Total Synthesis of Luotonin A and Rutaecarpine from an Aldimine via the Designed Cyclization

Article abstract of DOI:10.1021/acs.orglett.6b02597

The total synthesis of rutaecarpine (1) and luotonin A (2) is described through controlled cyclization of a common aldimine intermediate 5 derived from ethyl-2-aminocinnamate and quinazolinone-2-carbaldehyde. The cyanide-mediated imino-Stetter reaction of aldimine 5 provided the corresponding indole derivative 3, from which the total synthesis of rutaecarpine (1) was completed via the formation of a 6-membered C-ring. On the other hand, microwave-assisted thermal 6π-electrocyclization of the common intermediate 5, followed by the formation of a 5-membered C′-ring, allowed the completion of the total synthesis of luotonin A (2).

Full text of DOI:10.1021/acs.orglett.6b02597

Letter
pubs.acs.org/OrgLett
Total Synthesis of Luotonin A and Rutaecarpine from an Aldimine via
the Designed Cyclization
Se Hyun Kwon, Hong-Ahn Seo, and Cheol-Hong Cheon*
Department of Chemistry, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea
S
* Supporting Information
ABSTRACT: The total synthesis of rutaecarpine (1) and
luotonin A (2) is described through controlled cyclization of a
common aldimine intermediate 5 derived from ethyl-2-
aminocinnamate and quinazolinone-2-carbaldehyde. The cya-
nide-mediated imino-Stetter reaction of aldimine 5 provided
the corresponding indole derivative 3, from which the total
synthesis of rutaecarpine (1) was completed via the formation
of a 6-membered C-ring. On the other hand, microwave-
assisted thermal 6π-electrocyclization of the common inter-
mediate 5, followed by the formation of a 5-membered C′-ring, allowed the completion of the total synthesis of luotonin A (2).
conventional strategy for the total synthesis of natural
products is the design of a specific target molecule via an
Scheme 1. Synthetic Strategy for the Total Synthesis of
Rutaecarpine (1) and Luotonin A (2) via Controlled
Cyclization
A
independent synthetic pathway. However, recently, a divergent
strategy for total synthesis, in which several natural products
can be prepared from the same intermediate, has been receiving
much attention as a complementary method to the conven-
tional target-oriented total synthesis.1−3 Despite the consid-
erable number of divergent total syntheses of natural products
that have been reported to date,4,5 most of the previous
approaches have focused on the total synthesis of natural
products that bear a common skeleton with either different
appendages on the same skeleton (appendage divergent total
synthesis)4 or the same substituents with different stereo-
chemistry (stereochemical divergent total synthesis).5 However,
skeleton-divergent total syntheses, where natural products
bearing different skeletons are prepared from the same
intermediate, have been far less investigated.6
Since rutaecarpine (1) and luotonin A (2) (Scheme 1)
display a wide range of interesting biological activities, not
surprisingly, numerous synthetic endeavors have been made
toward the total syntheses of these natural products.7−10
Despite the fact that these two natural products belong to the
same family of quinazolinone alkaloids, most of the previous
syntheses of these natural products have been accomplished via
independent synthetic routes that utilize starting materials
bearing different skeletal frameworks. The synthesis of these
two quinazolinone alkaloids from a common intermediate has
not been reported to date.11 This is presumably due to the lack
of efficient methods to construct a divergent skeleton (i.e., both
indole and quinoline scaffolds) from the same intermediate.
Both alkaloids possess heterofused pentacyclic structures
bearing a quinazolinone moiety as the common building block.
The major structural difference is that rutaecarpine (1) has a
5,6-membered fused B,C-ring structure, while luotonin A (2)
has a 6,5-membered fused B′,C′-ring system. Based on their
structural similarity, we envisaged that rutaecarpine (1) and
luotonin A (2) could be prepared from the same intermediate 5
wherein the formation of the heterofused polycyclic B,C- and
B′,C′-ring systems in each respective natural product could be
controlled selectively (Scheme 1).12,13 Herein, we describe the
total synthesis of rutaecarpine (1) and luotonin A (2) from a
Received: August 30, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02597
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Letter
common aldimine 5, derived from ethyl-2-aminocinnamate 6
and quinazolinone-2-carbaldehyde 7.
