Total syntheses of (+)-alopecuridine, (+)-sieboldine A, and (-)-lycojapodine A

Article abstract of DOI:10.1021/jo301545y

(+)-Alopecuridine, (+)-sieboldine A, and (-)-lycojapodine A, three structurally unique and related lycopodium alkaloids, have been synthesized in enantiomeric forms through an efficient strategy. The main synthetic approach for (+)-alopecuridine features

Full text of DOI:10.1021/jo301545y

Article
pubs.acs.org/joc
Total Syntheses of (+)-Alopecuridine, (+)-Sieboldine A, and
(−)-Lycojapodine A
Xiao-Ming Zhang, Hui Shao, Yong-Qiang Tu,* Fu-Min Zhang, and Shao-Hua Wang*
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou,
Gansu 730000, P. R. China
S
* Supporting Information
ABSTRACT: (+)-Alopecuridine, (+)-sieboldine A, and
(−)-lycojapodine A, three structurally unique and related
lycopodium alkaloids, have been synthesized in enantiomeric
forms through an efficient strategy. The main synthetic
approach for (+)-alopecuridine features a semipinacol
rearrangement of hydroxyl epoxide to construct the spiro
6,9-azacarbocycles with an all-carbon quaternary center and a
late-stage SmI2-mediated intramolecular coupling to form the
5-membered ring. Subsequently, the biomimetic synthesis of
(+)-sieboldine A and (−)-lycojapodine A was accomplished
successfully through two different bioinspired oxidations after
a wide search for the oxidation methods. As a result,
(+)-sieboldine A was derived from (+)-alopecuridine through
an N-oxidation/nitrone formation process and (−)-lycojapodine A through an interesting cyclic hemiketal formation/oxidative
diol cleavage pathway. These results confirmed the biogenetic relationship among the three alkaloids.
sieboldine A and lycojapodine A even have an unprecedented
N,O-acetal or N,O-ketal moiety, whose unstability makes them
synthetically more challenging. Although the cyclic structure of
sieboldine A or lycojapodine A is somewhat different from
alopecuridine, they were supposed to have close biogenetic
relationship with alopecuridine,6,7 which made their biomimetic
syntheses very attractive.
INTRODUCTION
■
The lycopodium alkaloids consist of over 200 structurally
diverse natural products. These alkaloids have received
considerable attention over the years, owing not only to their
potential biological activities but also to their unique and
intricate structures.1 Among these compounds, (+)-alopecur-
idine (1), (+)-sieboldine A (2), and (−)-lycojapodine A (3) are
three structurally related fawcettimine-type alkaloids (Figure
1)2−4 that were isolated by Ayer et al. in 1974,5 Kobayashi et al.
In 2010, Overman group disclosed an elegant asymmetric
total synthesis of (+)-sieboldine A for the first time.3 More
recently, we have reported the total synthesis of ( )-alopecur-
idine, from which we also achieved the synthesis of
( )-sieboldine A via a biomimetic oxidation.4 However, the
total synthesis of lycojapodine A (3) has not been achieved to
date probably because the unprecedented carbinolamine
lactone motif is difficult to construct. Indeed, Yang and co-
workers reported in 2010 that direct cyclization of the ester 4
would give an unnatural alkaloid 7, which can be further
oxidized to 8 instead of the desired 3 (Scheme 1).8 Nearly at
the same time, we also met failure in assembling this intriguing
moiety either from compound 4 via a biomimetic cyclization or
from 1 via an oxidative cleavage/esterfication process.7 The
undesired unnatural alkaloids 7 or 8 were always obtained in
high yield through these approaches. The results indicated that
the free amine of 4 or the intermediate 5, generated by
oxidative cleavage of 1, tended to attack the ketone
functionality inside of the 9-membered azacycle to form a
Figure 1. Alopecuridine (1), sieboldine A (2), and lycojapodine A (3).
in 2003,6 and Zhao et al. in 2009,7 respectively. In particular,
both (+)-sieboldine A and (−)-lycojapodine A have important
biological activities. (+)-Sieboldine A inhibits acetylcholinester-
ase (AChE) significantly (IC50 = 2.0 μM) and is cytotoxic
against murine lymphoma L1210 cells (IC50 = 5.1 μg/mL),6
while (−)-lycojapodine A has anti-HIV-1 activity (EC50 = 85
μg/mL) and exhibits acetylcholinesterase (AChE) inhibition
(IC50 = 90.3 μM) as well.7 From a structural point of view, all
these compounds have a distinctive tetracyclic skeleton and
sterically hindered two contiguous quaternary carbons, one of
which is an all-carbon quaternary center. Additionally,
Received: July 21, 2012
Published: August 27, 2012
© 2012 American Chemical Society
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and the tetrahydrofuran ring in sieboldine A (2) could be
introduced through a biomimetic oxidation from alopecuridine
(1).4 We considered that the key carbinolamine lactone moiety
in lycojapodine A (3) could also be obtained from
alopecuridine (1) through the biogenetic proposal of Zhao
and co-workers7 or be generated via a biomimetic cyclization of
compound 4 under certain conditions.8 Alopecuridine may
exist in either a carbinolamine form 1 or an aminoketone form
1′,5 of which the five-membered ring B could be constructed
though a late stage SmI2-mediated pinacol coupling. As can be
seen by the structure, the advanced intermediate 9 contains a
sterically crowded α-quaternary-β-hydroxy carbonyl moiety and
an aza-cyclononane ring, which could be efficiently constructed
through a semipinacol rearrangement of epoxide 10. If there is
no racemization caused by Claisen rearrangement during the
experiment, epoxide 10 could be assembled from chiral
fragment 11 by coupling with ketone 15 and subsequent
epoxidation. We further expected that the fragment 11 would
be prepared from the well-known, optically active enone 149
through Corey−Bakshi−Shibata (CBS) reduction,10 Johnson−
Claisen rearrangement,11 and a series of functional group
interconversions.
Scheme 1. Attempts To Synthesize Lycojapodine A (3)
Improved Asymmetric Total Synthesis of Alopecur-
idine and Sieboldine A. In the beginning of our synthesis
(Scheme 3), iodide 16 and bromide 17, readily prepared from
bicyclic [6,5] enamine 6 which could undergo subsequent
intramolecular nucleophilic substitution/β-elimination reaction
to give 7 or an in situ oxidized product 8. Therefore, we
reconsidered that the biogenetic pathway from alopecuridine to
lycojapodine A would need the first formation of a required C−
O bond between ketone carbonyl and hydroxyl at carbinol-
amine moiety (as shown in hemiketal 1″, Scheme 1) and then
cleavage of the resulting diol. Based on this analysis, we made
an extensive screening of the oxidation conditions and finally
realized the biomimetic transformation. Herein, we report our
asymmetric total syntheses of (+)-alopecuridine (1) and
(+)-sieboldine A (2) and the first biomimetic total synthesis
of (−)-lycojapodine A (3) in detail.
