Synthesis of the azaphilones (+)-sclerotiorin and (+)-8- O -methylsclerotiorinamine utilizing (+)-sparteine surrogates in copper-mediated oxidative dearomatization

Article abstract of DOI:10.1021/jo102448n

Enantioselective syntheses of the azaphilone natural products (+)-sclerotiorin and (+)-8-O-methylsclerotiorinamine that possess the natural R-configuration at the quaternary center are reported. The syntheses were accomplished using copper-mediated asymmetric dearomatization employing bis-i-oxo copper complexes prepared from readily available (+)-sparteine surrogates. Of note, site-selective O-methylation of a vinylogous pyridone was used to access the isoquinolin-6(7H)-one core of (+)-8-O- methylsclerotiorinamine.

Full text of DOI:10.1021/jo102448n

ARTICLE
pubs.acs.org/joc
Synthesis of the Azaphilones (þ)-Sclerotiorin and (þ)-8-O-
Methylsclerotiorinamine Utilizing (þ)-Sparteine Surrogates in
Copper-Mediated Oxidative Dearomatization
Andrew R. Germain,† Daniel M. Bruggemeyer,† Jianglong Zhu,† Cedric Genet,‡ Peter O’Brien,‡ and
John A. Porco, Jr.*,†
†Department of Chemistry, Center for Chemical Methodology and Library Development (CMLD-BU), Boston University, 590
Commonwealth Avenue, Boston, Massachusetts 02215, United States
‡Department of Chemistry, University of York, Heslington, York YO105DD, U.K.
S Supporting Information
b
ABSTRACT:
Enantioselective syntheses of the azaphilone natural products (þ)-sclerotiorin and (þ)-8-O-methylsclerotiorinamine that possess
the natural R-configuration at the quaternary center are reported. The syntheses were accomplished using copper-mediated
asymmetric dearomatization employing bis-μ-oxo copper complexes prepared from readily available (þ)-sparteine surrogates. Of
note, site-selective O-methylation of a vinylogous pyridone was used to access the isoquinolin-6(7H)-one core of (þ)-8-O-
methylsclerotiorinamine.
’ INTRODUCTION
were found to be suitable for this transformation and provided
the desired (S)-enantiomer 11 in good to excellent enantiomeric
excess (Table 1).8 N-Ethyl-(þ)-sparteine mimic 6 was found to
be the optimal ligand to afford azaphilone core 11 in 70% yield
and 95% ee (entry 3, Table 1) and was therefore employed in
syntheses of (þ)-sclerotiorin 2 and (þ)-8-O-methylsclerotior-
inamine 3 (vide infra). Use of (þ)-sparteine surrogate 7 bearing
an N-isopropyl substituent decreased both the yield and ee of
azaphilone 11 (entry 4, Table 1). Likewise, ligand 8 bearing an N-
neopentyl group was not effective, likely due to steric hindrance
in the formation of the putative bis-μ-oxo complexes (entry 5,
Table 1).
(þ)-Sparteine surrogates were also found to be more suscep-
tible to oxidative modification8,9 under the reaction conditions
than the alkaloid (-)-sparteine, which may explain the slightly
lower yields observed relative to those using (-)-sparteine.
Through mass spectrometry analysis, we determined that the
(þ)-sparteine surrogates are oxidized preferentially on the
interior ring system and not on the N-alkyl side chain.8
Following development of an efficient route to the S-azaphi-
lone core, we initiated studies toward the synthesis of (þ)-
sclerotiorin 2 and 8-O-methylsclerotiorinamine (3, Figure 1).
Azaphilone 2 was the first azaphilone reported in the literature5a
The azaphilones1 are a structurally diverse family of natural
products containing a highly oxygenated bicyclic core and a
quaternary center. Our group has previously reported the
enantioselective synthesis of the azaphilone natural product
S-15183a 1 (Figure 1) bearing a (R)-quaternary center.2 The
synthesis was achieved utilizing enantioselective oxidative
dearomatization3 mediated by
a [(-)-sparteine]2Cu2O2
complex.4 A number of azaphilone natural products including
(þ)-sclerotiorin 2 and 8-O-methylsclerotiorinamine 3 possess
the opposite stereochemistry at C7 compared to 1 (Figure 1).5
Since (þ)-sparteine is not readily available or readily
synthesized,6 it was necessary to identify an appropriate (þ)-
sparteine surrogate for use in asymmetric oxidative dearomatiza-
tion. In this Article, we report the first asymmetric syntheses of
(þ)-2 and (þ)-3 employing readily available (þ)-sparteine
surrogates7 in copper-mediated oxidative dearomatization.
