A raney-cobalt-mediated tandem reductive cyclization route to the 1,5-methanoazocino[4,3-b]indole framework of the uleine and strychnos alkaloids

Article abstract of DOI:10.1021/jo302132d

The readily accessible enones 8, 17, and 18 undergo 2-fold reductive cyclization reactions upon exposure to hydrogen in the presence of Raney-cobalt and thereby afford compounds 11 (72%), 19 (47%), and 20 (84%), respectively. These products embody the ABC

Full text of DOI:10.1021/jo302132d

Article
pubs.acs.org/joc
A Raney-Cobalt-Mediated Tandem Reductive Cyclization Route to
the 1,5-Methanoazocino[4,3‑b]indole Framework of the Uleine and
Strychnos Alkaloids
Tristan A. Reekie, Martin G. Banwell,* and Anthony C. Willis
Research School of Chemistry, Institute of Advanced Studies, The Australian National University, Canberra ACT 0200, Australia
S
* Supporting Information
ABSTRACT: The readily accessible enones 8, 17, and 18 undergo 2-fold reductive cyclization reactions upon exposure to hydrogen
in the presence of Raney-cobalt and thereby afford compounds 11 (72%), 19 (47%), and 20 (84%), respectively. These products
embody the ABCD-ring system associated with the title alkaloids, and compound 11 can be converted, over four steps and in 33%
yield, into congener 24 incorporating the ABCDE-ring system of the Strychnos alkaloids.
Scheme 1
INTRODUCTION
■
The title framework is encountered, as a key structural element, in
both the Uleine and Strychnos alkaloid families, members of which
include dasycarpidone (1) and strychnine (2), respectively.1 The
biological properties and fascinating molecular architectures of such
compounds have resulted in a sustained focus on the development
of methods for the assembly of them. For example, recent work has
culminated in extraordinarily concise syntheses of strychnine,
arguably the structurally most demanding and certainly the most
well-known member of the latter class of alkaloid.2 Herein, we
report an effective new protocol for the construction of the
constituent tetracyclic 1,5-methanoazocino[4,3-b]indole or ABCD-
ring system that involves, as the key step, a highly chemoselective
Raney-cobalt-mediated tandem reductive cyclization of readily
accessible, bicyclic substrates. This protocol should provide a useful
means for the ready assembly of key substructures and analogues of
these important alkaloidal systems.3
K2CO3-mediated Michael addition reaction of methyl α-
cyanoacetate to cyclohexenone (3). The resulting adduct 4,4
which was obtained as a mixture of diastereoisomers in 88%
combined yield, was subjected to a LiCl-induced demethylation/
decarboxylation reaction sequence to give the previously re-
ported cyclohexenone 55 (81% yield). Dehydrogenation of com-
pound 5 was effected with o-iodoxybenzoic acid (IBX) in the
presence of p-toluenesulfonic acid monohydrate (p-TsOH-
H2O),6 and the enone 65 was thereby obtained in 58% yield.
Subjection of the latter compound to the Johnson α-iodination
RESULTS AND DISCUSSION
The reaction sequence used to prepare the substrate required for
preliminary studies is shown in Scheme 1 and starts with the
■
Received: September 28, 2012
Published: October 24, 2012
© 2012 American Chemical Society
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protocol7 using molecular iodine in chloroform/pyridine gave
the iodoenone 7 (89%) that readily engaged in a Pd[0]-catalyzed
Ullmann cross-coupling reaction8 with o-iodonitrobenzene to afford
α-arylcyclohexenone 8 (66%) that embodies all of the carbons
and the two nitrogens required in the target 1,5-methanoazocino-
[4,3-b]indole.
at C4, as would be required for their deployment in assembling
members of the Strychnos alkaloid family.13 Thus, for example,
successive treatment of compound 4 with ethanolic sodium hydro-
xide then paraformaldehyde (Scheme 3) afforded acrylonitrile 12
Scheme 3
Exposure of a methanolic solution of compound 8 to di-
hydrogen in the presence of 10% Pd on C afforded (Scheme 2)
Scheme 2
(85%) and exposure of either this compound or its precursor (4)
to IBX in the presence of p-TsOH·H2O afforded the corresponding
enone 13 (61%) or 14 (54%), respectively. Subjection of each of
these to the Johnson α-iodination protocol and engagement of
the ensuing products 15 (85%) and 16 (75%) in the Pd[0]-
catalyzed Ullmann cross-coupling reaction with o-iodonitroben-
zene then gave the substrates 17 (71%) and 18 (81%) required
for the pivotal tandem reductive cyclization reactions. The
structure of the latter substrate was confirmed by single-crystal
X-ray analysis.14 Exposure of compound 17 to dihydrogen in
the presence of Raney-cobalt and p-TsOH·H2O gave the C4-
carbomethoxy-substituted 1,5-methanoazocino[4,3-b]indole 19
which was obtained in 47% yield and as a ca. 1:1 mixture of
diastereoisomers. Analogous treatment of compound 18 afforded
the C4-methylated system 20 (84% combined yield of a ca. 1:1 and
chromatographically separable mixture of diastereoisomers).
With 1,5-methanoazocino[4,3-b]indoles such as the parent
compound 11 now readily to hand, various means for annulating
the E-ring, as encountered in the Strychnos alkaloid family, were
explored. To date, the only effective method we have found for
doing so is that due to Bosch (Scheme 4).15 Thus, treatment of
amine 11 with the dimethylacetal of α-bromoacetaldehyde in the
presence of K2CO3 afforded the anticipated tertiary amine 21
(88%)12 that underwent a smooth trans-acetalization reaction on
exposure to ethanethiol in the presence of boron trifluoride-diethyl
etherate to give the bis-thioacetal 22 in 83% yield. Treatment of the
last compound with dimethyl(methylthio)sulfonium tetrafluoro-
borate (DMSTF)1c,16 in the presence of 4 Å molecular sieves
resulted in a cationic cyclization reaction and the generation of the
annulated isoindole 23 that was obtained in 63% yield.
the annulated indole 99 in 98% yield. This product presumably
arises from reduction of both the nitro group and the carbon−
carbon double bond (no particular order implied) within sub-
strate 8 as well as an intramolecular Schiff base condensation
reaction between the resulting aniline and the pendant ketone.
Exposure of a refluxing THF solution of the starting com-
pound (8) to dihydrogen in the presence of Raney-nickel and
p-toluenesulfonic acid monohydrate (p-TsOH·H2O) afforded
the amine analogue, 10,10 of compound 9 in 87% yield [compound
9 could be convertedinto amine10 (98%) on exposure to hydrogen
in the presence of Raney-nickel]. Product 10 presumably arises via
the same processes as involved in the conversion 8 → 9, but the rate
of reduction of the carbon−carbon double bond must be faster than
that of the nitrile moiety and is thereby preventing the hoped-for
D-ring-forming intramolecular hetero-Michael addition reaction
from taking place. In contrast, when substrate 8 was treated
under the same conditions, but Raney-nickel was replaced
with Raney-cobalt, the desired tetracyclic compound 1111 was
obtained in 72% yield, and this could be separated from the small
amounts of coproduced amine 10 (8%) using conventional
chromatographic techniques. It was also possible to convert the
latter product into the former one by initial protection of the
amine (10) as its Cbz-protected derivative, cyclization of the
latter with DDQ (to give the Cbz-protected form of compound
11)12 followed by protecting group removal (62% overall yield of
11, see the Experimental Section for details).
The protocols defined above can be extended to the assembly
of 1,5-methanoazocino[4,3-b]indoles incorporating functionality
Finally, exposure of compound 23 to Raney-nickel resulted in
both reductive desulfurization and imine reduction, and thereby
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Scheme 4
Analytical thin-layer chromatography (TLC) was performed on aluminum-
backed 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) or
potassium permanganate/potassium carbonate/5% sodium hydroxide
aqueous solution/water (3 g : 20 g : 5 mL : 300 mL). Flash chromato-
graphic separations were carried out following protocols defined by Still
et al.20 with silica gel 60 (40−63 μm) as the stationary phase and using
the AR- or HPLC-grade 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 (DCM) were dried using a solvent purification
system that is based upon a technology originally described by Grubbs et al.21
Where necessary, reactions were performed under an argon atmosphere.
Compound 4. A magnetically stirred solution of 2-cyclohexen-1-one
(3) (2.93 g, 29.9 mmol) and methyl α-cyanoacetate (3.26 g, 32.9 mmol)
in acetonitrile (74 mL) was treated with K2CO3 (2.48 g, 17.9 mmol) and
the ensuing mixture stirred at 18 °C for 16 h. NaHCO3 (50 mL of a
saturated aqueous solution) was then added to the reaction mixture,
which was extracted with dichloromethane (3 × 50 mL). The combined
organic phases were dried (MgSO4) before being filtered and then
concentrated under reduced pressure. The ensuing yellow oil was
subjected to flash chromatography (silica, 1:9 → 1:1 v/v ethyl acetate/
hexane gradient elution), and concentration of the relevant fractions
(Rf = 0.4 in 1:1 v/v ethyl acetate/hexane) afforded the title compound 44
(5.14 g, 88%) as a clear, colorless oil and as a 1:1 mixture of dia-
affording the pentacyclic indoline 24 (81%) embodying the
ABCDE-ring system encountered in the Strychnos alkaloid
family. The spectral data derived from this material were in good
agreement with those reported previously by Shibasaki12 and
Bosch.15b A tabular comparison of the relevant 1H and 13C NMR
data is provided in the Supporting Information.
Attempts to deploy a procedure used by Heathcock17 for the
installation of the E-ring of aspidospermidine proved ineffective
in the present setting. So, while compound 11 was readily con-
verted into the corresponding α-chloroacetamide 2510 (63%)
under standard conditions and this, in turn, underwent a Finkelstein
reaction with sodium iodide in acetone to give congener 26 (92%),
this last compound proved to be unstable and failed to cyclize
upon exposure to silver triflate under the prescribed17 conditions.
