Stereocontrolled Diels - Alder cycloadditions of sugar-derived dihydropyranones with dienes

Article abstract of DOI:10.1021/jo020309w

2-Acetoxy-3,4-di-O-acetyl-D-arabinal (6), similar to its D-xylo analogue 4, reacted with benzyl alcohol by the tin(IV) chloride-promoted glycosylation to produce optically active (S)-2-benzyloxy-2H-pyran-3(6H)-one (8a). The L-arabinal derivative (5) gave 9a, the dihydropyranone enantiomer of 8a. These results indicated that the configuration of the C-4 stereocenter in the starting glycal defines the configuration of the new chiral center in the resulting dihydropyranone. The influence of other catalysts (BF₃ or iodine) employed for the glycosylation on the optical purity of the dihydropyranone was studied. Enantiomerically pure dihydropyranones 8b and 9c were obtained using chiral alcohols ((R)- and (S)-2-octanol, respectively) as glycosylating agents. Compounds 8a,b and 9a,c proved to be reactive dienophiles in thermal and Lewis acid-promoted Diels - Alder reactions. The addition of 2,3-dimethylbutadiene, cyclopentadiene, and 1,3-cyclohexadiene to the β-pyranones 8a,b led to the corresponding adducts 10a,b, 12a,b, and 16a,b as major products. Enantiomeric cycloadducts were synthesized from the α-pyranones 9a,c. The main products were formed by highly facial-diastereoselective addition of dienes to the pyranone ring, guided by the sterical hindrance of the alkoxy substituent of the C-2 stereocenter. As cycloadditions with cycloalkadienes were also highly endo diastereoselective, these reactions gave access to pure tetrahydrobenzopyranones that carry a multitude of stereogenic centers installed in a predictable way.

Full text of DOI:10.1021/jo020309w

Ster eocon tr olled Diels-Ald er Cycloa d d ition s of Su ga r -Der ived
Dih yd r op yr a n on es w ith Dien es
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, Pabello´n 2-Ciudad Universitaria, 1428, Buenos Aires, Argentina
varela@qo.fcen.uba.ar
Received May 2, 2002
2-Acetoxy-3,4-di-O-acetyl-D-arabinal (6), similar to its D-xylo analogue 4, reacted with benzyl alcohol
by the tin(IV) chloride-promoted glycosylation to produce optically active (S)-2-benzyloxy-2H-pyran-
3(6H)-one (8a ). The L-arabinal derivative (5) gave 9a , the dihydropyranone enantiomer of 8a . These
results indicated that the configuration of the C-4 stereocenter in the starting glycal defines the
configuration of the new chiral center in the resulting dihydropyranone. The influence of other
catalysts (BF3 or iodine) employed for the glycosylation on the optical purity of the dihydropyranone
was studied. Enantiomerically pure dihydropyranones 8b and 9c were obtained using chiral alcohols
((R)- and (S)-2-octanol, respectively) as glycosylating agents. Compounds 8a ,b and 9a ,c proved to
be reactive dienophiles in thermal and Lewis acid-promoted Diels-Alder reactions. The addition
of 2,3-dimethylbutadiene, cyclopentadiene, and 1,3-cyclohexadiene to the â-pyranones 8a ,b led to
the corresponding adducts 10a ,b, 12a ,b, and 16a ,b as major products. Enantiomeric cycloadducts
were synthesized from the R-pyranones 9a ,c. The main products were formed by highly facial-
diastereoselective addition of dienes to the pyranone ring, guided by the sterical hindrance of the
alkoxy substituent of the C-2 stereocenter. As cycloadditions with cycloalkadienes were also highly
endo diastereoselective, these reactions gave access to pure tetrahydrobenzopyranones that carry
a multitude of stereogenic centers installed in a predictable way.
In tr od u ction
pyran-5(6H)-ones,6 2-alkoxy-4-O-benzoyl-6-benzoyloxy-
methyl-2H-pyran-3(6H)-ones (enolones),7 levoglucose-
none,8 and isolevoglucosenone,9 have been conducted in
order to obtain optically pure carbocyclic derivatives.
In contrast with cyclohexenone derivatives10 and sugar
enolones7 that displayed low dienophilicity, the dihydro-
pyranones derived from D-xylal were excellent dieno-
philes toward butadienes.5 Furthermore the cycloaddi-
tions took place with high diastereofacial selectivity, with
the stereocontrol exerted by the chiral center of the
dihydropyranone. Therefore, as an extension of the
previous work, we report here the synthesis of the
enantiomeric (2R)- and (2S)-2-alkoxy-2H-pyran-3(6H)-
ones, as a way to control the facial diastereoselection of
the cycloaddition. For thermal and Lewis acid promoted
reactions of dihydropyranone dienophiles with cycloalka-
dienes the endo/exo diastereoselectivity was also estab-
lished, to determine the level of stereocontrol attainable.
Optically active dihydropyranones derived from com-
mon sugars are useful chiral templates for the synthesis
of natural products and their analogues.1 We have
reported a practical and large-scale procedure for the
synthesis of 6-acyloxymethyl dihydropyranones from
2-acyloxy-hex-1-enitol (glycal) derivatives.2 Due to the
highly stereoselective nature of addition reactions to such
chiral enones, they have been employed as precursors of
the diamino tetradeoxy sugars component of antibiotics3
and for the preparation of modified glycosides.4 We have
also described recently a convenient synthesis of 2-alkoxy-
2H-pyran-3(6H)-ones starting from D-xylose,5 and proved
their usefulness as dienophiles in Diels-Alder reactions
with butadienes. In fact, [4+2] cycloadditions of a number
of structurally related pyranones, such as 2-alkoxy-2H-
(1) (a) Lichtenthaler, F. W.; Nishiyama, S.; Weimer, T. Liebigs Ann.
Chem. 1989, 1163. (b) Lichtenthaler, F. W. Modern Synthetic Methods;
Scheffold, R., Ed.; VCH Publishers: Weinheim/New York, 1992; Vol.
6, p 273. (c) Lichtenthaler, F. W. Natural Products Chemistry; Atta-
ur-Rahman, Ed.; Springer: New York, 1986; p 227. (d) Fraser-Reid,
B. Acc. Chem. Res. 1996, 29, 57.
(2) De Fina, G. M.; Varela, O.; Lederkremer, R. M. Synthesis 1988,
891.
(3) (a) Iriarte Capaccio, C. A.; Varela, O. Tetrahedron: Asymmetry
2000, 11, 4945. (b) Zunszain, P. A.; Varela, O. Tetrahedron: Asymmetry
1998, 9, 1269.
(6) (a) Fraser-Reid, B.; Underwood, R.; Osterhout, M.; Grossman,
J . A.; Liotta, D. J . Org. Chem. 1986, 51, 2152. (b) Primeau, J . L.;
Anderson, R. C.; Fraser-Reid, B. J . Chem. Soc., Chem. Commun. 1980,
6. (c) J urczak, J .; Tkacz, M. Synthesis 1979, 42.
(7) Dauben, W. G.; Kowalczyk, B. A.; Lichtenthaler, F. W. J . Org.
Chem. 1990, 55, 2391.
(8) (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.
(9) Horton, D.; Roski, J . P.; Norris, P. J . Org. Chem. 1996, 61, 3783.
(10) (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.
(4) Varela, O.; De Fina, G. M.; Lederkremer, R. M. Carbohydr. Res.
1993, 246, 371.
(5) Iriarte Capaccio, C. A.; Varela, O. J . Org. Chem. 2001, 66, 8859.
10.1021/jo020309w CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/09/2002
J . Org. Chem. 2002, 67, 7839-7846
7839

Iriarte Capaccio and Varela
SCHEME 1a
TABLE 1. P r ep a r a tion of Dih yd r op yr a n on es 8a a n d 9a
starting
glycal
catalyst
(mol equiv)
temp time yield
ee
(%)
(°C) (min)
(%)
[R]D
4
5
6
4
6
4
SnCl4 (1.3)
SnCl4 (1.3)
SnCl4 (1.3)
Et2O‚BF3 (2.0)
Et2O‚BF3 (2.0)
I2 (1.0)
-18
-18
-18
5
5
25
30
30
30
30
30
45
85
81
83
82
81
75
-200.6 >86
+200.3 >86
-200.4 >86
-210.8 >91
-211.2 >91
-167.9 >72
SCHEME 2a
a
Reagents and conditions: (i) Ac2O, C5H5N, 0 °C, 16 h; (ii) 32%
HBr/AcOH, 0 °C, 1 h; (iii) DBU, -18 °C, 20 min.
