Synthesis of 1-deoxymannojirimycin analogues using N-tosyl and N-nosyl activated aziridines derived from 1-amino-1-deoxyglucitol

Article abstract of DOI:10.1016/S0040-4020(01)00650-0

3,4;5,6-Diisopropylidene protected 1-amino-1-deoxy-D-glucitol was transformed into N-tosyl and N-nosyl activated aziridine intermediates, which underwent ring opening by reaction with various nucleophiles. The 5,6-diols resulting from selective hydrolysis of the terminal acetal group were subjected to (2-N→6-OH) cyclisation using two different methods for activation of 6-OH. Final deprotection of the N-nosyl and 3,4-acetal group proceeded smoothly to afford 6-substituted analogues of 1-deoxymannojirimycin.

Full text of DOI:10.1016/S0040-4020(01)00650-0

TETRAHEDRON
Pergamon
Tetrahedron 57 12001) 6955±6967
Synthesis of 1-deoxymannojirimycin analogues using N-tosyl
and N-nosyl activated aziridines derived
from 1-amino-1-deoxyglucitol
Hua Mao, Gert J. Joly, Koen Peeters, Georges J. Hoornaert and Frans Compernollep
Laboratorium voor Organische Synthese, Department of Chemistry, K.U. Leuven, Celestijnenlaan 200F, B-3001 Heverlee-Leuven, Belgium
Received 30 March 2001; revised 1 June 2001; accepted 19 June 2001
AbstractÐ3,4;5,6-Diisopropylidene protected 1-amino-1-deoxy-d-glucitol was transformed into N-tosyl and N-nosyl activated aziridine
intermediates, which underwent ring opening by reaction with various nucleophiles. The 5,6-diols resulting from selective hydrolysis of the
terminal acetal group were subjected to 12-N!6-OH) cyclisation using two different methods for activation of 6-OH. Final deprotection of
the N-nosyl and 3,4-acetal group proceeded smoothly to afford 6-substituted analogues of 1-deoxymannojirimycin. q 2001 Elsevier Science
Ltd. All rights reserved.
1. Introduction
interesting route for the synthesis of variously substituted
polyhydroxypiperidines, which proceeds via nucleophilic
ring opening of an N-sulfonyl activated aziridine inter-
mediate. The present work forms an extension of our
`inversed chain strategy' concept, which implies that ring
closure to form the piperidine derivative occurs between the
original carbon C-6 of 1-aminoglucitol 1which is to become
C-1 of the iminosugar) and an amino group introduced at
C-29 1Fig. 1).
Many naturally occurring polyhydroxylated piperidines
show inhibitory activities towards glycosidases and may
have therapeutic value in the treatment of cancer,1 diabetes,2
and viral infections3 1including AIDS).4 Among these
azasugars 1-deoxynojirimycin 1 and 1-deoxymannoji-
rimycin 2, inhibitors of glucosidases5 and mannosidases6
respectively, represent archetypal structures where the ring
oxygen of the corresponding pyranosyl carbohydrates has
been replaced with a nitrogen atom.
2. Results and discussion
In our previous work, diverging strategies were applied in
order to transform 1-aminoglucitol 3 into various analogues
of 1-deoxynojirimycin7 and castanospermine.8 Thus, the
crystalline 3,4;5,6-di-O-isopropylidene ammonium salt
derivative 4 was isolated and converted to polyhydroxy-
piperidines modi®ed at C-2and C-6. We now describe an
Our synthetic approach involves conversion of the ammo-
nium salt 4 of 3,4;5,6-di-O-isopropylidene-1-deoxy-1-
aminoglucitol into an N-tosyl or N-nosyl-1,2-aziridine
inverted at the 2-position 1Scheme 1). Subsequent ring
opening of the N-sulfonyl aziridines is effected by reaction
Figure 1.
Keywords: aziridines; Mitsunobu reactions; carbohydrates; piperidines; deoxymannojirimycin.
Corresponding author. Tel.: 132-16-327407; fax: 132-16-327990; e-mail: frans.compernolle@chem.kuleuven.ac.be
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020101)00650-0

6956
H. Mao et al. / Tetrahedron 57 .2001) 6955±6967
Scheme 1.
with various nucleophiles to produce the corresponding
2-aminoalditol compounds. Final ring closure proceeds via
deprotection of the 5,6-diol and displacement of the
activated 6-OH group by the 2-amino nitrogen. A similar
strategy which involved the ring opening of bis1aziridines),
was applied by Depezay et al. to prepare analogues of
1-deoxynojirimycin and 1-deoxymannojirimycin.10
H-10 were differentiated into two doublet signals detected at
2.43 and 2.65 ppm, respectively 1geminal coupling value
2Jù0 Hz). In the 13C NMR spectrum the values observed
1
for the JC±H coupling constants 1171 and 179 Hz for C-1
and 171 Hz for C-2) were in agreement with those reported
for N-methylaziridine.11
In view of the harsh conditions12 required for removal of the
N-tosyl group at a later stage, it was of interest to extend the
preceding N-tosyl route to provide the corresponding
p-nitrobenzenesulfonyl 1N-nosyl) aziridine. Indeed, removal
of the N-nosyl protecting group proceeds under much milder
conditions, i.e. via attack of thiophenolate anion at the
sulfonyl ipso position.13 In our initial attempt to prepare
2-O-mesylate 7, we applied a similar one-pot procedure as
that described for the N-tosyl analogue 5, using triethyl-
amine as a base for both N-nosylation of 4 and subsequent
In a ®rst approach 1Scheme 2) the ammonium salt 4 was
converted to the N-tosyl derivative, and the latter was
mesylated at the 2-OH position using a `one-pot procedure'
to produce mesylate 5 in 92% overall yield. Upon treatment
with sodium hydride in THF, compound 5 was converted to
the N-tosylaziridine 6 in 90% yield. The aziridine structure
6 was con®rmed by 1H- and 13C NMR data. In the 1H NMR
spectrum 1CDCl3) the absorption due to the NH-proton of
the tosylamide 5 had disappeared, while the protons H-1 and
Scheme 2. Reagents and conditions: 1a) 4 equiv. Et3N, 1.5 equiv. p-TsCl, CH2Cl2, 2 08C, 30 min; then 1.3 equiv. MsCl, 208C, 1 h; 1b) 2equiv. NaH 180%),
THF, 208C, 1 h.
Scheme 3. Reagents and conditions: 1a) 4 equiv. Et3N, 1.5 equiv. p-NsCl, CH2Cl2, 2 08C, 30 min; then 1.3 equiv. MsCl, 208C, 1 h; 1b) Na2CO3 1aq. sat.
solution)/CH2Cl2 11.5:1), 1.5 equiv. p-NsCl, 208C, 30 min; CH2Cl2/pyridine 14:1), 1.5 equiv. MsCl, 0±208C, 4 h; 1c) 2equiv. NaH, THF, 20 8C, 4 h.

H. Mao et al. / Tetrahedron 57 .2001) 6955±6967
6957
Scheme 4. Reagents and conditions: see Table 1.
2-O-mesylation. However, due to the more acidic character
of the N-nosyl amide, these conditions led to formation of
the N,O-dimesylate 8 instead of 2-O-mesylate 7. The
unwanted N-mesylation could be avoided by using the
weaker base pyridine, but under these conditions a mixture
of N-nosyl and N-tosyl 2-O-mesylates was obtained,
probably due to formation of a mixed sulfonic anhydride
between nosyl chloride and the tosylate counterion of 4.
This problem could be avoided by using an aqueous
Na2CO3/CH2Cl2 two-phase system to remove the tosylate
anion from the organic phase. Subsequent 2-O-mesylation
in CH2Cl2-pyridine 189% overall yield from 4) and ®nal
treatment with NaH in THF afforded the required N-nosyl
aziridine 9 174%) 1Scheme 3).
formation was observed in the reactions with the more
nucleophilic carbanionic reagents producing 10e and 10g,
and in those cases where the intermediate N-sulfonylamide
anion could abstract an acidic proton, i.e. in the reaction
with amine 110f), malonate 110c), and sulfonylacetonitrile
110d). Only one of two possible diastereomers 10d was
1
detected by H- and 13C NMR analysis. Presumably this is
due to equilibration occurring at the acidic stereogenic
centre C-2to yield the more stable product. In analogy
to the copper1I)-catalysed ring opening of epoxides by
Grignard reagents,14 the reaction with phenylmagnesium
bromide only succeeded upon addition of catalytic copper-
1I)iodide. However, the latter copper1I) catalysed ring
opening reaction using PhMgBr as a nucleophile, did not
succeed when applied to the N-nosyl aziridine 9. Interest-
ingly, treatment of 9 with thiophenolate 1the reagent that is
also used later on for deprotection of the nosylamide func-
tion) at room temperature for 1 h led to clean production of
1-phenylthio compound 11h without any side reaction due
to cleavage of the N-nosyl protecting group.
The N-tosyl and N-nosyl aziridines 6 and 9 were submitted
to reaction with various nucleophiles to produce the corre-
sponding ring opened products 10 and 11 in good to excel-
lent yields 1Scheme 4). Reaction conditions and yields are
given in Table 1. Due to a better stabilisation of the inter-
mediate N-sulfonylamide anion formed by opening of the
aziridine ring, this reaction proceeds more readily for the
nosyl substrate 9. One problem encountered when using
sodium azide or potassium acetate as the nucleophile to
prepare the corresponding 1-azido and 1-acetoxy-N-tosyl
aziridines 10a,b was the formation of dimeric products.
This side reaction results from the competitive attack of
the N-tosylamide anion 1formed after ring opening) on a
second molecule of aziridine and could be suppressed
by using ten equivalents of the nucleophile. No dimer
Next, representative members of the N-tosyl 110a) and
N-nosyl 111a,h) 2-deoxy-2-aminomannitol derivatives
were subjected to a sequence consisting of cleavage of the
5,6-O-isopropylidene group and activation of the 6-OH
group to form the piperidine ring 1Scheme 5). Regio-
selective deprotection of the terminal acetal group was
accomplished by treatment with an acidic ion exchange
resin 1Dowex 50X8-200) to give the corresponding
5,6-diols 12a and 13a,h in good yields 172±92%). Both
Table 1.
Product
Nu
Conditions
Reaction time 1h)
1tosyl) 10
Reaction time 1h)
1nosyl) 11
Yield 1%)
1tosyl) 10
Yield 1%)
1nosyl) 11
10a, 11a
10b, 11b
10c, 11c
10d
10e
10f
N3
OAc
CH1COOMe)2
CH1CN)SO2Ph
Ph
NHBn
1,3-dithian-2-yl
SPh
a
b
c
d
e
f
30
18
48
24
1
24
8
1290
4
24
1
96
83
65
87
75
67
90
±
98
78
mixt.a
mixt.a
±
±
89
n. triedb
n. triedb
1
10g
11h
g
h
4
n. triedb
Reagents and conditions: 1a) 10 equiv. NaN3, DMF 908C; 1b) 10 equiv. KOAc, DMF, 908C; 1c) 2equiv. 1MeO 2C)2CH2, 2.5 equiv. NaH, THF, 08C±rt;
1d) 1.2equiv. PhSO 2CH2CN, 1.2equiv. NaH, THF, 0 8C±rt; 1e) 5 equiv. PhMgBr, 0.1 equiv. CuI, THF, rt; 1f) 1.2equiv. BnNH 2, DMF, 908C: 1g) 2equiv.
1,3-dithiane, 2equiv. BuLi, THF, 0 8C; 15 min; then rt, 4 h; 1h) 3 equiv. PhSH, 3 equiv. K2CO3, DMF, rt.
a
mixt.: Product mixture was not well characterized.
n.tried: Reaction was not tried
b

