Towards the synthesis of 1-deoxy-1-nitropiperidinoses

Article abstract of DOI:10.1002/hlca.201000326

In the course of the first of several attempts to elaborate methods for the synthesis of 1-nitropiperidinoses, lincosamine was transformed into lactam 6 via hemiacetal 1, lactone 2, amide 3, oxo amide 4, and its cyclic tautomer 5. Treatment of the N-Boc-protected lactam oxime 9, obtained from lactam 6, with brominating agents failed to provide the bromonitroso carbamate 10. The N-Boc-protected lactam 13 derived from 6 was reduced to hemiacetal 14, but the corresponding N-Boc-aminooxime did not tautomerise to the C(1)-hydroxylamine, and nitrone 17, a potential precursor of the nitropiperidine 12, was not formed. Oxidation of the anomeric azide 20 with HOF·MeCN failed to provide the expected nitropiperidine 21. The phosphinimines 22 derived from 20 did not react with O₃. In the next approach to 1-nitropiperidinoses, we treated the N-Boc-protected hemiacetal 25, obtained from the known gluconolactam 23 with N-benzylhydroxylamine. The resulting nitrone 26 exits in equilibrium with the anomeric N-benzyl-glycosylhydroxylamine that was oxidized to the anomeric nitrone 28. Ozonolysis of 28 led to the hemiacetal 25, resulting from the desired, highly reactive protected nitropiperidinose 29, that was evidenced by an IR band at 1561 cm^-1. Similarly to the synthesis of nitrone 26, reaction of the N-tosyl-protected hemiacetal 31 with N-benzylhydroxylamine and oxidation provided the anomeric N-benzylhydroxylamines 33 via the p-toluenesulfonamido nitrone 32. Their oxidation with MnO₂ led to the anomeric nitrone 34. Ozonolysis of 34 as evidenced by ¹H-NMR and ReactIR spectroscopy led to the highly reactive nitropiperidinose 35. Like 29, 35 was transformed during workup, and only the hemiacetal 31 was isolated. The similarly prepared lincosamine-derived nitrone 17 was subjected to ReactIR-monitored ozonolysis that evidenced the formation of the protected nitropiperidinose 12, but only led to the isolation of 14. The facile transformation of the nitropiperidinoses to hemiacetals is rationalised by heterolysis of the anomeric C,N bond, recombination of the ion pair, and denitrosation of the resulting anomeric nitrite by a nucleophile. Attempts to convert the 1-deoxy-1-nitropiperidinose 35 to uloses 43 by base-catalysed Michael additions or Henry reactions were unsuccessful.

Full text of DOI:10.1002/hlca.201000326

Helvetica Chimica Acta – Vol. 93 (2010)
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Towards the Synthesis of 1-Deoxy-1-nitropiperidinoses
by Marie-Pierre Collin and Andrea Vasella*
Laboratorium fꢀr Organische Chemie, ETH Zꢀrich, HCI, Wolfgang Pauli-Strasse 10, CH-8093 Zꢀrich
(e-mail: vasella@org.chem.ethz.ch)
In the course of the first of several attempts to elaborate methods for the synthesis of 1-
nitropiperidinoses, lincosamine was transformed into lactam 6 via hemiacetal 1, lactone 2, amide 3, oxo
amide 4, and its cyclic tautomer 5. Treatment of the N-Boc-protected lactam oxime 9, obtained from
lactam 6, with brominating agents failed to provide the bromonitroso carbamate 10. The N-Boc-
protected lactam 13 derived from 6 was reduced to hemiacetal 14, but the corresponding N-Boc-
aminooxime did not tautomerise to the C(1)-hydroxylamine, and nitrone 17, a potential precursor of the
nitropiperidine 12, was not formed. Oxidation of the anomeric azide 20 with HOF · MeCN failed to
provide the expected nitropiperidine 21. The phosphinimines 22 derived from 20 did not react with O3. In
the next approach to 1-nitropiperidinoses, we treated the N-Boc-protected hemiacetal 25, obtained from
the known gluconolactam 23 with N-benzylhydroxylamine. The resulting nitrone 26 exits in equilibrium
with the anomeric N-benzyl-glycosylhydroxylamine that was oxidized to the anomeric nitrone 28.
Ozonolysis of 28 led to the hemiacetal 25, resulting from the desired, highly reactive protected
nitropiperidinose 29, that was evidenced by an IR band at 1561 cmꢀ1. Similarly to the synthesis of nitrone
26, reaction of the N-tosyl-protected hemiacetal 31 with N-benzylhydroxylamine and oxidation provided
the anomeric N-benzylhydroxylamines 33 via the p-toluenesulfonamido nitrone 32. Their oxidation with
MnO2 led to the anomeric nitrone 34. Ozonolysis of 34 as evidenced by 1H-NMR and ReactIR
spectroscopy led to the highly reactive nitropiperidinose 35. Like 29, 35 was transformed during workup,
and only the hemiacetal 31 was isolated. The similarly prepared lincosamine-derived nitrone 17 was
subjected to ReactIR-monitored ozonolysis that evidenced the formation of the protected nitro-
piperidinose 12, but only led to the isolation of 14. The facile transformation of the nitropiperidinoses to
hemiacetals is rationalised by heterolysis of the anomeric C,N bond, recombination of the ion pair, and
denitrosation of the resulting anomeric nitrite by a nucleophile. Attempts to convert the 1-deoxy-1-
nitropiperidinose 35 to uloses 43 by base-catalysed Michael additions or Henry reactions were
unsuccessful.
Introduction. – 1-Deoxy-1-nitropiperidinoses, carbohydrates where the ring O-
atom of a nitropyranose is replaced by an NH or NR group, are not known. These
nitropiperidinoses should be deprotonated under mild conditions, without b-elimina-
tion, resulting in an inversion of polarity. This should allow elongating the C-chain at
the anomeric centre by a Michael addition, or reaction with an aldehyde, similarly as it
is known for 1-deoxy-1-nitropyranoses [1 – 4]. It appeared necessary to protect the ring
N-atom of nitropiperidinoses by a strong p- and s-acceptor substituent to prevent the
intrinsically facile heterolysis of the anomeric C,N bond, generating a nitrite anion and
an immonium cation. An even more readily occurring solvolysis of a chain-elongated,
N-protected nitropiperidine should allow introduction of a second substituent at the
anomeric centre, viz., a hetero-nucleophile, or a C-nucleophile derived from a weakly
basic carbanion, as in a Kornblum reaction [5]. Thus, 1-deoxy-1-C-nitropiperidinoses
ꢁ 2010 Verlag Helvetica Chimica Acta AG, Zꢀrich

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possess a high potential for the synthesis of a variety of piperidinoses modified at C(1)
and C(2), the introduction of substituents at the ring N-atom adding a further
dimension of diversity.
Naturally occurring [6] and synthetic piperidinose derivatives, and other saccharide
mimics possessing a ring N-atom, such as pyrrolidines, indolizidines, pyrrolizidines, and
nortropanes, with nojirimycin and deoxynojirimycin as prototypes, were thoroughly
studied as glycosidase inhibitors [7], and their chemistry has been reviewed periodi-
cally [6][8]. A range of biological properties of piperidinoses and other N-containing
sugars are known, beyond their activity as glycosidase inhibitors [9].
For these reasons, we considered it worthwhile to explore the synthesis and
transformations of 1-deoxy-1-nitropiperidinoses, in spite of the obvious obstacle of the
facile solvolysis of the anomeric C,N bond. We had a particular interest in exploring
their application to the synthesis of novel lincomycin analogues [10][11]. In spite of the
need for new antibiotics, pyranosyl moieties of carbohydrate-derived antibiotics have
not, to the best of our knowledge, been replaced by piperidinosyl analogues. Chain-
elongated, piperidine-derived analogues of lincomycin appeared attractive. Molecular
modelling1) of the crystal structure of the 50S ribosomal subunit of the eubacterium
Deinococcus radiodurans [12] in complex with clindamycin revealed a cavity around
C(1) that allows introducing two substituents at the anomeric centre besides replacing
C(5)ꢀO by a C(5)ꢀNH or NR group (R ¼ alkyl, acyl, sulfonyl).
We planned to prepare such lincomycin analogues via an intermediate nitro-
piperidinose, to be synthesized by analogy to the known methods for the preparation of
nitropyranoses [1][2]. The first route should proceed via an N-Boc-protected lincos-
amine-derived 1,5-lactam. We considered that the transformation of such a lactam into
the corresponding hydroximolactam [13], followed by treatment with Br2, oxidation of
the intermediate bromo-nitroso carbamate to the bromo-nitro carbamate, and
debromination should lead to the desired N-Boc-protected nitropiperidines. According
to the alternative route [3], we planned to reduce the N-Boc-protected lactam to an N-
protected piperidinose and transform it into an N-(acylamino)-alkylnitrone. Ozono-
lysis of this nitrone should lead to an N-Boc-protected nitropiperidinose.
Synthesis. – Following the first of the above mentioned methods for the synthesis of
nitropyranoses, we prepared the required lincosamine-derived lactam 6 (Scheme 1)
from the known protected galacto-octopyranose 1 [11] according to a method
developed by our group [13][14] and by others [15][16]. Oxidation of 1 with Dess –
Martinꢂs periodinane led to the lactone 2. Ammonolysis of crude 2 gave amide 3 that
was oxidized with Dess – Martinꢂs periodinane to the oxo amide 4. In situ acid-catalysed
tautomerisation to 5 and reduction with NaCNBH3 led to the desired lactam 6. It was
purified by column chromatography, and obtained as a colourless oil in 60% overall
yield on a 30-g scale.
To prepare the required lactam-oxime intermediate 9 (Scheme 2; cf. [13][17]), we
treated lactam 6 with Lawessonꢂs reagent. The expected thiolactam 7 was isolated
in a yield of 75%. N-Boc Protection of 7, followed by treatment of the resulting
1
)
Molecular modelling was performed using the Moloc program. We thank Paul Gerber, Gerber
Molecular Design, for access to the programme.

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Scheme 1
a) Dess – Martinꢂs periodinane, CH2Cl2. b) NH3, CH2Cl2, ꢀ 408 to 258. c) HCO2H, NaBH3CN, MeCN,
708; 58% from 1.
Scheme 2
a) Lawessonꢂs reagent, toluene, 608; 75%. b) Boc2O, 4-(Dimethylamino)pyridine (DMAP), CH2Cl2. c)
NH2OH · HCl, NaHCO3, MeOH; 90% from 7. d) Conditions tried: 1. Br2, NaOH, 08; 2. Br2, Py, ꢀ 788 to
258; 3. N-bromoacetamide, ZnO, H2O, CH2Cl2, 258; 4. N-bromosuccinimide, NaHCO3, CH2Cl2, H2O,
258; 5. oxone, KBr, Alox, CHCl3, 458 to reflux.
N-Boc-thiolactam 82) with NH2OH · HCl yielded 90% of the lactam oxime 9
(Scheme 2).
The coupling constants for the pyranose ring of lactone 2, lactam 6, thiolactam 7,
and lactam oxime 9 in CDCl3 solution, compiled in Table 1 (Exper. Part), evidence for
4
all these compounds a preferred C1 conformation. The equatorial orientation of the
2
)
Attempts to isolate thiolactam 8 resulted in decomposition; it was used directly for the synthesis of
9.

