Stereoselective Total Synthesis of (±)-Dasycarpidol and (±)-Dasycarpidone

Article abstract of DOI:10.1055/s-0035-1562528

The protecting-group-free and scalable total syntheses of (±)-dasycarpidol and (±)-dasycarpidone, as well as the formal total synthesis of (±)-uleine, are presented starting from a common tetrahydrocarbazole-fused lactone that is conveniently prepared on multigram scale. The key azocino[4,3-b]indole skeleton is constructed via the DDQ-mediated dehydrogenative cyclization of a tetrahydrocarbazole derivative possessing an amide side chain. The syntheses of the target natural products are accomplished in high yields and in a few steps by employing readily available conventional reagents.

Full text of DOI:10.1055/s-0035-1562528

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–F
paper
A
S. Patir et al.
Paper
Synthesis
Stereoselective Total Synthesis of (±)-Dasycarpidol and
(±)-Dasycarpidone
Me
Süleyman Patira
Mustafa A. Tezerenb
Bekir Salihc
Erkan Ertürk*b
H
N
5 steps
HN
+
N
.
NH2
H
HCl
N
O
H
H
O
X
a Department of Chemistry Education, Faculty of Education,
Hacettepe University, 06800 Beytepe, Ankara, Turkey
b Institute of Chemical Technology, TUBITAK Marmara Research
Center, 41470 Gebze, Kocaeli, Turkey
c Department of Chemistry, Hacettepe University, 06800
Beytepe, Ankara, Turkey
47% overall yield
on multigram scale
Dasycarpidol: X = b-OH
O
4 steps, 68% yield
Dasycarpidone: X = O
5 steps, 66% yield
erkan.erturk@tubitak.gov.tr
Received: 23.05.2016
Accepted after revision: 10.07.2016
Published online: 16.08.2016
from Brazilian Aspidosperma species in the 1960s,13 the
methods that have been hitherto developed for their syn-
theses need to be improved in terms of efficiency and stereo-
selectivity.8–10 For instance, there has not been any report
on the stereoselective synthesis of dasycarpidol.8 It is wor-
thy of mention that, besides uleine-type alkaloids (Figure
1), the 1,5-methanoazocino[4,3-b]indole scaffold is also
found as a key structural element in other Strychnos alka-
loids.14
DOI: 10.1055/s-0035-1562528; Art ID: ss-2016-n0374-op
Abstract The protecting-group-free and scalable total syntheses of
(±)-dasycarpidol and (±)-dasycarpidone, as well as the formal total syn-
thesis of (±)-uleine, are presented starting from a common tetrahydro-
carbazole-fused lactone that is conveniently prepared on multigram
scale. The key azocino[4,3-b]indole skeleton is constructed via the
DDQ-mediated dehydrogenative cyclization of a tetrahydrocarbazole
derivative possessing an amide side chain. The syntheses of the target
natural products are accomplished in high yields and in a few steps by
employing readily available conventional reagents.
Me
H
N
Key words dasycarpidone, dasycarpidol, uleine, azocino[4,3-b]indole,
lactone
N
H
H
X
1: X = α-OH, β-H (dasycarpidol)
2: X = O (dasycarpidone)
Natural products (NPs), the secondary metabolites of
terrestrial and marine plants as well as fungi and bacteria,
have been historically utilized in treating and preventing
human diseases. Although the search for de novo ‘truly new
synthetic’ entities as drug candidates was once widely re-
spected, the key role of NPs and their analogues in drug de-
velopment has been acclaimed again recently.1–3 This is be-
cause natural-product-like drug candidates have provided
screening collections with higher hit rate and lower side-ef-
fect probabilities.4
The indole alkaloids are encountered in a wide range of
plants with a very large number of members and also con-
tinue to attract interest from both medicinal and synthetic
standpoints.5,6 Among them, uleine-type NPs exhibit re-
markable biological activities such as anti-ulcer,7a anti-in-
flammatory,7b antimicrobial as well as acetylcholinesterase
inhibitory activities, and further research toward their po-
tential bioactivities is of current interest (Figure 1).7 Ac-
cordingly, significant efforts have been devoted to synthe-
size uleine-type alkaloids efficiently.8–12 As for dasycarpidol
(1) and dasycarpidone (2), however, after their isolation
3: X = CH2 (uleine)
4: X = α-CH2OH, β-H (13-hydroxyuleine)
Figure 1 Structures of uleine-type indole alkaloids
Recently, we observed that the trans-disubstituted tet-
rahydrocarbazol-1-one derivatives 5 and 6 could be con-
verted into the lactone 7 in high yield after their reduction
with NaBH4 and subsequent exposure of the reaction mix-
ture to aqueous HCl (Scheme 1).15 As depicted in Scheme 1,
a Brønsted acid catalyzed ring-closing mechanism might be
proposed for the formation of the lactone 7 since its forma-
tion is irrespective of whether the starting material bears a
carboxylic acid (5) or a carboxylic ester (6) functionality.16
Due to the cis configuration of the lactone ring, we rea-
soned that the lactone 7 might be a useful precursor for the
divergent and stereocontrolled synthesis of uleine-type al-
kaloids. On the other hand, it is noteworthy that the lactone
7 can be prepared in 47% overall yield and in just five steps
starting from phenylhydrazine hydrochloride and 4-ethyl-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–F

B
S. Patir et al.
Paper
Synthesis
cyclohexanone.15 Herein, we report our recent endeavors
dealing with the stereocontrolled total synthesis of racemic
dasycarpidol [(±)-1], dasycarpidone [(±)-2] as well as the
formal synthesis of racemic uleine [(±)-3] starting from 7.