6958
H. Mao et al. / Tetrahedron 57 .2001) 6955±6967
Scheme 5. Reagents and conditions: 1a) Dowex 50X8-200, 9:1/ MeOH/H2O, rt, 30 h±7 days; 1b) Ph3P, DEAD, THF, rt, 5 days; 1c) pyridine, Ac2O, rt, 2h.
Mitsunobu15 and Appel16 reaction conditions were applied
to achieve selective activation of the 6-OH group and subse-
quent cyclisation. Treatment of 12a with triphenylphos-
phine and diethyl azodicarboxylate in anhydrous THF
produced the piperidine compound 14a. At room tempera-
ture, and even at 40±608C, the cyclisation reaction was
found to proceed very slowly. After several days, TLC
and mass spectrometric analysis con®rmed that all starting
material had been consumed. However, due to co-eluting
substances originating from the Mitsunobu reagent, iso-
lation of the alcohol product 14a proved to be dif®cult,
and therefore the latter was converted to the less polar
acetate 15a, which was isolated in moderate yield
1combined yield for steps b and c 45%); spectroscopic
data were in accordance with the proposed piperidine
structure.
11a,h. However, although reaction of 16a,h with NaH in
THF gave the expected 5,6-epoxide, the latter failed to
cyclise even under more forcing re¯ux conditions using
t-BuOK in i-PrOH. To explore the alternative route
involving protection of the 5-OH group, acetylation of
compounds 16a,h was carried out under various conditions.
When using Ac2O, Et3N, and DMAP in CH2Cl2, the
N,O-diacetyl compounds 17a,h were produced. However,
selective O-acylation to form the mono-acetylated deriva-
tives 18a,h could be accomplished by replacing the Et3N
and DMAP reagents with the less basic pyridine. 1For most
experiments proceeding through mono-O-acetylation the
preceding Appel reaction of 5,6-diols 13a,h was carried
out using CI4 instead of CBr4, resulting in the production
of 16a,h and 18a,h as the 6-iodo derivatives.) Subsequent
conversion of 18a,h into piperidines 19a,h was achieved in
a separate slow cyclisation step using DMAP to effect
NH-deprotonation and intramolecular 6-I 16-Br) substi-
tution. Surprisingly, the required piperidines 19a,h could
also be prepared by reaction of the N,O-diacetyl compounds
17a,h with an excess of DMAP. TLC analysis revealed the
formation of N-deacetylated compounds 18a,h as inter-
mediates, presumably via deprotonation of the N-acetyl
group and expulsion of ketene to generate the nosylamide
anion. Finally, the three-step conversion 116!17!18!19)
proceeding via N,O-diacetylation, N-deacetylation and
cyclisation could be combined in an ef®cient one-pot pro-
cedure by using an excess of DMAP relative to acetic
In contrast, no cyclisation was observed when diols 13a,h
were submitted to the above Mitsunobu reaction conditions.
Therefore we resorted to the Appel reaction to introduce a
6-bromo 1or 6-iodo) leaving group. Subsequent N-2!C-6
cyclisation was envisioned to proceed either via base-
promoted generation of the 5,6-epoxide or via 5-OH protec-
tion prior to displacement of the 6-halogen atom by the
nosylamide anion. Treatment of the 5,6-diols 13a,h with
Ph3P and CBr4 in THF at room temperature for 30 min
afforded the 6-bromo compounds 16a,h in 75 and 83%
overall yield respectively, calculated from diacetonides
Scheme 6. Reagents and conditions: 1a) Ph3P, CBr4, THF, rt, 30 min 1or Ph3P, CI4, THF, rt, 18 h); 1b) Et3N 14 equiv.), DMAP 11 equiv.), Ac2O 14 equiv.),
CH2Cl2; 1c) CH2Cl2/pyridine 14:1), Ac2O 14 equiv.); 1d) see conditions 1b), excess of DMAP, 4 days; 1e) CH2Cl2, excess of DMAP, 4 days.

H. Mao et al. / Tetrahedron 57 .2001) 6955±6967
6959
Scheme 7. Reagents and conditions: 1a) MeOH, K2CO3, 2h; 1b) PhSH, K 2CO3 MeCN/DMSO 149:1), 508C, 2h; 1c) sat. HCl/MeOH.
anhydride, to produce 19a and 19h in 76 and 79% overall
yield, respectively 1Scheme 6).
3. Conclusion
In this work we used N-tosyl and N-nosyl activated aziri-
dines for the synthesis of monocyclic iminosugars, i.e.
6-substituted 1,6-dideoxymannojirimycin analogues. The
potential offered by N-sulfonylaziridines of type 6 and 9
as synthons for the construction of various iminosugars is
demonstrated by the varying nature of the nucleophiles
utilised for ring opening, i.e. nitrogen-, oxygen-, and
carbon-based reagents. In particular, application of carbon
nucleophiles may pave the way for the introduction of more
complex substituents, especially in view of the synthesis of
C-azadisaccharides.17 Although both N-tosyl and N-nosyl
aziridines appear to be attractive intermediates allowing
for ready opening of the three-membered ring and subse-
quent ring closure to form the piperidine ring, the N-nosyl
derivatives are preferred, as they can easily be removed at
the end of the synthetic sequence.
To ®nalise our synthetic sequence, we had to remove the
N-sulfonyl and alcohol protecting groups. At this point the
route proceeding via cleavage of the N-tosyl group was not
continued since application of the sodium-naphthalene
procedure12 resulted in poor yields of the free amine.
However, deprotection of the N-nosyl compounds 19a,h
was achieved without dif®culty. Following base-catalysed
solvolysis of the 2-O-acetyl group, the N-nosyl group was
removed by treatment with thiophenol and K2CO3 in aceto-
nitrile/DMSO 149:1) at 508C to afford free amines 20a,h.13
Final acid deprotection of the 3,4-O-isopropylidene group
followed by column chromatography on silica gel furnished
the 1-deoxymannojirimycin analogues 21a,h in good yields
1Scheme 7).
From the coupling constant values in the 1H NMR spectra it
appears that piperidines 20 and 21 with free amino group
adopt the expected chair conformation 1J3,4ˆJ4,5ˆca. 9 Hz
4. Experimental
P
for H-3ax and H-4ax, and Jˆca. 7 Hz for the coupling
of H-2eq with H-1, H-10, and H-3ax). However, for the
N-sulfonyl piperidines 15 and 19, divergent torsional angles
4.1. General methods
for H-1,H-2were indicated by the coupling values observed
Melting points are uncorrected. The optical rotations were
measured on a Propol polarimeter ®tted with a 7 cm cell. IR
spectra were recorded as thin ®lms between NaCl plates or
as KBr pellets on a Perkin±Elmer 297 grating IR spectro-
P
for H-2, i.e. J2,1ˆca. 8 and 6 Hz and J2,3ˆ5.2Hz 1 Jˆ
19 Hz). As reported already for some N-Boc analogues,7a
these values conform to the twist-boat conformer depicted
in Fig. 2. Apparently, the chair form of compounds 15 and
19 is disfavoured by the upward orientation imposed on the
N-sulfonyl substituent by the planar sp2 ring nitrogen,
resulting in a strong repulsive interaction with the nearly
coplanar side chain. This repulsion can be minimised by
adopting the twist-boat conformer.
1
photometer. H- and 13C NMR were recorded on Bruker
AMX 400 and WM 250 instruments operating at 400 and
250 MHz for 1H and 100 and 62.9 MHz for 13C. 1H and 13
C
chemical shifts are reported in ppm relative to tetramethyl-
silane as an internal reference. J values are reported in Hz.
EI and CI mass spectra were run on Hewlett±Packard
Figure 2.

6960
H. Mao et al. / Tetrahedron 57 .2001) 6955±6967
MS-Engine 5989A or Kratos MS50TC instruments; the ion
source temperature was 150±2508C as required. Exact mass
measurements were performed at a resolution of 10,000.
Analytical and preparative thin layer chromatography was
carried out using Merck silica gel 60 PF-224. Column
chromatography was done using 70±230 mesh silica gel
60 1E. M. Merck). The purity of compounds was checked
by TLC using the solvent systems mentioned for column
chromatography. Solutions were dried over MgSO4. All
reactions were performed under a nitrogen atmosphere.
Dry solvents were freshly distilled before use.
1), 2.44 1s, 3H, Me-Ts), 2.65 1d, 1H, Jˆ7.0 Hz, H-10), 3.11
1ddd, 1H, Jˆ7.0, 4.5, 4.0 Hz, H-2), 3.74 1t, 1H, Jˆ7.0 Hz,
H-4), 3.88 1dd, 1H, Jˆ8.5, 5.5 Hz, H-6), 3.96 1dd, 1H,
Jˆ7.0, 4.0 Hz, H-3), 3.97±4.00 1m, 1H, H-5), 4.08 1dd,
1H, Jˆ8.5, 6.0 Hz, H-60), 7.34 1d, 2H, Ts-H), 7.83 1d, 2H,
Ts-H); 13C NMR 1100 MHz, CDCl3) 2 1.6 M1 e,Ts), 25.2,
26.5, 26.8, 27.0 1Me2C), 30.4 1C-1), 40.1 1C-2), 67.1
1C-6), 76.4, 77.6, 79.1 1C-3, 4, 5), 109.8, 110.4 1Me2C),
128.2, 129.7 1CH, Ts), 134.7, 144.7 1C-ipso, Ts); MS 1CI,
methane), m/z 1%): 398 1MH1, 45%), 340 1MH12acetone,
100%), 282 1MH122acetone, 28%); HRMS: calcd for
C18H24O6NS 1M12Me) 382.1324, found 382.1329 167%).
4.1.1. 1-Deoxy-3,4;5,6-di-O-isopropylidene-2-O-methane-
sulfonyl-1-0N-p-toluenesulfonyl)-amino-d-glucitol
05).
4.1.3. 1-Deoxy-3,4;5,6-di-O-isopropylidene-2-O-methane-
sulfonyl-1-0N-p-nitrobenzenesulfonyl)-amino-d-glucitol
07). The ammonium salt 4 113.06 g, 30.2mmol) was added
to a two-phase system consisting of 100 mL CH2Cl2 and
150 mL Na2CO3 1aq. sat. solution), and the mixture was
stirred for 10 min. After adding p-NsCl 110.03 g,
45.3 mmol) the reaction mixture was stirred at room
temperature until TLC showed the disappearance of starting
materials 1about 1 h). The organic layer was separated and
the aqueous layer was extracted three times with CH2Cl2
13£20 mL). The organic layers were combined and dried
on MgSO4. After evaporation of the solvent, the residue
was redissolved in 100 mL, CH2Cl2 and the solution was
cooled to 08C. Pyridine 125 mL, 0.30 mol) and MsCl
14.67 mL, 60.4 mmol) were added. After reaction for 1 h
the mixture was worked up by adding 30 mL saturated
NH4Cl, and extracted three times with CH2Cl2 13£15 mL).
The organic phase was dried on MgSO4 and evaporated.
Column puri®cation on silica gel 1EtOAc/hexanes 40:60)
afforded a colourless oil 17) 114.13 g, 89%); [a]Dˆ145
The ammonium salt 4 110.00 g, 23.1 mmol) was suspended
in dry CH2Cl2 1100 mL), and to this suspension was added
13.0 mL, Et3N 192mmol) and 4.85 g p-TsCl 126 mmol) at
08C. The mixture was stirred at room temperature for
30 min until TLC showed the disappearance of starting
material. After cooling the mixture to 08C, MsCl 13.60
mL, 30.0 mmol) was added, and the mixture was stirred at
room temperature for 1 h. The reaction was worked up by
adding 30 mL NH4Cl 1aq. sat. solution). The mixture was
extracted three times with CH2Cl2 13£15 mL) the organic
phase was dried with MgSO4 and the product was puri®ed
by column chromatography on silica gel 1EtOAc/hexanes
50:50). A colourless oily product 15) was obtained 110.5 g,
92%); [a]Dˆ112.9 1c 0.42, CH2Cl2); IR 3295, 2995, 2940,
1450, 1380, 1345, 1165 cm21; 1H NMR 1400 MHz, CDCl3)
d 1ppm) 1.33 1s, 3H, Me2C), 1.37 1s, 3H, Me2C), 1.38 1s, 3H,
Me2C), 1.39 1s, 3H, Me2C), 2.43 1s, 3H, Me,Ts), 3.13 1s, 3H,
MeSO3), 3.31 1ddd, 1H, Jˆ14.0, 6.0, 5.0 Hz, H-1),
3.311ddd, 1H, Jˆ14.0, 8.0, 4.0 Hz, H-10), 3.88 1dd, 1H,
Jˆ8.5, 7.0 Hz, H-4), 3.91 1dd, 1H, Jˆ8.5, 5.5 Hz, H-6),
4.00 1ddd, 1H, Jˆ8.5, 6.0, 5.5 Hz, H-5), 4.05 1dd, 1H,
Jˆ7.0, 3.5 Hz, H-3), 4.17 1dd, 1H, Jˆ8.5, 6.0 Hz, H-60),
4.80 1ddd, 1H, Jˆ6.0, 4.0, 3.5 Hz, H-2), 5.31 1dd, 1H,
Jˆ8.0, 5.0 Hz, NH), 7.32 1d, 2H, Ts-H), 7.76 1d, 2H,
Ts-H); 13C NMR 1100 MHz, CDCl3) 21.5 1Me,Ts), 25.1,
26.2, 26.4, 27.2 1Me2C), 39.0 1MeSO3), 45.0 1C-1), 67.9
1C-6), 77.0, 77.5, 77.6, 80.21 C-2, 3, 4, 5), 110.2, 110.7
1Me2C), 127.1, 129.8 1CH, Ts), 136.7, 143.7 1C-ipso, Ts);
MS 1CI, methane), m/z 1%): 494 1MH1, 47%), 436 1MH12
acetone, 46%), 398 1MH12MsOH, 36%), 49 1100%);
HRMS: calcd for C19H28O9NS2 1M12Me) 478.1206,
found 478.1207 136%).
1CHCl3, c 0.22); IR 3290, 2990, 1532 cm21 1H NMR
;
1400 MHz, CDCl3) d 1ppm), 1.34 1s, 3H, Me2C), 1.37 1s,
3H, Me2C), 1.38 1s, 3H, Me2C), 1.39 1s, 3H, Me2C), 3.13 1s,
3H, MeSO3), 3.38 1ddd, 1H, Jˆ14.5, 6.0, 4.7 Hz, H-1), 3.60
1ddd, 1H, Jˆ14.5, 7.8, 3.9 Hz, H-10), 3.86 1dd, 1H, Jˆ8.5,
6.9 Hz, H-4), 3.921dd, 1H, Jˆ8.7, 5.5 Hz, H-6), 4.021dt,
1H, Jˆ8.5, ca. 6.2Hz, H-5), 4.05 1dd, 1H, Jˆ6.9, 3.9 Hz, H-
0
3), 4.17 1dd, 1H, Jˆ8.7, 6.2Hz, H-6 ), 4.77 1td, 1H, Jˆca.
6.5, 3.9 Hz, H-2), 5.83 1dd, 1H, Jˆ7.8, 4.7 Hz, NH), 8.08 1d,
2H, Jˆ8.9 Hz, Ns-H), 8.36 1d, 2H, Jˆ8.9 Hz, Ns-H); 13C
NMR 1100 MHz, CDCl3) 25.0, 26.1, 27.0, 27.1 1Me2C),
38.7 1Me-SO3), 44.9 1C-1), 67.8 1C-6), 76.9 1C-5), 77.7
1C-4), 78.0 1C-2), 79.9 1C-3), 110.2, 110.8 1Me2C), 124.4,
128.3 1CH, Ns), 145.7, 150.1 1C-ipso, Ns); MS 1CI, meth-
ane), m/z 1%): 525 1MH1, 29%), 467 1MH12acetone,
63%), 429 1MH12MsOH, 35%), 371 1MH12acetone±
MsOH, 100%); HRMS: calcd for C18H25O11N2S2 1M12
Me) 509.0900, found 509.0895 17%).
4.1.2. 1,2-Dideoxy-3,4;5,6-di-O-isopropylidene-1,2-0N-p-
toluenesulfonyl)-imino-d-mannitol 06). To an ice-cooled
solution of mesylate 5 12.68 g, 5.44 mmol) in dry THF
150 mL) was added NaH 10.33 g, 10.88 mmol) in small
portions, and the mixture was stirred at room temperature
for 1 h. When TLC showed the disappearance of starting
material, the mixture was cooled to 08C and worked up by
adding 20 mL NH4Cl 1aq. sat. solution). The mixture was
extracted three times with CH2Cl2 13£10 mL), the organic
phase was dried with MgSO4 and the product was puri®ed
by column chromatography on silica gel 1EtOAc/hexanes
50:50). The aziridine 16) was obtained as white crystals
11.70 g, 79%); mp 96.8±97.58C; [a]Dˆ144 1CHCl3, c
;
1H NMR
4.1.4. 1,2-Dideoxy-3,4;5,6-di-O-isopropylidene-1,2-0N-p-
nitrobenzenesulfonyl)-imino-d-mannitol 09). Compound
7 19.28 g, 17.6 mmol) was dissolved in dry THF 1150 mL)
and the solution cooled to 08C. NaH 11.06 g, 35.2mmol)
was added and the reaction mixture was stirred at room
temperature for 4 h. After cooling to 08C 30 mL saturated
NH4Cl was added, the mixture was extracted three times
with CH2Cl2 13£15 mL), and the organic phase dried on
MgSO4. Column puri®cation on silica gel 1EtOAc/hexanes
30:70) afforded a white crystalline product 19) 15.62g,
74%); mp 111.4±112.08C; [a]Dˆ150 1CHCl3, c 0.38);
0.39); IR 2990, 1380, 1320, 1160 cm21
1400 MHz, CDCl3) d 1ppm), 1.26 1s, 3H, Me2C), 1.34 1s,
6H, Me2C), 1.41 1s, 3H, Me2C), 2.43 1d, 1H, Jˆ4.5 Hz, H-

