SCHEME 1 Anti and Syn Diastereomers that Arise from (a)
Addition to Symmetrical Dialdehydes and (b) Reduction of
Symmetrical Diketones
Remote Asymmetric Induction about a Crowded
Aromatic Core
Andrew J. Lampkins, Osama Abdul-Rahim, and
Ronald K. Castellano*
Department of Chemistry, UniVersity of Florida,
P.O. Box 117200, GainesVille, Florida 32611-7200
ReceiVed April 13, 2006
(Scheme 1a)4 and reduction (Scheme 1b)3b,5 reactions of
symmetrical 1,2 (n ) 0)- and 1,3 (n ) 1)-dicarbonyl compounds
(and even specialized 1,4 (n ) 2)- or 1,5 (n ) 3)-dicarbonyl
substrates1g,5e,6,7) where cyclic (chelated) transition states8 and/
or rigid scaffolding are the basis for efficient communication
between the two developing chiral centers. Diastereocontrol is
generally lost, however, when the equivalent reactive centers
are remote (>1,4-) and a statistical 1:1 anti:syn product mixture
results.3b,h,5e,9 Described in this Note are among the first highly
Described are among the first highly diastereoselective, one-
pot organometallic addition and hydride reduction reactions
(>95% de) involving three symmetry-equivalent carbonyl
centers, each that bears a 1,5-relationship to its nearest
neighbor. Three-fold methyllithium addition to 2,4,6-tri-
methoxybenzene-1,3,5-tricarbaldehyde gives the anti,syn triol
exclusively (by 1H NMR); addition of HMPA to the reaction
or replacement of the substrate’s methoxy groups with ethyl
groups affords a statistical 3:1 (anti,syn:syn,syn) diastereo-
meric product ratio. Analogous asymmetric induction is
found upon hydride reduction (using LiAlH4 or NaBH4) of
the complementary triketone, 2,4,6-trimethoxybenzene-1,3,5-
triethanone. Chelation and steric (gearing) effects about the
crowded aromatic core contribute to the observed stereose-
lectivity.
(3) (a) Chong, J. M.; Clarke, I. S.; Koch, I.; Olbach, P. C.; Taylor, N. J.
Tetrahedron: Asymmetry 1995, 6, 409-418. (b) Quallich, G. J.; Keavey,
K. N.; Woodall, T. M. Tetrahedron Lett. 1995, 36, 4729-4732. (c) Prasad,
K. R. K.; Joshi, N. N. J. Org. Chem. 1996, 61, 3888-3889. (d) Kuwano,
R.; Sawamura, M.; Shirai, J.; Takahashi, M.; Ito, Y. Bull. Chem. Soc. Jpn.
2000, 73, 485-496. (e) Ohtsuka, Y.; Kubota, T.; Ikeno, T.; Nagata, T.;
Yamada, T. Synlett 2000, 535-537. (f) Aldous, D. J.; Dutton, D. M.; Steel,
P. G. Tetrahedron: Asymmetry 2000, 11, 2455-2462. (g) Zhou, H.-B.;
Zhang, J.; Lu¨, S.-M.; Xie, R.-G.; Zhou, Z.-Y.; Choi, M. C. K.; Chan, A. S.
C.; Yang, T.-K. Tetrahedron 2001, 57, 9325-9333. (h) Lagasse, F.;
Tsukamoto, M.; Welch, C. J.; Kagan, H. B. J. Am. Chem. Soc. 2003, 125,
7490-7491. (i) Sato, M.; Gunji, Y.; Ikeno, T.; Yamada, T. Synthesis 2004,
1434-1438.
(4) (a) Clausen, C.; Wartchow, R.; Butenschon, H. Eur. J. Org. Chem.
2001, 93-113. (b) Lemie`gre, L.; Lesetre, F.; Combret, J.-C.; Maddaluno,
J. Tetrahedron 2004, 60, 415-427.
(5) (a) Maier, G.; Roth, C.; Schmitt, R. K. Chem. Ber. 1985, 118, 704-
721. (b) Maier, G.; Schmitt, R. K.; Seipp, U. Chem. Ber. 1985, 118, 722-
728. (c) Barluenga, J.; Resa, J. G.; Olano, B.; Fustero, S. J. Org. Chem.
1987, 52, 1425-1428. (d) Tomooka, K.; Okinaga, T.; Suzuki, K.;
Tsuchihashi, G. Tetrahedron Lett. 1987, 28, 6335-6338. (e) Harada, T.;
Matsuda, Y.; Imanaka, S.; Oku, A. J. Chem. Soc., Chem. Commun. 1990,
1641-1643. (f) Bonini, C.; Bianco, A.; Difabio, R.; Mecozzi, S.; Proposito,
A.; Righi, G. Gazz. Chim. Ital. 1991, 121, 75-80. (g) Stiasny, H. C.
