Synthesis of Substituted Quinolizidines via a Gold-Catalyzed Double Cyclization Cascade

Article abstract of DOI:10.1002/adsc.201500907

A novel synthesis of quinolizidines by a cationic gold-catalyzed double cyclization cascade has been developed. The reaction was initiated by the gold-catalyzed 6-exo-dig cyclization of ynamides, which was followed by a second cyclization of an enamide intermediate to provide the corresponding quinolizidine derivatives. The utility of this reaction was demonstrated by application to the synthesis of multi-substituted quinolizidines and by the total synthesis of a quinolizidine alkaloid, (±)-lupinine.

Full text of DOI:10.1002/adsc.201500907

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DOI: 10.1002/adsc.201500907
Very Important Publication
Synthesis of Substituted Quinolizidines via a Gold-Catalyzed
Double Cyclization Cascade
Shiori Nonaka,a Kenji Sugimoto,a Hirofumi Ueda,a and Hidetoshi Tokuyamaa,*
a
Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba 6-3, Aramaki, Aoba-ku, Sendai 980-8578, Japan
Fax: (+81)-22-795-6877; e-mail: tokuyama@mail.pharm.tohoku.ac.jp
Received: September 29, 2015; Revised: December 9, 2015; Published online: January 22, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500907.
Abstract: A novel synthesis of quinolizidines by
a cationic gold-catalyzed double cyclization cascade
has been developed. The reaction was initiated by
the gold-catalyzed 6-exo-dig cyclization of yn-
amides, which was followed by a second cyclization
of an enamide intermediate to provide the corre-
sponding quinolizidine derivatives. The utility of
this reaction was demonstrated by application to
the synthesis of multi-substituted quinolizidines and
by the total synthesis of a quinolizidine alkaloid,
(Æ)-lupinine.
trol and/or regiocontrol for introducing the requisite
functionalities at the desired positions, which is not
always a straightforward task.
During the course of our continuing studies on the
synthesis of monoterpene indole alkaloids,[3] we re-
cently established a highly efficient synthesis of sub-
stituted indolizidines via a gold-catalyzed double cy-
clization cascade[3c] (Scheme 1). One of the advantag-
es of this cascade reaction is the facile preparation of
completely functionalized acyclic substrates with the
required substituents by assembling three components
in modular fashion, which results in multi-substituted
indolizidines after a simple one-pot operation. The
utility of this reaction was demonstrated by our total
Keywords: alkaloids; cyclization; domino reaction;
gold; quinolizidines
Numerous alkaloids containing a quinolizidine (octa-
hydro-2H-quinolizine, norlupinane) core (Figure 1),
including cytosine and sparteine, have been found in
Nature.[1] Because members of this class of natural
products often possess diverse and important biologi-
cal activities, these compounds have attracted broad
interest from the synthesis community and have pro-
vided an attractive platform to demonstrate the utility
of novel synthetic methodologies and tactics. One of
the conventional strategies to prepare this nitrogen-
containing bicyclic heterocycle is fusion of the second
ring on a piperidine ring with installation of peripher-
al substituents or conversion of pyridine derivatives
to bicyclic compounds, and subsequent hydrogenation
of the pyridine ring.[2] These stepwise strategies gener-
ally require lengthy sequences and careful stereocon-
Scheme 1. Construction of the indolizidine skeleton via
a gold-catalyzed double cyclization cascade.
Figure 1. Structure of quinolizidine.
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Synthesis of Substituted Quinolizidines
Table 1. Optimization of the reaction conditions.
Scheme 2. Working hypothesis for quinolizidine synthesis.
synthesis of (À)-rhazinilam and the first asymmetric
total synthesis of (À)-rhazinicine.[3c]
We envisaged that the reaction of a substrate de-
rived from aminopropionaldehyde dimethyl acetal in-
stead of amino acetaldehyde dimethyl acetal should
furnish a quinolizidine derivative (Scheme 2). Thus,
we anticipated that substrate 1 should undergo an in-
tramolecular nucleophilic addition of nitrogen to the
alkyne activated by the gold catalyst in a 6-exo-dig
fashion. Then, a second cyclization of enamide inter-
mediate 3 to the oxonium ion should provide the bi-
cyclic intermediate 5. Finally, the stepwise elimination
of methanol would lead to quinolizidine 6 or its tauto-
mer. Here we describe the development, scope, and
application of the novel construction of a quinolizidine
skeleton via a gold-catalyzed double cyclization cas-
cade.
