General Strategy for the Synthesis of Antirhine Alkaloids: Divergent Total Syntheses of (±)-Antirhine, (±)-18,19-Dihydroantirhine, and Their 20-Epimers

Article abstract of DOI:10.1021/acs.orglett.0c00544

A general synthetic strategy for antirhine alkaloids was developed in this study. The cyanide-catalyzed imino-Stetter reaction of ethyl 2-aminocinnamate and 4-bromopyridine-2-carboxaldehyde afforded the corresponding indole-3-acetic acid derivative. Subsequent formation of the six-membered C ring followed by trans-selective installation of the two-carbon unit at C-15 provided rapid access to the key intermediate. Stereoselective installation of substituents at C-20 allowed the total syntheses of (±)-antirhine, (±)-18,19-dihydroantirhine, and their 20-epimers, all of the known natural products in the antirhine family.

Full text of DOI:10.1021/acs.orglett.0c00544

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Letter
General Strategy for the Synthesis of Antirhine Alkaloids: Divergent
Total Syntheses of ( )-Antirhine, ( )-18,19-Dihydroantirhine, and
Their 20-Epimers
Cheolwoo Bae,§ Eunjoon Park,§ Cheon-Gyu Cho,* and Cheol-Hong Cheon*
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ABSTRACT: A general synthetic strategy for antirhine alkaloids was developed in this study. The cyanide-catalyzed imino-Stetter
reaction of ethyl 2-aminocinnamate and 4-bromopyridine-2-carboxaldehyde afforded the corresponding indole-3-acetic acid
derivative. Subsequent formation of the six-membered C ring followed by trans-selective installation of the two-carbon unit at C-15
provided rapid access to the key intermediate. Stereoselective installation of substituents at C-20 allowed the total syntheses of
( )-antirhine, ( )-18,19-dihydroantirhine, and their 20-epimers, all of the known natural products in the antirhine family.
ntirhine (1) and its congeners (2−4) comprise a small
a cis C−D ring junction. Moreover, as all of the C-20 epimers
of these natural products are found in nature, additional
structural diversity is imparted upon this family.
A
group within the indole monoterpene alkaloids possessing
very unique structural features (Figure 1).1,2 Unlike other
The unique structural features of the antirhine family have
attracted considerable attention from the synthetic chemists.3,4
Conventionally, the natural product in the antirhine family has
been synthesized from a specific starting material containing
the key fragment with the desired stereochemistry at C-15 and
C-20. Subsequent construction of the C and D rings with
tryptamine provides the desired natural product. On the basis
of these strategies, several total syntheses of antirhine and
18,19-dihydroantirhine have been reported.3−5 Unfortunately,
these conventional approaches have several limitations. First is
the lack of generality applicable for both antirhine (1) and its
congeners (2−4). Each of those previous syntheses was
tailored for a specific target natural product from a starting
material elaborated with specific substituents. To date there
have been no examples of the divergent total synthesis of 1−4.
This is rather surprising in view of the fact that these natural
products are derived biosynthetically from a common
Figure 1. (a) Structural features of antirhine alkaloids. (b) Structures
of antirhine (1), 18,19-dihydroantirhine (2), and their 20-Epimers (3
and 4).
Received: February 11, 2020
indole monoterpene alkaloids bearing the indoloquinolizidine
scaffold, the antirhine family has the C-18−C-19 vinyl (or
ethyl) group connected to the side chain at C-20 rather than to
the D ring at the carbon meta to the piperidine nitrogen (C-
16). In addition, they possess a thermodynamically less stable
anti relationship between the C-3 and C-15 stereocenters with
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intermediate. Second is the lengthy synthetic sequence needed
for the control of the C-15 and C-20 stereochemistry and/or
installation of the additional functional groups during the
construction of the C and D rings with tryptamine. Third is the
difficulty in controlling the trans relationship between the C-3
and C-15 stereocenters due to the competing formation of a
more stable cis product. To overcome these limitations, a
general protocol allowing for the total synthesis of all of the
products in this family from a common intermediate is highly
desired.
Scheme 2. Preparation of Key Intermediate 18
Recently, our group reported a novel cyanide-catalyzed
imino-Stetter reaction that provides rapid access to various
synthetically useful 2-substituted indole-3-acetic acid deriva-
tives6,7 and also demonstrated their utility for the syntheses of
indole alkaloid natural products.8 As a part of our continuing
efforts to use the cyanide-catalyzed imino-Stetter reaction in
the total synthesis of indole alkaloids, we herein report a
general synthetic strategy that allows the divergent total
synthesis of ( )-antirhine (1), ( )-18,19-dihydroantirhine
(2), ( )-20-epi-antirhine (3), and ( )-20-epi-18,19-dihy-
droantirhine (4).
