A stereodivergent approach to 5a-carba-α-D-gluco-, -α-D-galacto and -β-L-gulopyranose pentaacetates from D-mannose, based on 6-exo-dig radical cyclization and Barton-Mccombie radical deoxygenation

Article abstract of DOI:10.1002/ejoc.200300339

The three carbasugars, 5a-carba-α-D-gluco-, -α-D-galacto and -β-L-gulopyranose pentaacetates 42, 35 and 28 respectively, have been prepared in a stereodivergent manner from D-mannose. Alkynyl derivatives of 2,3:4,6-di-O-isopropylidene-D-mannopyranose, whi

Full text of DOI:10.1002/ejoc.200300339

FULL PAPER
A Stereodivergent Approach to 5a-Carba-α-
D
-gluco-, -α-
D
-galacto and -β- -
L
gulopyranose Pentaacetates from -Mannose, Based on 6-exo-dig Radical
D
Cyclization and Barton؊McCombie Radical Deoxygenation
[a]
[a]
[a]
[a]
´
´
´
´
Ana M. Gomez,* Eduardo Moreno, Serafın Valverde, and J. Cristobal Lopez*
Dedicated to Professor Bert Fraser-Reid on the occasion of his 70th birthday
Keywords: Carbohydrates / Radical cyclization / Radical deoxygenation / Synthesis design / -Mannose
The three carbasugars, 5a-carba-α-
and -β- -gulopyranose pentaacetates 42, 35 and 28 respect-
ively, have been prepared in a stereodivergent manner from
D
-gluco-, -α-
D
-galacto
Ozonolysis of the exocyclic double bond in the latter gener-
ated cyclohexanones which, upon stereoselective reduction
of the carbonyl moiety followed by site-selective deoxygena-
L
D-mannose. Alkynyl derivatives of 2,3:4,6-di-O-isopropylid- tion either at position C-4 or C-5a (parent carbohydrate num-
ene-
D-mannopyranose, which are homologated at C-1 by re-
bering), afforded the title carbasugars.
action with trimethylsilylacetylide, undergo a 6-exo-dig rad-
ical cyclization, from a radical located at C-5, to yield a mix-
ture of highly functionalized exo-methylenecyclohexanes.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
The term ‘‘pseudo-sugar’’, nowadays replaced by ‘‘carba-
sugar’’,[1] was coined by McCasland and co-workers in
1966[2] to describe carbocyclic analogs of monosaccharides
in which a methylene group has replaced the endocyclic
oxygen. They prepared the first ‘‘carbasugars’’ in racemic
forms: 5a-carba-α--talo- (1)[1], 5a-carba-β--galacto-
(2)[3] and 5a-carba-α--gulopyranose (3).[4] Carbasugars
and some of their derivatives, as anticipated by
McCasland,[2Ϫ4] display a wide range of biological proper-
ties owing to their close resemblance to carbohydrates.[5Ϫ7]
Interestingly, five years after its synthesis, optically pure 5a-
carba-α--galactopyranose (2) was isolated as a weak anti-
biotic from the fermentation broth of some Streptomyces
species.[8] Carbahexopyranoses have been studied exten-
sively during the past three decades, after their derivatives
were found to occur naturally. In fact, carbasugar deriva-
tives have been found as components of antibiotic
validamycins[9Ϫ11] and the α-glucosidase inhibitor acarbose
and its homologs[12] (amilostatins, adiposins, oligostatins,
trestatins and aminooligosaccharides NS-504).[6,13] As
consequence of these findings, an extensive synthetic effort
has been devoted to the preparation of carbasugars and
their analogs.[1,7,14Ϫ18]
Figure 1. Racemic carbasugars prepared by McCasland and co-
workers (shown: -enantiomers)
In this context, our group, which had been interested in
the preparation of carbocycles from carbohydrates,[19,20] has
recently paid attention to the synthesis of carbasugars from
monosaccharides.[21,22] Our synthetic strategies,[21,22] unlike
those of others based on radical cyclization of carbohydrate
derivatives,[23,24] were designed to allow the direct trans-
formation of a carbohydrate, 6, into its corresponding car-
basugar, 4 (Scheme 1). We have already shown the useful-
ness of these approaches by preparing 5a-carba--gluco-,[21]
5a-carba--galacto-,[21] and 5a-carba--mannopyranose[22]
pentaacetates from their corresponding monosaccharides.
[a]
´
´
Instituto de Quımica Organica General,
Juan de la Cierva 3, 28006 Madrid, Spain
Fax: (internat.) ϩ34-91-5644853
E-mail: anago@iqog.csic.es
Scheme 1. Retrosynthesis of 5a-carba-β--mannopyranose from
-mannose
clopez@iqog.csic.es
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DOI: 10.1002/ejoc.200300339
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A Stereodivergent Approach to D-Mannoses
FULL PAPER
These methods, however, are of limited use for the prep- 10. In this work, we illustrate the flexibility of this method-
aration of carbasugars derived from ‘‘rare’’ sugars, or those ology with the syntheses of 5a-carba-β--gulopyranose (28),
corresponding to the -series, because of the low availability 5a-carba-α--galactopyranose (35) and 5a-carba-α--gluco-
of the starting monosaccharides. Hence, we focused our pyranose (42) pentaacetates from -mannose.[29]
interest on developing an approach that, starting from a
readily available monosaccharide, could allow access to a
variety of carbasugars in a stereodivergent manner. In this
Results and Discussion
context, we turned our attention to the hydroxy compound
5 (Scheme 1), an intermediate in our retrosynthesis[22] of the
Synthesis of the Precursor for Radical Cyclization
5a-carba--mannopyranose 4. Compound 5 was prepared
-Mannose was transformed into 2,3:4,6-di-O-isopro-
by 6-exo-dig radical cyclization[25] of a carbohydrate-de-
pylidene--mannopyranose (6), in a single step, by kinetic
rived alkyne, followed by ozonolysis and reduction.
acetonation according to Gelas and Horton.[30] Addition
of lithium trimethylsilyl acetylide to the latter compound
Stereodivergent Strategy
afforded an inseparable (2:1) mixture of epimeric 1S and
1R isomers, 11 and 12, respectively,[31] (Scheme 3) in which
We have recently shown how a polyoxygenated intermedi-
ate, 5, could be transformed into two different carbasugars
by use of the BartonϪMcCombie radical deoxygen-
ation[26,27] either at C-5a or at C-4.[28] In this paper, we dis-
close how the stereodivergency in our approach can be en-
hanced by the use of polyhydroxylated cyclohexanone inter-
mediates (e.g. 7, Scheme 2) which could be transformed in
up to three different carbasugar derivatives as outlined in
Scheme 2. Accordingly, stereoselective reduction of the car-
bonyl group in compound 7 would give rise to a pair of
epimeric polyoxygenated intermediates 8, 9, which, upon
BartonϪMcCombie deoxygenation either at C-5a or at C-
4, would lead to the three different carbasugars 2, 3, and
the trimethylsilyl residues have been lost during workup.
The stereochemical outcome of this reaction differs from
the stereochemical result of the addition of lithium phenyl-
acetylide to the hemiacetal 6, which yields a (5:1) mixture
of the (1R) and (1S) isomers 13 and 14[31]
.
Scheme 3. Stereoselectivity of the addition of lithium acetylides to 6
Our synthetic route continued with the selective protec-
tion of the 1-hydroxy group (parent carbohydrate number-
Scheme 2. Stereodivergent access to three carbasugars from a com-
mon synthetic intermediate arising from -mannose
Scheme 4. Synthesis of epimeric carbonates 18, for radical cycliza-
tion
Eur. J. Org. Chem. 2004, 1830Ϫ1840
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A. M. Gomez, E. Moreno, S. Valverde, J. C. Lopez
FULL PAPER
ing) prior to activation of the 5-hydroxy group of diols 11, tempts for the transformation 23 Ǟ 22 by Mitsunobu inver-
12. Accordingly, the epimeric mixture (11 ϩ 12; Scheme 4) sion,[35] either with acetic acid or p-nitrobenzoic acid[36] as
was treated with ethyl chloroformate in CH2Cl2 in the pres- nucleophiles, left the starting material unchanged. The cor-
ence of pyridine to yield the carbonates 15, as an epimeric responding mesylate and triflate were prepared next, and
mixture at C-1, in 57% yield, along with mono- 16 and di- their nucleophilic displacement examined with sodium ni-
carbonates 17, which could be converted back to diols 11, trite in DMF;[37] decomposition of the starting material was
12 by base treatment. To activate the 5-hydroxy group and observed. The reaction of both derivatives (mesylate and
[38]
allow generation of the requisite secondary radical, com- triflate of 23) with NaOH and Bu4NHSO4
resulted in
pounds 15 were treated with an excess of phenyl chloro- the regeneration of the starting hydroxy compound 23. The
thionoformate[27] and pyridine in acetonitrile and refluxed preparation of different derivatives of 23 (activation of 1-
for 1 h to provide the desired thionocarbonates 18 in 76% OH by reaction with tosylimidazole) and the use of differ-
yield.
ent nucleophiles (sodium acetate) were also unsuccessful.
