DIBALH mediated reduction of the acetal moiety on perhydrofuro[2,3-b]pyran derivatives

Article abstract of DOI:10.1016/S0008-6215(01)00200-2

The reaction of DIBALH with bis(heteroannulated)-pyranosides containing the perhydrofuro[2,3-b]pyran moiety is described. The hydride attack at the anomeric carbon (C-9a) resulted in the exclusive tetrahydrofuran ring opening. The selectivity of this reaction has been evaluated as other benzylidene acetals built on these substrates remain practically or partially unaltered in these conditions depending on the steric volume of the O-protecting group located at C-4 (TBDMS vs. Me). This protocol can be considered as a new entry for the synthesis of chiral and highly functionalized cyclopentanes.

Full text of DOI:10.1016/S0008-6215(01)00200-2

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Carbohydrate Research 335 (2001) 63–70
Note
DIBALH mediated reduction of the acetal moiety on
perhydrofuro[2,3-b]pyran derivatives
Jose´ Marco-Contelles,* Juliana Ruiz-Caro
Laboratorio de Radicales Libres, Instituto de Quimica Organica General, CSIC, C/Juan de la Cier6a 3,
ES-28006 Madrid, Spain
Received 23 May 2001; received in revised form 9 July 2001; accepted 10 July 2001
Abstract
The reaction of DIBALH with bis(heteroannulated)-pyranosides containing the perhydrofuro[2,3-b]pyran moiety
is described. The hydride attack at the anomeric carbon (C-9a) resulted in the exclusive tetrahydrofuran ring opening.
The selectivity of this reaction has been evaluated as other benzylidene acetals built on these substrates remain
practically or partially unaltered in these conditions depending on the steric volume of the O-protecting group
located at C-4 (TBDMS vs. Me). This protocol can be considered as a new entry for the synthesis of chiral and highly
functionalized cyclopentanes. © 2001 Elsevier Science Ltd. All rights reserved.
Keywords: DIBALH; Furo[2,3-b]pyrans; Reductive cleavage of benzylidene acetals
1. Introduction
2. Results and discussion
A recent report on the reduction of spiroac-
etals in sugar templates,1 prompts us to report
here the results of the DIBALH mediated
reduction of the acetal group incorporated in
perhydrofuro[2,3-b]pyran derivatives (B)2 ob-
tained via Pauson–Khand reaction3 on suit-
able functionalized 2-propynyl hex-2-enopyra-
nosides (A). This protocol has resulted in a
new entry for the synthesis of enantiomerically
pure, highly functionalized cyclopentanes4 (C)
(Scheme 1) difficult to prepare by other strate-
gies (see Chart 1).5
In the course of our ongoing project,2 we
considered the reduction of ketone 15 (Scheme
2) with DIBALH (1.0 M in toluene, 2.0 equiv)
at −78 °C, in toluene as solvent. In these
conditions, in addition to product 2 (69%
yield), we isolated the unexpected allylic alco-
hol 3 in 9% yield (see Section 3). In both cases
the ketone reduction proceeded stereoselec-
tively from the less hindered b-face to give
compounds with the absolute S configuration
* Corresponding author. Tel.: +34-91-5622900; fax: +34-
91-5644853.
E-mail address: iqoc21@iqog.csic.es (J. Marco-Contelles).
Scheme 1. Reductive cleavage of perhydrofuro[2,3-b]pyrans.
0008-6215/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0008-6215(01)00200-2

64
J. Marco-Contelles, J. Ruiz-Caro / Carbohydrate Research 335 (2001) 63–70
and limitations of this protocol. In connection
with our current synthetic interests2 we con-
sidered products 8 and 9, containing a benzyl-
idene acetal at positions OꢀC-5/OꢀC-7. In
fact, reductive opening of carbohydrate
benzylidene acetals with AlCl3–LiAH4,6
NaCNBH3–HCl7 or DIBALH8 is a very well
known and exploited method for the regio-
selective cleavage of O-benzylidene acetals
leading to O-benzyl ethers.
Products 8 and 9 have been easily prepared
from compound 65 after mild ketone reduc-
tion followed by standard O-protection (8: 87,
9: 86%; Scheme 3) (see Section 3).
The reduction of compound 8 in toluene as
solvent, at −78 or at −40 °C afforded alco-
hol 10 in 26 or 57% yield, respectively. Using
methylene chloride at −78 °C, alcohol 10
(21%) was again obtained. Finally, when the
DIBALH mediated reduction was carried out
at −40 °C in methylene chloride, a clean and
complete reaction occurred affording product
10 in good yield (79%) along with minor
amounts of product 11 (8% yield) (Scheme 4).
The analytical and spectroscopic data of 10
clearly showed that this product was the result
of the exclusive and regioselective cleavage of
the glycosidic bond followed by tetra-
hydrofuran ring opening, as we could demon-
strate by additional chemical manipulation of
compound 10 giving acetate 12 (99%), and
aldehyde 14 (82%) after oxidation (Scheme 4).
Substrate 11 was the result of the cleavage of
the glycosidic bond followed by tetra-
hydrofuran ring opening plus the reduction of
the benzylidene group. Very interestingly, in
Chart 1.
Scheme 2. (a) DIBALH, −78 °C, toluene; (b) Ac2O, py, rt.
at the newly formed stereocenters.2 After
acetylation, compounds 2 and 3 gave acetate 4
(99%) and diacetate 5 (46%), respectively. Par-
ticularly significant in product 5 was the ab-
sence of the anomeric proton, substituted by
two protons at 3.38 ppm (t, J1,1%=J1,9a 11.5
Hz, H-1) and at 4.17 ppm (ddd, J1,1% 11.5, J1%,9a
6.6, J 0.5 Hz, H-1%), a fact which led us to
conclude that 3 was the product resulting after
hydride attack at C-9a and subsequent tetra-
hydrofuran ring opening, the formation of the
alternative product having a secondary alco-
hol after a possible tetrahydropyran ring
opening, being excluded.
Scheme 3. (a) DIBALH, −78 °C, toluene5; (b) ClTBDMS,
imidazole, CH2Cl2, rt; (c) NaH, ICH3, THF, rt.
