A Ten-Step Total Synthesis of Speradine C

Article abstract of DOI:10.1002/anie.201902004

The first total synthesis of speradine C has been achieved in only ten steps from a commercially available 4-bromoindole. Salient features of the work are the formation of four rings through three cyclizations, namely a bioinspired [3+2] annulation to form the C/D rings, an NCS-mediated oxidation to construct the E ring, and a Ru-catalyzed ketohydroxylation to assemble the F ring. This work highlights how strategic ring constructions can streamline the synthesis of polycyclic compounds.

Full text of DOI:10.1002/anie.201902004

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Accepted Article
Title: 10-Step Total Synthesis of Speradine C
Authors: Yanxing Jia, Haichao Liu, Lijun Chen, and Kuo Yuan
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COMMUNICATION
1
0-Step Total Synthesis of Speradine C
Haichao Liu, Lijun Chen, Kuo Yuan, and Yanxing Jia*
Abstract: The first total synthesis of speradine C has been achieved
in only 10 steps from a commercially available 4-bromoindole. Salient
features of the work are the formation of four rings via three
cyclizations including a bioinspired [3+2] annulation to form the C/D
rings, a NCS-mediated oxidation to construct the E ring, and a Ru-
catalyzed ketohydroxylation to assemble the F ring. This work
highlights how strategic ring constructions can streamline the
synthesis.
-Cyclopiazonic acid (-CPA, 1), an ergot-like alkaloid, is a
distinguished 3,4-fused indole alkaloid containing a 6/5/6/5/5
pentacyclic ring and a highly substituted tetramic acid moiety
(
Figure 1A).[1] It was firstly isolated from the fungus Penicillium
cyclopium as a mycotoxic metabolite in 1968,[2] and was
subsequently isolated from a number of species of Penicillium and
Aspergillus fungus. In addition, -CPA is a nanomolar inhibitor of
2
+
sarco/endoplasmic reticulum Ca -ATPase (SERCA) which is
essential for calcium reuptake in muscle contraction and
[
3]
relaxation cycles. Importantly, SERCA is a promising target for
the development of new drugs against various diseases and
insect pests. Thus, -CPA is one of the few potent, selective and
reversible SERCA inhibitors which could act as a lead in drug
development.
Figure 1. (A) Structures of -cyclopiazonic acid and speradines A-C. (B)
Biosynthesis of -CPA.
Since 2003, a number of highly oxygenated cyclopiazonic acid
(
CPA)-derived alkaloids, such as speradines A-C (2-4) and
aspergillines A-E, were isolated and identified (Figure 1A).[
Among them, speradine C (4) has an extraordinary chemical
structure containing an unprecedented 6/5/6/5/5/6 hexacyclic ring
system with a 5,6-dihydroxy-4-oxo-1,3-oxazinane unit, and six
stereocenters including four oxygen-bearing carbon centers.
Thus, the most substantial challenge in the synthesis of 4 is how
to construct the sterically congested C/D/E/F ring system and the
stereogenically correct installation of the four oxygen-bearing
carbon centers. A concise synthesis of 4 requires a carefully
choreographed introduction of these rings with correct
stereogenic carbons.
4-8]
To date, five total syntheses of the related but far less
functionalized -CPA have been reported.[10-14] However, of the
highly oxygenated CPA-derived alkaloids, only aspergilline A has
succumbed to total synthesis.[15] As part of our ongoing studies
towards the concise and efficient synthesis of 3,4-indole
alkaloids,[
1a,16]
we are attracted by the intricate molecular
architecture of the highly oxygenated CPA-derived alkaloids.
Herein, we report that we have achieved the first total synthesis
of speradine C (4) in only 10 steps.
As depicted in Scheme 1, the concise route to speradine C
was enabled by a unique retrosynthetic design featuring three
different cyclizations to forge the C/D/E/F four different ring
systems present in 4. Thus, the F ring of speradine C could be
generated from pentacycle 7 by direct ketohydroxylation followed
by in situ ketalization (Cyclization 3). The E ring could in principle
be assembled by an oxidative lactonization of tetracycle 8
(Cyclization 2), which also establish the stereochemistry of the
Biosynthetic studies have revealed that -CPA (1) is derived
from L-tryptophan (Figure 1B).[9] The initial formation of tetramic
acid ring followed by prenylation gives β-cyclopiazonic acid (β-
CPA, 5) which is the direct biosynthetic precursor of -CPA.
