Total synthesis of cyclopiamide A and speradine E

Article abstract of DOI:10.1016/j.tet.2018.02.039

Described is a total synthesis of the related alkaloids, cyclopiamide A and speradine E, via a unified strategy that also delivers the natural product aspergilline A. Key steps include metal-free conversion of a malonyl chloride and propargylamine to an intermediate pyrrolinone and a palladium catalyzed decarboxylation/aromatization sequence that delivers the requisite tetracyclic core.

Full text of DOI:10.1016/j.tet.2018.02.039

Accepted Manuscript
Total synthesis of cyclopiamide A and speradine E
Mina C. Nakhla, Kendall N. Weeks, Mauricio Navarro-Villalobos, John L. Wood
PII:
S0040-4020(18)30183-2
10.1016/j.tet.2018.02.039
TET 29310
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 25 January 2018
Revised Date: 15 February 2018
Accepted Date: 16 February 2018
Please cite this article as: Nakhla MC, Weeks KN, Navarro-Villalobos M, Wood JL, Total synthesis of
cyclopiamide A and speradine E, Tetrahedron (2018), doi: 10.1016/j.tet.2018.02.039.
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Total Synthesis of Cyclopiamide A and
Speradine E
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Mina C. Nakhla, Kendall N.Weeks, Mauricio Navarro-Villalobos,
and John L. Wood
Department of Chemistry and Biochemistry, Baylor University, Waco, TX 76798

1
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Tetrahedron
journal homepage: www.elsevier.com
Total Synthesis of Cyclopiamide A and Speradine E
Mina C. Nakhlaa, Kendall N. Weeksa, Mauricio Navarro-Villalobosb, and John L. Wooda
a Department of Chemistry and Biochemistry, Baylor University One Bear Place #97348 Waco, TX 76798.
b Facultad de Odontología Unidad Torreón, Universidad Autónoma de Coahuila, Av. Juárez y Calle 17, Torreón. Coah., 27200, México.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Described is a total synthesis of the related alkaloids, cyclopiamide A
and speradine E, via a unified strategy that also delivers the natural
product aspergilline A. Key steps include metal-free conversion of a
malonyl chloride and propargylamine to an intermediate pyrrolinone and
a palladium catalyzed decarboxylation/aromatization sequence that
delivers the requisite tetracyclic core.
Available online
Keywords:
Total Synthesis, Cyclopiamide A, Aspergilline A
Speradine E, Natural Products, Indole Alkaloids
The tetracyclic alkaloids cyclopiamide A (1) and speradine E
(2) were isolated from Penicillium cyclopium and Aspergillus
oryzae, respectively (Figure 1).1,2 Speradine E differs in structure
from cyclopiamide A by an additional β-dicarbonyl unit and
displays modest cyctotoxicity against HeLa and human gastric
cancer cells (MGC-803). Both compounds bear structural
similarity to aspergilline A (3, highlighted in red), a structurally
more complex compound also possessing activity against several
cancer cell lines.3 Given the limited natural abundance and
interesting structural/biological properties of 1-3, we initiated an
effort to develop a unified synthetic strategy that would enable
access to both the cyclopiamide/speradine and aspergilline class
of compounds. In initial studies our efforts focused primarily on
accessing 3,4 herein we report application of this unified strategy
to the successful syntheses of 1 and 2.
ring (thereby enabling access to 3); decarboxylative removal of
this moiety prior to reduction of the trisubstituted olefin was
expected to induce aromatization and provide unified access to 1
and 2.
Scheme 1 Unified Retrosynthetic Strategy for 1-3.
NR
DMB
O
O
N
N
O
O
H3C
1 R = H
2 R = C(O)CH2CO2CH3
Sonogashira
O
R’’
NH
R' O
OR
O
H
O
O
N
H3C
5-exo-dig
Cyclization
N
N
OH
H3C
H
O
H
4 R = TMS, R’ = CO2R’’
5
OH
OH
O
N
H3C
3
Br
Figure 1 Cyclopiamide A, Speradine E, and Aspergilline A.
