Protic-solvent-mediated cycloisomerization of quinoline and isoquinoline propargylic alcohols: Syntheses of (±)-3-demethoxyerythratidinone and (±)-cocculidine

Article abstract of DOI:10.1002/anie.201304687

Putting the benz in indolizinones: A cycloisomerization approach to benz[g]indolizinones and benz[e]indolizinones provides the first general route to these unique azacycles (see example). The utility of the benzindolizinone products was demonstrated by the application of this method to the total synthesis of the Erythrina alkaloids 3-demethoxyerythratidinone and cocculidine. Copyright

Full text of DOI:10.1002/anie.201304687

Angewandte
Chemie
DOI: 10.1002/anie.201304687
Alkaloid Synthesis
Protic-Solvent-Mediated Cycloisomerization of Quinoline and
Isoquinoline Propargylic Alcohols: Syntheses of
(
ꢀ)-3-Demethoxyerythratidinone and (ꢀ)-Cocculidine**
Stephen T. Heller, Toshihiro Kiho, Alison R. H. Narayan, and Richmond Sarpong*
Novel nitrogen-containing rings (azacycles) are particularly
valuable in the arenas of alkaloid synthesis and medicinal
chemistry. Our research group has been engaged in the
development of strategies for the cycloisomerization of
pyridine propargylic alcohols (e.g., 1, Scheme 1) for the
tertiary alcohols, respectively (see 2 and 3, Scheme 1), are not
formed efficiently under the metal-promoted cycloisomeriza-
tion conditions that were effective for the synthesis of
indolizines and indolizinones. Herein, we demonstrate that
benzindolizinones can be produced in high yields by the
cycloisomerization of quinoline or isoquinoline alcohols in
protic solvents (e.g., ethanol or n-propanol), which presum-
ably form a hydrogen-bonding network that activates the
substrate.
II
generation of indolizinones and indolizines with both Pt and
Surprisingly, the benzindolizinone framework has gone
virtually unexplored: only scattered reports of benz[e]indo-
[
3]
lizinones and only a single report of the isomeric benz[g]in-
[
4]
dolizinone had appeared prior to the study that is described
herein. To demonstrate the utility of the unique azacyclic
products that can now be effectively accessed by the protic-
solvent-mediated cycloisomerization, we applied the benz-
[
g]indolizinone scaffold to short syntheses of the Erythrina
[
5]
[6]
alkaloids (ꢀ)-3-demethoxyerythratidinone (4) and (ꢀ)-
[
7]
cocculidine (5).
The basis of our current studies rests on the concurrent
discovery by Kim et al. and our group that simple protic
solvents can mediate cycloisomerizations of pyridine prop-
[
8,9]
argylic alcohols to yield indolizines and indolizinones.
This
observation suggested a potential route to benzindolizinones,
given that the metal-mediated cycloisomerization (e.g., 6a!
7
a, Scheme 2) proceeds only in low yield (36%) owing to
Scheme 1. Cycloisomerization approaches to indolizines, indolizi-
nones, and benzindolizinones.
a competing ejection of the acetylide unit to give a ketone
[
10]
(e.g., 8a) and an alkyne (in this case hexyne). Alternatively,
[
11]
as demonstrated by Kim and co-workers, the subjection of
quinoline propargylic alcohol 6b to iodocycloisomerization
conditions results in the formation of iodopyrrolo[1,2-a]-
quinoline 9 and not the expected benzindolizinone 7b or its
iodinated derivative.
III
[1]
In catalysts. Similarly, others have shown that a wide
variety of p acids can mediate the cycloisomerization of
pyridine propargylic secondary alcohols to indolizines.
[2]
Unfortunately, benzannulated variants of these underutilized
scaffolds (especially benz[e]indolizinones and benz[g]indoli-
zinones) that would arise from quinoline or isoquinoline
We hypothesized that protic solvents would be less likely
than p Lewis acids to effect the ejection of acetylides from
substrates such as 6. Thus, protic-solvent-mediated cyclo-
isomerization could provide a possible solution to the
unsolved problem of access to benzindolizinones from
propargylic alcohols. Support for this assertion is evident in
the effectiveness of the protic-solvent-mediated cycloisome-
rization conditions (nPrOH, 1208C, 40 h), which led to the
formation of benz[g]indolizinone 7a in 91% yield (for the
isolated product) from the quinoline tertiary alcohol 6a.
Aryl, alkyl, and alkenyl groups functioned as migrating
groups when quinoline propargylic tertiary alcohol substrates
3 containing a terminal alkyne were employed, and the
desired products were obtained in good to excellent yields
(Scheme 3). Generally, these reactions were conducted at
[
*] S. T. Heller, T. Kiho, A. R. H. Narayan, Prof. R. Sarpong
Department of Chemistry, University of California, Berkeley
Berkeley, CA 94720 (USA)
E-mail: rsarpong@berkeley.edu
[**] The research was supported by a grant from the NIH-NIGMS (RO1
084906), the NSF-USA (graduate fellowship to STH), and Daiichi
Sankyo. We thank Daniel Sanner and Christina Kraml of Lotus
Separations (Princeton, NJ (USA)) for the preparative-scale sepa-
ration of the enantiomers of 28.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201304687.
