The first direct and enantioselective cross-aldol reaction of aldehydes

Article abstract of DOI:10.1021/ja0262378

The first enantioselective catalytic direct cross-aldol reaction that employs nonequivalent aldehydes has been accomplished using proline as the reaction catalyst. Structural variation in both the aldol donor (R₁ = Me, n-Bu, Bn, 91 to >99%) and aldol acceptor (R₂ = I-Pr, I-Bu, c-C6H11, Et, Ph, 97-99% ee) are possible while maintaining high reaction efficiency (75-88% yield). Significantly, this new aldol variant allows facile enantioselective access to a broad range of β-hydroxy aldehydes which are valuable intermediates in polyketide syntheses. Copyright

Full text of DOI:10.1021/ja0262378

Published on Web 05/08/2002
The First Direct and Enantioselective Cross-Aldol Reaction of Aldehydes
Alan B. Northrup and David W. C. MacMillan*
DiVision of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125
Received March 19, 2002
Over the last three decades, seminal research from the labora-
tories of Evans,1 Heathcock,2 Masamune,3 and Mukaiyama4 has
established the aldol reaction as the principal chemical reaction for
the stereoselective construction of complex polyol architecture.
Recently, studies by Barbas,5 List,6 Shibasaki,7 and Trost8 have
outlined the first examples of enantioselective direct aldol reactions,
an important class of metal- or proline-catalyzed transformations
that do not require the pregeneration of enolates or enolate
equivalents. With these remarkable advances in place, a new goal
for asymmetric aldol technology has become the development of
catalytic methods that allow the direct coupling of aldehyde
substrates9 (eq 1), a powerful yet elusive aldol variant that has only
been accomplished within the realm of enzymatic catalysis.10,11
aldol selectivity and excellent levels of enantiocontrol (eq 2, 80%
yield, 4:1 anti:syn, 99% ee). Despite the use of proline in previous
aldol reactions, to our knowledge, this is the first example of a
direct enantioselective aldehyde-aldehyde dimerization.14
As revealed in Table 1, this enantioselective aldehyde coupling
is readily accomplished in a wide variety of solvents (entries 1-9,
g96% ee) including low dielectric media such as benzene (entry
1, >99% ee) as well as highly polarized solvents such as dimethyl
sulfoxide (entry 7, >99% ee). It is important to note that byproducts
arising from dehydration of the initial â-hydroxy aldehyde adduct
were not isolated in significant quantities (e4% yield). The superior
levels of reaction efficiency observed with proline in DMF at +4
°C (entry 9, 91% conversion, 3:1 anti:syn, 99% ee), prompted us
to select these reaction conditions for further exploration.
The capacity of proline to catalyze asymmetric cross-aldol
reactions between nonequivalent aldehydes was next examined. As
highlighted in Table 2, syringe pump addition of propionaldehyde
(aldehyde donor) to a series of aldehyde acceptors in the presence
of the amine catalyst effectively suppressed homodimerization of
the donor aldehyde15 while providing excellent yields of the desired
cross-aldol product (Table 2, entries 1-5, 80-88% yield). Indeed,
propionaldehyde can be used as an aldol nucleophile with a broad
range of aldehyde acceptorssincluding both alkyl (entries 1-3, 5,
80-88% yield, 97-99% ee) and aromatic substituted aldehydes
(entry 4, 81% yield, 99% ee). Of particular note is the addition of
propionaldehyde to isovaleraldehyde to provide the cross-aldol
product in 88% yield and 97% ee. The principal issue in this
reaction is that both the aldol donor and acceptor bear enolizable
R-methylene protons; however, only a single regioisomer of the
cross-aldol product is obtained (as determined by 1H NMR analysis).
Structural variation in the aldehyde donor component has also been
examined. As revealed in entries 5-7, this cross-aldol reaction can
tolerate a range of substituted nucleophiles (R1 ) Me, n-Bu, Bn,
19:1 to 24:1 anti:syn, 91 to >99% ee).
It is important to note that the absolute and the relative
configurations of the aldol products obtained in this survey are in
complete accord with the previously proposed models for proline-
catalyzed aldol reactions.5a In contrast to proline-mediated ketone
additions, lower catalyst loadings (10 mol %) and shorter reaction
times (11 to 26 h) were possible without loss in reaction efficiency.12
Last, to illustrate the preparative utility of this new cross-aldol
process, the addition of propionaldehyde to isobutyraldehyde (Table
2, entry 5) was performed on a 25 mmol scale to afford 2.65 g
(82% yield) of (2S,3S)-3-hydroxy-2,4-dimethylpentanal in >99%
ee and with 24:1 anti-diastereoselectivity.
Traditionally, the enantioselective aldol coupling of nonequiva-
lent aldehydes has been viewed as a formidable synthetic chal-
lenge on account of (i) the propensity of aldehydes to polymerize
under metal-catalyzed conditions and (ii) the mechanistic require-
ment that nonequivalent aldehydes must selectively partition into
two discrete components, a nucleophilic donor and an electro-
philic acceptor. In this communication, we demonstrate that this
elusive aldol sequence can be accomplished using enamine cataly-
sis to allow the first highly enantioselective coupling of aldehyde
substrates. We expect this new variant of the Hajos-Parrish-
Barbas-List reaction5,6,12 will provide a powerful yet operationally
simple protocol for the rapid production of enantioenriched aldolate
architecture.
As part of an ongoing program to develop small organic catalysts
that have broad utility for asymmetric synthesis, we have recently
initiated studies toward the identification of chiral amines that
function as aldolase enzyme mimics. On the basis of preliminary
studies,13 we were inspired to investigate whether enantioselective
aldehyde-aldehyde couplings might also be accomplished using
proline catalysis, a mechanistic hypothesis based on the documented
utility of this amino acid in ketone based aldol reactions.5,6 To our
delight, exposure of propionaldehyde to catalytic quantities of
proline in DMF provided the desired aldol adduct with both anti-
In summary, we have documented the first direct enantioselective
catalytic aldol reaction using aldehydes as both the aldol donor
and the aldol acceptor. Significantly, this method allows enantio-
selective access to â-hydroxy aldehydes, important synthons in
* To whom correspondence should be addressed. E-mail: dmacmill@
caltech.edu.
9
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J. AM. CHEM. SOC. 2002, 124, 6798-6799
10.1021/ja0262378 CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Effect of Solvent on the Propionaldehyde Dimerization
Acknowledgment. We thank S. P. Brown, N. C. Goodwin, and
I. K. Mangion for early contributions to this work. Financial support
was provided by AstraZeneca, GlaxoSmithKline, Johnson and
Johnson, Lilly, Merck Research Laboratories, and Pfizer. A.B.N.
is grateful for an NSF predoctoral fellowship.
c
entry
solvent
conversiona
anti:synb
%ee (anti)
1
2
3
4
5
6
7
8
9
Ph-H
32
29
41
36
41
42
38
62
91
5:1
4:1
5:1
4:1
4:1
3:1
3:1
3:1
3:1
>99
98
99
98
98
96
>99
98
Supporting Information Available: Experimental procedures, and
spectral data for all new compounds (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
CHCl3
EtOAc
THF
dioxane
CH3CN
DMSO
NMP
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99
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a Yield represents the combined yield of diastereomers. b Relative
stereochemistry assigned by literature correlation. c Determined by GLC
or HPLC. d Absolute stereochemistry assigned by chemical correlation or
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(15) Syringe pump addition times were optimized for each aldehyde-aldehyde
combination (see Supporting Information).
polypropionate and polyacetate natural product synthesis. A full
account of these studies will be presented in due course.
JA0262378
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