Direct catalytic asymmetric Mannich reactions of malonates and β-keto esters

Article abstract of DOI:10.1002/chem.200204679

The first catalytic asymmetric direct Mannich reaction of malonates and β-keto esters has been developed. Malonates react with an activated N-tosyl-α-imino ester catalyzed by chiral tert-butyl-bisoxazoline/Cu(OTf)₂ to give the Mannich adducts in high yields and with up to 96% ee. These reactions create a chiral quaternary carbon center and it is demonstrated that this new direct Mannich reactions provides for example a new synthetic procedure for the formation of optically active β-carboxylic ester α-amino acid derivatives. A series of different β-keto esters with various ester substituents has been screened as substrates for the catalytic asymmetric direct Mannich reaction and it was found that the best results in terms of yield, diastereo- and enantioselectivity were obtained when tert-butyl esters of β-keto esters were used as the substrate. The reaction of different β-keto tert-butyl esters with the N-tosyl-α-imi-no ester gave the Mannich adducts in high yields, diastereo- and enantioselectivities (up to 95% ee) in the presence of chiral tert-butyl-bisoxazoline/Cu(OTf)₂ as the catalyst. To expand the synthetic utility of this direct Mannich reaction a diastereoselective decarboxylation reaction was developed for the Mannich adducts leading to a new synthetic approach to attractive optically active β-keto α-amino acid derivatives. Based on the stereochemical outcome of the reactions, various approaches of the N-tosyl-α-imino ester to the chiral bisoxazoline/Cu^II-substrate intermediate are discussed.

Full text of DOI:10.1002/chem.200204679

FULL PAPER
Direct Catalytic Asymmetric Mannich Reactions of Malonates and
b-Keto Esters
Mauro Marigo, Anne KjÒrsgaard, Karsten Juhl, Nicholas Gathergood, and
Karl Anker J˘rgensen*[a]
Abstract: The first catalytic asymmetric
direct Mannich reaction of malonates
and b-keto esters has been developed.
Malonates react with an activated N-
tosyl-a-imino ester catalyzed by chiral
tert-butyl-bisoxazoline/Cu(OTf)2 to give
the Mannich adducts in high yields and
with up to 96% ee. These reactions
create a chiral quaternary carbon center
and it is demonstrated that this new
direct Mannich reactions provides for
example a new synthetic procedure for
the formation of optically active b-
carboxylic ester a-amino acid deriva-
tives. A series of different b-keto esters
with various ester substituents has been
screened as substrates for the catalytic
asymmetric direct Mannich reaction and
it was found that the best results in terms
of yield, diastereo- and enantioselectiv-
ity were obtained when tert-butyl esters
of b-keto esters were used as the sub-
strate. The reaction of different b-keto
tert-butyl esters with the N-tosyl-a-imi-
no ester gave the Mannich adducts in
high yields, diastereo- and enantioselec-
tivities (up to 95% ee)in the presence of
chiral tert-butyl-bisoxazoline/Cu(OTf)2
as the catalyst. To expand the synthetic
utility of this direct Mannich reaction a
diastereoselective decarboxylation reac-
tion was developed for the Mannich
adducts leading to a new synthetic
approach to attractive optically active
b-keto a-amino acid derivatives. Based
on the stereochemical outcome of the
reactions, various approaches of the N-
tosyl-a-imino ester to the chiral bisox-
azoline/CuII-substrate intermediate are
discussed.
Keywords: asymmetric catalysis
¥
imines ¥ Mannich bases ¥ synthetic
methods
The first successful catalytic enantioselective Mannich-type
reaction was reported in 1997 by Kobayashi and co-workers
using chiral zirconium/BINOL complexes as catalysts.[3]
Catalytic enantioselective Mannich-type reactions of silyl
enol ethers and a-imino esters were published in two similar
and nearly simultaneous reports by Sodeoka et al.[4] and
Lectka et al.[5] in 1998, where palladium(ii)/BINAP and
copper(i)/BINAP complexes, respectively, were applied as
the catalysts. However, a disadvantage for these stereo-
selective Mannich reactions can be the preparation and
stability of the enolate, and an important step forward for this
class of reactions would be a catalytic enantioselective version
using carbonyl compounds rather than the enolates.[6]
Recently, we disclosed the first highly enantioselective
catalytic direct Mannich reaction where 2-keto esters were
treated with N-protected a-imino esters in the presence of
chiral copper(ii)/bisoxazoline complexes.[7] The advantage of
this reaction is that the formation of silyl enol ethers is not
required. Furthermore, it should also be noted that organo-
catalytic enantioselective direct Mannich reactions catalyzed
by organic molecules have been developed.[8]
Introduction
One of the great challenges in organic chemistry is the
development of reactions for the construction of complex
optically active molecules by bringing simple molecules to
react in a stereoselective manner. The catalytic asymmetric
À
aldol reaction is one of these important C C bond forming
reactions and many successful examples have been reported,
especially of the catalytic asymmetric Mukaiyama aldol
reaction.[1] A reaction that is closely related to the aldol
reaction is the Mannich reaction, where enols or enolates
react with imines to form b-amino esters or ketones. Despite
À
the importance of this C C bond forming reaction, only a few
examples of effective catalytic enantioselective Mannich-type
reactions have been reported.[2]
[a] Prof. Dr. K. A. J˘rgensen, M. Marigo,
A. KjÒrsgaard, Dr. K. Juhl, Dr. N. Gathergood
Danish National Research Foundation: Center for Catalysis
Department of Chemistry
In this paper, we disclose the use of malonic esters and b-
keto esters as pro-nucleophiles in catalytic asymmetric direct
Mannich reactions with an activated N-tosyl-a-imino ester[9]
[Eq. (1)].[10, 11]
Aarhus University
8000 Aarhus C (Denmark)
Fax : (‡45)8619 6199
E-mail: kaj@chem.au.dk
Chem. Eur. J. 2003, 9, 2359 2367
DOI: 10.1002/chem.200204679
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2359

K. A. J˘rgensen et al.
FULL PAPER
as additives in copper(ii)-catalyzed Mukaiyama aldol reac-
tions and a-amination reactions, 1.5 equiv of 1,1,1,3,3,3-
hexafluoropisopropanol (HFIP)was added to the reaction
resulting in a dramatic increase in enantioselectivity to 80%
ee (entry 2). The role of HFIP in the reaction is not clear, but
may be to assist catalyst turnover.
PG
O
O
O
HN
PG
N
R1
R1
OR3
(1)
CO2Et
CO2R3
R2
chiral
CO2Et
R2
catalyst
R
R
1 = OR, alkyl, benzyl,
2 = H, alkyl, benzyl
R3 = alkyl, aryl
Diethyl malonate having a methyl substituent at the a-
position (1b)also reacted with 2 giving the Mannich adduct
4b with a quaternary carbon atom in satisfying 88% yield and
61% ee (Table 1, entry 3). Addition of HFIP to the reaction
gave a slight increase in enantioselectivity, without affecting
the yield significantly (entry 4). Lowering of the reaction
temperature increased the enantioselectivities to 72% ee and
79% ee, at 0 and À208C, respectively (entries 5, 6). THF was
also tested as solvent for the catalytic enantioselective
Mannich reaction, but lower yield and enantiomeric excess
were obtained in this solvent (entry 5 vs 7). Other substituents
of the malonic esters were also allowed as ethyl, n-butyl,
isobutyl and benzyl substituted diethyl malonates (1c f)all
gave the corresponding Mannich adducts with enantioselec-
tivities from 79 87% ee and good yields after 4 days reaction
time at À208C (entries 9 11, 14).
This new chiral Lewis acid-catalyzed reaction gives access
to highly functionalized optically active molecules and,
furthermore, this reaction is also an easy entry to the
formation of chiral quaternary carbon centers.[12]
Results and Discussion
Catalytic enantioselective reactions of malonates: We decided
to commence our investigation of direct catalytic asymmetric
Mannich reactions of the malonic esters and b-keto esters
with the reaction of diethyl malonates 1a, b and the N-tosyl-
a-imino ester 2 catalyzed by 10 mol% of the chiral copper(ii)
bisoxazoline[13] (BOX)complex Cu(OTf) /(R)-Ph-BOX (3a)
2
The (S)-tBu-BOX ligand 3b was also used as ligand for
Cu(OTf)2 in the catalytic enantioselective Mannich reaction
of malonic esters 1a, b, d f with the N-tosyl-a-imino ester 2.
Representative results are shown in Table 2.
[Eq. (2)]. The results are shown in Table 1.
At À208C diethyl malonate 1a reacted smoothly with N-
tosyl-a-imino ester 2 in CH2Cl2 catalyzed by 10 mol%
Cu(OTf)2/(R)-Ph-BOX (3a)affording Mannich adduct 4a in
95% yield, but with moderate enantioselectivity (Table 1,
entry 1). Inspired by Evans×[14] use of electron-poor alcohols
The reaction of malonic esters 1a, b, d f with N-tosyl-a-
imino ester 2 also proceeded well with Cu(OTf)2/(S)-tBu-
BOX (3b)as catalyst. Surprisingly HFIP did not increase the
enantioselectivity of the reaction. However, cooling the
reaction to À208C gave a high yielding and highly enantio-
selective formation of Mannich adducts 4a, b, d f (entries3,
6, 8, 10, 12)as up to 96% ee was obtained; this is a significant
improvement compared with the Cu(OTf)2/(R)-Ph-BOX
catalyzed reaction (Table 1, entry 12 vs Table 2, entry 10).
Ts
Cu(OTf)2-3a
10 mol%
O
O
HN
Ts
N
EtO2C
R
(2)
EtO
OEt
CO2Et
CO2Et
CO2Et
R
2
1a: R = H
1b: R = Me
1c: R = Et
1d: R = n Bu
1e: R = i Bu
1f: R = B
4a: R = H
4b: R = Me
4c: R = Et
4d: R = n Bu
4e: R = i Bu
4f: R = Bn
Me
O
Me Me
Me
N
Ts
Ts
HN
O
O
O
1) 0.5 N NaOH
2) EtOH, H2SO4
HN
EtO2C
(3)
EtO2C
N
CO2Et
N
N
CO2Et
CO2Et
tBu
Ph
Ph
tBu
5
4a
3a
3b
The absolute configuration of
the Mannich base 4a was deter-
mined after hydrolysis and de-
carboxylation [Eq. (3)] by com-
paring the optical rotation of 5
obtained according to Equa-
tion (3)with the optical rotation
of 5 prepared from l-aspartic
acid (see Experimental Section).
The absolute configuration was
found to be the same for Man-
nich adducts prepared with
Cu(OTf)2-3a and Cu(OTf)2-3b,
although these catalysts have
opposite configurations.[15]
Table 1. Direct Mannich Reaction of 1a f with 2 catalyzed by Cu(OTf)2/(R)-Ph-BOX (3a).