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side chain of the N-Boc-protected lactam oxime 9 is surprising in view of the allylic
strain [18]. It is tempting to rationalise the ring conformation of 9 by postulating a (Z)-
configuration and an intramolecular H-bond to the N-alkoxy carbonyl group. There is,
however, no evidence for this H-bond, and the related N-Boc-protected piperidines 18
and 19 (see below Scheme 4) that cannot form such a H-bond (and possess an axial
C(1)OAc group) also adopt a 4C1 conformation.
We had expected bromination of 9 to yield the bromo-nitroso intermediate 10 that
we intended to oxidize to the bromo-nitro carbamate 11 and then debrominate to the
desired nitropiperidine 12. Unfortunately, all attempts to transform 9 into the bromo-
nitroso carbamate 10 (Scheme 2) failed to provide the desired product. Although 9 was
consumed, TLC revealed a complex mixture of products that could not be separated.
No blue or blue-green colour characteristic of nitroso compounds was ever observed,
and the IR spectrum of the reaction mixture did not show any nitroso band at
1560 cmꢀ1.
In a second approach, we first aimed at transforming the N-Boc-protected lactam 13
to one of the nitrones 17x (Scheme 3). N-Boc protection of lactam 6 yielded 80% of the
desired 13 that was reduced with Super-Hydrideꢃ to the N,O-hemiacetal 14. Treating 14
with NH2OH · HCl led to a 7:3 (E/Z)-mixture of the N-Boc-protected amino oximes
153) (85% from 13).
Scheme 3
a) Boc2O (Boc ¼ (tert-butoxy)carbonyl), DMAP, ClCH2CH2Cl, 708; 80%. b) Super-Hydrideꢃ (1.0m
LiEt3BH in THF), THF. c) NH2OH · HCl, NaHCO3, EtOH; 85% from 13.
1
The H-NMR spectrum of the N-Boc-protected lactam 13 in CDCl3 shows a W
coupling of 1.5 Hz between HꢀC(3) and HꢀC(5). Together with the other relevant
coupling constants (Table 1 in Exper. Part), this suggests a conformational equilibrium
with contributions of E4, 3H4, and 2S4. The configuration of 14 is evidenced by the J(1,2)
value of 3.6 Hz and the downfield shift of HꢀC(5); the ring conformation is close to 4C1.
The 1H-NMR spectrum of 15 in (D6)DMSO at 1008 shows the HꢀC(1) signal of the (E)-oxime at d
7.44 ppm (d, J ¼ 7.5 Hz, 0.7 H), while HꢀC(1) of the (Z)-oxime resonates at 6.95 ppm (d, J ¼
3
)
1
6.5 Hz, 0.3 H). The H-NMR spectrum did not show any signal of the cyclic tautomer 16.

Helvetica Chimica Acta – Vol. 93 (2010)
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The oximes 15 did not react with benzaldehyde, 4-chlorobenzaldehyde, or the more
highly electrophilic 4-nitrobenzaldehyde under neutral, acidic, or basic conditions to
form a desired nitrone 17x. It appeared that the N-Boc protecting group significantly
reduced the nucleophilicity of the N-atom, preventing tautomerisation to the cyclic
hydroxylamine 16 and condensation with the aldehydes.
In view of this result, we modified our approach. Recently, Carmeli and Rozen have
described the oxidation of alkyl azides to NO2 derivatives by a HOF · MeCN complex
[19]. To apply this method to lincosamine, we had to replace the N3 group at C(6) by a
NHCbz group, and to synthesise glycosyl azide 20 as precursor of the desired nitro
derivative (Scheme 4). Azide 20 was prepared from lactam 13 that was reduced to the
N,O-hemiacetal, and acetylated to yield 90% of 18 (Scheme 4). This azido acetate was
reduced with propane-1,3-dithiol in a pyridine/Et3N/H2O mixture [20], and the
resulting amine was N-(benzyloxy)carbonylated to 19 (75%). Treatment of 19 with
1
TMS-N3 and BF3 · OEt2 [21] yielded 83% of the glycosyl azides 20. The H-NMR
spectra of 18 and 19 in (D6)DMSO evidence a very similar 4C1 conformation. The a-d-
configuration of 18 and 19 was deduced from J(1,2) ¼ 4.2 Hz, while the spectrum of 20
in (D6)DMSO, recorded at 1008, evidenced a mixture of rotamers that precluded the
determination of the anomeric configuration.
Scheme 4
a) 1. Super-Hydrideꢃ, THF, 08; 2. Ac2O, DMAP, Et3N, CH2Cl2; 90%. b) 1. Propane-1,3-dithiol, Et3N, Py,
H2O; 2. CbzCl (Cbz ¼ (benzyloxy)carbonyl), Et3N, CH2Cl2; 75%. c) Me3SiN3 (TMS-N3), BF3 · OEt2,
CH2Cl2; 83%. d) HOF · MeCN, CHCl3.
Numerous attempts to oxidise azide 20 with HOF · MeCN failed to provide the
desired nitro derivative 21. Analysis of the reaction mixture by IR spectroscopy did not
show the characteristic bands of a NO2 group at 1560 and at 1360 cmꢀ1.
Our next approach to the desired 1-nitropiperidinose was based upon the
ozonolysis of phosphimines, according to a method reported by Corey et al. [22].
Me3P or Ph3P transformed the azide 20 to the methyl and phenyl phosphimines 22a and
22b, respectively. Solutions of the phosphimines in MeOH or CH2Cl2 were treated with
O3, and the reaction was followed by IR spectroscopy, monitoring the disappearance of
the N3 band at 2102 cmꢀ1. However, under these reaction conditions the phosphimines
22 did not react with O3 (Scheme 5).

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Scheme 5
a) R3P (R ¼ Me, Ph), THF. b) O3, CH2Cl2 or MeOH, ꢀ 788.
To avoid a conceivable influence of the galacto-configuration upon our attempts of
obtaining 1-nitropiperidinoses (cf. [23]), it appeared commendable to explore further
methods using the known 2,3,4,6-tetra-O-benzyl-gluconolactam 23 [14] (Scheme 6).
We aimed at treating the known N,O-hemiacetal 25 [24], obtained by reduction of the
N-protected gluconolactam 24, with BnNHOH · HCl to obtain an open-chain nitrone
26. This nitrone is significantly more highly electrophilic than oxime 15, and should thus
equilibrate with its cyclic tautomer, the N-Bn-hydroxylamine 27 (Scheme 6) that we
hoped to oxidise to the cyclic nitrone 28 and further to the desired nitropiperidinose 29.
Scheme 6
a) Boc2O, DMAP, MeCN; 88% [24]. b) NaBH4, 1n HCl to pH 6, EtOH; 75% [24]. c) BnNHOH, Py, 608;
80%. d) MnO2, ClCH2CH2Cl, reflux; 90%. e) O3, CH2Cl2, ꢀ 788.
The protected N,O-hemiacetal 25 was prepared from the O-benzylated glucono-
lactam 23 by N-Boc protection (88%), followed by reduction with NaBH4 at pH 6 in
75% yield [24] (Scheme 6). Reaction of 25 with BnNHOH in dry pyridine yielded 75%
of a 1:1 mixture of the open-chain nitrone 26 and its cyclic tautomer, hydroxylamine 27
[25 – 27]4). Treatment of the mixture 26/27 with MnO2 oxidised 27 to the cyclic nitrone
28 that was isolated in a yield of 90%, evidencing the shift of the equilibrium 26 > 27
towards the N-benzyl hydroxylamine 27. Not surprisingly, oxidation of 27 involves the
benzylic CH2 group, as reported for similar compounds [28]. The b-d-configuration of
1
4
)
Sharp H-NMR signals were observed in (D6)DMSO at 1008. Under these conditions, only signals
for 27 were observed.

Helvetica Chimica Acta – Vol. 93 (2010)
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the anomeric centre and the (Z)-configuration of the nitrone were established by X-ray
crystal structure analysis; the conformation will be discussed below. As expected, the
1
broad peaks in the H-NMR spectra of the carbamate 28 (in CDCl3) at ambient
1
temperature reveal the presence of rotamers. Sharp H-NMR signals of 28 were
1
observed only at 1008 in (D6)DMSO. Although the H-NMR spectra of the reaction
mixture resulting from ozonolysis at ꢀ 788 did not show sharp peaks, we refrained from
recording the spectra at a higher temperature, considering the presumed facile
solvolysis of the expected 1-nitropiperidinoses. The only isolated products obtained by
ozonolysis of 28 at ꢀ 788 are indeed the known N,O-hemiacetals 25 [24] suggesting that
the 1-nitropiperidinose 29 was formed, but rapidly solvolysed upon warming to ambient
temperature and/or during workup.
The conformation of the anomers of 25 – the B3,N conformation of the a-d anomer
is shown in Scheme 6 – was determined before [24].
Crystals of the N-Boc-protected nitrone 28 were obtained by slow evaporation of a
solution in MeOH/H2O, and their structure was established by X-ray analysis5) (Fig.),
2
revealing the b-d- and (Z)-configuration, and the SN conformation that lifts the
oxyimino and the substituent at C(5) out of the plane of the N-Boc group and is also
preferred in CDCl3 solution.
Figure. Ball-and-stick representation of the crystal structure of the nitrone 28
1
As it proved difficult to in situ analyse the product of ozonolysis by H-NMR
spectroscopy, we monitored the ozonolysis of nitrone 28 by ReactIR at ꢀ 788. The IR
spectrum of the N-Boc-protected nitrone 28 is characterised by a band at 1717 cmꢀ1,
typical of a carbamoyl group, while the N¼CH nitrone band (at ca. 1600 cmꢀ1) was
weak, so that the reaction could not be monitored by following the disappearance of
this band. Formation of the N-Boc-protected (presumably b-d-configured) 1-nitro-
piperidinose 29 is, however, supported by the appearance of a band at 1568 cmꢀ1,
characteristic of a NO2 group, and of a C¼O band at 1701 cmꢀ1 assigned to PhCHO.
5
)
The crystallographic data have been deposited with the Cambridge Crystallographic Data Centre as
deposition No. CCDC-699259. Copies of the data can be obtained free of charge via http://
www.ccdc.cam.ac.uk/data_request/cif (or from the CCDC, 12 Union Road, Cambridge CB21EZ
(fax: þ 44(1223)336033; e-mail: deposit@ccdc.cam.ac.uk).

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Helvetica Chimica Acta – Vol. 93 (2010)
The difficulty of analysing the product of ozonolysis by 1H-NMR spectroscopy (on
account of the rotamers) and the facile solvolysis of the bona fide 29 showed that the
Boc group is not an appropriate N-protecting group. It was, therefore, substituted by
the Ts group, although it has been evidenced that a N-sulfonyl group is rather a weaker
electron acceptor than a N-carbonyl group [29]. The Ts group has, however, the
advantage of not giving rise to discernible rotamers.
The O-benzylated gluconolactam 23 was N-tosylated by treatment with BuLi and
TsCl [21] to yield 77% of the N-Ts lactam 30 (Scheme 7). Similarly as described for the
Boc-protected gluconolactam 24 (Scheme 6), 30 was reduced with DIBAL-H to the
N,O-hemiacetals 31 (85%). The reaction of 31 with BnNHOH in dry pyridine (cf.
[25][26][28]) provided, after filtration through silica gel, mostly a ca. 3 :1 b-d/a-d-
mixture of the anomeric hydroxylamines a-33/b-33 and small amounts of the open-
chain nitrone 32 that correlated with a very polar spot on the TLC. The interpretation
of the 1H-NMR spectrum of the mixture 32/33 is based on J(1,2) of 2.0 Hz for the major
(b-d), and of 7.2 Hz for the minor (a-d) isomer, evidencing a flattening of the chair for
b-33. One large (8.0 Hz) and one small (2.0 Hz) J(5,6) value of b-33 is in agreement
with a pseudoaxial CH2OBn group, shifted to higher fields by the toluyl group. The
minor a-33 is characterized by two similar J(5,6) values, denoting an equatorial
CH2OBn group. Both HꢀC(1) are equatorial, and thus shifted to lower field.
Scheme 7
a) BuLi, TsCl, DMAP, THF, ꢀ 788 to 08; 77%. b) Diisobutylaluminum hydride (DIBAL-H), toluene, 08;
85%. c) BnNHOH, Py, 1008. d) MnO2, ClCH2CH2Cl, reflux; 78% from 30. e) O3, CH2Cl2, ꢀ 788.
By comparison to the N-Boc-protected analogues 26/27, the nitrone > hydroxyl-
amine equilibrium, 32 > 33, is displaced in favour of 33, in agreement with the weaker
electron-acceptor properties of the Ts group (cf. [29]) and, conceivably, less-
destabilizing steric interactions. Oxidation of the mixture 32/33 with MnO2 [28] led
to the cyclic nitrone 34 in a yield of 78%.
Similarly as in the N-Boc-protected series, the pyranose ring of the N-Ts lactam 30
exists as mixture of equilibrating 3H4 and 2SN conformers, as evidenced by the coupling
constants (Table 2 in Exper. Part) and particularly by the W coupling (J ¼

