Indolizinones as synthetic scaffolds: Fundamental reactivity and the relay of stereochemical information

Article abstract of DOI:10.1039/c1ob06423a

Indolizinones are under-explored N-heterocycles that react with exquisite chemo- and stereoselectivity. An exploration of the fundamental reactivity of these azabicycles demonstrates the potential to relay stereochemical information from the ring-fusion to newly formed stereocenters on the bicyclic core. The indolizinone diene undergoes selective hydrogenation and readily participates in Diels-Alder cycloadditions as well as ene reactions. The vinylogous amide embedded in the five-membered ring is resistant to reaction when the diene is in place. However, removal of the diene allows for diastereoselective hydrogenation of, and 1,4-additions to, the vinylogous amide. These fundamental reactions with indolizinones have provided a structurally diverse array of products that hold promise in the context of natural product synthesis.

Full text of DOI:10.1039/c1ob06423a

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PAPER
Indolizinones as synthetic scaffolds: fundamental reactivity and the relay of
stereochemical information†
Alison R. Hardin Narayan and Richmond Sarpong*
Received 19th August 2011, Accepted 20th September 2011
DOI: 10.1039/c1ob06423a
Indolizinones are under-explored N-heterocycles that react with exquisite chemo- and stereoselectivity.
An exploration of the fundamental reactivity of these azabicycles demonstrates the potential to relay
stereochemical information from the ring-fusion to newly formed stereocenters on the bicyclic core. The
indolizinone diene undergoes selective hydrogenation and readily participates in Diels–Alder
cycloadditions as well as ene reactions. The vinylogous amide embedded in the five-membered ring is
resistant to reaction when the diene is in place. However, removal of the diene allows for
diastereoselective hydrogenation of, and 1,4-additions to, the vinylogous amide. These fundamental
reactions with indolizinones have provided a structurally diverse array of products that hold promise in
the context of natural product synthesis.
such as 3 followed by a stereoretentive Wagner–Meerwein shift
of the propargylic substituent with concomitant proton transfer
to afford the indolizinone product (4). Indolizinones are also
accessible from propargylic alcohols using a greener protocol.
Both our group7 and the Kim group5 discovered that heating
tertiary alcohols such as 5 in a polar protic solvent (e.g., water
or ethanol) affords indolizinone products in excellent yields
(Fig. 2B).
Introduction
Indolizinones are N-heterocycles that have only recently appeared
in the chemical literature.1–5 These 6,5-N-fused bicycles contain
eight contiguous sp2-hybridized atoms and a single sp3-carbon
atom, which resides at the ring-fusion (see C9 of 1, Fig. 1). Both
the dienamine contained within the six-membered ring and the
vinylogous amide moiety in the five-membered ring could serve as
functional handles, rendering indolizinones as useful precursors
to indolizidine natural products, pharmaceutical agents and new
materials.
Although several protocols for the synthesis of indolizinones
have recently emerged, little is known about their innate re-
activity. Only two examples of reactions of indolizinones have
appeared in the literature. In 2008, Paquette and co-workers
described the dimerization of benzannulated indolizinones (see
7, Fig. 3A) via a light promoted [4+2] cyclization between the
diene component of one indolizinone molecule and a double
bond of the diene from another molecule of the indolizinone.8
The second disclosure of indolizinone chemistry came in 2010
from Kim and co-workers on the palladium-catalyzed cross-
coupling of 2-iodoindolizinones (Fig. 3B).9 They demonstrated
the competence of 2-iodoindolizinones as the halide component
in Heck, Sonogoshira, and Suzuki–Miyaura reactions.
The relative lack of knowledge regarding indolizinone reactiv-
ity compared to other nitrogen-heterocycles (e.g., indoles10 and
indolizines), coupled with our desire to use indolizinones as
building blocks in the synthesis of complex molecules, spurred
our investigation of these bicycles. In addition to understanding
the types of reactions indolizinones would participate in, we were
intrigued by the potential to relay the stereochemistry of the ring-
fusion position (i.e., C9, Fig. 4) to the installation of additional
stereocenters. Our studies have revealed the exquisite chemo- and
stereoselectivity of several reactions that transform indolizinones
into structurally diverse products with high diastereoselectivity
in the formation of bonds at C3, C5, C6 and C8 (see asterisked
Fig. 1 Indolizinone.
