A designer axially chiral amino sulfonamide as an efficient organocatalyst for direct asymmetric anti/-selective mannich reactions and syw-selective cross-aldol reactions

Article abstract of DOI:10.1002/chem.200900267

A direct asymmetric Mannich reaction using a novel axially chiral amino sulfonamide (S)-3 that is highly anti- and enantioselective has been developed. For instance, in the presence of a catalytic amount of (S)-3, the reactions between aldehydes and a-imino esters proceeded smoothly to give anti Mannich products with a significantly higher antilsyn ratio and enantioselectivity than previously possible. By utilizing N-Boc-protected aro-matic imines instead of a-imino esters, the synthetically useful Boc protecting group and various aromatic or heteroaromatic substituents were installed into the anti Mannich products and consequently the substrate scope of the anri'-selective Mannich reaction and the synthetic utility of the anti Mannich products have been expanded. The axially chiral amino sulfonamide (S)-3 has also been successfully applied to asymmetric direct cross-aldol reaction between two different aldehydes. The catalyst (S)-3 has the advantage of giving mainly syn products, whereas proline shows the opposite anti selectivity.

Full text of DOI:10.1002/chem.200900267

DOI: 10.1002/chem.200900267
A Designer Axially Chiral Amino Sulfonamide as an Efficient
Organocatalyst for Direct Asymmetric anti-Selective Mannich Reactions and
syn-Selective Cross-Aldol Reactions
Taichi Kano, Yukako Yamaguchi, and Keiji Maruoka*[a]
Abstract: A direct asymmetric Man-
nich reaction using a novel axially
chiral amino sulfonamide (S)-3 that is
highly anti- and enantioselective has
been developed. For instance, in the
presence of a catalytic amount of (S)-3,
the reactions between aldehydes and
a-imino esters proceeded smoothly to
give anti Mannich products with a sig-
nificantly higher anti/syn ratio and
enantioselectivity than previously pos-
sible. By utilizing N-Boc-protected aro-
matic imines instead of a-imino esters,
the synthetically useful Boc protecting
group and various aromatic or hetero-
aromatic substituents were installed
into the anti Mannich products and
consequently the substrate scope of the
anti-selective Mannich reaction and the
synthetic utility of the anti Mannich
products have been expanded. The ax-
ially chiral amino sulfonamide (S)-3
has also been successfully applied to
asymmetric direct cross-aldol reaction
between two different aldehydes. The
catalyst (S)-3 has the advantage of
giving mainly syn products, whereas
proline shows the opposite anti selec-
tivity.
Keywords: aldol reaction · sulfona-
mides
· asymmetric synthesis ·
Mannich reaction · organocatalysis
Introduction
center at the a carbon atom as the key structural features
for obtaining high reactivity and selectivity. Indeed, 2-azeti-
dinecarboxylic acid and pipecolic acid, which are proline an-
alogues with a four- and six-membered ring, respectively,
were found to be much less effective catalysts for the direct
asymmetric aldol reaction.[4] In addition to these observa-
tions, the design of new proline-type catalysts has intrinsic
limitations due to the difficulty in modifying the pyrrolidine
ring. Although asymmetric enamine catalysis has been de-
veloped significantly through the derivatization of the car-
boxylic acid moiety of the parent proline, there is still an
urgent need for structurally and electronically novel cata-
lysts to further expand the scope of this methodology. Other
amino acids and their derivatives have very recently also
been utilized as organocatalysts in some asymmetric reac-
tions, offering new possibilities for catalyst design. However,
non-amino acid derived catalysts are still rare in this
field.[2b,c] In this context, we were interested in the possibili-
ty of designing an amino sulfonamide catalyst with a readily
derivatizable binaphthyl backbone and also of developing
organocatalytic asymmetric reactions by utilizing its unique
molecular geometry and electronic properties. Thus, herein
we wish to report the synthesis of a novel binaphthyl-based
amino sulfonamide catalyst (S)-3 and its successful applica-
tion in direct asymmetric Mannich[5] and aldol reactions.[6]
In this study, rare examples of organocatalytic anti-selective
In recent years, asymmetric organocatalysis has attracted
great interest as a new catalytic method for the synthesis of
a wide variety of chiral molecules, and various organocata-
lysts have been developed to date.[1] Among them, proline
and its derivatives have proven to be effective organocata-
lysts in several powerful asymmetric transformations, such
as the aldol and Mannich reactions.[2] The first example of
such a proline-catalyzed asymmetric reaction, the intramo-
lecular aldol reaction, was reported in the early 1970s,[3] and
the proline-catalyzed intermolecular aldol reaction between
ketones and aldehydes was realized by List and Barbas et al.
nearly 30 years later.[4] Since these pioneering works in the
area of enamine catalysis, a number of proline derivatives
have been designed to demonstrate their efficiency in vari-
ous organocatalytic reactions.[2] Most of these catalysts pos-
sess a highly nucleophilic pyrrolidine ring and a chiral
[a] Dr. T. Kano, Y. Yamaguchi, Prof. K. Maruoka
Department of Chemistry, Graduate School of Science
Kyoto University, Sakyo
Kyoto 606-8502 (Japan)
Fax : (+81)75-753-4041
E-mail: maruoka@kuchem.kyoto-u.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200900267.
