Catalytic Dearomatization Approach to Quinolizidine Alkaloids: Five Step Total Synthesis of (±)-Lasubine II

Article abstract of DOI:10.1021/acs.orglett.6b03017

A series of high-yielding silver(I)-catalyzed cyclization reactions of pyridine-, isoquinoline-, and pyrazine-ynones are described. The operationally simple and mild reaction conditions are a significant improvement over previously reported thermal cycliz

Full text of DOI:10.1021/acs.orglett.6b03017

Letter
pubs.acs.org/OrgLett
Catalytic Dearomatization Approach to Quinolizidine Alkaloids:
Five Step Total Synthesis of ( )-Lasubine II
Michael J. James, Niall D. Grant, Peter O’Brien, Richard J. K. Taylor,* and William P. Unsworth*
Department of Chemistry, University of York, Heslington, York, YO10 5DD, U.K.
S
* Supporting Information
ABSTRACT: A series of high-yielding silver(I)-catalyzed
cyclization reactions of pyridine-, isoquinoline-, and pyrazine-
ynones are described. The operationally simple and mild
reaction conditions are a significant improvement over
previously reported thermal cyclizations. The quinolizinone
products were also used in a novel dearomatization strategy to
prepare 0.53 g of the alkaloid lasubine II in five steps and 36%
overall yield.
yridine and piperidine are the two most prevalent N-
was indentified.8 This previous work is based on the activation
Pheterocycles used in medicinal chemistry, with a recent of alkynes with π-acidic catalysts9 to promote cyclization to
generate spirocyclic/annulated products, and based on this, it
was considered that pyridine-ynones would serve as useful
precursors to 2H-quinolizin-2-ones. The viability of a related
cyclization protocol had already been briefly demonstrated by
both Katritzky and Natarajan (Scheme 1A);6d,e however, in this
study showing their presence in 12% of all US FDA approved
drugs.1 New methods for the synthesis of these heterocycles
and their derivatives, such as quinolizines/quinolizidines, are
therefore of high value. The saturated quinolizidine framework
is particularly notable for its presence in a number of bioactive
natural products, such as 1−3 (Figure 1A),2 which makes them
highly attractive synthetic targets.
Scheme 1. Pyridine-ynone Cyclizations
Figure 1. (A) Natural products containing the saturated quinolizidine
framework; (B) proposed dearomative retrosynthesis.
work the pyridine-ynone species is formed and cyclized in situ
via the acylation of 2-picoline under relatively harsh, thermal
conditions and the reported yields are modest. Herein, we
describe a simple and scalable alternative approach, in which
pyridine-, isoquinoline-, and pyrazine-ynones 5 can all be
cyclized into annulated products 6 at room temperature using
mild silver(I)-catalyzed conditions (Scheme 1B).
Using this new method, a diverse array of quinolizinone
products has been prepared in high yield, including reactions
performed on gram scale. The methodology is likely to be of
high value in natural product synthesis, and to demonstrate this,
An unexplored and expedient strategy by which to access
these bicyclic frameworks is by the dearomatization of a 2H-
quinolizin-2-one system 4 (Figure 1B). Dearomatization
reactions are important transformations as they enable high
value spiro-3 or bridged-compounds4 to be formed from
inexpensive and readily available aromatic feedstocks.5 How-
ever, current methods for the synthesis of 2H-quinolizin-2-ones
are limited, relying primarily on harsh thermal conditions,6 with
catalytic examples being rare.7 Seeking to address this
limitation, an opportunity to build upon our recent work on
the catalytic dearomatization/cyclization of aromatic alkynes
Received: October 7, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03017
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Organic Letters
Letter
an efficient five-step synthesis of 0.53 g of the alkaloid lasubine
II has also been developed, including a catalytic dearomatiza-
tion of a quinolizinone product as a key step.
Our studies began with the preparation of pyridine-ynone 5a
via the deprotonation and acylation 2-picoline with methyl
phenylpropiolate (Table 1). Ynone 5a was then reacted with
final quinolizinone product 6 and regenerates the silver(I)
catalyst.
The scope of this transformation was then examined, with
minor modifications made to the conditions shown in Table 1.
The solvent system was switched to a 1:1 mixture of ethanol/
