Total synthesis of the coccinellid alkaloid (±)-adalinine utilizing a nitrenium ion cyclization

Article abstract of DOI:10.1055/s-2003-40322

The total synthesis of (±)-adalinine, a piperidine alkaloid from the European two-spotted ladybird Adalia bipunctata, is reported. Central to this undertaking are (i) the use of an N-alkoxy-N-acylnitrenium ion-induced spirocyclization to rapidly access th

Full text of DOI:10.1055/s-2003-40322

1352
LETTER
Total Synthesis of the Coccinellid Alkaloid (±)-Adalinine Utilizing a Nitrenium
Ion Cyclization
Total
S
ynthesis of
u
the Coccinel
n
lid Alkaloid
c
(
±
)-Adalini
a
ne n J. Wardrop,* Chad L. Landrie, José A. Ortíz
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, IL, 60607-7061 USA
Fax +1(312)9960431; E-mail: wardropd@uic.edu
Received 20 January 2003
yield.4 Furthermore, they can be generated under mild
Abstract: The total synthesis of (±)-adalinine, a piperidine alkaloid
from the European two-spotted ladybird Adalia bipunctata, is re-
ported. Central to this undertaking are (i) the use of an N-alkoxy-N-
acylnitrenium ion-induced spirocyclization to rapidly access the
6,6′-disubstituted piperidinone ring of the natural product and (ii)
exploitation of the cyclohexa-2,5-dienone system generated in this
process as a latent 1,6-ketoaldehyde.
conditions by the treatment of O-alkylhydroxamates 1
with iodine(III) reagents.2a,g
Having recently reported the first application of this reac-
tion to the synthesis of 1-azaspiro[4.5]decane-based natu-
ral products,5 we became attracted to the possibility that
cleavage of one, or more, of the C-C bonds in the cyclo-
hexa-2,5-dienone ring present in 3 would also provide an
expeditious means of accessing a range of α,α-disubsti-
tuted pyrolidinone and piperidinone derivatives 4, includ-
ing the natural product adalinine (5, Figure 1).
Key words: adalinine, piperidine alkaloid, nitrenium ions, dearom-
atization, polyvalent iodine
Nitrenium ions are highly reactive intermediates, which
contain a divalent, positively charged nitrogen atom. Al-
though historically the primary motivation for studying
nitrenium ions has been their proposed role in the carcino-
genesis initiated by nitro and amino-aromatic compounds,
they have also garnered attention from a synthetic stand-
point.1 Despite this interest however, the application of ni-
trenium ions to complex target-directed synthesis has
hitherto been limited,2 in part, by the harsh conditions of-
ten required for their generation and the complication of
multiple reaction pathways which can result in modest
yields.3 In this context, N-alkoxy-N-acylnitrenium ions of
general structure 2 (Scheme 1) are notable since they effi-
ciently undergo azaspirocyclization to form 1-azaspiro-
[4.5]decane and -[5.5]undecane systems 3 in excellent
H
N
O
O
N
H
O
5
6
Figure 1 Adalinine (5) and adaline (6): Coccinellid alkaloids isola-
ted from Adalia bipunctata.
The piperidine nucleus is a ubiquitous structural motif
present in a diverse range of naturally occurring alkaloids
and synthetic compounds, many of which are imbued with
important biological activities.6 Adalinine (5) is an alka-
loid which was isolated from the hindquarters of the Eu-
ropean two-spotted ladybird beetle, Adalia bipunctata, in
1996.7 Although the biological activity of 5 has not been
disclosed, biosynthetic studies have revealed that this pi-
peridinone derivative is a biogenetic precursor of the ho-
motropane alkaloid adaline (6),8 which, when excreted by
the ladybird beetle, acts as an antifeedant against insects
and invertebrate predators.9 The presence of an asymmet-
ric nitrogen-bearing quaternary stereocenter in 5 coupled
with the interest in the development of methods for the
formation of such moieties has precipitated considerable
synthetic interest in this natural product.10 Herein, we re-
port the total synthesis of 5 utilizing an N-acylnitrenium
ion spirocyclization.
PIFA
n
n
O
NH
OMe
O
N
OMe
OMe
OMe
2
1, n = 1,2
Dienone
Cleavage
n
n
R2
R1
O
N
O
N
O
H
OMe
4
3
As illustrated in Scheme 2, we envisioned that 5 would be
accessible through chemoselective homologation of 1,6-
ketoaldehyde 7 which in turn could be accessed from 8
through a sequence involving oxidative cleavage of the
C(8′)-C(9′) bond. This spirolactam could then be prepared
through cyclization of the nitrenium ion generated from
amide 9.
Scheme 1 Nitrenium ion spirocyclization-dienone cleavage:
A novel route to α,α-disubstituted N-heterocycles.
Synlett 2003, No. 9, Print: 11 07 2003.
Art Id.1437-2096,E;2003,0,09,1352,1354,ftx,en;S00503ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
Total Synthesis of the Coccinellid Alkaloid (±)-Adalinine
1353
O
O
b
2
O
N
O
R1
OR2
