Conversion of fructose into a building block for the synthesis of carbocyclic mannose mimics

Article abstract of DOI:10.1016/j.tetasy.2011.02.013

Fructose was converted into C-1 diastereomeric carbocyclic building blocks resembling mannose using ruthenium-catalysed ring-closing metathesis as a key step. The potential use of the compounds in the synthesis of valienamine pseudodisaccharides is demons

Full text of DOI:10.1016/j.tetasy.2011.02.013

Tetrahedron: Asymmetry 22 (2011) 399–405
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Conversion of fructose into a building block for the synthesis
of carbocyclic mannose mimics
Clinton Ramstadius a, Mikael Boklund a, Ian Cumpstey a,b,
⇑
a Department of Organic Chemistry, The Arrhenius Laboratory, Stockholm University, 106 91 Stockholm, Sweden
b Institut de Chimie des Substances Naturelles, Centre National de la Recherche Scientifique, 91198 Gif-sur-Yvette Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Fructose was converted into C-1 diastereomeric carbocyclic building blocks resembling mannose using
ruthenium-catalysed ring-closing metathesis as a key step. The potential use of the compounds in the
synthesis of valienamine pseudodisaccharides is demonstrated using Mitsunobu coupling chemistry
directly between a carbohydrate sulfonamide and the carbasugar C-1 alcohols.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 4 November 2010
Revised 4 February 2011
Accepted 10 February 2011
6
6
5a
1. Introduction
OR
1
1
2
O
OR
OH
OH
OR
1
2
O
HO
RO
6
5
5
HO
2
D
-Fructose is amongst the most inexpensive of all known
3
3
4
4
4
HO
RO
5
3
HO
OH
organic materials, which makes its utilisation as a starting material
for synthesis attractive. Despite this, it has not been used as much
OH
OR
OH
III
I
II
as other carbohydrates.1
D
-Fructose II has an obvious structural
OR
similarity to
D-mannose I, with it being oxidised at C-5 and reduced
O
at C-1 (mannose numbering, Fig. 1).
OH
We have been interested in the synthesis of C-5@C-5a unsatu-
rated carbasugars III (valienamine derivatives) and their elabora-
tion into pseudooligosaccharide structures IV (Fig. 1). Efficient
and scalable routes to the benzyl-ether-protected building blocks
NH
OH
HO
HO
IV
OH
HO
mimicking
D-glucose (i.e., D D-galactose
-xylo configured)2 and
OH
(i.e., L-
L
-arabino configured)3 have been developed, starting from
Figure 1. Structures of
a
-mannoside I;
a
b-fructopyranoside II,
a
selectively
sorbose and lactose, respectively. We have reported the synthesis,
from mannose, of a carbocyclic building block with OH-1 and OH-2
free, and used this for the synthesis of valienamines, notably 1,2-
protected building block III for the synthesis of C-5@C-5 unsaturated carbocyclic
mannose mimics, for example, epi-valienamines and hydrolytically stable
analogue IV of Man( 1?6)Man incorporating a 2-epi-valienamine moiety. The
a
a
bis-epi-valienamine.4 The relationship between
D
-glucose and
-mannose and -fructose.
Herein we report the results of our investigation into how -man-
nose-mimicking (i.e., -lyxo configured) unsaturated carbasugars
-fructose using ring-closing metathesis
L-
numbering of the aldose, ketose and carbasugar is also illustrated.
sorbose is the same as that between
D
D
D
amine and its epimers11 and carbasugar pseudooligosaccharide
synthesis12 have all been recently reviewed.
D
may be synthesised from
as a key step.
D
Both of the C-1 diastereomeric mono-unprotected unsaturated
carbasugars 9 and 10 are new compounds, but related compounds
with different protecting group patterns have been synthesised be-
2. Results and discussion
The synthetic route began with the synthesis of the fructopyra-
fore, starting from D
-mannose4–6 or quinic acid.7,8 The areas of car-
nose hemiacetal 5 from
Fischer glycosylation with methanol gave the methyl
side as a single diastereomer in excellent yield.2 This reaction is
not extendable to fructose. Treatment of -fructose with HCl in
methanol gave a mixture of glycosides, including pyranosides
and furanosides. We found that the required methyl b- -pyrano-
D
-fructose 1 (Scheme 1). For sorbose,
basugar synthesis in general,9 ring-closing metathesis as a route to
carbasugars from carbohydrates,10 biological properties of valien-
a-L-pyrano-
D
D
⇑
Corresponding author. Tel.: +33(0)1 69 82 30 78; fax: +33(0)1 69 07 72 47.
E-mail addresses: ian.cumpstey@icsn.cnrs-gif.fr, ian.cumpstey@sjc.oxon.org
side could be isolated after perbenzylation of a partially purified
glycoside mixture in only 21% yield over two steps, both involving
(I. Cumpstey).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.02.013

400
C. Ramstadius et al. / Tetrahedron: Asymmetry 22 (2011) 399–405
X
OH
O
OR
O
O
O
HO
HO
BnO
BnO
(i)
(iii)
HO
OH
HO
OH
(ii)
OBn
(iv)
OH
OH
OBn
1
2
4
, X = Br
, X = H
, R = Et
5
, R = H
3
(v)
OH
O
OBz
OBn
OH
BnO
BnO
BnO
(vii)
(vi)
BnO
BnO
BnO
OBn
OBn
OBn
OBn
OBn
7
6
8
(viii)
OH
OH
OH
BnO
BnO
BnO
BnO
BnO
BnO
11
+
OBn
OBn
OBn
OBn
OBn
H
9
10
Scheme 1. Reagents and conditions: (i) 2-bromoethanol, 89%; (ii) Pd/C, H2, NaHCO3, H2O, 50 °C; (iii) BnBr, NaH, DMF, 74% from 2; (iv) AcOH, HCl(aq), 60 °C, 85%; (v) BzCl, py,
86%; (vi) (a) Ph3PCH3Br, tBuOK, PhMe, 0 °C; (b) NaOMe, MeOH, 84%; (vii) (a) (COCl)2, Me2SO, CH2Cl2, ꢀ78 °C, then Et3N, ꢀ78 °C?rt; (b) vinylmagnesium chloride, THF, 0 °C,
76%; (viii) Hoveyda–Grubbs II, toluene, 60 °C; 28% 9 + 59% 10.
difficult chromatographic separations. This problem has been
solved by Chittenden et al., who developed a Fischer glycosylation
in bromoethanol.13 The crystalline b-fructopyranoside 2 precipi-
tates from the reaction mixture, allowing an easy separation and
high-yielding reaction. We found that this procedure worked very
well, giving the fructopyranoside 2 in 89% yield, and was much
more reliable than a similar procedure reported by Chittenden
et al. using allyl alcohol,14 which worked poorly in our hands.
