Total synthesis of acortatarin A using a Pd(II)-catalyzed spiroketalization strategy

Article abstract of DOI:10.1021/jo301835e

The total synthesis of acortatarin A relying on a Pd(II)-catalyzed spiroketalization is reported. This strategy allows a single stereocenter in the spiroketalization substrate to produce the target efficiently under mild conditions, installing the necessa

Full text of DOI:10.1021/jo301835e

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Featured Article
Total Synthesis of Acortatarin A using a
Pd(II)-Catalyzed Spiroketalization Strategy
Nicholas V. Borrero, and Aaron Aponick
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 21 Sep 2012
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Total Synthesis of Acortatarin A using a Pd(II)-Catalyzed Spiroketalization Strategy
Nicholas V. Borrero and Aaron Aponick*
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University of Florida, Department of Chemistry, Gainesville, Florida 32611, USA
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aponick@chem.ufl.edu
O
OBn
O
O
O
O
HO
HO
Pd(PhCN)2Cl2
O
N
N
N
BnO
(10 mol %)
87 %
OH
MeO
N
MeO
Me
O
O
Me
H
N
acortatarin A
MeO
ABSTRACT
The total synthesis of acortatarin A relying on a Pd(II)-catalyzed spiroketalization is
reported. This strategy allows a single stereocenter in the spiroketalization substrate to produce
the target efficiently under mild conditions, installing the necessary oxygenation in the backbone
through an allylic transposition. The synthesis also verifies that pollenopyrroside B and
acortatarin A are the same compound, and electrochemical studies suggest that the reported
bioactivity is not due to simple antioxidant properties.
INTRODUCTION
In 2010, two groups independently isolated and simultaneously reported the unique
pyrrole-fused morpholine spiroketal natural product 1.1,2 Zhang and co-workers named this
compound pollenopyrroside B and also isolated the related spiroketal 2, named pollenopyrroside
A.1 Hou, Cheng, and co-workers named compound 1 acortatarin A and also isolated the more
highly oxidized analogue 3, which was named acortatarin B.2 Together with funebral 43 and two
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additional acyclic compounds, magnolamide4 and pyrraline,5 these compounds comprise a small
family of 2-formyl-5-hydroxymethylpyrrole-containing natural products.
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O
O O
O
HO
HO
HO
HO
N
N
O
O
H
H
2
1
pollenopyrroside A
acortatarin A
(pollenopyrroside B)
O
O
HO
HO
O
O
N
O
OH
N
H
O
H
HO
3
4
acortatarin B
funebral
Figure 1. Acortatarin A and related natural products.
Interestingly, pollenopyrroside B/acortatarin A6 is isolated in very small quantities from
two unrelated sources, both of which are used in traditional Chinese medicine. Zhang and co-
workers isolated 5 mg of acortatarin A from 15 kg of bee-collected Brassica campestris
(rapeseed) pollen, while Cheng et al. obtained 7.3 mg from 50 kg of dry rhizome (rootstock) of
Acorus tatarinowii Schott. In the latter report, a crystal structure was obtained for 1 and
Mosher’s ester analysis was used to assign the absolute configuration as the enantiomer of that
shown in Figure 1.2 The correct absolute configuration was proposed by Zhang and co-workers
who made their assignment by analogy to 2, for which they had obtained an X-ray crystal
structure.1 Three total syntheses have now been completed,7,8 and since each utilizes starting
materials from the chiral pool, the absolute configuration has been confirmed to be that
illustrated in Figure 1 for the material isolated by Hou and Cheng. Although Zhang and co-
workers’ assignment was confirmed, to the best of our knowledge this has not been referenced
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until this point.9 Furthermore, their NMR data was reported using acetone-d6 as the solvent1
while all other data has been reported in methanol-d4.2,7,8
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We initially became interested in acortatarin A because of its unique structure and the
fact that both natural sources are used in traditional medicine to treat a variety of ailments,
including central nervous system (CNS) disorders and prostatitis.2 The biological activities of
these natural sources of acortatarin A also include antitumor and antioxidant properties.1 Hou
and Cheng demonstrated that acortatarin A was able to inhibit high-glucose-induced reactive
oxygen species (ROS) in mesangial cells.2 Evidence suggests that ROS in renal cells play an
integral role in the development of diabetic nephropathy,10 and we sought to test whether 1 may
act as an antioxidant or if perhaps a different manifold is responsible for its bioactivity. Herein,
we report the total synthesis of acortatarin A using a Pd(II)-catalyzed spiroketalization strategy
as the key step and a preliminary study of its electrochemical properties and the implications
they may have on its mode of action.
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RESULTS AND DISCUSSION
Previous work from our laboratory has focused on developing metal-catalyzed
dehydrative cyclization reactions of unsaturated alcohols11 and we have recently been exploring
a Pd(II)-catalyzed method for spiroketalization.12 Given the interesting and uncommon pyrrole-
fused spiroketal architecture of acortatarin A, this target provided an attractive platform to test
this method. The core structure of the natural product is comprised of a [6,5]-spiroketal. In
studies on reaction scope, the parent spiroketal 6 was prepared from the acyclic substrate 5 in
high yield, but with poor diastereoselectivity (Scheme 1). It was also observed that
interchanging alcohols and ethers as leaving groups had no significant impact on the yield or
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reaction time, although the few preliminary test reactions conducted produced [6,6]-spiroketals
such as 8. The acyclic substrates 5 and 7 are likely in equilibrium with their cyclic hemiketal
counterparts under the reaction conditions. Alkoxypalladation followed by elimination then
provides the spiroketal products.13
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Scheme 1. Pd(II)-catalyzed spiroketalization.
OH
O
O
O
Pd(CH3CN)2Cl2
THF, 0 ˚C
84 % (1.5:1 dr)
OH
6
5
Bu
OH
O
MeO
O O
Pd(CH3CN)2Cl2
DCM, r.t.
Bu
7
53 % (10:1:0.8 dr)
8
From a retrosynthetic perspective, acortatarin A (Figure 2) would rely on conversion of
the penultimate intermediate 9, resulting from the key spiroketalization, to the natural product.
This would require oxidative cleavage of the vinyl group, reduction of both the resulting
aldehyde and Weinreb amide, and benzyl group removal. Spiroketal 9 should be available by
Pd(II)-catalyzed cyclization of the acyclic precursor 10, containing a single stereocenter. Using
our method, the newly formed stereocenter at the allylic carbon should be set during the
spiroketalization step, placing the vinyl group trans to the benzyl ether. Use of the methyl ether
leaving group also seemed advantageous as it would eliminate the need for protecting group
manipulation if an alcohol was required. Spiroketalization precursor 10 was envisioned to be
available from 2,5-functionalized pyrrole 11 by N-alkylation with bromoketone 12, which in turn
should be prepared from allylic alcohol 13.
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O
O
O
O
HO
N
5
N
BnO
HO
6
7
9
O
O
N
H
8
O
acortatarin A (1)
9
O
OBn
OH
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O
O
H
O
N
N
MeO
N
MeO
N
Me
OMe
OH
11
Me
10
OBn
+
O
OBn
Br
OMe
Br
12
13
Figure 2. Retrosynthetic analysis of acortatarin A.
Initial experiments were focused on the preparation of the required pyrrole 11 (Scheme
2). This was accomplished from pyrrole by first using a one-pot acylation / amidation
sequence14 to provide the Weinreb amide 16 in 97% yield. A Vilsmeier-Haack formylation was
then used for introduction of the aldehyde moiety.15 Inclusion of the formyl group in pyrrole 11
proved to be crucial as compounds bearing other protected hydroxymethyl synthons were
difficult to N-alkylate and/or unstable and difficult to work with.
