Total Synthesis of Indolizidine Alkaloids via Nickel-Catalyzed (4 + 2) Cyclization

Article abstract of DOI:10.1021/acs.orglett.9b04479

A Ni-catalyzed (4 + 2) cycloaddition of alkynes and azetidinones toward piperidinones was used as key reaction in the enantioselective synthesis of naturally occurring indolizidine alkaloids. The reaction benefits from the use of an easily accessible azet

Full text of DOI:10.1021/acs.orglett.9b04479

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Letter
Total Synthesis of Indolizidine Alkaloids via Nickel-Catalyzed (4 + 2)
Cyclization
Jonas Renner, Ashish Thakur, Philipp M. Rutz, Jacob M. Cowley, Judah L. Evangelista, Puneet Kumar,
Matthew B. Prater, Ryan M. Stolley, and Janis Louie*
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ABSTRACT: A Ni-catalyzed (4 + 2) cycloaddition of alkynes and
azetidinones toward piperidinones was used as key reaction in the
enantioselective synthesis of naturally occurring indolizidine alkaloids. The
reaction benefits from the use of an easily accessible azetidinone as an advanced
and divergent intermediate to build the indolizidine core. This methodology
has been applied in the total syntheses of (+)-septicine, (+)-ipalbidine, and
(+)-seco-antofine to illustrate the applicability of the general approach.
ndolizidine alkaloid natural products, such as (+)-septicine
(1), (+)-seco-antofine (2), and (+)-ipalbidine (3) as well as
phenanthroindolizidines (+)-tylophorine (4) and (+)-antofine
(5) (Figure 1), have been the center of much interest for some
The natural alkaloids have been isolated from diverse plant
families such as Tylophora (Asclepiadaceae) and Ficus
(Moraceae).25 However, given their potential in the treatment
of MDR cancer, effective synthetic routes to these natural
products and, perhaps more importantly, their synthetic
analogs have been developed. A closer look reveals that the
majority of these methods focus on building phenanthroindo-
lizidines by utilizing phenanthrene-based starting materi-
als.14,16,26−41 As such, access to indolizidine derivatives, such
as the seco-analogs of 4 and 5, remains difficult.42−48
I
Our group previously developed a method where a Ni(0)/
PPh3 system catalyzes the (4 + 2) cycloaddition of
azetidinones and internal alkynes.49,50 This provides access
to a piperidone moiety with high regioselectivity while
retaining the chirality of azetidinone substrates. We postulated
that this method could be used as general approach to
indolizidine alkaloids (as well as their pentacyclic analogs)
through reduction and cyclization of the resulting piperidone
to create the asymmetric bicyclic core structure. Our
azetidinone would serve as advanced and divergent inter-
mediate. Furthermore, this method would complement
previous methods that afford phenanthroindolizidine products
directly. Herein, we highlight this approach in the total
synthesis of (+)-septicine (1), and (+)-seco-antofine (2) and
(+)-ipalbidine (3).
Figure 1. Representative structures of indolizidine alkaloids.
time due to their anticancer,1−10 anti-inflammatory,11−14 and
antiviral15,16 properties. Tylophorine (4) and antofine (5) are
popular targets for total synthesis due to their well-
characterized various antitumor activities.17−20 Tylocrebrine
(6) even entered phase 1 clinical trials as an anticancer drug
candidate, though its progress halted due to central nervous
system toxicity.21,22 Despite this setback, interest in this family
of compounds has been greatly renewed due to the recent
discovery of their unique potency against multidrug-resistant
cancer (MDR) cell lines. For example, the synthetic analog
DCB 3503 (7) and tyloindicine I (8) were shown to be potent
against a variety of MDR cancer cells in the NCI’s 60 cell line
assay.7,23 Perhaps even more exciting is that preliminary data
suggest their mechanism of action is novel.7,24
We chose (+)-septicine as the initial target for proof-of-
concept for our convergent synthetic protocol due to the
symmetrical nature of the aryl rings. Our approach began with
alkyne 9, which was prepared in three steps from
Received: December 13, 2019
https://dx.doi.org/10.1021/acs.orglett.9b04479
© XXXX American Chemical Society
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Scheme 1. Synthesis of (+)-Septicine (1)
veratraldehyde. Azetidinone 10 served as our divergent
intermediate and was synthesized from glutamic acid according
to Seebachs’s procedure.51 Both reagents were transformed
into 3-piperidinone 11 using our developed Ni-catalyzed (4 +
2)-cycloaddition procedure. Compound 11 has also been
previously synthesized using our developed in situ generated
catalyst system.50 The stereo information on azetidinone 10
was retained during this transformation (97:3 er, Scheme 1).
Piperidinone 11 was reduced under Luche conditions to form
the alcohol. Subsequent deprotection using Pd/C and ester
aminolysis using triazabicyclodecene (TBD) furnished the
cyclized alcohol 12. Dehydroxylation using Et3SiH and
reduction of the amide with LiAlH4 provided (+)-septicine
(1) in 12 steps and 8.2% overall yield (Scheme 1).
Scheme 2. Proposed Mechanism of Cycloaddition
It is worth mentioning that the hydroxy group at C14 is
desired for high anticarcinogenic activity.36,52 Moreover, the
additional polarity was proposed to reduce CNS toxicity by
reducing transition into the blood−brain barrier.22 Several
syntheses were since designed to include functionalizations at
C14.33,35,36 However, inclusion of this functional group leads
to increased sensitivity to acids, and we noticed partial
racemization at C13a of ketone 11 during the Luche reduction,