Helvetica Chimica Acta – Vol. 93 (2010)
2305
1.5 Hz) between HꢀC(3) and HꢀC(5). The preferred conformation of the N-Ts
nitrone 34 is 2SN, avoiding the allylic strain resulting from destabilizing interactions of
the N-Ts group with an equatorial side chain at C(5) and the equatorial nitronyl
substituent. The pyranose ring of a-d-31 in CDCl3 adopts a B3,N conformation, as
depicted in Scheme 7, while b-d-31 most likely adopts a conformational equilibrium
1
between C4 and B3,N. The large J(1,OH) value of 11.8 Hz suggests an intramolecular
H-bond with the pseudoaxial C(3)OBn group of the 1C4 and the C(6)OBn group of the
B3,N conformer.
Ozonolysis of the N-Ts nitrone 34 at ꢀ 788 in CH2Cl2 led to the N,O-hemiacetals 31,
similarly as observed for the N-Boc-protected analogue 28, again suggesting that a 1-
nitropiperidinose (35) was formed in situ, but solvolysed upon increasing the
1
temperature. Ozonolysis of 34 in CD2Cl2 at ꢀ 788 was thus monitored by H-NMR
spectroscopy, starting at ꢀ 788 and slowly raising the temperature to ꢀ 108. The b-d-
nitrone 34 was characterized by a chemical shift for HꢀC(1) of 5.45 ppm (J(1,2) ¼
7.9 Hz), while the HꢀC(1) signal of the ozonolysis product at ꢀ 108 was shifted
downfield by 0.6 ppm (d 6.05 ppm, J(1,2) ¼ 3.6 Hz), and evidenced that a single
product was formed. This chemical shift is in agreement with those observed for
nitropyranoses [1][3]. J(1,2) of 3.6 Hz for the 1-nitropiperidinose 35 evidences either
2
1
that the conformation of the piperidinose ring changed from SN towards C4, or that
the expected 1-nitropiperidinose isomerised to the a-d-anomer. No signal of the
hydrolysis product 31 of 35 was observed up to ꢀ 108, indicating that the 1-
nitropiperidinose 35 is stable up to that temperature. Solvolysis appears to occur upon
warming to ambient temperature. The ozonolysis of the N-tosyl nitrone 34 was also
followed by ReactIR. A comparison of the IR spectra of the nitrone and of the
ozonolysis mixture revealed new bands of both the NO2 group (1569 cmꢀ1) and the
C¼O group of PhCHO (1701 cmꢀ1).
The method developed for the synthesis of 1-nitropiperidinoses from gluconolac-
tam 23 was then tested on the N-Boc-protected N,O-hemiacetal 14 derived from
lincomycin (Scheme 8). The hemiacetal 14 reacted with BnNHOH in BuOH to give
exclusively nitrone 36 as a single isomer in 90% yield. Attempted oxidation of 36 with
Scheme 8
a) BnNHOH, BuOH, 808; 90%. b) LiI, PbO2, Py, toluene, 608; 63%. c) O3, CH2Cl2, ꢀ 788.

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MnO2 in refluxing ClCH2CH2Cl did not lead to the desired cyclic nitrone 17, and
starting material was recovered. We had to conclude that, under these reaction
conditions, nitrone 36 did not cyclise to the cyclic hydroxylamine 37. To favour the
cyclisation, we explored activating 36 with a Lewis acid [30]. Treatment of 36 with
MnO2 and LiI in toluene and pyridine led indeed to the cyclic nitrone 17 in a yield of
30 – 35%. We assume that the Liþ cation coordinates with the Oꢀ of nitrone 36,
enhancing its electrophilic properties, and favouring cyclisation to the hydroxylamine
37 that is oxidised to nitrone 17. As it is conceivable that LiI is oxidized to I2 that might
act as the oxidant, we treated nitrone 36 with I2 in toluene and pyridine at 608, but did
not observe the desired nitrone 17.
We screened Lewis acids, oxidising agents, and bases to optimise the oxidation of 36
to the nitrone 17. The best result was obtained with 5 equiv. of PbO2 and 2 equiv. of LiI
in toluene/pyridine 2 :1 at 608, yielding 63% of a 1:2 mixture of two diastereoisomeric
nitrones 17.
1
The mixture of rotamers due to the N-Boc group and the overlapping H-NMR
signals allowed only a tentative determination of the configuration and conformation of
1
the two diastereoisomers of 17. The H-NMR spectrum of the mixture in (D6)DMSO
solution at 1008 is characterised by two singlets at 7.81 and at 7.73 ppm and two HꢀC(1)
doublets at 6.01 and 5.81 ppm (J(1,2) ¼ 5.1 and 5.7 Hz), respectively. The coupling
constants of the piperidinose ring of 17 are best interpreted in terms of a B3,N
conformation, avoiding the allylic strain resulting from the interaction of the N-Boc
group with an equatorial side chain at C(5) and the equatorial nitronyl substituents.
The similarity of the coupling constants and the chemical shift for HꢀC(1) evidence the
formation of (E/Z)-isomers rather than of two anomers.
Ozonolysis of nitrone 17 gave the N,O-hemiacetal 14 at ambient temperature, the
only product to be isolated. It is assumed that the desired 1-deoxy-1-nitropiperidinose
12 was generated in situ and transformed to the N,O-hemiacetal 14 upon workup. As
observed for the ozonolysis product of the N-Boc-protected gluconolactam derivative
28, it was not possible to analyze the ozonolysis product of 17 by 1H-NMR
spectroscopy, and the ozonolysis of 17 was monitored by ReactIR. Two prominent
new bands appeared, one characteristic of the NO2 group (1561 cmꢀ1) and one of the
C¼O group of PhCHO (1701 cmꢀ1).
The mechanism for the solvolysis of the 1-nitropiperidinose has to account for the
formation of the hemiacetals in the absence of H2O. Heterolysis of the 1-nitro-
piperidinose 35 is assumed to generate the ion pair 38 that may evolve, by internal
return, to the nitrite 40 that would be hydrolysed, during workup or chromatography,
and lead to the N,O-hemiacetal 31 (Scheme 9). The nitrite 40 is expected to show a
1
strong IR band at 1650 cmꢀ1. In agreement with ReactIR and H-NMR spectroscopy
following the progress of ozonolysis, no such band appeared during ozonolysis of the
nitrones 17, 28, or 34 at ꢀ 788, meaning that the heterolysis/recombination occurs only
at a higher temperature.
As the 1-nitropiperidinoses could not be isolated, we screened Michael additions
and Henry reactions of the crude mixture of the bona fide N-tosylated 1-nitro-
piperidinose 35 obtained by ozonolysis of nitrone 34 at ꢀ 788. The mixture was treated
with acrylonitrile, methyl acrylate, or 4-nitrobenzaldehyde, and a base (Et4NOH, DBU,
NaH, t-BuSNa, NaOMe, t-BuOK, Bu4NF, or KF), slowly raising the temperature from

Helvetica Chimica Acta – Vol. 93 (2010)
2307
Scheme 9
ꢀ 788 to ambient temperature, speculating that deprotonation of 34 would occur
before solvolysis. Addition of the resulting nitronate anion to the electrophile was
expected to give a tertiary nitropiperidinose, and further, by an even more facile
solvolysis, the corresponding ulose. However, none of the conditions led to the desired
products, and the hemiacetal 31 was isolated in every case, suggesting that
deprotonation was at least incomplete. Conceivably, the allylic strain of a nitronate
anion raises the pKHA value of these nitropiperidines, as the nitronate anions might
have to be pyramidalised, as it was evidenced for nitrofuranose-derived anions [31],
meaning that sensibly stronger bases are required. In our opinion, a combination of
strongly electron-accepting substituents of the hydroxy group, and of the ring N-atom
will stabilize such nitropiperidinose sufficiently to allow their isolation and selective
transformation.
We thank Dr. B. Bernet for carefully checking and commenting the analytical data, Dr. P. Seiler for
determining the crystal structure, and the Swiss National Science Foundation and Syngenta AG, Basel, for
their generous support.
Experimental Part
General. See [10].
6-Azido-2,3,4,7-tetra-O-benzyl-6,8-dideoxy-d-erythro-d-galacto-octono-1,5-lactone (2). A soln. of
the crude hemiacetal 1 (28 g, 46 mmol) in CH2Cl2 (1 l) was treated at 258 with a soln. of Dess – Martin
periodinane (30 g, 70 mmol) in CH2Cl2 (100 ml), stirred for 6 h, and diluted with a 1:1 mixture of a sat.
NaHCO3 soln. and a sat. Na2S2O3 soln. (500 ml). The layers were separated, and the aq. layer was
extracted twice with CH2Cl2. The combined org. layers were dried (MgSO4) and evaporated to afford 2
(27 g, quant.), which was used for the next step without further purification. Colourless oil. Rf (hexane/
AcOEt 4 :1) 0.48. [a]2D5 ¼þ 88.1 (c ¼ 1.51, CHCl3). IR (ATR): 3062w, 3031w, 2924w, 2888w, 2104s, 1740m,
1497w, 1464w, 1453w, 1407w, 1380w, 1360m, 1350m, 1291w, 1277w, 1234w, 1207w, 1184s, 1137s, 1092s,
1076s, 1054s, 1043s, 1025s, 999m, 984m, 955m, 940m, 899w, 874m, 827w, 809w, 789w, 743s, 732s, 694s, 662m,
1
611w. H-NMR (300 MHz, CDCl3; assignments based on selective homodecoupling experiments): see
Table 1; additionally, 7.45 – 7.25 (m, 20 arom. H); 5.18 (d, J ¼ 11.1), 5.05 (d, J ¼ 10.8), 4.81 (d, J ¼ 10.8),

2308
Helvetica Chimica Acta – Vol. 93 (2010)
4.80 (d, J ¼ 12.0), 4.74 (d, J ¼ 12.0), 4.69 (d, J ¼ 12.0), 4.60 (d, J ¼ 12.0), 4.53 (d, J ¼ 12.0) (4 PhCH2).
13C-NMR (75 MHz, CDCl3; assignments based on a HSQC spectrum): see Table 1; additionally, 138.04,
137.46, 137.23, 137.20 (4s); 128.46 – 127.25 (several d); 75.22, 74.91, 73.00, 71.02 (4t, 4 PhCH2). HR-ESI-
MS: 646.2337 (65, [M þ K]þ, C36H37KN3O6þ ; calc. 646.7932), 630.2577 (100, [M þ Na]þ, C36H37N3NaOþ6 ;
calc. 630.2575). Anal. calc. for C36H37N3O6 (607.70): C 71.15, H 6.14, N 6.91; found: C 70.88, H 6.18, N 7.01.
Table 1. Selected 1H-NMR Chemical Shifts [ppm] and Coupling Constants [Hz], and 13C-NMR Chemical
Shifts [ppm] of the Lactones and Lactames 2, 6, 7, 9, and 13, of the N,O-Hemiacetal 14 in CDCl3, and of the
Glycosyl Acetates 18 and 19 in (D6)DMSO
2
6
7
9
13a)
14
4.80
18
6.75
3.92
3.97
4.32
3.1
4.93
3.98
1.10
4.2
19b)
HꢀC(1)
HꢀC(2)
HꢀC(3)
HꢀC(4)
HꢀC(5)
HꢀC(6)
HꢀC(7)
H3C(8)
J(1,2)
–
–
–
–
–
4.30
6.81
3.89
3.73
4.19
3.43
5.25
3.82
1.01
4.2
4.49
3.87
4.23
3.79
4.17
4.10
1.22
–
4.38
3.82
4.27
3.16
3.73 – 3.71
3.73
1.32
–
4.49
3.78
4.27
3.21
3.66 – 3.58
3.66 – 3.58
1.39
–
4.55
3.83
4.24
3.12
3.89
3.77
1.32
–
3.94
3.70
4.26
3.25
4.77
4.08
11.23
3.6
3.96
3.95
4.30
4.38
3.61
1.32
–
J(2,3)
9.3
9.9
9.3
8.4
5.1
9.3
9.9
9.3
J(3,4)
2.4
1.5
1.2
2.1
4.5
3.3
3.0
3.3
J(4,5)
1.5
2.4
2.1
3.0
3.6
2.1
0
0
J(5,6)
J(6,7)
J(7,Me)
10.2
2.7
6.3
9.3
5.7
5.7
8.7
)
5.4
9.6
4.8
6.0
7.8
6.9
5.7
10.8
2.1
6.3
10.8
2.1
6.3
10.5
3.3
6.3
a
C(1)
C(2)
C(3)
C(4)
C(5)
C(6)
C(7)
C(8)
169.24
76.93
80.21
72.26
76.87
61.75
74.91
13.57
171.50
76.98
81.04
73.81
55.84
64.47
76.48
15.96
203.17
80.89
81.48
73.94
60.82
64.50
76.57
15.13
151.43
76.16
81.61
73.59
55.59
64.41
74.42
15.53
169.39
79.51
80.26
70.51
56.37
64.85
71.95
16.18
80.83
77.19
78.03
74.76
53.97
63.61
75.18
13.54
79.97
75.18
76.61
74.95
54.73
63.26
75.07
13.54
b
a) J(3,5) ¼ 1.5 Hz. ) The majority of the 13C-signals were broad and not assigned.
6-Azido-2,3,4,7-tetra-O-benzyl-6,8-dideoxy-d-erythro-d-galacto-octonamide (3). NH3 was con-
densed at ꢀ 408 into a soln. of 2 (27 g, 41 mmol) in CH2Cl2 (200 ml), and the mixture was stirred for
4 h. Evaporation gave 3 (25 g, quant.), which was used for the next step without further purification. Pale
yellow powder. Rf (hexane/AcOEt 3 :2) 0.43. [a]2D5 ¼ ꢀ11.7 (c ¼ 1.03, CHCl3). IR (ATR): 3445w, 3356w,
3188w, 3065w, 3031w, 2984w, 2942w, 2890w, 2101m, 1680s, 1587w, 1497w, 1454w, 1395w, 1380m, 1348w,
1327w, 1305w, 1274m, 1261m, 1217w, 1085s, 1072s, 1025m, 936w, 906w, 880w, 748s, 694s. 1H-NMR
(300 MHz, CDCl3; assignments based on selective homodecoupling experiments): 7.41 – 7.26 (m, 20
arom. H); 6.67 (br. s, NH); 5.84 (br. s, NH); 4.66 (d, J ¼ 11.4), 4.63 (s), 4.53 (d, J ¼ 12.0), 4.53 (d,
J ¼ 11.7), 4.47 (d, J ¼ 11.4), 4.44 (d, J ¼ 11.7), 4.43 (d, J ¼ 12.0) (4 PhCH2); 4.16 – 4.11 (m, HꢀC(2),
HꢀC(3)); 4.02 (qd, J ¼ 6.3, 2.4, HꢀC(7)); 3.96 (br. d, J ¼ 6.0, HꢀC(4)); 3.69 (dd, J ¼ 10.2, 3.0, HꢀC(6));
3.61 (br. dd, J ¼ 10.2, 7.8, HꢀC(5)); 2.75 (d, J ¼ 7.8, OH); 1.18 (d, J ¼ 6.3, Me). 13C-NMR (75 MHz,
CDCl3; assignments based on a HSQC spectrum): 174.49 (s, C¼O); 138.33, 137.58, 137.32, 136.42 (4s);
128.66 – 127.29 (several d); 79.84 (d, C(3)); 79.60 (d, C(2)); 77.08 (d, C(4)); 75.76 (d, C(7)); 75.42, 73.75,
73.29, 70.57 (4t, 4 PhCH2); 69.67 (d, C(5)); 64.45 (d, C(6)); 13.49 (q, Me). HR-ESI-MS: 663.2562 (38,