[a]
Au(PPh3)NTf2 was prepared by premixing Ph3PAuCl
with AgNTf2.
This reaction was conducted at 1008C.
We tested our working hypothesis by treating the
model ynamide substrate 1a with various gold cata-
lysts[4,5] (Table 1). Initial trials using AuCl, AuCl3, and
Ph3PAuCl in 1,4-dioxane at 808C did not give any bi-
cyclic product (Table 1, entries 1–3). When we heated
[b]
[8]
substrate 1a in the presence of a combination of Au(PPh3)NTf2 was more effective and the yield of
Ph3PAuCl and AgOTf, a cascade cyclization proceed- 7a was substantially improved to 41% (Table 1,
ed to give a quinolizidine product in low yield entry 7). We also observed that the choice of appro-
(Table 1, entry 2). Surprisingly, the structural determi- priate phosphine ligands was important for achieving
nation of this product revealed that it was not the ex- a high-yielding reaction. Thus, a gold catalyst with tri-
pected 6a but a tautomer 7a. This result indicates that arylphosphine bearing an electron-donating group (B)
7a is thermodynamically more stable than 6a, which is gave a better result (Table 1, entry 9). Moreover,
also supported by preliminary theoretical calcula- bulky dialkylphosphine ligands[9] possessing a biphenyl
tions.[6] Next, we continued our exploration of the op- moiety such as C or D improved the yield of 7a
timal catalyst. A slight improvement of the yield was (Table 1, entries 10 and 11). Interestingly, dramatic ac-
observed when a combination of Ph3PAuCl and celeration of the reaction rate was observed when the
AgNTf2 was used. An N-heterocyclic carbene gold gold catalyst E was used (Table 1, entry 12). Finally,
catalyst IPrAuCl[7] and AgNTf2 did not give the prod- we established the optimal conditions using a smaller
uct (Table 1, entry 6). Furthermore, the preformed amount of gold catalyst E (2.5 mol%) with heating at
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Shiori Nonaka et al.
Table 2. Substrate scope of acetylene moiety.
cyclization products in moderate to high yields
(Table 2, entries 2–7).[10] Substrates with an ortho-
methyl (1i) or ortho-bromophenyl group (1j) also
gave the desired products in modest yields (Table 2,
entries 8 and 9). In the case of an enyne derivative
(1k) and enyne derivatives with an aromatic group at
their end (1n and o), chloride-bridged dinuclear gold
catalyst F[11] proved to be a particularly suitable cata-
lyst. Thus, treatment of enynes with 2.5 mol% of F at
1208C under microwave irradiation gave the corre-
sponding products in good yields (Table 2, entries 10–
14).
To expand the scope of the established double cy-
clization cascade to multiple functionalized quinolizi-
dines, linear ynamide substrates with a different sub-
stitution pattern were prepared from the correspond-
ing b-amino acids and subsequently subjected to the
gold-catalysis reaction conditions (Scheme 3). Al-
though ynamide 8 required a higher catalyst loading
(10 mol%) and reaction temperature (1108C in
xylene), the expected 6,9-substituted quinolizidine 11
was obtained in good yield. Furthermore, ynamides 9
and 10 furnished the corresponding 7,9- and 8,9-sub-
stituted quinolizidines, respectively, in good yields.
The utility of the newly developed synthesis of sub-
stituted quinolizidine through the double cyclization
cascade was completely demonstrated by its applica-
tion to the total synthesis of the quinolizidine alka-
loid, lupinine (14). Lupinine alkaloids isolated from
Lupines luteus encompass structural diversity; they
are composed of bicyclic lupinine-type, tricyclic cyti-
sine-type, tetracyclic matrine-type, and sparteine-type
[a]
The reaction was performed with substrate, F (2.5 mol%)
in xylene/CH2Cl2 (0.25M) at 1208C under microwave ir-
radiation.
1008C, which provided 7a in 85% yield (Table 1,
entry 13).
