Enantioselective Total Syntheses of (+)-Fendleridine and (+)-Acetylaspidoalbidine

Article abstract of DOI:10.1021/acs.joc.9b00145

Enantioselective syntheses of hexacyclic aspidoalbidine alkaloids (+)-fendleridine (2) and (+)-acetylaspidoalbidine (3) are described. These syntheses feature an asymmetric decarboxylative allylation and photocyclization of a highly substituted enaminone. Also, the synthesis highlights the formation of a C19-hemiaminal ether via a reduction/condensation/intramolecular cyclization cascade with the C21-alcohol. The present synthesis provides convenient access to the aspidoalbidine hexacyclic alkaloid family in an efficient manner.

Full text of DOI:10.1021/acs.joc.9b00145

Article
pubs.acs.org/joc
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
Enantioselective Total Syntheses of (+)-Fendleridine and
(+)-Acetylaspidoalbidine
Arun K. Ghosh,* Joshua R. Born, and Luke A. Kassekert
Department of Chemistry and Department of Medicinal Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana
47907, United States
S
* Supporting Information
ABSTRACT: Enantioselective syntheses of hexacyclic aspidoalbidine alkaloids (+)-fendleridine (2) and (+)-acetylaspidoalbi-
dine (3) are described. These syntheses feature an asymmetric decarboxylative allylation and photocyclization of a highly
substituted enaminone. Also, the synthesis highlights the formation of a C19-hemiaminal ether via a reduction/condensation/
intramolecular cyclization cascade with the C21-alcohol. The present synthesis provides convenient access to the aspidoalbidine
hexacyclic alkaloid family in an efficient manner.
exhibit a broad range of intriguing pharmacological activity,
including anticancer and antibacterial among many others.5−7
Over the years, many strategies have been developed for their
syntheses in both racemic and enantioselective manner.1,2,8−10
However, general strategies for the synthesis of the subset
aspidoalbidine family of alkaloids received relatively less
attention because of further structural complexity. As shown,
(+)-fendleridine (2), also known as aspidoalbidine, and (+)-1-
acetylaspidoalbidine (3) contain a unique C19-hemiaminal
ether functionality in place of the C19 C−N linkage typical of
aspidosperma alkaloids.11,12 Other representative oxidized
forms of these natural products include (+)-haplocine (4),
(+)-haplocidine (5), (+)-cimicine (6), and (−)-aspidophytine
(7).13,14
INTRODUCTION
■
The indoline alkaloids constitute a large family of mono-
terpene natural products that display immense structural
diversity.1,2 The structural core of these natural products is
composed of polycyclic fused ring systems with contiguous
chiral centers as represented in aspidospermidine (1, Figure 1),
one of the parent members.3,4 Several Aspidosperma alkaloids
Fendleridine (2) was isolated from the Venezuelan tree
Aspidosperma fendleri Woodson in 1964.15 Later, it was also
isolated from the Venezuelan tree species Aspidosperma
rhombeosignatum Markgraph in 1979.16 The corresponding 1-
acetyl derivative, 1-acetylaspidoalbidine, was first isolated from
the Peruvian plant Vallesia dichotoma Ruiz et Pav in 1963.17
Fendleridine can be viewed as a biosynthetic product of the
cyclization of N-protected derivative of (+)-limaspermidine
(8). A few syntheses of 1-acetylaspidoalbidine were carried out
by the oxidation and cyclization of 8.18−20 The first total
synthesis of fendleridine (2) and 1-acetylaspidoalbidine (3)
was reported by Ban and co-workers in 1975 and 1976.19,21
Overman and co-workers in 1991 also reported a formal
synthesis of 1-acetylaspidoalbidine (3) in racemic form, using
the aza-Cope−Mannich reaction as the key transformation.22
Received: January 15, 2019
Figure 1. Structures of selected aspidosperma alkaloids.
© XXXX American Chemical Society
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Subsequently, syntheses of (−)-aspidophytine (7) and
haplophytine, related members of the aspidoalbine family,
were reported.23,24 Boger and co-workers first reported a total
synthesis of (+)-fendleridine (2) and (+)-1-acetylaspidoalbi-
dine (3) and unambiguously established an absolute
configuration of these parent members.25 They utilized a (4
+ 2)/(3 + 2) cycloaddition cascade reaction that constructed
the pentacyclic framework.26 Movassaghi and co-workers
recently reported the syntheses of these alkaloids via oxidation
of the C19-iminium ion to install the C19-hemiaminal
functionality.27 These two syntheses employed the use of
chiral high-performance liquid chromatography (HPLC) and
enzymatic resolution, respectively, to separate out the sought
after intermediates. In this paper, we report an enantioselective
synthesis of (+)-fendleridine (2) and (+)-acetylaspidoalbidine
(3) in 10 and 11 steps, respectively, starting from readily
accessible starting materials.
of an optically active enaminone 12 (R = Bn). Such
photocyclization would provide a mixture of diastereomers at
the C2 and C12 carbons. Our plan for photocyclization is
motivated by previous work by Gramain and co-workers who
have demonstrated photocyclization of related aryl enaminones
to form hexahydrocarbazolones with trans-ring junction
stereochemistry.28 The synthesis of enaminone 12 in an
optically active form can be achieved conveniently by using an
enantioselective Stoltz decarboxylative allylation reaction.29
Enaminone 13 (R = Bn) can be prepared on a multigram scale
from readily available starting materials, N-benzylaniline and
1,3-cyclohexanedione.
As shown in Scheme 2, our synthesis commenced with the
formation of a multigram quantity of enaminone 13 by
Scheme 2. Enantioselective Synthesis of Enaminone 17
RESULTS AND DISCUSSION
Our retrosynthetic analysis of (+)-fendleridine and (+)-1-
acetylaspidoalbidine is shown in Scheme 1. As depicted, an N-
■
Scheme 1. Retrosynthesis of (+)-fendleridine and
(+)-acetylaspidoalbidine
condensation of N-benzylaniline and 1,3-cyclohexanedione in
toluene in the presence of p-TSA·H2O at reflux for 40 h.
Subsequently, enaminone 13 was alkylated with LDA and
allylchloroformate at −78 to 23 °C for 18 h to afford β-keto
ester 14 in 62% yield. Alkylation of the β-keto ester 14 with
tert-butyl(2-iodoethoxy)dimethylsilane was carried out in
dimethylformamide (DMF) in the presence of Cs2CO3 at
100 °C for 32 h to furnish a racemic keto ester 15 in 70%
yield.30 For catalytic asymmetric allylation, we planned to
utilize Pd2(dba)3 in combination with (S)-t-Bu-Phox ligand as
the prior work by Stoltz and co-workers already established
that (S)-t-Bu-Phox provides the best enantioselectivity for
allylation of enaminones.31 Therefore, we investigated
enantioselective allylation in a number of solvents by exposure
of enaminone 15 to Pd2(dba)3 (5 mol %) and (S)-t-Bu-Phox
ligand (12.5 mol %) at 23 °C followed by heating the reaction
mixture to a specified temperature. As shown in Table 1, the
initial attempts to use toluene without deoxygenation resulted
in only a trace amount of the desired allylated product, with a
largely recovered starting material and a dealkylated by-
product.32 Subsequently, we deoxygenated all solvents by
bubbling with argon for at least an hour prior to use. The
reaction in methyl tert-butyl ether was carried out at lower
protected fendleridine would be obtained from the iminium
ion 9. We planned to construct the C19-hemiaminal ether
functionality with a defined stereochemistry through the
formation of a C19 imine from the C19 ketone and a C10
amine followed by intramolecular alkylation at C8 forming the
iminium ion structure 9. Removal of the protecting group on
the C21 alcohol would construct the C19-hemiaminal ether
functionality. The stereochemistry of the C19 stereocenter will
be defined based on the stereochemistry of the C12-
ethylamine and the C5 alkoxyethyl group on structure 10.
