Step-Economical Synthesis of the Marine Ascidian Antibiotics Cadiolide A, B, and D

Article abstract of DOI:10.1021/jo502503w

A concise, modular and efficient synthesis of the title natural products is reported. Prominent steps include (i) one-pot assembly of a key β-aryl-α-benzoylbutenolide building block by regiocontrolled "click-unclick" oxazole-ynone Diels-Alder cycloaddition/cycloreversion and ensuing 2-alkoxyfuran hydrolysis and (ii) a protecting group-free vinylogous Knoevenagel condensation enabling rapid access to cadiolides A, B, and D from a common precursor.

Full text of DOI:10.1021/jo502503w

Note
pubs.acs.org/joc
Step-Economical Synthesis of the Marine Ascidian Antibiotics
Cadiolide A, B, and D
John Boukouvalas* and Charles Thibault
Dep
Canada
́ ́ ́
artement de Chimie, Universite Laval, Pavillon Alexandre-Vachon, 1045 Avenue de la Medecine, Quebec City, Quebec G1V 0A6,
*
S Supporting Information
ABSTRACT: A concise, modular and efficient synthesis of the
title natural products is reported. Prominent steps include (i)
one-pot assembly of a key β-aryl-α-benzoylbutenolide building
block by regiocontrolled “click−unclick” oxazole−ynone Diels−
Alder cycloaddition/cycloreversion and ensuing 2-alkoxyfuran
hydrolysis and (ii) a protecting group-free vinylogous Knoevena-
gel condensation enabling rapid access to cadiolides A, B, and D
from a common precursor.
he continuing emergence of drug-resistant microorgan-
isms has become a major global threat to public health.
Cadiolides A−E (1−5, Figure 1) comprise a group of
1
,2
T
noncytotoxic, densely functionalized butenolides isolated in
1
998 and 2012 from Indonesian and Korean ascidians,
Among bacterial pathogens, the most deadly is methicillin-
resistant Staphylococcus aureus (MRSA) causing an alarming
number of infections worldwide, not only to hospitalized
7
−9
respectively.
Only recently, however, were their significant
8
,9
in vitro antibacterial activities brought to light. Against MRSA
strains in particular, cadiolides C and D are several-fold more
potent than linezolid and at least as potent as the injectable last-
3
patients but also to healthy individuals. In the US, for instance,
8
more people die from MRSA than from HIV/AIDS,
resort drug vancomycin. Another study revealed that cadiolide
4
Parkinson’s disease, and homicide combined. Nature’s
E strongly inhibits Candida albicans isocitrate lyase (ILC),
privileged structures have been the basis of nearly all antibiotics
suggesting that the cadiolides may also possess antifungal
activity. Furthermore, in 2014, cadiolide B was shown to
5
10
in clinical use. However, new classes of compounds are
6
inhibit Japanese encephalitis virus (JEV) at a concentration of 1
urgently needed to combat the rising tide of resistance. As
11
μg/mL.
such, small-molecule natural products possessing anti-MRSA
activity and novel structural features represent compelling
targets for synthesis and leads par excellence for chemical and
pharmacological exploration.
Given the limited availability of these compounds from
marine ascidia, where recollection and resupply is often
difficult, if not impossible, future biological studies will likely
depend on total synthesis. Structurally and biogenetically, the
12
cadiolides are closely related to rubrolides (e.g., 6−9), as both
co-occur in ascidia and share a common β-aryl-γ-benzylidene-
7
,8
butenolide unit. However, the former are clearly distin-
guished by an unusual α-benzoyl appendage which makes their
carbon skeleton unprecedented (Figure 1). While the “extra”
benzoyl substituent appears to improve antibacterial and
8
,11
antiviral activity,
it also poses some specific challenges to
13
14,15
their synthesis. Indeed, compared to rubrolides,
synthetic
accomplishments in the cadiolide area have been few and far
between. The first total synthesis of a cadiolide (cf. 2), reported
16
from these laboratories in 2005, relies on furanolate chemistry
and Suzuki cross-coupling to generate intermediates 10 and 11
(
Scheme 1). Recently, Franck and Leleu described a new
Received: October 31, 2014
Published: November 25, 2014
Figure 1. Structures of cadiolides and rubrolides.
