Palladium-catalyzed synthesis of cephalotaxine analogues

Article abstract of DOI:10.1002/(SICI)1521-3765(20000204)6:3<510::AID-CHEM510>3.0.CO;2-H

The synthesis of cephalotaxine ring analogues 10 was achieved by two successive intramolecular palladium-catalyzed reactions of 12 via 11, namely an allylic amination and a Heck reaction. The substrates 12 were obtained by alkylation of primary amines 13 with tosylates 14.

Full text of DOI:10.1002/(SICI)1521-3765(20000204)6:3<510::AID-CHEM510>3.0.CO;2-H

FULL PAPER
Palladium-Catalyzed Synthesis of Cephalotaxine Analogues
Lutz F. Tietze,* Hartmut Schirok, and Michael Wöhrmann[a]
Abstract: The synthesis of cephalotaxine ring analogues 10 was achieved by two
Keywords: alkaloids
´
antitumor
natural
successive intramolecular palladium-catalyzed reactions of 12 via 11, namely an
allylic amination and a Heck reaction. The substrates 12 were obtained by alkylation
of primary amines 13 with tosylates 14.
agents
products
spiro compounds
´
cephalotaxine ´
´
palladium
´
of the genus Cephalotaxus (Cephalotaxaceae)[5] are esters of 1
and show a pronounced antileukemic activity;[5, 6] moreover
homoharringtonine (5) has some potency in the treatment of
chloroquine-resistant malaria.[7]
Several syntheses of cephalotaxine (1) have already been
described;[4, 8] however, only very few attempts were made to
access cephalotaxine analogues.[9] In our highly efficient and
as yet the shortest synthesis of cephalotaxine (1) the
secondary amine 8, obtained by alkylation of the primary
amine 6 with the tosylate 7, was transformed stereoselectively
into the pentacyclic system 9 by a Pd-catalyzed allylation
followed by a Heck reaction;[4] cephalotaxine is accessible
from 9 in four steps (Scheme 1).[8i,n] We have now extended
Introduction
The development of highly efficient syntheses of natural
products and their analogues is one of the goals of modern
organic chemistry. One way to improve the efficiency is the
use of domino reactions.[1] We have recently shown that the
combination of transition metal mediated or catalyzed
reactions allows a facile entry to steroids,[2] antibiotics of the
CC-1065 type,[3] and the pentacyclic cephalotaxine.[4] Here we
describe the synthesis of analogues of cephalotaxine (1) by
variation of the size of the different rings by means of two Pd-
catalyzed reactions.
R =
O
N
HO
OH
OH
OH
NH2
TsO
O
O
: Harringtonine
CO
2
3
4
O
+
H
Br
CO2Me
CO
RO
OMe
OAc
6
7
: Deoxyharringtonine
: Isoharringtonine
1
: R = H, (–)-Cephalotaxine
H
N
Pd0
O
O
O
CO2Me
CO
N
1
O
Br
H
H
CO2Me
CO
OAc
8
9
OH
OH
Scheme 1. Synthesis of cephalotaxine (1).
5
: Homoharringtonine
HO
this study to include substrates which have different lengths of
the side chains and different ring sizes as the primary amines
13 and allylic acetates 14 to allow the synthesis of modified
pentacyclic ring structures of cephalotaxine (1) according to
Scheme 2.
CO2Me
Cephalotaxine (1), which itself shows no pronounced
biological activity, is the parent compound of the harringto-
nines, for example harringtonine (2), deoxyharringtonine (3),
isoharringtonine (4), and homoharringtonine (5). These
substances, which are found in south-east Asian plum yews
Results and Discussion
[a] Prof. Dr. L. F. Tietze, Dr. H. Schirok, Dipl.-Chem. M. Wöhrmann
Institut für Organische Chemie der Universität
Tammannstrasse 2, 37077 Göttingen (Germany)
Fax : (‡ 49)551-399476
The primary amines 13a ± d were synthesized from commer-
cially available compounds in a few steps according to known
procedures.[10] The best method for the regioselective bromi-
E-mail: ltietze@gwdg.de
510
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Chem. Eur. J. 2000, 6, No. 3

510±518
O
O
( )n
C
R
R
R
R
N
( )m
N
( )m
a, b
c, d
Cl
OH
A
B
A
( )n
+
( )o
D
( )o
( )o
OTs
C
Br
( )n
( )n
OEt
H
D
( )o
Prod.
n
o
Yield
10
11
15a : o = 1
15b : o = 2
16a : n = 1
16b : n = 2
16c : n = 3
17a
17b
17c
17d
1
2
3
1
1
1
1
2
50%
80%
38%
67%
OCH O or
R/R=
2
R
m
n
OMe
=
= 0, 1, 2
= 1, 2, 3
= 1, 2
H
N
R
R
( )m
( )n
A
o
OAc
Br
( )o
H
D
R
R
N
e
( )m
( )n
( )o
12
OAc
( )o
OTs
Br
( )n
OAc
Yield
R
R
NH2
TsO
Prod.
Prod.
m
R/R
n
o
Yield
n
o
( )m
( )n
A
+
14a
14b
14c
14d
12a
12b
12c
12d
12e
12f
0
0
1
1
1
1
1
2
OCH2O
OCH2O
OCH2O
OCH2O
OCH2O
OMe
1
2
3
1
1
1
1
2
93%
95%
92%
83%
1
2
1
1
2
2
3
2
1
1
1
2
1
1
1
2
82%
74%
72%
85%
62%
85%
79%
90%
Br
( )
o D
OAc
13a : m = 0, R/R = OCH2O
13b : m = 1, R/R = OCH2O
13c : m = 2, R/R = OCH2O
13d : m = 2, R = MeO
14a : n = 1, o = 1
14b : n = 2, o = 1
14c : n = 3, o = 1
14d : n = 1, o = 2
OCH2O
OCH2O
12g
12h
Scheme 2. Retrosynthesis of ring-size analogues 10 of cephalotaxine (1).
Scheme 3. Synthesis of the secondary amines 12. a) MeMgCl (3.6m in
THF), THF, 788C !room temperature; then Mg, reflux; then 15a/b,
108C !RT; then NH4Cl solution; HCl (2m); b) TsCl, py, 108C or TsCl,
DMAP, Et3N, 108C; c) DIBAL (1.5m in toluene), toluene, 508C;
d) Ac2O, Et3N, DMAP, CH2Cl2, 08C; e) 13, TBAI (1.5 equiv), THF, reflux.
nation of the aromatic ring consists of a protection of the
amino function, to avoid oxidation by the formation of the
hydrochloride, followed by treatment with bromine in acetic
acid, and a basic workup. In all cases, the crude products
obtained were clean enough to allow a further utilization
without purification.
THF as the solvent was superior to DMSO. The best results
were obtained with 2 ± 3.5 equivalents of the primary amine
13 without addition of any base. Thus, with a ratio of amine 13
to tosylate 14 ranging from 0.8:1 to 1.5:1 in the presence of 1
to 5 equivalents of triethylamine or diisopropylamine, the
yields of the secondary amines 12 were only 35 ± 65%. We also
used the preformed iodides obtained by a Finkelstein reaction
of 14 with NaI in quantitative yield; however, this procedure
did not show any advantage to the in-situ preparation of the
alkylating agent.
The palladium-catalyzed intramolecular amination[11a, 14] of
12a ± h was performed with [Pd(PPh3)4] and tetramethylgua-
nidine as the base at 40 ± 508C. In this way, the spirocyclic
tertiary amines 11a ± c,e,f,h could be obtained from 12a ±
c,e,f,h in 43 ± 88% yield (Scheme 4, Table 1). However, it
was not possible to transform the secondary amine 12d, which
contains a cyclohexenylacetate moiety, into the corresponding
spirocyclic compounds. This can be explained by the lower
reactivity of the cyclohexenyl compared to the cyclopentenyl
acetate which results in a preferred oxidative addition of the
Pd to the bromoarene moiety thus terminating the reaction. In
addition, 12g also failed to give a spirocyclic azepine moiety;
here again the activation energy seems to be too high so that
an oxidative addition takes place preferentially. To prove this
assumption, we prepared 18 without a halogen at the arene
moiety. Indeed, the reaction at 758C with [Pd(PPh3)4] gave the
desired spirocyclic amine 19 in 74% yield after 20 hours
(Scheme 5).
The synthesis of the allylic acetates 14a ± d[11] was found to
be more demanding on account of their instability, especially
in the case of the cyclopentene derivatives. The approach was
similar for all four compounds. The vinylogous esters 15a[12]
and 15b[13] were treated with a Grignard reagent obtained
from the w-chloro alkanols 16a ± c, wherein the hydroxy
function is protected as a magnesium salt by means of methyl
magnesium chloride. After aqueous workup, the crude
alcohols were tosylated to give the slightly more stable
tosylates 17a ± d.[11] For the synthesis of the necessary allylic
acetates 14a ± d the enone moiety in the tosylates 17a ± d was
reduced regioselectively with diisobutylaluminum hydride
(DIBAL) and the corresponding alcohols were then immedi-
ately transformed into the allylic acetates by treatment with
acetic anhydride in dichloromethane in nearly quantitative
yield. The allylic alcohols obtained as intermediates are very
unstable, whereas the allylic acetates can be kept in the
refrigerator for several days without decomposition. How-
ever, after several weeks these compounds also decompose;
the smell of acetic acid is evolved (Scheme 3).
The alkylation of the amines 13a ± d with the tosylates
14a ± d, after their in-situ transformation into the iodides with
tetrabutylammonium iodide (TBAI), afforded the secondary
amines 12a ± h in 70 ± 90% yield (Scheme 3). Several reaction
conditions for the alkylation reaction were tested; in all cases
Chem. Eur. J. 2000, 6, No. 3
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511

L. F. Tietze et al.
FULL PAPER
nitrogen. We assume that this can be attributed to steric
reasons; however, a coordinative influence of the nitrogen
cannot be excluded. From these reactions we obtained
analogues of cephalotaxine in which the pentacyclic core
had different sizes of the rings BCD, that is 10a (6,5,5), 10c
(7,6,5), 10d (6,6,5), and 10e (7,6,5). As expected, the
formation of the analogue 10 f, with a (8,6,5) pattern, did
not take place. So far we have not yet succeeded in obtaining
an eight-membered ring by a Heck reaction with a variety of
substrates.
catalyst 20 (4 - 10 mol%)
nBu4NOAc (2.0 - 3.0 equiv)
CH3CN / DMF / H2O (5 : 5 : 1)
110 - 120 °C, 3 - 7 h
( )n
R
R
N
[Pd(PPh3)4], TMG,
CH3CN, 45 °C
( )m
12
Br
11a-c,e,f,h
10
O
9
8
6
7
MeO
O
N
B
13b
A
13
C
5
N
N
O
12
O
4
MeO
H
D
3
H
H
1
2
The structures of the newly formed compounds were
determined by NMR spectroscopy. For example, the spectro-
scopic data of 10a show signals of the aromatic hydrogens at
d ˆ 6.55 and d ˆ 6.60, whereas the hydrogens of the double
bond resonate as a dddd at d ˆ 5.68 with J ˆ 6.0, 2.3, 2.3,
2.3 Hz for 1-H and at d ˆ 6.75 as a dddd with J ˆ 6.0, 2.3, 2.1,
2.0 Hz for 2-H. For 13b-H a broad singlet is observed at d ˆ
3.41. Significant signals in the 13C NMR spectrum are found at
d ˆ 129.6 for C1 and d ˆ 132.8 for C2, while C13b resonates at
d ˆ 50.29 and C3a at d ˆ 69.30.
10a: 80%
10b: 81%
10c: 87%
O
O
O
O
O
N
N
N
O
H
H
H
10d: 81%
10e: 84%
10f: --
oTol oTol
O
O
P
For all compounds 10a ± e, molecular peaks are found in the
high-resolution mass spectra.
Pd
Pd
P
O
O
oTol oTol
20
Scheme 4. Synthesis of the pentacyclic compounds 10 by intramolecular
Heck reaction of 11.
Conclusions
A new and highly efficient synthesis has been established for
analogues 10a,c ± e of the pentacyclic core of cephalotaxine
(1) by means of two successive Pd-catalyzed transformations.