Scheme 2. 2,5-Disubstituted pyrrole fragment.
O
H
N
H
N
i) triphosgene,
N,N-DMA
MeO
N
H
N
ii) TEA,
Me
Me
• HCl
OMe
14
16
POCl3
DMF
50 %
15
97 %
O
H
N
MeO
N
O
Me
11
The preparation of the alkylating agent, bromoketone fragment 12, was explored and
commenced with a one-pot bromination and reduction19 of the known δ-hydroxy ester 1716 to
provide allyl alcohol 13 in 79% yield (Scheme 3). Methylation of the hydroxyl group with
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methyl iodide and alkylation of dithiane 1917 with the resulting alkyl bromide 18 produced
dithiane 20. Conversion of the ester to a bromide and unmasking of the latent ketone were then
required. Reduction of the ester was readily accomplished with LAH and the ketone revealed
using oxidative conditions18 to afford acyloin 22. The Appel halogenation conditions used
previously19 were then employed to conclude the synthesis of bromoketone 12.
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With both the pyrrole and bromoketone fragments in hand, a variety of alkylation
protocols were tested for the union of these moieties and it was found that using 1 equivalent of
Cs2CO3 in acetonitrile at 0 ˚C gave the best result (Scheme 4). Under these conditions, the
competing elimination of the benzyloxy group, which was problematic with other conditions,
was suppressed. To complete the synthesis of the cyclization precursor, a chemoselective
reduction of an aldehyde in the presence of both a ketone and amide was needed. Initial
synthetic plans avoided this issue by introducing the hydroxymethyl group in the correct
oxidation state but proved untenable due to the problems of stability and nucleophilicity
mentioned above. Reducing agents such as sodium borohydride and others failed to give a clean
reaction, with varying amounts of reduced ketone observed even at low conversion. Fortunately,
reduction of 23 with lithium tris(3-ethyl-3-pentyloxy)aluminohydride (LTEPA)20 cleanly gave
desired hydroxymethyl pyrrole 10 in 93% yield. Keto-alcohol 10 was found to exist in
equilibrium with the corresponding hemiketal, on the NMR time scale, which seemed
advantageous for the key spiroketalization.
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Scheme 3. Synthesis of the methyl ether 12.
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6
7
8
OBn
OBn
i) CBr4, PPh3
ii) DIBAL-H
79 %
NaH. MeI
62 %
OH
CO2Et
17
13
OH
Br
9
10
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OBn
OBn
S
S
OMe
NaH, t-BuOH
EtO2C
20
LAH
OMe
Br
O
S
18
19
S
CO2Et
99 %
73 %
OBn
OBn
PhI(OCOCF3)2
95 %
S
S
OH
OMe
OH
OMe
21
22
CBr4, PPh3
72 %
O
OBn
Br
OMe
12
In the event, hydroxyketone 10 was treated with Pd(PhCN)2Cl2 in CH2Cl2 with MS 4Å to
produce 9 and epi-9 as a separable 1:1 mixture of diastereomers in a combined yield of 87%. It
was later found that these compounds were epimeric at the anomeric carbon C5 (see scheme 4
for numbering) and not at the allylic position C2, but at this stage, it was difficult to make the
stereochemical assignment. Since the two products were separable and only oxidative cleavage
of the olefin, reduction of the carbonyl groups, and benzyl deprotection remained, the synthesis
was carried out independently on both diastereomers.
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Scheme 4. Fragment coupling and spiroketalization.
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O
OBn
9
O
11
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Cs2CO3
79 %
N
R
+
MeO
N
OMe
12
Me
LTEPA
93 %
R = CHO, 23
R = CH2OH, 10
10 mol % Pd(PhCN)2Cl2
DCM, MS 4Å
2
2
O
O
O
O
5
5
N
N
BnO
BnO
+
O
N
O
Me
Me
N
9
epi-9
MeO
MeO
87%
(1:1)
The end game sequence commenced with oxidative cleavage, and it was found that OsO4
catalyzed dihydroxylation, followed by glycol cleavage was superior to ozonolysis (Schemes 5
and 6). Spiroketals 9 and epi-9 were subjected to this reaction sequence, and subsequent
reduction of the aldehyde furnished alcohols 24 and epi-24 in 70% and 89% respectively, over
the 3 steps. Reduction of the Weinreb amides to aldehydes 25 and epi-25 was accomplished in
good yield using an excess of LAH in THF. At this point, epimerization of the spiro compound
epi-25 with Brønsted acids (PPTS, p-TsOH, 1N HCl) was attempted, however conversion to the
desired diastereomer 25 was unsuccessful leading only to recovered starting material.21 Instead,
compounds 25 and epi-25 were each treated with TiCl4 to yield acortatarin A and epi-acortatarin
A in 78% and 84% combined yields respectively. Gratifyingly, this verified that the newly
formed, non-epimerizable allylic ether stereocenter C2 was formed in the spiroketalization
reaction with complete selectivity for the desired 1,2-trans relationship with respect to the
benzyloxy group C3 (see scheme 4). Moreover, acortatarin A was the major product of both
reactions with epi-1 as the byproduct. It is interesting to note that the ring-expanded natural
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product 2 was not formed. All spectral data and the optical rotation of synthetic acortatarin A
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1
13
satisfactorily matched previously reported values.2,7 Additionally, H and C NMR spectra of
acortatarin A were obtained in acetone-d6 and confirmed that acortatarin A and pollenopyrroside
B are indeed the same compound.
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Scheme 5. Elaboration of 9 to acortatarin A.
O
O
O
O
HO
BnO
i) OsO4, NMO
ii) NaIO4
N
N
BnO
iii) NaBH4
O
Me
O
N
70 %
R
9
R = N(OMe)Me, 24
R = H, 25
LAH
84%
MeO
TiCl4
O
O
O
O
HO
HO
HO
HO
+
N
N
O
O
H
H
1
epi-1
acortatarin A
epi-acortatarin A
70%
8%
Scheme 6. Elaboration of epi-9 to acortatarin A.
O
O
O
O
HO
BnO
i) OsO4, NMO
ii) NaIO4
N
N
BnO
iii) NaBH4
O
Me
O
N
89 %
R
epi-9
R = N(OMe)Me, epi-24
R = H, epi-25
LAH
89%
MeO
TiCl4
HO
HO
O
O
O
O
HO
+
N
N
HO
O
O
H
H
1
epi-1
acortatarin A
epi-acortatarin A
70%
14%
It has been suggested that the bioactivity of 1 against ROS was due to antioxidant
properties.2 However, antioxidants typically contain more electron-rich aromatic groups such as
phenols. While pyrrole is an electron-rich heterocycle, 1 contains an electron withdrawing group
and no resonance donating substituents. To test the antioxidant activity of 1, the oxidation
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potential was measured by cyclic voltammetry.22, 23 While the oxidation potential of most
compounds considered antioxidants is below +0.70 V,24 the first and second oxidation potentials
of 1 were measured to be +1.74 V and +1.90 V, respectively. Interestingly, the cyclic
voltammogram shows that the oxidation is not reversible. The high oxidation potentials
measured contrast the values typically obtained for antioxidants and these data suggest that 1 is
likely functioning by an alternative mechanism. This corroborates the original ROS
experiments2 that suggest that 1 actually inhibits ROS production instead of reacting with
reactive oxygen species. Further studies on the mode of action of 1 are underway and will be
reported in due course.
