Organocatalyzed highly enantioselective direct aldol reactions of aldehydes with hydroxyacetone and fluoroacetone in aqueous media: The use of water to control regioselectivity

Article abstract of DOI:10.1002/chem.200600801

An organocatalyst prepared from (2R,3R)-diethyl 2-amino-3-hydroxysuccinate and L-proline exhibited high regio- and enantioselectivities for the direct aldol reactions of hydroxyacetone and fluoroacetone with aldehydes in aqueous media. It was found that w

Full text of DOI:10.1002/chem.200600801

FULL PAPER
DOI: 10.1002/chem.200600801
Organocatalyzed Highly Enantioselective Direct Aldol Reactions of
Aldehydes with Hydroxyacetone and Fluoroacetone in Aqueous Media:
The Use of Water To Control Regioselectivity
Xiao-Hua Chen,[a, c] Shi-Wei Luo,[b] Zhuo Tang,[a] Lin-Feng Cun,[a] Ai-Qiao Mi,[a]
Yao-Zhong Jiang,[a] and Liu-Zhu Gong*[a, b]
Abstract: An organocatalyst prepared
from (2R,3R)-diethyl 2-amino-3-hy-
droxysuccinate and l-proline exhibited
high regio- and enantioselectivities for
the direct aldol reactions of hydroxya-
cetone and fluoroacetone with alde-
hydes in aqueous media. It was found
that water could be used to control the
regioselectivity. The presence of 20–30
mol% of the catalyst afforded the
direct aldol reactions of a wide range
of aldehydes with hydroxyacetone to
give the otherwise disfavored products
regioselectivities. Aldolizations of fluo-
roacetone with aldehydes mediated by
30 mol% of the organocatalyst in
aqueous media preferentially occurred
at the methyl group, yielding products
with high enantioselectivities (up to
91% ee); however, these additions
took place dominantly at the fluoro-
methyl group in THF. Optically active
3,5-disubstituted tetrahydrofurans and
(2S,4R)-dihydroxy-4-biphenylbutyric
acid were prepared by starting from
the aldol reaction of hydroxyacetone.
Theoretical studies on the role of water
in controlling the regioselectivity re-
vealed that the hydrogen bonds formed
between the amide oxygen of proline
amide, the hydroxy of hydroxyacetone,
and water are responsible for the regio-
selectivity by microsolvation with ex-
plicit one water molecule as a hydro-
gen-bond donor and/or an acceptor.
Keywords: aldol reaction · green
chemistry · organocatalysis · proline
amides · regioselectivity
with
excellent
enantioselectivities,
ranging from 91 to 99% ee, and high
Introduction
The development of highly selective organic reactions for
the formation of carbon–carbon bonds is an everlasting
topic of organic chemistry. The aldol reaction is considered
one of the most important carbon–carbon bond-forming re-
actions in organic synthesis. Its great usefulness for con-
structing natural products, in particular those with polyoxy-
genated subunits,[1] has promoted the rapid evolution of effi-
cient chiral catalysts.[2] Aldol reactions that employ enol or
enolate derivatives as donors have been well established.[2]
As opposed to reactions involving preactivated donors, the
direct aldol reaction is more atom efficient,[3] making it an
attractive alternative for the synthesis of polyoxygenated
compounds. Since the seminal studies on direct asymmetric
aldol reactions were reported,[4,5] a large number of chiral
catalysts, including transition-metal complexes[6] and organic
molecules,[7–12] have been applied to these transformations.
However, most of them were performed in organic solvents,
with the exception of a limited number of direct aldol reac-
tions which were attempted in ionic liquids[13] and in wa-
[a] X.-H. Chen, Z. Tang, L.-F. Cun, Prof. A.-Q. Mi, Y.-Z. Jiang,
Prof. L.-Z. Gong
Key Laboratory for Asymmetric Synthesis and Chirotechnology
of Sichuan Province, Chengdu Institute of Organic Chemistry
Chinese Academy of Sciences
Chengdu, 610041 (China)
[b] Dr. S.-W. Luo, Prof. L.-Z. Gong
Hefei National Laboratory for Physical Sciences at the Microscale
and Department of Chemistry
University of Science and Technology of China
Hefei, 230026 (China)
Fax : (+86)551-3606266
E-mail: gonglz@ustc.edu.cn
[c] X.-H. Chen
Graduate School of Chinese Academy of Sciences
Beijing (China)
Supporting information for this article is available on the WWW
under http://www.chemistry.org or from the author and includes car-
tesian coordinates and energies of all theoretical calculated structures
and selected NMR and HPLC spectra.
Chem. Eur. J. 2007, 13, 689 – 701
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
689

ter.[5d,8b,14] The discovery of a highly enantioselective organo-
catalyzed asymmetric aldolization in environmentally benign
medias is therefore desirable.
versible upon performing the reaction in the presence or ab-
sence of water. More valuably, we found that the regio- and
enantioselectivities altered as the peptide size varied. In
general, the regioselectivity decreased and enantioselectivity
increased as the peptide size increased. The peptides 1 and
2 were extended to catalyze aldol reactions of a limited
number of electron-poor aromatic aldehydes with hydroxy-
acetone, providing enantioselectivities ranging from 84 to
96% ee (Scheme 1).
Water is absolutely the most environmentally benign sol-
vent. Its use as a solvent not only makes the reaction envi-
ronmentally amenable, but much safer to handle, as aqueous
conditions principally avoid flammable organic solvents and
the strictly anhydrous conditions. In addition, the perform-
ance of the organic reactions in aqueous conditions leads to
certain unprecedented reactions as compared to those con-
ducted in organic solvents.[15] Water has unique physical and
chemical properties, such as a dielectric constant and high
polarity. To develop a water-compatible organic reaction is a
great challenge as water destroys moisture-sensitive transi-
tion states and breaks the hydrogen bond required for the
activation of substrates. Despite these drawbacks, in recent
years organic reactions in aqueous media have received a
great deal of interest and important advances have been
made on this area.[16] As for asymmetric catalysis, transition-
metal-catalyzed asymmetric reactions in aqueous media
have also been actively investigated.[15a,17] However, apart
from the asymmetric phase-transfer catalyses[18] and chiral
ketone-mediated asymmetric epoxidations,[19] few organoca-
talyzed asymmetric reactions in aqueous media have been
reported[5d,8b,14,20] and most of them gave lower enantioselec-
tivities than their counterparts in pure organic solvent.[14a–i]
In fact, water is essential for reactions in the biological
system. Enzyme-catalyzed organic reactions are usually per-
formed in water. Thus, studies on the organic reactions in
aqueous media might also lead to a better understanding of
enzyme catalysis. Proline and its derivatives catalyze direct
aldol reactions by means of an enamine mechanism, similar
to that which Class I aldolase enzymes[2e,21a] and aldolase
catalytic antibodies use to catalyze similar reactions in wa-
ter,[21b–d] indicating that such organic molecules would exhib-
it a catalytic ability similar to enzymes, and they may cata-
lyze highly enantioselective organic reactions in aqueous
media.[14k,j]
Scheme 1. Preparation of 1,4-diol 5 and 1,2-diol 6.
However, there are some inherent drawbacks in this proc-
[22]
ess,
which are as follows: 1) the regioselectivity (1,4-diol/
1,2-diol, up to 4:1) continues to be unsatisfactory, 2) the
process is limited to electron-deficient aryl aldehydes and
gives excellent enantioselectivity (>90%) for a limited
number of special cases, making it synthetically impractical,
3) oligopeptides 1 or 2 have much higher molecular weights
than either the substrate or the product, so this reaction is
not truly catalytic with respect to weight. To address these
problems and the importance of asymmetric reactions in
aqueous media, we herein report that a family of simple l-
proline amides 7–9 catalyzed direct aldol reactions of alde-
Recently, we reported that l-proline-based oligopeptides
(1, 2, and their analogues) catalyzed the direct aldol reaction
hydes with hydroxyacetone and fluoroacetone in aqueous
media with high enantioselectivities. Application of the opti-
cally active 1,4-diols to the syntheses of chiral 3,5-disubsti-
tuted tetrahydrofurans and a biologically active compound
is also presented. Moreover, theoretical studies on the possi-
ble roles of water in the control of regioselectivity of the
aldol reaction of hydroxyacetone with aldehydes are also
discussed.
Results and Discussion
of aldehydes 3 with hydroxyacetone 4 in aqueous media to
provide 1,4-diols 5 with high enantioselectivities.[22] Interest-
ingly, the regioselectivity to 1,4-diol 5 or 1,2-diol 6 was re-
Direct aldol reaction of hydroxyacetone with aldehydes:
The asymmetric direct aldol reaction of aldehydes with hy-
droxyketones provides a convenient entry to highly oxygen-
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Chem. Eur. J. 2007, 13, 689 – 701

