Novel 6-position modified 1-thioalkyl-lincosamines

Article abstract of DOI:10.1016/j.tetlet.2008.02.167

A general method for the synthesis of 6-position modified lincosamines via stereospecific nucleophilic addition to readily available galactose 6-nitrone has been developed. A new route for the stereospecific installation of thioalkyl groups at the 1-position was also developed. These methods allow access to a variety of new derivatives of antibacterial lincosamides.

Full text of DOI:10.1016/j.tetlet.2008.02.167

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Tetrahedron Letters 49 (2008) 2979–2981
Novel 6-position modified 1-thioalkyl-lincosamines
Hardwin O’Dowd *, Jason G. Lewis, Mikhail F. Gordeev
Pfizer Global Research and Development, Fremont , CA 94555, USA
Received 1 February 2008; revised 28 February 2008; accepted 28 February 2008
Available online 4 March 2008
Abstract
A general method for the synthesis of 6-position modified lincosamines via stereospecific nucleophilic addition to readily available
galactose 6-nitrone has been developed. A new route for the stereospecific installation of thioalkyl groups at the 1-position was also
developed. These methods allow access to a variety of new derivatives of antibacterial lincosamides.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Lincosamides; Thiogalactosides; Nitrones; Aminosugars; Diastereoselective addition
The lincosamide class of antibiotics is best represented
by clindamycin (CLI), which consists of two distinct struc-
tural subunits: N-methyl-40R-propyl-L-proline amino acid
(or 4-n-propylhygric acid) and an amino sugar, 7-chloro-
methylthio-lincosamine (7-Cl-MTL) fragment.1,2 Our
medicinal chemistry program targeting the next generation
of lincosamide antibacterial agents has identified the 7-
position of the lincosamine sugar as a site that is amenable
to modification. 7-Methyl-methylthio-lincosamine (7-Me-
MTL, see Fig. 1) shows similar antibacterial activity to
the 7-Cl-MTL progenitor3 when coupled to a suitable cyc-
lic amino acid.4 Reported herein is a general stereospecific
route to 6-position modified thiolincosamine sugars.
The Dondoni group has reported the stereospecific addi-
tion of 2-lithiothiazole to protected galactose nitrone 1,5 en
route to formal syntheses of lincosamine and destomic
acid.6 We sought to broaden the scope of this reaction in
order to access a range of novel lincosamines modified at
the 6-position. In our hands, a variety of organometallic
nucleophiles have shown equally high selectivity for the
natural 6(R)-diastereomer; in all cases, the undesired dia-
stereomer was not detected. By way of example, Scheme
1 shows the addition of cyclopropyl magnesium bromide
to nitrone 1 and subsequent conversion to trifluoroaceta-
mide 5a. Applying the reported methods of unmasking
the amino-functionality of 2a gave unsatisfactory results:
treatment of hydroxylamine 2a in methanol with aqueous
TiCl3 (20 wt %, freshly prepared)6,7 provided a mixture of
the desired imine 3a, and the undesired reduced benzyl
amine; whereas reacting 2a with anhydrous TiCl3 in
THF8 gave a mixture of imine 3a, amine 4a, and undesired
reduced benzyl amine. A superior method for the dehydra-
tion of 2?3 was found to be the treatment of 2a with meth-
anesulfonyl chloride and triethylamine in methylene
chloride. Liberation of imine 3a to amine 4a was accom-
plished by transimination with Girard’s reagent T ((car-
boxymethyl)trimethylammonium chloride hydrazide),9
which added the convenience of partitioning the reaction
byproducts into the aqueous layer upon workup. This
two-step process represents a generally applicable strategy
Fig. 1. Clindamycin and 7-Me-MTL.
*
Corresponding author.
E-mail address: hardwin@hotmail.com (H. O’Dowd).
