Carbene-mediated functionalization of the anomeric C-H bond of carbohydrates: Scope and limitations

Article abstract of DOI:10.1002/chem.201203725

Herein we investigate the scope and limitations of a new synthetic approach towards α- and β-ketopyranosides relying on the functionalization of the anomeric C-H bond of carbohydrates by insertion of a metal carbene. A key bromoacetate grafted at the 2-position is the cornerstone of a stereoselective glycosylation/diazotransfer/quaternarization sequence that makes possible the construction of a quaternary center with complete control of the stereochemistry. This sequence shows a good tolerance toward protecting groups commonly used in carbohydrate chemistry and gives rise to quaternary disaccharides with good efficiency. In the case of a disaccharide with a more restricted conformation, this functionalization process can be hampered by the steric demand next to the targeted anomeric position. In addition, the formation of transient orthoesters during the glycosylation step may also reduce the overall efficiency of the synthetic sequence. Copyright

Full text of DOI:10.1002/chem.201203725

DOI: 10.1002/chem.201203725
ꢀ
Carbene-Mediated Functionalization of the Anomeric C H Bond of
Carbohydrates: Scope and Limitations
Mꢀlissa Boultadakis-Arapinis,[a] Elise Prost,[b] Vincent Gandon,[c] Pascale Lemoine,[d]
Serge Turcaud,[a] Laurent Micouin,[a] and Thomas Lecourt*[a]
Abstract: Herein we investigate the
scope and limitations of a new synthet-
ic approach towards a- and b-ketopyra-
nosides relying on the functionalization
ry center with complete control of the
stereochemistry. This sequence shows a
good tolerance toward protecting
groups commonly used in carbohydrate
chemistry and gives rise to quaternary
disaccharides with good efficiency. In
the case of a disaccharide with a more
restricted conformation, this function-
alization process can be hampered by
the steric demand next to the targeted
anomeric position. In addition, the for-
mation of transient orthoesters during
the glycosylation step may also reduce
the overall efficiency of the synthetic
sequence.
ꢀ
of the anomeric C H bond of carbohy-
drates by insertion of a metal carbene.
A key bromoacetate grafted at the 2-
position is the cornerstone of a stereo-
Keywords: carbenes
·
carbohy-
selective
glycosylation/diazotransfer/
ꢀ
drates · C H functionalization ·
C-glycosides · insertion · rhodium
quaternarization sequence that makes
possible the construction of a quaterna-
Introduction
mechanism of carbohydrate-active enzymes.[4] However, the
preparation of such compounds is a long process during
which time-consuming modification of the sugar backbone
is required to selectively introduce quaternary centers.[5] The
transformation of pre-existing functional groups has also
been used to prepare sugars displaying a quaternary anome-
ric position.[6,7] Following this approach, the new anomeric
carbon–carbon bond is readily obtained by addition of an
organometallic reagent to a d-lactone, yet the access to the
desired ketopyranosides is then strongly limited by the sub-
sequent glycosylation step (Scheme 1a). Whereas a-anomers
were most often obtained in moderate yields,[8,9] b-ketopyra-
nosides exhibiting an equatorial aglycone were not accessi-
ble by this method, because 2-O-acyl protecting groups did
not provide the required anchimeric assistance.[10]
The prominent role played by complex carbohydrate struc-
tures in numerous physiological and pathological processes
strongly appeals for the development of new chemical tools
for glycobiology.[1] The modification of carbohydrate scaf-
folds, as well as the assembly of oligosaccharides and glyco-
conjugates, have attracted tremendous interest over the past
decades to investigate the complex nature of carbohydrate-
mediated molecular recognition processes.[2] In this context,
the design of locked-sugars proved essential to study the bi-
ologically-active conformations of carbohydrates[3] and the
[a] M. Boultadakis-Arapinis, Dr. S. Turcaud, Dr. L. Micouin,
Dr. T. Lecourt
UMR 8601 CNRS, Universitꢀ Paris Descartes
Sorbonne Paris Citꢀ, UFR Biomꢀdicale
45 rue des Saints Pꢁres, 75006 Paris (France)
E-mail: Thomas.Lecourt@parisdescartes.fr
[b] E. Prost
UMR 8638 CNRS
Universitꢀ Paris Descartes, Sorbonne Paris Citꢀ
Facultꢀ des Sciences Pharmaceutiques et Biologiques
4 avenue de l’Observatoire, 75006 Paris (France)
[c] Prof. V. Gandon
Institut de Chimie Molꢀculaire
et des Matꢀriaux d’Orsay (UMR 8182 CNRS)
Universitꢀ Paris-sud, 91400 Orsay (France)
[d] Dr. P. Lemoine
UMR 8015 CNRS
Universitꢀ Paris Descartes, Sorbonne Paris Citꢀ
Facultꢀ des Sciences Pharmaceutiques et Biologiques
4 avenue de lꢂObservatoire, 75006 Paris (France)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201203725.
Scheme 1. Synthetic approaches toward ketopyranosides.
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FULL PAPER
We reasoned that formation of the glycosidic linkage
before quaternarization might circumvent the limitations in-
herent to the classical approaches. If successful, this shift in
the retrosynthetic paradigm would lead to the functionaliza-
ꢀ
tion of the anomeric C H bond of readily available aldopyr-
anosides in
a
late stage of the synthetic route
(Scheme 1b).[11] However, methods already available for the
Scheme 3. i) a) BrCOCH2Br, pyridine, CH2Cl2, 08C; b) TsNHNHTs,
DBU, THF, 08C; 73% for 4, 64% for 5 and 75% for 6 over the two
steps; ii) catalyst (Table 1), 1,2-dichloroethane, 4 ꢄ MS, heat at reflux.
ꢀ
functionalization of anomeric or pseudo-anomeric C H
bonds can only give rise to spiroketals,[12] and, as a conse-
quence, ring-opening of these compounds in a late stage of
the synthetic process would result in the loss of the anome-
ric configuration.
Table 1. Catalytic decomposition of model diazomannosides.
In this context, in which no existing methods could give
rise to both anomers of ketopyranosides, we recently report-
ed an alternative strategy in which functionalization of the
anomeric position of carbohydrates was relying on the tem-
porary anchoring of a highly reactive carbene at the 2-posi-
tion of the sugar backbone.[13]
Thus, a bromoacetate anchored at the 2-position first in-
duces a stereoselective glycosylation by anchimeric assis-
tance, and, after conversion into a carbene precursor, pro-
motes functionalization of the anomeric position through a
Entry
Diazosugar
Cat.
([mol%])
g-Lactone
Yield
[%]
77[a]
49[b]
13[b]
9[b]
AHCTUNGTRENNUNG
1
2
3
4
5
6
7
8
4
4
4
4
4
4
4
4
5
5
5
5
5
6
6
A
U
7
7
7
7
7
7
7
7
8
8
8
8
8
9
9
A
CHTUNGTRENNUNG
A
CHTUNGTRENNUNG
A
CHTUNGTRENNUNG
A
U
35[b]
20[b]
15[b]
n.d.[c]
94[a]
30[b]
5[b]
[Cu
[Cu
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
A
CHTUNGTRENNUNG
9
A
CHTUNGTRENNUNG
10
11
12
13
14
15
A
CHTUNGTRENNUNG
ꢀ
1,5-C H insertion process (Scheme 2). Ring-opening of the
[Cu
[Cu
ACHTUNGTRENNUNG
A
15[b]
n.d.[c]
20[a,d]
10[b]
A
CHTUNGTRENNUNG
A
CHTUNGTRENNUNG
A
CHTUNGTRENNUNG
[a] Yield of the isolated product after purification by chromatography.
[b] Estimated by 1H NMR spectroscopic analysis of the crude material.
ꢀ
[c] Not detectable. [d] Additional 51% of the 1,7-C H insertion product
10.
adapting a bromoacetylation/diazotransfer sequence recent-
ly reported by Fukuyama and co-workers (Scheme 3).[18,19]
We studied the decomposition of diazosugars 4–6 under
dirhodium(II),[20,21] copper(II)[22] or ruthenium(II)[23] cataly-
sis (Table 1). Dimerization of the reactive carbenoid or in-
sertion of adventitious water were prevented by slow addi-
tion of the substrate to a refluxed suspension of the catalyst
in 1,2-dichloroethane, and by the use of freshly activated
molecular sieves (4 ꢄ MS) as an additive, respectively. De-
composition of diazosugars 4 and 5 revealed that [Rh2-
Scheme 2. Dual role of a 2-O-bromoacetate for the stereoselective prepa-
ration of ketopyranosides.
resulting fused g-lactone finally delivers both a- and b-keto-
pyranosides quaternarized at the anomeric position by a
pending chain.
Herein, we describe the scope and limitations of this new
method with a particular focus on the tolerance toward vari-
ous protecting groups and glycosidic linkages.
ACHTUNGTREN(NUG OAc)4], and, to a lesser extent, [Rh2CAHTUNGTREN(NGUN oct)4], were appropri-
ate for the selective quaternarization of 3-O-silylated or 3-
O-pivaloylated substrates (Table 1, entries 1, 2, and 9). How-
ever, dirhodium catalysts with electron-withdrawing or elec-
tron-donating ligands, as well as [Cu
ACHUTGTNERN(NGU acac)2], [CuACHTUNGTRNEN(UGN hfacac)2],
Results and Discussion
and [{RuCl2A(p-cymene)}2], gave the desired g-lactones 7 and
CHTUNGTRENNUNG
8 in moderate to low yields (Table 1, entries 3–8 and 10–13).
With a benzyl group at the 3-position (Table 1, entries 14
and 15), g-lactone 9 could only be obtained in 20% yield,
because of the competitive formation of 10 in 51% yield
(Scheme 4).
NMR spectroscopy revealed that 10 resulted from 1,7-in-
sertion of the metal carbene into the benzyl protecting
group. NOESY experiments showed that this side reaction
occurred selectively in one of the two diasteoreotopic ben-
Quaternarization of model compounds: We first investigated
the quaternarization of model methyl-glycosides to identify
the reaction conditions suitable for the functionalization of
[14]
the anomeric C H bond without dimerization[15] or other
ꢀ
side reactions arising from the formation of transient oxoni-
um ylides.[16,17] Methyl-2-O-diazoacetyl-a-mannopyranosides
4–6 having O4 and O6 engaged in a cyclic benzylidene were
prepared from the orthogonally protected precursors 1–3 by
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6053

T. Lecourt et al.
Table 2. Catalytic decomposition of model diazoglucosides.
Entry
Diazosugar
Cat.
([mol%])
g-Lactone
Yield
[%]
AHCTUNGTRENNUNG
1
2
3
4
5
6
7
8
14
14
14
14
14
14
15
15
15
15
15
16
16
N
G
17
17
17
17
17
17
18
18
18
18
18
19
19
90[a]
60[a]
85[a]
10[b]
20[b]
15[b]
92[a]
70[a]
10[b]
22[b]
6[b]
Scheme 4. Reaction of 3-O-benzylated diazomannoside 6.
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
9
ACHTUNGTRENNUNG
10
11
12
13
ACHTUNGTRENNUNG
CHTUNGTRENNUNG
35[b,c]
35[a]
[a] Yield of the isolated product after purification by chromatography.
[b] Estimated by 1H NMR spectroscopic analysis of the crude material.
ꢀ
[c] Additional 35% of the 1,7-C H insertion product.
ꢀ
products resulting from 1,5- and 1,7-C H insertions in a
70% combined yield after purification by chromatography
(Table 2, entry 12). In contrast, the use of [Rh2ACTHUNTRGNE(UGN acam)4] led
to the formation of a less electrophilic metal-carbene, which
gave rise to pure g-lactone 19 by preventing insertion into
Figure 1. ORTEP diagram of 10 with thermal ellipsoid at 50% probabili-
ty level.
ꢀ
the benzyl C H bond (Table 2, entry 13). However, the
yield of the isolated product remained modest.
ꢀ
zylic C H bonds, a remarkable feature that was further con-
firmed by X-ray structure analysis of 10 after recrystalliza-
tion from hexane/ethyl acetate (Figure 1).
Thus, as shown above, carbene-mediated functionalization
of the anomeric position of carbohydrates is efficient with
highly rigid scaffolds. We next focused on a methyl b-galac-
topyranoside in which protection of O4 and O6 as a benzyli-
dene gives the product in the cis configuration, instead of
the trans-fused bicyclic motif, thus making the substrate flex-
ible (Scheme 6).[24] For that purpose, the orthogonally pro-
Having investigated the functionalization of model
methyl-a-mannopyranosides, we next turned our attention
to the decomposition of methyl-2-O-diazoacetyl-b-glucopyr-
anosides 14–16, prepared from the orthogonally protected
precursors 11–13, by rhodium(II), copper(II) or rutheni-
ACHTUNGTRENNUNGum(II) catalysts (Scheme 5).
Scheme 6. i) (a) BrCOCH2Br, pyridine, CH2Cl2, 08C; b) TsNHNHTs,
DBU, THF, 08C, 89% over the two steps; ii) catalyst (Table 3), 1,2-di-
chloroethane, 4 ꢄ MS, heat at reflux.
Scheme 5. i) a) BrCOCH2Br, pyridine, CH2Cl2, 08C; b) TsNHNHTs,
DBU, THF, 08C, 74% for 14, 50% for 15 and 74% for 16 over the two
steps; ii) catalyst (Table 2), 1,2-dichloroethane, 4 ꢄ MS, heat at reflux.
tected methyl b-galactoside 20 was converted into the car-
bene precursor 21. Again, catalytic decomposition worked
best with [Rh2ACHTNUTRGNEUNG(OAc)4], with the g-lactone 22 being obtained
The use of these model b-glucosides revealed that [Rh2-
in good yield (Table 3). Even if the latter was isolated in
slightly lower yields than 17 or 18 (Table 2), similar trends
of reactivity in the b-gluco and b-galacto series show that
the insertion of RhII-carbenes into axially orientated anome-
G
2ACHTUNGTRENNUNG(acam)4], and, to a lesser extent [Rh2ACHUTNGTRENN(UGN oct)4],
A
A
ꢀ
G
E
E
ric C H bonds does not depend on the flexibility of the sub-
strate.
N
A
Ring-opening of g-lactones: Having performed the quater-
ꢀ
narization of the anomeric C H bond in a-manno, b-gluco,
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Carbene-Mediated Functionalization
FULL PAPER
Table 3. Catalytic decomposition of model diazoglucosides.
Entry
Cat.
([mol%])
Yield
[%]
AHCTUNGTRENNUNG
1
2
3
N
G
80[b]
64[b]
15[a]
[a] Estimated by 1H NMR spectroscopic analysis of the crude material.
[b] Yield of the isolated product after purification by chromatography.
and b-galacto series, we then investigated the ring-opening
of the resulting g-lactones to obtain “true” ketopyranosides
with an anomeric position substituted by a pending chain.
To this end, lactones 7, 17, and 22 were converted in ex-
cellent yields into Weinreb amides (23–25), which are well-
known versatile intermediates in organic synthesis
(Scheme 7).[25]
Scheme 8. i) Ac2O, I2, RT; ii) PhSH, SnCl4, CH2Cl2, 08C to RT; iii) MeO-
Na, MeOH, RT; iv) PhCHACHTNUTRGNE(NUG OMe)2, cat. CSA, DMF, 508C, 0.1 atm., 42%
over 4 steps; v) PivCl, pyridine, 08C to RT, 85%; vi) BrCOCH2Br, pyri-
dine, CH2Cl2, 08C; 87%; vii) TrCl, pyridine, DMF, RT; viii) MeI, NaH,
DMF, 08C to RT; ix) AcOH/H2O (4:1), 408C, 50% over 3 steps.
(TfOH) gave rise to a 1:1 mixture of orthoester 28, a sample
of which could be isolated in pure form for complete charac-
terization, and disaccharide 29, in a combined yield of 87%.
After filtration through a small pad of silica gel, smooth
equilibration to the thermodynamic compound 29 was in-
duced under Lewis acidic conditions (Scheme 9). Conver-
sion of the 2-O-bromoacetate under TsNHNHTs/1,8-
Scheme 7. Ring-opening of g-lactones 7, 17, and 22.
Preparation and quaternarization of disaccharides: Since
ꢀ
1,5-C H-insertion of a metal carbene temporary tethered at
the 2-position is suitable for inducing efficient functionaliza-
Scheme 9. i) N-Iodosuccinimide (NIS), cat. trifluoromethanesulfonic acid
(TfOH), CH2Cl2, 4 ꢄ MS, ꢀ208C, 87%; ii) cat. TMSOTf, CH2Cl2, 4 ꢄ
ꢀ
tion of axial or equatorial anomeric C H bonds, at least on
model compounds, we next attempted the preparation of
MS, 08C, 74%; iii) TsNHNHTs, DBU, THF, 08C; 84%; iv) [Rh2ACHTUNGTRENNUNG(OAc)4]
quaternary disaccharides. On the basis of reports from
(2 mol%), 1,2-dichloroethane, heat at reflux, 65%.