’ RESULTS AND DISCUSSION
In our initial studies, we investigated the utility of (þ)-sparteine
surrogates 5-8 developed by O’Brien and co-workers7 for forma-
tion of L2Cu2O2 complexes 9 to mediate oxidative dearomatization
of alkynylbenzaldehyde 102 in the presence of N,N-diisopropylethyl-
amine (DIEA) as base and 4-dimethylaminopyridine (DMAP) as
additive (Table 1). Gratifyingly, (þ)-sparteine surrogates 5-7
Received: December 10, 2010
Published: March 14, 2011
r
2011 American Chemical Society
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Figure 1. Azaphilone natural products.
Table 1. Oxidative Dearomatization Employing Sparteine
Surrogatesa
acylation and chlorination of 12. Azaphilone core structure 12 may
be obtained via diastereoselective oxidative dearomatization3 of
alkynylbenzaldehyde 13 followed by cycloisomerization.2
Synthesis of the requisite alkynyl benzaldehyde substrate 13
was initiated with preparation of an iodo-diene side-chain frag-
ment (Scheme 1). Swern oxidation of the commercially available
chiral alcohol 14, followed by treatment of the intermediate
aldehyde with (carbethoxyethylidene)triphenylphosphorane, af-
forded allylic ester 15 (85% yield, >20:1 E:Z selectivity).11
DIBAL-H reduction of 15 provided alcohol 16 (55%) which
was cleanly oxidized with manganese dioxide to produce enal 17.12
Chlorous chromium-mediated Takai olefination13 of 17 produced
iodo-diene 18 (65% yield over two steps, 10:1 E:Z selectivity).
For expedient access to the Sonogashira coupling partner for
18, we developed an optimized route to iodobenzaldehyde 19
(Scheme 2).14 We have previously reported a six step route to the
corresponding bromobenzaldehyde involving installation of a
nitro group to 3-methyl-2,4-dimethoxybenzaldehyde 20 to allow
for ortho-halogenation of the aldehyde.15 A more concise route
was developed utilizing the directed lithiation conditions origin-
ally reported by Comins and co-workers.16 Treatment of 20 with
N,N,N0-trimethylethylenediamine, followed by ortho-lithiation of
the amino-alkoxide intermediate with n-butyl lithium and sub-
sequent treatment with 1,2-diiodoethane, produced the desired
protected iodobenzaldehyde. Deprotection using boron tribro-
mide proceeded smoothly to yield iodobenzaldehyde 19 (33%
yield, three steps) using a single purification step. Sonogashira
coupling of iodobenzaldehyde 19 with trimethylsilylacetylene,
followed by silyl deprotection, afforded alkynylbenzaldehyde 21
(80% yield, Scheme 3).17 Alkynylbenzaldehyde 21 was subjected
to Sonogashira conditions with vinyl iodide 18 providing alky-
nylbenzaldehyde 13 in 55% yield.
(þ)-Sclerotiorin 2 was obtained in four steps (49% yield)
from alkynylbenzaldehyde substrate 13 (Scheme 4). Copper-
mediated, diastereoselective oxidative dearomatization of 13 af-
forded azaphilone 12 (76% yield, dr = 12:1) with (S)-stereochem-
a Conditions: (a) 2.2 equiv of Cu(CH3CN)4PF6, 2.4 equiv of ligand, 1.6
equiv of DIEA, 2.4 equiv of DMAP, O2, -78 to -10 °C; (b) aq H2PO4/
K2HPO4 buffer (pH 7.2), CH3CN, RT. DIEA = N,N-diisopropylethyla-
mine, DMAP = 4-(dimethylamino)pyridine. b Isolated yield after silica
gel chromatography.
