Palladium-Catalyzed Ullmann Cross-Coupling/Tandem Reductive Cyclization Route to Key Members of the Uleine Alkaloid Family

Article abstract of DOI:10.1021/acs.joc.6b00240

The trisubstituted cyclohexenone 12, generated through a palladium-catalyzed Ullmann cross-coupling reaction between o-iodonitrobenzene and a 4,5-trans-disubstituted 2-iodo-2-cyclohexen-1-one, engaged in a tandem reductive cyclization process upon exposur

Full text of DOI:10.1021/acs.joc.6b00240

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Article
A Palladium-catalyzed Ullmann Cross-coupling/Tandem Reductive
Cyclization Route to Key Members of the Uleine Alkaloid Family
Fei Tang, Martin Gerhardt Banwell, and Anthony C. Willis
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00240 • Publication Date (Web): 25 Feb 2016
Downloaded from http://pubs.acs.org on February 25, 2016
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A Palladium-catalyzed Ullmann Cross-coupling/Tandem Reductive Cyclization
Route to Key Members of the Uleine Alkaloid Family
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Fei Tang, Martin G. Banwell* and Anthony C. Willis
Research School of Chemistry, Institute of Advanced Studies
The Australian National University, Canberra, ACT 2601, Australia
Et
CN
H
N
R
N
tandem
reductive
cyclization
NO2
3ꢀ5 steps
Et
Et
O
55%
N
N
X
H
H
12
13
uleine (1, R = Me, X = CH2)
dasycarpidone (2, R = Me, X = O)
noruleine (3, R = H, X = CH2)
nordasycarpidone (4, R = H, X = O)
bond formed using
Pd[0]ꢀcatalyzed Ullmann
crossꢀcoupling reaction
ABSTRACT: The trisubstituted cyclohexenone 12, generated through a palladiumꢀ
catalyzed Ullmann crossꢀcoupling reaction between oꢀiodonitrobenzene and a 4,5ꢀtransꢀ
disubstitutedꢀ2ꢀiodoꢀ2ꢀcyclohexenꢀ1ꢀone, engaged in a tandem reductive cyclisation
process upon exposure to hydrogen gas in the presence of Raney cobalt. As a result, the
1,5ꢀmethanoazocino[4,3 b]indole 13 was obtained and this could be readily elaborated to
the racemic modifications of the alkaloids uleine, dasycarpidone, noruleine and
nordasycarpidone (1ꢀ4 respectively).
INTRODUCTION
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Like the more well known Strychnos alkaloids, the uleineꢀtype natural products embody
the tetracyclic 1,5ꢀmethanoazocino[4,3 b]indole framework.1 Uleine (1),2,3
dasycarpidone (2),3 noruleine (3)3 and nordasycarpidone (4)3 (Figure 1), all of which
have been isolated from a range of plants sources including the bark of the South
American shrub Aspidosperma dasycarpon A. DC., are the ‘original’ and representative
members of the family but others have since been identified including, for example, C20ꢀ
epimers4 and more highly oxygenated variants.5
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Me
N
Me
N
H
N
H
N
20
Et
Et
Et
Et
N
N
N
N
O
O
H
H
H
H
1
2
3
4
(uleine)
(dasycarpidone)
(noruleine)
(nordasycarpidone)
Figure 1: Structures of Uleines 1ꢀ4
A range of interesting biological properties has been attributed to uleine and its
congeners. These include analgesic, antiꢀinflammatory, bactericidal, antiꢀmalarial and
acetylcholinesterase (AChE)ꢀinhibiting activities.6 In addition, the capacity of compound
1 to promote the synthesis of nitric oxide has prompted investigations on the use of the
source plants as adjuvants in the treatment of patients with compromised immune
systems.7
Since the completion of the key studies2,4,8 on the elucidation of the structures of the
uleines, there have been numerous reports on the development of often ingenious total
syntheses of compounds 1ꢀ4.9,10 These have delivered both racemic and enantiomerically
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enriched forms of the target compounds. The presence of the 1,5ꢀ
methanoazocino[4,3 b]indole framework within other alkaloids has also prompted the
more general development of approaches to this scaffold.11 As part of our own efforts in
the area, in 2012 we described10f a Raneyꢀcobaltꢀmediated tandem reductive cyclization
route to this framework and the elaboration of it to the ABCDEꢀring system of the
Strychnos alkaloids. This work was an extension of slightly earlier studies on the
application of related processes to the assembly of the Aspidosperma alkaloids
limaspermidine and 1ꢀacetylaspidoalbidine12 that also exploited the capacity of the
palladiumꢀcatalyzed Ullmann crossꢀcoupling reaction13 to generate the relevant substrates
for the reductive cyclization events.
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Herein we report the extension of our earlier studies10f to the quite distinct and
stereocontrolled total syntheses of the racemic forms of uleine, dasycarpidone, noruleine
and nordasycarpidone. We also identify seemingly straightforward means by which this
work could be extended to the enantioselective assembly of these same alkaloids.
RESULTS AND DISCUSSION
The reaction sequence leading to the substrate required for the pivotal tandem reductive
cyclisation event is shown in Scheme 1. Thus, 4ꢀethylcyclohexanone (5) was converted
into the corresponding (and racemic) unsaturated analogue 6 (60%)14 by treating the
former compound with iodoxybenzoic acid (IBX) in DMSO under conditions defined by
Nicoloau and coꢀworkers.15 Nucleophilic cyclopropanation of the latter compound could
be achieved using the CoreyꢀChaykovsky ylide that had been generated in situ by wellꢀ
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established methods.16 As a result the diastereoselective formation of the
3
4
5
6
bicyclo[4.1.0]heptanone 7 (80%) was achieved although the presence of a ca. 10% of an
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13
isomeric material (presumably the corresponding cisꢀcompound) was evident in the C
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NMR spectrum of this material. Treament of compound 7 with sodium iodide in formic
acid resulted in a homoconjugate addition reaction17 and formation of ca. 10:1 mixture of
the desired iodomethylated product 8 (85%) and a chromatographically inseparable
isomer. The substitution of the iodine within compound 8 by a nitrile residue could not be
achieved directly by, for example, treating it with sodium cyanide. Rather, a 3ꢀ(enolexo)ꢀ
exoꢀtet cyclisation reaction18 took place under all conditions employed and thus
regenerating the precursor cyclopropane 7. Accordingly, and in a telescopedꢀtype
reaction sequence, compound 8 was converted into the corresponding dimethyl ketal that
could now be engaged in the desired nucleophilic substitution reaction with sodium
cyanide. The ensuing dimethyl ketal of the required nitrile was immediately treated with
aqueous hydrochloric acid and thereby affording the targeted compound 9 in 88% yield
over the three steps involved. Various attempts to effect the direct conversion of enone 6
into nitrile 9, including through addition of the acetonitrile anion to the former
compound, all failed.
Dehydrogenation of cyclohexanone 9 could be achieved with some levels of regiocontrol
using IBX in DMSO15 and the 4,5ꢀdisubstitutedꢀ2ꢀcyclohexenꢀ1ꢀone 10 was thus
obtained in 56% yield. Even after chromatographic purification, this material contained
IBXꢀderived impurities. There was also some evidence for the coꢀproduction of minor
amounts of the regioisomeric enone. The (albeit modest) regioselectivity observed in this
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conversion is presumably the result of the steric effects exerted by the cyanomethyl group
in substrate 9. In anticipation of perfoming a palladiumꢀcatalyzed Ullmann crossꢀ
coupling reaction,13 cyclohexenone 10 was subjected to a Johnsonꢀtype αꢀiodination
reaction19 and thus affording the iodoꢀderivative 11 (81%) that was readily obtained in
spectroscopically pure form after flash chromatography. The pivotal crossꢀcoupling of
compound 11 with oꢀiodonitrobenzene proceeded smoothly when a DMSO solution of
the two reaction partners was treated with copper powder and Pd2(dba)3 (ca. 8 mole %
wrt 11) and the ensuing mixture heated at 90 °C for 0.66 h. As a result, and after
chromatographic purification, the crystalline product 12 was obtained in 81% yield.