Since all of the natural products in this family bear a
tetracyclic indoloquinolizidine scaffold with a trans config-
uration at C-3 and C-15, they could be synthesized from the
key intermediate through the stereocontrolled installation of
the substituents at C-20. Based on this idea, our retrosynthetic
analysis of 1−4 is depicted in Scheme 1. Natural products 1−4
Scheme 1. Retrosynthetic Analysis
We next sought to install the 2-alkoxy-2-oxoethyl group at
C-15 using a suitable two-carbon nucleophile. When
dihydroindoloquinolizium salt 13 was treated with Meldrum’s
acid in the presence of triethylamine (TEA), the desired
product 14 bearing the 2-alkoxy-2-oxoethyl group at C-15 was
obtained after thermolysis in methanol in the presence of
HCl.9 Subsequent reduction of the pyridinium ring in 14 with
10
NaBH4 at room temperature gave the corresponding
indoloquinolizidine derivative 15 in 70% yield over three steps.
With compound 15 in hand, we turned our attention to the
trans-selective hydrogenation of the C-15−C-16 double bond
for the synthesis of key intermediate 18. However, palladium-
catalyzed hydrogenation of 15 resulted exclusively in the
production of ester 16 with the cis configuration between the
C-3 and C-15 stereocenters in quantitative yield. Previous
studies indicated that masking the indole nitrogen with a
sterically hindered bulky protecting group could change the
facial selectivity during hydrogenation.11 On the basis of that
work, Boc-protected indoloquinolizidine 17 was prepared
before submission to the catalytic hydrogenation conditions.
To our delight, hydrogenation of 17 provided compound 18
with the desired trans configuration between the C-3 and C-15
stereocenters in 85% yield along with its cis isomer (∼14%
yield) following chromatographic separation.
could be synthesized from indoloquinolizidine 5 through the
stereoselective installation of a vinyl (ethyl) group at C-20. We
expected that intermediate 5 could be prepared from 2-(2-
pyridyl)indole-3-acetic acid 6 via formation of the C ring
followed by the stereocontrolled installation of a 2-alkoxy-2-
oxoethyl group at C-15. Indole 6 could be obtained from 2-
aminocinnamic acid derivative 7 and pyridine-2-carboxalde-
hyde 8 via the cyanide-catalyzed imino-Stetter reaction.
Having identified a clear route to natural products 1−4, we
began the synthesis with the preparation of indoloquinolizidine
18 (Scheme 2). Toward this end, aldimine I, derived from
ethyl 2-aminocinnamate (9) and 4-bromopyridine-2-carbox-
aldehyde (10), was submitted to the cyanide-catalyzed imino-
Stetter reaction under the previously developed conditions.6−8
Gratifyingly, the corresponding indole product 11 was
obtained in 92% yield. Reduction of the ester moiety in 11
with L-Selectride followed by treatment of the resulting alcohol
12 with Tf2O provided dihydroindoloquinolizium salt 13 in
85% yield over the two steps.8d
Having successfully prepared key intermediate 18, we
investigated the installation of the C-20 vinyl group. Among
various α-vinylation methods and conditions, we opted to use
the protocol involving conjugate addition with vinyl sulfoxide
and thermal elimination (Scheme 3).12 When the enolate of
ester 18, generated by treatment with LiHMDS at −78 °C,
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conversion of the ester group into the vinyl group would give
( )-antirhine (1) and ( )-18,19-dihydroantirhine (2).
On the basis of this hypothesis, we carried out the synthesis
of ( )-antirhine (1) and ( )-18,19-dihydroantirhine (2) by
following the route shown in Scheme 4. When submitted to
Scheme 3. Total Syntheses of ( )-20-epi-Antirhine (3) and
( )-20-epi-18,19-Dihydroantirhine (4)
Scheme 4. Total Synthesis of ( )-Antirhine (1) and
( )-18,19-Dihydroantirhine (2)
reacted with phenyl vinyl sulfoxide, the desired conjugate
adduct 19 was obtained in moderate yield as a mixture of only
two diastereomers.13 Since compound 19 has two possible
stereogenic centers (C-20 and the sulfur atom) and thus can
have four possible diastereomers, we were not certain at this
stage which stereogenic center affected the diastereoselectivity.
