Efficient synthesis of six-membered ring D analogues of the pentacyclic alkaloid cephalotaxine by two palladium-catalyzed reactions

Article abstract of DOI:10.1002/1099-0690(200007)2000:13<2433::AID-EJOC2433>3.0.CO;2-G

D-homo-Cephalotaxine analogues 19 and 23 have been prepared by intramolecular Heck reactions of 12 and 22. The substrates 12 and 22 were obtained by alkylation and acylation, respectively, of the spirocyclic amines 17, which, in turn, were generated by in

Full text of DOI:10.1002/1099-0690(200007)2000:13<2433::AID-EJOC2433>3.0.CO;2-G

FULL PAPER
Efficient Synthesis of Six-Membered Ring D Analogues of the Pentacyclic
Alkaloid Cephalotaxine by Two Palladium-Catalyzed Reactions
Lutz F. Tietze,*[a] Hartmut Schirok,[a] Michael Wöhrmann,[a] and Klaus Schrader[a]
Dedicated to Professor Franz Effenberger on the occasion of his 70th birthday
Keywords: Nucleophilic allylation / Antitumor agents / Cephalotaxine / Heck reaction / Palladium / Spiro compounds
D-homo-Cephalotaxine analogues 19 and 23 have been pre-
pared by intramolecular Heck reactions of 12 and 22. The
ation, respectively, of the spirocyclic amines 17, which, in
turn, were generated by intramolecular palladium-catalyzed
substrates 12 and 22 were obtained by alkylation and acyl- allylic amination.
Introduction
Natural products are important lead structures in drug
development. However, for a variety of reasons the parent
compounds often prove unsuitable, e.g. due to low activity,
side effects, instability, complexity, etc. It is therefore im-
portant to prepare analogues and to explore their biological
activities. In recent years, we have developed a highly effi-
cient access to several families of natural products based on
two transition-metal-mediated or -catalyzed transforma-
tions.[1]
Scheme 2. Synthesis of cephalotaxine and analogues
cyclic tertiary amine 7 and the pentacyclic core 8. Esters of
cephalotaxine (1), namely harringtonine (2), deoxyharring-
tonine (3), isoharringtonine (4), and homoharringtonine
(5), show high antileukemic activity and clinical trials have
reached phases IIϪIII (Scheme 1).[2] More recently, homo-
harringtonine (5) has been investigated for the treatment of
chloroquine-resistant malaria.[3] Our two-step Pd-catalyzed
process could also be used for the synthesis of ring ana-
logues of the pentacyclic core of 1 with (6,5,5)-, (6,6,5)-,
and (7,6,5)-BCD rings (Scheme 2).[4] In this paper, we de-
scribe an access to D-6-ring analogues of cephalotaxine (1),
again using two Pd-catalyzed transformations. However, in
this case, a sequential approach had to be employed.
Results and Discussion
For the synthesis of the cephalotaxine analogues con-
taining a six-membered ring D, we first prepared several
secondary amines 11 by alkylation of the primary amines
Scheme 1. (Ϫ)-Cephalotaxine (1) and harringtonines 2؊5
9
[5] with iodides, which, in turn, were generated in situ from
In this way, we synthesized the unique pentacyclic alka-
loid cephalotaxine (1) through Pd-catalyzed amination of
the secondary amine 6 and a Heck reaction via the spiro-
tosylates 10.[6] However, all attempts to convert amines 11
into spirocyclic compounds with a cyclohexene moiety as
ring D through Pd-catalyzed intramolecular amination ac-
cording to our strategy failed, irrespective of whether a five-
or six-membered ring was to be formed (Scheme 3). We as-
sume that this may be attributed to the lower reactivity of
the cyclohexenyl acetate compared with the corresponding
[a]
Institut für Organische Chemie der Georg-August-Universität
Göttingen,
Tammannstraße 2, 37077 Göttingen, Germany
Fax: (internat.) ϩ 49-(0)551/399476
E-mail: ltietze@gwdg.de
Eur. J. Org. Chem. 2000, 2433Ϫ2444
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1434Ϫ193X/00/0713Ϫ2433 $ 17.50ϩ.50/0
2433

L. F. Tietze, H. Schirok, M. Wöhrmann, K. Schrader
FULL PAPER
synthesized in 90% yield from bromomethylenedioxy-
benzene by a Grignard reaction with oxirane,[8] did not re-
act in the same way. After bromination of the arene moiety,
the hydroxy group was thus transformed into a nosylate to
give 18b. In a similar way, 18c was obtained.[9,10] For the
syntheses of 18d and 18e, the corresponding phenylpro-
panol derivatives were prepared from safrol applying a pro-
cedure described by Kabalka et al.[11] Bromination and iod-
ination, respectively, followed by conversion to the nosyl-
ates led to the desired substrates.
The requisite primary amines 16 were obtained from the
tosylates 10a؊c[6] via the azides 15a؊c (Scheme 5). The lat-
ter were prepared in almost quantitative yield by stirring
10a؊c at room temperature in DMSO with sodium azide.
Several methods for reducing the azides were tested, but of
these only the catalytic hydrogenation proved applicable due
to the instability of the resulting primary amines 16a,b.
Staudinger reduction[12] led to the desired amines, as indi-
cated by TLC, but they could not be separated from the by-
products. Similar problems were encountered when redu-
cing agents containing sulfur, such as propane-1,3-dithiol
were employed.[13] However, hydrogenation using 3Ϫ4 mol-
% Lindlar’s catalyst in ethyl acetate for 1 h (longer stirring
resulted in an overreduction) led to crude and unstable 16a
and 16b, which were usually employed for the allylic amin-
ation without prior purification. The reactions were per-
formed in acetonitrile with triethylamine as base and 4 mol-
% of [Pd(PPh3)4] as catalyst and were allowed to proceed
for 18 h at 70 °C, thereby affording the desired spirocyclic
amines 17a and 17b as volatile liquids. The 6,7-spirocyclic
amine 17c could not be obtained in this way. For the syn-
thesis of the tertiary amines 12a؊e, it was found to be most
efficient to use the crude amines 17a,b as substrates for the
alkylation with various nosylates 18b؊e; the yields over the
three steps ranged from 52 to 79% (Scheme 6).
Scheme 3. Synthesis of secondary amines 11a؊e
cyclopentenyl compound. Thus, the oxidative addition of
palladium to the bromoarene moiety becomes the preferred
reaction, resulting in termination of the desired transforma-
tion. We have previously encountered the same problem
with iodoarenes connected to a cyclopentenyl acetate mo-
iety. Here again, the process comes to a halt, since the allylic
acetate is less reactive than the iodoarene group in this type
of double-functionalized substrate.[1j]
This assumption was verified by the fact that 13, lacking
a bromo substituent on the arene moiety, provided the de-
sired spirocyclic amine 14 in 74% yield using [Pd(PPh3)4] as
catalyst at 75 °C (Scheme 4).
Scheme 4. Synthesis of the tertiary amine 14
To circumvent the problem of the lack of chemoselectiv-
ity, we decided to prepare the spiroazacycle first, which was
then alkylated with ortho-iodo- or ortho-bromoarylalkyl
halides and nosylates 18, respectively. The tertiary amines
thus obtained could then be employed in intramolecular
Heck reactions.
Scheme 5. Synthesis of secondary spirocyclic amines 17
For the preparation of 12f, the amine 17b as its hydro-
The o-bromobenzyl bromide 18a[7] was prepared in one chloride was alkylated with the benzyl bromide 18a[7] in
step from piperonyl alcohol and bromine in 98% yield. 89% yield. In the same manner, 12g was prepared from the
Clearly, the HBr produced in the aromatic substitution re- amine 17a and benzyl bromide 18a in 71% yield. The struc-
action served as the reagent for the generation of the benzyl ture of the hydrochloride of the tertiary spirocyclic amine
bromide. The corresponding phenylethyl alcohol, which was 12f was verified by an X-ray analysis, as depicted in Fig-
2434
Eur. J. Org. Chem. 2000, 2433Ϫ2444

Six-Membered Ring D Analogues of the Pentacyclic Alkaloid Cephalotaxine
FULL PAPER
Scheme 7. Synthesis of the (5,6,6,6,6)-ring cephalotaxine anal-
ogue 19
Scheme 6. Alkylation of spirocyclic amines 17
but in most cases this problem has been overcome by using
higher temperatures. However, in the case of 12a؊e,g, use
of higher temperatures resulted in decomposition of the
substrates. We therefore prepared the corresponding amides
22a؊c, which indeed allowed us to synthesize the
(5,6,7,6,6)-cephalotaxine analogue 23.
Reaction of the readily available acid chlorides 21a and
21b[16,17] with the spirocyclic secondary amines 17a and 17b
1
furnished the amides 22a؊c in reasonable yields. The H-
and 13C-NMR spectra of 22a and 22b showed double sets
of signals, clearly due to a high inversion barrier at the
amide nitrogen atom. Heck reaction of 22a with the pallada-
cycle 20 as catalyst using a reaction temperature of 140 °C
and a reaction time of 30 h gave the desired product 23 in
55% yield as a 1:1.1 mixture of two diastereomers
(Scheme 8). The low stereoselectivity associated with
formation of the second stereogenic center was unexpected
since in the syntheses of cephalotaxine 1 and its analogues
Figure 1. X-ray crystal structure of tertiary spirocyclic amine 12f
ure 1.[14] As expected, the alkene moiety is equatorially dis-
posed.
The final Heck reactions of 12a؊g were performed using
the optimized conditions for our cephalotaxine syn-
thesis.[1i,1j] For these transformations, the bromoarenes
12a؊g were stirred in a degassed solvent mixture consisting
of acetonitrile, dimethylformamide, and water (ratio 5:5:1)
in the presence of 2.1 equiv. of tetra-n-butylammonium
acetate with catalytic amounts of the palladacycle trans-
di(µ-acetato)bis[o-(di-o-tolylphosphanyl)benzyl]dipalla-
dium(II)[15] (20). However, compared to the Heck reactions
of the analogous cyclopentene derivatives,[4] the substrates
12a؊g possessing a cyclohexene moiety proved to be much
less reactive. Thus, only in the case of the benzylic com-
pound 12f could a Heck reaction be achieved. This gave the
all-6-ring system 19 in 75% yield after a reaction time of
20 h, three times longer than needed for the corresponding
cyclopentene derivative (Scheme 7). The other substrates
12a؊e,g could not be converted to the expected Heck prod-
ucts, despite examining a multitude of different reaction
conditions. For example, the reaction of compound 12b in
the presence of 20 mol-% of palladium(II) acetate as cata-
lyst led to the deiodinated compound 14 in 20% yield after
work-up, indicating that the alkene insertion did not take
place. We have often found cyclohexene derivatives to be
Scheme 8. Synthesis of the (5,6,7,5,6)-ring cephalotaxine anal-
less reactive in Heck reactions than cyclopentene systems, ogue 23
Eur. J. Org. Chem. 2000, 2433Ϫ2444
2435

L. F. Tietze, H. Schirok, M. Wöhrmann, K. Schrader
FULL PAPER
and-freeze methodology. All reagents obtained from commercial
sources were used without further purification. Ϫ Thin-layer chro-
matography was performed on precoated silica gel SIL G/UV254
plates (MachereyϪNagel GmbH & Co. KG), while silica gel 32Ϫ63
(0.032Ϫ0.063 mm) (MachereyϪNagel GmbH & Co. KG) was used
for column chromatography. Ϫ UV/Vis spectra of samples in
CH3CN solution were recorded with a Mettler Lambda 2 spectro-
photometer. Ϫ IR spectra were recorded from samples in KBr pel-
lets or as films with Bruker IFS 25 or Vector 22 spectrometers. Ϫ
1H- and 13C-NMR spectra were recorded with Varian XL 200,
with (7,5,5)-, (7,6,5)-, (6,5,5)-, (6,6,5)-, and (6,6,6)-BCD
rings, only one diastereomer was obtained. One must there-
fore assume that the partial planarization of the nitrogen
atom due to the presence of the amide moiety renders the
on-side attack less favorable. One of the two diastereomers
of 23 could be separated by chromatography, but the spec-
tral data did not allow an unambiguous assignment of the
two isomers. Reactions of the amides 22b and 22c led to
unidentifiable products. The negative result in the case of
22c was not unexpected since all our attempts to prepare VXR 200, and VXR 500 spectrometers or a Bruker AM-300 spec-
trometer with samples in [D]chloroform or [D6]benzene using tetra-
methylsilane (TMS) as an internal standard. The multiplicities of
13C-NMR peaks were determined using the APT pulse sequence.
Mass spectra were measured at 70 eV with a Varian MAT 311A
spectrometer, high-resolution mass spectra with a Varian MAT 731
instrument. Ϫ Melting points were measured with a Mettler FP 61
apparatus and are uncorrected. The following abbreviations are
used in the text: MTBE ϭ tert-butyl methyl ether, PE ϭ petroleum
ether, TBAI ϭ tetra-n-butylammonium iodide, TFA ϭ triflu-
oroacetic acid.
eight-membered rings by a Heck reaction have hitherto met
with little success.
The structures of the newly formed compounds were
mainly established by NMR spectroscopy. However, for 12f
an X-ray analysis has been performed.[14] The 1H- and 13C-
NMR spectra of the azaspirocycle 17a and the compounds
12f and 19 are discussed here as representative cases. In
the 1H-NMR spectrum of the azaspirocycle 17a, signals are
found at δ ϭ 5.54 due to 6-H and 5.66 due to 7-H as a dt
with J ϭ 9.8, 1.7 Hz (6-H) and J ϭ 9.8, 3.4 Hz (7-H), and
at δ ϭ 2.94 and 3.04 as a dt (J ϭ 10.3, 6.6 Hz) due to the
CH2 group attached to the nitrogen atom (2-H). Significant
signals in the 13C-NMR spectrum are observed at δ ϭ 126.7
due to C-7 and at δ ϭ 134.0 due to C-6, while C-5 resonates
3-[5-(Tolyl-4-sulfonyloxy)pentyl]cyclohex-2-enyl Acetate (10c). ؊ 5-
(3-Oxocyclohex-1-enyl)pentyl Toluene-4-sulfonate: A solution of 5-
chloropentan-1-ol[18] (10.0 g, 81.6 mmol) in THF (160 mL) was co-
oled to Ϫ78 °C and methylmagnesium chloride (3.8  in THF,
21.5 mL, 81.6 mmol) was added dropwise. After the addition was
complete, the solution was allowed to warm to room temperature.
Once gas production had ceased, magnesium turnings (2.38 g,
97.9 mmol) were added, and the mixture was heated under reflux
1
at δ ϭ 59.7. The H-NMR spectrum of the alkylated com-
pound 12f features a doublet (J ϭ 10.0 Hz) due to the ole-
finic protons at δ ϭ 5.46 and a dt at δ ϭ 5.75 with J ϭ 10.0
and 3.7 Hz. In the pentacyclic compound 19, the olefinic for 3 h. The reaction mixture was subsequently cooled to Ϫ10 °C,
3-ethyloxycyclohex-2-enone[19] (7.19 g, 51.3 mmol) was added, and
the resulting mixture was stirred for 3 h. It was then allowed to
warm to 0 °C, whereupon saturated aq. NH4Cl solution (20 mL)
was added. The resulting mixture was partitioned between cold
ethyl acetate (200 mL) and 2  HCl (100 mL). The layers were sep-
arated, and the aqueous phase was extracted with ethyl acetate.
protons resonate at δ ϭ 5.66 as a broad doublet (J ϭ
10.0 Hz, 1-H) and at δ ϭ 6.09 as a dddd with J ϭ 10.0, 5.6,
2.0, and 2.0 Hz for 2-H. The corresponding signals in the
13C-NMR spectrum are found at δ ϭ 126.4 (C-1) and δ ϭ
128.6 (C-2).
The combined organic fractions were dried with Na2SO4 and con-
centrated to dryness in vacuo. The crude product was redissolved
in cold (Ϫ10 °C) pyridine (50 mL), and tosyl chloride (14.7 g,
Conclusion
77.0 mmol) was added. The resulting mixture was stirred for 18 h
at Ϫ10 °C, then poured into ethyl acetate (200 mL) and extracted
In our attempts to improve the pharmacological activity
of cephalotaxine and its esters, we have prepared novel ring-
size analogues of this pentacyclic alkaloid. Recently, we
showed that the combination of a Pd-catalyzed nucleophilic
addition of an amine to an allyl acetate with a subsequent
Heck reaction allows highly efficient access to cephalotax-
ine and several ring-size analogues with a five-membered
ring D, but that analogues with a six-membered ring D
could not be prepared in this way. However, by preforming
the spiroazacycles and then subjecting them to N-alkylation
and N-acylation, respectively, with a bromoarene derivative
and subsequent Heck reaction, we have now succeeded in
preparing ring-size analogues of cephalotaxine with
(5,6,6,6,6)- and (5,6,7,5,6)-ring systems.
twice with cold 2  HCl. The organic phase was washed with brine,
dried with Na2SO4, and concentrated to dryness in vacuo. Purifica-
tion of the residue by column chromatography (500 g SiO2; PE/
EtOAc, 1:1 Ǟ 1:2) gave the tosylate (4.96 g, 14.7 mmol) in 29%
1
yield; Rf ϭ 0.28 (PE/MTBE, 1:3). Ϫ H NMR (200 MHz, CDCl3):
δ ϭ 1.15 (m, 4 H, 3-H2, 4-H2), 1.67 (tt, J ϭ 7.0, 6.4 Hz, 2 H, 2-H2),
1.90Ϫ2.06 (m, 2 H, 5Ј-H2), 2.18 (t, J ϭ 6.7 Hz, 2 H, 5-H2), 2.26 (t,
J ϭ 6.0 Hz, 2 H, 6Ј-H2), 2.36 (t, J ϭ 6.7 Hz, 2 H, 4Ј-H2), 2.46 (s,
3 H, CH3), 4.02 (t, J ϭ 6.4 Hz, 2 H, OCH2), 5.82 (br. s, 1 H, 2Ј-H),
7.35 (d, J ϭ 8.0 Hz, 2 H, Ar-2-H, Ar-6-H), 7.78 (d, J ϭ 8.0 Hz,
2 H, Ar-3-H, Ar-5-H). Ϫ The cyclohexenone (1.68 g, 5.00 mmol)
was dissolved in toluene (25 mL) and the resulting solution was
cooled to Ϫ50 °C. A solution of DIBAL in toluene (1.5 , 4.00 mL,
6.00 mmol, 1.2 equiv.) was then added dropwise by means of a
syringe pump. After the addition of Celite (1.5 g), a 1:1 mixture of
methanol and water (4 mL) was added, and the resulting mixture
was allowed to warm to room temperature. It was then filtered,
rinsing with ethyl acetate. The combined filtrate and washings were
dried with Na2SO4 and the solvents were evaporated. The allylic
alcohol thus obtained was treated with acetic anhydride (535 mg,
5.24 mmol, 1.05 equiv.), triethylamine (607 mg, 6.00 mmol, 1.2
equiv.), and DMAP (61.1 mg, 500 µmol, 0.1 equiv.) in CH2Cl2 at 0
Experimental Section
General Remarks: All reactions were performed in flame-dried
flasks under nitrogen or argon; the reactants were introduced by
means of syringes. All solvents were dried by standard methods.
Solvents used for Pd-catalyzed reactions were degassed by pump-
2436
Eur. J. Org. Chem. 2000, 2433Ϫ2444