6678
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Chem. Eur. J. 2009, 15, 6678 – 6687

FULL PAPER
Mannich reactions and syn-selective cross-aldol reactions
between two different aldehydes have been realized. In par-
ticular, by using our catalyst (S)-3, highly anti- and enantio-
selective Mannich reactions of N-Boc-protected aromatic
imines have been achieved in enamine catalysis at a synthet-
ically useful level. Aromatic imines can now be applied in
hitherto difficult organocatalytic anti-selective Mannich re-
actions, thereby expanding the synthetic scope of this
system.
nich reactions catalyzed by carefully designed proline deriv-
atives have also been reported.[11] In this context we were in-
terested in the possibility of obtaining anti-6 via the s-cis-en-
amine intermediate B by using an amino acid that has a
longer spatial distance between the amino and carboxy
groups than the proline catalyst. Our recently designed ax-
ially chiral amino acid (S)-1,[13] which catalyzes direct asym-
metric aldol reactions between acetone and aldehydes,
seemed to be an appropriate candidate for achieving the
hitherto difficult s-cis-enamine intermediate B because there
is no substituent at the position a to the amine nitrogen
unlike proline. Thus, we first examined the direct Mannich
reaction between 3-methylbutanal and a-imino ester 5 de-
rived from p-anisidine and ethyl glyoxylate in the presence
of 5 mol% of (S)-1. As expected, the reaction proceeded in
dioxane at room temperature to afford a substantial amount
of the anti-b-amino aldehyde anti-6 (R=iPr), albeit with
low diastereoselectivity (Table 1, entry 1). This low anti se-
lectivity prompted us to modify (S)-1 and develop new ax-
ially chiral amino sulfonamides (S)-2, (S)-3, and (S)-4 with
an acidic proton further from the secondary amino group
than the carboxy group in (S)-1. The imine activated by the
remote acidic proton would be expected to react preferen-
tially with the s-cis-enamine intermediate C to give the de-
sired anti isomer, anti-6 (Scheme 2).
Results and Discussion
anti-Selective direct asymmetric Mannich reaction of N-
PMP-protected a-imino esters:[5a] The asymmetric Mannich
reaction remains a powerful method for synthesizing optical-
ly active b-amino carbonyl units, which are useful chiral
building blocks in a number of biologically active and phar-
maceutically important compounds.[7] In particular, direct
asymmetric Mannich reactions between unmodified carbon-
yl compounds and certain imines would be most desirable
for this purpose.[8–12] Recently, small organic molecules such
as proline and its derivatives were found to catalyze the re-
action between aldehydes and imines to furnish syn- or anti-
b-amino aldehydes as the major product, depending on the
choice of catalyst.[10,11] For instance, a proline-catalyzed
direct asymmetric Mannich reaction of a-imino ester 5 gives
the syn-b-amino aldehyde syn-6 preferentially with excellent
enantioselectivity via the s-trans-enamine intermediate A
(Scheme 1).[10] Some anti-selective direct asymmetric Man-
Scheme 2. Possible transition-state model for the anti-selective direct
asymmetric Mannich reaction catalyzed by (S)-3.
The requisite binaphthyl-based amino sulfonamides (S)-2–
4 were prepared in a seven-step sequence from dineopentyl
(S)-1,1’-binaphthyl-2,2’-dicarboxylate [(S)-7], as shown in
Scheme 3.[13] Bromination of the neopentyl ester (S)-7 was
achieved by ortho magnesiation using magnesium
bis(2,2,6,6-tetramethylpiperamide) [MgACTHNURTGNENG(U tmp)2] followed by
trapping with bromine.[14] Reduction of the resulting mixture
of di- and monobrominated esters (S)-8 with LiAlH4 gave
the corresponding diol (S)-9 (42% yield over two steps)
after chromatographic separation. Treatment of (S)-9 with
BBr3 afforded the tribromo compound (S)-10 in a yield of
86%, which was converted with allylamine into the cyclic
amine (S)-11 in a yield of 89%.[13] Amination of (S)-11 with
benzophenone imine and [Pd2ACHTNUTRGNENUG(dba)3] shown in the legend to
Scheme 3 gave diamine (S)-12 in a yield of 93%.[15] Treat-
ment of (S)-12 with the corresponding sulfonylating agents
gave methanesulfonamide (S)-13, trifluoromethanesulfona-
mide (S)-14, and pentafluorophenylsulfonamide (S)-15. Fi-
Scheme 1. Proposed transition-state models for the direct asymmetric
Mannich reactions catalyzed by l-proline and (S)-1.
nally, PdACTHGNUTRENNU(G OAc)2-catalyzed deallylation of (S)-13–15 provided
Chem. Eur. J. 2009, 15, 6678 – 6687
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6679

K. Maruoka et al.
Table 1. anti-Selective Mannich reactions between 3-methylbutanal and
a-imino ester 5 catalyzed by (S)-1–(S)-4.