Entry
R
Solvent
Treaction [8C]
t
Product (yield[a]/[%])Additive (mol%)
ee[b] [%]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
H (1a)CH
H (1a)CH
2Cl2
2Cl2
2Cl2
2Cl2
2Cl2
2Cl2
À 20
À 20
RT[d]
RT[d]
0
40 h
40 h
40 h
40 h
40 h
4 d
4a (95)none
4a (63)HFIP
4b (88)none
4b (70)HFIP
4b (70)HFIP
4b (71)HFIP
4b (57)HFIP
4c (47)HFIP
4c (70)HFIP
4d (80)HFIP
4e (60)HFIP
4 f (51)none
4 f (77)HFIP
4 f (65)HFIP
39
[c]
(150)80
Me (1b)CH
Me (1b)CH
Me (1b)CH
Me (1b)CH
Me (1b)THF
Et (1c)CH
Et (1c)CH
nBu (1d)CH
iBu (1e)CH
Bn (1 f)CH
Bn (1 f)CH
Bn (1 f)CH
61
[c]
(100)69
(100)72
(100)79
(100)59
(100)57
(100)87
(100)82
(100)79
[c]
[c]
[c]
[c]
[c]
[c]
[c]
À 20
0
40 h
2Cl2
2Cl2
2Cl2
2Cl2
2Cl2
2Cl2
2Cl2
RT[d]
À 20
À 20
À 20
RT[d]
RT[d]
À 20
16 h
4 d
4 d
4 d
16 h
16 h
4 d
35
[c]
(100)62
(100)79
[c]
Thus, the direct catalytic
enantioselective Mannich reac-
[a] Yield of isolated product. [b] Enantiomeric excess was determined by HPLC. [c] HFIP ˆ 1,1,1,3,3,3-
hexafluoroisopropanol. [d] RTˆ room temperature.
2360
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Chem. Eur. J. 2003, 9, 2359 2367

Asymmetric Mannich Reactions
2359 2367
Table 2. Direct Mannich reaction of 1a, b,d f with 2 catalyzed by Cu(OTf)2/(S)-tBu-BOX (3b).
The size of the ester moiety of
the b-keto esters has been shown
to have a significant influence on
enantioselectivities of other
asymmetric Lewis acid-cata-
lyzed reactions where b-keto
esters act as pro-nucleophiles.
Togni and co-workers investigat-
ed the catalytic enantioselective
halogenation of b-keto esters,
and found that bulky ester moi-
eties increased the enantioselec-
tivity of the reaction.[16, 17] This
effect was also investigated for
the present Mannich reaction.
Entry
R
Solvent
Treaction [8C]
t
Product (yield[a]/[%])Additive (mol%)
ee[b] [%]
1
2
3
4
5
6
7
8
9
H (1a)CH
H (1a)CH
H (1a)CH
H (1a)CH
Me (1b)CH
Me (1b)CH
nBu (1d)CH
nBu (1d)CH
iBu (1e)CH
iBu (1e)CH
Bn (1 f)CH
Bn (1 f)CH
2Cl2
2Cl2
2Cl2
2Cl2
2Cl2
2Cl2
2Cl2
2Cl2
2Cl2
2Cl2
2Cl2
2Cl2
RT[d]
RT[d]
À 20
À 20
RT[d]
À 20
RT[d]
À 20
RT[d]
À 20
RT[d]
À 20
40 h
40 h
4 d
4 d
40 h
4 d
40 h
4 d
40 h
4 d
40 h
4 d
4a (76)none
4a (80)HFIP
4a (80)none
4a (80)HFIP
4b (95)none
4b (99)none
4d (43)none
4d (63)none
4e (50)none
4e (64)none
4 f (77)none
4 f (54)none
59
[d]
(100)42
(100)45
74
[d]
82
85
70
91
88
96
89
94
10
11
12
[a] Yield of isolated product. [b] Enantiomeric excess was determined by HPLC. [c] HFIP ˆ 1,1,1,3,3,3-
hexafluoroisopropanol. [d] RTˆ room temperature.
tion of the malonates provides a new approach to the
attractive optically active b-carboxylic esters a-amino acid
derivatives.
Ts
Cu(OTf)2-3a
O
O
Ts
O
HN
10 mol%
N
(5)
Et
OR
Et
CO2Et
Me CO2R
CH2Cl2
CO2Et
-20 o
C
Me
8a-i
2
9a-i
Catalytic enantioselective reactions of b-keto esters: We were
happy to find that b-keto esters also underwent the Cu(OTf)2/
Table 4. Direct Mannich reaction of 8a i with 2 catalyzed by Cu(OTf)2/
(R)-Ph-BOX (3a).
Entry b-Keto ester
Product (yield[b]/[%]) dr[c]
ee[d] [%]
Ts
Cu(OTf)2-3a
10 mol%
R
O
O
O
HN
Ts
N
(4)
Me
OEt
Me
CO2Et
Me CO2Et
1
2
(8a) 9a (76)84:16
23
23
CO2Et
Me
2
6
7
(8b) 9b (81)78:22
(8c) 9c (73)72:28
Table 3. Direct Mannich reaction of 6 with 2 catalyzed by Cu(OTf)2/(R)-
Ph-BOX (3a).
3
4
20
Entry Solvent Treaction [8C] Yield[a] [%] Additive [mol%] dr[b] ee[c] [%]
1
2
3
4
5
CH2Cl2 RT[e]
CH2Cl2 RT[e]
> 98
93
90
90
97
none
86:14 24
HFIP[d] (100)88:12 22
CH2Cl2
CH2Cl2 À 20
THF
0
none
none
none
89:11 34
90:10 42
76:24 27
(8d) 9d (70)70:30
40
51
0
[a] Yield of isolated product. [b] Diastereomeric ratio measured by
1H NMR spectroscopic analysis of the crude reaction mixture. [c] Enantio-
meric excess of the major diastereomer was determined by HPLC.
[d] HFIP ˆ 1,1,1,3,3,3-hexafluoroisopropanol. [e] RTˆ room temperature.
5
6
7
(8e) 9e (75)93:7
(8 f) 9 f (81)
> 95: < 5
53
(8g) 9g (72)95:5
50
BOX catalyzed asymmetric Mannich reaction with the N-
tosyl-a-imino ester 2. For initial testing, the b-keto ester 6 was
chosen as pro-nucleophile [Eq. (4)] and the results are shown
in Table 3.
8
9
(8h) 9h (43)
(8i) 9i (33)
> 95: < 5 À 66
> 95: < 5 À 68
At room temperature the Mannich reaction proceeded to
completion affording Mannich adduct 7 in quantitative yield
and good diastereoselectivity, but with low enantioselectivity
(Table 3, entry 1). The addition of HFIP to the reaction did
not have any effect like in the Mannich reaction with diethyl
malonates (entry 2). Cooling the reaction had a positive effect
as the enantioselectivity rose to 34 and 42% ee, at 0 and À208,
respectively, with only a small reduction in yield (entries 3, 4).
Again, CH2Cl2 was the better solvent for this reaction as the
enantioselectivity and diastereoselectivity were lower in THF
(entry 3 vs 5).
[a] All reactions were performed in CH2Cl2 at À208C in the presence of
10 mol% Cu(OTf)2/(R)-Ph-BOX (3a)for 40 h. [b] Yield of isolated
product. [c] Diastereomeric ratio measured by 1H NMR spectroscopic
analysis of the crude reaction mixture. [d] Enantiomeric excess of the major
diastereomer was determined by HPLC.
Several b-keto esters (8a i)with different ester groups were
synthesized by the procedure published by Togni et al.[16] and
applied in the Cu(OTf)2/(R)-Ph-BOX catalyzed reaction with
Chem. Eur. J. 2003, 9, 2359 2367
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K. A. J˘rgensen et al.
FULL PAPER
Table 5. Direct Mannich reaction of 8i, 10a e with 2 in CH2Cl2 catalyzed
by Cu(OTf)2/(S)-tBu-BOX (3b).
the N-tosyl-a-imino ester 2 in CH2Cl2 at À208C [Eq. (5)]. The
results are shown in Table 4.
Entry R1 R2
Treaction [8C] t
Product
(yield[a]/[%])
dr[b] ee[c] [%]
It appears from the results in Table 4 that there is a good
correlation between the size of the ester moiety of the b-keto
esters 8a i and the enantioselectivity of the reaction with the
exception of 8c (R ˆ 2,4-dimethyl-3-pentyl). b-Keto esters
derived from primary alcohols (8a, b)gave the Mannich bases
9a, b in good yields and diastereoselectivities, but with low
enantioselectivities (Table 4, entries 1,2). b-Keto esters with
secondary alkyl groups on the ester moiety (8c f)were also
evaluated in the Mannich reaction under the same conditions.
The ester derived from 2,4-dimethyl-3-pentanol (8c)(entry 3)
gave a similar result as entries 1 and 2, while esters derived
from cyclohexanol and benzhydrol (8e, f)gave an increase in
enantioselectivities to 51 and 53% ee, respectively. Simulta-
neously, the diastereoselectivities rose from good to excellent
while maintaining the good yields (entries 5, 6). The free
rotation of the phenyl groups in benzhydrol was important for
the selectivity of the reaction, as the 9-fluorenol derived ester
(8d)gave the Mannich adduct 9d with lower enantio- and
diastereoselectivity (entry 4). It should also be noted that a
phenyl group on the ester moiety did not change the
stereoselectivity of the reaction (entry 7). For the catalytic
asymmetric Mannich reaction, b-keto esters derived from
tertiary alcohols (8h, i)were the best substrates of the tested
series. Although, the yields of the Mannich adducts 9h, i were
moderate, excellent diastereoselectivities and improved enan-
tioselectivities were obtained with these substrates (entries 8,
9).
