Reactions of Diels-Alder adducts of a sugar-derived dihydropyranone leading to fused polycyclic compounds

Article abstract of DOI:10.1016/j.carres.2004.01.008

Manipulation of the ketone and alkene functions of cycloadducts 2, 3, and 4, derived from optically active (ee >86%) (S)-2-benzyl-2H-pyran-3(6H)-one (1), led to polycyclic systems having three or four fused rings. Reduction of the carbonyl group of the butadiene adduct (2) took place with low facial selectivity affording the alcohols 5 and 6 in 1:1.4 ratio. In contrast, a higher diastereoselection was observed for the reduction of the carbonyl of the cyclopentadiene adducts 3 and 4 to give the endo alcohols 10 and 13, respectively. The epoxidation of 6 showed low facial selectivity in the formation 7 and 8, whereas epoxidation of 10 and 13 took place from the exo face of the norbornene system to give spontaneously the polycyclic alcohols 11 and 14 by opening of the epoxide by intramolecular attack of the hydroxyl group of the pyranoid ring. Similarly, addition of iodine to 10 led to the polycyclic iodide 12.

Full text of DOI:10.1016/j.carres.2004.01.008

Carbohydrate
RESEARCH
Carbohydrate Research 339 (2004) 1207–1213
Note
Reactions of Diels–Alder adducts of a sugar-derived
dihydropyranone leading to fused polycyclic compounds
Christian A. Iriarte Capaccio and Oscar Varela*
CIHIDECAR-CONICET, Departamento de Quꢀımica Orgꢀanica, Facultad de Ciencias Exactas yNaturales,
Universidad de Buenos Aires, Ciudad Universitaria, Pabellꢀon II, 1428 Buenos Aires, Argentina
Received 29 October 2003; accepted 12 January 2004
Abstract—Manipulation of the ketone and alkene functions of cycloadducts 2, 3, and 4, derived from optically active (ee >86%) (S)-
2-benzyl-2H-pyran-3(6H)-one (1), led to polycyclic systems having three or four fused rings. Reduction of the carbonyl group of the
butadiene adduct (2) took place with low facial selectivity affording the alcohols 5 and 6 in 1:1.4 ratio. In contrast, a higher dia-
stereoselection was observed for the reduction of the carbonyl of the cyclopentadiene adducts 3 and 4 to give the endo alcohols 10
and 13, respectively. The epoxidation of 6 showed low facial selectivity in the formation 7 and 8, whereas epoxidation of 10 and 13
took place from the exo face of the norbornene system to give spontaneously the polycyclic alcohols 11 and 14 by opening of the
epoxide by intramolecular attack of the hydroxyl group of the pyranoid ring. Similarly, addition of iodine to 10 led to the polycyclic
iodide 12.
Ó 2004 Elsevier Ltd. All rights reserved.
Keywords: Cyclizations; Cycloadducts; Diels–Alder; Dihydropyranones
1. Introduction
derived, chiral dihydropyranone. Several aspects of the
chemistry of the cycloadducts as versatile building
blocks have been explored. The level of stereocontrol
and facial selectivities in reduction, oxidation, and
addition reactions were determined. Stereochemical
features in the resulting structures are also discussed.
The regio- and stereospecific nature of the Diels–Alder
reaction has facilitated the construction of complex
molecules, mainly natural products.1;2 Elegant cascade
sequences or intramolecular versions of the cycloaddi-
tion reaction leads to polycyclic systems,3 which have
been alternatively constructed by manipulation of the
usually numerous functionalities of the Diels–Alder
cycloadducts.4 This last approach has succeeded in
installing stereocenters with high selectivity and it has
been employed for the synthesis of such natural prod-
ucts as (+)-curcudiol,5 ())-malyngolide,6 and conduri-
tols.7 In connection with these studies we describe here
the construction of polycyclic systems by intramolecular
cyclizations conducted in optically active cycloadducts.
These compounds have been prepared by Diels–Alder
addition of butadienes8 and cyclic dienes9 to a sugar-
2. Results and discussion
Optically active (S)-2-benzyl-2H-pyran-3(6H)-one (1, ee
>86%), derived from D-xylose, reacted with butadiene
under catalysis by boron trifluoride–ethyl etherate to
give the cycloadduct 2 in 81% yield8 (Scheme 1). To
promote the formation of a polycyclic alcohol, com-
pound 2 was subjected to carbonyl reduction and fur-
ther alkene epoxidation. The reduction of the carbonyl
group of 2 was conducted with sodium borohydride, to
afford alcohols 5 and 6 (1:1.4 ratio), readily separable by
flash chromatography (Scheme 2). The less polar prod-
uct was identified as 5, as the J3;4 (3.6 Hz) and J4;4a
(10.8 Hz) values were consistent with an axial disposi-
tion for H-4 (S configuration for C-4) in the chair
* Corresponding author. Tel./fax: +54-11-45763346; e-mail:
varela@qo.fcen.uba.ar
0008-6215/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2004.01.008

1208
C. A. Iriarte Capaccio, O. Varela / Carbohydrate Research 339 (2004) 1207–1213
times, a third even more polar product was detected.