Asymmetric Aldol Reactions
FULL PAPER
ated compounds. 2-Hydroxy-1-aryl ethanones serve as aldol
donors to react with aldehydes in the presence of chiral
transition-metal complexes, offering highly enantioselective
1,2-diols favoring the anti form.[4d–e,6a,c] In cases involving hy-
droxyacetone, biocatalysts, such as catalytic antibodies, were
found to be efficient for this reaction, leading to the forma-
tion of syn diols as major products with extremely high
enantioselectivity.[21d,23] Recent important advances with or-
ganocatalyzed direct aldol reactions revealed that l-proline
had a great ability to catalyze the aldol reaction of hydrox-
yacetone producing anti diols with a high stereochemical
outcome.[5d,e]
Direct aldol reactions of siloxy- and alkoxy-acetones with
aldehydes mediated either by TiCl4/Et3N or Bu2BOTf take
place regioselectively at the methyl group.[24] In these cases,
an excess of a Lewis acid is required to obtain high yields.
Antibody 84G3 preferentially catalyses the aldolization of
methoxylacetone at the methyl group with excellent enan-
tioselectivity, which only includes 4-nitrobenzaldehyde as an
acceptor.[25] However, these reactions all preclude the hy-
droxyacetone as a donor and can thus be considered indirect
alternatives to access the 1,4-diols 5 by aldolization.
7a–d, which catalyzed the direct aldol reaction of acetone
and 4-nitrobenzaldehyde with low enantioselectivities
(ꢀ45% ee),[10] also showed moderate enantioselectivities
(ꢀ52% ee) in this case, favoring the generation of 5a with a
regioselection of up to 5.7:1 (entries 1–4).[22] In the addition
to the unsatisfactory regio- and enantioselectivities with
these simple proline amides, the slow reactions had the
drawback of taking several days to give reasonable yields
(entries 1–4). The l-proline amides 8 and 9 derived from
chiral amino alcohols not only have a higher ability to con-
trol the regio- and enantioselectivity, but also are more cata-
lytically active than l-proline amides 7a–d, which lack the
terminal hydroxy group (entries 1–9). In particular, organo-
catalyst 9, a much more efficient catalyst in the direct aldol
reaction of acetone with aldehydes than 8,[11] provided the
highest degree of enantioselectivity (entries 8 and 9). These
observations indicate that the hydroxy group may be in-
volved in the catalysis and may exert an important influence
on stereocontrol. Performance of the reaction at a decreased
temperature (ꢁ158C) and alteration of the ratio of THF/
H2O led to further improvements in enantioselectivity (en-
tries 7 and 9). Even higher regioselectivity with respect to
1,4-diol 5a (>95: 5) and enantioselectivity (95% ee) than
those observed with either 1 or 2 were obtained under the
optimal conditions with organocatalyst 9 (entry 9).[22] In con-
trast, the 1,2-diol 6a became dominant when the reaction
was performed in THF (entry 10). These results confirmed
that the presence of water is crucial in forcing the reaction
to occur preferentially at the methyl group of hydroxyace-
tone. In contrast to the proline amides efficiently catalyzing
the reaction in aqueous media, proline did not have any cat-
alytic activity (entry 11).
In our previous studies,[22] we have noticed that the regio-
selectivity in the aldol reaction of hydroxyacetone with alde-
hydes depends to some degree on the peptide size, and that
regioselectivity generally decreases as the peptide size in-
creases. These observations point out that the use of simple
l-proline amides 7–9, which can be regarded as short pepti-
des, as catalysts would further enhance the regioselectivity.
We were therefore encouraged to employ the l-proline
amides 7–9 to catalyze the titled reaction in aqueous media.
Under similar conditions to those used for peptide cataly-
sis,[22] the l-proline amides 7–9 were examined for their abil-
ity to catalyze the direct aldol reaction of 4-nitrobenzalde-
hyde with hydroxyacetone. As the data in Table 1 indicate,
both reactivity and enantioselectivity are highly dependent
on the structure of the organocatalyst. The l-proline amides
The superior organocatalyst 9 was then extended to a
broad scope of aldehydes, and the results are summarized in
Table 2. Excellent enantioselectivities, with ee values ranging
from 91 to 99% ee, were observed for all the aldehydes
tested regardless of the sterical and electronic properties of
the substitutent. Notably, the
current process has much more
general applicability for alde-
Table 1. Screening catalysts and optimizing reaction conditions.[a]
hydes than that reported previ-
ously.[22] Peptides 1 and 2 were
unable to catalyze the aldol re-
action of the para-chloro- and
Entry Cat.
Amount of THF/H2O Amount of 4
T
t
Yield of 5a
ee
Yield of 6a
para-phenylbenzaldehydes (3k
and 3n) with hydroxyace-
tone,[22] but the organocatalyst
[mL]
[mL]
[8C] [d]
[%][b]
[%][c]
[%][b]
1
2
3
4
7a
7b
7c
7d
8
1/1
1/1
1/1
1/1
1/1
1/1
1/0.5
1/1
1/0.5
THF
0.4
0.4
0.4
0.4
0.4
0.4
0.5
0.4
0.5
0.5
0.4
0
0
0
0
25
0
5
10
10
10
1
73
44
47
68
80
91
87
9290
95
36
0
46
49
51
5212
78
25
10
13
9
gave high and moderate
yields for 3k and 3n, respec-
tively, both with an excellent
95% ee (entries 11 and 14).
Benzaldehyde, which was un-
reactive toward hydroxyace-
tone in aqueous media with
peptides as the catalysts, also
gave high enanantioselectivi-
ties of up to 97% ee with orga-
5
18
8
12
6
8
1.5
2.5
3
2.5
2.5
5
84
87
7
8
ꢁ15
8
9
0
7
9
9
ꢁ15
0
0
95
97
–
<5
58
0
10
11
9
proline 1/1
[a] Unless otherwise specified, the concentration of aldehyde is 0.25m. [b] Isolated yield based on aldehyde
and the product. [c] The ee values were determined by HPLC.
Chem. Eur. J. 2007, 13, 689 – 701
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691

L.-Z. Gong et al.
Table 2. Direct aldol reaction of various aldehydes.[a]
tempted (Table 3). In an or-
ganic solvent, such as THF, the
reaction dominantly afforded
12 in 94% yield with a regio-
meric ratio of 11/12 2:98 and
an excellent enantioselectivity
of 95% ee (entry 1). Interest-
ingly, the regioselectivity was
reversed when the reaction
was conducted in an aqueous
medium, demonstrating that
the water plays an important
role in the control of the other-
wise disfavored regioselectivity.
Compared with hydroxyace-
tone (Table 2), fluoroacetone is
less reactive toward aldehydes
in aqueous solution, with rela-
tively lower isolated yields.
Both the regioselectivity of 11/
12 and the enantioselectivity of
11 varied as the substituents of
the aldehyde changed. High
enantioselectivities of up to
91% ee were observed.
Entry
1
Aldehyde (3)
Loading of 9 [%]
t [d]
Product 5
Product 6
Yield of 6 [%]
Yield [%][b]
ee [%][c]
4-NO2C6H4 (3a)
6H4 (3b)
20
20
20
20
20
20
20
20
20
30
30
30
30
30
30
30
30
2.5
3
3
3.5
2.5
3
3.5
2.5
3.5
5
5
3.5
3
5
5
95 (76)
84 (56)
90 (66)
77 (71)
89 (80)
85 (59)
90 (70)
79
95 (87)
93 (86)
96 (88)
91 (93)
95 (89)
96 (92)
94 (84)
96
<5
9
8
5
7
7
8
12
8
12
11
10
10
11
9
-ClC 22
3
4
5
6
7
8
9
10
11
4-CF3C6H4 (3c)
2-NO2C6H4 (3d)
3-NO2C6H4 (3e)
3,5-Br2C6H3 (3 f)
4-CNC6H4 (3g)
3,5-(CF3)2C6H3 (3h)
2-BrC6H4 (3i)
4-BrC6H4 (3j)
4-ClC6H4 (3k)
6H4 (3l)
84
69
93
93
70 (trace)
80
95 (–)
93
-FC 122
13
2,6-Cl2C6H3 (3m)
4-PhC6H4 (3n)
1-BrC10H6 (3o)
Ph (3p)
84 (73)
40 (trace)
77
99 (96)
95 (–)
99
14
15
16
17
5
5
44 (0)
28 (0)
97 (–)
98 (–)
trace
trace
c-C6H11 (3q)
[a] Unless otherwise specified, the concentration of aldehyde is 0.25m. [b] Isolated yield. The yields in paren-
theses are those obtained with peptide 2 (reference [22]). [c] Determined by HPLC. The ee values in parenthe-
ses are those obtained with peptide 2 (reference [22]).
nocatalyst 9 (entry 16). More importantly, an aliphatic alde-
Table 3. Direct aldol reaction of fluoroacetone with aldehydes.[a]
hyde, such as cyclohexylformaldehyde, a very challenging
substrate for direct aldol reactions in water,[14j,22] reacted
with the hydroxyacetone in the presence of 9 with an excel-
lent enantioselectivity (98% ee, entry 17). Apparently, the l-
proline amide 9 is more enantioselective than either of pep-
tides 1 or 2, as indicated in the reactions that all of them cat-
alyzed (entries 1–3, 5–7, and 13). The regioselectivities to
1,4-diols 5 were also significantly improved in comparison
with those in the previous process.[22]
Entry Aldehyde
Solvent
THF
Ratio of
Yield of 11
ee of 11
(3)
11/12[b]
[%][c]
[%][d]
1
4-NO2C6H4
(3a)
2:98[e]
–
–
24-NO
2C6H4
THF/H2O 85:15
1:1
6280
57
(3a)
3
4
5
3,5-Br2C6H3 THF/H2O 67:33
(3 f)
3-NO2C6H4
(3e)
2,6-Cl2C6H3 THF/H2O 87:13
(3m) 1:1
84
83
91
Aldolization of aldehydes with fluoroacetone: Fluorinated
organic compounds play an important role in the prepara-
tion of pharmaceuticals.[26] A great number of studies have
indicated that the a-fluoro carbonyl compounds are particu-
larly useful in glycobiology research.[27] Asymmetric direct
aldol reactions between aldehydes and fluoroacetone con-
veniently access the optically active a-fluoro carbonyl com-
pounds, but it is a great challenge to control the reaction to
selectively generate a single isomer as a mixture of at least
six isomers is principally produced. Direct aldol reactions of
fluoroacetone with aldehydes catalyzed by an amino alcohol
preferentially gave anti-a-fluoro-b-hydroxy ketones 12 with
good enantioselectivities and with an excellent regioselectvi-
ty of 94%.[28] The enzyme-catalyzed direct aldol reaction of
fluoroacetone with an aldehyde favored the formation of 11
in a modest yield (40%).[29] The direct generation of 11 by
aldolization activated by small chiral catalysts has not been
realized yet and awaits further development.
1:1
THF/H2O 70:30
1:1
55
65
[a] Unless otherwise specified, the concentration of aldehyde is 0.25m.
[b] The ratio was determined by 1HNMR spectroscopic analysis of the
crude product. [c] Isolated yield. [d] Determined by HPLC. [e] Isolated
yield of 12 is 94%, the diastereomeric ratio of anti/syn is 2:1 on the basis
of the 1HNMR spectrum of the crude product, and the enantiomeric
excess of the anti diastereomer is 95%.
Preparation of optically active 1,2,4-triols and 3,5-disubsti-
tuted tetrahydrofurans: Optically active polyhydroxyl com-
pounds are very useful intermediates in asymmetric organic
syntheses.[1] The diastereoselective reduction of 1,4-diols 5
from the aldol reaction of hydroxyacetone and aldehydes
generated a class of enantioenriched 1,2,4-triols. To optimize
suitable conditions for the diastereoselective reduction of
5a, the effect of different reducing reagents was examined.
In the presence of 30 mol% of organocatalyst 9, the
direct aldol reaction of aldehydes with fluoroacetone was at-
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Chem. Eur. J. 2007, 13, 689 – 701

