Stereoselective synthesis by double reductive amination ring closure of novel aza-heteroannulated sugars

Article abstract of DOI:10.1016/j.tet.2009.04.011

We present here the stereoselective synthesis of a series of 2/3-N-pyrrolidine derivatives of glycosides produced by diastereoselective double reductive amination ring closure of 1,4-dicarbonyl compounds. These precursors were produced by tandem ozonolysi

Full text of DOI:10.1016/j.tet.2009.04.011

Tetrahedron 65 (2009) 4766–4774
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Stereoselective synthesis by double reductive amination ring closure of novel
aza-heteroannulated sugars
,
a
Dominic M. Laventine a, Michelle Davies a, Emma L. Evinson b, Paul R. Jenkins a , Paul M. Cullis ,
*
a
, ,
y
*
´
Marcos D. Garcıa
a Department of Chemistry, University of Leicester, Leicester LE1 7RH, UK
b MolecularNature Ltd, Plas Gogerddan, Aberystwyth, Ceredigion SY23 3EB, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
We present here the stereoselective synthesis of a series of 2/3-N-pyrrolidine derivatives of glycosides
produced by diastereoselective double reductive amination ring closure of 1,4-dicarbonyl compounds.
These precursors were produced by tandem ozonolysis–reduction or Wacker oxidation of known al-
kenes. The potential of these new compounds as glycosidase inhibitors is illustrated for compound 16,
Received 18 December 2008
Received in revised form 30 March 2009
Accepted 2 April 2009
Available online 10 April 2009
showing selective inhibition of b-D-galactosidase.
Ó 2009 Published by Elsevier Ltd.
1. Introduction
compounds.6 Extension of this approach to include aza-heterocycles
was expected to provide a facile route to substituted pyrrolidines.
Production of the desired compounds by double reductive amina-
tion of a 1,4-dicarbonyl precursor was envisaged. Several examples
of highly stereoselective double reductive amination ring closures
indicated the broad applicability of the intended approach.7
The potential to create a diverse range of derivatives by altering
the substituent on the nitrogen of the resulting pyrrolidine was also
attractive, as it allows for possible optimization of any observed
biological activity. The stereoselective synthesis of such compounds
has therefore attracted considerable interest.
The inhibition of glycosidase enzymes by small molecules is
a subject of considerable current interest inspired by potential
therapeutic applications in treatment of cancer, HIV and diabetes.1
Glycosidase inhibitors2 (Fig. 1) fall into two categories: structures
like nojirimycin 1 are amino sugars with an anomeric centre while
other compounds like castanospermine 2 lack an hydroxyl group
adjacent to the endocyclic heteroatom.3 In these compounds, the
presence of a nitrogen that can be protonated is apparently suffi-
cient to give high glycosidase inhibitory activity.2 Mannostatin A (3)
is a potent glycosidase inhibitor where the basic nitrogen has been
shown to be essential for activity,4 indeed acetylation of this amino
group destroys inhibitory activity.5
In the preliminary publication on this work,8 we demonstrated
that the project was indeed viable, developing a versatile and ef-
ficient methodology for the construction of 2-N-substituted pyr-
rolidine rings on carbohydrate scaffolds. In the present work, we
report in full an extended study of the methodology, including
modifications on the regio- and stereochemistry of the ring junc-
tion between the sugar and pyrrolidine moieties, leading to target
compounds of type I/II (Fig. 2). The potential of the resulting
Our previous work has focused on the use of carbohydrates as
scaffolds for the stereoselective construction of various cyclic
H
N
OH
OH
OH
OH
OH
H
HO
HO
HO
HO
HO
HO
NH2
N
SCH3
7
7
OH
1
6
6
OMe
O
3
OMe
5
5
O
3
1
1
O
O
2
3
H
8
H
4
2
4
2
R''
Ph
O
O
Figure 1. Selected glycosidase inhibitors nojirimycin 1, castanospermine 2 and man-
nostatin A 3.
Ph
N
H
R
9
N
9
8
R
R'
Type I target compounds
(2-N-pyrrolidine derivatives)
R = H, Me
Type II target compounds
(3-N-pyrrolidine derivatives)
R= alquil, aryl, etc...
* Corresponding authors. Tel.: þ44 (0)116 252 2124; fax: þ44 (0)116 252 3789.
E-mail addresses: kin@leicester.ac.uk (P.R. Jenkins), mdgarcia@udc.es
R' = H, α/β-Me
´
(M.D. Garcıa).
R'' = alquil, aryl, etc...
y
Present address: Departamento de Quı´mica Fundamental, Universidade da
Corun˜a, campus da Zapateira, A Corun˜a 15071, Spain.
Figure 2. Type I/II target aza-heteroannulated sugars.
0040-4020/$ – see front matter Ó 2009 Published by Elsevier Ltd.
doi:10.1016/j.tet.2009.04.011

D.M. Laventine et al. / Tetrahedron 65 (2009) 4766–4774
4767
Table 1
modified sugars as glycosidase inhibitors is exemplified by the
appreciable -galactosidase inhibition activity of the deprotected
sugar derivative 16.
2-N-Pyrrolidines synthesized in the present work
b-D
Compound
R1
R2
R3
Yielda (%)
11a
11b
11c
11d
11e
11f
11g
11h
11i
H
H
H
H
H
H
H
H
H
H
iPr
Et
H
H
H
H
H
H
H
H
H
H
49b
41b
45b
25b
86b
27b
37b
42b
41b
77b
2. Results and discussion
CH2CH2CH2OH
Ph
CH2Ph
CH2CH2Ph
NHPh
CH2CO2Et
CH2(CHC6H4OH)CO2Me
OH
2.1. 2-N-Pyrrolidine derivatives
The transformation of the known alkene 49 to a 1,4-dicarbonyl
compound can be achieved by various methods in which oxidation
of the alkene bond is a common feature (Scheme 1). The simplest
route was expected to be ozonolysis of the double bond. Formation
of ozonide 6 as a mixture of diastereoisomers in 85% yield was
achieved by bubbling O3 through a solution of alkene 6 in DCM at
ꢀ78 ꢁC.10 Attempts to decompose ozonide 6 with various standard
methods lead to unsatisfactory results,9 indicating an unusually
stable ozonide. Direct transformation of the alkene 6 into the
dicarbonyl compound 8 was achieved by tandem ozonolysis–re-
duction, in a 53% overall yield, using polymer-bound PPh3 as re-
ducing agent.11
An alternative approach for the conversion of ketone 4 to a 1,4-
dicarbonyl compound makes use of the Wacker oxidation. This
involves the oxidation of a terminal alkene to a methyl ketone using
PdCl2.12 The desired diketone 10 was produced according to the
literature procedure in 85% yield.13
11j
11k
11l
H
H
iPr
iPr
b
a
-Me
-Me
29c
15c
11m
H
H
H
94d
11n
11o
11p
11q
11r
Me
Me
Me
Me
Me
Et
Ph
CH2Ph
NHPh
OH
H
H
H
H
H
67e
49e
86e
58e
93e
a
Yields after purification by flash column chromatography.
Obtained by double reductive amination of 8.
Obtained by double reductive amination of 10 after separation by flash column
b
c
chromatography of the 2:1 mixture of diastereomers at C8.
d
Prepared by hydrogenation of 11j.
Obtained by double reductive amination of 9.
e
Ring closure of the dicarbonyl compound 8 was achieved by
treatment with an excess of the amine hydrochloride and a cata-
lytic amount of AcOH in THF at rt, followed by addition of NaCNBH3
(Scheme 1, Table 1). Encouraged by the initial success with aliphatic
amines, in which only one diastereoisomer was formed in moder-
ate yields,8 we decided to explore the applicability of the double
reductive amination to a number of amines containing diverse
functional groups, including aromatic rings, alcohols and esters
(Table 1). Removal of the hydroxyl group of 11j was achieved by
hydrogenation with a catalytic amount of 5% palladium on car-
bon,7b leading to the free amine 11t in nearly quantitative fashion.
In all cases, the reaction was diastereoselective, with moderate
yields after purification by flash column chromatography.
The configuration and stereochemistry of the ring junction in
the series were confirmed by single-crystal X-ray crystallography of
compounds 11j8 and 11f14 (Fig. 3) and 1H NMR NOESY experiments
(as illustrated in Fig. 4 for compounds 11i/l). For the double re-
ductive elimination of the diketone 10 with iso-propylamine, this
resulted in a 2:1 mixture of diastereomers at C8 in a 44% overall
yield that were efficiently separated by column chromatography.
The stereochemistry of 11k/11l was determined by 1H NMR NOESY
experiments (Fig. 2), showing convincing NOE effects between H9
–
b
H4/H8, H9a–H2/H10 for the 8-a-methyl isomer 11l.
The stereochemistry at the C-2 ring junction is thought to arise
due to an initial reductive amination at the less hindered (and more
reactive) aldehyde group at C-8, followed by ring closure. Reduction
of the imine formed could then be from the a- or b-face. Although
the preference for attack of the hydride from the face opposite from
the anomeric OMe group may still be a factor, reductive amination
at C-2 of analogous compounds was found to give the opposite
stereochemistry (i.e.,
a
-amines),15 the greater thermodynamic
O
OMe
O
OMe
O
O
i
O
stability of a cis ring junction for the fused five-membered rings
compared to their trans counterparts is expected to be more sig-
nificant in determining the orientation of reduction.16
O
O
O
O
Ph
O
Ph
H
R1
R1
4 R1 = H
6 R1 = H
8
O
The initial reductive amination reactions attempted were found
to vary significantly in yields. In order to improve the average yield
of these reactions, it was proposed that analogous pyrrolidines
should be synthesized that contain a quaternary centre at C-3. The
Thorpe–Ingold effect17 informs that the placement of a quaternary
carbon at the centre of a chain can substantially enhance the rate of
ring formation. This is due to a reduction in the C–C–C bond angle
and restriction of the degrees of freedom of the chain, and an in-
crease in the entropy of the open chain starting material, which
makes it easier for the ring to form.
5 R1 = Me
7 R1 = Me
i, ii
ii
iii
O
OMe
O
O
OMe
O
O
Ph
O
Ph
O
O
O
R1
10
8 R1 = H
1
e
9 R = M
O
Ozonolysis of the C-3 methylated alkene 56a proceeded as for
compound 4, again with the production of an unusually stable
ozonide (9) in 70% yield that could not be reduced using DMS or
thiourea. Reduction of 7 using polymer-bound PPh3 allowed the
isolation of the dicarbonyl compound 9 in a 70% yield after column
chromatography (Scheme 1).
The double reductive amination procedure was applied to 9
using a range of primary amines (Scheme 1 and Table 1). As
expected, the inclusion of the methyl group at C-3 increased the
yields to 49–93% for 11n–r, compared to 25–86% for 11a–l.
The replacement of the H-3 proton with a methyl greatly simplified
iv
O
iv
O
1 OMe
5
6
7
H
2
3
R2
4
Ph
O
N
R1
9
8
R3
11a-s
Scheme 1. Reagents and conditions (see Table 1 for R1, R2 and R3): (i) O3, DCM, rt, 1 h;
(ii) polymer-bound PPh3, PhMe, 90 ꢁC, 1 h; (iii) PdCl2, CuCl2, O2, 1:1 DMF–H2O, rt, 4 h;
(iv) R2NH2 or R2NH2$HCl (see Experimental section for details), AcOH, THF, then
NaCNBH3, rt, 2 h.

4768
D.M. Laventine et al. / Tetrahedron 65 (2009) 4766–4774
Figure 3. ORTEP plot (ellipsoids, 50% probability) of the solid state structure of 11f14 with arbitrary numbering scheme.
the 1H NMR spectra of 11a–l, allowing confirmation of the stereo-
chemistry by measuring the appropriate coupling constants. The
increased yields in this step were not deemed to be sufficiently high
to make the route more efficient than the previously described for
the non-methylated 2-N-pyrrolidines, due to loss of material dur-
ing the methylation step.
OMe
O
O
O
O
OMe
O
O
i
O
Ph
Ph
O
13
H
O
12
O
O
2.2. 3-N-Pyrrolidine derivatives
An isomeric set of aza-heteroannulated sugars of type II (3-N-
pyrrolidine derivatives) were prepared starting from the known
ketone 12.6a Ozonolysis of 12 proceeded in the usual way, with the
production of the ozonide intermediate 13 as a mixture of di-
astereoisomers in 86% yield (Scheme 2).18 This time, in situ re-
duction of the ozonide using thiourea afforded dicarbonyl 14 as
a colourless syrup in 70% yield.19
O
3
OMe
H
1
5
O
O
OMe
6
ii
O
O
2
4
H
O
Ph
8
Ph
O
N
9
R1
15a-f
14
O
iv
(15 f)
iii (15 f)
Ring closure of dicarbonyl 14 by reductive amination was
expected to give only the products with
(Scheme 2). The arm attached at C-2 is -equatorial in the starting
material, so the preference for cis ring junctions in fused five-
membered rings would favour the -amino product as for the 2-N-
a-cis ring junctions
O
OMe
H
O
N
OMe
H
a
HO
HO
O
Ph
O
a
H
H
N
pyrrolidine series. The reductive amination ring-closing reaction
was applied to the dicarbonyl compound 14 with a variety of
amines including alkyl and aryl amines, phenylhydrazine and hy-
droxylamine (Scheme 2, Table 2). The resulting type II target
compounds 15a–f were obtained in 37–72% yields as colourless
syrups after flash chromatography. Furthermore, the free amine
derivative 15g was obtained in good yield removing the hydroxyl
group of 15f by reaction with Mo(CO)6 (Table 2). Removal of the
benzylidene group of 15g using aqueous acetic acid lead to the
deprotected derivative 16 in good yield (Scheme 2).