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Et
I
Et
Et
Et
H2CS(O)Me2
DMSO
NaI, HCO2H
IBX, DMSO
70 °C, 3 h
60%
ca. 20 °C, 0.5 h
80%
40 °C, 0.5 h
85%
O
O
O
O
5
6
7
8
(ii) KCN, DMSO
40 °C, 0.5 h
(i) (MeO)3CH
MeOH
(iii) aq. HCl, THF
ca. 20 °C, 0.33 h
88% (over 3 steps)
BnMe3NBr3
ca. 20 °C, 0.5 h
Et
CN
Et
CN
Et
CN
Et
O
CN
I2, pyridine
CH2Cl2
oꢀC6H4INO2, Cu
Pd[0], DMSO
IBX, DMSO
NO2
ca. 20 °C, 12 h
81%
55 °C, 15 h
56%
90 °C, 0.66 h
81%
I
O
O
O
10
11
9
12
Scheme 1: Synthesis of Substrate 12 Required for the Tandem Reductive Cyclization
Reaction
All of the conventional spectroscopic data acquired on compound 12 were in complete
accord with the assigned structure but final confirmation of this followed from a singleꢀ
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crystal Xꢀray analysis, some details of which are provided in the Experimental Section
and the Supporting Information. Most importantly, this analysis confirmed the transꢀ
relationship between the ethyl and cyanomethyl residues within the compound. Such a
relationship was essential for establishing the correct relative stereochemistry of the ethyl
group at Cꢀ20 in target 1 (a vexed issue encountered in a number of earlier synthetic
studies9c).
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With compound 12 to hand, its capacity to engage in the pivotal tandem reductive
cyclisation reaction could be explored. When a THF/methanol solution of compound 12
containing pꢀtoluenesulfonic acid monohydrate (pꢀTsOH•H2O – introduced to suppress
intermolecular reductive alkylation reactions) was treated with 200 wt % of freshly
prepared Raney cobalt20 and exposed to an atmosphere of hydrogen gas then the desired
transform took place and such that after chromatographic purification the anticipated 1,5ꢀ
methanoazocino[4,3 b]indole 13 was obtained in 55% yield (Scheme 2). The modest
yields observed during this conversion are attributed to the rather unstable nature of the
product and, for example, the apparent ready propensity of it to oxidise on standing. All
of the spectral data acquired on compound 13 were in accord with the assigned structure
but final confirmation of this followed from a singleꢀcrystal Xꢀray analysis of a Bocꢀ
derivative (see below).
Et
CN
H
N
Raney cobalt
pꢀTsOH•H2O
H2
NO2
Et
THF/methanol
45 °C, 16 h
55%
O
N
H
12
13
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Scheme 2: The Pivotal Tandem Reductive Cyclization Reaction
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Interestingly, compound 13 has served as an advanced intermediate in a total synthesis of
the Strychnos alkaloid tubotaiwine reported by Bosch and coꢀworkers.11a
The route used in elaborating compound 13 to noruleine (3) and then, through Nꢀ
methylation, to uleine (1) is shown in Scheme 3. So, the 2°ꢀamine 13 was first converted
into the corresponding Bocꢀderivative 14 (80%), the structure of which was confirmed
through a singleꢀcrystal Xꢀray analysis (see Experimental Section and the Supporting
Information for some details). In CDCl3 solutions at room temperature, this material
existed as a ca. 1:1 mixture of rotamers. Upon treating a dichloromethane solution of
carbamate 14 with pyridinium chlorochromate (PCC), a relatively smooth oxidation
reaction took place to deliver ketone 15 (75%) and on reacting this with methyl lithium at
–78 °C, the 3°ꢀalcohol 16 was produced. This last compound was not isolated but simply
treated with a ca. fourꢀfold excess of trifluoroacetic acid at ambient temperature. As a
result, both dehydration and cleavage of the Bocꢀgroup took place (no specific order of
events implied). After work up and chromatographic purification then noruleine (3) was
obtained in 75% yield.
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Boc
N
H
N
Boc
N
Boc2O
5
6
7
8
TEA
PCC
Et
Et
Et
CH2Cl2,
ca. 20 °C, 12 h
80%
CH2Cl2,
ca. 20 °C, 0.66 h
75%
N
H
N
H
N
H
O
14
13
15
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MeLi, THF
–78°C
0.16 h
H
N
Me
N
Boc
TFA
CH2Cl2
ca. 20 °C, 12 h
H2CO (aq.)
NaBH3CN
MeCN
N
Et
Et
Et
ca. 20 °C
0.66 h
85%
75%
(from 15)
N
H
N
H
N
H
OH
3
1
16
Scheme 3: Elaboration of the Tandem Reductive Cyclization Product 13 to Noruleine (3)
and Uleine (1)
1
13
A comparison of the H and C NMR spectral data acquired on this material with those
recorded by Patir and Ertürk9e on their (synthetically derived) material revealed an
excellent match (see Table 1 for comparisons of the 13C NMR data sets).
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Table 1: Comparison of the 13C NMR Data Recorded for Syntheticallyꢀderived
Compounds 3 and 1 with those Reported for Noruleine (3) and Uleine (1)
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4
5
6
7
8
9
13C NMR Data for
Compound 3
(δC)a
13C NMR Data for
Noruleine
(δC)b
13C NMR Data for
Compound 1
(δC)a
13C NMR Data for
Uleine
(δC)b
138.7
138.7
138.6
138.7
137.1
137.1
136.6
136.6
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134.9
126.8
135.0
126.8
135.2
129.4
135.2
129.4
123.0
119.8
118.6
111.5
110.9
106.7
49.3
45.8
40.6
37.4
35.0
24.6
11.8
–
122.9
119.7
118.5
111.2
110.9
106.9
49.3
45.6
40.5
37.3
34.8
24.6
11.7
–
122.8
119.9
119.6
110.8
107.7
106.9
56.6 c
46.3
46.1
44.3
39.5
34.7
122.7
119.9
119.5
110.7
107.7
106.8
55.6 c
46.1
46.3
44.3
39.5
34.7
24.4
11.8
24.4
11.8
aspectrum recorded in CDCl3 at 100 MHz; b data obtained from reference 9e – spectrum recorded in CDCl3
at 125 or 150 MHz; c the difference in these δC values could arise from varitions in the pH of the medium in
which each spectrum was acquired.
The conversion of noruleine (3) into uleine (1) proved a straightforward matter and
simply involved (Scheme 3) subjecting the former compound to a reductive methylation
reaction using a combination of formaldehyde and sodium cyanoborohydride. By such
means parent compound 1 was obtained in 85% yield and all the derived spectral data
were, once again, a good match with those reported by others (see Table 1 for example).
Completion of syntheses of nordasycarpidone (4) and dasycarpidone (2) proved equally
straightforward and involved, as shown in Scheme 4, TFAꢀinduced cleavage of
compound 15 to give, in 84% yield, the former natural product. Reductive methylation of
this product (viz. 4) using formaldehyde and hydrogen gas in the presence of palladium
on carbon then gave dasycarpidone (2) in 70% yield.