a
O
N
H
98%
N
H
NHMe
OR
O
O
8: R = H
7
b
93%
a, b
9: R = Ac
CO2R
90%
N
N
c
H
H
O
O
O
Me
5: R = H
6: R = Et
Me
NH
H
H
7
N
O
O
– ROH2
96%
N
H
N
H
H
OAc
OAc
10
III
H2O
R
CO2R
N
N
H
– H2O
Scheme 2 Synthesis of the azocino[4,3-b]indole derivative 10. Re-
agents and conditions: (a) AlMe3 (2.0 M in hexanes), MeNH2, CH2Cl2, r.t.,
overnight; (b) Ac2O, Et3N, CH2Cl2, r.t., overnight; (c) DDQ, THF, r.t., 8 h.
H
OH2
O
O
I
II
Scheme 1 Formation of the tetrahydrocarbazole-fused lactone 7 via
Brønsted acid catalysis. Reagents and conditions: (a) NaBH4, THF–MeOH,
55 °C, 2 h (for 5); –78 °C, 2 h (for 6); (b) HCl (20%), 0 °C.
dasycarpidol [(±)-1], treatment of dasycarpidol with man-
ganese(IV) oxide in acetone furnished dasycarpidone in al-
most quantitative yield (97%). The overall yield of dasycar-
pidone was determined to be 66% starting from 7.
First, trimethylaluminum-mediated aminolysis of the
lactone 7 with methylamine was carried out (Scheme 2).17
This attempt led to the formation of the amide 8 in 98%
yield. The hydroxy group of the amide 8 had to be protected
before subjecting it to the DDQ-mediated ring-closing reac-
tion, because oxidation of the hydroxy group of 8 into the
oxo functionality took place instead of the formation of cor-
responding azocino[4,3-b]indole when it was treated with
DDQ. Therefore, the labile hydroxy group of the amide 8
was readily protected as an acetate ester in 93% yield by
treatment with acetic anhydride in the presence of triethyl-
amine. The obtained secondary amide 9 bearing an ester
functionality was then subjected to the DDQ-mediated de-
hydrogenative cyclization that was recently developed in
our laboratory.11f,14b Thus, the preparation of the key azoci-
no[4,3-b]indole derivative 10 was completed in high yield
and in a facile manner. Remarkably, there was no cis–trans
epimerization during the entire process.
Me
N
Me
N
H
H
O
a
N
78%
N
H
H
H
OAc
H
OH
H
H
10
( )-1
b
97%
Me
N
H
N
H
H
O
(
)-2
Scheme 3 Synthesis of racemic dasycarpidol [(±)-1] and dasycarpi-
done [(±)-2]. Reagents and conditions: (a) Red-Al®, THF, 0 °C to r.t., over-
night; (b) MnO2, acetone, r.t., 1 h.
Next, the azocino[4,3-b]indole derivative 10 was evalu-
ated as a precursor for the synthesis of dasycarpidol [(±)-1]
and dasycarpidone [(±)-2] (Scheme 3). Of the various hy-
dridic reducing agents utilized for the reduction of 10, Red-
Al® [sodium bis(2-methoxyethoxy)aluminum dihydride]
turned out to be the most effective. Indeed, treatment of 10
with Red-Al® in tetrahydrofuran directly delivered dasycar-
pidol in 78% yield. Thus, the first total synthesis of dasycar-
pidol [(±)-1] was accomplished in 68% overall yield from
the lactone 7 with full control of the stereochemistry.18 It
was then expected that dasycarpidol [(±)-1] could be con-
verted into dasycarpidone [(±)-2]. Whereas Swern, Corey–
Kim as well as Albright–Goldman oxidation protocols did
not give rise to the formation of dasycarpidone [(±)-2] from
Our attention then turned to exploiting azocino[4,3-
b]indole derivative 10 as a starting material for the synthe-
sis of uleine [(±)-3]. Attempts to hydrolyze the ester group
of 10 using aqueous NaOH gave the desired product 11 in
very low yield along with a number of unidentified side
products. Fortunately, treatment of 10 with an excess of
DIBAL-H (diisobutylaluminum hydride) in THF at –78 °C re-
sulted in reduction of the ester group into the hydroxy
group while the lactam group remained intact (Scheme 4).
Upon treatment with manganese(IV) oxide in acetone at
room temperature, the resulting indole derivative 11 could
be converted into 12 in 96% yield. Recently, we used com-
pound 12 for a convenient synthesis of uleine [(±)-3].11e As a
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–F

C
S. Patir et al.
Paper
Synthesis
result, besides dasycarpidol and dasycarpidone, the azoci-
no[4,3-b]indole derivative 10 was shown to be a useful in-
termediate for the synthesis of uleine.
