Rh(II) carbene-mediated synthesis of methyl α- And β-ketopyranosides: Preparation of carbene precursors, quaternarization of the anomeric position, and ring opening of γ-lactones

Article abstract of DOI:10.1080/07328303.2011.614983

Methyl α- and β-ketopyranosides were efficiently prepared by carbene-mediated quaternarization of the anomeric position of corresponding aldopyranosides. Preparation of carbene precursors proved to be tedious and required a two-step procedure involving fi

Full text of DOI:10.1080/07328303.2011.614983

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Rh(II) Carbene-Mediated Synthesis
of Methyl α- and β-Ketopyranosides:
Preparation of Carbene Precursors,
Quaternarization of the Anomeric
Position, and Ring Opening of γ-Lactones
Mélissa Boultadakis-Arapinis a , Camille Lescot a , Laurent Micouin a
& Thomas Lecourt a
a Laboratoire de Chimie Thérapeutique (UMR CNRS 8638),
Université Paris Descartes, Faculté des Sciences Pharmaceutiques et
Biologiques, 4, avenue de l’Observatoire, 75006, Paris, France
Published online: 14 Dec 2011.
To cite this article: Mélissa Boultadakis-Arapinis , Camille Lescot , Laurent Micouin & Thomas Lecourt
(2011): Rh(II) Carbene-Mediated Synthesis of Methyl α- and β-Ketopyranosides: Preparation of
Carbene Precursors, Quaternarization of the Anomeric Position, and Ring Opening of γ-Lactones,
Journal of Carbohydrate Chemistry, 30:7-9, 587-604
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Journal of Carbohydrate Chemistry, 30:587–604, 2011
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Copyright Taylor & Francis Group, LLC
ISSN: 0732-8303 print / 1532-2327 online
DOI: 10.1080/07328303.2011.614983
Rh(II) Carbene-Mediated
Synthesis of Methyl α- and
β-Ketopyranosides:
Preparation of Carbene
Precursors, Quaternarization of
the Anomeric Position, and
Ring Opening of γ-Lactones
Me´lissa Boultadakis-Arapinis, Camille Lescot, Laurent Micouin,
and Thomas Lecourt
Laboratoire de Chimie The´rapeutique (UMR CNRS 8638), Universite´ Paris Descartes,
Faculte´ des Sciences Pharmaceutiques et Biologiques, 4, avenue de l’Observatoire,
75006, Paris, France
Methyl α- and β-ketopyranosides were efficiently prepared by carbene-mediated qua-
ternarization of the anomeric position of corresponding aldopyranosides. Preparation
of carbene precursors proved to be tedious and required a two-step procedure involv-
ing first bromoacetylation, followed by diazo-transfer with N,Nꢁ-ditosylhydrazine and
DBU. Selective functionalization of the anomeric C-H bond was then achieved under
Rh2(OAc)4 or Rh2(acam)4 catalysis. Finally, ring opening of the resulting γ-lactones de-
livered α- and β-ketopyranosides with the anomeric position functionalized by an inde-
pendent chain.
Keywords Keptopyranosides; C-H activation; Carbene; Quaternarization
INTRODUCTION
New synthetic tools in carbohydrate chemistry have attracted tremen-
dous interest over the past decades due to the important role of complex
Received June 1, 2011; accepted August 2, 2011.
Address correspondence to Thomas Lecourt, Laboratoire de Chimie The´rapeutique
(UMR CNRS 8638), Universite´ Paris Descartes, Faculte´ des Sciences Pharmaceutiques
et Biologiques, 4, avenue de l’Observatoire, 75006 Paris, France. E-mail: Thomas.
Lecourt@parisdescartes.fr
587

M. Boultadakis-Arapinis et al.
588
oligosaccharides in many fundamental biological processes.[1] In this context,
quaternarization of a specific position represents a highly potent entry to-
ward chemical tools for glycobiology. Thus, quaternary sugars have been crit-
ical to determine the conformation of L-iduronic acid in active heparin,[2] and
also gave rise to powerful inhibitors of carbohydrate-processing enzymes.[3]
However, such a modification of the sugar backbone requires a multistep,
time-consuming approach relying on (1) selective protection/deprotection of a
given position, (2) oxidation of the resulting alcohol, and (3) addition of an
organometallic reagent that creates the new C-C bond. Following this strat-
egy,[4,5] α-ketopyranosides, with the anomeric position quaternarized by an in-
dependent equatorial chain, can be prepared from δ-lactones by formation of a
new anomeric C-C bond before a glycosylation (Sch. 1).
1) C-C bond
formation
2) C-O bond
formation
OP6
O
OP6
O
OP6
O
R'Li
ROH
P4O
P3O
P4O
P3O
P4O
P3O
R'
R'
O
P2O
P2O
OH
OR
P2O
α-ketopyranosides
Scheme 1: Classical approach toward ketopyranosides.
The scope of this approach is, however, strongly limited by the second
step. Thus, glycosylation of sterically demanding acceptors with ketopyra-
noside donors is usually low yielding.[6,7] Moreover, coupling with a donor hav-
ing an equatorial 2-O-acetate delivered the targeted β-ketopyranoside in poor
chemical yield.[8] In this context, preparation of both α- and β-ketopyranosides
without limitations resulting from the glycosylation step might rely on substi-
tution of the anomeric C-H bond in a late stage of the synthetic process. How-
ever, as methods allowing functionalization of anomeric or pseudo-anomeric
C-H bonds only deliver polycyclic compounds that cannot be reopened into ke-
topyranosides without loss of the anomeric configuration (Fig. 1),[9–13] we had
to develop a new quaternarization process where a 2-O-bromoacetate played
a key role.[14] Thus, this protecting group first induced stereoselective glyco-
sylation and, as a carbene precursor, then promoted functionalization of the
anomeric C-H bond (Sch. 2). Herein, we would like to report full results
concerning carbene-mediated quaternarization of model methyl α-manno- and
β-glucopyranosides, with special emphasis on preparation of carbene precur-
sors. We also disclose the influence of various metal catalysts on this quater-
narization process, and optimal conditions for ring opening of γ-lactones into
ketopyranosides.

