Synthesis of monosaccharide-derived spirocyclic cyclopropylamines and their evaluation as glycosidase inhibitors

Article abstract of DOI:10.1002/hlca.200390245

The glucose-, mannose-, and galactose-derived spirocyclic cyclopropylammonium chlorides 1a - 1d, 2a - 2d and 3a-3d were prepared as potential glycosidase inhibitors. Cyclopropanation of the diazirine 5 with ethyl acrylate led in 71% yield to a 4:5:1:20 mi

Full text of DOI:10.1002/hlca.200390245

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Helvetica Chimica Acta Vol. 86 (2003)
Synthesis of Monosaccharide-Derived Spirocyclic Cyclopropylamines and
Their Evaluation as Glycosidase Inhibitors
by Christian Bl¸chel, Chepuri Venkata Ramana, and Andrea Vasella*
Laboratorium f¸r Organische Chemie, ETH-Hˆnggerberg, Wolfgang-Pauli-Strasse 10, CH-8093 Z¸rich
The glucose-, mannose-, and galactose-derived spirocyclic cyclopropylammonium chlorides 1a 1d, 2a 2d
and 3a 3d were prepared as potential glycosidase inhibitors. Cyclopropanation of the diazirine 5 with ethyl
acrylate led in 71% yield to a 4 :5 :1 :20 mixture of the ethyl cyclopropanecarboxylates 7a 7d, while the Cu-
catalysed cycloaddition of ethyl diazoacetate to the exo-glycal 6 afforded 7a 7d (6 :2 :5 :3) in 93 98% yield
(Scheme 1). Saponification, Curtius degradation, and subsequent addition of BnOH or t-BuOH led in 60 80%
overall yield to the Z- or Boc-carbamates 11a 11d and 12a 12d, respectively. Hydrogenolysis of 11a 11d
afforded 1a 1d, while 12a 12d was debenzylated to 13a 13d prior to acidic cleavage of the N-Boc group. The
manno- and galacto-isomers 2a 2d and 3a 3d, respectively, were similarly obtained in comparable yields
(Schemes 2 and 4). Also prepared were the differentially protected manno-configured esters 24a 24d; they are
intermediates for the synthesis of analogous N-acetylglucosamine-derived cyclopropanes (Scheme 3).
The cyclopropylammonium chlorides 1a 1d, 2a 2d and 3a 3d are very weak inhibitors of several
glycosidases (Tables 1 and 2). Traces of Pd compounds, however, generated upon catalytic debenzylation,
proved to be strong inhibitors. PdCl24À is, indeed, a reversible, micromolar inhibitor for the b-glucosidases from
C. saccharolyticum and sweet almonds (non-competitive), the b-galactosidases from bovine liver and from E.
coli (both non-competitive), the a-galactosidase from Aspergillus niger (competitive), and an irreversible
inhibitor of the a-glucosidase from yeast and the a-galactosidase from coffee beans. The cyclopropylamines
derived from 1a 1d or 3a 3d significantly enhance the inhibition of the b-glucosidase from C. saccharolyticum
2À
by PdCl24À, lowering the Ki value from 40 mm (PdCl24À ) to 0.5 mm for a 1:1mixture of PdCl and 1d. A similar
4
effect is shown by cyclopropylamine, but not by several other amines.
Introduction. Two classes of glycosidases, anti- and syn-protonators, have been
discerned on the basis of the trajectory of the proton transfer from the catalytic acid to
the glycosidic O-atom [1]. The precise position, in individual glycosidases, of the
catalytic acid relative to the catalytic nucleophile and the bound substrate has thus
become of renewed interest. A couple of complementary inhibitors, one inhibiting anti-
protonators, and the other syn-protonators, would be most useful to specify the position
of the catalytic acid. Currently available inhibitors are not satisfactory in this respect
[2 4]. The complementary inhibitors should possess a functional group that is oriented
in a defined way so as to interact with the catalytic acid of either an anti- or a syn-
protonator. Ideally, this functional group will be attached to a common scaffold to
ensure that the complementary inhibitors bind in the same orientation in the active site
of a glycosidase of unknown structure. We considered spirocyclic cyclopropylamines of
type 1 promising candidates for this purpose and planned to prepare the gluco-, manno-,
and galacto-derivatives 1a 1d, 2a 2d, and 3a 3d (Schemes 1, 2, and 4)1).
1
)
Several carbohydrate-derived spirocyclic cyclopropanes are known [5 30]. The cyclopropylamines 1
are formally C-glycosides of ulopyranoses. For the use of cyclopropanes as scaffolds, see e.g., [31 48].
3

Helvetica Chimica Acta Vol. 86 (2003)
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We decided to first synthesise the glucose-derived spirocyclic cyclopropylamines
1a 1d, and to then apply the synthesis to the mannose- and galactose-derived
analogues 2a 2d and 3a 3d, respectively. Such cyclopropylamines are expected to
possess a pKHA value of ca. 8 9 [49 51]. At the acidic pH optimum typical for
glycosidases, these amines are protonated and interact with the catalytic nucleophile.
We planned to first evaluate this interaction and to prepare less-basic analogues of 1 3
at a later stage.
Results and Discussion. Molecular Modelling. To evaluate the possibility of an
interaction of the catalytic nucleophile with 1a 1d, we docked the corresponding
ammonium ions in the active site of the b-glucosidase from Sulfolobus solfataricus [52].
Molecular-modelling studies were restricted to the space defined by a maximal distance
of 10 ä from any atom of the glycon moiety of methyl b-d-glucopyranoside that was
docked in the active site according to a reported procedure (Fig. 1,a) [1]. The structure
of the substrate or inhibitor, and the structural domain of the enzyme located in an
inner shell (up to 5 ä from the substrate) of the space under consideration were
unconstrained, while those in an outer shell (5 10 ä from the substrate) were
constrained. The ammonium ions corresponding to 1a 1d were inserted manually at
the position of the substrate and in the same orientation. The geometry of the enzyme
inhibitor complex was energy-minimised with the Amber* force field (Macromodel V.
6.0 [53]). In the resulting optimised geometry, one of the isomers, 1b, showed a
geometrically favourable interaction between the ammonium group and the carbox-
ylate corresponding to the catalytic nucleophile, viz. a salt bridge with a N ¥¥¥ O distance
of 2.5 ä (cf. Fig. 1,b).
Fig. 1. Docking of a) methyl b-d-glucopyranoside (according to [1]), b) 1b in the active site of the b-glucosidase
from Sulfolobus solfataricus [52]
Synthesis of the gluco-Cyclopropylamines. We planned to prepare the cyclo-
propylammonium chlorides 1a 1d via a Curtius rearrangement of the O-benzylated
cyclopropanecarboxylic acids 8a 8d (Scheme 1). The nitriles 30a 30d (cf. Fig. 2)

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Helvetica Chimica Acta Vol. 86 (2003)
corresponding to these acids had been prepared by cycloaddition to acrylonitrile of a
carbene derived from perbenzylated glucono-1,5-lactone tosylhydrazone [16][20], or
from the diazirine 5 [54]2). The diazirine 5 [56][57] reacted with ethyl acrylate to yield
71% of a 4 :5 :1:20 mixture of the cyclopropane esters 7a 7d. The undesired
diastereoselectivity and the lengthy synthesis prompted us to look for an alternative.
The esters 7a 7d were obtained much more efficiently by cyclopropanating the readily
available enol ether 6 [58] with ethyl diazoacetate. Catalysis of the cyclopropanation
with Cu powder in toluene [59] led, in yields of 93 98%, to a 3 :1:3 :2 mixture of 7a
7d, while Rh2(OAc)4 required a large excess of diazoacetate to yield 42 69% of 7a 7d
(3 :2 :3 :2), depending on the choice of solvent and temperature3). The cyclopropa-
nation proceeded best when a toluene solution of excess ethyl diazoacetate at below 258
was slowly added to a suspension of Cu powder in a toluene solution of 6 at 1008. The
ester 7c was isolated by crystallisation from MeOH (28%), while isolation of the other
diastereoisomers required repeated purification by HPLC with different solvent
systems to give 7a (36%), 7b (12%), 7c (additional 3%), and 7d (18%). The individual
esters were hydrolysed, and the resulting acids 8a 8d were transformed into the
corresponding acyl azides 9a 9d. Thermolysis of the azides in toluene at 1008, and
treatment of the resulting isocyanates 10a 10d with BnOH or t-BuOH led, in overall
yields of 60 80%, to the carbamates 11a 11d and 12a 12d, respectively. The acyl
azides 9a 9d and the isocyanates 10a 10d were stable enough to be isolated and
characterised. Hydrogenolysis of the benzyl carbamates 11a 11d yielded the desired
ammonium chlorides 1a 1d in almost quantitative yields, while debenzylation of the
tert-butyl carbamates 12a 12d led in high yield to the tetrahydroxy tert-butyl
carbamates 13a 13d. These carbamates were nearly quantitatively deprotected to
1a 1d by treatment with 1n HCl at 508.
Synthesis of the manno-Cyclopropylamines. We had planned to prepare the O-
benzylated cyclopropanecarboxylates 15a 15d (Scheme 2) and the differentially
protected analogues 24a 24d (Scheme 3), the former as precursors of the manno-
cyclopropylammonium chlorides 2a 2d, and the latter as precursors of N-acetylglucos-
amine-derived cyclopropylamines4). Cyclopropanation of the enol ether 14 [58]
yielded 86% of a ca. 9 :51:11:29 mixture of the corresponding esters 15a 15d
(Scheme 2), which were readily separated by HPLC. Hydrolysis of the esters 15a 15d
and Curtius degradation of the resulting acids 16a 16d by using the same procedure as
in the gluco-series yielded the corresponding N-Boc-protected cyclopropylamines
17a 17d. These carbamates were also obtained by treating the acids 16a 16d with
diphenylphosphoryl azide in t-BuOH [61]. Yields were similar for both procedures
(56 74%), but treatment of the acids 16c and 16d with diphenylphosphoryl azide gave
also ca. 15% of the aminocarbonyl azides 19c and 19d, respectively (cf. [61][62]).
Hydrogenation of 17a 17d gave the N-Boc-cyclopropylamines 18a 18d (84 99%),
which were readily deprotected (1n aq. HCl) to the cyclopropylammonium chlorides
2a 2d. The differentially protected exo-glycal 22 (Scheme 3) was obtained from the
2
)
O-Acyl-protected nitriles corresponding to 8a 8d were obtained in low yields by the reaction of
acrylonitrile with 2,3,4,6-tetra-O-acetyl-1,5-anhydro-1,1-diazido-d-glucitol [15][55].
Comparable yields were obtained from the Rh2(OAc)4-catalysed cyclopropanation of glycals [60].
In view of the results discussed below, we did not pursue the synthesis of the glucosamine derivatives.
3
4
)
)

Helvetica Chimica Acta Vol. 86 (2003)
3001
Scheme 1
a) 1,4-Dioxane, 238; 7a/7b/7c/7d 4 :5 :1:20 (71%). b) Rh2(OAc)4, Et2O, 238, 7a/7b/7c/7d 3 :2 :3 :2 (69%). c) Cu
Powder, toluene, 1008, 7a/7b/7c/7d 3 :1:3 :2 (98%). d) KOH, EtOH/H2O, 808; 95 99%. e) 1. ClCO2Et, Et3N,
acetone, 08, 2. NaN3, H2O, 238. f) Toluene, 1008. g) BnOH, 1008; 11a (85%), 11b (82%), 11c (77%), 11d (68%).
h) H2, Pd/C, MeOH/HCl; quant. i) 1. Toluene, 1008, 2. t-BuOH, 908; 12a (78%), 12b (82%), 12c (85%), 12d
(78%). j) H2, Pd/C, MeOH; 13a (79%), 13b (73%), 13c (84%), 13d (79%). k) 1n HCl; quant.
hemiacetals 20 (a/b 9 :1) by oxidation and olefination. Thus, 20 was oxidised with
pyridinium chlorochromate (PCC) to the spontaneously crystallising lactone 21 (79%).
Treatment of 21 with the reagent of Petasis [63][64] gave the exo-glycal 22 (75%)
besides the bis-enolether 23 (3%). Cyclopropanation of 22 with excess ethyl

3002
Helvetica Chimica Acta Vol. 86 (2003)
Scheme 2
OBn
OBn
O
BnO
BnO
14
a)
OBn
OBn
OBn
OBn
OBn
OBn
OBn
OBn
O
O
O
O
R
BnO
BnO
BnO
BnO
BnO
BnO
BnO
BnO
R
R
R
15a
16a
R = CO2Et 15b
15c
16c
R = CO2Et 15d
R = CO2H 16d
b)
b)
b)
b)
R = CO2H
16b
c) or d)
c) or d)
c) or d)
c) or d)
OR
OR
OR
OR
OR
O
OR
O
OR
O
OR
O
NHBoc
RO
RO
RO
NHBoc RO
RO
RO
RO
RO
BocHN
17b
NHBoc
17a
17c
17d
18d
R = Bn
R = H
R = Bn
R = H
e)
e)
e)
e)
18a
18b
18c
f)
f)
f)
f)
OH
OH
OH
O
OH
OH
OH
OH
OH
O
O
O
NH3Cl
HO
HO
HO
NH3Cl
HO
HO
HO
HO
HO
NH3Cl
2d
2a
2b NH3Cl
2c
BnO
BnO
BnO
BnO
OBn
O
OBn
O
NHCON3
BnO
BnO
19c
19d
NHCON3
a) Ethyl diazoacetate, Cu powder, toluene, 708; 14 (9%), 15a/15b/15c/15d 9 :51:11:29 (86%). b) KOH, EtOH/
H2O, 608; 80 99%. c) 1. ClCO2Et, Et3N, acetone, 08, 2. NaN3, H2O, 238, 3. toluene, 1008. 4. t-BuOH, 1008; 17a
(67%), 17b (74%), 17c (67%), 17d (56%). d) (PhO)2PON3, Et3N, t-BuOH, 1008; 17a (69%), 17b (74%), 17c
(70%), 17d (57%), 19c (16%), 19d (16%). e) H2, Pd/C, MeOH; 18a (quant.), 18b (84%), 18c (94%), 18d
(90%). f) 1n HCl; 90% quant.
diazoacetate in the presence of Cu powder (0.2 equiv.) gave 91% of a ca. 18 :42 :17:23
mixture of the diastereoisomeric ethyl cyclopropanecarboxylates 24a 24d, which were
separated by HPLC (Scheme 3).
Synthesis of the galacto-Cyclopropylamines. Similarly as for the gluco-configured
derivatives, Cu-catalysed cyclopropanation of the exo-galactal 25 [58] with ethyl
diazoacetate yielded 71% of a 3 :2 :2 :3 mixture of the cyclopropanecarboxylates 26a

Helvetica Chimica Acta Vol. 86 (2003)
3003
Scheme 3
OBn
BnO
BnO
BnO
BnO
BnO
BnO
OAc
OAc
O
O
a)
b)
O
O
BnO
O
BnO
BnO
BnO
BnO
+
O
OH
OAc
21
22
23
20
OBn
OAc
O
BnO
BnO
22
c)
OBn
OAc
OBn
OAc
OBn
OAc
OBn
OAc
O
O
O
O
CO2Et
BnO
BnO
BnO
BnO
BnO
BnO
BnO
BnO
CO2Et
24a
24b
24c
24d
CO2Et
CO2Et
a) PCC, CH2Cl2, 238; 79%. b) Cp2TiMe2, toluene, 608; 22 (75%), 23 (3%). c) Ethyl diazoacetate, Cu powder,
toluene, 608, 24a/24b/24c/24d 18 :42 :17:23 (91%).
26d (Scheme 4). This mixture was subjected to ester hydrolysis and Curtius
degradation, providing the tert-butyl carbamates 28a 28d in an overall yield of
68%. At this stage, the isomers were readily separated by flash chromatography into
two groups of two isomers each, viz. 28a/28c and 28b/28d. Hydrogenolytic debenzyl-
ation of the carbamate mixtures, followed by chromatography, yielded 86 90% of the
pure, debenzylated carbamates 29a 29d. The desired cyclopropylammonium chlorides
3a 3d were obtained in a nearly quantitative yield by treatment of the individual
carbamates with 1n aq. HCl.
Structure Analysis. The structure determination of the isomeric gluco-, manno-, and
galacto-cyclopropanes requires essentially the identification of the position of the
cyclopropyl ring substituents X relative to C(2) and C(5)ÀO, and relative to the plane
determined by C(2), C(1), and C(5)ÀO. To this end, the four positions are labelled A
D (Fig. 2,a), A being anti to OÀC(5) and on top of the above-mentioned plane, B anti
and below the plane, C syn and above the plane, and D syn and below the plane. The
cyclopropane H-atoms were identified by their positions relative to the substituents X
as Hgem, Hcis, and Htrans. Hgem, characterised by Jcis (ca. 9 Hz) and Jtrans (ca. 7 Hz)5), is
expected to be the most strongly deshielded cyclopropane H. Hcis and Htrans are further
characterised by Jgem (ca. 6 Hz). The crystal structure of the gluco-configured
derivatives 7c, 11a, and 13d (Fig. 3)6), and the chemical correlation of the derivatives
5
)
Hgem, Hcis, and Htrans refer to the positions of the H-atoms relative to the one of the substituents X, while
Jgem, Jcis and Jtrans mean the coupling constants between gem-, cis-, and trans-oriented H-atoms.
The crystallographic data have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication No. CCDC-158320 (11a), 158321 (7c), 158322 (13d) and CCDC-207349 (29d).
Copies of the data can be obtained, free of charge, on application to the CCDC, 12 Union Road,
Cambridge CB2 1EZ (fax: ‡44(1223)336033; e-mail: deposit@ccdc.cam.ac.uk).
6
)

3004
Helvetica Chimica Acta Vol. 86 (2003)
Scheme 4
OBn
BnO
O
BnO
OBn
25
a)
OBn
OBn
OBn
OBn
BnO
BnO
BnO
BnO
BnO
BnO
BnO
BnO
O
O
O
O
R3
R3
BnO
BnO
BnO
R3
R = CO2Et 26b
BnO
R3
26a
27a
26c
27c
R = CO2Et 26d
R = CO2H 27d
b)
b)
b)
b)
R = CO2H 27b
c)
c)
OR
c)
OR
c)
OR
OR
OR
OR
RO
OR
RO
OR
RO
O
O
O
O
NHBoc
NHBoc
RO
OR
OR
OR
OR
BocHN
28b
NHBoc
28a
29a
28c
28d
29d
R = Bn
R = H
R = Bn
R = H
d)
d)
d)
d)
29b
29c
e)
e)
e)
e)
OH
OH
OH
O
OH
OH
HO
OH
HO
OH
HO
OH
HO
O
O
O
NH3Cl
NH3Cl
OH
OH
OH
3b NH3Cl
OH
NH3Cl
3a
3c
3d
a) Ethyl diazoacetate, Cu powder, toluene, 1008, 26a/26b/26c/26d 29 :17:21:33 (71%). b) KOH, EtOH/H2O,
808, 94%. c) 1. ClCO2Et, Et3N, acetone, 08, 2. NaN3, H2O, 238, 3. toluene, 1008, 4. t-BuOH, 1008; 28a/28c 1:1
(40%), 28b/28d 3 :2 (33%). d) H2, Pd/C, MeOH; 29a (45%) and 29c (41%) from the mixture 28a/28c, 29b
(51%) and 29d (36%) from the mixture 28b/28d. e) 1n HCl; quant.
possessing the same configuration and differing by the nature of X allowed
determination of the structures of all gluco-cyclopropanes. The NMR data of these
compounds and those of the cyclopropane nitriles 30a 30d provided a critical set of
coupling constants and chemical shifts. The structure determination of the manno-
cyclopropanes, as based on a comparison with these data and NOEs, was rather
straightforward, while that of the galacto-cyclopropanes, although facilitated by the
crystal structure of 29d (cf. Fig. 3), proved more difficult.
Depending on their relative arrangement, the substituents X on the cyclopropane
ring interact with substituents of the pyranose ring. Substituents in position A and B
(anti to OÀC(5)) should interact most strongly with the C(2) group, and substituents in
4
position C and D most strongly with OÀC(5) (Fig. 2). In the C1 conformation, the
equatorial nonbonding, doubly occupied orbital of OÀC(5) bisects the plane of the

Helvetica Chimica Acta Vol. 86 (2003)
3005
Fig. 2. a) Positions A D on the spirocyclic cyclopropane scaffold. b) Influence of the OÀC(5) lone-pairs on
d(Hcis) for X in positions C or D. c) Influence of the OÀC(5) lone-pairs on Dd(Hgem À Htrans) for X in positions A
or B. d) Graphical representation of the influence of X in positions A D on d(HÀC(2)), d(Hcis), and Dd(Hgem
À
Htrans), relative to the mean-values, for the tert-butyl carbamates 13a 13d, 18a 18d, and 29a 29d. e) Structures
of the nitriles 30a 30d.
cyclopropane ring and should have a similar deshielding effect on H in position C and D
(HC and HD), while the axial nonbonding, doubly occupied orbital should influence HC
more strongly than HD7); HcCis should then be more strongly deshielded than HDcis
(Fig. 2,b) and D(dHgCem À dHtDrans ) should be larger than D(dHDgem À dHtCrans ) (Fig. 2,c).
The influence of the C(2) group on HA and HB depends on the configuration of C(2).
The axial RO substituent at C(2) in the manno-configured derivatives should mainly
7
)
For related observations and calculations, see, e.g., [65 68].