(Ac2O), and manganese(IV) oxide (MnO2) were purchased from com-
mercial suppliers and used as received. Thin-layer chromatography
(TLC) was conducted on aluminum sheets that were pre-coated with
silica gel (SIL G/UV254 from MN GmbH & Co.); the spots were visual-
ized under UV light (λ = 254 nm) and/or by staining with phospho-
molybdic acid. Chromatographic separations were performed using
silica gel (MN-silica gel 60, 230–400 mesh). All melting points were
determined in open glass capillary tubes by means of a BÜCHI Melt-
ing Point B-540 apparatus and values are uncorrected. Infrared (FT-
IR) spectra were recorded on a PerkinElmer Spectrum One FT-IR spec-
trometer (νmax in cm–1). Bands are characterized as broad (br), strong
(s), medium (m), and weak (w). 1H and 13C NMR spectra were record-
ed on a 500 MHz NMR spectrometer at 25 °C. Chemical shifts (δ) are
reported in parts per million (ppm) relative to the residual protons in
the NMR solvent (CHCl3: δ 7.26, DMSO-d6: δ 2.50) and carbon reso-
nance of the solvent (CDCl3: δ 77.00, DMSO-d6: δ 39.52). NMR peak
multiplicities are given as follows: s = singlet, d = doublet, t = triplet,
q = quartet, m = multiplet, br = broad. High-resolution electrospray
ionization mass spectra (HR-ESI-MS) were obtained in MeOH on a
Bruker micrOTOF-Q.
Me
N
Me
N
H
H
O
O
a
N
70%
N
H
H
H
OAc
H
OH
H
H
10
11
b
96%
Me
H
N
O
ref. 11e
(
)-3
N
H
H
O
12
Scheme 4 Preparation of the precursor (±)-12 for uleine [(±)-3]. Re-
agents and conditions: (a) DIBAL-H (1.0 M in hexanes), THF, –78 °C, 0.5
h; (b) MnO2, acetone, r.t., 1 h.
N-Methyl-(3β-ethyl-1-hydroxy-1,2,3,4-tetrahydrocarbazol-2-yl)-
acetamide [(±)-8]
Anhydrous CH2Cl2 (30 mL) was placed in a 100 mL oven-dried round-
bottomed Schlenk flask equipped with a magnetic stir bar under N2.
MeNH2 (2 mL, 2.0 M solution in THF) was added into the reaction
flask at –10 °C under N2 using a syringe, which was followed by the
addition of AlMe3 (2 mL, 2.0 M solution in hexanes) using a syringe.
After stirring at –10 °C for 30 min under N2, the mixture was allowed
to warm to r.t. Next, a solution of 4-ethyl-3,3a,4,5-tetrahydro-10H-fu-
ro[2,3-a]carbazol-2(10bH)one [(±)-7] (0.37 g, 1.45 mmol) in anhy-
drous THF (10 mL) was added dropwise using a syringe and the reac-
tion mixture was stirred at r.t. overnight under N2. After quenching
with 10% Na2CO3 (50 mL), the organic layer was separated by using a
separating funnel and dried over Na2SO4. After removing all the vola-
tile components by rotary evaporation in vacuo, the residue was crys-
tallized from Et2O affording the amide (±)-8 (0.41 g, 1.42 mmol, 98%)
as a white solid.
In summary, we have developed divergent and efficient
routes for the stereoselective syntheses of dasycarpidol
[(±)-1], dasycarpidone [(±)-2], and uleine [(±)-3]. Our syn-
thetic strategy exhibits certain useful features: (1) Due to
the fact that the starting material, the lactone 7, is readily
available on multigram scale, our synthetic strategy pro-
vides a scalable approach.19 (2) No protection–deprotection
steps are needed which makes our syntheses protecting-
group-free.20 (3) Target molecules are accessible in a few
steps starting from 7, e.g., four steps for dasycarpidol and
five steps for dasycarpidone are required.21,22 (4) All syn-
thetic steps have high yields while utilizing conventional
reagents. In our opinion, all these features are in good ac-
cordance with the majority of criteria established for an
‘ideal synthesis’.21–23 Bearing in mind the above-mentioned
advantageous points of our synthetic strategy, its further
applications for the syntheses of other indole alkaloids as
well as the development of enantioselective versions are in
progress in our laboratory. Finally, we believe that conge-
ners of the lactone 7 will become versatile starting materi-
als for the synthesis of diverse alkaloids bearing carbazole
units.5
Mp 207 °C; Rf = 0.3 (silica gel; EtOAc).
FTIR (KBr): 3410 (s), 3231 (s), 2959 (s), 1652 (m), 935 (s) cm–1
.
1H NMR (500 MHz, DMSO-d6): δ = 0.94 (t, J = 7.2 Hz, 3 H), 1.23–1.31
(m, 1 H), 1.49–1.54 (m, 1 H), 1.88 (br s, 1 H), 2.15 (dd, J = 14.1, 6.8 Hz,
1 H), 2.25–2.32 (m, 2 H), 2.37 (dd, J = 14.1, 7.3 Hz, 1 H), 2.59 (d, J = 4.4
Hz, 3 H), 2.83 (dd, J = 15.7, 5.0 Hz, 1 H), 4.71 (t, J = 4.9 Hz, 1 H), 5.05 (d,
J = 6.4 Hz, 1 H), 6.93 (t, J = 7.4 Hz, 1 H), 7.02 (t, J = 7.4 Hz, 1 H), 7.29 (d,
J = 8.0 Hz, 1 H), 7.39 (d, J = 7.7 Hz, 1 H), 7.80 (d, J = 4.2 Hz, 1 H), 10.67
(s, 1 H).
