Hetero Diels-Alder reaction of olefin with o-quinone methides generated using (±)-binolphosphoric acid for the stereoselective synthesis of 2,4-diarylbenzopyrans: Application to the formal synthesis of myristinin B/C

Article abstract of DOI:10.1039/c3ra43526a

Hetero Diels-Alder reaction of olefin with o-quinone methides (o-QMs) generated using (±)-binolphosphoric acid was developed for the stereoselective synthesis of 2,4-diarylbenzopyrans. The method thus developed was utilized in the formal synthesis of myri

Full text of DOI:10.1039/c3ra43526a

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Hetero Diels–Alder reaction of olefin with o-quinone
methides generated using ( )-binolphosphoric acid for
the stereoselective synthesis of 2,4-diarylbenzopyrans:
application to the formal synthesis of myristinin B/C3
Cite this: RSC Advances, 2013, 3, 18279
Received 10th July 2013,
Accepted 5th August 2013
DOI: 10.1039/c3ra43526a
Santosh J. Gharpure,{*ab A. M. Sathiyanarayanana and Prasanna K. Vurama
www.rsc.org/advances
The 2,4-diarylbenzopyran skeleton is found in a small group of
bioactive flavonoid natural products like myristinins A–F (1–4),
dininsinone (5) and psiguadial C (6) and D (7) (Fig. 1). Even
though synthesis of 2-aryl chroman or flavans has attracted
considerable attention from synthetic chemists, there are only
scattered reports on the synthesis of 2,4-diarylbenzopyrans.6
We envisaged that 2,4-diarylbenzopyrans 8 could be rapidly
assembled using hetero Diels–Alder reaction between aryl
substituted o-quinone methides (o-QMs) and styrene derivatives
10 (Scheme 1). Further, we decided to explore the possibility of
Hetero Diels–Alder reaction of olefin with o-quinone methides
(o-QMs) generated using ( )-binolphosphoric acid was developed
for the stereoselective synthesis of 2,4-diarylbenzopyrans. The
method thus developed was utilized in the formal synthesis of
myristinin B/C.
Over the years, o-quinone methides (o-QMs) have emerged as an
important class of reactive intermediates in organic synthesis.1
o-QMs are generated under various reaction conditions and are
widely utilized as heterodienes in inverse electron demand [4 + 2]
cycloaddition reactions. o-QMs are highly ephemeral in nature and
require in situ generation often under harsh conditions like either
high temperature2 or use of strong acidic3 and basic conditions.4
The unwanted side reactions like dimerization and decomposition
of the o-QMs precursors in many cases necessitate use of huge
excess of dienophiles. The majority of the methods reported
earlier employ a labile protecting group on the phenol and/or a
good leaving group at the benzylic position so as to minimize their
extreme reactivity in forming o-QM in an uncontrolled manner.
This leads to added steps in the synthesis. Thus, a mild method for
the generation of o-QMs in a controlled manner at ambient
temperature is still highly desirable. In continuation of our interest
in developing concise strategies for the synthesis of flavonoids,5
herein we disclose a mild and efficient protocol for the synthesis
of 2,4-diarylbenzopyrans using o-QMs generated using (¡)-
binolphosphoric acid (BPA) and styrene derivatives. We further
demonstrate that the protection on phenol or conversion of
benzylic alcohol into a better leaving group is not necessary under
the reaction conditions employed. The application of this method
in a concise formal synthesis of myristinin B/C is also described.
utilizing the o-hydroxy bisbenzylic alcohols
9 without any
protection or converting the benzylic hydroxy group to a better
leaving group to generate requisite o-QMs.
Initial efforts were directed at identifying an appropriate
catalyst to effect the [4 + 2] cycloaddition of aryl substituted
o-QMs and styrenes. Thermolysis of the known7 alcohol 9a in the
presence of excess equiv. of olefin 10a resulted in the formation of
2,4-diarylbenzopyran 8a in moderate yield albeit with excellent
diastereoselectivity (Table 1, entry 1). In a quest to generate o-QM
at ambient temperature, the reactants were subjected to treatment
with various Lewis and Brønsted acids with varying efficiency. Use
aDepartment of Chemistry, Indian Institute of Technology Madras, Chennai –
600036, Tamil Nadu, India
bDepartment of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai –
400076, India. E-mail: sjgharpure@iitb.ac.in; Fax: (+91)-22 2576 7152; Tel: (+91)-22
2576 7171
Electronic supplementary information (ESI) available. CCDC 932655–932659. For
3
ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c3ra43526a
Fig. 1 Natural products bearing an arylbenzopyran moiety.