Formerly Vicuron Pharmaceuticals, Inc.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.167

2980
H. O’Dowd et al. / Tetrahedron Letters 49 (2008) 2979–2981
Scheme 2. Installation of a-thiomethyl group. Reagents and conditions:
(a) TFA, H2O, 0–23 °C; (b) Ac2O, Et3N; DMAP, CH2Cl2, 23 °C; (c) HBr,
AcOH, 0–23 °C, 74% (three steps); (d) AgOAc, AcOH, 23 °C; (e)
BF3ꢁOEt2, PCl5, CH2Cl2, 23 °C, 91% (two steps); (f) MeSNa, HMPA,
DMF, 23 °C; (g) Ac2O, Et3N, DMAP, CH2Cl2, 23 °C, 53% (two steps); (h)
NaOH aq, MeOH, 23 °C, 97%.
Scheme 1. Preparation of trifluoroacetamide 5a. Reagents and conditions:
(a) C3H5MgBr (0.5 M in THF), Et2AlCl (1.0 M in heptane), Et2O,
ꢀ78 °C, 89%; (b) MsCl, Et3N, CH2Cl2, 0–23 °C; (c) Girard’s reagent T,
MeOH, 23 °C; (d) TFAA, 2,6-lutidine, CH2Cl2, 0–23 °C, 78% (three
steps).
for the conversion of benzylhydroxylamines to primary
amines. Crude amine 4a was protected as trifluoroaceta-
mide 5a. At this stage, the trifluoroacetamide was subjected
to the first chromatographic purification of the sequence.
The lincosamine thiomethyl substituent and its configu-
ration are known to be important for antibacterial activ-
ity.1 The stereospecific introduction of the C1-thiomethyl
group is a largely unaddressed issue in lincosamine synthe-
sis.2,10 Scheme 2 details our approach to the installation of
the requisite thioalkyl group to our 6-position modified lin-
cosamine sugars. The acidic deprotection of diacetonide 5a
with aqueous trifluoroacetic acid was followed by global
acetylation to provide a mixture of a/b/pyranose/furanose
tetraacetates. This isomeric mixture of four compounds
was converted to a-bromopyranose triacetate 6a as a single
major isomer via treatment with hydrogen bromide in ace-
tic acid. a-Bromide 6a was transformed first to the 1,2-
trans-tetraacetate with silver acetate/acetic acid, then to
the b-chloride 7a using phosphorus pentachloride/boron-
trifluoride diethyletherate.11 Chloride 7a was subjected to
nucleophilic displacement with sodium thiomethoxide,
avoiding the b-directing effect of the 2-position acetate
observed under Lewis acid-catalyzed glycosylation condi-
tions. Partial deacetylation was observed under the reac-
tion conditions, the crude product was subjected to
reacylation prior to undergoing the second chromato-
graphic purification of the synthetic sequence.
The global deprotection of trifluoroacetamide triacetate
8a was effected with aqueous sodium hydroxide in metha-
nol. Isolation of 9a was achieved via first acidifying the
basic reaction mixture with aqueous hydrochloric acid;
then concentrating the resulting solution. The resulting
hydrochloride salt was dissolved in ethanol and filtered to
remove the precipitated NaCl. The resulting ethanolic solu-
tion of the hydrochloride salt was then neutralized with
Amberlite IRA-400 resin (OH form); the free base 9a was
obtained (>95% pure) upon concentrating the liquid phase.
In addition to C-6 cyclopropyl thiomethyl lincosamine,
isopropyl, cyclopentyl, allyl, and 4-chlorophenyl C-6 ana-
logs were also prepared via this route. Table 1 shows the
overall yields of trifluoroacetamides 5a–e from galactose
nitrone 1, and the yields obtained in each case for the
conversion of trifluoroacetamide diacetonides 5 to their
respective thiomethyl lincosamines 9. The selectivity for
the desired 6-R and 1-R stereochemistry was confirmed
by comparison of 9b to an authentic sample obtained via
our previously established route from 1-thiomethyl-lincos-
amine.4 It should be noted that the efficiency of the route is

H. O’Dowd et al. / Tetrahedron Letters 49 (2008) 2979–2981
2981
Table 1
10a,b are available. Supplementary data associated with
this article can be found, in the online version, at doi:
10.1016/j.tetlet.2008.02.167.