Cyclopentenylacetates were found to be much more reactive
in the palladium-catalyzed allylic aminations than the corre-
sponding cyclohexenyl compounds. In the Heck reactions, the
cyclopentene moiety reacts smoothly and with high yield to
give the final tetra- or pentacyclic products 10a ± e. Analogues
with a six-membered ring D and an eight-membered ring B
could not be obtained by the described process.
Table 1. Synthesis of the spirocyclic compounds 11 by palladium-catalyzed
allylic amination of 12.
Substrate
m
n
o
R/R
Product
Yield [%]
12a
12b
12c
12d
12e
12 f
12g
12h
0
0
1
1
1
1
1
2
1
2
1
1
2
2
3
2
1
1
1
2
1
1
1
1
OCH2O
OCH2O
OCH2O
OCH2O
OCH2O
MeO
11a
11b
11c
11d
11e
11 f
11g
11h
65
59
88
±
57
43
±
OCH2O
OCH2O
67
Experimental Section
H
[Pd(PPh3)4] (15 mol%),
Et3N, CH3CN, 75 °C
N
O
O
N
O
O
All reactions were performed under a nitrogen or argon atmosphere in
flame-dried flasks, and the reactants were introduced by syringe. All
solvents were dried by standard methods. Solvents used in Pd-catalyzed
reactions were degassed by pump and freeze methodology. All reagents
obtained from commercial sources were used without further purification.
Thin-layer chromatography was performed on precoated silica gel plates
(SIL G/UV254, Macherey-Nagel GmbH & Co. KG). Silica gel 32 ± 63
(0.032 ± 0.064 mm) (Macherey-Nagel GmbH & Co. KG) was used for
column chromatography.
74%
OAc
18
19
Scheme 5. Synthesis of spirocyclic amine 19.
The final Heck reaction of the spirocyclic amines 11 was
performed under the conditions which were optimized for our
cephalotaxine synthesis.[4] The substrates were stirred in a
degassed solvent mixture containing acetonitrile, dimethyl-
formamide, and water (ratio 5:5:1) in the presence of tetra-n-
butylammonium acetate (2.1 equiv), and catalytic amounts of
the palladacycle trans-di(m-acetato)-bis[o-(di-o-tolylphos-
phino)benzyl]dipalladium(ii) (20).[15] The transformations
proceeded in all cases except one (10 f) to give the desired
products 10a ± e stereoselectively and in high yields. Thus,
only one diastereomer is formed by a Re attack of the
bromoarene moiety to the cyclopentene system syn to the
UV/Vis spectra were recorded in CH3CN on
a Mettler Lambda 2
spectrometer. IR spectra were recorded as KBr pellets or as films on a
Bruker IFS25 or Vector 22 spectrometer. 1H and 13C NMR spectra were
recorded on a Varian XL200, VXR200 and VXR500 or a Bruker AM300
with tetramethylsilane (TMS) as the internal standard in [D]chloroform or
[D6]benzene. Multiplicities of 13C NMR peaks were determined with the
APT pulse sequence. Mass spectra were measured at 70 eV on a Varian
MAT311A, high-resolution mass spectra on a Varian MAT731 instrument.
Melting points were measured on a Mettler FP61.
3-(6-Bromo-benzo[1,3]dioxol-5-yl)-propylamine (13c): The hydrochloride
of 3-benzo[1,3]dioxol-5-yl-propylamine[16] (4.01 g, 18.5 mmol) was dis-
solved in acetic acid (50 mL) and treated with bromine (4.01 g, 25.1 mmol,
1.4 equiv). After 3 h, Na2SO3 solution (5%) was added, and the mixture
512
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Chem. Eur. J. 2000, 6, No. 3

Cephalotaxine Analogues
510±518
was basified with aqueous NaOH solution (20%). After extraction with
CH2Cl2 (4Â) the combined organic layers were dried over Na2SO4, and the
solvent was removed in vacuo to give the amine 13c (4.68 g, 18.1 mmol,
98%) as a pale yellow oil. An analytical probe was purified via the
hydrochloride, which was then recrystallized from MeOH/tert-butyl methyl
4'-H2), 4.00 (t, J ˆ 6.4 Hz, 2H, OCH2), 5.87 (s, 1H, 2'-H), 7.33 (d, J ˆ 8.0 Hz,
2H, Ar-2-H, Ar-6-H), 7.76 (d, J ˆ 8.0 Hz, 2H, Ar-3-H, Ar-5-H); 13C NMR
(50.3 MHz, CDCl3): d ˆ 21.56 (CH3), 25.07 (C3), 26.27 (C4), 28.47 (C2),
31.39 (C5'), 33.13 (C5), 35.19 (C4'), 70.11 (OCH2), 127.7 (Ar-C3, Ar-C5),
129.4 (C2'), 129.8 (Ar-C2, Ar-C6), 132.9 (Ar-C4), 144.7 (Ar-C1), 182.3
‡
‡
‡
ether (MTBE). IR (KBr): nÄ ˆ 3314 (N H), 2932 (C H), 1572 (NH3 ), 1478,
(C1'), 209.9 (C3'); MS (70 eV, EI): m/z (%): 322 (96) [M ], 167 (90) [M
1
‡
‡
‡
1232, 1113, 1038, 933 (C-O-C), 860, 826 cm (hydrochloride); UV
Ts], 155 (16) [Ts ], 151 (31) [M
TsO], 109 (100) [C7H9O ], 91 (91)
‡
(CH3CN): lmax (lge) ˆ 202.0 (4.597), 237.0 (3.690), 294.5 (3.661) nm
[PhCH3 ]; C17H22O4S (322.4): calcd C 63.33 H 6.88; found C 63.03, H 6.74.
1
(hydrochloride); H NMR (200 MHz, CDCl3): d ˆ 1.46 (s, 2H, NH2), 1.71
3-[5-(Toluene-4-sulfonyloxy)pentyl]cyclopent-2-enyl acetate (14c): Cyclo-
pentenone 17c (4.57 g, 14.2 mmol) was dissolved in toluene (70 mL) and
cooled to 508C. A DIBAL solution in toluene (1.5m, 11.5 mL, 17.3 mmol,
1.2 equiv) was added dropwise with the aid of a syringe pump. After the
addition of celite (4 g), a 1:1 mixture of methanol and water (4 mL) was
added, and the mixture was warmed to room temperature, filtered, and
flushed again with ethyl acetate. The filtrate was dried over Na2SO4 and
evaporated. The crude allylic alcohol, as a 0.3m solution in CH2Cl2, was
acetylated at 08C with acetic anhydride (1.53 g, 15.0 mmol, 1.06 equiv),
triethylamine (1.65 g, 16.3 mmol, 1.2 equiv), and DMAP (173 mg,
1.42 mmol, 0.1 equiv). The mixture was stirred for 1.5 h and then poured
into a cold, half-saturated solution of NaHCO3. The organic layer was
extracted with CH2Cl2 (3 Â ) and the combined organic fractions were dried
over Na2SO4 and evaporated. The residue was purified by chromatography
on silica gel (220 g SiO2, petroleum ether/ethyl acetate ˆ 7:2) to give the
allylic acetate 14c (4.76 g, 13.0 mmol, 92%) as a colorless oil. Rf ˆ 0.32 (PE/
(tt, J ˆ 7.7, 7.1 Hz, 2H, CH2), 2.64 ± 2.72 (m, 2H, ArCH2), 2.75 (t, J ˆ 7.1 Hz,
2H, NCH2), 5.94 (s, 2H, OCH2O), 6.71 (s, 1H, 4-H), 6.98 (s, 1H, 7-H);
13C NMR (50.3 MHz, CDCl3): d ˆ 33.31 (ArCH2), 34.11 (CH2), 41.61
(NCH2), 101.4 (OCH2O), 109.7 (C4), 112.6 (C7), 114.1 (C6), 134.3 (C5),
‡
146.4 (C3a), 147.2 (C7a); MS (70 eV, EI): m/z (%): 258 (6) [M ], 213 (8)
‡
‡
‡
[M
C2H6N], 178 (100) [M
Br], 150 (51) [C9H10O2 ], 131 (21);
C10H12BrNO2 (258.1): calcd C 40.63, H 4.77; found C 40.93, H 4.52
(hydrochloride).
4-(3-Oxocyclopent-1-enyl)butyl toluene-4-sulfonate (17b): A solution of
4-chlorobutan-1-ol (16b) (6.44 g, 59.3 mmol) in THF (60 mL) was cooled to
788C and methylmagnesium chloride (3.8m in THF, 15.6 mL, 59.3 mmol,
1.0 equiv) was added dropwise. After the addition was complete the
solution was allowed to warm to room temperature. When the gas
production ceased, magnesium turnings (1.59 g, 65.4 mmol, 1.1 equiv) were
added, and the solution was heated to reflux for 3 h. Subsequently, the
ˆ
EtOAc ˆ 7:2); IR (neat): nÄ ˆ 2931 (C H), 1713 (C O), 1598, 1359 (SO2),
reaction mixture was cooled to
108C, 3-ethoxy-cyclopent-2-enone
1268 (C ± O), 1176 (SO2), 1098, 947, 816 (arene), 664 cm 1; UV (CH3CN):
lmax (lge) ˆ 224.5 (4.079), 255.0 (2.800), 261.5 (2.837), 272.5 nm (2.707);
1H NMR (200 MHz, C6D6): d ˆ 0.85 ± 1.16 (m, 4H, 2'-H2, 3'-H2), 1.25 (tt,
J ˆ 6.8, 6.8 Hz, 2H, 4'-H2), 1.66 ± 1.89 (m, 4H, 1'-H2, 5-H2), 1.74 (s, 3H,
COCH3), 1.89 (s, 3H, Ar-CH3), 2.03 ± 2.24 (m, 2H, 4-H2), 3.80 (t, J ˆ 6.5 Hz,
2H, OCH2), 5.50 (brs, 1H, 2-H), 5.70 ± 5.82 (m, 1H, 1-H), 6.77 (d, J ˆ
8.1 Hz, 2H, Ar-2-H, Ar-6-H), 7.78 (d, J ˆ 8.1 Hz, 2H, Ar-3-H, Ar-5-H);
13C NMR (50.3 MHz, C6D6): d ˆ 20.99 (COCH3), 21.15 (Ar-CH3), 25.30
(C3'), 26.86 (C2'), 28.83 (C4'), 30.84 (C5), 31.03 (C1'), 33.59 (C4), 70.15
(OCH2), 80.89 (C1), 123.3 (C2), 128.1 (Ar-C3, Ar-C5), 129.8 (Ar-C2, Ar-
C6), 134.5 (Ar-C4), 144.2 (Ar-C1), 151.7 (C3), 170.2 (CO); C19H26O5S
(366.5).
(15a)[12] (5.05 g, 40.0 mmol) was added, and the mixture was stirred for
1.5 h. The mixture was warmed to 08C, and saturated NH4Cl solution
(10 mL) was added. The mixture was partitioned between cold ethyl
acetate (100 mL) and HCl (50 mL, 2n). The layers were separated, and the
aqueous phase was extracted with ethyl acetate. The combined organic
fractions were dried over Na2SO4 and evaporated. The crude product was
dissolved in CH2Cl2 (80 mL) and cooled to 108C. Tosyl chloride (8.31 g,
43.6 mmol, 1.1 equiv), triethylamine (7.40 mL, 53.0 mmol, 1.3 equiv), and
4-dimethylaminopyridine (DMAP) (242 mg, 1.98 mmol, 0.05 equiv) were
added, and the mixture was stirred at 108C for 18 h, then partitioned
between ethyl acetate and
a saturated solution of NaHCO3. After
separation, the organic layer was washed with HCl (1n) and brine, dried
over Na2SO4, and concentrated. Purification by column chromatography
(1000 g SiO2, petroleum ether/ethyl acetate ˆ 2:3) afforded 17b (9.82 g,
31.8 mmol, 80%) as a colorless oil. Rf ˆ 0.34 (PE/EtOAc ˆ 2:3); IR (KBr):
3-(3-Iodopropyl)cyclohex-2-enyl acetate: The tosylate 14d (5.11 g,
14.5 mmol) was dissolved in acetone (500 mL). After addition of sodium
iodide (10.2 g, 68.1 mmol, 4.7 equiv) the mixture was refluxed for 1.5 h.