The bromide must be reduced before benzylation, and catalytic
hydrogenolysis over palladium gave the ethyl glycoside 3.13 Benzy-
lation gave the fully protected glycoside 4, and hydrolysis gave the
hemiacetal 5.15
We then synthesised the carbocycles broadly following the
pathway developed for the sorbose series.2 The direct formation
of the alkene 7 by Wittig methylenation of the hemiacetal 5 gave
the desired product, but the competing formation of the elimina-
tion product 11 was always observed. For example, our best reac-
tion conditions [pre-treatment of 5 with KHMDS (1 equiv) at 0 °C,
then addition to the ylid suspension (8.2 equiv, formed using
KHMDS) at rt in toluene] gave 7 in 45% yield, along with 23% of
11. More commonly, 11 was the major or exclusive product. A
higher-yielding, but longer route is via the open-chain ketone 6,
which was formed by treatment of the hemiacetal 5 with benzoyl
chloride and pyridine.
The contrasting behaviour of the tetrabenzyl and tetrabenzoyl
fructopyranose hemiacetals is noteworthy. It has been reported
that the tetrabenzoyl compound 12 (Fig. 2) is acylated on the
hemiacetal hydroxyl (O-2), giving a pyranose product 13 (with
the addition of DMAP).16 Here we have shown that the tetrabenzyl
derivative 5 is acylated on the primary hydroxyl (O-1), giving an
open-chain ketone 6, as we found in the sorbo series.2 This differ-
ence can be explained by considering the electronic properties of
the protecting groups.17 The benzoate esters are more electron-
withdrawing than the benzyl ethers, hence the open-chain keto
form of the benzoate protected sugar is more destabilised with re-
spect to its cyclic hemiacetal form 12, presumably to the extent
that it is not present at all for acylation. It should be noted that
in the NMR spectra of the benzyl-ether-protected hemiacetal 5,
only the hemiacetal and none of the keto form is seen, but presum-
ably the rate of ring-opening to form the relatively stable benzyl-
ether-protected keto form is higher than the rate of acylation of
the hindered hemiacetal OH group, allowing acylation of the reac-
tive primary OH group to occur.
OR
O
BzO
BzO
OBz
OBz
12, R = H
13, R = Bz
Figure 2.
Ketone 6 underwent a smooth Wittig methylenation, and meth-
oxide-mediated deprotection of the benzoate ester from the crude
product gave alkene 7. In forming 8 with a Swern oxidation fol-
lowed by Grignard addition, we did not attempt to optimise the
diastereoselectivity. It is noteworthy that a slight difference be-
tween vinylmagnesium bromide (3:1) and chloride (2:1) was seen.
Ring-closing metathesis with the Hoveyda–Grubbs II complex gave
the carbocycles 9 and 10, which were separable by chromatogra-
phy. The stereochemistry of the ring-closed products was assigned
3
by 1H NMR J1,2 coupling constants:18 4.2 Hz for 9 and 7.9 Hz for
10, the latter being consistent with a trans-relationship and an
3H2 conformation.

C. Ramstadius et al. / Tetrahedron: Asymmetry 22 (2011) 399–405
401
We examined Mitsunobu coupling as a method for forming the
C–N bond in a pseudodisaccharide:19–21 treatment of an almost
equimolar mixture of the b-lyxo alcohol 9 and a mannose-6-sulfon-
amide nucleophile 14 with DIAD and triphenylphosphine resulted
in the formation of a pseudodisaccharide product 15 as a single
diastereomer (Scheme 2). The nosyl activating group was removed
by a treatment with phenyl thiolate, to give the pseudodisaccha-
disaccharide with a b-lyxo configuration has been synthesised. The
proposition that the pseudodisaccharide- or pseudotetrasaccha-
ride-forming coupling reactions in validoxylamine and acarbose
biosynthesis proceed via SN reactions on valienol-derived allylic
electrophiles with nucleotide diphosphates as C-1 leaving groups22
makes the strategy reported in this paper for valienamine pseudo-
disaccharide synthesis bioreminiscent. We will report the results
of our further studies on the coupling reactions of the building
blocks in due course.
ride 16. Treating
a-lyxo alcohol 10 with sulfonamide 14, DIAD
and triphenylphosphine also resulted in the formation of a single
diastereomer of a pseudodisaccharide coupling product 17, albeit
in a much lower yield. Alternative degradation pathways competed
successfully with coupling in this case. A major by-product, which
was not isolated pure, appeared to be the product of elimination, a
diene, arising from the loss of a proton from C-6 and of the leaving
group from C-1, as judged by its 1H NMR spectrum, in particular
the appearance of three alkene protons at 5.72, 6.09, and 6.65 ppm.
4. Experimental
4.1. General
Melting points were measured on a Stuart SMP3 device and are
uncorrected. Proton nuclear magnetic resonance (1H) spectra were
recorded on a Bruker Avance II 500 (500 MHz) or a Bruker Avance II
400 (400 MHz) spectrometer; multiplicities are quoted as singlet
(s), doublet (d), doublet of doublets (dd), doublet of doublet of dou-
blets (ddd), triplet (t), apparent triplet (at), doublet of apparent
triplets (dat), quartet (q), and multiplet (m). Carbon nuclear mag-
netic resonance (13C) spectra were recorded on a Bruker Avance
II 500 (125 MHz) or a Bruker Avance II 400 (100 MHz) spectrome-
ter. 1H and 13C spectra and 13C multiplicities were assigned using
COSY, HSQC and DEPT experiments. All chemical shifts are quoted
on the d-scale in parts per million (ppm). Residual solvent signals
or TMS were used as the internal reference. High-resolution
(HRMS) electrospray (ESI+) mass spectra were recorded using a
Bruker Microtof instrument. Infra-red spectra were recorded on a
Perkin–Elmer Spectrum One FT-IR spectrometer using the thin film
method on NaCl plates. Optical rotations were measured on a
Perkin–Elmer 241 polarimeter with a path length of 1 dm; concen-
trations are given in g/100 mL. Thin layer chromatography (TLC)
was carried out on Merck Kieselgel sheets, pre-coated with
60F254 silica. Plates were visualised with UV light and developed
using 10% sulfuric acid, or an ammonium molybdate (10% w/v)
and cerium (IV) sulfate (2% w/v) solution in 10% sulfuric acid. Flash
OMe
NHNs
OBn
OBn
O
O
OMe
OBn
R
N
(i)
+
9
OBn
BnO
OBn
BnO
OBn
OBn
14
15, R = Ns
16, R = H
(ii)
OBn
OMe
O
NHNs
OBn
OBn
O
OMe
Ns
N
(iii)
+
10
OBn
BnO
OBn
OBn
BnO
OBn
OBn
14
17
OBn
Scheme 2. Reagents and conditions: (i) PPh3, DIAD, toluene, 0 °C?rt; (ii) PhSH,
K2CO3, DMF, 50 °C, 51% from 9; (iii) PPh3, DIAD, toluene, 0 °C?rt, 20%.
column chromatography was carried out on silica gel (35–70 lm,
3
Grace). Dichloromethane was distilled from calcium hydride. THF
and toluene were dried over molecular sieves and dispensed from
a solvent purifier by VAC. Reactions performed under an atmo-
sphere of hydrogen or argon were maintained by an inflated
balloon.
