Regiodivergent Remote Arylation of Cycloalkanols to Dysideanone′s Fused Carbotetracycles and Its Bridged Isomers

Article abstract of DOI:10.1002/chem.201703094

Regiodivergent γ and γ′ arylations across an all-carbon quaternary center of cycloalkanols to access enantioenriched fused and bridged carbotetracycles are reported. The conformation of the carbocation guided either sequential stereospecific β-C-Me/γ-C?H-shifts or β-C-Me/γ′-C?H-shifts, providing fused carbotetracyclic analogs of dysideanone or bridged tetracycles, respectively. The reaction is highly stereoselective in building three contiguous stereocenters, where one, two, or three could be all-carbon quaternary centers. Interestingly, mechanistic studies revealed a crucial role of a methyl substituent in controlling regioselectivity.

Full text of DOI:10.1002/chem.201703094

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Title: Regiodivergent Remote Arylation of Cycloalkanols to
Dysideanone's Fused Carbotetracycles and Its Bridged Isomers
Authors: Md Ashraful Haque and Chandan K. Jana
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Regiodivergent Remote Arylation of Cycloalkanols to
Dysideanone’s Fused Carbotetracycles and Its Bridged Isomers
Md Ashraful Haque and Chandan K. Jana*
Dedication ((optional))
Abstract: Regiodivergent γ and γ’ arylations across an all-carbon
quaternary center of cycloalkanols to access enantioenriched fused
and bridged carbotetracycles are reported. The conformation of the
carbocation guided either sequential stereospecific β-C-Me/γ-C-H -
shifts or β-C-Me/γ’-C-H-shifts, providing fused carbotetracyclic
analogs of dysideanone or bridged tetracycles, respectively. The
reaction is highly stereoselective in building three contiguous
stereocenters, where one, two or three could be all-carbon quaternary
centers. Interestingly, mechanistic studies revealed a crucial role of a
methyl substituent in controlling regioselectivity.
challenges for the construction of dysideanone frameworks.
Moreover, heterofunctionality assisted intramolecular γ or γ’-
arylation (in I) across an all carbon quaternary center would be
hard to achieve. Preliminary biological studies on dysideanones
and dysiherbols revealed their interesting cytotoxic activities
against human cancer cell lines.[6] To promote a comprehensive
biological evaluation, we initiated a synthetic campaign for
developing an efficient synthetic route to these novel and
important tetracyclic terpenoids.
Terpenoids are one of the largest class of secondary metabolites.
They or their synthetic derivatives have long been the source of
medicinal drugs.[ Therefore, continued efforts have been
devoted to the isolation, synthesis and structure-activity studies of
new molecules for identifying the most potent one.[2] However, the
chemical synthesis of terpenoids often encounters significant
difficulty due to their inherent structural and stereochemical
complexities.[2b] Thus, the development of a novel synthetic
strategy to access structurally and stereochemically complex
terpenoids is necessary to drive further advancement in the
understanding of terpene chemistry and biology.
1]
In this regard, sesquiterpenes attached with functionalized arenes
are of particular interest due to their vast structural diversity and
wide spectrum of bioactivities.[3] Arenes are attached to the
terpene unit via two-point connection producing fused, spiro and
bridged structures of different subclasses of meroterpenoids
Scheme 1. Selected structure types of meroterpenoids.
(
Scheme 1).[3] The desired arene moiety (e.g. in akaol A and
others) was installed efficiently through the assistance of alkene
or heteroatom functionalities at the C1-C2 position of the decalin
system of type I. The decalin is synthesized either from
sclareolide or from Wieland-Miescher ketone derivatives.[4] In
addition, cationic polyene cyclizations were also used to build the
desired skeletons.[ However, in dysideanones, an oxidized
arene moiety was connected to both A and B ring of the decalin
The events of 1,2-shifts, cyclizations, and deprotonations are well
known in terpene chemistry and are the main reason for the
diverse skeleton types found in the natural terpenoids.[7] We
thought that the desired arylations can be achieved
intramolecularly, involving cationic intermediates 1-3 which can
be formed from isomeric carbocation 4, through the sequence of
stereospecific 1,2-H and methyl migrations (Scheme 2). The initial
cationic intermediate 4 can be generated via dehydration of the
tertiary alcohol 5 that can be prepared from the corresponding
5]
system, forming
a structurally distinct tetracyclic 6-6-6-6
framework.[ On the other hand, the isomeric natural products,
dysiherbols, which are built on 6-6-5-6 fused carbacycles,[6b]
contains three contiguous all-carbon quaternary stereocenters.