Water and MTBE were added and, after separation, the aqueous layer was
extracted with MTBE (3 Â ). The combined organic layers were dried over
Na2SO4 and evaporated. The residue was purified by column chromatog-
raphy (200 g SiO2, petroleum ether/ethyl acetate ˆ 14:1) to afford the title
compound (4.33 g, 14.1 mmol, 97%) as a colorless oil. Rf ˆ 0.37 (PE/
ˆ
ˆ
ˆ
nÄ ˆ 2961 ( C H), 1708 (C O), 1617 (C C), 1597, 1356 (SO2), 1188, 1174
(SO2), 942, 817, 665 cm 1; UV (CH3CN): lmax (lge) ˆ 194.0 (4.687), 224.0
(4.433), 255.0 (2.813), 261.5 (2.859), 266.5 (2.829), 272.5 (2.777), 302.0 nm
(2.395); 1H NMR (200 MHz, CDCl3): d ˆ 1.54 ± 1.76 (m, 4H, 2-H2, 3-H2),
2.32 ± 2.42 (m, 4H, 4-H2, 5'-H2), 2.44 (s, 3H, CH3), 2.55 (m, 2H, 4'-H2), 4.07
(t, J ˆ 6.4 Hz, 2H, OCH2), 5.87 (s, 1H, 2'-H), 7.36 (d, J ˆ 8.0 Hz, 2H, Ar-2-
H, Ar-6-H), 7.78 (d, J ˆ 8.0 Hz, 2H, Ar-3-H, Ar-5-H); 13C NMR (50.3 MHz,
CDCl3): d ˆ 21.57 (CH3), 22.90 (C3), 28.35 (C2), 31.33 (C5'), 32.58 (C4),
35.17 (C4'), 69.81 (OCH2), 127.7 (Ar-C3, Ar-C5), 129.5 (C2'), 129.8 (Ar-C2,
Ar-C6), 132.8 (Ar-C4), 144.8 (Ar-C1), 181.6 (C1'), 209.7 (C3'); MS (70 eV,
ˆ
ˆ
ˆ
EtOAc ˆ 14:1); IR (neat): nÄ ˆ 2937 ( C H), 1729 (C O), 1666 (C C),
1242 (C ± O), 1019 cm 1; UV (CH3CN): lmax (lge) ˆ 252.0 nm (2.855);
1H NMR (200 MHz, C6D6): d ˆ 1.43 ± 1.77 (m, 10H, 1'-H2, 2'-H2, 4-H2,
5-H2, 6-H2), 1.77 (s, 3H, CH3), 2.68 (t, J ˆ 6.9 Hz, 2H, 3'-H2), 5.34 ± 5.44 (m,
1H, 1-H), 5.55 (m, 1H, 2-H); 13C NMR (50.3 MHz, C6D6): d ˆ 5.99 (C3'),
19.41 (C5), 21.03 (CH3), 28.25, 28.48 (C4, C6), 31.35 (C2'), 38.18 (C1'), 68.44
(C1), 121.4 (C2), 142.0 (C3), 169.9 (CO); MS (70 eV, EI): m/z (%): 308 (5)
‡
‡
‡
EI): m/z (%): 308 (100) [M ], 206 (12), 155 (14) [Ts ], 153 (48) [M
136 (74) [M
Ts],
‡
‡
TsOH], 109 (80), 91 (87) [CH3Ph ]; C16H20O4S (308.4);
‡
‡
‡
‡
calcd C 62.32, H 6.54; found C 62.38, H 6.48; HRMS calcd 308.1082; found
308.1082.
[M ], 266 (38) [M
Ac‡H], 248 (100) [M
AcOH], 139 (19) [C9H14O ],
‡
‡
‡
‡
121 (17) [C9H13 ], 97 (50) [C6H9O ], 93 (78) [C7H9 ], 79 (54) [C6H7 ].
C11H17IO2 (308.2): calcd C 42.87, H 5.56; found C 43.05; H 5.57; HRMS
calcd 308.0273; found 308.0273.
5-(3-Oxocyclopent-1-enyl)pentyl toluene-4-sulfonate (17c): Analogous to
17b, 5-chloropentan-1-ol (16c) (7.30 g, 59.6 mmol) was deprotonated with
methylmagnesium chloride solution (3.8m in THF, 16.0 mL, 60.8 mmol,
1.0 equiv) and treated with magnesium turnings (1.60 g, 65.8 mmol,
1.1 equiv) in THF (120 mL). Subsequently, 3-ethoxycyclopent-2-enone
(15a)[12] (4.95 g, 39.2 mmol) was added. After aqueous workup, the crude
product was tosylated in CH2Cl2 with tosyl chloride (8.31 g, 43.6 mmol,
1.1 equiv), triethylamine (7.40 mL, 53.0 mmol, 1.3 equiv), and DMAP
(250 mg, 2.05 mmol, 0.05 equiv). Purification by column chromatography
(900 g SiO2, petroleum ether/ethyl acetate ˆ 1:1) afforded 17c (4.86 g,
15.1 mmol, 38%) as a colorless oil. Rf ˆ 0.30 (PE/EtOAc ˆ 1:1); IR (neat):
General procedure I: alkylation of primary amines 13: A 1m solution of the
amine 13 (2.5 equiv) in THF was heated with TBAI (1.5 equiv) to reflux
and a 0.5m solution of the tosylate 14 was added dropwise with an infusion
pump over a period of 8 h. The mixture was heated for additional 2 h,
poured into MTBE, and basified with cold 5% NaOH solution. The
aqueous layer was extracted with MTBE (4Â). The combined organic
layers were dried over Na2SO4 and evaporated. The crude product was
purified by column chromatography.
3-{3-[(6-Bromobenzo[1,3]dioxol-5-ylmethyl)amino]propyl}cyclopent-2-
enyl acetate (12a): According to general procedure I, 13a (1.01 g,
4.37 mmol, 2.5 equiv) in THF (5 mL) was alkylated with 14a (582 mg,
1.72 mmol) in THF (3 mL) in the presence of TBAI (1.00 g, 2.71 mmol,
1.6 equiv). Purification by column chromatography (70 g SiO2, gradient
column: 300 mL ethyl acetate; then ethyl acetate/MeOH ˆ 20:1, 1% Et3N)
afforded 12a (562 mg, 1.42 mmol, 82%) as a pale yellow oil. Rf ˆ 0.59
ˆ
ˆ
ˆ
nÄ ˆ 2933 ( C H), 1705 (C O), 1615 (C C), 1599, 1357 (SO2), 1188, 1176
(SO2), 947, 817, 665 cm 1; UV (CH3CN): lmax (lge) ˆ 194.0 (4.706), 224.5
(4.416), 261.5 (2.898), 266.5 (2.876), 272.5 (2.843), 304.0 nm (2.653);
1H NMR (500 MHz, CDCl3): d ˆ 1.36 (tt, J ˆ 7.7, 7.6 Hz, 2H, 3-H2), 1.52
(tt, J ˆ 7.7, 7.6 Hz, 2H, 4-H2), 1.66 (tt, J ˆ 7.6, 6.4 Hz, 2H, 2-H2), 2.34 (t, J ˆ
7.6 Hz, 2H, 5-H2), 2.36 (m, 2H, 5'-H2), 2.42 (s, 3H, CH3), 2.51 ± 2.54 (m, 2H,
Chem. Eur. J. 2000, 6, No. 3
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0603-0513 $ 17.50+.50/0
513

L. F. Tietze et al.
FULL PAPER
ˆ
ˆ
(EtOAc/MeOH ˆ 5:1, 1% Et3N); IR (neat): nÄ ˆ 3341 (N H), 2933 (C H),
1728 (C O), 1666 (C C), 1480, 1370, 1246 (C ± O), 1116, 1040, 934 (C-O-
C), 910, 860, 834 cm (arene); UV (CH3CN): lmax (lge) ˆ 201.0 (4.659),
1
ˆ
ˆ
1726 (C O), 1651 (C C), 1478, 1244 (C ± O), 1120, 1037, 932 (C-O-C), 877,
831 (arene) cm 1; UV (CH3CN): lmax (lge) ˆ 201.0 (4.609), 240.5 (3.758),
235.0 (3.720), 294.0 nm (3.661); 1H NMR (500 MHz, CDCl3): d ˆ 1.59 ± 1.82
(m, 7H, 2'-H2, 5-H2, 6-H2, NH), 1.89 ± 2.05 (m, 4H, 1'-H2, 4-H2), 2.04 (s, 3H,
CH3), 2.66 (t, J ˆ 7.4 Hz, 2H, 3'-H2), 2.82 ± 2.90 (m, 4H, 1''-H2, 2''-H2),
5.23 ± 5.27 (m, 1H, 1-H), 5.46 (m, 1H, 2-H), 5.96 (s, 2H, OCH2O), 6.75 (s,
1H, 4'''-H), 7.00 (s, 1H, 7'''-H); 13C NMR (50.3 MHz, CDCl3): d ˆ 19.05
(C5), 21.40 (CH3), 27.62 (C2'), 28.13, 28.21 (C4, C6), 35.19 (C1'), 43.63
(C2''), 48.57 (C3'), 53.49 (C1''), 68.67 (C1), 101.6 (OCH2O), 110.0 (C4'''),
112.6 (C7'''), 113.9 (C6'''), 119.6 (C2), 132.5 (C5'''), 144.1 (C3), 147.2 (C3a''',
1
293.5 nm (3.587); H NMR (500 MHz, CDCl3): d ˆ 1.78 (tt, J ˆ 7.6, 7.4 Hz,
2H, 2'-H2), 1.83 (dddd, J ˆ 14.2, 9.0, 4.0, 3.2 Hz, 5-Hcis), 2.02 (s, 3H, CH3),
2.16 ± 2.25 (m, 3H, 1'-H2, 4-H), 2.31 (dddd, J ˆ 14.2, 9.0, 7.5, 5.0 Hz, 1H,
5-Htrans), 2.41 ± 2.49 (m, 1H, 4-H), 2.68 (t, J ˆ 7.2 Hz, 2H, 3'-H2), 2.85 (brs,
1H, NH), 3.85 (s, 2H, 1''-H2), 5.47 (m, 1H, 2-H), 5.61 ± 5.66 (m, 1H, 1-H),
5.97 (s, 2H, OCH2O), 6.99 (s, 1H, Ar H), 7.01 (s, 1H, Ar H); 13C NMR
(50.3 MHz, CDCl3): d ˆ 21.36 (CH3), 27.33 (C2'), 28.82 (C1'), 30.30 (C5),
33.46 (C4), 48.36 (C3'), 53.12 (C1''), 80.87 (C1), 101.7 (OCH2O), 110.3
(C4'''), 112.7 (C7'''), 114.2 (C6'''), 122.6 (C2), 131.4 (C5'''), 147.3 (C3a'''),
147.5 (C7a'''), 151.9 (C3), 171.1 (CO); MS (70 eV, CI (NH3)): m/z (%): 396/
‡
C7a'''), 170.8 (CO); MS (70 eV, EI): m/z (%): 425/423 (<1) [M ], 210 (15)
‡
‡
‡
[C12H20NO2 ], 150 (100) [C10H16N ], 121 (6) [C9H13 ]; C20H26BrNO4
(424.3): calcd C 56.61, H 6.18, Br 18.83; found C 56.69, H 6.30, Br 18.87;
HRMS calcd 423.1045; found 423.1045.
‡
‡
‡
394 (4) [M‡H ], 338/336 (13/14) [M
AcO], 318 (20) [M
Br‡2H],
280/278 (8/11), 258 (27), 184/182 (42), 169 (100), 152/150 (93/90), 124 (56)
[C8H14N ]; C18H22BrNO4 (396.3).