Six-Membered Ring D Analogues of the Pentacyclic Alkaloid Cephalotaxine
FULL PAPER
°C. The crude product was purified by chromatography on silica gel
3-{3-[2-(6-Bromobenzo[1,3]dioxol-5-yl)ethylamino]propyl}cyclohex-
(100 g SiO2; PE/EtOAc, 3:1) to give the allylic acetate 10c (1.69 g, 2-enyl Acetate (11b): According to General Procedure I, amine 9b[5]
4.45 mmol, 89%) as a colorless oil; Rf ϭ 0.40 (PE/EtOAc, 3:1). Ϫ
(234 mg, 959 µmol, 3.7 equiv.) was alkylated with tosylate 10a[6]
IR (neat): ν˜ ϭ 2936 cmϪ1 (ϭCϪH), 1727 (CϭO), 1665 (CϭC), (92.0 mg, 261 µmol) in the presence of TBAI (144 mg, 390 µmol,
1598, 1362 (SO2), 1243 (CϪO), 1188, 1177 (SO2), 953, 816, 664. Ϫ 1.5 equiv.). Purification of the crude product by column chromato-
UV (CH3CN): λmax (lg ε) ϭ 194 nm (4.77), 225 (4.09), 256 (2.72), graphy (45 g SiO2; gradient column: 200 mL EtOAc/MeOH, 15:1,
1
262 (2.79), 267 (2.75), 273 (2.67). Ϫ H NMR (200 MHz, C6D6): ϩ 1% Et3N; then EtOAc/MeOH, 5:1, ϩ 1% Et3N) afforded 11b
δ ϭ 0.87Ϫ1.12 (m, 4 H, 2Ј-H2, 3Ј-H2), 1.26 (tt, J ϭ 6.6, 6.6 Hz,
(93.8 mg, 221 µmol, 85%) as a pale-yellow oil; Rf ϭ 0.45 (EtOAc/
2 H, 4Ј-H2), 1.30Ϫ1.50 (m, 2 H, 5-H2), 1.56Ϫ1.70 (m, 6 H, 1Ј-H2, MeOH, 5:1, ϩ 1% Et3N). Ϫ IR (neat): ν˜ ϭ 3322 cmϪ1 (NϪH),
4-H2, 6-H2), 1.75 (s, 3 H, COCH3), 1.90 (s, 3 H, ArϪCH3), 3.80 (t, 2936 (CϪH), 1728 (CϭO), 1666 (CϭC), 1480, 1370, 1246 (CϪO),
J ϭ 6.3 Hz, 2 H, OCH2), 5.35Ϫ5.45 (mc, 1 H, 1-H), 5.54 (br. s, 1 H, 1116, 1040, 934 (CϪOϪC), 910, 860, 834(arene). Ϫ UV (CH3CN):
2-H), 6.79 (d, J ϭ 8.3 Hz, 2 H, Ar-2-H, Ar-6-H), 7.78 (d, J ϭ λmax (lg ε) ϭ 201 nm (4.66), 235 (3.72), 294 (3.66). Ϫ 1H NMR
8.3 Hz, 2 H, Ar-3-H, Ar-5-H). Ϫ 13C NMR (50.3 MHz, C6D6): δ ϭ (500 MHz, CDCl3): δ ϭ 1.59Ϫ1.82 (m, 7 H, 2Ј-H2, 5-H2, 6-H2,
19.5 (C-5), 21.1 (COCH3), 21.2 (ArϪCH3), 25.2 (C-3Ј), 26.8 (C-
2Ј), 28.4, 28.6 (C-4, C-6), 28.9 (C-4Ј), 37.5 (C-1Ј), 68.7 (C-1), 70.2 (t, J ϭ 7.4 Hz, 2 H, 3Ј-H2), 2.82Ϫ2.90 (mc, 4 H, 1ЈЈ-H2, 2ЈЈ-H2),
(OCH2), 120.5 (C-2), 128.1 (Ar-C-3, Ar-C-5), 129.8 (Ar-C-2, Ar- 5.23Ϫ5.27 (mc, 1 H, 1-H), 5.46 (mc, 1 H, 2-H), 5.96 (s, 2 H,
NH), 1.89Ϫ2.05 (m, 4 H, 1Ј-H2, 4-H2), 2.04 (s, 3 H, CH3), 2.66
C-6), 134.5 (Ar-C-4), 143.7 (C-3), 144.2 (Ar-C-1), 170.0 (CO). Ϫ OCH2O), 6.75 (s, 1 H, 4ЈЈЈ-H), 7.00 (s, 1 H, 7ЈЈЈ-H). Ϫ 13C NMR
MS (70 eV, EI): m/z (%) ϭ 380 (Ͻ 1) [Mϩ], 337 (100) [Mϩ Ϫ Ac],
320 (13) [Mϩ Ϫ AcOH], 166 (13), 148 (21) [C11H16ϩ], 155 (4) [Tsϩ],
(50.3 MHz, CDCl3): δ ϭ 19.1 (C-5), 21.4 (CH3), 27.6 (C-2Ј), 28.1,
28.2 (C-4, C-6), 35.2 (C-1Ј), 43.6 (C-2ЈЈ), 48.6 (C-3Ј), 53.5 (C-1ЈЈ),
97 (25) [C8H9Oϩ], 91 (45) [CH3Phϩ]. Ϫ C20H28O5S (380.5): calcd. 68.7 (C-1), 101.6 (OCH2O), 110.0 (C-4ЈЈЈ), 112.6 (C-7ЈЈЈ), 113.9 (C-
C 63.13, H 7.42; found C 63.34, H 7.26.
6ЈЈЈ), 119.6 (C-2), 132.5 (C-5ЈЈЈ), 144.1 (C-3), 147.2 (C-3aЈЈЈ, C-
7aЈЈЈ), 170.8 (CO). Ϫ MS (70 eV, EI): m/z (%) ϭ 425/423 (Ͻ1)
[Mϩ], 210 (15) [C12H20NO2ϩ], 150 (100) [C10H16Nϩ], 121 (6)
[C9H13ϩ]. Ϫ C20H26BrNO4 (424.3): calcd. C 56.61, H 6.18, Br
18.83; found C 56.69, H 6.30, Br 18.87. Ϫ HRMS: calcd. 423.1045;
found 423.1045.
General Procedure I. ؊ Synthesis of the Secondary Amines 11a؊e
by Alkylation of Primary Amines 9a؊d: A 1  solution of the amine
9 (2.5 equiv.) in THF was refluxed with TBAI (1.5 equiv.) and a
0.5  solution of the tosylate 10 was added dropwise by means of
an infusion pump over a period of 8 h. No TBAI was added when
3-(3-iodopropyl)cyclohex-2-enyl acetate[4] was used instead of tos-
ylate 10. The reaction mixture was heated for a further 2 h, poured
into MTBE, and made basic with cold 5% aq. NaOH solution.
After separation of the layers, the aqueous layer was extracted four
times with MTBE. The combined organic layers were dried with
Na2SO4 and concentrated to dryness in vacuo. The crude product
was purified by column chromatography.
3-{3-[2-(2-Bromo-4,5-dimethoxyphenyl)ethylamino]propyl}cyclohex-
2-enyl Acetate (11c): According to General Procedure I, amine 9d[5]
(300 mg, 1.15 mmol, 3.4 equiv.) was alkylated with 3-(3-iodopro-
pyl)cyclohex-2-enyl acetate[4] (104 mg, 337 µmol) in THF. Purifica-
tion of the crude product by column chromatography (40 g SiO2;
EtOAc/MeOH, 15:1, ϩ 1% Et3N) afforded 11c (134 mg, 304 µmol,
90%) as a pale-yellow oil; Rf ϭ 0.23 (EtOAc/MeOH, 5:1, ϩ 1%
Et3N). Ϫ IR (neat): ν˜ ϭ 3426 cmϪ1 (NϪH), 2938 (CϪH), 1726
(CϭO), 1638 (CϭC), 1510, 1246 (CϪO), 1218 (ArϪOϪC), 1166,
1030 (ArϪOϪC), 910, 856, 800 (arene). Ϫ UV (CH3CN): λmax (lg
ε) ϭ 204 nm (4.65), 287 (3.49). Ϫ 1H NMR (200 MHz, CDCl3):
δ ϭ 1.42 (br. s, 1 H, NH), 1.54Ϫ1.85 (m, 6 H, 2Ј-H2, 5-H2, 6-H2),
1.91Ϫ2.08 (m, 4 H, 1Ј-H2, 4-H2), 2.04 (s, 3 H, COCH3), 2.63 (t,
J ϭ 7.2 Hz, 2 H, 3Ј-H2), 2.85 (s, 4 H, 1ЈЈ-H2, 2ЈЈ-H2), 3.85 (s, 6 H,
2 ϫ OCH3), 5.20Ϫ5.30 (mc, 1 H, 1-H), 5.45 (br. s, 1 H, 2-H), 6.75
(s, 1 H, 6ЈЈЈ-H), 7.00 (s, 1 H, 3ЈЈЈ-H). Ϫ 13C NMR (50.3 MHz,
CDCl3): δ ϭ 19.1 (C-5), 21.4 (COCH3), 27.7 (C-2Ј), 28.2, 28.3 (C-
4, C-6), 35.3 (C-1Ј), 36.4 (C-2ЈЈ), 49.4, 49.7 (C-1ЈЈ, C-3Ј), 56.0
(OCH3), 56.1 (OCH3), 68.7 (C-1), 113.2 (C-6ЈЈЈ), 114.1 (C-2ЈЈЈ),
115.5 (C-3ЈЈЈ), 119.6 (C-2), 131.2 (C-1ЈЈЈ), 144.2 (C-3), 147.9 (C-
5ЈЈЈ), 148.2 (C-4ЈЈЈ), 170.8 (CO). Ϫ MS [70 eV, CI (NH3)]: m/z
(%) ϭ 442/440 (100/94) [M ϩ Hϩ], 380 (6) [Mϩ Ϫ AcO], 362 (45)
3-{3-[(6-Bromobenzo[1,3]dioxol-5-ylmethyl)amino]propyl}cyclohex-
2-enyl Acetate (11a):
A
solution of amine 9a[5] (251 mg,
1.09 mmol), 3-(3-iodopropyl)cyclohex-2-enyl acetate[4] (410 mg,
1.33 mmol, 1.2 equiv.), and diisopropylethylamine (450 mg,
3.50 mmol, 3.2 equiv.) in THF (6 mL) was refluxed for 23 h. After
work-up according to General Procedure I, the crude product was
purified by column chromatography (100 g SiO2; PE/EtOAc, 1:1,
ϩ 1% Et3N) to give 11a (287 mg, 700 µmol, 64%) as a pale-yellow
oil; Rf ϭ 0.57 (EtOAc/MeOH, 15:1, ϩ 1% Et3N). Ϫ IR (neat): ν˜ ϭ
3338 cmϪ1 (NϪH), 2936 (CϪH), 1726 (CϭO), 1664 (CϭC), 1476,
1240 (CϪO), 1118, 1038, 932 (CϪOϪC), 912, 866, 832 (arene). Ϫ
UV (CH3CN): λmax (lg ε) ϭ 201 nm (4.61), 237 (3.68), 294 (3.61).
1
Ϫ H NMR (200 MHz, CDCl3): δ ϭ 1.57Ϫ1.83 (m, 7 H, 2Ј-H2, 5-
[Mϩ Ϫ Br ϩ 2 H], 279/277 (11) [C10H15BrNO2 ϩ NH3], 262/260
ϩ
H2, 6-H2, NH), 1.90Ϫ2.10 (m, 4 H, 1Ј-H2, 4-H2), 2.04 (s, 3 H,
CH3), 2.59 (t, J ϭ 7.0 Hz, 2 H, 3Ј-H2), 3.75 (s, 2 H, 1ЈЈ-H2),
5.20Ϫ5.30 (mc, 1 H, 1-H), 5.46 (mc, 1 H, 2-H), 5.96 (s, 2 H,
(10) [C10H15BrNO2ϩ], 200 (27). Ϫ C21H30BrNO4 (440.4).
OCH2O), 6.90 (s, 1 H, 4ЈЈЈ-H), 6.99 (s, 1 H, 7ЈЈЈ-H). Ϫ 13C NMR 3-{4-[2-(6-Bromobenzo[1,3]dioxol-5-yl)ethylamino]butyl}cyclohex-2-
(50.3 MHz, CDCl3): δ ϭ 19.1 (C-5), 21.5 (CH3), 27.7 (C-2Ј), 28.2,
enyl Acetate (11d): According to General Procedure I, amine 9b[5]
28.3 (C-4, C-6), 35.3 (C-1Ј), 48.6 (C-3Ј), 53.5 (C-1ЈЈ), 68.7 (C-1), (1.90 g, 7.78 mmol, 2.5 equiv.) was alkylated with tosylate 10b[6]
101.6 (OCH2O), 110.1 (C-7ЈЈЈ), 112.7 (C-4ЈЈЈ), 114.0 (C-6ЈЈЈ), 119.7 (1.15 g, 3.14 mmol) in the presence of TBAI (1.73 g, 4.68 mmol,
(C-2), 132.4 (C-5ЈЈЈ), 144.2 (C-3), 147.3 (C-3aЈЈЈ, C-7aЈЈЈ), 170.8 1.5 equiv.). Purification of the crude product by column chroma-
(CO). Ϫ MS [70 eV, CI (NH3)]: m/z (%) ϭ 412/410 (97/100) [M ϩ
tography (110 g SiO2; gradient column: 300 mL ethyl acetate; then
EtOAc/MeOH, 5:1, ϩ 1% Et3N) afforded 11d (1.02 g, 2.33 mmol,
74%) as a pale-yellow oil; Rf ϭ 0.51 (EtOAc/MeOH, 5:1, ϩ 1%
Hϩ], 352/350 (10) [Mϩ Ϫ AcO], 332 (75) [Mϩ Ϫ Br ϩ 2 H], 249/
ϩ
247 (15) [C8H9BrNO2 ϩ NH3], 232/230 (20/22) [C8H9BrNO2ϩ],
198 (70) [C11H20NO2], 169 (49) [C10H18Nϩ ϩ NH3], 152 (54) Et3N). Ϫ IR (neat): ν˜ ϭ 3326 cmϪ1 (NϪH), 2933 (CϪH), 1727
[C10H18Nϩ], 138 (31) [C9H16Nϩ]. Ϫ C19H24BrNO4 (410.3): calcd.
(CϭO), 1666 (CϭC), 1478, 1243 (CϪO), 1116, 1039, 933
C 55.62, H 5.90; found C 55.85, H 5.96. Ϫ HRMS: calcd. 409.0889; (CϪOϪC), 910, 860, 833 (arene). Ϫ UV (CH3CN): λmax (lg ε) ϭ
found 409.0889.
200 nm (4.64), 236 (3.66), 294 (3.61). Ϫ 1H NMR (500 MHz,
Eur. J. Org. Chem. 2000, 2433Ϫ2444
2437