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Helvetica Chimica Acta Vol. 86 (2003)
Fig. 3. ORTEP Representations of the crystal structures of the carbamates 11a, 13d, and 29d, and of the ester 7c.
Parts of the structures of 11a and 13d were found on a Fourier map. The non-H-atoms of 7c, 13d, and 29d were
refined anisotropically. Structural refinement for 11a was not possible (low crystal quality; cf. Exper. Part).
deshield HA. In the gluco- and galacto-series, the equatorial RO substituent at C(2)
bisects the plane of the cyclopropane ring and should deshield HA and HB to about the
same extent. Conversely, the substituents XA and XB (anti to OÀC(5)) should have an
effect on d(HÀC(2)). In the manno-series, this effect should be similar for XA and XB
and allow to distinguish isomers with XA or XB from isomers with XC and XD. In the
gluco- and galacto-series the effect should be stronger for XA than for XB. One also
expects an effect of XB on d(HÀC(3)), and of XD on d(HÀC(5)). The donor
(OÀC(5)) and acceptor (X) substituents of the cyclopropane ring may give rise to
through-bond effects that will strengthen or weaken the through-space effects
discussed above, and complicate the structure determination. We compared the
chemical shifts of the 1H and 13C signals of each of the four diastereoisomers with the
same X in the gluco-, manno-, and galacto-series, relative to the mean value for each
one of these series, and compared the results in the three series with each other.
Configuration of the gluco-Isomers. The pyranose ring of the gluco-configured
cyclopropanes 7b 7d, 8b 8d, 9b 9d, 10b 10d, 11b 11d, 12b 12d, 13b 13d, 1a 1d,
4
and 30b 30d [16][17] adopts the C1 conformation, as evidenced by the coupling
constants in Tables 3 and 5 7 (Exper. Part), while J(2,3) values between 5.0 and 7.8 Hz

Helvetica Chimica Acta Vol. 86 (2003)
3007
evidence a flattened chair conformation of 7a, 8a, 9a, 10a, 11a, 12a, 13a, and 30a. The
flattening of the pyranose ring correlates with the position A for X, suggesting that it is
due to an interaction between XA and C(2)ÀOR. In accordance with the above-
mentioned considerations, isomers possessing XA (with the exception of 8a and 9a)
show a deshielding of HÀC(2) relative to the mean values. Surprisingly, the deshielding
effect of substituents XB is even stronger, possibly reflecting the pyranose deformation
caused by XA8). As expected, HcCis (for isomers with XD) resonates at lower field than
HDcis (for isomers with XC), and D(dHCgem À dHDtrans ) (for isomers with XA) is always
larger than D(dHDgem À dHtCrans ) (for isomers with XB). CN, NCO, and carbonyl
substituents in position B have a deshielding effect on HÀC(3), evidencing their spatial
proximity. Similarly, CN in position D has a deshielding effect on HÀC(5), while
carbonyl substituents in position D have a shielding effect (Dd ˆ 0.27 0.37 ppm
relative to the mean values). The chemical shift of the ethyl ester methylene group in 7a
is shifted upfield by 0.23 ppm, indicating a shielding effect of the adjacent C(2)ÀOBn
group. The 13C-NMR spectra of all gluco-cyclopropanes show an upfield shift of the
resonance for the C-atom bearing X in the anti-isomers (possessing XA or XB) relative
to the syn-isomers (possessing XC or XD) (cf. Table 4 in Exper. Part). This may be a
consequence of the different electronic structures resulting from the trans- or cis-
arrangement of donor (OÀC(5)) and acceptor (X) substituents.
Relatively weak NOEs were found between H in position A and HÀC(2), H in
position B and HÀC(3), and H in position D and HÀC(5) for 1a, 7a, 7c, 7d, and 8b, in
agreement with the assigned configurations. There was also a weak NOE between H in
position B and HÀC(5) of 7d9).
Configuration of the manno-Isomers. The observed small J(3,4) (1.6 Hz) and
medium J(4,5) (7.0 Hz) values of the lactone 21 in CDCl3 solution evidence its B2,5
conformation, and are similar to J(3,4) and J(4,5) values of 2,3,4,6-tetra-O-benzyl-d-
mannono-1,5-lactone [69] and of d-mannono-1,5-lactone [70]. The dominant con-
4
formation of the exo-glycal 22 (4C1) and the bis-enolether 23 (flattened C1) was
deduced from a small J(2,3), and large and similar J(3,4) and J(4,5) values (J(3,4) ꢀ
J(4,5) ˆ 9.0 and 7.6 Hz for 22 and 23, resp.). The pyranose ring of all manno-configured
4
cyclopropanes adopts a C1 conformation (cf. Tables 8, 10, and 11 in Exper. Part). On
the basis of the considerations above, the manno-configured esters 15a and 15b
(d(HÀC(2)) ˆ 4.13 and 4.17 ppm, resp.) possess an anti-configuration, and the esters
15c and 15d (d(HÀC(2)) ˆ 3.13 and 3.11 ppm, resp.) a syn-configuration. The same
assignment results from the analysis of the d(HÀC(2)) values of the acids, carbamates,
and amines derived from the esters 15a 15d, and also for the esters 24a 24d (Tables 8,
10, and 11 in Exper. Part). The position of X in the anti-isomers 15a and 15b was
deduced from D(dHgCem À dHtDrans ) ˆ 0.99 ppm (15a) and D(dHDgem À dHtCrans ) ˆ 0.17 ppm
(15b). Analogous Dd values were found for all products derived from 15a and 15b,
respectively, and for 24a and 24b. The structure of the syn-isomers 15c and 15d was
8
)
In keeping with this hypothesis, the weaker deformation of the pyranose ring in the nitrile 30a and in the
Boc-carbamate 13a correlates with an almost equal influence on d(HÀC(2)) of the CN and NHBoc groups
in position A or B.
Unexpected intensity enhancements were observed for the signals of HÀC(2) and HÀC(4) of 8a upon
irradiation of Hgem in position C, and for the signal of HÀC(2) upon irradiation of Hcis in position B. They
correlate with the deformation of the pyranose ring.
9
)

3008
Helvetica Chimica Acta Vol. 86 (2003)
further evidenced by d(HDcis ) ˆ 1.44 ppm (15c) and by d(HcCis ) ˆ 1.93 ppm (15d). Similar
chemical-shift differences for Hcis were observed for the O-benzylated products derived
from either 15c or 15d, and for 24c and 24d. The spectra of the manno-esters and
manno-acids show shielding of HÀC(3) by CˆO substituents in position C (15c and
16c), and similarly of HÀC(5) by CˆO substituents in position D (15d and 16d). These
effects evidence the spatial proximity of these groups. The 13C chemical shifts for C(2')
in the manno-configured derivatives (cf. Table 9 in Exper. Part) do not differ as clearly
as is observed in the gluco-analogues. The C(2') signals of 15c, 16c, and 17c are
significantly shifted downfield relative to the corresponding signals in the gluco-
cyclopropanes.
The proposed configuration for the manno-cyclopropanes is further evidenced by
(relatively weak) NOEs between HA and HÀC(2) in 15d and 24b, between HB and
HÀC(2) in 15d and 24a, and between HD and HÀC(5) in 24a and 24b.
Configuration of the galacto-Isomers. Similar to what was found in the gluco-series,
all isomers of the debenzylated galacto-cyclopropanes 29a 29d and 3a 3d, but only
three isomers each of the O-benzylated esters (26b 26d) and O-benzylated Boc-
carbamates (28b 28d) adopt a 4C1 conformation (cf. Tables 12 and 14 in Exper. Part).
The isomers 26a and 28a adopt a flattened chair conformation, evidencing interaction
between XA and C(2)ÀOBn. Surprisingly, d(HÀC(2)) of 26a and 28a is not shifted
downfield as expected from the observations in the gluco-series. d(HÀC(2)) appears to
be influenced by the axial C(4)ÀOBn group. In agreement with this hypothesis,
HÀC(2) of the debenzylated carbamates 29a (d 4.20) and 29b (d 4.28) is deshielded
relative to HÀC(2) of 29c (d 4.09) and 29d (d 4.04), allowing to deduce that the
NHBoc group is anti to OÀC(5) in 29a and 29b, and syn to OÀC(5) in 29c and 29d. The
orientation as above or below the reference plane defined above was deduced on the
basis of D(dHCgem À dHtDrans ) ꢀ 1.72 1.83 ppm (29a) and D(dHDgem À dHtCrans ) ˆ 1.51 ppm
(29b) for the anti-isomers 29a and 29b, and of HDcis ˆ 0.65 ppm (29c) and HCcis ˆ 0.79 ppm
(29d) for the syn-isomers 29c and 29d. A similar analysis of the ammonium chlorides
3a 3d derived from the NBoc-carbamates leads to the same configurational assign-
ment. Similar to 7b and 7d, d(HÀC(3)) is shifted downfield by the proximal CˆO
substituent in 26b, while d(HÀC(5)) is shifted upfield by the CˆO substituent in 26d.
Similarly as in 7a, the ethyl ester CH2 group of 26a is shielded relative to 26b 26d,
indicating its proximity to the C(2)ÀOBn group. The 13C-NMR spectra of all galacto-
cyclopropanes (cf. Table 13 in Exper. Part) show an upfield shift for C(2') in the anti-
isomers (with XA or XB) relative to the syn-isomers (with XC or XD), as apparent in the
gluco-compounds.
Inhibition Studies. The gluco-, manno-, and galacto-cyclopropylammonium chlor-
ides 1a 1d, 2a 2d, and 3a 3d were tested against the b-glucosidases from
Caldocellum saccharolyticum and from sweet almonds, the a-glucosidase from brewer×s
yeast, the a-mannosidases from jack beans and from almonds, the b-mannosidase from
snails, the a-galactosidases from Aspergillus niger and from coffee beans, and the b-
galactosidases from bovine liver and from E. coli. The ammonium salts 1a 1d and 3a
3d proved to be millimolar inhibitors of these enzymes (Tables 1 and 2)10), while 2a
2d showed no inhibition even at a concentration of 1.5 mm. Although differences
10
)
For a discussion of the discrepancy with data reported earlier [71], see below.

Helvetica Chimica Acta Vol. 86 (2003)
3009
between the isomers were apparent, they were not significant in view of the weak
binding. Unambiguous determination of the inhibition type was problematic. This
unsatisfactory result may be attributed to the fact that the ammonium group in 1a 1d,
2a 2d, and 3a 3d is not at the position corresponding to the glycosidic O-atom in the
natural substrate, but shifted by one CÀC bond. Although small changes in the binding
geometry resulting from this shift were apparent in our modelling studies, the resulting
loss of binding energy seemed to be compensated by the interaction between the
ammonium group and the carboxylate corresponding to the catalytic nucleophile. That
this was not observed may mean that a conformation closer to the transition state (e.g.,
one deformed towards a half-chair or a 1,4B; cf. [72]) is essential for strong binding.
Table 1. Inhibition of a-Glucosidase from Yeast and b-Glucosidases from Almonds and Caldocellum
saccharolyticum at pH 6.8 by the gluco-Cyclopropylamines 1a 1d, PdCl24À, and 1 : 1 Mixtures of 1a 1d and
PdC24À : Ki and IC50 values [mm]
a-Glucosidase
b-Glucosidase
b-Glucosidase
(Brewer×s yeast)
(Sweet almonds)
(C. saccharolyticum)
PdCl24À
1a
19a)
6800b)
0.43a)
12000c)
0.46a)
1800d)
1.5a)
400e)
10000e)
45d)
40d)
12000b)
d
1a/PdCl24À
1b
1
)
.5
d
59000e)
52d)
25000
3.0d)
11000b)
2.0d)
8000c)
0.5d)
)
1b/PdCl24À
1c
17000e)
38d)
1c/PdCl24À
1d
7600d)
0.20a)
71000e)
52d)
1d/PdCl24À
a) Non-competitive, irreversible. b) Mixed, reversible. c) Competitive, reversible. d) Non-competitive, rever-
sible. e) IC50
.
Table 2. Inhibition of a-Galactosidase from Aspergillus niger at pH 4.0, a-Galactosidase from Coffee Beans at
pH 6.0, b-Galactosidase from Bovine Liver at pH 7.0, and b-Galactosidase from Escherichia coli and b-
glucosidase from Caldocellum saccharolyticum at pH 6.8 by the galacto-Cyclopropylamines 3a 3d, PdCl24À, and
1 : 1 Mixtures of 3a 3d and PdCl24À : Ki and IC50 values [mm]
a-Galactosidase a-Galactosidase b-Galactosidase b-Galactosidase b-Glucosidase
(A. niger)
(Coffee beans)
(Bovine liver)
(E. coli)
(C. saccharolyticum)
b
PdCl24À
3a
5.8a)
11000c)
8.1a)
4.8d)
36b)
22000c)
.7 45b)
17000c)
48b)
1
)
.2
.1
40b)
n.d.
1900c)
43000c)
c
b
3a/PdCl24À
3b
1
)
1
)
2.0b)
n.d.
5100c)
8.2a)
11000c)
5500c)
3b/PdCl24À
3c
0.3c)
0.9b)
0.6b)
n.d.
13000c)
7.3a)
5600c)
3.0c)
15000c)
0.7c)
18000c)
41b)
29000
2.0b)
)
c
3c/PdCl24À
3d
2.3b)
n.d.
8600c)
17a)
64000c)
35b)
5300c)
0.9b)
3d/PdCl24À
0.8b)
a) Competitive, reversible. b) Non-competitive, reversible. c) IC50 d) Uncompetitive, irreversible.
.
Our initial observations with samples of 1a 1d obtained by hydrogenolysis of the
corresponding benzyl carbamates 11a 11d differed considerably from this result.

3010
Helvetica Chimica Acta Vol. 86 (2003)
Unlike the samples prepared by acidic deprotection of the tert-butyl carbamates 13a
13d, those resulting from hydrogenolysis were micromolar inhibitors of the a-
glucosidase from yeast and the b-glucosidase from C. saccharolyticum. Investigation of
these conflicting results led to the identification of traces of Pd compounds
contaminating the products of the hydrogenolytic debenzylation as a possible origin
of the strong inhibition. In contact with air and acid, Pd0 on the heterogeneous catalyst
was readily oxidised in the reaction mixtures to soluble PdII compounds11).
The debenzylation of 11a was examined by drawing aliquots from the reaction
mixture, and measuring their effect on the activity of the C. saccharolyticum b-
glucosidase as a function of time and reaction conditions. Remarkably, a mixture of
11a, 10% Pd on charcoal, MeOH, and aqueous HCl already inhibited the enzyme more
strongly than samples prepared by cleaving the Boc-protected analogues. Upon
exposure to H2 (1bar), this inhibition decreased rapidly and remained low until the end
of the reaction (8 h), when H2 was displaced by air. Within minutes after the first
contact with air, the reaction mixture inhibited the b-glucosidase strongly. This effect
was reversed by replacing air with H2. Obviously then, filtration through the acidic ion
exchanger that was initially used to purify 1a 1d did not remove the PdII
contamination. All samples of 1a 1d, 2a 2d, and 3a 3d were thus purified by flash
chromatography prior to enzyme testing.
To learn more about the inhibition by PdII, solutions of PdCl42À, prepared from
PdCl2 and aqueous HCl, were tested against the b-glucosidases from C. saccharolyticum
and sweet almonds, the a-glucosidase from brewer×s yeast, the a-galactosidases from A.
niger and from coffee beans, and the b-galactosidases from bovine liver and from E. coli
(Tables 1 and 2). The yeast a-glucosidase and the coffee-bean a-galactosidase were
irreversibly inhibited. The other enzymes were inhibited reversibly, with Ki values in
the micromolar range. The a-galactosidase from A. niger was the only enzyme to be
inhibited competitively, while the b-glucosidases from C. saccharolyticum and sweet
almonds, and the b-galactosidases from bovine liver and from E. coli were inhibited
non-competitively. Addition of 1a 1d or 3a 3d to these PdII solutions strongly
enhanced the inhibition of some of these glycosidases (Tables 1 and 2). The addition of
1equiv. of 1d, for example, lowered Ki for the inhibition of the b-glucosidase from C.
saccharolyticum by PdCl24À from 40 to 0.5 mm. It is significant that different isomers
enhanced the inhibition by PdII to a different extent, and that even the galacto-
configured 3a 3d had a strong effect on the inhibition of the b-glucosidase from C.
saccharolyticum by PdCl24À. Ethanolamine, tris(hydroxymethyl)aminomethane (Tris),
glucosamine, or galactosamine had no effect. Cyclopropylamine, however, enhanced
the inhibition of the b-glucosidase from C. saccharolyticum by PdCl24À significantly. This
effect is under scrutiny; it evidences that the effect of added amines on the inhibition by
Pd2‡ is not simply due to solubilisation.
We thank Dr. B. Bernet for checking and commenting the Exper. Part, B. Brandenberg for NOE
experiments, Dr. B. Schweizer for the crystal-structure determination, and the Swiss National Science
Foundation, F. Hoffmann-La Roche AG, Basel, and Oxford Glycosciences Ltd., Abingdon (UK), for generous
financial support.
11
)
Evidenced on TLC by the typical greenish-brown colour developing upon spraying with SnCl2 and heating
[73].

Helvetica Chimica Acta Vol. 86 (2003)
3011
Experimental Part
General. Solvents were distilled before use. TLC: Merck silica gel 60F-254 plates; detection by heating with
mostain (400 ml of 10% H2SO4 soln., 20 g of (NH4)6Mo7O24 ¥ 6 H2O, 0.4 g of Ce(SO4)2); detection of Pd2‡ by
spraying with a soln. of 8 g of SnCl2 in 80 ml of 37% HCl, and heating. Flash chromatography (FC): silica gel
Fluka 60 (0.04 0.063 mm). Anal. HPLC: Spherisorb, 5 mm (4 Â 250 mm), Prep. HPLC: Kromasil 100 ä, 5 mm,
with a self-packed silica-gel column (20 Â 250 mm). MPLC: self-packed column with 2 kg of silica gel Fluka 60.
Molecular sieves 4 ä (Fluka): powder, activated by drying at 0.05 mbar for 12 h at 2508. M.p. uncorrected.
Optical rotations: 1-dm cell. IR Spectra: KBr, or 2% CHCl3 soln. 1H- and 13C-NMR spectra: at 300 and 75 MHz,
resp., if not indicated otherwise; chemical shifts d in ppm, coupling constants J in Hz. a-Glucosidase from
brewer×s yeast (maltase, 3.2.1.20, Type VI, G-4634, as lyophilised powder), b-glucosidases from sweet almonds
(3.2.1.21, as lyophilised powder), b-glucosidase from C. saccharolyticum (3.2.1.21, as lyophilised powder), a-
mannosidase from jack beans (EC 3.2.1.24, as suspension in 3.0m (NH4)2SO4 and 0.1m m zinc acetate, pH 7.5), a-
mannosidase from almonds (EC 3.2.1.24, as soln. in 10 mm potassium phosphate buffer and 0.1% NaN3,
pH 6.0), b-mannosidase from snails (EC 3.2.1.25, as suspension in 3.0m (NH4)2SO4 and 10 mm NaOAc, pH
around 4.0), a-galactosidase from A. niger (EC 3.2.1.22, as suspension in 3.5m (NH4)2SO4 and 50 mm NaOAc,
pH 5.5), a-galactosidase from green coffee beans (EC 3.2.1.22, as suspension in 3.2m (NH4)2SO4 containing
BSA, pH 6.0), b-galactosidase from bovine liver (3.2.1.23, as lyophilised powder), b-galactosidase from E. coli
(3.2.1.23, as lyophilised powder), and all nitrophenyl glycopyranosides were purchased from Sigma and used
without any further purification.
Preparation of 7a 7d. a) By Cyclopropanation of 5. A soln. of ethyl acrylate (5 ml, 46.0 mmol) in dry 1,4-
dioxane (5 ml) was treated with 0.5 g of activated, powdered 4-ä molecular sieves, stirred for 30 min at 238,
treated with 4.7 ml of a 0.15m soln. of 5 (0.71mmol) in CH 2Cl2, and stirred for an additional 8 h. The mixture
was diluted with CH2Cl2 (5 ml), filtered through Celite, and the residue was washed with CH2Cl2. Evaporation of
the combined filtrate and washings gave crude 7a 7d (0.45 g) as a colourless oil. MPLC (hexane/Et2O/CH2Cl2
8 :1:1) gave 7d (211.5 mg, 48%) and a mixture of 7a 7c. Prep. HPLC (hexane/Et2O 4 :1) of this mixture
afforded 7a (47.6 mg, 11%), 7b (39.3 mg, 9%), and 7c (13.7 mg, 3%).
b) By Rh2(OAc)4-Catalysed Cyclopropanation of 6. Under exclusion of air, a soln. of 6 (0.30 g, 0.56 mmol)
[58] and Rh2(OAc)4 (2.7 mg, 5.6 mmol) in dry Et2O (2 ml) at 238 was treated with a soln. of ethyl diazoacetate
(1.6 g, 14 mmol) in dry Et2O (1 5 ml)via syringe pump (1equiv./h). Filtration over Al 2O3 and evaporation gave
crude 7a 7d (540 mg). FC (hexane/Et2O 5 :1 ! 1:1) yielded a 26 :30 :20 :23 mixture 7a 7d (241mg, 69%),
which was separated as described above.
c) By Cu-Catalysed Cyclopropanation of 6. A suspension of Cu powder (0.25 g, 3.9 mmol) in a soln. of 6
(3.44 g, 6.41 mmol) in toluene (15 ml) in a 100-ml long-necked flask was heated to 1008 and treated dropwise
with a soln. of ethyl diazoacetate (1.83 g, 16.0 mmol) in dry toluene (15 ml) via syringe pump (1equiv./h), in
such a way that the injection needle resided only in the cooler upper part of the flask (ca. r.t.). After completed
addition, the soln. was stirred for an additional 30 min at 1008. Evaporation and crystallisation from MeOH
yielded pure 7c (1.10 g, 28%). FC (hexane/Et2O 5 :1 ! 1:1) of the mother liquor gave a mixture of 7a 7d
(2.83 g, 70%), which was separated as described above.
Ethyl (1S,2'S)-2,3,4,6-Tetra-O-benzylspiro[1,5-anhydro-d-glucitol-1,1'-cyclopropane]-2'-carboxylate (7a).
Colourless oil. Rf (hexane/Et2O 3 :2) 0.34. Anal. HPLC: tR (hexane/Et2O 7 :1, 2 ml/min) 6.7 min. Prep. HPLC:
tR (hexane/Et2O 4 :1, 10 ml/min) 20 min. [a]D25 ˆ ‡23.3 (c ˆ 1.00, CHCl3). IR (CHCl3): 3090w, 3068m, 2906m,
2870m, 1714s, 1603w, 1497m, 1454m, 1379w, 1358w, 1326w, 1262m, 1093s, 1028m, 871w. 1H-NMR (500 MHz,
CDCl3; assignment based on a DQFC.GRASP spectrum): see Table 3; additionally, 7.36 7.16 (m, 20 arom. H);
4.80 (d, J ˆ 11.7, PhCH); 4.78 (d, J ˆ 11.1, PhCH); 4.63 (d, J ˆ 11.2, PhCH); 4.61( d, J ˆ 12.1, PhCH); 4.59
(d, J ˆ 11.8, PhCH); 4.59 (d, J ˆ 11.8, PhCH); 4.56 (d, J ˆ 11.1, PhCH); 4.52 (d, J ˆ 12.2, PhCH); 3.96 (irrad. at
1.48! NOE of 1.7%, irrad. at 2.10! NOE of 0.7%); 3.88 (irrad. at 2.10 ! NOE of 1.3%); 3.79 (qd, J ˆ 7.1, 10.7,
MeCHO); 3.79 (irrad. at 1.48! NOE of 0.8%); 3.75 (irrad. at 1.19! NOE of 1.0%); 3.74 (qd, J ˆ 7.1, 10.7,
MeCHO); 2.10 (irrad. at 3.96 ! NOE of 1.0%, irrad. at 3.88! NOE of 1.5%); 1.48 (irrad. at 3.96! NOE of
2.0%); 1.06 (t, J ˆ 7.1, MeCH2O). 13C-NMR (75 MHz, CDCl3): see Table 4; additionally, 170.04 (s, CˆO);
138.50 (s); 137.82 (s, 2 C); 137.69 (s); 128.52 127.22 (several d); 74.43, 73.86, 73.51, 72.81 (4t, 4 PhCH2); 60.78
(t, MeCH2O); 14.11 (q, MeCH2O). Anal. calc. for C39H42O7 (622.76): C 75.22, H 6.80; found: C 75.08, H 6.84.
Ethyl (1R,2'R)-2,3,4,6-Tetra-O-benzylspiro[1,5-anhydro-d-glucitol-1,1'-cyclopropane]-2'-carboxylate (7b).
Colourless oil. Rf (hexane/Et2O 3 :2) 0.28. Anal. HPLC: tR (hexane/Et2O 7:1, 2 ml/min) 6.0 min. Prep. HPLC: tR
(hexane/Et2O 4 :1, 10 ml/min) 26 min. [a]2D5 ˆ ‡14.0 (c ˆ 1.55, CHCl3). IR (CHCl3): 3090w, 3067w, 2871m,
1
1726s, 1586w, 1497m, 1454m, 1375m, 1360m, 1322m, 1159w, 1093s, 1028w, 91 1w. H-NMR (500 MHz, CDCl3,