3-{4-[2-(6-Bromobenzo[1,3]dioxol-5-yl)ethylamino]butyl}cyclopent-2-enyl
acetate (12e): According to general procedure I, the amine 13b (1.73 g,
7.09 mmol, 2.5 equiv) was alkylated with tosylate 14b (995 mg, 2.82 mmol)
in the presence of TBAI (1.71 mg, 4.64 mmol, 1.6 equiv). Purification by
column chromatography (120 g SiO2, gradient column: 300 mL ethyl
acetate; then ethyl acetate/MeOH ˆ 15:1, 1% Et3N) afforded 12e (739 mg,
1.74 mmol, 62%) as a pale yellow oil. Rf ˆ 0.67 (EtOAc/MeOH ˆ 5:1, 1%
‡
3-{4-[(6-Bromobenzo[1,3]dioxol-5-ylmethyl)amino]butyl}cyclopent-2-enyl
acetate (12b): According to general procedure I, the amine 13a (2.61 g,
11.4 mmol, 2.5 equiv) was alkylated with tosylate 14b (1.63 g, 4.63 mmol) in
the presence of TBAI (2.56 g, 6.93 mmol, 1.5 equiv). Purification by column
chromatography (80 g AloxB, petroleum ether/MTBE ˆ 1:3) afforded 12b
(1.40 g, 3.41 mmol, 74%) as pale yellow oil. Rf ˆ 0.63 (PE/EtOAc/
MeOH ˆ 10:5:1, 1% Et3N); IR (neat): nÄ ˆ 3338 (N H), 2930 (C H),
ˆ
ˆ
Et3N); IR (neat): nÄ ˆ 3322 (N H), 2931 (C H), 1727 (C O), 1651 (C C),
1
1478, 1245 (C ± O), 1115, 1039, 933 (C-O-C), 861, 834 cm (arene); UV
ˆ
ˆ
1727 (C O), 1651 (C C), 1478, 1245 (C ± O), 1119, 1037, 933 (C-O-C), 875,
830 (arene) cm 1; UV (CH3CN): lmax (lge) ˆ 201.0 (4.623), 236.0 (3.714),
293.5 nm (3.622); 1H NMR (500 MHz, C6D6): d ˆ 0.83 (brs, 1H, NH),
1.23 ± 1.36 (m, 4H, 2'-H2, 3'-H2), 1.73 (s, 3H, CH3), 1.81 ± 1.93 (m, 4H, 1'-H2,
5-H2), 2.13 (dddd, J ˆ 14.8, 8.7, 7.6, 5.7 Hz, 1H, 4-H), 2.19 ± 2.26 (m, 1H,
4-H), 2.37 (t, J ˆ 6.8 Hz, 2H, 4'-H2), 3.66 (s, 2H, 1''-H2), 5.22 (s, 2H,
OCH2O), 5.60 (m, 1H, 2-H), 5.79 ± 5.83 (m, 1H, 1-H), 6.94 (s, 1H, Ar H),
7.01 (s, 1H, Ar H); 13C NMR (50.3 MHz, C6D6): d ˆ 20.99 (CH3), 25.37
(C2'), 30.23 (C5), 30.70 (C3'), 31.27 (C1'), 33.63 (C4), 49.11 (C4'), 53.61
(C1''), 80.96 (C1), 101.6 (OCH2O), 110.0 (C4'''), 112.8 (C7'''), 114.0 (C6'''),
123.3 (C2), 133.8 (C5'''), 147.6 (C3a'''), 147.9 (C7a'''), 151.9 (C3), 170.2
(CH3CN): lmax (lge) ˆ 201.0 (4.622), 237.5 (3.714), 294.0 nm (3.641);
1H NMR (200 MHz, CDCl3): d ˆ 1.51 (m, 5H, 2'-H2, 3'-H2, NH), 1.78 ±
1.92 (m, 1H, 5-Hcis), 2.03 (s, 3H, CH3), 2.14 (m, 2H, 1'-H2), 2.19 ± 2.54 (m,
3H, 4-H2, 5-Htrans), 2.65 (m, 2H, 4'-H2), 2.83 (m, 4H, 1''-H2, 2''-H2), 5.44 ±
5.50 (brs, 1H, 2-H), 5.60 ± 5.68 (m, 1H, 1-H), 5.95 (s, 2H, OCH2O), 6.74 (s,
1H, 4'''-H), 6.99 (s, 1H, 7'''-H); 13C NMR (50.3 MHz, CDCl3): d ˆ 21.37
(CH3), 25.14 (C2'), 29.84 (C3'), 30.29 (C5), 31.05 (C1'), 33.45 (C4), 36.48
(C2''), 49.54, 49.63 (C1'', C4'), 80.96 (C1), 101.5 (OCH2O), 110.1 (C4'''),
112.7 (C7'''), 114.4 (C6'''), 122.3 (C2), 132.3 (C5'''), 146.7 (C3a'''), 147.2
(C7a'''), 152.4 (C3), 171.1 (CO); MS (70 eV, EI): m/z (%): 426/424 (<1)
‡
‡
‡
‡
[M‡H ], 425/423 (<1) [M ], 366/364 (9/10) [M
AcO], 284 (4) [M
‡
‡
‡
(CO); MS (70 eV, CI (NH3)): m/z (%): 412/410 (87/92) [M‡H ], 352/350
Br AcOH], 210 (17) [C12H20NO2 ], 150 (100) [C10H16N ]; C20H26BrNO4
(424.3): calcd C 56.61, H 6.18; found C 56.37, H 6.00; HRMS calcd 423.1045;
found 423.1045.
‡
‡
‡
(73/75) [M
AcO], 332 (37) [M
Br‡2H], 249/247 (34/35)
‡
[C8H9BrNO2 ‡NH3], 232/230 (13/16) [C8H9BrNO2 ], 198/196 (31/27),
‡
‡
‡
169 (100) [C10H18N ‡NH3], 152 (36) [C10H18N ], 150 (43) [C10H16N ],
3-{4-[2-(2-Bromo-4,5-dimethoxyphenyl)ethylamino]butyl}cyclopent-2-en-
yl acetate (12 f): According to general procedure I, the amine 13d (1.87 g,
7.29 mmol, 2.5 equiv) was alkylated with tosylate 14b (1.00 g, 2.84 mmol) in
the presence of TBAI (1.58 g, 4.28 mmol, 1.5 equiv). Purification by column
chromatography (140 g AloxB, gradient column: 300 mL petroleum ether/
MTBE ˆ 1:3; then ethyl acetate/MeOH ˆ 30:1, 1% Et3N) afforded 12 f
(1.06 g, 2.41 mmol, 85%) as a pale yellow oil. Rf ˆ 0.46 (EtOAc/MeOH ˆ
‡
138 (49) [C9H16N ]; C19H24BrNO4 (410.3): calcd C 55.62, H 5.90; found C
55.76, H 5.95.
3-{3-[2-(6-Bromobenzo[1,3]dioxol-5-yl)ethylamino]propyl}cyclopent-2-en-
yl acetate (12c): According to general procedure I, the amine 13b (741 mg,
3.04 mmol, 2.0 equiv) was alkylated with tosylate 14a (505 mg, 1.49 mmol)
in the presence of TBAI (804 mg, 2.18 mmol, 1.5 equiv). Purification by
column chromatography (90 g SiO2, gradient column: 150 mL ethyl
acetate; 300 mL ethyl acetate/MeOH ˆ 15:1, 1% Et3N; then ethyl ace-
tate/MeOH ˆ 5:1, 1% Et3N) afforded 12c (438 mg, 1.07 mmol, 72%) as a
pale yellow oil. Rf ˆ 0.54 (EtOAc/MeOH ˆ 5:1, 1% Et3N); IR (neat): nÄ ˆ
ˆ
5:1, 1% Et3N); IR (neat): nÄ ˆ 3324 (N H), 2933 (C H), 1727 (C O), 1651
1
ˆ
(C C), 1508, 1380, 1255 (C ± O), 1164, 1024 (Ar-O-C), 877, 800 cm
(arene); UV (CH3CN): lmax (lge) ˆ 203.0 (4.684), 229.5 (3.993), 286.5 nm
(3.515); 1H NMR (200 MHz, C6D6): d ˆ 0.69 (brs, 1H, NH), 1.25 ± 1.45 (m,
4H, 2'-H2, 3'-H2), 1.72 (s, 3H, COCH3), 1.74 ± 1.98 (m, 4H, 1'-H2, 4-H,
5-Hcis), 2.15 (dddd, J ˆ 14.0, 9.0, 7.5, 5.0 Hz, 1H, 4-H), 2.15 ± 2.35 (m, 1H,
5-Htrans), 2.49 (t, J ˆ 6.5 Hz, 2H, 4'-H2), 2.87 (m, 4H, 1''-H2, 2''-H2), 3.36 (s,
3H, OCH3), 3.20 (s, 3H, OCH3), 5.60 (m, 1H, 2-H), 5.80 (m, 1H, 1-H), 6.64
(s, 1H, 6'''-H), 6.95 (s, 1H, 3'''-H); 13C NMR (75.5 MHz, C6D6): d ˆ 20.95
(CH3), 25.46 (C2), 30.36 (C5), 30.67 (C3'), 31.33 (C1'), 33.63 (C4), 36.96
(C2''), 49.87 (C4'), 50.38 (C1''), 55.54 (OCH3), 55.70 (OCH3), 80.94 (C1),
114.6 (C2'''), 116.5 (C3''', C6'''), 123.3 (C2), 132.0 (C1'''), 149.3 (C5'''), 149.5
(C4'''), 152.0 (C3), 170.2 (CO); MS (70 eV, EI): m/z (%): 441/439 (<1)
ˆ
ˆ
3330 (N H), 2932 (C H), 1726 (C O), 1650 (C C), 1478, 1246 (C ± O),
1116, 1038, 934 (C-O-C), 862, 834 cm 1 (arene); UV (CH3CN): lmax (lge) ˆ
201.0 (4.633), 236.5 (3.677), 294.0 nm (3.628); 1H NMR (500 MHz, CDCl3):
d ˆ 1.7 (brs, 1H, NH), 1.71 (tt, J ˆ 7.3, 7.2 Hz, 2H, 2'-H2), 1.83 (dddd, J ˆ
14.0, 8.7, 3.9, 3.2 Hz, 1H, 5-Hcis), 2.02 (s, 3H, CH3), 2.12 ± 2.26 (m, 3H, 1'-H2,
4-H), 2.32 (dddd, J ˆ 14.0 Hz, 8.7 Hz, 7.6 Hz, 5.1 Hz, 1H, 5-Htrans), 2.41 ±
2.49 (m, 1H, 4-H), 2.68 (t, J ˆ 7.2 Hz, 2H, 3'-H2), 2.86 (m, 4H, 1''-H2, 2''-
H2), 5.47 (m, 1H, 2-H), 5.95 (s, 2H, OCH2O), 6.62 ± 6.66 (m, 1H, 1-H), 6.74
(s, 1H, 4'''-H), 6.99 (s, 1H, 7'''-H); 13C NMR (50.3 MHz, CDCl3): d ˆ 21.40
(CH3), 27.82 (C2'), 28.97 (C1'), 30.35 (C5), 33.50 (C4), 36.51 (C2''), 49.42,
49.59 (C1'', C3'), 80.93 (C1), 101.6 (OCH2O), 110.2 (C4'''), 112.7 (C7'''),
114.4 (C6'''), 122.5 (C2), 132.3 (C5'''), 146.8 (C3a'''), 147.3 (C7a'''), 152.2
(C3), 171.1 (CO); MS (70 eV, CI (NH3)): m/z (%): 412/410 (100/98)
‡
‡
‡
[M ], 382/380 (3) [M
[C9H10BrO2 ], 210 (10) [C12H20NO2 ], 150 (100) [C10H16N ], 44 (22)
[CO2 ]; C21H30BrNO4 (440.4).
AcO], 300 (3) [M
AcOH Br], 231/229 (3)
‡
‡
‡
‡
3-{5-[2-(6-Bomobenzo[1,3]dioxol-5-yl)ethylamino]pentyl}cyclopent-2-enyl
acetate (12g): According to general procedure I, the amine 13b (1.67 g,
6.82 mmol, 2.6 equiv) was alkylated with tosylate 14c (943 mg, 2.57 mmol)
in the presence of TBAI (1.70 g, 4.61 mmol, 1.8 equiv). Purification by
column chromatography (120 g SiO2, gradient column: 300 mL ethyl
acetate; then ethyl acetate/MeOH ˆ 15:1, 1% Et3N) afforded 12g (894 mg,
2.04 mmol, 79%) as a pale yellow oil. Rf ˆ 0.57 (EtOAc/MeOH ˆ 5:1, 1%
‡
‡
‡
[M‡H ], 352/350 (18/19) [M
AcO], 332 (27) [M
Br‡2H];
C19H24BrNO4 (410.3): calcd C 55.62, H 5.90; found C 55.31, H 5.80.
