Synthesis and antifungal properties of papulacandin derivatives

Article abstract of DOI:10.3762/bjoc.8.82

Derivatives of an antifungal agent that targets the β-(1,3)-D-glucan synthase, papulacandin D, were synthesized and tested for activity. The papulacandin D structure contains a challenging benzannulated spiroketal unit, which is introduced in a palladiumcatalyzed cross-coupling reaction of a glycal silanolate and an aryl iodide followed by an oxidative spiroketalization. Four different variants were made, differing in the nature of the acyl side chain with respect to the length, and in the number and stereochemistry of the double bonds. Moderate biological activity was observed for the derivatives with a side chain based on palmitic acid and linoleic acid.

Full text of DOI:10.3762/bjoc.8.82

Synthesis and antifungal properties of
papulacandin derivatives
Marjolein van der Kaaden1, Eefjan Breukink2 and Roland J. Pieters*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 732–737.
1Department of Medicinal Chemistry and Chemical Biology. Utrecht
Institute for Pharmaceutical Sciences, Utrecht University, P.O. Box
80082, 3508 TB Utrecht, The Netherlands and 2Department of
Biochemistry of Membranes, Bijvoet Centre for Biomolecular
Research, Utrecht University, Padualaan 8, Utrecht, The Netherlands
doi:10.3762/bjoc.8.82
Received: 08 March 2012
Accepted: 24 April 2012
Published: 14 May 2012
Email:
This article is part of the Thematic Series "Synthesis in the
glycosciences II".
Roland J. Pieters* - R.J.Pieters@uu.nl
* Corresponding author
Guest Editor: T. K. Lindhorst
Keywords:
© 2012 van der Kaaden et al; licensee Beilstein-Institut.
License and terms: see end of document.
antifungal agents; carbohydrate; papulacandins; spiroketal
Abstract
Derivatives of an antifungal agent that targets the β-(1,3)-D-glucan synthase, papulacandin D, were synthesized and tested for
activity. The papulacandin D structure contains a challenging benzannulated spiroketal unit, which is introduced in a palladium-
catalyzed cross-coupling reaction of a glycal silanolate and an aryl iodide followed by an oxidative spiroketalization. Four different
variants were made, differing in the nature of the acyl side chain with respect to the length, and in the number and stereochemistry
of the double bonds. Moderate biological activity was observed for the derivatives with a side chain based on palmitic acid and
linoleic acid.
Introduction
In recent years, a steady increase in the incidence of oppor- the signature of a wide series of bioactive natural products [5]
tunistic fungal infections in immunocompromised patients has and has inspired ample synthetic activity [5-8]. The papulacan-
been observed [1]. Treatment failure is frequent and mortality is dins A–E were isolated from the fermentation broths of Papu-
unacceptably high in high-risk patients [2]. Reasons for this laria sphaerosperma [3]. They block the synthesis of β-(1,3)-D-
include delayed diagnosis, toxicity and low bioavailability of glucan by inhibition of β-(1,3)-D-glucan synthase [9-12]. The
current drugs, and the development of antifungal drug resis- β-(1,3)-D-glucan is an integral and essential component of the
tance [1]. Clearly, there is a need for new antifungal therapeu- fungal cell wall [13] and the dominant glucan in the cell wall of
tics. The papulacandins are a series of naturally occurring anti- most medically important fungi, and therefore it is a target that
fungal agents whose isolation and characterization were initially is being actively pursued [14]. The papulacandins have demon-
reported by Traxler and co-workers in 1977 (Figure 1) [3,4]. strated a very high specific activity against several yeasts, but
They contain a benzannulated spiroketal unit, which has been they are largely inactive against filamentous fungi, bacteria and
732