13C NMR (125 MHz, DMSO-d6): δ = 11.4 (CH3), 24.1 (CH2), 24.8 (CH2),
25.6 [C(O)HNCH3], 34.4 (CH2), 35.4 (CH), 41.2 (CH), 62.9 (CH), 107.9
(C), 111.1 (CH), 117.97 (CH), 118.02 (CH), 120.7 (CH), 126.8 (C), 135.7
(C), 136.3 (C), 172.9 (HN–C=O).
All reactions were carried out under an inert atmosphere of dry nitro-
gen (N2) using oven-dried glassware. All synthetic compounds are in
their racemic form. Tetrahydrofuran (THF) was freshly distilled under
N2 from sodium/benzophenone immediately prior to use. Acetone
was dried over magnesium sulfate (MgSO4) and distilled under N2.
Methanol (MeOH) was dried over magnesium (Mg) under N2 prior to
use. Triethylamine (Et3N) was distilled under N2 from calcium hydride
(CaH2). 2,3-Dichloro-5,6-dicyanobenzoquinone (DDQ), diisobutylalu-
minum hydride (DIBAL-H), sodium bis(2-methoxyethoxy)aluminum
hydride (Red-Al® 40% in toluene), methylamine (MeNH2, 2.0 M in
THF), trimethylaluminum (AlMe3, 2.0 M in hexanes), acetic anhydride
HRMS (ESI+): m/z [M + Na]+ calcd for C17H22N2O2Na: 309.1574; found:
309.1567.
N-Methyl-(1-acetoxy-3β-ethyl-1,2,3,4-tetrahydrocarbazol-2-yl)-
acetamide [(±)-9]
To an ice-cold solution of the amide (±)-8 (1.63 g, 5.69 mmol) in an-
hydrous CH2Cl2 (30 mL) under N2 were added Et3N (5 mL) and Ac2O
(3.5 mL) successively. After being stirred at r.t. overnight, the reaction
mixture was quenched with 10% Na2CO3 (30 mL) and extracted with
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–F

D
S. Patir et al.
Paper
Synthesis
CH2Cl2 (2 × 30 mL). The combined organic layers were dried over
Na2SO4, filtered, and concentrated in vacuo. Crystallization of the
crude product from MTBE–cyclohexane (1:1) yielded 1.73 g (5.27
mmol, 93%) of the title compound [(±)-9] as a white solid.
HRMS (ESI+): m/z [M + H]+ calcd for C19H23N2O3: 327.1703; found:
327.1699.
rac-Dasycarpidol [(±)-1]
Mp 145–157 °C; Rf = 0.5 (silica gel; EtOAc).
FTIR (KBr): 3357 (s), 3245 (s), 2960 (s), 1709 (s), 1635 (s), 739 (s) cm–1
An oven-dried 25 mL Schlenk tube, capped with a glass stopper and
equipped with a magnetic stir bar, was evacuated under heating with
a blow-drier for 15 min. After the tube had cooled to r.t., dry N2 was
back-filled and the glass stopper was replaced with a rubber septum
under a positive pressure of N2. The lactam (±)-10 (653 mg, 2.0 mmol,
1.00 equiv) was placed in the tube and dissolved by the addition of
absolute THF (8 mL) as the solvent. After the reaction mixture had
been cooled to 0 °C in an ice bath, sodium bis(2-methoxyethoxy)alu-
minum dihydride (Red-Al®) (3.25 mL of 60% in toluene, 10.0 mmol,
5.00 equiv) was added into the solution using a syringe. After stirring
at r.t. overnight, the reaction was quenched by the addition of sat.
NaHCO3 solution (8 mL). After THF had been removed by rotary evap-
oration under reduced pressure, the aq residue was extracted with
CH2Cl2 (3 × 30 mL). The combined organic layers were dried over
Na2SO4. After all the volatile components had been removed by rotary
evaporation in vacuo, the residue was purified by silica gel column
chromatography eluting with EtOAc–MeOH–Et3N (10:1:0.5) to give
racemic dasycarpidol [(±)-1] (421 mg, 1.56 mmol, 78%) as an amor-
phous white solid.
.
1H NMR (500 MHz, DMSO-d6): δ = 0.97 (t, J = 7.4 Hz, 3 H), 1.26–1.35
(m, 1 H), 1.52–1.60 (m, 1 H), 1.90 (m, 1 H), 2.05 (s, 3 H), 2.19–2.28 (m,
2 H), 2.37 (dd, J = 16.1, 7.3 Hz, 1 H), 2.53 (m, 1 H), 2.57 (d, J = 4.5 Hz, 3
H), 2.88 (dd, J = 16.1, 5.0 Hz, 1 H), 5.94 (d, J = 4.1 Hz, 1 H), 6.97 (t,
J = 7.3 Hz, 1 H), 7.07 (t, J = 7.3 Hz, 1 H), 7.34 (d, J = 8.1 Hz, 1 H), 7.44 (d,
J = 7.8 Hz, 1 H), 7.78 (br d, J = 4.4 Hz, 1 H), 10.56 (br s, 1 H).
