.;
Cuny, E. Carbohydr. Res. 1993, 249, 305.
(24) Ferrier, R. J . In The Carbohydrates Chemistry/ Biochemistry;
Pigman, W., Horton, D., Eds.; Academic Press: New York, 1980; Vol.
IB, p 852.
(25) (a) Halpern, Y.; Riffer, R.; Broido, A. J . Org. Chem. 1973, 38,
204. (b) Shafizadeh, F.; Chin, P. P. S. Carbohydr. Res. 1977, 58, 79.
(28) Saroli, A.; Descours, D.; Anker, D.; Pacheco, H. J . Heterocycl.
Chem. 1978, 15, 765.

8862 J . Org. Chem., Vol. 66, No. 26, 2001
Iriarte Capaccio and Varela
Ta ble 1. Diels-Ald er Rea ction s of Dih yd r op yr a n on es 4a -d w ith Bu ta d ien es u n d er Th er m a l a n d Et2O‚BF 3-Ca ta lyzed
Con d ition s
dienea
mol equiv
temp time deb yield of
dienea
mol equiv
temp time deb yield of
(°C) (h) (%) adductc
dienophile (mol equiv) Et2O‚BF3 solv (°C) (h) (%) adductc dienophile (mol equiv) Et2O‚BF3 solv
4a
4b
4c
4a
4c
4c
4c
4c
A (3.7)
A (3.7)
A (3.7)
B (3.7)
A (1.5)
A (1.5)
A (1.5)
A (1.7)
PhMe 115 90
PhMe 110 90
PhMe 115 90
PhMe 125 90
82
82
91
85
47
51
46
45
81
32
81
83
4c
4c
4c
4a
4b
4d
4a
4c
A (1.7)
A (2.8)
A (3.5)
A (1.7)
A (1.7)
A (1.7)
B (2.0)
B (2.0)
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
CH2Cl2 -18 0.25 98
80
70
CH3CN -18 0.25 99
THF
-18 0.25
PhMe
PhMe
PhMe
PhMe
PhMe
-18 0.25 96
-18 0.25 94
-18 0.25 98
25 0.90 99
25 0.90
81
80
81
81
80
1.0
0.2
1.6
1.0
PhMe -18 0.25 98
PhMe -18 0.50
PhMe -18 0.50 98
PhMe -18 0.25 98
a
b
1
A: 2,3-dimethylbutadiene. B: butadiene. Diastereomeric excess (de) was calculated from the H NMR spectrum of the crude reaction
mixture. c Yield of adducts 9a -d and 10a ,c after isolation by flash chromatography.
products in the reaction with 2,3-dimethylbutadiene were
9a -c, the adducts formed by attack of the diene from
the R face of the dihydropyranones 4a -c; thus, thermal
cycloadditions were diastereofacially selective (de > 80%).
When a preparative-scale thermal cycloaddition was
conducted starting from 4a , the minor product 11a
(formed by attack of the diene from the â face of the
pyranone) could be isolated in low yield. Similar yields
and selectivities were observed in the preparation of 10a
by thermal addition of butadiene to 4a . The determina-
tion of the structure of the cycloadducts is described
below.
For studying the Lewis acid mediated cycloaddition,
the dihydropyranone 4c was employed as a model dieno-
phile. From the various Lewis acids (AlCl3, Et2O‚BF3,
TiCl4) tested, boron trifluoride showed higher and more
reproducible yields, together with low polymer formation
and easy workup of the reaction mixtures. Experiments
were performed in order to evaluate the effect of the
concentration of boron trifluoride in the addition of 2,3-
dimethylbutadiene to 4c (Table 1). The best results were
obtained when 1 molar equiv of the Lewis acid was
employed. Decreasing the amount of catalyst led to lower
yields, and larger amounts did not improve it. The yield
of cycloaddition product was similar when the diene was
added to the solution of the dihydropyranone from 4 to 5
min after addition of the catalyst. This fact suggests that
the formation of enone-catalyst complex takes place
rapidly, in contrast to the catalyzed cycloadditions of
common cycloalkenones, in which the time of ketone-
catalyst complexation dramatically influenced the prod-
uct yield.29
The solvent effect was also evaluated; toluene and
dichloromethane proved to be adequate solvents for this
reaction since a small excess of diene was required for
completion and, hence, low polymer formation took place.
Reactions were also conducted in donor solvents such as
acetonitrile and tetrahydrofuran (THF). Thus, in the case
of acetonitrile, a larger amount of diene was needed,
although no increase in polymer formation was detected.
In THF, the cycloaddition was strongly inhibited even
for large concentrations of diene. The optimized condi-
tions established for reactions of 4c (1 molar equiv of
Et2O‚BF3, toluene, 15 min, -18 °C) with 2,3-dimethyl-
butadiene were applied to the cycloadditions of the other
dihydropyranones 4a ,b,d . As expected, very good yields
of the respective adducts 9a ,b,d were obtained. Similarly,
4a and 4c reacted with butadiene under the same
conditions to give ∼80% yield of 10a and 10c, respec-
tively. Boron trifluoride-promoted cycloadditions were
also very highly diastereoselective, as the adducts 9a -d
and 10a ,c were obtained in high diastereomeric excess
(>94%).
Reactions were also conducted in a preparative scale;
for example, starting from 4a , the major product 9a was
isolated in 82% yield, and the optically pure dihydropy-
ranone 4c afforded 9c as a single, enantiomerically pure
isomer in 79% yield. In contrast to the thermal reactions,
no significant amounts of other diastereoisomers were
formed. A similar trend, but a much more pronounced
facial stereoselection in Lewis acid mediated cycloaddi-
tion compared to the thermal induced reaction, has been
described13 for a reactive â-methoxy-substituted pyranoid
enolone ester. The high diastereoselection in cycloaddi-
tions to 4a -d should result from the steric effect of the
axially oriented alkoxy group at C-2, which prevents the
approach of the diene to the double bond from the â face.