OBn
3
1
2
Separation of the mixture by flash chromatography
afforded the stable epoxide 7, and the next compound
isolated, the epoxide 8, appeared somewhat contami-
nated with the most polar product. The latter was also
isolated and characterized as the polycyclic alcohol 9,
formed by rear side intramolecular attack of the C-4
hydroxyl group on C-6 of the epoxide 8. In fact, com-
pound 8 completely converts into 9 on standing in a
chloroform solution. This chemical transformation has
been reported for 5-norbornene-2-endo-methanol,11
which on epoxidation rendered an oxirane ring situated
in close proximity to a hydroxyl group. The 13C NMR
spectra of 8 and 9 confirmed their structures; for
example, the resonances of the carbons C-6 and C-7
(ꢀ52ppm) in 8 underwent a strong downfield shifting in
9 (>70 ppm), as result of the intramolecular epoxide
opening by HO-4. Moreover, the incorporation of C-4
into the five-membered tetrahydropyran ring was also
evidenced by the deshielding of the C-4 signal in 9,
compared with the same signal in 8.
O
4a
8a
8
4
5
6
O
7
OBn
2
O
O
OBn
1
2
O
1
3
OBn
4a
8a
8
O
4
O
+
5
9
O
6
7
3
4
Scheme 1.
OBn
OBn
OBn
O
O
H
O
H
NaBH4
H
H
+
The cycloadduct 3, readily obtained (64% yield) by
the Et2OÆBF3-promoted cycloaddition of cyclopenta-
diene to 1,9 was subjected to the same sequence of
reduction and epoxidation to prepare the corresponding
polycyclic alcohol (Scheme 3). Thus, sodium borohy-
dride reduction of 3 was highly diastereoselective in
OH
EtOH
O
OH
2
5
6
OBn
OBn
O
H
O
H
H
H
H
ArCO3H
CHCl3
+
6
OBn
OBn
OH
O
OH
H
O
O
H
H
H
NaBH4
EtOH
H
O
7
8
OH
O
OBn
10
3
O
O
H
H
OBn
OBn
HO
O
O
H
O
H
H
H
9
ArCO3H
CHCl3
OH
Scheme 2.
..
OBn
O
HO
11
O
H
H
conformation of the tetrahydropyran ring that satisfies
the anomeric effect.10 Accordingly, the small values for
OH
0
J1;8a and J1 ;8a indicated that H-8a is bisecting the angle
OBn
OBn
formed by H-1 and H-10. The other isomer isolated (6)
should possess the R configuration for the new stereo-
center at C-4.
10
O
O
H
O
H
H
I2
EtOH
H
OH
..
The absolute configuration at C-4 of 5 and 6 was
confirmed chemically by oxidation of 6 with m-chloro-
peroxybenzoic acid. The reaction was monitored by
TLC and showed formation of two more polar prod-
ucts. When the oxidation was conducted for longer
I
I
12
Scheme 3.

C. A. Iriarte Capaccio, O. Varela / Carbohydrate Research 339 (2004) 1207–1213
1209
favor of the endo alcohol 10 (diastereomeric excess
1
tion with sodium borohydride led to the predictable
alcohol 13 as the only detectable product. The structure
>95%, determined by H NMR). The configuration of
C-4a in 10 was not evident from the 1H NMR spectrum
of the compound, as the presence of the five-membered
ring fused to the pyranoid ring produced distorsion of
its normal chair conformation,12;13 and also because the
contribution of the opposite chair to the equilibrium, as
suggested by the averaging of coupling constants (note,
of 13 was deduced from its H NMR spectrum. Thus,
0
1
the large value for J1 ax;8a (11.8 Hz) indicates a preference
for a distorted chair conformation of the pyranoid ring
having the benzyloxy group axially oriented, as the
magnitude of J3;4 (3.2Hz) agreed with an equatorial–
axial disposition for H-3 and H-4, respectively. Epoxi-
dation of 13, in a manner similar to that employed for
norbornene 10, provided a conclusive demonstration of
the configuration of the stereocenters of the starting
unsaturated alcohol. As for 10, the intermediate oxirane
ring formed by epoxidation of the double bond of 13
underwent attack by the hydroxyl group to form a five-
membered ring. The crowding of substituents on the b
face of the pyran results in a distortion of this ring,
which is reflected in the small values observed for J1;8a
and J3;4 (<1 Hz) (Scheme 4).