1
2
3
4
5
6
7
8
9
Me Me
Et Me
iPr Me
Me Me
Et Me
iPr Me
(CH2)4 (10c)RT
Bn Me
Me allyl
(10a) À 20
40 h 11a (55)97:3 95
40 h 9i (17)98:2 93
40 h 11b (15)84:16 92
16 h 11a (87)93:7 88
16 h 9i (80)98:2 92
16 h 11b (55)84:16 91
16 h 11c (89)99:1 86
16 h 11d (83)96:4 93
16 h 11e (69)92:8 87
(8i) À 20
(10b) À 20
[d]
(10a)RT
(8i)RT
[d]
[d]
[d]
[d]
[d]
(10b)RT
(10d)RT
(10e)RT
1
[a] Yield of isolated product. [b] dr determined by H NMR spectroscopy
or HPLC. [c] Enantiomeric excess of the major diastereomer was
determined by HPLC. [d] RTˆ room temperature.
also reacted in highly stereoselective fashion, but the in-
creased steric bulk also resulted in much lower yields
(entries 2, 3). The stereoselectivity of the Cu(OTf)2/(S)-tBu-
BOX (3b)catalyzed reaction was not as temperature depend-
ent as the Cu(OTf)2/(R)-Ph-BOX (3a)catalyzed reaction (see
Table 3). With the exception of the methyl substituted b-keto
ester 10a (entry 4), the b-keto esters reacted with 2 at room
temperature with no significant decrease in either diastereo-
or enantioselectivity compared to the reaction at À208C, but
with greatly increased yields (entries 5, 6 vs 2, 3). The
generality of the reaction was displayed with the reaction of
tert-butyl b-keto esters with variable substituent patterns
(entries 7 9). In general, the Mannich adducts 9i, 11a
e
The Mannich adduct from the reaction of N-tosyl-a-imino
ester 2 and the b-keto ester derived from benzhydrol (8 f)was
recrystallised to 80% ee and X-ray crystallography revealed
(R,R)-configuration of the two chiral centers.[18] This infor-
mation was also used to determine the absolute configuration
of 9i. The two Mannich adducts 9h, i were found to have the
same relative configuration, but to our surprise, the absolute
configuration of the Mannich adducts was reversed when
going from a b-keto ester with an ester group derived from a
secondary to a tertiary alcohol. Apparently, a more bulky
substituent on the ester moiety caused a change in the
geometry of the reactive substrate-Lewis acid complex (see
above).
were obtained in good yields and with high diastereo- and
enantioselectivities. The b-keto esters 8e and 8 f with ester
moieties derived from secondary alcohols were also applied in
the Cu(OTf)2/(S)-tBu-BOX (3b)catalyzed reaction with the
N-tosyl-a-imino ester 2. The products from these reactions
were obtained with moderate selectivities (dr 75:25, 59% ee
and dr 89:11, 57% ee, respectively)but with the same relative
and absolute configuration as the tert-butyl b-keto esters (see
below).
Product modification: The utility of the enantioselective
catalytic direct Mannich reaction was enhanced by the
development of a diastereoselective decarboxylation reaction
of the Mannich adducts derived from b-keto esters.[19] Treat-
Ts
Cu(OTf)2-3b
O
O
O
HN
Ts
10 mol%
N
R1
CO2Et
R2 CO2tBu
R1
OtBu
(6)
Ts
Ts
CH2Cl2
O
HN
O
HN
CO2Et
R2
8i,10a-e
1) 1.5 equiv TMSOTf
2) sat NaHCO3
(7)
R1
CO2Et
R2 CO2tBu
R1
CO2Et
9i,11a-e
2
R2
9i:
R
1 = Et, R2 = Me
12a: R1 = Et, R2 = Me dr 89:11
12b: R1, R2 = (CH2)4 dr 85:15
11c: R1, R2 = (CH2)4
The Mannich reaction of the a-imino ester 2 and b-keto
esters with the optimized ester functionality–the tert-butyl
ester–was now investigated with the Cu(OTf)2/tBu-BOX
(3b)complex as the catalyst [Eq. (6)] and Table 5 shows some
representative results from this investigation.
At À208C the b-keto ester 10a reacted with the N-tosyl-a-
imino ester 2 to give Mannich adduct 11a with excellent
diastereo- and enantioselectivity in 55% yield after 40 h
(Table 5, entry 1). b-Keto esters with larger R1 substituents
ment of Mannich adduct 9i with 1.5 equiv of TMSOTf in
CHCl3 for 60 min followed by the addition of sat. aq.
NaHCO3 gave g-keto a-amino acid ester 12a in 76% yield
and with a diastereomeric ratio of 89:11 [Eq. (7)]. The same
reaction was performed on the Mannich base derived from
tert-butyl cyclohexanone-2-carboxylate (11c)with similar
diastereoselectivity. The high enantioselectivity was main-
2362
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2003, 9, 2359 2367

Asymmetric Mannich Reactions
2359 2367
tained through these transformations (see Experimental
Section for assignment of absolute configuration).
Thus, the direct catalytic enantioselective Mannich reaction
of the b-keto esters provides an attractive approach to
attractive optically active g-keto a-amino acid derivatives.
as the best class of substrates by reaction with an N-tosyl-a-
imino ester and the Mannich adducts could be obtained in
high yields, diastereo- and enantioselectivities in the presence
of Cu(OTf)2/(S)-tBu-BOX as the catalyst. A diastereoselec-
tive decarboxylation reaction was developed for the Mannich
adducts obtained leading to an
easy synthetic approach to at-
tractive optically active g-keto
a-amino acid derivatives. Based
on the absolute configuration of
the Mannich adducts, the mech-
anism for the direct catalytic
enantioselective Mannich reac-
tions was proposed involving a
keto to enol transformation of
the chiral Lewis acid before the
stereoselective formation of the
Scheme 1. Possible reactive intermediates in the copper bisoxazoline catalyzed enantioselective Mannich
reactions of b-keto esters.
À
C C bond.
Mechanistic considerations: The stereochemical outcome of
the copper bisoxazoline catalyzed asymmetric Mannich
reactions of the b-keto esters can be explained by the
Experimental Section
complexes shown in Scheme 1.
General methods: The 1H and 13C NMR spectra were recorded at 400 MHz
and 100 MHz, respectively. The chemical shifts are reported in ppm
downfield to CHCl3 (d ˆ 7.26)for 1H NMR and relative to the central
The surprising reversal of enantioselectivity we found when
going from a b-keto ester with an ester group derived from a
secondary to a tertiary alcohol in the Cu(OTf)2/(R)-Ph-BOX
(3a)catalyzed reaction may be accounted for by the approach
outlined in 13 and 14. Coordination of the enolate of 8 f in a
twisted tetrahedral-like geometry around the copper cen-
ter[15a] would allow reaction with the N-tosyl-a-imino ester 2
as shown in 13. A more square-planar-like intermediate of the
tert-butyl ester 8i coordinated to the Cu(OTf)2/(R)-Ph-BOX
would allow the reaction with the imine from above, with the
tosyl-group in the less crowded steric environment in the
upper left corner of 14 as shown in Scheme 1. The reversal of
enantioselectivity when changing the ester moiety is quite
remarkable and displays the flexibility of the Cu(OTf)2/(R)-
Ph-BOX complex as chiral catalyst.[15a] A complex similar to
complex 14 could explain the absolute and relative config-
uration of the Mannich bases formed in the Cu(OTf)2/(S)-tBu-
BOX (3b)catalyzed reaction (see 15, Scheme 1). The
mechanism for the stereochemical outcome of these catalytic
direct enantioselective Mannich reactions of malonates and b-
keto esters with the N-tosyl-a-imino ester seems to be more
complex compared to other chiral bisoxazoline/CuII-catalyzed
reactions.
1
CDCl3 resonance (d ˆ 77.0)for 13C NMR. Coupling constants in H NMR
are in Hz. Solvents were dried according to standard procedures. Flash
chromatography (FC)was carried out using silica gel 60 (230 400 mesh).
The enantiomeric excess (ee)of the products were determined by HPLC
using Daicel Chiracel OJ or Daicel Chiralpak AD or AS columns with
iPrOH/hexane as eluent. All optical rotations were measured in CH2Cl2.
Materials: 2,2'-Isopropylidene[(4S)-4-tert-butyl-2-oxazoline], 2,2'-isopro-
pylidene-bis[(4R)-4-phenyl-2-oxazoline],
methylene-bis[(4R,5S)-4,5-di-
phenyl-2-oxazoline], Cu(OTf)2, ethyl 2-methylacetoacetate (6), nBuLi,
tert-butylpropionate, N,O-dimethylhydroxylamine hydrochloride, p-tolue-
nesulfonyl isocyanate, trimethylsilyl trifluoromethanesulphonate and
TMSCHN2 are commercially available and used as received. b-Keto esters
8a
j were prepared by reaction of methylketene dimer with the
appropriate alcohol following a literature procedure.[16] b-Keto esters
10a, b, d, e were prepared by acylation of tert-butylpropionate, and tert-
butyl-4-pentenoate by N-methoxy-N-methylamides following a literature
procedure.[20] b-Keto ester 10c was prepared from pimelic di-tert-butylester
following a literature procedure.[21] The alcohols used are all commercially
available. The N-tosyl-a-imino ester (2)was prepared from ethyl glyoxylate
and p-toluenesulfonyl isocyanate by a literature procedure.[22]
General procedure for catalytic asymmetric direct Mannich reaction of
malonic esters: Cu(OTf)2 (18.1 mg, 0.050 mmol)and 2,2 '-isopropylidene-
bis[(4S)-4-tert-butyl-2-oxazoline] (15.5 mg, 0.05 mmol)were added to an
oven dried Schlenk tube equipped with a magnetic stirring bar. The mixture
was stirred under vacuum at 508C for 2 h and filled with Ar. Dry CH2Cl2
1
(2 mL)was added and the solution was stirred for ³2 h. N-Tosyl-a-imino
ester (2)(153 mg, 0.6 mmol)was added followed by the malonate
(0.5 mmol)and stirred over night under Ar at RT. The reaction mixture
was filtered through a plug of silica with 30% Et2O in CH2Cl2. The solvent
was removed in vacuo and the residue was purified by FC (silica 15% Et2O/
CH2Cl2 ! CH2Cl2).
Summary
The first direct catalytic enantioselective Mannich reactions
of malonates and b-keto esters with imines have been
developed. The different malonates tested reacted with an
N-tosyl-a-imino ester catalyzed by Cu(OTf)2/(S)-tBu-BOX to
give the Mannich adducts in high yields and with up to 96%
ee. The Mannich adducts obtained provides an easy synthetic
entry to optically active b-carboxylic ester a-amino acid
derivatives by decarboxylation. For the b-keto esters a
screening of the ester substituents gave the tert-butyl esters
2-Ethoxycarbonyl-3-tosyl-succinic diethyl ester (4a): The ee was deter-
mined by HPLC using a Daicel Chiralpak OJ column (hexane/iPrOH
85:15); flow rate 1.0 mLminÀ1; tmajor ˆ 23.4 min; tminor ˆ 18.6 min). [a]RDT
ˆ
À31.08 (c ˆ 10.0 mgmLÀ1, 74% ee); 1H NMR: d ˆ 7.69 (d, J ˆ 8.2, 2H,
ArH), 7.23 (d, J ˆ 8.2, 2H, ArH), 5.66 (d, J ˆ 8.2, 1H, NH), 4.45 (dd, J ˆ 8.2,
J ˆ 4.2, 1H, NHCH), 3.91 4.18 (m, 7H, CH(CO2CH2CH3)2, OCH2CH3),
2.35 (s, 3H, ArCH3), 1.10 (t, J ˆ 7.1, 6H, (CO2CH2CH3)2), 1.03 (t, J ˆ 7.2,
3H, OCH2CH3); 13C NMR: d ˆ 169.0, 167.2, 166.7, 144.0, 137.1, 129.8 (2C),
127.5 (2C), 62.7, 64.4, 62.3, 55.2 55.0, 21.8, 14.2 (2C), 13.9; HRMS: calcd for
‡
C18H25NNaO8S: 438.1199; found: 438.1208 [M‡Na] .