In agreement with this explanation, the bulkyness of
such a group modifies the diastereoselectivity in reactions
conducted under identical conditions (compare the selec-
tivity in the addition to octyl vs methyl derivatives 4c
and 4b in Table 1). A similar stereocontrol has been
reported in Diels-Alder reactions applied to structurally
related pyranones.10-13
Regarding the reactivity of the dihydropyranones
toward Diels-Alder reactions, it has been previously
demonstrated that the location of an oxygen atom in a
six-membered ring can modify the reactivity of an
enone.12b The ring oxygen of pyranoid enolone esters
makes the system much more reactive than the structur-
ally related cyclohexanoid enolone esters, in which the
ring oxygen has been formally replaced by a methylene
group.13 In the case of dihydropyranones 4a -d , a similar
“ring oxygen effect” seems to operate as Diels-Alder
cycloadditions, mainly under Lewis acid catalysis, re-
quired much smoother reaction conditions than those
described for normal cyclohexenones.29
The structures of cycloadducts were determined by
means of NMR techniques. The enantiomerically pure
adduct 9c was employed for complete structural elucida-
1
tion. The H NMR spectrum (500 MHz) of this compound
admitted a first-order analysis, and the assignments were
confirmed by bi-dimensional (2D COSY) NMR experi-
ments. Thus, the small J values between H-1-H-8a (2.3
Hz) and H-1′-H-8a (1.1 Hz) indicated that the C-H8a
bond bisects the dihedral angle of the H-1-C-H-1′ group,
and the J 4a,8a (5.3 Hz) value was compatible with a gauche
axial-equatorial relationship for H-4a and H-8a. Fur-
thermore, the coupling constants between H-4a and H-8a
(29) (a) Fringuelli, F.; Pizzo, F.; Taticchi, A.; Wenkert, E. J . Org.
Chem. 1983, 48, 2802. (b) Fringuelli, F.; Pizzo, F.; Taticchi, A.; Halls,
T. D. J .; Wenkert, E. J . Org. Chem. 1982, 47, 5056.

Cycloadditions to Optically Active 2-Alkoxy-2H-pyran-3(6H)-ones
J . Org. Chem., Vol. 66, No. 26, 2001 8863
a strong tendency to isomerize under base-catalyzed
conditions. To determine the stability of 9a and 11a to
alkali, they were treated with a solution of sodium
ethoxide in ethanol. The cycloadduct 9a was recovered
unchanged, whereas 11a underwent rapid conversion
into the trans tetrahydrobenzopyranone 12a . The ster-
1
eochemistry of 12a was readily deduced from its H NMR
spectrum, which showed large J values (11.0 Hz) for the
coupling of H-8a with H-1 and H-4a, consistent with a
trans diaxial disposition for the pyranone-ring-coupled
protons. It is noteworthy that 11a can isomerize without
substantial change of the conformation of the pyranoid
ring, whereas a shifting to the conformer having the
benzyloxy substituent in an equatorial orientation is
required for the isomerization of 9a .
F igu r e 1. Important correlations observed in the ROESY
spectrum of 9c.
Sch em e 5
Con clu sion s
A short route is described for the direct conversion of
the acetoxy groups of 2-acetoxy-3,4-di-O-acetyl-D-xylal
into an enone system of a dihydropyranone derivative.
These compounds may be otherwise synthesized by
multistep procedures that require protection-deprotec-
tion, oxidation, and elimination of hydroxyl groups in a
monosaccharide. The resulting optically active dihydro-
pyranones proved to be excellent dienophiles in Diels-
Alder cycloadditions under Lewis acid catalyzed condi-
tions. Their reactivity is probably enhanced by the ring-
oxygen atom. The high diastereofacial selectivity in the
cycloaddition provides straightforward access to optically
active tetrahydrobenzopyranones that carry a number of
stereogenic centers installed in a predictable way. Such
bicyclic compounds have significant synthetic potential
as chiral building blocks for the construction of complex
natural products.
with the vicinal methylene protons (at C-5 and C-8,
respectively) were consistent with a half chair conforma-
tion (4aH8a) for the cyclohexene ring. The structure of 9c
was further confirmed by means of 1H,1H-ROESY experi-
ments;30 the cross-peaks observed are indicated in Figure
1. In particular, the cross-peak between H-1 and H-4a
protons confirmed their 1,3-diaxial orientation in the
distorted chair conformation of the pyranone ring. The
structure of the other adducts 9a ,b,d was established by
comparison of their spectra to those of 9c.
Exp er im en ta l Section
Gen er a l Meth od s. Melting points are uncorrected. Optical
rotations were measured at 25 °C. Column chromatographic
separations were performed with silica gel 60, 240-400 mesh.
Analytical TLC was performed on silica gel 60 F254 precoated
plates (0.2 mm). Visualization of the spots was effected by
exposure to UV light or charring with a solution of 5% sulfuric
acid in EtOH, containing 0.5% p-anisaldehyde. Solvents were
reagent grade and, in most cases, were dried and distilled prior
to use according to standard procedures.
1,5-An h yd r o-2,3,4-tr i-O-a cetyl-D-th r eo-p en t-1-en itol (2-
Acetoxy-3,4-d i-O-a cetyl-D-xyla l, 3). To a mixture of anhy-
drous pyridine (40 mL) and acetic anhydride (32 mL) at 0 °C
was added D-xylose (1, 5.00 g, 33.30 mmol), and the mixture
was stirred overnight at room temperature. To this solution
was slowly added methanol (70 mL) at 0 °C, and after 1 h of
stirring at 0 °C and 1 h at room temperature, the mixture was
concentrated. Pyridine was removed by successive evapora-
tions with toluene. The resulting syrup, which was homoge-
neous by TLC (Rf ) 0.51, hexane/EtOAc 1.6:1), was dissolved
in anhydrous 1,2-dichloroethane (14 mL) and cooled to 0 °C,
and 32% HBr in glacial acetic acid (12.2 mL) was added
dropwise in the dark. After 2 h, TLC showed a main spot (Rf
) 0.62). The solution was evaporated in a vacuum (20 °C), and
successive dissolutions followed by evaporation with toluene
and ethyl ether afforded a partly crystalline product, which
was dissolved in 1,2-dichloroethane (20 mL). The solution was
cooled to -18 °C, and 1,8-diazabycyclo[5.4.0]undec-7-ene (DBU,
5.6 mL) was added dropwise in the dark. After stirring for 30
min at room temperature, TLC showed a main spot having
an Rf ) 0.55. The mixture was diluted with CH2Cl2 and washed
with 10% aqueous HCl, saturated (satd) aqueous (aq) NaHCO3
The minor product isolated in the thermal cycloaddi-
tion of 4a with 2,3-dimethyl-1,3-butadiene was identified
as 11a , the diastereoisomer of 9a that had the opposite
1
configuration at C-4a and C-8a (Scheme 5). The H NMR
spectrum of 11a showed relatively large coupling con-
stant values between H-8a-H-1 and H-8a-H-1′ (7.8 and
4.3 Hz, respectively) compared to those of 9a , indicating
an axial disposition for H-8a. The J 4a,8a (6.2 Hz) value
was consistent with an equatorial-axial disposition for
H-4a and H-8a.