13C NMR (125 MHz, DMSO-d6): δ = 11.1 (CH3), 20.9 [OC(O)CH3], 24.0
(CH2), 24.6 (CH2), 25.5 [C(O)HNCH3], 34.7 (CH2), 36.5 (CH), 38.3 (CH),
66.1 (CH), 110.4 (C), 111.6 (CH), 118.2 (CH), 118.4 (CH), 121.6 (CH),
126.2 (C), 130.6 (C), 136.6 (C), 170.4 (O–C=O), 171.6 (HN–C=O).
All attempts to detect a reasonable molecular ion peak failed by using
the ESI technique. HRMS analyses gave a strong peak around 269,
which is excellently consistent with the exact mass of the lactam (±)-
13 depicted in Figure 2.
HRMS (ESI+): m/z [M + H]+ calcd for C17H21N2O: 269.1648; found:
269.1644.
Mp 98–114 °C (dec.); Rf = 0.3 (silica gel; EtOAc–MeOH–Et3N,
10:1:0.5).
FTIR (KBr): 3400 (s), 3246 (s), 2931 (s), 1725 (m), 1454 (s), 740 (s)
cm–1
.
N
H
N
1H NMR (500 MHz, DMSO-d6): δ = 0.85 (t, J = 7.4 Hz, 3 H), 1.08–1.16
(m, 2 H), 1.48–1.55 (m, 1 H), 1.81 (dt, J = 12.3, 3.3 Hz, 1 H), 2.05 (m, 3
H), 2.07 (s, 3 H), 2.19 (dd, J = 11.4, 4.7 Hz, 1 H), 3.85 (d, J = 1.8 Hz, 1 H),
4.84 (d, J = 5.7 Hz, 1 H), 5.34 (br s, 1 H), 6.91 (dt, J = 15.0, 1.1 Hz, 1 H),
6.98 (dt, J = 15.0, 1.1 Hz, 1 H), 7.29 (d, J = 8.0 Hz, 1 H), 7.45 (d, J = 7.8
Hz, 1 H), 11.07 (br s, 1 H).
13C NMR (125 MHz, DMSO-d6): δ = 12.0 (CH3), 23.1 (CH2), 25.5 (CH2),
35.5 (CH), 44.2 (CH3), 46.1 (CH2), 46.9 (CH), 55.5 (CH), 63.3 (CH),
103.3 (C), 111.0 (CH), 118.3 (CH), 118.6 (CH), 120.1 (CH), 128.4 (C),
136.2 (C), 138.3 (C).
O
(
)-13
Figure 2 Structure of lactam (±)-13
6-Acetoxy-12β-ethyl-2-methyl-3-oxo-1,2,3,4,5,6-hexahydro-1,5-
methanoazocino[4,3-b]indole [(±)-10]
The acetoxy-amide (±)-9 (5.00 g, 15.22 mmol) was placed in a 250 mL
oven-dried round-bottomed Schlenk flask equipped with a magnetic
stir bar. The reaction flask was evacuated for 15 min and back-filled
with dry N2. The acetoxy-amide (±)-9 was then dissolved by adding
anhydrous THF (100 mL) into the reaction flask. DDQ (4.54 g, 20.00
mmol) was added in one portion and the resulting reaction mixture
was stirred at r.t. for 8 h under N2. After quenching the reaction mix-
ture with 10% Na2CO3 (100 mL), the mixture was extracted with
EtOAc (3 × 100 mL). The combined organic layers were dried over
Na2SO4. After all the volatile components had been removed by rotary
evaporation in vacuo, the residue was purified by silica gel chroma-
tography eluting with EtOAc–Et3N (10:1) to give 4.76 g (14.58 mmol,
96%) of the title compound [(±)-10] as a white solid.
HRMS (ESI+): m/z [M + H]+ calcd for C17H23N2O: 271.1810; found:
271.1821.
rac-Dasycarpidone [(±)-2]
An oven-dried 25 mL Schlenk tube, capped with a glass stopper and
equipped with a magnetic stir bar, was evacuated under heating with
a blow-drier for 15 min. After the tube had cooled to r.t., dry N2 was
back-filled and the glass stopper was replaced with a rubber septum
under a positive pressure of N2. Dasycarpidol [(±)-1] (50 mg, 0.185
mmol) was placed in the tube and dissolved by the addition of anhy-
drous acetone (6 mL) as the solvent. MnO2 (1.0 g, 11.5 mmol, 62.50
equiv) was added in one portion and the resulting reaction mixture
was stirred at r.t. for 1 h under N2. The mixture was filtered through a
pad of Celite® and rinsed with MeOH. The filtrate was concentrated
by rotary evaporation under reduced pressure and then dried under
high vacuum (10–3 mbar for 12 h) to afford racemic dasycarpidone
[(±)-2] as a pale oil in almost quantitative yield (48 mg, 0.179 mmol,
97%).
Mp 142–145 °C; Rf = 0.5 (silica gel; EtOAc–Et3N, 10:1).
FTIR (KBr): 3247 (m) 2930 (m), 1743 (s), 1628 (s), 744 (s) cm–1
1H NMR (500 MHz, DMSO-d6): δ = 0.97 (t, J = 7.4 Hz, 3 H), 1.30–1.38
(m, 2 H), 1.40 (s, 1 H), 2.18 (s, 3 H), 2.45–2.48 (m, 2 H), 2.75 (m, 1 H),
2.93 (s, 3 H), 4.52 (d, J = 1.4 Hz, 1 H), 6.12 (d, J = 6.0 Hz, 1 H), 7.04 (dt,
J = 7.5, 1.0 Hz, 1 H), 7.11 (dt, J = 7.5, 1.0 Hz, 1 H), 7.35 (d, J = 8.2 Hz, 1
H), 7.68 (d, J = 7.9 Hz, 1 H), 11.17 (s, 1 H).