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H
Boc
Me
N
TFA
CH2Cl2
ca. 20 °C, 12 h
N
N
H2CO (aq.), MeOH
H2, Pd on C
Et
Et
Et
84%
ca. 20 °C, 2 h
70%
9
N
N
H
N
O
O
O
H
H
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4
15
2
Scheme 4: Completion of Synthesis of Nordasycarpidon (4) and Dasycarpidone (2)
As before, all of the spectroscopic data obtained on compounds 2 and 4 were in accord
with the assigned structures and, with one minor discrepancy (see Table 2), matched
those reported by Bosch and coꢀworkers.9a
Table 2: Comparison of the 13C NMR Data Recorded for Syntheticallyꢀderived
Compounds 4 and 2 with those Reported for Nordasycarpidone (4) and
Dasycarpidone (2)
13C NMR Data for
Compound 4
(δC)a
13C NMR Data for
Nordasycarpidone
(δC)b
13C NMR Data for
Compound 2
(δC)a
13C NMR Data for
Dasycarpidone
(δC)b
193.2 c
138.7
132.8
127.1
193.9 c
193.2
138.0
132.8
127.7
126.8
121.9
121.1
119.7
112.6
56.4
49.7
46.4
46.1
44.1
30.2
25.0
11.8
193.5
138.1
132.9
127.8
126.9
122.0
121.1
119.9
112.7
56.2
49.6
46.3
46.0
44.0
30.1
24.8
11.8
139.0
132.9
127.0
125.1
122.8 c
121.0
121.0
112.9
49.0
48.7
47.2
37.2
29.8
25.2
11.7
–
125.1
123.8 c
121.0
120.8
113.0
49.0
49.0
47.4
37.2
30.2
25.0
11.5
–
aspectrum recorded in CDCl3 at 100 MHz; b data obtained from reference 9a – spectrum recorded in CDCl3
at 125 MHz; c the difference in these δC values could arise from varitions in the pH of the medium in which
each spectrum was acquired.
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CONCLUSION
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The work reported here, when considered in conjunction with our earlier studies,10f, 12,21
serves to emphasize the considerable utility of both the palladiumꢀcatalyzed Ullmann
crossꢀcoupling reaction and certain tandem reductive cyclization processes, especially
when these are applied together within a given synthetic sequence. The capacity to
exploit such processes in the assembly of other biologically relevant heterocyclic
frameworks is the subject of ongoing studies in our laboratories.
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It should also be noted that rather efficient methods for the synthesis of optically active 4ꢀ
substituted 2ꢀcyclohexenones, including the Sꢀenantiomer of 6, have been reported.22
Accordingly, there is every prospect that the work reported here could be applied in a
straightforward manner to the enantioselective synthesis of the uleines and, perhaps even,
the Strychnos alkaloids.
EXPERIMENTAL SECTION
General Protocols.
Unless otherwise specified, proton (1H) and carbon (13C) NMR spectra were
recorded at room temperature in baseꢀfiltered CDCl3 on a spectrometer operating at 400
MHz for proton and 100 MHz for carbon nuclei. The signal due to residual CHCl3
appearing at δH 7.26 and the central resonance of the CDCl3 “triplet” appearing at δC 77.0
were used to reference 1H and 13C NMR spectra, respectively. 1H NMR data are recorded
as follows: chemical shift (δ) [multiplicity, coupling constant(s) J (Hz), relative integral]
where multiplicity is defined as: s = singlet; d = doublet; t = triplet; q = quartet; m =
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multiplet or combinations of the above. Infrared spectra (νmax) were recorded on a FTIR
Spectrometer. Samples were analyzed as thin films on KBr plates. Lowꢀresolution ESI
mass spectra were recorded on a single quadrupole liquid chromatographꢀmass
spectrometer, while highꢀresolution measurements were conducted on a timeꢀofꢀflight
instrument. Lowꢀ and highꢀresolution EI mass spectra were recorded on a magneticꢀ
sector machine. Melting points were measured on an automated melting point system and
are uncorrected. Analytical thin layer chromatography (TLC) was performed on
aluminumꢀbacked 0.2 mm thick silica gel 60 F254 plates. Eluted plates were visualized
using a 254 nm UV lamp and/or by treatment with a suitable dip followed by heating.
These dips included phosphomolybdic acid : ceric sulfate : sulfuric acid (conc.) : water
(37.5 g : 7.5 g : 37.5 g : 720 mL), potassium permanganate : potassium carbonate : 5%
sodium hydroxide aqueous solution : water (3 g : 20 g : 5 mL : 300 mL) ), pꢀanisaldehyde
or vanillin: sulfuric acid (conc.): ethanol (15 g : 2.5 mL : 250 mL). Flash
chromatographic separations were carried out following protocols defined by Still et al.23
with silica gel 60 (40–63 ꢀm) as the stationary phase and using the ARꢀ or HPLCꢀgrade
solvents indicated. Starting materials, reagents, drying agents and other inorganic salts
were generally commercially available and were used as supplied. Tetrahydrofuran
(THF), methanol and dichloromethane were dried using a solvent purification system that
is based upon a technology originally described by Grubbs et al.24 Where necessary,
reactions were performed under an nitrogen atmosphere.
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Specific Chemical Transformations.
4-Ethylcyclohex-2-en-1-one (6). A magnetically stirred solution of 4ꢀ
ethylcyclohexanone (2.00 g, 15.9 mmol) in DMSO (50 mL) was treated with IBX (9.10
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g, 32.5 mmol) and the resulting mixture heated at 70 °C for 3 h then cooled to room
temperature and quenched with NaHCO3 (50 mL of a saturated aqueous solution). The
ensuing mixture was filtered through diatomaceous earth and the solids thus retained
washed with diethyl ether (3 × 20 mL). The aqueous phase was extracted with diethyl
ether (3 × 40 mL) and the combined organic phases were washed with brine (1 × 50 mL)
before being dried (Na2SO4), filtered and concentrated under reduced pressure. The
ensuring black oil was subjected to flash chromatography (silica, 1:50 → 1:20 v/v ethyl
acetate/hexane gradient elution) and concentration of relevant fractions (Rf = 0.4 in 1:7
v/v ethyl acetate/hexane elution) afforded the title compound 614 (1.18 g, 60%) as a clear,
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colorless oil. H NMR (CDCl3, 400 MHz) δ 6.88 (ddd, J = 10.2, 2.6 and 1.4 Hz, 1H),
5.98 (dd, J = 10.2 and 2.2 Hz, 1H), 2.50 (dt, J = 16.7 and 4.7 Hz, 1H), 2.42–2.27
(complex m, 2H), 2.16–2.08 (complex m, 1H), 1.76–1.62 (complex m, 1H), 1.62ꢀ1.39
13
(complex m, 2H), 1.01 (t, J = 7.5 Hz, 3H); C NMR (CDCl3, 100 MHz) δ 200.0, 155.0,
129.0, 37.7, 37.0, 28.2, 27.5, 11.4; IR νmax 2963, 1683, 1461, 1390, 1148, 942, 854, 742
cmꢀ1; MS (ESI, +ve) m/z 125 [(M + H)+, 100%]; HRMS (M + Na)+ calcd for C8H12NaO
147.0786, found 147.0787.