Asymmetric Aldol Reactions
FULL PAPER
As shown in Table 4, the diastereoselectivity varied with re-
spect to reductive reagents. Sodium boronhydride (NaBH4)
gives very low diastereoselectivity (2:1) favoring the syn-4-
(4’-nitrophenyl)butane-1,2,4-triol (13a) (entry 1). The com-
bined reagent of Et3B[30] and NaBH4, reduced 5a to 13a
with an improved diastereomeric ratio of 82:18 (entry 2).
The diastereoselectivity was further increased from 82:18 to
86:14 by the replacement of Et3B with Et2BOMe[31]
were then extended to the chiral 1,4-diols 5a, 5 f, 5g, and
5m for the syntheses of the optically active 3,5-disubstituted
tetrafurans 15. Table 5 summarizes the results. The diaster-
eoselectivity of the reduction reaction was highly dependent
on the substituent of the 1,4-diols 5 and it tended to increase
Table 5. Diastereoselective reduction of 5 and the preparation of 15.[a]
(entry 3). K-selectride also provided a good diastereomeric
[33]
ratio of 84:16 (entry 4).[32] The use of NaBH
A
to
reduce 5a favored the anti-4-(4’-nitrophenyl)butane-1,2,4-
triol (14a) in a diastereomeric ratio of 16:84 (entry 5).
[34]
Me4NBH(OAc)3 reduced 5a to give mainly 13a with a di-
G
astereomeric ratio of 75:25. Thus, the combined reagent of
Et2BOMe and NaBH4 is best for the generation of 13a by
reduction of 5a.
Entry R (5)
dr
Product Yield
[%][c]
Product Yield
15
A
[%][d]
Substituted tetrahydrofurans are very important synthetic
building blocks for the construction of many natural prod-
ucts. Recently, Borhan and co-workers discovered an effi-
cient one-pot stereoselective cyclization reaction of 1,2-n-
triols to give substituted tetrahydrofurans with high stereo-
selectivity.[35] Triols 13a and 14a, readily obtained from the
diastereoselective reduction of compounds 5a, were treated
1
4-NO2C6H4
(5a)
2C6H3
(5 f)
4-CNC6H4
86:14
13a
13b
13c
13d
71
84
75
78
15a
71
23,5-Br
91:9
15b
15c
15d
81
74
65
3
4
85:15
(5g)
2,6-Cl2C6H3 >99:1
(5m)
with a combined reagent of MeC(OMe)3, PPTS (PPTS=
A
[a] The reaction was carried out on a 0.5 mmol scale. [b] Determined by
1H NMR spectroscopy. [c] Isolated yield of 13. [d] Isolated yield based on
analytically pure 15 and 13.
pyridinium p-toluenesulphonate), and BF3·Et2O, respective-
ly, to give the (3S,5S)- and (3R,5S)-acetic acid 5-(4-nitrophe-
nyl)tetrahydrofuran-3-yl esters (15a and 16a) in high yields,
maintaining the enantiomeric excesses. Interestingly, the ab-
solute configuration of the chirality at C4 reversed from R
to S, and no diastereomers (17a of 15a or 18a of 16a) were
detected (Scheme 2).
as the bulkiness of the substituent increased. For example,
5 f and 5m provided much higher diastereomeric ratios
(91:9 and >99:1, respectively) than did 5a and 5g (86:14
and 85:15, respectively) with the combined reductive re-
agent of Et2BOMe/NaBH4. Following treatment with MeC-
The diastereoselective reduction with the combined re-
agent of Et2BOMe and NaBH4 and cyclization reactions
A
13a–d underwent cyclization
smoothly to give the 3,5-disub-
stituted tetrafurans 15a–d in
good yields; the diastereomers
of 15a–d were not observed.
Table 4. Optimization of the conditions for the diastereoselective reduction of 5a.
Entry
Reagent
NaBH4
3B/NaBH4
Et2BOMe/NaBH4
K-selectride
Solvent
T [8C]
t [h]
dr (13a: 14a)[a]
Yield [%] (13a+14a)[b]
Synthesis of (2S,4R)-dihy-
droxy-4-biphenylbutyric acid:
(2S,4R)-Dihydroxy-4-biphenyl-
butyric acid (19) and its struc-
tural analogues have shown
anti-inflammatory and antipla-
telet aggregation activity.[36]
(2S,4R)-Dihydroxy-4-biphenyl-
butyric acid (19) was originally
obtained from the urinary ex-
cretion of guinea pigs that
1
2Et
3
4
5
MeOH
THF
THF/MeOH
THF
AcOH/THF
AcOH/CH3CN
0
1
5
5
5
3
2:1
82:18
86:14
84:16
16:84
75:25
75
87
90
89
96
95
ꢁ78–RT
ꢁ78–RT
ꢁ78–RT
ꢁ78–RT
ꢁ40
NaBH
A
6
Me4BH
A
24
1
[a] Determined by H NMR spectroscopic analysis of the crude product. [b] Isolated yield.
Scheme 2. Synthesis of esters 15a and 16a.
Chem. Eur. J. 2007, 13, 689 – 701
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693

L.-Z. Gong et al.
were dosed with 3-(4-biphenylylcarbonyl)propionic acid, a
biological transformation precursor to both threo- and er-
ythro-2,4-dihydroxy-4-biphenylbutyric acids.[36]
structures, the energy of each structure was further evaluat-
ed by using hybrid density functional theory (B3LYP) and
the 6-31++G** basis set as implemented in Gaussian 03,
and corrected by calculated zero-point energies from the
frequency analysis using the HF/6-31+G* method. Solvation
was modeled by microsolvation with explicit solvent mole-
cule water as the donor and/or acceptor in the formation of
a hydrogen bond with the hydroxyl group of either the inter-
mediates or transition-state structures.
The organocatalyzed asymmetric direct aldol reaction pre-
sented here was the basis for the preparation of optically
pure 2S,4R-dihydroxy-4-biphenylbutyric acid (19), as illus-
trated in Scheme 3. (R)-1,4-Dihydroxy-4-biphenyl-butan-2-
one (5n), which was obtained from the direct aldol reaction
of 4-phenylbenzaldehyde with hydroxyacetone with 95% ee,
was treated with tert-butyldimethylsilylchloride (TBSCl) and
triethylamine to give compound 20. Diastereoselective re-
duction of 20 with a combined reagent of Et2BOMe/NaBH4
afforded 21 in 97% yield with a diastereomeric ratio of 97:3
in favor of the syn diastereomer. Compound 21 then under-
went an esterification reaction by using acetic anhydride in
pyridine with a catalytic amount of dimethylaminopyridine
(DMAP), generating compound 22 in 95% yield. Com-
pound 22 then underwent Jones oxidation to give 23 in 71%
yield. Finally, removal of the acyl groups in compound 23
with lithium hydroxide (LiOH) gave the target molecule 19
in 90% yield.
As shown in Figure 1, the intermediate enamine 01 was
predicted to be a little more favorable than the enol-enam-
ine with a slightly lower enthalpy of about 0.5 kcalmolꢁ1 in
the gas phase for the best two different intermediates (en-
amine 01 and enol-enamine 02), although there are various
orientations for the hydroxyl group. The difference is so
little that the reversible transformation between these two
isomers results in the competitive formation of products 1,2-
diols and 1,4-diols, which should be controlled by the addi-
tion reaction of either the enamine or enol-enamine to ben-
zaldehyde. The transition structures were located for the re-
action as shown also in Figure 1. The hydroxyl group can
adopt two conformations in both intermediates, enamine
and enol-enamine, and corresponding transition structures
were located as TS-1,2and TS-1,4 (TS =transition state), re-
spectively. The best transition structures for the aldolization
of hydroxylacetone with benzaldehyde are similar to those
for the aldol reaction of acetone with benzaldehyde in the
presence of a proline amide,[10] except that the hydroxyl
group functions differently in two isomers, TS-1,2and TS-
1,4. It was predicted that TS-1,2-01, which leads to the for-
mation of the major product observed experimentally in
polar aprotic solvents, such as THF, is much more stable
than TS-1,4 with a much lower enthalpy of about 6 kcal
molꢁ1 and a lower reaction barrier of about 4 kcalmolꢁ1,
due to the promotion of electron density from the hydroxyl
group conjugated to the carbon–carbon double bond of
enol-enamine in TS-1,2.
Theoretical studies on the role of water in controlling regio-
selectivity: The quantum mechanics calculation has been
carried out previously on the direct aldol reactions catalyzed
by proline[37] and proline amide derivatives.[10] These studies
revealed that the formation of a hydrogen bond between
the carboxylic acid of proline or amide group of proline
amide derivatives and the carbonyl group of aldehyde in the
process of the addition of the enamine intermediate, formed
from the condensation of acetone with proline or proline
amide derivatives, to aldehyde is crucial in controlling the
stereochemistry. To further understand the factors of con-
trolling the distinct regioselectivity in water from that in or-
ganic solvent, such as THF, we have studied the two kinds
of different intermediate, enamine model I and enol-enam-
ine model II, and the corresponding transition structures of
the two intermediates with benzaldehyde by theoretical cal-
culations with the Gaussian 03 program.[38] Geometries were
fully optimized and characterized by frequency analysis
using the HF/6-31+G* method, and each transition struc-
ture was validated with one imaginary frequency related to
However, the hydroxyl group in both enol-enamine and
enamine can act as a hydrogen-bond donor and/or acceptor
in aqueous media and it is just possible to be a donor in
THF. The regioselectivity of the reaction would vary as the
reaction solvent changes from an organic solvent to the
aqueous one. It is reasonable to explore the situations in
aqueous solution by consider-
ꢁ
the C C-bond formation. Based on the fully-optimized
ing the formation of a hydro-
gen bond between the solvent
molecule and the intermediate.
To investigate the special func-
tion of the solvent molecule
water in this reaction, the char-
acter of the complexes of the
water molecule with inter-
mediates enamine and enol-
enamine was also studied by
theoretical calculations.
Of all complexes of inter-
mediates, enol-enamine and
Scheme 3. Preparation of (2S,4R)-dihydroxy-4-biphenylbutyric acid. a) TBSCl, Et3N, DMAP (5 mol%),
CH2Cl2, 08C–RT, 18 h, 81%; b) Et2BOMe/NaBH4, THF/MeOH, ꢁ788C–RT, 5 h, 97%, dr=97:3; c) (AcO)2O,
pyridine, DMAP (5 mol%), 08C, 3 h, 95%; d) Jones oxidation, 71%; e) LiOH·H2O, THF/H2O/MeOH 2:1:2,
RT, 5 h, 90%.
694
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Chem. Eur. J. 2007, 13, 689 – 701