The elaboration of the C12 aminoethyl functionality can be
achieved by alkylation of the hexahydrocarbazol-4-one 11. The
alkylation reaction with an appropriate electrophile will
presumably ensure the desired cis-stereochemistry depicted
on the substituted cyclohexanone derivative 10. We plan to
construct the hexahydrocarbozolone 11 by a photocyclization
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benzene with a mercury lamp (450 W) provided an
inseparable mixture (1:1) of trans-diastereomic indoline
derivatives 19 and 20 along with the corresponding oxidized
indole byproduct 21. Gramain and co-workers reported such a
photocyclization on an unsubstituted enaminone to provide a
hexahydrocarbazolone and the corresponding oxidized indole
product.28 We attempted optimization of the photocyclization
to inhibit the formation of indole byproduct 21. It turns out
that careful degassing of the apparatus with benzene as the
solvent and shorter reaction times afforded indolines 19 and
20 as the major products and only a trace amount of indole
byproduct 21. It is important to note that the photochemical
trans-indoline products are quite prone to oxidation to the
indole byproduct 21. Mechanistic insights into this photo-
cyclization reaction were recently reported by Bach and co-
workers.33 For our synthesis, we utilized the crude mixture of
diastereomers for the next alkylation reaction immediately.
The crude photocyclization product mixture was treated with
KHMDS in THF at 23 °C, cooled to 0 °C, and then stirred
under the same temperature for 10 min. Bromoacetonitrile was
added and the reaction was stirred for 40 min at 0 °C. This
provided inseparable cis-diastereomeric products 22 and 23 in
63% yield in two steps.28b
Table 1. Asymmetric Allylation of Enaminone 15
temperature
solvent
(°C)
duration percent yield of 17 % ee of 18
a
toluene
MTBE
THF
70
40
70
70
70
12 h
12 h
30 min
30 min
30 min
trace
trace
97%
98%
88%
N/A
N/A
77%
81%
82%
benzene
b
toluene
a
b
Solvent not degassed. Reaction carried out on a multigram scale.
temperature because of the volatility of the solvent. This
condition resulted in a trace amount of allylated product 17.
The reactions in tetrahydrofuran (THF) and benzene at 70 °C
however resulted in excellent yields of the allylated product 17.
To determine enantiomeric purity, compound 17 was
converted to the benzoate derivative 18. The HPLC analysis
of 18 using a CHIRALCEL OD-H column showed that
enantioselectivity of 17 was 77 and 81% ee, respectively (see
the Supporting Information for further details). Freshly
deoxygenated toluene was tested last and found to furnish
the optically active enaminone 17 in 88% yield and 82% ee. We
utilized this condition to prepare optically active enaminone 17
on a multigram scale.
Hydroboration of the mixture of nitrile derivatives with in
situ formed Cy2BH in freshly distilled THF at 0−23 °C for 2.5
h followed by oxidation with NaBO3·4H2O afforded a 1:1
mixture of alcohols in 98% combined yield.34 The mixture was
separated by silica gel chromatography to provide alcohols 24
and 25 as pure separable compounds. The stereochemical
identity of 24 and 25 was primarily determined using extensive
1H NMR NOESY experiments (see the Supporting Informa-
tion for details).
The synthesis of the hexahydrocarbazolone ring system is
shown in Scheme 3. Our initial attempt to photocyclize 17 in
Scheme 3. Synthesis of Diastereomeric Alcohols 24 and 25
To further ascertain the stereochemical identity of alcohols
24 and 25, our plan was to convert them to the respective
spiroketal derivative, thus creating a more rigid conformation
for two-dimensional (2D) nuclear magnetic resonance (NMR)
analysis. As shown in Scheme 4, alcohols 24 and 25 were
converted to the corresponding tosylate derivatives 26 and 27
in 79 and 85% yields, respectively. The TBS group of tosylate
26 was then removed by exposure to TBAF in THF at 23 °C
for 7.5 h. This resulted in the formation of a spiroketal
derivative 28 in the near-quantitative yield. Similarly, we have
converted 27 to a spiroketal derivative 29 in excellent yields.
The stereochemical assignment of the diastereomeric spiroke-
tals 28 and 29 was carried out by extensive 2D NMR studies.
The results are summarized in Figure 2. The observed specific
NOESY interactions between Ha−Hb and Ha−Hc for
spiroketal 28 are consistent with the depicted chemistry.
Similarly, the observed NOESY interactions between Ha−Hd
and Ha−He support the assigned stereochemistry of spiroketal
29 (see the Supporting Information for more details). On the
basis of these stereochemical assignments of spiroketal
structures 28 and 29, we then speculated that if the assigned
stereochemistry of tosylate 27 is correct, our planned
formation of iminium ion 9 (R = Bn, PG = TBS) may not
be feasible upon reduction of nitrile to amine from 27.
Reduction of nitrile 27 was carried out by exposure to Ra−Ni
2800 in methanol under 60 psi hydrogen in a parr apparatus at
23 °C for 21 h. These conditions resulted in the formation of
the corresponding ethyl amine, which concomitantly cyclized
to imine 30. This further corroborated our assignment of
stereochemical identity.
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Scheme 4. Stereochemical Studies of Ketal Products 28 and
29
Scheme 5. Synthesis of (+)-Fendleridine and (+)-1-
Acetylaspidoalbidine
are in complete agreement with the reported25,27 spectra with
rotational isomers.
CONCLUSIONS
■
In summary, we have developed a short and enantioselective
total syntheses of (+)-fendleridine and (+)-1-acetylaspidoali-
bidine. The syntheses of (+)-fendleridine and (+)-1-
acetylaspidoalbidine were achieved in 10 and 11 steps,
respectively, from readily available starting materials. The
synthesis highlights the construction of the highly substituted
hexahydrocarbazolone ring system by a photochemical
reaction. The synthesis also utilizes the enantioselective
formation of an enaminone containing a quaternary carbon
center by Stoltz decarboxylative allylation processes. The
chirality on the enaminone ensures the formation of the unique
C19-hemiaminal ether functionality inherent to the aspidoal-
bine family of alkaloids. The Ra−Ni-catalyzed reduction of
nitrile and subsequent cascade cyclization to iminium salt lead
to the formation of C19-hemiaminal ether very efficiently.
Further application of photocyclization and synthesis of
pharmacologically important indoline alkaloids are underway.
Figure 2. Representative NOESY correlation of compounds 28 and
29.
Tosyl derivative 26 was readily converted to (+)-fendler-
idine 2 as shown in Scheme 5. Tosylate 26 was subjected to
Ra−Ni 2800 under hydrogen at 60 psi to afford a highly polar
iminium salt 31. Treatment of the crude salt 31 with TBAF at
0−23 °C for 13.5 h removed the silyl group and concomitantly
formed the C19-hemiaminal ether. Purification over basic
alumina provided benzyl derivative 32 in 62% yield over two
steps. The N-benzyl group was successfully deprotected using
lithium in liquid NH3 at −78 °C for 1.5 h to furnish synthetic
(+)-fendleridine 2 in 70% yield after purification by alumina
using 5% ethyl acetate in hexanes as the eluent. The 1H NMR
and 13C NMR spectra of synthetic (+)-fendleridine 2 {[α]2D0
+53.7 (c 0.2, CHCl3)} are in complete agreement with the
reported25,27 spectra for synthetic and natural (+)-fendleridine.
We have also converted (+)-fendleridine 2 to its acetyl
derivative by acetylation with acetic anhydride and pyridine in
CH2Cl2 at 23 °C for 1 h to provide synthetic (+)-1-acetyl-
aspidoalbidine 3 {[α]2D0 +30.2 (c 0.15, CHCl3)} in quantitative
yield after purification over alumina column. The 1H NMR and
13C NMR spectra of synthetic (+)-1-acetyl-aspidoalbidine 3
EXPERIMENTAL SECTION
■
General Procedural/Analytical Methods. All reactions were
performed in oven-dried round-bottom flasks followed by flame-
drying in the case of moisture-sensitive reactions. The flasks were
fitted with rubber septa and kept under a positive pressure of argon.
Cannula were used in the transfer of moisture-sensitive liquids.