[26]
ˇ
Kovꢅcs and co-workers,
we anticipated that a 2-O-bro-
moacetate would induce the stereoselective formation of a
glycosidic linkage by anchimeric assistance. As a participat-
ing group and precursor of diazoacetate, it would become
the cornerstone of a glycosylation/diazotransfer/carbene-
diazabicyclo
ered the carbene precursor 30 in 84% yield.
Decomposition under [Rh2A(OAc)4] catalysis finally gave
ACHTUNGTREN[NUNG 5.4.0]undec-7-ene (DBU) conditions then deliv-
CTHUNGTRENNUNG
ꢀ
mediated-C H functionalization sequence, thus providing a
stereospecific entry to a- or b-ketopyranosides.
the g-lactone 31 in 65% yield, showing that carbene-pro-
ꢀ
moted quaternarization of the anomeric C H bond could
also be promoted onto disaccharides.
The 2-O-bromoacetylated phenyl-thio-a-mannopyrano-
side donor 26, with a set of protecting groups that should be
compatible with the carbene-mediated functionalization
step, was prepared in six steps from d-mannose in an overall
yield of 31% (Scheme 8a). As a proof of concept, we first
set up a sequence involving the permethylated primary ac-
ceptor 27, which was prepared in 3 steps from methyl-a-d-
glucopyranoside in 50% overall yield (Scheme 8b).
To evaluate the influence of a more restricted conforma-
ꢀ
tional freedom close to the anomeric C H bond, we next
turned our attention to the functionalization of disacchar-
ides displaying secondary aglycones. Thus, we undertook the
glycosylation of acceptors 32 and 33, which only differ by
their configuration at the 2-O-branching point (Figure 2).[19]
In this case, coupling of 32 and 33 with the thio-glycosyl
donor 26 using NIS/TfOH followed by diazotransfer under
TsNHNHTs/DBU conditions delivered diazosugars 34 and
The coupling between donor 26 and acceptor 27 using N-
iodosuccinimide (NIS)/ trifluoromethanesulfonic acid
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6055

T. Lecourt et al.
at C3 of the reducing end is pointing toward the targeted
ꢀ
anomeric C H bond (Figure 3a). This steric clash might
have prevented the 1,5 insertion, and favored the complexa-
tion of the metal carbene with the endocyclic oxygen atom.
Decomposition of this oxonium ylide by loss of the reactive
moiety[28] might then have delivered alcohol 37. A similar
structural study performed with diazo sugar 34 revealed that
Figure 2. Secondary acceptors considered for the glycosylation/diazo-
ꢀ
transfer/C H-functionalization sequence.
ꢀ
the targeted anomeric C H bond was free from any steric
bulk resulting from the reducing end of the molecule (Fig-
ure 3b). This study on secondary dimannosides revealed
that a conformational restrain can induce a steric bulk close
to the targeted position, preventing the functionalization
process. As a consequence, insertion of carbenes into the
ꢀ
anomeric C H bond of substrates having a restricted confor-
mational freedom will have to be considered with care in
the future.
We next evaluated the tolerance of this reaction toward
other protecting groups commonly used in carbohydrate
chemistry. Thus, coupling of the 3-O-silylated donor 38 (see
the Supporting Information) with diacetone galactose 39
under NIS/TfOH conditions, followed by diazotransfer, de-
livered the carbene precursor 40 in 38% yield over the two
steps (Scheme 11). Decomposition of diazosugar 40 by using
[Rh2ACTHNUTRGNE(NUG OAc)4] gave the expected g-lactone 41 in 56% yield.
Scheme 10. i) NIS, cat. TfOH, CH2Cl2, 4 ꢄ MS, ꢀ208C; ii) TsNHNHTs,
DBU, THF, 08C; 70% for 34, 54% for 35 over two steps; iii) [Rh2-
ACHTUNGTRENNUNG(OAc)4] (2 mol%), 1,2-dichloroethane, 4 ꢄ MS, heat at reflux, 60% for
Thus, carbene-mediated functionalization of the anomeric
position of disaccharides is also compatible with isopropyli-
dene protecting groups on the reducing end of the molecule.
However, the bulky 3-O-tert-butyl silyl (TBS) protecting
group markedly reduced the efficiency of the diazotransfer
as already observed with compounds 5 and 15.
36, 36% for 37.
35 in 70 and 54% yields respectively over the two steps
(Scheme 10). With the carbene precursors in hand, we then
carried out their decomposition by [Rh
of the manno-(a-1,2)-gluco glycosidic linkage, g-lactone 36
was obtained in 60% yield from 34 by clean insertion of the
(OAc)4]. In the case
Since the glycosylation/diazotransfer/quaternarization se-
quence proved expedient to obtain quaternary a-dimanno-
sides, we next turned our attention to the functionalization
of b-diglucosides following a similar approach (Scheme 12).
Thus, we prepared the 2-O-bromoacetylated phenyl-thio-b-
glucopyranoside donor 42 in 6 steps from d-glucose (see the
Supporting Information) and undertook its coupling with ac-
ceptor 27. However, using NIS/TfOH, only traces of impure
disaccharide 43 could be collected because of massive degra-
ꢀ
metal carbene into the anomeric C H bond. However, cata-
lytic decomposition of 35 with a manno-(a-1,2)-manno link-
age resulted in the formation of compound 37 having a free
alcohol moiety at C2 in 36% yield. To get a better under-
standing of the divergent behavior of metallocarbenes gen-
erated upon decomposition of diazosugars 34 and 35 by
[Rh
structural analyses by NMR
spectroscopy and molecular
2ACHTUNGTRENNUNG(OAc)4], we undertook
A
ACHTUNGTRENNUNG
modeling of these carbene pre-
cusors.
The NOESY experiment car-
ried out with 35 showed corre-
lations between H1 of the ac-
ceptor and H5 of the donor on
the one hand, and between H2
of the acceptor and H1 of the
donor on the other hand (Fig-
[27]
ure 3a). Molecular modeling
confirmed the close proximity
between these positions (dis-
tance of 3.233 and 2.328 ꢄ, re-
spectively) and revealed a con-
formation in which the acetate Figure 3. Structural analysis of diazo sugars 34 and 35.
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Carbene-Mediated Functionalization
FULL PAPER
Scheme 11. i) NIS, cat. TfOH, CH2Cl2, 4 ꢄ MS, ꢀ208C; ii) TsNHNHTs,
DBU, THF, 08C; 38% over the two steps; iii) [Rh2ACHTNUTRGNE(UNG OAc)4] (2 mol%),
1,2-dichloroethane, 4 ꢄ MS, reflux, 56%.
Scheme 13.
reflux.
ACHTUGNTREN[UNNG Rh2L4] (2 mol%), 1,2-dichloroethane, 4 ꢄ MS, heat at
Lastly, catalytic decomposition of carbene precursor 45
was attempted to obtain the quaternary b-disaccharide 46
(Scheme 13). Under [Rh2ACHTUNTRGNEUNG(OAc)4] catalysis, g-lactone 46 was
obtained admixed with product 47 in a 94% combined
yield. Mass spectrometry analysis of this 1:1 mixture showed
a single peak corresponding to an insertion of the metal car-
bene into the disaccharidic scaffold. Characterization of the
side product was then achieved by careful NMR analysis of
the mixture of the two compounds. DEPT, HSQC, and
HMBC experiments revealed the conversion of the methyl
protecting group at the 4-position into a methylene that cor-
relates with the carbonyl of the starting diazoacetate.[32]
Scheme 12. i) Ph2SO, Tf2O, TTBP, CH2Cl2, 4 ꢄ MS, ꢀ70 to ꢀ208C, then
27, ꢀ708C, 1:1 mixture of 43+44, 94%; ii) TsNHNHTs, DBU, THF, 08C;
43% for 45, 38% for 44.
ꢀ
Macrolactone 47 then resulted from 1,11-C H insertion of
the metal carbene into the reducing end of the disaccharide.
ꢀ
Similar long range C H activation processes have already
dation. Furthermore, the use of dimethylthiosulfonium trif-
been reported by Suarez and co-workers from oxygen-cen-
tered radicals.[33] In their case, a 1,8-hydrogen shift supplants
the kinetically favored 1,5-hydrogen-transfer process be-
cause of a conformational bias that brings the two reactive
ACHTUNGTRENNUNG
late or tetrafluoroborate[29] as glycosylation promoters also
resulted in degradation. Finally, a 1:1 inseparable mixture of
b-diglucoside 43 and orthoester 44 could be obtained in
84% yield under neutral conditions involving a reverse acti-
vation protocol (Ph2SO, Tf2O, TTBP).[30]
moieties close to each other.[34] In our case, the 1,11-C H in-
sertion of the metal carbene into the methoxy group should
ꢀ
ꢀ
However, attempted rearrangement to the thermodynam-
ic disaccharide 43 under Lewis acidic conditions resulted in
decomposition. Thus, we directly carried out diazotransfer
on the 43/44 mixture, believing that the neopentyl position
of 44 would not undergo nucleophilic displacement. Treat-
ment of the mixture with TsNHNHTs and DBU eventually
gave rise to the carbene precursor 45 admixed with 44.
Since diazosugars are usually slightly more polar than the
corresponding bromoacetates, isolation of 45 was then possi-
ble by careful chromatography. With the pure material in
hand, we investigated the rearrangement of orthoester 44
under Lewis or Brønsted acid catalysis (TMSOTf, TESOTf,
be less favored than insertion into the anomeric C H bond
from an electronic point of view.[35] The long range C H ac-
ꢀ
tivation is then probably the consequence of a conforma-
tional bias resulting from the strong exo-anomeric effect. If
so, a less electrophilic carbene might favor the reaction at
ꢀ
the electronically most-activated anomeric C H bond. To
verify this hypothesis, we used [Rh
(acam)4] to promote the
decomposition of 45. Gratifyingly, a fully selective function-
alization process took place, resulting in isolation of the
pure g-lactone 46 in 61% yield.
Similarly to the a-manno series, we also investigated the
tolerance of the functionalization process toward temporary
protecting groups. Thus, the carbene precursor 48 was pre-
pared by coupling diacetone galactose 39 with donor 42
under reverse activation conditions (see the Supporting In-
formation), followed by diazotransfer. Finally, decomposi-
TBSOTf, TfOH, [YbACHTNUTRGNE(NUG OTf)3]) at temperature ranging from
ꢀ50 to 08C, in neat methylene chloride or with additional
diethylether. Unfortunately, under any of these conditions,
only degradation took place.[31] Additionally, decomposition
of orthoester 44 in the presence of NIS and catalytic TfOH
in methylene chloride at ꢀ208C revealed that degradation
of the substrates under normal glycosylation conditions
might have arisen from the formation of this intermediate.
tion of 48 under [Rh2ACHTNUTRGNE(NUG OAc)4] catalysis nicely delivered the
targeted g-lactone 49 in 60% yield with complete selectivity
(Scheme 14).
Chem. Eur. J. 2013, 19, 6052 – 6066
ꢃ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6057

T. Lecourt et al.
column chromatography was performed on silica gel 60 (230–400 mesh,
E. Merck). For reactions, solvents were purchased anhydrous from
Sigma–Aldrich (dichloromethane, 1,2-dichloroethane, and pyridine) or
distilled (tetrahydrofuran over sodium/benzophenone for diazotransfer,
dichloromethane over phosphorous pentoxide for glycosylations). All re-
actions were conducted under an argon atmosphere. Glycosylations and
carbene-insertion reactions were performed in flame-dried glassware.
Scheme 14.
reflux.
ACHTUNGTRENNUNG[Rh2ACHTUNGTRENNUNG(OAc)4] (2 mol%), 1,2-dichloroethane, 4 ꢄ MS, heat at
[Rh
G
N
2ACHTUNGTREN(NGU cap)4], and [Rh2HCATUNGTREN(NUGN oct)4] were purchased
from Sigma–Aldrich. [Rh2ACHNUTTGREG(NNUN acam)4] was prepared following Doyleꢂs pro-
cedure.[36] N,N’-ditosylhydrazine was prepared following Fukuyamaꢂs pro-
cedure.[18]
Conclusion
Methyl 4,6-O-benzylidene-2-O-diazoacetyl-3-O-pivaloyl-a-d-mannopyra-
noside 4: A Bromoacetyl bromide (717 mL, 8.237 mmol) was added drop-
wise over 10 min to a solution of 1 (1.503 g, 4.102 mmol) in anhydrous di-
chloromethane (20 mL) and anhydrous pyridine (830 mL, 10.262 mmol)
at 08C. After being stirred for 15 min at 08C, the reaction mixture was
quenched with methanol (0.5 mL) and TLC (cyclohexane/ethyl acetate
2:1) showed complete consumption of the starting material. The organic
layer was washed with a saturated aqueous solution of ammonium chlo-
This study reveals that 1,5 insertion of metal carbenes into
the anomeric C H bond of carbohydrates is highly efficient
for obtaining ketopyranosides in a-manno, b-gluco, and b-
galacto series. Thus, decomposition of carbene precursors
grafted at the 2-position of the sugar by [Rh2ACTHNUTRGNEU(GN OAc)4] or
ꢀ
[Rh2ACHTUNGTRENNUNG(acam)4] efficiently induces quaternarization of the car-
AHCTUNGTRENNUNG
bohydrate scaffold, whereas CuII or RuII salts gives the tar-
AHCTUNGTRENNUNG
16.241 mmol) was added to a solution of the residue and N,N’-ditosylhy-
drazine (2.793 g, 8.204 mmol) in distilled tetrahydrofuran (40 mL) at 08C.
After TLC analysis showed complete consumption of the starting materi-
ꢀ
geted g-lactones in poor yields. This C H functionalization
process, which is compatible with a wide range of protecting
groups commonly used in carbohydrate chemistry, also effi-
ciently delivers quaternary disaccharides following a stereo-
selective glycosylation/diazotranfer/quaternarization se-
quence. However, even if functionalization of disaccharides
is high yielding in the case of primary anomeric substituents,
steric bulk resulting from secondary aglycones sometimes
fully prevents the quaternarization process. Moreover, the
use of a bromoacetate at the 2-position to control the ste-
al (cyclohexane/ethyl acetate 2:1),
a saturated aqueous solution of
sodium hydrogen carbonate (40 mL) and dichloromethane (40 mL) were
added, and the organic layer was dried (anhydrous magnesium sulfate),
filtered and concentrated under vacuum. The residue was purified by
silica gel chromatography (cyclohexane/ethyl acetate 5:1) to give 4 as a
bright yellow oil (1.294 g, 73%). Rf =0.62 (silica, cyclohexane/ethyl ace-
tate 2:1). [a]2D0 =ꢀ36 (c=1.0, CHCl3); 1H NMR (300 MHz, CDCl3): d=
7.48–7.30 (m, 5H, Harom.), 5.61 (s, 1H, H7), 5.50–5.35 (m, 2H, H2, H3),
4.91 (brs, 1H, H8), 4.73 (s, 1H, H1), 4.33 (dd, J=9.6, 3.6 Hz, 1H,
H6equiv), 4.07–3.79 (m, 3H, H4, H5, H6ax.), 3.42 (s, 3H, OMe), 1.20 ppm
ACHTUNGTRENNUNGreoselectivity of the glycosylation step by anchimeric assis-
(s, 9H, ACHTUNGTRNEUNG
(CH3)3C); 13C NMR (75 MHz, CDCl3): d=177.0 (C=O), 165.7
tance reduces the efficiency of the overall sequence in the
b-gluco series by giving rise to transient orthoesters that de-
compose under acidic conditions. Having established the
scope and limitations of the functionalization of the anome-
(C=O), 137.2 (Cquat. arom.), 128.9 (CHarom.), 128.2 (CHarom.), 125.9
(CHarom.), 101.4 (C7), 99.7 (C1), 76.5 (C4), 70.4 (C2), 68.8 (C6), 68.1
(C3), 63.6 (C5), 55.3 (OMe), 46.4 (C8), 38.9 ((CH3)3C), 27.0 ppm
((CH3)3C); IR (film): n˜ =2974, 2115, 1733, 1698, 1457, 1384, 1283, 1177,
1134, 1097, 1031 cmꢀ1; HRMS: m/z calcd for C21H26N2O8Na: 457.1581;
found: 457.1581.
