Total Syntheses of Echitamine, Akuammiline, Rhazicine, and Pseudoakuammigine

Article abstract of DOI:10.1002/anie.201901086

Echitamine (1) and akuammiline (2) are representative members of a fascinating class of monoterpenoid indole alkaloids. We report the syntheses of 2 and its congener deacetylakuammiline (3). The azabicyclo[3.3.1]nonane motif was assembled through silver-catalyzed internal alkyne cyclization, and one-pot C?O bond cleavage/C?N bond formation furnished the pentacyclic scaffold. Compound 3 then served as a common intermediate for preparing a series of structurally diverse and synthetically challenging congeners including 1. A position-selective Polonovski–Potier reaction followed by formal N-4 migration built the core of N-demethylechitamine (4) and 1. An alternative route featuring Meisenheimer rearrangement gave 4 as well. Oxidation of the alcohol within 3 gave rhazimal (5), which underwent tandem indolenine hydrolysis, hemiaminalization, and hemiketalization to form rhazicine (6). A sequence of N,O-ketalization and reductive amination secured the chemoselectivity of N-methylation, leading to pseudoakuammigine (7).

Full text of DOI:10.1002/anie.201901086

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Total Syntheses of Echitamine, Akuammiline, Rhazicine, and
Pseudoakuammigine
Authors: Xiang Zhang, Badrinath Kakde, Rui Guo, Sonyabapu Yadav,
Yucheng Gu, and Ang Li
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201901086
Angew. Chem. 10.1002/ange.201901086
Link to VoR: http://dx.doi.org/10.1002/anie.201901086
http://dx.doi.org/10.1002/ange.201901086

10.1002/anie.201901086
Angewandte Chemie International Edition
COMMUNICATION
Total Syntheses of Echitamine, Akuammiline, Rhazicine, and
Pseudoakuammigine
Xiang Zhang,† Badrinath N. Kakde,† Rui Guo, Sonyabapu Yadav, Yucheng Gu, and Ang Li*
Dedicated to Professor Han-Dong Sun on the occasion of his 80th birthday
Abstract: Echitamine (1) and akuammiline (2) are representative
members of a fascinating class of monoterpenoid indole alkaloids.
We report the syntheses of 2 and its congener deacetylakuammiline
(3). The azabicyclo[3.3.1]nonane motif was assembled through
silver-catalyzed internal alkyne cyclization, and one-pot C−O bond
cleavage/C−N bond formation furnished the pentacyclic scaffold.
Compound 3 then served as a common intermediate for preparing a
series of structurally diverse and synthetically challenging congeners
including 1. A position-selective Polonovski−Potier reaction followed
by formal N-4 migration built the core of N-demethylechitamine (4)
and 1. An alternative route featuring Meisenheimer rearrangement
reached 4 as well. Oxidation of the alcohol within 3 gave rhazimal (5),
which underwent tandem indolenine hydrolysis, hemiaminalization,
and hemiketalization to form rhazicine (6). A sequence of N,O-
ketalization and reductive amination secured the chemoselectivity of
N-methylation, leading to pseudoakuammigine (7).
Garg and co-workers disclosed for the first time the syntheses of 2
and 7 featuring their signature interrupted Fisher indole synthesis.[21]
However, other molecules shown in Figure 1, in particular 1, the first
isolated member of this family, have not been conquered to our
knowledge. We recognized 3 as a versatile intermediate and thus
initiated
a
program toward collective syntheses of the
echitamine/akuammiline family members. Herein, we report the total
syntheses of 1–7.
