Total Syntheses of Naucleamides A-C and E, Geissoschizine, Geissoschizol, (E)-Isositsirikine, and 16-epi-(E)-Isositsirikine

Article abstract of DOI:10.1021/acs.orglett.7b00983

A divergent approach for the enantioselective total synthesis of eight monoterpenoid indole alkaloids was developed. The approach allows the first total syntheses of naucleamides A-C and E in only 6-8 steps and also enables the efficient synthesis of geissoschizine, geissoschizol, (E)-isositsirikine, and 16-epi-(E)-isositsirikine in 10-11 steps from commercially available crotonic aldehyde. The synthesis features a one-pot organocatalyzed asymmetric Michael addition/Pictet-Spengler reaction. Notably, biomimetic synthesis of naucleamide E was achieved by oxidative cyclization of naucleamide A.

Full text of DOI:10.1021/acs.orglett.7b00983

Letter
pubs.acs.org/OrgLett
Total Syntheses of Naucleamides A−C and E, Geissoschizine,
Geissoschizol, (E)‑Isositsirikine, and 16-epi-(E)‑Isositsirikine
Lei Li,† Paruke Aibibula,† Qianlan Jia,† and Yanxing Jia*,†,‡
†State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road,
Beijing 100191, China
‡State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road,
Shanghai 201203, China
S
* Supporting Information
ABSTRACT: A divergent approach for the enantioselective total synthesis of eight monoterpenoid indole alkaloids was
developed. The approach allows the first total syntheses of naucleamides A−C and E in only 6−8 steps and also enables the
efficient synthesis of geissoschizine, geissoschizol, (E)-isositsirikine, and 16-epi-(E)-isositsirikine in 10−11 steps from
commercially available crotonic aldehyde. The synthesis features a one-pot organocatalyzed asymmetric Michael addition/
Pictet−Spengler reaction. Notably, biomimetic synthesis of naucleamide E was achieved by oxidative cyclization of naucleamide
A.
he plants of the Nauclea species are widely used in folk
medicine in the tropical regions of Africa and Asia for
T
treating a variety of illnesses, such as malaria, pain, colds, and
fever. To date, more than 60 monoterpene indole alkaloids have
been isolated from this genus, and some of them have
antiproliferative, antiparasitic, and antimicrobial activities.1 In
2003, the search for structurally unique constituents from the
bark and wood of Nauclea latifolia by Kobayashi and co-workers
led to the isolation of five novel biogenetically related alkaloids,
which were named naucleamides A−E (1−5, Figure 1).2
Structurally, 1−3 share the common 6/5/6/6 tetracyclic
skeleton with the trans H(3)/H(15) configuration. Notably,
naucleamide E (5) possesses an unprecedented 6/5/6/6/6
pentacyclic ring system with an amino acetal bridge that is rarely
encountered in natural product. Biosynthetically, 5 could be
formed in vitro through enzymatic selective C−H oxidation of
naucleamide A (1). Surprisingly, 16-epi-naucleamide E (6) was
not isolated from the same plant, which could be theoretically
derived from enzymatic oxidation of naucleamide B (2). In
addition, naucleamides A−E were isolated from nature in only
0.8−1.6 mg. The scarce availability from natural sources has
limited their medicinal evaluation. Moreover, no total synthesis
of any of these specific compounds has been reported to date.3
Geissoschizine (7) and a number of congeners (8−10) also
have a common 6/5/6/6 tetracyclic skeleton with the cis H(3)/
H(15) configuration but are related by N(4)−C(22) bond
opening, ring chain tautomerization, and N(4)−C(21) bond
formation to naucleamides 1−5 (Figure 1).4−8 Importantly, 7,
isolated from a variety of plant species, occupies a unique place
among alkaloids by serving as the early biogenetic precursor to
Figure 1. Structures of the monoterpenoid indole alkaloids.
virtually all other families of monoterpenoid indole alkaloids.
Although numerous total syntheses of geissoschizine have been
reported,6 only the groups of Winterfeldt, Overman, Martin, and
Cook have achieved the asymmetric synthesis.7 The catalytic
asymmetric synthesis of 7 has not yet been reported.