ꢀ
ric C H bond of carbohydrates by 1,5 insertion of metal car-
benes, we will next turn our attention to the mechanism of
this transformation and to the development of new chemical
tools for glycobiology based on quaternary carbohydrate
scaffolds.
Methyl 4,6-O-benzylidene-2-O-diazoacetyl-3-O-tert-butyldimethylsilyl-a-
d-mannopyranoside 5: Yield 64%. Rf =0.52 (silica, cyclohexane/ethyl
1
acetate 3:1); [a]2D0 =ꢀ3 (c=1.0, CHCl3); H NMR (300 MHz, CDCl3): d=
7.60–7.30 (m, 5H, Harom.), 5.60 (s, 1H, H7), 5.26 (dd, J=3.7, 1.1 Hz,
1H, H2), 4.89 (br s, 1H, H8), 4.71 (d, J=1.1 Hz, 1H, H1), 4.29 (d, J=
5.7 Hz, 1H, H6), 4.22 (dd, J=9.0, 3.7 Hz, 1H, H3), 3.92–3.70 (m, 3H,
H4, H5, H6), 3.41 (s, 3H, OMe), 0.88 (s, 9H, CACTHNUTGRNEG(UN CH3)3), 0.10 (s, 3H,
Experimental Section
CH3Si), 0.07 ppm (s, 3H, CH3Si); 13C NMR (75 MHz, CDCl3): d=166.2
(C=O), 137.5 (Cquat. arom.), 128.9 (CHarom.), 128.1 (CHarom.), 126.1
(CHarom.), 101.8 (C7), 100.0 (C1), 79.4 (C4), 72.9 (C2), 68.8 (C6), 68.1
General: Optical rotations were measured at 208C with a Perkin–Elmer
Model 341 polarimeter, in a 10 cm, 1 mL cell. Concentrations are given
in g 100 mLꢀ1. Infrared spectra were recorded with a Nicolet 510 FT-IR
spectrometer. Mass spectrometry spectra were recorded on a Waters ZQ
2000 spectrometer. High Resolution mass spectra were recorded on a
(C3), 63.6 (C5), 55.2 (OMe), 46.5 (C8), 25.6 (CACHTNUTRGENN(UG CH3)3), 18.2 (SiCACHTUNGTRENNUNG(CH3)3),
ꢀ4.7 (SiCH3), ꢀ5.1 (SiCH3); IR (film): n˜ =2930, 2113, 1698, 1471, 1384,
1282, 1249, 1216, 1173, 1133, 1079, 1033, 1008 cmꢀ1; HRMS: m/z calcd for
C22H32N2O7SiNa: 487.18765; found: 487.1872.
Bruker MicrO-Tof-Q
2 spectrometer at CRMPO (Rennes, France).
1H NMR spectra were recorded at 400 MHz with a Bruker Avance 400
or at 300 MHz with a Bruker Avance 300 spectrometer. 13C NMR spectra
were recorded at 75 MHz with a Bruker AC 300 spectrometer with adop-
tion of 77.00 ppm for the central line of CDCl3. The relaxation delay
(D1) was increased to 60 seconds for 13C NMR spectra of diazo com-
pounds. Assignments were aided by DEPT, COSY, HSQC, and HMQC
Methyl 3-O-benzyl-4,6-O-benzylidene-2-O-diazoacetyl-a-d-mannopyra-
noside 6: Yield 75%. Rf =0.40 (silica, cyclohexane/ethyl acetate 3:1);
[a]2D0 =ꢀ21 (c=1.0, CHCl3). 1H NMR (300 MHz, CDCl3): d=7.56–7.28
(m, 10H, Harom.), 5.65 (s, 1H, H7), 5.52–5.48 (m, 1H, H2), 4.94 (brs,
1H, H8), 4.77 (d, J=12.2 Hz, 1H, CHPh), 4.76 (d, J=1.5 Hz, 1H, H1)
4.69 (d, J=12.2 Hz, 1H, CHPh), 4.29 (dd, J=13.3, 2.8 Hz, 1H, H6), 4.10–
3.96 (m, 2H, H3, H5), 3.93–3.78 (m, 2H, H4, H6), 3.40 ppm (s, 3H,
OMe); 13C NMR (75 MHz, CDCl3): d=166.2 (C=O), 138.0 (Cquat.
arom.), 137.9 (Cquat. arom.), 129.0 (CHarom.), 128.4 (CHarom.), 128.2
(CHarom.), 127.8 (CHarom.), 127.7 (CHarom.), 126.2 (CHarom.), 101.7
(C7), 99.9 (C1), 78.4 (C4), 73.8 (C3), 72.1 (CH2Ph), 69.9 (C2), 68.8 (C6),
63.7 (C5), 55.2 (OMe), 46.8 ppm (C8); IR (film): n˜ =3091, 2912, 2114,
1
experiments. In the H and 13C NMR spectra, signals for benzylidene and
lactone are numbered 7 and 8, respectively, whereas letters A and B
refer to the reducing and non-reducing end of disaccharides, respectively.
Reactions were monitored by thin-layer chromatography (TLC) on a pre-
coated silica gel 60 F254 plate (layer thickness 0.2 mm; E. Merck, Darm-
stadt, Germany) and detection by charring phosphomolybdic acid. Flash
6058
www.chemeurj.org
ꢃ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 6052 – 6066

Carbene-Mediated Functionalization
FULL PAPER
1691, 1497, 1454, 1383, 1282, 1240, 1174, 1133, 1077, 1029, 1005 cmꢀ1
HRMS: m/z calcd for C23H24N2O7Na: 463.1481; found: 463.1478.
;
H7), 5.34 (dd, J=10.3, 4.0 Hz, 1H, H3), 4.75 (d, J=4.0 Hz, 1H, H2), 4.32
(dd, J=9.5, 3.9 Hz, 1H, H6equiv), 4.06 (t, J=10.3 Hz, 1H, H4), 3.95–3.75
(m, 2H, H5, H6ax.), 3.39 (s, 3H, OMe), 2.83 (d, J=16.4 Hz, 1H, H8), 2.70
Methyl 4,6-O-benzylidene-2-O-diazoacetyl-3-O-pivaloyl-b-d-glucopyrano-
side 14: Yield 74%. Rf =0.62 (silica, cyclohexane/ethyl acetate 2:1);
[a]2D0 =ꢀ66 (c=1.0, CHCl3); 1H NMR (300 MHz, CDCl3): d=7.50–7.30
(m, 5H, Harom.), 5.54 (s, 1H, H7), 5.34 (t, J=8.0 Hz, 1H, H3), 5.11 (t,
J=8.0 Hz, 1H, H2), 4.80 (br s, 1H, H8), 4.52 (d, J=8.0 Hz, 1H, H1),
4.41 (dd, J=10.5, 4.9 Hz, 1H, H6equiv), 3.83 (t, J=10.5 Hz, 1H, H6ax.),
3.73 (t, J=8.0 Hz, 1H, H4), 3.62–3.46 (m, 4H, OMe, H5), 1.18 ppm (s,
(d, J=16.4 Hz, 1H, H8’), 1.26 ppm (s, 9H, ACTHNUTRGNEUNG
(CH3)3C); 13C NMR (75 MHz,
CDCl3): d=177.8 (C=O), 171.5 (C=O), 136.9 (Cquat. arom.), 129.0
(CHarom.), 128.2 (CHarom.), 125.9 (CHarom.), 103.7 (C1), 101.3 (C7),
79.0 (C2), 74.8 (C4), 68.21 (C6), 68.20 (C3), 64.5 (C5), 51.9 (OMe), 40.3
(C8), 39.0 ((CH3)3C), 27.0 ppm (ACTHNURTGNEUNG(CH3)3C); IR (film): n˜ =2971, 1806,
1734, 1704, 1279, 1154, 1098, 1073, 1004 cmꢀ1; HRMS: m/z calcd for
9H, ACHTUNGTRENNUNG
(CH3)3C); 13C NMR (75 MHz, CDCl3): d=177.5 (C=O), 165.4 (C=
C21H26O8Na: 429.1520; found: 429.1524.
O), 136.9 (Cquat. arom.), 129.0 (CHarom.), 128.2 (CHarom.), 125.9
(CHarom.), 102.4 (C1), 101.1 (C7), 78.7 (C4), 72.1 (C2), 71.3 (C3), 68.6
(C6), 66.4 (C5), 57.3 (OMe), 46.3 (C8), 38.9 ((CH3)3C), 26.8 ppm
g-Lactone 8: Yield 94%. Rf =0.41 (silica, cyclohexane/ethyl acetate 3:1);
[a]2D0 =ꢀ75 (c=1.0, CHCl3); 1H NMR (300 MHz, CDCl3): d=7.56–7.33
(m, 5H, Harom.), 5.57 (s, 1H, H7), 4.47 (d, J=4.0 Hz, 1H, H2), 4.33–
4.24 (m, 1H, H6), 4.19 (dd, J=9.5, 4.0 Hz, 1H, H3), 3.93–3.69 (m, 3H,
H4, H5, H6), 3.38 (s, 3H, OMe), 2.82 (d, J=16.3 Hz, 1H, H8), 2.70 (d,
(ACHTUNGTRENNUNG ;
(CH3)3C); IR (film): n˜ =2971, 2114, 1736, 1704, 1380, 1148, 1099 cmꢀ1
HRMS: m/z calcd for C21H26N2O8Na: 457.1581; found: 457.1587.
J=16.3 Hz, 1H, H8’), 0.90 (s, 9H,
CACHTGNUTERNNU(G CH3)3), 0.12 (s, 3H, SiCH3),
Methyl 4,6-O-benzylidene-2-O-diazoacetyl-3-O-tert-butyldimethylsilyl-b-
d-glucopyranoside 15: Yield 50%. Rf =0.46 (silica, cyclohexane/ethyl ace-
tate 3:1); [a]2D0 =ꢀ37 (c=1.0, CHCl3); 1H NMR (300 MHz, CDCl3): d=
7.60–7.31 (m, 5H, Harom.), 5.54 (s, 1H, H7), 5.02 (t, J=8.8 Hz, 1H, H2),
4.81 (br s, 1H, H8), 4.47–4.30 (m, 2H, H1, H6equiv), 3.89 (t, J=8.8 Hz,
1H, H3), 3.81 (t, J=10.2 Hz, 1H, H6ax.), 3.57 (m, 1H, H4), 3.53 (s, 3H,
0.07 ppm (s, 3H, SiCH3); 13C NMR (75 MHz, CDCl3): d=172.0 (C=O),
137.2 (Cquat. arom.), 129.0 (CHarom.), 128.2 (CHarom.), 126.1
(CHarom.), 103.7 (C1), 101.7 (C7), 82.4 (C2), 77.6 (C4), 68.5 (C3), 68.2
(C6), 64.7 (C5), 51.8 (OMe), 40.6 (C8), 25.7 (ACTHUNRTGNEUNG(CH3)3C), 18.3 ((CH3)3CSi),
ꢀ4.4 (SiCH3), ꢀ5.1 ppm (SiCH3); IR (film): n˜ =2930, 1795, 1457, 1386,
1250, 1213, 1174, 1118, 1099, 1027 cmꢀ1
C22H32O7SiNa: 459.1815; found: 459.1811.
; HRMS: m/z calcd for
OMe), 3.44 (dt, J=10.2, 4.8 Hz, 1H, H5), 0.85 (s, 9H, CACHTNUGTRNEG(UN CH3)3), 0.05 (s,
3H, SiCH3), 0.01 ppm (s, 3H, SiCH3); 13C NMR (75 MHz, CDCl3): d=
165.3 (C=O), 137.1 (Cquat. arom.), 129.1 (CHarom.), 128.2 (CHarom.),
126.3 (CHarom.), 102.5 (C1), 101.8 (C7), 81.4 (C4), 74.5 (C2), 72.8 (C3),
g-Lactone 9: Yield 20%. Rf =0.24 (silica, cyclohexane/ethyl acetate 3:1);
1
[a]2D0 =40 (c=1.0, CHCl3); H NMR (300 MHz, CDCl3): d=7.41–7.27 (m,
68.7 (C6), 66.4 (C5), 57.1 (OMe), 46.5 (C8), 25.6 (C
(CH3)3), 18.1 (SiC-
10H, Harom.), 5.61 (s, 1H, H7), 4.89 (d, J=12.2 Hz, 1H, CHPh), 4.78 (d,
J=12.2 Hz, 1H, CHPh), 4.58 (d, J=3.7 Hz, 1H, H2), 4.28 (dd, J=9.3,
3.8 Hz, 1H, H6equiv), 4.12–3.95 (m, 2H, H3, H4), 3.86–3.70 (m, 2H, H5,
H6ax.), 3.34 (s, 3H, OMe), 2.81 (d, J=16.3 Hz, 1H, H8), 2.67 ppm (d, J=
16.3 Hz, 1H, H8’); 13C NMR (75 MHz, CDCl3): d=171.5 (C=O), 137.8
(Cquat. arom.), 137.2 (Cquat. arom.), 129.1 (CHarom.), 128.5
(CHarom.), 128.3 (CHarom.), 127.9 (CHarom.), 126.1 (CHarom.), 103.7
(C1), 101.6 (C7), 80.1 (C2), 77.6 (C4), 73.1 (C3), 73.0 (CH2Ph), 68.3 (C6),
64.6 (C5), 51.8 (OMe), 40.3 ppm (C8); IR (film): n˜ =2933, 2871, 1797,
A
1471, 1380, 1237, 1134, 1098, 1029, 1009 cmꢀ1; HRMS: m/z calcd for
C22H32N2O7SiNa: 487.18765; found: 487.1874.
Methyl 3-O-benzyl-4,6-O-benzylidene-2-O-diazoacetyl-b-d-glucopyrano-
side 16: Yield 74%. Rf =0.33 (silica, cyclohexane/ethyl acetate 3:1);
1
[a]2D0 =14 (c=1.0, CHCl3); H NMR (300 MHz, CDCl3): d=7.62–7.22 (m,
10H, Harom.), 5.61 (s, 1H, H7), 5.10 (t, J=8.3 Hz, 1H, H2), 4.91 (d, J=
12.0 Hz, 1H, CHPh), 4.81–4.68 (m, 2H, H8, CHPh), 4.48–4.33 (m, 2H,
H1, H6equiv), 3.94–3.67 (m, 3H, H3, H4, H6ax.), 3.47 ppm (m, 4H, H5;
OMe); 13C NMR (75 MHz, CDCl3): d=165.4 (C=O), 138.1 (Cquat.
arom.), 137.2 (Cquat. arom.), 129.1 (CHarom.), 128.3 (CHarom.), 128.0
(CHarom.), 127.7 (CHarom.), 126.1 (CHarom.), 102.4 (C1), 101.3 (C7),
81.6 (C4), 78.2 (C3), 74.1 (CH2Ph), 73.1 (C2), 68.7 (C6), 66.2 (C5), 57.1
(OMe), 46.4 ppm (C8); IR (film): n˜ =2927, 2113, 1705, 1454, 1381, 1237,
1195, 1096, 1058, 1030, 1011 cmꢀ1; HRMS: m/z calcd for C23H24N2O7Na:
463.1481; found: 463.1483.
1493, 1454, 1377, 1302, 1282, 1217, 1177, 1155, 1096, 1077, 1004 cmꢀ1
;
HRMS: m/z calculated for C23H24O7Na: 435.1420; found: 435.1418.
e-Lactone 10: Recrystallization from ethyl acetate/hexane. Yield 51%.
Rf =0.16 (silica, cyclohexane/ethyl acetate 3:1); [a]2D0 =ꢀ69 (c=1.0,
CHCl3); 1H NMR (300 MHz, CDCl3): d=7.52–7.28 (m, 10H, Harom.),
5.62 (s, 1H, H7), 5.01 (s, 1H, H1), 4.89 (d, J=3.8 Hz, 1H, H2), 4.81 (dd,
J=9.2, 5.2 Hz, 1H, H9), 4.33 (dd, J=9.0, 3.3 Hz, 1H, H6equiv), 4.26 (dd,
J=9.2, 3.8 Hz, 1H, H3), 4.05 (t, J=9.2 Hz, 1H, H4), 3.99–3.82 (m, 2H,
H5, H6ax.), 3.63 (dd, J=15.6, 9.2 Hz, 1H, H8), 3.47 (s, 3H, OMe),
3.15 ppm (dd, J=15.6, 5.2 Hz, 1H, H8’); 13C NMR (75 MHz, CDCl3): d=
169.1 (C=O), 142.0 (Cquat. arom.), 137.2 (Cquat. arom.), 129.1
(CHarom.), 128.7 (CHarom.), 128.3 (CHarom.), 128.1 (CHarom.), 126.2
(CHarom.), 125.7 (CHarom.), 101.9 (C7), 99.1 (C1), 77.4 (C4), 74.4 (C2),
74.3 (C3), 71.2 (C9), 68.7 (C6), 62.3 (C5), 50.7 (OMe), 44.3 ppm (C8); IR
(film): n˜ =2920, 1449, 1496, 1455, 1367, 1301, 1246, 1218, 1134, 1093,
1040 cmꢀ1; HRMS: m/z calcd for C23H24O7Na: 435.1420; found: 435.1412.
