Total Synthesis of the Antitumor Antibiotic Basidalin

Article abstract of DOI:10.1021/acs.joc.6b01255

The first synthesis of the tetronamide antibiotic basidalin was accomplished in five steps and 39% overall yield from readily available 4-bromo-2-triisopropylsilyloxyfuran and 2-formyl-1,3-dithiane. Highlights include: (i) regio- and stereocontrolled assemblage of a pivotal (Z)-γ-ylidene-β-bromobutenolide intermediate by stereodirected vinylogous aldol condensation (SVAC), (ii) installation of the amino group via aza-Michael addition/elimination, and crucially (iii) facile access to basidalin by late-stage dithiane removal.

Full text of DOI:10.1021/acs.joc.6b01255

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Note
Total Synthesis of the Antitumor Antibiotic Basidalin
Jaime A. M. Acosta, Ramesh Muddala, Luiz CLaudio Almeida Barbosa, and John Boukouvalas
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01255 • Publication Date (Web): 27 Jun 2016
Downloaded from http://pubs.acs.org on June 28, 2016
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Total Synthesis of the Antitumor Antibiotic Basidalin
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Jaime A. M. Acosta,† Ramesh Muddala,† Luiz C. A. Barbosa,‡
and John Boukouvalas*,†
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†Department of Chemistry, Pavillon Alexandre-Vachon, Université Laval, 1045 Avenue
de la Médecine, Quebec City, Quebec G1V 0A6, Canada
‡Department of Chemistry, Instituto de Ciências Exatas, Universidade Federal de Minas
Gerais (UFMG), Av. Pres. Antônio Carlos, 6627, Campus Pampulha, Belo Horizonte,
31270-901, MG, Brazil.
E-mail: john.boukouvalas@chm.ulaval.ca
ABSTRACT:
Br
5 steps
3 purifications
H N
2
OTIPS
O
O
S
+
39% yield
O
O
O
S
basidalin
The first synthesis of the tetronamide antibiotic basidalin was accomplished in five steps
and 39% overall yield from readily available 4-bromo-2-triisopropylsilyloxyfuran and 2-
formyl-1,3-dithiane. Highlights include: (i) regio and stereocontrolled assemblage of a
pivotal (Z)−γ−ylidene−β−bromobutenolide intermediate by stereodirected vinylogous
aldol condensation (SVAC), (ii) installation of the amino group via aza-Michael
addition/elimination, and crucially (iii) facile access to basidalin by late-stage dithiane
removal.
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Basidalin (1, Figure 1) is a small but richly functionalized antibiotic first isolated in 1983
from the fungus Leucoagaricus naucina,1 and again in 1994 from a related fungus,
Leucoagaricus cameifolia.2 Its unique tetronamide structure, including the Z-geometry of
the formylmethylidene moiety, was firmly established by X-ray analysis.1
Notwithstanding the frequent use of tetronamides in chemical, pharmaceutical and
agrochemical research,3-5 basidalin holds the prominent position of being the first, and to
date only, tetronamide known to occur in Nature. In addition, 1 possesses antibacterial
properties and significant antitumor activity against leukemia,1,2 both in vitro (IC50 = 0.11
µg/mL) and in vivo, dose-dependently prolonging the survival of mice inoculated with
L1210 cells.1
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H N
2
H N
2
O
O
O
O
O
O
1
basidalin
2
(E)-basidalin
O
H N
2
H N
2
OMe
O
O
S
N
H
O
3
O
thiobasidalin
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Figure 1. Basidalin and Relatives
These attributes have stimulated considerable interest not only in the synthesis of 1 but
also in a variety of its analogues.6-10 However, while certain analogues have succumbed
to synthesis (e.g. 2-4, Figure 1),7-9 basidalin itself has so far proven remarkably
elusive.6,7,10
Thus, Hiyama’s advanced intermediates 5 and 6 (Scheme 1), each synthesized in five
steps, failed to undergo conversion to 1 under an extensive array of conditions.6 Using an
