Facile total synthesis of (±)-adalinine

Article abstract of DOI:10.1055/s-1999-2561

A useful construction of 6,6-disubstituted 2-piperidones has been developed based on allylation of the cyclic N-acyl-N,O-acetals using a combination of Lewis acid and allyltrimethylsilane, leading to the facile total synthesis of a new ladybird alkaloid a

Full text of DOI:10.1055/s-1999-2561

LETTER
37
Facile Total Synthesis of (±)-Adalinine
Naoki Yamazaki, Toshimasa Ito, and Chihiro Kibayashi*
School of Pharmacy, Tokyo University of Pharmacy & Life Science, Horinouchi, Hachioji, Tokyo 192-0392, Japan
Fax +81(426)76-4475; E-mail: kibayasi@ps.toyaku.ac.jp
Revised 14 October 1998
We envisioned the use of the cyclic N,O-acetal-based
methodology involving the creation of a nitrogenated qua-
ternary center6 for the synthesis of (±)-4. The protocol for
the adalinine synthesis illustrated in Scheme 2 was based
on the construction of the nitrogenated quaternary center
via addition of a carbon nucleophile to the cyclic N-
acyliminium intermediate 7, followed by cleavage of the
N-substituent of 8 to give 9. In this paper, we report details
of this sequence and provide an application of the process
to the synthesis of adalinine (4).
Abstract: A useful construction of 6,6-disubstituted 2-piperidones
has been developed based on allylation of the cyclic N-acyl-N,O-ac-
etals using a combination of Lewis acid and allyltrimethylsilane,
leading to the facile total synthesis of a new ladybird alkaloid adali-
nine in racemic form.
Key words: adalinine, piperidine alkaloid, cyclic N,O-acetals,
Lewis acid induced allylation, nitrogenated quaternary center
We have recently recognized that Lewis acid treatment of
the cyclic N,O-acetal 1 resulted in breaking of the C–O
bond to generate a bridgehead iminium ion 2, that served
to effect construction of a quaternary center at the a posi-
tion of the piperidine system to give 3 via subsequent
treatment with organometallics (Scheme 1).1
R
LA
R'M
+
O
N
O
O
N
R
O
LA–
6
7
R'
R
LA
RM
C–N bond cleavage
+
N
R'
R
O
N
N
R
N
O
O
N
H
9
O
LA–
OH
OH
3
1
8
2
Scheme 2
Scheme 1
A series of the cyclic N-acyl-N,O-acetals 12a–d were pre-
pared according to the reported procedure7 by dehydro-
condensation of the hydroxy amines 10, i.e., 2-
aminopropanol, 2-(aminomethyl)benzyl alcohol, 2-ami-
nophenol, and 2-hydroxybenzylamine, respectively, with
5-oxodecanoic acid (11)8 in benzene at reflux (for yields
of 12a–d, see Table 1).
In the course of this study, we were intrigued by the struc-
ture of a new piperidine alkaloid2 with a quaternary center
at the a position of the piperidine system, i.e., adalinine
(4),3 which has been isolated as a minor alkaloid from the
European ladybird beetles Adalia bipunctata and A. de-
cempunctata and suggested to be biosynthetically related
to adaline (5), the major defensive alkaloid from the
European ladybirds.4 The synthesis of (±)-4 has been re-
ported by Braekman et al.5 recently starting from cyclo-
pentanone in five steps and 4.4% overall yield.
We initially attempted to carry out nucleophilic allylation
with 12a based on our previously developed procedure9
with a combination of Et2AlCl (2 equiv) and allylmagne-
sium bromide (2 equiv) in THF at room temperature;
however, this reaction gave a complex mixture of prod-
ucts. The complexity in the reaction could be understood
by the possibility that nucleophiles were both accepted at
the iminium ion center and the carbonyl carbon of the
amide moiety.
N
H
O
N
H
To avoid this, we decided to utilize nucleophilic alkenes
which have been proven particularly useful for addition to
N-acyliminium ions because of the greater electrophilicity
of the N-acyliminium ion as compared with an ordinary
iminium ion.10 Thus, Lewis acid induced reaction of the
series of the cyclic N-acyl-N,O-acetals 12a–d using allyl-
trimethylsilane was next investigated. The results are
O
O
adalinine (4)
adaline (5)
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38
N. Yamazaki et al.
LETTER
summarized in Table 1. When 12a was treated with the al- to 72% and 70%, respectively (entries 6, 7). When the
lylsilane (3 equiv) in the presence of TiCl4 or HfCl4 (3 TiCl4-induced allylation was carried out using 12d with
equiv) at room temperature, the allylation reaction oc- the phenoxy moiety, it successfully gave the allylated
curred with rapid consumption of the substrate to afford product 13d in high yield (92%), although prolonged re-
the allylated product 13a in 46% or 30% yield, respective- action time (96 h) was needed (entry 8). In this case, the
ly (entries 1, 2). Application of the same conditions to Lewis acids HfCl4 and ZrCl4, however, did not work well
12b, however, led to the formation of an intractable com- with 12d and produced mostly recovered starting material
plex mixture with no detection of the desired 2-allylated with very low yield (1–2%) of 13d. Higher temperatures
piperidone (13b) (entries 3, 4). The TiCl4-induced allyla- and extended reaction times caused the destruction of the
tion using 12c involving the phenoxy moiety instead of substrate.