Resu lts a n d Discu ssion
2-Acetoxy-3,4-di-O-acetylglycal derivatives 4, 5, and 6,
the key precursors of dihydropyranones, were readily
prepared starting from the per-O-acetyl derivatives of
pentopyranoses 1, 2, and 3. Further conversion of the
peracetates into the corresponding glycosyl bromides,
followed by 1,8-diazabycyclo[5.4.0]undec-7-ene (DBU)-
promoted elimination of hydrogen bromide, afforded the
glycal derivatives 4-6 (Scheme 1). The conformational
preference for the enantiomeric compounds 5 and 6 was
1
deduced from their H NMR spectra. The large value for
the coupling constant between H-4 and H-5′ (10.2 Hz)
indicated a quasidiaxial disposition for these protons,
compatible with a 5H4 conformation for 5 (4H5 for 6).
Similar conformations were found for the D-xylal deriva-
tive 4,5 and for the 2-unsubstituted analogues of 4 and
6.11 For the latter compounds an entropy contribution has
been assessed to determine the equilibrium position
between the two half-chair forms.11 Also, stabilizing
nonbonded interactions12 (“allylic effect”) have been
invoked to account for the preference for one of the
conformers.
The glycal derivatives 4-6, as well as glycals derived
from hexoses,2 underwent a highly facial-diastereoselec-
tive tin(IV) chloride-promoted glycosylation, which is
accompanied by a double allylic rearrangement. This
way, glycal 4 reacted with benzyl alcohol to give the
optically active dihydropyranone 8a , having the â ano-
meric configuration.5 To obtain the enantiomeric R-di-
hydropyranone, and to assess the influence of the C-3
and C-4 configuration of the starting glycal on the
stereochemical course of the reaction, the glycosylation
of glycals 5 and 6 was conducted. As shown in Table 1,
the configuration of C-3 does not influence the stereo-
chemistry at C-1, since the derivatives of D-xylal (4) and
D-arabinal (6), which have opposite configurations at C-3,
afforded the same dihydropyranone 8a with identical
optical purity. However, the pyranone 9a (enantiomer of
8a ) could be readily obtained, as expected, from glycal 5
(enantiomer of 6). Therefore, the stereocenter at C-4
seems to direct the addition of the alcohol to C-1. This
result may be justified by assuming the formation of a
carbocation during the acid-promoted elimination of the
a
Reagents and conditions: (i) SnCl4, -18 °C, 30 min.
3-acetoxy group (Scheme 2). Such a carbocation, probably
stabilized by participation of the oxygen ring lone pair,
could shift its conformation to locate the allylic acetoxy
group at C-4 in the preferred axial orientation11,12 (“allylic
effect”). Hence, the nucleophilic addition of the alcohol
should be induced to occur preferentially from the op-
posite face, accounting for the stereochemistry at C-1 of
the intermediate enopyranoside (7a , when starting from
4). Such an intermediate could be isolated in some cases,
as explained later. The enopyranoside 7a (or its enanti-
omer when starting from 5) underwent a second allylic
rearrangement, which does not involve C-1, to give the
final product 8a (or 9a ). The enantiomeric composition
of 8a and 9a was established, as previously described,5
by means of NMR experiments conducted with chiral
lanthanide shift reagents. Thus, the enantiomeric ex-
cesses determined for 8a and 9a were higher than 86%
(ee >86%).
On the basis of the mechanism proposed we assumed
that isolating the enopyranoside (7a ), postulated as an
intermediate, could increase the optical purity of the
dihydropyranones. The stereocenter at C-4 of the enopy-
ranoside is maintained during the addition of the alcohol
to C-1, hence affording a mixture of anomers that may
be separated by standard procedures. However, 7a could
(11) Rico, M.; Santoro, J . Org. Magn. Reson. 1976, 8, 49.
(12) Chalmers, A. A.; Hall, R. H. J . Chem. Soc., Perkin Trans. 2
1974, 728.
7840 J . Org. Chem., Vol. 67, No. 22, 2002

Cycloadditions of Sugar-Derived Dihydropyranones with Dienes
SCHEME 3
not be isolated when tin(IV) chloride was employed as
catalyst under the usual reaction conditions, and the
dihydropyranone 8a was always the lone product ob-
tained.
Boron trifluoride etherate promoted also the reaction
of 4 or 6 with benzyl alcohol to give 8a . This catalyst was
less effective than tin(IV) chloride; therefore, higher
concentrations of BF3 and higher temperatures were
required for completion of the reaction.
We observed that the structure of the starting glycal
has incidence in the reactivity; thus, under the same
Lewis acid-catalyzed conditions, glycal 4 reacted more
rapidly than glycals 5 and 6. This behavior may be
attributed to the 4-acetoxy group in 4, which being
disposed anti to the C-3-O linkage, facilitates the
rupture of this bond by anchimeric participation. Simi-
larly, it has been reported that glycals derived from
hexoses having a trans arrangement for the substituents
at C-3 and C-4 take part in allylic rearrangements much
more readily than do those with a cis disposition of such
groups.13
On the other hand, iodine and electrophilic iodine
releasing agents have been widely used for the anomeric
activation of glycals.14 We have found that an alkyl
2-enopyranoside was the major product in the N-iodosuc-
cinimide-mediated glycosylation of glycals derived from
hexoses.15 Therefore, the iodine-promoted glycosylation
of 4-6 was attempted. The reaction led to somewhat
lower yields and poorer optical purity of 8a and 9a than
those obtained under catalysis by Lewis acids. Further-
more, it was observed that the reaction proceeded more
rapidly when conducted in the presence of higher con-
centrations of iodine or in polar solvents (acetonitrile >
dichloromethane > toluene). In particular, when the
reaction of 4 in acetonitrile was conducted in the presence
of 0.07 equiv of iodine (instead of 1 equiv) the elusive
enopyranoside 7a was detected by TCL. However, the
attempted chromatographic purification by column chro-
matography was not practical as 7a and its R anomer
had similar chromatographic mobility in a number of
solvents. Thus, compound 7a could be isolated in low
yield (∼20%) as an 8:1 mixture of â and R anomers, as
indicated by the NMR spectra. Interestingly, the ano-
meric composition of the mixture was in agreement with
the enantiomeric ratio determined for the dihydropyra-
none 8a , which is produced from 7a .
under thermal and Lewis acid-catalyzed conditions.5
Their reactivity, compared with that of common cyclo-
hexenones, was probably enhanced by the presence of an
oxygen atom in the six-membered ring.6a,7 Furthermore,
cycloadditions were highly diastereoselective, as a result
of the steric hindrance exerted by the axially oriented
alkoxy substituent (in the preferred E0 conformation5 of
8a ,b) on one of the faces of the double bond. Thus, the
C-2 configuration of 8a ,b controls the configuration of the
stereocenters (C-4a and C-8a) generated in the cycload-
dition of butadienes. This way, as 8a and 9a have
opposite configuration at C-2, the addition of a diene
should lead to enantiomeric cycloadducts. As expected,
boron trifluoride diethyl etherate-catalyzed addition of
2,3-dimethylbutadiene to 9a , under the optimized condi-
tions established for 8a ,5 led to the cycloadduct 11a , the
enantiomer of 10a (Scheme 3). The coincidence in the
absolute value of the optical rotation of both products
indicated that they possess the same optical purity (ee
>86%). To synthesize the enantiomerically pure cycload-
duct 11c, the dihydropyranone 9c (enantiomer of 8b) was
employed as the dienophile. The resulting tetrahydroben-
zopyranone 11c was the enantiomer of 10b.
Cycloadditions of cyclopentadiene and 1,3-cyclohexa-
diene with 2-alkoxy-2H-pyran-3(6H)-ones were conducted
to extend their use as dienophiles in the construction of
more complex chiral carbocycles. The resulting cycload-
ducts will carry in their structures four new stereo-
centers. The dihydropyranone 8a was used as a model
dienophile and the Diels-Alder additions were performed
under thermal conditions and boron trifluoride catalysis.
Reaction conditions which led to good yields of adducts
are shown in Table 2. Cycloadditions of 8a with cyclic
dienes, as with butadienes, were highly diastereofacial
selective, with a remarkable preference for the addition
of the cyclic diene (guided by the C-2 anomeric substitu-
ent) from the R face of the dihydropyranone. Addition of
cyclopentadiene to 8a gave the R-endo adduct 12a as the
main product, and the isomers 13a (R-exo) and 14a (â-
endo) were isolated in low yields (Scheme 4). Starting
from 9a (enantiomer of 8a ) the cycloadduct 15a (enan-
tiomer of 12a ) was obtained as the major product.
