A novel approach to the regioselective acylation of spirocyclic C-glucoside of papulacandins

Article abstract of DOI:10.1016/S0040-4039(02)00664-0

A novel approach to the regioselective acylation of spirocyclic C-glucoside of papulacandins is reported. Conditions were found to effect regioselective acylation of triol 2 to give 2-O-acyl derivatives (5), which after deprotection with TASF afforded exc

Full text of DOI:10.1016/S0040-4039(02)00664-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3875–3878
A novel approach to the regioselective acylation of spirocyclic
C-glucoside of papulacandins
Chafiq Hamdouchi,a,* Carlos Jaramillo,b Javier Lopez-Pradosb and Almudena Rubioa
aLilly Research Laboratories, A division of Eli Lilly and Company, Lilly Corporate Center, DC 0548, Indianapolis, IN 46285,
USA
bCentro de Investigacion Lilly, S.A., Avenida de la Industria, 30, 28108 Alcobendas, Madrid, Spain
Received 14 March 2002; revised 3 April 2002; accepted 4 April 2002
Abstract—A novel approach to the regioselective acylation of spirocyclic C-glucoside of papulacandins is reported. Conditions
were found to effect regioselective acylation of triol 2 to give 2-O-acyl derivatives (5), which after deprotection with TASF
afforded exclusively 2-O-acyl derivatives (8). An extensive migration of the acyl group from 2-O- to 3-O-position was observed
when the desilylation was conducted with TBAF. These findings provided with a convenient means for extending the SAR of
papulacandins at these positions. © 2002 Elsevier Science Ltd. All rights reserved.
In 1977, Traxler and co-workers reported the isolation
and characterization of a family of novel antifungal
antibiotics, named papulacandins A, B, C and D from
Papularia sphaerospema,1–3 with in vitro activity against
Candida albicans and other yeasts. In general these
compounds showed acceptable inhibition of b-1,3-glu-
can synthase and whole cell activity, though little or no
efficacy in animal models was found.
esters to two hydroxyl groups of the diglycosides. Papu-
lacandin D, a monosaccharide relative is the simplest
member of the family.4 The antifungal properties of
papulacandin D juxtaposed with lack of access to natu-
ral material and the synthetically challenging structural
features make this compound interesting synthetic
target.5–11
While the construction of the spirocyclic C-aryl glu-
coside moiety of papulacandin D has been widely docu-
mented, there is only one report that describes a
The papulacandins A, B and C contain a spirocyclic
diglycoside and two unsaturated fatty acids, linked as
OH
OH
OH
Papulacandin A, R =
HO
HO
O
HO
O
O
O
O
O
O
O
HO
HO
O
HO
O
O
O
Metabolic
pathway?
Papulacandin B, R =
R
O
O
O
OH
HO
OH
O
O
OH
O
OH
O
O
HO
OH
HO
OH
OH
OH
OH
Papulacandin C, R =
OH
OH
OH
Papulacandin D
Saricandin
Produced by Fusarium
Produced by Papularia Spherosperma
Produced by Papularia
Spherosperma
Figure 1. Members of the papulacandins family.
* Corresponding author. Tel.: 1-317-276-9582; fax: 1-317-2765431; e-mail: hamdouchi chafiq@lilly.com
–
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00664-0