Oxidation of 5 by the flavin-dependent monoamine oxidase Mao
A (CpaO) generates a stabilized benzylic cation 6, which
subsequently undergoes cascade cyclization resulting in
formation of the C/D rings and finally -CPA.
quaternary center at C3. Tetracycle
8 could be readily
synthesized from 9 via stereoselective -hydroxylation. Notably,
the C/D ring system could be generated from dehydrotryptophan
derivative 10 by an unprecedented acid-catalyzed [3+2]
annulation (Cyclization 1), which was serendipitously discovered
during attempts to simulate the biosynthesis of -CPA (Figure 1B).
To the best of our knowledge, although the dehydroamino acid
derivatives have been widely used in organic synthesis,[17] they
have never been used in this kind of [3+2] annulation. In turn, 10
could be readily obtained from commercially available
compounds 11-13.
[
a]
H. Liu,[†] L. Chen,[†] K. Yuan, and Prof. Y. Jia
State Key Laboratory of Natural and Biomimetic Drugs, School of
Pharmaceutical Sciences,
Peking University,
Xue Yuan Rd. 38, Beijing 100191, China
E-mail: yxjia@bjmu.edu.cn
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
[†
]
[
b]
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Considering the feasibility of in situ formation of
dehydrotryptophan derivative via acid-mediated elimination of β-
hydroxy in 17, we turned our attention to the critical bioinspired
cascade cyclization for the construction of C/D ring system. A
variety of Lewis and Brønsted acids, solvent, reaction
temperature, and concentration were screened (see SI for
detailed information). We were delighted to find that the desired
tetracycle
diastereomers (9a-c, dr = 1:0.3:0.5) at C-4 and C-5 under the
optimal reaction conditions (0.2 equiv of Tf NH in CH Cl at
5 °C).[20] It is noteworthy that upon the addition of Tf
NH to the
9
could be obtained as three inseparable
2
2
2
3
2
solution of 17, the starting material 17 was immediately consumed
to yield the E-dehydrotryptophan derivative 10 as the major
product and 9 as the minor product; as prolonging the reaction
time, 10 was further converted to 9. Attempts to catalyze this
transformation with the strong chiral Brønsted acids were
examined, however, the desired 9 was obtained in moderate yield
without any enantioselectivity (for detailed information see SI).[21]
Scheme 1. Retrosynthetic analysis of speradine C.
Our synthesis commenced with 4-bromoindole 11, which
underwent N-methylation to provide 14 (Scheme 2). The C4-
indole Grignard reagent was prepared by reacting 14 with Mg in
THF which in situ reacted with prenyl bromide 12 to successfully
afford 15 in 73% yield.[18] Vilsmeier-Haack formylation of 15
provided the desired aldehyde 16. Treatment of 13 with LHMDS
yielded the corresponding C,N-dianion which was treated with
aldehyde 16 to furnish -amino β-hydroxy ester 17 as a mixture
of two inseparable diastereoisomers (dr = 3:1).[19]
Scheme 3. Proposed mechanism for the formation of 9a-c.
In fact, the ratio of 9a-c was almost the same under different
reaction conditions (see SI). Based on the literature and the
aforementioned results,
stereochemical outcome of the cascade cyclization is proposed in
Scheme 3. Tf NH binds to the lone pair of ester to produce two
a
possible mechanism for the
2
possible transition states (TS), TS-1 and TS-2, which underwent
cascade cyclization to form the C4-C11 cis enol A and the C4-
C11 trans enol B, respectively. Since the disfavoured steric
repulsion between the methyl group in the prenyl group and the
indole core would be enhanced in TS-2, the sterically less
hindered TS-1 should be favoured, allowing the formation of A
predominantly. Intermediates A and B can be transformed into 9
through protonation. For enol A, since the concave face is less
sterically hindered than the convex face due to the C4-H and Ts
groups located on the convex face, the formation of 9a is
preferred comparing with the formation of 9b. For enol B, due to
Scheme 2. Synthesis of tetracycle 9.