Helvetica Chimica Acta – Vol. 93 (2010)
2309
[M þ K]þ, C36H40KN3Oþ6 ; calc. 663.2579), 647.2835 (100, [M þ Na]þ, C36H40N3NaOþ6 ; calc. 647.2840),
625.3008 (20, [M þ H]þ, C36H41N4O6þ ; calc. 625.3021).
6-Azido-2,3,4,7-tetra-O-benzyl-6,8-dideoxy-d-glycero-d-galacto-oct-5-ulosonamide (4). A soln. of 3
(25 g, 40 mmol) in CH2Cl2 (600 ml) was treated at 258 with a soln. of Dess – Martin periodinane (30 g,
70 mmol) in CH2Cl2 (200 ml), stirred for 6 h, and treated with a 1:1 mixture of a sat. NaHCO3 soln. and a
sat. Na2S2O3 soln. (200 ml). The layers were separated, and the aq. layer was extracted twice with CH2Cl2.
The combined org. layers were dried (MgSO4) and evaporated to afford 4 (23 g, quant.), which was used
for the next step without further purification. Colourless oil. Rf (hexane/AcOEt 1:1) 0.47. [a]2D5 ¼þ 54.3
(c ¼ 0.99, CHCl3). IR (ATR): 3473w, 3327w, 3063w, 3031w, 2975w, 2927w, 2872w, 2103m, 1726m, 1684m,
1584w, 1496w, 1454w, 1395w, 1379w, 1337w, 1268w, 1211w, 1107m, 1086m, 1068s, 1026m, 911w, 822w, 735s,
695s. 1H-NMR (300 MHz, CDCl3; assignments based on selective homodecoupling experiments): 7.41 –
7.10 (m, 20 arom. H); 6.61 (br. d, J ¼ 3.3, NH); 5.75 (br. d, J ¼ 3.3, NH); 4.53 (d, J ¼ 11.4), 4.51 (d, J ¼ 11.7,
2 H) (3 PhCH); 4.50 (d, J ¼ 7.2, HꢀC(2)); 4.48 (d, J ¼ 10.2), 4.40 (d, J ¼ 11.1), 4.37 (d, J ¼ 11.4), 4.34 (d,
J ¼ 11.4) (4 PhCH); 4.24 (d, J ¼ 6.6, HꢀC(6)); 4.17 (dd, J ¼ 7.2, 2.7, HꢀC(3)); 4.13 (d, J ¼ 3.0, HꢀC(4));
3.98 (quint., J ¼ 6.3, HꢀC(7)); 3.93 (d, J ¼ 11.4, PhCH); 1.25 (d, J ¼ 6.0, Me). 13C-NMR (75 MHz,
CDCl3): 206.78 (s, C(5)); 173.22 (s, C(1)); 137.37, 137.03, 136.83, 136.37 (4s); 128.55 – 127.64 (several d);
81.65 (d, C(3)); 81.12 (d, C(2)); 79.57 (d, C(4)); 75.77 (d, C(7)); 75.23, 74.10, 72.07, 70.83 (4t, 4 PhCH2);
67.82 (d, C(6)); 16.57 (q, Me). HR-MALDI-MS: 661.2391 (38, [M þ K]þ, C36H38KN4O6þ ; calc. 661.2423),
645.2679 (100, [M þ Na]þ, C36H38N4NaO6þ ; calc. 645.2684), 623.2854 (20, [M þ H]þ, C36H39N4Oþ6 ; calc.
623.2876).
5-Amino-6-azido-2,3,4,7-tetra-O-benzyl-5,6,8-trideoxy-d-erythro-d-galacto-octono-1,5-lactam (6). A
soln. of 4 (23 g, 36 mmol) in MeCN (670 ml) and 98% HCOOH (250 ml) was treated with NaCNBH3
(14 g, 22.3 mmol), heated to 708 for 4 h, cooled to 258, and poured into AcOEt/sat. aq. NaHCO3 soln. The
layers were separated, and the aq. layer was extracted twice with AcOEt. The combined org. layers were
washed with brine, dried (MgSO4), and evaporated. FC (hexane/AcOEt 95 :5 ! 1:1) gave 6 (13 g, 58%
from 1). Yellow oil. Rf (hexane/AcOEt 3 :1) 0.19. [a]2D5 ¼þ 106.2 (c ¼ 1.27, CHCl3). IR (ATR): 3212w,
3064w, 3030w, 2936w, 2869w, 2107s, 1672s, 1496w, 1453m, 1381w, 1345w, 1289m, 1208w, 1100s, 1046m,
1026m, 908w, 819w, 732s, 695s. 1H-NMR (300 MHz, CDCl3; assignments based on selective homodecou-
pling experiments): see Table 1; additionally, 7.47 – 7.26 (m, 20 arom. H); 6.80 (br. s, NH); 5.24 (d, J ¼
11.4), 5.19 (d, J ¼ 10.8), 4.86 (d, J ¼ 11.1), 4.84 (d, J ¼ 12.0), 4.77 (d, J ¼ 12.0), 4.65 (d, J ¼ 11.7), 4.63
(d, J ¼ 10.8), 4.48 (d, J ¼ 11.7) (4 PhCH2). 13C-NMR (75 MHz, CDCl3; assignments based on a HSQC
spectrum): see Table 1; additionally, 138.02, 137.92, 137.77, 136.93 (4s); 128.55 – 127.40 (several d); 75.42,
74.27, 73.14, 70.80 (4t, 4 PhCH2). HR-MALDI-MS: 645.2478 (38, [M þ K]þ, C36H38KN4O5þ ; calc.
645.2474), 629.2740 (60, [M þ Na]þ, C36H38N4NaO5þ ; calc. 629.2734), 607.2920 (100, [M þ H]þ,
C36H39N4Oþ5 ; calc. 607.2915). Anal. calc. for C36H38N4O5 (606.72): C 71.27, H 6.31, N 9.23; found: C
71.02, H 6.43, N 9.04.
5-Amino-6-azido-2,3,4,7-tetra-O-benzyl-5,6,8-trideoxy-d-erythro-d-galacto-octono-1,5-thiolactam
(7). A soln. of 6 (660 mg, 1.09 mmol) in toluene (20 ml) was treated with Lawessonꢂs reagent (400 mg,
0.98 mmol), heated to 608 for 2 h, and evaporated. FC (hexane/AcOEt 98 :2 ! 4 :1) gave 7 (520 mg,
75%). Yellow oil. Rf (hexane/AcOEt 4 :1) 0.46. [a]2D5 ¼þ 122.4 (c ¼ 0.46, CHCl3). IR (ATR): 3297w,
3063w, 3030w, 2870w, 2108s, 1595w, 1496m, 1453m, 1380w, 1356w, 1288m, 1263w, 1209w, 1177w, 1091m,
1059m, 1025m, 907m, 730s, 694s. 1H-NMR (300 MHz, CDCl3; assignments based on selective
homodecoupling experiments): see Table 1; additionally, 9.04 (br. s, NH); 7.53 – 7.49 (m, 2 arom. H);
7.40 – 7.21 (m, 18 arom. H); 5.45 (d, J ¼ 10.8), 5.20 (d, J ¼ 10.8), 4.89 (d, J ¼ 10.8), 4.81 (d, J ¼ 12.3), 4.74
(d, J ¼ 11.7), 4.71 (d, J ¼ 11.7), 4.63 (d, J ¼ 10.8), 4.47 (d, J ¼ 11.7) (4 PhCH2). 13C-NMR (75 MHz,
CDCl3): see Table 1; additionally, 138.23, 138.10, 137.96, 136.51 (4s); 129.10 – 127.78 (several d); 76.57,
74.07, 73.41, 71.08 (4t, 4 PhCH2). HR-MALDI-MS: 645.2506 (10, [M þ Na]þ, C36H38N4NaO4þ ; calc.
645.2506), 623.2687 (100, [M þ H]þ, C36H39N4O4þ ; calc. 623.2687). Anal. calc. for C36H38N4O4S (622.79):
C 69.43, H 6.25, N 8.69; found: C 69.26, H 6.25, N 8.69.
(Z)-6-Azido-2,3,4,7-tetra-O-benzyl-5-C-{[(tert-butoxy)carbonyl]amino}-5,6,8-trideoxy-d-erythro-d-
galacto-octonhydroximo-1,5-lactam (9). A soln. of 7 (100 mg, 0.16 mmol) in CH2Cl2 (5 ml) was treated
with DMAP (2 mg, 0.16 mmol) and Boc2O (70 mg, 0.32 mmol), stirred for 1 h, diluted with MeOH
(5 ml), treated with NH2OH · HCl (56 mg, 0.80 mmol) and NaHCO3 (68 mg, 0.80 mmol), heated to 608,