istry at C-7 based on the sign of the optical rotation ([R]22
=
D
þ163) after conversion to 2 (lit. reported [R]22 = þ133)5a
D
utilizing the N-ethyl (þ)-sparteine surrogate 6 to access the
desired L2Cu2O2 complex.7b,8 Since the optical rotation of the
final product 8-O-methylsclerotiorinamine (þ)-3 was consistent
with that reported in the literature (vide infra, [R]22D = þ104, lit.
and has been shown to be an inhibitor of several important
protein targets.10 Azaphilone 3 has been shown to significantly
inhibit binding between the Grb2-SH2 domain and the phos-
phopeptide derived from the Shc protein.5d According to our
retrosynthetic analysis (Figure 2), we anticipated that 8-O-
methylsclerotiorinamine 3 could be obtained by amination and
methylation of sclerotiorin 2, which itself could be derived from
reported [R]22 = þ102),5d the apparent erosion in stereose-
D
lectivity in the formation of (þ)-12 in comparison to the
formation of (þ)-11 may be an artifact of an inseparable impurity
(vida infra). Azaphilone 12 was acylated (Ac2O/DMAP) and
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Figure 2. Retrosynthetic analysis for 8-O-methylsclerotiorinamine 3.
Scheme 1. Synthesis of Iodo Diene 18a
a Conditions: (a) (COCl)2, DMSO, Et3N, CH2Cl2 0 °C, 3 h; (b) (carboethoxyethylidene)triphenylphosphorane, reflux, 12 h, 85%, 20:1 E:Z; (c) DIBAl-
H, CH2Cl2,rt, 2 h, 55%; (d) MnO2, THF, 24 h; (e) CrCl2, CHI3, dioxane/THF 6:1, 2 h, 0 °C, 65% yield 2 steps, 10:1 E:Z.
Scheme 2. Synthesis of Alkynylbenzaldehyde 13a
a Conditions: (a) N,N,N0-trimethylethylenediamine, n-BuLi, THF, 0 °C 30 min; n-BuLi, THF, -20 °C, 16 h, then 1,2-diiodoethane; BBr3, CH2Cl2, 18 h
(33% yield 3 steps; (b) CuI, trimethylsilylacetylene, (t-Bu)3P-HBF4, PdCl2(CH3CN)4, diisopropylamine, rt, 12 h, then K2CO3, MeOH, rt, 1 h 80%, 2
steps; (c) Pd(PPh3)4, CuI, Et3N, 12 h, rt, 55%.
chlorinated (N-chlorosuccinimide, NCS) to afford the natural
product sclerotiorin 2 (65% yield for two steps). Amination of 2
with ammonium acetate provided the vinylogous pyridone scler-
otiorinamine 22 (60% yield).18
a ∼10:1 ratio after silica gel purification. On the basis of
comparison with related azaphilones such as isochromophilone
I and II that contain the same dienyl side chain, we determined
that the minor compound was the azaphilone containing a Z-
double bond at C11-C12.19 The minor isomer is generally seen
as a minor component during isolation; however, the two olefin
During the synthesis of (þ)-sclerotiorin 2, we found that the
azaphilone core 12 was formed as a mixture of two compounds in
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Scheme 3. Synthesis of (þ)-Sclerotioin 2a
a Conditions: (a) 2.2 equiv of Cu(CH3CN)4PF6, 2.4 equiv of N-ethyl-(þ)-sparteine mimic 6, 1.6 equiv of DIEA, 2.4 equiv of DMAP, O2, -78 °C
to -10 °C; (b) aq H2PO4/K2HPO4 buffer (pH 7.2), CH3CN, rt 76% over two steps; (c) acetic anhydride, DMAP, DIEA, 0 °C, 30 min; (d) NCS,
CH3CN, rt, 24 h 65% over two steps; (e) NH4OAc, MeOH, 30 min, 60%.
Scheme 4. Isomerization of the C11-C12 Olefina
a Conditions: (a) SiO2, ethyl acetate, 1 h.
isomers have been reported to interconvert.20 Through analyses
of the isolation procedures of azaphilones containing the dienyl
side chain, it was determined that the minor E,Z isomer (cf.
