Total synthesis of papulacandin D

Article abstract of DOI:10.1021/ja070071z

A total synthesis of the antifungal agent papulacandin D is reported. The molecule is representative of a large class of C-aryl glycosides that exhibit significant antifungal activity. The synthetic strategy bifurcates the molecule into two nearly equal subunits, the arylglycoside and 18-carbon fatty acid side chain. The key strategic transformations are (1) the palladium catalyzed, organosilanolate-based cross-coupling of a protected glucal silanol and (2) a catalytic enantioselective allylation of a dienal using allyltrichlorosilane. The synthesis was accomplished in 31 steps overall from commercial starting materials to afford over 50 mg of the natural product. Copyright

Full text of DOI:10.1021/ja070071z

Published on Web 02/17/2007
Total Synthesis of Papulacandin D
Scott E. Denmark,* Christopher S. Regens, and Tetsuya Kobayashi
Department of Chemistry, UniVersity of Illinois at Urbana-Champaign, Urbana, Illinois 61801
Received January 5, 2007; E-mail: denmark@scs.uiuc.edu
The papulacandins and chaetiacandins constitute a family of
side-chain carboxylic acid was prepared from L-isoleucine using ki-
netic resolution to separate the C(7′′) epimers. The two fragments
were coupled by acylation using a mixed anhydride of the side chain.
Our synthetic plan for papulacandin D makes the obvious
disconnection at the O-C(3) ester linkage to acid 2 and glycopy-
ranoside 1 (Scheme 1). The major challenges in the synthesis
resided in these independent units, namely, (1) the construction of
the arylglycoside bond and (2) control of the C(7′′) and C(14′′)
stereogenic centers. Moreover, potential solutions to these problems
could be identified in ongoing methodological studies in these
laboratories. First, disconnection of 1 at C(1) reduced the problem
to a palladium-catalyzed cross-coupling of glucal silanol 3 and aryl
iodide 4.14 Although we had already reported the synthesis C-aryl-
2-H-pyrans from 2-pyranylsilanols,15 this transformation failed with
complex substrates and the fluoride activation was incompatible
with silicon protecting groups. Thus, the first challenge was to
determine whether the newly developed, fluoride-free variant16
could be adapted to generate the spirocyclic C-aryl glycopyranoside.
Second, inspection of 2 suggested that the C(6′′)-C(7′′) bond could
arise from enantioselective addition of allyltrichlorosilane (6) to
conjugated aldehyde 5. We have previously described in detail the
chiral bisphosphoramide-catalyzed addition of allylic trichlorosilanes
into aldehydes.17 Herein, we report an efficient, enantioselective
total synthesis of papulacandin D in which these methods serve as
the key strategic steps.
glycolipids that have shown potent in vitro antifugual activity
against Candida albicans, C. tropicalis, Pneumocystis carinii, and
related microorganisms (Chart 1).1 Opportunistic infections arising
from these pathogens are responsible for increased mortality among
immunocompromised patients.2
Papulacandins A-E were isolated and structurally characterized
by Traxler in 19771 from the fermentation broth of Papularia
spherosperma. All of the papulacandins contain a 1,7-dioxaspiro-
[5.4]decane skeleton with an aryl-â-D-C-glycopyranoside derived
from 5-(hydroxymethyl)resorcinol. In addition, the O-C(3) position
of the glucose ring is esterified with a branched 18-carbon
unsaturated fatty acid. The papulacandin structures A-C bear
different O-C(6)-acyl-â-galactoside subunits at the O-C(4) position
of papulacandin D (Chart 1).
Chart 1
Scheme 1
The antibiotic and antifungal properties along with the structural
complexity of these spiro C-arylated glycopyranosides have stimu-
lated the development of creative solutions for the construction of
the tricyclic spiro ketal ring system. Recent representative examples
include a synthesis of a racemic-spiro ketal unit via a hetero-Diels-
Alder3 reaction and dihydroxylation of 5-aryl-2-vinylfurans followed
by Achmatowicz rearrangement.4 The majority of work has focused
on condensation of functionalized organolithium reagents with
cyclic or acyclic derivatives of D-gluconolactone.5-9 These methods
provided rapid access to the spiro ketal core but suffer from
moderate to low yields. Alternatively, nucleophilic addition of a
lithiated hexenopyranose to a functionalized quinone has been
utilized to access the aryl-â-D-C-glycopyranoside.10 Finally, Pd-
(0)-catalyzed cross-coupling reactions of a protected (tributylstan-
nyl)-hexenopyranose with aryl bromides have been reported.
