Synthesis of 1,2,3-triazole analogues of lincomycin

Article abstract of DOI:10.1002/hlca.200890196

In search for new antibiotics we replaced the amide moiety of lincomycin 1 by a 1,2,3-triazole ring. The 1,2,3-triazoles 10a-10k were obtained as single regioisomers by 'click reaction' of azide 5 with the alkyne 9k, derived from propyl hygric acid, and the alkyl, aryl, or cycloalkyl alkynes ribosomes 9a-9j. The new analogues proved inactive towards wild-type and A2058G mutant.

Full text of DOI:10.1002/hlca.200890196

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Helvetica Chimica Acta – Vol. 91 (2008)
Synthesis of 1,2,3-Triazole Analogues of Lincomycin
by Marie-Pierre Collina), Sven N.Hobbie b), Erik C.Bçttger b), and Andrea Vasella*a)
a) Laboratorium für Organische Chemie, Department Chemie und Angewandte Biowissenschaften,
ETH-Zürich, HCI Hçnggerberg, Wolfgang-Pauli-Strasse 10, CH-8093 Zürich
b) Institut für Medizinische Mikrobiologie, Universität Zürich, Gloriastrasse 30/32, CH-8006 Zürich
In search for new antibiotics we replaced the amide moiety of lincomycin 1 by a 1,2,3-triazole ring.
The 1,2,3-triazoles 10a – 10k were obtained as single regioisomers by ꢀclick reactionꢁ of azide 5 with the
alkyne 9k, derived from propyl hygric acid, and the alkyl, aryl, or cycloalkyl alkynes ribosomes 9a – 9j.
The new analogues proved inactive towards wild-type and A2058G mutant.
Introduction. – Lincomycin (1; Scheme 1), isolated from Streptomyces lincolnensis,
is a broad-spectrum antibiotic active against most Gram-positive bacteria [1][2]. It is an
amide derived from methyl 6-amino-6,8-dideoxy-1-thio-d-erythro-a-d-galacto-octopyr-
anoside (lincosaminide (MLT); 2) and trans-N-methyl-4-propyl-l-proline (propylhyg-
ric acid (PHA); 4) [3][4]. Lincomycin (1) is used therapeutically for the treatment of
mixed anaerobic and aerobic infections, and as alternative in the treatment of patients
allergic to penicillin [5]. It inhibits peptide bond-formation by binding to 23S rRNA of
the bacterial ribosome, and thereby affects the peptide chain initiation at the 50S
subunit exit tunnel [2][6].
The known analogues of lincomycin can be categorized into three groups, according
to whether the glycosyl [7][8], the prolinyl [9], or the amide moiety [10][11] is
modified. Two analogues possessing a modified amide group are known, viz., the
thioamide that is four times less active than lincomycin [11], and deoxolincomycin that
is two times less active than lincomycin [10]. These results evidence that the C¼O
group is necessary for high activity [12], and suggest synthesizing additional lincomycin
analogues with a modified amide group.
1,2,3-Triazoles, readily prepared by cycloaddition [13 – 15], are known peptide
analogues [13][16][17] resistant to hydrolytic cleavage and oxidative transformations
that may affect esters, thioesters, and thioamides [12][18]. 1,2,3-Triazoles may act as H-
bond acceptors only, or also as H-bond donors, depending on their substitution. In 1,4-
disubstituted 1,2,3-triazoles, N(2) and N(3) act as H-bond acceptors. The strong dipole
moment of triazole polarizes HÀC(5) to a degree that it may function as a weak H-
bond donor [13][14][16][17][19]. The crystal structures of amprenavir, an HIV-1
protease inhibitor (Ki ¼ 0.6 nm), and of two biologically active 1,2,3-triazole analogues
(Ki ¼ 1.7 and 4 nm) in complex with the HIV-1 protease establish a near overlap of the
amide moiety of amprenavir with the 1,4-disubstituted triazole ring of its analogues,
demonstrating that the 1,2,3-triazole ring may act as bioisoster of the amide moiety
[17][20]. The trans configuration of the amide group of clindamycin is evidenced by the
ꢂ 2008 Verlag Helvetica Chimica Acta AG, Zürich

Helvetica Chimica Acta – Vol. 91 (2008)
1839
crystal structure of clindamycin (¼(7S)-7-chloro-7-deoxylincomycin [8][21]) in com-
plex with the 50S ribosomal subunit of the eubacterium Deinococcus radiodurans [22].
The distance of 3.42 Š between the C¼O group and OÀC(2’) of G25051) indicates a
weak H-bond.
To probe the interaction of the triazole analogue of clindamycin, we docked it into
the above-mentioned 50S ribosomal subunit2). This resulted in two conformations, A
and B, in favour of A (DE ca. 22 kcal/mol). In A, the amide and the triazole moieties of
clindamycin and its analogue occupy the same position, with OÀC(2’) of G2505 at a
distance of 3.1 and 2.8 Š, respectively, from N(2) and N(3) of the triazole ring,
suggesting a rather strong H-bond [23]. In conformation B, the triazole ring is rotated
by 1808 relative to its position in conformation A. The comparison of A and B with
clindamycin shows no difference in the orientation of the proline moiety. According to
conformation A, but not B, the triazolyl analogue may possess antibiotic properties.
In most of the proline-modified lincomycin derivatives that show antibacterial
activity, the ring size of the proline moiety was modified, the N-Me group was replaced
by other alkyl or by carbamoyl groups, and/or the propyl chain was replaced by other
alkyl groups, maintaining or changing the configuration and/or location on the ring
[9][24]. The convenience of the ꢀclick reactionꢁ [13 – 15] suggested examining the
structure – activity relation of a series of triazole analogues where the proline ring is
replaced by alkyl or aryl groups. We planned to synthesize and test a small library of
1,2,3-triazole analogues of lincomycin, substituting the proline ring by acyclic
substitutents, cycloalkyl groups, or by an aromatic ring.
Results and Discussion. – The known hydrazinolytic cleavage of lincomycin (1)
provided lincosaminide (2) and the hydrazide 3 that was hydrolyzed to PHA (4;
Scheme 1) [4]. The amino group of lincosaminide (2) was transformed into the azide 5
by diazo transfer in the presence of ZnCl2 and NEt3 in H2O/MeOH/CH2Cl2 1:3 :1 to
yield 5 (75% from 1) [25].