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acortatarin A (1)
100
90
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10
0
-10
-20
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
2
2.2
Potential (V vs Ag/AgNO3)
Figure 3. Voltammogram of 1 in CH3CN.
CONCLUSION
In conclusion, the total synthesis of acortatarin A using a Pd(II)-catalyzed
spiroketalization for the key step has been reported. The characterization data of synthetic 1 are
identical to those reported for both acortatarin A and pollenopyrroside B, verifying that they are
actually the same natural product. Furthermore, electrochemical studies suggest that the
bioactivity of this compound may not be due to simple antioxidant properties.
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EXPERIMENTAL SECTION
General
9
All reactions were carried out under an atmosphere of nitrogen unless otherwise
specified. Anhydrous solvents were transferred via syringe to flame-dried glassware, which had
been cooled under a stream of dry nitrogen. Anhydrous tetrahydrofuran (THF), acetonitrile,
ether, dichloromethane (DCM), pentane, toluene were dried using a solvent purification system.
Analytical thin layer chromatography (TLC) was performed using 250 µm silica gel. Flash
column chromatography was performed using 230-400 mesh 60 Å silica gel. The eluents
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1
employed are reported as volume:volume percentages. Melting points were uncorrected. H and
13C NMR spectra were recorded in CDCl3, CD3OD or acetone-d6 using tetramethylsilane as an
internal standard. Chemical shift (δ) is reported in parts per million (ppm) downfield relative to
tetramethylsilane, CDCl3, CD3OD, or acetone-d6. Multiplicities are reported using the following
abbreviations: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. Specific optical
rotations were obtained using wavelength = 589 nm. Infrared spectra were obtained using film
NaCl plate techniques. High resolution mass spectra (HRMS) were obtained with electrospray
ionization using a TOF mass analyzer (ESI-MS), and are reported as m/e (relative ratio).
N-methoxy-N-methyl-1H-pyrrole-2-carboxamide (16). According to a known procedure,14 a
solution of triphosgene (7.52 g, 25.3 mmol) in 35 mL toluene was added via dropping funnel to a
stirred solution of N,N-dimethylaniline (9.63 mL, 76 mmol) and pyrrole (5.27 mL, 76 mmol) in
toluene (75 mL) at 0 ˚C over 20 minutes. The resulting mixture was allowed to stir at room
temperature for 2 hours. In a separate flask, triethylamine (25.4 mL, 182 mmol) was added to a
suspension of N,O-dimethylhydroxylamine hydrochloride (15) (8.9 g, 91.2 mmol) in DCM (70
mL), and the mixture stirred at room temperature for 30 minutes. The free amine was filtered
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into a clean dropping funnel, the filter cake washed with DCM, and the resulting solution added
to the pyrrole mixture over 20 minutes at 0 ˚C. The reaction was allowed to reach room
temperature overnight before it was concentrated, taken up in 150 mL EtOAc, and washed with a
saturated aqueous solution of NaHCO3, followed by H2O, and then dried (Na2SO4) and
concentrated. The residue was purified by column chromatography (50% EtOAc/hexanes) to
furnish the product as a gray crystalline solid (11.39 g, 97%). Rf = 0.47 (50% EtOAc/hexanes);
MP 112-114 ˚C; 1H NMR (500 MHz, CDCl3): δ 9.72 (br s, 1H), 7.02 - 6.94 (m, 1H), 6.92 (ddd, J
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= 3.8, 2.4, 1.4 Hz, 1H), 6.45 - 6.13 (m, 1H), 3.78 (s, 3H), 3.35 (s, 3H); C NMR (125 MHz,
CDCl3): δ 161.6, 123.8, 122.0, 114.9, 110.7, 61.3, 33.2; IR (film): νmax 3269, 2974, 2937, 1755,
1690, 1597, 1547, 1438, 1296, 1178, 1104, 1045, 749; HRMS (ESI) calcd for C7H10N2O2Na
[M+Na]+ 177.0642, found 177.0632.
5-formyl-N-methoxy-N-methyl-1H-pyrrole-2-carboxamide (11). To pyrrole 16 (1.0 g, 6.49
mmol) in DMF (4.3 mL) at 0 ˚C was added 1.1 eq. of the Vilsmeier reagent (prepared by
dropwise addition of 0.65 mL POCl3 to 0.65 mL DMF at 5 ˚C) and the solution stirred for 1 h at
50 ˚C. The contents of the flask were cooled to room temperature, poured into 10 g crushed ice,
and quenched by the slow addition of saturated aqueous K2CO3 (15 mL) with stirring (15 min).
The mixture was extracted with EtOAc, dried over Na2SO4, and concentrated. Column
chromatography (30% EtOAc/hexanes) afforded the title compound as a crystalline white solid
(591 mg, 50 %). Rf = 0.34 (50% EtOAc/hexanes); MP 118-120 ˚C; 1H NMR (500 MHz, CDCl3)
δ 10.18 (br s, 1H), 9.66 (s, 1H), 6.98 - 6.95 (m, 1H), 6.94 - 6.92 (m, 1H), 3.79 (s, 3H), 3.39 (s,
13
3H); C NMR (125 MHz, CDCl3): δ 180.3, 160.1, 133.6, 129.4, 120.2, 115.6, 61.7, 33.3; IR
(film): νmax 3240, 1677, 1612, 1391, 1216, 1193, 811, 751; HRMS (ESI) calcd for C8H10N2O3Na
[M+Na]+ 205.0584, found 205.0582.
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(R,E)-4-(benzyloxy)-5-bromopent-2-en-1-ol (13). Based on a similar literature procedure,19 a
solution of (R,E)-ethyl 4-(benzyloxy)-5-hydroxypent-2-enoate16 (17) (250 mg, 1.0 mmol) and
CBr4 (663 mg, 2.0 mmol) in 6 mL of dichloromethane was treated with PPh3 (525 mg, 2.0
mmol), and the mixture stirred at 45 ˚C for 30 min before cooling to -78 ˚C. DIBAL-H (5.0 mL
of a 1.0 M solution in toluene, 5 mmol) was then added in a dropwise fashion, and the resulting
mixture allowed to stir for 30 min. The reaction was then quenched with 10 mL of a saturated
aqueous solution of Rochelle’s salt, and allowed to warm to ambient temperature over 2 h. The
biphasic system was separated, and the aqueous phase extracted with DCM (3 x 20 mL). The
combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. Purification of
the crude material by flash chromatography (40 % EtOAc/hexanes) provided the allylic alcohol
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as a colorless oil (214 mg, 79 %). Rf = 0.59 (60% EtOAc/hexanes); [α]25 = -31.8 (c 1.00,
D
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CHCl3); H NMR (500 MHz, CDCl3) δ 7.38 - 7.33 (m, 5H), 5.95 (dtd, J = 15.6, 5.1, 0.9 Hz,
1H), 5.68 (ddt, J = 15.6, 7.4, 1.7 Hz, 1H), 4.56 (dd, J = 73.5, 11.9 Hz, 2H), 4.21 (d, J = 3.5 Hz,
13
2H), 4.06 (dddd, J = 7.4, 6.4, 5.2, 0.8 Hz, 1H), 3.53 - 3.34 (m, 2H), 1.44 (br s, 1H); C NMR
(125 MHz, CDCl3): δ 138.1, 134.6, 128.7, 128.6, 128.1, 128.0, 78.7, 71.1, 62.9, 35.1; IR (film):
νmax 3379, 3030, 2866, 1454, 1217, 1090, 739, 698; HRMS (ESI) calcd for C12H15BrO2Na2
[M+2Na]+ 317.0155, found 317.0699.
