Transformation of Substituted Glycals to Chiral Fused Aromatic Cores via Annulative π-Extension Reactions with Arynes

Article abstract of DOI:10.1021/acs.orglett.8b00319

The Diels-Alder addition of arynes to appropriately substituted vinyl/aryl glycals followed by π-extension via pyran ring opening smoothly furnished meta-disubstituted fused aromatic cores containing a stereodefined orthogonally protected chiral side chai

Full text of DOI:10.1021/acs.orglett.8b00319

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Transformation of Substituted Glycals to Chiral Fused Aromatic
Cores via Annulative π‑Extension Reactions with Arynes
Nazar Hussain,†,‡ Kalyanashis Jana,∥,⊥ Bishwajit Ganguly,∥,⊥ and Debaraj Mukherjee*,†,‡
†Natural Product Chemistry Division, Indian Institute of Integrative Medicine (IIIM), Jammu 180001, India
‡Academy of Scientific and Innovative Research (AcSIR-IIIM), Jammu 180001, India
∥CSIR−Central Salt and Marine Chemicals Research Institute, Bhavnagar 364002, India
⊥Academy of Scientific and Innovative Research (AcSIR-CSMCRI), Bhavnagar 364002, India
S
* Supporting Information
ABSTRACT: The Diels−Alder addition of arynes to appropriately substituted vinyl/aryl glycals followed by π-extension via
pyran ring opening smoothly furnished meta-disubstituted fused aromatic cores containing a stereodefined orthogonally
protected chiral side chain. The method is broad in terms of aryl homologation, affording benzene, naphthalene, and
phenanthrene derivatives. Base-induced deprotonation followed by cleavage of the allylic C−O bond appear to be the crucial
steps leading to the development of aromaticity, which is the driving force behind the annulative π-extension process. The
present protocol can be used for the synthesis of meta-disubstituted naphthalene aldehydes and substrates for aldolases.
inearly fused aromatic ring systems can be found in various
bioactive natural products and π-conjugated functional
Scheme 1. Synthetic Strategies for Chiral Tagged
Naphthalene Cores
L
materials.1 Densely substituted fused aromatic cores with chiral
side chains are of particular interest because of their ability to
bind with receptor biomolecules via π-stacking and chiral
recognition.2a−f Further, chiral naphthalenes such as BINAP,
BINOL, or BINAM have attracted great attention as ligands in
transition-metal-catalyzed cross-coupling reactions2d or as
building blocks for the construction of chiral supramolecular
and polymeric materials. The naturally occurring gilvocarcin,
belonging to a family of naphthalene C-glucosides, has been
shown to exhibit high cytotoxicity with low overall toxicity.2f
However, gaining access to fused aromatic nuclei attached to
chiral side chains having defined stereochemistry remains a
challenge for synthetic chemists. Methods to achieve this
include an organocatalytic approach via an aldol reaction
(Scheme 1, reaction 1a)3a or stereospecific opening of
tetrahydropyrans attached to aryl moieties by a Ni catalyst
using diastereoselective cross coupling (Scheme 1, reaction
1b).3b Nevertheless, to date there is no method for synthesizing
fused aromatic cores containing defined chiral polyols side
chains via homologation of the aromatic core.
us to surmise that a properly functionalized dihydro aromatic
oxadecalin framework, easily constructed through Diels−Alder
reaction between an aryne and a glycal-based diene, might
undergo π-extension reaction via a translocation of the double
bond with concomitant pyran ring-opening while retaining the
other stereochemical centers (Scheme 1, reaction 1c) as
development of aromaticity would provide the driving force
The annulative π-extension reaction (APEX) using arynes is
recognized to have tremendous potential as it facilitates a one-
pot π-extension without the requirement for prefunctionaliza-
tion.3c Our long-standing interest in glycal chemistry4 allowed
Received: January 29, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00319
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
for such a transformation. The findings are described in this
communication.
Scheme 2. Substrate Scope for Polyol-Attached
Naphthalenes
a
We commenced the study by treating a benzyl-protected
glucal-based diene5 with an aryne precursor in the presence of a
suitable base and solvent at different temperatures. Thus, when
compounds 1a and 2a were allowed to react with CsF in
acetonitrile at room temperature, TLC after 4 h detected the
formation of a new compound with partial consumption of 1a.