L. F. Tietze, H. Schirok, M. Wöhrmann, K. Schrader
FULL PAPER
CDCl3): δ ϭ 1.38Ϫ1.52 (m, 4 H, 2Ј-H2, 3Ј-H2), 1.56Ϫ1.80 (m, 5 H, 36.0 (C-2ЈЈ), 49.4 (C-3Ј), 51.2 (C-1ЈЈ), 68.7 (C-1), 100.7 (OCH2O),
5-H2, 6-H2, NH), 1.85Ϫ1.95 (m, 2 H, 4-H2), 1.98 (t, J ϭ 7.4 Hz, 108.1 (C-4ЈЈЈ), 108.9 (C-7ЈЈЈ), 119.6 (C-2), 121.4 (C-6ЈЈЈ), 133.8 (C-
2 H, 1Ј-H2), 2.02 (s, 3 H, CH3), 2.65 (t, J ϭ 7.1 Hz, 2 H, 4Ј-H2), 5ЈЈЈ), 144.2 (C-3), 145.8 (C-7aЈЈЈ), 147.6 (C-3aЈЈЈ), 170.8 (CO). Ϫ
2.80Ϫ2.88 (mc, 4 H, 1ЈЈ-H2, 2ЈЈ-H2), 5.21Ϫ5.25 (mc, 1 H, 1-H), 5.43
MS [70 eV, CI (NH3)]: m/z (%) ϭ 346 (100) [M ϩ Hϩ], 286 (10)
(mc, 1 H, 2-H), 5.93 (s, 2 H, OCH2O), 6.73 (s, 1 H, 4ЈЈЈ-H), 6.97 (s, [Mϩ Ϫ AcO], 183 (11), 166 (13) [C11H20Nϩ]. Ϫ C20H27NO4 (345.4):
1 H, 7ЈЈЈ-H). Ϫ 13C NMR (50.3 MHz, CDCl3): δ ϭ 19.1 (C-5), 21.5 calcd. C 69.54, H 7.88; found C 69.63, H 7.99.
(CH3), 25.0 (C-2Ј), 28.2, 28.3 (C-4, C-6), 29.5 (C-3Ј), 36.2 (C-2ЈЈ),
1-(2-Benzo[1,3]dioxol-5-ylethyl)-1-azaspiro[4.5]dec-6-ene (14):
A
37.4 (C-1Ј), 49.5 (C-1ЈЈ, C-4Ј), 68.8 (C-1), 101.6 (OCH2O), 110.2
(C-4ЈЈЈ), 112.7 (C-7ЈЈЈ), 114.4 (C-6ЈЈЈ), 119.6 (C-2), 132.1 (C-5ЈЈЈ),
144.4 (C-3), 146.8 (C-3aЈЈЈ), 147.3 (C-7aЈЈЈ), 170.8 (CO). Ϫ MS
[70 eV, CI (NH3)]: m/z (%) ϭ 440/438 (56/59) [M ϩ Hϩ], 378 (6)
mixture of amine 13 (20.3 mg, 58.8 µmol), [Pd(PPh3)4] (10.0 mg,
8.70 µmol, 15 mol%), and triethylamine (18.2 mg, 179 µmol, 3.0
equiv.) in CH3CN was heated at 75 °C for 18 h. Work-up as de-
scribed for 17a and 17b, followed by column chromatography (20 g
SiO2; EtOAc) gave 14 (12.4 mg, 43.5 µmol, 74%) as a colorless oil;
Rf ϭ 0.45 (EtOAc/MeOH, 5:1, ϩ 1% Et3N). Ϫ IR (KBr): ν˜ ϭ
3013 cmϪ1 (ArϪH), 2936 (CϪH), 1490, 1247, 1109, 1042, 931
(CϪOϪC), 863, 808 (arene), 742 (ϭCϪH). Ϫ UV (CH3CN): λmax
(lg ε) ϭ 199 nm (4.63), 231 (3.72), 287 (3.58). Ϫ 1H NMR
(500 MHz, CDCl3): δ ϭ 1.45Ϫ1.90 (m, 8 H, 3-H2, 4-H2, 9-H2, 10-
H2), 1.93 (mc, 2 H, 8-H2), 2.56Ϫ2.72 (m, 4 H, 1Ј-H2, 2Ј-H2), 2.82
(br. s, 1 H, 2-H), 2.99 (m, 1 H, 2-H), 5.46 (d, J ϭ 10.1 Hz, 1 H, 6-
H), 5.76 (dt, J ϭ 10.1, 4.1 Hz, 1 H, 7-H), 5.91 (s, 2 H, OCH2O),
6.65 (dd, J ϭ 8.0, 1.6 Hz, 1 H, 6ЈЈ-H), 6.71 (d, J ϭ 1.6 Hz, 1 H,
7ЈЈ-H), 6.72 (d, J ϭ 8.0 Hz, 1 H, 4ЈЈ-H). Ϫ 13C NMR (50.3 MHz,
CDCl3): δ ϭ 21.1, 21.2 (C-3, C-9), 25.1 (C-8), 28.3 (C-4), 36.2 (C-
2Ј), 38.3 (C-10), 50.6 (C-2), 51.8 (C-1Ј), 63.7 (C-5), 100.6 (OCH2O),
108.0 (C-4ЈЈ), 109.1 (C-7ЈЈ), 121.3 (C-6ЈЈ), 128.9 (C-7), 133.2 (C-6),
134.7 (C-5ЈЈ), 145.5 (C-7aЈЈ), 147.3 (C-3aЈЈ). Ϫ MS (70 eV, EI): m/z
(%) ϭ 285 (Ͻ1) [Mϩ], 150 (100) [C10H16Nϩ], 135 (8) [C8H7O2ϩ]. Ϫ
C18H23NO2 (285.4): calcd. C 75.76, H 8.12; found C 75.62, H 7.89.
Ϫ HRMS: calcd. 285.1729; found 285.1728.
[Mϩ Ϫ AcO], 360 [Mϩ Ϫ Br ϩ 2 H], 263/261 (15) [C9H11BrNO2
ϩ
ϩ NH3], 246/244 (11) [C9H11BrNO2ϩ], 183 (75) [C11H20Nϩ
ϩ
NH3], 166 (51) [C11H20Nϩ]. Ϫ C21H28BrNO4 (438.4): calcd. C
57.54, H 6.44; found C 57.60, H 6.36.
3-{3-[3-(6-Bromobenzo[1,3]dioxol-5-yl)propylamino]propyl}cyclohex-
2-enyl Acetate (11e): According to General Procedure I, amine 9c[5]
(1.10 g, 4.26 mmol, 2.5 equiv.) was alkylated with tosylate 10a[6]
(600 mg, 1.70 mmol) in the presence of TBAI (943 mg, 2.55 mmol,
1.5 equiv.). Purification of the crude product by column chroma-
tography (70 g SiO2; gradient column: 150 mL of ethyl acetate; then
EtOAc/MeOH, 5:1, ϩ 1% Et3N) afforded 11e (566 mg, 1.29 mmol,
76%) as a pale-yellow oil; Rf ϭ 0.49 (EtOAc/MeOH, 5:1, ϩ 1%
Et3N). Ϫ IR (neat): ν˜ ϭ 3327 cmϪ1 (NϪH), 2935 (CϪH), 1726
(CϭO), 1665 (CϭC), 1478, 1243 (CϪO), 1114, 1038, 933
(CϪOϪC), 911, 859, 831 (arene). Ϫ UV (CH3CN): λmax (lg ε) ϭ
201 nm (4.65), 236 (3.68), 294 (3.63). Ϫ 1H NMR (200 MHz,
CDCl3): δ ϭ 1.55Ϫ1.84 (m, 9 H, 2Ј-H2, 2ЈЈ-H2, 5-H2, 6-H2, NH),
1.93Ϫ2.07 (m, 4 H, 1Ј-H2, 4-H2), 2.04 (s, 3 H, CH3), 2.57Ϫ2.72 (m,
6 H, 3Ј-H2, 1ЈЈ-H2, 3ЈЈ-H2), 5.20Ϫ5.31 (mc, 1 H, 1-H), 5.47 (br. s,
1 H, 2-H), 5.94 (s, 2 H, OCH2O), 6.98 (s, 1 H, 4ЈЈЈ-H), 6.71 (s, 1 H,
7ЈЈЈ-H). Ϫ 13C NMR (50.3 MHz, CDCl3): δ ϭ 19.1 (C-5), 21.5
(CH3), 27.6 (C-2Ј), 28.2, 28.3 (C-4, C-6), 30.3 (C-3ЈЈ), 33.7 (C-2ЈЈ),
35.4 (C-1Ј), 49.1 (C-1ЈЈ), 49.5 (C-3Ј), 68.8 (C-1), 101.5 (OCH2O),
109.8 (C-4ЈЈЈ), 112.6 (C-7ЈЈЈ), 114.2 (C-6ЈЈЈ), 119.7 (C-2), 134.3 (C-
5ЈЈЈ), 144.2 (C-3), 146.5 (C-3aЈЈЈ), 147.3 (C-7aЈЈЈ), 170.8 (CO). Ϫ
MS (70 eV, EI): m/z (%) ϭ 440/438 (Ͻ 1) [M ϩ Hϩ], 380/378 (17/
23) [Mϩ Ϫ AcO], 358 (70) [Mϩ Ϫ Br], 298 (100) [Mϩ Ϫ AcOH Ϫ
Br], 272/270 (9/10) [C11H13BrNO2ϩ], 215/213 (14) [C8H6BrO2ϩ],
204 (37) [C12H14NO2ϩ], 150 (39) [C10H16Nϩ], 121 (46) [C9H13ϩ],
44 (67) [CO2ϩ]. Ϫ C21H28BrNO4 (438.4): calcd. C 57.54, H 6.44;
found C 57.05, H 6.30.
General Procedure II. ؊ Formation of the Nosylates 18b؊e from
the Corresponding Alcohols: To a 0.2  solution of the alcohol in
CH2Cl2 at 0 °C were added triethylamine (1.2 equiv.) and DMAP
(0.1 equiv.), and then nosyl chloride (1.2 equiv.) was added por-
tionwise. The mixture was subsequently allowed to warm to room
temperature and stirred for 4 h. It was then diluted with CH2Cl2,
washed with brine, dried with Na2SO4, and concentrated to dryness
in vacuo. The residue was purified by recrystallization.
2-(6-Bromobenzo[1,3]dioxol-5-yl)ethyl
4-Nitrobenzenesulfonate
(18b) via 2-(6-Bromobenzo[1,3]dioxol-5-yl)ethanol: To a stirred solu-
tion of 2-benzo[1,3]dioxol-5-ylethanol[20] (6.26 g, 37.7 mmol) in
CH2Cl2 (60 mL), bromine (8.39 g, 52.5 mmol, 1.4 equiv.) was ad-
ded dropwise. After 0.5 h, the excess bromine was destroyed with
saturated Na2SO3 solution and the aqueous phase was extracted
twice with CH2Cl2. The combined organic layers were dried with
Na2SO4 and concentrated to dryness in vacuo. The residue was
recrystallized from PE/MTBE to afford the bromobenzoethanol
(8.42 g, 34.4 mmol, 91%) as colorless crystals; Rf ϭ 0.30 (PE/
MTBE, 1:1). Ϫ IR (KBr): ν˜ ϭ 3222 cmϪ1 (OH), 1482, 1240, 1046
3-{3-[(2-Benzo[1,3]dioxol-5-yl)ethylamino]propyl}cyclohex-2-enyl
Acetate (13): According to General Procedure I, 2-benzo[1,3]-
dioxol-5-ylethylamine (540 mg, 3.23 mmol, 2.0 equiv.) was al-
kylated with 3-(3-iodopropyl)cyclohex-2-enyl acetate[4] (503 mg,
1.63 mmol). Purification of the crude product by column chroma-
tography (100 g SiO2; gradient column: 100 mL ethyl acetate;
300 mL of ethyl acetate/MeOH, 15:1, ϩ 1% Et3N; then EtOAc/ (CϪO), 930 (CϪOϪC), 862, 832 (arene). Ϫ UV (CH3CN): λmax (lg
1
MeOH, 5:1, ϩ 1% Et3N) afforded 13 (450 mg, 1.30 mmol, 80%) as ε) ϭ 203 nm (4.55), 238 (3.64), 294 (3.61). Ϫ H NMR (200 MHz,
a pale-yellow oil; Rf ϭ 0.53 (EtOAc/MeOH, 5:1, ϩ 1% Et3N). Ϫ CDCl3): δ ϭ 1.57 (br. s, 1 H, OH), 2.93 (t, J ϭ 6.7 Hz, 2 H,
IR (neat): ν˜ ϭ 3328 cmϪ1 (NϪH), 2936 (CϪH), 1726 (CϭO), 1664 ArCH2), 3.83 (t, J ϭ 6.7 Hz, 2 H, OCH2), 5.95 (s, 2 H, OCH2O),
(CϭC), 1490, 1442, 1246 (CϪO), 1122, 1040, 934 (CϪOϪC), 912,
860, 810 (arene). Ϫ UV (CH3CN): λmax (lg ε) ϭ 199 nm (4.68), 234 CDCl3): δ ϭ 39.1 (ArCH2), 62.1 (OCH2), 101.6 (OCH2O), 110.7
6.77 (s, 1 H, 4-H), 7.01 (s, 1 H, 7-H). Ϫ 13C NMR (50.3 MHz,
1
(3.60), 287 (3.57). Ϫ H NMR (200 MHz, CDCl3): δ ϭ 1.17 (br. s,
1 H, NH), 1.50Ϫ1.85 (m, 6 H, 2Ј-H2, 5-H2, 6-H2), 1.90Ϫ2.05 (m, 7a). Ϫ MS (70 eV, EI): m/z (%) ϭ 246/244 (35) [Mϩ], 215/213 (96/
4 H, 1Ј-H2, 4-H2), 2.04 (s, 3 H, CH3), 2.59 (t, J ϭ 7.2 Hz, 2 H, 3Ј-
100) [Mϩ Ϫ CH3O], 164 (8), 135 (9) [C8H7O2ϩ]. Ϫ C9H9BrO3
H2), 2.65Ϫ2.86 (mc, 4 H, 1ЈЈ-H2, 2ЈЈ-H2), 5.19Ϫ5.29 (mc, 1 H, 1- (245.1): calcd. C 44.11, H 3.70; found C 44.05, H 3.52. Ϫ Accord-
H), 5.43 (br. s, 1 H, 2-H), 5.92 (s, 2 H, OCH2O), 6.65 (dd, J ϭ 7.8, ing to General Procedure II, the alcohol (4.54 g, 18.5 mmol) was
1.7 Hz, 1 H, 6ЈЈЈ-H), 6.69 (d, J ϭ 1.7 Hz, 1 H, 4ЈЈЈ-H), 6.74 (d, J ϭ treated with nosyl chloride (4.97 g, 22.4 mmol, 1.2 equiv.) in the
7.8 Hz, 1 H, 7ЈЈЈ-H). Ϫ 13C NMR (50.3 MHz, CDCl3): δ ϭ 19.1
presence of triethylamine (2.25 g, 22.2 mmol, 1.2 equiv.) and
(C-5), 21.4 (CH3), 27.7 (C-2Ј), 28.16, 28.21 (C-4, C-6), 35.3 (C-1Ј), DMAP (226 mg, 1.85 mmol, 0.1 equiv.). Recrystallization of the
(C-4), 112.7 (C-7), 114.6 (C-6), 130.7 (C-5), 147.0 (C-3a), 147.2 (C-
2438
Eur. J. Org. Chem. 2000, 2433Ϫ2444