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C. Hamdouchi et al. / Tetrahedron Letters 43 (2002) 3875–3878
OTIPS
OTIPS
successful attempt to address the incorporation of the
side chain.11 The main challenge in conducting an SAR
to improve the in vivo profile of these class of antifun-
gal agents is the regioselectivity of the acylation. Barrett
has reported the use of the mixed anhydride in combi-
nation with O-4%%,O-6%%-di-tert-butylsilylene and triiso-
propylsilyl protecting groups as a way of improving the
reactivity and regioselectivity. We recently applied this
combination of protecting groups to realize the total
synthesis of a saricandin analog (Fig. 1) corresponding
to papulacandin D.12 The use of protecting groups such
as di-t-butylsilyl(trifluoromethanesulfonate) makes the
development of analogues quite expensive. Moreover,
only a modest regioselectivty (3:1) and modest yield
(31%) were achieved.
TBSOTf
imidazole,
Bu2SnO, 130°C
toluene
TIPSO
TIPSO
O
O
HO
HO
TBSO
O
DMF
O
OH
HO
OH
Quant.
OH
OH
OTIPS
2
1
OTIPS
O
TIPSO
TIPSO
, CH Cl , rt
R
Cl
2
2
O
O
TBSO
HO
TBSO
HO
O
O
O
O
O
OH
O
R
SnBu2
5
We now wish to report a novel approach to the regiose-
lective acylation of spirocyclic C-glycoside that permit-
ted to extend the SAR at O-2 and O-3 position of
papulacandin D.
Scheme 1.
OH
OTIPS
HO
TIPSO
TASF
THF, rt
For the synthesis of the tricyclic spiroketal nucleus 1 we
used reaction sequences analogous to that described by
Barrett for the synthesis of papulacandin D.5 Our strat-
egy begins with a selective silylation of the primary
hydroxyl group of 1 that afforded cleanly 6-O-silyl
derivative 2. Representative examples of unsaturated
side chains of interest for the SAR were selected for the
present studies (Table 1).
O
O
HO
TBSO
HO
O
O
O
HO
O
O
O
OH
8
OH
5
R
R
TBAF
THF, rt
OH
The direct acylation of 2 with either acyl chlorides or
mixed anhydrides led to a mixture of several products.
However, we were pleased to find that activation of the
2,3-diol with dibutyltin oxide prior to the reaction with
acyl chlorides13 gave the 2-O-acyl derivative 5 as the
sole product14 (see Scheme 1 and Table 1). Presumably,
the oxygen atom of the spiroketal moiety is responsible
for the regioselectivity of the reaction. Surprisingly,
when bis(tributyltin oxide) was used as the promoter,13
no reaction was obtained, and starting material was
recovered unaltered.
HO
O
O
HO
HO
O
OH
O
R
9
Scheme 2.
products formed and isolated in a good yield were the
corresponding polyols 8. Interestingly, we found (partly
by chance!) that the deprotection of 5 with tetra-
butylammonium fluoride (TBAF) was accompanied by
an extensive migration of the acyl group from 2-O- to
3-O-position leading predominantly to the polyols 9.
These findings provided with a convenient means for
extending the SAR of papulacandin at these strategic
positions.
Next, we studied the deprotection of ester 5 (see
Scheme 2 and Table 2).15 When the esters 5 were
subjected to deprotection with tris(dimethylamino)-
sulfur (trimethylsilyl)difluoride (TAS-F),11 the sole
Table 1.
We investigated the scope of the migration reaction and
found that it was limited to the preparation of a,b-
unsaturated esters. Attempts to apply to saturated
esters or phenyl ester resulted in much lesser extent of
migration when treated with TBAF.
In summary, conditions were found to affect regioselec-
tive acylation of triol 2 to give 2-O-acyl derivatives (5),
which after deprotection with TASF afforded exclu-
sively 2-O- acyl derivatives (8). A extensive migration
of the acyl group from 2-O- to 3-O-position was
observed when the desilylation was conducted with