Rh(II) Carbene-Mediated Synthesis
589
1) C-O bond
formation
2) C-C bond
formation
O
O
O
Br
H
O
O
O
O
Ph
O
Ph
O
O
O
H
H
Ph
O
R
OH
O
O
H
R
O
PivO
PivO
PivO
SPh
O
O
R
Scheme 2: Carbene-mediated preparation of ketopyranosides.
RESULTS AND DISCUSSION
Preparation of Carbene Precursors
First, orthogonally protected methyl-pyranosides 1–7 were prepared in two
steps from commercially available methyl-glycosides. Initial attempts to intro-
duce the required diazoacetate at position 2 were made following Corey and
Myers’ modification of House’s procedure.[15] Unfortunately, acylation of 1 and
base-mediated decomposition of the resulting para-toluenesulfonylhydrazone
delivered the targeted diazosugar in less than 10% yield. We next turned our
attention to a two-step procedure involving first bromoacetylation and subse-
quent diazo-transfer with N,N’-ditosylhydrazine and DBU (Table 1).[16] How-
ever, following reaction conditions reported by Fukuyama for acylation of even
unreactive alcohols (bromoacetyl bromide, NaHCO3 in CH3CN at rt), we did
OBn
O
OBn
O
BnO
BnO
BnO
BnO
O
O
BnO
Ph
BnO
OH
Photochemically-induced
Intramolecular Hydrogen Abstraction
Hypoiodite-mediated
Intramolecular Hydrogen Abstraction
Crich et al 1995
Suarez et al 1995
OBn
OBn
O
H
N
O
BnO
BnO
BnO
BnO
SO2
BnO
O
O
Alkylidene-mediated C-H activation
Nitrene-mediated C-H activation
Wardrop et al 2002
Compain et al 2005
Figure 1: Spirobicyclic compounds resulting from anomeric C-H functionalization.

M. Boultadakis-Arapinis et al.
590
Table 1: Preparation of carbene precursors
O
N2
OH
O
O
O
Ph
Ph
O
Ph
O
O
O
R3O
R3O
OMe
OMe
1-4
5-7
1) BrCOCH2Br,
Base, CH2Cl2, 0°C
R3 = Ac 8
R3 = Piv 9
R3 = Bn 11
R3 = TBDMS 13
O
O
R3O
Ph
O
O
2) TsNHNHTs, DBU,
THF, 0°C
O
O
OMe
OMe
R3O
OH
O
O
N2
R3 = Piv 10
R3 = Bn 12
R3 = TBDMS 14
Entry
Substrate
R3 =
Base (eq.)
Yield
a
1
2
1
1
1
2
5
3
6
4
7
4
7
Ac
Ac
NaHCO3
—
73
73
73
74
75
74
30
25
64
50
Et3N (1.2)/DMAP (0.05)
Pyridine (3.5)
Pyridine (2.5)
DMAP (1.5)
3
Ac
4
Piv
5
Piv
6
Bn
DMAP (1.5)
7
Bn
DMAP (1.5)
8
TBDMS
TBDMS
TBDMS
TBDMS
DMAP (4.5)
9
DMAP (7.5)
10
11
Pyridine (3)
Pyridine (4)
aCH3CN used as solvent.
not observe any conversion into the corresponding bromoacetate. Bromoacety-
lation could finally be promoted in dichloromethane at 0◦C with Et3N as a
base and a catalytic amount of N-dimethylaminopyridine (DMAP). Treatment
of the crude product with N,N’-ditosylhydrazine and DBU in THF at 0◦C deliv-
ered the targeted diazoacetate 8 in 73% yield over two steps after purification
by silica gel flash chromatography (entry 2). Efficient bromoacetylation could
also be performed with stoechiometric pyridine without any detrimental effect
on the diazotransfer (entry 3). Similarly, 3-O-pivaloylated and 3-O-benzylated
compounds 2–5 were converted into the corresponding diazoacetates 9–12 in
73% to 75% yield over two steps after using either pyridine or DMAP as a base
in the acylation step (entries 4–7). However, bromoacetylation of more hin-
dered 3-O-tert-butyldimethylsilyl (TBDMS) substrates 6 and 7 with DMAP as
a base required repeated addition of reagents. The sluggish crude compounds

Rh(II) Carbene-Mediated Synthesis
591
containing pyridinium salts could then only be converted into the correspond-
ing diazosugars in low yields (entries 8 and 9). Clean bromoacetylation was
finally achieved with pyridine as a less nucleophilic base, thus delivering dia-
zoacetates 13 and 14 in 64% and 50% yield, respectively, over two steps (entries
10 and 11).
Metal-Mediated Decomposition of Diazosugars
Having in hand carbene precursors 9–14, we next studied their decompo-
sition by transition metals in refluxing 1,2-dichloroethane. Screening catalysts
that generate metal carbenes with different steric and electronic properties[17]
revealed that Rh2(OAc)4 was suitable to obtain the targeted γ-lactone 15 from
diazosugar 9 (Table 2, entry 1). However, Rh2(oct)4 and Rh2(cap)4 with bulky
ligands, Rh2(tfa)4 and Rh2(acam)4 with strongly and weakly electron with-
drawing ligands, respectively, and Cu(acac)2 and Cu(hfac)2 were detrimental
to the 1,5-C-H insertion process (entries 2–7). Moreover, quaternarization of
the anomeric position occurred in 94% yield with a TBDMS at position 3 (en-
try 8). However, when a potentially more reactive benzyl-protecting group was
Table 2: Metal-catalyzed insertion into the anomeric C-H bond of
methyl-α-mannosides
O
O
Catalyst (2 %)
N2
O
O
O
Ph
O
Ph
O
O
O
O
R3O
R3O
1,2-dichloroethane
reflux
OMe
R3 = Bn 11
OMe
R3 = Bn 16
R3 = Piv 9
R3 = Piv 15
R3 = TBDMS 13
R3 = TBDMS 17
Entry
Substrate
R3 =
Catalyst
Yield (%)
1
2
3
4
5
6
7
8
9
9
9
9
9
9
9
9
11
13
Piv
Piv
Piv
Piv
Piv
Rh2(OAc)4
Rh2(oct)4
Rh2(tfa)4
77a
49b
13b
9b
Rh2(cap)4
Rh2(acam)4
Cu(acac)2
Cu(hfac)2
Rh2(OAc)4
Rh2(OAc)4
35b
20b
15b
20a,c
94a
Piv
Piv
Bn
TBDMS
aIsolated after purification by chromatography.
bEstimated by 1H NMR of the crude product.
cIsolation of 51% of 1,7 insertion into the benzilic C-H bond.

