Intramolecular 1,5- versus 1,6-hydrogen abstraction reaction promoted by alkoxyl radicals in pyranose and furanose models

Article abstract of DOI:10.1016/j.tet.2007.06.023

The primary alkoxyl radical generated by reaction of 1-(2-hydroxyethyl)-glycosides with (diacetoxyiodo)benzene (DIB) and iodine can undergo regioselective intramolecular hydrogen abstraction (IHA) reactions to furnish four different dioxabicyclic systems

Full text of DOI:10.1016/j.tet.2007.06.023

Tetrahedron 63 (2007) 8910–8920
Intramolecular 1,5- versus 1,6-hydrogen abstraction reaction
promoted by alkoxyl radicals in pyranose and furanose models
ꢀ
Cosme G. Francisco, Raimundo Freire, Antonio J. Herrera, Ines Perez-Martın and
ꢀ
ꢀ
*
ꢀ
Ernesto Suarez
Instituto de Productos Naturales y Agrobiologꢀıa del C.S.I.C., Carretera de La Esperanza 3, 38206 La Laguna, Tenerife, Spain
Received 11 May 2007; accepted 6 June 2007
Available online 12 June 2007
Abstract—The primary alkoxyl radical generated by reaction of 1-(2-hydroxyethyl)-glycosides with (diacetoxyiodo)benzene (DIB) and
iodine can undergo regioselective intramolecular hydrogen abstraction (IHA) reactions to furnish four different dioxabicyclic systems derived
from carbohydrates. The results strongly suggest that the regiocontrol and feasibility of the cyclisation are dependant not only on geometric
and stereoelectronic factors, but also on polar and thermochemical factors. The correct selection of the substituents at the precursors can
favour the 1,6-IHA against the 1,5-IHA pathway.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
the polarity of the substituents can alter the regioselectivity
of the hydrogen atom transfer promoted by a highly electro-
philic alkoxyl radical. We have also found that either the ab-
sence of a substituent or the presence of alcohols protected
with electron-withdrawing groups (EWGs) inhibits oxida-
tion of the radical in the alkoxyl radical b-fragmentation re-
action, allowing faster reaction with radical species present
in the medium, typically capturing iodine.7,8
Remote intramolecular free radical functionalisation of inac-
tivated carbons via intramolecular hydrogen abstraction
(IHA) from alkoxyl radicals has attracted considerable inter-
est among synthetic organic chemists.1 The (diacetoxyiodo)-
benzene (DIB) in the presence of iodine is a convenient
reagent to generate alkoxyl radicals from alcohols in mild
conditions and has been widely used in synthesis. Earlier re-
ports from this laboratory have described a new methodo-
logy to obtain various bicyclic polyhydroxylated systems,
starting from a carbohydrate with a primary alkoxyl radical
attached to one, two, three and four carbon tethers extended
from the C1 of the sugar, through an IHA reaction.2 The 1,5-
hydrogen atom transfer (HAT) is by far the most common
reaction and is particularly useful for the synthesis of tetra-
hydrofuran derivatives.3,2f 1,6-HAT has also been frequently
observed, but high yields are only obtained when the trans-
ferring hydrogen is bonded to an oxygen-substituted car-
bon.4,5 Among other factors such as geometry and
stereoelectronic effects, the feasibility of the HAT reaction
is dependant on polar effects and the C–H dissociation
bond energy (DBE) involved in the process. To some extent
the C–H DBE can be conditioned by the electron-donating
ability of the substituents linked to the carbon atom. For in-
stance, we can observe a decrease in the experimental C–H
DBE values (kcal molꢀ1) if the electron-donating ability of
the O-substituent at the methane increases: CH3C–H, 105;
C6H5COOCH2–H, 100.2 and CH3OCH2–H, 93.6 In addition,
With all this in mind, the purpose of the present work was to
investigate whether substituents could be used to control the
reaction course in an IHA reaction. With this aim, we syn-
thesised a number of carbohydrate models possessing a
primary alkoxyl radical attached at C1 of pyranose and fura-
nose C-glycosides by a two-carbon tether. In these models
the alkoxyl radical may abstract hydrogen from two different
carbon atoms:9 from C6 and C7, in furanoses and pyranoses,
respectively, through a seven-membered transition state (TS)
and from C4 through a, in principle, more favourable six-
membered TS I (Scheme 1).
1,6-HAT
O
O
O
H
O
O
n( )
+
n( )
O
n( )
R
O
R
H
R
1,5-HAT
I
II
III
n = 1 a
n = 2 b
* Corresponding author. Tel.: +34 922 251004; fax: +34 922 260135;
e-mail: esuarez@ipna.csic.es
Scheme 1. Regioselectivity of the IHA reaction.
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.06.023

C. G. Francisco et al. / Tetrahedron 63 (2007) 8910–8920
8911
It therefore offers an opportunity to study the regioselectiv-
ity of the process (1,5- versus 1,6-HAT)10 and at the same
time to develop new methodology for the synthesis of four
especially interesting dioxabicyclic systems: hexahydro-
furo[3,2-b]furan IIa, hexahydro-2H-furo[3,2-b]pyran IIb,
2,8-dioxabicyclo[3.2.1]octane IIIa and 2,9-dioxabicy-
clo[3.3.1]nonane IIIb. These bicycles are substructural units
of many natural products. An example is azaspiracid, a ma-
rine toxin, which has units IIb and IIIb in its molecule.11
Units IIa and IIb are frequently related to ascorbic and
zaragozic acid derivatives, respectively.12
with NaBH4, which after suitable substitution of protecting
groups yielded compound 26 (Scheme 3).
TBSO
COOMe
HO
COOMe
O
18
O
O
a
90%
O
O
HO
OH
19
b
79%
COOMe
HO
O
MOMO
MOMO
O
c
2. Synthesis of substrates and results
82%
O
O
O
H
Preparation of the required octitols was accomplished fol-
lowing a well-established two-step protocol starting from
suitably protected derivatives of L-fucose, L-rhamnose,
D-mannose and 2-deoxy-D-arabinose. A Lewis acid-mediated
C-glycosidation with allyltrimethylsilane afforded the non-
8-enitols, in general with high stereoselectivity,13,18 which
upon subsequent ozonolysis followed by reductive workup
with NaBH4 provided the alcohols 2, 4, 6, 8, 10, 13 and 17
in good yield (Scheme 2).
21
20
R
O
O
O
H
O
O
d
O
90%
O
O
O
O
22
23 R = OH
24 R = OBn
e
92%
93%
f
O
O
OH
b
HO
BnO
RO
OR
RO
OR
O
O
O
H
O
H
OR
OR
O
O
O
g
O
O
a
1 R = Ac; L-Fuc
3 R = Me; L-Fuc
5 R = Ac; L-Rha
7 R = Me; L-Rha
2 R = Ac; L-Fuc (85%)
4 R = Me; L-Fuc (72%)
6 R = Ac; L-Rha (71%)
8 R = Me; L-Rha (96%)
68%
a
quant.
O
O
O
65%
O
26
O
25
RO
RO
RO
O
X
O
OH
Scheme 3. Synthesis of 3,6-anhydroheptitols and 3,6-anhydrooctitols: (a)
I2, MeOH, reflux, 4 h; (b) (MeO)2CH2, P2O5, CHCl3, rt, 3 h; (c) LiAlH4,
THF, rt, 1 h; (d) O3, CH2Cl2/MeOH, ꢀ78 ꢁC and then NaBH4, MeOH,
0 ꢁC; (e) NaH, BnBr, DMF, rt; (f) acid resin Dowex (50ꢂ8), MeOH, rt,
60 h followed by triphosgene, Py, CH2Cl2, ꢀ70 ꢁC/rt, 30 min; (g) H2,
Pd–C, MeOH, rt, 8 h.
b
OR
RO
OR
OR
OR
9 R = Ac, X = allyl
11 R = Me, X = OAc
12 R = Me, X = allyl
10 R = Ac (87%)
13 R = Me (79%)
c
83%
The IHA reactions were performed under the oxidative con-
ditions stated in Table 1, with (diacetoxyiodo)benzene and
iodine in CH2Cl2 at room temperature and irradiation with
two 80 W tungsten filament lamps.
Me
RO
O
O
X
O
OH
b
RO
c
MeO
OR
OMe
17 (88%)
Since the synthesis of the 2,9-dioxabicyclo[3.3.1]nonane
system has never been reported from an IHA reaction, we
decided to perform preliminary experiments to verify the
feasibility of this methodology. Alcohols 2 and 4 derived
from L-fucose were selected since C4 abstraction is stereo-
chemically blocked and the reaction, in a conformationally
14 R = Ac, X = OAc
15 R = Ac, X = allyl
16 R = Me, X = allyl
77%
a
88%
Scheme 2. Syntheses of 3,7-anhydrooctitols: (a) KOH/MeOH, rt followed
by NaH, MeI, DMF, rt; (b) O3, CH2Cl2/MeOH, ꢀ78 ꢁC and then NaBH4,
MeOH, 0 ꢁC; (c) ATMS, BF3$OEt2, MeCN, 0 ꢁC/rt.
1
restricted C4 pyranose ring, should proceed exclusively
by abstraction of the hydrogen at C7 (entries 1 and 2). In
both cases the reaction proceeded smoothly to give the
expected dioxabicyclic products 27 and 28, respectively,
in moderate yield.
We have also prepared three C-glycosides of the tetrahydro-
furan series in order to extend this methodology for the
synthesis of another two dioxabicyclic systems. The 3,6-
anhydro-heptitol 21 was prepared from the known ester 182c
by changing the protecting groups and subsequent reduction
of carboxyl moiety with LiAlH4. 3,6-Anhydro-octitol 23
was synthesised from 2,3:5,6-di-O-isopropylidene-D-man-
nofuranose by radical C-allylglycosidation as previously de-
scribed2a followed by ozonolysis with a reductive workup
In entry 3 we describe an IHA reaction over a C-glycoside
derived from D-mannose 13. In this case, a restricted C1
4
conformation of the pyranose ring allows the hydroxyl rad-
ical at C1 to abstract the hydrogen atoms located at either the
C4 equatorial or C7 axial position. The hexahydro-2H-

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C. G. Francisco et al. / Tetrahedron 63 (2007) 8910–8920
Table 1. IHA reaction of 3,7-anhydrooctitols and 3,6-anhydroheptitolsa
The results obtained with two differentially protected 3,7-
anhydro-2,8-dideoxyoctitols 8 and 6 derived from L-rham-
nose are shown in entries 5 and 6. The IHA reaction
proceeded analogously; the ester group at C4 inhibited the
reaction originated by hydrogen transfer from this position
and functionalisation occurred at C7 through a seven-
membered TS. The result obtained in the cyclisation of com-
pound 8 merits a brief comment. Although the reaction gave
mainly the expected product 31 corresponding to a H–C4
hydrogen transfer, a minor product 35, generated by a
H–C7 hydrogen abstraction, was also obtained with a ratio
31/35¼4:1. Interestingly, compound 13 reacts more selec-
tively than its pseudo-enantiomer 8 with which the only dif-
ference is the 8-methoxy group. Probably the presence of
a supplementary b-oxygen retards further the rate of hydro-
gen abstraction at C7, favouring the exclusive abstraction at
C4.14 A third minor compound 36 was isolated as a single
stereoisomer when NaHCO3 was added to the reaction mix-
ture, generated probably by a rarely observed double HATas
depicted in Scheme 4.15 A possible explanation is that a pre-
liminary H–C4 hydrogen abstraction was followed by an
intermolecular nucleophilic attack of an acetoxy group,
coming from the reagent (DIB), to the transient oxycarb-
enium intermediate generated, maintaining the primary
hydroxyl group enabled to carry out a second HAT and
cyclisation at C7.