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over the same time period. Similarly, the
aryl-substituted alkynol 11 underwent
complete conversion over 9 h at 1208C
to afford 12 in 95% yield. Importantly,
our observation that the reaction of the
methyl-substituted quinoline propargyl
alcohol substrate 13, which possesses
a terminal alkyne group, is slow at
1
008C and only proceeds to full con-
version at a higher reaction temperature
of 1208C indicates that the lower reac-
tivity of 6a and 11 is probably because of
peri strain and not because these sub-
strates are internal alkynes.
In analogy to the developments with
quinoline propargylic alcohols for access
to benz[e]indolizinones (Scheme 3), iso-
Scheme 2. Development of effective cycloisomerization conditions for benzindolizinone forma-
tion. JohnPhos=(2-biphenyl)di-tert-butylphosphine, n.d.=not detected, n.a.=not applicable.
Scheme 3. Scope of the reaction for benz[e]indolizinone formation with
respect to the migrating group. Boc=tert-butoxycarbonyl.
Scheme 4. The influence of peri strain on reactivity.
1
008C in sealed vessels with ethanol as the solvent. The
quinoline propargylic alcohols served as effective substrates
for the synthesis of benz[g]indolizinones. With both aryl and
alkyl migrating groups, the desired benz[g]indolizinones were
obtained in excellent yield (Scheme 5). Qualitatively, the
cycloisomerization reactions to afford benz[g]indolizinones
proceeded more quickly than the corresponding formation of
benz[e]indolizinones.
observed reaction rates approximately correlate with the
nature of the migrating group (aryl > alkenyl > alkyl). How-
ever, the rate of benzindolizinone formation does not appear
to correlate with the electronic nature of the aryl migrating
groups. Notably, saturated azacycles, such as a protected
piperidine (see 10h), also serve competently as migrating
groups. Additionally, in the case of propargylic–allylic alcohol
substrates (i.e., R = alkenyl in 3), complete chemoselectivity
for cycloisomerization involving the alkyne group was
observed (see 10d).
The most significant impact on the facility of the cyclo-
isomerization of quinoline alcohols to form benz[e]indolizi-
nones appears to arise in situations in which significant peri
strain develops en route to the product, as demonstrated in
Scheme 4. Thus, for substrates containing an internal alkyne
The benzindolizinone frameworks that can now be
effectively accessed may be manipulated selectively
(Scheme 6). For example, oxidation-level adjustments can
be performed chemoselectively by exploiting differences in
electronic bias between the vinylogous amide, enamine, and
[12]
alkene groups (see 17, 18, 20, and 21).
Alternatively,
iodination can be effected with N-iodosuccimide; thus, 19 and
22 were obtained as the major products from 10e and 16b,
[
13]
respectively.
(
1
e.g., 6a and 11), cycloisomerization proceeds only slowly at
008C (e.g., 50% conversion of 6a into 7a after heating in
Finally, substituted benzindolizinones (e.g., the methoxy-
benz[g]indolizinone 23, prepared in 93% yield from the
appropriate propargylic alcohol) can also undergo selective
hydrolysis to provide, for example, 24 [Eq. (1)], which
possesses a carbonyl group that may be further manipulated.
ethanol for 40 h). Gratifyingly, an increase in the reaction
temperature to 1208C (which necessitated a switch to the
higher-boiling solvent nPrOH) led to complete conversion
2
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Chemie
enantiomerically
pure
29
(> 99% ee), which demonstrates the
excellent enantiospecificity of the
cycloisomerization step. Following
a survey of various reduction proto-
cols (including hydrogenation and
the use of hydride reagents, such as
sodium borohydride and diisobutyl-
aluminum hydride), we found that
under carefully controlled condi-
tions, an ionic reduction of both the
enamine and vinylogous-amide moi-
eties of 29 could be effected with
attendant deprotection of the pend-
ant ketone group in a one-pot pro-
cess to give 30. Overall, this cyclo-
Scheme 5. Cycloisomerization of isoquinoline propargylic alcohols. (An ORTEP drawing of 16b is
shown with thermal ellipsoids drawn at the 50% probability level. Hydrogen atoms have been
removed for clarity.)
isomerization/reduction
sequence
provides a powerful alternative to
the Pictet–Spengler approach that
has historically been employed for
the synthesis of intermediates such as
0 in many syntheses of Erythrina alka-
3
[
17]
loids. Diketone 30 was then converted
into (ꢀ)-3-demethoxyerythratidinone (4)
by a base-mediated aldol condensation
as previously reported by Simpkins and
[
18]
co-workers.
was achieved in five steps from 25 and 26.