Yields obtained for analog synthesis via Schemes 1 and 2
References and notes
1. Magerlein, B. J. In Structure–Activity Relationships among the
Semisynthetic Antibiotics; Perlman, D., Ed.; Academic Press: New
York, 1977; pp 601–651.
2. Golebiowski, A.; Jurczak, J. In Recent Progress in the Chemical
Synthesis of Antibiotics; Lukacs, G., Ohno, M., Eds.; Springer: Berlin,
1990; pp 365–385.
R
Entry
c-Propyl
a
i-Propyl
b
c-Pentyl
c
Allyl
d
4-Cl–Ph
e
Yield of 5a (%)
Yield of 9b (%)
a
69
36
74
48
82
39
78
31
81
33
3. Livingston, D. A. Eur. Pat. Appl. EP 0161794, 1985.
4. Lewis, J. G.; Gu, S.; Kumar, S. A.; Chen, T.; O’Dowd, H.; Patel, D.
V.; Hackbarth, C. J.; Asano, R.; Park, C. K.; Blais, J.; Wu, C.; Wang,
W.; Yuan, Z.; Trias, J.; White, R. J.; Gordeev, M. F. ‘Novel
Antimicrobial 7-Methyl Lincosamides: Pipecolamide Analogs’; 44th
Interscience Conference on Antimicrobial Agents and Chemotherapy,
Washington, DC, Oct 30–Nov 2, 2004; F-1389.
Overall yield from nitrone (1?5).
Overall yield from diacetonide (5?9).
b
5. Dondoni, A.; Franco, S.; Junquera, F.; Merchan, F. L.; Merino, P.;
Tejero, T. Synth. Commun. 1994, 24, 2537–2550.
6. Dondoni, A.; Franco, S.; Merchan, F. L.; Merino, P.; Tejero, T.
Synlett 1993, 78–80.
7. Dondoni, A.; Junquera, F.; Merchan, F. L.; Merino, P.; Scherrmann,
M.-C.; Tejero, T. J. Org. Chem. 1997, 62, 5484–5496.
8. Murahashi, S.-I.; Kodera, Y. Tetrahedron Lett. 1985, 26, 4633–4636.
9. Watanabe, T.; Sugawara, S.; Miyadera, T. Chem. Pharm. Bull. 1982,
30, 2579–2582.
10. Knapp, S.; Kukkola, P. J. J. Org. Chem. 1990, 55, 1632–1636.
11. Ibatullin, F. M.; Selivanov, S. I. Tetrahedron Lett. 2002, 43, 9577–
9580.
Scheme 3. Installation of alternative a-thioalkyl groups. Reagents and
conditions: (a) Me2RCSNa, HMPA, DMF, 23 °C; (b) Ac2O, Et3N,
DMAP, CH2Cl2, 23 °C; (c) NaOH aq, MeOH, 23 °C, 58–61% (three
steps).
12. 1H NMR data (300 MHz, CD3OD) 9a: d 5.28 (d, J = 5.7 Hz, 1H),
4.13–4.06 (m, 2H), 3.97 (d, J = 6.6 Hz, 1H), 3.59 (dd, J = 3.3, 9.9 Hz,
1H), 2.33 (dd, J = 6.9, 9.0 Hz, 1H), 2.05 (s, 3H), 0.91–0.77 (m, 1H),
0.58–0.43 (m, 2H), 0.39–0.31 (m, 1H), 0.28–0.19 (m, 1H). Compound
9b: d 5.24 (d, J = 5.7 Hz, 1H), 4.04 (dd, J = 6.0, 10.8 Hz, 1H), 4.02
(dd, J = 1.2, 3.3 Hz, 1H), 3.93 (dd, J = 1.5, 8.7 Hz, 1H), 3.54 (dd,
J = 3.3, 10.5 Hz, 1H), 2.91 (dd, J = 3.6, 8.1 Hz, 1H), 2.08–1.96 (m,
1H), 2.06 (s, 3H), 0.99 (d, J = 6.9 Hz, 3H), 0.88 (d, J = 6.9 Hz, 3H).