Scheme 3. Synthesis of the Chiral Bromide 23
RESULTS AND DISCUSSION
Retrosynthetic Analysis. Our synthetic design is outlined
in Scheme 2. As we previously reported, the N-hydroxy group
■
a
Scheme 2. Retrosynthetic Analysis
the known enone 14,12,13 were subjected to diastereoselective
reduction with (R)-Corey−Bakshi−Shibata (CBS) reagent to
afford the corresponding trans-allyl alcohols 18 and 19,
respectively.14 After screening several solvents and temper-
atures, we found that the reaction of bromo enone 17
conducted in THF at room temperature could give the best
trans selectivity (trans:cis = 5:1). Thus, the obtained inseparable
diastereomers 19 was chosen for further transformations.
Treatment of 19 with trimethyl orthoester at 165 °C in the
presence of a small amount of propanoic acid generated bromo
ester 20 in good yield (80% based on consumed 19).
Subsequent LiAlH4 reduction of 20 followed by Dess−Martin
oxidation15 and Wittig methylenation produced fragment 23
with the same diastereoselectivity (dr = 5:1). Although the
synthetic approach from 14 to bromoalkene 23 had two more
steps than our previous reported racemic procedure for
iodoalkene ( )-25, the diastereomer ratio of the final fragment
was enhanced. In addition, the Lewis acid induced allylation,
a
Boc = tert-butoxycarbonyl, X = I or Br.
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which may cause racemerization in asymmetric synthesis, was
avoided in our present route.
(Scheme 5).8 It was obvious that the formation of the fused 6/5
ring was much more favorable than the formation of the
We next coupled bromoalkene 23 and known ketone 154
through the intermediacy of the vinylcerium species generated
from the lithium salt of 23 (Scheme 4).16 To avoid elimination,
Scheme 5. Attempted Biomimetic Cyclization Approach to
Lycojapodine A (3)
Scheme 4. Completion of Asymmetric Total Syntheses of
(+)-Alopecuridine·TFA (31) and (+)-Sieboldine A (2)
strained [4.3.1] bridge ring. However, we proposed that if we
could in situ protect the carbonyl group of the aza-nine-
membered ring as a silyl enol ether during N-Boc deprotection
(see 39), the free amine would probably attack the ketone in
the six-membered ring to furnish the desired product.
Therefore, we synthesized ( )-4 from ( )-9 in four
straightforward steps including Dess−Martin oxidation,15
ozonolysis, Pinnick oxidation,23 and esterfication. However,
when we added Et3N and TMSOTf to the substrate ( )-4, it
immediately converted to compound ( )-7 in high yield.
Further attempts by changing the solvent and temperature also
gave the same result. At last, we were forced to give up this
strategy and reconsider the proposed biomimetic path by Zhao
and co-workers.7 As they suggested, oxidative cleavage of ring B
in alopecuridine (1) would lead to the formation of acid 5′,
which would then be transformed to lycojapodine A (3) under
esterfication conditions (Scheme 6). Inspired by this proposal,
we prepared some ( )-alopecuridine·TFA (31). Unfortunately,
when ( )-31 was subjected to oxidation under Pb(OAc)4 in
toluene, neither acid 5′ nor lacojapodine A (3) was observed.
The only product was ( )-8, another unnatural alkaloid
the coupling product was directly epoxidized to give 10, which
are still inseparable diastereomers, in 71% yield over two steps
(dr = 6:1).17 Then, promoted by BF3·Et2O, the semipinacol
rearrangement of 10 took place to produce ketone 9 in 51%
yield. The HPLC analysis showed that compound 9 was
enantiomerically pure (>99% ee), which confirmed that there
was no racemization during the coupling and epoxidation.
Conversion of enantiopure ketone 9 to (+)-alopecuridine was
accomplished in six synthesis steps similar to our racemic route.
After a three-step sequence involving hydroxyl group
protection, ozonolysis, and SmI2 promoted intramolecular
pinacol coupling,18 the so obtained tricyclic compound 28 was
further subjected to one-pot deprotection,19 TPAP oxidation20
and final N-Boc deprotection to deliver (+)-alopecuridine·TFA
(31) ([α]13.3 = +70.0 (c 1.0, MeOH)).21 The biomimetic
D
oxidation from (+)-alopecuridine·TFA (31) to (+)-sieboldine
A could then be achieved in a one-pot manner. It should be
noted that the oxidation of N-hydroxide 33 with HgO22 might
form another N−C9 nitrone in addition to 34, but we did not
isolate any product corresponding to this regioisomer. Some
unexpected side reactions might occur from this intermediate
and cause the moderate yield of this oxidation. The synthetic
(+)-sieboldine A exhibited a rotation of +135.7 (c = 0.28,
MeOH), essentially identical to that of the natural product.6
Biomimetic Synthesis of Lacojapodine A. Having
achieved the asymmetric syntheses of 1 and 2, we turned our
attention to explore the biomimetic synthesis of lacojapodine A
(3) with our abundant racemic material. In 2010, Yang and co-
workers had reported that direct cyclization of diketone 38
would generate an unnatural alkaloid 7 in various conditions
Scheme 6. Attempted Oxidative Cleavage/Esterfication
Approach to Lycojapodine A (3)
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reported by Yang et al.8 Although the outcome was
disappointing, we realized that the existence of the five-
membered B ring played an essential role in stabilizing the
carbinolamine moiety. The cleavage of this ring would cause
the conversion of acid 5′ from its carbinolamine form into its
aminoketone form 5. Then 5 would followed the same tandem
process as 38 to give compound 7, which was in situ oxidized to
alkaloid 8 by Pb(OAc)4.
Table 1. Diol Cleavage of the Model Substrate ( )-41 and
(+)-Alopecuridine·TFA (31)
On the basis of above results, we envisioned that the
introduction of a C−O bond between ketone carbonyl and
hydroxyl at carbinolamine moiety in the presence of ring B
might avoid the unexpected tandem reaction since the cleavage
of the ring B and the formation of related lactone ring could be
carried out simultaneously. Accordingly, a new biogenetic
pathway of lycojapodine A (3) was proposed. As shown in
Scheme 7, alopecuridine (1) was probably in equilibrium with
from
from ( )-41
(+)-31
a
a
42
30
a
entry
1
oxidant
solvent
(%)
(%)
3
(%)
NaIO4 (4 equiv)
THF/H2O
= 5:1
b
b
b
Scheme 7. Proposed Biomimetic Pathway of Lycojapodine A
(3)
2
3
DMP (4 equiv)
CH2Cl2
CH2Cl2
69
29
29
60
c
c
TPAP (0.25 equiv)/
NMO (3 equiv)
d
4
5
PCC (3 equiv)
CH2Cl2
46
23
trace
e
CrO3·2C5H5N
(10 equiv)
CH2Cl2
f
f
27−32
6
MnO2
CH2Cl2
95
g
82
a
b
c
Isolated yield. No reaction at both room temperature and reflux. A
its hemiketal form 1″, which actually contained the expected
C−O bond. Subsequently, an oxidative cleavage of the so
formed 1,2-diol moiety of 1″ would deliver lycojapodine A.