Echitamine (1, Figure 1) is an intriguing monoterpene indole
alkaloid that first emerged in the literature in 1875.[1] A sterically
congested cyclohexane moiety bearing five stereocenters is
embedded in its compact pentacyclic scaffold.[2] In 1932, Henry
characterized a congener of 1 originally isolated from the seeds of
Picralima klaineana (natively known as “akuamma”) and named it
akuammiline (2).[3] It contains a doubly bridged tricyclic core with two
vicinal quaternary centers;[4] the connectivity of the bridged ring
system differed from that of 1. Since then, more than 100 structurally
relevant alkaloids (e.g. 3–7) have been discovered.[5] Among them,
some share the framework with 1, such as N-demethylechitamine[6]
(4) and vincorine,[7] and some correspond to 2, such as
deacetylakuammiline[8] (3), rhazimal[9] (5), and strictamine.[10,11]
Others possess skeletal connectivities that diverge from the two
original members while retaining a common biogenetic heritage,
such as rhazicine[12] (6), pseudoakuammigine[13] (7), aspidophylline
A,[14,10a] and scholarisine A.[15] This family of alkaloids exhibit a broad
range of biological activities, such as anti-inflammatory, anticancer,
and antimicrobial properties.[5,16] Not surprisingly, they have long
been attractive targets for chemical synthesis.[5,17] Qin and
colleagues pioneered the campaign by achieving the synthesis of
(±)-vincorine.[7a] Subsequently, a series of elegant syntheses of
members from this family were accomplished[7b,c,10,14,15,18] based on
the development of powerful strategies and methods.[19] In 2016, we
reported the syntheses of aspidodasycarpine and lonicerine,[20] both
of which belong to the aspidophylline A subclass.[14] Very recently,
Figure 1. The structures and retrosynthetic analysis of alkaloids 1–7.
We first envisioned a retrosynthetic network connecting the six
alkaloids (1, 2, and 4–7) to the common precursor 3 (Figure 1, the
upper half). Obviously, 2 could be derived from 3 through acetylation.
On the other hand, 7 may also arise from 3. We considered a
sequence of N,O-ketalization and N-1-methylation for assembling
the furoindoline motif of 7, although chemoselective methylation of
the less reactive nitrogen was a challenge. As highlighted in red, 1
and 4 were traced back to 3 via the intermediacy of ketone 8 and
amine N-oxide 9. The skeletal alteration of 9 could be triggered by a
position-selective Polonovski reaction.[22] The iminium ion species
containing a C-3═N-4 bond (the desired Polonovski product) was
[*]
X. Zhang,† Dr. B. N. Kakde,† R. Guo, S. Yadav, Prof. Dr. A. Li
State Key Laboratory of Bioorganic and Natural Products Chemistry
Center for Excellence in Molecular Synthesis
Shanghai Institute of Organic Chemistry
University of Chinese Academy of Sciences
Chinese Academy of Sciences
345 Lingling Road, Shanghai 200032 (China)
E-mail: ali@sioc.ac.cn; web: http://angligroup.sioc.ac.cn
Dr. Y. Gu
Syngenta, Jealott’s Hill International Research Centre
Bracknell, Berkshire RG42 6EY (UK)
These authors contributed equally.
[†]
This article is protected by copyright. All rights reserved.

10.1002/anie.201901086
Angewandte Chemie International Edition
COMMUNICATION
Scheme 1. Construction of pentacyclic intermediate 16.
anticipated to undergo hydrolysis upon aqueous workup. The
exposed secondary amine should be trapped by the indolenine imine
instantaneously and irreversibly, which would furnish the
pyrroloindoline moiety of 8. The path highlighted in blue revealed the
relationship between 6 and 3 with the intermediacy of 5. The
indolenine within 5 could be hydrolyzed to release an aniline, which
may attack the aldehyde to form the tetrahydroquinoline core of 6.
tertiary alcohol as a side product; the Jamison modification[28] [PbCl2
(cat.), Zn, CH2I2, ZrCl4] increased the yield to 89%. The next problem
was the chemo- and face-selective hydroboration of the newly
formed exocyclic C═C bond. BH3•THF and Sia2BH reacted with both
olefins within the substrate, while 9-BBN led to incomplete
conversion. Treatment with Cy2BH gave alcohol 20 as a single C-16
diastereomer in 84% yield after peroxide treatment. This compound
underwent O-alkylation with triflate 21 followed by Br−I exchange to
afford iodide 22, the structure of which was verified by X-ray
crystallographic analysis (Scheme 1). A variety of conditions were
tested for the intramolecular indole alkylation. The conditions
developed for our syntheses of aspidodasycarpine and lonicerine[20]
[tBuOLi, DMSO, 120 °C (microwave)] gave a trace amount of the
desired product 16; severe substrate decomposition was observed.
