Highly diastereo- and enantioselective Mukaiyama aldol reactions catalyzed by hydrogen bonding

Article abstract of DOI:10.1002/anie.200601638

(Chemical Equation Presented) Enzyme lite: Like a minimalist enzyme, a simple chiral alcohol of the taddol family, 1, catalyzes Mukaiyama aldol reactions between silyl enolates of amides and aldehydes to afford products with high diastereo- and enantiosel

Full text of DOI:10.1002/anie.200601638

Communications
Asymmetric Catalysis
DOI: 10.1002/anie.200601638
Highly Diastereo- and Enantioselective
Mukaiyama Aldol Reactions Catalyzed by
Hydrogen Bonding**
Jeff D. McGilvra, Aditya K. Unni, Kriti Modi, and
Viresh H. Rawal*
Although still in its infancy, the area of asymmetric catalysis
promoted by hydrogen bonds has seen explosive growth in
the past few years.[1–5] Reports from several research groups
have demonstrated that many asymmetric reactions that had
previously been the domain of metal-based Lewis acids, can
now be catalyzed by organic compounds capable of donating
a hydrogen bond. However, unlike traditional Lewis acids,
which catalyze a diverse range of reactions with useful levels
of enantioselectivity (> 90% ee), hydrogen-bond catalysts
have been shown to be efficacious for relatively few reactions,
such as the Diels–Alder, aza-Henry, Mannich, Michael,
Morita–Baylis–Hillman, and Strecker reactions.[2–4] In con-
nection with our interest in hydrogen-bond-promoted reac-
tions, we have examined the application of this mode of
catalysis to the Mukaiyama aldol.
The Mukaiyama aldol reaction has proven to be one of the
most powerful transformations for the controlled assembly of
b-hydroxycarbonyl units, a structural motif found in numer-
ous natural products.[6] The reaction involves the C C bond
À
coupling of two fragments, with the formation of up to two
new stereogenic centers. Much effort has been directed to
asymmetric catalysis of this reaction, and the vast majority of
the successes have been recorded with metal-based chiral
Lewis acids.[7] Among the few metal-free methods that have
been developed, the most successful have involved the use of
chiral phosphoramides as Lewis bases.[8] Despite its central
importance in the synthesis of complex molecules, there is, to
date, only a single report of the Mukaiyama aldol reaction
catalyzed by hydrogen bonding (3 examples, 30–56% ee).[5,9]
We now report that simple, chiral hydrogen-bond donors are
effective as metal-free catalysts for the promotion of highly
diastereo-and enantioselective Mukaiyama aldol reactions.
Among the many permutations of Mukaiyama aldol
reactions, we focused our efforts on the reaction of silylated
enolates of amides, since the presence of the enamine unit was
[*] J. D. McGilvra, A. K. Unni, K. Modi, Prof. V. H. Rawal
Department of Chemistry
The University of Chicago
Chicago, IL 60637 (USA)
Fax: (+1)773-702-0805
E-mail: vrawal@uchicago.edu
[**] This work was supportedby the NSF andthe NIH. Dr. Ian Steele is
acknowledged for determination of the X-ray crystal structure shown
in Figure 1.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 1: Asymmetric Mukaiyama aldol reaction catalyzed by a taddol
expected to render these compounds highly nucleophilic.
Indeed, Myers and Widdowson have reported that such O-
silyl-N,O-ketene acetals react with aldehydes at ambient
temperature to yield the expected aldol products as a mixture
of diastereomers.[10] We began our investigation with the
expectation that if the reaction were carried out in the
presence of a chiral hydrogen-bond donor, then the two
prochiral faces of the aldehyde could be differentiated on
complexation, and enantiomerically enriched aldol products
would be formed. Previous work from our research group has
shown that simple diols of the taddol family are highly
effective catalysts for enantioselective reactions (taddol =
a,a,a’,a’-tetraaryl-2,2-dimethyl-1,3-dioxolane-4,5-dimetha-
nol).[2a,b,d] In initial trials, O-silyl-N,O-acetal 2 was treated with
benzaldehyde in the presence of 10 mol% of commercially
available tetra-1-naphthyl-taddol (1a) at À408C in toluene.
