ortho-quinone methides from para-quinones: Total synthesis of rubioncolin B

Article abstract of DOI:10.1021/ja803498r

A concise synthesis of rubioncolin B is described, which features an unprecedented intramolecular Diels-Alder reaction involving an ortho-quinone methide and a naphthofuran moiety. The ortho-quinone methide is generated through a surprisingly facile tautomerization of a para-quinone. Copyright

Full text of DOI:10.1021/ja803498r

Published on Web 06/27/2008
ortho-Quinone Methides from para-Quinones: Total Synthesis of Rubioncolin B
Jean-Philip Lumb, Kevin C. Choong, and Dirk Trauner*
Department of Chemistry, UniVersity of California, Berkeley, California 94720
Received May 10, 2008; E-mail: trauner@berkeley.edu
Scheme 1. Retrosynthetic Analysis of Rubioncolin B
ortho-Quinone methides have proven to be remarkably versatile
reactive intermediates, and many methodologies, generally relying on
benzylic activation of ortho-substituted phenols, have been developed
to access them.1 In Nature, ortho-quinone methides appear to be often
formed via tautomerization of alkyl-substituted para-quinones (eqs 1
and 2).2 This surprisingly facile tautomerization can be a powerful
tool in total synthesis as well. Recently, we reported the tautomeriza-
tion/electrocyclization of prenylated para-quinones as a strategy for
the synthesis of chromene natural products (eq 1).3 Herein, we show
that this method can be modified to include intramolecular Diels-Alder
(IMDA) cycloadditions (eq 2).4 These efforts have resulted in a concise
total synthesis of the complex naphthohydroquinone dimer rubioncolin
B (1).
Scheme 2. Synthesis of the Tertiary Alcohola
Rubioncolin B (1) belongs to a class of unusual naphthohydro-
quinones isolated from the roots of Rubia oncotricha and R. cordifolia.5
The genus Rubia is well-known as a prolific source of biologically
active anthraquinones and naphthoquinones that are administered in
traditional Chinese and Ayurvedic medicine.6 Of these, the 6-hydroxy-
2H-chromene mollugin (5) is perhaps the most widely studied.
Interestingly, only a handful of dimeric natural products have been
isolated from Rubia, and each of these is found in racemic form.7
We reasoned that the complex molecular architecture of 1 could be
rapidly assembled via an intramolecular Diels-Alder reaction involv-
ing an ortho-quinone methide as the diene and a naphthofuran as the
dieneophile (Scheme 1). Retrosynthetically, this disconnection would
provide 2, which would be in equilibrium with its para-quinone
tautomer 3. In line with our hypothesis, density functional theory (DFT)
calculations, performed at the B3LYP/6-31G** level of theory, indicate
that the electronic energy (E) of the ground-state conformer of 2 is
favored over 3 by 4 kcal/mol. In addition, 1 is energetically favored
over 3 by 18 kcal/mol.8 In light of these calculations, we were confident
that a synthesis of 3 would readily provide the necessary ortho-quinone
methide for the formation of rubioncolin B. However, the feasibility
of the Diels-Alder reaction remained uncertain, as few examples of
benzo- or naphthofurans serving as dienophiles have been reported.9
Our key intermediate 3 could be formed via oxidation of a hydro-
quinone precursor, whose synthesis would hinge on the esterification
of a tertiary alcohol and a benzylic carboxylic acid.
a Reagents and conditions: (a) CAN (2 equiv), H2O/CH3CN (1:1), 0 °C, 15
min, 99%; (b) K2CO3 (5 equiv), DMF, 100 °C, 1 h, 70%; (c) Me2SO4, K2CO3,
(CH3)2CO, 23 °C, 12 h, 90%; (d) LDA (1.1 equiv), THF, -78 °C, 1 h;
(CH3)2CO (15 equiv), -78 to 0 °C, 1 h; NH4Cl, 0 °C, 84%.
Synthesis of the requisite tertiary alcohol began from the natural
product mollugin (5), whose biomimetic synthesis from 4 has been
reported (Scheme 2).3 Oxidation of 5 afforded 6, which was converted
to furomollugin (9)5 under basic conditions. This transformation pre-
sumably involves cyclization of para-quinone 7 to provide 8, followed
9
9230 J. AM. CHEM. SOC. 2008, 130, 9230–9231
10.1021/ja803498r CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3. Synthesis of Rubioncolin B via An Oxidation/Tautomerization/Diels-Alder Cycloaddition Cascadea
a Reagents and conditions: (a) allyltributyltin (1.1 equiv), BF3 ·Et2O (1.1 equiv), CH2Cl2, -78 °C, 90 min; H2O, 0 °C; TBSOTf (3 equiv), 2,6-lutidine (5 equiv),
CH2Cl2, 0 °C, 2 h, 35%; (b) K2OsO4 (0.01 equiv), NaIO4 (5 equiv), 1,4-dioxane, H2O, 23 °C, 12 h; NaClO2 (9 equiv), NaH2PO4 (7 equiv), 2-methyl-2-butene,
