Enantiospecific Total Syntheses of (+)-Hapalindole H and (?)-12-epi-Hapalindole U

Article abstract of DOI:10.1002/chem.201800970

Enantiospecific total syntheses of (+)-hapalindole H and (?)-12-epi-hapalindole U as well as the formal syntheses of (+)-hapalindole Q and (+)-12-epi-fischerindole U isothiocyanate have been described. Key steps of our approach feature expedient, highly regio- and diastereoselective Lewis acid catalyzed Friedel–Crafts reaction of indole with cyclic allylic alcohols and intramolecular reductive Heck reaction. Efficiency of the synthetic route also relies on an alkynyl aluminate complex driven regioselective nucleophilic epoxide opening from a sterically hindered site.

Full text of DOI:10.1002/chem.201800970

A Journal of
Accepted Article
Title: Enantiospecific total syntheses of (+)-Hapalindole H and (-)-12-
epi-Hapalindole U
Authors: Dattatraya Hanumant Dethe, Saikat Das, Vijay Kumar B., and
Nisar Ahmed Mir
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Enantiospecific total syntheses of ()-Hapalindole H and ()-12-
epi-Hapalindole U
Dattatraya H. Dethe,*[a] Saikat Das,[a] Vijay Kumar B,[a] and Nisar A. Mir [a]
Dedication ((optional))
Abstract: Enantiospecific total syntheses of (+)-hapalindole H, ()-
12-epi-hapalindole U, formal synthesis of (+)-hapalindole Q and (+)-
12-epi-fischerindole U isothiocyanate have been described. Key
steps of our approach feature expedient, highly regio- and
diastereoselective Lewis acid catalyzed Friedel-Crafts reaction of
indole with cyclic allylic alcohols and intramolecular reductive Heck
reaction. Efficiency of the synthetic route also relies on an alkynyl
aluminate complex driven regioselective nucleophilic epoxide
opening from sterically hindered site.
Hapalindoles and fisherindoles are two important classes of
bioactive indole alkaloids derived from marine cyanobacteria
belonging to Stigonemataceae family. Isolation of these marine
indole alkaloids was first reported by Moore et.al. in 19841 which
was followed by addition of more than eighty alkaloid members
to this family.2 Hapalindoles show prominent biological aspects
such as insecticidal, anti algal, antimycotic or antibacterial
activities along with the inhibitory activity against arginine
vasopression binding. These natural products possess unique
tri- or tetracyclic framework featuring indole moiety connected
Figure 1. Selected examples of natural products of Hapalindole type alkaloids.
through its C3 position to highly functionalized cyclohexyl ring
with an uncommon nitrile or isonitrile substituent. Owing to these
fascinating biological activities along with their challenging
structural features, developing new methods for total synthesis
of hapalindoles has been a rousing task in recent years.3
of (+)-hapalindole
H and ()-12-epi-hapalindole U
(13).7
Hapalindole H (1) has unique structure accommodating a trans
fused decalin ring junction with quaternary axial vinyl group at
C12 position and an equatorial isonitrile group at C11 position.
Hapalindole H (1) acts as a fungicide and also inhibits growth of
Staphylococcus aureus, Staphylococcus epidermidis and
Staphylococcus pyogenes.8 Till date, only two total syntheses of
(±)-hapalindole H are reported in literature.5c,5g The first total
synthesis was achieved by Natsume and coworkers in 1990 and
recently Li group reported another synthesis using bioinspired
oxidative cyclization reaction. But so far, the total synthesis of
enantiomerically pure hapalindole H is not reported. Thus, the
absolute configuration of the hapalindole H is still unknown.