Unfortunately, excess of the toxic tin reagent is required because
of dimerization of the donor.11,12
The synthetic plan began with the preparation of aromatic iodide
4. Esterification of commercially available 3,5-dihydroxybenzoic
acid to afford methyl ester 8 was followed by protection of the
resorcinol hydroxyl groups with benzyl bromide and reduction of
the ester with lithium aluminum hydride to afford benzyl alcohol
10 in near quantitative yield (three steps). Finally, iodination of 10
with N-iodosuccinimide provided the aromatic iodide, which was
protected as the pivaloyl ester (4) in excellent yield (93%, two steps)
(Scheme 2).
Barrett and co-workers reported the first and only total synthesis
of any member of the papulacandin family, papulacandin D.13 Their
approach features a condensation of an aryllithium reagent into a
protected D-gluconolactone to assemble the spiro ketal moiety. The
9
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C O M M U N I C A T I O N S
Scheme 2a
Scheme 4 a
a Conditions: (a) SOCl2, MeOH, reflux, 2 h, >99%; (b) BnBr, K2CO3,
acetone, room temp, 24 h, >99%; (c) LiAlH4, THF, 0 °C to room temp,
3 h, 98%; (d) N-iodosuccinimide, CHCl3, room temp, 24 h, 91%; (e) pivaloyl
chloride, pyridine, CH2Cl2, room temp, 3 h, 94%.
The preparation of the spirocyclic C-aryl glycopyranoside began
by saponification of triacetate 1118 to give the free hexenopyranose
which was immediately protected as its di(tert-butyl)silylene acetal
(Scheme 3).19 Protection of the C(3)-hydroxyl group with TES-Cl
provided fully silyl protected hexenopyranose 12 in 91% yield (two
steps). With 12 in hand, the stage was set for implementation of
the key cross-coupling reaction. Thus, lithiation and silylation of
12 with chlorodimethylsilane provided 13, which was subjected to
oxidative hydrolysis catalyzed by bis[chloro(p-cymene)ruthenium-
(II)]20 in the presence of 2.0 equiv of water to provide silanol 3 in
84% yield. Gratifyingly, the combination of aryl iodide 4 and the
silanol 3 proceeded smoothly to afford aryl-hexenopyranose 14 in
82% yield. The vital cross-coupling reaction was carried out with
5 mol % Pd2(dba)3‚CHCl3 as the catalyst and 2.0 equiv of NaOt-
Bu as the activator at 50 °C for 5 h. Removal of the pivaloyl group
set the stage to elaborate the aryl-hexenopyranose.
a Conditions: (a) m-CPBA, NaHCO3, CH2Cl2, 0 °C, 2 h (dr 5:1, 77%
R, 15% â); (b) triphosgene, DMAP, CHCl3, -56 °C to room temp; i-Pr2EtN,
16, CHCl3, -56 °C to room temp, 2-(trimethylsilyl) ethanol, room temp,
12 h, 92%; (c) Pd/C, NaHCO3, H2, THF, room temp, 5 h, >99%; (d) TEOC-
Cl, i-Pr2EtN, CH2Cl2, room temp, 9 h, 96%; (e) PPTS, EtOH, room temp,
4 h, 92%.
Synthesis of the side-chain unsaturated acid 2 began by asym-
metric hydrogenation of geraniol23 with Ru(OAc)2[(S)-BINAP] to
provide (S)-citronellol (99%, 97:3 er) (Scheme 5).24
Scheme 5 a
Scheme 3a
a Conditions: (a) K2CO3 (0.01 equiv), MeOH, room temp, 1 h;
t-Bu2Si(OTf)2, 2,6-lutidine, DMF, 0 °C to room temp, 2 h, 89%; (b) TES-
Cl, pyridine, CH2Cl2, room temp, 4 h, 92%; (c) t-BuLi, Me2SiHCl, THF,
-78 °C to room temp, 1 h, 89%; (d) [RuCl2(p-cymene)]2 (3.0 mol %),
H2O (2.0 equiv), 1:1 benzene/CH3CN, room temp, 1 h, 84%; (f)
Pd2(dba)3‚CHCl3, NaOt-Bu (2.0 equiv), toluene, 50 °C, 5 h, 82%; (g)
DIBAL-H, CH2Cl2, -78 °C to room temp, 1 h, 98%.
