Investigations into arylquinone atropisomers: Synthesis and evaluation

Article abstract of DOI:10.1016/j.tetlet.2003.09.214

An arylquinone capable of existing as two diastereromeric atropisomers was synthesized starting from dibenzofuran. Arylquinone 12 exists as a set of slowly interchanging diastereomeric atropisomers and arylquinone 4 exists as rapidly interchanging atropisomers.

Full text of DOI:10.1016/j.tetlet.2003.09.214

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 9021–9023
Investigations into arylquinone atropisomers: synthesis and
evaluationꢀ
Umar S. M. Maharoof and Gary A. Sulikowski*
Department of Chemistry, Texas A&M University, PO Box 30012, College Station, TX 77842–3012, USA
Received 2 September 2003; revised 26 September 2003; accepted 29 September 2003
Abstract—An arylquinone capable of existing as two diastereromeric atropisomers was synthesized starting from dibenzofuran.
Arylquinone 12 exists as a set of slowly interchanging diastereomeric atropisomers and arylquinone 4 exists as rapidly
interchanging atropisomers.
© 2003 Elsevier Ltd. All rights reserved.
A number of natural products occur as a single
atropisomer due to restricted rotation around a car-
bonꢀcarbon bond. Examples include highly substituted
biaryl natural products such as biphyscion (1)1 and the
bisquinone bismurrayaquinone A (2).2 In many cases
the identification of a natural atropisomer escapes the
attention of isolation chemists especially when these are
atropenantiomers.3 While examples of biaryl and
bisquinone atropisomers have been reported, no report
of the existence of arylquinone atropisomers has been
communicated in the literature despite their occasional
appearance within natural products.4 One recent exam-
ple is the class of hibarimicin antitumor antibiotics, that
share hibarimicinone (3) (Fig. 1) as a common agly-
cone.5 The central DE ring system of hibarimicinone
incorporates a sterically congested central arylquinone
sub-structure suggesting the hibarimicins may exist as
single atropisomers. As part of a program directed
towards the total synthesis of hibarimicinone we
desired, in a preliminary investigation, to evaluate the
possibility that arylquinones related to 3 exist as
atropisomers. To this end we planned to assemble
either an arylstannane or arylboronic acid.6 In the case
of congested arylquinones this approach can prove
challenging, especially when employing electron rich
aryl metal reagents as a coupling partner. We therefore
chose to explore an alternative strategy for the synthesis
of 4 starting from quinone monoketal 5 (Fig. 3). We
anticipated the latter intermediate to be produced from
dibenzofuran (6) (Scheme 1).
Hydroxylation of dibenzofuran in the C(2) and C(8)
positions were achieved by regioselective Friedel–Crafts
arylquinone
4
that could exist as
a
pair of
diastereomeric atropisomers (4a and 4b), easily distin-
guished by NMR analysis (Fig. 2). The synthesis and
NMR analysis of arylquinone 4 are the subjects of this
letter.
Arylquinones have typically been assembled by cross-
coupling of a haloquinone and aryl metal reagent,
ꢀ Supplementary data associated with this article can be found at
doi:10.1016/j.tetlet.2003.09.214
* Corresponding author. E-mail: g-sulikowski@tamu.edu
Figure 1.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.214

9022
U. S. M. Maharoof, G. A. Sulikowski / Tetrahedron Letters 44 (2003) 9021–9023
Figure 2.
Scheme 2. Reagents and conditions: (a) 1,3-cyclopentadiene,
PhMe, 23°C; (b) LiBF4, MeCN (aq.); (c) Et3N, CH2Cl2; (d)
MOMCl, i-Pr2NEt, DMF, 60°C.
single Diels–Alder adduct in 95% yield. Hydrolysis of
the latter using lithium tetrafluoroborate in aqueous
acetonitrile12 followed by dehydrobromination pro-
vided arylquinone 4. Interestingly arylquinone
4
appeared as a single isomer at room temperature
according to both 1H and 13C NMR analysis, indicating
rapid rotation around the aryl-quinone carbonꢀcarbon
bond. In contrast, alkylation of 4 with MOMCl gave
MOM ether 12 which emerged as an approximately 1:1
mixture of interchanging atropisomers according to
NMR analysis. The two conformers failed to coalesce
at temperatures as high as 148°C. Furthermore, analy-
sis of 12 by HPLC under various conditions did not
lead to separation of atropdiastereoisomers. Taken
together, a coalescence temperature greater than 148°C
and inseparable atropisomers at room temperature sug-
gests that the barrier to rotation is in the range of
20–25 kcal/mol (Scheme 2).13
Figure 3.
acylation followed by Baeyer–Villiger oxidation and
finally reduction to afford bis-phenol 7 in 67% overall
yield.7 Alklyation with MOMCl set the stage for an
ortho-directed metallation which following quenching
of the resulting aryllithium intermediate provided aro-
matic aldehyde 8.8 The aldehyde group was then con-
verted to methyl ether 9 by a standard three-step
procedure (1. m-CPBA, 2. K2CO3, MeOH, and 3. MeI,
K2CO3). Next, the neighboring MOM ether was
exchange for a methyl ether starting with removal of
both MOM groups and protection of the less hindered
of the two resulting phenolic hydroxyl groups as a
t-butyldiphenylsilyl ether.9 The remaining phenol was
methylated to provide the desired dimethyl ether 10.
Finally, removal of the silyl protecting group followed
by ortho bromination10 gave phenol 11 and oxidation of
the latter with (diacetoxyiodo)benzene11 in methanol
provided monoketal 5.
Steric hindrance alone cannot account for the signifi-
cant differences in aryl-quinone carbonꢀcarbon bond
rotational barriers between phenol 4 and MOM ether
12. We speculate that the rotational barrier of phenol 4
is significantly lowered due to stabilization of the tran-
sition state structure leading to the interconversion of
4a and 4b (Fig. 4) by tautomerization to intermediate
quinone methide 4c. In contrast, MOM ether 12 does
not have the low energy quinone methide pathway
available to assist bond rotation leaving only a higher
Monoketal quinone 5 proved to be a very reactive
dienophile. For example reaction with cyclopentadiene
in toluene occurred at room temperature to provide a
Scheme 1. Reagents and conditions: (a) AcCl, AlCl3, CH2Cl2, 0“23°C; (b) m-CPBA, CH2Cl2, 50°C; (c) DIBAL, CH2Cl2, −78°C;
(d) MOMCl, i-Pr2NEt, DMF, 0“23°C; (e) n-BuLi, TMEDA, Et2O, −10°C then DMF; (f) m-CPBA, CH2Cl2, 23°C; (g) K2CO3,
MeOH; (h) MeI, K2CO3, Me2CO; (i) HCl, MeOH, 40°C; (j) TBDPSCl, ImH, DMAP, DMF; (k) MeI, K2CO3, Me2CO; (l) TBAF,
THF, 0°C; (m) Bu4NBr3, CH2Cl2, MeOH; (n) PhI(OAc)2, MeOH, 0°C.

U. S. M. Maharoof, G. A. Sulikowski / Tetrahedron Letters 44 (2003) 9021–9023
9023
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In conclusion, we have identified for the first time that
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We thank the National Institutes of Health (CA59515-
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funds for the purchase of NMR instrumentation.
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