Entry Catalyst t [h] Solvent
Yield [%][b] anti/syn[c] ee [%][d]
1
2
3
4
5
6
7
8
9
(S)-1[e]
(S)-2
(S)-3
(S)-4
(S)-3
(S)-3
(S)-3
(S)-3
(S)-3
20
24
0.5
24
6
6
6
6
0.5
dioxane 60
dioxane 11
dioxane 93
dioxane 65
1:1.1
3.8:1
86
72
>99
>99
99
90
97
98
>99
>20:1
8.8:1
>20:1
8.3:1
6.3:1
9.1:1
THF
38
72
20
70
98
EtOAc
DMSO
CHCl3
toluene
9.1:1
[a] The reaction of 3-methylbutanal (0.75 mmol) and a-imino ester 5
(0.25 mmol) was carried out in solvent (2.5 mL) in the presence of cata-
lyst (S)-1–4 (0.005 mmol) at room temperature. [b] Isolated yield. [c] De-
termined by H NMR spectroscopy. [d] The ee of the anti isomer was de-
termined by HPLC analysis using a chiral column (Chiralpak AS-H,
Scheme 3. Synthesis of (S)-2–(S)-4. a) [Mg
THF; c) BBr3, CH2Cl2; d) allylamine, CH3CN; e) Ph2C=NH, [Pd
BINAP, NaOtBu, 1n HCl, THF; f) MeSO2Cl, CH2Cl2; g) Tf2O, CH2Cl2;
ACHTUNGTRENNUNG
1
CTHUNGTRENNUNG
Daicel Chemical Industries, Ltd.). [e] With 0.0125 mmol of (S)-1.
h) C6F5SO2Cl, CH2Cl2; i) Pd
CH2Cl2.
ACHTUNGTRNEN(UNG OAc)2, PPh3, N,N’-dimethylbarbituric acid,
hyde could be reduced to 1 equiv without significant loss of
yield when the reaction was carried out with a higher con-
centration of the catalyst (Table 2, entry 5). Although the re-
action of the sterically hindered 3,3-dimethylbutanal re-
quired a higher catalyst loading and proceeded in moderate
yield, optimal anti selectivity and enantioselectivity were ob-
served (Table 2, entry 9). When the a-imino ester was added
slowly using a syringe pump, the reaction of 3,3-dimethylbu-
tanal resulted in a somewhat improved yield (Table 2,
entry 10). This reaction system could also be applied to a-
imino allyl or tert-butyl esters (Table 2, entries 11 and 12).
the binaphthyl-based amino sulfonamides (S)-2–4, respec-
tively (yields of 58% for (S)-2, 78% for (S)-3 and 42% for
(S)-4 over two steps).
The efficiency of these new catalysts (S)-2–4 was evaluat-
ed under identical conditions to those used in the reaction
performed with (S)-1, except for the use of lower catalyst
loadings (2 mol%). Unfortunately, the reaction with (S)-2
resulted in a significant reduction in reactivity and enantio-
selectivity, although moderate anti selectivity was observed
(Table 1, entry 2). In marked contrast, however, switching
the catalyst from (S)-2 to (S)-3 or (S)-4, which contain a
more acidic sulfonamide group, enhanced both the reactivity
and stereoselectivity of the reaction (Table 1, entries 3 and
4). We then examined the effect of solvent by using (S)-3 in
the direct asymmetric Mannich reaction. Other solvents,
such as THF, EtOAc, DMSO, or CHCl3, were found to be
less satisfactory than dioxane in terms of chemical yield and
stereoselectivity (Table 1, entries 5–8). In toluene, however,
although the reaction proceeded smoothly and with excel-
lent enantioselectivity, a slight decrease in anti selectivity
was observed (Table 1, entry 9). Thus, dioxane was identified
as the solvent of choice.
The reactions between other aldehydes and a-imino
esters in the presence of a catalytic amount of (S)-3 were
carried out in dioxane at room temperature and the results
are summarized in Table 2. In the case of primary alkyl al-
dehydes, 1 mol% of (S)-3 was sufficient to produce the cor-
responding b-amino aldehydes in high yields (>92%) and
with nearly complete enantioselectivities (99% ee) and ex-
cellent anti selectivities (>11:1) (Table 2, entries 1, 3, and
7). The catalyst loading could be reduced to less than
1 mol% of (S)-3, but gave slightly decreased yields and ste-
reoselectivities (Table 2, entries 2 and 6). The reaction at a
higher concentration (1m) gave the same result, but with a
shorter reaction time (Table 2, entry 4). The amount of alde-
Table 2. anti-Selective Mannich reactions between various aldehydes and
a-imino esters catalyzed by (S)-3.
Entry
R1
R2
Cat.