O
O
DMB
N
O
R’’
H
Cl
O
HN
H
O
O
O
N
7
NH
N
O
O
6
8
OH
H
H
O
O
OH
OH
O
As illustrated in Scheme 2, our point of departure was
methylation of commercially available 4-bromo isatin (7)
followed by Sonogashira cross coupling of the derived product
(9) with protected propargylamine coupling partner 6 to furnish
homologated isatin 10.4
N
N
N
O
O
O
H3C
Aspergilline A (3)
Cyclopiamide A (1)
Speradine E (2)
From a retrosynthetic perspective, the approach we developed
for accessing 3 envisioned tetracycle 4 as a key intermediate
which, following reduction of the trisubstituted styrenyl olefin,
would be suited for conversion to aspergilline A (3, Scheme 1).
Tetracycle 4 was seen as arising via intramolecular aldol addition
of the extended enolate derived from 5 which, in turn, was
accessed from readily available materials (i.e., 6-8).
Strategically, compound 4 serves as the common intermediate in
our unified strategy and was specifically designed such that the
angular ester (R’ in 4) would prevent aromatization of the central
Scheme 2 Sonogashira Coupling.
DMB
N
H
6
DMB
Br
Br
MeI
N
H
K2CO3
Pd(PPh3)4 (4 mol%)
O
O
O
CuI (8 mol%)
Cs2CO3, i-Pr2NEt
PhMe, 85 °C
N
HN
DMF, 80 °C
(98% Yield)
N
O
O
O
10
7
9
(80% Yield)

2
Tetrahedron
ACCEPTED MANUSCRIPT
To advance 10 we were drawn to a method developed by
efforts of cyclopiamide noted that the natural product appeared
Marinelli wherein acylated propargylamines (e.g., 11, Scheme 3,
inset) were reported to undergo cyclization and double bond
migration to furnish the corresponding pyrrolinones (e.g. 12)
upon subjection to cesium carbonate in DMSO.5 Unfortunately,
for our particular substrates (i.e., variants of 10 acylated similarly
to 11) attempts to employ Marinelli’s chemistry resulted in
prohibitively low yields. However, during these latter studies,
we noticed trace amounts of the desired pyrrolinone when
preparing the acylated substrate. Hoping to capitalize on this
inert to acetylation, even on prolonged exposure to acetic
anhydride and pyridine.1 In accord with these results we found
that standard acylation conditions only gave returned starting
material while more forceful deprotonation with tert-butyl
lithium followed by exposure to methyl malonyl chloride gave
trace amounts (<5%) of speradine E. Suspecting that steric
encumbrance, resulting from the vicinal gem-dimethyl, was the
culprit, we consulted the literature and noted that acyl fluorides
are frequently utilized to circumnavigate issues of steric
hindrance.8 Intrigued by this notion, we were delighted to find
that exposing cyclopiamide A to an excess of methyl malonyl
fluoride results in conversion to speradine E upon heating to 90
oC for nineteen hours.
observation
we
attempted
Scheme 3 Pyrrolinone Formation.
Scheme 4 Completion of Cyclopiamide and Speradine E.
O
DMB
N
OH
Pd(PPh3)4 (1.2 mol%)
DDQ
N
O
O
N
4.9 equiv morpholine
THF, RT
CHCl3/H2O, 75 °C
O
O
O
O
N
O
15
(83% Yield)
16
(93% Yield)
O
O
O
F
O
W6
NH
N
O
90 o
C
O
O
O
N
N
(54% Yield)
O
O
Speradine E (2)
Cyclopiamide A (1)
to optimize the acylating conditions such that the desired
pyrrolinone would be produced as the major product in a single
operation. To this end (Scheme 3, bottom), we discovered that
premixing allyl malonyl chloride (13) with Hünig’s base
followed by addition of propargylamine 10 results in smooth
conversion to pyrrolinone 14 (for mechanistic details see the
supporting information of reference 4). With pyrrolinone 14 in
hand we next sought access to tetracycle 15. In our parallel
efforts directed toward aspergilline A, a similar but TMS-
protected tetracycle was produced (e.g., a reduced variant of 4,
Scheme 1) via application of a Mukaiyama-type aldol process.4
These latter conditions were critical in enabling the preparation
of 3 as they improved reaction efficiency in the aldol cyclization
and several subsequent steps by preventing deleterious retro aldol
chemistry. Given that the synthesis of 1 and 2 requires
aromatization of the central ring and essentially no further
manipulation, the need for a protected intermediate was not as
critical. Thus, we undertook an extensive optimization study to
find conditions that best delivered the free alcohol product and
minimized the tendency of 15 to ring open via retro aldol
reaction. Eventually we discovered that 15 can be cleanly
produced by exposing 14 to 0.6 equivalents of sodium hydride.