©
2014 American Chemical Society
681
dx.doi.org/10.1021/jo502503w | J. Org. Chem. 2015, 80, 681−684

The Journal of Organic Chemistry
Note
Scheme 1. Previous Syntheses of Cadiolide B
As outlined in Scheme 2, the synthesis began from easily
18
prepared ynone 13 and commercial 5-ethoxy-4-methyloxazole
19
1
4. Heating 13 with an excess of 14 in ethylbenzene
accomplished regioselective “click−unclick” Diels−Alder cyclo-
2
0,21
addition−cycloreversion
leading mainly to furan 15. The
product mixture was not purified but directly treated with
aqueous HBr/THF to give butenolides 10 and 16 in a ratio
approximating 9:1. Pleasingly, a single recrystallization of the so
obtained solid provided analytically pure 10 in a respectable
7
0% yield. Though of no consequence to the ensuing synthetic
operations, a small amount of isomer 16, arising from the
regioisomer of furan 15 (not shown), was also isolated for
characterization purposes by subjecting the filtrate to flash
chromatography. The serviceability of this ploy in generating
approach to 11 utilizing a multicomponent process as the
1
7
prominent step. On both occasions, crafting 11 into cadiolide
B (2) was achieved in two steps by demethylation and
10 in a single operation is notable given the paucity and
1
6,17
limitations of existing pathways to such α,β-disubstituted
bromination of the three identical aryl substituents.
1
3,16,17
butenolides.
Notwithstanding the individual merits of these strategies, as
yet, none have been shown to be applicable to the preparation
of cadiolides bearing nonidentical aryls, such as the highly
potent anti-MRSA agents cadiolide C and D. Herein, therefore,
we report a distinctly different, concise and modular generic
approach to these targets, illustrated by de novo acquisition of
butenolide 10 and a flexible end-game strategy enabling the
assembly of cadiolides A, B, and D from a common precursor.
Next, elaboration of the cadiolide progenitor 17 necessitated
cleavage of the methyl aryl ether groups in 10 with boron
tribromide and ensuing bromination of the phenolic moieties
16,22
with in situ generated
KBr (Scheme 2). Once again, this
3
two-step transformation was swiftly realized in one-pot fashion,
without the need for chromatographic purification, to deliver
17 (84%) after a simple recrystallization.
Scheme 2. Total Synthesis of Cadiolides A, B, and D
6
82
dx.doi.org/10.1021/jo502503w | J. Org. Chem. 2015, 80, 681−684

The Journal of Organic Chemistry
Note
At this point, the plan called for a vinylogous Knoevenagel
condensation of 17 with commercially available aldehydes 18−
0 to install the appropriate γ-arylmethylidene substituent
was chromatographed (CH
2
Cl
2
) to provide the minor regioisomer 16
1
(4.2 mg, 2%): H NMR (400 MHz, CDCl ) δ 7.75 (d, J = 8.9 Hz, 2H)
3
7
2
.46 (d, J = 8.9 Hz, 2H) 6.81 (d, J = 8.9 Hz, 2H) 6.77 (d, J = 8.9 Hz,
2
(
H) 5.10 (s, 2H) 3.82 (s, 3H) 3.75 (s, 3H); 13C NMR (100 MHz,
Scheme 2). To accomplish this as economically as possible, it
CDCl ) δ 190.7, 172.2, 164.9, 160.7, 152.4, 132.2, 130.7, 129.6, 127.3,
3
was imperative that the phenol groups in both partners remain
unprotected. Although related reactions have been used in the
1
21.2, 114.4, 114.1, 70.4, 55.7, 55.4; HRMS (ESI-TOF) m/z [M +
+
Na] calcd for C H O Na 347.0895, found 347.0901.