The cis octalones, obtained by Lewis acid induced
Diels-Alder reaction of butadienes with conjugated
cyclohexenones, equilibrate to the trans isomeric ad-
duct.29 In contrast, the analogous cis octalones 9a and
11a were stable and did not isomerize when treated with
solutions of Et2O‚BF3 during long periods. Similarly, the
hydrobenzosuberones derived from 2-cycloheptenone un-
derwent a very slow acid-induced isomerization during
the cycloaddition process.29b However, such adducts have
(30) Kessler, H.; Gehrke, M.; Griesinger, C. Angew. Chem., Int. Ed.
Engl. 1988, 27, 490.

8864 J . Org. Chem., Vol. 66, No. 26, 2001
Iriarte Capaccio and Varela
and satd aq NaCl. The organic extract was dried (MgSO4) and
concentrated to afford a partly crystalline product. Upon
purification by flash chromatography (hexane/EtOAc 7:1),
crystalline 3 was obtained (6.22 g, 72% from 1): mp 80-81
Further fractions from the column were enriched in 4e. The
1H and 13C NMR spectra showed a pattern of signals for 4e
that was identical to that of its enantiomer 4d (see below).
(2S)-[(S)-2′-Octyloxy]-2H-pyr an -3(6H)-on e (4d) an d (2R)-
[(S)-2′-Octyloxy]-2H-p yr a n -3(6H)-on e (4f). The mixture of
4d and 4f was obtained in 82% yield (0.72 g, de > 80%), and
it was processed as described for 4c,e. The more polar
diastereoisomer 4d (0.61 g, 70%; de > 96%) gave [R]D -152.6
(c 1.2, CHCl3): 1H NMR (500 MHz, CDCl3) δ 7.03 (ddd, 1, J 4,5
) 10.4 Hz, J 5,6 ) 1.8 Hz, J 5,6′ ) 4.0 Hz, H-5), 6.12 (dddd, 1,
J 2,4 ) 0.7 Hz, J 4,6 ) 2.6 Hz, J 4,6′ ) 1.5 Hz, H-4), 4.92 (bs, 1,
H-2), 4.58 (ddd, 1, J 6,6′ ) 18.9 Hz, H-6), 4.27 (ddd, 1, H-6′),
3.82 (sextet, 1, HCO octyl), 1.62-1.25 (m, 10, CH2 octyl), 1.27
(d, 3, J ) 6.4 Hz, CH3CO octyl), 0.88 (t, 3, J ) 6.7 Hz, CH3
octyl); 13C NMR (50.3 MHz, CDCl3) δ 188.9 (C-3), 147.9, 125.0
(C-vinylic), 97.7 (C-2), 76.7 (HCO octyl), 59.7 (C-6), 36.5, 31.8,
29.3, 25.2, 22.6, 21.2, 14.1 (C-octyl). Anal. Calcd for C13H22O3:
C, 68.99; H, 9.80. Found: C, 69.09; H, 9.84.
The first fractions of the column were enriched in 4f, which
showed spectra identical to those of its enantiomer 4c.
Con ver sion of 4a in to P a r tia lly Ra cem ic Ben zyl P en -
top yr a n osid es 7a a n d 8a . To a solution of 4a (131 mg, 0.64
mmol) in dry MeOH (13 mL) was added cerium(III) chloride
heptahydrate (64 mg, 0.17 mmol).31 The solution was stirred
for 10 min at room temperature and then cooled to 0 °C.
Sodium borohydride (25 mg, 0.66 mmol) was added, and the
stirring was maintained for 20 min, when TLC (hexane/EtOAc
2:1) showed two spots having Rf ) 0.44 (major) and 0.26, and
no starting material (Rf ) 0.50) remaining. The mixture (which
showed by NMR a 40:1 diastereomeric ratio) was diluted with
a large excess of ethyl ether, washed with satd aq NaHCO3,
dried (MgSO4), and concentrated. Flash chromatography of the
residue with hexane/EtOAc 10:1 gave the main product (116
mg, 88%), which was spectroscopically characterized32 as 5a :
1H NMR (200 MHz, CDCl3) δ 7.35 (bs, 5, H-aromatic), 5.82,
5.73 (2 bd, 2, J 3,4 ) 11.3 Hz, H-3,4), 4.96 (d, 1, J 1,2 ) 4.0 Hz,
H-1), 4.85, 4.63 (2 d, 2, J ) 11.8 Hz, PhCH2O), 4.69 (bs, 1,
HO), 4.18 (m, 2, H-2,5), 4.03 (bd, 1, J 5,5′ ) 17.2 Hz, H-5′); 13C
NMR (50.3 MHz, CDCl3) δ 137.4, 128.6, 128.0 (C-aromatic),
127.1, 126.2 (C-3,4), 96.0 (C-1), 70.0 (PhCH2O), 64.3 (C-2), 60.3
(C-5).
1
°C; [R]D -272.3 (c 1.0, CHCl3); H NMR (200 MHz, CDCl3) δ
6.73 (s, 1, H-1), 5.34 (dd, 1, J 3,4 ) 2.2 Hz, J 3,5 ) 1.8 Hz, H-3),
4.95 (ddd, 1, J 4,5 ) 2.2 Hz, J 4,5′ ) 1 Hz, H-4), 4.23 (ddd, 1, J 5,5′
) 12.4 Hz, H-5), 3.95 (dd, 1, H-5′), 2.11, 2.10, 2.07 (3 s, 9, 3
CH3CO); 13C NMR (50.3 MHz, CDCl3) δ 169.9, 169.8 (×2),
141.3, 127.5, 67.4, 64.3, 63.7, 20.9, 20.8, 20.6. Anal. Calcd for
C
11H14O7: C, 51.17; H, 5.46. Found: C, 51.12; H, 5.48.