Compound 9c: d 5.28 (d, J = 5.7 Hz, 1H), 4.16–4.08 (m, 2H), 3.93 (dd,
J = 0.9, 6.6 Hz, 1H), 3.54 (dd, J = 3.0, 10.2 Hz, 1H), 2.99 (t,
J = 6.6 Hz, 1H), 2.17–2.04 (m, 1H), 2.07 (s, 3H), 1.88–1.51 (m, 6H),
1.42–1.26 (m, 2H). Compound 9d: d 5.94–5.78 (m, 1H), 5.27 (d,
J = 5.7 Hz, 1H), 5.20–5.10 (m, 2H), 4.09 (dd, J = 5.7, 10.2 Hz, 1H),
4.04 (dd, J = 1.5, 3.3 Hz, 1H), 3.82 (dd, J = 0.9, 8.1 Hz, 1H), 3.57 (dd,
J = 3.3, 9.9 Hz, 1H), 3.13 (dt, J = 3.9, 8.4 Hz, 1H), 2.57–2.47 (m, 1H),
2.14–2.02 (m, 1H), 2.07 (s, 3H). Compound 9e: d 7.37 (d, J = 8.4 Hz,
2H), 7.31 (d, J = 9.0 Hz, 2H), 5.09 (d, J = 6.0 Hz, 1H), 4.13–4.03 (m,
4H), 3.58 (dd, J = 3.3, 10.2 Hz, 1H), 1.41 (s, 3H). Compound 10a: d
5.36 (d, J = 6.0 Hz, 1H), 4.05 (dd, J = 5.7, 10.2 Hz, 1H), 4.01 (dd,
J = 1.5, 3.3 Hz, 1H), 3.95 (dd, J = 1.2, 8.7 Hz, 1H), 3.48 (dd, J = 3.3,
10.5 Hz, 1H), 3.04–2.93 (m, 1H), 2.89 (dd, J = 3.6, 8.4 Hz, 1H), 2.07–
1.95 (m, 1H), 1.30 (d, J = 6.9 Hz, 3H), 1.26 (d, J = 6.9 Hz, 3H), 0.98
(d, J = 6.9 Hz, 3H), 0.87 (d, J = 6.6 Hz, 3H). Compound 10b: d 5.39
(d, J = 5.7 Hz, 1H), 4.05 (dd, J = 6.0, 10.8 Hz, 1H), 4.01 (dd, J = 1.2,
3.3 Hz, 1H), 3.90 (dd, J = 1.5, 8.7 Hz, 1H), 3.39 (dd, J = 3.3, 10.5 Hz,
1H), 2.88 (dd, J = 3.6, 8.1 Hz, 1H), 2.08–1.95 (m, 1H), 1.36 (s, 9H),
0.98 (d, J = 6.9 Hz, 3H), 0.89 (d, J = 6.9 Hz, 3H).
such that gram-quantities of the amino sugars 9 are readily
obtained from 5 to 6 g of nitrone 1.
This new route also provides stereoselective access to
additional 1-thioalkyl analogs via the b-chlorogalactose
intermediate 7. The synthesis of tert-butylthio- and isopro-
pylthio-lincosamines (10a,b) is shown in Scheme 3.
In summary, we have developed a novel route to thiolin-
cosamine sugars featuring access to structural diversity at
both the 6- and 1-positions.12 While consisting of several
individual synthetic steps, the basic route requires just
two chromatographic purifications, highlighting the high
average yield-per-step and the excellent stereoselectivity
for the desired isomer. These methods can be employed
to synthesize a variety of novel lincosamides with potential
for antibacterial therapy.
Supplementary data
Detailed experimental procedures for the conversion of
1
1?5a?9a and copies of H NMR spectra for 5a–e, 9a–e,