3012
Helvetica Chimica Acta Vol. 86 (2003)
Table 3. Selected 1H-NMR Chemical Shifts [ppm] and Coupling Constants [Hz] of the gluco-Cyclopropanes 7a
7d and 8a 8d in CDCl3
Compound
7aa)
7ba)
7c
2.01
1.37
1.26
3.92
3.69
3.85
7d
2.11
1.73
1.26
3.913.95
3.74
3.87
8a
2.04
1.43
1.19
8b
1.83
1.49
1.41
8c
2.07
1.39
1.43
3.93
3.73
3.82
8d
2.12
1.73
1.34
HÀC(2')
HcisÀC(3')
HtransÀC(3')
HÀC(2)
HÀC(3)
HÀC(4)
HÀC(5)
HaÀC(6)
HbÀC(6)
2.10
1.48
1.19
3.96
3.79
3.88
3.75
3.75
1.80
1.49
1.29
3.99
4.05
3.98
3.99
3.77
3.85
3.66
3.72
7.8
10.0
5.9
5.9
3.95
3.80
3.613.30
3.68
3.74
3.89
3.81 3.74
3.72 3.68
3.72 3.68
73.513.1 3.72
3.73
3.72
3.59
6.9
9.1
5.8
9.2
9.17.8
9.7
3.14.4
1.9
3.73
3.73
3.613.63 3.60
3.66
3.60
3.59
3.67
3.61
J(2',3'cis
)
7.7
10.0
5.9
5.8
7.7
7.7
10.1
6.3
6.2
9.0
5.4
9.0
9.0
9.7
3.5
1.9
7.8
10.3
6.5
7.2
9.0
5.6
8.7
9.1
9.3
3.3
4.4
10.9
6.6
9.1
5.8
9.1
J(2',3'trans
)
J(3'cis,3'trans
J(2,3)
)
8.8
9.3
8.7
J(3,4)
J(4,5)
J(5,6a)
J(5,6b)
J(6a,6b)
8.4
9.0
2.2
b
9.0
)
)
)
7.8
3.4
4.4
9.3
9.1
b
4.4
b
b
b
)
)
2.1
10.8
b
1
1)
.9 11.1
10.8
12.5
11.8
a) Assignment based on DQFC ¥ COSY spectrum. b) Not assigned.
assignment based on a DQFC.GRASP spectrum): see Table 3; additionally, 7.34 7.16 (m, 20 arom. H); 4.83
(d, J ˆ 10.9, PhCH); 4.78 (s, PhCH2); 4.66 (d, J ˆ 11.8, PhCH); 4.63 (d, J ˆ 11.2, PhCH); 4.59 (d, J ˆ 12.1,
PhCH); 4.53 (d, J ˆ 10.9, PhCH); 4.48 (d, J ˆ 12.1, PhCH); 4.09 (qd, J ˆ 7.1, 10.8, MeCHO); 3.87 (qd, J ˆ 7.1,
10.8, MeCHO); 1.12 (t, J ˆ 7.1, MeCH2O). 13C-NMR (75 MHz, CDCl3): see Table 4; additionally, 169.37
(s, CˆO); 138.67, 138.42, 138.13, 137.98 (4s); 128.52 126.91 (several d); 75.32 (t, 2 PhCH2); 74.87, 73.54
(2t, 2 PhCH2); 60.68 (t, MeCH2O); 14.15 (q, MeCH2O). Anal. calc. for C39H42O7 (622.76): C 75.22, H 6.80, O
17.98; found: C 75.35, H 6.91.
Ethyl (1S,2'R)-2,3,4,6-Tetra-O-benzylspiro[1,5-anhydro-d-glucitol-1,1'-cyclopropane]-2'-carboxylate (7c).
Colourless solid. Rf (hexane/Et2O 3 :2) 0.30. M.p. 898 (MeOH). Anal. HPLC: tR (hexane/Et2O 7 :1, 2 ml/min)
5.5 min. Prep. HPLC: tR (hexane/Et2O 4 :1, 10 ml/min) 25 min. [a]2D5 ˆ À6.1( c ˆ 0.68, CHCl3). IR (CHCl3):
3090w, 3067w, 2926m, 2855m, 1729s, 1497w, 1454m, 1380m, 1360m, 1280m, 1154m, 1092s, 1028s, 91 7w, 81 8w.
1H-NMR (500 MHz, CDCl3): see Table 3; additionally, 7.35 7.23 (m, 18 arom. H); 7.19 7.17 (m, 2 arom. H);
4.88 (d, J ˆ 11.3, 2 PhCH); 4.85 (d, J ˆ 11.2, 2 PhCH); 4.66 (d, J ˆ 11.3, PhCH); 4.60 (d, J ˆ 12.2, PhCH); 4.59
(d, J ˆ 10.7, PhCH); 4.49 (d, J ˆ 12.2, PhCH); 4.18 (qd, J ˆ 7.1, 10.8, MeCHO); 4.10 (qd, J ˆ 7.1, 10.8, MeCHO);
2.01(irrad. at 3.92 ! NOE of 2.3%); 1.37 (irrad. at 3.51! NOE of 4.6%); 1.26 (irrad. at 3.69! NOE of 3.1%);
1.24 (t, J ˆ 7.1, MeCH2O). 13C-NMR (50 MHz, CDCl3): see Table 4; additionally, 169.50 (s, CˆO); 138.71,
138.43, 138.36, 138.08 (4s); 128.65 127.73 (several d); 75.77, 75.39, 75.17, 73.58 (4t, 4 PhCH2); 60.79
(t, MeCH2O); 12.82 (q, MeCH2O). Anal. calc. for C39H42O7 (622.76): C 75.22, H 6.80, O 17.98; found: C
75.25, H 6.92, O 18.02.
X-Ray Analysis of 7c. Monoclinic P21; a ˆ 12.654(7), b ˆ 9.329(1), c ˆ 15.295(5), b ˆ 107.62(2); Vˆ
1720.8(7) ä3, Dcalc ˆ 1.202 Mg/m3, Z ˆ 2. The reflections were measured on an Enraf-Nonius-CAD4
diffractometer (graphite monochromator, CuKa radiation, l ˆ 1.54184) at 293(2) K. R ˆ 0.0432, Rw ˆ 0.1047.
The structure was solved with the direct-methods routine SIR97 [74]. The non-H-atoms were refined
anisotropically with SHELXL-97 [75]. H-Atoms were calculated at idealised positions and included in the
structure-factor calculation with fixed isotropic displacement parameters.
Ethyl (1R,2'S)-2,3,4,6-Tetra-O-benzylspiro[1,5-anhydro-d-glucitol-1,1'-cyclopropane]-2'-carboxylate (7d).
Colourless oil. Rf (hexane/Et2O 3 :2) 0.31. Anal. HPLC: tR (hexane/Et2O 7:1, 2 ml/min) 7.2 min. Prep. MPLC: tR
(hexane/Et2O/CH2Cl2 8 :1:1, 10 ml/min) 5.8 h. Prep. HPLC: tR (hexane/Et2O 4 :1, 10 ml/min) 20 min. [a]D25
ˆ

Helvetica Chimica Acta Vol. 86 (2003)
3013
Table 4. Selected 13C-NMR Chemical Shifts [ppm] of the gluco-Spirocyclopropanes 7 12 in CDCl3, and of 13a
13d and 1a 1d in D2O
C(2')
C(3')
C(1)
63.57
C(2)
75.51
C(3)
85.12
C(4)
76.33
C(5)
77.16
C(6)
68.90
7a
7b
7ca)
7d
8a
8b
8c
8d
9a
9b
9c
26.55
4.25.611
23.33
21.03
26.29
26.01
22.92
20.62
28.82
28.12
25.44
7.2738.611
31.16
30.17
34.87
34.36
30.00
29.55
34.57
34.03
29.73
29.23
35.63
33.68
28.95
31.00
34.14
34.57
3.3406.311
29.55
14.11
64.9177.89
14.32
15.93
14.48
15.51
14.12
17.03
16.06
15.58
14.23
69.62
15.67
17.65
13.61
15.75
14.65
14.51
13.38
15.63
14.47
14.41
15.08
13.27
12.38
14.59
13.92
15.75
63.28
14.37
84.59
78.33
78.62
68.68
65.39
66.92
64.28
65.88
65.71
67.94
65.16
68.66
67.16
77.99
77.92
75.36
78.16
77.63
77.82
74.84
78.15
77.34
86.94
86.59
84.76
84.49
86.77
86.54
84.24
84.15
86.75
78.47
78.00
76.49
78.20
78.45
77.82
75.98
78.15
77.94
78.88
78.60
77.17
78.47
78.92
78.67
76.68
78.40
78.63
68.37
68.22
68.79
68.54
68.39
68.20
68.68
67.10
67.76
9d
10c
77.35
86.35
77.35
78.97
67.66
61.41
61.55
61.71
61.37
60.77
60.72
61.88
61.50
60.78
60.75
65.44
62.43
61.83
64.29
62.73
63.02
76.90
77.86
76.48
78.04
77.35
77.90
76.51
77.87
77.51
77.80
71.72
70.12
69.07
72.33
71.23
72.93
86.55
86.74
87.69
86.06
86.36
86.67
87.77
86.09
86.39
86.62
80.60
76.34
76.78
79.47
80.30
79.88
78.33
78.09
76.74
78.94
78.30
78.16
76.85
78.99
78.43
78.40
72.80
71.23
70.56
72.77
72.47
72.93
78.93
78.77
78.50
79.14
78.37
78.28
78.58
79.23
78.43
78.40
80.70
79.45
79.64
81.85
81.21
82.64
68.48
68.56
68.68
68.49
68.49
68.80
68.76
68.50
68.55
68.94
63.71
61.01
61.16
63.57
63.43
63.62
10d
11a
11b
11c
11d
12a
12b
12c
12d
13a
13b
13c
13da)
1a
1b
1c
1d
70.89
63.88
79.28
71.40
72.99
78.86
82.75
72.08
63.82
82.71
63.43
a) Assignments based on HSQC-GRASP spectrum.
‡98.5 (c ˆ 0.68, CHCl3). IR (CHCl3): 3090w, 3067w, 2907m, 2870m, 1723s, 1497m, 1454s, 1397m, 1382m, 1360m,
1325w, 1289s, 1160s, 1126s, 1091s, 1028s, 1016m, 91 w1, 867w. 1H-NMR (500 MHz, CDCl3): see Table 3;
additionally, 7.35 7.12 (m, 20 arom. H); 4.90 (d, J ˆ 11.3, PhCH); 4.88 (d, J ˆ 11.2, PhCH); 4.85 (d, J ˆ 11.3,
PhCH); 4.83 (d, J ˆ 10.6, PhCH); 4.66 (d, J ˆ 12.1, PhCH); 4.58 (d, J ˆ 11.3, PhCH); 4.55 (d, J ˆ 10.6, PhCH);
4.46 (d, J ˆ 12.1, PhCH); 4.16 (qd, J ˆ 7.1, 10.8, MeCHO); 4.07 (qd, J ˆ 7.1, 10.8, MeCHO); 3.91(irrad. at 1.26 !
NOE of 0.8%); 3.74 (irrad. at 3.17 ! NOE of 3.5%, irrad. at 2.11 ! NOE of 1.8%); 3.17 (irrad. at 2.11 ! NOE
of 1.0%); 2.11 (irrad. at 3.17 ! NOE of 1.8%); 1.24 (t, J ˆ 7.1, MeCH2O). 13C-NMR (50 MHz, CDCl3): see
Table 4; additionally, 170.58 (s, CˆO); 138.75, 138.26, 138.16, 137.96 (4s); 128.59 27.77 (several d); 75.76, 75.44,
‡
75.27, 73.65 (4t, 4 PhCH2); 60.70 (t, MeCH2O); 14.23 (q, MeCH2O). CI-MS: 623 (1, [M ‡ 1] ), 285 (19), 263
(12), 181 (16), 108 (10), 92 (12), 91 (100). Anal. calc. for C39H42O7 (622.76): C 75.22, H 6.80, O 17.98; found: C
75.27, H 6.94.
(1S,2'S)-2,3,4,6-Tetra-O-benzylspiro[1,5-anhydro-d-glucitol-1,1'-cyclopropane]-2'-carboxylic Acid (8a). A
soln. of KOH (440 mg, 7.85 mmol) and 7a (646 mg, 1.04 mmol) in EtOH/H2O 1:4 (20 ml) was stirred at 80 8 in a
closed flask, until TLC indicated complete conversion of the ester (ca. 2 h). After concentration to 1/3 of the
volume in vacuo at 508, the residue was diluted with H2O (50 ml) and extracted once with Et2O (30 ml). The aq.
phase was acidified with 1n HCl to pH ca. 1and extracted with Et 2O (4 Â 30 ml). The combined org. phases were

3014
Helvetica Chimica Acta Vol. 86 (2003)
dried (Na2SO4) and evaporated to yield crude 8a (600 mg, 97%), which was sufficiently clean for the following
reaction. FC (hexane/Et2O 2 :1 ! 0 :1, then AcOEt/AcOH 99 :1) gave pure8a (586 mg, 95%). Colourless oil. Rf
(hexane/Et2O 1:20) 0.42. [ a]2D5 ˆ ‡23.4 (c ˆ 1.00, CHCl3). IR (CHCl3): 3516w, 3400 2400m (br.), 3089w,
3066w, 2924m, 2867m, 1728m, 1702s, 1497m, 1454s, 1361m, 1324w, 1092s, 1028m, 947w. 1H-NMR (300 MHz,
CDCl3): see Table 3; additionally, 7.35 7.13 (m, 20 arom. H); 4.78 (d, J ˆ 11.8, PhCH); 4.75 (d, J ˆ 10.9, PhCH);
4.65 (d, J ˆ 11.5, PhCH); 4.61( d, J ˆ 11.5, PhCH); 4.58 (d, J ˆ 12.1, PhCH); 4.56 (d, J ˆ 11.5, PhCH); 4.53
(d, J ˆ 11.2, PhCH); 4.50 (d, J ˆ 12.1, PhCH). 13C-NMR (75 MHz, CDCl3): see Table 4; additionally, 175.97
(s, CˆO); 138.41 (s); 138.33 (s, 2 C); 138.24 (s); 130.40 127.40 (several d); 74.44, 73.84, 73.55, 73.06
(4t, 4 PhCH2).
(1R,2'R)-2,3,4,6-Tetra-O-benzylspiro[1,5-anhydro-d-glucitol-1,1'-cyclopropane]-2'-carboxylic Acid (8b).
As described above, the reaction of KOH (220 mg, 3.92 mmol) and 7b (189 mg, 0.304 mmol) in EtOH/H2O
1:4 (10 ml) gave crude 8b (172 mg, 95%), which was sufficiently clean for the following reaction. FC (hexane/
Et2O 2 :1 ! 0 :1, then AcOEt/AcOH 99 :1) gave pure 8b (157 mg, 87%). Colourless oil. Rf (hexane/Et2O 1 :20)
0.56. [a]2D5 ˆ ‡18.2 (c ˆ 1.00, CHCl3). IR (CHCl3): 3520w, 3400 2400m (br.), 3089w, 3066w, 2926m, 2869m,
1729s, 1705s, 1497m, 1454s, 1400m, 1362m, 1320m, 1262w, 1126w, 1091s, 1028m, 947w, 91 1w, 864w. 1H-NMR
(300 MHz, CDCl3): see Table 3; additionally, 7.35 7.13 (m, 20 arom. H); 4.81( d, J ˆ 10.9, PhCH); 4.75
(s, PhCH2); 4.74 (d, J ˆ 11.2, PhCH); 4.67 (d, J ˆ 11.2, PhCH); 4.58 (d, J ˆ 12.1, PhCH); 4.51( d, J ˆ 10.9,
PhCH); 4.56 (d, J ˆ 12.1, PhCH); 4.05 (irrad. at 1.49! NOE of 1.1%); 3.66 (irrad. at 1.83! NOE of 3.7%);
1.49 (irrad. at 4.05! NOE of 1.4%). 13C-NMR (75 MHz, CDCl3): see Table 4; additionally, 174.03 (s, CˆO);
138.36, 138.24, 137.95, 137.21 (4s); 128.51 127.78 (several d); 75.59, 75.41, 74.88, 73.58 (4t, 4 PhCH2).
(1S,2'R)-2,3,4,6-Tetra-O-benzylspiro[1,5-anhydro-d-glucitol-1,1'-cyclopropane]-2'-carboxylic Acid (8c). As
described above, the reaction of KOH (220 mg, 3.92 mmol) and 7c (120 mg, 0.193 mmol) in EtOH/H2O 1 :4
(10 ml) gave crude 8c (117 mg, quant.), which was sufficiently clean for the following reaction. FC (hexane/Et2O
2 :1 ! 0 :1, then AcOEt/AcOH 99 :1) gave pure 8c (109 mg, 95%). Colourless oil. Rf (hexane/Et2O 1:20) 0.18.
[a]2D5 ˆ ‡3.6 (c ˆ 2.00, CHCl3). IR (CHCl3): 3522w, 3400 2400m (br.), 3090m, 3066m, 2911m, 2869m, 1740s,
1709m, 1497m, 1454s, 1360s, 1261m, 1126s, 1090s, 1028s, 1007m, 91 6m. 1H-NMR (300 MHz, CDCl3): see Table 3;
additionally, 9.60 7.80 (br. s, CO2H); 7.38 7.21( m, 20 arom. H); 4.91( s, PhCH2); 4.91( d, J ˆ 11.2, PhCH); 4.89
(d, J ˆ 11.8, PhCH); 4.67 (d, J ˆ 11.2, PhCH); 4.62 (d, J ˆ 12.1, PhCH); 4.62 (d, J ˆ 11.8, PhCH); 4.53 (d, J ˆ
12.1, PhCH). 13C-NMR (75 MHz, CDCl3): see Table 4; additionally, 174.27 (s, CˆO); 138.42, 138.05, 138.02,
137.68 (4s); 128.62 127.71 (several d); 75.80, 75.49, 75.23, 73.50 (4t, 4 PhCH2).
(1R,2'S)-2,3,4,6-Tetra-O-benzylspiro[1,5-anhydro-d-glucitol-1,1'-cyclopropane]-2'-carboxylic Acid (8d).
As described above, the reaction of KOH (220 mg, 3.92 mmol) and 7d (74.1 mg, 0.119 mmol) in EtOH/H2O
1:4 (10 ml) gave crude 8d (70.2 mg, 99%), which was sufficiently clean for the following reaction. FC (hexane/
Et2O 2 :1 ! 0 :1, then AcOEt/AcOH 99 :1) gave pure 8d (61.5 mg, 87%). Colourless oil. Rf (hexane/Et2O 1 :20)
0.30. [a]2D5 ˆ ‡114.4 (c ˆ 2.00, CHCl3). IR (CHCl3): 3519w, 3400 2400m (br.), 3090m, 3066m, 2908m, 2869m,
1728m (sh.), 1698s, 1497m, 1454s, 1400w, 1361m, 1290m, 1155m, 1127m, 1091s, 1028m, 954w, 91 1w, 867w.
1H-NMR (200 MHz, CDCl3): see Table 3; additionally, 7.36 7.20 (m, 18 arom. H); 7.15 7.10 (m, 2 arom. H);
4.89 (s, PhCH2); 4.86 (d, J ˆ 11.2, PhCH); 4.84 (d, J ˆ 10.4, PhCH); 4.66 (d, J ˆ 12.0, PhCH); 4.58 (d, J ˆ 11.2,
PhCH); 4.52 (d, J ˆ 10.8, PhCH); 4.43 (d, J ˆ 12.0, PhCH). 13C-NMR (75 MHz, CDCl3): see Table 4;
additionally, 176.87 (s, CˆO); 138.70, 138.25, 138.22, 137.91 (4s); 128.69 127.83 (several d); 75.83, 75.50,
75.30, 73.57 (4t, 4 PhCH2).
(1S,2'S)-2,3,4,6-Tetra-O-benzylspiro[1,5-anhydro-d-glucitol-1,1'-cyclopropane]-2'-carbonyl Azide (9a). A
soln. of 8a (12.9 mg, 21.7 mmol) in dry acetone (1ml) was cooled to 0 8, treated with Et3N (54 ml of a 0.5m soln. in
acetone, 27.1 mmol) and ClCO2Et (61 ml of a 0.5m soln. in acetone, 30.5 mmol), stirred for 1h at 0 8, treated with a
soln. of NaN3 (0.35 ml of a 0.1m soln. in H2O, 35 mmol), and stirred for another 30 min at 08 and for 2 h at 238.
After concentration to 1/3 of the volume in vacuo at 238, the residue was diluted with 5 ml of H2O and extracted
with Et2O (3 Â 2 ml). The combined org. phases were washed with H2O (1ml), dried (Na 2SO4), and evaporated
at 238. The residue was dried in high vacuum at 238 for 12 h to give crude 9a (13.4 mg, quant.). Colourless oil.
Rapid FC (hexane/Et2O 2 :1) yielded pure 9a (11.4 mg, 85%). Colourless oil. Rf (hexane/Et2O 1:1) 0.58, Rf
(hexane/AcOEt 1:1) 0.47. [ a]2D5 ˆ ‡49.8 (c ˆ 0.55, CHCl3). IR (CHCl3): 3089w, 3066m, 2909m, 2867m, 2139s,
1696s, 1497m, 1454s, 1363s, 1324m, 1172s, 1092s, 1028s, 1003m, 883w, 854m, 599w. 1H-NMR (300 MHz, CDCl3):
see Table 5; additionally, 7.36 7.17 (m, 20 arom. H); 4.79 (d, J ˆ 11.8, PhCH); 4.77 (d, J ˆ 11.2, PhCH); 4.60
(d, J ˆ 11.8, PhCH); 4.58 (s, PhCH2); 4.58 (d, J ˆ 12.1, PhCH); 4.57 (d, J ˆ 11.2, PhCH); 4.52 (d, J ˆ 12.1,
PhCH). 13C-NMR (50 MHz, CDCl3): see Table 4; additionally, 176.86 (s, CˆO); 138.33 (s, 2 C), 138.09, 138.02
(2s); 128.64 127.56 (several d); 74.24, 73.48, 73.41, 72.75 (4t, 4 PhCH2).