In summary, the steric hinderance in both the reduc-
tion of the carbonyl group and oxidation of the double
bond in the cycloadducts account for the diastereose-
lectivities observed. The high diastereoselection in the
reduction of the carbonyl group of 3 and 4 may be
attributed to the bulkiness of the vicinal norbornene
system that induces the approach of the hydride from the
opposite face. The epoxidation of the resulting alcohols
10 and 13 was also highly diastereoselective and took
place from the exo face of the double bond. In contrast, a
lower selectivity was determined for the reduction of 2 as
the cyclohexene ring fused to the pyranone exerts a
smaller stereocontrol compared with that of the bicy-
clo[2.2.1]hept-2-ene system. Similar reasons may be in-
voked to account for the lower facial selectivity in the
epoxidation of 6, in comparison with the epoxidation of
10 and 13. Furthermore, the formation of polycyclic
systems was also useful to confirm the relative stereo-
chemistry of the reacting groups, as cyclization reactions
are only possible when such groups are close in space and
have an adequate orientation. The resulting polycyclic
0
e.g., the averaged values for J1;8a and J1 ;8a). However, as
described later, the epoxidation of the olefinic unsatu-
ration of 10 proved conclusively the configuration of the
stereocenter at C-4. The high facial diastereoselection in
the reduction suggests that the attack by borohydride is
more hindered from the a face of the carbonyl, which is
endo to the bicyclo[2.2.1]hept-2-ene system of 3. In
contrast, the reduction of cyclopentadiene adducts of
levoglucosenone4b;14 and isolevoglucosenone13;15 was
much less stereoselective, indicating that the steric con-
tributions of 1,6-anhydro bridge and the annelated cy-
clopentene ring have an approximately equal role in
deciding the reaction outcome.
The epoxidation of 10 with m-chloroperoxybenzoic
acid led directly to the polycyclic alcohol 11, formed by
intramolecular nucleophilic attack of the hydroxyl
group at C-4 on the epoxide. As the reactive function-
alities of 10 were conveniently disposed for the sponta-
neous cyclization, the intermediate epoxide was detected
only as a faint spot by TLC. The analytical and spectral
data of 11 were completely consistent with the proposed
structure. For example, the J6;7 value (ꢀ0 Hz) indicated
that the two hydrogen atoms are trans disposed in the
norbornane system.4b;14 Also, the chemical shifts for the
signals of the carbons bonded to oxygen were in good
agreement with those found for the polycyclic alcohol 9
and with those of structurally related compounds.4b;13;14
In view of the results of the epoxidation–etherification
of the double bond of 10, the electrophilic addition of
iodine was attempted. Thus, treatment of 10 with an
ethanolic solution of the halogen afforded the crystalline
polycyclic iodide 12 as the only reaction product. The
1H NMR spectrum of 12 was very similar to that of 11,
and their 13C NMR spectra were also similar, except for
the upfield shift of the carbon bonded to iodine (C-7) in
12. The addition of iodine to 10 took place by a mech-
anism analogous to that of the iodolactonization,16
which consists of the anti stereospecific, irreversible
back-side opening of an iodonium ion intermediate by
the alcohol nucleophile.
OBn
OBn
OH
NaBH4
EtOH
O
O
H
H
H
H
O
13
4
ArCO3H
CHCl3
The sequence of reduction and epoxidation was also
applied to cycloadduct 4, which was synthesized using
SnCl4 or TiCl4 as catalyst for the Diels–Alder addition
of cyclopentadiene to 1.17 These catalysts promoted the
formation of diastereomers (such as 4) that could not be
otherwise obtained in preparative scale in thermally or
Et2OÆBF3-promoted cycloadditions. Because of the
crowding of substituents on the b face of 4, the reduc-
HO
H
O
O
OBn
H
14
Scheme 4.

1210
C. A. Iriarte Capaccio, O. Varela / Carbohydrate Research 339 (2004) 1207–1213
systems possess a number of reacting functionalities, and
carry a multitude of stereogenic centers that can be in-
stalled in a predictable way. In this regard, optically pure
polycycles can be prepared starting from enantiomeri-
cally pure cycloadducts derived from dihydropyranone
analogues of 1 but having an additional chiral center
located in the 2-alkoxy substituent.8;9
CDCl3+D2O) d 137.6, 128.5, 128.0, 127.9 (C-aromatic),
125.5, 124.3 (C-6,7), 97.8 (C-3), 69.4 (PhC2O), 66.4
(C-4), 63.8 (C-1), 34.1 (C-4a), 32.4 (C-8a), 24.7, 24.3
(C-5,8). Anal. Calcd for C16H20O3: C, 73.82; H, 7.74.
Found: C, 73.50; H, 8.01.