(R,E)-(((1-bromo-5-methoxypent-3-en-2-yl)oxy)methyl)benzene (18). To a suspension of
NaH (660 mg, 27.51 mmol) in THF (69 mL) at 0 ˚C was added allylic alcohol 13 (7.46 g, 27.51
mmol) in 69 mL THF over 10 min. After the mixture was stirred for an additional 5 min.,
iodomethane (4.28 mL, 68.8 mmol) was added dropwise in a dropwise fashion, followed by
stirring for 45 min. at the same temperature. The reaction was then quenched with a saturated
aqueous solution of NH4Cl, and extracted with DCM (3 x 150 mL). The combined organic
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extracts were concentrated under reduced pressure and purified by column chromatography on
silica gel (7% EtOAc/hexanes) to afford the title compound as a colorless oil (4.82 g, 62 %). Rf =
0.58 (25% EtOAc/hexanes); [α]25D = -28.6 (c 1.91, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.41 -
7.29 (m, 5H), 6.04 - 5.84 (m, 1H), 5.69 (ddtd, J = 15.6, 7.4, 1.5, 0.5 Hz, 1H), 4.58 (dd, J = 91.0,
11.9 Hz, 2H), 4.07 (dddt, J = 7.2, 6.5, 5.1, 0.7 Hz, 1H), 4.00 (ddd, J = 5.5, 1.5, 0.6 Hz, 2H), 3.50
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- 3.39 (m, 2H), 3.39 (s, 3H); C NMR (125 MHz, CDCl3): δ 138.1, 132.2, 130.2, 128.7, 128.1,
128.1, 129.0, 78.8, 72.3, 71.1, 58.4, 35.2; IR (film): νmax 3030, 2927, 2870, 1452, 1383, 1102,
1066, 974, 738, 698; HRMS (ESI) calcd for C12H13BrNaO [M-MeOH-Na]+ 275.0047, found
275.0901.
(S,E)-ethyl 2-(2-(benzyloxy)-5-methoxypent-3-en-1-yl)-1,3-dithiane-2-carboxylate (20).
Ethyl 1,3-dithiane-2-carboxylate17 (19) (4.88 g, 25.24 mmol) in DMF (35 mL) was added slowly
to a stirred suspension of NaH (606 mg, 25.24 mmol) and catalytic t-BuOH in DMF (35 mL) at 0
˚C over 10 min and allowed to continue stirring for an additional 45 min. Bromide 18 (3.60 g,
12.62 mmol) in DMF (35 mL) was then added dropwise to the reaction mixture, and the
temperature was maintained for 5 h. After the reaction was complete by TLC analysis, the
solution was diluted with Et2O and poured into a cold saturated aqueous solution of NH4Cl. The
organic phase was separated, and the aqueous layer extracted with EtOAc. The combined
organic extracts were washed with brine, dried over Na2SO4, and concentrated. Flash
chromatography (5-10% EtOAc/hexanes) of the crude material afforded the title compound as a
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colorless oil (3.68 g, 73 %). Rf = 0.41 (25% EtOAc/hexanes); [α]25D = -9.91 (c 0.76, CHCl3); H
NMR (500 MHz, CDCl3) δ 7.46 - 7.14 (m, 5H), 5.96 - 5.76 (m, 1H), 5.72 - 5.59 (m, 1H), 4.42
(dd, J = 67.2, 11.0 Hz, 2H), 4.25 (td, J = 8.3, 3.5 Hz, 1H), 4.13 - 3.84 (m, 4H), 3.36 (s, 3H), 3.31
(ddd, J = 14.2, 11.6, 2.6 Hz,, 1H), 3.12 (ddd, J = 14.2, 11.6, 2.6 Hz, 1H), 2.71 (ddd, J = 14.3, 5.2,
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3.1 Hz, 2H), 2.58 (dd, J = 14.4, 9.0 Hz, 1H), 2.23 (dd, J = 14.4, 3.7 Hz, 1H), 2.13 (ddt, J = 13.7,
5.3, 2.6 Hz, 1H), 2.01 - 1.82 (m, 1H), 1.18 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ
170.8, 138.5, 132.6, 130.0, 128.3, 127.6, 76.3, 72.5, 71.0, 62.0, 58.3, 52.7, 44.9, 28.1, 28.0, 25.1,
14.2; IR (film): νmax 2979, 2927, 1723, 1204, 1094, 1027, 737, 698; HRMS (ESI) calcd for
C20H28O4S2Na [M+Na]+ 419.1329, found 419.1326.
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(S,E)-(2-(2-(benzyloxy)-5-methoxypent-3-en-1-yl)-1,3-dithian-2-yl)methanol (21). To ester
20 (3.62 g, 9.11 mmol) in THF (60 mL) at 0 ˚C was added LAH (864 mg, 22.8 mmol) in 3
portions over 5 min. After 2.5 h, the reaction was quenched at the same temperature via slow
addition of 60 mL of a saturated aqueous solution of Rochelle’s salt. The mixture was stirred for
2 h, then extracted with EtOAc (3 x 175 mL). The organic extracts were dried over Na2SO4,
filtered, and concentrated to yield the title compound as a colorless oil, which was used without
further purification (3.23 g, 99 %). Rf = 0.20 (25% EtOAc/hexanes); [α]25 = -32.9 (c 0.26,
D
CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.56 - 7.14 (m, 5H), 5.83 (dtd, J = 15.6, 5.5, 0.7 Hz,
1H), 5.68 (ddt, J = 15.6, 7.8, 1.4 Hz, 1H), 4.46 (dd, J = 92.7, 11.1 Hz, 2H), 4.30 - 4.19 (m, 2H),
3.96 (d, J = 6.2 Hz, 2H), 3.90 - 3.69 (m, 2H), 3.36 (s, 1H), 3.20 (t, J = 7.3 Hz, 1H), 2.87 (dddd, J
= 29.0, 14.4, 10.2, 3.0 Hz, 2H), 2.75 - 2.57 (m, 2H), 2.25 (dd, J = 15.4, 9.1 Hz, 1H), 2.14 - 1.96
13
(m, 2H), 1.91 (dtt, J = 13.4, 10.1, 3.2 Hz, 1H). C NMR (125 MHz, CDCl3): δ 137.6, 132.7,
130.0, 128.7, 128.4, 128.1, 76.5, 72.4, 71.0, 65.6, 58.4, 53.5, 44.2, 26.4, 25.9, 25.4; IR (film):
νmax 3454, 2930, 2360, 2341, 1063, 981, 909, 738, 699; HRMS (ESI) calcd for C18H26O3S2Na
[M+Na]+ 377.1223, found 377.1221.