Entry
Substrate
DIB Time
(mmol) (h)
Products
Yield
(%)
HO
1
O
O
H
O
7
4
1
2
1.5
1.5
1
1.5
47
57
RO
OR
RO
OR
RO
27 R = Ac
28 R = Me
RO
2 R = Ac
4 R = Me
HO
MeO
MeO
MeO
MeO
H
O
O
3
4
5
6
7
1.3
1.6
1.5
1.3
1.5
1.5
1.25
2.75
4.5
9
70
48
45b
53
64
57
O
OMe
OAc
OMe
OMe
MeO
MeO
13
29
HO
AcO
AcO
AcO
AcO
O
H
O
O
OAc
Ac
O
30
AcO
10
HO
O
H
O
O
MeO
AcO
OMe
MeO
AcO
Me
O
MeO
8
31
HO
O
O
HO
O
O
O
O
a
H
O
31
OAc
O
+
+
(36%)
MeO
OMe MeO
OMe
MeO
OMe
OAc
MeO
MeO
OAc
MeO
8
AcO
32
AcO
6
35
36
(14%)
(4.5%)
HO
Me
O
MeO
Scheme 4. (a) DIB (1.3 equiv), I2 (1 equiv), NaHCO3 (100%), CH2Cl2,
100 W tungsten filament lamp, 1 h.
O
H
O
O
1.5
MeO
MeO
Aware of the previously observed products of double IHA in
our laboratory,2a,b where in the first instance a primary
alkoxyl radical prefers a 1,5-HAT from a deoxygenated
CH2 position instead of a 1,6-HAT from a pseudoanomeric
position similar to our cases, we decided to synthesise the
precursor 17 with a deoxygenated C4 position. For this sub-
strate, 1,6-HAT dominated, furnishing exclusively product
33 in good yield instead of 1,5-HAT, which was expected
to insert an iodine atom at position C4 (entry 7). For this
pyranose model, the approximation of the alkoxyl radical
to the H–C7 atom in a respective 1,3-diaxial position is
favoured with a smaller entropical penalty than in the case
of a linear chain.
Me
O
33
MeO
17
HO
MOMO
1
MOMO
O
O
6
4
8
1
O
O
O
O
O
34
21
a
Octitol or heptitol derivative (1 mmol) in CH2Cl2 (25 mL) containing DIB
and iodine (1 mmol) was irradiated with two 80 W tungsten filament
lamps at room temperature.
2,8-Anhydro-1,7-dideoxy-3,4,5-tri-O-methyl-b-L-altro-oct-2-ulopyranose
(35, 11%) was also obtained.
b
This IHA-cyclisation sequence was further extended to fura-
nose models such as 21, 23 and 26. Model 21, derived from
D-ribose, yielded smoothly the single expected compound 34
although with a quite tensioned tricyclic skeleton (entry 8).
The use of acetal instead of methyl ethers as protecting
group aimed to expand the scope of this methodology for
further transformation of the products.
furo[3,2-b]pyran derivative 29, generated by the transfer of
the hydrogen at C4, was formed exclusively.
The influence of the protective group at C4 was subsequently
studied in entry 4 of Table 1. The substitution of the methyl
ether by an acetyl group (such as compound 10) affected the
regiochemical courseofthe reaction; the H–C7wasnow trans-
ferred and the 2,9-dioxabicyclo[3.3.1]nonane derivative 30
was obtained instead. Although the yield was moderate, no
other compounds could be detected in the reaction mixture.
The D-mannofuranosyl derivatives 23 behaved similarly
to the pyranose model 8 with poorer regiocontrol where
1,5-HAT dominated versus the 1,6-HAT, although both

C. G. Francisco et al. / Tetrahedron 63 (2007) 8910–8920
8913
processes took place furnishing dioxabicyclic compounds 37
and 38 with a 67% yield in a ratio of (1.6:1) (Scheme 5). The
regioselectivity decreased with respect to model 8 and no
products of double HAT were observed. The yield of the re-
action but not the products’ ratio was optimised by neutral-
ising the medium with a suspension of NaHCO3.
hydrogen or an alcohol protected with an EWG (acetate or
carbonate). The electrophilic alkoxyl radical abstracted the
hydrogen exclusively on the electron-richer C6 or C7, n¼1
or 2, respectively, despite the less favourable seven-
membered TS, and the reaction went exclusively through
path [b] to give the [3.3.1] or [3.2.1] bicycles (III) (models
6, 10, 17, 26).16 No compounds derived from abstraction
of the hydrogen at the C4 position were detected in this case.
HO
O
O
O
O
O
O
R
O
R
O
R
R
+
R
Intermolecular nucleophilic attack of anion acetate on the
transient oxycarbenium cation intermediate is possible, the
acetyl derivatives being isolable in some cases.
6
O
O
O
(a) or (b)
4
O
O
O
O
O
O
R
23 R = Me2
26 R = O
37 R = Me2 41%
39 R = O 0%
38 R = Me2 26%
40 R = O 65%
3. Conclusions
Scheme 5. 1,5- versus 1,6-IHA of mannofuranosyl derivatives. Reagent and
conditions: (a) 23, DIB (2 equiv), I2 (1 equiv), NaHCO3 (30%), CH3CN,
2ꢂ80 W tungsten filament lamps, rt, 1 h; (b) 26, DIB (1.5 equiv), I2
(1 equiv), CH2Cl2, 1ꢂ80 W tungsten filament lamps, rt, 0.5 h, and then
BF3$OEt2 (1 equiv), CH2Cl2, 0 ꢁC, 0.5 h.
With these examples we have now demonstrated the possi-
bility of using an EWG substituent to avoid the intramole-
cular functionalisation at a favoured position and trigger
the reaction in a less favoured carbon atom. Indeed, the cor-
rect choice of the C4 substituent has been the switch to either
1,5-HAT or 1,6-HAT control in the reaction and hence to the
specific synthesis of hexahydrofuro[3,2-b]furan, hexahydro-
2H-furo[3,2-b]pyran, 2,8-dioxabicyclo[3.2.1]octane or 2,9-
dioxabicyclo[3.3.1]nonane systems.17 As observed, the
reaction, which may be conceptually considered to be an
intramolecular glycosidation is, in reality, a selective oxida-
tion of specific carbons of the carbohydrate skeleton and
constitute a mild procedure for the synthesis of protected
uloses, which are not readily accessible by other methods.
To our delight, we observed that upon switching the di-O-
isopropylidene protecting group to carbonate, as depicted
for model 26, the course of the reaction diverted exclusively
to the 1,6-HAT at position C6 affording the product 40 in
good yield. The carbonate group proved to be an EWG suf-
ficient to inhibit the abstraction of H–C4 to give compound
39. This time, the reaction procedure was modified, and
a second step was necessary to complete the cyclisation
stage with the addition of the Lewis acid (BF3$OEt2). Other-
wise, intermediate products of acetylation at C6 were
isolated.
4. Experimental
4.1. General
A mechanism to explain the observed regioselectivity of
these IHA reactions is depicted in Scheme 6. When the sub-
stituent at C4 was an oxygenated electron-releasing group
(R¼ether or acetals), the alkoxyl radical I abstracted the
hydrogen preferentially at this carbon atom through a six-
membered TS. The [3.3.0] and [4.3.0] bicycle, n¼1 and 2
(II), respectively, were subsequently formed, after oxidation
at the C4 radical and intramolecular attack of the nucleo-
philic alcohol (path [a], models 8, 13, 21 and 23). Neverthe-
less, the situation changed dramatically when R was
Melting points were determined with a hot-stage apparatus
and are uncorrected. Optical rotations were measured at
the sodium line at ambient temperature in CHCl3 solutions.
IR spectra were measured as thin films on NaCl plate. NMR
spectra were determined at 500 MHz for 1H and 125.7 MHz
for 13C in CDCl3 unless otherwise stated, in the presence of
TMS as internal standard. Mass spectra were determined at
70 eV. Merck silica gel 60 PF (0.063–0.2 mm) was used for
column chromatography. Circular layers of 1 mm of Merck
silica gel 60 PF254 were used on a Chromatotron for centri-
fugally-assisted chromatography. Commercially available re-
agents and solvents were of analytical grade or were purified
by standard procedures prior to use. All reactions involving
air- or moisture-sensitive materials were carried out under
a nitrogen atmosphere. The spray reagents for TLC analysis
were conducted with 0.5% vanillin in H2SO4–EtOH (4:1)
and further heating until development of colour.
O
O
O
-e
( )
( )
( )
n
-H
n
n
OH
OH
O
R1
O
O
O
R1
R1
[a]
II
H
O
O
4
1
( )
n
H
R
I
[b]
4.2. Syntheses of precursors for cyclisation via IHA
reaction
HO
HO
O
O
O
O
-e
-H
( )
( )
( )
n
n
n
4.2.1. 3,4,5-Tri-O-acetyl-2,6-anhydro-1,7-dideoxy-L-glyc-
ero-D-galacto-octitol (2). General procedure for reductive
ozonolysis. A solution of 3,4,5-tri-O-acetyl-2,6-anhydro-
R
R
R
III
R = H, ethers, acetals, esters, carbonates
O-R1 = ethers, acetals
n = 1 or 2
1,7,8,9-tetradeoxy-L-glycero-D-galacto-non-8-enitol13a
1
(434 mg, 1.38 mmol) in dry CH2Cl2–MeOH (50 mL, 1:1)
Scheme 6. Mechanism of the IHA reaction.
was cooled to ꢀ78 ꢁC and ozone was introduced into the

8914
C. G. Francisco et al. / Tetrahedron 63 (2007) 8910–8920
solution until it became blue. Then nitrogen was bubbled
through the solution to expel excess of ozone, and the mix-
ture was heated to 0 ꢁC. Afterwards, NaBH4 (313 mg,
8.29 mmol) was added slowly and the solution stirred for
30 min at room temperature. The reaction mixture was
then poured into water and extracted with CH2Cl2, dried
over Na2SO4, and concentrated. Column chromatography
(hexanes–EtOAc, 25:75) of the residue afforded the title al-
cohol 2 (375 mg, 1.18 mmol, 85%) as a colourless oil: [a]D
ꢀ7.3 (c, 0.48); IR 3478, 2942, 1748, 1732, 1434, 1372,
2936, 2829, 1732, 1651, 1463, 1362, 1362, 1194,
1
1102 cmꢀ1; H NMR 1.28 (3H, d, J¼6.6 Hz), 1.73 (1H,
m), 1.94 (1H, m), 3.46 (3H, s), 3.49 (3H, s), 3.51 (3H, s),
3.52 (3H, m), 3.77 (2H, m), 3.95 (1H, dq, J¼2.8, 6.6 Hz),
4.21 (1H, ddd, J¼3.6, 9.9, 9.9 Hz); 13C NMR 15.4 (CH3),
29.5 (CH2), 58.3 (CH3), 58.9 (CH3), 59.9 (CH3), 61.5
(CH2), 68.5 (CH), 70.8 (CH), 77.7 (CH), 77.9 (CH), 78.9
(CH); MS (EI) m/z (rel intensity) 235 (M++H, <1), 217
(<1), 202 (<1), 170 (1); HRMS calcd for C11H22O5
234.1467, found 234.1468. Anal. Calcd for C11H22O5: C,
56.39; H, 9.46. Found: C, 56.20; H, 9.70.