Six-Membered Ring D Analogues of the Pentacyclic Alkaloid Cephalotaxine
crude product from CH2Cl2/ethyl acetate afforded 18b (7.07 g, Ϫ 1H NMR (200 MHz, CDCl3): δ ϭ 1.51 (br. s, 1 H, OH), 1.84 (tt,
FULL PAPER
16.4 mmol, 89%) as yellow crystals; Rf ϭ 0.45 (PE/MTBE, 1:1). Ϫ
J ϭ 7.7, 6.4 Hz, 2 H, CH2), 2.74 (t, J ϭ 7.7 Hz, 2 H, ArCH2), 3.68
IR (KBr): ν˜ ϭ 1532 cmϪ1 (NO2), 1478, 1362 (NO2), 1246, 1190 (t, J ϭ 6.4 Hz, 2 H, OCH2), 5.94 (s, 2 H, OCH2O), 6.73 (s, 1 H, 4-
(SO2), 1034, 970, 912 (CϪOϪC), 850, 832 (arene). Ϫ UV H), 6.98 (s, 1 H, 7-H). Ϫ 13C NMR (50.3 MHz, CDCl3): δ ϭ 32.2,
(CH3CN): λmax (lg ε) ϭ 202 nm (4.60), 248 (4.08), 291 (3.88). Ϫ 1H 32.8 (ArCH2, CH2), 61.9 (OCH2), 101.5 (OCH2O), 109.9 (C-4),
NMR (200 MHz, CDCl3): δ ϭ 3.01 (t, J ϭ 6.5 Hz, 2 H, ArCH2),
112.6 (C-7), 114.2 (C-6), 134.0 (C-5), 146.5 (C-3a), 147.2 (C-7a). Ϫ
4.35 (t, J ϭ 6.5 Hz, 2 H, OCH2), 5.94 (s, 2 H, OCH2O), 6.57 (s, MS (70 eV, EI): m/z (%) ϭ 260/258 (56/58) [Mϩ], 215/213 (98/100)
1 H, 4-H), 6.86 (s, 1 H, 7-H), 7.96 (d, J ϭ 8.8 Hz, 2 H, Ar-2-H, [Mϩ Ϫ C2H5O], 135 (97) [C8H7O2ϩ]. Ϫ C10H11BrO3 (258.0): calcd.
Ar-6-H), 8.31 (d, J ϭ 8.8 Hz, 2 H, Ar-3-H, Ar-5-H). Ϫ 13C NMR
C 46.36, H 4.28; found C 46.67, H 4.26. Ϫ According to General
(50.3 MHz, CDCl3): δ ϭ 35.5 (ArCH2), 70.4 (OCH2), 101.9 Procedure II, the alcohol (6.00 g, 23.2 mmol) was treated with no-
(OCH2O), 110.9 (C-4), 112.8 (C-7), 114.5 (C-6), 124.2 (Ar-C-3, Ar- syl chloride (6.46 g, 29.2 mmol, 1.3 equiv.) in the presence of trie-
C-5), 127.9 (C-5), 129.0 (Ar-C-2, Ar-C-6), 141.5 (Ar-C-1), 147.3 thylamine (3.03 g, 29.9 mmol, 1.3 equiv.) and DMAP (300 mg,
(C-3a), 147.6 (C-7a), 150.4 (Ar-C-4). Ϫ MS (70 eV, EI): m/z (%) ϭ
2.46 mmol, 0.1 equiv.). Recrystallization from CH2Cl2/ethyl acetate
afforded 18d (9.66 g, 21.7 mmol, 94%) as yellow crystals; Rf ϭ 0.45
431/429 (8/7) [Mϩ], 356/354 (8/9), 229/227 (19/26) [Mϩ Ϫ NsO],
228/226 (38) [Mϩ Ϫ NsOH], 215/213 (54/56) [Mϩ Ϫ NsOCH2], (PE/MTBE, 1:1); m.p. 115 °C. Ϫ IR (KBr): ν˜ ϭ 1533 cmϪ1 (NO2),
148 (20) [C9H8O2ϩ], 44 (100) [C2H4Oϩ]. Ϫ C15H12BrNO7S (430.2): 1477 (CϪOϪC), 1370 (NO2), 1351 (SO2), 1184 (SO2), 1034, 955,
calcd. C 41.88, H 2.81; found C 41.63, H 2.84. Ϫ HRMS: calcd.
428.9518; found 428.9518.
932 (CϪOϪC), 858, 834 (arene). Ϫ UV (CH3CN): λmax (lg ε) ϭ
201 nm (4.67), 247 (4.15), 292 (3.77). Ϫ 1H NMR (200 MHz,
CDCl3): δ ϭ 1.98 (tt, J ϭ 7.4, 6.1 Hz, 2 H, CH2), 2.69 (t, J ϭ
7.4 Hz, 2 H, ArCH2), 4.14 (t, J ϭ 6.1 Hz, 2 H, OCH2), 5.93 (s, 2 H,
OCH2O), 6.48 (s, 1 H, 4-H), 6.94 (s, 1 H, 7-H), 8.12 (d, J ϭ 9.1 Hz,
2 H, Ar-2-H, Ar-6-H), 8.41 (d, J ϭ 9.1 Hz, 2 H, Ar-3-H, Ar-5-H).
2-(6-Iodobenzo[1,3]dioxol-5-yl)ethyl 4-Nitrobenzenesulfonate (18c)
via 2-(6-Iodobenzo[1,3]dioxol-5-yl)ethanol:[9,10] To a stirred solution
of 2-benzo[1,3]dioxol-5-ylethanol[20] (505 mg, 3.04 mmol) in
CH2Cl2 (30 mL) was added CF3COOAg (750 mg, 3.40 mmol, 1.1
equiv.) and iodine (940 mg, 3.70 mmol, 1.2 equiv.). After 2 h, the
excess iodine was destroyed with saturated Na2SO3 solution and
the aqueous phase was extracted twice with CH2Cl2. The combined
organic layers were dried with Na2SO4 and concentrated to dryness
in vacuo. Purification by column chromatography (20 g SiO2; PE/
MTBE, 1:1) gave the iodobenzoethanol (861 mg, 2.95 mmol, 97%);
Ϫ
13C NMR (75.5 MHz, CDCl3): δ ϭ 28.7 (ArCH2), 31.6 (CH2),
70.5 (OCH2), 101.7 (OCH2O), 109.8 (C-4), 112.7 (C-7), 114.1 (C-
6), 124.4 (Ar-C-3, Ar-C-5), 129.1 (Ar-C-2, Ar-C-6), 132.0 (C-5),
141.6 (Ar-C-1), 146.9 (C-3a), 147.2 (C-7a), 150.7 (Ar-C-4). Ϫ MS
(70 eV, EI): m/z (%) ϭ 445/443 (100/92) [Mϩ], 242/240 (32/33) [Mϩ
Ϫ NsOH], 215/213 (63/66) [C8H6BrO2ϩ], 131 (35), 103 (19). Ϫ
C16H14BrNO7S (444.3): calcd. C 43.26, H 3.18; found C 43.55, H
3.37. Ϫ HRMS: calcd. 442.9674; found 442.9674.
1
Rf ϭ 0.29 (PE/MTBE, 1:1); m.p. 69 °C (ref.[9]: 68Ϫ69.5 °C). Ϫ H
NMR (200 MHz, CDCl3): δ ϭ 1.59 (br. s, 1 H, OH), 2.93 (t, J ϭ
6.7 Hz, 2 H, ArCH2), 3.81 (t, J ϭ 6.7 Hz, 2 H, OCH2), 5.95 (s, 2 H,
OCH2O), 6.79 (s, 1 H, 4-H), 7.24 (s, 1 H, 7-H). Ϫ 13C NMR
(50.3 MHz, CDCl3): δ ϭ 43.4 (ArCH2), 62.4 (OCH2), 88.0 (C-6),
101.5 (OCH2O), 110.1 (C-4), 118.7 (C-7), 134.2 (C-5), 147.1, 147.2
(C-3a, C-7a). Ϫ According to General Procedure II, the alcohol
(875 mg, 3.00 mmol) was treated with nosyl chloride (837 mg,
3.78 mmol, 1.3 equiv.) in the presence of triethylamine (378 mg,
3.73 mmol, 1.2 equiv.) and DMAP (40.0 mg, 330 µmol, 0.1 equiv.).
Recrystallization of the crude product from CH2Cl2/ethyl acetate
afforded 18c (1.23 g, 2.58 mmol, 86%) as yellow crystals; Rf ϭ 0.40
3-(6-Iodobenzo[1,3]dioxol-5-yl)propyl 4-Nitrobenzenesulfonate (18e)
via 3-(6-Iodobenzo[1,3]dioxol-5-yl)propan-1-ol: To a solution of 3-
benzo[1,3]dioxol-5-ylpropan-1-ol[11] (3.09 g, 17.2 mmol) in CH2Cl2
(40 mL) was added ICl (3.34 g, 20.6 mmol, 1.2 equiv.) and the re-
sulting mixture was stirred for 3 h at room temperature. The excess
ICl was then destroyed with Na2SO3 solution. The aqueous layer
was extracted three times with CH2Cl2. The combined organic
layers were dried with Na2SO4 and concentrated to dryness. The
residue was recrystallized from PE/MTBE to give the alcohol
(3.08 g, 10.1 mmol, 59%) as colorless crystals; Rf ϭ 0.32 (PE/
MTBE, 1:1). Ϫ IR (KBr): ν˜ ϭ 3281 cmϪ1 (OH), 1484, 1243, 1040
(CϪO), 932 (CϪOϪC), 862 (arene). Ϫ UV (CH3CN): λmax (lg ε) ϭ
207 nm (4.54), 241 (3.83), 295 (3.62). Ϫ 1H NMR (200 MHz,
CDCl3): δ ϭ 1.69 (br. s, 1 H, OH), 1.82 (tt, J ϭ 7.8, 6.3 Hz, 2 H,
CH2), 2.74 (t, J ϭ 7.8 Hz, 2 H, ArCH2), 3.70 (t, J ϭ 6.3 Hz, 2 H,
OCH2), 5.94 (s, 2 H, OCH2O), 6.76 (s, 1 H, 4-H), 7.22 (s, 1 H, 7-
H). Ϫ 13C NMR (50.3 MHz, CDCl3): δ ϭ 33.2 (ArCH2), 36.8
(CH2), 61.9 (OCH2), 87.6 (C-6), 101.4 (OCH2O), 109.2 (C-4), 118.5
(C-7), 137.6 (C-5), 146.6, 148.4 (C-3a, C-7a). Ϫ MS (70 eV, EI):
m/z (%) ϭ 306 (29) [Mϩ], 261 (25) [Mϩ Ϫ C2H5O], 135 (100)
[C8H7O2ϩ]. Ϫ C10H11IO3 (306.1): calcd. C 39.24, H 3.62; found C
39.23, H 3.72. Ϫ According to General Procedure II, the alcohol
(3.08 g, 10.1 mmol) was treated with nosyl chloride (2.68 g,
12.1 mmol, 1.2 equiv.) in the presence of triethylamine (1.32 g,
1
(PE/MTBE, 1:1); m.p. 127 °C (ref.[9]: 126.5Ϫ127 °C). Ϫ H NMR
(200 MHz, CDCl3): δ ϭ 3.01 (t, J ϭ 6.5 Hz, 2 H, ArCH2), 4.33 (t,
J ϭ 6.5 Hz, 2 H, OCH2), 5.94 (s, 2 H, OCH2O), 6.59 (s, 1 H, 4-H),
7.09 (s, 1 H, 7-H), 7.96 (d, J ϭ 8.8 Hz, 2 H, Ar-2-H, Ar-6-H), 8.31
(d, J ϭ 8.8 Hz, 2 H, Ar-3-H, Ar-5-H). Ϫ 13C NMR (50.3 MHz,
CDCl3): δ ϭ 39.5 (ArCH2), 70.7 (OCH2), 88.0 (C-6), 101.8
(OCH2O), 110.3 (C-4), 118.8 (C-7), 124.2 (Ar-C-3, Ar-C-5), 131.4
(C-5), 129.0 (Ar-C-2, Ar-C-6), 141.5 (Ar-C-1), 147.4 (C-3a), 148.8
(C-7a), 150.4 (Ar-C-4).
3-(6-Bromobenzo[1,3]dioxol-5-yl)propyl
4-Nitrobenzenesulfonate
(18d) via 3-(6-Bromobenzo[1,3]dioxol-5-yl)propan-1-ol: To a solu-
tion of 3-benzo[1,3]dioxol-5-ylpropan-1-ol[11] (6.79 g, 37.7 mmol)
in CH2Cl2 (60 mL), bromine (7.22 g, 45.2 mmol, 1.2 equiv.) was ad-
ded dropwise and the resulting mixture was stirred for 1 h at room 13.0 mmol, 1.3 equiv.) and DMAP (123 mg, 1.01 mmol, 0.1 equiv.).
temperature. The excess bromine was then destroyed with Na2SO3
solution (2 ϫ 100 mL). The aqueous layer was extracted twice with
CH2Cl2. The combined organic layers were dried with Na2SO4 and
concentrated to dryness. The residue was recrystallized from PE/
MTBE to give the bromo compound (8.42 g, 32.5 mmol, 86%) as
colorless crystals; Rf ϭ 0.31 (PE/MTBE, 1:1). Ϫ IR (KBr): ν˜ ϭ
Recrystallization of the crude product from CH2Cl2/ethyl acetate/
PE afforded 18e (4.21 g, 8.57 mmol, 85%) as yellow crystals; Rf ϭ
0.40 (PE/EtOAc, 3:1). Ϫ IR (KBr): ν˜ ϭ 1532 cmϪ1 (NO2), 1480,
1367 (NO2), 1352 (SO2), 1232, 1185 (SO2), 1041, 940 (CϪOϪC),
860, 844 (arene). Ϫ UV (CH3CN): λmax (lg ε) ϭ 204 nm (4.62), 246
(4.24), 292 (3.77). Ϫ 1H NMR (200 MHz, CDCl3): δ ϭ 1.95 (tt,
3277 cmϪ1 (OH), 1485, 1040 (CϪO), 933 (CϪO-C), 864 (arene). Ϫ J ϭ 7.6, 6.2 Hz, 2 H, CH2), 2.68 (t, J ϭ 7.6 Hz, 2 H, ArCH2), 4.15
UV (CH3CN): λmax (lg ε) ϭ 202 nm (4.55), 237 (3.64), 294 (3.62).
Eur. J. Org. Chem. 2000, 2433Ϫ2444
(t, J ϭ 6.2 Hz, 2 H, OCH2), 5.92 (s, 2 H, OCH2O), 6.51 (s, 1 H, 4-
2439