Scheme 3. Total Synthesis of Rutaecarpine (1)
The retrosynthetic analysis of rutaecarpine (1) (Scheme 2a)
is based on our synthetic plan illustrated in Scheme 1. In this
Scheme 2. (a) Retrosynthetic Analysis of Rutaecarpine (1)
and (b) Working Hypothesis of the Imino-Stetter Reaction
as a Key Step in the Synthesis of Indole 3
aldimines possessing an acidic proton generally require a
stoichiometric amount of cyanide to promote the imino-Stetter
reaction15,16 and 5 possesses an acidic proton on the
quinazolinone ring, we performed the same transformation
with a stoichiometric amount of cyanide. Delightfully, aldimine
5 was completely consumed, and the desired product 3 was
obtained in 77% yield. Reduction of the ester moiety in 3 with
LiAlH4 provided the corresponding alcohol 8 with 85% yield,
and subsequent formation of the 6-membered C-ring via the
intramolecular Mitsunobu reaction afforded rutaecarpine (1) in
61% yield. Overall, we completed the total synthesis of
rutaecarpine (1) from known starting materials in only four
steps with an overall yield of 38%.
With the successful application of 5 to the synthesis of
rutaecarpine (1), we further attempted to develop a new
synthetic route for luotonin A (2) from the same intermediate
(Scheme 4). We postulated that luotonin A (2) could be
prepared by 5-membered C′-ring formation in ethyl 2-
quinazolinonylquinoline-3-carboxylate 4 via reduction of an
ester moiety followed by an intramolecular Mitsunobu
reaction.18 In turn, 4 could be prepared through 6-membered
B′-ring formation of aldimine 5, which was used as a key
intermediate in the synthesis of rutaecarpine(1).
pathway, the 6-membered C-ring in rutaecarpine (1) could
possibly be prepared via intramolecular cyclization from ethyl
2-quinazolinonylindole-3-acetate 3. Indole compound 3 was
anticipated to be prepared from aldimine 5 that in turn is
formed from ethyl 2-aminocinnamate 6 and quinazolinone-2-
carbaldehyde 7.14 The success of this approach depends on the
choice of a proper transformation reaction in which aldimine 5
could be converted into indole compound 3.
Very recently, our group developed a novel protocol for the
synthesis of 2-arylindole-3-acetic acid derivatives from
aldimines obtained from 2-aminocinnamic acid derivatives
and aromatic aldehydes via a cyanide-catalyzed imino-Stetter
reaction.15,16 Based on this methodology, we envisaged that if a
similar transformation were performed with 5 this reaction
would provide the corresponding indole-3-acetic acid derivative
3 carrying the quinazolinone moiety present in the 5-
membered B-ring of rutaecarpine (1) (Scheme 2b). For
example, cyanide adduct I of aldimine 5 would undergo
tautomerization, generating umpolung II of aldimine 5,17 and
the subsequent imino-Stetter reaction of umpolung II to the
adjacent α,β-unsaturated ester moiety would afford indole
compound 3.
Scheme 4. Retrosynthetic Analysis of Luotonin A (2)
With this working hypothesis in mind, we first explored the
imino-Stetter reaction of aldimine 5 in the presence of cyanide
(Scheme 3). When 5 was subjected to the reaction conditions
used in our previous work15 in the presence of a catalytic
amount of cyanide, the desired indole product 3 was obtained
in only low yield. Since our previous studies suggested that
B
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We next needed to determine the proper protocol required
to construct the quinoline scaffold (B′-ring) in luotonin A (2)
from aldimine 5. Among several choices of the 6-membered B′-
ring formation reactions, thermal 6π-electrocyclization was
chosen to construct the quinoline scaffold in luotonin A (2).19
With this synthetic plan in mind, we investigated the thermal
6π-electrocyclization of 5 (Table 1). When 5 was treated at 200
Scheme 5. . Total Synthesis of Luotonin A (2)
Table 1. Thermal Electrocyclization of Aldimine 5
entry
1
conditions
result
1,2,4-C6H3Cl3 air, 200 °C,
4 (23%) + 9 (27%) + 10 (26%) +
unidentifiable mixture
24 h
2
3
4
5
1,2,4-C6H3Cl3 MW (100 W), no reaction
Since we were unable to directly convert the ester moiety in
4 to an alcohol, we decided to search for an alternative strategy
to affect this transformation. Basic hydrolysis of the ester
moiety in 4 provided the corresponding carboxylic acid 11 with
quantitative yield. When compound 11 was treated with BH3,21
the starting material remained in solution, even after prolonged
reaction times, and the desired alcohol was not detected. On
the basis of these results, we deduced that the ester moiety
could be converted into a more reactive functional group, such
as acyl chloride 12, to increase reactivity toward the reducing
agent. Therefore, we converted carboxylic acid 11 into acyl
chloride 12 with the use of oxalyl chloride. The resulting crude
product was subsequently treated with NaBH4 in THF, without
further purification, to give the desired alcohol 13 in 94% yield
from carboxylic acid 11 over two steps. Intramolecular
Mitsunobu reaction18 of the resultant alcohol product
generated the 5-membered C′-ring needed to complete the
total synthesis of luotonin A (2). Thus, the total synthesis of
luotonin A (2) from 5 was completed in only four steps with an
overall yield of 34%.