Finally, an oxidation (Swern conditions[39])-reduction
(NaBH4, boraneϪmethyl sulfide) sequence served only to
regenerate the starting β-hydroxy derivative 23 as the major
or only isomer.
Radical Cyclization of the Thionocarbonates 18
6-exo-digonal Radical cyclization was first described by
Clive and co-workers[25] for the synthesis of cyclic ketones,
and has since found ample use in organic synthesis. In gen-
eral, radical ring-closure of cyclic radicals onto alkenes[32]
and alkynes[25,33,34] is known to afford fused systems with
predominantly or exclusively cis ring closure (Scheme 5). In
keeping with literature references[32Ϫ34] then, radical cycli-
zation of 18 yielded a (15:1) mixture of cis- and trans-fused
adducts in which the cis-fused isomers prevailed
(Scheme 6). The epimeric mixture of cis-fused products (20/
21, 2:1 ratio) could be separated by chromatography at
this point.
Scheme 7. Synthesis of exo-methylenecyclohexane derivative 22
Scheme 5. 6-exo-Digonal ring closure of cyclic radicals
Synthesis of 5a-Carba-β-L-gulopyranose
The preparation of carba--gulopyranose required, ac-
cording to our synthetic strategy, deoxygenation of the 5a-
OH. Therefore, a benzyl protecting-group was installed at
1-OH in compound 22 (Scheme 8). The resulting benzylated
compound 24 was ozonolyzed (O3, MeOH, followed by
Scheme 6. 6-exo-Digonal radical cyclization of 18 to afford cis or
trans ring-fused systems
Syntheses of the exo-Methylene Precursor 22
Our synthetic route to carbasugars of the galacto, gluco
and gulo series required the use of the exo-methylene de-
rivative 22, with the appropriate stereochemistry at C-1, as
the starting material (Scheme 7). Compound 22 could be
readily obtained by treatment of minor isomer 21 with
K2CO3 in MeOH. However, it would be better to devise a
synthetic route to 22 from the carbonate 20, the major iso-
mer of the radical cyclization of 18. Accordingly, compound
Scheme 8. Synthesis of 5a-carba-β--gulopyranose pentaacetate
20 was saponified to the hydroxy derivative 23. First at- (28)
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A Stereodivergent Approach to D-Mannoses
FULL PAPER
treatment with Me2S) to yield an unstable ketone 25, which
was not characterized. Accordingly, reduction of 25
(NaBH4, CeCl3) without further purification gave a 3:1
mixture of 5a-OH epimers 26 in 90% yield from 24. The
xanthate of the major isomer was prepared next (NaH, CS2,
MeI, 80% yield) and submitted to deoxygenation with
Bu3SnH and AIBN in toluene at 85 °C to yield the deoxy
derivative 27 in 70% yield. Finally, hydrogenolysis of the
benzyl group (H2, Pd/C) followed by acid hydrolysis of the
isopropylidene acetals (AcOH/THF/H2O, 4:2:1, 85 °C) and
acetylation (Ac2O, Pyridine) yielded 5a-carba-β--gulopyr-
anose pentaacetate (28).[40,41]
Synthesis of 5a-Carba-α-D-galactopyranose
According to our synthetic strategy (Scheme 2), prep-
aration of carba--galactopyranose requires (a) reduction
of the 5a-keto group to give an α-oriented hydroxy group,
and (b) deoxygenation at C-4 (Scheme 2). Thus, alkene 22
was submitted to ozonolysis to give the unstable hydroxy
ketone 29 which, without purification, was treated with
NaBH4 in the presence of CeCl3 to afford the syn-diol 30
with complete stereoselectivity; this was benzylated to the
fully protected derivative 31. Unveiling of the 4-OH group
for deoxygenation was carried out in two steps: a) chemose-
lective deprotection of the six-membered isopropylidene
group upon treatment with pyridinium p-toluenesulfonate
(PPTS) in MeOH to yield the diol 32 (85% yield), and b)
selective protection of the 6-OH by treatment with tert-bu-
tyldiphenylsilyl chloride (TPSCl) and imidazole to furnish
33 (90% yield) (Scheme 9). BartonϪMcCombie radical de-
oxygenation of 4-OH in compound 33 paved the way to the
protected 5a-carba--galactopyranose derivative 34. Fi-
nally, deprotection and peracetylation of 34, as for 33, led
to 5a-carba-α--galactopyranose pentaacetate (35)[8,42]
Scheme 9. Synthesis of 5a-carba-α--galactopyranose pentaacet-
ate (35)
nones with stereoselectivity opposed to that of conventional
reagents. In our case, however, the starting material was re-
covered unchanged.
Synthesis of 5a-Carba-α-D-glucopyranose
The synthetic process for the preparation of 5a-carba--
glucopyranose implied: (a) preparation of a β-oriented 5a-
OH rather than an α-isomer (as in 9, Scheme 2), and (b)
deoxygenation at C-4 (Scheme 2). Preliminary results
showed us that reduction of the cyclohexanones 25 and 29
was taking place by β-approach of the incoming hydride to
give preferentially an α-5a-OH. This tendency was observed
for reagents like NaBH4 and LiAlH4. In an attempt to in-
vert the ‘‘preferred’’ stereoselectivity of the reduction we
tested sodium triacetoxyborohydride. The latter becomes a
reducing species towards a ketone only when complexed
with a suitably placed hydroxy group (see Scheme 10), and
contrasts with other reducing agents in which competing
inter vs. intramolecular hydride transfer might afford mix-
tures of epimeric alcohols.[43,44] Unfortunately, under the
standard reaction conditions the starting material was reco-
vered unchanged, thus reinforcing the hypothesis of the in-
termolecular hydride transfer for the reduction of the car-
bonyl group in 29. Other attempts were carried out with the
reagent system Bu2SnCl2/Bu2SnH2, introduced by Clive et
Scheme 10. Attempted reduction of hydroxy ketone 29 with so-
dium triacetoxyborohydride
These negative results led us to reconsider our strategy.
We hypothesized that the strong stereochemical bias for the
reduction of the cyclohexanones 25 and 29 was originated
by the possible axial orientation of the oxygen substituent
at C-4 in the cis-dioxadecalin skeleton (Scheme 11).
al.[45] for the reduction of highly functionalized cyclohexa- Scheme 11. Stereochemical outcome of the reduction of 25 and 29
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A. M. Gomez, E. Moreno, S. Valverde, J. C. Lopez
FULL PAPER
We supposed that deoxygenation at C-4, previous to ke-
tone reduction, could result in a reversal of the observed
stereochemical preference since it would eliminate the sub-
stituent at O-4. Accordingly, chemoselective deprotection of
the primary isopropylidene acetal in 24 afforded diol 38
(Scheme 12). Regioselective silylation at 6-OH in the latter
yielded compound 39, in which the 4-OH was free. Deoxy-
genation at 4-OH via the corresponding xanthate resulted
in the formation of the methylenecyclohexane 40. Ozonoly-
sis of the latter furnished a ketone, which, without further
purification, was submitted to reductive conditions
(NaBH4, CeCl3) to yield the desired 5a-OH isomer 41
(60%) as the major isomer of the reaction mixture (2.5:1
ratio), together with its 5a-OH epimer (24%); these were
separable by chromatography. Conventional deprotection
steps on 41, followed by acetylation, finally led to 5a-carba-
α--glucopyranose pentaacetate (42).[46]
Scheme 13. 6-exo-Digonal ring closure of cyclic radicals onto
alkynes to afford tricyclic systems
Our rationale for this opposite behavior lies in the work
of RajanBabu,[49] who has shown for cyclohexyl radicals
that transition states having an equatorial and an axial but-
enyl side chain may compete. Axial orientation of the chain
in the transition state of the radical cyclization of 2-pent-4-
ynyl radicals (Scheme 14), because of geometrical restric-
tions, would lead to cis-decalin-type systems (6,6-cis ring
fusion). On the other hand, an equatorial disposition of the
side chain could give rise to either cis- or trans-dioxadecal-
ins depending on the facial approach of the side chain to
the radical (see Scheme 14). We believe that in our case,
although tricyclic structures rather than bicyclic ones are
originated, the radical cyclization of the unsubstituted al-
Scheme 12. Synthesis of 5a-carba-α--glucopyranose pentaacetate
(42)
Stereochemical Outcome of the 6-exo-dig Radical
Cyclization
Radical ring closure of cyclic radicals onto alkenes and
alkynes, to afford fused systems, is known to follow a very
general guideline: the ring fusion obtained is predominantly
or exclusively cis (1,2 cis, radical numbering) for ‘‘small
rings’’ (see Scheme 5).[32,47] The stereochemical outcome of
the radical cyclization described in this work takes place,
then, according to literature precedents[32Ϫ34] [Scheme 13,
(a) ]. This result, however, is noticeably different from the
stereochemical result of the radical cyclization of closely re-
lated dioxa-decalin systems recently reported by us,[22,48] in
which the only difference is the substitution (H or Ph) of
the alkyne [Scheme 13, compare (a), (b), and (c) ].