L. F. Tietze, H. Schirok, M. Wöhrmann, K. Schrader
FULL PAPER
H), 7.17 (s, 1 H, 7-H), 8.13 (d, J ϭ 8.8 Hz, 2 H, Ar-2-H, Ar-6-H),
C-3Ј), 28.2 (C-4Ј), 28.2, 28.6 (C-4, C-6), 37.3 (C-1Ј), 51.2 (C-5Ј),
8.41 (d, J ϭ 8.8 Hz, 2 H, Ar-3-H, Ar-5-H).
(75.5 MHz, CDCl3): δ ϭ 29.1 (ArCH2), 36.1 (CH2), 70.5 (OCH2), (NH3)]: m/z (%) ϭ 269 (19) [M ϩ NH4ϩ], 209 (40) [Mϩ Ϫ N3], 164
87.5 (C-6), 101.6 (OCH2O), 109.2 (C-4), 118.7 (C-7), 124.5 (Ar-C-
(60) [C11H18Nϩ], 122 (4) [C9H14ϩ]. Ϫ C13H21N3O2 (251.3): calcd.
Ϫ
13C NMR 68.7 (C-1), 119.6 (C-2), 144.2 (C-3), 170.7 (CO). Ϫ MS [70 eV, CI
3, Ar-C-5), 129.2 (Ar-C-2, Ar-C-6), 135.6 (C-5), 141.7 (Ar-C-1), C 62.13, H 8.42; found C 61.82, H 8.43.
147.0, 148.4 (C-3a, C-7a), 150.8 (Ar-C-4). Ϫ MS (70 eV, EI): m/z
(%) ϭ 491 (100) [Mϩ], 365 (10), 288 (29) [Mϩ Ϫ NsOH], 261 (48)
[C8H6IO2ϩ], 162 (13) [C10H10O2ϩ], 131 (37). Ϫ C16H14INO7S
(491.3): calcd. C 39.12, H 2.87; found C 39.38, H 3.08. Ϫ HRMS:
calcd. 490.9536; found 490.9536.
1-Azaspiro[4.5]dec-6-ene (17a): To a solution of azide 15a (2.00 g,
8.96 mmol) in ethyl acetate (120 mL) was added Lindlar’s catalyst
(700 mg, 5% Pd on CaCO3). The mixture was stirred for 1 h under
hydrogen, then filtered through Celite, and the solvent was evapo-
rated. The crude primary amine 16a was redissolved in acetonitrile
(40 mL) and was cyclized in the presence of triethylamine (2.32 g,
23.0 mmol, 2.6 equiv.) and [Pd(PPh3)4] (350 mg, 303 µmol, 3.4 mol-
%) at 70 °C for 18 h. The mixture was then diluted with MTBE
and extracted twice with cold 1  HCl. The combined aqueous
layers were extracted with MTBE, then made basic with cold
10% aq. NaOH solution and extracted a further four times with
MTBE. The combined organic layers were dried with Na2SO4 and
the solvent was evaporated. The secondary spirocyclic amine 17a
thus obtained was used directly in the next step without further
purification. For analytical purposes, a small sample was purified
by kugelrohr distillation (100Ϫ150 °C, 13 mbar). Ϫ IR (KBr): ν˜ ϭ
2800Ϫ3000 cmϪ1 (NϪH), 2915 (CϪH), 1650, 1402, 1022, 941,
868, 744 (ϭCϪH) (hydrochloride). Ϫ UV (CH3CN): no absorp-
tion. Ϫ 1H NMR (200 MHz, CDCl3): δ ϭ 1.56Ϫ1.68 (m, 7 H, 3-
H2, 4-H2, 9-H2, NH), 1.70Ϫ1.89 (m, 2 H, 10-H2), 1.91Ϫ2.03 (m,
2 H, 8-H2), 2.94 (dt, J ϭ 10.3, 6.6 Hz, 1 H, 2-H), 3.04 (dt, J ϭ 10.3,
6.6 Hz, 1 H, 2-H), 5.54 (dt, J ϭ 9.8, 1.7 Hz, 1 H, 6-H), 5.66 (dt,
J ϭ 9.8, 3.4 Hz, 1 H, 7-H). Ϫ 13C NMR (50.3 MHz, CDCl3): δ ϭ
20.3 (C-3), 24.8 (C-9), 25.3 (C-8), 36.0 (C-4), 38.8 (C-10), 45.5 (C-
2), 59.7 (C-5), 126.7 (C-7), 134.0 (C-6). Ϫ MS (70 eV, EI): m/z
(%) ϭ 137 (35) [Mϩ], 109 (97) [Mϩ Ϫ C2H4], 91 (100). Ϫ C9H16ClN
(173.7) (hydrochloride): calcd. C 62.24, H 9.29; found C 61.70, H
9.34.
3-(3-Azidopropyl)cyclohex-2-enyl Acetate (15a): The tosylate 10a[6]
(8.51 g, 24.1 mmol) was dissolved in DMSO (50 mL) and sodium
azide (3.55 g, 54.6 mmol, 2.3 equiv.) was added. After stirring for
27 h at room temperature, MTBE (200 mL) and water (200 mL)
were added. The aqueous layer was extracted twice with MTBE.
The combined organic phases were dried with Na2SO4 and concen-
trated to dryness. The residue was purified by column chromatog-
raphy (210 g SiO2; PE/MTBE, 5:1) to afford 15a (5.10 g,
22.9 mmol, 95%) as a colorless oil; Rf ϭ 0.64 (PE/MTBE, 1:1). Ϫ
IR (neat): ν˜ ϭ 2940 cmϪ1 (CϪH), 2100 (N3), 1732 (CϭO), 1666
(CϭC), 1450, 1370, 1244 (CϪO), 1020, 912. Ϫ UV (CH3CN): no
absorption. Ϫ 1H NMR (200 MHz, CDCl3): δ ϭ 1.60Ϫ1.84 (m,
6 H, 2Ј-H2, 5-H2, 6-H2), 1.93 (dt, J ϭ 17.5, 5.5 Hz, 1 H, 4-H), 2.01
(dt, J ϭ 17.5, 5.5 Hz, 1 H, 4-H), 2.05 (s, 3 H, CH3), 2.08 (t, J ϭ
7.7 Hz, 2 H, 1Ј-H2), 3.27 (t, J ϭ 6.9 Hz, 2 H, 3Ј-H2), 5.24Ϫ5.28
(mc, 1 H, 1-H), 5.49 (mc, 1 H, 2-H). Ϫ 13C NMR (50.3 MHz,
CDCl3): δ ϭ 19.1 (C-5), 21.4 (CH3), 26.6 (C-2Ј), 28.2, 28.3 (C-4,
C-6), 34.5 (C-1Ј), 51.0 (C-3Ј), 68.6 (C-1), 120.5 (C-2), 143.0 (C-3),
170.8 (CO). Ϫ MS [70 eV, CI (NH3)]: m/z (%) ϭ 258 (10) [M ϩ
NH4 ϩ NH3], 241 (6) [M ϩ NH4ϩ], 164 (100) [Mϩ Ϫ AcO], 136
ϩ
(16) [C7H10N3ϩ]. Ϫ C11H17N3O2 (223.3): calcd. C 59.17, H 7.67;
found C 59.29, H 7.91.
3-(4-Azidobutyl)cyclohex-2-enyl Acetate (15b): As described for
15a, a solution of tosylate 10b[6] (7.03 g, 19.2 mmol) in DMSO
(40 mL) was treated with sodium azide (2.98 g, 45.8 mmol, 2.4
equiv.). The crude product was purified by column chromatography
(210 g SiO2; PE/MTBE, 5:1) to give 15b (4.35 g, 18.4 mmol, 96%)
as a colorless oil; Rf ϭ 0.65 (PE/MTBE, 1:1). Ϫ IR (neat): ν˜ ϭ
2939 cmϪ1 (CϪH), 2997 (N3), 1730 (CϭO), 1666 (CϭC), 1455,
1371, 1243 (CϪO), 1020, 911. Ϫ UV (CH3CN): λmax (lg ε) ϭ
191 nm (4.10). Ϫ 1H NMR (200 MHz, CDCl3): δ ϭ 1.40Ϫ1.90 (m,
8 H, 2Ј-H2, 3Ј-H2, 4Ј-H2, 5-H2), 1.92Ϫ2.08 (m, 4 H, 1Ј-H2, 4-H2),
2.05 (s, 3 H, CH3), 3.28 (t, J ϭ 6.4 Hz, 2 H, 4Ј-H2), 5.20Ϫ5.30 (mc,
1 H, 1-H), 5.47 (br. s, 1 H, 2-H). Ϫ 13C NMR (50.3 MHz, CDCl3):
δ ϭ 19.1 (C-5), 21.4 (CH3), 24.4 (C-2Ј), 28.2 (C-3Ј), 28.2, 28.4 (C-
4, C-6), 37.0 (C-1Ј), 51.2 (C-4Ј), 68.7 (C-1), 120.0 (C-2), 143.8 (C-
3), 170.8 (CO). Ϫ MS [70 eV, CI (NH3)]: m/z (%) ϭ 255 (7) [M ϩ
NH4ϩ], 212 (6), 195 (2), 178 [Mϩ Ϫ Ac], 150 (100) [C8H12N3ϩ]. Ϫ
C12H19N3O2 (237.1): calcd. C 60.74, H 8.07; found C 60.85, H 7.95.
1-Azaspiro[5.5]undec-7-ene (17b): As described for 17a, azide 15b
(1.06 g, 4.45 mmol) was reduced in ethyl acetate (70 mL) in the
presence of Lindlar’s catalyst (335 mg). The crude primary amine
16b was redissolved in acetonitrile (20 mL) and was cyclized in the
presence of [Pd(PPh3)4] (210 mg, 182 µmol, 4 mol%) and triethyl-
amine (1.16 g, 11.5 mmol, 2.6 equiv.). The spirocyclic amine 17b
thus obtained was used directly in the next step. For analytical
purposes, a small sample was purified by kugelrohr distillation
(100Ϫ150 °C, 13 mbar) to give a colorless liquid. Ϫ IR (KBr): ν˜ ϭ
2800Ϫ3000 cmϪ1 (NϪH), 2934 (CϪH), 1583, 1443, 1091, 995,
866, 802, 741 (ϭCϪH). Ϫ UV (CH3CN): no absorption. Ϫ 1H
NMR (200 MHz, CDCl3): δ ϭ 1.35Ϫ1.75 (m, 11 H, 3-H2, 4-H2, 5-
H2, 10-H2, 11-H2, NH), 1.92Ϫ2.04 (m, 2 H, 9-H2), 2.80Ϫ2.90 (m,
2 H, 2-H2), 5.68 (dt, J ϭ 10.0, 3.3 Hz, 1 H, 8-H), 5.80 (dt, J ϭ 10.0,
1.5 Hz, 1 H, 7 H). Ϫ 13C NMR (50.3 MHz, CDCl3): δ ϭ 18.8 (C-
4), 20.2 (C-10), 25.7 (C-3), 26.2 (C-9), 33.8 (C-5), 37.2 (C-11), 40.8
(C-2), 50.4 (C-6), 127.4 (C-8), 133.5 (C-7). Ϫ MS (70 eV, EI): m/z
(%) ϭ 151 (58) [Mϩ], 136 (15), 123 (100) [Mϩ Ϫ C2H4], 109 (54)
[Mϩ Ϫ C3H6], (hydrochloride). Ϫ C10H18ClN (187.7) (hydro-
chloride): calcd. C 63.99, H 9.67; found C 64.19, H 9.75. Ϫ HRMS:
calcd. 151.1361; found 151.1360.
3-(5-Azidopentyl)cyclohex-2-enyl Acetate (15c): As described for
15a, a solution of tosylate 10c (2.00 g, 5.26 mmol) in DMSO
(10 mL) was treated with sodium azide (854 mg, 13.1 mmol, 2.5
equiv.). The crude product was purified by column chromatography
(70 g SiO2, PE/MTBE, 5:1) to give 15c (1.12 g, 4.94 mmol, 94%)
as a colorless oil; Rf ϭ 0.68 (MTBE). Ϫ IR (neat): ν˜ ϭ 2936 cmϪ1
(CϪH), 2096 (N3), 1730 (CϭO), 1667 (CϭC), 1454, 1371, 1242 General Procedure III. ؊ Alkylation of Secondary Spirocyclic
(CϪO), 1019, 911. Ϫ UV (CH3CN): no absorption. Ϫ 1H NMR
Amines 17 with Nosylates 18b؊e: To a stirred solution of the crude
(200 MHz, CDCl3): δ ϭ 1.30Ϫ1.50 (m, 4 H, 2Ј-H2, 3Ј-H2), secondary amine 17 in acetonitrile (0.15 to 0.20 ), the nosylate
1.50Ϫ1.90 (m, 6 H, 4Ј-H2, 5-H2, 6-H2), 1.90Ϫ2.10 (m, 4 H, 1Ј-H2, 18b؊e (1.2 equiv.) and diisopropylethylamine (3.0 equiv.) were ad-
4-H2), 2.04 (s, 3 H, CH3), 3.26 (d, J ϭ 6.8 Hz, 2 H, 5Ј-H2), ded at room temperature. Stirring was continued at 50 °C for
5.20Ϫ5.32 (mc, 1 H, 1-H), 5.46 (br. s, 1 H, 2-H). Ϫ 13C NMR
15Ϫ20 h. Thereafter, the mixture was diluted with MTBE and ex-
(50.3 MHz, CDCl3): δ ϭ 19.1 (C-5), 21.4 (CH3), 26.3, 26.8 (C-2Ј, tracted with 5% aq. NaOH solution. The organic layer was dried
2440
Eur. J. Org. Chem. 2000, 2433Ϫ2444