O
O
N
O
N
OMe
CHO
OMe
8
H
10 R1=OH, R2=Me
9 R1=NH(OMe), R2 = Me
11 R1=NH(OMe), R2 = H
a
7
Adalinine (5)
c, d
Dienone
Cleavage
8'
e, f
Dearomatization
O
N
2
O
N
8'
X
OMe
9'
OMe
O
N
O
NH
OMe
O
12 X=O
13 X=H,OH
OMe
OMe
9'
14
g, h
9
8
Scheme 2 Retrosynthetic analysis of adalinine.
O
O
i, j
O
N
O
N
Our synthetic route to adalinine (5) commenced from
known carboxylic acid 10,11 which was converted to the
corresponding mixed anhydride and coupled in situ with
O-methylhydroxylamine, to provide N-methoxyamide 9
in quantitative yield (Scheme 3). Upon treatment of a so-
lution of this compound in CH2Cl2 and MeOH with one
equivalent of phenyliodine(III) bis(trifluoroacetate) (PI-
FA), azaspirocyclization proceeded smoothly to afford di-
enone 8 in excellent yield after in situ hydrolysis of the
dimethyl acetal intermediate.5,12 Notably, this type of aza-
spirocyclization can be accomplished without recourse to
expensive non-nucleophilic solvents, such as trifluoroeth-
anol and hexafluoroisopropanol. In contrast, the oxidative
spirocyclization of phenolic substrates, such as amines
and carboxylic acids, often requires the use of such sol-
vents to prevent competitive intermolecular capture of the
arenium intermediate.13
H
OMe
(±)-Adalinine (5)
15
Scheme 3 Total synthesis of (±)-adalinine. Reagents and conditi-
ons: (a) i-BuOCOCl, Et3N, –20 °C to 0 °C; MeONH2⋅HCl, Et3N,
0 °C, 1 h (quant.); (b) 9, PIFA, CH2Cl2–MeOH (1:1), –78 °C to
15 °C, 1.5 h then H2O, 10 min (90%); (c) H2 (1 atm.), PtO2 (1%, w/
w), EtOAc, 24 h (70%); (d) NaBH4, MeOH, –30 °C to 0 °C (95%);
(e) CH3SO2Cl, Et3N, CH2Cl2, 30 min (90%); (f) 100 °C, DMSO, 24
h (64%); (g) O3/O2, CH2Cl2, –78 °C, 5 min; Me2S, r.t., 24 h (74%);
(h) CrCl2 (4.1 equiv), CH3CHI2 (1.1 equiv), DMF (1 equiv), THF,
r.t., 4 h (53%); (i) H2 (1 atm.), 10% Pd/C, EtOAc, r.t., 6 h (100%);
(j) Mo(CO)6, CH3CN–H2O (15:1), reflux, 30 h (98%).
a direct bearing on our synthesis, this material was carried
forward and converted to the corresponding mixture of
mesylate esters with MsCl and Et3N. Upon thermolysis
(100 °C) in a solution of DMSO, this mixture of com-
pounds underwent regioselective elimination to provide
trisubstituted olefin 14 together with a small amount of its
disubstituted regioisomer (ca. 10%). Ozonolytic cleavage
of 14, followed by reductive workup with Me2S provided
ketoaldehyde 7 (Scheme 2) as a single compound. The re-
maining carbon atoms present in the natural product were
then installed via chemoselective Takai ethylidenation us-
ing the gem-dichromium reagent generated by the reac-
tion of 1,1-diiodoethane with chromium(II) chloride.15
Pd-catalyzed hydrogenation of 15 now served to reduce
the C-6 pentenyl side chain, but failed to cleave the N-
methoxyl substituent. Selective reduction of the N-O bond
was, however, efficiently accomplished by heating the hy-
drogenation product with one equivalent of Mo(CO)6 in
aqueous acetonitrile.16 Although slow; this reaction pro-
ceeded smoothly to provide (±)-adalinine (5) in excellent
yield. The spectroscopic and physical data (1H NMR, 13C
NMR, MS) of this synthetic material were identical to
those previously reported.17
Having established the piperidinone ring and nitrogen-
bearing quaternary center, we now directed our attention
to converting 8 to advanced intermediate 7, by way of ole-
fin 14. Thus, atmospheric hydrogenation of 8 in the pres-
ence of Adams catalyst (PtO2) furnished cyclohexanone
12 as a chromatographically inseparable 4:1 mixture of C-
8′ epimers (1H NMR). Smaller quantities of phenol 11
(20%) and alcohol 13 (10%) were also isolated from this
reaction. While 11 presumably arises through reductive
rearomatization of spirodienone 8,14 compound 13 ap-
pears to be formed from reduction of 12. Hydrogenation
of 8 for extended periods led to an increase in the yield of
alcohol 13 with a concomitant drop in the yield of 12. Al-
though in the context of our planned route to 14, the direct
formation of 13 from 8 was fortuitous, efforts to optimize
this process failed to yield satisfactory results. Hydroge-
nation of the ketone proved to be impractically slow with
PtO2, while other heterogeneous catalysts, including Pd/
C, Pd(OH)2, and Raney nickel, favored the rearomatiza-
tion process. Accordingly, ketone 12 was simply reduced
with sodium borohydride in MeOH to provide 13 as a
complex mixture of diastereomers. Given that the stere-
ochemistry of the C-8′ and C-9′ stereocenters did not have
In summary, we report a total synthesis of the ladybird al-
kaloid adalinine (5), which proceeds in ten steps and with
a 13% overall yield. The central features of this work
Synlett 2003, No. 9, 1352–1354 ISSN 0936-5214 © Thieme Stuttgart · New York