Scheme 1
a) H2NNH2 · H2O, reflux. b) 6n HCl, reflux. c) TfN3, ZnCl2, Et3N, CH2Cl2/MeOH/H2O; 75%. Tf ¼
Trifluoromethylsulfonyl.
1
)
All rRNA residues in this article are numbered according to their homologous position in
Escherichia coli 16S rRNA.
Molecular modeling was performed using the Moloc programme. We thank Paul Gerber, Gerber
Molecular Design, for access to the programme.
2
)

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Helvetica Chimica Acta – Vol. 91 (2008)
Crystals of 5 were obtained by slow evaporation of a solution in MeOH, and their
structure was established by X-ray analysis3). As expected, the pyranose ring adopts
the 4C1 conformation (Fig. 1) that is also preferred in CD3OD solution, as evidenced by
the coupling constants compiled in Table 2 (see Exper. Part). The conformation of the
side chain is discussed below.
Fig. 1. ORTEP Representation of the crystal structure of the azide 5
The alkyne 9k was prepared from PHA (4) via aldehyde 8 (Scheme 2). Treating 4
with SOCl2 in MeOH yielded 80% of the methyl ester 6 [26] that was reduced to the
alcohol 7 (LiAlH4 in Et2O; > 98%) and oxidized to the aldehyde 8. The alkyne 9k was
obtained by treating crude 8 with a solution of Ph3P¼CBr2 in CH2Cl2 and then with
BuLi, followed by chromatography, to afford the alkyne 9k in 30% yield from 6 [27].
The reaction of azide 5 with the acetylenes 9a – 9k (Scheme 2) in the presence of
CuSO4 · 5 H2O and ascorbic acid in a 1:1 mixture of H2O and i-PrOH [13 – 15] afforded
the expected 1,4-disubstituted triazoles 10a – 10k. It was not necessary to protect the
OH groups of 5. The triazoles were obtained as single regioisomers in moderate-to-
good yields.
The chemical shifts for C(4) and C(5) of the 1,2,3-triazolyl unit of 10a – 10k (142.8 –
155.2 and 124.7 – 129.6 ppm) confirm the formation of 1,4-disubstituted 1,2,3-tria-
zoles4). As expected, the 4C1 conformation of the pyranose ring is also preferred for the
triazole analogues 10a – 10k in CD3OD (see Table 2 in the Exper. Part).
The conformation of the side chain of crystalline 5 is characterized by the trans-
arrangement between C(6)ÀN3 and C(5)ÀO, and a gauche arrangement between the
N3 group and C(4) (tg conformation about C(5)ÀC(6)). C(7)ÀO is gauche to the N3
group and trans to C(5) (gt conformation about C(6)ÀC(7)). The (5,6)tg/(6,7)gt
conformation is also adopted by 5 in CD3OD solution, as evidenced by J(5,6) of 10.2
and J(6,7) of 2.7 Hz. A similar conformation is adopted by lincomycin hydrochloride in
the solid state (Fig. 2 [29]), by lincomycin in a buffered aqueous solution (pH 7.6)
3
)
The crystallographic data have been deposited with the Cambridge Cryistallographic Data Centre as
deposition No. CCDC-688469. Copies of the data can be obtained free of charge via http://
www.ccdc.cam.ac.uk/data_request/cif (or from the Cambridge Christallographic Data Centre, 12
Union Road, Cambridge CB21EZ (fax: þ 44(1223)336033; e-mail: deposit@ccdc.cam.ac.uk).
Typical C(4) and C(5) chemical shifts for 1,4-disubstituted 1,2,3-triazoles are 143 – 148 and 117 –
126 ppm, differing from the C(4) and C(5) chemical shifts of 1,5-disubstituted 1,2,3-triazoles (131
and 139 ppm) [28].
4
)

Helvetica Chimica Acta – Vol. 91 (2008)
1841
Scheme 2
a) SOCl2, MeOH, 08; 80%. b) LiAlH4, Et2O; quant. c) C2O2Cl2, DMSO, NEt3, CH2Cl2, À 788; quant. d)
1. CBr4, Ph3P, CH2Cl2, 08; quant.; 2. BuLi, THF, À 788; 30% from 6. e) CuSO4, ascorbic acid, i-PrOH,
H2O; 66% of 10a, 47% of 10b, 43% of 10c, 70% of 10d, 55% of 10e, 94% of 10f, 75% of 10g, 74% of 10h,
88% of 10i, 90% of 10j, 60% of 10k.
[30][31] and in complex with the ribosome [22], and by peracetylated lincomycin in
CDCl3 [32]. As expected, H-bonding in aqueous solution does not play a decisive role
for the conformation. However, both lincomycin and its hydrochloride in CD3OD
solution are characterized by J(5,6) of 6.8 Hz and J(6,7) of 6.4 Hz, evidencing a ca. 1:1
equilibrium of the (5,6)tg/(6,7)gt and the (5,6)gg/(6,7)tg conformers (Fig. 2). The
population of the (5,6)gg/(6,7)tg conformation in CD3OD solution suggests a partially
persistant C(7)NÀH ··· OÀC(4) H-bond that is completely cleaved in aqueous
1
solution. The H-NMR spectra of the triazoles 10a – 10k in CD3OD solution show a
Fig. 2. Conformations of lincomycin in the solid state (a) and in CD3OD solution (a and b)

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Helvetica Chimica Acta – Vol. 91 (2008)
large J(5,6) and a small J(6,7) value (see Table 2 in the Exper. Part), evidencing a
(5,6)tg/(6,7)gt conformation of the side chain similar to the one of the azide 5 and of the
lincomycin hydrochloride in the solid state.
Biological Studies. – The antibacterial activity of the triazoles 10a – 10k was
assessed by determining 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 [33].
Growth of wild-type M. smegmatis cells was completely inhibited at lincomycin
concentrations as little as 4 – 8 mg/ml, while M. smegmatis cells with a drug-resistance
adenine to guanine mutation at 23S rRNA position 2058 [34 – 36] were highly resistant
to lincomycin (Table 1). As compared to lincomycin, all 1,2,3-triazole analogues proved
inactive against the wild-type and A2058G mutant M. smegmatis cells.
Table 1. Ribosomal Drug Susceptibilitya)
Wild type
2058A ! G
Lincomycin
10a – 10d, 10f, 10h – 10j
10e
10g
10k
4 – 8
> 512
128 – 256
64 – 128
> 256
1024
> 512
512
64 – 128
> 256
a) As minimal inhibitory concentrations (MIC [mg/ml])
We thank Dr. B. Bernet for checking the analytical data, and Dr. P. Seiler for determining the crystal
structure.