However, the, J1,2 coupling constants for the pseudodisaccha-
rides 15 and 16 could not be obtained due to spectral overlap. Nev-
ertheless, since the reactions were stereospecific (i.e., 9 led only to
15, and 10 led only to 17), we assigned the stereochemistry of the
pseudodisaccharides with inversion of configuration at C-1, as is
expected for stereospecific (SN2) Mitsunobu reactions. Moreover,
the coupling constants that could be obtained for the carbocyclic
rings were consistent with the assigned conformations. In 16, J2,3
(1.8 Hz) and J3,4 (3.5 Hz) are both small values, consistent with
the respective axial–equatorial and pseudodiequatorial relation-
ships in the expected 3H2 conformation.4 In 17, J1,2 (<1 Hz) and
J2,3 (<1 Hz) are both small, which is consistent with the
(pseudo)equatorial–axial relationships, while J3,4 (8.6 Hz) is large,
which is consistent with the pseudodiaxial relationship in the ex-
pected 2H3 conformation.4
4.2. 20-Bromoethyl b-
D-fructopyranoside 2
D-Fructose 1 (6.04 g, 33.5 mmol) was suspended in 2-bromoeth-
anol (35 mL) under Ar. After 16 h, an off-white precipitate had
formed, and Et3N (0.25 mL) was added. The solid material was fil-
tered and washed with cold EtOH (10 mL), EtOH–Et2O (1:10,
15 mL) and Et2O (15 mL) to yield the b-pyranoside 2 (8.53 g, 89%)
as a white powder, which could be recrystallised from water con-
taining 5% NaOAc; mp 140–142 °C (decomp.) (lit.13 126–129 °C
(decomp.)); ½a 2D6
ꢁ
¼ ꢀ114 (c 1.0, H2O) [lit.13 ꢀ131.5 (H2O)]; dH
(500 MHz, D2O) 3.58–3.63 (2H, m), 3.72–4.04 (9H, m); dC
(100 MHz, D2O) 34.5 (t, CH2CH2Br), 64.2, 64.4, 67.1 (3 ꢂ t, C-1, C-
6, CH2CH2Br), 71.2, 72.0, 72.4 (3 ꢂ d, C-3, C-4, C-5), 103.5 (s, C-
2); m/z (ESI+) Isotope distribution 325.1 (M+K+, 26), 323.1 (M+K+,
27), 311.0 (M+Na+, 98), 309.0 (M+Na+, 100%); HRMS (ESI+) calcd
for C8H15O6BrNa (M+Na+) 308.9944; found 308.9949.
3. Conclusion
Carbocyclic mannose mimics, differentially unprotected at
OH-1, are available from fructose in eight steps. The overall yield
for the synthesis of the major diastereomer was 19%. These epi-
valienol derivatives coupled with a carbohydrate sulfonamide to
give epi-valienamine pseudodisaccharides. The coupling reaction
of the b-lyxo C-1 alcohol to give the 1,2-trans-a-lyxo pseudodisac-
4.3. Ethyl 1,3,4,5-tetra-O-benzyl-b-D-fructopyranoside 4
charide is efficient. The -lyxo alcohol underwent decomposition
to a larger extent, although a pseudodisaccharide was formed in
low yield; in fact this is the first time such a valienamine pseudo-
a
20-Bromoethyl b-
NaHCO3 (4.1 g, 38.5 mmol) and Pd/C (675 mg, 10%, 0.63 mmol)
D-fructopyranoside (8.98 g, 31.9 mmol),

402
C. Ramstadius et al. / Tetrahedron: Asymmetry 22 (2011) 399–405
were suspended in water (75 mL). The suspension was degassed
and refilled with H2(g), and the mixture heated to 50 °C. After
22 h, the reaction mixture was allowed to cool to rt. Further Pd/C
(245 mg, 0.23 mmol) was added, and the suspension was degassed
and refilled with H2(g). The reaction mixture was stirred at 50 °C for
a further 17 h, after which the mixture was allowed to cool and
then filtered through cotton wool and sand. The resulting clear
solution was concentrated in vacuo to yield the crude ethyl glyco-
side 313 as a white solid (11 g, containing salts), which was used
without further purification; dH (400 MHz, D2O) 1.16 (3H, t, J
7.0 Hz, OCH2CH3), 3.57–3.67 (2H, m), 3.74–3.88 (4H, m), 3.95–
3.97 (2H, m), 4.05 (1H, m); dC (100 MHz, D2O) 14.6 (q, CH3), 56.7,
61.3, 63.8 (3 ꢂ t, C-1, C-6, CH2CH3), 71.2, 72.0, 72.4 (3 ꢂ d, C-3, C-
4, C-5), 103.5 (s, C-2); m/z (ESI+) 439 (2M+Na+, 59), 231 (M+Na+,
100%); HRMS (ESI+) calcd for C8H16O6Na (M+Na+) 231.0839; found
(125 MHz, CDCl3) 61.0 (t, C-6), 71.3, 72.1, 72.2, 73.9, 75.6 (5 ꢂ t,
C-1, 4 ꢂ PhCH2), 73.3, 75.9, 79.0 (3 ꢂ d, C-3, C-4, C-5), 98.2 (s, C-
2), 137.8, 138.2, 138.5, 138.5 (4 ꢂ s, 4 ꢂ Ar-C); selected data for
a-anomer: dC (125 MHz, CDCl3) 57.4 (t, C-6), 71.6, 73.6, 73.9,
74.2 (4 ꢂ t, 4 ꢂ PhCH2, C-1), 71.8, 74.5, 74.6 (3 ꢂ d, C-3, C-4, C-5),
97.5 (s, C-2), 137.2, 137.9, 138.2, 138.2 (4 ꢂ s, 4 ꢂ Ar-C); m/z
(ESI+) 1103 (2M+Na+, 15), 563 (M+Na+, 100%); HRMS (ESI+) calcd
for C34H36O6Na (M+Na+) 563.2404; found 563.2378.
4.5. 1,3,4,5-Tetra-O-benzyl-6-O-benzoyl-D-fructose 6
Hemiketal 5 (3.0 g, 5.55 mmol) was dissolved in pyridine
(10 mL) and BzCl (1.6 mL, 13.8 mmol) was added, which resulted
in the solution turning brown. After 17 h, TLC (pentane–EtOAc,
4:1) indicated complete consumption of the starting material (Rf
0.1) and formation of a major product (Rf 0.3). The reaction mixture
was diluted with EtOAc (150 mL) and washed with HCl (1 M aq,
3 ꢂ 50 mL). The combined aqueous phases were extracted with
EtOAc (2 ꢂ 50 mL). The combined organic extracts were washed
with NaHCO3 (satd aq, 2 ꢂ 50 mL), dried (MgSO4), filtered and con-
centrated in vacuo. The crude product was purified by flash column
chromatography (pentane–EtOAc, 7:1?6:1?5:1) to yield the
231.0828; calcd for
439.1763.