In order to validate this hypothesis, we first prepared a model
substrate ( )-41 from ( )-28 through TEMPO oxidation24
and deprotection (Scheme 8). To our delight, the NMR data
d
complex mixture was obtained. Low conversion accompanied by
decomposition. The reaction temperature was 25 °C. This condition
was not tried on ( )-41. Compound 30 was not detected.
e
f
g
improve the yield to 82% (Table 1, entry 6). Combined with
our model study, the above results verified the existence of the
isomerization from 1 to 1″, whose diol group could also be
efficiently cleavaged by MnO2. The synthetic lycojapodine A
was spectroscopically identical (1H and 13CNMR) to the
Scheme 8. Synthesis of Model Substrate
reported values.7 Its rotation ([α]16.5 = −144.1 (c 0.34,
D
CHCl3)) were identical to that of the natural product {[α]24.7
D
= −140.98 (c 0.2, CHCl3)}, which also confirmed the absolute
configuration of 3.
CONCLUSION
showed substrate ( )-41 existed as a hemiketal. When ( )-41
was subjected to the diol cleavage, we found that the commonly
used NaIO4 could not promote this reaction (Table 1, entry 1
from ( )-41), while some other oxidants, such as DMP, PCC,
or TPAP (Table 1, entries 2−4), could oxidize the 1,2-diol
group to give lactone ( )-42 in moderate to good yield with
diketone ( )-30 as the byproduct. When we further changed
the oxidant to MnO2 (Table 1, entry 6), ( )-42 could be
obtained as the sole product in high yield.
Having realized our assumption on the model substrate, we
focused on the real biomimetic transformation. We mainly
screened the oxidants used in our model study to see whether
they were also efficient in our real substrate. For comparison,
the results are also summarized in Table 1. (+)-Alopecur-
idine·TFA (31) did not react with NaIO4 (Table 1, entry 1
from (+)-31). However, unlike the model substrate, alopecur-
idine·TFA easily decomposed under the oxidation of DMP or
TPAP (Table 1, entries 2 and 3). When PCC was used as the
oxidant (Table 1, entry 4), we were pleased to observe a slow
oxidation of the starting material to lycojapodine A, and a full
conversion was achieved by using Collins’ reagent, generating
lycojapodine A (3) in 27−32% yield (Table 1, entry 5).25
Eventually, we found that previously used MnO2 could greatly
■
In summary, we have described the asymmetric total syntheses
of (+)-alopecuridine, (+)-sieboldine A, and (−)-lycojapodine A
in 15, 16, and 16 steps from chiral enone 14, featuring a
semipinacol rearrangement and a SmI2-promoted intramolec-
ular pinacol coupling. In the course of our exploration on the
biomimetic synthesis of (−)-lycojapodine A, three plausible
ways were attempted, from which its biogenetic pathway from
(+)-alopecuridine through our proposed diol formation/diol
cleavage process was realized for the first time.
EXPERIMENTAL SECTION
■
General Experimental Details. Silica gel (200−300 mesh) and
basic alumina (200−300 mesh), light petroleum ether (bp 60−90 °C),
ethyl acetate, dichloromethane, and methanol were used for product
purification by flash column chromatography. All solvents were
purified and dried by standard techniques and distilled prior to use. All
organic extracts were dried over Na2SO4 unless otherwise noted. IR
spectra were recorded on a Fourier transform infrared spectrometer.
1H and 13C NMR spectra were recorded in CDCl3 solution or in
CD3OD solution on 400 or 600 MHz instruments. The MS data were
obtained with EI (70 eV) or ESI. High-resolution mass spectral
analysis (HRMS) data were determined on a FT-ICR spectrometer.
Enantioselectivities were determined by high-performance liquid
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chromatography (HPLC) analysis employing a Chiralpak IC column.
Melting points were measured on a melting point apparatus and are
uncorrected.
substrate 20 (353 mg, 1.43 mmol, 1 equiv) in Et2O (7.2 mL) was
added slowly. The mixture was stirred for 30 min at 0 °C and then
carefully quenched with aqueous 10% NaOH. The resulting mixture
was extracted with Et2O, and the organic phase was washed with water
and brine, dried with Na2SO4, and concentrated in vacuo. The crude
product was purified by column chromatography (EtOAc/petroleum
ether = 1:10) to give product 21 as a colorless oil (275 mg, 88% yield):
[α]25.9D = −100.0 (c = 1.0, CHCl3); [α]21.7D = +91.0 (c = 1.0, CHCl3);
IR (neat) 3331, 2921, 1644 cm−1; 1H NMR (400 MHZ, CDCl3) δ 6.09
(d, J = 6.4 Hz, 0.15H), 6.01 (dd, J = 2.4, 2.4 Hz, 0.74H), 3.86−3.64
(m, 2H), 2.64−2.46 (m, 1H), 2.27−2.00 (m, 2H), 1.98−1.90 (m,
0.20H), 1.85−1.43 (m, 5.76H), 1.15 (dd, J = 23.6, 12.0 Hz, 0.20H),
0.95 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHZ, CDCl3) δ 130.5, 129.2,
128.6, 127.4, 61.0, 60.2, 39.9, 39.8, 39.3, 37.9, 36.2, 36.2, 36.1, 36.1,
28.5, 23.1, 21.5, 21.3; ESI MS m/z = 241 and 243 [M + Na]+; HRMS
ESI calcd for C9H15BrNaO [M + Na]+ 241.0204 and 243.0184, found
241.0198 and 243.0178, error 2.5 and 2.5 ppm.
Bromo α,β-Unsaturated Ketone 17. To a stirred solution of α,β-
unsaturated ketone 14 (1.522 g, 13.8 mmol) in CH2Cl2 (34 mL)
under argon at 0 °C was added a solution of bromine (0.74 mL, 14.4
mmol, 1.05 equiv) in CH2Cl2 (34 mL) slowly (over 1 h). Then Et3N
(3.27 mL, 23.5 mmol, 1.7 equiv) was added, and the resulting mixture
was allowed to warm at room temperature and stirred for 1.5 h before
it was quenched with aqueous HCl (1 M). The layers were separated,
and the organic layer was washed with brine, dried with Na2SO4, and
concentrated in vacuo. The crude product was purified by column
chromatography (EtOAc/petroleum ether = 1:8) to give product 17
(2.537 g, 97% yield) as a colorless oil: [α]23.9 = −70.0 (c = 1.0,
D
1
CHCl3); IR (neat) 2959, 1691, 1603 cm−1; H NMR (400 MHZ,
CDCl3) δ 7.38 (dd, J = 6.0, 2.8 Hz, 1H), 2.78−2.63 (m, 1H), 2.50
(ddd, J = 18.4, 6.4, 4.0 Hz, 1H), 2.39−2.24 (m, 2H), 2.15 (ddd, J =
18.4, 6.4, 2.8 Hz, 1H), 1.08 (d, J = 6.0 Hz, 3H); 13C NMR (100 MHZ,
CDCl3) δ 191.4, 150.2, 123.7, 46.2, 36.3, 30.3, 20.7; ESI MS m/z =
189 and 191 [M + H]+; HRMS ESI calcd for C7H13BrNO [M +
NH4]+ 206.0175 and 208.0160, found 206.0181 and 208.0159, error
2.9 and 0.5 ppm.
