Highly efficient organocatalyzed direct asymmetric aldol reactions of hydroxyacetone and aldehydes

Article abstract of DOI:10.1002/adsc.200800558

Novel organocatalysts derived from L-threonine and L-leucine have been synthesized for catalyzing direct aldol reactions of hydroxycetone and unactivated aliphatic aldehydes with as low as 2 mol% loading of the catalyst, good to excellent yields and excel

Full text of DOI:10.1002/adsc.200800558

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DOI: 10.1002/adsc.200800558
Highly Efficient Organocatalyzed Direct Asymmetric Aldol
Reactions of Hydroxyacetone and Aldehydes
Xiaoyu Wu,a,* Zhixiong Ma,b Zhengqing Ye,b Shan Qian,b and Gang Zhaob,*
a
Department of Chemistry, Shanghai University, 99 Shangda Rd, Shanghai 200444, Peopleꢀs Republic of China
Fax : (+86)-21-6683-4856; e-mail: wuxy@shu.edu.cn
Laboratory of Modern Organic Synthetic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
b
Sciences, 354 Fenglin Lu, Shanghai 200032, Peopleꢀs Republic of China
Fax : (+86)-21-6416-6128; e-mail: zhaog@mail.sioc.ac.cn
Received: September 11, 2008; Revised: November 30, 2008; Published online: January 2, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200800558.
Abstract: Novel organocatalysts derived from l-
threonine and l-leucine have been synthesized for
catalyzing direct aldol reactions of hydroxycetone
and unactivated aliphatic aldehydes with as low as
2 mol% loading of the catalyst, good to excellent
yields and excellent enantioselectivities have been
achieved for aliphatic aldehydes, whereas aromatic
aldehydes yield only moderate enantioselectivities.
targets for synthetic organic chemists.[2] As for the
construction of the key a,b-dihydroxy ketone moiety,
several approaches have been reported.[2] Typically
two strategies are used to control the stereochemistry:
one uses chiral auxiliary,[2a–e] and the other one uses
the Sharpless AD process.[2g–i] Nonetheless, both
methods require several additional steps to transform
the initial amide or ester groups into the desired
ketone functional group via the corresponding Wein-
reb amide.
Keywords: aldehydes; aldol reaction; 1,2-diols; hy-
droxyacetone; organic catalysis
As part of our efforts in the total synthesis of am-
phidinolides H, G and B,[2h,i] we envisioned that a
direct aldol reaction of hydroxyacetone with the cor-
responding aldehydes should produce the C3 unit with
the simultaneous control of the two hydroxy-substitut-
The a,b-dihydroxy ketone moiety is the core structure ed stereogenic centers. Since the pioneering work of
unit in a number of natural macrolide amphidinolides List[3] and Barbas,[4] organocatalysts have been widely
(Scheme 1).[1] Many of these compounds have shown utilized in the direct aldol reactions between ketones
strong cytotoxicity in anti-cancer studies.[1b,c] Their and aldehydes, and notable advances have been
biological activities make them extremely attractive achieved over the last a few years in this field.[5]
The use of hydroxyacetone as a donor in the direct
aldol reaction was firstly introduced by List and co-
workers.[3b] This reaction provided a product with a
valuable 1,2-diol moiety. Since then extensive efforts
have been made to improve the stereocontrol in this
reaction with either hydroxyacetone or protected hy-
droxyacetone as the substrates.[6] So far high levels of
enantioselectivity have been achieved with both the
syn and the anti products by utilizing chiral catalysts
derived from primary and secondary amines.
However, the aldol acceptors of these reactions are
usually limited to aromatic aldehydes and a-hydroxy