C
16H32O12Na (2M+Na+) 439.1786; found
Crude ethyl b-D-fructopyranoside 3 (11 g, 31.9 mmol) was sus-
pended in DMF (150 mL) under Ar, and benzyl bromide (23 mL,
194 mmol) was added. The resulting suspension was cooled to
0 °C, and NaH (60% in oil, 10.2 g, 255 mmol) was added portion-
wise over the course of 6 h. After a further 15 h, TLC (pentane–
EtOAc, 3:1) indicated the complete consumption of starting
material (Rf ꢃ0) and the formation of a major product (Rf 0.7).
The reaction was quenched by the addition of MeOH (25 mL),
and the mixture was transferred to a separatory funnel, diluted
with Et2O (200 mL) and washed with brine (200 + 100 mL). The
combined aqueous phases were extracted with Et2O
(3 ꢂ 100 mL). The combined organic extracts were dried (MgSO4),
filtered and concentrated in vacuo. The crude product was purified
by flash column chromatography (pentane–EtOAc, 10:1?8:1?6:1
?4:1) to yield the tetrabenzyl derivative 4 (13.5 g, 74% over two
steps) as a colourless oil, which could be recrystallised from
Et2O–heptane to give white crystals; mp 52–54 °C (Et2O–heptane);
open-chain ketone 6 (3.06 g, 86%) as a yellow oil; ½a D21
ꢁ
¼ ꢀ4:2 (c
1.0, CHCl3);
m
max/cmꢀ1 1720 (C@O); dH (500 MHz, CDCl3) 3.97
0
(1H, ddd, J5,6 2.6 Hz, J5,6 3.8 Hz, J4,5 7.8 Hz, H-5), 4.22–4.28 (2H,
m, H-4, PhCHH0 or H-1), 4.33–4.54 (8H, m, H-3, H-6, 2 ꢂ PhCH2,
PhCHH0 or H-1, PhCHH0 or H-10), 4.54, 4.60 (2H, 2 ꢂ d, J 10.8 Hz,
PhCH2), 4.73 (1H, d, J 11.3 Hz, PhCHH0 or H-10), 4.96 (1H, dd, J5,6
0
2.6 Hz, J6,6 12.3 Hz, H-60), 7.21–7.32 (20H, m, Ar-H), 7.47 (2H, m,
0
Ar-H), 7.60 (1H, m, Ar-H), 8.05 (2H, m, Ar-H); dC (125 MHz, CDCl3)
62.2 (t, C-6), 71.8, 73.4, 74.3, 74.5, 75.0 (5 ꢂ t, C-1, 4 ꢂ PhCH2), 76.7
(d, C-5), 79.4 (d, C-4), 84.4 (d, C-3), 128.1, 128.3, 128.3, 128.5,
128.5, 128.5, 128.5, 128.7 (8 ꢂ d, Ar-CH), 129.8, 133.2 (2 ꢂ d, Ar-
CH), 130.1 (s, Ar-C), 136.9, 137.3, 137.4, 137.8 (4 ꢂ s, Ar-C), 166.4
(s, OC@O), 208.5 (s, C-2); m/z (ESI+) 683 (M+K+, 27), 667 (M+Na+,
100%); HRMS (ESI+) calcd for C41H40O7Na (M+Na+) 667.2666; found
667.2697.
½
a 2D1
ꢁ
¼ ꢀ45:4 (c 1.0, CHCl3); dH (400 MHz, CDCl3) 1.17 (3H, t, J
7.1 Hz, CH2CH3), 3.49–3.66 (4H, m, H-1, H-6, CH2CH3), 3.78–3.81
(2H, m, H-10, H-5), 3.87 (1H, dd, J5,6 1.9 Hz, J6,6 12.5 Hz, H-60),
4.00 (1H, dd, J4,5 3.3 Hz, J3,4 10.1 Hz, H-4), 4.37 (1H, d, J3,4
10.1 Hz, H-3), 4.41 (1H, d, J 11.9 Hz, PhCHH0), 4.60–4.69 (4H, m,
PhCH2, PhCHH0, PhCHH0), 4.72, 4.78 (2H, 2 ꢂ d, J 12.6 Hz, PhCH2),
4.93 (1H, d, J 11.3 Hz, PhCHH0), 7.20–7.41 (20 H, m, Ar-H); dC
(100 MHz, CDCl3) 15.9 (q, CH3), 56.6 (t, CH2CH3), 61.1 (t, C-6),
70.3 (t, C-1), 71.2, 72.3, 73.6, 75.7 (4 ꢂ t, 4 ꢂ PhCH2), 73.9 (d, C-
5), 76.4 (d, C-3), 79.0 (d, C-4), 101.8 (s, C-2), 127.4, 127.5, 127.5,
127.7, 127.8, 127.8, 128.2, 128.3, 128.3, 128.3, 128.6 (11 ꢂ d, Ar-
CH), 138.2, 138.7, 138.9, 139.1 (4 ꢂ s, 4 ꢂ Ar-C); m/z (ESI+) 607
(M+K+, 5), 591 (M+Na+, 100%); HRMS (ESI+) calcd for C36H40O6Na
(M+Na+) 591.2717; found 591.2714.
0
0
4.6. (3R,4R,5R) 1,3,4,5-Tetra-O-Benzyl-2-methylene-hexane-
1,3,4,5,6-pentaol 7
4.6.1. Method 1: from the open-chain ketone 6
Triphenylmethylphosphonium bromide (4.0 g, 11.2 mmol) was
suspended in dry toluene (20 mL) under Ar, and potassium tert-
butoxide (1.2 g, 10.7 mmol) was added. The resulting suspension
was heated to 80 °C, and after a few minutes, the suspension
turned yellow. After a further 45 min, the suspension containing
the ylid was allowed to cool to rt, and then cooled to 0 °C. Ketone
6 (3.03 g, 4.70 mmol) was dissolved in dry toluene (10 + 5 mL) and
added to the ylid by cannula. After 10 min, TLC (pentane–EtOAc,
4:1) indicated complete consumption of the starting material (Rf
0.4) and the formation of a major product (Rf 0.7). Next, MeOH
(0.5 mL) was added to the reaction mixture, and after a further
2 h, no change was observed according to TLC. The reaction mix-
ture was diluted with toluene–EtOAc (1:1, 50 mL), filtered through
Celite and concentrated in vacuo.
The crude residue was dissolved in MeOH (15 mL). Sodium
(65 mg, 2.8 mmol) was added to MeOH (8 mL), and the resulting
solution was added to the carbohydrate solution by pipette. After
22 h, TLC (pentane–EtOAc, 3:1) indicated the complete consump-
tion of the starting material (Rf 0.8) and the formation of a major
product (Rf 0.3). Next, HCl (1 M aq, 4 mL) was added, and the mix-
ture was concentrated in vacuo. The resulting residue was dis-
solved in EtOAc (100 mL) and washed with HCl (1 M aq, 100 mL).