In conclusion, we have developed a novel approach to
skeletal-divergent synthesis to access both rutaecarpine (1) and
luotonin A (2) from the common intermediate. This approach
proceeds through the controlled formation of a B,C- and B′,C′-
fused polycyclic ring system, respectively. Treatment of
aldimine 5, obtained from ethyl 2-aminocinnamate 6 and
quinazolinone-2-carbaldehyde 7, with cyanide led to 3, an
indole-3-acetic acid ethyl ester bearing a quinazolinone moiety
at the 2-position (i.e., the formation of the 5-membered B-ring
in rutaecarpine (1) via a cyanide mediated imino-Stetter
reaction). Subsequent reduction of the ester moiety into an
alcohol, followed by the Mitsunobu reaction, afforded
rutaecarpine (1) in only four steps in 38% overall yield from
known starting materials. On the other hand, microwave-
assisted thermal 6π-electrocyclization of the same aldimine
intermediate 5 afforded the corresponding quinoline 4 [i.e., the
formation of the 6-membered B′-ring in luotonin A (2)].
Hydrolysis of the ester moiety and subsequent conversion of
the carboxylic acid to acyl chloride with oxalyl chloride,
<150 °C, 10 h
1,2,4-C6H3Cl3 MW (100 W), 4 (42%) + 9 (12%) + 10 (15%) +
160 °C, 10 h
unidentifiable mixture
1,2,4-C6H3Cl3 MW (100 W), 4 (28%) + 9 (18%) + 10 (21%) +
180 °C, 10 h unidentifiable mixture
1,2,4-C6H3Cl3 MW (100 W), 4 (19%) + 9 (28%) + 10 (25%) +
200 °C, 10 h unidentifiable mixture
°C in 1,2,4-trichlorobenzene for 24 h, the desired product 4
was afforded with low yield (∼20% yield). This was
accompanied by the formation of several unexpected side-
products (entry 1). The careful structural analysis of these side
products determined that decarboxylated compound 9 and
quinazolinone 10 (12% and 15% yields, respectively) formed
via unexpected carbon−carbon bond cleavage. Despite
numerous efforts to improve the yield of compound 4 in this
reaction, we were unable to suppress the formation of the side
products. In order to improve the yield of the desired product,
electrocyclization was carried out under microwave irradi-
ation.20 The reaction temperature played a crucial role in the
efficiency of this transformation. The desired product was not
afforded when electrocyclization was carried out at temper-
atures <150 °C, and the aldimine remained unreacted (entry
2). On the other hand, at higher temperatures, there was a
considerable increase in the amount of side-products, without
any improvement in the yield of the desired product 4 (entries
3−5). After further investigation of the electrocyclization, 4 was
finally obtained in 42% yield (entry 3).
With compound 4 in hand, we attempted to complete the
total synthesis of luotonin A (2) (Scheme 5). Initially, we
attempted to convert compound 4 into compound 13 by the
reduction of the ester moiety to an alcohol following the
reported procedures.10a,d However, treatment of 4 with NaBH4
and CaCl2 did not afford 13, and 4 remained unreacted.
Furthermore, attempts to reduce the ester moiety with other
reducing agents, including LiBH4, DIBAL-H, L-Selectride, and
LiAlH4, were also unsuccessful. These resulted in either no
reaction or an unidentifiable complex mixture.
C
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Organic Letters
Letter
(b) Granger, B. A.; Kaneda, K.; Martin, S. F. Org. Lett. 2011, 13, 4542.
(c) Tseng, M.-C.; Cheng, H.-T.; Shen, M.-J.; Chu, Y.-H. Org. Lett.
2011, 13, 4434. (d) Zhang, C.; De, C. K.; Mal, R.; Seidel, D. J. Am.
Chem. Soc. 2008, 130, 416.
(9) For a review on the total synthesis of luotonin A (2), see: Liang,
J. L.; Cha, H. C.; Jahng, Y. Molecules 2011, 16, 4861 and references
cited therein..
(10) For recent examples of the total synthesis of luotonin A (2), see:
(a) Nagarapu, L.; Gaikwad, H. K.; Bantu, R. Synlett 2012, 23, 1775.