Methyl 4,6-O-benzylidene-2-O-diazoacetyl-3-O-pivaloyl-b-d-galactopyra-
noside 21: Yield 89%. Rf =0.51 (silica, cyclohexane/ethyl acetate 1:1);
1
[a]2D0 =74 (c=1.0, CHCl3); H NMR (300 MHz, CDCl3): d=7.54–7.42 (m,
2H, Harom.), 7.40–7.29 (m, 3H, Harom.), 5.52 (s, 1H, H7), 5.47 (dd, J=
10.3, 8.1 Hz, 1H, H2), 4.91 (dd, J=10.3, 3.7 Hz, 1H, H3), 4.77 (br s, 1H,
H8), 4.44 (d, J=8.1 Hz, 1H, H1), 4.40 (d, J=3.7 Hz, 1H, H4), 4.36 (dd,
J=12.5, 1.3 Hz, 1H, H6), 4.08 (dd, J=12.3, 1.3 Hz, 1H, H6’), 3.58–3.44
(m, 1H, H5), 3.52 (s, 3H, OMe), 1.19 ppm (s, 9H, ACTHNUTRGNEUNG
(CH3)3C); 13C NMR
(75 MHz, CDCl3): d=178.1 (C=O), 165.2 (C=O), 137.4 (Cquat. arom.),
128.7 (CHarom.), 128.0 (CHarom.), 125.9 (CHarom.), 101.5 (C1), 100.4
(C7), 73.2 (C4), 71.8 (C3), 68.8 (C6), 68.7 (C2), 66.3 (C5), 56.4 (OMe),
g-Lactone 17: Yield 90%. Rf =0.60 (silica, cyclohexane/ethyl acetate
2:1); [a]2D0 =1 (c=1.0, CHCl3); 1H NMR (300 MHz, 508C, CDCl3): d=
7.51–7.31 (m, 5H, Harom.), 5.57 (s, 1H, H7), 5.31 (dd, J=10.3, 6.1 Hz,
1H, H3), 4.47 (d, J=6.1 Hz,1H, H2), 4.42–4.33 (m, 1H, H6), 4.03–3.91
(m, 1H, H4), 3.85–3.71 (m, 2H, H5, H6), 3.42 (s, 3H, OMe), 2.92 (d, J=
17.1 Hz, 1H, H8), 2.69 (d, J=17.1 Hz, 1H, H8’), 1.24 (s, 9H ppm
46.1 (C8), 38.8 (CACHTUNGTRENNUNG(CH3)3), 26.8 ppm (ACHTUNGTREN(NUGN CH3)3C). IR (film): n˜ =2974, 2113,
1731, 1702, 1480, 1453, 1370, 1279, 1181, 1146, 1102, 1057, 1027,
1003 cmꢀ1
457.1589.
; HRMS: m/z calcd for C21H26N2O8Na: 457.15869; found:
AHCTUNGTRENNUNG
(CH3)3C); 13C NMR (75 MHz, CDCl3): d=177.0 (C=O), 171.0 (C=O),
136.6 (Cquat. arom.), 129.1 (CHarom.), 128.3 (CHarom.), 125.9
(CHarom.), 103.9 (C1), 101.4 (C7), 82.0 (C2), 76.1 (C4), 71.9 (C3), 68.9
(C6), 66.4 (C5), 50.7 (OMe), 38.8 ((CH3)3C), 36.5 (C8), 27.0 ppm
g-Lactone 7: A solution of 4 (216 mg, 0.5 mmol) in anhydrous 1,2-di-
chloroethane (2 mL) was added dropwise through syringe pump
(20 mmolhꢀ1) to a suspension of [Rh
2A(OAc)4] (1.1 mg, 2.5 mmol) in anhy-
a
CTHUNGTRENNUNG
(ACTHNURGTNEG(UN CH3)3C); IR (film): n˜ =2971, 1798, 1740, 1457, 1375, 1277, 1135, 1078,
drous 1,2-dichloroethane (80 mL) heated at reflux. After the end of the
addition, the reaction mixture was cooled to room temperature and con-
centrated under vacuum. The residue was purified by silica gel chroma-
tography (cyclohexane/ethyl acetate 5:2) to give 7 as a colorless solid
(159 mg, 77%). Recrystalization from dichloromethane gave single crys-
tals suitable for characterization by X-ray crystallography. Rf =0.57
(silica, cyclohexane/ethyl acetate 2:1); [a]2D0 =ꢀ82 (c=1.0, CHCl3);
1H NMR (300 MHz, CDCl3): d=7.53–7.30 (m, 5H, Harom.), 5.59 (s, 1H,
1031 cmꢀ1; HRMS: m/z calcd for C21H26O8Na: 429.1520; found: 429.1521.
g-Lactone 18: Yield 92%. Rf =0.49 (silica, cyclohexane/ethyl acetate
3:1); [a]2D0 =ꢀ8 (c=1.0, CHCl3); 1H NMR (300 MHz, CDCl3): d=7.57–
7.32 (m, 5H; Harom.), 5.58 (s, 1H, H7), 4.47–4.29 (m, 2H, H2, H6), 3.89
(dd, J=9.6, 5.8 Hz, 1H, H3), 3.83–3.71 (m, 2H, H4, H6), 3.69–3.55 (m,
1H, H5), 3.41 (s, 3H, OMe), 2.86 (d, J=17.2 Hz, 1H, H8), 2.68 (d, J=
17.2 Hz, 1H, H8’), 0.90 (s, 9H, CACTHNUTRGEN(UNG CH3)3), 0.13 (s, 3H, SiCH3), 0.06 ppm
Chem. Eur. J. 2013, 19, 6052 – 6066
ꢃ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6059

T. Lecourt et al.
(s, 3H, SiCH3); 13C NMR (75 MHz, CDCl3): d=171.8 (C=O), 136.9
(Cquat. arom.), 129.2 (CHarom.), 128.2 (CHarom.), 126.1 (CHarom.),
103.8 (C1), 101.8 (C7), 85.4 (C2), 78.6 (C4), 74.1 (C3), 68.8 (C6), 66.5
1457, 1378, 1282, 1091, 1031 cmꢀ1; HRMS: m/z calcd for C30H42O13Na:
490.2047; found: 490.2046.
Weinreb amide 25: Yield 89%. Rf =0.13 (silica, cyclohexane/ethyl acetate
1:1); [a]2D0 =113 (c=1.0, CHCl3); 1H NMR (300 MHz, CDCl3): d=7.53–
7.31 (m, 5H, Harom.), 5.50 (s, 1H, H7), 4.98 (dd, J=10.5, 3.4 Hz, 1H,
H3), 4.62 (br s, 1H, OH), 4.58–4.47 (m, 1H, H2), 4.43–4.29 (m, 2H, H4,
H6), 4.04 (dd, J=12.5, 1.4 Hz, 1H, H6), 3.82–3.71 (m, 4H, H5, NOMe),
3.50 (s, 3H, OMe), 3.30–3.12 (m, 4H, H8, NCH3), 3.02 (d, J=14.0 Hz,
(C5), 50.5 (OMe), 36.5 (C8), 25.7 (
(CH3)3C), 18.2 ((CH3)3CSi), ꢀ4.5
(SiCH3), ꢀ4.9 ppm (SiCH3); IR (film): n˜ =2930, 1800, 1462, 1386, 1282,
1254, 1095, 1063, 1004 cmꢀ1
459.1815; found: 459.1812.
; HRMS: m/z calcd for C22H32O7SiNa:
g-Lactone 19: Yield 35%. Rf =0.34 (silica, cyclohexane/ethyl acetate
1H, H8’), 1.23 ppm (s, 9H, ACHTNUTGRNEUNG
(CH3)3C); 13C NMR (75 MHz, CDCl3): d=
1
3:1); [a]2D0 =5 (c=1.0, CHCl3); H NMR (300 MHz, CDCl3): d=7.52–7.31
178.6 (C=O), 170.4 (C=O), 138.0 (Cquat. arom.), 128.8 (CHarom.), 128.1
(CHarom.), 125.9 (CHarom.), 101.7 (C1), 100.4 (C7), 73.4 (C4), 73.3
(C3), 69.3 (C6), 65.4 (C2), 65.3 (C5), 61.5 (NOMe), 49.3 (OMe), 39.0
(m, 10H, Harom.), 5.63 (s, 1H, H7), 4.85 (s, 2H, CH2Ph), 4.56 (d, J=
5.6 Hz, 1H, H2), 4.37 (dd, J=10.3, 4.8 Hz, 1H, H6equiv), 3.99 (t, J=
9.7 Hz, 1H, H4), 3.87–3.74 (m, 2H, H3, H6ax.), 3.67 (dt, J=9.7, 4.8 Hz,
1H, H5), 3.40 (s, 3H, OMe), 2.86 (d, J=17.2 Hz, 1H, H8), 2.69 ppm (d,
J=17.2 Hz, 1H, H8’); 13C NMR (75 MHz, CDCl3): d=171.6 (C=O),
137.4 (Cquat. arom.), 136.9 (Cquat. arom.), 129.2 (CHarom.), 128.5
(CHarom.), 128.4 (CHarom.), 128.0 (CHarom.), 126.1 (CHarom.), 103.9
(C1), 101.6 (C7), 83.9 (C2), 78.8 (C3), 78.2 (C4), 73.7 (CH2Ph), 68.9 (C6),
66.4 (C5), 50.7 (OMe), 36.8 ppm (C8); IR (film): n˜ =2933, 1793, 1605,
1497, 1454, 1372, 1331, 1268, 1245, 1213, 1170, 1091, 1028 cmꢀ1; HRMS:
m/z calcd for C23H24O7Na: 435.1420; found: 435.1415.
((CH3)3C), 35.1 (C8), 32.1 (NCH3), 27.0 ppm (ACHTNUGTRNEUNG(CH3)3C); IR (film): n˜ =
3415, 2972, 2939, 1726, 1634, 1480, 1457, 1397, 1368, 1288, 1173, 1100,
1042, 1003 cmꢀ1; MS: m/z=468 [M+H+].
Phenyl 4,6-O-benzylidene-2-O-bromoacetyl-3-O-pivaloyl-1-thio-a-d-man-
nopyranoside 26: Pivaloyl chloride (1.228 mL, 10.445 mmol) was added
to a stirred solution of phenyl-4,6-O-benzylidene-1-thio-a-d-mannopyra-
noside[37] (1.506 g, 4.178 mmol) in anhydrous pyridine (30 mL) at 08C.
The reaction mixture was stirred overnight (08C to room temperature)
and quenched with methanol (2 mL) and TLC (cyclohexane/ethyl acetate
2:1) showed complete consumption of the starting material. After being
concentrated under vacuum, the residue was dissolved in dichlorome-
thane (30 mL) and washed with a saturated aqueous solution of ammoni-
um chloride (15 mL). The organic layer was dried (anhydrous magnesium
sulfate), filtered, and concentrated under vacuum. The residue was puri-
fied by silica gel chromatography (cyclohexane/ethyl acetate 3:1) to give
phenyl-4,6-O-benzylidene-3-O-pivaloyl-1-thio-a-d-mannopyranoside as a
white solid (1.578 g, 85%). Rf =0.66 (silica, cyclohexane/ethyl acetate
2:1); [a]2D0 =76 (c=1.0, CHCl3); 1H NMR (300 MHz, CDCl3): d=7.57–
7.29 (m, 10H, Harom.), 5.61 (s, 1H, H7), 5.58 (d, J=1.2 Hz, 1H, H1),
5.39 (dd, J=10.2, 3.3 Hz, 1H, H3), 4.43–4.51 (m, 2H, H2, H5), 4.31–4.18
(m, 2H, H4, H6equiv), 3.90 (t, J=10.3 Hz, 1H, H6ax.), 2.38 (br s, 1H, OH),
g-Lactone 22: Yield 80%. Rf =0.61 (silica, cyclohexane/ethyl acetate
1:1); [a]2D0 =76 (c=1.0, CHCl3); 1H NMR (300 MHz, 508C, CDCl3): d=
7.51–7.34 (m, 5H, Harom.), 5.53 (s, 1H, H7), 4.93–4.81 (m, 2H, H2, H3),
4.42 (dd, J=2.3, 1.6 Hz,1H, H4), 4.35 (dd, J=12.6, 1.5 Hz, 1H, H6), 4.09
(dd, J=12.6, 1.6 Hz, 1H, H6), 3.77 (d, J=1.5 Hz, 1H, H5), 3.47 (s, 3H,
OMe), 2.85 (d, J=17.5 Hz, 1H, H8), 2.70 (d, J=17.5 Hz, 1H, H8’),
1.24 ppm (s, 9H, ACHTUNGTRENNUNG
(CH3)3C); 13C NMR (75 MHz, CDCl3): d=178.1 (C=O),
172.0 (C=O), 137.4 (Cquat. arom.), 129.1 (CHarom.), 128.3 (CHarom.),
125.9 (CHarom.), 103.4 (C1), 100.9 (C7), 76.3 (C2), 73.2 (C3), 72.0 (C4),
69.6 (C6), 66.2 (C5), 50.3 (OMe), 38.9 ((CH3)3C), 37.4 (C8), 26.9 ppm
(ACHTUNGTRENNUNG(CH3)3C); IR (film): n˜ =2976, 2934, 2873, 1794, 1732, 1479, 1457, 1404,
1370, 1324, 1276, 1261, 1176, 1147, 1101, 1077, 1040, 1005 cmꢀ1; HRMS:
m/z calcd for C21H26O8Na: 429.1525; found: 429.1523.
1.26 ppm (s, 9H, ACTHNUTRGNEUNG
(CH3)3C); 13C NMR (75 MHz, CDCl3): d=170.3 (C=O),
137.2 (Cquat. arom.), 133.3 (Cquat. arom.), 131.9 (CHarom.), 129.2
(CHarom.), 128.9 (CHarom.), 128.2 (CHarom.), 127.8 (CHarom.), 125.9
(CHarom.), 101.5 (C7), 88.4 (C1), 76.3 (C4), 71.4 (C2), 70.6 (C3), 68.5
Weinreb amide 23:
0.4 mmol) (prepared by stirring N,O-dimethylhydroxylamine hydrochlo-
ACHTUNGTRENNUNGride (390 mg, 4 mmol) and trimethylaluminum (2 mL of a 2m solution in
A solution of Cl(Me)AlN(Me)OMe (400 mL,
toluene) in anhydrous dichloromethane (2 mL) for 30 min at 08C) was
added to a solution of lactone 7 (61 mg, 0.150 mmol) in anhydrous di-
chloromethane (1.5 mL) at 08C. After being stirred for 20 min, TLC (cy-
clohexane/ethylacetate 1:1) showed complete consumption of the starting
material. The reaction mixture was quenched with a 1m solution of Ro-
chelleꢂs salt (5 mL), diluted with dichloromethane (10 mL) and stirred
for 1 hour at room temperature. The organic layer was separated, dried
(anhydrous magnesium sulfate), filtered and concentrated under vacuum
to give 23 (73 mg, 99%). Rf =0.26 (silica, cyclohexane/ethyl acetate 2:1);
(C6), 65.1 (C5), 39.1 ((CH3)3C), 27.2 ppm (ACHTNUTRGNE(UNG CH3)3C); IR (film): n˜ =3365,
2970, 1738, 1476, 1268, 1099, 1083; HRMS: m/z calcd for C24H28O6NaS:
467.1499; found: 467.1502.