1
1246, 1059 cmꢀ1; H NMR 1.11 (3H, d, J¼6.3 Hz), 1.64
(1H, m), 1.93 (1H, m), 1.96 (3H, s), 2.01 (3H, s), 2.10
(3H, s), 3.69 (2H, m), 3.98 (1H, ddd, J¼1.9, 6.5, 6.5 Hz),
4.34 (1H, ddd, J¼3.3, 5.5, 5.5 Hz), 5.13 (1H, dd, J¼3.3,
9.9 Hz), 5.22 (1H, dd, J¼1.5, 5.4 Hz), 5.24 (1H, dd,
J¼5.4, 9.9 Hz); 13C NMR 15.8 (CH3), 20.6 (CH3), 20.7
(CH3), 20.7 (CH3), 27.8 (CH2), 59.8 (CH2), 66 (CH), 68
(CH), 68.5 (CH), 70.4 (CH), 70.6 (CH), 169.9 (C), 170.1
(C), 170.5 (C); MS (EI) m/z (rel intensity) 319 (M++H, 1),
301 (<1), 273 (10); HRMS calcd for C14H23O8 319.1393,
found 319.1359. Anal. Calcd for C14H22O8: C, 52.82; H,
6.97. Found: C, 52.72; H, 7.25.
4.2.4. 3,4,5-Tri-O-acetyl-2,6-anhydro-1,7-dideoxy-L-glyc-
ero-L-manno-octitol (6). Following the general procedure,
3,4,5-tri-O-acetyl-2,6-anhydro-1,7,8,9-tetradeoxy-L-glycero-
L-manno-non-8-enitol13b 5 (500 mg, 1.591 mmol) afforded
compound 6 (361 mg, 1.13 mmol, 71%) as a colourless
oil: [a]D +0.6 (c, 0.36); IR 3479, 2940, 2889, 1746, 1372,
1
1228, 1048 cmꢀ1; H NMR 1.21 (3H, d, J¼6.3 Hz), 1.77
(1H, m), 1.98 (3H, s), 2.00 (3H, m), 2.04 (3H, s), 2.08
(3H, s), 2.37 (1H, br d), 3.69–3.80 (3H, m), 4.08 (1H, ddd,
J¼3.2, 3.2, 10.0 Hz), 4.99 (1H, dd, J¼8.5, 8.5 Hz), 5.14–
5.17 (2H, m); 13C NMR 17.4 (CH3), 20.6 (CH3), 20.7
(CH3), 20.8 (CH3), 31.1 (CH2), 59.4 (CH2), 68.4 (CH), 69
(CH), 70.9 (CH), 71.4 (CH), 72.6 (CH), 169.8 (C), 170
(C), 170.2 (C); MS (EI) m/z (rel intensity) 319 (M++H, 1),
273 (2), 258 (1), 198 (32), 183 (48); HRMS calcd for
C14H23O8 319.1393, found 319.1470. Anal. Calcd for
C14H22O8: C, 52.82; H, 6.97. Found: C, 52.56; H, 7.27.
4.2.2. 2,6-Anhydro-1,7,8,9-tetradeoxy-3,4,5-tri-O-methyl-
L-glycero-D-galacto-non-8-enitol (3).
A
solution of
3,4,5-tri-O-acetyl-2,6-anhydro-1,7,8,9-tetradeoxy-L-glycero-
D-galacto-non-8-enitol 1 (3.6 g, 11.45 mmol) in MeOH
(25 mL) containing KOH (0.75 g, 0.013 mmol) was stirred
at room temperature for 1 h. The reaction mixture was
then neutralised with Dowex 50ꢂ8 acid resin, filtered and
concentrated in vacuum to afford an oily residue, which
was used in the following reaction without purification. To
a suspension of NaH (1.65 g, 68.72 mmol) in dry DMF
(50 mL) was added the crude triol previously obtained in
DMF (50 mL) and the mixture stirred at 0 ꢁC under nitrogen
until hydrogen evolution had ceased. Then an excess of
methyl iodide (4.3 mL, 69.9 mmol) was added dropwise
and stirring continued at room temperature for 2 h. Excess
reagent was destroyed by slow addition of MeOH and the so-
lution poured into water and extracted with EtOAc. The or-
ganic extracts were dried over Na2SO4 and concentrated in
vacuum. Column chromatography (hexanes–EtOAc, 70:30)
of the residue afforded the title compound 3 (1.81 g,
7.87 mmol, 68.6%) as a colourless oil: [a]D ꢀ86.7 (c,
4.2.5. 2,6-Anhydro-1,7,8,9-tetradeoxy-3,4,5-tri-O-methyl-
L-glycero-L-manno-non-8-enitol (7).
A
solution of
3,4,5-tri-O-acetyl-2,6-anhydro-1,7,8,9-tetradeoxy-L-glycero-
L-manno-non-8-enitol13b 5 (11.5 g, 36.59 mmol) in MeOH
(200 mL) containing KOH (6.0 g, 150.0 mmol) was stirred
at room temperature for 1 h. The reaction mixture was
then neutralised with Dowex 50ꢂ8 acid resin, filtered and
concentrated in vacuum to give an oil (8.5 g), which was
used in the following reaction without purification. To a sus-
pension of NaH (5.26 g, 219.5 mmol) in dry DMF (350 mL)
was added the crude triol previously obtained in DMF
(150 mL) and the mixture stirred at 0 ꢁC under nitrogen until
all hydrogen evolution had ceased. Then an excess of methyl
iodide (15.9 mL, 256.1 mmol) was added dropwise and stir-
ring continued at room temperature for 3 h. Excess reagent
was destroyed by slow addition of MeOH and the solution
poured into water and extracted with EtOAc. The organic ex-
tracts were dried over Na2SO4 and concentrated in vacuum.
Column chromatography (hexanes–EtOAc, 85:15) of the
residue afforded the title compound 7 (5.5 g, 23.88 mmol,
65.5%) as a colourless oil: [a]D ꢀ8.2 (c, 0.73); IR 3077,
2977, 2933, 2825, 1644, 1455, 1382, 1196, 1102 cmꢀ1; 1H
NMR 1.28 (3H, d, J¼6.3 Hz), 2.27 (1H, m), 2.42 (1H, m),
3.16 (1H, dd, J¼7.7, 7.7 Hz), 3.43 (1H, m), 3.43 (3H, s),
3.45 (1H, m), 3.47 (3H, s), 3.52 (3H, s), 3.56 (1H, m),
4.02 (1H, dq, J¼6.5, 3.3 Hz), 5.09 (1H, dd, J¼17.0,
1.5 Hz), 5.12 (1H, d, J¼10.0 Hz), 5.79 (1H, ddd, J¼17.0,
10.2, 6.8 Hz); 13C NMR 17.8 (CH3), 34.1 (CH2), 57.6
(2ꢂCH3), 60.2 (CH3), 69.1 (CH), 71.9 (CH), 77.7 (CH),
80 (CH), 81.8 (CH), 117.1 (CH2), 134.2 (CH); MS (EI)
m/z (rel intensity) 189 (44), 157 (139); HRMS calcd for
C9H17O4 189.1127, found 189.1155. Anal. Calcd for
C12H22O4: C, 62.58; H, 9.63. Found: C, 62.61; H, 9.64.
0.82); IR 2978, 2933, 2826, 1643, 1360, 1193, 1104 cmꢀ1
;
1H NMR 1.27 (3H, d, J¼6.6 Hz), 2.30 (1H, m), 2.37 (1H,
m), 3.44 (3H, s), 3.48 (3H, s), 3.49 (3H, s), 3.51 (3H, m),
3.92 (1H, dq, J¼6.5, 3.3 Hz), 4.03 (1H, ddd, J¼9.1, 5.3,
3.8 Hz), 5.05 (1H, d, J¼10.2 Hz), 5.10 (1H, dd, J¼17.0,
1.5 Hz), 5.81 (1H, ddd, J¼17.0, 10.2, 6.8 Hz); 13C NMR
15.0 (CH3), 31.9 (CH2), 58.3 (CH3), 58.5 (CH3), 59.5
(CH3), 68.2 (CH), 70.0 (CH), 77.5 (CH), 77.6 (CH), 78.4
(CH), 116.6 (CH2), 135.2 (CH); MS (EI) m/z (rel intensity)
230 (M+, 21), 189 (29); HRMS calcd for C12H22O4
230.1518, found 230.1519. Anal. Calcd for C12H22O4: C,
62.58; H, 9.63. Found: C, 62.49; H, 9.65.
4.2.3. 2,6-Anhydro-1,7-dideoxy-3,4,5-tri-O-methyl-
L-glycero-D-galacto-octitol (4). Following the general
procedure for ozonolysis, 2,6-anhydro-1,7,8,9-tetradeoxy-
3,4,5-tri-O-methyl-L-glycero-D-galacto-non-8-enitol 3 (1.4 g,
6.08 mmol) afforded compound 4 (1.025 g, 4.38 mmol,
72%) as a colourless oil: [a]D ꢀ65.5 (c, 0.6); IR 3444,

C. G. Francisco et al. / Tetrahedron 63 (2007) 8910–8920
8915
4.2.6. 2,6-Anhydro-1,7-dideoxy-3,4,5-tri-O-methyl-
L-glycero-L-manno-octitol (8). Following the general pro-
cedure, 2,6-anhydro-1,7,8,9-tetradeoxy-3,4,5-tri-O-methyl-
4.2.9. 2,6-Anhydro-7-deoxy-1,3,4,5-tetra-O-methyl-
D-glycero-D-manno-octitol (13). Following the general
procedure, 2,6-anhydro-7,8,9-trideoxy-1,3,4,5-tetra-O-methyl-
D-glycero-D-manno-non-8-enitol 12 (500 mg, 1.921 mmol)
afforded compound 13 (398 mg, 1.51 mmol, 79%) as a col-
ourless oil: [a]D +19.2 (c, 0.24); IR 3471, 2930, 1738,
L-glycero-L-manno-non-8-enitol
7 (2.0 g, 8.685 mmol)
afforded compound 8 (1.95 g, 8.32 mmol, 96%) as a colour-
less oil: [a]D ꢀ17.1 (c, 0.34); IR 3453, 2935, 2828, 1725,
1642, 1452, 1383, 1197, 1099 cmꢀ1; 1H NMR 1.28 (3H, d,
J¼6.5 Hz), 1.67 (1H, m), 1.89 (1H, m), 3.17 (1H, dd,
J¼8.1, 8.1 Hz), 3.36 (1H, dd, J¼2.8, 3.7 Hz), 3.41 (3H, s),
3.45 (3H, s), 3.46 (3H, s), 3.47 (1H, m), 3.64 (1H, dq,
J¼6.5, 8.1 Hz), 3.73 (2H, t, J¼6.0 Hz), 4.11 (1H, ddd,
J¼3.7, 8.2, 8.2 Hz); 13C NMR 17.5 (CH3), 31.7 (CH2),
57.6 (CH3), 57.8 (CH3), 59.7 (CH3), 60.6 (CH2), 69.3
(CH), 70.7 (CH), 78.6 (CH), 79 (CH), 81.1 (CH); MS
(EI) m/z (rel intensity) 234 (M+, 1), 202 (2), 189 (1);
HRMS calcd for C11H22O5 234.1467, found 234.1487.