Conventional basic conditions for indole C-alkylation such as
CsF/DMF and LDA/HMPA/THF were ineffective in this case, and 22
was mostly recovered. AgOTf and 2,6-di-tert-butylpyridine caused
rapid decomposition of 22. We then examined the combinations of
nonpolar solvents and strong bases and found that treatment with
tBuOK in refluxing toluene significantly improved cyclization
efficiency. The optimal conditions (tBuOK, 1,2-dichlorobenzene,
180 °C) led to 16 as a single C-7 diastereomer in 70% yield.
A retrosynthetic analysis of 3 was illustrated in the lower half of
Figure 1. The quaternary C-16 could be constructed through a late-
stage aldol reaction. Thus, pentacyclic alcohol 10 was considered a
sub-target. This compound may arise from tetrahydropyran 11
through migration of C-5 from O to N-4. This bold proposal could be
achieved by using
a one-pot halogenation/amination protocol;
halogenation at C-5 should be more feasible than that at C-17
because of the steric bias. This strategy avoided releasing the C-5
hydroxy group which would attack the imine instantaneously to form
an N,O-ketal. Simplification of 11 led to tetracyclic ketone 12. Face-
selective homologation was required to establish the C-16
stereochemistry, and the C-6−C-7 bond could be built through
intramolecular
indole
alkylation.
Disassembly
of
the
azabicyclo[3.3.1]nonane core of 12 revealed silyl enol ether 13 as a
Toste cyclization substrate.[23,24,10a,20] Very recently, we exploited
silver-catalyzed Toste type cyclization of the terminal alkyne in the
syntheses of Daphniphyllum alkaloids,[25] which demonstrated the
advantage of the silver version in the scale and cost aspects.
Despite few literature precedents,[26] similar cyclization of the
unfunctionalized internal alkyne should provide 12 with defined
geometry of the C-19═C-20 bond. Compound 13 was further traced
back to known precursors 14 and 15.[20]
Table 1. Studies of the transformation from 16 to 10.
entry
conditions[a]
TMSI (4.0 equiv), CH2Cl2
overall yield (%)
We developed an expedient route to pentacycle 16 as depicted
in Scheme 1. This route started with the preparation of 13 that was
based on a sequence used in our syntheses of aspidodasycarpine
and lonicerine.[20] In the presence of Noyori catalyst 17, transfer
hydrogenation of the imine generated from 14 and 15 afforded
amine 18 in 95% ee. Protection of this amine with Cbz followed by
benzylic oxidation and indole N-nosylation furnished tricyclic ketone
19, which was then converted to the corresponding silyl enol ether
13. The use of Cbz allowed an orthogonal removal in the presence
of an indolenine functionality (vide infra). The study of the silver-
catalyzed cyclization was summarized in Table S1 of the SI. Under
the optimal conditions [AgNTf2 (20 mol%), 2,4,6-tri-tert-
butylpyrimidine[20,25a] (TTBP; 40 mol%), water (2.0 equiv.), 40 °C], the
desired 6-exo-dig cyclization product 12 was obtained in 83% yield
on decagram scale. Removal of its nosyl group provided a substrate
for methylenation. The Takai−Utimoto protocol[27] [PbCl2 (cat.), Zn,
CH2Br2, TiCl4] gave the desired product in 70% yield, along with a
1
2
3
4
5
0
0
Me2BBr (4.0 equiv), CH2Cl2
BI3 (4.0 equiv), CH2Cl2
0
BBr3 (4.0 equiv), CH2Cl2
33
45
BBr3 (12 equiv), Bu4NI (3.0 equiv), CH2Cl2
[a]0 °C, 30 min, then 22 °C, 8 h. Worked up with aq. NH3•H2O.