Scheme 14. Possible dispositions of the side chain in the radical
cyclization of 2-pent-4-ynylcyclohexyl radicals
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A Stereodivergent Approach to D-Mannoses
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HSnBu3 (1.6 equiv.) and AIBN (0.1 equiv.) in toluene (5 mL/mmol)
was then added and the reaction mixture was kept at that tempera-
ture for 30 min. After cooling, the organic solvent was evaporated
and the residue purified by flash chromatography.
kyne takes place via an axial disposition of the side chain
(RЈ ϭ H, Scheme 14), whereas the phenyl-substituted al-
kyne (RЈ ϭ Ph, Scheme 14) might cyclize through an axial
or an equatorial orientation of the side chain.
General Method for Sequential Isopropylidene Group Hydrolysis-
Peracetylation: The compound containing the isopropylidene
group was dissolved in a previously prepared mixture of AcOH/
THF/H2O (4:2:1, 10 mL/mmol). The resulting solution was
warmed to 85 °C, and stirred at that temperature until consump-
tion of the starting material was observed (TLC, usually between
40 and 60 min). The solvent was then evaporated from the reaction
mixture. The crude polyols were subjected to standard acetylation
conditions by treatment with pyridine and an excess of acetic anhy-
dride. After stirring overnight, the mixture was concentrated to
yield a crude material, which was purified by flash chromatography.
Conclusion
We have reported a stereodivergent strategy for the prep-
aration of carbasugars from monosaccharides. The strategy
features
a
6-exo-dig radical cyclization and
a
BartonϪMcCombie radical deoxygenation as the key steps.
The approach is based on the preparation and synthetic
manipulation of polyhydroxycyclohexanones readily access-
ible by ozonolysis of methylenecyclohexane derivatives aris-
ing from -mannose. We have illustrated how a single cyclo-
hexanone derivative can give rise to three different carbasu-
gar derivatives by stereoselective reduction of the carbonyl
group at C-5a followed by a site-selective deoxygenation
either at C-4 or at C-5a (parent carbohydrate numbering).
During the course of this work, we have applied this strat-
egy to the preparation of pentaacetylated carbasugars 28,
35 and 42. The scope of this methodology is yet to be ex-
tended either by stereoselective transformations (alkyne ad-
dition to the reducing monosaccharide, radical cyclization,
and ketone reduction) leading to different polyoxygenated
cyclohexanones, or by the use of different monosaccharide
starting materials.
Diols 11؊12: BuLi (86.4 mmol, 54 mL solution 1.6  in n-hexane)
was added to a solution of trimethylsilylacetylene (16.4 mL,
115.3 mmol) in dry THF (100 mL) under argon at Ϫ78 °C. A solu-
tion of 6[30] (7.5 g, 28.8 mmol) in dry THF (80 mL) was added
dropwise and the reaction mixture was allowed to reach room tem-
perature, after which time stirring was continued for 10 h. The reac-
tion mixture was then diluted with Et2O (250 mL) and washed with
water. The organic layer was dried and concentrated and the resi-
due was purified by flash chromatography (hexane/EtOAc, 8:2) to
give the diols 11 and 12 as a 2:1 inseparable mixture of dia-
stereomers (5.6 g, 68%). 1H NMR (300 MHz, CDCl3): δ ϭ 4.67
(m, 2 H), 4.60 (dd, J ϭ 1.5, 6.7 Hz, 1 H), 4.54 (d, J ϭ 6.8 Hz, 1
H), 4.33 (m, 2 H), 4.22 (dd, J ϭ 1.4, 9.1 Hz, 1 H), 4.11 (dd, J ϭ
8.3 Hz, 1 H), 4.02Ϫ4.11 (m, 4 H), 3.69 (m, 2 H), 2.54 (d, J ϭ
2.2 Hz, 1 H), 2.49 (d, J ϭ 2.3 Hz, 1 H,), 1.57 (s, 3 H), 1.54 (s, 6
H), 1.51(s, 3 H), 1.45 (s, 3 H), 1.41 (s, 3 H), 1.39 (s, 3 H), 1.38 (s,
3 H) ppm. 13C NMR (50 MHz, CDCl3): δ ϭ 109.7, 108.9, 99.1,
98.6, 82.5, 80.9, 80.0, 78.3 (ϫ 2), 77.2, 74.3, 74.1, 73.8, 72.0, 71.5,
64.4, 64.3, 62.3, 62.2, 61.0, 28.1, 26.1 (ϫ 2), 25.7, 24.4 (ϫ 2), 18.5
(ϫ 2) ppm.
Experimental Section
General Remarks: All reactions were performed in dry flasks fitted
with a glass stopper or rubber septum under a positive pressure of
argon, unless otherwise noted. Air- and moisture-sensitive liquids
and solutions were transferred by syringe or stainless-steel cannula.
Flash column chromatography was performed with 230Ϫ400 mesh
silica gel. Thin-layer chromatography was conducted with Kieselgel
60 F254 (Merck). Detection was first by UV (254 nm) then charring
with a solution of 20% aqueous sulfuric acid (200 mL) in acetic
acid (800 mL). Anhydrous MgSO4 or NaSO4 was used to dry the
organic solutions during work-up, and the removal of the solvents
was done under vacuum with a rotary evaporator. Solvents were
dried and purified using standard methods.1H and 13C NMR spec-
tra were recorded in CDCl3 at 300, 400 or 500 and 75 or 50 MHz
respectively. Chemical shifts are expressed in parts per million (δ
scale) downfield from tetramethylsilane and are referenced to the
residual protonated NMR solvent (CHCl3: δ ϭ 7.25 ppm).
Carbonates 15: Pyridine (3 mL, 37 mmol) and ethyl chloroformate
(3.5 mL, 37 mmol) were added to a solution of the diol 11 (5.3 g,
18.5 mmol) in dry CH2Cl2 (110 mL) under argon at 0 °C. The solu-
tion was stirred for 2 h. The mixture was then diluted with CH2Cl2
and successively washed with 10% HCl, aqueous sodium hydrogen-
carbonate, water and brine. The organic layer was dried (Na2SO4)
and concentrated, giving a residue that was purified by flash chro-
matography (hexane/EtOAc, 8:2) to give the monocarbonates 15
(3.77 g, 57%) and 16 (1.1 g, 16%) and the dicarbonate 17 (1.9 g,
24%). 15: (Two diastereomers at C-1). MS: m/z ϭ 343.1 [Mϩ Ϫ15].
1H NMR (300 MHz, CDCl3): δ ϭ 5.67 (dd, J ϭ 2.2, 7.1 Hz, 1 H),
5.50 (dd, J ϭ 2.2, 9.3 Hz, 1 H), 4.56Ϫ4.31 (m, 2 H), 4.43 (dd, J ϭ
6.6, 9.3 Hz, 1 H), 4.29Ϫ4.20 (m, 4 H), 4.01Ϫ3.87 (m, 5 H),
3.74Ϫ3.61 (m, 4 H), 2.62 (d, J ϭ 2.2 Hz, 1 H), 2.59 (d, J ϭ 2.2 Hz,
1 H), 1.56 (s, 3 H), 1.55 (s, 3 H), 1.52 (s, 3 H), 1.43 (s, 3 H), 1.42
(s, 6 H), 1.40 (s, 3 H), 1.38 (s, 3 H), 1.34 (t, J ϭ 7.1 Hz, 3 H), 1.26
(t, J ϭ 7.1 Hz, 3 H) ppm. 13C NMR (50 MHz, CDCl3): δ ϭ 153.6,
153.1, 110.1, 109.3, 98.3, 98.2, 78.9, 76.8, 76.7, 76.1, 75.9, 74.9,
73.8, 73.7, 72.1, 71.7, 65.9, 65.7, 64.3, 64.2 (ϫ 2), 64.1, 61.9, 61.7,
28.1, 27.9, 26.1, 25.9, 25.5, 25.3, 18.6, 18.2, 13.7 (ϫ 2) ppm. 16:
(Only one diastereomer was observed). [α]2D1 ϭ Ϫ57.0 (c ϭ 1.1,
CHCl3). 1H NMR (200 MHz, CDCl3): δ ϭ 4.84 (dt, J ϭ 5.5,
13.2 Hz, 1 H), 4.59 (m, 1 H), 4.23Ϫ3.99 (m, 6 H), 3.70Ϫ3.62 (m,
2 H), 2.47 (d, J ϭ 2.2 Hz, 1 H), 1.48 (s, 3 H), 1.46 (s, 3 H), 1.36
(s, 3 H), 1.30 (s, 3 H), 1.25 (t, J ϭ 7.1 Hz, 3 H) ppm. 13C NMR
(50 MHz, CDCl3): δ ϭ 153.8, 109.1, 99.6, 82.7, 78.3, 74.5, 73.9,
General Procedure for Xanthate Formation: A solution of the al-
cohol in dry THF (5 mL/mmol) was treated with NaH (2 equiv.)
at 0 °C for 30 min. Then, the mixture was treated with CS2 (2
equiv.) at room temperature for 60 min after which MeI was added
(6 equiv.). Stirring was maintained for an additional 30 min and
then the reaction was diluted with CH2Cl2, washed with water,
dried and concentrated to give a residue which was purified by
flash chromatography.