Scheme 4) is present in compounds that have been purified using
silica gel chromatography. Accordingly, we suspected that aza-
philones bearing dienyl side chains were prone to mild acid-
catalyzed olefin isomerization. The latter was confirmed by
treating a natural sample of (þ)-sclerotiorin 2 with silica gel
which resulted in a mixture of 2:23 in ∼10:1 ratio (Scheme 4).
We believe that the facile isomerization results from protonation
of 2 to afford the stabilized carbocation 24, which allows for
equilibration between 2 and 23.8 The minor isomer 23 may affect
the optical rotation of (þ)-sclerotiorin, limiting comparison of
tetrafluoroborate (Me3OBF4) with diisopropylamine as base
(0 °C) to afford N-methylsclerotiorinamine 25 (Scheme 5)
(85% yield). The selectivity for N-methylation was confirmed
by alternative synthesis of 25 by treatment of (þ)-sclerotiorin 2
with methylamine (>95%).22 Interestingly, methylation of 22
with Me3OBF4 and 2,6-di-tert-butylpyridine (DTBP) as base led
to apparent methylation of the C6-oxygen based on the crude
NMR spectra. However, the presumed 7,8-dihydroisoquinoline
was found to be unstable to purification and isolation. It is
possible that utilization of a weaker base may alter the selectivity
from N- to O-methylation by not significantly deprotonating the
N-H of the vinylogous amide until activation by O-alkylation.
Other attempts to employ alternant electrophilic methylating
agents (e.g., methyl triflate) and various weak bases did not result
in isolable products.
optical rotations of synthetic ([R]22 = þ163) and natural
D
samples ([R]22D = þ133).
With a sample of sclerotiorinamine 22 in hand, we next
investigated conditions for O-methylation21 to access the congener
8-O-methylsclerotiorinamine. After screening of various reported
methylation procedures, it was found that selective N-methylation
could be obtained upon treatment of 22 with trimethyloxonium
A related method for O-methylation of amides involves treatment
with diazomethane (CH2N2).23 These reactions generally proceed
without the need for base, likely arising from methylation of the
enol tautomer of the amide. Gratifyingly, treatment of vinylogous
pyridine 22 with trimethylsilyldiazomethane24 in a mixture of
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Scheme 5. Synthesis of N-Methylsclerotiorinamine 25a
a Conditions: (a) Me3OBF4, iPr2NH, THF, 85%; (b) methylamine, THF, >95%
Scheme 6. Synthesis of (þ)-8-O-Methylsclerotiorinamine 3a
a Conditions: (a) TMSCHN2, CH2Cl2:MeOH 9:1, quantitative.
Figure 3. Proposed mechanism for O-methylation.
Figure 4. Epimers of the azaphilone natural products.
dichloromethane and methanol resulted in quantitative formation of
8-O-methylsclerotiorinamine 3 (Scheme 6), which had spectro-
scopic data consistent with that reported in the literature including
the optical rotation ([R]22D = þ104, lit. reported [R]22D = þ102)
(Scheme 7).5d In the case at hand, derived enol 26 may be
deprotonated by CH2N2 to give ion pair 27, which may expel
nitrogen to yield 3 (Figure 3). Presumably, in this case selective
methylation at C8 was observed8 due to steric congestion around
the C6 ketone.
7-epi-Sclerotiorin 28, a naturally occurring diasteromer of
(þ)-sclerotiorin varying only at the C7 stereocenter5c and the
analogous 7-epi-8-O-methylsclerotiorinamine 29 were synthe-
sized using the same synthetic sequence described above8 by
substituting N-ethyl (þ)-sparteine surrogate 6 for (-)-sparteine
in the copper-mediated, oxidative dearomatization (Figure 4).