Chem. Eur. J. 2003, 9, 2359 2367
www.chemeurj.org
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2363

K. A. J˘rgensen et al.
FULL PAPER
2-Ethoxycarbonyl-2-methyl-3-tosyl-succinic diethyl ester (4b): The ee was
determined by HPLC using a Daicel Chiralpak OJ column (hexane/iPrOH
(2 mL)and excess tosylchloride was added. Tosylation of the amino group
was accomplished by stirring this solution at room temperature over night.
The product which precipitated as white crystals, was filtered off and
washed with water and diluted hydrochloric acid. The l-N-tosyl-aspartic
acid diethyl ester was recrystallized in EtOAc/pentane.
95:5); flow rate 1.0 mLminÀ1; tmajor ˆ 30.1 min; tminor ˆ 38.2 min). [a]RDT
ˆ
À26.28 (c ˆ 10.0 mgmLÀ1, 85% ee); 1H NMR: d ˆ 7.67 (d, J ˆ 8.4, 2H,
ArH), 7.22 (d, J ˆ 8.4, 2H, ArH), 5.42 (d, J ˆ 9.8, 1H, NH), 4.30 (d, J ˆ 9.8,
1H, CH), 4.04 4.17 (m, 4H, (CO2CH2CH3)2), 3.82 (q, J ˆ 7.1, 2 H,
OCH2CH3), 2.34 (s, 3H, ArCH3), 1.56 (s, 3H, CH3), 1.21 (t, J ˆ 7.2, 3H,
CO2CH2CH3), 1.19 (t, J ˆ 7.2, 3H, CO2CH2CH3), 0.94 (t, J ˆ 7.1, 3 H,
OCH2CH3); 13C NMR: d ˆ 170.0, 169.8, 168.6, 143.6, 136.9, 129.6 (2C),
127.3 (2C), 62.0, 61.9, 61.8, 59.9, 58.1, 21.4, 20.2, 13.8 (2C), 13.5; HRMS:
(1-Isopropyl-2-methyl)-propyl 2-methyl-3-oxopentanoate (8c): 1H NMR:
d ˆ 4.62 (t, J ˆ 6.2, 1H, OCH(CH3)2), 3.59 (q, J ˆ 7.2, 1H, CHCH3), 2.61 (m,
2H, CH2CH3), 1.90 (sext, J ˆ 6.6, 2H, CH(CH3)2), 1.36 (d, J ˆ 7.2, 3H,
CHCH3), 0.92 0.83 (m, 12H, CH(CH3)); 13C NMR: d ˆ 206.6, 170.6, 83.7,
52.6, 35.4, 29.4, 19.7, 19.7, 17.2, 17.0, 13.0, 7.6; HRMS: calcd for C13H24NaO3:
‡
‡
calcd for C19H27NNaO8S: 452.1355; found: 452.1347 [M‡Na] .
251.1623; found: 251.1310 [M‡Na] .
(9H-Fluoren-9-yl) 2-methyl-3-oxopentanoate (8d): 1H NMR: d ˆ 7.67 (d,
J ˆ 7.7, 2 H, ArH), 7.53 (m, 2H, ArH), 7.42 (t, J ˆ 7.7, 2 H, ArH), 7.31 (t, J ˆ
7.7, 2 H, ArH), 6.84, (s, 1H, OCH), 3.66 (q, J ˆ 7.4, 1H, CHCH3), 2.57 (m,
2H, CH2CH3), 1.44 (d, J ˆ 7.4, 3H, CH3CH), 1.04 (t, J ˆ 7.1, 3 H, CH2CH3);
13C NMR: d ˆ 206.1, 171.5, 141.5, 141.0, 140.9, 129.6, 129.5, 127.9, 127.9,
125.8, 125.7, 120.1, 75.7, 52.6, 34.7, 13.0, 7.6; HRMS: calcd for C19H18O3:
2-Ethoxycarbonyl-2-ethyl-3-tosyl-succinic diethyl ester (4c): The ee was
determined by HPLC using a Daicel Chiralpak AS column (hexane/iPrOH
99:1); flow rate 1.0 mLminÀ1; tmajor ˆ 53.4 min; tminor ˆ 66.5 min). [a]RDT
ˆ
À10.18 (c ˆ 10.0 mgmLÀ1, 56% ee); 1H NMR: d ˆ 7.72 (d, J ˆ 8.2, 2H,
ArH), 7.28 (d, J ˆ 8.2, 2H, ArH), 5.64 (d, J ˆ 10.2, 1H, NH), 4.41 (d, J ˆ
10.2, 1H, CH), 4.13 4.26 (m, 4H, (CO2CH2CH3)2), 3.77 3.82 (m, 2H,
OCH2CH3), 2.40 (s, 3H, ArCH3), 2.05 (q, J ˆ 7.6, 2H, CH3CH2), 1.24 1.31
(m, 6H, (CO2CH2CH3)2), 0.94 1.05 (m, 6H, CH2CH3, OCH2CH3);
13C NMR: d ˆ 169.5, 169.0, 168.8, 143.4, 137.1, 129.3 (2C), 127.2 (2C),
61.9, 61.7, 61.6, 61.3, 59.5, 27.4, 21.4, 13.8, 13.7, 13.4, 9.3; HRMS: calcd for
‡
317.1154, found: 317.1155 [M‡Na] .
Cyclohexyl 2-methyl-3-oxopentanoate (8e): 1H NMR: d ˆ 4.79 (m, 1H,
OCH(CH2)2), 3.48 (q, 1H, J ˆ 7.0, CHCH3), 2.55 (m, 2H, CH2CH3), 1.85
1.63 (m, 4H, CH2), 1.54 1.27 (m, 6H, CH2), 1.33 (d, J ˆ 7.0, 3H, CHCH3),
1.06 (t, J ˆ 7.2, CH2CH3); 13C NMR: d ˆ 206.6, 170.1, 73.5, 52.8, 34.6,31.3,
21.2, 25.5, 23.5, 12.7, 7.7; HRMS: calcd for C10H20NaO3: 235.1310; found:
‡
C20H29NNaO8S: 466.1512; found: 466.1519 [M‡Na] .
2-Butyl-2-ethoxycarbonyl-3-tosyl-succinic diethyl ester (4d): The ee was
determined by HPLC using a Daicel Chiralpak AD column (hexane/iPrOH
‡
235.1230 [M‡Na] .
99:1); flow rate 1.0 mLminÀ1; tmajor ˆ 84.2 min; tminor ˆ 75.2 min). [a]RDT
ˆ
1
Phenyl 2-methyl-3-oxopentanoate (8g): H NMR: d ˆ 7.40 (t, J ˆ 7.3, 2H,
À23.28 (c ˆ 10.0 mgmLÀ1, 91% ee). 1H NMR: d ˆ 7.67 (d, J ˆ 8.0, 2H,
ArH), 7.22 (d, J ˆ 8.0, 2H, ArH), 5.60 (d, J ˆ 10.4, 1H, NH), 4.36 (d, J ˆ
10.4, 1H, CH), 4.07 4.19 (m, 4H, (CO2CH2CH3)2), 3.71 3.85 (m, 2H,
OCH2CH3), 2.34 (s, 3H, ArCH3), 1.85 (t, J ˆ 8.2, 2H, CH2), 1.17 1.37 (m,
10H, 2  CH2, (CO2CH2CH3)2), 0.96 (t, J ˆ 7.4, 3H, OCH2CH3), 0.81 (t, J ˆ
7.2, 3H, CH3); 13C NMR: d ˆ 169.5, 169.0, 168.9, 143.4, 137.1, 129.3 (2C),
127.2 (2C), 61.8, 61.7, 61.6, 60.8, 59.6, 33.7, 26.6, 22.8, 21.3, 13.8, 13.7, 13.6,
13.4; HRMS: calcd for C22H33NNaO8S: 494.1825; found: 494.1821
ArH), 7.25 (t, J ˆ 7.3, 1H, ArH), 7.10 (d, J ˆ 7.3, 2H, ArH), 3.79 (q, J ˆ 6.9,
1H, CHCH3), 2.71 (m, 2H, CH3CH2CO), 1.49 (d, J ˆ 6.9, 3H, CHCH3), 1.13
(t, 7.3, 3H, CH2CH3); 13C NMR: d ˆ 206.0, 169.2, 150.4, 129.4, 126.1, 121.2,
52.5, 34.6, 12.9, 7.7; HRMS: calcd for C12H14NaO3: 229.0841; found:
‡
229.0844 [M‡Na] .
1
Adamantyl 2-methyl-3-oxopentanoate (8h): H NMR: d ˆ 3.41 (q, J ˆ 7.1,
1H, CHCH3), 2.56 (m, 2H, CH2CH3), 2.16 (s, 3H, CH), 2.09 (s, 6H, CH2),
1.66, (s, 6H, CH2), 1.28 (d, J ˆ 7.1, 3H, CHCH3), 1.07 (t, J ˆ 7.2, 3H,
CH2CH3); 13C NMR: d ˆ 206.9, 196.6, 81.6, 53.7, 41.1, 36.0, 34.5, 30.6, 12.7,
‡
[M‡Na] .
‡
7.8; HRMS: calcd for C19H18NaO3: 317.1154; found: 317.1155 [M‡Na] .