Elution of the column with 30:1 hexane–EtOAc gave
25
the more polar product 6 (0.35 g, 53%, ee >86%); ½aŠ
D
)92.0° (c 1.0, CHCl3); 1H NMR (500 MHz,
CDCl3+D2O) d 7.35 (br s, 5H, H-aromatic), 5.73, 5.69
(m, 2H, H-6,7), 4.87, 4.55 (2d, 2H, J 11.8 Hz, PhCH2O),
3. Experimental
0
4.68 (d, 1H, J3;4 5.4 Hz, H-3), 3.79 (dd, 1H, J1;1 11.4 Hz,
3.1. General methods
J1;8a 3.7 Hz, H-1), 3.62(dd, 1H, J4;4a 4.6 Hz, H-4), 3.52
(dd, 1H, J1 ;8a 7.7 Hz, H-10), 2.41–2.04 (m, 6H, H-
0
Melting points were determined with a Fisher–Johns
apparatus and are uncorrected. Optical rotations were
measured at 25 °C with a Perkin–Elmer 343 digital
polarimeter. Column chromatographic separations were
performed with Silica Gel 60, 240–400 mesh. Analytical
TLC was conducted on Silica Gel 60 F254 precoated
plates (0.2mm). Visualization of the spots was effected
by exposure to UV light and charring with a solution of
5% H2SO4 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. Nuclear magnetic resonance (NMR) spectra
were recorded with a Bruker AM 500 instrument, in
CDCl3 solutions using Me4Si as an internal standard.
4a,5,50,8,80,8a); 13C NMR (50.3 MHz, CDCl3+D2O) d
137.5, 128.5, 128.1, 127.9 (C-aromatic), 125.7, 125.2 (C-
6,7), 99.7 (C-3), 72.1 (C-4), 70.2 (PhC2O), 64.9 (C-1),
32.4, 31.6 (C-4a,8a), 26.1, 23.3 (C-5,8). Anal. Calcd for
C16H20O3: C, 73.82; H, 7.74. Found: C, 73.99; H, 7.76.
The diastereoselectivity of this reaction was estab-
lished from the 1H NMR spectrum of the crude mixture,
which showed a 1.0:1.4 ratio for 5:6.
3.3. (3S,4R,4aR,6S,7R,8aS)-3-Benzyloxy-6,7-epoxy-4-
hydroxyperhydro-1H-2-benzopyran (7), its (6R,7S) iso-
mer (8), and the polycylic alcohol 9
To a solution of 6 (0.15 g, 0.58 mmol, ee >86%) in
CHCl3 (4 mL) was added a solution of m-chloroper-
oxybenzoic acid (80% purity; 0.20 g, 0.93 mmol) in
CHCl3 (4 mL). The mixture was stirred at room tem-
perature for 20 min, when TLC (1:1 hexane–EtOAc)
indicated the absence of 6 and the formation of two
lower moving products (Rf 0.41 and 0.38) and a third
spot (Rf 0.25), which became more intense when the
reaction was conducted for longer times. The mixture
was diluted with CH2Cl2 and washed with satd aq
NaHCO3, dried (MgSO4), and concentrated. The resi-
due was subjected to flash chromatography with 4:1
1
The identity of the protons in the H NMR spectra of
