Synthesis of bavachromanol from resorcinol via a tandem cationic cascade/EAS sequence

Article abstract of DOI:10.1016/j.tetlet.2018.02.041

The natural chalcone bavachromanol has been prepared through a tandem reaction sequence that joins cationic cyclization of an epoxide to an adjacent MOM-acetal with electrophilic aromatic substitution by a presumed methoxymethylene cation. Only a single regioisomer of the tandem product was observed, with substitution taking place exclusively ortho to the position of the original acetal. This regiocontrol provided a key intermediate from a symmetrical precursor, and allowed preparation of the meroterpenoid through a short reaction sequence.

Full text of DOI:10.1016/j.tetlet.2018.02.041

Accepted Manuscript
Synthesis of bavachromanol from resorcinol via a tandem cationic cascade/EAS
sequence.
Parin A. Shah, David F. Wiemer
PII:
S0040-4039(18)30230-2
https://doi.org/10.1016/j.tetlet.2018.02.041
TETL 49726
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
26 January 2018
13 February 2018
15 February 2018
Please cite this article as: Shah, P.A., Wiemer, D.F., Synthesis of bavachromanol from resorcinol via a tandem
cationic cascade/EAS sequence., Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.02.041
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Synthesis of bavachromanol from resorcinol
via a tandem cationic cascade/EAS sequence.
Parin A. Shah and David F. Wiemer*
Department of Chemistry, University of Iowa, Iowa City, IA 52242-1294, U.S.A.
OH
OMOM
OH
OMOM
OH
OH
O
O
OH
Resorcinol
O
OMOM
H3C
O
O
Bavachromanol
OH

Tetrahedron Letters
1
TETRAHEDRON
LETTERS
Pergamon
Synthesis of bavachromanol from resorcinol via a tandem
cationic cascade/EAS sequence.
Parin A. Shah and David F. Wiemer*
Department of Chemistry, The University of Iowa, Iowa City, Iowa, 52242-1294, USA
.
Abstract— The natural chalcone bavachromanol has been prepared through a tandem reaction sequence that joins cationic cyclization of
an epoxide to an adjacent MOM-acetal with electrophilic aromatic substitution by a presumed methoxymethylene cation. Only a single
regioisomer of the tandem product was observed, with substitution taking place exclusively ortho to the position of the original acetal. This
regiocontrol provided a key intermediate from a symmetrical precursor, and allowed preparation of the meroterpenoid through a short
reaction sequence.
Keywords: tandem reaction, cationic cascade, electrophilic aromatic substitution, epoxide © 2018 Elsevier Science. All rights reserved
The chalcone bavachromanol (1, Figure 1) was first reported in 1980 as a component of the seeds of Psoralea
corylifolia,1,2 a plant which is widely used in both traditional Chinese medicine (where it is known as “bu gu zhi”) and
Ayurvedic medicine.3 It also was identified during a recent, and more exhaustive, study of this plant.4 The structure of this
meroterpenoid caught our attention because introduction of the ketone substituent through chemical modification of a
bicyclic precursor containing the aromatic ring would be required adjacent to the ether functionality rather than the free
phenol. While there are synthetic methods that allow ortho C-alkylation of phenolate anions,5,6 regiospecific introduction of
an alkyl group adjacent to the ether linkage might be expected to be more challenging.
Recently we have reported the synthesis of angelichalcone (2)7,8 and schweinfurthin A (3)9-11 through sequences based on
tandem cyclization/electrophilic aromatic substitution reactions, where a geranyl epoxide was employed to initiate a cationic
cascade.12 Tandem reactions can afford an attractive strategy for synthesis of complex natural products,13 perhaps especially
when the reactions follow a biomimetic pathway,14-16 and linking ring formation to electrophilic aromatic substitution is
highly conservative in terms of atom economy. If a strategy similar to those we have used with geranyl-substituted
compounds could be employed with a resorcinol bearing only a 5-carbon chain, and more importantly if the high ortho
regioselectivity in the electrophilic aromatic substitution component still held true, it could afford an efficient strategy for
preparation of bavachromanol. In this report the synthesis of this meroterpenoid through an application of this strategy is
described.
* Corresponding author: david-wiemer@uiowa.edu