Methods for the synthesis of indolizinones were pioneered in
our laboratories with platinum(II) and indium(III) salts1,3 and
have been further developed by others with salts or complexes
of copper,2 silver,6 gold6 and iodine.4 This transformation is
proposed to proceed by cyclization of the pyridine moiety (see
2, Fig. 2A) onto a metal-activated alkyne to form an intermediate
Department of Chemistry, University of California, Berkeley, CA
94720, USA. E-mail: rsarpong@berkeley.edu; Web: http://www.cchem.
berkeley.edu/rsgrp/; Fax: (+1) 0-510-642-8369
† Electronic supplementary information (ESI) available. CCDC reference
numbers 834076 and 834077. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c1ob06423a
70 | Org. Biomol. Chem., 2012, 10, 70–78
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Fig. 2 Cycloisomerization of tertiary alcohols to form indolizinones (A) metal-catalyzed cyclization and (B) metal-free cyclization.
Table 1 Hydrogenation of the indolizinone diene
Entry
1
Substrate
Product
Yield
98%
Fig.
3 (A) Paquette’s photodimerization of pyrido[2,1-a]isoindol-
6(4H)-one (7); (B) palladium-catalyzed cross couplings of 2-iodoin-
dolizinone (9).
2
94%
3
78%
Fig. 4 The relay of stereochemistry from the ring-fusion to positions on
the indolizinone core.
positions in 11). The potential application of these products to the
synthesis of indolizidine alkaloids is also discussed.
Results and discussion
4
5
93%
99%
1. Hydrogenation
Indolizinones undergo regio- and diastereoselective hydrogenation
under a variety of conditions. The electron-rich diene component
is selectively reduced in the presence of the relatively electron-poor
vinylogous amide double bond. Heterogeneous catalysts, such as
R
Pd/C and RANEYꢀ nickel, reduce only the indolizinone diene
using pressures of hydrogen ranging from 1 to 15 atm.
Exposing several indolizinones to Pd/C in methanol under
hydrogen (150 psi) for 12 h led to high yields of the corresponding
piperidine products (Table 1). Shorter reaction times and lower
pressures of hydrogen led to incomplete conversion in some cases.
Ethyl acetate and ethanol are also competent solvents for this
transformation; however, the use of these solvents also led to
incomplete conversion of starting material in some cases. The
hydrogenation of indolizinones with alkyl or aryl substituents
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Scheme 1 Synthesis of (A) tricyclic indolizinone 26 and (B) alkylated indolizinone 29.
at C9 (entries 1–2) proceeded without event. Substitution on
the vinylogous amide component is also tolerated and does not
qualitatively affect the course of the reaction (entries 3–5).
Exposure of 6,6,5-tricycle 26 to Pd/C under 150 psi of hydrogen
provided a single diastereomer of the reduction product, which
was assigned as 30 (Scheme 2A). The cis-ring fused product
(30) constitutes the tricyclic core conserved throughout several
members of the cylindricine family of marine alkaloids (e.g.,
32, Scheme 2C).12–16 The alternative trans-ring fusion of the six-
membered rings, which is not accessed by this method, is present
in a related family of alkaloids, the lepadiformines (e.g., 33).17
To probe the facial selectivity of the hydrogenation of the
dienamine double bond most proximal to the indolizinone ni-
trogen (D5,6), tricyclic indolizinone 29 was exposed to the standard
hydrogenation conditions. After 12 h, 29 was converted to 31,
whereby the hydrogenation of both double bonds of the diene
took place from the less hindered face, providing an entry to the
9-epi-lepadiformine core.
The hydrogenation of more substituted indolizinones provided
insight into the facial selectivity of this transformation. We
expected hydrogenation to occur from the less sterically hin-
dered face of the bicycle, opposite the ring-fusion substituent.
Tricyclic indolizinones 26 and 29 (Scheme 1) were synthesized
and subjected to the hydrogenation conditions. The synthesis of
indolizinones 26 and 29 began with a Boekelheide sequence on 2,3-
cycloheptenopyridine (23) to regioselectively install the requisite
hydroxyl group, affording alcohol 24 in 87% yield over three
steps.11 Alcohol 24 was oxidized under Swern conditions to the
corresponding ketone followed by 1,2-addition of the lithium
acetylide of trimethylsilylacetylene. Subsequent removal of the
silyl group provided cyclization substrate 25 in 52% yield over three
steps. Upon heating in ethanol, 25 underwent ring-contractive
cyclization to afford tricyclic indolizinone 26 in quantitative yield.