Gen er a l P r oced u r e for 2-Alk oxy-2H-p yr a n -3(6H)-on es
(4a -d ). A solution of 3 (1.00 g, 3.87 mmol) and the alcohol
(7.45 mmol) in anhydrous CH2Cl2 (45 mL) was cooled to -18
°C, and tin(IV) chloride (0.58 mL, 4.92 mmol) was added. When
TLC (hexane/EtOAc 2:1) revealed complete consumption (∼20
min) of the starting 3, the mixture was diluted with CH2Cl2.
This solution was washed with satd aq NaHCO3, dried
(MgSO4) and concentrated. The residue was purified by flash
chromatography to afford dihydropyranones 4a -d as colorless
oils.
The absolute configuration at C-2 of 4a and 4b was
established by their conversion into the partially racemic
pentopyranosides (next section). The enantiomeric composition
1
was also determined directly from 4a and 4b by H NMR in
the presence of a chiral shift reagent.
(2S)-2-Ben zyloxy-2H-p yr a n -3(6H)-on e (4a ): 85% yield
(0.67 g). The enantiomeric excess (ee) for 4a was determined
by 1H NMR using ytterbium tris[3-(heptafluoropropylhy-
droxymethylene)-(+)-camphorate] as a chiral resolving re-
agent. To a solution of 4a (0.05 mmol) in carbon tetrachloride
containing 1% benzene-d6 (0.5 mL) was added the shift
reagent. Upon addition of 0.6 molar equiv, the 1H NMR
spectrum showed a splitting of the H-2 signal into two broad
singlets (enantiomeric shift difference23 ∆∆δ ) 0.14). From the
integral of these signals (14:1 ratio), the enantiomeric com-
position (ee > 86%) was established for 4a . This compound
had [R]D -200.6 (c 1.1, CHCl3): 1H NMR (200 MHz, CDCl3) δ
7.38 (bs, 5, H-aromatic), 7.05 (ddd, 1, J 4,5 ) 10.6 Hz, J 5,6 ) 1.8
Hz, J 5,6′ ) 3.8 Hz, H-5), 6.15 (dddd, 1, J 2,4 ) 0.7 Hz, J 4,6 ) 2.5
Hz, J 4,6′ ) 1.8 Hz, H-4), 4.96 (bs, 1, H-2), 4.85, 4.73 (2 d, 2, J
) 11.8 Hz, PhCH2O), 4.56 (ddd, 1, J 6,6′ ) 19.0 Hz, H-6), 4.27
(ddd, 1, H-6′); 13C NMR (50.3 MHz, CDCl3) δ 188.6 (C-3), 147.9
(C-5), 136.8, 128.6, 128.1 (C-aromatic), 124.9 (C-4), 97.1 (C-
2), 70.8 (PhCH2O), 59.8 (C-6). Anal. Calcd for C12H12O3: C,
70.58; H, 5.92. Found: C, 70.28; H, 5.92.
Upon elution of the column with hexane/EtOAc 9:1, the
minor product was isolated (4 mg, 3%) and identified as 6a :
1H NMR (200 MHz, CDCl3) δ 7.35 (bs, 5, H-aromatic), 5.91
(m, 2, H-3,4), 4.84, 4.61 (d, 2, J ) 12.0 Hz, PhCH2O), 4.79 (d,
1, J 1,2 ) 2.5 Hz, H-1), 4.70 (bs, 1, HO), 4.27 (bd, 1, J 5,5′ ) 16.8
Hz, H-5), 4.12 (bd, 1, H-5′); 13C NMR (50.3 MHz, CDCl3) δ
137.5, 128.6, 128.1 (C-aromatic), 129.0, 124.7 (C-3,4), 100.0 (C-
1), 70.2 (PhCH2O), 65.0 (C-2), 61.0 (C-5).
(2R)-2-Meth oxy-2H-pyr an -3(6H)-on e (4b): 77% yield (0.38
1
g). As for 4a , the ee of 4b was established from the H NMR
spectra recorded in the presence of 0.40 molar equiv of the Yb
resolving agent, which caused a splitting of the methyl group
resonance. Compound 4b (ee > 77%) had [R]D -160.5 (c 1.2,
CHCl3): 1H NMR (200 MHz, CDCl3) δ 7.04 (ddd, 1, J 4,5 ) 10.6
Hz, J 5,6 ) 1.8 Hz, J 5,6′ ) 3.7 Hz, H-5), 6.10 (dddd, 1, J 2,4 ) 0.7
Hz, J 4,6 ) 2.4 Hz, J 4,6′ ) 1.8 Hz, H-4), 4.72 (bs, 1, H-2), 4.53
(ddd, 1, J 6,6′ ) 19.0 Hz, H-6), 4.27 (ddd, 1, H-6′), 3.52 (s, 3,
OCH3); 13C NMR (50.3 MHz, CDCl3) δ 188.7 (C-3), 148.0, 124.7
(C-vinylic), 98.9 (C-2), 59.6 (C-6), 56.7 (CH3O). Anal. Calcd for
C6H8O3: C, 56.25; H, 6.29. Found: C, 55.90; H, 6.62.
Compound 5a (75 mg, 0.36 mmol) was dissolved in tert-butyl
alcohol (1.5 mL)-water (0.15 mL), and to this solution was
added N-methylmorpholine N-oxide (70 mg, 0.60 mmol). The
mixture was cooled to 0 °C and treated with a 2% (w/v) solution
(38 µL) of osmium tetroxide in tert-butyl alcohol. The mixture
was stirred at room temperature for 16 h, when TLC (EtOAc)
showed complete conversion of 5a (Rf ) 0.80) into two products
having Rf ) 0.25 and 0.18 (1:6 ratio from 1H NMR). The
solution was diluted with tert-butyl alcohol (4 mL), stirred with
solid sodium hydrogen sulfite (0.3 g), and filtered. The residue
was washed with an excess of tert-butyl alcohol, and the filtrate
and the washing liquids were pooled and concentrated. The
resulting syrup was purified by flash chromatography (EtOAc/
hexane 10:1) to afford crystalline, partially racemic benzyl â-D-
arabinopyranoside (7a , 72 mg, 82%): mp 168-169 °C (lit.19
167-169 °C); [R]D -184.0 (c 0.6, H2O); [R]D -217.0, for the
optically pure glycoside; 1H NMR (200 MHz, DMSO-d6) δ 7.34
(m, 5, H-aromatic), 4.75 (bs, 1, H-1), 4.64, 4.44 (2 d, 2, J )
12.4 Hz, PhCH2O), 3.70-3.62 (m, 5), 3.45 (dd, 1, J 4,5′ ) 2.7
Hz, J 5,5′ ) 12.0 Hz, H-5′); 13C NMR (50.3 MHz, DMSO-d6) δ
138.3, 128.4 (×2), 127.8 (×2), 127.6 (C-aromatic), 99.0 (C-1),
69.1, 68.7, 68.4 (C-2,3,4), 68.8 (PhCH2O), 63.4 (C-5).