23
19 16
5
synthesis of (Z)-γ-benzylidenebutenolides, including cadio-
3
-(3,5-Dibromo-4-hydroxybenzoyl)-4-(3,5-dibromo-4-
hydroxyphenyl)furan-2(5H)-one (17). To a solution of butenolide
10 (286.9 mg, 0.89 mmol) in freshly distilled and degassed CH Cl (7
mL) was added BBr in CH Cl (1 M, 3.55 mL, 3.55 mmol) dropwise
1
6
14b−i,15a−c
lide B and rubrolides,
protecting group free variants
have yet to be reported. In the present instance, the α-benzoyl
2
2
substituent was considered advantageous because of the
3
2
2
24
at −78 °C. After 15 min, the mixture was slowly warmed to rt, stirred
for 24 h, and quenched with brine (10 mL) at 0 °C. The aqueous layer
was extracted with EtOAc, and the organic phase was dried (NaSO4)
and concentrated in vacuo. The crude product was triturated with
increased acidity of the γ-methylene protons and, more
importantly, the enhanced reactivity of the corresponding
25
carbanion toward aldehydes. Indeed, under classical Knoeve-
nagel conditions (piperidine, MeOH, rt), butenolide 17
Et O to give a beige solid, which was dissolved in a mixture of water
23
2
smoothly underwent Z-selective condensation with aldehyde
(
1.5 mL) and 1,4-dioxane (7.5 mL) “solution A”. Next, KBr (1.5 g)
1
8 to afford isomerically pure cadiolide A (1, 80%), whose
and Br (0.32 mL, 1 g) were dissolved in nanopure water (10 mL) to
2
26
structure was confirmed by X-ray diffraction analysis.
form KBr3 “solution B”. At this point, 5.66 mL (3.54 mmol) of
solution B were added dropwise to solution A. The mixture was
allowed to stir at rt for 2 h and then quenched with brine (15 mL), and
the aqueous layer was extracted with EtOAc. The organic phase was
successively washed with a saturated solution of sodium thiosulfate (2
Likewise, cadiolides B and D, 2 and 4, were obtained from
7 and the corresponding aldehyde in yields of 65 and 73%,
respectively (Scheme 2).
In conclusion, the first synthesis of cadiolide A and D and a
new synthesis of cadiolide B have been achieved in three
operational steps and overall yields of 47, 43, and 38% from
ynone 13. The foregoing work serves to demonstrate the power
of click-unclick Diels−Alder chemistry for constructing β-aryl-
α-benzoylbutenolides and a versatile late-stage strategy enabling
direct access to cadiolides from a single precursor.
1
×
25 mL) and brine (25 mL), dried (MgSO ), and concentrated in
vacuo. The crude product was triturated with EtOAc, filtered and
4
rinsed with cold Et O to furnish 17 (454.5 mg, 84%) as a yellow solid:
2
mp 226−229 °C dec; IR (NaCl, film) 3348, 1743, 1656, 1578, 1476,
−1
1
1
327, 1234, 1150, 1067, 738 cm ; H NMR (400 MHz, (CD ) CO)
3 2
13
δ 8.15 (s, 2H) 7.75 (s, 2H) 5.52 (s, 2H); C NMR (100 MHz,
(CD ) CO) δ 188.6, 171.1, 161.5, 156.9, 154.5, 134.7, 133.1, 131.3,
3
2
+
1
25.3, 124.9, 111.9, 111.8, 71.8; HRMS (ESI-TOF) m/z [M + H]
EXPERIMENTAL SECTION
calcd for C17 Br 614.7122, found 614.7128.
Cadiolide A (1). To a solution of 17 (50.7 mg, 0.08 mmol) in
freshly distilled methanol (1.5 mL) was added piperidine (41.0 μL,
H
9
O
5
4
■
General Protocols. All commercial reagents were used as received.
Methylene chloride and methanol were distilled from calcium hydride.