Heated reactions were allowed to run using an oil bath on a hot plate
equipped with a temperature probe. Hydrogenations were carried out
using a Parr shaking apparatus inside a thick-walled nonreactant
borosilicate glass vessel. Photochemical transformations were done
using a Hanovia 450 W Hg lamp. TLC analysis was conducted using
glass-backed thin-layer silica gel chromatography plates (60 Å, 250
μm thickness, F-254 indicator) or with glass-backed thin-layer
alumina N chromatography plates (250 μm thickness, UV 254).
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Flash chromatography was done using a 230−400 mesh, a 60 Å pore
diameter silica gel, or a with 80−200 mesh alumina. Organic solutions
were concentrated at 30−35 °C on rotary evaporators capable of
achieving a minimum pressure of ∼30 Torr and further concentrated
on a Hi-vacuum pump capable of achieving a minimum pressure of
∼4 Torr. 1H NMR spectra were recorded on 400, 500, and 800 MHz
spectrometers. 13C NMR spectra were recorded at 100, 125, and 200
MHz on the respective NMRs. Chemical shifts are reported in parts
per million and referenced to the deuterated residual solvent peak
and a reflux condenser, racemic 14 (21.8 g, 60.2 mmol, 1 equiv) in
DMF (500 mL) was added. To this solution, tert-butyl(2-
iodoethoxy)dimethylsilane (33.4 mL, 150.4 mmol, 2.5 equiv)
followed by Cs2CO3 (39.2 g, 120.4 mmol, 2.0 equiv) was added.
The resulting reaction was heated in an oil bath to 100 °C for 32 h.
After this period, the reaction was quenched with H2O and brine (100
mL each). The resulting mixture was extracted with CH2Cl2 and
washed with 5% aqueous LiCl solution. The crude mixture was
concentrated and purified via column chromatography over silica gel
using 25−55% EtOAc/hexanes as the eluent to yield allyl carbonate
15 (21.9 g, 70.1% yield) as an orange amorphous solid. An unreacted
starting material was recovered (3.2 g, 82% yield, brsm). TLC: silica
gel (25% EtOAc/hexanes), Rf = 0.2. 1H NMR (400 MHz, CDCl3): δ
7.38−7.27 (m, 5H), 7.25 (d, J = 7.0 Hz, 1H), 7.18 (d, J = 6.7 Hz,
2H), 7.10 (d, J = 6.8 Hz, 2H), 5.89 (ddt, J = 17.2, 10.7, 5.5 Hz, 1H),
5.36 (s, 1H), 5.29 (dq, J = 16.8, 1.4 Hz, 1H), 5.19 (dq, J = 10.5, 1.4
Hz, 1H), 4.81 (s, 2H), 4.61 (dtdd, J = 14.9, 13.4, 5.0, 1.5 Hz, 2H),
3.72 (t, J = 6.6 Hz, 2H), 2.60−2.26 (m, 4H), 1.98 (dq, J = 14.0, 7.4,
6.6 Hz, 2H), 0.85 (s, 9H), 0.02 (d, J = 2.7 Hz, 6H); 13C{1H} NMR
(101 MHz, CDCl3): δ 193.5, 172.2, 163.9, 144.2, 136.3, 132.2, 129.8,
128.8, 127.9, 127.8, 127.6, 127.0, 118.0, 100.3, 65.5, 60.2, 56.7, 54.4,
36.5, 29.6, 26.0, 25.9, 18.3, −5.3; HRMS-ESI (+) m/z: calcd for
C31H42NO4Si [M + H]+, 520.2878; found, 520.2874.
( S ) - 6 - A l l y l - 3 - ( b e n z y l ( p h e n y l ) a m i n o ) - 6 - ( 2 - ( ( t e r t -
butyldimethylsilyl)oxy)ethyl)cyclohex-2-en-1-one (17). To a flame-
dried round-bottom flask under argon equipped with a stir bar and a
reflux condenser, (S)-tBu-Phox (429.6 mg, 1.11 mmol, 12.5 mol %)
and Pd2(dba)3 (406 mg, 0.44 mmol, 5 mol %) were added.
Deoxygenated toluene (61 mL) was added and the resulting mixture
was stirred at 23 °C for 30 min. A solution of allyl carbonate 15 (4.61
g, 8.87 mmol, 1 equiv) in toluene (61 mL) was then slowly
cannulated to the orange solution containing the catalyst at 23 °C.
The resulting reaction mixture was heated to 70 °C for 35 min. After
this period, the orange reaction mixture was cooled and then filtered
over Celite. The filter cake was washed with CH2Cl2. The solvent was
concentrated, and the residue was purified via column chromatog-
raphy over silica gel using 15−20% EtOAc/hexanes as the eluent to
provide the allylated product 17 (3.69 g, 88% yield) as viscous brown
oil. TLC: silica gel (15% EtOAc/hexanes), Rf = 0.16. [α]2D0 −2.9 (c
0.068, CHCl3); 1H NMR (500 MHz, CDCl3): δ 7.37−7.27 (m, 5H),
7.24 (m, 1H), 7.19 (d, J = 7.2 Hz, 2H), 7.12 (d, J = 7.1 Hz, 2H),
5.82−5.70 (m, 1H), 5.29 (s, 1H), 5.04 (s, 1H), 5.02 (d, J = 4.3 Hz,
1H), 4.82 (s, 2H), 3.72 (ddd, J = 10.1, 8.5, 6.2 Hz, 1H), 3.63 (ddd, J
= 10.3, 8.7, 5.7 Hz, 1H), 2.42 (m, 2H), 2.30 (dt, J = 17.5, 5.7 Hz,
1H), 2.21 (dd, J = 13.9, 8.0 Hz, 1H), 1.87−1.78 (m, 3H), 1.75−1.69
(m, 1H), 0.87 (s, 9H), 0.03 (s, 6H); 13C{1H} NMR (126 MHz,
CDCl3): δ 200.5, 163.2, 144.5, 136.7, 135.2, 129.8, 128.8, 128.0,
127.59, 127.55, 127.1, 117.6, 100.9, 59.9, 56.7, 44.5, 40.3, 37.9, 31.0,
26.1, 25.5, 18.4, −5.1, −5.2; HRMS-ESI (+) m/z: calcd for
C30H42NO2Si [M + H]+, 476.2979; found, 476.2969.
1
(CDCl3, 7.26 ppm for H and 77.16 ppm for 13C). NMR data are
reported as δ value (chemical shift), J-value (Hz), and integration,
where s = singlet, bs = broad singlet, d = doublet, t = triplet, q =
quartet, p = quintet, m = multiplet, dd = doublet doublets, and so on.
Optical rotations were recorded on a digital polarimeter. Low-
resolution mass spectra (LRMS) spectra were recorded using a
quadrupole LCMS under positive electrospray ionization (ESI+).
High-resolution mass spectrometry (HRMS) spectra were recorded at
the Purdue University Department of Chemistry Mass Spectrometry
Center. These experiments were performed under ESI+ and positive
atmospheric pressure chemical ionization (APCI+) conditions using
an Orbitrap XL Instrument.
3-(Benzyl(phenyl)amino)cyclohex-2-en-1-one (13).28c,35 To a
500 mL one-neck round-bottom flask equipped with a stir bar, 1,3-
dicyclohexadiene (15 g, 133.8 mmol, 1.0 equiv), N-benzylaniline
(26.97 g, 147.2 mmol, 1.1 equiv), and p-toluenesulfonic acid
monohydrate (4.07 g, 21.4 mmol, 0.16 equiv) were added
sequentially. A Dean−Stark apparatus with a reflux condenser was
then attached and the entire vessel was evacuated and flushed with
argon several times. Toluene (267 mL) was added, and the reaction
was heated at 160 °C for 40 h. After this period, the reaction was
cooled, diluted with EtOAc, washed with 1 M NaOH, brine, dried
over Na2SO4, and concentrated. The crude mixture was purified via
column chromatography over silica gel using 100% EtOAc as the
eluent. Enaminone 13 was obtained as brown oil (34.57 g, 93%)
TLC: silica gel (100% EtOAc), Rf = 0.31. 1H NMR (400 MHz,
CDCl3): δ 7.36−7.15 (m, 8H), 7.11 (d, J = 7.1 Hz, 2H), 5.36 (s, 1H),
4.80 (s, 2H), 2.28 (dd, J = 14.2, 6.4 Hz, 4H), 1.88 (p, J = 6.4 Hz, 2H);
13C{1H} NMR (101 MHz, CDCl3): δ 197.6, 164.9, 144.4, 136.3,
129.6, 128.6, 127.7, 127.5, 127.4, 126.8, 101.6, 56.6, 36.1, 28.6, 22.5;
LRMS-ESI (+) m/z: 278.1 [M + H]+.