2-Ethoxycarbonyl-2-isobutyl-3-tosyl-succinic diethyl ester (4e): The ee was
determined by HPLC using a Daicel Chiralpak AD column (hexane/iPrOH
tert-Butyl 1-phenyl-2-methyl-3-oxopentanoate (8i): 1H NMR: d ˆ 7.28 (m,
3H, ArH), 7.21 (d, J ˆ 6.9, 2H, ArH), 3.88 (d, J ˆ 15.7, 1H, ArCH2CO), 3.82
(d, J ˆ 15.7, 1H, ArCH2CO), 3.56 (q, J ˆ 7.2, 1H, CHCH3), 1.46 (s, 9H,
C(CH3)3), 1.28 (d, J ˆ 7.1, 3H, CHCH3); 13C NMR: d ˆ 203.6, 169.5, 133.5,
129.5, 128.6, 127.1, 81.8, 52.7, 48.5, 27.8, 12.7; HRMS: calcd for C15H20NaO3:
95:5); flow rate 1.0 mLminÀ1; tmajor ˆ 29.6 min; tminor ˆ 26.0 min). [a]RDT
ˆ
À20.38 (c ˆ 10.0 mgmLÀ1, 96% ee); 1H NMR: d ˆ 7.66 (d, J ˆ 8,0, 2H,
ArH), 7.21 (d, J ˆ 8.0, 2H, ArH), 5.66 (d, J ˆ 10.0, 1H, NH), 4.36 (d, J ˆ
10.0, 1H, CH), 4.08 4.18 (m, 4H, (CO2CH2CH3)2), 3.65 3.82 (m, 2H,
OCH2CH3), 2.34 (s, 3H, ArCH3), 1.70 1.89 (m, 3H, CH2CH), 1.23 (t, J ˆ
7.2, 3H, OCH2CH3), 1.20 (t, J ˆ 7.2, 3H, OCH2CH3), 0.96 (t, J ˆ 7.2, 3H,
OCH2CH3), 0.83 (d, J ˆ 6.4, 3H, CH3), 0.80 (d, J ˆ 6.4, 3H, CH3); 13C NMR:
d ˆ 169.4, 169.1, 168.7, 143.4, 137.1, 129.3 (2C), 127.1 (2C), 61.9, 61.6 (2C),
60.1, 59.9, 42.1, 24.5, 23.8, 23.6, 21.3, 13.7, 13.6, 13.4; HRMS: calcd for
‡
271.1310; found: 271.1308 [M‡Na] .
General procedure for catalytic asymmetric direct Mannich reaction of b-
keto esters: In a oven dried Schlenk tube equipped with a magnetic stirring
bar, Cu(OTf)2 (9 mg, 0.025 mmol)and 2,2 '-isopropylidene [(4S)-4-tert-
butyl-2-oxazoline] (9.2 mg 0.026 mmol)were added. The mixture was
stirred under vacuum for 2 h and filled with N2. Dry CH2Cl2 (2 mL)was
added and the solution was stirred for 1 h. A 0.3m solution (1 mL)of a-
imino ester (2)in dry CH 2Cl2 and 0.25 mmol of the b-keto esters were
added. After 16 h the product was isolated by FC.
‡
C22H33NNaO8S: 494.1825; found: 494.1817 [M‡Na] .
2-Benzyl-2-ethoxycarbonyl-3-tosyl-succinic diethyl ester (4 f): The ee was
determined by HPLC using a Daicel Chiralpak AD column (hexane/iPrOH
95:5); flow rate 1.0 mLminÀ1; tmajor ˆ 51.9 min; tminor ˆ 40.1 min). [a]RDT
ˆ
À52.78 (c ˆ 10.0 mgmLÀ1, 94% ee); 1H NMR: d ˆ 7.67 (d, J ˆ 8.4, 2H,
ArH), 7.13 7.23 (m, 7H, ArH), 5.70 (d, J ˆ 10.4, 1H, NH), 4.50 (d, J ˆ 10.4,
1H, CH), 4.06 (q, J ˆ 7.2, 2H, OCH2CH3), 3.96 (q, J ˆ 7.2, 2H, OCH2CH3),
3.68 3.84 (m, 2H, OCH2CH3), 3.28 (dd, J ˆ 23.2, J ˆ 14.0, 2H, ArCH2),
2.34 (s, 3H, ArCH3), 1.12 (t, J ˆ 7.2, 3H, OCH2CH3), 1.02 (t, J ˆ 7,2, 3H,
OCH2CH3), 0.97 (t, 7.2, 3H, OCH2CH3); 13C NMR: d ˆ 168.3, 168.2, 168.1,
143.1, 136.6, 134.9, 130.3 (2C), 129.0 (2C), 127.4 (2C), 126.8 (2C), 126.6,
61.8, 61.5 (2C), 61.4, 59.4, 38.9, 21.0, 13.3, 13.1 (2C); HRMS: calcd for
Ethyl 3-methyl-4-oxo-3-ethoxycarbonyl-2-(tosylamino)pentanoate (7):
The ee was determined by HPLC using a Daicel Chiralpak AD column
(hexane/iPrOH 92:8): flow rate 1.0 mLminÀ1: tmajor ˆ 33.7 min; tminor
ˆ
30.9 min; t2nd diast. ˆ 28.8 and 28.8 min). 1H NMR: d ˆ 7.74 (d, J ˆ 8.0, 2H,
ArH), 7.29 (d, J ˆ 8.0, 2H, ArH), 5.34 (d, J ˆ 9.9, 1H, NH), 4.35 (d, J ˆ 9.7,
1H, CH), 4.22 (m, 2H, OCH2CH3), 3.85 (m, 2H, OCH2CH3), 2.41 (s, 3H,
ArCH3), 2.28 (s, 3H, COCH3), 1.28 (t, J ˆ 7.2, 3H, OCH2CH3); 0.96 (t, J ˆ
7.2, 3H, OCH2CH3); 13C NMR: d ˆ 205.7, 170.8, 168.9, 143.5, 129.4, 127.3,
62.9, 61.9, 61.8, 59.6, 27.1, 21.4, 20.1, 13.8, 13.4; HRMS: calcd for
‡
C25H31NNaO8S: 528.1668; found: 528.1668 [M‡Na] .
‡
C18H25NNaO7S: 422.1249; found: 422.1259 [M‡Na] .
Decarboxylation of 2-ethoxycarbonyl-3-tosyl-succinic diethyl ester (4a):
Mannich adduct 4a (100 mg)was stirred in 0.5 n NaOH (10 mL)at room
temperature for 2 h. The mixture was neutralised with 1n KHSO4 and
stirred at 508C over night. Water was removed in vacuo and the residue was
redissolved in EtOH. H2SO4 (0.5 mL)was added, and the solution was
heated under reflux over night. After cooling to room temperature, NaOH
was added to pH 8 9. The mixture was extracted with Et2O (3 Â ), and the
combined organic extracts was washed with sat. NaCl, dried with Na2SO4
and concentrated in vacuo. Absolute configuration was determined by
optical rotation, compared to the corresponding tosylated amino ester
prepared from l-aspartic acid. Esterfication of l-aspartic acid was carried
out as mentioned above. The just prepared ester was dissolved in pyridine
Ethyl 3-methyl-4-oxo-3-ethoxycarbonyl-2-(tosylamino)hexanoate (9a):
The ee was determined by HPLC using a Daicel Chiralpak AD column
(hexane/iPrOH 90:10): flow rate 1.0 mLminÀ1: tmajor ˆ 30.4 min; tminor
ˆ
24.5 min; t2nd diast. ˆ 20.8 and 24.5 min)and Daicel Chiralpak OJ column
(hexane/iPrOH 90:10): flow rate 1.0 mLminÀ1: tmajor ˆ 17.7 min; tminor
19.9 min; t2nd diast. ˆ 31.9 and 67.4 min). 1H NMR: d ˆ 7.73 (d, J ˆ 8.1, 2H,
ArH), 7.29 (d, J ˆ 8.1, 2H, ArH), 5.41 (d, J ˆ 10.1, 1H, NH), 4.36 (d, J ˆ
10.1, 1H, CH), 4.20 (m, 2H, OCH2), 3.84 (m, 2H, OCH2), 2.77 (m, 1H,
COCH2CH3), 2.45 (m, 1H, COCH2CH3), 2.41 (s, 3H, ArCH3), 1.63 (s, 3H,
CCH3), 1.28 (t, J ˆ 7.0, 3H, OCH2CH3), 1.03 (t, J ˆ 7.3, 3H, COCH2CH3),
0.95 (t, J ˆ 7.0, 3H, OCH2CH3); 13C NMR: d ˆ 208.5, 171.0, 169.0, 143.5,
ˆ
2364
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2003, 9, 2359 2367

Asymmetric Mannich Reactions
2359 2367
137.0, 129.4, 129.3, 127.3, 127.2, 62.7, 62.6, 61.8, 59.7, 32.5, 21.4, 13.8, 13.4, 7.8,
7.6; HRMS: calcd for C19H27NNaO7S: 436.1406; found: 436.1414 [M‡Na] .
13C NMR: d ˆ 208.3, 169.8, 169.1, 150.1, 143.7, 137.0, 129.6, 129.5, 127.4,
‡
126.3, 121.2, 62.9, 62.1, 59.9, 32.6, 21.5, 20.2, 13.5, 7.9; HRMS: calcd for
‡
C23H27NO7S: 484.1406; found: 484.1410 [M‡Na] .
Ethyl
3-methyl-4-oxo-3-(1-naphthyl)-methoxycarbonyl-2-(tosylamino)-
hexanoate (9b): The ee was determined by HPLC using a Daicel Chiralpak
AD column (hexane/iPrOH 80:20): flow rate 1.0 mLminÀ1: tmajor ˆ 7.3 min;
tminor ˆ 7.8 min; t2nd diast. ˆ 6.0 and 6.0 min). 1H NMR: d ˆ 8.00 (m, 1H,
ArH), 7.88 (m, 2H, ArH), 7.64 (m, 2H, ArH), 7.54 (m, 3H, ArH), 7.45 (m,
1H, ArH), 7.25 (m, 2H, ArH), 5.69 (d, J ˆ 22.3, 1H, OCH2Ar), 5.50 (d, J ˆ
22.3, 1H, OCH2Ar), 5.32 (d, J ˆ 10.1, 1H, NH), 4.36, (d, J ˆ 10.1, 1H, CH),
3.72 (m, 2H, OCH2), 2.67 (m, 1H, COCH2CH3), 2.36 (m, 1H, COCH2CH3),
2.41 (s, 3H, ArCH3), 1.62 (s, 3H, CCH3), 0.89 (t, J ˆ 7.3, 3H, COCH2CH3),
0.84 (t, J ˆ 7.0, 3H, OCH2CH3); 13C NMR: d ˆ 208.3, 170.9, 169.0, 143.5,
136.8, 133.6, 131.6, 130.4, 139.6, 129.4, 128.7, 128.0, 127.3, 126.6, 125.9, 125.2,
123.3, 66.1, 62.9, 61.9, 59.8, 32.5, 21.4, 20.0, 13.4, 7.7; HRMS: calcd for
Ethyl
3-methyl-4-oxo-3-adamantoxycarbonyl-2-(tosylamino)hexanoate
(9h): The ee was determined by HPLC using a Daicel Chiralpak AD
column (hexane/iPrOH 95:5): flow rate 1.0 mLminÀ1: tmajor ˆ 18.0 min;
tminor ˆ 13.0 min; t2nd diast. ˆ 9.2 and 11.8 min). [a]D ˆ À18.88 (c ˆ
52 mgmLÀ1, 90% ee); 1H NMR: d ˆ 7.73 (d, J ˆ 8.0, 2H, ArH), 7.28 (d,
J ˆ 8.0, 2H, ArH), 5.37 (d, J ˆ 10.0, 1H, NH), 4.30 (d, J ˆ 10.0, 1H, CH),
3.83 (q, J ˆ 6.8, 2H, OCH2CH3), 2.77 (m, 1H, COCH2CH3), 2.45 (m, 1H,
COCH2CH3), 2.41 (s, 3H, ArCH3), 2.18 (s, 3H, CH), 2.13 (s,6H, CH2), 1.66
(s, 6H, CH2), 1.57 (s, 3H, CCH3), 0.96, (t, J ˆ 7.4, 3H, OCH2CH3), 0.91 (t,
J ˆ 7.2, 3H, COCH2CH3); 13C NMR: d ˆ 208.7, 169.7, 169.2, 143.5, 137.0,
129.4, 127.4, 83.1, 63.4, 61.7, 59.8, 41.0, 36.0, 30.8, 21.4, 13.6, 8.0; HRMS:
‡
‡
C28H31NNaO7S: 548.1719; found: 548.1719 [M‡Na] .
calcd for C27H37NO7S: 542.2188, found: 542.2186 [M‡Na] .