This interesting result prompted us to pre-
pare new related derivatives in order to ad-
dress the selectivity of the reduction regarding
other functional groups, as well as the scope
Scheme 4. (a) DIBALH, −40 °C, CH2Cl2; (b) Ac2O, py, rt;
(c) PCC, CH2Cl2, rt.

J. Marco-Contelles, J. Ruiz-Caro / Carbohydrate Research 335 (2001) 63–70
65
spectra, we could also detect the same trends:
in 16, C-4 was observed at 67.5 ppm, and in
17 at 69.3 ppm (Dl= +1.8).
In summary, the most interesting result of
this work is the preferred reduction of the
acetal at the glycosidic bond with regard to
the benzylidene acetal in these perhydro-
furo[2,3-b]pyrans. From the mechanistic point
of view, it is proposed that in the DIBALH
reduction, coordination of the aluminum
reagent to the oxygens induced the formation
of the oxonium intermediates followed by
rapid intramolecular capture of the oxonium
ion by the hydride source (see Scheme 6).
Comparing the reactivity of 8 and 9, it ap-
pears that the presence of a more sterically
demanding group at OꢀC-4 in compound 8
directs the preferential, regioselective cleavage
at the acetal moiety of the glycosidic bond,
and regarding the reductive opening of the
benzylidene acetal, the formation of the 4-O-
benzyl protected cyclopentane-annulated py-
ranoside (11) (intermediate A, Scheme 6). As a
result, the ratio of products 10/11 is above
that in compounds 15/16. Presumably, the less
sterically demanding methyl ether in com-
pound 9 allows a possible aluminum coordi-
nation with the oxygens at OꢀC-5/OꢀC-4
which should result in the hydride delivery
giving rise to compound 16 with the O-benzyl
ether in C-3a via intermediate B (Scheme 6).
In this analysis, we cannot exclude a concerted
bond breaking and hydride transfer versus the
oxy-cationic DIBALH complexes in rapid
equilibrium, as discussed. Regardless of the
exact mechanism of the process, the bond
breaking should be the rate determining step
Scheme 5. (a) DIBALH, −40 °C, CH2Cl2; (b) Ac2O, py, rt.
product 11, the resulting O-benzyl group was
located at the secondary carbon (C-4), in good
agreement with similar trends observed for the
reduction of benzylidene groups.6 As ex-
pected, diol 11 gave diacetate 13 (7% overall
yield from precursor 8) in the usual
conditions.
The reduction of product 9 using DIBALH
at −40 °C, in methylene chloride, afforded
two compounds in good overall yield: alcohol
15 (32%) and diol 16 (34%) (Scheme 5). Their
analytical data and the comparison of their
spectroscopic data with those of compounds
10 and 11 (see above) clearly supported and
confirmed these structures (see Section 3). Par-
ticularly interesting in this case was, first of
all, the preferred glycosidic reduction giving
tetrahydrofuran ring opening molecules; sec-
ondly, the absence of selectivity, as an almost
equimolecular ratio of the unreduced benzyli-
dene acetal 15 and the reduced benzylidene
acetal 16 having the O-benzyl group at C-3a
resulted. This was confirmed after peracetyla-
tion of 16 giving diacetate 17 (90%). The
structure of this product has been inequivo-
cally demonstrated by detailed spectroscopic
analysis and by comparison of these data with
those of compound 16. It was observed that in
16, H-4 appeared at 3.85 ppm, and in 17 at
5.13 ppm (Dl= +1.28), while protons at
C-3a in compound 16 or in 17 practically
remained at the same field. In the 13C NMR
Scheme 6. Proposed mechanism for the DIBALH-mediated reduction of acetals 8 and 9.

66
J. Marco-Contelles, J. Ruiz-Caro / Carbohydrate Research 335 (2001) 63–70
and, in consequence, the key point here
should be the quality of the leaving group. In
this regard, the allylic oxy group should be a
better leaving group than the benzyloxy carbe-
nium intermediate. The exclusive bond cleav-
age of the pseudoaxial OR group exo to the
tretrahydropyran ring is probably a conse-
quence of the resulting highly stabilized a-py-
ranosyl carbenium intermediate (C) (Scheme
6). But one cannot exclude the release of
strain in these perhydrofuro[2,3-b]pyran
derivatives as an additional fact operating also
in the same sense. In fact, simple, differently
substituted a-methyl glycosides are stable to
the hydride mediated reduction of benzylidene
acetals.6
When the reaction was complete (3 h), MeOH
was added to destroy the excess of reagent
and the mixture was warmed at rt. The sus-
pension was filtered over Celite, the solvent
removed and the crude reaction mixture was
submitted to chromatography.
General method for acetylation.—The com-
pound was treated with a mixture of 1:1
Ac2O–pyridine at rt overnight. The solvent
was evaporated and the residue was submitted
to chromatography.
Reduction of ketone (1).—Following the
method in Section 3.2, 1 (358 mg, 1.42 mmol)
was treated with DIBALH (1.6 mL, 1.1 equiv,
1.0 M in toluene). After 1 h, a further portion
of DIBALH (1.3 mL, 0.9 equiv) was added.
After usual work-up and flash chromatogra-
phy of the crude product (from hexane to 3:2
hexane–EtOAc), we obtained compounds
(4S,4aR,4bS,8aR,9aS,9bS)-6,6%-dimethyl-4,4a,
4b,6,8,8a,9a,9b - octahydro - 2H - 1,5,7,9 - tetra-
oxacyclohexa[g]cyclopenta[cd]indene-4-ol (2)
(249 mg, 69%) and 3 (33.2 mg, 9%), character-
ized as its diacetate {(2aR,6aS,6bR,7S,9aS)-7-
acetyloxy - 5,5% - dimethyl - 1,2a,3,5,6a,6b,7,9a-
octahydro-4,6-dioxacyclohexa[e]cyclopenta[c]-
pyran-9-methanol acetate} (5). 2: mp 101–
104 °C; [h]2D5 −6° (c 0.04, CHCl3); IR (BrK) w
Finally, from the synthetic point of view,
these results have afforded a new and simple
protocol for the synthesis of chiral and highly
polyfunctionalized cyclopentanes.
