Highly practical BINOL-derived acid-base combined salt catalysts for the asymmetric direct mannich-type reaction

Article abstract of DOI:10.1055/s-0030-1258296

The catalytic asymmetric direct Mannich-type reaction between aldimines and 1,3-dicarbonyl compounds is one of the most important carbon-carbon bond-forming reactions in organic chemistry. The resulting Mannich adducts can be efficiently transformed into pharmaceutically useful, optically active -amino ketones, -amino esters, -lactams, etc. In the course of our study of chiral acid-base combined salt catalysts for asymmetric reactions, we developed a series of simple, practical, chiral BINOL-derived salt catalysts, such as chiral pyridinium 1,1-binaphthyl-2,2-disulfonates 1, chiral lithium(I) binaphtholate 2, chiral magnesium(II) binaphtholate (3), chiral calcium(II) phosphate 4, and chiral phosphoric acid 5, which were particularly effective for direct Mannich-type reactions. 1 Introduction 2 1,1-Binaphthyl-2,2-disulfonic Acid (BINSA)-Pyridinium Salts 3 Lithium(I) Binaphtholate Salts 4 Magnesium(II) Binaphtholate Salts 5 Calcium(II) Phosphate Salts and Chiral Phosphoric Acids 6 Conclusions. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1258296

FEATURE ARTICLE
3785
Highly Practical BINOL-Derived Acid–Base Combined Salt Catalysts for the
Asymmetric Direct Mannich-Type Reaction
Asymmetric
D
irect Ma
a
nnich-Type
n
Catalysis abu Hatano,a Kazuaki Ishihara*a,b
a
Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa, Nagoya, 464-8603, Japan
Japan Science and Technology Agency (JST), CREST, Furo-cho, Chikusa, Nagoya, 464-8603, Japan
Fax +81(52)7893222; E-mail: ishihara@cc.nagoya-u.ac.jp
b
Received 17 September 2010
the 3,3¢-positions by sterically demanding or functional
groups, and easily transformed by changing the OH
groups at the 2,2¢-positions into other functional groups.
In the course of our study on the design of chiral acid–base
Abstract: The catalytic asymmetric direct Mannich-type reaction
between aldimines and 1,3-dicarbonyl compounds is one of the
most important carbon–carbon bond-forming reactions in organic
chemistry. The resulting Mannich adducts can be efficiently trans-
formed into pharmaceutically useful, optically active b-amino ke- combined catalysts for asymmetric reactions involving
tones, b-amino esters, b-lactams, etc. In the course of our study of
chiral acid–base combined salt catalysts for asymmetric reactions,
we developed a series of simple, practical, chiral BINOL-derived
salt catalysts, such as chiral pyridinium 1,1¢-binaphthyl-2,2¢-disul-
fonates 1, chiral lithium(I) binaphtholate 2, chiral magnesium(II)
binaphtholate (3), chiral calcium(II) phosphate 4, and chiral phos-
phoric acid 5, which were particularly effective for direct Mannich-
type reactions.
carbon–carbon bond formation, we have developed a sim-
ple family of chiral binaphthyl-derived salt catalysts.5
With regard to the asymmetric direct Mannich-type reac-
tion, chiral acid–base combined salt catalysts would be
highly attractive since they should activate the substrates
(aldimines) and reagents (1,3-dicarbonyl compounds) on
the acid moiety and the base moiety, respectively. Gener-
ally, the reactivity of 1,3-dicarbonyl compounds varies
among diketones, ketoesters, ketolactones, diesters (mal-
onates), ketoamides, ketothioesters, and dithioesters (thi-
omalonates).6 Therefore, Brønsted base-assisted effective
a-deprotonation from less-reactive 1,3-dicarbonyl com-
pounds leading to the corresponding enolates should be
critical, since keto/enol equilibrium is usually disfavor-
able for the corresponding enolates. To address the prob-
lem of the reactivity of 1,3-dicarbonyl compounds, we
consider simple, three catalytic systems (types a–c): (a)
Brønsted acid–Brønsted base combined salts, (b) cation–
anion pair salts, and (c) cation–anion conjugate salts
(Scheme 1). Overall, the driving force of direct Mannich-
type reactions should be controlled by the balance be-
tween the Brønsted or Lewis acidity and the Brønsted ba-
sicity in these acid–base catalysts. Here we report the
development of chiral acid–base combined salt catalysts
for use in asymmetric direct Mannich-type reactions, such
as chiral pyridinium 1,1¢-binaphthyl-2,2¢-disulfonates 1
(type a), chiral lithium(I) binaphtholates 2 (type b), chiral
magnesium(II) binaphtholates (3, type b), chiral calci-
um(II) phosphates 4 (type c), and chiral phosphoric acids
5 (type c) (Figure 1).
1
2
Introduction
1,1¢-Binaphthyl-2,2¢-disulfonic Acid (BINSA)–Pyridinium
Salts
3
4
5
6
Lithium(I) Binaphtholate Salts
Magnesium(II) Binaphtholate Salts
Calcium(II) Phosphate Salts and Chiral Phosphoric Acids
Conclusions
Key words: acid–base combined salt catalyst, aldimine, asymmet-
ric catalysis, 1,3-dicarbonyl compound, direct Mannich-type reac-
tion
1
Introduction
Optically active a-branched amines are common, biolog-
ically active compounds that are widely found in natural
products and medicines. The asymmetric direct Mannich-
type reaction between aldimines and carbonyl compounds
is highly useful for the synthesis of chiral building blocks
of b-carbonyl-a-branched amines, i.e., b-amino carbonyl
compounds (Scheme 1).1 Due to the importance of these
enantio-enriched derivatives such as b-lactams in biolog-
ical and pharmaceutical chemistry, considerable effort has
been devoted over the last decade to establishing method-
ology for direct Mannich-type reactions with chiral metal
catalysts2 or organocatalysts.3 Among these catalysts, a
chiral binaphthyl skeleton has often been used since chiral
1,1¢-bi-2-naphthol (BINOL),4 as the origin of chiral auxil-
iary, is commercially available in bulk quantities as both
R- and S-enantiomers, inexpensive, easily substituted at
2
1,1¢-Binaphthyl-2,2¢-disulfonic Acid
(BINSA)–Pyridinium Salts7
Chiral organic salts of Brønsted acids and Brønsted bases,
such as ammonium sulfonates,8,9 are some of the most
promising catalysts in modern asymmetric syntheses
(Scheme 1, type a). In general, acid–base-combined salts
have several advantages over single-molecule catalysts
with regard to flexibility in the design of their dynamic
complexes. In this context, 1,1¢-binaphthyl-2,2¢-disulfon-
SYNTHESIS 2010, No. 22, pp 3785–3801
x
x.
x
x
.
2
0
1
0
Advanced online publication: 14.10.2010
DOI: 10.1055/s-0030-1258296; Art ID: Z23510SS
© Georg Thieme Verlag Stuttgart · New York