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Helvetica Chimica Acta – Vol. 93 (2010)
stirred for 1 h, and evaporated. A soln. of the residue in AcOEt was washed with H2O and brine, dried
(MgSO4), and evaporated. FC (hexane/AcOEt 95 :5 ! 1:1) gave 9 (103 mg, 90%). Colourless oil. Rf
(hexane/AcOEt 1:1) 0.59. [a]2D5 ¼þ 38.2 (c ¼ 0.84, CHCl3). IR (ATR): 3365w, 3063w, 3030w, 2869w,
2106s, 1710m, 1644m, 1496w, 1453m, 1381w, 1358w, 1288m, 1207w, 1069m, 1026m, 953w, 911w, 732s, 694s.
1H-NMR (300 MHz, CDCl3; assignments based on selective homodecoupling experiments): see Table 1;
additionally, 7.42 – 7.25 (m, 20 arom. H); 7.07 (br. s, OH); 5.09 (d, J ¼ 11.1), 4.94 (d, J ¼ 11.4), 4.79 (d, J ¼
11.7), 4.73 (d, J ¼ 11.4), 4.71 (d, J ¼ 11.4), 4.66 (d, J ¼ 11.4), 4.62 (d, J ¼ 12.0), 4.50 (d, J ¼ 12.0)
(4 PhCH2); 1.49 (s, t-Bu). 13C-NMR (75 MHz, CDCl3): see Table 1; additionally, 158.90 (s, C¼O); 138.06,
137.92, 137.85, 137.40 (4s); 128.37 – 127.54 (several d); 81.84 (s, Me3C); 73.98 (2 C), 72.79, 70.77 (3t,
4 PhCH2); 28.18 (q, Me3C). HR-MALDI-MS: 644.2860 (5, [M ꢀ Boc þ H þ Na]þ, C36H39N5NaO5þ ; calc.
644.2843), 622.3035 (100, [M ꢀ Boc þ 2 H]þ, C36H40N5O5þ ; calc. 622.3024).
6-Azido-2,3,4,7-tetra-O-benzyl-5-C-{[(tert-butoxy)carbonyl]amino}-5,6,8-trideoxy-d-erythro-d-gal-
acto-octono-1,5-lactam (13). A soln. of 6 (100 mg, 0.16 mmol) and DMAP (20 mg, 0.16 mmol) in
ClCH2CH2Cl was heated to 708, treated with Boc2O (70 mg, 0.32 mmol), stirred for 6 h, and evaporated.
FC (hexane/AcOEt 98 :2 ! 4 :1) gave 13 (90 mg, 80%). Colourless oil. Rf (hexane/AcOEt 4 :1) 0.53.
[a]2D5 ¼þ 59.1 (c ¼ 1.08, CHCl3). IR (ATR): 3030w, 2977w, 2930w, 2870w, 2114m, 1709s, 1693m, 1654w,
1496w, 1453w, 1367m, 1308w, 1278w, 1251m, 1207w, 1150m, 1122m, 1074s, 1027m, 965w, 934w, 909w, 857w,
790w, 773w, 732s, 695s. 1H-NMR (300 MHz, CDCl3; assignments based on selective homodecoupling
experiments): see Table 1; additionally, 7.41 – 7.25 (m, 20 arom. H); 4.80 (d, J ¼ 11.7), 4.77 (d, J ¼ 11.4),
4.74 (d, J ¼ 11.1), 4.71 (d, J ¼ 11.4), 4.70 (d, J ¼ 11.7), 4.52 (d, J ¼ 10.8), 4.25 (d, J ¼ 10.8), 4.22 (d, J ¼ 11.4)
(4 PhCH2); 1.50 (s, t-Bu). 13C-NMR (75 MHz, CDCl3): see Table 1; additionally, 152.44 (s, C¼O of Boc);
137.90, 137.66, 137.51, 137.27 (4s); 128.35 – 127.61 (several d); 81.14 (s, Me3C); 75.33, 74.78, 74.10, 73.42 (4t,
4 PhCH2); 28.11 (q, Me3C). HR-MALDI-MS: 729.3246 (30, [M þ Na]þ, C41H46N4NaO7þ ; calc. 729.3259),
629.2734 (41, [M ꢀ Boc þ H þ Na]þ, C36H38N4NaOþ5 ; calc. 629.2734), 607.2913 (100, [M ꢀ Boc þ 2 H]þ,
C36H39N4Oþ5 ; calc. 607.2915). Anal. calc. for C41H46N4O7 (706.84): C 69.67, H 6.56, N 7.93; found: C 69.51,
H 6.65, N 7.86.
6-Azido-2,3,4,7-tetra-O-benzyl-5-C-{[(tert-butoxy)carbonyl]amino}-5,6,8-trideoxy-d-erythro-a-d-
galacto-octopyranose (14). At 08, a soln. of 13 (870 mg, 1.23 mmol) in THF (10 ml) was treated dropwise
with a 1m Super-Hydrideꢃ soln. (6.2 ml, 6.2 mmol), stirred for 1 h, and treated with a sat. aq. NaHCO3
soln. THF was evaporated, and the aq. layer was extracted twice with CH2Cl2. The combined org. layers
were dried (MgSO4) and evaporated to afford 14 (880 mg, quant.), which was used for the next step
without further purification. Colourless oil. Rf (hexane/AcOEt 4 :1) 0.35. [a]2D5 ¼þ 48.2 (c ¼ 1.05,
CHCl3). IR (ATR): 3212w, 3064w, 3031w, 2980w, 2931w, 2871w, 2110m, 1734m, 1714m, 1496w, 1454w,
1393w, 1368w, 1285m, 1256m, 1208w, 1147s, 1094s, 1051m, 1026m, 911w, 848w, 733s, 695s. 1H-NMR
(300 MHz, CDCl3, 608; assignments based on selective homodecoupling experiments): 7.46 – 7.25 (m, 20
arom. H); 4.80 (br. s, HꢀC(1), after addition of D2O: d, J ¼ 3.3); 4.77 (br. d, J ¼ 10.8, HꢀC(6)); 4.91 (d,
J ¼ 11.7), 4.81 (d, J ¼ 11.7), 4.79 (d, J ¼ 11.4), 4.78 (d, J ¼ 11.4) (2 PhCH2); 4.74, 4.66 (2s, 2 PhCH2); 4.26
(br. d, J ¼ 2.1, HꢀC(4)); 4.08 (qd, J ¼ 6.3, 2.1, HꢀC(7)); 3.94 (dd, J ¼ 9.3, 3.6, HꢀC(2)); 3.70 (dd, J ¼ 9.0,
3.3, HꢀC(3)); 3.25 (br. d, J ¼ 10.8, HꢀC(5)); 3.02 (br. s, exchange with D2O, OH); 1.36 (s, t-Bu); 1.23 (d,
J ¼ 6.3, Me). 13C-NMR (75 MHz, CDCl3, 608): 154.24 (s, C¼O); 138.85, 138.62, 138.38, 138.08 (4s);
128.30 – 127.15 (several d); 80.95 (s, Me3C); 80.83 (d, C(1)); 78.03 (d, C(3)); 77.19 (d, C(2)); 75.80 (d,
C(7)); 74.76 (d, C(4)); 74.22, 73.45, 72.89, 70.52 (4t, 4 PhCH2); 63.31 (d, C(6)); 53.97 (d, C(5)); 28.21 (q,
Me3C); 13.54 (q, Me). HR-MALDI-MS: 747.3167 (30, [M þ K]þ, C41H48KN4O7þ ; calc. 747.3155),
731.3421 (100, [M þ Na]þ, C41H48N4NaO7þ ; calc. 731.3415), 607.2877 (80, [M ꢀ Boc þ H]þ, C36H39N4Oþ5 ;
calc. 607.2920), 591.2970 (55, [M ꢀ Boc ꢀ OH þ 2 H]þ, C36H39N4O4þ ; calc. 591.2966). Anal. calc. for
C41H48N4O7 (708.85): C 69.47, H 6.83, N 7.90; found: C 69.51, H 6.85, N 7.83.
(E/Z)-6-Azido-2,3,4,7-tetra-O-benzyl-5-C-{[(tert-butoxy)carbonyl]amino}-5,6,8-trideoxy-d-eryth-
ro-d-galacto-octose Oxime (15). A soln. of crude 14 (880 mg, 1.23 mmol) in abs. EtOH (50 ml) was added
to a soln. of NH2OH · HCl (2.78 g, 0.041 mmol) and NaHCO3 (1.39 g, 0.02 mmol) in abs. EtOH (150 ml).
The mixture was heated to 808 for 24 h, cooled to 258, and evaporated. A soln. of the residue in AcOEt
was washed with H2O and brine, dried (Na2SO4), and evaporated. FC (hexane/AcOEt 95 :5 ! 4 :1) gave
15 (760 mg, 85% from 13). Colourless oil. Rf (hexane/AcOEt 2 :1) 0.53. [a]2D5 ¼þ 7.2 (c ¼ 1.1, CHCl3). IR
(ATR): 3428w (br.), 3064w, 3031w, 2978w, 2872w, 2104m, 1712m, 1688w, 1495m, 1454m, 1391w, 1366w,

Helvetica Chimica Acta – Vol. 93 (2010)
2311
1307w, 1254w, 1162m, 1069s, 1027m, 939w, 912w, 733s, 695s. 1H-NMR (300 MHz, (D6)DMSO, 1008, (E/Z)
7:3; assignments based on selective homodecoupling experiments): 11.09 (s, OH (Z)); 10.81 (s, OH (E));
7.44 (d, J ¼ 7.5, HꢀC(1) (E)); 7.37 – 7.25 (m, 20 arom. H); 6.95 (d, J ¼ 6.0, HꢀC(1) (Z)); 5.97 (br. s,
NHBoc); 5.05 (dd, J ¼ 6.0, 2.7, HꢀC(2) (Z)); 4.73 – 4.39 (m, 4 PhCH2); 4.32 (dd, J ¼ 7.5, 4.2, HꢀC(2)
(E)); 4.02 (t, J ¼ 7.2, 1 H); 3.87 – 3.68 (m, 4 H); 1.35 (s, t-Bu (Z)); 1.33 (s, t-Bu (E)); 1.20 (d, J ¼ 6.0, Me).
13C-NMR (75 MHz, (D6)DMSO, 1008; (E/Z) 7:3): 154.92 (s, C¼O); 149.74 (d, C(1) (E)); 147.72 (d, C(1)
(Z)); 138.35 – 137.87 (several s); 127.95 – 127.02 (several d); 80.39 (d, 1 C (E)); 78.55 (d, 1 C (Z)); 77.10
(d, 1 C (E)); 76.71 (d, 1 C (Z)); 75.22 (d, 1 C (E)); 73.84 (t, PhCH2 (E)); 73.62 (t, PhCH2 (Z)); 73.53 (t,
PhCH2 (Z)); 73.19 (t, PhCH2 (E)); 71.84 (d, 1 C (E)); 70.85 (t, PhCH2 (Z)); 70.22 (t, PhCH2 (E)); 69.83
(t, PhCH2); 64.99 (d, C(6)); 50.44 (d, C(5)); 28.07 (q, Me3C); 13.92 (q, Me); s of Me3C hidden by the
noise. HR-MALDI-MS: 762.3274 (6, [M þ K]þ, C41H49KN5O7þ ; calc. 762.3264), 746.3533 (17, [M þ Na]þ,
C41H49N5NaOþ7 ; calc. 746.3524), 724.3709 (100, [M þ H]þ, C41H50N5O7þ ; calc. 724.3405). Anal. calc. for
C41H49N5O7 (723.87): C 68.03, H 6.82, N 9.67; found: C 67.79, H 6.85, N 9.42.
1-O-Acetyl-6-azido-2,3,4,7-tetra-O-benzyl-5-{[(tert-butoxy)carbonyl]amino}-5,6,8-trideoxy-d-eryth-
ro-a-d-galacto-octopyranose (18). At 08, a soln. of 13 (460 mg, 0.66 mmol) in THF (50 ml) was treated
dropwise with a 1m Super-Hydrideꢃ soln. (2.6 ml, 2.6 mmol), stirred for 1 h, and treated with a sat. aq.
NaHCO3 soln. After evaporation of THF, the aq. layer was extracted twice with CH2Cl2. The combined
org. layers were dried (MgSO4) and evaporated to afford crude 14. A soln. of crude 14 in CH2Cl2 (20 ml)
was treated with Et3N (2 ml), DMAP (40 mg, 0.30 mmol), and Ac2O (1 ml), stirred for 12 h, and
evaporated. A soln. of the residue in AcOEt was washed with sat. aq. NaHCO3 soln. and brine, dried
(MgSO4), and evaporated. FC (hexane/AcOEt 95 :5 ! 4 :1) gave 18 (470 mg, 90% from 13). Rf (hexane/
AcOEt 4 :1) 0.40. [a]2D5 ¼þ 30.0 (c ¼ 1.17, CHCl3). IR (ATR): 3031w, 2978w, 2932w, 2870w, 2107m,
1754m, 1734m, 1715m, 1496w, 1454w, 1368w, 1340w, 1286m, 1254m, 1225w, 1154s, 1118m, 1093m, 1053s,
1026s, 938w, 862w, 817w, 735s, 696s. 1H-NMR (300 MHz, (D6)DMSO, 1008; assignments based on
selective homodecoupling experiments): see Table 1, additionally: 7.40 – 7.23 (m, 20 arom. H); 4.86 (d,
J ¼ 11.7), 4.80 (d, J ¼ 12.0), 4.72 (d, J ¼ 11.7, 2 H), 4.64 (d, J ¼ 11.7), 4.58 (d, J ¼ 11.7), 4.56 (d, J ¼ 10.5),
4.53 (d, J ¼ 11.7) (4 PhCH2); 2.06 (s, AcO); 1.31 (s, t-Bu). 13C-NMR (75 MHz, CDCl3, 608): see Table 1,
additionally, 168.23 (s, OC¼O); 152.98 (s, NC¼O); 138.52, 138.42, 137.92, 138.08 (4s); 127.88 – 127.03
(several d); 81.10 (s, Me3C); 73.64, 72.33, 71.95, 69.87 (4t, 4 PhCH2); 27.71 (q, Me3C); 20.32 (q, MeC¼O).
HR-MALDI-MS: 789.3310 (27, C43H50KN4O8þ, [M þ K]þ; calc. 789.3260), 773.3527 (71, [M þ Na]þ,
C43H50N4NaOþ7 ; calc. 773.3521), 591.2960 (100, [M ꢀ Boc ꢀ OAc þ 2 H]þ, C36H39N4Oþ4 ; calc. 591.2966).
Anal. calc. for C43H50N4O8 (750.89): C 68.78, H 6.71, N 7.46; found: C 69.84, H 6.68, N 7.31.
1-O-Acetyl-2,3,4,7-tetra-O-benzyl-6-{[(benzyloxy)carbonyl]amino}-5-{[(tert-butoxy)carbonyl]ami-
no}-5,6,8-trideoxy-d-erythro-a-d-galacto-octopyranose (19). A 1m soln. of 18 (770 mg, 1.03 mmol) in
pyridine/H2O 5 :1 (12 ml) was treated with propane-1,3-dithiol (2.1 ml, 20.7 mmol) and Et3N (2 ml),
stirred for 6 h, and evaporated. At 08, a soln. of the residue in CH2Cl2 (20 ml) was treated with Et3N (1 ml,
7.21 mmol) and CbzCl (740 ml, 5.15 mmol), warmed to 258, stirred for 4 h, and diluted with sat. aq.
NaHCO3 soln. The layers were separated, and the aq. layer was extracted with CH2Cl2. The combined
org. layers were dried (MgSO4) and evaporated. FC (hexane/AcOEt 85 :5 ! 4 :1) gave 19 (677 mg,
75%). Rf (hexane/AcOEt 4 :1) 0.20. [a]2D5 ¼þ 44.7 (c ¼ 1, CHCl3). IR (ATR): 3335w, 3032w, 2977w,
1720s, 1498m, 1454m, 1369m, 1307m, 1228s, 1159m, 1092s, 1032m, 953w, 902w, 856w, 738s, 698s. 1H-NMR
(300 MHz, (D6)DMSO, 1008): see Table 1, additionally: 7.40 – 7.16 (m, 25 arom. H); 6.8 (br. s, NH); 5.15
(br. d, J ¼ 12.6), 5.03 (d, J ¼ 12.6) (PhCH2); 4.64 (s, PhCH2); 4.61 – 4.52 (m, 5 PhCH); 4.45 (d, J ¼ 12.0,
PhCH); 3.89 (dd, J ¼ 9.3, 4.2, HꢀC(2)); 3.82 (qd, J ¼ 6.3, 3.6, HꢀC(7)); 3.73 (dd, J ¼ 9.3, 3.3, HꢀC(3));
2.03 (s, AcO); 1.27 (s, t-Bu). 13C-NMR (300 MHz, (D6)DMSO, 1008): 168.21 (s, OC¼O); 155.93, 153.11
(2s, 2 NC¼O); 139.22, 138.71, 138.49, 137.95, 137.25 (5s); 129.00 – 126.00 (several d); 80.57 (s, Me3C);
80.00 – 51.00 (broad signals); 27.83, 27.70 (2q, 2 Me3C); 21.00 – 20.00 (broad signals, Me). HR-MALDI-
MS: 897.3760 (14, [M þ K]þ, C51H58KN2Oþ10 ; calc. 897.3723), 881.3983 (22, [M þ Na]þ, C51H58N2NaOþ10
;
calc. 881.3984), 699.3413 (100, [M ꢀ Boc ꢀ OAc þ 2 H]þ, C44H47N2O6þ ; calc. 699.3434).
2,3,4,7-Tetra-O-benzyl-6-{[(benzyloxy)carbonyl]amino}-5-{[(tert-butoxy)carbonyl]amino}-5,6,8-tri-
deoxy-d-erythro-a-d-galacto-octopyranosyl Azide (20). A soln. of 19 (670 mg, 0.78 mmol) and TMS-N3
(1.04 ml, 7.8 mmol) in CH2Cl2 (20 ml) was treated with 4-ꢄ mol. sieves, stirred for 30 min at 258, cooled to
ꢀ 508, treated with BF3 · OEt2 (106 ml, 0.86 mmol), stirred for 15 min, diluted with sat. aq. NaHCO3 soln.,