Having established the optimal conditions, we then
focused on the substrate scope (Table 2). Ynamides
having phenyl (1b) and various substituted phenyl
groups with a methyl, methoxy, carbamate, bromo,
iodo, or methoxycarbonyl groups at their para posi-
tions (1c–1h) uneventfully gave the corresponding Scheme 3. Syntheses of diverse substituted quinolizidines.
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Synthesis of Substituted Quinolizidines
19[15] to ynecarboxylic acid 18 was followed by con-
densation with aminopropionaldehyde dimethyl
acetal 17 to provide 16, the substrate for the key
double cyclization (Scheme 5). Unexpectedly, treat-
ment of 16 under the established optimal conditions
did not give the desired quinolizidine product. After
extensive optimization of the reaction conditions, we
deduced that using the dimeric gold catalyst F at
1008C under microwave irradiation was essential to
promote the initial cyclization to generate a monocy-
clic enamide intermediate; we subsequently observed
that the addition of PPTS to this intermediate induces
a second cyclization in one pot to form the desired bi-
cyclic product. To our surprise, the structure of the bi-
cyclic product 20 differed from that obtained in the
case of a substrate bearing an aryl group. In this case,
a conjugated enamide with an ester should clearly be
more stable than the simple enamide form. Finally,
because of its instability, the resultant product 20 was
directly subjected to hydrogenation. Further hydroge-
Scheme 4. Retrosynthetic analysis of lupinine.
alkaloids.[12] In addition to being diverse, these alka- nation of the resulting enamide 21 followed by reduc-
loids possess a wide range of biological activities, in- tion of the ester moiety with LAH completed the
cluding antimicrobial and k-opioid receptor-mediated total synthesis of lupinine (14). All properties of syn-
antinociceptive effects. Thus, these quinolizidine alka- thesized 14 were identical to published data.[14]
loids have attracted the attention of synthetic and bio-
In summary, we have developed a highly efficient
logical chemists.[13] Among these alkaloids, lupinine synthesis of substituted quinolizidines via a gold-cata-
(14) bearing a fundamental quinolizidine skeleton, lyzed double cyclization cascade. The advantage of
provides an opportunity to demonstrate synthetic this reaction is that multi-substituted quinolizidine de-
strategies, and numerous reactions and total syntheses rivatives could be synthesized in a one-pot reaction
involving 14 have been reported to date.[14] Our retro- from readily assembled acyclic substrates. The peri-
synthetic analysis of 14 is shown in Scheme 4. We en- pheral functionality was easily introduced before cyc-
visaged that a quinolizidine ring system was readily lization in a modular fashion by switching three seg-
constructed via a gold-catalyzed double cyclization ments. In addition, we demonstrated the utility of this
cascade using an acyclic ynamide possessing an ester methodology by achieving the total synthesis of the
functionality at the terminus followed by subsequent quinolizidine alkaloid, lupinine.
reduction.
The synthesis of lupinine commenced with prepara-
tion of ynamide 16. Stepwise oxidation of alcohol
Scheme 5. Total synthesis of lupinine.
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Shiori Nonaka et al.
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Experimental Section
General Procedure for Synthesis of Quinolizinone
A 10-mL threaded Pyrex test tube equipped with a magnetic
stirring bar, a rubber septum, and argon inlet needle was
charged with ynamide 1a (33.0 mg, 0.10 mmol) in 1,4-diox-
ane (1.0 mL, 0.10m). To the solution was added gold catalyst
E (1.9 mg, 2.5 mmol) at room temperature. Then, the test
tube was sealed under argon with a threaded Teflon screw
cap. After stirring at 1008C for 75 min, the reaction was
quenched with saturated aqueous NaHCO3, and the result-
ing mixture was extracted with CH2Cl2 three times. The
combined organic extracts were washed with brine, dried
over Na2SO4, filtered, and concentrated under reduced pres-
sure. The residue was purified by preparative TLC on silica
gel (hexanes/ethyl acetate, 40:60) to afford the correspond-
ing quinolizinone 7a in 85% yield.
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Acknowledgements
This work was financially supported by the Cabinet Office,
Government of Japan through its “Funding Program for
Next Generation World-Leading Researchers” (LS008),
a Grant-in-aid for Scientific Research (A) (26253001) and
Young Scientists (B) (26860004 and 21790004), and JSPS,
Japan.
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