3-{3-[2-(6-Bromo-benzo[1,3]dioxol-5-yl)ethylamino]propyl}cyclohex-2-en-
yl acetate (12d): According to general procedure I, the amine 13b (234 mg,
959 mmol, 3.7 equiv) was alkylated with tosylate 14d (92.0 mg, 261 mmol) in
the presence of TBAI (144 mg, 390 mmol, 1.5 equiv). Purification by
column chromatography (45 g SiO2, gradient column: 200 mL ethyl
acetate/MeOH ˆ 15:1, 1% Et3N; then ethyl acetate/MeOH ˆ 5:1, 1%
Et3N) afforded 12d (93.8 mg, 221 mmol, 85%) as a pale yellow oil. Rf ˆ 0.45
(EtOAc/MeOH ˆ 5:1, 1% Et3N); IR (neat): nÄ ˆ 3322 (N H), 2936 (C H),
ˆ
ˆ
Et3N); IR (neat): nÄ ˆ 3325 (N H), 2930 (C H), 1727 (C O), 1650 (C C),
1
1478, 1245 (C ± O), 1115, 1039, 934 (C-O-C), 861, 834 cm (arene); UV
(CH3CN): lmax (lge) ˆ 200.5 (4.636), 236.5 (3.712), 294.0 nm (3.643);
1H NMR (200 MHz, C6D6): d ˆ 0.58 (brs, 1H, NH), 1.13 ± 1.42 (m, 6H,
514
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0603-0514 $ 17.50+.50/0
Chem. Eur. J. 2000, 6, No. 3

Cephalotaxine Analogues
510±518
2'-H2, 3'-H2, 4'-H2), 1.73 (s, 3H, CH3), 1.80 ± 2.00 (m, 3H, 1'-H2, 5-Hcis),
2.06 ± 2.34 (m, 3H, 4-H2, 5-Htrans), 2.44 (t, J ˆ 6.3 Hz, 2H, 5'-H2), 2.74 (m,
4H, 1''-H2, 2''-H2), 5.19 (s, 2H, OCH2O), 5.62 (brs, 1H, 2-H), 5.76 ± 5.87 (m,
1H, 1-H), 6.62 (s, 1H, 4'''-H), 6.93 (s, 1H, 7'''-H); 13C NMR (125.7 MHz,
C6D6): d ˆ 20.96 (CH3), 27.42 (C2'), 27.66 (C3'), 30.36 (C5), 30.68 (C4'),
31.40 (C1'), 33.65 (C4), 37.03 (C2''), 49.90, 50.08 (C1'', C5'), 80.97 (C1), 101.5
(OCH2O), 110.6 (C4'''), 112.9 (C7'''), 114.9 (C6'''), 123.2 (C2), 133.3 (C5'''),
147.2 (C3a'''), 147.7 (C7a'''), 152.1 (C3), 170.2 (CO); MS (70 eV, CI (NH3)):
1-(6-Bromobenzo[1,3]dioxol-5-ylmethyl)-1-aza-spiro[4.4]non-6-ene (11a):
According to general procedure II, the amine 12a (205 mg, 517 mmol) was
cyclized with [Pd(PPh3)4] (54.0 mg, 47.0 mmol, 7 mol%) and tetramethyl-
guanidine (138 mg, 1.20 mmol, 2.3 equiv). Column chromatography (50 g
SiO2, EtOAc) furnished 11a (112 mg, 334 mmol, 65%) as a colorless oil.
Rf ˆ 0.61 (EtOAc); IR (neat): nÄ ˆ 3048 (Ar H), 2956 (C H), 1477, 1235,
1
ˆ
1101, 1039, 936 (C-O-C), 869, 831 (arene), 720 cm ( C H); UV
(CH3CN): lmax (lge) ˆ 202.0 (4.596), 233.5 (3.790), 293.0 nm (3.619);
1H NMR (200 MHz, CDCl3): d ˆ 1.60 2.10 (m, 6H, 3-H2, 4-H2, 9-H2),
2.38 (m, 2H, 8-H2), 2.50 ± 2.83 (m, 2H, 2-H2), 3.46 (m, 2H, 1'-H2), 5.60 ± 5.66
(m, 1H, 6-H), 5.83 ± 5.91 (m, 1H, 7-H), 5.94 (s, 2H, OCH2O), 6.95 (s, 1H,
4''-H), 7.02 (s, 1H, 7''-H); 13C NMR (125.7 MHz, CDCl3): d ˆ 21.56 (C3),
30.09 (C8), 31.56 (C9), 38.17 (C4), 51.11 (C2), 52.59 (C1'), 101.5 (OCH2O),
110.2 (C4''), 112.3 (C7''), 113.9 (C6''), 135.1 (C6), 146.9 (C3a''), 147.4
‡
‡
‡
m/z (%): 442/440 (15) [M‡H ], 380/378 (56) [M
AcO], 360 (33) [M
‡
‡
Br‡2H], 300 (100) [C19H26NO2 ], 263/261 (14/16) [C9H11BrNO2 ‡NH3],
‡
‡
246/244 (37/40) [C9H11BrNO2 ], 183 (42) [C11H20N ‡NH3], 166 (93)
‡
‡
[C11H20N ], 152 (52) [C10H18N ]; C21H28BrNO4 (438.4): calcd C 57.65, H
6.46; found C 57.76, H 6.53.
3-{4-[3-(6-Bromobenzo[1,3]dioxol-5-yl)propylamino]butyl}cyclopent-2-
enyl acetate (12h): According to general procedure I, the amine 13c
(2.77 g, 10.7 mmol, 2.5 equiv) was alkylated with tosylate 14b (1.50 g,
4.26 mmol) in the presence of TBAI (2.40 g, 6.50 mmol, 1.5 equiv).
Purification by column chromatography (100 g AloxB, petroleum ether/
MTBE ˆ 1:3) afforded 12h (1.68 g, 3.83 mmol, 90%) as a pale yellow oil.
Rf ˆ 0.37 (PE/EtOAc/MeOH ˆ 10:5:1, 1% Et3N); IR (neat): nÄ ˆ 3348
‡
(C7a''); MS (70 eV, EI): m/z (%): 338/336 (100/98) [M‡H ], 258 (61)
‡
‡
‡
[M
Br‡2H], 150 (29) [C8H8NO2 ], 124 (58) [C8H14N ]; C16H18BrNO2
(336.22): calcd C 57.16, H 5.40; found C 57.38, H 5.30.
6-(6-Bromobenzo[1,3]dioxol-5-ylmethyl)-6-aza-spiro[4.5]dec-1-ene (11b):
According to general procedure II, the amine 12b (700 mg, 1.71 mmol) was
cyclized with [Pd(PPh3)4] (130 mg, 112 mmol, 7 mol%) and tetramethyl-
guanidine (441 mg, 3.83 mmol, 2.3 equiv). Column chromatography (20 g
SiO2, EtOAc) afforded 11b (353 mg, 1.01 mmol, 59%) as a colorless oil.
Rf ˆ 0.77 (EtOAc/MeOH ˆ 5:1, 1% Et3N); IR (KBr): nÄ ˆ 3053 (Ar H),
ˆ
ˆ
(N H), 2930 (C H), 1726 (C O), 1651 (C C), 1477, 1229 (C ± O), 1112,
1040, 937 (C-O-C), 860, 833 cm 1 (arene); UV (CH3CN): lmax (lge) ˆ 200.5
(4.644), 236.5 (3.710), 294.0 nm (3.632); 1H NMR (500 MHz, C6D6): d ˆ 0.6
(brs, 1H, NH), 1.32 (tt, J ˆ 7.5, 7.1 Hz, 2H, 2'-H2), 1.39 (tt, J ˆ 7.1, 7.1 Hz,
2H, 3'-H2), 1.66 (tt, J ˆ 7.6, 7.1 Hz, 2H, 2''-H2), 1.73 (s, 3H, CH3), 1.82 ± 1.98
(m, 2H, 5-H2), 1.92 (t, J ˆ 7.5 Hz, 2H, 1'-H2), 2.14 (dddd, J ˆ 14.0, 9.0, 7.5,
5.0 Hz, 1H, 4-H), 2.21 ± 2.29 (m, 1H, 4-H), 2.41 (t, J ˆ 7.1 Hz, 2H, 1''-H2),
2.47 (t, J ˆ 7.1 Hz, 2H, 4'-H2), 2.68 (t, J ˆ 7.6 Hz, 2H, 3''-H2), 5.21 (s, 2H,
OCH2O), 5.63 (m, 1H, 2-H), 5.80 ± 5.84 (m, 1H, 1-H), 6.60 (s, 1H, 4'''-H),
6.94 (s, 1H, 7'''-H); 13C NMR (125.7 MHz, C6D6): d ˆ 20.97 (CH3), 25.48
(C2'), 30.34 (C5), 30.68 (C3''), 30.84 (C3'), 31.34 (C1'), 33.65 (C4), 33.96
(C2''), 49.32, 49.91 (C1'', C4'), 80.96 (C1), 101.5 (OCH2O), 110.3 (C4'''),
112.9 (C7'''), 114.6 (C6'''), 123.3 (C2), 135.1 (C5'''), 147.1 (C3a'''), 147.8
(C7a'''), 152.0 (C3), 170.2 (CO); MS (70 eV, CI (NH3)): m/z (%): 440/438 (8/
2957, 2925 (C H), 1464, 1367, 1236, 1100, 1037, 937 (C-O-C), 881, 854, 831
1
ˆ
(arene), 743 cm ( C H); UV (CH3CN): lmax (lge) ˆ 202.0 (4.650), 232.0
1
(3.834), 293.5 nm (3.665); H NMR (200 MHz, CDCl3): d ˆ 1.45 ± 2.00 (m,
8H, 4-H2, 8-H2, 9-H2, 10-H2), 2.19 ± 2.56 (m, 4H, 3-H2, 7-H2), 3.20 (d, J ˆ
15.4 Hz, 1H, 1'-H), 3.57 (d, J ˆ 15.4 Hz, 1H, 1'-H), 5.53 ± 5.59 (m, 1H, 1-H),
5.73 ± 5.79 (m, 1H, 2-H), 5.94 (s, 2H, OCH2O), 6.94 (s, 1H, 4''-H), 7.19 (s,
1H, 7''-H); 13C NMR (50.3 MHz, CDCl3): d ˆ 21.93 (C9), 26.08 (C3), 26.42
(C8), 31.68 (C4), 37.80 (C10), 48.90 (C1'), 54.52 (C7), 72.60 (C5), 101.4
(OCH2O), 109.8 (C4''), 112.1 (C7''), 113.7 (C6''), 131.0 (C2), 133.6 (C5''),
137.8 (C1), 146.5 (C3a''), 147.3 (C7a''); MS (70 eV, EI): m/z (%): 351/349
‡
‡
‡
(12) [M ], 322/320 (6) [M
C2H5], 294/292 (6) [C13H11BrNO2 ], 270 (100)
‡
‡
‡
‡
‡
‡
9) [M‡H ], 380/378 (8/9) [M
AcO], 360 (14) [M
Br‡2H], 300 (6)
[M
Br], 242 (7) [C15H16NO2 ], 238 (7) [C14H14NO2 ], 215/213 (29/31)
[C8H6BrO2 ], 136 (10) [C9H14N ], (hydrochloride); C17H20BrNO2 (350.3):
HRMS calcd 349.0677, found 349.0677.
‡
‡
‡
‡
[C19H26NO2 ], 277/275 (5) [C10H13BrNO2 ‡NH3], 260/258 (4/5)
‡
‡
[C10H13BrNO2 ], 213 (26), 198 (57), 180 (15) [C12H22N ], 155 (44)
‡
‡
[C9H16N ‡NH3], 138 (100) [C9H16N ]; C21H28BrNO4 (438.4): calcd C
1-[2-(6-Bromobenzo[1,3]dioxol-5-yl)ethyl]-1-aza-spiro[4.4]non-6-ene
(11c): According to general procedure II, the amine 12c (625 mg,
1.52 mmol) was cyclized with [Pd(PPh3)4] (130 mg, 112 mmol, 7 mol%)
and tetramethylguanidine (230 mg, 1.99 mmol, 1.3 equiv). Column chro-
matography (70 g SiO2, EtOAc) furnished 11c (471 mg, 1.35 mmol, 88%)
as a colorless oil. Rf ˆ 0.57 (EtOAc/MeOH ˆ 5:1, 1% Et3N); IR (neat): nÄ ˆ
57.65, H 6.46; found C 57.59, H 6.58.
