Total Syntheses of Festuclavine, Pyroclavine, Costaclavine, epi-Costaclavine, Pibocin A, 9-Deacetoxyfumigaclavine C, Fumigaclavine G, and Dihydrosetoclavine

Article abstract of DOI:10.1021/acs.orglett.7b01504

A new approach for the divergent total synthesis of eight ergot alkaloids is reported. The approach allows the first total syntheses of pyroclavine, pibocin A, 9-deacetoxyfumigaclavine C, and fumigaclavine G and also enables the efficient synthesis of festuclavine, costaclavine, epi-costaclavine, and dihydrosetoclavine. The main feature of the synthesis is the use of an unprecedented Pd-catalyzed intramolecular Larock indole annulation/Tsuji-Trost allylation cascade to assemble the tetracyclic core in one step.

Full text of DOI:10.1021/acs.orglett.7b01504

Letter
pubs.acs.org/OrgLett
Total Syntheses of Festuclavine, Pyroclavine, Costaclavine, epi-
Costaclavine, Pibocin A, 9‑Deacetoxyfumigaclavine C, Fumigaclavine
G, and Dihydrosetoclavine
Haichao Liu,† Xiwu Zhang,† Dong Shan,† Mallesham Pitchakuntla,† Yongfan Ma,† 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 new approach for the divergent total
synthesis of eight ergot alkaloids is reported. The approach
allows the first total syntheses of pyroclavine, pibocin A, 9-
deacetoxyfumigaclavine C, and fumigaclavine G and also
enables the efficient synthesis of festuclavine, costaclavine, epi-
costaclavine, and dihydrosetoclavine. The main feature of the
synthesis is the use of an unprecedented Pd-catalyzed
intramolecular Larock indole annulation/Tsuji−Trost allylation cascade to assemble the tetracyclic core in one step.
he ergot alkaloids produced by the fungus Claviceps
Tpurpurea are a diverse class of indole natural products
with a broad spectrum of potent pharmacological activities
(Figure 1).1 They are among the most important groups of
natural products since many of them are important pharmaceut-
icals and are also recognized as important natural toxins in
human history. To date, two natural alkaloids and nine
semisynthetic derivatives such as pergolide and cabergoline
have been used clinically for the treatment of migraines,
Parkinson’s disease, and other ailments.2 Structurally these
molecules have a unique tetracyclic ergoline skeleton containing
several chiral centers of various configurations. As a result, since
the first total synthesis of lysergic acid by Woodward in 1956,3
the total synthesis of the ergot alkaloids has been the subject of
extensive study over the last six decades.4,5 Interestingly, despite
the many successful synthetic approaches already reported,
recent efforts have shifted toward devising innovative and elegant
approaches to construct the C/D rings or B/C rings in one step,
thus improving their synthetic efficiency.5a,b,e,f,j,l,m However, no
approach to construct the B/C/D rings in one step has been
reported yet.
As part of our ongoing studies toward the concise and efficient
synthesis of 3,4-indole alkaloids,6 we have recently developed a
novel strategy for the construction of 3,4-fused indoles and
benzofurans through a palladium-catalyzed intramolecular
Larock annulation.7 We initiated further studies to demonstrate
the utility of this method and facilitate the preparation of ergot
alkaloid analogues bearing deep-seated structural changes and
not readily accessible by conventional approaches.