The new product was characterized as the meta-disubstituted
naphthalene derivative 3a (Table 1, entry 1). The presence of a
a
Table 1. Optimization of the Reaction
b
c
base
(mmol)
additive
temp
(°C)
time
(h)
yield (%)
of 3a
entry
solvent
(equiv)
1
2
3
4
5
6
7
CsF (2)
CsF (2)
CsF (2)
CsF (3)
KF (3)
MeCN
MeCN
THF
rt
60
60
rt
6
6
15
18
10
35
67
43
89
6
MeCN
MeCN
MeCN
MeCN
(2.0)
(2.0)
(2.0)
(2.5)
8
rt
8
TBAF(3)
KF (4)
rt
8
rt
10
a
Reaction conditions: 1a (1 equiv), 2a (1.2 equiv), KF (4 equiv), 18-
b
crown-6 (2.5 equiv) in 2 mL of solvent at 30 °C. Additive: 18-crown-
6. Yield after column chromatography.
c
singlet at δ 8.01 (s, 1H) besides peaks for six additional protons
1
between δ 7.83 and 8.80 in the H NMR (400 MHz, CDCl3)
clearly indicated the formation of a meta-disubstituted
naphthalene core. Opening of the pyran moiety was further
confirmed by acetylation of the newly generated hydroxyl
group (see the Supporting Information). We noted that
increasing the reaction temperature did not have any
remarkable effect on the yield of 3a (Table 1, entry 2), while
changing the solvent from acetonitrile to THF decreased it
(Table 1, entry 3). The use of 2 equiv of 18-crown-6 along with
3 equiv of CsF noticeably enhanced the yield of the desired
product (Table 1, entry 4). These findings prompted us to keep
18-crown-6 as the additive for further optimization studies.
When we replaced CsF with KF, a further improvement in the
yield of the desired product was recorded (Table 1, entry 5),
but TBAF did not appear to give satisfactory results (Table 1,
entry 6). Finally, increasing the amount of KF and 18-crown-6
while carrying out the reaction in acetonitrile at rt for 10 h
resulted in complete conversion of the starting diene 1a to 3a
(Table 1, entry 7), and these proved to be the optimized
reaction conditions.
We next explored application of the methodology to react
benzyne sources with a series of glycal-based dienes having a
broad array of substituent patterns and stereochemical
relationships. Screening of different dienes showed that
electron-withdrawing groups such as esters in conjugation
with the diene moiety accelerated the ring opening. Thus,
alkoxycarbonyl or cyano attached at the terminal carbon of
glucal-based dienes yielded meta-disubstituted naphthalenes in
good-to-excellent yields (Scheme 2, 3a−c). A phenyl sulfonyl
substituent also yielded the desired product, albeit in somewhat
lower yield (Scheme 2, 3d). Examination of other arynes
a
Reaction conditions: 1 (1 equiv), 2 (1.2 equiv), KF (4 equiv), 18-
crown-6 (2.5 equiv) in 2 mL of MeCN at 30 °C for 8 h.
revealed the formation of single regioisomers in good yield
employing a 3-methoxy-substituted aryne (Scheme 2, 3e), but a
4-methyl-substituted aryne yielded the product as an
inseparable mixture of regioisomers (Scheme 2, 3f). As
anticipated, a 4,5-dimethoxyaryne gave the desired product as
a single regioisomer (Scheme 2, 3g).
In order to broaden the substrate scope, dienes from other
glycals such as L-rhamnal, D-galactal, and D-xylal were next
tested under the optimized conditions. Dienes derived from L-
rhamnal gave the desired product in good-to-excellent yields
(Scheme 2, 3h−j). Xylal- and galactal-derived dienes were also
viable substrates for the π-annulation reaction (Scheme 2, 3k,l).
These experiments established the generality of substrate scope.
Next, dienes having different protecting groups on the sugar
moiety were tested. Ethers such as tri-O-methyl-protected
glucal derived diene afforded the desired product in comparable
yields with benzyl-protected derivatives (Scheme 2, 3m). An
ester protecting group as in tri-O-benzoyl-D-glucal-derived
diene 1n survived under the optimized reaction conditions,
affording the product 3n in excellent yield. However, in the case
of acetyl protection, two products (3o, 3oo) were obtained in
almost 1:1 ratio due to migration of the acetyl group from the
C-4 to the C-5 position. The diene derived from 3,4-dihydro-
2H-pyran also reacted under the optimized reaction conditions,
B
DOI: 10.1021/acs.orglett.8b00319
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
generating the naphthalene-based long chain alcohol 3p
(Scheme 2) in good yield.