the products was confirmed by 2D COSY NMR
experiments; and for the assignment of the signals in the
13C NMR spectra, DEPT experiments were conducted.
3.2. (3S,4S,4aR,8aS)-3-Benzyloxy-4-hydroxy-
3,4,4a,5,8,8a-hexahydro-1H-2-benzopyran (5) and its
(4R)-isomer (6)
A solution of 28 (0.66 g, 2.55 mmol, ee >86%) in 96%
EtOH (25 mL) was cooled to 0 °C and NaBH4 (0.11 g,
2.91 mmol) was added. The mixture was stirred at 0 °C
during 15 min, when TLC (6:1 hexane–EtOAc) showed
complete conversion of 2 (Rf 0.63) into two more polar
products (Rf 0.45 and 0.33). The mixture was diluted
with MeOH and concentrated. This procedure was
repeated three times, and the residue was dissolved in
CH2Cl2 (50 mL). The organic solution was washed with
saturated (satd) aqueous (aq) NaCl, dried (MgSO4), and
concentrated. The resulting syrup was purified by flash
chromatography with 45:1 hexane–EtOAc to afford
hexane–EtOAc. The less polar component was identified
as the oxirane derivative 7 (85 mg, 53%, ee >86%); ½aŠ
25
D
1
)70.5° (c 1.0, CHCl3); H NMR (500 MHz, CDCl3) d
7.33 (m, 5H, H-aromatic), 4.75 (d, 1H, J3;4 2.1 Hz, H-3),
4.75, 4.51 (2d, 2H, J 11.6 Hz, PhCH2O), 3.96 (dd, 1H,
0
J1;1 11.4 Hz, J1;8a 3.4 Hz, H-1), 3.49 (dd, 1H, J4;4a 3.2Hz,
H-4), 3.45 (dd, 1H, J1 ;8a 2.4 Hz, H-10), 3.37 (dd, 1H, J6;7
0
0
4.0 Hz, J7;8 < 1 Hz, J7;8 5.8 Hz, H-7), 3.25 (ddd, 1H, J5;6
0
0
2.7 Hz, J5 ;6 ꢀ 1:4 Hz, H-6), 2.34 (dd, 1H, J8;8 16.0 Hz,
0
J8;8a 11.6 Hz, H-8), 2.33 (dd, 1H, J4a;5 8.0 Hz, J4a;5
compound 5 (0.22 g, 33%); mp 60 °C; ½aŠ25 )101.4° (c 1.0,
2.8 Hz, J4a;8a 6.0 Hz, H-4a), 2.21 (ddd, 1H, J5;5 16.4 Hz,
0
D
1
H-5), 2.16 (ddd, 1H, H-50), 1.96 (ddd, 1H, J8 ;8a 7.0 Hz,
0
CHCl3) (this value corresponded to an ee >86%); H
NMR (500 MHz, CDCl3+D2O) d 7.36 (m, 5H, H-aro-
matic), 5.69, 5.61 (m, 2, H-6,7), 4.92 (d, 1, J3;4 3.6 Hz,
H-3), 4.81, 4.51 (2d, 2H, J 11.6 Hz, PhCH2O), 3.96 (dd,
H-80), 1.51 (dddd, 1H, H-8a); 13C NMR (50.3 MHz,
CDCl3) d 137.6, 128.4, 127.9, 127.7 (C-aromatic), 99.0
(C-3), 69.3 (C-4), 69.1 (PhC2O), 63.0 (C-1), 53.1, 51.3
(C-6,7), 30.0, 28.6 (C-4a,8a), 26.5, 24.4 (C-5,8). Anal.
Calcd for C16H20O4: C, 69.55; H, 7.29. Found: C, 69.68;
H, 7.49.
0
1H, J1;1 11.0 Hz, J1;8a 1.9 Hz, H-1), 3.60 (dd, 1H, J4;4a
10.8 Hz, H-4), 3.34 (d, 1H, J1 ;8a ꢀ 0 Hz, H-10), 2.44–1.90
0
(m, 6H, H-4a,5,50,8,80,8a); 13C NMR (50.3 MHz,