Helvetica Chimica Acta Vol. 86 (2003)
3015
Table 5. Selected 1H-NMR Chemical Shifts [ppm] and Coupling Constants [Hz] of the Acyl Azides 9a 9d and of
the Isocyanates 10a 10d in CDCl3
Compound
9a
2.07
1.56
1.33
9b
9c
2.05
1.53
1.41
9d
10a
3.21
1.32
1.04
10b
2.51
1.14
1.28
3.94
10c
2.67
0.70
1.32
3.90
10d
2.82
HÀC(2')
HcisÀC(3')
HtransÀC(3')
HÀC(2)
HÀC(3)
HÀC(4)
HÀC(5)
HaÀC(6)
HbÀC(6)
1.80
1.56
1.36
2.18
1.90
1.41
0.97
1.20
3.913.99 3.93
3.97
3.95
43..0919
4.06
3.79
3.90
3.84
3.74
3.59
7.5
3.99 3.93
3.73
3.90
3.55
3.77
3.72
6.5
3.74
3.78 3.713.913.74
3.95
3.53
3.68
3.80 3.74
3.71 3.64
3.71 3.64
3.63 3.57
7.8
3.913.78 3.713.79
3.90
3.60
3.84
3.74
4.7
3.20
3.38
3.66
3.55
5.9
3.59
3.83
3.76
5.0
3.76
3.65
6.5
3.65
3.55
5.9
J(2',3'cis
)
J(2',3'trans
)
9.7
9.7
8.7
8.7
9.3
9.3
8.4
8.1
J(3'cis,3'trans
J(2,3)
J(3,4)
)
6.2
5.0
6.8
9.0
4.4
2.5
10.6
6.5
5.3
9.0
9.0
9.7
3.1
1
11.2
5.9
9.0
9.3
9.6
6.5
7.2
9.3
8.7
6.3
8.7
9.0
9.7
3.4
1.9
11.2
7.2
9.0
9.0
a
a
)
)
)
)
)
)
a
a
a
J(4,5)
9.19.7
3.7
1.9
9.7
a
J(5,6a)
J(5,6b)
J(6a,6b)
ꢁ 1.5
4.0
1.9
10.9
2.5
a
)
ꢁ 1.5 .9
ꢁ 1.5
a
)
10.9
10.9
10.9
a) Not assigned.
(1R,2'R)-2,3,4,6-Tetra-O-benzylspiro[1,5-anhydro-d-glucitol-1,1'-cyclopropane]-2'-carbonyl Azide (9b).
As described above, a soln. of 8b (22.4 mg, 37.7 mmol) in dry acetone (1ml) was treated with Et 3N (0.94 ml
of a 0.5m soln. in acetone, 47 mmol), ClCO2Et (0.106 ml of a 0.5m soln. in acetone, 53.1 mmol), and NaN3 (0.60 ml
of a 0.1m soln. in H2O, 60 mmol). Usual workup gave crude 9b (23.5 mg, quant). Rapid FC (hexane/Et2O 2 :1 )
yielded pure 9b (11.2 mg, 48%). Colourless oil. Rf (hexane/Et2O 1:1) 0.53, Rf (hexane/AcOEt 1:1) 0.44. [ a]D25
ˆ
‡31.8 (c ˆ 0.11, CHCl3). IR (CHCl3): 3089w, 3066w, 2912m, 2868m, 2138s, 1707m, 1497m, 1454s, 1362s, 1319m,
1168s, 1091s, 1028s, 861w. 1H-NMR (300 MHz, CDCl3): see Table 5; additionally, 7.32 7.25 (m, 18 arom. H);
7.18 7.15 ( m, 2 arom. H); 4.81( d, J ˆ 10.9, PhCH); 4.81( s, PhCH2); 4.70 (d, J ˆ 11.2, PhCH); 4.58 (d, J ˆ 10.9,
PhCH); 4.58 (d, J ˆ 12.5, PhCH); 4.52 (d, J ˆ 11.2, PhCH); 4.47 (d, J ˆ 12.5, PhCH). 13C-NMR (50 MHz,
CDCl3): see Table 4; additionally, 176.13 (s, CˆO); 138.58, 138.39, 138.14, 137.73 (4s); 128.62 127.95 (several
d); 75.36, 74.23, 74.85, 73.64 (4t, 4 PhCH2).
(1S,2'R)-2,3,4,6-Tetra-O-benzylspiro[1,5-anhydro-d-glucitol-1,1'-cyclopropane]-2'-carbonyl Azide (9c). As
described above, a soln. of 8c (94.4 mg, 0.159 mmol) in dry acetone (3 ml) was treated with Et3N (20.0 mg,
0.198 mmol), ClCO2Et (24.2 mg, 0.223 mmol), and NaN3 (2.54 ml of a 0.1m soln. in H2O, 0.254 mmol). Usual
workup gave crude 9c (98 mg, quant). Colourless oil. Rf (hexane/Et2O 1:1) 0.64, Rf (hexane/AcOEt 1:1) 0.55.
[a]2D5 ˆ À44.7 (c ˆ 2.00, CHCl3). IR (CHCl3): 3089w, 3066w, 2910m, 2869m, 2146m, 1712m, 1497m, 1454m,
1
1362m, 1262m, 1090s, 1028m, 1009m, 91 6m. H-NMR (300 MHz, CDCl3): see Table 5; additionally, 7.40 7.21
(m, 20 arom. H); 4.94 (d, J ˆ 10.9, PhCH); 4.92 (d, J ˆ 11.2, PhCH); 4.90 (d, J ˆ 10.6, PhCH); 4.90 (d, J ˆ 10.9,
PhCH); 4.67 (d, J ˆ 11.5, PhCH); 4.66 (d, J ˆ 12.1, PhCH); 4.64 (d, J ˆ 10.9, PhCH); 4.55 (d, J ˆ 12.1, PhCH).
13C-NMR (75 MHz, CDCl3): see Table 4; additionally, 175.70 (s, CˆO); 138.31, 138.01, 137.88, 137.62 (4s);
128.70 127.85 (several d); 75.82, 75.24, 75.19, 73.36 (4t, 4 PhCH2).
(1R,2'S)-2,3,4,6-Tetra-O-benzylspiro[1,5-anhydro-d-glucitol-1,1'-cyclopropane]-2'-carbonyl Azide (9d). As
described above, a soln. of 8d (57.5 mg, 96.7 mmol) in dry acetone (2 ml) was treated with Et3N (12.2 mg,
0.121 mmol), ClCO2Et (14.8 mg, 0.136 mmol), and NaN3 (1.55 ml of a 0.1m soln. in H2O, 0.155 mmol). Usual
workup gave crude 9d (57 mg, quant). Colourless oil. Rf (hexane/Et2O 1:1) 0.61, Rf (hexane/AcOEt 1:1) 0.53.
[a]2D5 ˆ ‡163.9 (c ˆ 2.00, CHCl3). IR (CHCl3): 3089w, 3067w, 2907w, 2869w, 2148m, 1808w, 1704m, 1497w,
1454m, 1381w, 1362m, 1327w, 1283m, 1162s, 1129s, 1093s, 1028m, 91 1w, 864w, 598w. 1H-NMR (300 MHz,
CDCl3): see Table 5; additionally, 7.40 7.15 (m, 20 arom. H); 4.95 (d, J ˆ 11.2, PhCH); 4.91( d, J ˆ 11.2, PhCH);
4.87 (br. d, J ˆ 10.9, 2 PhCH); 4.70 (d, J ˆ 12.1, PhCH); 4.60 (br. d, J ˆ 10.0, PhCH); 4.57 (br. d, J ˆ 10.6,

3016
Helvetica Chimica Acta Vol. 86 (2003)
PhCH); 4.50 (d, J ˆ 12.1, PhCH). 13C-NMR (75 MHz, CDCl3): see Table 4; additionally, 176.59 (s, CˆO);
138.41, 137.81, 137.76, 137.53 (4s); 128.68 127.94 (several d); 75.83, 75.43, 75.36, 73.55 (4t, 4 PhCH2).
(1S,2'S)-2,3,4,6-Tetra-O-benzylspiro[1,5-anhydro-d-glucitol-1,1'-cyclopropane]-2'-yl Isocyanate (10a). A
soln. of 9a (11.4 mg, 18.4 mmol) in dry toluene (1ml) was kept at 100 8 until TLC showed complete consumption
of 9a (ca. 2 h). Evaporation gave 10a (11.0 mg, quant.). Colourless oil. Rf (hexane/AcOEt 1:1) 0.75. [ a]D25
ˆ
‡27.4 (c ˆ 0.50, CHCl3). IR (CHCl3): 3089w, 3066w, 2925s, 2865m, 2268s, 1497m, 1454s, 1359m, 1258w, 1152m,
1122s, 1092s, 1028s, 1007m, 948w, 602w. 1H-NMR (300 MHz, CDCl3): see Table 5; additionally, 7.35 7.11
(m, 20 arom. H); 4.87 (s, PhCH2); 4.86 (d, J ˆ 10.3, PhCH); 4.83 (d, J ˆ 10.9, PhCH); 4.73 (d, J ˆ 10.6, PhCH);
4.59 (d, J ˆ 12.1, PhCH); 4.53 (d, J ˆ 10.9, PhCH); 4.47 (d, J ˆ 12.1, PhCH); 4.01 3.99 (irrad. at 3.76 ! br. s);
3.78 3.71(irrad. at 4.00 ! changed m, irrad. at 3.38 ! changed m); 3.38 (irrad. at 3.76 ! br. s).
(1R,2'R)-2,3,4,6-Tetra-O-benzylspiro[1,5-anhydro-d-glucitol-1,1'-cyclopropane]-2'-yl Isocyanate (10b). As
described above, thermolysis of 9b (11.2 mg, 18.1 mmol) in dry toluene (1ml), and evaporation yielded 10b
(11.0 mg, quant.). Colourless oil. Rf (hexane/AcOEt 1:1) 0.72. [ a]2D5 ˆ À32.6 (c ˆ 0.50, CHCl3). IR (CHCl3):
3089w, 3066w, 2925s, 2865m, 2284s, 1497m, 1454m, 1361m, 1262w, 1152m, 1090s, 1028s, 1003m, 950w, 861w.
1H-NMR (300 MHz, CDCl3): see Table 5; additionally, 7.35 7.23 (m, 18 arom. H); 7.15 7.09 (m, 2 arom. H);
4.98 (d, J ˆ 11.2, PhCH); 4.90 (d, J ˆ 11.2, 2 PhCH); 4.88 (d, J ˆ 10.6, PhCH); 4.69 (d, J ˆ 11.5, PhCH); 4.58
(d, J ˆ 12.1, PhCH); 4.50 (d, J ˆ 10.6, PhCH); 4.44 (d, J ˆ 12.1, PhCH); 4.06 (irrad. at 3.91 ! m); 3.91(irrad. at
4.06 ! d, J ˆ 8.7, irrad. at 3.79 ! d, J ˆ 9.3); 3.79 (irrad. at 3.91 ! d, J ˆ 9.7); 3.53 (irrad. at 3.79 ! m).
(1S,2'R)-2,3,4,6-Tetra-O-benzylspiro[1,5-anhydro-d-glucitol-1,1'-cyclopropane]-2'-yl Isocyanate (10c). As
described above, thermolysis of 9c (101 mg, 0.163 mmol) in dry toluene (10 ml), and evaporation yielded 10c
(96.2 mg, quant.). Colourless oil. Rf (hexane/AcOEt 1:1) 0.71. [ a]2D5 ˆ À7.6 (c ˆ 2.00, CHCl3). IR (CHCl3):
3089w, 3066w, 2911m, 2869m, 2254s, 1497m, 1454m, 1360m, 1264m, 1151m, 1091s, 1028s, 91 4w. 1H-NMR
(300 MHz, CDCl3): see Table 5; additionally, 7.40 7.23 (m, 20 arom. H); 4.95 (d, J ˆ 10.9, PhCH); 4.93 (d, J ˆ
10.9, PhCH); 4.90 (d, J ˆ 10.6, PhCH); 4.88 (d, J ˆ 10.6, PhCH); 4.71( d, J ˆ 12.1, PhCH); 4.69 (d, J ˆ 10.6,
PhCH); 4.61( d, J ˆ 11.5, PhCH); 4.60 (d, J ˆ 12.5, PhCH). 13C-NMR (75 MHz, CDCl3): see Table 4;
additionally, 138.46 (s); 138.17 (s, 2 C); 137.76 (s); 128.61 127.64 (several d); 123.03 (s, NˆCˆO); 75.74,
75.24, 75.17, 73.82 (4t, 4 PhCH2).
(1R,2'S)-2,3,4,6-Tetra-O-benzylspiro[1,5-anhydro-d-glucitol-1,1'-cyclopropane]-2'-yl Isocyanate (10d). As
described above, thermolysis of 9d (57.0 mg, 96.0 mmol) in dry toluene (5 ml), and evaporation yielded 10d
(57.0 mg, quant.). Colourless oil. Rf (hexane/AcOEt 1:1) 0.69. [ a]2D5 ˆ ‡101.7 (c ˆ 2.00, CHCl3). IR (CHCl3):
1
3089w, 3067w, 2925s, 2868m, 2273s, 1496m, 1454m, 1360m, 1263m, 1154m, 1090s, 1028s, 91 0w, 862w. H-NMR
(300 MHz, CDCl3): see Table 5; additionally, 7.35 7.12 (m, 20 arom. H); 4.90 (d, J ˆ 11.2, PhCH); 4.84
(br. d, J ˆ 11.2, 2 PhCH); 4.81( d, J ˆ 10.6, PhCH); 4.71( d, J ˆ 12.1, PhCH); 4.56 (d, J ˆ 10.3, PhCH); 4.53
(d, J ˆ 11.2, PhCH); 4.47 (d, J ˆ 12.1, PhCH). 13C-NMR (75 MHz, C6D6): see Table 4; additionally, 139.32,
139.19, 138.80, 138.36 (4s); 128.58 127.82 (several d); 122.91 (s, NˆCˆO); 75.55, 75.26, 75.06, 73.72
(4t, 4 PhCH2).
Benzyl [(1S,2'S)-2,3,4,6-Tetra-O-benzylspiro[1,5-anhydro-d-glucitol-1,1'-cyclopropane]-2'-yl]carbamate
(11a). As described above, the reaction of 8a (106 mg, 0.175 mmol) in dry acetone (3 ml) with Et3N
(22.7 mg, 0.224 mmol), ClCO2Et (27.1mg, 0.250 mmol), and NaN 3 (18.6 mg, 0.280 mmol) in H2O (1ml), and
usual workup gave crude 9a (111 mg, 0.179 mmol), which was dissolved in dry toluene (10 ml) and kept at 1008
until TLC showed complete consumption of 9a (ca. 2 h). After the addition of dry BnOH (10 ml), heating was
continued for another 18 h. Evaporation yielded crude 11a (148 mg). Crystallisation from Et2O and FC (hexane/
Et2O 4 :1 ! 1:1) of the mother liquors afforded pure 11a (106 mg, 85%). Colourless solid. Rf (hexane/AcOEt
1:1) 0.57. Prep. HPLC: tR (hexane/Et2O 5 :1, 10 ml/min) 40 min. M.p. 138 1398 (MeOH). [a]2D5 ˆ ‡13.0 (c ˆ
1.70, CHCl3). IR (CHCl3): 3443m, 3090w, 3067w, 2906m, 2867m, 1718s, 1522m, 1497m, 1454s, 1401w, 1558m,
1326m, 1151m, 1123m, 1090s, 1060s, 1028s, 91 0w. 1H-NMR (300 MHz, CDCl3): see Table 6; additionally, 7.36
7.17 ( m, 25 arom. H); 5.1 4.8 (br. s, NH); 5.11 (d, J ˆ 12.8, PhCH); 5.03 (d, J ˆ 12.8, PhCH); 4.98 (d, J ˆ 10.9,
PhCH); 4.98 (d, J ꢀ 10, PhCH); 4.89 (d, J ˆ 11.2, PhCH); 4.84 (d, J ˆ 10.9, PhCH); 4.63 (d, J ˆ 12.1, PhCH);
4.61( d, J ˆ 10.9, PhCH); 4.52 (d, J ꢀ 10, PhCH); 4.52 (d, J ˆ 12.5, PhCH). 13C-NMR (75 MHz, CDCl3): see
Table 4; additionally, 156.63 (s, CˆO); 138.54, 138.31, 138.27, 137.54, 136.66 (5s); 128.74 127.75 (several d);
‡
75.58, 75.04, 74.49, 73.63 (4t, 4 PhCH2); 66.84 (t, PhCH2ÀOÀC(O)ÀN). FAB-MS: 700 (6, [M ‡ 1] ), 699 (6,
‡
‡
‡
M ), 698 (8, [M À 1] ), 564 (5, [M À Cbz] ), 485 (12), 484 (31), 253 (10), 155 (13), 154 (37), 152 (12), 147 (16),
138 (11), 137 (20), 136 (35), 133 (100), 107 (14), 91 (69). Anal. calc. for C44H45NO7 (699.85): C 75.51, H 6.48, N
2.00, O 16.00; found: C 75.43, H 6.68, N 2.13.
X-Ray Analysis of 11a. Monoclinic P1; a ˆ 5.106(3), b ˆ 17.819(11), c ˆ 20.635(9), a ˆ 94.74(4), b ˆ
89.77(4), g ˆ 93.49(5); Vˆ 1867.6(18) ä3, Dcalc ˆ 1.244 Mg/m3, Z ˆ 1. The reflections were measured on an