By similar approach to that
Thus, the synthesis of 4
a
employed in the synthesis of 4, we
prepared cocculidine (5) in five steps
[
19]
from iodoisoquinoline 31 and Weinreb
[
20]
amide 32
(Scheme 8). The sequence
began with the coupling of 31 and 32 to
afford the ketone adduct 33. The ethy-
nylation of 33 proceeded in quantitative
yield but with modest diastereoselectiv-
ity (d.r. 1.2:1) to give 34 as the major
product. Because the mixture of diaste-
Scheme 6. Selective manipulation of benzindolizinones.
reomers of the propargylic alcohol could not be separated
easily by flash chromatography, the mixture was subjected to
the cycloisomerization conditions to give the diastereomeric
benzindolizinone products 35 and its diastereomer in quanti-
tative yield. The diastereomers could be readily separated at
this stage to give 35 in 53% yield. On the basis of the
observations made during the cycloisomerization of enantio-
merically pure 28 to 29 (Scheme 7), we believe that excellent
chirality transfer from the propargylic stereocenter in 34 to
the ring-fusion position in 35 occurs even in the presence of
the methoxy-substituted stereocenter. In line with our
previous studies, the vinylogous-amide and enamine double
bonds of benzindolizinone 35 were readily reduced (in the
presence of the terminal alkene group) to give 36. A survey of
As a testament to the utility of the benzindolizinone
scaffolds that can now be accessed by our cycloisomerization
approaches, we employed benz[g]indolizinones in syntheses
of the Erythrina alkaloids 3-demethoxyerythratidinone (4)
and cocculidine (5). The synthesis of 4 commenced with the
preparation of benzindolizinone 29, which is available from
[
14]
iodoisoquinoline 25 in three steps (Scheme 7). The union of
[15]
2
5 and Weinreb amide 26 provided ketone 27. The treat-
[21]
ment of 27 with ethynylmagnesium bromide afforded the
propargylic tertiary alcohol 28 in 68% yield over the two
steps. Cycloisomerization of 28 to the desired benzindolizi-
none 29 proceeded in quantitative yield in 1 h upon heating in
ethanol. Notably, enantiomerically pure 28 (> 99% ee;
numerous direct and indirect ring-closing tactics led us to
conclude that a carbonyl–ene ring-closing metathesis reaction
[22,23]
with the Schrock molybdenum complex 37
provided the
best way to convert 36 into cocculidine (5). This shortest
reported synthesis of cocculidine highlights the significance of
the benzindolizinone framework as a starting point for the
[16]
obtained by preparative HPLC on a chiral phase) afforded
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synthesis of the Erythrina alkaloids. Synthetic 5 provided
spectral data that are in full agreement with those reported
previously. Furthermore, its structure was unambiguously
[
24]
confirmed by single-crystal X-ray analysis (Figure 1).
Figure 1. ORTEP representation of the X-ray crystallography data for
cocculidine. (Thermal ellipsoids are shown at the 50% probability
level. Most hydrogen atoms have been removed for clarity.)
Scheme 7. Synthesis of (ꢀ)-3-demethoxyerythratidinone (4). Reagents
and conditions: a) iPrMgCl, 25, THF, 08C, 2 h; 26, THF, 08C!RT,
overnight; b) HCCMgBr (2 equiv), THF, room temperature, 2 h;
In conclusion, we have described the development of
protic-solvent-mediated conditions for the synthesis of ben-
z[e]indolizinones and benz[g]indolizinones from quinoline
propargylic alcohols and isoquinoline propargylic alcohols,
respectively. These unusual heterocycles can be manipulated
selectively to afford partially saturated variants (e.g., benzin-
dolizidinones). These observations have been applied to short
syntheses of the Erythrina alkaloids (ꢀ)-3-demethoxyery-
thratidinone and (ꢀ)-cocculidine. Our synthesis of (ꢀ)-
cocculidine also provides a rare example of the utility of the
Schrock molybdenum complex 37 for a carbonyl–ene ring-
closing reaction in the context of natural products synthesis.
Our future studies are aimed at the application of benzindo-
lizinone azacycles in the synthesis of other complex natural
products.
c) EtOH, 1008C, 1 h; d) TFA, MeOH, NaBH CN (2.3 equiv), 08C;
3
acetone; 1m HCl. TFA=trifluoroacetic acid.
Received: May 30, 2013
Published online: && &&, &&&&
Keywords: cycloisomerization · Erythrina alkaloids ·
.
heterocycles · molybdenum · Schrock catalysts
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4
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Communications
Alkaloid Synthesis
Putting the “benz” in indolizinones: A
cycloisomerization approach to benz-
[g]indolizinones and benz[e]indolizinones
provides the first general route to these
unique azacycles (see example). The
utility of the benzindolizinone products
was demonstrated by the application of
this methodology to the total synthesis of
the Erythrina alkaloids 3-demethoxyery-
thratidinone and cocculidine.
S. T. Heller, T. Kiho, A. R. H. Narayan,
R. Sarpong*
&&&& — &&&&
Protic-Solvent-Mediated
Cycloisomerization of Quinoline and
Isoquinoline Propargylic Alcohols:
Syntheses of (ꢀ)-3-
Demethoxyerythratidinone and (ꢀ)-
Cocculidine
6
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Angew. Chem. Int. Ed. 2013, 52, 1 – 6
These are not the final page numbers!