Versatile Route to Benzoannulated Medium-Ring Carbocycles via Aryne Insertion into Cyclic 1,3-Diketones: Application to a Synthesis of Radermachol

Article abstract of DOI:10.1021/acs.orglett.6b01078

A general approach involving the insertion of in situ generated aryne into the C-C bond of cyclic 1,3-diketones for rapidly assembling functionalized benzo-fused medium ring carbocycles is delineated. The efficacy of the methodology has been demonstrated

Full text of DOI:10.1021/acs.orglett.6b01078

Letter
pubs.acs.org/OrgLett
Versatile Route to Benzoannulated Medium-Ring Carbocycles via
Aryne Insertion into Cyclic 1,3-Diketones: Application to a Synthesis
of Radermachol
Ramesh Samineni,†,‡ Pabbaraja Srihari,*,‡ and Goverdhan Mehta*,†
†School of Chemistry, University of Hyderabad, Hyderabad 500 046, India
‡Division of Natural Products Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
S
* Supporting Information
ABSTRACT: A general approach involving the insertion of in situ
generated aryne into the C−C bond of cyclic 1,3-diketones for rapidly
assembling functionalized benzo-fused medium ring carbocycles is
delineated. The efficacy of the methodology has been demonstrated
through a concise total synthesis of pentacyclic natural product
radermachol.
rameworks based on mono- and dibenzoannulated
Over the years, several synthetic approaches to benzoannu-
Fmedium-sized carbocyclic rings have been found among lated medium rings bearing carbocyclic frameworks have been
devised.2−7 These involve intramolecular Friedel−Crafts
a relatively small but rapidly growing group of natural
reaction,2 ring-closing metathesis,3 intermolecular cationic
cyclization reactions,4 intramolecular ene reactions,5 intra-
molecular cycloadditions,6 and intramolecular Rh- and Pt-
mediated hydroacylation,7 among others. However, structural
and bioactivity attributes of some of the recently isolated
natural products (Figure 1) embodying the benzoannulated
medium ring motifs and their bioactivity have rekindled
interest in rapidly accessing these natural products through
generally applicable strategies.
products.1 Besides embodying interesting structural features,
some members of this class exhibit broad and varied range of
bioactivity profile. Some of the notable natural products in
this group are rubialatin (1) (modulator of TNF-α and NF-κB
pathways),1a hamigeran G (2) (H-60 active against human
myelocytic leukemic cell lines),1b merochlorin A (3)
(antibacterial activity against MRSA),1c diptoindonesin D
(4) (cytotoxic against P-388 murine leukemia cells),1d
radermachol (5) (folk medicines in China, India),1e and
amurensinine (6) (CNS activity related to Parkinson’s and
Alzheimer’s diseases)1f,g (Figure 1).
We were drawn to explore a short, simple, and generally
applicable approach to mono- and dibenzocycloheptanes and
cyclooctanes from readily available precursors employing an
aryne insertion reaction8−10 as the key step. Stoltz et al.10a
have reported a protocol based on aryne insertion into the
C−C bond of cyclic β-ketoesters to access mono- and
dibenzocycloheptanes and applied it for the synthesis of
natural product (+)-amurensinine (6)10b (Figure 2). Very
recently, Zeng et al.10c have reported similar aryne insertion
into the C−C bond of α-arylated cyclic ketones (Figure 2).
This report prompts us to disclose our findings of smooth
aryne insertion into the C−C bond of cyclic β-diketones to
furnish mono- and dibenzocycloheptanes and cyclooctanes
(Figure 2). A distinctive advantage of this strategy is that it
directly installs a very desirable and differentiated 1,5-diketo
functionality on the medium ring for orchestrating further
Figure 1. Representative examples for benzoannulated carbocyclic
natural products.