With 16 in hand, we investigated the formal C-5 migration from
O to N-4 (see Table 1). Treatment with BF3•OEt2 and Me2S afforded
the secondary amine,[29] which was directly subjected to the
conditions for ether cleavage.[30] Exposure to TMSI resulted in
substrate decomposition (entry 1). Powerful reagents such as
Me2BBr (entry 2) and BI3 (entry 3) performed similarly to TMSI. BBr3
was more effective for the cyclic ether opening, leading to 10 in 33%
overall yield from 16 (entry 4). TLC analysis showed that the product
This article is protected by copyright. All rights reserved.

10.1002/anie.201901086
Angewandte Chemie International Edition
COMMUNICATION
Scheme 4. Second synthesis of N-demethylechitamine (4).
We turned our attention to the more challenging targets 1 and 4
(Scheme 3). Silylation of 3 with reagent 25 followed by mCPBA
oxidation provided amine N-oxide 26 in 87% overall yield; protection
of the primary hydroxy group was required for the efficient oxidation.
We then studied conditions for the conversion of 26 into 8. The
standard Polonovski protocol[22] using Ac2O as an activator for the N-
oxide proved to be ineffective. The Potier modification[31] in which
Ac2O was replaced with TFAA gave a small amount of 8 after
aqueous workup, presumably through a sequence of acylation,
position-selective elimination (to generate iminium ion species 27),
hydrolysis, aminal formation, and desilylation. The use of more
powerful Tf2O resulted in a complex reaction profile. To our delight,
2,6-di-tert-butylpyridine was found to be a crucial additive to TFAA in
this case, which improved the yield of 8 to 72%. Notably, we did not
observe products arising from less substituted iminium ion species,
Scheme 2. Syntheses of akuammiline (2) and deacetylakuammiline (3).
spot appeared after aqueous workup, which suggested that stepwise
halogenation and amination constituted the formal C-5 migration. We
then exploited Bu4NI as an extra nucleophile source and improved
the yield to 45% (entry 5).
Compound 10 was further elaborated into 2 and 3 (Scheme 2).
Swern oxidation followed by aldol reaction [DBU, (CH2O)n][20,25a,18c,21]
furnished β-hydroxyaldehyde 23 as a single diastereomer. This
compound underwent acetylation and Jones oxidation to give
carboxylic acid 24, the structure of which was confirmed by X-ray
crystallographic
Lindgren−Krauss−Pinnick conditions caused decomposition of 23.
Conventional esterification conditions such as CH2N2,
analysis
(Scheme
2).
Of
Note,
the
TMSCHN2/MeOH, and MeI/K2CO3 resulted in N-4-methylation of 24,
and the combination of DCC (or MNBA) and 4-DMAP was ineffective
to activate this sterically hindered carboxylic acid. Treatment of 24
with (COCl)2 and DMF furnished the corresponding acyl chloride,
which was exposed to K2CO3/MeOH for esterification and
deacetylation. Thus, 3 was obtained in 65% overall yield from 24.
Re-acetylation afforded 2; more than 100 mg of this alkaloid were
prepared in total.
which
indicated
excellent
position-selectivity
of
the
Polonovski−Potier reaction.[32] Reduction of 8 with NaBH4 afforded 4
in 79% yield, the structure of which was verified by X-ray
crystallographic analysis of its HCl salt (Scheme 3). Treatment of 4
with MeI afforded 1 in 86% yield.
Scheme 5. Syntheses of rhazimal (5) and rhazicine (6).
The versatile chemistry with amine N-oxide[33] inspired us to
explore an alternative path from 26 to 4 (Scheme 4). A [1,2]-
Meisenheimer rearrangement reaction[33,34] occurred at 110 °C under
microwave irradiation, affording a ring expansion product 28 albeit in
a poor yield. The N-oxide predominantly underwent deoxygenation
to give silylated 3.[35] Me3NO turned out to be a suitable suppressant
for this undesired reaction, elevating the yield of 28 to 76%. The
structure of 28 was corroborated by X-ray crystallographic analysis
of its derivative, the 3,5-dinitrobenzoate of desilyl-28 (Scheme 4).