(S,E)-4-(benzyloxy)-1-hydroxy-7-methoxyhept-5-en-2-one (22). To dithiane 21 (78 mg, 0.22
mmol) in THF-MeOH-H2O 5:9:1 (1.5 mL) was added [bis(trifluoroacetoxy)iodo]benzene18 (146
mg, 0.33 mmol) in 1 portion at 0 ˚C. The reaction mixture was quenched after 45 min. with
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NaHCO3 (1.0 mL, saturated aqueous solution), and then extracted with Et2O. The crude product
was purified by flash chromatography (40 % EtOAc/hexanes) to furnish the ketone (55 mg, 95
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%) as a colorless oil. Rf = 0.35 (50% EtOAc/hexanes); [α]25 = -35.9 (c 2.40, CHCl3); 1H NMR
D
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(500 MHz, CDCl3) δ 7.43 - 7.14 (m, 5H), 5.85 (dtd, J = 15.8, 5.3, 0.7 Hz, 1H), 5.65 (ddt, J =
15.6, 7.7, 1.4 Hz, 1H), 4.57 (d, J = 11.6 Hz, 1H), 4.41 - 4.28 (m, 2H), 4.25 (t, J = 5.1 Hz, 2H),
3.96 (dd, J = 5.3, 1.5 Hz, 2H), 3.36 (s, 3H), 3.10 (t, J = 5.0 Hz, 1H), 2.79 (dd, J = 14.8, 8.8 Hz,
1H), 2.52 (dd, J = 14.9, 4.3 Hz, 1H); 13C NMR (125 MHz, CDCl3): δ 208.0, 137.9, 131.2, 130.9,
128.6, 128.0, 100.1, 75.9, 72.2, 70.9, 69.7, 58.4, 40.0; IR (film): νmax 3393, 2783, 1723, 1090,
1070, 740, 699; HRMS (ESI) calcd for C15H20O4Na [M+Na]+ 287.1254, found 287.1248.
(S,E)-4-(benzyloxy)-1-bromo-7-methoxyhept-5-en-2-one (12). To alcohol 22 (1.26 g, 4.77
mmol) and CBr4 (1.90 g, 5.72 mmol) in 48 mL DCM was added PPh3 (1.50 g, 5.72 mmol). The
solution changed color from yellow to dark brown, then orange after stirring for 1 h. The
reaction mixture was diluted with Et2O, then filtered over a pad of silica, and the filter cake
washed with additional Et2O.
The filtrate and washings were concentrated, then
chromatographed (20 % EtOAc/hexanes) to yield the title compound as a colorless oil (1.13 g,
72 %). Rf = 0.32 (20% EtOAc/hexanes); [α]23 = -6.06 (c 1.00, CHCl3); 1H NMR (500 MHz,
D
CDCl3) δ 7.41 - 7.20 (m, 5H), 5.88 (dtd, J = 15.6, 5.4, 0.9 Hz, 1H), 5.68 (ddt, J = 15.6, 7.7, 1.5
Hz, 1H), 4.59 (d, J = 11.3 Hz, 1H), 4.43 - 4.31 (m, 2H), 3.98 (dd, J = 5.5, 1.4 Hz, 2H), 3.95 (d, J
= 0.4 Hz, 2H), 3.38 (s, 3H), 3.02 (dd, J = 15.4, 8.7 Hz, 1H), 2.75 (dd, J = 15.4, 4.3 Hz, 1H); 13C
NMR (125 MHz, CDCl3): δ 199.8, 138.1, 131.3, 130.8, 128.7, 128.1, 128.0, 76.3, 72.3, 71.0,
58.5, 46.2, 35.9; IR (film): νmax 2873, 2825, 1725, 1587, 1452, 1383, 1093, 1069, 739, 699;
HRMS (ESI) calcd for C15H19BrO3Na [M+Na]+ 349.0418, found 349.0400.
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(S,E)-1-(4-(benzyloxy)-7-methoxy-2-oxohept-5-en-1-yl)-5-formyl-N-methoxy-N-methyl-1H-
pyrrole-2-carboxamide (23). To pyrrole 11 (128 mg, 0.70 mmol) and bromide 12 (229 mg,
0.70 mmol) in MeCN (5 mL) was added Cs2CO3 (228 mg, 0.70 mmol) in 2 portions over 0.5 h at
0 ˚C. The mixture was stirred for 8 h, then diluted with EtOAc (50 mL) and washed with H2O
and brine. The organic phase was dried over Na2SO4, concentrated, and purified by column
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chromatography (33-50% EtOAc/hexanes) to yield 236 mg, 79 % of the aldehyde as a yellow
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oil. Rf = 0.51 (50% EtOAc/hexanes); [α]23 = +11.5 (c 0.10, CHCl3); H NMR (500 MHz,
D
CDCl3) δ 9.59 (s, 1H), 7.38 - 7.29 (m, 5H), 6.95 (d, J = 4.2 Hz, 1H), 6.86 (d, J = 4.2 Hz, 1H),
5.96 - 5.54 (m, 4H), 4.56 (d, J = 11.4 Hz, 1H), 4.42 (d, J = 11.4 Hz, 1H), 4.40 - 4.32 (m, 1H),
3.95 (dd, J = 5.6, 1.5 Hz, 2H), 3.63 (s, 3H), 3.34 (s, 3H), 3.26 (s, 3H), 2.92 (dd, J = 15.9, 8.0 Hz,
1H), 2.69 (dd, J = 15.9, 4.8 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 202.1, 181.1, 161.3, 138.4,
133.4, 131.9, 130.3, 128.5, 127.9, 127.7, 123.2, 115.2, 75.4, 72.4, 70.8, 61.7, 58.2, 56.4, 46.6,
33.4, 29.9; IR (film): νmax 2926, 1732, 1668, 1634, 1522, 1447, 1374, 1261, 1211, 1098; HRMS
(ESI) calcd for C23H28N2O6Na [M+Na]+ 451.1847, found 451.1825.
(2R,4S,5R)-4-(benzyloxy)-N-methoxy-N-methyl-5-vinyl-1',4,4',5-tetrahydro-3H-
spiro[furan-2,3'-pyrrolo[2,1-c][1,4]oxazine]-6'-carboxamide
(9)
and
(2S,4S,5R)-4-
(benzyloxy)-N-methoxy-N-methyl-5-vinyl-1',4,4',5-tetrahydro-3H-spiro[furan-2,3'-
pyrrolo[2,1-c][1,4]oxazine]-6'-carboxamide (epi-9). Aldehyde 23 (1.12 g, 2.62 mmol) in THF
(17.0 mL) was cooled to 0 ˚C and treated with 13.0 mL of LTEPA20 (0.2 M in THF). After 2.5
h, TLC analysis indicated the reaction was complete, and the mixture was quenched via slow
addition of 5 % AcOH until evolution of H2 gas ceased. The resulting mixture was extracted
with EtOAc, washed with a saturated aqueous solution of NaHCO3 followed by brine and then
dried over Na2SO4. The extracts were concentrated under reduced pressure and subjected to
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flash chromatography (60 % EtOAc/hexanes) to yield a mixture of ketoalcohol 10 and the
corresponding hemiketal (1.05 g, 93 %) as a viscous yellow oil, which was used in the key Pd-
catalyzed cyclization.
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The ketoalcohol 10 (20 mg, 0.046 mmol) obtained above was dissolved in 5.0 mL DCM
with 4 Å MS and cooled to 0 ˚C. To the solution was added Pd(PhCN)2Cl2 (1.8 mg) and stirring
was continued for 12 h. The reaction was filtered over a silica plug with EtOAc, and the
combined organics were concentrated in vacuo. The crude material was purified by
chromatography to yield 9 (8 mg, 43 %) and epi-9 (8 mg, 43 %) as viscous yellow oils.