3. Experimental
General methods.—Reactions were moni-
tored by TLC using precoated silica gel alu-
minum plates containing
a
fluorescent
indicator (E. Merck, 5539). Detection was
done by UV (254 nm) followed by charring
with sulfuric–AcOH spray, 1% aq KMnO4
solution or 0.5% phosphomolybdic acid in
95% EtOH. Anhydrous Na2SO4 was used to
dry organic solutions during work-ups and the
removal of solvents was carried out under
diminished pressure with a rotary evaporator.
Flash column chromatography was performed
using Silica Gel 60 (230–400 mesh, E. Merck)
and hexane–EtOAc mixtures as eluent unless
1
3390, 1360, 1080, 990, 835 cm−1; H NMR
(300 MHz, CDCl3): l 5.83–5.79 (m, 1 H,
H-3), 5.43–5.37 (m, 1 H, H-4), 5.35 (d, J9a,9b
5.5 Hz, 1 H, H-9a), 5.30 (d, JOH,4 6.4 Hz, 1 H,
OH), 4.54 (ddd, J2,2% 13.0, J 3.5, J 1.8 Hz, 1 H,
H-2), 4.21 (ddt, J2%,2 13.0, J 4.0, J 2.2 Hz, 1 H,
H-2%), 4.16 (ddd, J8a,4b 10.3, J8a,8 9.4, J8a,8% 5.5
Hz, 1 H, H-8a), 4.06 (dd, J4b,8a 10.3, J4b,4a 7.5
Hz, 1 H, H-4b), 3.88 (dd, J8%,8 11.2, J8%,8a 5.5
Hz, 1 H, H-8%), 3.51 (dd, J8,8% 11.2, J8,8a 9.4 Hz,
1 H, H-8), 3.32–3.26 (m, 1 H, H-9b), 3.16 (dt,
J4a,4b 7.5, J4a,4 =J4a,9b 6.6 Hz, 1 H, H-4a), 1.46,
1.42 [s, s, 2×3 H, OC(CH3)2O]; 13C NMR (75
MHz, CDCl3): l 144.0 (C-2a), 127.3 (C-3),
100.1 (C-6), 95.6 (C-9a), 86.4 (C-4), 72.8 (C-
4b), 64.1 (C-2), 63.4 (2 C, C-8a, C-8), 51.7
(C-9b), 39.5 (C-4a), 29.0, 18.3 [OC(CH3)2O];
EIMS: m/z 153 (54), 124 (22), 107 (53), 101
(26), 79 (100), 43 (93). Anal. Calcd for
C13H18O5: C, 61.41; H, 7.13. Found: C, 61.72;
H, 7.40. 5 [obtained from 3 (33 mg, 0.13
mmol) following the method in Section 3.3
after flash chromatography of the crude (4:2
1
otherwise stated. H spectra were recorded
with a Varian VXR-300(400)S spectrometers,
using tetramethylsilane as internal standard
and 13C NMR spectra were recorded with a
Bruker WP-200-SY. Values with (*) can be
interchanged.
General method for DIBALH reduction.—
The compound to be reduced was dissolved
(0.15 M) and cooled in dry toluene (−78 °C)
or CH2Cl2 (−40 °C) at the selected tempera-
ture. Thus DIBALH (1.1 equiv, 1.0 M in
toluene) was added and after 3 h, a further
amount of DIBALH (1.9 equiv) was added.

J. Marco-Contelles, J. Ruiz-Caro / Carbohydrate Research 335 (2001) 63–70
67
(4), 195 (17), 178 (13), 107 (40), 101 (28), 91
(15), 79 (88), 43 (100). Anal. Calcd for
C15H20O6: C, 60.80; H, 6.80. Found: C, 60.64;
H, 6.62.
hexane–EtOAc): 5 (17.9 mg, 46%)]: mp 74–
77 °C; [h]2D5 +210° (c 0.74, CHCl3); IR (BrK):
w 1737, 1380, 1234, 1108, 1073, 1029, 867
1
cm−1; H NMR (300 MHz, CDCl3): l 5.92–
(4S,4aR,4bS,8aR,9aS,9bS)-4-O-[((1,1-Di-
methylethyl)dimethylsilyloxy] - 4,4a,4b,6,8,8a,
9a,9b-octahydro-6-phenyl-2H-1,5,7,9-tetra-
oxacyclohexa[g]cyclopent[cd]indene (8).—To a
solution of alcohol 7 (151 mg, 0.5 mmol) in
dry CH2Cl2 (4.2 mL, 0.12 M) cooled in an
ice-bath (0 °C), under Ar and stirring, imida-
zole (37 mg, 0.55 mmol, 1.1 equiv), tert-
butyldimethylsilyl chloride (88 mg, 0.55 mmol,
1.1 equiv) and 4-DMAP (cat.) were added.