Experimental Part
General. Solvents were distilled: Et2O from Na/benzophenone, and 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 ꢀmostainꢁ (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; concentration c in g/100 ml. FT-IR Spectra: neat (ATR), absorption in cmÀ1. 1H-
and 13C-NMR spectra: chemical shift d in ppm rel. to SiMe4 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-
hydroxypropanal matrix.
Methyl 6-Azido-6,8-dideoxy-1-thio-d-erythro-a-d-galacto-octopyranoside (5). A vigorously stirred
suspension of NaN3 (5 g, 400 mmol) in CH2Cl2 (75 ml) was treated dropwise with Tf2O (13.2 ml,
80 mmol). 18-Crown-6 (53 mg, 0.2 mmol) was added, and the mixture was stirred at 258 for 24 h. It was
treated carefully with H2O until complete dissolution of NaN3. The aq. phase was extracted with CH2Cl2
(2 Â 60 ml). The combined org. layers were washed with NaHCO3 soln. The resulting soln. of TfN3 in
CH2Cl2 (200 ml) was used for azidation without further purification; a 50% conversion to TfN3 was
assumed. A soln. of crude lincosaminide (2; 5 g, 20 mmol), obtained from commercial lincomycin
according to a standard procedure [4], and ZnCl2 (28 mg, 0.2 mmol) in H2O (200 ml) was treated with
Et3N (8.4 ml, 60 mmol) and slowly with MeOH (600 ml). A CH2Cl2 soln. of TfN3 (200 ml, ca. 40 mmol)
was radiply added to the above vigorously stirred soln. The mixture was kept at 258 for 24 h, and

Helvetica Chimica Acta – Vol. 91 (2008)
1843
evaporated. Crystallisation from MeOH/CH2Cl2 gave 5 (4.1 g, 75% from lincomycin). Colourless
crystals. Rf (AcOEt/MeOH 9 :1) 0.77. M.p. 195 – 1968. [a]2D5 ¼ þ255.6 (c ¼ 0.96, MeOH). IR (ATR):
3217w (br.), 2977w, 2923w, 2881w, 2117s, 1451m, 1392w, 1347w, 1318w, 1295m, 1260m, 1240m, 1147w,
1123m, 1102m, 1078m, 1038s, 988m, 952w, 918w, 900w, 866m, 830w, 802m, 738m, 703m, 668m, 613s.
1H-NMR (300 MHz, CD3OD): see Table 2; additionally, 2.07 (s, MeS). 13C-NMR (75 MHz, CD3OD):
see Table 2; additionally, 13.80 (q, MeS). HR-ESI-MS: 302.0779 (100, [M þ H]þ, C9H18N3O5Sþ; calc.
302.0781). Anal. calc. for C9H17N3O5S (279.32): C 38.70, H 6.13, N 15.04; found: C 38.55, H 6.03, N 14.83.
Table 2. Selected 1H-NMR Chemical Shifts [ppm] and Coupling Constants [Hz], and 13C-NMR Chemical Shifts
[ppm] of the Azide 5 and of the Triazoles 10a – 10k in CD3OD
5
10a
5.34
4.12
3.53
3.36
4.93
10b
5.32
10c
5.32
10d
5.31
4.10
3.51
3.34
4.88
10e
5.34
4.10
3.50
3.27
4.90
10f
5.32
10g
5.32
10h
5.34
4.12
3.53
3.36
4.93
10i
5.32
4.11
3.50
3.27
4.86
10j
5.32
10k
5.33
4.11
3.50
3.21
4.86
HÀC(1)
HÀC(2)
HÀC(3)
HÀC(4)
HÀC(5)
5.21
4.08
3.49
3.96
3.80
4.10
3.49
3.24
4.88 –
4.84
4.97
4.36
1.13
5.7
4.10
3.49
3.24
4.90 –
4.84
4.99
4.37
1.12
6.0
4.11
3.51
3.28
4.91 –
4.82
4.94
4.38
1.15
5.7
4.10
3.50
3.26
4.89 –
4.84
4.94
4.36
1.15
5.7
4.10
3.50
3.26
4.88 –
4.84
4.98
4.37
1.12
6.0
HÀC(6)
HÀC(7)
Me(8)
J(1,2)
J(2,3)
J(3,4)
J(4,5)
J(5,6)
J(6,7)
J(7,8)
C(1)
C(2)
C(3)
C(4)
C(5)
C(6)
C(7)
C(8)
3.98
4.15
5.05
4.42
1.15 1.18
4.95
4.37
1.13
6.0
5.01
4.37
1.13
5.7
10.5
3.3
0.9
5.04
4.41
1.18
6.0
10.2
3.3
1.2
4.95
4.37
1.10
5.7
10.2
3.3
0.6
4.98
4.38
1.13
5.4
5.7
5.7
10.2
3.3
10.5
2.7
10.2
3.6
0.9
10.2
3.3
0.9
10.2
10.2
10.2
3.2
0.9
10.2
3.3
0.6
10.2
3.3
)
3.0
)
3.3
)
a
a
a
a
0.8
)
10.2
3.0
6.3
10.2
3.6
6.3
10.2
3.6
6.6
10.5
3.7
6.3
10.5
3.9
6.6
10.2
3.6
6.6
10.2
3.9
6.6
10.2
3.6
6.3
10.5
3.6
6.6
10.5
3.9
6.6
10.2
3.6
6.3
10.2
3.9
6.3
90.02 90.19 90.18
68.98 68.82 68.93
71.81 71.50 71.55
69.87 69.05 69.03
70.76 70.18 70.30
66.64 65.67 65.56
67.97 66.75 66.83
15.60 16.90 17.09
90.21
68.90
71.55
69.07
70.28
65.59
66.78
17.07
90.25 90.20 90.20
68.86 68.90 68.92
71.56 71.54 71.57
69.15 69.07 69.13
70.28 70.27 70.31
65.51 65.65 65.57
66.74 66.81 66.85
17.03 17.07 17.12
90.13
68.82
71.50
69.04
70.29
65.31
66.83
16.96
90.22 90.17 90.15
68.90 68.90 68.88
71.58 71.63 71.55
69.14 69.18 69.10
70.28 70.40 70.34
65.72 65.37 65.47
66.86 66.95 66.87
17.09 17.16 17.09
90.13
68.84
71.51
68.97
70.33
65.60
66.70
17.00
a) Not assigned.