Beilstein J. Org. Chem. 2012, 8, 732–737.
protozoa [3]. Recently, in a direct comparison, papulacandin B The papulacandins represent a synthetic challenge and as such
was shown to be superior in some aspects compared to the drug the class has stimulated numerous synthetic studies. So far, only
caspofungin and a few drug candidates [15]. Its interesting bio- the total synthesis of papulacandin D, the simplest member of
logical activity has stimulated the search for new members of the family, has been published. This was reported by two
the papulacandin family, and several new compounds that are different research groups [30-33] and additionally a number of
structurally related have been isolated, such as chaetiacandein different synthetic routes [34-38] to the spiroketal core struc-
[16,17], L-687,781 [18,19], Mer-WF3010 [20,21], BU-4794F ture have been published, including a hetero Diels–Alder reac-
[22], fusacandins [23,24], saricandin and PF-1042 [25], tion [39], a palladium(0)-catalyzed coupling [40-45] and a con-
corynecandin [26,27] and the F-10748 series [28]. These struc- densation reaction [46,47]. We herein report our efforts on the
tures vary mostly with respect to the two partially unsaturated synthesis of papulacandin derivatives by total synthesis and the
acyl chains on the sugars. Small changes in these fatty acid tails evaluation of their antifungal properties. The synthetic ap-
have only small effects on the activity. However, more drastic proach is largely based on the Denmark route [31] with a few
changes in these tails or the lack of one of the tails drastically notable deviations.
reduce activity, in comparison with the most active member of
this family: papulacandin B. For the papulacandins it was Results
shown that the substituted galactose is not essential for activity, The synthesis started with the anomeric aromatic group, i.e., the
since papulacandin D is still active, but it does increase the eventual spiroketal group of the glucose, to be introduced as an
potency. Apparently, the situation is different for the related aryliodide with an ortho hydroxymethylene as in 12. The
disaccharide saricandan carrying different acyl chains, for commercially available 3,5-dihydroxybenzoic acid (1) was
which the monosaccharide analogue was not active [29]. esterified, followed by benzylation of the aromatic hydroxy
Removing the galactose acyl chain from papulacandin B results groups and reduction of the ester to the primary alcohol to give
in material that can still inhibit the target (in a spheroplasts 7 (Scheme 1). This compound was iodinated by using
glucan synthesis assay) but cannot reach the target site of C. N-iodosuccinimide (NIS), and finally the free hydroxy group
albicans [12]. The same is true for the hydrogenated form of was protected with a pivaloyl group to give aryl iodide 12.
papulacandin D [12]. Clearly some form of unsaturation is Derivatives 13 and 14, providing alternative core structures,
needed to maintain biological activity, but it is not known to were prepared similarly.
what extent unsaturation (and alkylation and/or hydroxylation)
needs to be present for the compound to reach the target site.
Scheme 1: (a) H2SO4, MeOH, reflux, 18 h, 3: 98%; (b) BnBr, K2CO3,
acetone, reflux, 18 h; (c) LiAlH4, THF, rt, 10–30 min, 7: 92% over three
steps, 8: 65% over three steps; (d) NIS, CHCl3, rt, 18 h, 9 and 11
quant. or I2, CF3COOAg, CHCl3, rt, 1 h, 10: 96%; (e) pivaloyl chloride,
Figure 1: The papulacandins.
pyridine, CH2Cl2, rt, 3–18 h, 12: 95% over 2 steps, 13: 96%, 14: 98%.
733