Received: April 14, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01078
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Accessing Simple Benzoannulated Carbocycles by
a
Reaction of Aryne with Cyclic 1,3-Diketones
Figure 2. Aryne insertion based approaches for benzoannulated
carbocyclic motifs.
functional group manipulations. As a demonstration of the
utility of this aryne insertion approach and the advantage it
offers in terms of carbonyl group disposition on the medium
ring, we outline a short synthesis of natural product
radermachol (5).1e
As an initial demonstrator of our projected theme, reaction
of aryne generated from 2-(trimethylsilyl)phenyl trifluorome-
thanesulfonate 7a in the presence of CsF11 with dimedone 8a
as the 1,3-dicarbonyl-bearing reaction partner was investigated
to furnish the benzocyclooctanone 9a in decent yield (Scheme
1). Although several reaction conditions, solvents, and
Scheme 1. Ready Access to Benzoannulated Cyclooctane-
1,5-dione from an Aryne Precursor with Dimedone
a
Standard reaction conditions: aryne presursor (0.125 mmol), cyclic
1,3-diketone (0.1 mmol), and CsF (0.25 mmol) in acetonitrile at 80
b
c
°C. Yield of the isolated product. Prepared by following the known
procedure.12a
Scheme 2. General Mechanism
different fluoride sources (KF, KF-18-Crown-6, TBAF,
TBAT, etc.) were explored, it was found that the reported11
conditions using CsF and acetonitrile as solvent were the
most productive and gave consistent outcomes. This set the
stage for studying the reaction between various arynes 7a−c
and diverse cyclic 1,3-dicarbonyl partners 8b−d and
demonstrated a fair degree of generalization. Thus, insertion
of arynes 7a−c into the C−C bond of 1,3-cyclopentane
diones 8b led to benzoannulated cycloheptane-1,5-diones
9b,d,e (Table 1), and insertion of aryne 7a into the 1,3-
diketone 8c led to 9c, respectively. Similarly, reaction of aryne
7a with 2-methylcyclohexane-1,3-dione 8d and aryne 7b with
dimedone 8a delivered benzocyclooctanoids 9f and 9g,
respectively (Table 1). In all cases, reactions were scalable,
yields were preparatively exploitable, and isolation of products
was straightforward.
For the formation of benzoannulated medium-ring products
through formal C−C insertion, it is reasonable to extend the
previously10c advanced mechanism for the reaction. Thus,
nucleophilic attack of in situ generated enolate of 1,3-diketone
onto aryne results in the formation of intermediate aryl anion
A, which undergoes intramolecular nucleophilic attack onto
the carbonyl group and forms a cyclobutane intermediate B
which on fragmentation undergoes ring expansion to furnish
the benzoannulated carbocycle (Scheme 2).
aryne-1,3-diketone C−C insertion approach and validate it to
access such tricyclic systems. For this purpose, several indan-
1,3-diones (10a,b) were exposed to aryne generated from
precursors 7a,b to furnish dibenzocycloheptane diones 11a−d
in fair yields in a one-pot protocol (Table 2). Similarly, aryne
generated from 7a was treated with 10c to result in allylated
dibenzocycloheptane dione 11e. The resulting tricyclic
scaffolds are useful and versatile constructs. For example,
11c represents the core framework present in the natural
product diptoindonesin D (4) (Figure 1). On the other hand,
the allylated dibenzocycloheptanoid 11e could be readily
elaborated to furano-fused tetracyclic system 12 through the
intermediacy of Wacker oxidation13 product and acid-
mediated cyclodehydration of the 1,4-dicarbonyl moiety
(Scheme 3).
Since many natural products bear a dibenzo-fused cyclo-
heptanoid scaffold (Figure 1), it was relevant to extend our
B
DOI: 10.1021/acs.orglett.6b01078
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 2. Accessing Fused Benzoannulated Carbocycles by
Reaction of Aryne with Benzofused Cyclic 1,3-Diketones
Scheme 4. Retrosynthetic Analysis of Radermachol (5)
a
provide bromoacetoxylated compound 1615 in 78% yield.
