Synthesis of parvistemin a via biomimetic oxidative dimerization

Article abstract of DOI:10.1021/ol201246e

The first synthesis of the naturally occurring benzoquinone dimer parvistemin A is reported. The key step is the late stage iron(III) mediated dimerization of a 1,2,4-trihydroxyarene to give the natural product in good yield, a phenol oxidative coupling t

Full text of DOI:10.1021/ol201246e

ORGANIC
LETTERS
2011
Vol. 13, No. 13
3396–3398
Synthesis of Parvistemin A via Biomimetic
Oxidative Dimerization
Marcus J. Smith, Christopher C. Nawrat, and Christopher J. Moody*
School of Chemistry, University of Nottingham, University Park, Nottingham NG7
2RD, U.K.
c.j.moody@nottingham.ac.uk
Received May 10, 2011
ABSTRACT
The first synthesis of the naturally occurring benzoquinone dimer parvistemin A is reported. The key step is the late stage iron(III) mediated
dimerization of a 1,2,4-trihydroxyarene to give the natural product in good yield, a phenol oxidative coupling that is believed to be biomimetic. The
route proceeds in seven steps from an inexpensive commercially available acetophenone in 14% overall yield.
The parvistemins 3 (Scheme 1) were isolated from the
aerial parts of the flowering plant Stemona parviflora
Wright in 2007 by Bringmann and co-workers.1 The roots
of this plant have long been used as a substitute for those of
Stemona tuberose, a popular plant in Chinese medicine for
respiratory disorders such as bronchitis and tuberculosis.2
The Stemona genus is well-known for producing the Ste-
mona alkaloids, which have been popular targets for the
synthetic chemistry community for a number of years,3À6
but this was the first report of quinonoid metabolites from
these plants. Interestingly, these axially chiral compounds
were isolated entirely in their racemic forms, and separation
of the atrop-enantiomers using HPLC on a chiral stationary
phase showed that they did not interconvert at room tem-
perature. This lack of enantioenrichment is not uncommon
in naturally occurring axially chiral compounds.7
It has been proposed that the parvistemins themselves
might arise from the known stilbenoid natural products
stilbostemins BÀD 1, isolated from another Stemona
species in 2002 by Greger and co-workers.8,9 Oxidation
of the resorcinol ring in these compounds would give the
corresponding 1,2,4-trihydroxy compounds 2 that could
undergo dimerization via oxidative phenolic coupling, fol-
lowed by further oxidation to the parvistemins 3(Scheme1),
although the intermediates 2 (or the corresponding qui-
nones) have not yet been isolated from the producing
organism.
Oxidative phenolic coupling is well established as a pow-
erful method in the synthetic chemist’s repertoire,10,11 and
the late stage oxidative dimerization that is apparently
employed here by Nature represents the most efficient and
aesthetically satisfying approach to these compounds. The
oxidative homocoupling of phenolic compounds has pro-
ven itself useful as a method for the synthesis of dimeric
natural products; recent examples include the kotanins,12,13
(1) Yang, X. Z.; Gulder, T. A. A.; Reichert, M.; Tang, C. P.; Ke,
C. Q.; Ye, Y.; Bringmann, G. Tetrahedron 2007, 63, 4688–4694.
(2) Sakata, K.; Aoki, K.; Chang, C. F.; Sakurai, A.; Tamura, S.;
Murakoshi, S. Agric. Biol. Chem. 1978, 42, 457–463.
(3) Lin, W. H.; Xu, R. S.; Zhong, Q. X. Acta Chim. Sin. 1991, 49, 927–
931.
(8) Pacher, T.; Seger, C.; Engelmeier, D.; Vajrodaya, S.; Hofer, O.;
Greger, H. J. Nat. Prod. 2002, 65, 820–827.
(9) Kostecki, K.; Engelmeier, D.; Pacher, T.; Hofer, O.; Vajrodaya,
S.; Greger, H. Phytochemistry 2004, 65, 99–106.
(10) Scott, A. I. Quarterly Reviews 1965, 19, 1–35.
(4) Lin, W. H.; Xu, R. S.; Zhong, Q. X. Acta Chim. Sin. 1991, 49,
1034–1037.
(5) Pilli, R. A.; de Oliveira, M. Nat. Prod. Rep. 2000, 17, 117–127.
(6) Pilli, R. A.; Rosso, G. B.; de Oliveira, M. D. F. Nat. Prod. Rep.
2010, 27, 1908–1937.
(11) Guillaume, L.; Feldman, K. S. In Modern Arene Chemistry;
Astruc, D., Ed.; Wiley-VCH: Weinheim, 2002; pp 479À538.
€
€
(12) Huttel, W.; Nieger, M.; Muller, M. Synthesis 2003, 1803–1808.
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(13) Drochner, D.; Huttel, W.; Nieger, M.; Muller, M. Angew.
(7) Bringmann, G.; Tasler, S.; Endress, H.; Kraus, J.; Messer, K.;
Wohlfarth, M.; Lobin, W. J. Am. Chem. Soc. 2001, 123, 2703–2711.
Chem., Int. Ed. 2003, 42, 931–933.
r
10.1021/ol201246e
Published on Web 06/06/2011
2011 American Chemical Society