C. A. Iriarte Capaccio, O. Varela / Carbohydrate Research 339 (2004) 1207–1213
1211
From the next fractions of the column was isolated
the epoxide 8 (9 mg, 6%) somewhat contaminated with
the more polar product; H NMR (500 MHz, CDCl3) d
6.11 (2dd, 2H, J6;7 5.6 Hz, J5;6 ꢀ J7;8 ¼ 3:0 Hz, H-6,7),
4.77, 4.44 (2d, 2H, J 11.7 Hz, PhCH2O), 4.35 (d, 1H, J3;4
1
0
6.5 Hz, H-3), 3.97 (dd, 1H, J1;1 11.9 Hz, J1;8a 5.8 Hz, H-
0
7.34 (m, 5H, H-aromatic), 4.79, 4.51 (2d, 2H, J 11.8 Hz,
PhCH2O), 4.68 (d, 1H, J3;4 3.9 Hz, H-3), 3.85 (dd, 1H,
1), 3.94 (dd, 1H, J4;4a 7.8 Hz, H-4), 3.51 (dd, 1H, J1 ;8a
4.9 Hz, H-10), 3.01, 2.82 (2br s, 2H, H-5,8), 2.75 (ddd,
1H, J4a;5 3.5 Hz, J4a;8a 10.4 Hz, H-4a), 2.59 (m, 1H,
J8;8a ꢀ 4:0 Hz, H-8a), 1.76 (br s, 1H, HO), 1.47 (br d,
0
J1;1 11.4 Hz, J1;8a 3.8 Hz, H-1), 3.53 (t, 1H, J4;4a 3.9 Hz,
H-4), 3.43 (dd, 1H, J1 ;8a 5.2Hz, H-1 0), 3.23 (br t, 1H,
0
1H, J9;9 8.2Hz, H-9), 1.34 (br d, 1H, H-9 0); 13C NMR
0
0
J6;7 ꢀ J7;8 ꢀ 4:0 Hz, H-7), 3.21 (m, 1H, H-6), 2.24 (dd,
0
1H, J8;8 15.5 Hz, J8;8a 8.2Hz, H-8), 2.18 (m, 1H, H-4a),
(50.3 MHz, CDCl3) d 137.9, 128.4, 127.9, 127.7 (C-aro-
matic), 135.8, 134.5 (C-6,7), 100.5 (C-3), 70.3 (C-4), 69.6
(PhC2O), 63.8 (C-1), 51.1 (C-9), 46.5, 44.8, 40.5, 39.4
(C-4a,5,8,8a). Anal. Calcd for C17H20O3: C, 74.97; H,
7.40. Found: C, 75.29; H, 7.07.
0
2.11 (ddd, 1H, J4a;5 8.2Hz, J5;5 15.5 Hz, J5;6 2.7 Hz, H-5),
2.05 (ddd, 1H, J4a;5 1.4 Hz, J5 ;6 6.6 Hz, H-50), 1.88 (dt,
0
0
1H, J8 ;8a ꢀ 4:0 Hz, H-80), 1.82(m, 1H, H-8a); 13C NMR
0
(50.3 MHz, CDCl3) d 137.4, 128.5, 128.0, 127.9 (C-aro-
matic), 99.6 (C-3), 71.9 (C-4), 69.5 (PhC2O), 64.3 (C-1),
52.9, 51.8 (C-6,7), 28.5, 28.1 (C-4a,8a), 25.6, 23.9
(C-5,8).
3.5. Conversion of 10 into the polycyclic alcohol 11
Upon elution of the column with mixtures of
increasing polarity of hexane–EtOAc (from 4:1 to 2:1)
the more polar product was isolated and identified as the
A solution of 10 (105 mg, 0.39 mmol, ee >86%) in CHCl3
(4 mL) was treated with a solution of m-chloroperoxy-
benzoic acid (80% purity, 150 mg, 0.70 mmol) in CHCl3
(4 mL). The mixture was stirred at room temperature for
5 min, when TLC (2:1 hexane–EtOAc) showed no
starting material (10; Rf 0.52) remaining and the for-
mation of a lower migrating product (Rf 0.29). This
compound was gradually converted into an even more
polar product (Rf 0.14), which was the major one
detected by TLC after 3 h of reaction. The mixture was
diluted with CH2Cl2, washed with satd aq NaHCO3,
dried (MgSO4), and concentrated. The product having
Rf 0.14 was isolated by flash chromatography (2.5:1
25
polycyclic alcohol 9 (34 mg, 21%, ee >86%); ½aŠ )67.4°
D
1
(c 1.4, CHCl3); H NMR (500 MHz, CDCl3) d 7.34 (m,
5H, H-aromatic), 4.94 (br s, 1H, H-3), 4.75, 4.52(2d,
2H, J 11.8 Hz, PhCH2O), 4.13 (dd, 1H, J5 ;6 6.1 Hz, J6;7
0
0
3.2Hz, H-6), 4.06 (ddd, 1H, J7;8 7.1 Hz, J7;8 3.7 Hz, H-
0
7), 3.88 (dd, 1H, J1;1 11.2Hz, J1;8a 2.1 Hz, H-1), 3.70 (d,
1H, J4;4a 3.6 Hz, H-4), 3.27 (dd, 1H, J1 ;8a 1.8 Hz, H-10),
0
0
2.42 (m, 1H, H-4a), 2.19 (ddd, 1H, J8;8 15.0 Hz, J8;8a
0
6.0 Hz, H-8), 2.17 (d, 1H, J4a;5 < 1 Hz, J5;5 11.6 Hz, H-
0
5), 1.97 (m, 1H, H-8a), 1.75 (ddd, 1H, J4a;5 ꢀ5.5 Hz, H-
50), 1.54 (ddd, 1H, J8 ;8a 9.8 Hz, H-80); 13C NMR
hexane–EtOAc) and identified as the polycyclic alcohol
0
25
(50.3 MHz, CDCl3) d 137.7, 128.4, 128.0, 127.8 (C-aro-
matic), 95.8 (C-3), 78.6 (C-6), 76.2(C-4), 70.4 (C-7), 69.0
(PhC2O), 63.0 (C-1), 32.7 (C-4a), 29.9, 29.8 (C-5,8), 28.1
(C-8a). Anal. Calcd for C16 H20O4: C, 69.55; H, 7.29.
Found: C, 69.83; H, 7.38.
On standing at room temperature, oxirane 8 in CHCl3
solution underwent almost quantitative conversion into
the polycyclic alcohol 9. The diastereoselectivity of the
reaction, determined from the 1H NMR spectrum of the
crude mixture after complete conversion of 8 into 9,
showed a 1.9:1.0 ratio for 7:9.