General Procedure for Radical Deoxygenation of Thionocarbonates
or Xanthates: A thoroughly degassed (argon) solution of the sub-
strate in toluene (0.02 ) was heated to 85 °C. A solution of 69.0, 68.5, 64.2, 61.3, 60.9, 27.1, 26.1, 25.3, 19.9, 13.9 ppm. 17:
Eur. J. Org. Chem. 2004, 1830Ϫ1840
www.eurjoc.org  2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 1835

´
´
A. M. Gomez, E. Moreno, S. Valverde, J. C. Lopez
FULL PAPER
(Two diastereomers at C-1). 1H NMR (300 MHz, CDCl3): δ ϭ 5.65 Alcohol 22: A solution of the carbonate 21 (490 mg, 1.43 mmol) in
(dd, J ϭ 2.0, 9.4 Hz, 1 H), 5.44 (dd, J ϭ 1.9, 9.3 Hz, 1 H), methanol (50 mL) was treated with K2CO3 (395 mg, 2.86 mmol).
4.94Ϫ4.89 (m, 2 H), 4.52 (dd, J ϭ 6.8, 9.4 Hz, 1 H), 4.44Ϫ4.17 (m, The reaction mixture was stirred overnight and then the solution
12 H), 4.12 (dd, J ϭ 3.3, 4.9 Hz, 1 H), 4.08 (dd, J ϭ 2.9, 4.9 Hz,
was diluted with CH2Cl2 and washed successively with water and
1 H), 3.89 (d, J ϭ 9.0 Hz, 1 H), 3.77Ϫ3.68 (m, 2 H), 2.63 (d, J ϭ brine. The organic phase was dried, filtered and concentrated under
2.0 Hz, 1 H,), 2.59 (d, J ϭ 1.9 Hz, 1 H), 1.57 (s, 3 H), 1.56 (s, 3
vacuum giving a residue which was purified by flash chromatogra-
H), 1.54 (s, 3 H), 1.50 (s, 3 H), 1.42 (s, 3 H), 1.41(s, 3 H), 1.40 (s,
phy (hexane/EtOAc, 8:2) to give the alcohol 22 (271 mg, 70%). M.p.
1
6 H), 1.34 (t, J ϭ 7.1 Hz, 3 H), 1.22 (t, J ϭ 7.1 Hz, 3 H) ppm. 13C 97Ϫ99 °C. [α]2D1 ϭ ϩ94.4 (c ϭ 1.3, CHCl3). H NMR (400 MHz,
NMR (50 MHz, CDCl3): δ ϭ 154.1, 153.9 (ϫ 2), 153.4, 110.6, CDCl3): δ ϭ 5.41 (s, 1 H), 5.26 (d, J ϭ 2.0 Hz, 1 H), 4.33 (dd, J ϭ
109.9, 99.6, 99.2, 79.3, 77.9, 77.5, 77.3, 76.9, 76.2, 75.3, 74.4, 69.6,
69.2, 69.1, 68.7, 66.1, 66.0, 64.6, 64.4, 64.3, 64.2, 61.8, 61.3, 27.4,
26.6, 26.4, 26.3, 25.9, 25.6, 20.5, 19.6, 14.1 (ϫ 4) ppm.
4.2, 6.6 Hz, 1 H), 4.29 (t, J ϭ 2.3 Hz, 1 H), 4.25 (dd, J ϭ 2.3,
6.6 Hz, 1 H), 4.15 (dd, J ϭ 3.6, 12.0 Hz, 1 H), 4.12 (dd, J ϭ 4.2,
9.6 Hz, 1 H), 4.02 (dd, J ϭ 2.0, 12.0 Hz, 1 H), 3.78 (d, J ϭ 9.6 Hz,
1 H), 2.40 (m, 1 H, H-5), 1.45 (s, 3 H), 1.38 (s, 3 H), 1.35 (s, 3 H),
1.31 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 143.3, 116.2,
108.5, 99.6, 78.1, 75.1, 73.2, 68.7, 63.7, 34.1, 29.0, 26.8, 24.5,
18.9 ppm. C14H22O5 (270.3): calcd. C 62.20, H 8.20; found C 62.24,
H 7.98.
Thionocarbonate 18:
A solution of the alcohols 15 (3.0 g,
8.37 mmol) in acetonitrile (160 mL) was treated with pyridine
(2 mL, 25.1 mmol) and phenyl chlorothionoformate (3.5 mL,
25.1 mmol). The reaction mixture was heated at 85 °C for 1 h after
which time it was cooled to room temperature and then quenched
with water. The solution was diluted with CH2Cl2 and washed suc-
cessively with HCl (10%), saturated NaHCO3, and brine. The or-
ganic phase was dried, filtered and concentrated under vacuum giv-
ing a residue which was purified by flash chromatography (hexane/
EtOAc, 95:5) to give thionocarbonate 18 (3.18 g, 76%) (two dia-
stereomers at C-1). 1H NMR (200 MHz, CDCl3): δ ϭ 7.49Ϫ7.37
(m, 3 H), 7.34Ϫ7.19 (m, 2 H), 7.12Ϫ7.07 (m, 3 H), 6.97Ϫ6.79 (m,
2 H), 5.67 (dd, J ϭ 2.2, 9.3 Hz, 1 H), 5.53 (m, 2 H), 5.47 (dd, J ϭ
2.1, 8.7 Hz, 1 H), 4.57 (dd, J ϭ 6.6, 9.3 Hz, 1 H), 4.46Ϫ4.34 (m, 4
H), 4.32Ϫ4.19 (m, 6 H), 4.07 (dd, J ϭ 1.3, 8.4 Hz, 1 H), 3.95 (dd,
J ϭ 4.9, 12.6 Hz, 1 H), 3.89 (dd, J ϭ 6.2, 12.3 Hz, 1 H), 2.64 (d,
J ϭ 2.2 Hz, 1 H,), 2.60 (d, J ϭ 2.1 Hz, 1 H), 1.60 (s, 3 H), 1.55 (s,
3 H), 1.52 (s, 3 H), 1.46 (s, 3 H), 1.42 (s, 9 H), 1.38 (s, 3 H), 1.36
(t, J ϭ 7.1 Hz, 3 H), 1.35 (t, J ϭ 7.1 Hz, 3 H) ppm. 13C NMR
(50 MHz, CDCl3): δ ϭ 193.5 (ϫ 2), 153.5, 153.3, 128.4 (ϫ 3), 125.7
(ϫ 2), 121.7 (ϫ 3), 120.6, 115.3, 110.8, 109.0, 100.3, 99.9, 78.9,
77.6, 76.7, 76.2, 76.1, 75.9, 75.3, 75.1, 74.5, 74.4, 68.3 (ϫ 2), 65.9,
65.7, 64.4, 64.2, 61.0, 60.4, 26.4, 26.1, 26.0, 25.6, 25.4, 25.3, 21.2,
20.2, 13.8 (ϫ 2) ppm.
Benzyl Ether 24: The alcohol 22 (270 mg, 1.0 mmol) was dissolved
in dry THF (45 mL) and treated with NaH (79 mg 60%,
1.97 mmol) at 0 °C under argon for 30 min. Then, benzyl bromide
(170 µL, 1.43 mmol) and Bu4NI (405 mg, 1.1 mmol) were added.
After 3 h the reaction was diluted with Et2O and washed with
water. The organic phase was dried, concentrated and the residue
purified by flash chromatography (hexane/EtOAc, 95:5) to yield 24
(288 mg, 80%) as an colourless oil. [α]2D1 ϭ ϩ115.3 (c ϭ 0.9,
CHCl3). 1H NMR (300 MHz, CDCl3): δ ϭ 7.42Ϫ7.29 (m, 5 H),
5.49 (s, 1 H), 5.41 (s, 1 H), 4.78 (d, J ϭ 12.3 Hz, 1 H), 4.62 (d, J ϭ
12.3 Hz, 1 H), 4.48 (d, J ϭ 2.3 Hz, 1 H), 4.13Ϫ4.06 (m, 4 H), 3.82
(d, J ϭ 7.1 Hz, 1 H), 2.19 (m, 1 H), 1.46 (s, 3 H), 1.36 (s, 3 H),
1.33 (s, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 140.5, 138.7,
128.5 (ϫ 2), 128.0 (ϫ 2), 127.7, 111.6, 108.4, 99.3, 81.1, 80.6, 77.5,
71.8, 69.3, 61.0, 36.8, 29.5, 28.2, 26.3, 19.1 ppm. C21H28O5 (360.4):
calcd. C 69.98, H 7.83; found C 69.74, H 7.93.