3786
M. Hatano, K. Ishihara
FEATURE ARTICLE
R2
R1
H
*
ic acid (BINSA, 6) should be a promising chiral Brønsted
acid catalyst, since both the Brønsted acidity and bulki-
ness can be easily controlled by complexation with achiral
amines (Scheme 2). Remarkably, unlike common binaph-
thyl compounds, considerable bulkiness can be achieved
in situ without directly introducing substituents at the 3,3¢-
positions in the binaphthyl skeleton. However, at the start
of our study, there had been no reports on the practical ap-
plications of chiral 6 in asymmetric catalyses after the first
synthesis of racemic 6 in 1928 by Barber and Smiles.10,11
chiral acid–base
salt catalysts
O
N
*
O
O
R2
N
R5
R3
R5
+
R4
R3
R1
H
H
R4
C–C bond formation
O
chiral β-amino
carbonyl compounds
type a: Brønsted acid–Brønsted base combined salts
R
R
+
X–
+
R
N
H
X
R
N
H
R
R
type b: cation–anion pair salts
First, we examined the efficient synthesis of (R)-BINSA
(6) from (R)-BINOL via the oxidation of dithiol as a key
reaction (Scheme 3). Thermolysis in the Newman–Kwart
rearrangement was dramatically improved by using a mi-
crowave technique at a milder temperature (200 °C) than
reported.12,13 For the key step of the oxidation of thiols to
sulfonic acids, the unprecedented oxidation of dithiol (R)-
7 proceeded smoothly to give the product in 82% yield
without epimerization under 7 bar of oxygen/potassium
– HX
–
M+
R
O
H
X M
+
R
O
type c: cation–anion conjugate salts
δ–
O
R
O
δ+
R
R
M
P
M
P
R
O
O
Scheme 1 Catalytic asymmetric direct Mannich-type reactions
Biographical Sketches
Manabu Hatano was born ciate professor in 2007. He istry, Japan (2007). His re-
in Tokyo, Japan, in 1975, has received the Tejima Re- search interests include
and received his Ph.D. from search Award for Young asymmetric catalysis with
the Tokyo Institute of Tech- Scientists
(2004),
the carbon–carbon bond-form-
nology in 2003 under the di- TORAY Award in Synthet- ing reactions with chiral
rection of Professor Koichi ic Organic Chemistry, Japan acid–base salt catalysts, the
Mikami. He was a JSPS Fel- (2006), the Lectureship chemistry of ate complexes
low under the Japanese Jun- Award of the Young Gener- for efficient catalytic asym-
ior Scientists Program from ation Special Forum from metric reactions, and the de-
2000 to 2003. In 2003, he the Chemical Society of Ja- sign
of
chiral
self-
joined Professor Kazuaki pan (2007), and the Encour- assembled complexes to-
Ishihara’s group at Nagoya agement Prize from the ward supramolecular asym-
University as an assistant Tokai Branch of the Society metric catalysts.
professor, and became asso- of Synthetic Organic Chem-
Kazuaki Ishihara was born turned to Japan and joined (2003), the JSPS Prize
in Aichi, Japan, in 1963, and Professor Hisashi Yamamo- (2005), the BCSJ Award
received his Ph.D. from to’s group at Nagoya Uni- (2005), the 0th International
Nagoya University in 1991 versity as an assistant Conference on Cutting-
under the direction of Pro- professor in 1992, and be- Edge Organic Chemistry in
fessor Hisashi Yamamoto. came associate professor in Asia Lectureship Award
He had the opportunity to 1997. In 2002, he was ap- (2006), Japan/UK GSC
work under the direction of pointed to his current posi- Symposium
Lectureship
Professor Clayton H. Heath- tion as a full professor at (2007), the IBM Japan Sci-
cock at the University of Nagoya University. He has ence Prize (2007), and the
California, Berkeley, as a received the Inoue Research Mukaiyama Award (2009).
visiting graduate student for Award for Young Scientists His research interests in-
three months in 1988. He (1994), the Chemical Soci- clude asymmetric catalysis,
was a JSPS Fellow under ety of Japan Award for biomimetic catalysis in-
the Japanese Junior Scien- Young Chemists (1996), the duced by artificial enzymes,
tists Program from 1989 to Thieme Chemistry Journal dehydrative condensation
1991. After he completed Award (2001), the Green catalysis toward green and
his postdoctoral studies with and Sustainable Chemistry sustainable chemistry, and
Professor E. J. Corey at Har- Award from the Ministry of acid–base
vard University (15 months Education, Culture, Sports, chemistry.
beginning in 1991), he re- Science, and Technology
combination
Synthesis 2010, No. 22, 3785–3801 © Thieme Stuttgart · New York