(2S)-[(R)-2′-Octyloxy]-2H-pyr an -3(6H)-on e (4c) an d (2R)-
[(R)-2′-Octyloxy]-2H-p yr a n -3(6H)-on e (4e). The mixture of
1
4c and 4e (9.5:1 ratio from H NMR) was obtained in 84% yield
(0.74 g). Two successive purifications by column chromatog-
raphy with hexane/EtOAc 35:1 afforded the less polar enulo-
side 4c (0.60 g, 68%; de > 97%), [R]D -183.6 (c 1.0, CHCl3):
1H NMR (500 MHz, CDCl3) δ 7.05 (ddd, 1, J 4,5 ) 10.5 Hz, J 5,6
) 1.8 Hz, J 5,6′ ) 4.0 Hz, H-5), 6.13 (dddd, 1, J 2,4 ) 0.5 Hz, J 4,6
) 2.5 Hz, J 4,6′ ) 1.6 Hz, H-4), 4.93 (bs, 1, H-2), 4.58 (ddd, 1,
J 6,6′ ) 18.9 Hz, H-6), 4.27 (ddd, 1, H-6′), 3.87 (sextet, 1, HCO
octyl), 1.64-1.22 (m, 10, CH2 octyl), 1.20 (d, 3, J ) 6.5 Hz,
CH3O octyl), 0.89 (t, 3, J ) 6.6 Hz, CH3 octyl); 13C NMR (50.3
MHz, CDCl3) δ 189.1 (C-3), 147.9, 125.0 (C-vinylic), 95.7 (C-
2), 74.6 (HCO octyl), 59.7 (C-6), 37.2, 31.8, 29.3, 25.8, 22.6,
19.4, 14.1 (C-octyl). Anal. Calcd for C13H22O3: C, 68.99; H, 9.80.
Found: C, 69.30; H, 10.08.
(31) Gemal, A. L.; Luche, J .-L. J . Am. Chem. Soc. 1981, 103, 5454.
(32) Haque, E. M.; Kikuchi, T.; Kanemitsu, K.; Yoshisuke, T. Chem.
Pharm. Bull. 1987, 35, 1016.

Cycloadditions to Optically Active 2-Alkoxy-2H-pyran-3(6H)-ones
J . Org. Chem., Vol. 66, No. 26, 2001 8865
The presence of the minor component of the mixture was
(C-8a), 31.2, 28.6 (C-5,8), 19.2, 18.7 (2 CH3). Anal. Calcd for
detected in the first fractions of the column, and its structure
was assigned as benzyl R-L-ribopyranoside20 (8a ) by NMR
spectroscopy: 13C NMR (50.3 MHz, DMSO-d6) sugar ring
carbons δ 98.7 (C-1), 70.3, 69.5, 67.3 (C-2,3,4), 60.9 (C-5).
C
18H22O3: C, 75.50; H, 7.74. Found: C, 75.18; H, 8.06.
(3R,4aR,8aS)-6,7-Dim eth yl-3-m eth oxy-4a,5,8,8a-tetr ah y-
d r o-1H-2-ben zop yr a n -4(3H)-on e (9b). Cycloadduct 9b (ee
> 75%) gave [R]D +20.4 (c 1.1, CHCl3): 1H NMR (500 MHz,
CDCl3) δ 4.50 (bs, 1, H-3), 4.33 (dd, 1, J 1,8a ) 2.3 Hz, J 1,1′
)
Con ver sion of 4b in to P a r tia lly Ra cem ic Meth yl P en -
top yr a n osid es 7b a n d 8b. Compound 4b (0.394 g, 3.08 mmol)
dissolved in dry MeOH (65 mL) was reduced with NaBH4 (0.15
g, 3.97 mmol) in the presence of CeCl3‚7H2O (0.31 g, 0.83
mmol) as described for 4a . After the workup, the crude syrup,
which showed a main product by TLC (Rf ) 0.33, hexane/
EtOAc 2:1), was dissolved in a mixture of tert-butyl alcohol
(10 mL) and water (1 mL) and N-methylmorpholine N-oxide
was added (0.60 g, 5.12 mmol). The resulting solution, cooled
to 0 °C, was treated with 2% (w/v) OsO4 in tert-butyl alcohol
(0.34 mL). After stirring at room temperature for 16 h, the
mixture was processed as described for 7a , and purified by
flash chromatography (EtOAc/MeOH 10:1) to afford crystal-
line, partially racemic methyl â-D-arabinopyranoside (7b, 0.365
g, 72% from 4b). Recrystallization from ethanol gave: mp 162-
164 °C (lit.21 167-168 °C); [R]D -180.9 (c 1.1, H2O); [R]D
-240.6, for the optically pure glycoside.
The minor component of the mixture (8b) was detected in
the following fractions of the column, and its 13C NMR
spectrum was identical to that reported20 for its enantiomer
(methyl R-D-ribopyranoside).
(4a R,8a S)-6,7-Dim eth yl-3-a lk oxy-4a ,5,8,8a -tetr a h yd r o-
1H-2-ben zop yr a n -4(3H)-on es (9a -d ) a n d (4a R,8a S)-3-
Alk oxy-4a ,5,8,8a -t e t r a h yd r o-1H -2-b e n zop yr a n -4(3H )-
on es (10a ,c).