tert-butanol, 23 °C, 3 h, 45%; (c) i. (COCl)2 (1.5 equiv), DMF (1 drop), CH2Cl2, 2 h, 23 °C, then concentrate in vacuo; ii. 11 (1.2 equiv), Et3N (5 equiv), CH2Cl2,
23 °C, 12 h, 70%; (d) PhI(OAc)2 (1.1 equiv), TASF (2.1 equiv), CH3CN/H2O (20:1), 23 °C, 2 h, 60%; (e) BBr3 (1.1 equiv), CH2Cl2, -78 °C, 15 min, 95%. TASF
) tris(dimethylamino)sulfonium difluorotrimethylsilicate.
by expulsion of acetone to afford 9. Methylation, followed by lithiation
(f10) and addition to acetone afforded the tertiary alcohol 11.
Coupling partner 14 was synthesized in two straightforward steps
from the known naphthoquinone 1210 (Scheme 3; see Supporting
Information for details). The key esterification was accomplished by
conversion of 14 to the acid chloride 15, followed by exposure to 11
in the presence of triethylamine to provide hydroquinone bis-TBS ether
16 in 70% yield.
Acknowledgment. We thank Novartis, Roche Biosciences, and
the Lawrence Berkeley National Laboratory for supporting this work
and Pfizer Pharmaceuticals and the ACS Organic Division for a
predoctoral fellowship to J.-P.L. We also thank Dr. Jamin Krinsky
and Dr. Kathy Durkin for assistance with computations, and Dr. Fred
Hollander for X-ray structure analysis.
Supporting Information Available: Detailed synthetic and compu-
tational protocols. This material is available free of charge via the Internet
at http://pubs.acs.org.
Initial attempts to elaborate 16 to the para-quinone were met with
difficulties as both acidic and basic conditions resulted in cleavage of
the benzylic ester. However, exposure of 16 to 2 equiv of TASF in
the presence of PhI(OAc)2 directly proVided rubioncolin B methyl ether
(22) in 60% isolated yield. Deprotection of 22 in the presence of BBr3
afforded synthetic rubioncolin B (1), whose structure was confirmed
by X-ray analysis (Scheme 1; see Supporting Information for details).
Presumably, this oxidation/tautomerization/Diels-Alder cascade
begins by TASF-mediated desilylation to provide a phenoxide 17.
Oxidation with PhI(OAc)2 then provides oxonium ion 18, which is
readily desilylated by a second equivalent of TASF, yielding quinone
19. As anticipated, 19 is in equilibrium with its ortho-quinone methide
tautomer 20. Endo transition state 21 was located at the B3LYP/6-
31G** level and is merely 15 kcal/mol higher in energy than the
ground-state conformation of 20. Therefore, once formed, 20 should
undergo a facile cycloaddition to afford rubioncolin B methyl ether
(22).
References
(1) For a comprehensive review, see: Van de Water, R. W.; Pettus, T. R. R.
Tetrahedron 2002, 58, 5367–5405. For recent examples in total synthesis,
see: Bulger, P. G.; Bagal, S. K.; Marquez, R Nat. Prod. Rep. 2008, 25,
254–297, and references therein.
(2) Peter, M. G. Angew. Chem., Int. Ed. Engl. 1989, 28, 555–570.
(3) Lumb, J. P.; Trauner, D. Org. Lett. 2005, 7, 5865–5868.
(4) A tautomerization/intermolecular cycloaddition has been reported by
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Chem., Int. Ed. 2005, 44, 7917–7921.
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1993, 41, 1869–1872, and references therein.
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1264.
(7) For the biomimetic synthesis of another member in this family, see: Lumb,
J. P.; Trauner, D. J. Am. Chem. Soc. 2005, 127, 2870–2871.
(8) Jaguar, version 6.5; Schro¨dinger, LLC: New York, NY, 2006. See
Supporting Information for details.
(9) (a) Ciganek, E. J. Am. Chem. Soc. 1981, 103, 6261–6262, and references
therein. (b) An intramolecular Diels–Alder addition to a benzofuran has
been used in a total synthesis of morphine. Gilbert Stork, private
communication. (c) Chen, C. H.; Rao, P. D.; Liao, C. C. J. Am. Chem.
Soc. 1998, 120, 13254–13255. (d) Noland, W. E.; Kedrowski, B. L. J. Org.
Chem. 1999, 64, 596–603.
(10) For a synthesis of quinone 12, see: Barker, D.; Brimble, M. A.; Do, P.;
Turner, P. Tetrahedron 2003, 59, 2441–2449. For a similar Sakurai-type
allylation, see: Uno, H. J. Org. Chem. 1986, 51, 350–358.
We believe that our synthesis sheds light onto the biosynthetic origin
of rubioncolin B. The spontaneous conversion of 19 into 22 provides
further evidence that ortho-quinone methides can be formed in Nature
via facile tautomerization of para-quinone precursors. This process
does not necessitate enzymatic assistance and, as a result, provides a
reasonable explanation for the isolation of 1 as a racemate.
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