Organocatalytic asymmetric mannich reactions with JV-Boc and JV-Cbz protected α-amido sulfones (Boc: Tert-butoxycarbonyl, Cbz: Benzyloxycarbonyl)

Article abstract of DOI:10.1002/chem.200700908

Different malonates and βketoesters can react with N-tert-butoxycarbonyl- (N-Boc) and N-benzyloxycarbonyl- (N-Cbz) protected α-amido sulfones in an organocatalytic asymmetric Mannich-type reaction. The reaction makes use of a simple and easily obtained ph

Full text of DOI:10.1002/chem.200700908

DOI: 10.1002/chem.200700908
Organocatalytic Asymmetric Mannich Reactions with N-Boc and N-Cbz
Protected a-Amido Sulfones (Boc: tert-Butoxycarbonyl, Cbz:
Benzyloxycarbonyl)
Olindo Marianacci, Gabriele Micheletti, Luca Bernardi,* Francesco Fini,
Mariafrancesca Fochi, Daniel Pettersen, Valentina Sgarzani, and Alfredo Ricci*[a]
Abstract: Different malonates and b-
ketoesters can react with N-tert-butoxy-
carbonyl- (N-Boc) and N-benzyloxycar-
bonyl- (N-Cbz) protected a-amido sul-
fones in an organocatalytic asymmetric
Mannich-type reaction. The reaction
makes use of a simple and easily ob-
tained phase-transfer catalyst and pro-
ceeds under very mild and user-friendly
conditions. The optimised protocol
avoids the preparation and the isola-
tion of the relatively unstable N-Boc
and N-Cbz imines that are generated in
situ from the bench-stable a-amido sul-
fones. The corresponding Mannich
bases are generally obtained in good
yields and enantioselectivities, and can
be readily transformed into key com-
pounds, such as optically active b3-
amino acids in one easy step. Enan-
tioenriched N-Boc and N-Cbz protect-
ed b-amino acids that are suitable for
peptide synthesis are also available
from the Mannich adducts through
simple manipulations. Control experi-
ments showed the dual role of the eno-
late–catalyst ion pair in this reaction,
as well as the crucial role of the pres-
ence of water to achieve high enantio-
selectivities.
Keywords: amido sulfones · amino
acids · asymmetric catalysis · Man-
nich bases · organocatalysis
Introduction
and electrophile. The first and simplest approach involves
the use of pre-formed enolates, in particular silylenol ethers
or silylketene acetals, in combination with chiral Lewis or
Brønsted acids for the activation of the imine moiety (indi-
rect Mannich reaction).[3] However, unmodified carbonyl
compounds can also be used directly, which avoid prior
functionalisation of the nucleophile (direct Mannich reac-
tion).[4] In this context, coordinating appropriate chiral
Lewis acid complexes to carbonyl compounds can considera-
bly increase their acidity, thus triggering the enolisation pro-
cess to form a reactive chiral metal enolate.[5] Another possi-
bility is given by the use of chiral secondary amine catalysts,
which are able to combine with aldehydes or ketones to
form reactive nucleophilic enamine species that add to the
imine in an enantioselective fashion.[6] Also b-dicarbonyl
and related compounds (malonates, b-ketoesters, b-dike-
tones etc.) can be conveniently employed as donors in direct
Mannich reactions, not only with chiral Lewis or Brønsted
acids,[7] but also under very mild basic conditions.[8,9] Even
weakly basic chiral tertiary amines or mild inorganic bases
in combination with a chiral phase-transfer catalyst[10] are
able to promote the enolisation of these relatively acidic
compounds, which gives chiral ion pairs that can eventually
react enantioselectively with an electrophilic imine.
The Mannich reaction, which involves the nucleophilic addi-
tion of enolates to the C=N double bond of imines and re-
lated compounds, is arguably one of the most direct meth-
ods to prepare b-amino carbonyl derivatives.[1] Owing to the
strategic importance of these derivatives in an enantioen-
riched form, tremendous efforts have been made over the
past few years towards the development of enantioselective
protocols for this transformation, with a special focus on cat-
alytic asymmetric methodologies.[2] Several conceptually dif-
ferent approaches have been devised, each based on a dif-
ferent strategy for the formation/activation of nucleophile
[a] O. Marianacci, G. Micheletti, Dr. L. Bernardi, F. Fini, Dr. M. Fochi,
Dr. D. Pettersen, V. Sgarzani, Prof. A. Ricci
Department of Organic Chemistry “A. Mangini”
Faculty of Industrial Chemistry, University of Bologna
V. Risorgimento 4, 40136 Bologna (Italy)
Fax : (+39)051-209-3654
E-mail: nacca@ms.fci.unibo.it
ricci@ms.fci.unibo.it
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
8338
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Chem. Eur. J. 2007, 13, 8338 – 8351

FULL PAPER
The direct asymmetric Mannich reaction of b-dicarbonyl
compounds has been recently intensively investigated, espe-
cially with chiral bifunctional catalysts derived from cincho-
na alkaloids,[8a–h] to give the first examples of asymmetric
Mannich reactions of malonates with simple imines, which
may be considered one of the simplest approaches to pre-
pare highly valuable b3-amino acid derivatives.[11] However,
the synthetic utility of this transformation depends on the
protecting group (PG) on the nitrogen atom of the resulting
amine, which should be, in principle, either easily removed
after the catalytic reaction or inserted without difficulty into
a broader synthetic sequence. tert-Butoxycarbonyl (Boc)
and benzyloxycarbonyl (Cbz) protecting groups certainly
fulfil these requirements, but the corresponding parent N-
Boc and Cbz imines are relatively unstable, especially if
they are derived from aliphatic enolisable aldehydes.[12]
However, by using the corresponding a-amido sulfones (2)
it is possible to prepare these imines in situ in some cases to
avoid their synthesis and isolation, thus circumventing their
instability.[13] On these grounds, we[8i] and others[8h] have re-
cently employed a-amido sulfones 2 in catalytic asymmetric
Mannich reactions of malonates 1 with N-Boc and Cbz
imines, thus broadening the scope and the synthetic utility
of this asymmetric transformation.[14,15] Our approach in-
volved the use of a phase-transfer catalyst that was easily
obtained from quinine in combination with a mild inorganic
base, which was able to promote both the formation of the
N-carbamoyl imine in situ and the asymmetric addition of
the enolate derived from tailor-made malonate 1a that has
p-methoxyphenyl ester groups (Scheme 1).[8i]
cially available malonates, and more importantly, which
gives the opportunity of using b-ketoesters in an asymmet-
ric, catalytic Mannich reaction with a-amido sulfones for the
first time. The high synthetic versatility of b-ketoesters, as
well as the broad scope connected with the use of a-amido
sulfones as imine surrogates, render this reaction a useful
platform for the asymmetric synthesis of nitrogen-containing
compounds.
Results and Discussion
Asymmetric Mannich reactions of malonates: During the
development of the asymmetric Mannich reaction of 1a by
using cinchona alkaloid-derived phase-transfer catalysts, we
became aware of the requirement of some specific features
of the catalyst structure for obtaining satisfactory enantiose-
lectivities in the reaction. In particular, catalysts derived
from quinine with a free hydroxy group at the 9-position
and an ortho-substituted aromatic at the benzylic moiety of
the quinuclidinic nitrogen,[16] such as 4a, afforded consistent-
ly better results in terms of activity and enantioselectivity.
Based on the assumption that a fine tuning of this structure
might also render the catalyst suitable for the reaction with
different malonates, we prepared other different quaternary
ammonium salts (4b–e) that are derived from quinine and
have these common structural features.
These catalysts were then tested in the reaction between
dimethyl malonate (1b) and N-Boc a-amido sulfone 2a as
representative substrates, under similar conditions to those
that proved to be successful with malonate 1a, that is, by
using a mild, aqueous inorganic base, such as K2CO3 (50%
w/w), with toluene as the organic phase at À248C. Some
representative results are collected in Table 1.
An initial experiment with catalyst 4a strongly indicated
the possibility of developing an asymmetric Mannich reac-
tion with 1b (Table 1, entry 1) because product 3a was ob-
tained with a moderate conversion and a promising enantio-
selectivity. Following our working hypothesis, other quater-
nary ammonium salts 4b–e were screened in the reaction.
Whereas catalysts 4b–d, which contain electron-withdrawing
groups at the ortho position of the N-benzylic substituent,
gave slightly worse or similar results to those obtained with
4a (Table 1, entries 2–4), catalyst 4e with a methoxy sub-
stituent[17] on the aromatic ring proved to be superior and
Scheme 1. Catalytic asymmetric Mannich reaction with malonate 1a.
PTC: phase-transfer catalysis.
Although excellent results could be achieved, even with
low catalyst loadings, the use of that specific malonate for
targeting optically active b3-amino acid derivatives posed
some concerns owing to the requirement for two additional
synthetic steps, that is, the preparation of 1a and a transes-
terification prior to decarboxylation. Therefore, we thought
it would be of interest to continue our investigations into
the development of new catalytic systems and/or reaction
conditions that are able to accommodate simpler malonates,
and possibly different b-dicarbonyl derivatives. Herein we
present our efforts towards this goal, uncovering a structur-
ally related catalyst that allows the reaction with commer-
Chem. Eur. J. 2007, 13, 8338 – 8351
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8339

L. Bernardi, A. Ricci et al.
Table 1. Representative results from screening different catalysts and re-
action conditions for the catalytic asymmetric Mannich reaction between
1b and 2a.[a]
Table 2. Scope of the catalytic asymmetric Mannich reaction of malo-
nates 1a–d with a-amido sulfones 2a–k.[a]
Entry
1
R1
2
R2
PG Product Yield[b] ee[c]
Entry
Catalyst
([mol%])
Solvent
Conversion[b] [%]
ee[c] [%]
[%]
[%]
ACHTREUNG
1
2
3
4
5
1b Me
1b Me
1b Me
1b Me
1b Me
2a Ph
2b Ph
2c o-BrC6H4
2d p-ClC6H4
2e p-MeO-
Boc
Cbz
Boc
Boc
Cbz
3a
3b
3c
3d
3e
85[d]
97
98
97
99
90[e]
94[e]
90
83
94
1
2
3
4
5
6
7
8
4a (10)
4b (10)
4c (10)
4d (10)
4e (10)
4e (10)
4e (10)
4e (10)
4e (5)
toluene
toluene
toluene
toluene
80
90
78
>95
>95
>95[d]
75
81
79
70
82
91
81
85
73
90
83
45[f]
toluene
C6H4
toluene/CH2Cl2 7:1
o-xylene
mesitylene
toluene
toluene
toluene
6
7
8
1b Me
1b Me
1b Me
1b Me
1b Me
1b Me
1c allyl
1c allyl
1c allyl
1d Bn
1d Bn
1d Bn
1a p-MeO-
C6H4
2 f 1-naphthyl Cbz
2g PhCH2CH2 Boc
2h iBu
2i Me
2j iPr
2k cyclohexyl Cbz
2a Ph
2b Ph
3 f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
97
80
78
99
88
90
97
95
84
96
92
77
90
91
78
83
65
9[e]
10
11
>95
>95
>95
Boc
Cbz
Cbz
9
81
4e (2.5)
5 (10)
10
11
12
13
14
15
16
17
18[g]
85[f]
97
[a] Reactions carried out with 2a (0.10 mmol), 1b (0.12 mmol), catalyst
4–5 (2.5–10 mol%) and K2CO3 (50% w/w, 27 mL, 0.15 mmol) in the
stated solvent (2 mL) at À248C for 60 h. [b] Determined by 1H NMR
spectroscopy. [c] Determined by chiral stationary phase HPLC. [d] 22 h
reaction time. [e] K2CO3 (50% w/w, 6 equiv) were used. [f] ent-3a was
obtained.
Boc
Cbz
90
92
2k cyclohexyl Cbz
94
2a Ph
2b Ph
2h iBu
2a Ph
Boc
Cbz
Boc
Boc
92[e]
93
91
98[e]
resulted in the formation of product 3a with full conversion
and a satisfactory enantioselectivity (Table 1, entry 5). By
using this catalyst, different solvents were then tested in an
attempt to increase the reaction rate (Table 1, entries 6–8).
Only the reaction performed in a mixture of toluene/CH2Cl2
gave 3a with full conversion in a shorter time (Table 1,
entry 6), however, the enantioselectivity was considerably
lower compared with the reaction in toluene. By using tolu-
ene as the organic phase, the catalyst loading could be re-
duced to 5 mol% without affecting the enantioselectivity, al-
though a further decrease to 2.5 mol% had a negative effect
on the enantiomeric excess (ee) of the product (Table 1, en-
tries 9 and 10). It was also found that performing the reac-
tion with a larger excess of base (6 equiv) improved the re-
producibility of the reaction in terms of conversion without
affecting the enantioinduction in the product (Table 1,
entry 9). Unfortunately, the use of quasienantiomeric cata-
lyst 5 derived from quinidine gave the corresponding enan-
tiomeric product ent-3a with reduced enantiopurity
(Table 1, entry 11).