Beilstein J. Org. Chem. 2012, 8, 732–737.
The glucose moiety at the core of the structure, as present in
papulacandin D, was approached from glycal 15. The aim was
to obtain a silanol such as 22 for coupling to an aryl iodide in
the palladium-catalyzed cross-coupling reactions of silanolates,
as pioneered and applied by the Denmark group (Scheme 2)
[48]. The synthesis started with the saponification of 15, fol-
lowed by the protection of O-4 and O-6 by using di-tert-
butylsilyl bis(trifluoromethanesulfonate). Subsequent protec-
tion of O-3 with TES-Cl, gave the fully protected glucal 18.
According to Denmark et al. [31], lithiation and silylation of 18
should give 20, but in our hands a more complicated mixture
resulted. We concluded that under our conditions deprotonation
of the protecting group (protons α to silicon) may be competi-
tive with the desired α-lithiation next to oxygen. Use of the
more substituted TIPS silyl protecting group in 19 indeed
solved this problem and yielded 21 in almost quantitative yield.
Additional test reactions confirmed this trend as the corres-
ponding 3,4,6-tri-O-(triisopropylsilyl)-D-glucal (52) yielded a
single product after lithiation (Supporting Information File 1)
and the 3,4,6-tri-O-(tert-butyldimethylsilyl)-D-glucal gave a
mixture of products. Finally, compound 21 was oxidized to give
silanol building block 22.
Scheme 2: (a) NaOMe in MeOH, MeOH, rt, 1 h, 96%; (b)
(t-Bu)2Si(OTf)2, pyridine, DMF, −40 °C to rt, 2 h, 90%; (c) TESCl, pyri-
dine, CH2Cl2, rt, 18 h, 93%; (d) TIPSCl, imidazole, DMF, 60 °C, 2 d,
74%; (e) t-BuLi, Me2SiHCl, Et2O, −78 °C to rt, 3 h, 20: no yield, 21:
99%; (f) [RuCl2(p-cymene)]2, H2O, benzene/CH3CN, rt, 4 h, 95%.
Pd2(dba)3 to give 23 (Scheme 3). Then the pivaloyl ester was
selectively cleaved by using DIBAL-H, followed by oxidative
With building blocks 13 and 22 in hand, the palladium- spiroketalization under basic conditions to give the α- and
catalyzed cross-coupling reaction was performed by using β-anomers 29, which were separable using column chromatog-
Scheme 3: (a) Pd2(dba)3∙CHCl3, NaOt-Bu, toluene, 50 °C, 6–20 h, 23: 72%, 24: 79%, 25: 62%; (b) DiBAL-H, CH2Cl2, −78 °C to rt, 0.5–1 h, 26: 86%,
27: 70%, 28: 75%; (c) m-CPBA, NaHCO3, CH2Cl2, 0 °C to rt, 2–2.5 h; (d) HCl, CHCl3, rt, 1 h, 32: 91% over two steps, 33: 83% over two steps, 34:
86% over two steps.
734

Beilstein J. Org. Chem. 2012, 8, 732–737.
raphy. However this was not necessary: The β-anomer could (Scheme 4). The liberated hydroxy groups were reprotected
readily be converted into the more stable α-anomer 32 by using with MOM groups by using MOM-Cl to give 36. Then the
a solution of 0.1 M HCl in chloroform. Similarly, the related glucose O(3) needed to be selectively deprotected for the
iodides 14 and 15 performed well in this sequence yielding 33 incorporation of the fatty acid tail. Unfortunately, this was not
and 34.
possible from 36 because of the use of the more stable TIPS
group in this synthesis. Therefore, the cyclic silyl protecting
The first step in the synthesis of the mimics of papulacandin D group was first removed by using TBAHF in THF, followed by
was debenzylation of 32, since these groups cannot be removed the deprotection of the TIPS group with TBAF and reintroduc-
in the presence of olefines in the final product side chain tion of the cyclic silyl protecting group, giving 39. To circum-
Scheme 4: (a) Pd/C, NaHCO3, H2, THF, rt, 1.5 h, 98%; (b) MOMCl, DiPEA, DMAP, CH2Cl2, rt, 4 d, 78%; (c) TBAHF, THF, rt, 2 d, 84%; (d)
TBAF∙3H2O, THF, rt, 3 d; (e) t-Bu2Si(OTf)2, pyridine, DMF, −40°C to rt, 2 h, 84% over two steps; (f) RCOOH, NEt3, 2,4,6-trichlorobenzoyl chloride,
toluene, rt, 1 h, 39, DMAP, toluene, rt, 3 h, 40: 89%, 41: quant., 42: 92%, 43: 90%; (g) TBAHF, THF, rt, 2–3 d, 44: 25%, 45: 85%, 46: 86%, 47: 39%;
(h) Dowex 50 × 8, MeOH, 50 °C, 20 h 48: 13%, 50: 43%, 51: 7% or Sc(OTf)3, 1,3-propanediol, CH3CN, 50 °C, 3 h, 49: 9%, isolated yields after
preparative HPLC and lyophilization.
735