Pyridine (513 mL, 6.343 mmol) and bromoacetyl bromide (444 mL,
5.078 mmol) were added to a stirred solution of phenyl-4,6-O-benzyli-
dene-3-O-pivaloyl-1-thio-a-d-mannopyranoside (1.129 g, 2.539 mmol) in
anhydrous dichloromethane (20 mL) at 08C. After the mixture had been
stirred for 20 min at 08C, TLC (cyclohexane/ethyl acetate 5:1) showed
complete consumption of the starting material, and methanol (1 mL) was
added. The reaction mixture was diluted with dichloromethane (20 mL)
and washed with a saturated aqueous solution of ammonium chloride
(20 mL). The organic layer was dried (anhydrous magnesium sulfate), fil-
tered, and concentrated under vacuum. The residue was purified by silica
gel chromatography (cyclohexane/ethyl acetate 7:1) to give 26 as a white
foam (1.249 g, 87%). Rf =0.67 (silica, cyclohexane/ethyl acetate 5:1);
1
[a]2D0 =12 (c=1.0, CHCl3); H NMR (300 MHz, CDCl3): d=7.45–7.34 (m,
5H, Harom.), 5.59 (s, 1H, H7), 5.40 (dd, J=10.4, 3.4 Hz, 1H, H3), 4.36–
4.06 (m, 4H, H2, H4, H6, OH), 3.87 (t, J=10.2 Hz, 1H, H6’), 3.79–3.61
(m, 4H OMe, H5), 3.46–3.11 (m, 7H, OMe, NMe, H8), 2.81 (d, J=
14.6 Hz, 1H, H8’), 1.26 ppm (s, 9H, ACHTUNGTRNEUNG
(CH3)3C); 13C NMR (75 MHz,
CDCl3): d=177.6 (C=O), 169.5 (C=O), 137.4 (Cquat. arom.), 128.8
(CHarom.), 128.2 (CHarom.), 125.9 (CHarom.), 103.0 (C1), 101.2 (C7),
75.5 (C4), 70.6 (C2), 70.0 (C3), 68.7 (C6), 65.1 (C5), 61.6 (OMe), 48.4
1
[a]2D0 =84 (c=1.0, CHCl3); H NMR (300 MHz, CDCl3): d=7.54–7.34 (m,
10H, Harom.), 5.74 (dd, J=3.4, 1.4 Hz, 1H, H2), 5.68 (s, 1H, H7), 5.53
(dd, J=10.2, 3.4 Hz, 1H, H3), 5.51 (d, J=1.4 Hz, 1H, H1), 4.53 (td, J=
10.2, 4.8 Hz, 1H, H5), 4.32 (dd, J=10.3, 4.8 Hz, 1H, H6equiv), 4.23 (t, J=
10.2 Hz, 1H, H4.), 3.97–3.20 (m, 3H, H8, H8’, H6ax.), 1.25 ppm (s, 9H,
(OMe), 39.0 ((CH3)3C), 33.2 (C8), 32.0 (NMe), 27.2 ppm (ACHTUNTRGNEUNG(CH3)3C); IR
(film): n˜ =3441, 2970, 1731, 1645, 1457, 1385, 1284, 1163, 1097, 1030 cmꢀ1
;
HRMS: calcd for C23H33NO9Na: 490.2047; found: 490.2048.
AHCTUNGTRENNUNG
(CH3)3C); 13C NMR (75 MHz, CDCl3): d=177.2 (C=O), 166.1 (C=O),
Weinreb amide 24: Yield 98%. Rf =0.27 (silica, cyclohexane/ethyl acetate
2:1); [a]2D0 =ꢀ8 (c=1.0, CHCl3); 1H NMR (300 MHz, CDCl3): d=7.50–
7.30 (m, 5H, Harom.), 5.54 (s, 1H, H7), 5.23 (dd, J=8.2, 6.9 Hz, 1H,
H3), 5.09 (d, J=4.3 Hz, 1H, OH), 4.38 (dd, J=9.9, 3.6 Hz, 1H, H6), 3.97
(t, J=6.9 Hz, 1H, H4), 3.93–3.80 (m, 2H, H2, H5), 3.79–3.67 (m, 4H,
H6’, OMe), 3.42 (s, 3H, OMe), 3.33–3.04 (m, 5H, NMe, 2ꢆH8),
137.1 (Cquat. arom.), 132.7 (Cquat. arom.), 132.4 (CHarom.), 129.4
(CHarom.), 129.1 (CHarom.), 128.4 (CHarom.), 128.3 (CHarom.), 126.0
(CHarom.), 101.5 (C7), 86.7 (C1), 76.4 (C4), 73.4 (C2), 68.4 (C3 and C6),
65.4 (C5) 39.0 ((CH3)3C), 27.1 (ACHTNUTGRENUNG(CH3)3C), 25.2 ppm (C8); IR (film): n˜ =
2972, 1736, 1478, 1264, 1139, 1100, 1084 cmꢀ1; HRMS: m/z calcd for
C26H29O779BrNaS: 587.0710; found: 587.0708.
1.23 ppm (s, 9H, ACHTUNGTRENNUNG
(CH3)3C); 13C NMR (75 MHz, CDCl3): d=178.2 (C=O),
170.1 (C=O), 137.1 (Cquat. arom.), 129.0 (CHarom.), 128.2 (CHarom.),
126.0 (CHarom.), 102.1 (C1), 101.3 (C7), 78.9 (C4), 74.3 (C3), 73.0 (C2),
69.3 (C6), 65.3 (C5), 61.6 (OMe), 49.1 (OMe), 38.9 ((CH3)3C), 35.2 (C8),
Methyl 2,3,4-tri-O-methyl-a-d-glucopyranoside 27: Anhydrous pyridine
(6.1 mL,
74.948 mmol)
and
triphenylmethylchloride
(18.282 g,
65.579 mmol) was added to a stirred suspension of methyl-a-d-glucopyra-
32.2 (NMe), 27.2 ppm (
G
noside (12.128 g, 62.457 mmol) in DMF (60 mL) at room temperature.
6060
www.chemeurj.org
ꢃ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 6052 – 6066

Carbene-Mediated Functionalization
FULL PAPER
1
After being stirred for 18 h, methanol (2 mL) was added and the reaction
mixture was concentrated under vacuum. Methyl iodide (17.5 mL,
281.104 mmol) and sodium hydride (60% in mineral oil, 6.745 g,
281.104 mmol) were then added portion wise at 08C to a solution of the
residue in DMF (250 mL). After the mixture had been stirred for 18 h at
room temperature, methanol was added (20 mL) and the reaction mix-
ture was concentrated under vacuum. The residue was dissolved in di-
chloromethane (400 mL) and washed with a saturated aqueous solution
of ammonium chloride (200 mL). The organic layer was dried (anhydrous
magnesium sulfate), filtered, and concentrated under vacuum. The resi-
due was dissolved in a 4:1 mixture of acetic acid and water (200 mL) and
heated for 4 h at 408C. The reaction mixture was filtered to remove the
precipitate, and concentrated under vacuum. The residue was dissolved
in dichloromethane (400 mL) and washed with a saturated aqueous solu-
tion of sodium hydrogen carbonate (20 mL). The organic layer was dried
(anhydrous magnesium sulfate), filtered, and concentrated under
vacuum. The residue was purified by silica gel chromatography (ethyl
acetate) to give 27 as a pale yellow viscous liquid (7.3 g, 50%). Rf =0.28
(silica, cyclohexane/ethyl acetate 1:1); [a]2D0 =158 (c=1.0, CHCl3);
1H NMR (300 MHz, CDCl3): d=4.82 (d, J=3.6 Hz, 1H, H1), 3.85 (dd,
J=11.8, 2.9 Hz, 1H, H6), 3.74 (dd, J=11.8, 2.9 Hz, 1H, H6’), 3.65 (s, 3H,
OMe), 3.61–3.48 (m, 8H, H3, H5, 2ꢆOMe), 3.42 (s, 3H, OMe), 3.14–3.21
(m, 2H, H2, H4), 2.58 ppm (m, 1H, OH). 13C NMR (75 MHz, CDCl3):
d=97.5 (C1), 83.4 (C3), 81.8 (C2), 79.5 (C4), 70.6 (C5), 61.8 (C6), 60.9
(OMe), 60.6 (OMe), 59.0 (OMe), 55.1 ppm (OMe); IR (film): n˜ =3471,
2932, 2833, 1190, 1159, 1098, 1051, 1002 cmꢀ1; HRMS: m/z calcd for
C10H20O6Na: 259.1152; found: 252.1154.
[a]2D0 =68 (c=1.0, CHCl3); H NMR (300 MHz, CDCl3): d=7.45–7.39 (m,
5H, Harom.), 5.62 (s, 1H, H7), 5.53–5.43 (m, 2H, H2B, H3B), 4.92 (d,
J=1.2 Hz, 1H, H1B), 4.79 (d, J=3.6 Hz, 1H, H1A), 4.34 (dd, J=10.1,
4.0 Hz, 1H, H6B), 4.12–4.01 (m, 2H, H4B, H5B), 3.96–3.84 (m, 4H, 2ꢆ
H6A, 2ꢆH8B), 3.71 (dd, J=11.2, 1.8 Hz, 1H, H6B), 3.67–3.61 (m, 4H,
OMe, H5A), 3.58 (s, 3H, OMe), 3.57–3.47 (m, 4H, OMe, H3A) 3.42 (s,
3H, OMe), 3.24 (dd, J=9.6, 3.6 Hz, 1H, H2A), 3.14 (dd, J=10.0, 8.9 Hz,
1H, H4A), 1.19 ppm (s, 9H, ACHTNUTGRNEUNG
(CH3)3C); 13C NMR (75 MHz, CDCl3): d=
177.1 (C=O), 166.1 (C=O), 137.1 (Cquat. arom.), 129.0 (CHarom.), 128.2
(CHarom.), 125.9 (CHarom.), 101.5 (C7B), 98.5 (C1B), 97.4 (C1A), 83.6
(C3A), 81.7 (C2A), 79.4 (C4A), 71.8 (C4B), 69.7 (C5A), 68.7 (C6B),
68.0 (C3B), 66.6 (C6A), 64.0 (C5B), 60.8 (OMe), 60.7 (OMe), 59.1
(OMe), 55.3 (OMe), 38.9 ((CH3)3C), 27.1 (ACTHNUGTRNEG(UN CH3)3C), 25.2 ppm (C8B); IR
(film): n˜ =2932, 1737, 1375, 1282, 1099 cmꢀ1; HRMS: m/z calcd for
C30H43O1379BrNa: 713.1779; found: 713.1777.
Methyl (4,6-O-benzylidene-2-O-diazoacetyl-3-O-pivaloyl-a-d-mannopyra-
noside)-(1!6)-2,3,4-O-methyl-a-d-glucopyranoside 30: 1,8-Diazabicyclo-
AHCTUNGERTG[NNUN 5.4.0]undec-7-ene (374 mL, 2.5 mmol) was added to a solution of 29
(346 mg, 0.5 mmol) and N,N’-ditosylhydrazine (341 g, 1 mmol) in distilled
tetrahydrofuran (4 mL) at 08C. After TLC analysis showed complete
consumption of the starting material (cyclohexane/ethyl acetate 1:1), a
saturated aqueous solution of sodium hydrogen carbonate (10 mL) and
dichloromethane (20 mL) were added, and the organic layer was dried
(anhydrous magnesium sulfate), filtered and concentrated under vacuum.
The residue was purified by silica gel chromatography (cyclohexane/ethyl
acetate 1.5:1) to give 30 as a bright yellow oil (269 mg, 84%). Rf =0.46
(silica, cyclohexane/ethyl acetate 1:1); [a]2D0 =58 (c=1.0, CHCl3);
1H NMR (300 MHz, CDCl3): d=7.45–7.33 (m, 5H, Harom.), 5.60 (s, 1H,
H7B), 5.49 (dd, J=3.6, 1.2 Hz, 1H, H2B), 5.42 (dd, J=9.7, 3.6 Hz, 1H,
H3B), 4.93 (d, 4.90, J=1.2 Hz, 1H, H1B), 4.90 (br s, 1H, H8B), 4.79 (d,
J=3.6 Hz, 1H, H1A), 4.32 (dd, J=10.1, 4.3 Hz, 1H, H6B), 4.11–3.94 (m,
2H, H5B, H6A), 3.87 (m, 2H, H4B, H6A), 3.70 (dd, J=10.1, 1.7 Hz,
1H, H6B), 3.68–3.37 (m, 14H, 4ꢆOMe, H3A, H5A), 3.24 (dd, J=9.6,
3.6 Hz, 1H, H2A), 3.14 (t, J=9.1 Hz, 1H, H4A), 1.19 ppm (s, 9H,
Methyl (4,6-O-benzylidene-2-O-bromoacetyl-3-O-pivaloyl-a-d-mannopyr-
anoside)-(1!6)-2,3,4-O-methyl-a-d-glucopyranoside 29: A solution of 26
(264 mg, 1.117 mmol) and 27 (486 mg, 0.859 mmol) in distilled dichloro-
methane (8 mL) were stirred for 1 hour at room temperature over acti-
vated 4 ꢄ MS (700 mg). N-iodosuccinimide (NIS, 387 mg, 1.720 mmol)
was added, and after cooling to ꢀ208C, trifluoromethanesulfonic acid
(23 mL, 0.258 mmol) was added dropwise. After being stirred for 30 min
at ꢀ208C, the reaction mixture became dark brown. A saturated aqueous
solution of sodium hydrogen carbonate (8 mL) was added, followed by a
saturated aqueous solution of sodium thiosulfate (8 mL). The colorless
reaction mixture was then diluted with dichloromethane (20 mL) and fil-
tered through a Celite pad. The organic layer was dried (anhydrous mag-
nesium sulfate), filtered, and concentrated under vacuum. The residue
was purified by silica gel chromatography (cyclohexane/ethyl acetate
1.5:1) to give a 1:1 mixture of disaccharide 29 and orthoester 28 (a
sample of which was collected in a pure form for complete characteriza-
tion) as a white foam (514 mg, 87%). Orthoester 28: Rf =0.48 (silica, cy-
clohexane/ethyl acetate 1:1); [a]2D0 =12 (c=1.0, CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.50–7.31 (m, 5H, Harom.), 5.63 (s, 1H, H7B),
5.57 (d, J=2.2 Hz, 1H, H1B), 5.13 (dd, J=9.9, 4.1 Hz, 1H, H3B), 4.84
(d, J=3.4 Hz, 1H, H1A), 4.78 (dd, J=4.1, 2.2 Hz, 1H, H2B), 4.37 (dd,
J=10.7, 5.2 Hz, 1H, H6B), 4.05 (t, J=9.9 Hz, 1H, H4B), 3.56 (m, 21H,
H3A, H4A, H5A, H5B, 2ꢆH6A, H6B, 2ꢆH8A, 4ꢆOMe), 3.23 (dd, J=
AHCTUNGTRENNUNG
(CH3)3C); 13C NMR (75 MHz, CDCl3): d=177.1 (C=O), 165.6 (C=O),
137.2 (Cquat. arom.), 128.9 (CHarom.), 128.2 (CHarom.), 125.9
(CHarom.), 101.4 (C7B), 98.9 (C1B), 97.4 (C1A), 83.6 (C3A), 81.7
(C2A), 79.4 (C4A), 76.7 (C4B), 70.3 (C2B), 69.7 (C5A), 68.8 (C6B),
68.1 (C3B), 66.5 (C6A), 63.8 (C5B), 60.8 (OMe), 60.7 (OMe), 59.1
(OMe), 55.3 (OMe), 46.3 (C8B), 38.9 ((CH3)3C), 27.0 ppm (ACHTUNTRGNEUNG(CH3)3C); IR
(film): n˜ =2933, 2114, 1736, 1700, 1382, 1282, 1143, 1099 cmꢀ1; HRMS:
m/z calcd for C30H42N2O13Na: 661.2579; found: 661.2581.
g-Lactone 31: A solution of 30 (120 mg, 0.190 mmol) in anhydrous 1,2-di-
chloroethane (2 mL) was added dropwise through
a syringe pump
(20 mmolhꢀ1) to a suspension of [Rh
CTHUNGTRENNUNG
drous 1,2-dichloroethane (25 mL) heated at reflux. After the end of the
addition, the reaction mixture was cooled to room temperature and con-
centrated under vacuum. The residue was purified by silica gel chroma-
tography (cyclohexane/ethylacetate 3:2) to give 31 as a colorless solid
(78 mg, 65%). Rf =0.51 (silica, cyclohexane/ethyl acetate 1:1); [a]2D0 =11
(c=1.0, CHCl3); 1H NMR (300 MHz, CDCl3): d=7.53–7.32 (m, 5H,
Harom.), 5.59 (s, 1H, H7B), 5.32 (dd, J=9.8, 4.0 Hz, 1H, H3B), 4.81 (d,
J=4.0 Hz, 1H, H2B), 4.80 (d, J=3.6 Hz, 1H, H1A), 4.31 (dd, J=10.2,
4.7 Hz, 1H, H6B), 4.07 (t, J=9.8 Hz, 1H, H4B), 3.97 (dt, J=9.8, 4.7 Hz,
1H, H5B), 3.84 (m, 2H, H6A, H6B), 3.68–3.48 (m, 12H, 3ꢆOMe, H6A,
H3A, H5A), 3.43 (s, 3H OMe), 3.20 (dd, J=9.6, 3.6 Hz, 1H, H2A), 3.11
(dd, J=10.0, 8.9 Hz, 1H, H4A), 2.83 (br s, 2H, H8B), 1.25 ppm (s, 9H,
9.6, 3.4 Hz, 1H, H2A), 1.26 ppm (s, 9H, ACTHNUTRGNEUNG
(CH3)3C); 13C NMR (75 MHz,
CDCl3): d=178.0 (C=O), 136.9 (Cquat. arom.), 129.1 (CHarom.), 128.3
(CHarom.), 125.9 (CHarom.), 121.6 (C9B), 101.2 (C7B), 97.61 (C1),
97.59 (C1), 83.7 (C3A), 81.6 (C4A), 78.7 (C2A), 77.9 (C2B), 74.9 (C4B),
70.0 (C3B), 69.0 (C5), 68.4 (C6B), 65.2 (C5), 61.0 (OMe), 60.7 (OMe),
60.5 (C6A), 59.1 (OMe), 55.2 (OMe), 39.0 ((CH3)3C), 34.1 (C8B),
27.0 ppm
(ACHTUNGTRENNUNG(CH3)3C); IR (film): n˜ =2930, 1734, 1280, 1160, 1102,
1061 cmꢀ1; HRMS: m/z calcd for C30H43O1379BrNa: 713.1779; found:
AHCTUNGTRENNUNG
(CH3)3C); 13C NMR (75 MHz, CDCl3): d=177.9 (C=O), 171.6 (C=O),
713.1781.