1,2-dichloroethane (see ref 12 for details) and 2 mol % of
AgNO3 was used as the catalyst in all of the examples for
consistency (Scheme 3).
Table 1. Optimization of the Pyridine-Ynone Cyclization
Scheme 3. Substrate Scope for the Silver(I)-Catalyzed
Cyclization
a
b
entry
[catalyst] (equiv)
[solvent]
time (h)
conv (%)
1
2
3
4
5
6
7
8
Cu(MeCN)4PF6 (0.1)
Cu(OTf)2 (0.1)
Ph3PAuNTf2 (0.1)
AgOTf (0.1)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
16
16
16
16
2
0
0
0
>95
90
25
>95
50
AgOTf (0.02)
AgSbF6 (0.02)
AgNO3 (0.02)
2
2
AgNO3 (0.01)
0.5
a
Reactions performed with 0.2 mmol of 5a and catalyst in the stated
b
solvent (0.1 M) at rt. Calculated by measuring the ratio of starting
material to product in the 1H NMR spectrum of the unpurified
reaction mixture, rounded to the nearest 5%.
four π-acidic catalysts in dichloromethane (Table 1, entries 1−
4), of which only AgOTf was effective for the formation of
quinolizinone 6a. This prompted further scrutiny of other
silver(I) catalysts, and of those tested, AgNO3 provided the best
reactivity (entries 7 and 8).
The silver(I) catalyst is proposed to catalyze this trans-
formation as depicted in Scheme 2. The ynone starting
Scheme 2. Proposed Mechanism for the Silver(I)-Catalyzed
Cyclization
First, the electronics of the aryl ynone subunit were varied to
afford quinolizinones 6a−c in quantitative/near-quantitative
yield. Pleasingly, these reactions were equally effective on gram
scale; for example, 2.09 g of quinolizinone 6b were prepared in
a single reaction in 99% yield. The aliphatic quinolizinone 6d
was also afforded in near-quantitative yield. Thiophene-
substituted and methylated-quinolizinones 6e and 6f were
also prepared, albeit in lower yield, which is believed to be a
direct consequence of the instability of the ynone precursors
(see Supporting Information for details). Substituents on the
pyridine ring were also well tolerated, with quinolizinones 6g−i
bearing cyano, bromo, and methyl substituents, all being
furnished in excellent to quantitative yield. The structure of the
bromide 6h was also confirmed by X-ray crystallography.11
Finally, this methodology was also demonstrated on other
heteroaromatic systems, to afford isoquinoline and pyrazine
derived products 6j and 6k in excellent yield. The fully
unsubstituted quinolizinone 6l was also synthesized in excellent
yield from TMS-ynone 5l by using 20 mol % AgNO3 and
acetone to promote a one-pot desilylation−cyclization
sequence (Scheme 4).13,14 This reaction is particularly pleasing,
material, which exists as an equilibrium of keto−enol tautomers
(with the enol tautomer believed to be an unproductive resting
state), is presumably activated by the π-acidic silver(I) catalyst
(A), promoting nucleophilic attack from the pyridine lone pair
to form pyridinium species B (which is likely a reversible
process).10 Deprotonation of the pyridinium species B at the
acidic α-keto position then forms vinyl silver intermediate C;
subsequent protodemetalation of this species then affords the
B
DOI: 10.1021/acs.orglett.6b03017
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Letter
as the TMS ynone 5l is completely unreactive under the
previously reported thermal conditions.6e
enabling the enantioselective synthesis of lasubine II and other
related alkaloids.
ASSOCIATED CONTENT
* Supporting Information
Scheme 4. Tandem Ag(I)-Catalyzed Desilylation−
Cyclization
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03017.
Experimental procedures and compound characterization
data (PDF)
AUTHOR INFORMATION
Corresponding Authors
The ease of formation of these quinolizinone products is
likely to be of significant value in target synthesis projects,
especially given the prevalence of saturated quinolizidine
frameworks in Nature.2 This was demonstrated in the five-
step dearomative synthesis of ( )-lasubine II (Scheme 5).
■
*E-mail: richard.taylor@york.ac.uk.
*E-mail: william.unsworth@york.ac.uk.
ORCID
William P. Unsworth: 0000-0002-9169-5156
Notes
Scheme 5. Five-Step Total Synthesis of ( )-Lasubine II
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors wish to thank the University of York (M.J.J. and
W.P.U.) and the Leverhulme Trust (for an Early Career
Fellowship, ECF-2015-013, W.P.U.) for financial support and
Dr. A. C. Whitwood and R. R. Bean (University of York) for X-
ray crystallography.
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