Alcohol 26: Ozone was bubbled through a solution of the methyl-
enecyclohexane 24 (280 mg, 0.78 mmol) in MeOH/CH2Cl2 (1:1
mixture, 6 mL) at Ϫ78 °C until TLC showed complete consump-
tion of the starting compound. Oxygen was then bubbled through
the solution for 5 min. Next, the mixture was treated with dimethyl
sulfide (1 mL) and the solution was warmed to room temperature
over 2 h. After stirring for an additional hour, the solvent was re-
moved to yield the ketone 25. 25: 1H NMR (200 MHz, CDCl3):
δ ϭ 7.40Ϫ7.20 (m, 5 H), 4.89 (d, J ϭ 12.2 Hz, 1 H, benzyl-H), 4.72
(dd, J4,5 ϭ 3.7, J3,4 ϭ 2.2 Hz, 1 H, H-4), 4.60 (d, J ϭ 12.3 Hz, 1
H, benzyl-H), 4.45 (dd, J1,2 ϭ 6.2, J2,3 ϭ 5.4 Hz, 1 H, H-2), 4.43
(dd, J6,6Ј ϭ 11.5, J5,6 ϭ 1.5 Hz, 1 H, H-6), 4.23 (dd, J3,4 ϭ 2.2,
J2,3 ϭ 5.4 Hz, 1 H, H-3), 3.95 (d, J1,2 ϭ 6.2 Hz, 1 H, H-1), 3.90
(dd, J6,6Ј ϭ 11.9, J6Ј,5 ϭ 3.5 Hz, 1 H, H-6Ј), 2.48 (m, 1 H, H-5),
1.46 (s, 3 H), 1.38 (s, 3 H), 1.32 (s, 3 H), 1.28 (s, 3 H) ppm.
Radical Cyclization of Thionocarbonates 18: A thoroughly degassed
(argon) solution of the thionocarbonate 18 (3.18 g, 6.27 mmol) in
toluene (0.02 ) was heated to 85 °C under argon. A solution of
HBu3Sn (2.8 mL, 10.3 mmol) and AIBN (130 mg, 0.6 mmol) in
toluene (3 mL) was then added and the reaction mixture was kept
at that temperature for 12 h. After cooling, the organic solvent was
evaporated and the residue purified by flash chromatography (hex-
ane/EtOAc, 95:5) to give the methylenecyclohexanes 19 (107 mg,
5%), 20 (1.09 g, 51%) and 21 (494 mg, 23%). 20: M.p. 68Ϫ70 °C.
[α]2D1 ϭ ϩ153.7 (c ϭ 0.7, CHCl3). 1H NMR (300 MHz, CDCl3):
δ ϭ 5.96 (s, 1 H), 5.35 (s, 1 H), 5.14 (s, 1 H), 4.62 (dd, J ϭ 3.3,
7.4 Hz, 1 H), 4.37 (dd, J ϭ 2.7, 7.4 Hz, 1 H), 4.27Ϫ4.19 (m, 3 H),
4.15 (dd, J ϭ 3.8, 11.7 Hz, 1 H), 3.91 (dd, J ϭ 2.8, 11.7 Hz, 1 H),
The residue, containing ketone 25, was then dissolved in MeOH
2.60 (m, 1 H), 1.45 (s, 3 H), 1.41 (s, 3 H), 1.40 (s, 3 H), 1.33 (s, 3 (15 mL) and treated with CeCl3·H2O (581 mg, 1.56 mmol). The
H), 1.32 (t, J ϭ 7.1 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): mixture was cooled to 0 °C, treated with NaBH4 (118 mg,
δ ϭ 154.6, 140.2, 111.2, 109.6, 99.0, 75.5, 74.6, 73.9, 66.9, 65.3, 3.12 mmol) and then warmed to room temperature and stirred
64.1, 35.4, 28.8, 25.9, 24.0, 19.1, 14.1 ppm. C17H26O7 (342.4): calcd.
C 59.64, H 7.65; found C 59.88, H 7.41. 21: [α]2D1 ϭ ϩ75.85 (c ϭ washed with water and brine. The organic layer was dried and con-
1.0, CHCl3). 1H NMR (200 MHz, CDCl3): δ ϭ 5.34 (t, J ϭ 1.5 Hz,
centrated to give a residue, which was purified by flash chromatog-
overnight. The reaction mixture was then diluted with EtOAc and
1 H), 5.27 (s, 1 H), 5.11 (d, J ϭ 6.6 Hz, 1 H), 4.53 (d, J ϭ 3.1 Hz, raphy (hexane/EtOAc, 8:2) to give the alcohol 26 (255 mg, 90%).
1
1 H), 4.22 (q, J ϭ 7.1 Hz, 2 H), 4.18Ϫ4.12 (m, 4 H), 2.33 (m, 1 26: [α]2D1 ϭ ϩ72.9 (c ϭ 0.5, CHCl3). H NMR (400 MHz, CDCl3):
H), 1.58 (s, 3 H), 1.54 (s, 3 H), 1.46 (s, 3 H), 1.33 (s, 3 H), 1.32 (t,
δ ϭ 7.44Ϫ7.26 (m, 5 H), 4.80 (s, 2 H), 4.55 (dd, J ϭ 5.5, 8.0 Hz, 1
J ϭ 7.1 Hz, 3 H) ppm. 13C NMR (50 MHz, CDCl3): δ ϭ 154.7, H, H-2), 4.48 (d, J ϭ 3.2 Hz, 1 H, H-4), 4.31Ϫ4.24 (m, 3 H), 4.06
138.8, 111.0, 108.9, 99.2, 79.2, 78.2, 77.6, 68.7, 64.1, 60.5, 36.4,
29.2, 27.9, 26.1, 18.7, 14.2 ppm. C17H26O7 (342.4): calcd. C 59.64,
H 7.65; found C 59.79, H 7.38.
(d, J ϭ 12.2 Hz, 1 H, H-6), 3.28 (dd, J ϭ 2.2, 8.0 Hz, 1 H, H-1),
3.21 (d, J ϭ 2.4 Hz, 1 H, OH), 1.58 (m, 1 H, H-5), 1.52 (s, 3 H),
1.39 (s, 3 H), 1.38 (s, 3 H), 1.33 (s, 3 H) ppm. 13C NMR (50 MHz,
1836
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 1830Ϫ1840

A Stereodivergent Approach to D-Mannoses
FULL PAPER
CDCl3): δ ϭ 138.4, 128.3 (ϫ 2), 127.9 (ϫ 2), 127.5, 108.1, 99.5, After 3 h the reaction was diluted with Et2O and washed with
79.4, 77.8, 72.4, 71.0, 67.6 (ϫ 2), 63.4, 33.4, 29.3, 28.0, 26.2, water. The organic phase was dried, concentrated and the residue
18.4 ppm. C20H28O6 (364.2): calcd. C 65.91, H 7.74; found C 66.10, purified by flash chromatography (hexane/EtOAc, 9:1) to yield 31
H 7.88.
(245 mg, 72%) as a colourless oil. [α]2D1 ϭ Ϫ2.0 (c ϭ 0.3, CHCl3).
1H NMR (300 MHz, CDCl3): δ ϭ 7.41Ϫ7.27 (m, 10 H), 4.85 (d,
J ϭ 11.9 Hz, 1 H), 4.77 (d, J ϭ 11.9 Hz, 1 H), 4.65 (d, J ϭ 11.9 Hz,
2 H), 4.57 (t, J ϭ 6.6 Hz, 1 H), 4.46 (dd, J ϭ 4.5, 6.6 Hz, 1 H),
4.14 (dd, J ϭ 4.5, 7.6 Hz, 1 H), 3.98 (t, J ϭ 9.8 Hz, 1 H), 3.83 (m,
1 H, H-4), 3.71 (dd, J ϭ 6.0, 9.8 Hz, 1 H), 3.49 (d, J ϭ 6.6 Hz, 1
H), 2.11 (m, 1 H), 1.42 (s, 3 H), 1.40 (s, 3 H), 1.36 (s, 3 H), 1.34
(s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 140.5, 138.7, 128.5
(ϫ 2), 128.0 (ϫ 2), 127.7, 111.6, 108.4, 99.3, 81.1, 80.6, 77.5, 71.8,
69.3, 61.0, 36.8, 29.5, 28.2, 26.3, 19.1 ppm. C27H34O6 (454.5): calcd.