[36]
Reductive cleavage of the N−O bond with Mo(CO)6 followed by
desilylation with aq. HF furnished 4 smoothly, presumably via the
Scheme 3. Syntheses of echitamine (1) and N-demethylechitamine (4).
This article is protected by copyright. All rights reserved.

10.1002/anie.201901086
Angewandte Chemie International Edition
COMMUNICATION
intermediacy of alkanolamine 29. The stereospecific rearrangement
defined the stereochemistry of the secondary alcohol within 4.
Program for Support of Top-Notch Young Professionals of China,
and the K. C. Wong Education Foundation. X.Z. is grateful to
Syngenta for a graduate fellowship.
We then prepared 5 and 6 from 3 (Scheme 5). Dess−Martin
oxidation of the primary alcohol within 3 afforded 5 in 85% yield.
Upon exposure to aq. HCl, the indolenine was hydrolyzed,
presumably forming an aniline intermediate 31 which then
underwent sequential hemiaminalization and hemiketalization to give
6 in 71% yield. Release of the strain of the congested indolenine
may serve as a driving force for this cascade reaction.
Keywords: indole alkaloids • collective syntheses • cascade
reactions • Polonovski−Potier reaction • [1,2]-Meisenheimer
rearrangement
[1] v. Gorup-Besanez, Justus Liebigs Ann. Chem. 1875, 176, 88.
[2] J. A. Hamilton, T. A. Hamor, J. M. Robertson, G. A. Sim, J. Chem. Soc.
1962, 0, 5061.
[3] T. A. Henry, J. Chem. Soc. 1932, 2759.
[4] a) L. Olivier, J. Levy, J. Le Men, M. M. Janot, H. Budzikiewicz, C. Djerassi,
Bull. Soc. Chim. Fr. 1965, 868; b) S. Benayad, K. Ahamada, G. Lewin, L.
Evanno, E. Poupon, Eur. J. Org. Chem. 2016, 1494.
[5] “The Chemistry of the Akuammiline Alkaloids”: G. L. Adams, A. B. Smith III,
in The Alkaloids, Vol. 76 (Ed.: H.-J. Knölker), Elsevier: New York, 2016, pp.
171−257.
[6] W. Boonchuay, W. E. Court, Planta Med. 1976, 29, 380.
[7] a) M. Zhang, X. Huang, L. Shen, Y. Qin, J. Am. Chem. Soc. 2009, 131,
6013; b) W. Zi, W. Xie, D. Ma, J. Am. Chem. Soc. 2012, 134, 9126; c) B. D.
Horning, D. W. C. MacMillan, J. Am. Chem. Soc. 2013, 135, 6442.
[8] a) Y. Ahmad, K. Fatima, P. W. Le Quesne, Atta-Ur-Rahman,
Phytochemistry 1983, 22, 1017; b) X. Cai, C. Zeng, T. Feng, Y. Li, X. Luo,
Helv. Chim. Acta. 2010, 93, 2037.
Scheme 6. Synthesis of pseudoakuammigine (7).
[9] a) Y. Ahmad, K. Fatima, P. W. Le Quesne, Atta-Ur-Rahman, J. Chem. Soc.
Pakistan. 1979, 1, 69; b) A. Ahmed, W. Li, F.-F. Chen, J.-S. Zhang, Y.-Q.
Tang, L. Chen, G.-H. Tang, S. Yin, Fitoterapia 2018, 128, 1.