Asymmetric Aldol Reactions
FULL PAPER
Figure 1. Model intermediates and TS structures in the gas phase with optimized geometries, partial structural parameters, and relative energies (kcal
molꢁ1): enthalpy in () and activation free energy in [].
enamine, with water (Figure 2),
although there was a good H-
bond for each case, as indicat-
ed by the shorter hydrogen
bond as shown in complexes I
and II, theoretical calculations
predicted that the best com-
plex for the formation of hy-
drogen bonds between two in-
termediates and solvent mole-
cules H2O was complex II with
a
higher
stability
of
ꢀ6.6 kcalmolꢁ1. The explana-
tion for this is that the water
molecule acts like a bridge to
form a hydrogen bond with the
proton of the hydroxy group in
the enamine moiety and the
amide oxygen, respectively.
Such a strong solvation effect
made the formation of the en-
amine (complex II) much more
favorable than the enol-enam-
ine (complex I) in the aqueous
Figure 2. Optimized geometries of H2O-solvated intermediates and TS structures, partial structural parameters
and relative energies (kcalmolꢁ1): enthalpy in () and activation free energy in [].
Chem. Eur. J. 2007, 13, 689 – 701
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695

L.-Z. Gong et al.
media. This hydrogen-bonding network should exist in the
whole reaction process. As indicated by the located transi-
tion-state structures, TS-1,2-03 was an early TS compared to
Experimental Section
General data: NMR spectra were recorded on a Brucker 300 MHz spec-
trometer. Optical rotations were measured on a Perkin–Elmer 241 Polar-
imeter at l=589 nm. FTICR-MS spectra were recorded on P-SIMS-Gly
of Bruker Daltonics. IR spectra were recorded on a Nicolet MX-1E
FTIR spectromter. HPLC analysis was performed on Waters-Breeze
(2487 Dual l Absorbance Detector and 1525 Binary HPLC Pump). Chir-
alpak AS, AD, OD, and OJ columns were purchased from Daicel Chemi-
cal Industries. Hexane and ethyl acetate for column chromatography
were distilled before use.
ꢁ
TS-1,4-03, the distance of the C C bond being formed in
TS-1,2-03 is longer than that in TS-1,4-03 by about 0.1 Š.
However, the later is favored with a lower enthalpy of
about 1.2kcalmol ꢁ1 due to stabilization by the two hydro-
gen bonds formed between water and both the hydroxyl
group and amide oxygen. The solvation interactions stabi-
lized the late TS of TS-1,4-03 and reduced the activation
energy highly. Although the lower stability of the intermedi-
ate enol-enamine reduced the activation energy of TS-1,2-03
substantially, the barrier of TS-1,2-03 is slightly lower than
TS-1,4-04 by about 3.3 kcalmolꢁ1. Considering the evaluated
total barrier reaching to 23–26 kcalmolꢁ1, the selectivity to
generate either of the 1,2- or 1,4-diols should not only
depend on the activation barrier, but also on the stability of
the two intermediates, complexes I and II. The favorable
formation of the excellent H-bonding bridge in complex II
in aqueous media was beneficial to the regioselective forma-
tion of 1,4-diol, which was the major product observed ex-
perimentally in the aqueous solution. While in pure THF, it
was impossible to form such a bridged H-bond to stabilize
both intermediate and TS, therefore the formation of the
1,2-diol became a dominant product.
Materials: All starting materials were purchased from Acros or Aldrich
and used directly
General procedure for the aldol reaction: Hydroxyacetone (0.5 mL) was
added to a solution of the aldehyde (0.5 mmol) and catalyst (20–30
mol%) in a solvent mixture of H2O (0.5 mL) and THF (1.0 mL). After
the reaction mixture had been stirred at ꢁ158C for 2.5–5 days, the reac-
tion was quenched with saturated aqueous ammonium chloride solution
and the layers were separated. The aqueous layer was extracted with
ethyl acetate (3”10 mL). The combined organic layers were washed with
brine and dried over anhydrous MgSO4. After removal of solvent, the
residue was purified by flash-column chromatography on silica gel
(CH2Cl2/AcOEt 6:1) to give the pure adducts.
1,4-Dihydroxy-4-(4-nitrophenyl)butan-2-one (5a): Table 2, entry 1; Yield:
95%; white solid; m.p. 80–828C; [a]2D5 =+51.6 (c=0.31 in EtOAc);
1H NMR (300 MHz, CDCl3): d=2.75–2.92 (m, 2H), 2.95–2.99 (t, J=
5.0 Hz, 1H), 3.14 (d, J=3.5 Hz, 1H), 4.3 (d, J=4.9 Hz, 2H), 5.3 (m, 1H),
7.6 (d, J=8.8 Hz, 2H), 8.23 ppm (d, J=8.8 Hz, 2H); 13C NMR (75 MHz,
CDCl3): d=46.9, 68.2, 68.5, 123.0, 126.4, 147.5, 151.9, 208.2 ppm; IR
(KBr): n˜ =3382, 2898, 1735, 1604, 1516, 1344, 1081, 1052, 858 cmꢁ1
;
95% ee, determined by HPLC (Daicel Chiralpak AS-H, iPrOH/hexane
30:70), detection method=UV spectroscopy (l=254 nm), flow rate=
1.0 mLminꢁ1, R isomer: tR =12.8 min, S isomer: tR =16.8 min.
Conclusions
4-(2-Chlorophenyl)-1,4-dihydroxybutan-2-one (5b): Table 2, entry 2;
Yield: 84%; colorless oil; [a]2D5 =+73.9 (c=0.41 in EtOAc); 1H NMR
(300 MHz, CDCl3): d=2.34–2.92 (m, 2H), 3.47 (m, 1H), 4.29 (dd, J=
19.2, 23.4 Hz, 2H), 5.57 (m, 1H), 7.22–7.34 (m, 3H), 7.60 ppm (m, 1H);
13C NMR (75 MHz, CDCl3): d=45.3, 66.6, 68.8, 126.8, 127.3, 128.8, 129.4,
139.8, 209.2 ppm; IR (KBr): n˜ =3334, 2904, 1721, 1594, 1489, 1088,
l-Proline amides derived from simple amines and optically
pure b-amino alcohols have been evaluated for their ability
at catalyzing the direct aldol reaction of hydroxyacetone
with 4-nitrobenzaldehyde in aqueous media, demonstrating
that the organocatalyst prepared from (2R,3R)-diethyl 2-
amino-3-hydroxysuccinate and l-proline shows superior
stereo- and regiocontrol for the reaction. In the presence of
20–30 mol% of the catalyst, excellent enantioselectivities
ranging from 91 to 99% ee and high regioselectivities were
observed for the otherwise disfavored products from direct
aldol reactions of hydroxyacetone with a broad scope of al-
dehydes. Aldolizations of fluoacetone with aldehydes medi-
ated by 30 mol% of the organocatalyst in aqueous media
preferentially occurred at the methyl group with good regio-
selectivities (up to 7:1) and high enantioselectivities (up to
91% ee). The aldol adducts from the reaction of hydroxya-
cetone have been used for the preparation of chiral 3,5-dis-
ubstituted tetrafurans in high optical purity and a biological-
ly active compound, (2S,4R)-dihydroxy-4-biphenylbutyric
acid. Theoretical studies on the transition states by using a
microsolvation model revealed that the role of water in con-
trolling the regioselectivity arises from the hydrogen bonds
formed between water and the amide oxygen of the proline
amide and hydroxy of hydroxyacetone.
1056 cmꢁ1
; 93% ee, determined by HPLC (Daicel Chiralpak AS-H,
iPrOH/hexane 30:70), detection method=UV spectroscopy (l=254 nm),
flow rate=1.0 mLminꢁ1, R isomer: tR =7.6 min, S isomer: tR =6.5 min.
1,4-Dihydroxy-4-(4-trifluoromethylphenyl)butan-2-one (5c): Table 2,
entry 3; Yield: 90%; white solid; m.p. 104–1058C; [a]2D5 =+52.3 (c=0.30
in EtOAc); 1H NMR (300 MHz, CDCl3): d=2.71–2.92 (m, 2H), 4.26 (s,
2H), 5.29 (m, 1H), 7.48 (d, J=8.1 Hz, 2H), 8.24 ppm (d, J=8.1 Hz, 2H);
13C NMR (75 MHz, CDCl3): d=47.2, 69.1, 69.5, 124.1 (q, J=270 Hz),
125.8 (q, J=3.8 Hz), 126.0, 130.3 (q, J=32Hz), 146.5, 209.0 ppm; IR
(KBr): n˜ =3392, 2907, 1722, 1618, 1304, 1110, 1068, 842 cmꢁ1; 96% ee, de-
termined by HPLC (Daicel Chiralpak AS-H, iPrOH/hexane 15:85), de-
tection method=UV spectroscopy (l=254 nm), flow rate=1.0 mLminꢁ1
R isomer: tR =16.0 min, S isomer: tR =19.0 min.
;
1,4-Dihydroxy-4-(2-nitrophenyl)butan-2-one (5d): Table 2, entry 4; Yield:
82%; white solid; m.p. 108–110 8C; [a]2D8 =ꢁ105.9 (c=0.32in EtOAc);
1H NMR (300 MHz, CDCl3): d=2.84 (m, 2H), 4.29 (s, 2H), 5.67 (m,
1H), 7.48 (m, 1H), 7.71 (m, 1H), 7.91 ppm (m, 2H); 13C NMR (75 MHz,
CDCl3): d=47.9, 66.0, 69.3, 125.1, 129.2, 129.3, 134.4, 141.1, 148.8,
209.3 ppm; IR (KBr): n˜ =3361, 2941, 1715, 1608, 1577, 1523, 1514, 1089,
1019, 741 cmꢁ1; 92 %ee, determined by HPLC (Daicel Chiralpak AS-H,
iPrOH/hexane=30:70), detection method=UV spectroscopy (l=
254 nm), flow rate=1.0 mLminꢁ1, R isomer: tR =12.6 min, S isomer: tR =
10.2min.
1,4-Dihydroxy-4-(3-nitrophenyl)butan-2-one (5e): Table 2, entry 5; Yield:
89%; white solid; m.p. 132–1348C; [a]2D5 =+24.4 (c=0.32in EtOAc);
1H NMR (300 MHz, CDCl3): d=2.16–2.94 (m, 2H), 4.24 (dd, J=18.7,
23.2 Hz, 2H), 5.27 (m, 1H), 7.58 (t, J=8.0 Hz, 1H), 7.79 (d, J=7.7 Hz,
1H), 8.13 (m, 1H), 8.30 ppm (d, J=1.7 Hz, 1H); 13C NMR (75 MHz,
696
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Chem. Eur. J. 2007, 13, 689 – 701