Although the yields are modest, significant amounts of starting
material can be recovered and recycled.6
In summary, total syntheses of the indole alkaloids
cyclopiamide A and speradine E have been completed using a
unified synthetic strategy that also provides access to aspergilline
A. Efforts to adapt this strategy to the production of analogs
possessing improved biological activity are underway and will be
reported in due course.
Experimental section
Unless otherwise stated, all reactions were performed in flame
dried glassware under a nitrogen atmosphere, using reagents as
received from the manufacturers. The reactions were monitored
and analytical samples purified by normal phase thin-layer
chromatography (TLC) using Millipore glass-backed 60 Å plates
(indicator F-254, 250 ꢀM). Tetrahydrofuran, dichloromethane,
and toluene were dried using a solvent purification system
manufactured by SG Water U.S.A., LLC. Manual flash
chromatography was preformed using the indicated solvent
systems with Silicycle SiliaFlash® P60 (230–400 mesh) silica
gel as the stationary phase. Flash Chromatography on a Teledyne
RF+UV-Vis Ms Comp MPLC was preformed using the indicated
solvent systems, and Teledyne RediSep® Rf normal phase
disposable columns of the indicated size and at the indicated flow
rate. 1H and 13C NMR spectra were recorded on a Bruker Avance
III 300, a Bruker AscendTM 400 autosampler or a Bruker
AscendTM 600 autosampler. Chemical shifts (δ) are reported in
parts per million (ppm) relative to the residual solvent resonance
and coupling constants (J) are reported in hertz (Hz). NMR peak
pattern abbreviations are as follows: s = singlet, d = doublet, dd =
doublet of doublets, t = triplet, at = apparent triplet, q = quartet,
ABq = AB quartet, m = multiplet. NMR spectra were calibrated
relative to their respective residual NMR solvent peaks, CDCl3 =
7.26 ppm (H NMR)/ 77.16 ppm (C NMR), DMSO = 2.50
ppm (H NMR)/ 39.52 ppm (C NMR) MeOH = 3.31 ppm,
MeCN = 1.94 ppm. IR spectra were recorded on Bruker
Platinum-ATR IR spectrometer using a diamond window. High
Resolution mass spectra (HRMS) were obtained in the Baylor
Having accessed tetracyclic intermediate 15 we turned toward
decarboalkoxylation of the allyl ester. In the event (Scheme 4),
we observed that exposure of 15 to 0.012 equiv of Pd(PPh3)4 in
the presence of morpholine smoothly promotes not only the
desired decarboalkoxylation but also subsequent dehydrative
aromatization to furnish 16. At this stage, all that remained to
access 1 and 2 was N-deprotection and acylation, respectively.
The former of these proved routine, requiring simple exposure of
15 to DDQ.7 However, efforts to acylate the derived product,
cyclopiamide A (1), so as to access speradine E (2) proved non-
trivial. This potential difficulty had been noted by Holzapfel,
who in the course of the isolation and structural characterization

3
University Mass Spectrometry Center on a Thermo Scientific
LTQ Orbitrap Discovery spectrometer using +ESI or –ESI and
reported for the molecular ion ([M+H]+ & [M+Na]+ or [M-H]-
respectively).