Only complex mixtures of products were observed. Attempts to
engage compound 25 in a radical-mediated cyclization reaction by
treating it with tri-n-butyltin hydride only afforded the direct
reduction product 2710 (89%).
Efforts are now underway to adapt the protocols detailed
above to the synthesis of various alkaloids. In particular, given the
capacity to readily access optically active 4-substituted 2-cyclohex-2-
en-1-ones,18 the enantioselective synthesis of tubotaiwine-type
alkaloids (which incorporate, inter alia, a two-carbon substituent at
C12 on the ABCDE-framework of compound 24)1c,19 is now being
pursued. Results will be reported in due course.
1
stereoisomers: H NMR (CDCl3, 400 MHz) δ 3.85 (s, 1.5H), 3.83
(s, 1.5H), 3.62 (d, J = 4.4 Hz, 0.5H), 3.48 (d, J = 5.2 Hz, 0.5H), 2.58−
2.26 (complex m, 5H), 2.15 (m, 1H), 1.96 (m, 1H), 1.69 (m, 2H); 13C
NMR (CDCl3, 100 MHz) δ 207.8 (C, two overlapping signals), 165.1
(C), 165.0 (C), 114.5 (C, two overlapping signals), 53.4 (CH3, two
overlapping signals), 45.2 (CH2), 43.6 (CH2), 43.2 (CH), 43.1 (CH),
40.4 (CH2), 40.3 (CH2), 38.4 (CH, two overlapping signals), 29.0
(CH2), 27.3 (CH2), 24.0 (CH2), 23.9 (CH2); IR νmax 2956, 2249, 1746,
1713, 1437, 1317, 1263, 1227, 1104, 1009, 871 cm−1; MS (EI, 70 eV) m/
z 195 (M+•, 14), 164 (16), 152 (25), 124 (15), 108 (35), 100 (28), 97
(100), 96 (30), 69 (56), 68 (45); HRMS M+• calcd for C10H13NO3
195.0895, found 195.0894.
Compound 5. A magnetically stirred solution of ester 4 (5.82 g,
29.8 mmol) in DMSO (152 mL) was treated with water (0.75 mL,
41.7 mmol) and LiCl (2.65 g, 62.6 mmol) and the resulting mixture
heated to 140 °C for 2 h, cooled to 18 °C, and diluted with diethyl ether
(200 mL) and water (300 mL). The separated aqueous phase was
extracted with ethyl acetate (3 × 100 mL), and the combined organic
phases were then washed with brine (1 × 100 mL) before being dried
(MgSO4), filtered, and concentrated under reduced pressure. The ensuing
EXPERIMENTAL SECTION
General Experimental Procedures. Unless otherwise specified,
proton (1H) and carbon (13C) NMR spectra were recorded at 18 °C in
base-filtered CDCl3 on a spectrometer operating at 400 MHz for proton
■
1
and 100 MHz for carbon nuclei. For H NMR spectra, signals arising
from the residual protio-forms of the solvent were used as the internal
1
standards. H 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 = multiplet or combinations of the above. 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. Low-resolution ESI mass spectra were recorded on
a single quadrupole liquid chromatograph−mass spectrometer, while
high-resolution measurements were conducted on a time-of-flight
instrument. Low- and high-resolution EI mass spectra were recorded on
a magnetic-sector machine. Samples were analyzed by infrared spectro-
metry (νmax) as thin films on KBr plates. Melting points are uncorrected.
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yellow oil was subjected to flash chromatography (silica, 3:7 v/v ethyl
acetate/hexane elution), and concentration of the relevant fractions
(Rf = 0.3 in 1:1 v/v ethyl acetate/hexane) afforded the title compound 55
(3.76 g, 92%) as a clear, colorless oil: 1H NMR (CDCl3, 400 MHz) δ
2.50 (m, 1H), 2.40 (m, 3H), 2.27 (m, 1H), 2.19 (m, 2H), 2.11 (m, 1H),
2.02 (m, 1H), 1.69 (m, 1H), 1.58 (m, 1H); 13C NMR (CDCl3,
100 MHz) δ 208.9 (C), 117.5 (C), 46.6 (CH2), 40.6 (CH2), 35.3 (CH),
30.2 (CH2), 24.3 (CH2), 24.0 (CH2); IR νmax 2930, 2245, 1711, 1629,
1449, 1423, 1368, 1347, 1226, 1057 cm−1; MS (EI, 70 eV) m/z 137
(M+•, 58), 108 (21), 97 (56), 94 (50), 81 (22), 69 (33), 55 (100);
HRMS M+• calcd for C8H11NO 137.0841, found 137.0841.
1H NMR (CDCl3, 400 MHz) δ 8.05 (dd, J = 8.0 and 1.2 Hz, 1H), 7.63
(td, J = 7.6 and 1.2 Hz, 1H), 7.50 (td, J = 8.0 and 1.6 Hz, 1H), 7.25
(dd, J = 7.6 and 1.6 Hz, 1H), 6.98 (dd, J = 5.6 and 3.2 Hz, 1H), 2.85−
2.66 (complex m, 3H), 2.60−2.48 (complex, 4H); 13C NMR (CDCl3,
100 MHz) δ 193.9 (C), 148.4 (C), 143.5 (CH), 139.8 (C), 133.5 (CH),
131.5 (CH), 131.2 (C), 129.2 (CH), 124.0 (CH), 117.3 (C), 43.1
(CH2), 31.7 (CH), 31.1 (CH2), 23.0 (CH2); IR νmax 2924, 2245, 1676,
1572, 1521, 1428, 1349, 1181, 1139, 957, 913 cm−1; MS (EI, 70 eV) m/z
256 (M+•, 2), 210 (92), 170 (75), 169 (100), 168 (91), 157 (82), 146
•
(62), 134 (66), 115 (63), 104 (58), 77 (55); HRMS (M − NO2 )+ calcd
for C14H12N2O3 210.0919, found 210.0914.
Compound 6. A magnetically stirred solution of ketone 5 (3.00 g,
21.9 mmol) in toluene/DMSO (225 mL of a 2:1 v/v mixture) was
treated with p-TsOH·H2O (1.25 g, 6.57 mmol) and IBX (8.59 g,
30.7 mmol) then heated at 55 °C for 16 h. The resulting solution was
cooled to 18 °C and treated with diethyl ether (150 mL) followed by
NaHCO3 (250 mL of a 5% aqueous solution). The ensuing mixture was
filtered through diatomaceous earth, and the solids thus retained were
washed with diethyl ether (3 × 30 mL). The aqueous phase was
separated from the combined filtrates and then extracted with ethyl
acetate (3 × 100 mL). The combined organic phases were washed with
brine (1 × 100 mL) before being dried (MgSO4), filtered, and con-
centrated under reduced pressure. The ensuing black oil was subjected
to flash chromatography (silica, 3:7 v/v ethyl acetate/hexane elution),
and concentration of the relevant fractions (Rf = 0.3 in 1:1 v/v ethyl
acetate/hexane) afforded the title compound 65 (1.72 g, 58%) as a clear,
colorless oil: 1H NMR (CDCl3, 400 MHz) δ 6.98 (m, 1H), 6.06 (dd, J =
13.2 and 4.0 Hz, 1H), 2.62−2.45 (complex m, 5H), 2.32 (m, 2H); 13C
NMR (CDCl3, 100 MHz) δ 197.0 (C), 148.0 (CH), 129.8 (CH), 117.3
(C), 42.9 (CH2), 31.8 (CH2), 30.6 (CH), 23.1 (CH2); IR νmax 3016,
2933, 2247, 1679, 1426, 1408, 1389, 1334, 1313, 1299, 1251, 1140, 933,
885 cm−1; MS (EI, 70 eV) m/z 135 (M+•, 100), 95 (17), 77 (10), 68
(83); HRMS M+• calcd for C8H9NO 135.0684, found 135.0685.
Compound 7. A magnetically stirred solution of enone 6 (1.22 g,
9.03 mmol) in CHCl3/pyridine (45 mL of a 1:1 v/v mixture) maintained at
18 °C was treated dropwise with a solution of molecular iodine (9.17 g,
36.1 mmol) in CHCl3/pyridine (45 mL of a 1:1 v/v mixture). The
ensuing mixture was stirred at 18 °C for 0.5 h and then diluted with
diethyl ether (300 mL), and the resulting solution washed sequentially
with water (1 × 100 mL), HCl (1 × 100 mL of a 1 M aqueous solution),
and Na2S2O3 (1 × 100 mL of a 5% w/v aqueous solution).
The combined aqueous phases were extracted with ethyl acetate
(3 × 100 mL), and the combined organic phases were washed with brine
(1 × 200 mL) before being dried (MgSO4), filtered, and concentrated
under reduced pressure. The ensuing black oil was subjected to flash
chromatography (silica, 3:7 v/v ethyl acetate/hexane elution), and
concentration of the relevant fractions (Rf = 0.4 in 1:1 v/v ethyl acetate/
hexane) afforded the title iodide 7 (2.10 g, 89%), as a clear, colorless oil:
1H NMR (CDCl3, 400 MHz) δ 7.73 (dd, J = 5.6 and 3.2 Hz, 1H), 2.89
(dm, J = 15.2 Hz, 1H), 2.67−2.40 (complex m, 6H); 13C NMR (CDCl3,
100 MHz) δ 189.9 (C), 156.4 (CH), 116.9 (C), 103.5 (C), 41.8 (CH2),
34.6 (CH2), 31.9 (CH) 22.8 (CH2); IR νmax 2921, 2245, 1675, 1590,
1423, 1319, 1136, 940, 905 cm−1; MS (EI, 70 eV) m/z 261 (M+•, 92),
221 (10), 194 (100), 166 (15), 94 (40), 66 (17); HRMS M+• calcd for
C8H8INO 260.9651, found 260.9651.