Allyl 4-(Benzyl(phenyl)amino)-2-oxocyclohex-3-ene-1-carboxy-
late (( )-14). To a flame-dried 1 L round-bottom flask under
argon, diisopropylamine (34.1 mL, 243 mmol, 2.5 equiv) in freshly
distilled THF (144 mL) was added. To this solution at 0 °C, n-BuLi
(1.6 M in hexanes, 152 mL, 243 mmol, 2.5 equiv) was added and the
reaction was stirred for 50 min. In a separate flame-dried 1 L flask,
enaminone 13 (27 g, 97.2 mmol, 1 equiv) was dissolved in THF (125
mL) and the solution was cannulated to the yellow solution with the
above LDA at −78 °C. The resulting mixture was stirred at −78 °C
for 1 h and then allyl chloroformate (13.4 mL, 126.4 mmol, 1.3 equiv)
was added dropwise. The resulting reaction was allowed to warm
slowly to 23 °C for 12 h. The reaction was quenched with saturated
NH4Cl (250 mL), extracted with EtOAc (3×), washed with brine,
dried over Na2SO4, and concentrated. The crude mixture was purified
via column chromatography over silica gel to provide the product as a
viscous dark red oil (21.8 g, 62% yield) and an unreacted starting
material (4.9 g) was recovered (76% yield, brsm). TLC: silica gel
(S)-2-(1-Allyl-4-(benzyl(phenyl)amino)-2-oxocyclohex-3-en-1-yl)-
ethyl Benzoate (18). To a flame-dried round-bottom flask under
argon equipped with a stir bar, allyl derivative 17 (21 mg, 0.04 mmol,
1.0 equiv) was added in freshly distilled THF (0.5 mL, 0.1 M). To
this solution, TBAF (1.0 M in THF, 46 μL, 0.05 mmol, 1.05 equiv)
was added dropwise at 0 °C and the resulting mixture was stirred at
0−23 °C for 12 h. The reaction was then quenched with H2O and
brine (∼0.5 mL each), extracted with EtOAc (3×), washed with
brine, dried over Na2SO4, and concentrated. The crude mixture was
purified via silica gel column chromatography, using 65% EtOAc/
hexanes as the eluent to provide the corresponding alcohol as an
amorphous solid (16 mg, 100% yield). TLC: silica (65% EtOAc/
hexanes), Rf = 0.50 (UV and PMA). 1H NMR (400 MHz, CDCl3): δ
7.40−7.19 (m, 6H), 7.19 (m, 2H), 7.13 (m, 2H), 5.72 (m, 1H), 5.34
(s, 1H), 5.09 (m, 1H), 5.06 (m, 1H), 4.84 (s, 2H), 3.86 (br s, 1H),
3.81 (ddd, J = 12.1, 8.2, 4.4 Hz, 1H), 3.64 (dt, J = 10.7, 4.9 Hz, 1H),
2.46−2.29 (m, 4H), 1.84−1.67 (m, 4H). 13C{1H} NMR (101 MHz,
CDCl3): δ 202.6, 164.4, 144.2, 136.3, 134.2, 129.9, 128.9, 127.9 (2C),
127.7, 127.1, 118.4, 100.5, 58.9, 56.9, 45.0, 38.9, 37.9, 32.0, 25.4.
LRMS-ESI (+) m/z: 362.1[M + H]+.
1
(50% EtOAc/hexanes), Rf = 0.34. H NMR (400 MHz, CDCl3): δ
7.37−7.20 (m, 6H), 7.17 (d, J = 7.0 Hz, 2H), 7.11 (d, J = 7.0 Hz,
2H), 5.90 (ddt, J = 17.2, 10.5, 5.6 Hz, 1H), 5.39 (s, 1H), 5.31 (dq, J =
17.2, 1.5 Hz, 1H), 5.19 (dq, J = 10.4, 1.2 Hz, 1H), 4.82 (s, 2H), 4.69−
4.58 (m, 2H), 3.32 (dd, J = 8.7, 5.0 Hz, 1H), 2.57−2.46 (m, 1H),
2.36−2.23 (m, 2H), 2.17−2.06 (m, 1H); 13C{1H} NMR (101 MHz,
CDCl3): δ 191.0, 170.7, 164.6, 144.0, 136.0, 132.0, 129.7, 128.7,
127.8, 127.7, 127.5, 126.9, 118.1, 100.5, 65.5, 56.7, 51.5, 26.6, 25.2;
HRMS-ESI (+) m/z: calcd for C23H23NO3 [M + H]+, 362.1751;
found, 362.1755.
Allyl 4-(Benzyl(phenyl)amino)-1-(2-((tert-butyldimethylsilyl)oxy)-
ethyl)-2-oxocyclohex-3-ene-1-carboxylate (( )-15). To a flame-
dried 1 L round-bottom flask under argon equipped with a stir bar
E
DOI: 10.1021/acs.joc.9b00145
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The Journal of Organic Chemistry
Article
To a flame-dried round-bottom flask under argon, equipped with a
stir bar, the above alcohol (15 mg, 41 μmol, 1.0 equiv) was added in
CH2Cl2 (0.5 mL). To this solution at 0 °C, DMAP (1.0 mg, 8 μmol,
0.2 equiv), triethylamine (8.4 mg, 12 μL, 0.08 mmol, 2.0 equiv), and
benzoyl chloride (7 mg, 6 μL, 0.05 mmol, 1.2 equiv) were added. The
resulting reaction mixture was stirred at 0−23 °C for 2.5 h. The
reaction was then quenched with H2O and brine (∼0.5 mL each),
extracted with CH2Cl2 (3×), washed with brine, dried over Na2SO4,
and concentrated. The crude mixture was purified via column
chromatography over silica gel to provide benzoate 18 (18.5 mg, 96%
yield) as an oil. TLC: silica (30% EtOAc/hexanes), Rf = 0.32 (UV and
PMA); 1H NMR (400 MHz, CDCl3): δ 8.01 (d, J = 7.1 Hz, 2H), 7.54
(t, J = 7.4 Hz, 1H), 7.41 (t, J = 7.7 Hz, 2H), 7.35 (t, J = 7.5 Hz, 2H),
7.31−7.22 (m, 4H), 7.18 (d, J = 6.8 Hz, 2H), 7.12 (d, J = 7.6 Hz,
2H), 5.85−5.75 (m, 1H), 5.34 (s, 1H), 5.09 (s, 1H), 5.06 (d, J = 4.4
Hz, 1H), 4.81 (s, 2H), 4.44−4.34 (m, 2H), 2.48−2.28 (m, 4H),
2.23−2.16 (m, 1H), 1.93−1.85 (m, 3H). 13C{1H} NMR (101 MHz,
CDCl3): δ 199.78, 166.71, 163.20, 144.34, 136.49, 134.45, 132.92,
130.51, 129.82, 129.69, 128.86, 128.44, 127.97, 127.70, 127.60,
127.02, 118.25, 100.73, 62.13, 56.71, 44.42, 40.41, 33.79, 30.44, 25.32.
LRMS-ESI (+) m/z: 466.2 [M + H]+.
2-((3S)-3-Allyl-9-benzyl-3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-
4-oxo-1,2,3,4,9,9a-hexahydro-4aH-carbazol-4a-yl)acetonitrile (22
and 23). To a flame-dried round-bottom flask under argon fitted
with a reflux condenser and a stir bar, allylated 17 (1.55 g, 3.26 mmol,
1.0 equiv) was added. Deoxygenated benzene (163 mL) was added
and the resulting mixture was flushed under argon multiple times.