.
13C NMR (125 MHz, DMSO-d6): δ = 11.9 (CH3CH2), 21.0 [OC(O)CH3],
22.3 (CH3CH2), 31.6 [CH2–C(O)N], 33.6 (CH3N), 34.0 (CH), 43.9 (CH),
52.9 (CH), 66.9 (CH), 111.6 (CH), 112.9 (C), 118.5 (CH), 119.3 (CH),
121.8 (CH), 125.8 (C), 129.5 (C), 136.4 (C), 169.3 (O–C=O), 170.2 (N–
C=O).
Rf = 0.5 (silica gel; CH2Cl2–MeOH, 9:1).
FTIR (KBr): 3258 (s), 2931 (s), 1651 (s), 1468 (s), 746 (s) cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–F

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S. Patir et al.
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Synthesis
1H NMR (500 MHz, CDCl3): δ = 0.88 (t, J = 7.5 Hz, 3 H), 1.26–1.34 (m, 3
H), 1.94–1.99 (m, 1 H), 2.08–2.17 (m, 1 H), 2.34 (s, 3 H), 2.36 (tt,
J = 7.5, 2.4 Hz, 1 H), 2.61–2.65 (m, 1 H), 2.73 (m, 1 H), 4.35 (d, J = 2.3
Hz, 1 H), 7.19 (dt, J = 7.5, 1.0 Hz, 1 H), 7.38 (dt, J = 7.5, 1.0 Hz, 1 H),
7.53 (d, J = 8.4 Hz, 1 H), 7.72 (d, J = 8.1 Hz, 1 H), 10.39 (br s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 11.8 (CH3), 24.9 (CH2), 30.1 (CH2), 44.0
(CH3), 46.0 (CH2), 46.4 (CH), 49.6 (CH), 56.3 (CH), 112.9 (CH), 119.7
(C), 120.9 (CH), 121.8 (CH), 126.7 (CH), 127.6 (C), 132.9 (C), 138.4 (C),
193.5 (C=O).
high vacuum (10–3 mbar for 12 h), the title compound (±)-12 was ob-
tained as a white solid in almost quantitative yield (190 mg, 0.673
mmol, 96%).
Mp 285–290 °C (dec.); Rf = 0.5 (silica gel; EtOAc).
FTIR (KBr): 3215 (m), 2927 (m), 1666 (s), 1629 (s), 746 (s) cm–1
.
1H NMR (500 MHz, DMSO-d6): δ = 0.88 (t, J = 7.5 Hz, 3 H), 1.22–1.35
(m, 2 H), 2.24 (d, J = 17.5 Hz, 1 H), 2.58 (m, 1 H), 2.94 (s, 3 H), 2.98 (m,
2 H), 4.88 (d, J = 1.7 Hz, 1 H), 7.17 (dt, J = 7.5, 0.8 Hz, 1 H), 7.35 (dt,
J = 7.7, 1.0 Hz, 1 H), 7.44 (d, J = 8.0 Hz, 1 H), 7.95 (d, J = 8.0 Hz, 1 H),
12.02 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): δ = 11.6 (CH3), 23.8 (CH2), 33.6 (CH3),
36.0 (CH2), 45.3 (CH), 46.6 (CH), 53.2 (CH), 113.1 (CH), 120.8 (CH),
121.2 (CH), 125.0 (C), 126.5 (C), 126.6 (CH), 128.5 (C), 138.2 (C), 167.5
(N–C=O), 191.1 (C=O).
HRMS (ESI+): m/z [M + H]+ calcd for C17H21N2O: 269.1648; found:
269.1639.
12β-Ethyl-6-hydroxy-2-methyl-3-oxo-1,2,3,4,5,6-hexahydro-1,5-
methanoazocino[4,3-b]indole [(±)-11]
An oven-dried 25 mL Schlenk tube, capped with a glass stopper and
equipped with a magnetic stir bar, was evacuated under heating with
a blow-drier for 15 min. After the tube had cooled to r.t., dry N2 was
back-filled and the glass stopper was replaced with a rubber septum
under a positive pressure of N2. The lactam (±)-10 (653 mg, 2.0 mmol,
1.00 equiv) was placed in the tube and dissolved by the addition of
absolute THF (8 mL) as the solvent. After the reaction mixture had
been cooled to –78 °C in a dry-ice/i-PrOH bath, DIBAL-H (8 mL of a 1.0
M solution in hexanes, 8.0 mmol, 4.00 equiv) was added into the reac-
tion mixture using a syringe. After stirring the reaction mixture at
–78 °C for 30 min under N2, the reaction was quenched by the addi-
tion of sat. NaHCO3 solution (8 mL). After the THF had been removed
by rotary evaporation under reduced pressure, the aq residue was ex-
tracted with CH2Cl2 (3 × 30 mL). The combined organic layers were
dried over Na2SO4. The volatile components were removed by rotary
evaporation in vacuo and the residue was purified by silica gel col-
umn chromatography eluting with EtOAc–MeOH (10:0.5) to yield 400
mg (1.41 mmol, 70%) of the title compound [(±)-11] as a white solid.