mg (25% Yield) of the desired tetracycle 15 along with 72.4 mg
ACCEPTED MANUSCRIPT
(72.4%) of recovered pyrrolinone 14, which could be resubjected
to the reaction conditions. 1H NMR (400 MHz, Acetonitrile-d3) δ
7.31 – 7.21 (m, 2H), 6.81 (d, J = 7.7 Hz, 1H), 6.75 (d, J = 7.8 Hz,
1H), 6.71 (s, 1H), 6.53 (d, J = 2.4 Hz, 1H), 6.44 (dd, J = 8.5, 2.4
Hz, 1H), 5.65 (ddt, J = 16.4, 10.9, 5.6 Hz, 1H), 5.14 – 5.04 (m,
2H), 4.55 – 4.35 (m, 4H), 3.86 (s, 3H), 3.76 (s, 3H), 3.12 (s, 3H),
1.41 (s, 3H), 1.41 (s, 3H) (very closely overlapping singlets) .13C
NMR (151 MHz, Chloroform-d) δ 175.5, 166.3, 166.2, 160.2,
157.5, 145.1, 144.8, 131.6, 131.3, 130.9, 130.5, 123.6 (observed
through HMBC correlation, see SI), 119.4, 119.2, 118.8, 118.8,
108.2, 104.6, 98.3, 71.2, 66.9, 64.1, 62.7, 55.5, 55.5, 36.5, 28.1,
26.7, 26.5. +ESI-HRMS m/z: calc’d for [M+Na]+ C29H30N2O7Na+
= 541.19507, found C29H30N2O7Na+ = 541.19464. FTIR (Neat)
3430, 2970, 2936, 1733, 1693, 1646, 1616, 1593, 1508, 1474,
1437, 1407, 1369, 1298, 1264, 1209, 1156, 1127, 1085, 1036,
987, 917, 833, 782, 746, 730, 646 cm−1.
allyl
1-(2,4-dimethoxybenzyl)-5,5-dimethyl-4-((1-methyl-2,3-
dioxoindolin-4-yl)methyl)-2-oxo-2,5-dihydro-1H-pyrrole-3-
carboxylate (14)
To a flame dried round bottom flask was added Hünig’s base (5
mL, 28.7 mmol 7.55 equiv) and 48 mL dry DCM, the solution
o
was then cooled to –78 C in a dry ice/acetone bath. To the
Hünig’s base solution was then dropwise added allyl malonyl
chloride (2.2 g, 13.5 mmol, 3.55 equiv)9 and the solution stirred
for 1 hour . The substrate 10 (1.5 g, 3.8 mmol, 1 equiv), which
had been placed in a flame dried flask and dissolved in 17 mL of
dry DCM was then taken up into a syringe and added slowly over
fifteen minutes to the flask containing the Hünig’s base/acyl
chloride solution. After addition the reaction mixture was
allowed to stir for an additional 1 hour at –78 oC and
subsequently was quenched with 24 mL of saturated NaHCO3
aqueous solution. The dry ice acetone/bath was removed and the
flask was allowed to warm slightly. The mixture was then
transferred to a separatory funnel which contained a half
saturated brine solution and extracted several times with DCM.
The organic layer was dried over sodium sulfate and solvent
removed by rotary evaporation. The residue was purified by
MPLC. A gradient from 0% ethyl acetate in hexanes to 56%
ethyl acetate in hexanes was used. this yielded 892 mg (45.0%
Yield) of pyrrolinone 14 as an orange foam. 1H NMR (400
MHz, Chloroform-d) δ 7.44 (t, J = 7.9 Hz, 1H), 7.32 (d, J =
8.3 Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H), 6.73 (d, J = 7.8 Hz, 1H),