The mixture was warmed at rt for 5 h; then,
more imidazole (31 mg, 0.45 mmol, 0.9 equiv),
tert-butyldimethylsilyl chloride (68 mg, 0.45
mmol, 0.9 equiv) were added. After 24 h the
operation was repeated again. Finally, after
48 h the mixture was diluted with CH2Cl2,
extracted with aq satd NaHCO3 solution and
brine. The organic phase was dried (Na2SO4),
filtered, evaporated and submitted to flash
chromatography (9:1 hexane–EtOAc) to give
8 (180 mg, 87%): mp 61–64 °C; [h]2D5 +28° (c
0.29, CHCl3); IR (KBr) w 1371, 1104, 1092,
5.91 (m, 1 H, H-7), 5.89–5.88 (m, 1 H, H-8),
4.68 (d, J9%A,9%B 14.3 Hz, 1 H, H-9%A), 4.58 (d,
J9%A,9%B 14.3 Hz, 1 H, H-9%B), 4.17 (ddd, J1%,1
11.5, J1%,9a 6.6, J 0.5 Hz, 1 H, H-1%), 4.01 (dd,
J6a,2a 9.9, J6a,6b 6.6 Hz, 1 H, H-6a), 3.89 (dd,
J3%,3 9.9, J3%,2a 4.4 Hz, 1 H, H-3%), 3.71 (td,
J2a,6a=J2a,3 9.9, J2a,3% 4.4 Hz, 1 H, H-2a), 3.62
(t, J3,3%=J3,2a 9.9 Hz, 1 H, H-3), 3.38 (t,
J1,1%=J1,9a 11.5 Hz, 1 H, H-1), 2.94 (dt, J9a,1
11.5, J9a,6b =J9a,1% 6.6 Hz, 1 H, H-9a), 2.67 (q,
J6b,6a =J6b,7=J6b,9a 6.6 Hz, 1 H, H-6b), 2.09,
2.08 (s, s, 2×3 H, 2 OCOCH3), 1.50, 1.35 [s,
13
s, 2×3 H, OC(CH3)2O]; C NMR (75 MHz,
CDCl3): l 170.4, 169.9 (2 C, OCOCH3), 147.6
(C-9), 127.8 (C-8), 99.6 (C-5), 75.5 (C-7), 71.4
(C-1), 71.0 (2 C, C-6a, C-2a), 70.8 (C-3), 61.6
(C-9%), 45.0 (C-9a), 41.5 (C-6b), 29.2, 18.7
[OC(CH3)2O], 21.6, 20.8 (2 C, OCOCH3);
EIMS: m/z 239 (20), 137 (20), 134 (25), 91
(100), 43 (51). Anal. Calcd for C17H24O7: C,
59.99; H, 7.11. Found: C, 59.67; H, 6.95.
(4S,4aR,4bS,8aR,9aS,9bS) - 6,6% - Dimethyl-
4,4a,4b,6,8,8a,9a,9b-octahydro-2H-1,5,7,9-tet-
raoxacyclohexa[g]cyclopent[cd]indene-4-ol ace-
tate (4).—Following the method in Section
3.3 from 2 (23.3 mg, 0.077 mmol), compound
4 (23 mg, 99%)] was obtained after flash chro-
matography (3:1 hexane–EtOAc): mp 141–
144 °C; [h]2D5 −91° (c 0.1, CHCl3); IR (KBr) w
1
1071, 1028, 985, 891, 855 cm−1; H NMR
(300 MHz, CDCl3): l 7.48–7.28 (m, 5 H,
C6H5), 5.66 (s, 1 H, H-3), 5.47–5.43 (m, 1 H,
H-4), 5.42 (d, J9a,9b 4.4 Hz, 1 H, H-9a), 5.39 (s,
1 H, H-6), 4.52 (dm, J2,2% 12.5 Hz, 1 H, H-2),
4.39 (td, J8a,4b=J8a,8 10.0, J8a,8% 5.5, 1 H, H-
8a), 4.31 (dd, J8,8% 10.0, J8%,8a 5.5 Hz, 1 H,
H-8%), 4.23 (dm, J2,2% 12.5 Hz, 1 H, H-2%), 3.88
(dd, J4b,8a 10.0, J4b,4a 5.9 Hz, 1 H, H-4b), 3.47
(t, J8,8%=J8,8a 10.0 Hz, 1 H, H-8), 3.36–3.33
(m, 1 H, H-9b), 3.23 (dt, J4a,4 8.8, J4a,4b =J4a,9b
1
1733, 1241, 1115, 1015, 863 cm−1; H NMR
(300 MHz, CDCl3): l 6.27–6.23 (m, 1 H,
H-4), 5.70–5.67 (m, 1 H, H-3), 5.42 (d, J9a,9b
4.0 Hz, 1 H, H-9a), 4.54 (dm, J2,2% 13.0 Hz, 1
H, H-2), 4.26 (dm, 1 H, H-2%), 4.15 (ddd, J8a,4b
10.1, J8a,8 9.1, J8a,8% 5.9 Hz, 1 H, H-8a), 3.91
(ddm, J4b,8a 10.1, J4b,4a 6.5 Hz, 1 H, H-4b),
3.88 (dd, J8%,8 11.5, J8%,8a 5.9 Hz, 1 H, H-8%),
3.54 (dd, J8,8% 11.5, J8,8a 9 Hz, 1 H, H-8),
3.39–3.36 (m, 2 H, H-4a, H-9b), 2.08 (s, 3 H,
COOCH3), 1.44, 1.36 [s, s, 2×3 H,
OC(CH3)2O]; 13C NMR (75 MHz, CDCl3): l
170.6 (OCOCH3), 147.1 (C-2a), 122.7 (C-3),
99.3 (C-6), 95.1 (C-9a), 84.3 (C-4), 70.0 (C-
4b), 63.9 (C-8a), 63.6 (C-8), *63.5 (C-2), *53.9
(C-9b), 39.5 (C-4a), 28.8, 18.5 [2 C,
OC(CH3)2O], 21.4 (OCOCH3); EIMS: m/z 281
5.9 Hz,
1
H, H-4a), 0.74 [s,
9
H,
Si(CH3)2C(CH3)3], 0.03, −0.28 [s, s, 2×3 H,
Si(CH3)2C(CH3)3]; 13C NMR (75 MHz,
CDCl3): l 143.5 (C-2a) 137.7–126.3 (C6H5),
127.7 (C-3), 101.9 (C-6), 95.3 (C-9a), 84.4
(C-4), 77.9 (C-4b), 70.9 (C-8), 63.7 (C-2), 63.4
(C-8a), 54.3 (C-9b), 41.4 (C-4a), 26.0
[Si(CH3)2C(CH3)3], 18.5 [Si(CH3)2C(CH3)3],
−5.2, −5.5 [2 C, Si(CH3)2C(CH3)3]; EIMS:
m/z 359 (49), 225 (43), 207 (58), 181 (35), 161
(38), 129 (35), 105 (36), 91 (100). Anal. Calcd
for C23H32O5Si: C, 66.32; H, 7.74. Found: C,
66.08, H, 7.45.

