One-pot synthesis of (±)-crispine A and its C-ring-substituted analogs

Article abstract of DOI:10.1002/ejoc.200600314

A straightforward access to crispine A and C-ring-substituted analogs by 1,4-addition of a deprotonated α-amino nitrile to α,β- unsaturated carbonyl compounds is described. If the reduction step is omitted, substituted 5,6-dihydropyrrolo[2,1-α]isoquinolin

Full text of DOI:10.1002/ejoc.200600314

FULL PAPER
DOI: 10.1002/ejoc.200600314
One-Pot Synthesis of (± ±-ꢀCisꢁine A and Its ꢀ-Ring-Substituted Analogs
[a]
[a]
Nino MeyeC and Till Oꢁatz*
KeywoCds: Natural products / Heterocycles / Umpolung / 1,4-Addition / Amino nitriles
A straightforward access to crispine A and C-ring-substituted
analogs by 1,4-addition of a deprotonated α-amino nitrile to
α,β-unsaturated carbonyl compounds is described. If the re-
duction step is omitted, substituted 5,6-dihydropyrrolo[2,1-
a]isoquinolines can be obtained.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
IntCoduction
Results and Discussion
Despite the success of both combinatorial and rational
approaches in the process of drug development, natural
products still represent a rich source of novel pharmaceuti-
cally active compounds. Particularly ingredients of plants
used in traditional medicine are attractive candidates for
the discovery of new lead structures. In Chinese folk medi-
cine, the welted thistle (Carduus crispus) was used for the
treatment of cold, stomach ache and rheumatism. Pharma-
cological screening of its extracts revealed a cytotoxic ac-
tivity against some human cancer cell lines.[ The search
for the antiproliferative principle of the plant led to the dis-
covery of five novel isoquinoline alkaloids, among them the
Deprotonated N-mono or N-unsubstituted α-amino ni-
triles can be used as nucleophiles in 1,4- and 1,2-addition
reactions. As previously reported by our group, they can
serve as key intermediates in a convenient one-pot synthesis
[
7,8]
[9]
of highly substituted pyrrolidines
Scheme 1).
and 1,2-diamines
(
1]
[
1]
hexahydropyrrolo[2,1-a]isoquinoline alkaloid crispine A
Figure 1).
(
Figure 1. Structure of crispine A.
Scheme 1. Synthesis of pyrrolidines from α-amino nitriles.
Due to the renewed interest in this molecule, two total
Encouraged by the simplicity and efficiency of this
method, we sought for possible applications in the con-
struction of polycyclic fused ring systems. Crispine A
should be easily accessible by the above mentioned method
using 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-car-
bonitrile (1) as a precursor. This amino nitrile can be syn-
thesized from N-formylhomoveratrylamine by Bischler-
Napieralski cyclization, followed by addition of HCN to
syntheses have recently been published by Knölker et al.
and Szawkalo et al.[
2,3]
Herein, we report on a facile one-
pot synthesis of (±)-crispine A and analogs based on the
conjugate addition of a deprotonated α-amino nitrile to
α,β-unsaturated carbonyl compounds. This simple ap-
proach not only allows the introduction of various substitu-
ents but also permits the formation of pyrrole derivatives.
The latter method represents an improvement of the von
Miller–Plöchl pyrrole synthesis.[
[10]
the resulting dihydroisoquinoline (Scheme 2).
4–6]
Deprotonation of amino nitrile 1 by KHMDS in THF
at –78 °C, 1,4-addition to acrolein and one-pot reduction
of the resulting unstable intermediate by sodium cyano-
borohydride in acidic solution furnishes (±)-crispine A.
However, the yield of the desired product was only 13% and
unfortunately, neither the addition of crown ethers nor the
[
a] Institut für Organische Chemie, Universität Mainz
Duesbergweg 10–14, 55128 Mainz, Germany
Fax: +49-6131-392-4786
E-Mail: opatz@uni-mainz.de
Supporting information for this article is available on the
WWW under http://www. eurjoc.com
Eur. J. Org. Chem. 2006, 3997–4002
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3997

N. Meyer, T. Opatz
FULL PAPER
ination of HCN from 1, which may compete with the de)
sired α)deprotonation, could also account for the low yield.
When switching to methacrolein as the electrophile, 2)
methyl)substituted crispine A (2b± was obtained as a 4.5:1
diastereomeric mixture in favor of the cis product in 41%
yield. The reaction of deprotonated 1 with 1)(4)chlo)
rophenyl±)4,4)dimethylpent)1)en)3)one furnished the 1,3)di)
substituted crispine derivative 2c in 87% yield as a single
diastereomer, the relative configuration of which could be
assigned by NOE measurements to be all)cis. These results
clearly indicate that deterioration of 1 in the deprotonation
step does not occur to a significant extent. The results of
Scheme 2. Retrosynthetic analysis of (± ±)crispine A.
use of different solvents allowed to improve the obtained the reaction of 1 with various Michael acceptors are sum)
yield. Our previous findings in the synthesis of simple pyr) marized in Table 1.
rolidines from deprotonated Strecker products indicate that
In the case of the products derived from substituted
acrolein tends to give somewhat lower yields than other chalcones (2d–2f±, again the all)cis diastereomers are
Michael acceptors. On the other hand, the base)induced elim) formed exclusively. Besides the introduction of substituents
Table 1. Preparation of C)ring)substituted analogs of crispine A.
1
[
a] Determined by H NMR spectroscopy.
3998
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© 2006 Wiley)VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 3997–4002

One)Pot Synthesis of (± ±)Crispine A and Its C)Ring)Substituted Analogs
FULL PAPER
to the C)ring, the described synthetic method also allows ExꢁeCimental Section
the variation of the A)ring if different 1,2,3,4)tetrahydroiso)
GeneCal: All reactions were carried out under argon unless stated
otherwise. THF was dried by distillation from Na/benzophenone.