Six-Membered Ring D Analogues of the Pentacyclic Alkaloid Cephalotaxine
FULL PAPER
with Na2SO4 and the solvent was evaporated. The residue was puri-
fied by column chromatography.
2Ј-H2, 1Ј-H, 2-Heq), 5.33 (ddt, J ϭ 10.1, 1.8, 1.8 Hz, 1 H, 7-H),
5.70 (ddt, J ϭ 10.1, 3.9, 0.5 Hz, 1 H, 8-H), 5.94 (s, 2 H, OCH2O),
6.71 (s, 1 H, 4ЈЈ-H), 6.98 (s, 1 H, 7ЈЈ-H). Ϫ 13C NMR (50.3 MHz,
CDCl3): δ ϭ 20.1 (C-4), 22.9 (C-10), 25.2 (C-9), 26.2 (C-3), 35.9
(C-2Ј), 36.3 (C-5), 46.5 (C-11), 51.8, 57.2 (C-1Ј, C-2), 101.4
(OCH2O), 110.6 (C-4ЈЈ), 112.5 (C-7ЈЈ), 114.4 (C-6ЈЈ), 128.1 (C-8),
133.2 (C-5ЈЈ), 136.3 (C-7), 146.5 (C-3aЈЈ), 147.0 (C-7aЈЈ). Ϫ MS
(70 eV, EI): m/z (%) ϭ 380/378 (Ͻ1) [M ϩ Hϩ], 215/213 (4)
[C8H6BrO2ϩ], 164 (100) [C11H18Nϩ]. Ϫ C19H24BrNO2 (378.3):
calcd. C 60.32, H 6.39; found C 60.42, H 6.24.
1-[2-(6-Bromobenzo[1,3]dioxol-5-yl)ethyl]-1-azaspiro[4.5]dec-6-ene
(12a): According to General Procedure III, the crude amine 17a
(143 mg, 1.04 mmol) was treated with the nosylate 18b (673 mg,
1.56 mmol, 1.5 equiv.) in the presence of diisopropylethylamine
(450 mg, 3.50 mmol, 3.4 equiv.). Column chromatography (50 g
SiO2; gradient column: 200 mL EtOAc; then EtOAc/MeOH, 15:1,
ϩ 1% NEt3) of the crude product afforded 12a (231 mg, 631 µmol,
61% over 3 steps); Rf ϭ 0.55 (EtOAc/MeOH, 15:1, ϩ 1% Et3N). Ϫ
IR (neat): ν˜ ϭ 3012 cmϪ1 (ArϪH), 2930 (CϪH), 1478, 1230, 1114,
1040, 936 (CϪOϪC), 860, 834 (arene), 736 (ϭCϪH). Ϫ UV
(CH3CN): λmax (lg ε) ϭ 202 nm (4.60), 294 (3.65). Ϫ 1H NMR
(200 MHz, CDCl3): δ ϭ 1.42Ϫ2.00 (m, 10 H, 3-H2, 4-H2, 8-H2, 9-
H2, 10-H2), 2.53Ϫ2.63 (m, 2 H, 2Ј-H2*), 2.77Ϫ2.87 (m, 2 H, 1Ј-
H2*), 2.85Ϫ3.08 (m, 2 H, 2-H2*), 5.46 (d, J ϭ 10.0 Hz, 1 H, 6-H),
5.75 (dt, J ϭ 10.0, 3.7 Hz, 1 H, 7-H), 5.93 (s, 2 H, OCH2O), 6.74
(s, 1 H, 4ЈЈ-H), 6.97 (s, 1 H, 7ЈЈ-H). Ϫ 13C NMR (50.3 MHz,
CDCl3): δ ϭ 21.1, 21.3 (C-3, C-9), 25.2 (C-8), 28.6 (C-4), 36.6 (C-
2Ј), 38.3 (C-10), 49.8 (C-1Ј), 50.7 (C-2), 63.8 (C-5), 101.5 (OCH2O),
110.3 (C-4ЈЈ), 112.5 (C-7ЈЈ), 114.4 (C-6ЈЈ), 128.9 (C-7), 133.1 (C-6,
C-5ЈЈ), 146.6 (C-3aЈЈ), 147.1 (C-7aЈЈ). Ϫ MS [70 eV, CI (NH3)]: m/z
(%) ϭ 366/364 (98/100) [M ϩ Hϩ], 286 (86) [Mϩ Ϫ Br ϩ 2 H].
Ϫ C18H22BrNO2 (364.3): calcd. C 59.35, H 6.09; found C 59.15,
H 6.27.
1-[3-(6-Bromobenzo[1,3]dioxol-5-yl)propyl]-1-azaspiro[4.5]dec-6-ene
(12d): According to General Procedure III, the crude amine 17a
(395 mg, 2.88 mmol) was treated with the nosylate 18d (1.68 g,
3.79 mmol, 1.3 equiv.) in the presence of diisopropylethylamine
(1.30 g, 9.90 mmol, 3.4 equiv.). Column chromatography (70 g
SiO2; EtOAc/MeOH, 15:1, ϩ 1% Et3N) of the crude product
yielded 12d (574 mg, 1.52 mmol, 53% over 3 steps); Rf ϭ 0.47
(EtOAc/MeOH, 15:1, ϩ 1% Et3N). Ϫ IR (neat): ν˜ ϭ 3014 cmϪ1
(ArϪH), 2931 (CϪH), 1476, 1230, 1039, 936 (CϪOϪC), 839, 832
(arene), 735 (ϭCϪH). Ϫ UV (CH3CN): λmax (lg ε) ϭ 202 nm
1
(4.55), 295 (3.59). Ϫ H NMR (500 MHz, CDCl3): δ ϭ 1.41Ϫ1.45
(m, 1 H, 4-H), 1.50Ϫ1.60 (m, 2 H, 3-H2), 1.69 (ddt, J ϭ 7.8, 7.6,
7.2 Hz, 2 H, 2Ј-H2), 1.70Ϫ1.85 (m, 5 H, 4-H, 9-H2, 10-H2),
1.91Ϫ1.96 (m, 2 H, 8-H2), 2.43 (dt, J ϭ 12.1, 7.2 Hz, 1 H, 1Ј-H),
2.48 (dt, J ϭ 12.1, 7.6 Hz, 1 H, 1Ј-H), 2.59 (dt, J ϭ 14.2, 7.8 Hz,
1 H, 3Ј-H), 2.64 (dt, J ϭ 14.2, 7.8 Hz, 1 H, 3Ј-H), 2.71 (dt, J ϭ 8.8,
5.7 Hz, 1 H, 2-H), 2.89 (dt, J ϭ 8.8, 5.3 Hz, 1 H, 2-H), 5.45 (ddt,
J ϭ 10.3, 1.8, 1.8 Hz, 1 H, 6-H), 5.75 (ddt, J ϭ 10.3, 3.2, 0.5 Hz,
1 H, 7-H), 5.92 (s, 2 H, OCH2O), 6.70 (s, 1 H, 4ЈЈ-H), 6.95 (s, 1 H,
7ЈЈ-H). Ϫ 13C NMR (50.3 MHz, CDCl3): δ ϭ 21.2, 21.3 (C-3, C-
9), 25.2 (C-8), 28.4 (C-4), 30.0 (C-2Ј), 34.1 (C-3Ј), 38.5 (C-10), 48.8
(C-1Ј), 50.5 (C-2), 63.5 (C-5), 101.4 (OCH2O), 109.8 (C-4ЈЈ), 112.6
(C-7ЈЈ), 114.2 (C-6ЈЈ), 128.7 (C-7), 133.7 (C-6), 135.0 (C-5ЈЈ), 146.3
(C-3aЈЈ), 147.2 (C-7aЈЈ). Ϫ MS (70 eV, EI): m/z (%) ϭ 379/377 (2)
[Mϩ], 351/349 [Mϩ Ϫ C2H4], 254 (100), 150 (18) [C10H16Nϩ]. Ϫ
C19H25BrClNO2 (414.8) (hydrochloride): calcd. C 55.02, H 6.08;
found C 55.31, H 6.35. Ϫ HRMS: calcd. 377.0990; found 377.0990.
1-[2-(6-Iodobenzo[1,3]dioxol-5-yl)ethyl]-1-azaspiro[4.5]dec-6-ene
(12b): According to General Procedure III, the crude amine 17a
(140 mg, 1.02 mmol) was treated with the nosylate 18c (787 mg,
1.65 mmol, 1.6 equiv.) in the presence of diisopropylethylamine
(450 mg, 3.50 mmol, 3.4 equiv.). Column chromatography (60 g
SiO2; gradient column: 200 mL EtOAc; then EtOAc/MeOH, 15:1,
ϩ 1% NEt3) of the crude product afforded 12b (219 mg, 532 µmol,
52% over 3 steps); Rf ϭ 0.64 (EtOAc/MeOH, 5:1, ϩ 1% Et3N). Ϫ
IR (neat): ν˜ ϭ 3012 cmϪ1 (ArϪH), 2930 (CϪH), 1476, 1226, 1112,
1040, 934 (CϪOϪC), 860, 830 (arene), 736 (ϭCϪH). Ϫ UV
(CH3CN): λmax (lg ε) ϭ 206 nm (4.56), 240 (3.87), 296 (3.62). Ϫ 1H
NMR (200 MHz, CDCl3): δ ϭ 1.45Ϫ2.00 (m, 10 H, 3-H2, 4-H2, 8-
H2, 9-H2, 10-H2), 2.52Ϫ2.61 (m, 2 H, 2Ј-H2*), 2.79Ϫ2.88 (m, 2 H,
1Ј-H2*), 2.88Ϫ3.14 (m, 2 H, 1-H2*), 5.48 (d, J ϭ 10.2 Hz, 1 H, 6-
H), 5.76 (dt, J ϭ 10.2, 3.7 Hz, 1 H, 7-H), 5.93 (s, 2 H, OCH2O),
6.77 (s, 1 H, 4ЈЈ-H), 7.21 (s, 1 H, 7ЈЈ-H). Ϫ 13C NMR (125.7 MHz,
CDCl3): δ ϭ 21.1, 21.2 (C-3, C-9), 25.1 (C-8), 28.6 (C-4), 38.2 (C-
10), 40.9 (C-2Ј), 50.0 (C-1Ј), 50.7 (C-2), 64.1 (C-5), 87.8 (C-6ЈЈ),
101.4 (OCH2O), 109.6 (C-4ЈЈ), 118.4 (C-7ЈЈ), 129.2 (C-7), 132.8 (C-
6), 136.6 (C-5ЈЈ), 146.7 (C-7aЈЈ), 148.3 (C-3aЈЈ). Ϫ MS (70 eV, EI):
m/z (%) ϭ 411 (Ͻ 1) [Mϩ], 254 (13), 150 (100) [C10H16Nϩ]. Ϫ
C18H22INO2 (411.3): calcd. C 52.57, H 5.39; found C 52.86, H 5.41.
1-[3-(6-Iodobenzo[1,3]dioxol-5-yl)propyl]-1-azaspiro[4.5]dec-6-ene
(12e): According to General Procedure III, the crude amine 17a
(395 mg, 2.88 mmol) was treated with the nosylate 18e (1.70 g,
3.46 mmol, 1.2 equiv.) in the presence of diisopropylethylamine
(1.13 g, 8.76 mmol, 3.0 equiv.). Column chromatography (120 g
SiO2; gradient column: 300 mL EtOAc; then EtOAc/MeOH, 15:1,
ϩ 1% Et3N) of the crude product afforded 12e (962 mg, 2.26 mmol,
79% over 3 steps); Rf ϭ 0.54 (EtOAc/MeOH, 15:1, ϩ 1% Et3N). Ϫ
IR (neat over 3 steps): ν˜ ϭ 3013 cmϪ1 (ArϪH), 2930 (CϪH), 1475,
1226, 1109, 1039, 935 (CϪOϪC), 858, 829 (arene), 736 (ϭCϪH).
Ϫ UV (CH3CN): λmax (lg ε) ϭ 206 nm (4.53), 240 (3.87), 296
(3.60). Ϫ 1H NMR (500 MHz, CDCl3): δ ϭ 1.46Ϫ1.51 (m, 1 H, 4-
H), 1.60Ϫ1.64 (m, 3 H, 3-H2, 4-H), 1.71 (tt, J ϭ 7.9, 7.2 Hz, 2 H,
2Ј-H2), 1.72Ϫ1.81 (m, 2 H, 10-H2), 1.75Ϫ1.87 (m, 2 H, 9-H2), 2.49
1-[2-(6-Bromobenzo[1,3]dioxol-5-yl)ethyl]-1-azaspiro[5.5]undec-7-
ene (12c): According to General Procedure III, the crude amine
17b (540 mg, 3.57 mmol) was treated with the nosylate 18b (2.29 g,
5.33 mmol, 1.5 equiv.) in the presence of diisopropylethylamine
(1.62 g, 12.5 mmol, 3.5 equiv.). Column chromatography (100 g (dt, J ϭ 12.0, 7.2 Hz, 1 H, 1Ј-H), 2.53 (dt, J ϭ 12.0, 7.7 Hz, 1 H,
SiO2; gradient column: 100 mL EtOAc; then EtOAc/MeOH, 5:1,
ϩ 1% NEt3) of the crude product afforded 12c (840 mg, 2.22 mmol,
62% over 3 steps); Rf ϭ 0.65 (EtOAc/MeOH, 15:1, ϩ 1% Et3N);
1Ј-H), 2.63 (dt, J ϭ 14.2, 7.9 Hz, 1 H, 3Ј-H), 2.68 (dt, J ϭ 14.2,
7.9 Hz, 1 H, 3Ј-H), 2.76 (dt, J ϭ 8.5, 5.5 Hz, 1 H, 2-H), 2.94 (dt,
J ϭ 8.5, 5.5 Hz, 1 H, 2-H), 5.50 (ddt, J ϭ 10.2, 1.8, 1.8 Hz, 1 H, 6-
m.p. 71 °C. Ϫ IR (KBr): ν˜ ϭ 3012 cmϪ1 (ArϪH), 2948 (CϪH), H), 5.79 (ddt, J ϭ 10.2, 3.6, 0.5 Hz, 1 H, 7-H), 5.96 (s, 2 H,
1478, 1230, 1115, 1083, 1038, 928 (CϪOϪC), 857, 834 (arene), 733 OCH2O), 6.77 (s, 1 H, 4ЈЈ-H), 7.24 (s, 1 H, 7ЈЈ-H). Ϫ 13C NMR
(ϭCϪH). Ϫ UV (CH3CN): λmax (lg ε) ϭ 202 nm (4.57), 232 (3.74), (50.3 MHz, CDCl3): δ ϭ 21.2 (C-9), 21.3 (C-3), 25.2 (C-8), 28.4 (C-
295 (3.63). Ϫ 1H NMR (500 MHz, CDCl3): δ ϭ 1.35Ϫ1.68 (m,
9 H, 3-H2, 4-H2, 5-H2, 10-H2, 11-H), 1.83Ϫ1.88 (m, 1 H, 11-H),
4), 30.3 (C-2Ј), 38.5 (C-10), 38.8 (C-3Ј), 48.7 (C-1Ј), 50.6 (C-2), 63.4
(C-5), 87.7 (C-6ЈЈ), 101.3 (OCH2O), 109.1 (C-4ЈЈ), 118.4 (C-7ЈЈ),
1.92 (mc, 2 H, 9-H2), 2.17Ϫ2.24 (m, 1 H, 1Ј-H), 2.48 (dt, J ϭ 11.5, 128.6 (C-7), 133.6 (C-6), 138.5 (C-5ЈЈ), 146.4 (C-7aЈЈ), 148.3 (C-
3.0 Hz, 1 H, 2-Hax), 2.60Ϫ2.67 (m, 1 H, 1Ј-H), 2.74Ϫ2.85 (m, 5 H, 3aЈЈ). Ϫ MS (70 eV, EI): m/z (%) ϭ 425 (17) [Mϩ], 397 (29) [Mϩ
Ϫ
Eur. J. Org. Chem. 2000, 2433Ϫ2444
2441