The reaction proceeded rapidly at this temperature, with
complete consumption of 2 within 4 h, to give the aldol
adducts in 83% yield, as a 6:1 mixture of syn and anti
diastereomers, with ee values of 90 and 77%, respectively
(Scheme 1). Crude b-hydroxyamide product 3a was isolated
after stirring the reaction mixture in the presence of HF
(1–2 h), with no observed erosion in the diastereomeric ratio.
derivative.[a]
Entry Product
R
Yield [%][b] d.r.[c]
ee syn [%](anti)[d]
1
2
3
4
3a[e]
3a[f]
3b
3c
3d
3e
3 f
3g
3h
3i
3j
3k
3l
3m
3n
3o
Ph
Ph
94
88
93
86
84
77
77
84
71
15:1
14:1
13:1
20:1
>25:1 96
16:1
9:1
9:1
9:1
5:1
13:1
8:1
98 (84)
98
94 (82)
97
4-(NO2)-C6H4
4-Cl-C6H4
4-(CF3)-C6H4
4-(CH3)-C6H4
3-(CH3)-C6H4
3-Br-C6H4
3,4-(Cl)2-C6H3
4-(MeO)-C6H4 47
3-(MeO)-C6H4 81
2-(MeO)-C6H4 50
5[g]
6
97
7
8
9
10
11
12
13
14
15
16
96 (73)
95 (67)
94 (58)
87 (72)
97
91 (58)
90 (86)
97
[h]
1-naphthyl
2-naphthyl
2-thiophene
n-propyl
80
50
88
47
2:1
10:1
10:1
9:1
95 (48)
91
[a] Reactions were performedusing 1 equiv ketene acetal 2, 2 equiv
aldehyde, and 0.1 equiv catalyst 1b in 0.5 mL of toluene for 2 days in an
argon atmosphere. Following workup with 5 mmol aq HF, the products
were isolatedby flash column chromatography on silica gel. [b] Yieldof
isolatedproudct. [c] Determinedby
1H NMR analysis of the crude
reaction mixture prior to separation by column chromatography.
[d] Determined by chiral HPLC analysis. [e] 1S,2S absolute configura-
tion.[11] [f] Reaction time was 16 h. [g] Reaction time was 20 h. [h] Reac-
tion run at À408C for 2 days.
lectivities. For the sake of consistency, most of the reactions
were performed for 2 days, although comparable results were
obtained with shorter reaction times: quenching the reactions
after 16 and 20 h gave the expected products in good yield and
high selectivity (Table 1, entries 2 and 5 ). The reaction of 2
with para-substituted aromatic aldehydes possessing either
electron-withdrawing or weakly electron-donating function-
alities in the presence of 1b gave superior results (Table 1,
entries 3–6). Substrates containing a strong electron-donating
group para to the aldehyde were found to be less reactive. For
example, the reaction of p-anisaldehyde proceeded sluggishly
at À788C. At higher temperature (À408C), the reaction
progressed to afford 3i in modest yield (47%), but with lower
d.r. and ee values (Table 1, entry 10). Meta substitution is
tolerated well and affords products in reasonable diastereo-
selectivity and with high ee values (Table 1, entries 7, 8 and
11). Substrates with a substituent ortho to the aldehyde, such
as o-anisaldehyde and 1-naphthaldehyde (Table 1, entries 12
and 13), gave diminished diastereoselectivity, although still
with high enantioselectivity. Heteroaromatic aldehydes are
also good Mukaiyama aldol partners, as demonstrated by the
reaction of 2-thiophenecarboxaldehyde (Table 1, entry 15).
Although we have not fully explored the taddol-catalyzed
aldol reactions of aliphatic aldehydes, a preliminary study
Scheme 1. Initial discovery of taddol-catalyzed aldol reaction of 2. 1a:
tetra-1-naphthyl-taddol, 1b: cyclohexylidene-taddol, TBS=tert-butyldi-
methylsilyl.
Through a brief study, where nearly a dozen readily
prepared taddol catalysts were screened, it was determined
that the cyclohexylidene-taddol derivative 1b gave the best
combination of diastereo-and enantioselectivity for the aldol
reaction of 2 with benzaldehyde. Catalysts bearing various
alkyl-and alkoxy-substituted phenyl rings gave products with
diminished d.r. and ee values. The selectivities increased
significantly when the reaction was carried out at À788C.
Optimal conditions for the reaction of 2 with benzaldehyde
were realized using 10 mol% of 1b and 2 equivalents of
benzaldehyde in toluene at À788C for 2 days, which gave 3a
in 94% yield with a 15:1 syn:anti ratio and 98% ee for the
major diastereomer (84% ee minor diastereomer).