Cyclohexadiene was less reactive than cyclopentadiene
toward dihydropyranones as cycloadditions, under ther-
mal conditions or Lewis acid catalysis, required higher
temperatures and longer reaction times. Thermal Diels-
Alder reaction of 8a with 1,3-cyclohexadiene afforded
In view of the results discussed above, and taking into
account that the enantiomerically pure dihydropyranone
8b had been successfully prepared with (R)-2-octanol as
glycosylating agent under Lewis acid catalysis,5 the
synthesis of 9c, the enantiomer of 8b, was attempted.
For this purpose (S)-2-octanol was employed for the tin-
(IV) chloride-promoted glycosylation of 5. After purifica-
tion by column chromatography, compound 9c exhibited
identical spectral properties as 8b and a diastereomeric
excess higher than 97% (de >97%).
Dihydropyranones 8a ,b proved to be useful as dieno-
philes for Diels-Alder cycloadditions with butadienes,
(13) Ferrier, R. J .; Prasad, N.; Sankey, G. H. J . Chem. Soc. (C) 1968,
974.
(14) Vaino, A. R.; Szarek W. A. Adv. Carbohydr. Chem. Biochem.
2001, 56, 9.
(15) Varela, O.; De Fina, G. M.; Lederkremer, R. M. Carbohydr. Res.
1987, 167, 187.
J . Org. Chem, Vol. 67, No. 22, 2002 7841

Iriarte Capaccio and Varela
TABLE 2. Diels-Ald er Rea ction s of Dih yd r op yr a n on e 8a w ith Cyclic Dien es u n d er Th er m a l a n d Et2O‚BF 3 Ca ta lyzed
Con d ition s
mol equiv of
Et2O‚BF3
temp
(°C)
time
(h)
dra
R/â endo
dra
endo/exo
yield of
diene (mol equiv)
adductsb
cyclopentadiene (3.4)
1,3-cyclohexadiene (11.2)
cyclopentadiene (2.0)
1,3-cyclohexadiene (12.7)
90
130
-18
0
96
21.4:1
10.9:1
18.7:1
3.3:1c
10.1:1
>30:1
13.4:1
>30:1
79
70
64
68
110
0.25
0.75
1.0
1.0
a
1
b
The diastereomeric ratio (dr) was calculated from the H NMR spectrum of the crude reaction mixture. Yield of adducts after isolation
by flash chromatography. c Includes also the isomerization product 18a (see text).
SCHEME 4
SCHEME 5
employed for the cycloaddition. Monitoring of the mixture
by TLC showed the gradual conversion of 16a into a more
polar product having the same mobility as 17a . Moreover,
the spectra of the reaction mixture evidenced the pres-
ence of both 16a and the isomerization product 18a ,
which is spectroscopically identical with 17a . The Lewis
acid seems to promote the isomerization of 16a to 18a
under the higher temperature and longer times required
for the BF3-catalyzed cycloaddition of 8a with 1,3-
cyclohexadiene (compared with those employed for cy-
clopentadiene). The isomerization of the R-endo adduct
was further proved, as explained later, by addition of 1,3-
cyclohexadiene to pyranone 8b. This reaction led to the
diastereomeric adducts 17b and 18b (the respective
analogues of 17a and 18a ) which could be isolated and
characterized.
Cycloadditions of cyclopentadiene and 1,3-cyclohexa-
diene to 8a were also highly endo diastereoselective, as
predicted by the Alder endo rule.16 For example, in the
reaction of 8a with 1,3-cyclohexadiene the formation of
exo adducts was negligible. The endo stereoselectivity has
been rationalized satisfactorily in terms of interplay of
stabilizing secondary interactions and steric effects be-
tween diene and dienophile in the endo transition state.17
The structure of cycloadducts 12a -17a was deter-
mined on the basis of their NMR spectra as well as by
2D NMR experiments. As reported for related systems,7
the R or â facial annulation of the carbocyclic portion onto
the pyranone ring was clearly revealed by the coupling
constants of H-1 and H-1′ to the vicinal H-8a. In two of
the isomers (12a and 13a ) the relatively small J values
mainly the R-endo adduct 16a , the analogue of 12a ,
together with the â-endo diastereomer (17a ) (Scheme 5).
The observed proportion of the latter compound (17a ) was
remarkably increased in the boron trifluoride-promoted
reaction, indicating an apparently poor stereoselection
for the addition of the diene to 8a . However, in this case,
compound 17a exhibited an optical rotation value op-
posite in sign to that of the same product obtained under
thermal conditions. The unexpected change in its optical
rotation could be justified if we assume that, under the
Lewis acid catalysis, the acetal carbon (C-3) of the R-endo
adduct 16a undergoes isomerization to produce 18a , the
enantiomer of 17a . This way, the partial conversion of
16a into 18a would result in an apparent increment of
17a and in a modification of its optical rotation. To
confirm the proposed isomerization, compound 16a was
treated with boron trifluoride, under the conditions
(16) Alder, K.; Stein, G. Angew. Chem. 1937, 50, 510.
(17) (a) Gleiter, R.; Bohm, M. C. Pure Appl. Chem. 1983, 55, 237.
(b) Ginsburg, D. Tetrahedron 1983, 39, 2095.
7842 J . Org. Chem., Vol. 67, No. 22, 2002

Cycloadditions of Sugar-Derived Dihydropyranones with Dienes
indicated that the C-H-8a bond bisects the angle of the
H-1-C-H-1′ group, an arrangement characteristic of
R-adducts. In contrast, the isomer 14a showed a large J
value between H-8a and H-1′, consistent with a diaxial
orientation of such protons, as expected for a â-adduct.
The endo/exo assignments were aided greatly by NMR
data reported for adducts of cycloalkadienes with 2-cy-
clohexenones18,19 and enolones.7 The δ values of the
olefinic protons (H-6 and H-7) were diagnostic of the
stereochemistry of the cycloadducts. Two of the isomers
(12a and 14a ) showed larger shift differences for H-6 and
H-7, compared with that of 13a . The magnetic similarity
for the vinylic protons in 13a is consistent with the
absence of any shielding effects exerted by the pyranoid
ring or its substituents, as expected for an exo adduct.
In contrast, the olefinic protons in the endo adducts 12a
and 14a are relatively closer to the pyranoid ring, and
its anisotropy induces larger chemical shift differences
between H-6 and H-7. Furthermore, the chemical shift
of the protons of the fused rings (H-4a and H-8a) is
stereochemistry dependent. Such protons appeared
strongly shielded in the exo compound (as they are facing
the double bond that exerts its shielding effect) and
deshielded in the endo products (because of the removal
of the anisotropy of the olefinic bond). Similar anisotropic
effects on H-1ax and H-3 in 12a -14a supported the
assignment of the R or â and endo/exo orientation of the
carbocycle. Thus H-1ax, which is facing the π bond in
the â-endo isomer 14a , resonates upfield (∼1 ppm)
compared to H-1ax in 12a and 13a , where such a proton
is located far away from the double bond. The pattern of
signals in the endo and exo adducts of levoglucosenone
with cyclopentadiene was similar to those of 12a and 13a ,
respectively.8
The foregoing assignments agreed with chemical shift
data obtained from the 13C NMR spectra of the adducts.
Thus, the carbon signal of the 5,8-methano bridge (C-9)
is much more shielded (∼4 ppm) in the exo adduct (13a )
than in the endo products (12a and 14a ). Also, the C-1
signal is shifted upfield (∼2 ppm) in 12a compared with
13a , as described for endo isomers and their exo coun-
terparts.19
A similar spectroscopic analysis was performed for the
structural assignment of the cycloadducts derived from
8a and 1,3-cyclohexadiene. The configuration of the C-4a
and C-8a of the two isomers, which resulted from the
addition of the diene to the R-face (16a ) or from the â-face
(17a ) of the pyranone, was readily deduced, as for the
cyclopentadiene products, on the basis of the magnitude
of the coupling constants between H-1 and H-1′ with
H-8a. The endo stereochemistry for 16a and 17a was
assigned taking into account characteristic chemical
shifts of certain signals (H-6, H-7, H-4a, H-8a, etc).