68
J. Marco-Contelles, J. Ruiz-Caro / Carbohydrate Research 335 (2001) 63–70
hexahydro - cyclopenta[c]pyran - 7 - methanol
(4S,4aR,4bS,8aR,9aS,9bS) - 4 - Methoxy-
acetate} (13). Compound 10: mp 81–84 °C;
4,4a,4b,6,8,8a,9a,9b-octahydro-6-phenyl-2H-
1,5,7,9-tetraoxacyclohexa[g]cyclopent[cd]indene
(9).—To a solution of 7 (110 mg, 0.36 mmol)
in dry DMF (2.4 mL, 0.15 M) cooled at 0 °C,
under Ar and stirring, NaH (66 mg, 1.1 mmol,
3 equiv, 60% dispersion in oil) and methyl
iodide (0.07 mL, 1.1 mmol, 3 equiv) were
added. The mixture was warmed at rt in 6 h.
The solvent was removed and the crude reac-
tion mixture was diluted with EtOAc (20 mL),
and extracted with aq satd NaCl solution. The
organic phase was dried (Na2SO4), filtered,
and the solvent was evaporated and the crude
reaction mixture was submitted to flash chro-
matography (3:2 hexane–EtOAc) to give 9 (99
mg, 86%): oil; [h]2D5 −26° (c 0.29, CHCl3); IR
(KBr) w 1372, 1125, 1037, 1014, 976, 700
[h]2D5 +144° (c 0.20, CHCl3); IR (KBr) w 3437,
1
1115, 1077, 1048, 837, 697 cm−1; H NMR
(300 MHz, CDCl3): l 7.54–7.34 (m, 5 H,
C6H5), 5.86 (br s, 1 H, H-8), 5.58 (s, 1 H,
H-5), 4.82 (dd, J7,6b 6.1, J7,8 2.2 Hz, 1 H, H-7),
4.33 (dd, J3%,3 10.0, J3%,2a 5.0 Hz, 1 H, H-3%),
4.24 (td, J2a,6a=J2a,3 10.0, J2a,3% 5.0 Hz, 1 H,
H-2a), 4.20 (br s, 2 H, 2 H-9%), 4.14 (dd, J1%,1
11.0, J1%,9a 6.1 Hz, 1 H, H-1%), 3.96 (dd, J6a,2a
10.0, J6a,6b 6.1 Hz, 1 H, H-6a), 3.59 (t, J3,3%
=
J3,2a 10.0 Hz, 1 H, H-3), 3.56 (t, J1,1%=J1,9a
11.0 Hz, 1 H, H-1), 2.91 (dt, J9a,1 11.0, J9a,1%
J9a,6b 6.1 Hz, 1 H, H-9a), 2.56 (q, J6b,7
=
=
J
6b,6a=J6b,9a 6.1 Hz, 1 H, H-6b), 1.59 (br s, 1
H, OH), 0.89 [s, 9 H, Si(CH3)2C(CH3)3], 0.04,
0.03 [s, s, 2×3 H, Si(CH3)2C(CH3)3]; 13C
NMR (75 MHz, CDCl3): l 149.1 (C-9),
137.8–126.4 (C6H5), 129.7 (C-8), 102.6 (C-5),
80.1 (C-6a), 75.1 (C-7), 71.7 (C-1), 70.3 (C-3),
68.8 (C-2a), 61.1 (C-9%), 45.3 (C-9a), *43.9
1
cm−1; H NMR (300 MHz, CDCl3): l 7.51–
7.32 (m, 5 H, C6H5), 5.80 (s, 1 H, H-3), 5.41
(d, J9a,9b 4.2 Hz, 1 H, H-9a), 5.37 (s, 1 H,
H-6), 4.97 (m, 1 H, H-4), 4.53 (d, J2,2% 12.8 Hz,
1 H, H-2), 4.35–4.22 (m, 3 H, H-8a, H-2%,
H-8), 3.85 (dd, J4b,8a 9.8, J4b,4a 5.9 Hz, 1 H,
H-4b), 3.35 (s, 3 H, OCH3), 3.50–3.48 (m, 1
(C-6b),
*25.9
[Si(CH3)2C(CH3)3],
17.9
[Si(CH3)2C(CH3)3], −4.5, −4.8 [2 C,
Si(CH3)2C(CH3)3]; EIMS: m/z 269 (36), 251
(30), 133 (30), 129 (27), 105 (50), 75(100).
Anal. Calcd for C23H34O5Si: C, 65.99; H, 8.19.