Compound 9. A magnetically stirred solution of compound 8
(10 mg, 0.039 mmol) in methanol (1.95 mL) was treated with 10%
palladium on carbon (2 mg), and the resulting suspension was stirred at
18 °C under an atmosphere of hydrogen (1 atm) for 18 h. The ensuing
reaction mixture was filtered through diatomaceous earth, and the solids
thus retained were washed with methanol (2 × 10 mL). The combined
filtrates were concentrated under reduced pressure to give the title
indole 99 (8 mg, 98%) as a clear, colorless oil: Rf = 0.5 (in 1:1 v/v ethyl
1
acetate/hexane); H NMR (CDCl3, 400 MHz) δ 7.75 (broad s, 1H),
7.46 (d, J = 6.8 Hz, 1H), 7.30 (dd, J = 7.6 and 1.6 Hz, 1H), 7.15 (td, J =
7.6 and 1.6 Hz, 1H), 7.15 (td, J = 6.8 and 1.6 Hz, 1H), 2.99 (dd, J = 16.0
and 5.2 Hz, 1H), 2.88−2.71 (complex m, 2H), 2.62 (m, 1H), 2.50
(dd, J = 7.2 and 3.2 Hz, 2H), 2.40 (m, 1H), 2.11 (m, 1H), 1.76 (m, 1H);
13C NMR (CDCl3, 100 MHz) δ 136.0 (C), 131.4 (C), 127.2 (C), 121.5
(CH), 119.4 (CH), 118.6 (C), 117.9 (CH), 110.6 (CH), 109.4 (C),
31.8 (CH), 28.7 (CH2, two signals overlapping), 23.3 (CH2), 19.6
(CH2); IR νmax 3396, 2919, 2846, 2246, 1622, 1467, 1453, 1430, 1347,
1325, 1304, 1237, 1143, 1066, 1010 cm−1; MS (EI, 70 eV) m/z 210
(M+•, 85), 168 (58), 143 (100), 130 (19), 115 (20), 77 (15); HRMS
M
+• calcd for C14H14N2 210.1157, found 210.1156.
Compound 10. A magnetically stirred mixture of nitrile 8 (20 mg,
0.078 mmol), p-TsOH·H2O (59 mg, 0.31 mmol), and Raney-nickel
(40 mg, 200% w/w) in THF (3 mL) was heated at reflux under an
atmosphere of hydrogen (1 atm) for 18 h. The cooled reaction mixture
was filtered through diatomaceous earth, and the residual solids were
washed with methanol (3 × 5 mL). The combined filtrates were
concentrated under reduced pressure to afford a yellow oil that was
subjected to column chromatography (silica, 1:19 → 1:4 v/v methanol/
dichloromethane gradient elution). Concentration of the relevant
fractions (Rf = 0.2 in 1:4 v/v methanol/dichloromethane) then afforded
the title compound 1010 (15 mg, 87%) as a clear, colorless oil: 1H NMR
(CD3OD, 400 MHz) δ 7.33 (d, J = 7.6 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H),
6.95 (m, 2H), 2.86−2.73 (complex m, 4H), 2.64 (m, 1H), 2.39 (m, 1H),
1.98 (m, 2H), 1.66−1.47 (complex m, 3H), (signals due to NH protons
not observed); 13C NMR (CD3OD, 100 MHz) δ 137.8 (C), 135.0 (C),
128.9 (C), 121.3 (CH), 119.2 (CH), 118.2 (CH), 111.4 (CH), 109.6
(C), 40.4 (CH2), 40.2 (CH2), 33.8 (CH), 31.1 (CH2), 30.5 (CH2), 21.4
(CH2); IR νmax 3398, 3051, 2912, 2842, 1567, 1466, 1302, 1235, 1142,
1009 cm−1; MS (EI, 70 eV) m/z 214 (M+•, 85), 197 (27), 182 (16), 170
(68), 169 (83), 168 (100), 156 (17), 143 (89), 130 (33), 115 (19);
HRMS M+• calcd for C14H18N2 214.1470, found 214.1475.
Conversion of Compound 9 into 10. A magnetically stirred
mixture of nitrile 9 (25 mg, 0.12 mmol) and Raney-nickel (40 mg, 200%
w/w) in THF (3 mL) was maintained at 18 °C under an atmosphere of
hydrogen (1 atm) for 2 h. The reaction mixture was then filtered
through diatomaceous earth, and the solids thus retained washed with
methanol (3 × 5 mL). The combined filtrates were concentrated under
reduced pressure to afford a yellow oil that was subjected to column
chromatography (silica, 1:19 → 1:4 v/v methanol/dichloromethane
gradient elution). Concentration of the relevant fractions (Rf = 0.2 in 1:4
v/v methanol/dichloromethane) afforded compound 10 (24 mg, 96%)
as a clear, colorless oil. This material was identical, in all respects, with
that obtained as described immediately above.
Compound 8. A magnetically stirred solution of iodide 7 (1.91 g,
7.32 mmol) and o-iodonitrobenzene (3.65 g, 14.6 mmol) in DMSO
(15 mL) was treated with Pd2(dba)3 (536 mg, 0.59 mmol) and Cu
powder (2.30 g, 36.6 g-atom). The resulting mixture was heated at 70 °C
for 2 h and then cooled to 18 °C before being diluted with diethyl ether
(100 mL). The ensuing mixture was filtered through diatomaceous
earth, and the solids thus retained were washed with diethyl ether
(3 × 30 mL). The combined filtrates were washed with water (2 × 100 mL)
and the combined aqueous phases extracted with ethyl acetate (3 × 50 mL).
The combined organic phases were then dried (MgSO4), filtered, and
concentrated under reduced pressure to afford a light-yellow residue.
Subjection of this material to flash chromatography (silica, 1:9 → 3:7 v/v
ethyl acetate/hexane gradient elution) and concentration of the relevant
fractions (Rf = 0.2 in 1:1 v/v ethyl acetate/hexane) afforded the title
compound 8 (1.24 g, 66%) as a white, crystalline solid: mp 130−134 °C;
Compound 11. A magnetically stirred mixture of nitrile 8 (362 mg,
1.41 mmol), p-TsOH·H2O (1.07 g, 5.64 mmol), and Raney-cobalt
(700 mg, 200% w/w) in THF (35 mL) was heated at reflux for 18 h
while being maintained under an atmosphere of hydrogen (1 atm).
The cooled reaction mixture was filtered through diatomaceous earth,
and the solids thus retained were washed with methanol (3 × 30 mL).
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The combined filtrates were then concentrated under reduced pressure
to afford a yellow oil that was subjected to column chromatography
(silica, 1:19 → 1:4 v/v methanol/dichloromethane gradient elution)
and thereby afforded two fractions, A and B.
3309, 3034, 2928, 1669, 1464, 1455, 1426, 1365, 1351, 1318, 1300,
1270, 1231, 1194, 1099, 1067, 1027 cm−1; MS (EI, 70 eV) m/z 346
(M+•, 90), 211 (13), 194 (73), 182 (17), 169 (77), 168 (100), 143 (12),
91 (85); HRMS M+• calcd for C22H22N2O2 346.1681, found 346.1682.
Step iii. A magnetically stirred solution of the Cbz-derivative of
compound 11 (130 mg, 0.37 mmol) in methanol (3.7 mL) was treated
with 10% palladium on carbon (5 mg), and the resulting suspension
maintained under an atmosphere of hydrogen (1 atm) at 18 °C for 8 h.
The reaction mixture was then filtered through diatomaceous earth and
the solids thus retained were washed with methanol (2 × 10 mL). The
combined filtrates were concentrated under reduced pressure to afford
compound 11 (75 mg, 96%) as a clear, colorless oil. This material was
identical, in all respects, with that obtained as described earlier.
Compound 12. Step i. A magnetically stirred solution of ester 4
(2.00 g, 10.2 mmol) in ethanol (23 mL) was treated with NaOH (23 mL
of a 2 M aqueous solution, 46.1 mmol) and then stirred at 18 °C for
0.17 h before being concentrated under reduced pressure. The residue
thus obtained was diluted with diethyl ether (75 mL) and the resulting
solution treated with HCl (40 mL of a 2 M aqueous solution). The
separated aqueous phase was extracted with diethyl ether (3 × 40 mL),
and the combined organic phases were then dried (MgSO4), filtered,
and concentrated under reduced pressure to give the corresponding
carboxylic acid as a light-yellow oil. This material was used, without
purification, in step ii.
Step ii. The carboxylic acid obtained from ester 4 by the method
detailed immediately above was dissolved in ethyl acetate (26 mL) and
the resulting solution treated with HNEt2 (1.21 mL, 11.73 mmol) and
paraformaldehyde (429 mg, 14.3 mmol) and then heated at reflux for
2 h. The cooled reaction mixture was diluted with diethyl ether (75 mL)
and then acidified with HCl (40 mL of a 2 M aqueous solution). The
separated aqueous phase was extracted with diethyl ether (3 × 40 mL),
and the combined organic phases were then dried (MgSO4), filtered,
and concentrated under reduced pressure to give a light-yellow oil.
Subjection of this material to flash column chromatography (silica, 3:7
v/v ethyl acetate/hexane elution) and concentration of the relevant
fractions (Rf = 0.3 in 3:7 v/v ethyl acetate/hexane) afforded the title
compound 12 (1.29 g, 85% over two steps) as a clear, colorless oil: 1H
NMR (CDCl3, 400 MHz) δ 5.91 (s, 1H), 5.77 (s, 1H), 2.69 (m, 1H),
2.52 (m, 1H), 2.48−2.25 (complex m, 3H), 2.10 (m, 2H), 1.77 (m, 2H);
13C NMR (CDCl3, 100 MHz) δ 208.6 (C), 129.8 (CH2), 126.0 (C),
117.2 (C), 45.4 (CH2), 43.0 (CH), 40.8 (CH2), 29.7 (CH2), 24.3
(CH2); IR νmax 2943, 2868, 2221, 1713, 1619, 1449, 1408, 1346, 1318,
1224, 1098, 1036, 945, 874 cm−1; MS (EI, 70 eV) m/z 149 (M+•, 23),
133 (19), 121 (35), 106 (100), 93 (24), 79 (30), 68 (30); HRMS M+•
calcd for C9H11NO 149.0841, found 149.0842.