Friedel-Crafts reaction is one of the most powerful synthetic
methods in organic chemistry as it directly constructs carbon-
carbon bond in an atom economical manner and provides
advanced intermediates for total synthesis of natural products.9a-i
In particular, enantio- and diastereoselective Friedel-Crafts
reaction has been a fascinating and perplexing exercise as the
carbocation intermediate involved in the reaction would bring
about racemic and diastereomeric mixture or it would undergo a
carbocationic rearrangement giving rise to regioisomers. Grieco
and coworkers have also developed a Friedel-Crafts reaction of
indole nucleophile with allylic alcohols using lithium perchlorate-
diethyl ether and a catalytic amount of Bronsted acid. Their
strategy was limited to allylic alcohols with β,β-disubstitution.
Diastereoselectivities and wide substrate scope remained
unexplored or unexplained.10a Herein, we report a highly regio-
and diastereoselective Friedel-Crafts reaction between indole
So far, there are multiple approaches4 towards synthesis of the
natural products belonging to the class of hapalindoles and a
few of them have succeeded in synthesizing the natural
products both in racemic5 or enantiomerically pure6 form. First
total synthesis of hapalindoles J, M, H, and U were reported by
Natsume and coworkers.5a-c Albizati group synthesized ()-
hapalindole Q 6a and subsequently Fukuyama and Natsume et
al. independently described enantiospecific syntheses of ()-
hapalindoles G and O from ()-carvone.6b-c Kerr group reported
organocatalytic asymmetric Diels Alder reaction for the formation
of ()-hapalindole Q.6d Baran group achieved total synthesis of a
number of hapalindole alkaloids by using copper mediated
unique oxidative coupling protocol.6e-h Syntheses of hapalindole
K, A and G were also achieved by Johnston group.5e Very
recently Zhou et. al. reported total syntheses of (+)-hapalindole
Q and ()-12-epi-fischerindole U isothiocyanate using DKR
method.6n Herein, we report a first enantiospecific total synthesis
[a]
Dr. D. H. Dethe, S. Das, Vijay Kumar B. Nisar A. Mir
Department of Chemistry, Indian Institute of Technology Kanpur,
Kanpur – 208016, India
E-mail: ddethe@iitk.ac.in
Homepage: http://home.iitk.ac.in/~ddethe/ourlab_dethe.html
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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derivatives and chiral allylic alcohols which was then practiced in
an enantiospecific synthesis of the two natural products (+)-
hapalindole H (1) and ()-12-epi-hapalindole U (13).
single step as depicted in Table 2. It is worth mentioning that
scope of the reaction was broadened to the indoles having
substitution not just on the benzene moiety but also at C2
position. Reaction worked with equal efficiency when an ester
functional group was placed at C2 position. A couple of these
indoloterpene derivatives were further converted into tetra- cyclic
core of fischerindole (22 and 22a) in good yields
Table 1. Optimization of Friedel-Crafts reaction condition. [a]
Entry
mol %
catalyst
solvent
yield[%][b]
dr
1
2
20
20
20
20
20
20
20
20
10
20
Cu(OTf)2
Sc(OTf)2
SnCl4
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
32
47
43
26
56
38
35
68
62
44
(19:1)
(17:1)
(9:1)
Scheme 1. Retrosynthetic analysis for hapalindole H (1).
3
It was envisioned that hapalindole H (1) could be obtained from
the tetracyclic keto compound 15 by a functional group switch
from ketone to isonitrile group. The required vinyl group could be
introduced by applying a two step hydrogenation and oxidation
protocol on compound 16. All-carbon quaternary centre at C12
could be installed by regioselective nucleophilic epoxide ring
opening of compound 17 by TMS-acetylene. Epoxide 17 could
be prepared easily from the corresponding olefin. Tetracyclic
core 18 of hapalindole could be constructed using a two step
protocol constituting a highly regio- and diastereoselective
Friedel-Crafts reaction between 4-Bromo indole (20) and sec-
allylic alcohol (21), followed by an intramolecular reductive Heck
reaction.
4
TiCl3
(10:1)
(15:1)
(8:1)
5
TMSOTf
p-TSA
AlCl3
6
7
(12:1)
(>19:1)
(>19:1)
(10:1)
.
8
BF3 OEt2
.