M. Boultadakis-Arapinis et al.
592
Table 3: Metal-catalyzed insertion into the anomeric C-H bond of
methyl-β-glucosides
O
Catalyst (2 %)
Ph
O
Ph
O
O
O
O
O
O
OMe
OMe
R3O
R3O
1,2-dichloroethane
reflux
O
N2
R3 = Bn 12
O
R3 = Piv 10
R3 = Piv 18
R3 = Bn 19
R3 = TBDMS 14
R3 = TBDMS 20
Entry
Substrate
R3 =
Catalyst
Yield (%)
1
2
3
4
5
6
7
8
10
10
10
10
10
12
12
14
Piv
Piv
Rh2(OAc)4
Rh2(tfa)4
90a
10b
85a
Piv
Rh2(acam)4
Cu(acac)2
Cu(hfac)2
Rh2(OAc)4
Rh2(acam)4
Rh2(OAc)4
b
Piv
—
Piv
7b
35a,c
35a
Bn
Bn
TBDMS
92a
aIsolated after purification by chromatography.
bEstimated by 1H NMR of the crude product.
cIn mixture with 35% of 1,7 insertion into the benzylic C-H bond.
close to the carbene intermediate, γ-lactone 17 was only obtained in 20% yield
because of competitive 1,7 insertion into the benzylic position (entry 9).
In the β-gluco series, extensive screening of catalysts revealed that
Rh2(OAc)4 and Rh2(acam)4 were suitable to promote quaternarization of the
anomeric position (Table 3, entries 1 and 3), whereas Rh(II) salts with strongly
electron-withdrawing ligands (entry 2), as well as copper(II) catalysts (entries
4 and 5), failed to deliver γ-lactone 18. Moreover, the quaternarization process
was also compatible with a TBDMS at position 3 (entry 6). However, with a
benzyl-protecting group, results were highly dependent on the catalyst. Thus,
Rh2(OAc)4 gave an inseparable mixture of γ-lactone 19 and 1,7-C-H insertion
into the benzylic position (entry 7), whereas a fully selective insertion pro-
cess was restored by generating a less electrophilic carbene under Rh2(acam)4
catalysis (entry 8).
Ring Opening of γ-Lactones
Having identified the catalysts of choice to promote clean quaternarization
of the anomeric position in both series, we next turned our attention to ring
opening of γ-lactones in order to obtain the targeted α- and β-ketopyranosides
with the anomeric position substituted by an independent chain. We first

Rh(II) Carbene-Mediated Synthesis
593
treated γ-lactone 15 under William’s conditions (MeNHOMe.HCl, iPrMgCl,
THF 0◦C) in order to convert it into a Weinreb amide.[18] However, because
of strongly basic conditions, we only obtained a compound resulting from β-
elimination that quickly decomposed during NMR analysis. We next submitted
15 to conditions initially reported by Weinreb (MeNHOMe.HCl, AlMe3, THF
0◦C)[19] and obtained the targeted α-ketopyranoside 21 in quantitative yield
without purification (Sch. 3). Under similar reaction conditions, γ-lactone 18
was also cleanly converted into the corresponding β-ketopyranoside 22 ready
for further modifications. We were very pleased to see that conversion of γ-
lactones into Weinreb amides proceeds cleanly under harsh Lewis acid condi-
tions in the presence of 4,6-O-benzylidene-protecting groups.
Ph
O
Ph
O
O
O
O
O
O
OMe
OMe
Me
R3O
R3O
HO
N
OMe
MeNHOMe.HCl,
AlMe3, CH2Cl2, 0°C
15
21 99 %
O
O
O
O
O
OH
O
Ph
O
Ph
O
Me
N
O
O
R3O
R3O
OMe
OMe
OMe O
18
22 98 %
Scheme 3: Ring opening of γ -lactones.
CONCLUSION
In conclusion, we showed that 2-O-diazoacetyl β-gluco- and α-
mannopyranosides can be efficiently prepared following a two-step procedure
involving bromoacetylation and subsequent treatment of the crude product by
N,Nꢁ-ditosylhydrazine and DBU in THF at 0◦C. Presumably because of strong
electronic deactivation of the hydroxyl group at position 2, the acylation step
required modification of conditions reported by Fukuyama on nonfunctional
substrates. Thus, efficient bromoacetylation was only achieved when using a
stoichiometric amount of nucleophilic base that generates a highly reactive
acylpyridium intermediate. We also showed that Rh2(OAc)4 nicely induced
quaternarization of the anomeric position in both α-manno and β-gluco
series, whereas a less electrophilic carbene generated under Rh2(acam)4
catalysis only promoted clean functionalization of axial anomeric C-H bonds.
However, other Rh(II) salts with bulky or strongly electron-withdrawing
ligands, as well as Cu(II) catalysts, only delivered γ-lactones in low yields.
This quaternarization process proved to be compatible with pivaloyl- and
tert-butyldimethylsilyl-protecting groups at position 3, while 3-O-benzylated

M. Boultadakis-Arapinis et al.
594
compounds gave rise to competitive 1,7-insertion into the benzylic C-H bond.
Finally, ring opening of γ-lactones was achieved under Lewis acid conditions
to deliver α- and β-ketopyranosides ready for further functionalization.
EXPERIMENTAL
General Methods
Optical rotations were measured at 20◦C with a Perkin-Elmer Model
341 polarimeter, in a 10-cm, 1-mL cell. Concentrations are given in g/100
mL. Infrared spectra were recorded with a Nicolet 510 FT-IR spectrometer.
Mass spectrometry spectra were recorded on a Waters ZQ 2000 spectrome-
ter. High-resolution mass spectra were recorded on a Bruker MicrO-Tof-Q 2
1
spectrometer at CRMPO (Rennes, France). H 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 adoption of 77.00 ppm for the central line of
CDCl3. The relaxation delay (D1) was increased to 60 sec for 13C NMR spec-
tra of diazosugars. Assignments were aided by DEPT, COSY, and HSQC ex-
periments. Reactions were monitored by thin-layer chromatography (TLC)
on a precoated silica gel 60 F254 plate (layer thickness 0.2 mm; E. Merck,
Darmstadt, Germany) and detection by charring phosphomolybdic acid. Flash
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 (tetrahydrofu-
ran over sodium/benzophenone for diazotransfer). All reactions were conducted
under an argon atmosphere. Carbene insertion reactions were performed in
flame-dried glassware. Rh2(OAc)4, Rh2(tfa)4, Rh2(cap)4, and Rh2(oct)4 were
purchased from Sigma-Aldrich. Rh2(acam)4 was prepared following Doyle’s
procedure.[20] N,Nꢁ-ditosylhydrazine was prepared following Fukuyama’s
procedure.[16]
Preparation of 3-O-TBDMS Protected Precursors 4 and 7
Methyl 4,6-O-benzylidene-3-O-tert-butyldimethylsilyl-α-D-mannopyranoside 4
Methyl-4,6-O-benzylidene-α-D-mannopyranoside (1.00 g, 3.542 mmol) was
dissolved in anhydrous dichloromethane and dimethylformamide (7 mL,
11:1 v/v) and cooled to –20◦C. Anhydrous triethylamine (543 µL, 3.896 mmol)
and tert-butyldimethylsilyl trifluoromethanesulfonate (894 µL, 3.896 µmol)
were subsequently added and the mixture was stirred for 1.5 h, after which it
was quenched with a saturated aqueous solution of sodium hydrogen carbon-
ate. The layers were separated and the aqueous layer was extracted twice with