Aldehyde 22. Substrate 21 (990 mg, 4.5 mmol, 1.0 equiv) was
dissolved in CH2Cl2 (55 mL) under argon at room temperature. The
solution was cooled to 0 °C. Then Dess−Martin oxidant (2.876 g, 6.8
mmol, 1.5 equiv) was added sequentially. The mixture was stirred at
room temperature for 3 h. After the reaction was quenched with
saturated Na2S2O3, the resulting mixture was extracted with EtOAc.
The organic phase was washed with saturated Na2S2O3, saturated
NaHCO3, and brine, dried with Na2SO4, and concentrated in vacuo.
The residue was chromatographed (EtOAc/petroleum ether = 1:20)
Bromoalkene 19. The flame-dried round-bottom flask (100 mL)
under argon was charged with D-diphenylprolinol (204 mg, 0.81
mmol, 0.1 equiv), THF (13 mL), and B(OMe)3 (0.09 mL, 0.81 mmol,
0.1 equiv). The mixture was stirred at room temperature for 0.5 h.
Then borane−N,N-diethylaniline complex (1.44 mL, 8.1 mmol, 1
equiv) was added followed by addition of the solution of compound
17 (1.522 g, 8.1 mmol, 1 equiv) in THF (13 mL). The mixture was
stirred for 1 h and then carefully quenched with MeOH at 0 °C. The
solvent was removed with a rotary evaporator. The remaining oil was
dissolved with Et2O, washed with saturated Na2CO3 solution, 10%
NaHSO4, and brine, and dried over Na2SO4. The crude product was
purified by column chromatography (EtOAc/petroleum ether = 1:16)
to give compound 22 (824 mg, 84% yield) as a colorless oil: [α]26.1
=
D
1
+76.0 (c = 1.0, CHCl3); IR (neat) 2920, 1724, 1645 cm−1; H NMR
(400 MHZ, CDCl3) δ 9.79 (s, 1H), 6.16 (d, J = 6.4 Hz, 0.15H), 6.08
(dd, J = 2.4, 2.4 Hz, 0.74H), 3.09−2.99 (m, 1H), 2.92 (dd, J = 17.2, 3.2
Hz, 1H), 2.50 (ddd, J = 17.2, 10.0, 2.4 Hz, 1H), 2.21−2.06 (m, 1H),
2.03−1.95 (m, 0.20H), 1.85−1.54 (m, 3.68H), 1.14 (dd, J = 23.6, 12.0
Hz, 0.21H), 0.94 (d, J = 6.0 Hz, 3H); 13C NMR (100 MHZ, CDCl3) δ
201.3, 201.2, 131.6, 130.6, 126.0, 125.1, 49.2, 47.5, 39.9, 38.2, 37.7,
36.7, 36.0, 35.8, 28.3, 23.1, 21.3, 21.0; ESI MS m/z = 217 and 219 [M
+ H]+; HRMS ESI calcd for C9H14BrO [M + H]+ 217.0228 and
219.0208, found 217.0223 and 219.0202, error 2.3 and 2.7 ppm.
Bromoalkene 23. A solution of potassium tert-butoxide (512 mg,
4.57 mmol, 2.5 equiv) in 5.5 mL of dry toluene was stirred under
argon at room temperature as methyltriphenylphosphonium bromide
(1.961 g, 5.49 mmol, 3.0 equiv) was added. The resulting bright yellow
solution was stirred for 1 h and cooled to 0 °C before 22 (397 mg,
1.83 mmol, 1.0 equiv) was added in dry toluene (5.5 mL). The ice
bath was removed, and the solution was stirred at room temperature
for 1.5 h. After the reaction was quenched with saturated NH4Cl, the
resulting mixture was extracted with EtOAc. The organic phase was
washed with water and brine, dried with Na2SO4, and concentrated in
vacuo. The residue was chromatographed (petroleum ether) to give
compound 23 (346 mg, 88% yield) as a colorless oil: [α]28.8D = +94.0
to give product 19 as a colorless oil (1.246 g, 81% yield): [α]25.9
=
D
−100.0 (c = 1.0, CHCl3); IR (neat) 3369, 2953, 1643 cm−1; 1H NMR
(400 MHZ, CDCl3) δ 6.18 (dd, J = 5.6, 2.4 Hz, 0.75H), 6.13 (d, J = 5.2
Hz, 0.15H), 4.33−4.16 (m, 1H), 2.41−2.23 (m, 1H), 2.23−2.12 (m,
1H), 2.12−1.86 (m, 2H), 1.80−1.64 (m, 1H), 1.55 (ddd, J = 13.2,
13.2, 4.4 Hz, 0.87H), 1.48−1.38 (ddd, J = 12.4, 12.4, 9.6 Hz, 0.17H),
1.07−0.92 (m, 3H); 13C NMR (100 MHZ, CDCl3) δ 132.4, 131.4,
127.4, 124.7, 70.6, 70.2, 40.7, 39.9, 36.1, 36.0, 27.9, 22.6, 21.3, 20.9;
ESI MS m/z = 191 and 193 [M + H]+; HRMS ESI calcd for
C7H11BrNaO [M + Na]+ 212.9891 and 214.9871, found 212.9884 and
214.9865, error 3.3 and 2.8 ppm.
Ester 20. To a solution of 19 (733 mg, 3.8 mmol) in trimethyl
orthoacetate (40 mL) was added 20 drops of propanoic acid. The flask
was equipped with a Dean−Stark apparatus and a condenser. The
mixture was heated at 165 °C for 30 h, during which time the
methanol produced and most of the excess trimethy1 orthoacetate
were collected in the Dean−Stark apparatus. The residue was diluted
with ether (60 mL) and the organic solution washed with 10%
aqueous HC1, saturated NaHCO3 solution, and brine. The organic
phase was dried over Na2SO4 and concentrated to give the crude
product. Flash chromatography on silica gel (EtOAc/petroleum ether
= 1:100) afforded compound 20 as a colorless oil (645 mg, 68% yield,
80% yield based on consumed starting material): [α]26.4D = +53.0 (c =
1
(c = 1.0, CHCl3); IR (neat) 2919, 1641, 1451 cm−1; H NMR (400
MHZ, CDCl3) δ 6.12 (d, J = 6.4 Hz, 0.15H), 6.02 (dd, J = 4.0, 2.8 Hz,
0.76H), 5.84−5.69 (m, 1H), 5.14−5.01 (m, 2H), 2.68−2.47 (m, 1H),
2.45−2.36 (m, 1H), 2.29−2.01 (m, 2H), 1.87−1.61 (m, 3H), 1.44
(ddd, J = 12.8, 12.8, 6.0 Hz, 0.84H), 1.17 (dd, J = 23.6, 12.0 Hz,
0.17H), 0.99−0.87 (m, 3H); 13C NMR (100 MHZ, CDCl3) δ 136.7,
135.5, 130.9, 129.4, 128.3, 127.2, 117.0, 116.6, 42.7, 42.2, 39.2, 38.9,
37.4, 36.3, 36.1, 35.2, 28.4, 22.9, 21.5, 21.2; EI MS m/z = 214 (3)
[M]+, 216 (2) [M]+, 173 (18), 175 (17), 135 (62), 93 (88); HRMS
APCI Calcd for C10H16Br [M + H]+ 215.0435 and 217.0415, found
215.0434 and 217.0415, error 0.5 and 0.0 ppm.