rac-(1S,5R,6S)-5-Ethylbicyclo[4.1.0]heptan-2-one (7). A magnetically stirred
suspension of NaH (82 mg, 3.4 mmol) in dry DMSO (10 mL) was treated with Me3SOI
(441 mg, 2.0 mmol) and after being maintained at room temperature for 0.17 h the
reaction mixture was warmed to 50 °C and stirred for a further 0.34 h. The cooled
mixture was treated with enone 6 (224 mg, 1.8 mmol) then stirred at room temperature
for 0.5 h before being quenched with H2O (15 mL) and extracted with ethyl acetate (3 ×
20 mL). The combined organic phases were washed with brine (1 × 50 mL) then dried
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(Na2SO4), filtered and concentrated under reduced pressure. The ensuing yellow oil was
subjected to flash chromatography (silica, 1:15 → 1:10 v/v ethyl acetate/hexane gradient
elution) and concentration of relevant fractions (Rf = 0.3 in 1:7 v/v ethyl acetate/hexane)
afforded a ca. 10:1 mixture of the title compound 7 and the diastereoisomeric
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cyclopropane (224 mg, 90%) as a clear, colorless oil. H NMR (CDCl3, 400 MHz) δ
2.17–2.05 (complex m, 2H), 1.93–1.83 (complex m, 1H), 1.82–1.65 (complex m, 2H),
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1.66–1.32 (complex m, 4H), 1.27–1.09 (complex m, 2H), 0.97 (t, J = 7.5 Hz, 3H); C
NMR (CDCl3, 100 MHz) δ 209.8, 33.5, 33.1, 27.4, 25.5, 24.2, 23.8, 12.8, 12.0; IR νmax
2960, 1686, 1462, 1345, 1246, 1197, 939, 883, 824 cmꢀ1; MS (ESI, +ve) m/z 161 [(M +
Na)+, 3%], 139 [(M + H)+, 100]; HRMS (M + Na)+ calcd for C9H14NaO 161.0942, found
161.0939.
rac-(3R,4R)-4-Ethyl-3-(iodomethyl)cyclohexan-1-one (8).
A
magnetically
stirred solution of ketone 7 (510 mg, 4.0 mmol) and NaI (2.20 g, 14.7 mmol) in HCOOH
(10 mL) was heated at 40 °C for 0.5 h then cooled to room temperature and quenched
with H2O (15 mL). The resulting mixture was extracted with ethyl acetate (3 × 20 mL)
and the combined organic phases washed with NaHCO3 (50 mL of a saturated aqueous
solution) and brine (1 × 50 mL) before being dried (Na2SO4), filtered and concentrated
under reduced pressure. The ensuing yellow oil was subjected to flash chromatography
(silica, 1:18 v/v ethyl acetate/hexane elution) and concentration of relevant fractions (Rf =
0.5 in 1:7 v/v ethyl acetate/hexane) afforded a ca. 10:1 mixture of the title compound 8
1
and a diastereoisomer (930 mg, 95%) as a clear, colorless oil. H NMR (CDCl3, 400
MHz) δ 3.41 (dd, J = 10.3 and 4.9 Hz, 1H), 3.24 (dd, J = 10.3 and 2.9 Hz, 1H), 2.46–2.25
(complex m, 4H), 2.16–2.04 (complex m, 1H), 1.73–1.40 (complex m, 3H), 1.36–1.14
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(complex m, 2H), 0.95 (t, J = 7.4 Hz, 3H); C NMR (CDCl3, 100 MHz) δ 210.7, 47.1,
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41.6, 40.9, 40.7, 28.8, 24.2, 15.2, 10.4; IR νmax 2960, 2873, 1716, 1461, 1427, 1318,
1218, 1177 cmꢀ1; MS (ESI, +ve) m/z 289 [(M + Na)+, 100%], 267 [(M + H)+, 23]; HRMS
(M + Na)+ calcd for C9H15INaO 289.0065, found 289.0067.
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rac-2-[(1R,2R)-2-Ethyl-5-oxocyclohexyl]acetonitrile (9). Step i. A magnetically
stirred solution of iodide 8 (1.08 g, 4.1 mmol) in anhydrous MeOH (10 mL) was treated
with trimethyl orthoformate (480 ꢀL, 4.5 mmol) and benzyltrimethylammonium
tribromide (30 mg, 0.08 mmol). The resulting mixture was stirred at room temperature
for 0.5 h then quenched with NaHCO3 (10 mL of a saturated aqueous solution) and
extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with
brine (1 × 50 mL) before being dried (Na2SO4), filtered and concentrated under reduced
pressure. The resulting yellow oil, presumed to contain the dimethyl ketal of compound
8, was immediately subjected to the reaction conditions defined in Step ii.
Step ii. A magnetically stirred solution of crude material obtained from Step i in DMSO
(6 mL) was treated with KCN (480 mg, 7.4 mmol). The resulting solution was stirred at
40 °C for 0.5 h then quenched with H2O (15 mL) and extracted with ethyl acetate (3 × 20
mL). The combined organic phases were concentrated under reduced pressure and the
yellow oil thus obtained, and presumed to contain the dimethyl ketal of compound 9, was
immediately subjected to the reaction conditions defined in Step iii.
Step iii. A magnetically stirred solution of the oil obtained from Step ii in THF (10 mL)
was treated with HCl (5 mL of a 1 M aqueous solution) (CAUTION: possibility of HCN
generation) and the resulting mixture stirred at room temperature for 0.33 h before being
quenched with NaHCO3 (20 mL of a saturated aqueous solution) then extracted with
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ethyl acetate (3 × 20 mL). The combined organic phases were washed with brine (1 × 50
mL) then dried (Na2SO4), filtered and concentrated under reduced pressure. The ensuing
yellow oil was subjected to flash chromatography (silica, 1:9 v/v ethyl acetate/hexane
elution) and concentration of relevant fractions (Rf = 0.2 in 1:3 v/v ethyl acetate/hexane)
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afforded the title compound 9 (590 mg, 88%) as a clear, colorless oil. H NMR (CDCl3,
400 MHz) δ 2.50 (dd, J = 17.1 and 6.3 Hz, 1H), 2.45–2.25 (complex m, 5H), 2.13–2.03
(complex m, 1H), 1.93–1.85 (complex m, 1H), 1.66–1.59 (complex m, 2H), 1.49–1.32
(complex m, 1H), 1.31–1.15 (complex m, 1H), 0.90 (t, J = 7.3 Hz, 3H); 13C NMR
(CDCl3, 100 MHz) δ 209.2, 117.5, 45.6, 40.4, 39.9, 38.3, 29.1, 24.5, 21.9, 10.5; IR νmax
2964, 2877, 2245, 1715, 1464, 1426, 1328, 1250, 1193, 954, 853 cmꢀ1; MS (ESI, +ve)
m/z 188 [(M + Na)+, 45%], 188 [(M + H)+, 30], 122 (100); HRMS (M + Na)+ calcd for
C10H15NNaO 188.1051, found 188.1052.
rac-2-[(1R,2S)-2-Ethyl-5-oxocyclohex-3-en-1-yl]acetonitrile
(10).
A
magnetically stirred solution of ketone 9 (280 mg, 1.7 mmol) in DMSO (10 mL) was
treated with pꢀTsOH•H2O (90 mg, 0.5 mmol) and IBX (960 mg, 3.4 mmol) then heated at
55 °C for 15 h. The cooled reaction mixture was quenched with NaHCO3 (15 mL of a
saturated aqueous solution) then filtered through a pad of diatomaceous earth. The solids
thus retained were washed with ethyl acetate (3 × 20 mL) and the separated aqueous
phase associated with the filtrate was extracted with ethyl acetate (3 × 40 mL). The
combined organic phases washed with brine (1 × 50 mL) then dried (Na2SO4), filtered
and concentrated under reduced pressure. The yellow oil thus obtained was subjected to
flash chromatography (silica, 1:9 → 1:4 v/v ethyl acetate/hexane gradient elution) and
concentration of relevant fractions (Rf = 0.3 in 1:3 v/v ethyl acetate/hexane) afforded the
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title compound 10 (150 mg, 56%) as a clear, colorless oil. 1H NMR (CDCl3, 400 MHz) δ
6.81 (dd, J = 10.2 and 2.9 Hz, 1H), 6.00 (dd, J = 10.2 and 2.1 Hz, 1H), 2.58 (dd, J = 16.2
and 4.0 Hz, 1H), 2.46 (t, J = 6.0 Hz, 2H), 2.42–2.21 (complex m, 3H), 1.73–1.63
(complex m, 1H), 1.59–1.43 (complex m, 1H), 0.94 (t, J = 7.5 Hz, 3H); 13C NMR
(CDCl3, 100 MHz) δ 197.1, 152.4, 129.3, 117.5, 41.5, 40.9, 34.9, 24.4, 21.6, 10.4; IR νmax
2966, 2257, 1679, 1389, 1249, 868, 504 cmꢀ1; MS (ESI, +ve) m/z 186 [(M + Na)+, 100%];
HRMS (M + Na)+ calcd for C10H13NNaO 186.0895, found 186.0897.