1354
D. J. Wardrop et al.
LETTER
(10) Previous syntheses of 5: (a) Broeders, F.; Braekman, J. C.;
Daloze, D. Bull. Soc. Chim. Belg. 1997, 106, 377.
(b) Yamazaki, N.; Ito, T.; Kibayashi, C. Synlett 1999, 37.
(c) Yamazaki, N.; Ito, T.; Kibayashi, C. Tetrahedron Lett.
1999, 40, 739. (d) Honda, T.; Kimura, M. Org. Lett. 2000, 2,
3925.
(11) Compound 10 is readily available in two steps and in 78%
overall yield from 2-methylanisole: Zubaidha, P. K.;
Chavan, S. P.; Racherla, U. S.; Ayyangar, N. R. Tetrahedron
1991, 47, 5759.
include i) construction the 6,6′-disubstituted piperidinone
ring using an N-alkoxy-N-acylnitrenium ion-induced spi-
rocyclization and ii) exploitation of the cyclohexa-2,5-di-
enone generated in this transformation as a latent 1,6-
dicarbonyl. Further application of the nitrenium ion spiro-
cyclization-dienone cleavage strategy outlined herein is
now underway in this laboratory. Our progress will be re-
ported in due course.
(12) Experimental Procedure for Preparation of Dienone 8:
To a suspension of phenyliodine(III) bis(trifluoroacetate)
(PIFA) (2.290 g, 5.16 mmol) in MeOH (10 mL), at –78 °C,
was added a cold (–78 °C) solution of N-methoxyamide 9
(1.020 g, 4.30 mmol) in CH2Cl2 (10 mL) via cannula. The
reaction mixture was then allowed to warm to 15 °C (internal
temperature) over 1.5 h whereupon H2O (10 mL) was added
and the cooling bath removed. After stirring for 10 min, the
organic and aqueous phases were separated and the aqueous
phase was extracted with CH2Cl2 (3 × 20 mL). The
combined organic extracts were dried (Na2SO4), filtered, and
concentrated under reduced pressure and the residue purified
by flash chromatography over silica gel (EtOAc/hexanes,
1:1) to provide 8 (855 mg, 90%) as a colorless oil.
Recrystallization from EtOAc/hexanes yielded 8 as white
crystals: Mp 97–99 °C. Rf = 0.35 (EtOAc). FT-IR(film):
Acknowledgment
We thank the University of Illinois at Chicago, the National Institu-
tes of Health (GM59157), and the National Science Foundation
(HRD0000341) for financial support. J.A.O. thanks the UIC Sum-
mer Research Opportunities Program (SROP) for financial support.
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Synlett 2003, No. 9, 1352–1354 ISSN 0936-5214 © Thieme Stuttgart · New York