136.9 (Cquat. arom.), 129.1 (CHarom.), 128.3 (CHarom.), 125.9
(CHarom.), 103.6 (C1B), 101.4 (C7B), 97.5 (C1A), 83.6 (C3A), 81.9
(C2A), 79.2 (C4A), 78.9 (C2B), 74.7 (C4B), 69.1 (C5A), 68.3 (C3B),
68.2 (C6B), 64.7 (C5B), 63.9 (C6A), 60.8 (OMe), 60.6 (OMe), 59.1
A solution of the 1:1 mixture of 28 and 29 (468 mg, 0.677 mmol) in distil-
led dichloromethane (10 mL) was stirred for 1 hour over activated 4 ꢄ
MS (500 mg). After cooling to 08C, trimethylsilyl trifluoromethanesulfo-
nate (25 mL, 0.138 mmol) was added dropwise to give a bright yellow sol-
ution. After 20 min, TLC analysis (cyclohexane/ethyl acetate 1:1) showed
complete conversion of 28 to 29. The reaction mixture was quenched
with triethylamine (0.5 mL), filtered through a Celite pad, and concen-
trated under vacuum. The residue was purified by silica gel chromatogra-
phy (cyclohexane/ethyl acetate 1.5:1) to give 29 as a white foam (346 mg,
74%). TLC analysis: Rf =0.52 (silica, cyclohexane/ethyl acetate 1:1);
(OMe), 55.4 (OMe), 40.9 (C8B), 39.0 ((CH3)3C), 27.0 ppm (ACHTUNTRGNEUNG(CH3)3C); IR
(film): n˜ =2935, 1804, 1735, 1281, 1155, 1099 cmꢀ1; HRMS: m/z calcd for
C23H33NO9Na: 633.2518; found: 633.2519.
Methyl (4,6-O-benzylidene-2-O-diazoacetyl-3-O-pivaloyl-a-d-mannopyra-
noside)-(1!2)-4,6-O-benzylidene-3-O-acetyl-a-d-glucopyranoside 34: A
solution of donor 26 (109 mg, 0.193 mmol) and acceptor 33 (65 mg,
Chem. Eur. J. 2013, 19, 6052 – 6066
ꢃ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6061

T. Lecourt et al.
0.251 mmol) in distilled dichloromethane (3.5 mL) was stirred for 1 hour
at room temperature over activated 4 ꢄ MS (175 mg). NIS (87 mg,
0.386 mmol) was added, and after cooling to ꢀ208C, trifluoromethanesul-
fonic acid (5 mL, 0.058 mmol) was added dropwise. After being stirred for
2 h at ꢀ208C, the reaction mixture became dark-brown. A saturated
aqueous solution of sodium hydrogen carbonate (5 mL) was added, fol-
lowed by a saturated aqueous solution of sodium thiosulfate (3 mL). The
colorless reaction mixture was then diluted with dichloromethane
(10 mL) and filtered through a Celite pad. The organic layer was dried
(anhydrous magnesium sulfate), filtered, and concentrated under
vacuum. The residue was purified for complete characterization by silica
gel chromatography (dichloromethane/ethyl acetate 24:1) to give the di-
residue was purified for full characterization by silica gel chromatography
(dichloromethane/ethyl acetate 24:1) to give the disaccharide as a white
foam (35 mg, 67%). Rf =0.24 (silica, cyclohexane/ethyl acetate 3:1);
[a]2D0 =ꢀ19 (c=1.0, CHCl3); 1H NMR (300 MHz, CDCl3): d=7.52–7.32
(m, 10H, Harom.), 5.64 (s, 1H, H7A or H7B), 5.62 (s, 1H, H7A or
H7B), 5.58–5.47 (m, 2H, H2B, H3B), 5.29 (dd, J=10.3, 3.3 Hz, 1H,
H3A), 4.87 (d, J=1.1 Hz, 1H, H1B), 4.71 (d, J=1.3 Hz, 1H, H1A),
4.34–4.22 (m, 2H, H6A, H6B), 4.18–4.02 (m, 4H, H2A, H4B, H5A,
H5B), 3.99–3.81 (m, 5H, H4A, H6A, H6B, H8B), 3.40 (s, 3H, OMe),
2.10 (s, 3H, (CH3)C=O), 1.22 ppm (s, 9H, ACTHNUTRGNEUNG
(CH3)3C); 13C NMR (75 MHz,
CDCl3): d=177.4 (C=O), 170.4 (C=O), 166.1 (C=O), 137.2 (Cquat.
arom.), 136.9 (Cquat. arom.), 129.0 (2ꢆCHarom.), 128.2 (2ꢆCHarom.),
126.2 (CHarom.), 125.7 (CHarom.), 101.8 (C7A or C7B), 101.3 (C7A or
C7B), 100.4 (C1A), 100.3 (C1B), 77.2 (C2A), 76.1 (C5A or C5B), 75.9
(C5A or C5B), 71.6 (C2B), 70.0 (C3A), 68.6 (C6A or C6B), 68.3 (C6A
or C6B), 67.7 (C3B), 64.4 (C4B), 63.7 (C4A), 55.0 (OMe), 39.0
ACHTUNGTRENNUNGsaccharide as a white foam (130 mg, 87%). Rf =0.64 (silica, cyclohexane/
ethyl acetate 1:1); [a]D20 =46 (c=1.0, CHCl3); 1H NMR (300 MHz,
CDCl3): d=7.50–7.31 (m, 10H, Harom.), 5.65–5.54 (m, 2H, H3A, H7A
or H7B), 5.49 (s, 1H, H7A or H7B), 5.46–5.36 (m, 2H, H2B, H3B), 4.93
(d, J=1.1 Hz, 1H, H1B), 4.91 (d, J=3.5 Hz, 1H, H1A), 4.38–4.27 (m,
2H, H6A, H6B), 4.11–4.02 (m, 2H, H6A, H6B), 4.00–3.81 (m, 5H,
H2A, H5A, H6B, 2ꢆH8B), 3.75 (t, J=10.2 Hz, 1H, H6A), 3.59 (t, J=
9.6 Hz, 1H, H4A), 3.47 (s, 3H, OMe), 2.13 (s, 3H, (CH3)C=O), 1.18 ppm
((CH3)3C), 27.0 (ACTHUNRGTENUNG(CH3)3C), 24.9 (C8B), 20.9 ppm ((CH3)C=O); IR (film):
n˜ =2972, 2929, 2868, 1739, 1457, 1372, 1276, 1267, 1232, 1129, 1097, 1064,
1028 cmꢀ1; HRMS: m/z calcd for C36H43N2O1479BrNa: 801.17284; found:
801.1726.
(s, 9H, ACHTUNGTRENNUNG
(CH3)3C); 13C NMR (75 MHz, CDCl3): d=176.7 (C=O), 169.5
1,8-DiazabicycloACHTNUTGRNEUNG[5.4.0]undec-7-ene (33 mL, 224.47 mmol) was added to a
(C=O), 166.1 (C=O), 137.0 (Cquat. arom.), 136.9 (Cquat. arom.), 129.0
(CHarom.), 128.9 (CHarom.), 128.2 (2ꢆCHarom.), 126.1 (CHarom.),
125.8 (CHarom.), 101.5 (C7A and C7B), 97.4 (C1A), 95.9 (C1B), 79.5
(C4A), 76.1 (C5B), 74.5 (C2A), 72.0 (C2B), 69.4 (C3A), 68.9 (C6A),
68.4 (C6B), 67.4 (C3B), 64.3 (C4B), 62.4 (C5A), 55.6 (OMe), 38.8
solution of the disaccharide (35 mg, 44.894 mmol) and N,N’-ditosylhydra-
zine (31 mg, 89.788 mmol) in distilled tetrahydrofuran (3 mL) at 08C.
After TLC analysis showed complete consumption of the starting materi-
al (cyclohexane/ethyl acetate 5:1),
a saturated aqueous solution of
sodium hydrogen carbonate (2 mL) and dichloromethane (5 mL) were
added, and the organic layer was dried (anhydrous magnesium sulfate),
filtered and concentrated under vacuum. The residue was purified by
silica gel chromatography (dichloromethane/ethyl acetate 24:1) to give 35
as a bright-yellow oil (26 mg, 81%). Rf =0.63 (silica, cyclohexane/ethyl
acetate 1:1); [a]2D0 =ꢀ37 (c=1.0, CHCl3); 1H NMR (300 MHz, CDCl3):
d=7.54–7.31 (m, 10H, Harom.), 5.63 (s, 2H, H7A, H7B), 5.56–5.46 (m,
2H, H2B, H3B), 5.28 (dd, J=10.3, 3.4 Hz, 1H, H3A), 4.90 (br s, 2H,
H1B, H8B), 4.71 (d, J=1.5 Hz, 1H, H1A), 4.33–4.24 (m, 2H, H6A,
H6B), 4.18–3.99 (m, 4H, H2A, H4A, H4B, H5B), 3.92–3.79 (m, 3H,
H5A, H6A, H4B, H6B), 3.40 (s, 3H, OMe), 2.12 (s, 3H, CH3C=O),
((CH3)3C), 27.0 (ACHTUNGTRENNUNG(CH3)3C), 25.1 (C8B), 21.0 ppm ((CH3)C=O); IR (film):
n˜ =2976, 2929, 2868, 1740, 1457, 1372, 1276, 1261, 1228, 1125, 1098, 1074,
1038 cmꢀ1; HRMS: m/z calcd for C36H43N2O1479BrNa: 801.17284; found:
801.1728.
1,8-DiazabicycloACHTUNGTRENNUNG[5.4.0]undec-7-ene (280 mL, 1.860 mmol) was added to a
solution of the disaccharide (290 mg, 0.372 mmol) and N,N’-ditosylhydra-
zine (253 mg, 0.744 mmol) in distilled tetrahydrofuran (25 mL) at 08C.
After TLC analysis showed complete consumption of the starting materi-
al (dichloromethane/ethyl acetate 15:1), a saturated aqueous solution of
sodium hydrogen carbonate (15 mL) and dichloromethane (20 mL) were
added, and the organic layer was dried (anhydrous magnesium sulfate),
filtered and concentrated under vacuum. The residue was purified by
silica gel chromatography (dichloromethane/ethyl acetate 15:1) to give 34
as a bright yellow oil (200 mg, 74%). Rf =0.53 (silica, cyclohexane/ethyl
acetate 1:1); [a]2D0 =25 (c=1.0, CHCl3); 1H NMR (300 MHz, CDCl3): d=
7.49–7.31 (m, 10H, Harom.), 5.66–5.55 (m, 2H, H7A or H7B, H3A),
5.50 (s, 1H, H7A or H7B), 5.45–5.33 (m, 2H, H2B, H3B), 4.97 (br s, 2H,
H1B, H8B), 4.92 (d, J=3.4 Hz, 1H, H1A), 4.38–4.27 (m, 2H, H6A,
H6B), 4.11–3.79 (m, 5H, H2A, H5A, H4B, H5B, H6B), 3.75 (t, J=
10.3 Hz, 1H, H6A), 3.59 (t, J=9.6 Hz, 1H, H4A), 3.47 (s, 3H, OMe),
1.23 ppm (s, 9H, ACTHNUTRGNEUNG
(CH3)3C); 13C NMR (75 MHz, CDCl3): d=177.3 (C=O),
170.5 (C=O), 137.3 (Cquat. arom.), 137.0 (Cquat. arom.), 129.0
(CHarom.), 128.2 (2ꢆCHarom.), 126.2 (CHarom.), 126.0 (CHarom.),
125.8 (CHarom.), 101.8 (C7A or C7B), 101.3 (C7A or C7B), 100.9
(C1B), 100.5 (C1A), 77.2 (C2A), 76.3 (C4B), 75.9 (C4A), 70.2 (C2B),
70.0 (C3A), 68.7 (C6A or C6B), 68.4 (C6A or C6B), 67.8 (C3B), 64.2
(C5B), 63.7 (C5A), 55.0 (OMe), 46.2 (C8B), 38.9 ((CH3)3C), 26.9
(ACHTUNRTGNEUNG(CH3)3C), 20.9 ppm (CH3C=O); IR (film): n˜ =2974, 2933, 2868, 2116,
1738, 1705, 1457, 1380, 1277, 1261, 1236, 1133, 1098, 1064, 1029 cmꢀ1
;
HRMS: m/z calcd for C36H42N2O14Na: 749.25282; found: 749.2530.
2.13 (s, 3H, CH3C=O), 1.19 ppm (s, 9H, ACTHNUTRGNEUNG
(CH3)3C); 13C NMR (75 MHz,
g-Lactone 36: a solution of 34 (60 mg, 82.563 mmol) in anhydrous 1,2-di-
chloroethane (5 mL) was added dropwise through syringe pump
(0.01 mmolhꢀ1) to a suspension of [Rh
2A(OAc)4] (0.73 mg, 1.651 mmol) in
CDCl3): d=176.6 (C=O), 169.5 (C=O), 165.7 (C=O), 137.0 (Cquat.
arom.), 136.9 (Cquat. arom.), 128.9 (CHarom.), 128.8 (CHarom.), 128.1
(CHarom.), 126.1 (CHarom.), 125.7 (CHarom.), 101.4 (C7A and C7B),
97.4 (C1A), 96.5 (C1B), 79.4 (C4A), 76.1 (C4B), 74.5 (C2A), 70.4
(C2B), 69.4 (C3A), 68.8 (C6A), 68.4 (C6B), 67.5 (C3B), 64.0 (C5B), 62.3
a
CTHUNGTRENNUNG
anhydrous 1,2-dichloroethane (30 mL) heated at reflux. After the end of
the addition, the reaction mixture was cooled to room temperature and
concentrated under vacuum. The residue was purified by silica gel chro-
matography (cyclohexane/ethyl acetate 2.5:1) to give 36 as a white foam
(34 mg, 60%). Rf =0.52 (silica, cyclohexane/ethyl acetate 1:1); [a]2D0 =ꢀ1
(c=1.0, CHCl3); 1H NMR (300 MHz, CDCl3): d=7.49–7.32 (m, 10H,
Harom.), 5.63–5.54 (m, 2H, H3A, H7A or H7B), 5.50 (s, 1H, H7A or
H7B), 5.25 (dd, J=9.8, 3.9 Hz, 1H, H3B), 4.79 (d, J=3.9 Hz, 1H, H2B),
4.76 (d, J=3.6 Hz, 1H, H1A), 4.39–4.28 (m, 2H, H6A and H6B), 4.06 (t,
J=9.8 Hz, 1H, H4B), 4.02–3.78 (m, 4H, H2A, H5A, H5B, H6B), 3.76 (t,
J=10.2 Hz, 1H, H6A), 3.62 (t, J=9.6 Hz, 1H, H4A), 3.44 (s, 3H, OMe),
2.78 (d, J=15.9 Hz, 1H, H8B), 2.70 (d, J=15.9 Hz, 1H, H8B), 2.18 (s,
(C5A), 55.6 (OMe), 46.3 (C8B), 38.7 ((CH3)3C), 26.8
(ACHTNGUTERNNU(G CH3)3C),
20.9 ppm (CH3C=O); IR (film): n˜ =2974, 2932, 2868, 2117, 1753, 1737,
1699, 1457, 1379, 1278, 1229, 1148, 1096, 1073, 1038 cmꢀ1; HRMS: m/z
calcd for C36H42N2O14Na: 749.25282; found: 749.2528.