Having established an efficient protocol for the enantiose-
lective Mannich reaction of 1b with 2a, we investigated the
generality of the reaction, first focusing on possible varia-
tions on the a-amido sulfone partner (Table 2, entries 1–11).
Aside from the reaction with 2a, which could also be per-
formed with identical results on a preparative scale (Table 2,
entry 1), its Cbz-protected counterpart 2b was found to be a
competent substrate for this transformation to give the cor-
responding product 3b in a very good yield (97%) and
enantioselectivity (94% ee) (Table 2, entry 2). The tolerance
19[g]
1a p-MeO-
C6H4
2b Ph
Cbz
3s
96
99[e]
[a] Reactions carried out with 2 (0.10 mmol), 1 (0.12 mmol), catalyst 4e
(5 mol%) and K2CO3 (50% w/w, 108 mL, 0.60 mmol) in toluene (2 mL)
at À248C for 60 h. [b] Isolated yield. [c] Determined by chiral stationary
phase HPLC. [d] Reaction performed on a 1.0 mmol scale. [e] Absolute
configuration was determined to be S (see the Experimental Section).
[f] Absolute configuration was found to be R (see Experimental Section).
[g] K2CO3 (1.5 equiv, 50% w/w) were used.
of the catalytic reaction to these two different protecting
groups on the nitrogen atom of the a-amido sulfones is of
considerable interest when considering the possibility of ob-
taining the corresponding N-protected b3-amino acid deriva-
tives (see below). The catalytic asymmetric reaction of 1b
with a-amido sulfones 2c–f, which were derived from aro-
matic aldehydes (Table 2, entries 3–6), further demonstrated
the possibility of using different substrates and/or protecting
groups with the present system. The corresponding products
3c–f were in fact obtained in very good yields (97–99%)
and enantioselectivities (83–94% ee), irrespective of the
electronic and/or steric properties of the substituents at the
aromatic ring and the protecting group on the nitrogen
atom. Sulfones 2g–k, which were derived from aliphatic,
enolisable aldehydes, were then tested in the catalytic reac-
tion (Table 2, entries 7–11) because a major advantage of
the present method is the avoidance of the isolation of the
corresponding, somewhat unstable, imines. By using catalyst
4e under standard reaction conditions, the corresponding
products 3g–k were obtained in good yields (78–99%) and
8340
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Asymmetric Mannich Reactions
FULL PAPER
enantioselectivities (78–97% ee), although in most cases the
optical purity of 3g–k was not as high as for their aromatic
counterparts 3a–f. Exploring the possibility of using other
malonates in the catalytic reaction, we focused our attention
on diallyl malonate 1c and dibenzyl malonate 1d because
the Mannich adducts that result from these compounds can
be transformed into the corresponding N-Boc protected b3-
amino acids without the use of acidic or basic hydrolytic
conditions.[8f] Good yields (77–97%) and enantioselectivities
(90–94% ee) for products 3l–q were obtained (Table 2, en-
tries 12–17), with results that were comparable to that ob-
tained for 1b. For the sake of comparison, we also tested 1a
in the catalytic reaction with the newly developed catalyst
4e (Table 2, entries 18–19). Catalyst 4e was also found to be
superior to our previously employed catalyst 4a,[8i] to give
the corresponding products 3r and 3s in very high yields (90
and 96%, respectively) and outstanding enantioselectivities
(98 and 99% ee, respectively).
b-Amino acids and their derivatives are key compounds
in organic and pharmaceutical chemistry. Aside from being
present in a variety of natural products, they are finding in-
creasing use as pharmaceutically active agents, often incor-
porated into peptides and b-peptides, because of the prom-
ise shown by b-peptides as biostable peptidomimetics.[11]
The asymmetric Mannich reaction of malonates is conceiva-
bly a very direct route to prepare optically active b3-amino
acids. In particular, our approach, which involves the use of
simple malonates and easily removed protecting groups on
the nitrogen atom, allows the straightforward transformation
of either N-Boc or N-Cbz protected Mannich adducts into
the corresponding b3-amino acid hydrochlorides (Scheme 2,
As anticipated from the results in Table 1 (entry 11), the
present system does not allow the preparation of the oppo-
site enantiomer of the products derived from 1b with satis-
factory levels of enantioselectivity because 5 was found to
be a much less efficient catalyst. However, access to the an-
tipodal Mannich adducts can be achieved by using 1a
(Table 3). Exploiting the superior affinity of this malonate
Table 3. Catalytic asymmetric Mannich reaction of 1a by using catalyst 5
to give enantiomeric products 3.[a]
Scheme 2. Preparation of unprotected and protected b3-amino acids 6
and 7 from Mannich adducts 3a and 3j.
top). For example, treatment of 3a and 3j with 6m aqueous
HCl for several hours resulted in malonate hydrolysis, decar-
boxylation and nitrogen deprotection in a single step, which
cleanly gave the corresponding b3-amino acid hydrochlor-
ides 6a and 6b (Scheme 2, top) irrespective of the nature of
the side chain and the nitrogen protecting group.[18] Mild
basic hydrolysis followed by thermal decarboxylation in-
stead afforded the analogous N-protected b3-amino acids 7a
and 7b (Scheme 2, bottom), thus showing the possibility of
obtaining both b-aryl and b-alkyl amino acids with orthogo-
nal carbamate protecting groups that are suitable for pep-
tide synthesis.[8e]
Entry
2
R
PG
Product
Yield[b] [%]
ee[c] [%]
1
2
3
4
2a
2b
2g
2k
Ph
Ph
Boc
Cbz
Boc
Cbz
ent-3r
ent-3s
3t
98
95
88
89
93
99
77
93
PhCH2CH2
Cyclohexyl
3u
[a] Reactions carried out using 2 (0.10 mmol), 1a (0.12 mmol), catalyst 5
(5 mol%) and K2CO3 (50% w/w, 27 mL, 0.15 mmol) in toluene (2 mL) at
À248C for 60 h. [b] Yield of isolated product. [c] Determined by chiral
stationary phase HPLC.
for this class of catalysts, it was indeed possible to prepare
some representative products with the opposite absolute
configuration with good results, in terms of both yields (88–
98%, Table 3) and enantioselectivities (77–99% ee). As we
have previously demonstrated the possibility of transforming
these types of adducts into the corresponding dimethyl ester
derivatives,[8i] also the opposite enantiomer of the Mannich
adducts derived from 1b are available by using the present
method, although an additional transesterification step is re-
quired.
Asymmetric Mannich reactions of b-ketoesters: We then
proceeded to evaluate the possibility of extending the cata-
lytic asymmetric Mannich reaction of 2 to a different class
of b-dicarbonyl compounds, namely, b-ketoesters 8. The cat-
alytic asymmetric Mannich reaction of these compounds has
received a great deal of attention in recent times owing to
their obvious synthetic utility as masked ketone donors.[7a,-
c,8a–f]
However, to the best of our knowledge catalytic asym-
metric versions of the Mannich reaction of b-ketoesters by
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8341

L. Bernardi, A. Ricci et al.
using a-amido sulfones are still unexplored. We therefore
thought to develop an efficient protocol for this transforma-
tion based on our approach. In the search for suitable pa-
rameters to enable an enantioselective transformation, we
began our investigations by performing the catalytic reaction
of b-ketoesters 8a–d derived from cyclopentanone with 2a
by using catalysts 4. In the first instance, we attempted the
reaction by using conditions similar to the corresponding
transformation with malonates 1. As shown in Table 4, ini-
tial experiments with 8a indicated that an enantioselective
effects on the optical purity of the product 9d (Table 4,
entry 8), although a further reduction to 1 mol% gave a
more significant decrease in the enantioselectivity observed
(Table 4, entry 9). Unfortunately, catalyst 5 was found to be
much less efficient also for this reaction in terms of enan-
tioinduction (Table 4, entry 10).
We then explored the possibility of using different a-
amido sulfones with 8d under the optimised reaction condi-
tions. As shown in Table 5, sulfone 2b, which is the N-Cbz
Table 5. Scope of the catalytic asymmetric Mannich reaction of b-ke-
toesters 8 with a-amido sulfones 2 determined by varying of the a-amido
sulfone partner.[a]
Table 4. Representative results from screening different catalysts and re-
action conditions for the catalytic asymmetric Mannich reaction between
b-ketoesters 8a–d and a-amido sulfone 2a.[a]
Entry
2
R
PG Product
Yield
[%][b]
d.r.[c]
ee
Entry
8
R
Catalyst
([mol%])
Product Conversion[b]
[%]
d.r.[c]
98:2
98:2
98:2
98:2
ee
[%][d]
G
[%][d]
1
2
3
4
5
6
2a Ph
2b Ph
2c o-BrC6H4
2l o-BrC6H4
2m p-ClC6H4
2e p-
Boc
Cbz
Boc
Cbz
Cbz
Cbz
9d
9e
9 f
9g
9h
9i
98
90
60
85
98
70
>98:2 95
>98:2 92
94:6 69
96:4 77
96:4 73
95:5 77
1
2
3
4
5
6
7
8
9
8a Et 4a (10)
8a Et 4b (10)
8a Et 4d (10)
8a Et 4e (10)
8b Bn 4e (10)
8c tBu 4e (10)
8d Me 4e (10)
8d Me 4e (2.5)
8d Me 4e (1.0)
8d Me 5 (2.5)
9a
9a
9a
9a
9b
>90
>90
>90
>90
>90
77
80
83
84
88
87:13 87
9c
95:5[e] 71[e]
MeOC6H4
9d
9d
9d
>90
>90
>90
>90
>98:2
>98:2
97:3
93
91
88
54
7
8
9
10
11
2 f 1-naphthyl Cbz
2g PhCH2CH2 Boc
2i Me
2j iPr
9j
9k
9l
9m
9n
50
55
70
74
77
90:10 85
97:3 90
97:3 75
96:4 74
>98:2 99
Cbz
Cbz
10
ent-9d
98:2
[a] Reactions carried out with 2a (0.10 mmol), 8 (0.12 mmol), catalyst 4
(1.0–10 mol%) and K2CO3 (50% w/w, 27 mL, 0.15 mmol) in toluene
(2 mL) at À208C for 20 to 29 h. [b] Determined by 1H NMR spectrosco-
py on the crude reaction mixture. [c] Diastereomeric ratio, determined
by 1H NMR spectroscopy on the crude reaction mixture. [d] Major
isomer, ee value determined by chiral stationary phase HPLC. [e] Rel-
ative and absolute configuration determined by comparison of the
1H NMR spectrum and HPLC retention times with literature values. See
ref.[7c]
2k Cyclohexyl Cbz
[a] Reactions carried out with 2 (0.12 mmol), 8d (0.10 mmol), catalyst 4e
(2.5 mol%), in toluene (2 mL) with K2CO3 (50% w/w, 27 mL, 0.15 mmol)
at À248C for 21 to 84 h. [b] Isolated yield of the diastereomeric mixture.
[c] Diastereomeric ratio, determined by 1H NMR spectroscopy on the
crude reaction mixture. [d] Major isomer, ee value determined by chiral
stationary phase HPLC.
analogoue of 2a, also gave the corresponding product 9e
with an excellent yield and excellent diastereo- and enantio-
selectivities (Table 5, entries 1 and 2, 98 and 90% yield, and
95 and 92% ee, respectively). Having shown the tolerance
of the reaction to both Boc and Cbz protecting groups,
other aromatic and aliphatic a-amido sulfones 2 were subse-
quently tested in the catalytic reaction with b-ketoester 8d
(Table 5, entries 3–11). Mannich adducts 9 f–n were obtained
in moderate to good yields (50–98%), generally good diaste-
reomeric ratios, but variable enantiopurities (69–99% ee).