2
Tetrahedron Letters
OH
HO
OH
O
O
O
O
HO
OH
H
OH
1 (bavachromanol)
2 (angelichalcone)
OH
HO
HO
O
OH
H
H
2
OH
3 (schweinfurthin A)
Figure 1. Bavachromanol and some related meroterpenoids.
From a retrosynthetic perspective (Figure 2), the enone of the target compound could be seen arising from an intermediate
such as compound 4 through oxidation of the benzyl methyl ether to the corresponding aldehyde followed by transformation
to the methyl ketone and ultimately an aldol condensation. The keystone of the sequence would be to convert the
symmetrical resorcinol derivative 5 to the unsymmetrical ether 4. This transformation could be envisioned through a tandem
cationic cyclization followed by electrophilic aromatic substitution of the cation released upon cyclization, as long as the
substitution reaction proceeded at the position ortho to the newly formed ether. While this regiochemical outcome would be
consistent with the major product found in one geranyl-substituted system we have studied,8 in another system the liberated
MOM group was either lost (presumably to reactions with solvent) or found on a distant alcohol.17 Thus, while it might be
challenging to predict the course of the reaction sequence with the epoxide 5, given that this epoxide can be easily derived
from readily available and inexpensive resorcinol (6) it was reasonable to explore the viability of a tandem process in this
system.
OH
OMOM
OH
OH
O
O
H3C
4
O
O
1
OH
OH
OMOM
O
OMOM
OH
6
5
Figure 2. Retrosynthesis of bavachromanol.
Synthesis of the key intermediate 5 began with protection of resorcinol (6) as the di-MOM acetal 7 (Scheme 1). Directed
ortho metalation18,19 of compound 7 was achieved in good yield upon treatment with n-BuLi, and subsequent reaction of the
resulting anion with prenyl bromide gave the symmetrical aromatic system 8 in good yield.20 Epoxidation was accomplished
in quantitative yield upon treatment with mCPBA to give compound 5. Brief treatment of compound 5 with BF3·OEt2 at low
temperature yielded three products; one tandem cyclization-electrophilic aromatic substitution product in 37% yield, and
compounds 10 and 11 in yields of 16% and 33% respectively. The structures of compounds 10 and 11 were readily apparent.
1
For both compounds three aromatic hydrogens were observed in the H NMR spectrum. Furthermore, the spectrum of
compound 10 showed only the aromatic MOM substituent (5.19 and 3.49 ppm), while the spectrum of compound 11 revealed

Tetrahedron Letters
3
the presence of both an aromatic MOM acetal and an aliphatic MOM acetal (5.20 and 3.50; 4.84 and 4.69, two doublets from
the diastereotopic methylene hydrogens and 3.42, respectively).
OMOM
OH
DIPEA, MOMCl
DCM, 0 oC
81%
OMOM
65%
OH
6
7
n-Buli
(80% brsm)
prenyl bromide
THF, 0 oC
OMOM
OMOM
mCPBA, DCM
0 oC to rt
O
100%
OMOM
OMOM
5
8
.
BF3 EtO2
DCM, TEA
-78 oC
OMOM
OMOM
R1
OR2
OH
O
O
R1
4
R1 = MOM, R2 = H (37%)
9 R1 = MOM, R2 = H
10 R1 = H; R2 = H (16%)
(not observed)
11 R1 = H; R2 = MOM (33%)
Scheme 1. Synthesis of the key intermediate 5 and its tandem cyclization/EAS products.
1
Assignment of the structure of the tandem reaction product required a more detailed analysis of its spectral data. In the H
NMR spectrum of this compound, two aromatic hydrogens are apparent as coupled doublets (J = 8.4 Hz), requiring the
product to display two ortho hydrogens (i.e. isomers 4 and 9). Assuming that compound 10 is an intermediate in the reaction
sequence, a priori both positions ortho to oxygen might be expected to be comparably activated for an electrophilic aromatic
substitution reaction. Two methyl groups bearing oxygen also are observed. The more downfield of the two methyl groups
(3.47 ppm) could be assigned to the methoxy component of the MOM acetal, while the more upfield of the two methoxy
groups (3.38 ppm) was assigned as the benzyl methyl ether. Each of these methyl groups was correlated to an aromatic
hydrogen in the NOESY spectrum, leaving the isomer 4 as the only reasonable structure assignment (Figure 3). Fortunately,
this isomer is the one required for synthesis of bavachromanol. The isolated yield of this tandem product was moderate, but
both the short sequence and the formation of a single regioisomer encouraged continuation of the effort. Furthermore, it may
be possible to recycle compound 10 and/or compound 11 into the main sequence, although in this case the brevity of the
synthetic design suggested that such efforts were unnecessary and they were not pursued.
Figure 3. NOESY correlations in the tandem reaction product 4.
* Corresponding author: david-wiemer@uiowa.edu