Anal. Calcd for C11H22O5: C, 56.39; H, 9.46. Found: C,
56.34; H, 9.45.
1
1454, 1093 cmꢀ1; H NMR 1.63 (1H, m), 1.84 (1H, m),
3.29 (3H, s), 3.30 (1H, m), 3.32 (1H, m), 3.35 (3H, s), 3.39
(3H, s), 3.40 (3H, s), 3.45 (1H, m), 3.48 (1H, dd, J¼7.2,
10.0 Hz), 3.56 (1H, dd, J¼8.1, 10.0 Hz), 3.66 (1H, m), 3.68
(2H, t, J¼5.7 Hz), 4.06 (1H, ddd, J¼4.7, 9.5, 9.5 Hz); 13C
NMR 31.7 (CH2), 57.5 (CH3), 58.2 (CH3), 58.9 (CH3),
59.4 (CH3), 60.5 (CH2), 71.2 (CH), 71.4 (CH2), 72.3 (CH),
76.6 (CH), 78.4 (CH), 78.9 (CH); MS (EI) m/z (rel intensity)
264 (M+, <1), 232 (1), 219 (4), 200 (1), 187 (35); HRMS
calcd for C12H24O6 264.1573, found 264.1530. Anal.
Calcd for C12H24O6: C, 54.53; H, 9.15. Found: C, 54.58; H,
9.18.
4.2.7. 1,3,4,5-Tetra-O-acetyl-2,6-anhydro-7-deoxy-
D-glycero-D-manno-octitol (10). Following the general
procedure, 1,3,4,5-tetra-O-acetyl-2,6-anhydro-7,8,9-trideoxy-
D-glycero-D-manno-non-8-enitol18 9 (240 mg, 8.685 mmol)
afforded compound 10 (212 mg, 0.56 mmol, 87%) as a col-
ourless oil: [a]D ꢀ3.1 (c, 0.64); IR 3542, 2960, 2888, 1756,
4.2.10. 6,7,9-Tri-O-acetyl-4,8-anhydro-1,2,3,5-tetra-
deoxy-D-manno-non-1-enitol (15). To a solution of com-
pound 1420 (6.2 g, 18.6 mmol) in dry MeCN (60 mL) were
added allyltrimethylsilane (9.3 mL, 58.5 mmol) and
BF3$OEt2 (6.2 mL, 48.9 mmol) at 0 ꢁC. After 1 h at room
temperature, the reaction mixture was poured into ice-water
and extracted with EtOAc. The organic extracts were dried
over Na2SO4 and concentrated under reduced pressure. Col-
umn chromatography (hexanes–EtOAc, 7:3) of the residue
afforded the title compound 15 (4.5 g, 14.3 mmol, 77%) as
a colourless oil: [a]D +38.0 (c, 0.30); IR (CCl4) 3080,
2955, 1748, 1643, 1433, 1367, 1231, 1050 cmꢀ1; 1H NMR
(400 MHz) 1.85 (1H, ddd, J¼4.8, 8.9, 13.6 Hz), 2.03 (1H,
m), 2.05 (3H, s), 2.07 (3H, s), 2.08 (3H, s), 2.27 (1H, m),
2.51 (1H, m), 3.91 (1H, ddd, J¼3.3, 6.7, 6.7 Hz), 4.04
(1H, m), 4.08 (1H, dd, J¼3.4, 11.9 Hz), 4.38 (1H, dd,
J¼6.3, 11.9 Hz), 4.86 (1H, dd, J¼7.3, 7.3 Hz), 5.08–5.16
(3H, m), 5.78 (1H, dddd, J¼7.0, 7.0, 10.2, 17.1 Hz); 13C
NMR (100.6 MHz) 20.8 (3ꢂCH3), 32.0 (CH2), 36.7
(CH2), 62.1 (CH), 68.7 (CH), 68.7 (CH2), 69.8 (CH), 70.7
(CH), 117.6 (CH2), 133.9 (CH), 169.7 (C), 169.9 (C),
170.6 (C); MS (EI) m/z (rel intensity) (FAB) 337 (M++Na,
7), 315 (M++H, 75); HRMS calcd for C15H22NaO7
337.1263, found 337.1258. Anal. Calcd for C15H22O7: C,
57.31; H, 7.05. Found: C, 57.40; H, 7.33.
1
1651, 1434, 1372, 1242, 1049 cmꢀ1; H NMR 1.75 (1H,
m), 1.92 (1H, m), 1.98 (3H, s), 2.01 (3H, s), 3.66 (2H, m),
3.90 (1H, ddd, J¼2.8, 7.5, 7.5 Hz), 4.00 (1H, dd, J¼2.8,
12.2 Hz), 4.13 (1H, ddd, J¼3.8, 10.3, 10.3 Hz), 4.41 (1H,
dd, J¼7.5, 12.2 Hz), 5.06 (1H, dd, J¼7.5, 7.5 Hz), 5.09
(1H, dd, J¼3.8, 3.8 Hz), 5.18 (1H, dd, J¼3.8, 7.5 Hz); 13C
NMR 21.0 (2ꢂCH3), 21.1 (CH3), 21.2 (CH3), 32.0 (CH2),
59.6 (CH2), 62.4 (CH2), 67.7 (CH), 68.8 (CH), 70.7 (CH),
71.7 (CH), 72.3 (CH), 170.2 (C), 170.5 (2ꢂC), 171.2 (C);
MS (EI) m/z (rel intensity) 377 (M+ꢀH, <1), 359 (<1),
345 (<1), 317 (1), 214 (73); HRMS calcd for C16H25O10
377.1448, found 377.1454. Anal. Calcd for C16H24O10: C,
51.06; H, 6.43. Found: C, 50.70; H, 6.75.
4.2.8. 2,6-Anhydro-7,8,9-trideoxy-1,3,4,5-tetra-O-methyl-
D-glycero-D-manno-non-8-enitol (12). To a solution of
1-O-acetyl-2,3,4,6-tetra-O-methyl-D-mannopyranose19 11
(104 mg, 0.374 mmol) in dry MeCN (1.5 mL) were added
allyltrimethylsilane (0.176 mL, 1.122 mmol) and BF3$OEt2
(0.114 mL, 0.935 mmol) at 0 ꢁC. After 30 min at room tem-
perature, the reaction mixture was poured into ice-water and
extracted with EtOAc. The organic extracts were dried over
Na2SO4 and concentrated under reduced pressure. Column
chromatography (hexanes–EtOAc, 1:1) of the residue af-
forded the title compound 12 (82 mg, 0.31 mmol, 83%) as
4.2.11. 4,8-Anhydro-1,2,3,5-tetradeoxy-6,7,9-tri-O-meth-
yl-D-manno-non-1-enitol (16). Compound 15 (4.3 g,
13.7 mmol) was stirred in a KOH–MeOH 3% solution
(50 mL) at room temperature for 12 h. The reaction mixture
was then neutralised with Dowex 50ꢂ8 acid resin, filtered
and concentrated in vacuum to give an oily residue, which
was used in the following reaction without purification. To
a suspension of NaH (1.78 g, 74.2 mmol) in dry DMF
(70 mL) was added the crude tetrol previously obtained in
DMF (65 mL) and the mixture stirred at 0 ꢁC under nitrogen
until all hydrogen evolution had ceased. Then an excess of
methyl iodide (5.2 mL, 83.2 mmol) was added dropwise
and stirring continued at room temperature for 3 h. Excess
reagent was destroyed by slow addition of MeOH and the
solution poured into water and extracted with EtOAc. The
organic extracts were dried over Na2SO4 and concentrated
in vacuum. Column chromatography (hexanes–EtOAc, 6:4)
of the residue afforded 16 (2.8 g, 12.2 mmol, 88%) as
1
a colourless oil: [a]D +15.6 (c, 0.52); H NMR 2.33 (1H,
m), 2.41 (1H, m), 3.37 (3H, s), 3.40 (3H, s), 3.41 (1H, m),
3.43 (1H, m), 3.47 (3H, s), 3.47 (3H, s), 3.57 (1H, m),
3.58 (2H, d, J¼4.7 Hz), 3.63 (1H, m), 4.02 (1H, ddd,
J¼1.9, 7.2, 7.2 Hz), 5.07 (1H, d, J¼9.9 Hz), 5.10 (1H, d,
J¼17.1 Hz), 5.80 (1H, dddd, J¼7.3, 7.3, 10.0, 17.1 Hz);
13C NMR 34.1 (CH2), 57.4 (CH3), 57.6 (CH3), 58.9 (CH3),
59.6 (CH3), 71.5 (CH2), 71.8 (CH), 72.6 (CH), 76.4 (CH),
77.1 (CH), 79.3 (CH), 117.1 (CH2), 134.1 (CH); MS (EI)
m/z (rel intensity) 219 (M+ꢀC3H5, 35), 187 (63), 183 (15);
HRMS calcd for C10H19O5 219.1232, found 219.1218.
Anal. Calcd for C13H24O5: C, 59.98; H, 9.29. Found: C,
59.84; H, 9.14.

8916
C. G. Francisco et al. / Tetrahedron 63 (2007) 8910–8920
a colourless oil: [a]D +42.2 (c, 0.40); IR (CCl4) 3078, 2981,
2929, 2822, 1642, 1446, 1377, 1193, 1107 cmꢀ1; 1H NMR
(400 MHz) 1.65 (1H, ddd, J¼4.8, 9.0, 13.5 Hz), 1.93 (1H,
ddd, J¼4.4, 8.9, 8.9 Hz), 2.23 (1H, m), 2.45 (1H, m), 3.13
(1H, dd, J¼7.1, 7.1 Hz), 3.39 (3H, s), 3.41 (3H, s), 3.48
(1H, m), 3.49 (3H, s), 3.55 (1H, m), 3.62 (1H, dd, J¼4.9,
12.3 Hz), 3.65 (1H, m), 4.00 (1H, dddd, J¼4.7, 4.7, 7.4,
7.4 Hz), 5.04–5.11 (2H, m), 5.78 (1H, dddd, J¼6.9, 6.9,
10.1, 17.1 Hz); 13C NMR (100.1 MHz) 32.0 (CH2), 37.2
(CH2), 57.1 (CH3), 59.3 (CH3), 59.8 (CH3), 70.4 (CH),
71.8 (CH2), 72.7 (CH), 78.2 (CH), 78.9 (CH), 117.2
(CH2), 134.9 (CH); MS (EI) m/z (rel intensity) (FAB) 253
(M++Na, 1), 231 (M++H, 2); HRMS calcd for
C12H22NaO4 253.1416, found 253.1441. Anal. Calcd for
C12H22O4: C, 62.58; H, 9.63. Found: C, 62.41; H, 9.33.
