A flexible strategy for the divergent modification of pleuromutilin

Article abstract of DOI:10.1039/b206568a

The complex antibacterial natural product, pleuromutilin, can be directly modified by the radical addition reaction of various xanthates to the unactivated terminal olefin present on C-12.

Full text of DOI:10.1039/b206568a

A flexible strategy for the divergent modification of pleuromutilin
a
b
b
Eric Bacqué, François Pautrat and Samir Z. Zard*
a
Aventis, Centre de Recherche de Romainville, 102 Route de Noisy, F-93235 Romainville, France
Laboratoire de Synthèse Organique Associé au CNRS, Ecole Polytechnique, F-91128 Palaiseau, France.
E-mail: zard@poly.polytechnique.fr; Fax: +33 (0)169333851; Tel: +33 (0)169334872
b
Received (in Cambridge, UK) 8th July 2002, Accepted 12th September 2002
First published as an Advance Article on the web 23rd September 2002
The complex antibacterial natural product, pleuromutilin,
can be directly modified by the radical addition reaction of
various xanthates to the unactivated terminal olefin present
on C-12.
formed a reductive elimination using tributylstannane or a
stoichiometric amount of lauroyl peroxide in 2-propanol. The
latter reagent system is better suited for biological testing since
no heavy metals are involved. The relatively low yield in the
reduction of 2e is due in part to ring closure of the intermediate
radical onto the aromatic ring.7
The addition of a benzothiazole group as in 2f (Scheme 2),
albeit inefficient (10 or 50% based on recovered starting
material), highlights the possibility of directly incorporating
heteroaromatic moieties. More interestingly, the direct and
efficient introduction of an activated carboxylic function under
the guise of an N-acyloxazolidinone, as in 3g, provides an
opportunity for the expedient creation of large libraries of
amides and esters since numerous amines and alcohols are
commercially available. This is examplified by the synthesis of
amides 4a and 4b. The glycolate ester on C-14 is not affected in
these transformations.†
6
The chemical modification of biologically active natural
products is essential for determining their structure–activity
profile and for improving their potency. The complexity of a
lead structure often imposes severe limitations on the type of
transformations that can be accomplished. Pleuromutilin, a
naturally occuring antibacterial isolated from various basido-
mycete microorganisms (e.g. Pleurotus mutilus and Pleurotus
1
passeckerianus), is a case in point. Most of the modifications
have concerned the ester side-chain on C-14 and have led to two
more potent drugs Tiamulin and Valnemulin, now in veterinary
2
use (Fig. 1). On a structure of this complexity, it is not easy to
manipulate the unactivated and relatively hindered olefin on C-
1
2 without extensive protection of the remaining functional
The above derivatives represent only a tiny sample of the
variety of functionality that can be introduced by this strategy,
and none is easily accessible by conventional routes. Given the
compatibility of radical reactions with many commonly en-
countered functional groups, this approach represents a new and
powerful strategy for the modification of complex, biologically
active compounds, with minimal need for protection steps.
Moreover, even though only a few natural compounds contain
a terminal olefin amenable to this type of functionalisation, it is
possible, by a simple allylation or vinylation reaction, to
groups. We have now found that the radical chain xanthate
transfer process is of sufficient mildness to allow the direct
creation of new C–C bonds on the olefin in Pleuromutilin
without the need for any prior protection.
Heating Pleuromutilin with 3 equivalents of nitrile containing
xanthate 1a in refluxing 1,2-dichloroethane in the presence of a
small amount of lauroyl peroxide (ca. 40 mol%) gave the
addition product 2a in 80% yield (Scheme 1). We were relieved
to find that no complication arose from the glycolate ester
portion which contains easily abstractable hydrogens (abstrac-
tion of a hydrogen from the methylene group gives a capto-
dative radical).
3
Under similar conditions, xanthate 1b proved less efficient
since the yield of addition product 2b was only 35%. Xanthates
1
c, 1d, and 1e however, all of which contain a ketone group,
added smoothly to give the corresponding adducts 2c–e in 60,
0, and 55% yield, respectively. The possibility of introducing
7
a trifluoromethyl ketone as in the case of 2d is worth
4
underlining. Such ketones readily and reversibly form hydrates
and these are mimics for the tetrahedral intermediates involved
in the hydrolysis of esters and amides. They therefore tend to
5
bind well with various types of hydrolytic enzymes. In the case
of 2e, the aromatic group represents in contrast a hydrophobic
unit that could significantly modify the lipophilicity of the
native pleuromutilin.
The xanthate group in these various adducts represents a
further point for the introduction of diversity. There is, however,
a poor control of the stereochemisty of the carbon bearing the
xanthate and, in order to simplify characterisation, we per-
Fig. 1 Pleuromutilin and congeners.
Scheme 1 Radical addition of xanthates to pleuromutilin.
2
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CHEM. COMMUN., 2002, 2312–2313
This journal is © The Royal Society of Chemistry 2002

