Concerning the application of the1H NMR ABX analysis for assignment of stereochemistry to aldols deriving from aldehydes lacking β-branches

Article abstract of DOI:10.1021/jo051773e

Attempts to apply the ₁H NMR ABX method for assignment of stereochemistry of β-hydroxy ketones to aldols 4-10 deriving from α-methyl aldehydes lacking β-branches reveals that the presence of a β-branch in the aldehyde reaction partner is necess

Full text of DOI:10.1021/jo051773e

1
Concerning the Application of the H NMR ABX Analysis for
Assignment of Stereochemistry to Aldols Deriving from Aldehydes
Lacking â-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 1H NMR ABX method for assignment of stereochemistry of â-hydroxy ketones
to aldols 4-10 deriving from R-methyl aldehydes lacking â-branches reveals that the presence of
a â-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 â-branch, as in the case of the
aldehyde precursors to 4-10, the conformational energies of E and F (for the Felkin â-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
1
application of the H NMR ABX pattern analysis to other â-hydroxy ketone derivatives.
Introduction
This method involves analysis of the ABX system for
1
the methylene unit R to the carbonyl group in the H
During studies on aldol addition reactions of enolbori-
nates from R-methyl-â-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 â-hydroxy ketones re-
ported in 2002 by Roush and co-workers.7
NMR spectra of the â-hydroxy ketones.2,7 The Michigan
1
group reported that the H NMR spectra (measured in
CDCl3 or C6D6) of aldol adducts with 3,4-syn (or Felkin)
stereochemistry exhibit a characteristic doublet of dou-
(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.
§ 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.
10.1021/jo051773e CCC: $30.25 © 2005 American Chemical Society
Published on Web 11/05/2005
J. Org. Chem. 2005, 70, 10461-10465
10461

Dias et al.
FIGURE 1. Synthesis of aldols 4-11.
blet for Ha with a large Ja,x (7.8-10.0 Hz) downfield of
the resonance for Hb, which shows a small Jb,x (1.1-5.4
Hz). For anti-Felkin aldol adducts (3,4-anti), the 1H NMR
displays the downfield resonance for Ha with a small Ja,x
(1.5-2.8 Hz), and the higher field resonance for Hb, with
a larger Jb,x (9.2-12.5 Hz). These results are consistent
with the aldols adopting the internally hydrogen-bound
conformations indicated in Figure 2.
It was also noted that Hb of the anti-Felkin diastereo-
isomers appears downfield from Hb of the Felkin isomer,
while Ha of the Felkin aldol appears downfield of Ha in
the anti-Felkin diastereoisomer. The authors also ob-
served that Hx resonance for the Felkin aldols appears
downfield of Hx in the corresponding anti-Felkin dia-
stereomers.7
Reported herein is a refinement of the previously
reported model,7 supported by data for aldols 4-11, that
demonstrates that a â-branch in the original aldehyde
reaction partner is necessary to create magnetically
distinct NMR environments for Ha and Hb in the
diastereomeric aldol products.
(5) (a) Evans, D. A.; Coleman, P. J.; Coˆte´, B. J. Org. Chem. 1997,
62, 788. (b) Evans, D. A.; Trotter, B. W.; Coleman, P. J.; Coˆte´, B.; Dias,
L. C.; Rajapakse, H. A.; Tyler, A. N. Tetrahedron 1999, 29, 8671. (c)
Paterson, I.; Collett, L. A. Tetrahedron Lett. 2001, 42, 1187. (d)
Paterson, I.; Gibson, K. R.; Oballa, R. M. Tetrahedron Lett. 1996, 37,
8585. (e) Tanimoto, N.; Gerritz, S. W.; Sawabe, A.; Noda, T.; Filla, S.
A.; Masamune, S. Angew Chem., Int. Ed. Engl. 1994, 33, 673. (f) Roush,
W. R.; Bannister, T. D.; Wendt, M. D.; Jablonowski, J. A.; Scheidt, K.
A. J. Org. Chem. 2002, 67, 4275.
Results and Discussion
1
(6) Arefolov, A.; Panek. J. S. Org. Lett. 2002, 4, 2397.
Pertinent H NMR data for compounds 4-11 appear
(7) Roush, W. R.; Bannister, T. D.; Wendt, M. D.; VanNieuwenhze,
M. S.; Gustin, D. J.; Dilley, G. J.; Lane, G. C.; Scheidt, K. A.; Smith,
W. J., III J. Org. Chem. 2002, 67, 4284.
in Figure 3 and Table 1. During attempts to assign the
relative stereochemistry of aldols 4-11 by using the
10462 J. Org. Chem., Vol. 70, No. 25, 2005