C 71.34, H 7.54; found C 71.09, H 7.63.
Benzyl Carbagulopyranose 27: Alcohol 26 (130 mg, 0.36 mmol) was
converted into the corresponding xanthate and this material deoxy-
genated according to the general procedure. The residue was puri-
fied by flash chromatography (hexane/EtOAc, 95:5) to yield the
carbagulose derivative 27 (70 mg, 70%). [α]2D1 ϭ ϩ53.3 (c ϭ 0.2,
CHCl3). 1H NMR (300 MHz, CDCl3): δ ϭ 7.40Ϫ7.29 (m, 5 H),
4.76 (d, J ϭ 12.2 Hz, 1 H), 4.69 (d, J ϭ 12.2 Hz, 1 H), 4.35 (s, 1
H), 4.16 (dd, J ϭ 5.5, 7.7 Hz, 1 H), 4.10Ϫ4.07 (m, 2 H), 3.63 (d,
J ϭ 11.8 Hz, 1 H), 3.49 (ddd, J ϭ 4.5, 7.7, 12.3 Hz, 1 H), 2.14 (q,
J ϭ 12.3 Hz, 1 H), 1.65 (m, 2 H), 1.46 (s, 3 H), 1.39 (s, 3 H), 1.38
(s, 3 H), 1.36 (s, 3 H) ppm. 13C NMR (50 MHz, CDCl3): δ ϭ 139.4,
128.3 (ϫ 2), 127.7 (ϫ 2), 127.4, 108.3, 99.0, 79.2, 78.8, 78.0, 71.2,
67.6, 63.8, 31.4, 29.6, 28.1, 27.1, 26.3, 18.5 ppm. C20H28O5 (348.4):
calcd. C 68.94, H 8.10; found C 69.10, H 8.08.
Diol 32: A solution of 31 (245 mg, 0.54 mmol) in MeOH (12 mL)
was treated with PPTS (23 mg, 0.05 mmol) and the solution was
stirred for 24 h. The mixture was concentrated and the residue puri-
fied by flash chromatography (hexane/EtOAc, 6:4) to yield 32
(190 mg, 85%) as white crystals. m.p. 87Ϫ88 °C. [α]2D1 ϭ ϩ42.8 (c ϭ
5a-Carba-β-L-gulopyranose Pentaacetate (28): A solution of the
1
0.3, CHCl3). H NMR (300 MHz, CDCl3): δ ϭ 7.44Ϫ7.29 (m, 10
benzyl ether 27 (70 mg, 0.20 mmol) in MeOH (25 mL) was hydro-
genolyzed in the presence of 10% Pd/C (10 mg) at 35 psi at room
temperature for 60 min. The reaction mixture was filtered through
a short pad of Celite and concentrated to give a residue which was
subjected to the general procedure for the cleavage of the isopro-
pylidene moiety and acetylation. Purification of the residue was
carried out by flash chromatography (hexane/EtOAc, 7:3) to yield
carba-β--gulopyranose pentaacetate (28, 54 mg, 70% overall).
[α]2D1 ϭ Ϫ18.7 (c ϭ 0.4, CHCl3), 1H NMR (400 MHz, CDCl3): δ ϭ
5.38 (m, 1 H), 5.16 (m, 2 H), 5.10 (m, 1 H), 4.01 (dd, J ϭ 8.2,
11.2 Hz, 1 H), 3.84 (dd, J ϭ 6.4, 11.2 Hz, 1 H), 2.43 (m, 1 H, H-
5), 2.13 (s, 6 H), 2.05 (m, 1 H, H-5a), 2.04 (s, 6 H), 1.99 (s, 3 H),
1.58 (m, 1 H) ppm. C17H24O10 (414.5): calcd. C 52.57, H 6.23;
found C 52.28, H 6.45.
H), 4.98 (d, J ϭ 11.3 Hz, 1 H), 4.86 (d, J ϭ 12.3 Hz, 1 H), 4.75 (d,
J ϭ 12.3 Hz, 1 H), 4.61 (d, J ϭ 11.3 Hz, 1 H), 4.54 (dd, J ϭ 5.4,
7.7 Hz, 1 H), 4.39 (dd, J ϭ 2.2, 5.4 Hz, 1 H), 4.18 (s, 1 H), 4.09
(m, 1 H), 3.87Ϫ3.81 (m, 3 H), 3.49 (dd, J ϭ 2.3, 7.7 Hz, 1 H), 1.95
(ddt, J ϭ 1.5, 3.5, 8.0 Hz, 1 H), 1.59 (s, 1 H), 1.38 (s, 3 H),1.36 (s,
3 H) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 138.2, 137.6, 128.4
(ϫ 2), 128.2 (ϫ 2), 128.1 (ϫ 2), 128.0, 127.5 (ϫ 3), 108.6, 81.6,
79.2, 77.3, 76.8, 74.9, 71.9, 68.8, 60.3, 41.4, 28.1, 26.2 ppm.
C24H3oO6 (414.5): calcd. C 69.54, H 7.30; found C 69.83, H 7.58.
Silyl Ether 33: Imidazole (56 mg, 0.83 mmol) and tert-butylchloro-
diphenylsilane (TPSCl) (194 mg, 0.70 mmol) was added to a solu-
tion of diol 32 (190 mg, 0.46 mmol) in DMF (5 mL) and the reac-
tion mixture was stirred at room temperature for 12 h. It was then
diluted with Et2O and washed with water. The organic layer was
dried and concentrated, giving a residue which was purified by
flash chromatography (hexane/EtOAc, 9:1) to yield the silyl ether
33 (269 mg, 90%). [α]2D1 ϭ ϩ55.1 (c ϭ 0.8, CHCl3). 1H NMR
(200 MHz, CDCl3): δ ϭ 7.68Ϫ7.61 (m, 4 H), 7.43Ϫ7.17 (m, 16 H),
4.97 (d, J ϭ 11.0 Hz, 1 H), 4.85 (d, J ϭ 12.5 Hz, 1 H), 4.74 (d, J ϭ
12.5 Hz, 1 H), 4.50 (dd, J ϭ 5.3, 8.0 Hz, 1 H), 4.43 (d, J ϭ 11.0 Hz,
1 H), 4.34Ϫ4.30 (m, 2 H), 4.00 (d, J ϭ 10.2 Hz, 1 H), 3.99 (m, 1
H), 3.79 (dd, J ϭ 6.6, J ϭ 10.2 Hz, 1 H, H-6), 3.41 (dd, J ϭ 2.2,
J ϭ 8 Hz, 1 H, H-1), 1.90 (m, 1 H, H-5), 1.57 (s, 1 H, OH de C-
4), 1.36 (s, 6 H), 1.07 (s, 9 H) ppm. 13C NMR(50 MHz, CDCl3):
δ ϭ 138.3, 137.8, 135.4 (ϫ 4), 133.3, 133.2, 129.6 (ϫ 2), 128.4 (ϫ
2), 128.3 (ϫ 2), 127.8 (ϫ 3), 127.7 (ϫ 2), 127.6 (ϫ 2), 127.5 (ϫ 3),
108.6, 81.5, 79.5, 77.4, 77.3, 75.2, 71.7, 68.7, 61.5, 41.7, 28.2, 26.9
(ϫ 3), 26.3, 19.1 ppm.
Diol 30: Ozone was bubbled through a solution of the methylene-
cyclohexane 22 (270 mg, 1.0 mmol) in MeOH/CH2Cl2 (1:1 mixture,
8 mL) at Ϫ78 °C until TLC showed complete consumption of the
starting compound. Oxygen was then bubbled through the solution
for 5 min. Next, the mixture was treated with dimethyl sulfide
(1 mL) and the solution was warmed to room temperature over 2 h.
After stirring for an additional hour, the solvent was removed. The
residue containing ketone 29 was not purified but was then dis-
solved in MeOH (15 mL) and treated with CeCl3·H2O (581 mg,
1.56 mmol). The mixture was cooled to 0 °C, treated with NaBH4
(118 mg, 3.12 mmol) and then warmed to room temperature and
stirred overnight. The reaction mixture was then diluted with
EtOAc and washed with water and brine. The organic layer was
dried and concentrated to give a residue, which was purified by
flash chromatography (hexane/EtOAc, 6:4) to give the diol 30
(205 mg (75%). [α]2D1 ϭ ϩ56.9 (c ϭ 1.4, CHCl3). 1H NMR
(300 MHz, CDCl3): δ ϭ 4.49 (m, 1 H), 4.34 (dd, J ϭ 5.8, J ϭ
7.0 Hz, 1 H), 4.29Ϫ4.21 (m, 2 H), 4.18Ϫ4.12 (m, 2 H), 3.58 (ddd,
J ϭ 3.3, 7.0, 9.7 Hz, 1 H), 3.18 (d, J ϭ 5.2 Hz, 1 H), 2.84 (d, J ϭ
9.7 Hz, 1 H), 1.77 (m, 1 H, H-5), 1.52 (s, 3 H), 1.48 (s, 3 H), 1.39
(s, 3 H), 1.37(s, 3 H) ppm. 13C NMR (50 MHz, CDCl3): δ ϭ 138.4,
128.3 (ϫ 2), 127.9 (ϫ 2), 127.5, 108.1, 99.5, 79.4, 77.8, 72.4, 71.0,
67.6 (ϫ 2), 63.4, 33.4, 29.3, 28.0, 26.2, 18.4 ppm. C13H22O6 (274.1):
calcd. C 56.92, H 8.08; found C 56.77, H 7.78.