Ethyl 3-methyl-4-oxo-3-(1'-isopropyl-2'-methyl-propanoxycarbonyl)-2-(to-
Ethyl
3-methyl-4-oxo-3-tert-butoxycarbonyl-2-(tosylamino)hexanoate
sylamino)hexanoate (9c): The ee was determined by HPLC using a Daicel
(9i): The ee was determined by HPLC using a Daicel Chiralpak AD
column (hexane/iPrOH 95:5): flow rate 1.0 mLminÀ1: tmajor ˆ 36.6 min;
tminor ˆ 22.6 min; t2nd diast. ˆ 14.4 and 38.1 min). [a]D ˆ À21.68 (c ˆ
43 mgmLÀ1, 92% ee); 1H NMR: d ˆ 7.73 (d, J ˆ 8.4, 2H, ArH), 7.28 (d,
J ˆ 8.4, 2H, ArH), 5.36 (d, J ˆ 10.4, 1H, NH), 4.31 (d, J ˆ 10.4, 1H, CH),
3.86 (q, J ˆ 7.3, 2H, OCH2CH3), 2.76 (m, 1H, COCH2CH3), 2.47 (m, 1H,
COCH2CH3), 2.41 (s, 3H, ArCH3), 1.58 (s, 3H, CCH3), 1.49 (s, 9H,
C(CH3)3), 1.03 (t, J ˆ 7.3, 3H, OCH2CH3), 0.96 (t, J ˆ 7.3, 3H, COCH2CH3);
13C NMR: d ˆ 208.6, 169.5, 169. 0, 143.5, 137.0, 129.4, 127.3, 82.9, 62.3, 61.6,
59.7, 32.5, 27.7, 21.4, 13.5, 7.9; HRMS: calcd for C21H31NNaO7S: 464.1719,
Chiralpak AD column (hexane/iPrOH 80:20): flow rate 1.0 mLminÀ1
:
tmajor ˆ 7.3 min; tminor ˆ 7.8 min; t2nd diast. ˆ 6.0 and 6.0 min). 1H NMR: d ˆ
7.73 (d, J ˆ 8.1, 2H, ArH), 7.29 (d, J ˆ 8.1, 2H, ArH), 5.50 (d, J ˆ 9.9, 1H,
NH), 4.67 (t, J ˆ 5.8, 1H, OCH(CH2)2), 4.44, (d, J ˆ 9.9, 1H, CH), 3.82 (m,
2H, OCH2), 2.71 (m, 1H, COCH2CH3), 2.41 (s, 3H, ArCH3), 1.93 (m, 1H,
CH(CH3)2), 1.67 (s, 1H, CH3), 1.04 (t, J ˆ 7.1, 3H, COCH2CH3), 0.92 0.83
(m, 15H, CH(CH3), OCH2CH3); 13C NMR: d ˆ 208.4, 170.9, 168.9, 143.5,
137.0, 129.4, 129.4, 127.3, 127.3, 84.9, 62.1, 61.8, 59.7, 32.4, 29.6, 29.5, 21.4,
19.7, 19.6, 17.5, 17.4, 13.5, 7.9, 7.7; HRMS: calcd for C24H37NO7S: 506.2188;
‡
‡
found: 506.2185 [M‡Na] .
found: 464.1715 [M‡Na] .
Ethyl 3-methyl-4-oxo-3-(9'H-fluoren-9'-oxycarbonyl)-2-(tosylamino)hexa-
noate (9d): The ee was determined by HPLC using a Daicel Chiralpak AD
column (hexane/iPrOH 95:5): flow rate 1.0 mLminÀ1: tmajor ˆ 58.4 min;
Ethyl
3-methyl-4-oxo-3-tert-butoxycarbonyl-2-(tosylamino)pentanoate
(11a): The ee was determined by HPLC using a Daicel Chiralpak AD
column (hexane/iPrOH 90:10): flow rate 1.0 mLminÀ1: tmajor ˆ 24.2 min;
tminor ˆ 16.0 min; t2nd diast. ˆ 11.4 and 26.5 min). [a]D ˆ À27.78 (c ˆ
38 mgmLÀ1, 88% ee); 1H NMR: d ˆ 7.73 (d, J ˆ 8.1, 2H, ArH), 7.28 (d,
J ˆ 8.1, 2H, ArH), 5.34 (d, J ˆ 9.9, 1H, NH), 4.33 (d, J ˆ 9.9, 1H, CH), 3.85
(m, 2H, OCH2CH3), 2.41 (s, 3H, ArCH3), 2.26 (s, 3H, COCH3), 1.59 (s, 3H,
CCH3), 1.49 (s, 9H, C(CH3)3), 0.96 (t, J ˆ 7.2, 3H, OCH2CH3); 13C NMR:
d ˆ 206.0, 169.7, 169.2, 143.5, 137.0, 129.5, 127.4, 83.1, 63.6, 61.8, 59.6, 27.8,
27.2, 21.5, 20.4, 13.6; HRMS: calcd for C20H29NNaO7S: 450.1562, found:
1
tminor ˆ 44.2 min; t2nd diast. ˆ 30.3 and 39.7 min). H NMR: d ˆ 7.75 7.27 (m,
10H, ArH), 6.80, (s, 1H, OCH), 5.42 (d, J ˆ 9.5, 1H, NH), 4.40 (d, J ˆ 9.5,
1H, CH), 3.87 (q, J ˆ 7.1, 2 H, OCH2CH3), 2.77 (m, 1H, COCH2CH3), 2.48
(m, 1H, COCH2CH3), 2.42 (s, 3H, ArCH3), 1.67 (s, 1H, CH3), 1.00 0.95
(m, 6H, OCH2CH3, COCH2CH3); 13C NMR: d ˆ 208.4, 171.9, 169.0, 143.5,
141.1, 141.1, 141.0, 140.9, 136.8, 129.6, 129.4, 127.8, 127.7, 127.3, 125.9, 125.7,
120.0, 76.3, 62.7, 61.9, 59.8, 32.5, 21.4, 20.2, 13.4, 1.8; HRMS: calcd for
‡
‡
C30H31NO7S: 572.1719; found: 572.1718 [M‡Na] .
450.1565 [M‡Na] .
Ethyl
3-methyl-4-oxo-3-cyclohexoxycarbonyl-2-(tosylamino)hexanoate
Ethyl 3,5-dimethyl-4-oxo-3-tert-butoxycarbonyl-2-(tosylamino)hexanoate
(11b): The ee was determined by HPLC using a Daicel Chiralpak AD
column (hexane/iPrOH 95:5): flow rate 1.0 mLminÀ1: tmajor ˆ 19.8 min;
tminor ˆ 14.2 min; t2nd diast. ˆ 11.9 and 32.4 min). [a]D ˆ À10.88 (c ˆ
38 mgmLÀ1, 91% ee); 1H NMR: d ˆ 7.75 (d, J ˆ 8.1, 2H, ArH), 7.29 (d,
J ˆ 8.1, 2H, ArH), 5.34 (d, J ˆ 9.9, 1H, NH), 4.31 (d, J ˆ 9.9, 1H, CH), 3.85
(m, 2H, OCH2CH3), 3.09 (q, J ˆ 6.5, 1H, COCH(CH3)2), 2.41 (s, 3H,
ArCH3), 1.64 (s, 3H, CCH3), 1.48 (s, 9H, C(CH3)3), 1.10 (d, J ˆ 6.9, 3H,
CH(CH3)2), 1.05 (d, J ˆ 6.9, 3H, CH(CH3)2), 0.93 (t, J ˆ 7.1, 3 H,
OCH2CH3); 13C NMR: d ˆ 213.1, 170.0, 169.2, 143.4, 137.0, 129.4, 127.4,
83.1, 64.3, 61.7, 59.6, 37.2, 27.8, 21.5, 20.9, 20.2, 19.5, 13.6; HRMS: calcd for
(9e): The ee was determined by HPLC using a Daicel Chiralpak AD
column (hexane/iPrOH 80:20): flow rate 1.0 mLminÀ1: tmajor ˆ 9.7 min;
tminor ˆ 12.4 min; t2nd diast. ˆ 7.6 and 8.6 min). 1H NMR: d ˆ 7.73 (d, J ˆ 8.0,
2H, ArH), 7.28 (d, J ˆ 8.0, 2H, ArH), 5.46 (d, J ˆ 9.9, 1H, NH), 4.67 (sep,
J ˆ 4.2, 1H, OCH(CH2)2), 4.44 (d, J ˆ 9.9, 1H, CH), 3.83 (m, 2H,
OCH2CH3), 2.81 (dq, J ˆ 18.0, J ˆ 7.2, 1H, COCH2CH3), 2.57 (m, 1H,
COCH2CH3), 2.41 (s, 3H, ArCH3), 1.85 1.63 (m, 4H, CH2), 1.61 (s, 3H,
CCH3), 1.54 1.27 (m, 6H, CH2), 1.03, (t, J ˆ 7.2, 3H, OCH2CH3), 1.03 (t,
J ˆ 7.2, 3H, COCH2CH3); 13C NMR: d ˆ 208.5, 170.4, 168.9, 143.4, 136.9,
129.4, 127.2, 74.3, 62.6, 61.7, 59.7, 33.4, 32.6, 31.1, 25.1, 23.4, 21.4, 21.0, 20.2,
13.4, 7.8; HRMS: calcd for C23H33NNaO7S: 490.1875; found: 490.1877
‡
C22H33NO7S: 478.1875; found: 478.1872 [M‡Na] .
‡
[M‡Na] .
