C O M M U N I C A T I O N S
Table 2. Intramolecular Aldehyde-Ketone Benzoin Reactionsa
Scheme 2
Hydrolysis of 18 afforded dantron (19), which was in all respects
identical to an authentic sample.
In conclusion, we have reported a novel approach to the synthesis
of stereodefined preanthraquinones via the first crossed aldehyde-
ketone benzoin reaction. This process offers a simple and remark-
ably mild entry to useful, orthogonally protected polycyclic
quinones with a high degree of regio- and stereoselectivity. The
discovery that ketones can serve as electrophiles for benzoin-type
processes opens new pathways for the development of catalytic,
stereoselective reactions.13,14
Acknowledgment. We are grateful to Dr. Hidehiro Uekusa for
the X-ray analysis of 10. J.W.B. thanks the Japan Society for the
Promotion of Science for a postdoctoral fellowship. Partial support
was provided by the 21st Century COE Program.
Supporting Information Available: Experimental procedures and
characterization for benzoin products and X-ray crystallographic data
for 10 (PDF and CIF). This material is available free of charge via the
References
(1) Schneider, C. Angew. Chem., Int. Ed. 1998, 37, 1375-1378.
(2) For leading references, see: (a) Ro¨mpp Encyclopedia of Natural Products;
Steglich, W., Fugmann, B., Lang-Fugmann, S., Eds.; Georg Thieme
Verlag: Stuttgart, 2000. (b) Thomas, R. ChemBioChem 2001, 2, 612-
627.
(3) Krohn, K.; Rohr, J. In Bioorganic Chemistry; Rohr, J., Ed.; Topics in
Current Chemistry 188; Springer: Berlin, 1997; pp 127-195.
(4) (a) Gallagher, P. T. Contemp. Org. Synth. 1996, 3, 433-446. (b) Mitchell,
A. S.; Russell, R. A. Tetrahedron 1995, 51, 5207-5236.
(5) Preanthraquinones were defined in ref 2a as “polyketide anthraquinones,
in which the aromatic ring is not completely formed.”
(6) (a) Bode, J. W.; Hachisu, Y.; Matsuura, T.; Suzuki, K. Tetrahedron Lett.
2003, 44, 3555-3558. (b) Bode, J. W.; Hachisu, Y.; Matsuura, T.; Suzuki,
K. Org. Lett. 2003, 5, 391-394. (c) Bode, J. W.; Suzuki, K. Tetrahedron
Lett. 2003, 44, 3559-3563.
(7) All isoxazole aldehydes were prepared by cyclocondensation of readily
prepared, stable nitrile oxides and commercially available diketones,
followed by acetal deprotection. For procedures, see ref 6 and Supporting
Information.
(8) (a) Kitamura, M.; Ohmori, K.; Kawase, T.; Suzuki, K. Angew. Chem.,
Int. Ed. 1999, 38, 1229-1232. (b) Ohmori, K.; Kitamura, M.; Suzuki, K.
Angew. Chem., Int. Ed. 1999, 38, 1226-1229. (c) Matsumoto, T.;
Yamaguchi, H.; Tanabe, M.; Yasui, Y.; Suzuki, K. Tetrahedron Lett. 2000,
41, 8393-8396.
(9) For reviews, see: (a) Ide, W. S.; Buck, J. S. Org. React. 1948, 4, 269-
304. (b) Stetter, H.; Kuhlmann, H. Org. React. 1991, 40, 407-496. (c)
Hassner, A.; Rai, K. M. L. In ComprehensiVe Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; pp 1: 541-
577.
a Unless otherwise indicated, all reactions were performed at 0.05 M in
tBuOH at 40 °C for 0.5 h using 20 mol % 4 and 70 mol % DBU. b Yield
refers to the chemical yield of isolated, analytically pure products. c This
reaction was performed at 0.1 M using 5 mol % 4 and 10 mol % DBU.
d Determined by 1H NMR analysis of the unpurified reaction products. For
comparison, the other stereoisomer was obtained under alternative reaction
conditions. e Relative stereochemistry assigned by analogy to 10. f Structure
determined by X-ray analysis.
The isoxazole moiety serves as a convenient masking group for
the synthesis of anthraquinoid structures; however, it is not a
prerequisite for the crossed benzoin reaction, and keto-aldehyde
15 gave benzoin product 16 in good yield, albeit in competition
with intramolecular aldol product 17 (Scheme 1).12
Scheme 1
(10) For examples of intramolecular benzoin reactions, see: (a) Gleiter, R.;
Krennich, G. Angew. Chem., Int. Ed. Engl. 1986, 25, 449-450. (b)
Cookson, R. C.; Lane, R. M. J. Chem. Soc., Chem. Commun. 1976, 804-
805.
(11) Stetter, H.; Kuhlmann, H. Org. Synth. 1984, 62, 170-178.
(12) At the current stage of development, we have found this reaction to be
viable for a variety of keto-aldehydes, including aliphatic systems. Further
reaction development to exclude the competing aldol processes as well
as mechanistic studies are underway and will be reported in due course.
(13) For enantioselective catalysts for intermolecular benzoin and intramolecular
Stetter reactions, see: (a) Enders, D.; Kallfass, U. Angew. Chem., Int.
Ed. 2002, 41, 1743-1745. (b) Kerr, M. S.; de Alaniz, J. R.; Rovis, T. J.
Am. Chem. Soc. 2002, 124, 10298-10299.
Although we expect the full potential of this reaction to be
realized in its application to stereochemically elaborate polycyclic
compounds, the ease of starting material preparation, rapid reaction
times, and complete regiocontrol already offer a useful protocol
for the synthesis of functionalized anthraquinones. Benzoin product
2 was readily converted to imino-anthraquinone 18 by a one-pot
procedure simply by treatment with Pd/C in a hydrogen atmosphere
followed by in situ Pd-catalyzed oxidation in air (Scheme 2).
(14) For the use of imines as electrophiles in a benzoin-type reaction, see: (a)
Murry, J. A.; Frantz, D. E.; Soheili, A.; Tillyer, R.; Grabowski, E. J.;
Reider, P. J. J. Am. Chem. Soc. 2001, 123, 9696-9697. (b) Katritzky, A.
R.; Cheng, D.; Musgrave, R. P. Heteroycles 1996, 42, 273-281.
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