H. Mao et al. / Tetrahedron 57 .2001) 6955±6967
6961
1
IR, 3449, 2989, 1534, 1350, 1220 cm21; H NMR 1400
MHz, CDCl3), d 1ppm), 1.23 1s, 3H, Me2C), 1.33 1s, 3H,
Me2C), 1.34 1s, 3H, Me2C), 1.421s, 3H, Me 2C), 2.58 1d, 1H,
Jˆ4.6 Hz, H-1), 2.77 1d, 1H, Jˆ7.4 Hz, H-10), 3.29 1ddd,
1H, Jˆ7.4, 4.6, 3.2Hz, H-2), 3.70 1t, 1H, J ca. 7.6 Hz, H-4),
3.91 1dd, 1H, Jˆ8.5, 5.4 Hz, H-6), 4.04 1dt, 1H, Jˆ7.9, ca.
5.7 Hz, H-5), 4.07 1dd, 1H, Jˆ7.3, 3.2Hz, H-3), 4.11 1dd,
54.6 1C-2), 62.8 1C-1), 67.8 1C-6), 76.8, 79.1, 79.3
1C-3, 4, 5), 110.1, 110.4 1Me2C), 127.1, 129.5 1CH,
Ts), 137.7, 143.6 1C-ipso, Ts), 170.6 1MeCO2);); MS
1CI, methane), m/z 1%): 458 1MH1, 82%), 400 1MH12
acetone, 100%), 3421MH 122acetone, 38%); HRMS:
calculated for C20H28NO8S 1M12Me) 442.4536, found
442.4538 117%).
0
1H, Jˆ8.5, 6.2Hz, H-6 ), 8.17 1d, 2H, Ns-H), 8.39 1d, 2H,
Ns-H); 13C NMR 1100 MHz, CDCl3) 25.1, 26.5, 26.7, 26.9
1Me2C), 30.9 1C-1), 40.8 1C-2), 67.5 1C-6), 76.5, 77.2, 79.0
1C-3, 4, 5), 109.9, 110.4 1Me2C), 124.2, 129.5 1CH, Ns),
143.7, 150.7 1C-ipso, Ns); MS 1CI, methane), m/z 1%):
429 1MH1, 41%), 371 1MH12acetone, 100%), 313 1MH12
2acetone, 20%); HRMS: calculated for C17H21N2O8S
1M12Me) 413.1019, found 413.1023 157%).
4.1.7. Methyl 3,4-dideoxy-5,6;7,8-di-O-isopropylidene-2-
0methoxycarbonyl)-4-0N-p-toluenesulfonyl)-amino-d-
manno-octanoate 010c). To an ice-cooled solution of
dimethyl malonate 1625 mL, 5.46 mmol) in dry THF
112mL) was added NaH 10.25 g, 9.19 mmol). A solution
of N-tosyl aziridine 6 11.09 g, 2.73 mmol) in THF 112 mL)
was added dropwise, and the mixture was stirred at room
temperature for 48 h. Sat. aq. NH4Cl 110 mL) was added,
the reaction mixture was extracted three times with CH2Cl2
13£10 mL), and the organic phase was dried on MgSO4.
Column puri®cation on silica gel 1EtOAc/hexanes 40:60)
afforded 10c as a light yellow oil 10.88 g, 65%); IR, 2988,
4.1.5. 1-Azido-1,2-dideoxy-3,4;5,6-di-O-isopropylidene-
2-0N-p-toluenesulfonyl)-amino-d-mannitol 010a). To a
solution of N-tosyl aziridine 6 13.0 g, 7.6 mmol) in dry
DMF 150 mL) was added NaN3 14.91 g, 75.5 mmol) and
the reaction mixture was stirred at 908C for 8 h. Saturated
aq. NH4Cl 120 mL) was added, and the mixture was
extracted three times with CH2Cl2 13£10 mL). The organic
phase was dried on MgSO4. Column puri®cation on silica
gel 1EtOAc/hexanes 50:50) afforded an oil 110a) 13.2g,
1
1736 cm21; H NMR 1400 MHz, CDCl3), d 1ppm) 1.20 1s,
3H, Me2C), 1.27 1s, 3H, Me2C), 1.36 1s, 3H, Me2C), 1.48 1s,
3H, Me2C), 2.02 1ddd, 1H, Jˆ14.5, 9.5, 5.2 Hz, H-3), 2.24
1ddd, 1H, Jˆ14.5, 9.0, 3.8 Hz, H-30), 2.43 1s, 3H, MeSO3),
3.45 1t, 1H, Jˆ7.9 Hz, H-5), 3.58±3.61 1m, 1H, H-2), 3.60±
3.65 1m, 1H, H-4), 3.72±3.76 1m, 8H, MeO2C1H-7, 8),
4.05±4.121m, 2H, H-6, 8 0), 5.03 1d, 1H, Jˆ9.0 Hz, NH),
7.28 1d, 2H, Ts-H), 7.77 1d, 2H, Ts-H); 13C NMR 1100 MHz,
CDCl3) 21.5 1Me-Ts), 25.1, 26.3, 26.6, 26.8 1Me2C), 29.8
1C-3), 47.9, 53.4, 77.0, 78.3, 81.6 1CH, C-2, 4, 5, 6, 7), 52.5,
52.6 1CO2Me), 67.93 1C-8), 109.9, 110.1 1Me2C), 127.3,
129.6 1CH, Ts), 137.8, 149.6 1C-ipso,Ts), 169.4, 170.2
1CO2Me); MS 1CI, methane), m/z 1%): 530 1MH1, 100%),
498 1MH12MeOH, 97%), 4721MH 12acetone, 39%),
440 1MH12MeOH2acetone, 67%); HRMS: calcd for
C24H35NO10S 1M1) 529.1982, found 529.1980 1100%).
96%); [a]Dˆ28.21CH Cl2, c 0.19); IR 3245, 2995, 2940,
2
2105, 1450, 1380, 1340, 1160 cm21; H NMR 1400 MHz,
CDCl3), d 1ppm) 1.26 1s, 3H, Me2C), 1.321s, 3H, Me C),
1
2
1.38 1s, 3H, Me2C), 1.54 1s, 3H, Me2C), 2.44 1Me,Ts), 3.36
1ddt, 1H, Jˆ8.5, 6.0, ca. 3.5 Hz, H-2), 3.47 1dd, 1H, Jˆ12.5,
3.0 Hz, H-1), 3.53 1dd, 1H, Jˆ12.5, 3.5 Hz, H-10), 3.55 1dd,
1H, Jˆ8.5, 6.5 Hz, H-4), 3.77 1dd, 1H, Jˆ9.0, 6.5 Hz, H-6),
3.94 1dt, 1H, Jˆ8.5, 6.5 Hz, H-5), 3.96 1dd, 1H, Jˆ8.5,
6.5 Hz, H-3), 4.15 1dd, 1H, Jˆ9.0, 6.5 Hz, H-60), 5.70 1d,
1H, Jˆ6.0 Hz, NH), 7.34 1d, 2H, Ts-H), 7.78 1d, 2H, Ts-H);
13C NMR 1100 MHz, CDCl3) 21.4, 1Me,Ts), 24.9, 26.2,
26.7, 26.9 1Me2C), 51.21 C-1), 55.7 1C-2), 67.8 1C-6),
76.6, 78.1 1C-3, 5), 79.7 1C-4), 110.1, 110.4 1Me2C),
127.1, 129.6 1CH, Ts), 137.0, 143.8 1C-ipso, Ts); MS 1CI,
methane), m/z 1%): 441 1MH1, 7%), 383 1MH12acetone,
49%), 325 1MH122acetone, 100%); HRMS: calculated
for C18H25N4O6S 1M12Me) 425.1495, found 425.1499
122%).
4.1.8. 3,4-Dideoxy-5,6;7,8-di-O-isopropylidene-2-phenyl-
sulfonyl-4-0N-p-toluenesulfonyl)amino-d-manno-octano-
nitrile 010d). To an ice-cooled solution of 1phenyl-
sulfonyl)acetonitrile 10.9 g, 5.0 mmol) in dry THF
135 mL) was added NaH 10.2g, 6.0 mmol), and then drop-
wise a solution of the N-tosyl aziridine 6 12.0 g, 5.0 mmol)
in THF 125 mL). After reaction at room temperature for
24 h, 15 mL sat. aq. NH4Cl was added, the mixture was
extracted with CH2Cl2 13£10 mL), and the organic phase
dried on MgSO4. Column puri®cation on silica gel
1EtOAc/hexanes 50:50) afforded 10d as a white solid
12.5 g, 87%); mp184±1858C; [a]Dˆ256 1CH2Cl2, c 0.43);
4.1.6. 1-O-Acetyl-2-deoxy-3,4;5,6-di-O-isopropylidene-2-
0N-p-toluenesulfonyl)-amino-d-mannitol 010b). To a solu-
tion of N-tosyl aziridine 6 12.5 g, 6.3 mmol) in dry THF
150 mL) was added KOAc 16.2g, 63 mmol). After reaction
at 908C for 18 h, 20 mL sat. aq. NH4Cl was added and the
mixture was extracted three times with CH2Cl2 13£10 mL).
The organic phase was dried on MgSO4. Column puri®-
cation on silica gel 1EtOAc/hexanes 50:50) afforded 10b
as white crystals 12.6 g, 90%); mp 100±1018C; [a]Dˆ
13.4 1CH2Cl2, c 0.13); IR 3265, 2990, 2935, 1745, 1440,
1
IR 3280, 2990, 2360, 1445, 1375, 1360, 1160 cm21; H
NMR 1400 MHz, CDCl3), d 1ppm) 1.22 1s, 3H, Me2C),
1.23 1s, 3H, Me2C), 1.34 1s, 3H, Me2C), 1.49 1s, 3H,
Me2C), 2.29 1ddd, 1H, Jˆ14.0, 12.0, 2.5 Hz, H-3), 2.42 1s,
Me,Ts), 2.44 1ddd, 1H, Jˆ14.0, 10.5, 3.5 Hz, H-30), 3.22
1dd, 1H, Jˆ8.5, 7.0 Hz, H-6), 3.52±3.58 1m, 1H, H-4), 3.61
1dd, 1H, Jˆ7.0, 5.5 Hz, H-5), 3.64±3.69 1m, 1H, H-8), 3.71
1dd, 1H, Jˆ11.5, 6.0 Hz, H-80), 4.05±4.10 1m, 1H, H-7),
4.47 1dd, 1H, Jˆ12.0, 3.5 Hz, H-2), 5.45 1d, 1H, Jˆ
8.0 Hz, NH), 7.31 1d, 2H, Ts-H), 7.65 1d, 2H, Ts-H),
7.78±8.03 1m, 5H, Ph-H); 13C NMR 1100 MHz, CDCl3)
21.5 1Me,Ts), 24.7, 26.3, 26.4, 26.7 1Me2C), 29.2 1C-3),
52.7 1C-4), 54.8 1C-2), 67.9 1C-8), 76.6, 78.1, 81.4 1C-5,
6, 7), 110.1, 110.5 1Me2C), 113.9 1C-1), 127.5, 129.5,
1370, 1335, 1165 cm21; H NMR 1400 MHz, CDCl3), d
1
1ppm) 1.29 1s, 3H, Me2C), 1.31 1s, 3H, Me2C), 1.38 1s,
3H, Me2C), 1.51 1s, 3H, Me2C), 1.93 1s, 3H, MeCO2),
2.43 1s, 3H, Me,Ts), 3.62 1ddd, 1H, Jˆ7.0, 4.5, 3.0 Hz, H-
2), 3.71 1dd, 1H, Jˆ8.5, 6.5 Hz, H-4), 3.83 1dd, 1H, Jˆ8.5,
6.0 Hz, H-6), 3.92±4.01 1m, 2H, H-3, 5), 4.12±4.21 1m, 3H,
H-1, 10, 60), 5.41 1d, 1H, Jˆ7.0 Hz, NH), 7.30 1d, 2H, Ts-H),
7.77 1d, 2H, Ts-H); 13C NMR 1100 MHz, CDCl3) 2 0.6
1MeCO2), 21.4 1Me,Ts), 25.1, 26.3, 26.7, 27.0 1Me2C),