0 ꢁC and a saturated solution of Na2CO3 was added dropwise
with vigorous stirring until the effervescence disappeared.
The mixture was poured into water, extracted with CH2Cl2
and the organic layer was dried over Na2SO4 and concen-
trated in vacuum. Column chromatography of the residue
(hexanes–EtOAc, 6:4) gave compound 20 (1.9 g,
7.4 mmol, 79%) as a yellow oil: [a]D ꢀ0.8 (c, 0.13); IR
(CCl4) 2955, 1747, 1438, 1393, 1343, 1036 cmꢀ1 1H
;
NMR (400 MHz) 2.72 (2H, d, J¼6.3 Hz), 3.37 (3H, s),
3.66–3.73 (2H, m), 3.71 (3H, s), 4.03 (1H, ddd, J¼4.5,
4.5, 4.5 Hz), 4.23 (1H, ddd, J¼4.8, 6.3, 6.3 Hz), 4.49 (1H,
dd, J¼4.8, 6.9 Hz), 4.56 (1H, dd, J¼4.8, 6.9 Hz), 4.66
(2H, s), 5.08 (1H, s), 5.13 (1H, s); 13C NMR (100.6 MHz)
38.5 (CH2), 52.2 (CH3), 55.7 (CH3), 68.1 (CH2), 79.5
(CH), 81.9 (2ꢂCH), 84.1 (CH), 95.8 (CH2), 97.1 (CH2),
171.1 (C); MS (EI) m/z (rel intensity) 261 (M+ꢀH, 1), 247
(1), 231 (6); HRMS calcd for C11H17O7 261.0974, found
261.1002. Anal. Calcd for C11H18O7: C, 50.38; H, 6.92.
Found: C, 50.11; H, 7.10.
4.2.12. 2,6-Anhydro-5,7-dideoxy-1,3,4-tri-O-methyl-D-
manno-octitol (17). Following the general procedure for
reductive ozonolysis, compound 16 (2.4 g, 10.6 mmol) af-
forded compound 13 (2.18 g, 9.3 mmol, 88%) as a colourless
oil: [a]D +34.2 (c, 0.26); IR 3638, 3530, 2929, 2822, 1455,
4.2.15. 3,6-Anhydro-2-deoxy-7-O-(methoxymethyl)-4,5-
O-methylen-D-allo-heptitol (21). To a solution of com-
pound 20 (992 mg, 3.78 mmol) in dry THF (100 mL) was
added LiAlH4 (574 mg, 15.1 mmol) in small portions and
stirred for 1 h at room temperature under nitrogen atmo-
sphere. The excess hydride was destroyed by adding a satu-
rated aqueous solution of Na2SO4, and the white salts were
separated by filtration. The solvent was evaporated in vacuo
and the residue purified by column chromatography (hex-
anes–EtOAc, 2:8) to afford compound 21 (723 mg,
3.09 mmol, 82%) as a colourless oil: [a]D ꢀ5.5 (c, 0.20);
IR 3637, 3549, 2941, 2884, 1424, 1214, 1154, 1081,
1
1385, 1191, 1113 cmꢀ1; H NMR 1.43 (1H, m), 1.56 (1H,
ddd, J¼4.9, 8.2, 13.2 Hz), 1.73–1.86 (2H, m), 2.92 (1H,
dd, J¼6.4, 6.4 Hz), 3.01 (1H, br s), 3.24 (3H, s), 3.26 (3H,
s), 3.33 (3H, s), 3.34 (1H, m), 3.39 (1H, dd, J¼3.6,
10.2 Hz), 3.53 (1H, dd, J¼6.7, 10.0 Hz), 3.57 (2H, t,
J¼6.0 Hz), 3.61 (1H, ddd, J¼3.5, 6.5, 6.5 Hz), 3.99 (1H,
dddd, J¼4.8, 4.8, 4.8, 9.8 Hz); 13C NMR 32.4 (CH2), 34.5
(CH2), 56.7 (CH3), 58.8 (CH3), 59.1 (CH3), 60.2 (CH2),
68.6 (CH), 71.2 (CH2), 72.1 (CH), 77.3 (CH), 78.2 (CH);
MS (FAB) m/z (rel intensity) 257 (M++Na, 5), 235 (M++H,
100); HRMS calcd for C11H22NaO5 257.1365, found
257.1340. Anal. Calcd for C11H22O5: C, 56.39; H, 9.46.
Found: C, 56.27; H, 9.48.
1
1043 cmꢀ1; H NMR 1.84–1.97 (2H, m), 2.32 (1H, br s,
OH), 3.34 (3H, s), 3.66 (1H, dd, J¼5.2, 11.0 Hz), 3.71
(1H, dd, J¼3.8, 11.0 Hz), 3.77 (2H, t, J¼5.7 Hz), 3.91–
3.96 (2H, m), 4.36 (1H, dd, J¼5.5, 6.9 Hz), 4.48 (1H,
dd, J¼5.0, 6.9 Hz), 4.63 (2H, s), 5.02 (1H, s), 5.10 (1H, s);
13C NMR 35.5 (CH2), 55.4 (CH3), 60.1 (CH2), 67.5
(CH2), 81.2 (3ꢂCH), 84.0 (CH), 95.3 (CH2), 96.6
(CH2); MS m/z (rel intensity) 219 (M+ꢀCH3, 1), 203 (7);
HRMS calcd for C9H15O6 219.087, found 219.0827. Anal.
Calcd for C10H18O6: C, 51.27; H, 7.74. Found: C, 51.21;
H, 8.09.
4.2.13. Methyl 3,6-anhydro-2-deoxy-D-allo-heptonate
(19). A solution of 1821 (214 mg, 0.44 mmol) and iodine
(38 mg, 0.15 mmol) in methanol was refluxed for 4 h. A sat-
urated solution of Na2S2O3 was added dropwise while the re-
action mixture was stirred until complete reduction of the
remaining iodine and the solvent was removed in vacuum.
Purification of the residue by column chromatography
(CHCl3–MeOH, 9:1) gave compound 19 (81.5 mg,
0.40 mmol, 90%) as a colourless oil: [a]D ꢀ2.3 (c, 2.05);
IR (CCl4) 3360, 2931, 1732, 1652, 1442, 1285, 1108,
4.2.16. 3,6-Anhydro-7-deoxy-1,2:4,5-di-O-isopropyl-
idene-D-glycero-D-manno-octitol (23). Following the gen-
eral procedure for reductive ozonolysis, compound 222a
(154 mg, 0.54 mmol) afforded compound 23 (140 mg,
0.49 mmol, 90%) as a colourless oil: [a]D –17 (c, 0.6); IR
1
1040 cmꢀ1; H NMR 2.52 (1H, dd, J¼8.4, 15.4 Hz), 2.67
(1H, dd, J¼4.3, 15.5 Hz), 3.54 (1H, dd, J¼4.5, 12.0 Hz),
3.63 (1H, dd, J¼3.6, 12.0 Hz), 3.67 (3H, s), 3.76 (1H, dd,
J¼6.0, 6.0 Hz), 4.80 (1H, ddd, J¼4.4, 4.4, 8.1 Hz), 3.95
(1H, dd, J¼4.4, 5.6 Hz), 4.09 (1H, m), 4.83 (3H, br s); 13C
NMR 37.7 (CH2), 50.7 (CH3), 61.9 (CH2), 71.0 (CH), 74.4
(CH), 78.8 (CH), 84.8 (CH), 172.0 (C); MS (EI) m/z (rel in-
tensity) (FAB) 229 (M++Na, 100), 207 (M++H, 100). Anal.
Calcd for C8H14O6: C, 46.60; H, 6.84. Found: C, 46.26; H,
7.22.
1
3552, 2987, 2873, 1350, 1215 cmꢀ1; H NMR 1.30 (3H,
s), 1.34 (3H, s), 1.40 (3H, s), 1.46 (3H, s), 1.58 (1H, m),
1.73 (1H, m), 2.20 (1H, br s, OH), 3.74 (2H, m), 3.81 (1H,
dd, J¼4.2, 6.9 Hz), 3.96 (1H, dd, J¼4.9, 8.7 Hz), 4.05
(1H, dd, J¼6.4, 8.7 Hz), 4.23 (1H, ddd, J¼0.0, 4.4,
10.7 Hz), 4.36 (1H, ddd, J¼6.5, 6.5, 6.5 Hz), 4.51 (1H, dd,
J¼0.0, 6.0 Hz), 4.73 (1H, dd, J¼3.8, 6.0 Hz); 13C NMR
24.6 (CH3), 25.1 (CH3), 26.0 (CH3), 26.7 (CH3), 32.5
(CH2), 60.3 (CH2), 66.6 (CH2), 73.3 (CH), 80.0 (CH), 80.5
(CH), 83.1 (CH), 85.4 (CH), 109.0 (C), 112.6 (C); MS (EI)
m/z (rel intensity) 273 (M+ꢀCH3, 50), 215 (22), 101
(100); HRMS calcd for C13H21O6 273.1338, found
273.1344. Anal. Calcd for C14H24O6: C, 58.32; H, 8.39.
Found: C, 58.25; H, 8.58.