Rh(II) Carbene-Mediated Synthesis
595
dichloromethane. The combined organic layers were washed with brine, dried
(anhydrous magnesium sulfate), filtered, and concentrated under vacuum. The
residue was purified by silica gel chromatography (cyclohexane/ethyl acetate
4:1) to give 4 as a colorless oil (927 mg, 66%). TLC analysis: Rf = 0.47 (silica,
1
cyclohexane/ethyl acetate 3:1). H NMR (300 MHz, CDCl3): δ (ppm) 7.53–7.37
(m, 5H, Harom.), 5.57 (s, 1H, H-7), 4.82 (s, 1H, H-1), 4.36–4.25 (m, 1H, H-6), 4.10
(dd, J = 9.0, 3.5 Hz, 1H, H-3), 3.97–3.75 (m, 4H, H-2, H-4, H-5, H-6), 3.43 (s,
3H, OMe), 2.90 (br s, 1H, OH), 0.93 (s, 9H, C(CH3)3), 0.13 (s, 3H, CH3Si), 0.09
(s, 3H, CH3Si). 13C NMR (75 MHz, CDCl3): 137.6 (Cquat. arom.), 128.9 (CHarom.),
128.1 (CHarom.), 126.2 (CHarom.), 101.9 (C-7), 100.9 (C-1), 79.1 (C-4), 72.0 (C-3),
69.8 (C-2), 68.9 (C-6), 63.0 (C-5), 55.0 (OMe), 25.8 (C(CH3)3), 18.2 (SiC(CH3)3),
–4.3 (SiCH3), –5.0 (SiCH3). IR (film): 3566; 2928; 1472; 1386; 1253; 1215; 1125;
1100; 1076; 1050; 1006; 978; 918; 862; 837; 777; 746; 697; 669. HRMS calcu-
20
lated for C20H32O6SiNa: 419.1866, found: 419.1863. [α]D = + 39 (c = 1.0,
CHCl3).
Methyl 4,6-O-benzylidene-3-O-tert-butyldimethylsilyl-β-D-glucopyranoside 7
To a solution of methyl-4,6-O-benzylidene-β-D-glucopyranoside (300 mg,
1.063 mmol) and imidazole (433 mg, 6.360 mmol) in anhydrous dimethyl-
formamide (6 mL) was added dropwise a solution of tert-bultyldimethylsilyl
chloride (241 mg, 1.599 mmol) in dimethylformamide (1.5 mL). The reaction
mixture was stirred at rt for 2 h and quenched with methanol (2 mL). The
organic layer was washed with a saturated aqueous solution of ammonium
chloride (6 mL), dried (anhydrous magnesium sulfate), filtered, and concen-
trated under vacuum. The residue was purified by silica gel chromatography
(cyclohexane/ethyl acetate 5:1) to give 7 as a white solid (265 mg, 63%). TLC
1
analysis: Rf = 0.39 (silica, cyclohexane/ethyl acetate 3:1). H NMR (300 MHz,
CDCl3): δ (ppm) 7.59–7.32 (m, 5H, Harom.), 5.54 (s, 1H, H-7), 4.37 (dd, J = 11.1,
5.3 Hz 1H, H-6eq.), 4.33 (d, J = 7.9 Hz, 1H, H-1), 3.86–3.74 (m, 2H, H-3, H-6ax.),
3.60 (s, 3H, OMe), 3.56–3.38 (m, 3H, H-2, H-4, H-5), 2.64 (d, J = 2.7 Hz, 1H,
OH), 0.91 (s, 9H, C(CH3)3), 0.14 (s, 3H, SiCH3), 0.08 (s, 3H, SiCH3). 13C NMR
(75 MHz, CDCl3): δ (ppm) 137.2 (Cquat. arom.), 129.0 (CHarom.), 128.2 (CHarom.),
126.2 (CHarom.), 104.4 (C-1), 101.7 (C-7), 81.3 (C-4), 75.5 (C-2), 74.5 (C-3), 68.8
(C-6), 66.5 (C-5), 57.6 (OMe), 25.9 (C(CH3)3), 18.4 (SiC(CH3)3), –4.3 (SiCH3),
–4.7 (SiCH3). IR (film): 3506; 2854; 1471; 1428; 1388; 1249; 1215; 1195; 1169;
1112; 1069; 1019; 998; 837; 779; 697; 668. HRMS calculated for C20H32O6SiNa:
20
419.1866, found: 419.1862. [α]D = –58 (c = 1.0, CHCl3).
Preparation of Diazosugars
General procedure
To a solution of orthogonally protected precursors 1–7 (4.102 mmol) in an-
hydrous dichloromethane (20 mL) and anhydrous pyridine (10.262 mmol) at

M. Boultadakis-Arapinis et al.
596
0◦C was added dropwise over 10 min bromoacetyl bromide (8.237 mmol). Af-
ter being stirred for 15 min at 0◦C, the reaction mixture was quenched with
methanol (0.5 mL) while TLC (cyclohexane/ethyl acetate 2:1) showed com-
plete consumption of the starting material. After addition of a solution of
hydrochloric acid (1N, 10 mL), the organic layer was separated, the aqueous
layer was extracted with dichloromethane (3 × 10 mL), and the combined or-
ganic layers were dried (anhydrous magnesium sulfate), filtered, and concen-
trated under vacuum. To a solution of the residue and N,Nꢁ-ditosylhydrazine
(8.204 mmol) in distilled tetrahydrofuran (40 mL) at 0◦C was added 1,8-
diazabicyclo[5.4.0]undec-7-ene (16.241 mmol). After TLC analysis showed com-
plete consumption of the starting material (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 (an-
hydrous magnesium sulfate), filtered, and concentrated under vacuum. The
residue was purified by silica gel chromatography (cyclohexane/ethyl acetate)
to give diazosugars 8–14 as bright yellow oils.
Methyl 4,6-O-benzylidene-2-O-diazoacetyl-3-O-acetyl-α-D-mannopyranoside 8
Yield: 73%. TLC analysis: Rf = 0.15 (silica, cyclohexane/ethyl acetate
1
2.5:1). H NMR (300 MHz, CDCl3): δ (ppm) 7.48–7.28 (m, 5H, Harom.), 5.58
(s, 1H, H-7), 5.46–5.31 (m, 2H, H-2, H-3), 4.91 (br s, 1H, H-8), 4.72 (s, 1H, H-1),
4.30 (dd, J = 10.0, 4.0 Hz, 1H, H-6eq), 4.06–3.91 (m, 2H, H-4, H-5), 3.90–3.79
(m, 1H, H-6ax), 3.42 (s, 3H, OMe), 2.05 (s, 3H, (CH3)C=O). 13C NMR (75 MHz,
CDCl3): δ (ppm) 169.9 (C=O), 165.9 (C=O), 137.0 (Cquat. arom.), 129.1 (CHarom.),
128.2 (CHarom.), 126.1 (CHarom.), 101.9 (C-7), 99.5 (C-1), 76.0 (C-4), 70.2(C-2),
68.7 (C-6), 68.3 (C-3), 63.6 (C-5), 55.2 (OMe), 46.5 (C-8), 20.8 ((CH3)C=O). IR
(film): 3110, 2935, 2116, 1746, 1698, 1457, 1384, 1370, 1283, 1229, 1175, 1133,
1097, 1077, 1029, 997, 897, 758, 736, 700MS: m/z = 415 (MNa+). HRMS cal-
20
culated for C18H20N2O8Na: 415.1117, found: 415.1115. [α]D = –25 (c = 1.0,
CHCl3).
Methyl 4,6-O-benzylidene-2-O-diazoacetyl-3-O-pivaloyl-α-D-mannopyranoside
9
Yield: 73%. TLC analysis: Rf = 0.62 (silica, cyclohexane/ethyl acetate 2:1).
1H NMR (300 MHz, CDCl3): δ (ppm) 7.48–7.30 (m, 5H, Harom.), 5.61 (s, 1H,
H-7), 5.50–5.35 (m, 2H, H-2, H-3), 4.91 (br s, 1H, H-8), 4.73 (s, 1H, H-1), 4.33
(dd, J = 9.6, 3.6 Hz, 1H, H-6eq), 4.07–3.79 (m, 3H, H-4, H-5, H-6ax), 3.42 (s,
3H, OMe), 1.20 (s, 9H, (CH3)3C). 13C NMR (75 MHz, CDCl3): δ (ppm) 177.0
(C=O), 165.7 (C=O), 137.2 (Cquat. arom.), 128.9 (CHarom.), 128.2 (CHarom.), 125.9
(CHarom.), 101.4 (C-7), 99.7 (C-1), 76.5 (C-4), 70.4 (C-2), 68.8 (C-6), 68.1 (C-3),
63.6 (C-5), 55.3 (OMe), 46.4 (C-8), 38.9 ((CH3)3C), 27.0 ((CH3)3C). IR (film):
2974; 2115; 1733; 1698; 1457; 1384; 1283; 1177; 1134; 1097; 1031; 699. MS:

Rh(II) Carbene-Mediated Synthesis
597
m/z = 457 (MNa+). HRMS calculated for C21H26N2O8Na: 457.1581, found:
20
457.1581. [α]D = –36 (c = 1.0, CHCl3).
Methyl 4,6-O-benzylidene-2-O-diazoacetyl-3-O-pivaloyl-β-D-glucopyranoside
10
Yield: 74%. TLC analysis: Rf = 0.62 (silica, cyclohexane/ethyl acetate 2:1).
1H NMR (300 MHz, CDCl3): δ (ppm) 7.50–7.30 (m, 5H, Harom.), 5.54 (s, 1H, H-
7), 5.34 (t, J = 8.0 Hz, 1H, H-3), 5.11 (t, J = 8.0 Hz, 1H, H-2), 4.80 (br s, 1H,
H-8), 4.52 (d, J = 8.0 Hz, 1H, H-1), 4.41 (dd, J = 10.5, 4.9 Hz, 1H, H-6eq), 3.83
(t, J = 10.5 Hz, 1H, H-6ax), 3.73 (t, J = 8.0 Hz, 1H, H-4), 3.62–3.46 (m, 4H,
OMe, H-5), 1.18 (s, 9H, (CH3)3C). 13C NMR (75 MHz, CDCl3): δ (ppm) 177.5
(C=O), 165.4 (C=O), 136.9 (Cquat. arom.), 129.0 (CHarom.), 128.2 (CHarom.), 125.9
(CHarom.), 102.4 (C-1), 101.1 (C-7), 78.7 (C-4), 72.1 (C-2), 71.3 (C-3), 68.6 (C-
6), 66.4 (C-5), 57.3 (OMe), 46.3 (C-8), 38.9 ((CH3)3C), 26.8 ((CH3)3C). IR (film):
2971; 2114; 1736; 1704; 1380; 1148; 1099. MS: m/z = 457 (MNa+). HRMS
20
calculated for C21H26N2O8Na: 457.1581, found: 457.1587. [α]D = - 66 (c =
1.0, CHCl3).
Methyl 3-O-benzyl-4,6-O-benzylidene-2-O-diazoacetyl-α-D-mannopyranoside
11
Yield: 75%. TLC analysis: Rf = 0.40 (silica, cyclohexane/ethyl acetate 3:1).
1H NMR (300 MHz, CDCl3): δ (ppm) 7.56–7.28 (m, 10H, Harom.), 5.65 (s, 1H,
H-7), 5.52–5.48 (m, 1H, H-2), 4.94 (br s, 1H, H-8), 4.77 (d, J = 12.2 Hz, 1H,
CHPh), 4.76 (d, J = 1.5 Hz, 1H, H-1) 4.69 (d, J = 12.2 Hz, 1H, CHPh), 4.29
(dd, J = 13.3, 2.8 Hz, 1H, H-6), 4.10–3.96 (m, 2H, H-3, H-5), 3.93–3.78 (m,
2H, H-4, H-6), 3.40 (s, 3H, OMe). 13C NMR (75 MHz, CDCl3): δ (ppm) 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 (C-7),
99.9 (C-1), 78.4 (C-4), 73.8 (C-3), 72.1 (CH2Ph), 69.9 (C-2), 68.8 (C6), 63.7 (C-
5), 55.2 (OMe), 46.8 (C-8). IR (film): 3091; 2912; 2114; 1691; 1497; 1454; 1383;
1282; 1240; 1174; 1133; 1077; 1029; 1005; 977; 913; 886; 734; 698; 666. HRMS
20
calculated for C23H24N2O7Na: 463.1481, found: 463.1478. [α]D = – 21 (c =
1.0, CHCl3).
Methyl 3-O-benzyl-4,6-O-benzylidene-2-O-diazoacetyl-β-D-glucopyranoside 12
Yield: 74%. TLC analysis: Rf = 0.33 (silica, cyclohexane/ethyl acetate 3:1).
1H NMR (300 MHz, CDCl3): δ (ppm) 7.62–7.22 (m, 10H, Harom.), 5.61 (s, 1H,
H-7), 5.10 (t, J = 8.3 Hz, 1H, H-2), 4.91 (d, J = 12.0 Hz, 1H, CHPh), 4.81–4.68
(m, 2H, H-8, CHPh), 4.48–4.33 (m, 2H, H-1, H-6eq.), 3.94–3.67 (m, 3H, H-3, H-
4, H-6ax.), 3.47 (m, 4H, H-5; OMe). 13C NMR (75 MHz, CDCl3): δ (ppm) 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 (C-1), 101.3 (C-7), 81.6
(C-4), 78.2 (C-3), 74.1 (CH2Ph), 73.1 (C-2), 68.7 (C-6), 66.2 (C-5), 57.1 (OMe),