We therefore chose to determine their stereochemistry after
converting sulfoxide 19 into the known natural product(s) and
comparing their spectroscopic data. Toward this end, the
indole N-Boc group in 19 was removed with formic acid at 40
°C, and the methyl ester was reduced with LiAlH4 to deliver
alcohol 20 as a mixture of two diastereomers with a similar
diastereomeric ratio as compound 19. Surprisingly, the final
thermal elimination of the sulfoxide group in alcohol 20
afforded the product as a single entity.14 Since the
spectroscopic data of the resulting homoallylic alcohol were
identical to those of ( )-20-epi-antirhine (3),1c ester 19 was
found to have the α-H configuration at C-20. Its stereo-
chemistry was further confirmed by comparing the spectro-
scopic data for the product of hydrogenation of the resulting
homoallylic alcohol 3 with those of the reported ( )-20-epi-
18,19-dihydroantirhine (4).1b,4e It should be noted that the
diastereoselectivity at C-20 can be controlled during enolate
alkylation, and the diastereomeric relationship in ester 19 can
be attributed to the chirality of the sulfur atom. Furthermore,
the electrophile approaches from the Si face to the enolate,
predominantly leading to the formation of the α-H isomer.
After obtaining the 20-epimers 3 and 4, we continued with
the synthesis of ( )-antirhine (1) and ( )-18,19-dihydroan-
tirhine (2), which requires 20-β-H-selective installation of the
vinyl (or ethyl) group at C-20 in ester 18. In light of this,
various alkylating partners and reaction conditions were
explored. However, all of the efforts to reverse the stereo-
chemical outcome of the alkylation reaction were fruitless. In
most of these reactions, the electrophiles approached from the
Si face of the enolate, leading to the 20-α-H configuration as
the major product. At this point, we decided to take advantage
of the strong Si face selectivity observed in the C-20 alkylation
reactions rather than trying to reverse it, envisioning that the
introduction of a hydroxymethyl group at C-20 and the
the reaction with methoxymethyl (MOM) chloride, the
enolate of 18 showed reasonable facial selectivity to give the
desired 20-α-H-isomer 21 in 64% yield along with its 20-
epimer, 20-epi-21 in 16% yield after column chromatography
separation. Reduction of the ester moiety in 21 with DIBAL
afforded the corresponding alcohol 22 in 95% yield. Dess−
Martin oxidation of alcohol 22 afforded the corresponding
aldehyde. However, this aldehyde was quite unstable and
underwent rapid β-elimination to furnish the α,β-unsaturated
aldehyde during flash column chromatography.15 To bypass
this issue, we directly converted the resulting aldehyde to the
corresponding double bond without isolating the aldehyde.
The crude aldehyde product was directly submitted to the
Wittig reaction at −30 °C without purification and provided
homoallyl ether 23 in 41% overall yield.16 Deprotection of the
N-Boc group and demethylation under conditions developed
by Yamada and co-workers17 provided ( )-antirhine (1) in
30% yield. Saturation of the homoallylic double bond in 1
using palladium-catalyzed hydrogenation afforded ( )-18,19-
dihydroantirhine (2). The spectroscopic data of 1 and 2 agreed
with the reported values.3,4
To rationalize the strong Si face selectivity during the
alkylation of the enolate derived from compound 18, we
proposed a possible transition state for the alkylation reaction
of enolate 25 with electrophiles (Scheme 5a). The lithium
cation in enolate 25 might interact with the tertiary nitrogen
atom to form a rather rigid cyclic structure. In this cyclic
structure, the Re face would be blocked by the bulky Boc
group, and thus, the electrophile would approach from the Si
C
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Scheme 5. (a) Plausible Transition State for Alkylation of
Enolate 25; (b) Synthesis of ( )-20-epi-18,19-
Dihydroantirhine (4) and ( )-18,19-Dihydroantirhine (2)
AUTHOR INFORMATION
Corresponding Authors
■
Cheol-Hong Cheon − Center for New Directions in Organic
Synthesis, Department of Chemistry, Korea University, Seoul
02841, Republic of Korea; orcid.org/0000-0002-6738-
6193; Email: cheon@korea.ac.kr
Cheon-Gyu Cho − Center for New Directions in Organic
Synthesis, Department of Chemistry, Hanyang University, Seoul
04763, Republic of Korea; orcid.org/0000-0003-4851-
5671; Email: ccho@hanyang.ac.kr
Authors
Cheolwoo Bae − Center for New Directions in Organic
Synthesis, Department of Chemistry, Korea University, Seoul
02841, Republic of Korea
Eunjoon Park − Center for New Directions in Organic Synthesis,
Department of Chemistry, Korea University, Seoul 02841,
Republic of Korea; orcid.org/0000-0002-6253-3406
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00544
Author Contributions
§C.B. and E.P. contributed equally.