11.3 Hz, H-1), 3.51 (dd, 1, J 1′,8a ) 1.2 Hz, H-1′), 3.46 (s, 3,
CH3O), 3.24 (ddd, 1, J 4a,5 < 1 Hz, J 4a,5′ ) 6.4 Hz, J 4a,8a ) 5.4
Hz, H-4a), 2.48 (bd, 1, J 5,5′ ) 17.5 Hz, H-5), 2.37 (m, 1, H-8a),
2.23 (bdd, 1, J 8a,8 ) 12.0 Hz, J 8,8′ ) 16.3 Hz, H-8), 1.97 (bd, 1,
H-5′), 1.81 (bdd, 1, J 8a,8′ ) 6.4 Hz, H-8′), 1.68 (2 bs, 6, 2 CH3),
1.65; 13C NMR (50.3 MHz, CDCl3) δ 203.4 (C-4), 123.3, 122.8
(C-6,7), 101.0 (C-3), 63.3 (C-1), 43.2 (C-4a), 38.1 (C-8a), 31.1,
28.5 (C-5,8), 19.1, 18.6 (2 CH3). Anal. Calcd for C12H18O3: C,
68.55; H, 8.63. Found: C, 68.21; H, 8.92.
(3S,4a R,8a S)-6,7-Dim eth yl-3-[(R)-2′-octyloxy]-4a ,5,8,8a -
tetr a h yd r o-1H-2-ben zop yr a n -4(3H)-on e (9c): [R]D -39.7 (c
1.1, CHCl3); 1H NMR (500 MHz, CDCl3) δ 4.71 (bs, 1, H-3),
4.40 (dd, 1, J 1,8a ) 2.3 Hz, J 1,1′ ) 11.4 Hz, H-1), 3.84 (sextet, 1,
J ) 6.3 Hz, H-2 octyl), 3.50 (dd, 1, J 1′,8a ) 1.1 Hz, H-1′), 3.27
(ddd, 1, J 4a,5 ∼ 1 Hz, J 4a,5′ ) 6.1 Hz, J 4a,8a ) 5.3 Hz, H-4a),
2.49 (bd, 1, J 5,5′ ) 17.6 Hz, H-5), 2.38 (m, 1, J 8a,8 ) 11.8 Hz,
J 8a,8′ ) 4.6 Hz, H-8a), 2.25 (bdd, 1, J 8,8′ ) 16.5 Hz, H-8), 1.98
(bd, 1, H-5′), 1.81 (bdd, 1, H-8′), 1.65, 1.59 (2 bs, 6, 2 CH3),
1.62-1.25 (m, 10, CH2 octyl), 1.14 (d, 3, J ) 6.3 Hz, CH3-1
octyl), 0.90 (t, 3, J ) 6.0 Hz, CH3-8 octyl); 13C NMR (125 MHz,
CDCl3) δ 203.6 (C-4), 123.4, 123.0 (C-6,7), 97.6 (C-3), 73.3 (C-
2′), 63.6 (C-1), 43.3 (C-4a), 38.2 (C-8a), 37.3, 31.9, 31.2, 29.3,
28.7, 25.8, 22.7 (C-5,8 and 5 CH2 octyl), 19.2, 19.1, 18.7, 14.1
(4 CH3). Anal. Calcd for C19H32O3: C, 73.98; H, 10.46. Found:
C, 73.65; H, 10.78.
Th er m a l Cycloa d d ition Gen er a l P r oced u r e. The re-
spective dienophile 4a -c (0.25 mmol) and dry toluene (0.02
mL) were placed in a thick-walled glass tube, and hydro-
quinone (1 mg) was added. Argon was bubbled through the
solution, and upon addition of the diene, the glass tube was
sealed and heated in a sand bath at a temperature and for
the time indicated in Table 1. The reaction mixture was then
concentrated and purified by flash chromatography (1-2%
EtOAc in hexane) to afford adducts 9a -c and 10a .
Lew is Acid Ca ta lyzed Cycloa d d ition Gen er a l P r oce-
d u r e. The respective dihydropyranone 4a -d (0.24 mmol) was
weighed into a vial equipped with a magnetic stirrer and
septum seal. The anhydrous solvent (0.5 mL) was added, and
the vial was flushed with dry argon and sealed. The mixture
was cooled to -18 °C, and the Lewis acid catalyst was added.
The mixture was stirred at -18 °C for 5 min, and the flask
was placed in a bath at the temperature desired for the
cycloaddition. A solution of the diene in the dry solvent (0.6
mL) was then slowly injected, and the temperature was
maintained for the time indicated in Table 1. The reaction
mixture was diluted with ethyl ether (30 mL), except for the
reaction in CH2Cl2 in which case the same solvent was used
for the dilution. The resulting solution was washed with satd
aq NaHCO3, satd aq NaCl, dried (MgSO4), and concentrated.
The residue was purified by flash chromatography (1-2%
EtOAc in hexane) to afford the corresponding cycloadducts
9a -d and 10a ,c. The yields are reported in Table 1.
(3S,4a R,8a S)-6,7-Dim eth yl-3-[(S)-2′-octyloxy]-4a ,5,8,8a -
tetr a h yd r o-1H-2-ben zop yr a n -4(3H)-on e (9d ): [R]D -14.3 (c
0.9, CHCl3); 1H NMR (500 MHz, CDCl3) δ 4.69 (bs, 1, H-3),
4.42 (dd, 1, J 1,8a ) 2.2 Hz, J 1,1′ ) 11.3 Hz, H-1), 3.77 (sextet, 1,
J ) 6.2 Hz, H-2 octyl), 3.49 (dd, 1, J 1′,8a ) 1.2 Hz, H-1′), 3.27
(ddd, 1, J 4a,5 < 1 Hz, J 4a,5′ ) 6.3 Hz, J 4a,8a ) 5.4 Hz, H-4a),
2.49 (bd, 1, J 5,5′ ) 17.5 Hz, H-5), 2.37 (m, 1, J 8a,8 ) 11.8 Hz,
J 8a,8′ ) 4.4 Hz, H-8a), 2.24 (bdd, 1, J 8,8′ ) 17.2 Hz, H-8), 1.98
(bd, 1, H-5′), 1.80 (bdd, 1, H-8′), 1.65, 1.59 (2 bs, 6, 2 CH3),
1.63-1.24 (m, 10, CH2 octyl), 1.27 (d, 3, J ) 6.2 Hz, CH3-1
octyl), 0.88 (t, 3, J ) 6 Hz, CH3-8 octyl); 13C NMR (50.3 MHz,
CDCl3) δ 203.5 (C-4), 123.5, 123.0 (C-6,7), 99.7 (C-3), 75.7 (C-
2′), 63.6 (C-1), 43.2 (C-4a), 38.3 (C-8a), 36.5, 31.8, 31.2, 29.4,
28.7, 25.2, 22.6 (C-5,8 and 5 CH2 octyl), 21.4, 19.2, 18.8, 14.1
(4 CH3). Anal. Calcd for C19H32O3: C, 73.98; H, 10.46. Found:
C, 73.82; H, 10.57.