the alkoxy moiety as in 12a and 12b resulted in the forma-
tion of the allylated product 13c in low yield (26%), ac-
companied by a complex mixture of products (entry 5). In
this reaction, change of the Lewis acid from TiCl4 to
Having established that the Lewis acid induced allylation
at the C-6 position in the 6-pentyl-2-piperidone occurred
with the use of 12c and 12d with the phenoxy moieties,
the remaining transformation necessary for obtaining ad-
HfCl4 and ZrCl4 remarkably increased the yields of 13c up
alinine was construction of the 2-oxopropyl moiety at the
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LETTER
Facile Total Synthesis of (±)-Adalinine
39
C-6 position and cleavage of the N-substituent group. To
this end, Wacker oxidation was performed with 13c; how-
ever, the formation of the desired oxo compound 14
(35%) was accompanied by the formation of the cycliza-
tion product 15 (33%). The formation of 15 was under-
stood by internal attack of phenolic OH group to the
intermediacy of the p-allylpalladium species instead of
H2O as in a usual Wacker process. Thus, to prevent the
formation of 15, 13c was converted to the methyl ether 16
(MeI, K2CO3, 99% yield), which was subjected to Wacker
oxidation to afford the oxo compound 17 in 74% yield.11
Oxidative cleavage of the N-(o-methoxyphenyl) group
was performed using ceric ammonium nitrate (CAN)12 to
provide (±)-adalinine (4) in 62% yield (Scheme 3). The
spectral data (1H and 13C NMR, MS) of synthetic material
were identical to those reported3 for the natural product.
Scheme 4
TPAP (tetrapropylammonium perruthenate) oxidation14
to furnish (±)-4 in quantitative yield (Scheme 4).
In conclusion, we have developed a useful approach for
the elaboration of the nitrogenated quaternary center
based on Lewis acid induced allylation of the cyclic N-
acyl-N,O-acetals to afford the 6,6-disubstituted 2-piperi-
dones 13c and 13d, which allowed facile two entries to
(±)-adalinine (4) via oxidative de-N-arylation and reduc-
tive de-N-benzylation in 32% (5 steps) and 33% (6 steps)
overall yields, respectively, from the known d-keto acid
11.
References and Notes
(1) Yamazaki, N.; Suzuki, H.; Kibayashi, C. J. Org. Chem. 1997,
62, 8280.
(2) For a review of the piperidine alkaloids, see: (a) Fodor, G. B.;
Colasanti, B. In Alkaloids: Chemical and Biological Perspec-
tive, Vol. 3; Pelletier, S. W., Ed.; Wiley: New York, 1985; Ch.
1, pp. 1–90. (b) Schneider, M. J. In Alkaloids: Chemical and
Biological Perspective, Vol. 10; Pelletier, S. W., Ed.; Elsevier
Science: Oxford, 1996; Ch. 2, pp. 155–299.
(3) Lognay, G.; Hemptinne, J. L.; Chan, F. Y.; Gaspar, CH.; Mar-
lier, M.; Braekman, J. C.; Daloze, D.; Pasteels, J. M. J. Nat.
Prod. 1996, 59, 510.
Scheme 3
(4) For a recent review of the coccinellid alkaloids, see: King, A.
G.; Meinwald, J. Chem. Rev. 1996, 96, 1105.
(5) Broeders, F.; Braekman, J. C.; Daloze, D. Bull. Soc. Chim.
Belg. 1997, 106, 377.
(6) For the enantioselective construction of a quaternary center at
the a position of the pyrrolidine system by Lewis acid–allyl-
silane alkylation of cyclic N-acyl-N,O-acetals, see: Burgess,
L. E.; Meyers, A. I. J. Am. Chem. Soc. 1991, 113, 9858.
(7) Burgess, L. E.; Meyers, A. I. J. Org. Chem. 1992, 57, 1656.
(8) (a) Jpn. Kokai Tokkyo Koho JP 81,161,348; Chem. Abst.
1982, 96, 142275z. (b) Fréville, S.; Célérier, J. P.; Thuy, V.
M.; Lhommet, G. Tetrahedron: Asymmetry 1995, 6, 2651.
Similarly, allylated compound 13d was converted to the
oxo compound 19 in 73% yield via O-methylation (to
form 18) followed by Wacker oxidation. Subsequent re-
moval of the N-(o-methoxybenzyl) group from the mole-
cule was first attempted according to the previously
described method13 for oxidative removal of the N-(p-
methoxybenzyl) group with CAN; however, it led to a
complex mixture of products. Thus, reductive cleavage of
the N-benzyl moiety was conducted under the Birch con-
ditions to give a 1:1 mixture of the diastereomeric alco-
hols 20 (60% yield), which without separation underwent
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N. Yamazaki et al.
LETTER
(9) (a) Yamazaki, N.; Suzuki, H.; Aoyagi, S.; Kibayashi, C. Te-
trahedron Lett. 1996, 37, 6161. (b) Yamazaki, N.; Kibayashi,
C. Tetrahedron Lett. 1997, 38, 4623.
(10) Hiemstra, H.; Speckamp, W. N. In Comprehensive Organic
Synthesis, Vol. 2; Heathcock, C. H., Ed.; Pergamon Press: Ox-
ford, 1991; Ch. 4.5, pp. 1047–1082.
silica gel chromatography and assigned their relative stereo-
chemistry as shown based on NOESY data. In this work, this
mixture was used without separation in the next reaction.
(12) Kronenthal, D. R.; Han, C. Y.; Taylor, M. K. J. Org. Chem.
1982, 47, 2765.
(13) Yoshimura, J.; Yamaura, M.; Suzuki, T.; Hashimoto, H.
Chem. Lett. 1983, 1001.
(14) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthe-
sis 1994, 639.
(11) The oxo compound 17 was actually isolated as a 1:1 mixture
of two atropisomers i and ii, which were easily separated by
Synlett 1999, No. 1, 37–40 ISSN 0936-5214 © Thieme Stuttgart · New York