Stereodivergent Total Synthesis of Hapalindoles, Fischerindoles, Hapalonamide H, and Ambiguine H Alkaloids by Developing a Biomimetic, Redox-Neutral, Cascade Prins-Type Cyclization

Article abstract of DOI:10.1021/acs.orglett.8b02804

A stereoselective, redox-neutral, Br?nsted acid-catalyzed cascade Prins-type cyclization between indole and aldehyde is described to access several structurally diverse indole terpenoid scaffolds in a single step. Applying this concept, stereodivergent to

Full text of DOI:10.1021/acs.orglett.8b02804

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Stereodivergent Total Synthesis of Hapalindoles, Fischerindoles,
Hapalonamide H, and Ambiguine H Alkaloids by Developing a
Biomimetic, Redox-Neutral, Cascade Prins-Type Cyclization
Samrat Sahu, Beauty Das, and Modhu Sudan Maji*
Department of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur 721302, India
S
* Supporting Information
ABSTRACT: A stereoselective, redox-neutral, Brønsted acid-cata-
lyzed cascade Prins-type cyclization between indole and aldehyde is
described to access several structurally diverse indole terpenoid
scaffolds in a single step. Applying this concept, stereodivergent total
syntheses of nine hapalindole-type alkaloids are accomplished. Key
transformations include allylation using geometrically isomeric
allylboronic acid followed by a p-toluenesulfonic acid mediated
deprotection−cyclization cascade.
atural products possess an exclusive chemical and
structural diversity which has evolved over the years
N
for their ultimate interaction with biomolecules, enabling them
to be a fundamental source of drugs. Hapalindoles are arguably
the largest and most comprehensive subclass of indole
alkaloids isolated from secondary metabolites released by
cyanobacteria.1 Originally isolated by Moore et al.,1a these
secondary metabolites exhibit a wide array of biological
activities2 such as antimicrobial,3 insecticidal,4 anticancer,5
antialgal,6 phytotoxic,7 and antimycotic,8 etc. For example,
hapalindole C (2) and hapalindole H (10) were found to have
potent anticancer activity against human HT-29 (colon),
MCF-7 (breast), NCI-H460 (large cell lungs), and SF268
(glioblastoma) cancer cell lines with moderate IC50 values.3d,5c
Parallel pharmacological research has also found these to be a
potential lead for drug discovery.3b,c Structural investigation of
over 80 indole alkaloids isolated to date has revealed certain
similarities, likely to originate from shared biosynthetic
pathways. It contains a trans-1-indolyl-2-isopropenylcyclohex-
ane 1 framework (Figure 1) where an indole core is connected
to a highly functionalized cyclohexane unit (with up to five
contiguous stereocenters) through the C3-position.The
aforementioned biological importance coupled with a unique
amalgamation of rings, stereocenters, and functionalities has
stimulated the interest of synthetic chemists, resulting in a
Figure 1. Hapalindole-type natural products.
elusive and still a challenging task. In view of the above
literature and our interest in developing efficient synthetic
methods for functionalized indoles,11 we herein report
synthesis of 1 in one step by a direct reaction of unprotected
indoles and aldehydes (Scheme 1b) through Brønsted acid
catalysis and its application toward the total synthesis of
hapalindoles, fischerindoles, and the hapalonamide series of
nine alkaloids in 9−12 steps.
number of racemic9 as well as asymmetric syntheses.10
A
Cu(II)-mediated enolate coupling of indoles with carvone 11
by Baran et al. (Scheme 1a)10c and DDQ-promoted benzylic
oxidation of 3-alkylated indoles9j are the two prominent
methods for synthesizing 1. However, it requires tedious
prefunctionalization of indoles (up to seven steps to get the
product), stoichiometric use of Sc(III) triflate, an oxidizing
agent, and high temperature. In addition, the corresponding
indolyl ketone is formed as a side product.9j Despite several
reports, direct access to these structurally unique scaffolds is
Received: September 3, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02804
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
clohexane scaffold 17 via an all equatorial chairlike TS. The
success of this strategy exclusively depends on the selectivity at
which two competing reactions namely, (a) the generation of
15 and (b) the intramolecular ene reaction of 14 (a
decomposition pathway), takes place.