(3S,4a R,8a S)-3-Ben zyloxy-4a ,5,8,8a -t et r a h yd r o-1H -2-
ben zop yr a n -4(3H)-on e (10a ). Cycloadduct 10a (ee > 86%)
had [R]D -83.8 (c 1.0, CHCl3): 1H NMR (200 MHz, CDCl3) δ
7.34 (bs, 5, H-aromatic), 5.62 (m, 2, H-6,7), 4.82, 4.57 (2 d, 2,
J ) 11.7 Hz, PhCH2), 4.74 (bs, 1, H-3), 4.40 (dd, 1, J 1,8a ) 2.2
Hz, J 1,1′ ) 11.3 Hz, H-1), 3.53 (dd, 1, J 1′,8a ) 0.8 Hz, H-1′), 3.37
(bt, 1, J ∼ 5.7 Hz, H-4a), 2.62 (bd, 1, J 5,5′ ) 17.5 Hz, H-5), 2.41
(m, 1, H-8a), 2.26 (m, 1, H-8), 2.00 (m, 2, H-5′,8′); 13C NMR
(50.3 MHz, CDCl3) δ 203.0 (C-4), 136.9, 128.5, 128.1 (C-
aromatic), 124.9, 124.3 (C-6,7), 99.4 (C-3), 69.7 (PhCH2O), 63.9
(C-1), 42.7 (C-4a), 37.7 (C-8a), 24.7, 22.3 (C-5,8). Anal. Calcd
for C16H18O3: C, 74.40; H, 7.02. Found: C, 74.57; H, 7.21.
(3S,4a R,8a S)-3-[(R)-2′-Octyloxy]-4a ,5,8,8a -tetr a h yd r o-
1H-2-ben zop yr a n -4(3H)-on e (10c): [R]D -63.0 (c 1.1, CHCl3);
1H NMR (500 MHz, CDCl3) δ 5.64 (m, 2, H-6,7), 4.73 (bs, 1,
H-3), 4.42 (dd, 1, J 1,8a ) 2.2 Hz, J 1,1′ ) 11.3 Hz, H-1), 3.85
(sextet, 1, J ) 6.0 Hz, H-2 octyl), 3.49 (dd, 1, J 1′,8a ) 1.3 Hz,
H-1′), 3.34 (bt, 1, J 4a,8a ∼ J 4a,5′ ) 5.6 Hz, H-4a), 2.64 (bd, 1,
J 5,5′ ) 17.5 Hz, H-5), 2.42 (m, 1, J 8a,8 ) 11.2 Hz, H-8a), 2.27
(m, 1, J 8,8′ ) 16.8 Hz, H-8), 2.00 (m, 2, H-5′,8′), 1.62-1.32 (m,
10, CH2 octyl), 1.14 (d, 3, J ) 6.0 Hz, CH3-1 octyl), 0.91 (t, 3,
J ) 6.0 Hz, CH3-8 octyl); 13C NMR (50.3 MHz, CDCl3) δ 203.5
(C-4), 124.9, 124.3 (C-6,7), 97.6 (C-3), 73.3 (C-2′), 63.9 (C-1),
42.7 (C-4a), 37.7 (C-8a), 37.3, 31.9, 29.3, 25.8, 24.7, 22.7, 22.3
(C-5,8 and 5 CH2 octyl), 19.3, 14.2 (2 CH3 octyl). Anal. Calcd
for C17H28O3: C, 72.82; H, 10.06. Found: C, 73.09; H, 10.25.
P r ep a r a tive Syn th esis of 9a u n d er Th er m a l Con d i-
tion s. Isola tion of Isom er ic (3S,4a S,8a R)-6,7-Dim eth yl-
For the preparation of 9c,d and 10c, the optically pure
dihydropyranones 4c and 4d have been employed. The enan-
tiomeric composition of 9a ,b and 10a was established by 1H
NMR experiments with ytterbium tris[3-(heptafluoropropyl-
hydroxymethylene)-(+)-camphorate].
(3S,4a R,8a S)-6,7-Dim et h yl-3-b en zyloxy-4a ,5,8,8a -t et -
r a h yd r o-1H-2-ben zop yr a n -4(3H)-on e (9a ). The adduct 9a
(ee > 86%) gave [R]D -49.7 (c 1.1, CHCl3): 1H NMR (500 MHz,
CDCl3) δ 7.34 (bs, 5, H-aromatic), 4.81, 4.57 (2 d, 2, J ) 11.5
Hz, PhCH2), 4.71 (bs, 1, H-3), 4.40 (dd, 1, J 1,8a ) 2.2 Hz, J 1,1′
) 11.2 Hz, H-1), 3.53 (dd, 1, J 1′,8a ) 1.1 Hz, H-1′), 3.30 (ddd, 1,
J 4a,5 < 1 Hz, J 4a,5′ ) 6.5 Hz, J 4a,8a ) 5.6 Hz, H-4a), 2.48 (bd, 1,
J 5,5′ ) 17.4 Hz, H-5), 2.37 (m, 1, H-8a), 2.24 (bdd, 1, J 8a,8
)
11.5 Hz, J 8,8′ ) 17.2 Hz, H-8), 1.96 (bd, 1, H-5′), 1.81 (bdd, 1,
H-8′), 1.64, 1.58 (2 bs, 6, 2 CH3); 13C NMR (125 MHz, CDCl3)
δ 203.2 (C-4), 137.0, 128.5, 128.1 (C-aromatic), 123.4, 123.0
(C-6,7), 99.4 (C-3), 69.7 (PhCH2O), 63.7 (C-1), 43.2 (C-4a), 38.2

8866 J . Org. Chem., Vol. 66, No. 26, 2001
Iriarte Capaccio and Varela
3-ben zyloxy-4a,5,8,8a-tetr ah ydr o-1H-2-ben zopyr an -4(3H)-
on e (11a ). The general procedure for thermal cycloadditions
was followed starting from 4a (0.94 g, 4.60 mmol), hydro-
quinone (18 mg), and dry toluene (0.37 mL). After addition of
2,3-dimethyl-1,3-butadiene (1.42 g, 17.3 mmol), the mixture
was heated in a sealed tube, under argon, at 120 °C for 168 h.