elegant ring transformation of cyclobutenones 7, Eguchi and co-workers were able to
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synthesize (Z)−γ−formylmethylenetetronate 8, but when this chemistry was applied to
basidalin, the E-isomer 2 was obtained instead.7 Recently, Dechoux’s group employed a
decarboxylative Knoevenagel-type reaction to assemble Z-configured intermediates 9 and
10. However, neither of them could be transformed into 1.10
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Scheme 1. Attempted Syntheses of 1
H N
2
H N
2
O
O
O
O
O
MeO
HO
5
H N
2
10
6
10
H
Hiyama
Dechoux
O
O
O
1
H N
2
PMB
N
O
O
O
O
EtO
7
O
Eguchi
6
9
3 steps
H N
2
O
Cl
X
(X = NH )
2
O
O
O
O
OH
7
2
MeO
3 steps
O
(X = OMe)
O
O
8
Herein we describe the first successful synthetic approach to basidalin (1), which
illustrates a new and potentially general strategy for constructing (Z)−γ−alkylidene-
tetronamides. Considering the difficulties experienced in generating 1 from seemingly
ideal precursors10 (cf. 9-10, Scheme 1), it was not a priori possible to predict with
confidence which endgame tactics would succeed. After reviewing several options, we
came to favor S,S-acetal A as the ultimate precursor (Scheme 2). The availability of
highly specific and mild conditions for cleavage of the thioacetal group11 was expected to
greatly simplify the task of acquiring basibalin. Access to A was to be gained from
bromobutenolide B, which would in turn derive from C with D by utilizing our
stereodirected vinylogous aldol condensation (SVAC) method.12 Previously, we had used
bromine as a removable stereocontrol element for making (Z)−β−unsubstituted−γ−alkyl-
idenebutenolides.12 In the present instance, bromine would serve the dual purpose of
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stereodirecting and activating group, thereby enabling its replacement by an amino
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substituent (B g A, Scheme 2).
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Scheme 2. Our Retrosynthetic Analysis
H N
2
H N
2
?
O
O
O
O
O
RS
1
A
SR
Br
Br
O
SVAC
+
OSiR'
O
3
O
O
RS
SR
RS
D
SR
C
B
The synthesis began with 2-formyl-1,3-dithiane 11 and 2-silyloxyfuran 12 (Scheme 3),
each prepared in one step from commercial chemicals.13,14 In keeping with previous
experience,15 BF3-mediated vinylogous Mukaiyama aldol reaction (VMAR)16 of 11 with
12 swiftly provided 13 in essentially quantitative yield as a 10:1 mixture of the syn and
anti diastereoisomers. To ascertain their respective identities, the major isomer (syn-13)
was isolated and subjected to X-ray analysis. However, since both stereoisomers were
deemed capable of undergoing Z-selective elimination,12,17 the syn/anti mixture was
carried forward without purification. Initial attempts to bring about elimination under
standard conditions (cf. MsCl/Et3N)12,18 led to complex mixtures containing only ca. 10-
25% of the desired (Z)-ylidenebutenolide 14 and traces of (E)-14 (1-2%). On the positive
side, the ketene thioacetal isomer of 14 could not be observed among the products.19
Conceivably, complications may stem from the high acidity of the allylic C-H in 14 and
enhanced reactivity of the corresponding carbanion. Pleasingly, recourse to a weaker base
than triethylamine solved the problem. Thus, treatment of the crude syn/anti-13 mixture
with mesyl chloride and pyridine in CH2Cl2 at -10 °C afforded 14 as the only detectable
isomer, isolated in 82% yield after flash chromatography.
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Scheme 3. Total Synthesis of Basidalin
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O
S
Br
Br
S
Br
S
MsCl, py, CH2Cl2
-10 °C to rt, 15 h
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.