11 (93 mg, 84%, ee >86%); mp 137 °C; ½aŠ )58.3° (c 1.1,
D
CHCl3); 1H NMR (500 MHz, CDCl3+D2O) d 7.33 (br s,
5H, H-aromatic), 4.80 (d, 1H, J3;4 1.6 Hz, H-3), 4.72,
4.49 (2d, 2H, J 11.8 Hz, PhCH2O), 4.20 (br s, 1H,
0
J6;7 ꢀ 0 Hz, H-7), 4.07 (dd, 1H, J1;1 12.3 Hz, J1;8a 5.5 Hz,
H-1ax), 4.04 (d, 1H, J5;6 4.8 Hz, H-6), 3.92(dd, 1H, J4;4a
5.3 Hz, H-4), 3.72(d, 1H, J1 ;8a ꢀ 0 Hz, H-10eq), 2.82
0
(ddd, 1H, J4a;5 5.1 Hz, J5;9 1.2Hz, H-5), 2.49 (ddd, 1H,
J4a;8a 10.2Hz, H-4a), 2.12(br s, 1H, H-8), 1.92(br d, 1H,
0
J8;9 ꢀ 1:4 Hz, J9;9 10.7 Hz, H-9), 1.74 (ddd, 1H, J8;8a
3.9 Hz, H-8a), 1.38 (br d, 1H, H-90); 13C NMR
(50.3 MHz, CDCl3+D2O) d 137.4, 128.5, 127.9, 127.8
(C-aromatic), 95.3 (C-3), 88.9 (C-6), 76.4, 76.2(C-4,7),
69.1 (PhC2O), 58.2 (C-1), 48.0, 46.7 (C-5,8), 32.9, 32.7
(C-4a,8a), 31.8 (C-9). Anal. Calcd for C17H20O4: C,
70.81; H, 6.99. Found: C, 70.48; H, 6.86.
3.4. (3S,4R,4aR,5S,8R,8aS)-3-Benzyloxy-4-hydroxy-
3,4,4a,5,8,8a-hexahydro-5,8-methano-1H-2-benzopyran
(10)
The ketone group of 39 (0.55 g, 2.03 mmol, ee >86%) was
reduced with NaBH4 (95 mg, 2.51 mmol) as previously
described for the reduction of 2. After 15 min TLC (3:1
hexane–EtOAc) showed complete consumption of the
starting 3 (Rf 0.40) and formation of a more polar
product (Rf 0.23). The usual workup of the reaction
mixture followed by chromatographic purification led to
3.6. Conversion of 10 into the polycyclic iodide 12
A solution of iodine (0.12g, 0.47 mmol) in 96% EtOH
(7 mL) was added dropwise to a solution of 10 (0.10 g,
0.37 mmol, ee >86%) in 96% EtOH (7 mL). After 30 min
of stirring at room temperature, the mixture showed by
TLC (2:1 hexane–EtOAc) complete conversion of 10 (Rf
0.52) into a less polar product (Rf 0.68). The solution
was concentrated and the residue diluted with CH2Cl2.
the endo alcohol 10 (0.46 g, 83%, ee >86%) as an
25
D
amorphous solid; ½aŠ )103.4° (c 1.1, CHCl3); 1H NMR
(500 MHz, CDCl3) d 7.32(br s, 5H, H-aromatic), 6.18,

1212
C. A. Iriarte Capaccio, O. Varela / Carbohydrate Research 339 (2004) 1207–1213
The organic solution was washed with satd aq Na2S2O3,
dried (MgSO4), and concentrated. The residue was
purified by flash chromatography (50:1 hexane–EtOAc)
CDCl3+D2O) d 7.33 (m, 5H, H-aromatic), 4.90, 4.64
(2d, 2H, J 12.5 Hz, PhCH2O), 4.32(br s, 1H, J6;7 ꢀ 0 Hz,
0
H-7), 4.24 (br s, 1H, J3;4 ꢀ 0 Hz, H-3), 4.18 (d, 1H, J1;1
to afford 12 (0.12g, 81%, ee >86%) as a colorless,
12.8 Hz, J1;8a < 1 Hz, H-1eq), 4.16 (d, 1H, J5;6 4.7 Hz, H-
25
D
0
crystalline solid; mp 126 °C; ½aŠ )18.9° (c 1.1, CHCl3);
6), 4.02(d, 1H, J4;4a 5.2Hz, H-4), 3.77 (dd, 1H, J1 ;8a
1H NMR (500 MHz, CDCl3) d 7.33 (br s, 5H, H-aro-
matic), 4.80-4.79 (m, 2H, H-3,6), 4.71, 4.50 (2d, 2H, J
5.2Hz, H-1 0ax), 2.78 (br dt, 1H, J4a;5 5.0 Hz, J5;9 1.1 Hz,
0
H-5), 2.43 (ddd, 1H, J4a;8a 10.0 Hz, H-4a), 2.12 (br s, 1H,
0
0
11.8 Hz, PhCH2O), 4.42(d, 1H, J6;7 ꢀ 0 Hz, J7;9 2.5 Hz,
H-8), 1.95 (d, 1H, J9;9 10.6 Hz, H-9), 1.66 (ddd, 1H,
J8;8a ꢀ 4:0 Hz, H-8a), 1.36 (br dd, 1H, H-90); 13C NMR
(50.3 MHz, CDCl3+D2O) d 137.4, 128.3, 128.2, 127.7
(C-aromatic), 98.7 (C-3), 89.1 (C-6), 77.1, 76.2(C-4,7),
70.0 (PhC2O), 66.1 (C-1), 47.5, 46.2(C-5,8), 38.8, 34.1
(C-4a,8a), 32.6 (C-9). Anal. Calcd for C17H20O4: C,
70.81; H, 6.99. Found: C, 70.45; H, 6.97.