Cinnamaldehyde and benzaldehyde were distilled before use. All
other solvents and reagents were purchased from commercial sup)
pliers and were used without further purification. TLC was per)
formed on TLC aluminium sheets (silica gel 60 F254, E. Merck or
alumina N/UV254, Macherey–Nagel±. Preparatvie TLC was per)
formed on PSC glass plates (silica gel 60 F254, 2 mm, 20×20 cm,
with concentration zone, E. Merck±. If not otherwise stated, flash
chromatography was carried out on silica gel (32–63 µm, 60 Å, MP
Biomedicals GmbH±. Alternatively, alumina N (50–200 µm, Acros±
was used. Preparative RP)HPLC separations were performed with
quinoline)1)carbonitriles are used. As an example, com)
[
11,12]
pound 4 can be obtained from amino nitrile 3
Scheme 3±.
(
Scheme 3. One)pot synthesis of 1,3)diphenyl)1,2,3,5,6,10b)hexahy) Knauer MiniStar K)500 pumps and a Knauer variable)wavelength
1
13
dropyrrolo[2,1)a]isoquinoline.
monitor. H NMR and C NMR spectra were recorded with a
Bruker AC 300, AMX 400 or DRX 400 instrument, chemical shifts
were referenced to the residual solvent signal (CDCl
3 H
: δ =
It turned out to be necessary to hydrolyze amine–borane
7
.26 ppm; δ = 77.0 ppm±. Where indicated, signals were assigned
C
complexes formed in the reduction step by addition of etha)
based on DEPT, gs)COSY or gs)HMQC experiments. Some of the
spin)spin coupling constants were determined by Lorentz)Gauss
transformation of the FID. The relative configurations of the prod)
ucts were assigned with the aid of transient NOE experiments. ESI
mass spectra were recorded with a Finnigan Navigator instrument
nolamine or citric acid to the reaction mixture.[
13,14]
By
omission of the reduction step, the corresponding 5,6)dihy)
dropyrrolo[2,1)a]isoquinolines can be obtained. Acetic acid
and ethanol are added to the reaction mixture in order to
promote the eliminiation of the hydroxy and the nitrile from a solution of the analyte in MeCN/H O (70:30±, ESI)HR
2
function (Scheme 4±.
mass spectra were measured with a Waters Q)TOF)Ultima 3 (Na)
CH as internal reference±, or with the same apparatus equipped
with a LockSpray interface (NaO CH or NaI/CsI as external refer)
O
2
2
ence±. FD mass spectra were recorded with a Finnigan MAT 95 at
a desorption voltage of 5 kV and a heater current ramp of 10 mA/
min. IR spectra were recorded with a Perkin–Elmer 1760X FTIR
spectrometer. Melting points were measured with a Dr. Tottoli ap)
paratus and are uncorrected. Elemental analyses were performed
with a Vario Micro Cube (Elementar±.
PCeꢁaCation of the Isoquinolines 2. Tyꢁical PCoceduCe: To a stirred
solution of the α)amino nitrile (1.24 mmol± in dry THF (13 mL±
was added a freshly prepared solution of KHMDS (1.36 mmol,
1
3
.1 equiv.± in dry THF (1.2 mL± at –78 °C under argon. After 1–
min, a solution of the α,β)unsaturated carbonyl compound
(
1.36 mmol, 1.1 equiv.± in dry THF (1.2 mL± was added and the
mixture was stirred at –78 °C for 30 min. A mixture of ethanol
4.7 mL, 60 equiv.± and acetic acid (0.42 mL, 6 equiv.± was added,
the cooling bath was removed and solid NaBH CN (234 mg,
equiv.± was added immediately. The mixture was stirred at room
temperature overnight. After addition of ethanolamine (1.19 mL,
6 equiv.± and stirring for 3 h, the reaction mixture was diluted with
ethyl acetate, washed with water and brine and dried with Na SO
(
3
3
1
2
4
.
Scheme 4. Synthesis of 5,6)dihydropyrrolo[2,1)a]isoquinolines.
Evaporation of the solvent in vacuo gave a crude product which
was further purified by column chromatography.
(
± ±-ꢀCisꢁine A (2a±: The reaction was conducted according to the
general procedure. Reagents: 6,7)Dimethoxy)1,2,3,4)tetrahydroiso)
quinoline)1)carbonitrile (1± (182 mg, 0.83 mmol± in THF (7.6 mL±,
KHMDS (183 mg, 0.92 mmol± in THF (0.7 mL±, acrolein (61.9 µL,
ꢀ
onclusions
0
.92 mmol± in THF (0.7 mL±, ethanol (3.1 mL±, acetic acid
In summary, we present a simple one)pot synthesis of
(
0.28 mL±, NaCNBH (156 mg, 2.48 mmol±. Before extractive
3
crispine A and some C)ring)substituted analogs. A) and C)
ring)substituted products can conveniently be obtained by
variation of the building blocks. Apart from the synthesis
of the saturated C)ring, the formation of the unsaturated
pyrrole ring is also possible. The reported transformations
demonstrate the extension of the synthesis of simple pyr)
workup, ethanolamine (0.9 mL± was added and the reaction mix)
ture was stirred at room temperature for 3 h. The organic phase
was washed twice with 1  NaOH, and the organic layer was ex)
tracted three times with 1  HCl. The combined aqueous layers
where adjusted to pH = 12 by addition of NaOH. Extraction with
2 2 2 4
CH Cl (3×±, drying with Na SO and evaporation of the solvent
rolidines and pyrroles from α)amino nitriles to the prepara) in vacuo gave the crude product (186.1 mg± as a brown oil. A por)
tion of polycyclic fused ring systems.
tion of the crude product (152.7 mg± was purified by flash
Eur. J. Org. Chem. 2006, 3997–4002
© 2006 Wiley)VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3999

N. Meyer, T. Opatz
FULL PAPER
chromatography [cyclohexane/ethyl acetate, 1:4
+
1% (v/v±
citric acid (1 mL± was added. The mixture was left for 12 h and
heated to reflux for 1 h. The mixture was adjusted to pH = 14 by
addition of NaOH. After addition of ethyl acetate, the organic layer
EtNMe
troscopic data are in accordance with data from the literature.