6]
ketone derivative 6. Similar carbocations were proposed to
mediate the related cyclization reactions.[8] Arylation in 1 at γ-
Installing the carbon-aryl bond at C
8
in the A-ring, which is away
from the heteroatom functionality, demands substantial synthetic
position and in 3 at γ’-position will lead to dysideanones skeleton
9]
7
and bridged tetracycle 8,[ respectively, while arylation in 2 at β-
position will furnish dysiherbols’ tetracyclic core 9. Moreover, the
reactions of carbocation 4 or its rearranged isomers 1-3, leading
to other products like olefins and O-alkylated derivatives should
be avoided to obtain the desired tetracyclic carbon skeleton.
[
a]
M.Sc. M. A. Haque, Prof. Dr. C. K. Jana
Department of Chemistry
Indian Institute of Technology Guwahati
Guwahati, India-781039
E-mail: ckjana@iitg.ernet.in
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the document.((Please delete this text if not appropriate))
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γ-arylation of tertiary alcohol 10 (Scheme 3 and Table s1). Boron
tribromide was identified to be superior to other Lewis and
Bronsted acids (e.g. BF , PTSA, PPA) in providing the desired
3
tetracyclic skeleton of dysideanones (11 and 12). Dehydration, γ-
arylation, and de-O-methylation proceeded smoothly in the
3
presence of BBr providing tetracyclic phenol derivative 12 with
the highest yield (72%). The relative syn-orientation of hydrogens
and the methyl group of newly formed stereocenters is confirmed
from the X-ray structure of 11. Surprisingly, tetracycles 8 and 9
arising from γ’-arylation and β–arylation were not detected.
Scheme 2. Synthetic plan for the tetracyclic skeleton: challenges and
opportunities.
At the outset of our investigation, the desired ketone 6 was
synthesized in an enantioenriched form over four steps starting
from the Wieland-Miescher ketone derivative[10] (see Scheme s1).
Several attempts to obtain tertiary alcohol 10 via the addition of
corresponding
benzylmagnesium
chloride/bromide
were
unsuccessful. However, the desired addition product 10 as a
mixture of diastereoisomers was obtained from a reaction of
ketone 6 and o-methoxybenzyl bromide in the presence of lithium
under sonication (Scheme 3).[11] Arylmethylation preferentially
occurred from the face opposite to the angular methyl group
providing 10 as the major isomer.
Scheme 4. Scope of γ-C-H arylation to produce dysideanone’s fused
carbotetracyclic skeletons.
A series of tertiary alcohols 13a-m, which were prepared from
ketone 6 or its derivatives and arylmethyl bromide/chloride with a
diversely substituted aryl moiety, reacted under the optimized
condition to provide fused tetracycles 14a-m with very good yields
(
Scheme 4). Tertiary carbinols (13a and 13b) having m- and p-
methoxy groups provided corresponding tetracyclic phenol
derivatives 14a and 14b. Interestingly, the desired arylation also
occurred involving simple benzylated derivative 13c to produce
the corresponding tetracyclic hydrocarbon 14c with very good
yields and excellent stereoselectivity. Substrates (13d and 13e)
with p-methyl and p-tert-butyl were also reacted smoothly
providing desired products 14d and 14e, respectively, as the
single isomer. On the other hand, two regioisomeric tetracyclic
products 14j and 14k were formed with ratio 1.4:1 from the alcohol
Scheme 3. Synthesis of alcohol 10 and optimization of remote C-H arylation
reaction.
Different reaction conditions in the presence of various Bronsted/
Lewis acids were evaluated to achieve proposed intramolecular
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containing m-methyl arene. Desired dihydroxy derivatives 14f-h
were formed from the corresponding carbinols 13f-h. In contrary,
the substrate 13i having a p-dimethoxy aryl group provided
sesquiterpene quinone 14i, which probably resulted via aerial
oxidation of corresponding hydroquinone.
involving conformer 22 could lead to the more stable tertiary
carbocation 24 that would react further via γ’-arylation to provide
the bridged carbotetracycle corresponding to 26. However, γ’-
arylation did not occur probably because of the less preferred
conformer 22 with the cis-decalin unit containing geminal dimethyl
groups. Moreover, nucleophilic addition to the carbon in 24
adjacent to the geminal methyl groups probably is restricted due
to steric reason. To examine this, we decided to study arylation
reaction of the substrate lacking geminal methyl groups.
Accordingly, tertiary carbinols 28a-f were prepared from ketone
27 (Scheme 6 and s1). As expected, under the standard reaction
conditions, regioselective γ’-arylation occurred involving
carbocations 18, 23 and 25 providing bridged tetracyclic
skeletons 29a-f along with a minor amount of corresponding fused
tetracycles (Scheme 6). The relative stereochemistry of 29d was
confirmed from the X-ray structure of the corresponding p-
nitrobenzyl ether 30.