Compared to the model reaction with 2a and 2b the enan-
tioselectivities observed for these products were generally
lower; however, the possibility of reaching excellent levels
of enantiopurity in some cases (Table 5, entries 8 and 11)
must be recognised.
reaction with b-ketoesters 8 could be developed under these
conditions because the corresponding product 9a was ob-
tained with excellent diastereoselectivity and with promising
levels of enantioselectivity (Table 4, entries 1–4). Also in
this case, catalyst 4e, which has an ortho-methoxy substitu-
ent at the benzyl moiety of the quinuclidinic nitrogen, was
found to be more effective (Table 4, entry 4) than the other
ortho-substituted catalysts tested (4a–d, Table 4, entries 1–
3). A brief inspection of the influence of the steric hin-
drance of the ester group revealed that an increase in the
bulkiness of this moiety by using benzyl (8b) or tert-butyl b-
ketoesters (8c) was detrimental to the enantioselectivity of
the products (Table 4, entries 5–6), whereas the least bulky
methyl b-ketoester (8d) gave the best results (Table 4,
entry 7). By using 8d under these conditions, the catalyst
loading could be decreased to 2.5 mol% with only marginal
Finally, we investigated the behaviour of some other dif-
ferent cyclic b-ketoesters in the reaction with 2b. A practical
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Chem. Eur. J. 2007, 13, 8338 – 8351

Asymmetric Mannich Reactions
FULL PAPER
asset of the present method is the use of methyl b-ketoesters
as donors. The synthesis of these compounds is straightfor-
ward, especially those that are cyclic and ring fused, if com-
pared with other b-ketoesters that have more bulky ester
groups, such as tert-butyl, which are often used in catalytic
asymmetric transformations.[19] Accordingly, cyclic b-ketoest-
ers 8e–h with different ring sizes and/or ring fused were
readily synthesised and tested in the reaction (Table 6). In
accordance with previous reports,[17a,19,20] the different reac-
tivity of these compounds reflected in the necessity for
tuning the strength of the inorganic base and/or reaction
temperature employed in the catalytic reaction. For exam-
ple, cyclohexanone- and cycloheptanone-derived b-ketoest-
ers 8e and 8 f did not give the expected Mannich adducts
under the conditions used with the more reactive cyclopen-
tanone derivative 8d (K2CO3 50% w/w, À248C). However,
by using a stronger base (K3PO4 50% w/w) it was possible
to obtain the corresponding products 9o and 9p in satisfac-
tory yields (77 and 96%, respectively) and enantioselectivi-
ties (91 and 95% ee, respectively) (Table 6, entries 1 and 2).
Instead ring-fused b-ketoesters 8g and 8h proved to be
more reactive since the reactions performed with aqueous
K2CO3 as the base gave Mannich products 9q and 9r with
good results (Table 6, entries 3 and 4, 95 and 96% yield, and
87 and 92% ee, respectively). In the former case, a less con-
centrated K2CO3 solution (30% w/w instead of 50% w/w)
resulted in a slight improvement of the enantioselectivity of
product 9q, presumably owing to a background reaction, al-
though the low diastereomeric ratio was unchanged. Non-
cyclic b-ketoesters were also tested in the reaction, but un-
surprisingly,[17a,19,20] gave the corresponding products with
low enantioselectivity with the present catalytic system.
Mechanistic considerations: A few ancillary experiments
were then carried out with 1b to get some insights into the
possible reaction pathways. These can be summarised as fol-
lows: 1) under the standard reaction conditions, but in the
absence of either malonate 1b or catalyst 4e, formation of
the imine from 2a proceeded only sluggishly (<60% after
84 h); 2) a reaction with the pre-formed N-Boc imine de-
rived from 2a gave very similar results, both in terms of
yield and enantioselectivity, to the reaction performed with
2a; 3) a sterically demanding a-amido sulfone derived from
pivalaldehyde did not produce the expected Mannich prod-
uct in the reaction, presumably for steric reasons, although
it did provide substantial amounts of the corresponding
imine. On these grounds we propose the following catalytic
cycle (Scheme 3), wherein the malonate, which is deproton-
ated by the inorganic base at the interface, combines with
the quaternary ammonium salt to give an organic soluble
anion that acts first as a base to promote the formation of
the imine from the a-amido sulfone. The sulfinate formed
can be dissolved in the aqueous phase, whereas the malo-
nate can be deprotonated again to give a chiral ion pair with
the catalyst, which adds in an enantioselective fashion to the
formed imine. An anionic carbamate adduct is then formed
with the catalyst as the counterion. This highly basic species
presumably deprotonates the most acidic compound in the
reaction mixture, that is, an-
other molecule of malonate,
Table 6. Scope of the catalytic asymmetric Mannich reaction of b-ketoesters 8 with a-amido sulfones 2: varia-
tion of the b-ketoester partner.[a]
thus restoring the catalytic
cycle.[21]
The absolute configuration
of adducts 3 and 9 has been
determined for some deriva-
tives by comparison of their
optical and/or HPLC proper-
ties with literature values (see
Tables 2 and 4). The simple
diastereoselectivity observed
in the asymmetric Mannich re-
action of b-ketoesters 8 can be
explained by an open transi-
tion state,[7c] whereas the abso-
lute configuration of the ad-
ducts results from attack of the
ion pair catalyst–enolate on
the Re face of the intermediate
imine in all cases when qui-
nine-derived catalysts 4 were
used. Previous reports based
on X-ray structures of this
class of catalysts showed the
importance of the presence of
a molecule of water in rigidify-
ing the structure of these am-
Entry
1[e]
b-Ketoester
8
Base
Product
Yield[b] [%]
77[g]
d.r.[c]
ee[d] [%]
[f]
[f]
[h]
8e
K3PO4
9o
85:15
91
2
3
4
8 f
8g
8h
K3PO4
9p
9q
9r
96[g]
95
96:4
95
K2CO3
58:42
80:20
87[i]
92
[f]
K2CO3
96
[a] Reactions carried out with 2b (0.12 mmol), 8 (0.10 mmol), catalyst 4e (2.5 mol%) and the stated base (1.5–
5 equiv) in toluene (2 mL) at À248C for 24 to 71 h. [b] Isolated yield of the diastereomeric mixture. [c] Deter-
mined by 1H NMR spectroscopy on the crude reaction mixture. [d] Major isomer, ee value determined by
chiral stationary phase HPLC. [e] Reaction performed at 08C with catalyst 4e (10 mol%). [f] 50% w/w.
[g] Isolated yield of the enriched major diastereoisomer. [h] 30% w/w. [i] Minor diastereoisomer 85% ee, de-
termined by chiral stationary phase HPLC.
Chem. Eur. J. 2007, 13, 8338 – 8351
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8343

L. Bernardi, A. Ricci et al.
N-Boc and N-Cbz b3-amino
acids that are suitable for pep-
tide synthesis. Unprotected b3-
amino acids can also be readily
obtained in a single step by
acidic hydrolysis. Mild, user-
friendly reaction conditions
and avoiding the need for iso-
lating the N-Boc and N-Cbz
imines are good assets for this
organocatalytic
asymmetric
Mannich reaction. As demon-
strated by control experiments,
the catalyst–enolate ion pair
first acts as a base to promote
the elimination of sulfinic acid
and then it adds to the imine
that is formed in an enantiose-
lective fashion. The presence
of water in the reaction was
Scheme 3. Proposed reaction pathway. (Q+XÀ =4e).
also found to be essential for
monium salts.[16] This conformational control, which occurs
through hydrogen-bond interactions between the oxygen
atom at the 9-position of the cinchona scaffold, a molecule
of water and the ortho group of the quinuclidinic benzyl
substituent, was found to be essential in attaining optimal
enantioselectivities in the alkylation of the benzophenone
imine derived from tert-butyl glycine ester. Accordingly, we
tested the catalytic reaction between 1b and 2a with catalyst
4e under anhydrous conditions with dry K2CO3 as the base.
Aside from lowering the conversion, presumably owing to a
less efficient interfacial exchange of the enolate anion, we
also observed a dramatic decrease in the enantioselectivity
of product 3a, which was obtained with an ee value of 27%,
instead of 90% when aqueous K2CO3 was employed. This
result suggests that the presence of water is also a require-
ment, in our case, for obtaining high enantioselectivities by
using this class of catalysts. The higher efficiency of catalyst
4e, which has a methoxy moiety at the ortho position, with
respect to the other catalysts 4 may, therefore, be attributed
to a more efficient contribution to this hydrogen-bond inter-
action, thus giving a better conformational control that re-
sults in a better recognition of the Re face of the imine by
the chiral ion pair.
obtaining high enantioselectivities, presumably by influenc-
ing the conformational rigidity of the catalyst through hy-
drogen-bond interactions.
Experimental Section
General methods: 1H and 13C NMR spectra were recorded by using a
Varian AS 400 spectrometer running at 400 and 100 MHz, respectively.
Chemical shifts are reported relative to residual solvent peaks (1H NMR:
7.26 ppm for CDCl3, 3.31 ppm for CD3OD, 4.79 ppm for D2O; 13C NMR:
77.0 ppm for CDCl3, 48.0 ppm for CD3OD, sodium 3-(trimethylsilyl)-pro-
pionate external reference, 0.0 ppm for D2O). 13C NMR were recorded
by using a broad band decoupled mode. Mass spectra were recorded by
using a Micromass LCT spectrometer with electrospray (ES) ionisation
techniques. Optical rotations were measured by using a Perkin–Elmer
241 polarimeter. The ee value of the products was determined by chiral
stationary phase HPLC equipped with a UV detector operating at l=
215 or 254 nm. Melting points were measured on a Büchi smp-20 appara-
tus and are uncorrected. Chromatographic purifications were performed
by using 70–230 mesh silica.
Materials: All commercially available solvents and reagents were used as
received. Malonate 1a,[8i] a-amido sulfones 2a–m,[22] and b-ketoesters 8b,
8c, 8g, and 8h[23] were obtained by following literature procedures. Race-
mic samples were obtained at room temperature by using tetrabutylam-
monium bromide as the catalyst.
Preparation of N-(2-methoxybenzyl)-quininium chloride (4e): Quinine
(648 mg, 2.0 mmol) was added to a solution of o-methoxybenzyl chloride
(360 mL, 2.6 mmol) in toluene (6 mL). The resulting mixture was heated
to 808C with stirring. After 5 h the reaction mixture was allowed to cool
to room temperature and evaporated in vacuo. The residue was purified
by column chromatography (CH2Cl2/MeOH mixtures) to give 4e as a
pale red solid (63%). M.p. >1208C (dec); [a]2D0 =À166 (c=0.31 in
CHCl3); 1H NMR (400 MHz, CDCl3): d=8.76 (d, J=4.7 Hz, 1H), 8.07–
7.99 (m, 2H), 7.79 (d, J=4.5 Hz, 1H), 7.51–7.44 (m, 2H), 7.37 (dd, J=
9.5, 2.8 Hz, 1H), 7.16 (d, J=2.8 Hz, 1H), 7.09 (dt, J=7.3, J=1.2 Hz,
1H), 6.98 (d, J=7.7 Hz, 1H), 6.70 (brs, 1H), 6.23 (d, J=11.7 Hz, 1H),
5.63–5.49 (m, 1H), 5.25–5.12 (m, 1H), 5.08–4.93 (m, 2H), 4.67 (d, J=
11.9 Hz, 1H), 3.96 (s, 3H), 3.86 (s, 3H), 3.64 (dd, J=10.2–6.3 Hz, 1H),
3.31–3.12 (m, 2H), 3.04 (ddd, J=13.1, 6.5, 3.0 Hz, 1H), 2.60–2.48 (m,
1H), 2.48–2.25 (m, 2H), 2.05–1.98 (m, 1H), 1.82–1.69 (m, 1H), 1.52–
Conclusion
We have developed a new catalytic system that allows the
asymmetric Mannich reaction of different malonates and b-
ketoesters with N-Boc and N-Cbz protected a-amido sul-
fones. The reaction makes use of a simple phase-transfer
catalyst that is easily obtained from quinine in a single step.
The Mannich adducts are generally obtained in good yields
and diastereo- and enantioselectivities. The synthetic rele-
vance of the present asymmetric transformation is shown by
the straightforward conversion of the catalytic adducts into
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Chem. Eur. J. 2007, 13, 8338 – 8351

Asymmetric Mannich Reactions
FULL PAPER
1.38 ppm (m, 1H); 13C NMR (100 MHz, CDCl3): d=158.4, 158.0, 147.8,
144.2, 143.6, 136.7, 136.1, 132.6, 132.3, 125.6, 121.9, 121.6, 120.4, 117.7,
115.3, 111.1, 100.4, 71.1, 63.3, 60.6, 58.7, 55.7, 55.6, 50.8, 38.1, 26.4, 24.8,
21.2 ppm; ESIMS: m/z: 445 [M+].
2-[S-Benzyloxyamino(4-methoxyphenyl)methyl]malonic acid dimethyl
ester (3e): Following the general procedure, compound 3e was obtained
as white solid in a yield of 99% after column chromatography on silica
gel (CH2Cl2). The ee value of the product was determined by HPLC with
a
Daicel Chiralpak AD-H column (hexane/iPrOH=80:20, flow rate
General procedure for the catalytic reaction of 1 with a-amido sulfone 2:
Malonate 1 (0.12 mmol) was added to a test tube that contained a mix-
0.75 mLminÀ1
,
t
major =76.5 min; minor =63.9 min; 94% ee). M.p. 108–
t
1108C; [a]2D0 =+1 (c=0.95 in CHCl3); 1H NMR (400 MHz, CDCl3): d=
7.39–7.26 (m, 5H), 7.24–7.19 (m, 2H), 6.87–6.83 (m, 2H), 6.38 (brd, J=
8.3 Hz, 1H), 5.49 (brdd, J=9.4, 4.9 Hz, 1H), 5.11 (d, J=12.5 Hz, 1H),
5.08 (d, J=12.5 Hz, 1H), 3.90 (brd, J=4.1 Hz, 1H), 3.78 (s, 3H), 3.68 (s,
3H), 3.65 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=168.4, 167.3,
159.0, 155.6, 136.4, 131.1, 128.4, 128.0, 127.4, 114.0, 66.8, 56.6, 55.2, 53.5,
52.7, 52.5 ppm; ESIMS: m/z: 424 [M++Na].
ture of a-amido sulfone
2 (0.10 mmol) and catalyst 4e (2.3 mg,
0.005 mmol) in toluene (2 mL). After the resulting mixture had been
cooled to À248C, a pre-cooled aqueous K2CO3 solution (50% w/w,
108 mL, 0.60 mmol) was added in one portion. The reaction mixture was
then vigorously stirred at the same temperature without any precaution
to exclude moisture or air. After 60 h, the reaction product was directly
isolated by column chromatography on silica gel.