[mol%]
t
Yield
[%][b]
anti/syn[c]
ee
G
[h]
[%][d]
1
2
3
Me
Me
Bu
Bu
Bu
Bu
Bn
iPr
tBu
tBu
iPr
iPr
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
allyl
tBu
1
0.2
1
1
1
0.5
1
2
5
5
0.5
22
4
0.5
0.5
8
93
82
93
93
86
92
92
93
42
68
99
99
13:1
11:1
>20:1
20:1
16:1
>20:1
11:1
>20:1
>20:1
20:1
16:1
16:1
>99
97
99
>99
99
97
>99
>99
>99
99
>99
>99
4[e]
5[e,f]
6
7
8
9
4
0.5
16
38
0.5
0.5
10[g]
11
12
2
2
[a] Unless otherwise specified, the reaction between the aldehyde
(0.75 mmol) and the a-imino ester (0.25 mmol) was carried out in diox-
ane (2.5 mL) in the presence of (S)-3 at room temperature. [b] Isolated
yield. [c] Determined by 1H NMR spectroscopy. [d] The ee of the anti
isomer was determined by HPLC analysis using a chiral column. [e] With
250 mL of dioxane. [f] With 1 equiv of hexanal (0.25 mmol). [g] a-Imino
ester 5 was added slowly using a syringe pump. Details are given in the
Supporting Information.
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Chem. Eur. J. 2009, 15, 6678 – 6687

anti-Selective Mannich and syn-Selective Cross-Aldol Reactions
FULL PAPER
Note that self-aldol products were not detected even in the
presence of excess aldehyde (3 equiv).
We next turned our attention to the anti-selective Man-
nich reactions of ketones with a-imino ester 5 (Table 3).[11]
The reactions of the six-membered cyclic ketones with cata-
lyst (S)-3 proceeded smoothly to give satisfactory results in
terms of both reactivity and selectivity (Table 3, entries 1–3).
The observed high levels of stereoselectivity and absolute
stereochemistry in the reactions of the ketones could be ex-
plained by a transition-state model similar to the one pro-
posed for the reaction of aldehydes in Scheme 2.
Scheme 4. Reaction between 3-methylbutanal and the N-PMP-protected
aromatic imine 16.
dioxane gave predominantly the desired anti adduct in mod-
erate yield and with excellent enantioselectivity (Table 4,
entry 1). The use of DMSO resulted in a significant decrease
in both the anti selectivity and the enantioselectivity
(Table 4, entry 2). In the case of DMF, a slightly improved
anti selectivity was observed (Table 4, entry 3). When aceto-
nitrile and chloroform were used, the anti adduct was ob-
tained in good yields and with excellent enantioselectivities
(Table 4, entries 5 and 6). However, the use of 3-methylbu-
tanal as the substrate instead of propanal lowered the yield
(Table 4, entry 7). Accordingly, further optimization of the
reaction conditions was investigated. The addition of water
slightly increased the yield and the anti selectivity (Table 4,
entry 8). Switching the solvent from acetonitrile to chloro-
form and lowering the reaction temperature did not improve
the yield, although a higher anti selectivity was observed
(Table 4, entries 9 and 10). Because a similar low yield of
the anti adduct was obtained even with a higher catalyst
loading (10 mol%) (Table 4, entry 11), we suspected that
the low yield might be due to catalyst deactivation by N-
Boc-imine 17. Indeed, when a solution of N-Boc-imine 17
was slowly added to the reaction mixture using a syringe
pump, the anti adduct was obtained in good yield with satis-
Table 3. anti-Selective Mannich reactions between ketones and a-imino
ester 5 catalyzed by (S)-3.
Entry
X
Yield [%][b]
anti/syn[c]
ee [%][d]
1
2
3
CH2
O
S
93
81
86
10:1
7.4:1
7.8:1
98
98
99
[a] Unless otherwise specified, the reactions between the ketones
(0.75 mmol) and a-imino ester 5 (0.25 mmol) were carried out in dioxane
(2.5 mL) in the presence of (S)-3 (0.005 mmol) at room temperature.
1
[b] Isolated yield. [c] Determined by H NMR spectroscopy. [d] The ee of
the anti isomer was determined by HPLC analysis using a chiral column.
anti-Selective direct asymmetric Mannich reactions of N-
Boc-protected aromatic imines:[5b] Proline-catalyzed direct
asymmetric Mannich reactions between N-PMP-protected
aromatic imines and aldehydes are known to give the corre-
sponding syn-b-amino-b-aryl aldehydes preferentially with
excellent enantioselectivity.[10d,f,g] To the best of our knowl-
edge, however, a general and selective method for obtaining
the opposite anti-b-amino-b-aryl aldehyde remains unattain-
able, although a few exceptional examples that give anti-
Mannich adducts have been reported using an N-Boc-pro-
tected aromatic imine.[11m,r] Accordingly, we next turned our
attention to the reaction of aromatic imines and attempted
to expand the substrate scope of the present anti-selective
Mannich reaction catalyzed by (S)-3. Unfortunately, howev-
er, the reaction between the N-PMP-protected aromatic
imine 16 and 3-methylbutanal did not proceed under the op-
timized conditions used for the reaction of N-PMP-protect-
ed a-imino esters, probably due to the low reactivity of the
aromatic imine 16 (Scheme 4). We then decided to explore
the anti-selective Mannich reaction by using the more reac-
tive N-Boc-protected aromatic imines, which were success-
fully utilized by List[10w] and Cꢁrdova[10x] and their co-work-
ers in the syn-selective Mannich reaction catalyzed by pro-
line.
Table 4. anti-Selective Mannich reactions of N-Boc-protected imine 17
catalyzed by (S)-3.