Notes
The authors declare no competing financial interest.
face, leading to the strong 20-α-H selectivity. To further prove
this facial selectivity, we envisaged that ( )-20-epi-18,19-
dihydroantirhine (4) could be prepared from compound 18 via
ethylation of enolate 25 as long as the same facial selectivity
was obtained (Scheme 5b). Treatment of enolate 25 with ethyl
iodide provided the ethylated product 26 and its 20-epimer in
64% and 16% yield, respectively. Subsequent deprotection of
the Boc group followed by reduction of the ester afforded 4 as
the major product along with 2.
In conclusion, we have developed a general strategy that
allows the synthesis of the antirhine family of alkaloids,
including ( )-antirhine (1), ( )-18,19-dihydroantirhine (2),
and their 20-epimers. The key to the success is the cyanide-
catalyzed imino-Stetter reaction to give indole-3-acetic acid
derivatives bearing a pyridine ring at the 2-position.
Subsequent construction of the piperidine C ring and trans-
selective installation of the two-carbon unit at C-15 effectively
delivered the key intermediate. Stereoselective alkylation at C-
20 followed by functional group manipulations completed the
total syntheses of ( )-antirhine, ( )-18,19-dihydroantirhine,
and their 20-epimers.
ACKNOWLEDGMENTS
■
This work was supported by grants from the National Research
Foundation of Korea (NRF) funded by the Korean Govern-
ment (NRF-2018R1D1A1A02086110 and NRF-2014-011165,
Center for New Directions in Organic Synthesis).
REFERENCES
■
(1) For the isolation of antirhine (1), see: (a) Johns, S. R.;
Lamberton, J. A.; Occolowitz, J. L. Chem. Commun. 1967, 229b−230.
For the isolation of 18,19-dihydroantirhine (2) and its 20-epimer (4),
̀
see: (b) Robert, G. M. T.; Ahond, A.; Poupat, C.; Potier, P.; Jolles, C.;
Jousselin, A.; Jacquemin, H. J. Nat. Prod. 1983, 46, 694−707. For the
isolation of 20-epi-antirhine (3), see: (c) Weniger, B.; Anton, R.;
Varea, T.; Quirion, J.-C.; Bastida, J.; Garcia, R. J. Nat. Prod. 1994, 57,
287−290.
́
(2) Buckingham, J.; Baggaley, K. H.; Roberts, A. D.; Szabo, L. F.
Dictionary of Alkaloids, 2nd ed.; CRC Press: Boca Raton, FL, 1994.
(3) For the total synthesis of rac-antirhine (1), see: (a) Takano, S.;
Takahashi, M.; Ogasawara, K. J. Am. Chem. Soc. 1980, 102, 4282−
4283. For asymmetric total syntheses of antirhine (1), see:
(b) Takano, S.; Tamura, N.; Ogasawara, K. J. Chem. Soc., Chem.
Commun. 1981, 0, 1155−1156. (c) Suzuki, T.; Sato, E.; Unno, K.;
Kametani, T. Heterocycles 1985, 23, 839−842. (d) Suzuki, T.; Sato, E.;
Unno, K.; Kametani, T. Chem. Pharm. Bull. 1986, 34, 3135−3141.
(e) Brown, R. T.; Dauda, B. E. N.; Santos, C. A. M. J. Chem. Soc.,
Chem. Commun. 1991, 825−826. (f) Pancrazi, A.; Kervagoret, J.;
Khuong-Huu, Q. Tetrahedron Lett. 1991, 32, 4483−4486. (g) Danieli,
B.; Lesma, G.; Mauro, M.; Palmisano, G.; Passarella, D. Tetrahedron
1994, 50, 8837−8852. (h) Kawamura, M.; Ogasawara, K. Tetrahedron
Lett. 1995, 36, 3369−3372.
(4) For the total syntheses of rac-18,19-dihydroantirhine (2), see:
(a) Wenkert, E.; Sprague, P. W.; Webb, R. L. J. Org. Chem. 1973, 38,
4305−4308. (b) Chevolot, L.; Husson, H.-P.; Potier, P. Tetrahedron
1975, 31, 2491−2494. (c) Ficini, J.; Guingant, A.; d’Angelo, J. J. Am.
Chem. Soc. 1979, 101, 1318−1319. (d) Lounasmaa, M.; Jokela, R.