NMR (300 MHz, CDCl
.84 (s, 6 H, 2 OCH ±, 3.42 (t, 1 H, JH,H = 8.1 Hz, 10b)H±, 3.17 aqueous phases were reextracted with ethyl acetate and the com)
ddd, 1 H, JH,H = 10.9, 6.1, 2.7 Hz, 5)H)a±, 3.11–2.93 (m, 2 H, 3) bined organic layers were dried with Na SO . The amorphous, yel)
H)a, 6)H)a±, 2.78–2.48 (m, 3 H, 3)H)b, 5)H)b, 6)H)b±, 2.38–2.24 low solid (160 mg, 0.40 mmol, 87%± obtained by removal of the
m, 1 H, 1)H)a±, 1.99–1.80 (m, 2 H, 2)H)a,b±, 1.80–1.63 (m, 1 H, solvent in vacuo did not require chromatographic purification. IR
2
] to yield crispine A as a colorless oil (20.4 mg, 13%±. Spec)
[2] 1
H
3
±: δ = 6.60, 6.56 (2 s, 2 H, 7)H, 10)H±, was extracted three times with 1  NaOH solution. The combined
3
3
(
3
3
2
4
(
1
)H)b± ppm.
(KBr±: ν˜ = 2959, 1520, 1490, 1474, 1259, 1218, 1131, 1090, 1016,
–
1 1
8
25 cm . H NMR, NOESY (400 MHz, CDCl
H, 3Ј,5Ј)H±, 7.03 (m , 2 H, 2Ј,6Ј)H±, 6.52, 6.09 (2 s, 2 H, 7)H, 10)
H±, 3.78 (s, 3 H, OCH ±, 3.62–3.71 (m, 2 H, 5)H)a, 10b)H±, 3.48–
.54 (m, 4 H, OCH , 1)H±, contained in this multiplet: 3.51 (s, 3
H, OCH ±, 3.13 (m
H, 6)H)b±, 2.49 (ddd, JH,H = 13.2, 9.9, 8.4 Hz, 1 H, 2)H)a±, 2.35
3 c
±: δ = 7.23 (m , 2
PCeꢁaCation of cis-8,9-Dimethoxy-2-methyl-1,2,3,5,6,10b-hexahy-
dCoꢁyCColo[2,1-a]isoquinoline (2b±: The reaction was conducted ac)
cording to the general procedure. Reagents: 6,7)Dimethoxy)1,2,3,4)
tetrahydroisoquinoline)1)carbonitrile (1± (171 mg, 0.78 mmol± in
THF (5.6 mL±, KHMDS (178 mg, 0.89 mmol± in THF (1.0 mL±,
methacrolein (71 µL, 0.86 mmol± in THF (1.0 mL±, ethanol
c
3
3
3
3
3
c
, 1 H, 6)H)a±, 2.66 (dd, JH,H = 16.1, 3.5 Hz,
3
1
3
(
t, JH,H = 8.4 Hz, 1 H, 3)H±, 2.28–2.33 (m, 1 H, 5)H)b±, 1.60 (ddd,
J
3
(2.9 mL±, acetic acid (0.27 mL±, NaCNBH (152 mg±, ethanola)
3
13
H,H = 13.2, 8.4, 3.5 Hz, 1 H, 2)H)b±, 0.99 (s, 9 H, CH
NMR (75.5 MHz, CDCl ±: δ = 146.6, 146.2 (C)8, C)9±, 144.6 (C)
Ј±, 130.9 (C)4Ј±, 130.6 (C)2Ј,6Ј±, 128.7 (C)6a±, 127.7 (C)3Ј,5Ј±,
27.3 (C)10a±, 110.6, 110.0 (C)7, C)10±, 72.7 (C)3±, 69.9 (C)10b±,
5.6 (OCH ±, 50.3 (C)5±, 42.5 (C)1±, 38.2 (C)2±, 33.4 [C(CH ],
9.8 (C)6±, 28.1 (CH ± ppm. ESI)MS: m/z (%± = 422.2 (73± [M +
3
± ppm.
C
mine (0.76 mL±. The reaction yielded a yellow oil (198.9 mg±. Puri)
fication of a portion (184 mg± of the crude product by flash
chromatography [cyclohexane/ethyl acetate, 1:6
EtNMe ] gave a diastereomeric mixture (cis/trans = 4:1± of 2)
methyl)substituted crispine A (73 mg, 41%± as a yellowish amorph)
3
1
1
5
2
+ 1% (v/v±
2
3
3 3
±
3
ous solid. IR (film±: ν˜ = 2952, 1610, 1511, 1464, 1377, 1263, 1232,
+
+
–
1
1
Na] , 400.2 (100± [M + H] . HRMS: calcd. for [C24
H] 400.2043, found 400.2053.