M. Boultadakis-Arapinis et al.
598
46.4 (C-8). IR (film): 2927; 2113; 1705; 1454; 1381; 1237; 1195; 1096; 1058;
1030; 1011; 751; 698; 696. HRMS calculated for C23H24N2O7Na: 463.1481,
20
found: 463.1483. [α]D = +14 (c = 1.0, CHCl3).
Methyl 4,6-O-benzylidene-2-O-diazoacetyl-3-O-tert-butyldimethylsilyl-
α-D-mannopyranoside 13
Yield: 64%. TLC analysis: Rf = 0.52 (silica, cyclohexane/ethyl acetate 3:1).
1H NMR (300 MHz, CDCl3): δ (ppm) 7.60–7.30 (m, 5H, Harom.), 5.60 (s, 1H, H-7),
5.26 (dd, J = 3.7, 1.1 Hz, 1H, H-2), 4.89 (br s, 1H, H-8), 4.71 (d, J = 1.1 Hz, 1H,
H-1), 4.29 (d, J = 5.7 Hz, 1H, H-6), 4.22 (dd, J = 9.0, 3.7 Hz, 1H, H-3), 3.92–3.70
(m, 3H, H-4, H-5, H-6), 3.41 (s, 3H, OMe), 0.88 (s, 9H, C(CH3)3), 0.10 (s, 3H,
CH3Si), 0.07 (s, 3H, CH3Si). 13C NMR (75 MHz, CDCl3): δ (ppm) 166.2 (C=O),
137.5 (Cquat. arom.), 128.9 (CHarom.), 128.1 (CHarom.), 126.1 (CHarom.), 101.8 (C-7),
100.0 (C-1), 79.4 (C-4), 72.9 (C-2), 68.8 (C-6), 68.1 (C-3), 63.6 (C-5), 55.2 (OMe),
46.5 (C-8), 25.6 (C(CH3)3), 18.2 (SiC(CH3)3), –4.7 (SiCH3), –5.1 (SiCH3). IR
(film): 2930; 2113; 1698; 1471; 1384; 1282; 1249; 1216; 1173; 1133; 1079; 1033;
1008; 978; 914; 888; 863; 838; 779; 758; 734; 698; 668. HRMS calculated for
20
C22H32N2O7SiNa: 487.18765, found: 487.1872. [α]D = − 3 (c = 1.0, CHCl3).
Methyl 4,6-O-benzylidene-2-O-diazoacetyl-3-O-tert-butyldimethylsilyl-
β-D-glucopyranoside 14
Yield: 50%. TLC analysis: Rf = 0.46 (silica, cyclohexane/ethyl acetate 3:1).
1H NMR (300 MHz, CDCl3): δ (ppm) 7.60–7.31 (m, 5H, Harom.), 5.54 (s, 1H,
H-7), 5.02 (t, J = 8.8 Hz, 1H, H-2), 4.81 (br s, 1H, H-8), 4.47–4.30 (m, 2H,
H-1, H-6eq.), 3.89 (t, J = 8.8 Hz, 1H, H-3), 3.81 (t, J = 10.2 Hz, 1H, H-6ax.),
3.57 (m, 1H, H-4), 3.53 (s, 3H, OMe), 3.44 (dt, J = 10.2, 4.8 Hz, 1H, H-5),
0.85 (s, 9H, C(CH3)3), 0.05 (s, 3H, SiCH3), 0.01 (s, 3H, SiCH3). 13C NMR
(75 MHz, CDCl3): δ (ppm) 165.3 (C=O), 137.1 (Cquat. arom.), 129.1 (CHarom.),
128.2 (CHarom.), 126.3 (CHarom.), 102.5 (C-1), 101.8 (C-7), 81.4 (C-4), 74.5 (C-
2), 72.8 (C-3), 68.7 (C-6), 66.4 (C-5), 57.1 (OMe), 46.5 (C-8), 25.6 (C(CH3)3),
18.1 (SiC(CH3)3), –4.2 (SiCH3), –5.1 (SiCH3). IR (film): 2929; 2112; 1709; 1471;
1380; 1237; 1134; 1098; 1029; 1009; 838; 777; 731; 698; 668. HRMS calcu-
20
lated for C22H32N2O7SiNa: 487.18765, found: 487.1874. [α]D = –37 (c = 1.0,
CHCl3).
Metal-Catalyzed Decomposition of Diazosugars
(General Procedure)
To a suspension of Rh2(OAc)4 (2.5 µmol) in refluxing anhydrous 1,2-
dichloroethane (80 mL) was added dropwise via syringe pump (20 µmol/h)
a solution of diazosugars 9–14 (0.5 mmol) in anhydrous 1,2-dichloroethane
(2 mL). After the end of the addition, the reaction mixture was cooled to rt

Rh(II) Carbene-Mediated Synthesis
599
and concentrated under vacuum. The residue was purified by silica gel chro-
matography (cyclohexane/ethyl acetate) to give γ-lactones 15–20.
15: Yield: 77%. TLC analysis: Rf = 0.57 (silica, cyclohexane/ethyl acetate 2:1).
1H NMR (300 MHz, CDCl3): δ (ppm) 7.53–7.30 (m, 5H, Harom.), 5.59 (s, 1H,
H-7), 5.34 (dd, J = 10.3, 4.0 Hz, 1H, H-3), 4.75 (d, J = 4.0 Hz, 1H, H-2), 4.32
(dd, J = 9.5, 3.9 Hz, 1H, H-6eq.), 4.06 (t, J = 10.3 Hz, 1H, H-4), 3.95–3.75
(m, 2H, H-5, H-6ax.), 3.39 (s, 3H, OMe), 2.83 (d, J = 16.4 Hz, 1H, H-8), 2.70
(d, J = 16.4 Hz, 1H, H-8’), 1.26 (s, 9H, (CH3)3C). 13C NMR (75 MHz, CDCl3):
δ (ppm) 177.8 (C=O), 171.5 (C=O), 136.9 (Cquat. arom.), 129.0 (CHarom.), 128.2
(CHarom.), 125.9 (CHarom.), 103.7 (C-1), 101.3 (C-7), 79.0 (C-2), 74.8 (C-4),
68.21 (C-6), 68.20 (C-3), 64.5 (C-5), 51.9 (OMe), 40.3 (C-8), 39.0 ((CH3)3C),
27.0 ((CH3)3C). IR (film): 2971; 1806; 1734; 1704; 1279; 1154; 1098; 1073;
1004; 964. MS: m/z = 429 (MNa+). HRMS calculated for C21H26O8Na:
20
429.1520, found: 429.1524. [α]D = –82 (c = 1.0, CHCl3).
16: Yield: 20%. TLC analysis: Rf = 0.24 (silica, cyclohexane/ethyl acetate 3:1).
1H NMR (300 MHz, CDCl3): δ (ppm) 7.41–7.27 (m, 10H, Harom.), 5.61 (s,
1H,H-7), 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, H-2), 4.28 (dd, J = 9.3, 3.8 Hz, 1H, H-6eq.), 4.12–3.95
(m, 2H, H-3, H-4), 3.86–3.70 (m, 2H, H-5, H-6ax.), 3.34 (s, 3H, OMe), 2.81 (d,
J = 16.3 Hz, 1H, H-8), 2.67 (d, J = 16.3 Hz, 1H, H-8’). 13C NMR (75 MHz,
CDCl3): δ (ppm) 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 (C-7), 80.1 (C-2), 77.6 (C-4), 73.1 (C-3), 73.0 (CH2Ph), 68.3
(C-6), 64.6 (C-5), 51.8 (OMe), 40.3 (C-8). IR (film): 2933; 2871; 1797; 1493;
1454; 1377; 1302; 1282; 1217; 1177; 1155; 1096; 1077; 1004; 962; 750; 698.
20
HRMS calculated for C23H24O7Na: 435.1420, found: 435.1418. [α]D = –40
(c = 1.0, CHCl3).
17: Yield: 94%. TLC analysis: Rf = 0.41 (silica, cyclohexane/ethyl acetate 3:1).
1H NMR (300 MHz, CDCl3): δ (ppm) 7.56–7.33 (m, 5H, Harom.), 5.57 (s,
1H, H-7), 4.47 (d, J = 4.0 Hz, 1H, H-2), 4.33–4.24 (m, 1H, H-6), 4.19 (dd,
J = 9.5, 4.0 Hz, 1H, H-3), 3.93–3.69 (m, 3H, H-4, H-5, H-6), 3.38 (s, 3H,
OMe), 2.82 (d, J = 16.3 Hz, 1H, H-8), 2.70 (d, J = 16.3 Hz, 1H, H-8ꢁ),
0.90 (s, 9H, C(CH3)3), 0.12 (s, 3H, SiCH3), 0.07 (s, 3H, SiCH3). 13C NMR
(75 MHz, CDCl3): δ (ppm) 172.0 (C=O), 137.2 (Cquat. arom.), 129.0 (CHarom.),
128.2 (CHarom.), 126.1 (CHarom.), 103.7 (C-1), 101.7 (C-7), 82.4 (C-2), 77.6 (C-
4), 68.5 (C-3), 68.2 (C-6), 64.7 (C-5), 51.8 (OMe), 40.6 (C-8), 25.7 ((CH3)3C),
18.3 ((CH3)3CSi), –4.4 (SiCH3), –5.1 (SiCH3). IR (film): 2930; 1795; 1457;
1386; 1250; 1213; 1174; 1118; 1099; 1027; 838; 779; 697; 669. HRMS calcu-
20
lated for C22H32O7SiNa: 459.1815, found: 459.1811. [α]D = –75 (c = 1.0,
CHCl3).