Epoxide 10. Substrate 23 (303 mg, 1.41 mmol) was dissolved in
THF (3 mL) under argon at room temperature. The solution was
cooled to −78 °C. Then t-BuLi (1.6 M, 1.64 mL, 1.85 equiv) was
added at the same temperature. After 5 min, anhydrous CeCl3 (348
mg, 1.41 mmol, 1 equiv) in THF (6 mL) was added slowly to the
reaction mixture at −78 °C. The mixture was stirred at −78 °C for
another 20 min. Then substrate 15 (320 mg, 1.41 mmol, 1 equiv) in
THF (1.5 mL) was added, and the reaction was quenched by saturated
NH4Cl 30 min later. The resulting mixture was extracted with Et2O/
EtOAc = 1:1 three times. The combined organic phases were washed
1
1.0, CHCl3); IR (neat) 2953, 1740, 1645 cm−1; H NMR (400 MHZ,
CDCl3) δ 6.13−6.09 (m, 0.15H), 6.08−6.00 (m, 0.75H), 3.78−3.65
(m, 3H), 3.03−2.82 (m, 2H), 2.32 (dd, J = 16.4, 11.6 Hz, 0.85H), 2.20
(dd, J = 15.6, 10.0 Hz, 0.22H), 2.18−2.02 (m, 1H), 1.85−1.62 (m,
3H), 1.57 (ddd, J = 12.4, 12.4, 5.6 Hz, 0.90H), 1.15 (dd, J = 23.6, 12.0
Hz, 0.20H), 1.01−0.89 (m, 3H); 13C NMR (100 MHZ, CDCl3) δ
172.7, 131.2, 130.4, 126.4, 125.4, 51.6, 51.6, 40.3, 40.0, 39.9, 39.4, 37.8,
36.4, 36.1, 36.0, 28.3, 22.9, 21.3, 21.1; ESI MS m/z = 247 and 249 [M
+ H]+; HRMS ESI calcd for C10H15BrNaO2 [M + Na]+ 269.0153 and
271.0133, found 269.0153 and 271.0120, error 0.0 and 4.8 ppm.
Alcohol 21. The flame-dried round-bottom flask 50 mL under
argon was charged with LiAlH4 (110 mg, 2.86 mmol, 2 equiv) and
Et2O (7.2 mL). The mixture was stirred at 0 °C for 5 min. Then
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with saturated NH4Cl and brine, dried with Na2SO4, and concentrated
in vacuo. The crude residue was directly subjected to the next reaction.
The crude residue was dissolved in CH2Cl2 (7 mL) under argon.
The solution was cooled to 0 °C. Then NaHCO3 (237 mg, 2.82 mmol,
2 equiv) and m-CPBA (243 mg, 95%, 1.41 mmol, 1 equiv) were added
sequentially. The mixture was stirred at 0 °C for 45 min. After the
reaction was quenched with water, the resulting mixture was extracted
with Et2O/EtOAc = 1:1. The organic phase was washed with saturated
K2CO3 (three times), water, and brine, dried with Na2SO4, and
concentrated in vacuo. The residue was chromatographed (EtOAc/
petroleum ether = 1:10) to give compound 10 (379 mg, 71% yield) as
reaction was completed by TLC. After PPh3 (84 mg, 0.32 mmol, 1.5
equiv) addition, the reaction was stirred at room temperature for 4 h.
Concentration of the reaction mixture gave a yellow oil, which was
chromatographed (EtOAc/petroleum ether = 1:4) to give compound
( )-36 (75 mg, 93% yield) as a colorless foam: IR (neat) 2925, 1725,
1
1693 cm−1; H NMR (400 MHZ, CDCl3) δ 9.72 (s, 1H), 3.53−3.20
(m, 1H), 3.14−2.83 (m, 3H), 2.83−2.55 (m, 3H), 2.48−2.38 (m, 1H),
2.38−2.16 (m, 5H), 2.14−2.00 (m, 2H), 1.94−1.57 (m, 4H), 1.47 (s,
9H), 1.42−1.32 (m, 1H), 1.03 (d, J = 6.4 Hz, 3H); 13C NMR (100
MHZ, CDCl3) δ 211.5, 210.8, 200.8, 157.1, 155.7, 79.9, 79.7, 70.0,
69.9, 49.0, 47.8, 46.9, 46.3, 45.1, 44.7, 37.8, 37.4, 34.6, 34.4, 34.3, 30.8,
30.6, 28.4, 23.4, 22.3, 21.6, 21.5, 21.2, 20.9; ESI MS m/z = 380 [M +
H]+, 402 [M + Na]+; HRMS ESI calcd for C21H34NO5 [M + H]+
380.2431, found 380.2429, error 0.5 ppm.
a colorless foam: [α]25.1 = +28.0 (c = 1.0, CHCl3); IR (neat) 3469,
D
2926, 1689 cm−1; 1H NMR (400 MHZ, CDCl3) δ 5.87−5.68 (m, 1H),
5.07−4.94 (m, 2H), 3.72−3.37 (m, 2H), 3.35−3.29 (m, 1H), 3.24−
3.07 (m, 2H), 2.83−2.74 (m, 0.13H), 2.37−2.29 (m, 0.78H), 2.19−
2.06 (m, 2H), 2.04−1.89 (m, 2H), 1.85−1.75 (m, 2H), 1.73−1.54 (m,
6H), 1.51−1.41 (m, 2H), 1.44 (s, 9H), 1.26−1.16 (m, 1H), 0.94 (s,
1H), 0.85 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHZ, CDCl3) δ 155.9,
155.6, 137.2, 116.3, 115.8, 79.2, 79.1, 75.3, 73.4, 67.7, 58.3, 56.9, 56.7,
47.0, 46.9, 46.7, 46.3, 39.2, 37.9, 35.4, 35.0, 34.2, 33.9, 33.7, 33.6, 33.1,
32.9, 32.6, 32.4, 31.9, 28.5, 28.5, 27.9, 25.8, 21.8, 21.5, 20.2; ESI MS
m/z = 380 [M + H]+; HRMS ESI calcd for C22H37NO4Na [M + Na]+
402.2615, found 402.2621, error 1.5 ppm.