Finally, the structural assignments of the adducts 12a -
14a and 16a ,17a were confirmed by NOESY experi-
ments.20 The observed cross-peaks in the NOESY spectra
of 12a -14a were fully consistent with the structures
previously proposed. The stereochemistry of 16a and 17a
was also firmly established by diagnostic cross-peaks in
their spectra. For example, cross-peaks between the
interacting 1,3-disposed protons H-4a with H-1′ax and
H-10, and H-8a with H-9 clearly defined the R-endo
configuration of 16a ; whereas the cross-peaks between
H-1eq and H-8, H-8a with H-9, and H-4a with H-10 were
indicative of a â-endo structure for 17a .
The optically active cycloadducts 12a -14a and 16a
exhibited the same enantiomeric purity (>86%) as their
precursor pyranone 8a . To obtain enantiomerically pure
Diels-Alder products, thermal and Et2O‚BF3-promoted
reactions were conducted starting from the optically pure
dihydropyranones 8b and 9c and cyclopentadiene. Thus,
optically pure cycloadducts 12b and 14b were synthe-
sized from 8b, whereas the endo cycloadduct 15c (enan-
tiomer of 12b) was obtained from 9c (enantiomer of 8b).
As for reactions with 2,3-dimethylbutadiene, the C-2
stereocenter of the starting dihydropyranone (8b or 9c)
efficiently controlled the facial addition of the diene, and
together with the high endo selectivity afforded good
yields of the corresponding major adducts (12b and 15c)
having opposite configuration for all the stereocenters.
The structure of the enantiomerically pure compounds
12b and 15c was established from their NMR spectra
that greatly resemble to those of the analogous 3-benzyl-
oxy-5,8-methano-1H-2-benzopyran-4(3H)-one 12a and
15a .
Similar to the reaction with cyclopentadiene, the
addition of 1,3-cyclohexadiene to 8b under thermal
conditions afforded the R-endo adduct (16b) as the main
product. However, the same reaction promoted by a
Lewis acid brought additional evidence of the isomeriza-
tion of the C-3 acetal stereocenter of 16b, similar to that
observed for 16a . Thus, isomerization of the R-endo
adduct 16b afforded 18b, which has the opposite config-
uration for all the chiral centers compared to 17b, except
for that of the alkoxy substituent which is R in both
compounds. Therefore, in contrast with 17a and 18a (its
enantiomeric isomerization product), the diastereomeric
adducts 17b and 18b could be separated by column
chromatography. Although their 1H NMR spectra were
very similar, the 13C NMR spectrum of 17b showed
distinctive signals for C-3 and for the carbons located
near the stereocenter in the alkoxy chain of 18b, whereas
the signals for the carbocycle backbone remained un-
changed. Finally, as described for 16a , compound 16b
gradually converted into 18b when exposed to a solution
of the Lewis acid.
In summary, in this work we reported the synthesis,
starting from readily accessible glycal derivatives, of both
optically active (2R)- and (2S)-benzyloxydihydropyra-
nones. The enantiomerically pure analogues were ob-
tained using chiral alcohols as glycosylating agents of the
glycals. The dihydropyranones were employed as reactive
dienophiles in Diels-Alder reactions with 2,3-dimethyl-
butadiene, cyclopentadiene, and 1,3-cyclohexadiene, un-
der thermal and Lewis acid-promoted conditions. The
cycloadditions were highly facial and endo diastereo-
selective, providing a straightforward access to both
enantiomers of carbocycles that possess a number of
stereocenters, which can be generated with remarkable
stereocontrol.
(18) Fringuelli, F.; Guo, M.; Minuti, L.; Pizzo, F.; Taticchi, A.;
Wenkert, E. J . Org. Chem. 1989, 54, 710.
(19) Angell, E. C.; Fringuelli, F.; Guo, M.; Minuti, L.; Taticchi, A.;
Wenkert, E. J . Org. Chem. 1988, 53, 4325.
(20) (a) Bodenhausen, G.; Ernst, R. R. J . Am. Chem. Soc. 1982, 104,
1304. (b) Derome, A. E. Modern NMR Techniques for Chemistry
Research, Tetrahedron Organic Chemistry Series; Baldwin, J . E.,
Magnus, P. D., Eds.; Pergamon: Oxford, 1997; Vol. 6, p 239.
J . Org. Chem, Vol. 67, No. 22, 2002 7843

Iriarte Capaccio and Varela
The dihydropyranones 8a and 9a were isolated as colorless
Exp er im en ta l Section
oils; their yields and specific rotations are reported in Table
1
1. Compound 9a exhibited H and 13C NMR spectra identical
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 conducted on silica gel 60 F254 precoated
plates (0.2 mm). Visualization of the spots was effected by
exposure to UV light and charring with a solution of 5%
sulfuric acid in EtOH, containing 0.5% p-anisaldehyde. Sol-
vents were reagent grade and, in most cases, were dried and
distilled prior to use according to standard procedures.
2,3,4-Tr i-O-a cet yl-1,5-a n h yd r o-L-er yth r o-p en t -1-en i-
tol (2-Acetoxy-3,4-d i-O-a cetyl-L-a r a bin a l, 5). L-Arabinose
(2, 4.50 g, 29.97 mmol) was dissolved in boiling anhydrous
pyridine (20 mL) with vigorous stirring. The mixture was
rapidly cooled to 0 °C and acetic anhydride (35 mL) was added
dropwise. After standing overnight at 0 °C, the solution was
poured into ice-water and the mixture extracted several times
with CH2Cl2. The organic layer was washed with ice-saturated
(satd) aqueous (aq) NaHCO3, then with ice-water, dried
(MgSO4), and concentrated. Pyridine was removed by succes-
sive evaporations at room temperature with toluene. The
resulting product was dissolved in 32% HBr in glacial acetic
acid (34 mL) keeping the temperature to 0 °C, and then acetic
anhydride (0.34 mL) was added dropwise in the dark. After 1
h, TLC showed a main spot (Rf ) 0.53, hexane/EtOAc 2:1) and
no starting material (Rf ) 0.34) remaining. The solution was
concentrated in a vacuum and successively dissolved and
evaporated with toluene and ethyl ether to afford a partly
crystalline product, which was rapidly washed with anhydrous
ethyl ether. The residue was dissolved in anhydrous CH2Cl2
(20 mL), and to the resulting solution, cooled to -18 °C, was
added 1,8-diazabycyclo[5.4.0]undec-7-ene (DBU, 5 mL) drop-
wise in the dark. After stirring for 20 min TLC showed a main
spot having Rf ) 0.39; and the mixture was diluted with CH2-
Cl2, washed with 10% aq HCl, satd aq NaHCO3, and satd aq
NaCl. The organic extract was dried (MgSO4), concentrated,
and purified by flash chromatography (hexane/EtOAc 7:1) to
afford crystalline 5 (3.33 g, 43% from 2); mp 61-62 °C; [R]D
with those of the enantiomeric 8a .5
Isola tion of Ben zyl 2,4-Di-O-a cetyl-3-d eoxy-â-D-glycer o-
h ex-2-en op yr a n osid e (7a ). The iodine-promoted glycosyla-
tion of 4 (442 mg, 1.71 mmol) was performed with benzyl
alcohol (187 µL, 1.82 mmol) in the presence of iodine (29.1 mg,
0.11 mmol). The reaction was conducted in dry acetonitrile (6
mL) for 20 min, according to the procedure described above.
After the usual workup, the reaction mixture was chromato-
graphed with hexane/EtOAc 14:1 to afford 7a (106 mg, 20%
yield) as a 8:1 mixture of â and R anomers, determined from
1
the H NMR spectrum (200 MHz, CDCl3); for the â anomer δ
7.32 (br s, 5, H-aromatic), 5.89 (d, 1, J 3,4 ) 5.8 Hz, H-3), 5.16
(dd, 1, J 4,5 ) 2.7 Hz, H-4), 5.08 (br s, 1, H-1), 4.78, 4.58 (2 d,
2, J ) 12.2 Hz, PhCH2O), 4.18 (dd, 1, J 5,5′ ) 13.2 Hz, H-5ax),
3.83 (d, 1, J 4,5′ < 1 Hz, H-5′eq), 2.11, 2.07 (2 s, 6, CH3CO); for
the R anomer (distinctive signals) δ 5.75 (d, J 3,4 ) 2.9 Hz, H-3),
5.10 (br s, 1, H-1); 13C NMR (50.3 MHz, CDCl3) δ 170.5, 167.9
(CH3CO), 149.2 (C-2), 137.4, 128.5, 128.0, 127.9 (C-aromatic),
111.7 (C-3), 92.1 (C-1), 70.1 (PhCH2O), 65.0 (C-4), 61.2 (C-5),
21.0, 20.9 (CH3CO); for the R anomer (partial spectrum) δ
115.3 (C-3), 92.9 (C-1), 70.3 (PhCH2O), 65.3 (C-4), 60.2 (C-5).