9
BF3 OEt2
.
10
BF3 OEt2
[a] Reaction conditions: 20a (1.08 mmol), 21 (0.98 mmol),
To quickly check the viability of our hypothesis, Lewis acid
catalysed Friedel-Crafts reaction of indole and diastereomeric
mixture (4:1) of sec-allylic alcohols (21) (prepared by CrO3
mediated allylic oxidation of (R)-limonene followed by reduction
with NaBH4 and CeCl3·7H2O)9a was attempted. To our delight,
after screening various Lewis and Brønsted acids, the mixture of
indole and sec allylic alcohol (21), on treatment with 20 mol%
BF3·OEt2 in CH2Cl2 at room temperature for 30 min, afforded
coupling product 19a with 68% yield in a highly regio- and
diastereoselective manner (dr ≥19:1, confirmed by crude 1H
NMR) (Table 1) having water as only by product of the reaction.
It is worth mentioning that, LAH reduction of the enone obtained
by CrO3 mediated allylic oxidation of (R)-limonene prodcued 2:3
diastereomeric mixture of allylic alcohols (21).9j Interestingly,
Friedel-Crafts reaction of indole and alcohols (21) obtained by
LAH reduction generated product 19a in 65% yield with more
than 19:1 diastereomeric ratio. This result further supports that,
the reaction proceeds via SN1 pathway. Bulky isopropenyl group
present nearby the reactive site in allylic alcohol 21 is indeed
responsible for the observed excellent diastereoselectivity by
CH2Cl2 (5 mL). [b] Isolated yields.
constraining indole nucleophile to take
a path of attack
selectively from the opposite side to furnish the trans isomer.
This result encouraged us to generalize Friedel-Crafts reaction
with various indole derivatives as well as allylic alcohols to
generate diverse optically active indoloterpene derivatives in a
Table 2. Substrates scope of the Friedel-Crafts reaction.
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
using Mont. K-10 in microwave irradiation at 120 C. After finding
appropriate condition for Friedel-Crafts reaction and C-2
cyclization of indole derivatives, we next directed our attention
towards our eventual task, enantiospecific total synthesis of
Scheme 4. Mechanism of epoxide 24 opening with alkynyl aluminate reagent
Our next focus was opening of -epoxide by acetylide followed
by Lindlar hydrogenation of triple bond to obtain the desired
alcohol 30. As per our assumption, treating epoxide 24 with
TMS- acetylene in presence of AlMe3 and BF3·OEt2 afforded
highly regio- and diastereoselective opening of corresponding
epoxide to furnish compound 28 in 75% yield.13 Excellent
regioselectivity was observed for opening of epoxide 24 which
is apparently due to preferential axial attack of alkynyl
aluminate reagent on quaternary carbon of epoxide in
compound 24 (path-a) to furnish compound 28 via chair like
transition state. On the other hand, equatorial attack through
path b would give diequatorial product 28a via an energetically
less favourable twist-boat transition state (Scheme 4).
