Biomimetic Total Syntheses of Clavine Alkaloids

Article abstract of DOI:10.1021/acs.orglett.7b03683

Biomimetic total syntheses of either enantiomers of a number of ergot alkaloids, chanoclavine I (1b), chanoclavine I aldehyde (1c), pyroclavine (1e), festuclavine (1f), pibocin A (1g), 9-deacetoxyfumigaclavine C (1h), and fumigaclavine G (1i), have been achieved from seco-agroclavine (1a). The advanced intermediate for seco-agroclavine (1a) was synthesized via a key thiourea-catalyzed intramolecular nitronate addition onto α,β-unsaturated ester.

Full text of DOI:10.1021/acs.orglett.7b03683

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Biomimetic Total Syntheses of Clavine Alkaloids
†
†
Saikat Chaudhuri, Subhajit Bhunia, Avishek Roy, Mrinal K. Das, and Alakesh Bisai*
Department of Chemistry, Indian Institute of Science Education and Research Bhopal, Bhopal Bypass Road, Bhauri, Bhopal 462 066,
Madhya Pradesh, India
*
S Supporting Information
ABSTRACT: Biomimetic total syntheses of either enantiomers of a number of ergot alkaloids, chanoclavine I (1b),
chanoclavine I aldehyde (1c), pyroclavine (1e), festuclavine (1f), pibocin A (1g), 9-deacetoxyfumigaclavine C (1h), and
fumigaclavine G (1i), have been achieved from seco-agroclavine (1a). The advanced intermediate for seco-agroclavine (1a) was
synthesized via a key thiourea-catalyzed intramolecular nitronate addition onto α,β-unsaturated ester.
ecause of their striking physiological properties, the clavine
members of this class of natural compounds have been
reported.
3
B
alkaloids of the ergot family (1a−l, Figure 1) have been
1
They act as agonists or antagonists toward neuroreceptors
for dopamine, serotonin, and adrenaline. Therefore, they are
considered as potential drug candidates. Ergot alkaloids exhibit
a broad spectrum of pharmacological effects and have already
been extensively used as medicines over the centuries.
Consequently, total synthesis of ergot alkaloids has recently
the subject of longstanding interest. Most of these alkaloids
have been derived from the fungus Claviceps purpurea on rye
grain. Biosynthetically derived from tryptophan through
2
intriguing enzymatic pathways, total syntheses of several
4
received considerable attention, even in its racemic forms. The
majority of these alkaloids have the characteristic structure of a
tetracyclic ring system (ergoline), which is believed to rise from
seco-agroclavine (1a) via a series of oxidation reduction
sequence (Figure 1). Herein, we report biomimetic collective
total syntheses of either enantiomers of clavine alkaloids from
simplest congener, seco-agroclavine (1a).
Retrosynthetically, we envisioned that vicinal stereocenters of
seco-agroclavine (1a) can be accessed from tricyclic γ-nitroester
derivative 2, which in turn can be synthesized from a key5
organocatalytic enantioselective Michael addition of nitronate
6
onto conjugated esters (see 3) in an intramolecular fashion.
The asymmetric Michael reaction of conjugated enone, enal, or
7
,8
nitroalkene variant remains an important challenge for the
9
,10
construction of vicinal stereogenic centers.
We argued that
the use of nitronates in the catalytic intramolecular Michael
addition to conjugated esters could afford γ-nitroester
derivative 2 sharing a vicinal stereogenic center (Scheme 1).
Received: November 28, 2017
Figure 1. Selected naturally occurring clavine alkaloids 1a−l.
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03683
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Retrosynthetic Analysis of Clavine Alkaloids 1
6a,11
Toward this end, encouraged by Cobb’s report,
recently, we
have investigated the catalytic intramolecular nitronate Michael
addition in the presence of bifunctional organocatalysts such as
1
2
13
thiourea and squaramide catalysts1 to synthesize compounds
4
(
S,S)-2a and (R,R)-2a (Scheme 2).
Scheme 2. Thiourea Catalyzed Nitronate Michael Reactions
Figure 2. Stereochemical rational using thiourea.
product (S,S)-2a in 86% yield with 93% ee (dr = 3:1) and
R,R)-2a in 84% yield with 92% ee (dr = 2.8:1). More
(
importantly, minor products (S,R)-2a and (R,S)-2a can be
converted to (S,S)-2a and (R,R)-2a in 72% and 69% yields,
respectively, by epimerization in the presence of 6 equiv of
Et N in refluxing toluene (6−7 h). This ensures the overall
3
efficiency of our strategy.
Having Michael product (R,R)-2a in hand, our effort was
focused thereafter on its utilization for the synthesis of seco-
agroclavine (1a) (Scheme 3). Toward this, we reduced the
nitro functionality in the presence of Zn-AcOH followed by
Boc protection to afford γ-aminoester (R,R)-7 in 82% over two
steps (Scheme 3). The latter was then N-methylation [see,
(R,R)-8] followed by reaction with MeLi to furnish tertiary
alcohol (R,R)-9 in 93% over two steps. Further, compound
It was hypothesized that the thiourea needs to coordinate to
both the nitro group (essentially a nitronate generated in situ
by abstraction of α-proton by quinuclidine base) and the ester
(
electrophile here) in order to proceed the reaction
efficiently. In fact, this can only occur effectively with the
E ester” and stabilizes TS-I (4) as a favored transition state
15
“
(
Figure 2) through H-bonding via three acidic N−H groups of
15
the protonated catalyst.
Scheme 3. Total Synthesis of Natural seco-Agroclavine (1a)
On the other hand, the geometry of the “Z ester” prevents