Helvetica Chimica Acta Vol. 86 (2003)
3017
Table 6. Selected 1H-NMR Chemical Shifts [ppm] and Coupling Constants [Hz] of the O-Benzylated
Carbamates 11a 11d, and 12a 12d in CDCl3
Compound 11a
11b
3.14
0.92
1.29
4.06
3.76
11c
11d
12a
12b
12c
12d
HÀC(2')
3.43 3.32
1.07 0.97
3.13 3.37 3.10 3.33 3.22 3.09 2.98 3.14 2.84 3.32 2.95
0.54 0.74
1.32 1.14
3.88 3.89 3.78 4.07 3.98 4.08
3.74 3.89 3.78 3.80 3.83
3.83
HcisÀC(3')
1.01 0.92 0.92
1.01 0.92 1.29
0.48
1.28
3.86
3.37.1738.91
0.72
1.13
3.91 3.78
HtransÀC(3') 1.07 0.97
HÀC(2)
HÀC(3)
HÀC(4)
HÀC(5)
HaÀC(6)
HbÀC(6)
4.07 3.95
3.86 3.75
3.86 3.75
3.51 3.43
3.67413.713.75 3.70 3.45 3.69
3.62
3.813.84 3.70 3.45 3.78
3.58
3.88
3.72 3.55
3.56 3.70 3.45 3.44
3.64 3.57 3.55
3.72 3.55
3.77 3.68 3.72 3.65 3.72 3.55
3.72 3.55
3.77 3.68 3.75
3.71 3.64
6.5
8.7
6.9
8.7
3.67 3.70 3.45 3.61
a
a
a
a
J(2',3'cis
)
)
)
)
)
)
)
ꢁ 1.5
ꢁ 1.5
ꢁ 1.5
8.4
9.3
9.0
3.4
1.9
10.9
5.6
8.7
7.2
)
)
)
6.5
8.7
7.0
8.7
8.4
8.4
5.3
7.8
5.9
8.7
9.3
9.0
3.7
5.6
8.7
6.9
a
a
a
a
a
J(2',3'trans
)
J(3'cis,3'trans
J(2,3)
J(3,4)
)
a
a
)
)
)
)
)
)
6.5
9.0
8.7
4.0
1
)
)
)
)
)
)
a
a
a
a
a
a
a
a
a
a
8.7
J(4,5)
ꢁ 1.5
a
J(5,6a)
J(5,6b)
J(6a,6b)
4.0
1
10.9
ꢁ 1.5
)
a
.9 ꢁ 1.5
a).9
)
a
a
)
10.9
)
10.9
a) Not assigned.
Enraf-Nonius-CAD4 diffractometer (graphite monochromator, CuKa radiation, l ˆ 1.54184) at 230(2) K. R ˆ
0.1764, Rw ˆ 0.3897. Part of the structure was solved by direct methods with SIR97 [74], the remaining non-H-
atoms were found from a difference Fourier map. Poor crystal quality did not allow anisotropic refinement. The
Ph rings were refined with fixed geometry. Some of the isotropic ADPs were also fixed. The non-H-atoms were
refined isotropically with SHELXL-97 [75].
Benzyl [(1R,2'R)-2,3,4,6-Tetra-O-benzylspiro[1,5-anhydro-d-glucitol-1,1'-cyclopropane]-2'-yl]carbamate
(11b). As described above, the reaction of 8b (35 mg, 59 mmol) in dry acetone (3 ml) with Et3N (148 ml of a
0.5m soln. in acetone, 74 mmol), ClCO2Et (166 ml of a 0.5m soln. in acetone, 83 mmol), and NaN3 (0.94 ml of a
0.1m soln. in H2O, 94 mmol), and usual workup gave crude 9b (34.9 mg, 56 mmol), which was heated in dry
toluene (10 ml) for 2 h, then treated with dry BnOH (10 ml), and heated for 18 h. FC (hexane/Et2O 4 :1 ! 1:1)
afforded pure 11b (32.1mg, 82%). Colourless oil. Rf (hexane/AcOEt 1:1) 0.61. Prep. HPLC: tR (hexane/Et2O
5 :1, 10 ml/min) 33 min. [a]2D5 ˆ ‡65.2 (c ˆ 0.42, CHCl3). IR (CHCl3): 3416m, 3090w, 3067w, 2914m, 2868m,
1715s, 1519s, 1497s, 1454s, 1404w, 1354m, 1324m, 1152m, 1090s, 1063s, 1028s, 1004m, 91 0w. 1H-NMR (500 MHz,
CDCl3): see Table 6; additionally, 7.33 7.13 (m, 25 arom. H); 5.53 (d, J ˆ 7.8, NH); 5.14 (d, J ˆ 12.5, PhCH);
5.09 (d, J ˆ 12.5, PhCH); 4.85 (d, J ˆ 11.2, PhCH); 4.83 (d, J ˆ 10.6, PhCH); 4.81( d, J ˆ 10.6, PhCH); 4.76
(d, J ˆ 11.2, PhCH); 4.64 (d, J ˆ 11.2, PhCH); 4.60 (d, J ˆ 11.5, PhCH); 4.53 (d, J ˆ 10.9, PhCH); 4.44 (d, J ˆ
12.1, PhCH). 13C-NMR (50 MHz, CDCl3): see Table 4; additionally, 156.89 (s, CˆO); 138.59, 138.49, 138.14,
137.72, 136.92 (5s); 128.80 127.93 (several d); 75.79 (t, 2 PhCH2); 75.04, 73.60 (2t, 2 PhCH2); 66.74
(t, PhCH2ÀOÀC(O)ÀN). Anal. calc. for C44H45NO7 (699.85): C 75.51, H 6.48, N 2.00, O 16.00; found: C
75.61, H 6.60, N 2.11.
Benzyl [(1S,2'R)-2,3,4,6-Tetra-O-benzylspiro[1,5-anhydro-d-glucitol-1,1'-cyclopropane]-2'yl]carbamate
(11c). As described above, the reaction of 8c (117.0 mg, 0.197 mmol) in dry acetone (3 ml) with Et3N
(24.9 mg, 0.246 mmol), ClCO2Et (29.7 mg, 0.274 mmol), and NaN3 (20.4 mg, 0.314 mmol) in H2O (1ml), and
usual workup gave crude 9c (122.8 mg, 0.198 mmol), which was heated in dry toluene (10 ml) for 2 h, then
treated with dry BnOH (10 ml), and heated for 18 h. FC (hexane/Et2O 4 :1 ! 1:1) gave pure 11c (107 mg,
77%), which was recrystallised from hexane/Et2O 10 :1. Colourless solid. Rf (hexane/AcOEt 1:1) 0.58. Prep.
HPLC: tR (hexane/Et2O 5 :1, 10 ml/min) 46 min M.p. 100 1018 (hexane/Et2O). [a]2D5 ˆ ‡0.1( c ˆ 2.00, CHCl3).
IR (CHCl3): 3438m, 3090w, 3067w, 2904m, 2869m, 1717s, 1511m, 1498w, 1454m, 1402m, 1361m, 1271m, 1152w,
1126w, 1091s, 1028m, 91 4m. 1H-NMR (300 MHz, CDCl3): see Table 6; additionally, 7.42 7.18 (m, 25 arom. H);

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Helvetica Chimica Acta Vol. 86 (2003)
5.29 (br. d, J ˆ 5.3, NH); 5.19 (d, J ˆ 12.1, PhCH); 5.15 (d, J ˆ 12.1, PhCH); 4.90 (d, J ˆ 10.6, PhCH); 4.89
(s, PhCH2); 4.84 (d, J ˆ 11.2, PhCH); 4.67 (d, J ˆ 11.5, PhCH); 4.62 (d, J ˆ 12.1, PhCH); 4.60 (d, J ˆ 10.9,
PhCH); 4.52 (d, J ˆ 12.1, PhCH). 13C-NMR (75 MHz, CDCl3): see Table 4; additionally, 157.03 (s, CˆO);
138.55, 138.21, 137.95, 137.82, 136.63 (5s); 128.62 127.78 (several d); 75.59, 75.19, 75.14, 73.45 (4t, 4 PhCH2);
66.94 (t, PhCH2ÀOÀC(O)ÀN). Anal. calc. for C44H45NO7 (699.85): C 75.51, H 6.48, N 2.00; found: C 75.69, H
6.58, N 2.13.
Benzyl [(1R,2'S)-2,3,4,6-Tetra-O-benzylspiro[1,5-anhydro-d-glucitol-1,1'-cyclopropane]-2'-yl]carbamate
(11d). As described above, the reaction of 8d (55.1mg, 93 mmol) in dry acetone (3 ml) with Et3N (0.116 ml
of a 0.5m soln. in acetone, 58 mmol), ClCO2Et (0.129 ml of a 0.5m soln. in acetone, 65 mmol), and NaN3 (9.60 mg,
0.148 mmol) in H2O (0.5 ml), and usual workup gave crude 9d (61.6 mg, 99.0 mmol), which was heated in dry
toluene (10 ml) for 2 h, then treated with dry BnOH (10 ml), and heated for 18 h. FC (hexane/Et2O 4 :1 ! 1:1)
gave pure 11d (44.4 mg, 68%), which was recrystallised from hexane. Colourless solid. Rf (hexane/AcOEt 1:1)
0.58. Prep. HPLC: tR (hexane/Et2O 5 :1, 10 ml/min) 37 min. M.p. 84 858 (hexane). [a]2D5 ˆ ‡60.0 (c ˆ 2.00,
CHCl3). IR (CHCl3): 3447m, 3089w, 3067w, 2905m, 2867m, 1717s, 1513m, 1498s, 1454s, 1402w, 1361m, 1271m,
1155m, 1127m, 1090s, 1075s, 1028s, 91 1w. 1H-NMR (300 MHz, CDCl3): see Table 6; additionally, 7.36 7.17
(m, 25 arom. H); 5.12 (s, PhCH2); 4.97 (d, J ˆ 6.2, NH); 4.89 (s, PhCH2); 4.87 (d, J ˆ 11.2, PhCH); 4.86 (d, J ˆ
11.8, PhCH); 4.57 (d, J ˆ 12.1, PhCH); 4.57 (d, J ˆ 11.8, PhCH); 4.53 (d, J ˆ 11.2, PhCH); 4.45 (d, J ˆ 12.1,
PhCH). 13C-NMR (75 MHz, CDCl3): see Table 4; additionally, 156.95 (s, CˆO); 138.65, 138.28, 138.07, 138.00,
136.71 (5s); 128.62 127.65 (several d); 75.83, 75.28, 75.01, 73.50 (4t, 4 PhCH2); 66.90 (t, PhCH2ÀOÀC(O)ÀN).
Anal. calc. for C44H45NO7 (699.85): C 75.51, H 6.48, N 2.00; found: C 75.68, H 6.58, N 2.15.
tert-Butyl [(1S,2'S)-2,3,4,6-Tetra-O-benzylspiro[1,5-anhydro-d-glucitol-1,1'-cyclopropane]-2'-yl]carbamate
(12a). As described above, the reaction of 8a (760 mg, 1.28 mmol) in dry acetone (20 ml) with Et3N (165 mg,
1.63 mmol), ClCO2Et (197 mg, 1.82 mmol), and NaN3 (133 mg, 2.05 mmol) in H2O (6 ml), and usual workup
gave crude 9a (798 mg, quant), which was dissolved in dry toluene (60 ml) and kept at 1008 until TLC showed
complete consumption of 9a (ca. 2 h). After the addition of dry t-BuOH (60 ml), heating was continued for
another 24 h at 908. Evaporation and FC (hexane/AcOEt 4 :1 ! 1:1) gave 12a (668 mg, 78%), which was
recrystallized from hexane/Et2O. Colourless solid. Rf (hexane/AcOEt 1:1) 0.65. Prep. HPLC: tR (hexane/
AcOEt 4 :1, 10 ml/min) 14 min. M.p. 928 (hexane/Et2O). [a]2D5 ˆ ‡12.4 (c ˆ 1.00, CHCl3). IR (CHCl3): 3448m,
3065w, 2909m, 2871m, 1708s, 1500s, 1455m, 1364s, 1327w, 1165s, 1089s, 91 0w, 850w. 1H-NMR (300 MHz, CDCl3):
see Table 6; additionally, 7.35 7.16 (m, 20 arom. H); 4.97 (d, J ˆ 10.9, PhCH); 4.97 (d, J ˆ 11.2, PhCH); 4.90
(d, J ˆ 11.2, PhCH); 4.87 4.78 (m, NH); 4.83 (d, J ˆ 10.9, PhCH); 4.61( d, J ˆ 12.1, PhCH); 4.60 (d, J ˆ 10.9,
PhCH); 4.57 (d, J ˆ 10.9, PhCH); 4.50 (d, J ˆ 12.1, PhCH); 1.43 (s, Me3C). 13C-NMR (75 MHz, CDCl3): see
Table 4; additionally, 156.18 (s, CˆO); 138.67 (s); 138.37 (s, 2 C); 137.75 (s); 128.74 127.74 (several d); 79.52
(s, Me3C); 75.62, 75.07, 74.54, 73.63 (4t, 4 PhCH2); 28.41( q, Me3C). Anal. calc. for C41H47NO7 (665.81): C 73.96,
H 7.12, N 2.10; found: C 73.94, H 7.30, N 2.10.
tert-Butyl [(1R,2'R)-2,3,4,6-Tetra-O-benzylspiro[1,5-anhydro-d-glucitol-1,1'-cyclopropane]-2'-yl]carba-
mate (12b). As described above, the reaction of 8b (230 mg, 0.388 mmol) in dry acetone (6 ml) with Et3N
(49.0 mg, 0.484 mmol), ClCO2Et (59.2 mg, 0.546 mmol), and NaN3 (40.3 mg, 0.620 mmol) in H2O (2.5 ml), and
usual workup gave crude 9b (240 mg, quant), which was heated in dry toluene (20 ml) for 2 h, then treated with
dry t-BuOH (20 ml) and heated for 24 h. FC (hexane/AcOEt 4 :1 ! 1:1) gave pure 12b (212 mg, 82%).
Colourless oil. Rf (hexane/AcOEt 1:1) 0.67. Prep. HPLC: tR (hexane/AcOEt 4 :1, 10 ml/min) 13 min. [a]D25
ˆ
‡58.7 (c ˆ 2.00, CHCl3). IR (CHCl3): 3428m, 3065w, 2911m, 2870m, 1705s, 1503s, 1453m, 1363s, 1325w, 1166s,
1090s, 91 0w, 861w, 603w, 536w. 1H-NMR (500 MHz, CDCl3): see Table 6; additionally, 7.38 7.17 (m, 20 ar-
om. H); 5.22 (br. d, J ˆ 6.2, NH); 4.92 (d, J ˆ 11.5, PhCH); 4.87 (s, PhCH2); 4.87 (d, J ˆ 12.1, PhCH); 4.68
(d, J ˆ 11.5, PhCH); 4.61( d, J ˆ 12.1, PhCH); 4.57 (d, J ˆ 12.1, PhCH); 4.46 (d, J ˆ 12.1, PhCH); 1.48 (s, Me3C).
13C-NMR (75 MHz, CDCl3): see Table 4; additionally, 156.54 (s, CˆO); 138.62, 138.59, 138.16, 138.04 (4s);
128.70 127.41 (several d); 78.99 (s, Me3C); 75.78, 75.56, 74.91, 73.55 (4t, 4 PhCH2); 28.48 (q, Me3C). Anal. calc.
for C41H47NO7 (665.81): C 73.96, H 7.12, N 2.10; found: C 74.10, H 7.22, N 2.18.
tert-Butyl [(1S,2'R)-2,3,4,6-Tetra-O-benz ylspiro[1,5-anhydro-d-glucitol-1,1'-cyclopropane]-2'-yl]carba-
mate (12c). As described above, the reaction of 8c (190 mg, 0.319 mmol) in dry acetone (5 ml) with Et3N
(40.5 mg, 0.400 mmol), ClCO2Et (48.7 mg, 0.449 mmol), and NaN3 (33.1mg, 0.510 mmol) in H 2O (1.5 ml), and
usual workup gave crude 9c (205 mg, quant), which was heated in dry toluene (25 ml) for 2 h, then treated with
dry t-BuOH (25 ml) and heated for 24 h. FC (hexane/AcOEt 4 :1 ! 1:1) gave pure 12c (180 mg, 85%).
Colourless oil. Rf (hexane/AcOEt 1:1) 0.66. Prep. HPLC: tR (hexane/AcOEt 4 :1, 10 ml/min) 17 min. [a]D25
ˆ
‡3.6 (c ˆ 2.00, CHCl3). IR (CHCl3): 3444m, 3065w, 2909m, 2872m, 1707s, 1501s, 1453m, 1366s, 1161s, 1092s,
1026s, 91 5m, 853w. 1H-NMR (300 MHz, CDCl3): see Table 6; additionally, 7.37 7.18 (m, 20 arom. H); 5.02

Helvetica Chimica Acta Vol. 86 (2003)
3019
(d, J ˆ 4.7, NH); 4.89 (d, J ˆ 12.1, PhCH); 4.87 (s, PhCH2); 4.82 (d, J ˆ 11.2, PhCH); 4.67 (d, J ˆ 11.2, PhCH);
4.64 (d, J ˆ 12.1, PhCH); 4.60 (d, J ˆ 12.1, PhCH); 4.54 (d, J ˆ 12.1, PhCH); 1.49 (s, Me3C). 13C-NMR (50 MHz,
CDCl3): see Table 4; additionally, 156.70 (s, CˆO); 138.70, 138.35, 138.16, 138.01 (4s); 128.61 127.78 (several
d); 79.57 (s, Me3C); 75.60, (t, PhCH2); 75.19 (t, 2 PhCH2); 73.44 (t, PhCH2); 28.46 (q, Me3C). Anal. calc. for
C41H47NO7 (665.81): C 73.96, H 7.12, N 2.10; found: C 74.01, H 7.28, N 2.14.
tert-Butyl [(1R,2'S)-2,3,4,6-Tetra-O-benzylspiro[1,5-anhydro-d-glucitol-1,1'-cyclopropane]-2'-yl]carba-
mate (12d). As described above, the reaction of 8d (380 mg, 0.639 mmol) in dry acetone (10 ml) with Et3N
(82.3 mg, 0.813 mmol), ClCO2Et (98.7 mg, 0.910 mmol), and NaN3 (66.5 mg, 1.02 mmol) in H2O (3 ml), and
usual workup gave crude 9d (395 mg, quant), which was heated in dry toluene (30 ml) for 2 h, then treated with
dry t-BuOH (30 ml) and heated for 24 h. FC (hexane/AcOEt 4 :1 ! 1:1) gave pure 12d (330 mg, 78%), which
was recrystallised from hexane. Colourless solid. Rf (hexane/AcOEt 1:1) 0.66. Prep. HPLC: tR (hexane/AcOEt
4 :1, 10 ml/min) 15 min. M.p. 69 708 (hexane). [a]2D5 ˆ ‡56.5 (c ˆ 2.00, CHCl3). IR (CHCl3): 3449m, 3065w,
2909m, 2870m, 1707s, 1500s, 1454m, 1366s, 1163s, 1090s, 91 0w, 837w. 1H-NMR (300 MHz, CDCl3): see Table 6;
additionally, 7.34 7.17 (m, 20 arom. H); 4.88 (s, PhCH2); 4.88 (d, J ˆ 11.2, PhCH); 4.86 (d, J ˆ 11.8, PhCH);
4.76 (br. d, J ˆ 5.3, NH); 4.61( d, J ˆ 11.8, PhCH); 4.58 (d, J ˆ 11.2, PhCH); 4.56 (d, J ˆ 11.5, PhCH); 4.51
(d, J ˆ 11.8, PhCH); 1.45 (s, Me3C). 13C-NMR (50 MHz, CDCl3): see Table 4; additionally, 156.65 (s, CˆO);
138.78 (s, 2 C); 138.27 (s, 2 C); 128.59 127.63 (several d); 86.62 (s, Me3C); 75.80, 75.26, 74.88, 73.48
(4t, 4 PhCH2); 28.44 (q, Me3C). Anal. calc. for C41H47NO7 (665.81): C 73.96, H 7.12, N 2.10; found: C 73.97, H
7.31, N 2.14.
tert-Butyl [(1S,2'S)-Spiro[1,5-anhydro-d-glucitol-1,1'-cyclopropane]-2'-yl]carbamate (13a). Hydrogenation
of 12a (108 mg, 0.162 mmol) in MeOH (5 ml) containing 10% Pd/C (200 mg) at 4 bar for 18 h, filtration through
Celite, washing the residue with MeOH (5 ml), and evaporation of the combined filtrates and washings gave
crude 13a (47.5 mg, quant.). FC (CHCl3/EtOH/20% aq. NH3 15 :15 :2) gave pure 13a (39.3 mg, 79%), which was
recrystallised from MeOH or acetone. Colourless solid. Rf (CHCl3/EtOH/20% aq. NH3 9 :5 :1) 0.42. M.p. 173
1748 (acetone). [a]2D5 ˆ ‡18.5 (c ˆ 2.00, H2O). IR (KBr): 3700 3000s (br.), 2978m, 2931m, 1690s, 1527m,
1394m, 1367m, 1254w, 1171s, 1078s, 1024m, 847w. 1H-NMR (300 MHz, D2O): see Table 7; additionally, 1.47
(s, Me3C). 13C-NMR (75 MHz, D2O): see Table 4; additionally, 161.65 (s, CˆO); 84.37 (s, Me3C); 30.51
(q, Me3C). Anal. calc. for C13H23NO7 (305.32): C 51.14, H 7.59, N 4.59; found: C 51.09, H 7.34, N 4.48.
Table 7. Selected 1H-NMR Chemical Shifts [ppm] and Coupling Constants [Hz] of the Debenzylated Boc-
Carbamates 13a 13d and of the Ammonium Chlorides 1a 1d in D2O
Compound 13a
13b
2.89
1.26
1.34
3.99
3.63
3.48
3.77 3.58
3.88
3.77 3.58
5.6
8.7 10.0
7.2 7.5;
9.7
13c
2.88
0.68
1.24
3.83
13d
2.94
0.87
1.27
1a
2.99
1.39
1.34
1b
1c
1d
HÀC(2')
HcisÀC(3')
HtransÀC(3')
HÀC(2)
HÀC(3)
HÀC(4)
HÀC(5)
HaÀC(6)
HbÀC(6)
2.94
2.912.90
1.52 1.48
1.52 1.48
2.93
1.03
1.38
1.22 1.04
1.22 1.04
4.00
3.52
3.47
3.43 3.35
3.85
3.67
7.16.5 6.9
8.4
1.14
1.41
3.814.019 3.942.1 3.84 3.87
3.52 3.40 3.59
3.52 3.40 3.47
3.52 3.40 3.41 3.28 3.39
3.88
3.70
5.6
8.7
6.5
8.7
3.55
3.46
3.63
3.53
3.55 3.47 3.59 3.49
3.55 3.47 3.59 3.49
3.55 3.47 3.44 3.37
3.53 3.45
3.83
3.82
3.69
5.8
8.6
7.5 8.18.1
9.0
8.7
9.6
1.4
5.3
3.80
3.65
3.92
3.73
5.3
8.7
8.18.1
)
)
)
3.90
3.75
5.0
3.68
J(2',3'cis
)
ꢁ 1.5
J(2',3'trans
)
9.6 ꢁ 1.5
8.7
a
J(3'cis,3'trans
J(2,3)
)
)
a
)
a
7.8
9.0
8.9
9.8
9.3
8.4
9.6
8.1
a
a
J(3,4)
J(4,5)
8.7
8.7
9.0
9.3
ꢁ 1.5
)
)
a
a
ꢁ 1.5
ꢁ 1.5
4.7
J(5,6a)
J(5,6b)
J(6a,6b)
ꢁ 1.5
ꢁ 1.5
2.2 ꢁ 1.5
ꢁ 1.5
2.2
5.3
12.5
6.2
ꢁ 1.5
6.0
5.3
3.4
12.5
10.6
12.8
12.1
12.4
11.8
12.8
a) Not assigned.