0
H-7), 4.08 (dd, 1H, J1;1 12.5 Hz, J1;8a 5.2Hz, H-1ax),
3.89 (dd, 1H, J3;4 1.7 Hz, J4;4a 5.4 Hz, H-4), 3.73 (d, 1H,
J1 ;8a ꢀ 0 Hz, H-10eq), 2.79 (ddd, 1H, J4a;5 5.1 Hz, J5;6
0
4.8 Hz, J5;9 1.3 Hz, H-5), 2.54 (ddd, 1H, J4a;8a 10.0 Hz, H-
0
4a), 2.44 (br s, 1H, H-8), 2.11 (br d, 1H, J8;9 1.1 Hz, J9;9
10.9 Hz, H-9), 1.86 (ddd, 1H, J8;8a 3.7 Hz, H-8a), 1.65 (br
d, 1H, H-90); 13C NMR (50.3 MHz, CDCl3) d 137.3,
128.5, 128.0, 127.9 (C-aromatic), 95.0 (C-3), 90.8 (C-6),
75.7 (C-4), 69.2(Ph C2O), 58.1 (C-1), 50.0 (C-5), 49.9 (C-
8), 36.3 (C-9), 35.0 (C-8a), 33.2(C-7), 32.8 (C-4a). Anal.
Calcd for C17H19IO3: C, 51.27; H, 4.81; I, 31.87. Found:
C, 51.69; H, 4.92; I, 31.46.
Acknowledgements
This work was supported by grants from the University
of Buenos Aires (Project TX108) and the National Re-
ꢀ
search Council of Republica Argentina (CONICET).
O.V. is a Research Member of CONICET.
3.7. (3S,4S,4aS,5R,8S,8aR)-3-Benzyloxy-4-hydroxy-
3,4,4a,5,8,8a-hexahydro-5,8-methano-1H-2-benzopyran
(13)
The ketone group of 417 (0.33 g, 1.22 mmol, ee >86%)
was reduced with NaBH4 (57 mg, 1.51 mmol) as previ-
ously described for the reduction of 3. After 1 h, the
usual workup of the reaction mixture followed by
chromatographic purification led to alcohol 13 (0.29 g,
References
25
D
87%, ee >86%) as an amorphous solid; ½aŠ )57.3° (c
1
1. Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.; Vassiliko-
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1.1, CHCl3); H NMR (500 MHz, CDCl3+D2O) d 7.33
(br s, 5H, H-aromatic), 6.26, 5.87 (2dd, 2H, J6;7 5.6 Hz,
J5;6 ꢀ J7;8 ¼ 3:1 Hz, H-6,7), 4.85, 4.57 (2d, 2H, J
11.9 Hz, PhCH2O), 4.65 (dd, 1H, J3;4 3.2Hz, H-3), 4.08
0
(dd, 1H, J4;4a 5.6 Hz, H-4), 3.74 (ddd, 1H, J1;1 10.2Hz,
J1;8a 6.2Hz, H-1eq), 3.50 (dd, 1H, J1 ;8a 11.8 Hz, H-10ax),
3.01 (br s, 1H, H-5), 2.76 (br s, 1H, H-8), 2.52 (dddd,
0
1H, J4a;8a 10.0 Hz, J5;8a 3.6 Hz, H-8a), 2.27 (ddd, 1H, J4a;5
0
3.4 Hz, H-4a), 1.50 (dt, 1H, J5;9 ꢀ J8;9 ¼ 1:8 Hz, J9;9
8.0 Hz, H-9), 1.37 (br d, 1H, H-90); 13C NMR
(50.3 MHz, CDCl3) d 137.9, 131.1 (C-6,7), 137.8, 128.4,
127.9, 127.7 (C-aromatic), 95.7 (C-3), 69.2 (PhC2O),
68.0 (C-4), 65.0 (C-1), 51.3 (C-9), 45.6, 44.1, 40.7, 39.7
(C-4a,5,8,8a). Anal. Calcd for C17H20O3 : C, 74.97; H,
7.40. Found: C, 75.09; H, 7.39.
3.8. Conversion of 13 into the polycyclic alcohol 14
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benzoic acid (80% purity, 150 mg, 0.70 mmol) in CHCl3
(4 mL). After 3 h, the usual workup of the reaction
mixture followed by chromatographic purification led to
25
the polycyclic alcohol 14 (71 mg, 65%, ee >86%); ½aŠ
D
)43.9° (c 1.2, CHCl3); 1H NMR (500 MHz,

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