such an H-bonding interaction, leading to the disfavored
transition state TS-II (5) (Figure 2). It was also argued that a
balance between steric and electronic effects should be
maintained in order to have optimum results. In fact, a bulky
ester might disturb the H-bonding (see, TS-I), whereas an
electron-withdrawing group at the indole nitrogen might ease
the reaction by pulling electrons toward it and create proper
electronics (Figure 2).
In practice, we were delighted to obtain cyclized product 2 in
dichloromethane in the presence of TU-1 to afford 93% yields
16
with 3.7:1 dr and 97% ee in favor of (S,S)-2a (Scheme 2).
Later, in our search for a flexible route to naturally occurring
ergot alkaloids, (R,R)-2a was synthesized in 90% yield (dr =
2
.8:1) with 93% ee from 3 using by using TU-2 catalyst
17
(
synthesized from cinchonidine). To our delight, the
intramolecular nitronate Michael reaction can be performed
on 1 g scale of compound 3 using 5 mol % of TU-1 and TU-2
at 25 °C (20 mL dichloroethane, ∼7 d), which afforded
B
DOI: 10.1021/acs.orglett.7b03683
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
R,R)-9 was treated with triflic acid to give (R,R)-10, which was
further treated with Mg in MeOH, without further purification,
to complete the total synthesis of seco-agroclavine (1a) (90%
over two steps) (Scheme 3). Further utilizing a similar strategy,
total synthesis of unnatural seco-agroclavine (ent-1a) has been
accomplished from (S,S)-2a (see the Supporting Information
for details).
Letter
(
Scheme 5. Biomimetic Total Syntheses of Naturally
Occurring Pyroclavine (1e) and Festuclavine (1f)
For further synthetic elaboration, the secondary amine of
R,R)-10 was protected with tosyl group to furnish (R,R)-11
Scheme 3). Bistosylated compound (R,R)-11 was reacted
(
(
under the condition of allylic oxidation to afford a mixture of
allylic alcohol (R,R)-12 and aldehyde (R,R)-13 in 56% and 26%
yields, respectively (Scheme 4). We could obtain 81% yield of
Scheme 4. Total Syntheses of Chanoclavine I (1b) and
Chanoclavine I Aldehyde (1c)
of chanoclavine I (1b), and chanoclavine I aldehyde (1c). A
reduction cascade involving a hydrogenation, iminium−
enamine tautomerization, and imine reduction from chanocla-
vine I aldehyde (1c) ensures total syntheses of 1e,f. Further
utilizing a similar strategy, biomimetic total syntheses of
unnatural (+)-festuclavine (ent-1f) and (+)-pyroclavine (ent-
1
e) have also been accomplished from unnatural seco-
agroclavine (ent-1a) via chanoclavine I (ent-1b) and chanocla-
vine I aldehyde (ent-1c). Further efforts toward a rational
extension of this strategy to access medicinally important drug
molecules sharing ergoline scaffolds are currently under active
investigation.
alcohol (R,R)-12 when a crude mixture was reduced with
NaBH , from where total synthesis of chanoclavine I (1b) was
4
completed by treatment of Na-naphthalide at −78 °C (90%
yield). Further oxidation of chanoclavine I (1b) to chanoclavine
I aldehyde (1c) was performed using MnO oxidation (Scheme
ASSOCIATED CONTENT
Supporting Information
2
■
4
). Along a similar line, total syntheses of unnatural
*
S
chanoclavine I (ent-1b) to chanoclavine I aldehyde (ent-1c)
have been accomplished from ent-1a (see the SI for details).
With the synthesis of chanoclavine I aldehyde (1c) secured,
it was hydrogenated to access festuclavine (1f) and pyroclavine
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03683.
General experimental procedures and analytical data for
all new compounds (PDF)
(
(
(
1e) following a biomimetic proposal in a one-pot fashion
Scheme 5). This one-pot cascade featured a hydrogenation
14) and iminium (15)−enamine (16) tautomerization
followed by reduction using NaBH which afforded a pair of
AUTHOR INFORMATION
Corresponding Author
4
■
*
diastereomers in 1.6:1 ratio (Scheme 5). Chromatographic
separation of these diastereomers ensures total syntheses of
pyroclavine (1e) (35% yield) and festuclavine (1f) (54% yield)
E-mail: alakesh@iiserb.ac.in.
ORCID
(
Scheme 5). Further utilizing a similar reaction sequence, the
total synthesis of unnatural festuclavine (ent-1f) and
pyroclavine (ent-1e) have also been accomplished from ent-1c
Alakesh Bisai: 0000-0001-5295-9756
Author Contributions
(
see the SI for details). Since the total syntheses of pibocin A
†
S.C. and S.B. contributed equally to this work.
Notes
(1g) and 9-deacetoxyfumigaclavine C (1h) are reported from
18
festuclavine (1f) in one step, our effort culminated in the total
The authors declare no competing financial interest.
syntheses of 1g,h (Scheme 5). Further, as the total synthesis of
18
fumigaclavine G (1i) is reported from pyroclavine (1e), we
have also shown formal total synthesis of 1i (Scheme 5).
In conclusion, biomimetic total syntheses of tetracyclic
clavine alkaloids pyroclavine (1e) and festuclavine (1f) have
been achieved from seco-agroclavine (1a) via the intermediacy
ACKNOWLEDGMENTS
■
Financial support from the SERB, DST (EMR/2016/000214),
and CSIR [02(0295)/17/EMR-II], Government of India, is
gratefully acknowledged. S.C. thanks the UGC for a SRF
C
DOI: 10.1021/acs.orglett.7b03683
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
senior research fellowship). S.B. and M.K.D. thank the CSIR
for SRF’s. A.B. sincerely thanks the Director, IISER Bhopal, for
financial support.
Letter
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