Photocyclization reaction then was carried out with a 450 W Hg lamp
for 1.5 h. After this period, the reaction was concentrated under
reduced pressure in the dark. The resulting crude product was
immediately subjected to the next step.
To the above mixture, freshly distilled THF (21.7 mL) and
KHMDS (0.7 M in toluene, 5.12 mL, 3.58 mmol, 1.1 equiv) were
added sequentially at 23 °C (the solution went from orange gold to
dark brown). The reaction was cooled to 0 °C, and after 10 min,
BrCH2CN (238 μL, 3.42 mmol, 1.05 equiv) was added dropwise. The
resulting mixture was stirred for 40 min at 0 °C. After this period, the
reaction was quenched with saturated NH4Cl (15 mL). The reaction
was extracted with EtOAc (3×), and the combined extracts were
washed with brine, dried with Na2SO4, and concentrated. The crude
mixture was purified via column chromatography over silica gel using
5% EtOAc/hexanes as the eluent to provide 22 and 23 as an
inseparable mixture as an oil (1.05 g, 63% over two steps). TLC: silica
gel (15% EtOAc/hexanes), Rf = 0.44. 1H NMR (500 MHz, CDCl3): δ
7.40−7.28 (m, 5H), 7.13 (t, J = 7.0 Hz, 1H), 6.93 (d, J = 7.6 Hz, 1H),
6.66 (t, J = 8.7 Hz, 1H), 6.49 (d, J = 7.9 Hz, 1H), 5.76 (m, 0.5H),
5.54 (m, 0.5H), 5.08 (m, 1H), 5.00 (d, J = 10.1 Hz, 0.5H), 4.87 (d, J
= 17.0 Hz, 0.5H), 4.53 (d, J = 12.4 Hz, 1H), 4.32 (d, J = 12.4 Hz,
1H), 3.95 (m, 1H), 3.68 (t, J = 7.1 Hz, 1H), 3.50−3.45 (m, 0.5H),
3.42−3.38 (m, 0.5H) 3.07 (d, J = 10.4 Hz, 1H), 2.59−2.52 (m, 1.5H),
2.28 (dd, J = 11.1, 6.38, Hz, 0.5H), 2.09−2.05 (m, 0.5H), 2.02−1.96
(m, 1H), 1.91−1.45 (m, 5.5H), 0.89 (s, 5H), 0.83 (s, 4H), 0.06 (d, J
= 4.1 Hz, 3H), −0.04 (d, J = 9.4 Hz, 3H). 13C{1H} NMR (126 MHz,
CDCl3): δ 210.9, 210.5, 150.1, 149.9, 137.7, 137.7, 133.9, 132.6,
130.5, 130.4, 128.9, 127.7, 127.5, 127.03, 126.97, 124.0, 123.8, 118.9,
118.8, 118.5, 118.3, 117.69, 117.67, 107.7, 68.99, 68.97, 59.6, 59.0,
58.2, 57.9, 49.7, 49.6, 49.5, 43.2, 41.0, 40.3, 39.3, 31.7, 27.2, 26.7,
26.6, 26.1, 26.0, 25.4, 22.8, 22.3, 22.2, 18.4, 18.3, 14.2, −5.2, −5.3;
HRMS-ESI (+) m/z: calcd for C32H43N2O2Si [M + H]+, 515.3088;
found, 515.3095.
in THF (5 mL) at 0 °C and the resulting reaction was warmed slowly
to 23 °C for 2.5 h. The reaction was quenched with slow addition of
NaBO3·4H2O (3.3 g, 21.3 mmol, 10 equiv) and H2O (7 mL, 0.3 M),
and the resulting reaction mixture was continuously stirred for 12 h.
The reaction was diluted in brine, extracted with EtOAc (3×), dried
with Na2SO4, and concentrated. The crude mixture was purified via
column chromatography over silica gel using 40% EtOAc/hexanes as
the eluent to provide alcohol diastereomers 24 and 25 (1.12 g, 98%
combined yield), which were separated. TLC: silica gel (40% EtOAc/
hexanes), Rf = 0.52 and 0.38 (lower spot desired diastereomer).
2-((3S,4aS,9aS)-9-Benzyl-3-(2-((tert-butyldimethylsilyl)oxy)-
ethyl)-3-(3-hydroxypropyl)-4-oxo-1,2,3,4,9,9a-hexahydro-4aH-car-
bazol-4a-yl)acetonitrile (25). 1H NMR (500 MHz, CDCl3): δ 7.39−
7.28 (m, 5H), 7.12 (td, J = 7.7, 1.3 Hz, 1H), 6.90 (dd, J = 7.5, 1.2 Hz,
1H), 6.64 (td, J = 7.5, 1.0 Hz, 1H), 6.49 (d, J = 7.8 Hz, 1H), 4.53 (d, J
= 15.5 Hz, 1H), 4.31 (d, J = 15.5 Hz, 1H), 3.95 (dd, J = 7.1, 4.3 Hz,
1H), 3.65 (m, 2H), 3.35 (m, 2H), 3.04 (d, J = 16.4 Hz, 1H), 2.56 (d,
J = 16.4 Hz, 1H), 2.04 (m, 1H), 1.88−1.65 (m, 5H), 1.44−1.35 (m,
1H), 1.34−1.29 (m, 2H), 1.25 (m, 1H), 0.88 (s, 9H), 0.05 (d, J = 3.9
Hz, 6H); 13C{1H} NMR (126 MHz, CDCl3): δ 210.6, 150.0, 137.6,
130.6, 129.0, 127.8, 127.6, 127.1, 123.6, 118.1, 117.8, 107.9, 69.1,
62.9, 59.6, 58.0, 49.6, 49.4, 38.7, 35.0, 28.4, 26.9, 26.7, 26.1, 22.5,
18.4, −5.2; LRMS-ESI (+) m/z: 533.3 [M + H]+.
2-((3S,4aR,9aR)-9-Benzyl-3-(2-((tert-butyldimethylsilyl)oxy)-
ethyl)-3-(3-hydroxypropyl)-4-oxo-1,2,3,4,9,9a-hexahydro-4aH-car-
bazol-4a-yl)acetonitrile (24). [α]2D0 −144 (c 0.08, CHCl3); 1H NMR
(500 MHz, CDCl3): δ 7.39−7.28 (m, 5H), 7.12 (td, J = 7.7, 1.3 Hz,
1H), 6.91 (dd, J = 7.5, 1.2 Hz, 1H), 6.66 (td, J = 7.5, 0.9 Hz, 1H),
6.48 (d, J = 7.9 Hz, 1H), 4.52 (d, J = 15.4 Hz, 1H), 4.30 (d, J = 15.4
Hz, 1H), 3.93 (m, 1H), 3.62 (m, 2H), 3.47 (m, 1H), 3.39 (m, 1H),
3.08 (d, J = 16.3 Hz, 1H), 2.52 (d, J = 16.3 Hz, 1H), 1.87−1.76 (m,
4H), 1.69−1.59 (m, 3H), 1.55 (m, 1H), 1.51−1.40 (m, 2H), 0.81 (s,
9H), −0.06 (d, J = 9.4 Hz, 6H); 13C{1H} NMR (126 MHz, CDCl3):
δ 211.4, 149.8, 137.7, 130.4, 129.0, 127.8, 127.5, 127.3, 123.8, 118.6,
117.9, 107.9, 69.0, 63.3, 59.0, 58.1, 49.6, 49.4, 40.3, 32.5, 27.6, 27.3,
26.6, 26.0, 22.1, 18.3, −5.3; HRMS-ESI (+) m/z: calcd for
C32H44N2O3SiNa [M + Na]+, 555.3013; found, 555.3009.