2312
Helvetica Chimica Acta – Vol. 93 (2010)
and filtered over Celite. The layers were separated, and the aq. layer was extracted with CH2Cl2. The
combined org. layers were dried (MgSO4) and evaporated. FC (hexane/AcOEt 95 :5 ! 4 :1) gave 20
(550 mg, 83%). Rf (hexane/AcOEt 4 :1) 0.30. [a]2D5 ¼þ 16.8 (c ¼ 1; CHCl3). IR (ATR): 3064w, 3031w,
2976w, 2931w, 2865w, 2101m, 1719m, 1700m, 1586w, 1497w, 1453w, 1367m, 1326m, 1304m, 1223m, 1159m,
1092s, 1065s, 1053s, 1026m, 908m, 856w, 729s, 695s. 1H-NMR (300 MHz, (D6)DMSO, 1008): broad signals.
HR-MALDI-MS: 880.3664 (14, [M þ K]þ, C49H55KN5Oþ8 ; calc. 880.3682), 864.3959 (34, [M þ Na]þ,
C49H55N5NaOþ8 ; calc. 864.3943), 699.3404 (100, [M ꢀ Boc ꢀ N3 þ 2 H]þ, C44H47N2Oþ6 ; calc. 699.3434).
2,3,4,6-Tetra-O-benzyl-5-{[(tert-butoxy)carbonyl]amino}-1,5-deoxy-d-glucopyranose N-Benzyl-
imine N-Oxide (26) and 2,3,4,6-Tetra-O-benzyl-1-N-benzyl-5-{[(tert-butoxy)carbonyl]amino}-5-deoxy-
1-N-hydroxy-b-d-glucopyranosylamine (27). A soln. of BnNHOH · HCl (490 mg, 3.06 mmol) in MeOH
was treated with NaHCO3 (120 mg, 1.41 mmol), stirred for 15 min, and evaporated. A soln. of the residue
in CH2Cl2 was washed with H2O and brine. The org. layer was dried (MgSO4) and evaporated to afford
BnNHOH. A soln. of 25 [14] (390 mg, 0.61 mmol) in dry pyridine (5 ml) was treated with BnNHOH and
4-ꢄ mol. sieves, heated for 12 h at 808, filtered, and evaporated. TLC showed two spots in a ratio of ca.
1:1. FC (hexane/AcOEt 98 :2 ! 0 :100) provided two fractions that revealed the same two spots on TLC
(ca. 1:1) corresponding to 26/27 (340 mg, 75%). Colourless oil. 26: Rf (hexane/AcOEt 4 :1) 0.59. 27: Rf
(AcOEt) 0.50. 26/27: [a]2D5 ¼þ 13.25 (c ¼ 1.18, CHCl3). IR (ATR): 3251w, 3030w, 2869w, 1692m, 1604w,
1496w, 1453w, 1391w, 1365w, 1340w, 1257w, 1208w, 1164m, 1090m, 1056s, 1025s, 1006s, 862w, 818w, 735s,
1
696s. H-NMR (300 MHz, (D6)DMSO, 1008; assignments based on selective homodecoupling experi-
ments): see Table 2; additionally, 7.77 (br. s, 1 arom. H); 7.38 – 7.21 (m, 24 arom. H); 4.76 (d, J ¼ 12.9),
4.76 (d, J ¼ 10.8), 4.64 (d, J ¼ 11.7), 4.61 (d, J ¼ 11.1), 4.46 (d, J ¼ 12.3), 4.40 (d, J ¼ 12.0), 4.08 (d, J ¼
13.8), 3.70 (d, J ¼ 14.1) (4 PhCH2); 3.02 (s, OH, HDO); 1.41 (s, t-Bu). 13C-NMR (75 MHz, (D6)DMSO,
1008): see Table 2; additionally, 154.76 (s, C¼O); 138.70, 138.59, 138.44 (2 C), 138.06 (4s); 128.52 – 126.21
(several d); 79.95 (s, Me3C); 73.27, 73.01, 72.17, 71.15, 59.25 (5t, 5 PhCH2); 27.96 (q, Me3C). HR-MALDI-
MS: 783.3411 (38, [M þ K]þ, C46H52KN2Oþ7 ; calc. 783.3412), 767.3652 (77, [M þ Na]þ, C46H52N2NaOþ7 ;
calc. 767.3667, 544.2460 (13, [M ꢀ Boc ꢀ BnNHOH þ H þ Na]þ, C34H35NNaO4þ ; calc. 544.2458),
522.2629 (55, [M ꢀ Boc ꢀ BnNOH þ 2 H]þ, C34H36NO4þ ; calc. 522.2639). Anal. calc. for C46H52N2O7
(744.93): C 74.17, H 7.04, N 3.76; found: C 73.90, H 7.17, N 3.83.
2,3,4,6-Tetra-O-benzyl-5-{[(tert-butoxy)carbonyl]amino}-5-deoxy-1-N-(phenylmethylidene)-b-d-
glucopyranosylamine N-Oxide (28). A soln. of 26/27 (130 mg, 0.17 mmol) and MnO2 (73 mg, 0.85 mmol)
in ClCH2CH2Cl (5 ml) was kept at reflux for 48 h, cooled to r.t., filtered over Celite, and evaporated. FC
(hexane/AcOEt 95 :5 ! 4 :1) gave 28 (120 mg, 90%). Colourless crystals. M.p. 68 – 708. Rf (hexane/
AcOEt 4 :1) 0.44. [a]2D5 ¼ꢀ 60.6 (c ¼ 1.0, CHCl3). IR (ATR): 3062w, 3030w, 2975w, 2931w, 2868w, 1705m,
1578w, 1564w, 1496w, 1454m, 1391w, 1366m, 1331m, 1255w, 1213w, 1156m, 1133m, 1067s, 1027s, 924w,
881w, 852w, 806w, 773w, 733s, 693s. 1H-NMR (300 MHz, (D6)DMSO, 1008; assignments based on
selective homodecoupling experiments): see Table 2; additionally, 8.29 – 8.22 (m, 2 arom. H); 7.91 (br. s,
CH¼N); 7.44 – 7.08 (m, 23 arom. H); 4.75 (s, PhCH2); 4.73 (d, J ¼ 11.8), 4.67 (d, J ¼ 11.7) (2 PhCH); 4.62
(s, PhCH2); 4.56 (d, J ¼ 11.7), 4.41 (d, J ¼ 11.1) (2 PhCH); 1.36 (s, t-Bu). 13C-NMR (75 MHz, (D6)DMSO,
1008): see Table 2; additionally, 153.66 (s, C¼O); 138.30, 138.15, 137.93, 137.53 (4s); 134.45 (d, CH¼N);
130.44 (s); 129.77 – 127.17 (several d); 81.20 (s, Me3C); 74.46, 72.87, 72.32, 71.34 (4t, 4 PhCH2); 27.84 (q,
Me3C). HR-MALDI-MS: 781.3248 (38, [M þ K]þ, C46H50KN2O7þ ; calc. 781.3250), 765.3506 (77, [M þ
H þ Na]þ, C46H50N2NaO7þ ; calc. 765.3510), 544.2460 (13, [M ꢀ Boc ꢀ PhCHNO þ H þ Na]þ,
C34H35NNaOþ4 ; calc. 544.2458), 522.2629 (55, [M ꢀ Boc ꢀ PhCHNO þ H]þ, C34H36NOþ4 ; calc.
522.2639). Anal. calc. for C46H50N2O7 (742.91): C 74.37, H 6.78, N 3.77; found: C 74.18, H 6.87, N 3.66.
Crystal-Structure Analysis of 28. Crystals of 28 were obtained by slow evaporation of a soln. of 28 in
MeOH/H2O (dimensions of the analyzed crystal: cube 0.15 ꢁ 0.13 ꢁ 0.10 mm). C46H50N2O7, Mr 742.88,
orthorhombic P212121; a ¼ 9.1192(11), b ¼ 12.2196(12), c ¼ 36.9155(16), V¼ 4113.6(7) ꢄ3, Dx ¼
1.200 Mg/m3, Z ¼ 4. The reflections were measured on a Bruker Nonius-Kappa CCD diffractometer
(graphite monochromator, MoKa radiation, l ¼ 0.71070) at 220 K. All the calculations were performed
using maXus (Bruker Nonius, Delft, MacScience, Japan). The structure was solved by direct methods and
refined by full-matrix least-squares analysis (SHELXL-97) including an isotropic extinction correction.
All non-H-atoms were refined anisotropically (H-atoms isotropic, whereby H-positions are based on