Methyl (4,6-O-benzylidene-2-O-diazoacetyl-3-O-pivaloyl-a-d-mannopyra-
noside)-(1!2)-4,6-O-benzylidene-3-O-acetyl-a-d-mannopyranoside 35:
A solution of donor 26 (32 mg, 67.20 mmol) and acceptor 32 (28 mg,
87.36 mmol) in distilled dichloromethane (1.5 mL) was stirred for 1 hour
at room temperature over activated 4 ꢄ MS (75 mg). NIS (30 mg, 134.4
mmol) was added, and after cooling to ꢀ208C, trifluoromethanesulfonic
acid (1.8 mL, 20.16 mmol) was added dropwise. After being stirred for
45 min at ꢀ208C, the reaction mixture became dark-brown. A saturated
aqueous solution of sodium hydrogen carbonate (2 mL) was added, fol-
lowed by a saturated aqueous solution of sodium thiosulfate (2 mL). The
colorless reaction mixture was then diluted with dichloromethane (5 mL)
and filtered through a Celite pad. The organic layer was dried (anhy-
drous magnesium sulfate), filtered, and concentrated under vacuum. The
3H, CH3C=O), 1.22 ppm (s, 9H, ACHTNUGRTNEUNG
(CH3)3C); 13C NMR (75 MHz, CDCl3):
d=177.3 (C=O), 171.0 (C=O), 169.4 (C=O), 136.8 (Cquat. arom.), 136.7
(Cquat. arom.), 129.1 (2ꢆCHarom.), 128.2 (2ꢆCHarom.), 126.1
(CHarom.), 125.8 (CHarom.), 102.3 (C1B), 101.6 (C7A and C7B), 98.2
(C1A), 79.3 (C4A), 79.1 (C2B), 74.4 (C4B), 71.5 (C2A), 69.2 (C3A),
68.7 (C6A), 67.8 (C6B), 67.4 (C3B), 65.1 (C5B), 62.3 (C5A), 55.2
(OMe), 42.4 (C8B), 38.9 ((CH3)3C), 27.0 (
ACHTNUGTRENN(UGN CH3)3C), 20.9 ppm (CH3C=
O); IR (film): n˜ =3010, 2974, 2926, 2853, 1788, 1755, 1734, 1450, 1371,
6062
www.chemeurj.org
ꢃ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 6052 – 6066

Carbene-Mediated Functionalization
FULL PAPER
1276, 1261, 1231, 1183, 1130, 1099, 1071, 1043, 1012 cmꢀ1; HRMS: m/z
calcd for C36H42O14Na: 721.24668; found: 721.2467.
tate 3:1); [a]2D0 =ꢀ30 (c=1.0, CHCl3); 1H NMR (300 MHz, CDCl3): d=
7.55–7.46 (m, 2H, Harom.), 7.42–7.31 (m, 3H, Harom.), 5.57 (s, 1H,
H7B), 5.53 (d, J=5.0 Hz, 1H, H1A), 5.25 (d, J=2.6 Hz, 1H, H2B), 4.85
(br s, 2H, H1B, H8B), 4.64 (dd, J=7.9, 2.4 Hz, 1H, H3A), 4.32 (dd, J=
5.0, 2.4 Hz, 1H, H2A), 4.31–4.16 (m, 3H, H3B, H4A, H6A), 4.00 (t, J=
6.2 Hz, 1H, H5B), 3.89 (dd, J=9.5, 4.4 Hz, 1H, H5A), 3.84–3.66 (m, 4H,
H4B, H6A, 2ꢆH6B), 1.56 (s, 3H, CH3), 1.45 (s, 3H, CH3), 1.36 (s, 3H,
Decomposition of diazo-sugar 35: A solution of 35 (25 mg, 34.40 mmol) in
anhydrous 1,2-dichloroethane (5 mL) was added dropwise through a sy-
ringe pump (5 mmolhꢀ1
) to a suspension of [Rh2ACHTUGNTREN(NNGU OAc)4] (0.30 mg,
0.688 mmol) in anhydrous 1,2-dichloroethane (20 mL) heated at reflux.
After the end of the addition, the reaction mixture was cooled to room
temperature and concentrated under vacuum. The residue was a complex
mixture, which was purified by silica gel chromatography (dichlorome-
thane/ethyl acetate 24:1) to give 37 as a white foam (8 mg, 36%). Rf =
0.53 (silica, cyclohexane/ethyl acetate 1:1); [a]2D0 =ꢀ6 (c=0.5, CHCl3);
1H NMR (300 MHz, CDCl3): d=7.51–7.32 (m, 10H, Harom.), 5.60 (2 s,
2H, H7A and H7B), 5.45 (dd, J=10.1, 3.3 Hz, 1H, H3B), 5.32 (dd, J=
10.2, 3.4 Hz, 1H, H3A), 4.95 (d, J=1.2 Hz, 1H, H1B), 4.74 (d, J=
1.3 Hz, 1H, H1A), 4.33–4.22 (m, 3H, H2B, H6A, H6B), 4.19–3.98 (m,
4H, H2A, H4A, H4B, H5B), 3.95–3.80 (m, 3H, H5A, H6A, H6B), 3.40
CH3), 1.35 (s, 3H, CH3), 0.85 (s, 9H, ACHTNUGTREN(UNG CH3)3C), 0.07 (s, 3H, CH3Si),
0.05 ppm (s, 3H, CH3Si); 13C NMR (75 MHz, CDCl3): d=166.0 (C=O),
137.4 (Cquat. arom.), 128.8 (CHarom.), 128.0 (CHarom.), 126.1
(CHarom.), 109.4 (Cquat. isoprop.), 108.6 (Cquat. isoprop.), 101.7 (C7B),
99.2 (C1B), 96.2 (C1A), 79.2 (C4B), 72.8 (C2B), 70.9 (C4A), 70.5 (C3A
or C2A), 70.6 (C3A or C2A), 68.7 (C6A), 68.0 (C3B), 66.9 (C6B), 66.3
(C5B), 63.7 (C5A), 46.4 (C8B), 26.1 (CH3), 25.9 (CH3), 25.6 (ACHTUNGTRENNUNG(CH3)3C),
24.9 (CH3), 24.4 (CH3), 18.1 ((CH3)3C), ꢀ4.7 (CH3Si), ꢀ5.1 ppm (CH3Si);
IR (film): n˜ =2985, 2929, 2857, 2113, 1701, 1463, 1382, 1276, 1259, 1213,
1174, 1132, 1115, 1092, 1071, 1030, 1007 cmꢀ1; HRMS: m/z calcd for
C33H48N2O12NaSi: 715.28687; found: 715.2869.
(s, 3H, OMe), 2.09 (s, 3H, CH3C=O), 1.28 ppm (s, 9H, ACHTUNTRGNEUNG(CH3)3C);
13C NMR (75 MHz, CDCl3): d=177.4 (C=O), 170.1 (C=O), 137.2 (Cquat.
arom.), 137.1 (Cquat. arom.), 129.0 (CHarom.), 128.9 (CHarom.), 128.2
(2ꢆCHarom.), 126.2 (CHarom.), 125.8 (CHarom.), 102.4 (C1B), 101.8
(C7A or C7B), 101.3 (C7A or C7B), 100.5 (C1A), 77.2 (C2A), 76.1
(C4B), 76.0 (C4A), 70.2 (C3B), 70.2 (C3A), 69.9 (C2B), 68.7 (C6A or
C6B), 68.5 (C6A or C6B), 64.3 (C5B), 63.8 (C5A), 55.0 (OMe), 39.1
g-Lactone 41: A solution of 40 (145 mg, 0.209 mmol) in anhydrous 1,2-di-
chloroethane (5 mL) was added dropwise through
a syringe pump
(10 mmolhꢀ1) to a suspension of [Rh
CTHUNGTRENNUNG
fluxing anhydrous 1,2-dichloroethane (65 mL). After the end of the addi-
tion, the reaction mixture was cooled to room temperature and concen-
trated under vacuum. The residue was purified by silica gel chromatogra-
phy (dichloromethane/ethyl acetate 20:1) to give 41 as a colorless solid
(82 mg, 59%). Rf =0.29 (silica, cyclohexane/ethyl acetate 3:1); [a]2D0 =ꢀ68
(c=1.0, CHCl3); 1H NMR (300 MHz, CDCl3): d=7.51–7.42 (m, 2H,
Harom.), 7.41–7.29 (m, 3H, Harom.), 5.57–5.48 (m, 2H, H7B, H1A),
4.65 (dd, J=7.9, 2.4 Hz, 1H, H3A), 4.48 (d, J=4.1 Hz, 1H, H2B), 4.36
(dd, J=5.0, 2.4 Hz, 1H, H2A), 4.29–4.21 (m, 2H, H4A, H6A), 4.21–4.15
(m, 1H, H3B), 3.96 (m, 1H, H5B), 3.86–3.69 (m, 4H, H4B, H5A, H6A,
H6B), 3.61 (dd, J=9.8, 7.5 Hz, 1H, H6B), 2.82 (s, 2H, H8B), 1.57 (s, 3H,
((CH3)3C), 27.2 (ACHTUNGTRENNUNG(CH3)3C), 21.0 ppm (CH3C=O); IR (film): n˜ =3520,
2964, 2917, 1743, 1722, 1458, 1371, 1244, 1130, 1097, 1074, 1056,
1026 cmꢀ1; MS: m/z=681 [M+Na+].
4,6-O-benzylidene-2-O-diazoacetyl-3-O-tert-butyldimethylsilyl-a-d-man-
nopyranoside-(1!6)-1,2–3,4-diacetone-a-d-galactopyranoside 40: A solu-
tion of donor 38 (90 mg, 0.151 mmol) and acceptor 39 (51 mg,
0.196 mmol) in distilled dichloromethane (5 mL) were stirred for 1 hour
at room temperature over activated 4 ꢄ MS (150 mg). NIS (68 mg,
0.302 mmol) was added, and after cooling to ꢀ208C, trifluoromethanesul-
fonic acid (4 mL, 0.045 mmol) was added dropwise. After being stirred for
2 h at ꢀ208C, the reaction mixture became dark-brown. A saturated
aqueous solution of sodium hydrogen carbonate (5 mL) was added, fol-
lowed by a saturated aqueous solution of sodium thiosulfate (3 mL). The
colorless reaction mixture was then diluted with dichloromethane
(10 mL) and filtered through a Celite pad. The organic layer was dried
(anhydrous magnesium sulfate), filtered, and concentrated under
vacuum. The residue was purified by silica gel chromatography (cyclo-
hexane/ethyl acetate 6:1) to give the disaccharide (73 mg, 65%) as a
white foam. Rf =0.38 (silica, cyclohexane/ethyl acetate 3:1); [a]2D0 =ꢀ20
(c=1.0, CHCl3); 1H NMR (300 MHz, CDCl3): d=7.57–7.31 (m, 5H,
Harom.), 5.59 (s, 1H, H7), 5.53 (d, J=4.9 Hz, 1H, H1A), 5.25 (d, J=
2.2 Hz, 1H, H2B), 4.83 (s, 1H, H1B), 4.64 (dd, J=7.9, 2.3 Hz, 1H,
H3A), 4.39–4.19 (m, 4H, H2A, H3B, H4A, H6B), 4.06–3.67 (m, 8H,
H4B, H5A, H5B, 2ꢆH6A, H6B, 2ꢆH8B), 1.56 (s, 3H, CH3), 1.45 (s, 3H,
CH3), 1.45 (s, 3H, CH3), 1.36 (s, 6H, 2ꢆCH3), 0.89 (s, 9H, ACHTNUGTRNEUNG(CH3)3C), 0.10
(s, 3H, CH3Si), 0.05 ppm (s, 3H, CH3Si); 13C NMR (75 MHz, CDCl3): d=
172.1 (C=O), 137.2 (Cquat. arom.), 128.9 (CHarom.), 128.1 (CHarom.),
126.1 (CHarom.), 109.5 (Cquat. isoprop.), 108.7 (Cquat. isoprop.), 103.6
(C1B), 101.6 (C7B), 96.2 (C1A), 82.2 (C2B), 77.5 (C4B), 70.7 (C4A),
70.6 (C3A), 70.5 (C2A), 68.5 (C3B), 68.1 (C6A), 65.9 (C5B), 64.7
(C5A), 63.3 (C6B), 41.0 (C8B), 26.1 (CH3), 25.9 (CH3), 25.7 (ACHTUNGTRENNUNG(CH3)3C),
24.9 (CH3), 24.6 (CH3), 18.2 ((CH3)3C), ꢀ4.4 (CH3Si), ꢀ5.1 ppm (CH3Si);
IR (film): n˜ =2990, 2933, 2898, 2858, 1800, 1472, 1459, 1383, 1276, 1259,
1215, 1174, 1117, 1096, 1070, 1008 cmꢀ1
C33H48O12NaSi: 687.2807; found: 687.2813.
; HRMS: m/z calcd for
Phenyl 4,6-O-benzylidene-2-O-bromoacetyl-3-O-pivaloyl-1-thio-b-d-glu-
copyranoside 42: Bromoacetyl bromide (179 mL, 2.051 mmol) was added
to a stirred solution of 4,6-O-benzylidene-3-O-pivaloyl-1-thio-b-d-gluco-
pyranoside (600 mg, 1.350 mmol) and 4-dimethylaminopyridine (255 mg,
2.000 mmol) in anhydrous dichloromethane (18 mL) at 08C. After the
mixture had been stirred for 30 min at 08C, TLC (cyclohexane/ethyl ace-
tate 1.5:1) showed complete consumption of the starting material, and
methanol (1 mL) was added. The reaction mixture was diluted with di-
chloromethane (20 mL) and washed with a saturated aqueous solution of
ammonium chloride (15 mL). The organic layer was dried (anhydrous
magnesium sulfate), filtered, and concentrated under vacuum. The resi-
due was purified by silica gel chromatography (dichloromethane/cyclo-
hexane 4:1) to give 42 as a white solid (672 mg, 88%). Rf =0.49 (silica,
cyclohexane/ethyl acetate 5:1); [a]2D0 =ꢀ40 (c=1.0, CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.58–7.31 (m, 10H, Harom.), 5.54 (s, 1H, H7),
5.40 (dd, J=9.4, 9.2 Hz, 1H, H3), 5.09 (dd, J=10.0, 9.2 Hz, 1H, H2), 4.86
(d, J=10.0 Hz, 1H, H1), 4.44 (dd, J=10.5, 4.9 Hz, 1H, H6ax.), 3.94–3.74
(m, 3H, H6equiv, H8, H8’), 3.72 (t, J=9.4 Hz, 1H, H4.), 3.61 (m, 1H, H5),
CH3), 1.36 (s, 3H, CH3), 1.35 (s, 3H, CH3), 0.84 (s, 9H, ACHTNUGTRNEUGN(CH3)3C), 0.07 (s,
3H, CH3Si), 0.04 ppm (s, 3H, CH3Si); 13C NMR (75 MHz, CDCl3): d=
166.3 (C=O), 137.4 (Cquat. arom.), 128.8 (CHarom.), 128.0 (CHarom.),
126.1 (CHarom.), 109.4 (Cquat. isoprop.), 108.6 (Cquat. isoprop.), 101.8
(C7B), 98.6 (C1B), 96.2 (C1A), 79.0 (C5B), 74.2 (C2B), 70.8 (C4A), 70.5
(C2A and C3A), 68.6 (C6B), 68.0 (C3B), 66.8 (C6A), 66.1 (C5A), 63.8
(C4B), 26.1 (2ꢆCH3), 25.9 (C8B), 25.7 (ACHTNURGTNEG(UN CH3)3C), 24.9 (CH3), 24.4
(CH3), 18.1 ((CH3)3C), ꢀ4.7 (CH3Si), ꢀ5.2 ppm (CH3Si); IR (film): n˜ =
2990, 2929, 2857, 1747, 1458, 1382, 1257, 1213, 1167, 1113, 1092, 1071,
1028, 1007 cmꢀ1; HRMS: m/z calcd for C33H49O1279BrNaSi: 767.20689;
found: 767.2069.