6962
H. Mao et al. / Tetrahedron 57 .2001) 6955±6967
129.6, 129.9, 135.3 1CH Ts, Ph), 135.8, 136.5, 144.3
1C-ipsoTs, Ph); MS 1CI, methane), m/z 1%): 579 1MH1,
51%), 521 1MH12acetone, 18%), 57 1100%); HRMS: cal-
culated for C27H34N2O8S2 1M1) 578.1757, found 578.1742
135%).
1CI, methane), m/z 1%): 505 1MH1, 100%), 447 1MH12
acetone, 12%); HRMS: calcd for C25H33O6N2S 1M12Me)
489.2059, found 489.2060 120%).
4.1.11. 2,3-Dideoxy-4,5;6,7-di-O-isopropylidene-3-0N-p-
toluenesulfonyl)-amino-d-manno-heptose propane-1,3-
diyl-dithioacetal 010g). A mixture of dithiane 11.11 g,
9.27 mmol) and BuLi 11.6 M in THF, 5.8 mL, 9.27 mmol)
in dry THF 135 mL) was stirred at 08C for 30 min. To this
mixture was added dropwise a solution of N-tosyl aziridine
6 11.84 g, 4.63 mmol) in dry THF 135 mL) during 20 min.
After being stirred at room temperature for 21 h, the mixture
was cooled to 08C, and worked up by adding 15 mL sat. aq.
NH4Cl. The mixture was extracted with CH2Cl2 13£10 mL)
and the organic phase was dried on MgSO4. Column
puri®cation on silica gel 1EtOAc/hexanes 40:60) afforded
10g as a yellow foam 12.14 g, 90%); [a]Dˆ26.1 1CHCl3, c
4.1.9. 1,2-Dideoxy-3,4;5,6-di-O-isopropylidene-1-C-phenyl-
2-0N-p-toluenesulfonyl)amino-d-mannitol 010e). To a
cooled 108C) solution of PhBr 12.7 mL, 25 mmol) in dry
THF 125 mL) was added Mg wire 10.6 g, 25 mmol) and a
crystal of I2. The mixture was allowed to react ®rst at room
temperature and then at re¯ux until complete consumption
of Mg 130±45 min). The mixture was cooled to 2788C, and
CuI 10.1 g, 2.5 mmol) was added followed by dropwise
addition of a solution of N-tosyl aziridine 6 12.0 g, 5.0
mmol) in THF 130 mL). After reaction at room temperature
for 1 h, the mixture was cooled to 08C and worked up by
adding 25 mL sat. aq. NH4Cl. The mixture was extracted
three times with CH2Cl2 13£15 mL), and the organic phase
dried on MgSO4. Column chromatography on silica gel
1EtOAc/hexanes 30:70) afforded 10e as white crystals
11.8 g, 75%); mp 101±1028C; [a]Dˆ21.7 1CH2Cl2, c
1
0.61); H NMR 1400 MHz, CDCl3), d 1ppm) 1.24 1s, 3H,
Me2C), 1.28 1s, 3H, Me2C), 1.37 1s, 3H, Me2C), 1.48 1s, 3H,
Me2C), 1.81±1.87 1m, 1H, dithiane H-5), 1.95 1dt, 2H, Jˆ
8.9, 3.7 Hz, H-2), 2.02±2.06 1m, 1H, dithiane H-50), 2.60
1ddd, 1H, Jˆ13.7, 11.0, 2.6 Hz, dithiane H-4), 2.72±2.82
1m, 3H, dithiane H-40,6,60), 3.49 1dd, 1H, Jˆ7.0, 8.0 Hz,
H-7), 3.76±3.85 1m, 4H, H-3, H-4, H-6, H-70), 4.00 1dd,
1H, Jˆ8.9, 5.2Hz, H-1), 4.10 1dd, 1H, Jˆ8.0, 5.8 Hz,
H-5), 5.14 1d, 1H, Jˆ8.4 Hz, NH), 7.29 1d, 2H, Jˆ8.3 Hz,
Ts-H), 7.83 1d, 2H, Jˆ8.3 Hz, Ts-H); 13C NMR 1100 MHz,
CDCl3) 21.45 1Me,Ts), 25.11, 26.55, 26.74, 26.83 1Me2C),
25.73 1C-2), 29.26, 29.84 1dithiane C-4,6), 36.61 1dithiane
C-5), 42.80 1C-3), 52.36 1C-1), 67.70 1C-7), 76.86, 78.48,
82.09 1C-4, C-5, C-6), 109.85, 109.98 1Me2C), 127.43,
129.50 1CH, Ts), 137.78, 143.321 C-ipso,Ts); MS 1EI),
m/z 1%): 517 1M1, 5%), 5021M 12CH3, 9%), 444 15022
Me2CO, 2%), 384 1M12CH3CH21SCH2)2CH2, 1%), 362
1M12Ts, 7%), 230 13622CHCH21SCH2)2CH2, 100%),
1721230 2Me2CO, 26%); HRMS: calcd for C23H35O6NS3
1M1) 517.1626, found 517.1627 17%).
0.26); IR 3280, 2985, 2935, 1455, 1370, 1330, 1170 cm21
;
1H NMR 1400 MHz, CDCl3), d 1ppm) 1.33 1s, 3H, Me2C),
1.34 1s, 6H, Me2C), 1.44 1s, 3H, Me2C), 2.39 1s, 3H, Me,Ts),
2.80 1dd, 1H, Jˆ14.0, 4.5 Hz, H-1), 2.91 1dd, 1H, Jˆ14.0,
7.0 Hz, H-10), 3.63 1dd, 1H, Jˆ8.0, 7.0 Hz, H-4), 3.62±3.69
1m, 1H, H-2), 3.80 1dd, 1H, Jˆ8.5, 6.0 Hz, H-6), 3.90±3.96
1m, 2H, H-3, 5), 4.09 1dd, 1H, Jˆ8.5, 6.7 Hz, H-60), 4.98 1d,
1H, Jˆ7.0 Hz, NH), 6.96±7.12 1m, 2H, Ph-H), 7.03±7.22
1m, 3H, Ph-H), 7.18 1d, 2H, Ts-H), 7.59 1d, 2H, Ts-H); 13C
NMR 1100 MHz, CDCl3) 21.3 1Me,Ts), 25.0, 26.4, 26.9,
1Me2C), 35.5 1C-1), 55.9 1C-2), 67.6 1C-6), 76.7, 78.9 80.5
1C-3, 4, 5), 109.7, 109.8 1Me2C), 126.3, 127.1, 128.2, 129.3,
129.7 1CH Ts, Ph), 136.3, 136.9, 143.1 1C-ipso,Ts; Ph); MS
1CI, methane), m/z 1%): 476 1MH1, 41%), 418 1MH12
acetone, 100%), 360 1MH122acetone, 29%); HRMS:
calculated for C24H30NO6S 1M12Me) 460.1794, found
460.1797 116%).
4.1.12. 1-Azido-1,2-dideoxy-3,4;5,6-di-O-isopropylidene-
2-0N-p-nitrobenzenesulfonyl)amino-d-mannitol 011a).
To a solution of N-nosyl aziridine 9 13.00 g, 7.02mmol)
in dry DMF 150 mL) was added NaN3 14.56 g, 70.2
mmol). After reaction at 908C for 8 h, 25 mL sat. aq.
NH4Cl was added and the mixture extracted with CH2Cl2
13£15 mL). The organic phase was dried on MgSO4 and
evaporated. Column puri®cation on silica gel 1EtOAc/
hexanes 30:70) afforded 11a as a white crystalline product
13.24 g, 98%); mp 98.8±99.38C; [a]Dˆ114.3 1CHCl3, c
4.1.10. 1-Benzylamino-1,2-dideoxy-3,4;5,6-di-O-isopropyl-
idene-2-0N-p-toluenesulfonyl)-amino-d-mannitol 010f).
To a solution of N-tosyl aziridine 6 11.5 g, 3.8 mmol) in
dry DMF 140 mL) was added BnNH2 10.5 mL, 4.6 mmol).
The reaction mixture was stirred at 908C for 24 h, then
cooled to room temperature, and treated with 15 mL sat.
aq. NH4Cl. The mixture was extracted with CH2Cl2
13£10 mL), and the organic phase dried on MgSO4 and
evaporated. Column puri®cation on silica gel 1EtOAc/
hexanes 50:50) gave 10f as a light yellow oil 11.3 g,
67%); IR 3265, 2985, 2935, 1455, 1375, 1335,
1
0.38); IR 3263, 2989, 2107, 1532, 1350, 1166 cm21; H
NMR 1400 MHz, CDCl3), d 1ppm) 1.321s, 3H, Me C),
2
1.34 1s, 3H, Me2C), 1.40 1s, 3H, Me2C), 1.53 1s, 3H,
Me2C), 3.51±3.55 1m, 3H, H-1, 10, 2), 3.66 1dd, 1H, Jˆ
8.6, 6.8 Hz, H-4), 3.85 1dd, 1H, Jˆ8.7, 6.2Hz, H-6), 3.97
1dt, 1H, Jˆ8.6, 6.2Hz, H-5), 4.01 1t, 1H, Jˆ6.8 Hz, H-3),
1
1165 cm21; H NMR 1400 MHz, CDCl3), d 1ppm) 1.26 1s,
3H, Me2C), 1.30 1s, 3H, Me2C), 1.37 1s, 3H, Me2C), 1.421s,
3H, Me2C), 2.40 1s, 3H, Me,Ts), 2.48 1dd, 1H, Jˆ12.5,
4.5 Hz, H-1), 2.84 1dd, 1H, Jˆ12.5, 4.0 Hz, H-10), 3.38±
3.46 1m, 1H, H-2), 3.58 1d, 1H, Jˆ13.5 Hz, CH2Ph), 3.61 1d,
1H, Jˆ13.5 Hz, CH02Ph), 3.621dd, 1H, Jˆ7.0, 6.0 Hz, H-3),
4.04±4.18 1m, 1H, H-60), 7.23 1m, 5H, Ph-H), 7.30 1d, 2H,
Ts-H), 7.721d, 2H, Ts-H); 13C NMR 1100 MHz, CDCl3)
21.5 1Me,Ts), 25.2, 26.5, 26.8, 27.0 1Me2C), 47.5
1CH2Ph), 53.6 1C-1), 54.21 C-2), 67.6 1C-6), 76.8, 78.9,
80.7 1C-3, 4, 5), 109.9, 110.0 1Me2C), 127.3, 128.0, 128.4,
129.6 1CH Ts, Ph), 137.3, 139.9, 143.4 1C-ipsoTs, Ph); MS
0
4.20 1dd, 1H, Jˆ8.7, 6.2Hz, H-6 ), 5.94 1d, 1H, Jˆ4.1 Hz,
NH), 8.11 1d, 2H, Jˆ7.1 Hz, Ns-H), 8.39 1d, 2H, Jˆ7.1 Hz,
Ns-H); 13C NMR 1100 MHz, CDCl3) 25.0, 26.3, 26.8, 26.9
1Me2C), 51.21 C-1), 56.0 1C-2), 68.0 1C-6), 76.7, 78.6, 79.8
1C-3, 4, 5), 110.5, 110.7 1Me2C), 124.3, 128.3 1CH, Ns),
146.4, 150.1 1C-ipso, Ns); MS 1CI, methane), m/z 1%): 472
1MH1, 100%), 414 1MH12acetone, 84%), 356 1MH12
2acetone, 20%); HRMS: calcd for C18H25O8N5S 1M1)
471.1424, found 471.1434 165%).