Herein, we report an unprecedented palladium-catalyzed
intramolecular Larock indole annulation/Tsuji−Trost allylation
cascade, which allowed the assembly of the B/C/D rings of ergot
alkaloids in one step and enabled the expedient synthesis of the
advanced common intermediate. This approach could be used
for the efficient and divergent total syntheses of festuclavine
(1),8,9 pyroclavine (2),10,9c,d,11 costaclavine (3),10,9a,b,12 epi-
costaclavine (4),12a,b pibocin A (5),13 9-deacetoxyfumigaclavine
C (6),14 fumigaclavine G (7),15 and dihydrosetoclavine (8) via
late-stage manipulations.16,17
Received: May 17, 2017
Figure 1. Structures of ergot alkaloids, pergolide, and cabergoline.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01504
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Organic Letters
Letter
The biosynthesis of ergot alkaloid starts with the prenylation
of L-tryptophan (11) followed by a series of transformations to
give chanoclavine-I (12), which is the advanced common
biosynthetic precursor of all ergot alkaloids.18 Inspired by the
biosynthetic sequence, we envisioned that the ergot alkaloids
could be divergently synthesized from the advanced common
intermediate 13 (relative to 12) by late-stage manipulations
(Scheme 1). Since both 10R and 10S configurations of natural
by alkylation of the corresponding nitrile with the known allylic
bromide 16 furnished 19. Reduction of nitrile 19 with DIBAL-H
followed by condensation of the resulting aldehyde with (SR)-N-
tert-butanesulfinamide (17) afforded a mixture of two insepa-
rable diastereoisomers of 20 (dr = 1:1) in 80% yield. Reduction
of 20 with Zn/HOAc followed by acetylation of the
corresponding aniline with Ac2O provided inseparable acetani-
lide 15 in 91% overall yield. Propargylation of N-tert-
butylsulfinylimine 15 with 1-(trimethylsilyl)allenylzinc bromide
proceeded smoothly to afford the homopropargylic amines 14a,b
and its C5 diastereoisomer in excellent overall yield (dr =
1:3.4).20 The absolute configurations of 14a and 14b were
determined by X-ray crystallographic analysis of downstream
product or after completion of the synthesis of ergot alkaloids
(vide infra).
Scheme 1. Retrosynthetic Analysis
With the desired cyclization precursors 14 in hand, the
intramolecular Pd-catalyzed Larock indole annulation of 14a was
performed under our optimized catalyst system (Pd(OAc)2 and
Me-phos at 100 °C), giving the desired tricyclic indole 13a in
92% yield (Scheme 3). The structure of 13a was unequivocally
Scheme 3. Total Synthesis of Festuclavine and Pyroclavine
products are found in ergot alkaloids, two diastereoisomers of 13
at C(10) are welcomed. The tricycle 13 would be readily
assembled by a Pd-catalyzed intramolecular Larock indole
annulation of 14.7 The chemoselectivity of carbapalladation of
acetylene versus olefin posed a significant challenge at this step.19
The stereogenic center (5R) of 14 at the propargylic position,
which was required and fixed in all the natural ergot alkaloids, was
introduced by propargylation of chiral N-tert-butylsulfinylimine
15.20 In turn, 15 could be readily obtained from commercially
available or known compounds.
Our synthesis commenced with bromide 18, which was
prepared in one step from commercially available 2-bromo-1-
methyl-3-nitrobenzene following the reported procedure
(Scheme 2).21 Cyanidation of bromide 18 with NaCN followed
confirmed by X-ray crystallographic analysis.22 Surprisingly,
when the reaction was run on a gram scale, an unexpected
tetracyclic compound 21 was isolated in a small amount.
Compound 21 was produced most likely from Tsuji−Trost
allylation of tricyclic indole 13a.23 To gain insights into such
unprecedented reactions, the indole 13a was subjected to the
aforementioned reaction conditions. The allylation reaction did
occur, and 21 was formed in 50% yield with recovery of 13a in
35% yield. This result implied that 13a was indeed the cyclization
precursor of 21, and an unprecedented Pd-catalyzed intra-
molecular Larock indole annulation/Tsuji−Trost allylation
cascade occurred for 14a. Most importantly, this cascade reaction
constructs three rings, two C−C bonds, and one C−N bond in one
step, forming the tetracyclic skeleton of ergot alkaloids. Since
compound 21 could be used as the advanced intermediate to
Scheme 2. Synthesis of Cyclization Precursors 14
B
DOI: 10.1021/acs.orglett.7b01504
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Organic Letters
Letter
streamline the synthesis and shorten the synthetic route, further
optimization of the cascade reaction of 14a to improve the yield
of 21 was investigated. Considering the Tsuji−Trost allylation
also needs Pd catalyst and ligand, the optimal ratios of Pd catalyst
and ligand were examined. When the reaction was conducted
with 0.3 equiv of Pd(OAc)2 and 0.9 equiv of Me-phos, the
desired 21 was obtained in 65% yield accompanied by 25% of
13a. An extensive literature search did not show any report on
the use of such a TBS-protected allylic alcohol for the Tsuji−
Trost reaction. Thus, this unprecedented Tsuji−Trost reaction
of TBS-protected allylic alcohol to form a piperidine ring is
reported for the first time.