Synthesis 1996, 259-264. (h) Yamada, M.; Horie, T.; Kawai, M.;
Yamamura, H.; Araki, S. Tetrahedron 1997, 53, 15685-15690. (i)
Ravikumar, K. S.; Sinha, S.; Chandrasekaran, S. J. Org. Chem. 1999, 64,
5841-5844. (j) Bartoli, G.; Bosco, M.; Bellucci, M. C.; Dalpozzo, R.;
Marcantoni, E.; Sambri, L. Org. Lett. 2000, 2, 45-47. (k) Clerici, A.;
Pastori, N.; Porta, O. Eur. J. Org. Chem. 2002, 3326-3335.
(6) Although modest diastereomeric ratios are generally observed.
Diastereoselectivity is definitively not found for alkene conjugated 1,4-
diketones; see: Fleming, I.; Kuhne, H.; Takaki, K. J. Chem. Soc., Perkin
Trans. 1 1986, 725-728.
(7) The remote stereocontrol demonstrated in addition and reduction
reactions involving 1,5- and 1,6-hydroxyketones (mediated by metal
chelation) by Maryanoff and co-workers is mechanistically relevant: (a)
Zhang, H.-C.; Harris, B. D.; Costanzo, M. J.; Lawson, E. C.; Maryanoff,
C. A.; Maryanoff, B. E. J. Org. Chem. 1998, 63, 7964-7981. (b) Lawson,
E. C.; Zhang, H. C.; Maryanoff, B. E. Tetrahedron Lett. 1999, 40, 593-
596.
(8) (a) Cram, D. J.; Wilson, D. R. J. Am. Chem. Soc. 1963, 85, 1245-
1249. (b) Cram, D. J.; Wilson, D. R. J. Am. Chem. Soc. 1963, 85, 1249-
1257. (c) Reetz, M. T. Acc. Chem. Res. 1993, 26, 462-468. (d) Mengel,
A.; Reiser, O. Chem. ReV. 1999, 99, 1191-1223.
(9) (a) Neudeck, H.; Schlo¨gl, K. Monatsh. Chem. 1975, 106, 229-259.
(b) Rodr´ıguez, D.; Castedo, L.; Dom´ınguez, D.; Saa´, C. Org. Lett. 2003, 5,
3119-3121.
Modern organic synthesis offers numerous strategies to exert
stereocontrol in addition and reduction reactions at single
prochiral carbonyl centers (i.e., aldehydes and ketones) in
acyclic, achiral substrates and these have been extensively
reviewed.1 Suitable chiral additives (e.g., reagents or catalysts)
can be used analogously to achieve high anti:syn diastereomeric
ratios and high enantioselectivities (for the otherwise racemic
diol product) in the addition2 and reduction3 reactions of two
symmetry-equivalent carbonyl centers in one-pot reactions
(Scheme 1). Unique to these substrates is the potential to realize
moderate to excellent diastereomeric excesses even in the
absence of a chiral additive. Such is the case for the addition
(1) (a) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds;
John Wiley & Sons: New York, 1994. (b) Oishi, T.; Nakata, T. Acc. Chem.
Res. 1984, 17, 338-344. (c) Soai, K.; Niwa, S. Chem. ReV. 1992, 92, 833-
856. (d) Sailes, H.; Whiting, A. J. Chem. Soc., Perkin Trans. 1 2000, 1785-
1805. (e) Noyori, R.; Ohkuma, T. Angew. Chem., Int. Ed. 2001, 40, 40-
73. (f) Pu, L.; Yu, H.-B. Chem. ReV. 2001, 101, 757-824. (g) Mikami, K.;
Shimizu, M.; Zhang, H. C.; Maryanoff, B. E. Tetrahedron 2001, 57, 2917-
2951. (h) Goldfuss, B. Synthesis 2005, 2271-2280.
(2) (a) Soai, K.; Inoue, Y.; Takahashi, T.; Shibata, T. Tetrahedron 1996,
52, 13355-13362. (b) Ramachandran, P. V.; Chen, G. M.; Brown, H. C.
Tetrahedron Lett. 1997, 38, 2417-2420.
10.1021/jo060794l CCC: $33.50 © 2006 American Chemical Society
Published on Web 06/22/2006
J. Org. Chem. 2006, 71, 5815-5818
5815