6.48 – 6.35 (m, 2H), 5.92 (ddt, J = 16.3, 10.9, 5.7 Hz, 1H),
5.40 (dd, J = 17.3, 1.6 Hz, 1H), 5.23 (dd, J = 10.6, 1.4 Hz,
1H), 4.73 – 4.70 (m, 2H), 4.58 (s, 2H), 4.46 (s, 2H), 3.81 (s,
3H), 3.77 (s, 3H), 3.23 (s, 3H), 1.11 (s, 6H).13C NMR (151
MHz, Chloroform-d) δ 184.1, 170.3, 165.7, 162.9, 160.2,
157.9, 157.6, 151.9, 139.6, 138.4, 131.7, 131.0, 126.2, 124.5,
119.0, 119.0, 115.1, 108.3, 104.7, 98.2, 65.9, 65.9, 55.5, 55.5,
35.8, 27.0, 26.4, 23.6. +ESI-HRMS m/z: calc’d for [M+Na]+
8-(2,4-dimethoxybenzyl)-2,7,7-trimethyl-7,8-dihydro-1H-
isoindolo[4,5,6-cd]indole-1,9(2H)-dione (16)
To a flame dried round bottom flask was added tetracycle 15
(38.9 mg, 0.075 mmol, 1.0 equiv), 1.7 mL THF and morpholine
(32 µL, 0.366 mmol, 4.9 equiv). Following this was added
Pd(PPh3)4 (1 mg, 0.00087 mmol, 0.012 equiv). The solution
quickly becomes deep yellow in color. The reaction mixture was
allowed to stir for 2 hours and fifteen minutes. Half saturated
brine and DCM were then added and the aqueous layer extracted
with DCM several times, until all the yellow compound had been
extracted into the organic layers. The organic layers were
combined and dried over sodium sulfate and the solvent removed
by rotary evaporation. The residue was purified by MPLC using
a 2.5 g column with a flow rate of 25 mL/min. A gradient which
began at 0% ethyl acetate in hexanes and progressed to 90% ethyl
acetate in hexanes was used for purification. This gave 26.0 mg
(83% Yield) of the title compound 16 as a yellow solid. 1H NMR
(600 MHz, Chloroform-d) δ 7.93 (s, 1H), 7.54 – 7.50 (m, 2H),
7.48 (d, J = 8.5 Hz, 1H), 6.90 – 6.85 (m, 1H), 6.45 – 6.43 (m,
1H), 6.40 (dd, J = 8.5, 2.4 Hz, 1H), 4.82 (s, 2H), 3.88 (s, 3H),
3.77 (s, 3H), 3.47 (s, 3H), 1.49 (s, 6H). 13C NMR (151 MHz,
Chloroform-d) δ 165.5, 164.9, 160.2, 157.6, 152.4, 141.7,
131.2, 130.7, 130.2, 129.2, 125.9, 123.7, 122.5, 120.1, 119.2,
104.6, 104.5, 98.3, 63.8, 55.6, 55.5, 35.8, 26.9, 26.6. +ESI-
HRMS m/z: calc’d for [M+Na]+ C25H24N2O4Na+ = 439.16338,
found C25H24N2O4Na+ = 439.16312. FTIR (Neat) 2971,
2936, 2836, 1708, 1636, 1615, 1589, 1506, 1463, 1388, 1293,
1265, 1208, 1180, 1157, 1128, 1044, 998, 968, 909, 834, 766,
729, 669 cm−1.
C29H30N2O7Na+ = 541.19507, found C29H30N2O7Na+
=
541.19501. FTIR (Neat) 2972, 2937, 2838, 1737, 1688, 1605,
1508, 1464, 1438, 1397, 1359, 1324, 1293, 1265,1208,
1157,1128,1106,1055, 1035,1012, 935, 896, 834 cm−1.
allyl-8-(2,4-dimethoxybenzyl)-9b-hydroxy-2,7,7-trimethyl-1,9-
dioxo-1,2,7,8,9,9b-hexahydro-9aH-isoindolo[4,5,6-cd]indole-9a-
carboxylate (15)
To a flame dried vial was added pyrrolinone starting material
14 (100 mg, 0.193 mmol, 1.0 equiv) and 0.65 mL of dry THF.