Compound 13. A magnetically stirred solution of ketone 4 (7.03 g,
36.0 mmol) in toluene/DMSO (120 mL of a 2:1 v/v mixture) was
treated with p-TsOH·H2O (2.05 g, 10.8 mmol) and IBX (14.1 g,
50.4 mmol) and the ensuing mixture heated at 55 °C for 18 h. The
reaction mixture was then cooled to 18 °C, treated with diethyl ether
(200 mL) and NaHCO3 (250 mL of a 5% aqueous solution), and then
filtered through diatomaceous earth. The solids thus retained were
washed with diethyl ether (3 × 30 mL), and the separated aqueous phase
was extracted with ethyl acetate (3 × 75 mL). The combined organic
phases were washed with brine (1 × 100 mL) before being dried
(MgSO4), filtered, and concentrated under reduced pressure. The
ensuing black oil was subjected to flash column chromatography (silica,
3:7 → 1:1 v/v ethyl acetate/hexane gradient elution), and concentration
of the relevant fractions (Rf = 0.2 in 1:1 v/v ethyl acetate/hexane)
afforded the title compound 13 (4.24 g, 61%) as a pale-yellow oil and a 1:1
mixture of diastereoisomers: 1H NMR (CDCl3, 400 MHz) δ 6.98
(m, 1H), 6.09 (dd, J = 10.4 and 2.0 Hz, 1H), 3.85 (s, 1.5H), 3.84
(s, 1.5H), 3.65 (d, J = 5.2 Hz, 0.5H), 3.59 (d, J = 5.6 Hz, 0.5H), 2.85
(m, 1H), 2.60−2.39 (complex m, 4H); 13C NMR (CDCl3, 100 MHz) δ
196.1(4) (C), 196.1(2) (C), 164.9 (C), 164.8 (C), 147.7 (CH), 147.5
(CH), 129.9 (CH), 129.8 (CH), 114.3 (C, two overlapping signals),
53.8 (CH3), 53.7 (CH3), 42.5 (CH, two overlapping signals), 41.7
(CH2), 40.3 (CH2), 35.3 (CH), 35.2 (CH), 29.5 (CH2), 28.3 (CH2); IR
νmax 2957, 2250, 1746, 1682, 1618, 1435, 1389, 1255, 1219, 1164, 1097,
1045, 1007, 965, 885 cm−1; MS (EI, 70 eV) m/z 194 [(M + H)+, <1%],
Concentration of fraction A (Rf = 0.3 in 1:4 v/v methanol/
dichloromethane) afforded the title compound 1111 (215 mg, 72%) as a
clear, colorless oil: 1H NMR (CD3OD, 400 MHz) δ 7.46 (d, J = 7.2 Hz,
1H), 7.27 (d, J = 7.6 Hz, 1H), 7.00 (m, 2H), 4.35 (m, 1H), 3.12
(dd, J = 17.6 and 6.8 Hz, 1H), 2.69 (d, J = 17.6 Hz, 1H), 2.59 (m, 2H),
2.40 (m, 1H), 2.15 (dt, J = 12.4 and 3.2 Hz, 1H), 1.91 (m, 2H), 1.62
(m, 1H) (signal due to NH proton not observed); 13C NMR (CD3OD,
100 MHz) δ 138.2 (C), 138.0 (C), 127.4 (C), 121.5 (CH), 119.7 (CH),
118.2 (CH), 111.6 (CH), 109.5 (C), 45.7 (CH), 38.0 (CH2), 33.9
(CH2), 33.7 (CH2), 29.9 (CH2), 27.4 (CH); IR νmax 3394, 3221, 3052,
2922, 1618, 1527, 1453, 1426, 1362, 1303, 1273, 1236, 1197, 1070, 1029
cm−1; MS (EI, 70 eV) m/z 212 (M+•, 23), 194 (6), 182 (17), 169 (100),
168 (75), 167 (55), 154 (6), 143 (11), 130 (6), 115 (6), 82 (11); HRMS
M
+• calcd for C14H16N2 212.1313, found 212.1313.
Concentration of fraction B (Rf = 0.2 in 1:4 v/v methanol/
dichloromethane) afforded the title compound 10 (24 mg, 8%) as a
clear, colorless oil. This material was identical, in all respects, with that
obtained via the method described immediately above.
Conversion of Compound 10 into 11. Step i. A solution of amine
10 (115 mg, 0.54 mmol) and Na2CO3 (114 mg, 1.07 mmol) in water
(5.4 mL) was treated with benzyl chloroformate (84 μL, 0.59 mmol)
and the ensuing mixture stirred magnetically at 18 °C for 0.5 h.
Dichloromethane (10 mL) was then added and the separated aqueous
phase extracted with additional dichloromethane (2 × 10 mL). The
combined organic phases were then dried (MgSO4), filtered, and
concentrated under reduced pressure to afford the Cbz-derivative of
compound 10 (133 mg, 81%) as a yellow foam: 1H NMR (CDCl3, 400
MHz) δ 7.80 (s, 1H), 7.46 (d, J = 7.6 Hz, 1H), 7.34 (m, 5H), 7.21
(d, J = 8.0 Hz, 1H), 7.11 (m, 2H), 5.12 (s, 2H), 4.98 (s, 1H), 3.26 (m,
2H), 2.76 (m, 1H), 2.66 (m, 2H), 2.24 (m, 1H), 1.90 (m, 2H), 1.51 (m,
3H); 13C NMR (CDCl3, 100 MHz) δ 156.4 (C), 136.4 (C), 135.7 (C),
133.3 (C), 128.3 (CH), 127.9 (CH), 127.8 (CH), 127.2 (C), 120.7
(CH), 118.8 (CH), 117.5 (CH), 110.4 (CH), 109.3 (C), 66.4 (CH2),
38.8 (CH2), 35.8 (CH2), 31.8 (CH), 29.4 (CH2), 28.9 (CH2), 20.1
(CH2); IR νmax 3400, 3334, 3055, 3032, 2916, 2844, 1697, 1520, 1467,
1453, 1327, 1302, 1239, 1138, 1063, 1010 cm−1; MS (EI, 70 eV) m/z
348 (M+•, 16), 284 (13), 256 (15), 143 (15), 129 (16), 111 (18), 97
(33), 91 (22), 83 (41), 69 (100); HRMS M+• calcd for C22H24N2O2
348.1838, found 348.1830.
Step ii. A magnetically stirred solution of the Cbz-derivative of
compound 10 (65 mg, 0.19 mmol) in THF (1.9 mL) maintained at 0 °C
was treated, dropwise over 1 h via syringe pump, with a solution of DDQ
(47 mg, 0.20 mmol) in THF (1.9 mL). The resulting solution was
warmed to 18 °C and stirred at this temperature for a further 1 h and
then diluted with NaOH (10 mL of a 2 M solution). The mixture thus
obtained was extracted with ethyl acetate (3 × 10 mL), and the com-
bined organic phases were then dried (MgSO4), filtered, and concen-
trated under reduced pressure. The ensuing yellow oil was subjected to
flash chromatography (silica, 1:9 → 1:1 v/v ethyl acetate/hexane
gradient elution), and concentration of the relevant fractions (Rf = 0.4 in
1:1 v/v ethyl acetate/hexane) afforded the Cbz-derivative of compound
11 (46 mg, 80%) as a white foam and a 1:1 mixture of rotamers:
1HNMR(CDCl3, 400MHz)δ7.89 (s, 1H), 7.63 (d, J = 7.6 Hz, 0.5H), 7.44
(d, J = 7.6 Hz, 0.5H), 7.32 (m, 1H), 7.21 (m, 4H), 7.05 (m, 1.5H), 6.86
(t, J = 7.6 Hz, 0.5H), 5.66 (s, 0.5H), 5.53 (s, 0.5H), 5.25 (d, J = 12.0 Hz,
0.5H), 5.12 (m, 1H), 4.96 (d, J = 12.0 Hz, 0.5H), 3.80 (dd, J = 12.0 and
6.0 Hz, 0.5H), 3.70 (dd, J = 12.0 and 6.0 Hz, 0.5H), 3.02 (m, 1H), 2.65
(m, 2H), 2.38 (s, 1H), 2.01−1.80 (complex m, 4.5H), 1.51 (m, 0.5H);
13C NMR (CDCl3, 100 MHz) δ 155.3 (C), 155.1 (C), 136.6 (C, two
overlapping signals), 136.3(1) (C), 136.2(8) (C), 135.9 (C), 135.8 (C),
128.4 (CH), 128.2(1) (CH), 128.1(7) (CH), 128.0 (CH), 127.6 (CH),
127.4 (CH), 125.8 (C), 125.6 (C), 121.0 (CH), 120.9 (CH), 119.2
(CH), 119.1 (CH), 118.5 (CH), 117.9 (CH), 110.5 (CH), 110.4 (CH),
108.8 (C), 108.3 (C), 67.0 (CH2), 66.7 (CH2), 43.9 (CH), 43.6 (CH),
36.8 (CH2), 36.6 (CH2), 32.3 (CH2), 32.0 (CH2), 31.9 (CH2), 31.7
(CH2), 28.1 (CH2), 28.0 (CH2), 25.2 (CH), 25.1 (CH); IR νmax 3398,
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193 (M+•, <1), 178 (3), 162 (6), 95 (94), 77 (12), 68 (100); HRMS
(M + H)+ calcd for C10H11NO3 194.0817, found 194.0815.
123.8 (C), 116.6 (C), 103.2 (C), 40.5 (CH2), 39.2 (CH), 33.9 (CH2);
IR νmax 3104, 3041, 2955, 2222, 1678, 1588, 1424, 1410, 1318, 1136,
999, 958, 932, 912 cm−1; MS (EI, 70 eV) m/z 273 (M+•, 93), 230 (41),
193 (100), 165 (40), 104 (15), 91 (14), 65 (14); HRMS M+• calcd for
C9H8INO 272.9651, found 272.9651.