Found: C, 66.15; H, 8.48. Compound 13 [ob-
tained from 11 (7.4 mg, 0.018 mmol) following
the method in Section 3.3 after flash chro-
matography (4:1 hexane–EtOAc): 13 (7.2 mg,
81%)]: oil; [h]D25 +162° (c 0.36, CHCl3); IR
(KBr) w 1742, 1455, 1367, 1246, 1104, 1075,
13
H, H-8%), 3.40–3.28 (m, 2 H, H-4a, H-9b); C
NMR (75 MHz, CDCl3): l 144.8 (C-2a),
144.7–126.4 (C6H5), 125.1 (C-3), 102.4 (C-6),
95.2 (C-9a), 84.2 (C-4), 77.7 (C-4b), 70.6 (C-
8), 63.6 (C-8a), 62.7 (C-2), 59.5 (OCH3), 53.3
(C-9b), 39.8 (C-4a); EIMS: m/z 180 (29), 149
(25), 109 (64), 107 47), 105 (66), 91 (94), 79
(100). Anal. Calcd for C18H20O5: C, 68.34; H,
6.37. Found: C, 68.45; H, 6.24.
1
1042, 880, 837, 776 cm−1; H NMR (300
MHz, CDCl3): l 7.35–7.26 (m, 5 H, C6H5),
5.84 (br s, 1 H, H-6), 4.77 (dd, J5,4a 6.0, J5,6 2.4
Hz, 1 H, H-6), 4.63 (d, J7%A,7%B 13.9 Hz, 1 H,
H-7%A), 4.63 (d, J 11.7 Hz, 1 H, OCH2C6H5),
4.56 (d, J7%A,7%B 13.9 Hz, 1 H, H-7%B), 4.51 (d,
J 11.7 Hz, 1 H, OCH2C6H5), 4.34 (dm, J3a%,3a
9.7 Hz, 1 H, H-3a%), 4.19–4.13 (m, 2 H, H-3,
H-3a), 4.10 (dd, J1%,1 11.2, J1%,7a 6.0 Hz, 1 H,
H-1%), 3.69 (dd, J4,3 9.8, J4,4a 6.0 Hz, 1 H, H-4),
3.49 (t, J1,1%=J1,7a 11.2 Hz, 1 H, H-1), 2.73
(dt, J7a,1 11.2, J7a,1%=J7a,4a 6.0 Hz, 1 H, H-7a),
2.55 (q, J4a,5 =J4a,4=J4a,7a 6.0 Hz, 1 H, H-4a),
2.05, 2.01 (s, s, 2×3 H, 2 OCOCH3), 0.83 [s,
9 H, Si(CH3)2C(CH3)3], 0.05, −0.016 [s, s,
2×3 H, Si(CH3)2C(CH3)3]; 13C NMR (75
MHz, CDCl3): l 171.0 (OCOCH3), 170.5
(OCOCH3), 144.5 (C-7), 138.2–127.7 (C6H5),
Reduction of compound 8 in methylene chlo-
ride.—Following the method in Section 3.2 in
CH2Cl2 at −40 °C, 8 (92 mg, 0.22 mmol) was
treated with DIBALH (0.66 mL, 3.0 equiv, 1.0
M in toluene). After 4 h, more DIBALH (0.44
mL, 2.0 equiv) were added. After usual work-
up and flash chromatography of the crude
reaction mixture (7:3 hexane–EtOAc) we iso-
lated compounds (2aR,6aS,6bR,7S,9aS)-7-
[(1,1-dimethylethyl)dimethylsilyloxy]-1,2a,3,5,
6a,6b,7,9a-octahydro-5-phenyl-4,6-dioxacyclo-
hexa[e]cyclopenta[c]pyran-9-methanol (10) (73
mg, 79%) and 11 (7.4 mg, 8%), characterized
as its diacetate {(3R,4S,4aR,5S,7aS)-3-acety-
loxymethyl - 5 - [(1,1 - dimethylethyl)dimethyl-
silyloxy] - 4 - (phenylmethoxy) - 1,3,4,4a,5,7a-

J. Marco-Contelles, J. Ruiz-Caro / Carbohydrate Research 335 (2001) 63–70
69
0.35 mmol, 0.3 equiv), powdered molecular
131.8 (C-6), 75.8 (C-5), 75.4 (C-3), 73.5 (C-4),
71.6 (2 C, C-1, OCH2C6H5), 64.2 (C-3a), 62.1
(C-7%), 45.0 (C-7a), 43.2 (C-4a), 25.8
[Si(CH3)2C(CH3)3], 20.9, 20.8 (2 OCOCH3),
17.9 [Si(CH3)2C(CH3)3], −4.6, −5.0 [2 C,
Si(CH3)2C(CH3)3]; EIMS: m/z 339 (25), 297
(37), 295 (42), 235 (29), 145 (24), 117 (38), 92
(26), 91 (100). Anal. Calcd for C27H40O7Si: C,
64.26; H, 7.99. Found: C, 64.18; H, 7.65.
(2aR,6aS,6bR,7S,9aS) - 7 - [(1,1 - Dimethyl-
,
sieves 4 A (55 mg) and PCC (75 mg, 0.35
mmol, 2 equiv) were added. The mixture was
stirred at rt for 5 h. Filtration over Celite,
evaporation and flash chromatography (19:1
hexane–EtOAc) afforded aldehyde 14 (59 mg,
82%): oil; [h]2D5 +141° (c 0.54, CHCl3); IR
(KBr) w 1685, 1471, 1383, 1255, 1158, 1114,
1
1084, 1003, 837, 757 cm−1; H NMR (300
MHz, CDCl3): l 9.82 (s, 1 H, CHO), 7.54–
7.34 (m, 5 H, C6H5), 6.87 (d, J8,7 2.6 Hz, 1 H,
H-8), 5.60 (s, 1 H, H-5), 5.01 (dd, J7,6b 6.2, J7,8
2.6 Hz, 1 H, H-7), 4.34 (dd, J3%,3 9.9, J3%,2a 5.0
Hz, 1 H, H-3%), 4.28 (dd, J1%,1 11.4, J1%,9a 6.2
Hz, 1 H, H-1%), 4.16 (td, J2a,6a =J2a,3 9.9, J2a,6a%
5.0 Hz, 1 H, H-2a), 4.01 (dd, J6a,2a 9.9, J6a,6b
6.2 Hz, 1 H, H-6a), 3.61 (t, J3,3%=J3,2a 9.9 Hz,
1 H, H-3), 3.41 (t, J1,1%=J1,9a 11.4 Hz, 1 H,