Entry
R
Solvent T [8C] t [h] Yield [%][b] anti/syn[c] ee [%][d]
1
2
3
4
5
6
7
Me dioxane RT
Me DMSO RT
3.5
18
24
4.5
24
4
24
24
24
24
24
5
53
98
70
52
78
80
30
37
32
31
30
77
4.4:1
2.3:1
5.5:1
5.5:1
5.1:1
5.1:1
5.0:1
6.7:1
8.6:1
11:1
97
53
95
99
99
99
99
99
99
99
99
99
Me DMF
RT
Me CH3CN RT
Me CH3CN RT
Me CHCl3
RT
iPr CH3CN RT
iPr CH3CN RT
8[e]
9
10
11[f]
12[g]
iPr CHCl3
iPr CHCl3
iPr CHCl3
iPr CHCl3
RT
0
0
11:1
11:1
0
[a] Unless otherwise specified, the reactions between the aldehydes
(0.75 mmol) and N-Boc-protected imine 17 (0.25 mmol) were carried out
in solvent (250 mL) in the presence of (S)-3 (5 mol%). [b] Isolated yield.
[c] Determined by 1H NMR spectroscopy. [d] The ee of the anti isomer
was determined by HPLC analysis using a chiral column (Chiralpak AS-
H, Daicel Chemical Industries, Ltd.). [e] H2O (5 mol%) was added.
[f] With 10 mol% of (S)-3. [g] N-Boc-protected imine 17 was added
slowly using a syringe pump. Details are given in the Supporting Infor-
mation.
We first examined the reaction between the benzalde-
hyde-derived N-Boc-imine 17 and propanal in the presence
of 5 mol% of (S)-3 in various solvents at room temperature
and the results are summarized in Table 4. The reaction in
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K. Maruoka et al.
factory anti selectivity and enantioselectivity (Table 4,
entry 12).
18 with NaClO2 followed by the addition of TMSCHN2 re-
sulted in the clean formation of the corresponding methyl
ester 19 (97% yield over two steps). Subsequent N-Boc de-
protection and treatment of the resulting b-amino ester 20
with LDA gave b-lactam 21 without loss of enantiopurity
(82% yield over two steps).[16] By comparison of the optical
rotation of b-lactam 21 with the literature value,[17] the abso-
lute configuration of anti-b-amino aldehyde anti-18 was de-
termined to be (1S,2R).
We then applied our system to various aldehydes and N-
Boc-protected aromatic imines. As shown in Table 5, under
the optimized conditions, the corresponding anti Mannich
adducts were obtained with good anti selectivities and excel-
lent enantioselectivities in all the cases examined. When a
solution of N-Boc-imine 17 was slowly added to the reaction
mixture using a syringe pump, the catalyst loading could be
reduced to 1 mol% without loss of stereoselectivity
(Table 5, entry 4 vs. 3). In addition, an aliphatic N-Boc-
imine was found to be suitable for the present reaction
system (entry 10).
syn-Selective direct asymmetric cross-aldol reaction between
aldehydes:[6] The aldol reaction is one of the most funda-
mental carbon–carbon bond-forming reactions.[18] However,
the cross-aldol reaction between two different aldehydes is
often known to be problematic because of undesired side-re-
actions, including dehydration of the product, self-aldol re-
actions, and multiple additions of the enolate to the aldol
product. To date, however, several cross-aldol reactions per-
formed with aldehyde-derived metal enolates, including silyl
enol ethers as nucleophiles and/or slowly or non-enolizable
aldehydes as electrophiles, have been reported.[19–26] Further-
more, some rare examples of the catalytic asymmetric ver-
sion of this reaction have recently been developed.[27–37] For
instance, diastereo- and enantioselective cross-aldol reac-
tions between aldehydes and silyl enol ethers were first ac-
complished by Denmark and co-workers with chiral Lewis
base catalysts,[27] and recently Kobayashi and co-workers
demonstrated chiral Lewis acid catalyzed diastereo- and
enantioselective reactions using aldehyde-derived enecarba-
mates as activated aldehyde nucleophiles.[28] Through these
methods, both syn and anti diastereomers were formed in a
highly enantioselective fashion. On the other hand, to the
best of our knowledge, most organocatalytic direct enantio-
selective cross-aldol reactions of unmodified aldehydes, first
reported by MacMillan and co-workers, provide predomi-
nantly anti-aldol adducts,[29–36] albeit with a few exceptions
giving the syn adducts.[29d,38] In this context, we were inter-
ested in the possibility of developing a syn-selective direct
cross-aldol reaction between two different aldehydes using a
chiral organocatalyst.
Table 5. anti-Selective Mannich reactions between various aldehydes and
N-Boc-protected imines catalyzed by (S)-3.
Entry
R1
R2
Cat.