Assignment of Stereochemistry to Aldols
SCHEME 1. Stereostructure Assignments for
Aldols 4 and 5
1
FIGURE 2. Summary of the H NMR ABX pattern analysis
for stereochemical assignments of â-hydroxy ketones.
The vast majority of the compounds examined in the
2002 Roush paper7 were aldols deriving from â-branched
aldehydes with a large “R” group (as is the case for the
aldol reaction leading to 11).9 In these cases, conforma-
tion A (Figure 4) is believed to be the major conformer
for the Felkin diastereomers, as the large “R” substituent
is positioned anti to CR-Câ in the internally hydrogen-
bound conformation of the aldol product.7,10 (In contrast,
the “R” substituent is in a higher energy gauche relation-
ship with CR-Câ in B.) Similarly, conformation D is
believed to be the most important for the anti-Felkin
aldols, when the “R” substituent is branched (note the
gauche relationship between “R” and CR-Câ in confor-
mation C). As long as these conformational preferences
apply, Ha and Hb in the Felkin and anti-Felkin aldol
products are in very different (average) magnetic envi-
ronments, giving rise to the characteristic visual and
diagnostic ABX 1H NMR patterns previously described.7
The situation is much different for aldols deriving from
aldehydes lacking â-branches (such as 4-10, vide supra).
In these cases, the steric size of “ROCH2-” and “Me-”
is comparable, and as a result the difference in energy
between conformations E and F for the Felkin aldol
diastereomers, and between G and H for the anti-Felkin
diasteomers, is negligible (Figure 5). Conformers E and
G are pseudo-enantiomeric, as are F and H. Conse-
quently, the average chemical environment of Ha and Hb
in the two diastereomers is comparable, and the NMR
properties of Ha (and Hb) in the Felkin and anti-Felkin
diastereomers are not easily distinguishable.
TABLE 1. Selected 1H NMR Data for Aldols 4-11a
compd
Ha (δ)
Hb (δ)
Ja,x (Hz)
Jb,x (Hz)
4
2.73
2.73
2.72
2.76
2.71
2.40
2.41
2.78
2.58
2.51
2.58
2.49
2.55
2.29
2.18
2.58
8.7
9.0
8.9
9.5
8.7
8.9
9.3
2.6
3.0
3.3
3.0
2.9
2.9
2.9
2.7
8.6
5
6
7
8
9b
10b
11
a All NMR data are reported in C6D6 as solvent except for aldol
11 (measured in CDCl3). b 1H NMR data for 9 and 10 were
measured in the 58:42 diastereoisomeric mixture.
NMR method reported by Roush and co-workers,7 we
observed that in all of the cases studied with aldehydes
lacking â-branching, leading to aldols 4-10, the down-
field resonance for Ha exhibits a doublet of doublet with
a large coupling constant. On the basis of the results
disclosed by Roush et al.,7 this should be consistent with
a Felkin aldol product.
However, in one of the casessspecifically aldol 4swe
prepared the corresponding benzylidene acetal 12 by
treatment of 4 with DDQ (Scheme 1).8 Analysis of the
1H NMR coupling constants, specifically J ) 9.9 Hz,
proved that Ha and Hb are both axial in 12. This
indicates that benzylidene acetal 12 derives from an anti-
Felkin aldol product.
Similarly, the relative stereochemistry of aldol 5 was
determined after conversion to the p-methoxybenzylidene
acetal 13 by DDQ oxidation of the PMB ether. The
coupling constant measured between Ha and Hb (J )
2.1 Hz) in 13 confirmed the Felkin stereochemistry for
aldol 5.
In conclusion, the data summarized here for aldols
1
4-10 demonstrate that the H NMR ABX method for
assignment of stereochemistry of â-hydroxy ketones is
of limited utility for aldols deriving from R-methyl
1
In contrast to the situation with 4-10, the H NMR
(9) Only one set of aldols deriving from an aldehyde lacking a
â-branch was presented in the 2002 J. Org. Chem. paperscompounds
27 and 49 reported therein (ref 7). The data for 27 were consistent
with the 1H ABX NMR pattern analysis, but the coupling constants
and proton assignments for anti-Felkin aldol 49 could not be made
(as reported in footnote e of Table 2 in the 2002 publication).
(10) Heathcock, C. H.; Pirrung, M.; Sohn, J. E. J. Org. Chem. 1979,
44, 4294.
data measured for compound 11 were completely consis-
tent with the assignment of the anti-Felkin aldol stere-
ochemistry by application of the ABX NMR method.7
(8) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982,
23, 889.
J. Org. Chem, Vol. 70, No. 25, 2005 10463