The aqueous phase was re-extracted with EtOAc (50 mL), and the
combined organic extracts were washed with NaHCO3 (satd aq,
4.4. 1,3,4,5-Tetra-O-benzyl-a,b-D-fructopyranose 5
Ethyl glycoside 4 (5.25 g, 9.2 mmol) was dissolved in AcOH
(25 mL) and HCl (1 M aq, 2 mL) was added. The resulting solution
was heated to 60 °C. After 3.5 h, TLC (pentane–EtOAc, 3:1) indi-
cated complete consumption of the starting material (Rf 0.7) and
the formation of a minor (Rf 0.6) and a major product (Rf 0.2).
The reaction mixture was allowed to cool to rt and then partitioned
between EtOAc (150 mL) and H2O (200 mL). Solid NaHCO3 was
added until the resulting evolution of gas ceased. The aqueous
phase was re-extracted with EtOAc (2 ꢂ 100 mL). The combined
organic extracts were dried (MgSO4), filtered and concentrated in
vacuo. The crude product was purified by flash column chromatog-
raphy (pentane–EtOAc, 4:1?5:2?2:1) to yield the hemiketal 5
(4.23 g, 85%,
a
:b, 1:5) as a yellow oil;15 selected data for b-anomer:
dH (400 MHz, CDCl3) 3.46, 3.53 (2H, 2 ꢂ d, J1,1 10.0 Hz, H-1, H-10),
0
4.78 (1H, d, J 12.6 Hz, PhCHH0), 4.94 (1H, d, J 12.6 Hz, PhCHH0); dC

C. Ramstadius et al. / Tetrahedron: Asymmetry 22 (2011) 399–405
403
2 ꢂ 100 mL). The aqueous phases were combined and extracted
with EtOAc (50 mL). The combined organic phases were dried
(MgSO4), filtered and concentrated in vacuo. The crude product
was purified by flash column chromatography (CH2Cl2–Et2O,
50:1?40:1?30:1) to yield the alkene 7 (2.12 g, 84%) as a colour-
(100 mL). The aqueous phase was re-extracted with CH2Cl2
(2 ꢂ 30 mL). The combined organic extracts were dried (Na2SO4),
filtered and concentrated in vacuo, to yield the crude aldehyde
(6.8 g) as a yellow solid.
The crude aldehyde was dissolved in THF (10 mL), and cooled to
0 °C under Ar. Vinylmagnesium chloride (2.4 mL, 4.1 mmol) was
added. After 15 min, TLC (pentane–EtOAc, 3:1) indicated the com-
plete consumption of aldehyde (Rf 0.8) and the formation of a ma-
jor product (Rf 0.7). The reaction was quenched by the addition of
NH4Cl (satd aq, 6 mL). The mixture was diluted with EtOAc
(100 mL) and washed with saturated NH4Cl (satd aq, 100 mL).
The aqueous phase was extracted with EtOAc (2 ꢂ 50 mL) and
the combined organic extracts were dried (MgSO4), filtered and
concentrated in vacuo. The crude product was purified by flash col-
umn chromatography (pentane–EtOAc, 6:1?5:1) to yield the
dienes 8a,b (941 mg, dr 2:1, 76% over two steps), an inseparable
mixture of diastereomers, as a yellow oil; Selected data for major
diastereomer: dH (400 MHz, CDCl3) 3.04 (1H, d, JOH,6 7.7 Hz, OH-
6), 3.74 (1H, dd, J5,6 1.9 Hz, J4,5 6.8 Hz, H-5); dC (125 MHz, CDCl3)
70.7, 70.7, 72.9, 73.4, 75.3 (5 ꢂ t, C-1, 4 ꢂ PhCH2), 71.4 (d, C-6),
79.9 (d, C-5), 80.4 (d, C-3), 80.7 (d, C-4), 115.1 (t, C-8), 116.4 (t,
C-2a), 139.2 (d, C-7), 142.8 (s, C-2); Selected data for minor diaste-
reomer: dH (400 MHz, CDCl3) 2.92 (1H, br s, OH-6), 3.66 (1H, dd, J
5.2 Hz, J 5.9 Hz, H-5); dC (125 MHz, CDCl3) 70.8, 70.9, 72.9, 73.1,
74.9 (5 ꢂ t, C-1, 4 ꢂ PhCH2), 73.1 (d, C-6), 81.0, 81.9, 82.3 (3 ꢂ d,
C-5), 115.9 (t, C-8), 116.9 (t, C-2a), 142.9 (s, C-2); m/z (ESI+) 587
(M+Na+, 100%); HRMS (ESI+) calcd for C37H40O5Na (M+Na+)
587.2768; found 587.2803.
less oil; ½a 2D2
¼ ꢀ6:5 (c 1.0, CHCl3); dH (500 MHz, CDCl3) 2.26 (1H,
ꢁ
at, J 6.2 Hz, OH-6), 3.66 (1H, m, H-5), 3.79–3.81 (2H, m, H-6, H-
60), 3.89 (1H, at, J 5.3 Hz, H-4), 4.03, 4.08 (2H, 2 ꢂ d, J1,1 12.7 Hz,
0
H-1, H-10), 4.19 (1H, d, J3,4 5.1 Hz, H-3), 4.28, 4.40 (2H, 2 ꢂ d, J
11.5 Hz, PhCH2), 4.32, 4.61 (2H, 2 ꢂ d, J 11.7 Hz, PhCH2), 4.51,
4.55 (2H, 2 ꢂ d, J 11.5 Hz, PhCH2), 4.70, 4.73 (2H, 2 ꢂ d, J 11.1 Hz,
PhCH2), 5.41 (1H, br s, H-2a), 5.47 (1H, m, H-2a0), 7.21–7.38
(20H, m, Ar-H); dC (125 MHz, CDCl3) 60.9 (t, C-6), 70.6 (t, C-1),
71.0, 71.6, 72.9, 75.3 (4 ꢂ t, 4 ꢂ PhCH2), 79.2 (d, C-5), 80.5 (d, C-
4), 81.2 (d, C-3), 116.6 (t, C-2a), 127.8, 128.3, 128.4, 128.4, 128.5,
128.5, 128.5 (7 ꢂ d, Ar-CH), 138.3, 138.4 (2 ꢂ s, Ar-C), 142.8 (s, C-
2); m/z (ESI+) 1099 (2M+Na+, 32), 561 (M+Na+, 100%); HRMS
(ESI+) calcd. for C35H38O5Na (M+Na+) 561.2612; found 561.2612.
