Total synthesis of the antipode of alkaloid 205 B

Article abstract of DOI:10.1002/anie.200351906

Forming the tetrasubstituted piperidine ring with stereocontrol in a Michael-type conjugate addition is a key step in the first enantioselective synthesis of the antipode 1 of alkaloid 205 B. The absolute stereo-chemistry of the natural product could be d

Full text of DOI:10.1002/anie.200351906

Communications
Figure 1. Original (1) and revised (2) structures of alkaloid 205B, and
the structure of its antipode, 3.
asymmetric centers in its compact, fourteen-carbon-atom
frame; however, no synthesis of this unique alkaloid has been
reported, and its absolute stereochemistry is still unknown.
As part of a program directed at studying the synthesis of
biologically active alkaloids,[5] we report here the first total
synthesis of 3 (see Figure 1), the antipode of natural 205B,
and the determination of the absolute stereochemistry of
natural 205B.
The synthesis began with enaminoester 4,[6] which was
treated with lithium dimethylcuprate to give adduct 5 as a
single isomer (Scheme 1).[7] The oxazolizinone ring was
constructed in a two-step sequence to provide 6, which was
transformed into the desired cyclic carbamate 8 via ester 7 by
using the protocol developed by Matsumura et al.[8]
Alkaloid Total Synthesis
Total Synthesis of the Antipode of
Alkaloid 205B**
Naoki Toyooka,* Ayako Fukutome, Hiroyuki Shinoda,
and Hideo Nemoto*
A remarkably diverse array of biologically active alkaloids,
for example, blockers of neuromuscular-type, ganglionic-type,
and nicotinic receptor channels, occurs in amphibian skin, and
over 500 alkaloids have been isolated to date.[1] The structural
diversity and pharmacological activity associated with these
alkaloids have stimulated research in numerous synthetic
groups.[2] Alkaloid 205B, one of the compounds isolated from
skin extracts of the Panamanian frog Dendrobates pumilio,
possesses an unusual and unique 8b-azaacenaphthylene ring
system (Figure 1). The structure of alkaloid 205B was first
reported to be 1,[3] and recently revised to be 2 based upon
FTIR, NMR, and MS data.[4] This alkaloid contains five
Scheme 1. Synthesis of enaminoester 8. Reagents and conditions:
a) (Me)2CuLi, Et2O, À78 to À308C (98%); b) Lithium triethylborohy-
dride, THF, 08C (92%); c) NaH, THF, 08C (99%); d) TBAF, THF,
08C–RT (99%); e) 1. Swern oxidation, À788C to 08C, 2. NaClO2,
NaH2PO4, tBuOH/H2O, 3. CH2N2, EtOAc (86% over 3 steps);
f) LiHMDS, PhSSPh, THF, À78–08C (99%); g) mCPBA, 2,6-lutidine,
CH2Cl2, RT (85%). LiHMDS=lithium bis(trimethylsilyl)amide,
mCPBA=meta-chloroperbenzoic acid, RT=room temperature,
TBAF=tetrabutylammonium fluoride, X=tert-butyldiphenylsilyl.
The second and key Michael reaction of 8 with in situ
generated lithium dimethylcuprate proceeded smoothly to
afford adduct 9, again as a single isomer (Scheme 2). The
stereochemistry of 9 was confirmed by the NOE interactions
indicated. The observed stereoselectivity of the Michael
reaction of 8 can be explained by the stereoelectronic
effect[9] illustrated in Figure 2.
[*] Dr. N. Toyooka, Prof. Dr. H. Nemoto, A. Fukutome, Dr. H. Shinoda
Faculty of Pharmaceutical Sciences
Toyama Medical and Pharmaceutical University
Sugitani 2630, Toyama 930-0194 (Japan)
Fax:( +81)76-434-4656
An Arndt–Eistert sequence was used for carbon-chain
extension of 9 to give the homologated ester 10, which was
transformed into ketone 11 by reaction with Weinreb's amide
(Scheme 3).[10] Acid-catalyzed protection of the carbonyl
group in 11 with ethylene glycol followed by hydrolysis of
the oxazolidinone ring with base and protection of the
E-mail:toyooka@ms.toyama-mpu.ac.jp
nemotoh@ms.toyama-mpu.ac.jp
[**] We thank Professors Shigetoshi Kadota and Yasuhiro Tezuka for
recording the NOE spectra of 14.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200351906
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Angewandte
Chemie
tricyclic compound 14 in 62% overall yield along with
acetal 15 (15%), which was transformed into 14 by treatment
with acid.
The stereochemistry at the newly formed position in 14
was confirmed by the NOE (2%) between H2a and H5a, and
the stereoselectivity of the acid-catalyzed intramolecular
Mannich-type cyclization is rationalized as depicted in
Figure 3.
Scheme 2. Synthesis of tetrasubstituted piperidine 9.
Figure 3. Stereochemical course of intramolecular Mannich-type cycli-
zation reaction of 13 and the stereochemistry of 14.