Scheme 1. Previous Report and Proposed Hypothesis
To explore this hypothesis, 2-methylindole 13a and 3,3,7-
trimethyloct-6-enal 14a were chosen as the model substrate
and treated with various acid catalysts in CH2Cl2 (Scheme
2).12 A brief optimization study shows 20 mol % of diphenyl
phosphate is an excellent acid promoter giving 17a in 98%
yield in 30 min with exclusive trans geometry. The generality of
the reaction was subsequently investigated by a reaction with
various aldehydes. Citronellal was found to be a suitable
reaction partner, providing 17b in 93% yield. Remarkably the
mild reaction conditions have enabled us to use the ketal
functional group which remained intact, furnishing 17c,d in
40% and 64% yields, respectively. Five-membered as well as
six-membered ring formations proceeded elegantly with
aldehydes bearing benzyl- and methyl-protected ethers at the
backbone (17e,f,m, 42−89%). Chromane derivative 17g can
also be synthesized with good diastereoselectivity by taking O-
homoprenylated salicylaldehyde 14g as a coupling partner.
Nitrogenous aldehydes 14h−j were also subjected to the
standard reaction conditions, and products 17h−j were
isolated in moderate to good yields (56−73%).
Development of a new C−C bond-forming strategy is one of
the central pillars of organic synthesis, providing easy access to
complex structural architectures. The proposed idea is based
on a one-pot tandem reaction pathway. First, in situ generated
indolyl alcohol 15, formed by reaction of indole 13 and
aldehyde 14 in the presence of Brønsted acid, should undergo
a rapid water elimination to generate vinylogous iminium
intermediate 16, which would undergo intramolecular Prins-
type cyclization to provide the trans-1-indolyl-2-isopropenylcy-
Tolerance of a variety of aldehydes next prompted us to
extend the scope of this reaction to other substituted indoles.
In the case of 2-phenylindole, the optimized conditions gave
65% of the desired product 17n. Sterically hindered 2-tert-
a
Scheme 2. Scope of Aldehydes and Indoles
a
All of the reactions were carried with 13 (0.25 mmol), 14 (0.25 mmol), and catalyst A (0.025−0.05 mmol) or catalyst B (0.0125 mmol) in
b
CH2Cl2 (2.5 mL) or cyclohexane (2.5 mL) at rt. Batchwise addition of aldehyde at 60 °C. dr = diastereomeric ratio.
B
DOI: 10.1021/acs.orglett.8b02804
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Organic Letters
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Scheme 3. Total Synthesis of ( )-Deschloro-12-epi-fischerindole W Nitrile and ( )-Hapalindole Q
a
Scheme 4. Total Synthesis of ( )-12-epi-Hapalindole Q Isonitrile, ( )-Hapalindole C, and ( )-Hapalindole D
a
PTSA = p-toluenesulfonic acid, IBX = 2-iodoxybenzoic acid, CDMT = 2-chloro-4,6-dimethoxy-1,3,5-triazene, DMAP = 4-(dimethylamino)-
pyrridine; NMM = N-methylmorpholine; CS(Imid)2 = 1,1′-thiocarbonyldimidazole.
butylindole was reactive enough and provided 17o in excellent
yield (92%), although the reaction required higher temperature
and the batchwise addition of 14a to minimize the intra-
molecular ene reaction. Compatibility of 2-styrylindole under
the standard reaction conditions opens up the further
possibility of functional group transformation for product
17p. Indoles bearing −Br, −NO2, and −CN functionalities in
the benzene ring were also found to be suitable reaction
partners, providing 17r−t in 55−81% yields.