1,8-DiazabicycloACHTUNGTRENNUNG[5.4.0]undec-7-ene (296 mL, 1.980 mmol) was added to a
solution of the disaccharide (295 mg, 396 mmol) and N,N’-ditosylhydra-
zine (270 g, 792 mmol) in distilled tetrahydrofuran (15 mL) at 08C. After
TLC analysis showed complete consumption of the starting material (cy-
clohexane/ethyl acetate 5:1), a saturated aqueous solution of sodium hy-
drogen carbonate (10 mL) and dichloromethane (15 mL) were added,
and the organic layer was dried (anhydrous magnesium sulfate), filtered
and concentrated under vacuum. The residue was purified by silica gel
chromatography (dichloromethaneane/ethyl acetate 25:1) to give 40 as a
bright-yellow oil (165 mg, 60%). Rf =0.33 (silica, cyclohexane/ethyl ace-
1.19 ppm (s, 9H, ACTHNUTRGNEUNG
(CH3)3C); 13C NMR (75 MHz, CDCl3): d=177.4 (C=O),
165.8 (C=O), 136.7 (Cquat. arom.), 133.2 (CHarom.), 131.4 (Cquat.
arom.), 129.2 (CHarom.), 129.1 (CHarom.), 128.6 (CHarom.), 128.3
(CHarom.), 125.9 (CHarom.), 101.1 (C7), 86.3 (C1), 78.3 (C4), 72.3 (C3),
72.0 (C2), 70.7 (C5), 68.4 (C6), 38.9 ((CH3)3C), 27.1 (ACHTNUGTRENUNG(CH3)3C), 25.3 ppm
(C8); IR (film): n˜ =2971, 1742, 1480, 1373, 1278, 1180, 1137, 1100,
1013 cmꢀ1; HRMS: m/z calcd for C26H29O779BrNaS: 587.0710; found:
587.0709.
Chem. Eur. J. 2013, 19, 6052 – 6066
ꢃ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6063

T. Lecourt et al.
Methyl (4,6-O-benzylidene-2-O-diazoacetyl-3-O-pivaloyl-b-d-glucopyra-
noside)-(1!6)-2,3,4-O-methyl-a-d-glucopyranoside 45: A solution of 42
(281 mg, 497 mmol), diphenylsulfoxide (151 mg, 747 mmol), and 2,4,6-tri-
tert-butylpyridine (369 mg, 1.49 mmol) in distilled dichloromethane
(15 mL) was stirred for 1 hour at room temperature over activated 4 ꢄ
MS (350 mg) and cooled to ꢀ708C under argon. Trifluoromethanesulfon-
ic acid (142 mL, 845 mmol) was then added and the mixture was stirred at
ꢀ208C for 10 min. The reaction mixture was then cooled to ꢀ708C, and
a solution of 27 (235 mg, 995 mmol) in distilled dichloromethane (3 mL)
was added dropwise. After 2 h of stirring at ꢀ708C, a saturated aqueous
solution of sodium hydrogen carbonate (6 mL) was added. The reaction
mixture was then diluted with dichloromethane (10 mL) and filtered
through a Celite pad. The organic layer was dried (anhydrous magnesium
sulfate), filtered, and concentrated under vacuum. The residue was puri-
fied by silica gel chromatography (cyclohexane/ethyl acetate 1.5:1) to
give an inseparable mixture (1:1) of disaccharide 43 and orthoester 44 as
H6B, H5B, H6A), 3.68–3.60 (m, 4H, H5A, OMe), 3.59–3.23 (m, 7H,
H3A, 2ꢆOMe), 3.41 (s, 3H, OMe), 3.20 (dd, J=9.8, 3.7 Hz, 1H, H2A),
3.08 (dd, J=9.8, 8.9 Hz, 1H, H4A), 2.93 (d, J=17.6 Hz, 1H, H8B), 2.83
(d, J=17.6 Hz, 1H, H8B’), 1.23 ppm (s, 9H, ACTHNUTRGNEUNG
(CH3)3C); 13C NMR
(75 MHz, CDCl3): d=176.9 (C=O), 171.0 (C=O), 136.5 (Cquat. arom.),
129.2 (CHarom.), 128.3 (CHarom.), 125.9 (CHarom.), 104.0 (C1B), 101.4
(C7B), 97.4 (C1A), 83.6 (C3A), 82.6 (C2B), 81.8 (C2A), 79.3 (C4A),
76.1 (C4B), 72.0 (C3B), 69.2 (C5A), 68.7 (C6B), 66.3 (C5B), 62.7 (C6A),
60.9 (OMe), 60.6 (OMe), 59.1 (OMe), 55.2 (OMe), 38.8 ((CH3)3C), 36.1
(C8B), 27.1 ppm (ACTHNUTRGNEUNG(CH3)3C); IR (film): n˜ =2932, 1801, 1743, 1458, 1276,
1219, 1101 cmꢀ1; MS: m/z=633 [M+Na+].
Macrolactone 47: A solution of 45 (19 mg, 30 mmol) in anhydrous 1,2-di-
chloroethane (1.5 mL) was added dropwise through a syringe pump
(0.02 mmolhꢀ1) to a suspension of [Rh
2ACHTNUTRGENNG(U OAc)4] (0.27 mg, 0.600 mmol) in
anhydrous 1,2-dichloroethane (20 mL) heated at reflux. After the end of
the addition, the reaction mixture was cooled to room temperature and
concentrated under vacuum. The residue was purified by silica gel chro-
matography (cyclohexane/ethyl acetate 1:1) to give a 1:1 46/47 mixture as
a white foam (17 mg, 94%). Macrolactone 47: Rf =0.39 (silica, cyclohex-
ane/ethyl acetate 1:1); 1H NMR (300 MHz, CDCl3): d=7.46–7.31 (m,
5H, Harom.), 5.52 (s, 1H, H7B’), 5.44 (t, J=9.8 Hz, 1H, H3B’), 5.1 (dd,
J=9.8, 8.0 Hz, 1H, H2B’), 4.81 (m, 1H, H1A’), 4.62 (d, J=8.0 Hz, 1H,
H1B’), 4.56–4.47 (m, 1H, H7A’), 4.40 (m, 1H, H6B’), 4.15–4.07 (m, 2H,
H6A’, H7A’), 4.02–3.98 (m, 1H, H6A’), 3.82 (t, J=10.4 Hz, 1H, H6B’),
3.78–3.67 (m, 1H, H4B’), 3.66–3.47 (m, 13H, H3A’, H4A’, H5A’, H5B’,
3ꢆOMe), 3.38 (s, 3H, OMe), 3.21 (m, 1H, H2A’), 2.57 (td, J=13.7,
a bright yellow foam (297 mg, 86%). 1,8-diazabicycloACTHNUGRTENUNG[5.4.0]undec-7-ene
(160 mL, 1.07 mmol) was added to a solution of the 1:1 mixture of 43 and
44 (297 mg, 429 mmol) and N,N’-ditosylhydrazine (146 mg, 429 mmol) in
distilled tetrahydrofuran (6 mL) at 08C. After the mixture had been stir-
red for 40 min at 08C, a saturated aqueous solution of sodium hydrogen
carbonate (8 mL) and dichloromethane (15 mL) were added. The organic
layer was then dried (anhydrous magnesium sulfate), filtered and concen-
trated under vacuum. The residue was purified by silica gel chromatogra-
phy (cyclohexane/ethyl acetate 1.5:1) to give orthoester 44 as a colorless
oil (113 mg, 38%) and diazoacetate 45 as a bright yellow oil (118 mg,
43%). Orthoester 44: Rf =0.44 (silica, cyclohexane/ethyl acetate 1:1);
3.3 Hz, 1H, H8B’), 2.30 (m, 1H, H8B’), 1.17 ppm (s, 9H, ACHTUNGTRENNUNG(CH3)3C);
1
[a]2D0 =22 (c=1.0, CHCl3); H NMR (300 MHz, CDCl3): d=7.52–7.34 (m,
13C NMR (75 MHz, CDCl3): d=176.9 (C=O), 171.0 (C=O), 136.5 (Cquat.
arom.), 129.2 (CHarom.), 128.3 (CHarom.), 125.9 (CHarom.), 104.0
(C1B), 101.4 (C7B), 97.4 (C1A), 83.6 (C3A), 82.6 (C2B), 81.8 (C2A),
79.3 (C4A), 76.1 (C4B), 72.0 (C3B), 69.2 (C5A), 68.7 (C6B), 66.3 (C5B),
62.7 (C6A), 60.9 (OMe), 60.6 (OMe), 59.1 (OMe), 55.2 (OMe), 38.8
5H, Harom.), 5.90 (d, J=5.5 Hz, 1H, H1B), 5.54 (s, 1H, H7B), 5.38 (dd,
J=9.3, 4.3 Hz, 1H, H3B), 4.81 (d, J=3.5 Hz, 1H, H1A), 4.49–4.38 (m,
2H, H2B, H6B), 4.09 (dt, J=10.4 Hz, 5.3 Hz, 1H, H5B), 3.81–3.67 (m,
6H, H6B, 2ꢆH6A, H4B, 2ꢆH8B), 3.65–3.55 (m, 7H, H5A, 2ꢆOMe),
3.55–3.45 (m, 4H, H3A, OMe), 3.40 (s, 3H, OMe), 3.23–3.15 (m, 2H,
((CH3)3C), 36.1 (C8B), 27.1 ppm (ACTHNURTGNEUNG(CH3)3C); IR (film): n˜ =3479, 2934,
H2A, H4A), 1.24 ppm (s, 9H, ACHTNUGRTNEUNG
(CH3)3C); 13C NMR (75 MHz, CDCl3):
1741, 1450, 1367, 1281, 1187, 1157, 1098, 1047, 1002 cmꢀ1; MS: m/z=633
[M+Na+].
d=177.3 (C=O), 136.8 (Cquat. arom.), 129.1 (CHarom.), 128.3
(CHarom.), 125.9 (CHarom.), 118.1 (C9B), 101.2 (C7B), 98.9 (C1B), 97.5
(C1A), 83.5 (C3A), 81.7 (C4A), 79.0 (C2A), 77.6 (C2B), 76.9 (C4B),
73.1 (C3B), 69.2 (C5A), 68.6 (C6B), 63.1 (C5B), 61.9 (C6A), 60.9
(OMe), 60.6 (OMe), 59.1 (OMe), 55.2 (OMe), 38.8 ((CH3)3C), 31.8
g-Lactone 49: A solution of 48 (52 mg, 78.470 mmol) in anhydrous 1,2-di-
chloroethane (4 mL) was added dropwise through
a syringe pump
(10 mmolhꢀ1) to a suspension of [Rh
CTHUNGTRENNUNG
hydrous 1,2-dichloroethane (25 mL) heated at reflux. After the end of
the addition, the reaction mixture was cooled to room temperature and
concentrated under vacuum. The residue was purified by silica gel chro-
matography (dichloromethane/ethylacetate 30:1) to give 49 as a colorless
(C8B), 27.1 ppm (ACHTUNGTRENNUNG(CH3)3C); IR (film): n˜ =2934, 1739, 1457, 1375, 1276,
1140, 1100, 1028 cmꢀ1. HRMS: calculated for C30H43O1379BrNa: 713.1779,
found: 713.1778. 45: Rf =0.33 (silica, cyclohexane/ethyl acetate 1:1);
1
[a]2D0 =86 (c=1.0, CHCl3); H NMR (300 MHz, CDCl3): d=7.52–7.34 (m,
oil (33 mg, 60%). Rf =0.21 (silica, cyclohexane/ethyl acetate 3:1); [a]D20
=
ꢀ44 (c=1.0, CHCl3); 1H NMR (300 MHz, CDCl3): d=7.46–7.31 (m, 5H,
Harom.), 5.58–5.50 (m, 2H, H7B, H1A), 5.28 (dd, J=10.2, 6.1 Hz, 1H,
H3B), 4.71–4.60 (m, 2H, H2B, H3A), 4.41–4.30 (m, 2H, H2A, H6B),
4.26 (dd, J=7.9, 1.7 Hz, 1H, H4A), 4.02–3.90 (m, 2H, H4B, H5A), 3.88–
3.64 (m, 4H, H5B, H6B, 2ꢆH6A), 2.93 (d, J=17.2 Hz, 1H, H8B), 2.73
(d, J=17.2 Hz, 1H, H8B’), 1.55 (s, 3H, CH3), 1.49 (s, 3H, CH3), 1.37 (s,
5H, Harom.), 5.53 (s, 1H, H7B), 5.34 (t, J=9.5 Hz, 1H, H3B), 5.18 (dd,
J=9.5, 7.9 Hz, 1H, H2B), 4.83 (d, J=3.6 Hz, 1H, H1A), 4.75 (br s, 1H,
H8B), 4.69 (d, J=7.9 Hz, 1H, H1B), 4.40 (dd, J=10.4, 4.9 Hz, 1H, H6B),
4.10 (dd, J=10.7, 1.6 Hz, 1H, H6A), 3.85 (t, J=10.4 Hz, 1H, H6B),
3.79–3.67 (m, 2H, H6A, H4B), 3.66–3.44 (m, 12H, 3ꢆOMe, H5A, H5B,
H3A), 3.40 (s, 1H, OMe), 3.20 (dd, J=9.5, 3.6 Hz, 1H, H2A), 3.13 (t,
J=9.3 Hz, 1H, H4A), 1.19 (s, 9H ppm ACHTUNGTRNEUNG
(CH3)3C); 13C NMR (75 MHz,
3H, CH3), 1.35 (s, 3H, CH3), 1.22 ppm (s, 9H, ACTHNUTRGNEUNG
(CH3)3C); 13C NMR
CDCl3): d=177.6 (C=O), 164.9 (C=O), 136.8 (Cquat. arom.), 129.0
(CHarom.), 128.2 (CHarom.), 125.9 (CHarom.), 101.5 (C1B), 101.1
(C7B), 97.4 (C1A), 83.5 (C3A), 81.6 (C2A), 79.0 (C4A), 78.5 (C4B),
72.2 (C2B), 71.4 (C3B), 69.5 (C5A), 68.6 (C6A and C6B), 66.6 (C5B),
60.9 (OMe), 60.3 (OMe), 59.0 (OMe), 55.2 (OMe), 46.1 (C8B), 38.9
(75 MHz, CDCl3): d=176.8 (C=O), 171.1 (C=O), 136.5 (Cquat. arom.),
129.1 (CHarom.), 128.2 (CHarom.), 125.8 (CHarom.), 109.2 (Cquat. iso-
prop.), 108.7 (Cquat. isoprop.), 104.0 (C1B), 101.3 (C7B), 96.2 (C1A),
81.5 (C2B), 76.0 (C4B), 71.9 (C3B), 70.6 (C2A), 70.4 (C3A), 70.3
(C4A), 68.6 (C6B), 66.3 (C5B), 66.0 (C5A), 62.2 (C6A), 38.7 ((CH3)3C),
((CH3)3C), 27.0 ppm (ACHTUNGTRENNUNG(CH3)3C); IR (film): n˜ =2925, 2113, 1739, 1706,
37.4 (C8B), 27.0 (
(CH3); IR (film): n˜ =2981, 2939, 1801, 1744, 1479, 1457, 1382, 1256, 1212,
1136, 1114, 1070, 1002 cmꢀ1
ACTHGNUTERN(NUNG CH3)3C), 26.1 (CH3), 26.0 (CH3), 24.8 (CH3), 24.3 ppm
1380, 1277, 1154, 1100 cmꢀ1; MS: m/z=661 [M+Na+].
.
g-Lactone 46: A solution of 45 (50 mg, 79 mmol) in anhydrous 1,2-di-
chloroethane (1.5 mL) was added dropwise through a syringe pump
(10 mmolhꢀ1) to a suspension of [Rh
2ACTHNUTRGNE(UNG acam)4] (0.70 mg, 1.58 mmol) in an-
hydrous 1,2-dichloroethane (20 mL) heated at reflux. After the end of
the addition, the reaction mixture was cooled to room temperature and
concentrated under vacuum. The residue was purified by silica gel chro-
matography (diethyloxide/petroleum ether 3.5:1) to give 46 as a colorless
Acknowledgements
The authors would like to thank the University Paris Descartes (MESR
Grant to M.B.A.) and the CNRS (Research Fellowship to T.L.) for finan-
cial support.
oil (29 mg, 61%). Rf =0.39 (silica, cyclohexane/ethyl acetate 1:1); [a]D20
=
23 (c=0.5, CHCl3); 1H NMR (300 MHz, CDCl3): d=7.47–7.33 (m, 5H,
Harom.), 5.55 (s, 1H, H7B), 5.30 (dd, J=10.2, 6.4 Hz, 1H, H3B), 4.83 (d,
J=3.7 Hz, 1H, H1A), 4.53 (d, J=6.4 Hz, 1H, H2B), 4.39 (dd, J=9.9,
4.5 Hz, 1H, H6B), 3.98–3.84 (m, 2H, H6A, H4B), 3.83–3.68 (m, 3H,
6064
www.chemeurj.org
ꢃ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 6052 – 6066

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