Tetrahedron 1989, 45, 7449−7458. (e) Tietze, L. F.; Bachmann, J.;
Wichmann, J.; Zhou, Y.; Raschke, T. Liebigs Ann. 1997, 1997, 881−
886. For the asymmetric total synthesis of 18,19-dihydroantirhine
This work continues to display the utility and versatility of
our indole-3-acetic acid protocol via the cyanide-catalyzed
imino-Stetter reaction. Furthermore, this method allowed us
not only to access a unique molecule class but also to develop a
previously unseen divergent synthesis that has clear potential
for applications outside of this specific group.
ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00544.
Experimental details and full characterization data
(PDF)
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(2), see: (f) Kametani, T.; Suzuki, T.; Sato, E.; Nishimura, M.; Unno,
K. J. Chem. Soc., Chem. Commun. 1982, 1201−1203.
(5) Although 20-epimers of antirhine (1) and 18,19-dihydroantir-
hine (2) are found in nature, there have been no total syntheses of 20-
epi-antirhine (3) and 20-epi-18,19-dihydroantirhine (4).
(6) For a review of the synthesis of 2-substituted indole-3-acetic acid
derivatives via the cyanide-catalyzed imino-Stetter reaction, see: Park,
E.; Jeon, J.; Cheon, C.-H. Chem. Rec. 2018, 18, 1474−1488.
(7) For the seminal reports on the synthesis of 2-substituted indole-
3-acetic acid derivatives via the cyanide-catalyzed imino-Stetter
reaction, see: (a) Lee, S. J.; Seo, H.-A.; Cheon, C.-H. Adv. Synth.
Catal. 2016, 358, 1566−1570. (b) Seo, H.-A.; Cheon, C.-H. J. Org.
Chem. 2016, 81, 7917−7923.
(8) For the total syntheses of several natural products using the
cyanide-catalyzed imino-Stetter reaction as the key step, see:
(a) Kwon, S. H.; Seo, H.-A.; Cheon, C.-H. Org. Lett. 2016, 18,
5280−5283. (b) Lee, S. E.; Lee, S. J.; Cheon, C.-H. Synthesis 2017,
49, 4247−4253. (c) Lee, S.; Kim, K.-H.; Cheon, C.-H. Org. Lett.
2017, 19, 2785−2788. (d) Park, E.; Cheon, C.-H. Org. Biomol. Chem.
2017, 15, 10265−10275. (e) Jeon, J.; Cheon, C.-H. Org. Chem. Front.
2019, 6, 456−467. (f) Park, E.; Cheon, C.-H. Adv. Synth. Catal. 2019,
361, 4888−4892.
(9) For selected examples using Meldrum’s acid as a surrogate for
acetic acid functionality, see: Lipson, V. V.; Gorobets, N. Y. Mol.
Diversity 2009, 13, 399−419.
(10) Our group has developed several total syntheses of alkaloids via
the preparation of the piperidine ring through the reduction of the
pyridinium ring. See ref 8d and: (a) Jo, Y.-I.; Burke, M. D.; Cheon, C.-
H. Org. Lett. 2019, 21, 4201−4204. (b) Jo, Y.-I.; Cheon, C.-H. J. Org.
Chem. 2019, 84, 11902−11910.
(11) Lounasmaa, M.; Jokela, R. Tetrahedron 1989, 45, 3975−3992.
(12) For recent examples of α-vinylation of carbonyl groups using
vinyl sulfoxides, see: Bissember, A. C.; Banwell, M. G. Tetrahedron
2009, 65, 8222−8230.
(13) Phenyl vinyl sulfoxide has been known to undergo anionic
polymerization. See: Kanga, R. S.; Hogen-Esch, T. E.;
Randrianalimanana, E.; Soum, A.; Fontanille, M. Macromolecules
1990, 23, 4235−4240.
(14) We were able to rule out the possibility of kinetic elimination
from only one of the two diastereomers since the ratio of the two
diastereomers in the reaction mixture did not change at all during the
course of the thermal elimination.
(15) The structure of the α,β-unsaturated aldehyde was confirmed
1
by H and 13C NMR spectroscopy and HRMS (see the Supporting
Information).
(16) Controlling the reaction temperature during the Wittig reaction
was very important to improve the yield of the desired product 23.
The reaction at temperatures above −30 °C generated a considerable
amount of the α,β-unsaturated aldehyde.
(17) Niwa, H.; Hida, T.; Yamada, K. Tetrahedron Lett. 1981, 22,
4239−4240.
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