3-((3S,4aR,9aR)-9-Benzyl-3-(2-((tert-butyldimethylsilyl)oxy)-
ethyl)-4a-(cyanomethyl)-4-oxo-2,3,4,4a,9,9a-hexahydro-1H-carba-
zol-3-yl)propyl 4-Methylbenzenesulfonate (26). To a flame-dried
round-bottom argon flask equipped with a stir bar, TsCl (50.1 mg,
0.26 mmol, 2.0 equiv) and DMAP (1.6 mg, 0.01 mmol, 10 mol %) in
0.3 mL of CH2Cl2were added at 0 °C. To this solution, alcohol 24
(70 mg, 0.13 mmol, 1.0 equiv) in CH2Cl2 (0.3 mL) followed by
triethylamine addition (20.1 μL, 0.14 mmol, 1.1 equiv) was added.
Additional amounts of TsCl and trimethylamine (0.5 and 0.4 equiv,
respectively) were further added. The resulting reaction was warmed
to 23 °C, quenched with saturated NaHCO3 (5 mL), extracted with
CH2Cl2 (3×), washed with brine, dried with Na2SO4, and
concentrated. The crude mixture was purified via column chromatog-
raphy over silica gel using 10−15% EtOAc/hexanes as the eluent to
provide tosylate 26 as an oil (71.4 mg, 79% yield). TLC: silica gel
(20% EtOAc/hexanes), Rf = 0.31. [α]2D0 −101.20 (c 0.171, CHCl3);
1H NMR (500 MHz, CDCl3): δ 7.78 (d, J = 8.3 Hz, 2H), 7.39−7.28
(m, 7H), 7.12 (td, J = 7.7, 1.3 Hz, 1H), 6.87 (dd, J = 7.5, 1.2 Hz, 1H),
6.65 (td, J = 7.5, 1.0 Hz, 1H), 6.47 (d, J = 7.9 Hz, 1H), 4.51 (d, J =
15.4 Hz, 1H), 4.28 (d, J = 15.4 Hz, 1H), 4.00 (m, 2H), 3.89 (dd, J =
7.4, 4.5 Hz, 1H), 3.46−3.40 (m, 1H), 3.38−3.31 (m, 2H), 3.03 (d, J =
16.3 Hz, 1H), 2.48 (d, J = 16.3 Hz, 1H), 2.44 (s, 3H), 1.84−1.77 (m,
2H), 1.77−1.65 (m, 3H), 1.58−1.47 (m, 4H), 1.40 (ddd, J = 14.0,
8.3, 5.7 Hz, 1H), 0.80 (s, 9H), −0.07 (d, J = 9.0 Hz, 6H); 13C{1H}
NMR (126 MHz, CDCl3): δ 210.9, 149.6, 144.9, 137.6, 133.1, 130.5,
130.0, 129.0, 128.1, 127.8, 127.5, 127.2, 123.7, 118.6, 117.8, 107.9,
71.0, 68.9, 58.8, 58.1, 49.5, 49.3, 40.0, 32.3, 27.3, 26.4, 26.0, 24.0,
22.0, 21.8, 18.3, −5.3; HRMS-ESI (+) m/z: calcd for C39H51N2O5SSi
[M + H]+, 687.3283; found, 687.3276.
2-((3S)-9-Benzyl-3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-(3-hy-
droxypropyl)-4-oxo-1,2,3,4,9,9a-hexahydro-4aH-carbazol-4a-yl)-
acetonitrile (24 and 25). To a flame-dried round-bottom flask under
argon equipped with a stir bar, cyclohexene (1.4 mL, 13.9 mmol, 6.5
equiv) was added to freshly distilled THF (6 mL) at 0 °C. To this
solution at 0 °C, a borane dimethyl sulfide complex (neat, 607 μL, 6.4
mmol, 3.0 equiv) was added dropwise. A thick white slurry started to
form after 1 min. Additional amounts of THF (1 mL) was added and
the reaction was continuously stirred at 0 °C for 1 h. After this period,
a solution of 22 and 23 (1.10 g, 2.1 mmol, 1.0 equiv) was cannulated
3-((3S,4aS,9aS)-9-Benzyl-3-(2-((tert-butyldimethylsilyl)oxy)-
ethyl)-4a-(cyanomethyl)-4-oxo-2,3,4,4a,9,9a-hexahydro-1H-carba-
zol-3-yl)propyl 4-Methylbenzenesulfonate (27). The experimental is
same as in the transformation of 24 to 26. The crude mixture was
isolated via column chromatography over silica gel using 15−20%
F
DOI: 10.1021/acs.joc.9b00145
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Article
EtOAc/hexanes as the eluent to provide tosylate 27 as yellow oil
(463.2 mg, 85% yield). TLC: silica (20% EtOAc/hexanes), Rf = 0.29.
1H NMR (400 MHz, CDCl3): δ 7.68 (d, J = 8.3 Hz, 2H), 7.40−7.28
of tosylate 27 (403 mg, 0.59 mmol, 1.0 equiv) in MeOH (22 mL, 27
mM) was then cannulated in the flask. The mixture was shaken in a
Parr apparatus under hydrogen at 60 psi pressure for 46 h. After this
period, the resulting white solution mixture was filtered through
Celite and the filter cake was washed with MeOH and CH2Cl2 (15
mL each). Solvents were evaporated to yield imine 30 (359.5 mg,
90.8% yield). TLC: silica (30% EtOAc/hexanes), Rf = 0.46. 1H NMR
(500 MHz, CDCl3): δ 7.68 (d, J = 8.3 Hz, 2H), 7.36−7.27 (m, 7H),
7.03 (td, J = 7.7, 1.3 Hz, 1H), 6.63 (dd, J = 7.3, 1.2 Hz, 1H), 6.48 (t, J
= 5.9 Hz, 1H), 6.40 (d, J = 7.9 Hz, 1H), 4.48 (d, J = 15.5 Hz, 1H),
4.24 (d, J = 15.5 Hz, 1H), 3.91 (dd, J = 15.4, 8.5 Hz, 1H), 3.80 (m,
1H), 3.74 (m, 1H), 3.68 (m, 1H), 3.62 (td, J = 7.2, 3.0 Hz, 2H), 3.47
(t, J = 5.7 Hz, 1H), 2.45 (s, 3H), 2.19 (dt, J = 12.2, 6.6 Hz, 1H), 1.91
(m, 1H), 1.80 (dt, J = 13.9, 6.7 Hz, 1H), 1.69 (m, 2H), 1.57 (m, 2H),
1.46 (m, 2H), 1.16 (td, J = 13.0, 5.3 Hz, 1H), 1.04 (td, J = 13.1, 3.2
Hz, 1H), 0.85 (s, 9H), 0.01 (d, J = 1.9 Hz, 7H); 13C{1H} NMR (126
MHz, CDCl3): δ 180.8, 149.2, 144.5, 138.4, 133.2, 132.4, 129.8,
128.7, 128.7, 127.9, 127.4, 127.3, 122.0, 117.4, 107.2, 71.6, 71.0, 61.0,
59.4, 56.9, 49.2, 43.5, 41.8, 38.6, 32.6, 31.4, 26.0, 23.7, 22.5, 21.7,
18.3, −5.3; LRMS-ESI (+) m/z: 673.3 [M + H]+.
(m, 7H), 7.11 (td, J = 7.7, 1.3 Hz, 1H), 6.80 (dd, J = 7.6, 1.3 Hz, 1H),
6.58 (td, J = 7.4, 0.9 Hz, 1H), 6.49 (d, J = 7.9 Hz, 1H), 4.52 (d, J =
15.5 Hz, 1H), 4.30 (d, J = 15.5 Hz, 1H), 3.97−3.87 (m, 1H), 3.76 (m,
1H), 3.67 (m, 1H), 3.59 (td, J = 6.8, 1.5 Hz, 2H), 3.00 (d, J = 16.3
Hz, 1H), 2.53 (d, J = 16.4 Hz, 1H), 2.45 (s, 3H), 1.95 (m, 1H), 1.84−
1.65 (m, 4H), 1.61 (m, 1H), 1.54−1.44 (m, 1H), 1.44−1.32 (m, 1H),
1.27 (td, J = 12.7, 4.5 Hz, 2H), 1.09 (td, J = 13.1, 3.4 Hz, 1H), 0.86 (s,
9H), 0.02 (d, J = 2.6 Hz, 6H); 13C{1H} NMR (101 MHz, CDCl3): δ
210.4, 150.1, 144.8, 137.6, 133.1, 130.7, 129.9, 129.0, 128.0, 127.8,
127.6, 126.8, 123.4, 118.3, 117.7, 107.9, 70.4, 69.0, 59.5, 58.0, 49.7,
49.1, 38.4, 34.7, 28.3, 26.7, 26.1, 23.4, 22.5, 21.8, 18.4, −5.2; LRMS-
ESI (+) m/z: 687.3 [M + H]+.