X-Ray Analysis of 5. Crystals of 5 were obtained by slow evaporation of a soln. of 5 in MeOH
(dimensions of the analyzed crystal: cube 0.21 Â 0.19 Â 0.17 mm). C9H17N3O5S · MeOH, Mr 311.36,
monoclinic C2; a ¼ 32.416(7), b ¼ 7.9775(16), c ¼ 5.8808(12), a ¼ 90.000, b ¼ 93.190(3), g ¼ 90.008, V¼
1518.4(5) Š3, Dx ¼ 1.362 Mg/m3, Z ¼ 4. The reflections were measured on a Bruker Nonius-KappaCCD
diffractometer (graphite monochromator, MoKa radiation, l ¼ 0.71070) at 250 K. All the calculations
were performed using maXus (Bruker Nonius, Delft & MacScience, Japan). The structure was solved by
direct methods and refined by full-matrix least-squares analysis (SHELXL-97) including an isotropic
extinction correction. All non-H-atoms were refined anisotropically (H-atoms isotropic, whereby H-
positions are based on stereochemical considerations). R ¼ 0.0735, Rw ¼ 0.2006 for 194 parameters and
2762 reflections, q < 26.038.
Methyl (2S,4R)-1-Methyl-4-propylpyrrolidine-2-carboxylate (6). A soln. of 4 · HCl (1 g, 4.8 mmol) in
MeOH (10 ml) was treated dropwise at 08 with SOCl2 (1.76 ml, 24.1 mmol), warmed to 258, stirred for

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Helvetica Chimica Acta – Vol. 91 (2008)
18 h, and evaporated. A soln. of the residue in AcOEt was washed with a sat. NaHCO3 soln. The aq. layer
was extracted four times with AcOEt. The combined org. layers were dried (MgSO4) and evaporated to
afford 6 (700 mg, 80%), which was used for the next step without further purification. Colourless oil. Rf
(AcOEt) 0.77. [a]D25 ¼ À76.3 (c ¼ 0.98, CHCl3). IR (ATR): 2953m, 2924m, 2844w, 2773w, 1734s, 1454m,
1
1435m, 1358w, 1275m, 1194s, 1171s, 1138m, 1114m, 1037m, 1016m, 910w, 820w, 762w, 733w. H-NMR
(300 MHz, CDCl3): 3.64 (s, MeO); 3.14 (dd, J ¼ 9.0, 6.9, HaÀC(5)); 2.91 (dd, J ¼ 9.6, 6.6, HÀC(2)); 2.29
(s, MeN); 2.25 – 2.14 (m, HÀC(4)); 2.09 – 1.98 (m, HaÀC(3)); 1.87 (t, J ¼ 9.0, HbÀC(5)); 1.71 – 1.61 (m,
HbÀC(3)); 1.27 – 1.14 (m, Me(CH2)2); 0.83 – 0.78 (m, Me(CH2)2). 13C-NMR (300 MHz, CDCl3): 173.99
(s, C¼O); 67.15 (d, C(2)); 63.11 (t, C(5)); 51.86 (q, MeO); 41.29 (q, MeN)); 36.91 (d, C(4)); 36.72 (t,
C(3)); 36.39 (t, MeCH2CH2); 21.40 (t, MeCH2CH2); 14.17 (q, MeCH2CH2). EI-MS: 126.1278 (100, [M À
CO2Me]þ, C8H16Nþ; calc. 126.1283).
(2S,4R)-1-Methyl-4-propylpyrrolidine-2-methanol (7). A soln. of 6 (500 mg, 2.7 mmol) in Et2O
(10 ml) was treated at 08 with LiAlH4 (205 mg, 5.4 mmol), warmed to 258, stirred for 1 h, treated with ice
cubes, and stirred for 30 min. Filtration through a pad of Celite and evaporation of the filtrate gave crude
7 (420 mg, quant.), which was used for the next step without further purification. Colourless oil. Rf
(AcOEt) 0.77. [a]2D5 ¼ À11.1 (c ¼ 1.01, CHCl3). IR (ATR): 3395w (br.), 2954s, 2917s, 2870s, 2844s, 2781s,
1
1454s, 1378w, 1210w, 1186w, 1159m, 1086m, 998m, 977w, 920w, 771w, 741w, 661w. H-NMR (300 MHz,
CDCl3): 3.59 (dd, J ¼ 11.1, 3.6, CHaÀC(2)); 3.37 (dd, J ¼ 11.1, 2.7, CHbÀC(2)); 3.11 (dd, J ¼ 8.4, 6.0,
HaÀC(5)); 2.46 – 2.39 (m, HÀC(2)); 2.29 (s, MeN); 2.11 – 2.00 (m, HÀC(4)); 1.98 – 1.88 (m, HbÀC(5),
HaÀC(3)); 1.53 – 1.42 (m, HbÀC(3)); 1.31 – 1.24 (m, Me(CH2)2); 0.91 – 0.83 (m, Me(CH2)2). 13C-NMR
(300 MHz, CDCl3): 65.83 (d, C(2)); 64.12 (t, C(5)); 61.99 (t, CH2OH); 40.62 (q, MeN); 36.99 (d, C(4));
36.67 (t, MeCH2CH2); 34.64 (t, C(3)); 21.40 (t, MeCH2CH2); 14.15 (q, MeCH2CH2). HR-ESI-MS:
158.1540 (23, [M þ H]þ, C9H20NOþ; calc. 158.1539), 140.1434 (52, [M À OH]þ, C9H18Nþ; calc. 140.1434),
96.0807 (100, C6H10Nþ, [M À C3H7O]þ; calc. 96.0813).
(2S,4R)-1-Methyl-4-propylpyrrolidine-2-carbaldehyde (8). A soln. of C2O2Cl2 (215 ml, 2.54 mmol) in
CH2Cl2 (10 ml) at À 788 was treated dropwise with a soln. of DMSO (360 ml) in CH2Cl2 (2 ml), stirred for
30 min, treated dropwise with a soln. of 7 (200 mg, 1.27 mmol) in CH2Cl2 (1.5 ml), and stirred for 1 h. The
mixture was treated with Et3N (890 ml, 6.35 mmol), warmed to 08, stirred for 30 min, and diluted with sat.