HO
H
15g
16
Scheme 2. Reagents and conditions: (i) (a) O3, DCM, rt, 1 h, 86%; (b) thiourea, rt, 1 h,
70%; (ii) R1NH2 or R1NH2$HCl (see Experimental section for details), AcOH, THF, then
NaCNBH3, rt, 2 h (Table 2); (iii) 80% aq AcOH, reflux, 4 h, 44%; (iv) Mo(CO)6, MeOH/
CH3CN, reflux, 12 h, 85%.
the 3-N-pyrrolidines showed similar distribution of signals for
protons on the five-membered ring. The signals for H-3 appeared as
doublet of doublets or triplet (except where obscured) between
3.27 and d 4.02 ppm with an axial–equatorial coupling to H-4 and
a di-equatorial coupling to H-2 of approximately 5 Hz each. The
The products (15a–g) were identified by 1H and 13C NMR
spectroscopy and MS and HRMS (FAB). The 1H NMR spectra of all
d
Table 2
3-N-Pyrrolidines synthesized in the present work
7
MeO
7 MeO
1
H
H
Compound
R1
Yielda (%)
H
H
5
5
1
2
15a
15b
15c
15d
15e
15f
Et
Ph
37
36
62
62
72
6
O
6
O
O
O
H
O
Ph
2
9α
N
H
O
Ph
3
3
4
H
14
CH2Ph
CH2CH2Ph
NHPh
OH
4
9α
14
H
H
H
N
H
9β
H
R
9β
R
44
85b
8
H
Me
10
8
11l
15g
H
i
11i
: R = CH2(CHC6H4OH)CO2Me
: R = Pr
a
Yields after purification by flash column chromatography.
Prepared by reaction of 15f with Mo(CO)6.
b
Figure 4. Selected NOE effects observed for compounds 11i and 11l.

D.M. Laventine et al. / Tetrahedron 65 (2009) 4766–4774
4769
signal for H-4 appeared as doublet of doublets in all the products,
which also showed that H-3 was equatorial as expected. This sug-
gests that the cis geometry of the ring junction is present in all of
the products. The large number of overlapping signals in these
products made 1H NMR NOE experiments of limited use.
3.3.
b
-
D
-Galactosidase inhibition tests
b
-Galactosidase enzyme (bovine liver) and PNP-
b
-D-galacto-
pyranoside were purchased from Sigma. Enzyme and substrate
(PNP- -galactopyranoside) solutions were made using 0.2 M so-
dium phosphate buffers at suitable pH and protein concentrations
(pH 7.3 and 2.0 U mLꢀ1). PNP-
-galactopyranoside was used as
b-D
b-D
2.3. Biological activity
substrate at a concentration of 5 mM.
Compounds tested for enzyme inhibition were dissolved in
In the previous communication on this work,8 we showed that
removal of the benzylidene group in 2-N-pyrrolidine derivatives
11a,c,h,j,k,l leading to compounds 17a–f (Fig. 5) could be achieved
by acidic hydrolysis. Measurement of the inhibitory activities of the
corresponding deprotected derivatives against a range of glycosi-
dases indicated that 17a–e were not significant inhibitors of those.
The exception to this trend was compound 17f that was found to be
distilled water at a concentration of 1 mg mLꢀ1. Where required,
compounds were dissolved in methanol (ca. 20 mL) before dilution
using distilled water. Inhibitor solutions were stored at ꢀ20 ꢁC. All
assays were carried out in triplicate using water as a blank in place
of the inhibitor. Reaction time was determined based on the length
of time needed to give a final absorbance of 0.3–1.5 units.
Linearity of the reaction time course was checked using a series
of incubation times. Rate of colour development after the addition
of Trinder glucose reagent was determined using a linear time
course.
a
weak, but specific, inhibitor of
b-D-galactosidase with an
IC50¼0.77 mM.
In order to prove the potential of compound 16 as glycosidase
inhibitor compared with its counterpart 17f, this compound was
tested for inhibitory activity against a range of glycosidase pro-
cessing enzymes. As 17f, compound 16 showed weak, but specific
Enzyme solution (10
solution (50 L) were combined in the well of a flat bottomed 96-
well (300 L) microtitre plate. The reaction mixture was incubated
at 25 ꢁC for 5–20 min and was stopped using glycine solution
(70 L, 0.4 M, adjusted to pH 10.4 using NaOH). Absorbance at
mL), inhibitor solution (10 mL) and substrate
m
m
activity as
b
-
D
-galactosidase inhibitor with an IC50¼0.81 mM. It is
worthy to mention that inhibition of b-galactosidases is significant
m
because these enzymes are overexpressed in senescent cells.20
In conclusion, we have developed a methodology for the ster-
405 nm was measured immediately in a microtitre plate reader
(Molecular Devices VersaMax microplate reader). Percentage ac-
tivity was calculated by reference to the control reaction for each
assay and percentage inhibition determined by subtraction from
100%.
For IC50 determinations, the inhibitors were serially diluted,
starting with a tenfold series (0.1–0.0001 mg mLꢀ1) to establish the
approximate range, and then diluted within a selected range. IC50
values were taken from the resulting curve of percentage absor-
bance (relative to an uninhibited control) versus concentration.
eoselective synthesis of
a wide range of 2/3-N-pyrrolidine
derivatives by double reductive amination ring closure of 1,4-
dicarbonyl derivatives of glycosides. Work is in progress for the
optimization of the observed biological activities of these new se-
ries of carbohydrate derivatives.
3. Experimental
3.1. General
3.4. Chemistry
Flash column chromatography was performed on Sorbil C-60
silica gel (Crossfield Chemicals) 40–60 nm. Thin layer chromato-
graphy analysis was conducted on pre-coated aluminium-backed
sheets (60–254) with a 0.2 mm thickness manufactured by Merck
and Co. Melting points were measured on a Ko¨fler block and are
uncorrected. NMR spectra were recorded on BrukerARX250,
AM300 or DRX400 spectrometer. Chemical shifts are given in parts
per million and coupling constants J are given in hertz (Hz). Mass
spectra were recorded on a Kratos Concept 1H spectrometer. X-ray
3.4.1. Synthesis of 1,4-dicarbonyl derivatives 8, 9, 10 and 14
3.4.1.1. Methyl-
a-D-(R)-4,6-O-benzylidene-3-deoxy-3-C-(2-oxo-ethyl)-
glucopyranosid-2-ulose (6). Previously reported.8
3.4.1.2. Methyl-
(3-(S)-methyl[1,2,4]trioxolane)-glucopyranosid-2-ulose and methyl-
-(R)-4,6-O-benzylidene-3-deoxy-3-(S)-methyl-3-C-(3-(R)-methyl-
a-D-(R)-4,6-O-benzylidene-3-deoxy-3-(S)-methyl-3-C-
a-D
diffraction data were collected using
diffractometer.
a Bruker APEX 2000
[1,2,4]trioxolane)-glucopyranosid-2-ulose (7). Nitrogen gas was
bubbled through a solution of the known olefin 5 (500 mg,
1.64 mmol) in dry CH2Cl2 (30 mL) for 2–3 min. The solution was
cooled to ꢀ78 ꢁC. Ozone was bubbled through the solvent until TLC
showed no starting material. Thiourea (130 mg, 1.70 mmol) was
added in portions and the solution warmed to 0 ꢁC and stirred for
1 h, then allowed to stir at rt overnight. The reaction was filtered,
washed with satd NaCl solution (2ꢂ25 mL) and extracted into
CH2Cl2 (2ꢂ5 mL), dried and concentrated to leave a colourless oil.
Chromatography on silica gel with 3:1 petrol–ether as the eluent
yielded 341 mg (70% yield) of the mixture of diastereoisomers 7 as
a colourless syrup. Rf (3:1 petrol–Et2O)¼0.40. 1H NMR (250 MHz,
CDCl3, major diastereoisomer) dH 1.40 (3H, s, H3-11), 2.05/2.11 (1H,
3.2. Crystal structure of compound 11f14
A single crystal of 11f was obtained by recrystallization from
dichloromethane–methanol, mounted on inert oil and transferred
to the cold gas stream of the diffractometer. Crystal data:
C24H29NO4, M¼395.48, monoclinic, a¼8.949(1), b¼11.187(3),
c¼10.867(3) Å, U¼1034.4(4) Å3, T¼200(2) K, space group P21, Z¼2,
absorption coefficient¼0.086 mmꢀ1, 2223 reflections measured,
2087 unique (Rint¼0.0207). The final wR(F2) was 0.0911 for all data.
2
2ꢂdd, J8a,8b¼14.8, J8a,9¼6.3/5.0, H-8), 2.25/2.40 (1H, 2ꢂdd,
17a: R1 = Pr, R2 = H
2J8a,8b¼14.8, J8b,9¼4.7/3.8, H-8), 3.45 (3H, s, H3-7), 3.88/3.91 (1H,
i
O
OMe
H
HO
HO
i
17b: R1 = Pr, R2 = β-Me
2
2ꢂd, J4,5¼9.1, H-4), 3.76/3.78 (1H, 2ꢂt, J6ax,6eq¼J5,6ax¼9.9, H-6ax),
i
17c: R1 = Pr, R2 = α-Me
4.30 (1H, td, J4,5¼J5,6ax¼9.8, J¼4.9, H-5), 4.42 (1H, dd, 2J6ax,6eq¼10.1,
J5,6eq¼5.0, H-6eq), 4.61 (1H, s, H-1), 5.04–5.12 (2H, m, H2-10), 5.30–
5.35 (2H, m, 9-H), 5.50/7.58 (1H, s, H-12), 7.32–7.52 (5H, Ph) ppm.
13C NMR (62.9 MHz, CDCl3, major diastereoisomer) dC 18.9/19.1
(CH3, C-11), 36.1 (CH2, C-8), 49.7/49.8 (C, C-3), 56.7 (CH3, C-7), 60.1
R1
N
17d: R1 = CH2CH2CH2OH, R2 = H
17e: R1 = CH2CO2Et, R2 = H
17f: R1 = OH, R2 = H
H
R2
Figure 5. Previously reported deprotected 2-N-pyrrolidine derivatives.8

4770
D.M. Laventine et al. / Tetrahedron 65 (2009) 4766–4774
2
(CH, C-5), 69.7 (CH2, C-6), 80.6/80.9 (CH, C-4), 94.0/94.4 (CH2, C-10),
101.6 (CH, C-9), 101.8 (CH, C-12), 126.6 (2ꢂCH, o-Ph), 128.7 (2ꢂCH,
m-Ph), 129.5 (CH, p-Ph), 137.7 (C, Ph), 203.0/203.1 (C, C2) ppm. MS
(FABþ) m/z 367 [MH]þ. FAB HRMS for C18H23O8 [MH]þ requires m/z
367.1393; found m/z 367.1393.
J2,3¼J3,9 ¼6.1, H-3), 2.60 (1H, dt, J10a,10b¼J10a,(11a,b)¼3.5, H-10a),
b
2
2.64 (1H, d, J2,3¼5.5, H-2), 3.02 (1H, td, J10a,10b¼J10b,11b¼12.3,
J10b,11a¼3.6 H-10b), 3.44 (3H, s, H3-7), 3.54 (2H, ov m, H-4, H-8
b),
3.75 (1H, t, J5,6ax¼2J6ax,6eq¼10.2, H-6ax), 3.83 (3H, ov m, H-5, H-12a,
2
H-12b), 4.27 (1H, dd, J6ax,6eq¼14.3, J5,6eq¼4.6, H-6eq), 4.78 (1H, s,
H-1), 5.55 (1H, s, H-13), 7.33–7.41 (3H, ov m, m-Ph, p-Ph), 7.47–7.52
(2H, m, o-Ph) ppm. 13C NMR (75.5 MHz, CDCl3) dC 24.9 (CH2, C-9),
29.2 (CH2, C-11), 39.3 (CH, C-3), 52.2 (CH2, C-8), 54.9 (CH3, C-7), 55.7
(CH2, C-10), 62.8 (CH, C-5), 64.5 (CH2, C-12), 67.9 (CH, C-2), 69.3
(CH2, C-6), 78.5 (CH, C-4), 97.8 (CH, C-1), 102.1 (CH, C-13), 126.2
(2ꢂCH, o-Ph), 128.3 (2ꢂCH, m-Ph), 129.0 (CH, p-Ph), 137.7 (C,
Ph) ppm. MS (FABþ) m/z 350 [MH]þ. FAB HRMS for C19H27O4N
[MH]þ requires m/z 350.1967; found m/z 350.1968.
