Enantioselective activation of aldehydes by chiral phosphoric acid catalysts in an aza-ene-type reaction between glyoxylate and enecarbamate

Article abstract of DOI:10.1002/anie.200800232

(Chemical Equation Presented) Double interaction doesit: Highly enantio- and diastereoselective aza-ene-type reaction of glyoxylate with an enecarbamate is accomplished by using a binol-derived phosphoric acid catalyst (see scheme). DFT computational analysis revealed that two hydrogen bonds formed between the catalyst and the aldehyde are critical for the high enantioselectivity.

Full text of DOI:10.1002/anie.200800232

Communications
DOI: 10.1002/anie.200800232
Organocatalysis
Enantioselective Activation of Aldehydes by Chiral Phosphoric Acid
Catalysts in an Aza-ene-type Reaction between Glyoxylate and
Enecarbamate**
Masahiro Terada,* Kazuyo Soga, and Norie Momiyama
Carbonyl compounds play a central role in a diverse array of
organic reactions. In particular, the activation of aldehydes
for reaction represents the most fundamental transformation
available to synthetic chemists, and has developed into a
broad reaction class that occupies a privileged place in
synthetic organic chemistry.[1] In recent years, chiral Brønsted
acids have emerged as efficient enantioselective catalysts,[2]
and as an attractive class of organocatalysts.[3] The activation
of aldehydes by using a chiral Brønsted acid was first reported
by Rawal and co-workers, who performed a hetero Diels–
Alder reaction in the presence of a catalytic amount of taddol
(taddol = tetraaryl-1,3-dioxolane-4,5-dimethanol).[4a] Since
this milestone achievement, chiral Brønsted acid catalysis
through the activation of carbonyl com-
derivatives. In our continuous efforts to extend the synthetic
applicability of chiral phosphoric acid catalysts,[6,7] we de-
scribe herein the first example of the activation of aldehydes
by using chiral phosphoric acid 1 to efficiently accelerate an
aza-ene-type reaction[6d,i,10] of glyoxylate 3, as a reactive
aldehyde, with enecarbamate 4 in a highly enantioselective
manner [Eq. (1)]. We also disclose some mechanistic aspects
pounds has attracted considerable
attention in organic chemistry.[4,5]
Binol-derived (binol = 1,1’-bi-2-naph-
thol) phosphoric acid 1 is an extensively
studied chiral Brønsted acid, which has
been shown to be a versatile catalyst in
enantioselective transformations.[2,6,7]
Most of these transformations include
imines as the electrophilic component;
in contrast, activation of carbonyl com-
of the enantiofacial selectivity based on DFTcomputational
analysis of the hydrogen-bonded pair formed between
glyoxylate 3 and phosphoric acid 1. The two hydrogen-
bonding interactions (A) are shown to be crucial to achieve
high enantioselectivity.[11]
pounds has been scarcely explored despite their synthetic
utility. Recently, Yamamoto and co-workers reported the
enantioselective Diels–Alder reaction of a,b-unsaturated
ketones with silyloxy dienes by using binol-derived N-triflyl
phosphoramide 2 as the acid catalyst.[8] The activation of
carbonyl compounds was subsequently accomplished by
Rueping et al.[9] in which they reported that 2 functioned as
an efficient enantioselective catalyst for the Nazarov cycliza-
tion and the Friedel–Crafts reaction by activating ketones.
These reports are the only publications that demonstrate the
activation of carbonyl compounds by chiral phosphoric acid
[*] Prof. Dr. M. Terada, K. Soga, Dr. N. Momiyama
Department of Chemistry
Our study commenced with the reaction of glyoxylate 3
and enecarbamates 4a and 4b, respectvely, in the presence of
4 Š molecular sieves [12] and 5 mol% phosphoric acid catalyst
1a, which contains phenyl substituents (Ar= Ph) at the 3,3’-
positions of the binaphthyl group. As shown in Equation (1),
the reaction proceeded smoothly to provide the correspond-
ing aza-ene-type products (5a and b) in high yields within
1 hour. The enantioselectivity was determined after the
hydrolysis of 5 to give the b-hydroxy ketone (6a and b).