2
8 4 2
67 (Found (%): C, 38.3; H, 4.5. C H11NO S requires (%): C, 38.5; H,
4
.5).
Compound 3g: lauroyl peroxide (60 mg; 0.1 eq.) was added to a refluxing
solution of xanthate 1g (1.8 g; 7 mmol) and (+)-pleuromutiline (0.54 g; 1.4
mmol) in 2 ml of 1,2-dichloroethane under nitrogen. Further portions of
lauroyl peroxide (30 mg; 0.05 eq.) were added every 90 min until
completion of the reaction, which took about 10 h. The solvent was removed
under reduced pressure and the residue purified by column chromatography
on silica gel to give 2g (0.67 g; ca. 75%; mixture of epimers) as a colourless
oil. This oil was dissolved in propan-2-ol (20 ml) and the resulting solution
refluxed under nitrogen. After a few minutes, lauroyl peroxide (84 mg; 0.2
eq.) was added. Further portions of peroxide (42 mg; 0.1 eq.) were then
added every 90 min until completion of the reaction, which took about 17
h of heating. The solvent was removed under reduced pressure and the
residue purified by chromatography on silica gel to give compound 3g as a
white foam (0.43 g; 80%); d
4
2
H
(400 MHz; CDCl
.5–4.4 (2H, m), 4.2–3.9 (4H, m), 3.40 (1H, d, J 4.5 Hz), 3.1–2.8 (3H, m),
.5–2.0 (4H, m), 1.9–0.8 (14H, m), 1.40 (3H, s), 1.00 (3H, s), 0.97 (3H, d,
(100 MHz; CDCl ) 217.3, 174.1, 172.5,
53.7, 76.5, 69.5, 62.2, 61.5, 58.6, 45.6, 42.7, 41.8, 41.4, 40.8, 36.7, 35.6,
4.6, 34.5, 30.3, 27.7, 26.90, 26.85, 25.0, 19.3, 16.5, 14.9, 11.3; nmax (CCl )/
3
) 5.73 (1H, d, J 8 Hz),
J 7 Hz), 0.68 (3H, d, J 7 Hz); d
C
3
1
3
4
21
cm 3540, 2937, 1791, 1737, 1701, 1462, 1384, 1281, 1225, 1152, 1098;
+
MS(CI): [MH 2 HOCH
2
COOH 2 H
2
O] m/z 414, [MNH
4
2 HOCH-
] 525 (Found (%): C, 63.8;
8
requires (%): C, 63.9; H, 8.1).
+
+
+
2
COOH] 449, [MNH
H, 8.2. C27 41NO
4
2 4
2 H O] 507, [MNH
H
Scheme 2 Radical addition and amide formation.
Compound 4a: compound 3g (60 mg; 0.12 mmol) was dissolved in 2 ml
of a 1+1 mixture of N,N-dimethylethylene diamine and acetonitrile. After
stirring at room temperature under nitrogen for 2 h, the solvent was removed
under reduced pressure and the residue dissolved in EtOAc and extracted
with 1 M aqueous HCl. The aqueous phase was made basic using solid
introduce such an olefin and therefore expand considerably the
scope of this technology.
We thank Aventis and the CNRS for generous financial
support to one of us (FP).
NaHCO
over MgSO
residue was purified by chromatography on silica gel to give 30 mg (50%)
of compound 4a as a white foam; d (400 MHz; CDCl ) 6.83 (1H, t, J 5 Hz),
.71 (1H, d, J 7.5 Hz), 4.11 (1H, d, J 17 Hz), 3.99 (1H, d, J 17 Hz), 3.52 (1H,
m), 3.34 (1H, d, J 6 Hz), 3.17 (1H, m), 2.6–0.9 (23H, m), 2.26 (6H, s), 1.37
(3H, s), 0.95 (3H, s), 0.94 (3H, m), 0.67 (3H, d, J 6.5 Hz); d (100 MHz;
CDCl ) 217.3, 174.6, 172.9, 76.3, 69.1, 61.1, 59.0, 58.8, 45.5, 45.3, 41.7,
41.0, 40.9, 37.8, 36.7, 36.6, 34.7, 34.5, 30.4, 28.0, 26.94, 26.90, 25.1, 21.7,
3
and extracted with dichloromethane. The organic layer was dried
4
, filtered, and the solvent removed under reduced pressure. The
H
3
5
Notes and references
†
Typical experimental procedure: compound 1g: At 210 °C and under
C