Acid ( )-37. To a stirred solution of aldehyde ( )-36 (40 mg, 0.11
mmol) in t-BuOH/H2O (4.2 mL/1.2 mL) at room temperature were
added 2-methyl-2-butene (0.05 mL, 0.47 mmol, 4.5 equiv),
NaH2PO4·2H2O (18 mg, 0.12 mmol, 1.1 equiv), and NaClO2 (34
mg, 0.38 mmol, 3.5 equiv). The resulting mixture was stirred for 30
min before it was quenched by saturated NH4Cl. The resulting mixture
was extracted with EtOAc, and the organic phase was washed with
brine, dried with Na2SO4, and concentrated in vacuo. The residue was
chromatographed (EtOAc/petroleum ether = 1:1) to provide ( )-37
(37 mg, 88% yield) as a colorless foam: IR (neat) 3373, 2923, 1693
cm−1; 1H NMR (400 MHZ, CDCl3) δ 3.53−2.56 (m, 6H), 2.47−2.10
(m, 7H), 2.07−2.01 (m, 1H), 1.97−1.87 (m, 1H), 1.81−1.66 (m, 3H),
1.65−1.53 (m, 1H), 1.47 (s, 9H), 1.43−1.29 (m, 2H), 1.04 (d, J = 6.4
Hz, 3H); 13C NMR (100 MHZ, CDCl3) δ 211.3, 210.8, 177.8, 177.7,
157.2, 80.0, 79.8, 70.1, 60.4, 49.2, 47.7, 47.0, 46.9, 46.3, 45.0, 37.5,
37.3, 37.0, 34.9, 34.8, 33.8, 33.7, 30.5, 29.7, 28.4, 28.3, 23.3, 21.4, 21.0;
ESI MS m/z = 396 [M + H]+, 418 [M + Na]+; HRMS ESI calcd for
C21H34NO6 [M + H]+ 396.2381, found 396.2373, error 2.0 ppm.
Alkaloid ( )-7. Substrate ( )-4 (24 mg, 0.06 mmol) was dissolved
in CH2Cl2 (1.2 mL) under argon at room temperature. Then Et3N
(0.018 mL, 0.13 mmol, 2.2 equiv) and TMSOTf (0.012 mL, 0.07
mmol, 1.1 equiv) were added sequentially. The mixture was stirred at
room temperature for 30 min. After the reaction with saturated
NaHCO3, the resulting mixture was extracted with CHCl3 three times.
The organic phase was combined and dried with Na2SO4 and
concentrated in vacuo. The residue was chromatographed (MeOH/
CH2Cl2 = 1:40) to give compound ( )-7 (13 mg, 87% yield) as a
β-Hydroxy Ketone 9. To a stirred solution of substrate 10 (93 mg,
0.25 mmol) in Et2O (2.1 mL) under argon at −30 °C was added
BF3·Et2O (0.06 mL). Then the mixture was stirred at −20 °C for 40
min and −15 °C for 40 min. After the reaction was quenched with
water, the mixture was extracted with Et2O/EtOAc = 1:1. The organic
phase was washed with water and brine, dried with Na2SO4, and
concentrated in vacuo. The residue was chromatographed (EtOAc/
petroleum ether = 1:8) to give 9 (47 mg, 51% yield) as a colorless
foam and the other isomer (8 mg, 9% yield) as a white solid: [α]24.4
=
D
+64.0 (c = 1.0, CHCl3); IR (neat) 3545, 2971, 1693 cm−1; H NMR
(400 MHZ, CDCl3) δ 5.68−5.56 (m, 1H), 4.99−4.89 (m, 2H), 4.14−
4.04 (m, 1H), 3.68−3.33 (m, 2H), 3.27−3.14 (m, 1H), 3.07−2.91 (m,
1H), 2.90−2.58 (m, 3H), 2.23−1.79 (m, 6H), 1.76−1.65 (m, 2H),
1.65−1.39 (m, 3H), 1.46 (s, 9H), 1.35−1.22 (m, 2H), 1.21−1.10 (m,
1H), 0.86 (d, J = 6.0 Hz, 3H); 13C NMR (100 MHZ, CDCl3) δ 219.8,
157.0, 156.1, 138.2, 115.7, 79.7, 79.6, 68.7, 59.6, 59.2, 48.7, 47.6, 45.2,
43.8, 40.1, 39.9, 36.4, 36.4, 32.1, 31.5, 31.3, 29.5, 28.5, 23.0, 22.1, 21.8,
21.1, 20.2; ESI MS m/z = 397 [M + NH4]+; HRMS ESI calcd for
C22H37NO4Na [M + Na] + 402.2615, found 402.2624, error 2.2 ppm.
Enantiomeric excess is >99% determined by HPLC (Chiralpak IC,
hexane/2-propanol = 90/10, flow rate = 1.0 mL/min, 315 nm): major
isomer, tR = 11.68 min; minor isomer, tR = 10.52 min.
1
1
white solid: IR (neat) 3376, 2925, 1705, 1657, 1549 cm−1; H NMR
(600 MHZ, CDCl3) δ 3.76 (ddd, J = 10.8, 10.8, 4.8 Hz, 1H), 3.34 (dd,
J = 12.0, 6.0 Hz, 1H), 3.31 (t, J = 10.8 Hz, 1H), 2.90−2.73 (m, 3H),
2.57−2.47 (m, 2H), 2.42−2.30 (m, 3H), 2.28−2.19 (m, 1H), 2.15 (dd,
J = 16.8, 4.2 Hz, 1H), 1.94−1.83 (m, 2H), 1.68−1.50 (m, 3H), 1.07
(d, J = 6.0 Hz, 3H); 13C NMR (150 MHZ, CDCl3) δ 209.8, 188.1,
167.0, 109.3, 54.3, 52.8, 46.4, 45.0, 44.1, 39.8, 33.2, 29.9, 29.7, 23.6,
22.2, 19.2; EI MS m/z = 259 (19) [M]+, 176 (48), 91 (16), 56 (35),
41 (100); HRMS ESI calcd for C16H22NO2 [M + H]+ 260.1645, found
260.1646, error 0.4 ppm.