Finally, tuning the reactivity of the nitrogen atoms of 3 enabled a
rapid access to 7 (Scheme 6). Direct N-alkylation of the imine should
facilitate the N,O-ketalization via the intermediacy of an iminium ion
species; however, treatment of 3 with MeI selectively methylated the
tertiary amine. Interestingly, we observed a dynamic equilibrium
between 3 and its N,O-ketal form 32. This explained the existence of
a trace amount of “impurity” accompanying the naturally occurring 3
indicated by the authentic 1H NMR spectrum.[8b] The equilibrium
favored the N,O-ketal side under strongly acidic conditions. Thus, we
subjected 3 to acid-mediated reductive amination (1,3,5-trioxane,
Et3SiH, TFA).[37] Under these conditions, the secondary amine within
32 was methylated exclusively, presumably via the intermediacy of
alcohol 33. This tandem reaction furnished 7 in 85% yield.
[10] a) J. Moreno, E. Picazo, L. A. Morrill, J. M. Smith, N. K. Garg, J. Am.
Chem. Soc. 2016, 138, 1162; b) W. Ren, Q. Wang, J. Zhu, Angew. Chem. Int.
Ed. 2016, 55, 3500; Angew. Chem. 2016, 128, 3561; c) X. Xie, B. Wei, G. Li, L.
Zu, Org. Lett. 2017, 19, 5430; d) D. Nishiyama, A. Ohara, H. Chiba, H.
Kumagai, S. Oishi, N. Fujii, H. Ohno, Org. Lett. 2016, 18, 1670; e) R.
Eckermann, M. Breunig, T. Gaich, Chem. Commun. 2016, 52, 11363; f) R.
Eckermann, M. Breunig, T. Gaich, Chem. Eur. J. 2017, 23, 3938; g) M. W.
Smith, Z. Zhou, A. X. Gao, T. Shimbayashi, S. A. Snyder, Org. Lett. 2017, 19,
1004; h) T. Xiao, Z. Chen, L. Deng, D. Zhang, X. Liu, H. Song, Y. Qin, Chem.
Commun. 2017, 53, 12665; i) Z.-T. Chen, T. Xiao, P. Tang, D. Zhang, Y. Qin,
Tetrahedron 2018, 74, 1129.
[11] Qin and co-workers submitted a manuscript describing elegant syntheses
of strictamine and rhazinoline as we submitted this one.
[12] a) Atta-Ur-Rahman, S. Khanum, Heterocycles 1984, 22, 2183; b) W.-L.
Hu, J.-P. Zhu, U. Piantini, R. Prewo, M. Hesse, Phytochemistry 1987, 26, 2625.
[13] a) W.-L. Hu, J.-P. Zhu, M. Hesse, Planta Medica 1989, 55, 463; b) O. S.
Ajala, A. M. Piggott, F. Plisson, Z. Khalil, X.-c. Huang, S. A. Adesegun, H. A. B.
Coker, R. J. Capon, Tetrahedron Lett. 2011, 52, 7125; for a synthesis of the
furoindoline core of 7, see: c) E. S. Andreansky, S. B. Blakey, Org. Lett. 2016,
18, 6492.
In summary, we have accomplished the total syntheses of
alkaloids 1–7. The formal C-5 migration from O to N-4 furnished the
pentacyclic core of 3. We took advantage of the inherent synthetic
versatility of 3 and converted it into a series of congeners, in
particular 1. These endeavors may facilitate studies of the biology of
this fascinating class.
[14] a) L. Zu, B. W. Boal, N. K. Garg, J. Am. Chem. Soc. 2011, 133, 8877; b)
W. Ren, Q. Wang, J. Zhu, Angew. Chem. Int. Ed. 2014, 53, 1818; Angew.
Chem. 2014, 126, 1849; c) M. Teng, W. Zi, D. Ma, Angew. Chem. Int. Ed.
2014, 53, 1814; Angew. Chem. 2014, 126, 1845; d) S.-Z. Jiang, X.-Y. Zeng, X.
Liang, T. Lei, K. Wei, Y.-R. Yang, Angew. Chem. Int. Ed. 2016, 55, 4044;
Angew. Chem. 2016, 128, 4112; e) T. Wang, X. Duan, H. Zhao, S. Zhai, C.
Tao, H. Wang, Y. Li, B. Cheng, H. Zhai, Org. Lett. 2017, 19, 1650.