3.4.1.3. Methyl-
a-D-(R)-4,6-O-benzylidene-3-deoxy-3-C-(2-oxo-ethyl)-
glucopyranosid-2-ulose (8). Previously reported.8
3.4.1.4. Methyl-a-D-(R)-4,6-O-benzylidene-3-deoxy-3-(S)-methyl-3-
C-(2-oxo-ethyl)-glucopyranosid-2-ulose (9). The triphenyl phos-
phine polymer was washed with CH2Cl2 (10 mL), acetone (10 mL),
and MeOH (10 mL), and then dried at 60 ꢁC under vacuum for 24 h.
The polymer beads (133 mg, 0.40 mmol) were allowed to swell in
n-heptane for 0.5 h, without stirring, before the start of the re-
action and a Teflon blade was positioned above the beads. Ozonide
7 (100 mg, 0.27 mmol) was added. The reaction mixture was
heated to reflux for 1 h and then filtered through a fritted funnel
and washed with n-heptane (2ꢂ25 mL). The solvent was removed
by vacuum to give a colourless oil. Flash column chromatography
with 2:1 petrol–Et2O as eluent yielded 79 mg of 9 (79 mg, 62%). Rf
(1:1 petrol–Et2O)¼0.33. 1H NMR (250 MHz, CDCl3) dH 1.22 (3H, s,
H3-10), 2.80 (1H, d, 2J8a,8b¼18.6, H-8a), 3.02 (1H, d, 2J8a,8b¼18.6, H-
8b), 3.41 (3H, s, H3-7), 3.67 (1H, t, 2J6ax,6eq¼J5,6ax¼9.9, H-6ax), 3.91
(1H, d, J4,5¼9.4, H-4), 4.19 (1H, td, J4,5¼J5,6ax¼9.4, J5,6eq¼4.7, H-5),
4.31 (1H, dd, 2J6ax,6eq¼10.3, J5,6eq¼5.7, H-6eq), 4.60 (1H, s, H-1), 5.41
(1H, s, H-10), 7.35–7.50 (5H, m, Ph), 9.73 (1H, br s, H-9). 13C NMR
(62.9 MHz, CDCl3) dC 18.8 (CH3, C-10), 48.3 (CH2, C-8), 49.6 (C, C-3),
56.7 (CH3, C-7), 60.2 (CH, C-5), 69.7 (CH2, C-6), 80.5 (CH, C-4), 100.1
(CH, C-1), 101.8 (CH, C-11), 126.7 (2ꢂCH, o-Ph), 128.8 (2ꢂCH, m-Ph),
129.7 (Ch, p-Ph), 137.8 (C, Ph), 200.3 (C]O, C-2) 201.6 (HC]O, C-9).
C17H20O5 [MH]þ requires m/z 321.1338; HR-FABMS found m/z
321.1338.
3.4.2.3. Methyl-
N,3-C-((2S)-2-propane-2,3-diyl)-2-N-iso-propyl-mannopyranoside
(11k) and methyl- -2-amino-(R)-4,6-O-benzylidene-2,3-dideoxy-
a-D-2-amino-(R)-4,6-O-benzylidene-2,3-dideoxy-2-
a-D
2-N,3-C-((2R)-2-propane-2,3-diyl)-2-N-iso-propyl-mannopyranoside
(11l). Compound 10 as starting material. Purification by flash col-
umn chromatography and separation by FC in 5:1 petrol–Et2O
afforded crude samples of diastereotopic amines 11k and 11l that
were further purified by chromatotron in 7:1 petrol–Et2O and 15:1
petrol–Et2O, respectively, yielding 29% yield of amine 11k and 15%
of amine 11l.
Compound 11k. Colourless syrup. 1H NMR dH (300 MHz, CDCl3)
1.03 (3H, d, J11,12a¼6.6, H3-12a), 1.10 (3H, d, J11,12b¼6.8, H3-12b), 1.20
(3H, d, J8,10¼6.4, H3-10(
b
)), 1.68 (1H, dd, 2J9 ¼13.3, J8(
¼2.7, H-
a
,9
b
a),9a
9a
), 2.20 (1H, ddd, 2J9 ¼13.4, J8(
¼10.2, J3,9 ¼7.5, H-9
b), 2.37
a,9
b
a
),9
b
b
(1H, dt, J3,4¼9.9, J2,3¼J3,9 ¼6.6, H-3), 3.05 (1H, sept,
b
J11,12a¼J11,12b¼6.8, H-11), 3.10 (2H, ov d, J2,3¼6.2, H-2, and m, H-8
a),
3.40 (3H, s, H3-7), 3.75 (1H, obs td, J4,5¼J5,6ax¼9.8, J5,6eq¼4.1, H-5),
3.80 (2H, 2ꢂt, J3,4¼J4,5¼9.3, J5,6ax¼2J6ax,6eq¼10.0, H-4, H-6ax), 4.29
(1H, dd, 2J6ax,6eq¼9.7, J5,6eq¼4.2, H-6eq), 4.71 (1H, s, H-1), 5.58 (1H, s,
H-13), 7.25–7.50 (5H, m, Ph) ppm.13C NMR (75.5 MHz, CDCl3) dC 16.6
(CH3, C-12a), 22.1 (CH3, C-12b), 26.6 (CH3, C-10), 34.6 (CH2, C-9), 39.5
(CH, C-3), 49.5 (CH, C-11), 52.9 (CH, C-8), 55.3 (CH3, C-7), 63.1 (CH, C-
2), 65.4 (CH, C-5), 69.8 (CH2, C-6), 79.8 (CH, C-4), 99.8 (CH, C-1),102.4
(CH, C-13), 126.6 (2ꢂCH, o-Ph), 128.7 (2ꢂCH, m-Ph), 129.4 (CH, p-
Ph),138.2 (C, Ph) ppm. MS (FABþ) m/z 348 [MH]þ. C20H30O4N [MH]þ
requires m/z 348.2175; HR-FABMS found m/z 348.2175.
3.4.1.5. Methyl-
a-D-(R)-4,6-O-benzylidene-3-deoxy-3-C-(2-oxo-pro-
pyl)-glucopyranoside-2-ulose (10). Previously reported.13
3.4.1.6. Methyl-a-D-(R)-4,6-O-benzylidene-2-deoxy-2-C-(2-oxo-eth-
yl)-glucopyranosid-3-ulose (14). Previously reported.19
3.4.2. General procedure for the double reductive amination using
amines: synthesis of compounds 11a,c,k,l
Compound 11l. Colourless syrup. 1H NMR (300 MHz, CDCl3) dH
0.93 (3H, d, J8,10¼6.5, H3-10( )), 0.98 (3H, d, J11,12a¼6.8, H3-12a), 1.10
a
The corresponding dicarbonyl compound 8 or 10 was dissolved
in dry THF, and an equivalent weight of dry, cooled 4 Å molecular
sieves added. AcOH (1 equiv) was added, followed by 8 equiv of the
appropriate amine. The flask was flushed with N2 and the solution
stirred at rt for 1 h. NaCNBH3 (3 equiv) was then added and the
mixture stirred for a further 2 h at rt. Saturated aqueous NH4Cl
solution was added followed by Et2O. The organic layer was col-
lected and washed with H2O. The solvent was removed in vacuo
and the resulting yellow syrup was purified by flash
chromatography.
(3H, d, J11,12b¼6.8, H3-12b), 1.28 (1H, ddd, 2J9 ¼12.9, J3,9 ¼7.5,
a,9
b
b
J8 ¼5.2, H-9
b
), 2.02 (1H, ddd, 2J9 ¼13.1, J8 ¼7.6, J3,9 ¼1.6, H-
b
,9
b
a
,9
b
b,9
a
a
9
a
), 2.31 (1H, dddd, J3,4¼9.2, J3,9 ¼7.4, J2,3¼5.9, J3,9 ¼1.6, H-3), 3.16
b
a
(1H, obs d, J2,3¼5.5, H-2), 3.17 (1H, obs sept, J11,12a¼J11,12b¼6.9, H-11),
3.30 (3H, s, H3-7), 3.51 (1H, obs t, J3,4¼J4,5¼9.4, H-4), 3.56 (1H, m, H-
2
8
b
), 3.61 (1H, obs t, J6ax,6eq¼J5,6ax¼9.3, H-6ax), 3.68 (1H, obs td,
2
J4,5¼J5,6ax¼10.0, J5,6eq¼4.4, H-5), 4.17 (1H, dd, J6ax,6eq¼9.3,
J5,6eq¼4.1, H-6eq), 4.70 (1H, s, H-1), 5.43 (1H, s, H-13), 7.20–7.30 (3H,
ov m, m-Ph, p-Ph), 7.36–7.43 (2H, m, o-Ph) ppm. 1H NMR (400 MHz,
C6D6) dH 0.90 (3H, d, J8,10¼6.4, H3-10), 1.08 (3H, d, J11,12a¼6.9, H3-
12a), 1.20 (3H, d, J11,12b¼6.9, H3-12b), 1.32 (1H, ddd, 2J9 ¼12.4,
a,9b
3.4.2.1. Methyl-
a
-D-2-amino-(R)-4,6-O-benzylidene-2,3-dideoxy-2-N,3-
J3,9 ¼7.6, J8,9 ¼4.6, H-9
b
), 2.26 (1H, ddd, 2J9 ¼13.1, J8,9 ¼7.8,
b
b
a
,9
b
a
C-(ethane-1,2-diyl)-2-N-iso-propyl-mannopyranoside (11a). Previously
J3,9 ¼1.8, H-9
a
), 2.58 (1H, dddd, J3,4¼10.0, J3,9 ¼7.7, J2,3¼5.7,
a
b
reported.8
J3,9 ¼1.9, H-3), 3.29 (4H, ov s, H3-7, and sept, J11,12a¼J11,12b¼6.9, H-
a
11), 3.39 (1H, d, J2,3¼5.7, H-2), 3.64 (1H, dqd, J8,9 ¼7.6, J8,10¼6.3,
a
3.4.2.2. Methyl-
a
-
D
-2-amino-(R)-4,6-O-benzylidene-2,3-dideoxy-2-
J8,9 ¼4.8, H-8(
b
)), 3.72 (1H, obs t, 2J6ax,6eq¼J5,6ax¼10.2, H-6ax), 3.76
b
N,3-C-(ethane-1,2-diyl)-2-N-(3-hydroxy-propyl)-mannopyranoside
(11c). Compound 8 as starting material. Purification by flash col-
umn chromatography using an eluant solvent gradient of 1:1 pet-
rol–Et2O to Et2O. Yield 45%, colourless syrup. 1H NMR (400 MHz,
(1H, obs t, J3,4¼J4,5¼9.7, H-4), 4.00 (1H, td, J4,5¼J5,6ax¼9.9, J5,6eq¼5.0,
H-5), 4.32 (1H, dd, 2J6ax,6eq¼10.1, J5,6eq¼5.0, H-6eq), 4.93 (1H, s, H-1),
5.48 (1H, s, H-13), 7.20–7.32 (3H, ov m, m-Ph, p-Ph), 7.66–7.73 (2H,
m, o-Ph). 13C NMR (75.5 MHz, CDCl3) dC 20.2 (CH3, C-12a), 20.4 (CH3,
C-12b), 21.0 (CH3, C-10), 35.2 (CH2, C-9), 38.4 (CH, C-3), 46.4 (CH, C-
11), 53.6 (CH, C-8), 55.1 (CH3, C-7), 59.3 (CH, C-2), 62.7 (CH, C-5), 69.5
(CH2, C-6), 79.9 (CH, C-4), 98.8 (CH, C-1), 102.2 (CH, C-13), 126.2
(2ꢂCH, o-Ph), 128.3 (2ꢂCH, m-Ph), 128.9 (CH, p-Ph), 138.0 (C, Ph)
2
CDCl3) dH 1.58 (1H, dquint, J11a,11b¼14.6, J(10a,b),11a¼J(12a,b),11a¼3.4,
H-11a), 1.89 (1H, obs ddt, 2J9 ¼13.5, J8 ¼11.0, J3,9 ¼J8 ¼6.7,
a
,9
b
a
,9
b
b
a,9b
H-9b), 1.97 (3H, ov m, H-11b, H-9a, OH-19), 2.42 (1H, td,
2J8 ¼J8 ¼10.6, J8 ¼4.8, H-8
), 2.49 (1H, dt, J3,4¼10.3,
a
a
,8
b
a
,9
b
a,9a

D.M. Laventine et al. / Tetrahedron 65 (2009) 4766–4774
4771
ppm. MS (FABþ) m/z 348 [MH]þ. C20H30O4N [MH]þ requires m/z
348.2175; HR-FABMS found m/z 348.2174.