Compound 14. A magnetically stirred solution of ketone 12 (4.00 g,
26.8 mmol) in toluene/DMSO (57 mL of a 2:1 v/v mixture) was treated
with p-TsOH·H2O (1.53 g, 8.04 mmol) and IBX (10.50 g, 37.5 mmol)
and the ensuing mixture heated at 55 °C for 17 h before being cooled to
18 °C and diluted with diethyl ether (200 mL) followed by NaHCO3
(250 mL of a 5% aqueous solution). The mixture thus obtained was
filtered through diatomaceous earth, and the solids thus retained were
washed with diethyl ether (3 × 30 mL). The separated aqueous phase
was extracted with ethyl acetate (3 × 150 mL), and the combined
organic phases themselves washed with brine (1 × 150 mL) before being
dried (MgSO4), filtered, and concentrated under reduced pressure. The
ensuing black oil was subjected to flash column chromatography (silica,
3:7 v/v ethyl acetate/hexane elution), and concentration of the relevant
fractions (Rf = 0.3) afforded the title compound 14 (2.12 g, 54%) as a
white, crystalline solid: mp 56−58 °C; 1H NMR (CDCl3, 400 MHz) δ
6.99 (m, 1H), 6.10 (dm, J = 10.0 Hz, 1H), 5.96 (d, J = 0.8 Hz, 1H), 5.82
(d, J = 0.8 Hz, 1H), 3.01 (m, 1H), 2.65−2.45 (m, 4H); 13C NMR
(CDCl3, 100 MHz) δ 196.6 (C), 147.8 (CH), 130.5 (CH), 129.9
(CH2), 125.0 (C), 117.0 (C), 41.7 (CH2), 39.5 (CH), 30.2 (CH2); IR
νmax 3041, 2929, 2221, 1681, 1619, 1430, 1407, 1388, 1247, 1167, 1140,
1086, 948, 915, 883 cm−1; MS (EI, 70 eV) m/z 147 (M+•, 61), 119 (30),
105 (20), 104 (20), 69 (33), 68 (100); HRMS M+• calcd for C9H9NO
147.0684, found 147.0685.
Compound 17. A magnetically stirred solution of iodide 15 (2.12 g,
6.64 mmol) and o-iodonitrobenzene (3.31 g, 13.29 mmol) in DMSO
(14 mL) was treated with Pd2(dba)3 (304 mg, 0.332 mmol) and Cu
powder (2.11 g, 32.2 g-atom). The resulting mixture was heated at 55 °C
for 2 h, cooled to 18 °C, diluted with diethyl ether (100 mL), and filtered
through diatomaceous earth. The solids thus retained were washed with
diethyl ether (3 × 30 mL) and the combined filtrates washed with water
(2 × 100 mL). The combined aqueous phases were, in turn, extracted
with ethyl acetate (3 × 50 mL). The combined organic phases were
dried (MgSO4) before being filtered and concentrated under reduced
pressure to afford a light-yellow residue. Subjection of this material to
flash column chromatography (silica, 1:9 → 1:1 v/v ethyl acetate/
hexane gradient elution) and concentration of the relevant fractions
(Rf = 0.2 in 1:1 v/v ethyl acetate/hexane) afforded the title compound 17
(1.48 g, 71%) as a white foam and as a 1:1 mixture of diastereoisomers:
1H NMR (CDCl3, 400 MHz) δ 8.04 (d, J = 8.4 Hz, 1H), 7.62 (t, J = 7.2
Hz, 1H), 7.50 (t, J = 7.2 Hz, 1H), 7.25 (m, 1H), 6.98 (m, 1H), 3.87 (s,
1.5H), 3.86 (s, 1.5H), 3.73 (d, J = 4.2 Hz, 0.5H), 3.62 (d, J = 4.6 Hz,
0.5H), 3.03 (m, 1H), 2.80−2.58 (complex m, 4H); 13C NMR (CDCl3,
100 MHz) δ 193.3 (C, two overlapping signals), 164.8(3) (C), 164.7(7)
(C), 148.2 (C, two overlapping signals), 143.8 (CH), 143.7 (CH), 139.4
(C), 139.3 (C), 133.5(1) (CH), 133.4(8) (CH), 131.5 (CH, two
overlapping signals), 130.9 (C), 130.8 (C), 129.1 (CH, two overlapping
signals), 124.1 (CH, two overlapping signals), 114.4 (C, two
overlapping signals), 53.6 (CH3, two overlapping signals), 42.1 (CH,
two overlapping signals), 41.6 (CH2), 40.4 (CH2), 34.9 (CH), 34.7
(CH), 29.8 (CH2), 28.7 (CH2); IR νmax 3034, 2956, 2250, 1747, 1682,
1608, 1573, 1524, 1479, 1435, 1354, 1262, 1218, 1182, 1144, 1113,
1047, 1005, 956, 909, 855 cm−1; MS (EI, 70 eV) m/z 314 (M+•, 4%),
284 (10), 268 (21), 216 (70), 199 (22), 198 (71), 185 (57), 170 (68),
169 (100), 162 (36), 145 (37), 134 (51), 115 (50), 104 (53), 77 (38);
HRMS M+• calcd for C16H14N2O5 314.0903, found 314.0907.
Compound 18. A magnetically stirred solution of iodide 16 (1.23 g,
4.50 mmol) and o-iodonitrobenzene (2.24 g, 9.00 mmol) in DMSO
(9 mL) was treated with Pd2(dba)3 (329 mg, 0.36 mmol) and Cu
powder (1.43 g, 22.5 g-atom). The resulting mixture was heated at 50 °C
for 1.5 h and then cooled to 18 °C before being diluted with diethyl ether
(100 mL) and then filtered through a pad of diatomaceous earth. The
solids thus retained were washed with diethyl ether (3 × 30 mL), and the
combined filtrates were themselves washed with water (2 × 100 mL).
The combined aqueous phases were, in turn, extracted with ethyl acetate
(3 × 50 mL) and the combined organic phases then dried (MgSO4),
filtered, and concentrated under reduced pressure to give a yellow oil.
Subjection of this oil to flash column chromatography (silica, 1:9 → 3:7
v/v ethyl acetate/hexane gradient elution) and concentration of the
relevant fractions (Rf = 0.4 in 3:7 v/v ethyl acetate/hexane) afforded the
title compound 18 (978 mg, 81%) as a white, crystalline solid: mp 87−89
°C; 1H NMR (CDCl3, 400 MHz) δ 8.03 (d, J = 8.4 Hz, 1H), 7.62 (m,
1H), 7.50 (m, 1H), 7.25 (m, 1H), 7.00 (m, 1H), 5.99 (s, 1H), 5.88
(s, 1H), 3.18 (m, 1H), 2.90−2.60 (complex m, 4H); 13C NMR (CDCl3,
100 MHz) δ 193.7 (C), 148.3 (C), 143.7 (CH), 139.6 (C), 133.5 (CH),
131.5 (C), 131.0 (C), 130.9 (CH2), 129.2 (CH), 124.6 (C), 124.3 (C),
116.9 (C), 41.8 (CH2), 39.1 (CH), 30.7 (CH2); IR νmax 2873, 2219,
1679, 1522, 1350, 1184, 945, 854 cm−1; MS (EI, 70 eV) m/z 268 (M+•,
2), 238 (26), 222 (100), 169 (32), 162 (78), 145 (46), 134 (48), 115
(35), 106 (36), 104 (43), 77 (43); HRMS M+• calcd for C15H12N2O3
268.0848, found 268.0846.
Compound 15. A magnetically stirred solution of enone 13 (3.64 g,
18.84 mmol) in CHCl3/pyridine (50 mL of a 1:1 v/v mixture)
maintained at 18 °C was treated dropwise with a solution of molecular
iodine (19.1 g, 75.4 mmol) in CHCl3/pyridine (50 mL of a 1:1 v/v
mixture). The solution thus obtained was stirred for 4 h and then diluted
with diethyl ether (500 mL) before being washed sequentially with
water (1 × 300 mL), HCl (1 × 300 mL of a 1 M aqueous solution) and
Na2S2O3 (1 × 500 mL of a 5% w/v aqueous solution). The combined
aqueous phases were extracted with ethyl acetate (3 × 200 mL) and the
combined organic phases washed with brine (1 × 200 mL) before being
dried (MgSO4), filtered, and concentrated under reduced pressure. The
ensuing black oil was subjected to flash column chromatography (silica,
3:7 → 1:1 v/v ethyl acetate/hexane gradient elution) and concentration
of the relevant fractions (Rf = 0.5 in 1:1 v/v ethyl acetate/hexane)
afforded the title compound 15 (5.19 g, 85%) as a pale-yellow oil and as a
1
1:1 mixture of diastereoisomers: H NMR (CDCl3, 400 MHz) δ 7.72
(t, J = 4.4 Hz, 1H), 3.83 (s, 1.5H), 3.83 (s, 1.5H), 3.66 (d, J = 4.8 Hz,
0.5H), 3.62 (d, J = 5.2 Hz, 0.5H), 2.96−2.81 (complex m, 2H), 2.66
(d, J = 2.8 Hz, 0.5H), 2.62 (t, J = 2.8 Hz, 0.5H), 2.56 (m, 2H); 13C NMR
(CDCl3, 100 MHz) δ 189.4 (C, two overlapping signals), 164.6 (C),
164.5 (C), 156.2 (CH), 156.0 (CH), 114.0 (C, two overlapping signals),
103.3 (CH), 103.1 (C), 53.9 (CH3), 53.8 (CH3), 41.9(4) (CH), 41.8(8)
(CH), 40.5 (CH2), 39.2 (CH2), 35.1 (CH), 35.0 (CH), 33.3 (CH2),
32.2 (CH2); IR νmax 2955, 2250, 1746, 1686, 1594, 1435, 1330, 1260,
1000, 940 cm−1; MS (EI, 70 eV) m/z 319 (M+•, 5), 221 (61), 220 (94),
194 (30), 166 (13), 100 (27), 94 (100), 66 (34), 65 (40); HRMS M+•
calcd for C10H10INO3 318.9705, found 318.9671.