4.6.2. Method 2: directly from the hemiketal 5
Triphenylmethylphosphonium bromide (1.25 g, 3.50 mmol)
was suspended in dry toluene (2 mL) under Ar and cooled to
0 °C. Potassium bis(trimethylsilyl)amide (5.15 mL, 3.40 mmol,
15% solution in toluene by weight) was added, upon which the
resulting suspension turned yellow. After 55 min, hemiketal 5
(225 mg, 0.416 mmol) was dissolved in toluene (1.5 mL) under Ar
and cooled to 0 °C. Potassium bis(trimethylsilyl)amide (620 lL,
0.410 mmol) was added to this hemiketal solution. After 5 min,
the hemiketal solution was transferred to the ylid suspension by
cannula (rinsing with 0.5 mL toluene). The resulting reaction mix-
ture was maintained at 0 °C for 1 h, after which it was slowly al-
lowed to warm to rt. After 12 h 40 min, TLC (CH2Cl2–Et2O, 30:1)
indicated the complete consumption of starting material (Rf 0.4)
and the formation of the desired alkene (Rf 0.3) and of the unde-
sired diene (Rf 0.2). The mixture was filtered through Celite, eluting
with toluene–EtOAc (10:1) and the filtrate was concentrated in va-
cuo. The crude residue was purified by flash column chromatogra-
phy (CH2Cl2–Et2O, 50:1?40:1?30:1?20:1) to yield 7 (100 mg,
45%) as a colourless oil identical to that described above and elim-
ination product 11 (42 mg, 23%) as a colourless oil. Data for 11: dH
(400 MHz, CDCl3) 2.12 (1H, s, OH-6), 3.39–3.50 (2H, m, H-6, H-60),
4.19 (2H, m, H-1, H-10), 4.28, 4.51 (2H, 2 ꢂ d, J 11.7 Hz, PhCH2), 4.43
(1H, ddd, J 3.9 Hz, J 7.6 Hz, J4,5 9.1 Hz, H-5), 4.59 (2H, s, PhCH2),
4.69, 4.75 (2H, 2 ꢂ d, J 11.4 Hz, PhCH2), 5.15 (1H, d, J4,5 9.1 Hz, H-
4), 5.50 (1H, d, J 1.3 Hz, H-2a), 5.61 (1H, d, J 1.4 Hz, H-2a0), 7.28–
7.40 (15H, m, Ar-H); dC (100 MHz, CDCl3) 65.3 (t, C-6), 70.5, 72.4,
73.5 (3 ꢂ t, 3 ꢂ PhCH2), 70.6 (t, C-1), 74.7 (d, C-5), 113.7 (d, C-4),
117.1 (t, C-2a), 137.0, 138.1, 138.6, 138.9, 155.8 (5 ꢂ s, C-2, C-3,
3 ꢂ Ar-C).
4.8. 2,3,4,6-Tetra-O-benzyl-5a-carba-b-D-lyxo-hex-5(5a)-
enopyranose 9 and 2,3,4,6-tetra-O-benzyl-5a-carba-a-D-lyxo-
hex-5(5a)-enopyranose 10
Dienes 8a,b (941 mg, 1.67 mmol) were dissolved in dry toluene
(60 mL) under Ar. Next, Hoveyda–Grubbs’ 2nd generation complex
(10 mg, 0.016 mmol) was added, and the dark green reaction mix-
ture was heated to 60 °C. After 4.5 h, TLC (toluene–EtOAc, 6:1) indi-
cated the presence of the starting material (Rf 0.6) and the
formation of two major products (Rf’s 0.3 and 0.1). An additional
portion of Hoveyda–Grubbs’ 2nd generation complex (5 mg,
0.008 mmol) was added, and after a further 2 h 15 min, TLC indi-
cated complete consumption of the starting material and the for-
mation of the products. The reaction mixture was allowed to cool
to rt and DMSO (90 lL, 50 equiv vs Hoveyda–Grubbs’ complex)
was added. After 16 h, the reaction mixture was concentrated in
vacuo and the residue was purified by flash column chromatogra-
phy (toluene?toluene–EtOAc, 20:1?15:1?10:1) to yield carbocy-
cle 9 (251 mg, 28%) as a white solid, which was recrystallised; mp
72–73 °C (Et2O–pentane); ½a D24
ꢁ
¼ ꢀ56:0 (c 1.0, CHCl3);
m
max/cmꢀ1
3525 (OH); dH (400 MHz, CDCl3) 3.03 (1H, d, JOH,1 11.1 Hz, OH-1),
3.87–3.93 (2H, m, H-3, H-6), 3.96 (1H, dd, J2,3 1.8 Hz, J1,2 4.2 Hz,
H-2), 4.18–4.27 (3H, m, H-1, H-4, H-60), 4.37 (1H, d, J 11.9 Hz,
PhCHH0), 4.49–4.52 (2H, m, PhCHH0, PhCHH0), 4.58 (1H, d, J
11.2 Hz, PhCHH0), 4.64, 4.72 (2H, 2 ꢂ d, J 11.9 Hz, PhCH2), 4.77
(2H, s, PhCH2), 5.92 (1H, d, J 5.9 Hz, H-5a), 7.19–7.39 (20H, m,
Ar-H); dC (125 MHz, CDCl3) 65.8 (d, C-1), 70.5 (t, C-6), 71.8, 72.0,
73.2, 73.9 (4 ꢂ t, 4 ꢂ PhCH2), 75.3 (d, C-2 and C-4), 79.4 (d, C-3),
127.7, 127.8, 127.9, 128.0, 128.0, 128.2, 128.5, 128.5, 128.6, 128.6
(10 ꢂ d, Ar-CH), 129.0 (d, C-5a), 135.1, 138.0, 138.2, 138.3, 138.5
(5 ꢂ s, C-5, 4 ꢂ Ar-C); m/z (ESI+) 1095 (2M+Na+, 17), 559 (M+Na+,
100%); HRMS (ESI+) calcd for C35H36O5Na (M+Na+) 559.2455; found
559.2427; calcd for C70H72O10Na (2M+Na+) 1095.5018; found
1095.4967.