[mol%]
Yield
[%][b]
anti/syn[c]
ee
N
[%][d]
1
2
Me
iPr
Bu
Bu
Bn
Bu
Bu
Bu
Bu
Me
Ph
Ph
Ph
Ph
5
5
5
1
5
5
5
5
5
92
77
93
88
80
91
78
88
92
66
7.7:1
8.8:1
16:1
15:1
15:1
8.2:1
11:1
7.5:1
16:1
99
99
99
99
99
98
99
99
99
99
3[e]
4[f]
5
Ph
6
7
8
9
4-MeOC6H4
4-ClC6H4
2-furyl
3-pyridyl
cyclohexyl
10[e,g]
10
>20:1
[a] Unless otherwise specified, the reactions between the aldehydes
(0.75 mmol) and the N-Boc-protected imines (0.25 mmol) were carried
out in CHCl3 in the presence of (S)-3 at 08C. The N-Boc-protected
imines were added by using a syringe pump over 4 h. Stirring was then
continued for 1 h. [b] Isolated yield. [c] Determined by 1H NMR spec-
troscopy. [d] The ee of the anti isomer was determined by HPLC analysis
using a chiral column. Details are given in the Supporting Information.
[e] Stirred for 2 h after addition of the N-Boc-protected imine. [f] The N-
Boc-protected imine was added by using a syringe pump over 12 h. Stir-
ring was then continued for 1 h. [g] With 1.25 mmol of propanal.
Our strategy was based on the observation that a direct
asymmetric Mannich reaction can be catalyzed by the
amino sulfonamide (S)-3 to give predominantly the anti
product, which is a minor diastereomer in the proline-cata-
lyzed reaction.[5a] Because it would be difficult for s-trans-
enamine D, which is generated from a donor aldehyde and
(S)-3, to react with an acceptor aldehyde activated by the
distal acidic proton of the triflamide of (S)-3, the cross-aldol
reaction catalyzed by (S)-3 would be expected to proceed
through the s-cis-enamine intermediate E to give the hither-
to unattainable syn product, as shown in Scheme 6.
To assign the absolute configurations of the anti-b-amino
aldehydes obtained and to extend the synthetic utility of this
asymmetric transformation, an optically enriched anti-b-
amino aldehyde anti-18 was successfully converted into the
corresponding b-lactam (Scheme 5). Thus, treatment of anti-
We first examined the reaction between 4-nitrobenzalde-
hyde and hexanal in the presence of 5 mol% of (S)-3 in var-
ious solvents at room temperature. In this reaction, large
solvent effects were observed and the results are summar-
ized in Table 6. The reaction in dioxane, toluene, or CH2Cl2
gave the cross-aldol product 22 in poor yield and with low
Scheme 5. Determination of the absolute configuration of anti-18.
a) i) NaClO2, NaH2PO4·2H2O, 2-methyl-2-butene, tBuOH, H2O;
ii) TMSCHN2, toluene, MeOH; b) TFA, CH2Cl2; c) LDA, THF.
6682
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Chem. Eur. J. 2009, 15, 6678 – 6687

anti-Selective Mannich and syn-Selective Cross-Aldol Reactions
FULL PAPER
the reactions conducted at higher concentrations were found
to give syn-22 in improved yields without loss of stereoselec-
tivity (Table 6, entries 9 and 10). In addition, the reactions
with other amide solvents, 1,3-dimethyl-2-imidazolidinone
(DMI) and N,N-dimethylacetamide (DMAc), provided simi-
lar results (Table 6, entries 11 and 12). The observed large
solvent effect on the selectivity of the reaction might be at-
tributed to the change in the pKa of the acidic proton of cat-
alyst (S)-3, depending on the solvent used.[39] When the
amino acid catalyst (S)-1 was used instead of (S)-3, a low
diastereoselectivity was observed, as expected from our pre-
vious studies of the Mannich reaction (Table 6, entry 13 and
Table 1, entry 1).[5a]
With the optimized reaction conditions, the syn- and
enantioselective direct cross-aldol reactions of several other
reactive acceptor aldehydes with donor aliphatic aldehydes
were examined (Table 7). The reactions of 4-nitrobenzalde-
hyde with various aliphatic aldehydes gave the correspond-
ing syn-aldol adducts in moderate-to-good yields and with
excellent diastereo- and enantioselectivities (Table 7, en-
tries 1–5). Although the reaction of a simple acceptor alde-
hyde such as benzaldehyde with hexanal proceeded slowly
in low yield, good stereoselectivity was observed (Table 7,
entry 6). On the other hand, reactive aldehydes such as fluo-
rinated aromatic and heteroaromatic aldehydes as well as
ethyl glyoxylate were found to be suitable electrophiles
(Table 7, entries 7–9). The reaction catalyzed by (S)-3 was
also applicable to phenylglyoxal in its monohydrate form
(Table 7, entry 10). In all cases, the reactions catalyzed by
(S)-3 were complementary to the proline-catalyzed reactions
in terms of the syn/anti selectivity. In addition, only trace
Scheme 6. Possible transition-state model for the syn-selective direct
asymmetric aldol reaction catalyzed by (S)-3.
stereoselectivity (Table 6, entries 1–3). In the case of aceto-
nitrile, only a trace amount of 22 was observed, although
syn-22 was slightly dominant over anti-22 (Table 6, entry 4).
The use of DMSO, which is an ordinary solvent for aldol re-
actions catalyzed by proline or related organocatalysts, led
to the formation of the desired syn-22 in a highly diastereo-
and enantioselective manner in low yield (Table 6, entry 5).