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Spiro compound 9: Rf = 0.55 (50% EtOAc/hexanes); [α]23 = +66.5 (c 0.15, CHCl3); H NMR
D
(500 MHz, CDCl3) δ 7.42 - 7.27 (m, 5H), 6.98 (d, J = 4.1 Hz, 1H), 5.91 (d, J = 4.2 Hz, 1H), 5.82
(dddd, J = 17.2, 10.4, 6.7, 0.5 Hz, 1H), 5.34 (dt, J = 17.1, 1.1 Hz, 1H), 5.17 (dt, J = 10.4, 1.1 Hz,
1H), 5.01 (d, J = 14.5 Hz, 1H), 4.84 (d, J = 14.8 Hz, 1H), 4.63 - 4.49 (m, 4H), 4.33 (d, J = 14.2
Hz, 1H), 3.92 (ddd, J = 7.9, 5.0, 3.4 Hz, 1H), 3.69 (s, 3H), 3.29 (s, 3H), 2.30 (dd, J = 14.1, 3.2
13
Hz, 1H), 2.23 (dd, J = 14.1, 8.2 Hz, 1H); C NMR (125 MHz, CDCl3) δ 162.5, 138.0, 136.1,
131.0, 128.7, 128.0, 117.5, 117.1, 103.3, 103.0, 85.6, 82.0, 77.5, 77.2, 77.0, 72.2, 61.1, 58.5,
51.8, 42.7, 33.7, 29.9; IR (film): νmax 3445, 2925, 2361, 2343, 1622, 1496, 1456, 1351, 1098,
1053, 1026; HRMS (ESI) calcd for C22H26N2O5Na [M+Na]+ 421.1742, found 421.1740.
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Spiro compound epi-9: Rf = 0.68 (50% EtOAc/hexanes); [α]23 = -85.9 (c 0.26, CHCl3); H
D
NMR (500 MHz, CDCl3) δ 7.45 - 7.28 (m, 5H), 6.97 (d, J = 4.1 Hz, 1H), 5.93 (ddd, J = 17.4,
10.4, 7.9 Hz, 1H), 5.88 (d, J = 4.1 Hz, 1H), 5.32 (ddd, J = 17.1, 1.0 Hz, 1H), 5.20 (ddd, J = 10.3,
1.4, 1.0 Hz, 1H), 5.02 (d, J = 14.7 Hz, 1H), 4.77 (d, J = 14.7 Hz, 1H), 4.63 (d, J = 14.1 Hz, 1H),
4.59 - 4.51 (m, 3H), 4.32 (d, J = 13.9 Hz, 1H), 4.22 (ddd, J = 7.2, 6.8, 5.1 Hz, 1H), 3.68 (s, 3H),
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3.29 (s, 3H), 2.51 (dd, J = 13.1, 6.7 Hz, 1H), 2.13 (dd, J = 13.1, 6.7 Hz, 1H); C NMR (125
MHz, CDCl3) δ 162.4, 137.9, 137.8, 130.5, 128.7, 128.0, 127.9, 122.3, 118.0, 116.9, 103.6,
102.9, 86.8, 82.2, 72.3, 61.1, 58.9, 52.1, 43.1, 33.7, 29.9. IR (film): νmax 3445, 2925, 2361, 2343,
1622, 1496, 1456, 1351, 1098, 1053, 1026; HRMS (ESI) calcd for C22H26N2O5Na [M+Na]+
421.1742, found 421.1740.
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(2S,4S,5R)-4-(benzyloxy)-5-(hydroxymethyl)-N-methoxy-N-methyl-1',4,4',5-tetrahydro-3H-
spiro[furan-2,3'-pyrrolo[2,1-c][1,4]oxazine]-6'-carboxamide (epi-24). To spiro compound
epi-9 (95 mg, 0.238 mmol) in THF-H2O 10:1 (5.5 mL) was added NMO (70 mg, 0.595 mmol)
then OsO4 (4 wt. % in H2O) (45 µL) and the mixture was allowed to stir for 24 h. The reaction
was quenched with 100 mg of Na2SO3 followed by stirring for 0.5 h. The resulting mixture was
then diluted with EtOAc (85 mL), washed with H2O, then brine, and concentrated. The crude
diol was then immediately subjected to periodate cleavage.
The oil obtained above was dissolved in THF-pH 7 buffer 5:1 (7.2 mL), cooled to 0 ˚C,
then treated with NaIO4 (102 mg, 0.476 mmol). Stirring was continued for 12 h, at which time
the reaction was quenched with 2 mL of phosphate buffer, diluted with EtOAc, and phases
separated. The organic layer was concentrated under reduced pressure to furnish the crude
aldehyde, which was dissolved in EtOH (6 mL), cooled to 0 ˚C, and treated with NaBH4 (13 mg,
0.357 mmol). After 1 h, the reaction mixture was quenched with 2 mL H2O, diluted with EtOAc,
and the layers separated. The organic phase was washed with brine and concentrated to give
essentially pure title compound (92 mg, 89 %). Rf = 0.39 (50% EtOAc/hexanes) as a yellow oil;
[α]23 = -19.1 (c 0.65, CHCl3); H NMR (500 MHz, CDCl3) δ 7.39 - 7.27 (m, 5H), 6.98 (d, J =
1
D
4.1 Hz, 1H), 5.91 (d, J = 4.1 Hz, 1H), 5.00 (d, J = 14.7 Hz, 1H), 4.82 (d, J = 14.7 Hz, 1H), 4.69
(d, J = 14.2 Hz, 1H), 4.59 - 4.44 (m, 2H), 4.36 (d, J = 14.2 Hz, 1H), 4.33 - 4.25 (m, 2H), 3.69 (s,
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3H), 3.30 (s, 3H), 2.55 (dd, J = 13.6, 6.4 Hz, 1H), 2.17 (dd, J = 13.5, 6.1 Hz, 1H); 13C NMR (125
MHz, CDCl3) δ 162.1, 137.6, 129.8, 128.5, 127.9, 127.7, 116.8, 104.1, 102.8, 86.5, 78.4, 72.0,
64.2, 61.0, 59.0, 51.9, 43.5, 33.5, 29.7; IR (film): νmax 2926, 2855, 2363, 2346, 1719, 1686, 1654,
1560, 1508, 1458, 1350, 1260, 1106, 1042; HRMS (ESI) calcd for C21H26N2O6Na [M+Na]+
425.1691, found 425.1677.
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(2R,4S,5R)-4-(benzyloxy)-5-(hydroxymethyl)-N-methoxy-N-methyl-1',4,4',5-tetrahydro-3H-
spiro[furan-2,3'-pyrrolo[2,1-c][1,4]oxazine]-6'-carboxamide (24). Prepared from spiro
compound 9 as described for spiro compound epi-24. Yield: 70 mg, 70 %, yellow oil; Rf = 0.42
1
(75% EtOAc/hexanes); [α]23D = +94.5 (c 1.20, CHCl3); H NMR (500 MHz, CDCl3) δ 7.45 -
7.28 (m, 5H), 6.99 (d, J = 4.0 Hz, 1H), 5.92 (d, J = 4.1 Hz, 1H), 4.99 (d, J = 14.8 Hz, 1H), 4.85
(d, J = 14.8 Hz, 1H), 4.68 - 4.55 (m, 2H), 4.52 (d, J = 12.2 Hz, 1H), 4.28 (d, J = 14.1 Hz, 1H),
4.26 - 4.20 (m, 2H), 4.19 - 4.04 (m, 1H), 3.76 (dd, J = 12.1, 3.1 Hz, 1H), 3.69 (s, 3H), 3.56 (dd, J
= 12.2, 4.0 Hz, 1H), 3.28 (s, 3H), 2.31 (dd, J = 14.1, 2.4 Hz, 1H), 2.17 (dd, J = 14.1, 8.4 Hz, 1H);
13C NMR (125 MHz, CDCl3): δ 162.4, 138.0, 131.0, 128.7, 128.0, 122.0, 117.2, 103.9, 103.0,
85.6, 78.2, 72.2, 62.7, 61.1, 58.6, 51.5, 43.0, 33.6, 29.9; IR (film): νmax 2926, 2855, 2363, 2346,
1719, 1686, 1654, 1560, 1508, 1458, 1350, 1260, 1106, 1042; HRMS (ESI) calcd for
C21H26N2O6Na [M+Na]+ 425.1691, found 425.1677.