Flash chromatography was performed on an automated system (UV−
vis detector) using silica gel as stationary phase. Melting points are
uncorrected. NMR spectra were recorded at room temperature in
CDCl3 or (CD ) CO. Chemical shifts are reported relative to
0
.41 mmol), and the mixture was allowed to stir for 30 min at rt. A
solution of 4-hydroxybenzaldehyde (15.2 mg, 0.12 mmol) in methanol
0.5 mL) was then added. After 15 h, the reaction was quenched with
(
aqueous 1 M HCl (5 mL) and extracted with EtOAc. The organic
phase was dried with sodium sulfate and concentrated in vacuo. Flash
3
2
1
chloroform (δH 7.26; δC 72.2) or acetone (δH 2.05; δC 29.8). H
NMR data are recorded as follows: chemical shift (δ) [multiplicity,
coupling constant(s) J (Hz), relative integral] where multiplicity is
defined as s = singlet; d = doublet; t = triplet; q = quartet; m =
multiplet or combinations of the above. High-resolution mass spectra
were obtained on a time-of-flight instrument using electrospray
ionization (ESI).
chromatography (100:0:0 to 39:60:1 hexanes/Et O/AcOH) provided
2
cadiolide A (47.3 mg, 80%) as a red solid: mp 245−250 °C dec; IR
−
1 1
(
(
(
1
1
NaCl, film) 3397, 1740, 1598, 1165, 741 cm ; H NMR (400 MHz,
CD ) CO) δ 8.05 (s, 2H) 7.84 (d, J = 8.8 Hz, 2H) 7.69 (s, 2H) 6.97
d, J = 8.8 Hz, 2H) 6.48 (s, 1H); C NMR (100 MHz, (CD ) CO) δ
86.0, 166.3, 160.6, 156.7, 156.4, 153.3, 146.2, 134.8, 134.4, 134.1,
31.4, 125.9, 124.3, 123.0, 118.8, 117.0, 111.6, 111.4; HRMS (ESI-
3
2
13
3
2
3
-(4-Methoxybenzoyl)-4-(4-methoxyphenyl)furan-2(5H)-
+
TOF) m/z [M + H] calcd for C H O Br 716.7405, found
one (10) and 4-(4-Methoxybenzoyl)-3-(4-methoxyphenyl)-
24 13
6
4
18
furan-2(5H)-one (16). To a solution of ynone 13 (170.4 mg,
.64 mmol) in anhydrous ethylbenzene (5 mL) was added 5-ethoxy-4-
716.7396. Anal. Calcd for C24
H O Br : C, 40.26; H, 1.69. Found: C,
12 6 4
0
40.29; H, 1.36. Suitable crystals for X-ray crystallography were
obtained by partial evaporation of the eluent (hexanes/Et
over 9 days.
methyloxazole (446.5 mg, 3.51 mmol). The vial was capped, subjected
to strong vacuum under agitation, and then purged with nitrogen. This
process was repeated three times. The vial was covered with aluminum
paper, magnetically stirred, and heated in an oil bath maintained at
O/AcOH)
2
Cadiolide B (2). To a solution of 17 (37.3 mg, 0.06 mmol) in
freshly distilled methanol (1 mL) were added three molecular sieves
and piperidine (24.0 μL, 0.24 mmol), and the mixture was allowed to
stir for 30 min at rt. A solution of 3,5-dibromo-4-hydroxybenzaldehyde
(17.9 mg, 0.06 mmol) in methanol (0.5 mL) was then added. After 28
h, the reaction was quenched with aqueous 1 M HCl (10 mL) and
extracted with EtOAc. The organic phase was dried (MgSO
concentrated in vacuo, and the residue was purified by flash column
chromatography (100% hexanes to 60:38:1:1 hexanes/Et O/MeOH/
1
45−150 °C for 15 h. After cooling, the volatiles were evaporated
under vacuum at 60 °C. The crude product was dissolved in THF (6.5
mL), and aq 48% HBr (34.5 μL, 0.31 mmol) was slowly added. After