BF3 OEt2, CH2Cl2
HO
S
+
S
OTIPS
O
O
-78 °C, 1 h, ca. 100%
82%, 2 steps
O
O
O
S
(Z only)
12
syn-13
14
11
(dr = 10:1)
not purified
NaN3
DMF
X-ray
0 °C, 2 h
N3
H2N
H2N
SnCl2, MeOH
0 °C, 30 min
MeI, CaCO3
aq. acetone
O
O
O
O
O
O
60 °C, 5 h
72%
66%, 2 steps
O
S
S
1
16
15
not purified
S
S
(basidalin)
Next, the plan called for aza-Michael addition/elimination to introduce the amino group
(cf. 14 g 16, Scheme 3). Given the propensity of γ−alkylidenebutenolides to undergo
facile ring opening with ammonia, leading to 5-hydroxypyrrol-2(5H)-ones,20 the desired
transformation was not apt to be realized directly.21 Ultimately, a two-step process via
azide 15 was explored and found highly effective. In the event, exposure of 14 to sodium
azide in DMF at 0 °C led smoothly to the conjugate addition/elimination product 15. The
azide proved to be somewhat unstable at room temperature and was therefore
immediately reduced with SnCl2/MeOH22 at 0 °C to furnish tetronamide 16 in an overall
yield of 66% after purification. To the best of our knowledge, only β−halobutenolides
lacking the γ−ylidene functionality have been previously converted to azides (NaN3,
MeOH, rt).23 Interestingly, the use of MeOH instead of DMF as solvent, led to
substantially slower, incomplete conversion of 14 to 15 at 0 °C. Even after running the
reaction for 24 h at rt, some unreacted 14 could be observed by TLC, resulting in a lower
yield of 16 after reduction (57%). Finally, alkylative hydrolysis of the dithiane group
under the mild Fetizon conditions (MeI/CaCO3)24 uneventfully delivered basidalin (1,
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72%) whose H and C NMR spectra were in full agreement with those reported in the
literature.1
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In summary, the first synthesis of the tetronamide antibiotic basidalin has been achieved
in 5 steps and 39% overall yield from readily available compounds. In addition to
providing unfettered access to the natural product for further biological evaluation, the
synthesis demonstrates the utility of SVAC technology for rapid, regio and
stereocontrolled assemblage of densely functionalized (Z)−γ−ylidenebutenolides and
tetronamides.
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EXPERIMENTAL SECTION
General Protocols. The following procedures were used unless otherwise noted.
Moisture-sensitive reactions and dry solvent distillation were carried out in flame-dried
glassware sealed under a positive pressure of dry argon. Moisture-sensitive liquids,
by syringe or cannula through rubber
solutions and anhydrous solvents were transferred
septa.
Unless noted otherwise, all commercial reagents were used as received. Anhydrous DMF
was used as received. Dry dichloromethane and methanol were distilled from calcium
hydride. Dry pyridine was distilled from potassium hydroxide.
Flash chromatography was performed on an automated system (UV- vis detector) using
silica gel as stationary phase. NMR spectra were recorded at room temperature in CDCl3,
(CD3)2CO and (CD3)2SO. Chemical shifts are reported relative to chloroform (δH 7.26; δC
77.16), acetone (δH 2.05; δC 29.84, 206.26) and dimethyl sulfoxide (δH 2.50; δC 39.52). 1H
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;
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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).
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5-((1,3-Dithian-2-yl)(hydroxy)methyl)-4-bromofuran-2(5H)-one (13). To a solution of
silyloxyfuran 12 (300 mg, 0.94 mmol) in dry CH2Cl2 (6 mL) that had been cooled to -78
°C, were sequentially added in a dropwise fashion 1,3-dithiane-2-carbaldehyde 11 (120
µL, 1.03 mmol, 1.1 equiv) and BF3•OEt2 complex (140 µL, 1.13 mmol, 1.2 equiv). After
1 h, the mixture was poured to saturated aq NaHCO3 (20 mL). The aqueous layer was
extracted with CH2Cl2 (3 × 15 mL) and the combined organic layers were dried (MgSO4)
and concentrated under reduced pressure to afford 13 (292 mg, 100%) as a 10:1 mixture
of the syn and anti isomers. Their stereostructures were assigned by integration of
diagnostic NMR signals (1H NMR: δsyn 5.56, 4.31, 3.97 ppm; δanti 4.87, 4.41, 4.18 ppm;
and 13C NMR: δsyn 148.2, 122.9, 83.6, 67.7, 26.0, 25.2, 24.9 ppm; δanti 146.5, 123.8, 84.5,
71.2, 27.0, 25.9, 25.0 ppm). The 10:1 mixture (syn/anti-13) was used as obtained in the
synthesis of compound 14.