The crucial spiro ketalization was effected by treatment of 15
with m-CPBA in the presence of NaHCO3 to afford a mixture of
chromatographically separable anomers 16R (77%) and 16â (15%)
(Scheme 4).21 Initially, protection of the C(2) hydroxyl group was
problematic; however, treatment of 16 with a preformed acylpy-
ridinium species followed by addition of 2-(trimethylsilyl)ethanol
gave 2-(trimethylsilyl)ethyl carbonate (TEOC)-protected spiro ketal
in 92% yield. Debenzylation of 17 with Pd/C proceeded quantita-
tively. Subsequent TEOC protection of the resorcinol portion was
achieved using TEOC-Cl22 in the presence of 2,6-lutidine to produce
the fully silylated spiro ketal 19 in 96% yield overall. Selective
removal of the O-C(3) TES group with PPTS/EtOH afforded 20 in
93% yield.
a Conditions: (a) Ru(OAc)2[(S)-BINAP] (0.7 mol %), H2 (1500 psi),
95% MeOH, room temp, 20 h, 99% (97:3 er); (b) Ts-Cl, pyridine, room
temp, 10 h, 89%; (c) LiHBEt3, THF, NaOH-H2O2, room temp, 1 h, 86%;
(d) O3, NaHCO3, CH2Cl2-MeOH, -78 °C to room temp, DMS, 2.5 h; (e)
(EtO)2POCH2CdC(CH3)CO2Et, LiOH, MS 4 Å, THF, reflux, 2 h, 78%
(two steps) (E,E/E,Z 91:9); (f) DIBAL-H, THF, 0 °C, 0.5 h, 85% (pure
E,E); (g) MnO2, CHCl3, reflux, 4 h, 89%; (h) (R,R)-26 (10 mol %), 6,
CH2Cl2, i-Pr2EtN, -78 °C, 8 h, 88% (96:4 dr); (i) Grubbs’ second gen.
catalysts (5.0 mol %), acrolein (13 equiv), CH2Cl2, 90%; (j) TES-Cl, 2,6-
lutidine, CH2Cl2, room temp, 4 h, 92%; (k) Ph3PdCCO2Me, ClCH2CH2Cl,
reflux, 18 h, 90% (E/Z 90:10); (l) TMSOK, THF, room temp, 4 h, >99%.
Tosylation followed by deoxygenation with LiHBEt3 afforded
hydrocarbon 23 in good yield (88%, two steps). Subsequent
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C O M M U N I C A T I O N S
ozonolysis and Horner-Wadsworth-Emmons25 olefination af-
forded unsaturated ester 24, an inseparable mixture of isomers
(∆10′′,11′′ E/Z, 91:9)). Subsequently, DIBAL-H reduction fol-
lowed by chromatographic separation of the geometrical isomers
and oxidation afforded aldehyde (E,E)-5 in 84% yield (four
steps).
The enantioselective allylation of 5 using chiral bisphosphora-
mide (R,R)-2617 smoothly provided 27 in good yield and excellent
diastereomeric selectivity (88%, dr 96/4). The expected C(7′′) S
configuration was confirmed by analysis of Mosher esters.26 Olefin
metathesis with acrolein using Grubbs’ second generation catalyst,27
and protection of the C(7′′) hydroxyl group with TES-Cl gave 29
(91%, two steps). The synthesis of 2 was completed by Wittig
olefination and saponification with potassium trimethylsilanoate28
in excellent yield (90%, two steps).
The coupling of fragments 2 and 20 was achieved via the mixed
anhydride of acid 1 from 2,4,6-trichlorobenzoyl chloride29 and
DMAP in good yield (87%) (Scheme 6). Global deprotection
proceeded smoothly with HF/Et3N (60:40 ratio) in DMSO to afford
papulacandin D (89% yield). Synthetic papulacandin D exhibited
spectroscopic and physical properties identical to those reported
for the natural and synthetic material (1H NMR, 13C NMR, HRMS,
optical rotation, UV-vis).1,13
spectra. This material is available free of charge via the Internet at
http://pubs.acs.org.
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a Conditions: (a) 2,4,6-Cl3C6H2COCl, Et3N, room temp, 1 h, 20, toluene,
room temp, 3 h, 87%; (b) HF‚Et3N (60:40 ratio), DMSO, 60 °C, 15 h,
89%.
In conclusion, papulacandin D has been synthesized by a
convergent synthetic strategy that features a silicon-based, cross-
coupling reaction to construct the key spirocyclic C-aryl glycopy-
ranoside 16 and an enantioselective allylation reaction using a chiral
bisphosphoramide for the construction of the C(7′′) stereocenter.
The application of palladium-catalyzed, silicon-based, cross-
coupling reactions in the synthesis of more complex molecules is
currently under investigation.
Acknowledgment. We are grateful to the National Institutes
of Health for generous financial support (Grant R01 GM63167).
We are grateful to Prof. A. G. M. Barrett for kindly providing
spectra of synthetic papulacandin D.
Supporting Information Available: Detailed experimental pro-
cedures, full characterization of all products, and comparison NMR
JA070071Z
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