being stirred for 8 h at rt, the mixture was quenched with brine (10
mL) and extracted with EtOAc. The organic phase was dried (MgSO )
),
4
4
1
and concentrated in vacuo. H NMR analysis of the crude product
indicated a 9:1 ratio of regioisomers 10/16. The crude mixture was
recrystallized from chloroform/light petroleum ether to afford 10
2
AcOH) to give cadiolide B (34.5 mg, 65%) as a yellow solid: mp 253−
1
6
(
145.0 mg, 70%) as a yellow solid: mp 166−168 °C (lit. mp 166−
257 °C dec; IR (NaCl, film) 3477, 3067, 1758, 1475, 1296, 1250,
−
1 1
1
1
2
67 °C); IR (NaCl, film) 3007, 2936, 2841, 1748, 1598, 1253, 1166,
1153, 739 cm ; H NMR (400 MHz, (CD
3
)
2
CO) 8.16 (s, 2H) 8.06
−1
1
13
025, 834 cm ; H NMR (400 MHz, CDCl ) δ 7.91 (d, J = 8.9 Hz,
(s, 2H) 7.70 (s, 2H) 6.52 (s, 1H); C NMR (100 MHz, (CD CO)
)
3 2
3
H) 7.35 (d, J = 9.0 Hz, 2H) 6.91 (d, J = 9.0 Hz, 2H) 6.84 (d, J = 8.9
Hz, 2H) 5.29 (s, 2H) 3.84 (s, 3H) 3.79 (s, 3H); C NMR (75 MHz,
185.9, 165.8, 156.4, 156.3, 153.5, 152.9, 147.9, 135.7, 134.8, 134.2,
131.3, 128.9, 124.4, 123.8, 114.8, 111.8, 111.7, 111.4; HRMS (ESI-
13
+
CDCl ) δ 190.4, 171.4, 164.9, 162.6, 160.0, 132.2, 129.8, 129.0, 123.6,
TOF) m/z [M + H] calcd for C H O Br 874.5595, found
3
24 11
6
6
+
1
21.7, 114.8, 114.3, 70.5, 55.7, 55.6; HRMS (ESI-TOF) m/z [M + H]
874.5589.
calcd for C H O 325.1076, found 325.1075. Anal. Calcd for
Cadiolide D (4). Using a procedure similar to that described above,
17 (38.5 mg, 0.06 mmol) and 3-bromo-4-hydroxybenzaldehyde (13.3
19
17
5
C H O : C, 70.36; H, 4.97. Found: C, 70.62; H, 4.74. The filtrate
19
16
5
6
83
dx.doi.org/10.1021/jo502503w | J. Org. Chem. 2015, 80, 681−684

The Journal of Organic Chemistry
Note
mg, 0.07 mmol) were stirred in distilled MeOH (0.5 mL), and three
molecular sieves were added. The mixture was cooled to 0 °C, and
piperidine (25.0 μL, 0.25 mmol) was added. After being stirred for 10
min at 0 °C, the mixture was slowly warmed to rt and stirring
continued for 28 h. Usual workup and flash chromatography (100%
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2002, 43, 2023−2027. (e) Kar, A.; Argade, N. P. Synthesis 2005,
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Synth. Commun. 2007, 37, 4253−4263. (g) Cacchi, S.; Fabrizi, G.;
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hexanes to 60:38:1:1 hexanes/Et O/MeOH/AcOH) afforded cadio-
2
lide D (36.5 mg, 73%) as an orange solid: mp 244−245 °C dec; IR-
ATR (ZnSe, neat) 3190, 3078, 2923, 1738, 1538, 1371, 1292, 1148,
−
1 1
7
8
41 cm ; H NMR (500 MHz, (CD ) CO) 8.14 (d, J = 1.9 Hz, 1H)
3 2
.05 (s, 2H) 7.84 (dd, J = 8.6, 1.8 Hz, 1H) 7.70 (s, 2H) 7.14 (d, J = 8.6
Hz, 1H) 6.50 (s, 1H); C NMR (125 MHz, (CD ) CO) 186.0, 166.1,
13
3
2
1
1
56.7, 156.5, 156.4, 153.4, 147.0, 137.0, 134.8, 134.2, 133.1, 131.4,
27.6, 124.1, 123.8, 117.7, 116.8, 111.7, 111.4, 111.0; HRMS (ESI-
(15) Select syntheses of rubrolide analogues: (a) Barbosa, L. C. A.;
+
TOF) m/z [M + H] calcd for C H O Br 794.6510, found
Maltha, C. R. A.; Lage, M. R.; Barcelos, R. C.; Dona,
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A.; Varneiro, J. W.