3020
Helvetica Chimica Acta Vol. 86 (2003)
tert-Butyl [(1R,2'R)-Spiro[1,5-anhydro-d-glucitol-1,1'-cyclopropane]-2'-yl]carbamate (13b). As described
above, hydrogenation of 12b (41.7 mg, 62.6 mmol) in MeOH (5 ml) containing 10% Pd/C (60 mg) gave crude
13b (21.1 mg, quant.). FC (CHCl3/EtOH/20% aq. NH3 15 :15 :2) gave pure 13b (13.9 mg, 73%), which was
recrystallised from hexane/AcOEt. Colourless solid. Rf (CHCl3/EtOH/20% aq. NH3 9 :5 :1) 0.47. M.p. 195 1968
(hexane/AcOEt). [a]2D5 ˆ ‡75.7 (c ˆ 0.90, H2O). IR (KBr): 3700 3000s (br.), 2978m, 2935w, 1688s, 1521m,
1448w, 1394m, 1367m, 1248m, 1169s, 1100m, 1077m, 1057m, 1024m, 970w. 1H-NMR (300 MHz, D2O): see
Table 7; additionally, 1.49 (s, Me3C). 13C-NMR (50 MHz, D2O): see Table 4; additionally, 158.61 (s, CˆO); 81.90
(s, Me3C); 27.77 (q, Me3C). Anal. calc. for C13H23NO7 (305.32): C 51.14, H 7.59, N 4.59; found: C 50.87, H 7.39, N
4.43.
tert-Butyl [(1S,2'R)-Spiro[1,5-anhydro-d-glucitol-1,1'-cyclopropane]-2'-yl]carbamate (13c). As described
above, hydrogenation of 12c (74.4 mg, 0.112 mmol) in MeOH (5 ml) containing 10% Pd/C (100 mg) gave crude
13c (34.6 mg, quant.). FC (CHCl3/EtOH/20% aq. NH3 15 :15 :2) gave pure 13c (28.6 mg, 84%). Colourless oil.
Rf (CHCl3/EtOH/20% aq. NH3 9 :5 :1) 0.40. [a]2D5 ˆ ‡41.0 (c ˆ 2.00, H2O). IR (KBr): 3700 3000s (br.), 2977m,
2929m, 1685s, 1522m, 1394m, 1367m, 1252m, 1169s, 1103m, 1079m, 1053m, 1026m, 909w, 851w, 774w. 1H-NMR
(300 MHz, D2O): see Table 7; additionally, 1.45 (s, Me3C). 13C-NMR (50 MHz, D2O): see Table 4; additionally,
159.44 (s, CˆO); 81.61 (s, Me3C); 27.71( q, Me3C). Anal. calc. for C13H23NO7 (305.32): C 51.14, H 7.59, N 4.59;
found: C 51.13, H 7.65, N 4.47.
tert-Butyl [(1R,2'S)-Spiro[1,5-anhydro-d-glucitol-1,1'-cyclopropane]-2'-yl]carbamate (13d). As described
above, hydrogenation of 12d (153.0 mg, 0.230 mmol) in MeOH (10 ml) containing 10% Pd/C (200 mg) gave
crude 13d (77.4 mg, quant.). FC (CHCl3/EtOH/20% aq. NH3 15 :15 :2) gave pure 13d (55.8 mg, 79%), which
was recrystallised from acetone. Colourless solid. Rf (CHCl3/EtOH/20% aq. NH3 9 :5 :1) 0.36. M.p. 177 1788
(acetone). [a]2D5 ˆ À5.4 (c ˆ 2.00, MeOH). IR (KBr): 3700 3000s (br.), 2979m, 2929m, 1689s, 1523s, 1393m,
1
1367m, 1279m, 1253m, 1169s, 1099s, 1077s, 1029m, 974w, 945w, 855w. H-NMR (300 MHz, D2O): see Table 7;
additionally, 1.45 (s, Me3C). 13C-NMR (75 MHz, D2O): see Table 4 ; additionally, 161.70 (s, CˆO); 84.19 (s, Me3C);
30.55 (q, Me3C). Anal. calc. for C13H23NO7 (305.32): C 51.14, H 7.59, N 4.59; found: C 51.14, H 7.55, N 4.42.
X-Ray Analysis of 13d. Orthorhombic P212121; a ˆ 5.357(3), b ˆ 12.810(3), c ˆ 28.362(14); Vˆ 1946.3(15)
ä3, Dcalc ˆ 1.240 Mg/m3, Z ˆ 4. The reflections were measured on an Enraf-Nonius-CAD4 diffractometer
(graphite monochromator, CuKa radiation, l ˆ 1.54184) at 200(2) K. R ˆ 0.0680, Rw ˆ 0.1837. Part of the
structure was solved by direct methods with SIR97 [74], the remaining non-H-atoms were found from a
difference Fourier map. The non-H-atoms were refined anisotropically with SHELXL-97 [75]. H-Atoms were
calculated at idealised positions and included in the structure-factor calculation with fixed isotropic
displacement parameters.
(1S,2'S)-Spiro[1,5-anhydro-d-glucitol-1,1'-cyclopropane]-2'-ammonium Chloride (1a). a) Hydrogenolysis
of 11a. Hydrogenation of 11a (68.2 mg, 97.4 mmol) in MeOH (10 ml) containing 37% aq. HCl (0.3 ml) and 10%
Pd/C (100 mg) at 4 bar for 2 h, filtration through Celite, washing the residue with H2O (5 ml) and MeOH (5 ml),
and evaporation of the combined filtrates and washings gave a colourless oil. Dissolution of the oil in H2O (5 ml)
and lyophilisation gave 1a (24.0 mg, quant.).
b) Hydrolysis of 13a. Compound 13a (39.3 mg, 0.129 mmol) was dissolved in 1n HCl (5 ml) and evaporated
with MeOH (2 Â 10 ml) at 508. Dissolution of the residue in H2O (5 ml) and lyophilisation gave 1a (31.1 mg,
quant.). Slightly yellow, hygroscopic solid. pKHA ˆ 7.79 (H2O). Rf (CHCl3/MeOH/20% aq. NH3 2 :3 :1) 0.53.
[a]2D5 ˆ ‡49.5 (c ˆ 1.00, MeOH). 1H-NMR (500 MHz, D2O): see Table 7; additionally, 3.55 (irrad. at 1.37!
NOE of 1.2%); 3.39 (irrad. at 1.37! NOE of 3.2%). 13C-NMR (75 MHz, D2O): see Table 4. ESI-MS (negative
‡
‡
mode): 240 (100, [M À 1]À). HR-MALDI-MS: 228.0844 ([M À HCl ‡ Na] , C8H15NaNO5 ; calc. 228.0848),
‡
‡
206.1025 ([M À Cl] , C8H16NO5 ; calc. 206.1028).
(1R,2'R)-Spiro[1,5-anhydro-d-glucitol-1,1'-cyclopropane]-2'-ammonium Chloride (1b). a) Hydrogenolysis
of 11b. As described above, hydrogenation of 11b (48.6 mg, 69.4 mmol) in MeOH (10 ml) containing 37% HCl
(0.3 ml) and 10% Pd/C (80 mg), followed by the usual workup, gave 1b (17.0 mg, quant.).
b) Hydrolysis of 13b. Compound 13b (9.6 mg, 31.4 mmol) was dissolved in 1n HCl (5 ml) and evaporated
with MeOH (2 Â 10 ml) at 508. Dissolution of the residue in H2O (5 ml) and lyophilisation gave 1b (7.60 mg,
quant.). Slightly yellow, hygroscopic solid. pKHA ˆ 7.88 (H2O). Rf (CHCl3/MeOH/20% aq. NH3 2 :3 :1) 0.51.
[a]2D5 ˆ ‡37.3 (c ˆ 1.00, MeOH). 1H-NMR (300 MHz, D2O): see Table 7. 13C-NMR (50 MHz, D2O): see Table 4.
‡
‡
‡
HR-MALDI-MS: 228.0844 ([M À HCl ‡ Na] , C8H15NaNO5
;
calc. 228.0848), 206.1025 ([M À Cl] ,
‡
C8H16NO5 ; calc. 206.1028).
(1S,2'R)-Spiro[1,5-anhydro-d-glucitol-1,1'-cyclopropane]-2'-ammonium Chloride (1c). a) Hydrogenolysis
of 11c. As described above, hydrogenation of 11c (43.9 mg, 62.7 mmol) in MeOH (10 ml) containing 37% HCl
(0.3 ml) and 10% Pd/C (80 mg), followed by the usual workup, gave 1c (16.0 mg, quant.).

Helvetica Chimica Acta Vol. 86 (2003)
3021
b) Hydrolysis of 13c. Compound 13c (28.6 mg, 93.7 mmol) was dissolved in 1n HCl (5 ml) and evaporated
with MeOH (2 Â 10 ml) at 508. Dissolution of the residue in H2O (5 ml) and lyophilisation gave 1c (23.3 mg,
quant.). Colourless, hygroscopic solid. pKHA ˆ 8.16 (H2O). Rf (CHCl3/MeOH/20% aq. NH3 2 :3 :1) 0.45. [a]D25
ˆ
‡37.0 (c ˆ 1.00, MeOH). 1H-NMR (300 MHz, D2O): see Table 7. 13C-NMR (75 MHz, D2O): see Table 4. HR-
‡
‡
‡
‡
MALDI-MS: 228.0844 ([M À HCl ‡ Na] , C8H15NaNO5 ; calc. 228.0848), 206.1024 ([M À Cl] , C8H16NO5
;
calc. 206.1028).
(1R,2'S)-Spiro[1,5-anhydro-d-glucitol-1,1'-cyclopropane]-2'-ammonium Chloride (1d). a) Hydrogenolysis
of 11d. As described above, hydrogenation of 11d (74.6 mg, 0.107 mmol) in MeOH (10 ml) containing 37% HCl
(0.3 ml) and 10% Pd/C (100 mg), followed by the usual workup, gave 1d (26.1mg, quant.).
b) Hydrolysis of 13d. Compound 13d (55.8 mg, 0.183 mmol) was dissolved in 1n HCl (5 ml) and evaporated
with MeOH (2 Â 10 ml) at 508. Dissolution of the residue in H2O (5 ml) and lyophilisation gave 1d (44.2 mg,
quant.). Slightly yellow, hygroscopic solid. pKHA ˆ 7.68 (H2O). Rf (CHCl3/MeOH/20% aq. NH3 2 :3 :1) 0.42.
[a]2D5 ˆ ‡84.6 (c ˆ 1.00, MeOH). 1H-NMR (300 MHz, D2O): see Table 7. 13C-NMR (75 MHz, D2O): see Table 4.
‡
‡
‡
HR-MALDI-MS: 228.0844 ([M À HCl ‡ Na] , C8H15NaNO5
;
calc. 228.0848), 206.1024 ([M À Cl] ,
‡
C8H16NO5 ; calc. 206.1028).
Cyclopropanation of 14. At 708, a soln. of 14 (4.74 g, 8.8 mmol) [58] in dry toluene (20 ml) was treated with
Cu powder (250 mg, 3.9 mmol) and with a soln. of ethyl diazoacetate (4.03 g, 35 mmol) in dry toluene (15 ml)
over a period of 8 h (using a syringe pump) and stirred for an additional 30 min at 708. Evaporation and FC
(AcOEt/hexane 1:50 ! 1:10) gave 14 (450 mg, 9%) and a ca. 9 :51:11:29 mixture of 15a 15d (4.7 g, 86%).
Prep. HPLC (hexane/Et2O/AcOEt 8 :1:1, 10 ml/min) afforded pure samples of 15a 15d.
Ethyl (1S,2'S)-2,3,4,6-Tetra-O-benzylspiro[1,5-anhydro-d-mannitol-1,1'-cyclopropane]-2'-carboxylate
(15a). Colourless oil. Rf (AcOEt/hexane 1:3) 0.61. Prep. HPLC: tR (hexane/Et2O/AcOEt 8 :1:1, 10 ml/min)
16.6 min. [a]2D5 ˆ 5.6 (c ˆ 1.5, CHCl3). IR (CHCl3): 3007m, 2908m, 2871m, 1747s, 1602w, 1450m, 1373m, 1327m,
1272w, 1177s, 1095s, 1045m, 968m. 1H-NMR (300 MHz, CDCl3): see Table 8 ; additionally, 7.39 7.15
(m, 20 arom. H); 4.91( d, J ˆ 10.9, PhCH); 4.78 (d, J ˆ 11.5, PhCH); 4.73 (d, J ˆ 11.5, PhCH); 4.66 (d, J ˆ
11.8, PhCH); 4.61( d, J ˆ 12.5, PhCH); 4.59 (d, J ˆ 11.5, PhCH); 4.53 (d, J ˆ 10.6, PhCH); 4.51( d, J ˆ 12.1,
PhCH); 4.14, 4.03 (2qd, J ˆ 7.2, 10.9, MeCH2O); 1.21 (t, J ˆ 7.2, Me). 13C-NMR (75 MHz, CDCl3): see Table 9;
additionally, 171.95 (s, CˆO); 139.65, 139.44, 138.61, 138.55 (4s); 128.63 127.37 (sevaral d); 75.42, 73.59, 72.86,
‡
‡
71.86 (4t, 4 PhCH2); 61.16 (t, MeCH2O); 14.18 (q, Me). HR-MALDI-MS: 645.3131 ([M ‡ Na] , C39H42NaO7
;
calc. 645.2828).
Table 8. Selected 1H-NMR Chemical Shifts [ppm] and Coupling Constants [Hz] of the manno-Cyclopropyl
Esters 15a 15d and 24a 24d in CDCl3
Compound
15a
2.25
1.13
1.26
4.13
15b
1.81
1.44
1.64
4.17
15c
1.86
1.44
0.59
3.13
15d
1.43
1.93
1.11
3.11
24a
2.23
1.37
1.27
5.54
24b
1.92
1.56 1.62
1.56 1.62
5.86
3.84
3.98
3.56
3.66
24c
2.06
1.61
1.03
4.88
24d
1.83
1.80
1.32
4.86
HÀC(2')
HcisÀC(3')
HtransÀC(3')
HÀC(2)
HÀC(3)
HÀC(4)
HÀC(5)
HaÀC(6)
HbÀC(6)
3.813.513.76
3.85
3.83
3.59
3.91
4.07
3.53
3.68
3.713.76
6.7
4.11
3.56
3.70
4.17
3.55
3.73
4.21
3.24
3.67
3.91
3.54
3.66
4.00
3.57
3.713.62
3.77
6.9
4.05
3.27
3.78
3.78
3.74
3.76
3.79
J(2',3'cis
)
7.0
9.5
5.9
6.9
9.0
5.9
3.4
9.5
9.7
4.4
1.9
6.5
9.0
6.2
6.9
9.3
5.6
8.4
8.4
6.7
10.6
6.7
J(2',3'trans
)
9.3
5.6
9.0
5.9
a
J(3'cis,3'trans
J(2,3)
)
)
3.13.13.13.13.4
9.2
9.7
4.7
2.5
3.7
3.4
J(3,4)
J(4,5)
J(5,6a)
J(5,6b)
J(6a,6b)
9.3
9.5
5.3
3.2
10.9
9.5
9.7
4.4
1.9
9.2
9.3
4.7
1.9
9.3
9.7
4.7
1.9
10.8
9.3
9.7
4.13.7
1.9
11.2
9.5
9.7
1.9
10.9
11.2
11.5
11.2
10.9
a) Not assigned.

3022
Helvetica Chimica Acta Vol. 86 (2003)
Table 9. Selected 13C-NMR Chemical Shifts [ppm] of the manno-Spirocyclopropanes 15a 15d, 16a 16d, 17a
17d, 19c, 19d, and 24a 24d in CDCl3 and of 18a 18d and 2a 2d in D2O Solution.
C(2')
C(3')
C(1)
C(2)
C(3)
C(4)
C(5)
C(6)
15a
15b
15c
15da)
24a
24ba)
24c
24d
16a
16b
16c
16d
17a
17b
17c
17d
18a
18b
18ca)
18d
19c
19d
2a
25.83
24.43
27.70
23.27
26.85
26.56
26.38
25.42
25.73
24.20
26.73
22.74
8.3532.811
32.87
33.53
31.43
34.83
35.34
34.41
34.65
33.73
31.54
34.25 8.37
34.88
32.62
32.94
17.85
20.49
13.60
19.39
17.94
19.88
16.66
18.03
18.52
21.26
15.04
20.22
66.05
65.09
62.92
65.09
65.22
65.59
64.50
65.68
66.60
66.00
63.15
65.84
73.74
71.85
75.19
74.57
67.95
67.38
72.35
72.64
73.48
72.36
75.11
74.45
83.87
82.50
82.73
83.00
81.59
80.58
80.86
80.89
83.87
82.52
82.5
82.78
77.99
83.56
82.12
83.48
75.08
74.79
76.10
77.76
74.38
74.29
74.58
74.04
74.94
74.71
75.69
77.62
78.77
79.11
80.08
79.52
78.42
78.88
79.59
79.09
78.77
79.27
79.67
79.47
69.58
69.42
69.19
69.09
69.04
68.93
68.79
68.56
69.39
69.39
68.95
68.95
63.32
75.23
84.25
79.92
69.35
18.38
15.99
17.79
19.46
16.82
19.27
16.89
15.83
17.83
1
62.17
59.17
60.36
66.82
65.20
65.07
65.00
59.28
60.43
75.29
75.30
74.76
70.15
69.21
70.18
69.00
75.20
74.60
75.29
76.60
76.81
73.31
71.66
75.59
75.75
76.60
76.59
78.31
79.27
78.74
81.38
80.83
82.68
82.09
79.05
79.16
69.58
69.42
69.76
63.73
62.97
64.04
63.71
69.47
69.55
76.22
75.39
75.83
75.83
81.94
83.34
64.5169.95
76.05
.7525.9181 63.73
75.90
2b
18.32
17.49
16.89
63.55
64.12
64.43
69.36
70.04
68.77
71.75
74.92
75.09
82.48
83.21
83.23
64.68
63.79
63.94
2c
75.46
75.56
2da)
a) Assignments based on HSQC-GRASP spectrum.
Ethyl (1R,2'R)-2,3,4,6-Tetra-O-benzylspiro[1,5-anhydro-d-mannitol-1,1'-cyclopropane]-2'-carboxylate
(15b). Colourless oil. Rf (AcOEt/hexane 1:3) 0.61. Prep. HPLC: tR (hexane/Et2O/AcOEt 8 :1:1, 10 ml/min)
14.2 min. [a]2D5 ˆ À2.0 (c ˆ 1, CHCl3). IR (CHCl3): 3066w, 3007m, 2870m, 1713s, 1602w, 1555w, 1496w, 1452m,
1369w, 1272w, 1176s, 1090s, 1027m, 961w, 91 0w. 1H-NMR (300 MHz, CDCl3): see Table 8; additionally, 7.48
7.17 ( m, 20 arom. H); 4.96 (d, J ˆ 10.6, PhCH); 4.88 (d, J ˆ 12.5, PhCH); 4.79 (d, J ˆ 12.1, PhCH); 4.63 (d, J ˆ
12.1, 2 PhCH); 4.56 4.52 (m, 2 PhCH); 4.46 (d, J ˆ 12.1, PhCH); 4.04, 3.90 (2qd, J ˆ 7.2, 10.9, MeCH2O); 1.17
(t, J ˆ 7.2, Me). 13C-NMR (75 MHz, CDCl3): see Table 9; additionally, 171.30 (s, CˆO); 138.91 (s); 138.58 (2s);
138.45 (s); 128.65 127.81 (several d); 75.64, 73.53, 72.06, 71.03 (4t, 4 PhCH2); 60.99 (t, MeCH2O); 14.21
‡
‡
(q, Me). HR-MALDI-MS: 645.31 00 (M[ ‡ Na] , C39H42NaO7 ; calc. 645.2828). Anal. calc. for C39H42O7
(622.75): C 75.22, H 6.80; found: C 75.32, H 6.79.
Ethyl (1S,2'R)-2,3,4,6-Tetra-O-benzylspiro[1,5-anhydro-d-mannitol-1,1'-cyclopropane]-2'-carboxylate
(15c). Colourless solid. Rf (AcOEt/hexane 1:3) 0.46. Prep. HPLC: tR (hexane/Et2O/AcOEt 8 :1:1, 10 ml/
min) 26.4 min. [a]2D5 ˆ À28.5 (c ˆ 1, CHCl3). M.p. 103 1058 (AcOEt/hexane). IR (CHCl3): 3007m, 2873m,
1732s, 1602w, 1496w, 1452s, 1370m, 1262s, 1177s, 1095s, 91 w3. 1H-NMR (300 MHz, CDCl3): see Table 8;
additionally, 7.49 7.23 (m, 20 arom. H); 4.97 (d, J ˆ 12.8, PhCH); 4.96 (d, J ˆ 10.9, PhCH); 4.83 (d, J ˆ 12.8,
PhCH); 4.69 (d, J ˆ 11.8, PhCH); 4.63 (d, J ˆ 12.1, 2 PhCH); 4.62 (d, J ˆ 10.6, PhCH); 4.53 (d, J ˆ 12.1, PhCH);
4.21, 4.17 (2qd, J ˆ 7.2, 10.9, MeCH2O); 1.28 (t, J ˆ 7.2, Me). 13C-NMR (75 MHz, CDCl3): see Table 9;
additionally, 168.35 (s, CˆO); 138.98, 138.82, 138.53, 138.47 (4s); 128.71 127.64 (several d); 75.50, 73.56, 72.10,
‡
‡
70.28 (4t, 4 PhCH2); 61.12 (t, MeCH2O); 14.38 (q, Me). HR-MALDI-MS: 645.2980 ([M ‡ Na] , C39H42NaO7
;
calc. 645.2828). Anal. calc. for C39H42O7 (622.75): C 75.22, H 6.80; found: C 74.97, H 6.64.