Alkaloid ( )-8. To a stirred solution of alopecuridine·TFA ( )-31
(6.6 mg, 0.017 mmol) in toluene (2 mL) under argon was added
Pb(OAc)4 (11 mg, 0.025 mmol, 1.5 equiv) at room temperature. The
resulting solution was allowed to stir for 1 h and then quenched by
water. The aqueous layer was extracted with EtOAc, and the combined
organic layers were washed with saturated NaHCO3 and brine, dried
over Na2SO4, and concentrated in vacuo. Flash column chromatog-
raphy (EtOAc/petroleum ether =1:1) afforded compound ( )-8 (3.6
mg, 83%) as a white solid: IR (neat) 3364, 2922, 1702, 1644 cm−1; 1H
NMR (600 MHZ, CDCl3) δ 6.63 (d, J = 3.0 Hz, 1H), 6.59 (d, J = 3.0
Hz, 1H), 4.10 (dd, J = 12.6, 6.6 Hz, 1H), 3.80 (ddd, J = 12.0, 12.0, 6.0
Hz, 1H), 2.73−2.66 (m, 1H), 2.63 (ddd, J = 13.2, 3.6, 3.6 Hz, 1H),
2.57 (dd, J = 16.8, 13.2 Hz, 1H), 2.44−2.37 (m, 2H), 2.31 (dd, J =
13.2, 3.6 Hz, 1H), 2.33−2.25 (m, 1H), 2.08−2.01 (m, 1H), 1.97 (ddd,
J = 14.4, 12.6, 4.2 Hz, 1H), 1.92−1.82 (m, 1H), 1.72−1.65 (m, 2H),
1.12 (d, J = 6.0 Hz, 3H); 13C NMR (150 MHZ, CDCl3) δ 211.5, 191.8,
142.4, 122.9, 118.8, 106.3, 51.9, 45.7, 45.5, 43.8, 42.1, 33.7, 29.8, 29.6,
22.3, 19.1; ESI MS m/z = 258 [M + H]+; HRMS ESI Calcd for
Diketone ( )-35. Substrate ( )-9 (90 mg, 0.24 mmol) was
dissolved in CH2Cl2 (5 mL) under argon at room temperature. The
solution was cooled to 0 °C. Then NaHCO3 (70 mg, 0.83 mmol, 3.5
equiv) and Dess−Martin oxidants (151 mg, 0.36 mmol, 1.5 equiv)
were added sequentially. The mixture was stirred at 25 °C for 4 h.
After the reaction was quenched with saturated Na2S2O3, the resulting
mixture was extracted with EtOAc. The organic phase was washed
with saturated Na2S2O3, saturated NaHCO3, and brine, dried with
Na2SO4, and concentrated in vacuo. The residue was chromato-
graphed (EtOAc/petroleum ether = 1:8) to give compound ( )-35
(86 mg, 96% yield) as a colorless foam: IR (neat) 2922, 1726, 1655
cm−1; 1H NMR (400 MHZ, CDCl3) δ 5.77−5.61 (m, 1H), 5.06−4.85
(m, 2H), 3.49−2.85 (m, 4H), 2.73−2.52 (m, 1H), 2.45−2.26 (m, 4H),
2.26−2.06 (m, 4H), 2.06−1.97 (m, 1H), 1.94−1.81 (m, 1H), 1.77−
1.51 (m, 4H), 1.45 (s, 9H), 0.97 (d, J = 6.4 Hz, 3H), 0.90−0.80 (m,
1H); 13C NMR (100 MHZ, CDCl3) δ 211.2, 157.1, 155.7, 137.3,
116.0, 115.8, 79.7, 79.5, 70.4, 49.0, 47.6, 47.1, 47.0, 46.2, 44.9, 40.9,
39.9, 38.1, 37.7, 33.6, 33.1, 31.6, 31.2, 29.7, 28.9, 28.7, 28.4, 23.2, 22.6,
22.2, 21.9, 21.6, 21.1, 20.9; ESI MS m/z = 400 [M + Na]+; HRMS ESI
calcd for C22H36NO4 [M + H]+ 378.2639, found 378.2648, error 2.4
ppm.
Aldehyde ( )-36. Substrate ( )-35 (80 mg, 0.21 mmol) was
dissolved in CH2Cl2 (3 mL) at room temperature. The reaction
mixture was cooled to −78 °C. After a brief oxygen purge (5 min),
ozone was bubbled through the reaction mixture slowly until the
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C16H20NO2 [M + H]+ 258.1489, found 258.1482, error 2.7 ppm; mp
246−247 °C.
CHCl3, washed with saturated NaHCO3, dried with Na2SO4, and
concentrated in vacuo. The mixture obtained was purified by column
chromatography with basic Al2O3 (EtOAc/petroleum ether = 0:1−
1:4) to afford lycojapodine A 3 (1.7 mg for three pots, 30% yield) as a
white solid. (b) Reaction using MnO2: To a stirred solution of
alopecuridine·TFA 31 (1.6 mg for one pot, 4.07 μmol, 9.6 mg for six
pots) in CH2Cl2 under argon was added MnO2 (10.4 mg every time,
62.4 mg in total) every 6 h. The mixture was stirred at room
temperature for 36 h. Then the reaction mixture was filtered though a
short basic Al2O3 column (EtOAc) and the filtrate was concentrated in
vacuo. The mixture obtained was purified by column chromatography
with basic Al2O3 (EtOAc/petroleum ether = 0:1 to 1:4) to afford
lycojapodine A 3 (5.6 mg for six pots, 82% yield) as a white solid:
α-Hydroxy Ketone ( )-40. To a stirred solution of ( )-28 (47
mg, 0.11 mmol) in CH2Cl2 (1 mL) at 0 °C were added saturated
aqueous NaHCO3 (0.22 mL), potassium bromide (2.6 mg, 0.02 mmol,
0.2 equiv), TEMPO (3.4 mg, 0.02 mmol, 0.2 equiv), and aqueous
sodium hypochlorite (0.33 mL, 0.22 mmol, 2.0 equiv) sequentially.
The reaction mixture was stirred at 0 °C for 6 h. After the reaction was
quenched with saturated aqueous KHSO4, the ice bath was removed
and the reaction mixture allowed to warm to room temperature. The
aqueous layer was extracted with EtOAc, and the combined organic
layers were washed with brine, dried over Na2SO4, and concentrated in
vacuo. Flash column chromatography (EtOAc/petroleum ether = 1:2)
afforded compound ( )-40 (42 mg, 89%) as a colorless foam: IR
[α]16.5 = −144.1 (c = 0.34, CHCl3); IR (neat) 2926, 2868, 1737,
D
1
1685, 1181, 1128 cm−1; H NMR (600 MHZ, CDCl3) δ 3.89−3.80
1
(neat) 3382, 2926, 1739, 1689 cm−1; H NMR (600 MHZ, CDCl3) δ
(m, 1H), 3.44−3.35 (m, 1H), 3.06 (dd, J = 15.6, 5.4 Hz, 1H), 2.94 (d,
J = 15.0 Hz, 1H), 2.78−2.70 (m, 1H), 2.70−2.63 (m, 1H), 2.52−2.40
(m, 2H), 2.33−2.27 (m, 1H), 2.21 (dd, J = 13.8, 12.0 Hz, 1H), 2.14−
2.08 (m, 1H), 2.08−1.98 (m, 2H), 1.84−1.77 (m, 1H), 1.77−1.66 (m,
2H), 1.57−1.41 (m, 4H), 0.99 (d, J = 6.0 Hz, 3H); 13CNMR (150
MHZ, CDCl3) δ 217.3, 170.6, 93.4, 54.9, 50.5, 49.2, 46.6, 41.4, 36.5,
36.0, 34.9, 31.5, 26.6, 24.4, 24.0, 21.2; ESI MS m/z = 278 [M + H]+;
HRMS ESI Calcd for C16H24NO3 [M + Na]+ 278.1756, found
278.1755, error 0.4 ppm; mp 176−177 °C.