Dias et al.
FIGURE 3. 1H NMR characterization of aldols 4-11.
FIGURE 5. Analysis of the hydrogen-bound conformations
of Felkin and anti-Felkin â-hydroxy ketones in cases where
the â-carbon of the precursor RCHO is unbranched.
FIGURE 4. Hydrogen-bound conformations of Felkin and
anti-Felkin â-hydroxy ketones in Cases where “R” is a large
(branched) substituent.
Felkin aldols, are too close in energy (within each pair),
such that the average chemical and magnetic environ-
ments of Ha and Hb in the two diastereomers cannot be
easily distinguished. In such cases, one must resort to
chemical derivatization methods to make appropriate
stereochemical assignments.
The analysis presented herein provides a rational basis
for other investigators to apply the 1H NMR ABX pattern
analysis to other â-hydroxy ketone derivatives.
aldehydes lacking â-branches. The presence of the
â-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 â-branch, as in the
case of the aldehyde precursors to 4-10, the conforma-
tional energies of E and F (for the Felkin â-hydroxy
ketone derivatives), and conformers G and H for the anti-
10464 J. Org. Chem., Vol. 70, No. 25, 2005

Assignment of Stereochemistry to Aldols
Experimental Section11
v/v) solution. The ice bath was removed and the reaction
was allowed to warm to room temperature and stirred
for 1 h. The solution was diluted with CH2Cl2 and water,
the layers were separated, and the aqueous layer was
extracted with CH2Cl2. The combined organic extracts
were washed with water and brine, dried (MgSO4), and
concentrated in vacuo. Purification of the products by
silica gel chromatography gave the aldol adducts.
Representative Procedure for Methyl Ketone
Aldol Reaction. Dicyclohexylboron chloride (1.5 equiv)
was added to a cooled (0 °C) solution of the corresponding
methyl ketone (1.5 equiv) in CH2Cl2 (8 mL), followed by
dropwise addition of Et3N (1.7 equiv), leading to the
precipitation of Et3N‚HCl. The resulting white hetero-
geneous reaction mixture was stirred at 0 °C for 1 h, then
cooled to -78 °C, and a solution of the aldehyde (1.5
equiv) in CH2Cl2 was added dropwise (aldehyde was
added as a 1.0 M solution in CH2Cl2). After 4 h at -78
°C and 10 h at -20 °C, the reaction mixture was
quenched by addition of 7 mL of a pH 7 buffer/MeOH
solution (1/6, v/v), and 2 mL of a 30% H2O2/MeOH (1/2,
Acknowledgment. L.C.D. is grateful to FAPESP
and CNPq (Brazil) for financial support. W.R.R. grate-
fully acknowledges the National Institutes of Health for
financial support (GM 38436).
Supporting Information Available: Product character-
ization for compounds 4-12. This material is available free
of charge via the Internet at http://pubs.acs.org.
(11) New compounds and the isolated intermediates gave satisfac-
tory 1H and 13C NMR, IR, and HRMS data. Yields refer to chromato-
graphically and spectroscopically homogeneous materials. Tabulations
of spectroscopic data are provided in the Supporting Information.
JO051773E
J. Org. Chem, Vol. 70, No. 25, 2005 10465