Ethyl
3-(2'-oxocyclohexyl)-3-tert-butoxycarbonyl-2-(tosylamino)propa-
Ethyl 3-methyl-4-oxo-3-(diphenyl)-methoxycarbonyl-2-(tosylamino)hexa-
noate (9 f): The ee was determined by HPLC using a Daicel Chiralpak AD
column (hexane/iPrOH 90:10): flow rate 1.0 mLminÀ1: tmajor ˆ 42.6 min;
tminor ˆ 28.4 min; t2nd diast. ˆ 19.1 and 22.7 min). 1H NMR: d ˆ 7.70 (d, J ˆ 8.4,
2H, ArH), 7.38 7.25 (m, 12H, ArH), 5.41 (d, J ˆ 9.9, 1H, NH), 4.39 (d, J ˆ
9.9, 1H, CH), 3.68 (m, 2H, OCH2CH3), 2.71 (m, 1H, COCH2CH3), 2.41 (m,
1H, COCH2CH3)and (s, 3H, ArC H3), 1.67 (s, 3H, CCH3), 1.00 (t, J ˆ 7.1,
3H, OCH2CH3), 0.80 (t, J ˆ 7.1, 3H, COCH2CH3); 13C NMR: d ˆ 208.1,
170.0, 168.7, 143.5, 139.3, 139.1, 136.7, 129.4, 128.6, 128.4, 128.1, 127.3, 127.1,
126.9, 78.3, 62.6, 61.9, 59.8, 32.6, 21.4, 20.1, 13.3, 7.7; HRMS: calcd for
noate (11c): The ee was determined by HPLC using a Daicel Chiralpak
AS column (hexane/iPrOH 97:3): flow rate 1.0 mLminÀ1: tmajor ˆ 25.2 min;
tminor ˆ 33.1 min. [a]D ˆ À1.98 (c ˆ 83 mgmLÀ1, 86% ee); 1H NMR: d ˆ 7.73
(d, J ˆ 8.1, 2H, ArH), 7.29 (d, J ˆ 8.1, 2H, ArH), 5.20 (d, J ˆ 9.9, 1H, NH),
4.17 (d, J ˆ 9.7, 1H, CH), 3.86 (m, 2H, OCH2CH3), 2.94 (m, 1H, CH2), 2.41
(s, 3H, ArCH3), 2.30 (m, 3H, CH2), 2.04 (m, 1H, CH2), 1.83 (m, 1H, CH2),
1.64 (m, 2H, CH2), 1.51 (s, 9H, C(CH3)3), 0.94 (t, J ˆ 7.2, 3H, OCH2CH3);
13C NMR: d ˆ 208.3 169.5, 168.9, 143.5, 136.9, 129.4, 127.4, 83.1, 66.3, 61.7,
59.0, 40.7, 36.0, 27.8, 26.7, 21.5, 21.1, 13.6; HRMS: calcd for C22H31NNaO7S:
‡
476.1719, found: 476.1716 [M‡Na] .
‡
C30H33NNaO7S: 574.1875, found: 574.1876 [M‡Na] .
Ethyl 3-methyl-4-oxo-3-phenoxycarbonyl-2-(tosylamino)hexanoate (9g):
The ee was determined by HPLC using a Daicel Chiralpak AD column
Ethyl 5-phenyl-3-methyl-4-oxo-3-tert-butoxycarbonyl-2-(tosylamino)pen-
tanoate (11d): The ee was determined by HPLC using a Daicel Chiralpak
OD column (hexane/iPrOH 98:2): flow rate 1.0 mLminÀ1: tmajor ˆ 18.0 min;
tminor ˆ 21.7 min; t2nd diast. ˆ 17.0 and 20.2 min). [a]D ˆ ‡2.78 (c ˆ
70 mgmLÀ1, 93% ee); 1H NMR: d ˆ 7.75 (d, J ˆ 8.1, 2H, ArH), 7.30 (m,
5H, ArH), 7.29 (d, J ˆ 8.1, 2H, ArH), 5.40 (d, J ˆ 9.9, 1H, NH), 4.42 (d, J ˆ
9.9, 1H, CH), 4.09 (d, J ˆ 10.3, 1H, ArCH2CO), 3.86 (m, 3H, ArCH2CO
and OCH2CH3), 2.42 (s, 3H, ArCH3), 1.71 (s, 3H, CCH3), 1.56 (s, 9H,
C(CH3)3), 0.93 (t, J ˆ 7.1, 3H, OCH2CH3); 13C NMR: d ˆ 205.7, 169.7, 169.0,
(hexane/iPrOH 90:10): flow rate 1.0 mLminÀ1: tmajor ˆ 38.6 min; tminor
ˆ
34.7 min. 1H NMR: d ˆ 7.56 (d, J ˆ 8.0, 2H, ArH), 7.40 (t, J ˆ 7.9, 2H,
ArH), 7.32 7.25 (m, 3H, ArH), 7.14 (d, J ˆ 8.0, 2H, ArH), 5.38 (d, J ˆ 10.2,
1H, NH), 4.51 (d, J ˆ 10.2, 1H, CH), 3.90 (m, 2H, OCH2CH3), 2.91 (m, 1H,
COCH2CH3), 2.56 (m, 1H, COCH2CH3), 2.42 (s, 3H, ArCH3), 1.83 (s, 3H,
CCH3), 1.08 (t, J ˆ 7.0, 3H, OCH2CH3), 0.95 (t, J ˆ 7.0, 3H, COCH2CH3);
Chem. Eur. J. 2003, 9, 2359 2367
www.chemeurj.org
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2365

K. A. J˘rgensen et al.
FULL PAPER
143.4, 137.0, 133.7, 129.6, 129.4, 128.3, 127.2, 126.8, 83.3, 63.6, 61.7, 59.8, 45.6,
27.7, 21.4, 20.4, 13.5; HRMS: calcd for C26H33NNaO7S: 526.1875; found:
526.1870 [M‡Na] .
Acknowledgement
‡
This work was made possible by a grant from The Danish National
Research Foundation and EU: HMPT-CT-2001-00317. We are grateful to
Dr. R. G. Hazell for X-ray crystallographic analysis.
Ethyl 3-(3'-propenyl)-4-oxo-3-tert-butoxycarbonyl-2-(tosylamino)penta-
noate (11e): The ee was determined by HPLC using a Daicel Chiralpak
AD column (hexane/iPrOH 95:5): flow rate 1.0 mLminÀ1: tmajor ˆ 27.1 min;
tminor ˆ 22.8 min; t2nd diast. ˆ 17.0 and 33.5 min). [a]D ˆ À27.78 (c ˆ
38.5 mgmLÀ1, 87% ee). 1H NMR: d ˆ 7.73 (d, J ˆ 8.2, 2H, ArH), 7.28 (d,
J ˆ 8.2, 2H, ArH), 5.91 (m, 1H, CH2CHCH2), 5.73 (d, J ˆ 10.3, 1H, NH),
5.17 (m, 2H, CH2CH), 4.48 (d, J ˆ 10.3, 1H, CH), 3.80 (m, 2H, OCH2CH3),
2.78 (dd, J ˆ 14.7, J ˆ 6.3, 1H, CCHCH), 2.62 (dd, J ˆ 14.7, J ˆ 6.3, 1H,
CCHCH), 2.60 (s, 3H, CH3CO), 2.41 (s, 3H, ArCH3), 1.49 (s, 9H, C(CH3)3),
0.96 (t, J ˆ 7.0, 3H, OCH2CH3); 13C NMR: d ˆ 205.8, 169.2, 168.4, 143.3,
137.4, 132.0, 129.3, 127.2, 119.9, 83.5, 66.0, 59.4, 38.3, 29.2, 27.7, 21.4, 13.5;
[1] See e.g.: a)E. M. Carreira in Comprehensive Asymmetric Catalysis
Vol. 3 (Eds.: E. N. Jacobsen, A. Pfaltz, H. Yamamoto), Springer,
Berlin, 1999, p. 997; b)S. G. Nelson, Tetrahedron: Asymmetry 1998, 9,
357.
[2] S. Kobayashi, H. Ishitani, Chem. Rev. 1999, 99, 1069.
[3] a)H. Ishitani, M. Ueno, S. Kobayashi, J. Am. Chem. Soc. 1997, 119,
7153; see also: b)S. Kobayashi, T. Hamada, K. Manabe, J. Am. Chem.
Soc. 2002, 124, 5640; c)S. Kobayashi, R. Matsubara, H. Kitagawa,
Org. Lett. 2002, 4, 143; d)H. Ishitani, M. Ueno, S. Kobayashi, J. Am.
Chem. Soc. 2000, 122, 8180; e)K. Manabe, H. Oyamada, K. Sugita, S.
Kobayashi, J. Org. Chem. 1999, 64, 8054; f)H. Ishitani, M. Ueno, S.
Kobayashi, J. Am. Chem. Soc. 2000, 122, 8180.
‡
HRMS: calcd for C22H31NNaO7S: 476.1719; found: 476.1714 [M‡Na] .
Procedure for the transesterification of ethyl 3-methyl-4-oxo-3-(diphenyl-
methoxycarbonyl)-2-(tosylamino)hexanoate and ethyl 3-methyl-4-oxo-3-
tert-butoxycarbonyl-2-(tosylamino)hexanoate: 0.20 mmol of 9 f or 9i was
dissolved in CDCl3 (1 mL). Trimethylsilyl trifluoromethanesulfonate
(0.30 mmol)was added and the solution was stirred for 20 and 60 min,
respectively. After this time TMSCHN2 (0.30 mmol)was added. The
reaction was quenched with sat. NaHCO3, extracted with Et2O (3 Â 10 mL)
and the organic phase was dried with Na2SO4 and concentrated in vacuo.
[4] a)E. Hagiwara, A. Fujii, M. Sodeoka, J. Am. Chem. Soc. 1998, 120,
2474; see also: b)A. Fujii, E. Hagiwara, M. Sodeoka, J. Am. Chem.
Soc. 1999, 121, 545; c)Y. Hamashima, K. Yagi, H. Tamas, M. Sodeoka,
J. Am. Chem. Soc. 2002, 124,
14530; d)Y. Hamashima, D. Hot-
ta, M. Sodeoka, J. Am. Chem.
Soc. 2002, 124, 11240 12240.
O
NHTs
CO2Et
O
NHTs
CO2Et
O
NHTs
CO2Et
1) TMSOTf
1) TMSOTf
Et
Et
Et
2) TMSCHN2
2) TMSCHN2
Me CO2CHPh2
Me CO2Me
Me CO2tBu
[5] a)D. Ferraris, B. Young, T. Dud-
ding, T. Lectka, J. Am. Chem.