Comparison of both diastereomers of the natural products with
the rotation of the natural samples thus confirms the stereo-
chemistry of 8-O-methylsclerotiorinamine.8
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’ CONCLUSION
sodium sulfate, filtered, and concentrated in vacuo. The concentrated
material was passed through a plug of neutral alumina (hexanes) to afford
vinyl iodide 18 as a light yellow oil 1.28 g (65% yield, 10:1 E:Z by 1H NMR
analysis). Due to stability issues, 18 was used immediately and was not fully
characterized. 1H NMR (400 MHz, CDCl3) δ 7.05 (1H, d, J = 15.3 Hz),
6.12 (1H, d, J= 15.3 Hz), 5.24 (1H, d, J =10.2Hz), 2.35(1H, m), 1.70(3H,
s), 1.40 (2H, m), 0.95 (3H d), 0.83 (3H,t, J = 7.5 Hz).
We have developed methodology to access azaphilone natural
products containing the natural S-configuration at the quaternary
center found in various members of this family utilizing (þ)-
sparteine surrogates. The methodology has been utilized in the
asymmetric syntheses of the azaphilone natural products (þ)-
sclerotiorin 2 and (þ)-8-O-methylsclerotiorinamine 3. Further
studies toward the synthesis of related natural products and
biological evaluation of 2, 3, and related molecules will be
reported in due course.
Dienyne-benzaldehyde 13. An oven-dried round-bottom flask
containing a mixture of vinyl iodide 18 (639 mg, 2.556 mmol), PdCl2-
(PPh3)2 (60 mg, 0.084 mmol), and CuI (6.6 mg, 0.033 mmol) was
evacuated and refilled with argon. Anhydrous triethylamine (6.0 mL, x
mmol) was added dropwise, and the reaction was stirred at rt for 10 min.
Alkynylbenzaldehyde 21 (300 mg, 1.70 mmol) in 3 mL of THF was
added. The resulting mixture was stirred at room temperature until
complete conversion of 21 was observed (TLC analysis). The reaction
mixture was diluted with water, carefully neutralized with 0.1 N aqueous
HCl, and extracted with ethyl acetate. The combined organic layers were
washed with water and brine, dried over anhydrous Na2SO4, filtered, and
concentrated in vacuo. Purification on silica gel (hexane/EtOAc = 10:1)
provided 279 mg (55%) of enyne benzaldehyde 13 as a yellow solid. Mp
149-154 °C; 1H NMR (400 MHz, CDCl3) δ 12.34 (1H, s), 10.21 (1H,
s), 6.72 (1H, d, J = 16 Hz), 6.49 (1H, s), 5.69 (1H, d, J = 16 Hz), 5.44
(2H, ovrlp), 2.40 (1H, m), 2.10 (3H, s) 1.76 (3H, s), 1.36 (2H, m), 0.97
(3H, d, J = 6.8 Hz), 0.84 (3H, t, J = 7.6 Hz) ; 13C NMR (75.0 MHz,
acetone-d6) δ 195.3, 163.3, 160.7, 148.8, 144.4, 132.6, 131.9, 128.7,
127.3, 114.3, 112.2, 104.0, 96.3, 85.5, 34.9, 30.4, 20.6, 12.3, 7.4; IR (thin
film) 3161 (br), 2922, 2360, 1595, 1457, 1288, 1259 cm-1; ESIHRMS
[M þ H]þ calculated for C19H23O3 299.1667, found C19H23O3
299.1647. [R]22D = þ14.0 (c 0.3, CHCl3).
’ EXPERIMENTAL SECTION
Azaphilone Core 11. Alkynylbenzaldehyde 10 (27 mg, 0.10
mmol) and N,N-diisopropylethylamine (DIEA) (28 μL, 0.16 mmol)
in 400 μL of CH2Cl2 solution were added to the Cu2L2O2 complex
prepared from Cu(CH3CN)4PF6 (82 mg, 0.22 mmol) and (-)-
sparteine (56 μL, 0.24 mmol) in 1.6 mL of anhydrous CH2Cl2 under
an oxygen atmosphere at -78 °C. After 5 min, 4-dimethylaminopyridine
(29.2 mg, 0.24 mmol) in 400 μL of CH2Cl2 was added, and the mixture
was warmed and stirred at -10 °C for 30 h under an oxygen atmosphere.