4.2.14. Methyl 3,6-anhydro-2-deoxy-7-O-(methoxy-
methyl)-4,5-O-methylen-D-allo-heptonate (20). To a solu-
tion of compound 19 (1.9 g, 9.4 mmol) in dry CHCl3
(55 mL) was added an excess of dimethoxymethane
(55 mL, 632.5 mmol), phosphorous pentoxide (28 g,
197 mmol) and stirred at room temperature under nitrogen
atmosphere for 3 h. The reaction mixture was cooled to

C. G. Francisco et al. / Tetrahedron 63 (2007) 8910–8920
8917
4.2.17. 3,6-Anhydro-1-O-benzyl-2-deoxy-4,5:7,8-di-O-
isopropylidene-D-manno-octitol (24). Alcohol 23 (1.64 g,
5.73 mmol) and BnBr (1.36 mL, 11.5 mmol) were dissolved
in dry DMF (15 mL) under argon. NaH (60% in oil)
(458 mg, 11.5 mmol) was added in portions at 0 ꢁC. After
stirring for 2 h at room temperature, the reaction mixture
was quenched with MeOH (5 mL), poured into an aqueous
sat. solution of NH4Cl and extracted with ether. The organic
phase was separated, dried with anhydrous Na2SO4, filtered
and concentrated under vacuum. Column chromatography
(hexanes–EtOAc, 7:3) of the residue afforded compound
24 (1.98 g, 5.24 mmol, 92%) as a colourless oil: [a]D +18
was dissolved in MeOH (4 mL) and Pd black (17 mg) was
added. The reaction vessel was purged from air and stirred
for 8 h under a hydrogen atmosphere. Filtration through
a Celite plug eluted with MeOH and concentration afforded
the alcohol 26 (127 mg, 0.49 mmol, quant.) as a colourless
crystalline compound: [a]D ꢀ7 (c, 0.4, EtOAc); mp 116–
117 ꢁC (EtOAc–n-pentane); 1H NMR 1.80 (2H, ddd,
J¼5.8, 6.0, 7.0 Hz), 3.82 (2H, dd, J¼5.7, 5.7 Hz), 4.28
(1H, dd, J¼3.6, 4.9 Hz), 4.51 (1H, dd, J¼6.2, 8.9 Hz),
4.60 (1H, dd, J¼8.4, 8.4 Hz), 4.64 (1H, dd, J¼7.3,
7.3 Hz), 5.01 (1H, ddd, J¼5.1, 6.2, 8.2 Hz), 5.20 (1H, d,
J¼6.6 Hz), 5.27 (1H, dd, J¼3.7, 7.1 Hz); 13C NMR
(CD3OD) 33.7 (CH2), 59.0 (CH2), 67.8 (CH2), 75.5 (CH),
79.9 (CH), 82.2 (CH), 83.6 (CH), 86.1 (CH), 155.9 (C),
156.8 (C); MS (FAB+) m/z (rel intensity) 283 (M++Na,
38), 261 (M++H, 100); HRMS calcd for C10H13O8
261.0610, found 261.0602. Anal. Calcd for C10H13O8: C,
46.16; H, 4.65. Found: C, 45.91; H, 4.82.
1
(c, 0.5, EtOAc); H NMR 1.33 (3H, s), 1.37 (3H, s), 1.44
(3H, s), 1.50 (3H, s), 1.73 (2H, ddd, J¼6.2, 6.4, 8.1 Hz),
3.55 (2H, dd, J¼6.5, 6.5 Hz), 3.72 (1H, dd, J¼3.7,
7.7 Hz), 4.01 (1H, dd, J¼4.5, 8.7 Hz), 4.09 (1H, dd,
J¼6.4, 8.7 Hz), 4.24 (1H, dd, J¼7.4, 7.4 Hz), 4.39 (1H,
ddd, J¼4.4, 6.2, 7.7 Hz), 4.50 (2H, s), 4.59 (1H, dd,
J¼0.8, 6.1 Hz), 4.75 (1H, dd, J¼3.8, 6.2 Hz), 7.27–7.38
(5H, m); 13C NMR 25.1 (CH3), 25.6 (CH3), 26.5 (CH3),
27.3 (CH3), 67.2 (CH2), 67.4 (CH2), 73.5 (CH2), 73.9
(CH), 80.6 (CH), 81.1 (CH), 82.0 (CH), 85.9 (CH), 109.5
(C), 112.9 (C), 127.9 (3ꢂCH), 128.7 (2ꢂCH), 138.7 (C);
MS (FAB+) m/z (rel intensity) 401 (M++Na, 1), 379
(M++H, 4), 363 (6); HRMS calcd for C21H31O6 379.2121,
found 379.2117. Anal. Calcd for C21H30O6: C, 66.65; H,
7.99. Found: C, 66.70; H, 7.91.
4.3. IHA reaction of 3,7-anhydrooctitols and
3,6-anhydroheptitols
4.3.1. General procedure. A solution of 3,7-anhydroocti-
tols or 3,6-anhydroheptitols (1 mmol) in dry CH2Cl2
(25 mL) containing (diacetoxyiodo)benzene (DIB) and
iodine (1 mmol) was irradiated with two 80 W tungsten
filament lamps at room temperature under nitrogen until the
reaction was completed. The reaction mixture was then
poured into 10% aqueous Na2S2O3 and extracted with
CH2Cl2. The organic layer was dried and concentrated under
vacuum. Chromatotron chromatography of the residue (hex-
anes–EtOAc mixtures) afforded the anhydrosugars. Equiva-
lents of DIB used and reaction times are shown in Table 1
and Schemes 4 and 5.
4.2.18. 3,6-Anhydro-1-O-benzyl-2-deoxy-4,5:7,8-di-O-
oxomethylene-D-manno-octitol (25). Acid resin Dowex
(50ꢂ8) (29.0 g, 9 equiv) was added to a solution of com-
pound 24 (1.95 g, 5.15 mmol) in methanol (100 mL) and
stirred for 60 h at room temperature. The reaction mixture
was filtered and the solvent removed under vacuum. The res-
idue (1.58 g) and pyridine (6.10 g, 77 mmol) dissolved in
dry CH2Cl2 (21 mL) was added slowly to a solution of tri-
phosgene (3.36 g, 11.3 mmol) in CH2Cl2 (15 mL) stirred
at ꢀ70 ꢁC. After the addition was completed, the reaction
mixture was allowed to warm up to room temperature. The
resulting solution was poured into aqueous sat. solution of
NH4Cl and extracted with CH2Cl2. The organic phase was
washed with 1 N HCl, aqueous sat. solution of NaHCO3
and brine successively, dried over Na2SO4 and concentrated
under vacuum. Column chromatography (hexanes–EtOAc,
4:6) of the residue afforded compound 25 (1.68 g,
4.80 mmol, 93%) as a white crystalline compound: [a]D
+13 (c, 0.5, EtOAc); mp 118–120 ꢁC (EtOAc–n-pentane);
1H NMR 1.81 (2H, m), 3.56 (2H, dd, J¼5.8, 5.8 Hz), 4.13
(1H, dd, J¼2.9, 5.6 Hz), 4.40 (1H, dd, J¼6.4, 8.7 Hz),
4.46 (1H, d, J¼11.7 Hz), 4.49 (1H, d, J¼11.7 Hz), 4.52
(1H, dd, J¼8.6, 8.6 Hz), 4.55 (1H, dd, J¼7.0, 7.0 Hz),
4.93 (1H, ddd, J¼5.6, 6.4, 8.2 Hz), 5.14 (1H, d,
J¼9.8 Hz), 5.17 (1H, d, J¼9.8 Hz), 7.28–7.38 (5H, m);
13C NMR 30.9 (CH2), 66.0 (CH2), 66.5 (CH2), 73.5 (CH),
73.7 (CH2), 79.2 (CH), 80.4 (CH), 83.0 (CH), 84.5 (CH),
128.2 (2ꢂCH, 128.4 (CH), 128.9 (2ꢂCH), 138.0 (C),
153.8 (C), 154.6 (C); MS (FAB+) m/z (rel intensity) 373
(M++Na, 7), 349 (M+ꢀH, 11); HRMS calcd for C17H17O8
349.0923, found 349.0915. Anal. Calcd for C17H18O8: C,
58.28; H, 5.18. Found: C, 58.17; H, 5.45.
4.3.2. Tri-O-acetyl-2,8-anhydro-1,7-dideoxy-b-L-gulo-
oct-2-ulopyranose (27). Following the general procedure,
precursor 2 (33 mg, 0.104 mmol) afforded the anhydrosugar
27 (15 mg, 0.05 mmol, 47%) as a colourless oil: [a]D ꢀ18.1
(c, 0.16); IR 2978, 1732, 1715, 1372, 1234, 1064 cmꢀ1
;
1H NMR 1.25 (3H, s), 1.90 (1H, m), 1.98 (3H, s), 2.04
(3H, s), 2.11 (1H, m), 2.14 (3H, s), 3.76 (1H, dd, J¼7.1,
10.7 Hz), 3.87 (1H, ddd, J¼4.7, 11.3, 11.3 Hz), 4.51 (1H,
ddd, J¼3.2, 5.9, 9.6 Hz), 5.22 (1H, d, J¼4.1 Hz), 5.24
(1H, dd, J¼5.9, 10.5 Hz), 5.68 (1H, dd, J¼4.0, 10.5 Hz);
13C NMR (50.3 MHz) 20.7 (3ꢂCH3), 22.2 (CH3), 23.6
(CH2), 55.9 (CH2), 65.9 (CH), 67.1 (CH), 67.8 (CH), 71.4
(CH), 98.3 (C), 169.7 (C), 169.9 (C), 170.1 (C); MS (EI)
m/z (rel intensity) 316 (M+, 1), 257 (17), 214 (5), 196 (16);
HRMS calcd for C14H20O8 316.1158, found 316.1175.
Anal. Calcd for C14H20O8: C, 53.16; H, 6.37. Found: C,
53.06; H, 6.70.
4.3.3. 2,8-Anhydro-1,7-dideoxy-3,4,5-tri-O-methyl-b-
L-gulo-oct-2-ulopyranose (28). Following the general
procedure, precursor 4 (131 mg, 0.559 mmol) afforded the
anhydrosugar 28 (75 mg, 0.32 mmol, 57%) as a colourless
oil: [a]D ꢀ30.5 (c, 0.59); IR 2936, 2826, 1462, 1377,
1
1223, 1102, 1074 cmꢀ1; H NMR 1.33 (3H, s), 1.76 (1H,
m), 2.06 (1H, m), 3.37 (1H, d, J¼2.8 Hz), 3.4 (3H, s), 3.5
(3H, s), 3.56 (3H, s), 3.60 (1H, dd, J¼3.3, 9.9 Hz), 3.62
(1H, d, J¼6.1 Hz), 3.79 (1H, dd, J¼3.3, 9.9 Hz), 3.84 (1H,
ddd, J¼4.3, 9.9, 9.9 Hz), 4.37 (1H, ddd, J¼3.8, 6.1,
4.2.19. 3,6-Anhydro-2-deoxy-4,5:7,8-di-O-oxomethylene-
D-manno-octitol (26). Benzyl ether 25 (170 mg, 0.49 mmol)

8918
C. G. Francisco et al. / Tetrahedron 63 (2007) 8910–8920
10.0 Hz); 13C NMR 22.6 (CH3), 23.3 (CH2), 55.9 (CH2),
58.1 (CH3), 58.4 (CH3), 61.6 (CH3), 66.3 (CH), 77 (CH),
79 (CH), 80.2 (CH), 99.5 (C); MS (EI) m/z (rel intensity)
231 (M+, <1), 203 (4), 187 (4); HRMS calcd for
C11H19O5 231.1232, found 231.1291. Anal. Calcd for
C11H20O5: C, 56.88; H, 8.68. Found: C, 56.54; H, 9.02.
217 (<1), 201 (2); HRMS calcd for C11H20O5 232.1310,
found 232.1334. Anal. Calcd for C11H20O5: C, 56.88; H,
8.68. Found: C, 56.87; H, 8.58. Compound 31: colourless
oil; [a]D ꢀ8.4 (c, 0.55); IR 2934, 2827, 1446, 1103,
1
1050 cmꢀ1; H NMR 1.29 (3H, d, J¼6.7 Hz), 1.89 (1H,
m), 2.35 (1H, m), 3.07 (1H, dd, J¼2.4, 6.2 Hz), 3.26 (3H,
s), 3.45 (3H, m), 3.52 (3H, s), 3.61 (1H, d, J¼2.4 Hz),
3.66 (1H, dq, J¼6.2, 6.7 Hz), 3.82 (1H, ddd, J¼6.4, 8.8,
8.8 Hz), 4.11 (1H, ddd, J¼5.5, 8.8, 8.8 Hz), 4.21 (1H, dd,
J¼1.7, 6.9 Hz); 13C NMR 18.6 (CH3), 31.4 (CH2), 48.5
(CH3), 57.9 (CH3), 58.1 (CH3), 66.4 (CH2), 68.7 (CH),
76.7 (2ꢂCH); MS (EI) m/z (rel intensity) 232 (M+, 16),
217 (1), 201 (4), 185 (2), 169 (2); HRMS calcd for
C11H20O5 232.1310, found 232.1282. Anal. Calcd for
C11H20O5: C, 56.88; H, 8.68. Found: C, 57.08; H, 8.32.