24
12
6
5
794.6507.
(
ASSOCIATED CONTENT
Supporting Information
■
1
*
S
Chem. 2003, 2290−2302. (d) Zhang, R.; Iskander, G.; da Silva, P.;
Chan, D.; Vignevich, V.; Nguyen, V.; Bhadbhade, M. M.; Black, D. S.;
Kumar, N. Tetrahedron 2011, 67, 3010−3016.
Proton and carbon NMR spectra of all isolated compounds,
and full crystallographic data for 1. This material is available
free of charge via the Internet at http://pubs.acs.org.
(16) Boukouvalas, J.; Pouliot, M. Synlett 2005, 343−345.
(
́
17) Peixoto, P. A.; Boulange, A.; Leleu, S.; Franck, X. Eur. J. Org.
Chem. 2013, 3316−3327.
AUTHOR INFORMATION
■
(18) Ynone 13 was prepared in 96% yield by Pd-catalyzed coupling
Corresponding Author
E-mail: john.boukouvalas@chm.ulaval.ca.
of commercial p-MeOPhCOCl and p-MeOPhCCH as previously
described: (a) Liang, J.; Hu, W.; Tao, P.; Jia, Y. J. Org. Chem. 2013, 78,
*
5
810−5815. (b) Roy, S.; Davydova, M. P.; Pal, R.; Gilmore, K.;
Notes
Tolstikov, G. A.; Vasilevsky, S. F.; Alabugin, I. V. J. Org. Chem. 2011,
The authors declare no competing financial interest.
7
9
6, 7482−7490. (c) Waldo, J. P.; Larock, R. C. J. Org. Chem. 2007, 72,
643−9647. See also: (d) Kim, W.; Park, K.; Park, A.; Choe, J.; Lee, S.
ACKNOWLEDGMENTS
Org. Lett. 2013, 15, 1654−1657.
(
■
19) Alternatively, oxazole 14 can be inexpensively prepared on a
We are grateful to the Natural Sciences and Engineering
Research Council of Canada (NSERC) and the FRQNT-
large scale from d,l-alanine: Dean, A.; Ferlin, M. G.; Brun, P.;
Castagliuolo, I.; Badocco, D.; Pastore, P.; Venzo, A.; Bombi, G. G.; Di
Marco, V. B. Dalton Trans. 2008, 1689−1697.
́
Quebec Centre in Green Chemistry and Catalysis (CGCC) for
financial support. We also thank NSERC-CGS for a doctoral
scholarship to C.T.
(20) (a) Boukouvalas, J.; Loach, R. P. Org. Lett. 2013, 15, 4912−
4914. (b) Boukouvalas, J.; Thibault, C.; Loach, R. P. Synlett 2014, 25,
139−2142.
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(
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(
2
(
25) In general, condensation rates closely correlate with the pK ’s of
a
Knoevenagel donors; see, for example: (a) Li, W.; Fedosov, S. N.; Tan,
T.; Xu, X.; Guo, Z. ACS Catal. 2014, 4, 3294−3300. (b) Burgoyne, A.
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(
(26) The solid-state structure of synthetic 1 (cocrystallized with two
(
molecules of water) further reveals that the brominated aromatic rings
undergo intra- and intermolecular π-stacking; see the Supporting
Information for details.
(
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3
6
84
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