Compound 16. A magnetically stirred solution of enone 14 (1.50 g,
10.20 mmol) in CHCl3/pyridine (50 mL of a 1:1 v/v mixture)
maintained at 18 °C was treated dropwise with a solution of molecular
iodine (10.3 g, 40.8 mmol) in CHCl3/pyridine (50 mL of a 1:1 v/v
mixture). The resulting solution was stirred at 18 °C for 2.5 h before
being diluted with diethyl ether (400 mL) and then washed sequentially
with water (1 × 150 mL), HCl (1 × 150 mL of a 1 M aqueous solution),
and Na2S2O3 (1 × 150 mL of a 5% w/v aqueous solution). The combined
aqueous phases were extracted with ethyl acetate (3 × 100 mL), and the
combined organic phases were then washed with brine (1 × 200 mL), before
being dried (MgSO4), filtered, and concentrated under reduced
pressure. The ensuing black oil was subjected to flash column chroma-
tography (silica, 3:7 v/v ethyl acetate/hexane elution) and concen-
tration of the relevant fractions (Rf = 0.4) afforded the title iodide 16
(2.09 g, 75%) as a white, crystalline solid: mp 108.5−110 °C; 1H NMR
(CDCl3, 400 MHz) δ 7.74 (t, J = 4.4 Hz, 1H), 5.99 (s, 1H), 5.83 (s, 1H),
3.08 (m, 1H), 2.92 (dm, J = 16.8 Hz, 1H), 2.71 (m, 1H), 2.62 (m, 2H);
13C NMR (CDCl3, 100 MHz) δ 189.6 (C), 156.3 (CH), 131.1 (CH2),
Compound 19. A magnetically stirred mixture of compound 17
(230 mg, 0.73 mmol), p-TsOH·H2O (557 mg, 2.93 mmol), and Raney-
cobalt (460 mg, 200% w/w) in THF (15 mL) was heated at reflux under
an atmosphere of hydrogen (1 atm) for 18 h. The cooled reaction
mixture was filtered through diatomaceous earth, and the solids thus
retained were washed with methanol (3 × 30 mL). The combined
filtrates were concentrated under reduced pressure to afford a light-
yellow oil that was dissolved in dichloromethane (25 mL). The solution
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thus formed was washed with NaHCO3 (40 mL, saturated aqueous
solution) and the separated aqueous layer extracted with dichloro-
methane (3 × 25 mL). The combined organic layers were then dried
(MgSO4), filtered, and concentrated under reduced pressure to afford a
light-yellow oil that was subjected to flash column chromatography
(silica, 1:19 → 1:9 v/v methanol/dichloromethane gradient elution) to
afford compound 19 (93 mg, 47%) as a white, crystalline solid and as a 1:1
mixture of diastereoisomers: mp 78−90 °C; Rf = 0.2 (in 1:4 v/v
methanol/dichloromethane); 1H NMR (CDCl3, 400 MHz) δ 8.05
(s, 0.5H), 7.93 (s, 0.5H), 7.51 (t, J = 6.8 Hz, 1H), 7.31 (t, J = 7.6 Hz, 1H),
7.11 (m, 2H), 4.43 (m, 1H), 3.77 (s, 1.5H), 3.70 (s, 1.5H), 3.23 (dd, J =
17.2 and 7.2 Hz, 0.5H), 3.11 (d, J = 13.2 Hz, 0.5H), 3.02−2.60 (complex
m, 4H), 2.43 (m, 1H), 2.18 (tm, J = 3.2 Hz, 1H), 1.98 (tm, J = 2.8 Hz,
0.5H), 1.91 (s, 1H), 1.76 (m, 0.5H); 13C NMR (CDCl3, 100 MHz) δ
174.9 (C), 173.9 (C), 136.0(8) (C), 136.0(5) (C), 135.2(5) (C),
135.2(2) (C), 126.1 (C), 125.8 (C), 121.3 (CH), 121.2 (CH), 119.6
(CH), 119.5 (CH), 117.6 (CH), 117.3 (CH), 110.6 (CH), 110.5 (CH),
110.0 (C), 109.9 (C), 52.0 (CH3), 51.6 (CH3), 46.4 (CH), 46.2 (CH),
44.1 (CH), 43.8 (CH), 38.5(0) (CH2), 38.4(6) (CH2), 33.1 (CH2),
30.4 (CH2), 29.6 (CH2), 28.8 (CH), 28.0 (CH), 25.1 (CH2); IR νmax
3390, 3053, 2925, 2853, 1724, 1619, 1587, 1454, 1434, 1200, 1106,
1064, 1011, 924 cm−1; MS (ESI, +ve ion) m/z 271 [(M + H)+, 100)],
170 (80); HRMS (M + H)+ calcd for C16H18N2O2 271.1447, found
271.1448.
Epimeric Forms of Compound 20. A magnetically stirred mixture
of nitrile 18 (24 mg, 0.09 mmol), p-TsOH·H2O (51 mg, 0.27 mmol),
and Raney-cobalt (50 mg, 200% w/w) in THF (3 mL) was heated at
reflux under an atmosphere of hydrogen (1 atm) for 18 h. The cooled
reaction mixture was then filtered through diatomaceous earth and the
solids thus retained washed with methanol (3 × 10 mL). The combined
filtrates were concentrated under reduced pressure to afford a light-
yellow oil that was subjected to flash column chromatography (silica,
1:19 → 1:9 v/v methanol/dichloromethane gradient elution) and thereby
afforded two fractions, A and B.
Concentration of fraction A [Rf = 0.5(1) in 1:4 v/v methanol/
dichloromethane] afforded the first epimeric form of compound 20
(9 mg, 44%) as a clear, colorless oil: 1H NMR (CD3OD, 400 MHz) δ
7.48 (dd, J = 7.2 and 0.8 Hz, 1H), 7.28 (dd, J = 7.2 and 1.2 Hz, 1H), 7.01
(m, 2H), 4.46 (t, J = 2.4 Hz, 1H), 3.22 (dd, J = 17.6 and 2.8 Hz, 1H), 2.86
(dd, J = 12.8 and 4.0 Hz, 1H), 2.75 (d, J = 17.6 Hz, 1H), 2.45 (d, J = 13.2
Hz, 1H), 2.37 (dt, J = 13.2 and 3.6 Hz, 1H), 2.17 (m, 1H), 1.84 (m, 1H),
1.72 (dm, J = 13.2 Hz, 1H), 1.28 (d, J = 7.2 Hz, 3H) (signals due to NH
protons not observed); 13C NMR (CD3OD, 100 MHz) δ 138.6 (C),
138.0 (C), 127.2 (C), 121.8 (CH), 120.0 (CH), 118.3 (CH), 111.7
(CH), 107.2 (C), 46.2 (CH), 43.2 (CH2), 35.8 (CH), 33.1 (CH), 31.4
(CH2), 27.9 (CH2), 19.4 (CH3); IR νmax 3396, 3220, 2907, 1457, 1324,
1069, 920 cm−1; MS (ESI, +ve ion) m/z 227 [(M + H)+, 100]; HRMS
(M + H)+ calcd for C15H18N2 227.1548, found 227.1549.
Concentration of fraction B [Rf = 0.4(9) in 1:4 v/v methanol/
dichloromethane] afforded the second epimeric form of compound 20
(8 mg, 40%) as a clear, colorless oil: 1H NMR (CD3OD, 400 MHz) δ
7.46 (dd, J = 7.2 and 1.6 Hz, 1H), 7.26 (dd, J = 7.2 and 1.2 Hz, 1H), 7.00
(m, 2H), 4.36 (t, J = 3.2 Hz, 1H), 2.86 (m, 2H), 2.52 (dd, J = 12.0 and 1.2
Hz, 1H), 2.19 (m, 2H), 2.12 (dt, J = 12.8 and 3.2 Hz, 1H), 1.98 (m, 2H),
0.94 (d, J = 7.2 Hz, 3H) (signals due to NH protons not observed); 13C
NMR (CD3OD, 100 MHz) δ 138.0 (C), 137.9 (C), 127.3 (C), 121.6
(CH), 119.8 (CH), 118.2 (CH), 111.5 (CH), 109.3 (C), 45.2 (CH and
CH2, two overlapping signals), 36.2 (CH), 35.0 (CH2), 33.3 (CH), 23.2
(CH2), 17.8 (CH3); IR νmax 3397, 3215, 2921, 1617, 1453, 1320, 1291,
1238, 1073 cm−1; MS (ESI, +ve ion) m/z 227 [(M + H)+, 100]; HRMS
(M + H)+ calcd for C15H18N2 227.1548, found 227.1547.
ethyl acetate/hexane gradient elution) afforded, after concentration of
the relevant fractions (Rf = 0.2 in 1:19 v/v methanol/dichloromethane),
the title compound 2112 (222 mg, 78%) as a light-brown oil: 1H NMR
(CDCl3, 400 MHz) δ 8.50 (broad s, 1H), 7.60 (dd, J = 6.2 and 2.0 Hz,
1H), 7.28 (dd, J = 6.4 and 1.2 Hz, 1H), 7.08 (m, 2H), 4.69 (t, J = 5.2 Hz,
1H), 4.31 (m, 1H), 3.43 (s, 3H), 3.32 (s, 3H), 3.03 (dd, J = 17.6 and 6.8
Hz, 1H), 2.98 (dd, J = 13.2 and 5.6 Hz, 1H), 2.68 (dd, J = 11.6 and 4.0
Hz, 1H), 2.58 (d, J = 17.2 Hz, 1H), 2.40−2.14 (complex m, 4H), 2.08
(m, 1H), 1.81 (dm, J = 12.4 Hz, 1H), 1.58 (dm, J = 12.8 Hz, 1H); 13C
NMR (CDCl3, 100 MHz) δ 137.0 (C), 135.7 (C), 128.0 (C), 120.6
(CH), 119.5 (CH), 118.3 (CH), 110.4 (CH), 106.3 (C), 103.1 (CH),
58.7 (CH2), 53.5 (CH3), 53.2 (CH3), 51.6 (CH), 45.4 (CH2), 32.9
(CH2), 32.7 (CH2), 29.1 (CH2), 25.0 (CH); IR νmax 3397, 3299, 3054,
2926, 2831, 1653, 1619, 1583, 1562, 1461, 1427, 1362, 1330, 1309,
1278, 1231, 1191, 1129, 1071, 1013, 1001, 964, 930, 900 cm−1; MS (EI,
70 eV) m/z 300 (M+•, 12), 269 (7), 225 (100), 194 (49), 182 (8), 168
(28), 167 (22), 144 (10), 75 (13); HRMS M+• calcd for C18H24N2O2
300.1838, found 300.1838.