The reaction was quenched at -10 °C with 2 mL of 10% sulfuric acid
and 2 mL of satd brine. The mixture was extracted three times with
EtOAc, and the combined extracts were concentrated in vacuo. The
crude residue was dissolved in 2.0 mL of CH3CN, and 1.0 mL of 1:1.6
aqueous KH2PO4/K2HPO4 buffer (pH 7.2, prepared by dissolving 1.7 g
KH2PO4 and 3.5 g K2HPO4 in 50 mL of distilled water) was added to the
solution. The resulting heterogeneous mixture was stirred at room
temperature for 1 h. 10% H2SO4 was added dropwise to the reaction
mixture to adjust the pH to 2-3. The resulting mixture was extracted
three times with EtOAc. The organic extracts were dried over anhydrous
Na2SO4, concentrated, and purified on silica gel (hexane/EtOAc = 10:1
to 2:1) to afford azaphilone core 11. The 1H, 13C NMR, IR, and
CIHRMS were found to be identical to those previously reported.2 The
enantiomeric excesses for 11 was determined using a HPLC (Chiralcel
OD, 15% iPrOH in hexane, 1.0 mL/min) using UV detection at 320 nm
and are listed in Table 1 corresponding to the ligand used.
Azaphilone 12. Alkynylbenzaldehyde 13 (27 mg, 0.10 mmol) and
N,N-diisopropylethylamine (DIEA) (28 μL, 0.16 mmol) in 400 μL of
CH2Cl2 solution were added to the Cu2L2O2 complex prepared from
Cu(CH3CN)4PF6 (82 mg, 0.22 mmol) and N-ethyl-(þ)-sparteine
mimic 6 (56 μL, 0.24 mmol) in 1.6 mL of anhydrous CH2Cl2 under
an oxygen atmosphere at -78 °C. After 5 min, 4-dimethylaminopyridine
(29 mg, 0.24 mmol) in 400 μL was added, and the mixture was warmed
and stirred at -10 °C for 30 h under an oxygen atmosphere. The
reaction was quenched at -10 °C with 2 mL of 10% sulfuric acid and
2 mL of satd brine. The mixture was extracted three times with EtOAc,
and the combined extracts were concentrated in vacuo. The crude
residue was dissolved in 2.0 mL of CH3CN, and 1.0 mL of 1:1.6 aqueous
KH2PO4/K2HPO4 buffer (pH 7.2, prepared by dissolving 1.7 g
KH2PO4 and 3.5 g K2HPO4 in 50 mL of distilled water) was added to
the solution. The resulting heterogeneous mixture was stirred at room
temperature for 1 h. 10% H2SO4 was added dropwise to the reaction
mixture to adjust the pH to 2-3. The resulting mixture was extracted
three times with EtOAc. The organic extracts were dried over anhydrous
Na2SO4, concentrated, and purified on silica gel (hexane/EtOAc = 10:1
to 2:1) to afford azaphilone core 12 as a red oil (76% over two steps). 1H
NMR (400 MHz, CDCl3) δ 7.85 (1H, s), 6.95 (1H, d, J = 15.6 Hz), 6.13
(1H, s), 5.90 (1H, d, J = 15.6 Hz), 5.60 (1H, d, J = 9.6 Hz), 5.51 (1H, s),
3.88 (1H, s), 2.40 (2H, m) 1.75 (3H, s), 1.50 (3H, s), 1.33 (2H, m), 0.93
(3H, d, J = 6.4 Hz), 0.79 (3H, s); 13C NMR (75.0 MHz, CDCl3) δ 196.0,
156.9, 152.5, 148.3, 144.2, 142.1, 131.8, 115.9, 108.8, 105.5, 83.4, 35.1,
30.1, 28.7, 12.3, 12.0; IR (thin film) 3431 (br), 2961, 2360, 1616, 1540,
1172, 838 cm-1 [R]22D = þ82.0 (c 0.1, CHCl3).
2-Iodo-4,6-dihydroxy-5-methylbenzaldehyde 19. N,N,N0-
Trimethylethylenediamine (4.0 mL, 30.5 mmol) was dissolved in 200 mL of
THF. A solution of 1.9 M nBuLi (15 mL, 36.7 mmol) was added at 0 °C.