Figure 2. Stereochemical course of the Michael reaction of the enami-
noester 8.
With the requisite tricyclic core 14 in hand, we next
focused our attention on the final step for the completion of
total synthesis of alkaloid 205B. First we examined the
formation of the alkene unit by using triflate 16. Thus
treatment of 14 with chiral lithium amide base followed by
Comins's triflating agent[11] provided triflate 16 in 54% yield
(Scheme 4). The structure of 16 was confirmed by the H,H
COSYexperiment and the coupling constant between H2a and
Scheme 4. Attempted synthesis of 3 via triflate 16. Reagents and con-
ditions:a) 1. R-(R*,R*)-(+)-bis(a-methylbenzyl)amine, nBuLi, THF ,
2. [N,N-bis(trifluoromethylsulfonyl)amino]-5-chloropyridine (Comins's
reagent), À78 to À408C (54%); b) [Pd(Ph3P)4], Me3Al, ClCH2CH2Cl,
708C; c) (Me)2CuLi, THF, 08C.
Scheme 3. Synthesis of compound 14 with the tricyclic core. Reagents
H3. The cross-coupling reaction of 16 with trimethylalumi-
nium in the presence of catalytic amounts of [Pd(Ph3P)4][12]
afforded a complex mixture and no desired compound was
isolated. The coupling reaction with lithium dimethylcup-
rate[13] resulted in the complete recovery of starting material.
Thus, we were forced to introduce the C–C double bond
by using the exo-alkene 17. Wittig reaction of 14 afforded 17
in good yield (Scheme 5). Brief calculations (B3LYP method
in Gaussian98, 6-31 + G** basis set) revealed that the desired
isomer 3 is lower in energy than the other isomer 18.[14] Thus,
the acid-catalyzed isomerization of 17 provided the isomeric
products in a ratio of 6.5:1 (from crude NMR), and the major
isomer 3 was isolated in 63% yield. The spectroscopic data
(1H and 13C NMR, IR, MS) of 3 ([a]2D6 = + 8.1) were identical
with those of the natural product ([a]D = À8.5), and the
absolute stereochemistry was determined unambiguously to
be 2aR,5aR,6S,8S,8aR by comparison of the optical rota-
tions.
and conditions:a) 1. LiOH, MeOH/H O, reflux, 2. ClCO2Et, Et3N, THF,
2
08C, 3. CH2N2, Et2O, 4. PhCO2Ag, Et3N, MeOH, RT (71% over 4
steps); b) 1. LiOH, MeOH/H2O, reflux, 2. 1,1’-carbonyldiimidazole,
THF, RT, 3. Et3N, (MeO)MeNH·HCl, THF, RT (98% over 2 steps);
c) MeMgBr, THF, 08C to RT (73%); d) ethylene glycol, pTsOH, ben-
zene, reflux (86%); e) 1. 2m KOH in iPrOH, 1208C in a sealed tube,
2. Boc2O, NaOH, dioxane/H2O (74% over 2 steps); f) Swern oxida-
tion, À788C to 08C; g) (EtO)2P(O)CH2CO2Et, NaH, THF (74% over
2 steps); h) 1. 10% Pd/C, H2, EtOAc, 2. DIBAL, CH2Cl2, À788C;
i) pTsOH, benzene/acetone, reflux (14; 62%, 15; 15% over 3 steps);
j) pTsOH, acetone, reflux (80%). Boc=tert-butoxycarbonyl, DIBAL=
diisobutylaluminum hydride, pTsOH=para-toluenesulfonic acid.
resulting amine with Boc2O provided alcohol 12 in 74%
overall yield. Swern oxidation of 12 and Wittig–Horner
reaction of the resulting aldehyde afforded the a,b-unsatu-
rated ester 13. Hydrogenation of 13 and reduction of the
resulting ester with DIBAL followed by treatment with
pTsOH in refluxing benzene/acetone provided the key
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Communications
[9] R. W. Hoffmann, Chem. Rev. 1989, 89, 1841 – 1873.
[10] S. Nahm, S. M. Weinreb, Tetrahedron Lett. 1981, 22, 3815 – 3818.
[11] D. L. Comins, A. Dehghani, Tetrahedron Lett. 1992, 33, 6299 –
6302.
[12] K. Takai, M. Sato, K. Oshima, H. Nozaki, Bull. Chem. Soc. Jpn.
1984, 57, 108 – 115.
[13] J. E. McMurry, W. J. Scott, Tetrahedron Lett. 1980, 21, 4313 –
4316.
Scheme 5. Completion of the total synthesis of 3. Reagents and condi-
tions:a) MeP +Ph3IÀ, nBuLi, THF, 08C to RT (84%); b) pTsOH, ben-
[14] Calculations were performed by using the B3LYP method in
Gaussian98 with the 6-31 + G** basis set. The desired isomer 3 is
zene, reflux (63%).
more stable than isomer 18 by 2.01 kcalmolÀ1
.
In summary, we have demonstrated the first enantiose-
lective total synthesis of the antipode 3 of the structurally
unique alkaloid 205B. The key step in this synthesis is the
stereocontrolled Micheal-type conjugate addition reaction of
the enaminoester 8 to form the 2,3,5,6-tetrasubstituted
piperidine ring system in 9. Furthermore, we determined
the absolute stereochemistry of the natural product to be
2aR,5aR,6S,8S,8aR.
Received: May 15, 2003 [Z51906]
Keywords: alkaloids · Michael addition · natural products ·
.
nitrogen heterocycles · stereoelectronic effects
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