Compound 22. A magnetically stirred solution of acetal 21 (85 mg,
0.28 mmol), ethanethiol (6.3 mL, 84.9 mmol), and 3 Å molecular sieves
(0.5 g) in dichloromethane (14 mL) maintained at 0 °C was treated with
BF3·OEt (354 μL, 2.8 mmol). The ensuing mixture was warmed to
18 °C, stirred at this temperature for 48 h, and then treated with
NaHCO3 (20 mL of a saturated aqueous solution). The ensuing mixture
was filtered through diatomaceous earth, and the solids thus retained
were washed with dichloromethane (3 × 20 mL). The combined organic
phases were then dried (MgSO4) before being filtered and concentrated
under reduced pressure. Subjection of the ensuing light-yellow oil to
column chromatography (silica, 1:19 → 1:0 v/v ethyl acetate/hexane
gradient elution) and concentration of the relevant fractions (Rf = 0.5 in
ethyl acetate) afforded the title compound 2212 (84 mg, 83%) as a
yellow oil: 1H NMR (CDCl3, 400 MHz) δ 7.93 (s, 1H), 7.54 (d, J = 8.8
Hz, 1H), 7.29 (d, J = 8.8 Hz, 1H), 7.10 (m, 2H), 4.21 (m, 1H), 4.06
(m, 1H), 3.10 (m, 1H), 3.05 (dd, J = 17.6 and 7.2 Hz, 1H), 2.81−2.55
(complex m, 5H), 2.49 (m, 1H), 2.37 (m, 1H), 2.30−1.96 (complex m,
2H), 1.86−1.50 (complex m, 4H), 1.30 (t, J = 7.2 Hz, 3H), 1.25
(t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 136.7 (C), 135.7
(C), 128.0 (C), 120.9 (CH), 119.7 (CH), 118.4 (CH), 110.3 (CH),
107.4 (C), 62.9 (CH2), 51.3 (CH), 49.8 (CH), 45.0 (CH2), 33.2 (CH2),
32.9 (CH2), 29.2 (CH2), 25.4 (CH), 24.6 (CH2), 24.4 (CH2) 14.6
(CH3, two overlapping signals); IR νmax 3399, 3054, 2923, 1618, 1583,
1562, 1458, 1474, 1328, 1308, 1264, 1230, 1157, 1142, 1099, 1084,
1055, 1012, 995, 970 cm−1; MS (EI, 70 eV) m/z 360 (M+•, 1), 225
(100), 194 (38), 182 (9), 169 (19), 168 (30), 167 (22), 144 (9), 82
(10); HRMS M+• calcd for C20H28N2S2 360.1694, found 360.1695.
Compound 23. A magnetically stirred solution of DMSTF1c,16 (45
mg, 0.23 mmol) in dichloromethane (3 mL) containing 4 Å molecular
sieves (100 mg of anhydrous material) maintained at 0 °C under an
atmosphere of nitrogen was treated with a solution of compound 22
(39 mg, 0.11 mmol) in dichloromethane (10 mL). The ensuing mixture
was stirred magnetically at 0 °C for 3 h and then concentrated under
reduced pressure to afford a light-yellow oil. Subjection of this material
to column chromatography (silica, 1:19 v/v methanol/dichloro-
methane) and concentration of the relevant fractions (Rf = 0.2)
afforded the title compound 2312 (21 mg, 63%) as a pale-yellow oil:
1H NMR (CDCl3, 400 MHz) δ 7.51 (d, J = 7.2 Hz, 1H), 7.35 (m, 2H), 7.19
(t, J = 7.2 Hz, 1H), 4.16 (dd, J = 11.2 and 5.6 Hz, 1H), 3.91 (m, 1H), 3.45
(dd, J = 11.6 and 5.6 Hz, 1H), 3.30 (m, 1H), 3.08 (m, 3H), 2.70 (m, 1H),
2.47 (m, 1H), 2.09 (m, 1H), 2.02−1.78 (complex m, 3H), 1.59 (m, 1H),
1.05 (dm, J = 12.4 Hz, 1H), 0.93 (t, J = 7.6 Hz, 3H); 13C NMR (CDCl3,
100 MHz) δ 189.7 (C), 155.2 (C), 139.8 (C), 128.3 (CH), 124.8 (CH),
124.1 (CH), 119.9 (CH), 70.1 (CH), 69.1 (C), 64.9 (CH2), 45.4 (CH
and CH2, two overlapping signals), 31.0 (CH2), 30.5 (CH2), 28.3 (CH),
27.3 (CH2), 26.2 (CH2), 14.5 (CH3); IR νmax 2926, 2864, 1659, 1566,
1455, 1329, 1288, 1194, 1116, 1096, 1071, 1016, 958, 927 cm−1; MS (EI,
70 eV) m/z 298 (M+•, 72), 284 (18), 269 (23), 267 (20), 240 (50), 237
(100), 226 (23), 194 (54), 180 (29), 167 (25), 156 (33), 95 (66);
HRMS M+• calcd for C18H22N2S 298.1504, found 298.1505.
Compound 21. A magnetically stirred solution of amine 11 (202
mg, 0.95 mmol) and bromoacetaldehyde dimethyl acetal (169 μL, 1.43
mmol) in 1,4-dioxane (12 mL) was treated with K2CO3 (197 mg, 1.43
mmol) and the resulting mixture heated at reflux for 16 h. The cooled
reaction mixture was concentrated under reduced pressure and then
diluted with dichloromethane (40 mL) and washed with NaHCO3
(20 mL of a saturated aqueous solution) before being dried (MgSO4),
filtered, and concentrated under reduced pressure to give a yellow oil.
Subjection of this material to column chromatography (silica, 1:19 →1:1 v/v
Compound 24. A magnetically stirred solution of imine 23 (15 mg,
0.05 mmol) in ethanol was treated with Raney Ni (excess) and the
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ensuing mixture heated at reflux for 3 h. The cooled reaction mixture was
filtered through diatomaceous earth and the solids retained were washed
with ethanol (2 × 10 mL). The combined filtrates were concentrated
under reduced pressure to give a yellow oil that was subjected to column
chromatography (silica, 1:9 → 1:10 v/v diethylamine/diethyl ether
gradient elution). Concentration of the relevant fractions (Rf = 0.1 in
1:49 v/v diethylamine/diethyl ether) then gave the title compound
2412,15b (10 mg, 81%) as a pale-yellow oil: 1H NMR (CDCl3, 500 MHz)
δ 7.04 (m, 2H), 6.75 (t, J = 7.5 Hz, 1H), 6.62 (d, J = 8.5 Hz, 1H), 3.77
(t, J = 8.0 Hz, 1H), 3.63 (broad s, 1H), 3.36 (broad s, 1H), 3.13 (m, 1H),
3.03 (m, 1H), 2.87 (m, 1H), 2.51 (m, 1H), 2.40 (dt, J = 15.5 and 8.0 Hz,
1H), 1.98−1.83 (complex m, 5H), 1.69−1.50 (complex m, 3H); 13C
NMR (CDCl3, 125 MHz) δ 149.4 (C), 133.6 (C), 127.7 (CH), 122.2
(CH), 119.1 (CH), 109.6 (CH), 65.1 (CH), 62.3 (CH), 54.0 (CH2),
52.7 (C), 47.7 (CH2), 42.3 (CH2), 37.4 (CH2), 29.1 (CH2), 26.6 (CH2),
23.2 (CH); IR νmax 3196, 2922, 1605, 1483, 1464, 1359, 1310, 1284,
1249, 1118, 1080, 1020, 963, 928 cm−1; MS (EI, 70 eV) m/z 240 (M+•,
46), 212 (10), 143 (26), 130 (15), 110 (100), 96 (17), 82 (12), 55 (14);
HRMS M+• calcd for C16H20N2 240.1626, found 240.1625.
(d, J = 8.0 Hz, 0.3H), 7.30 (m, 1H), 7.10 (m, 2H), 6.20 (m, 0.7H), 5.23
(m, 0.3H), 4.38 (dd, J = 13.2 and 5.6 Hz, 0.3H), 3.42 (dd, J = 5.6 and
13.2 Hz, 0.7H), 3.16 (dd, J = 6.8 and 17.2 Hz, 1H), 3.03 (dt, J = 3.6 and
13.6 Hz, 1H), 2.73 (m, 1H), 2.53 (m, 1H), 2.43 (s, 0.9H), 2.01 (s, 2.1H),
2.10−1.88 (complex m, 3H), 1.66 (m, 1H); 13C NMR (CDCl3, 100 MHz)
δ 168.7 (C), 167.9 (C), 136.8 (C), 136.3 (C, two overlapping signals),
136.0 (C), 126.0 (C), 125.8 (C), 121.5 (CH, two overlapping signals),
119.8 (CH), 119.7 (CH), 119.0 (CH), 117.5 (CH), 110.8 (CH), 110.3
(CH), 109.7 (C), 108.6 (C), 47.0 (CH), 40.6 (CH), 39.6 (CH2, two
overlapping signals), 34.4 (CH2), 33.4 (CH2), 32.7 (CH2), 32.1 (CH2),
32.0 (CH2), 28.6 (CH2), 25.7 (CH, two overlapping signals), 22.0
(CH3), 21.8 (CH3); IR νmax 3227, 2924, 1609, 1425, 1360, 1330, 1270,
1247, 1216, 1194, 1121, 1072, 1023, 1000, 986 cm−1; MS (EI, 70 eV)
m/z 254 (M+•, 71), 239 (3), 211 (9), 195 (47), 182 (21), 169 (50), 168
(100), 167 (40), 143 (10), 87 (30), 72 (14); HRMS M+• calcd for
C16H18N2O 254.1419, found 254.1416.