NaHCO3 soln. The aq. layer was extracted twice with Et2O. The combined org. layers were dried
(MgSO4) and evaporated to afford 8 (200 mg, quant.), which was used for the next step without further
purification. Colourless oil. Rf (AcOEt/MeOH 9 :1) 0.77. IR (ATR): 2955m, 2924m, 2871m, 2846m,
2779m, 1729s, 1451m, 1379w, 1294w, 1264w, 1210w, 1160m, 1114w, 1086w, 1055w, 1024w, 915w, 807w, 761w,
1
741w. H-NMR (300 MHz, CDCl3): 9.47 (d, J ¼ 3.6, CHO); 3.20 (dd, J ¼ 8.4, 6.3, HaÀC(5)); 2.76 (ddd,
J ¼ 9.9, 6.6, 3.3, HÀC(2)); 2.36 (s, MeN); 2.28 – 2.14 (m, HÀC(4)); 2.04 (ddd, J ¼ 12.9, 9.0, 6.3,
HaÀC(3)); 1.98 (dd, J ¼ 9.6, 9.0, HbÀC(5)); 1.62 (ddd, J ¼ 12.9, 9.9, 7.5, HbÀC(3)); 1.35 – 1.22 (m,
Me(CH2)2); 0.92 – 0.85 (m, Me(CH2)2). 13C-NMR (75 MHz, CDCl3): 202.46 (d, CHO); 72.84 (d, C(2));
129.56 (t, C(5)); 41.40 (q, MeN); 37.83 (d, C(4)); 36.43 (t, MeCH2CH2); 32.20 (t, C(3)); 21.37 (t,
MeCH2CH2); 14.04 (q, CH2CH2Me). EI-MS: 126.1276 (100, [M À CHO]þ, C8H16Nþ; calc. 126.1283).
(2S,4R)-2-Ethynyl-1-methyl-4-propylpyrrolidine (9k). A stirred soln. of PPh3 (2.67 g, 10.18 mmol) in
CH2Cl2 (5 ml) was cooled to À 58 to À 108 and treated with a soln. of CBr4 (1.69 g, 5.09 mmol) in CH2Cl2
(2 ml). The resulting orange-brown suspension was stirred at À 108 for 15 min, and decanted at À 108 to
give a light brown soln. and a yellow precipitate. The soln. was added via a syringe to a vigorously stirred
and cooled (À108 to À 58) soln. of 8 (200 mg, 1.27 mmol) in CH2Cl2 (5 ml). The resulting brown soln.
was stirred at À 58 to À 108 for 40 min, and treated dropwise with Et3N (1.27 ml) and sat. aq. NaHCO3
soln. The mixture was passed through a short pad of silica gel, and the main product was collected.
A stirred soln. of the above crude product (dibromoethene) in THF (8 ml) was cooled to À 788, and
treated dropwise with 1.6m BuLi in hexane (2 ml, 2.54 mmol). The yellow soln. was stirred at À 768 for
1 h, warmed to 258, diluted with Et2O, and washed with sat. NaHCO3 soln. The combined org. layers were
dried and evaporated. FC (hexane/AcOEt 95 :5 to 3 :1) gave 9k (60 mg, 30% from 6). Orange oil. Rf
(hexane/AcOEt 9 :1) 0.77. IR (ATR): 3310w, 2956s, 2926s, 2872m, 2843m, 2772m, 2105w, 1643w, 1452m,
1378w, 1343w, 1259w, 1233w, 1189w, 1159w, 1138w, 1116w, 1079w, 1040w, 930w, 795w, 741w, 642s, 623s.
1H-NMR (300 MHz, CDCl3): 3.10 (ddd, J ¼ 8.0, 6.0, 2.1, HÀC(2)); 3.08 (dd, J ¼ 9.0, 7.8, HaÀC(5)); 2.36
(s, MeN); 2.34 – 2.20 (m, HÀC(4)); 2.25 (d, J ¼ 1.8, C ꢀ CH); 2.08 (ddd, J ¼ 12.6, 9.6, 6.3, HaÀC(3)); 1.97

Helvetica Chimica Acta – Vol. 91 (2008)
1845
(dd, J ¼ 9.3, 7.8, HbÀC(5)); 1.70 (ddd, J ¼ 12.4, 7.8, 6.6, HbÀC(3)); 1.35 – 1.17 (m, Me(CH2)2); 0.89 – 0.83
(m, Me(CH2)2). 13C-NMR (75 MHz, CDCl3)5): 83.61 (s, C ꢀ CH)); 71.65 (d, C ꢀ CH); 61.64 (d, C(2));
56.06 (t, C(5)); 40.02 (q, MeN); 39.17 (d, C(4)); 37.72 (t, CH2CH2Me); 36.20 (t, C(3)); 21.38 (t,
MeCH2CH2); 14.22 (q, MeCH2CH2). EI-MS: 152.1364 (27, [M þ H]þ, C10H18Nþ; calc. 152.1434),
150.1265 (67, [M À H]þ, C10H16Nþ; calc. 150.1283), 126.1271 (100, [M À C ꢀ CH]þ, C8H16Nþ; calc.
126.1283), 68.9949 (100, C4H6N, [C10H18N]þ; calc. 68.0500).
General Procedure for the Triazole Synthesis (GP). To a stirred soln. of 5 (50 mg, 0.17 mmol) in i-
PrOH/H2O 1:1 (1 ml) were added CuSO4 (0.05 equiv.),, ascorbic acid (0.2 equiv.), and the corresponding
alkyne (1.5 equiv.). The mixture was heated to 608 for 1 to 12 h, cooled to 258, and evaporated to give the
crude triazole.
Methyl 6,8-Dideoxy-6-(4-phenyl-1H-1,2,3-triazol-1-yl)-1-thio-d-erythro-a-d-galacto-octopyranoside
(10a). GP and FC (amino phase gel, AcOEt/MeOH 98 :2 to 4 :1) gave 10a (45 mg, 66%). White solid. Rf
(AcOEt/MeOH 9 :1) 0.14. M.p. 183 – 1858. [a]D25 ¼ þ199.3 (c ¼ 1.05, MeOH). IR (ATR): 3364w (br.),
2975w, 2922w, 1657w, 1609w, 1581w, 1483m, 1435w, 1381w, 1302w, 1219m, 1077m, 1050m, 983w, 910w,
865w, 801w, 770s, 714w, 694m, 664w, 631w. 1H-NMR (300 MHz, CD3OD): see Table 2; additionally, 8.29
(s, HÀC(5) of triazolyl); 7.85 – 7.80 (m, 2 arom. H); 7.46 – 7.40 (m, 2 arom. H); 7.36 – 7.30 (m, 1 arom. H);
2.19 (s, MeS). 13C-NMR (75 MHz, CD3OD): see Table 2; additionally, 147.26 (s, C(4) of triazolyl); 131.25
(s); 129.56 (d, C(5) of triazolyl); 128.89 (d, 2 C); 126.25 (d, 2 C); 124.76 (d); 13.66 (q, MeS). HR-
MALDI-MS: 382.1433 (100, [M þ H]þ, C17H24N3O5Sþ; calc. 382.1431).