Helvetica Chimica Acta – Vol. 93 (2010)
2313
Table 2. Selected 1H-NMR Chemical Shifts [ppm] and Coupling Constants [Hz], and 13C-NMR Chemical
Shifts [ppm] of the N-Bocylated and N-Tosylated 5-Amino-5-deoxyglucopyranose Derivatives 27 and 28 in
(D6)DMSO at 1008, of 30 and 31 in CDCl3, and of 34 and 35 in CD2Cl2
27
5.08
4.25 – 4.18
3.58
3.96
4.25 – 4.18
3.78
28
5.53
4.31
3.77
3.95
3.91 – 3.82
3.91 – 3.82
3.91 – 3.82
30
a-d-31a)
b-d-31a)
34
5.43
35c)
HꢀC(1)
HꢀC(2)
HꢀC(3)
HꢀC(4)
HꢀC(5)
HaꢀC(6)
HbꢀC(6)
J(1,OH)
J(1,2)
J(2,3)
J(3,4)
J(3,5)
J(4,5)
–
5.37
3.62
3.19
3.86
4.03 – 3.99
3.69
3.53
6.2
3.5
8.1
8.2
–
5.70
3.74
3.81
6.04
4.51
3.54
3.88
4.07
3.82
3.70
–
3.6
6.3
5.3
–
4.31
3.72
4.01
4.82
3.83
3.78
–
4.30
3.40
3.82
4.36 – 4.29
3.86
3.66
–
7.9
10.8
6.0
–
1.1
4.07
3.97 – 3.91
3.97 – 3.91
3.69 – 3.65
11.8
3.0
6.8
3.78
–
–
b
)
8.4
9.9
5.1
–
–
6.6
9.3
–
7.2
5.7
5.7
5.7
7.5
2.7
1.5
2.7
10.8
6.6
5.6
–
2.3
b
)
)
)
)
4.8
5.9
3.1
9.7
1.2
b
b
b
b
J(5,6a)
J(5,6b)
J(6a,6b)
)
)
)
10.1
4.8
10.1
4.0
8.8
9.3
b
b
10.8
C(1)
C(2)
C(3)
C(4)
C(5)
C(6)
83.17
78.42
80.57
77.44
59.25
71.00
84.71
80.42
81.82
76.05
55.76
70.29
168.83
79.69
81.73
75.90
60.14
70.06
85.95
75.71
82.04
81.64
57.99
71.91
a) The majority of the 13C-signals were not assigned. b) Not determined.
stereochemical considerations). R ¼ 0.0398, Rw ¼ 0.0872 for 500 parameters and 3189 reflections,
q < 24.108.
2,3,4,6-Tetra-O-benzyl-5-deoxy-5-[(4-methylphenylsulfonyl)amino]-d-glucono-1,5-lactam (30). A
soln. of 23 [14] (1 g, 1.86 mmol) in THF (20 ml) was cooled to ꢀ 788, treated with a 1.6m BuLi in
hexane (1.5 ml, 1.86 mmol), stirred for 15 min, treated with DMAP (227 mg, 1.86 mmol) and TsCl
(710 mg, 3.72 mmol), allowed to warm to 258, stirred for 1 h, diluted with sat. NH4Cl soln., and extracted
with CH2Cl2 (3ꢁ). The combined org. layers were washed with H2O and brine, dried (MgSO4), and
evaporated. FC (hexane/AcOEt 95 :5 ! 4 :1) gave 30 (1.0 g, 77%). Colourless oil. Rf (hexane/AcOEt
3 :1) 0.63. [a]2D5 ¼ þ1.3 (c ¼ 1.58, CHCl3). IR (ATR): 3063w, 3031w, 2923w, 2866w, 1721m, 1596w, 1495w,
1453m, 1397w, 1352m, 1307w, 1292w, 1264w, 1187m, 1168s, 1072s, 1026m, 909w, 888w, 811w, 732s, 695s,
674m, 655m. 1H-NMR (300 MHz, CDCl3; assignments based on selective homodecoupling experiments):
see Table 2; additionally, 7.86 (br. d, J ¼ 8.1, 2 arom. H); 7.32 – 7.25 (m, 16 arom. H); 7.21 (br. dd, J ¼ 5.7,
2.4, 2 arom. H); 7.12 (br. dd, J ¼ 7.2, 3.9, 2 arom. H); 7.06 (br. d, J ¼ 8.1, 2 arom. H); 4.98 (d, J ¼ 11.4,
PhCH); 4.61 (d, J ¼ 11.7), 4.53 (d, J ¼ 11.4) (2 PhCH); 4.51 (s, PhCH2); 4.47 (d, J ¼ 11.4, PhCH); 4.39 (s,
PhCH2); 2.36 (s, Me). 13C-NMR (75 MHz, CDCl3; assignments based on a HSQC spectrum): see Table 2;
additionally, 144.50, 137.45, 137.37, 137.26, 136.86, 135.41 (6s); 129.03 – 127.68 (several d); 74.06, 73.50,
72.95, 71.29 (4t, 4 PhCH2); 21.74 (q, Me). HR-MALDI-MS: 730.2221 (38, [M þ K]þ, C41H41KNO7Sþ;
calc. 730.2235), 714.2486 (100, [M þ Na]þ, C41H41NNaO7Sþ; calc. 714.2496). Anal. calc. for C41H41NO7S
(691.84): C 71.18, H 5.97, N 2.02; found: C 70.90, H 6.16, N 1.99.
2,3,4,6-Tetra-O-benzyl-5-deoxy-5-[(4-methylphenylsulfonyl)amino]-a/b-d-glucopyranose (31). A
soln. of DIBAL-H (4.2 ml, 4.16 mmol) in toluene (20 ml) was cooled to 08, treated dropwise with a

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Helvetica Chimica Acta – Vol. 93 (2010)
soln. of 30 (720 mg, 1.04 mmol) in toluene (5 ml), stirred for 30 min, treated with ice cubes, and stirred
for 30 min at 258. After filtration over Celite, evaporation and FC (hexane/AcOEt 95 :5 ! 3 :1) gave 31
(616 mg, 85%). Colourless oil. Rf (hexane/AcOEt 3 :1) 0.54. [a]2D5 ¼ þ27.6 (c ¼ 1.05, CHCl3). IR (ATR):
3422w, 3063w, 3030w, 2923w, 2869w, 1598w, 1496w, 1453m, 1397w, 1347m, 1307w, 1208w, 1161s, 1088s,
1070s, 1027s, 983m, 965m, 915w, 814w, 734s, 696s, 665s. 1H-NMR (400 MHz, CDCl3; assignments based on
a DQF-COSY spectrum; a/b 7:3): 7.92 (d, J ¼ 8.3, 2 arom. H (b)); 7.74 (d, J ¼ 8.3, 2 arom. H (a)); 7.38 –
7.13 (m, 20 arom. H); 7.10 (d, J ¼ 8.6, 2 arom. H (a)); 6.78 (d, J ¼ 8.1, 2 arom. H (b)); 5.70 (dd, J ¼ 11.8,
2.9, HꢀC(1) (b)); 5.37 (dd, J ¼ 6.2, 3.5, HꢀC(1) (a)); 4.80 (d, J ¼ 11.5, PhCH (b)); 4.68 (d, J ¼ 11.4,
PhCH (a)); 4.61 (2d, J ¼ 10.9 and 11.6, 2 PhCH (a)); 4.55 (d, J ¼ 11.4, 2 PhCH (a)); 4.49 (s, PhCH2 (b));
4.46 – 4.40 (m, PhCH (a), 3 PhCH (b)); 4.41 (d, J ¼ 11.5, PhCH (a)); 4.35 (d, J ¼ 11.6, PhCH (a)); 4.09 (d,
J ¼ 5.7, HO (a)); 4.07 (dd, J ¼ 5.6, 2.3, HꢀC(4) (b)); 4.03 – 3.99 (m, PhCH (b), HꢀC(5) (a), HO (b));
3.97 – 3.91 (m, PhCH (b), HꢀC(5) (b), HaꢀC(6) (b)); 3.86 (dd, J ¼ 8.4, 4.8, HꢀC(4) (a)); 3.81 (br. d,
J ꢂ 5.9, HꢀC(3) (b)); 3.74 (dd, J ¼ 6.8, 3.0, HꢀC(2) (b)); 3.69 (dd, J ¼ 9.7, 5.9, HaꢀC(6) (a)); 3.69 – 3.65
(m, HbꢀC(6) (b)); 3.62 (dd, J ¼ 8.1, 3.1, HꢀC(2) (a)); 3.53 (dd, J ¼ 9.7, 3.1, HbꢀC(6) (a)); 3.19 (t, J ¼ 8.2,
HꢀC(3) (a)); 2.35 (s, Me (b)); 2.33 (s, Me (a)). 13C-NMR (100 MHz, CDCl3; assignments based on a
HSQC spectrum; a/b 7:3): 143.55 – 135.92 (several s); 129.48 – 127.49 (several d); 83.26 (d, C(2) (a));
81.61 (d, C(1) (a)); 81.23 (d, C(2) (b)); 80.99 (d, C(3) (a)); 79.70 (d, C(3) (b)); 76.59 (d, C(1) (b)); 76.49
(d, C(4) (a)); 74.64 (d, C(4) (b)); 74.41 (t, PhCH2 (a)); 73.54 (t, PhCH2 (a)); 73.29 (t, PhCH2 (b)); 73.14
(t, PhCH2 (a)); 72.88 (t, PhCH2 (a)); 72.20 (t, PhCH2 (b)); 71.82 (t, PhCH2 (b)); 71.35 (t, PhCH2 (b));
70.42 (t, C(6) (b)); 69.71 (t, C(6) (a)); 58.64 (d, C(5) (a)); 55.08 (d, C(5) (b)); 21.58 (q, Me (b)); 21.52 (q,
Me (a)). HR-MALDI-MS: 732.2383 (38, [M þ K]þ, C41H43KNO7Sþ; calc. 732.2392), 716.2664 (100,
[M þ Na]þ, C41H43NNaO7Sþ; calc. 716.2652). Anal. calc. for C41H43NO7S (693.86): C 70.97, H 6.25, N
2.02; found: C 70.88, H 6.45, N 1.96.
2,3,4,6-Tetra-O-benzyl-1,5-dideoxy-5-[(4-methylphenylsulfonyl)amino]-d-glucopyranose N-Benzyl-
imine N-Oxide (32) and 2,3,4,6-Tetra-O-benzyl-1-N-benzyl-5-deoxy-1-N-hydroxy-5-[(4-methylphenyl-
sulfonyl)amino]-a-d- and -b-d-glucopyranosylamine (33). A soln. of BnNHOH · HCl (230 mg,
1.44 mmol) in MeOH (5 ml) was treated with NaHCO3 (120 mg, 1.44 mmol), stirred for 15 min, and
evaporated. A soln. of the residue in CH2Cl2 was washed with H2O and brine. The org. layer was dried
(MgSO4) and evaporated to afford BnNHOH. A mixture of the crude BnNHOH, 31 (200 mg,
0.28 mmol), and 4-ꢄ mol. sieves in dry pyridine (5 ml) was heated for 12 h at 1008 and evaporated. FC
1
(hexane/AcOEt 98 :2 ! 1:1) afforded 32/33. H-NMR (300 MHz, CDCl3; a-33/b-33 ca. 3 :1, traces of
32): 7.76 (d, J ¼ 8.2, 2 arom. H); 7.62 (d, J ¼ 8.2, 2 arom. H); 7.40 – 7.05 (m, 26 arom. H, 1 H of a-33); 6.92
(d, J ¼ 7.4, 1 arom. H of b-33); 5.60 (d, J ¼ 7.1, H ꢀC(1) of a-33); 5.26 (d, J ¼ 2.2, HꢀC(1) of b-33); 5.19
(dd, J ¼ 6.1, 7.4, HꢀC(2) of b-33); 4.82 (d, J ¼ 11.8, PhCH of a-33); 4.70 (d, J ¼ 12.1 and 11.6, 2 PhCH of
a-33); 4.32 (d, J ¼ 11.3, PhCH of a-33); 4.30 (d, J ¼ 11.6, PhCH of a-33); 4.23 (dt, J ¼ 4.7, 2.9, 1 H of a-33);
4.14 (dd, J ¼ 9.9, 3.6, 1 H of a-33); 4.65 – 3.94 (m, 10 H and 4 H of a-33); 3.60 (dd, J ¼ 4.7, 9.6, HaꢀC(6) of
b-33); 3.46 (dq, J ¼ 8.8, 2.2, HaꢀC(6) of a-33); 3.16 (dd, J ¼ 6.9, 9.6, HbꢀC(6) of b-33); 2.77 (dd, J ¼ 7.9,
10.2, HbꢀC(6) of a-33); 2.37 (s, Me of a-33); 2.31 (s, Me of b-33).
2,3,4,6-Tetra-O-benzyl-5-deoxy-5-[(4-methylphenylsulfonyl)amino]-1-N-(phenylmethylidene)-b-d-
glucopyranosylamine N-Oxide (34). A soln. of 32/33 in ClCH2CH2Cl (5 ml) was treated with MnO2
(625 mg, 7.20 mmol), kept at reflux for 48 h, and filtered over Celite. Evaporation and FC (hexane/
AcOEt 95 :5 ! 4 :1) gave 34 (120 mg, 78% from 30). Colourless oil. Rf (hexane/AcOEt 4 :1) 0.38. [a]D25
¼
ꢀ 45.4 (c ¼ 1.0, CHCl3). IR (ATR): 3062w, 3030w, 2869w, 1735m, 1597w, 1578w, 1563w, 1495w, 1453m,
1350m, 1305w, 1241w, 1207w, 1187m, 1165s, 1142w, 1086s, 1069s, 1027m, 982w, 904w, 836w, 811w, 734s,
693s, 665m. 1H-NMR (300 MHz, CD2Cl2; assignments based on selective homodecoupling experiments):
see Table 2; additionally, 8.19 – 8.14 (m, 2 arom. H); 7.64 (s, HC¼N); 7.65 – 7.41 (m, 2 arom. H); 7.47 – 7.41
(m, 3 arom. H); 7.35 – 6.97 (m, 22 arom. H); 4.70 (d, J ¼ 10.6), 4.67 (d, J ¼ 11.3), 4.62 (d, J ¼ 11.8), 4.61 (d,
J ¼ 11.3) (4 PhCH); 4.53 (s, PhCH2); 4.42 (d, J ¼ 11.7), 4.37 (d, J ¼ 10.8) (2 PhCH); 2.28 (s, Me).
13C-NMR (75 MHz, CDCl3; assignments based on a HSQC spectrum): see Table 2; additionally, 143.98
(d, CH¼N); 138.06, 137.98, 137.87, 137.23, 136.13, 135.83 (6s); 130.75 – 127.39 (several d); 75.99, 74.38,
73.14, 70.72 (4t, 4 PhCH2); 21.74 (q, Me). HR-MALDI-MS: 835.2850 (38, [M þ K]þ, C48H48KN2O7Sþ;
calc. 835.2814); 819.3059 (100, [M þ Na]þ, C48H48N2NaO7Sþ; calc. 819.3074). Anal. calc. for C48H48N2O7S
(796.98): C 72.34, H 6.07, N 3.51; found: C 72.05, H 6.14, N 3.42.