For indole having no C2-substitution, cyclohexane was
found to be the solvent of choice. In the presence of BINOL-
derived phosphoric acid catalyst B (5 mol %), we pleasingly
found that fully cyclized product 18a was the major product
(56% yield) along with 17k as the minor (11%). Single-crystal
X-ray analysis of 18a confirmed the stereochemical outcome of
Prins-type cyclization. This cascade reaction provided an
unprecedented direct access to the fischerindole scaffold which
previously required two separate steps,10c,f,h whereas, catalyst A
was not selective, providing 17k and 18a in 41 and 34% yields,
respectively. Similar results were recorded for aldehyde 14b
when reacted with indole in the presence of either catalyst A or
B (17l, 18b). Gratifyingly product 18c was isolated as the sole
product in 68% yield. Even prolonging the reaction time does
not convert the monocyclized products 17k,l to their fully
cyclized counterpart 18a,b.
With the developed method in hand, we were curious to
learn whether this method could be applied to the synthesis of
hapalindole-type natural products. The reaction of geranyl
boronic acid13 with ethyl glyoxalate furnished homoallylic
alcohol 20 in >20:1 dr and 90% yield (Scheme 3). In contrast,
Zn-mediated allylation of geranyl bromide under similar
conditions yielded 20 with almost no diastereoselectivity.
Then 20 was protected as TBDPS as well as p-methoxybenzyl
ethers, and finally, the esters were converted to their
corresponding aldehydes. However, under the standard
conditions both aldehydes did not give any desired products,
probably due to steric bulk adjacent to the aldehydes retarding
the initial attack of indole. We then moved toward
methoxymethyl ether as a protecting group, which possesses
moderate steric bulk and can also be deprotected under acidic
conditions. However, it also did not provide fruitful results. To
overcome this, MOM-protected aldehyde 14k was coupled
first with Grignard generated from 28 to obtain secondary
alcohol 22 as a single diastereomer in 75% yield over two steps
as we envisioned using Cram’s chelate model.12 To our joy, the
treatment of 22 with 2.0 equiv of PTSA in ethyl acetate
C
DOI: 10.1021/acs.orglett.8b02804
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Scheme 5. Total Synthesis of ( )-Hapalindole H, ( )-Hapalonamide H, ( )-Hapalindole U, and ( )-Ambiguine H
proceeded smoothly to furnish deprotected monocyclized
secondary alcohol 23 as a single diastereomer in 69% yield
over two steps in one pot. It is important to mention that lower
equivalency as well as changing to other acids or solvents were
found to be less effective for this transformation. The relative
stereochemistry of 23 was assigned by comparing its spectral
data with the literature report after desulfonylation.9j After
desulfonylation, Pd(OAc)2/1,4-benzoquinone-mediated oxida-
tive Heck annulation gave carbazole alcohol 24 in 35% yield.9j
Total synthesis of deschloro-12-epi-fischerindole W nitrile 4
was accomplished in 38% overall yield as the major
diastereomer (dr 2.5:1) by treatment of 24 with TMSCN in
the presence of BF3·Et2O.9j To synthesize hapalindole Q, 23
was oxidized to the corresponding ketone 25 using Dess−
Martin periodinane oxidant. The resulting ketone was then
converted to amine 26 in 48% yield (85% brsm) through
reductive amination using NH4OAc and NaBH3CN.10h
Removal of the protecting group followed by isothiocyanate
formation using CS(Imid)2 gave hapalindole Q 27 in 55% yield
over two steps.
In a similar fashion as described above, cis-boronic acid 29
was converted to its secondary alcohol 30 (Scheme 4).