4.3.4. Methyl 3,7-anhydro-2-deoxy-5,6,8-tri-O-methyl-a-
D-manno-oct-4-ulofuranoside (29). Following the general
procedure, precursor 13 (249 mg, 0.942 mmol) afforded
the anhydrosugar 29 (174 mg, 0.66 mmol, 70%) as a colour-
less oil: [a]D +13.3 (c, 0.42); IR 2933, 2828, 1740, 1456,
1
1194, 1106 cmꢀ1; H NMR 1.87 (1H, m), 2.27 (1H, m),
3.17 (1H, dd, J¼2.6, 6.9 Hz), 3.19 (3H, s), 3.30 (3H, s),
3.36 (3H, s), 3.42 (1H, dd, J¼3.3, 10.4 Hz), 3.45 (3H, s),
3.52 (1H, dd, J¼7.2, 10.4 Hz), 3.54 (1H, d, J¼2.6 Hz),
3.65 (1H, ddd, J¼3.4, 6.9, 6.9 Hz), 3.75 (1H, ddd, J¼6.4,
8.8, 8.8 Hz), 4.05 (1H, ddd, J¼5.8, 8.7, 8.7 Hz), 4.16 (1H,
br d, J¼5.6 Hz); 13C NMR 31.3 (CH2), 48.4 (CH3), 57.8
(CH3), 58.1 (CH3), 59.1 (CH3), 66.4 (CH2), 72.1 (CH2),
72.3 (CH), 76.5 (CH), 76.9 (CH), 77.2 (CH), 105.1 (C);
MS (EI) m/z (rel intensity) 262 (M+, 17), 231 (1), 217
(23); HRMS calcd for C12H22O6 262.1416, found
262.1379. Anal. Calcd for C12H22O6: C, 54.95; H, 8.45.
Found: C, 55.27; H, 8.10.
4.3.7. Formation of compounds 31, 35 and 3-acetyl-2,8-
anhydro-1,7-didesoxy-3,4,5-tri-O-methyl-L-arabino-
octo-2,5-diulo-2,6-pyranose (36). Following the general
procedure for IHA reactions adding NaHCO3 (100%) to
the reaction mixture, precursor 8 (360 mg, 1.53 mmol) af-
forded anhydrosugars 35 (50 mg, 0.215 mmol, 14%), 31
(130 mg, 0.56 mmol, 37%) and 36 (20 mg, 0.07 mmol,
4.5%). Compound 36: [a]D +11.1 (c, 0.28); IR 2943, 2747,
1
1222, 1112 cmꢀ1; H NMR 1.35 (3H, s), 1.77 (1H, dddd,
J¼3.7, 6.8, 10.6, 14.2 Hz), 1.99 (1H, dddd, J¼2.8, 4.0,
10.5, 14.0 Hz), 2.10 (3H, s), 3.08 (1H, d, J¼8.9 Hz), 3.59
(3H, s), 3.62 (3H, s), 3.66 (3H, s), 3.72 (1H, ddd, J¼2.5,
6.7, 11.2 Hz), 3.82 (1H, ddd, J¼4.4, 10.8, 10.8 Hz), 3.85
(1H, d, J¼8.9 Hz), 5.21 (1H, dd, J¼3.8, 10.6 Hz), 13C
NMR 21.8 (CH3), 22.7 (CH3), 24.5 (CH2), 53.3 (CH3),
56.0 (CH2), 61.6 (CH3), 61.8 (CH3), 67.1 (CH), 83.3 (CH),
84.4 (CH), 98.5 (C), 105.0 (C), 169.6 (C); MS (EI) m/z
(rel intensity) 290 (M+, 3), 259 (7), 231 (6), 199 (8);
HRMS calcd for C13H22O7 290.1365, found 290.1314.
Anal. Calcd for C13H22O7: C, 53.78; H, 7.64. Found: C,
53.80; H, 7.39.
4.3.5. 1,3,4,5-Tetra-O-acetyl-2,8-anhydro-7-deoxy-b-
D-altro-oct-2-ulopyranose (30). Following the general
procedure, precursor 10 (75 mg, 0.2 mmol) afforded the an-
hydrosugar 30 (36 mg, 0.096 mmol, 48%) as a colourless
oil: [a]D ꢀ36.9 (c, 0.36); IR 2966, 1747, 1434, 1372,
1
1225, 1056 cmꢀ1; H NMR 1.97 (1H, m), 1.99 (3H, s),
2.07 (3H, s), 2.08 (1H, m), 2.11 (3H, s), 2.16 (3H, s), 3.92
(1H, ddd, J¼2.7, 10.8, 10.8 Hz), 3.93 (1H, d, J¼12.0 Hz),
3.98 (1H, ddd, J¼4.7, 11.2, 11.2 Hz), 4.17 (1H, d,
J¼12.0 Hz), 4.36 (1H, ddd, J¼2.0, 3.7, 11.1 Hz), 5.25
(1H, dd, J¼2.1, 3.9 Hz), 5.38 (1H, d, J¼10.3 Hz), 5.66
(1H, dd, J¼3.9, 10.3 Hz); 13C NMR 20.6 (2ꢂCH3), 20.7
(CH3), 20.9 (CH3), 26.1 (CH2), 57.7 (CH2), 63.4 (CH2),
67.2 (CH), 67.8 (CH), 69.6 (CH), 71.9 (CH), 97.7 (C),
169.8 (C), 170.1 (C), 170.3 (C), 170.5 (C); MS (EI) m/z
(rel intensity) 375 (M++H, 1), 331 (2), 315 (14); HRMS
calcd for C16H23O10 375.1291, found 375.1266. Anal. Calcd
for C16H22O10: C, 51.33; H, 5.92. Found: C, 51.48; H, 6.11.
4.3.8. 3,4,5-Tri-O-acetyl-2,8-anhydro-1,7-dideoxy-b-L-
altro-oct-2-ulopyranose (32). Following the general pro-
cedure, precursor 6 (52 mg, 0.163 mmol) afforded the
anhydrosugar 32 (27 mg, 0.085 mmol, 53%) as a colourless
oil: [a]D +65 (c, 0.36); IR 2972, 2747, 1372, 1226,
1059 cmꢀ1; 1H NMR 1.31 (3H, s), 1.87 (1H, m), 1.98 (3H,
s), 2.09 (3H, s), 2.11 (1H, m), 2.14 (3H, s), 3.83–3.94 (2H,
m), 4.25 (1H, ddd, J¼2.2, 2.2, 10.8 Hz), 5.21 (1H, d,
J¼9.9 Hz), 5.23 (1H, dd, J¼1.9, 3.9 Hz), 5.63 (1H, dd,
J¼3.9, 9.9 Hz); 13C NMR 20.6 (CH3), 20.8 (CH3), 20.9
(CH3), 22.9 (CH3), 26 (CH2), 56.8 (CH2), 67.4 (CH), 69.4
(CH), 71.7 (CH), 72.2 (CH), 98.7 (C), 170.1 (C), 170.2
(C), 170.5 (C); MS (EI) m/z (rel intensity) 316 (M+, 7),
273 (1), 257 (10), 197 (7), 155 (25); HRMS calcd for
C14H20O8 316.1158, found 316.1189. Anal. Calcd for
C14H20O8: C, 53.16; H, 6.37. Found: C, 53.23; H, 6.10.
4.3.6. Methyl 3,7-anhydro-2,8-dideoxy-5,6-di-O-methyl-
a-L-manno-oct-4-ulofuranoside (31) and 2,8-anhydro-
1,7-dideoxy-3,4,5-tri-O-methyl-b-L-altro-oct-2-ulopyra-
nose (35). Following the general procedure, precursor 8
(63 mg, 0.269 mmol) afforded the anhydrosugar 35 (7 mg,
0.03 mmol, 11%), and anhydrosugar 31 (28 mg,
0.12 mmol, 44.5%). Compound 35: crystalline compound,
mp 80.5–82.5 ꢁC; [a]D +97.8 (c, 0.45); IR 2940, 2885,
1
2831, 1469, 1378, 1119, 1064 cmꢀ1; H NMR 1.37 (3H,
s), 1.58 (1H, dddd, J¼3.5, 6.8, 10.3, 13.7 Hz), 2.04 (1H,
dddd, J¼2.7, 4.8, 10.8, 13.5 Hz), 3.25 (1H, d, J¼9.2 Hz),
3.43 (1H, dd, J¼2.1, 3.8 Hz), 3.48 (3H, s), 3.51 (3H, s),
3.58 (3H, s), 3.74 (1H, ddd, J¼2.7, 6.7, 11.2 Hz), 3.87
(1H, dd, J¼3.8, 9.2 Hz), 3.90 (1H, ddd, J¼4.7, 11.0,
11.0 Hz), 4.36 (1H, ddd, J¼1.9, 3.6, 10.8 Hz); 13C NMR
23.0 (CH3), 25.7 (CH2), 56.5 (CH2), 57.9 (CH3), 58.1
(CH3), 61.4 (CH3), 66.9 (CH), 78.7 (CH), 80.1 (CH), 82.7
(CH), 99.2 (C); MS (EI) m/z (rel intensity) 232 (M+, <1),
4.3.9. (2R)-2,8-Anhydro-5,7-dideoxy-1,3,4-tri-O-methyl-
D-arabino-oct-2-ulopyranose (33). Following the general
procedure, precursor 17 (140 mg, 0.60 mmol) afforded the
cyclised compound 33 (88.3 mg, 0.38 mmol, 64%) as a col-
ourless oil: [a]D ꢀ3.3 (c, 0.09); IR 2931, 2830, 1731, 1450,
1
1260, 1195, 1113 cmꢀ1; H NMR 1.62 (1H, m), 1.83 (1H,
m), 2.04 (1H, m), 2.17 (1H, m), 3.29–3.37 (2H, m), 3.39
(3H, s), 3.45 (1H, m), 3.45 (3H, s), 3.55 (3H, s), 3.75–3.86

C. G. Francisco et al. / Tetrahedron 63 (2007) 8910–8920
8919
(2H, m), 3.91 (1H, m), 4.34 (1H, m); 13C NMR 28.9 (CH2),
35.8 (CH2), 57.4 (CH3), 58.2 (CH2), 59.3 (CH3), 60.8 (CH3),
66.3 (CH), 73.2 (CH2), 78.1 (CH), 81.7 (CH), 98.5 (C); MS
m/z (rel intensity) 232 (M+, 1), 231 (2); HRMS calcd for
C11H20O5 232.1310, found 232.1297. Anal. Calcd for
C11H20O5: C, 56.88; H, 8.68. Found: C, 56.81; H, 8.90.