RSC Adv., 2013, 3, 18279–18282 | 18279
{ Present address: Indian Institute of Technology Bombay.
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(Table 2, entry 8). Most notably, electron deficient enone 10f
served as an excellent dienophile in the reaction with alcohol 9a
furnishing the densely functionalized chroman 8j in excellent
yields and moderate selectivity favouring the trans-2,4-diarylisomer
as the major product (Table 2, entry 9). This example is particularly
interesting as use of an acyclic enone is uncommon in a [4 + 2]
cycloaddition with o-QM. In continuation of our interest on using
vinylogous functional groups in organic synthesis,9 we also
explored the reaction of trans-methoxyacrylate (10g) as dienophile.
Gratifyingly, the reaction was found to be effective leading to
chroman acetal 8k–l in good yields (Table 2, entries 10–11). The
relative stereochemistry of the chromans was deduced on the
basis of a 1H-1H NOESY and NOE spectra. It was further
unambiguously ascertained by single crystal X-ray diffraction
analysis on the chromans 8b, 8d, 8f and 8j.10 Good diastereos-
electivity observed under thermal condition is an outcome of a
concerted, endo approach of the dienophile. On the contrary, the
moderate diastereoselectivity observed in the (¡)-BPA mediated
cycloaddition reaction is consistent with the ionic pathway
involving formation of benzylic cation and stepwise reaction.
The cis isomer is dominant perhaps due to preference of both the
bulky substituents to occupy equatorial orientation.
Attention was next turned towards applying the developed
method for the synthesis of myristinin B/C (2). Myristinins A–F (1–
4) were isolated independently from Myristica cinnamomea,11
Knema elegans12 and Horsfieldia amygdaline.13 These were the first
atropisomeric flavonoids isolated from nature. Further, they were
found to be anti-inflammatory, antifungal and also exhibited
biochemical activity, both as a potent DNA-damaging agent and
DNA polymerase b inhibitor. Hecht et al. reported the first and the
only total synthesis of myristinin A (1) and B/C (3a/b) involving a
fairly lengthy strategy.12,6b It was envisaged that the synthesis of
myristinins B/C can be achieved by the regioselective Friedel–
Crafts reaction of the trimethoxy aryl ring in arylchroman 8f or 8g
with lauroyl chloride. However, all our attempts using a variety of
conditions met with failure. Similarly, regioselective directed ortho
lithiation of flavan 8f, g or lithium halogen exchange on 8h
followed by trapping of the aryllithium intermediate with lauroyl
Scheme 1 Retrosynthetic analysis of 2,4-diarylbenzopyrans 8.
of strong Lewis acid like BF3?OEt2 and milder Lewis acid like
Bi(OTf)3 improved the efficiency of the reaction significantly, but
the diastereoselectivity was poor (Table 1, entries 2 and 3). Many
Brønsted acids like p-TSA, (¡)-BPA, H3PO4, HClO4 and CF3CO2H
too were tested as catalysts (Table 1, entries 4–8). The best result
was obtained with (¡)-BPA as the catalyst where the product 8a
was formed in 90% yield and moderate diastereoselectivity (d.r. =
3 : 1) favouring cis isomer and hence this was used as the catalyst
of choice for studying the scope of the reaction.8 The most notable
feature of this study was that only slight excess of styrene (1.1 equiv.)
was necessary for efficient Diels-Alder reaction. This is in contrast to
many literature reported methods, where huge excess of dienophile
was found to be necessary for suppressing side reactions.
Table 2 outlines the scope of the (¡)-BPA mediated [4 + 2]
cycloaddition reaction with various o-QM precursors and dieno-
philes. Reaction of o-QM, generated in situ from variety of
o-hydroxy bisbenzylic alcohols 9a–f, with different styrene
derivatives 10 that are electronically rich produced the diaryl-
flavans 8b–h in good yields and moderate selectivity favouring the
cis isomer (Table 2, entries 1–7). Alkyl substituted o-hydroxy
benzylalcohol 9f was also found to participate in this reaction
efficiently furnishing the alkyl chroman 8i in very good yield
Table 1 Optimization of the [4 + 2] cycloaddition of styrene 10a and o-QM generated from alcohol 9a
Entry
Catalyst
Styrene equiv.