Excellent enantioselectivities were observed with catalyst 1a,
which bears unmodified phenyl groups (Ar= Ph). The fact
Graduate School of Science
Tohoku University
Aramaki, Aoba-ku, Sendai 980-8578 (Japan)
Fax: (+81)22-795-6602
E-mail: mterada@mail.tains.tohoku.ac.jp
Homepage: http://hanyu.chem.tohoku.ac.jp/~web/lab/
index2.html
[**] This work was supported byJSPS for a Grant-in-Aid for Scientific
Research (B) (Grant No. 17350042).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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that the simple, phenyl-substituted catalyst provides excellent
enantioselectivity is noteworthy because experiments on the
activation of imines showed that catalyst 1 required modified
phenyl substituents, typically bulky ones, to obtain high
enantioselectivities.[6,7]
To gain mechanistic insight into the high enantioselectiv-
ity observed when using 1a, we investigated a series of
catalysts (1) bearing substituted phenyl rings. As shown in
Table 1, there was a marked relationship between the
Table 1: Enantioselective aza-ene-type reaction of glyoxylate (3) with
enecarbamate (4a) catalyzed by (R)-1 ([Eq. (2)]).[a]
Entry
1: Ar
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
1b: 4-CH3C6H4
1c: 4-CF3C6H4
1d: 4-tBuC6H4
1e: 4-b-naphthylphenyl
1 f: b-naphthyl
1g: 3,5-tBu2C6H3
1h: 2,4,6-(CH3)3C6H2
1i: 9-anthryl
93
82
99
81
80
37
40
35
95
94
98
95
91
2
8[d]
18
[a] Unless otherwise noted, all reactions were carried out byusing ( R)-1
(0.005 mmol ,5 mol%), freshlydistilled 3 (0.17 mmol , 1.7 equiv), and
4a (0.1 mmol) in CH2Cl2 (1.0 mL) for 1 h at room temperature in the
presence of powdered 4 Š molecular sieves (85 mg). [b] Yield of 6a after
isolation. [c] Determined bychiral HPLC analysis. Absolute stereochem-
istryof 6a was determined to be S.[13] [d] (R)-6a as a major enantiomer.
Figure 1. Three-dimensional structures of the hydrogen-bonded com-
plexes formed between 1 and 3’. P tan, O red, C gray, H white. a) (R)-
1a/3’; b) (R)-1h/3’.
substituent pattern on the phenyl ring and the catalytic
performance in terms of both activity and enantioselectivity.
The catalyst performance was maintained when the substitu-
ents were introduced to the para position of the phenyl ring,
phenyl rings would be applicable to the para-substituted
catalysts (1b–1 f). In contrast, the mesityl rings of (R)-1h are
irrespective of their stereoelectronic properties (Table 1, forced into a perpendicular arrangement with respect to the
entries 1–5). In contrast, if the phenyl ring was substituted
by bulky groups at the 3,5-positions or by small substituents at
basal naphthyl moiety because of the two ortho-methyl
substituents, and hence overlapping with the aldehyde
the 2,6-positions (Table 1, entries 6–8) the catalytic activity occurs (Figure 1b). Both enantiotopic faces are well shielded
and enantioselectivty was compromised.
by the Ar groups and as a result there is a significant decrease
in catalytic activity and enantioselectivty in catalysis by 1h.
Similar conformational restrictions would occur with the
other catalysts having bulky Ar groups (1g and i).
Next we used various enecarbamates 4 in the aza-ene-type
reaction to investigate the stereochemical aspects of diaster-
eoselection [Eq. (2)]. Among the catalysts (1) that were
examined (Table 1), 1d exhibited excellent performance in
terms of both catalytic activity and enantioselectivity and
hence the subsequent reactions were carried out by using 1d.
As shown in Table 2, the (Z)-enecarbamates required longer
In an effort to understand the high enantioselectivity
observed for catalyst (R)-1a, having simple phenyl substitu-
ents, we conducted a computational study into the hydrogen
bonding between catalyst (R)-1 and methyl glyoxylate (3’) at
the B3LYP/6-31G** level of theory.[14] The lowest energy
conformers of the (R)-1a/3’ pair and the (R)-1h/3’ pair are
shown in Figures 1a and b, respectively. The key feature of
the complexation mode is the presence of a double hydrogen
bond,[15] where the hydrogen bond between the formyl
hydrogen atom and the phosphoryl oxygen atom forces a
coplanar orientation of the formyl group and the phosphoric
acid subunit.[11] The experimental results can be rationalized
by these double hydrogen-bonding models. In the 3D-
structure of hydrogen-bonded pair 1a/3’ (Figure 1a), one
enantiotopic face (re face) of the aldehyde is effectively
shielded by one of the phenyl rings. In contrast, the other face
(si face) is fully accessible and hence the enecarbamate
attacks from the front side (blue arrow indicated in
Figure 1a). This attack affords the product with the S confi-
guration, which is the absolute configuration observed
experimentally. Such a conformational arrangement of the
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aqueous solution, 150 mL) at room temperature and the resulting
mixture was stirred at room temperature for 1 h. The reaction mixture
was then quenched with saturated NaHCO3 aq. at 08C, and extracted
with CH2Cl2 (” 4). The organic layer was dried over Na2SO4, filtered,
and concentrated. The residue was purified by flash column
chromatography to give 6a (20.6 mg, 0.0927 mmol) in 99% yield as
a slightly yellow liquid. The enantioselectivity of 6a was determined
to be 98% ee by using chiral HPLC analysis.