3-{3-[(2-Benzo[1,3]dioxol-5-yl)ethylamino]propyl}cyclohex-2-enyl acetate
(18): According to general procedure I, 2-benzo[1,3]dioxol-5-yl-ethylamine
(540 mg, 3.23 mmol, 2.0 equiv) was alkylated with 3-(3-iodopropyl)-cyclo-
hex-2-enyl acetate (503 mg, 1.63 mmol). Purification by column chroma-
tography (100 g SiO2, gradient column: 100 mL ethyl acetate; 300 mL ethyl
acetate/MeOH ˆ 15:1, 1% Et3N; then ethyl acetate/MeOH ˆ 5:1, 1%
Et3N) afforded 18 (450 mg, 1.30 mmol, 80%) as a pale yellow oil. Rf ˆ 0.53
(EtOAc/MeOH ˆ 5:1, 1% Et3N); IR (neat): nÄ ˆ 3328 (N H), 2936 (C H),
3048 (Ar H), 2954 (C H), 1478, 1230, 1112, 1040, 936 (C-O-C), 860, 834
1
ˆ
(arene), 748 cm ( C H); UV (CH3CN): lmax (lge) ˆ 201.0 (4.592),
294.0 nm (3.639); 1H NMR (200 MHz, CDCl3): d ˆ 1.61 (dt, J ˆ 13.6,
6.8 Hz, 1H, 4-H), 1.74 ± 1.98 (m, 5H, 3-H2, 4-H, 9-H2), 2.30 (tdd, J ˆ 7.1, 2.2,
2.1 Hz, 2H, 8-H2), 2.38, 2.56 (m, 2H, 2'-H2*), 2.69 ± 2.85 (m, 3H, 1'-H2*,
2-H*), 2.88 ± 3.02 (m, 1H, 2-H*), 5.56 (dt, J ˆ 5.6, 2.1 Hz, 1H, 6-H), 5.80 (dt,
J ˆ 5.6, 2.2 Hz, 1H, 7-H), 5.93 (s, 2H, OCH2O), 6.71 (s, 1H, 4''-H), 6.96 (s,
1H, 7''-H); 13C NMR (50.3 MHz, CDCl3): d ˆ 21.32 (C3), 29.56 (C8), 31.45
(C9), 36.39 (C2'), 38.19 (C4), 49.65 (C1'), 51.22 (C2), 101.5 (C2''), 110.2
(C4''), 112.5 (C7''), 114.3 (C6''), 132.1 (C7), 133.1 (C5''), 134.7 (C6), 146.6
(C3a''), 147.1 (C7a''); MS (70 eV, CI (NH3)): m/z (%): 352/350 (98/100)
ˆ
ˆ
1726 (C O), 1664 (C C), 1490, 1442, 1246 (C ± O), 1122, 1040, 934 (C-O-
C), 912, 860, 810 cm (arene); UV (CH3CN): lmax (lge) ˆ 198.5 (4.680),
1
234.0 (3.603), 287.0 nm (3.565); 1H NMR (200 MHz, CDCl3): d ˆ 1.17 (brs,
1H, NH), 1.50 ± 1.85 (m, 6H, 2'-H2, 5-H2, 6-H2), 1.90 ± 2.05 (m, 4H, 1'-H2,
4-H2), 2.04 (s, 3H, CH3), 2.59 (t, J ˆ 7.2 Hz, 2H, 3'-H2), 2.65 ± 2.86 (m, 4H,
1''-H2, 2''-H2), 5.19 ± 5.29 (m, 1H, 1-H), 5.43 (brs, 1H, 2-H), 5.92 (s, 2H,
OCH2O), 6.65 (dd, J ˆ 7.8, 1.7 Hz, 1H, 6'''-H), 6.69 (d, J ˆ 1.7 Hz, 1H, 4'''-
H), 6.74 (d, J ˆ 7.8 Hz, 1H, 7'''-H); 13C NMR (50.3 MHz, CDCl3): d ˆ 19.07
(C5), 21.42 (CH3), 27.65 (C2'), 28.16, 28.21 (C4, C6), 35.27 (C1'), 36.02
(C2''), 49.43 (C3'), 51.22 (C1''), 68.68 (C1), 100.7 (OCH2O), 108.1 (C4'''),
108.9 (C7'''), 119.6 (C2), 121.4 (C6'''), 133.8 (C5'''), 144.2 (C3), 145.8
(C7a'''), 147.6 (C3a'''), 170.8 (CO); MS (70 eV, CI (NH3)): m/z (%): 346
‡
‡
‡
[M‡H ], 272 (8) [M
Br‡2H], 136 (10) [C9H14N ], (hydrochloride);
C17H20BrNO2 (350.3): HRMS calcd 349.0677; found 349.0677.
6-[2-(6-Bromobenzo[1,3]dioxol-5-yl)ethyl]-6-aza-spiro[4.5]dec-1-ene
(11e): According to general procedure II, the amine 12e (474 mg,
1.12 mmol) was cyclized with [Pd(PPh3)4] (112 mg, 96.9 mmol, 9 mol%)
and tetramethylguanidine (320 mg, 2.80 mmol, 2.5 equiv). Column chro-
matography (50 g SiO2, EtOAc) furnished 11e (233 mg, 640 mmol, 57%) as
a colorless oil. Rf ˆ 0.66 (EtOAc/MeOH ˆ 5:1, 1% Et3N); UV (CH3CN):
lmax (lge) ˆ 201.5 (4.558), 294.0 nm (3.648); 1H NMR (500 MHz, CDCl3):
d ˆ 1.42 ± 1.50 (m, 2H, 9-H, 10-H), 1.53 ± 1.65 (m, 4H, 8-H2, 9-H, 10-H),
1.74 ± 1.80 (m, 2H, 3-H2), 2.11 (ddd, J ˆ 12.1, 10.5, 4.8 Hz, 1H, 7-Hax), 2.24 ±
2.30 (m, 2H, 4-H2), 2.35 (m, 1H, 1'-H), 2.56 ± 2.64 (m, 1H, 7-Heq), 2.65 ± 2.69
(m, 1H, 2'-H), 2.77 ± 2.81 (m, 1H, 2'-H), 2.81 ± 2.85 (m, 1H, 1'-H), 5.50 (dt,
J ˆ 5.6, 2.0 Hz, 1H, 1-H), 5.69 (dt, J ˆ 5.6, 2.4 Hz, 1H, 2-H), 5.91 (s, 2H,
OCH2O), 6.67 (s, 1H, 4''-H), 6.94 (s, 1H, 7''-H); 13C NMR (125.7 MHz,
CDCl3): d ˆ 21.79 (C9), 26.30 (C3, C8), 31.56 (C4), 35.76 (C2'), 37.69 (C10),
49.04 (C1'), 51.66 (C7), 72.92 (C5), 101.5 (OCH2O), 110.5 (C4''), 112.5
‡
‡
‡
(100) [M‡H ], 286 (10) [M
AcO], 183 (11), 166 (13) [C11H20N ];
C20H27NO4 (345.4): calcd C 69.54, H 7.88; found C 69.63, H 7.99.
General procedure II: palladium-catalyzed allylic amination of 12: A
solution of the secondary amine (0.25 ± 0.05m) in acetonitrile was degassed
by pump and freeze methodology. Then of [Pd(PPh3)4] (5 ± 10 mol%) and
triethylamine or tetramethylguanidine (2.5 equiv) was added. The mixture
was degassed a second time and heated to 458C until the reaction was
complete (TLC). The mixture was diluted with MTBE and extracted twice
with cold HCl (1m). The aqueous phase was washed twice with MTBE and
basified with cold NaOH solution (10%). The mixture was extracted with
MTBE (4Â), the organic layer dried over Na2SO4, evaporated, and the
residue purified by column chromatography.
Chem. Eur. J. 2000, 6, No. 3
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0603-0515 $ 17.50+.50/0
515

L. F. Tietze et al.
FULL PAPER
(C7''), 114.4 (C6''), 130.7 (C2), 133.3 (C5''), 137.4 (C1), 146.6 (C3a''), 147.1
n-butylammonium acetate (2.1 equiv). The mixture was degassed by pump
and freeze methodology and then heated to 1208C until the reaction was
completed (TLC), diluted with MTBE, and extracted with diluted NaOH
solution. Subsequently, the organic layer was extracted with HCl (1m, 3Â).
The aqueous layer was basified with NaOH solution and extracted with
MTBE (3Â). The combined organic layers were dried over Na2SO4 and the
solvent was evaporated. The residue was purified by column chromatog-
raphy.
‡
‡
(C7a''); MS (70 eV, EI): m/z (%): 365/363 (<1) [M ], 284 (<1) [M
‡
‡
Br‡2H], 215/213 (3) [C8H6BrO2 ], 150 (100) [C10H16N ]; C18H22BrNO2
(364.3): calcd C 53.95, H 5.78 (hydrochloride); found C 54.18, H 6.12;
HRMS calcd 363.0834; found 363.0834.
6-[2-(2-Bromo-4,5-dimethoxy-phenyl)ethyl]-6-aza-spiro[4.5]dec-1-ene
(11 f): According to general procedure II, the amine 12 f (576 mg,
1.31 mmol) was cyclized with [Pd(PPh3)4] (147 mg, 127 mmol, 10 mol%)
and tetramethylguanidine (372 mg, 3.23 mmol, 2.5 equiv). Column chro-
matography (18 g SiO2, EtOAc) furnished 11 f (213 mg, 560 mmol, 43%) as
a colorless oil. Rf ˆ 0.60 (EtOAc/MeOH ˆ 5:1, 1% Et3N); IR (neat): nÄ ˆ
3,5,6,7,8,13b-Hexahydro-4H-cyclopenta[c][1,3]dioxolo[4,5-g]pyrrolo[1,2-b]-
isoquinoline (10a): According to general procedure III, the tertiary amine
11a (29.0 mg, 86.0 mmol), the palladium catalyst 20 (6.2 mg, 6.6 mmol,
8 mol%), and tetra-n-butylammonium acetate (55.0 mg, 182 mmol,
2.1 equiv) were reacted in the solvent mixture (1.5 mL). The crude product
was purified via its hydrochloride by recrystallization from CH2Cl2/MTBE
to afford 10a (20.0 mg, 68.7 mmol, 80%). Rf ˆ 0.28 (EtOAc/MeOH ˆ 5:1,
1% Et3N); 1H NMR (500 MHz, CDCl3): d ˆ 1.72 ± 1.91 (m, 4H, 4-H2,
5-H2), 2.30 (brd, J ˆ 17.2 Hz, 1H, 3-H), 2.69 (ddd, J ˆ 10.6, 10.6, 5.7 Hz, 1H,
6-H), 2.72 (brd, J ˆ 17.2 Hz, 1H, 3-H), 2.92 (m, 1H, 6-H), 3.41 (brs, 1H,
13b-H), 3.67 (d, J ˆ 15.6 Hz, 1H, 8-H), 3.92 (d, J ˆ 15.6 Hz, 1H, 8-H), 5.68
(dddd, J ˆ 6.0, 2.3, 2.3, 2.3 Hz, 1H, 1-H), 5.75 (dddd, J ˆ 6.0, 2.3, 2.1, 2.0 Hz,
1H, 2-H), 5.87 (d, J ˆ 1.5 Hz, 1H, 11-H), 5.90 (d, J ˆ 1.5 Hz, 1H, 11-H), 6.55
(s, 1H, 13-H), 6.60 (s, 1H, 9-H); 13C NMR (125.7 MHz, CDCl3): d ˆ 21.06
(C5), 39.80, 40.61 (C3, C4), 48.39 (C6), 50.29 (C13b), 50.68 (C8), 69.30
(C3a), 100.5 (C11), 107.5 (C13), 108.0 (C9), 125.6 (C8a), 129.6 (C1), 130.8
(C13a), 132.8 (C2), 145.4 (C9a), 146.3 (C12a); MS (70 eV, EI): m/z (%): 255
3048 (Ar H), 2931 (C H), 1508, 1440, 1217 (Ar-O-C), 1098, 1034 (Ar-O-
1
ˆ
C), 854, 798 (arene), 731 cm ( C H); UV (CH3CN): lmax (lge) ˆ 204.0
(4.613), 286.5 nm (3.545); 1H NMR (500 MHz, C6D6): d ˆ 1.33 ± 1.44 (m,
2H, 10-H2), 1.49 ± 1.66 (m, 5H, 4-H, 8-H2, 9-H2), 1.70 ± 1.76 (m, 1H, 4-H),
2.17 (m, 2H, 7-H2), 2.28 ± 2.38 (m, 2H, 3-H2), 2.82 ± 3.00 (m, 4H, 1'-H2, 2'-
H2), 3.19 (s, 3H, OCH3), 3.38 (s, 3H, OCH3), 5.54 (dt, J ˆ 5.7, 2.0 Hz, 1H,
1-H), 5.60 (dt, J ˆ 5.7, 2.2 Hz, 1H, 2-H), 6.70 (s, 1H, 6''-H), 6.96 (s, 1H, 3''-
H); 13C NMR (125.7 MHz, C6D6): d ˆ 22.38 (C9), 27.04 (C3, C8), 31.80
(C4), 36.00 (C2'), 37.99 (C10), 49.20 (C1'), 51.98 (C7), 55.68 (2OCH3), 73.08
(C5), 114.7 (C2''), 115.2 (C6''), 116.3 (C3''), 130.4 (C2), 132.7 (C1''), 138.6
‡
(C1), 149.1 (C4'', C5''); MS (70 eV, EI): m/z (%): 382/380 (<1) [M‡H ],
‡
‡
231/229 (2) [C9H10BrO2 ], 189 (7), 150 (100) [C10H16N ], (hydrochloride);
C19H26BrNO2 (380.3): calcd C 60.00, H 6.89; found C 59.70, H 6.86.