Helvetica Chimica Acta Vol. 86 (2003)
3023
Ethyl (1R,2'R)-2,3,4,6-Tetra-O-benzylspiro[1,5-anhydro-d-mannitol-1,1'-cyclopropane]-2'-carboxylate
(15d). Colourless solid. M.p. 83.5 84.58 (CH2Cl2/hexane). Rf (AcOEt/hexane 1:3) 0.46. Prep. HPLC: tR
(hexane/Et2O/AcOEt 8 :1:1, 10 ml/min) 22.2 min. [ a]2D5 ˆ 70.5 (c ˆ 1, CHCl3). IR (CHCl3): 3007m, 2872m,
1725s, 1602w, 1496w, 1453m, 1358m, 1259m, 1174w, 1092s, 91 3w. 1H-NMR (300 MHz, CDCl3): see Table 8;
additionally, 7.41 7.17 ( m, 20 arom. H); 4.92 (d, J ˆ 10.6, PhCH); 4.87 (d, J ˆ 12.5, irrad. at 1.11 ! NOE of
1.4%, PhCH); 4.73 (d, J ˆ 12.1, PhCH); 4.72 (d, J ˆ 11.8, PhCH); 4.69 (d, J ˆ 11.8, PhCH); 4.60 (d, J ˆ 11.5,
PhCH); 4.57 (d, J ˆ 10.6, PhCH); 4.51( d, J ˆ 11.8, PhCH); 4.21(irrad. at 3.24 ! d, J ˆ 9.7); 4.14, 4.07 (2qd, J ˆ
7.2, 10.9, MeCH2O); 3.85 (irrad. at 3.11 ! d, J ˆ 9.3, irrad. at 1.43! NOE of 3.2%, irrad. at 3.11 ! NOE of
6.7%, irrad. at 3.24 ! NOE of 6.2%); 3.78 (irrad. at 3.24 ! d, J ˆ 11.3, irrad. at 3.24 ! NOE of 3.2%); 3.67
(irrad. at 3.24 ! d, J ˆ 10.9, irrad. at 3.24 ! NOE of 3.1%); 3.24 (irrad. at 3.67 ! br. dd, J ˆ 3.4, 9.3, irrad. at
4.21 ! dd, J ꢀ 1.8, 4.1); 3.11 (irrad. at 1.43 ! NOE of 8.4%, irrad. at 1.11! NOE of 5%); 1.93 (irrad. at 1.11!
NOE of 32%); 1.43 (irrad. at 1.11! NOE of 8.4%, irrad. at 1.93! NOE of 1.6%, irrad. at 3.11! NOE of
8.1%); 1.22 (t, J ˆ 7.2, Me); 1.11 (irrad. at 1.43! NOE of 3.1%, irrad. at 1.93 ! NOE of 18%, irrad. at 3.11 !
NOE of 3.1%). 13C-NMR (75 MHz, CDCl3; assignments based on a HSQC-GRASP spectrum): see Table 9;
additionally, 169.54 (s, CˆO); 138.78, 138.72, 138.62, 138.54 (4s); 128.71 127.69 (several d); 75.56, 73.59, 72.47,
‡
‡
71.48 (4t, 4 PhCH2); 61.07 (t, MeCH2O); 14.23 (q, Me). HR-MALDI-MS: 645.3119 ([M ‡ Na] , C39H42NaO7
;
calc. 645.2828). Anal. calc. for C39H42O7 (622.75): C 75.22, H 6.80; found: C 75.20, H 6.94.
(1S,2'S)-2,3,4,6-Tetra-O-benzylspiro[1,5-anhydro-d-mannitol-1,1'-cyclopropane]-2'-carboxylic Acid (16a).
A soln. of 15a (250 mg, 0.40 mmol) in EtOH (10 ml) was heated to 608, treated with 1n KOH (3 ml), stirred for
3 h, cooled to r.t., concentrated to 1/3 of its volume, treated with 3n HCl (6 ml), and extracted with CH2Cl2. The
combined org. layers were dried and evaporated to yield crude 16a (214 mg). FC (AcOEt/hexane 3 :2) gave
pure 16a (190 mg, 80%). Colourless solid. Rf (AcOH/AcOEt/hexane 1:25 :75) 0.19. [ a]2D5 ˆ 4.6 (c ˆ 1, CHCl3).
IR (CHCl3): 3510w, 3400 2400w (br.), 3066w, 3007m, 2871m, 1698s, 1603w, 1496m, 1363m, 1318w, 1269w,
1178m, 1091s, 1041m, 1 02s8, 924w. 1H-NMR (300 MHz, CDCl3): see Table 10; additionally, 7.40 7.16
(m, 20 arom. H); 4.92 (d, J ˆ 10.6, PhCH); 4.77 (d, J ˆ 11.8, PhCH); 4.68 (d, J ˆ 11.8, PhCH); 4.67 (d, J ˆ
11.2, PhCH); 4.61( d, J ˆ 12.5, PhCH); 4.59 (d, J ˆ 11.2, PhCH); 4.54 (d, J ˆ 10.6, PhCH); 4.52 (d, J ˆ 12.2,
PhCH); 3.74 3.67 (irrad. at 3.54 ! s). 13C-NMR (75 MHz, CDCl3): see Table 9; additionally, 176.95 (s, CˆO);
138.91, 138.51, 138.41, 138.36 (4s); 128.65 127.54 (sevaral d); 75.39, 73.50, 72.82, 72.09 (4t, 4 PhCH2). HR-
‡
‡
MALDI-MS: 617.2516 ([M ‡ Na] , C37H38NaO7 ; calc. 617.2515). Anal. calc. for C37H38O7 ¥ 1.9 H2O (630.72): C
70.86, H 6.69; found: C 70.86, H 6.63.
(1R,2'R)-2,3,4,6-Tetra-O-benzylspiro[1,5-anhydro-d-mannitol-1,1'-cyclopropane]-2'-carboxylic Acid (16b).
A soln. of 15b (1.78 g, 2.86 mmol) and 1n KOH (15 ml) in EtOH (50 ml) was stirred at 608 for 3 h. Workup as
described above gave crude 16b (1.667 g, quantitative). Colourless oil. Rf (AcOH/AcOEt/hexane 1:25 :75) 0.21.
[a]2D5 ˆ À14.0 (c ˆ 1, CHCl3). IR (CHCl3): 3511w, 3400 2400m (br.), 3511w, 3089m, 3065s, 3007s, 2866s, 1688s,
1
1606w, 1494m, 1454s, 1362s, 1318m, 1279s, 1177s, 1090s, 1041s, 1027s, 953m, 91 3m, 839w. H-NMR (300 MHz,
CDCl3): see Table 10; additionally, 7.44 7.14 (m, 20 arom. H); 4.92 (d, J ˆ 10.9, PhCH); 4.82 (d, J ˆ 12.1,
PhCH); 4.75 (d, J ˆ 12.1, PhCH); 4.61( d, J ˆ 12.1, PhCH); 4.58 (d, J ˆ 11.8, PhCH); 4.52 (d, J ˆ 10.6, PhCH);
4.51( d, J ˆ 11.5, PhCH); 4.47 (d, J ˆ 11.8, PhCH). 13C-NMR (75 MHz, CDCl3): see Table 9; additionally, 175.46
(s, CˆO); 138.79, 138.59, 138.51, 138.37 (4s); 128.61 127.84 (several d); 75.53, 73.56, 72.30, 71.55 (4t, 4 PhCH2).
‡
‡
HR-MALDI-MS: 617.2504 ([M ‡ Na] , C37H38NaO7 ; calc. 617.2515). Anal. calc. for C37H38NaO7 ¥ 0.5 H2O
(603.69): C 73.61, H 6.51; found: C 73.51, H 6.58.
(1S,2'R)-2,3,4,6-Tetra-O-benzylspiro[1,5-anhydro-d-mannitol-1,1'-cyclopropane]-2'-carboxylic Acid (16c).
A soln. of 15c (290 mg, 0.47 mmol) in EtOH (12 ml) was heated to 608, treated with 1n KOH (3 ml) and stirred
for 3 h. Usual workup gave crude 16c (280 mg, quantitative). Colourless solid. M.p. 145 1468 (CH2Cl2/hexane).
Rf (AcOH/AcOEt/hexane 1:25 :75) 0.14. [ a]D25 ˆ 2.5 (c ˆ 1, CHCl3). IR (CHCl3): 3520w, 3400 2400w (br.),
3212w, 3088m, 3066m, 3007s, 2873m, 1742s, 1713s, 1603w, 1496m, 1454s, 1402m, 1361m, 1309w, 1263m, 1089s,
1027s, 91 3w. 1H-NMR (300 MHz, CDCl3): see Table 10; additionally, 7.43 7.21( m, 20 arom. H); 4.97 (d, J ˆ
10.9, PhCH); 4.91( d, J ˆ 13.1, PhCH); 4.79 (d, J ˆ 12.8, PhCH); 4.68 (d, J ˆ 11.8, PhCH); 4.63 (d, J ˆ 12.1,
PhCH); 4.57 (d, J ˆ 12.1, PhCH); 4.55 (d, J ˆ 12.5, PhCH); 4.51( d, J ˆ 11.8, PhCH). 13C-NMR (75 MHz,
CDCl3): see Table 9; additionally, 171.87 (s, CˆO); 138.47, 138.29, 138.18, 138.05 (4s); 128.81 127.87 (several
‡
‡
d); 75.58, 73.48, 72.20, 70.74 (4t, 4 PhCH2). HR-MALDI-MS: 617.2502 ([M ‡ Na] , C37H38NaO7 ; calc.
617.2515). Anal. calc. for C37H38O7 (594.69): C 74.73, H 6.44; found: C 74.70, H 6.45.
(1R,2'S)-2,3,4,6-Tetra-O-benzylspiro[1,5-anhydro-d-mannitol-1,1'-cyclopropane]-2'-carboxylic Acid (16d).
A soln. of 15d (270 mg, 0.43 mmol) and 1n KOH (3 ml) in EtOH (10 ml) was heated at 608 for 3 h. Workup as
described above gave crude 16d (250 mg, 97%). Colourless oil. Rf (AcOH/AcOEt/hexane 1:25 :75) 0.12.
[a]2D5 ˆ 98.6 (c ˆ 2, CHCl3). IR (CHCl3): 3510w, 3400 2400w (br.), 3088m, 3066m, 3007s, 2871m, 1702s, 1603w,

3024
Helvetica Chimica Acta Vol. 86 (2003)
Table 10. Selected 1H-NMR Chemical Shifts [ppm] and Coupling Constants [Hz] of the Cyclopropanecarboxylic
Acids 16a 16d and of the Protected Cyclopropylamine 17a in CDCl3, and of the Protected Cyclopropylamines
17b, 17d, and 17c in CD3OD (16a 16d, 17a, and 17c at 258; 17b and 17d at 508)
Compound
16a
16b
1.81
1.42
1.68
4.10
16c
1.84
1.38
0.76
3.14
16d
1.42
1.93
1.14
3.08
17a
2.93
0.60
1.17
3.58
3.95 3.97
4.13
3.49
17b
2.68
0.97
1.31
3.69
3.77
3.95 3.97
3.84
17c
2.92
0.63
0.73
3.30
17d
2.54
0.99
1.05
3.33
HÀC(2')
HcisÀC(3')
HtransÀC(3')
HÀC(2)
HÀC(3)
HÀC(4)
HÀC(5)
HaÀC(6)
HbÀC(6)
2.27
1.15
1.34
4.07
3.813.57
4.08
3.54
3.67 3.74
3.67 3.74
6.7
3.75
3.83
3.85
4.09
4.08
3.54
3.67
3.73
6.8
4.11
3.62
3.68
3.77
6.7
4.18
3.35
3.66
3.67
6.5
3.97
3.49
3.67
3.72
5.5
3.93
3.59 3.68
3.59 3.68
3.59 3.68
5.5
3.67
3.74
5.0
3.62 3.68
3.62 3.68
5.6
J(2',3'cis
)
J(2',3'trans
)
9.5
9.3
9.3
9.0
8.4
9.7
8.3
9.2
J(3'cis,3'trans
J(2,3)
J(3,4)
)
5.5
5.9
3.13.12.8
6.2
2.8
9.3
9.3
5.9
6.2
2.8
9.2
9.7
4.4
6.8
7.2
7.0
7.2
3.1
9.3
9.7
4.4
2.8
3.13.2
a
9.3
9.8
5.0
1.9
9.3
9.7
5.0
2.2
11.4
)
9.3
9.5
4.5
3.1
9.1
9.3
J(4,5)
9.7
7.2
3.7
a
J(5,6a)
J(5,6b)
J(6a,6b)
)
)
)
a
a
1.6
10.3
1.6
11.2
a
a
)
10.9
)
1
1
.2
a) Not assigned.
1496m, 1454s, 1410w, 1359m, 1309w, 1261m, 1090s, 1041m, 1027s, 980m, 91 2w. 1H-NMR (300 MHz, CDCl3): see
Table 10; additionally, 7.39 7.16 (m, 20 arom. H); 4.91( d, J ˆ 10.6, PhCH); 4.82 (d, J ˆ 12.5, PhCH); 4.72
(d, J ˆ 12.5, PhCH); 4.70 (d, J ˆ 11.5, PhCH); 4.66 (d, J ˆ 12.5, PhCH); 4.64 (d, J ˆ 11.8, PhCH); 4.55 (d, J ˆ
10.9, PhCH); 4.47 (d, J ˆ 11.8, PhCH). 13C-NMR (75 MHz, CDCl3): see Table 9; additionally, 174.28 (s, CˆO);
138.69, 138.57, 138.48, 138.39 (4s); 128.75 127.70 (several d); 75.54, 73.47, 72.66, 71.72 (4t, 4 PhCH2). HR-
‡
‡
MALDI-MS: 617.2512 ([M ‡ Na] , C37H38NaO7 ; calc. 617.2515). Anal. calc. for C37H38O7 ¥ 0.5 H2O (603.69): C
73.61, H 6.51; found: C 73.95, H 6.80.
tert-Butyl [(1S,2'S) 2,3,4,6-Tetra-O-benzylspiro[1,5-anhydro-d-mannitol-1,1'-cyclopropane]-2'-yl]carba-
mate (17a). a) A soln. of crude 16a (190 mg, 0.32 mmol) in acetone (5 ml) was cooled to 08, treated with
Et3N (59 mg, 0.57 mmol) and ClCO2Et (73 mg, 0.67 mmol), stirred for 1h, treated with a soln. of NaN 3 (50 mg,
0.77 mmol) in H2O (1.6 ml), and stirred for 2 h. The mixture was diluted with CH2Cl2, washed with H2O, dried
(MgSO4), evaporated, and dried under high vacuum overnight. The crude carbonyl azide was dissolved in dry
toluene (10 ml) and kept at 1008 until TLC showed complete consumption of the azide (ca. 2 h). After addition
of dry t-BuOH (10 ml), heating was continued for another 12 h. Evaporation and FC (AcOEt/hexane 1 :9 !
1:4) gave 17a (164 mg, 67%).
b) A soln. of 16a (212 mg, 0.36 mmol) in t-BuOH (12 ml) was treated with Et3N (163 mg, 1.6 mmol) and
(PhO)2PON3 (293 mg, 1.1 mmol) and stirred at r.t. for 15 min and at 1008 for 12 h. Evaporation and FC (AcOEt/
hexane 1:9 ! 1:4) gave 17a (165 mg, 69%). Colourless glassy solid forming a gel in AcOEt/hexane mixtures. Rf
(AcOEt/hexane 1:3) 0.21. [ a]2D5 ˆ 66.0 (c ˆ 1, CHCl3). IR (CHCl3): 3411w, 3089w, 3068w, 3007s, 2912w, 2869w,
1714s, 1602w, 1495s, 1453s, 1392m, 1367s, 1163s, 1098s, 1051m, 1027s, 91 3w. 1H-NMR (300 MHz, CDCl3): see
Table 10; additionally, 7.43 7.17 (m, 20 arom. H); 4.97 (d, J ˆ 11.8, PhCH); 4.90 (d, J ˆ 10.9, PhCH); 4.79
(d, J ˆ 11.8, PhCH); 4.76 (d, J ˆ 11.8, PhCH); 4.74 (d, J ˆ 11.8, PhCH); 4.63 (d, J ˆ 12.5, PhCH); 4.54 (br. d, J ꢀ
1.9, NH), 4.57 (d, J ˆ 10.9, PhCH); 4.49 (d, J ˆ 12.1, PhCH); 1.42 (s, Me3C). 13C-NMR (75 MHz, CDCl3): see
Table 9; additionally, 156.35 (s, CˆO); 138.96 (s); 138.63 (2s); 138.47 (s); 128.83 127.75 (several d); 79.92
‡
(s, Me3C); 75.34, 73.58, 72.80, 72.75 (4t, 4 PhCH2); 28.43 (q, Me3C). HR-MALDI-MS: 688.3252 ([M ‡ Na] ,
‡
C41H47NNaO7 ; calc. 688.3250).
tert-Butyl [(1R,2'R)-2,3,4,6-Tetra-O-benzylspiro[1,5-anhydro-d-mannitol-1,1'-cyclopropane]-2'-yl]carba-
mate (17b). a) As described above, treatment of crude 16b (525 mg, 0.88 mmol) in acetone (18 ml) at 08 with
Et3N (126 mg, 1.24 mmol), ClCO2Et (160 mg, 1.47 mmol), and a soln. of NaN3 (104 mg, 1.6 mmol) in H2O

Helvetica Chimica Acta Vol. 86 (2003)
3025
(6 ml), and usual workup gave the crude carbonyl azide. Heating of the carbonyl azide in dry toluene (20 ml) at
1008 (2 h), treatment with dry t-BuOH (20 ml), heating for another 12 h, evaporation, and FC (AcOEt/hexane
1:9 ! 1:4) gave 17b (435 mg, 74%).
b) Treatment of crude 16b (1.670 g, 2.85 mmol) in t-BuOH (60 ml), with Et3N (1.275 g, 12.5 mmol) and
(PhO)2PON3 (2.31 g, 8.4 mmol), stirring at r.t. for 15 min and at 1008 for 18 h, evaporation, and FC (AcOEt/
hexane 1:9 ! 1:4) gave 17b (1.39 g, 74%). Colourless oil. Rf (AcOEt/hexane 1:3) 0.22. [a]2D5 ˆ 48.8 (c ˆ 2,
CHCl3). IR (CHCl3): 3477m, 3088m, 3066w, 3007s, 2912w, 2866w, 1711s, 1603w, 1495s, 1453s, 1392m, 1367s,
1162s, 1098s, 1027m, 91 2w, 834w. 1H-NMR (CD3OD, 508): see Table 10; additionally, 7.43 7.15 (m, 20 arom. H);
4.85 (d, J ˆ 11.2, PhCH); 4.75 (d, J ˆ 11.8, PhCH); 4.67 (d, J ˆ 11.8, PhCH); 4.61( d, J ˆ 11.5, PhCH); 4.56
(d, J ˆ 11.5, PhCH); 4.54 (d, J ˆ 11.2, 2 PhCH); 4.45 (d, J ˆ 12.1, PhCH); 1.44 (s, Me3C). 13C-NMR (75 MHz,
CDCl3): see Table 9; additionally, 156.51 (s, CˆO); 139.18, 139.04, 138.95, 138.73 (4s); 128.68 127.58 (several
d); 77.24 (s, Me3C); 75.29, 73.43, 72.55, 72.07 (4t, 4 PhCH2); 28.35 (q, Me3C). HR-MALDI-MS: 688.3242 ([M ‡
‡
‡
Na] , C41H47NNaO7 ; calc. 688.3250). Anal. calc. for C41H47NO7 (665.81): C 73.96, H 7.12, N 2.10; found: C 73.82,
H 7.17, N 2.21.
tert-Butyl [(1S,2'R)-2,3,4,6-Tetra-O-benzylspiro[1,5-anhydro-d-mannitol-1,1'-cyclopropane]-2'-yl]carba-
mate (17c). a) As described above, treatment of crude 16c (280 mg, 0.47 mmol) in acetone (12 ml) at 08 with
Et3N (68 mg, 0.66 mmol), ClCO2Et (85 mg, 0.78 mmol), and a soln. of NaN3 (38 mg, 0.58 mmol) in H2O
(1.5 ml), and usual workup gave the crude carbonyl azide. Heating the crude carbonyl azide in dry toluene
(10 ml) at 1008 (2 h), treatment with dry t-BuOH (10 ml), heating for another 12 h, evaporation, and FC
(AcOEt/hexane 1:9 ! 1:4) gave 17c (208 mg, 67%).
b) Treatment of 16c (269 mg, 0.45 mmol) in t-BuOH (20 ml) with Et3N (218 mg, 2.15 mmol) and
(PhO)2PON3 (340 mg, 1.39 mmol), heating at 1008 for 6 h, evaporation, and FC (AcOEt/hexane 1:9 ! 1:4)
gave 17c (214 mg, 70%) and 19c (39 mg, 16%). Colourless solid. Rf (AcOEt/hexane 1:3) 0.33. [ a]2D5 ˆ À21.6
(c ˆ 1, CHCl3). M.p. 92.5 938 (CH2Cl2/hexane). IR (CHCl3): 3440m, 3089w, 3066s, 3006s, 2871s, 1708s, 1604w,
1585w, 1496s, 1454s, 1392m, 1367s, 1342m, 1165s, 1108s, 1027s, 91 3m, 850w. 1H-NMR (CD3OD, 508): see
Table 10; additionally, 7.43 7.18 (m, 20 arom. H); 4.86 (d, J ˆ 11.2, 2 PhCH); 4.71 4.48 (several d, 6 PhCH);
1.44 (s, Me3C). 13C-NMR (75 MHz, CDCl3): see Table 9; additionally, 156.62 (s, CˆO); 138.76 (s); 138.65 (2s);
138.42 (s); 128.68 127.82 (several d); 79.82 (s, Me3C); 75.50, 73.44, 71.97, 71.10 (4t, 4 PhCH2); 28.48 (q, Me3C).
‡
‡
HR-MALDI-MS: 688.3241([ M ‡ Na] , C41H47NNaO7 ; calc. 688.3250). Anal. calc. for C41H47NO7 (665.81): C
73.96, H 7.12, N 2.10; found: C 73.80, H 7.23, N 2.16.
(1S,2'R)-2'-[(Azidocarbonyl)amino]-2,3,4,6-tetra-O-benzylspiro[1,5-anhydro-d-mannitol-1,1'-cyclopro-
pane] (19c). Colourless solid. Rf (AcOEt/hexane 1:3) 0.33. IR (CHCl 3): 3422w, 3089w, 3066w, 3006m, 2924w,
2143s, 1704s, 1602w, 1507m, 1498m, 1454m, 1365s, 1262m, 1090s, 1027m, 91 1w. 1H-NMR (300 MHz, CDCl3): see
Table 11; additionally, 7.35 7.11 (m, 20 arom. H); 5.78 (d, J ˆ 5.9, irrad. at 2.88 ! s, NH); 4.89 (d, J ˆ 12.8,
PhCH); 4.72 (d, J ꢀ 12.8, 2 PhCH); 4.58 4.55 (m, 2 PhCH); 4.50 (d, J ˆ 11.8, PhCH); 4.49 (d, J ˆ 10.6, PhCH);
4.43 (d, J ˆ 12.1, PhCH); 3.97 (t, J ꢀ 9.3, HÀC(4)); 3.66 (dd, J ꢀ 3.1, 9.3, irrad. at 3.00! d, J ˆ 9.3, HÀC(3));
3.65 3.60 (AB, 2 HÀC(6)); 3.45 (ddd, J ꢀ 3.0, 4.8, 9.7, HÀC(5)); 3.00 (d, J ˆ 3.1, HÀC(2)); 2.88 (td, J ꢀ 7.5, 5.7,
irrad. at 5.78 ! dd, J ˆ 7.5, 5.9, HÀC(2')); 0.56 (t, J ꢀ 7.8, HtransÀC(3')); 0.53 (dd, J ꢀ 5.6, 7.2, HcisÀC(3')).
13C-NMR (75 MHz, CDCl3): see Table 9; additionally, 157.30 (s, CˆO); 138.37, 138.26, 138.06, 138.02 (4s);
128.60 127.91 (several d); 75.52, 73.43, 72.92, 71.21 (4t, 4 PhCH2). HR-MALDI-MS: 564.2755 ([M À CON3 ‡
‡
‡
‡
‡
H] , C36H38NO5 ; calc. 564.2750), 586.2581([ M À CON3 ‡ Na] , C36H37NNaO5 ; calc. 586.2569), 629.2621
‡
‡
‡
‡
([M À N2 ‡ Na] , C37H38N2NaO6 ; calc. 629.2628), 657.2686 ([M ‡ Na] , C37H38N4NaO6 ; calc. 657.2689).
tert-Butyl [(1R,2'S)-2,3,4,6-Tetra-O-benzylspiro[1,5-anhydro-d-mannitol-1,1'-cyclopropane]-2'-yl]carba-
mate (17d). a) As described above, treatment of 16d (190 mg, 0.32 mmol) in acetone (5 ml) at 08 with Et3N
(46 mg, 0.45 mmol), ClCO2Et (58 mg, 0.53 mmol), and a soln. of NaN3 (38 mg, 0.58 mmol) in H2O (1.5 ml), and
usual workup gave crude carbonyl azide. Heating the crude carbonyl azide in dry toluene (10 ml) at 1008 (2 h),
treatment with dry t-BuOH (10 ml), heating for another 18 h, evaporation, and FC (AcOEt/hexane 1 :9 ! 1:4)
gave 17d (121 mg, 56%).
b) Treatment of 16d (492 mg, 0.82 mmol) in t-BuOH (40 ml), with Et3N (377 mg, 3.7 mmol) and
(PhO)2PON3 (683 mg, 2.48 mmol), stirring at r.t. for 15 min and at 1008 for 18 h, evaporation, and FC (AcOEt/
hexane 1:9 ! 1:4) gave 17d (316 mg, 57%) and 19d (83 mg, 16%). Colourless oil. Rf (AcOEt/hexane 1:3) 0.20.
[a]2D5 ˆ 39.4 (c ˆ 2, CHCl3). IR (CHCl3): 3448m, 3088w, 3066w, 3007s, 2931m, 2868m, 1707s, 1603w, 1497s, 1453s,
1392m, 1367s, 1306w, 1164s, 1102s, 1027s, 942w, 91 4w. 1H-NMR (CD3OD, 508): see Table 10; additionally, 7.38
7.18 ( m, 20 arom. H); 4.85 (d, J ˆ 11.5, PhCH); 4.74 (d, J ˆ 11.8, PhCH); 4.68 4.61( m, 2 PhCH); 4.68 (d, J ˆ
11.5, PhCH); 4.56 (d, J ˆ 11.2, PhCH); 4.55 (d, J ˆ 11.5, PhCH); 4.45 (d, J ˆ 11.8, PhCH); 1.42 (br. s, Me3C).
13C-NMR (75 MHz, CDCl3): see Table 9; additionally, 156.74 (s, CˆO); 138.77 (2s); 138.67(2s); 128.70 127.73