H. Mao et al. / Tetrahedron 57 .2001) 6955±6967
6963
4.1.13. 1-O-Acetyl-2-deoxy-3,4;5,6-di-O-isopropylidene-
2-0N-p-nitrobenzenesulfonyl)amino-d-mannitol 011b).
To a solution of N-nosyl aziridine 9 12.24 g, 5.23 mmol)
in dry DMF 145 mL) was added KOAc 15.13 g,
52.3 mmol). After being stirred at 908C for 18 h, the
reaction mixture was diluted with 20 mL sat. aq. NH4Cl.
The mixture was extracted with CH2Cl2 13£15 mL) and
the organic phase was dried on MgSO4. After evaporation,
the residue was puri®ed on silica gel 1EtOAc/hexanes
30:70) to yield 11b as a slightly yellow oil 12.12 g, 83%);
[a]Dˆ129.6 1CHCl3, c 0.52); IR 3445, 2989, 1740, 1532,
nitrobenzenesulfonyl)-amino-1-phenylthio-d-mannitol
011h). To a solution of the N-nosyl aziridine 9 12.54 g,
5.93 mmol) in dry DMF 150 mL) was added K2CO3
12.46 g, 17.8 mmol) and PhSH 10.91 mL, 8.90 mmol). The
reaction mixture was stirred at room temperature for 1 h.
Sat. aq. NH4Cl 125 mL) was added, the mixture was
extracted with CH2Cl2 13£15 mL) and the organic layer
dried on MgSO4. Column puri®cation on silica gel
1EtOAc/hexanes 20:80) afforded 11h as a white crystalline
product 12.84 g, 89%); mp 85.0±85.58C; [a]Dˆ155
1CHCl3, c 0.60); IR 3404, 1354, 1176 cm21 1H NMR
;
1
1350, 1166 cm21; H NMR 1400 MHz, CDCl3), d 1ppm)
1400 MHz, CDCl3), d 1ppm) 1.31 1s, 3H, Me2C), 1.34 1s,
3H, Me2C), 1.40 1s, 3H, Me2C), 1.44 1s, 3H, Me2C), 3.08
1dd, 1H, Jˆ14.0, 4.5 Hz, H-1), 3.19 1dd, 1H, Jˆ14.0,
5.9 Hz, H-10), 3.74 1dd, 1H, Jˆ8.5, 6.9 Hz, H-4), 3.74±
3.79 1m, 1H, H-2), 3.89 1dd, 1H, Jˆ8.6, 6.2Hz, H-6),
4.00 1dt, 1H, Jˆ8.5, 6.2Hz, H-5), 4.17 1dd, 1H, Jˆ8.6,
1.31 1s, 3H, Me2C), 1.39 1s, 3H, Me2C), 1.39 1s, 3H,
Me2C), 1.51 1s, 3H, Me2C), 1.921s, 3H, MeCO ), 3.75
2
1dd, 1H, Jˆ8.5, 6.8 Hz, H-4), 3.76±3.81 1m, 1H, H-2),
3.88 1dd, 1H, Jˆ8.6, 5.8 Hz, H-6), 3.95 1t, 1H, Jˆ6.8 Hz,
H-3), 3.92±3.98 1m, 1H, H-5), 4.12 1dd, 1H, Jˆ11.8,
5.5 Hz, H-1), 4.18 1dd, 1H, Jˆ8.6, 6.1 Hz, H-60), 4.21
1dd, 1H, Jˆ11.8, 3.8 Hz, H-10), 5.68 1d, 1H, Jˆ7.2Hz,
NH), 8.09 1d, 2H, Jˆ9.2Hz, Ns-H), 8.36 1d, 2H, Jˆ
9.2Hz, Ns-H); 13C NMR 1100 MHz, CDCl3) 20.6
1MeCO2), 25.1, 26.3, 26.8, 26.9 1Me2C), 54.9 1C-2), 62.5
1C-1), 67.9 1C-6), 76.9, 79.3, 79.5 1C-3, 4, 5), 110.3, 110.6
1Me2C), 124.2, 128.3 1CH, Ns), 146.9, 150.0 1C-ipso,
Ns); MS 1CI, methane), m/z 1%): 489 1MH1, 33%), 431
1MH12acetone, 100%), 373 1MH122acetone, 18%);
HRMS: calcd for C20H28O10N2S 1M1) 488.1465, found
488.1469 126%).
0
6.2Hz, H-6 ), 4.20 1t, 1H, Jˆ6.9 Hz, H-3), 5.67 1d, 1H,
Jˆ6.5 Hz, NH), 7.10 1m, 5H, SPh-H), 7.97 1s, 2H, Ns-H),
8.17 1d, 2H, Jˆ7.0 Hz, Ns-H); 13C NMR 1100 MHz, CDCl3)
25.2, 26.4, 26.9, 27.7 1Me2C), 34.9 1C-1), 54.8 1C-2), 68.0
1C-6), 76.9, 79.2, 80.4 1C-3, 4, 5), 110.2, 110.4 1Me2C),
124.0, 126.4, 128.4 1CH, SPh), 128.9, 129.0 1CH, Ns),
135.3 1C-ipso, SPh), 146.0, 149.9 1C-ipso, Ns); MS 1CI,
methane), m/z 1%): 539 1MH1, 37%), 481 1MH12acetone,
100%), 423 1MH122acetone, 27%); HRMS: calcd for
C23H27O8N2S2 1M12Me) 523.1209, found 523.1216 112%).
4.1.16. 2-O-Acetyl-6-azido-1,6-dideoxy-3,4-O-isopropyl-
idene-0N-p-toluenesulfonyl)-mannojirimycin 015a). To a
solution of compound 10a 11.01 g, 2.3 mmol) in MeOH/
H2O 9:1 140 mL) was added Dowex 50X8-200 11.2 g) and
the mixture was allowed to react at room temperature for
30 h. The mixture was ®ltered and the resin washed
thoroughly with MeOH. Following concentration under
diminished pressure, the residue was puri®ed by column
chromatography on silica gel 1EtOAc/hexanes 80:20) to
afford diol 12a 10.65 g, 72%). To an ice-cooled solution
of the diol 10.20 g, 0.5 mmol) in dry THF 140 mL) was
added Ph3P 10.20 g, 0.75 mmol) and DEAD 10.13 g,
0.75 mmol). The mixture was allowed to react at room
temperature for 5 days. Sat. aq. NH4Cl was added and the
mixture was extracted three times with CH2Cl2 13£10 mL),
the organic phase dried on MgSO4 and evaporated. The
residue was made to react with pyridine 15 mL) and Ac2O
11 mL). After reaction at room temperature for 5 h, the
mixture was concentrated under diminished pressure and
the residue was puri®ed by column chromatography on
silica gel 1EtOAc/hexanes 50:50) to give 15a as a slightly
yellow oil 10.09 g; 45%); IR 2985, 2935, 2105, 1755, 1450,
4.1.14. Methyl 3,4-dideoxy-5,6;7,8-di-O-isopropylidene-
2-0methoxycarbonyl)-4-0N-p-nitrobenzenesulfonyl)amino-
d-manno-octanoate 011c). To an ice-cooled solution of
dimethyl malonate 11.08 mL, 9.46 mmol) in dry THF
130 mL) was added NaH 10.43 g, 14.1 mmol), and then
dropwise a solution of N-nosyl aziridine 9 12.02 g,
4.73 mmol) in THF 130 mL). The mixture was stirred at
room temperature for 4 h. Sat. aq. NH4Cl 125 mL) was
added and the two layers were separated. The aqueous
layer was extracted with CH2Cl2 13£15 mL) and the organic
phase was dried on MgSO4. Column puri®cation on silica
gel 1EtOAc/hexanes 40:60) afforded 11c as a slightly yellow
1
oil 12.07 g, 78%); IR 3278, 2989, 1737, 1532 cm21; H
NMR 1400 MHz, CDCl3), d 1ppm) 1.21 1s, 3H, Me2C),
1.28 1s, 3H, Me2C), 1.38 1s, 3H, Me2C), 1.49 1s, 3H,
Me2C), 2.10 1ddd, 1H, Jˆ14.7, 9.7, 5.2 Hz, H-3), 2.23
1ddd, 1H, Jˆ14.7, 9.4, 3.6 Hz, H-30), 3.58 1t, 1H, Jˆ
7.5 Hz, H-5), 3.68 1dd, 1H, Jˆ9.4, 5.2Hz, H-2),
3.67±3.70 1m, 1H, H-6), 3.77±3.80 1m, 1H, H-4), 3.76 1s,
6H, MeO2C), 3.80±3.821m, 1H, H-7), 3.83 1dd, 1H, Jˆ
0
13.7, 5.4 Hz, H-8), 4.121dd, 1H, Jˆ13.7, 7.2Hz, H-8 ),
1
5.61 1d, 1H, Jˆ9.0 Hz, NH), 8.11 1d, 2H, Jˆ8.9 Hz,
Ns-H), 8.36 1d, 2H, Jˆ8.9 Hz, Ns-H); 13C NMR 1100
MHz, CDCl3) 24.9, 26.2, 26.5, 26.7 1Me2C), 29.2 1C-3),
47.8 1C-2), 52.5, 52.6 1MeO2C±), 53.7 1C-4), 67.7 1C-8),
1370, 1360, 1180 cm21; H NMR 1400 MHz, CDCl3), d
1ppm) 1.31 1s, 1H, Me2C), 1.37 1s, 3H, Me2C), 2.07 1s,
3H, Me,Ts), 2.43 1s, 3H, OAc), 2.97 1dd, 1H, Jˆ10.0,
5.5 Hz, H-3), 3.20 1dd, 1H, Jˆ15.5, 6.5 Hz, H-1), 3.58
1dd, 1H, Jˆ12.5, 3.0 Hz, H-6), 3.82 1dd, 1H, Jˆ12.5,
4.5 Hz, H-60), 3.86±3.91 1m, 1H, H-5), 4.01 1dd, 1H, Jˆ
10.0, 9.0 Hz, H-4), 4.26±4.30 1m, 1H, H-10), 5.23 1ddd, 1H,
Jˆ8.5, 6.5, 5.5 Hz, H-2), 7.35 1d, 2H, Jˆ7 Hz, Ts-H), 7.73
1d, 2H, Jˆ7 Hz, Ts-H); 13C NMR 1100 MHz, CDCl3) 20.6
1MeCO2), 21.4 1Me,Ts), 26.4, 26.8 1Me2C), 46.5 1C-1), 53.3
1C-6), 58.6, 64.1, 70.8, 75.5 1C-2, 3, 4, 5), 113.2 1Me2C),
126.9, 130.0 1CH, Ts), 136.0, 144.3 1C-ipso,Ts), 169.8
1MeCO2); MS 1CI, methane), m/z 1%): 425 1MH1, 34%),
77.0 1C-7), 78.21 C-6), 81.8 1C-5), 109.9, 110.21Me C),
2
124.1, 128.4 1CH, Ns), 146.7, 149.9 1C-ipso, Ns), 169.0,
169.7 1Me2O2C); MS 1CI, methane), m/z 1%): 561 1MH1,
31%), 529 1MH12MeOH, 30%), 503 1MH12acetone,
76%), 471 1MH12acetone2MeOH, 64%), 445 1MH12
2acetone, 75%); HRMS: calcd for C23H32O12N2S 1M1)
560.1676, found 560.1669 128%).
4.1.15. 1,2-Dideoxy-3,4;5,6-di-O-isopropylidene-2-0N-p-