2-((4aS,6aR,11bR,11cS)-7-Benzyl-3,4,5,6,6a,7-hexahydro-
2H,11bH-11c,4a-(epoxyethano)pyrano[3,2-c]carbazol-11b-yl)-
acetonitrile (28). To a flame-dried round-bottom flask under argon
equipped with a stir bar, tosylate 26 (27 mg, 39 μmol, 1.0 equiv) was
dissolved in freshly distilled THF (0.4 mL, 0.1 M). To this solution at
23 °C, TBAF (1.0 M in THF, 47 μL, 47 μmol, 1.2 equiv) was added
dropwise and the reaction mixture was stirred for 12 h. Reaction was
then quenched with H2O and brine (∼0.5 mL each), extracted with
EtOAc (3×), washed with brine, dried with Na2SO4, and
concentrated. The crude mixture was purified via column chromatog-
raphy over silica gel using 15% EtOAc/hexanes as the eluent to
provide tosylate 28 (15.7 mg, 99% yield) as a white amorphous solid.
TLC: silica (20% EtOAc/hexanes), Rf = 0.34. [α]2D0 +45.13 (c 0.203,
1-Benzyl Fendleridine (32).25 To a Parr reactor vessel under argon,
2800 Ra−Ni (51 mg, 300 wt %) was added. A solution of tosylate 26
(17 mg, 25 μmol, 1.0 equiv) in MeOH (1 mL, 27 mM) was then
cannulated in the flask. The mixture was shaken in a Parr apparatus
under hydrogen at 60 psi pressure for 21 h. After this period, the
resulting white solution mixture was filtered through Celite and the
filter cake was washed with MeOH and CH2Cl2 (10 mL each).
Solvents were evaporated and the crude material (31) was used
directly for the next reaction. LRMS-ESI (+) m/z: 501.3 [M]+.
To a flame-dried flask under argon equipped with a stir bar, the
above crude product (31) was dissolved in freshly distilled THF (0.3
mL, 0.1 M), TBAF (1 M in THF, 30 μL, 0.03 mmol, 1.2 equiv) was
added, and the resulting reaction mixture was stirred for 12 h. The
reaction was then quenched with H2O (∼0.5 mL), extracted with
EtOAc (3×), washed with brine, dried with Na2SO4, and
concentrated. The crude mixture was purified via column chromatog-
raphy over silica gel using 70−80% EtOAc/hexanes as the eluent to
provide benzyl derivative 32 (5.9 mg, 62% yield over 2 steps) as an
off-white amorphous solid. TLC: alumina (5% EtOAc/hexanes), Rf =
1
CHCl3); H NMR (400 MHz, chloroform-d): δ 7.34−7.24 (m, 6H),
7.07 (td, J = 7.7, 1.3 Hz, 1H), 6.62 (td, J = 7.4, 1.0 Hz, 1H), 6.34 (d, J
= 8.3 Hz, 1H), 4.45 (d, J = 16.0 Hz, 1H), 4.35 (d, J = 16.0 Hz, 1H),
4.09 (ddd, J = 10.8, 8.4, 6.2 Hz, 1H), 3.91 (td, J = 8.6, 1.1 Hz, 1H),
3.77 (m, 2H), 3.68 (m, 1H), 2.95 (d, J = 16.6 Hz, 1H), 2.80 (d, J =
16.6 Hz, 1H), 2.02 (tt, J = 13.6, 3.5 Hz, 1H), 1.81−1.58 (m, 6H),
1.54−1.36 (m, 3H); 13C{1H} NMR (101 MHz, chloroform-d): δ
152.1, 138.9, 129.9, 129.5, 128.7, 127.4, 127.2, 125.9, 119.3, 117.2,
108.8, 105.9, 68.3, 67.3, 61.3, 54.9, 50.9, 41.4, 38.6, 36.5, 31.3, 28.0,
24.9, 21.3; HRMS-APCI (+) m/z: calcd for C26H29N2O2 [M + H]+,
401.2223; found, 401.2220.
0.50. [α]2D0 +3.0 (c 0.155, CHCl3); H NMR (400 MHz, CDCl3): δ
1
2-((4aS,6aS,11bS,11cS)-7-Benzyl-3,4,5,6,6a,7-hexahydro-
2H,11bH-11c,4a-(epoxyethano)pyrano[3,2-c]carbazol-11b-yl)-
acetonitrile (29). To a flame-dried round-bottom flask under argon
equipped with a stir bar, compound 27 (30 mg, 44 μmol, 1.0 equiv)
was added in freshly distilled THF (0.44 mL, 0.1 M). To this solution
at 23 °C, TBAF (1.0 M in THF, 52 μL, 52 μmol, 1.2 equiv) was
added and the resulting reaction was stirred for 12 h. The reaction
was then quenched with H2O (0.5 mL), extracted with EtOAc (3×),
washed with brine, dried with Na2SO4, and concentrated. The crude
mixture was purified via column chromatography over silica gel using
20% EtOAc/hexanes as the eluent to provide product 29 (17.5 mg,
quantitative yield) as an amorphous white solid. TLC: silica (20%
EtOAc/hexanes), Rf = 0.30. [α]2D0 −68.82 (c 0.364, CHCl3); 1H NMR
(500 MHz, CDCl3): δ 7.53 (dd, J = 7.5, 1.3 Hz, 1H), 7.37−7.30 (m,
4H), 7.26 (m, 1H), 7.05 (td, J = 7.7, 1.4 Hz, 1H), 6.58 (td, J = 7.5, 1.0
Hz, 1H), 6.30 (dd, J = 7.9, 0.9 Hz, 1H), 4.47 (d, J = 15.9 Hz, 1H),
4.39 (d, J = 15.9 Hz, 1H), 4.17 (ddd, J = 10.6, 8.7, 4.9 Hz, 1H), 3.98
(ddd, J = 12.0, 9.8, 1.9 Hz, 1H), 3.93 (ddd, J = 9.6, 8.6, 7.5 Hz, 1H),
3.75 (ddd, J = 12.3, 10.4, 6.9 Hz, 1H), 3.66 (d, J = 3.7 Hz, 1H), 2.98
(d, J = 16.6 Hz, 1H), 2.93 (d, J = 16.5 Hz, 1H), 2.51 (ddd, J = 13.5,
10.6, 7.5 Hz, 1H), 1.99−1.89 (m, 1H), 1.83 (ddd, J = 14.0, 9.6, 4.9
Hz, 1H), 1.73−1.63 (m, 2H), 1.58−1.45 (m, 3H), 1.38−1.34 (m,
1H), 1.23−1.15 (m, 1H); 13C{1H} NMR (126 MHz, CDCl3): δ
152.4, 138.9, 129.4, 128.7, 128.4, 127.5, 127.2, 126.5, 119.2, 116.7,
109.4, 105.2, 67.8, 67.0, 58.6, 53.1, 50.4, 43.3, 38.2, 35.1, 28.4, 27.8,
23.8, 19.0; HRMS-APCI (+) m/z: calcd for C26H29N2O2 [M + H]+,
401.2223; found, 401.2219.