Subsequent removal of TMS and benzenesulfonyl groups
furnished alcohol 16 in excellent yield. Hydrogenation of alkyne
moiety of 16 assisted by H2/Lindlar catalyst in presence of
quinoline yielded compound 30 in 96% yield. Oxidation of the
sec-alcohol by IBX in CH3CN under reflux condition afforded
corresponding ketone 15 in 88% yield. Microwave aided
reductive amination14 of ketone 15 at 180 °C for 3 min followed
by subsequent dehydration by Burgess reagent furnished 1 and
13 in 2:7 diastereomeric ratio. Formation of diastereomers, 1
and 13, in an uneven ratio can be rationalized by selective
equatorial attack of hydride ion onto the iminium ion during
reductive amination step. Because hydride ion, if takes the axial
approach, would have strong 1,3 diaxial interactions with
cyclohexane ring hydrogens. This completes the first
enantiospecific total synthesis of (+)-hapalindole-H (1) and ()-
Scheme 2. Synthesis of compound (-)-27
hapalindole H (1) which was commenced by a reductive Heck
reaction on compound 19 using 10 mol% [Pd(PPh3)4] in presence
of sodium formate to furnish compound 18 (72% yield) generating
the tetracyclic carbon skeleton of hapalindoles.6g Epoxidation of
the olefin using various oxidizing reagents such as m-CPBA and
DMDO led to decomposition of the starting material probably due
to free -NH group of the indole. To overcome this problem, indole-
nitrogen of compound 18 was protected by reaction with NaH and
benzenesulfonyl chloride in DMF. Epoxidation of olefin 23 using
m-CPBA in CH2Cl2 at 0 °C then generated 2:1 mixture of
diastereomers 24 and 25 in 70% combined yield which were
readily separated by silica gel column chromatography. Our
attempts to get single crystal of 24 or 25 for the confirmation of
stereostructure of epoxides were not successful. However,
structure and stereochemistry of compound 25 was established
unambiguously by single crystal X-ray diffraction analysis11 of 27
generated from 26 by semipinacol rearrangement12 (Scheme 2).
1
12-epi-hapalindole U (13). Spectral data (IR, H, 13C NMR and
HRMS) and optical rotation of synthetic 1 and 13 were identical
with those of isolated molecules.1b,7
We also became interested to showcase utility of indoloterpene
19a and ent-19a for the synthesis of (+)-hapalindole Q and (+)-
12-epi-fischerindole
U isothiocyanate. Towards this goal,
nitrogen of indole terpenoid 19a was protected using
benzenesulfonyl chloride.15 Regio- and diastereoselective
epoxidation of electron rich endocyclic olefin 31 using m-CPBA,
generated compound 32. Stereochemistry of epoxide of
compound 32 was directed by bulky indole moiety by hindering
one face of the olefin. Semi-pinacol rearrangement of epoxide
using BF3·OEt2 in CH2Cl2 at room temperature furnished ketone
33 in 73 % yield.12 Ent-ketone 33 was prepared using same
synthetic sequence starting from (S)-limonene. Ketone 33 and
its enantiomer were converted in five steps to (+)-hapalindole Q
Scheme 3. Synthesis of (+)-hapalindole H (1) and (-)-12-epi-hapalindole U (13)
(6) and (+)-12-epi-fischerindole
U
isothiocyanate (9)
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the formal synthesis of these two natural products.
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Scheme 5. Synthesis of compound (+)-33 and ent-33
In summary, a highly regio- and diastereoselective Friedel-
Crafts reaction between secondary allylic alcohol and indole
was developed. The potential of this methodology has been
amply demonstrated by the total synthesis of (+)-hapalindole H
(1), ()-12-epi-hapalindole U (13) which involves 11 steps in the
longest linear sequence starting from readily available R-(+)
limonene. This method is fairly general and amenable to
synthesis of other natural products of this class as well as their
analogues.
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Acknowledgements
We thank Mr. Dinesh De, IIT Kanpur, for crystal structure
analysis. S. D. and V.K.B. thank CSIR, New Delhi for the award
of research fellowship
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Keywords: Total Synthesis • Hapalindoles • Friedel-Crafts •
Natural Products
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Dattatraya H. Dethe,*[a] Saikat Das,[a]
Vijay Kumar B,[a] and Nisar A. Mir [a]
Page No. – Page No.
Enantiospecific total syntheses of ()-
Hapalindole
H
and
()-12-epi-
Hapalindole U
Enantiospecific total syntheses of (+)-hapalindole-H, (-)-12-epi-hapalindole-U and
formal syntheses of (+)-hapalindole Q, (+)-12-epi-fischerindole U isothiocyanate
have been described. Key steps feature gram scale, highly regio- and
diastereoselective Lewis acid catalyzed Friedel-Crafts reaction of a cyclic allylic
alcohol with indole, alkynyl aluminate complex driven regioselective nucleophilic
This article is protected by copyright. All rights reserved.