Methyl 6-[4-(Aminomethyl)-1H-1,2,3-triazol-1-yl]-6,8-dideoxy-1-thio-d-erythro-a-d-galacto-octo-
pyranoside (10b). GP and FC (amino phase gel, AcOEt/MeOH 95 :5 to 0 :1) gave 10b (28 mg, 47%).
Colourless oil. Rf (AcOEt/MeOH 1:1) 0.33. [a]2D5 ¼ þ235.1 (c ¼ 0.83, MeOH). IR (ATR): 3348m (br.),
2979w, 2921w, 1651w, 1377w, 1338w, 1244w, 1076s, 1048s, 978s, 907w, 864w, 799m, 699w, 678w, 630w.
1H-NMR (300 MHz, CD3OD): see Table 2; additionally, 7.82 (s, HÀC(5) of triazolyl); 3.89 (s, NH2CH2);
2.07 (s, MeS). 13C-NMR (75 MHz, CD3OD): see Table 2; additionally, 147.94 (s, C(4) of triazolyl); 125.87
(d, C(5) of triazolyl); 37.21 (t, CH2NH2); 13.88 (q, MeS). HR-MALDI-MS: 357.1199 (25, [M þ Na]þ,
C12H22N4NaO5Sþ; calc. 357.1203), 335.1385 (100, [M þ H]þ, C12H23N4O5Sþ; calc. 335.1384).
Methyl 6,8-Dideoxy-{6-[4-(dimethylamino)methyl]-1H-1,2,3-triazol-1-yl}-1-thio-d-erythro-a-d-gal-
acto-octopyranoside (10c). GP and FC (amino phase gel, AcOEt/MeOH 98 :2 to 3 :1) gave 10c
(28 mg, 43%). Colourless oil. Rf (AcOEt/MeOH 4 :1) 0.22. [a]2D5 ¼ þ228.1 (c ¼ 1.07, MeOH). IR (ATR):
3353m (br.), 2889w, 1642w, 1458m, 1336m, 1303w, 1242m, 1174s, 1094s, 1078s, 1047s, 1029m, 1009m, 982s,
908w, 851w, 801m, 749s, 700m, 678m, 664m, 630w, 591w. 1H-NMR (300 MHz, CD3OD): see Table 2;
additionally, 7.87 (s, HÀC(5) of triazolyl); 3.66, 3.60 (2d, J ¼ 13.8, Me2NCH2); 2.27 (s, Me2N); 2.18 (s,
MeS). 13C-NMR (75 MHz, CD3OD): see Table 2; additionally, 142.87 (s, C(4) of triazolyl); 127.79 (d,
C(5) of triazolyl); 53.93 (t, Me2NCH2); 44.64 (q, Me2N); 13.84 (q, MeS). HR-MALDI-MS: 385.1517 (13,
[M þ Na]þ, C16H32N4NaO5Sþ; calc. 385.1516), 363.1700 (100, C16H33N4O5Sþ, [M þ H]þ; calc. 363.1697).
Methyl 6,8-Dideoxy-6-{4-[hydroxy(diphenyl)methyl]-1H-1,2,3-triazol-1-yl}-1-thio-d-erythro-a-d-
galacto-octopyranoside (10d). GP and FC (amino phase gel, AcOEt/MeOH 98 :2 to 3 :1) gave 10d
(60 mg, 70%). Colourless oil. Rf (AcOEt/MeOH 4 :1) 0.50. [a]2D5 ¼ þ109.5 (c ¼ 1.58, MeOH). IR (ATR):
3374m (br.), 3009w, 2922w, 1634w, 1491w, 1448w, 1297w, 1216w, 1076m, 1048m, 1011m, 982m, 892w, 801w,
750s, 699s, 665w, 638w. 1H-NMR (300 MHz, CD3OD): see Table 2; additionally, 7.62 (s, HÀC(5) of
triazolyl); 7.39 – 7.21 (m, 10 arom. H); 2.15 (s, MeS). 13C-NMR (75 MHz, CD3OD): see Table 2;
additionally 153.95 (s, C(4) of triazolyl); 147.10 (s, 2 C); 128.38 (d, 4 C); 128.05 (d, 4 C); 127.84 (d, 2 C);
127.02 (d, C(5) of triazolyl); 77.46 (s, Ph2C); 13.85 (q, MeS). HR-MALDI-MS: 526.1405 (28, [M þ K]þ,
C24H29KN3O6Sþ; calc. 526.1409), 510.1660 (38, [M þ Na]þ, C24H29N3NaO5Sþ; calc. 510.1669), 488.1849
(31, [M þ H]þ, C24H30N3O6Sþ; calc. 488.1850), 470.1738 (100, [M À OH]þ, C24H28N3O5Sþ; calc.
470.1744).
Methyl 6-{4-[(Benzyloxy)methyl]-1H-1,2,3-triazol-1-yl}-6,8-dideoxy-1-thio-d-erythro-a-d-galacto-
octopyranoside (10e). GP and FC (amino phase gel, AcOEt/MeOH 98 :2 to 4 :1) gave 10e (42 mg,
55%). Colourless oil. Rf (AcOEt/MeOH 9 :1) 0.14. [a]2D5 ¼ þ218.0 (c ¼ 0.64, CH3OH). IR (ATR): 3362w
1
5
)
Displays ꢀbizarreꢁ signals for the C ꢀ CH group in the DEPT spectrum due to large J(C,H) and
2J(C,H) couplings [37].