2.67 (1H, d, J2,3¼5.7, H-2), 3.05 (1H, m, H-8
b
), 3.26 (1H, d, J10a,10b¼13.5,
H-10a), 3.30 (3H, s, H3-7), 3.58 (1H, dt, J4,5¼J5,6ax¼9.6, J5,6eq¼3.5, H-5),
3.59 (1H, t, J3,4¼J4,5¼9.5, H-4), 3.68 (1H, t, 2J6ax,6eq¼J5,6ax¼9.5, H-6ax),
3.95 (1H, d, J10a,10b¼13.3, H-10b), 4.20 (1H, dd, 2J6ax,6eq¼9.7, J5,6eq¼3.6,
H-6eq), 4.63 (1H, s, H-1), 5.50 (1H, s, H-11), 7.20 (8H, m, m-Ph, p-Ph,
Ph0), 7.50 (2H, m, o-Ph) ppm. 13C NMR dC (62.9 MHz, CDCl3) 25.5 (CH2,
C-9), 39.9 (CH, C-3), 52.6 (CH2, C-8), 53.5 (CH3, C-7), 59.5 (CH2, C-10),
62.3 (CH, C-5), 67.8 (CH, C-2), 69.8 (CH2, C-6), 79.3 (CH, C-4), 98.6 (CH,
C-1), 102.4 (CH, C-11), 126.6 (2ꢂCH, o-Ph), 127.4 (2ꢂCH, o-Ph0), 128.0
(2ꢂCH, m-Ph), 128.7 (2ꢂCH, m-Ph0), 129.0 (CH, p-Ph), 129.4 (CH, p-
Ph0), 138.2 (C, Ph), 139.6 (C, Ph0) ppm. MS (FABþ) m/z 382 [MH]þ.
C23H28O4N [MH]þ requires m/z 382.2018; HR-FABMS found m/z
382.2018.
3.4.2.4. Methyl-a-D-(R)-4,6-O-benzylidene-2-deoxy-2-C-(2-oxo-ethyl)-
glucopyranosid-3-ulose (14). Previously reported.
3.4.3. General procedure for the double reductive amination using
amine hydrochlorides: synthesis of compounds 11b,d–j,n–r and
15a–g
The dicarbonyl starting material 8, 9 or 12 (1 equiv) was dis-
solved in dry methanol (0.5 M solution) and cooled to 0 ꢁC. The
appropriate amine hydrochloride (1.25 equiv) was added, followed
by NaCNBH3 (3 equiv). The reaction mixture was stirred at 0 ꢁC for
2 h and, then, allowed to warm to rt and stirred for a further 2 h.
The methanol was removed under vacuum and the residue washed
with water (2 mL mmolꢀ1 starting material) and satd aq NaOH
solution (2ꢂ2 mL mmolꢀ1 starting material). The organic product
3.4.3.4. Methyl-a-D-2-amino-(R)-4,6-O-benzylidene-2,3-dideoxy-2-N,3-
C-(ethane-1,2-diyl)-2-N-(phenethyl)-mannopyranoside (11f). Compound
8 as starting material. Purification by flash column chromatography in
2:1 petrol–Et2O. Yield 27%, low melting point (<50 ꢁC) solid. Rf (1:1
was extracted into
a
10% propanol in CHCl3 mixture
(6ꢂ5 mL mmolꢀ1 starting material). Concentration under reduced
pressure gave a yellow oil that upon chromatography on silica gel
afforded the ring-closed products as white solids or colourless
syrups.
petrol–Et2O)¼0.51. 1H NMR (250 MHz, CDCl3) dH 1.85 (2H, m, H2-9
a,b),
2.38 (3H, m, H-3, H-8
11a,b), 2.96 (1H, m, H-8b), 3.30 (3H, s, H3-7), 3.32 (1H, m, H-10b), 3.57
a
, H-10a), 2.58 (1H, d, J2,3¼5.7,H-2),2.77(2H,m,H2-
(1H, t, J3,4¼J4,5¼9.5, H-4), 3.71 (2H, m, H-5, H-6ax), 4.18 (1H, dd,
2J6ax,6eq¼9.9, J5,6eq¼4.7, H-6eq), 4.60 (1H, s, H-1), 5.50 (1H, s, H-12), 7.12
(5H, m, Ph0), 7.27 (3H, m, m-Ph, p-Ph), 7.50 (2H, m, o-Ph) ppm. 13C NMR
(62.9 MHz, CDCl3)dC 25.7 (CH2,C-9),35.2(CH2,C-11),39.8(CH,C-3),52.4
(CH2, C-10), 55.3(CH3, C-7), 57.6 (CH2, C-8), 63.3 (CH, C-5), 68.3 (CH, C-2),
69.7 (CH2, C-6), 79.0 (CH, C-4), 98.3 (CH, C-1), 102.5 (CH, C-12), 126.6
(2ꢂCH, o-Ph),128.7(4ꢂCH, m-Ph, o-Ph0),128.9(2ꢂCH, m-Ph0),129.1 (CH,
p-Ph0), 129.3 (CH, p-Ph), 138.3 (C, Ph), 140.5 (C, Ph0) ppm. MS (FABþ) m/z
396 [MH]þ. C24H30O4N [MH]þ requires m/z 396.2175; HR-FABMS found
m/z 396.2175. Crystals suitable for X-ray diffractometry were grown by
slow evaporation of a sample of 11f dissolved in 10:1 CH2Cl2–petrol
solution (white solid, mp¼82–84 ꢁC).
3.4.3.1. Methyl-a-D-2-amino-(R)-4,6-O-benzylidene-2,3-dideoxy-2-N,3-
C-(ethane-1,2-diyl)-2-N-ethyl-mannopyranoside (11b). Compound 8
as starting material. Purification by flash column chromatography in
1:1 petrol–Et2O. Yield 41%, colourless syrup. Rf (1:1 petrol–
Et2O)¼0.35. 1H NMR (250 MHz, CDCl3) dH 1.03 (3H, t, J10(a,b),11¼7.1,
H-11), 1.82 (2H, m, H2-9
a
,
b
), 2.12 (1H, dq, 2J10a,10b¼13.9, J10a,11¼6.9, H-
2
10a), 2.17 (1H, dq, J10a,10b¼13.9, J10b,11¼7.6, H-10b), 2.25 (1H, td,
2J8 ¼J8 ¼10.7, J8 ¼5.7, H-8
a), 2.37 (1H, m, H-3), 2.51 (1H, d, J
a,8b
a,9b
a,9a
6.0, H-2), 3.23 (1H, m, H-8
b), 3.41 (3H, s, H3-7), 3.55 (1H, t,
J3,4¼J4,5¼9.1, H-4), 3.70 (1H, t, 2J6ax,6eq¼J5,6ax¼10.1, H-6ax), 3.73 (1H, td,
J4,5¼J5,6ax¼10.1, J5,6eq¼5.1, H-5), 4.17 (1H, m, H-6eq), 4.60 (1H, s, H-1),
5.50 (1H, s, H-12), 7.30 (3H, m, m-Ph, p-Ph), 7.50 (2H, m, o-Ph) ppm.
13C NMR (62.9 MHz, CDCl3) dC 13.4 (CH3, C-11), 25.7 (CH2, C-9), 39.9
(CH, C-3), 49.4 (CH2, C-10), 51.6 (CH2, C-8), 55.3 (CH3, C-7), 63.1 (CH, C-
5), 68.1 (CH, C-2), 69.6 (CH2, C-6), 79.3 (CH, C-4), 98.6 (CH, C-1), 102.3
(CH, C-12), 126.2 (CH, o-Ph), 128.6 (CH, m-Ph), 129.3 (CH, p-Ph), 138.3
(C, Ph) ppm. MS (FABþ) m/z 320 [MH]þ. C18H26O4N [MH]þ requires
m/z 320.1862; HR-FABMS found m/z 320.1862.
3.4.3.5. Methyl-a-D-2-amino-(R)-4,6-O-benzylidene-2,3-dideoxy-2-N,3-C-
(ethane-1,2-diyl)-2-N-phenylamino-mannopyranoside (11g). Compound
8 as starting material. Purification by flash column chromatography in
1:1 petrol–Et2O. Yield 37%, colourless syrup. Rf (1:1 petrol–Et2O)¼0.42.1H
NMR (250 MHz, CDCl3) dH 1.90 (2H, m, H2-9a,b), 2.25 (1H, m, H-8a), 2.38
(1H, m, H-3), 2.74 (1H, d, J2,3¼6.0, H-2), 3.27 (3H, s, H3-7), 3.51 (1H, m, H-
8b
), 3.64 (1H, t, J3,4¼J4,5¼9.4, H-4), 3.71 (1H, t, 2J6ax,6eq¼J5,6ax¼10.1, H-6ax),
3.74 (1H, td, J4,5¼J5,6ax¼10.1, J5,6eq¼5.1, H-5), 4.12 (1H, s, H–N), 4.22 (1H,
dd, 2J6ax,6eq¼9.9, J5,6eq¼4.8, H-6eq), 4.48 (1H, s, H-1), 5.51 (1H, s, H-10),
6.72 (1H, m, p-Ph0), 6.83 (2H, m, m-Ph0), 7.12 (2H, m, o-Ph0), 7.28 (3H, m,
m-Ph, p-Ph), 7.42 (2H, m, o-Ph) ppm. 13C NMR (62.9 MHz, CDCl3) dC 24.6
(CH2, C-9), 37.6 (CH, C-3), 55.0 (CH2, C-8), 55.4 (CH3, C-7), 63.2 (CH, C-5),
69.4 (CH, C-2), 69.9 (CH2, C-6), 80.2(CH, C-4), 98.3 (CH, C-1),102.5 (CH, C-
10), 113.4 (2ꢂCH, o-Ph0), 119.9 (2ꢂCH, m-Ph0), 126.6 (2ꢂCH, o-Ph), 127.5
(2ꢂCH, m-Ph), 129.4 (CH, p-Ph), 129.5 (CH, p-Ph0), 138.2 (C, Ph), 149.5 (C,
Ph0) ppm. MS (FABþ) m/z 383 [MH]þ. C22H26O4N2 [M]þ requires m/z
382.1893; HR-FABMS found m/z 382.1893.
3.4.3.2. Methyl-a-D-2-amino-(R)-4,6-O-benzylidene-2,3-dideoxy-2-N,3-
C-(ethane-1,2-diyl)-2-N-phenyl-mannopyranoside (11d). Compound 8
as starting material. Purification by flash column chromatography in
5:1 petrol–Et2O. Yield 25% yield, colourless syrup. Rf (5:1 petrol–
Et2O)¼0.41. 1H NMR (250 MHz, CDCl3) dH 1.71 (1H, m, H-9
b), 2.05 (1H,
a), 2.64 (1H, m, H-3), 3.29
ddd, 2J9 ¼12.7, J8 ¼8.2, J8 ¼5.1, H-9
a
,9
b
b,9a
a,9a
(1H, m, H-8
a
), 3.33 (3H, s, H3-7), 3.50 (1H, t, J3,4¼J4,5¼9.8, H-4), 3.62 (1H,
t, 2J6ax,6eq¼J5,6ax¼10.0, H-6ax), 3.75 (3H, m, H-2, H-5, H-8
b), 4.20 (1H,
dd, 2J6ax,6eq¼9.9, J5,6eq¼4.6, H-6eq), 4.60 (1H, s, H-1), 5.50 (1H, s, H-10),
0
0
0
0
0
0
6.55 (2H, d, Jo-Ph ,m-Ph ¼8.0, o-Ph ), 6.69 (1H, t, Jm-Ph ,p-Ph ¼7.2, p-Ph ), 7.16
(2H, m, m-Ph0), 7.29 (3H, m, m-Ph, p-Ph), 7.44 (2H, m, o-Ph) ppm. 13C
NMR (62.9 MHz, CDCl3) dC 26.8 (CH2, C-9), 40.5 (CH, C-3), 51.4 (CH2, C-
8), 55.5 (CH3, C-7), 61.7 (CH, C-5), 62.1 (CH, C-2), 69.7 (CH2, C-6), 76.9
(CH, C-4), 97.4 (CH, C-1),102.5 (CH, C-10),114.5 (CH, o-Ph0),114.9 (CH, m-
Ph0), 118.0 (CH, p-Ph0), 126.6 (CH, o-Ph), 128.7 (CH, m-Ph),þ129.5 (CH, p-
Ph), 138.1 (C, Ph), 149.1 (C, Ph0). MS (FABþ) m/z 368 [MH] . C22H25O4N
[M]þ requires m/z 367.1784; HR-EIMS found m/z 367.1784.