2-(S-Benzyloxycarbonylaminonaphthalen-1-ylmethyl)malonic acid dimeth-
yl ester (3 f): Following the general procedure, compound 3 f was ob-
tained as a waxy white solid in a yield of 97% after column chromatogra-
phy on silica gel (CH2Cl2). The ee value of the product was determined
by HPLC with a Daicel Chiralpak AD-H column (hexane/iPrOH=80:20,
2-(S-tert-Butoxycarbonylaminophenylmethyl)malonic acid dimethyl ester
(3a): Following the general procedure and by performing the reaction on
a 1.0 mmol scale, 3a was obtained as a white solid in a yield of 85% after
column chromatography on silica gel (petroleum ether/Et2Omixtures).
The ee value of the product was determined by HPLC by using a Daicel
flow rate 0.75 mLminÀ1
, tmajor =30.2 min; tminor =38.3 min; 91% ee).
Chiralpak
AD-H (hexane/iPrOH=80:20,
column
flow
rate
[a]2D0 =+38 (c=0.80 in CHCl3); 1H NMR (400 MHz, CDCl3): d=8.14 (d,
J=8.8 Hz, 1H), 7.88 (d, J=8.8 Hz, 1H), 7.78 (d, J=8.2 Hz, 1H), 7.60 (t,
J=6.4 Hz, 1H), 7.56–7.46 (m, 2H), 7.43 (t, J=7.7 Hz, 1H), 7.39–7.27 (m,
5H), 6.88 (brd, J=10.0 Hz, 1H), 6.38 (brdd, J=9.4, 3.9 Hz, 1H), 5.15
(brd, J=12.4 Hz, 1H), 5.08 (d, J=12.4 Hz, 1H), 4.13 (brd, J=3.3 Hz,
1H), 3.78 (s, 3H), 3.55 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=
168.5, 167.6, 155.6, 136.4, 134.4, 133.8, 129.9, 129.2, 128.7, 128.5, 128.0,
126.9, 125.8, 125.2, 123.6, 122.1, 66.9, 55.2, 53.1, 52.4, 50.7 ppm; ESIMS:
m/z: 444 [M++Na].
0.75 mLminÀ1
,
t
major =15.9 min; tminor =20.2 min; 90% ee). M.p. 102–
1038C; [a]2D0 =+15 (c=1.10 in CHCl3); 1H NMR (400 MHz, CDCl3): d=
7.35–7.22 (m, 5H), 6.14 (brs, 1H), 5.49 (brs, 1H), 3.92 (brs, 1H), 3.74 (s,
3H), 3.63 (s, 3H), 1.42 ppm (s, 9H); 13C NMR (100 MHz, CDCl3): d=
168.4, 167.5, 155.1, 139.4, 128.6, 127.6, 126.2, 79.8, 56.7, 53.4, 52.8, 52.5,
28.3 ppm; ESIMS: m/z: 360 [M+ +Na]. The absolute configuration of 3a
was assigned as the S isomer by comparison of its optical rotation with a
literature value (lit.:[8e] [a]D25 =+17 (c=1.14 in CHCl3), for the S isomer
89% ee).
2-(R-1-tert-Butoxycarbonylamino-3-phenylpropyl)malonic acid dimethyl
ester (3g): Following the general procedure, compound 3g was obtained
as a colourless oil in a yield of 80% after column chromatography on
silica gel (petroleum ether/Et2Omixtures). The ee value of the product
was determined by HPLC with a Daicel Chiralpak AS column (hexane/
iPrOH=80:20, flow rate 0.75 mLminÀ1, tmajor =29.3 min; tminor =35.3 min;
78% ee). [a]2D0 =+31 (c=0.70 in CHCl3); 1H NMR (400 MHz, CDCl3):
d=7.31–7.24 (m, 2H), 7.21–7.15 (m, 3H), 5.39 (brd, J=10.4 Hz, 1H),
4.34–4.24 (m, 1H), 3.73 (s, 3H), 3.72 (s, 3H), 3.62 (brd, J=4.2 Hz, 1H),
2.80–2.70 (m, 1H), 2.68–2.58 (m, 1H), 1.98–1.85 (m, 1H), 1.85–1.74 (m,
1H), 1.44 ppm (s, 9H); 13C NMR (100 MHz, CDCl3): d=168.6, 168.2,
155.4, 141.2, 128.4, 128.3, 126.0, 79.4, 55.1, 52.6, 52.4, 50.1, 35.5, 32.7,
28.3 ppm; ESIMS: m/z: 388 [M++Na].
2-(S-Benzyloxycarbonylaminophenylmethyl)malonic acid dimethyl ester
(3b): Following the general procedure, compound 3b was obtained as a
white waxy solid in a yield of 97% after column chromatography on
silica gel (CH2Cl2). The ee value of the product was determined by
HPLC with a Daicel Chiralpak AD-H column (hexane/iPrOH=80:20,
flow rate 0.75 mLminÀ1
, tmajor =50.7 min; tminor =73.5 min; 94% ee).
[a]2D0 =+11 (c=0.97 in CHCl3); 1H NMR (400 MHz, CDCl3): d=7.39–
7.24 (m, 10H), 6.46 (brd, J=8.5 Hz, 1H), 5.56 (dd, J=9.1, 4.4 Hz, 1H),
5.10 (d, J=12.6 Hz, 1H), 5.06 (d, J=12.2 Hz, 1H), 3.95 (brd, J=3.4 Hz,
1H), 3.70 (s, 3H), 3.63 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=
168.3, 167.3, 155.7, 139.0, 136.4, 128.7, 128.4, 128.1, 127.8, 126.2, 66.9,
56.5, 53.9, 52.9, 52.6 ppm; ESIMS: m/z: 394 [M+ +Na]. The absolute con-
figuration of 3b was assigned as the S isomer by comparison of its optical
rotation with a literature value (lit.:[8e] [a]D25 =+9 (c=1.0 in CHCl3), for
the S isomer, 92% ee).
2-(R-1-tert-Butoxycarbonylamino-3-methylbutyl)malonic acid dimethyl
ester (3h): Following the general procedure, compound 3h was obtained
as a colourless oil in a yield of 78% after column chromatography on
silica gel (CH2Cl2). The ee value of the product was determined by
HPLC with a Daicel Chiralpak AD-H column (hexane/iPrOH=98:2,
2-[S-(2-Bromo-phenyl)-tert-butoxycarbonylaminomethyl]malonic acid di-
methyl ester (3c): Following the general procedure, compound 3c was ob-
tained as a colourless thick oil in a yield of 98% after column chromatog-
raphy on silica gel (CH2Cl2). The ee value of the product was determined
by HPLC with a Daicel Chiralpak AD-H column (hexane/iPrOH=80:20,
flow rate 0.75 mLminÀ1
, tmajor =26.3 min; tminor =30.7 min; 83% ee).
[a]2D0 =+44 (c=0.80 in CHCl3); 1H NMR (400 MHz, CDCl3): d=5.26
(brd, J=10.2 Hz, 1H), 4.37–4.24 (m, 1H), 3.75 (s, 3H), 3.72 (s, 3H), 3.59
(brd, J=4.4 Hz, 1H), 1.64–1.44 (m, 1H), 1.41 (s, 9H), 1.32–1.18 (m, 2H),
0.91 (d, J=4.2 Hz, 3H), 0.89 ppm (d, J=5.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=168.7, 168.4, 155.3, 79.3, 55.2, 52.6, 52.4, 48.5, 42.7,
28.3, 25.0, 23.0, 21.9 ppm; ESIMS: m/z: 340 [M++Na].
flow rate 0.75 mLminÀ1, tmajor =8.9 min; tminor =10.9 min; 90% ee). [a]2D0
=
+37 (c=0.80 in CHCl3); 1H NMR (400 MHz, CDCl3): d=7.53 (dd, J=
7.9, 1.2 Hz, 1H), 7.37 (dd, J=7.7, 1.5 Hz, 1H), 7.28 (dt, J=7.5, 1.2 Hz,
1H), 7.13 (dt, J=7.8, 1.7 Hz, 1H), 6.52 (brd, J=9.2 Hz, 1H), 5.76 (brdd,
J=8.8, 2.8 Hz, 1H), 4.16 (brd, J=3.0 Hz, 1H), 3.79 (s, 3H), 3.60 (s, 3H),
1.41 ppm (s, 9H); 13C NMR (100 MHz, CDCl3): d=168.5, 167.5, 154.9,
138.1, 133.1, 129.3, 128.2, 127.5, 122.6, 79.9, 53.7, 53.3, 52.9, 52.4,
28.2 ppm; ESIMS: m/z: 438 [M++Na].
2-(R-1-Benzyloxycarbonylaminoethyl)malonic acid dimethyl ester (3i):
Following the general procedure, compound 3i was obtained as a colour-
less oil in a yield of 99% after column chromatography on silica gel
(CH2Cl2). The ee value of the product was determined by HPLC with a
Daicel Chiralpak AD-H column (hexane/iPrOH=80:20, flow rate
0.75 mLminÀ1, tmajor =18.2 min; tminor =15.9 min; 81% ee). [a]2D0 =+29 (c=
0.97 in CHCl3); 1H NMR (400 MHz, CDCl3): d=7.37–7.28 (m, 5H), 5.61
(brd, J=8.7 Hz, 1H), 5.08 (brs, 2H), 4.49–4.37 (m, 1H), 3.75 (s, 3H),
3.69 (s, 3H), 3.62 (brd, J=4.1 Hz, 1H), 1.28 ppm (d, J=7.1 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=168.4, 167.9, 155.5, 136.4, 128.4, 128.0,
127.9, 66.6, 55.6, 52.6, 52.5, 46.5, 19.0 ppm; ESIMS: m/z: 332 [M++Na].
2-[S-tert-Butoxycarbonylamino(4-chloro-phenyl)methyl]malonic acid di-
methyl ester (3d): Following the general procedure, compound 3d was
obtained as a white solid in a yield of 97% after column chromatography
on silica gel (CH2Cl2). The ee value of the product was determined by
HPLC with a Daicel Chiralpak AD-H column (hexane/iPrOH=80:20,
flow rate 0.75 mLminÀ1, tmajor =21.8 min; tminor =18.0 min; 83% ee). M.p.
94–968C; [a]2D0 =+10 (c=0.97 in CHCl3); 1H NMR (400 MHz, CDCl3):
d=7.31–7.22 (m, 4H), 6.13 (brs, 1H), 5.44 (brs, 1H), 3.87 (brd, J=
3.4 Hz, 1H), 3.74 (s, 3H), 3.65 (s, 3H), 1.40 ppm (s, 9H); 13C NMR
(100 MHz, CDCl3): d=168.2, 167.3, 154.9, 138.0, 133.5, 128.7, 127.6, 80.0,
56.4, 52.9, 52.6, 28.2 ppm; ESIMS: m/z: 394 [M++Na].
2-(R-1-Benzyloxycarbonylamino-2-methylpropyl)malonic acid dimethyl
ester (3j): Following the general procedure, compound 3j was obtained
as a colourless oil in a yield of 88% after column chromatography on
silica gel (CH2Cl2). The ee value of the product was determined by
Chem. Eur. J. 2007, 13, 8338 – 8351
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8345

L. Bernardi, A. Ricci et al.
HPLC with a Daicel Chiralpak AD-H column (hexane/iPrOH=80:20,
flow rate 0.75 mLminÀ1
major =22.7 min; minor =10.6 min; 85% ee).
2-(S-tert-Butoxycarbonylaminophenylmethyl)malonic acid dibenzyl ester
(3o): Following the general procedure, compound 3o was obtained as a
white solid in a yield of 96% after column chromatography on silica gel
(petroleum ether/Et2Omixtures). The ee value of the product was deter-
mined by HPLC with a Daicel Chiralpak AS column (hexane/iPrOH=
98:2, flow rate 1.5 mLminÀ1, tmajor =12.6 min; tminor =10.8 min; 92% ee).