6-[3-(6-Bromobenzo[1,3]dioxol-5-yl)propyl]-6-aza-spiro[4.5]dec-1-ene
(11h): According to general procedure II, the amine 12h (80.0 mg,
182 mmol) was cyclized with [Pd(PPh3)4] (21 mg, 18.0 mmol, 10 mol%)
and tetramethylguanidine (52.0 mg, 454 mmol, 2.5 equiv). Column chro-
matography (8 g SiO2, EtOAc) furnished 11h (45.8 mg, 121 mmol, 67%) as
a colorless oil. Rf ˆ 0.54 (EtOAc/MeOH ˆ 5:1, 1% Et3N); IR (neat): nÄ ˆ
‡
‡
‡
(70) [M ], 254 (100) [M
H], 214 (28) [M
C3H5], (hydrochloride);
C16H17NO2 (255.3): calcd 255.1259; found 255.1259.
3,5,6,8,9,14b-Hexahydro-4H-cyclopenta[a][1,3]dioxolo[4,5-h]-pyrrolo[2,1-b]-
[3]benzazepine (10b):[8n] According to general procedure III, the tertiary
amine 11c (179 mg, 511 mmol) was cyclized with the palladium catalyst 20
(19.0 mg, 20.0 mmol, 4 mol%) and tetra-n-butylammonium acetate
(310 mg, 1.03 mmol, 2.0 equiv). The crude product was purified by column
chromatography (25 g SiO2, ethyl acetate) to give 10b (112 mg, 416 mmol,
81%). Rf ˆ 0.22 (EtOAc/MeOH ˆ 5:1, 1% Et3N); 1H NMR (200 MHz,
CDCl3): d ˆ 1.66 ± 1.87 (m, 2H, 4-H2), 1.91 ± 2.07 (m, 3H, 3-H, 5-H2), 2.34
(dd, J ˆ 14.2, 6.1 Hz, 1H, 8-H), 2.43 (ddd, J ˆ 9.3, 9.3, 6.8 Hz, 1H, 6-H), 2.58
(dd, J ˆ 11.7, 7.3 Hz, 1H, 9-H), 2.76 (ddd, J ˆ 17.8, 4.9, 2.4 Hz, 1H, 3-H), 2.96
(ddd, J ˆ 12.7, 11.7, 6.1 Hz, 1H, 9-H), 3.11 (ddd, J ˆ 9.3, 7.6, 4.9 Hz, 1H,
6-H), 3.20 (ddd, J ˆ 14.2, 12.7, 7.3 Hz, 1H, 8-H), 3.88 (brs, 1H, 14b-H), 5.52
(dddd, J ˆ 5.9, 2.4, 2.2, 2.2 Hz, 1H, 1-H), 5.79 (dddd, J ˆ 5.9, 2.7, 2.7, 2.1 Hz,
1H, 2-H), 5.88 (d, J ˆ 1.5 Hz, 1H, 12-H), 5.89 (d, J ˆ 1.5 Hz, 1H, 12-H), 6.59
(s, 1H, 10-H), 6.65 (s, 1H, 14-H); 13C NMR (50.3 MHz, CDCl3): d ˆ 19.80
(C5), 30.42 (C9), 34.89 (C4), 42.94 (C3), 48.92 (C7), 53.50 (C8), 62.13
(C14b), 68.30 (C3a), 100.7 (C12), 109.8 (C10), 110.7 (C14), 128.6 (C1), 131.6
(C14a), 132.0 (C2), 133.5 (C9a), 146.0 (C13a), 146.3 (C10a); C17H19NO2
(269.3).
3048 (Ar H), 2929 (C H), 1477, 1408, 1354, 1229, 1112, 1040, 936 (C-O-C),
1
ˆ
858, 833 (arene), 720 cm ( C H); UV (CH3CN): lmax (lge) ˆ 201.0
(4.574), 294.5 nm (3.620); 1H NMR (500 MHz, C6D6): d ˆ 1.31 ± 1.46 (m,
2H, 9-H, 10-H), 1.48 ± 1.61 (m, 4H, 8-H2, 9-H, 10-H), 1.61 ± 1.79 (m, 4H,
2-H2, 4-H2), 2.00 (ddd, J ˆ 13.0, 6.9, 5.0 Hz, 1H, 1'-H), 2.11 (ddd (J ˆ 11.2,
11.2, 3.0 Hz, 1H, 7-Hax), 2.21 (ddt, J ˆ 7.0, 1.8, 1.4 Hz, 2H, 3-H2), 2.57 (ddd,
J ˆ 14.0, 10.0, 6.0 Hz, 1H, 3'-H), 2.60 (ddd, J ˆ 14.0, 7.8, 7.8 Hz, 1H, 3'-H),
2.68 (ddd, J ˆ 11.2, 3.2, 0.6 Hz, 1H, 7-Heq), 2.79 (ddd, J ˆ 13.0, 10.1, 5.7 Hz,
1H, 1'-H), 5.21 (s, 2H, OCH2O), 5.61 (m, 2H, 1-H, 2-H), 6.60 (s, 1H, 4''-H),
6.95 (s, 1H, 7''-H); 13C NMR (125.7 MHz, C6D6): d ˆ 22.37 (C9), 26.93 (C3,
C8), 29.45 (C2'), 31.95 (C4), 34.39 (C3'), 38.07 (C10), 48.60 (C1'), 50.34
(C7), 73.02 (C5), 101.4 (OCH2O), 110.2 (C4''), 112.9 (C7''), 114.7 (C6''),
130.1 (C2), 135.7 (C5''), 139.0 (C1), 146.9 (C3a''), 147.7 (C7a''); MS (70 eV,
‡
‡
EI): m/z (%): 379/377 (24/25) [M ], 324/322 (9/10) [C15H17BrNO2 ], 298
‡
‡
‡
(80) [M
Br], 242/240 (8) [C10H9BrO2 ], 215/213 (13) [C8H6BrO2 ], 164
‡
‡
‡
(100) [C11H18N ], 150 (92) [C10H16N ], 136 (46) [C9H14N ]; C19H24BrNO2
(378.3): calcd C 60.32, H 6.39; found C 60.51, H 6.44; HRMS calcd 377.0990;
found 377.0990.
3,4,5,6,7,9,10,14b-Octahydro-12,13-dimethoxycyclopenta[a]pyrido[2,1-b]-
[3]benzazepine (10c): According to general procedure III, the tertiary
amine 11 f (37.0 mg, 97.0 mmol) was cyclized with the palladium catalyst 20
(5.5 mg, 5.9 mmol, 6 mol%) and tetra-n-butylammonium acetate (87.0 mg,
290 mmol, 3.0 equiv). The crude product was purified by column chroma-
tography (15 g SiO2, ethyl acetate) to give 10c (25.2 mg, 84.2 mmol, 87%).
Rf ˆ 0.25 (EtOAc/MeOH ˆ 5:1, 1% Et3N); IR (neat): nÄ ˆ 3057 (Ar H),
1-(2-Benzo[1,3]dioxol-5-yl-ethyl)-1-aza-spiro[4.5]dec-6-ene (19): Analo-
gous to general procedure II; however, at 758C, the amine 18 (20.3 mg,
58.8 mmol) was cyclized with [Pd(PPh3)4] (10.0 mg, 8.70 mmol, 15 mol%)
and triethylamine (18.2 mg, 179 mmol, 3.0 equiv). Column chromatography
(20 g SiO2, EtOAc) gave 19 (12.4 mg, 43.5 mmol, 74%) as a colorless oil.
Rf ˆ 0.45 (EtOAc/MeOH ˆ 5:1, 1% Et3N); IR (KBr): nÄ ˆ 3013 (Ar H),
1
2935 (C H) 1517, 1465, 1266 (Ar-O-C), 1127, 1022 (Ar-O-C), 733 cm
ˆ
2936 (C H), 1490, 1247, 1109, 1042, 931 (C-O-C), 863, 808 (arene),
( C H); UV (CH3CN): lmax (lge) ˆ 203.5 (4.472), 234.0 (3.694), 282.5 nm
1
742 cm ( C H); UV (CH3CN): lmax (lge) ˆ 198.5 (4.627), 230.5 (3.718),
(3.313); 1H NMR (200 MHz, CDCl3): d ˆ 1.42 ± 1.84 (m, 6H, 4-H2, 5-H2,
6-H2), 2.17 (brd, J ˆ 17.6 Hz, 1H, 3-H), 2.25 ± 2.40 (m, 2H, 7-H, 10-H), 2.42
(ddd, J ˆ 13.2, 7.1, 2.2 Hz, 1H, 7-H), 2.58 (ddd, J ˆ 12.7, 3.9, 3.4 Hz, 1H,
9-H), 2.68 ± 2.95 (m, 2H, 3-H, 9-H), 3.25 (ddd, J ˆ 13.9, 9.5, 8.8 Hz, 1H, 10-
H), 3.58 (brs, 1H, 14b-H), 3.87 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 5.56
(dddd, J ˆ 6.0, 2.2, 2.2, 2.0 Hz, 1H, 1-H), 5.79 (dddd, J ˆ 6.0, 2.5, 2.5, 2.2 Hz,
1H, 2-H), 6.62 (s, 1H, 11-H), 6.67 (s, 1H, 14-H); 13C NMR (50.3 MHz,
CDCl3): d ˆ 21.45 (C5), 24.89 (C6), 30.75 (C10), 34.69 (C3), 40.54 (C4),
51.94 (C9), 53.03 (C7), 55.78 (OCH3), 56.07 (OCH3), 64.82 (C14b), 65.09
(C3a), 112.4 (C11), 113.7 (C14), 128.4 (C2), 130.6 (C14a), 130.8 (C10a),
132.0 (C1), 147.8 (C13), 147.7 (C12); MS (70 eV, EI): m/z (%): 299 (100)
ˆ
287.0 nm (3.577); 1H NMR (500 MHz, CDCl3): d ˆ 1.45 ± 1.90 (m, 8H, 3-H2,
4-H2, 9-H2, 10-H2), 1.93 (m, 2H, 8-H2), 2.56 ± 2.72 (m, 4H, 1'-H2, 2'-H2),
2.82 (brs, 1H, 2-H), 2.99 (m, 1H, 2-H), 5.46 (d, J ˆ 10.1 Hz, 1H, 6-H), 5.76
(dt, J ˆ 10.1, 4.1 Hz, 1H, 7-H), 5.91 (s, 2H, OCH2O), 6.65 (dd, J ˆ 8.0,
1.6 Hz, 1H, 6''-H), 6.71 (d, J ˆ 1.6 Hz, 1H, 7''-H), 6.72 (d, J ˆ 8.0 Hz, 1H,
4''-H); 13C NMR (50.3 MHz, CDCl3): d ˆ 21.09, 21.21 (C3, C9), 25.13 (C8),
28.32 (C4), 36.24 (C2'), 38.28 (C10), 50.63 (C2), 51.75 (C1'), 63.71 (C5),
100.6 (OCH2O), 108.0 (C4''), 109.1 (C7''), 121.3 (C6''), 128.9 (C7), 133.2
(C6), 134.7 (C5''), 145.5 (C7a''), 147.3 (C3a''); MS (70 eV, EI): m/z (%): 285
‡
‡
‡
(<1) [M ], 150 (100) [C10H16N ], 135 (8) [C8H7O2 ]; C18H23NO2 (285.4):
calcd C 75.76, H 8.12; found C 75.62, H 7.89; HRMS calcd 285.1729; found
285.1728.