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Helvetica Chimica Acta – Vol. 91 (2008)
(br.), 2889w, 2765w, 1635w, 1495s, 1452m, 1370w, 1336w, 1299w, 1230m, 1075s, 1044s, 1028m, 981m, 907w,
863w, 800w, 747s, 698s, 664w. 1H-NMR (300 MHz, CD3OD): see Table 2; additionally, 7.94 (s, HÀC(5) of
triazolyl); 7.38 – 7.24 (m, 5 arom. H); 4.64 (s, BnOCH2); 4.58 (s, PhCH2O); 2.18 (s, MeS). 13C-NMR
(75 MHz, CD3OD): see Table 2; additionally, 144.23 (s, C(4) of triazolyl); 138.73 (s); 128.99 (d, 2 C);
128.68 (d, C(5) of triazolyl); 128.42 (d, 2 C); 127.56 (d); 73.15 (t, PhCH2O); 63.67 (t, PhCH2OCH2); 13.87
(q, MeS). HR-MALDI-MS: 464.1254 (27, [M þ K]þ, C19H27KN3O6Sþ; calc. 464.1252), 448.1512 (36,
[M þ Na]þ, C19H27N3NaO6Sþ; calc. 448.1513), 426.1686 (100, [M þ H]þ, C19H28N3O6Sþ; calc. 426.1693).
Methyl 6-(4-{[(Benzyl(methyl)amino]methyl}-1H-1,2,3-triazol-1-yl)-6,8-dideoxy-1-thio-d-erythro-
a-d-galacto-octopyranoside (10f). GP and FC (amino phase gel, AcOEt/MeOH 98 :2 to 3 :1) gave 10f
(74 mg, 94%). Colourless oil. Rf (AcOEt/MeOH 9 :1) 0.13. [a]2D5 ¼ þ192.2 (c ¼ 1.03, MeOH). IR (ATR):
3364w (br.), 2980w, 2922w, 2795w, 1638w, 1495w, 1453w, 1368w, 1333w, 1219m, 1074m, 1049m, 982w,
908w, 861w, 801w, 771s, 699w, 664w, 631w. 1H-NMR (300 MHz, CD3OD): see Table 2; additionally, 7.87
(s, HÀC(5) of triazolyl); 7.37 – 7.22 (m, 5 arom. H); 3.73, 3.70 (2d, J ꢁ 11.1, BnNCH2); 3.56 (s, PhCH2N);
2.21 (s, MeN); 2.07 (s, MeS). 13C-NMR (75 MHz, CD3OD): see Table 2; additionally, 143.47 (s, C(4) of
triazolyl); 138.59 (s); 130.17 (d, 2 C); 128.95 (d, C(5) of triazolyl); 128.01 (d, 2 C); 127.74 (d); 61.96 (t,
PhCH2N); 51.99 (t, PhCH2NCH2); 41.83 (q, MeN); 13.89 (q, MeS). HR-MALDI-MS: 439.2009 (100,
[M þ H]þ, C20H31N4O5Sþ; calc. 439.2010).
Methyl 6-(4-Decyl-1H-1,2,3-triazol-1-yl)-6,8-dideoxy-1-thio-d-erythro-a-d-galacto-octopyranoside
(10g). GP and FC (amino phase gel, AcOEt/MeOH 98 :2 to 4 :1) gave 10g (60 mg, 75%). White solid.
Rf (AcOEt/MeOH 9 :1) 0.15. M.p. 120 – 1228. [a]2D5 ¼ þ144.3 (c ¼ 1.2, MeOH). IR (ATR): 3344m (br.),
2923m, 2854m, 2493w, 1647w, 1556w, 1530w, 1455w, 1377w, 1324w, 1239w, 1240m, 1087m, 1048s, 1028w,
1007w, 983m, 908w, 874w, 794w, 754w, 698w, 647w. 1H-NMR (300 MHz, CD3OD): see Table 2;
additionally, 7.68 (s, HÀC(5) of triazolyl); 2.68 (t, J ¼ 7.5, Me(CH2)8CH2); 2.17 (s, MeS); 1.67 (quint., J ¼
7.5, Me(CH2)7CH2CH2); 1.40 – 1.22 (m, 14 H); 0.89 (t, J ¼ 6.9, Me(CH2)8CH2). 13C-NMR (75 MHz,
CD3OD): see Table 2; additionally, 147.62 (s, C(4) of triazolyl); 125.50 (d, C(5) of triazolyl); 32.64, 30.32,
30.27, 30.15, 30.07, 30.05, 29.91, 25.84, 23.31 (9t, Me(CH2)9); 14.04 (q, MeS); 13.64 (q, Me(CH2)9). HR-
MALDI-MS: 468.2507 (10, [M þ Na]þ, C21H39NaN3O5Sþ; calc. 468.2503), 446.2687 (100, [M þ H]þ,
C21H40N3O5Sþ; calc. 446.2683).
Methyl 6,8-Dideoxy-6-[4-(4-pentylphenyl)-1H-1,2,3-triazol-1-yl]-1-thio-d-erythro-a-d-galacto-octo-
pyranoside (10h). GP and FC (amino phase gel, AcOEt/MeOH 98 :2 to 4 :1) gave 10h (60 mg, 74%).
White solid. Rf (AcOEt/MeOH 9 :1) 0.14. M.p. 182 – 1858. [a]2D5 ¼ þ186.7 (c ¼ 1.08, MeOH). IR (ATR):
3423w, 3341w, 3281w, 3172w (br.), 2927w, 2853w, 1501w, 1467w, 1445w, 1421w, 1378w, 1338w, 1322w,
1292m, 1263w, 1233m, 1206w, 1186w, 1140m, 1125m, 1084s, 1049s, 1037s, 1028w, 1003w, 984s, 908w, 881w,
842m, 795s, 785s, 756w, 735w, 707w, 685w, 646w. 1H-NMR (300 MHz, CD3OD): see Table 2; additionally,
8.24 (s, HÀC(5) of triazolyl); 7.75 – 7.70 (br. d, J ¼ 8.1, 2 arom. H); 7.25 (br. d, J ¼ 8.4, 2 arom. H); 2.63 (t,
J ¼ 7.2, Me(CH2)3CH2); 2.19 (s, MeS); 1.64 (quint., J ¼ 7.5, Me(CH2)2CH2CH2); 1.40 – 1.28 (m,
Me(CH2)2CH2CH2); 0.90 (t, J ¼ 6.9, Me(CH2)3CH2). 13C-NMR (75 MHz, CD3OD): see Table 2;
additionally, 147.30 (s, C(4) of triazolyl); 143.93 (s); 129.55 (d, 2 C); 128.61 (d, C(5) of triazolyl);
126.21 (d, 2 C); 124.40 (d); 33.36, 32.33, 32.05, 23.33 (4t, Me(CH2)4); 14.16 (q, MeS); 13.87 (q,
Me(CH2)4). HR-MALDI-MS: 452.2218 (100, [M þ H]þ, C21H40N3O5Sþ; calc. 452.2214).