4.46 (s, 2H), 3.88 (s, 1H), 3.66−3.49 (m, 2H), 3.28 (s, 3H), 3.00−
2.90 (m, 1H), 2.90−2.78 (m, 1H), 2.43−2.27 (m, 4H), 2.18−2.08 (m,
1H), 1.94−1.79 (m, 4H), 1.77−1.65 (m, 3H), 1.65−1.59 (m, 1H),
1.58−1.51 (m, 1H), 1.51−1.40 (m, 1H), 1.46 (s, 9H), 1.37−1.30 (m,
1H), 1.17 (dd, J = 13.2, 13.2 Hz, 1H), 0.93 (d, J = 6.6 Hz, 3H); 13C
NMR (150 MHZ, CDCl3) δ 212.8, 157.0, 97.0, 79.8, 79.5, 77.9, 56.4,
49.6, 49.5, 49.3, 37.8, 37.4, 34.7, 32.2, 28.5, 25.0, 24.3, 22.7, 22.0, 21.8,
20.4; ESI MS m/z = 426 [M + H]+; HRMS ESI calcd for C23H40NO6
[M + H]+ 426.2850, found 426.2848, error 0.5 ppm.
Hemiketone ( )-41. To a stirred solution of substrate ( )-40 (33
mg, 0.078 mmol) in iPrOH (3 mL) was added CBr4 (103 mg, 0.31
mmol, 4 equiv) at room temperature. The mixture was refluxed for 3.5
h. Then the solvent was evaporated. The crude mixture was dissolved
in MeOH (2.5 mL) under argon at room temperature. Then Et3N
(0.087 mL, 0.63 mmol, 8 equiv) and (Boc)2O (0.027 mL, 0.12 mmol,
1.5 equiv) were added sequentially to the reaction mixture. After 30
min, the solvent was evaporated, and the residue was diluted with
water and extracted with EtOAc. The organic phase was dried over
anhydrous Na2SO4 and concentrated in vacuo. The residue obtained
was purified by column chromatography (EtOAc/petroleum ether =
1:2) to afford ( )-41 (29 mg, 96% yield) as a colorless foam: IR
(neat) 3379, 2921, 1666 cm−1; 1H NMR (600 MHZ, CDCl3) δ 3.98 (s,
1H), 3.47−3.35 (m, 2H), 3.30−3.10 (m, 2H), 2.35−2.28 (m, 1H),
2.28−2.17 (m, 1H), 2.04−1.72 (m, 7H), 1.72−1.57 (m, 3H), 1.57−
1.51 (m, 1H), 1.51−1.37 (m, 1H), 1.46 (s, 9H), 1.20−1.10 (m, 1H),
1.06−0.94 (m, 1H), 0.92 (d, J = 6.6 Hz, 3H); 13C NMR (150 MHZ,
CDCl3) δ 156.8, 107.3, 82.0, 79.6, 78.0, 49.6, 48.4, 47.7, 36.2, 34.4,
32.2, 28.5, 24.7, 23.4, 23.2, 21.8, 21.2, 20.7; ESI MS m/z = 382 [M +
H]+; HRMS ESI calcd for C21H36NO5 [M + H]+ 382.2588, found
382.2593, error 1.3 ppm.
ASSOCIATED CONTENT
* Supporting Information
■
S
Spectra of all new synthetic compounds including (+)-alope-
curidine·TFA (31), (+)-sieboldine A (2), and (−)-lycojapodine
A (3). This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: (Y.-Q.T.) tuyq@lzu.edu.cn, (S.-H.W.) wangshh@lzu.
edu.cn.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge financial support from the NSFC
(Nos. 21202073, 21072085, 20921120404, 21102061, and
20972059), MOST (“973” Program, No. 2010CB833203), Key
National S&T Program “Major New Drug Development”of
Ministry of Health of China (2012ZX09201101-003), and
MOE (“111” Program) and fundamental research funds for the
central universities (lzujbky-2012-86). We thank Professor Qin-
Shi Zhao of Kunming Institute of Botany for kindly providing
us the sample of lycojapodine A (3) and measuring the NMR
of our synthetic 3. We also thank Professor Yuan-Jiang Pan of
Zhejiang University for HRMS analysis of the bromo
compounds.
Lactone ( )-42. To a stirred solution of substrate ( )-41 (10 mg,
0.026 mmol) in CH2Cl2 were added PCC (17 mg, 0.079 mmol, 3
equiv) and silica (17 mg) at room temperature. The mixture was
stirred at room temperature for 3 h. Then the reaction mixture was
filtered though a short basic Al2O3 column (EtOAc) and the filtrate
was concentrated in vacuo. The resulting material was purified by
column chromatography (EtOAc/petroleum ether = 1:4) to afford
( )-42 (4.6 mg, 46% yield) as a colorless foam and ( )-30 (2.3 mg,
1
23% yield) as a colorless foam: IR (neat) 2925, 1723, 1689 cm−1; H
NMR (600 MHZ, CDCl3) δ 4.88 (s, 1H), 3.65−2.80 (m, 5H), 2.52−
2.18 (m, 3H), 2.18−1.85 (m, 4H), 1.81−1.69 (m, 1H), 1.69−1.42 (m,
7H), 1.50 (s, 9H), 0.98 (d, J = 6.0 Hz, 3H); 13C NMR (150 MHZ,
CDCl3) δ 211.9, 171.4, 157.0, 155.9, 80.0, 79.7, 79.1, 54.1, 53.7, 49.3,
48.4, 47.0, 45.4, 35.6, 34.9, 32.2, 28.5, 26.9, 23.0, 22.1, 21.5, 21.3, 20.5,
19.9; ESI MS m/z = 380 [M + H]+, 397 [M + NH4]+; HRMS ESI
calcd for C21H37N2O5 [M + NH4]+ 397.2697, found 397.2691, error
1.5 ppm.
Lycojapodine 3. (a) Reaction using Collins’ reagent: Alopecur-
idine·TFA 31 (2.7 mg for one pot, 6.87 μmol, 8.1 mg for three pots)
was dissolved in CH2Cl2 (1 mL) under argon. The reaction mixture
was cooled to 0 °C. Then freshly prepared Collins’ reagent
CrO3·2C5H5N (0.18 mL, 0.38 M, 10 equiv) was added. The mixture
was stirred at 25−30 °C for 1 or 2 h. Then the reaction mixture was
filtered though a short basic Al2O3 column (EtOAc), and the filtrate
was concentrated in vacuo. The resulting material was dissolved in
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