H30ClNO
2
+
1216, 1141, 1014 cm . H NMR, HMQC (400 MHz, CDCl
3
±: δ =
+
6
J
.60, 6.54 (2 s, 2 H, 7)H, 10)H±, 3.84 (s, 6 H, 2 OMe±, 3.65 (br. dd,
3
3
c
c
H,H = 8.6 Hz, JH,H = 7.4 Hz, 0.8 H, 10b)H ±, 3.45 (m , 0.2 H, PCeꢁaCation of all-cis-8,9-Dimethoxy-1,3-diꢁhenyl-1,2,3,5,6,10b-
t
3
3
t
1
3
5
0
0b)H ±, 3.24 (dd, JH,H = 9.2 Hz, JH,H = 7.7 Hz, 0.2 H, 3)H)a ±,
hexahydCoꢁyCColo[2,1-a]isoquinoline (2d±: The reaction was con)
ducted according to the general procedure. Reagents: 6,7)Dimeth)
.13 (ddt, JH,H = 8.3 Hz, 3JH,H = 5.8 Hz, JH,H = 2.6 Hz, 0.8 H,
3
3
c
t
c
3
)H)a ±, 2.94–3.06 (m, 1 H, 5)H)a , 6)H ±, 2.77 (t, JH,H = 8.5 Hz, oxy)1,2,3,4)tetrahydroisoquinoline)1)carbonitrile (1± (139.3 mg,
.8 H, 3)H)a ±, 2.58–2.73 (m, 3 H, 5)H)b , 6)H)a,b , 3)H)b , 5)H) 0.64 mmol± in THF (4.6 mL±, KHMDS (141.6 mg, 0.71 mmol± in
c
t
t
c
c
c
3
H,H = 6.7 Hz, 3
3
b , 6)H)b ±, 2.54 (ddd,
J
J
H,H = 7.8 Hz,
J
H,H
3
=
THF (0.8 mL±, chalcone (146.7 mg, 0.70 mmol± in THF (0.8 mL±,
ethanol (2.4 mL±, acetic acid (0.22 mL±, NaCNBH (120.3 mg,
c
c,t
11.8 Hz, 0.8 H, 1)H)a ±, 2.27–2.44 (m, 1 H, 2)H ±, 2.14 (dd, JH,H
3
3
t
=
9.3 Hz, JH,H = 7.9 Hz, 0.2 H, 3)H)b ±, 1.95–2.04 (m, 0.2 H, 1)
1.91 mmol±, ethanolamine (0.62 mL±. The reaction yielded an
amorphous yellow solid (243.0 mg±. Purification of a portion
t
3
3
3
H)a ±, 1.87 (ddd, JH,H = 11.7 Hz, JH,H = 7.1 Hz, JH,H = 4.1 Hz,
t
3
3
0.2 H, 1)H)b ±, 1.29 (td, JH,H = 11.9 Hz, JH,H = 9.2 Hz, 0.8 H, 1) (224 mg± of the crude product by flash chromatography [petroleum
c
3
t
3
H)b ±, 1.08 (d, JH,H = 7.0 Hz, 0.6 H, Me ±, 1.06 (d, JH,H = 6.7 Hz,
2
ether/ethyl acetate, 10:1 + 1% (v/v± EtNMe ] gave pure cis)1,3)di)
phenylcrispine A as a yellowish amorphous solid (132 mg, 58%±.
c
13
2.4 H, Me ± ppm. C NMR, HMQC (100.6 MHz, CDCl
3
±: δ =
1
47.3, 147.2 (C)8, C)9±, 131.6, 126.3 (C)6a, C)10a±, 111.4, 108.8
IR (film±: ν˜ = 2940, 1603, 1519, 1456, 1276, 1216, 1136, 1028, 761,
c
c
t
t
c
t
–1 1
(
(
(
C)7 , C)10 ±, 108.6 (C)7 , C)10 ±, 62.6 (C)10b ±, 62.4 (C)10b ±, 61.9 730, 701 cm . H NMR, COSY, HMQC (400 MHz, CDCl
C)3 ±, 60.3 (C)3 ±, 56.0, 55.9 (OMe±, 48.6 (C)5 ±, 48.2 (C)5 ±, 40.8
C)1 ±, 39.2 (C)1 ±, 31.4 (C)2 ±, 30.2 (C)2 ±, 28.1 (C)6 ±, 26.9 (C)6 ±,
0.5 (CH ± ppm. Note: The superscripts c and t denote the cis and
the trans isomer, respectively. ESI)MS: m/z (%± = 248.3 (100± [M +
3
±: δ =
t
c
t
c
3
7.47 (pseudo)d, JH,H Ϸ 8.2 Hz, 2 H, 2Ј,6Ј)H±, 7.41 (pseudo)d,
JH,H Ϸ 7.0 Hz, 2 H, 2ЈЈ,6ЈЈ)H±, 7.36 (pseudo)t, JH,H Ϸ 7.5 Hz, 2
H, 3Ј,5Ј)H±, 7.24–7.29 (m, 1 H, 4Ј)H±, 7.13 (pseudo)t, JH,H Ϸ 7.5
Hz, 2 H, 3ЈЈ,5ЈЈ)H±, 7.02 (m , 1 H, 4ЈЈ)H±, 6.54, 6.16 (2 s, 2 H, 7)
c
t
c
t
t
c
3
3
3
2
3
c
+
+
3
H] . HRMS: calcd. for [C15
48.1646.
2
H21NO + H] 248.1615, found H, 10)H±, 3.79 (d, JH,H = 7.6 Hz, 1 H, 10b)H±, 3.78 (s, 3 H, OMe±,
3.72 (ddd, JH,H = 9.7 Hz, 3JH,H = 7.6 Hz, JH,H = 4.2 Hz, 1 H, 1)
3
3
2
3
H±, 3.50 (s, 3 H, OMe±, 3.46 (t, JH,H = 8.5 Hz, 1 H, 3)H±, 3.18–
.06 (m, 2 H, 5)H)a, 6)H)a±, 2.97 (ddd, JH,H = 13.3 Hz, JH,H =
PCeꢁaCation of all-cis-3-tert-Butyl-1-(4-chloCoꢁhenyl±-8,9-dimethoxy-
,2,3,5,6,10b-hexahydCoꢁyCColo[2,1-a]isoquinoline (2c±: The reaction
2
3
3
9
1
3
c
.5 Hz, JH,H = 8.0 Hz, 1 H, 2)H)a±, 2.66 (m , 1 H, 6)H)b±, 2.21–
was conducted according to the general procedure. Instead of etha)
nolamine a saturated solution of citric acid was used for the de)
struction of borane–amine complexes. Reagents: 6,7)Dimethoxy)
1
1
.31 (m, 1 H, 5)H)b±, 1.85 (ddd, JH,H = 13.3 Hz, 3JH,H = 9.1 Hz,
2
2
3
13
J
H,H = 4.2 Hz, 1 H, 2)H)b± ppm. C NMR, HMQC (100.6 MHz,
CDCl
3
±: δ = 146.5, 146.2, 145.8, 142.7 (q)C±, 129.2 (C)2Ј,6Ј±, 128.7
,2,3,4)tetrahydroisoquinoline)1)carbonitrile
(1±
(242 mg,
(
C)6a/C)10a±, 128.5 (C)3ЈЈ,5ЈЈ±, 127.9 (C)3Ј,5Ј±, 127.7 (C)2ЈЈ,6ЈЈ±,
.11 mmol± in THF (11.5 mL±, KHMDS (243 mg, 1.22 mmol± in
[15]
127.5 (C)6a/C)10a±, 127.1 (C)4ЈЈ±, 125.6 (C)4Ј±, 110.9, 110.3 (C)7,
C)10±, 69.3 (C)3±, 69.1 (C)10b±, 55.6 (OMe±, 47.9 (C)5±, 45.5 (C)2±,
THF (1.0 mL±, 4,4)dimethyl)1)(4)chlorophenyl±pent)1)en)3)one
(271 mg, 1.22 mmol± in THF (1.0 mL±, ethanol (4.2 mL±, acetic
4
4.9 (C)1±, 29.8 (C)6± ppm. ESI)MS: m/z (%± = 386.3 (100± [M +
3
acid (0.38 mL±, NaCNBH (209 mg, 3.32 mmol±. The reduction
+
+
H] , 384.8 (45± [M – 2 H] , 248.2 (28±. HRMS: calcd. for
[C H27NO + H] 386.2120, found 386.2130. C26H27NO (385.50±:
26 2 2
was conducted for 4 d. After complete reduction, a saturated aq.