3.4.3.6. Methyl-a-D-2-amino-(R)-4,6-O-benzylidene-2,3-dideoxy-2-N,
3-C-(ethane-1,2-diyl)-2-N-(2-ethoxycarbonyl-methyl)-mannopyranoside
(11h). Compound 8 as starting material. Purification by flash col-
umn chromatography using an eluant solvent gradient of 2:1 pet-
rol–Et2O to 1:1 petrol–Et2O. Yield 42% yield, colourless syrup. Rf
(1:1 petrol–Et2O): 0.17. 1H NMR (400 MHz, CDCl3) dH 1.28 (3H, t,
J12,13¼7.1, H3-13), 1.98 (2H, m, H2-
a
,
b
), 2.50 (1H, dq, J3,4¼9.9,
J2,3¼J3,9 ¼J3,9 ¼5.0, H-3), 2.80 (1H, dt, 2J8 ¼9.5, J8 ¼J8 ¼7.4,
a
b
a
,8
b
a
,9a
a,9b
3.4.3.3. Methyl-
a-D
-2-amino-2-N-benzyl-(R)-4,6-O-benzylidene-2,3-
H-8
a
), 3.01 (1H, d, J2,3¼5.5, H-2), 3.29 (1H, obs d, H-10a), 3.32 (3H, s,
dideoxy-2-N,3-C-(ethane-1,2-diyl)-mannopyranoside (11e). Compound
8 as starting material. Purification by flash column chromatography in
1:1 petrol–Et2O. Yield 86%, colourless syrup. Rf (1:1 petrol–
H3-7), 3.38 (1H, obs m, H-8
b
), 3.53 (2H, t, J3,4¼J4,5¼9.6, H-4, and d,
2J10a,10b¼17.3, H-10b), 3.76 (1H, obs t, J5,6ax¼2J6ax,6eq¼10.3, H-6ax),
3.80 (1H, td, J4,5¼J5,6ax¼10.2, J5,6eq¼3.7, H-5), 4.11 (2H, q, J12,13¼7.1,
H2-12), 4.19 (1H, dd, 2J6ax,6eq¼8.9, J5,6eq¼3.7, H-6eq), 4.54 (1H, s, H-
1), 5.49 (1H, s, H-14), 7.24–7.35 (3H, ov m, m-Ph, p-Ph), 7.38–7.45
Et2O)¼0.70. 1H NMR (250 MHz, CDCl3) dH 1.76 (2H, m, H2-9
a,b), 2.25
a), 2.40 (1H, m, H-3),
(1H, td, 2J8 ¼J8 ¼10.1, J8 ¼5.7, 10.1, H-8
a,8b
a,9b
a,9a

4772
D.M. Laventine et al. / Tetrahedron 65 (2009) 4766–4774
2
(2H, m, o-Ph) ppm. 13C NMR (75.5 MHz, CDCl3) dC 14.3 (CH3, C-13),
25.9 (CH2, C-9), 39.9 (CH, C-3), 51.2 (CH2, C-8), 53.5 (CH2, C-10), 55.0
(CH3, C-7), 60.5 (CH2, C-12), 62.6 (CH, C-5), 65.2 (CH, C-2), 69.2 (CH2,
C-6), 77.8 (CH, C-4), 97.7 (CH, C-1), 102.0 (CH, C-14), 126.2 (2ꢂCH, o-
Ph), 128.3 (2ꢂCH, m-Ph), 129.0 (CH, p-Ph), 137.8 (C, Ph),170.7 (C]O,
C-11) ppm. MS (FABþ) m/z 378 [MH]þ. C20H28O4N [MH]þ requires
m/z 378.1917; HR-FABMS found m/z 378.1917.
H-5), 4.23 (1H, dd, J6ax,6eq¼10.3, J5,6eq¼5.1, H-6eq), 4.65 (1H, br s,
H-1), 5.53 (1H, s, H-13), 7.38 (3H, m, m-Ph, p-Ph), 7.49 (2H, m, o-
Ph) ppm. 13C NMR (62.9 MHz, CDCl3) dC 13.0 (CH3, C-10), 19.9 (CH3,
C-12), 35.3 (CH2, C-9), 43.2 (C, C-3), 49.6 (CH2, C-8), 51.1 (CH2, C-11),
55.6 (CH3, C-7), 59.8 (CH, C-5), 69.8 (CH2, C-6), 73.5 (CH, C-2), 80.8
(CH, C-4), 99.4 (CH, C-1), 102.3 (CH, C-12), 126.6 (CH, o-Ph), 128.6
(CH, o-Ph0), 128.7 (4ꢂCH, m-Ph, m-Ph0), 129.3 (CH, p-Ph), 129.7 (CH,
p-Ph0), 137.1 (C, Ph), 138.1 (C, Ph0) ppm. MS (FABþ) m/z 334 [MH]þ.
C19H28O4N [MH]þ requires m/z 334.2018; HR-FABMS found m/z
334.2018.
3.4.3.7. Methyl-a-D-2-amino-(R)-4,6-O-benzylidene-2,3-dideoxy-2-N,
3-C-(ethane-1,2-diyl)-2-N-(2-(4-hydroxy-phenyl)-1-(R)-methoxycarbonyl-
ethyl)-mannopyranoside (11i). Compound 8 as starting material.
Purification by flash column chromatography using an eluant sol-
vent gradient of 2:1 petrol–Et2O to 1:1 petrol–Et2O. Yield 41%,
colourless syrup. Rf (1:1 petrol–Et2O): 0.17. 1H NMR (400 MHz,
3.4.3.10. Methyl-a-D-2-amino-(R)-4,6-O-benzylidene-2,3-dideoxy-2-
N,3-C-(ethane-1,2-diyl)-(3R)-3-methyl-2-N-phenyl-mannopyranoside
(11o). Compound 9 as starting material. Purification by flash col-
umn chromatography using 1:1 petrol–Et2O. Yield 49%, colourless
syrup. Rf (1:1 petrol–Et2O)¼0.53. 1H NMR (250 MHz, CDCl3) dH 1.29
CDCl3) dH 1.83 (1H, m, H-9
b
), 1.98 (1H, ddd, 2J9 ¼12.2, J8 ¼7.1,
a
,9
b
b,9a
J8 ¼3.6, H-9 ), 2.49 (1H, dt, J3,4¼10.1, J2,3¼J3,9 ¼5.9, H-3), 2.97
a
a
,9
a
b
2
(1H, dd, J11a,11b¼14.0, J10,11a¼6.8, H-11a), 3.06 (1H, obs d, J2,3¼5.3,
(1H, ddd, 2J9 ¼13.6, J8 ¼4.7, J8 ¼3.0, H-9
b), 1.30 (3H, s, H3-
a
,9
b
a
,9
b
b,9b
H-2), 3.10 (1H, dd, 2J11a,11b¼14.0, J10,11b¼7.9, H-11b), 3.20 (2H, ov m,
10), 2.08 (1H, ddd, 2J8 ¼7.6, J8 ¼4.8, J8 ¼2.2, H-8
a), 2.38 (2H,
a
,8
b
a
,9
b
a,9a
H2-8
a
,
b
), 3.39 (3H, s, H3-7), 3.52 (1H, t, J3,4¼J4,5¼9.8, H-4), 3.66 (3H,
m, H2-11(a,b)), 2.52 (1H, ddd, 2J9 ¼13.6, J8 ¼5.0, J8 ¼2.2, H-
a
,9
b
b,9
a
a,9a
s, H3-13), 3.70 (1H, t, J5,6ax¼2J6ax,6eq¼10.3, H-6ax), 3.74 (1H, t,
J10,11a¼J10,11b¼7.4, H-10), 3.82 (1H, td, J4,5¼J5,6ax¼9.9, J5,6eq¼4.9, H-
5), 4.28 (1H, dd, 2J6ax,6eq¼10.1, J5,6eq¼4.8, H-6eq), 4.65 (1H, s, H-1),
5.54 (1H, s, H-14), 6.74 (2H, br d, Jo-Ar,m-Ar¼8.5, o-Ar), 7.10 (2H, dt,
Jo-Ar,m-Ar¼8.5, m-Ar), 7.36–7.43 (3H, ov m, m-Ph, p-Ph), 7.50–7.54
(2H, m, o-Ph) ppm. 13C NMR (75.5 MHz, CDCl3) dC 25.2 (CH2, C-9),
36.4 (CH2, C-13), 39.5 (CH, C-3), 44.6 (CH2, C-8), 51.2 (CH3, C-12),
55.0 (CH3, C-7), 62.8 (CH, C-10), 62.9 (CH, C-5), 64.2 (CH, C-2), 69.3
(CH2, C-6), 77.7 (CH, C-4), 97.5 (CH, C-1), 102.1 (CH, C-14), 115.2
(2ꢂCH, o-Ar),126.2 (2ꢂCH, o-Ph), 128.3 (2ꢂCH, m-Ph), 129.0 (CH, p-
Ph), 130.1 (2ꢂCH, m-Ar), 130.2 (CH, i-Ar), 137.7 (C, i-Ph), 154.3 (COH,
p-Ar), 172.7 (C]O, C-12) ppm. MS (FABþ) m/z 470 [MH]þ.
C26H32O7N [MH]þ requires m/z 470.2179; HR-FABMS found m/z
470.2179.
9a
), 2.64 (1H, m, H-8
b
), 3.27 (1H, d, J4,5¼9.5, H-4), 3.36 (3H, s, H3-7),
2
3.53 (1H, d, J1,2¼4.1, H-2), 3.80 (1H, t, J6ax,6eq¼J5,6ax¼10.5, H-6ax),
3.89 (1H, dt, J4,5¼J5,6ax¼9.8, J5,6eq¼4.8, H-5), 4.22 (1H, dd,
2J6ax,6eq¼10.2, J5,6eq¼5.2, H-6eq), 4.650(1H, br s, H-1), 5.43 (1H, s, H-
0
0
0
0
11), 6.55 (2H, d, Jo-Ph ,m-Ph ¼8.2, o-Ph ), 6.70 (1H, t, Jm-Ph ,p-Ph ¼7.4,
p-Ph0), 7.20 (2H, dd, Jo-Ph ,m-Ph ¼8.4, Jm-Ph ,p-Ph ¼7.3, m-Ph ), 7.30 (3H,
m, m-PH, p-Ph), 7.45 (2H, m, o-Ph) ppm. 13C NMR (62.9 MHz, CDCl3)
dC 19.5 (CH3, C-10), 35.3 (CH2, C-9), 43.5 (C, C-3), 51.4 (CH2, C-8),
55.5 (CH3, C-7), 58.6 (CH, C-5), 67.2 (CH, C-2), 69.8 (CH2, C-6), 78.7
(CH, C-4), 97.5 (CH, C-1), 102.3 (CH, C-11), 125.7 (CH, o-Ph0), 126.6
(CH, o-Ph), 128.5 (CH, m-Ph), 129.2 (CH, m-Ph0), 129.3 (CH, þp-Ph),
129.7 (CH, p-Ph0), 138.6 (C, Ph), 149.1 (C, Ph0) ppm. MS (FAB ) m/z
382 [MH]þ. C23H28O4N [MH]þ requires m/z 382.2018; HR-FABMS
found m/z 382.2018.
0
0
0
0
0
3.4.3.8. Methyl-a-D-2-amino-(R)-4,6-O-benzylidene-2,3-dideoxy-2-N,
3.4.3.11. Methyl-a-D-2-amino-2-N-benzyl-(R)-4,6-O-benzylidene-2,3-
3-C-(ethane-1,2-diyl)-2-N-hydroxyl-mannopyranoside (11j). Compound
8 as starting material. Purification by flash column chromatography
using 1:1 petrol–Et2O. Yield 77%, colourless syrup. Rf (1:1 petrol–
Et2O)¼0.17. 1H NMR (300 MHz, CDCl3) dH 1.88 (1H, dtd, 2J9 ¼14.0,
dideoxy-2-N,3-C-(ethane-1,2-diyl)-(3R)-3-methyl-mannopyranoside
(11p). Compound 9 as starting material. Purification by flash col-
umn chromatography using 1:1 petrol–Et2O. Yield 86%, colourless
syrup. Rf (1:1 petrol–Et2O)¼0.15. 1H NMR (400 MHz, CDCl3) dH 1.22
a,9b
J8 ¼J8 ¼8.3, J3,9 ¼1.9, H-9
a
), 2.01 (1H, m, J3,9 ¼8.4, J8 ¼3.4, H-
(3H, s, H3-10), 1.26 (1H, ddd, 2J9 ¼14.7, J8
¼12.1, J8 ¼2.6, H-
a,9
a
b,9
a
a
b
b
,9b
a
,9
b
a,9
b
,
b,9b
9
b
), 2.40 (1H, dddd, J3,4¼10.0, J3,9 ¼8.2, J2,3¼6.7, J3,9 ¼1.8, 3-H), 2.78
9
b
), 2.08 (1H, ddd, 2J9 ¼15.0, J8 ¼4.9, J8 ¼2.1, H-9
a), 2.63
), 2.73 (1H, ddd,
b
a
a
,9
b
b
,9
a
a
,9a
(1H, td, 2J8 ¼J8 ¼10.6, J8 ¼8.1, H-8
a
), 2.92 (1H, d, J¼6.5, H-2),
(1H, td, 2J8 ¼J8 ¼13.2, J8 ¼2.0, H-8
a
a
,8
b
a
,9
b
a,9a
a
,8
b
a
,9
b
a,9a
3.34 (3H, s, H3-7), 3.37 (1H, obs t, J3,4¼J4,5¼10.1, H-4), 3.46 (1H, td,
2J8 ¼12.7, J8 ¼4.9, J9 ¼2.9, H-8
b
), 3.13 (1H, d, J4,5¼9.5, H-4),
a
,8b
b,9
a
b,8b
2J8 ¼J8 ¼9.2, J8 ¼3.7, H-8
b
), 3.64 (1H, t, 2J6ax,6eq¼J5,6ax¼10.1, H-
3.36 (3H, s, H3-7), 3.43 (1H, d, J1,2¼4.1, H-2), 3.59 (1H, t,
2J6ax,6eq¼J5,6ax¼10.2, H-6ax), 3.68 (1H, d, 2J11a,11b¼12.8, H-11a), 3.72
(1H, d, 2J11a,11b¼12.8, H-11b), 3.89 (1H, td, J4,5¼J5,6ax¼9.9, J5,6eq¼4.9,
a
,8b
b
,9
a
b,9b
6ax), 3.74 (1H, td, J4,5¼J5,6¼10.1, J5,6eq¼4.8, H-5), 4.19 (1H, dd,
2J6ax,6eq¼9.9, J5,6eq¼4.7, H-6eq), 4.85 (1H, s, H-1), 5.44 (1H, s, H3-7),
7.25–7.33 (3H, m, m-Ph, p-Ph), 7.37–7.42 (2H, m, o-Ph), 7.90 (1H, s, HO–
N) ppm. 13C NMR (75.0 MHz, CDCl3) dC 24.3 (CH2, C-9), 36.1 (CH, C-3),
55.6 (CH3, C-7), 56.3 (CH2, C-8), 62.9 (CH, C-5), 69.6 (CH2, C-6), 70.6
(CH, C-2), 80.6 (CH, C-4), 98.0 (CH, C-1), 102.5 (CH, C-10), 126.5 (2ꢂCH,
o-Ph), 128.7 (2ꢂCH, m-Ph), 129.4 (CH, p-Ph), 137.9 (C, Ph) ppm. MS
(FABþ) m/z 307 [MH]þ. C16H21O5N [M]þ requires m/z 307.1420; HR-
FABMS found m/z 307.1420.