4.7. (3R,4R,5R,6RS)-1,3,4,5-Tetra-O-benzyl-1,3,4,5,6-
pentahydroxy-2-methylene-oct-7-ene 8a,b
Oxalyl chloride (0.65 mL, 7.6 mmol) was dissolved in CH2Cl2
(5 mL, freshly distilled) under Ar at ꢀ78 °C. Next, Me2SO
(1.15 mL, 16.2 mmol) was dissolved in CH2Cl2 (20 mL, freshly dis-
tilled) under Ar at ꢀ78 °C and then transferred to the oxalyl chlo-
ride solution by cannula. After 45 min, a solution of alcohol 7
(1.18 g, 2.19 mmol) in CH2Cl2 (8 + 4 mL) was transferred to the
reaction vessel at ꢀ78 °C. After 30 min, Et3N (2.9 mL, 20.9 mmol)
was added to the reaction mixture at ꢀ78 °C, and the mixture
was then allowed to warm to rt. After an additional 15 min, TLC
(pentane–EtOAc, 3:1) indicated the complete consumption of
starting material (Rf 0.3) and the formation of a major product
(Rf 0.8). The reaction mixture was diluted with CH2Cl2 (100 mL),
And carbocycle 10 (532 mg, 59%) as
¼ þ10:4 (c 1.0, CHCl3);
max/cmꢀ1 3435 (OH); dH (400 MHz,
CDCl3) 2.22 (1H, s, OH-1), 3.73 (1H, dd, J1,2 7.9 Hz, J2,3 2.2 Hz,
a colourless oil;
½
a 2D3
ꢁ
m
transferred to
a separatory funnel and washed with H2O

404
C. Ramstadius et al. / Tetrahedron: Asymmetry 22 (2011) 399–405
H-2), 3.89–3.92 (2H, m, H-3, H-6), 4.07 (1H, d, J3,4 3.1 Hz, H-4), 4.17
J2,3 1.8 Hz, J3,4 3.5 Hz, H-3II), 4.03 (1H, d, J3,4 3.5 Hz, H-4II), 4.10
II
(1H, dat, Jat 1.4 Hz, J6,6 12.4 Hz, H-60), 4.38 (1H, d, J 11.8 Hz,
(1H, d, J6,6 12.1 Hz, H-60 ), 4.24 (1H, d, J 11.8 Hz, PhCHH0),
0
0
PhCHH0), 4.46 (2H, s, PhCH2), 4.51 (1H, d, J 11.8 Hz, PhCHH0),
4.58–4.60 (4H, m, H-1, PhCH2, PhCHH), 4.66 (1H, d, J 12.4 Hz,
PhCHH0), 5.87 (1H, m, H-5a), 7.21–7.23 (2H, m, Ar-H), 7.30–7.37
(18H, m, Ar-H); dC (125 MHz, CDCl3) 68.2 (d, C-1), 70.6 (t, C-6),
71.8, 72.1, 72.6, 73.6 (4 ꢂ t, 4 ꢂ PhCH2), 74.1 (d, C-3), 74.9 (d, C-
4), 80.5 (d, C-2), 127.9, 127.9, 127.9, 128.0, 128.0, 128.1, 128.4,
128.5, 128.5, 128.6 (10 ꢂ d, Ar-CH), 129.5 (d, C-5a), 134.3, 138.3,
138.4, 138.4, 138.5 (5 ꢂ s, C-5, 4 ꢂ Ar-C); m/z (ESI+) 559 (M+Na+,
100%); HRMS (ESI+) calcd for C35H36O5Na (M+Na+) 559.2455; found
559.2454.
4.38–4.58 (11H, m, H-1I, PhCHH0, PhCHH0, 4 ꢂ PhCH2), 4.62,
4.68 (2H, 2 ꢂ d, J 12.3 Hz, PhCH2), 4.80 (1H, d, J 11.8 Hz, PhCHH0),
5.73 (1H, s, H-5aII), 7.12–7.29 (35H, m, Ar-H); dC (125 MHz,
CDCl3) 47.2 (t, C-6I), 54.9 (q, OCH3), 54.9 (d, C-1II), 71.0 (t, C-
6II), 71.5, 71.8, 72.3, 73.0, 73.7, 75.1 (6 ꢂ t, PhCH2), 71.3, 74.9⁄,
75.0, 75.2, 76.8, 77.2 (6 ꢂ d, C-2I, C-4I, C-5I, C-2II, C-3II, C-4II),
80.4 (d, C-3I), 99.1 (d, C-1I), 127.6, 127.6, 127.7, 127.7, 127.7,
127.8, 127.8, 127.9, 128.0, 128.1, 128.4, 128.4, 128.5 (13 ꢂ d,
Ar-CH), 129.3⁄ (d, C-5aII), 134.2⁄ (s, C-5II), 138.5, 138.5, 138.6,
138.6, 138.7, 138.8 (6 ꢂ s, Ar-C); m/z (ESI+) 1004 (M+Na+, 27),
982 (M+H+, 100%); HRMS (ESI+) calcd for C63H68O9N 982.4889
(M+H+); found 982.4856; calcd for C63H67O9NNa 1004.4714
(M+Na+); found 1004.4639.
4.9. Methyl 6-N-[2,3,4,6-tetra-O-benzyl-5a-carba-
5(5a)-enopyranosyl]-6-amino-2,3,4-tri-O-benzyl-6-deoxy-6-N-
(2-nitrobenzenesulfonyl)- -mannopyranoside 15
a-D-lyxo-hex-
a
-D
⁄Low intensity signals.
Alcohol 9 (31 mg, 0.058 mmol) and sulfonamide 14 (46 mg,
0.071 mmol) were dissolved in toluene (2 mL) under Ar. Triphenyl-
phosphine (60 mg, 0.23 mmol) was added, and the resulting yel-
4.11. Methyl 6-N-[2,3,4,6-tetra-O-benzyl-5a-carba-b-
5(5a)-enopyranosyl]-6-amino-2,3,4-tri-O-benzyl-6-deoxy-6-N-
(2-nitrobenzenesulfonyl)- -mannopyranoside 17
D-lyxo-hex-
a-D
lowish solution was cooled to 0 °C. Next, DIAD (50 lL,
0.26 mmol) was added, and the reaction mixture was left to warm
slowly to rt. After 5.5 h, TLC (toluene–EtOAc, 4:1) indicated the for-
mation of a major product (Rf 0.6) and the presence of some
remaining alcohol (Rf 0.4) and sulfonamide (Rf 0.5) starting mate-
rials. The reaction mixture was concentrated in vacuo and the
crude residue was purified twice by flash column chromatography
(toluene?toluene–EtOAc, 30:1?15:1?10:1) to yield pseudodi-
saccharide 15 (41 mg, slightly contaminated by DIAD residue) as
a yellow oil; dH (500 MHz, CDCl3) 3.16 (3H, s, OCH3), 3.64–3.77
Alcohol 10 (30 mg, 0.056 mmol) and sulfonamide 14 (46 mg,
0.071 mmol) were dissolved in toluene (2 mL) under Ar. Triphenyl-
phosphine (60 mg, 0.23 mmol) was added, and the resulting yel-
lowish solution was cooled to 0 °C. Next, DIAD (48 lL,
0.25 mmol) was added, and the reaction mixture was left to warm
slowly to rt. After 5.5 h, TLC (toluene–EtOAc, 4:1) indicated the for-
mation of two products (Rf’s 0.7 and 0.6) and the presence of some
alcohol (Rf 0.2) and sulfonamide (Rf 0.5) starting materials. The
reaction mixture was concentrated in vacuo and the crude residue
purified twice by column chromatography (toluene?toluene–
EtOAc, 30:1?15:1 ?10:1), to yield an elimination product
(17 mg, 59%) as a colourless oil; data for the major component:
dH (400 MHz, CDCl3) 3.95–4.01 (2H, m, H-2, H-3), 4.39, 4.53 (2H,
2 ꢂ d, J 12.2 Hz, PhCH2), 4.44 (1H, m, H-4), 4.64–4.75 (4H, m,
2 ꢂ PhCH2), 4.89, 4.95 (2H, 2 ꢂ d, J 12.6 Hz, PhCH2), 5.72 (1H,
ddd, J 1.3 Hz, J 2.6 Hz, J1,5a 10.2 Hz, H-1), 6.09 (1H, s, H-6), 6.65
(1H, dat, Jat 1.0 Hz, J1,5a 10.2 Hz, H-5a), 7.15–7.17 (2H, m, Ar-H),
7.24–7.48 (18H, m, Ar-H).