(b) Boisse, T.; Gavara, L.; Gautret, P.; Baldeyrou, B.; Lansiaux, A.;
followed by reduction of the resulting acid chloride with
NaBH4, afforded the corresponding alcohol 13. This latter
compound underwent Mitsunobu reaction [i.e., the formation
of the 5-membered C′-ring in luotonin A (2)] to complete the
total synthesis of luotonin A (2) from 5, in four steps, with 34%
yield. Further development of skeleton-divergent total synthesis
designed by unique reaction mechanisms is currently underway
in our laboratory and will be reported in due course.
ASSOCIATED CONTENT
* Supporting Information
́
Goossens, J.-F.; Henichart, J.-P.; Rigo, B. Tetrahedron Lett. 2011, 52,
■
1592. (c) Tseng, M.-C.; Chu, Y.-W.; Tsai, H.-P.; Lin, C.-M.; Hwang, J.;
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M. K.; Chothe, A. S.; Srinivasan, K. V. Eur. J. Chem. 2011, 2, 235.
(11) A few reports on the synthesis of these two natural products are
available to date, although a starting material already possessed a
proper skeleton in previous total syntheses. See: (a) Bowman, W. R.;
Elsegood, M. R. J.; Stein, T.; Weaver, G. W. Org. Biomol. Chem. 2007,
5, 103. (b) Harayama, T.; Hori, A.; Serban, G.; Morikami, Y.;
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(c) Lee, E. S.; Park, J.-G.; Jahng, Y. Tetrahedron Lett. 2003, 44, 1883.
(12) Since a quinoline scaffold would be generated from an indole
scaffold in a biosynthetic pathway, luotonin A (2) could be prepared
from rutaecarpine (1) in biosynthesis. For a review on the biosynthesis
of indole monoterpene alkaloids, see: O’Connor, S. E.; Maresh, J. J.
Nat. Prod. Rep. 2006, 23, 532.
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02597.
Detailed experimental procedure and spectral data for all
compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: cheon@korea.ac.kr.
Notes
The authors declare no competing financial interest.
(13) For an example of divergent construction of either an indole or
a quinoline scaffold from quinone imides, see: Parker, K. A.; Mindt, T.
L. Org. Lett. 2002, 4, 4265.
(14) Khalil, Z. H.; Koraiem, A. I. M.; El-Maghraby, M. A.; Abu-El-
Hamd, R. M. J. Chem. Technol. Biotechnol. 1986, 36, 379.
(15) Lee, S. J.; Seo, H.-A.; Cheon, C.-H. Adv. Synth. Catal. 2016, 358,
1566.
(16) For the synthesis of 2-vinylindole-3-acetic acid derivatives via a
cyanide-catalyzed imino-Stetter reaction, see: Seo, H.-A.; Cheon, C.-H.
J. Org. Chem. 2016, 81, 7917.
ACKNOWLEDGMENTS
■
This work was supported by National Research Foundation of
Korea (NRF) grants funded by the Korean Government (NRF-
2015R1D1A1A01057200 and NRF-20100020209). C.-H.C. is
also thankful for financial support from an NRF grant funded
by the Korean Government (NRF-2014-011165; Center for
New Directions in Organic Synthesis).
(17) For our initial discovery of umpolung of aldimines with cyanide,
see: Seo, H.-A.; Cho, Y.-H.; Lee, Y.-S.; Cheon, C.-H. J. Org. Chem.
2015, 80, 11993.
(18) For previous examples of the total synthesis of luotonin A (2)
via 5-membered C′-ring formation through intramolecular Mitsunobu
reaction, see: (a) Chavan, S. P.; Sivappa, R. Tetrahedron 2004, 60,
9931. (b) Mhaske, S. B.; Argade, N. P. J. Org. Chem. 2004, 69, 4563.
(c) See also refs 10a and 10d.
(19) For the use of thermal 6π-electrocyclization of aldimines to
construct a quinoline moiety, see: Qiang, L. G.; Baine, N. H. J. Org.
Chem. 1988, 53, 4218.
(20) For examples of microwave-assisted thermal 6π-electrocycliza-
tion of imines, see: (a) Markey, S. J.; Lewis, W.; Moody, C. J. Org. Lett.
2013, 15, 6306. (b) Portela-Cubillo, F.; Scott, J. S.; Walton, J. C. J. Org.
Chem. 2009, 74, 4934. (c) Trost, B. M.; Gutierrez, A. C. Org. Lett.
2007, 9, 1473.
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