H-1), 3.29 (dt, J9a,1 11.4, J9a,1%=J9a,6b 6.2 Hz, 1
H, H-9a), 2.59 (q, J6b,7=J6b,6a=J6b,9a 6.2 Hz,
1 H, H-6b), 0.89 [s, 9 H, Si(CH3)2C(CH3)3],
0.061, 0.059 [s, s, 2×3 H, Si(CH3)2C(CH3)3];
13C NMR (75 MHz, CDCl3): l 190.0 (CHO),
151.2 (C-8), 149.3 (C-9); 137.6–126.3 (C6H5),
102.5 (C-5), 79.5 (C-6a), 75.0 (C-7), 70.7 (C-
1), 70.2 (C-3), 68.9 (C-2a), 43.1 (C-9a), 42.3
ethyl)dimethylsilyloxy]-
1,2a,3,5,6a,6b,7,9a-
octahydro - 5 - phenyl - 4,6 - dioxacyclohexa[e]-
cyclopenta[c]pyran-9-methanol acetate (12).—
Following the method in Section 3.3: from
compound 10 (17 mg, 0.041 mmol), product
12 (18.5 mg, 99%) was isolated after flash
chromatography (9:1 hexane–EtOAc): oil;
[h]2D5 +140° (c 0.27, CHCl3); IR (KBr) w 1739,
1381, 1241, 1114, 1083, 1062, 832, 779, 700
1
cm−1; H NMR (300 MHz, CDCl3): l 7.53–
7.34 (m, 5 H, C6H5), 5.90 (br s, 1 H, H-8),
5.57 (s, 1 H, H-5), 4.80 (dd, J7,6b 6.4, J7,8 2.3
Hz, 1 H, H-7), 4.68 (d, J9%A,9%B 13.5 Hz, 1 H,
H-9%A), 4.59 (d, J9%A,9%B 13.5 Hz, 1 H, H-9%B),
4.32 (dd, J3%,3 10.0, J3%,2a 5.0, 1 H, H-3%), 4.22
(td, J2a,6a=J2a,3=10.0, J2a,3% 5.0 Hz, 1 H, H-
2a), 4.13 (dd, J1%,1 11.0, J1%,9a 6.4 Hz, 1 H,
H-1%), 3.94 (dd, J6a,2a 10.0, J6a,6b 6.4 Hz, 1 H,
H-6a), 3.58 (t, J3,3%=J3,2a 10.0 Hz, 1 H, H-3),
3.55 (t, J1,1%=J1,9a 11.0 Hz, 1 H, H-1), 2.88
(dt, J9a,1 11.0, J9a,1%=J9a,6b 6.4 Hz, 1 H, H-9a),
2.56 (q, J6b,7=J6b,6a =J6b,9a 6.4 Hz, 1 H, H-
6b), 2.10 (s, 3 H, OCOCH3), 0.88 [s, 9 H,
Si(CH3)2C(CH3)3], 0.08, 0.015 [s, s, 2×3 H,
Si(CH3)2C(CH3)3]; 13C NMR (75 MHz,
CDCl3): l 170.5 (OCOCH3), 143.9 (C-9),
137.8–126.4 (C6H5), 132.6 (C-8), 102.6 (C-5),
80.0 (C-6a), 75.1 (C-7), 71.5 (C-1), *70.3 (C-
3), *68.8 (C-2a), 62.0 (C-9%), 45.6 (C-9a), 43.9
(C-6b),
25.8
[Si(CH3)2C(CH3)3],
17.9
[Si(CH3)2C(CH3)3], −4.6, −4.9 [2 C,
Si(CH3)2C(CH3)3]; EIMS: m/z 359 (76), 267
(38), 253 (51), 181 (43), 129 (35), 105 (66), 75
(100). Anal. Calcd for C23H32O5Si: C, 66.31;
H, 7.74. Found: C, 66.16; H, 7.52.
Reduction of compound 9.—Following the
method in Section 3.2, 9, in CH2Cl2 at −
40 °C, (99 mg, 0.31 mmol), was treated with
DIBALH (0.94 mL, 3.0 equiv). After 4 h,
more DIBALH (0.6 mL, 2.0 equiv) and after 3
h further, DIBALH (0.3 mL, 1 equiv) was
added. After usual work-up and flash chro-
matography of the crude reaction product (7:3
hexane–EtOAc) we isolated compounds
(2aR,6aS,6bR,7S,9aS)-7-methoxy-1,2a,3,5,6a,
6b,7,9a-octahydro-5-phenyl-4,6-dioxacyclo-
hexa[e]cyclopenta[c]pyran-9-methanol (15) (32
mg, 32%) and (3R,4S,4aR,5S,7aS)-3-hydrox-
ymethyl-1,3,4,4a,5,7a-hexahydro-5-methoxy-4-
phenylmethoxy - cyclopenta[c]pyran - 7 - metha-
nol (16) (34 mg, 34%). Compound 15: mp
107–110 °C; [h]D25 +159° (c 0,07, CHCl3); IR
(C-6b),
25.9
[Si(CH3)2C(CH3)3],
20.8
(OCOCH3), 17.9 [Si(CH3)2C(CH3)3], −4.5,
−4.8 [2 C, Si(CH3)2C(CH3)3]; EIMS: m/z 219
(25), 207 (56), 193 (25), 117 (64), 105 (36), 91
(100). Anal. Calcd for C25H36O6Si: C, 65.19;
H, 7.88. Found: C, 65.02; H, 7.46.
(2aR,6aS,6bR,7S,9aS) - 7 - [(1,1 - Dimethyl-
ethyl)dimethylsilyloxy] - 1,2a,3,5,6a,7,9a - octa-
hydro - 5 - phenyl - 4,6 - dioxacyclohexa[e]cyclo-
penta[c]pyran-9-carbaldehyde (14).—To a so-
lution of alcohol 10 (73 mg, 0.17 mmol) in dry
CH2Cl2 (2 mL, 0.087 M), AcONa (4.3 mg,
1
(KBr) w 3426, 1110, 1083, 1005 cm−1; H
NMR (300 MHz, CDCl3): l 7.53–7.34 (m, 5

70
J. Marco-Contelles, J. Ruiz-Caro / Carbohydrate Research 335 (2001) 63–70
1372, 1238, 1092, 1035, 924, 737, 699 cm−1
;
H, C6H5), 6.00 (d, J8,7 1.5 Hz, 1 H, H-8), 5.58
(s, 1 H, H-5), 4.30 (dd, J3%,3 10.0, J3%,2a 4.9 Hz,
1 H, H-3%), 4.29 (dd, J7,6b 6.2, J7,8 1.5 Hz, 1 H,
H-7), 4.18 (br d, J9%,OH 4.4 Hz, 2 H, 2 H-9%),