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rac-2-[(1R,2S)-2-Ethyl-4-iodo-5-oxocyclohex-3-en-1-yl]acetonitrile (11).
A
magnetically stirred solution of enone 10 (140 mg, 0.48 mmol) in CH2Cl2/pyridine (4 mL
of a 1:1 v/v mixture) maintained at room temperature was treated dropwise with a
solution of molecular iodine (330 mg, 1.20 mmol) in CH2Cl2/pyridine (4 mL of a 1:1 v/v
mixture). The ensuing solution was stirred at room temperature for 12 h then treated with
H2O (10 mL). The separated aqueous phase was extracted with CH2Cl2 (3 × 15 mL) and
the combined organic phases were washed, sequentially, with HCl (1 × 20 mL of a 1 M
aqueous solution), Na2S2O3 (1 × 20 mL of a 10% w/w aqueous solution) and brine (1 ×
20 mL) before being dried (Na2SO4), filtered and concentrated under reduced pressure.
The yellow oil thus obtained was subjected to flash chromatography (silica, 1:6 → 1:3
v/v ethyl acetate/hexane gradient elution) and concentration of relevant fractions (Rf = 0.4
in 1:3 v/v ethyl acetate/hexane) afforded the title compound 11 (190 mg, 81%) as a clear,
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colorless oil. H NMR (CDCl3, 400 MHz) δ 7.63 (d, J = 3.2 Hz, 1H), 2.90 (dd, J = 16.3
and 4.1 Hz, 1H), 2.72–2.49 (complex m, 4H), 2.46–2.33 (complex m, 1H), 1.81–1.71
(complex m, 1H), 1.68–1.53 (complex m, 1H), 1.04 (t, J = 7.5 Hz, 3H); 13C NMR
(CDCl3, 100 MHz) δ 190.0, 160.8, 117.0, 103.0, 45.3, 40.5, 35.1, 24.3, 21.4, 10.6; IR νmax
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2964, 2245, 1686, 1589, 1461, 1421, 1329, 1191, 1116, 948, 899, 772 cmꢀ1; MS (ESI,
+ve) m/z 312 [(M + Na)+, 100%], 290 [(M + H)+, 14]; HRMS (M + Na)+ calcd for
C10H12INNaO 311.9861, found 311.9862.
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Compound 12. A magnetically stirred solution of iodide 11 (240 mg, 0.86 mmol)
and oꢀiodonitrobenzene (420 mg, 1.7 mmol) in DMSO (4 mL) was treated with Pd2(dba)3
(60 mg, 0.07 mmol) and Cu powder (260 mg, 4.1 g.atom). The resulting mixture was
heated at 90 °C for 0.66 h before being cooled to room temperature then diluted with
ethyl acetate (10 mL). The mixture thus obtained was filtered through diatomaceous earth
and the solids thus retained washed with ethyl acetate (3 × 10 mL). The combined
filtrates were washed with water (2 x 30 mL) and the combined aqueous phases extracted
with ethyl acetate (3 × 30 mL). The combined organic phases were washed with brine (1
× 30 mL) before being dried (Na2SO4), filtered and concentrated under reduced pressure.
The ensuing yellow oil was subjected to flash chromatography (silica, 1:10 → 1:5 v/v
ethyl acetate/hexane gradient elution) and concentration of relevant fractions (Rf = 0.2 in
1:3 v/v ethyl acetate/hexane) afforded the title compound 12 (190 mg, 81%) as a yellow,
crystalline solid, m.p. = 109ꢀ113°C. 1H NMR (CDCl3, 400 MHz) δ 8.07 (dd, J = 8.2 and
1.2 Hz, 1H), 7.65 (td, J = 7.9 and 1.3 Hz, 1H), 7.53 (td, J = 7.9 and 1.5 Hz, 1H), 7.36–
7.18 (complex m, 1H), 6.89 (d, J = 3.5 Hz, 1H), 2.81 (dd, J = 16.1 and 4.0 Hz, 1H), 2.76–
2.43 (complex m, 5H), 1.95–1.78 (complex m, 1H), 1.76–1.67 (complex m, 1H), 1.11 (t,
J = 7.5 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 193.9, 148.5, 148.0, 139.3, 133.6, 131.6,
131.3, 129.3, 124.5, 117.6, 41.3, 41.2, 34.8, 24.9, 21.6, 10.8; IR νmax 2971, 2245, 1683,
1524, 1353, 1184, 854, 788 cmꢀ1; MS (ESI, +ve) m/z 307 [(M + Na)+, 100%], 285 [(M +
H)+, 22]; HRMS (M + Na)+ calcd for C16H16N2NaO3 307.1059, found 307.1059.
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Compound 13. A magnetically stirred solution of nitrile 12 (200 mg, 0.70 mmol),
pꢀTsOH•H2O (700 mg, 3.7 mmol) and Raneyꢀcobalt (430 mg, 200% w/w) in
THF/methanol (15 mL of a 1:1 v/v mixture) was heated at 45 °C for 16 h while being
maintained under an atmosphere of hydrogen. The resulting mixture was cooled to room
temperature then filtered through diatomaceous earth and the solids thus retained washed
with methanol (3 × 20 mL). The combined filtrates were concentrated under reduced
pressure to afford a yellow oil that was subjected to flash chromatography (silica, 1:20 →
1:5 v/v methanol/dichloromethane gradient elution). Concentration of relevant fractions
(Rf = 0.4 in 1:4 v/v methanol/dichloromethane) afforded the title compound 139a,11a (93
mg, 55%) as a clear, unstable yellow oil. 1H NMR (CDCl3, 400 MHz) δ 8.20 (s, 1H), 7.43
(d, J = 7.6 Hz, 1H), 7.25 (d, J = 7.5 Hz, 1H), 7.03 (m, 2H), 2.91 (dd, J = 17.4 and 6.6 Hz,
1H), 2.67–2.35 (complex m, 3H), 2.20 (broad s, 1H), 2.01–1.75 (complex m, 2H), 1.54
(d, J = 13.4 Hz, 2H), 1.31–1.01 (complex m, 3H), 0.81 (t, J = 7.4 Hz, 3H); 13C NMR
(CDCl3, 100 MHz) δ 136.3, 136.0, 126.8, 121.1, 119.4, 117.4, 110.6, 107.2, 48.8, 43.4,
37.1, 34.0, 29.9, 25.6, 24.0, 11.8; IR νmax 2958, 2925, 2873, 1617, 1456, 1304, 1238,
1010, 906, 727 cmꢀ1; MS (ESI, +ve) m/z 241 [(M + H)+, 100%], 224 (45), 198 (30);
HRMS (M + H)+ calcd for C16H21N2 241.1705, found 241.1702.