Asymmetric Aldol Reactions
FULL PAPER
CDCl3): d=47.0, 68.2, 68.4, 120.3, 121.8, 129.2, 131.8, 146.8, 148.4,
208.3 ppm; IR (KBr): n˜ =3482, 3379, 2909, 1716, 1599, 1508, 1344, 1081,
1058, 810, 741 cmꢁ1; 95% ee, determined by HPLC (Daicel Chiralpak
AS-H, iPrOH/hexane 20:80), detection method=UV spectroscopy (l=
254 nm), flow rate=1.0 mLminꢁ1, R isomer: tR =24.3 min, S isomer: tR =
28.6 min.
scopy (l=254 nm); flow rate=1.0 mLminꢁ1, R isomer: tR =17.1 min, S
isomer: tR =19.5 min; HRMS (FTICR-MS): m/z: calcd for
C10H11ClO3+Na+: 237.0289; found: 237.0294.
1,4-Dihydroxy-4-(2-fluorophenyl)butan-2-one (5l): Table 2, entry 12;
Yield: 80%; white solid; m.p. 67–698C; [a]2D5 =+70.5 (c=0.60 in
EtOAc); 1H NMR (300 MHz, CDCl3): d=2.81–2.94 (m, 2H), 3.07 (s,
2H), 4.23 (s, 2H), 5.50 (m, 1H), 7.03 (m, 1H), 7.18 (m, 1H), 7.27 (m,
1H); 7.52ppm (m, 1H); 13C NMR (75 MHz, CDCl3): d=45.7, 64.3, 68.7
(d, J=12.2 Hz), 115.4 (d, J=21 Hz), 124.5, 127.1 (d, J=3.5 Hz), 129.4 (d,
J=8.3 Hz), 157.7, 161.0, 209.2 ppm; IR (KBr): n˜ =3356, 2922, 1716, 1615,
1586, 1490, 1454, 1075, 1051, 765 cmꢁ1; 93% ee, determined by HPLC
(Daicel Chiralpak AS-H, iPrOH/hexane 15:85), detection method=UV
spectroscopy (l=254 nm), flow rate=mLminꢁ1, R isomer: tR =14.4 min,
S isomer: tR =13.4 min; HRMS (FTICR-MS): m/z: calcd for C10H11FO3 +
Na+: 221.0584; found: 221.0578.
4-(3,5-Dibromophenyl)-1,4-dihydroxybutan-2-one (5 f): Table 2, entry 6;
Yield: 85%; white solid; m.p. 91–938C; [a]2D5 =+38.2( c=0.51 in
EtOAc); 1H NMR (300 MHz, CDCl3): d=2.34–2.94 (m, 2H), 4.28 (s,
2H), 5.16 (m, 1H), 7.44 (d, J=1.4 Hz, 1H), 7.58 ppm (m, 1H); 13C NMR
(75 MHz, CDCl3): d=46.9, 68.6, 68.9, 123.2, 127.4, 133.5, 146.4,
208.7 ppm; IR (KBr): n˜ =3432, 2882, 1719, 1583, 1554, 1122, 1035, 850,
741 cmꢁ1
; 96% ee, determined by HPLC (Daicel Chiralpak AS-H,
iPrOH/Hexane 20:80), detection method detection method=UV spectro-
scopy (l=254 nm), flow rate=1.0 mLminꢁ1; R isomer: tR =8.6 min, S
isomer: tR =10.8 min.
4-(2,6-Dichlorophenyl)-1,4-dihydroxybutan-2-one (5m): Table 2, entry 13;
Yield: 82%; white solid; m.p. 94–96 8C; [a]2D5 =ꢁ10.0 (c=0.34 in EtOAc);
1H NMR (300 MHz, CDCl3): d=2.74 (m, 1H), 3.47 (m, 1H), 4.35 (m,
2H), 6.01 (m, 1H), 7.17 (m, 1H), 7.32ppm (m, 2H); 13C NMR (75 MHz,
CDCl3): d=43.4, 67.5, 129.4, 129.6, 134.5, 135.9, 207.8 ppm; IR (KBr):
n˜ =3400, 2986, 1729, 1576, 1558, 1433, 1074, 1062, 790, 766 cmꢁ1; 99% ee,
determined by HPLC (Daicel Chiralpak OJ-H, iPrOH/hexane 10:90), de-
1,4-Dihydroxy-4-(4-cyanophenyl)butan-2-one (5g): Table 2, entry 7;
Yield: 90%; colorless oil; [a]2D5 =+24.4 (c=0.32in EtOAc); 1H NMR
(300 MHz, CDCl3): d=2.71–3.26 (m, 2H), 4.27 (s, 2H), 5.29 (m, 1H),
7.49 (d, J=8.2Hz, 2H), 7.65 ppm (d, J=8.2Hz, 2H); 13C NMR
(75 MHz, CDCl3): d=46.9, 68.9, 69.1, 111.7, 118.5, 126.2, 132.4, 147.7,
208.7 ppm; IR (KBr): n˜ =3411, 2922, 2229, 1720, 1609, 1559, 1504, 1409,
1110, 1072, 842, 681 cmꢁ1; 94% ee, determined by HPLC (Daicel Chiral-
pak AS-H, iPrOH/hexane 30:70), detection method=UV spectroscopy
(l=254 nm), flow rate=1.0 mLminꢁ1, R isomer: tR =13.4 min, S isomer:
tR =21.0 min.
tection method=UV spectroscopy (l=254 nm), flow rate=1.0 mLminꢁ1
R isomer: tR =27.0 min, S isomer: tR =25.1 min.
,
4-Biphenyl-4-yl-1,4-dihydroxybutan-2-one (5n): Table 2, entry 14; Yield:
40%; white solid; m.p. 123–1348C; [a]3D0 =+43.3 (c=0.40 in EtOAc);
1H NMR (300 MHz, CDCl3): d=2.73–2.99 (m, 2H), 3.10 (brs, 1H), 4.29
(d, J=3.7 Hz, 2H), 5.27 (m, 2H), 7.41 (m, 5H), 7.59 ppm (m, 4H);
13C NMR (75 MHz, CDCl3): d=47.2, 69.0, 69.9, 126.0, 127.0, 127.4, 128.8,
140.5, 141.0, 141.5, 209.1 ppm; IR (KBr): n˜ =3409, 3330, 2868, 1712, 1608,
1566, 1486, 1406, 1077, 1050, 843 cmꢁ1; 95% ee, determined by HPLC
(Daicel Chiralpak AS-H, iPrOH/Hexane 10:90), detection method=UV
4-(3,5-Bis-trifluoromethylphenyl)-1,4-dihydroxybutan-2-one
(5h):
Table 2, entry 8; Yield: 79%; white solid; m.p. 119–1218C; [a]2D5 =+39.7
(c=0.30 in EtOAc); 1H NMR (300 MHz, CDCl3): d=2.77–2.94 (m, 2H),
3.29 (d, J=3.0 Hz, 1H), 4.33 (d, J=3.0 Hz, 2H), 5.39 (d, J=4.5 Hz, 1H),
7.82(s, 1H), 7.9 ppm (s, 2H); 13C NMR (75 MHz, CDCl3): d=46.9, 68.6,
68.9, 121.9, 124.9, 125.9, 131.8, 144.9, 208.7 ppm; IR (KBr): n˜ =3424,
2919, 1719, 1623, 1279, 1132, 1074, 842, 681 cmꢁ1; 96% ee, determined by
HPLC (Daicel Chiralpak AS-H, iPrOH/hexane 5:95), detection
spectroscopy (l=254 nm), flow rate=1.0 mLminꢁ1
, R isomer: tR =
24.5 min, S isomer: tR =29.9 min; HRMS (FTICR-MS): m/z: calcd for
C16H16O3+Na+: 279.0992; found: 279.0982.