3026
Helvetica Chimica Acta Vol. 86 (2003)
1
Table 11. Selected H-NMR Chemical Shifts [ppm] and Coupling Constants [Hz] of the Carbamates 18a 18d,
and of the manno-Ammonium Chlorides 2a 2d in D2O, and the Aminocarbonyl Azides 19c and 19d in CDCl3
(18a, 18c, 19c, 19d, and 2a 2d at 258; 18b at 508, and 18d at 608)
Compound
18a
2.88
18b
2.75
0.91
1.20
18c
2.89
18d
2.74
19c
2.88
0.53
0.56
3.00
3.66
19d
2.84
0.94
0.90
3.14
3.84
2a
3.06
1.20
1.51
3.82
3.85
2b
2.96
1.25
1.51
3.81
3.76
2c
2.96
1.25
1.32
3.48
3.84
2d
2.90
1.21
1.36
3.46
3.84
HÀC(2')
HcisÀC(3')
HtransÀC(3')
HÀC(2)
HÀC(3)
HÀC(4)
HÀC(5)
HaÀC(6)
HbÀC(6)
0.84
1.17
3.59
3.76
3.69
3.36
3.66
3.83
5.3
0.89
1.15
3.39
3.84
3.74
3.49
3.76
3.94
5.3
0.92
1.19
3.35
3.87
3.713.97
3.36
3.69
3.82
5.3
3.53
3.59 3.73
3.59 3.73
3.59 3.73
3.59 3.73
3.80
3.93
3.73
3.70
3.74
3.81
3.45
3.513.42
3.613.69
3.73
5.3
3.44
3.64
3.87
5.6
3.55
3.76
3.83
5.9
3.46
3.79
3.98
5.3
3.60 3.65
3.60 3.65
5.7
3.87
5.0
J(2',3'cis
)
5.6
J(2',3'trans
)
8.6
9.3
8.3
8.3
7.5
8.4
9.3
9.7
8.6
8.4
J(3'cis,3'trans
J(2,3)
J(3,4)
)
7.2
3.13.1
9.5
9.0
7.0
7.2
6.9
7.5
7.2
3.13.4
7.5
3.4
9.0
9.0
7.2
1.9
10.3
8.18.4
3.1
9.7
9.3
6.9
8.18.4
3.4
3.7
3.1
3.5
a
)
)
)
9.7
9.3
6.7
2.2
9.3
9.2
5.5
1.9
9.3
9.7
4.8
3.0
9.3
9.0
6.8
9.7
9.3
7.2
1.9
8.9
9.0
6.3
1.9
a
a
J(4,5)
J(5,6a)
J(5,6b)
J(6a,6b)
2.2
12.0
2.1
11.2
2.5
12.3
2.1
a
12.5
12.5
)
12.8
12.3
12.5
a) Not assigned.
(several d); 79.95 (s, Me3C); 75.08, 73.37, 72.69, 72.35 (4t, 4 PhCH2); 28.42 (q, Me3C). HR-MALDI-MS:
‡
‡
688.3243 ([M ‡ Na] , C41H47NNaO7 ; calc. 688.3250). Anal. calc. for C41H47NO7 (665.81): C 73.96, H 7.12, N
2.10; found: C 73.80, H 7.21, N 2.19.
(1R,2'S)-2'-[(Azidocarbonyl)amino]-2,3,4,6-tetra-O-benzylspiro[1,5-anhydro-d-mannitol-1,1'-cyclopro-
pane] (19d). Colourless solid. Rf (AcOEt/hexane 1:3) 0.19. IR (CHCl 3): 3432m, 3088m, 3060s, 3005s, 2931s,
2870s, 2144s, 1704s, 1605w, 1585w, 1496s, 1453s, 1364s, 1305m, 1261s, 1106s, 1028s, 948m, 91 s4. 1H-NMR
(300 MHz, CDCl3): see Table 11; additionally, 7.38 7.18 (m, 20 arom. H); 5.48 (d, J ˆ 6.8, NH); 4.92 (d, J ˆ 10.9,
PhCH); 4.80 (d, J ˆ 12.5, PhCH); 4.74 (d, J ˆ 12.5, PhCH); 4.72 (d, J ˆ 11.8, PhCH); 4.67 (d, J ˆ 11.5, PhCH);
4.57 (d, J ˆ 11.8, PhCH); 4.54 (d, J ˆ 10.9, PhCH); 4.51( d, J ˆ 12.1, PhCH); 3.93 (t, J ꢀ 9.3, HÀC(4)); 3.84
(dd, J ˆ 3.1, 9.0, irrad. at 3.14! d, J ˆ 9.0, HÀC(3)); 3.73 (dd, J ˆ 1.9, 10.3, H'ÀC(6)); 3.61( dd, J ˆ 7.2, 10.3,
HÀC(6)); 3.51( ddd, J ˆ 1.9, 7.2, 9.0, HÀC(5)); 3.14 (d, J ˆ 3.1, HÀC(2)); 2.84 (ddd, J ꢀ 5.3, 6.8, 8.4, irrad. at
5.48 ! dd, J ˆ 5.3, 8.4, HÀC(2')); 0.94 (dd, J ꢀ 5.3, 7.5, HcisÀC(3')); 0.90 (t, J ꢀ 7.9, HtransÀC(3')). 13C-NMR
(75 MHz, CDCl3): see Table 9; additionally, 157.37 (s, CˆO); 138.49 (s); 138.33 (s); 13.44 (2s); 128.73 127.86
‡
(several d); 75.26, 73.47, 72.90, 72.55 (4t, 4 PhCH2). HR-MALDI-MS: 564.2769 ([M À CON3 ‡ H] ,
‡
‡
‡
C36H38NO5 ; calc. 564.2750), 586.2589 ([M À CON3 ‡ Na] , C36H37NNaO5 ; calc. 586.2569), 629.2649 ([M À
‡
‡
N2 ‡ Na] , C37H38N2NaO6 ; calc. 629.2628).
tert-Butyl [(1S,2'S)-Spiro[1,5-anhydro-d-mannitol-1,1'-cyclopropane]-2'-yl]carbamate (18a). Hydrogena-
tion of 17a (155 mg, 0.23 mmol) in MeOH (15 ml) containing 10% Pd/C (75 mg) at 6 bar for 12 h, filtration
through Celite, and evaporation gave a colourless oil. Dissolution of the oil in H2O (10 ml), filtration through
Celite, and lyophilisation gave 18a (69 mg, quant.). Colourless hygroscopic solid. Rf (MeOH/AcOEt 1:4) 0.51.
[a]2D5 ˆ 44.7 (c ˆ 1 , HO). IR (KBr): 3389s (br.), 2977m, 2930m, 1682s, 1537m, 1505m, 1455m, 1393m, 1367s,
2
1251s, 1168s, 1069s (br.), 974w. 1H-NMR (D2O): see Table 11; additionally, 1.42 (s, Me3C). 13C-NMR (D2O): see
‡
Table 9; additionally, 161.89 (s, CˆO); 84.46 (s, Me3C); 30.30 (q, Me3C). ESI-MS: 633 (28, [2M ‡ Na] ), 328
‡
‡
(26, [M ‡ Na] ), 323 (53, [M ‡ NH4] ), 279 (28), 180 (35), 50 (100). Anal. calc. for C13H23NO7 ¥ H2O (323.34):
C 48.27, H 7.79, N 4.33; found: C 48.29, H 7.38, N 4.22.
tert-Butyl [(1R,2'R)-Spiro[1,5-anhydro-d-mannitol-1,1'-cyclopropane]-2'-yl]carbamate (18b). As de-
scribed above, hydrogenation of 17b (135 mg, 0.20 mmol) in MeOH (10 ml) containing 10% Pd/C (72 mg) at
6 bar for 10 h gave 18b (52 mg, 84%). Colourless hygroscopic solid. Rf (MeOH/AcOEt 1:4) 0.39. [ a]2D5 ˆ 73.0
(c ˆ 1 , HO). IR (KBr): 3378s (br.), 2977m, 2931m, 1694s, 1519m, 1455m, 1393m, 1367s, 1282m, 1254m, 1223m,
2

Helvetica Chimica Acta Vol. 86 (2003)
3027
1168s, 1095m, 1085m, 1066s, 1023m, 976w, 934w. 1H-NMR (D2O, 508): see Table 11; additionally, 1.46 (s, Me3C).
13C-NMR (D2O): see Table 9; additionally, 159.01 (s, CˆO); 80.47 (s, Me3C); 28.78 (q, Me3C). ESI-MS: 633 (84,
‡
‡
‡
[2M ‡ Na] ), 328 (49, [M ‡ Na] ), 323 (33, [M ‡ NH4] ), 279 (28), 213 (53), 65 (100). Anal. calc. for
C13H23NO7 ¥ 0.5 H2O (314.33): C 49.67, H 7.70, N 4.46; found: C 50.08, H 7.49, N 4.34.
tert-Butyl [(1S,2'R)-Spiro[1,5-anhydro-d-mannitol-1,1'-cyclopropane]-2'-yl]carbamate (18c). Hydrogena-
tion of 17c (120 mg, 0.18 mmol) in MeOH (10 ml) containing 10% Pd/C (60 mg) at 6 bar for 18 h gave 18c
(52 mg, 94%). Colourless hygroscopic solid. Rf (MeOH/AcOEt 1:4) 0.48. [ a]2D5 ˆ 16.0 (c ˆ 1 , HO). IR (KBr):
2
3382s (br.), 2978m, 2932m, 2873w, 1698s, 1519m, 1455m, 1393m, 1367s, 1272m, 1254m, 1170s, 1099m, 1063s,
1028m, 852w. 1H-NMR (D2O): see Table 11; additionally, 1.48 (s, Me3C).13C-NMR (D2O): see Table 9;
‡
additionally, 161.96 (s, CˆO); 84.34 (s, Me3C); 30.30 (q, Me3C). ESI-MS: 633 (20, [2M ‡ Na] ), 328 (48, [M ‡
‡
‡
Na] ), 323 (49, [M ‡ NH4] ), 279 (62), 50 (100). Anal. calc. for C13H23NO7 ¥ 0.5 H2O (314.33): C 49.67, H 7.70, N
4.46; found: C 49.60, H 7.33, N 4.29.
tert-Butyl [(1R,2'S)-Spiro[1,5-anhydro-d-mannitol-1,1'-cyclopropane]-2'-yl]carbamate (18d). Hydrogena-
tion of 17d (220 mg, 0.33 mmol) in MeOH (15 ml) containing 10% Pd/C (110 mg) at 6 bar for 12 h,
concentration and reversed-phase chromatography (C18-RP packing material (Fluka, cat. no. 60757), MeOH/
H2O 1 :9! 1:4) gave 18d (91mg, 90%). Colourless hygroscopic solid. Rf (MeOH/AcOEt 1:4) 0.42. [a]D25
ˆ
À57.5 (c ˆ 0.8, H2O). IR (KBr): 3380s (br.), 3312s, 2978w, 2935w, 2880w, 1690s, 1519m, 1459w, 1420w, 1391w,
1364m, 1275m, 1255m, 1162s, 950w, 91 w6, 870w. 1H-NMR (D2O, 608): see Table 11; additionally, 1.43
(br. s, Me3C). 13C-NMR (D2O): see Table 9; additionally, 161.63 (s, CˆO); 84.11 (s, Me3C); 30.30 (q, Me3C).
‡
‡
‡
ESI-MS: 633 (46, [2M ‡ Na] ), 328 (40, [M ‡ Na] ), 323 (32, [M ‡ NH4] ), 279 (52), 213(53), 50 (100). Anal.
calc. for C13H23NO7 ¥ 0.5 H2O (314.33): C 49.67, H 7.70, N 4.46; found: C 50.07, H 7.67, N 4.42.
(1S,2'S)-Spiro[1,5-anhydro-d-mannitol-1,1'-cyclopropane]-2'-ammonium Chloride (2a). Treatment of 18a
(22 mg, 0.072 mmol) with 1n HCl (0.5 ml) for 15 min, addition of MeOH (5 ml) and evaporation, dissolution in
H2O (1ml), filtration through a small cotton plug, and lyophilisation gave 2a (17 mg, quant.). Colourless
hygroscopic solid. pKHA ˆ 6.7 (H2O). 1H-NMR (D2O): see Table 11. 13C-NMR (D2O): see Table 9. ESI-MS: 433
‡
‡
‡
(28, [2M À 2 HCl ‡ Na] ), 228 (24, [M À HCl ‡ Na] ), 206 (45, [M À Cl] ), 180 (88), 97 (32), 82 (50), 50 (100).
(1R,2'R)-Spiro[1,5-anhydro-d-mannitol-1,1'-cyclopropane]-2'-ammonium Chloride (2b). Treatment of 18b
(20 mg (0.065 mmol)) with 1n HCl (0.5 ml) for 15 min, addition of MeOH (5 ml), and evaporation, dissolution
in H2O (1ml), filtration through a small cotton plug, and lyophilisation gave 2b (14 mg, ca. 90%). Pale brown
hygroscopic solid. pKHA ˆ 6.7 (H2O). 1H-NMR (D2O): see Table 11. 13C-NMR (D2O): see Table 9. ESI-MS: 433
‡
‡
‡
(40, [2M À 2 HCl ‡ Na] ), 228 (14, [M À HCl ‡ Na] ), 206 (95, [M À Cl] ), 180 (60), 97 (42), 82 (65), 50 (100).
Anal. calc. for C8H16ClNO5 ¥ 1.33 H2O (265.62): C 36.17, H 7.08, N 5.27; found: C 36.31, H 7.44, N 4.93.
(1S,2'R)-Spiro[1,5-anhydro-d-mannitol-1,1'-cyclopropane]-2×-ammonium Chloride (2c). Treatment of 18c
(22 mg, 0.072 mmol) with 1n HCl (0.5 ml) for 15 min, addition of MeOH (5 ml), evaporation, dissolution in H2O
(1ml), filtration through a small cotton plug, and lyophilisation gave 2c (17 mg, quant.). Colourless hygroscopic
solid. pKHA ˆ 7.8 ( H2O). 1H-NMR (D2O): see Table 11. 13C-NMR (D2O): see Table 9. ESI-MS: 433 (30, [2M À
‡
‡
‡
2 HCl ‡ Na] ), 279 (64), 228 (30, [M À HCl ‡ Na] ), 206 (64, [M À Cl] ), 180 (80), 97 (12), 82 (3), 50 (100).
Anal. calc. for C8H16ClNO5 ¥ 1.33 H2O (265.62): C 36.17, H 7.08, N 5.27; found: C 36.54, H 7.08, N 5.01.
(1R,2'S)-Spiro[1,5-anhydro-d-mannitol-1,1'-cyclopropane]-2'-ammonium Chloride (2d). Treatment of 18d
(25 mg, 0.082 mmol) with 1n HCl (0.5 ml) for 15 min, addition of MeOH (5 ml), evaporation, dilution with H2O
(1ml), filtration through a small cotton plug, and lyophilisation gave 2d (19 mg, quant.). Pale-brown-coloured
hygroscopic solid. pKHA ˆ 7.7 ( H2O). 1H-NMR (D2O): see Table 11. 13C-NMR (D2O): see Table 9. ESI-MS: 433
‡
‡
‡
(52, [2M À 2 HCl ‡ Na] ), 228 (38, [M À HCl ‡ Na] ), 206 (65, [M À Cl] ), 180 (22), 97 (30), 82 (30), 50 (100).
Anal. calc. for C8H16ClNO5 ¥ 2.5 H2O (286.71): C 33.51, H 7.38, N 4.89; found: C 33.78, H 7.18, N 4.72.
2-O-Acetyl-3,4,6-tri-O-benzyl-d-mannono-1,5-lactone (21). A soln. of 3,4,6-tri-O-benzyl-1,2-O-(methoxy-
ethylidene)-b-d-mannopyranose [76] (2 g, 3.95 mmol) in AcOH/H2O 3 :2 (100 ml) was stirred at 238 for 16 h,
evaporated, and co-evaporated with toluene [77][78]. A soln. of the residue (1.94 g of crude 20) in CH2Cl2
(80 ml) was treated with 4-ä molecular sieves (2 g) and pyridinium chlorochromate (PCC; 2.6 g, 12.1 mmol),
and stirred at 238 for 14 h. Filtration through a small silica-gel column (hexane/Et2O 1:1) and evaporation gave
21 (1.53 g 79%). Colourless solid. M.p. 75 768 (Et2O/hexane). Rf (AcOEt/hexane 1:3) 0.28. [ a]2D5 ˆ 54.5 (c ˆ 2,
CHCl3). IR (CHCl3): 3067m, 3008m, 2975w, 2927m, 2867m, 1781s, 1752s, 1606w, 1586w, 1496m, 1454s, 1386m,
1370s, 1339m, 1309w, 1091s, 1073s, 1028m, 91 5w, 835w. 1H-NMR (300 MHz, CDCl3): 7.39 7.15 (m, 15 arom. H);
5.64 (d, J ˆ 2.8, irrad. at 4.06 ! s, HÀC(2)); 4.70 (d, J ˆ 12.1, PhCH); 4.59 (d, J ˆ 12.5, PhCH); 4.57 (d, J ˆ 12.1,
PhCH); 4.51( d, J ˆ 11.8, PhCH); 4.41( td, J ꢀ 4.2, 7.2, irrad. at 3.67 ! d, J ˆ 6.3, irrad. at 3.90 ! t, J ˆ 4.7,
HÀC(5)); 4.41( d, J ˆ 11.5, PhCH); 4.31( d, J ˆ 12.5, PhCH); 4.06 (dd, J ˆ 1.6, 2.8, irrad. at 5.64! d, J ˆ 1.3,
HÀC(3)); 3.90 (dd, J ꢀ 1.4, 7.0, irrad. at 4.06! d, J ˆ 6.9, irrad. at 4.41 ! d, J ˆ 1.4, HÀC(4)); 3.68 3.66