(2S)-[(R)-2′-Octyloxy]-2H-pyr an -3(6H)-on e (8b) an d (2R)-
[(S)-2′-Octyloxy]-2H-p yr a n -3(6H)-on e (9c). Compound 8b
was prepared by the tin(IV) chloride-promoted glycosylation
of 4 with (R)-2-octanol, as previously reported.5 The same
procedure was employed for the synthesis of 8b from 6, and
for the preparation of 9c from 5 and (S)-2-octanol.
Compound 9c (de > 97%) gave [R]D +183.5 (c 1.0, CHCl3)
(lit.5 [R]D -183.6 for the enantiomer 8b (de > 97%)). Dihydro-
pyranones 8b and 9c showed identical 1H and 13C NMR
spectra.
Ad d u cts of Dih yd r op yr a n on es 9a ,c w ith 2,3-Dim eth -
ylb u t a d ien e: (3R,4a S,8a R)-3-Ben zyloxy-6,7-d im et h yl-
4a,5,8,8a-tetr ah ydr o-1H-2-ben zopyr an -4(3H)-on e (11a) an d
(3R,4a S,8a R)-6,7-Dim et h yl-3-[(S)-2′-oct yloxy]-4a ,5,8,8a -
tetr a h yd r o-1H-2-ben zop yr a n -4(3H)-on e (11c). The boron
trifluoride-promoted cycloaddition of 2,3-dimethylbutadiene to
9a (51.3 mg, 0.25 mmol, ee > 86%) and to 9c (54.6 mg, 0.24
mmol, de > 97%) afforded respectively 11a (59.1 mg, 82% yield)
and 11c (60.3 mg, 81% yield). Adduct 11a gave [R]D +49.8 (c
1.0, CHCl3) (lit.5 [R]D -49.7 for the enantiomer 10a (ee > 86%));
11c gave [R]D +39.9 (c 1.0, CHCl3) (lit.5 [R]D -39.7 for the
enantiomer 10b). The 1H and 13C NMR spectra of 11a and 11c
were identical with those of 10a and 10b, respectively.5
Ad d u cts of Dih yd r op yr a n on e 8a w ith Cyclop en ta d i-
en e a n d 1,3-Cycloh exa d ien e: 3-Ben zyloxy-4a ,5,8,8a -tet-
r a h yd r o-5,8-m eth a n o-1H-2-ben zop yr a n -4(3H)-on es (12a -
14a ) a n d 3-Ben zyloxy-4a ,5,8,8a -tetr a h yd r o-5,8-eth a n o-
1H-2-ben zop yr a n -4(3H)-on es (16a , 17a ). Th er m a l Cyclo-
a d d ition Gen er a l P r oced u r e. A solution of the dihydropy-
ranone 8a (204 mg, 1 mmol) and hydroquinone (10 mg) in dry
toluene (0.2 mL) was placed in a thick-walled glass tube and
the freshly distilled diene (see Table 2) was added. The glass
tube was flushed with dry argon, sealed, and heated at the
temperature and for the time indicated in Table 2. The solution
was then concentrated and purified by flash chromatography
(1-2% EtOAc in hexane) to afford adducts 12a -14a and
16a ,17a . This procedure led to the following isolated yields of
cycloadducts for the reaction of 8a (75.0 mg, 0.37 mmol) with
cyclopentadiene: 12a (70.2 mg, 70.7%), 13a (5.8 mg, 5.8%),
and 14a (3.0 mg, 3.0%). Whereas, thermal cycloaddition of 8a
(263 mg, 1.29 mmol) with 1,3-cyclohexadiene afforded 16a (238
mg, 65.0%) and 17a (17.4 mg, 4.8%).
1
-207.8 (c 1.0, CHCl3); H NMR (200 MHz, CDCl3) δ 6.67 (br
s, 1, H-1), 5.72 (dd, 1, J 3,4 ) 4.4 Hz, J 3,5 ) 1.2 Hz, H-3), 5.29
(ddd, 1, J 4,5 ) 4.0 Hz, J 4,5′ ) 10.2 Hz, H-4), 4.03 (ddd, 1, J 5,5′
)
10.6 Hz, H-5), 3.92 (dd, 1, H-5′), 2.11, 2.08, 2.05 (3 s, 9, CH3-
CO); 13C NMR (50.3 MHz, CDCl3) δ 170.4, 169.6, 169.4
(CH3CO), 141.2 (C-1), 127.1 (C-2), 65.4, 64.4 (C-3,4), 62.7 (C-
5), 20.8, 20.6, 20.5 (CH3CO). Anal. Calcd for C11H14O7: C,
51.17; H, 5.46. Found: C, 51.33; H, 5.64.
2,3,4-Tr i-O-a cet yl-1,5-a n h yd r o-D-er yth r o-p en t -1-en i-
tol (2-Acetoxy-3,4-d i-O-a cetyl-D-a r a bin a l, 6). Compound 6
was prepared as described for 5, starting from D-arabinose (3,
4.24 g, 28.24 mmol). The glycal 6 (3.21 g, 44% from 3) gave
[R]D +207.6 (c 1.0, CHCl3) (lit.21 [R]D +202) and 1H and 13C
NMR spectra identical with those of 5.
2-Ben zyloxy-2H-p yr a n -3(6H)-on es (8a a n d 9a ). The
procedure described for the SnCl4-promoted glycosylation of
glycal derivatives was essentially followed.5 A solution of glycal
4, 5, or 6 (0.10 g, 0.39 mmol) and benzyl alcohol (50 µL, 0.49
mmol) in anhydrous CH2Cl2 (6.5 mL) was cooled to the
temperature indicated in Table 1, and the corresponding Lewis
acid was added. The mixture was stirred for 30 min and then
diluted with CH2Cl2. After the usual workup, the residue was
purified by flash chromatography (hexane/EtOAc 14:1).
For the iodine-promoted glycosylation, a solution of 4 (135
mg, 0.52 mmol) and benzyl alcohol (108 µL, 1.05 mmol) in
anhydrous acetonitrile (2 mL) was treated, in the dark, with
iodine (132 mg, 0.52 mmol) at room temperature for 45 min.
Upon dilution with CH2Cl2, the solution was washed with a
5:1 (v/v) mixture of satd aq Na2S2O3 and satd aq NaHCO3,
dried (MgSO4), and concentrated and the resulting residue
purified by flash chromatography as above.
Gen er a l Et2O‚BF 3-P r om oted Cycloa d d ition . A solution
of 8a (204.2 mg, 1 mmol) in dry toluene (4 mL) was cooled to
-18 °C and Et2O‚BF3 (125 µL, 1 mmol) was added under
argon. The vial was sealed and the mixture was stirred at -18
°C for 15 min, then the diene dissolved in toluene (1 mL) was
slowly injected into the solution. When the addition was
(21) Bock, K.; Pedersen, C. Acta Chem. Scand. 1970, 24, 2465.
7844 J . Org. Chem., Vol. 67, No. 22, 2002

Cycloadditions of Sugar-Derived Dihydropyranones with Dienes
1
finished, the mixture was stirred at the temperature and for
the time indicated in Table 2. The reaction mixture was diluted
with ethyl ether, washed with satd aq NaHCO3, dried (MgSO4),
and concentrated. Addition of hexane to the residue produced
the precipitation of polymeric material. The hexane solution
was subjected to flash chromatography with 1-2% EtOAc in
hexane affording the corresponding cycloadducts. Thus, start-
ing from 8a (137 mg, 0.67 mmol) and cyclopentadiene, 12a
(103.3 mg, 57.0%), 13a (7.0 mg, 3.9%), and 14a (5.3 mg, 2.9%)
were obtained. Similarly, reaction of 8a (416 mg, 2.04 mmol)
with 1,3-cyclohexadiene gave 16a (314 mg, 54.2%) and 17a
(together with 18a , total 80 mg, 13.8%).