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Compound 14. A magnetically stirred solution of amine 13 (87 mg, 0.36 mmol)
in dichloromethane (5 mL) was treated with Boc2O (157 mg, 0.72 mmol) and
triethylamine (300 ꢀL, 2.2 mmol). The ensuing mixture was stirred at room temperature
for 12 h then quenched with H2O (20 mL) and extracted with dichloromethane (3 × 20
mL). The combined organic phases were washed with brine (1 × 30 mL) before being
dried (Na2SO4), filtered and concentrated under reduced pressure. The yellow oil thus
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obtained was subjected to flash chromatography (silica, 1:10 → 1:5 v/v ethyl
acetate/hexane gradient elution) and concentration of relevant fractions (Rf = 0.5 in 1:3
v/v ethyl acetate/hexane) afforded the title compound 14 (98 mg, 80%) as a white,
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crystalline solid and a ca. 1:1 mixture of rotamers, m.p. = 216°C. H NMR (DMSOꢀd6,
400 MHz) δ (mixture of rotamers) 10.91 (s, 0.5H), 10.85 (s, 0.5H), 7.41 (d, J = 7.6 Hz,
1H), 7.27 (dd, J = 10.7 and 7.8 Hz, 1H), 7.02–6.89 (complex m, 2H), 5.36 (s, 0.5H), 5.27
(s, 0.5H), 3.62 (dd, J = 13.2 and 5.5 Hz, 0.5H), 3.52 (dd, J = 13.3 and 5.7 Hz, 0.5H), 2.96
(dd, J = 17.8 and 6.7 Hz, 1H), 2.60 (dd, J = 17.7 and 13.1 Hz, 1H), 2.46–2.35 (complex
m, 1H), 2.25 (broad s, 1H), 1.85–1.59 (complex m, 3H), 1.52 (s, 4.5H), 1.35 (s, 4.5H),
1.25–1.10 (complex m, 2H), 0.89 (t, J = 7.4 Hz, 3H); 13C NMR (DMSOꢀd6, 100 MHz) δ
(mixture of rotamers) 154.6, 154.1, 136.8, 136.7, 126.9, 126.8, 120.7(1), 120.6(5), 118.8,
118.2, 117.6, 111.3, 111.1, 105.9, 105.5, 78.9, 78.6, 48.1, 46.9, 43.6, 43.2, 37.2, 36.0,
33.4, 33.2, 29.3, 28.7, 28.5, 25.0, 23.7, 23.6, 12.2, 12.1; IR νmax 3402, 3301, 2961, 2929,
2874, 1662, 1462, 1416, 1365, 1308, 1169, 1127, 864, 742 cmꢀ1; MS (ESI, +ve) m/z 363
[(M + Na)+, 100%], 341 [(M + H)+, 33]; HRMS (M + Na)+ calcd for C21H28N2NaO2
363.2048, found 363. 2047.
Compound 15. A magnetically stirred solution of compound 14 (45 mg, 0.13
mmol) in dichloromethane (5 mL) was treated with PCC (57 mg, 0.27 mmol) and the
ensuing mixture stirred at room temperature for 0.66 h then quenched with isoꢀpropanol
(3 mL). The resulting mixture was treated with water (15 mL) then extracted with
dichloromethane (3 × 20 mL). The combined organic phases were washed with brine (1 ×
30 mL) before being dried (Na2SO4), filtered and concentrated under reduced pressure.
The ensuing yellow oil was subjected to flash chromatography (silica, 1:10 → 1:5 v/v
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ethyl acetate/hexane gradient elution) and concentration of relevant fractions (Rf = 0.5 in
1:3 v/v ethyl acetate/hexane) afforded the title compound 15 (35 mg, 75%) as a clear,
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yellow oil and a ca. 1:1 mixture of rotamers. H NMR (CDCl3, 400 MHz) δ (mixture of
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rotamers) 9.89 (s, 0.5H), 9.81 (s, 0.5H), 7.95 (d, J = 8.2 Hz, 0.5H), 7.80 (d, J = 8.1 Hz,
0.5H), 7.53 (t, J = 9.3 Hz, 1H), 7.41 (t, J = 7.8 Hz, 1H), 7.21 (m, 1H), 5.85 (s, 0.5H), 5.67
(s, 0.5H), 3.99 (dd, J = 14.0 and 5.5 Hz, 0.5H), 3.79 (dd, J = 14.3 and 5.7 Hz, 0.5H), 2.86
(s, 1H), 2.79–2.60 (complex m, 1H), 2.22 (t, J = 7.3 Hz, 1H), 2.15–1.87 (complex m,
2H), 1.65 (s, 4.5H), 1.45 (s, 4.5H), 1.43 –1.34 (complex m, 2H), 0.96 (t, J = 7.4 Hz, 3H);
13C NMR (CDCl3, 100 MHz) δ (mixture of rotamers) 193.0, 155.0, 154.3, 138.6, 132.4,
127.3, 125.4, 125.3, 123.0, 122.7, 122.3, 121.6, 121.1, 112.9, 112.5, 80.3, 79.9, 48.3,
48.1, 47.8, 47.0, 46.7, 36.9, 35.7, 31.6, 30.2, 28.7, 28.4, 24.9, 24.8, 22.7, 11.8; IR νmax
3268, 2964, 2932, 2876, 1649, 1470, 1407, 1366, 1277, 1254, 1154, 1127, 1019, 867, 747
cmꢀ1; MS (ESI, +ve) m/z 731 [(2M + Na)+, 100%], 377 [(M + Na)+, 50]; HRMS (M +
Na)+ calcd for C21H26N2NaO3 377.1841, found 377.1843.
Noruleine (3). Step i. A magnetically stirred solution of ketone 15 (14 mg, 0.04
mmol) in THF (4 mL) was cooled to –78 °C then treated with methyllithium (40.0 µL of
a 3.0 M solution in diethoxymethane). The resulting mixture was stirred at –78 °C for
0.16 h then quenched with water (15 mL). After warming the resulting mixture to room
temperature, the aqueous phase was extracted with dichloromethane (3 × 20 mL) and the
combined organic phases were washed with brine (1 × 30 mL) before being dried
(Na2SO4), filtered and concentrated under reduced pressure. The ensuing yellow oil,
presumed to contain the anticipated tertꢀalcohol, was subjected to the Step ii of the
reaction sequence as described immediately below.
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Step ii. A magnetically stirred solution of the yellow oil obtained from Step i in
dichloromethane (4 mL) was treated with trifluoroacetic acid (15 µL, 0.19 mmol). The
resulting mixture was stirred at room temperature for 12 h then concentrated under
reduced pressure to afford a yellow oil that was subjected to flash chromatography (silica,
1:25 → 1:7 v/v methanol / dichloromethane gradient elution). Concentration of relevant
fractions (Rf = 0.5 in 1:4 v/v methanol / dichloromethane) afforded the title compound 39e
(7.5 mg, 75%) as a clear, yellow oil. 1H NMR (CDCl3, 400 MHz) δ 8.13 (s, 1H), 7.51 (d,
J = 7.8 Hz, 1H), 7.29 (d, J = 7.8 Hz, 1H), 7.13 (t, J = 7.8 Hz, 1H), 7.04 (t, J = 7.8 Hz,
1H), 5.20 (s, 1H), 4.93 (s, 1H), 4.32 (s, 1H), 2.89–2.36 (complex m, 3H), 2.26–1.88
(complex m, 3H), 1.60 (d, J = 12.6 Hz, 1H), 1.18–0.98 (complex m, 2H), 0.79 (t, J = 7.4
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Hz, 3H); C NMR (CDCl3, 100 MHz) δ see Table 1; IR νmax 3230, 2960, 2930, 1672,
1613, 1454, 1325, 1201, 1179, 1134, 906, 798, 740 cmꢀ1; MS (ESI, +ve) m/z 253 [(M +
H)+, 40%], 236 (100); HRMS (M + H)+ calcd for C17H21N2 253.1705, found 253.1701.