method=UV spectroscopy (l=254 nm), flow rate=1.0 mLminꢁ1
, R
isomer: tR =11.1 min, S isomer: tR =13.6 min; HRMS (FTICR-MS): m/z:
calcd for C12H9F6O3: 315.0450 [M]+; found: 315.0460.
4-(1-Bromonaphthalen-2-yl)-1,4-dihydroxybutan-2-one (5o): Table 2,
entry 15; Yield: 77%; white solid; m.p. 103–1058C; [a]3D0 =+59.8 (c=0.61
in EtOAc); 1H NMR (300 MHz, CDCl3): d=2.76–3.00 (m, 2H), 3.08
(brs, 1H), 3.15 (brs, 1H), 4.35 (s, 2H), 5.90 (d, J=9.6 Hz, 1H), 7.57 (m,
2H), 7.74 (d, J=8.6 Hz, 1H), 7.85 (m, 2H), 8.31 ppm (d, J=8.4 Hz, 1H);
13C NMR (75 MHz, CDCl3): d=45.5, 68.8, 69.8, 121.0, 123.8, 126.8, 127.2,
127.7, 128.2, 128.4, 132.0, 134.2, 139.3, 209.1 ppm; IR (KBr): n˜ =3401,
2915, 1715, 1630, 1498, 1086, 1054, 1013, 821, 744 cmꢁ1; 99% ee, deter-
mined by HPLC (Daicel Chiralpak AS-H, iPrOH/hexane 30:70), detec-
tion method=UV spectroscopy (l=254 nm), flow rate=1.0 mLminꢁ1, R
isomer: tR =8.0 min, S isomer: tR =6.9 min; HRMS (FTICR-MS): m/z:
calcd for C14H13BrO3 +Na+: 330.9940; found: 330.9933.
1,4-Dihydroxy-4-(2-bromophenyl)butan-2-one (5i): Table 2, entry 9;
Yield: 84%; white solid; m.p. 72.5–73.58C; [a]2D5 =+63.1 (c=0.71 in
EtOAc); 1H NMR (300 MHz, CDCl3): d=2.64–2.94 (m, 2H), 3.19 (brs,
2H), 4.31 (s, 2H), 5.52 (m, 1H), 7.17 (m, 1H), 7.36 (m, 1H), 7.52 (m,
1H); 7.61 ppm (m, 1H); 13C NMR (75 MHz, CDCl3): d=45.5, 68.7, 68.8,
121.1, 127.1, 127.9, 129.2, 132.7, 141.4, 209.1 ppm; IR (KBr): n˜ =3394,
2909, 1718, 1566, 1466, 1071, 1056, 758 cmꢁ1; 93% ee, determined by
HPLC (Daicel Chiralpak AS-H, iPrOH/hexane 15:85), detection
method=UV spectroscopy (l=254 nm), flow rate=1.0 mLminꢁ1
, R
isomer: tR =14.9 min, S isomer: tR =13.2min; HRMS (FTICR-MS) m/z:
calcd for C10H11BrO3 +Na+: 280.9784; found: 280.9774.
1,4-Dihydroxy-4-phenylbutan-2-one (5p): Table 2, entry 16; Yield: 44%;
white solid; m.p. 119–1228C; [a]3D0 =+43.6 (c=0.25 in EtOAc); 1H NMR
(300 MHz, CDCl3): d=2.71–2.96 (m, 2H), 2.82 (brs, 1H), 3.07 (brs, 1H),
4.27 (s, 2H), 2.21–5.24 (m, 1H), 7.26–7.36 ppm (m, 5H); 13C NMR
(75 MHz, CDCl3): d=47.3, 69.0, 70.2, 125.5, 128.1, 128.7, 142.5,
209.1 ppm; IR (KBr): n˜ =3526, 3312, 2921, 1716, 1499, 1452, 1390, 1075,
1050, 765, 709 cmꢁ1; 97% ee, determined by HPLC (Daicel Chiralpak
AS-H, iPrOH/hexane 15:85), detection method=UV spectroscopy (l=
222 nm), flow rate=1.0 mLminꢁ1, R isomer: tR =16.0 min, S isomer, tR =
17.4 min; HRMS (FTICR-MS): m/z: calcd for C10H12O3+Na+: 203.0679;
found: 203.0686.
4-(4-Bromophenyl)-1,4-dihydroxybutan-2-one (5j): Table 2, entry 10;
Yield: 69%; white solid; m.p. 110–1128C; [a]2D5 =+54.1 (c=0.32in
EtOAc); H NMR (300 MHz, CDCl3): d=2.68–2.91 (m, 2H), 2.93 (d, J=
1
3.0 Hz, 1H), 3.04 (t, J=4.9 Hz, 1H), 4.27 (d, J=3.1 Hz, 2H), 5.19 (m,
1H), 7.23 (d, J=6.6 Hz, 2H), 7.48 ppm (d, J=6.6 Hz, 2H); 13C NMR
(75 MHz, CDCl3): d=47.1, 68.9, 69.4, 121.9, 127.2, 131.8, 141.5,
208.9 ppm; IR (KBr): n˜ =3318, 2902, 1721, 1589, 1484, 1397, 1077, 1054,
825 cmꢁ1
; 93% ee, determined by HPLC (Daicel Chiralpak AS-H,
iPrOH/hexane 15:85), detection method=UV spectroscopy (l=254 nm),
flow rate=1.0 mLminꢁ1, R isomer: tR =16.9 min, S isomer: tR =20.1 min;
HRMS (FTICR-MS): m/z: calcd for C10H11BrO3 +Na+: 280.9784; found:
280.9777.
1,4-Dihydroxy-4-(cyclohexyl)butan-2-one (5q): Table 2, entry 17; Yield:
28%; colorless oil; m.p. 103–1058C; [a]2D5 =+10.2( c=0.46 in EtOAc);
1H NMR (300 MHz, CDCl3): d=0.96–1.40 (m, 6H), 1.63–1.84 (m, 5H),
2.53 (brs, 1H), 2.54–2.62 (m, 2H), 3.16 (brs, 1H), 3.84–3.90 (m, 1H),
4.28 ppm (s, 2H); 13C NMR (75 MHz, CDCl3): d=25.9, 26.0, 26.3, 28.1,
28.7, 42.4, 43.3, 68.9, 71.9, 210.6 ppm; IR (neat): n˜ =3359, 2924, 2851,
1720, 1672, 1447, 1093, 1059 cmꢁ1; 98% ee, determined by HPLC (Daicel
Chiralpak AD-H, iPrOH/hexane 30:70), detection method=UV spectro-
scopy (l=254 nm), flow rate=1.0 mLminꢁ1, R isomer: tR =20.7 min, S
4-(4-Chlorophenyl)-1,4-dihydroxybutan-2-one (5k): Table 2, entry 11;
Yield: 70%; white solid; m.p. 103–1058C; [a]3D0 =+45.0 (c=0.30 in
EtOAc); 1H NMR (300 MHz, CDCl3): d=2.68–2.91 (m, 2H), 2.88 (s,
1H), 3.01 (s, 1H), 4.28 (s, 2H), 5.21 (m, 1H), 7.30 (d, J=6.2Hz, 2H),
7.34 ppm (d, J=6.2Hz, 2H); 13C NMR (75 MHz, CDCl3): d=47.2, 69.0,
69.4, 126.9, 128.8, 133.7, 141.0, 209.0 ppm; IR (KBr): n˜ =3434, 3329, 2921,
1729, 1623, 1470, 1109, 1078 cmꢁ1; 95% ee, determined by HPLC (Daicel
Chiralpak AS-H, iPrOH/hexane 15:85); detection method=UV spectro-
Chem. Eur. J. 2007, 13, 689 – 701
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697