Scheme 6. Synthetic Applications of Downstream Products
Fused aromatic rings flanked by two sugar units are reported
to serve in the defense mechanism of plants against herbivores.6
We therefore thought of synthesizing their C-analogues using
our methodology. Toward this, we prepared a chiral
difunctionalized naphthalene glucoside derivative in a single
step by subjecting substrate 4 (Scheme 3) to this reaction with
a 3-methoxyaryne derived from 5. The reaction indeed
furnished the desired product 6 in good yield (73%).
Scheme 3. Utilization of Pseudo-disaccharides as Coupling
Partners
́
Zemplen deacetylation and thereafter oxidative cleavage of the
vicinal diol to form a meta-disubstituted naphthaldehyde moiety
in quantitative yield, which would otherwise be difficult to
obtain. Another application of our methodology utilizes the
availability of a free hydroxyl group at C-5 position, which can
easily be oxidized to obtain putative substrates for aldolases
(reaction 2).
To gain insights into the tandem annulative π-extension and
ring-opening reaction, we performed a few control experiments.
Though benzyne produced the meta-disubstituted naphthalene
derivative having a chiral side chain 6 (Scheme 7, eq 2), maleic
After achieving success in the synthesis of chiral naphthalene
derivatives, we tested whether the same strategy would work for
the homologation of other chiral-fused aromatic cores. Thus, a
glucal-derived diene was reacted with 1,2-naphthyne precursor
8 to generate the chiral phenanthrene regioisomers 9a and 9b
(Scheme 4) in equal amounts and in excellent yield.
Scheme 7. Control Experiments
Scheme 4. Synthesis of Polyol-Attached Phenanthrene
Derivatives from Sugar Dienes
anhydride 13a underwent only [4 + 2] cycloaddition and no
subsequent ring opening (eq 1). On the basis of control
experiments, we arrived at a possible mechanism for this
tandem reaction as depicted in Scheme 8. Initially, the normal
cycloaddition takes place between diene 1a and benzyne source
2a. The Diels−Alder adduct A thereafter undergoes a base-
catalyzed proton abstraction from the benzylic carbon to form
an allylic carbanion B, which eliminates alkoxide with
Gratifyingly, when we used tri-O-benzyl-2-aryl-D-glucals7 10a
(derived from 2-iodo-D-glucal under Suzuki coupling con-
ditions) instead of a conjugated diene and reacted with the
benzyne precursor 2a (Scheme 5), the chiral phenanthrene
derivatives (11a, 11b) were obtained in moderate yields.
Aromatic aldehydes are very important substrates in
multicomponent reactions of value for drug discovery and
natural product total synthesis. As an application of the current
protocol, we subjected product 3o (Scheme 6, reaction 1) to
Scheme 8. Plausible Mechanism of the Annulative π-
Extension Reaction
Scheme 5. Synthesis of Polyol-Attached Phenanthrene
Derivatives Using a 2-Aryl-D-glucal
C
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(6) Bringmann, G.; Irmer, A.; Buttner, T.; Schaumloffel, A.; Zhang,
G.; Seupel, R.; Feineis, D.; Fester, K. J. Nat. Prod. 2016, 79, 2094.
(7) Jana, S.; Rainier, J. Org. Lett. 2013, 15, 4426.
̈
̈
subsequent protonation from the solvent leading to the
annulative π-extension. Development of aromaticity is the
driving force for this transformation as maleic anhydride failed
to give the desired ring-opened product (Scheme 8).
In summary, we have demonstrated the formation of the
benzannulated dihydro aromatic framework via a cycloaddition
of glycal-derived dienes and benzynes, which undergo
annulative π-extension reaction to generate meta-substituted
fused aromatic moieties carrying chiral side chain(s) with
tunable defined stereochemistry. The method is broad in terms
of substrate scope and can be applied in the homologation of
benzene to naphthalene and phenanthrene. It can be applied to
the synthesis of meta-disubstituted naphthaldehydes and
putative substrates for aldolases.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00319.
1
Experimental procedures, H and 13C NMR spectra, and
characterization of all compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: dmukherjee@iiim.ac.in.
ORCID
Kalyanashis Jana: 0000-0001-9792-8195
Bishwajit Ganguly: 0000-0002-9858-3165
Debaraj Mukherjee: 0000-0002-2162-7465
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are thankful to DST-India (EMR-2016-004710)
for funding. N.H. and K.J. thank UGC New Delhi for SRF.
IIIM Publication No. IIIM-2191-2018.
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DOI: 10.1021/acs.orglett.8b00319
Org. Lett. XXXX, XXX, XXX−XXX