Treatment of 30 with PTSA proceeded as anticipated,
providing 31 in 50% yield over two steps. Alcohol functionality
was converted to ketone using IBX oxidation, and the resulting
ketone was then subjected to reductive amination giving two
isomeric amines 32 and 33 in 16% and 55% yields,
respectively.10h Desulfonylation of 33 followed by isocyanide
formation gave 12-epi-hapalindole-Q-isonitrile (34) in 54%
yield over three steps. Similarly, desulfonylation of another
isomeric amine 32 followed by isothiocyanate as well as
isocyanate formation gave hapalindole D (3) and hapalindole
C (2), respectively.
decalin ring system with a quaternary vinyl group at the C12-
position and isonitrile group at the C11-position. To achieve
this, we took 4-bromo-N-(benzenesulfonyl)-3-iodoindole 43 as
an indole coupling partner.10d The reaction of aldehyde 14k
with Grignard generated from 43 provided alcohol 35 as a
single diastereomer in 72% yield (Scheme 5). Treatment of 35
with 2.0 equiv of PTSA at a lower temperature (∼20 °C)
proceeded as hypothesized to give 36 in 40% overall yield over
two steps. It is important to maintain the temperature at
around 20 °C for optimal yield. DMP oxidation of 36 gave the
ketone 37. Similar reductive amination as mentioned
previously proceeded smoothly to give amine 38 as a mixture
of inseparable diastereomers (dr 4:1) in 53% combined yield.
In the next step, amine was converted to the formamide
functionality, and the benzenesulfonyl group was deprotected.
During this time, major diastereomer 39 was separated and
obtained in 67% yield. Formamide 39 was subjected to
reductive Heck annulation and successive dehydration using
triphosgene to give hapalindole H (10) in 46% yield over two
steps.9j Hapalindole H has been used as an advanced
intermediate for the synthesis of hapalonamide H (5) by Li
et al.9j Thus, the formal synthesis of hapalonamide H (5) was
also achieved.
The other isomeric alcohol 40, prepared by using 43 and
aldehyde 14l obtained from 29, was similarly treated with
PTSA to obtain 41 in 35% yield. Desulfonylation followed by
DMP oxidation gave ketone 42, which has been used as a
synthetic intermediate for the synthesis of hapalindole U (6)
and ambiguine H (8), thus completing their formal
synthesis.10d
In conclusion, we have successfully synthesized diverse
functionalized trans-1-indolyl-2-isopropenylcyclohexane scaf-
folds via Brønsted acid catalyzed one-pot cascade protocol.
Simplicity and mild conditions significantly enhance the appeal
of this method toward other systems. To show the
Having achieved tricyclic hapalindoles, we next concentrated
our attention toward tetracyclic subclass having trans-fused
D
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02804.
Experimental procedures and spectroscopic data of
compounds; NMR spectra of compounds (PDF)
Accession Codes
CCDC 1860967 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: msm@chem.iitkgp.ac.in.
ORCID
Modhu Sudan Maji: 0000-0001-9647-2683
Notes
The authors declare no competing financial interest.
(11) (a) Sahu, S.; Banerjee, A.; Maji, M. S. Org. Lett. 2017, 19, 464.
(b) Banerjee, A.; Sahu, S.; Maji, M. S. Adv. Synth. Catal. 2017, 359,
1860. (c) Sk, M. R.; Bera, S. S.; Maji, M. S. Org. Lett. 2018, 20, 134.
(12) See the Supporting Information for details.
ACKNOWLEDGMENTS
■
M.S.M. gratefully acknowledges SERB, Department of Science
and Technology, New Delhi, India (Sanction No. EMR/2015/
000994), and Council of Scientific & Industrial Research, India
(Sanction No. 02(0322)/17/EMR-II) for funding. S.S. thanks
CSIR India and B.D. thanks IIT Kharagpur for fellowships. We
thank Prof. M. C. Das from IIT Kharagpur for solving the
crystal structure.
́
(13) (a) Raducan, M.; Alam, R.; Szabo, K. J. Angew. Chem., Int. Ed.
́
2012, 51, 13050. (b) Alam, R.; Vollgraff, T.; Eriksson, L.; Szabo, K. J.
J. Am. Chem. Soc. 2015, 137, 11262.
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