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For the purpose of characterization, the experiment was repeated and the major (syn)
isomer was purified by preparative TLC (100% CH2Cl2): syn-13 (86%); white solid: mp
106-112 °C dec; IR (NaCl, film) ν 3436, 3100, 2895, 1755, 1603, 1422, 1281, 1159,
1
1102, 1023, 994, 907, 823, 775, 823 cm−1; H NMR (400 MHz, CDCl3) δ 6.38 (s, 1H),
5.56 (s, 1H), 4.31 (d, J = 10.0 Hz, 1H), 3.97 (d, J = 10.0 Hz, 1H), 2.93−3.05 (m, 2H),
13
2.86 (d, J = 1.6 Hz, 1H), 2.58−2.73 (m, 2H), 2.05−2.15 (m, 2H); C NMR (100 MHz,
CDCl3) δ 170.1, 148.2, 122.9, 83.6, 67.6, 45.2, 26.0, 25.1, 24.9; HRMS (ESI-TOF) m/z
[M + H]+ calcd for C9H12BrO3S2 310.9406, found 310.9405.
Suitable crystals for X-ray crystallography were obtained by recrystallization from hot
absolute ethanol.
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(Z)-5-((1,3-Dithian-2-yl)methylene)-4-bromofuran-2(5H)-one (14). Crude 13 (dr =
10:1, 170 mg, 0.55 mmol) was dissolved in dry CH2Cl2 (4 mL) and the solution was
cooled to -10 °C. To this solution was added pyridine (90 µL, 1.09 mmol, 2 equiv) before
dropwise addition of methanesulfonyl chloride (80 µL, 0.98 mmol, 1.8 equiv). The
mixture was allowed to stir at the same temperature for 1 h, another 90 µL of pyridine
was added and the solution was slowly allowed to warm to room temperature while
stirred overnight. After 15 h, the mixture was poured to aq 1 N HCl (15 mL) and the
aqueous layer was extracted with CH2Cl2 (3 × 15 mL). The combined organic layers were
dried (MgSO4) and concentrated in vacuo. The product was purified by flash column
chromatography (5% EtOAc in hexanes) to provide 14 (132 mg, 82%) as a pale brown
solid: mp 97-100 °C dec; IR (NaCl, film) ν 3133, 2901, 1781, 1670, 1559, 1422, 1293,
1000, 967, 905, 660 cm−1; 1H NMR (400 MHz, CDCl3) δ = 6.45 (s, 1H), 5.68 (d, J = 11.0
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Hz, 1H), 5.19 (d, J = 11.0 Hz, 1H), 2.90−2.96 (m, 4H), 2.04−2.20 (m, 1H), 1.85−2.03 (m,
1H); 13C NMR (100 MHz, CDCl3) δ = 165.8, 147.9, 137.3, 121.8, 110.7, 40.2, 29.2, 24.8;
HRMS (ESI-TOF) m/z [M + H]+ calcd for C9H10BrO2S2 292.9300, found 292.9286. Anal.
Calcd for C9H9BrO2S2: C, 36.87; H, 3.09: Found: C, 36.47; H, 2.77.
(Z)-5-((1,3-Dithian-2-yl)methylene)-4-azidofuran-2(5H)-one (15). A mixture of 14
(120.4 mg, 0.41 mmol) and sodium azide (29.3 mg, 0.45 mmol, 1.1 equiv) in DMF (0.4
mL) were stirred at 0 °C for 2 h. The mixture was diluted with ethyl acetate (30 mL) and
washed successively with cold water (20 mL) and brine (15 mL). The organic layer was
dried (MgSO4) and concentrated under reduced pressure to give crude azide 15 (102.5
mg), which was unstable at rt and was used in the next step without purification: IR
(NaCl, film) ν 2927, 2126, 1765, 1468, 1243, 1171, 930, 847 cm−1; 1H NMR (300 MHz,
CDCl3) δ 5.85 (s, 1H), 5.52 (d, J = 11.1 Hz, 1H), 5.13 (d, J = 11.1 Hz, 1H), 2.89−2.92 (m,
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2H), 2.07−2.18 (m, 2H), 1.87−2.01 (m, 2H); C NMR (125 MHz, CDCl3) δ = 165.9,
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155.6, 143.8, 107.3, 102.3, 40.0, 29.2, 24.9; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C9H10N3O2S2 256.0209, found 256.0197.