In parallel, alcohol 24 was elaborated to alkylated indolizinone
29 in five steps (Scheme 1B). Several strategies for alkylation
of pyridine 24 at C6 were explored, but ultimately, only the
Chichibabin-type addition of n-butyllithium provided a single
isomer of the desired product (27) in high yield. Alkylation product
27 was carried forward to indolizinone 29 in a manner analogous
to the conversion of alcohol 24 to indolizinone 26.
2. Diels–Alder cycloaddition
In addition to hydrogenation, the indolizinone dienamine par-
ticipates in Diels–Alder cycloadditions with high regio- and
diastereoselectivity. Using the Diels–Alder reaction, indolizinones
are transformed into complex [2.2.2]azabicycles, which can be
further processed into a structurally diverse set of products.
Cognizant of the possibility for dimerization of the indolizinone
as observed by Paquette and co-workers under photo-irradiation
Scheme 2 (A) Hydrogenation of tricyclic indolizinone 26, (B) hydrogenation of alkylated indolizinone 29, and (C) select tricyclic marine natural products.
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Table 2 Diels–Alder cycloadditions of methylindolizinone (6) with vari-
ous dienophiles
Entry
1
Dienophile
Product
Yield
96%
Scheme 3 Reaction of methylindolizinone (6) with DMAD (48).
2
84%
49. Attempts to isolate Diels–Alder adduct 49 were not fruitful,
but dimethyl phthalate (50) was consistently isolated as the major
product. The generation of dimethyl phthalate (50) via a retro
[4+2] of 49 would also produce azacyclopentadienone 51, which
could not be isolated or trapped with either dienes or dienophiles.
A variety of indolizinones bearing different substituents readily
participate in Diels–Alder cycloadditions, which have been inves-
tigated with maleic anhydride (Table 3). In addition to varied
substitution at the ring fusion of the indolizinone, alkyl and aryl
groups on the vinylogous amide component (see entries 4 and 5)
do not qualitatively affect the reaction. Tricyclic indolizinone 29
provided an extra challenge in the Diels–Alder reaction, where
a productive cycloaddition generates a quaternary and tertiary
center in quantitative yield (see 59).
3
4
94%
91%
As illustrated (Tables 2 and 3), the Diels–Alder reactions
consistently afforded a single diastereomer of the [2.2.2]azabicyclic
product (>20 : 1 d.r. by 1H NMR). To determine the relative
stereochemistry of the Diels–Alder adducts, X-ray diffraction
studies of 55 and 64 were undertaken. The crystal structures
of 55 and 64 (Fig. 5) confirm the syn relationship between
the unsaturated two-carbon bridge and the C9 substituent that
results from the approach of the dienophile from the face of the
indolizinone opposite the ring-fusion substituent. Furthermore,
the crystal structures of 55 and 64 provide additional information
about the Diels–Alder transition states. In 55, the syn relationship
between the anhydride moiety and the two-carbon unsaturated
bridge suggests an endo-transition state. The cyano group of 64 is
anti to the unsaturated bridge providing evidence for a transition
state in which the chlorine atom resides in the endo-position.
The rapid generation of complexity afforded by indolizinones
through Diels–Alder cycloadditions presents an intriguing op-
portunity to assemble highly caged skeletons by employing an
intramolecular variant. To this end, two indolizinone substrates
were investigated which possessed a tethered dienophile: homoal-
lylindolizinone 54 and ester 62. Heating homoallylindolizinone
6
6
93%
73%
(see Fig. 3A), reactive dienophiles were first investigated. Heating
methylindolizinone (6) with maleic anhydride (36) in benzene at
80 ◦C afforded [2.2.2]azabicycle 37 as a single diastereomer in
96% yield (entry 1, Table 2). Under the same conditions, high
yields as well as high diastereoselectivity (>20 : 1 d.r. by 1H NMR)
were also observed in the reaction of methylindolizinone (6) with
acrolein (38), methyl acrylate (40), t-butyl acrylate (42) and 2-
chloroacrylonitrile (44). Methylindolizinone (6) reacted with 4-
phenyl-1,2,4-triazole-3,5-dione (46) at 0 ◦C in dichloromethane to
provide the hetero-Diels–Alder adduct 47 in 73% yield.