Uleine (1). A magnetically stirred solution of amine 3 (15 mg, 0.06 mmol) in
acetonitrile (4 mL) was treated, sequentially, with formaldehyde (100 ꢀL of a 35% w/w
aqueous solution, 1.2 mmol) and NaCNBH3 (8 mg, 0.13 mmol). The resulting mixture
was stirred at room temperature for 0.66 h then quenched with NaHCO3 (10 mL of a
saturated aqueous solution). The separated aqueous phase was extracted with
dichloromethane (3 × 20 mL) and the combined organic phases were washed with brine
(1 × 30 mL) before being dried (Na2SO4), filtered and concentrated under reduced
pressure. The resulting yellow oil was subjected to flash chromatography (silica, 1:25 →
1:7 v/v methanol/dichloromethane gradient elution) and concentration of relevant
fractions (Rf = 0.6 in 1:4 v/v methanol/dichloromethane) afforded the title compound 19e
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(13 mg, 85%) as a clear, yellow oil. 1H NMR (CDCl3, 400 MHz) δ 8.27 (s, 1H), 7.58 (d, J
= 7.9 Hz, 1H), 7.37 (d, J = 7.9 Hz, 1H), 7.21 (t, J = 7.9 Hz, 1H), 7.12 (t, J = 7.9 Hz, 1H),
5.29 (s, 1H), 5.02 (s, 1H), 4.12 (d, J = 2.0 Hz, 1H), 2.72 (d, J = 2.0 Hz, 1H), 2.58–2.42
(complex m, 1H), 2.32 (s, 3H), 2.25–1.96 (complex m, 3H), 1.72 (d, J = 7.6 Hz, 1H),
1.22–1.04 (complex m, 2H), 0.87 (t, J = 7.4 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ see
Table 1; IR νmax 3231, 2957, 2926, 1668, 1456, 1320, 1050, 880, 738 cmꢀ1; MS (ESI,
+ve) m/z 267 [(M + H)+, 85%], 236 (100); HRMS (M + H)+ calcd for C18H23N2 267.1861,
found 267.1860.
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Nordasycarpidone (4). A magnetically stirred solution of ketone 15 (17 mg, 0.05
mmol) in dichloromethane (4 mL) was treated with trifluoroacetic acid (15 µL, 0.19
mmol) and the ensuing mixture stirred at room temperature for 12 h before being
concentrated under reduced pressure to afford a yellow oil. Subjection of this material to
flash chromatography (silica, 1:25 → 1:7 v/v methanol/dichloromethane gradient elution)
and concentration of relevant fractions (Rf = 0.6 in 1:4 v/v methanol/dichloromethane)
1
afforded the title compound 49a (10 mg, 84%) as a clear, yellow oil. H NMR (CDCl3,
400 MHz) δ 9.89 (s, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.34 (t, J =
8.0 Hz, 1H), 7.13 (t, J = 8.0 Hz, 1H), 6.14 (broad s, 1H), 4.83 (s, 1H), 2.97 (broad s, 1H),
2.75 (s, 2H), 2.49 (s, 1H), 2.17 (m, 1H), 1.86 (d, J = 12.7 Hz, 1H), 1.31–1.23 (complex
13
m, 2H), 0.83 (t, J = 7.4 Hz, 3H); C NMR (CDCl3, 100 MHz) δ see Table 2; IR νmax
3255, 2960, 1654, 1541, 1474, 1328, 1199, 1132, 908, 800, 746 cmꢀ1; MS (ESI, +ve) m/z
255 [(M + H)+, 55%], 238 (100); HRMS (M + H)+ calcd for C16H19N2O 255.1497, found
255.1499.
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Dasycarpidone (2). A magnetically stirred solution of compound 4 (15 mg, 0.06
mmol) in methanol (5 mL) was treated with 10% Pd on carbon (3 mg) and formaldehyde
(200 ꢀL of a 35% w/v aqueous solution, 2.3 mmol). The resulting mixture was stirred at
room temperature for 2 h while being maintained under an atmosphere of hydrogen. The
mixture thus obtained was filtered through diatomaceous earth and the solids thus
retained washed with methanol (3 × 10 mL). The combined filtrates were diluted with
water (30 mL) and dichloromethane (30 mL) and the separated aqueous phase was
extracted with dichloromethane (3 × 30 mL). The combined organic phases were washed
with brine (1 × 30 mL) before being dried (Na2SO4), filtered and concentrated under
reduced pressure. The yellow oil thus obtained was subjected to flash chromatography
(silica, 1:25 → 1:7 v/v methanol/dichloromethane gradient elution) and concentration of
relevant fractions (Rf = 0.7 in 1:4 v/v methanol/dichloromethane) afforded the title
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compound 29a (11 mg, 70%) as a yellow oil. H NMR (CDCl3, 400 MHz) δ 9.20 (s, 1H),
7.63 (d, J = 8.1 Hz, 1H), 7.41 (d, J = 8.1 Hz, 1H), 7.31 (m, 1H), 7.12 (m, 1H), 4.24 (s,
1H), 2.63 (broad s, 1H), 2.55 (d, J = 7.0 Hz, 1H), 2.32 (s, 1H), 2.27 (s, 3H), 2.15–1.94
(complex m, 2H), 1.85 (d, J = 9.7 Hz, 1H), 1.34–1.04 (complex m, 2H), 0.82 (t, J = 7.4
13
Hz, 3H); C NMR (CDCl3, 100 MHz) δ see Table 2; IR νmax 3262, 2929, 1650, 1531,
1467, 1325, 1151, 1021, 744, 489 cmꢀ1; MS (ESI, +ve) m/z 269 [(M + H)+, 73%], 238
(100); HRMS (M + H)+ calcd for C17H21N2O 269.1654, found 269.1655.
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Crystallographic Studies
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Crystallographic Data for Compound 12. C16H16N2O2, M = 284.31, T = 150 K,
orthorhombic, space group P212121, Z = 4, a = 8.56836(10) Å, b = 12.02612 (14) Å, c =
14.15115(14) Å; β = 103.2795(16)°; V = 1458.19(3) Å3, Dx = 1.295 g cm–3, 2890 unique
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data (2θmax = 144.8°), R = 0.027 [for 2828 reflections with I > 2.0σ(I)]; Rw = 0.069 (all
data), S = 1.0.
Crystallographic Data for Compound 14. C21H28N2O2, M = 340.47, T = 150 K,
monoclinic, space group P21/n, Z = 4, a = 10.1738(2) Å, b = 10.6826(1) Å, c = 17.3464(3)
Å; V = 1834.84(5) Å3, Dx = 1.232 g cm–3, 3623 unique data (2
θmax = 144.6°), R = 0.031 [for
3271 reflections with I > 2.0σ(I)]; Rw = 0.075 (all data), S = 0.99.
Structure Determinations. Images were measured on a diffractometer (Cu Kα, mirror
monochromator, λ = 1.54184 Å) fitted with an area detector and data extracted using the
CrysAlis package.25 Structure solution was by direct methods (SIR92).26 The structures of
compounds 12 and 14 were refined using the CRYSTALS program package.27 Atomic
coordinates, bond lengths and angles, and displacement parameters for compounds 12
and 14 have been deposited at the Cambridge Crystallographic Data Centre (CCDC nos.
1450903 and 1450904). These data can be obtained freeꢀofꢀcharge via
www.ccdc.cam.ac.uk/data_request/cif, by emailing data_request@ccdc.cam.ac.uk, or by
contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
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ASSOCIATED CONTENT
Supporting Information
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Crystallographic data (CIF); anisotropic displacement ellipsoid plot derived from the
singleꢀcrystal analyses of compounds 12 and 14; 1H and 13C NMR spectra for compounds
1ꢀ4 and 6ꢀ15. This material is available free of charge via the Internet at
http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: Martin.Banwell@anu.edu.au
Notes
The authors declare no competing financial interest.