HRMS (ESI+): m/z [M + Na]+ calcd for C17H18N2O2Na: 305.1260; found:
305.1262.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1562528.
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References
(1) Clardy, J.; Walsh, C. Nature 2004, 432, 829.
(2) Paterson, I.; Anderson, E. A. Science 2005, 310, 451.
(3) For reviews on the impact of natural products upon drug dis-
covery, see: (a) Chin, Y.-W.; Balunas, M. J.; Chai, H. B.; Kinghorn,
A. D. AAPS J. 2006, 8, EE239. (b) Newman, D. J.; Cragg, G. M.
J. Nat. Prod. 2007, 70, 461. (c) Ganesan, A. Curr. Opin. Chem. Biol.
2008, 12, 306. (d) Newman, D. J.; Cragg, G. M. J. Nat. Prod. 2016,
79, 629.
Mp 176–200 °C (dec.); Rf = 0.5 (silica gel; EtOAc–MeOH, 10:0.5).
FTIR (KBr): 3450 (s), 3292 (s), 2926 (s), 1602 (s), 740 (s) cm–1
.
(4) Ortholand, J. Y.; Ganesan, A. Curr. Opin. Chem. Biol. 2004, 8, 271.
(5) (a) Leonard, J. Nat. Prod. Rep. 1999, 16, 319. (b) Kim, J.;
Movassaghi, M. Chem. Soc. Rev. 2009, 38, 3035. (c) Schmidt, A.
W.; Reddy, K. R.; Knölker, H.-J. Chem. Rev. 2012, 112, 3193.
(6) (a) Mizoguchi, H.; Oikawa, H.; Oguri, H. Nat. Chem. 2014, 6, 57.
(b) Wang, Y.; Tu, M.-S.; Yin, L.; Sun, M.; Shi, F. J. Org. Chem. 2015,
80, 3223.
(7) (a) Baggio, C. H.; Otofuji, G. M.; Souza, W. M.; Santos, C. A. M.;
Torres, L. M. B.; Rieck, L.; Marques, M. C. A.; Mesia-Vale, S. Planta
Med. 2005, 71, 733. (b) Nardin, J. M.; Souza, W. M.; Lopes, J. F.;
Florão, Â.; Santos, C. A. M.; Weffort-Santos, A. M. Planta Med.
2008, 74, 1253. (c) Seidl, C.; Correia, B. L.; Stinghen, E. M.;
Santos, C. A. M. Z. Naturforsch. 2010, 65c, 440.
1H NMR (500 MHz, DMSO-d6): δ = 0.96 (t, J = 7.4 Hz, 3 H), 1.23–1.36
(m, 3 H), 2.34–2.40 (m, 2 H), 2.71 (d, J = 18.7 Hz, 1 H), 2.94 (s, 3 H),
4.43 (s, 1 H), 4.97 (t, J = 5.7 Hz, 1 H), 5.49 (d, J = 5.8 Hz, 1 H), 6.99 (t,
J = 7.3 Hz, 1 H), 7.05 (t, J = 7.3 Hz, 1 H), 7.33 (d, J = 7.8 Hz, 1 H), 7.63 (d,
J = 7.8 Hz, 1 H), 11.05 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): δ = 12.1 (CH3), 22.2 (CH2), 31.0 (CH2),
34.1 (CH3), 36.5 (CH), 44.1 (CH), 53.4 (CH), 63.4 (CH), 110.7 (C), 111.4
(CH), 118.2 (CH), 118.9 (CH), 121.0 (CH), 126.2 (C), 134.7 (C), 136.3
(C), 170.1 (N–C=O).
HRMS (ESI+): m/z [M + H]+ calcd for C17H21N2O2: 285.1598; found:
285.1593.
(8) For syntheses of dasycarpidol in the form of an isomeric mix-
ture, see: (a) Bonjoch, J.; Casamitjana, N.; Gràcia, J.; Bosch, J.
J. Chem. Soc., Chem. Commun. 1991, 1687. (b) Gràcia, J.;
Casamitjana, N.; Bonjoch, J.; Bosch, J. J. Org. Chem. 1994, 59,
3939.
(9) For syntheses of dasycarpidone, see: (a) ref. 8a. (b) ref. 8b.
(c) Jackson, A.; Gaskell, A. J.; Wilson, N. D. V.; Joule, J. A. Chem.
Commun. 1968, 364. (d) Dolby, L. J.; Biere, H. J. Am. Chem. Soc.
1968, 90, 2699. (e) Jackson, A.; Wilson, N. D. V.; Gaskell, A. J.;
Joule, J. A. J. Chem Soc. C 1969, 2738. (f) Dolby, L. J.; Biere, H.
J. Org. Chem. 1970, 35, 3843. (g) Kametani, T.; Suzuki, T. J. Org.
Chem. 1971, 36, 1291. (h) Kametani, T.; Suzuki, T. Chem. Pharm.
Bull. 1971, 19, 1424. (i) Tang, F.; Banwell, M. G.; Willis, A. C.