[15] a) G. L. Adams, P. J. Carroll, A. B. Smith III, J. Am. Chem. Soc. 2012, 134,
4037; b) G. L. Adams, P. J. Carroll, A. B. Smith III, J. Am. Chem. Soc. 2013,
135, 519; c) M. W. Smith, S. A. Snyder, J. Am. Chem. Soc. 2013, 135, 12964.
[16] A. Ramirez, S. Garcia-Rubio, Curr. Med. Chem. 2003, 10, 1891.
[17] a) R. Echermann, T. Gaich, Synthesis 2013, 45, 2813; b) J. M. Smith, J.
Moreno, B. W. Boal, N. K. Garg, Angew. Chem. Int. Ed. 2015, 54, 400; Angew.
Chem. 2015, 127, 410.
Acknowledgements
We thank Profs. Xiao-Dong Luo, Xiang-Hai Cai, and Tao Feng for
1
1
providing the authentic H NMR spectrum of 1 and H and 13C NMR
1
spectra of 3, Dr. Dongbo Zhang for providing the authentic H and
13C NMR spectra of 6, Prof. Rob Capon for providing the authentic
1H NMR spectrum of protonated 7, and Xiaoli Bao and Lingling Li
from the Instrumental Analysis Center of Shanghai Jiao Tong
University for X-ray crystallographic analysis. We also thank Dr.
David Edmonds and Yu Chen for discussion. This work was
supported by National Natural Science Foundation of China
(21525209, 21621002, 21772225, and 21761142003), Chinese
Academy of Sciences (Strategic Priority Research Program
XDB20000000 and Key Research Program of Frontier Sciences
QYZDB-SSW-SLH040), Shanghai Science and Technology
Commission (15JC1400400 and 17XD1404600), the National
[18] a) J. M. Smith, J. Moreno, B. W. Boal, N. K. Garg, J. Am. Chem. Soc.
2014, 136, 4504; b) J. M. Smith, J. Moreno, B. W. Boal, N. K. Garg, J. Org.
Chem. 2015, 80, 8954; c) G. Li, X. Xie, L. Zu, Angew. Chem. Int. Ed. 2016, 55,
10483; Angew. Chem. 2016, 128, 10639; d) D. Wang, M. Hou, Y. Ji, S. Gao,
Org. Lett. 2017, 19, 1922; e) B. Zhang, X. Wang, C. Cheng, D. Sun, C. Li,
Angew. Chem. Int. Ed. 2017, 56, 7484; Angew. Chem. 2017, 129, 7592.
This article is protected by copyright. All rights reserved.

10.1002/anie.201901086
Angewandte Chemie International Edition
COMMUNICATION
[19] a) D. Zhang, H. Song, Y. Qin, Acc. Chem. Res. 2011, 44, 447; b) W. Zi, Z.
Zuo, D. Ma, Acc. Chem. Res. 2015, 48, 702; c) R. B. Susick, L. A. Morrill, E.
Picazo, N. K. Garg, Synlett 2017, 28, 1; d) A. B. Dounay, P. G. Humphreys, L.
E. Overman, A. D. Wrobleski, J. Am. Chem. Soc. 2008, 130, 5368; e) S. B.
Jones, B. Simmons, A. Mastracchio, D. W. C. MacMillan, Nature 2011, 475,
183.
[20] Y. Li, S. Zhu, J. Li, A. Li, J. Am. Chem. Soc. 2016, 138, 3982.
[21] E. Picazo, L. A. Morrill, R. B. Susick, J. Moreno, J. M. Smith, N. K. Garg, J.
Am. Chem. Soc. 2018, 140, 6483.
[22] D. Grierson, Org. React. 1990, 39, 85.
[23] a) S. T. Staben, J. J. Kennedy-Smith, D. Huang, B. K. Corkey, R. L.
LaLonde, F. D. Toste, Angew. Chem. Int. Ed. 2006, 45, 5991; Angew. Chem.
2006, 118, 6137.
[24] Z. Lu, Y. Li, J. Deng, A. Li, Nat. Chem. 2013, 5, 679.