Having successfully completed the total synthesis of 1, 2, and
5−7, we next turned to the synthesis of dihydrosetoclavine (8)
(Scheme 5). Initial attempts to the direct hydrofunctionalization
Scheme 5. Total Syntheses of Dihydrosetoclavine and
Isodihydrosetoclavine
Having constructed the requisite tetracyclic basic skeleton 21,
we sought to complete the synthesis of festuclavine (1) and
pyroclavine (2) (Scheme 3). Removal of the tert-butanesulfinyl
group and subsequent N-protection of the resulting secondary
amine with ClCO2Me gave carbamate 22 in 80% overall yield. In
addition, tricyclic indole 13a could be also converted to 22 in a
three-step sequence by removal of the silyl group and tert-
butanesulfinyl group with HCl, chlorination of the resulting free
hydroxyl group with SOCl2 followed by treatment with NaOH,
and subsequent N protection of the secondary amine. Reduction
of the carbamate 22 with LiAlH4 gave the desired olefin 23 in
93% yield. Finally, selective reduction of the olefin 23 with 5%
Pd/C afforded 1 and 2 in 95% yield in a ratio of 8:1. In addition,
reduction of the olefin 23 with Raney Ni furnished the target
molecules 1 and 2 in 90% yield with a ratio of 5:3. The physical
data of our synthesized products 1 and 2 are identical to those
reported in the literature.8−11 Thus, we have achieved the first
asymmetric total synthesis of festuclavine and pyroclavine.
After the synthesis of 1 and 2, we investigated the synthesis of
pibocin A (5), 9-deacetoxyfumigaclavine C (6), and fumigacla-
vine G (7) by direct functionalization of 1 and 2 (Scheme 4).
of advanced intermediate 22 under a variety of conditions failed.
We thought that carbamate might affect this reaction.25 Thus,
hydrofunctionalization of 21 with Mn(dpm)3 was further
examined.25b This reaction proceeded smoothly and gave the
desired alcohol 24a accompanied by its diastereoisomer 24b in
35% and 28% yield, respectively. Removal of the tert-
butanesulfinyl group in 24a and subsequent N-protection of
the resulting secondary amine with ClCO2Me gave carbamate
25a in 55% overall yield. Finally, reduction of 25a with LiAlH4
furnished the target molecule 8 in 67% yield. Using the same
procedure as described for 24a, 24b was converted to
isodihydrosetoclavine (26).
Scheme 4. Total Synthesis of Pibocin A, 9-
Deacetoxyfumigaclavine C, and Fumigaclavine G
Having successfully completed the total synthesis of 1, 2, and
5−8 from intermediate 14a, we then conducted the trans-
formation of 14b into 3 and 4 following the same sequence as
described for 14a (Scheme 6). Compound 14b could be
Scheme 6. Total Syntheses of Costaclavine and epi-
Costaclavine
Chemoselective bromination of the 2-position of 1 with NBS
provided pibocin A (5) in 80% yield. The synthesis of 9-
deacetoxyfumigaclavine C (6) and fumigaclavine G (7) from 1
and 2 by formation of the C-2 reverse prenylated indole was
carried out following the excellent procedure established by
Danishefsky and co-workers.24 Thus, chlorination of 1 with
tBuOCl followed by treatment with prenyl-9-BBN in the
presence of Et3N provided 9-deacetoxyfumigaclavine C (6) in
80% yield. In the same manner, 2 was transformed to target
molecule 7 in 50% yield. The physical data of our synthesized
products 5−7 are identical to those reported in the
literature.13−15 Thus, we have achieved the first total synthesis
of 5−7.
smoothly converted to teracycle 27. Finally, hydrogenation of the
exocyclic CC bond with Pd/C or Raney Ni in a variety of
conditions gave epi-costclavine (4) as the sole product, but
reduction with Crabtree’s catalyst provided 3 and 4 in 92% with a
ratio of 1:1.2.26
In summary, we have developed a unified strategy for the
enantioselective synthesis of ergot alkaloids and accomplished
the total syntheses of festuclavine (1), pyroclavine (2),
C
DOI: 10.1021/acs.orglett.7b01504
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Letter
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The significant feature of this strategy is the tetracyclic skeleton
of the ergot alkaloids are rapidly and efficiently constructed
through an unprecedented Pd-catalyzed intramolecular Larock
indole annulation/Tsuji−Trost allylation cascade.
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ASSOCIATED CONTENT
* Supporting Information
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■
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S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b01504.
1
Full experimental procedures and H and 13C NMR
spectra of compounds 1−8, 13−15, and 19−27 (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: yxjia@bjmu.edu.cn.
ORCID
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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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