4.14 (dd, J1%,1 11.2, J1%,9a 6.2 Hz, 1 H, H-1%),
4.04 (td, J2a,6a=J2a,3 10.0, J2a,3% 4.9 Hz, 1 H,
H-2a), 3.95 (dd, J6a,2a 10.0, J6a,6b 6.2 Hz, 1 H,
H-6a), 3.59 (t, J3,3%=J3,2a 10.0 Hz, 1 H, H-3),
3.48 (s, 3 H, OCH3), 3.47 (t, J1,1%=J1,9a 11.2
Hz, 1 H, H-1), 2.90 (dt, J9a,1 11.2, J9a,1%=J9a,6b
6.2 Hz, 1 H, H-9a), 2.59 (q, J6b,7=J6b,6a
=J6b,9a 6.2 Hz, 1 H, H-6b), 1.69 (t, JOH,9% 4.4
1H NMR (300 MHz, CDCl3): l 7.35–7.28 (m,
5 H, C6H5), 6.06 (br d, J6,5 1.2 Hz, 1 H, H-6),
5.13 (dd, J4,3 10.4, J4,4a 6.6 Hz, 1 H, H-4), 4.65
(d, J7%A,7%B 14.0 Hz, 1 H, H-7%A), 4.65 (d, J 12.2
Hz, 1 H, OCH2C6H5), 4.57 (d, J7%A,7%B 14.0 Hz,
1 H, H-7%B), 4.47 (d, J 12.2 Hz, 1 H,
CH2C6H5), 4.16 (ddd, J1,1% 11.0, J1%,7a 6.6, J 1.2
Hz, 1 H, H-1%), 4.07 (dd, J5,4a 6.6, J 2.3 Hz, 1
H, H-5), 4.01 (ddd, J3,4 10.4, J3,3a 5.0, J3,3a% 2.3
Hz, 1 H, H-3), 3.56 (dd, J3a%,3a 10.5, J3a%,3 2.3
Hz, 1 H, H-3a%), 3.47 (dd, J3a,3a% 10.5, J3a,3 5.0
Hz, 1 H, H-3a), 3.44 (t, J1,1%=J1,7a=11.0 Hz,
H-1), 3.13 (s, 3 H, OCH3), 2.85 (dt, J7a,1 11.0,
J7a,1%=J7a,4a 6.6 Hz, 1 H, H-7a), 2.80 (q,
13
Hz, 1 H, OH); C NMR (75 MHz, CDCl3): l
150.6 (C-9), 137.8–126.3 (C6H5), 127.3 (C-8),
102.7 (C-5), 84.5 (C-7), 79.6 (C-6a), 71.9 (C-
1), 70.3 (C-3), 69.1 (C-2a), 61.2 (C-9%), 58.8
(OCH3), 45.2 (C-9a), 43.6 (C-6b); EIMS: m/z
270 (7), 164 (21), 135 (51), 105 (52), 91(76), 79
(100). Anal. Calcd for C18H22O5: C, 67.91; H,
6.96. Found: C, 67.96; H, 7.30. Compound 16:
oil; IR (KBr) w 3436, 2239, 1453, 1077, 910,
J
4a,5=J4a,4=J4a,7a 6.6 Hz, 1 H, H-4a), 2.07,
13
1.99 (s, s, 2×3 H, 2 OCOCH3); C NMR (75
MHz, CDCl3): l 170.8, 170.7 (2 OCOCH3),
146.4 (C-7), 138.3–127.8 (C6H5), 129.0 (C-6),
84.5 (C-5), 75.9 (C-3), 73.7 (OCH2C6H5), 71.6
(C-1), 69.4 (C-3a), 69.3 (C-4), 62.3 (C-7%), 57.8
(OCH3), 45.2 (C-7a), 42.8 (C-4a), 21.2, 21.1 (2
OCOCH3); EIMS: m/z 372 (4), 266 (11), 163
(35), 121 (26), 91 (100), 43 (57). Anal. Calcd
for C22H28O7: C, 65.33; H, 6.98. Found: C,
65.47; H, 6.77.
1
734 cm−1; H NMR (300 MHz, CDCl3): l
7.36–7.26 (m, 5 H, C6H5), 6.03 (br d, J6,5 1.8
Hz, 1 H, H-6), 4.59 (s, 2 H, OCH2C6H5), 4.46
(dm, J5,4a 6.5 Hz, 1 H, H-5), 4.17 (br s, 2 H, 2
H-7%), 4.11 (ddm, J1%,1 11.0, J1%,7a 6.4 Hz, 1 H,
H-1%), 3.85 (dd, J4,3 9.8, J4,4a 7.5 Hz, 1 H, H-4),
3.80 (dm, J3a%,3a 9.9, J3a%,3 2.2 Hz, 1 H, H-3a%),
3.63 (ddd, J3,4 9.8, J3,3a 6.1, J3,3a% 2.2 Hz, 1 H,
H-3), 3.56 (dd, J3a,3a% 9.9, J3a,3 6.1 Hz, 1 H,
H-3a), 3.31 (t, J1,1%=J1,7a 11.0 Hz, 1 H, H-1),
3.30 (s, 3 H, OCH3), 3.04 (d, JOH,3a 10.9 Hz, 1
H, OH), 2.83–2.75 (m, 1 H, H-7a), 2.55 (q,
Acknowledgements
J.R.C. is a fellow of the Consejer´ıa de Edu-
cacio´n y Cultura (CAM). The authors thank
one of the referees for attracting our attention
to some details of the mechanism of the
DIBALH reduction process.
J
4a,5=J4a,4=J4a,7a 6.0 Hz, 1 H, H-4a), 1.68 (br
d, JOH,7% 14.7 Hz, 1 H, OH); 13C NMR (75
MHz, CDCl3): l 153.5 (C-7), 138.1–127.5
(C6H5), 123.7 (C-6), 84.8 (C-5), 80.0 (C-3),
73.6 (OCH2C6H5), 71.1 (C-1), *70.8 (C-3a),
*67.5 (C-4), 61.2 (C-7%), 55.8 (OCH3), 44.7
(C-7a), *43.8 (C-4a); *EIMS: m/z 288 (9), 107
(29), 91 (100). Anal. Calcd for C18H24O5: C,
67.48; H, 7.55. Found: C, 67.32; H, 7.87.
(3R,4S,4aR,5S,7aS)-4-Acetyloxy-3-(phenyl-
methoxy)methyl - 1,3,4,4a,5,7a - hexahydro - 5-
methoxy-cyclopenta[c]pyran-7-methanol ace-
tate (17).—Following the method in Section
3.3, compound 16 (15 mg, 0.047 mmol) af-
forded 17 (17 mg, 90%), after chromatography
(7:3 hexane–EtOAc): oil; [h]2D5 +169° (c 1.44,
CHCl3); IR (film) w 2929, 2869, 1738, 1454,
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