In a further exploration of dienophiles for the Diels–Alder
cycloaddition with methylindolizinone (6), dimethylacetylenedi-
carboxylate (DMAD, 48) was combined with 6 and heated to 80 ◦C
in benzene for 12 h (Scheme 3). The sole product recovered from
this reaction was a highly symmetrical aromatic compound that
was identified as dimethyl phthalate (50), which could arise from
the retro-Diels–Alder of the anticipated product, [2.2.2]azabicycle
◦
54 at temperatures up to 120 C resulted only in recovery of the
starting material (Scheme 4). Presumably, the [4+2] cycloaddition
of 54 does not proceed because of poorly matched electronics.
To access a substrate with an electron deficient dienophile,
homoallylindolizinone 54 was converted to a,b-unsaturated ester
62 via cross metathesis with methyl crotonate mediated by the
Grubbs II catalyst.
Despite the strain inherent in the desired product, heating 62
in m-xylenes at 150 ◦C for 12 h led to the desired [2.2.2]bicycle
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Table 3 Diels–Alder cycloadditions of indolizinones and maleic
anhydride
Entry
1
Indolizinone
Product
Yield
96%
Scheme 4 Intramolecular Diels–Alder cycloadditions.
2
67%
natural product-like structures was investigated. Efforts to synthe-
size tricyclic marine alkaloids (e.g., cylindricine and lepadiformine
alkaloids, see 32 and 33, respectively, Fig. 2C) from Diels–Alder
adducts led to several unanticipated discoveries.
For example, efforts to remove the chlorine and nitrile groups
from [2.2.2]azabicycle 6418 provided an example of the anomalous
reactivity of the Diels–Alder adducts (Scheme 5). Exposure of
64 to dissolving metal conditions afforded a single disubstituted
aromatic compound, which was identified (by 1H NMR and mass
spectral analysis) as 66. Arene 66 could arise from an initial
reductive C–Cl bond cleavage to afford anion 65. Subsequent
fragmentation to cleave the C–N bond of the [2.2.2]bicycle (see
arrows, 65) would form a cyclohexadiene intermediate, which upon
oxidation in air, would give arene 66. Although fragmentation
of the [2.2.2]azabicycle was unproductive in the synthesis of in-
dolizidine alkaloids, the potential exists for transforming products
such as 66 into biologically relevant classes of molecules, such as
protease inhibitors.19
The carbon framework of the [2.2.2]azabicycle can be manipu-
lated to afford a functionalized piperidine ring via oxidative cleav-
age of the unsaturated two-carbon bridge. The oxidative cleavage
substrate 70 was accessed in two steps from indolizinone 29 via
Diels–Alder cycloaddition with acryloyl chloride and a subsequent
Barton decarboxylation (Scheme 6). Attempts to dihydroxylate
the unsaturated two-carbon bridge of 70 were accompanied by
oxidation of the vinylogous amide moiety. Over-oxidation was
avoided by first reducing the double bond of the vinylogous amide,
then subjecting the tertiary amine product to catalytic osmium
tetroxide followed by sodium periodate. This protocol provided
dialdehyde 71 as a mixture with its hydrate forms. Conversion of
[2.2.2]azabicycle 70 to functionalized piperidine 71 could be useful
in the context of natural product total synthesis. For example,
stereoretentive decarbonylation of 71 would afford tricycle 72,
which could lead to marine alkaloids such as lepadiformine C
(73). Our efforts in this regard have thus far led only to complex
mixtures from which 72 could not be isolated.
3
4
89%
93%
5
6
91%
88%
63, which could be isolated in quantitative yield (Scheme 4).
The intramolecular Diels–Alder provides a product with a dif-
ferent stereochemical relationship between the C9 ring-fusion
substituent and the unsaturated two-carbon bridge as compared
to the intermolecular reaction. The tethered dienophile can only
approach the diene from the same face of the molecule, resulting
in an anti relationship between the unsaturated two-carbon
bridge and the ring-fusion substituent. The highly caged skeleton
(see 63) generated in the intramolecular Diels–Alder reaction is
unprecedented.
Alternatively, the unsaturated two-carbon bridge of
[2.2.2]azabicycle 64 (Scheme 7) can be engaged in olefin
metathesis reactions. Treatment of [2.2.2]azabicycle 64 with
Grubbs second generation catalyst 81 in refluxing benzene
effected a ring-opening/ring-closing metathesis to afford tricycle
79 in 73% yield. The syn relationship between the homoallyl
group and the two-carbon unsaturated bridge of 64 enforces the
With rapid access to [2.2.2]azabicycles, the potential to convert
these complex intermediates to indolizidine natural products and
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Fig. 5 X-ray crystal structures of Diels–Alder adducts 55 and 64.