When the amide solvents DMF and N-methylpyrrolidone
(NMP) were used, the desired syn-22 was obtained in mod-
erate yields with excellent diastereo- and enantioselectivities
(Table 6, entries 6 and 7). A longer reaction time resulted in
a slight decrease in both the diastereo- and enantioselectivi-
ty but a higher yield (Table 6, entry 8). On the other hand,
Table 6. syn-Selective aldol reaction of 4-nitrobenzaldehyde with hexanal
catalyzed by (S)-3.
Table 7. syn-Selective aldol reactions between various aldehydes cata-
lyzed by (S)-3.
Entry R1
R2
t [h] Yield [%][b] syn/anti[c] ee [%][d]
Entry Solvent Conc. [m] t [h] Yield [%][b] syn/anti[c] ee [%][d]
1
2
3
Me
Bu
Bn
4-NO2-C6H4 36
4-NO2-C6H4 36
4-NO2-C6H4 36
73
77
80
79
61
22
73
12:1
>20:1
>20:1
>20:1
>20:1
6.3:1
>20:1
6.4:1
2.3:1
98
99
98
98
96
92
99
94
95
96
1
2
3
4
5
6
7
8
dioxane 0.1
toluene 0.1
36
36
36
36
36
36
36
72
36
36
36
36
30
22
26
31
<5
25
60
62
74
73
77
65
77
50
1:3.4
1:1.5
1:1.6
1.2:1
13:1
17:1
>20:1
13:1
>20:1
>20:1
>20:1
>20:1
8
6
25
–
96
98
99
97
99
99
98
98
CH2Cl2
0.1
4
allyl 4-NO2-C6H4 36
CH3CN 0.1
5
6
7
8
iPr
Bu
Bu
Bu
Bu
Bu
4-NO2-C6H4 40
Ph
C6F5
4-pyridyl
EtO2C
benzoyl
DMSO
DMF
NMP
NMP
NMP
NMP
DMI
0.1
0.1
0.1
0.1
0.25
1.0
0.25
0.25
0.1
36
78
69
4.5
20
71
9[e]
10[f]
99[g]
91[g]
9
>20:1
10
11
12
13[e]
[a] Unless otherwise specified, the reactions of the acceptor aldehydes
(0.25 mmol) with the donor aldehydes (0.5 mmol) in NMP (250 mL) were
carried out in the presence of (S)-3 (0.0125 mmol) at room temperature.
[b] Isolated yield after acetalization or reduction of the product. Details
are given in the Supporting Information. [c] Determined by 1H NMR
spectroscopy. [d] The ee of the syn product was determined by HPLC
using a chiral column (Chiralpak AS-H, AD-H, Chiralcel OD-H or OJ-
H, Daicel Chemical Industries, Ltd.). Details are given in the Supporting
Information. [e] With 3 equiv of ethyl glyoxylate (0.75 mmol) and 1 equiv
of hexanal (0.25 mmol). [f] Phenylglyoxal was used in the monohydrate
form. [g] Isolated yield.
DMAc
DMF
1:1.6
85 (94)[f]
[a] The reactions of 4-nitrobenzaldehyde (0.25 mmol) with hexanal
(0.5 mmol) in different solvents were carried out in the presence of (S)-3
(0.0125 mmol) at room temperature. [b] Isolated yield after acetalization
of the product with 2,2-dimethyl-1,3-propanediol. [c] Determined by
1H NMR spectroscopy. [d] The ee of syn-22 was determined by HPLC
using a chiral column (Chiralpak AD-H, Daicel Chemical Industries,
Ltd.). [e] With catalyst (S)-1. [f] The ee of anti-22.
Chem. Eur. J. 2009, 15, 6678 – 6687
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www.chemeurj.org
6683

K. Maruoka et al.
amounts of byproducts arising from dimerization of donor
aldehydes were observed. Note that more than 95% of (S)-
3 was recovered unchanged after column chromatography.
The absolute configuration of the anti-aldol product anti-
22 obtained in the l-proline catalyzed reaction was deduced
to be (2S,3R).[29a] Based on this information, the absolute
configuration of the syn-aldol product syn-22 obtained from
the reaction of hexanal and 4-nitrobenzaldehyde catalyzed
by (S)-3 was determined to be (2R,3R) by converting it into
the anti-aldol product using standard Mitsunobu conditions
and by comparison of the signs of the optical rotation
(Scheme 7). This absolute configuration of syn-22 agrees
with the prediction based on the transition-state model
shown in Scheme 6.
through the same transition state as that which gives
(2R,3R)-syn-22 itself. This hypothesis is also consistent with
the observation that both the syn selectivity and the enan-
tioselectivity of the aldol product decreased with longer re-
action times (Table 6, entry 8 vs. 7). As a consequence, the
above observations indicate that the diastereoselection origi-
À
nates from the C C bond-formation step in both the Man-
nich and the aldol reactions catalyzed by (S)-3.