Table 2: Aza-ene-type reaction of various enecarbamates (4) with 3
catalyzed by (R)-1d ([Eq. (2)]).[a]
Entry
4
t [h]
Yield [%][b]
anti:syn
ee [%][c]
anti
syn
1
2
(E)-4c
(E)-4d
(E)-4e
4 f
(Z)-4c
(Z)-4d
(Z)-4e
2
2
4
1
24
2
24
73
73
75
89
11
74
67
>99:<1
96:4
99:1
89:11
72:28
50:50
92:8
>99
99
99
99
26
28
8
53
56
74
98
88
69
74
3[d]
4
5
Received: January 16, 2008
Published online: April 17, 2008
6
7[d]
Keywords: asymmetric catalysis · Brønsted acids · ene reactions ·
phosphoric acids · transition states
[a] Unless otherwise noted, all reactions were carried out byusing
0.005 mmol of (R)-1d (5 mol%), 0.17 mmol of freshlydistilled
(1.7 equiv), and 0.1 mmol of 4 in 1.0 mL of CH2Cl2 in the presence of
powdered 4 Š molecular sieves (85 mg). [b] Yield of 6 after isolation.
[c] Determined bychiral HPLC analysis. [d] 0.3 mmol of freshlydistilled
(3.0 equiv).
.
3
3
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reaction times and low enantioselectivities were observed in
the major isomers (anti) (Table 2, entries 5–7). However,
extremely high enantioselectivities and anti selectivities were
observed in the reactions of the E isomers (Table 2, entries 1–
4). It seems likely that the reaction proceeds through a cyclic
transition state because of the significant difference in both
the reactivity and the enantioselectivity observed between
each geometric isomer. The slower reaction observed with
Z enecarbamates could be caused by unfavorable interactions
between the enecarbamate (4) and the hydrogen-bonded
complex of 1d and 3. Whereas the exclusive formation of
anti products from the E isomers could be attributed to the
well defined exo transition state.[10b]
In conclusion, we have demonstrated the highly enantio-
and diastereoselective aza-ene-type reaction of glyoxylate
with enecarbamates catalyzed by a chiral phosphoric acid.
DFTcomputational analysis of the complexation modes
allowed us to demonstrate that the double hydrogen bonding
interaction between the phosphoric acid and the glyoxylate is
crucial in providing the high enantioselectivity. The present
hydrogen-bonding model could be applicable to other
enantioselective reactions of aldehydes, and also provides a
guiding principle for the design of novel chiral Brønsted acid
catalysts. Additional studies to develop other enantioselective
transformations of aldehydes and to elucidate the transition
states of the phosphoric acid catalyzed aza-ene-type reaction
are in progress.
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Experimental Section
Representative procedure for aza-ene-type reaction of glyoxylate
with enecarbamates catalyzed by chiral phosphoric acid (Table 1):
Freshly distilled ethyl glyoxylate (3) (16.9 mL, 0.17 mmol) was added
to a suspension of phosphoric acid (R)-1d (2.5 mg, 5 mmol) and
activated 4 Š molecular sieves (< 5 micron powder, 85 mg) in CH2Cl2
(1 mL) at room temperature under N2 gas. After stirring the mixture
for 5 min, enecarbamate 4a (18.5 mL, 0.1 mmol) was introduced and
the reaction mixture was stirred at room temperature for 1 h. The
resulting mixture was quenched with saturated NaHCO3 aq. at room
temperature and then extracted with CH2Cl2 (” 4). The organic layer
was dried over Na2SO4, filtrated, and concentrated to give crude 5a.
A solution of crude 5a in EtOH (1.5 mL) was treated with HBr (47%
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