Received: April 1, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00983
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Letter
We sought to develop a novel asymmetric approach to these
alkaloids based on the nature-inspired divergent concept.9−11
More importantly, inspired by the biogenetic relationship
between 1 and 5, we envisioned that 5 could be obtained from
1 through a final-stage biomimetic selective C−H oxidation
strategy. As C−H oxidative coupling can directly construct
carbon−carbon and carbon−heteroatom bonds in a single step
without prefunctionalization, it has been a powerful strategy in
the total syntheses of natural products in recent years.12−14
Despite these advances, the synthesis of such a bridged-ring
system through direct C−H oxidation of N-carbamoyl
derivatives has rarely been reported.15 In addition, the non-
enzymatic oxidation of unprotected 1 is more challenging due to
the sensitivity of the electron-rich indole to oxidation, the site-
selectivity between C(3) and C(6), as well as the difficulty in
accessing the amino acetal bridged-ring versus β-hydrogen
elimination to form naucleamide D (4). Here, we report the
efficient and divergent total syntheses of naucleamides A−C (1−
3) and E (5), geissoschizine (7), geissoschizol (8), (E)-
isositsirikine (9), and 16-epi-(E)-isositsirikine (10) in only 6−
11 steps. In these syntheses, the challenging stereochemical
problems of the relative and absolute configuration at C(3) and
C(15) were effectively controlled.9,16 Among them, the total
syntheses of target molecules 1−3 and 5 were achieved for the
first time. The total synthesis of naucleamide E was achieved via
biomimetic oxidative cyclization of 1.
1,2-addition and 1,6-addition of the first nucleophilic attack is
crucial.
2,4-Dienal 14 was not reported before, so we devised a short
route for its synthesis from the known alcohol 16, which could be
readily prepared from commercially available crotonic aldehyde
15 by iodination and reduction (Scheme 2).24 Protection of
alcohol 16 with TBDPSCl gave product 17. Heck reaction of
vinyl iodide 17 and acrolein afforded the desired 2,4-dienal 14.
Scheme 2. Four-Step Synthesis of 2,4-Dienal 14
With the dienal 14 in hand, the organocatalyzed asymmetric
Michael addition between 13 and 14 was investigated (Scheme
3). Initial attempts under Franzen’s and Rios’ optimized reaction
Scheme 3. Concise Synthesis of Intermediate 11
Retrosynthetically, we envisioned 1−3, 5−10, and other
related indole alkaloids could be prepared from the common
intermediate 11 by late-stage manipulation (Scheme 1).
Scheme 1. Retrosynthetic Analysis
conditions revealed that no reaction occurred. Gratifyingly, when
the reaction was run in toluene at 40 °C for 8 days, the desired
hemiaminal (E)-12 accompanied by unexpected (Z)-12 was
obtained in 8% yield in a 1:1 ratio. Following extensive reaction
optimization (catalyst, additive, solvent, temperature; for
detailed information, see Supporting Information), we finally
found that the addition of an acid additive is essential for high
yields, and benzoic acid was the best. Under the optimized
reaction conditions, 12 could be obtained in 52% yield (E/Z =
1:1), which could be readily separated by flash column
chromatography.
The acid-catalyzed cyclization of 12 was then investigated
(Scheme 3). Inspired by the elegant studies by Sarpong group
during their synthesis of the yohimbinoid alkaloids,16a we found
that treatment of (E)-12 with HCl in Et2O at −78 °C afforded
(E)-11 and 3-epi-(E)-11 in 80% yield (dr 3.5:1), in favor of our
desired product (E)-11. Both (E)-11 and 3-epi-(E)-11 were
subjected to the aforementioned acid-catalyzed cyclization
conditions. However, the interconversion of (E)-11 and 3-epi-
(E)-11 was not observed. These results indicated that (E)-11 is a
Naucleamide E could be prepared from 1 by a final-stage
selective C−H oxidation.17−19 In turn, the tetracyclic indole 11
with all carbon and functional groups might be convergently
prepared from the known amidomalonate 13 and 2,4-dienal 14
via organocatalyzed asymmetric Michael addition followed by a
Pictet−Spengler reaction.20,21 Although the catalytic asymmetric
conjugate addition of amidomalonates to cinnamic aldehyde
derivatives has been independently developed by Franzen’s and
Rios’ groups, 2,4-dienal has never been employed in such a
reaction. Several challenging issues have to be addressed. First,
2,4-dienal was usually employed as nucleophile but not
electrophile.22,23 Second, the competition between 1,4- versus
B
DOI: 10.1021/acs.orglett.7b00983
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Letter
kinetically controlled product and 3-epi-(E)-11 is a thermody-
namically controlled product, and this process was determined
by a transition state.20 The enantioselectivity of (E)-11 could be
easily determined at this stage, with an enantiomeric excess value
of 96% (see Supporting Information). The stereochemistry at C-
16 is assigned by following the literature reported by the group of
Scheme 5. Syntheses of Geissoschizine, Geissoschizol, (E)-
Isositsirikine, and 16-epi-(E)-Isositsirikine
Franzen 20b
and the H−H coupling constants between H-15 and
́
,
H-16 (for (E)-11, J = 11.6 Hz; for 3-epi-(E)-11, J = 12.4 Hz). It is
worthy to note that the conjugate addition and the acid-catalyzed
cyclization could be performed in a one-pot process with the
same diastereoselectivity. Thus, we have successfully established
a five-step route to 11, which needed only three flash column
chromatography purifications.