The resulting mixture was concentrated and the residue flash
chromatographed with 1.5% EtOAc in hexane. From fractions
containing the product of Rf ) 0.68 (hexane/EtOAc 6:1) was
isolated the cycloadduct 9a (0.67 g, 51%).
Ep im er iza tion of 11a . Compound 11a (20 mg) was dis-
solved in 0.05 M sodium ethoxide in ethanol (2 mL) and the
solution stirred at room temperature for 30 min. Monitoring
of the mixture by TLC (hexane/EtOAc 6:1) showed complete
conversion of 11a (Rf ) 0.52) into a less polar product (Rf )
0.69). The solution was neutralized with acetic acid in ethanol
and concentrated. Flash chromatography with 1.5% EtOAc in
hexane afforded 12a : 1H NMR (500 MHz, CDCl3) δ 7.35 (bs,
5H-aromatic), 4.81, 4.58 (2 d, 2, J ) 11.7 Hz, PhCH2O), 4.76
(bs, 1, H-3), 3.94 (t, 1, J 1,1′ ) 11.3 Hz, J 1,8a ∼ 11.0 Hz, H-1),
3.69 (dd, 1, J 1′,8a ) 4.5 Hz, H-1′), 2.78 (ddd, 1, J 4a,5 ) 12.4 Hz,
J 4a,5′ ) 5.1 Hz, J 4a,8a ) 11.0 Hz, H-4a), 2.21 (bt, 1, J 5,5′ ) 17.7
Hz, H-5), 2.16 (ddddd, 1, J 8a,8 ) 11.0 Hz, J 8a,8′ ) 8.2 Hz, H-8a),
2.03 (bdd, 1, H-5′), 1.88 (bd, 2, H-8,8′), 1.64, 1.60 (2 bs, 6, 2
CH3); 13C (50.3 MHz) δ 203.6 (C-4), 137.0, 128.6, 128.0
(C-aromatic), 124.7, 123.2 (C-6,7), 99.3 (C-3), 69.6 (PhCH2O),
64.2 (C-1), 45.8 (C-4a), 41.4 (C-8a), 33.8, 29.2 (C-5,8), 19.1, 18.8
(2 CH3).
From further fractions of the column was isolated a second
cycloaddition product, having Rf ) 0.52. It was characterized
as 11a (26.6 mg, 2%): [R]D -11.6 (c 1.1, CHCl3); 1H NMR (500
MHz, CDCl3) δ 7.35 (bs, 5, H-aromatic), 4.82, 4.61 (2 d, 2, J )
12.1 Hz, PhCH2), 4.76 (bs, 1, H-3), 4.02 (dd, 1, J 1,8a ) 7.8 Hz,
J 1,1′ ) 11.4 Hz, H-1), 3.69 (dd, 1, J 1′,8a ) 4.3 Hz, H-1′), 2.83
(dd, 1, J 4a,5 ∼ J 4a,8a ) 6.2 Hz, J 4a,5′ ∼ 6.0 Hz, H-4a), 2.73 (bdd,
1, J 5,5′ ) 16.5 Hz, H-5), 2.51 (m, 1, H-8a), 2.08 (bdd, 1, J 8,8a
)
5.1 Hz, J 8,8′ ) 17.4 Hz, H-8), 1.93 (m, 2, H-5′,8′), 1.62, 1.58 (2
bs, 6, CH3); 13C NMR (50.3 MHz, CDCl3) δ 204.0 (C-4), 137.1,
128.5, 127.9, 122.9 (C-aromatic, C-6,7), 98.9 (C-3), 69.9
(PhCH2O), 63.3 (C-1), 45.7 (C-4a), 35.6 (C-8a), 32.0, 28.4 (C-
5,8), 19.0, 18.8 (2 CH3). Anal. Calcd for C18H22O3: C, 75.50;
H, 7.74. Found: C, 75.20; H, 8.09.
P r ep a r a tive Syn th esis of 9a a n d 9c u n d er Ca ta lysis
w ith Et2O‚BF 3. To a solution of 4a (0.95 g, 4.65 mmol) in dry
toluene (10 mL) cooled to -18 °C was added Et2O‚BF3 (584
µL, 4.65 mmol) under argon. The flask was sealed with a
septum, and after 5 min, a solution of 2,3-dimethy-1,3-
butadiene (1.14 g, 13.9 mmol) in dry toluene (10 mL) was
slowly injected. The mixture was stirred at -18 °C for 15 min,
and then it was processed as described in the general proce-
dure and flash chromatographed with 1.5% EtOAc in hexane,
affording the cycloadduct 9a (1.09 g, 82%).
Compound 9a was subjected to the same treatment, but it
was isolated from the reaction mixture without any change
(identical Rf and spectral data).
Ack n ow led gm en t. This work was supported by
grants from the Universidad de Buenos Aires (Project
TW70) and ANPCyT (National Agency for Promotion
of Science and Technology, PICT 01698). We thank
UMYMFOR-CONICET for the microanalyses, and Drs.
K. Kover and L. Szilagyi (University of Debrecen,
Hungary) for the ROESY spectrum of 9c. O.V. is a
Research Member of the National Research Council
(CONICET).
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra for
4a , 9a , 9c; 13C and DEPT NMR spectra for 9a ; 2D COSY and
ROESY NMR spectra for 9c. This material is available free of
charge via the Internet at http://pubs.acs.org.
Under the same conditions, enantiomerically pure 4c (0.42
g, 1.86 mmol) afforded 9c (0.45 g, 79%) after chromatographic
purification. Compounds 9a and 9c showed the same proper-
ties as the respective products isolated in small-scale synthe-
ses.
J O0106896