Scheme 5 Fragmentation of [2.2.2]azabicycle under dissolving metal conditions.
Scheme 6 Oxidative cleavage of [2.2.2]azabicycle 70.
stereochemistry in 79, which possesses appropriate functional
handles for elaboration to cylindricine K (80).
indolizinone 29 with PTAD (46) gave rise to the ene product (82)
as a single diastereomer (Scheme 8).
3. Ene reaction
4. Chemistry of the vinylogous amide
As previously illustrated (Table 2, entry 6), indolizinone dienes
can readily engage in Diels–Alder cycloadditions; however, with
an appropriate substituent on the diene (e.g., 29, Scheme 8), the
ene reaction can be a competing pathway. For example, although
cycloaddition of methyl indolizinone 6 with PTAD (46) provided
the Diels–Alder adduct 47 (entry 6, Table 2), treatment of tricyclic
In our exploration of the reactivity of the dienamine moiety of
indolizinones, the vinylogous amide was left untouched under
the vast majority of the reaction conditions. We, therefore,
were interested in learning (1) the identity of nucleophiles and
conditions necessary for successful additions to the vinylogous
amide and (2) to which position nucleophiles would add. To
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Scheme 7 Synthesis of the tricyclic cylindricine core via ring-opening/ring-closing metathesis of 64.
of 14 with vinylmagnesium bromide at temperatures ranging
from -78 ◦C to ambient temperature, the starting material was
recovered. However, when several equivalents of Grignard reagent
were employed in conjunction with increased reaction tempera-
tures, the 1,4-addition product was obtained as a 3 : 1 mixture of
diastereomers 87:86 (Scheme 9). The major diastereomer possesses
a trans relationship between the ring-fusion methyl group and
the newly added vinyl substituent as established through nOe
experiments.
Scheme 8 Ene reaction of indolizinone 29 with PTAD.
answer these questions, we first focused our efforts on two classes
of nucleophiles: Grignard reagents and hydride sources.
A series of experiments wherein methylindolizinone (6) was
treated with Grignard reagents in THF or diethyl ether at
temperatures ranging from -78 to -42 ◦C resulted in the recovery
of the indolizinone starting material. At temperatures above
-42 ◦C, only complex mixtures of extremely polar products were
obtained. Likewise, treatment of 6 with a variety of hydride sources
including sodium borohydride, diisobutylaluminum hydride, and
triethylsilane did not accomplish clean reduction and led only to
recovery of starting material or the isolation of an unidentifiable
mixture of products.
These unfruitful attempts to add nucleophiles to the in-
dolizinone vinylogous amide led us to consider the potential out-
comes of nucleophilic addition. In one scenario, the nucleophile
could add in a 1,2-fashion to the vinylogous amide to generate an
allylic alcohol such as 83 (Fig. 6). This product is a trienamine
(83), which was expected to be highly reactive. The alternative
reaction pathway, 1,4-addition to the vinylogous amide, would
result in dienamine 84. Although dienamine 84 might be slightly
more stable than trienamine 83, similar undesired reactions would
likely ensue from this product as well.
Scheme 9 Grignard addition to vinylogous amide 14.
It was expected that addition from the more sterically accessible
face of the vinylogous amide, opposite the methyl group at C9,
would provide a single diastereomer. However, the mixture of
diastereomers implied one of the following scenarios: (1) the
vinylmagnesium bromide was adding from both faces of the
five-membered ring or (2) the enolate, formed as a direct result
of 1,4-addition, could collapse to eliminate the nitrogen group
(Scheme 10, see 88 → 89). In addition to isolating a mixture of
diastereomers of the ketone product (86 and 87), a trace amount of
product was obtained that did not possess a terminal vinyl group,
yet contained two more carbon atoms than vinylogous amide 14.
1H NMR data for this minor product suggests a mixture of similar
products, which were assigned as 6,7-bicycles 90 and 91 that differ
only in the position of the double bond contained within the seven-
membered ring. Mechanistically, the seven-membered ring could
form from the ring-opened intermediate (89) by 1,6-addition of
the amide to form the seven-membered ring.