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Angewandte Chemie International Edition
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COMMUNICATION
the steric hinderance of C11-H and Ts groups, water can only
attack from the β face to give 9c.
single diastereoisomer. The one-step formation of the desired 7
obviously streamlined the synthesis. It is noteworthy that the use
of ester gave the same result as that of acid and amide.
Importantly, it was also the first time that NCS was used as
oxidant in this kind of oxidative cyclization.
Indeed, both 9a and 9b could be used for the synthesis of
speradine C (4) (vide infra). Deprotection of Ts in 9a-c with Mg in
MeOH/THF gave amines 18a-c, and 18a could be readily
separated from 18b and 18c by chromatography. The relative
configurations of 18a-c were determined by extensive NMR
spectra analysis. Finally, protection of 18a with TsCl provided
pure 9a, and its structure was further confirmed by X-ray
crystallographic analysis.[22]
At this stage, all that remained to complete the synthesis of 4
was the formation of F ring via ketohydroxylation/ketalization with
the requisite configuration of the hydroxyl groups. After several
trials, direct ketohydroxylation of 7 with RuCl
3
and Oxone in the
presence of NaHCO stereoselectively afforded the natural
3
product 4, which not only generated the F ring, but also
established the C7 and C19 stereochemistry.[
25,26]
The physical
data of our synthesized speradine C (4) were identical to those
reported in the literature.[4a]
In summary, we have achieved the first total synthesis of
speradine C in only 10 steps from commercially available 4-
bromoindole (11). Significantly, of the 10 discrete steps of this
synthesis, only one was not used for the formation of the C-C, C-
O, and C-N bonds (step 6). The critical C/D/E/F ring system in 4
was strategically generated by employing three key cyclizations.
Two of them are oxidative cyclizations, NCS-mediated
spriolactonization
(step
9)
and
Ru-catalyzed
ketohydroxylation/ketalization (step 10), that constructed two
sterically congested E and F rings and installed three oxygen-
bearing carbon centers with correct configuration. The other one
is the newly developed intramolecular [3+2] annulation using
dehydrotryptophan derivative (step 5) for assembling the C/D ring
system in tryptophan-derived tetracyclic building block, which
could be applied to the syntheses of -CPA and the related
natural products as well as their analogues. These studies are
ongoing and will be reported in due course.
Scheme 4. Total synthesis of speradine C.
Having successfully constructed the C/D ring system, the
completion of the synthesis of 4 is shown in Scheme 4. Coupling
1
8a with crotonic acid smoothly afforded 19a. The next step was
the -hydroxylation of 19a. After several trials, we found that the
oxidation of enolates with O in the presence of Ph P produced
Acknowledgements
2
3
the desired -hydroxyl ester 8 in 45% yield.[23] Of note, this
reaction proceeded with complete diastereoselectivity,
presumably due to the caged ring system of 19a, with molecular
oxygen attacking the enloates from the less sterically hindered
convex face. It is worth noting that the base also played a pivotal
role in this reaction and NaHMDS gave the best result. In addition,
coupling the mixture of 18b and 18c with crotonic acid provided
the corresponding 19b and 19c, which could be readily separated
by chromatography. -Hydroxylation of 19b also yielded 8 (see
SI).
We thank Prof. Benjamin List for providing the strong chiral
Brønsted acids and Prof. Dehai Li for providing the authentic H
and 13C NMR spectra. This research was supported by the
National Natural Science Foundation of China (Nos. 21871013
and 21572008) and the Drug Innovation Major Project (Grant No.
2018ZX09711-001-005-005).
1
Keywords: indole alkaloids • total synthesis • oxidative
cyclization • cascade cyclization • natural products
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Layout 2:
COMMUNICATION
Haichao Li, Lijun Chen, Kuo Yuan, and
Yanxing Jia*
Page No. – Page No.
10-Step Total Synthesis of Speradine
C
The first total synthesis of speradine C has been achieved in only 10 steps from a
commercially available 4-bromoindole. Salient features of the work are the
formation of four rings via three cyclizations.
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