2
H-5), 4.23 (1H, dd, J6ax,6eq¼10.3, J5,6eq¼5.1, H-6eq), 4.67 (1H, d,
J1,2¼4.1, H-1), 5.43 (1H, s, H-12), 7.15–7.33 (8H, ov m, m-Ph, p-Ph,
o-Ph0, m-Ph0 p-Ph0), 7.38–7.45 (2H, m, o-Ph) ppm. 13C NMR
(62.9 MHz, CDCl3) dC 12.5 (CH3, C-10), 39.1 (CH2, C-9), 42.0 (C, C-3),
44.3 (CH2, C-8), 53.6 (CH2, C-11), 55.9 (CH3, C-7), 59.3 (CH, C-5), 69.6
(CH2, C-6), 74.0 (CH, C-2), 83.9 (CH, C-4), 100.7 (CH, C-1), 102.2 (CH,
C-12), 127.7 (CH, o-Ph), 127.9 (CH, o-Ph0), 128.7 (CH, m-Ph), 128.9
(CH, m-Ph0), 129.þ2 (CH, p-Ph), 129.5 (CH, p-Ph0), 137.1 (C, Ph), 138.1
(C, Ph0). MS (FAB ) m/z 396 [MH]þ. C24H30O4N [MH]þ requires m/z
396.2175; HR-FABMS found m/z 396.2174.
3.4.3.9. Methyl-a-D-2-amino-(R)-4,6-O-benzylidene-2,3-dideoxy-2-
N,3-C-(ethane-1,2-diyl)-2-N-ethyl-(3R)-3-methyl-mannopyranoside
(11n). Compound 9 as starting material. Purification by flash col-
umn chromatography using 2:1 petrol–Et2O. Yield 67%, colourless
syrup. Rf (1:1 petrol–Et2O)¼0.20. 1H NMR (250 MHz, CDCl3) dH 1.10
(3H, t, J11(a,b),12¼5.0, H3-12), 1.32 (1H, ddd, 2J9 ¼13.8, J8 ¼4.7,
3.4.3.12. Methyl-a-D-2-amino-(R)-4,6-O-benzylidene-2,3-dideoxy-2-N,3-
C-(ethane-1,2-diyl)-(3R)-3-methyl-2-N-(phenylamino)-mannopyranoside
(11q). Compound 9 as starting material. Purification by flash col-
umn chromatography using 1:1 petrol–Et2O. Yield 58%, colourless
syrup. Rf (1:1 petrol–Et2O)¼0.47. 1H NMR (250 MHz, CDCl3) dH 1.30
a
,9
b
a,9b
J8 ¼2.9, H-9
b
), 1.34 (3H, s, H3-10), 2.04 (1H, ddd, 2J8 ¼7.7,
b
,9
b
a,8b
J8 ¼4.7, J8 ¼2.2, H-8
a), 2.38 (2H, m, H2-11(a,b)), 2.61 (1H, ov
a
,9
b
a,9a
ddd, 2J9 ¼13.8, J8 ¼4.9, J8 ¼2.2, H-9
a), 2.70 (1H, d, J1,2¼4.0,
(3H, s, H3-10),1.49 (1H, br s, H–N),1.58 (1H, m, H-9b), 2.04 (1H, ddd,
a
,9
b
b,9
a
a,9a
H-2), 2.74 (1H, ddd, 2J8 ¼7.9, J8 ¼4.9, J8 ¼2.9, H–8
b), 3.36
2J9 ¼13.5, J8 ¼9.1, J8 ¼7.2, H-9
a
), 2.37 (1H, ddd, 2J8 ¼9.8,
a
,8
b
b
,9
a
b,9
b
a
,9
b
b
,9
a
a
,9
a
a,8b
(3H, s, H3-7), 3.43 (1H, d, J4,5¼9.5, H-4), 3.59 (1H, t,
J8 ¼11.0, J8 ¼6.9, H-8
,9
a), 2.50 (1H, s, H-2), 3.28 (3H, s, H3-7),
a
b
a,9a
2J6ax,6eq¼J5,6ax¼10.0, H-6ax), 3.89 (1H, td, J4,5¼J5,6ax¼9.9, J5,6eq¼4.9,
3.52 (1H, td, 2J8 ¼J8 ¼9.1, J8 ¼4.4, H-8
b), 3.74 (1H, t,
a
,8
b
b,9
a
b,9b

D.M. Laventine et al. / Tetrahedron 65 (2009) 4766–4774
4773
2J6ax,6eq¼J5,6ax¼10.1, H-6ax), 3.78 (1H, d, J4,5¼9.4, H-4), 3.85 (1H, td,
(CH2, C-9), 43.7 (CH, C-2), 55.9 (CH3, C-7), 58.9 (CH, C-5), 68.7 (CH, C-
3), 69.8 (CH2, C6), 78.0 (CH, C4), 102.4 (CH, C7), 102.7 (CH, C1), 113.2
(2ꢂCH, o-Ph0), 118.1 (2ꢂCH, m-Ph0), 126.7 (2ꢂCH, o-Ph), 128.7
(2ꢂCH, m-Ph), 129.5 (CH, p-Ph0), 129.8 (CH, p-Ph), 137.7 (C, i-Ph),
148.2 (C, i-Ph0) ppm. MS (FABþ) m/z 368 [MH]þ. C22H26O4N [MH]þ
requires m/z 368.1862; HR-FABMS found m/z 368.1862.
2
J4,5¼J5,6ax¼9.8, J5,6eq¼4.9, H-5), 4.25 (1H, dd, J6ax,6eq¼10.1,
J5,6eq¼4.7, H-6eq), 40.65 (1H, s, H-1), 5.60 (1H, s, H-11), 06.72 (1H, t,
0
0
0
0
Jm-Ph ,p-Ph ¼7.3, p-Ph ), 6.84 (2H, d, Jm-Ph ,p-Ph ¼7.5, m-Ph ), 7.15 (2H,
m, o-Ph0), 7.30 (3H, m, m-Ph, p-Ph), 7.45 (2H, m, o-Ph) ppm. 13C
NMR (62.9 MHz, CDCl3) dC 19.9 (CH3, C-10), 34.1 (CH2, C-9), 40.8 (C,
C-3), 53.8 (CH2, C-8), 55.5 (CH3, C-7), 59.9 (CH, C-5), 67.4 (CH, C-2),
68.6 (CH2, C-6), 82.1 (CH, C-4), 98.9 (CH, C-1),102.4 (CH, C-11),126.7
(CH, o-Ph), 128.7 (CH, m-Ph), 129.2 (CH, p-Ph), 129.4 (CH, o-Ph0),
129.5 (CH, m-Ph0), 131.3 (CH, p-Ph0), 138.4 (C, Ph), 149.5 (C, Ph0). MS
(FABþ) m/z 323 [MH]þ. C23H28O4N2 [M]þ requires m/z 396.2049;
HR-FABMS found m/z 396.2049.
3.4.3.16. Methyl-a-D-3-amino-3-N-benzyl-(R)-4,6-O-benzylidene-2,3-
dideoxy-2-C,3-N-(ethane-1,2-diyl)-allopyranoside (15c). Compound
12 as starting material. Purification by flash column chromato-
graphy using 49:49:2 petrol–Et2O–Et3N. Yield 62%, colourless
syrup. Rf (49:49:2 petrol–Et2O–Et3N)¼0.25. 1H NMR (400 MHz,
CDCl3) dH 1.77 (2H, m, H-8
a
, H-8
b
), 2.34 (1H, td, 2J9 ¼J8 ¼8.9,
a
,9
b
b,9a
3.4.3.13. Methyl-
a-
D
-2-amino-(R)-4,6-O-benzylidene-2,3-dideoxy-2-
J8 ¼5.1, H-9
a
), 2.61 (1H, dtd, J2,8 ¼8.4, J1,2¼J2,3¼5.7, J2,8 ¼3.2, H-
a
,9
a
a
b
N,3-C-(ethane-1,2-diyl)-2-N-hydroxyl-(3R)-3-methyl-mannopyranoside
(11r). Compound 9 as starting material. Purification by flash col-
umn chromatography using 2:1 petrol–Et2O. Yield 93%, colourless
syrup. Rf (2:1 petrol–Et2O)¼0.21. 1H NMR (250 MHz, CDCl3) dH 1.28
(3H, s, H3-10), 1.60 (1H, ddd, 2J9 ¼13.5, J8 ¼11.3, J8 ¼3.8, H-
2), 3.24 (1H, q, 2J9 ¼J8 ¼J8 ¼8.0, H-9
b
), 3.30 (1H, t,
a
,9
b
a
,9
a
b,9a
2
J2,3¼J3,4¼4.2, H-3), 3.42 (4H, s and d, J10a,10b¼13.1, H3-7, H-10a),
2
3.76 (1H, t, J6ax,6eq¼J5,6ax¼10.5, H-6ax), 3.96 (1H, dd, J4,5¼9.5,
2
J3,4¼3.5, H-4), 4.38 (1H, dd, J6ax,6eq¼10.3, J5,6eq¼5.5, H-6eq), 4.53
2
(1H, td, J4,5¼J5,6ax¼9.9, J5,6eq¼5.4, H-5), 4.60 (1H, d, J10a,10b¼13.5,
a
a
,9
b
a
,9
b
b,9b
9
b
), 1.97 (1H, dt, 2J9 ¼13.2, J8(
¼8.5, H-9
a
), 2.62 (1H, s, H-2),
H-10b), 4.67 (1H, d, J1,2¼5.3, 1-H), 5.55 (1H, s, H-11), 7.30 (6H, m, m-
Ph, p-Ph, m-Ph0, p-Ph0), 7.43 (4H, m, o-Ph, o-Ph0) ppm. 13C NMR
(75.5 MHz, CDCl3) dC 24.7 (CH2, C-8), 43.9 (CH, C-2), 54.6 (CH2, C-9),
55.1 (CH3, C-7), 57.9 (CH, C-5), 60.7 (CH2, C-10), 60.9 (CH, C-3), 69.8
(CH2, C-6), 80.9 (CH, C-4), 99.6 (CH, C-1), 102.7 (CH, C-11), 126.3
(CH, o-Ph), 128.0 (2ꢂCH, o-Ph0), 128.3 (2ꢂCH, m-Ph), 128.8 (4ꢂCH,
m-Ph, p-Ph0), 129.0 (CH, p-Ph), 137.8 (2ꢂC, Ph, Ph0) ppm. MS (FABþ)
m/z 382 [MH]þ. C23H28O4N [MH]þ requires m/z 382.2018; HR-
FABMS found m/z 382.2018.
a
,9
b
,b
),9a
2.84 (1H, ddd, J8 ¼11.3, 2J8 ¼10.1, J8 ¼8.5, H-8
a
), 3.35 (3H, s,
a
,9
b
a
,8
b
a,9a
H3-7), 3.42 (1H, obs td, 2J8 ¼J8 ¼9.1, J8 ¼3.4, H-8
b), 3.50 (1H,
a
,8
b
b
,9
a
b,9b
d, J4,5¼9.8, H-4), 3.64 (1H, t, 2J6ax,6eq¼J5,6ax¼10.3, H-6ax), 3.87 (1H,
2
td, J4,5¼J5,6ax¼9.8, J5,6eq¼5.2, H-5), 4.21 (1H, dd, J6ax,6eq¼10.2,
J5,6eq¼5.2, H-6eq), 4.78 (1H, s, H-1), 5.42 (1H, s, H-11), 5.72 (1H, br s,
HO–N), 7.35 (3H, m, m-Ph, p-Ph), 7.50 (2H, m, o-Ph) ppm. 13C NMR
(62.9 MHz, CDCl3) dC 13.0 (CH3, C-10), 38.6 (CH2, C-9), 42.0 (C, C-3),
54.3 (CH3, C-7), 54.9 (CH2, C-8), 58.4 (CH, C-5), 68.5 (CH2, C-6), 74.5
(CH, C-2), 81.3 (CH, C-4), 100.4 (CH, C-1), 101.0 (CH, C-11), 125.2
(2ꢂCH, o-Ph), 127.2 (2ꢂCH, m-Ph), 128.0 (CH, p-Ph), 138.5 (C,
Ph) ppm. MS (FABþ) m/z 322 [MH]þ. C17H24O5N [MH]þ requires m/z
322.1654; HR-FABMS found m/z 322.1654.