7.36 (dd, J = 7.4, 1.3 Hz, 1H), 7.29−7.15 (m, 5H), 6.94 (td, J = 7.6,
1.3 Hz, 1H), 6.59 (td, J = 7.4, 1.1 Hz, 1H), 6.27 (dd, J = 7.8, 1.0 Hz,
1H), 4.34 (d, J = 15.4 Hz, 1H), 4.06 (d, J = 15.4 Hz, 1H), 3.89−3.75
(m, 2H), 3.22 (dd, J = 7.6, 4.1 Hz, 1H), 2.91−2.82 (m, 2H), 2.74−
2.64 (m, 1H), 2.59−2.51 (m, 1H), 2.14 (ddd, J = 13.2, 8.9, 6.6 Hz,
1H), 1.98−1.84 (m, 2H), 1.77 (dd, J = 21.1, 10.6 Hz, 1H), 1.64−1.50
(m, 3H), 1.50−1.38 (m, 3H), 1.29−1.19 (m, 2H); 13C{1H} NMR
(101 MHz, CDCl3): δ 151.2, 139.0, 135.0, 128.6, 127.7, 127.5, 127.1,
125.9, 117.9, 106.5, 101.9, 71.5, 64.9, 57.9, 49.6, 49.2, 44.1, 38.6, 38.3,
36.9, 34.7, 27.4, 21.64, 21.56; HRMS-ESI (+) m/z: calcd for
C26H31N2O [M + H]+, 387.2431; found, 387.2429.
(+)-Fendleridine (2).25,27a A flame-dried round-bottom flask under
argon was equipped with a stir bar and a cold-finger condenser with
dry ice and acetone. NH3 was allowed to condense into the flask (1
mL), the cold finger condenser was removed, and a septum with an
argon balloon quickly replaced it. To this, small chunks of freshly cut
Li (30 mg, 167 equiv) washed with hexanes were added. The solution
turned dark blue. The benzyl derivative 32 (10 mg, 0.03 mmol, 1
equiv) in a mixture (10:1) of THF and t-BuOH (0.5 mL) was added
and the reaction was stirred for 2 h. Reaction was quenched with solid
NH4Cl (∼100 mg, 72.3 equiv), the cooling bath was removed, and
the reaction was warmed to 23 °C. The reaction was diluted with
EtOAc (1 mL), filtered through cotton plug with CH2Cl2 and EtOAc
(5 mL each), and concentrated. The crude mixture was purified via
column chromatography over alumina using 5% EtOAc/hexanes as
the eluent to provide synthetic (+)fendleridine, (+)-2 as off-white
amorphous solid (5.3 mg, 70%). TLC: alumina (5% EtOAc/hexanes),
Rf = 0.13. [α]2D0 +53.7 (c 0.177, CHCl3); 1H NMR (800 MHz,
CDCl3): δ 7.45 (d, J = 7.5 Hz, 1H), 7.01 (t, J = 7.6 Hz, 1H), 6.73 (t, J
= 7.5 Hz, 1H), 6.60 (d, J = 7.7 Hz, 1H), 4.03−3.95 (m, 2H), 3.52 (br
3-((4S,6aS,11bS)-7-Benzyl-4-(2-((tert-butyldimethylsilyl)oxy)-
ethyl)-2,4,5,6,6a,7-hexahydro-1H-pyrrolo[2,3-d]carbazol-4-yl)-
propyl 4-Methylbenzenesulfonate (30). To a Parr reactor vessel
under argon, 2800 Ra−Ni (1.21 g, 300 wt %) was added. A solution
G
DOI: 10.1021/acs.joc.9b00145
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
s, 1H), 3.40 (dd, J = 9.5, 4.8 Hz, 1H), 3.00 (td, J = 8.7, 4.1 Hz, 1H),
2.92 (dt, J = 15.6, Hz, 1H), 2.79 (t, J = 11.4 Hz, 1H), 2.65 (d, J = 11.1
Hz, 1H), 2.24 (ddd, J = 13.4, 8.7, 5.9 Hz, 1H), 1.92−1.83 (m, 2H),
1.81 (td, J = 12.9, 4.0 Hz, 1H), 1.78−1.71 (m, 2H), 1.71−1.59 (m,
2H), 1.51 (dt, J = 12.1, 3.2 Hz, 1H), 1.45 (dt, J = 13.8, 4.8 Hz, 1H),
1.35 (d, J = 13.0 Hz, 1H), 1.24 (dd, J = 11.9, 5.5 Hz, 1H); 13C{1H}
NMR (201 MHz, CDCl3): δ 150.3, 134.4, 127.3, 126.1, 119.4, 110.0,
102.1, 66.6, 64.9, 58.9, 49.3, 44.1, 39.2, 37.0, 35.8, 34.1, 27.3, 27.0,
21.5; HRMS-ESI (+) m/z: calcd for C19H25N2O [M + H]+, 297.1961;
found, 297.1964.
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(+)-Acetylaspidoalbidine (3).25,27a To a flame-dried round-bottom
flask under argon equipped with a stir bar, synthetic fendleridine (7.9
mg, 0.027 mmol, 1.0 equiv) was dissolved in CH2Cl2 (1 mL).
Pyridine (11 μL, 0.13 mmol, 5.0 equiv) and acetic anhydride (7.5 μL,
0.08 mmol, 3.0 equiv) were added sequentially. The reaction was
quenched with saturated NaHCO3 (∼0.1 mL), extracted 3× with
CH2Cl2, dried with Na2SO4, and concentrated. The crude mixture
was purified via column chromatography using 15−20% EtOAc/
hexanes as the eluent to provide products (+)-3 (rotamers) as white
amorphous solid (9 mg, quantitative yield). TLC: alumina (5%
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EtOAc/hexanes), Rf = 0.08. [α]2D0 +30.2 (c 0.145, CHCl3); H NMR
1
(800 MHz, CDCl3): δ 8.14 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 3.5 Hz,
0.3H) 7.60 (d, J = 7.7 Hz, 1H, minor rotamer), 7.19 (t, J = 7.7 Hz,
1H), 7.05 (t, J = 7.5 Hz, 1H), 4.42 (dd, J = 9.12, 4.16 Hz, minor
rotamer), 4.16 (t, J = 8.6 Hz, 1H), 4.09 (dt, J = 10.5, 7.5 Hz, 1H),
3.86 (dd, J = 11.0, 5.2 Hz, 1H), 3.02 (td, J = 8.8, 4.1 Hz, 1H), 2.93
(dd, J = 15.7, 9.0 Hz, 1H), 2.80 (td, J = 11.5, 2.8 Hz, 1H), 2.65 (d, J =
10.7 Hz, 1H), 2.39 (s, 0.6H, minor rotamer), 2.26 (s, 2.1H), 2.10
(ddd, J = 14.6, 9.1, 6.1 Hz, 1H), 2.07−2.00 (m, 1H), 1.93 (m, 1H),
1.86 (m, 1H), 1.83−1.66 (m, 4H), 1.55 (dt, J = 12.7, 3.6 Hz, 0.8H),
1.50 (t, J = 13.9 Hz, 0.2H, minor rotamer), 1.43 (dt, J = 14.0, 3.9 Hz,
1H), 1.38 (d, J = 12.9 Hz, 1H), 1.27 (m, 1H); 13C{1H} NMR (201
MHz, CDCl3, major rotamer): δ 168.2, 141.2, 137.9, 127.5, 124.9,
124.8, 117.9, 102.2, 69.0, 65.1, 58.4, 49.1, 44.1, 39.8, 37.3, 34.9, 33.2,
26.6, 25.5, 23.5, 21.2; 13C{1H} NMR (201 MHz, CDCl3, minor
rotamer): δ 168.0, 140.6, 140.1, 127.1, 126.1, 124.3, 115.1, 102.5,
67.1, 65.0, 57.2, 48.9, 43.9, 39.6, 37.0, 35.2, 33.5, 26.8, 24.4, 23.8,
21.2; HRMS-ESI (+) m/z: calcd for C21H27N2O2 [M + H]+,
339.2067; found, 339.2064.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.9b00145.
■
S
1H and 13C NMR spectra for all new compounds and
HPLC data for asymmetric allylation reaction (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: akghosh@purdue.edu.
■
ORCID
Arun K. Ghosh: 0000-0003-2472-1841
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support of this work was provided by the National
Institutes of Health (GM122279) and Purdue University.
■
(10) (a) Horinouchi, R.; Kamei, K.; Watanabe, R.; Hieda, N.;
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stituted Cyclic Ketones at High Pressure. Eur. J. Org. Chem. 2015,
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DOI: 10.1021/acs.joc.9b00145
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