M.p. 56–578C; [a]2D0 =+23 (c=1.00 in CHCl3); 1H NMR (400 MHz,
CDCl3): d=7.37–7.21 (m, 13H), 7.13–7.08 (m, 2H), 6.20 (brs, 1H), 5.56
(brs, 1H), 5.18 (d, J=12.6 Hz, 1H), 5.13 (d, J=12.6 Hz, 1H), 5.06 (s,
2H), 4.02 (brs, 1H), 1.41 ppm (s, 9H); 13C NMR (100 MHz, CDCl3): d=
167.8, 166.8, 155.0, 139.3, 135.0, 134.8, 128.6, 128.5, 128.4, 128.3, 128.2,
128.0, 127.6, 126.2, 79.7, 67.6, 67.3, 56.9, 53.5, 28.3 ppm; ESIMS: m/z: 512
[M++Na]. The absolute configuration of 3n was assigned as the S isomer
,
t
t
[a]2D0 =+56 (c=0.97 in CHCl3); 1H NMR (400 MHz, CDCl3): d=7.37–
7.28 (m, 5H), 5.75 (brd, J=9.8 Hz, 1H), 5.11 (d, J=12.3 Hz, 1H), 5.06
(d, J=12.3 Hz, 1H), 4.09–4.01 (m, 1H), 3.74 (s, 3H), 3.72 (brd, J=
4.1 Hz, 1H), 3.63 (s, 3H), 1.83–1.68 (m, 1H), 0.95 (d, J=6.8 Hz, 3H),
0.91 ppm (d, J=6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=168.9,
168.4, 156.2, 136.7, 128.4, 127.9, 66.6, 56.6, 52.8, 52.5, 52.4, 31.9, 19.8,
19.2 ppm; ESIMS: m/z: 360 [M++Na]. The absolute configuration of 3j
was assigned as (R) after the transformation in the corresponding N-Cbz
protected acid 7b (see below).
2-(R-1-Benzyloxycarbonylaminocyclohexylmethyl)malonic acid dimethyl
ester (3k): Following the general procedure, compound 3k was obtained
as a colourless oil in a yield of 90% after column chromatography on
silica gel (CH2Cl2). The ee value of the product was determined by
HPLC with a Daicel Chiralpak AD-H column (hexane/iPrOH=80:20,
by comparison of its optical rotation with a literature value (lit.:[8f] [a]D25
+14 (c=0.98 in CHCl3), for the S isomer, 96% ee).
=
2-(S-Benzyloxycarbonylaminophenylmethyl)malonic acid dibenzyl ester
(3p): Following the general procedure, compound 3p was obtained as a
white solid in a yield of 92% after column chromatography on silica gel
(petroleum ether/Et2Omixtures). The ee value of the product was deter-
flow rate 0.75 mLminÀ1
, tmajor =20.6 min; tminor =16.3 min; 97% ee).
[a]2D0 =+50 (c=1.03 in CHCl3); 1H NMR (400 MHz, CDCl3): d=7.37–
7.26 (m, 5H), 5.76 (brd, J=10.7 Hz, 1H), 5.10 (d, J=12.1 Hz, 1H), 5.04
(d, J=12.1 Hz, 1H), 4.08 (dt, J=9.8, 4.0 Hz, 1H), 3.76 (d, J=4.1 Hz,
1H), 3.75 (s, 3H), 3.63 (s, 3H), 1.88–1.56 (m, 5H), 1.47–1.35 (m, 1H),
1.22–0.95 ppm (m, 5H); 13C NMR (100 MHz, CDCl3): d=169.0, 168.6,
156.2, 136.7, 128.3, 127.9, 66.6, 55.7, 52.6, 52.5, 52.3, 40.9, 30.1, 29.5, 26.0,
25.8, 25.7 ppm; ESIMS: m/z: 400 [M++Na].
mined by HPLC with
a Daicel Chiralpak AD-H column (hexane/
iPrOH=80:20, flow rate 0.75 mLminÀ1, tmajor =89.5 min; tminor =68.2 min;
93% ee). M.p. 85–878C; [a]2D0 =+13 (c=1.12 in CHCl3); 1H NMR
(400 MHz, CDCl3): d=7.40–7.23 (m, 18H), 7.13–7.08 (m, 2H), 6.48 (brd,
J=8.3 Hz, 1H), 5.63 (brdd, J=9.1, 4.3 Hz, 1H), 5.13 (d, J=12.1 Hz,
1H), 5.10 (d, J=12.1 Hz, 1H), 5.08 (brs, 2H), 5.05 (brs, 2H), 4.04 ppm
(brd, J=5.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=167.8, 166.6,
155.9, 138.9, 136.4, 134.9, 134.8, 128.7, 128.6, 128.5, 128.4, 128.3, 128.1,
128.0, 127.8, 126.2, 67.7, 67.4, 66.9, 56.8, 53.7 ppm; ESIMS: m/z: 546 [M+
+Na].
2-(S-tert-Butoxycarbonylaminophenylmethyl)malonic acid diallyl ester
(3l): Following the general procedure, compound 3l was obtained as a
white solid in a yield of 97% after column chromatography on silica gel
(petroleum ether/Et2Omixtures). The ee value of the product was deter-
mined by HPLC with
a Daicel Chiralpak AD-H column (hexane/
iPrOH=80:20, flow rate 0.75 mLminÀ1, tmajor =19.0 min; tminor =14.8 min;
90% ee). M.p. 77–798C; [a]2D0 =+10 (c=1.17 in CHCl3); 1H NMR
(400 MHz, CDCl3): d=7.34–7.21 (m, 5H), 6.17 (brs, 1H), 5.94–5.82 (m,
1H), 5.79–5.68 (m, 1H), 5.52 (brs, 1H), 5.31 (dq, J=17.1, 1.3 Hz, 1H),
5.24 (dq, J=10.4, 1.1 Hz, 1H), 5.20–5.11 (m, 2H), 4.69–4.59 (m, 2H),
4.58–4.47 (m, 2H), 3.97 (brs, 1H), 1.41 ppm (s, 9H); 13C NMR
(100 MHz, CDCl3): d=167.6, 166.7, 155.0, 139.4, 131.2, 131.1, 128.5,
127.6, 126.2, 118.9, 118.7, 79.7, 66.4, 66.1, 56.8, 53.4, 28.2 ppm; ESIMS: m/
z: 412 [M++Na].
2-(R-1-tert-Butoxycarbonylamino-3-methylbutyl)malonic acid dibenzyl
ester (3q): Following the general procedure, compound 3g was obtained
as a colourless oil in a yield of 77% after column chromatography on
silica gel (CH2Cl2). The ee value of the product was determined by
HPLC with a Daicel Chiralpak AD-H column (hexane/iPrOH=95:5,
flow rate 0.75 mLminÀ1
, tmajor =27.9 min; tminor =30.8 min; 91% ee).
[a]2D0 =+40 (c=0.75 in CHCl3); 1H NMR (400 MHz, CDCl3): d=7.37–
7.28 (m, 10H), 5.26 (brd, J=9.6 Hz, 1H), 5.21 (d, J=11.4 Hz, 1H), 5.18
(d, J=12.8 Hz, 1H), 5.16 (d, J=11.4 Hz, 1H), 5.10 (d, J=12.8 Hz, 1H),
4.41–4.31 (m, 1H), 3.70 (d, J=4.4 Hz, 1H), 1.65–1.44 (m, 2H), 1.41 (s,
9H), 1.29–1.18 (m, 1H), 0.87 ppm (d, J=6.6 Hz, 6H); 13C NMR
(100 MHz, CDCl3): d=168.0, 167.7, 155.2, 135.1, 128.5, 128.4, 128.3,
128.2, 79.2, 67.3, 67.2, 55.3, 48.6, 42.2, 28.3, 25.0, 22.9, 21.8 ppm; ESIMS:
m/z: 492 [M++Na].
2-(S-Benzyloxycarbonylaminophenylmethyl)malonic acid diallyl ester
(3m): Following the general procedure, compound 3m was obtained as a
white solid in a yield of 95% after column chromatography on silica gel
(petroleum ether/Et2Omixtures). The ee value of the product was deter-
mined by HPLC with
a Daicel Chiralpak AD-H column (hexane/
iPrOH=70:30, flow rate 0.50 mLminÀ1, tmajor =41.9 min; tminor =40.0 min;
92% ee). M.p. 88–898C; [a]2D0 =+8 (c=0.92 in CHCl3); 1H NMR
(400 MHz, CDCl3): d=7.39–7.23 (m, 10H), 6.47 (brd, J=9.5 Hz, 1H),
5.89–5.79 (m, 1H), 5.78–5.67 (m, 1H), 5.59 (brdd, J=9.0, 5.0 Hz, 1H),
5.29 (dq, J=17.2, 1.4 Hz, 1H), 5.21 (dq, J=10.4, 1.3 Hz, 1H), 5.18–5.15
(m, 1H), 5.15–5.12 (m, 1H), 5.12–5.05 (m, 2H), 4.62–4.58 (m, 2H), 4.58–
4.48 (m, 2H), 3.99 ppm (brd, J=4.4 Hz, 1H); 13C NMR (100 MHz,
CDCl3): d=167.6, 166.5, 155.6, 138.9, 136.4, 131.2, 131.0, 128.6, 128.4,
128.1, 127.8, 126.2, 119.1, 118.8, 66.9, 66.5, 66.2, 56.7, 53.9 ppm; ESIMS:
m/z: 446 [M++Na].
2-(S-tert-Butoxycarbonylaminophenylmethyl)malonic acid bis(4-methoxy-
phenyl)ester ( 3r): Following the general procedure and by adding aque-
ous K2CO3 solution (1.5 equiv, 50% w/w, 27 mL, 0.15 mmol), compound
3r was obtained as a white solid in a yield of 90% after column chroma-
tography on silica gel (CH2Cl2). The ee value of the product was deter-
mined by HPLC with
a Daicel Chiralpak AD-H column (hexane/
iPrOH=80:20, flow rate 0.75 mLminÀ1, tmajor =47.5 min; tminor =77.0 min;
98% ee). M.p. 144–1468C; [a]2D0 =+3 (c=0.700 in CHCl3); 1H NMR
(400 MHz, CDCl3): d=7.45–7.31 (m, 5H), 7.06–7.03 (m, 2H), 6.90–6.87
(m, 2H), 6.83 (brs, 4H), 6.18 (brs, 1H), 5.82 (brs, 1H), 4.40 (brs, 1H),
3.80 (s, 3H), 3.77 (s, 3H), 1.44 ppm (s, 9H); 13C NMR (100 MHz, CDCl3):
d=166.8, 166.0, 157.6, 155.1, 143.8, 143.5, 139.0, 128.8, 127.9, 126.4, 122.1,
122.0, 114.4, 80.0, 57.1, 55.6, 53.4, 28.3 ppm; ESIMS: m/z: 544 [M++Na].
The absolute configuration of 3p has been assigned as the S isomer in
our previous work.[8i]
2-(R-Benzyloxycarbonylaminocyclohexylmethyl)malonic acid diallyl ester
(3n): Following the general procedure, compound 3n was obtained as
colourless oil in a yield of 84% after column chromatography on silica
gel (CH2Cl2). The ee value of the product was determined by HPLC with
a
Daicel Chiralpak AD-H column (hexane/iPrOH=80:20, flow rate
0.75 mLminÀ1, tmajor =15.4 min; tminor =10.4 min; 94% ee). [a]2D0 =+37 (c=
0.83 in CHCl3); 1H NMR (400 MHz, CDCl3): d=7.37–7.27 (m, 5H),
5.95–5.75 (m, 3H), 5.34 (dq, J=17.1, 1.2 Hz, 1H), 5.28 (dq, J=9.2,
1.2 Hz, 1H), 5.26–5.24 (m, 1H), 5.19 (dq, J=10.4, 1.0 Hz, 1H), 5.09 (d,
J=12.6 Hz, 1H), 5.05 (d, J=12.6 Hz, 1H), 4.68–4.63 (m, 2H), 4.57–4.47
(m, 2H), 4.12 (dt, J=9.7, 3.7 Hz, 1H), 3.80 (d, J=3.7 Hz, 1H), 1.89–1.54
(m, 5H), 1.48–1.36 (m, 1H), 1.22–0.92 ppm (m, 5H); 13C NMR
(100 MHz, CDCl3): d=168.3, 167.7, 156.1, 136.7, 131.4, 131.3, 128.4,
127.9, 119.0, 118.9, 66.6, 66.4, 66.0, 55.7, 52.5, 41.1, 30.1, 29.5, 25.9, 25.8,
25.7 ppm; ESIMS: m/z: 452 [M++Na].
2-(S-Benzyloxycarbonylaminophenylmethyl)malonic acid bis(4-methoxy-
phenyl)ester ( 3s): Following the general procedure and by adding aque-
ous K2CO3 solution (1.5 equiv, 50% w/w, 27 mL, 0.15 mmol), compound
3s was obtained as a white solid in a yield of 96% after column chroma-
tography on silica gel (CH2Cl2). The ee value of the product was deter-
mined by HPLC with a Daicel Chiralcel OD column (hexane/iPrOH=
80:20, flow rate 1.0 mLminÀ1, tmajor =30.9 min; tminor =26.5 min; 99% ee).