The scope of the Mukaiyama aldol reaction of 2 with a
range of aldehydes was examined under optimized conditions
using taddol 1b as the catalyst (Table 1). Examination of the
results shows that the aldol products are generally formed in
good yields with high to excellent diastereo-and enantiose-
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Communications
with butyraldehyde showed that the reaction proceeded with
good diastereoselectivity and high enantioselectivity (Table 1,
entry 16).
To render the above method more broadly applicable to
the synthesis of complex molecules, we examined methods for
the transformation of the amide functionality into an
aldehyde group. Provided this conversion could be accom-
plished without eroding the high diastereo-and enantiose-
lectivities, then the outcome would correspond to the
products of crossed-aldol reactions of aldehydes. After a
brief examination of aluminum-based reducing agents,[12] we
directed out attention to the use of Schwartzꢀs reagent. Georg
and co-workers showed previously the direct reduction of
achiral N,N-dialkylamides to the corresponding aldehydes
using this reagent.[13] Subjecting amide 4a to the conditions
reported by Georg and co-workers produced the desired
aldehyde product, but with considerable diminution in the
diastereomeric ratio. This erosion in diastereoselectivity can
be understood by considering the suggested mechanism for
the reduction, wherein the proposed iminium intermediate
can isomerize to an enamine, with loss of stereochemistry at
the carbon atom a to the carbonyl group. Consistent with this
rationale is the observation that the diastereoselectivity
decreases with longer reaction times. Examination of the
reaction parameters showed that the reduction proceeded
rapidly in CH2Cl2 and gave the desired aldol product in high
yield. Under optimized conditions (using three equivalents of
Schwartzꢀs reagent in CH2Cl2) the amide aldol products 4
were converted into the corresponding chiral aldehydes 5 in
high yields with limited or no epimerization of the a stereo-
center (Scheme 2).
Figure 1. X-ray structure of the complex formedbetween the catalyst
rac-1a and p-anisaldehyde. Red=oxygen atom, blue=hydrogen atom
involved in hydrogen bonding.
catalyst. Since hydrogen bonding is a subset of the Lewis acid
type of interaction, the present mode of activation represents
a form of Lewis acid assisted Lewis acid catalysis.[1c]
In this report, we have described the catalysis of highly
diastereo-and enantioselective Mukaiyama aldol reactions of
O-silyl-N,O-ketene acetals mediated solely through activa-
tion by hydrogen bonding. The catalyzed reaction was
effective for a range of aldehydes, and gave products in
synthetically useful yields and selectivities. The mild con-
version of the amide aldol products into the corresponding
aldehydes using Schwartzꢀs reagent, with little or no erosion
in diastereoselectivity, renders this reaction useful for further
synthetic applications. The crystal structure of the taddol–
aldehyde complex clearly shows coordination of the aldehyde
carbonyl group through a single-point hydrogen-bonding
interaction. This mode of activation is likely critical for the
Mukaiyama aldol reaction presented here as well as for the
[2]
cycloaddition reactions that we reported previously.
Scheme 2. Reduction of chiral amides to aldehydes under mild con-
ditions. Cp=cyclopentadienyl
A desired characteristic of any highly useful catalyst is the
capacity to effect a broad range of reactions. The results
presented herein when taken in conjunction with our previous
studies shows that taddol may well be considered a “priv-
ileged” scaffold for asymmetric catalysis mediated by hydro-
gen bonding.[15,16] Further investigation of taddol ligands as
chiral hydrogen-bond donors should provide exciting new
developments in asymmetric catalysis.
The high enantioselectivity observed in the above reac-
tions implies the intermediacy of a highly ordered transition
state, generated by hydrogen bonding between the chiral diol
and the aldehyde. In our study of taddol-catalyzed Diels–
Alder reactions, we presented a hypothesis based on the X-
ray structures of uncomplexed taddols to rationalize the
observed enantioselectivities.[2b,14a] We have now succeeded in
obtaining the first crystal structure of a complex between a
taddol (racemic 1a) and an aldehyde (Figure 1).[14b] The X-ray
structure clearly supports some of the basic tenets of our
hypothesis by showing the presence of an intramolecular
hydrogen bond between the two hydroxy groups of the
catalyst and an intermolecular hydrogen bond to the carbonyl
oxygen atom of p-anisaldehyde. This complex is consistent
with the suggested mode of activation of the carbonyl group
through a single-point hydrogen bond to a preorganized
Received: April 25, 2006
Revised: June 28, 2006
Published online: August 14, 2006
Keywords: asymmetric catalysis · enantioselectivity ·
.
hydrogen bonds · Mukaiyama aldol · organocatalysis
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