L. F. Tietze, H. Schirok, M. Wöhrmann, K. Schrader
FULL PAPER
C2H4], 298 (19) [Mϩ Ϫ I], 270 (23) [Mϩ Ϫ I Ϫ C2H4], 164 (11)
3,4,5,6,7,8,9,10-Octahydro-15bH-[1,3]dioxolo[4,5-j]pyrido[2,1-e]-
phenanthridine (19): To a solution of the tertiary amine 12f (113 mg,
[C11H18Nϩ], 150 (100) [C10H16Nϩ], 136 (46) [C9H14Nϩ].
Ϫ
C19H24INO2 (425.3): calcd. C 49.42, H 5.46; found C 49.72, H 5.78. 365 µmol) in a mixture of acetonitrile, dimethylformamide, and
Ϫ HRMS: calcd. 425.0852; found 425.0851.
water (5:5:1) (5 mL) were added the palladium catalyst 20 (20.6 mg,
21.9 µmol, 6 mol-%) and tetra-n-butylammonium acetate (231 mg,
766 µmol, 2.1 equiv.), and the mixture was degassed by pump-and-
freeze methodology. It was subsequently heated to 120 °C for 20 h,
then diluted with MTBE, and extracted with dilute aq. NaOH solu-
tion. The organic layer was extracted three times with 1  HCl.
The combined aqueous extracts were basified with NaOH solution
and extracted three times with MTBE. The combined organic
layers were dried with Na2SO4 and the solvent was evaporated. The
crude product was purified by column chromatography (25 g SiO2;
EtOAc/MeOH, 20:1, ϩ 1% Et3N) to give 19 (77.6 mg, 274 µmol,
75%); Rf ϭ 0.54 (EtOAc/MeOH, 5:1, ϩ 1% Et3N); m.p. 122 °C. Ϫ
IR (KBr): ν˜ ϭ 3019 cmϪ1 (Ar-H), 2927 (CϪH), 1489, 1242, 1141,
1034, 927 (CϪOϪC), 852, 838, 806 (arene), 704 (ϭCϪH). Ϫ UV
(CH3CN): λmax (lg ε) ϭ 200 nm (4.54), 293 (3.66). Ϫ 1H NMR
(200 MHz, CDCl3): δ ϭ 1.3Ϫ1.8 (m, 6 H, 5-H2, 6-H2, 7-H2),
1.90Ϫ2.10 (m, 3 H, 3-H, 4-H2), 2.45Ϫ2.80 (m, 3 H, 8-H2, 3-H),
3.12 (mc, 1 H, 15bϪH), 3.49 (d, J ϭ 16.2 Hz, 1 H, 10-H), 3.82 (d,
J ϭ 16.2 Hz, 1 H, 10-H), 5.66 (br. d, J ϭ 10.0 Hz, 1 H, 1-H), 5.84
(d, J ϭ 1.4 Hz, 1 H, 13-H), 5.88 (d, J ϭ 1.4 Hz, 1 H, 13-H), 6.09
(dddd, J ϭ 10.0, 5.6, 2.0, 2.0 Hz, 1 H, 2-H), 6.46 (s, 1 H, 15-H),
6.75 (s, 1 H, 11-H). Ϫ 13C NMR (50.3 MHz, CDCl3): δ ϭ 20.4 (C-
6), 23.3 (C-3), 26.9 (C-7), 33.0 (C-5), 42.6 (br., C-15b), 49.4 (C-8),
52.6 (C-10), 53.5 (C-4a), 100.5 (C-13), 105.9 (C-15), 107.3 (C-11),
125.0 (C-10a), 126.4 (C-1), 128.6 (C-2), 130.8 (C-15a), 145.2 (C-
11a), 146.3 (C-14a). Ϫ MS (70 eV, EI): m/z (%) ϭ 283 (39) [Mϩ],
282 (48) [Mϩ Ϫ H], 228 (30) [Mϩ Ϫ C4H7], 84 (96) [C5H10Nϩ], 69
(29), 56 (100) [C3H6Nϩ], 41 (53) [C3H5ϩ]. Ϫ C18H21NO2 (283.4):
calcd. C 76.30, H 7.47; found C 76.46, H 7.60. Ϫ HRMS: calcd.
283.1572; found 283.1572.
1-(6-Bromobenzo[1,3]dioxol-5-ylmethyl)-1-azaspiro[5.5]undec-7-ene
(12f): To a stirred solution of dibromide 18a[7] (415 mg, 1.41 mmol,
1.6 equiv.) in acetonitrile (5 mL), the hydrochloride of amine 17b
(170 mg, 905 µmol), TBAI (502 mg, 1.36 mmol, 1.5 equiv.), and di-
isopropylethylamine (428 mg, 3.31 mmol, 3.7 equiv.) were added at
20 °C. Stirring was continued at 70 °C for 120 h. Thereafter, the
mixture was diluted with MTBE, washed with 5% aq. NaOH solu-
tion, and the aqueous phase was extracted three times with MTBE.
The combined organic layers were dried with Na2SO4 and concen-
trated to dryness. The residue was purified by column chromato-
graphy (25 g SiO2; PE/EtOAc, 15:1) to give 12f (293 mg, 804 µmol,
89%); Rf ϭ 0.60 (PE/EtOAc, 5:1); m.p. 68 °C. Ϫ IR (KBr): ν˜ ϭ
3015 cmϪ1 (ArϪH), 2926 (CϪH), 1474, 1437, 1366, 1239, 1100,
1040, 934 (CϪOϪC), 885, 830 (arene), 736 (ϭCϪH). Ϫ UV
(CH3CN): λmax (lg ε) ϭ 202 nm (4.62), 235 (3.81), 294 (3.64). Ϫ 1H
NMR (200 MHz, CDCl3): δ ϭ 1.40Ϫ1.73 (m, 10 H, 3-H2, 4-H2, 5-
H2, 10-H2, 11-H2), 1.92Ϫ2.00 (m, 2 H, 9-H2), 2.41 (mc, 2 H, 2-H2),
3.32 (d, J ϭ 15.5 Hz, 1 H, 1Ј-H), 3.64 (d, J ϭ 15.5 Hz, 1 H, 1Ј-H),
5.39 (dddd, J ϭ 10.2, 2.3, 1.5, 1.5 Hz, 1 H, 7-H), 5.71 (dddd, J ϭ
10.2, 3.8, 2.9, 0.7 Hz, 1 H, 8-H), 5.92 (d, J ϭ 1.5 Hz, 1 H, OCHO),
5.93 (d, J ϭ 1.5 Hz, 1 H, OCHO), 6.92 (s, 1 H, 4ЈЈ-H), 7.23 (s, 1 H,
7ЈЈ-H). Ϫ 13C NMR (50.3 MHz, CDCl3): δ ϭ 20.2 (C-4), 23.3 (C-
10), 25.3 (C-9), 26.4 (C-3), 36.2 (C-5), 46.3 (C-11), 54.6, 56.7 (C-
1Ј, C-2), 101.3 (OCH2O), 109.5 (C-4ЈЈ), 112.1 (C-7ЈЈ), 113.5 (C-6ЈЈ),
128.5 (C-8), 134.0 (C-5ЈЈ), 136.6 (C-7), 146.4 (C-3aЈЈ), 147.3 (C-
7aЈЈ). Ϫ MS (70 eV, EI): m/z (%) ϭ 365/363 (18) [Mϩ], 284 (100)
[Mϩ Ϫ Br], 256 (66) [C16H18NO2ϩ], 215/213 (71/66) [C8H6BrO2ϩ],
150 (39) [C10H16Nϩ] (hydrochloride). Ϫ C18H23BrClNO2 (400.7)
(hydrochloride): calcd. C 53.95, H 5.78; found C 54.23, H 5.88. Ϫ
HRMS calcd. 363.0834; found 363.0834.
1-(1-Azaspiro[4.5]dec-6-en-1-yl)-2-(6-bromobenzo[1,3]dioxol-5-
yl)ethanone (22a): At 0 °C, a solution of 6-bromobenzo[1,3]dioxol-
5-ylacetyl chloride[16] (4.91 mmol, 1.1 equiv.) in diethyl ether
(4 mL) was added dropwise to a solution of crude 17a (642 mg,
4.68 mmol) and triethylamine (726 mg, 7.20 mmol, 1.5 equiv.) in
CH2Cl2 (6 mL) and the mixture was stirred for 0.5 h at this temper-
ature. It was subsequently diluted with MTBE and washed with
1-(6-Bromobenzo[1,3]dioxol-5-ylmethyl)-1-azaspiro[4,5]dec-6-ene
(12g): To a stirred solution of dibromide 18a[7] (2.40 g, 8.16 mmol,
1.6 equiv.) in acetonitrile (28 mL), the hydrochloride of amine 17a
(880 mg, 5.1 mmol), TBAI (2.81 g, 7.61 mmol, 1.5 equiv.), and di-
isopropylethylamine (2.67 g, 20.6 mmol, 4.1 equiv.) were added at
20 °C. Stirring was continued at 70 °C for 120 h. Thereafter, the water. The organic layer was dried with Na2SO4, and the solvent
mixture was diluted with MTBE, washed twice with 5% aq. NaOH was evaporated. The residue was purified by column chromatog-
solution, and the aqueous phase was extracted three times with
MTBE. The combined organic layers were dried with Na2SO4 and
concentrated to dryness. The residue was purified by column chro-
matography (190 g SiO2; PE/EtOAc, 15:1) to give 12g (1.26 g,
3.59 mmol, 71%); Rf ϭ 0.21 (PE/EtOAc, 15:1); m.p. 68 °C. Ϫ IR
(KBr): ν˜ ϭ 3014 cmϪ1 (ArϪH), 2929 (CϪH), 1502, 1476, 1233,
1107, 1039, 935 (CϪOϪC), 831 (arene), 735 (ϭCϪH). Ϫ UV
raphy (120 g SiO2; PE/MTBE, 1:2) to give 22a (794 mg, 2.10 mmol,
45% over 3 steps); Rf ϭ 0.38 (PE/MTBE, 1:2); m.p. 128 °C. Ϫ IR
(KBr): ν˜ ϭ 3013 cmϪ1 (ArϪH), 2925 (CϪH), 1649 (CϭO), 1483,
1407, 1229, 1172, 1118, 1031, 920 (CϪOϪC), 865, 831, 798 (arene),
736 (ϭCϪH). Ϫ UV (CH3CN): λmax (lg ε) ϭ 203 nm (4.60), 294
(3.59). Ϫ The NMR spectra showed double sets of signals (ratio
2:1): 1H NMR (500 MHz, CDCl3): δ ϭ 1.48Ϫ2.16 (m, 10 H, 3Ј-H2,
(CH3CN): λmax (lg ε) ϭ 202 nm (4.61), 236 (3.89), 293 (3.65). Ϫ 4Ј-H2, 8Ј-H2, 9Ј-H2, 10Ј-H2); major isomer: 2.48 (dddd, J ϭ 13.8,
1H NMR (200 MHz, CDCl3): δ ϭ 1.56Ϫ1.65 (m, 3 H, 3-H, 4-H2), 12.6, 3.4, 1.4 Hz, 1 H, 3Ј-H), 3.54Ϫ3.59 (m, 1 H, 2Ј-H), 3.62 (s,
1.72Ϫ1.83 (m, 5 H, 3-H, 9-H2, 10-H2), 1.95Ϫ2.03 (m, 2 H, 8-H), 2 H, ArCH2), 3.67 (ddd, J ϭ 11.0, 7.6, 2.3 Hz, 1 H, 2Ј-H), 5.48
2.63Ϫ2.72 (m, 1 H, 2-H), 2.76Ϫ2.85 (m, 1 H, 2-H), 3.58 (s, 2 H, (dddd, J ϭ 10.1, 2.8, 1.4, 1.4 Hz, 1 H, 6Ј-H), 5.73 (dddd, J ϭ 10.1,
1Ј-H), 5.56 (d, J ϭ 10.2 Hz, 1 H, 6-H), 5.81 (m, 1 H, 7-H), 5.94 (s,
5.3, 2.1, 1.1 Hz, 1 H, 7Ј-H), 5.93 (d, J ϭ 1.4 Hz, 1 H, OCHO), 5.94
2 H, OCH2O), 6.96 (s, 1 H, 4ЈЈ-H), 7.07 (s, 1 H, 7ЈЈ-H). Ϫ 13C (d, J ϭ 1.4 Hz, 1 H, OCHO), 6.83 (s, 1 H, 4-H), 6.99 (s, 1 H, 7-H);
NMR (50.3 MHz, CDCl3): δ ϭ 21.2, 21.5 (C-3, C-9), 25.2 (C-8), minor isomer: 3.49Ϫ3.55 (m, 1 H, 2Ј-H), 3.75 (d, J ϭ 16.5 Hz, 1 H,
29.3 (C-4), 38.3 (C-10), 50.5 (C-2), 52.7 (C-1Ј), 63.6 (C-5), 101.4 ArCH), 3.82 (d, J ϭ 16.5 Hz, 1 H, ArCH), 3.83 (ddd, J ϭ 10.5,
(OCH2O), 110.0, 112.2 (C-4ЈЈ, C-7ЈЈ), 113.6 (C-6ЈЈ), 129.2 (C-7), 6.9, 2.1 Hz, 1 H, 2Ј-H), 5.58 (dddd, J ϭ 10.1, 2.8, 1.4, 1.4 Hz, 1 H,
133.6 (C-5ЈЈ), 133.7 (C-6), 146.7 (C-3aЈЈ), 147.3 (C-7aЈЈ). Ϫ MS
(70 eV, EI): m/z (%) ϭ 351/349 (12) [Mϩ], 270 (19) [Mϩ Ϫ Br], 242 J ϭ 1.4 Hz, 1 H, OCHO), 5.94 (d, J ϭ 1.4 Hz, 1 H, OCHO), 6.80
(100) [C15H16NO2ϩ], 215/213 (34) [C8H6BrO2ϩ]. Ϫ C17H20BrNO2 (s, 1 H, 4-H), 7.00 (s, 1 H, 7-H). Ϫ 13C NMR (75.5 MHz, CDCl3):
(350.3): calcd. C 58.30, H 5.76; found C 57.97, H 5.50. Ϫ HRMS δ ϭ 20.8, 21.4* (C-3Ј), 21.4, 22.9* (C-9Ј), 24.0*, 24.2 (C-8Ј), 30.0*
6Ј-H), 5.86 (dddd, J ϭ 10.1, 3.2, 2.3, 1.8 Hz, 1 H, 7Ј-H), 5.95 (d,
calcd. 349.0677; found 349.0677.
, 33.2 (C-4Ј), 38.7*, 40.5 (C-10Ј), 41.3, 42.9* (ArCH2), 48.2, 48.3
2442
Eur. J. Org. Chem. 2000, 2433Ϫ2444