(2S,4S,5R)-4-(benzyloxy)-5-(hydroxymethyl)-1',4,4',5-tetrahydro-3H-spiro[furan-2,3'-
pyrrolo[2,1-c][1,4]oxazine]-6'-carbaldehyde (epi-25). To spiro compound epi-24 (92 mg,
0.212 mmol) in 5 mL THF at -78 ˚C was added LAH (16 mg, 0.423 mmol), and the temperature
allowed to rise to 0 ˚C over 0.5 h. The temperature was maintained an additional 1 h, then the
reaction was quenched with KHSO4 (92 mg) then 5 mL 1 N HCl. The reaction was diluted with
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70 mL EtOAc, separated, then dried over Na2SO4. The dry organics were concentrated to yield
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an essentially pure compound (61 mg, 84 %) as a viscous orange oil. Rf = 0.55 (66%
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EtOAc/hexanes); [α]23 = -31.6 (c 0.20, CHCl3); H NMR (500 MHz, CDCl3) δ 9.45 (s, 1H),
D
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7.62 - 7.26 (m, 5H), 6.91 (d, J = 4.1 Hz, 1H), 6.00 (d, J = 4.1 Hz, 1H), 5.02 (d, J = 15.5 Hz, 1H),
4.82 (d, J = 15.5 Hz, 1H), 4.77 (d, J = 14.3 Hz, 1H), 4.53 (d, J = 2.5 Hz, 2H), 4.37 - 4.22 (m,
3H), 3.76 (dd, J = 11.9, 3.4 Hz, 1H), 3.66 (dd, J = 11.9, 5.1 Hz, 2H), 2.55 (dd, J = 13.5, 6.3 Hz,
1H), 2.18 (dd, J = 13.6, 6.2 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 179.0, 137.7, 134.3, 131.3,
128.7, 128.1, 127.9, 124.3, 105.0, 103.7, 86.7, 78.5, 72.2, 64.3, 58.7, 51.7, 43.4; IR (film): νmax
2920, 2852, 2360, 2342, 1716, 1652, 1558, 1507, 1465, 1260, 1185, 1042; HRMS (ESI) calcd
for C19H21NO5Na [M+Na]+ 366.1320, found 366.1299.
(2R,4S,5R)-4-(benzyloxy)-5-(hydroxymethyl)-1',4,4',5-tetrahydro-3H-spiro[furan-2,3'-
pyrrolo[2,1-c][1,4]oxazine]-6'-carbaldehyde (25). Prepared from 24 as described for spiro
compound epi-25. Yield: 50 mg, 89 %, orange oil. Rf = 0.66 (75% EtOAc/hexanes); [α]23
=
D
+87.8 (c 0.68, CHCl3); 1H NMR (500 MHz, CDCl3) δ 9.44 (s, 1H), 7.47 - 7.28 (m, 5H), 6.92 (d,
J = 4.1 Hz, 1H), 6.02 (d, J = 4.1 Hz, 1H), 5.01 (dd, J = 15.5, 1.1 Hz, 1H), 4.87 (d, J = 15.5 Hz,
1H), 4.68 - 4.56 (m, 2H), 4.53 (d, J = 12.1 Hz, 1H), 4.32 - 4.20 (m, 2H), 4.16 (ddd, J = 8.3, 4.7,
2.4 Hz, 1H), 3.78 (dd, J = 12.2, 3.1 Hz, 1H), 3.73 - 3.65 (m, 1H), 3.59 (dd, J = 12.0, 3.9 Hz, 1H),
2.33 (dd, J = 14.2, 2.4 Hz, 1H), 2.20 (dd, J = 14.2, 8.4 Hz, 1H); 13C NMR (125 MHz, CDCl3): δ
179.0, 137.9, 135.3, 131.2, 128.1, 128.0, 124.5, 105.1, 103.4, 85.9, 78.1, 72.3, 62.6, 58.1, 51.0,
42.8, 30.0;IR (film): νmax 2920, 2852, 2360, 2342, 1716, 1652, 1558, 1507, 1465, 1260, 1185,
1042; HRMS (ESI) calcd for C19H21NO5Na [M+Na]+ 366.1320, found 366.1299.
Acortatarin A (1) and epi-Acortatarin A (epi-1). According to a known procedure7, spiro
compound 25 (31 mg, 0.090 mmol) in DCM (3.0 mL) was added 0.9 mL of TiCl4 solution (1.0M
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/ DCM) at 0 ˚C, and the reaction stirred for 3 h. At the same temperature, the reaction was then
quenched with a saturated aqueous solution of NaHCO3 (3.0 mL), extracted with EtOAc (3 x 50
mL), and the combined extracts dried over Na2SO4. Careful purification by column
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chromatography (100% EtOAc) separated the anomeric mixture yielding acortatarin A (1) (16
mg, 70 %) and (epi-1) (1.5 mg, 7 %) as off-white crystals.
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Acortatarin A (1): Rf = 0.29 (100 % EtOAc); [α]23 = +185.2 (c 0.15, MeOH); H NMR (500
D
MHz, CD3OD) δ 9.36 (s, 1H), 7.02 (d, J = 4.1 Hz, 1H), 6.08 (d, J = 4.1 Hz, 1H), 5.02 (d, J =
15.8 Hz, 1H), 4.85 (d, J = 15.8 Hz, 1H), 4.59 (d, J = 14.0 Hz, 1H), 4.29 (ddd, J = 8.3, 4.5, 2.7
Hz, 1H), 4.23 (d, J = 14.0 Hz, 1H), 4.07 (td, J = 4.8, 3.2 Hz, 1H), 3.71 (dd, J = 12.1, 3.3 Hz, 1H),
3.62 (dd, J = 12.1, 4.9 Hz, 1H), 2.35 (dd, J = 14.1, 8.3 Hz, 1H), 2.15 (dd, J = 14.0, 2.7 Hz, 1H);
13C NMR (125 MHz, CD3OD) δ 180.4, 137.8, 132.6, 126.2, 106.4, 104.7, 89.4, 72.4, 63.2, 58.9,
52.2, 46.1; HRMS (ESI) calcd for C12H15NO5Na [M+Na]+ 276.0850, found 276.0851.