J. Org. Chem. 2016, 81, 2950.
12β-Ethyl-2-methyl-3,6-dioxo-1,2,3,4,5,6-hexahydro-1,5-meth-
anoazocino[4,3-b]indole [(±)-12]11e
The azocino[4,3-b]indole derivative (±)-11 (200 mg, 0.70 mmol) was
placed in a 50 mL oven-dried round-bottomed Schlenk flask, which
was capped with a glass stopper and equipped with a magnetic stir
bar. The reaction flask was evacuated for 15 min, back-filled with dry
N2, and the glass stopper was replaced with a rubber septum under a
positive pressure of dry N2. The indole (±)-11 was dissolved by adding
anhydrous acetone (10 mL). MnO2 (600 mg, 6.90 mmol, ca. 10.00
equiv) was added in one portion and the resulting mixture was
stirred at r.t. for 1 h under N2. The mixture was filtered through a pad
of Celite® and rinsed with MeOH. After the filtrate had been concen-
trated by rotary evaporation under reduced pressure and dried under
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–F

F
S. Patir et al.
Paper
Synthesis
(10) For enantioselective syntheses of dasycarpidone, see: (a) Saito,
M.; Kawamura, M.; Hiroya, K.; Ogasawara, K. Chem. Commun.
1997, 765. (b) Amat, M.; Pérez, M.; Llor, N.; Martinelli, M.;
Molins, E.; Bosch, J. Chem. Commun. 2004, 1602.
(11) For racemic total syntheses of uleine, see: (a) Wilson, N. D. V.;
Jackson, A.; Gaskell, A. J.; Joule, J. A. Chem. Commun. 1968, 584a.
(b) ref. 9e. (c) Büchi, G.; Gould, S. J.; Näf, F. J. Am. Chem. Soc.
1971, 93, 2492. (d) Schmitt, M. H.; Blechert, S. Angew. Chem. Int.
Ed. 1997, 36, 1474. (e) Patir, S.; Uludag, N. Tetrahedron 2009, 65,
115. (f) Patir, S.; Ertürk, E. Org. Biomol. Chem. 2013, 11, 2804.
(g) ref. 9i.
(12) For enantioselective total syntheses of uleine, see: (a) ref. 10a.
(b) ref. 10b. (c) Amat, M.; Pérez, M.; Llor, N.; Escolano, C.; Luque,
F. J.; Molins, E.; Bosch, J. J. Org. Chem. 2004, 69, 8681.
(13) Joule, J. A.; Ohashi, M.; Gilbert, B.; Djerassi, C. Tetrahedron 1965,
21, 1717.
(14) For selected publications on the construction of the hexahydro-
1,5-methano-1H-azocino[4,3-b]indole ring, see: (a) Magnus, P.;
Sear, N. L.; Kim, C. S.; Vicker, N. J. Org. Chem. 1992, 57, 70.
(b) Patir, S.; Ertürk, E. J. Org. Chem. 2011, 76, 335. (c) Martin, C.
L.; Nakamura, S.; Otte, R.; Overman, L. E. Org. Lett. 2011, 13, 138.
(d) Reekie, T. A.; Banwell, M. G.; Willis, A. C. J. Org. Chem. 2012,
77, 10773; and references cited therein.
(16) For acid-catalyzed lactone formation, see: (a) Smith, M. B.;
March, J. March’s Advanced Organic Chemistry, 6th ed.; John
Wiley
& Sons: Hoboken, 2007, 1415–1420. (b) Yu, S. H.;
Ferguson, M. J.; McDonald, R.; Hall, D. G. J. Am. Chem. Soc. 2005,
127, 12808. (c) Ramachandran, P. V.; Pratihar, D.; Biswas, D. Org.
Lett. 2006, 8, 3877.
(17) (a) Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett. 1977,
18, 4171. (b) Lipton, M. F.; Basha, A.; Weinreb, S. M. Org. Synth.
1979, 59, 49. (c) Ghosh, A. K.; Cappiello, J.; Shin, D. Tetrahedron
Lett. 1998, 39, 4651. (d) Nicolaou, K. C.; Xu, J.; Murphy, F.;
Barluenga, S.; Baudoin, O.; Wei, H.-X.; Gray, D. L.; Ohshima, T.
Angew. Chem. Int. Ed. 1999, 38, 2447. (e) Takayama, H.; Fujiwara,
R.; Kasai, Y.; Kitajima, M.; Aimi, N. Org. Lett. 2003, 5, 2967.
(f) Belmar, J.; Funk, R. L. J. Am. Chem. Soc. 2012, 134, 16941.
(18) Bosch and co-workers previously reported the total synthesis of
dasycarpidol [(±)-1] in epimeric form; see: refs. 8a and 8b.
(19) For a critical review on scalable total synthesis, see: Kuttruff, C.
A.; Eastgate, M. D.; Baran, P. S. Nat. Prod. Rep. 2014, 31, 419.
(20) For a very important review on protecting-group-free synthe-
sis, see: Young, I. S.; Baran, P. S. Nat. Chem. 2009, 1, 193.
(21) Newhouse, T.; Baran, P. S.; Hoffman, R. W. Chem. Soc. Rev. 2009,
38, 3010.
(22) Wender, P. A.; Miller, B. L. Nature 2009, 460, 197.
(23) Hendrickson, J. B. J. Am. Chem. Soc. 1975, 97, 5784.
(15) (a) Uludag, N.; Hökelek, T.; Patir, S. J. Heterocycl. Chem. 2006, 43,
585. (b) Uzgoren, A.; Uludag, N.; Okay, G.; Patir, S. J. Heterocycl.
Chem. 2009, 46, 1416.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–F