-114.3 (c 0.9, CHCl3); H NMR (500 MHz, CDCl3) δ 7.30 (br
s, 5, H-aromatic), 6.25 (br t, 1, J 6,7 ) 7.6 Hz, J 7,8 ) 6.5 Hz, J 5,7
< 1 Hz, H-7), 6.18 (ddd, 1, J 5,6 ) 6.5 Hz, J 6,8 ) 1.1 Hz, H-6),
4.75, 4.59 (2 d, 2, J ) 11.9 Hz, PhCH2O), 4.51 (br s, 1, H-3),
4.06 (dd, 1, J 1,8a ) 5.1 Hz, J 1,1′ ) 12.1 Hz, H-1), 3.33 (dd, 1,
J 1′,8a ) 6.3 Hz, H-1′), 3.07 (m, 1, H-5), 2.86 (dd, 1, J 4a,5 ) 3.0
Hz, J 4a,8a ) 10.0 Hz, H-4a), 2.53 (dddd, 1, J 8a,8 ) 1.5 Hz, H-8a),
2.50 (m, 1, H-8), 1.62 (m, 1, H-9), 1.55 (m, 1, H-10), 1.32 (m, 1,
H-10′), 1.27 (m, 1, H-9′); 13C NMR (50.3 MHz, CDCl3) δ 206.2
(C-4), 137.0, 128.5, 128.1, 127.9 (C-aromatic), 134.1, 132.7 (C-
6,7), 97.9 (C-3), 70.1 (PhCH2O), 64.6 (C-1), 49.4 (C-4a), 39.3
(C-8a), 34.1, 32.6 (C-5,8), 26.1, 23.3 (C-9,10). Anal. Calcd for
C
18H20O3: C, 76.03; H, 7.09. Found: C, 75.77; H, 7.33.
The starting dihydropyranone 8a , employed for all these
reactions, had an ee >86%; therefore, the respective cycload-
ducts 12a -14a and 16a exhibited the same optical purity. The
enantiomeric composition for the major products was deter-
mined by 1H NMR experiments with ytterbium tris[3-(hep-
tafluoropropylhydroxymethylene)-(+)-camphorate] and it is
indicated in any individual case. Compounds 12a -14a and
16a -18a showed the following properties (the reported Rf
values were determined using hexane/EtOAc, 5:2).
(3S,4a R,5S,8R,8a S)-3-Ben zyloxy-4a ,5,8,8a -tetr a h yd r o-
5,8-m et h a n o-1H -2-b en zop yr a n -4(3H )-on e (r-E n d o-Ad -
d u ct, 12a ). The major product 12a (ee > 86%, Rf ) 0.56) gave
[R]D -123.4 (c 1.2, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.33
(br s, 5, H-aromatic), 6.20 (dd, 1, J 6,7 ) 5.6 Hz, J 7,8 ) 3.0 Hz,
H-7), 6.07 (dd, 1, J 5,6 ) 2.9 Hz, H-6), 4.71, 4.55 (2 d, 2, J )
11.7 Hz, PhCH2O), 4.38 (br s, 1, H-3), 4.21 (dd, 1, J 1,8a ) 6.0
Hz, J 1,1′ ) 12.2 Hz, H-1ax), 3.49 (dd, 1, J 1′,8a ) 3.3 Hz, H-1′eq),
3.35 (m, 1, H-5), 3.05 (dd, 1, J 4a,5 ) 4.3 Hz, J 4a,8a ) 9.3 Hz,
H-4a), 2.95 (br s, 1, H-8), 2.67 (dddd, 1, J 8,8a ) 3.0 Hz, H-8a),
1.43 (dt, 1, J 5,9 ∼ J 8,9 ∼ 1.8 Hz, J 9,9′ ) 8.4 Hz, H-9), 1.32 (br d,
1, J 5,9′ ∼ J 8,9′ < 1 Hz, H-9′); 13C NMR (50.3 MHz, CDCl3) δ
204.8 (C-4), 136.9, 128.5, 128.1, 128.0 (C-aromatic), 136.0,
135.1 (C-6,7), 96.9 (C-3), 69.9 (PhCH2O), 61.0 (C-1), 49.3 (C-
9), 48.3, 47.5, 47.4 (C-4a,5,8), 37.5 (C-8a). Anal. Calcd for
Compound 16a , obtained by the Et2O‚BF3-catalyzed cy-
cloaddition, showed the same properties as those described
above.
(3S,4a S,5R,8S,8a R)-3-Ben zyloxy-4a ,5,8,8a -tetr a h yd r o-
5,8-eth a n o-1H-2-ben zop yr a n -4(3H)-on e (â-En d o-Ad d u ct,
17a ) a n d (3R,4a R,5S,8R,8a S)-3-Ben zyloxy-4a ,5,8,8a -tet-
r a h yd r o-5,8-eth a n o-1H-2-ben zop yr a n -4(3H)-on e (18a , C-3
Isom er iza tion P r od u ct of 16a ). The byproduct (17a ) of the
thermal cycloaddition of 8a with 1,3-cyclohexadiene was
isolated by flash chromatography (Rf ) 0.60). Compound 17a
1
gave [R]D +10.4 (c 1.0, CHCl3); H NMR (500 MHz, CDCl3) δ
7.32 (m, 5, H-aromatic), 6.32 (ddd, 1, J 6,7 ) 7.2 Hz, J 5,6 ) 6.4
Hz, J 6,8 ) 1.1 Hz, H-6), 6.05 (t, 1, J 7,8 ) 6.7 Hz, J 5.7 < 1 Hz,
H-7), 4.74, 4.60 (2 d, 2, J ) 12.2 Hz, PhCH2O), 4.73 (br s, 1,
H-3), 3.73 (dd, 1, J 1,8a ) 6.4 Hz, J 1,1′ ) 11.7 Hz, H-1eq), 3.30
(dd, 1, J 1′,8a ) 12.1 Hz, H-1′ax), 3.17 (br m, 1, H-5), 2.80 (dddd,
1, J 4a,8a ) 10.5 Hz, J 8,8a ) 1.3 Hz, H-8a), 2.59 (dd, 1, J 4a,5 ) 2.7
Hz, H-4a), 2.38 (br s, 1, H-8), 1.59 (m, 1, H-9), 1.53 (m, 1, H-10),
1.33 (m, 2, H-9′,10′); 13C NMR (50.3 MHz, CDCl3) δ 206.4 (C-
4), 137.1, 128.3, 128.0, 127.7 (C-aromatic), 135.0, 132.0 (C-
6,7), 96.7 (C-3), 69.1 (PhCH2O), 64.5 (C-1), 49.7 (C-4a), 41.5
(C-8a), 31.0, 30.1 (C-5,8), 25.5, 23.4 (C-9,10). Anal. Calcd for
C
18H20O3: C, 76.03; H, 7.09. Found: C, 75.70; H, 7.28.
C
17H18O3: C, 75.53; H, 6.71. Found: C, 75.29; H, 6.76.
(3S,4a R,5R,8S,8a S)-3-Ben zyloxy-4a ,5,8,8a -tetr a h yd r o-
The analogous Et2O‚BF3-promoted reaction afforded a minor
1
product having [R]D -6.7 (c 1.0, CHCl3) and H and 13C NMR
spectra identical with those of 17a , described above. In fact,
the product proved to be (see next) a partially racemic mixture
of 18a and 17a (4:1 ratio).
5,8-m eth a n o-1H-2-ben zop yr a n -4(3H)-on e (r-Exo-Ad d u ct,
13a ). For the less polar adduct 13a (ee > 86%, Rf ) 0.62); 1H
NMR (500 MHz, CDCl3) δ 7.35 (br s, 5, H-aromatic), 6.27, 6.19
(2 dd, 2, J 5,6 ) J 7,8 ) 2.9 Hz, J 6,7 ) 5.5 Hz, H-6,7), 4.77, 4.61
(2 d, 2, J ) 11.7 Hz, PhCH2O), 4.68 (br s, 1, H-3), 4.35 (dd, 1,
J 1,8a ) 5.5 Hz, J 1,1′ ) 12.4 Hz, H-1ax), 3.70 (dd, 1, J 1′,8a ) 3.1
Hz, H-1′eq), 3.24 (br s, 1, H-5), 2.76 (br s, 1, H-8), 2.35 (br d,
1, J 4a,8a ) 8.8 Hz, H-4a), 1.89 (dddd, 1, J 8,8a ) 1.8 Hz, H-8a),
1.59 (d, 1, J 5,9 ∼ J 8,9 < 1.0 Hz, J 9,9′ ) 9.1 Hz, H-9), 1.28 (ddd,
1, J 5,9′ ) J 8,9′ ) 1.8 Hz, H-9′); 13C NMR (50.3 MHz, CDCl3) δ
205.9 (C-4), 139.0, 136.4 (C-6,7), 136.8, 128.5, 128.2, 128.0 (C-
aromatic), 96.9 (C-3), 70.1 (PhCH2O), 63.1 (C-1), 48.6, 48.1,
46.9 (C-4a,5,8), 44.9 (C-9), 36.9 (C-8a).
