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Highly Efficient Synthesis of Cephalotaxine by Two Palladium-Catalyzed Cyclizations.

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[8] H. Aharr, G. A. Ozin, R. L. Bedard, S.Petrov. D. Young, A&. Muter. 1995, 7,
370; P. Enzel, G. S . Henderson, G. A. Ozin, R. L. Bedard, Adv. Marer. 1995.
7. 64.
[9] R. L. Bedard, L. D. Vail, S . L Wilson, E. M. Flanigen, US Pat 4.880.761.
1989.
[lo] C. L. Bowes, G . A. Ozin. Adv. Marer. 1996, 8 , 13.
[11] F. Liebau. X. Wang, Am. Crystallogr. Ass., Annual Meeting Abstract Book
1992. 128.
[12] C. Sabelli, 1. Nakai. S . Katsura, Am. Mineral. 1988, 73. 398.
[13) F. Liehau, X. Wang, Beih. Eur J. Minerd. 1995. 7, 152; X. Wang, 2. Krislallogr. 1995. 210, 693.
I141 R. H. Bube, Photoconductivifj ofSolrds, Robert E. Krieger Publishing Company, New York, 1978.
[15] J. R. Macdonald. Impedance Spectroscopj, Wiley, New York, 1987.
-
1
\
OMe
3b
2
2.2 equiv nBu4NOAc
CH3CN I DMF I H20
(5/5/1)
80%
n
Highly Efficient Synthesis of Cephalotaxine by
Two Palladium-Catalyzed Cyclizations""
Lutz F. Tietze* and Hartmut Schirok
Dedicated to Professor Peter Welzel
on the occasion of his 60th birthday
Cephalotaxine 1 is the parent compound of the antileukemicactive harringtonines, a group of uniquely structured pentacyclic alkaloids that were isolated from the southeast Asian yew
tree of the genus Cephaloraxus.['] In the harringtonines the free
hydroxyl group of 1, which itself is not biologically active, is
esterified by a substituted methyl hydroxymonosuccinate. Although several totaI syntheses of racemic cephalotaxine have
been described,12]and even the enantiomerically pure natural
product has been ~ynthesized,[~'
new synthetic approaches are
especially attractive when they either surpass former methods in
efficiency or allow modifications of the structure of the naturally occurring compound.
Both of these requirements are fulfilled by the method reported herein, which is used to construct the racemic intermediate 2,
which, according to Kuehne et
is easily converted in four
steps into cephalotaxine 1 in a total yield of 75%. Retrosynthetic analysis of 2 suggests that the cleavage of the seven-membered ring would provide the spirocyclic compound 3a, which
should be available from allyl acetate 4a. This compound can be
readily obtained from 5 e und 6 by alkylation. The intramolecular Pd-catalyzed substitution of an allyl acetate with an amine
has already been reported by Godleski et al.,141and the stereoselective construction of benzazepines by intramolecular Heck
reaction from appropriate iodoarenes has been carried out with
other compounds by our group.[51The combination of both
Pd-catalyzed reactions should therefore lead to a highly efficient
synthesis of cephalotaxine. It had to be clarified first, however,
whether the difference in reactivity between the allyl acetates
and the iodoarenes is sufficient for a selective reaction process.
For the synthesis of 5e,16]amine 5a,17]readily available from
piperonal, was protected with di-tert-butyldicarbonate to form
5 b and subsequently halogenated with iodine and silver trifluoroacetate['] to yield 5c. Subsequent cleavage of the tert-butoxycarbonyl (tBoc) protecting group with trifluoroacetic acid
provided the known amine 5 e in 91 % yield. Initially, the iodina[*] Prof. Dr. L. F. Tietze, Dip1.-Chem. H. Schirok
Institut fur Organische Chemie der Universitat
Tammannstrasse 2, D-37077 Gottingen (Germany)
Fax: Int. code +(551)39-9476
[**I This research was supported by the Deutsche Forschungsgemeinschaft (Sonderforschungshereich 416) and the Fonds der Chemischen Industrie. We thank
the Degussa AG for their generous donation of precious metals.
1124
0 VCH Verlagsgesellschafi mbH, 0-69451
85 Yo
It
Weinheim. 1997
+
AcO
e
WOC t i
BOC 1
Woc Br
H
I
f
H
b
c
d
6
Br
tion of 5 b proved difficult. By other methods, such as the reaction with iodine and iodic acid as reported by KOnigstein,"l 5 c
was obtained only in very low yields. This results from the fact
that the electron density of methylenedioxyarenes such as 5 b is
lower than that of I ,2-dimethoxybenzene, because the steric
arrangement of the methylenedioxy group restricts the overlapping of the oxygen atoms' orbitals containing nonbonding electron pairs with the x-orbitals of the arene.['Ol
Alkylation of 5 e with iodide 6 (Table I), readily available
from 3-ethoxycyclopentenone in four steps, provides the secondary amine 4a, the starting material for the double cycliza-
Table 1. 1H NMR spectroscopic data of 2, 3b, 4b, and 6.
2: 1H NMR (200 MHz, CDC13): 6 =1.66- 1.87 (m. 2H), 1.91-2.07 (m, 3H), 2.34
(dd, J = 14.2, 6.1 Hz, 1 H), 2.43 (ddd, J = 9.3, 9.3. 6.8 Hz, 1 H), 2.58 (dd, J = 11.7,
7.3 Hz, 1 H),2.76 (ddd, J = 17.8,4.9.2.4 Hz, 1 H), 2.96 (ddd, J = 12.7,11.7,6.1 Hz,
1H). 3.11 (ddd, J = 9 . 3 . 7.6,4.9Hz, l H ) , 3.20(ddd.J=14.2, 12.7.7.3H~.IH),
3.88(br.s, 1 H),5.52(ddd, J = 5.9,4.4,2.2 Hz, 1 H), 5.79(ddd,J= 5.9,5.1.2.4Hz,
lH),5.88(d,J~1.5H~,1H),5.89(d,J=1.5H~,1H),6.59(s,lH),6.65(~,
= 1.61 (tt. J = 6.8,6.8 Hz. 1 H). 1.74-1.98 (m.