solution of citric acid (1 mL± was added and the solution was
stirred for 1 h. The reaction mixture was adjusted to pH = 14 by
addition of NaOH and partitioned between ethyl acetate and a 1:1
mixture of 1  NaOH/brine. The aqueous phase was reextracted
with ethyl acetate and the combined organic phases were dried with
Na SO . The solvent was removed under reduced pressure to yield
2 4
a brown)white solid (496 mg±. A portion (204 mg± of the raw prod)
uct was dissolved in THF (3 mL± and a saturated aq. solution of
+
calcd. C 81.01, H 7.06, N 3.63; found C 80.94, H 7.07, N 3.58.
PCeꢁaCation of all-cis-3-(4-FluoCoꢁhenyl±-8,9-dimethoxy-1-(4-meth-
oxyꢁhenyl±-1,2,3,5,6,10b-hexahydCoꢁyCColo[2,1-a]isoquinoline (2e±:
The reaction was conducted according to the general procedure.
Instead of ethanolamine, a saturated solution of citric acid was
used for the destruction of borane–amine complexes. Reagents:
6,7)Dimethoxy)1,2,3,4)tetrahydroisoquinoline)1)carbonitrile
(1±
4000
www.eurjoc.org
© 2006 Wiley)VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 3997–4002

One)Pot Synthesis of (± ±)Crispine A and Its C)Ring)Substituted Analogs
FULL PAPER
4
(271 mg, 1.24 mmol± in THF (13 mL±, KHMDS (278 mg, 146.6, 146.5 (C)8, C)9±, 143.0 (C)1Ј±, 138.0 ( JC,F = 3.1 Hz, C)1ЈЈ±,
3
1.39 mmol± in THF (1.2 mL±, 4Ј)fluoro)4)methoxychalcone
133.5 (C)2Ј±, 131.1 (C)6Ј±, 129.1 ( JC,F = 7.9 Hz, C)2ЈЈ,6ЈЈ±, 128.3
(
348 mg, 1.36 mmol± in THF (1.2 mL±, ethanol (4.7 mL±, acetic (C)3Ј±, 128.2, 127.1 (C)6a, C)10a±, 126.9 (C)5Ј±, 126.8 (C)4Ј±, 115.3
2
acid (0.42 mL±, NaCNBH
3
(234 mg, 3.72 mmol±. After complete
( JC,F = 21.2 Hz, C)3ЈЈ, 5ЈЈ±, 110.9, 109.3 (C)7, C)10±, 69.1, 68.4
(C)3, C)10b±, 55.6 (OCH ±, 55.5 (OCH ±, 47.7 (C)5±, 44.7 (C)1±,
39.1 (C)2±, 29.7 (C)6± ppm. ESI)MS: m/z (%± = 460.2 (38± [M +
reduction, a saturated aq. solution of citric acid (3 mL± was added.
The mixture was stirred at room temperature for 2 h and heated to
reflux 1 h. The solution was cooled, ethyl acetate was added and
the reaction mixture was adjusted to pH = 14 by addition of
NaOH. The two phases were separated and the organic layer was
3
3
+
+
Na] , 438.2 (100± [M + H] . HRMS: calcd. for [C26
H
25ClFNO
(437.93±: calcd. C
71.31, H 5.75, N 3.20; found C 71.40, H 5.73, N 3.10.
2
+
+
H] 438.1636, found 438.1636. C26H25ClFNO
2
2 4
washed three times with 1  NaOH. Drying with Na SO and evap)
oration of the solvent yielded a brown oil (477 mg±. Purification of
a portion (222 mg± of the crude product by flash chromatography
1
,3-Diꢁhenyl-1,2,3,5,6,10b-hexahydCoꢁyCColo[2,1-a]isoquinoline (4±:
The reaction was conducted according to the general procedure.