‡
‡
‡
‡
‡
[M ], 284 (49) [M
CH3], 258 (72) [M
C3H5], 202 (44) [C12H12NO2 ],
134 (54) [C9H12N ]; C19H25NO2 (299.4): calcd C 67.94, H 7.80 (hydro-
chloride); found C 67.76, H 7.83; HRMS calcd 299.1885; found 299.1885.
General procedure III: intramolecular Heck reaction of 11: To a 0.05m
solution of the bromoarenes 11 in a mixture of acetonitrile, dimethylfor-
mamide, and water (5:5:1) were added the catalyst 20 (5 mol%) and tetra-
3,4,5,6,7,8,9,14b-Octahydro-cyclopenta[c][1,3]dioxolo[4,5-g]pyrido[1,2-b]iso-
quinoline (10d): According to general procedure III, the tertiary amine
516
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Chem. Eur. J. 2000, 6, No. 3

Cephalotaxine Analogues
510±518
11b (55.0 mg, 157 mmol) was cyclized with the palladium catalyst 20 (10 mg,
11.0 mmol, 7 mol%) and tetra-n-butylammonium acetate (104 mg,
345 mmol, 2.2 equiv). The crude product was purified by column chroma-
tography (8 g SiO2, EtOAc) to give 11d (34.1 mg, 127 mmol, 81%). Rf ˆ
0.56 (EtOAc/MeOH ˆ 5:1, 1% Et3N); IR (KBr): nÄ ˆ 3066 (Ar H), 2933
[4] a) L. F. Tietze, H. Schirok, Angew. Chem. 1997, 109, 1159 ± 1160;
Angew. Chem. Int. Ed. Engl. 1997, 36, 1124 ± 1125; b) L. F. Tietze, H.
Schirok, J. Am. Chem. Soc. 1999, 121, 10264 ± 10269.
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Brossi), Academic Press, New York, 1984, pp. 157 ± 226; b) T.
Hudlicky, L. D. Kwart, J. W. Reed in Alkaloids: Chemical and
Biological Perspectives, Vol. 5 (Ed. S. W. Pelletier), Wiley, New York,
1987, pp. 639 ± 690; c) M. A. Jalil Miah, T. Hudlicky, J. W. Reed in The
Alkaloids, Vol. 51 (Ed. A. Brossi), Academic Press, New York, 1998,
pp. 199 ± 269.
[6] a) S. Sinha, S. Jain in Prog. Drug Res. 1994, 42, 53 ± 132; b) D. C. Zhou,
R. Zittoun, J. P. Marie, Bull. Cancer 1995, 82, 987 ± 995.
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237; b) R. M. Ekong, G. C. Kirby, G. Patel, J. D. Phillipson, D. C.
Warhurst, Biochem. Pharmacol. 1990, 40, 297 ± 301.
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7173; b) M. F. Semmelhack, B. P. Chong, L. D. Jones, J. Am. Chem.
Soc. 1972, 94, 8629 ± 8630; c) M. F. Semmelhack, R. D. Stauffer, T. D.
Rogerson, Tetrahedron Lett. 1973, 4519 ± 4522; d) S. M. Weinreb, M. F.
Semmelhack, Acc. Chem. Res. 1975, 158 ± 164; e) S. M. Weinreb, J.
Auerbach, J. Am. Chem. Soc. 1975, 97, 2503 ± 2506; f) M. F. Semmel-
hack, B. P. Chong, R. D. Stauffer, T. D. Rogerson, A. Chong, L. D.
Jones, J. Am. Chem. Soc. 1975, 97, 2507 ± 2516; g) S. Yasuda, T.
Yamada, M. Hanaoka, Tetrahedron Lett. 1986, 27, 2023 ± 2026; h) T. P.
Burkholder, P. L. Fuchs, J. Am. Chem. Soc. 1988, 110, 2341 ± 2342;
i) M. E. Kuehne, W. G. Bornmann, W. H. Parsons, T. D. Spitzer, J. F.
Blount, J. Zubieta, J. Org. Chem. 1988, 53, 3439 ± 3450; j) S. Yasuda, Y.
Yamamoto, S. Yoshida, M. Hanaoka, Chem. Pharm. Bull. 1988, 36,
4229 ± 4231; k) H. Ishibashi, M. Okano, H. Tamaki, K. Maruyama, T.
Yakura, M. Ikeda, J. Chem. Soc. Chem. Commun. 1990, 1436 ± 1437;
l) T. P. Burkholder, P. L. Fuchs, J. Am. Chem. Soc. 1990, 112, 9601 ±
9613; m) M. Ikeda, M. Okano, K. Kosaka, M. Kido, H. Ishibashi,
Chem. Pharm. Bull. 1993, 41, 276 ± 281; n) N. Isono, M. Mori, J. Org.
Chem. 1995, 60, 115 ± 119; o) X. Lin, R. W. Kavash, P. S. Mariano, J.
Org. Chem. 1996, 61, 7335 ± 7347; p) T. Nagasaka, H. Sato, S.-i. Saeki,
Tetrahedron Asymm. 1997, 8, 191 ± 194.
1
(C H), 1485, 1242, 1119, 1041, 933 (C-O-C), 874, 859 (arene), 702 cm
ˆ
( C H); UV (CH3CN): lmax (lge) ˆ 200.5 (4.563), 293.5 nm (3.676);
1H NMR (500 MHz, CDCl3): d ˆ 1.53 ± 1.76 (m, 5H, 4-H, 5-H2, 6-H2),
1.84 (m, 1H, 4-H), 2.08 (ddd, J ˆ 16.8, 2.7, 1.8 Hz, 1H, 3-H), 2.43 (ddd, J ˆ
11.5, 11.5, 2.7 Hz, 1H, 7-Hax), 2.58 (brd, J ˆ 16.8 Hz, 1H, 3-H), 2.73 (ddd,
J ˆ 11.5, 3.7, 3.7 Hz, 1H, 7-Heq), 3.34 (d, J ˆ 15.2 Hz, 1H, 9-H), 3.44 (brs,
1H, 14b-H), 3.62 (d, J ˆ 15.2 Hz, 1H, 9-H), 5.64 (dddd, J ˆ 6.0, 2.8, 1.8,
1.8 Hz, 1H, 1-H), 5.76 (dddd, J ˆ 6.0, 2.7, 2.7, 1.6 Hz, 1H, 2-H), 5.82 (d, J ˆ
1.4 Hz, 1H, 12-H), 5.86 (d, J ˆ 1.4 Hz, 1H, 12-H), 6.50 (s, 1H, 14-H), 6.55 (s,
1H, 10-H); 13C NMR (50.3 MHz, CDCl3): d ˆ 20.81 (C5), 25.50 (C6), 30.32
(br, C3), 38.06 (C4), 51.41 (C7), 52.99 (C9), 54.85 (br, C14b), 64.05 (C3a),
100.4 (C12), 106.7 (C14), 107.6 (C10), 126.7 (C9a), 128.6 (C1), 130.5 (C14a),
133.5 (C2), 145.1 (C10a), 146.3 (C13a); MS (70 eV, EI): m/z (%): 269 (81)
‡
‡
‡
[M ], 268 (95) [M
H], 228 (100) [M
C3H5]; C17H19NO2 (269.3): calcd
C 75.81, H 7.11; found C 75.59, H 7.05; HRMS calcd 269.1416; found
269.1415.
3,4,5,6,7,9,10,15b-Octahydrocyclopenta[a][1,3]dioxolo[4,5-h]-pyrido[2,1-b]-
[3]benzazepine (10e): According to general procedure III, the tertiary
amine 11e (23.0 mg, 63.0 mmol) was cyclized with the palladium catalyst 20
(5.0 mg, 5.0 mmol, 8 mol%) and tetra-n-butylammonium acetate (47.0 mg,
156 mmol, 2.5 equiv). The crude product was purified by column chroma-
tography (8 g SiO2, ethyl acetate) to give 10e (15.0 mg, 52.9 mmol, 84%):
Rf ˆ 0.29 (EtOAc/MeOH ˆ 5:1, 1% Et3N); IR (KBr): nÄ ˆ 3038 (Ar H),
2919 (C H), 1489, 1229, 1109, 1037, 934 (C-O-C), 839, 849 (arene),
1
ˆ
737 cm ( C H); UV (CH3CN): lmax (lge) ˆ 200.5 (4.597), 231.5 (3.602),
292.5 nm (3.654); 1H NMR (200 MHz, CDCl3): d ˆ 1.36 ± 1.76 (m, 6H,
4-H2, 5-H2, 6-H2), 2.15 (brd, J ˆ 17.3 Hz, 1H, 3-H), 2.30 ± 2.43 (m, 2H, 7-H,
10-H), 2.53 (ddd, J ˆ 13.2, 3.9, 3.4 Hz, 1H, 7-H), 2.59 (ddd, J ˆ 9.3, 8.6,
2.7 Hz, 1H, 9-H), 2.66 ± 2.79 (m, 2H, 3-H, 9-H), 3.23 (ddd, J ˆ 14.2, 9.5,
8.6 Hz, 1H, 10-H), 3.53 (m, 1H, 15b-H), 5.56 (dddd, J ˆ 6.0, 2.2, 2.2, 2.0 Hz,
1H, 1-H), 5.79 (dddd, J ˆ 6.0, 2.5, 2.5, 2.2 Hz, 1H, 2-H), 5.88 (s, 2H, 13-H2),
6.58 (s, 1H, 11-H), 6.64 (s, 1H, 15-H); 13C NMR (125.7 MHz, CDCl3): d ˆ
21.53 (C5), 24.90 (br, C6), 31.06 (C10), 34.66 (br, C3), 41.00 (br, C4), 51.75
(br, C9), 52.88 (C7), 64.66, 64.98 (C3a, C15b), 100.6 (C13), 109.3 (C11),
110.2 (C15), 128.5 (C2), 131.8 (C15a), 131.8 (C1), 132.0 (C10a), 145.7
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‡
(C14a), 146.1 (C11a); MS (70 eV, EI): m/z (%): 283 (100) [M ], 268 (23),
‡
‡
‡
242 (79) [M
C3H5], 186 (31) [C11H8NO2 ], 134 (40) [C9H12N ];
C18H21NO2 (283.4): calcd C 67.60, H 6.93 (hydrochloride); found C 67.54,
H 6.83; HRMS calcd 283.1572; found 283.1572.
Â
Â
3167; g) M. Nyerges, I. Bitter, I. Kadas, G. Toth, L. Töke, Tetrahedron
Â
Â
Lett. 1994, 35, 4413 ± 4414; h) M. Nyerges, I. Bitter, I. Kadas, G. Toth,
L. Töke, Tetrahedron 1995, 51, 11489 ± 11502; i) M. Nyerges, M.
Â
Rudas, I. Bitter, L. Töke, C. Szantay, Jr., Tetrahedron 1997, 53, 3269 ±
3280; j) I. Takano, I. Yasuda, M. Nishijima, Y. Hitotsuyanagi, K.
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Chem. Pharm. Bull. 1998, 46, 1084 ± 1089.
Acknowledgments
This research was supported by the Deutsche Forschungsgemeinschaft
(Sonderforschungsbereich 416) and the Fonds der Chemischen Industrie.
We thank the Degussa AG for their generous donation of precious
metals.
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Chem. Eur. J. 2000, 6, No. 3
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0603-0517 $ 17.50+.50/0
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