M.p. 161–1638C; [a]2D0 =+3 (c=0.70 in CHCl3); 1H NMR (400 MHz,
CDCl3): d=7.45–7.34 (m, 10H), 6.97–6.95 (m, 4H), 6.86–6.84 (m, 4H),
6.48 (d, J=10.1 Hz, 1H), 5.88 (brs, 1H), 5.20 (d, J=12.4 Hz, 1H), 5.10
8346
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 8338 – 8351

Asymmetric Mannich Reactions
FULL PAPER
(d, J=12.4 Hz, 1H), 4.43 (d, J=4.1 Hz, 1H), 3.80 (s, 3H), 3.77 ppm (s,
3H); 13C NMR (100 MHz, CDCl3): d=166.7, 165.8, 157.6, 155.3, 143.7,
143.4, 138.6, 128.8, 128.5, 128.1, 126.4, 122.0, 121.9, 114.5, 67.0, 56.9, 55.6,
55.5, 54.0 ppm; ESIMS: m/z: 578 [M++Na]. The absolute configuration
of 3q has been assigned as the S isomer in our previous work.[8i]
+3 (c=0.47 in H2O); 1H NMR (400 MHz, D2O):d=7.54–7.48 (m, 5H),
3.19 (dd, J=17.2, 7.9 Hz, 1H), 3.11 ppm (dd, J=17.2, 6.9 Hz, 1H), [CHN
signal below the residual solvent peak]; 13C NMR (100 MHz, D2O): d=
177.0, 138.4, 132.8, 132.6, 130.2, 54.8, 41.1 ppm; ESIMS: m/z: 166 [M+].
S-3-Amino-4-methylpentanoic acid hydrochloride (6b): Following the
general procedure, compound 6b was obtained as a white solid in a yield
of 88%. The ee value of the product was determined on the correspond-
ing N-Cbz methyl ester (prepared by Cbz protection (CbzCl, 1m aqueous
NaOH) followed by esterification with trimethylsilyldiazomethane)[24]
with a Daicel Chiralpak AD-H column (hexane/iPrOH=90:10, flow rate
0.75 mLminÀ1, tmajor =21.4 min; tminor =17.3 min; 85% ee), and was found
to be consistent with the ee value of 3j (85% ee). M.p. 180–1818C;
[a]2D0 =À24 (c=0.55 in H2O); 1H NMR (400 MHz, D2O):d=3.55–3.49 (m,
1H), 2.86 (dd, J=17.8, 4.1 Hz, 1H), 2.69 (dd, J=17.4, 9.0 Hz, 1H), 2.08–
1.99 (m, 1H), 1.03 (d, J=6.6 Hz, 3H), 1.01 ppm (d, J=6.6 Hz, 3H);
13C NMR (100 MHz, D2O): d=177.9, 56.6, 36.5, 32.9, 20.3, 19.9 ppm;
ESIMS: m/z: 132 [M+].
Preparation of the N-protected b3-amino acids: A 1m solution of LiOH
in H2O(0.4 mL) was added to a cooled (0 8C) solution of 3a or 3j
(0.10 mmol) in THF (0.4 mL). The solution was stirred at 08C for 2 h,
then at room temperature for an additional 4 h. H2Owas then added and
the mixture acidified to pHꢀ2 by using a 0.5m aqueous KHSO4 solution.
The malonic acid was then extracted with EtOAc (3”3 mL), the organic
phases dried over Na2SO4, filtered and the solvent evaporated. The ma-
lonic acid obtained was then suspended in toluene (4 mL) and then
heated to reflux for 2 h 30 min. After cooling to room temperature, the
solvent was evaporated and the residue purified by chromatography on
silica gel.
2-(R-tert-Butoxycarbonylaminophenylmethyl)malonic acid bis(4-methoxy-
phenyl)ester ( ent-3r): Following the general procedure and by adding
catalyst 5 and aqueous K2CO3 solution (1.5 equiv, 50% w/w, 27 mL,
0.15 mmol), compound ent-3r was obtained as a white solid in a yield of
98% after column chromatography on silica gel (CH2Cl2). The ee value
of the product was determined by HPLC with a Daicel Chiralpak AD-H
column (hexane/iPrOH=80:20, flow rate 0.75 mLminÀ1, tmajor =77.0 min;
t
minor =47.5 min; 93% ee). M.p. 147–1498C; [a]2D0 =À4 (c=1.10 in CHCl3);
spectral data were identical to compound 3p.
2-(S-Benzyloxycarbonylaminophenylmethyl)malonic acid bis(4-methoxy-
phenyl)ester ( ent-3s): Following the general procedure and by adding
catalyst 5 and aqueous K2CO3 solution (1.5 equiv, 50% w/w, 27 mL,
0.15 mmol), compound ent-3s was obtained as a white solid in a yield of
95% after column chromatography on silica gel (CH2Cl2). The ee value
of the product was determined by HPLC with a Daicel Chiralcel OD
column (hexane/iPrOH=80:20, flow rate 1.0 mLminÀ1, tmajor =26.5 min;
t
minor =30.9 min; 99% ee). M.p. 166–1688C; [a]2D0 =À2 (c=0.96 in CHCl3);
spectral data were identical to compound 3q.
2-(S-tert-Butoxycarbonylamino-3-phenylpropyl)malonic acid bis(4-me-
thoxy-phenyl)ester ( 3t): Following the general procedure and by adding
catalyst 5 and aqueous K2CO3 solution (1.5 equiv, 50% w/w, 27 mL,
0.15 mmol), compound 3t was obtained as a white solid in a yield of
88% after column chromatography on silica gel (CH2Cl2). The ee value
of the product was determined by HPLC with a Daicel Chiralcel OD
column (hexane/iPrOH=80:20, flow rate 1.0 mLminÀ1, tmajor =10.6 min;
S-3-tert-Butoxycarbonylamino-3-phenylpropionic acid (7a): Following the
general procedure, compound 7a was obtained as a white solid in a yield
of 77% after column chromatography on silica gel (hexane/EtOAc/
AcOH 80:20:1). The ee value of the product was determined on the cor-
responding methyl ester (prepared by esterification with trimethylsilyl-
diazomethane)[24] with a Daicel Chiralcel OD column (hexane/iPrOH=
95:5, flow rate 1.5 mLminÀ1, tmajor =7.4 min; tminor =6.1 min; 90% ee), and
was found to be consistent with the ee value of the starting 3a (90% ee).
M.p. 127–1298C; [a]2D0 =À26 (c=0.50 in CH3OH); 1H NMR (400 MHz,
CD3OD):d=7.35–7.20 (m, 6H), 5.02 (brs, 1H), 2.75 (dd, J=15.4, 8.3 Hz,
1H), 2.66 (dd, J=15.9, 13.4 Hz, 1H), 1.41 ppm (s, 9H); 13C NMR
(100 MHz, CD3OD): d=174.4, 157.5, 134.6, 129.5, 128.3, 127.4, 80.3, 52.9,
42.3, 28.7 ppm; ESIMS: m/z: 288 [M++Na].
t
minor =8.9 min; 77% ee). M.p. 114–1168C; [a]2D0 =À32 (c=0.76 in CHCl3);
1H NMR (400 MHz, CDCl3): d=7.33–7.27 (m, 2H), 7.25–7.19 (m, 3H),
7.09 (brd, J=9.6 Hz, 2H), 7.05 (brd, J=8.6 Hz, 2H), 6.88 (brd, J=
8.2 Hz, 4H), 5.50 (d, J=10.2 Hz, 1H), 4.66–4.56 (m, 1H), 4.08 (d, J=
3.9 Hz, 1H), 3.80 (s, 6H), 2.89–2.79 (m, 1H), 2.79–2.67 (m, 1H), 2.17–
1.96 (m, 2H), 1.46 ppm (s, 9H); 13C NMR (100 MHz, CDCl3): d=167.1,
166.6, 157.6, 157.5, 155.5, 143.8, 143.6, 141.1, 128.5, 128.4, 126.1, 122.2,
122.1, 114.5, 114.4, 79.7, 55.6, 55.4, 50.2, 35.8, 32.7, 28.3 ppm; ESIMS: m/
z: 572 [M++Na].
2-(S-1-Benzyloxycarbonylaminocyclohexylmethyl)malonic acid bis(4-me-
thoxyphenyl)ester ( 3u): Following the general procedure and by adding
catalyst 5 and aqueous K2CO3 solution (1.5 equiv, 50% w/w, 27 mL,
0.15 mmol), compound 3u was obtained as a white solid in a yield of
89% after column chromatography on silica gel (CH2Cl2). The ee value
of the product was determined by HPLC with a Daicel Chiralcel OD
column (hexane/iPrOH=80:20, flow rate 1.0 mLminÀ1, tmajor =11.1 min;
S-3-Benzyloxycarbonylamino-4-methylpentanoic acid (7b): Following the
general procedure, compound 7b was obtained as a white solid in a yield
of 78% after column chromatography on silica gel (CH2Cl2/CH3OH
95:5). The ee value of the product was determined on the corresponding
methyl ester, (prepared by esterification with trimethylsilyldiazome-
thane)[24] with a Daicel Chiralpak AD-H column (hexane/iPrOH=90:10,
flow rate 0.75 mLminÀ1, tmajor =21.4 min; tminor =17.3 min; 84% ee), and
was found to be consistent with the ee value obtained for 3j (85% ee).
M.p. 82–848C; [a]2D0 =+24 (c=0.20 in CHCl3); 1H NMR (400 MHz,
CD3OD):d=7.38–7.23 (m, 5H), 6.97 (brd, J=8.0 Hz, 1H), 5.07 (s, 2H),
3.91–3.82 (m, 1H), 2.51 (dd, J=15.4, 5.8 Hz, 1H), 2.39 (dd, J=15.4,
8.9 Hz, 1H), 1.79 (oct, J=6.5 Hz, 1H), 0.93 (d, J=6.6 Hz, 3H), 0.91 ppm
(d, J=6.6 Hz, 3H); 13C NMR (100 MHz, CD3OD): d=175.4, 158.6, 138.5,
129.4, 128.9, 128.6, 67.3, 55.0, 38.0, 33.5, 19.5, 18.4 ppm; ESIMS: m/z: 288
[M++Na]. The absolute configuration of 7b was assigned as the S isomer
t
minor =13.9 min; 93% ee). M.p. 101–1028C; [a]2D0 =À54 (c=0.64 in
CHCl3); 1H NMR (400 MHz, CDCl3): d=7.34–7.30 (m, 5H), 7.07–6.80
(m, 8H), 5.85 (d, J=10.4 Hz, 1H), 5.16 (d, J=12.4 Hz, 1H), 5.08 (d, J=
12.4 Hz, 1H), 4.40 (dt, J=9.6, 3.9 Hz, 1H), 4.22 (d, J=3.9 Hz, 1H), 3.80
(s, 3H), 3.79 (s, 3H), 1.95–1.60 (m, 6H), 1.29–1.09 ppm (m, 5H);
13C NMR (100 MHz, CDCl3): d=167.5, 167.1, 157.7, 157.5, 156.3, 143.8,
143.6, 136.5, 128.4, 128.0, 127.9, 122.1, 114.5, 114.4, 66.7, 55.8, 55.6, 55.5,
52.8, 41.3, 30.3, 29.6, 26.0, 25.9, 25.7 ppm;. ESIMS: m/z: 550 [M++Na].
Preparation of the b3-amino acid hydrochlorides:[18] Malonic acid dimeth-
yl ester 3a or 3j (0.20 mmol) was suspended in 6m aqueous HCl
(0.80 mL), and the mixture was then heated at 1008C for 1 h 30 min for
3a and 5 h for 3j. After cooling to room temperature, the solution was
evaporated to dryness under reduced pressure. Crude b3-amino acid hy-
drochlorides were then purified by trituration with Et2O.
by comparison of its optical rotation with a literature value (lit.:[25] [a]D25
À33 (c=0.2 in CHCl3), for the (R)-isomer).
=
General procedure for the catalytic reaction of b-ketoesters 8 with a-
amido sulfones 2: b-Ketoester 8 (0.10 mmol) was added to a test tube
that contained a mixture of a-amido sulfone 2 (0.12 mmol) and catalyst
4e (1.2 mg, 0.025 mmol) in toluene (2 mL). After the resulting mixture
had been cooled to À248C, a pre-cooled aqueous solution of K2CO3
(50% w/w, 27 mL, 0.15 mmol) was added in one portion. The reaction
mixture was then vigorously stirred at the same temperature without any
precaution to exclude moisture or air. After the time stated, the reaction
product was filtered through a short plug of silica, the plug was washed
with CH2Cl2 (4 mL) and Et2O(4 mL) and the solvent was evaporated.