3 b : 1H NMR (200 MHz, CDC13): d
5H), 2.30 (tdd, J z 7 . 1 . 2.2, 2.1 Hz, 2H). 2.38-2.56 (m, 2H), 2.69-2.85 (m, 3H).
2.88-3.02(m,1H),5.56(dt,J=5.6,2.1Hz,lH),580(dt,J=5.6,2.2Hz,lH),
5 93 (s, 2H). 6.71 (s, 1 H). 6.96 (s, 1 H)
4b:lHNMR(500MHz,CDC13):6=1.7(hr.s,lH).1.71(tt,J=7.3,7.3Hz.2H),
1.83(dddd,J=14.2,8.7,3.9,3.2Hz,lH),2.02(s,3H),2.12-2.25(m,3H),2.32
(dddd, J = 13.9.8.8. 7.6, 5.1 Hz, 1 H), 2.41 -2.49 (m, 1H), 2.68 (t. J = 7.2 Hz. 2H),
2.82-2.89 (m, 4H). 5.47 (m, 1 H), 6.62-6.66 (m, 1 H), 5.95 (s, 2H). 6.74 (s, 1 H),
6.99 (s, 1 H)
6: l H N M R (200MHz, C6D6): 6 =1.35 (tt, J = 7 . 1 , 7.1 Hz, 2H). 1.59 ( s , 3H).
147-1.71(m,4H),2.49(t,J=6.8Hz,2H),5.32(m.1H),5.53-5.64(m,1H)
OS70-0833/97f36/O-f124 $17.50+ .SO/O
Angew. Chem. In!. Ed. Engl. 1997, 36. No. 10
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tion, in a yield of 80%. In contrast, alkylation of deprotonated
5 b with 6 yields only poor results. During the Pdo-catalyzed
transformation of 4 a , the reaction between the ally1 acetate and
the iodoaryl unit is not selective. Thus, bromoarene 4 b was
synthesized in a similar fashion from 5 b; 5 b could be converted
into 5 d with bromine and without the addition of silver trifluoroacetate. Reaction of the hydrochloride of 5 a with
bromine in acetic acid led directly to bromide 5f in 97%
yield."
Intramolecular Pd-catalyzed allylic amination of
4 b afforded the spirocyclic compound 3 b in 85 YO yield
(Table 1).["] However, attempts to cyclize the less reactive bromoarene 3 b to 2 under normal Heck conditions were unsuccessful. Use of the palladacycle trans-di(p-acetato)bis[o-(di-otolylphosphanyl)benzyl]dipalladium(~~),~'~~
which we recently
used successfully in an efficient total synthesis of estr~nes,I'~'
allowed for the construction of the pentacyclic 2 in 80%
yield." Due to the steric interactions, the intermediate palladium-aryl compound formed during the oxidative addition attacks the double bond very selectively syn to the nitrogen substituent, and the subsequent reductive syn elimination of the
PdH species leads exclusively to 2. Thus, as expected, neither a
second diastereomer nor a double bond isomer were obtained.
The high yield in the Heck reaction with the relatively unreactive
bromoarene 3 is probably due to the fact that the low donor
ability of the methylenedioxy group has a positive effect. The
spectroscopic data of 2 (Table 1) agree with known values.r31
The synthesis of 2 by two consecutive Pd-catalyzed reactions
reported herein provides not only a short and highly efficient
route to cephalotaxine 1 and the derived structures, the harringtonines, but should also enable a wide variation in the ring
structure. Furthermore, by starting with both enantiomers of 6 ,
enantiomerically pure 1 and ent-1 should also be accessible.
Received: December 19, 1996 IZ9908IEI
German version: Angew. Chem. 1997, 109, 1159-1160
Keywords: alkaloids
tions . palladium
- allylations - benzazepines
Angeu. Cheni. Inr. Ed Engl. 1997, 36. No. 10
*
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Weinreb. M. F. Sernmelhack. Acc. Chrm. Res. 1975,8. 1 % : e) S. M. Weinreb.
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Kuehne, W. G. Bornmann, W. H. Parsons, T. D. Spitzer. J. F. Blount. J. Zubieta. J. Org. Chem. 1988, 53, 3439; j) H. Ishibashi, M. Okano. H Tamaki,
K. Maruyama, T. Yakura, M. Ikeda, J. Chem. Sue Chum. C'omrnun. 1990.1436;
k) T. P. Burkholder. P. L. Fuchs, J. Am. Chem. Soc. 1990. 112, 9601; I) M.
Ikeda, M. Okano, K. Kosaka, M. Kido, H. Ishihashi, Chenr Pharni. BuU. 1993,
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8 mol % [Pd(PPh,).J, 1.7 equiv NEt,, CH,CN, 50 'C, 10 h
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[15] rrons-Di(~-acetato)bis[o-(di-o-tolylphosphanyl)benzy~]dipail~diurn(~~)
(611101%). nBu,NOAc (2 Zequiv), DMF/CH,CN/H,O ( 5 , 5 , l ) , 4 h , 115°C.
$> VCH Verlug.~geselIsrhafrmbH, 0-69451 Weinheim, 1997
0570-0X33/97/3610-1125$17.50+ ,5010
1125
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two, efficiency, synthesis, palladium, cyclization, cephalotaxine, highly, catalyzed
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