Reagents: 1,2,3,4)tetrahydroisoquinoline)1)carbonitrile (3± (62 mg,
(cyclohexane/ethyl acetate, 10:1± yielded a yellowish amorphous so)
0
.35 mmol± in THF (2.5 mL±, KHMDS (78 mg, 0.39 mmol± in
THF (0.4 mL±, chalcone (79 mg, 0.38 mmol± in THF (0.4 mL±, eth)
anol (1.3 mL±, acetic acid (0.12 mL±, NaCNBH (65 mg,
lid (72 mg, 29%±. IR (film±: ν˜ = 2936, 1610, 1510, 1465, 1246, 1219,
–
1 1
1
3
176, 1136, 1033, 832 cm . H NMR (300 MHz, CDCl ±: δ = 7.39
3
3
(m
c
, 2 H, 2Ј,6Ј)H±, 7.28 (pseudo)d, JH,H Ϸ 8.7 Hz, 2 H, 3Ј,5Ј)H±,
.01 (pseudo)t, 3
1.64 mmol±, ethanolamine (0.33 mL±. The reaction yields a yellow)
orange oil (121.4 mg±. A portion (62.6 mg± of the crude product
was dissolved in THF (1 mL± and saturated citric acid was added in
order to destroy remaining borane–amine complexes. The reaction
mixture was adjusted to pH = 14 after 10 d at room temperature
and extracted twice with 1  NaOH. The combined aqueous phases
were extracted with ethyl acetate and the combined organic layers
were dried with Na SO . The solvent was removed under reduced
2 4
pressure. The crude product (56.9 mg± was purified by semiprepar)
ative HPLC [Phenomenex Luna C18(2±, 10 µ, 250 × 21.2 mm, ace)
tonitrile/water, 90:10, 20 mL/min] to yield a colorless oil (10.0 mg,
7
JH,H Ϸ 8.7 Hz, 2 H, 2ЈЈ,6ЈЈ)H±, 6.65 (pseudo)d,
3
J
H,H Ϸ 8.7 Hz, 2 H, 3ЈЈ,5ЈЈ)H±, 6.52, 6.15 (2 s, 2 H, 7)H, 10)H±,
.60–3.79 (m, 8 H, 2 OCH , 1)H, 10b)H±, contained in this mul)
tiplett: 3.76 (s, 3 H, OCH ±, 3.69 (s, 3 H, OCH ±, 3.51 (s, 3 H,
±, 3.40 (t, JH,H = 8.5 Hz, 1 H, 3)H±, 2.98–3.14 (m, 2 H, 5)
3
3
3
3
3
OCH
H)a, 6)H)a±, 2.92 (ddd, JH,H = 13.2 Hz, JH,H = 9.3 Hz, JH,H
3
3
3
3
=
8
5
1
=
(
=
.1 Hz, 1 H, 2)H)a±, 2.58–2.68 (m, 1 H, 6)H)b±, 2.17–2.28 (m, 1 H,
3
3
3
)H)b±, 1.73 (ddd, JH,H = 13.2 Hz, JH,H = 9.0 Hz, JH,H = 4.0 Hz,
13
±: δ = 162.0 (1JC,F
H, 2)H)b± ppm. C NMR (75.5 MHz, CDCl
3
244.6 Hz, C)4Ј±, 157.4 (C)4ЈЈ±, 146.5, 146.2 (C)8, C)9±, 138.3
4JC,F = 3.1 Hz, C)1Ј±, 137.8 (C)1ЈЈ±, 129.9 (C)2ЈЈ,6ЈЈ±, 129.1 ( JC,F
3
1
2
37%±. H NMR (300 MHz, CDCl
7
aryl±, 6.84 (t, JH,H = 7.4 Hz, 1 H, aryl±, 6.71 (d, JH,H = 7.7 Hz, 1
H, aryl±, 3.87 (d, JH,H = 6.7 Hz, 1 H, 10b)H±, 3.73–3.83 (m, 1 H,
3
±: δ = 7.39–7.50 (m, 5 H, aryl±,
7.9 Hz, C)2Ј,6Ј±, 128.6, 127.3 (C)6a, C)10a±, 115.3 ( JC,F
=
.31–7.39 (m, 2 H, aryl±, 7.13 (mc, 2 H, aryl±, 6.93–7.08 (m, 3 H,
2
6
1.2 Hz, C)3Ј, 5Ј±, 113.2 (C)3ЈЈ,5ЈЈ±, 110.8, 110.2 (C)7, C)10±, 68.9,
8.4 (C)3, C)10b±, 55.5 (2 OCH ±, 55.0 (OCH ±, 47.8 (C)5±, 45.6
3
3
3
3
3
(
C)2±, 43.8 (C)1±, 29.7 (C)6± ppm. ESI)MS: m/z (%± = 456.2 (18±
3
+
+
1)H±, 3.46 (t, 1 H, JH,H = 8.5 Hz, 3)H±, 3.07–3.28 (m, 2 H, 5)H)
[
M + Na] , 434.2 (100± [M+H] . HRMS: calcd. for [C27H28FNO
3
a, 6)H)a±, 2.98 (ddd, 3JH,H = 13.2 Hz,
3
3
+
H,H
JH,H = 9.5 Hz, J =
+
H] 434.2131, found 434.2147.
3
3
8
.5 Hz, 1 H, 2)H)a±, 2.76 (dd, JH,H = 15.4 Hz, JH,H = 3.7 Hz, 1
H, 6)H)b±, 2.23–2.37 (m, 1 H, 5)H)b±, 1.84 (ddd, 3JH,H = 13.2,
PCeꢁaCation of all-cis-1-(2-ꢀhloCoꢁhenyl±-3-(4-fluoCoꢁhenyl±-8,9-di-
methoxy-1,2,3,5,6,10b-hexahydCoꢁyCColo[2,1-a]isoquinoline (2f±: The
reaction was conducted according to the general procedure. Instead
of ethanolamine, a saturated solution of citric acid was used for the
destruction of borane–amine complexes. Reagents: 6,7)Dimethoxy)
3
3
13
J
H,H = 8.5 Hz, JH,H = 3.9 Hz, 1 H, 2)H)b±. C NMR (75.5 MHz,
CDCl ±: δ = 145.6, 142.6, 136.5, 135.4 (q)C±, 129.1 (2 C±, 128.4 (2
C±, 128.2 (1 C±, 127.8 (2 C±, 127.7 (2 C±, 127.1 (1 C±, 126.8 (1 C±,
25.4 (1 C±, 125.3 (1 C±, 125.0 (1 C±, 69.3, 69.2 (C)3, C)10b±, 47.8
C)5±, 45.2 (C)2±, 44.5 (C)1±, 30.3 (C)6±. ESI)MS: m/z (%± = 326.2
3
1
(
(
3
1
1
,2,3,4)tetrahydroisoquinoline)1)carbonitrile
.31 mmol± in THF (13.7 mL±, KHMDS (290 mg, 1.44 mmol± in
(1±
(287 mg,
+
+
100± [M + H] . HRMS: calcd. for [M + H] 326.1909, found
26.1908.
THF (1.2 mL±, 2)chloro)4Ј)fluorochalcone (353 mg, 1.44 mmol± in
THF (1.2 mL±, ethanol (5.0 mL±, acetic acid (0.45 mL±, NaCNBH
247 mg, 3.93 mmol±. After complete reduction, a saturated aq.