The solution was then cooled in an ice bath and 60% dispersion
of sodium hydride in mineral oil was added (4.5 mg, 0.113
mmol, 0.58 equiv). The solution was stirred in the ice bath for an
additional fifteen minutes and then allowed to warm to room
temperature. An additional 0.65 mL THF was added and the
2,7,7-trimethyl-7,8-dihydro-1H-isoindolo[4,5,6-cd]indole-
1,9(2H)-dione (1)
To a round bottom flask was added starting material 16 (146.6
mg, 0.035 mmol, 1.0 equiv), 3.4 mL CHCl3, 0.05 mL H2O, and
DDQ (2,3-Dichloro-5,6-dicyano-p-benzoquinone, 119.7 mg,
0.053 mmol, 1.51 equiv). The flask was purged with nitrogen and
o
solution warmed to 55 C in an oil bath. As the solution warms
the solution’s colour darkens and progresses to a green color and
finally to a deep blue color. After fifteen minutes of heating at 55
oC the solution was quenched with 1 mL of 0.5 M NH4Cl and the
reaction mixture extracted several times with DCM. The
combined organic layers were dried over sodium sulfate and the
solvent removed by rotary evaporation. The residue was purified
by flash chromatography using a gradient which began at 50%
ethyl acetate in hexanes and progressed to 100% ethyl acetate
(the 50% ethyl acetate solution was utilized to elute the
remaining starting material from the column and the following
100% ethyl acetate was used to elute the product) This gave 25
o
sealed. The flask was then placed in a preheated 75 C oil bath
for 55 minutes, the flask was then removed from the heat cooled
for ten minutes and an additional 119.7 mg ( 0.053 mmol, 1.51
equiv) of DDQ were added. The flask was once again purged
o
with nitrogen, sealed and replaced into the 75 C oil bath for an
additional 50 minutes. The flask was then removed from the oil
bath, allowed to cool and then DCM was added. The reaction
solution was poured into a separatory funnel and washed three
times with aqueous half saturated NaHCO3. To the aqueous layer

4
Tetrahedron
ACCEPTED MANUSCRIPT
was then added brine, and the aqueous layer was extracted
Chloroform-d) δ 8.03 (s, 1H), 7.63 – 7.53 (m, 2H), 6.90 (d, J
several times with DCM.
= 5.9 Hz, 1H), 4.21 (s, 2H), 3.76 (s, 3H), 3.46 (s, 3H), 1.91 (s,
6H). 13C NMR (101 MHz, Chloroform-d) δ 168.2, 167.2,
165.0, 164.9, 152.8, 141.8, 132.5, 131.7, 126.6, 125.8, 125.5,
123.3, 120.3, 105.1, 66.3, 52.5, 45.7, 27.0, 26.7. +ESI-HRMS
m/z: calc’d for [M+Na]+ C20H18N2O5Na+ = 389.11134, found
C20H18N2O5Na+ = 389.11093. . FTIR (Neat) 2951, 1737,
1698, 1636, 1500, 1436, 1391, 1373, 1323,1292, 1197, 1178,
1140, 1047, 1017, 886, 767, 730, 672 cm−1.
All the organic layers were combined and dried over sodium
sulfate, the solvent was then removed by rotary evaporation. The
residue was then purified by MPLC using a 24 gram column with
a flow rate of 35 mL/min. A gradient beginning at 0% ethyl
acetate in hexanes and progressing to 100% ethyl acetate in
hexanes was used to purify the material. This gave 87.5 mg (93%
Yield) of cyclopiamide (1) as a yellow powder. 1H NMR (600
MHz, Chloroform-d) δ 7.96 (s, 1H), 7.58 – 7.52 (m, 2H), 6.89
(dd, J = 4.9, 2.7 Hz, 1H), 6.32 (s, 1H br), 3.46 (s, 3H), 1.66 (s,
6H). 13C NMR (101 MHz, Chloroform-d) δ 166.3, 165.4,
153.3, 141.7, 131.0, 130.6, 128.9, 125.8, 124.3, 122.8, 120.2,
104.7, 59.7, 28.9, 26.6. +ESI-HRMS m/z: calc’d for [M+Na]+
Acknowledgments
The authors gratefully acknowledge financial support from Baylor
University, the Welch Foundation (Chair, AA-006), and the Cancer
Prevention and Research Institute of Texas (CPRIT, R1309). MNV
would like to gratefully acknowledge financial support, as a visiting
scholar, from Mexico's SEP (Federal fund PFCE-2016) and thank
Professor Wood and the W6 for their hospitality.
C16H14N2O2Na+ = 289.09530, found C16H14N2O2Na+
289.09531. FTIR (Neat) 3229, 2971, 2932, 1723, 1637, 1499,
1421, 1393, 1381, 1309, 1209, 1188, 1046, 1018, 986, 912,
761, 730, 689 cm−1.