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Tetrahedron Letters
Completion of the synthesis was accomplished through relatively straightforward transformations (Scheme 2). From the
outset, we viewed the benzyl methyl ether as a latent aldehyde, and treatment of the ether 4 with DDQ gave the expected
aldehyde 12 in quantitative yield. Reaction of this aldehyde with excess methyl lithium was complicated by a competing
dehydration reaction, but reaction with excess methyl magnesium chloride, where excess was employed to circumvent the
need to protect the free alcohol, gave the benzylic alcohol 13 in very good yield. While compound 13 was clearly a mixture
1
of diastereomers based on the H NMR spectrum, this was of no long-term importance given that the stereocenter was
destroyed by smooth oxidation to the ketone 14 in the next step (96%). A base-mediated aldol condensation with p-
hydroxybenzaldehyde was exceedingly slow, but condensation with the MOM-protected benzaldehyde 15 proceeded
smoothly, albeit still slowly, to afford the enone 16. Final deprotection of both MOM groups by treatment with pTsOH in
methanol gave the desired product 1. While the yield for hydrolysis of the two MOM groups is only moderate, it is
consistent with other reports for hydrolysis of two aromatic MOM acetals.21 Despite this yield, the final step gave sufficient
material for characterization, and the spectra of this material proved to be identical with those reported for the natural product
bavachromanol.1
DDQ
DCM:H2O(10:1)
OMOM
OH
rt, 2 hours
4
100%
O
CHO
12
MeMgCl (3M in Et2O)
93%
THF, 0 oC
OMOM
OMOM
OH
OH
MnO2, DCM
96%
O
O
14
13
O
HO
6M KOH, EtOH
rt, 6 days
58%
MOMO
OR
OH
15
CHO
O
O
OR
TsOH·H2O
MeOH, rt, 72 hours
54%
16 R = MOM
1 R = H
Scheme 2. Completion of the bavachromanol synthesis.
In conclusion, the meroterpenoid bavachromanol has been prepared in 9 steps and 7% yield. The key step, a tandem
cationic cyclization/electrophilic aromatic substitution reaction, gave a single regioisomer determined to have undergone
substitution only ortho to the newly formed ether, despite the probability that the para position is equally activated. While
this product was obtained in moderate yield, the short sequence needed to prepare the intermediate as well as the short
sequence needed to complete the natural product allowed reasonably efficient access to this natural product. Perhaps more
importantly, this new example of the tandem reaction sequence extends its ortho selectivity to a new system, and thus
supports planning similar routes to other meroterpenoids. Given that the number of meroterpenoids continues to grow
rapidly,22 further applications of the tandem cationic cascade/electrophilic aromatic substitution strategy will follow.
Acknowledgments

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5
We thank the University of Iowa Graduate College for summer fellowships (to PAS). Financial support from the Roy J.
Carver Charitable Trust through its Research Program of Excellence (to DFW) is gratefully acknowledged.
References and Notes.
(1)
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(2)
(3)
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Chopra, B.; Dhingra, A. K.; Dhar, K. L. Fitoterapia 2013, 90, 44.
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Ma, S. N.; Huang, Y. W.; Zhao, Y. Y.; Du, G. X.; Feng, L.; Huang, C.; Li, Y. M.; Guo, F. J. Phytochemistry Letters
2016, 16, 213.
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Bouzbouz, S.; Kirschleger, B. Synthesis 1994, 714.
Blunt, S. B.; Chen, T. B.; Wiemer, D. F. J. Nat. Prod. 1998, 61, 1400.
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(8)
Topczewski, J. J.; Callahan, M. P.; Neighbors, J. D.; Wiemer, D. F. J. Am. Chem. Soc. 2009, 131, 14630.
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Supplementary data
Experimental procedures and/or spectral data for compounds 4–8, 10–14, and 16 are available. Supplementary data
associated with this article can be found in the online version at doi:
* Corresponding author: david-wiemer@uiowa.edu

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Tetrahedron Letters
Highlights
 A tandem reaction sequence converts a symmetrical resorcinol derivative to a
single bicyclic substitution product.
 Only a single regioisomer of the tandem cyclization/EAS product was observed.
 The meroterpenoid bavachromanol has been prepared in 9 steps and 7% yield.