Organic Letters
Letter
Csp3 attached-ring system with high control of stereo- and
regioselectivity, forming one out of eight possible isomers.
Assembly of the core Csp3−Csp3 attached-ring system
allowed us to pursue the late-stage Hauser−Kraus annulation
and Mizoroki-Heck reaction (Scheme 2). Removal of the silyl
group with TBAF provided the free phenol of 4. Higher
equivalents (>1.5) of TBAF epimerized the C18 lactone
center, hinting toward its propensity to undergo stereo-
chemical reconfiguration, possibly through either an addition
to the C18 lactone center or deprotonation at the C18 position
of the vinylogous ester. Oxidation of the free phenol with
(diacetoxyiodo)benzene (PIDA) formed the p-quinone
monoketal 17 in 60% yield over two steps.
Initial examination of the Hauser-Kraus annulation with
typical bases such as lithium diisopropylamide (LDA) or the
dimsyl anion with matching equivalents of p-quinone
monoketal 17 and sulfone 18, accessible in six steps from
commercially available starting materials,20 gave poor yields of
the bright red anthraquinone solid 3 (see the Supporting
Information for more details).21 Use of lithium tert-butoxide
(LTB) as a base gave an increase in yields; however, at higher
base equivalents (>3) or upon heating, scrambling of the C18
stereocenter was observed to give undesired epimer 19
through either addition of the butoxide and opening of the
ring system or through a deprotonation event to give an
alkoxyfuran species that reprotonates on the opposite face.
Careful examination of base equivalents led us to employ 2.65
equiv of LTB to achieve high yield of anthraquinone 3 with
preservation of stereochemistry. The absolute stereochemistry
of the undesired C18 epimer 19 formed in the Hauser−Kraus
reaction with excess base was confirmed by X-ray crystallog-
raphy, which also further established our stereochemical
assignment of the allylation preceding this step.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
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sı
Experimental procedures, spectroscopic data, crystallo-
graphic data, and NMR comparison for synthetic and
previously isolated (+)-rubellin C (PDF)
Accession Codes
tallographic data for this paper. These data can be obtained
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
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Uttam K. Tambar − Department of Biochemistry, University of
Texas Southwestern Medical Center, Dallas, Texas 75390-
Author
Jackson A. Gartman − Department of Biochemistry, University
of Texas Southwestern Medical Center, Dallas, Texas 75390-
Complete contact information is available at:
Notes
The authors declare no competing financial interest.
To complete the synthesis, we attempted triflation,
subsequent Mizoroki−Heck reaction, and deprotection of the
near-complete rubellin system (Scheme 2). Treatment of
anthraquinone 3 with excess sodium hydride in CH2Cl2
followed by addition of trifluoromethanesulfonic anhydride
(Tf2O) and pyridine supplied the triflate with minimal loss of
stereochemical fidelity at the C18 center, which was
immediately used in the subsequent Mizoroki−Heck reaction
to deliver one diastereomer of the rubellin architecture 20,
with its stereochemistry confirmed by NOE correlations.
Surprisingly, O-demethylation proved challenging; after vast
screening of conditions, the mild nucleophilic iodide source
magnesium iodide etherate suitably removed all of the methyl
groups at higher temperatures.22 Acidic hydrolysis of the
acetonide produced one enantiomer of the natural product
(+)-rubellin C (1), whose characterization data matched that
described in the literature.4 Our synthetic efforts therefore also
confirm the absolute stereochemistry reported of natural
(+)-rubellin C (1).
The first total synthesis of a member of the rubellin family of
natural products has been accomplished with high stereo-
selectivity in 16 steps (longest linear sequence) from readily
available D-(−)-quinic acid (7). The expedient construction of
the core ring system relied on an efficient sequence of steps to
install topological and stereochemical complexity, which may
provide the means to explore structure−activity relationships.
Exploration of these methods, the syntheses of the remaining
rubellins, and biological studies are currently underway in our
laboratory.
ACKNOWLEDGMENTS
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Financial support was provided by the W. W. Caruth, Jr.
Endowed Scholarship, Welch Foundation (I-1748), National
Institutes of Health (R01GM102604), American Chemical
Society Petroleum Research Fund (59177-ND1), Teva
Pharmaceuticals Marc A. Goshko Memorial Grant (60011-
TEV), and Sloan Research Fellowship. J.A.G. gratefully
acknowledges an NIH Pharmacological Sciences Training
Grant (GM007062). We thank Vincent Lynch (UT Austin)
for X-ray crystal structural analysis, Hamid Baniasadi (UTSW)
for high-resolution mass spectrometry assistance, and Jef De
Brabander (UTSW), Joseph Ready (UTSW), Chuo Chen
(UTSW), Tian Qin (UTSW), and Myles Smith (UTSW) for
productive discussions. We also thank our diverse collection of
lab members for creating an environment that supported the
success of this project.
REFERENCES
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drugs. Expert Opin. Drug Discovery 2006, 1, 549−568. (b) Scott, L. J.;
CNS Drugs 2004, 18, 379−396. (c) Oshio, H.; Imai, S.; Fujioka, S.;
Bull. 1974, 22, 823−831. (d) Fidelix, T. S. A.; Macedo, C. R.;
Cochrane Database of Systematic Reviews 2014, 2, 1−56.
(2) (a) Altersolanols: Debbab, A.; Aly, A. H.; Edrada-Ebel, R.;
Wray, V.; Mueller, W. E. G.; Totzke, F.; Zirrgiebel, U.; Schaechtele,
D
Org. Lett. XXXX, XXX, XXX−XXX