Silyl Ether 34: Alcohol 33 (265 mg, 0.4 mmol) was converted into
the corresponding xanthate and this material deoxygenated accord-
ing to the general procedure. The residue was purified by flash
chromatography (hexane/EtOAc, 95:5) to yield the carbagalactose
derivative 34 (201 mg, 77%). 1H NMR (300 MHz, CDCl3): δ ϭ
7.65Ϫ7.61 (m, 4 H), 7.42Ϫ7.27 (m, 16 H), 5.01 (d, J ϭ 11.2 Hz, 1
H), 4.85 (d, J ϭ 12.5 Hz, 1 H), 4.76 (d, J ϭ 12.5 Hz, 1 H), 4.45 (d,
J ϭ 11.2 Hz, 1 H), 4.32 (m, 2 H), 4.21 (d, J ϭ 1.5 Hz, 1 H), 3.65
(t, J ϭ 9.5 Hz, 1 H), 3.52 (dd, J ϭ 5.6, 9.5 Hz, 1 H), 3.43 (d, J ϭ
7.7 Hz, 1 H), 2.15 (m, 1 H), 1.78Ϫ1.60 (m, 2 H), 1.40 (s, 3 H), 1.35
(s, 3 H), 1.06 (s, 9 H) ppm. 13C NMR (50 MHz, CDCl3): δ ϭ 139.4,
138.8, 135.5 (ϫ 3), 133.5, 129.6 (ϫ 2), 128.3 (ϫ 2), 128.1 (ϫ 2),
Dibenzyl Ether 31: The diol 30 (205 mg, 0.75 mmol) was dissolved
in dry THF (45 mL) and treated with NaH (120 mg 60%,
2.25 mmol) at 0 °C under argon for 30 min. Then, benzyl bromide
(260 µL, 2.25 mmol) and Bu4NI (810 mg, 2.2 mmol) were added. 127.7 (ϫ 3), 127.6 (ϫ 2), 127.5 (ϫ 2), 127.4 (ϫ 2), 127.3 (ϫ 2),
Eur. J. Org. Chem. 2004, 1830Ϫ1840
www.eurjoc.org  2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 1837

´
´
A. M. Gomez, E. Moreno, S. Valverde, J. C. Lopez
FULL PAPER
127.2, 108.0, 82.0, 79.0, 74.7, 74.2, 74.1, 71.5, 64.1, 38.3, 28.3, 26.9 16 H), 5.14 (s, 1 H, Hsp2), 5.13 (s, 1 H, Hsp2), 4.49 (d, J ϭ 12.1 Hz,
(ϫ 3), 26.8, 26.4, 19.2 ppm.
5a-Carba-α- -galactopyranose Pentaacetate (35): Bu4NF (1.4 g,
1 H), 4.48 (m, 1 H, H-1), 4.30 (d, J ϭ 12.1 Hz, 1 H), 4.21 (dd, J ϭ
3.5, 6.6 Hz, 1 H, H-2), 3.74Ϫ3.62 8m, 3 H, H-3, H-6, H-6Ј), 2.74
(m, 1 H, H-5), 2.25 (ddd, J ϭ 3.2, 5.9, 14.9 Hz, 1 H, H-5eq), 1.80
(ddd, J ϭ 2.8, 11.5, 14.9 Hz, 1 H, H-5ax), 1.37 (s, 3 H), 1.32 (s, 3
H), 1.05 (s, 9 H). 13C NMR (50 MHz, CDCl3): δ ϭ 142.1, 138.2,
134.8, 133.7, 129.6, 128.3, 127.6, 127.5, 115.8, 108.3, 81.4, 78.4,
72.8, 70.2, 68.0, 37.2, 27.7, 26.9 (ϫ 3), 24.9, 19.3 ppm.
D
3.1 mmol) was added to a solution of the silyl ether 34 (170 mg,
0.27 mmol) in THF (15 mL) and the reaction mixture was stirred
overnight. The reaction was then diluted with CH2Cl2 and washed
with water and brine. The organic layer was dried, filtered and
concentrated to give a residue which was purified by flash chroma-
tography (hexane/EtOAc, 7:3). The pure material was dissolved in
MeOH (25 mL) and hydrogenolyzed in the presence of 10% Pd/C
(10 mg) at 35 psi at room temperature for 60 min. The reaction
mixture was then filtered through a short pad of Celite and concen-
trated to give a residue which was subjected to the general pro-
cedure for the cleavage of the isopropylidene moiety and acety-
lation. The crude material was purified by flash chromatography
(hexane/EtOAc, 7:3) to yield carba-α--galactopyranose pentaacet-
ate (35, 78 mg, 70%). [α]2D1 ϭ ϩ35.8 (c ϭ 0.4, CHCl3). {Ref.[42a]
[α]2D0 ϭ ϩ35.16 (c ϭ 1.77, CHCl3), ref.[42b][42d] [α]2D0 ϭ ϩ43.2 (c ϭ
1.1, CHCl3), ref.[42c] [α]2D0 ϭ ϩ43.2 (c ϭ 1.06, CHCl3), ref.[42e]
[α]2D5 ϭ ϩ30.6 (c ϭ 1, CHCl3)}. 1H NMR (300 MHz, CDCl3): δ ϭ
5.57 (t, J ϭ 2.3 Hz, 1 H), 5.51 (m, 1 H), 5.23 (dd, J ϭ 2.3, 10.8 Hz,
1 H), 5.17 (dd, J ϭ 2.7, 10.8 Hz, 1 H), 3.96 (t, J ϭ 10.4 Hz, 1 H),
3.88 (dd, J ϭ 6.1, 10.4 Hz, 1 H), 2.47 (m, 1 H), 2.11 (s, 6 H), 2.04
(s, 3 H), 2.01 (s, 3 H), 1.99 (s, 3 H), 1.79Ϫ1.75 (m, 2 H) ppm.
C17H24O10 (414.5): calcd. C 52.57, H 6.23; found C 52.34, H 6.48.
Alcohols 41 and epi-5a-41: Ozone was bubbled through a solution
of the methylenecyclohexane 46 (115 mg, 0.21 mmol) in MeOH/
CH2Cl2 (1:1 mixture, 5 mL) at Ϫ78 °C until TLC showed complete
consumption of the starting compound. Oxygen was then bubbled
through the solution for 5 min. Next, the mixture was treated with
dimethyl sulfide (0.5 mL) and the solution was warmed to room
temperature over 2 h. After stirring for an additional hour, the sol-
vent was removed. The residue was then dissolved in MeOH
(10 mL) and treated with CeCl3·H2O (156 mg, 0.42 mmol). The
mixture was cooled to
0 °C, treated with NaBH4 (32 mg,
0.84 mmol) and then warmed to room temperature and stirred
overnight. The reaction mixture was then diluted with EtOAc and
washed with water and brine. The organic layer was dried and con-
centrated to give a residue, which was purified by flash chromatog-
raphy (hexane/EtOAc, 95:5) to give the alcohol 41 (70 mg, 60%)
along with its epimer epi-5a-41 (28 mg, 24%). epi-5a-41: [α]2D1
ϭ
ϩ34.4 (c ϭ 0.5, CHCl3). 1H NMR (300 MHz, C6D6): δ ϭ
7.69Ϫ7.63 (m, 5 H), 7.46Ϫ7.28 (m, 6 H), 4.81 (d, J ϭ 12.4 Hz, 1
H), 4.73 (d, J ϭ 12.4 Hz, 1 H), 4.35 (m, 1 H), 4.26 (m, 2 H), 3.71
(m, 2 H), 3.34 (dd, J ϭ 2.6, 7.5 Hz, 1 H), 2.00Ϫ1.78 (m, 3 H, H-5
and 2H-5a), 1.36 (s, 6 H), 1.06 (s, 9 H) ppm. 13C NMR (75 MHz,
C6D6): δ ϭ 138.4, 135.6 (ϫ 3), 135.5 (ϫ 3), 133.2, 129.2 (ϫ 2),
128.3 (ϫ 2), 127.9 (ϫ 2), 127.7 (ϫ 3), 127.6, 108.2, 80.7, 78.5, 74.1,
71.2, 68.4, 65.3, 36.7, 28.2, 26.8 (ϫ 3), 26.4, 23.3, 19.2 ppm. 41:
Diol 38: A solution of 24 (592 mg, 1.66 mmol) in MeOH (20 mL)
was treated with PPTS (73 mg, 0.16 mmol) and the solution was
stirred for 24 h. The mixture was concentrated and the residue puri-
fied by flash chromatography (hexane/EtOAc, 6:4) to yield 38
(400 mg, 75%) as a colourless oil. [α]2D1 ϭ ϩ87.7 (c ϭ 0.6, CHCl3).