Six-Membered Ring D Analogues of the Pentacyclic Alkaloid Cephalotaxine
(C-2Ј), 63.0, 64.2* (C-5Ј), 101.6 (OCH2O), 110.7, 111.0* (C-4), Ϫ C19H22BrNO3 (392.3): calcd. C 58.17, H 5.65; found C 58.46,
FULL PAPER
112.4 (C-7), 115.0*, 115.1 (C-6), 126.5*, 129.0 (C-7Ј), 128.5*, 129.2
(C-5), 132.9, 133.3 (C-6Ј), 146.9, 147.3* (C-7a), 147.2 (C-3a),
167.5*, 169.1 (CO) (asterisks* denote signals of the major isomer).
Ϫ MS [70 eV, CI (NH3)]: m/z (%) ϭ 397/395 (40/50) [M ϩ NH4ϩ],
380/378 (100/98) [M ϩ Hϩ]. Ϫ C18H20BrNO3 (378.3): calcd. C
57.15, H 5.33; found C 57.11, H 5.11.
H 5.71.
3,4,6,7-Tetrahydro-5H,15bH-cyclohexa[a][1,3]dioxolo[4,5-h]pyrrolo-
[2,1-b][3]benzazepin-9(10H)-one (23): To a solution of tertiary
amide 22a (268 mg, 708 µmol) in acetonitrile, dimethylformamide,
and water (5:5:1) (11 mL) were added the palladium catalyst 20
(34 mg, 36.2 µmol, 5 mol-%) and tetra-n-butylammonium acetate
(560 mg, 1.86 mmol, 2.6 equiv.), and the mixture was degassed by
pump and freeze methodology. It was subsequently heated to 140
°C for 30 h and, after cooling, was diluted with MTBE and ex-
tracted with water. The organic layer was dried with Na2SO4 and
the solvent was evaporated. The crude product was purified by col-
umn chromatography (27 g SiO2; MTBE) to give 23 (116 mg,
390 µmol, 55%) as a mixture of two components (ratio 1:1.1). From
a second column chromatography, 17 mg of the less polar compo-
nent was isolated, which allowed an interpretation of the NMR
signals; Rf ϭ 0.28 (MTBE). Ϫ 1H NMR (500 MHz, CDCl3): δ ϭ
1.51 (ddd, J ϭ 13.5, 10.1, 6.2 Hz, 1 H, 5-H), 1.68Ϫ1.82 (m, 3 H,
4-H, 6-H2), 1.86Ϫ1.95 (m, 1 H, 4-H), 2.04 (dddd, J ϭ 13.5, 3.4,
3.4, 0.7 Hz, 1 H, 5-H), 2.08Ϫ2.13 (m, 2 H, 3-H), 3.12 (d, J ϭ
14.6 Hz, 1 H, 10-H), 3.30 (ddd, J ϭ 12.9, 10.3, 3.7 Hz, 1 H, 7-H),
3.68 (ddd, J ϭ 5.4, 2.7, 2.7 Hz, 1 H, 15b-H), 3.78 (ddd, J ϭ 12.9,
9.9, 6.9 Hz, 1 H, 7-H), 4.45 (d, J ϭ 14.6 Hz, 1 H, 10-H), 5.48
(dddd, J ϭ 9.9, 3.9, 1.4, 1.1 Hz, 1 H, 1-H), 5.90 (d, J ϭ 1.4 Hz,
1 H, 13-H), 5.91 (d, J ϭ 1.4 Hz, 1 H, 13-H), 6.03 (ddddd, J ϭ 9.9,
5.7, 2.5, 2.5, 0.9 Hz, 1 H, 2-H), 6.65 (s, 1 H, 15-H), 6.65 (s, 1 H,
11-H). Ϫ 13C NMR (125.7 MHz, CDCl3): δ ϭ 18.4 (C-6), 21.2 (C-
3), 32.0 (C-5), 38.5 (C-4), 40.8 (C-10), 45.3 (C-7), 47.7 (C-15b), 64.2
(C-4a), 101.0 (C-13), 110.0 (C-15), 111.2 (C-11), 129.0 (C-2), 129.4
(C-1), 129.4 (C-10a), 129.5 (C-15a), 146.5 (C-11a), 146.7 (C-14a),
1-(1-Azaspiro[5.5]undec-7-en-1-yl)-2-(6-bromobenzo[1,3]dioxol-5-yl)-
ethanone (22b): At 0 °C, a solution of 6-bromobenzo[1,3]dioxol-5-
ylacetyl chloride[16] (3.00 mmol, 1.0 equiv.) in diethyl ether (2 mL)
was added dropwise to a solution of crude 17b (437 mg, 2.89 mmol)
and triethylamine (440 mg, 4.34 mmol, 1.5 equiv.) in diethyl ether
(3 mL) and the mixture was stirred for 1 h at this temperature. It
was subsequently diluted with MTBE and washed with water. The
organic layer was dried with Na2SO4, and the solvent was evapor-
ated. The residue was purified by column chromatography (100 g
SiO2; PE/MTBE, 3:2) to give 22b (567 mg, 1.45 mmol, 50% over
3 steps): Rf ϭ 0.34 (PE/MTBE, 3:2). Ϫ IR (neat): ν˜ ϭ 3021 cmϪ1
(ArϪH), 2935 (CϪH), 1645 (CϭO), 1481, 1234, 1117, 1038, 927
(CϪOϪC), 863, 837 (arene), 731 (ϭCϪH). Ϫ UV (CH3CN): λmax
(lg ε) ϭ 203 nm (4.59), 295 (3.63). Ϫ 1H NMR (200 MHz, CDCl3):
δ ϭ 1.50Ϫ2.27 (m, 12 H, 3Ј-H2, 4Ј-H2, 5Ј-H2, 9Ј-H2, 10Ј-H2, 11Ј-
H2), 3.08Ϫ3.25 (m, 1 H, 2Ј-H), 3.70 (s, 2 H, ArCH2), 3.70Ϫ3.84
(m, 1 H, 2Ј-H), 5.53 (ddd, J ϭ 10.0, 4.4, 2.4 Hz, 1 H, 8Ј-H), 5.70
(dddd, J ϭ 10.0, 2.8, 2.4, 2.4 Hz, 1 H, 7Ј-H), 5.94 (s, 2 H, OCH2O),
6.77 (s, 1 H, 4-H), 6.99 (s, 1 H, 7-H). Ϫ 13C NMR (50.3 MHz,
CDCl3): δ ϭ 17.8 (C-4Ј), 19.8 (C-10Ј), 24.1, 24.1 (C-3Ј, C-9Ј), 35.2
(C-5Ј), 41.7 (C-11Ј), 43.1 (ArϪCH2), 57.6 (C-6Ј), 101.6 (OCH2O),
110.6 (C-4), 112.5 (C-7), 114.9 (C-6), 122.9 (br., C-8Ј), 129.0 (C-5),
137.4 (C-7Ј), 147.1 (C-3a), 147.3 (C-7a), 170.2 (CO). Ϫ MS (70 eV,
EI): m/z (%) ϭ 393/391 (9) [Mϩ], 312 (48) [Mϩ Ϫ Br], 242/240 (26/
27) [C9H5BrO3ϩ], 215/213 (88/100) [C8H6BrO2ϩ], 178 (21)
[C11H16NOϩ]. Ϫ C19H22BrNO3 (392.3): calcd. C 58.17, H 5.65;
found C 58.29, H 5.55.
1
169.8 (C-9). Second component; Rf ϭ 0.23 (MTBE). Ϫ H NMR
(500 MHz, CDCl3): δ ϭ 1.45 (dddd, J ϭ 17.2, 6.6, 4.4, 2.3 Hz, 1 H,
5-H), 1.54Ϫ1.86 (m, 3 H, 4-H, 6-H2), 1.99 (dd, J ϭ 17.2, 6.0 Hz,
1 H, 5-H), 2.23 (ddd, J ϭ 11.5, 7.6, 1.2 Hz, 1 H, 4-H), 2.51Ϫ2.57
(m, 1 H, 3-H), 2.61 (ddddd, J ϭ 18.6, 7.6, 4.6, 2.3, 2.3 Hz, 1 H, 3-
H), 3.19 (dddd, J ϭ 12.9, 10.1, 4.3, 0.7 Hz, 1 H, 7-H), 3.35 (ddd,
J ϭ 5.3, 2.7, 2.7 Hz, 1 H, 15b-H), 3.50 (d, J ϭ 16.1 Hz, 1 H, 10-
H), 4.22 (ddd, J ϭ 12.9, 10.1, 6.7 Hz, 1 H, 7-H), 5.58 (dddd, J ϭ
11.5, 5.7, 2.8, 1.6 Hz, 1 H, 1-H), 5.84Ϫ5.88 (m, 1 H, 2-H), 5.90 (d,
J ϭ 1.4 Hz, 1 H, 13-H), 5.91 (d, J ϭ 1.4 Hz, 1 H, 13-H), 6.66 (s,
1 H, 11-H), 6.83 (s, 1 H, 15-H). Ϫ 13C NMR (125.7 MHz, CDCl3):
δ ϭ 18.6 (C-6), 30.0 (C-3), 30.9 (C-5), 35.7 (C-4), 41.3 (C-15b), 43.2
(C-10), 44.9 (C-7), 66.5 (C-4a), 100.9 (C-13), 107.0 (C-15), 109.5
(C-11), 125.2 (C-2), 127.0 (C-1), 127.5 (C-10a), 132.3 (C-15a), 146.0
(C-11a), 146.4 (C-14a), 166.8 (C-9). Ϫ IR (KBr): ν˜ ϭ 3032 cmϪ1
(Ar-H), 2891 (CϪH), 1599 (CϭO), 1503, 1482, 1262, 1034, 937
(CϪOϪC), 858 (arene), 727 (ϭCϪH). Ϫ UV (CH3CN): λmax (lg
ε) ϭ 203 nm (4.61), 291 (3.63). Ϫ MS (70 eV, EI): m/z (%) ϭ 297
(23) [Mϩ], 243 (100) [Mϩ Ϫ C4H6], 214 (20) [C12H8NO3ϩ]. Ϫ
C18H19NO3 (297.3): HRMS calcd. 297.1365; found 297.1365.
1-(1-Azaspiro[4.5]dec-6-en-1-yl)-3-(6-bromobenzo[1,3]dioxol-5-yl)-
propan-1-one (22c): At 0 °C, a solution of 3-(6-bromobenzo[1,3]-
dioxol-5-yl)propionyl chloride[16] (4.16 mmol, 1.0 equiv.) in diethyl
ether (4 mL) was added dropwise to a solution of crude 17a
(549 mg, 4.00 mmol) and triethylamine (620 mg, 6.13 mmol, 1.5
equiv.) in diethyl ether (5 mL) and the mixture was stirred for 0.5 h
at this temperature. It was subsequently diluted with MTBE and
washed with water. The organic layer was dried with Na2SO4, and
the solvent was evaporated. The residue was purified by column
chromatography (100 g SiO2; PE/MTBE, 1:2) to give 22c (1.39 g,
3.54 mmol, 89% over 3 steps); Rf ϭ 0.27 (PE/MTBE, 1:2); m.p. 111
°C. Ϫ IR (KBr): ν˜ ϭ 3021 cmϪ1 (ArϪH), 2943 (CϪH), 1640 (Cϭ
O), 1473, 1223, 1110, 1035, 925 (CϪOϪC), 872, 842 (arene), 735
(ϭCϪH). Ϫ UV (CH3CN): λmax (lg ε) ϭ 203 nm (4.61), 236 (3.66),
294 (3.60). Ϫ 1H NMR (200 MHz, CDCl3): δ ϭ 1.42Ϫ2.30 (m,
9 H, 3Ј-H, 4Ј-H2, 8Ј-H2, 9Ј-H2, 10Ј-H2), 2.38Ϫ2.53 (m, 2 H,
COCH2), 2.62 (ddd, J ϭ 7.6, 7.0, 3.5 Hz, 1 H, 3Ј-H), 2.99 (mc, 2 H,
ArCH2), 3.32Ϫ3.54 (m, 1.5 H, 2Ј-H), 3.77 (mc, 0.5 H, 2Ј-H), Acknowledgments
5.27Ϫ5.50 (m, 1 H, 6Ј-H), 5.68Ϫ5.82 (m, 1 H, 7Ј-H), 5.94 (s, 2 H,
This research was supported by the Deutsche Forschungsgemein-
OCH2O), 6.77, 6.78 (s, 1 H, 4-H), 6.96, 6.97 (s, 1 H, 7-H). Ϫ 13C
NMR (50.3 MHz, CDCl3): δ ϭ 20.9, 20.4 (C-3Ј), 20.4, 22.8 (C-9Ј),
24.07, 24.09 (C-8Ј), 30.2, 33.4 (C-4Ј), 31.4, 32.3 (ArCH2), 34.4, 36.0
(COCH2), 38.7, 40.3 (C-10Ј), 48.0, 48.1 (C-2Ј), 62.6, 63.9 (C-5Ј),
101.4, 101.5 (OCH2O), 110.3, 110.4 (C-4), 112.4, 112.5 (C-7), 114.1,
114.3 (C-6), 126.3, 128.5 (C-7Ј), 133.2, 133.4 (C-6Ј), 133.9, 134.0
(C-5), 146.6, 147.1 (C-3a), 146.7, 147.2 (C-7a), 169.5, 171.3 (CO).
Ϫ MS (70 eV, EI): m/z (%) ϭ 411/409 (19/17) [M ϩ NH4ϩ], 394/
392 (100/95) [M ϩ Hϩ], 314 (40) [Mϩ Ϫ Br], 136 (49) [C9H14Nϩ].
schaft (Sonderforschungsbereich 416) and the Fonds der Che-
mischen Industrie. We thank the Degussa-Hüls AG, BASF AG,
and Wacker AG for this generous donations of chemicals.
[1]
[1a]L. F. Tietze, T. Nöbel, M. Spescha, Angew. Chem. 1996, 108,
2385Ϫ2386; Angew. Chem. Int. Ed. Engl. 1996, 35, 2259Ϫ2261.
Ϫ
[1b]L. F. Tietze, T. Nöbel, M. Spescha, J. Am. Chem. Soc.
1998, 120, 8971Ϫ8977. Ϫ [1c]L. F. Tietze, R. Hannemann, W.
Buhr, M. Lögers, P. Menningen, M. Lieb, D. Starck, T. Grote,
Eur. J. Org. Chem. 2000, 2433Ϫ2444
2443

L. F. Tietze, H. Schirok, M. Wöhrmann, K. Schrader
FULL PAPER
[11]
[12]
[13]
[14]
A. Döring, I. Schuberth, Angew. Chem. 1996, 108, 2840Ϫ2842;
Angew. Chem. Int. Ed. Engl. 1996, 35, 2674Ϫ2677. Ϫ [1d]L. F.
Tietze, T. Grote, J. Org. Chem. 1994, 59, 192Ϫ196. Ϫ [1e]L. F.
Tietze, T. Grote, Chem. Ber. 1993, 126, 2733Ϫ2737. Ϫ [1f]L. F.
Tietze, W. Buhr, Angew. Chem. 1995, 107, 1485Ϫ1487; Angew.
Chem. Int. Ed. Engl. 1995, 34, 1366Ϫ1368. Ϫ [1g]L. F. Tietze,
W. Buhr, J. Looft, T. Grote, Chem. Eur. J. 1998, 4, 1554Ϫ1560.
G. W. Kabalka, T. M. Shoup, N. M. Goudgaon, J. Org. Chem.
1989, 54, 5930Ϫ5933.
Y. G. Gololobov, I. N. Zhmurova, L. F. Kasukhin, Tetrahedron
1981, 37, 437Ϫ472.
H. Bayley, D. N. Standring, J. R. Knowles, Tetrahedron Lett.
1978, 3633Ϫ3634.
Crystallographic data (excluding structure factors) for the
structure reported in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication no. CCDC-141208. Copies of the data can be ob-
tained free of charge on application to the CCDC, 12 Union
Road, Cambridge CB2 1 EZ, U.K. [Fax: (internat.) ϩ 44-1223/
336-033; E-mail: deposit@ccdc.cam.ac.uk].
Ϫ
[1h]L. F. Tietze, R. Ferraccioli, Synlett 1998, 145Ϫ146. Ϫ
[1i]L. F. Tietze, H. Schirok, Angew. Chem. 1997, 109,
1159Ϫ1160; Angew. Chem. Int. Ed. Engl. 1997, 36, 1124Ϫ1125.
Ϫ
[1j]L. F. Tietze, H. Schirok, J. Am. Chem. Soc. 1999, 121,
10264Ϫ10269.
[2a]S. Sinha, S. Jain, in: Prog. Drug Res. 1994, 42, 53Ϫ132. Ϫ
[2b]D. C. Zhou, R. Zittoun, J. P. Marie, Bull. Cancer 1995, 82,
987Ϫ995.
[2]
[3]
[15] [15a]
W. A. Herrmann, C. Brossmer, K. Öfele, C.-P. Reisinger,
T. Priermeier, M. Beller, H. Fischer, Angew. Chem. 1995, 107,
[3a]J. M. Whaun, N. D. Brown, Ann. Trop. Med. Parasit. 1990,
84, 229Ϫ237. Ϫ [3b]R. M. Ekong, G. C. Kirby, G. Patel, J. D.
Phillipson, D. C. Warhurst, Biochem. Pharmacol. 1990, 40,
297Ϫ301.
1989Ϫ1992; Angew. Chem. Int. Ed. Engl. 1995, 34, 1844Ϫ1848.
[15b]
Ϫ
M. Beller, H. Fischer, W. A. Herrmann, K. Öfele, C.
Brossmer, Angew. Chem. 1995, 107, 1992Ϫ1993; Angew. Chem.
Int. Ed. Engl. 1995, 34, 1848Ϫ1849. Ϫ [15c] W. A. Herrmann, C.
Brossmer, C.-P. Reisinger, T. H. Riermeier, K. Öfele, M. Beller,
Chem. Eur. J. 1997, 3, 1357Ϫ1364. Ϫ [15d] M. Beller, T. H. Rier-
meier, C.-P. Reisinger, W. A. Herrmann, Tetrahedron Lett.
1997, 38, 2073Ϫ2074.
[4]
[5]
L. F. Tietze, H. Schirok, M. Wöhrmann, Chem. Eur. J. 2000,
6, 510Ϫ518.
[5a]9a: P. W. Clark, S. F. Dyke, J. Organomet. Chem. 1985, 281,
389Ϫ396. Ϫ [5b]9b: K. Ito, H. Tamaka, M. Kayama, Chem.
[16]
[17]
[18]
[5c]
Derived from the acid: M. Pailer, A. Schleppnik, Monatsh.
Chem. 1958, 89, 175Ϫ185.
´
Pharm. Bull. 1977, 25, 1249Ϫ1255. Ϫ G. Rodrıguez, M. M.
´
´
Cid, C. Saa, L. Castedo, D. Domınguez, J. Org. Chem. 1996,
61, 2780Ϫ2782; 9c: ref.[4]; 9d: J. Fidalgo, L. Castedo, D. Do-
Derived from the acid: R. D. Haworth, W. H. Perkin, T. Ste-
vens, J. Chem. Soc. 1926, 1764Ϫ1769.
´
mınguez, Heterocycles 1994, 39, 581Ϫ589.
N. Mori, E. Nakamura, Y. Tsuzuki, Bull. Chem. Soc. Jpn. 1967,
[6]
[7]
10a,b: S. A. Godleski, J. D. Meinhart, D. J. Miller, S. Van Wal-
lendael, Tetrahedron Lett. 1981, 22, 2247Ϫ2250.
W. F. Barthel, B. H. Alexander, J. Org. Chem. 1958, 23,
1012Ϫ1014.
B. Weinstein, A. R. Craig, J. Org. Chem. 1976, 41, 875Ϫ878.
M. F. Semmelhack, B. P. Chong, R. D. Stauffer, T. D.
Rogerson, A. Chong, L. D. Jones, J. Am. Chem. Soc. 1975,
97, 2507Ϫ2516.
X. Lin, R. W. Kavash, P. S. Mariano, J. Org. Chem. 1996, 61,
7335Ϫ7347.
40, 2189Ϫ2190.
[19] [19a]
W. F. Gannon, H. O. House, Org. Synth. 1960, 40, 41Ϫ42.
J. B. Lambert, K. M. Taba, J. Org. Chem. 1980, 45,
[19b]
Ϫ
452Ϫ455.
[8]
[9]
[20] [20a]
J. C. Boehm, J. G. Gleason, I. Pendrak, H. M. Sarau, D.
B. Schmidt, J. J. Foley, W. D. Kingsbury, J. Med. Chem. 1993,
[20b]
36, 3333Ϫ3340. Ϫ
E. R. de Oliveira, F. Dumas, J.
d’Angelo, Tetrahedron Lett. 1997, 38, 3723Ϫ3726.
[10]
Received December 22, 1999
[O99688]
2444
Eur. J. Org. Chem. 2000, 2433Ϫ2444