Scheme 1. (a, R = H; b, R = OH; c, R = OMe) Parvistemins
AÀC (3) and Their Putative Biosynthesis from Stilbostemins
BÀD (1)
Scheme 2. Retrosynthesis of Parvistemins AÀC
conditions (hexamine in refluxing acetic acid)17 followed
by Wittig reaction on the resulting benzaldehyde gave 7.
This olefination reaction required some optimization to
obtain a good yield of 7 without recourse to protection of
the phenol, with DBU being far superior to alkoxide bases
for this step. Thus, using 2 equiv of DBU and benzylpho-
sphonium bromide, stilbene 7 was formed exclusively as
1
the E-isomer as evidenced by H NMR spectroscopy.
mastigophorenes A and B,14,15 and the dimeric core of
murrayafoline A.16 We therefore envisioned a retrosynthe-
sis based on this transformation (Scheme 2). It was decided
thatthe keymonomeric building block2 could be prepared
from the commercially available acetophenone 4 using
classic aromatic chemistry. Additionally it was planned
to introduce the arylethyl moieties shortly before the
dimerization by Wittig reaction on a substituted benzalde-
hyde derived from 4 to impart flexibility to the route, and
allow easy access to the other members of the parvistemin
family. We now report the successful use of this strategy in
the first synthesis of parvistemin A.
Simultaneous hydrogenation of the stilbene double bond
and hydrogenolysis of the benzyl protecting groups gave
the hydroxyquinol 2a. Careful workup, including filtration
and removal of the palladium catalyst under argon, was
necessary, asquinol2aisrapidly oxidized inthe presenceof
palladium to the monomeric quinone 8.18 In the absence of
palladium, 2a is moderately stable to air and can be purified
by flash column chromatography if required. Neverthe-
less, oxidation to the monomeric quinone 8 occurs cleanly
in approximately 24 h upon standing in air as a solution in
CH2Cl2 or slightly faster in the presence of silica gel. None
of the desired dimer 3a was observed under these mild
conditions.
Although the oxidative dimerization of 1,2,4-trimethox-
benzene is a well-known reaction, facilitated by a number
of diverse reagents, only one report exists for the same
reaction on the closely related 1,2,4-trimethoxy-benzene
system. This was dimerization of 3-neopentylbenzene-1,2,4-
triol carried out by Anderson and co-workers in studies
toward a biomimetic synthesis of popolohuanone E,19
using silica supported iron(III) chloride under anhydrous
The synthesis started with dibenzyl protection of the
resorcinol 4 using benzyl bromide and K2CO3 in DMF
(Scheme 3). BaeyerÀVilliger oxidation of the acetophe-
none 5 followed by hydrolysis of the resulting acetate ester
gave phenol 6 in good yield. Ortho-formylation using Duff
(14) Bringmann, G.; Pabst, T.; Busemann, S.; Peters, K.; Peters,
E. M. Tetrahedron 1998, 54, 1425–1438.
(15) Bringmann, G.; Pabst, T.; Rycroft, D. S.; Connolly, J. D.
Tetrahedron Lett. 1999, 40, 483–486.
(16) Bringmann, G.; Ledermann, A.; Francois, G. Heterocycles 1995,
40, 293–300.
(17) Kitahara, Y.; Nakahara, S.; Numata, R.; Kubo, A. Chem.
Pharm. Bull. 1985, 33, 2122–2128.
(18) Lei, X. G.; Porco, J. A. J. Am. Chem. Soc. 2006, 128, 14790–
14791.
(19) Anderson, J. C.; Denton, R. M.; Wilson, C. Org. Lett. 2005, 7,
123–125.
(20) Jempty, T. C.; Gogins, K. A. Z.; Mazur, Y.; Miller, L. L. J. Org.
Chem. 1981, 46, 4545–4551.
(21) Sarhan, A. A. O.; Bolm, C. Chem. Soc. Rev. 2009, 38, 2730–2744.
Org. Lett., Vol. 13, No. 13, 2011
3397

Scheme 3. Synthesis of Parvistemin A 3a
conditions in dichloromethaneÀacetonitrile.20,21 We were
pleased to find that after some optimization, the applica-
tion of this reagent to the 1,2,4-trihydroxyarene 2a gave a
reasonable yield of parvistemin A 3a, whose spectroscopic
data closely matched those reported for the natural pro-
duct (see Supporting Information). In our case the condi-
tions successfully applied by Anderson et al., i.e. slow
addition of the monomer to a stirred suspension of the
oxidant, only returnedtheundesired monomeric quinone8
regardless of the number of equivalents used. It was found
that portionwise addition of the oxidant to a solution of 2a
favored the formation of 3a and that freshly prepared (and
rigorously dry) FeCl3•SiO2 was required to ensure repro-
ducibility. The dimer 3a was accompanied by a small
amount of monomeric quinone 8, which could be readily
recycled by reduction back to 2a using sodium dithionite in
essentially quantitative yield.
step. This is the first time this powerful transformation,
used to form the otherwise challenging biaryl bond, has
been applied to the synthesis of a natural product. It was
found that dimerization did not occur spontaneously upon
oxidation in air, thus implying that some enzymatic assis-
tanceisinvolvedin Nature’ssynthesisofthese compounds,
despite the fact that natural parvistemin A is a racemate.
The route delineated above is high yielding and, by varying
the phosphonium salt used in the Wittig reaction, could
easily be adapted to the synthesis of other members of this
class of natural products.
Acknowledgment. We thank Dr. Ross Denton (Univer-
sity of Nottingham) for helpful discussions and the
EPSRC for funding (DTA award to C.C.N.).
Supporting Information Available. Full experimental
procedures, characterization data, and copies of 1H and
13C NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
In conclusion, the first total synthesis of parvistemin A
3a has been achieved using a biomimetic oxidative dimer-
ization of a 1,2,4-trihydroxybenzene derivative as the key
3398
Org. Lett., Vol. 13, No. 13, 2011