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(Z)-5-((1,3-Dithian-2-yl)methylene)-4-aminofuran-2(5H)-one (16). To a stirred
suspension of stannous chloride (113.6 mg, 0.61 mmol, 1.5 equiv) in MeOH (0.5 mL)
cooled at 0 °C was added dropwise a solution of the crude azide 15 (102.5 mg) in MeOH
(5 mL). The reaction was exothermic and N2 gas was evolved. After the addition, the
reaction mixture was stirred at 0 °C for 30 min. Methanol was removed under reduced
pressure, the residue was diluted with cold water (10 mL) and freshly prepared alkaline
with 2 N NaOH. Ethyl acetate (20 mL) was added and the layers separated. The aqueous
layer was saturated with solid sodium chloride (~ 5 g) and re-extracted with ethyl acetate
(2 × 10 mL). The combined organic layers were dried (Na2SO4) and concentrated under
reduced pressure and the residue was purified by flash column chromatography (50%
EtOAc in hexanes) to furnish tetronamide 16 (62.2 mg, 66% for 2 steps) as a yellow
solid: mp 150-153 °C dec; IR (NaCl, film) ν 3197, 1716, 1642, 1584, 1568, 1355, 937,
1
771, 664 cm−1; H NMR (400 MHz, (CD3)2CO) δ 6.67 (broad s, 2H), 5.67 (d, J = 10.7
Hz, 1H), 5.19 (d, J = 10.7 Hz, 1H), 4.88 (s, 1H), 2.01−3.10 (m, 2H), 2.85−2.94 (m, 2H),
2.07−2.15 (m, 1H), 1.78−1.92 (m, 1H); 13C NMR (100 MHz, (CD3)2CO) δ 169.4, 159.6,
146.3, 103.5, 85.0, 41.0, 29.6, 25.8; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C9H12NO2S2 230.0304, found 230.0292.
Basidalin (1). To tetronamide 16 (50.3 mg, 0.22 mmol) and CaCO3 (327.3 mg, 3.27
mmol, 15 equiv), suspended in 5 mL of acetone/H2O (4:1), MeI (0.27 mL, 4.36 mmol, 20
equiv) was added dropwise. The reaction mixture was heated at 60 °C for 5 h. After
cooling to rt, the volatiles were evaporated under reduced pressure, and the residue was
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diluted with ethyl acetate (10 mL) and washed with water (10 mL). The mixture was
dried (Na2SO4), and concentrated in vacuo. Purification by flash column chromatography
(40% EtOAc in hexanes) provided 1 (22.1 mg, 72%) as a yellowish solid: mp 138-142 °C
dec; lit.1 142-149 °C dec; IR (NaCl, film) ν 3300, 2200, 1754, 1671, 1584, 1416, 1400,
1320, 1184, 1028, 926, 835, 786 cm−1; 1H NMR (500 MHz, (CD3)2SO) δ 10.01 (d, J = 7.8
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13
Hz, 1H), 7.73 (br s, 2H), 6.11 (d, J = 7.8 Hz, 1H), 4.96 (s, 1H); C NMR (125 MHz,
1
(CD3)2SO) δ 189.3, 168.2, 159.5, 158.5, 102.9, 81.8; H NMR (400 MHz, (CD3)2CO) δ
13
10.11 (d, J = 7.7 Hz, 1H), 7.01 (br s, 2H), 5.96 (d, J = 7.7 Hz, 1H), 5.05 (s, 1H); C
NMR (125 MHz, (CD3)2CO) δ 189.2, 168.6, 160.0, 159.6, 103.4, 84.7; HRMS (ESI-
TOF) m/z [M + H]+calcd for C6H6NO3 140.0342, found 140.0346.
1
Supporting Information: Copies of H and 13C NMR spectra of all products and
crystallographic data for syn-13 (PDF and CIF). This material is available free of charge
at http://pubs.acs.org.
Acknowledgments. We are grateful to the Natural Sciences and Engineering Research
Council of Canada (NSERC) and the FRQNT-Québec Centre in Green Chemistry and
Catalysis (CGCC) for financial support. We also thank the Emerging Leaders in the
Americas Program (ELAP-Canada) for a visiting scholarship (JAMA) and the Brazilian
agency CNPq for a research fellowship (LCAB), a special visiting researcher fellowship
(JB) and a doctoral scholarship (JAMA), and FAPEMIG for a research grant (LCAB).
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