nitrogen, a 1.5 M solution of n-BuLi in hexane (11.5 ml; 1 eq.) was added
dropwise to a stirred solution of oxazolidin-2-one (1.5 g; 17 mmol) in dry
THF (35 ml). Chloroacetyl chloride (1.5 ml; 1.1 eq.) was then added
dropwise. After 15 min of stirring, the reaction mixture was poured into a
3
21
4
16.4, 14.8, 11.5; nmax (CCl )/cm 3406, 2930, 1740, 1682, 1656, 1510,
+
+
2
1461, 1376, 1204, 1105; MS(CI): [MH 2 HOCH COOH] m/z 433, [MH]
mixture of a saturated solution of NH
extracted with EtOAc and the combined organic layers were washed with
brine, dried over MgSO and filtered. The solvent was removed under
4
Cl and EtOAc. The aqueous layer was
= 509.
4
1 F. Kavanagh, A. Hervey and W. J. Robbins, Proc. Natl. Acad. Sci. USA,
1951, 37, 570; F. Kavanagh, A. Hervey and W. J. Robbins, Proc. Natl.
Acad. Sci. USA, 1952, 38, 550; D. E. Cane, Tetrahedron, 1980, 36, 1109;
M. Dobler and B. G. Dürr, Cryst. Struct. Commun., 1975, 4, 259.
2 (a) E. Hunt, Drugs Fut., 2000, 25, 1163; (b) H. Berner, H. Vyplel and G.
Schultz, Tetrahedron, 1987, 43, 765.
3 For reviews, see: S. Z. Zard, in Radicals in Organic Synthesis, ed. P.
Renaud and M. Sibi, Wiley YCH, Weinheim, 2001, pp. 90–108; S. Z.
Zard, Angew. Chem., Int. Ed. Engl., 1997, 36, 672; B. Quiclet-Sire and S.
Z. Zard, Phosphorus, Sulfur Silicon, 1999, 153–154, 137.
4 M.-P. Denieul, B. Quiclet-Sire and S. Z. Zard, Chem. Commun., 1996,
2511.
reduced pressure and the residue was purified by chromatography on silica
gel to give 1.8 g (65%) of 3-(2-chloroacetyl)oxazolidin-2-one as a white
solid, which was used directly in the next step; d
H
(400 MHz; CDCl
2H, s), 4.49 (2H, t, J 8 Hz), 4.05 (2H, t, J 8 Hz); d (100 MHz; CDCl
)/cm 2923, 1796, 1727, 1711,
3
) 4.69
(
C
3
)
21
1
1
1
66.1; 153.4, 63.0, 43.3, 42.6; nmax (CCl
386, 1363, 1343 1255, 1172, 1106, 1045; MS(CI): [MNH
83. At r.t. and under nitrogen, 1.9 g (1.1 eq.) of KSC(S)OEt were slowly
4
+
4
] m/z 181 and
added to a stirred solution containing 1.75 g (10.7 mmol) of 3-(2-chloro-
acetyl)oxazolidin-2-one in 5 ml of acetone. After a few minutes of stirring,
the solvent was removed under reduced pressure. The residue was dissolved
in EtOAc and washed with water and brine. The organic layer was dried
over MgSO
.9 g of a yellow solid. Recrystallisation from heptane–EtOAc afforded 2.4
g (90%) of compound 1g as colourless needles (mp 96 °C); d (400 MHz;
CDCl ) 4.65 (2H, q, J 7 Hz), 4.58 (2H, s), 4.49 (2H, t, J 8 Hz), 4.08 (2H, t,
J 8 Hz), 1.43 (3H, t, J 7 Hz); d (100 MHz; CDCl ) 212.9, 166.9, 153.6,
)/cm 2990, 2923, 1794, 1716,
4
and the solvent was removed under reduced pressure to give
5 J.-P. Bégué and D. Bonnet-Delpon, Tetrahedron, 1991, 47, 3207; M. A.
McClinton and D. A. McClinton, Tetrahedron, 1992, 48, 6555; P. Lin
and J. Jiang, Tetrahedron, 2000, 56, 3635.
6 A. Liard, B. Quiclet-Sire and S. Z. Zard, Tetrahedron Lett., 1996, 37,
5877.
2
H
3
C
3
21
7
0.9, 62.6, 42.8, 39.6, 13.8; nmax (CCl
480, 1384, 1227, 1113, 1054, 1011; MS(CI): [MH] m/z 250, [MNH
4
7 A. Liard, B. Quiclet-Sire, R. N. Saicic and S. Z. Zard, Tetrahedron Lett.,
1997, 38, 1759.
+
+
1
4
]
CHEM. COMMUN., 2002, 2312–2313
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