In order to gain insight into the poor diastereoselectivity
observed in the addition of vinyl Grignard to the vinylogous
amide, we sought to trap the enolate intermediate (88). In the
event the enolate was leading to fragmentation of the five-
membered ring, trapping the enolate could avoid racemization
of the stereocenter created upon conjugate addition. If instead the
lack of diastereoselectivity stemmed from a lack of facial selectivity
Fig. 6 Potential products of nucleophilic addition to the vinylogous
amide.
With this insight into the challenges associated with nucleophilic
additions to indolizinones, we sought to isolate the vinylogous
amide in order to study its chemistry. Methylindolizinone (6) was
hydrogenated to provide vinylogous amide 14. Upon treatment
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Scheme 10 Potential mechanism for erosion of diastereoselectivity in conjugate addition.
in the addition, the same mixture of diastereomers should be
obtained when the enolate is trapped. In practice, the addition
of TBSOTf to the reaction mixture successfully intercepted the
enolate and led to a single diastereomer of silyl enol ether 92, which
hydrolyzed to afford ketone 87 (Scheme 11). The TBSOTf had
two effects on this transformation: (1) a single diastereomer of the
product could be obtained and (2) the activation of the vinylogous
amide by the TBSOTf made it possible for the nucleophile to add
at lower temperatures.
for the conjugate reduction of the vinylogous amide. DIBAL-H,
Superhydride, and L-Selectride were competent in this reduction
in the presence of an exogenous Lewis acid. Superhydride provided
the highest and most reproducible yields (Scheme 12).
Scheme 12 Conjugate reduction of the vinylogous amide.
Further experimentation unveiled conditions for the selective
reduction of the vinylogous amide in the presence of esters,
anhydrides, and ketones. Under strongly acidic conditions, the
vinylogous amide was reduced by NaCNBH3 (Fig. 7). This
reagent, famous for its ability to reduce iminium ions formed
in reductive amination over carbonyls, can competently deliver a
hydride to the iminium ion (95) formed upon treatment of the
vinylogous amide with 2 N HCl.
Scheme 11 Activation and trapping with TBSOTf.
Similar to the addition of carbon nucleophiles, hydrides also
add in a conjugate fashion to the vinylogous amide. To achieve
synthetically useful yields of the reduced product, it was necessary
to first activate the vinylogous amide to increase its electrophilicity.
A variety of Lewis acids were screened for this purpose. In
addition to silylating reagents such as TBSOTf and TMSOTf
that provide silyl enol ether products, boron trifluoride diethyl
etherate was also sufficient for amide activation. In parallel with
the Lewis acid screen, a variety of hydride sources were evaluated
Conclusions
The first in depth exploration of the innate reactivity of in-
dolizinones has uncovered several regio- and stereoselective re-
actions. Specifically, the indolizinone diene can be hydrogenated,
Fig. 7 Reduction of the vinylogous amide with sodium cyanoborohydride.
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engaged in a Diels–Alder cycloaddition, or participate in an ene
reaction. The vinylogous amide has proven to be significantly less
reactive, requiring activation for the addition of nucleophiles to
occur.
4 J. Choi, G. H. Lee and I. Kim, Synlett, 2008, 1243–1249.
5 I. Kim, J. Choi, S. Lee and G. H. Lee, Synlett, 2008, 2334–
2338.
6 I. V. Seregin, A. W. Schammel and V. Gevorgyan, Org. Lett., 2007, 9,
3433–3436.
7 The cyclization of tertiary alcohols such as 5 in water to obtain
indolizinone products was developed in our laboratories concurrently
with Kim and coworkers’ (see ref. 5) report of the EtOH version of this
metal-free reaction.
8 L. A. Paquette, R. D. Dura and J. C. Gallucci, Heterocycles, 2008, 76,
129–132.
Beyond illuminating the reactivity of indolizinones, we antici-
pate that the reactions discussed herein, will set the stage for the
synthesis of complex molecules from indolizinone building blocks.
Our initial endeavors have provided access to the core of tricyclic
marine alkaloids such as the cylindricines and lepadiformines. We
intend to apply these new discoveries in indolizinone reactivity to
the synthesis of indolizidine alkaloids and other complex natural
product-like alkaloid structures. Overall, indolizinones are unique
molecules that hold promise across a broad range of fields from
materials to medicine.
9 K. Kim and I. Kim, J. Comb. Chem., 2010, 12, 379–382.
10 R. J. Sundberg, Indoles, Academic Press, London, 1996.
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White, Tetrahedron, 1993, 49, 8645–8656.
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