1H NMR (500 MHz, Acetone-d6) δ 9.48 (s, 1H), 6.99 (d, J = 4.1 Hz, 1H), 6.07 (d, J = 3.8 Hz,
1H), 5.01 (d, J = 15.1 Hz, 1H), 4.85 (d, J = 15.5 Hz, 1H), 4.55 (d, J = 14.1 Hz, 1H), 4.36 (dt, J =
7.6, 3.5 Hz, 1H), 4.21 (d, J = 14.0 Hz, 1H), 4.11 (q, J = 4.3 Hz, 1H), 3.70 (dd, J = 12.0, 3.5 Hz,
1H), 3.63 (dd, J = 12.0, 4.4 Hz, 1H), 2.41 (dd, J = 13.9, 8.1 Hz, 1H), 2.15 (dd, J = 13.9, 2.7 Hz,
13
1H); C NMR (125 MHz, Acetone-d6) δ 179.0, 135.9, 132.2, 124.3, 105.4, 105.3, 104.0, 89.5,
62.7, 58.2, 51.7, 45.8; HRMS (ESI) calcd for C12H15NO5Na [M+Na]+ 276.0850, found 276.0851.
epi-Acortatarin A (epi-1): Rf = 0.30 (100 % EtOAc); [α]23D = -73.1 (c 0.05, MeOH); 1H NMR
(500 MHz, CD3OD) δ 9.38 (s, 1H), 7.03 (d, J = 4.1 Hz, 1H), 6.07 (d, J = 3.9 Hz, 1H), 5.10 (d, J
= 15.9 Hz, 1H), 4.82 (d, J = 15.7 Hz, 1H), 4.68 (d, J = 13.9 Hz, 1H), 4.52 - 4.30 (m, 1H), 4.23 (d,
J = 14.8 Hz, 1H), 4.09 - 3.87 (m, 1H), 3.71 (dd, J = 11.8, 4.5 Hz, 1H), 3.62 (dd, J = 11.6, 6.9 Hz,
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1H), 2.51 (dd, J = 13.3, 6.9 Hz, 1H), 2.10 (dd, J = 13.3, 6.9 Hz, 1H). HRMS (ESI) calcd for
C12H15NO5Na [M+Na]+ 276.0850, found 276.0851.
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Acortatarin A (1) and epi-Acortatarin A (epi-1). Compounds (1) and (epi-1) were prepared
from spiro compound epi-25 as described for the preparation of the same compounds from spiro
compound 25.
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ACKNOWLEDGMENTS
We thank Prof. Lisa McElwee-White and Sarah Goforth for their assistance with CV
studies. We thank the Herman Frasch Foundation (647-HF07) and the James and Ester King
Biomedical Research Program (09KN-01) for their generous support of our programs.
1
Supporting Information Available: H- and 13C-NMR spectra for all new compounds.
Additional details on the electrochemical experiments. This material is available free of charge
via the Internet at http://pubs.acs.org.
References
(1) Guo, J.-L.; Feng, Z.-M.; Yang, Y.-J.; Zhang, Z.-W.; Zhang, P.-C. Chem. Pharm. Bull. 2010,
58, 983.
(2) (a) Tong, X.-G.; Zhou, L.-L.; Wang, Y.-H.; Xia, C.; Wang, Y.; Liang, M.; Hou, F.-F.; Cheng,
Y.-X. Org. Lett. 2010, 12 1844. (b) Tong, X.-G.; Zhou, L.-L.; Wang, Y.-H.; Xia, C.; Wang, Y.;
Liang, M.; Hou, F.-F.; Cheng, Y.-X. Org. Lett. 2011, 13 4478.
(3) Zennie, T. M.; Cassady, J. M.; Raffauf, R. F. J. Nat. Prod. 1986, 49, 695.
(4) Yu, H.-J.; Chen, C.-C.; Shieh, B.-J. J. Nat. Prod. 1998, 61, 1017.
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(5) Nakayama, T.; Hayase, F.; Kato, H. Agric. Biol. Chem. 1980, 44, 1201.
6
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8
(6) To the best of our knowledge, compound 1 is reported in 4 papers, but the name
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pollenopyrroside B only appears in the Zhang isolation paper (ref. 1). To avoid confusion and
redundancy, we suggest that it be referred to as acortatarin A forthwith.
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(7) (a) Sudhakar, G.; Kadam, V. D.; Bayya, S.; Pranitha, G.; Jagadeesh, B. Org. Lett. 2011, 13,
5452. (b) Geng, H. M.; Chen, J. L.-Y.; Furkert, D. P.; Jiange, S.; Brimble, M. A. Synlett 2012,
23, 855.
(8) After our initial submission, the third total synthesis of acortatarin A appeared: Wurst, J. M.;
Verano, A. L.; Tan, D. S. Org. Lett. 2012, 14, 4442.
(9) Tan and co-workers correctly conclude that acortatarin A and pollenopyrroside B are the
same natural product based on X-ray structures of a related natural product, pollenopyrroside A
(ref 1). Although spectra of natural pollenopyrroside B were reported in acetone-d6, to date, no
spectra of synthetic acortatarin A/pollenopyrroside B in acetone-d6 have appeared.
(10) Brownlee, M. Nature 2001, 414, 813.
(11) (a) Aponick, A.; Li, C.-Y.; Biannic, B. Org. Lett. 2008, 10, 669. (b) Aponick, A.; Biannic,
B. Synthesis 2008, 3356. (c) Aponick, A.; Li, C.-Y.; Palmes, J. A. Org. Lett. 2009, 11, 121. (d)
Aponick, A.; Li, C.-Y.; Malinge, J.; Marques, E. F. Org. Lett. 2009, 11, 4624. (e) Aponick, A.;
Biannic, B.; Jong, M. R. Chem. Commun. 2010, 46, 6849. (f) Aponick, A.; Biannic, B. Org. Lett.
2011, 13, 1330. (g) Biannic, B.; Ghebreghiorgis, T.; Aponick, A. Beilstein J. Org. Chem. 2011,
7, 802. (h) Biannic, B.; Aponick, A. Eur. J. Org. Chem. 2011, 6605.
(12) Palmes, J. A. Ph.D. Thesis, University of Florida, 2012.
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(13) For leading references see: (a) Uenishi, J.; Vikhe, Y. S.; Kawai, N. Chem. Asian J. 2008, 3,
473; (b) Awasaguchi, K.-i.; Miyazawa, M.; Uoya, I.; Inoue, K.; Nakamura, K.; Yokoyama, H.,
Kakuda, H.; Hirai, Y. Synlett 2010, 16, 2392.
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(14) Cho, H.; Matsuki, S.; Mizuno, A.; Annoura, H.; Tatsuoka, T. J. Heterocyclic Chem. 1997,
34, 87.
(15) Silverstein, R. M.; Ryskiewicz, E. E.; Willard, C. Org. Synth. 1963, 4, 831.
(16) Steuer, B.; Wehner, V.; Lieberknecht, A.; Jäger, V. Org. Synth. 1997, 74, 1, (Coll. Vol IX,
p. 39).
(17) Eliel, E. L.; Hartmann, A. A. J. Org. Chem. 1972, 37, 505.
(18) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 287.
(19) Chen, C.; Tan, X. Angew. Chem. Int. Ed. 2006, 45, 4345.
(20) Krishnamurthy, S. J. Org. Chem. 1981, 46, 4628.
(21) Similar observations were made by Brimble and coworkers (ref 7b). Alternatively, Tan (ref
8) reports that both acortatarin A and its epimer at the spiro carbon converge to a 65:35 mixture
favoring the natural product upon acid-catalyzed equilibration.
(22) See Supporting Information for full details.
(23) Although the presence of water shifts oxidation potential towards more negative values,
acetonitrile was used as solvent due to lack of solubility of the analytes and the internal standard
in water. At the moment, it is unclear if acortatarin A exists in the bilayer, as many antioxidants
do, or elsewhere. Additionally, acetonitrile was used to allow comparison to the oxidation
potential of the well known antioxidant vitamin E. For leading references see: Tan, Y. S.; Chen,
S.; Hong, W. M.; Kan, J. M.; Kewk, E. S. H.; Lim, S. Y.; Lim, Z. H.; Tessensohn, M. E.; Zhang,
Y.; Webster, R. D. Phys. Chem. Chem. Phys., 2011, 13, 12745.
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(24) Penketh, G. E. J. Appl. Chem. 1957, 7, 512.
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