6964
H. Mao et al. / Tetrahedron 57 .2001) 6955±6967
367 1MH12acetone, 100%); HRMS: calculated for
C17H21NO6S 1M12Me) 409.1182, found 409.1188 19%).
Jˆ14.2, 6.2 Hz, H-1), 3.22 1dd, 1H, Jˆ14.2, 4.0 Hz,
H-10), 3.51 1dd, 1H, Jˆ11.1, 6.7 Hz, H-6), 3.72±3.80 1m,
4H, H-2, 4, 5, 60), 4.25 1t, 1H, Jˆ6.2Hz, H-3), 6.00 1d, 1H,
Jˆ7.2 Hz, NH), 7.10±7.21 1m, 5H, SPh), 7.96 1d, 2H, Jˆ
8.9 Hz, Ns-H), 8.19 1d, 2H, Jˆ8.9 Hz, Ns-H); 13C NMR
1100 MHz, CDCl3) 26.9 1Me2C), 35.4 1C-1), 37.7 1C-6),
55.6 1C-2), 73.0 1C-5), 78.7, 80.6 1C-3, 4), 110.7 1Me2C),
124.1, 126.3, 128.4, 128.8, 129.0 1CH, Ns; CH, SPh),
135.4 1C-ipso, SPh), 145.8, 150.0 1C-ipso, Ns); MS 1CI,
methane), m/z 1%): 563 1MH1, 2%), 481 1MH12HBr,
16%), 423 1MH12 HBr2acetone, 100%); HRMS: calcd
for C21H25O7N2BrS2 1M1) 560.0287, found 560.0279
110%).
4.1.17. 1-Azido-6-bromo-3,4-O-isopropylidene-2-0N-p-
nitrobenzenesulfonyl)amino-1,2,6-trideoxy-d-mannitol
016a). To a solution of compound 11a 10.87 g, 1.85 mmol)
in MeOH/H2O 113.5 mL, 9:1) was added Dowex 50X8-200
10.73 g) and the reaction mixture was stirred at room
temperature for 2days. The mixture was ®ltered and the
resin washed thoroughly with MeOH. Following evapo-
ration of the solvent, the residue containing diol 13a was
freed from residual water by co-evaporation with toluene. In
another ¯ask, the Appel reagent was prepared by reaction of
Ph3P 10.73 g, 2.78 mmol) and CBr4 10.86 g, 2.59 mmol) in
dry THF 140 mL) at 08C. When a yellow precipitate had
formed, a THF 130 mL) solution of the diol 13a was
added and the mixture was stirred for 30 min at room
temperature. Then MeOH 10.3 mL) was added dropwise to
destroy the excess of reagent. Following addition of 20 mL
sat. aq. NH4Cl, the organic layer was collected and the
aqueous phase was further extracted with CH2Cl2 13£
10 mL). Puri®cation by ¯ash column chromatography on
silica gel 1EtOAc/hexanes 40:60) afforded 16a as a slightly
yellow oil 10.68 g, 75%); [a]Dˆ18.1 1CHCl3, c 0.92); IR
4.1.19. 2-O-Acetyl-6-azido-1,6-dideoxy-3,4-O-isopropyl-
idene-0N-p-nitrobenzenesulfonyl)-mannojirimycin 019a).
Procedure A: To an ice-cooled solution of 6-bromo deriva-
tive 16a 12.58 g, 5.8 mmol) in CH2Cl2 1100 mL) was added
Et3N 13.2 mL, 23.0 mmol), DMAP 14.21 g, 34.5 mmol) and
Ac2O 12.2 mL, 23.0 mmol). After reaction at room tempera-
ture for 4 days, 30 mL sat. aq. solution of Na2CO3 was
added. The mixture was extracted with CH2Cl2 13£
15 mL). The organic phase was dried on MgSO4 and evapo-
rated. The residue was puri®ed by column chromatography
on silica gel 1EtOAc/hexanes 30:70) to give 19a as white
crystals 12.00 g, 76%); mp 56.3±57.88C; [a]Dˆ236
1CHCl3, c 0.91); IR 3468, 2990, 2106, 1740, 1534, 1350,
3498, 2106, 1637, 1534, 1160, 1010 cm21 1H NMR
;
1400 MHz, CDCl3), d 1ppm) 1.321s, 3H, Me C), 1.35 1s,
2
3H, Me2C), 3.06 1s, 1H, ±OH), 3.421dd, 1H, Jˆ10.3,
2.5 Hz, H-6), 3.44±3.46 1m, 1H, H-2), 3.48±3.52 1m, 1H,
H-4), 3.54 1dd, 1H, Jˆ10.3, 6.4 Hz, H-60), 3.61 1dd, 1H,
Jˆ12.7, 3.5 Hz, H-1), 3.70±3.73 1m, 1H, H-5), 3.75 1dd,
1H, Jˆ12.7, 2.5 Hz, H-10), 4.10 1dd, 1H, Jˆ8.0, 6.4 Hz,
H-3), 6.10 1s, 1H, NH), 8.121d, 2H, Jˆ9.0 Hz, Ns-H),
8.39 1d, 2H, Jˆ9.0 Hz, Ns-H); 13C NMR 1100 MHz,
CDCl3) 26.8, 26.9 1Me2C), 37.5 1C-6), 52.0 1C-1), 56.6
1C-2), 73.2 1C-5), 78.5, 79.3 1C-3, 4), 110.1 1Me2C),
124.4, 128.5 1CH, Ns), 146.0, 150.21 C-ipso, Ns); MS 1CI,
methane), m/z 1%): 496 1MH1, 2%), 414 1MH12HBr, 7%),
356 1MH12HBr2acetone, 100%); HRMS: calcd for
C14H19O7N5BrS 1M12Me), 478.0032, found 478.0064
125%).
1
1166, 1100 cm21; H NMR 1400 MHz, CDCl3), d 1ppm)
1.37 1s, 3H, Me2C), 1.41 1s, 3H, Me2C), 2.09 1s, 3H,
OAc), 3.27 1dd, 1H, Jˆ9.0, 5.2Hz, H-3), 3.29 1dd, 1H,
Jˆ15.5, 6.5 Hz, H-1), 3.621dd, 1H, Jˆ13.0, 3.3 Hz, H-6),
3.821dd, 1H, Jˆ13.0, 3.6 Hz, H-60), 4.00±4.06 1m, 1H,
H-5), 4.04 1t, 1H, Jˆ9.0 Hz, H-4), 4.22 1dd, 1H, Jˆ15.5,
7.8 Hz, H-10), 5.321ddd, 1H, Jˆ7.8, 6.5, 5.2Hz, H-2), 8.06
1d, 2H, Jˆ6.9 Hz, Ns-H), 8.40 1d, 2H,Jˆ6.9 Hz, Ns-H); 13C
NMR 1100 MHz, CDCl3) 20.6 1CH3COO), 26.4, 26.9
1Me2C), 47.0 1C-1), 52.7 1C-6), 59.1 1C-5), 64.1 1C-2),
70.8 1C-4), 75.9 1C-3), 113.6 1Me2C), 124.6, 128.2 1CH,
Ns), 145.0, 150.21 C-ipso, Ns), 169.8 1CH3COO); MS 1CI,
methane), m/z 1%): 456 1MH1, 27%), 428 1MH12N2, 7%),
398 1MH12acetone, 100%), 213 1MH12Ns, 10%);
HRMS: calculated for C16H19N5O8S 1M12Me) 440.0876,
found 440.0876 12.8%).
4.1.18. 1-Phenylthio-6-bromo-3,4-O-isopropylidene-2-
0N-p-nitrobenzenesulfonyl)amino-1,2,6-trideoxy-d-man-
nitol 016h). To a solution of compound 11h 10.52g, 0.96
mmol) in MeOH/H2O 17.05 mL, 9:1) was added Dowex
50X8-200 10.38 g), and the reaction mixture was stirred at
room temperature for 7 days. The mixture was ®ltered and
the resin washed thoroughly with MeOH. After evaporation
of the solvent, the residue was puri®ed by column chroma-
tography on silica gel 1EtOAc/hexanes 80:20) to give diol
13h as an oil 10.43 g, 89%). To a solution of the diol 10.42g,
0.84 mmol) in dry THF 130 mL) was added Ph3P 10.74 g,
2.84 mmol) and CBr4 10.47 g, 1.42mmol) at 0 8C. The
reaction mixture was stirred at room temperature for
30 min. Then MeOH 10.2mL) was added dropwise to
destroy the excess of reagent. Sat. aq. NH4Cl 120 mL) was
added and the organic layer was collected. The aqueous
layer was further extracted with CH2Cl2 13£10 mL). Flash
column chromatography on silica gel 1EtOAc/hexanes
40:60) afforded 16h as a slightly yellow oil 10.46 g, 98%);
[a]Dˆ143 1CHCl3, c 0.64); IR 3500, 3280, 2990, 1530,
Procedure B proceeding via 5-O-acetyl-6-iodo derivative
18a: To a solution of diol 13a 11.25 g, 2.90 mmol) in dry
THF 150 mL) was added Ph3P 12.28 g, 8.70 mmol) and CI4
12.26 g, 4.35 mmol). The reaction mixture was stirred at
room temperature for 18 h. MeOH 115 mL) and sat. aq.
NH4Cl 120 mL) were added and the mixture was extracted
three times with CH2Cl2 13£20 mL). The organic phase was
dried on MgSO4 and evaporated, and the residue was
puri®ed on silica gel using EtOAc/Hexane 140:60) to give
the 6-iodo analogue of 16a as an oil 11.10 g, 70%).
The 6-iodo derivative 16a 11.10 g, 2.03 mmol) was dis-
solved in CH2Cl2 110 mL). Pyridine 10.98 mL, 12.2 mmol)
and Ac2O 10.77 mL, 8.1 mmol) were added and the mixture
was stirred at room temperature for 2h. Sat. aq. NH 4Cl
110 mL) was added and the mixture was extracted three
times with CH2Cl2 13£15 mL). The organic phase was
dried on MgSO4 and evaporated. Column puri®cation on
silica gel using EtOAc/Hexane 130:70) yielded the 6-iodo
1
1350, 1165 cm21; H NMR 1400 MHz, CDCl3), d 1ppm)
1.321s, 3H, Me C), 1.35 1s, 3H, Me2C), 3.13 1dd, 1H,
2