After stirring for 15 min, the reaction was cooled to -20 °C, and a solution of
benzaldehyde 20 (5.0 g, 27.7 mmol) in 50 mL of THF was added. The
mixture was stirred for 30 min, and then a solution of 1.9 M nBuLi (45 mL,
73.3 mmol) was added dropwise. The reaction was stirred overnight. The
solution was cooled to -40 °C, and a solution of diiodoethane (23.5 g, 83.2
mmol) in 50 mL of THF was added dropwise. After 5 min, the reaction was
warmed to room temperature, and the reaction was quenched by addition of
saturated ammonium chloride (100 mL), followed by saturated sodium
thiosulfate (40 mL), and finally extracted three times with diethyl ether (3 ꢀ
120 mL). The organic layer was concentrated in vacuo and purified on silica
(ethyl acetate/hexanes 1:10) to yield 19 (2.8 g, 33% yield, three steps) as a
faint yellow powder. Mp 75-77 °C; 1H NMR (400 MHz, CDCl3) δ 10.25
(1H, s), 6.91 (1H, s), 3.88 (3H, s), 3.79 (3H, s), 2.08 (3H, s); 13C NMR
(75.0MHz, CDCl3) δ189.6, 162.7, 161.8, 124.0, 120.68, 120.65, 112.2, 62.3,
55.9, 8.1; IR (thin film) 2944, 1685, 1584, 1559, 1456, 1376, 1283, 1234,
1133, 1019, 816 cm-1; CIHRMS Mþ calculated for C8H7IO3 278.9518,
found 278.9520.
Vinyl Iodide 18. To CrCl2 (5.4 g, 43.7 mmol) was added anhydrous
THF (75 mL) at 0 °C. In a separate flask, unsaturated aldehyde 17 (1.0 g,
7.9 mmol) and iodoform (4.3 g, 11.0 mmol) were added to anhydrous THF
(45 mL). The aldehyde mixture was added to the reaction mixture via
cannula dropwise, and the resulting mixture was stirred for 1 h. The reaction
was filtered through Celite and then washed with ether. The filtrate was
finally washed with water and brine, and the organic layer was dried with
7-epi-Azaphilone 30. Azaphilone 30 was synthesized following
the same procedure as above for (þ)-12, except for the replacement of
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ligand 6 with (-)-sparteine 4. All spectroscopic data was indistinguish-
able from (þ)-12. [R]22D = -62.0 (c 0.1, CHCl3).
170.1, 162.4, 159.6, 149.5, 146.6, 143.1, 132.5, 130.5, 124.6, 119.1, 115.5,
111.5, 80.7, 61.9, 34.9, 30.2, 23.1, 20.4, 20.4, 12.6, 12.0; IR (thin film)
2961, 2871, 1742, 1696, 1611, 1579, 1279, 1248 cm-1 CIHRMS Mþ
calculated for C22H26NO4Cl 404.1629, found 404.1635. [R]22D = þ104
(lit. reported = þ102) (c 0.1, CH3OH). All spectroscopic data matched
those reported in the literature.5d
7-epi-8-O-Methylsclerotiorinamine 29. Starting from (-)-
sclerotiorinamine 30, the same procedure to synthesize (þ)-22 and
(þ)-3 was followed to produce 29. All spectroscopic data were indis-
tinguishable from (þ)-3. ([R]22D = -80 (c 0.1, CH3OH).