3.4.3.17. Methyl-a-D-3-amino-(R)-4,6-O-benzylidene-2,3-dideoxy-2-C,3-
N-(ethane-1,2-diyl)-3-N-(phenethyl)-allopyranoside (15d). Compound
12 as starting material. Purification by flash column chromatography
using 49:49:2 petrol–Et2O–Et3N. Yield 62%, colourless syrup. Rf
(49:49:2 petrol–Et2O–Et3N)¼0.44. 1H NMR (250 MHz, CDCl3) dH 1.80
3.4.3.14. Methyl-a-D-3-amino-(R)-4,6-O-benzylidene-2,3-dideoxy-2-
C,3-N-(ethane-1,2-diyl)-3-N-ethyl-allopyranoside (15a). Compound
12 as starting material. Purification by flash column chromatogra-
phy using 74:24:2 petrol–Et2O–Et3N. Yield 37%, colourless syrup. Rf
(74:24:2 petrol–Et2O–Et3N)¼0.27. 1H NMR (400 MHz, CDCl3) dH
1.20 (3H, obs t, H3-11), 1.50 (1H, dt, 2J8 ¼14.6, J2,8 ¼J8 ¼7.4, H-
(1H, m, H-8
a
), 1.99 (1H, m, H-8
b
), 2.50 (1H, dtd, J2,8 ¼8.3,
a
J2,3¼J2,8 ¼6.6, J1,2¼0.9, H-2), 2.9 (6H, m, H-9
a
, H-9b, H2-10, H2-11),
b
3.30 (3H, s, H-7), 3.30 (1H, m, H-3), 3.63 (1H, t, 2J6ax,6eq¼J5,6ax¼9.1, H-
6ax), 3.71 (1H, m, H-4), 3.79 (1H,,td, J4,5¼J5,6ax¼9.1, J5,6eq¼4.3, H-5),
4.28 (1H, m, H-6eq), 4.49 (1H, s, H-1), 5.55 (1H, s, H-12), 7.02 (2H, m,
m-Ph0), 7.15 (3H, m, o-Ph0, p-Ph), 7.40 (3H, m, m-Ph, p-Ph), 7.55 (2H,
m, o-Ph) ppm. 13C NMR (62.9 MHz, CDCl3) dC 24.9 (CH2, C-8), 32.2
(CH2, C-11), 41.2 (CH, C-2), 49.3 (CH2, C-10), 52.7 (CH3, C-7), 54.3 (CH2,
C-9), 58.2 (CH, C-5), 59.0 (CH, C-3), 67.3 (CH2, C-6), 76.1 (CH, C-4), 98.5
(CH, C-1), 99.5 (CH, C-12), 123.7 (2ꢂCH, o-Ph0), 124.2 (CH, 2ꢂm-Ph0),
124.3 (CH, p-Ph0), 126.5 (2ꢂCH, o-Ph), 126.7 (2ꢂCH, m-Ph), 126.9 (CH,
p-Ph), 135.6 (C, i-Ph0), 138.4 (C, i-Ph) ppm. MS (FABþ) m/z 396 [MH]þ.
C24H30O4N [MH]þ requires m/z 396.2175; HR-FABMS found m/z
396.2175.
a,8
b
a
a,9a
8
a
), 1.62 (1H, dt 2J8 ¼14.7, J2,8 ¼J8 ¼7.4, H-8
b), 2.12 (1H, dt,
), 2.44 (3H, m, H-2, H2-10), 3.20
a
,8
b
b
b,9a
2J9 ¼10.8, J8 ¼J8 ¼7.4, H-9
a
a
,9
b
a
,9
a
b,9a
(1H, m, H-9
b
), 3.35 (3H, s, H3-7), 3.65 (1H, dd, J4,5¼9.4, J3,4¼2.8, H-
4), 3.73 (1H, t, 2J6ax,6eq¼J5,6ax¼9.9, H-6ax), 3.90 (1H, br s, H-3), 4.14
2
(1H, dt, J4,5¼J5,6ax¼9.9, J5,6eq¼5.1, H-5), 4.25 (1H, dd, J6ax,6eq¼9.6,
J5,6eq¼5.1, H-6eq), 4.60 (1H, s, H-1), 5.70 (1H, s, H-12), 7.35 (3H, m,
m-Ph, p-Ph), 7.50 (2H, m, o-Ph). 1H NMR (100 MHz, CDCl3) dC 11.6
(CH3, C-11), 27.6 (CH2, C-8), 43.8 (CH, C-2), 47.0 (CH2, C-10), 52.0
(CH2, C-9), 55.6 (CH3, C-7), 58.5 (CH, C-5), 69.4 (CH and CH2, C-3,
C-6), 76.6 (CH, C-4), 102.3 (CH, C-1), 102.4 (CH, C-12), 126.3 (2ꢂCH,
o-Ph), 128.3 (2ꢂCH, m-Ph), 129.1 (CH, p-Ph), 135.2 (C, i-Ph). MS
(FABþ) m/z 320 [MH]þ. C18H26O4N [MH]þ requires m/z 320.1862;
HR-FABMS found m/z 320.1862.
3.4.3.18. Methyl-a-D-3-amino-(R)-4,6-O-benzylidene-2,3-dideoxy-C,3-
N-(ethane-1,2-diyl)-3-N-(phenylamino)-allopyranoside (15e). Compound
12 as starting material. Purification by flash column chromatography
using 74:24:2 petrol–Et2O–Et3N. Yield 72%, colourless syrup. Rf (74:24:2
petrol–Et2O–Et3N)¼0.48. 1H NMR (400 MHz, CDCl3) dH 1.70 (2H, m,
3.4.3.15. Methyl-a-D-3-amino-(R)-4,6-O-benzylidene-2,3-dideoxy-2-
C,3-N-(ethane-1,2-diyl)-3-N-phenyl-allopyranoside (15b). Compound
12 as starting material. Purification by flash column chromatography
using 49:49:2 petrol–Et2O–Et3N. Yield 36%, colourless syrup. Rf
(49:49:2 petrol–Et2O–Et3N)¼1.7. 1H NMR (250 MHz, CDCl3) dH 1.75
H2-8
a
,
b
), 2.51 (1H, m, H-2), 2.68 (1H, dd, 2J9 ¼10.1, J8 ¼5.8, H-9
a),
a
,9
b
a,9a
2.87 (1H, td, 2J9 ¼J8 b 9.8, J8 ¼5.6, H-9
), 3.32 (1H, t, J2,3¼J4,5 H-3),
b
a
,9
b
a,9
b,9b
3.35 (3H, s, H3-7), 3.65 (2H, m, H-4, H-6ax), 3.90 (1H, m, H-5), 4.30 (1H,
dd, 2J6ax,6eq¼10.0, J5,6eq¼4.8, 6eq-H), 4.48 (1H, s, H-1), 5.60 (1H, s, H-10),
7.28 (2H, m, o-Ph0), 7.30 (3H, m, m-Ph0, p-Ph0), 7.35 (3H, m, m-Ph, p-Ph),
7.50 (2H, m, o-Ph) ppm. 13C NMR (100 MHz, CDCl3) dC 26.4 (CH2, C-8),
43.1 (CH, C-2), 54.8 (CH3, C-7), 58.9 (CH2, C-9), 61.3 (CH, C-5), 61.9 (CH, C-
3), 69.5 (CH2, C-6), 78.8 (CH, C-4), 101.3 (CH, C-1), 102.7 (CH, C-10), 125.0
(2ꢂCH, o-Ph0), 126.1 (2ꢂCH, m-Ph0), 126.3 (CH, p-Ph0), 126.8 (2ꢂCH,
o-Ph), 128.2 (2ꢂCH, m-Ph), 128.8 (CH, p-Ph), 135.2 (C, Ph0), 137.8 (C,
Ph) ppm. MS (FABþ) m/z 383 [MH]þ. C22H27O4N2 [M]þ requires m/z
383.1971; HR-FABMS found m/z 383.1970.
(2H, m, H2-8
3.20 (2H, t, J2,3¼J3,4¼7.1, H2-9
a
,
b
), 2.28 (1H, ddd, J2,8 ¼8.3, J2,3¼6.2, J2,8 ¼2.5, H-2),
a
b
a,b), 3.40 (3H, s, H3-7), 3.68 (1H, dd,
2
J4,5¼9.6, J3,4¼2.8, H-4), 3.78 (1H, t, J6ax,6eq¼J5,6eq¼9.9, H-6ax), 4.02
(1H, m, H-3), 4.22 (1H, td, J4,5¼J5,6ax¼9.9, J5,6eq¼5.1, H-5), 4.32 (1H,
dd, J 5.1, 9.9, H-6eq), 4.60 (1H, s, H-1), 5.61 (1H, s, H-10), 6.65 (2H,0t,
0
0
0
0
0
0
0
Jo-Ph ,m-Ph ¼Jm-Ph ,p-Ph ¼7.3, m-Ph ), 6.78 (1H, t, Jm-Ph ,p-Ph ¼7.8, p-Ph ),
0
0
0
7.10 (2H, d, Jo-Ph ,m-Ph ¼7.3, o-Ph ), 7.40 (3H, m, m-Ph, p-Ph), 7.55 (2H,
m, o-Ph) ppm. 1H NMR (62.9 MHz, CDCl3) dC 30.1 (CH2, C-8), 42.6

4774
D.M. Laventine et al. / Tetrahedron 65 (2009) 4766–4774
3.4.3.19. Methyl-
a
-
D
-3-amino-(R)-4,6-O-benzylidene-2,3-dideoxy-2-
C-10), 126.5 (2ꢂCH, o-Ph), 128.2 (2ꢂCH, m-Ph), 129.1 (CH, p-Ph),
137.6 (C, i-Ph) ppm. MS (FABþ) m/z 292 [MH]þ. C16H22O4N [MH]þ
requires m/z 292.1549; HR-FABMS found m/z 292.1548.
C,3-N-(ethane-1,2-diyl)-3-N-hydroxyl-allopyranoside (15f). Compound
12 as starting material. Purification by flash column chromatography
using 49:49:2 petrol–Et2O–Et3N. Yield 44%, colourless syrup. Rf
(65:33:2 Et2O–petrol–Et3N)¼0.47. 1H NMR (400 MHz, CDCl3) dH 1.74–
3.4.4.3. Synthesis of methyl-a-D-3-amino-(R)-4,6-O-benzylidene-2,
1.77 (2H, m, H2-8
a
,b
), 2.57 (1H, dtd, J2,8 ¼8.5, J1,2¼J2,3¼6.0, J2,8 ¼1.8, H-
3-dideoxy-2-C,3-N-(ethane-1,2-diyl)-3-N-hydroxyl-allopyranoside
(16). Compound 15f (67 mg, 0.218 mmol) was dissolved in 80% aq
AcOH (1 mL) and heated to reflux for 4 h. The solvent was removed in
vacuo and the residue was dissolved in methanol (2 mL), and K2CO3
added. Column chromatography on silica gel with 49:49:2 petrol–
Et2O–Et3N as the eluent yielded 21 mg of 15f (0.096 mmol, 44% yield)
as a colourless syrup. Rf 0.47, petroleum ether–diethyl ether (1:2), 1%
a
b
2), 2.75 (1H, ddd, J9 ¼11.2, 2J9 ¼10.3, J8 ¼6.4, H-9
a), 3.27 (1H, dd,
a
,8
b
a,9b
a,9a
J2,3¼6.3, J4,3¼4.2, H-3), 3.33 (3H, s, H3-7), 3.51 (1H, td, 2J9 ¼J8 ¼9.4,
a,9b
a,9b
J8 ¼5.4, H-9
b
), 3.66 (1H, t, 2J6ax,6eq¼J5,6ax¼9.4, H-6ax), 3.84 (1H, dd,
b,9b
J4,5¼9.4, J3,4¼4.2, H-4), 4.21 (2H, ov m, H-5, H-6eq), 4.46 (1H, d, J1,2¼5.7,
H-1), 5.22 (1H, s, HO–N), 5.50 (1H, s, H-10), 7.23–7.35 (3H, m, m-Ph, p-
Ph), 7.23–7.35 (2H, m, o-Ph) ppm. 13C NMR (100.6 MHz, CDCl3) dC 22.3
(CH2, C-8), 41.3 (CH, C-2), 56.3 (CH3, C-7), 56.8 (CH2, C-9), 58.0 (CH, C-5),
66.2 (CH, C-3), 69.9 (CH2, C-6), 79.5 (CH, C-4), 99.5 (CH, C-1),102.9 (CH,
C-10), 126.6 (2ꢂCH, o-Ph), 128.7 (2ꢂCH, m-Ph), 129.5 (CH, p-Ph), 138.0
(C, Ph) ppm. MS (FABþ) m/z 307 [MH]þ. C16H22O5N [MH]þ requires m/z
308.1498; HR-FABMS found m/z 308.1498.