[25] a) J. Li, W. Zhang, F. Zhang, Y. Chen, A. Li, J. Am. Chem. Soc. 2017, 139,
14893; b) Y. Chen, W. Zhang, L. Ren, J. Li, A. Li, Angew. Chem. Int. Ed. 2018,
57, 952; Angew. Chem. 2018, 130, 964; c) W. Zhang, M. Ding, J. Li, Z. Guo, M.
Lu, Y. Chen, L. Liu, Y.-H. Shen, A. Li, J. Am. Chem. Soc. 2018, 140, 4227.
[26] For silver-catalyzed cyclization of internal ynamides, see: C. F. Heinrich, I.
Fabre, L. Miesch, Angew. Chem. Int. Ed. 2016, 55, 5170; Angew. Chem. 2016,
128, 5256.
[27] K. Takai, T. Kakiuchi, Y. Kataok, K. Utimoto, J. Org. Chem. 1994, 59,
2668.
[28] E. A. Colby, K. C. O′Brien, T. F. Jamison, J. Am. Chem. Soc. 2004, 126,
998.
[29] I. H. Sanchez, F. J. Lopez, J. J. Soria, M. I. Larraza, H. J. Flores, J. Am.
Chem. Soc. 1983, 105, 7640.
[30] a) M. E. Jung, M. A. Lyster, J. Org. Chem. 1977, 42, 3761; b) Y. Guindon,
M. Therien, Y. Girard, C. Yoakim, J. Org. Chem. 1987, 52, 1680; c) T. P.
Povlock, Tetrahedron Lett. 1967, 8, 4131; d) S. U. Kulkarni, V. D. Patil,
Heterocycles 1982, 18, 163.
[31] A. Cave, C. Kan-Fan, P. Potier, J. Le Men, Tetrahedron 1967, 23, 4681.
[32] The selectivity of the elimination may be attributable to the higher acidity
of H-3.
[33] a) A. Albini, Synthesis 1993, 25, 263; b) D. Bernier, U. K. Wefelscheid, S.
Woodward, Org. Prep. Proced. Int. 2009, 41, 173.
[34] For application of [1,2]-Meisenheimer rearrangement in natural product
synthesis, see: a) P. Magnus, J. Rodríguez-López, K. Mulholland, I. Matthews,
Tetrahedron 1993, 49, 8059; b) R. Yoneda, Y. Sakamoto, Y. Oketo, K. Minami,
S. Harusawa, T. Kurihara, Tetrahedron Lett. 1994, 35, 3749; c) C. Didier, D. J.
Critcher, N. D. Walshe, Y. Kojima, Y. Yamauchi, A. G. M. Barrett, J. Org.
Chem. 2004, 69, 7875; d) D. Schwaebisch, K. Tchabanenko, R. M. Adlington,
A. M. Cowley, J. E. Baldwin, Chem. Commun. 2004, 2552; e) H. Wei, C. Qiao,
G. Liu, Z. Yang, C.-c. Li, Angew. Chem. Int. Ed. 2013, 52, 620; Angew. Chem.
2013, 125, 648.
[35] L. D. Quin, F. A. Shelburne, J. Org. Chem. 1965, 30, 3135.
[36] M. Nitta, T. Kobayashi, J. Chem. Soc. Perkin Trans. 1. 1985, 1401.
[37] T. A. Popp, F. Bracher, Synthesis 2015, 47, 3333.
This article is protected by copyright. All rights reserved.

10.1002/anie.201901086
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
X. Zhang,† B. N. Kakde,† R. Guo, S.
Yadav, Y. Gu, A. Li*
Page No. – Page No.
Total Syntheses of Echitamine,
Akuammiline, Rhazicine, and
Pseudoakuammigine
Collective total syntheses of echitamine, N-demethylechitamine, akuammiline,
rhazimal, rhazicine, and pseudoakuammigine have been achieved by using their
congener deacetylakuammiline as a versatile intermediate.
This article is protected by copyright. All rights reserved.