C. Hamdouchi et al. / Tetrahedron Letters 43 (2002) 3875–3878
3877
Table 2.
TBAF. These findings provided with a convenient mean
for extending the SAR of papulacandin at these
postions.
solvent was removed in vacuo under N2, and
dichloromethane (5 mL) was added. The resulting solu-
tion (ca. 1.2 equiv.) was added under N2 to a solution of
2 (0.402) in toluene (5 mL) which had been treated, in the
,
presence of 4 A molecular sieves (500 mg) with Bu2SnO
(1.0 equiv.) at 130°C for 20 h and then cooled to rt.
When the reaction was judged complete by TLC, the
mixture was filtered through a pad of Celite and concen-
trated in vacuo. Compounds 5a–d were purified by flash
chromatography (eluent:hexanes/EtOAc). All new com-
Acknowledgements
This research was supported by the CDTI program
(Plan Concertado 96/0036) and the Spanish Farma III
program (Ministerio de Industria y Ministerio de
Sanidad). We are also grateful to the Lilly Antifungal
Action Group for their advice and interest in this work.
1
pounds gave satisfactory elemental analyses, H and 13C
NMR spectra.
1
15. Compound 5a: oil; [h]D –57.7° (c 2.4, CHCl3); H NMR
(CDCl3, 200 MHz) l 7.04–6.91 (m, 1H, ꢀCH), 6.28 (d,
J=1.5, 1H, ArH), 6.18 (d, J=1.5, 1H, ArH), 6.03–6.00
(m, 2H, 2ꢀCH), 5.62 (d, J=10.0, 1H, H–2), 5.54 (d,
J=15.1, 1H,ꢀCH), 5.12 (d, J=12.6, 1H, ArCH), 5.07 (d,
J=12.6, 1H, ArCH), 4.14–3.61 (m, 5H, H-3, H-4, H-5,
H-6a, H-6b), 2.94 (d, J=4.3, 1H, OH), 2.09 (m, 2H,
References
1. Traxler, P.; Gruner, J.; Auden, J. A. L. J. Antibiot. 1977,
30, 289–296.
2. Traxler, P.; Fritz, H.; Richter, W. J. Helv. Chim. Acta
1977, 60, 578–584.
CH2), 1.41 (m, 2H, CH2), 1.35–1.03 (m, 42H,
6
(CH3)2CH and 6 (CH3)2CH), 0.88 (t, 3H, CH3), 0.87 (s, 9
H, (CH3)3C), 0.05 (s, 3H, CH3Si), and 0.03 (s, 3H,
CH3Si); 13C NMR (CDCl3, 50 MHz) l 167.4, 158.6,
152.3, 145.8, 144.7, 143.3, 128.4, 118.7, 118.3, 109.4,
109.1, 104.5, 75.2, 73.9, 73.8, 72.9, 71.6, 65.6, 34.9, 29.7,
25.8, 21.8, 18.1, 17.8, 13.6, 13.1, 12.5, –5.5, and –5.7;
HRMS (FAB+) 849.516593 (calcd for C45H81O9Si3
849.518845)
3. Traxler, P.; Fritz, H.; Fuhrer, H.; Richter, W. J. J.
Antibiot. 1980, 33, 967–978.
4. For a review on C-aryl glycosides, see: Jaramillo, C.;
Knapp, S. Synthesis 1994, 1–20.
5. Danishefsky, S.; Phillips, G.; Ciufolini, M. Carbohydr.
Res. 1987, 171, 317–327.
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sian, S., Ed.; Marcel Dekker: New York, 1997; pp. 69–83.
14. Experimental procedure: A solution of the corresponding
acid (0.500 mmol) in dichloromethane (5 mL) was treated
under N2 with oxalyl chloride (2 M in dichloromethane,
2.0 equiv.) and DMF (0.10 equiv.) at 0°C. After 1 h, the
Compound 8a: mp >135°C (dec.); [h]D –44.4° (c 1.0,
1
CH3OH); H NMR (CD3OD, 200 MHz) l 7.12–6.99 (m,
1H,ꢀCH), 6.21–6.08 (m, 4H, 2 ArH and 2ꢀCH), 5.63 (d,
J=9.8, 1H, H-2), 5.61 (d, J=15.8, 1H,ꢀCH), 5.05 (d,
J=12.6, 1H, ArCH), 4.95 (d, J=12.6, 1H, ArCH), 3.92
(dd, J=9.1, 9.7, 1H, H-3), 3.86 (ddd, J=2.3, 2.4, 9.7, 1H,
H-5), 3.79–3.76 (m, 2H, H-6a, H-6b), 3.64 (dd, J=9.2,
9.6, 1H, H-4), 2.12 (ddd, J=5.4, 7.1, 7.4, 2H, CH2), 1.42
(ddq, J=7.1, 7.4, 7.4, 2H, CH2), and 0.90 (t, J=7.4, 3H,
CH3); 13C NMR (CD3OD, 50 MHz) l 167.8, 161.7,
154.8, 146.6, 145.7, 145.0, 129.8, 119.8, 115.5, 110.7,
103.1, 99.7, 76.1, 74.9, 74.6, 74.0, 71.3, 62.5, 36.0, 23.0,
and 14.0; HRMS (FAB+) 423.165610 (calcd for
C21H27O9 423.165508)
Compound 9a: mp >124°C (dec.); [h]D +15.3° (c 0.5,
CH3OH); 1H NMR (CD3OD, 200 MHz) l 7.32 (dd,
J=10.0, 15.4, 1H,ꢀCH), 6.34–6.17 (m, 2H, 2ꢀCH), 6.19
(s, 1H, ArH), 6.18 (s, 1H, ArH), 5.91 (d, J=15.4,

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C. Hamdouchi et al. / Tetrahedron Letters 43 (2002) 3875–3878
3H, CH3); 13C NMR (CD3OD, 50 MHz) l 169.1, 161.6,
1H,ꢀCH), 5.34 (dd, J=9.3, 10.0, 1H, H-3), 5.06 (d,
J=12.6, 1H, ArCH), 4.98 (d, J=12.6, 1H, ArCH), 4.33
(d, J=10.0, 1H, H-2), 3.92–3.59 (m, 4H, H-4, H-5,
H-6a, H-6b), 2.17 (ddd, J=6.1, 6.9, 7.3, 2H, CH2), 1.47
(ddq, J=6.9, 7.3, 7.5, 2H, CH2), and 0.93 (t, J=7.5,
154.7, 146.7, 145.7, 145.5, 129.9, 120.5, 116.6, 112.1,
102.9, 99.9, 78.3, 75.8, 73.8, 71.9, 69.8, 62.5, 36.0, 23.0,
and 14.0; HRMS (FAB+) 423.166496 (calcd for
C21H27O9 423.165508)