ACKNOWLEDGEMENTS
We thank the Australian Research Council and the Instiute of Advanced Studies for
financial support. FT is the grateful recipient of a CSC PhD Scholarship provided by the
Government of the People’s Republic of China.
REFERENCES
1. Joule, J. A. in Indoles, Saxton, J. E., Ed. In The Chemistry of Heterocyclic
Compounds, Weissberger, A.; Taylor, E. C. Eds.; Wiley, New York 1983, Vol.
25, Part 4, pp 265ꢀ292.
2. Schmutz, J.; Hunziker, F.; Hirt, R. Helv. Chim. Acta 1957, 40, 1189.
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3. Joule, J. A.; Ohashi, M.; Gilbert, B.; Djerassi, C. Tetrahedron 1965, 21, 1717.
4. See, for example, Gaskell, A. J.; Joule, J. A. Chem. Ind. (London) 1967, 1089.
5. Miranda, E. C.; Blechert, S. Tetrahedron Lett. 1982, 23, 5395.
10
11
12
13
14
15
16
17
18
19
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21
22
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24
25
26
27
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37
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41
42
43
44
45
46
47
48
49
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53
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55
56
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58
59
60
6. (a) Seidl, C.; Correia, B. L.; Stinghen, A. E. M.; Santos, C. A. M. Z. Naturforsch.
2010, 65c, 440; (b) dos Santos Torres, Z. E.; Silveira, E. R.; Rocha e Silva, L. F.;
Lima, E. S.; Carvalho de Vasconcellos, M.; Uchoa, D. E. de A.; Filho, R. B.;
Pohlit, A. M. Molecules 2013, 18, 6281; (c) Chierrito, T. P. C.; Aguiar, A. C. C.;
de Andrade, I. M.; Ceravolo, I. P.; Gonçalves, R. A. C.; de Oliveira, A. J. B.;
Krettli, A. U. Malaria J. 2014, 13, 142; (d) Uludag, N.; Yakup, M. Org. Prep.
Proced. Int. 2015, 47, 454 and references cited therein.
7. Maes, D.; Maes, R. Rev. Bras. Farmacogn. 2015, 25, 42.
8. (a) Büchi, G.; Warnhoff, E. W. J. Am. Chem. Soc. 1959, 81, 4433; (b) Shamma,
M.; Weiss, J. A.; Shine, R. J. Tetrahedron Lett. 1967, 2489. Also see (c) Borris,
R. P.; Lankin, D. C.; Cordell, G. A. J. Nat. Prod. 1983, 46, 200.
9. See, for example, (a) Gracia, J.; Casamitjana, N.; Bonjoch, J.; Bosch, J. J. Org.
Chem. 1994, 59, 3939 and references cited therein; (b) Saito, M.; Kawamura, M.;
Hiroya, K.; Ogasawara, K. Chem. Commun. 1997, 765; (c) Schmitt, M. H.;
Blechert, S. Angew. Chem. Int. Ed. 1997, 36, 1474; (d) Bennasar, M.ꢀL.; Roca, T.;
GarcíaꢀDíaz, D. J. Org. Chem. 2008, 73, 9033; (e) Patir, S.; Ertük, E. Org.
Biomol. Chem. 2013, 11, 2804.
10. For studies on the synthesis of the tetracyclic framework of the uleine alkaloids
see: (a) Feliz, M.; Bosch, J.; Mauleón, D.; Amat, M.; Domingo, A. J. Org. Chem.
1982, 47, 2435; (b) Bonjoch, J.; Casamithana, N.; Gracia, J.; Bosch, J.
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Tetrahedron Lett. 1989, 30, 5659; (c) Rubiralta, M.; Torrens, A.; Reig, I.;
Grierson, D. S.; Husson, H.ꢀP. Heterocycles 1989, 29, 2121; (d) Micouin, L.;
Diez, A.; Castells, J.; López, D.; Rubiralta, M.; Quirion, J.ꢀC.; Husson, H.ꢀP.
Tetrahedron Lett. 1995, 36, 1693; (e) Uludag, N.; Uyar, T.; Patir, S. Org. Prep.
Proced. Int. 2003, 35, 397; (f) Reekie, T. A.; Banwell, M. G.; Willis, A. C. J. Org.
Chem. 2012, 77, 10773; (g) see ref. 6d.
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11. (a) Gracia, J.; Bonjoch, J.; Casmitjana, N.; Amat, M.; Bosch, M. J. Chem. Soc.,
Chem. Commun. 1991, 614; (b) Magnus, P.; Sear, N. L.; Kim, C. S.; Vicker, N. J.
Org. Chem., 1992, 57, 70; (c) Jiricek, J.; Blechert, S. J. Am. Chem. Soc. 2004,
126, 3534; (d) Martin, C. L.; Nakamura, S.; Otte, R.; Overman, L. E. Org. Lett.
2011, 13, 138.
12. Tan, S. H.; Banwell, M. G.; Willis, A. C.; Reekie, T. A. Org. Lett. 2012, 14, 5621.
13. Banwell, M. G.; Jones, M. T.; Reekie, T. A. Chemistry in New Zealand 2011, 75,
122.
14. (a) Ergün, Y.; Bayraktar, N.; Patir, S.; Okay, G. J. Heterocyclic Chem. 2000, 37,
11; (b) Tokunaga, M.; Harad, S.; Iwasawa, T.; Obora, Y.; Tsuji, Y. Tetrahedron
Lett. 2007, 48, 6860.
15. Nicolaou, K. C.; Montagnon, T.; Baran, P. S.; Zhong, Y.ꢀL. J. Am. Chem. Soc.,
2002, 124, 2245.
16. Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353.
17. For other examples of such processes see: (a) Demuth, M.; Raghavan, P. R. Helv.
Chem. Acta 1979, 62, 2338; (b) Wong, H. N. C.; Hon, M.ꢀY.; Tse, C.ꢀW.; Yip,
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Y.ꢀC. Chem. Rev. 1989, 89, 165; (c) Jiang, X.; Lim, Z.; Yeumg, Y.ꢀY.
Tetrahedron Lett. 2013, 54, 1798.
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18. Baldwin, J. E.; Lusch, M. J. Tetrahedron 1982, 38, 2939 and references cited
therein.
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19. Johnson, C. R.; Adams, J. P.; Braun, M. P.; Senanayake, C. B. W.; Wovkulich, P.
M.; Uskokovic, M. R. Tetrahedron Lett. 1992, 33, 917.
20. Banwell, M. G.; Jones, M. T.; Reekie, T. A.; Schwartz, B. D.; Tan, S. H.; White,
L. V. Org. Biomol. Chem. 2014, 12, 7433.
21. White, L. V.; Banwell, M. G. J. Org. Chem. 2016, 81, 1617.
22. (a) Evarts, J.; Torres, E.; Fuchs, P. L. J. Am. Chem. Soc. 2002, 124, 11093; (b)
Houjeiry, T. I.; Poe, S. L.; McQuade, D. T. Org. Lett. 2012, 14, 4394.
23. Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.
24. Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J.
Organometallics 1996, 15, 1518.
25. CrysAlis PRO Version 1.171.37.35h (release 09ꢀ02ꢀ2015 CrysAlis171.NET)
(compiled Feb 9 2015,16:26:32) Agilent Technologies: Oxfordshire, UK.
26. SIR92. Altomare, A.; Cascarano, G.; Giacovazzo, C.; Guagliardi, A.; Burla, M.
C.; Polidori, G.; Camalli, M. J. Appl. Crystallogr. 1994, 27, 435.
27. Betteridge, P. W.; Carruthers, J. R.; Cooper, R. I.; Prout, K.; Watkin, D. J. J.
Appl. Crystallogr. 2003, 36, 1487.
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