L.-Z. Gong et al.
isomer: tR =24.1 min; HRMS (FTICR-MS): m/z: calcd for
C10H18O3+Na+: 209.1148; found: 209.1140.
al of solvent, the residue was azeotroped a few times with methanol until
the hydrolysis of boronate was complete. The crude product was purified
by flash-column chromatography on silica gel (CH2Cl2/MeOH 40:1).
General procedure for the aldol reaction of aldehydes and fluoroacetone:
Fluoroacetone (0.3 mL) was added to
a
solution of the aldehyde
General procedure for the syntheses of anti 1,2,4-triols: Acetic acid
(0.25 mol) and catalyst (30 mol%) in a solvent mixture of H2O (0.5 mL)
and THF (0.5 mL). After the reaction mixture had been stirred at ꢁ158C
for 2–3 days, the reaction was quenched with saturated aqueous ammoni-
um chloride solution and the layers were separated. The aqueous layer
was extracted with ethyl acetate. The combined organic layers were
washed with brine and dried over anhydrous MgSO4. After removal of
solvent, the residue was purified by flash-column chromatography on
silica gel (hexane/ethyl acetate 4:1) to give the pure adducts.
(1.5 mL) was added to a suspension of NaBH(OAc)3 (3.0 mmol) in THF
A
(3 mL) at ꢁ788C under argon. After 10 min, a solution of 1,4-diols
(1.0 mmol) in THF (2mL) was added. The reaction mixture was stirred
at this temperature for 3 h, and then it was warmed to room temperature.
The reaction was quenched with water (2mL). After being neutralized
with 20% aqueous NaOH solution, the aqueous layer was extracted with
ethyl acetate (3”10 mL). The combined organic layers were washed with
brine and dried over MgSO4. After removal of solvent, the residue was
purified by flash-column chromatography on silica gel (CH2Cl2/MeOH
40:1) to give the pure product.
1-Fluoro-4-hydroxy-4-(4-nitrophenyl)butan-2-one (11a): Table 3, entry 2:
Yield: 62%; white solid; m.p. 76–78 8C; [a]2D5 =+41.0 (c=0.30 in
EtOAc); 1H NMR (300 MHz, CDCl3): d=2.91–3.06 (m, 2H), 3.23 (brs,
1H), 4.71 (d, J=47.4 Hz, 2H), 5.33–5.37 (m, 1H), 7.6 (d, J=8.9 Hz, 2H),
8.22 ppm (d, J=8.8 Hz, 2H); 13C NMR (75 MHz, CDCl3): d=46.9, 68.3,
85.0 (d, J=184.0 Hz), 123.9, 126.4, 147.4, 149.6, 206.3 ppm (d, J=
20.1 Hz); IR (KBr): n˜ =3446, 2922, 1733, 1606, 1518, 1347, 1108, 1052,
General procedure for the cyclization of 1,2,4-triols: Trimethylorthoace-
tate (0.6 mmol) and a catalytic amount of PPTS (0.01 mmol) were added
to a solution of triols (0.5 mmol) in anhydrous CH2Cl2 (10 mL). The reac-
tion mixture was stirred at room temperature for 30 min, and then
cooled down to 08C. Boron trifluoroetherate (0.05 mmol) was added and
the reaction mixture was stirred at 08C for 2h, and then it was gradually
warmed to room temperature. The reaction was quenched with saturated
aqueous sodium bicarbonate. The resultant aqueous solution was diluted
with water (5 mL) and extracted with CH2Cl2 (3”10 mL). The combined
organic layers were washed with brine and dried over sodium sulfate.
After the solvent had been removed under reduced pressure, the residue
was purified by column chromatography (hexane/ethyl acetate 4:1) on
silica gel to give the pure product
857 cmꢁ1
; 80% ee, determined by HPLC (Daicel Chiralpak AS-H,
iPrOH/hexane 30:70), detection method=UV spectroscopy (l=254 nm),
flow rate=1.0 mLminꢁ1, R isomer: tR =13.6 min, S isomer: tR =20.1 min;
HRMS (FTICR-MS): m/z: calcd for C10H10FNO4+Na+: 250.0486; found:
250.0490.
4-(3,5-Dibromophenyl)-1-fluoro-4-hydroxybutan-2-one (11 f): Table 3,
entry 3; Yield: 57%; white solid; m.p. 82–848C; [a]2D5 =+40.3 (c=0.34 in
EtOAc); 1H NMR (300 MHz, CDCl3): d=2.90–3.02 (m, 2H), 3.07 (brs,
1H), 4.84 (d, J=47.4 Hz, 2H), 5.16–5.20 (m, 1H), 7.45 (s, 2H), 7.57 ppm
(s, 1H); 13C NMR (75 MHz, CDCl3): d=46.9, 51.5, 85.0 (d, J=184.2Hz),
123.2, 127.5, 133.1, 133.4, 206.3 ppm (d, J=20.2 Hz); IR (KBr): n˜ =3432,
2924, 1729, 1586, 1557, 1424, 1109, 1054, 741 cmꢁ1; 84% ee, determined
by HPLC (Daicel Chiralpak AD-H, iPrOH/hexane 10:90), detection
(3S,5S)-acetic acid 5-(4-nitrophenyl)tetrahydrofuran-3-yl ester (15a):
Table 5, entry 1; Yield: 71%; white solid; m.p. 108–1108C; [a]3D0 =ꢁ3.6
(c=0.14 in EtOAc); 1H NMR (300 MHz, CDCl3): d=1.92–2.02
(m, 1H),
U
2.12 (s, 3H), 2.47–2.53 (m, 1H), 3.97–4.01 (m, 1H), 4.33–4.38 (m, 1H),
5.14–5.19 (m, 1H), 5.42(m, 1H), 7.50 (m, 2H), 8.02 ppm (m, 2H);
13C NMR (75 MHz, CDCl3): d=21.1, 41.3, 73.9, 75.0, 78.8, 123.8, 126.3,
147.4, 149.1, 170.6 ppm; IR (KBr): n˜ =2986, 2853, 1722, 1605, 1514, 1344,
1248, 1084, 859 cmꢁ1; 96% ee, determined by HPLC (Daicel Chiralpak
AS-H, iPrOH/Hexane 30:70), detection method=UV spectroscopy (l=
method=UV spectroscopy (l=254 nm), flow rate=1.0 mLminꢁ1
; R
isomer: tR =15.4 min, S isomer: tR =17.5 min; HRMS (FTICR-MS): m/z:
calcd for C10H9Br2FO2 +Na+: 360.8846; found: 360.8845.
1-Fluoro-4-hydroxy-4-(3-nitrophenyl)butan-2-one (11e): Table 3, entry 4;
Yield: 55%; white solid; m.p. 88–908C; [a]2D5 =+47.5 (c=0.20 in
EtOAc); 1H NMR (300 MHz, CDCl3): d=2.92–3.10 (m, 2H), 3.21 (brs,
1H), 4.87 (d, J=47.5 Hz, 2H), 5.34–5.38 (m, 1H), 7.55 (t, J=7.9 Hz,
1H), 7.73 (d, J=7.7 Hz, 1H), 8.16 (m, 1H), 8.27 ppm (s, 1H); 13C NMR
(75 MHz, CDCl3): d=47.0, 68.2, 85.0 (d, J=184.2 Hz), 120.7, 122.8, 129.6,
131.7, 144.5, 206.2 ppm (d, J=20.1 Hz); IR (KBr): n˜ =3550, 2937, 1729,
1582, 1529, 1071, 1026, 810, 717 cmꢁ1; 83% ee, determined by HPLC
(Daicel Chiralpak OJ-H, iPrOH/hexane 30:70), detection method=UV
254 nm), flow rate=1.0 mLminꢁ1
; (R,R) isomer: tR =14.4 min, (S,S)
isomer: tR =20.1 min; HRMS (FTICR-MS): calcd for C12H13NO5+Na+:
m/z: 275.0686; found: 274.0696.
A
Yield: 74%; white solid; m.p. 81.5–83; [a]3D0 =+13.5 (c=0.23 in EtOAc);
1H NMR (300 MHz, CDCl3): d=1.94–2.00 (m, 4H), 2.75–2.85 (m, 1H),
3.99–4.04 (m, 1H), 4.16–4.20 (m, 1H), 4.99–5.04 (m, 1H), 5.35 (m, 1H),
7.53 (m, 2H), 8.21 ppm (m, 2H); 13C NMR (75 MHz, CDCl3): d=20.9,
40.7, 73.7, 74.8, 79.1, 123.6, 126.5, 147.3, 149.7, 170.6 ppm; IR (KBr): n˜ =
2919, 2862, 1739, 1605, 1514, 1347, 1246, 1094, 854 cmꢁ1; HRMS (FTICR-
MS) calcd for C12H13NO5+Na+: m/z: 275.0686; found: 274.0678.
spectroscopy (l=254 nm), flow rate=1.0 mLminꢁ1
; R isomer: tR =
13.8 min, S isomer: tR =16.5 min; HRMS (FTICR-MS): m/z: calcd for
C10H10FNO4+Na+: 250.0486; found: 250.0490.
A
4-(2,6-Dichlorophenyl)-1-fluoro-4-hydroxybutan-2-one (11m): Table 3,
entry 5; Yield: 65%; colorless oil; [a]2D5 =ꢁ12.5 (c=0.52in EtOAc);
1H NMR (300 MHz, CDCl3): d=2.83–2.90 (m, 1H), 3.13 (brs, 1H), 3.60–
3.69 (m, 1H), 4.89 (d, J=47.5 Hz, 2H), 6.02–6.06 (m, 1H), 7.15–7.20 (m,
1H), 7.29–7.34 ppm (m, 2H); 13C NMR (75 MHz, CDCl3): d=43.2, 66.9,
85.2(d, J=184.1 Hz), 129.5, 134.4, 135.8, 205.3 ppm (d, J=20.2 Hz); IR
(15b): Table 5, entry 2; Yield: 81%; colorless oil; [a]3D0 =ꢁ4.8 (c=0.40 in
EtOAc); 1H NMR (300 MHz, CDCl3): d=1.89–2.01 (m, 1H), 2.10 (s,
3H), 2.39–2.46 (m, 1H), 3.93–3.96 (m, 1H), 4.29–4.34 (m, 1H), 4.98–5.03
(m, 1H), 5.37–5.40 (m, 1H), 7.41 (s, 2H), 7.57 ppm (s, 1H); 13C NMR
(75 MHz, CDCl3): d=21.1, 41.3, 73.8, 75.0, 78.3, 123.0, 127.4, 133.1, 145.7,
170.6 ppm; IR (neat): n˜ =2936, 2875, 1738, 1587, 1557, 1242, 1221, 1081,
855, 740 cmꢁ1; HRMS (FTICR-MS): m/z: calcd for C12H12Br2O3+Na+:
384.9045; found: 384.9048.
(neat): n˜ =3455, 2928, 1719, 1580, 1561, 1437, 1089, 1049, 768, 732 cmꢁ1
;
91% ee, determined by HPLC (Daicel Chiralpak OD-H, iPrOH/hexane
5:95), detection method=UV spectroscopy (l=254 nm), flow rate=
1.0 mLminꢁ1; R isomer: tR =21.1 min, S isomer: tR =17.8 min; HRMS
(FTICR-MS): m/z: calcd for C10H9Cl2FO2+Na+: 272.9856; found:
272.9860.
(3S,5S)-acetic acid 5-(4-cyanophenyl)tetrahydrofuran-3-yl ester (15c):
Table 5, entry 3; Yield: 74%; colorless oil; [a]3D0 =ꢁ2.2 (c=0.27 in
EtOAc); 1H NMR (300 MHz, CDCl3): d=1.92–2.00 (m, 1H), 2.10 (s,
3H), 2.43–2.50 (m, 1H), 3.94–3.99 (m, 1H), 4.31–4.36 (m, 1H), 5.08–5.13
(m, 1H), 5.39 (m, 1H), 7.44 (d, J=8.1 Hz, 2H), 7.63 ppm (m, 2H);
13C NMR (75 MHz, CDCl3): d=20.0, 41.3, 73.9, 75.0, 78.9, 111.4, 118.7,
126.2, 132.3, 147.1, 170.6 ppm; IR (neat): n˜ =2941, 2879, 2228, 1738, 1609,
1505, 1374, 1245, 1087, 837 cmꢁ1; HRMS (FTICR-MS): m/z: calcd for
C13H13NO3+Na+: 254.0788; found, 254.0794.
General procedure for the syntheses of syn 1,2,4-triols: Alkoxydialkylbor-
ane (1.1 mmol, 1.1 mL) was added dropwise to a solution of 1,4-diols
(1.0 mmol) in anhydrous THF (8 mL) and MeOH (2mL) at ꢁ788C.
After the resulting mixture had been stirred for 15 min, sodium borohy-
dride (42mg, 1.1 mmol) was added and the mixture was stirred for 3–5 h
depending on the substrate used. When the reaction was completed, the
addition of AcOH (1 mL) quenched the reaction and the mixture was di-
luted with AcOEt (30 mL). The organic solution was washed with aque-
ous sodium bicarbonate and dried over anhydrous Na2SO4. After remov-
(3S,5S)-acetic acid 5-(2,6-dichlorophenyl)tetrahydrofuran-3-yl (15d):
Table 5, entry 4; Yield: 65%; colorless oil; [a]3D0 =ꢁ29.0 (c=0.40 in
EtOAc); 1H NMR (300 MHz, CDCl3): d=2.13 (s, 3H), 2.25–2.31 (m,
698
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ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 689 – 701