With the tetracyclic intermediate 11 in hand, we turned our
attention to the synthesis of 1−3 and 5 (Scheme 4). Thus,
Scheme 4. Synthesis of Naucleamides A−C (1−3) and E (5)
the allylic chloride 19 in 53% yield over three steps. At this stage,
methanolysis of amide 19 via the corresponding imidate salts
successfully afforded amino ester 20 in good yield, which was
prone to cyclization to generate the known deformyl
geissoschizine 21 in 80% yield, together with 15% of the starting
lactam 19.7 Finally, according to the protocol reported in the
literature, compound 21 was readily converted to 7,7 8,7d 9, and
10.8 Thus, we have achieved the catalytic asymmetric syntheses
of 7−10 for the first time, and our total syntheses of these natural
products required only 10−11 steps from 15.
In summary, we have developed a unified strategy for the
enantioselective synthesis of monoterpene indole alkaloids. The
pivotal common intermediate (E)-11 was synthesized in only five
steps from commercially available 15, which featured a one-pot
organocatalyzed asymmetric Michael addition/Pictet−Spengler
reaction. The approach allows the first total syntheses of
naucleamide A (7 steps, 3.2% overall yield), naucleamide B (7
steps, 3.0% overall yield), naucleamide C (6 steps, 6.6% overall
yield), and naucleamide E (8 steps, 2.4% overall yield), as well as
the catalytic asymmetric total syntheses of geissoschizine (10
steps, 3.5% overall yield), geissoschizol (10 steps, 3.5% overall
yield), (E)-isositsirikine (11 steps, 1.4% overall yield), and 16-
epi-(E)-isositsirikine (11 steps, 1.9% overall yield). Notably, the
total synthesis of 5 was achieved by a final-stage biomimetic
selective C−H oxidation strategy. The synthesis and biological
studies of the other members of the related indole alkaloids and
analogues are currently under investigation.
deprotection of the TBDPS group of compound (E)-11 with
anhydrous TBAF in THF accompanied by spontaneous
cyclization furnished 3 in 87% yield.2 We observed that the
solubility of 3 was not very good in CD3OD. When recorded in
DMSO-d6, the NMR spectra of 3 indicated the presence of a
keto-form at C(16) instead of an enol-form reported in
literature.2 Reduction of lactone 3 with NaBH4 in MeOH and
THF gave 1 and 2 in 48 and 46% yield, respectively.2
With 1 in hand, we performed the direct conversion of 1 to 5
through a selective C−H oxidation (Scheme 4). The initial
attempt to oxidation of 1 with iodine failed to give the desired
product 5.17 Oxidation of 1 with iodosobenzene diacetate yielded
complex product, and no desired product was obtained.18
Aerobic oxidation of 1 was further investigated.19 However, no
reaction occurred. This result also proved that 5 is not an artificial
product in the laboratory. Oxidation of 1 with DDQ proceeded
smoothly and successfully afforded 5 in 75% yield.25 Interest-
ingly, oxidation of 2 with DDQ readily yielded 6 in 72% yield,
which has not been isolated from nature. Thus, we have achieved
the first total synthesis of 1−3 and 5, which required only 6−8
steps from commercially available crotonic aldehyde 15. The first
asymmetric total syntheses of these four alkaloids demonstrated
that our strategy offered an efficient route to a broad range of
indole alkaloids.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b00983.
We next turned to the synthesis of 7, 8, and 9 and 10 (Scheme
5).4−8 Removal of the methyl ester followed by deprotection of
the silicon group on (E)-11 yielded the corresponding alcohol,
which was subsequently treated with MsCl and Et3N to provide
1
Full experimental procedures and H and 13C NMR
spectra of compounds 1−3, 5−12, 14, and 17−21 (PDF)
C
DOI: 10.1021/acs.orglett.7b00983
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
6156. (b) Anagnostaki, E. E.; Zografos, A. L. Chem. Soc. Rev. 2012, 41,
5613.
(11) For an excellent example on divergent total syntheses of the
monoterpene indole alkaloids, see: (c) Xu, Z.; Wang, Q.; Zhu, J. J. Am.
Chem. Soc. 2015, 137, 6712.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: yxjia@bjmu.edu.cn.
ORCID
(12) For recent reviews on C−H functionalization in natural product
synthesis, see: (a) McMurray, L.; O’Hara, F.; Gaunt, M. J. Chem. Soc.
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Felding, J.; Baran, P. S. Nature 2016, 532, 90. Chuang, K. V.; Xu, C.;
Reisman, S. E. Science 2016, 353, 912. (c) Yuan, C.; Jin, Y.; Wilde, N. C.;
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Yanxing Jia: 0000-0002-9508-6622
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the National Natural Science
Foundation of China (Nos. 21372017, 21402003, 21290183, and
21572008) and the State Key Laboratory of Drug Research.
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