H. Mao et al. / Tetrahedron 57 .2001) 6955±6967
6965
analogue of 18a as a slightly yellow oil 11.12g, 95%); IR
®ed on silica gel using EtOAc/Hexane 140:60) to give the
6-iodo analogue of 16h as an oil 10.54 g, 71%).
1
3283, 2107, 1741, 1531, 1350, 1230, 1165, 1085 cm21; H
NMR 1400 MHz, CDCl3), d 1ppm) 1.36 1s, 3H, Me2C), 1.37
1s, 3H, Me2C), 2.22 1s, 3H, OAc), 3.38 1dd, 1H, Jˆ12.0,
5.5 Hz, H-6), 3.40±3.421m, 1H, H-1), 3.54±3.56 1m, 2H,
H-101H-2), 3.58 1dd, 1H, Jˆ12.0, 3.5 Hz, H-60), 4.00 1dd,
1H, Jˆ7.7, 6.0 Hz, H-4), 4.06 1t, 1H, Jˆ6.0 Hz, H-3), 4.63
1ddd, 1H, Jˆ7.7, 5.5, 3.5 Hz, H-5), 5.48 1d, 1H, Jˆ8.9 Hz,
NH), 8.10 1d, 2H, Jˆ7.0 Hz, Ns-H), 8.39 1d, 2H, Jˆ7.0 Hz,
H-Ns); 13C NMR 1100 MHz, CDCl3) 5.29 1C-6), 21.0
1MeCO2), 27.0 1Me2C), 27.2 1Me2C), 50.8 1C-1), 55.7
1C-2), 72.7 1C-5), 78.6, 79.21 C-3, 4), 111.21Me 2C),
124.5, 128.2 1CH, Ns), 146.4, 150.21 C-ipso, Ns), 170.0
1MeCO2); MS 1CI, methane), m/z 1%): 556 1MH12N2,
1%), 496 1MH12N22AcOH, 19%), 456 1MH12HI, 29%),
398 1MH12HI2acetone, 100%).
The 6-iodo derivative 16h 10.41 g, 0.68 mmol) was
dissolved in CH2Cl2 15 mL). Pyridine 10.33 mL, 4.05
mmol) and Ac2O 10.26 mL, 2.70 mmol) were added and
the mixture was stirred at room temperature for 2h. Sat.
aq. NH4Cl 15 mL) was added and the mixture extracted
three times with CH2Cl2 13£10 mL). The organic phase
was dried on MgSO4 and evaporated. Column puri®cation
on silica gel using EtOAc/Hexane 130:70) yielded the 5-O-
acetyl-6-iodo derivative 18h as a slightly yellow oil 10.44 g,
96%); IR 3443, 1740, 1649, 1530, 1348, 1226, 1160,
1
1087 cm21; H NMR 1400 MHz, CDCl3), d 1ppm) 1.321s,
3H, Me2C), 1.39 1s, 3H, Me2C), 2.10 1s, 3H, OAc), 3.06 1d,
2H, Jˆ6.2Hz, H-1 1H-10), 3.421dd, 1H, Jˆ11.2, 4.8 Hz,
H-6), 3.60 1dd, 1H, Jˆ11.2, 3.6 H-60), 3.67±3.721m, 1H,
H-2), 4.07 1dd, 1H, Jˆ8.0, 7.0 Hz, H-4), 4.19 1dd, 1H,
Jˆ7.0, 4.1 Hz, H-3), 4.53 1ddd, 1H, Jˆ8.0, 4.8, 3.6 Hz,
H-5), 5.26 1d, 1H, Jˆ8.3 Hz, NH), 7.12±7.28 1m, 5H,
H-SPh), 7.91 1d, 2H, Jˆ8.9 Hz, H-Ns), 8.20 1d, 2H, Jˆ
8.9 Hz, H-Ns); 13C NMR 1100 MHz, CDCl3) 6.20 1C-6),
20.9 1MeCO2), 26.9 1Me2C), 27.1 1Me2C), 33.8 1C-1), 54.9
1C-2), 72.6 1C-5), 77.9, 80.9 1C-3,4), 111.0 1Me2C), 124.1,
126.8, 128.2, 129.2, 129.3 1CH-SPh), 134.6 1C-ipso, SPh),
146.2, 150.0 1C-ipso, Ns), 169.8 1MeCO2); MS 1CI,
methane), m/z 1%): 651 1MH1, 2%), 591 1MH12AcOH,
65%), 533 1MH12AcOH2acetone, 45%), 523 1MH12
HI, 43%), 465 1MH12HI2acetone, 100%).
The 6-iodo derivative 18a 10.90 g, 1.54 mmol) was dis-
solved in CH2Cl2 120 mL), DMAP 11.88 g, 15.4 mmol)
was added, and the mixture was stirred at room temperature
for 3 days. Sat. aq. NH4Cl 110 mL) was added, and the
mixture extracted three times with CH2Cl2 13£15 mL).
The organic phase was dried on MgSO4 and evaporated.
Column puri®cation on silica gel using EtOAc/Hexane
130:70) gave 19a as white crystals 10.49 g, 70%).
4.1.20. 2-O-Acetyl-6-phenylthio-1,6-dideoxy-3,4-O-iso-
propylidene-0N-p-nitrobenzenesulfonyl)-mannojirimycin
019h). Procedure A: To an ice-cooled solution of 6-bromo
derivative 16h 10.15 g, 0.27 mmol) in CH2Cl2 110 mL) was
added Et3N 10.15 mL, 1.1 mmol), DMAP 10.20 g, 1.6
mmol) and Ac2O 10.10 mL, 1.1 mmol). After reaction at
room temperature for 4 days, 10 mL sat. aq. solution of
Na2CO3 was added. The mixture was extracted three times
with CH2Cl2 13£10 mL). The organic phase was dried on
MgSO4 and evaporated. The residue was puri®ed by column
chromatography on silica gel 1EtOAc/hexanes 40:60) to
give 19h as a colourless oil 10.11 g, 79%); [a]Dˆ272
1CH2Cl2, c 0.45); IR 3454, 2987, 1747, 1532, 1350, 1165,
6-Iodo compound 18h 10.44 g, 0.68 mmol) was dissolved in
CH2Cl2 115 mL). DMAP 10.83 g, 6.77 mmol) was added,
and the mixture was stirred at room temperature for
3 days. Sat. aq. NH4Cl 110 mL) was added, and the mixture
extracted three times with CH2Cl2 13£15 mL). The organic
phase was dried on MgSO4 and evaporated. Column puri®-
cation on silica gel using EtOAc/Hexane 130:70) gave 19h
as a colourless oil 10.25 g, 71%).
1
1090 cm21; H NMR 1400 MHz, CDCl3), d 1ppm) 1.28 1s,
4.1.21. 6-Azido-1,6-dideoxy-3,4-O-isopropylidene manno-
jirimycin 020a). To an ice-cooled solution of compound
19a 12.00 g, 4.4 mmol) in MeOH 150 mL) was added
K2CO3 10.30 g, 2.2 mmol). After reaction at room tempera-
3H, Me2C), 1.36 1s, 3H, Me2C), 2.07 1s, 3H, OAc), 3.27 1dd,
0
1H, Jˆ9.9, 5.2Hz, H-3), 3.34±3.44 1m, 3H, H-1, 6, 6 ), 4.05
1t, 1H, Jˆ9.9 Hz, H-4), 4.18±4.20 1m, 1H, H-5), 4.21 1dd,
1H, Jˆ15.2, 8.0 Hz, H-10), 5.31 1ddd, 1H, Jˆ8.0, 6.4,
5.2 Hz, H-2), 7.20±7.35 1m, 5H, SPh), 7.98 1d, 2H, Jˆ
9.0 Hz, Ns-H), 8.31 1d, 2H, Jˆ9.0 Hz, Ns-H); 13C NMR
1100 MHz, CDCl3) 20.6 1CH3COO), 26.2, 26.9 1Me2C),
37.3 1C-6), 47.21 C-1), 59.6 1C-5), 64.4 1C-2), 72.4 1C-4),
76.0 1C-3), 113.3 1Me2C), 124.5, 126.7, 128.3, 129.1, 129.4
1CH, Ns; CH, SPh), 135.5 1C-ipso, SPh), 145.2, 150.1
1C-ipso, Ns), 169.9 1CH3COO); MS 1CI, methane), m/z
1%): 523 1MH1, 29%), 465 1MH12acetone, 100%);
HRMS: calcd for C23H26O8N2S2 1M1) 522.1131, found
522.1141 122%).
ture for 2h, 20 mL sat. aq. solution of NH Cl was added.
4
The mixture was extracted with CH2Cl2 13£15 mL). The
organic phase was dried and evaporated. The residue was
puri®ed by column chromatography on silica gel 1EtOAc/
hexanes 40:60) to afford the alcohol product as an oil
11.26 g, 70%). To a solution of the alcohol 11.02 g,
2.5 mmol) in MeCN/DMSO 149:1) 150 mL) was added
K2CO3 11.37 g, 9.9 mmol) and PhSH 11.27 mL, 12.4
mmol). After reaction at 508C for 2h, 15 mL sat. aq.
NH4Cl was added. The mixture was extracted with
CH2Cl2 13£10 mL), and the organic phase was dried and
evaporated. The residue was puri®ed by column chroma-
tography on silica gel 1CH3Cl/MeOH 92:8) to afford 20a
as a colouress oil 10.54 g, 96%); [a]Dˆ219 1CHCl3, c
Procedure B proceeding via 5-O-acetyl-6-iodo derivative
18h: To a solution of diol 13h 10.62g, 1.24 mmol) in dry
THF 130 mL) was added Ph3P 10.98 g, 3.73 mmol) and CI4
10.97 g, 1.87 mmol). The reaction mixture was stirred at
room temperature for 18 h. MeOH 110 mL) and sat. aq.
NH4Cl 120 mL) were added and the mixture was extracted
three times with CH2Cl2 13£15 mL). The organic phase was
dried on MgSO4 and evaporated, and the residue was puri-
0.29); IR 3414, 2986, 2910, 2103, 1658, 1230, 1024 cm21
;
1H NMR 1400 MHz, CDCl3), d 1ppm) 1.43 1s, 3H, Me2C),
1.45 1s, 3H, Me2C), 2.23 1s, 2H, OH1NH), 2.73 1dd, 1H,
Jˆ14.6, 1.8 Hz, H-1), 2.85 1ddd, 1H, Jˆ9.4, 5.6, 3.2Hz,
H-5), 3.16 1dd, 1H, Jˆ14.6, 2.3 Hz, H-10), 3.421dd, 1H,
Jˆ9.4, 2.4 Hz, H-3), 3.53 1dd, 1H, Jˆ12.5, 5.6 Hz, H-6),