or a-amino aliphatic aldehydes. While it has been re-
ported that branched aliphatic aldehydes are also ef-
fective aldol acceptors in some cases,[3,4] linear aliphat-
ic aldehydes are bad substrates in terms of yield and
stereoselectivities.[6] Furthermore, the catalyst loading
Scheme 1. The a,b-dihydroxy ketone unit in amphidinolides. in these reactions typically ranges from 15 to
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Highly Efficient Organocatalyzed Direct Asymmetric Aldol Reactions
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30 mol%. Such a high catalyst loading will cause cost
concerns if the reaction is to be applied in a large-
scale synthesis. Herein we would like to report our
preliminary results on using organocatalysts prepared
from primary amino acids and an aminol derived
from tryptophan.[7] As shown by our results, these
new catalysts are able to address both of the afore-
mentioned issues.
Bifunctional prolinamide catalysts were firstly re-
ported by List and co-workers.[8a] With continuous
contributions from Gongꢀs and other groups,[6h,p,8]
These catalysts have proved to be highly effective in
promoting aldol reactions and Mannich reactions.
As for the hydroxyacetone substrate, it is well ac-
cepted that the formation of a Z-enamine with a sta-
bilizing hydrogen bond predominates.[6n,8f] As shown
in the favored transition state TS-I of the catalysis
(Scheme 2), the lack of steric repulsion between the
OH and Me groups in the Z-enamine may also help
to favor this intermediate.[8h] According to Gongꢀs hy-
pothesis, the two hydrogen bonds formed between the
aldehyde and the amide and hydroxy moieties of the
catalyst activate the substrate and control its ap-
proach.[8] Thus, the favored transition state TS-I leads
to the formation of the syn aldol product with high
level of stereocontrols (both de and ee).
Figure 1. Catalysts screened in the direct aldol reactions.
Table 1. Results of catalyst screening.[a]
With isobutyraldehyde and hydroxyacetone as the
model substrates, we screened several bifunctional
amide catalysts (5–7) synthesized in this lab (Figure 1)
for the direct aldol reactions. For comparison purpos-
es, four readily available amino acids (1–4) with simi-
lar structural features were also studied. The screen-
ing results are collected in Table 1.
Entry Cat.
(mol%)
Solvent Time Yield[b] syn/
ee[d]
[h]
[%]
anti[c] [%]
The reactions were initially carried out using xylene
as the solvent.[9] As shown in Table 1, simple amino
acids (such as l-threonine 3, l-tryptophan 4) and
[e]
1
2
3
4
5
6
7
8
1 (15)
2 (15)
3 (20)
4 (20)
5 (8)
6 (8)
7 (8)
7 (2)
7 (0.4)
7 (8)
7 (8)
7 (8)
xylene 48
xylene 48
xylene 48
xylene 48
xylene 24
xylene 24
xylene 24
xylene 80
xylene 48
–
–
–
–
–
–
–
–
–
–
–
<10
91
91
93
95
47
93
93
95
>20:1 95
>20:1 96
>20:1 98
>20:1 98
>20:1 95
>20:1 97
>20:1 97
>20:1 97
9f
10
11
12
THF
DCM
24
24
Toluene 24
[a]
All the reactions were performed with 8 (3 mmol,
3 equiv.) and 9a (1 mmol) in 1 mL solvent at room tem-
perature. For details see Supporting Information.
Isolated yield.
Determined by H NMR.
The ee of the major isomer, determined by chiral HPLC.
Almost no formation of the product.
[b]
[c]
[d]
[e]
[f]
1
The reaction was conducted at 608C.
their siloxyl derivatives (such as 1 and 2) are not suit-
able organocatalysts for this reaction (Table 1, en-
tries 1–4) due to their poor catalytic activities. In
Scheme 2. Plausible transition states in the bifunctional
amide-catalyzed aldol reaction of hydroxyacetone.
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159

