New potent C2-symmetric malaria plasmepsin I and II inhibitors.

Article abstract of DOI:10.1016/S0968-0896(02)00643-0

A series of malaria plasmepsin (Plm) I and II inhibitors containing a C(2)-symmetric core structure have been synthesised and tested for protease inhibition activity. These compounds can be prepared using a straightforward synthesis involving a phenol nuc

Full text of DOI:10.1016/S0968-0896(02)00643-0

Bioorganic & Medicinal Chemistry 11 (2003) 1235–1246
New Potent C2-Symmetric Malaria Plasmepsin I and II Inhibitors
Karin Oscarsson,a Stefan Oscarson,a Lotta Vrang,b Elizabeth Hamelink,b
Anders Hallbergc and Bertil Samuelssona,b,
*
aDepartment of Organic Chemistry, Arrhenius Laboratory, Floor 6, Stockholm University, S-106 91 Stockholm, Sweden
bMedivir AB, Lunastigen 7, S-141 44 Huddinge, Sweden
cDepartment of Organic Pharmacutical Chemistry, BMC, Uppsala University, Box 574, S-75123 Uppsala, Sweden
Received 24 September 2002; accepted 3 December 2002
Abstract—A series of malaria plasmepsin (Plm) I and II inhibitors containing a C2-symmetric core structure have been synthesised
and tested for protease inhibition activity. These compounds can be prepared using a straightforward synthesis involving a phenol
nucleophilic ring opening of a diepoxide. Exemplar compounds synthesised exhibited remarkable inhibitory activity against both
Plm I and II, notably 15c with Ki values of 2.7 nM and 0.25 nM respectively, as well as showing >100-fold selectivity against
Cathepsin D.
# 2003 Elsevier Science Ltd. All rights reserved.
Introduction
been solved both as zymogen proplasmepsin and in
complex with pepstatin A, which is the classical non
selective statine-based peptide aspartic protease inhi-
bitor.17,18 Although Pepstatin A and other related sta-
tine type containing peptide inhibitors as well as
inhibitors containing hydroxyethylamine scaffolds have
been described, only a limited number of non-peptide
potent inhibitors of Plm II have been dis-
closed.8,9,11,13,19ꢀ22 Moreover, there is today an
increased awareness that Plm I is acting in synergy with
Plm II, underscoring the importance to develop and
characterise broad based inhibitors against Plm I and II.
Cathepsin D (Cat D), a human protease in the endoso-
mal-lysosomal pathway, exhibits an overall 35%
sequence homology to Plm II, and thus, for develop-
ment of Plm I and II inhibitors it is desirable to achieve
a high selectivity against Cat D in order to minimize
potential adverse effects. We herein report on a new
class of inhibitors that potently inhibits both Plm I and
II whilst showing excellent selectivity against Cat D.
Malaria is one of the most serious infectious diseases in
the world today, affecting approximately 500 million
people yearly.1 Mortality from malaria exceeds 1 mil-
lion people per year, most of them being children in
Africa under the age of 4 years, a number that is con-
tinuously increasing due to the rapid spread of drug
resistant parasites.2ꢀ5 This underscores the paramount
importance of discovering new pharmaceuticals active
against both wild type and resistant parasite strains and
consequently to identify novel molecular targets for
drug discovery. Recently proteases have emerged as new
and promising targets for antimalarials.4,6ꢀ9 Of the four
major species of the malaria parasite, Plasmodium falci-
parum is responsible for more than 95% of malaria-
related mortality.10,11 The intraerythrocytic stages of
Plasmodium rely on red blood cell haemoglobin for
nutrient supply.12 Two homologous aspartic proteases,
plasmepsin I and II (Plm I and Plm II) appear to initiate
this haemoglobin degradation process in the parasite
digestive acid vacuole, and blockages of these enzymes
has been demonstrated to result in parasite death.4,13ꢀ15
Today, at least 10 aspartic protease genes have been
identified in the P. falciparum genome, potentially com-
plicating the picture of target selection and target
redundancy.12,16 The crystal structure for Plm II has
Chemistry and Structure–Activity Relationship
As starting point for this work, an acyclic C2-symmetric
diol derived from d-mannitol was used which pre-
viously has been developed for the synthesis of HIV-1
protease inhibitors.23 Although weak HIV-1 protease
inhibition was generally observed, the potential of the
template for the design and synthesis of aspartic pro-
tease inhibitors was demonstrated. The inhibitors in this
*Corresponding author. Tel.: +46-8-608-3104; fax: +46-8-608-3199;
e-mail: bertil.samuelsson@medivir.se
0968-0896/03/$ - see front matter # 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0968-0896(02)00643-0

1236
K. Oscarsson et al. / Bioorg. Med. Chem. 11 (2003) 1235–1246
Table 1. Reaction yields and synthetic method for compounds 2–5a–k
report were made starting from d-mannitol which was
converted into a 3,4-O-protected diepoxide and subse-
quently ring-opened with phenol derivatives (Scheme 1).
The resulting diols were then converted into the corres-
ponding diazides, which were reduced and thereafter
coupled to a series of selected acylating derivatives deli-
vering the target inhibitor compounds (Schemes 1 and 3).
Ar–
Compd (yields)
Ph–
2a, 81% 3a, 100%a 4a, 95% 5a, 30%c
2b, 63% 3b, 100%a 4b, 73% 5b, 48%c
p-MeOPh–
p-CNPh–
m-MeOPh–
p-BrPh–
m-CNPh–
o-CNPh–
2c, 79% 3c, 66%a
4c, 86% 5c, 51%c
2d, 75% 3d, 98%a 4d, 100% 5d, 65%c
2e, 74% 3e, 95%a
4e, 87% 5e, 68%d
2f, 72% 3f, 84%b 4f, 100% 5f, 67%d
2g, 75% 3g, 86%b 4g, 81% 5g, 58%d
From readily available d-mannitol, the starting material
1,2:5,6-dianhydro-3,4-O-isopropylidene-d-mannitol (1)
was synthesised in three steps according to the proce-
dure of Merrer et al.,24 (Scheme 1). The diepoxide (1)
was then reacted with phenols in DMF at 110 ꢁC in the
presence of potassium carbonate to give the diols 2a–k
in 63–81% yield (Table 1).23
p-(thiazol-2-yl)Ph- (10) 2h, 80% 3h, 76%b 4h, 80% 5h, 47%d
m-(thiazol-2-yl)Ph- (11) 2i, 87% 3i, 73%b
p-(thiazol-5-yl)Ph- (12) 2j, 63% 3j, 58%b
4i, 72% 5i, 57%d
4j, 85% 5j, 45%d
m-(thiazol-5-yl)Ph- (13) 2k, 65% 3k, 70%b 4k, 92% 5k, 57%d
aCondition A (see Scheme 1).
bCondition B (see Scheme 1).
cCondition C (see Scheme 1).
dCondition D (see Scheme 1).
The diols 2a–e were converted to the corresponding
diazides 3a–e in 66% to quantitative yields, using Mit-
sunobu conditions with DIAD, triphenylphosphine,
diphenylphosporazidate (DPPA) (Scheme 1, Condition
A).25 However, this methodology was less useful for the
transformation of the diols 2f–k into the diazides 3f–k
and low yields were encountered. Applying an altern-
ative procedure, where the diols were treated with tri-
fluoromethanesulfonic anhydride in the presence of
pyridine followed by reaction with sodium azide in
DMF delivered the diazides 3f–k in 58–86% overall
yields (Scheme 1, Condition B).
C), afforded the corresponding diamino diols, that sub-
sequently were transformed into the target compounds
5a–d. To avoid reductive debromation of 4e, H2S in
pyridine-triethylamine was used for selective reduction
of the azido groups (Scheme 1, Condition D).26 This
method also proved useful for the diazide reduction of
compounds 4f–k.
The target compounds 5a–d were obtained in 30–65%
overall yield over two steps, by reduction of the dia-
zides, followed by reaction with benzyl chloroformate in
the presence of pyridine in CH2Cl2. Reacting the corre-
sponding diamine of 4e–k with benzyl chlorofomate
resulted in poor yields. However, using N-(benzyloxy-
carbonyloxy)-succinimide instead delivered the com-
pounds 5e–k in 45–68% overall yields.
Hydrolysis of the isopropylidene acetal in 3a–k by 3 M
HCl in methanol gave the diazido diols 4a–k in 73% to
quantitative yields. Catalytic hydrogenolysis of 4a–d
over 10% palladium on carbon (Scheme 1, Condition
To obtain the corresponding thiazole substituted phe-
nols two different approaches were applied (Scheme 2).
The p- and m-thiazole-2-yl-phenols 10 and 11 were syn-
thesised from a Stille type coupling using 2-trimethyl-
stannylthiazole, prepared in good yield by quenching
2-lithiothiazole with trimethyltin chloride.27 The stan-
nylated reagents were reacted with p- and m-bromoani-
sole in the presence of Pd(Ph3)4 affording the anisoles 6
and 7.28 Demethylation of the anisoles was subsequently
achieved with 48% HBr in water after which phenols 10
and 11 were isolated in 63 and 61% overall yield
respectively, over the two steps.
The p- and m-thiazole-5-yl-phenols 12 and 13 were pre-
pared in two steps in 60 and 44% yields respectively by
reacting thiazole with p- and m-bromanisole in the pre-
29
sence of Pd(Ph3)4 followed by 48% HBr in water
(Scheme 2). The structures were confirmed by the pre-
sence of the 1H NMR signals at 7.88 ppm (s, 1H) for 12
and 8.05 ppm for 13 (s, 1H), assigned to the C(4) proton
of the thiazole ring. The isomeric thiazole-4-yl deriva-
tive would give rise to a doublet at ꢂ7.4 ppm [H-C(5)].
From this first set of compounds very promising inhibi-
tors were rapidly identified (Table 2).
Scheme 1. Synthesis of compound set I, 5a–k. Condition: (A) Ph3P,
DIAD, THF; (B) 1.Tf2O, pyridine, CH2Cl2 2. NaN3, DMF; (C) 1. H2,
Pd/C, EtOAc 2. benzyl chloroformate, pyridine, CH2Cl2; (D) 1. H2S,
pyridine, Et3N 2. N-(benzyloxycarbonyloxy)-succinimide, Et3N,
CH2Cl2.
It was evident from the limited SAR available that the
electron withdrawing cyano substituent attached to the

K. Oscarsson et al. / Bioorg. Med. Chem. 11 (2003) 1235–1246
1237
Scheme 2. Synthesis of phenols 10–13; * overall yields.
Table 2. Percentage inhibition at 0.5 mM against Plm I and II and
inhibition constant for Plm I, Plm II and Cat D for compound set I
desired target molecules of the new series, compound set
II, were obtained by reducing the appropriate diazides
followed by coupling of the resulting diamines with the
chosen acylating groups (Scheme 3 and Table 3).
Compounds 14a–d were formed in 45–92% yield by
reduction of the azido groups followed by in situ acyla-
tion of the resulting amine using hydrogen over 10%
palladium on carbon in ethyl acetate in the presence of
di-tert-butyl dicarbonate (Boc2O) (Scheme 3, Table 3).30
For 14e, the diazide was reduced with H2S and the dia-
mine was isolated and subsequently reacted with Boc2O.
Compounds 15a–e were obtained in 56–90% yield by
coupling the diamines, from the reduced azides, vide
supra, with the amino acid Z-Val-OH using PyBop as
coupling reagent.31
Compd
Ar–
% inh.at 0.5 mM
Ki (nM)
Plm I
Plm II Plm I Plm II Cat D
5c
5f
5g
5h
5j
p-CNPh–
m-CNPh–
o-CNPh–
49
19
2
100
5
0
350
nd
nd
nd
nd
nd
140 >6000
nd
nd
nd
nd
nd
nm
nm
nm
nm
nm
p-(thiazol-2-yl)Ph–
p-(thiazol-5-yl)Ph–
m-(thiazol-2-yl)Ph–
3
0
0
2
5k
5
0
Compounds 5a–b, d–e and i were found to be inactive; nd=not
detected, nm=not measured.
Finally, the diazides 4a–d were converted to amides
16a–d, 17a–d and 18a–d by reduction of the diazides,
using hydrogen, over 10% palladium on carbon, and
coupling of the resulting diamines with the anhydrides
benzoic anhydride, p-methoxybenzoic anhydride and
p-nitrobenzoic anhydride. The anhydrides used were
prepared in a one-pot reaction by mixing the correspond-
ing carboxylic acids with triphosgene in the presence of
triethylamine in ethyl acetate, which produced the anhy-
drides in high yields.32 Attempts to isolate compounds
16e, 17e and 18e in pure form were unsuccessful, partly
attributed to the very low solubility of the amides.
phenoxy groups rendered the best activity. Thus inhi-
bitor 5c, having a para cyano phenoxy group, inhibits
Plm I and II with Ki values of 350 and 140 nM, respec-
tively, whilst the corresponding unsubstituted phenoxy
groups as well as electron rich methoxy substituted
phenoxy groups failed to exhibit inhibition activity
towards Plm I and II to any degree. With these highly
promising inhibition data at hand an expanded set of
compounds were prepared. A limited number of the
substituted phenoxy entities from the original set were
retained while exploring replacements for the benzylox-
ycarbonyl moiety with amides and carbamates. It was
also decided to maintain the C2-symmetric feature that
had shown promise from the initial compound set. The
From this expanded compound set II even more potent
inhibitors of Plm I and II were discovered (Table 4).
Notably the Z-Val series of inhibitors, exemplified by
15c, show remarkable Plm I and II inhibitory activity,

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K. Oscarsson et al. / Bioorg. Med. Chem. 11 (2003) 1235–1246
Scheme 3. Synthesis of compound set II, 14a–e, 15a–e, 16a–d, 17a–d and 18a–d (a) H2, Pd/C, (Boc)2O, EtOAc; (b) 1. H2S, pyridine, Et3N 2.
(Boc)2O, Et3N, EtOAc; (c) H2, Pd/C, EtOAc; (d) H2S, pyridine, Et3N; (e) Z-Val-OH, PyBOP, DIPEA; CH2Cl2; (f) benzoic anhydride, CH2Cl2; (g)
4-methoxybenzoic anhydride, CH2Cl2; (h) 4-nitrobenzoic anhydride CH2Cl2.
Table 3. Reaction yields of amides and carabamate couplings for compound set II
R
Ar–
Compound (yield)
Ph–
14a, 92%
14b, 45%
14c, 71%
14d, 68%
14e, 61%
15a, 56%
15b, 63%
15c, 73%
15d, 71%
15e, 90%
16a, 93%
16b, 56%
16c, 63%
16d, 74%
17a, 52%
17b, 76%
17b, 59%
17d, 57%
18a, 97%
18b, 50%
18c, 72%
18d, 56%
p-MeOPh–
p-CNPh–
m-MeOPh–
p-BrPh–
with Ki values of 2.7 and 0.25 nM respectively, as well as
showing >100-fold selectivity against Cathepsin D.
Plasmepsin II, although lacking the C2-symmetry prop-
erties of the HIV-1 protease, shows the typical bilobal
structure topology of eukaryotic aspartic proteases, and
it has herein been documented that Plm II can bind with
high affinity to C2-symmetric inhibitors such as 15c.
Statine-based inhibitors like pepstatin A, show pref-
erence to lipofilic amino acids in the amino terminus,
like Leu-Val-Val. It is highly likely that Z-Val occupy
this site as well.
Table 4. Inhibition constants for Plm I, Plm II and Cat D for com-
pound set II
Compd
Ar–
Ki(nM)
Plm I
Plm II
Cat D
15a
15b
15c
15d
15e
Ph–
29
9
2.7
31
58
86
23
0.25
44
23
>3000
>3000
340
>3000
1840
p-MeOPh–
p-CNPh–
m-MeOPh–
p-BrPh–
Conclusion
By exploring C2-symmetric templates, we have dis-
covered compounds that exhibit potent inhibition of
Compounds 14a–e, 16a,b,d, 17a–d and 18a–d were found to be inactive.

K. Oscarsson et al. / Bioorg. Med. Chem. 11 (2003) 1235–1246
1239
both Plm I and II. Moreover, selected inhibitors from
this set of compounds show very favourable selectivity
towards Cathepsin D. Another attractive feature is their
relative simplicity, which could translate into favourable
cost of goods. There thus appear to be a good founda-
tion for further optimisation of this set of inhibitors.
matrix. Unless stated otherwise, all materials were
obtained from commercial suppliers and used without
further purification. Compounds 2–4a–b and 14a–b
were synthesised according to Zuccarello et al.23
General method for the preparation of compounds 2c–k.
K2CO3 (0.5 equiv) was added to a stirred solution of
1,2:5,6-dianhydro-3,4-O-isopropylidene-d-mannitol, 124
(1 equiv) and phenol (3–4 equiv) in DMF (30 mL/g of 1).
The reaction mixture was heated at 110 ꢁC for 4–5 h.
The reaction mixture was, after cooling, added to satu-
rated aqueous NH4Cl and extracted with Et2O. The
organic phase was washed with H2O (2Â) and the com-
bined aqueous layers were extracted with Et2O (2Â).
The organic layers were combined dried with MgSO4
and concentrated. Purification of the residue by silica
gel column chromatography (solvent system A; toluene;
toluene–EtOAc 6:1, solvent system B; toluene–EtOAc
3:1) gave the target compounds 2c–k.
Experimental
Plasmepsin assay and Ki determination
Pro-plasmepsin II was a generous gift from Helena
Danielson (Department of Biochemistry, Uppsala Uni-
versity, Uppsala, Sweden) and the expression and pur-
ification of plasmepsin I will be published elsewhere.33
Human liver cathepsin D was purchased from Sigma-
Aldrich, Sweden. The activities of plasmepsin I (Plm I),
plasmepsin II (Plm II) and cathepsin D (Cat D) was
measured essentially as described earlier,11 using a total
reaction volume of 100 mL The concentration of pro-
Plm II was 3 nM, the amount of Plm I was adjusted to
give similar catalytic activity and 50 ng/mL pro-cathe-
psin D was used. The pro-sequence of Plm II was
cleaved off by preincubation in assay reaction buffer
(100 mM sodium acetate buffer (pH 4.5), 10% glycerol
and 0.01% Tween 20) at room temperature for 40 min
and Cat D was activated by incubation in the same reac-
tion buffer at 37 ꢁC for 20 min. The reaction was initiated
by the addition of 3 mM substrate (DABCYL-Glu-Arg-
Nle-Phe-Leu-Ser-Phe-Pro-EDANS, AnaSpec Inc, San
Jose, CA, USA) and hydrolysis was recorded as the
increase in fluorescence intensity over a 10 min time per-
iod, during which the rate increased linearly with time.
1,6-Di-O-(4-cyanophenyl)-3,4-O-isopropylidene-D-manni-
tol, 2c. The title compound was prepared in 79% yield
(1.26 g, 2.97 mmol) according to general procedure, vide
20
supra (solvent system A). ½ꢀꢃD +23.6 (c 0.67, MeOH);
1H NMR (400 MHz, CDCl3) d 7.57–7.55 (d, 4H),
7.01–7.00 (d, 4H), 4.33–4.31 (d, 2H), 4.14–4.10 (dd, 2H),
4.03 (m, 4H), 3.91 (s, 2H) 1.40 (s, 6H); 13C NMR
(100 MHz, CDCl3) d 162.2, 134.2, 119.3, 115.6, 110.4,
104.5, 79.9, 71.8, 70.3, 27.2; anal. calcd for:
(C23H24N2O6) C, 65.1, H, 5.7, N, 6.6. Found: C, 64.9,
H, 5.7, N, 6.4.
3,4-O-Isopropylidene-1,6-di-O-(3-methoxyphenyl)-D-man-
nitol, 2d. The title compound was prepared in 75% yield
(1.22 g, 2.82mmol) according to general procedure, vide
20
Stock solutions of inhibitors in DMSO were serially
diluted in DMSO and added directly before addition of
substrate, giving a final DMSO concentration of 1%.
supra (solvent system A). ½ꢀꢃD +32 (c 1.87, MeOH); 1H
NMR (300 MHz, CDCl3)
d 7.21–7.15 (m, 2H),
6.57–6.51 (m, 6H), 4.28–4.25 (d, 2H), 4.06–4.04 (m, 6H),
3.78 (s, 6H), 3.76 (s, 2H), 1.39 (s, 6H); 13C NMR
(75 MHz, CDCl3) d 161.1, 160.2, 130.2, 110.1, 107.1,
107.1, 101.5, 80.0, 71.9, 69.9, 55.5, 27.1; anal. calcd for:
(C23H30O6) C, 63.6, H, 7.0, found: C, 63.7, H, 7.0.
IC50-values were obtained by assuming competitive
inhibition and fitting a Langmuir isotherm (vi/vo=1/
(1+[I] /IC50)) to the dose response data (Grafit), where
vi and vo are the initial velocities for the inhibited and
uninhibited reaction respectively and [I] is the inhibitor
concentration.34 The Ki was subsequently calculated by
using Ki=IC50/(1+[S]/Km)35 and Km value determined
according to Michaelis–Menten.
1,6-Di-O-(4-bromophenyl)-3,4-O-isopropylidene-D-manni-
tol, 2e. The title compound was prepared in 74% yield
(1.48 g, 2.78 mmol) according to general procedure, vide
20
supra (solvent system A). ½ꢀꢃD +24 (c 1.03, MeOH); 1H
NMR (300 MHz, CDCl3) d 7.38–7.35 (d, 4H), 6.83–6.81
(d, 4H), 4.25–4.22 (d, 2H), 4.02 (m, 6H), 3.68 (s, 2H),
1.38 (s, 6H); 13C NMR (75 MHz, CDCl3) d 157.9, 132.5,
116.7, 113.6, 110.2, 80.0, 71.9, 70.1, 27.1. Anal. calcd for:
(C21H24Br2O6) C, 47.4, H, 4.6., found: C, 47.3, H, 4.6.
General
All glassware was dried over an open flame before use in
connection with an inert atmosphere. Concentrations
were performed under reduced pressure at <40 ꢁC (bath
temperature). Thin layer chromatography was per-
formed using silica gel 60 F-254 plates with detection by
UV and charring with 8% sulfuric acid. Silica gel
(0.040–0.063 mm) was used for column chromato-
graphy. Me4Si (0.0 ppm) was used as an internal stan-
1,6-Di-O-(3-cyanophenyl)-3,4-O-isopropylidene-D-manni-
tol, 2f. The title compound was prepared in 72% yield
(246 mg, 0.58 mmol) according to general procedure, vide
20
supra (solvent system A). ½ꢀꢃD +27.1 (c 1.53, MeOH);
1H NMR (400 MHz, CDCl3) d 7.38–7.33 (m, 2H),
7.24–7.17 (m, 6H), 4.30–4.28 (d, 2H), 4.10–4.03 (m, 8H),
1.40 (s, 6H); 13C NMR (100 MHz, CDCl3) d 159.0,
130.7, 125.2, 120.3, 118.8, 118.0, 113.4, 110.4, 79.9, 71.8,
70.3, 27.1; anal. calcd for: (C23H24N2O6) C, 65.1, H, 5.7,
N, 6.6, found: C, 65.0, H, 5.7, N, 6.5.
1
dard in H NMR and Me4Si or CDCl3 (77.0 ppm) were
used in 13C NMR. Optical rotations were measured on
a Perkin–Elmer 241 polarimeter. MALDI-TOF spectra
were recorded on a Bruker Biflex III using 20,40,60-tri-
hydroxy-acetophenone monohydrate (THAP) as

1240
K. Oscarsson et al. / Bioorg. Med. Chem. 11 (2003) 1235–1246
1,6-Di-O-(2-cyanophenyl)-3,4-O-isopropylidene-D-manni-
tol, 2g. The title compound was prepared in 75% yield
(257mg, 0.60mmol) according to general procedure, vide
General method for the preparation of compounds 4c–e.
To a stirred solution of triphenylphosphine (2 equiv) in
THF under an argon atmosphere at 0 ꢁC, diisopropyla-
zodicarboxylate (DIAD) (5 equiv) was added dropwise
during 5 min. The mixture was stirred for 30 min to
yield a white precipitate of triphenylphosphine-DIAD
complex. A solution of 2c–e (1 equiv) in THF was added
and the mixture was stirred for 15 min before diphenyl
phosphorazidate (DPPA) (2.5 equiv) was added. The
mixture was allowed to warm to room temperature.
After stirring overnight, the solvent was removed and
the crude material was purified by silica gel column
chromatography (toluene; toluene–EtOAc 9:1) to give
the target compounds 3c–e. To 3c–e (1 equiv) was added
a cold (0 ꢁC) solution of acetyl chloride (25 equiv) in
MeOH (35 mL/mmol 3c–e), which had been stirred for
10 min. After stirring for 4 h at room temperature, the
reaction mixture was concentrated. The residue was
purified by silica gel column chromatography (toluene;
toluene–EtOAc 3:1) to give the target compounds 4c–e.
20
supra (solvent system A). ½ꢀꢃD +34.5 (c 1.36, MeOH);
1H NMR (400 MHz, CDCl3) d 7.53–7.49 (m, 4H),
7.03–6.97 (m, 4H), 4.40–4.38 (dd, 2H), 4-34–4.33 (d,
2H), 4.19–4.11 (m, 6H), 1.40 (s, 6H); 13C NMR
(100 MHz, CDCl3) d 160.8, 134.7, 133.8, 121.3, 116.8,
113.0, 110.3, 102.3, 79.5, 71.7, 71.0, 27.1; anal. calcd for:
(C23H24N2O6) C, 65.1, H, 5.7, N, 6.6, found: C, 65.0, H,
5.8, N, 6.7.
3,4-O-Isopropylidene-1,6-Di-O-(4-thiazol-2-yl-phenyl)-D-
mannitol, 2h. The title compound was prepared in 80%
yield (279 mg, 0.52 mmol) according to general proce-
20
dure, vide supra (solvent system B). ½ꢀꢃD +30.5 (c 0.72,
MeOH–DCM 2:1); 1H NMR (400 MHz, CDCl3) d
7.80–7.77 (d, 4H), 7.71–7.70 (d, 2H), 7.22–7.21 (d, 2H),
6.96–6.94 (d, 4H), 4.27–4.25 (dd, 2H), 4.07–4.03 (dd,
2H), 4.01–3.94 (m, 4H), 3.47 (s, 2H), 1.35 (s, 6H); 13C
NMR (100 MHz, CDCl3) d 168.9, 160.7, 143.2, 128.4,
126.6, 118.4, 115.3, 110.1, 80.0, 71.6, 70.2, 27.0; anal.
calcd for: (C27H28N2O6S2) C, 60.0, H, 5.2, N, 5.2,
found: C, 60.1, H, 5.2, N, 5.0.
2,5-Diazido-1,6-di-O-(4-cyanophenyl)-2,5-dideoxy-L-idi-
tol, 4c. The title compound was prepared in a two step
synthesis according to general procedure, vide supra.
The intermediate 3c was prepared in 66% yield (603 mg,
1.27 mmol); 13C NMR (75 MHz, CDCl3) d 161.3, 134.4,
119.1, 115.6, 111.5, 105.3, 76.5, 68.6, 59.3, 27.0. The title
compound was produced in 86% yield (472 mg,
3,4-O-Isopropylidene-1,6-Di-O-(3-thiazol-2-yl-phenyl)-D-
mannitol, 2i. The title compound was prepared in 87%
yield (505 mg, 0.93 mmol) according to general proce-
20
20
dure, vide supra (solvent system B). ½ꢀꢃD +25.8 (c 1.77,
1.09 mmol). ½ꢀꢃD +14.8 (c 1.60, MeOH); 1H NMR
1
MeOH); H NMR (300 MHz, CDCl3) d 7.84–7.83 (d,
(400 MHz, CDCl3:CD3OD) d 7.53–7.51 (d, 4H),
2H) 7.55–7.53 (m, 2H), 7.49–7.46 (bd, 2H), 7.31–7.25
(m, 4H), 6.97–6.93 (m, 2H), 4.97 (s, 2H), 4.36–4.33 (d,
2H), 4.14–4.07 (m, 6H), 1.37 (s, 6H); 13C NMR
(75 MHz, CDCl3) d 168.6, 159.4, 143.7, 134.8, 130.2,
119,7, 119.3, 117.1, 112.5, 110.1, 80.1, 71.9, 70.3, 27.1;
anal. calcd for: (C27H28N2O6S2) C, 60.0, H, 5.2, N, 5.2,
found: C, 60.3, H, 5.2, N, 5.1.
6.93–6.91 (d, 4H), 4.29–4.20 (m, 4H), 3.91–3.87 (m, 2H),
3.83–3.81 (m, 2H), 3.46 (s, 2H); 13C NMR (100 MHz,
CDCl3:CD3OD) d 161.8, 134.3, 119.1, 115.5, 104.6,
79.1, 68.6, 62.3; IR: 2229, 2103 cmꢀ1; anal. calcd for
(C20H18N8O4) C, 55.3, H, 4.2, N, 25.8, found: C, 55.0,
H, 4.1, N, 25.3.
2,5-Diazido-2,5-dideoxy-1,6-di-O-(3-methoxyphenyl)-L-
iditol, 4d. The title compound was prepared in a two
step synthesis according to general procedure, vide
supra. The intermediate 3d was prepared in 98% yield
(874 mg, 1.80); 13C NMR (75 MHz, CDCl3) d 161.2,
159.4, 130.3, 111.14, 107.5, 106.9, 101.5, 77.2, 68.1, 59.8,
55.5, 27.1. The title compound was produced in 99%
3,4-O-Isopropylidene-1,6-Di-O-(4-thiazol-5-yl-phenyl)-D-
mannitol, 2j. The title compound was prepared in 63%
yield (195 mg, 0.36 mmol) according to general proce-
20
dure, vide supra (solvent system B). ½ꢀꢃD +34.0 (c 0.67,
MeOH–DCM 2:1); 1H NMR (400 MHz, CDCl3:
CD3OD) d 8.62 (s, 2H), 7.85 (s, 2H), 7.39–7.37 (d, 4H),
6.92–6.89 (d, 4H), 4.26–4.24 (d, 2H), 4.06–3.98 (m, 6H),
3.22 (bs, 2H), 1.34 (s, 6H); 13C NMR (100 MHz, CDCl3:
CD3OD) d 159.4, 151.8, 139.6, 137.7, 128.4, 123.8,
115.5, 110.1, 80.0, 71.6, 70.2, 27.1; anal. calcd for:
(C27H28N2O6S2) C, 60.0, H, 5.2, N, 5.2, found: C, 59.6,
H, 5.6, N, 4.9.
20
yield (545 mg, 1.23 mmol). ½ꢀꢃD ꢀ1.25 (c 1.60, MeOH);
1H NMR (400 MHz, CDCl3) d 7.22–7.18 (t, 2H),
6.56–6.48 (m, 6H), 4.27–4.25 (m, 4H), 3.95–3.94 (m,
4H), 3.78 (s, 6H), 2.93–2.92 (d, 2H); 13C NMR
(100 MHz, CDCl3) d 161.2, 159.4, 130.3, 107.5, 106.9,
101.4, 69.2, 62.7, 55.6; IR: 2101 cmꢀ1; anal. calcd for:
(C20H24N6O4) C, 54.1, H, 5.4, N, 18.9, found: C, 54.6,
H, 5.5, N, 18.6.
3,4-O-Isopropylidene-1,6-Di-O-(3-thiazol-5-yl-phenyl)-D-
mannitol, 2k. The title compound was prepared in 65%
yield (164 mg, 0.30 mmol) according to general proce-
1,6-Di-O-(4-bromophenyl)-2,5-diazido-2,5-dideoxy-L-idi-
tol, 4e. The title compound was prepared in a two step
synthesis according to general procedure, vide supra.
The intermediate 3e was prepared in 95% yield (831 mg,
1.43 mmol); 13C NMR (75 MHz, CDCl3) d 157.2, 132.7,
116.7, 114.2, 111.3, 76.9, 68.4, 59.6, 27.1. The title com-
pound was produced in 87% yield (488 mg, 0.90 mmol).
20
dure, vide supra (solvent system B). ½ꢀꢃD +25.8 (c 2.15,
1
MeOH); H NMR (400 MHz, CDCl3) d 8.72 (s, 2H),
8.03 (s, 2H), 7.29–7.24 (t, 2H), 7.17–7.12 (m, 4H),
6.94–6.92 (dd, 2H), 4.8 (s, 2H), 4.36–4.34 (d, 2H),
4.16–4.09 (m, 6H), 1.39 (s, 6H); 13C NMR (100 MHz,
CDCl3) d 159.5, 152.5, 139.2, 132.4, 130.4, 120.0, 114.7,
113.9, 110.1, 80.2, 71.9, 70.3, 27.2; anal. calcd for:
(C27H28N2O6S2) C, 60.0, H, 5.2, N, 5.2, found: C, 59.5,
H, 5.3, N, 5.3.
20
½ꢀꢃD +11.9 (c 1.30, MeOH); 1H NMR (300 MHz,
CDCl3) d 7.41–7.38 (d, 4H), 6.81–6.78 (d, 4H),
4.29–4.19 (m, 4H), 3.99–3.91 (m, 4H), 2.80–2.79 (d, 2H);

K. Oscarsson et al. / Bioorg. Med. Chem. 11 (2003) 1235–1246
1241
13C NMR (75 MHz, CDCl3) d 157.2, 132.7, 116.6,
114.3, 70.9, 68.5, 62.6; IR: 2103 cmꢀ1; anal. calcd for:
(C18H18Br2N6O4) C, 39.9, H, 3.4, N, 15.5, found: C,
39.6, H, 3.3, N, 15.9.
supra. The intermediate 3h was prepared in 58% yield
(101 mg, 0.17 mmol); 13C NMR (75 MHz, CDCl3) d
168.3, 159.6, 143.6, 128.4, 127.6, 118.5, 115.2, 111.3,
77.0, 68.3, 59.7, 27.1. The title compound was produced
in 80% yield (103 mg, 0.19 mmol) (solvent system B).
20
General method for the preparation of compounds 4f–k.
To a stirred solution of 2f–k (1 equiv) in DCM (4 mL)
and pyridine (2 mL) at 0 ꢁC was added triflic anhydride
(4 eqiuv.) and the mixture was stirred for 1 h at 0 ꢁC.
The mixture was diluted with DCM and washed with
saturated aqueous NaHCO3 (1Â) and H2O (1Â) and the
combined aqueous layers were extracted with EtOAc
(2Â). All the organic layers were combined dried with
MgSO4 and concentrated. The residue was added to a
solution of sodium azide (10 equiv) in DMF (3 mL) at
70 ꢁC. After 2 h the mixture was filtrated through a plug
of Celite, the solvent was removed and the crude mate-
rial was purified by silica gel column chromatography
(toluene; toluene–EtOAc 9:1) to give the target com-
pounds 3f–k.
½ꢀꢃD +4.09 (c 1.11, DCM–MeOH 1:1); 1H NMR
(300 MHz, CDCl3) d 7.87–7.84 (d, 4H), 7.82–7.81 (d,
2H), 7.26–7.25 (d, 2H), 6.92–6.89 (d, 4H), 4.27–4.25 (m,
4H), 3.97 (m, 6H); 13C NMR (75 MHz, CDCl3) d 168.5,
159.7, 143.6, 128.4, 127.4, 118.6, 115.2, 70.8, 68.3, 63.5;
IR: 2110 cmꢀ1; anal.calcd for: (C24H22N8O4S2) ) C,
52.3, H, 4.0, N, 20.4, found: C, 52.5, H, 4.1, N, 20.5.
2,5-Diazido-2,5-dideoxy-1,6-di-O-(3-thiazol-2-yl-phenyl)-
L-iditol, 4i. The title compound was prepared in a two
step synthesis according to general procedure, vide
supra. The intermediate 3i was prepared in 73% yield
(239 mg, 0.41 mmol); 13C NMR (75 MHz, CDCl3) d
168.1, 158.6, 143.9, 135.2, 130.4, 120.4, 119.3, 117.2,
112.0, 111.3, 76.8, 68.3, 59.7, 27.1. The title compound
was produced in 72% yield (93 mg, 0.17 mmol) (solvent
20
To 3f–k (1 equiv) was added a cold (0 ꢁC) solution of
acetyl chloride (25 equiv) in MeOH (35 mL/ mmol
3f–k), which had been stirred for 10 min. After stirring
for 4 h at room temperature, the reaction mixture was
concentrated. The residue was purified by silica gel col-
umn chromatography (solvent system A; toluene; tolu-
ene–EtOAc 3:1, solvent system B; toluene;
toluene–EtOAc 1:1) to give the target compounds 4f–k.
system B). ½ꢀꢃD +2.2 (c 1.72, DCM–MeOH 1:1); H
NMR (400 MHz, CDCl3) d 7.86–7.85 (d, 2H), 7.52–7.47
(m, 4H), 7.30–7.26 (m, 4H), 6.93–6.90 (dd, 2H),
4.38–4.31 (m, 4H), 4.00 (bs, 6H); 13C NMR (100 MHz,
CDCl3) d 168, 4, 158.7, 143.7, 134.9, 130.4, 120.3, 119,5,
117.3, 112.0, 70.9, 68.4, 62.8; IR: 2102 cmꢀ1; anal. calcd
for: (C24H22N8O4S2) ) C, 52.3, H, 4.0, N, 20.4, found: C,
51.9, H, 4.1, N, 20.7.
1
2,5-diazido-1,6-di-O-(3-cyanophenyl)-2,5-dideoxy-L-idi-
tol, 4f. The title compound was prepared in a two step
synthesis according to general procedure, vide supra.
The intermediate 3f was prepared in 84% yield (186 mg,
0.40 mmol); 13C NMR (75 MHz, CDCl3) d 158.2, 130.9,
125.7, 120.4, 119.9, 117.8, 114.1, 111.05, 70.7, 68.7, 59.3,
27.1. The title compound was produced in 99% yield
2,5-Diazido-2,5-dideoxy-1,6-di-O-(4-thiazol-5-yl-phenyl)-
L-iditol, 4j. The title compound was prepared in a two
step synthesis according to general procedure, vide
supra. The intermediate 3j was prepared in 76% yield
(132 mg, 0.22 mmol); 13C NMR (75 MHz, CDCl3) d
158.3, 151.8, 139.1, 138.6, 128.6, 125.0, 115.5, 111.3,
77.0, 68.3, 59.7, 27.1. The title compound was prepared
in 85% yield (86 mg, 0.16 mmol) according to general
20
(145 mg, 0.33 mmol) (solvent system A). ½ꢀꢃD ꢀ7.6 (c
20
1
1.50, MeOH); H NMR (300 MHz, CDCl3) d 7.42–7.15
procedure, vide supra (solvent system B). ½ꢀꢃD +2.36 (c
1
(m, 8H), 4.37–4.26 (m, 4H), 4.00–3.97 (m, 4H), 2.91 (s,
2H); 13C NMR (75 MHz, CDCl3) d 158.4, 130.8, 125.7,
120.1, 118.5, 118.0, 113.7, 70.8, 69.7, 62.8; IR: 2233,
2101 cmꢀ1; anal. calcd for: (C20H18N8O4) C, 55.3, H,
4.2, N, 25.8. Found: C, 55.0, H, 4.3, N, 25.9.
1.55, DCM–MeOH 1:1); H NMR (400 MHz, CDCl3,
CD3OD) d 8.72 (s, 2H), 7.91 (s, 2H), 7.45–7.43 (d, 4H),
6.90–6.88 (d, 4H), 4,26–4.13 (m, 4H), 3.92–3.50 (m, 6H);
13C NMR (100 MHz, CDCl3,CD3OD) d 158.7, 152.0,
139.2, 137.5, 128.0, 124.0, 115.2, 70.5, 68.0, 62.8; IR:
2103 cmꢀ1; anal. calcd for: (C24H22N8O4S2) C, 52.3, H,
4.0, N, 20.4, found: C, 52.5, H, 4.1, N, 20.6.
1,6-Di-O-(2-cyanophenyl)-2,5-diazido-2,5-dideoxy-L-idi-
tol, 4g. The title compound was prepared in a two step
synthesis according to general procedure, vide supra.
The intermediate 3g was prepared in 86% yield (192 mg,
0.41 mmol); 13C NMR (75 MHz, CDCl3) d 159.8, 134.7,
134.1, 122.0, 116.3, 112.7, 111.3, 102.5, 77.0, 68.8, 60.0,
27.2, The title compound was produced in 81% yield
2,5-Diazido-2,5-dideoxy-1,6-di-O-(3-thiazol-5-yl-phenyl)-
L-iditol, 4k. The title compound was prepared in a two
step synthesis according to general procedure, vide
supra. The intermediate 3k was prepared in 70% yield
(107 mg, 0.18 mmol); 13C NMR (75 MHz, CDCl3) d
158.6, 152.5, 139.6, 139.1, 132.8. 130.6, 120.7, 114.6,
113.6, 111.3, 77.1, 68.3, 59.7, 27.1. The title compound
20
(89 mg, 0.20 mmol (solvent system A). ½ꢀꢃD ꢀ14.9 (c
1
2.05, MeOH); H NMR (400 MHz, CDCl3) d 7.56–7.43
20
(m, 4H), 7.05–6.97 (m, 4H), 4.44–4.34 (m, 4H), 4.11 (bs,
4H), 3.52 (bs, 2H); 13C NMR (75 MHz, CDCl3) d 159.9,
134.9, 133.8, 121.8, 116.5, 112.7, 102.0, 70.7, 68.8, 62.8;
IR: 2231, 2103 cmꢀ1; anal. calcd for: (C20H18N8O4) ) C,
55.3, H, 4.2, N, 25.8, found: C, 55.5, H, 4.3, N, 25.9.
was produced in 92% yield (84 mg, 0.16 mmol); ½ꢀꢃD
1
+2.73 (c 1.65, DCM–MeOH 1:1); H NMR (400 MHz,
CDCl3) d 8.72 (s, 2H), 8.00 (s, 2H), 7.29–7.26 (t, 2H),
7.15–7.13 (d, 2H), 7.05–7.04 (m, 2H), 6.88–6.86 (dd,
2H), 4.36–4.31 (m, 4H), 4.05–3.97 (m, 6H); 13C NMR
(100 MHz, CDCl3) d 158.7, 152.8, 139.3, 139.2, 132.5,
130.6, 120.5, 114.7, 113.5, 71.0, 68.2, 62.6; IR:
2106 cmꢀ1; anal. calcd for: (C24H22N8O4S2) C, 52.3, H,
4.0, N, 20.4, found: C, 52.5, H, 4.2, N, 20.4.
2,5-Diazido-2,5-dideoxy-1,6-di-O-(4-thiazol-2-yl-phenyl)-
L-iditol 4h. The title compound was prepared in a two
step synthesis according to general procedure, vide

1242
K. Oscarsson et al. / Bioorg. Med. Chem. 11 (2003) 1235–1246
General method for the preparation of compounds 5a–d.
To 4a–d (1 equiv) in EtOAc was added a catalytic
amount of Pd/C (10%). Hydrogen was added at atmo-
spheric pressure to the system and the reaction mixture
was stirred for 1 h. The suspension was then filtrated
through Celite and the solvent was removed. To the
diamines and Et3N (4 equiv) in DCM was added benzyl
chloroformate (2 equiv). After stirring over night the
reaction mixture was concentrated and the residue was
purified by silica gel column chromatography
(DCM–MeOH 20:1) to give the target compounds 5a–d.
general procedure, vide supra; 13C NMR (75 MHz,
CDCl3) d 157.7, 156.9, 136.5, 132.3, 128.5, 128.1, 127.9,
116.6, 113.3, 69.9, 67.7, 67.0, 51.6; MS (MALDI-TOF)
m/z mass calcd for: C34H34Br2N2O8, 756.07, found:
779.00 (MNa+).
2,5-Bis[N-(benzyloxycarbonyl)amino]-1,6-di-O-(3-cyano-
phenyl)-2,5-dideoxy-L-iditol, 5f. The title compound was
prepared in 67% yield (40 mg, 0.062 mmol) according to
general procedure, vide supra; 13C NMR (75 MHz,
CDCl3) d 158.1, 157.0, 140.9, 129.3, 129.0, 128.5, 128.2,
128.1, 127.8, 120.6, 119, 118.7, 112.8, 70.0, 67.6, 67.0,
51.1; MS (MALDI-TOF) m/z mass calcd for:
C36H34N4O8, 650.25, found: 673.28 (MNa+).
2,5-Bis[N-(benzyloxycarbonyl)amino]-2,5-dideoxy-1,6-di-
O-phenyl-L-iditol, 5a. The title compound was prepared
in 30% yield (19 mg, 0.032 mmol) according to general
procedure, vide supra; 13C NMR (75 MHz, CDCl3) d
158.4, 156.9, 136.4, 129.7, 128.7, 128.7, 128.4, 128.3,
121.6, 114.8, 71.5, 68.4, 67.4, 51.6; MS (MALDI-TOF)
m/z mass calcd for: C34H36N2O8, 660.25, found: 639.22
(MK+) 623.27 (MNa+).
2,5-Bis[N-(benzyloxycarbonyl)amino]-1,6-di-O-(2-cyano-
phenyl)-2,5-dideoxy-L-iditol, 5g. The title compound
was prepared in 58% yield (43 mg, 0.066 mmol) accord-
ing to general procedure, vide supra; 13C NMR
(75 MHz, CDCl3) d 160.1, 157.0, 136.4, 134.7, 133.5,
133.4, 128.4, 128.3, 128.1, 127.9, 121.3, 121.2, 112.8,
69.6, 67.1, 67.0, 51.3; MS (MALDI-TOF) m/z mass
calcd for: C36H34N4O8, 650.25, found: 673.30 (MNa+).
2,5-Bis[N-(benzyloxycarbonyl)amino]-2,5-dideoxy-1,6-di-
O-(4-methoxyphenyl)-L-iditol, 5b. The title compound
was prepared in 48% yield (22 mg, 0.033 mmol) accord-
ing to general procedure, vide supra; 13C NMR
(75 MHz, CDCl3) d 156.9, 154.5, 152.5, 136.4, 128.8,
128.3, 115.9, 114.9, 71.5, 69.3, 67.3, 55.9, 51.6; MS
(MALDI-TOF) m/z mass calcd for: C36H40N2O10,
600.27, found: 699.22 (MK+) 683.28 (MNa+).
2,5-Bis[N-(benzyloxycarbonyl)amino]-2,5-dideoxy-1,6-di-
O-(4-thiazol-2-yl-phenyl)-L-iditol, 5h. The title com-
pound was prepared in 47% yield (26 mg, 0.034 mmol)
according to general procedure, vide supra; 13C NMR
(75 MHz, CDCl3) d 168.9, 160.2, 157.0, 143.0, 136.5,
128.5, 128.1,127.9, 126.6, 118.3, 115.1, 70.0, 67.6, 67.0,
51.7; MS (MALDI-TOF) m/z mass calcd for:
C40H38N4O8S2, 766.21, found: 789.25 (MNa+) 767.27
(MH+).
2,5-Bis[N-(benzyloxycarbonyl)amino]-1,6-di-O-(4-cyano-
phenyl)-2,5-dideoxy-L-iditol, 5c. The title compound was
prepared in 51% yield (21 mg, 0.033 mmol) according to
general procedure, vide supra; 13C NMR (75 MHz,
CDCl3) d 161.9, 156.9, 136.4, 134.1, 128.6, 128.3, 128.0,
119.1, 115.6, 104.3, 69.9, 67.8, 67.1, 51.3; MS (MALDI-
TOF) m/z mass calcd for: C36H34N4O8, 650.24, found:
689.25 (MK+) 673.28 (MNa+) 651.30 (MH+).
2,5-Bis[N-(benzyloxycarbonyl)amino]-2,5-dideoxy-1,6-di-
O-(3-thiazol-2-yl-phenyl)-L-iditol, 5i. The title compound
was prepared in 57% yield (47 mg, 0.062 mmol) accord-
ing to general procedure, vide supra; 13C NMR
(75 MHz, CDCl3) d 168.7, 159.1, 157.0, 143.2, 136.5,
134.6, 130.1, 128.4, 128.0, 127.8, 119.6, 119.3, 116.9,
112.5, 70.1, 67.8, 66.9, 51.9; MS (MALDI-TOF) m/z
mass calcd for: C40H38N4O8S2, 766.21, found: 789.12
(MNa+) 767.15 (MH+).
2,5-Bis[N-(benzyloxycarbonyl)amino]-2,5-dideoxy-1,6-di-
O-(3-methoxyphenyl)-L-iditol, 5d. The title compound
was prepared in 65% yield (26 mg, 0.040 mmol) accord-
ing to general procedure, vide supra; 13C NMR
(75 MHz, CDCl3) d 161.1, 159.6, 157.0, 136.4, 130.2,
128.8, 128.4, 128.3, 127.2, 107.3, 106.9, 101.3, 71.5, 68.5,
67.4, 55.5, 51.7; MS (MALDI-TOF) m/z mass calcd for:
C36H40N2O10, 660.27, found: 699.31 (MK+) 683.32
(MNa+) 661.31 (MH+).
2,5-Bis[N-(benzyloxycarbonyl)amino]-2,5-dideoxy-1,6-di-
O-(4-thiazol-5-yl-phenyl)-L-iditol, 5j. The title compound
was prepared in 45% yield (31 mg, 0.040 mmol) accord-
ing to general procedure, vide supra; 13C NMR
(75 MHz, CDCl3) d 159.2, 157.2, 152.1, 139.8, 137.5,
136.8, 128.5, 128.3, 128.0, 127.8, 123.9, 115.5, 70.0, 67.7,
66.9, 51.7; MS (MALDI-TOF) m/z mass calcd for:
C40H38N4O8S2, 766.21, found: 789.26 (MNa+) 767.28
(MH+).
General method for the preparation of compounds 5e–k.
H2S (g) was bubbled through a solution of 4e–k
(1 equiv) in pyridine (3 mL) and Et3N (1.5 mL) for 1 h.
After stirring for additional 2 h the reaction mixture was
concentrated. The residue was dissolved in DCM, and
Et3N (2.1 equiv) and N-(benzyloxycarbonyloxy)-
succinimide was added. After stirring over night the
reaction mixture was concentrated and the residue was
purified by silica gel column chromatography
(DCM–MeOH 40:1) to give the target compounds 5e–k.
2,5-Bis[N-(benzyloxycarbonyl)amino]-2,5-dideoxy-1,6-di-
O-(3-thiazol-5-yl-phenyl)-L-iditol, 5k. The title com-
pound was prepared in 57% yield (32 mg, 0.041 mmol)
according to general procedure, vide supra; 13C NMR
(75 MHz, CDCl3) d 159.1, 157.0, 152.6, 139.5, 138.6,
132.1, 130.2, 128.4, 128.0, 127.7, 119.8, 114.8, 113.4,
69.9, 67.7, 66.9, 51.7; MS (MALDI-TOF) m/z mass
calcd for: C40H38N4O8S2, 766.21, found: 789.23
(MNa+) 767.26 (MH+).
2,5-Bis[N-(benzyloxycarbonyl)amino]-1,6-di-O-(4-bromo-
phenyl)-2,5-dideoxy-L-iditol, 5e. The title compound was
prepared in 68% yield (44 mg, 0.058 mmol) according to

K. Oscarsson et al. / Bioorg. Med. Chem. 11 (2003) 1235–1246
1243
4-Thiazol-2-yl-phenol, 10. 4-Bromoanisole (700 mL,
5.35 mmol), tetrakis(triphenylphosphine)palladium (0)
(100 mg, 0.09 mmol) and 2-trimethylstannylthiazole
(2.0 g, 5.35 mmol) in toluene (25 mL) was refluxed over
night. The mixture was filtrated through Celite and
concentrated. The residue was purified by silica gel col-
umn chromatography (toluene; toluene–EtOAc 20:1) to
give 6; 13C NMR (75 MHz, CDCl3) d 168.5, 161.3,
143.6, 128.3, 126.8, 118.2, 114.5, 55.6. HBr in H2O
(48%, 15 mL) was added to the 2-(4-methoxy-
phenyl)thiazole and the mixture was stirred at reflux for
2 h. The mixture was added to NaHCO3 (aq) and
extracted with EtOAc (3Â), dried with MgSO4 and
concentrated to give 10 (576 mg 3.26 mmol) as a white
solid in 61% yield; 1H NMR (400 MHz, CDCl3) d
7.63–7.57 (m, 3H), 7.13–7.12 (d, 1H), 6.74–6.71 (d,
2H), 4.10 (bs, 1H); 13C NMR (75 MHz, CDCl3,
CD3OD) d 169.6, 159.3, 142.6, 128.3, 125.0, 118.0,
115.9.
phine)palladium (0) (240 mg, 0.20 mmol) in dimethyl-
acetamide (20 mL) was heated to 100 ꢁC and stirred over
night. The mixture was filtrated through Celite and
concentrated. The residue was purified by silica gel col-
umn chromatography (toluene; toluene–EtOAc 20:1) to
give 9; 13C NMR (75 MHz, CDCl3) d 160.2, 152.3,
139.5, 139.4, 132.6, 130.4, 119.7, 114.0, 112.3, 55.6. HBr
in H2O (48%, 15 mL) was added to the 5-(3-methoxy-
phenyl)thiazole and the mixture was stirred at reflux for
2 h. The mixture was added to saturated aqueous
NaHCO3 and extracted with EtOAc (3Â), dried with
MgSO4 and concentrated to give 13 (490 mg 2.57 mmol)
as a white solid in 60% yield; 1H NMR (300 MHz,
CDCl3) d 8.76 (s, 1H), 8.05, (s, 1H), 7.28–7.22 (m, 1H),
7.10–7.08 (m, 1H), 6.88–6.84 (m, 2H); 13C NMR
(75 MHz, CDCl3) d 157.6, 152.5, 138.7, 132.3, 130.6,
118.9, 116.3, 114.5.
General method for the preparation of compounds 14c
and d. To 4c and d. (1 equiv) and tert-butoxycarbonyl
anhydride (Boc2O; 2.1 equiv) in EtOAc was added a
catalytic amount of Pd/C (10%). Hydrogen was added
at atmospheric pressure to the system and the reaction
mixture was stirred for 3 h. The suspension was then
filtrated through Celite, the solvent was removed and
the crude material was purified by silica gel column
chromatography (toluene–EtOAc 1:1) to give the target
compounds 14c and d.
3-Thiazol-2-yl-phenol, 11. 3-Bromoanisole (745 mL,
5.90 mmol), tetrakis(triphenylphosphine)palladium (0)
(110 mg, 0.096 mmol) and 2-trimetylstannylthiazole
(2.2 g, 5.89 mmol) in toluene (30 mL) was refluxed over
night. The mixture was filtrated through Celite and
concentrated. The residue was purified by silica gel col-
umn chromatography (toluene; toluene–EtOAc 20:1) to
give 7; 13C NMR (75 MHz, CDCl3) d 168.5, 160.3,
143.8, 135.0, 130.2, 119.4, 119.2, 115.5, 111.4, 55.6. HBr
in H2O (48%, 15 mL) was added to the 2-(3-methoxy-
phenyl)thiazole and the mixture was stirred at reflux for
2 h. The mixture was added to saturated aqueous
NaHCO3 and extracted with EtOAc (3Â), dried with
MgSO4 and concentrated to give 11 (658 mg 3.72 mmol)
as a white solid in 63% yield; 1H NMR (400 MHz,
CDCl3) d 7.76–7.75 (dd, 1H), 7.38–7.19 (m, 4H),
6.89–6.87 (dd, 1H); 13C NMR (100 MHz, CDCl3) d
169.5, 157.7, 143.1, 134.3, 130.5, 119.4, 118.5, 117.9,
113.2.
2,5-Bis[N-(tert-butoxycarbonyl)amino]-1,6-di-O-(4-cya-
nophenyl)-2,5-dideoxy-L-iditol, 14c. The title compound
was prepared in 71% yield (38 mg, 0.065 mmol) accord-
ing to general procedure, vide supra; 13C NMR
(75 MHz, CDCl3) d 157.7, 156.6, 132.5, 116.4, 113.7,
104.6, 80.5, 71.4, 68.4, 51.2, 28.5; MS (MALDI-TOF)
m/z mass calcd for: C30H38N4O8, 582.27, found: 605.31
(MNa+).
2,5-Bis[N-(tert-butoxycarbonyl)amino]-2,5-dideoxy-1,6-
di-O-(3-methoxyphenyl)-L-iditol, 14d. The title com-
pound was prepared in 68% yield (34 mg, 0.057 mmol)
according to general procedure, vide supra; 13C NMR
(75 MHz, CDCl3) d 161.1, 159.8, 130.1, 107.2, 106.9,
101,3, 71.1, 68.4, 55.5, 51.3, 28.5; MS (MALDI-TOF)
m/z mass calcd for: C30H44N2O10, 592.30, found: 631.36
(MK+) 615.40 (MNa+).
4-Thiazol-5-yl-phenol, 12. 4-Bromoanisole (810 mL,
6.42 mmol), thiazole (2.3 mL, 32 mmol), potassium ace-
tate (936 mg, 9.52 mmol) and tetrakis(triphenylphos-
phine)palladium
(0)
(300 mg,
0.26 mmol)
in
dimethylacetamide (20 mL) was heated to 100 ꢁC and
stirred over night. The mixture was filtrated through
Celite and concentrated. The residue was purified by
silica gel column chromatography (toluene; toluene–
EtOAc 15:1) to give 8; 13C NMR (75 MHz, CDCl3) d
160.1, 151.5, 139.4, 138.3, 128.5, 123.9, 114.8, 55.6. HBr
in H2O (48%, 15 mL) was added to the 5-(4-methoxy-
phenyl)thiazole and the mixture was stirred at reflux for
2 h. The mixture was added to saturated aqueous
NaHCO3 and extracted with EtOAc (3Â), dried with
MgSO4 and concentrated to give 12 (540 mg 2.83 mmol)
as a white solid in 44% yield; 1H NMR (400 MHz,
CDCl3) d 8.69 (s, 1H), 7.89 (s, 1H), 7.40–7.38 (dd, 2H),
6.84–6.82 (dd, 2H); 13C NMR (100 MHz, CDCl3) d
158.0, 151.7, 140.4, 136.9, 128.4, 122.3, 116.1.
2,5-Bis[N-(tert-butoxycarbonyl)amino]-1,6-di-O-(4-bro-
mophenyl)-2,5-dideoxy-L-iditol, 14e. H2S (g) was bub-
bled through a solution of 4e (100 mg, 0.18 mmol) in
pyridine (3 mL) and Et3N (1.5 mL) for 1 h. After stirring
for additional 2 h the reaction mixture was con-
centrated. The residue was dissolved in DCM (2 mL)
and Et3N (54 mL, 0.38 mmol) and tert-butoxycarbonyl
anhydride (Boc2O; 82 mg, 0.38 mmol) was added. After
stirring overnight the mixture was concentrated and
purified by silica gel column chromatography
(DCM–MeOH 40:1) to give the target compounds 14e
as a white solid (76 mg, 0.11 mmol, 61%); 13C NMR
(75 MHz, CDCl3) d 157.8, 156.7, 132.6, 116.7, 113.7,
80.6, 71.4, 68.4, 51.1, 28.6; MS (MALDI-TOF) m/z
mass calcd for: C28H38Br2N2O8, 688.10, found: 711.16
(MNa+).
3-Thiazol-5-yl-phenol, 13. 3-Bromoanisole (540 mL,
4.28 mmol), thiazole (1.5 mL, 20.8 mmol), potassium
acetate (624 mg, 6.34 mmol) and tetrakis(triphenylphos-

1244
K. Oscarsson et al. / Bioorg. Med. Chem. 11 (2003) 1235–1246
General method for the preparation of compounds 15a–d.
To 4a–d (1 equiv) in EtOAc was added a catalytic
amount of Pd/C (10%). Hydrogen was added at atmo-
spheric pressure to the system and the reaction mixture
was stirred for 1 h. The suspension was then filtrated
through Celite and the solvent was removed. DIPEA
(4 equiv) was added to the diamines, Z–Val–OH
(2 equiv) and PyBop (2 equiv) in DCM. After stirring
over night the mixture was diluted with DCM and
washed with NaHCO3 (1Â) and brine (1Â), and the
combined aqueous layers were extracted with DCM
(2Â). The organic layers were combined, dried with
MgSO4 and concentrated. The residue was purified by
silica gel column chromatography (DCM–MeOH 20:1)
to give the target compounds 15a–d.
0.29 mmol), PyBop (151 mg, 0.29 mmol) and DIPEA
(100 mL, 0.6 mmol) was added. After stirring overnight
the mixture was diluted with DCM and washed with
NaHCO3 (1Â) and brine (1Â) and the combined aqu-
eous layers were extracted with DCM (2Â). The organic
layers were combined with the mixture above, dried
with MgSO4 and concentrated. The residue was purified
by silica gel column chromatography (DCM–MeOH
40:1) to give the target compound 15e as a white solid
(125 mg, 0.13 mmol, 90%); 13C NMR (75 MHz, CDCl3)
d 172.5, 157.3, 156.7, 136.0, 131.8, 128.0, 127.6, 127.3,
116.1, 112.8, 69.6, 67.0, 66.6, 60.6, 50.0, 30.3, 18.6, 17.1;
MS
(MALDI-TOF)
m/z
mass
calcd
for:
C44H52Br2N4O10, 954.21, found: 977.21 (MNa+).
General method for the preparation of compounds 16a–d,
17a–d, 18a–d. To 4a–d (1 equiv) in EtOAc was added a
catalytic amount of Pd/C (10%). Hydrogen was added
at atmospheric pressure to the system and the reaction
mixture was stirred for 1 h. The suspension was then
filtrated through Celite and the solvent was removed.
To the diamines and Et3N (4 equiv) in DCM was added
anhydride (2 eqiuv.). The mixture was stirred overnight
and the formed precipitate was filtered of and the solid
was washed with DCM to give the target compounds
16a–d, 17a–d and 18 a–d.
2,5 - Bis[N - (2 - benzyloxycarbonylamino - 3 - methylbutyl-
oxy)amino]-2,5-dideoxy-1,6-di-O-phenyl-L-iditol,
15a.
The title compound was prepared in 56% yield (34 mg,
0.042 mmol) according to general procedure, vide supra;
13C NMR (75 MHz, CDCl3) d 172.5, 158.1, 156.6,
135.9, 129.0, 128.0, 127.7, 127.4, 114.1, 69.7, 66.5, 60.0,
50.1, 30.4, 18.7, 17.3; MS (MALDI-TOF) m/z mass
calcd for: C44H54N4O10, 798.38, found: 836.36 (MK+)
821.34 (MNa+).
2,5 - Bis[N - (2 - benzyloxycarbonylamino - 3 - methylbutyl-
oxy)amino]-2,5-dideoxy-1,6-di-O-(4-methoxyphenyl)-L-
iditol, 15b. The title compound was prepared in 63%
yield (37 mg, 0.043 mmol) according to general proce-
dure, vide supra; 13C NMR (75 MHz, CDCl3) d 172.9,
157.0, 154.1, 152.7, 136.3, 128.6, 128.3, 128.0, 115.7,
114.7, 70.4, 67.8, 67.1, 60.9, 55.8, 50.8, 31.0, 19.3, 17.7;
MS (MALDI-TOF) m/z mass calcd for: C46H58N4O12,
858.41, found: 897.34 (MK+) 881.38 (MNa+) 859.40
(MH+).
2,5-Bis[N-(benzoyl)amino]-2,5-dideoxy-1,6-di-O-phenyl-
L-iditol, 16a. The title compound was prepared in 93%
yield (26 mg, 0.048 mmol) according to general proce-
dure, vide supra; 13C NMR (75 MHz, CDCl3) d 169.2,
158.4, 134.8, 130.5, 129.4, 129.0, 128.6, 127.2, 121.1,
114.6, 70.6, 66.7, 51.5; MS (MALDI-TOF) m/z mass
calcd for: C32H32N2O6, 540.23, found: 579.12 (MK+)
563.18 (MNa+) 541.28 (MH+).
2,5-Bis[N-(benzoyl)amino]-2,5-dideoxy-1,6-di-O-(4-meth-
oxyphenyl)-L-iditol, 16b. The title compound was pre-
pared in 56% yield (21 mg, 0.035 mmol) according to
general procedure, vide supra; 13C NMR (75 MHz,
CDCl3) d 168.9, 153.8, 152.4, 133.5, 131.7, 128.4, 127.0,
116.3, 115.4, 114.4, 70.5, 67.3, 53.5, 51.3; MS (MALDI-
TOF) m/z mass calcd for: C34H36N2O8, 600.25, found:
639.16 (MK+) 623.18 (MNa+).
2,5 - Bis[N - (2 - benzyloxycarbonylamino - 3 - methylbutyl-
oxy)amino]-(4-cyanophenyl)-2,5-dideoxy-1,6-di-O-L-idi-
tol, 15c. The title compound was prepared in 73% yield
(64 mg, 0.076 mmol) according to general procedure,
vide supra; 13C NMR (75 MHz, CDCl3) d 172.9, 162.0,
136.3, 134.0, 128.5, 128.2, 127.7, 119.1, 115.5, 104.1,
70.0, 67.3, 67.1, 61.0, 50.0, 30.7. 29.6, 19.1, 17.6; MS
(MALDI-TOF) m/z mass calcd for: C46H52N6O10,
848.37, found: 871.42 (MNa+).
2,5-Bis[N-(benzoyl)amino]-(4-cyanophenyl)-2,5-dideoxy-
1,6-di-O-L-iditol, 16c. The title compound was prepared
in 63% yield (22 mg, 0.037 mmol) according to general
procedure, vide supra; 13C NMR (75 MHz, CDCl3) d
168.8, 161.9, 134.0, 133.7, 132.0, 128.7, 127.2, 119.0,
115.5, 104.0, 70.2, 67.0, 51.5; MS (MALDI-TOF) m/z
mass calcd for: C34H30N4O6, 590.25, found: 629.19
(MK+) 613.25 (MNa+).
2,5 - Bis[N - (2 - benzyloxycarbonylamino - 3 - methylbutyl-
oxy)amino]-2,5-dideoxy-1,6-di-O-(3-methoxyphenyl)-L-
iditol, 15d. The title compound was prepared in 71%
yield (36 mg, 0.042 mmol) according to general proce-
dure, vide supra; 13C NMR (75 MHz, CDCl3) d 172.7,
161.0, 159.7, 157.0, 136.4, 130.1, 128.7, 128.4, 128.3,
107.1, 107.0, 101.3, MS (MALDI-TOF) m/z mass calcd
for: C46H58N4O12, 658.41, found: 881.43 (MNa+).
2,5-Bis[N-(benzoyl)amino]-2,5-dideoxy-1,6-di-O-(3-meth-
oxyphenyl)-L-iditol, 16d. The title compound was pre-
pared in 74% yield (40 mg, 0.067 mmol) according to
general procedure, vide supra; 13C NMR (75 MHz,
CDCl3) d 169.3, 160.9, 159.9, 134.1, 131.9, 130.0, 128.7,
127.4, 107, 106.8, 101.1, 70.5, 66.8, 55.2, 51.5; MS
(MALDI-TOF) m/z mass calcd for: C34H36N2O8,
600.25, found: 639.83 (MK+) 623.28 (MNa+) 601.30
(MH+).
2,5 - Bis[N - (2 - benzyloxycarbonylamino - 3 - methylbutyl-
oxy)amino]-(4-bromophenyl)-2,5-dideoxy-1,6-di-O-L-idi-
tol, 15e. H2S (g) was bubbled through a solution of 4e
(81 mg, 0.15 mmol) in pyridine (3 mL) and Et3N
(1.5 mL) for 1 h. After stirring for additional 2 h. the
reaction mixture was concentrated. The residue was
dissolved in DCM (2 mL) and Z–Val–OH (73 mg,

K. Oscarsson et al. / Bioorg. Med. Chem. 11 (2003) 1235–1246
1245
2,5-Bis[N-(4-methoxybenzoyl)amino]-2,5-dideoxy-1,6-di-
O-phenyl-L-iditol, 17a. The title compound was pre-
pared in 52% yield (23 mg, 0.038 mmol) according to
general procedure, vide supra; 13C NMR (75 MHz,
CDCl3) d 168.4, 162.3, 158.1, 129.1, 128.9, 120.7, 114.2,
113.4, 69.9, 66.3, 55.0, 51.1; MS (MALDI-TOF) m/z
mass calcd for: C34H36N2O8, 600.25, found: 639.24
(MK+) 623.29 (MNa+) 601.32 (MH+).
2,5-Bis[N-(4-nitrobenzoyl)amino]-2,5-dideoxy-1,6-di-O-
(3-methoxyphenyl)-L-iditol, 18d. The title compound
was prepared in 56% yield (27 mg, 0.040 mmol) accord-
ing to general procedure, vide supra; 13C NMR
(75 MHz, CDCl3) d 166.9, 160.9, 159.6, 149.7, 139.6,
130.1, 128.7, 123.7, 106.8, 106.7, 101.2, 70.5, 66.7, 55.3,
51.7; MS (MALDI-TOF) m/z mass calcd for:
C34H34N4O12, 690.22, found: 713.15 (MNa+).
2,5-Bis[N-(4-methoxybenzoyl)amino]-2,5-dideoxy-1,6-di-
O-(4-methoxyphenyl)-L-iditol, 17b. The title compound
was prepared in 76% yield (37 mg, 0.056 mmol) accord-
ing to general procedure, vide supra; 13C NMR
(75 MHz, CDCl3) d 168.1, 162.0, 153.4, 152.1, 128.4,
114.9, 113.8, 112.9, 69.6, 66.7, 54.5, 54.4, 50.7; MS
(MALDI-TOF) m/z mass calcd for: C36H40N2O10,
660.27, found: 699.20 (MK+) 683.24 (MNa+).
Acknowledgements
We gratefully acknowledge Medivir AB, Huddinge,
Sweden for financial support and for the biological
testings.
References and Notes
2,5-Bis[N-(4-methoxybenzoyl)amino]-1,6-di-O-(4-cyano-
phenyl)-2,5-dideoxy-L-iditol, 17c. The title compound
was prepared in 59% yield (22 mg, 0.034 mmol) accord-
ing to general procedure, vide supra; 13C NMR
(75 MHz, CDCl3) d 168.0, 162.5, 159.7, 133.6, 128.7,
125.5, 119.6, 115.2, 113.5, 103.6, 70.0, 66.7, 54.9, 50.1;
MS (MALDI-TOF) m/z mass calcd for: C36H34N4O8,
650.24, found: 689.15 (MK+) 673.28 (MNa+) 651.20
(MH+).
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17, 532.
2,5-Bis[N-(4-methoxybenzoyl)amino]-2,5-dideoxy-1,6-di-
O-(3-methoxyphenyl)-L-iditol, 17d. The title compound
was prepared in 57% yield (26 mg, 0.040 mmol) accord-
ing to general procedure, vide supra; 13C NMR
(75 MHz, CDCl3) d 168.2, 162.8,161.1, 160.0, 129.9,
129.2, 126.4, 113.9, 107.2, 107.0, 101.4; MS (MALDI-
TOF) m/z mass calcd for: C36H40N2O10, 660.27, found:
683.29 (MNa+).
2,5-Bis[N-(4-nitrobenzoyl)amino]-2,5-dideoxy-1,6-di-O-
phenyl-L-iditol, 18a. The title compound was prepared
in 97% yield (38 mg, 0.061 mmol) according to general
procedure, vide supra; 13C NMR (75 MHz, CDCl3) d
166.8, 158.4, 149.8, 139.8, 129.6, 128.6, 123.6, 121.4,
114.7, 70.5, 66.9, 51.9; MS (MALDI-TOF) m/z mass
calcd for: C32H30N4O10, 630.20, found: 669.09 (MK+)
653.12 (MNa+).
17. Khazanovich Bernstein, N.; Cherney, M. M.; Loetscher,
H.; Ridley, R. G.; James, M. N. G. Nature Structural Biology
1999, 6, 32.
2,5-Bis[N-(4-nitrobenzoyl)amino]-2,5-dideoxy-1,6-di-O-
(4-methoxyphenyl)-L-iditol, 18b. The title compound
was prepared in 56% yield (28 mg, 0.040 mmol) accord-
ing to general procedure, vide supra; 13C NMR
(75 MHz, CDCl3) d 166.8, 155.8, 154.1, 149.3, 128.2,
123.3, 115.2, 114.4, 70.0, 67.0, 55.3, 51.4; MS (MALDI-
TOF) m/z mass calcd for: C34H34N4O12, 690.22, found:
729.17 (MK+) 713.14 (MNa+).
18. Silva, A. M.; Lee, A. Y.; Gulnik, S. V.; Majer, P.; Collins,
J.; Bhat, T. N.; Collins, P. J.; Cachau, R. E.; Luker, K. E.;
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22. Tyas, L.; Gluzman, I. Y.; Moon, R. P.; Rupp, K.; Wes-
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2,5-Bis[N-(4-nitrobenzoyl)amino]-1,6-di-O-(4-cyanophe-
nyl)-2,5-dideoxy-L-iditol, 18c. The title compound was
prepared in 72% yield (28 mg, 0.041 mmol) according to
general procedure, vide supra; 13C NMR (75 MHz,
CDCl3) d 165.0, 161.8, 149.0, 139.8, 134.2, 128.9, 123.3,
119.1, 115.5, 102.9, 69.0, 67.1, 51.4; MS (MALDI-TOF)
m/z mass calcd for: C34H28N6O10, 680.19, found: 703.22
(MNa+).
23. Zuccarello, G.; Bouzide, A.; Kvarnstrom, I.; Niklasson,
¨
G.; Svensson, S. C. T.; Brisander, M.; Danielsson, H.; Nill-

1246
K. Oscarsson et al. / Bioorg. Med. Chem. 11 (2003) 1235–1246
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