Temp. (uC)
Time (h)
Yield (%)a
d.r.b cis : trans
1
2
3
4
5
6
7
8
—
5
110
0–rt
rt
rt
rt
0–rt
0–rt
0–rt
24
1
4
2.5
20
3
53
66
86
60
¢19 : 1
1 : 1
1 : 1
3 : 1
3 : 1
—
BF3?OEt2
Bi(OTf)3
p-TSA
( )-BPA
HClO4
H3PO4
CF3CO2H
1.1
1.1
1.1
1.1
1.1
1.1
1.1
90
n.d.c
n.d.c
60
3
4
—
1 : 1
a
b
c
Isolated yield. In all the cases, d.r. was determined on the crude reaction mixtures by 1H-NMR on a 400 MHz instrument. Not detected.
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subjected to reaction with ethyl vinyl ether (10h) under standard
Heck reaction conditions, followed by hydrolytic work up procured
the ketone 14 in excellent yield. Alkylation reaction of the ketone
14 was attempted using a variety of bases and was found to be
particularly challenging, perhaps due to steric hindrance. Finally,
generation of the enolate of the ketone 14 using t-BuOK as the
base and its alkylation with n-decyl iodide (16) furnished the
ketone 15 in moderate yield. Recovered starting ketone was re-
subjected to alkylation and after two iterations, the product was
obtained in 36% yield [66%, based on recovered starting material
(brsm)]. The spectral data of this ketone was found to be in
agreement with that reported by Hecht and co-workers. Since they
have already transformed the ketone 15 into myristinin B/C by
global deprotection using BBr3 in one step, the present synthesis
of the ketone 15 constitutes the formal synthesis of myristinin B/C
(2). The overall reaction sequence involves just 4 steps from known
intermediate with an overall yield of 34%. The brevity of the
approach is eminently suitable for the synthesis of library of this
biologically important natural product family.
Table 2 Scope of the [4 + 2] cycloaddition reaction of o-QM, generated from
alcohols 9 using (¡)-BPA with various dienophiles 10
Time Yield d.r.b
Entry Alcohol Dienophilec Product (h)
(%)a
cis : trans
1
2
3
4
5
6
7
8
9a
9a
9a
9b
9c
9d
9e
9f
10b
10c
10d
10a
10e
10e
10e
10a
10f
8b
8c
8d
8e
8f
8g
8h
8i
24
22
22
23
24
22
2d
22
10
12
3.5
62
61
79
94
90
80
66
74
90
68
73
3 : 1
2 : 1
3 : 1
3 : 1
3 : 1
3 : 1
5 : 1
3 : 1
1 : 2
2 : 1
8 : 1
Conclusions
9
10
11
9a
9a
9c
8j
8k
8l
10g
10g
In conclusion, a (¡)-BPA catalyzed, mild and efficient protocol for
the synthesis of 2,4-diaryl substituted flavans involving [4 + 2]
cycloaddition reaction of o-QM generated from o-hydroxy
arylmethyl phenols and styrene derivatives was developed. We
have demonstrated that electron deficient enones can participate
in cycloaddition with o-QM. The method was employed in a
concise formal synthesis of atropisomeric myristinin B/C. The
method can be potentially extended to the synthesis of other
members of this family in a divergent manner. Efforts in this
direction are underway in our laboratory and will be reported in
due course.
a
b
Isolated yield. In all the cases, d.r. was determined on the crude
reaction mixtures by 1H-NMR on a 400 MHz instrument. 1.1 equiv.
of dienophile was used. 50 mol% of BPA and 2 equiv. of
c
d
dienophile.
chloride too did not furnish the required 1,4-diaryl benzopyran
derivative. Hence, an alternate strategy for the formal synthesis of
myristinin B/C was envisaged.
Towards this end, selective monolithiation of diiodide 12a14
followed by its addition to aldehyde 11c15 furnished the o-QM
precursor, the iodoalcohol 9h. (¡)-BPA catalyzed [4
+ 2]
Acknowledgements
cycloaddition reaction of the iodoalcohol 9h with the olefin 10a
furnished the iodoflavan 13 in excellent yield and good
diastereoselectivity favouring cis isomer (Scheme 2). Instability of
the iodide 13 necessitated the use of excess of dienophile 10a (4
equiv.) and BPA (0.5 equiv.) in this case. The iodoflavan 13 when
In memory of Prof. A. Srikrishna (1955–2013), an outstanding
organic chemist and a great mentor. We thank CSIR and DST,
New Delhi for financial support and Mr. V. Ramkumar of the
Department of Chemistry, IIT Madras for the crystallographic
data. Research fellowships from CSIR, New Delhi (SAM) and
IIT Madras (PKV) are gratefully acknowledged.
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Scheme 2 Formal synthesis of myristinin B/C.
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