(þ)-Sclerotiorin 2. To azaphilone (þ)-12 (120 mg, 0.41 mmol) in
3 mL of methylene chloride at 0 °C were added acetic anhydride (77 μL,
0.82 mmol) and N, N-diisopropylethylamine (80 μL, 0.45 mmol). The
resulting mixture was stirred at 0 °C for 30 m. The reaction mixture was
quenched with water, extracted three times with ethyl acetate, washed
with 1 N HCl, washed three times with water, dried over anhydrous
Na2SO4, filtered, and concentrated in vacuo. The residue was dissolved in
acetonitrile (3 mL) and N-chlorosuccinimide (129 mg, 0.96 mmol) was
added. The reaction vessel was covered with aluminum foil and stirred at
room temperature until 1H NMR analysis indicated completion of the
reaction. The reaction mixture was diluted with ethyl acetate, washed
with water, the organic extracts dried over anhydrous Na2SO4, concen-
trated, and purified on silica gel (hexane/EtOAc = 10:1 to 2:1) to yield
sclerotiorin 2 as a red oil (65%, two steps). The synthetic samplematched
the 1H, 13C, and mass spectrum of the natural product. However due to
the presence of a small amount of olefin isomer the optical rotations were
not comparable. 1H NMR (400 MHz, CDCl3) δ 7.91 (1H, s), 7.05 (1H,
d, J = 15.6 Hz), 6.62 (1H, s), 6.07 (1H, d, J = 15.6 Hz), 5.69 (1H, d, J = 9.6
Hz), 2.45 (1H, m), 2.15 (3H, s), 1.82 (3H, s) 1.54 (3H, s), 1.39 (2H, m),
1.33 (2H, m), 0.99 (3H, s), 0.85 (3H, t, J = 7.2 Hz); 13C NMR (75.0
MHz, CDCl3) δ 196.0, 186.2, 170.3, 158.3, 152.9, 149.1, 143.1, 138.9,
132.2, 115.9, 114.7, 111.0, 106.6, 84.8, 35.3, 30.3, 22.7, 20.4, 20.3, 12.6,
12.2; IR (thin film) 3438 (br), 2924, 2853, 1631 cm-1 CIHRMS Mþ
calculated for C21H24O5Cl 391.1312, found 391.1333. [R]22D = þ163.0
(c 0.1, EtOH), lit. reported [R]22D = þ133.0° (c 0.3, EtOH).
’ ASSOCIATED CONTENT
S
Supporting Information. Complete experimental proce-
b
dures and compound characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: porco@bu.edu.
’ ACKNOWLEDGMENT
This work was generously supported by the National Insti-
tutes of Health (GM-073855), Wyeth Research, and Merck
Research Laboratories. We also thank the NSF (CHE-
0443618) for the high resolution mass spectrometer used in
this work.
7-epi-Sclerotiorin 28. Starting from 30, the same procedure
employed to prepare (þ)-2 was followed. All spectroscopic data was
undistinguishable from (þ)-2. [R]22D = -103.0 (c 0.1, EtOH).
Sclerotiorinamine (þ)-22. To sclerotiorin (þ)-2 (217 mg, 0.59
mmol) in THF (6 mL) was added ammonium acetate (54.8 mg, 0.71
mmol). The reaction mixture was stirred at room temperature until TLC
indicated completion of the reaction. The mixture was diluted with
water, extracted three times with ethyl acetate, washed with water, dried
over anhydrous Na2SO4, filtered, and concentrated in vacuo to yield
sclerotiorinamine 22 as an orange oil (229 mg, 100%) which was used
directly in the next step without further purification.
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1
methylsclerotiorinamine (þ)-25 as a red oil (3.4 mg, 85%). H NMR
(400 MHz, CDCl3) δ 7.76 (1H, s), 7.04 (1H, s), 6.97 (1H, d, 15.6 Hz),
6.12 (1H, d, 15.6 Hz), 5.72 (1H, d, 9.8 Hz), 3.62 (3H, s), 2.46 (1H, m),
2.17 (3H, s), 1.86 (3H, s), 1.54 (3H, s), 1.43 (1H, ovrlp), 1.34 (1H,
ovrlp), 1.01 (3H, d, 6.9 Hz), 0.88 (3H, t, 7.5 Hz); 13C NMR (75.0 MHz,
CDCl3) δ194.0, 184.6, 170.4, 148.7, 146.3, 145.3, 145.0, 142.1, 131.9,
114.8, 114.7, 111.4, 102.4, 85.0, 42.1, 35.3, 30.3, 23.5, 20.6, 20.5, 12.8,
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d, 16 Hz), 5.71 (1H, d, 9.6 Hz), 4.01 (3H, s), 2.49 (1H, m), 2.10 (3H, s),
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9.6 Hz), 0.87 (3H, t, J = 7.5 Hz); 13C NMR (75.0 MHz, CDCl3) δ192.7,
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