Soc. 1998, 120, 4548; see also:
b)D. Ferraris, B. Young, C. Cox,
T. Dudding, W. J. Drury III, L.
Ryzhkov, A. E. Taggi, T. Lectka,
J. Am. Chem. Soc 2002, 124, 67;
c)D. Ferraris, B. Young, C. Cox,
9f
16
9i
Absolute configuration
known from X-ray structure
The product was isolated by FC. Comparison of HPLC traces showed
identical absolute configuration of compound 16 derived from 9 f and 9i.
W. J. Drury III, T. Dudding, T. Lectka, J. Org. Chem. 1998, 63, 6090.
[6] For a new approach to catalytic asymmetric Mannich reactions using
imines of glycine esters reacting with aromatic and alkyl imines see
e.g.: L. Bernardi, A. S. Gothelf, R. G. Hazell, K. A. J˘rgensen, J. Org.
Chem. 2003, 69, in press.
Ethyl 3-methyl-4-oxo-3-methoxycarbonyl-2-(tosylamino)hexanoate (15):
The ee was determined by HPLC using a Daicel Chiralpak AD column
(hexane/iPrOH 90:10): flow rate 1.0 mLminÀ1: tmajor ˆ 25.1 min; tminor
ˆ
23.3 min; t2nd diast. ˆ 19.6 and 21.2 min). [a]D ˆ À39.68 (c ˆ 2 mgmLÀ1
,
92% ee). 1H NMR: d ˆ 7.73 (d, J ˆ 8.1, 2H, ArH), 7.28 (d, J ˆ 8.1, 2H,
ArH), 5.35 (d, J ˆ 9.8, 1H, NH), 4.33 (d, J ˆ 9.8, 1H, CH), 3.84 (m, 2H,
OCH2CH3), 3.77 (s, 3H, OCH3), 2.77 (m, 1H, COCH2CH3), 2.52 (m, 1H,
COCH2CH3), 2.41 (s, 3H, ArCH3), 1.64 (s, 3H, CCH3), 1.49 (s, 9H,
C(CH3)3), 1.06 (t, J ˆ 7.3, 3H, OCH2CH3), 0.96 (t, J ˆ 7.3, 3H, COCH2CH3);
13C NMR: d ˆ 208.5, 171.6, 169.1, 143.6, 137.0, 129.5, 127.3, 62.7, 61.9, 59.9,
52.7, 32.5, 21.5, 20.1, 13.5, 7.9; HRMS: calcd for C18H25NNaO7S: 422.1249;
[7] K. Juhl, N. Gathergood, K. A. J˘rgensen, Angew. Chem. 2001, 113,
3083; Angew. Chem. Int. Ed. 2001, 40, 2995.
¬
[8] See e.g.: a)A. Co rdova, S.-i. Watanabe, F. Tanaka, W. Notz, C. F.
¬
Barbas III, J. Am. Chem. Soc. 2002, 124, 1842; b)A. Co rdova, W.
Notz, G. Zhong, J. M. Betancort, C. F. Barbas III, J. Am. Chem. Soc.
2002, 124, 1866; c)B. List, J. Am. Chem. Soc. 2000, 122, 9336; d)B.
List, P. Pojarliev, W. T. Biller, H. J. Martin, J. Am. Chem. Soc. 2002,
124, 827; e)A. G. Wenzel, E. N. Jacobsen, J. Am. Chem. Soc. 2002,
124, 12964.
‡
found: 422.1234 [M‡Na] .
General procedure for decarboxylation of ethyl-3-methyl-4-oxo-3-tert-
butoxycarbonyl-2-(tosylamino)alkanoate: TMSOTf (0.26 mmol)was add-
[9] For the use of N-tosyl-a-imino esters in catalytic enantioselective
reactions see e.g.: a)A. E. Taggi, A. M. Hafez, T. Lectka, Acc. Chem.
Res. 2002, 36, 10 and references therein; b)S. Yao, M. Johannsen,
R. G. Hazell, K. A. J˘rgensen, Angew. Chem. 1998, 110, 3318; Angew.
Chem. Int. Ed. 1998, 37, 3121; c)K. Juhl, R. G. Hazell, K. A.
J˘rgensen, J. Chem. Soc. Perkin Trans. 1 1999, 2293; d)M. Johannsen,
Chem. Commun. 1999, 2233.
[10] A racemic nickel catalyzed Mannich reaction of malonic esters has
been developed: N. Shida, Y. Kubota, H. Fukui, N. Asao, I. Kadota, Y.
Yamamoto, Tetrahedron Lett. 1995, 36, 5023.
[11] For other examples of catalytic enantioselective addition to this class
of compounds see e.g.: a)D. M. Barnes, J. Ji, M. G. Fickes, M. A.
Fitzgerald, S. A. King, H. E. Morton, F. A. Plagge, M. Preskill, S. H.
Wagaw, S. J. Wittenberger, J. Zhiang, J. Am. Chem. Soc. 2002, 124,
13097; b)N. Yoshikawa, Y. M. A. Yamada, J. Das, H. Sasai, M.
Shibasaki, J. Am. Chem. Soc. 1999, 121, 4168; c)H. Brunner, B. Kimel,
Monatsh. Chem. 1996, 127, 151; d)J. Christoffers, J. Chem. Soc. Perkin
Trans. 1 1997, 3141; e)M. P. Sibi, S. Manyerm, Tetrahedron 2000, 56,
8033.
ed to the purified Mannich adduct (0.20 mmol)stirred in CHCl (1 mL).
3
After 1 h sat. NaHCO3 (10 mL)was added to the solution. After 16 h the
mixture was extracted with Et2O (3 Â 10 mL). The organic phase was dried
with Na2SO4 and concentrated in vacuo. The product was isolated by FC.
Ethyl 3-methyl-4-oxo-2-(tosylamino)hexanoate (12a): The ee was deter-
mined by HPLC using a Daicel Chiralpak AD column (hexane/iPrOH
90:10): flow rate 1.0 mLminÀ1: tmajor ˆ 19.3 min; tminor ˆ 22.4 min; t2nd diast.
ˆ
13.8 and 16.1 min). [a]D ˆ À44.78 (c ˆ 10 mgmLÀ1, 92% ee); 1H NMR: d ˆ
7.71 (d, J ˆ 8.0, 2H, ArH), 7.27 (d, J ˆ 8.0, 2H, ArH), 5.61 (d, J ˆ 9.5, 1H,
NH), 3.99 (dd, J ˆ 9.5, 4.2, 1H, CHCHNH), 3.85 (m, 2H, OCH2CH3), 3.20
(dq, J ˆ 7.3, 4.2, 1H, CH3CHCH), 2.44 (m, 2H, CH2CH3), 2.40 (s, 3H,
ArCH3), 1.27 (d, J ˆ 7.3, 3H, CH3CH), 0.98 (t, J ˆ 7.2, 3H, OCH2CH3);
13C NMR: d ˆ 212.6, 170.2, 143.3, 137.3, 129.4, 127.2, 61.6, 57.7, 48.1, 21.4,
13.6, 13.6, 7.4; HRMS: calcd for C16H23NNaO5S: 364.1195; found: 364.1195
‡
[M‡Na] .
(2-Oxocyclohexyl)-(toluene-4-sulfonylamino)-acetic ethyl ester (12b): The
major diastereomer was isolated in 74% yield from the starting compound
by FC using pentane/diethyl ether. Spectral data were in agreement with
literature data.[5b] [a]D ˆ À368 (corrected to enantiopurity). Literature
value for opposite enantiomer: [a]D ˆ ‡38.58.[5b]
[12] For reviews concerning catalytic formation of molecules with quater-
nary carbon centers see: a)E. J. Corey, A. Guzman-Perez, Angew.
Chem. 1998, 110, 402; Angew. Chem. Int. Ed. 1998, 37, 388; b)J.
2366
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2003, 9, 2359 2367

Asymmetric Mannich Reactions
2359 2367
Christoffers, A. Mann, Angew. Chem. 2001, 113, 4725; Angew. Chem.
Int. Ed. 2001, 40, 4591.
[17] This effect was also observed in an enantioselective Michael addition
of b-keto esters to methyl vinyl ketone: M. Nakajima, Y. Yamaguchi,
S. Hashimoto, Chem. Commun. 2001, 1596.
[13] For reviews of C2-bisoxazoline/Lewis acid complexes as catalysts see
e.g.: a)A. K. Ghosh, P. Mathivanen, J. Cappiello, Tetrahedron:
Asymmetry 1998, 9, 1; b)K. A. J˘rgensen, M. Johannsen, S. Yao, H.
Audrain, J. Thorhauge, Acc. Chem. Res. 1999, 32, 605; c)J. S. Johnson,
D. A. Evans, Acc. Chem. Res. 2000, 33, 325.
[14] a)D. A. Evans, T. Rovis, M. C. Kozlowski, J. S. Tedrow, J. Am. Chem.
Soc. 1999, 121, 1994; b)D. A. Evans, D. S. Johnson, Org. Lett. 1999, 1,
595; c)D. A. Evans, K. A. Scheidt, J. N. Johnson, M. C. Willis, J. Am.
Chem. Soc. 2001, 123, 4480.
[18] CCDC-199879 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge via www.ccdc.ca-
m.ac.uk/conts/retrieving.html (or from the Cambridge Crystallo-
graphic Data Centre, 12 Union Road, Cambridge CB21EZ, UK;
(fax: (‡44)1223-336-033; or e-mail: deposit@ccdc.cam.ac.uk).
[19] For other diastereoselective decarboxylation reactions see: W. B.
Choi, J. Lee, J. E. Lynch, R. P. Volante, P. J. Reider, R. A. Reamer,
Chem. Commun. 1998, 1817 and references therein.
[15] For a thorough investigation of this phenomenon see: a)J. Thorhauge,
M. Roberson, R. G. Hazell, K. A. J˘rgensen, Chem. Eur. J. 2002, 8,
1888 and references therein. For a review on reversal of stereo-
chemistry see: b)M. P. Sibi, M. Liu, Curr. Org. Chem. 2001, 5, 719.
[16] a)L. Hintermann, A. Togni, Angew. Chem. 2000, 112, 4530; Angew.
Chem. Int. Ed. 2000, 39, 4359; b)L. Hintermann, A. Togni, Helv.
Chem. Acta 2000, 83, 2425.
[20] J. A. Turner, W. S. Jacks, J. Org. Chem. 1989, 54, 4229.
[21] D. Henderson, K. A. Richardson, R. J. K. Taylor, J. Saunders, Syn-
thesis 1983, 996.
[22] G. R. Heintzelman, S. M. Weinreb, M. Parvez, J. Org. Chem. 1996, 61,
4594.
Received: December 18, 2002 [F4679]
Chem. Eur. J. 2003, 9, 2359 2367
www.chemeurj.org
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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