Reaction mechanism: To understand the origin of the dia-
stereoselectivity observed in the reactions catalyzed by (S)-
3, diastereomixtures of Mannich adducts 23 (anti/syn=1:8.6)
and 24 (anti/syn=2:1) were treated with (S)-3 under the re-
action conditions. Both diastereomixtures were recovered
quantitatively with no change in the diastereomeric ratios
observed in either case (Scheme 8a and b). Because the two
anti/syn ratios remained below that obtained in the Mannich
reactions catalyzed by (S)-3, the anti selectivity must origi-
À
nate from the C C bond-forming step, not from isomeriza-
tion between the anti and syn adducts under the reaction
conditions.[11m] On the other hand, when the diastereomix-
Scheme 8. Behavior of the reaction products under the reaction condi-
tions.
Based on the stereochemistry observed in the Mannich
and aldol reactions catalyzed by (S)-3, transition-state
models can be proposed, as shown in Figure 1.[11m] In each
case, the Si face of the imines or the Re face of the alde-
hydes approaches the enamine intermediate, as directed by
the distant acidic proton of the triflamide group, and conse-
À
quently the C C bond-forming reaction takes place on the
Si face of the s-cis-enamine in a highly diastereo- and enan-
tioselective fashion to give anti-Mannich or syn-aldol ad-
ducts, respectively (Figure 1a and b). Very recently we re-
ported a direct asymmetric aminoxylation of aldehydes with
nitrosobenzene catalyzed by (S)-3, which gave almost exclu-
sively the aminoxylated product with an S configuration
(Scheme 9).[41] The observed stereochemistry can be ration-
alized by an analogous transition-state model in which nitro-
sobenzene approaches the Si face of the s-cis-enamine, as di-
rected by the triflamide group (Figure 1c). Because activa-
tion of nitrosobenzene by strong acids such as carboxylic
acid and tetrazole is necessary to obtain the aminoxylation
product,[42] only a combination of the s-cis-enamine and ni-
trosobenzene activated on the Si face of the enamine can
provide the S isomer. This observation strongly suggests the
existence of the s-cis-enamine intermediate in the Mannich
and aldol reactions catalyzed by (S)-3 reported herein.
Scheme 7. Determination of the absolute configuration of syn-22.
a) 5 mol% (S)-3, NMP; b) 2,2-dimethylpropane-1,3-diol, CHACTHNUTRGNEUNG(OEt)3,
PTSA, CH2Cl2; c) i) 4-nitrobenzoic acid, DEAD, PPh3, THF; ii) 1n
NaOH, MeOH; d) l-proline (30 mol%), DMF.
ture of aldol adduct 22 (anti/syn=3.0:1) was treated with
(S)-3 under the reaction conditions, the retro-aldol and de-
hydration products were obtained and 71% of 22 was recov-
ered (Scheme 8c).[40] Interestingly, the ratio of syn-22 to anti-
22 in the recovered diastereomixture was found to have de-
creased. Moreover, the recovered syn-22 was optically en-
riched, with (2S,3S)-syn-22, which is the minor enantiomer
in the aldol reaction catalyzed by (S)-3, predominant. This
result suggests that the major stereoisomer (2R,3R)-syn-22
obtained in the aldol reaction might be consumed selectively
6684
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Chem. Eur. J. 2009, 15, 6678 – 6687

anti-Selective Mannich and syn-Selective Cross-Aldol Reactions
FULL PAPER
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Figure 1. Transition-state models for reactions catalyzed by (S)-3.
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Conclusions
We have designed and synthesized a novel binaphthyl-based
axially chiral amino sulfonamide, which has been utilized as
a catalyst in the direct asymmetric Mannich and aldol reac-
tions of aldehydes. The reactions reported herein are com-
plementary to the proline-catalyzed reactions in terms of
diastereoselectivity and hence represent a rare example of
an anti-selective Mannich reaction using N-Boc-protected
imines as well as of a highly syn- and enantioselective direct
cross-aldol reaction with a non-proline-derived artificial or-
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by the use of N-Boc-protected aromatic imines. Thus, our
axially chiral amino sulfonamide represents a new catalyst
design in enamine catalysis.
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Experimental Section
General procedure for the catalytic asymmetric Mannich reactions be-
tween N-PMP-protected iminoacetates and aldehydes: The correspond-
ing aldehyde (0.75 mmol) and N-PMP-protected iminoacetate
(0.25 mmol) were added in this order to a stirred solution of chiral amino
sulfonamide (S)-3 (1.1 mg, 0.0025 mmol) in dioxane (2.5 mL) at room
temperature. After stirring at room temperature for the time indicated in
Table 2, the reaction mixture was quenched with saturated NH4Cl and
extracted with ethyl acetate. The combined organic layers were washed
with brine, dried over Na2SO4, and concentrated. The residue was puri-
fied by flash column chromatography on silica gel (hexane/ethyl ace-
tate=20:1 as eluent) to afford the corresponding Mannich adduct.
For full details of instruments used, experimental procedures, and charac-
terization data obtained, please see the Supporting Information.
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Acknowledgements
This work was partially supported by a Grant-in-Aid for Scientific Re-
search in Priority Areas “Advanced Molecular Transformation of Carbon
Resources” from the Ministry of Education, Culture, Sports, Science, and
Technology, Japan. Y.Y. thanks the Japan Society for the Promotion of
Science for Young Scientists for Research Fellowships.
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Received: January 31, 2009
Published online: May 28, 2009
Chem. Eur. J. 2009, 15, 6678 – 6687
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6687