Carbinols 13l-m having additional methyl groups in the B-ring,
which were prepared from the corresponding methylated ketone
(
s-II and S-III, Scheme s1), were then allowed to react with boron
tribromide under standard conditions. The desired arylated
tetracycles 14l-m were isolated with very good yields. Compound
14m was isolated as the single isomer while a mixture of
diastereomers, which was observed for 14l, resulted from
diastereoisomers of the starting alcohol 13l. The relative
stereochemistry of 14i was confirmed from the structures
obtained from the single crystal X-ray analysis. Stereochemistry
of other derivatives were assigned in an analogy. However, the
substrates having a keto or hydroxyl functionality at A-ring of
decalinol failed to provide corresponding arylated products
(
Scheme s2).
Scheme 5. Mechanistic rationale for regiodivergent arylations.
Scheme 6. Scope of selective γ’-C-H arylation of trans-decalinol lacking geminal
methyl groups to bridged carbotetracycles. Ratio of γ’- and γ-arylated products
are mentioned in parenthesis.
Despite the possibilities of γ-, γ’-, and β-arylation, interestingly,
only γ-arylated products were isolated in all the reactions.
Therefore, we invested our attention in the examination of the
reason for exclusive regioselectivity in arylation reaction. Boron
tribromide mediated the dehydration of carbinol 15 to provide the
carbocation 16 (Scheme 5). A thermally allowed stereospecific
syn-[1,2]-methyl shift which set the relative orientation of the
benzyl moiety occurred, providing the isomeric carbocation 17.
Direct arylation of carbocation 17 with the preferred conformation
having a trans-decalin system[12] did not provide 6-trans-6-trans-
5-carbatricycle 19, probably due to high ring strain in the trans-
fused indane moiety. In contrast, the stable trans-decalin system
was recreated (in 20) via a specific syn-[1,2]-hydride migration
that occurred readily on the face from which methyl group
departed. The relatively less stable carbocation 20 was then
readily trapped by the arene via aromatic electrophilic substitution
reaction producing the observed 6-6-6-6 carbotetracycle 21. On
the other hand, we speculated that stereospecific H-migration
Scheme 7. Selective γ’-C-H arylation of cis-decalinol. Minor diastereoisomers,
which were formed from the inseparable minor trans-isomer of 31, are
mentioned in parenthesis.
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We were then interested in examining the effect of
stereochemistry of the decalin units on the regioselectivity of the
arylation reaction. Similar to the trans-decalin system, tertiary
carbinols 31a-d having the cis-decalin unit, which were prepared
from ketone S-VI (Scheme s1), provided bridged tetracycles 32a-
d (Scheme 7).
To summarize, we have developed a novel regiodivergent remote
arylation of decalinols to access structurally complex
enantioenriched fused and bridged carbotetracycles. Arylation
beyond an all carbon quaternary center at γ-position of alcohol
gave fused tetracycles, while bridged tetracycles were obtained
by γ’-arylation. The structure-reactivity relationship (SRR) studies
revealed an important role of methyl substituent at A-ring of
decalin unit in controlling regioselectivity. However, in this regard,
the stereochemistry at fused position of decalinols remained
innocent. A series of close structural analogs of the anti-cancer
natural product, dysideanone, were synthesized (20-32% yields
over six steps). Studies to evaluate their anti-cancer potential are
ongoing in our laboratory and will be reported in future.
Acknowledgements ((optional))
We acknowledge SERB and CSIR for financial support.
Keywords: terpenoids • arylation • diastereoselectivity •
synthetic method• natural products
Scheme 8. Bridged carbotetracycle via γ’-C-H arylation through double [1,2]-Me
o
shifts. (a) CuI/MeLi, Et
2
O, 0 C−rt, 4.5 h, 96% (b) 2-Ethyl-2-methyl-1,3-dioxolane,
PTSA, rt, 36 h, 87% (c) Li, p-MeOBnBr, sonication, THF, 0 oC−rt, 1.7 h, 64%;
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2
H
4
.H
2
O, KOH, DEG, 8 h, 210 oC,
BnBr, acetone, K CO , 6
o
8
9%; (f) BBr
3
, CH
2
Cl
2
, −78 C−rt, 5 h, 71%; (g) p-NO
2
2
3
o
h, 56 C, 87%.
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fused tetracycles.
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Entry for the Table of Contents (Please choose one layout)
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Md Ashraful Haque and Chandan K.
Jana*
Page No. – Page No.
Regiodivergent Remote Arylation of
Cycloalkanols to Dysideanone’s
Fused Carbotetracycles and Its
Bridged Isomers
Intramolecular remote arylation reactions crossing an all carbon stereocenter were
developed. Methyl groups on A-ring of decalinol and conformation of carbocation
play key role in controlling regioselectivity to produce either fused- or bridged-
carbotetracycles.
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