1H NMR (200 MHz, CDCl3): δ ϭ 7.32 (m, 5 H), 5.41 (s, 1 H), 5.34
(s, 1 H), 4.69 (d, J ϭ 11.7 Hz, 1 H), 4.49 (m, 2 H), 4.43 (d, J ϭ
11.7 Hz, 1 H), 4.13Ϫ3.95 (m, 4 H), 2.86 (m, 1 H, H-5), 2.53 (s, 1
H, OH), 1.65 (s, 1 H, OH), 1.36 (s, 3 H), 1.33 (s, 3 H) ppm. 13C
NMR (50 MHz, CDCl3): δ ϭ 139.4, 136.7, 128.6 (ϫ 2), 128.0 (ϫ
2), 119.3 (ϫ 2), 108.8, 80.2, 76.3 (ϫ 2), 70.6, 69.3, 64.0, 41.5, 26.5,
24.4 ppm. C18H24O5 (320.4): calcd. C 67.48, H 7.55; found C 67.24,
H 7.67.
[α]D21 ϭ ϩ22.6 (c ϭ 0.6, CHCl3). H NMR (300 MHz, C6D6): δ ϭ
1
7.82Ϫ7.73 (m, 4 H), 7.31Ϫ7.05 (m, 11 H), 5.05 (d, J ϭ 11.7 Hz, 1
H), 4.63 (d, J ϭ 11.7 Hz, 1 H), 4.01 (dd, J ϭ 4.6, 9.9 Hz, 1 H),
3.94 (m, 1 H), 3.86 (t, J ϭ 5.8 Hz, 1 H), 3.74 (dd, J ϭ 3.1, 9.9 Hz,
1 H), 3.50 (m, 2 H), 2.70 (s, 1 H), 2.40 (m, 2 H), 2.10 (td, J ϭ 3.4,
J ϭ 14.4 Hz, 1 H, Hax-CH2), 1.37 (s, 3 H), 1.25 (s, 3 H), 1.14 (s, 9
H) ppm. 13C NMR (75 MHz, C6D6): δ ϭ 140.0, 136.7 (ϫ 3), 136.6
(ϫ 3), 134.7, 134.6, 130.6 (ϫ 2), 129.3 (ϫ 2), 128.9 (ϫ 3), 109.4,
86.2, 81.7, 75.0, 74.0, 72.1, 65.2, 39.5, 29.1, 28.4, 27.8 (ϫ 3), 27.1,
20.3 ppm.
Alcohol 39: Imidazole (56 mg, 0.83 mmol) and tert-butyldiphen-
ylchlorosilane (TPSCl) (194 mg, 0.70 mmol) were added to a solu-
tion of the diol 38 (150 mg, 0.47 mmol) in DMF (5 mL) and the
reaction mixture was stirred at room temperature for 12 h. It was
then diluted with Et2O and washed with water. The organic layer
was dried and concentrated, giving a residue which was purified by
flash chromatography (hexane/EtOAc, 9:1) to yield the alcohol 39
(235 mg, 90%). [α]2D1 ϭ ϩ52.0 (c ϭ 1.1, CHCl3). 1H NMR
(200 MHz, CDCl3): δ ϭ 7.75Ϫ7.69 (m, 4 H), 7.41Ϫ7.29 (m, 11 H),
5.26 (s, 1 H), 5.23 (s, 1 H), 4.56 (d, J ϭ 11.5 Hz, 1 H), 4.48 (dd,
J ϭ 3.1, 6.6 Hz, 1 H), 4.39 (m, 2 H), 4.27 (dt, J ϭ 3.1, 10.5 Hz, 1
H), 4.05 (dd, J ϭ 8.4, 9.7 Hz, 1 H), 3.85 (m, 2 H), 3.67 (d, J ϭ
10.5 Hz, 1 H), 2.86 (m, 1 H), 1.37 (s, 3 H), 1.35 (s, 3 H), 1.07 (s, 9
H) ppm. 13C NMR (50 MHz, CDCl3): δ ϭ 140.2, 135.8 (ϫ 3),
135.7 (ϫ 3), 133.7, 133.6, 129.7 (ϫ 2), 128.5 (ϫ 2), 127.9 (ϫ 2),
127.7 (ϫ 4), 118.1, 108.9, 80.8, 77.5, 76.8, 70.8, 66.0, 64.4, 42.4,
26.9 (ϫ 4), 24.9, 19.2 ppm.
5a-Carba-α-D-glucopyranose Pentaacetate (42): Bu4NF (700 mg,
1.6 mmol) was added to a solution of silyl ether 41 (70 mg,
0.13 mmol) in THF (7 mL) and the reaction mixture was stirred
overnight. The reaction was then diluted with CH2Cl2 and washed
with water and brine. The organic layer was dried, filtered and
concentrated to give a residue which was purified by flash chroma-
tography (hexane/EtOAc, 1:1). The pure material was dissolved in
MeOH (7 mL) and hydrogenolyzed in the presence of 10% Pd/C
(5 mg) at 35 psi at room temperature for 60 min. The reaction mix-
ture was then filtered through a short pad of Celite and concen-
trated to give a residue which was subjected to the general pro-
cedure for the cleavage of the isopropylidene moiety and acety-
lation. The crude material was purified by flash chromatography
(hexane/EtOAc, 6:4) to yield carba-α--glucopyranose pentaacet-
ate (42, 30 mg, 56%). [α]2D1 ϭ ϩ32.1 (c ϭ 0.4, CHCl3). {Ref.[46a]
[α]2D2 ϭ ϩ37 (c ϭ 0.79, CHCl3), ref.[46b] [α]2D2 ϭ ϩ57 (c ϭ 0.90,
Silyl Ether 40: Alcohol 39 (230 mg, 0.41 mmol) was converted into
the corresponding xanthate and this material deoxygenated accord-
ing to the general procedure. The residue was purified by flash
chromatography (hexane/EtOAc, 95:5) to yield the carba--glucose
derivative 40 (160 mg, 72%). [α]2D1 ϭ ϩ62.6 (c ϭ 1.2, CHCl3). 1H
CHCl3), ref.[46c] [α]2D0 ϭ ϩ63 (c ϭ 1.0, CHCl3), ref.[46d] [α]2D0
ϭ
ϩ36.7 (c ϭ 0.791, CHCl3)}. 1H NMR (300 MHz, CDCl3): δ ϭ 5.45
(m, 1 H), 5.40 (t, J ϭ 10.2 Hz, 1 H), 5.03 (t, J ϭ 10.2 Hz, 1 H),
NMR (300 MHz, CDCl3): δ ϭ 7.65Ϫ7.61 (m, 4 H), 7.42Ϫ7.27 (m, 4.93 (dd, J ϭ 3.2, 10.4 Hz, 1 H), 4.15 (dd, J ϭ 4.6, 11.6 Hz, 1 H),
1838  2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org
Eur. J. Org. Chem. 2004, 1830Ϫ1840

A Stereodivergent Approach to D-Mannoses
FULL PAPER
L. Auzzas, L. Pinna, L. Battistini, F. Zanardi, L. Marzocchi,
3.90 (dd, J ϭ 3.2, 11.6 Hz, 1 H), 2.34 (m, 1 H), 2.14 (s, 3 H), 2.06
(s, 3 H), 2.04 (s, 3 H), 2.01 (s, 3 H), 1.99 (s, 3 H), 1.96 (m, 1 H),
1.72 (dt, J ϭ 2.2, 15.2 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3):
δ ϭ 170.8, 171.9, 170.0, 169.9 (ϫ 2), 71.7, 71.3, 67.9, 67.8, 62.8,
34.9, 28.6, 25.6, 21.0, 20.7, 20.6 (ϫ 2) ppm. C17H24O10 (414.5):
calcd. C 52.57, H 6.23; found C 52.46, H 6.35.
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A. M. Gomez, G. O. Danelon, S. Valverde, J. C. Lopez, J. Org.
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This work was supported by research grants from the Direccion
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A. M. Gomez, G. O. Danelon, E. Moreno, S. Valverde, J. C.
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´
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´
General de Investigacion Cientıfica y Tecnica (grants: PB96Ϫ0822,
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A. M. Gomez, E. Moreno, S. Valverde, J. C. Lopez
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Received June 5, 2003
1840
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Eur. J. Org. Chem. 2004, 1830Ϫ1840