triethylamine. 1H NMR (300 MHz, CDCl3) dH 1.65 (1H, m, H-8
a), 1.82
(1H, m, J8 ¼4.3, H-8 ), 2.43 (1H, dtd, J2,8 ¼9.2, J1,2¼J2,3¼5.6,
b
b
,9
b
a
J2,8 ¼1.5, H-2), 2.77 (1H, ddd, J9 ¼11.2, 2J9 ¼9.9, J8 ¼7.0, H-9
a),
b
a,8b
a,9b
a,9a
3.22 (3H, s, H3-7), 3.26 (1H, dd, J2,3¼6.4, J4,3¼2.8, H-3), 3.51 (1H, td,
2J9 ¼J8 ¼9.3, J8 ¼4.3, H-9
b
), 3.74 (1H, dd, 2J6a,6b¼11.8, J5,6a¼4.5,
a,9b
a,9
b
b,9b
H-6a), 3.83 (2H, ov m, H-4, H-5), 3.87 (1H, dd, 2J6a,6b¼11.8, J5,6b¼2.1, H-
6a), 4.42 (1H, d, J1,2¼5.2, H-1) ppm. 13C NMR (75.5 MHz, CDCl3) dC 22.3
(CH2, C-8), 41.3 (CH, C-2), 56.3 (CH3, C-7), 56.8 (CH2, C-9), 58.0 (CH, C-
5), 66.2 (CH, C-3), 69.9 (CH2, C-6), 79.5 (CH, C-4), 99.5 (CH, C-1), 102.9
(CH, C-10), 126.6 (2ꢂCH, o-Ph), 128.7 (2ꢂCH, m-Ph), 129.5 (CH, p-Ph),
138.0 (C, Ph) ppm. MS (FABþ) m/z 220 [MH]þ, C9H18O5N [MH]þ re-
quires m/z 220.1185; HR-FABMS found m/z 220.1185.
3.4.4. Removal of the hydroxyl group on compounds 11m and 15g
3.4.4.1. Methyl-
a
-
D
-2-amino-(R)-4,6-O-benzylidene-2,3-dideoxy-2-
11j
N,3-C-(ethane-1,2-diyl)-mannopyranoside (11m). Compound
(252 mg, 0.82 mmol) was dissolved in 1:1 methanol–water (2 mL).
This solution was degassed with N2 three times before adding palla-
dium on carbon (5%) catalyst. The mixture was allowed to stir at rt for
1 h under H2 atmosphere until TLC analysis showed no starting ma-
terial. The catalyst was filtered off and washed with MeOH (10ꢂ2 mL).
The solvent was removed under high vacuum, and FC using 12:12:1
petrol–Et2O–Et3N afforded 229 mg of 11m (94% yield) as a colourless
oil. Rf (12:12:1 petrol–Et2O–Et3N)¼0.20. 1H NMR (250 MHz, CDCl3) dH
Acknowledgements
We would like to acknowledge the ESPRC and the University of
Leicester for financial support of this research. M.D.G. thanks the
Xunta de Galicia (‘programa Isidro Parga Pondal’ and ‘axudas para
1.72 (1H, br s, H–N), 1.73 (1H, obs m, H-9
b
), 1.96 (1H, ddd, 2J9 ¼12.5,
a,9b
´
estadıas no extranxeiro’) for financial support. Many thanks to K.
J8 ¼8.0, J8 ¼4.0, H-9 ), 2.33 (1H, dt, J3,4¼9.9, J2,3¼J3,9 ¼5.5, H-3),
a
b,9a
a,9a
b
Singh for X-ray data.
2.96 (1H, td, 2J8 ¼J8 ¼10.4, J8 ¼4.1, H-8
a), 3.09 (1H, obs dt,
a
,8
b
a,9b
a,9a
2J8 ¼10.6, J8 ¼J8 ¼8.0, H-8
), 3.15 (1H, d, J2,3¼5.5, H-2),
b
a,8b
b,9
a
b,9b
References and notes
3.34 (3H, s, H3-7), 3.38 (1H, t, J3,4¼J4,5¼9.6, H-4), 3.65 (1H, t,
2J6ax,6eq¼J5,6ax¼10.0, H-6ax), 3.73 (1H, td, J4,5¼J5,6ax¼9.4, J5,6eq¼4.7, H-
5), 4.20 (1H, dd, 2J6ax,6eq¼9.4, J5,6eq¼4.2, H-6eq), 4.60 (1H, s, H-1), 5.45
(1H, s, H-10), 7.25–7.33 (3H, m, m-Ph, p-Ph), 7.36–7.44 (2H, m, o-
Ph) ppm. 13C NMR (62.9 MHz, CDCl3) dC 28.1 (CH2, C-9), 39.4 (CH, C-3),
44.0 (CH2, C-8), 55.3 (CH3, C-7), 62.5 (CH, C-2), 62.9 (CH, C-5), 69.7
(CH2, C-6), 78.5 (CH, C-4), 99.9 (CH, C-1), 102.6 (CH, C-10), 128.5
(2ꢂCH, o-Ph),128.7 (2ꢂCH, m-Ph),129.3 (CH, p-Ph),138.1 (C, Ph) ppm.
MS (FABþ) m/z 292 [MH]þ. C16H22O4N [MH]þ requires m/z 292.1549;
HR-FABMS found m/z 292.1549.
1. (a) Asano, N. Glycobiology 2003, 13, 93; (b) Watson, A. A.; Fleet, G. W. J.; Asano,
N.; Molyneux, R. J.; Nash, R. J. Phytochemistry 2001, 56, 265; (c) Asano, N.; Nash,
R. J.; Molyneux, R. J.; Fleet, G. W. J. Tetrahedron: Asymmetry 2000, 11, 1645.
2. (a) Stu¨tz, A. E. Iminosugars as Glycosidase InhibitorsdNojirimycin and Beyond; Wiley
VCH: Weinheim,1999; (b) Lillelund, V. H.; Jensen, H. H.; Liang, X.; Bols, M. Chem. Rev.
2002,102, 515; (c) Heightman, T. D.; Vasella, A. T. Angew. Chem., Int. Ed.1999, 38, 750.
3. Pearson, W. H.; Hembre, E. J. J. Org. Chem. 1996, 61, 5546.
4. Winkler, D. A. J. Med. Chem. 1996, 39, 4332.
5. Tropea, J. E.; Kaushal, G. P.; Pastuszak, I.; Mitchel, M.; Aoyagi, T.; Molyneux, R. J.;
Elbein, A. D. Biochemistry 1990, 29, 10062.
6. (a) Wood, A. J.; Holt, D. J.; Dominguez, M.; Jenkins, P. R. J. Org. Chem. 1998, 63,
8522; (b) Holt, D. J.; Barker, W. D.; Jenkins, P. R. J. Org. Chem. 2000, 65, 482; (c)
Holt, D. J.; Barker, W. D.; Jenkins, P. R.; Davies, D. L.; Garratt, S.; Fawcett, J.;
Russell, D. R.; Ghosh, S. Angew. Chem., Int. Ed. 1998, 37, 3298.
3.4.4.2. Methyl-a-D-3-amino-(R)-4,6-O-benzylidene-2,3-dideoxy-2-
7. See for instance: (a) Baxter, E. W.; Reitz, A. B. J. Org. Chem. 1994, 59, 3175; (b)
Cheng, X.; Kumaran, G.; Mootoo, D. R. Chem. Commun. 2001, 811.
8. Laventine, D. M.; Davies, M.; Evinson, E. L.; Jenkins, P. R.; Cullis, P. M.; Fawcett, J.
Tetrahedron Lett. 2005, 46, 307.
9. Ferrier, R. J.; Lee, C.-K.; Wood, T. A. J. Chem. Soc., Chem. Commun. 1991, 690.
10. Meyers, A. I.; Bienz, S.; Kwon, H.; Wallace, R. H. Helv. Chim. Acta 1996, 79, 1026.
11. Hon, Y.; Yan, J. Tetrahedron Lett. 1993, 41, 6591.
12. Mereyala, B.; Lingannagaru, S. R. Tetrahedron 1997, 53, 17501.
13. Pougny, J. R.; Sinay, P. J. Chem. Res. 1982, 186.
C,3-N-(ethane-1,2-diyl)-allopyranoside (15g). Hydroxylamine 15f
(25 mg, 0.081 mmol) was dissolved in 3:1 MeOH–MeCN (1 mL).
Molybdenum hexacarbonyl (32.3 mg, 1.22 mmol) was added and
the solution heated to reflux until TLC showed no starting material.
The reaction mixture was filtered through a silica gel plug and
washed with CH2Cl2 (3ꢂ2 mL) and Et3N (3ꢂ2 mL). This was further
filtered through Celite and the solvents removed under high vac-
uum. Column chromatography on silica gel with 98:2 Et2O–Et3N
yielded 20.2 mg (85% yield) of 15g as a colourless syrup. Rf (98:2
14. CCDC 704156 contains the supplementary crystallographic data for compound
11f. These data can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Et2O–Et3N)¼0.59. 1H NMR (400 MHz, CDCl3) dH 1.78 (1H, m, H-8
a),
15. See for instance: Hanessian, S.; Faucher, A. M.; Leger, S. Tetrahedron 1990, 46, 231.
16. The same stereochemical results were found in the synthesis by double reductive
amination ring closure of a series of indolizidine derivatives by Gravier-Pelletier
et al.: (a) Gravier-Pelletier, C.; Maton, W.; Bertho, G.; Le Merrer, Y. Tetrahedron
2003, 59, 8721; (b) Gravier-Pelletier, C.; Maton, W.; Le Merrer, Y. Synlett 2003, 333.
17. Beesley, R. M.; Ingold, C. K.; Thorpe, J. F. J. Chem. Soc., Trans. 1915, 1080.
18. This product was identified by the characteristic methylene ozonide proton
1.90 (1H, m, H-8b), 1.98 (1H, br s, H–N), 2.48 (1H, m, H-2), 2.96 (1H,
td, 2J9 ¼J8 ¼10.1, J8 ¼4.6, H-9
a
), 3.20 (1H, ddd, 2J9 ¼9.9
a
,9
b
a
,9
a
b
,9
a
a,9b
J8 ¼9.0 J8 ¼6.4, H-9
b), 3.35 (3H, s, H3-7), 3.41 (1H, t,
b
,9
b
a,9b
2
J2,3¼J3,4¼4.8, H-3), 3.73 (1H, t, J6ax,6eq¼J5,6ax¼10.1, 6ax-H), 3.87
(1H, dd, J4,5¼9.8, J3,4¼4.5, H-4), 4.14 (1H, td, J4,5¼J5,6ax¼9.9,
J5,6eq¼5.0, H-5), 4.30 (1H, dd, 2J6ax,6eq¼10.1, J5,6eq¼5.0, H-6eq), 4.59
(1H, d, J1,2¼5.5,1-H), 5.60 (1H, s, H-10), 7.35 (3H, s, m-Ph, p-Ph), 7.50
(2H, m, o-Ph) ppm. 13C NMR (400 MHz, CDCl3) dC 26.2 (CH2, C-8),
42.8 (CH, C-2), 46.0 (CH2, C-9), 55.9 (CH3, C-7), 56.8 (CH, C-5), 57.7
(CH, C-3), 69.6 (CH2, C-6), 78.8 (CH, C-4), 100.4 (CH, C-1), 102.6 (CH,
signals at
NMR spectra of the crude product.
d 4.99–5.07 and methine doublet of doublet signals at d H
5.23 in the 1
19. Ogawa, S.; Fujieda, S.; Sakata, Y.; Ishizaki, M.; Hisamatsu, S.; Okazaki, K. Bioorg.
Med. Chem. Lett. 2003, 13, 3461.
20. Dimri, G. P.; Lee, X.; Basile, G.; Acosta, M.; Scott, G.; Roskelley, C.; Medrano, E. E.;
Linskensi, M.; Rubelj, I.; Pereira-Smith, O.; Peacocke, M.; Campisi, J. Proc. Natl.
Acad. Sci. U.S.A. 1995, 92, 9363.