Con ver sion of th e r-En d o Ad d u ct 16a in to 18a . A
solution of 16a (52 mg, 0.18 mmol) in dry toluene (1 mL) was
cooled to -18 °C and Et2O‚BF3 (22.6 µL, 0.18 mmol) was added
under argon. The mixture was stirred at 0 °C, and TLC showed
gradual conversion of the starting 16a (Rf ) 0.68) into a slower
migrating product (Rf ) 0.60) that had the same mobility of
17a . After 25 min the mixture was subjected to the usual
workup, and the resulting crude product was flash chromato-
graphed to afford 18a ; [R]D -11.2 (c 0.9, CHCl3) and 1H and
13C NMR spectra identical with those of its enantiomer 17a .
(3S,4a S,5R,8S,8a R)-3-Ben zyloxy-4a ,5,8,8a -tetr a h yd r o-
5,8-m et h a n o-1H -2-b en zop yr a n -4(3H )-on e (â-E n d o-Ad -
d u ct, 14a ). The more polar product 14a (ee > 86%, Rf ) 0.46)
Ad d u cts of Dih yd r op yr a n on e 8b w ith Cyclop en ta d i-
en e: (3S,4a R,5S,8R,8a S)-3-[(R)-2′-Octyloxy]-4a ,5,8,8a -tet-
r a h yd r o-5,8-m eth a n o-1H-2-ben zop yr a n -4(3H)-on e (12b)
a n d (3S,4a S,5R,8S,8a R)-3-[(R)-2′-Octyloxy]-4a ,5,8,8a -tet-
r a h yd r o-5,8-m eth a n o-1H-2-ben zop yr a n -4(3H)-on e (14b).
The general Et2O‚BF3-promoted cycloaddition procedure was
followed starting from 8b (72 mg, 0.32 mmol) and freshly
distilled cyclopentadiene (57 mg, 0.86 mmol). The usual
workup of the reaction mixture and flash chromatography
purification afforded first the less polar R-endo-adduct 12b (54
mg, 58%); [R]D -100.3 (c 1.0, CHCl3); 1H NMR (500 MHz,
CDCl3) δ 6.20 (dd, 1, J 6,7 ) 5.6 Hz, J 7,8 ) 3.1 Hz, H-7), 6.10
(dd, 1, J 5,6 ) 2.8 Hz, H-6), 4.38 (br s, 1, H-3), 4.22 (dd, 1, J 1,1′
) 12.3 Hz, J 1,8a ) 6.1 Hz, H-1), 3.74 (m, 1, J ) 6.1 Hz, HCO
octyl), 3.44 (dd, 1, J 1′,8a ) 3.4 Hz, H-1′), 3.37 (br s, 1, H-5),
3.07 (dd, 1, J 4a,5 ) 4.3 Hz, J 4a,8a ) 9.5 Hz, H-4a), 2.96 (br s, 1,
H-8), 2.67 (dddd, 1, J 8,8a ) 3.2 Hz, H-8a), 1.44 (dt, 1, J 5,9 ∼ J 8,9
∼ 1.8 Hz, J 9,9′ ) 8.5 Hz, H-9), 1.34 (br d, 1, H-9′), 1.62-1.27
(m, 10, CH2 octyl), 1.14 (d, 3, J ) 6.1 Hz, CH3-1 octyl), 0.90 (t,
3, J ) 6.1 Hz, CH3-8 octyl); 13C NMR (125 MHz, CDCl3) δ 205.5
(C-4), 136.1, 134.9 (C-6,7), 95.6 (C-3), 73.9 (C-2 octyl), 61.0 (C-
1
gave mp 59-60 °C; [R]D +29.2 (c 1.1, CHCl3); H NMR (500
MHz, CDCl3) δ 7.35 (m, 5, H-aromatic), 6.27 (dd, 1, J 5,6 ) 2.8
Hz, J 6,7 ) 5.7 Hz, H-6), 5.95 (dd, 1, J 7,8 ) 3.0 Hz, H-7), 4.73,
4.60 (2 d, 2, J ) 12.4 Hz, PhCH2O), 4.67 (br s, 1, H-3), 3.91
(dd, 1, J 1,1′ ) 11.5 Hz, J 1,8a ) 6.6 Hz, H-1eq), 3.32 (br s, 1,
H-5), 3.17 (dd, 1, J 1′,8a ) 12.0 Hz, H-1′ax), 3.06 (dddd, 1, J 4a,8a
) 9.9 Hz, J 8,8a ) 3.3 Hz, H-8a), 2.86 (br s, 1, H-8), 2.83 (dd, 1,
J 4a,5 ) 3.9 Hz, H-4a), 1.58 (ddd, 1, J 5.9 ) J 8,9 ) 1.8 Hz, J 9,9′
)
8.5 Hz, H-9), 1.38 (br d, 1, J 5,9′ ∼ J 8,9′ < 1 Hz, H-9′); 13C NMR
(50.3 MHz, CDCl3) δ 207.9 (C-4), 138.3, 134.0 (C-6,7), 137.0,
128.4, 128.1, 127.8 (C-aromatic), 95.8 (C-3), 69.2 (PhCH2O),
64.5 (C-1), 49.2 (C-4a), 48.7 (C-9), 44.1, 43.4, 41.6 (C-5,8,8a).
Anal. Calcd for C17H18O3: C, 75.53; H, 6.71. Found: C, 75.18;
H, 6.68.
(3S,4a R,5S,8R,8a S)-3-Ben zyloxy-4a ,5,8,8a -tetr a h yd r o-
5,8-eth a n o-1H-2-ben zop yr a n -4(3H)-on e (r-En d o-Ad d u ct,
16a ). The major product of the thermal cycloaddition of 8a
with 1,3-cyclohexadiene was 16a (ee > 86%, Rf ) 0.68); [R]D
J . Org. Chem, Vol. 67, No. 22, 2002 7845

Iriarte Capaccio and Varela
1), 49.3 (C-9), 48.2, 47.4, 47.2 (C-4a,5,8), 37.6 (C-8a), 37.1, 31.8,
29.3, 25.7, 22.6 (CH2 octyl), 19.2, 14.1 (CH3 octyl). Anal. Calcd
for C18H28O3: C, 73.93; H, 9.65. Found: C, 73.78; H, 9.84.
Concentration of the next fractions from the column afforded
the minor â-endo-adduct 14b (5 mg, 5%); 1H NMR (500 MHz,
CDCl3) δ 6.26 (dd, 1, J 5,6 ) 2.8 Hz, J 6,7 ) 5.7 Hz, H-6), 5.95
(dd, 1, J 7,8 ) 2.9 Hz, H-7), 4.69 (br s, 1, H-3), 3.86 (dd, 1, J 1,1′
) 11.2 Hz, J 1,8a ) 6.6 Hz, H-1), 3.72 (m, 1, J ) 6.1 Hz, HCO
octyl), 3.33 (br s, 1, H-5), 3.17 (t, 1, J 1′,8a ) 12.0 Hz, H-1′), 3.05
(dddd, 1, J 4a,8a ) 10.0 Hz, J 8,8a ) 3.4 Hz, H-8a), 2.86 (br s, 1,
H-8), 2.83 (dd, 1, J 4a,5 ) 3.9 Hz, H-4a), 1.57 (ddd, 1, J 5,9 ∼ J 8,9
∼ 1.8 Hz, J 9,9′ ) 8.6 Hz, H-9), 1.39 (br d, 1, H-9′), 1.60-1.24
(m, 10, CH2 octyl), 1.14 (d, 3, J ) 6.1 Hz, CH3-1 octyl), 0.88 (t,
3, J ) 7.0 Hz, CH3-8 octyl); 13C NMR (50.3 MHz, CDCl3) δ
208.4 (C-4), 138.2, 134.0 (C-6,7), 94.9 (C-3), 72.8 (C-2 octyl),
64.0 (C-1), 49.2 (C-4a), 48.7 (C-9), 44.3, 43.5, 41.5 (C-5,8,8a),
37.0, 31.8, 29.2, 25.7, 22.6 (CH2 octyl), 19.1, 14.1 (CH3 octyl).
Thermal cycloaddition of 8b with cyclopentadiene afforded
12b and 14b, which exhibited the same properties as those of
the same products synthesized under Lewis acid catalysis.
Ad d u cts of Dih yd r op yr a n on es 9a a n d 9c w ith Cyclo-
p en ta d ien e: (3R,4a S,5R,8S,8a R)-3-Ben zyloxy-4a ,5,8,8a -
tetr ah ydr o-5,8-m eth an o-1H-2-ben zopyr an -4(3H)-on e (15a).