Acetate hydrolysis to the corresponding bromonaphthol 17
and further one-pot HMDS-mediated O-silylation of the
phenolic hydroxyl group, lithium−halogen exchange using n-
BuLi with concomitant O- to C-silyl group migration, and O-
triflation16 gave o-trimethylsilyl naphthyl triflate 13 (Scheme
5). The O-silyl naphthyl triflate 13 on exposure to 1,3-
Scheme 5. Total synthesis of Radermachol (5)
a
Standard reaction conditions: aryne presursor (0.125 mmol), cyclic
1,3-diketone (0.1 mmol), and CsF (0.25 mmol) in acetonitrile at 65
b
c
°C. Yield of the isolated product. Prepared by the known
procedure.12b
Scheme 3. Synthesis of Furano-Fused Benzocarbocycle
To demonstrate the efficacy of the present aryne strategy
for complex synthesis, dibenzo-annulated cycloheptanoid
dione radermachol (5)1e was chosen as an interesting natural
product target. Radermachol (5)1e is a red pigment isolated
from two different Indian plant sources, Radermachera
xylocarpa K. Schum and Tecomella undulate, described and
used in folk medicine. The pentacyclic structure of 5 was
secured from X-ray crystallographic analysis,1e and to date,
three total syntheses14 have been documented employing PPA
mediated intramolecular acylation,14a condensation of iso-
benzofuranone with preformed benzocycloheptenone,14b and
Yb(OTf)3-mediated furannulation−intramolecular nucleophilic
acylation14c as the key steps, respectively.
A retrosynthetic perspective on our approach to raderma-
chol (5) is outlined in Scheme 4 and can be traced to the
insertion of napthyne (generated from precursor 13 prepared
from readily available 1,4-dimethoxynaphthalene 14) onto
indan-1,3-dione 10a. The resulting advanced naphtho- and
benzoannulated cycloheptanedione 15 can be further
elaborated to the pentacyclic natural product radermachol
(5) following routine steps.
indandione 10a in the presence of CsF led to the desired
tetracyclic C−C insertion product 15 in 78% yield. The key
tetracyclic compound 15 was evolved to the natural product
radermachol (5) through precedented steps, i.e., C-acylation
with 3-methylcrotonoyl chloride, trimethylsilyl iodide medi-
ated demethylation, and acid-induced cyclo-dehydration of the
1,4-dicarbonyl functionality to generate the fused furanoid
moiety (Scheme 5). The resulting product 5 was found to be
spectroscopically (1H and 13C NMR) identical to the natural
product radermachol (5), thus leading to a short synthesis.
In short, we have meaningfully extended the aryne insertion
strategy to access a range of benzoannulated 7- and 8-
membered carbocycles by partnering with varied cyclic 1,3-
diketones. The advantage in using cyclic 1,3-diketone as co-
reactants is the facilitation of installation of desirable 1,5-
diketo functionality on the medium ring with enhanced
functional group maneuverability. The protocol has been
successfully utilized for a short synthesis of the pentacyclic
natural product radermachol (5).
Commercially available 1,4-dimethoxynaphthalene 14 was
subjected to a one-pot bromoacetoxylation reaction with
iodobenzene diacetate and trimethylsilyl bromide (TMSBr) to
C
DOI: 10.1021/acs.orglett.6b01078
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(7) (a) Beletskiy, E. V.; Sudheer, C.; Douglas, C. J. J. Org. Chem.
ASSOCIATED CONTENT
■
2012, 77, 5884−5893. (b) Hildebrandt, D.; Huggenberg, W.;
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01078.
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AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: srihari@iict.res.in.
*E-mail: gmehta43@gmail.com.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
R.S. thanks UGC for the award of a Dr. D. S. Kothari
Postdoctoral fellowship. P.S. thanks CSIR−New Delhi for
funding from the XII Five Year Plan project ORIGIN (under
budget head CSC-0108). G.M. thanks Eli Lilly and the
Jubilant−Bhartia Foundation for research support. This
research was carried out under the Indo-French “Joint
Laboratory for Sustainable Chemistry at Interfaces”.
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DOI: 10.1021/acs.orglett.6b01078
Org. Lett. XXXX, XXX, XXX−XXX