=
methyl 3-oxo-3-(2,7,7-trimethyl-1,9-dioxo-1,2,7,9-tetrahydro-8H-
isoindolo[4,5,6-cd]indol-8-yl)propanoate (2)
References and notes
To a flame dried vial was added cyclopiamide 1 (9.1 mg, 0.034
mmol, 1.0 equiv) and methyl malonyl fluoride (206.7 mg , 0.98
mmol, 28.8 equiv, the compound was used crude after
preparation, Q NMR showed that the solution used was 56.9%
acyl fluoride by weight, see SI for preparation method and
spectroscopic data.) The reaction vial was purged with argon,
1. (a) Holzapfel, C. W.; Bredenkamp, M. W.; Snyman, R. M.;
Boeyensa, J. C. A.; Allen, C. C. Phytochemistry 1990, 29, 639 –
642. (b) Xu, X.; Zhang, X.; Nong, X.; Wei, X.; Qi, S. Tetrahedron,
71, 610-615. (c) Uka, V.; Moore, G. G.; Arroyo-Manzanares, N.;
Nebija, D.; De Saeger, S.; Di Mavungu, J. D. Toxins, 2017, 9, 35.
2. Hu, X.; Xia, Q.–W.; Zhao, Y.–Y; Zheng, Q.–H.; Liu, Q.–Y.;
Chen, L.; Zhang, Q.–Q. Heterocycles 2014, 89, 1662-1669
3. Zhou, M.; Miao, M.-M.; Du, G.; Li, X.-N.; Shang, S.-Z.; Zhao,
W.; Liu, Z.-H.; Yang, G.-Y.; Che, C.-T.; Hu, Q.-F.; Gao, X.-M.;
Org. Lett. 2014, 16, 5016–5019.
4. For the implementation of the first phase of these efforts and the
completed total synthesis of aspergilline A, see: Nakhla, M. C.;
Wood, J. L. J. Am. Chem. Soc. 2017, 139, 18504-18507.
5. Arcadi, A.; Marinelli, F.; Rossi, L.; Verdecchi, M. Synthesis 2006,
12, 2019–2030.
6. Li, W.; Liu, X.; Zhou, X.; Lee, C.–S. Org. Lett. 2010, 12, 548–551
7. McAlonan. H; Stevenson, P. J.; Tetrahedron: Asymmetry 1995, 6,
239–244.
8. a) Prabhu, G.; Narendra, N.; Basavaprabhu; Pandurangaa, V.;
Sureshbabu, V. V. RSC Adv. 2015, 5, 48331–48362; b) Due-
Hansen, M. E.; Pandey, S. K.; Christiansen, E.; Andersen, R.;
Hansen, S. V. F.; Ulven, T. Org. Biomol. Chem. 2016, 14, 430–
433.
o
sealed and placed in a 90 C oil bath for six hours and fifteen
minutes. The vial was then allowed to cool and an additional
105.0 mg (0.5 mmol, 14.6 equiv) of the acyl fluoride was added.
The vial was once again purged with argon, sealed and placed in
o
a 90 C oil bath. The reaction mixture was heated in the oil bath
for an additional thirteen hours and eight minutes. The vial was
then removed from the oil bath and allowed to cool. DCM was
added and the reaction solution transferred to a larger 20 mL vial.
Saturated NaHCO3 was then added and the solution stirred
vigorously to quench the remaining acyl fluoride. The reaction
mixture was then extracted several times with DCM. Solid NaCl
was then added to the aqueous layer and the aqueous layer was
again extracted once with DCM. The combined organic layers
were dried over sodium sulfate and the solvent removed by rotary
evaporation. The residue was then purified by prep TLC using
1:1 ethyl acetate : hexanes as the eluent. The plate was eluted
twice with this solvent system. The purified material was then
triturated twice with diethyl ether to give 6.7 mg (54% Yield)
of speradine E (2) as an orange powder. 1H NMR (400 MHz,
9. Navarro, I.; Basset, J.-F.; Severine, H.; Major, S. M.; Werner, T.;
Howsham, C.; Brackow, J.; Barrett. A. G. M. J. Am. Chem. Soc.
2008, 130, 10293-10298.
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