M. Boultadakis-Arapinis et al.
600
ε-lactone: Yield: 51%. TLC analysis: Rf = 0.16 (silica, cyclohexane/ethyl acetate
3:1). 1H NMR (300 MHz, CDCl3): δ (ppm) 7.38 (m, 10H, Harom.), 5.62 (s, 1H,
H-7), 5.01 (s, 1H, H-1), 4.89 (d, J = 3.8 Hz, 1H, H-2), 4.81 (dd, J = 9.2, 5.2
Hz, 1H, CHPh), 4.33 (dd, J = 9.0, 3.3 Hz, 1H, H-6eq.), 4.26 (dd, J = 9.2,
3.8 Hz, 1H, H-3), 4.05 (t, J = 9.2 Hz, 1H, H-4), 3.99–3.82 (m, 2H, H-5, H-
6ax.), 3.63 (dd, J = 15.6, 9.2 Hz, 1H, H-8), 3.47 (s, 3H, OMe), 3.15 (dd, J =
15.6, 5.2 Hz, 1H, H-8ꢁ). 13C NMR (75 MHz, CDCl3): δ (ppm) 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 (C-7), 99.1
(C-1), 77.4 (C-4), 74.4 (C-2), 74.3 (C-3), 71.2 (CHPh), 68.7 (C-6), 62.3 (C-
5), 50.7 (OMe), 44.3 (C-8). IR (film): 2920; 1449; 1496; 1455; 1367; 1301;
1246; 1218; 1134; 1093; 1040; 919; 848; 754; 699; 669. HRMS calculated for
20
C23H24O7Na: 435.1420, found: 435.1412, [α]D = –69 (c = 1.0, CHCl3).
18: Yield: 90%. TLC analysis: Rf = 0.60 (silica, cyclohexane/ethyl acetate 2:1).
1H NMR (300 MHz, 50◦C, CDCl3) δ (ppm): 7.51–7.31 (m, 5H, Harom.), 5.57
(s, 1H, H-7), 5.31 (dd, J = 10.3, 6.1 Hz, 1H, H-3), 4.47 (d, J = 6.1 Hz,1H,
H-2), 4.42–4.33 (m, 1H, H-6), 4.03–3.91 (m, 1H, H-4), 3.85–3.71 (m, 2H,
H-5, H-6), 3.42 (s, 3H, OMe), 2.92 (d, J = 17.1 Hz, 1H, H-8), 2.69 (d,
J = 17.1 Hz, 1H, H-8ꢁ), 1.24 (s, 9H, (CH3)3C). 13C NMR (75 MHz, CDCl3)
δ (ppm): 177.0 (C=O), 171.0 (C=O), 136.6 (Cquat. arom.), 129.1 (CHarom.), 128.3
(CHarom.), 125.9 (CHarom.), 103.9 (C-1), 101.4 (C-7), 82.0 (C-2), 76.1 (C-4),
71.9 (C-3), 68.9 (C-6), 66.4 (C-5), 50.7 (OMe), 38.8 ((CH3)3C), 36.5 (C-8), 27.0
((CH3)3C). IR (film): 2971; 1798; 1740; 1457; 1375; 1277; 1135; 1078; 1031;
699. MS: m/z = 429 (MNa+). HRMS calculated for C21H26O8Na: 429.1520,
20
found: 429.1521. [α]D = +1 (c = 1.0, CHCl3).
19: Yield: 35%. TLC analysis: Rf = 0.34 (silica, cyclohexane/ethyl acetate 3:1).
1H NMR (300 MHz, CDCl3): δ (ppm) 7.52–7.31 (m, 10H, Harom.), 5.63 (s, 1H,
H-7), 4.85 (s, 2H, CH2Ph), 4.56 (d, J = 5.6 Hz, 1H, H-2), 4.37 (dd, J = 10.3,
4.8 Hz, 1H, H-6eq.), 3.99 (t, J = 9.7 Hz, 1H, H-4), 3.87–3.74 (m, 2H, H-3, H-
6ax.), 3.67 (dt, J = 9.7, 4.8 Hz, 1H, H-5), 3.40 (s, 3H, OMe), 2.86 (d, J =
17.2 Hz, 1H, H-8), 2.69 (d, J = 17.2 Hz, 1H, H-8ꢁ). 13C NMR (75 MHz,
CDCl3): δ (ppm) 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 (C-1), 101.6 (C-7), 83.9 (C-2), 78.8 (C-3), 78.2 (C-4), 73.7 (CH2Ph), 68.9
(C-6), 66.4 (C-5), 50.7 (OMe), 36.8 (C-8). IR (film): 2933; 1793; 1605; 1497;
1454; 1372; 1331; 1268; 1245; 1213; 1170; 1091; 1028; 916; 890; 752; 698;
20
601. HRMS calculated for C23H24O7Na: 435.1420, found: 435.1415. [α]D
+5 (c = 1.0, CHCl3).
=
20: Yield: 92%. TLC analysis: Rf = 0.49 (silica, cyclohexane/ethyl acetate 3:1).
1H NMR (300 MHz, CDCl3): δ (ppm) 7.57–7.32 (m, 5H; Harom.), 5.58 (s, 1H,
H-7), 4.47–4.29 (m, 2H, H-2, H-6), 3.89 (dd, J = 9.6, 5.8 Hz, 1H, H-3),