S-3-Amino-3-phenylpropionic acid hydrochloride (6a): Following the
general procedure, compound 6a was obtained as a white solid in a yield
of 93%. The ee value of the product was determined on the correspond-
ing N-Boc ethyl ester, (prepared by esterification (SOCl2, EtOH)[18] fol-
lowed by Boc protection (Boc2O, EtOAc/Na CO3 aq)) with by using a
2
Daicel Chiralcel OD column (hexane/iPrOH=98:2, flow rate
1.5 mLminÀ1, tmajor =8.6 min; tminor =7.5 min; 90% ee), and was found to
be consistent with the ee value of 3a (90% ee). M.p. 204–2058C; [a]D20
=
Chem. Eur. J. 2007, 13, 8338 – 8351
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8347

L. Bernardi, A. Ricci et al.
The crude product was analysed by 1H NMR spectroscopy to determine
the diastereomeric ratio before it was purified by chromatography on
silica gel.
determined on the crude mixture). The ee value of the products was de-
termined by HPLC with a Daicel Chiralpak AD-H column (hexane/
iPrOH=80:20, flow rate 0.75 mLminÀ1, major diastereoisomer: tmajor
=
51.0 min;
tminor =16.2 min, 73% ee, minor diastereoisomer: tmajor
=
S-1-(R-tert-Butoxycarbonylaminophenylmethyl)-2-oxocyclopentanecar-
boxylic acid methyl ester (9d): Following the general procedure (21 h re-
action time), compound 9d was obtained as a colourless oil in a yield of
98% after column chromatography on silica gel (hexane/Et2O1:1) and as
a single diastereoisomer, as determined by measurements on the crude
mixture. The ee value of the product was determined by HPLC with a
Daicel Chiralpak AD-H column (hexane/iPrOH=98:2, flow rate
0.75 mLminÀ1, tmajor =118.0 min; tminor =36.2 min, 95% ee). [a]2D0 =+25
(c=0.85 in CH2Cl2); 1H NMR (400 MHz, CDCl3): d=7.33–7.21 (m, 5H),
5.95 (brs, 1H), 5.20 (d, J=9.7 Hz, 1H), 3.67 (s, 3H), 2.57–2.25 (m, 1H),
2.37–2.25 (m, 2H), 2.05–1.82 (m, 3H), 1.38 ppm (s, 9H); 13C NMR
(100 MHz, CDCl3): d=210.9, 170.0, 155.2, 138.3, 128.4, 128.1, 127.8, 79.8,
64.9, 55.7, 52.7, 37.5, 30.6, 28.2, 18.8 ppm; ESIMS: m/z: 370 [M++Na].
99.6 min; tminor =25.6 min, 61% ee). 1H NMR (400 MHz, CDCl3, major
diastereoisomer, 508C): d=7.40–7.21 (m, 9H), 6.08 (brs, 1H), 5.20 (d,
J=8.8 Hz, 1H), 5.08 (d, J=11.8 Hz, 2H), 5.03 (d, J=11.8 Hz, 1H), 3.81
(s, 3H), 2.56–2.47 (m, 1H), 2.43–2.32 (m, 2H), 2.04–1.84 ppm (m, 3H);
13C NMR (100 MHz, CDCl3, major diastereoisomer): d=210.8, 169.7,
155.8, 136.6, 136.1, 133.9, 129.7, 128.7, 128.6, 128.5, 128.1, 67.0, 64.5, 55.9,
52.9, 37.6, 30.9, 19.0 ppm; ESIMS: m/z: 438 [M++Na].
1-[1-Benzyloxycarbonylamino(4-methoxyphenyl)methyl]-2-oxocyclopenta-
necarboxylic acid methyl ester (9i): Following the general procedure (65 h
reaction time), compound 9i was obtained as a colourless oil in a yield of
70% after column chromatography on silica gel (hexane/EtOAc 80:20)
and as a mixture of diastereoisomers (95:5 diastereomeric ratio, as deter-
mined on the crude mixture). The ee value of the products was deter-
mined by HPLC with
iPrOH=95:5, flow rate 0.75 mLminÀ1
50.3 min; minor =20.7 min, 77% ee, minor diastereoisomer: tmajor
S-1-(R-Benzyloxycarbonylaminophenylmethyl)-2-oxocyclopentanecarbox-
ylic acid methyl ester (9e): Following the general procedure (28 h reac-
tion time), compound 9e was obtained as a colourless oil in a yield of
90% after column chromatography on silica gel (hexane/Et2O6:4) and
as a single diastereoisomer, as determined by measurements on the crude
mixture. The ee value of the product was determined by HPLC with a
Daicel Chiralpak AD-H column (hexane/iPrOH=80:20, flow rate
0.75 mLminÀ1, tmajor =49.3 min; tminor =19.4 min, 92% ee). [a]2D0 =+30 (c=
0.88 in CH2Cl2); 1H NMR (400 MHz, CDCl3): d=7.40–7.20 (m, 10H),
6.23 (brd, J=8.3 Hz ,1H), 5.23 (brd, J=8.3 Hz, 1H), 5.05 (s, 2H), 3.65
(s, 3H), 2.57–2.46 (m, 1H), 2.42–2.22 (m, 2H), 2.07–1.80 ppm (m, 3H),
13C NMR (100 MHz, CDCl3): d?210.5, 169.7, 155.8, 138.2, 136.5, 128.5,
128.4, 128.1, 127.9, 66.9, 64.6, 56.8, 52.6, 37.6, 30.4, 18.9 ppm; ESIMS: m/
z: 404 [M++Na].
a Daicel Chiralpak AD-H column (hexane/
,
major diasteroisomer: tmajor
=
t
=
87.1 min; tminor =32.9 min, 53% ee); 1H NMR (400 MHz, CDCl3, major
diastereoisomer): d=7.41–7.19 (m, 7H), 6.85–6.80 (m, 2H), 6.18 (brs,
1H), 5.18 (brd, J=9.2 Hz, 1H), 5.05 (s, 2H), 3.78 (s, 3H), 3.65 (s, 3H),
2.51 (dt, J=13.6, 6.6 Hz, 1H), 2.40–2.23 (m, 2H), 2.05–1.86 ppm (m,
3H);.13C NMR (100 MHz, CDCl3, major diastereoisomer): d=211.0,
169.8, 159.2, 155.8, 136.3, 130.1, 129.3, 128.4, 128.0, 113.8, 66.9, 64.8, 55.9,
55.2, 52.7, 37.5, 29.2, 18.9 ppm, ESIMS: m/z: 434 [M++Na].
1-(1-Benzyloxycarbonylaminonaphthalen-1-ylmethyl)-2-oxocyclopentane-
carboxylic acid methyl ester (9j): Following the general procedure (40 h
reaction time), compound 9j was obtained as a colourless oil in a yield of
50% after column chromatography on silica gel (hexane/Et2O80:20) and
as a mixture of diastereoisomers (90:10 diastereomeric ratio, as deter-
mined on the crude mixture). The ee value of the products was deter-
1-[(2-Bromophenyl)-tert-butoxycarbonylaminomethyl]-2-oxocyclopenta-
necarboxylic acid methyl ester (9 f): Following the general procedure
(73 h reaction time), compound 9 f was obtained as a colourless oil in a
yield of 60% after column chromatography on silica gel (CH2Cl2) and as
a mixture of diastereoisomers (94:6 diastereomeric ratio, as determined
on the crude mixture). The ee value of the products was determined by
HPLC with a Daicel Chiralpak AD-H column (hexane/iPrOH=90:10,
mined by HPLC with
a
Daicel Chiralpak AD-H column (hexane/
major diasteroisomer: tmajor
iPrOH=95:5, flow rate 0.75 mLminÀ1
,
=
55 min; tminor =57 min, 85% ee, enantiomers of the minor diastereoisomer
not separated). 1H NMR (400 MHz, CDCl3): d=8.28 (d, J=7.7 Hz,
1Hmajor, 1Hminor), 7.85 (d, J=8.0 Hz, 1Hmajor, 1Hminor), 7.79 (d, J=8.0 Hz,
flow rate 0.75 mLminÀ1, major diastereoisomer: tmajor =16.1 min; tminor
=
1Hmajor
1Hmajor
,
,
1Hminor), 7.68–7.45 (m, 3Hmajor
,
3Hminor), 7.41 (t, J=8.2 Hz,
5Hminor), 6.42 (d, J=9.7 Hz,
18.3 min, 69% ee, enantiomers of the minor diastereoisomer not separat-
ed). H NMR (400 MHz, CDCl3, major diastereoisomer): d=7.59–7.50 (t,
1
1Hminor), 7.36–7.21 (m, 5Hmajor
,
1Hminor), 6.20 (brd, J=9.4 Hz, 1Hmajor), 6.08 (d, J=9.4 Hz, 1Hmajor
1Hminor), 5.12 (d, J=12.4 Hz, 1Hmajor), 5.06 (d, J=12.4 Hz, 1Hmajor
1Hminor), 4.96 (d, J=12.4 Hz, 1Hminor), 3.76 (s, 3Hminor), 3.63 (s, 3Hmajor),
,
,
J=8.3 Hz, 2H), 7.30–7.22 (t, J=7.3 Hz, 1H), 7.14–7.08 (t, J=7.3 Hz,
1H), 6.22 (brs, 1H), 5.62 (brd, J=7.8 Hz, 1H), 3.66 (s, 3H), 2.65–2.50
(m, 1H), 2.49–2.33 (m, 2H), 2.33–2.18 (m, 1H), 2.15–2.05 (m, 1H), 2.05–
1.91 (m, 1H), 1.39 ppm (s, 9H); 13C NMR (100 MHz, CDCl3, major dia-
stereoisomer): d=210.7, 170.3, 155.4, 138.6, 133.2, 129.4, 129.3, 127.9,
125.1, 79.8, 64.3, 54.0, 52.6, 37.5, 31.3, 28.3, 19.1 ppm; ESIMS: m/z: 448
[M++Na].
2.69–2.26 (m, 3Hmajor, 3Hminor), 2.22–1.87 ppm (m, 3Hmajor, 3Hminor);
13C NMR (100 MHz, CDCl3, major diastereoisomer): d=211.4, 171.2,
156.2, 136.5, 134.5, 133.9, 131.9, 128.8, 128.4, 128.0, 127.9, 126.8, 125.8,
125.3, 125.0, 123.3, 67.0, 64.4, 52.7, 50.9, 37.7, 32.8, 19.2 ppm; ESIMS: m/
z: 454 [M++Na].
1-[1-Benzyloxycarbonylamino(2-bromophenyl)methyl]-2-oxocyclopenta-
necarboxylic acid methyl ester (9g): Following the general procedure
(73 h reaction time), compound 9g was obtained as a colourless oil in a
yield of 85% after column chromatography on silica gel (hexane/EtOAc
8:2) and as a mixture of diastereoisomers (96:4 diastereomeric ratio, as
determined on the crude mixture). The ee value of the products was de-
termined by HPLC with a Daicel Chiralpak AD-H column (hexane/
S-1-(R-1-tert-Butoxycarbonylamino-3-phenylpropyl)-2-oxocyclopentane-
carboxylic acid methyl ester (9k): Following the general procedure (45 h
reaction time), compound 9k was obtained as a colourless oil in a yield
of 55% after column chromatography on silica gel (CH2Cl2) and as a
mixture of diastereoisomers (97:3 diastereomeric ratio, as determined on
the crude mixture). The ee value of the product was determined by
HPLC with a Daicel Chiralpak AD-H column (hexane/iPrOH=80:20,
iPrOH=90:10, flow rate 0.75 mLminÀ1, major diastereoisomer: tmajor
33.2 min; minor =26.0 min, 77% ee, minor diastereoisomer: tmajor
=
flow rate 0.75 mLminÀ1, major diastereoisomer: tmajor =8.1 min; tminor
=
t
=
27.0 min; tminor =30.1 min, 47% ee). 1H NMR (400 MHz, CDCl3, major
diastereoisomer): d=7.60–7.51 (m, 2H), 7.38–7.22 (m, 5H), 7.12 (t, J=
7.6 Hz, 1H), 6.55 (brd, J=8.7 Hz, 1H), 5.65 (d, J=8.7 Hz, 1H), 5.05 (s,
2H), 3.66 (s, 3H), 2.69–2.50 (m, 1H), 2.50–2.34 (m, 2H), 2.14–1.89 ppm
(m, 3H); 13C NMR (100 MHz, CDCl3, major diastereoisomer): d=210.7,
170.1, 155.7, 138.3, 136.3, 133.2, 129.4, 129.3, 128.4, 128.0, 125.1, 67.0,
64.0, 54.6, 52.7, 37.6, 31.4, 19.2 ppm; ESIMS: m/z: 482 [M++Na].