when HCl was used during workup. Similar instabilities have
previously been observed.53,54 We therefore recommend the
use of mild acids, such as NH4Cl, to avoid acid catalyzed
epimerization.
A key element to expand our approach to indolizidine
alkaloids with different aryl substituents, such as (+)-ipalbidine
and (+)-seco-antofine, is the regiocontrolled cycloaddition of
unsymmetrical alkynes into the Csp3−Csp2 bond of azetidinone
10. We previously observed regiocontrol in Ni-catalyzed
cycloadditions with unsymmetrical alkynes where the larger
group was distal to the carbonyl carbon (C, Scheme 2) unless
silyl or stannyl substituted alkynes were employed. In these
cases, the larger silyl and stannyl substituents are adjacent to
the carbonyl carbon in the product (F, Scheme 2). Though we
originally proposed a mechanism that involved minimizing
steric interactions in an initial oxidative addition between the
alkyne and the azetidinone carbon and subsequent β-carbon-
elimination (red pathway, Scheme 2), computational studies
and the ligand (intermediate H) also contributes to the
regioselectivity. However, silyl and stannyl substituents
increase the electron density of the alkyne carbons resulting
in an alkyne insertion where the alkyne acts as nucleophile to
attack the electron-deficient carbonyl carbon and inserts into
the other Ni−C bond, namely the Ni−C(O) bond, to form
metallacycle E via intermediate G2.
With this in mind, we used both steric and electronic factors
to our advantage to develop a regioselective synthesis of
(+)-ipalbidine and (+)-seco-antofine. Ni-catalyzed (4 + 2)
cycloaddition of alkyne 14 and azetidinone 10 yielded desired
piperidinone 15 with high regioselectivity (10:1 rr). The
1
regioselectivity was analyzed by H NMR spectroscopy using
suggest a mechanism involving oxidative addition of the Csp3
−
the crude reaction mixture, and the desired regioisomer was
supported by 2D NOE correlation. Importantly, a lower
reaction temperature was necessary to avoid alkyne trimeriza-
tion.
In a similar approach to (+)-septicine, Luche reduction of
piperidinone 15 to alcohol 16 and subsequent deprotection
and cyclization and deoxygenation afforded intermediate 18.
Finally, demethylation using BBr3 yielded (+)-ipalbidine (3)
in 8.4% total yield (Scheme 3A).
Csp2 bond of azetidinone alone (blue pathway, Scheme 2)
rather than oxidative coupling with the alkyne.55 The
regioselectivity was then determined by the alkyne insertion
(G1 vs G2, Scheme 2) and, furthermore, the alkyne either
acted as an electrophile or a nucleophile. When the alkynes
possess only alkyl or aryl substituents, the alkyne acts as an
electrophile in the insertion step, and the more nucleophilic
Ni−Csp3 carbon forms a bond with the more electrophilic
carbon (i.e., the aryl substituted carbon in unsymmetrical
alkyl/aryl alkynes) to form metallacycle H via intermediate G1.
Minimizing steric interactions between the alkyne substituent
In an attempt to synthesize (+)-seco-antofine, we utilized
alkyne 19 to access piperidone 22. However, the marginally
unsymmetrically methoxy substituted alkyne 19 underwent
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Scheme 3. Synthesis of (+)-Ipalbidine (3) and Seco-antofine (2)
Other Authors
cycloaddition with unsurprisingly poor regioselectivity. As
such, we utilized alkyne 20 that included a bulky stannyl group,
which would electronically dictate and override the steric
preference. The Ni-catalyzed insertion into azetidinone 10
proceeded with high regioselectivity resulting in the stannyl
group being proximal to the carbonyl group as only observed
regioisomer. A subsequent Stille coupling was used to install
the unsymmetrical additional arene moiety of (+)-seco-antofine
resulting in piperidinone 22 (Scheme 3B). In accordance to
previous pathways, cyclization of the appendix and removal of
excess oxygen functionalities resulted in (+)-seco-antofine (2)
in 7.7% overall yield.
In summary, we leveraged our Ni-catalyzed (4 + 2)-
cycloaddition of alkynes and azetidinones to yield chiral
piperidinones with high regio- and stereoselectivities in the
facile synthesis of natural occurring indolizidine alkaloids. This
approach allows for the syntheses of nonphenanthroindolizi-
dine-based alkaloid products. Efforts to increase the efficiency
of this approach are currently underway in our laboratories.
Jonas Renner − University of Utah, Salt Lake City, Utah
Ashish Thakur − University of Utah, Salt Lake City,
Utah; orcid.org/0000-0002-8456-1088
Philipp M. Rutz − University of Utah, Salt Lake City,
Utah
Jacob M. Cowley − University of Utah, Salt Lake City,
Utah
Judah L. Evangelista − University of Utah, Salt Lake
City, Utah
Puneet Kumar − University of Utah, Salt Lake City, Utah
Matthew B. Prater − University of Utah, Salt Lake City,
Utah
Ryan M. Stolley − University of Utah, Salt Lake City,
Utah
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.9b04479
Notes
ASSOCIATED CONTENT
■
The authors declare no competing financial interest.
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04479.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the National Institute of Health
(GM076125) for financial support. We thank Professor
Sigman at the University of Utah for the use of their SFC-
instrument. We thank Brianna Esslinger for thoughtful
discussions.
Experimental considerations, synthetic procedures,
HPLC traces, NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
REFERENCES
■
Janis Louie − University of Utah, Salt Lake City, Utah;
orcid.org/0000-0003-3569-1967; Email: louie@
chem.utah.edu
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