3
PCeꢁaCation of the PyCColes 5. Tyꢁical PCoceduCe: To a stirred solu)
tion of the α)amino nitrile 1 (0.91 mmol± in dry THF (8.3 mL± was
(
solution of citric acid (3 mL± was added. The mixture was stirred
at room temperature for 2 h and heated to reflux for 1 h. The solu)
tion was cooled, ethyl acetate was added and the reaction mixture
was adjusted to pH = 14 by addition of NaOH. The two phases
were separated and the organic layer was washed three times with
added
.1 equiv.± in THF (0.8 mL± at –78 °C under argon. After 1–3 min,
a solution of the α,β)unsaturated carbonyl compound (1.0 mmol,
.1 equiv.± in THF (0.8 mL± was added and the mixture was stirred
for 30 min. A mixture of ethanol (3.7 mL, 60 equiv.± and acetic acid
0.31 mL, 6 equiv.± was added. The cooling was removed and the
reaction mixture was refluxed for 30 min. The reaction mixture was
partitioned three times between saturated NaHCO solution and
ethyl acetate. Drying of the organic layer with Na SO and evapo)
a freshly prepared solution of KHMDS (1.0 mmol,
1
1
1
2 4
 NaOH. Drying with Na SO and evaporation of the solvent
(
yielded a brown oil (566 mg±. Purification of a portion (226 mg±
of the crude product by flash chromatography [cyclohexane/ethyl
3
acetate, 10:1 + 1% (v/v± EtNMe
2
] yielded a yellow amorpohous
2
4
solid (93 mg, 41%±. IR (film±: ν˜ = 2945, 1606, 1509, 1466, 1363,
ration of the solvent in vacuo gave a crude product, which was
further purified by column chromatography.
–1 1
1
=
2
219, 1156, 1136, 1036, 838 cm . H NMR (300 MHz, CDCl
3
±: δ
7.74 (dd, JH,H = 7.4 Hz, JH,H = 2.2 Hz, 1 H, 3Ј)H±, 7.40 (m
H, 2ЈЈ,6ЈЈ)H±, 7.18–7.26 (m, 1 H, aryl±, 7.04 (m , 2 H, aryl±, 6.97
3
3
c
,
c
PCeꢁaCation of 8,9-Dimethoxy-1,3-diꢁhenyl-5,6-dihydCoꢁyCColo[2,1-
(
c
m , 2 H, 3ЈЈ,5ЈЈ)H±, 6.54, 6.20 (2 s, 2 H, 7)H, 10)H±, 4.39 (ddd, a]isoquinoline (5a±: The reaction was conducted according to the
3
3
3
JH,H = 9.8 Hz, JH,H = 7.5 Hz, JH,H = 4.2 Hz, 1 H, 1)H±, 3.84 (d,
general procedure. Reagents: 6,7)Dimethoxy)1,2,3,4)tetrahydroiso)
3
JH,H = 7.5 Hz, 1 H, 10b)H±, 3.78, 3.58 (2 s, 6 H, OCH
3
±, 3.47 (t,
quinoline)1)carbonitrile (1± (219 mg, 1.00 mmol± in THF (9.2 mL±,
3JH,H = 8.5 Hz, 1 H, 3)H±, 2.92–3.11 (m, 3 H, 2)H)a, 5)H)a, 6)H) KHMDS (215 mg, 1.10 mmol± in THF (0.8 mL±, chalcone
a±, 2.61–2.72 (m, 1 H, 6)H)b±, 2.20–2.32 (m, 1 H, 5)H)b±, 1.71 (ddd,
(230 mg, 1.10 mmol± in THF (0.8 mL±, ethanol (3.8 mL±, acetic
acid (0.34 mL±. The reaction yielded a light brown solid (367 mg±.
3
3
3
J
H,H = 13.3 Hz, JH,H = 9.0 Hz, JH,H = 4.2 Hz, 1 H, 2)H)b± ppm.
1
3
C NMR (75.5 MHz, CDCl
3
±: δ = 162.0 (1JC,F = 244.9 Hz C)4ЈЈ±, Purification of a portion (64 mg± of the crude product by flash
Eur. J. Org. Chem. 2006, 3997–4002
© 2006 Wiley)VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4001

N. Meyer, T. Opatz
FULL PAPER
chromatography [cyclohexane/ethyl acetate, 11:1
+
1% (v/v±
= 21.5 Hz, C)3ЈЈ,5ЈЈ±, 111.1 (C)2±, 110.8 (C)7±, 107.2 (C)10±, 55.9
EtNMe
2
] yielded the product as amorphous colorless solid (46 mg,
(8)OCH
m/z (%± = 432.9 (100± [M] . C26
137, 801, 763, 702 cm . H NMR, COSY, HMBC, NOESY 71.97, H 4.88, N 3.23; found C 71.93, H 4.91, N 3.32.
±: δ = 7.55–7.59 (m, 2 H, phenyl±, 7.46 (s, 2 H,
phenyl±, 7.43–7.46 (m, 2 H, phenyl±, 7.31–7.43 (m, 3 H, phenyl±,
.28 (m , 1 H, phenyl±, 6.92 (s, 1 H, 10)H±, 6.74 (s, 1 H, 7)H±, 6.39
s, 1 H, 2)H±, 4.13 (t, JH,H = 6.4 Hz, 2 H, 5)H
3 3
±, 55.2 (9)OCH ±, 42.3 (C)5±, 29.6 (C)6± ppm. FD)MS:
+
6
1
9%±. IR (KBr±: ν˜ = 2905, 1602, 1508, 1488, 1286, 1233, 1214,
2
H21ClFNO (433.90±: calcd. C
–1
1
(400 MHz, CDCl
3
SuꢁꢁoCting InfoCmation (see footnote on the first page of this arti)
1
13
cle±: H and C NMR spectra of all products.
7
c
3
(
2
±, 3.89 (s, 3 H, 8)
±, 2.99 (t, JH,H = 6.4 Hz, 2 H, 6)H
ppm. 13C NMR, HMQC, HMBC (100.6 MHz, CDCl
±: δ = 147.3
C)9±, 147.0 (C)8±, 137.4 (C)1Ј or C)1ЈЈ±, 133.1 (C)3±, 132.6 (C)1Ј
or C)1ЈЈ±, 129.3 (2 C±, 128.7 (2 C±, 128.5 (2 C±, 128.3 (2 C±, 126.9
C)4Ј±, 126.2 (C)4ЈЈ±, 126.0 (C)10b±, 124.7 (C)6a±, 122.6 (C)10a±,
3
Acknowledgments
OCH
3
±, 3.46 (s, 3 H, 9)OCH
3
2
±
3
This work was supported by the Deutsche Forschungsgemeinschaft
and the Fonds der Chemischen Industrie. We thank H. Kolshorn
for performing the two)dimensional NMR experiments.