ASSOCIATED CONTENT
■
S
* Supporting Information
Compound 25. A magnetically stirred mixture of amine 11 (140 mg,
0.66 mmol), dichloromethane (6.6 mL), and NaOH (3.6 mL of a 1.0 M
aqueous solution) was treated, dropwise, with a solution of α-chloro-
acetyl chloride (105 μL, 1.32 mmol) in dichloromethane (3.6 mL). The
biphasic reaction mixture was stirred at 18 °C for 5 h after which time the
organic phase was separated and the aqueous one extracted with
dichloromethane (3 × 10 mL). The combined organic phases were then
dried (MgSO4), filtered, and concentrated under reduced pressure to
afford a light-yellow oil that was subjected to flash column chroma-
tography (neutral alumina, 1:9 → 1:1 v/v ethyl acetate/hexane gradient
elution). Concentration of the relevant fractions (Rf = 0.3 in 1:1 v/v
ethyl acetate/hexane) afforded the title compound 2510 (120 mg, 63%)
as a colorless, crystalline solid and as a 4:1 mixture of rotamers: mp 178−
179 °C; 1H NMR (CDCl3, 400 MHz) δ 8.14 (s, 0.2H), 8.02 (s, 0.8H),
7.60 (d, J = 7.2 Hz, 0.8H), 7.43 (d, J = 8.0 Hz, 0.2H), 7.33 (d, J = 7.6 Hz,
0.2H), 7.30 (d, J = 8.4 Hz, 0.8H), 7.11 (m, 2H), 6.11 (s, 0.8H), 5.26 (s,
0.2H), 4.40 (m, 0.4H), 3.99 (q, J = 12.0 Hz, 1.6H), 3.44−2.20 (complex
m, 3H), 2.01 (m, 3H), 1.67 (m, 3H); 13C NMR (CDCl3, 100 MHz) δ
164.7 (C, two overlapping signals), 137.0 (C), 136.4 (C, two over-
lapping signals), 135.9 (C), 125.9 (C, two overlapping signals), 121.7
(CH, two overlapping signals), 120.0 (CH), 119.9 (CH), 118.9 (CH),
117.5 (CH), 110.9 (CH), 110.4 (CH), 109.1 (C, two overlapping
signals), 47.2 (CH), 41.7 (CH2), 41.6 (CH), 41.5 (CH2), 39.5 (CH2,
two overlapping signals), 33.4 (CH2), 32.6 (CH2), 32.0 (CH2), 31.9
(CH2), 28.7 (CH2), 28.6 (CH2), 25.7 (CH), 25.7 (CH); IR νmax 3401,
2924, 2853, 1630, 1455, 1378, 1071 cm−1; MS (EI, 70 eV) m/z 290 and
288 (M+•, 52 and 17), 239 (22), 193 (53), 180 (27), 169 (40), 168
(100), 167 (50), 149 (27), 97 (33), 83 (35), 71 (48), 57 (65); HRMS
Crystallographic data (CIF), anisotropic displacement ellipsoid plot,
and unit cell packing diagram derived from the single-crystal analysis
of compound 18; 1H and 13C NMR spectra for compounds 4−25,
27, the Cbz-derivative of compound 10, and the Cbz-derivative of
compound 11. This material is available free-of-charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: mgb@rsc.anu.edu.au.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the Australian Research Council and the Institute of
Advanced Studies for generous financial support.
■
REFERENCES
■
(1) See, for example: (a) Jiricek, J.; Blechert, S. J. Am. Chem. Soc. 2004,
126, 3534. (b) Bennasar, M.-L.; Roca, T.; García-Díaz, D. J. Org. Chem.
2008, 73, 9033 and references cited therein. (c) Martin, C. L.;
Nakamura, S.; Otte, R.; Overman, L. E. Org. Lett. 2011, 13, 138.
(2) (a) Mori, M. Heterocycles 2010, 81, 259. (b) Cannon, J. S.;
Overman, L. E. Angew. Chem., Int. Ed. 2012, 51, 4288.
(3) For the application of related protocols to total syntheses of the
Aspidosperma alkaloids limaspermidine and 1-acetylaspidoalbidine, see:
Tan, S. H.; Banwell, M. G.; Willis, A. C.; Reekie, T. A. Org. Lett. 2012,
DOI: 10.1021/ol3026846.
M
+• calcd for C16H1735ClN2O 288.1029, found 288.1030.
Compound 26. A magnetically stirred solution of acetamide 25
(80 mg, 0.28 mmol) in acetone (5 mL) was treated with NaI (410 mg,
2.8 mmol) and the resulting solution heated at reflux for 2 h, cooled to
18 °C, and concentrated under reduced pressure to give a white solid.
This material was dissolved in ethyl acetate (10 mL) and the resulting
solution washed with water (1 × 5 mL) before being dried (MgSO4),
filtered, and concentrated under reduced pressure to give compound 26
(97 mg, 92%) as a yellow oil (Rf = 0.3 in 1:1 v/v ethyl acetate/hexane).
This unstable material was immediately treated with silver triflate in an
unsuccessful attempt to effect a Heathcock annulation reaction (see text
for details).
(4) Kim, S. H.; Kim, K. H.; Kim, J. N. Adv. Synth. Catal. 2011, 353,
3335.
(5) Kim, S. H.; Kim, E. S.; Kim, T. H.; Kim, J. N. Tetrahedron Lett.
2009, 50, 6256.
(6) (a) Nicolaou, K. C.; Montagnon, T.; Baran, P. S. Angew. Chem., Int.
Ed. 2002, 41, 993. (b) Nicolaou, K. C.; Gray, D. L. F.; Montagnon, T.;
Harrison, S. T. Angew. Chem., Int. Ed. 2002, 41, 996.
(7) Johnson, C. R.; Adams, J. P.; Braun, M. P.; Senanayake, C. B. W.;
́
Wovkulich, P. M.; Uskokovic, M. R. Tetrahedron Lett. 1992, 33, 917.
Compound 27. A magnetically stirred solution of amide 25 (53 mg,
0.18 mmol) and AIBN (6 mg, 0.02 mmol) in benzene (12.3 mL) was
treated, at 18 °C, with tri-n-butyltin hydride (148 μL, 0.54 mmol). The
ensuing mixture was heated at reflux for 1 h, cooled to 18 °C, and
concentrated under reduced pressure to give a light-yellow oil. This oil
was subjected to flash column chromatography (silica, 0:1 → 1:4 v/v
ethyl acetate/hexane gradient elution) and concentration of the relevant
fractions (Rf = 0.1 in 1:1 v/v ethyl acetate/hexane) afforded the title
compound 2710 (41 mg, 89%) as a white, crystalline solid and 5:2
(8) Banwell, M. G.; Jones, M. T.; Reekie, T. A. Chem. New Zealand
2011, 75, 122.
(9) Nitrile 9 has been obtained previously via an organo-catalyzed
Diels−Alder reaction between N-phenylmaleimide and 3-vinylindole,
and its acquisition constitutes a formal total synthesis of the racemic
modification of the Strychnos alkaloid tubifolidine: Gioia, C.; Hauville,
A.; Bernardi, L.; Fini, F.; Ricci, A. Angew. Chem., Int. Ed. 2008, 47, 9236.
(10) Amine 10 has been obtained as a byproduct from the LiAlH4-
mediated reduction of 20-deethyl-4-demethyldasycarpidine: Bosch, J.;
Amat, M.; Sanfeliu, E.; Miranda, M. A. Tetrahedron 1985, 41, 2557.
1
mixture of rotamers: mp 192−198 °C; H NMR (CDCl3, 400 MHz)
δ 8.38 (s, 0.3H), 8.21 (s, 0.7H), 7.64 (d, J = 7.2 Hz, 0.7H), 7.40
10780
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(11) Bosch and co-workers have reported a nine-step synthesis of
compound 11 from N-benzylpiperidin-4-one: Bonjoch, J.; Quirante, J.;
Rodriguez, M.; Bosch, J. Tetrahedron 1988, 44, 2087.
(12) These conditions are similar to those employed by Shibasaki and
co-workers in a closely related conversion: Shimizu, S.; Ohori, K.; Arai,
T.; Sasai, H.; Shibasaki, M. J. Org. Chem. 1998, 63, 7547.
(13) For a distinctly different route to such frameworks carrying a
substituent at this position, see: Shin, K.; Moriya, M.; Ogasawara, K.
Tetrahedron Lett. 1998, 39, 3765.
(14) CCDC 900779 contains the supplementary crystallographic data
for compound 18. These data can be obtained free of charge from the
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
(15) (a) Bosch, J.; Amat, M. Tetrahedron Lett. 1985, 26, 4951.
(b) Amat, M.; Linares, A.; Bosch, J. J. Org. Chem. 1990, 55, 6299.
̀
(c) Gracia, J.; Casamitjana, N.; Bonjoch, J.; Bosch, J. J. Org. Chem. 1994,
59, 3939.
(16) Trost, B. M.; Sato, T. J. Am. Chem. Soc. 1985, 107, 719.
(17) Toczko, M. A.; Heathcock, C. H. J. Org. Chem. 2000, 65, 2642.
(18) Houjeiry, T. I.; Poe, S. L.; McQuade, D. T. Org. Lett. 2012, 14,
4394.
(19) Wu, Y.; Kitajima, M.; Kogure, N.; Wang, Y.; Zhang, R.; Takayama,
H. J. Nat. Med. 2009, 63, 283.
(20) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.
(21) Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.;
Timmers, F. J. Organometallics 1996, 15, 1518.
10781
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