The general Et2O‚BF3-catalyzed procedure was followed for the
cycloaddition of 9a (122 mg, 0.60 mmol) with cyclopentadiene
(81 mg, 1.22 mmol) to give 15a (91 mg, 56% yield, ee > 86%);
[R]D +122.9 (c 1.0, CHCl3); having spectral data identical with
those of 12a .
(3R,4aS,5R,8S,8aR)-3-[(S)-2′-Octyloxy]-4a,5,8,8a-tetr ah y-
d r o-5,8-m eth a n o-1H-2-ben zop yr a n -4(3H)-on e (15c). The
Et2O‚BF3-promoted cycloaddition of cyclopentadiene (91 mg,
1.38 mmol) with 9c (156 mg, 0.69 mmol) afforded the major
endo adduct 15c (115 mg, 57% yield), which showed [R]D
+100.4 (c 1.1, CHCl3) and NMR spectra identical with those
of 12b.
Ad d u cts of th e d ih yd r op yr a n on e 8b w ith 1,3-Cyclo-
h exa d ien e: (3S,4a R,5S,8R,8a S)-3-[(R)-2′-Octyloxy]-4a ,5,
8,8a -tetr a h yd r o-5,8-eth a n o-1H-2-ben zop yr a n -4(3H)-on e
(16b ), (3S,4a S,5R,8S,8a R)-3-[(R)-2′-Oct yloxy]-4a ,5,8,8a -
tetr a h yd r o-5,8-eth a n o-1H-2-ben zop yr a n -4(3H)-on e (17b),
a n d (3R,4a R,5S,8R,8a S)-3-[(R)-2′-Octyloxy]-4a ,5,8,8a -tet-
r ah ydr o-5,8-eth an o-1H-2-ben zopyr an -4(3H)-on e (18b). The
general procedure for the cycloaddition promoted by Et2O‚BF3
was followed starting from 8b (407 mg, 1.80 mmol) and 1,3-
cyclohexadiene (1.75 g, 21.8 mmol). The reaction was con-
ducted at 0 °C for 45 min. After the usual workup, flash
chromatography afforded three products. The faster migrating
was 16b (71 mg, 13% yield); [R]D -95.3 (c 1.0, CHCl3); 1H NMR
(500 MHz, CDCl3) δ 6.26 (br t, 1, J 6,7 ∼ J 7,8 ) 7.0 Hz, H-7),
6.21 (dt, 1, J 5,6 ∼ 7.0 Hz, J 6,8 ) 1.3 Hz, H-6), 4.51 (br s, 1,
H-3), 4.03 (dd, 1, J 1,8a ) 5.2 Hz, J 1,1′ ) 12.0 Hz, H-1eq), 3.76
(sextet, 1, J ) 6.2 Hz, HCO octyl), 3.28 (dd, 1, J 1′,8a ) 6,6 Hz,
) 6.2 Hz, CH3-1 octyl), 0.90 (t, J ) 6.2 Hz, CH3-8 octyl)); 13C
NMR (125 MHz, CDCl3) δ 206.7 (C-2), 133.9, 132.8 (C-6,7),
96.8 (C-3), 74.2 (HCO octyl), 64.5 (C-1), 49.2 (C-4a), 39.4 (C-
8a), 37.1, 34.0, 29.2, 26.1, 25.6, 23.3, 22.6 (C-9, 10, CH2 octyl),
32.3, 31.8 (C-5,8), 19.4 (CH3-1 octyl), 14.1 (CH3-8 octyl). Anal.
Calcd for C19H30O3: C, 74.47; H, 9.87. Found: C, 74.26; H,
9.79.
The second compound eluted from the column was 18b (206
1
mg, 37% yield); [R]D -1.0 (c 1.1, CHCl3); H NMR (200 MHz,
CDCl3) δ 6.33 (dd, J 6,7 ) 7.7 Hz, J 5,6 ) 6.5 Hz, H-6), 6.05 (dd,
J 7,8 ) 7.3 Hz, H-7), 4.77 (br s, 1, H-3), 3.70 (m, 2, J 1,8a ) 6.2
Hz, J 1,1′ ) 12.1 Hz, H-1eq, HCO octyl), 3.30 (t, 1, J 1′,8a ) 12.1
Hz, H-1′ax), 3.18 (br s, 1, H-5), 2.79 (ddd, 1, J 4a,8a ) 10.5 Hz,
H-8a), 2.60 (dd, 1, J 4a,5 ) 2.7 Hz, H-4a), 2.39 (br s, 1, H-8),
1.59 (m, 2, H-9,10), 1.40-1.28 (m, 12, H-9′,10′,CH2 octyl), 1.17
(d, 3, J ) 6.1 Hz, CH3-1 octyl), 0.88 (t, 3, J ) 6.1 Hz, CH3-8
octyl); 13C NMR (50.3 MHz, CDCl3) δ 207.0 (C-4), 135.1, 132.0
(C-6,7), 97.7 (C-3), 75.1 (HCO octyl), 64.1 (C-1), 49.7 (C-4a),
41.6 (C-8a), 36.4, 31.8, 29.4, 25.6, 25.4, 23.5, 22.6 (C-9,10,CH2
octyl), 31.0, 30.2 (C-5,8), 21.3 (CH3-1 octyl), 14.1 (CH3-8 octyl).
Anal. Calcd for C19H30O3: C, 74.47; H, 9.87. Found: C, 74.09;
H, 9.84.
The lower migrating product was the â-endo adduct 17b
(11.3 mg, 2.1% yield); [R]D -39.9 (c 1.1, CHCl3); 1H NMR (200
MHz, CDCl3) δ 6.32 (dd, J 6,7 ) 7.7 Hz, J 5,6 ) 6.5 Hz, H-6),
6.05 (dd, J 7,8 ) 7.3 Hz, H-7), 4.76 (br s, 1, H-3), 3.70 (m, 2,
J 1,8a ) 6.3 Hz, J 1,1′ ) 12.1 Hz, H-1eq, HCO octyl), 3.30 (t, 1,
J 1′,8a ) 12.1 Hz, H-1′ax), 3.18 (br s, 1, H-5), 2.79 (ddd, 1, J 4a,8a
) 10.2 Hz, H-8a), 2.60 (dd, 1, J 4a,5 ) 2.6 Hz, H-4a), 2.39 (br s,
1, H-8), 1.60 (m, 2, H-9,10), 1.40-1.26 (m, 12, H-9′,10′,CH2
octyl), 1.14 (d, 3, J ) 6.2 Hz, CH3-1 octyl), 0.88 (t, 3, J ) 6.2
Hz, CH3-8 octyl); 13C NMR (50.3 MHz, CDCl3) δ 207.3 (C-4),
135.1, 132.0 (C-6,7), 95.9 (C-3), 72.9 (HCO octyl), 64.1 (C-1),
49.7 (C-4a), 41.5 (C-8a), 37.0, 31.9, 29.2, 25.7, 25.5, 23.6, 22.6
(C-9,10,CH2 octyl), 31.0, 30.4 (C-5,8), 19.2 (CH3-1 octyl), 14.1
(CH3-8 octyl). Anal. Calcd for C19H30O3: C, 74.47; H, 9.87.
Found: C, 74.18; H, 9.82.
The thermal cycloaddition of 1,3-cyclohexadiene (718 mg,
8.96 mmol) with 8b (180 mg, 0.80 mmol) afforded as major
adduct 16b (123 mg, 50%) with a negligible amount of 17b.
The adduct 16b showed the same physical and spectral
properties as those previously described.
Ack n ow led gm en t. This work was supported by
grants from the University of Buenos Aires (Project
TX108) and the National Research Council of Repu´blica
Argentina (CONICET). O.V. is a Research Member of
CONICET.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for 12a -14a ; 13C NMR spectra for 17b and 18b; DEPT
and 2D COSY NMR spectra for 12a and 14a . This material is
available free of charge via the Internet at http://pubs.acs.org.
H-1′ax), 3.08 (m, 1, H-5), 2.87 (dd, 1, J 4a,5 ) 3.0 Hz, J 4a,8a
)
10.0 Hz, H-4a), 2.55 (dddd, 1, J 8a,8 ) 1.6 Hz, H-8a), 2.49 (m, 1,
H-8), 1.65-1.27 (m, 14, H-9,9′, H-10,10′, CH2 octyl), 1.14 (d, J
J O020309W
7846 J . Org. Chem., Vol. 67, No. 22, 2002