(
(
1
5
3
3
21.4 (C)1±, 110.8 (C)7±, 110.6 (C)2±, 108.0 (C)10±, 55.9 (8)OCH
5.3 (9)OCH ±, 42.6 (C)5±, 29.8 (C)6± ppm. FD)MS: m/z (%± =
81.0 (100± [M] . C26
.67; found C 81.88, H 6.04, N 3.67.
3
±,
[1] Q. Zhang, G. Tu, Y. Zhao, T. Cheng, Tetrahedron 2002, 58,
6795–6798.
3
+
H
2
23NO (381.47±: calcd. C 81.86, H 6.08, N
[
2] H.)J. Knölker, S. Agarwal, Tetrahedron Lett. 2005, 46, 1173–
1175.
[
3] J. Szawkalo, A. Zawadzka, K. Wojtasiewicz, A. Leniewski, J.
PCeꢁaCation of 1-(2-ꢀhloCoꢁhenyl±-3-(4-fluoCoꢁhenyl±-8,9-dimeth-
oxy-5,6-dihydCoꢁyCColo[2,1-a]isoquinoline (5b±: The reaction was
conducted according to the general procedure for the pyrroles. Rea)
gents: 6,7)Dimethoxy)1,2,3,4)tetrahydroisoquinoline)1)carbonitrile
Drabowicz, Z. Czarnocki, Tetrahedron: Asymmetry 2005, 16,
3619–3621.
[4] W. von Miller, J. Plöchl, Ber. Dtsch. Chem. Ges. 1898, 31, 2718–
2720.
(
1
1
1± (199 mg, 0.91 mmol± in THF (8.3 mL±, KHMDS (200 mg, [5] S. Bodforss, Ber. Dtsch. Chem. Ges. 1931, 64, 1111–1115.
.00 mmol± in THF (0.8 mL±, 2)chloro)4Ј)fluorochalcone (262 mg,
.00 mmol± in THF (0.8 mL±, ethanol (3.7 mL±, acetic acid
[6] A. Treibs, R. Derra, Justus Liebigs Ann. Chem. 1954, 589, 176–
87.
1
[
[
[
7] N. Meyer, T. Opatz, Synlett 2003, 1427–1430.
(
0.31 mL±. The reaction yielded a slightly brown solid (352 mg±.
Purification of a portion (143 mg± of the crude product by flash
chromatography [cyclohexane/ethyl acetate, 5:1 1% (v/v±
EtNMe ] gave the product as amorphous white solid (60 mg, 37%±.
IR (KBr±: ν˜ = 2934, 1508, 1484, 1239, 1214, 1141, 1030, 800,
8] N. Meyer, F. Werner, T. Opatz, Synthesis 2005, 945–956.
9] C. Kison, N. Meyer, T. Opatz, Angew. Chem. 2005, 117, 5807–
+
5
809.
10] J. Kobor, K. Koczka, Szegedi Tanarkepzo Foiskola Tud. Kozl.
969, 179–183.
2
[
1
–1 1
7
68 cm . H NMR, HMBC (400 MHz, CDCl
H, o)ClC ±, 7.42 (m , 2 H, 2ЈЈ,6ЈЈ)H±, 7.23–7.31 (m, 2 H, o)
ClC ±, 7.13 (pseudo)t, JH,H = 8.7 Hz, 2 H, 3ЈЈ,5ЈЈ)H±, 6.71 (s, 1
H, 7)H±, 6.51 (s, 1 H, 10)H±, 6.33 (s, 1 H, 2)H±, 4.12 (t, JH,H
3
±: δ = 7.48 (m
c
, 2
[11] M. C. Elliott, E. Williams, Org. Biomol. Chem. 2003, 1, 3038–
6
H
4
c
3047.
3
[12] D. Beaumont, R. D. Waigh, M. Sunbhanich, M. W. Nott, J.
Med. Chem. 1983, 26, 507–515.
6
H
4
3
=
[
[
[
13] M. Couturier, J. L. Tucker, B. M. Andresen, P. Dube, J. T. Ne)
6
3
.2 Hz, 2 H, 5)H
2
±, 3.87 (s, 3 H, 9)OCH
H,H = 6.2 Hz, 2 H, 6)H ± ppm. C NMR, HMQC
±: δ = 161.9 ( JC,F = 247.2 Hz, C)4ЈЈ±, 147.5 (C)
±, 147.0 (C)8±, 136.5 (C)2Ј±, 134.3 (C)1Ј±, 132.8 (o)ClC ±, 131.6
±, 128.7
±, 127.0 (C)3±, 126.7 (o)
3 3
±, 3.38 (s, 3 H, 8)OCH ±,
.00 (t, 3
13
gri, Org. Lett. 2001, 3, 465–467.
J
2
14] V. Schanen, M. P. Cherrier, S. J. deMelo, J. C. Quirion, H. P.
Husson, Synthesis 1996, 833–837.
1
(400 MHz, CDCl
3
9
6 4
H
15] H. H. Weinstock, Jr., R. C. Fuson, J. Am. Chem. Soc. 1934, 56,
3
(
(
6 4
C)1±, 130.3 ( JC,F = 7.7 Hz, C)2ЈЈ,6ЈЈ±, 129.7 (o)ClC H
1241–1242.
4
JC,F = 3.6 Hz, C)1ЈЈ±, 128.1 (o)ClC
6
H
4
Received: April 10, 2006
2
ClC
6
H
4
±, 124.1 (C)6a±, 122.6 (C)10b±, 117.8 (C)10a±, 115.4 ( JC,F
Published Online: June 28, 2006
4002
www.eurjoc.org
© 2006 Wiley)VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 3997–4002