Asymmetric Aldol Reactions
FULL PAPER
1H), 2.45–2.60 (m, 1H), 3.98–4.02 (m, 1H), 4.42–4.47 (m, 1H), 5.50–5.53
(m, 1H), 5.87–5.92(m, 1H), 7.14 (m, 1H), 7.29 ppm (m, 2H);
(75 MHz, CDCl3): d=21.2, 36.4, 73.6, 75.9, 79.4, 129.4, 129.8, 134.6, 135.0,
170.7 ppm; IR (neat): n˜ =2955, 2878, 1740, 1581, 1562, 1438, 1243, 1098,
769, 724 cmꢁ1; HRMS (FTICR-MS): m/z: calcd for C12H12Cl2O3+Na+:
297.0056; found: 297.0047.
d=2.05 (s, 3H), 2.14 (s, 3H), 2.36–2.65 (m, 2H), 5.03–5.07 (m, 1H), 5.30
(brs, 2H), 5.97–6.92 (m, 1H), 7.42 (m, 5H), 7.58 ppm (m, 4H); 13C NMR
(75 MHz, CDCl3): d=20.4, 21.0, 37.0, 68.6, 71.7, 126.9, 127.1, 127.5, 128.8,
137.9, 140.5, 141.5, 170.1, 170.2, 174.5 ppm; IR (KBr): n˜ =3416, 3303,
2855, 1739, 1695, 1600, 1488, 1244, 1066, 847, 769, 698 cmꢁ1; HRMS
(FTICR-MS): m/z: calcd for C20H20O6+Na+ 379.1152; found: 379.1155.
13C NMR
4-Biphenyl-4-yl-2,4-dihydroxybutyric acid (19): LiOH·H2O (1.2mmol,
50.4 mg) was added to a solution of 23 (106.2mg, 0.3 mmol) in a solvent
mixture of THF/H2O/CH3OH (2:1:2, 10 mL). After the reaction mixture
had been stirred at room temperature for 5 h, the organic solvent was re-
moved, then aqueous HCl solution (1.0m) was added slowly to adjust the
pH to pH 4. The material was recrystallized from water to give 19. Yield:
90% (73 mg); white solid; m.p. 144–1468C; [a]3D0 =+26.3 (c=0.27 in
MeOH); 1H NMR (300 MHz, DMSO): d=1.94–1.99 (m, 2H), 3.77–3.79
(m, 1H), 4.74–4.78 (m, 1H), 7.42(m, 5H), 7.64 ppm (m, 4H); 13C NMR
(75 MHz, DMSO): d=43.6, 67.6, 69.4, 126.5, 126.6, 126.7, 127.3, 128.9,
138.9, 140.1, 144.6, 175.7 ppm; IR (KBr): n˜ =3446, 2923, 1710, 1647, 1484,
1098, 837, 762, 726 cmꢁ1; HRMS (FTICR-MS): m/z: calcd for C16H15O4:
271.0965 [M]+; found: 271.0959.
4-Biphenyl-4-yl-1-(tert-butyldimethylsilanyloxy)-4-hydroxybutan-2-one
(20): DMAP (0.174 mmol, 40 mg) and Et3N (3.82mmol, 0.53 mL) were
added to a solution of diol 5n (3.47 mmol, 890 mg) in CH2Cl2 (5 mL) and
CH3CN (5 mL) at RT. The resulting mixture was stirred for 30 min at
08C, and then TBSCl (1.2equiv, 4.17 mmol, 628 mg) in CH 2Cl2 was
added dropwise over 1 h. The reaction mixture was stirred at 08C for an-
other 2h, and then at room temperature for 18 h. After the solvent had
been removed, AcOEt was added to dissolve the residue. The organic
solution was washed with KH2PO4 (1m, 10 mL”2), and the aqueous
phase was extracted with AcOEt (10 mL”3). The combined organic
layers were dried over anhydrous MgSO4. After removal of solvent, the
residue was purified by flash-column chromatography on silica gel
(hexane/ethyl acetate 10:1) to give the pure product. Yield: 81%
(1.039 g); white solid; m.p. 62–63.58C; [a]3D0 =+36.5 (c=0.20 in EtOAc);
1H NMR (300 MHz, CDCl3): d=0.09 (s, 6H), 0.93 (s, 9H), 2.91–3.05 (m,
2H), 3.29 (brs, 1H), 4.21 (s, 2H), 5.21–5.25 (m, 1H), 7.36 (m, 1H), 7.44
(m, 4H), 7.60 ppm (m, 4H); 13C NMR (75 MHz, CDCl3): d=ꢁ5.5, 18.3,
25.7, 45.9, 69.6, 69.7, 126.1, 127.0, 127.3, 128.7, 140.6, 140.7, 141.9,
210.0 ppm; IR (KBr): n˜ =3397, 2928, 2856, 1729, 1640, 1597, 1483, 1260,
1253, 1090, 1050, 837, 767, 698 cmꢁ1; HRMS (FTICR-MS): calcd for
C22H30O3Si+Na+: 393.1856; found: 393.1865.
Acknowledgements
We are grateful for financial support from the National Natural Science
Foundation of China (Grants 20472082, 203900505, and 20325211). We
thank the USTC-HP laboratory of high performance computing for the
generosity in providing computing resources.
1-Biphenyl-4-yl-4-(tert-butyldimethylsilanyloxy)butane-1,3-diol (21): The
procedure described for the synthesis of syn 1,3-diol was same as that for
the syntheses of syn 1,2,4-triols. Yield 97% (syn/anti 97:3); colorless oil;
[a]3D0 =+12.4 (c=0.21 in EtOAc); 1H NMR (300 MHz, CDCl3): d=0.08
(s, 6H), 0.91 (s, 9H), 1.82–1.90 (m, 2H), 3.03 (brs, 1H), 4.21 (s, 2H),
3.45–3.64 (m, 2H), 3.75 (brs, 1H), 3.98 (m, 2H), 5.01–5.05 (m, 1H), 7.41
(m, 1H), 7.46 (m, 4H), 7.59 ppm (m, 4H); 13C NMR (75 MHz, CDCl3):
d=ꢁ5.4, 18.3, 25.9, 41.6, 67.1, 72.4, 73.9, 125.9, 126.2, 127.1, 127.2, 128.7,
140.4, 140.9, 143.4 ppm; IR (neat): n˜ =3387, 3029, 2953, 2856, 1599, 1486,
1471, 1462, 1256, 1124, 1076, 837, 765, 696 cmꢁ1; HRMS (FTICR-MS):
m/z: calcd for C22H32O3Si+Na+: 395.2013; found: 395.2020.
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Acetic acid 3-acetoxy-3-biphenyl-4-yl-1-(tert-butyldimethylsilanyloxyme-
thyl)propyl ester (22): DMAP (0.079 mmol, 18 mg) and acetic anhydride
(2mL) at 0 8C were added to a solution of diol 21 (1.57 mmol, 600 mg) in
pyridine (8 mL), and the mixture was stirred at room temperature for
3 h. After removal of pyridine, AcOEt (20 mL) was added and the organ-
ic solution was washed with aqueous KH2PO4 (1m, 2”10 mL). The aque-
ous solution was extracted with AcOEt (3”10 mL) and the combined or-
ganic layers were washed with brine and dried over anhydrous MgSO4.
After removal of solvent, the residue was purified by flash-column chro-
matography on silica gel (hexane/ethyl acetate 20:1) to give the pure
product. Yield: 95% (TBS ether 677 mg); colorless oil; [a]3D0 =+31.5 (c=
0.31 in EtOAc); 1H NMR (300 MHz, CDCl3): d=0.04 (s, 6H), 0.88 (s,
9H), 2.01 (s, 3H), 2.09 (s, 3H), 2.22–2.28 (m, 2H), 3.62–3.68 (m, 2H),
4.81–4.85, 1H), 5.84–5.88 (m, 1H), 7.37 (m, 5H), 7.56 ppm (m, 4H);
13C NMR (75 MHz, CDCl3); d=ꢁ5.5, 18.2, 21.1, 21.3, 25.8, 36.9, 63.7,
71.4, 73.0, 126.9, 127.1, 127.3, 128.7, 138.9, 140.7, 141.0, 170.1, 170.4 ppm;
IR (neat): n˜ =2955, 2929, 2857, 1741, 1600, 1487, 1471, 1371, 1235, 836,
767, 697 cmꢁ1; HRMS (FTICR-MS): m/z: calcd for C26H36O5Si+Na+:
479.2224; found: 479.2244.
2,4-Diacetoxy-4-biphenyl-4-ylbutyric acid (23): To a solution of Jones re-
agent (4.4 mmol) at 08C in acetone (15 mL) was added dropwise a solu-
tion of 22 (500 mg, 1.1 mmol) in acetone (15 mL). The brown mixture
was stirred for 4 h at room temperature, and then 2-propanol was added
dropwise until the reaction mixture became blue. After filtration and re-
moval of the solvent, water (10 mL) was added. The aqueous phase was
extracted with ethyl acetate (6”10 mL). The combined organic layers
were washed with brine and dried over MgSO4. After evaporation of the
solvent, the residue was purified by flash chromatography (hexane/ethyl
acetate 2:1!1:1), to give 23. Yield 71% (276 mg); white solid; m.p. 125–
1278C; [a]2D5 =+44.1 (c=0.17 in EtOAc); 1H NMR (300 MHz, CDCl3):
Chem. Eur. J. 2007, 13, 689 – 701
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Chem. Eur. J. 2007, 13, 689 – 701

Asymmetric Aldol Reactions
FULL PAPER
J. B. Cross, C. Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann,
O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, P. Y.
Ayala, K. Morokuma, G. A. Voth, P. Salvador, J. J. Dannenberg,
V. G. Zakrzewski, S. Dapprich, A. D. Daniels, M. C. Strain, O.
Farkas, D. K. Malick, A. D. Rabuck, K. Raghavachari, J. B. Fores-
man, J. V. Ortiz, Q. Cui, A. G. Baboul, S. Clifford, J. Cioslowski,
B. B. Stefanov, G. Liu, A. Liashenko, P. Piskorz, I. Komaromi, R. L.
Martin, D. J. Fox, T. Keith, M. A. Al-Laham, C. Y. Peng, A. Na-
nayakkara, M. Challacombe, P. M. W. Gill, B. Johnson, W. Chen,
M. W. Wong, C. Gonzalez, J. A. Pople, Gaussian, Inc., Wallingford
CT, 2004.
Received: June 8, 2006
Published online: October 2, 2006
Chem. Eur. J. 2007, 13, 689 – 701
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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701