Concerning the Application of the
1
H NMR ABX Analysis for
Assignment of Stereochemistry to Aldols Deriving from Aldehydes
Lacking -Branches
Luiz C. Dias,*
,§
Andrea M. Aguilar,
§
Airton G. Salles Jr.,
§
Leonardo J. Steil,
§
and
William R. Roush*
,‡
Instituto de Quı ´mica, Universidade Estadual de Campinas, UNICAMP, C. P. 6154, CEP 13084-971,
Campinas, SP, Brazil, and Department of Chemistry, The Scripps Research Institute,
Jupiter, Florida 33458
ldias@iqm.unicamp.br; roush@scripps.edu
Received August 22, 2005
Attempts to apply the
1
H NMR ABX method for assignment of stereochemistry of -hydroxy ketones
to aldols 4-10 deriving from R-methyl aldehydes lacking -branches reveals that the presence of
a -branch in the aldehyde reaction partner is necessary so that the average chemical environment
of Ha and Hb is different for the Felkin and anti-Felkin aldols (see conformational pairs A/B and
C/D, respectively). When the chiral R-methyl aldehyde lacks a -branch, as in the case of the
aldehyde precursors to 4-10, the conformational energies of E and F (for the Felkin -hydroxy
ketone derivatives), and conformers G and H for the anti-Felkin aldols, are too close in energy
(within each pair), such that the average chemical and magnetic environments of Ha and Hb in
the two diastereomers cannot be easily distinguished. This analysis provides a rational basis for
application of the
1
H NMR ABX pattern analysis to other -hydroxy ketone derivatives.
Introduction
During studies on aldol addition reactions of enolbori-
nates from R-methyl--alkoxy methyl ketones,
1
we (the
Campinas group) have examined boron-mediated aldol
reactions of methyl ketones 1-3 with chiral aldehydes
leading to aldol adducts 4-11 (Figure 1).
2-6
These
compounds appeared ideally suited for stereochemical
analysis by using the very simple method for assigning
the relative stereochemistry of -hydroxy ketones re-
ported in 2002 by Roush and co-workers.
7
This method involves analysis of the ABX system for
the methylene unit R to the carbonyl group in the
1
H
NMR spectra of the -hydroxy ketones.
2,7
The Michigan
group reported that the
1
H NMR spectra (measured in
CDCl
3
or C
6
D
6
) of aldol adducts with 3,4-syn (or Felkin)
stereochemistry exhibit a characteristic doublet of dou-
§
Universidade Estadual de Campinas.
‡
The Scripps Research Institute.
(1) Dias, L. C.; Bau ´ , R. Z.; de Sousa, M. A.; Zuckerman-Schpector,
J. Org. Lett. 2002, 4, 4325.
(2) Liu, C. M.; Smith, W. J., III; Gustin, D. J.; Roush, W. R. J. Am.
Chem. Soc. 2005, 127, 5770.
(3) Reviews of the aldol reaction: (a) Cowden, C. J.; Paterson, I.
Org. React. 1997, 51, 1. (b) Franklin, A. S.; Paterson, I. Contemp. Org.
Synth. 1994, 1, 317. (c) Heathcock, C. H. In Comprehensive Organic
Synthesis; Heathcock, C. H., Ed.; Pergamon Press: New York, 1991;
Vol. 2, p 181. (d) Kim, B. M.; Williams, S. F.; Masamune, S. In
Comprehensive Organic Synthesis; Heathcock, C. H., Ed.; Pergamon
Press: New York, 1991; Vol. 2, p 239. (e) Paterson, I. In Comprehensive
Organic Synthesis; Heathcock, C. H., Ed.; Pergamon Press: New York,
1991; Vol. 2, p 301. (f) Braun, M. Angew. Chem., Int. Ed. Engl. 1987,
26, 24. (g) Heathcock, C. H. Asymmetric Synth. 1984, 3, 111. (h) Evans,
D. A.; Nelson, J. V.; Taber, T. R. Top. Stereochem. 1982, 13, 1.
(4) (a) Paterson, I.; Goodman, J. M. Tetrahedron Lett. 1989, 30, 997.
(b) Paterson, I.; Florence, G. J. Tetrahedron Lett. 2000, 41, 6935.
10.1021/jo051773e CCC: $30.25 © 2005 American Chemical Society
J. Org. Chem. 2005, 70, 10461-10465 10461 Published on Web 11/05/2005