Rh(II) Carbene-Mediated Synthesis
601
3.83–3.71 (m, 2H, H-4, H-6), 3.69–3.55 (m, 1H, H-5), 3.41 (s, 3H, OMe),
2.86 (d, J = 17.2 Hz, 1H, H-8), 2.68 (d, J = 17.2 Hz, 1H, H-8ꢁ), 0.90
(s, 9H, C(CH3)3), 0.13 (s, 3H, SiCH3), 0.06 (s, 3H, SiCH3). 13C NMR (75
MHz, CDCl3): δ (ppm) 171.8 (C=O), 136.9 (Cquat. arom.), 129.2 (CHarom.), 128.2
(CHarom.), 126.1 (CHarom.), 103.8 (C-1), 101.8 (C-7), 85.4 (C-2), 78.6 (C-4),
74.1 (C-3), 68.8 (C-6), 66.5 (C-5), 50.5 (OMe), 36.5 (C-8), 25.7 ((CH3)3C), 18.2
((CH3)3CSi), –4.5 (SiCH3), –4.9 (SiCH3). IR (film): 2930; 1800; 1462; 1386;
1282; 1254; 1095; 1063; 1004; 964; 867; 837; 778; 752; 698; 669. HRMS cal-
20
culated for C22H32O7SiNa: 459.1815, found: 459.1812. [α]D = –8 (c = 1.0,
CHCl3).
Ring Opening of γ-Lactones (General Procedure)
To
a solution of lactone 15 or 18 (0.150 mmol) in anhydrous
dichloromethane (1.5 mL) at 0◦C was added a solution of Cl(Me)AlN(Me)OMe
(400 µL, 0.4 mmol) prepared by stirring N,O-dimethylhydroxylamine hy-
drochloride (390 mg, 4 mmol) and trimethylaluminum (2 mL of a 2 M solu-
tion in toluene) in anhydrous dichloromethane (2 mL) for 30 min at 0◦C. After
being stirred for 20 min, TLC (cyclohexane/ethylacetate 1:1) showed complete
consumption of the starting material. The reaction mixture was quenched with
a 1 M solution of Rochelle’s salt (5 mL), diluted with dichloromethane (10 mL),
and stirred for 1 h at rt. The organic layer was separated, dried (anhydrous
magnesium sulfate), filtered, and concentrated under vacuum to give 21 or 22.
21: Yield: 99%. TLC analysis: Rf = 0.26 (silica, cyclohexane/ethyl acetate 2:1).
1H NMR (300 MHz, CDCl3): δ (ppm) 7.45–7.34 (m, 5H, Harom.), 5.59 (s, 1H,
H-7), 5.40 (dd, J = 10.4, 3.4 Hz, 1H, H-3), 4.36–4.06 (m, 4H, H-2, H-4, H-6,
OH), 3.87 (t, J = 10.2 Hz, 1H, H-6’), 3.79–3.61 (m, 4H OMe, H-5), 3.46–3.11
(m, 7H, OMe, NMe, H-8), 2.81 (d, J = 14.6 Hz, 1H, H-8ꢁ), 1.26 (s, 9H,
(CH3)3C). 13C NMR (75 MHz, CDCl3): δ (ppm) 177.6 (C=O), 169.5 (C=O),
137.4 (Cquat. arom.), 128.8 (CHarom.), 128.2 (CHarom.), 125.9 (CHarom.), 103.0 (C-
1), 101.2 (C-7), 75.5 (C-4), 70.6 (C-2), 70.0 (C-3), 68.7 (C-6), 65.1 (C-5), 61.6
(OMe), 48.4 (OMe), 39.0 ((CH3)3C), 33.2 (C-8), 32.0 (NMe), 27.2 ((CH3)3C).
IR (film): 3441; 2970; 1731; 1645; 1457; 1385; 1284; 1163; 1097; 1030; 754;
699. MS: m/z = 490 (MNa+). HRMS calculated for C23H33NO9Na: 490.2047,
20
found: 490.2048. [α]D = +12 (c = 1.0, CHCl3).
22: Yield: 98%. TLC analysis: Rf = 0.27 (silica, cyclohexane/ethyl acetate 2:1).
1H NMR (300 MHz, CDCl3) δ (ppm): 7.50–7.30 (m, 5H, Harom.), 5.54 (s, 1H,
H-7), 5.23 (dd, J = 8.2, 6.9 Hz, 1H, H-3), 5.09 (d, J = 4.3 Hz, 1H, OH), 4.38
(dd, J = 9.9, 3.6 Hz, 1H, H-6), 3.97 (t, J = 6.9 Hz, 1H, H-4), 3.93–3.80 (m,
2H, H-2, H-5), 3.79–3.67 (m, 4H, H-6’, OMe), 3.42 (s, 3H, OMe), 3.33–3.04
(m, 5H, NMe, 2 × H-8), 1.23 (s, 9H, (CH3)3C). 13C NMR (75 MHz, CDCl3) δ
(ppm): 178.2 (C=O), 170.1 (C=O), 137.1 (Cquat. arom.), 129.0 (CHarom.), 128.2

M. Boultadakis-Arapinis et al.
602
(CHarom.), 126.0 (CHarom.), 102.1 (C-1), 101.3 (C-7), 78.9 (C-4), 74.3 (C-3),
73.0 (C-2), 69.3 (C-6), 65.3 (C-5), 61.6 (OMe), 49.1 (OMe), 38.9 ((CH3)3C),
35.2 (C-8), 32.2 (NMe), 27.2 ((CH3)3C). IR (film): 3437; 2970; 1734; 1634;
1457; 1378; 1282; 1091; 1031. MS: m/z = 490 (MNa+). HRMS calculated for
20
C23H33NO9Na: 490.2047, found: 490.2046. [α]D = –8 (c = 1.0, CHCl3).
ACKNOWLEDGEMENTS
Financial support of this work by CNRS (Research Fellowship to T.L.) and Uni-
versite´ Paris Descartes (MESR grant to M.B.A.) is gratefully acknowledged.
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