Helvetica Chimica Acta – Vol. 93 (2010)
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2,3,4,6-Tetra-O-benzyl-1,5-dideoxy-5-[(4-methylphenylsulfonyl)amino]-1-nitro-a-d-glucopyranose
(35). A soln. of 34 (100 mg, 0.14 mmol) in CD2Cl2 (5 ml) was cooled to ꢀ 788. O3 was bubbled through
the soln. until disappearance of 34. The soln. was purged with N2, and a 1H-NMR spectrum of the
reaction mixture was recorded. 1H-NMR (300 MHz, CD2Cl2, ꢀ 108 assignments based on selective
homodecoupling experiments): see Table 2; additionally, 7.72 (d, J ¼ 8.3, 1 arom. H); 7.36 – 6.99 (m, 23
arom. H); 4.67 (s, PhCH2); 4.49 (d, J ¼ 11.8), 4.41 (d, J ¼ 12.1) (2 PhCH); 4.39 (s, PhCH2); 4.28 (d, J ¼
11.6), 4.21 (d, J ¼ 11.6) (2 PhCH); 2.27 (s, Me). TLC showed two spots, one of PhCHO, and one of 31,
1
identified by H-NMR after evaporation of the solvent.
6-Azido-2,3,4,7-tetra-O-benzyl-5-{[(tert-butoxy)carbonyl]amino}-1-5,6,8-trideoxy-d-erythro-d-gal-
acto-octose N-Benzylimine N-Oxide (36). A soln. of BnNHOH · HCl (225 mg, 1.41 mmol) in MeOH
(5 ml) was treated with NaHCO3 (120 mg, 1.41 mmol), stirred for 15 min, and evaporated. A soln. of the
residue in CH2Cl2 was washed with H2O and brine. The org. layer was dried (MgSO4) and evaporated. A
mixture of the residue (BnNHOH), 14 (200 mg, 0.282 mmol), and 4-ꢄ mol. sieves in BuOH (10 ml) was
heated to 808 for 12 h, cooled to 258, filtered over Celite, and evaporated. A soln. of the residue in AcOEt
was washed with 0.1n HCl and brine, dried (MgSO4), and evaporated. FC (hexane/AcOEt 95 :5 ! 1:1)
gave 36 (208 mg, 90%). Colourless oil. Rf (hexane/AcOEt 4 :1) 0.19. [a]2D5 ¼þ 6.7 (c ¼ 1.02, CHCl3). IR
(ATR): 3434w, 3064w, 3031w, 2978w, 2927w, 2869w, 2103m, 1711m, 1584w, 1495m, 1454m, 1391w, 1381w,
1366w, 1306w, 1247w, 1220w, 1162m, 1070s, 1048m, 1027m, 940w, 909w, 859w, 733s, 695s. 1H-NMR
(300 MHz, CDCl3; assignments based on selective homodecoupling experiments): 7.39 – 7.20 (m, 20
arom. H, NH); 6.60 (d, J ¼ 6.6, HꢀC(1)); 5.09 (dd, J ¼ 6.9, 2.4, HꢀC(2)); 4.98 (d, J ¼ 10.2), 4.59 (d, J ¼
11.4), 4.57 (d, J ¼ 11.1), 4.52 (d, J ¼ 11.1), 4.51 (d, J ¼ 12.0), 4.43 (d, J ¼ 12.0, 2 H), 4.41 (d, J ¼ 10.2), 4.37
(d, J ¼ 12.0) (9 PhCH); 4.23 (br. d, J ꢂ 9.0, HꢀC(4)); 4.09 (d, J ¼ 11.1, PhCH); 3.77 (br. t, J ¼ 10.2,
HꢀC(5)); 3.73 (dd, J ¼ 8.4, 2.4, HꢀC(3)); 3.71 (qd, J ¼ 6.3, 2.4, HꢀC(7)); 3.55 (dd, J ¼ 10.5, 2.1,
HꢀC(6)); 1.37 (s, t-Bu); 1.31 (d, J ¼ 6.0, Me). 13C-NMR (75 MHz, CDCl3; assignments based on a HSQC
spectrum): 155.00 (s, C¼O); 138.16 (2d, HC¼N, 1 arom. C); 137.88 (2 C), 137.59, 132.13 (3s, 4 arom. C);
129.35 – 127.25 (several d); 79.68 (s, Me3C); 78.13 (d, C(3)); 76.45 (d, C(4)); 75.77 (d, C(7)); 74.87, 74.40
(2t, 2 PhCH2); 73.69 (d, C(2)); 72.14, 70.35, 69.85 (3t, 3 PhCH2); 65.44 (d, C(6)); 50.26 (d, C(5)); 28.30 (q,
Me3C); 14.10 (q, Me). HR-MALDI-MS: 852.3735 (69, [M þ K]þ, C48H55KN5O7þ ; calc. 852.3733),
836.3989 (100, [M þ Na]þ, C48H55N5NaO7þ ; calc. 836.3994), 814.4170 (41, [M þ H]þ, C48H56N5Oþ7 ; calc.
814.4174), 606.3075 (51, [M ꢀ Boc ꢀ BnNOH þ H þ OH]þ, C36H38N4O5þ ; calc. 606.2842), 591.2963 (21,
[M ꢀ Boc ꢀ BnNOH þ H]þ, C36H38N4O4þ ; calc. 591.2971). Anal. calc. for C48H55N5O7 (813.99): C 70.83,
H 6.81, N 8.60; found: C 70.56, H 6.90, N 8.35.
(E/Z)-6-Azido-2,3,4,7-tetra-O-benzyl-5-{[(tert-butoxy)carbonyl]amino}-5,6,8-trideoxy-1-N-(phe-
nylmethylidene)-d-erythro-b-d-galacto-octopyranosylamine N-Oxide (17). A soln. of 36 (110 mg,
0.13 mmol), LiI (36 mg, 0.27 mmol), and PbO2 (325 mg, 1.35 mmol) in toluene/pyridine 2 :1 (6 ml)
was heated to 608 for 4 h, cooled to r.t., filtered over Celite, and evaporated. FC (Al2O3 Akt. 1, hexane/
AcOEt 98 :2 ! 4 :1) gave 17 (79 mg, 63%). Slightly pink oil. Rf (hexane/AcOEt 3 :1) 0.17. [a]2D5 ¼ ꢀ2.5
(c ¼ 1.2, CHCl3). IR (ATR): 3031w, 2978w, 2932w, 2865w, 2107m, 1710m, 1578w, 1563w, 1496w, 1454m,
1368m, 1326m, 1244m, 1150w, 1091s, 1047m, 1026m, 922w, 875w, 849w, 805w, 776w, 732s, 693s. 1H-NMR
(300 MHz, (D6)DMSO, 1008; (E)/(Z) 3 :2; assignments based on selective homodecoupling experi-
ments): 7.39 – 7.20 (m, 2 arom. H); 7.84 (s, HC¼N (E)); 7.73 (s, HC¼N (Z)); 7.45 – 7.18 (m, 23 arom. H);
6.01 (d, J ¼ 5.7, HꢀC(1) (Z)); 5.81 (d, J ¼ 5.1, HꢀC(1) (E)); 4.92 – 4.26 (m, 11.4 H); 4.10 (br. t, J ¼ 7.5,
1 H (E)); 3.96 – 3.86 (m, 1.4 H); 3.83 (dd, J ¼ 8.1, 1.8, 1 H (E)); 1.38 (s, t-Bu (E)); 1.34 (s, t-Bu (Z)); 1.23
(d, J ¼ 6.0, Me (E)); 1.15 (d, J ¼ 6.3, Me (Z)). 13C-NMR (75 MHz, CDCl3, 608; (E)/(Z) 3 :2); 154.94 (s,
C¼O); 138.87 – 137.87 (several s); 131.91 (s); 130.32 (s); 130.23 (d, HC¼N (Z)); 129.93 (d, HC¼N (E));
128.63 – 127.04 (several d); 86.46 (d, 1 C); 83.00 (s, Me3C); 81.46 (d, C (E)); 80.37 (d, C (Z)); 77.87 (d, C
(E)); 76.44 (d, C (Z)); 76.20 (d, C (Z)); 75.59 (d, C (E)); 75.08 (d, C (Z)); 74.32 (t, PhCH2 (E)); 73.99 (d,
C (E)); 73.84 (t, PhCH2 (Z)); 73.68 (t, PhCH2 (Z)); 73.43 (t, PhCH2 (E), PhCH2); 70.51 (t, PhCH2 (Z));
70.35 (t, PhCH2 (E)); 65.25 (d, C(6)); 55.72 (d, C(5) (Z)); 55.59 (d, C(5) (E)); 28.21 (q, Me3C (E)); 28.12
(q, Me3C (Z)); 15.57 (q, Me). HR-ESI-MS: 850.3611 (2, [M þ K]þ, C48H53KN5O7þ ; calc. 850.3577);
834.3838 (100, [M þ Na]þ, C48H53N5NaOþ7 ; calc. 834.3837). Anal. calc. for C48H53N5O7 (811.98): C 71.00,
H 6.58, N 8.63; found: C 71.00, H 6.64, N 8.46.

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Received August 29, 2010