Methyl 6-[4-(Cyclopentylmethyl)-1H-1,2,3-triazol-1-yl]-6,8-dideoxy-1-thio-d-erythro-a-d-galacto-
octopyranoside (10i). GP and FC (amino phase gel, AcOEt/MeOH 98 :2 to 4 :1) gave 10i (61 mg,
88%). White solid. Rf (AcOEt/MeOH 9 :1) 0.14. M.p. 165 – 1678. [a]2D5 ¼ þ216.5 (c ¼ 1.45, MeOH). IR
(ATR): 3288w (br.), 2977w, 2966m, 2938m, 2923m, 2866m, 2844m, 1557w, 1454w, 1372w, 1359w, 1345w,
1322w, 1239w, 1220m, 1095m, 1050s, 1032s, 1006s, 952w, 908w, 876w, 854w, 791m, 772m, 685m, 648m,
1
597m, 579m, 536m, 522m. H-NMR (300 MHz, CD3OD): see Table 2; additionally, 7.70 (s, HÀC(5) of
triazolyl); 2.69 (d, J ¼ 7.5, CH2C¼CH); 2.18 (heptet, J ¼ 7.5, CH2CHCH2); 2.17 (s, MeS); 1.82 – 1.50 (m,
6 H); 1.30 – 1.17 (m, 2 H). 13C-NMR (75 MHz, CD3OD): see Table 2; additionally, 147.04 (s, C(4) of
triazolyl); 125.79 (d, C(5) of triazolyl); 41.11 (d, C(1) of cyclopentyl); 33.13 (t, C(2) and C(5) of
cyclopentyl); 32.00 (t, CH2C¼CH), 25.76 (t, C(3) and C(4) of cyclopentyl); 13.86 (q, MeS). HR-
MALDI-MS: 398.1900 (100, [M þ H]þ, C17H30N3O5Sþ; calc. 398.1901).
Methyl 6,8-Dideoxy-6-{4-[(1-hydroxycyclohexyl)]-1H-1,2,3-triazol-1-yl}-1-thio-d-erythro-a-d-galac-
to-octopyranoside (10j). GP and FC (amino phase gel, AcOEt/MeOH 98 :2 to 3 :1) gave 10j (65 mg,

Helvetica Chimica Acta – Vol. 91 (2008)
1847
90%). Colourless oil. Rf (AcOEt/MeOH 4 :1) 0.33. M.p. 100 – 1028. [a]2D5 ¼ þ176.5 (c ¼ 1.12, MeOH). IR
(ATR): 3358m (br.), 2930w, 2854w, 2766w, 1635w, 1446w, 1337w, 1303w, 1244m, 1215m, 1076s, 1043s,
1029w, 979m, 906w, 850w, 801w, 750s, 699w, 664w, 632w. 1H-NMR (300 MHz, CD3OD): see Table 2;
additionally, 7.78 (s, HÀC(5) of triazolyl); 2.18 (s, MeS); 2.07 – 1.97 (m, 2 H); 1.85 – 1.70 (m, 4 H); 1.63 –
1.33 (m, 4 H); 1.12 (d, J ¼ 6.3, Me). 13C-NMR (75 MHz, CD3OD): see Table 2; additionally, 155.13 (s,
C(4) of triazolyl); 124.76 (d, C(5) of triazolyl); 69.95 (s, C(1) of cyclohexyl); 38.56 (t, 2 C); 26.32 (t); 22.82
(t, 2 C); 13.83 (q, MeS). HR-MALDI-MS: 442.1415 (16, [M þ K]þ, C17H29KN3O6Sþ; calc. 442.1409),
426.1676 (20, [M þ Na]þ, C17H29N3NaO6Sþ; calc. 426.1669), 404.1848 (100, [M þ H]þ, C17H30N3O6Sþ;
calc. 404.1850).
Methyl 6,8-Dideoxy-6-{4-[(2S,4R)-1-methyl-4-propylpyrrolidin-1-yl]-1H-1,2,3-triazol-1-yl}-1-thio-d-
erythro-a-d-galacto-octopyranoside (10k). GP and FC (amino phase gel, AcOEt/MeOH 98 :2 to 4 :1)
gave 10k (46 mg, 60%). White solid. Rf (AcOEt/MeOH 9 :1) 0.13. M.p. 90 – 928. [a]2D5 ¼ þ169.6 (c ¼ 1.04,
MeOH). IR (ATR): 3352w (br.), 2956w, 2921w, 2874w, 2848w, 2791w, 1552w, 1453w, 1379w, 1299w,
1216w, 1138w, 1094m, 1076m, 1049s, 980m, 945w, 908w, 865w, 801w, 749s, 700w, 683w, 665w, 630w.
1H-NMR (300 MHz, CD3OD): see Table 2; additionally, 7.88 (s, HÀC(5) of triazolyl); 3.53 – 3.47, 3.30 –
3.27 (2m, 2 H of pyrrolidinyl); 2.41 – 2.31, 2.25 – 2.20 (2m, 2 H of pyrrolidinyl); 2.25 (s, MeN); 2.18 (s,
MeS); 2.08 – 2.01 (m, 2 H of pyrrolidinyl); 1.95 – 1.85 (m, 2 H of pyrrolidinyl); 1.30 – 1.17 (m, Me(CH2)2);
0.94 (t, J ¼ 6.9, Me(CH2)2). 13C-NMR (75 MHz, CD3OD): see Table 2; additionally, 148.19 (s, C(4) of
triazolyl); 126.17 (d, C(5) of triazolyl); 68.84 (d, C(2) of pyrrolidinyl); 64.43 (t, C(5) of pyrrolidinyl);
40.52 (q, MeN); 39.48 (t, MeCH2CH2); 38.10 (t, C(3) of pyrrolidinyl); 36.83 (d, C(4) of pyrrolidinyl);
21.99 (t, MeCH2CH2); 14.19 (q, MeS); 13.70 (q, MeCH2CH2). HR-MALDI-MS: 431.2329 (100, [M þ
H]þ, C19H35N4O5Sþ; calc. 431.2323).
REFERENCES
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[2] C. Lewis, H. W. Clapp, J. E. Grady, Antimicrob. Agents Chemother. 1962, 570.
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Received June 6, 2008