Xiaoyu Wu et al.
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striking contrast, when 8 mol% of the bifunctional were achieved (93–98% ee) in all cases (entries 1–8).
amide catalysts 5–7 were employed, high levels of dia- Surprisingly enough, for some of the substrates, reac-
stereoselectivity (>20:1) and ee values (95–98%) as tions with low loadings of the catalyst produce higher
well as excellent yield (>91%) may be obtained for chemical yield and diastereoselectivity as compared
the desired aldol product (entries 5–7). Among these with those with high loadings (entry 2 vs. 1, 4 vs. 3).
three bifunctional amide catalysts employed, catalyst The reason for this abnormal behavior is still not
7 derived from l-threonine provides the best results clear. It should be noted that the current method pro-
in terms of yield and enantioselectivity (entry 7).
vides a highly efficient way for the preparation of the
It was also gratifying to find that reducing the cata- syn dihydroxy ketones. For example, the previous syn-
lyst loading to 2 mol% leads to no loss of stereoselec- thesis of syn-10b by the Sharpless AD reaction re-
tivity. It just takes a longer time for the reaction to quires
complete at this loading (entry 8).
1 mol%
K2OsO2(OH)4
and
5 mol%
(DHQD)2PHAL to secure a high conversion.[12]
Recently Gongꢀs and Barbasꢀ groups reported that
Further reduction in the catalyst loading (to
0.4 mol%) and elevated reaction temperature (608C) bifunctional amide catalysts successfully promote the
lead to the aldol adduct with only slightly inferior aldol reaction between aromatic aldehydes and hy-
enantioselectivity. Nevertheless, the yield of product droxyacetone or dihydroxyacetone.[8] To further un-
decreased significantly (entry 9). To the best of our derstand the scope and limitations of our catalysts,
knowledge, this is the first example where a relatively some aromatic aldehydes were also studied as the
low catalyst loading (2 mol%) has been achieved in aldol acceptors (Table 3). It is interesting to find that
the organocatalyzed direct aldol reaction of simple o-substituted aldehydes are better substrates than
aliphatic aldehydes.[10] Such catalytic efficiency is com- their p-substituted counterparts in terms of reactivity
parable to that of the metal-catalyzed aldol reac- and stereoselectivity (entry 4 vs. 3 and 6 vs. 5). Fur-
tions.[11] Other solvents, such as THF, DCM and tolu- thermore, p-nitrobenzaldehyde, which has been
ene, are also good solvents for this reaction, as no loss widely used as a model substrate in the direct adol
of diastereoselectivity and enantioselectivity was ob- chemistry due to its reactivity, is not as reactive as o-
served with these solvents (entries 10–12).
choro- and o-bromobenzaldehydes (entries 2, 4 and
The scope of this novel aldol reaction was then in- 6).
vestigated, and the results are summarized in Table 2.
In order to show the synthetic potential of the de-
Several aliphatic aldehydes were tested as the accept- veloped method, aldehyde 13 was prepared and used
ors. As shown in Table 2, excellent enantioselectivities as an acceptor in the aldol reaction with hydroxyace-
tone, with 7 as the catalyst (Figure 2). The reaction
Table 2. Reaction of 8 with aliphatic aldehydes 9.[a]
Table 3. Reaction of 8 with aromatic aldehydes 11.[a]
Entry Cat.
(mol%)
R
Yield[b] syn/anti[c] ee[d]
G
[%]
[%]
Entry Ar
Solvent Time Yield[b] syn/anti[c] ee[d]
1
2
3
4
5
6
7
8
7 (8)
7 (2)
7 (8)
7 (2)
5 (8)
7 (8)
7 (2)
7 (2)
n-Pr (9b)
n-Pr (9b)
n-Bu (9c)
n-Bu (9c)
n-pentyl (9d) 76
n-pentyl (9d) 83
n-pentyl (9d) 87
50
92
88
93
15:1
>15:1
8:1
15:1
10:1
10:1
>10:1
>30:1
97
98
93
97
97
97
97
96
[h]
[%]
[%]
1
2
3
4
5
6
4-NO2C6H4 Toluene 36
4-NO2C6H4 Xylene 50
4-ClC6H4
2-ClC6H4
4-BrC6H4
2-BrC6H4
91
68
86
99
68
94
4:1
5:1
4:1
9:1
3:1
5:1
80
82
76
83
76
79
Xylene 50
Xylene 12
Xylene 60
Xylene 12
i-Bu (9e)
98
[a]
[a]
All the reactions were performed with 8 (3 mmol,
3 equiv.) and 9 (1 mmol) in 1 mL xylene at room temper-
ature for 24–100 h. For details, see Supporting Informa-
tion.
All the reactions were performed with 8 (3 mmol,
3 equiv.) and 11 (1 mmol) in 1 mL xylene at room tem-
perature for 12–60 h. For details, see Supporting Informa-
tion.
[b]
[b]
Yield of the isolated product after column chromatogra-
phy.
Yield of the isolated product after column chromatogra-
phy.
[c]
[d]
1
[c]
[d]
1
Determined by H NMR analysis of the crude product.
Determined by H NMR analysis of the crude product.
The ee value of the major isomer as determined by chiral
The ee value of the major isomer as determined by chiral
HPLC analysis.
HPLC analysis.
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Highly Efficient Organocatalyzed Direct Asymmetric Aldol Reactions
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Figure 2. Aldol reaction of aldehyde 13 and hydoryxacetone.
was carried out with 5 mol% 7 as the catalyst under Acknowledgements
the standard reaction conditions with a reaction time
The authors thank Natural Science Foundation of China for
financial support (No. 20802043). Manuscript control and re-
vision by Cong-gui Zhao is also gratefully acknowledged. Yi-
xin Lu is acknowledged for helpful discussions.
of 18 h. The desired product 14 was obtained in 75%
yield.[13] The absolute stereochemistry of 14 was deter-
mined by comparison with the syn-isomer obtained
from Sharpless asymmetric dihydroxylation using
AD-mix-a.[2e,12] Compound 14 is a key building block
of amphidinolide B1. These results demonstrate that
our methodology is very useful in the synthesis of
building blocks of natural products.
In summary, we have developed novel l-threonine-
and l-leucine-derived organocatalysts for the direct
aldol reactions of hydroxyacetone and unactivated ali-
phatic aldehydes. Excellent yields, diastereoselectivi-
ties, and enantioselectivities have been achieved with
as low as 2 mol% of these catalysts. These catalysts
prove to be highly specific for aliphatic aldehydes,
while for aromatic aldehydes only moderate enantio-
selectivities can be obtained. The method developed
herein is of high synthetic potential. The application
of this method in the synthesis of amphidinolide is
currently underway in our laboratory and will be re-
ported in due course.
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Representative Procedure
To a mixture of catalyst 7 (11 mg, 0.02 mmol) and hydroxya-
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compounds are available as Supporting Information.
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But the isolation of the syn isomer from other isomers
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[7] See Supporting Information for the synthesis of the cat-
alysts.
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