6966
H. Mao et al. / Tetrahedron 57 .2001) 6955±6967
3.61 1dd, 1H, Jˆ12.5, 3.2 Hz, H-60), 3.65 1t, 1H, Jˆ9.4 Hz,
H-4), 4.25 1m, 1H, S3Jˆ6.5 Hz, H-2); 13C NMR 1100 MHz,
CDCl3) 26.6, 26.8 1Me2C), 49.6 1C-1), 52.8 1C-6), 58.4
rated methanolic HCl 110 mL) for 2h. The solution was
evaporated and the residue was co-evaporated twice with
MeOH. Puri®cation by column chromatography on silica
gel 1CHCl3/MeOH/H2O/NH4OH 70:28:1:1) afforded 21h
as a slightly yellow oil 10.30 g, 91%); [a]Dˆ135 1MeOH,
c 0.50); IR 3350, 2910, 1260, 1090 cm21 1H NMR
;
1400 MHz, CD3OD), d 1ppm) 2.55 1ddd, 1H, Jˆ9.3, 7.8,
3.0 Hz, H-5), 2.68 1dd, 1H, Jˆ13.8, 1.6 Hz, H-1), 2.98
1dd, 1H, Jˆ13.8, 2.9 Hz, H-10), 3.04 1dd, 1H, Jˆ13.5,
7.8 Hz, H-6), 3.34 1dd, 1H, Jˆ9.3, 3.2Hz, H-3), 3.49 1dd,
1H, Jˆ13.5, 3.0 Hz, H-60), 3.50 1t, 1H, Jˆ9.3 Hz, H-4),
3.84 1m, 1H, S3Jˆ7.7 Hz, H-2), 7.15±7.42 1m, 5H, SPh);
13C NMR 1100 MHz, CD3OD) 37.1 1C-6), 50.6 1C-1), 61.2
1C-5), 70.5 1C-2), 72.9 1C-4), 76.6 1C-3), 127.1, 130.0,
130.4 1CH, SPh), 137.9 1C-ipso SPh); MS 1CI, methane),
m/z 1%): 256 1MH1, 100%), 238 1MH12H2O, 12%);
HRMS: calcd for C12H17O3NS 1M1) 255.0929, found
255.0930 18%).
1C-5), 67.4 1C-2), 72.1 1C-4), 80.8 1C-3), 109.21Me C);
2
MS 1CI, methane), m/z 1%): 229 1MH1, 100%), 171
1MH12acetone, 81%), 153 1MH12acetone2H2O, 22%);
HRMS: calcd for C8H13O3N4 1M12Me) 213.0988, found
213.0977 15%).
4.1.22. 6-Phenylthio-1,6-dideoxy-3,4-O-isopropylidene
mannojirimycin 020h). To an ice-cooled solution of
compound 19h 11.73 g, 3.3 mmol) in MeOH 150 mL) was
added K2CO3 10.23 g, 1.7 mmol). After reaction at room
temperature for 2h, 20 mL sat. aq. NH Cl was added. The
4
mixture was extracted with CH2Cl2 13£15 mL), and the
organic phase was dried and evaporated. The residue was
puri®ed by column chromatography on silica gel 1EtOAc/
hexanes 40:60) to give the alcohol product as an oil 11.21 g,
76%). To a solution of the alcohol 10.79 g, 1.6 mmol) in
MeCN/DMSO 149:1) 150 mL) was added K2CO3 10.19 g,
6.6 mmol) and PhSH 10.84 mL, 8.2mmol). After reaction
Acknowledgements
at 508C for 2h, 20 mL sat. aq. NH Cl was added. The
4
mixture was extracted three times with CH2Cl2 13£
15 mL), and the organic phase was dried and evaporated.
The residue was puri®ed by column chromatography on
silica gel 1CHCl3/MeOH 92:8) to afford 20h as a slightly
yellow oil 10.46 g, 96%); [a]Dˆ27.6 1CHCl3, c 0.28); IR,
The authors wish to thank the F.W.O. 1Fund for Scienti®c
ResearchÐFlanders, Belgium) for ®nancial support. We
are also indebted to R. De Boer and Professor S. Toppet
for mass and NMR measurements. H. Mao also thanks the
K.U. Leuven for a fellowship.
1
3300, 2983, 2914, 1583, 1090 cm21, H NMR 1400 MHz,
CDCl3), d 1ppm) 1.34 1s, 3H, Me2C), 1.411s, 3H, Me2C),
2.28 12H, NH1OH), 2.73 1dd, 1H, Jˆ14.3, 1.8 Hz, H-1),
2.93 1ddd, 1H, Jˆ9.4, 7.6, 3.1 Hz, H-5), 3.06 1dd, 1H, Jˆ
13.6, 7.6 Hz, H-6), 3.16 1dd, 1H, Jˆ14.3, 2.4 Hz, H-10),
3.37 1dd, 1H, Jˆ9.4, 2.4 Hz, H-3), 3.39 1dd, 1H, Jˆ13.6,
3.16 Hz, H-60), 3.60 1t, 1H, Jˆ9.4 Hz, H-4), 4.22 1m, 1H,
S3Jˆ6.6 Hz, H-2), 7.17±7.42 1m, 5H, SPh); 13C NMR
1100 MHz, CDCl3) 26.4, 26.8 1Me2C), 36.7 1C-6), 49.7
1C-1), 58.3 1C-5), 67.1 1C-2), 74.1 1C-4), 80.9 1C-3),
109.0 1Me2C), 126.0, 128.8, 129.3 1CH, SPh), 136.2
1C-ipso, SPh); MS 1CI, methane), m/z 1%): 296 1MH1,
100%), 238 1MH12acetone, 39%), 220 1MH12aceto-
ne2H2O, 5%); HRMS: calcd for C15H21O3NS 1M1)
295.1242, found 295.1245 128%).
References
1. Liu, P. S.; Kang, M. S.; Sunkara, P. S. Tetrahedron Lett. 1991,
32, 719.
2. 1a) Liu, P. S.; Rhinehart, B. L.; Daniel, J. K. U.S. Patent US
5,017,563, 1991; Chem. Abstr., 1991, 115, 136471e.
1b) Schroeder, T.; Stubbe, M. Ger. Offen. DE 3,611,841,
1987; Chem. Abstr., 1988, 109, 55168k.
3. Karpas, A.; Fleet, G. W. J.; Dwek, R. A.; Petursson, S.;
Namgoong, S. K.; Ramsden, H. G.; Jacob, G. S.; Rademacher,
T. W. Proc. Natl Acad. Sci. USA 1988, 85, 9229.
4. Gruters, R. A.; Neefjes, J. J.; Tersmette, M.; de Goede, R. E. Y.;
Tulp, A.; Huisman, H. G.; Miedema, F.; Ploegh, H. L. Nature
1987, 330, 74.
4.1.23. 6-Azido-1,6-dideoxy-mannojirimycin 021a). Com-
pound 20a 10.52g, 2.3 mmol) was treated with saturated
methanolic HCl 110 mL) for 2h. The solution was evapo-
rated and the residue was co-evaporated twice with MeOH.
Puri®cation by column chromatography on silica gel
1CHCl3/MeOH/H2O/NH4OH 70:28:1:1) afforded 21a as an
oil 10.38 g, 89%); [a]Dˆ246 1MeOH, c 1.12); IR, 3360,
5. Truscheit, E.; Frommer, W.; Junge, B.; Mueller, L.; Schmidt,
D. D.; Wingender, W. Angew. Chem., Int. Ed. Engl. 1981, 20,
744.
6. Fuhrmann, U.; Bause, E.; Legler, G.; Ploegh, H. Nature 1984,
307, 755. In contrast to glucosidase inhibitors, which often
have structures closely resembling glucose, potent manno-
sidase inhibitors generally do not overlay well with the ground
state of mannopyranose, with the exception of deoxymanno-
jirimycin, see: Winkler, D. A; Holan, G. J. Med. Chem. 1989,
32, 2084.
1
2094, 1290, 1060 cm21; H NMR 1400 MHz, CD3OD), d
1ppm) 2.48 1dt, 1H, Jˆ9.5, 4.2Hz, H-5), 2.72 1dd, 1H,
Jˆ14.0, 1.5 Hz, H-1), 2.98 1dd, 1H, Jˆ14.0, 2.8 Hz,
H-10), 3.38 1dd, 1H, Jˆ9.5, 3.2Hz, H-3), 3.51 1t, 1H, Jˆ
9.5 Hz, H-4), 3.63 1d, 2H, Jˆ4.2Hz, H-6); 3.86 1m, 1H,
S3Jˆ7.5 Hz, H-2),; 13C NMR 1100 MHz, CD3OD) 50.5
1C-1), 53.3 1C-6), 61.1 1C-5), 70.6 1C-2, 4), 76.5 1C-3););
MS 1CI, methane), m/z 1%): 189 1MH1, 100%), 171
1MH12H2O, 14%); HRMS: calcd for C5H10O3N 1M12
CH2N3) 132.0661, found 132.0674 1100%).
7. 1a) Kilonda, A.; Compernolle, F.; Hoornaert, G. J. Org. Chem.
1995, 60, 5820±5824. 1b) Kilonda, A.; Compernolle, F.;
Toppet, S.; Hoornaert, G. J. Chem. Soc., Chem. Commun.
1994, 2147.
8. Compernolle, F.; Joly, G. J.; Peeters, K.; Toppet, S.;
Hoornaert, G.; Kilonda, A.; Babady, B. Tetrahedron 1997,
53, 12739.
9. Joly, G. J.; Peeters, K.; Mao, H.; Brossette, T.; Hoornaert, G.;
Compernolle, F. Tetrahedron Lett. 2000, 41, 2223.
Â
10. 1a) Dureault, A.; Tranchepain, I.; Depezay, J.-C. J. Org.
4.1.24. 6-Phenylthio-1,6-dideoxy-mannojirimycin 021h).
Compound 20h 10.38 g, 1.3 mmol) was treated with satu-

H. Mao et al. / Tetrahedron 57 .2001) 6955±6967
6967
Â
Chem. 1989, 54, 5324. 1b) Fitremann, J.; Dureault, A.; Depe-
zay, J.-C. Tetrahedron Lett. 1994, 35, 1201. 1c) Fitremann, J.;
1995, 36, 6373. 1b) Maligres, P. E.; See, M. M.; Askin, D.;
Reider, P. J. Tetrahedron Lett. 1997, 38, 5253.
Â
Dureault, A.; Depezay, J.-C. Synlett 1995, 235. 1d) McCort, I.;
14. Huynh, C.; Derguini-Boumechal, F.; Linstrumelle, G.
Tetrahedron Lett. 1979, 20, 1503.
15. Mitsunobu, O. Synthesis 1981, 1.
Â
Dureault, A.; Depezay, J.-C. Tetrahedron Lett. 1996, 37, 7717.
1
11. The values JC±Hˆ161 and 171 Hz are cited for N-methyl-
16. Anisuzzaman, A. K. M.; Whistler, R. L. Carbohydr. Res.
1978, 61, 511.
aziridine by Kalinowski, H.-O.; Berger, S.; Braun, S. In
Carbon-13 NMR Spectroscopy, Wiley: Chichester, 1988,
p 441.
17. For C-azadisaccharides, see 1a) Johnson, C. R.; Miller, M. W.;
Gedebiowski, A.; Ksebati, M. B. Tetrahedron Lett. 1994, 35,
8991. 1b) Martin, O. R.; Liu, L.; Yang, F. Tetrahedron Lett.
1996, 37, 1991. 1c) Frerot, E.; Marquis, C.; Vogel, P.
Tetrahedron Lett. 1996, 37, 2023. 1d) Johns, B.; Pan, Y.;
Elbein, A.; Johnson, C. J. Am. Chem. Soc. 1997, 119, 4856.
12. 1a) Ji, S.; Gortler, L. B.; Waring, A.; Battisti, A.; Bank, S.;
Closson, W. D.; Wriede, P. J. Am. Chem. Soc. 1967, 89, 5311.
1b) Zhou, W.-S.; Xie, W.-G.; Lu, Z.-H.; Pan, X.-F. J. Chem.
Soc., Perkin Trans. 1 1995, 2599.
13. 1a) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett.