Synthesis and evaluation of S- and C(1) -substituted analogues of Lincomycin

Article abstract of DOI:10.1002/hlca.200800343

New thioglycosides and C(1)-alkylated thioglycosides (S-ulosides) of lincomycin were synthesized, and their antibiotic activities were determined. The S-aryl and S-arylalkyl analogues 11a- 11i were obtained by S-glycosylation of the sulfoxides 7 with aren

Full text of DOI:10.1002/hlca.200800343

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Helvetica Chimica Acta – Vol. 92 (2009)
Synthesis and Evaluation of S- and C(1)-Substituted Analogues of
Lincomycin
by Marie-Pierre Collina), Sven N. Hobbieb), Erik C. Bçttgerb), and Andrea Vasella*a)
a) Laboratorium fꢀr Organische Chemie, ETH Zꢀrich, HCI, CH-8093 Zꢀrich
b) Institut fꢀr Medizinische Mikrobiologie, Universitꢁt Zꢀrich, Gloriastrasse 30/32, CH-8006 Zꢀrich
New thioglycosides and C(1)-alkylated thioglycosides (S-ulosides) of lincomycin were synthesized,
and their antibiotic activities were determined. The S-aryl and S-arylalkyl analogues 11a – 11i were
obtained by S-glycosylation of the sulfoxides 7 with arenethiols, or by S-alkylation of the thiol 14 with
alkyl bromides. Lincomycin derivatives 27, 32a, 32b, 38a, 38b, 44, and 47 were prepared via Henry
reaction or Michael addition of the lincosamine-derived 1-deoxy-1-nitropyranoses 22. The S-alkyl
derivatives showed a similar activity and specificity as lincomycin. Lipophilic S-uloside analogues were
two- to fourfold less active than the parent antibiotic, whilst the hydrophilic analogues were inactive.
Introduction. – Lincomycin (1; Fig. 1), an antibiotic isolated from Streptomyces
lincolnensis and active against most Gram-positive bacteria [1], inhibits peptide-bond
formation by selectively binding to bacterial 23S rRNA [2][3]. Lincomycin and
clindamycin (¼(7S)-7-chloro-7-deoxylincomycin; 2) [4] are in clinical use [5]. Some
analogues of lincomycin, such as celesticetin (3) [6] and desalicetin (4) [7] (Fig. 1) were
isolated from the culture broth of several microorganisms [8], and many were
synthesized [8].
Fig. 1. Lincomycin (1), clindamycin (2), celesticetin (3), and desalicetin (4)
The known lincomycin analogues may be categorised into three groups, according
to whether the glycosyl, the prolinyl, or the amide moiety is modified. Glycosyl
analogues were prepared by modifying the substituents, and/or the configuration at
C(1 – 4) and at C(7). The hemiacetal resulting from formal hydrolysis of the
thioglycoside and several O-glycosides are known, but no biological data were
ꢂ 2009 Verlag Helvetica Chimica Acta AG, Zꢀrich

Helvetica Chimica Acta – Vol. 92 (2009)
231
reported [9]. The diastereoisomeric sulfoxides, (MIC1) ꢀ 100) and the sulfone (MIC
50) proved less active against Staphylococcus aureus KB 210 than lincomycin (MIC
0.78). A few S-alkyl analogues of lincomycin were isolated, or synthesized [10].
Celesticetin (3) showed a similar antibacterial activity against S. aureus UC 80 as
lincomycin (MIC 1.6 and 0.8, resp.), while desalicetin (4), the O-deacylation product of
celesticetin, proved less active (MIC 64). The a-d-thioethyl analogue of lincomycin is
as active as lincomycin in vitro and in vivo. The b-d-thioethyl analogue, one of the very
few b-d-configured analogues, was less active against S. aureus UC 76, with a MIC value
of 3.2 that compares to MIC of 0.2 for the a-d-anomer and MIC of 0.4 for lincomycin.
The activity of these analogues shows that both the nature of the substituent at C(1) and
the configuration affect the biological activity.
Examination of the crystal structure of the 50S ribosomal subunit of the
eubacterium Deinococcus radiodurans in complex with clindamycin [4] revealed a
cavity around C(1)2). This cavity should allow to replace the thiomethyl substituent at
C(1) by larger groups that may lead to additional favourable interactions with the
nucleobases in the peptidyl transferase cavity, suggesting to synthesize new thioalkyl or
thioaryl derivatives. Molecular modelling suggested that both hydrophilic and hydro-
phobic substituents at C(1) should be considered, with the prospect of forming
additional H-bonds and/or hydrophobic interactions with the ribosome.
Ulose analogues of lincomycin, i.e., analogues with two substituents at the anomeric
centre, are not known, but may also display a higher activity. Ulose derivatives were
prepared from aldoses under mild conditions by Michael addition or Henry reaction of
1-deoxy-1-nitroaldoses [11]. It appeared of interest to investigate the application of this
methodology to lincomycin, and to prepare lincosamine-derived 1-deoxy-1-nitro-
pyranoses. Solvolysis of tertiary nitro ethers was reported [11], and we planned to
explore the so far unknown solvolytic cleavage of nitropyranoses by thiols to obtain
lincosamine derived S-ulosides.
Results and Discussion. – We first aimed at a few representative S-aryl and S-
arylalkyl analogues of lincomycin. The S-aryl analogues 11a – 11c of lincomycin were
synthesized by S-glycosylation of the sulfoxides 7. These were obtained as a 2 :1 mixture
of diastereoisomers3) by a high-yielding O-silylation of the known azido derivative 5
[12] to 6 (Scheme 1) and oxidation of 6 with mCPBA at ꢁ 308. Glycosylation of
arenethiols with 7, promoted by triflic anhydride and 2,6-di-(tert-butyl)-4-methylpyr-
idine [13] gave the desired a-d-thioglycosides 8a – 8c as single anomers in yields of 60
to 70% from 6. The azides 8a – 8c were reduced to the amines 9a – 9c by a Staudinger
reaction, followed by hydrolysis [14]. Coupling of the amines with a mixed anhydride
derived from propylhygric acid hydrochloride (PHA) [15] led in 60 to 75% yield to the
protected amides 10a – 10c that were desilylated with Bu4NF · 3 H2O in THF to afford
the lincomycin analogues 11a – 11c in yields of 70 to 85%.
1
)
)
MIC ¼ Minimal inhibitory concentration (mg/ml)
2
Molecular modelling was performed with the Moloc programme. We thank Paul Gerber, Gerber
Molecular Design, for access to the programme.
3
)
Their configurations were not determined.

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Helvetica Chimica Acta – Vol. 92 (2009)
Scheme 1
a) TBSOTf (Tf ¼ trifluoromethylsulfonyl), pyridine, 1008; 90%. b) m-Chloroperbenzoic acid
(mCPBA), CH2Cl2, ꢁ 308. c) R1ꢁSH, Tf2O, 2,6-di-(tert-butyl)-4-methylpyridine, 4-ꢃ mol. sieves,
CH2Cl2, ꢁ 788; 70% of 8a, 65% of 8b, 60% of 8c. d) Me3P, NaOH, THF, 508. e) 4-Propylhygric acid (¼1-
Methyl-4-propyl-l-proline; PHA) hydrochloride, ClCOOEt, NEt3, CH2Cl2; 75% of 10a, 70% of 10b,
60% of 10c (two steps). f) Bu4NF · 3 H2O, THF; 67% of 11a, 85% of 11b, 80% of 11c.
The S-arylalkyl analogues 11d – 11i (Scheme 2) were synthesized by S-alkylation of
the thiol 14. This intermediate was generated via the S-glycoside 12, obtained by
glycosylating 2-(trimethylsilyl)ethanethiol with the sulfoxides 7, to yield 70% of the a-
d-thioglycoside 12. It was selectively O-desilylated by treatment with Bu4NF · 3 H2O
and acetylated to provide 80% of the tetraacetate 13. Removal of the 2-(trimethylsi-
lyl)ethyl group required treating 13 with a 1m solution of Bu4NF · 3 H2O in THF that
was dried over 4-ꢃ molecular sieves. The resulting thiolate anion was alkylated by the
alkyl bromides 15d – 15i to yield 75 – 90% of the a-d-thioglycosides 16d – 16i. We chose
arylalkyl bromides with different chain lengths and substituted with either an electron-
donating or an electron-withdrawing group. We also used this procedure to prepare the
S-allyl glycoside. Deacetylation and reduction of the N3 group led to the amines 17d –
17i that were treated with PHA methyl ester [16] to afford the lincomycin analogues
11d – 11i in yields of 20 – 35%.
The a-d-configuration of 8a – 8c, 12, and 16d – 16i is evidenced by J(1,2) ¼ 4.8 –
1
5.7 Hz (see Tables 3 and 5 in the Exper. Part). A comparison of the H-NMR spectra
of the silylated azides and of the acetylated azides (in CDCl3), and of the lincomycin
analogues (in CD3OD) showed that the pyranose ring adopts approximately the
4
expected C1 conformation (see Table 3 – 5 in the Exper. Part), J(1,2) of 4.8 – 5.7 Hz
suggesting that the pyranose ring is slightly flattened around C(1)4). The conformation
of the side chain of the silylated derivatives 6, 8a – 8c, 18, and 10a – 10c and of the
acetylated analogues 13 and 16d – 16i in CDCl3 solution is evidenced by a large J(5,6)
4
)
Typical J(1,2) values for a-d-configured galactopyranosides are ꢂ 4 Hz [17].

Helvetica Chimica Acta – Vol. 92 (2009)
233
Scheme 2
a) mCPBA, CH2Cl2, ꢁ 308. b) Me3SiCH2CH2SH, Tf2O, 2,6-di-(tert-butyl)-4-methylpyridine, 4-ꢃ mol.
sieves, CH2Cl2, ꢁ 788; 70% from 6. c) i. Bu4NF · 3 H2O, THF; ii. Ac2O, 4-(Dimethylamino)pyridine
(DMAP), Et3N, CH2Cl2; 80%. d) 1m Bu4NF in THF. e) 15d – 15i, THF; 90% of 16d, 80% of 16e, 60% of
16f, 75% of 16g, 75% of 16h, 75% of 16i. f) i. MeONa, MeOH; ii. Me3P, NaOH, THF, 508. g) PHA
methyl ester, MeONa, MeOH, 608; 35% of 11d, 36% of 11e, 20% of 11f, 27 of 11g, 20% of 11h, 20% of
11i (over three steps).
value of 10.2 – 10.5 Hz and a small J(6,7) value of 2.1 – 3.3 Hz as mainly tg about
C(5)ꢁC(6) and gt about C(6)ꢁC(7) [12]. J(5,6) ¼ 6.6 – 7.2 and J(6,7) ¼ 6.0 – 6.6 Hz of
the analogues 11a – 11i in CD3OD evidence a ca. 1:1 equilibrium of the (5,6)tg/(6,7)gt
and (5,6)gg/(6,7)tg conformers [12].
To prepare ulose analogues of lincomycin, we aimed at the protected lincosamine-
derived 1-deoxy-1-nitropyranoses a-22/b-22. These anomers were prepared according
to a known method [18 – 20] from the azide 5 that was benzylated to 18 (Scheme 3), and
subjected to bromolysis [21 – 23], followed by Ag2CO3 promoted hydrolysis of the
resulting glycosyl bromide to yield 94% of the hemiacetals 19 (94%) [21 – 24]. The
corresponding oximes (E/Z)-20 reacted via their hydroxylamine tautomers with 4-
chlorobenzaldehyde to give the anomeric glycosyl nitrones a-21/b-21 (a/b 1:3; 84%).
Ozonolysis of 21 yielded 84% of the desired 1-deoxy-1-nitropyranoses a-22/b-22 [20].
Henry reaction of the nitro aldoses a-22/b-22 with paraformaldehyde gave the nitro
acetate 23 (Scheme 4), which was partially hydrolysed during workup, and completely

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Helvetica Chimica Acta – Vol. 92 (2009)
Scheme 3
a) PhCH2Br (BnBr) NaH, Bu4NI, DMF; 80%. b) i. Br2, CH2Cl2; ii. Ag2CO3, acetone; 94%. c) NH2OH ·
HCl, EtONa, EtOH, 608; 95%. d) 4-Chlorobenzaldehyde, CH2Cl2, 408; 24% of a-21 and 60% of b-21. e)
O3, CH2Cl2, ꢁ 788; 18% of a-22 and 75% of b-22.
Scheme 4
a) (CH2O)n, 1m Bu4NF in THF, CH2Cl2. b) i. 7m HCl, 508; ii. Ac2O, DMAP, Et3N, CH2Cl2, 508; 80% of 24
from 22. c) MeSH, 4-ꢃ mol. sieves, BF3 · OEt2, CH2Cl2, ꢁ 308; 57% of a-25 and 27% of a-25/b-25 1:1.
d) i. Me3P, NaOH, THF, 508; ii. PHA, EtOCOCl, Et3N, CH2Cl2; 70% of 26. e) Na, NH3, THF, ꢁ 788;
65% of 27.
hydrolysed by treatment with 7n HCl. The resulting single dihydroxy compound was
acetylated to the diacetate 24 (80% from a-22/b-22). Thioglycosylation of MeSH with
24 afforded a mixture of anomers 25 (a/b 4 :1; 84%). Staudinger reduction/hydrolysis of
a-25 and coupling with PHA afforded the protected analogue 26 (70%) [25] that was
deprotected under Birch conditions [26] to 27 (65%).

Helvetica Chimica Acta – Vol. 92 (2009)
235
The analogues 32a, 32b, 38a, and 38b of lincomycin were synthesised similarly, by
deprotonating the nitro ethers a-22/b-22 in DMF with Et4NOH, and treating the
nitronate anions with octanaldehyde or (benzyloxy)acetaldehyde to afford two
diastereoisomers each of the nitro alcohols, viz. 28a and 28b, and 33a and 33b, column
chromatography providing the pure diastereoisomers (Scheme 5 and 6). Unfortunately,
all attempts to substitute the NO2 group of 28a and 28b with MeSH, or its derivatives
and analogues, such as TMS – SMe, thioacetic acid, and (4-methoxyphenyl)methane-
thiol, or activating the nitro ether with Lewis acids such as BF3 · OEt2, TMSOTf, ZnCl2,
Zn(OTf)2, and FeCl3 were unsuccessful.
Scheme 5
a) Octanal, Et4NOH, DMF; 53% of 28a and 15% of 28b. b) i. 7m HCl, 508; ii. Ac2O, DMAP, Et3N,
CH2Cl2, 508; 86% of a-29a, 87% of 29b. c) MeSH, 4-ꢃ mol. sieves, BF3 · OEt2, CH2Cl2, ꢁ 308; 46% of a-
30a and 23% of b-30a; 80% of 30b. d) i. Me3P, NaOH, THF, 508; ii. PHA, EtOCOCl, Et3N, CH2Cl2; 80%
of 31a from a-30a, 70% of 31b. e) Na, NH3, THF, ꢁ 788; 50% of 32a, 60% of 32b.
The nitro alcohols 28a, 28b, 33a, and 33b were hydrolysed with aqueous HCl to the
corresponding diols that were acetylated to the diacetates a-29a, 29b, b-l-34a, and 34b,
respectively. The diacetates were transformed into the thioglycosides 30a, 30b, 35a, and
35b by treatment with MeSH in the presence of BF3 · OEt2. Thioglycosylation of the
acetates a-29a and b-l-34a gave a mixture of the anomeric thioglycosides 30a and 35a,
whereas the diastereoisomeric acetates 29b and 34b led only to the axial anomer. The

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Helvetica Chimica Acta – Vol. 92 (2009)
anomers 35a were deacetylated, and the resulting alcohols 36a were separated by
column chromatography. Reduction of the N3 group of the thioglycosides a-30a, 30b,
35b, and b-l-36a, and coupling of the resulting amine with PHA led to the protected
amides 31a, 31b, 37a, and 37b that were deprotected to the C(1)-disubstituted
lincomycin analogues 32a, 32b, 38a, and 38b.
Scheme 6
a) 2-(Benzyloxy)acetaldehyde, Et4NOH, DMF; 70% of 33a and 20% of 33b. b) i. 7m HCl, 508; ii. Ac2O,
DMAP, Et3N, CH2Cl2, 508; 75% of b-l-34a, 75% of 34b. c) MeSH, 4-ꢃ mol. sieves, BF3 · OEt2, CH2Cl2,
ꢁ 308; 65% of 35b. d) MeONa, MeOH; 37% of b-l-36a and 30% of a-l-36a from b-l-34a. e) i. Me3P,
NaOH, THF, 508; ii. PHA, EtOCOCl, Et3N, CH2Cl2; 86% of 37a, 65% of 37b. f) Na, NH3, THF, ꢁ 788;
55% of 38a, 60% of 38b.
To determine the configuration of the nitro alcohols 28a, 28b, 33a, and 33b, we
transformed them into cyclic derivatives (Scheme 7). For this, we hydrolyzed the
tertiary nitro ethers 28a and 28b, and treated the resulting dihydroxy compounds with
1,1’-carbonyldiimidazole to obtain the cyclocarbonates 39a and 39b, respectively. As
these derivatives did not crystallize, we transformed the dihydroxy compounds
resulting from hydrolysis of the nitro ethers 33a and 33b into the cyclothiocarbonates
40a and 40b, respectively. To our disappointment, the cyclothiocarbonates did not
crystallize either. However, NOEs between HꢁC(2) and HꢁC(1’) of one of the

Helvetica Chimica Acta – Vol. 92 (2009)
237
diastereoisomers each, 39b and 40b, evidenced the (S)-configuration at C(1’)5). There
were no NOEs between HꢁC(2) and HꢁC(1’) for 39a and 40a, in agreement with the
(R)-configuration of C(1’).
Scheme 7
a) for 28a and 28b: i. 7n HCl, 508; ii. 1,1’-Carbonyldiimidazole, CH2Cl2, 508; 77% of 39a; 73% of 39b. b)
for 33a and 33b: i. 7m HCl, 508; ii. 1,1’-Thiocarbonyldiimidazole, CH2Cl2, 508; 75% of 40a, 80% of 40b.
Michael addition of the nitro ethers a-22/b-22 to acrylonitrile (Scheme 8), followed
by hydrolysis of the product in a 2m LiClO4 solution in MeCN/H2O and acetylation of
the resulting hemiacetal gave the chain-elongated glycosyl acetate 41 (56%). In
agreement with the literature [11], these tertiary nitro ethers were solvolyzed more
readily than the products of the Henry reaction. Thioglycosylation of 41 with MeSH in
the presence of BF3 · OEt2 afforded the thioglycoside 42 (80%) as a single anomer.
Azide reduction, coupling with PHA to the amide 43, and debenzylation yielded 60%
of the lincomycin analogue 44. Michael addition of the nitro ethers a-22/b-22 to methyl
acrylate (1m Bu4NF in THF) proceeded similarly, to afford the expected tertiary nitro
ether that was directly subjected to thioglycosylation with MeSH/BF3 · OEt2 to yield
85% of 45 (Scheme 8)6). Reduction of the N3 group of 45, coupling with PHA to the
amide 46, and debenzylation led to the lincomycin analogue 47 (40%).
5
)
For 39b: irradiation at HꢁC(2), NOE of 1.1% at HꢁC(1’), and irradiation at HꢁC(1’), NOE of
3.8% at HꢁC(2). For 40b: irradiation at HꢁC(2), NOE of 3.0% at HꢁC(1’), and irradiation at
HꢁC(1’), NOE of 4.7% at HꢁC(2).
6
)
Scouting experiments showed that the analogous thioglycosylation of the addition product to
acrylonitrile gave a mixture of compounds.

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Helvetica Chimica Acta – Vol. 92 (2009)
Scheme 8
a) i. Acrylonitrile, t-BuONa, t-BuOH/CH2Cl2 (6 :1); ii. 2m LiClO4, 508; iii. Ac2O, DMAP, Et3N, CH2Cl2,
508; 56%. b) MeSH, 4-ꢃ mol. sieves, BF3 · OEt2, ꢁ 308; 80%. c) i. Me3P, NaOH, THF, 508; ii. PHA,
EtOCOCl, Et3N, CH2Cl2; 65% of 43, 60% of 46. d) Na, NH3, THF, ꢁ 788; 60% of 44, 40% of 47. e) i.
Methyl acrylate, 1m Bu4NF in THF, THF; ii. MeSH, 4-ꢃ mol. sieves, BF3 · OEt2, ꢁ 308; 85%.
Remarkably, J(1,2) of b-22 (5.4 Hz) is smaller than J(1,2) for a-22 (6.0 Hz), due to
flattening of the pyranose ring around C(1), similarly as for analogous nitropyranoses
[27]. The anomeric configuration is, however, evidenced by the specific rotations that
are in agreement with Hudsonꢄs rule (cf. [27]), and the a-d-configuration is evidenced
by the deshielding of HꢁC(3) and HꢁC(5) by the pseudoaxial NO2 group (see Table 6
in Exper. Part)7).
The coupling constants compiled in Tables 7 – 11 in the Exper. Part confirm the 4C1
conformation of the pyranose ring of the protected and unprotected lincomycin
analogues in CDCl3 or in CD3OD. The 1H-NMR spectra also evidence a mixture of the
(5,6)tg/(6,7)gt and (5,6)gg/(6,7)tg conformers of the lincomycin analogues in CDCl3
and CD3OD, respectively, while the benzylated azides 18 – 25, a-29a, 29b, a-30a, 30b, a-
34a, 34b, 35b, b-l-36a, 41, 42, and 45 that cannot form a H-bond with the axial C(4)OR
adopt a (5,6)tg/(6,7)gt conformation (see Tables 7 – 9 in the Exper. Part) [12]. For the
benzylated lincomycin analogues, the ratio of the two conformers is ca. 1:1, except for
26, 31b, and 37b where the (5,6)gg/(6,7)tg conformer predominates. For the
deprotected lincomycins, a 1:1 ratio of conformers is observed for 32b and 47, while
the (5,6)gg/(6,7)tg conformer is favoured for 32a, 38a, and 44, and the (5,6)tg/(6,7)gt
conformation is preferred by 27 (Table 10 in Exper. Part).
The substituents at C(1) of 24 – 27, 29b – 32b, and 34b – 38b are expected to adopt
the gt conformation about C(1’)ꢁC(1), while a gg conformation is expected for the
diastereoisomers a-29a, a-30a, 31a, 32a, a-34a – a-36a, 37a, and 38a (Fig. 2). These
conformers avoid a 1,3-diaxial interaction between OꢁC(2), and OꢁC(1’) or CꢁC(1’),
7
)
Similar results were observed in the synthesis of 4,6-O-benzylidene-1-deoxy-1-nitro-a/b-d-
glucopyranose [27].

Helvetica Chimica Acta – Vol. 92 (2009)
239
and are favoured by the gauche effect. HꢁC(2) is expected to be more deshielded when
OꢁC(1’) is gg-oriented, on account of the 1,5 interactions between HꢁC(2) and
OꢁC(1’). However, this effect is observed only for 37a/37b (Dd ¼ 0.14 ppm) and 32a/
32b (Dd ¼ 0.49 ppm). An intramolecular H-bond of HOꢁC(1’) to BnOꢁC(2) of the
thioglycoside a-d-36a is evidenced by a 1.9 Hz W-coupling between HOꢁC(1’) and
HaꢁC(2’) [28][29].
Fig. 2. Favoured conformers of the chain at C(1) of the axial anomers
Antibacterial Activity. – The antibacterial activity of the thioethers 11a – 11i was
studied by determining their minimal inhibitory concentrations (MICs) against both
lincomycin-sensitive and lincomycin-resistant Mycobacterium smegmatis strains in at
least three independent broth microdilution experiments, as described in [30].
Growth of wild-type M. smegmatis cells was completely inhibited at lincomycin
concentrations of 4 – 8 mg/ml, while M. smegmatis cells with an adenine-to-guanine
mutation at 23S rRNA position 2058 [31 – 33] were resistant to the drug (see Table 1).
Similarly as lincomycin, all 1-de(methylsulfanyl)-1-(alkylsulfanyl)lincomycins were
active against the wild type and inactive towards the mutant A2058G (see Table 1). The
electronic nature of the substituent of the phenyl ring and the number of CH2 groups
between the S-atom and the phenyl ring has little effect on the drugꢄs activity and
specificity.
Table 1. Antibacterial Activity of Thioether Analogues of Lincomycina)
Wild type
Mutant A2058G
Lincomycin
11a
11b
4 – 8
4
4
> 512
512
256
11c
4
512
11d
4
512
11e
11f
11g
11h
4 – 8
2 – 4
8
4
16
> 256
512
> 256
ꢀ 256
ꢀ 256
11i
a) Antibacterial activity as minimal inhibitory concentrations (MIC [mg/ml]).
The hydrophilic S-uloside analogues, i.e., 27, 38a, 38b, and 47, were inactive against
the wild type (see Table 2). The lipophilic S-uloside analogues, i.e., 32a, 32b, and 44,

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Helvetica Chimica Acta – Vol. 92 (2009)
proved less active (two- to fourfold lower) than the parent antibiotic. All S-uloside
analogues of lincomycin were inactive against A2058G mutant ribosomes. Finally, we
found that the configuration at C(1’) of the analogues 32a, 32b, 38a, and 38b had a small
influence on the activity towards the wild type.
Table 2. Antibacterial Activity of C(1)-Substituted Analogues of Lincomycina)
Wild type
Mutant A2058G
Lincomycin
27
4 – 8
64 – 128
8 – 16
16
128
256
> 512
> 512
32a
32b
38a
38b
44
128 – 256
128 – 256
ꢀ 512
> 256
16 – 32
256 – 512
ꢀ 512
47
ꢀ 512
a) Antibacterial activity as minimal inhibitory concentrations (MIC [mg/ml]).
We thank the Swiss National Science Foundation for financial support and Dr. B. Bernet for critically
checking the analytical data.
Experimental Part
General. Solvents were distilled: Et2O from Na/benzophenone, MeOH, CH2Cl2, Et3N from CaH2.
Reactions were carried out under N2, unless stated otherwise. Qual. TLC: precoated silica-gel glass plates
(Merck silica gel 60 F254); detection by heating with ꢅmostainꢄ (400 ml of 10% H2SO4 soln., 20 g of
(NH4)6Mo7O24 · 6 H2O, 0.4 g of Ce(SO4)2). Flash chromatography (FC): silica gel Merck (0.04 –
0.063 mm) using distilled technical solvents as eluent. M.p.: uncorrected. Optical rotation ([a]2D5 ): 1-
dm cell, at 589 nm and 258; c concentration in g/100 ml. FT-IR Spectra: neat (ATR), absorption in cmꢁ1
.
1H- and 13C-NMR spectra: chemical shifts d in ppm rel. to TMS as external standard; coupling constants J
in Hz. HR-MALDI-MS and HR-ESI-MS: in gentisic acid (¼2,5-dihydroxybenzoic acid (DHB)) or 3-
hydroxypropionaldehyde (3-PHA) matrix.
Methyl 6-Azido-2,3,4,7-tetrakis-O-[(tert-butyl)dimethylsilyl]-6,8-dideoxy-1-thio-d-erythro-a-d-gal-
acto-octopyranoside (6). A soln. of 5 (1 g, 3.6 mmol) and DMAP (45 mg, 0.36 mmol) in pyridine
(20 ml) was treated with TBDMSOTf (6.6 ml, 28.7 mmol), kept at 1108 for 12 h, cooled to 258, and
evaporated. FC (hexane/CH2Cl2 98 :2 ! 4 :1) gave 6 (2.38 g, 90%). Colourless oil. Rf (hexane/CH2Cl2
4 :1) 0.53. [a]2D5 ¼þ 109.3 (c ¼ 1.1, CHCl3). IR (ATR): 2953w, 2929w, 2887w, 2857w, 2106m, 1472w, 1463w,
1388w, 1361w, 1342w, 1321m, 1293w, 1252m, 1166w, 1137m, 1091m, 1066m, 1015w, 1005w, 989w, 962w,
935w, 887m, 871m, 858m, 827s, 810m, 773s, 726w, 686w. 1H-NMR (300 MHz, CDCl3; assignment based on
selective homodecoupling experiments): see Table 3; additionally, 2.01 (s, MeS); 0.95, 0.93, 0.92, 0.89 (4s,
4 Me3CSi); 0.21 – 0.07 (several s, 4 Me2Si). 13C-NMR (75 MHz, CDCl3; assignment based on a HSQC
spectrum): see Table 3; additionally, 26.70, 26.37, 26.27, 25.80 (4q, 4 Me3C); 18.98, 18.51, 18.48, 18.05 (4s,
4 Me3C); 13.61 (q, MeS); ꢁ 3.05 to ꢁ 5.04 (several q, 4 Me2Si). HR-ESI-MS: 758.4241 (100, [M þ Na]þ,
C33H73N3NaO5SSiþ4 ; calc. 758.4240). Anal. calc. for C33H73N3O5SSi4 (736.35): C 53.83, H 9.99, N 5.71;
found: C 54.06, H 9.91, N 5.55.
General Procedure for Thioglycosylation (GP 1). At ꢁ 308, a 1m soln. of 6 in CH2Cl2 was treated
dropwise over 4 h with 70% mCPBA (1 equiv.), then with Me2S (1 equiv.) and with sat. aq. NaHCO3
soln. The layers were separated, and the aq. layer was extracted with CH2Cl2. The combined org. layers
were dried (MgSO4) and evaporated, to afford the sulfoxides 7.

Helvetica Chimica Acta – Vol. 92 (2009)
241
Table 3. Selected 1H-NMR Chemical Shifts [ppm] and Coupling Constants [Hz], and 13C-NMR Chemical
Shifts [ppm] of the Silylated Azides 6 and 8a – 8d and of the Silylated Pyrrolidine-2-carboxamides 10a – 10c
a
in CDCl3
)
6
8a
5.76
8b
5.68
8c
12
5.20
10a
5.78
10b
5.73
10c
5.62
HꢁC(1)
HꢁC(2)
HꢁC(3)
HꢁC(4)
HꢁC(5)
HꢁC(6)
HꢁC(7)
H3C(8)
J(1,2)
5.07
4.28
3.66
4.05
3.56
3.97
4.22
1.15
5.1
5.54
4.36
3.76
4.05
3.57
3.89
3.95
0.91
5.1
4.43
3.82
4.10
3.57
3.92
4.75
0.76
4.8
4.40
3.76
4.07
3.50
3.89
3.88
0.75
4.8
4.29
3.67
4.04
3.57
3.95
4.20
1.14
5.1
4.48
3.73
3.96
3.89
4.29
3.94
0.58
5.7
4.47
3.71
3.96
3.90
4.26
3.91
0.61
5.4
4.45
3.70
3.96
3.92
4.29
3.95
0.74
5.4
J(2,3)
9.9
9.6
9.6
9.6
9.9
9.6
9.9
9.9
J(3,4)
2.1
1.8
1.8
1.8
1.8
1.8
1.8
1.8
J(5,6)
J(6,7)
10.5
2.1
10.5
2.1
10.2
2.4
10.5
2.1
10.5
2.4
10.5
2.7
10.5
3.0
10.2
3.3
J(7,Me)
C(1)
C(2)
C(3)
C(4)
C(5)
C(6)
C(7)
C(8)
6.0
6.3
6.0
6.3
6.0
6.0
6.3
6.3
89.72
69.37
73.26
72.43
70.96
64.48
69.16
16.48
88.34
69.27
73.32
72.19
71.31
64.30
69.14
15.85
88.67
69.30
73.38
72.19
71.60
64.30
69.17
16.11
90.17
69.53
73.39
72.27
71.27
64.63
69.15
16.50
87.11
69.12
73.36
72.44
70.83
64.47
69.12
16.50
89.04
69.15
74.33
72.20
73.10
52.06
67.03
15.86
89.30
69.39
74.28
72.16
73.19
52.27
67.06
16.12
90.79
69.36
74.15
72.15
72.84
52.10
66.93
16.11
a) J(4,5) < 1.5 Hz (line broadening).
A 1m soln. of the sulfoxides 7 in Et2O was treated with 2,6-di(tert-butyl)-4-methylpyridine (2 equiv.)
and 4-ꢃ mol. sieves, stirred for 30 min at 258, cooled to ꢁ 788, treated with Tf2O (1.1 equiv.), and stirred
for 15 min. After the addition of the thiol (2 equiv.), the mixture was warmed to 08 over 30 min, stirred
for 2 h, treated with sat. aq. NaHCO3 soln., and filtered over Celite. The layers were separated, and the
aq. layer was extracted with Et2O. The combined org. layers were dried (MgSO4) and evaporated to yield
the crude S-glycosides.
Phenyl 6-Azido-2,3,4,7-tetrakis-O-[(tert-butyl)dimethylsilyl]-6,8-dideoxy-1-thio-d-erythro-a-d-gal-
acto-octopyranoside (8a). According to GP 1, 7 obtained from 100 mg (0.13 mmol) of 6 was treated
with 17 ml (0.26 mmol) of PhSH. FC (hexane/CH2Cl2 98 :2 ! 4 :1) gave 8a (80 mg, 70%). Colourless oil.
Rf (hexane/CH2Cl2 4 :1) 0.64. [a]2D5 ¼þ 114.3 (c ¼ 1.0, CHCl3). IR (ATR): 2953w, 2929w, 2887w, 2857w,
2107m, 1585w, 1472w, 1463w, 1439w, 1388w, 1361w, 1342w, 1253m, 1166w, 1136m, 1091m, 1068m, 1023w,
1005w, 990w, 964m, 936w, 888s, 870m, 857m, 827s, 810m, 774s, 734s, 687m. 1H-NMR (300 MHz, CDCl3;
assignments based on selective homodecoupling experiments): see Table 3; additionally, 7.37 – 7.32 (m, 2
arom. H); 7.29 – 7.23 (m, 2 arom. H); 7.20 – 7.14 (m, 1 arom. H); 0.98, 0.94, 0.88 (3s, 4 Me3CSi); 0.25 – 0.02
(several s, 4 Me2Si). 13C-NMR (75 MHz, CDCl3): see Table 3; additionally, 135.56 (s); 128.78 (d, 2 C);
128.59 (d, 2 C); 125.63 (d); 26.52, 26.16, 26.11, 25.58 (4q, 4 Me3C); 18.76, 18.63, 18.16, 17.79 (4s, 4 Me3C);
ꢁ 3.35 to ꢁ 5.16 (several q, 4 Me2Si). HR-ESI-MS: 820.4400 (100, [M þ Na]þ, C38H75N3NaO5SSi4þ ; calc.
820.4397).
4-Chlorophenyl 6-Azido-2,3,4,7-tetrakis-O-[(tert-butyl)dimethylsilyl]-6,8-dideoxy-1-thio-d-erythro-
a-d-galacto-octopyranoside (8b). According to GP 1, 7 obtained from 150 mg (0.20 mmol) of 6 was S-
glycosylated with 58 mg (0.40 mmol) of 4-chlorothiophenol. FC (hexane/CH2Cl2 98 :2 ! 4 :1) gave 8b
(110 mg, 65%). Colourless oil. Rf (hexane/CH2Cl2 4 :1) 0.64. [a]2D5 ¼þ 99.7 (c ¼ 1.1, CHCl3). IR (ATR):

242
Helvetica Chimica Acta – Vol. 92 (2009)
2953w, 2929w, 2895w, 2857w, 2107m, 1472w, 1463w, 1389w, 1361w, 1342w, 1253m, 1167w, 1136m, 1092m,
1069m, 1012w, 990w, 963m, 936w, 887s, 869m, 856m, 827s, 810s, 773s, 733m, 684m, 665m. 1H-NMR
(300 MHz, CDCl3; assignments based on selective homodecoupling experiments): see Table 3; addi-
tionally, 7.27 – 7.19 (m, 4 arom. H); 0.95, 0.91, 0.86 (3s, 4 Me3C); 0.22 – 0.02 (several s, 4 Me2Si). 13C-NMR
(75 MHz, CDCl3): see Table 3; additionally, 134.17 (s); 131.57 (s); 129.93 (d, 2 C); 128.69 (d, 2 C); 26.65,
26.29, 26.22, 25.72 (4q, 4 Me3C); 18.92, 18.79, 18.32, 17.99 (4s, 4 Me3C); ꢁ 3.15 to ꢁ 5.09 (several q,
4 Me2Si). HR-ESI-MS: 854.4014 (60, [M þ Na]þ, C38H75N3ClNaO5SSi4þ ; calc. 854.4007).
4-Methoxyphenyl 6-Azido-2,3,4,7-tetrakis-O-[(tert-butyl)dimethylsilyl]-6,8-dideoxy-1-thio-d-ery-
thro-a-d-galacto-octopyranoside (8c). According to GP 1, 7 obtained from 150 mg (0.20 mmol) of 6
was treated with 49 ml (0.40 mmol) of 4-methoxythiophenol. FC (hexane/CH2Cl2 98 :2 ! 4 :1) gave 8c
(100 mg, 60%). Colourless oil. Rf (hexane/CH2Cl2 4 :1) 0.42. [a]2D5 ¼þ 94.7 (c ¼ 1.0, CHCl3). IR (ATR):
2953w, 2929w, 2895w, 2857w, 2107m, 1594m, 1572w, 1494w, 1494m, 1471w, 1463w, 1441w, 1388w, 1361w,
1342w, 1285w, 1246m, 1168w, 1136m, 1091m, 1068m, 1036w, 1005w, 990w, 964m, 936w, 888m, 871m, 857m,
1
825s, 773s, 733m, 685m, 665w, 640w, 628w. H-NMR (300 MHz, CDCl3; assignments based on selective
homodecoupling experiments): see Table 3; additionally, 7.28 (m, 2 arom. H); 6.81 (m, 2 arom. H); 3.78
(s, MeO); 0.95, 0.94, 0.93, 0.86 (4s, 4 Me3CSi); 0.22 to ꢁ 0.01 (several s, 4 Me2Si). 13C-NMR (75 MHz,
CDCl3): see Table 3; additionally, 158.37 (s); 131.71 (s); 125.86 (d, 2 C); 114.31 (d, 2 C); 55.28 (s, MeO);
26.65, 26.29, 25.73 (3q, 4 Me3C); 18.92, 18.80, 28.35, 17.96 (4s, 4 Me3C); ꢁ 3.13 to ꢁ 5.12 (several q,
4 Me2Si). HR-ESI-MS: 850.4499 (100, [M þ Na]þ, C39H77N3NaO6SSi4þ ; calc. 850.4502).
2-(Trimethylsilyl)ethyl 6-Azido-2,3,4,7-tetrakis-O-[(tert-butyl)dimethylsilyl]-6,8-dideoxy-1-thio-d-
erythro-a-d-galacto-octopyranoside (12). According to GP 1, 7 obtained from 1.47 g (2.01 mmol) of 6
was treated with 645 ml (4.02 mmol) of 2-(trimetrhylsilyl)ethanethiol. FC (hexane/CH2Cl2 98 :2 ! 4 :1)
gave 12 (1.16 g, 70%). Colourless oil. Rf (hexane/CH2Cl2 4 :1) 0.65. [a]2D5 ¼þ 78.6 (c ¼ 0.89, CHCl3). IR
(ATR): 2953w, 2929w, 2896w, 2857w, 2107m, 1472w, 1463w, 1388m, 1361w, 1341w, 1250m, 1164w, 1136m,
1091m, 1066m, 1005w, 989w, 967m, 935w, 888m, 857m, 827s, 810s, 773s, 688w. 1H-NMR (300 MHz,
CDCl3; assignments based on selective homodecoupling experiments): see Table 3; additionally, 2.51 –
2.40 (m, CH2S); 0.95, 0.93, 0.89 (3s, 4 Me3C); 0.90 – 0.70 (m, Me3SiCH2); 0.21 – 0.07 (several s, 4 Me2Si);
0.01 (s, Me3Si). 13C-NMR (75 MHz, CDCl3): see Table 3; additionally, 26.66, 26.34, 26.30, 25.76 (4q,
4 Me3C); 25.88 (t, CH2S); 18.93, 18.81, 18.40, 17.99 (4s, 4 Me3C); 17.31 (t, Me3SiCH2); ꢁ 1.76 (q, Me3Si);
ꢁ 3.13 to ꢁ 5.12 (several q, 4 Me2Si). HR-ESI-MS: 844.4791 (100, [M þ Na]þ, C37H83N3NaO5SSi5þ ; calc.
844.4792).
General Procedure for Coupling of the Lincosamine Derivatives with Propyl Hygric Acid (GP 2). A
0.03m soln. of the azido derivative (1 equiv.) in THF/0.1n NaOH 4 :1 was treated with 1m PMe3 in THF
(1.5 equiv.), stirred for 4 – 8 h at 508, and evaporated. A soln. of the residue in CH2Cl2 was washed with
H2O and brine, and the org. layer was dried (MgSO4) and evaporated to provide the corresponding
amine.
A 0.03m suspension of PHA (1.3 equiv.) in CH2Cl2 was treated with Et3N (4 equiv.), followed by
ClCOOEt (1.1 equiv.), stirred at 258 for 1 h, and treated with a 0.1m soln. of the amine in CH2Cl2. The
soln. was stirred for 1 h at 258 and evaporated to afford the crude amide.
Phenyl 2,3,4,7-Tetrakis-O-[(tert-butyl)dimethylsilyl]-6,8-dideoxy-6-[(2S,4R)-1-methyl-4-propylpyr-
rolidine-2-carboxamido]-1-thio-d-erythro-a-d-galacto-octopyranoside (10a). According to GP 2, 68 mg
(0.08 mmol) of 8a and FC of the crude amide (hexane/AcOEt 98 :2 ! 9 :1) gave 10a (60 mg, 75%).
Colourless oil. Rf (hexane/AcOEt 95 :5) 0.23. [a]2D5 ¼þ 98.3 (c ¼ 0.62, CHCl3). IR (ATR): 2953m, 2928m,
2856m, 2787w, 1695m, 1510w, 1472w, 1388w, 1361w, 1303w, 1253m, 1144m, 1090m, 1069m, 1026w, 991m,
1005w, 963m, 890m, 866m, 835s, 776s, 737w, 687w. 1H-NMR (300 MHz, CDCl3): see Table 3; additionally,
7.38 – 7.10 (m, 5 arom. H, NH); 3.16 – 3.02 (m), 2.84 (dd, J ¼ 10.5, 5.2) (2 H of prolinyl); 2.33 (s, MeN);
2.09 – 1.70 (m, 4 H); 1.32 – 1.23 (m, MeCH2CH2); 0.97, 0.93, 0.90, 0.80 (4s, 4 Me3C); 0.58 (d, J ¼ 6.0,
MeCH2CH2); 0.16 to ꢁ 0.03 (m, 4 Me2Si). 13C-NMR (75 MHz, CDCl3): see Table 3; additionally, 174.30
(s, C¼O); 136.73 (s); 128.66 (d, 2 C); 127.82 (d, 2 C); 125.26 (d); 69.44 (d, C(2) of prolinyl); 62.85 (t, C(5)
of prolinyl); 41.67 (d, MeN); 37.99 (d, C(4) of prolinyl); 37.55 (t, C(3) of prolinyl); 35.87 (t, MeCH2CH2);
26.54, 26.48, 26.15, 25.66 (4q, 4 Me3C); 21.58 (t, MeCH2CH2); 18.85, 18.20, 17.85 (3s, 4 Me3C); 14.37 (q,
MeCH2CH2); ꢁ 3.15 to ꢁ 5.08 (several q, 4 Me2Si)). HR-ESI-MS: 925.5838 (100, [M þ H]þ,
C47H93N2O6SSiþ4 ; calc. 925.5826).

Helvetica Chimica Acta – Vol. 92 (2009)
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4-Chlorophenyl 2,3,4,7-Tetrakis-O-[(tert-butyl)dimethylsilyl]-6,8-dideoxy-6-[(2S,4R)-1-methyl-4-
propylpyrrolidine-2-carboxamido]-1-thio-d-erythro-a-d-galacto-octopyranoside (10b). According to
GP 2, 110 mg (0.13 mmol) of 8b and FC of the crude amide (hexane/AcOEt 98 :2 ! 9 :1) gave 10b
(90 mg, 70%). Colourless oil. Rf (hexane/AcOEt 95 :5) 0.26. [a]2D5 ¼þ 185.3 (c ¼ 1.6, CHCl3). IR (ATR):
2953m, 2928m, 2892w, 2856m, 2787w, 1651s, 1509w, 1472s, 1463w, 1389w, 1361w, 1304w, 1252m, 1144m,
1094s, 1069m, 1010w, 990w, 963m, 887m, 865m, 834s, 811m, 775s, 732w, 669w. 1H-NMR (300 MHz,
CDCl3): see Table 3; additionally, 7.30 – 7.19 (m, 4 arom. H, NH); 3.10 (br. dd, J ¼ 7.5, 5.1), 2.85 (dd, J ¼
10.5, 4.5) (2 H of prolinyl); 2.33 (s, MeN); 2.09 – 1.88 (m, 3 H); 1.84 – 1.70 (m, 1 H); 1.32 – 1.18 (m,
MeCH2CH2); 0.97, 0.93, 0.89, 0.81 (4s, 4 Me3CSi); 0.16 to ꢁ 0.01 (m, 4 Me2Si, MeCH2CH2). 13C-NMR
(75 MHz, CDCl3): see Table 3; additionally, 174.23 (s, C¼O); 135.29 (s); 131.06 (s); 129.91 (d, 2 C);
128.68 (d, 2 C); 69.39 (d, C(2) of prolinyl); 62.88 (t, C(5) of prolinyl); 41.78 (q, MeN); 38.09 (d, C(4) of
prolinyl); 37.63 (t, C(3) of prolinyl); 35.92 (t, MeCH2CH2); 26.63, 26.55, 26.22, 25.75 (4q, Me3C); 21.71 (t,
MeCH2CH2); 18.95, 18.30, 17.90 (3s, 4 Me3C); 14.50 (q, MeCH2CH2); ꢁ 3.02 to ꢁ 4.92 (8q, 4 Me2Si).
HR-ESI-MS: 959.5436 (100, [M þ H]þ, C47H92N2ClO6SSi4þ ; calc. 959.5436).
4-Methoxyphenyl 2,3,4,7-Tetrakis-O-[(tert-butyl)dimethylsilyl]-6,8-dideoxy-6-[(2S,4R)-1-methyl-4-
propylpyrrolidine-2-carboxamido]-1-thio-d-erythro-a-d-galacto-octopyranoside (10c). According to
GP 2, 100 mg (0.12 mmol) of 8c and FC of the crude amide (hexane/AcOEt 98 :2 ! 9 :1) gave 10c
(70 mg, 60%). Colourless oil. Rf (hexane/AcOEt 95 :5) 0.20. [a]2D5 ¼þ 147.3 (c ¼ 0.98, CHCl3). IR (ATR):
2953m, 2928m, 2856w, 2787w, 1694m, 1594m, 1509w, 1494m, 1471m, 1463m, 1388w, 1361m, 1284w, 1247s,
1173w, 1144m, 1093m, 1069m, 1034w, 1005w, 991w, 963m, 890m, 866m, 835s, 775s, 724w, 669w, 640w.
1H-NMR (300 MHz, CDCl3): see Table 3; additionally, 7.34 – 7.22 (m, 2 arom. H, NH); 6.84 – 6.78 (m, 2
arom. H); 3.79 (s, MeO); 3.11 (br. d, J ¼ 7.5, 4.8), 2.86 (dd, J ¼ 10.8, 4.5) (2 H of prolinyl); 2.35 (s, MeN);
2.05 – 1.99 (m, 3 H); 1.84 – 1.72 (m, 1 H); 1.32 – 1.20 (m, MeCH2CH2); 0.96, 0.93, 0.91, 0.81 (4s, 4 Me3C);
0.16 to ꢁ 0.01 (m, 4 Me2Si, MeCH2CH2). 13C-NMR (75 MHz, CDCl3): see Table 3; additionally, 174.21
(s, C¼O); 157.97 (s); 130.13 (s); 127.20 (d, 2 C); 114.29 (d, 2 C); 69.36 (d, C(2) of prolinyl); 62.75 (t, C(5)
of prolinyl); 55.18 (q, MeO); 41.60 (q, MeN); 37.90 (d, C(4) of prolinyl); 37.42 (t, C(3) of prolinyl); 35.75
(t, MeCH2CH2); 26.41, 26.35, 26.06, 25.55 (4q, 4 Me3C); 21.47 (t, MeCH2CH2); 18.73, 18.09, 17.75 (3s,
4 Me3C); 14.26 (q, MeCH2CH2); ꢁ 3.24 to ꢁ 5.15 (several q, 4 Me2Si). HR-ESI-MS: 955.5928 (100,
[M þ H]þ, C48H95N2O7SSiþ4 ; calc. 955.5932).
General Procedure for the Desilylation (GP 3). A 1m soln. of the silyl ether in THF was treated with
Bu4NF · 3 H2O (6 equiv.), stirred at 258 for 24 h, and evaporated to afford the corresponding crude
alcohol.
Phenyl 6,8-Dideoxy-6-[(2S,4R)-1-methyl-4-propylpyrrolidine-2-carboxamido]-1-thio-d-erythro-a-d-
galacto-octopyranoside (11a). The crude alcohol, obtained from 52 mg (0.06 mmol) of 10a according to
GP 3, was purified by FC (AcOEt/MeOH 98 :2 ! 4 :1) to give 11a (19 mg, 67%). Colourless oil. Rf
(AcOEt/MeOH 9 :1) 0.31. [a]2D5 ¼ þ169.5 (c ¼ 0.73, MeOH). IR (ATR): 3320m (br.), 2955w, 2923m,
2871w, 2852w, 2789w, 1646s, 1584w, 1521m, 1480w, 1455w, 1438w, 1379w, 1306w, 1243w, 1209w, 1180w,
1083s, 1052s, 1026w, 992m, 907m, 869w, 805w, 734s, 690m, 645w. 1H-NMR (300 MHz, CD3OD): see
Table 4; additionally, 7.48 – 7.44 (m, 2 arom. H); 7.33 – 7.18 (m, 3 arom. H); 3.13 (br. d, J ¼ 8.4, 6.0), 2.90
(dd, J ¼ 10.5, 4.8) (2 H of prolinyl); 2.34 (s, MeN); 2.20 – 1.88 (m, 3 H); 1.83 – 1.71 (m, 1 H); 1.31 – 1.26
(m, MeCH2CH2); 0.92 – 0.86 (m, MeCH2CH2). 13C-NMR (75 MHz, CD3OD): see Table 4; additionally,
177.80 (s, C¼O); 136.15 (s); 131.01 (d, 2 C); 129.55 (d, 2 C); 127.18 (d); 69.66 (d, C(2) of prolinyl); 63.49
(t, C(5) of prolinyl); 41.53 (q, MeN); 38.60 (d, C(4) of prolinyl); 38.39 (t, C(3) of prolinyl); 36.63 (t,
MeCH2CH2); 22.36 (t, MeCH2CH2); 14.33 (q, MeCH2CH2). HR-MALDI-MS: 469.2368 (100, [M þ H]þ,
C23H37N2O6Sþ; calc. 469.2367).
4-Chlorophenyl 6,8-Dideoxy-6-[(2S,4R)-1-methyl-4-propylpyrrolidine-2-carboxamido]-1-thio-d-ery-
thro-a-d-galacto-octopyranoside (11b). The crude alcohol, obtained from 89 mg (0.09 mmol) of 10b
according to GP 3 was purified by FC (AcOEt/MeOH 98 :2 ! 4 :1) gave 11b (39 mg, 85%). Colourless
oil. Rf (AcOEt/MeOH 9 :1) 0.42. [a]2D5 ¼ þ255.6 (c ¼ 0.96, MeOH). IR (ATR): 3322m (br.), 2956w,
2924w, 2872w, 2789w, 1651s, 1521m, 1477m, 1455w, 1389w, 1307w, 1235w, 1206w, 1179w, 1091s, 1053s,
1
1011m, 992w, 906w, 867w, 811w, 731m, 691w. H-NMR (300 MHz, CD3OD): see Table 4; additionally,
7.47 – 7.41 (m, 2 arom. H); 7.33 – 7.28 (m, 2 arom. H); 3.13 (dd, J ¼ 8.1, 5.7), 2.89 (dd, J ¼ 10.5, 4.5) (2 H of
prolinyl); 2.33 (s, MeN); 2.20 – 1.90 (m, 3 H); 1.82 – 1.70 (m, 1 H); 1.33 – 1.22 (m, MeCH2CH2); 0.92 – 0.86

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Helvetica Chimica Acta – Vol. 92 (2009)
Table 4. Selected 1H-NMR Chemical Shifts [ppm] and Coupling Constants [Hz], and 13C-NMR Chemical
Shifts [ppm] of the Lincomycin Analogues 11a – 11i in CD3OD
11a
5.70
11b
5.70
11c
5.49
11d
5.28
11e
5.08
11f
5.36
11g
5.31
11h
5.34
11i
5.34
HꢁC(1)
HꢁC(2)
HꢁC(3)
HꢁC(4)
HꢁC(5)
HꢁC(6)
HꢁC(7)
H3C(8)
J(1,2)
4.19
3.64
3.97
4.33
4.12
3.89
1.00
5.4
4.19
3.64
4.01
4.31
4.10
3.88
1.00
5.7
4.15
3.63
4.01
4.41
4.10
3.90
1.10
5.4
4.10
3.58
3.98
4.29
4.12
3.97
1.19
5.7
3.99
3.61
4.04
4.33
4.19
3.95
1.23
5.7
4.09
3.57
3.98
4.29
4.13
3.99
1.17
5.7
4.07
3.57
3.95
4.27
4.11
3.94
1.13
5.4
4.08
3.56
3.97
4.29
4.12
3.98
1.16
5.7
4.08
3.56
4.00
4.31
4.11
3.93
1.17
5.4
J(2,3)
10.5
10.2
10.2
10.2
9.6
10.5
9.9
10.5
10.2
J(3,4)
J(4,5)
3.3
)
3.3
)
3.3
)
3.6
0.9
3.3
)
3.6
)
3.3
1.2
3.0
)
3.3
1.2
a
a
a
a
a
a
J(5,6)
J(6,7)
J(7,Me)
C(1)
C(2)
C(3)b)
C(4)b)
C(5)b)
C(6)
C(7)
C(8)
7.8
6.3
6.3
6.6
6.3
6.3
7.2
6.6
6.3
7.2
6.3
6.3
6.9
6.3
6.3
7.2
6.0
6.3
6.9
6.3
6.3
7.2
6.0
6.3
6.9
6.3
6.3
90.68
69.16
71.67
70.23
71.08
55.60
67.26
18.43
90.53
69.10
71.62
70.19
71.04
55.68
67.29
18.67
92.29
69.23
71.56
70.30
70.70
55.81
67.46
18.82
86.11
69.25
72.19
70.34
70.66
56.34
68.00
19.60
85.15
68.79
71.69
69.66
70.30
56.33
67.75
19.70
88.13
70.07
71.91
70.69
70.50
56.31
67.97
19.51
88.38
70.06
71.94
70.56
70.68
56.20
67.88
19.27
88.13
69.49
71.93
70.52
70.73
56.37
67.99
19.53
88.04
70.15
71.88
70.33
70.70
56.57
68.18
19.97
a) Not assigned. b) Assignments may be interchanged.
(m, MeCH2CH2). 13C-NMR (75 MHz, CD3OD): see Table 4; additionally, 177.80 (s, C¼O); 135.04,
133.10 (2s); 132.44 (d, 2 C); 129.60 (d, 2 C); 69.68 (d, C(2) of prolinyl); 63.49 (t, C(5) of prolinyl); 41.53
(q, MeN); 38.60 (d, C(4) of prolinyl); 38.40 (t, C(3) of prolinyl); 36.63 (t, MeCH2CH2); 22.38 (t,
MeCH2CH2); 14.34 (q, MeCH2CH2). HR-MALDI-MS: 503.1973 (100, [M þ H]þ, C23H36ClN2O6Sþ; calc.
503.1977).
4-Methoxyphenyl 6,8-Dideoxy-6-[(2S,4R)-1-methyl-4-propylpyrrolidine-2-carboxamido]-1-thio-d-
erythro-a-d-galacto-octopyranoside (11c). The crude alcohol, obtained from 70 mg (0.07 mmol) of 10c
according to GP 3, was purified by FC (AcOEt/MeOH 98 :2 ! 9 :1) to give 11c (29 mg, 80%). Colourless
oil. Rf (AcOEt/MeOH 9 :1) 0.42. [a]2D5 ¼ þ255.6 (c ¼ 0.96, MeOH). IR (ATR): 3330w (br.), 2953w,
2927w, 2870w, 2788w, 1651m, 1593w, 1571w, 1522m, 1493s, 1461w, 1406w, 1379w, 1284m, 1245s, 1178w,
1
1153w, 1089m, 1053m, 1031m, 992w, 906w, 827w, 804w, 731m, 695w, 641m, 623w. H-NMR (300 MHz,
CD3OD; assignments based on selective homodecoupling experiments): see Table 4; additionally, 7.45 –
7.39 (m, 2 arom. H); 6.90 – 6.85 (m, 2 arom. H); 3.77 (s, MeO); 3.14 (br. dd, J ¼ 8.1, 5.7), 2.89 (dd, J ¼
10.2, 4.2) (2 H of prolinyl); 2.34 (s, MeN); 2.23 – 2.10 (m, 1 H); 2.04 – 1.90 (m, 2 H); 1.80 – 1.69 (m, 1 H);
1.32 – 1.20 (m, MeCH2CH2); 0.91 – 0.86 (m, MeCH2CH2). 13C-NMR (75 MHz, CD3OD): see Table 4;
additionally, 177.88 (s, C¼O); 160.41 (s); 134.45 (d, 2 C); 125.99 (s); 115.26 (d, 2 C); 69.63 (d, C(2) of
prolinyl); 63.43 (t, C(5) of prolinyl); 55.36 (q, MeO); 41.43 (q, MeN); 38.45 (d, C(4) of prolinyl); 38.24 (t,
C(3) of prolinyl); 36.48 (t, MeCH2CH2); 22.19 (t, MeCH2CH2); 14.16 (q, MeCH2CH2). HR-MALDI-MS:
499.2 (100, [M þ H]þ, C24H39N2O7Sþ; calc. 499.2472).
2-(Trimethylsilyl)ethyl 2,3,4,7-Tetra-O-acetyl-6-azido-6,8-dideoxy-1-thio-d-erythro-a-d-galacto-oc-
topyranoside (13). A soln. of 12 (200 mg, 0.24 mmol) in THF (20 ml) was treated with Bu4NF · 3 H2O
(614 mg, 1.95 mmol), stirred for 6 h at 238, treated with Et3N (1 ml), Ac2O (0.5 ml), and DMAP (13 mg,

Helvetica Chimica Acta – Vol. 92 (2009)
245
0.10 mmol), stirred for 6 h, and evaporated. A soln. of the residue in AcOEt was washed with sat. aq.
NaHCO3 soln. and brine, dried (MgSO4), and evaporated. FC (hexane/AcOEt 95 :5 ! 3 :1) gave 13
(107 mg, 80%). Colourless oil. Rf (hexane/AcOEt 3 :1) 0.38. [a]2D5 ¼ þ197.3 (c ¼ 1.12, CHCl3). IR (ATR):
3005w, 2989w, 2110w, 1745m, 1370w, 1275s, 1260s, 1221w, 1162w, 1119w, 1065w, 1041w, 1007w, 937w, 911w,
896w, 859w, 840w, 763s, 750s, 706w, 662w, 623w. 1H-NMR (300 MHz, CDCl3; assignments based on
selective homodecoupling experiments): see Table 5; additionally, 2.54 (m, CH2S); 2.17, 2.07, 2.05, 1.98
(4s, 4 AcO); 0.94 – 0.69 (m, Me3SiCH2); 0.01 (s, Me3Si). 13C-NMR (75 MHz, CDCl3; assignments based
on a HSQC spectrum): see Table 5; additionally, 169.93, 169.61, 169.55, 169.48 (4s, 4 C¼O); 26.75 (t,
CH2S); 21.06, 20.89, 20.66 (3q, 4 MeC¼O); 17.04 (t, Me3SiCH2); ꢁ 1.77 (q, Me3Si). HR-MALDI-MS:
556.1753 (100, [M þ Na]þ, C21H35N3NaO6Sþ; calc. 556.1755).
Table 5. Selected 1H-NMR Chemical Shifts [ppm] and Coupling Constants [Hz], and 13C-NMR Chemical
Shifts [ppm] of the Acetylated Azides 13 and 16d – 16i in CDCl3
13
5.68
16d
5.62
16e
5.49
16f
5.66
16g
5.67
16h
5.64
16i
5.69
HꢁC(1)
HꢁC(2)
HꢁC(3)
HꢁC(4)
HꢁC(5)
HꢁC(6)
HꢁC(7)
H3C(8)
J(1,2)
5.19
5.09
5.55
4.05
3.75
5.21
1.22
5.4
5.23
5.10
5.56
4.04
3.76
5.25
1.26
5.7
5.16
5.07
5.55
4.07
3.75
5.25
1.27
5.4
5.20
5.09
5.55
4.04
3.76
5.24
1.20
5.7
5.20
5.09
5.54
4.03
3.74
5.17
1.15
5.7
5.19
5.07
5.53
4.04
3.76
5.20
1.19
5.7
5.16
5.05
5.53
3.98
3.74
5.21
1.18
5.7
J(2,3)
10.8
11.1
10.8
11.1
10.8
10.8
11.1
J(3,4)
J(4,5)
3.3
)
3.0
0.9
3.0
)
3.0
1.2
3.0
0.9
2.4
)
3.0
0.9
a
a
a
J(5,6)
J(6,7)
J(7,Me)
C(1)
C(2)
9.6
2.4
6.3
10.2
2.4
6.6
9.9
2.1
6.3
10.2
3.0
6.3
9.9
2.4
6.3
9.9
2.4
6.3
10.5
2.4
6.6
82.75
70.32
68.20
67.84
67.30
62.86
67.62
13.00
81.88
70.39
68.39
67.86
67.43
62.94
67.74
13.03
82.49
70.41
68.29
67.96
67.33
62.98
67.85
13.28
83.28
70.41
68.12
67.88
67.62
62.86
67.67
12.96
83.19
70.37
68.10
67.84
67.50
62.79
67.72
12.98
83.16
70.37
68.08
67.83
67.53
62.81
67.62
12.03
82.92
70.16
67.90
67.62
67.62
62.74
67.62
12.99
C(3)
C(4)b)
C(5)b)
C(6)
C(7)b)
C(8)
a) J < 1.2 Hz (line broadening). b) Assignments may be interchanged.
General Procedure for the S-Alkylation (GP 4). A 1m soln. of 13 in THF was treated with a 1m
Bu4NF soln. in THF (5 equiv.), stirred for 1 h, treated with the corresponding alkyl bromide 15 (2 equiv.),
stirred for 15 min, and poured into brine. The layers were separated, and the aq. layer was extracted with
AcOEt. The combined org. layers were dried (MgSO4) and evaporated to afford the crude sulfide.
Prop-2-enyl 2,3,4,7-Tetra-O-acetyl-6-azido-6,8-dideoxy-1-thio-d-erythro-a-d-galacto-octopyranoside
(16d). According to GP 4, the crude sulfide, obtained from 50 mg (0.09 mmol) of 13, was purified by FC
(hexane/AcOEt 95 :5 ! 3 :1) to give 16d (40 mg, 90%). Colourless oil. Rf (hexane/AcOEt 3 :1) 0.23.
[a]2D5 ¼ þ211.7 (c ¼ 1.0, CHCl3). IR (ATR): 2983w, 2109m, 1744s, 1430w, 1371m, 1219s, 1118w, 1065m,
1
1041m, 1008w, 937w, 911w, 778w, 739w, 707w, 623w. H-NMR (300 MHz, CDCl3; assignments based on
selective homodecoupling experiments): see Table 5; additionally, 5.71 (dddd, J ¼ 15.3, 10.5, 7.2, 6.0,

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Helvetica Chimica Acta – Vol. 92 (2009)
CH2¼CHCH2S); 5.16 (br. d, J ¼ 16.8), 5.13 (br. d, J ¼ 10.8) (CH2¼CHCH2S); 3.20 – 3.06 (m,
CH2¼CHCH2S); 2.18, 2.09, 2.06, 1.99 (4s, 4 AcO). 13C-NMR (75 MHz, CDCl3): see Table 5; additionally,
170.04, 169.89, 169.78 (3s, 4 C¼O); 132.24 (d, CH2¼CHCH2S); 118.81 (t, CH2¼CHCH2S); 33.13 (t,
CH2¼CHCH2S); 21.05, 20.79, 20.67, 20.62 (4q, 4 MeC¼O). HR-ESI-MS: 496.1360 (100, [M þ Na]þ,
C19H27N3NaO9Sþ; calc. 496.1360).
Benzyl 2,3,4,7-Tetra-O-acetyl-6-azido-6,8-dideoxy-1-thio-d-erythro-a-d-galacto-octopyranoside
(16e). According to GP 4, the crude sulfide, obtained from 100 mg (0.18 mmol) of 13, was purified by
FC (hexane/AcOEt 95 :5 ! 3 :1) to give 16e (85 mg, 80%). Colourless oil. Rf (hexane/AcOEt 3 :1) 0.16.
[a]2D5 ¼ þ384.1 (c ¼ 0.67, CHCl3). IR (ATR): 3059w, 3024w, 2980w, 2939w, 2109m, 1742s, 1495w, 1454w,
1430w, 1370m, 1213s, 1117w, 1065m, 1039s, 1007m, 988w, 937w, 910m, 776w, 729s, 700m, 647w, 622w.
1H-NMR (300 MHz, CDCl3; assignments based on selective homodecoupling experiments): see Table 5;
additionally, 7.35 – 7.21 (m, 5 arom. H); 3.74, 3.65 (2d, J ¼ 13.2, PhCH2); 2.16, 2.09, 1.97, 1.95 (4s, 4 AcO).
13C-NMR (75 MHz, CDCl3): see Table 5; additionally, 169.71, 169.68, 169.57 (3s, 4 C¼O); 136.47 (s);
128.76 (d, 2 C); 128.63 (d, 2 C); 127.49 (d); 34.95 (t, PhCH2); 21.18, 20.77, 20.73 (3q, 4 MeC¼O). HR-
MALDI-MS: 562.1259 (42, [M þ K]þ, C23H29KN3O9Sþ; calc. 562.1256), 546.1514 (100, [M þ Na]þ,
C23H29N3NaO9Sþ; calc. 546.1517). Anal. calc. for C23H29N3O9S (523.56): C 52.76, H 5.58, N 8.03; found: C
52.91, H 5.64, N 7.81.
2-Phenylethyl 2,3,4,7-Tetra-O-acetyl-6-azido-6,8-dideoxy-1-thio-d-erythro-a-d-galacto-octopyrano-
side (16f). According to GP 4, the crude sulfide, obtained from 70 mg (0.13 mmol) of 13, was purified
by FC (hexane/AcOEt 95 :5 ! 3 :1) to give 16f (60 mg, 60%). Colourless oil. Rf (hexane/AcOEt 3 :1)
0.16. [a]2D5 ¼ þ185.2 (c ¼ 0.56, CHCl3). IR (ATR): 3019w, 2993w, 2939w, 2110m, 1745m, 1497w, 1449w,
1
1432w, 1371w, 1222s, 1118w, 1066m, 1041m, 1008w, 937w, 911w, 781w, 699w, 622w. H-NMR (300 MHz,
CDCl3; assignments based on selective homodecoupling experiments): see Table 5; additionally, 7.33 –
7.14 (m, 5 arom. H); 2.92 – 2.75 (m, PhCH2CH2); 2.19, 2.08, 2.04, 1.99 (4s, 4 AcO). 13C-NMR
(75 MHz, CDCl3): see Table 5; additionally, 170.19, 169.91, 169.75 (3s, 4 C¼O); 139.52 (s); 128.60 (d,
2 C); 128.53 (d, 2 C); 126.65 (d); 35.70 (t, PhCH2); 32.12 (t, CH2S); 21.05, 20.83, 20.68, 20.62 (4q,
4 MeC¼O). HR-MALDI-MS: 560.1667 (100, [M þ Na]þ, C24H31N3NaO9Sþ; calc. 560.1673). Anal. calc.
for C24H31N3O9S (537.59): C 53.62, H 5.81, N 7.82; found: C 53.49, H 5.89, N 7.64.
3-Phenylpropyl 2,3,4,7-Tetra-O-acetyl-6-azido-6,8-dideoxy-1-thio-d-erythro-a-d-galacto-octopyra-
noside (16g). According to GP 4, the crude sulfide, obtained from 200 mg (0.37 mmol) of 13, was
purified by FC (hexane/AcOEt 95 :5 ! 3 :1) to give 16g (160 mg, 75%). Colourless oil. Rf (hexane/
AcOEt 3 :1) 0.16. [a]2D5 ¼ þ123.2 (c ¼ 1.13, CHCl3). IR (ATR): 3028w, 2938w, 2857w, 2108m, 1742s,
1603w, 1496w, 1453w, 1432w, 1370m, 1212s, 1117w, 1064m, 1039m, 1007w, 987w, 936w, 910w, 779w, 730m,
1
700m, 647w, 622w, 613w. H-NMR (300 MHz, CDCl3; assignments based on selective homodecoupling
experiments): see Table 5; additionally, 7.30 – 7.24 (m, 2 arom. H); 7.20 – 7.12 (m, 3 arom. H); 2.75 – 2.36
(m, PhCH2CH2CH2); 2.17, 2.07, 2.06, 1.98 (4s, 4 AcO); 1.97 – 1.82 (m, PhCH2CH2CH2). 13C-NMR
(75 MHz, CDCl3): see Table 5; additionally, 169.97, 169.66, 169.53 (3s, 4 C¼O); 140.71 (s); 128.36 (d,
2 C); 128.29 (d, 2 C); 125.97 (d); 35.65 (t, PhCH2CH2); 30.90, 30.07 (2t, PhCH2CH2CH2); 21.11, 20.90,
20.74, 20.70 (4q, 4 MeC¼O). HR-MALDI-MS: 590.1566 (30, [M þ K]þ, C25H33KN3O9Sþ; calc.
590.1569), 574.1834 (100, [M þ Na]þ, C25H33N3NaO9Sþ; calc. 574.1830). Anal. calc. for C25H33N3O9S
(551.62): C 54.44, H 6.03, N 7.53; found: C 54.57, H 6.05, N 7.53.
2-(4-Methoxyphenyl)ethyl 2,3,4,7-Tetra-O-acetyl-6-azido-6,8-dideoxy-1-thio-d-erythro-a-d-galacto-
octopyranoside (16h). According to GP 4, the crude sulfide obtained from 120 mg (0.22 mmol) of 13
was purified by FC (hexane/AcOEt 95 :5 ! 3 :1) to give 16h (95 mg, 75%). Colourless oil. Rf (hexane/
AcOEt 3 :1) 0.33. [a]2D5 ¼ þ159.3 (c ¼ 0.88, CHCl3). IR (ATR): 2938w, 2830w, 2109m, 1744s, 1611w,
1513w, 1440w, 1370w, 1301w, 1221s, 1178w, 1117w, 1065m, 1039m, 1008w, 937w, 911w, 895w, 822w, 756w,
704w, 623w. 1H-NMR (300 MHz, CDCl3; assignments based on selective homodecoupling experiments):
see Table 5; additionally, 7.06 – 7.04 (m, 2 arom. H); 6.83 – 6.80 (m, 2 arom. H); 3.77 (s, MeO); 2.84 – 2.67
(m, CH2CH2S); 2.17, 2.06, 2.03, 1.97 (4s, 4 AcO). 13C-NMR (75 MHz, CDCl3): see Table 5; additionally,
169.94, 169.67, 169.51 (3s, 4 C¼O); 158.12 (s); 131.45 (s); 129.34 (d, 2 C); 113.86 (d, 2 C); 55.25 (q, MeO);
34.86 (t, CH2CH2S); 32.45 (t, CH2CH2S); 21.12, 20.91, 20.74, 20.69 (4q, 4 MeC¼O). HR-MALDI-MS:
606.1539 (30, [M þ K]þ, C25H33KN3O10Sþ; calc. 606.1518), 590.1780 (100, [M þ Na]þ, C25H33N3NaO10Sþ;

Helvetica Chimica Acta – Vol. 92 (2009)
247
calc. 590.1779). Anal. calc. for C25H33N3O10S (567.62): C 52.90, H 5.86, N 7.40; found: C 52.85, H 5.95, N
7.33.
2-(4-Nitrophenyl)ethyl 2,3,4,7-Tetra-O-acetyl-6-azido-6,8-dideoxy-1-thio-d-erythro-a-d-galacto-oc-
topyranoside (16i). According to GP 4, the crude sulfide, obtained from 100 mg (0.18 mmol) of 13,
was purified by FC (hexane/AcOEt 95 :5 ! 3 :1) to give 16i (80 mg, 75%). Colourless oil. Rf (hexane/
AcOEt 3 :1) 0.16. [a]2D5 ¼ þ184.4 (c ¼ 0.56, MeOH). IR (ATR): 2940w, 2109m, 1741s, 1605w, 1519w,
1431w, 1370w, 1345w, 1213s, 1111w, 1064m, 1040m, 1007w, 988w, 937w, 910w, 867w, 855w, 780w, 730w,
647w, 614w. 1H-NMR (300 MHz, CDCl3; assignments based on selective homodecoupling experiments):
see Table 5; additionally, 8.17 – 8.13 (m, 2 arom. H); 7.35 – 7.30 (m, 2 arom. H); 3.04 – 2.70 (m, CH2CH2S);
2.17, 2.08, 2.02, 1.98 (4s, 4 AcO). 13C-NMR (75 MHz, CDCl3): see Table 5; additionally, 169.90, 169.65,
169.45 (3s, 4 C¼O); 146.78, 146.65 (2s); 129.27 (d, 2 C); 123.68 (d, 2 C); 35.33 (t, CH2CH2S); 31.12 (t,
CH2CH2S); 21.06, 20.82, 20.67, 20.62 (4q, 4 MeC¼O). HR-MALDI-MS: 621.1265 (15, [M þ K]þ,
C24H30KN4O11Sþ; calc. 621.1263), 605.1521 (97, [M þ Na]þ, C24H30N4NaO11Sþ; calc. 605.1524), 600.1969
(100, [M þ NH4]þ, C24H34N5O11Sþ; calc. 600.1976). Anal. calc. for C24H30N4O11S (582.59): C 49.48, H
5.19, N 9.62; found: C 49.67, H 5.31, N 9.53.
General Procedure for the Deprotection and Reduction of Azides, and Coupling of the Corresponding
Amines with PHA (GP 5). A 1m soln. of the azido tetraacetate in MeOH was treated with a 0.02n
MeONa in MeOH (6 equiv.), stirred for 12 h, and neutralized with 1.2m HCl in MeOH. Evaporation gave
the crude azido tetrol.
A 0.03m soln. of the crude azido tetrol in THF/0.1n NaOH 4 :1 was treated with 1m PMe3 in THF
(1.5 equiv.), and stirred for 4 – 8 h at 508. Evaporation gave the crude amino tetrol 17.
A 10m soln. of the crude amino tetrol 17 in MeOH was treated with PHA methyl ester (10 equiv.)
and NaOMe (1 equiv.) in MeOH, heated to 608 for 60 h, and evaporated.
Prop-2-enyl 6,8-Dideoxy-6-[(2S,4R)-1-methyl-4-propylpyrrolidine-2-carboxamido]-1-thio-d-ery-
thro-a-d-galacto-octopyranoside (11d). The crude alcohol, obtained from 60 mg (0.12 mmol) of 16d
according to GP 5, was purified by FC (AcOEt/MeOH 98 :2 ! 4 :1) to give 11d (20 mg, 35%). Colourless
oil. Rf (AcOEt/MeOH 9 :1) 0.40. [a]2D5 ¼ þ136.3 (c ¼ 1.53, MeOH). IR (ATR): 3331w (br.), 2957w,
2921w, 2872w, 2788w, 1645m, 1521m, 1454w, 1425w, 1403w, 1379w, 1306w, 1230w, 1175w, 1157w, 1075s,
1051s, 989m, 913w, 865w, 803w, 750s, 694w, 664w, 635w, 611w. 1H-NMR (300 MHz, CD3OD): see Table 4;
additionally, 5.88 – 5.73 (dddd, J ¼ 16.8, 10.2, 8.4, 6.0, CH2 ¼ CHCH2S); 5.13 (dq, J ꢃ 17.1, 1.5), 5.08 (dq,
J ¼ 10.2, 1.5) (CH2 ¼ CHCH2S); 3.26 – 3.08 (m, CH2 ¼ CHCH2S, 1 H of prolinyl); 2.91 (dd, J ¼ 10.5, 4.2,
1 H of prolinyl); 2.36 (s, MeN); 2.30 – 2.14 (m, 1 H); 2.09 – 1.90 (m, 2 H); 1.83 – 1.72 (m, 1 H); 1.38 – 1.23
(m, MeCH2CH2); 0.95 – 0.87 (m, MeCH2CH2). 13C-NMR (75 MHz, CD3OD): see Table 4; additionally,
178.27 (s, C¼O); 134.93 (d, CH¼CH2); 117.76 (t, CH¼CH2); 70.05 (d, C(2) of prolinyl); 63.82 (t, C(5) of
prolinyl); 41.82 (q, MeN); 38.92 (d, C(4) of prolinyl); 38.76 (t, C(3) of prolinyl); 36.86 (t, MeCH2CH2);
33.25 (t, CH2S); 22.67 (t, MeCH2CH2); 14.60 (q, MeCH2CH2). HR-MALDI-MS: 455.2190 (8, [M þ
Na]þ, C24H38N2NaO6Sþ; calc. 455.2186), 433.2361 (100, [M þ H]þ, C24H39N2O6Sþ; calc. 433.2367).
Benzyl 6,8-Dideoxy-6-[(2S,4R)-1-methyl-4-propylpyrrolidine-2-carboxamido]-1-thio-d-erythro-a-d-
galacto-octopyranoside (11e). The crude alcohol, obtained from 60 mg (0.11 mmol) of 16e according to
GP 5, was purified by FC (AcOEt/MeOH 98 :2 ! 4 :1) to give 11e (20 mg, 36%). Colourless oil. Rf
(AcOEt/MeOH 9 :1) 0.34. [a]2D5 ¼ þ255.6 (c ¼ 0.96, MeOH). IR (ATR): 3331w (br.), 2958w, 2925w,
2873w, 2790w, 1646m, 1521m, 1495w, 1453w, 1419w, 1379w, 1309w, 1296w, 1239w, 1216w, 1180w, 1160w,
1080w, 1072m, 1050m, 991m, 943w, 904w, 859w, 803w, 749s, 697m, 664m, 634w, 604w. 1H-NMR (300 MHz,
CD3OD): see Table 4; additionally, 7.35 – 7.16 (m, 5 arom. H); 3.70 (s, PhCH2S); 3.15 (dd, J ¼ 7.8, 5.7),
2.94 (dd, J ¼ 10.5, 3.9) (2 H of prolinyl); 2.35 (s, MeN); 2.23 – 1.97 (m, 3 H); 1.84 – 1.72 (m, 1 H); 1.35 –
1.17 (m, MeCH2CH2); 0.85 (br. t, J ¼ 7.2, MeCH2CH2). 13C-NMR (75 MHz, CD3OD): see Table 4;
additionally, 178.06 (s, C¼O); 138.85 (s); 129.93 (d, 2 C); 128.97 (d, 2 C); 127.48 (d); 69.53 (d, C(2) of
prolinyl); 63.41 (t, C(5) of prolinyl); 41.41 (q, MeN); 38.54 (d and t, C(4) of prolinyl, CH2S); 36.35 (t,
C(3) of prolinyl); 33.73 (t, MeCH2CH2); 22.27 (t, MeCH2CH2); 14.16 (q, MeCH2CH2). HR-MALDI-MS:
521.2102 (12, [M þ K]þ, C24H38KN2O6Sþ; calc. 521.2188), 505.2358 (31, [M þ Na]þ, C24H38N2NaO6Sþ;
calc. 505.2348), 483.2528 (100, [M þ H]þ, C24H39N2O6Sþ; calc. 483.2523).
2-Phenylethyl 6,8-Dideoxy-6-[(2S,4R)-1-methyl-4-propylpyrrolidine-2-carboxamido]-1-thio-d-ery-
thro-a-d-galacto-octopyranoside (11f). The crude alcohol, obtained from 80 mg (0.14 mmol) of 16f

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Helvetica Chimica Acta – Vol. 92 (2009)
according to GP 5, was purified by FC (AcOEt/MeOH 98 :2 ! 4 :1) to give 11f (15 mg, 20%). Colourless
oil. Rf (AcOEt/MeOH 9 :1) 0.42. [a]2D5 ¼ þ132.4 (c ¼ 1.35, MeOH). IR (ATR): 3331w (br.), 2956w,
2923w, 2872w, 2789w, 1646m, 1520m, 1453m, 1379w, 1307w, 1216w, 1180w, 1076s, 1049s, 990w, 904w, 866w,
804w, 749s, 696m, 664w, 635w, 607w. 1H-NMR (300 MHz, CD3OD): see Table 4; additionally, 7.30 – 7.13
(m, 5 arom. H); 3.15 (dd, J ¼ 8.1, 6.0, 1 H of prolinyl); 2.94 – 2.69 (m, 1 H of prolinyl, SCH2CH2Ph); 2.34
(s, MeN); 2.21 (br. s, 1 H); 2.08 – 1.94 (m, 2 H); 1.84 – 1.72 (m, 1 H); 1.35 – 1.26 (m, MeCH2CH2); 0.94 –
0.86 (m, MeCH2CH2). 13C-NMR (75 MHz, CD3OD): see Table 4; additionally, 178.24 (s, C¼O); 141.99
(s); 129.59 (d, 2 C); 129.45 (d, 2 C); 127.28 (d); 69.44 (d, C(2) of prolinyl); 63.83 (t, C(5) of prolinyl);
41.84 (q, MeN); 38.91 (d, C(4) of prolinyl); 38.75 (t, PhCH2); 37.42 (t, C(3) of prolinyl); 36.91 (t,
MeCH2CH2); 32.96 (t, PhCH2CH2S); 22.67 (t, MeCH2CH2); 14.62 (q, MeCH2CH2). HR-MALDI-MS:
535.2259 (5, [M þ K]þ, C25H40KN2O6Sþ; calc. 535.2244), 519.2511 (19, [M þ Na]þ, C25H40N2NaO6Sþ;
calc. 519.2505), 497.2674 (100, [M þ H]þ, C25H41N2O6Sþ; calc. 497.2685).
3-Phenylpropyl 6,8-Dideoxy-6-[(2S,4R)-1-methyl-4-propylpyrrolidine-2-carboxamido]-1-thio-d-ery-
thro-a-d-galacto-octopyranoside (11g). The crude alcohol, obtained from 80 mg (0.14 mmol) of 16g
according to GP 5, was purified by FC (AcOEt/MeOH 98 :2 ! 4 :1) to give 11g (20 mg, 27%). Colourless
oil. Rf (AcOEt/MeOH 9 :1) 0.42. [a]2D5 ¼ þ255.6 (c ¼ 0.96, MeOH). IR (ATR): 3328m (br.), 2924m,
2872m, 2789w, 1650s, 1522s, 1453m, 1379w, 1306w, 1254w, 1215w, 1182w, 1162w, 1077s, 1051s, 991m, 905w,
864w, 804w, 748s, 698s, 664m, 604w, 519s. 1H-NMR (300 MHz, CD3OD): see Table 4; additionally, 7.29 –
7.12 (m, 5 arom. H); 3.17 (dd, J ¼ 8.1, 6.0), 2.91 (dd, J ¼ 10.2, 4.2) (2 H of prolinyl); 2.72 (br. t, J ¼ 7.2,
PhCH2); 2.64 – 2.47 (m, PhCH2CH2); 2.35 (s, MeN); 2.20 (br. s, 1 H); 2.06 – 1.88 (m, 2 H of prolinyl,
CH2S); 1.83 – 1.72 (m, 1 H); 1.37 – 1.29 (m, MeCH2CH2); 0.94 – 0.88 (m, MeCH2CH2). 13C-NMR
(75 MHz, CD3OD): see Table 4; additionally, 178.32 (s, C¼O); 142.86 (s); 129.53 (d, 2 C); 129.40 (d,
2 C); 126.92 (d); 69.43 (d, C(2) of prolinyl); 63.85 (t, C(5) of prolinyl); 41.84 (q, MeN); 38.91 (d, C(4) of
prolinyl); 38.73 (t, PhCH2); 36.92 (t, PhCH2CH2); 35.86 (t, C(3) of prolinyl); 32.63 (t, MeCH2CH2); 30.82
(t, CH2S); 22.67 (t, MeCH2CH2); 14.60 (q, MeCH2CH2). HR-MALDI-MS: 549.2418 (2, [M þ K]þ,
C26H42KN2O6Sþ; calc. 549.2401), 533.2668 (19, [M þ Na]þ, C26H42N2NaO6Sþ; calc. 533.2661), 511.2844
(100, [M þ H]þ, C26H43N2O6Sþ; calc. 511.2836).
2-(4-Methoxyphenyl)ethyl 6,8-Dideoxy-6-[(2S,4R)-1-methyl-4-propylpyrrolidine-2-carboxamido]-1-
thio-d-erythro-a-d-galacto-octopyranoside (11h). The crude alcohol, obtained from 80 mg (0.13 mmol)
of 16h according to GP 5, was purified by FC (AcOEt/MeOH 98 :2 ! 4 :1) to give 11h (13 mg, 20%).
Colourless oil. Rf (AcOEt/MeOH 9 :1) 0.34. [a]2D5 ¼ þ122.6 (c ¼ 0.86, MeOH). IR (ATR): 3327w (br.),
2923w, 2788w, 1647m, 1611w, 1511s, 1453w, 1376w, 1300w, 1244s, 1177m, 1078m, 1047s, 991m, 942w, 903w,
850w, 820w, 805w, 773w, 691w. 1H-NMR (300 MHz, CD3OD): see Table 4; additionally, 7.19 – 7.12 (m, 2
arom. H); 6.85 – 6.80 (m, 2 arom. H); 3.75 (s, MeO); 3.15 (dd, J ¼ 8.4, 6.0), 2.91 (dd, J ¼ 10.5, 5.2) (2 H of
prolinyl); 2.87 – 2.68 (m, PhCH2CH2); 2.35 (s, MeN); 2.28 – 2.12 (m, 1 H); 2.08 – 1.94 (m, 2 H); 1.84 – 1.72
(m, 1 H); 1.33 – 1.23 (m, MeCH2CH2); 0.93 – 0.87 (m, MeCH2CH2). 13C-NMR (100 MHz, CD3OD): see
Table 4; additionally, 178.31 (s, C¼O); 159.70 (s); 134.06 (s); 130.54 (d, 2 C); 114.87 (d, 2 C); 70.13 (d,
C(2) of prolinyl); 63.86 (t, C(5) of prolinyl); 55.65 (q, MeO); 41.84 (q, MeN); 38.93 (d, C(4) of prolinyl);
38.78 (t, CH2CH2S); 36.92 (t, C(3) of prolinyl); 36.55 (t, MeCH2CH2); 33.21 (t, CH2S); 22.66 (t,
MeCH2CH2); 14.58 (q, MeCH2CH2). HR-MALDI-MS: 565.2350 (5, [M þ K]þ, C26H42KN2O7Sþ; calc.
565.2350), 549.2608 (15, [M þ Na]þ, C26H42N2NaO7Sþ; calc. 549.2610), 527.2783 (100, [M þ H]þ,
C26H43N2O7Sþ; calc. 527.2785).
2-(4-Nitrophenyl)ethyl 6,8-Dideoxy-6-[(2S,4R)-1-methyl-4-propylpyrrolidine-2-carboxamido]-1-
thio-d-erythro-a-d-galacto-octopyranoside (11i). The crude alcohol, obtained from 80 mg (0.13 mmol)
of 16i according to GP 5, was purified by FC (AcOEt/MeOH 98 :2 ! 4 :1) to give 11i (17 mg, 20%).
Colourless oil. Rf (AcOEt/MeOH 9 :1) 0.28. [a]2D5 ¼ þ124.6 (c ¼ 0.73, MeOH). IR (ATR): 3337m (br.),
2949w, 2925m, 2876w, 2791w, 1650m, 1604w, 1518s, 1454w, 1344s, 1095m, 1080m, 1052m, 992w, 901w,
855w, 806w, 749w, 695w. 1H-NMR (300 MHz, CD3OD): see Table 4; additionally, 8.19 – 8.14 (m, 2 arom.
H); 7.53 – 7.49 (m, 2 arom. H); 3.16 (dd, J ¼ 8.1, 6.0, 1 H of prolinyl); 3.06 (br. t, J ¼ 7.2, CH2CH2S); 2.96 –
2.77 (m, 1 H of prolinyl, CH2S); 2.35 (s, MeN); 2.30 – 2.14 (m, 1 H); 2.08 – 1.94 (m, 2 H); 1.84 – 1.73 (m,
1 H); 1.36 – 1.23 (m, MeCH2CH2); 0.93 – 0.87 (m, MeCH2CH2). 13C-NMR (75 MHz, CD3OD): see
Table 4; additionally, 178.25 (s, C¼O); 150.00, 148.05 (2s); 130.93 (d, 2 C); 124.55 (d, 2 C); 69.45 (d, C(2)
of prolinyl); 63.85 (t, C(5) of prolinyl); 41.82 (q, MeN); 38.94 (d, C(4) of prolinyl); 38.82 (t, CH2CH2S);

Helvetica Chimica Acta – Vol. 92 (2009)
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37.01 (t, C(3) of prolinyl); 36.94 (t, MeCH2CH2); 32.04 (t, CH2S); 22.70 (t, MeCH2CH2); 14.60 (q,
MeCH2CH2). HR-MALDI-MS: 542.2535 (100, [M þ H]þ, C25H40N3O8Sþ; calc. 542.2531).
Methyl 6-Azido-2,3,4,7-tetra-O-benzyl-6,8-dideoxy-1-thio-d-erythro-a-d-galacto-octopyranoside
(18). A soln. of 5 (3.5 g, 13 mmol) in dry DMF (50 ml) under N2 was treated at 08 with 60% NaH in
mineral oil (3.12 g, 78 mmol), BnBr (10.80 g, 63 mmol), and Bu4NI (193 mg, 0.52 mmol), warmed to 258,
stirred for 24 h, and cautiously treated with H2O until complete consumption of NaH. The mixture was
diluted with AcOEt, washed with sat. aq. NH4Cl soln., dried (Na2SO4), and evaporated. FC (hexane/
AcOEt 98 :2 ! 9 :1) gave 18 (6.64 g, 80%). Colourless oil. Rf (hexane/AcOEt 9 :1) 0.69. [a]2D5 ¼þ 107.6
(c ¼ 0.99, CHCl3). IR (ATR): 3209w (br.), 3031w, 2978w, 2921w, 2885w, 2110m, 1586w, 1496w, 1453m,
1388w, 1347m, 1319w, 1295m, 1264m, 1209w, 1157w, 1123m, 1079s, 1065s, 1037s, 1026s, 989m, 917m, 900w,
867m, 830w, 803w, 786w, 748s, 731s, 694s, 635m, 616m. 1H-NMR (400 MHz, CDCl3; assignments based on
a DQFCOSY spectrum): see Table 6; additionally, 7.40 – 7.24 (m, 20 arom. H); 5.08 (d, J ¼ 11.0), 4.85 (d,
J ¼ 11.7), 4.75 (d, J ¼ 11.4, 2 H), 4.70 (d, J ¼ 11.7), 4.65 (d, J ¼ 11.4), 4.54 (d, J ¼ 11.7), 4.50 (d, J ¼
12.0) (4 PhCH2); 2.01 (s, MeS). 13C-NMR (75 MHz, CDCl3; assignments based on a HSQC spectrum):
see Table 6; additionally, 138.54, 138.37, 138.34, 138.12 (4s); 128.66 – 127.49 (several d); 75.39, 73.63, 72.82,
70.94 (4t, 4 PhCH2); 13.94 (q, MeS). HR-ESI-MS: 662.2661 (100, [M þ Na]þ, C37H41N3NaO5Sþ; calc.
662.2659). Anal. calc. for C37H41N3O5S (639.81): C 69.46, H 6.46, N 6.57; found: C 69.29, H 6.29, N 6.54.
Table 6. Selected 1H-NMR Chemical Shifts [ppm] and Coupling Constants [Hz], and 13C-NMR Chemical Shifts
[ppm] of the Lincosamine Derivatives 18 – 22 in CDCl3
18
a-19a)
b-19a)
(E)-20a)
(Z)-20a)
a-21 b-21
a-22 b-22
HꢁC(1) 5.22
HꢁC(2) 4.30
HꢁC(3) 3.71
HꢁC(4) 4.07
HꢁC(5) 3.76
HꢁC(6) 4.17
HꢁC(7) 3.91
5.15
4.54
7.42
4.22
3.91 – 3.84
3.91 – 3.84
3.61
3.72
4.05 – 3.99
1.16
7.9
6.91
4.98
4.97
4.31
4.86 – 4.46
4.86 – 4.46
3.65
4.09
3.16
5.76
4.31
4.06
4.20
4.37
4.09
3.88
1.16
6.0
5.23
4.56
3.66
4.11 – 4.09
3.39
4.38
4.12
1.19
5.4
9.0
2.1
2.1
10.2
4.04 – 3.98 3.74
3.82 3.52
4.12 – 4.08 4.04 – 3.98
3.57 3.04
4.12 – 4.08 4.16
3.95
1.18
4.0
9.9
2.6
0.3
10.7
4.05 – 3.99 4.80
3.91 – 3.84 4.26
3.53
3.74
4.05 – 3.99 3.88
1.18
6.5
4.66
4.08
4.26
3.97
4.04 – 3.98
H3C(8)
J(1,2)
J(2,3)
J(3,4)
J(4,5)
J(5,6)
J(6,7)
1.20
5.6
1.17
7.2
9.6
2.7
1.1
10.0
2.6
6.3
1.13
5.4
9.6
1.8
0.9
10.2
1.15
b
)
10.2
2.6
0.3
10.2
2.4
4.8
3.9
9.6
1.8
0.3
10.2
2.7
6.3
10.2
2.4
b
b
)
)
b
6.3
10.1
2.0
6.0
5.7
10.2
2.8
6.3
)
9.3
2.7
6.0
2.8
6.3
2.7
6.3
2.7
6.3
J(7,Me) 6.3
C(1)
C(2)
C(3)
C(4)
C(5)
C(6)
C(7)
C(8)
87.12 91.75
75.90c) 76.38
79.91 78.98
74.86 74.08
69.65 69.35
62.11 61.77
75.48c) 75.22
13.61 13.23
97.97
80.43
82.30
73.20
73.50
61.73
75.18
13.67
151.91
71.66
79.67
76.30
70.17
64.37
75.75
13.54
149.88
76.86
80.95
76.04
69.98
64.16
75.69
13.90
95.38 100.31
75.33 76.19
79.57 82.47
74.12 74.78
74.68 72.59
61.82 61.55
75.27 75.95
13.32 13.58
105.07 106.68
74.99 78.67
77.76 81.71
72.59 74.91
73.64 72.14
61.86 61.45
74.79 77.83
13.20 14.08
a) Assignments on DQFCOSY and HSQC spectra. b) Not assigned. c) Assignments may be interchanged.
6-Azido-2,3,4,7-tetra-O-benzyl-6,8-dideoxy-d-erythro-a/b-d-galacto-octopyranose (a-19/b-19). A
soln. of 18 (7.04 g, 11.02 mmol) in CH2Cl2 (200 ml) was treated at 08 with Br2 (566 ml, 11.02 mmol),
stirred for 15 min, and treated with sat. aq. Na2S2O5 soln. After extraction with CH2Cl2, the org. layer was

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Helvetica Chimica Acta – Vol. 92 (2009)
dried (Na2SO4) and evaporated to give the corresponding galactopyranosyl bromide, which was used
immediately in the next step.
A soln. of the crude galactopyranosyl bromide in acetone (200 ml) was treated at 08 with H2O
(800 ml) and Ag2CO3 (2.43 g, 8.82 mmol), warmed to 258, stirred for 4 h, and filtered over Celite.
Evaporation and FC (hexane/AcOEt 95 :5 ! 80 :20) gave a-19/b-19 (6.34 g, 94%). Colourless oil. Rf
(hexane/AcOEt 3 :1) 0.54. [a]2D5 ¼þ 31.1 (c ¼ 0.76, CHCl3). IR (ATR): 3455w (br.), 3029w, 2970w,
2937w, 2104s, 1496w, 1453m, 1365s, 1269w, 1228m, 1216s, 1125m, 1058s, 1026s, 903m, 788w, 733s, 695s.
1H-NMR (400 MHz, CDCl3, a/b 1:1; assignments based on a DQFCOSY spectrum): see Table 6;
additionally, 7.55 – 6.98 (m, 20 arom. H); 5.06 (d, J ¼ 11.2, PhCH (b)); 5.05 (d, J ¼ 11.1, PhCH (a));
4.90 – 4.77 (m, PhCH2, PhCH (a)); 4.70 – 4.65 (m, 2 PhCH (b), PhCH (a), PhCH); 4.52 (s, PhCH2 (b));
4.51 (s, PhCH2 (a)); 2.99 (d, J ¼ 7.0, OH (b)); 2.86 (d, J ¼ 2.0, OH (a)). 13C-NMR (75 MHz, CDCl3, a/b
1:1; assignments based on a DEPT and a HSQC spectrum): see Table 6; additionally, 138.47 – 138.13
(several s); 128.51 – 127.30 (several d); 74.99 (t, PhCH2 (a)); 74.95 (t, 2 PhCH2 (b)); 73.72 (t, PhCH2 (a));
73.06 (t, PhCH2 (b)); 72.94 (t, PhCH2 (a)); 70.78 (t, PhCH2 (b)); 70.69 (t, PhCH2 (a)). HR-ESI-MS:
648.2491 (11, [M þ K]þ, C36H39KN3O6þ ; calc. 648.2470); 632.2721 (100, [M þ Na]þ, C36H39N3NaOþ6 ; calc.
632.2731). Anal. calc. for C36H39N3O6 (609.72): C 70.92, H 6.45, N 6.89; found: C 70.79, H 6.38, N 6.92.
(E)/(Z)-6-Azido-2,3,4,7-tetra-O-benzyl-6,8-dideoxy-d-erythro-d-galacto-octose Oxime (20). A soln.
of 19 (6.18 g, 0.01 mmol) in abs. EtOH (100 ml) was added to a soln. of NH2OH · HCl (2.78 g,
0.041 mmol) and EtONa (1.39 g, 0.02 mmol) in abs. EtOH (150 ml). The mixture was stirred at 608 for
24 h, cooled to 258, and evaporated. A soln. of the residue in AcOEt was washed with H2O and brine,
dried (Na2SO4), and evaporated to afford 20 (6.58 g, 95%). Colourless oil, which was used for the next
step without further purification. Rf (hexane/AcOEt 3 :1): 0.38. [a]2D5 ¼ ꢁ5.6 (c ¼ 0.85, CHCl3). IR
(ATR): 3355w (br.), 3063w, 3029w, 2970w, 2940w, 2104s, 1586w, 1496w, 1454m, 1376s, 1304w, 1267w,
1
1229m, 1216m, 1065s, 1026m, 939m, 910m, 820w, 733s, 695s. H-NMR (400 MHz, CDCl3, (E)/(Z) 7:3;
assignments based on a DQFCOSY spectrum): see Table 6; additionally, 7.81 (s, NOH (E)); 7.52 (s, NOH
(Z)); 7.38 – 7.22 (m, 20 arom. H); 4.73 – 4.63 (m, 3 PhCH); 4.58 – 4.40 (m, 5 PhCH); 3.12 (d, J ¼ 6.0, OH
(Z)); 3.03 (d, J ¼ 6.3, OH (E)). 13C-NMR (75 MHz, CDCl3; assignments based on a HSQC spectrum):
see Table 6; additionally, 138.50 – 137.09 (several s); 128.62 – 127.33 (several d); 75.32 (t, PhCH2 (E));
75.25 (t, PhCH2 (Z)); 73.43 (t, PhCH2 (E)); 73.39 (t, PhCH2 (Z)); 72.07 (t, PhCH2 (E)); 71.21 (t, PhCH2
(Z)); 70.65 (t, PhCH2). HR-ESI-MS: 647.2848 (100, [M þ Na]þ, C36H40N4NaO6þ ; calc. 647.2840).
6-Azido-2,3,4,7-tetra-O-benzyl-N-[(4-chlorophenyl)methylidene]-6,8-dideoxy-d-erythro-a/b-d-gal-
acto-octopyranosylamine N-Oxide (a-21/b-21). A mixture of 20 (6.58 g, 10.1 mmol) and 4-chlorobenz-
aldehyde (4.28 g, 30.3 mmol) in dry CH2Cl2 (100 ml) was refluxed for 48 h, cooled to 258, and evaporated.
FC (hexane/AcOEt 95 :5 ! 1:1) gave a-21 (1.50 g, 24%) and b-21 (4.50 g, 60%).
Data of a-21. Colourless powder. Rf (hexane/AcOEt 4 :1) 0.42. M.p. 143 – 1468. [a]2D5 ¼ þ44.1 (c ¼
1.08, CHCl3). IR (ATR): 3085w, 3063w, 3030w, 2980w, 2927w, 2862w, 2106m, 1588w, 1573w, 1556w,
1496w, 1485w, 1453m, 1398w, 1377w, 1346w, 1331w, 1274w, 1207w, 1131s, 1088s, 1045m, 1026m, 1012m,
952w, 904w, 881w, 836w, 730s, 693s, 673w, 632w, 618w. 1H-NMR (300 MHz, CDCl3; assignments based on
selective homodecoupling experiments): see Table 6; additionally, 8.16 (d, J ¼ 6.6, 2 arom. H); 7.46 – 7.25
(m, 22 arom. H); 7.00 (s, CH¼N); 5.11 (d, J ¼ 10.8), 4.94 (d, J ¼ 12.3), 4.92 (d, J ¼ 11.7), 4.86 (d, J ¼
11.7), 4.70 (d, J ¼ 10.8), 4.65 (d, J ¼ 12.6) (6PhCH); 4.50 (s, PhCH2). 13C-NMR (75 MHz, CDCl3): see
Table 6; additionally, 138.42, 138.34, 138.11, 138.02, 136.07 (5s, 6 C); 134.45 (d, CH¼N); 129.91 – 127.08
(several d); 75.27, 75.08, 73.29, 70.56 (4t, 4 PhCH2). HR-ESI-MS: 769.2766 (100, [M þ Na]þ,
C43H43ClN4NaOþ6 ; calc. 769.2769). Anal. calc. for C43H43ClN4O6 (747.29): C 69.11, H 5.80, N 7.50; found:
C 68.82, H 5.99, N 7.40.
Data of b-21. Colourless powder. Rf (hexane/AcOEt 4 :1) 0.22. M.p. 191 – 1928. [a]2D5 ¼ ꢁ35.7 (c ¼
1.0, CHCl3). IR (ATR): 3085w, 3063w, 3032w, 2975w, 2931w, 2856w, 2109m, 1586w, 1556w, 1496w,
1484w, 1453m, 1396m, 1378m, 1346m, 1299m, 1270m, 1213m, 1155m, 1130s, 1089s, 1046s, 1027s, 1010m,
960m, 931m, 912m, 865m, 832m, 793w, 731s, 695s, 674s, 620w. 1H-NMR (300 MHz, CDCl3; assignments
based on selective homodecoupling experiments): see Table 6; additionally, 8.23 (d, J ¼ 8.7, 2 arom. H);
7.45 – 7.09 (m, 22 arom. H, CH¼N); 5.12 (d, J ¼ 11.7, PhCH); 4.86 – 4.46 (m, 3 PhCH2, PhCH). 13C-NMR
(75 MHz, CDCl3): see Table 6; additionally, 138.46, 138.34, 138.02, 137.78, 136.66 (5s, 6 C); 134.24 (d,
CH¼N); 130.49 – 127.21 (several d); 75.45, 74.78, 72.81, 70.75 (4t, 4 PhCH2). HR-ESI-MS: 769.2770 (100,

Helvetica Chimica Acta – Vol. 92 (2009)
251
[M þ Na]þ, C43H43ClN4NaO6þ ; calc. 769.2769). Anal. calc. for C43H43ClN4O6 (747.29): C 69.11, H 5.80, N
7.50; found: C 69.23, H 5.91, N 7.46.
6-Azido-2,3,4,7-tetra-O-benzyl-1-6,8-trideoxy-1-nitro-d-erythro-a/b-d-galacto-octopyranose (a-22/b-
22). A soln. of a-21/b-21 1:3 (6.00 g, 8.03 mmol) in CH2Cl2 (500 ml) was cooled to ꢁ 788. O3 was bubbled
through the soln. until disappearance of a-21/b-21. The soln. was purged with N2, treated with Me2S,
warmed to 258, and evaporated. FC (hexane/AcOEt 95 :5 ! 3 :1) gave b-22 (3.1 g, 75%) and a-22 (0.9 g,
18%).
Data of a-22. Colourless oil. Rf (hexane/AcOEt 3 :1) 0.72. [a]2D5 ¼þ 76.5 (c ¼ 1.02, CHCl3). IR
(ATR): 3064w, 3031w, 2984w, 2940w, 2914w, 2873w, 2107m, 1557m, 1496w, 1453m, 1368w, 1347w, 1309w,
1268m, 1208w, 1091s, 1158w, 1125m, 1091s, 1045m, 1025m, 913w, 874w, 821w, 732s, 695s, 619w. 1H-NMR
(300 MHz, CDCl3; assignments based on selective homodecoupling experiments): see Table 6; addi-
tionally, 7.40 – 7.24 (m, 20 arom. H); 5.05 (d, J ¼ 11.1), 4.82 (d, J ¼ 11.7, 2 H), 4.75 (d, J ¼ 11.7), 4.74 (d, J ¼
11.7), 4.65 (d, J ¼ 10.5), 4.55 (d, J ¼ 11.7), 4.49 (d, J ¼ 12.0) (8 PhCH). 13C-NMR (75 MHz, CDCl3): see
Table 6; additionally, 138.13, 137.80, 137.66, 136.73 (4s); 128.46 – 127.19 (several d); 75.33, 74.21, 73.51,
70.73 (4t, 4 PhCH2). HR-MALDI-MS: 677.2389 (59, [M þ K]þ, C36H38KN4O7þ ; calc. 677.2372), 661.2623
(100, [M þ Na]þ, C36H38N4NaO7þ ; calc. 661.2633). Anal. calc. for C36H38N4O7 (638.72): C 67.70, H 6.00, N
8.77; found: C 67.92, H 5.99, N 8.52.
Data of b-22. Colourless oil. Rf (hexane/AcOEt 3 :1) 0.73. [a]2D5 ¼þ 45.9 (c ¼ 1.12, CHCl3). IR
(ATR): 3030w, 2970w, 2937w, 2106m, 1565s, 1496w, 1454m, 1369m, 1268w, 1229m, 1216m, 1127m, 1091s,
1047s, 1026s, 910w, 873w, 843w, 792w, 732s, 695s. 1H-NMR (300 MHz, CDCl3; assignments based on
selective homodecoupling experiments): see Table 6; additionally, 7.42 – 7.26 (m, 20 arom. H); 5.03 (d,
J ¼ 11.1), 4.84 (d, J ¼ 10.8), 4.78 (d, J ꢃ 12.3), 4.74 (d, J ¼ 11.1), 4.72 (d, J ꢃ 11.2), 4.68 (d, J ¼ 11.7) (6
PhCH); 4.61 (s, PhCH2). 13C-NMR (75 MHz, CDCl3): see Table 6; additionally, 138.50, 137.72, 137.64,
137.24 (4s); 128.81 – 127.71 (several d); 75.08, 74.67, 72.99, 71.08 (4t, 4 PhCH2). ESI-MS: 661.2640 (100,
[M þ Na]þ, C36H38N4NaO7þ ; calc. 661.2633). Anal. calc. for C36H38N4O7 (638.72): C 67.70, H 6.00, N 8.77;
found: C 67.52, H 5.88, N 8.77.
1,2-Di-O-acetyl-7-azido-3,4,5,8-tetra-O-benzyl-7,9-dideoxy-d-erythro-a-d-galacto-non-2-ulopyra-
nose (24). A soln. of 22 (100 mg, 0.15 mmol) and paraformaldehyde (24 mg, 0.78 mmol) in CH2Cl2 (2 ml)
was treated with 1m Bu4NF in THF (5 ml, 0.15 mmol), stirred for 15 min at 258, treated with 6n HCl
(3 ml), and heated to 508 for 3 h. After evaporation of THF, the aq. layer was extracted with CH2Cl2. The
combined org. layers were washed with sat. aq. NaHCO3 soln. and brine, dried (MgSO4), and evaporated.
A soln. of the residue in CH2Cl2 (5 ml) was treated with Et3N (2 ml), DMAP (20 mg, 0.15 mmol), and
Ac2O (1 ml), stirred for 12 h, and evaporated. A soln. of the residue in AcOEt was washed with sat. aq.
NaHCO3 soln. and brine, dried (MgSO4), and evaporated. FC (hexane/AcOEt 95 :5 ! 4 :1) gave 24
(94 mg, 80%). Rf (hexane/AcOEt 85 :15) 0.22. [a]2D5 ¼þ 27.9 (c ¼ 1.0, CHCl3). IR (ATR): 3031w, 2938w,
2965w, 2107m, 1749m, 1607w, 1587w, 1496w, 1454w, 1367w, 1346w, 1265w, 1218m, 1178w, 1127m, 1094m,
1042m, 1027m, 1009m, 961w, 908m, 729s, 695s, 648w. 1H-NMR (300 MHz, CDCl3; assignments based on
selective homodecoupling experiments): see Table 7; additionally, 7.43 – 7.23 (m, 20 arom. H); 5.14 (d, J ¼
11.1), 4.94 (d, J ¼ 11.1), 4.84 (d, J ¼ 11.4), 4.77 (d, J ¼ 11.7), 4.69 (d, J ¼ 11.7, 2 H), 4.58 (d, J ¼ 11.7),
4.50 (d, J ¼ 11.4) (4 PhCH2); 2.05, 1.92 (2s, 2 AcO). 13C-NMR (75 MHz, CDCl3; assignments based on a
HSQC spectrum): see Table 7; additionally, 169.68, 168.26 (2s, 2 C¼O); 138.48, 138.37, 137.90, 137.84 (4s);
128.43 – 127.30 (several d); 75.43, 74.56, 72.63, 70.80 (4t, 4 PhCH2); 21.58, 20.63 (2q, 2 MeC¼O). HR-
ESI-MS: 746.3047 (100, [M þ Na]þ, C41H45N3NaO9þ ; calc. 746.3048). Anal. calc. for C41H45N3O9 (723.82):
C 68.03, H 6.27, N 5.81; found: C 68.26, H 6.33, N 5.80.
General Procedure for Additions of 22 to Aldehydes (GP 6). A 1m soln. of a-22/b-22 in DMF was
treated with the aldehyde (5 equiv.) and then in four portions, one every 30 min, with a 1.5m soln. of
Et4NOH (0.1 equiv.), stirred for 24 h at 258, and evaporated to afford the crude ulose derivative.
Addition of 22 to Octanal. According to GP 6, 1 g (1.57 mmol) of a-22/b-22 was treated with 1.23 ml
(7.85 mmol) of octanal. FC (hexane/AcOEt 98 :2) of the crude gave 28b (180 mg, 15%) and 28a (640 mg,
53%).
(1R)-7-Azido-3,4,5,8-tetra-O-benzyl-2,7,9-trideoxy-1-C-heptyl-2-nitro-d-erythro-a-d-galacto-non-2-
ulopyranose (28a). Rf (hexane/AcOEt 85 :15) 0.73. 1H-NMR (300 MHz, CDCl3): 7.40 – 7.24 (m, 20 arom.
H); 5.06 (d, J ¼ 10.8), 4.87 (d, J ¼ 11.4), 4.78 (d, J ¼ 11.2), 4.75 (d, J ¼ 11.2), 4.67 (d, J ¼ 11.4), 4.65 (d,

252
Helvetica Chimica Acta – Vol. 92 (2009)
Table 7. Selected 1H-NMR Chemical Shifts [ppm] and Coupling Constants [Hz], and 13C-NMR Chemical
Shifts [ppm] of the Acetates 24, a-29a, 29b, b-l-34a, 34b, and 41 in CDCl3 (numbering as for lincosamine)
24a)
a-29a
29ba)
b-l-34aa)
34ba)
41
HꢁC(2)
HꢁC(3)
HꢁC(4)
HꢁC(5)
HꢁC(6)
HꢁC(7)
H3C(8)
HaꢁC(1’)
HbꢁC(1’)
HaꢁC(2’)
HbꢁC(2’)
J(2,3)
J(3,4)
J(4,5)
J(5,6)
J(6,7)
J(7,Me)
J(1’,2’a)
J(1’,2’b)
J(1’a,1’b)
C(1)
4.31
4.12
3.93
4.13
3.52
4.15
4.01
1.17
5.83
–
4.43
3.98
4.13
3.34
4.02
4.03
1.13
5.93
–
4.27
3.95
4.17
3.56
4.19
3.98
1.20
6.23
–
3.79
3.70
9.6
2.4
0.6
4.44
3.95
4.14
3.36
4.05
4.04
1.16
6.35
–
3.83
4.07
4.13
3.28
3.94
3.95
1.20
)
)
)
)
3.97
4.17
3.37
4.13
3.98
1.13
5.05
4.31
–
b
b
b
b
1.74 – 1.42
1.74 – 1.42
9.3
1.83 – 1.53
1.83 – 1.53
9.9
3.72 – 3.65
3.72 – 3.65
9.9
–
9.9
2.7
0.9
9.9
2.4
6.3
–
9.6
2.1
2.7
1.8
2.4
c
c
c
c
)
)
)
)
10.2
2.4
6.3
3.3
9.3
10.2
2.1
6.0
10.8
1.5
–
10.2
2.4
6.3
3.0
6.9
10.5
1.8
6.3
7.2
4.5
10.2
2.4
6.0
d
)
)
)
d
–
11.4
d
–
–
–
103.41
74.93
80.30
73.62
71.78
62.20
75.07
13.28
63.16
–
104.43
75.47
81.17
73.38
71.94
62.40
74.92
13.14
73.38
104.76
74.47
81.29
73.65
71.80
62.53
75.49
13.87
74.57
103.82
76.29
81.00
73.55
72.24
62.51
75.04
13.44
71.22
68.27
103.93
74.25
81.04
73.57
71.79
62.52
75.41
13.76
72.26
68.63
104.10
74.56
80.45
73.57
71.74
62.28
74.95
13.39
30.07
11.68e)
C(2)
C(3)
C(4)
C(5)
C(6)
C(7)
C(8)
C(1’)
d
d
C(2’)
)
)
a) Assignments based on a HSQC spectrum. b) 2.79 – 2.64 ppm (m, 1 H); 2.22 – 2.05 (m, 2 H); 1.74 – 1.55
(m, 1 H). c) J < 1.5 Hz (line broadening). d) Not assigned. e) s of C ꢄ N at 119.17 ppm.
J ¼ 11.1), 4.60 (d, J ¼ 12.0), 4.47 (d, J ¼ 12.0) (4 PhCH2); 4.30 (dd, J ¼ 10.1, 2.1, HꢁC(6)); 4.25 (d, J ¼
9.7, HꢁC(3)); 4.18 (dd, J ¼ 2.6, 1.9, HꢁC(5)); 4.03 (dd, J ¼ 10.1, 2.6, HꢁC(4)); 4.05 – 4.00 (m,
HꢁC(1)); 3.88 (dd, J ¼ 9.6, 2.2, HꢁC(7)); 3.77 (qd, J ¼ 6.0, 2.2, HꢁC(8)); 1.99 (d, J ¼ 8.4, OH); 1.48 –
1.38 (m, 1 H), 1.35 – 1.09 (m, 11 H) (Me(CH2)6); 1.23 (d, J ¼ 6.3, Me); 0.88 (t, J ¼ 6.6, Me(CH2)6).
(1S)-7-Azido-3,4,5,8-tetra-O-benzyl-2,7,9-trideoxy-1-C-heptyl-2-nitro-d-erythro-a-d-galacto-non-2-
ulopyranose (28b). Rf (hexane/AcOEt 85 :15) 0.74. 1H-NMR (300 MHz, CDCl3): 7.44 – 7.22 (m, 20 arom.
H); 5.10 (d, J ¼ 11.0, PhCH), 4.87 (br. s, PhCH2); 4.78 (d, J ¼ 10.0, HꢁC(3)); 4.72 (d, J ¼ 11.5), 4.67 (d,
J ¼ 12.0), 4.64 (d, J ¼ 11.0), 4.60 (d, J ¼ 12.1), 4.48 (d, J ¼ 12.1) (5 PhCH); 4.36 (dd, J ¼ 10.0, 1.3,
HꢁC(6)); 4.17 – 4.14 (m, HꢁC(1), HꢁC(5)); 4.02 (dd, J ¼ 10.1, 2.6, HꢁC(4)); 3.83 (dd, J ¼ 10.1, 2.1,
HꢁC(7)); 3.79 (qd, J ¼ 6.3, 2.1, HꢁC(8)); 1.52 – 1.40 (m, 1 H), 1.39 – 1.19 (m, 11 H) (Me(CH2)6); 1.20
(d, J ¼ 6.3, Me); 0.88 (t, J ¼ 6.3, Me(CH2)6).
General Procedure for the Hydrolysis and Acetylation of the 2-Nitroaldulopyranosides (GP 7). A 1m
soln. of the nitro compound in 7n HCl was kept at 508 for 36 h and evaporated. A soln. of the residue in
CH2Cl2 was washed with H2O, sat. aq. NaHCO3 soln., and brine, dried (MgSO4), and evaporated. A soln.

Helvetica Chimica Acta – Vol. 92 (2009)
253
of the residue in CH2Cl2 (5 ml) was treated with Et3N (2 ml), DMAP (2 equiv.), and Ac2O (1 ml), heated
for 24 h at 508, and evaporated. A soln. of the residue in AcOEt was washed with sat. aq. NaHCO3 soln.
and brine, dried (MgSO4), and evaporated to give the crude acetates.
(1R)-1,2-Di-O-acetyl-7-azido-3,4,5,8-tetra-O-benzyl-7,9-dideoxy-1-C-heptyl-d-erythro-a-d-galacto-
non-2-ulopyranose (a-29a). According to GP 7, 300 mg (0.39 mmol) of 28a and FC of the crude acetate
(hexane/AcOEt 95 :5 ! 4 :1) gave a-29a (280 mg, 87%). Rf (hexane/AcOEt 85 :15) 0.42. [a]2D5 ¼þ 66.3
(c ¼ 1.0, CHCl3). IR (ATR): 3031w, 2927w, 2857w, 2107m, 1743m, 1496w, 1454m, 1368m, 1225m, 1094s,
1
1044s, 1027s, 1008m, 930m, 840w, 781w, 733s, 695s. H-NMR (300 MHz, CDCl3; assignments based on
selective homodecoupling experiments): see Table 7; additionally, 7.42 – 7.23 (m, 20 arom. H); 5.12 (d,
J ¼ 11.1), 4.86 (d, J ¼ 11.1), 4.80 (d, J ¼ 11.4), 4.79 (d, J ¼ 11.1), 4.69 (d, J ¼ 11.4), 4.67 (d, J ¼ 11.4),
4.61 (d, J ¼ 12.0), 4.52 (d, J ¼ 12.0) (4 PhCH2); 1.99, 1.91 (2s, 2 AcO); 1.74 – 1.42 (m, 2 H); 1.38 – 1.12 (m,
10 H) ((CH2)6Me); 0.88 (t, J ¼ 6.9, (CH2)6Me). 13C-NMR (75 MHz, CDCl3; assignments based on a
HSQC spectrum): see Table 7; additionally, 170.17, 168.03 (2s, 2 C¼O); 138.60, 138.55, 138.32, 137.91
(4s); 128.36 – 127.26 (several d); 74.92, 74.55, 72.64, 70.64 (4t, 4 PhCH2); 31.71, 29.54, 29.41, 29.10, 25.69,
22.56 (6t, Me(CH2)6); 21.90, 20.80 (2q, 2 MeC¼O); 14.01 (q, Me(CH2)6). ESI-MS: 844.1 (100, [M þ
Na]þ). Anal. calc. for C48H59N3O9 (822.01): C 70.14, H 7.23, N 5.11; found: C 69.85, H 7.33, N 5.24.
(1S)-1,2-Di-O-acetyl-7-azido-3,4,5,8-tetra-O-benzyl-7,9-dideoxy-1-C-heptyl-d-erythro-a-d-galacto-
non-2-ulopyranose (29b). According to GP 7, 79 mg (0.10 mmol) of 28b and FC of the crude acetate
(hexane/AcOEt 95 :5 ! 4 :1) gave 29b (73 mg, 86%). Rf (hexane/AcOEt 85 :15) 0.42. [a]2D5 ¼þ 45.3 (c ¼
1.0, CHCl3). IR (ATR): 3031w, 2926w, 2857w, 2106m, 1753s, 1497w, 1454w, 1368m, 1346w, 1213m, 1155w,
1127m, 1090s, 1046m, 1027m, 1009m, 983m, 927m, 783w, 732s, 695s. 1H-NMR (300 MHz, CDCl3;
assignments based on selective homodecoupling experiments): see Table 7; additionally, 7.42 – 7.24 (m, 20
arom. H); 5.12 (d, J ¼ 10.5), 5.01 (d, J ¼ 11.4), 4.83 (d, J ¼ 11.4), 4.78 (d, J ¼ 11.4), 4.73 (d, J ¼ 11.7),
4.63 (d, J ¼ 10.8), 4.59 (d, J ¼ 11.1), 4.50 (d, J ¼ 11.4) (4 PhCH2); 2.06, 1.85 (2s, 2 AcO); 1.83 – 1.53 (m,
2 H), 1.28 – 1.14 (m, 10 H) (Me(CH2)6); 0.87 (t, J ¼ 7.2, Me(CH2)6). 13C-NMR (75 MHz, CDCl3;
assignments based on a HSQC spectrum): see Table 7; additionally, 169.55, 168.16 (2s, 2 C¼O); 138.58,
138.52, 137.95, 137.91 (4s); 128.44 – 127.30 (several d); 74.97, 74.71, 72.66, 71.14 (4t, 4 PhCH2); 31.86, 29.78,
29.25 (2 C), 26.32, 22.77 (5t, Me(CH2)6); 21.88, 20.95 (2q, 2 MeC¼O); 14.26 (q, Me(CH2)6). ESI-MS:
844.2 (100, [M þ Na]þ). Anal. calc. for C48H59N3O9 (822.01): C 70.14, H 7.23, N 5.11; found: C 69.87, H
7.26, N 5.26.
Addition of 22 to (Benzyloxy)acetaldehyde. According to GP 6, 800 mg (1.25 mmol) of a-22/b-22
were treated with 880 ml (6.25 mmol) of (benzyloxy)acetaldehyde. FC (hexane/AcOEt 98 :2 ! 90 :10)
gave 33b (220 mg, 22%) and 33a (690 mg, 70%).
8-Azido-1,4,5,6,9-penta-O-benzyl-3,8,10-trideoxy-3-nitro-d-ribo-b-l-gluco-dec-3-ulopyranose (33a).
1
Rf (hexane/AcOEt 85 :15) 0.63. H-NMR (300 MHz, CDCl3): 7.40 – 7.22 (m, 25 arom. H); 5.08 (d, J ¼
11.1, PhCH); 4.87 (br. s, PhCH2); 4.81 (d, J ¼ 10.2, HꢁC(4)); 4.73 – 4.62 (m, HꢁC(7), PhCH2);
4.60 – 4.52 (ddd, J ¼ 8.7, 6.3, 3.6, HꢁC(2)); 4.46 (d, J ¼ 12.3, PhCH); 4.40 (br. s, PhCH2); 4.36 (d, J ¼
12.0), 4.32 (d, J ¼ 10.2) (2 PhCH); 4.15 (br. s, HꢁC(6)); 4.05 (dd, J ¼ 10.2, 3.0, HꢁC(8)); 3.86 (dd,
J ¼ 9.9, 1.8, HꢁC(5)); 3.74 (qd, J ¼ 6.3, 3.0, HꢁC(9)); 3.44 (dd, J ¼ 10.2, 3.6, HaꢁC(1)); 3.36 (dd, J ¼
10.2, 6.6, HbꢁC(1)); 2.43 (d, J ¼ 8.7, OH); 1.16 (d, J ¼ 6.3, Me).
8-Azido-1,4,5,6,9-penta-O-benzyl-3,8,10-trideoxy-3-nitro-d-ribo-b-l-manno-dec-3-ulopyranose
(33b). Rf (hexane/AcOEt 85 :15) 0.64. 1H-NMR (300 MHz, CDCl3): 7.42 – 7.16 (m, 25 arom. H); 5.03 (d,
J ¼ 10.5, PhCH); 4.77 (br. s, PhCH2); 4.72 (d, J ¼ 11.6), 4.66 (d, J ¼ 11.6), 4.65 (d, J ¼ 10.8) (3 PhCH);
4.56 – 4.53 (m, HꢁC(2) overlapping with PhCH); 4.54 (d, J ¼ 12.0, PhCH); 4.47 (d, J ¼ 9.6, HꢁC(4));
4.40 (d, J ¼ 12.0, PhCH); 4.35 (br. d, J ¼ 10.2, HꢁC(7)); 4.27 (d, J ¼ 11.8), 4.20 (d, J ¼ 12.0) (2 PhCH);
4.18 (br. s, HꢁC(6)); 4.04 (dd, J ¼ 10.2, 2.7, HꢁC(8)); 3.86 (dd, J ¼ 9.6, 2.4, HꢁC(5)); 3.85 (qd, J ¼ 6.3,
2.4, HꢁC(9)); 3.42, 3.34 (2dd, J ¼ 10.2, 5.1, 2 HꢁC(1)); 2.41 (d, J ¼ 7.5, OH); 1.21 (d, J ¼ 6.3, Me).
2,3-Di-O-acetyl-8-azido-1,4,5,6,9-penta-O-benzyl-8,10-dideoxy-d-ribo-b-l-gluco-dec-3-ulopyranose
(b-l-34a). According to GP 7, 200 mg (0.25 mmol) of 33a and FC of the crude acetate (hexane/AcOEt
95 :5 ! 4 :1) gave b-l-34a (165 mg, 75%). Rf (hexane/AcOEt 85 :15) 0.33. [a]2D5 ¼þ 75.7 (c ¼ 1.0,
CHCl3). IR (ATR): 3063w, 3030w, 2936w, 2868w, 2107m, 1748w, 1605w, 1587w, 1496w, 1453m, 1368m,
1346w, 1232m, 1216m, 1095s, 1047m, 1026m, 1008m, 915m, 781w, 733s, 695s. 1H-NMR (300 MHz, CDCl3;
assignments based on selective homodecoupling experiments): see Table 7; additionally, 7.47 – 7.24 (m, 25

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Helvetica Chimica Acta – Vol. 92 (2009)
arom. H); 5.15 (d, J ¼ 11.4, PhCH); 4.86 (br. s, PhCH2); 4.81 (d, J ¼ 11.4), 4.73 (d, J ¼ 11.7), 4.72 (d, J ¼
11.4), 4.60 (d, J ¼ 12.0), 4.59 (d, J ¼ 11.7), 4.51 (d, J ¼ 11.7), 4.43 (d, J ¼ 11.7) (7 PhCH); 2.02, 1.97 (2s,
2 AcO). 13C-NMR (75 MHz, CDCl3; assignments based on a HSQC spectrum): see Table 7; additionally,
169.95, 168.15 (2s, 2 C¼O); 138.65, 138.57, 138.30, 137.96 (4s); 128.42 – 127.28 (several d); 75.04, 74.78,
72.85, 72.83, 70.85 (5t, 5 PhCH2); 22.17, 21.06 (2q, 2 MeC¼O); 13.44 (q, Me). ESI-MS: 866.0 (100, [M þ
Na]þ). Anal. calc. for C49H53N3O10 (843.97): C 69.73, H 6.33, N 4.98; found: C 69.68, H 6.35, N 4.93.
2,3-Di-O-acetyl-8-azido-1,4,5,6,9-penta-O-benzyl-8,10-dideoxy-d-ribo-b-l-manno-dec-3-ulopyranose
(34b). According to GP 7, 190 mg (0.21 mmol) of 33b and FC of the acetate (hexane/AcOEt 95 :5 !
4 :1) gave 34b (150 mg, 75%). Rf (hexane/AcOEt 85 :15) 0.33. [a]2D5 ¼þ 46.7 (c ¼ 0.98, CHCl3). IR
(ATR): 3063w, 3031w, 2931w, 2867w, 2107m, 1753w, 1605w, 1587w, 1496w, 1453m, 1368m, 1346w, 1214m,
1
1126m, 1090s, 1044m, 1027m, 1009m, 925m, 851w, 732s, 695s. H-NMR (300 MHz, CDCl3; assignments
based on selective homodecoupling experiments): see Table 7; additionally, 7.42 – 7.20 (m, 25 arom. H);
5.12 (d, J ¼ 11.1), 4.86 (d, J ¼ 10.8), 4.82 (d, J ¼ 11.1), 4.72 (d, J ¼ 11.4), 4.71 (d, J ¼ 11.4), 4.65 (d, J ¼
10.5), 4.61 (d, J ¼ 11.7), 4.51 (d, J ¼ 11.7), 4.50 (d, J ¼ 12.3), 4.38 (d, J ¼ 12.0) (5 PhCH2); 1.97, 1.93 (2s,
2 AcO). 13C-NMR (75 MHz, CDCl3; assignments based on a HSQC spectrum): see Table 7; additionally,
169.29, 168.23 (2s, 2 C¼O); 138.67, 138.62, 138.09, 137.91 (4s); 128.55 – 127.44 (several d); 74.92, 74.71,
72.60, 72.09, 71.14 (5t, 5 PhCH2); 21.64, 20.88 (2q, 2 MeC¼O). HR-ESI-MS: 866.3620 (100, [M þ Na]þ,
C49H53N3NaOþ10 ; calc. 866.3623). Anal. calc. for C49H53N3O10 (843.97): C 69.73, H 6.33, N 4.98; found: C
69.68, H 6.35, N 4.93.
4-O-Acetyl-9-azido-5,6,7,10-tetra-O-benzyl-2,3,9,11-tetradeoxy-d-erythro-a-d-galacto-undec-4-ulo-
pyranosononitrile (41). A soln. of a-22/b-22 (200 mg, 0.31 mmol) and acrylonitrile (45 ml, 0.63 mmol) in t-
BuOH/CH2Cl2 6 :1 (7 ml) was treated with t-BuONa (31 mg, 0.31 mmol), stirred for 3 h, and evaporated.
A soln. of the residue in 2m aq. LiClO4 (5 ml), stirred for 48 h at 258, and evaporated. A soln. of the
residue in CH2Cl2 was washed with H2O and brine, dried (MgSO4), and evaporated. A soln. of the
residue in CH2Cl2 (5 ml) was treated with Et3N (2 ml), DMAP (39 mg, 0.31 mmol), and Ac2O (1 ml),
stirred for 12 h, and evaporated. FC (hexane/AcOEt 95 :5 ! 4 :1) gave 41 (120 mg, 56%). Rf (hexane/
AcOEt 85 :15) 0.11. [a]2D5 ¼þ 16.5 (c ¼ 1.0, CHCl3). IR (ATR): 3030w, 2933w, 2108s, 1748m, 1586w,
1496w, 1454m, 1367m, 1346w, 1305w, 1270w, 1212m, 1127m, 1092s, 1047m, 1026s, 1009m, 967m, 927m,
1
735s, 697s. H-NMR (300 MHz, CDCl3; assignments based on selective homodecoupling experiments):
see Table 7; additionally, 7.45 – 7.22 (m, 20 arom. H); 5.07 (d, J ¼ 11.4), 4.94 (d, J ¼ 11.4), 4.83 (d, J ¼
11.4), 4.77 (d, J ¼ 11.4), 4.75 (d, J ¼ 11.4), 4.67 (d, J ¼ 10.8), 4.59 (d, J ¼ 11.7), 4.50 (d, J ¼ 11.7)
(4 PhCH2); 2.03 (s, AcO). 13C-NMR (75 MHz, CDCl3): see Table 7; additionally, 168.26 (s, C¼O);
138.18, 138.63, 137.03 (4s); 128.93 – 127.47 (several d); 75.15, 74.95, 72.57, 70.79 (4t, 4 PhCH2); 22.17 (q,
MeC¼O). ESI-MS: 727.1 (100, [M þ Na]þ). Anal. calc. for C41H44N4O7 (704.82): C 69.87, H 6.29, N 7.95;
found: C 69.89, H 6.41, N 7.88.
Methyl (Methyl 9-Azido-5,6,7,10-tetra-O-benzyl-2,3,9,11-tetradeoxy-4-thio-d-erythro-a-d-galacto-
undec-4-ulopyranosid)onate (45). A soln. of a-22/b-22 (150 mg, 0.24 mmol) and methyl acrylate (43 ml,
0.48 mmol) in THF (5 ml) was treated with a 1m Bu4NF · 3 H2O soln. in THF (24 ml, 0.24 mmol), stirred
for 30 min, and evaporated. A suspension of the residue and 4-ꢃ mol. sieves in CH2Cl2 (5 ml) was stirred
for 30 min at 258, cooled to ꢁ 788, and treated with bubbling MeSH for 2 min, warmed to ꢁ 308, treated
with BF3 · OEt2 (22 ml, 0.24 mmol), and stirred for 1 h. The mixture was treated with sat. aq. NaHCO3
soln. and filtered over Celite. The layers were separated, and the aq. layer was extracted with CH2Cl2. The
combined org. layers were dried (MgSO4) and evaporated. FC (hexane/AcOEt 95 :5 ! 4 :1) gave 45
(146 mg, 85%). Rf (hexane/AcOEt 85 :15) 0.36. [a]2D5 ¼þ 42.6 (c ¼ 1.0, CHCl3). IR (ATR): 3063w, 3030w,
2925w, 2105s, 1735m, 1496w, 1453m, 1435w, 1380w, 1345w, 1268w, 1194w, 1171w, 1127m, 1086s, 1026m,
951w, 910w, 732s, 695s. 1H-NMR (300 MHz, CDCl3; assignments based on selective homodecoupling
experiments): see Table 8; additionally, 7.41 – 7.20 (m, 20 arom. H); 5.10 (d, J ¼ 11.1), 4.94 (d, J ¼ 11.7),
4.78 (d, J ¼ 11.4), 4.73 (d, J ¼ 11.4), 4.71 (d, J ¼ 11.4), 4.64 (d, J ¼ 11.4), 4.56 (d, J ¼ 11.7), 4.48 (d, J ¼
11.7) (4 PhCH2); 3.57 (s, MeO); 1.87 (s, MeS). 13C-NMR (75 MHz, CDCl3): see Table 8; additionally,
173.64 (s, C¼O); 138.80, 138.18, 138.06, 137.83 (4s); 128.43 – 127.38 (several d); 75.12, 74.67, 72.58, 70.76
(4t, 4 PhCH2); 9.74 (q, MeS). ESI-MS: 747.9 (100, [M þ Na]þ). Anal. calc. for C41H47N3O7S (725.90): C
67.84, H 6.53, N 5.79; found: C 67.96, H 6.39, N 5.80.

Helvetica Chimica Acta – Vol. 92 (2009)
255
Table 8. Selected 1H-NMR Chemical Shifts [ppm] and Coupling Constants [Hz], and 13C-NMR Chemical
Shifts [ppm] of the Thioglycosides a-25, a-30a, 30b, b-l-36a, 35b, 42, and 45 in CDCl3 (numbering as for
lincosamine)
a-25a)
a-30aa)
30ba)
b-l-36aa)
35ba)
42a)
45
4.09 – 4.03
4.09 – 4.03
4.09 – 4.03
3.62
4.09 – 4.03
3.86
1.19
HꢁC(2)
HꢁC(3)
HꢁC(4)
HꢁC(5)
HꢁC(6)
HꢁC(7)
H3C(8)
HaꢁC(1’)
HbꢁC(1’)
HaꢁC(2’)
HbꢁC(2’)
J(2,3)
4.43
4.02
4.12
3.66
4.10
3.91
1.21
4.64
4.00
–
4.29
3.99
4.08
3.64
4.10
3.90
1.25
5.07
–
4.43
3.98
4.09
3.59
4.10
3.96
1.21
5.16
–
4.46
3.99
4.09
3.67
4.07
3.88 – 3.80
1.20
3.88 – 3.80
–
3.88 – 3.80
3.60
4.44
3.99 – 3.94
4.10
3.63
4.09
3.99 – 3.94
1.21
5.51
–
4.21
3.95
4.07
4.11
3.63
4.08
3.88
1.21
b
c
)
)
)
)
)
)
)
)
)
)
)
b
c
c
b
b
b
)
)
)
)
b
b
b
c
–
9.9
3.53
d
d
e
9.3
2.7
9.6
2.1
0.9
9.6
9.9
9.6
2.4
e
J(3,4)
J(4,5)
2.4
2.4
)
e
e
e
e
)
)
)
0.9
)
J(5,6)
J(6,7)
9.9
1.8
6.6
–
–
10.8
83.93
74.50
81.20
74.15
71.20
62.96
75.09
14.44
64.04
–
9.6
2.7
6.0
2.1
9.9
9.9
2.4
6.3
1.5
11.4
–
92.84
74.86
82.75
73.81
70.63
62.80
75.51
14.24
75.74
–
9.6
2.4
6.3
)
6.6
10.5f)
92.79
76.95
81.80
73.91
71.61
62.81
72.87
14.25
74.72
70.94
9.9
2.1
6.3
2.1
9.9
2.1
6.3
9.9
2.1
6.6
J(7,Me)
J(1’,2’a)
J(1’,2’b)
J(1’a,1’b)
C(1)
C(2)
C(3)
C(4)
C(5)
C(6)
C(7)
C(8)
C(1’)
d
d
d
)
)
)
)
)
)
d
d
d
9.3
d
–
11.4f)
91.14
74.39
82.19
73.67
70.50
62.65
75.32
14.73
74.39
69.46
92.53
76.21
82.10
73.92
70.98
63.23
74.78
14.24
73.77
89.89
73.54
81.57
73.92
71.20
62.59
74.40
13.91
32.40
11.09
91.13
73.32
81.75
74.95
71.06
63.04
75.96
13.97
32.02
28.28
b
C(2’)
)
a) Assignments based on a HSQC spectrum. b) See Exper. Part. c) 2.32 – 2.19 (m, 2 H); 2.17 – 2.01 (m,
e
f
1 H); 1.99 – 1.89 (m, 5 H). d) Not assigned. ) < 1.5 Hz (line broadening). ) J(2a’ ,2’b).
General Procedure for Thioglycosylation of Aldulopyranosyl Acetates (GP 8). A 1m soln. of the
acetate in CH2Cl2 was treated with 4-ꢃ mol. sieves, stirred for 30 min at 258, and cooled to ꢁ 788. MeSH
was passed through the mixture for 2 min. The mixture was warmed to ꢁ 308, treated with BF3 · Et2O
(1 equiv.), stirred for 1 h, diluted with sat. aq. NaHCO3 soln., and filtered over Celite. The layers were
separated, and the aq. layer was extracted with CH2Cl2. The combined org. layers were dried (MgSO4)
and evaporated.
Methyl 1-O-Acetyl-7-azido-3,4,5,8-tetra-O-benzyl-7,9-dideoxy-2-thio-d-erythro-a/b-d-galacto-non-2-
ulopyranoside (a-25/b-25). According to GP 8, 100 mg (0.14 mmol) of 24 and FC of the crude
thioglycoside (hexane/AcOEt 95 :5 ! 4 :1) gave a-25 (57 mg, 57%) and a-25/b-25 1:1 (27 mg, 27%). FC
of a-25/b-25 1:1 afforded an anal. sample of b-25.
Data of a-25. Colourless oil. Rf (hexane/AcOEt 85 :15) 0.45. [a]2D5 ¼þ 48.9 (c ¼ 1.0, CHCl3). IR
(ATR): 3028w, 2970w, 2943w, 2104m, 1739s, 1496w, 1454m, 1365s, 1228s, 1216s, 1091m, 1047m, 1026m,
951w, 906w, 900w, 781w, 733m, 695m. 1H-NMR (300 MHz, CDCl3; assignments based on selective

256
Helvetica Chimica Acta – Vol. 92 (2009)
homodecoupling experiments): see Table 8; additionally, 7.43 – 7.23 (m, 20 arom. H); 5.15 (d, J ¼ 11.4),
4.95 (d, J ¼ 11.7), 4.81 (d, J ¼ 11.4), 4.75 (d, J ¼ 11.4), 4.74 (d, J ¼ 11.4), 4.61 (d, J ¼ 11.4), 4.55 (d, J ¼
11.4), 4.49 (d, J ¼ 11.4) (4 PhCH2); 1.90 (s, MeS); 1.84 (s, AcO). 13C-NMR (75 MHz, CDCl3;
assignments based on a HSQC spectrum): see Table 8; additionally, 170.12 (s, C¼O); 138.82, 138.17,
138.02, 137.91 (4s); 128.37 – 127.33 (several d); 75.34, 74.43, 72.59, 70.85 (4t, 4 PhCH2); 20.75 (q,
MeC¼O); 9.30 (q, MeS). ESI-MS: 734.01 (100, [M þ Na]þ). Anal. calc. for C40H45N3O7S (711.98): C
67.49, H 6.37, N 5.90; found: C 67.54, H 6.40, N 5.86.
Data of b-25. Rf (hexane/AcOEt 85 :15) 0.44. Colourless oil. IR (ATR): 3030w, 2926w, 2865w, 2107s,
1744m, 1496w, 1453m, 1378m, 1346w, 1269w, 1227s, 1090s, 1054m, 1027m, 909w, 781w, 734m, 697m.
1H-NMR (400 MHz, CDCl3; assignments based on selective homodecoupling experiments): 7.31 – 7.14
(m, 20 arom. H); 5.05 (d, J ¼ 11.2), 4.86 (d, J ¼ 10.8), 4.78 (d, J ¼ 10.4), 4.68 (d, J ¼ 11.6, 2 H), 4.59 (d,
J ¼ 11.2) (6 PhCH); 4.52 (d, J ¼ 12.8, HaꢁC(1)); 4.49 (d, J ¼ 10.8), 4.44 (d, J ¼ 12.0) (2 PhCH); 4.19 (d,
J ¼ 12.4, HbꢁC(1)); 4.17 (d, J ¼ 9.6, HꢁC(3)); 4.02 (dd, J ¼ 9.6, 2.8, HꢁC(7)); 3.98 (dd, J ¼ 2.4, 0.8,
HꢁC(5)); 3.91 (qd, J ¼ 6.4, 2.4, HꢁC(8)); 3.72 (dd, J ¼ 10.0, 2.4, HꢁC(4)); 3.28 (dd, J ¼ 9.6, 0.8,
HꢁC(6)); 2.00 (s, MeS); 1.86 (s, AcO); 1.10 (d, J ¼ 6.4, Me). 13C-NMR (100 MHz, CDCl3; assignments
based on a HSQC spectrum): 170.14 (s, C¼O); 138.62, 138.28, 138.20, 138.06 (4s); 128.57 – 127.49 (several
d); 86.80 (s, C(2)); 80.85, (d, C(4)); 78.09 (d, C(3)); 76.26 (t, PhCH2); 74.84 (d, C(8)); 74.76 (t, PhCH2);
73.99 (d, C(5)); 73.20 (d, C(6)); 72.76, 70.74 (2t, 2 PhCH2); 64.12 (t, C(1)); 62.56 (d, C(7)); 20.81 (q,
MeC¼O); 13.37 (q, Me); 10.63 (q, MeS). ESI-MS: 750.2833 (55, [M þ K]þ, C40H45KN3O7Sþ; calc.
750.2615); 734.2879 (100, [M þ Na]þ, C40H45N3NaO7Sþ; calc. 734.2870).
Methyl (1R)-1-O-Acetyl-7-azido-3,4,5,8-tetra-O-benzyl-7,9-dideoxy-1-C-heptyl-2-thio-d-erythro-a/b-
d-galacto-non-2-ulopyranoside (30a). According to GP 8, 165 mg (0.20 mmol) of a-29a and FC of the
crude thioglycoside (hexane/AcOEt 95 :5 ! 4 :1) gave b-30a (37 mg, 23%) and a-30a (73 mg, 46%).
Data of a-30a. Colourless oil. Rf (hexane/AcOEt 85 :15) 0.64. [a]2D5 ¼þ 97.5 (c ¼ 1.0, CHCl3). IR
(ATR): 3030w, 2926w, 2857w, 2105m, 1739m, 1496w, 1453w, 1370w, 1346w, 1303w, 1232s, 1088s, 1046s,
1
1027s, 979w, 909w, 820w, 783w, 731s, 695s. H-NMR (300 MHz, CDCl3; assignments based on selective
homodecoupling experiments): see Table 8; additionally, 7.41 – 7.22 (m, 20 arom. H); 5.15 (d, J ¼ 11.4),
4.89 (d, J ¼ 11.4), 4.86 (d, J ¼ 11.4), 4.75 (d, J ¼ 11.7), 4.68 (d, J ¼ 11.4), 4.65 (d, J ¼ 11.4), 4.57 (d, J ¼
11.7), 4.50 (d, J ¼ 11.7) (4 PhCH2); 1.90 (s, MeS); 1.82 (s, AcO); 1.98 – 1.88 (m, 1 H), 1.66 – 1.48 (m, 1 H),
1.38 – 1.25 (m, 10 H) (Me(CH2)6); 0.87 (t, J ¼ 6.0, Me(CH2)6). 13C-NMR (75 MHz, CDCl3; assignments
based on a HSQC spectrum): see Table 8; additionally, 170.35 (s, C¼O); 138.83, 138.75, 138.07, 137.93
(4s); 128.29 – 126.83 (several d); 74.48, 74.34, 72.86, 70.68 (4t, 4 PhCH2); 31.90, 30.02, 29.65, 29.26, 26.64,
22.75 (6t, Me(CH2)6); 21.14 (q, MeC¼O); 14.41 (q, Me(CH2)6); 9.72 (q, MeS). ESI-MS: 832.1 (100,
[M þ Na]þ). Anal. calc. for C47H59N3O7S (810.07): C 69.69, H 7.34, N 5.19; found: C 69.70, H 7.44, N 5.21.
Data of b-30a. Colourless oil. Rf (hexane/AcOEt 85 :15) 0.65. IR (ATR): 3031w, 2924w, 2856w,
2105m, 1739m, 1496w, 1454w, 1369w, 1345w, 1232s, 1092s, 1057s, 1027s, 961w, 924w, 732s, 696s. 1H-NMR
(300 MHz, CDCl3; assignments based on selective homodecoupling experiments): 7.45 – 7.24 (m, 20
arom. H); 5.56 (dd, J ¼ 10.5, 1.2, HꢁC(1)); 5.19 (d, J ¼ 11.1), 4.91 (d, J ¼ 11.7), 4.82 (br. s, 2 H), 4.80 (d,
J ¼ 12.6), 4.64 (d, J ¼ 11.4), 4.57 (d, J ¼ 11.4), 4.53 (d, J ¼ 11.7) (4 PhCH2); 4.31 (d, J ¼ 10.2, HꢁC(3));
4.12 (dd, J ¼ 10.5, 2.7, HꢁC(4)); 4.09 (dd, J ¼ 9.6, 2.1, HꢁC(7)); 4.05 (dd, J ¼ 2.4, 1.2, HꢁC(5)); 4.01
(qd, J ¼ 6.3, 1.8, HꢁC(8)); 3.39 (dd, J ¼ 9.9, 1.2, HꢁC(6)); 2.08 (s, MeS); 1.51 (s, AcO); 1.85 – 1.54 (m,
2 H), 1.32 – 1.20 (m, 10 H) (Me(CH2)6); 1.23 (d, J ¼ 6.3, Me); 0.88 (t, J ¼ 6.6, Me(CH2)6). 13C-NMR
(75 MHz, CDCl3; assignments based on a HSQC spectrum): 170.64 (s, C¼O); 138.79, 138.53, 138.17,
138.03 (4s); 128.75 – 127.38 (several d); 88.68 (s, C(2)); 79.89 (d, C(4)); 78.30 (d, C(3)); 76.69 (t, PhCH2);
75.54 (d, C(5)); 74.80 (t, PhCH2); 74.73 (d, C(8)); 73.39 (t, PhCH2); 72.66 (d, C(6)); 70.92 (d, C(1)); 70.78
(t, PhCH2); 63.23 (d, C(7)); 31.84, 30.36, 29.63, 29.33, 25.94, 22.72 (6t, Me(CH2)6); 20.87 (q, MeC¼O);
14.41 (q, Me(CH2)6); 9.90 (q, MeS). HR-ESI-MS: 832.3968 (100, [M þ Na]þ, C48H53N3NaO8Sþ; calc.
832.3966).
Methyl (1S)-1-O-Acetyl-7-azido-3,4,5,8-tetra-O-benzyl-7,9-dideoxy-1-C-heptyl-2-thio-d-erythro-a-d-
galacto-non-2-ulopyranoside (30b). According to GP 8, 90 mg (0.11 mmol) of 29b and FC of the crude
thioglycoside (hexane/AcOEt 95 :5 ! 4 :1) gave 30b (74 mg, 80%). Colourless oil. Rf (hexane/AcOEt
85 :15) 0.58. [a]D25 ¼þ 62.1 (c ¼ 1.0, CHCl3). IR (ATR): 3064w, 3031w, 2925w, 2856w, 2104s, 1743m,
1496w, 1454m, 1370m, 1347w, 1264w, 1228s, 1124m, 1090s, 1072s, 1045m, 1027s, 983w, 945w, 909w, 822w,

Helvetica Chimica Acta – Vol. 92 (2009)
257
785w, 732s, 696s. 1H-NMR (300 MHz, CDCl3; assignments based on selective homodecoupling
experiments): see Table 8; additionally, 7.43 – 7.23 (m, 20 arom. H); 5.12 (d, J ¼ 10.5, 2 H), 4.79 (d,
J ¼ 11.4), 4.72 (d, J ¼ 11.8), 4.66 (d, J ¼ 11.4), 4.59 (d, J ¼ 10.5), 4.56 (d, J ¼ 11.7), 4.52 (d, J ¼ 12.0)
(4 PhCH2); 2.22 – 2.02 (m, 1 H), 1.65 – 1.55 (m, 1 H), 1.28 – 1.15 (m, 10 H) (Me(CH2)6); 1.91 (s, MeS);
1.77 (s, AcO); 0.85 (t, J ¼ 6.9, Me(CH2)6). 13C-NMR (75 MHz, CDCl3; assignment based on a HSQC
spectrum): see Table 8; additionally, 170.61 (s, C¼O); 138.57, 138.48, 138.35, 137.85 (4s); 128.41 – 126.90
(several d); 74.86, 74.51, 72.45, 71.08 (4t, 4 PhCH2); 31.89, 30.02, 29.26, 29.20, 26.77, 22.74 (6t, Me(CH2)6);
20.91 (q, MeC¼O); 14.42 (q, Me(CH2)6); 9.19 (q, MeS). ESI-MS: 832.2 (100, [M þ Na]þ). Anal. calc. for
C47H59N3O7S (810.07): C 69.69, H 7.34, N 5.19; found: C 69.60, H 7.37, N 5.19.
Methyl 8-Azido-1,4,5,6,9-penta-O-benzyl-8,10-dideoxy-3-thio-d-ribo-b/a-l-gluco-dec-3-ulopyrano-
side (b-l-36/a-l-36a). According to GP 8, 140 mg of b-l-34a (0.16 mmol) gave a mixture of epimeric
acetates a-l-35/b-l-35a which could not be separated. A soln. of the crude acetates a-l-35/b-l-35a in
CH2Cl2/MeOH 1:1 (10 ml) was treated with MeONa (100 mg, 1.66 mmol), stirred for 48 h at 258, and
evaporated. A soln. of the residue in AcOEt was washed with H2O and brine, and dried (MgSO4), and
evaporated. FC (hexane/AcOEt 95 :5 ! 4 :1) gave a-l-36a (37 mg, 30%) and b-l-36a (47 mg, 37%).
Data of b-l-36a. Colourless oil. Rf (hexane/AcOEt 85 :15) 0.32. [a]2D5 ¼þ 48.7 (c ¼ 1.0, CHCl3). IR
(ATR): 3506w (br.), 3063w, 3030w, 2866w, 2105m, 1496w, 1453m, 1380w, 1345w, 1304w, 1271w, 1208w,
1088s, 1072s, 1026m, 910w, 732s, 695s. 1H-NMR (300 MHz, CDCl3; assignments based on selective
homodecoupling experiments): see Table 8; additionally, 7.95 – 7.22 (m, 25 arom. H); 5.11 (d, J ¼ 11.1),
4.87 (d, J ¼ 10.8), 4.80 (d, J ¼ 10.8), 4.77 (d, J ¼ 11.7), 4.70 (d, J ¼ 11.7), 4.65 (d, J ¼ 11.1), 4.57 (d, J ¼
11.7), 4.49 (d, J ¼ 11.7, 2 H), 4.43 (d, J ¼ 11.7) (5 PhCH2); 3.03 (d, J ¼ 4.5, OH); 1.86 (s, MeS). 13C-NMR
(75 MHz, CDCl3; assignments based on a HSQC spectrum): see Table 8; additionally, 138.61, 138.13,
137.97 (2 C), 137.90 (4s); 128.39 – 127.40 (several d); 75.03, 74.72, 73.68, 72.66, 70.74 (5t, 5 PhCH2); 9.42
(q, MeS). HR-ESI-MS: 828.3305 (33, [M þ K]þ, C46H51KN3O7Sþ; calc. 828.3079), 812.3340 (100, [M þ
Na]þ, C46H51N3NaO7Sþ; calc. 812.3340). Anal. calc. for C46H51N3O7S (789.99): C 69.94, H 6.51, N 5.32;
found: C 69.84, H 6.46, N 5.26.
Data of a-l-36a. Colourless oil. Rf (hexane/AcOEt 85 :15) 0.33. IR (ATR): 3467w (br.), 3063w,
3030w, 2923w, 2869w, 2106m, 1496w, 1453m, 1381w, 1345w, 1273w, 1209w, 1088s, 1066s, 1027m, 960w,
911w, 733s, 696s. 1H-NMR (400 MHz, CDCl3; assignments based on selective homodecoupling
experiments): 7.42 – 7.24 (m, 25 arom. H); 5.04 (d, J ¼ 11.1), 4.81 (d, J ¼ 10.0, 2 H), 4.70 (d, J ¼ 11.9,
2 H), 4.56 (d, J ¼ 11.2), 4.47 (d, J ¼ 11.9), 4.43 (d, J ¼ 11.9), 4.39 (d, J ¼ 11.9), 4.31 (d, J ¼ 11.8) (5
PhCH2); 4.32 – 4.29 (m, HꢁC(2) overlapping with PhCH); 4.26 (d, J ¼ 10.1, HꢁC(4)); 3.99 – 3.97 (m,
HꢁC(6), OH); 3.93 (dd, J ¼ 9.6, 2.2, HꢁC(8)); 3.84 (dd, J ¼ 10.8, 2.4, HꢁC(5)); 3.82 (qd, J ¼ 6.3, 2.2,
HꢁC(9)); 3.65 (dt, J ¼ 10.4, 1.9, HaꢁC(1)); 3.54 (dd, J ¼ 10.4, 7.5, HbꢁC(1)); 3.67 (dd, J ¼ 9.6, 1.0,
HꢁC(7)); 1.91 (s, MeS); 1.02 (d, J ¼ 6.3, Me). 13C-NMR (100 MHz, CDCl3; assignments based on a
HSQC spectrum): 138.68, 138.23, 138.10, 137.80, 137.16 (5s); 128.63 – 127.45 (several d); 88.12 (s, C(3));
80.69 (d, C(5)); 79.25 (d, C(4)); 77.14, 74.81 (2t, 2 PhCH2); 74.76 (d, C(9)); 74.60 (d, C(6)); 73.54 (t,
PhCH2); 73.40 (d, C(2)); 73.10 (d, C(7)); 72.90 (t, PhCH2); 72.03 (t, C(1)); 70.77 (t, PhCH2); 63.25 (d,
C(8)); 13.73 (q, Me); 9.35 (q, MeS). HR-ESI-MS: 812.3341 (100, [M þ Na]þ, C46H51NaN3O7Sþ; calc.
812.3340).
Methyl 2-O-Acetyl-8-azido-1,4,5,6,9-penta-O-benzyl-8,10-dideoxy-3-thio-d-ribo-b-l-manno-dec-3-
ulopyranoside (35b). According to GP 8, 127 mg (0.15 mmol) of 34b and FC the crude thioglycoside
(hexane/AcOEt 95 :5 ! 4 :1) gave 35b (80 mg, 65%). Colouress oil. Rf (hexane/AcOEt 85 :15) 0.42.
[a]2D5 ¼þ 59.3 (c ¼ 1.09, CHCl3). IR (ATR): 3063w, 3030w, 2927w, 2864w, 2104m, 1747m, 1496w, 1453m,
1369m, 1346w, 1300w, 1270w, 1225m, 1124m, 1073s, 1042m, 1026m, 985m, 947m, 905w, 731s, 695s.
1H-NMR (300 MHz, CDCl3; assignments based on selective homodecoupling experiments): see Table 8;
additionally, 7.41 – 7.16 (m, 25 arom. H); 5.12 (d, J ¼ 10.8), 4.78 (d, J ¼ 11.4), 4.64 (d, J ¼ 11.7), 4.60 (d,
J ¼ 11.4), 4.57 (d, J ¼ 11.4), 4.56 (d, J ¼ 11.3), 4.52 (d, J ¼ 11.7), 4.51 (d, J ¼ 11.7), 4.43 (d, J ¼ 11.7),
4.34 (d, J ¼ 12.3) (5 PhCH2); 1.93 (s, MeS); 1.86 (s, MeC¼O). 13C-NMR (75 MHz, CDCl3; assignments
based on a HSQC spectrum): see Table 8; additionally, 170.10 (s, C¼O); 138.57, 138.39, 138.16, 137.96,
137.71 (5s); 128.41 – 126.74 (several d); 74.73, 74.48, 72.50, 72.21, 70.98 (5t, 5 PhCH2); 20.73 (q, MeC¼O);
9.00 (q, MeS). HR-ESI-MS: 870.3435 (33, [M þ K]þ, C48H53KN3O8Sþ; calc. 870.3185), 854.3444 (100,

258
Helvetica Chimica Acta – Vol. 92 (2009)
[M þ Na]þ, C48H53N3NaO8Sþ; calc. 854.3446). Anal. calc. for C48H53N3O8S (832.03): C 69.29, H 6.42, N
5.05; found: C 69.38, H 6.43, N 4.95.
Methyl 9-Azido-5,6,7,10-tetra-O-benzyl-2,3,9,11-tetradeoxy-4-thio-d-erythro-a-d-galacto-undec-4-
ulopyranosidonitrile (42). According to GP 8, 110 mg (0.15 mmol) of 41 and FC the crude thioglycoside
(hexane/AcOEt 95 :5 ! 4 :1) gave 42 (90 mg, 80%). Colourless oil. Rf (hexane/AcOEt 85 :15) 0.35.
[a]2D5 ¼þ 17.7 (c ¼ 1.0, CHCl3). IR (ATR): 3063w, 3030w, 2926w, 2105s, 1496w, 1453m, 1380w, 1346m,
1304w, 1267w, 1209w, 1128m, 1085s, 1026s, 951m, 910m, 733s, 696s. 1H-NMR (300 MHz, CDCl3;
assignments based on selective homodecoupling experiments): see Table 8; additionally, 7.46 – 7.24 (m, 20
arom. H); 5.08 (d, J ¼ 11.1), 4.95 (d, J ¼ 11.7), 4.83 (d, J ¼ 11.4), 4.79 (d, J ¼ 12.3), 4.75 (d, J ¼ 11.7),
4.67 (d, J ¼ 11.1), 4.59 (d, J ¼ 11.7), 4.52 (d, J ¼ 12.0) (4 PhCH2); 2.09 – 2.00 (m, 2 H); 1.99 – 1.92 (m,
1 H); 1.84 (s, MeS); 1.52 – 1.41 (m, 1 H). 13C-NMR (75 MHz, CDCl3; assignments based on a HSQC
spectrum): see Table 8; additionally, 138.50, 138.05, 137.78, 137.16 (4s); 129.04 – 127.46 (several d); 119.74
(s, CN); 74.55, 73.57, 72.37, 70.68 (4t, 4 PhCH2); 9.31 (q, MeS). ESI-MS: 715.0 (100, [M þ Na]þ). Anal.
calc. for C37H41N3O5S (692.88): C 69.34, H 6.40, N 8.09; found: C 69.29, H 6.43, N 7.98.
General Procedure for the Reduction of the Azides and Coupling with Propylhygric Acid (GP 9). A
1m soln. of the azido compound in THF/0.1n NaOH 4 :1 was treated with 1m PMe3 in THF (1.5 equiv.),
stirred for 6 h at 508, and evaporated. A soln. of the residue in CH2Cl2 was washed with H2O and brine.
The org. layer was dried (MgSO4) and evaporated to afford the corresponding amine.
A 2m suspension of PHA (2 equiv.) in CH2Cl2 was treated with Et3N (6 equiv.), followed by
ClCOOEt (2 equiv.), and stirred at 258 for 1 h. After addition of a 2m soln. of the crude amine in CH2Cl2,
the mixture was stirred for 1 h at 258 and evaporated.
Methyl 1-O-Acetyl-3,4,5,8-tetra-O-benzyl-7,9-dideoxy-7-[(2S,4R)-1-methyl-4-propylpyrrolidine-2-
carboxamido]-2-thio-d-erythro-a-d-galacto-non-2-ulopyranoside (26). According to GP 9, 120 mg
(0.16 mmol) of a-25 and FC of the crude amide (amino phase gel, hexane/AcOEt 4 :1 ! 1:1) gave 26
(100 mg, 70%). Colourless oil. Rf (amino phase TLC, hexane/AcOEt 3 :2) 0.50. [a]2D5 ¼þ 17.9 (c ¼ 1.0,
CHCl3). IR (ATR): 3030w, 2926w, 2870w, 2784w, 1742m, 1676m, 1497m, 1453m, 1375m, 1305w, 1223m,
1089s, 1027s, 949w, 909w, 732s, 696s. 1H-NMR (300 MHz, CDCl3; assignments based on selective
homodecoupling experiments): see Table 9; additionally, 7.77 (d, J ¼ 9.6, NH); 7.31 – 7.17 (m, 20 arom.
H); 4.84 (d, J ¼ 10.4), 4.80 (d, J ¼ 11.6), 4.63 (d, J ¼ 11.1) (3 PhCH); 4.61 (br. s, PhCH2), 4.43 (d, J ¼
11.6), 4.43 (d, J ¼ 10.4), 4.30 (d, J ¼ 11.2) (3 PhCH); 2.81 (dd, J ¼ 8.4, 6.0), 2.77 (dd, J ¼ 10.4, 5.2)
(2 H of prolinyl); 2.11 (s, MeN); 1.86 (s, MeS); 1.96 – 1.72 (m, 4 H); 1.71 (s, AcO); 1.28 – 1.20 (m,
MeCH2CH2); 0.89 (br. t, J ¼ 6.6, MeCH2CH2). 13C-NMR (75 MHz, CDCl3; assignments based on a
HSQC spectrum): see Table 9; additionally, 174.23 (s, NC¼O); 170.23 (s, OC¼O); 139.05, 138.33, 138.15,
137.93 (4s); 128.35 – 127.13 (several d); 75.07, 73.44, 72.53, 70.65 (4t, 4 PhCH2); 68.99 (d, C(2) of prolinyl);
62.62 (t, C(5) of prolinyl); 41.46 (q, MeN); 37.57 (d, C(4) of prolinyl); 37.46 (t, C(3) of prolinyl); 36.10 (t,
MeCH2CH2); 21.49 (t, MeCH2CH2); 20.43 (q, MeC¼O); 14.20 (q, MeCH2CH2); 9.28 (q, MeS). ESI-MS:
839.4 (100, [M þ Na]þ). Anal. calc. for C49H62N2O8S (839.10): C 70.14, H 7.45, N 3.34; found: C 70.43, H
7.62, N 3.39.
Methyl (1R)-1-O-Acetyl-3,4,5,8-tetra-O-benzyl-7,9-dideoxy-1-C-heptyl-7-[(2S,4R)-1-methyl-4-pro-
pylpyrrolidine-2-carboxamido]-2-thio-d-erythro-a-d-galacto-non-2-ulopyranoside (31a). According to
GP 9, 200 mg (0.25 mmol) of a-30a and FC of the crude amide (amino phase gel, hexane/AcOEt 4 :1 !
1:1) gave 31a (185 mg, 80%). Colourless oil. Rf (amino phase TLC, hexane/AcOEt 3 :2) 0.56. [a]D25
¼
þ 60.4 (c ¼ 1.0, CHCl3). IR (ATR): 3356w (br.), 3030w, 2958w, 2925m, 2856w, 2781w, 1739m, 1674m,
1
1497m, 1453m, 1369w, 1305m, 1233s, 1179w, 1087s, 1027s, 912w, 820w, 732s, 695s. H-NMR (300 MHz,
CDCl3; assignments based on selective homodecoupling experiments): see Table 9; additionally, 8.02 (d,
J ¼ 9.3, NH); 7.39 – 7.21 (m, 20 arom. H); 4.92 (d, J ¼ 11.4, PhCH); 4.83, 4.63 (2s, 2 PhCH2); 4.58 (d, J ¼
11.4), 4.50 (d, J ¼ 11.4), 4.32 (d, J ¼ 11.4) (3 PhCH); 2.82 (dd, J ¼ 10.8, 5.4), 2.81 – 2.75 (m) (2 H of
prolinyl); 2.13 (s, MeN); 2.04 – 1.52 (m, Me(CH2)5CH2); 1.90 (s, MeS); 1.89 (s, AcO); 1.38 – 1.18 (m,
MeCH2CH2, Me(CH2)5CH2); 0.92 – 0.85 (m, Me(CH2)6, MeCH2CH2). 13C-NMR (75 MHz, CDCl3;
assignments based on a HSQC spectrum): see Table 9; additionally, 174.10 (s, NC¼O); 170.33 (s,
OC¼O); 138.99, 138.73, 138.13 (2 C) (3s); 128.30 – 126.95 (several d); 74.46, 73.21, 72.96, 70.86 (4t,
4 PhCH2); 69.13 (d, C(2) of prolinyl); 62.71 (t, C(5) of prolinyl); 41.53 (q, MeN); 37.59 (d and t, C(3) and
C(4) of prolinyl); 36.56 (t, MeCH2CH2); 31.92, 29.77, 29.67, 29.46, 26.60, 22.78 (6t, Me(CH2)6); 21.74 (t,

Helvetica Chimica Acta – Vol. 92 (2009)
259
Table 9. Selected 1H-NMR Chemical Shifts [ppm] and Coupling Constants [Hz], and 13C-NMR Chemical
Shifts [ppm] of the Protected Lincomycin Analogues 26, 31a, 31b, 37a, 37b, 43, and 46 in CDCl3
(numbering as for lincosamine)a)
26b)
31ab)
31b
4.36
4.00
3.94
3.90
4.64 – 4.58
3.82
1.22
37ab)
37bc)
43b)
46b)
HꢁC(2)
HꢁC(3)
HꢁC(4)
HꢁC(5)
HꢁC(6)
HꢁC(7)
H3C(8)
HaꢁC(1’)
HbꢁC(1’)
HaꢁC(2’)
HbꢁC(2’)
NH
J(2,3)
J(3,4)
J(5,6)
J(6,7)
J(7,Me)
J(6,NH)
J(1’,2’a)
J(1’,2’b)
J(1’a,1’b)
C(1)
4.29
3.93
3.91
3.97
4.42 – 4.40
3.60
1.14
4.36
4.05
–
–
7.77
8.8
2.4
6.8
4.26
3.99
4.07
4.08
4.42
3.67
1.27
5.15
–
4.50
3.99
3.96
4.07
4.42
3.45
1.20
3.92 – 3.96
–
3.87
3.63
7.97
9.3
2.1
6.3
6.3
6.3
9.9
2.4
6.9
4.36
3.90
3.84
3.87
4.57 – 4.53
3.72
1.14
5.46
–
4.06
3.44
7.67
9.6
2.4
8.4
3.2
6.4
10.0
2.8
8.8
3.92
4.04
3.99
4.06
4.36
3.52
1.21
4.05 – 3.98
4.05 – 3.98
4.05 – 3.98
4.10
4.37
3.53
1.22
d
d
5.19
–
)
)
)
)
)
)
)
)
d
d
d
d
d
d
d
)
)
)
)
d
d
d
8.02
9.3
2.1
6.0
6.3
6.3
9.3
1.5f)
10.2f)
–
7.77
9.3
2.1
8.4
3.3
6.3
9.9
1.5f)
8.1f)
–
7.99
9.9
2.4
6.3
6.0
6.3
9.6
8.07
e
)
)
e
6.0
5.7
6.0
9.6
4.4
6.4
9.6
–
e
e
)
)
)
)
)
)
e
e
e
–
e
11.6
89.46
74.40
81.88
74.91
70.89
51.67
75.37
16.01
65.07
–
9.9g)
91.96
77.23
82.31
74.11
70.64
52.56
74.91
16.13
74.11
70.64
11.6g)
91.36
75.43
82.81
74.03
71.12
50.52
75.57
15.90
75.11
70.90
92.29
76.47
82.78
74.46
69.99
53.05
75.44
16.46
74.26
92.67
76.35
83.10
73.91
70.79
50.39
75.21
15.66
75.29
89.53
74.66
82.43
74.41
70.21
52.69
75.08
16.21
33.60
11.15
90.83
76.54
82.62
75.02
70.07
53.10
75.34
16.35
33.17
28.27
C(2)
C(3)
C(4)
C(5)
C(6)
C(7)
C(8)
C(1’)
d
d
C(2’)
)
)
c
a) J(4,5) < 1.5 Hz (line broadening). b) Assignments based on a HSQC spectrum. ) Assignments based
on DQFCOSY and HSQC spectra. d) See Exper. Part. e) Not assigned. f) Can be interchanged.
g) J(2’a,2’b).
MeCH2CH2); 21.14 (q, MeC¼O); 14.48 (q, MeCH2CH2); 14.24 (q, Me(CH2)6); 9.84 (q, MeS). ESI-MS:
937.4 (100, [M þ H]þ). Anal. calc. for C56H76N2O8S (937.29): C 71.76, H 8.17, N 2.99; found: C 71.67, H
8.11, N 2.98.
Methyl (1S)-1-O-Acetyl-3,4,5,8-tetra-O-benzyl-7,9-dideoxy-1-C-heptyl-7-[(2S,4R)-1-methyl-4-pro-
pylpyrrolidine-2-carboxamido]-2-thio-d-erythro-a-d-galacto-non-2-ulopyranoside (31b). According to
GP 9, 100 mg (0.12 mmol) of 30b and FC of the crude amide (amino phase gel, hexane/AcOEt 4 :1 !
1:1) gave 31b (82 mg, 70%). Colourless oil. Rf (amino phase TLC, hexane/AcOEt 3 :2) 0.56. [a]D25
¼
þ 23.8 (c ¼ 1.0, CHCl3). IR (ATR): 3346w (br.), 3030w, 2953w, 2924w, 2855w, 2785w, 1743m, 1681m,
1497m, 1453m, 1369w, 1304m, 1229m, 1122m, 1086s, 1027m, 946w, 910w, 822w, 787w, 731s, 695s. 1H-NMR
(300 MHz, CDCl3; assignments based on selective homodecoupling experiments): see Table 9; addi-
tionally, 7.77 (d, J ¼ 9.9, NH); 7.48 – 7.21 (m, 20 arom. H); 5.03 (d, J ¼ 11.7), 4.89 (d, J ꢃ 9.9), 4.72 (d, J ¼