Beilstein J. Org. Chem. 2012, 8, 732–737.
vent this problem a silanol building block analogue of 22 activity was observed for linoleic acid derivative 50, which
bearing three TIPS protecting groups was also used (Supporting contains two cis double bonds in contrast to the four trans
Information File 1).
double bonds of papulacandin D. The highest activity was
observed for the saturated palmitic acid derivative 49, whose
At this stage, four commercially available side-chain acids, tail was of the same length as the one from papulacandin D. The
comprising variations in their degree of unsaturation, length and fact that we observed some activity with 49 is encouraging,
branching, were coupled: sorbic acid (sor), palmitic acid (pal), since this was not the case for the hydrogenated form of papula-
linoleic acid (lin) and trans-retinoic (ret) acid. Their coupling candin D [12], although that compound was able to block the
by 2,4,6-trichlorobenzoyl chloride to 39 gave the desired com- target in vitro. This could be the case for the compounds
pounds 40–43 in good yields. Following this the cyclic disilyl described here as well, but this was not investigated. In
protecting group was removed by TBAHF yielding 44–47. summary, we synthesized a number of papulacandin D deriva-
Finally, removal of the MOM group proved to be a challenge. tives with differing acyl side chains. Even though the com-
The use of Dowex (50 × 8) acidic resin in dry MeOH gave the pounds were moderately active at best it is clear that the side
most consistent results, but also the use of Sc(OTf)3 in dry chains are of crucial importance. The synthetic route taken will
acetonitrile in the presence of 1,3-propanediol [49] yielded the allow future variation of the aromatic core and will extend the
deprotected product. The final compounds were purified by synthesis to the more potent disaccharide papulacandins.
preparative HPLC. Due to some degradation during deprotec-
tion, the final yields were low. For 51 no clear NMR spectra
Supporting Information
could be obtained, possibly caused by aggregation. This was not
a problem for the other three compounds.
Supporting Information File 1
Synthetic procedures, the biological assay procedure and
The final products were tested for inhibition of Candida albi-
cans. No inhibition was observed for the all-trans-retinoic acid
derivative 51 and the sorbic acid derivative 48. The MIC for the
linoleic acid derivative 50 was measured as 100 μg/mL. The
saturated palmitic acid derivative 49 was slightly more potent
with an MIC of 88 μg/mL.
spectral data.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-8-82-S1.pdf]
Acknowledgements
The Utrecht Institute for Pharmaceutical Sciences (UIPS) is
Discussion
gratefully acknowledged for support of this research.
Starting from glycal the synthesis of papulacandin D deriva-
tives was undertaken with an initial focus on the acyl side chain,
a clearly sensitive area for activity. The synthesis followed the
general approach of Denmark et al. [31] with the palladium-
catalyzed cross-coupling reactions of silanolates as its main
feature. In our hands the reaction between glycal 18 and t-BuLi
gave a mixture of products, possibly due to competing deproto-
nation of the hydrogens α to the Si in the TES group. Moving to
the more substituted TIPS group at this position gave a clean
reaction and allowed us to proceed, albeit with a more compli-
cated endgame. It should be pointed out that the unplanned syn-
thetic route eventually taken here due to the troublesome lithia-
tion of glycal 18, led us to compound 37. This compound opens
the way to a total synthesis of disaccharides such as the papula-
candins A–C. Selective protection of the hydroxy group of C(6)
followed by glycosylation of the hydroxy group at C(4), should
accomplish this.
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