extracted with EtOAc. The organic phase was concentrated
in vacuum. The residue was dissolved in dry CH2Cl2 and
BF3$OEt2 (24 mL, 0.19 mmol) was added at 0 ꢁC under ni-
trogen atmosphere. After 30 min at 0 ꢁC, the reaction mix-
ture was poured into aqueous sat. solution of NaHCO3 and
extracted with AcOEt. The organic phase was dried with
Na2SO4 and concentrated under vacuum. Column chromato-
graphy of the residue (hexanes–EtOAc, 1:1) afforded the
anhydrosugar 40 (32 mg, 0.12 mmol, 65%) as a colourless
crystalline compound; [a]D ꢀ42.6 (c, 0.6, EtOAc); mp
4.3.10. 3,6-Anhydro-2-deoxy-7-O-(methoxymethyl)-4,5-
O-methylene-b-D-ribo-hept-4-ulofuranose (34). Follow-
ing the general procedure, precursor 21 (66.2 mg,
0.28 mmol) afforded the cyclised compound 34 (37.4 mg,
0.16 mmol, 57%) as a colourless oil: [a]D +61.0 (c, 1.41);
1
209–213 ꢁC (EtOAc–n-pentane); H NMR 1.60 (1H, dddd,
J¼0.8, 2.1, 3.9, 14.1 Hz), 2.38 (1H, dddd, J¼3.9, 6.9,
13.0, 14.0 Hz), 3.71 (1H, ddd, J¼3.9, 12.9, 12.9 Hz), 4.12
(1H, dddd, J¼1.1, 1.1, 6.8, 12.5 Hz), 4.52 (1H, dd, J¼8.6,
8.6 Hz), 4.70 (1H, ddd, J¼1.6, 1.6, 3.5 Hz), 4.73 (1H, dd,
J¼4.5, 8.7 Hz), 4.88 (1H, dd, J¼4.5, 8.5 Hz), 5.20 (1H, d,
J¼6.1 Hz), 5.26 (1H, d, J¼6.1 Hz); 13C NMR 27.0 (CH2),
60.6 (CH2), 65.2 (CH2), 73.2 (CH), 80.3 (CH), 81.2 (CH),
81.3 (CH), 104.5 (C), 153.5 (C), 154.8 (C); MS (FAB+)
m/z (rel intensity) 281 (M++Na, 18), 259 (M++H, 100);
HRMS calcd for C10H11O8 259.0454, found 259.0445.
Anal. Calcd for C10H10O8: C, 46.52; H, 3.90. Found: C,
46.19; H, 4.20.
1
IR 2930, 2886, 1732, 1440, 1367, 1153, 1109 cmꢀ1; H
NMR 1.99–2.17 (2H, m), 3.37 (3H, s), 3.70 (1H, dd,
J¼6.4, 10.7 Hz), 3.76 (1H, dd, J¼4.0, 10.7 Hz), 4.04–4.10
(2H, m), 4.18–4.22 (2H, m), 4.39 (1H, dd, J¼1.4, 5.7 Hz),
4.67 (2H, s), 5.25 (2H, s), 5.34 (2H, s); 13C NMR 31.1
(CH2), 55.4 (CH3), 67.3 (CH2), 69.5 (CH2), 82.5 (CH),
84.0 (CH), 84.2 (CH), 96.6 (CH2), 98.4 (CH2), 123.2 (C);
MS m/z (rel intensity) 232 (M+, 2), 231 (7); HRMS calcd
for C10H16O6 232.0947, found 232.0991. Anal. Calcd for
C10H16O6: C, 51.72; H, 6.94. Found: C, 51.62; H, 6.88.
4.3.11. (4R)-3,6-Anhydro-2-deoxy-4,5:7,8-di-O-isopropyl-
idene-a-D-manno-oct-4-ulofuranose (37) and 7-deoxy-
1,2:4,5-di-O-isopropylidene-D-altro-oct-3-ulofuranose
(38). Following the general procedure, precursor 23 (90 mg,
0.31 mmol) afforded compounds 38 (23 mg, 0.08 mmol,
26%) and 37 (36 mg, 0.13 mmol, 41%). Compound 37:
amorphous solid; [a]D ꢀ19.0 (c, 0.5); IR 2988, 2891,
Acknowledgements
This work was supported by the investigation programmes
CTQ2004-06381/BQU and CTQ20004-02367/BQU of the
ꢀ
Direccion General de Investigacion Cientıfica y Tecnica,
Spain. A.J.H. and I.P.-M. thank the Ministerio de Educacion
ꢀ
ꢀ
ꢀ
1
1374, 1210, 1085 cmꢀ1; H NMR 1.34 (3H, s), 1.42 (3H,
ꢀ
s), 1.46 (3H, s), 1.48 (3H, s), 1.93 (1H, m), 2.13 (1H, m),
4.04 (4H, m), 4.13 (1H, dd, J¼3.9, 7.3 Hz), 4.35 (1H, ddd,
J¼4.8, 6.3, 7.3 Hz), 4.45 (1H, d, J¼3.9 Hz), 4.54 (1H, dd,
J¼7.1, 7.1 Hz); 13C NMR 25.0 (CH3), 25.1 (CH3), 26.6
(CH3), 26.8 (CH3), 30.8 (CH2), 66.4 (CH2), 69.0 (CH2),
73.1 (CH), 80.3 (CH), 83.5 (CH), 86.4 (CH), 109.1 (C),
114.0 (C), 122.8 (C); MS m/z (rel intensity) 271
(M+ꢀCH3, 35), 213 (30); HRMS calcd for C13H19O6
271.1181, found 271.1192. Anal. Calcd for C14H22O6: C,
58.73; H, 7.74. Found: C, 58.85; H, 7.95. Compound 38:
amorphous solid; [a]D ꢀ24.1 (c, 0.8); IR 2986, 2873,
y Ciencia, Spain, and the programme I3P-CSIC, respec-
tively, for fellowships.
References and notes
1. Recent reviews: (a) Majetich, G. Tetrahedron 1995, 51, 7095–
7129; (b) Feray, L.; Kuznersov, N.; Renaud, P. Radicals in
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Weinheim, 2001; Vol. 2, pp 246–278; (c) Robertson, J.;
Pillai, J.; Lush, R. K. Chem. Soc. Rev. 2001, 30, 94–103.
1
1732, 1378, 1260, 1209, 1077 cmꢀ1; H NMR 1.34 (1H,
ꢀ
2. (a) Martın, A.; Salazar, J. A.; Suarez, E. J. Org. Chem. 1996, 61,
3999–4006; (b) Dorta, R. L.; Martın, A.; Salazar, J. A.; Suarez,
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m), 1.34 (3H, s), 1.36 (3H, s), 1.43 (3H, s), 1.46 (3H, s),
2.19 (1H, m), 3.70 (1H, ddd, J¼4.2, 12.5, 12.5 Hz), 3.98
(1H, ddd, J¼0.0, 6.7, 12.6 Hz), 4.03 (1H, dd, J¼7.5,
7.5 Hz), 4.20 (1H, dd, J¼5.6, 8.4 Hz), 4.33 (1H, ddd,
J¼0.0, 6.0, 6.0 Hz), 4.36 (1H, m), 4.68 (1H, d, J¼5.6 Hz),
4.73 (1H, d, J¼5.6 Hz); 13C NMR 24.4 (CH3), 25.0 (CH3),
25.8 (CH3), 25.9 (CH3), 27.5 (CH2), 59.9 (CH2), 64.9
(CH2), 74.7 (CH), 79.3 (CH), 82.2 (CH), 82.8 (CH),
105.6(C), 109.7 (C), 112.5 (C); MS m/z (rel intensity) 271
(M+ꢀCH3, 47), 213 (86); HRMS calcd for C13H19O6
271.1181, found 271.1212. Anal. Calcd for C14H22O6: C,
58.73; H, 7.74. Found: C, 58.63; H, 7.70.
E. J. Org. Chem. 1998, 63, 2251–2261; (c) Francisco, C. G.;
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Herrera, A. J.; Suarez, E. J. Org. Chem. 2002, 67, 7439–7445;
For a preliminary communication on this work, see: (d)
ꢀ
Francisco, C. G.; Freire, R.; Herrera, A. J.; Perez-Martın, I.;
Suarez, E. Org. Lett. 2002, 4, 1959–1961; For other IHA reac-
ꢀ
ꢀ
tions in carbohydrate chemistry, see: (e) Descotes, G.
J. Carbohydr. Chem. 1988, 7, 1–20; (f) Chatgilialoglu, C.;
Giminis, T.; Spada, G. P. Chem.—Eur. J. 1999, 5, 2866–2876;
(g) Robins, M. J.; Guo, Z.; Samano, M. C.; Wnuk, S. F. J. Am.
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4081–4082.
4.3.12. 7-Deoxy-1,2:4,5-di-O-oxomethylene-D-altro-oct-3-
ulofuranose (40). A solution of the alcohol 26 (50 mg,
0.19 mmol) in dry CH2Cl2 (4 mL) containing DIB (93 mg,
0.29 mmol) and iodine (49 mg, 0.19 mmol) was stirred and
irradiated with an 80 W tungsten filament lamp at room tem-
perature under nitrogen atmosphere for 35 min. The reaction
mixture was then poured into 10% aqueous Na2S2O3 and
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Selnick, H. G.; Hungate, R. J. Am. Chem. Soc. 1989, 111,
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2967–2980; (b) Brimble, M. A.; Fares, F. A. Tetrahedron

8920
C. G. Francisco et al. / Tetrahedron 63 (2007) 8910–8920
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14. Evidence for a deactivating influence of the b-oxygen on the in-
termolecular hydrogen abstraction reaction has been described:
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ꢀ
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ꢀ
5. HAT reaction through eight-membered transition states or
higher promoted by alkoxyl radicals which suffer a severe
entropic penalty are practically unknown. Recently an IHA
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pyranose units in a disaccharide model has been observed in
this laboratory: Francisco, C. G.; Herrera, A. J.; Kennedy,
ꢀ
A. R.; Melian, D.; Suarez, E. Angew. Chem., Int. Ed. 2002,
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ꢀ
6. CRC Handbook of Chemistry and Physics, 73rd ed.; CRC:
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15. An example of a double IHA reaction:
ꢀ
7. (a) Gonzalez, C. C.; Kennedy, A. R.; Leon, E. I.; Riesco-
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OP
OP
OP
R
O
HO
O
ꢀ
a
O
O
+
ꢀ
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ꢀ
O
OMe
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OMe
OMe
(22%)
8. An example of the influence of the substituents on the 1,5-HAT
reaction compared with competing b-fragmentation of alkoxyl
radicals has been published: Allen, P. R.; Brimble, M. A.;
R = H (29%)
R = I (15%)
(a) DIB, I2, cyclohexane, hν, 40 ºC, 70 min
ꢁ
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For other double IHA reactions in carbohydrate models, see
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17. Bicyclic ketals can be easily converted into the corresponding
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ꢀ
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