I
(4H, m, H-2I, H-6I, H-60 ), 3.85–3.91 (3H, m), 4.00–4.03 (2H, m),
4.09–4.14 (2H, m, H-2II), 4.23 (2H, m, PhCH2), 4.33 (1H, d, J
11.8 Hz, PhCHH0), 4.44–4.71 (11H, m, H-1I, 4 ꢂ PhCH2, PhCHH0,
PhCHH0), 4.95–4.97 (2H, m, H-1II, PhCHH0), 5.80 (1H, s, H-5aII),
7.11–7.44 (38H, m, Ar-H), 7.90 (1H, d,
J 7.9 Hz, Ar-H); dC
(125 MHz, CDCl3) 47.7⁄ (t, C-6I), 55.4 (q, OCH3), 57.3⁄ (d, C-1II),
70.4, 70.7, 71.4, 72.1, 72.6, 72.8, 73.6, 74.5 (8 ꢂ t, C-6II, 7 ꢂ PhCH2),
74.4, 74.8, 77.0, 80.2 (4 ꢂ d), 99.0 (d, C-1I), 124.0, 127.4, 127.5,
127.6, 127.6, 127.7, 127.7, 127.8, 127.9, 128.1, 128.3, 128.3,
128.4, 128.4, 128.4, 128.5, 128.5 (17 ꢂ d, C-5aII, Ar-CH), 131.1,
131.2, 132.8 (3 ꢂ d, Ar-CH), 133.6 (s, C-5II), 138.2, 138.4, 138.4,
138.5, 138.5, 138.7, 138.8 (7 ꢂ s, Ar-C), 148.0, 150.2 (2 ꢂ s, Ar-C);
m/z (ESI+) 1189 (M+Na+, 100%); HRMS (ESI+) calcd for C69H70O13
N2SNa (M+Na+) 1189.4491; found 1189.4517.
And pseudodisaccharide 17 (13 mg, 20%) as a colourless oil;
dH (500 MHz, CDCl3) 2.97 (3H, s, OCH3), 3.24 (1H, at, J 9.0 Hz,
H-4I), 3.59–3.71 (4H, m, H-2I, H-3I, H-5I, H-6I), 3.90 (1H, d, J3,4
8.6 Hz, H-3II), 3.93 (1H, d, J6,6 12.6 Hz, H-6II), 4.09–4.12 (2H, m,
0
I
H-60 , PhCHH0), 4.28 (1H, d, J 10.7 Hz, PhCHH0), 4.33 (1H, d, J
⁄Signals nearly invisible, can be perceived as minor ‘bumps’
only. Many signals in the 1H NMR spectrum appear very broad. Sig-
nals are not observed for some carbons in the 13C NMR spectrum.
11.6 Hz, PhCHH0), 4.39 (1H, s, H-2II), 4.47–4.60 (8H, m, H-1I, H-
II
4II, H-60 , PhCHH0, 2 ꢂ PhCH2), 4.67 (1H, d, J 11.6 Hz, PhCHH0),
4.72–4.78 (3H, m, PhCHH0, 2 ꢂ PhCHH0), 4.83 (1H, s, H-1II), 4.86
(1H, d, J 10.8 Hz, PhCHH0), 4.97 (1H, d, J 10.8 Hz, PhCHH0), 6.15
(1H, s, H-5aII), 7.05–7.60 (36H, m, Ar-H), 7.61–7.66 (2H, m, Ar-
H), 7.98 (1H, d, J 8.0 Hz, Ar-H); dC (125 MHz, CDCl3) 49.8 (t, C-
6I), 54.7 (q, OCH3), 58.6 (d, C-1II), 70.1, 74.3, 80.1 (3 ꢂ d, C-2I,
C-3I, C-5I), 77.0⁄ (d, C-4II), 77.5⁄ (d, C-4I), 80.0 (d, C-2II), 83.9
(d, C-3II), 98.8 (d, C-1I), 123.9 (d, Ar-CH), 125.4 (d, C-5aII),
127.4, 127.5, 127.6, 127.7, 127.8, 127.8, 128.0, 128.2, 128.4,
128.4, 128.5, 128.5 (12 ꢂ d, Ar-CH), 131.8, 132.2, 133.6 (3 ꢂ d,
Ar-CH), 134.7 (s, C-5II), 138.0, 138.2, 138.4, 138.5, 138.7, 138.8,
138.9, 138.9, 148.1 (9 ꢂ s, 9 ꢂ Ar-C); m/z (ESI+) 1189 (M+Na+,
100%); HRMS (ESI+) calcd for C69H70O13N2SNa (M+Na+)
1189.4491; found 1189.4458.
4.10. Methyl 6-N-[2,3,4,6-tetra-O-benzyl-5a-carba-a-D-lyxo-hex-
5(5a)-enopyranosylamino]-2,3,4-tri-O-benzyl-6-deoxy-a-D-
mannopyranoside 16
Sulfonamide 15 (40 mg) was dissolved in DMF (1 mL), and
thiophenol (15 L, 0.15 mmol) was added. Potassium carbonate
l
(34 mg, 0.24 mmol) was added, and the resulting mixture was
heated to 50 °C. After 1 h 15 min, TLC (toluene–EtOAc, 4:1) indi-
cated the complete consumption of the starting material (Rf 0.7)
and the formation of a major product (Rf 0.1). The reaction mix-
ture was allowed to cool to rt and then concentrated in vacuo.
The crude product was purified by flash column chromatography
(toluene–EtOAc, 8:1?5:1?2:1, 1% NEt3) to yield the pseudodi-
saccharide amine 16 (29 mg, 51% over two steps) as a colourless
⁄Chemical shifts estimated from HSQC spectrum due to overlap
with CDCl3 peaks.
oil; ½a 2D2
ꢁ
þ 27:6 (c 1.0, CHCl3); dH (500 MHz, CDCl3) 2.69 (1H, dd,
Acknowledgement
J5,6 8.1 Hz, J6,6 12.0 Hz, H-6I), 2.86 (1H, dd, J5,6 2.1 Hz, J6,6
0
0
0
11.9 Hz, H-60 ), 3.17 (3H, s, OCH3), 3.58–3.71 (5H, m, H-2I, H-4I,
H-5I, H-1II, H-2II), 3.74–3.80 (2H, m, H-3I, H-6II), 3.84 (1H, dd,
We are grateful to Vetenskapsrådet (the Swedish research
council) for support.
I

C. Ramstadius et al. / Tetrahedron: Asymmetry 22 (2011) 399–405
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