7.4 min, 90% ee, enantiomers of the minor diastereoisomer not separat-
ed). 1H NMR (400 MHz, CDCl3, major diastereoisomer): d=7.28 (t, J=
7.8 Hz, 2H), 7.22–7.14 (m, 3H), 5.12 (d, J=10.3 Hz, 1H), 3.96 (t, J=
11.0 Hz, 1H), 3.69 (s, 3H), 2.99–2.73 (m, 1H), 2.63–2.23 (m, 4H), 1.99–
1.83 (m, 4H), 1.76–1.65 (m, 1H), 1.44 ppm (s, 9H); 13C NMR (100 MHz,
CDCl3, major diastereoisomer): d=211.9, 170.6, 156.2, 141.4, 128.5, 128.4,
126.0, 79.5, 64.5, 52.5, 52.1, 37.7, 33.7, 33.0, 31.8, 28.3, 18.9 ppm; ESIMS:
m/z: 398 [M++Na].
1-[1-Benzyloxycarbonylamino(4-chlorophenyl)methyl]-2-oxocyclopenta-
necarboxylic acid methyl ester (9h): Following the general procedure
(21 h reaction time), compound 9h was obtained as a colourless oil in a
yield of 98% after column chromatography on silica gel (hexane/EtOAc
85:15) and as a mixture of diastereoisomers (96:4 diastereomeric ratio, as
1-(1-Benzyloxycarbonylaminoethyl)-2-oxocyclopentanecarboxylic
acid
methyl ester (9l): Following the general procedure (47 h reaction time),
compound 9l was obtained as a colourless oil in a yield of 70% after
column chromatography on silica gel (CH2Cl2) and as a mixture of diaste-
8348
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 8338 – 8351

Asymmetric Mannich Reactions
FULL PAPER
reoisomers (97:3 diastereomeric ratio, as determined on the crude mix-
ture). The ee value of the product was determined by HPLC with a
Daicel Chiralpak AD-H column (hexane/iPrOH=90:10, flow rate
0.75 mLminÀ1
,
t
major =62.3 min;
t
minor =35.1 min, 95% ee). M.p. 113–
1158C; [a]2D0 =+22 (c=0.95 in CHCl3); 1H NMR (400 MHz, CDCl3): d=
7.37–7.22 (m, 10H), 6.73 (d, J=10.2 Hz, 1H), 5.23 (d, J=10.2 Hz, 1H),
5.02 (d, J=12.1 Hz, 1H), 4.98 (d, J=12.2 Hz, 1H), 3.66 (s, 3H), 2.82 (t,
J=13.3 Hz, 1H), 2.52–2.42 (m, 1H), 2.13–2.03 (m, 1H), 1.93–1.72 (m,
3H), 1.73–1.60 (m, 1H), 1.56–1.32 ppm (m, 3H); 13C NMR (100 MHz,
CDCl3): d=208.6, 171.8, 155.6, 137.8, 136.2, 128.7, 128.4, 128.3, 127.98,
127.94, 66.8, 60.4, 53.4, 52.1, 40.6, 33.5, 30.2, 26.4, 25.5 ppm; ESIMS: m/z:
432 [M++Na].
0.75 mLminÀ1
, major diasteroisomer: tmajor =13.1 min; tminor =18.4 min,
75% ee, enantiomers of the minor diasteroisomer not separated).
1H NMR (400 MHz, CDCl3, major diastereoisomer): d=7.38–7.27 (m,
5H), 5.38 (brd, J=8.5 Hz ,1H), 5.16–4.97 (m, 2H), 4.24–4.12 (m, 1H),
3.71 (s, 3H), 2.61–2.47 (m, 1H), 2.43–2.30 (m, 2H), 2.10–1.84 (m, 3H),
1.25 ppm (d, J=6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3, major diaste-
reoisomer): d=212.1, 170.4, 156.0, 136.4 ,128.4, 128.03, 128.00, 66.7, 64.1,
52.6, 48.8, 37.8, 31.7, 19.1, 17.4 ppm, ESIMS: m/z: 342 [M++Na].
2-(1-Benzyloxycarbonylaminophenylmethyl)-1-oxoindan-2-carboxylic acid
methyl ester (9q): Following the general procedure (39 h reaction time)
by adding K2CO3 (1.5 equiv, 30% w/w) as the base, compound 9q was
obtained after column chromatography on silica gel (hexane/Et2O80:20)
as a colourless oil in a yield of 95% and as a mixture of diastereoisomers
(58:42 diastereomeric ratio, as determined on the crude mixture). The ee
value of the products was determined by HPLC with a Daicel Chiralpak
AD-H column (hexane/iPrOH=85:15, flow rate 0.6 mLminÀ1, major dia-
stereoisomer: tmajor =205.6 min; tminor =58.3 min, 87% ee; minor diastereo-
isomer: tmajor =221.9 min; tminor =90.3 min, 85% ee). 1H NMR (400 MHz,
CDCl3, both diastereoisomers): d=7.76–7.69 (m, 1H), 7.57 (t, J=7.0 Hz,
1H), 7.49 (t, J=7.0 Hz, 1H), 7.41–7.20 (m, 12H), 7.19–7.10 (m, 1H), 7.04
(brd, J=8.8 Hz, 1H), 6.38 (brs, 1H), 5.52 (d, J=9.2 Hz, 1H), 5.31 (brs,
1H), 5.14–4.98 (m, 1H), 3.78 (d, J=17.4 Hz, 1H), 3.70 (s, 3H), 3.68 (s,
3H), 3.47 (d, J=17.4 Hz, 1H), 3.26–3.17 ppm (m, 2H); 13C NMR
(100 MHz, CDCl3, both diastereoisomers): d=198.4, 171.1, 155.7, 151.9,
138.4, 137.2, 136.4, 136.3, 135.7, 135.5, 134.3, 128.5, 128.4, 128.3, 128.2,
128.03, 128.00, 127.9, 126.1, 126.0, 125.1, 124.4, 66.9, 66.8, 58.8, 58.3, 53.0,
36.1, 34.7 ppm; ESIMS: m/z: 452 [M++Na].
1-(1-Benzyloxycarbonylamino-2-methylpropyl)-2-oxocyclopentanecarbox-
ylic acid methyl ester (9m): Following the general procedure (64 h reac-
tion time), compound 9m was obtained as a colourless oil in a yield of
74% after column chromatography on silica gel (hexane/Et2O70:30) and
as a mixture of diastereoisomers (96:4 diastereomeric ratio, as deter-
mined on the crude mixture). The ee value of the products was deter-
mined by HPLC with
iPrOH=80:20, flow rate 0.75 mLminÀ1, major diastereoisomer: tmajor
10.3 min; minor =9.5 min, 74% ee; minor diastereoisomer: tmajor
a Daicel Chiralpak AD-H column (hexane/
=
t
=
13.3 min; tminor =15.6 min, 67% ee). 1H NMR (400 MHz, CDCl3, major
diastereoisomer): d=7.43–7.24 (m, 5H), 5.59 (d, J=10.7 Hz, 1H), 5.12
(d, J=12.2 Hz, 1H), 5.06 (d, J=12.2 Hz, 1H), 3.92 (dd, J=10.5, 4.7 Hz,
1H), 3.69 (s, 3H), 2.62 (dt, J=14.3, 6.5 Hz, 1H), 2.51–2.23 (m, 2H), 2.13–
1.84 (m, 4H), 0.95 (d, J=6.5 Hz, 3H), 0.85 ppm (d, J=6.5 Hz, 3H);
13C NMR (100 MHz, CDCl3, major diastereoisomer): d=210.9, 170.2,
156.9, 136.6, 128.4, 128.0, 127.9, 66.8, 63.5, 57.7, 52.6, 37.5, 31.9, 30.5, 21.8,
19.1, 18.1 ppm; ESIMS: m/z: 370 [M++Na].
2-(Benzyloxycarbonylaminophenylmethyl)-1-oxo-1,2,3,4-tetrahydronaph-
thalene-2-carboxylic acid methyl ester (9r): Following the general proce-
dure (63 h reaction time), compound 9r was obtained as a colourless oil
in a yield of 96% after column chromatography on silica gel (hexane/
EtOAc 80:20) and as a mixture of diastereoisomers (93:7 diastereomeric
ratio, as determined on the crude mixture). The ee value of the products
S-1-(R-1-Benzyloxycarbonylaminocyclohexylmethyl)-2-oxocyclopentane-
carboxylic acid methyl ester (9n): Following the general procedure (84 h
reaction time), compound 9n was obtained as a colourless oil in a yield
of 77% after column chromatography on silica gel (hexane/Et2O80:20)
and as a single diastereoisomer, as determined on the crude mixture. The
ee value of the product was determined by HPLC with a Daicel Chiral-
was determined by HPLC with
(hexane/iPrOH=80:20, flow rate 0.75 mLminÀ1, major diastereoisomer:
major =70.6 min; tminor =76.5 min, 92% ee, enantiomers of the minor dia-
a Daicel Chiralpak AD-H column
pak AD-H column (hexane/iPrOH=80:20, flow rate 0.75 mLminÀ1
major =14.4 min;
minor =17.1 min, 99% ee). [a]2D0 =+43 (c=0.0.87 in
,
t
t
t
CHCl3); 1H NMR (400 MHz, CDCl3): d=7.38–7.27 (m, 5H), 5.57 (brd,
J=10.8 Hz, 1H), 5.13–5.03 (m, 2H), 3.94–3.82 (m, 1H), 3.68 (s, 3H),
2.66–2.54 (m, 1H), 2.49–2.37 (m, 1H), 2.37–2.25 (m, 1H), 2.13–1.84 (m,
3H), 1.81–1.67 (m, 2H), 1.66–1.49 (m, 3H), 1.32–0.97 ppm (m, 6H),
13C NMR (100 MHz, CDCl3): d=211.1, 170.4, 156.8, 136.6 ,128.4, 128.0,
66.8, 66.7, 64.1, 57.3, 40.7, 37.5, 32.1, 31.7, 28.7, 26.4, 25.9, 25.3, 19.1 ppm;
ESIMS: m/z: 410 [M++Na].
stereoisomer not separated); 1H NMR (400 MHz, CDCl3, major diaste-
reoisomer): d=8.01 (dd, J=7.9, 1.1 Hz, 1H), 7.56–7.18 (m, 13H), 6.30
(brd, J=10.5 Hz, 1H), 5.38 (d, J=10.5 Hz, 1H), 5.04 (d, J=12.4 Hz,
1H), 5.00 (d, J=12.4 Hz, 1H), 3.47 (s, 3H), 3.11–3.02 (m, 2H), 2.78–2.66
(m, 1H), 2.36–2.26 ppm (m, 1H); 13C NMR (100 MHz, CDCl3, major dia-
stereoisomer): d=194.5, 170.3, 155.8, 142.3, 138.5, 136.2, 133.8, 132.2,
128.76, 128.70, 128.4, 128.25, 128.20, 128.0, 127.8, 126.9, 125.7, 66.9, 63.0,
58.7, 52.5, 30.7, 25.9 ppm; ESIMS: m/z: 466 [M++Na].
1-(1-Benzyloxycarbonylaminophenylmethyl)-2-oxocyclohexanecarboxylic
acid methyl ester (9o): Following the general procedure (24 h reaction
time) with K3PO4 (5 equiv, 50% w/w) as the base and performing the re-
action at 08C, compound 9o was obtained as a colourless oil in a yield of
77% after column chromatography on silica gel (hexane/Et2O70:30) and
as a mixture of diastereoisomers (97:3 diastereomeric ratio after column
chromatography, 85:15 diastereomeric ratio determined on the crude
mixture). The ee value of the products was determined by HPLC with a
Daicel Chiralpak AD-H column (hexane/iPrOH=95:5, flow rate
0.75 mLminÀ1, major diastereoisomer: tmajor =74.4 min; tminor =39.7 min,
91% ee, minor diastereoisomer: tmajor =48.2 min; tminor =42.0 min, 9% ee).
1H NMR (400 MHz, CDCl3, major diastereoisomer): d=7.40–7.22 (m,
10H), 6.52 (brd, J=9.9 Hz ,1H), 5.25 (d, J=9.9 Hz, 1H), 5.10–4.99 (m,
2H), 3.52 (s, 3H), 2.66–2.55 (m, 1H), 2.55–2.39 (m, 2H), 2.05–1.79 (m,
4H), 1.74–1.60 ppm (m, 1H); 13C NMR (100 MHz, CDCl3, major diaste-
reoisomer): d=208.4, 170.9, 155.9, 138.1, 136.2, 128.4, 128.3, 128.2, 128.1,
128.0, 127.9, 66.9, 66.8, 58.4, 52.2, 40.8, 34.8, 27.7, 27.8 ppm; ESIMS: m/z:
418 [M++Na].
Acknowledgements
We acknowledge financial support by the Consorzio CINMPIS and Ster-
eoselezione in Sintesi Organica Metodologie e Applicazioni 2005. D.P. is
grateful for a post-doctoral fellowship received from the Blanceflor foun-
dation, Sweden. The financial support of a Merck-ADP grant is also
gratefully recognised.
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Chem. Eur. J. 2007, 13, 8338 – 8351
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´
´
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8350
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Asymmetric Mannich Reactions
FULL PAPER
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Received: June 15, 2007
Published online: August 20, 2007
Chem. Eur. J. 2007, 13, 8338 – 8351
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8351