FEATURE ARTICLE
Asymmetric Direct Mannich-Type Catalysis
3787
type a:
S
1) NaH, DMF
OH
OH
O
O
NMe2
NMe2
Ar
HN
Ar
2) ClC(=S)NMe2
85 °C, 2 h
SO3
SO3
S
(R)-BINOL, 13.6 g
19.3 g, 88%
2
1
O
microwave
(300 W)
type b:
S
S
NMe2
Ar
NMe2
200 °C
O
O
O
O
10–20 min
Li(t-BuOH)2
Mg
14.5 g, 75%
O
H
1) O2 (7 bar)
Ar
KOH, HMPA
80 °C, 5 d
3
2
LiAlH4
SH
SH
SO3H
SO3H
2) H+
type c:
THF
reflux, 4 h
Ar
Ar
O
7, 9.6 g, 95%
(R)-BINSA (6)
O
O
O
O
10.2 g, 82%
P
P
Ca
O
O
O
Scheme 3 Synthesis of (R)-BINSA 6 from (R)-BINOL
Ar
Ar
4
lutidine was not effective, partially due to the lower solu-
bility of the corresponding salts. In sharp contrast, 2,6-di-
tert-butylpyridine improved the enantioselectivity to 76%
ee. Ultimately, we found that 2,6-diphenylpyridine (11a),
which led to a homogeneous catalyst in situ, was an opti-
mal amine, and 10a was obtained in 74% yield with 92%
ee. Interestingly, the enantioselectivity of 10a was dra-
matically improved when a greater than 1:1 ratio of 6/11a
was examined. However, the addition of excess equimolar
amounts of 11a (15 mol%) per 6 had a slightly negative
influence on the catalytic activity. The wide range of suit-
able ratios of 6/11a may reflect the postulated dynamic
structure of the catalysts (Scheme 2).
Ar
O
O
P
OH
O
Ar
5
Figure 1 BINOL-derived acid–base combined salt catalysts 1–5
R
N
H
R
N
H
R
R
R
R
+ NR3
– NR3
SO3
SO3
SO3
SO3H
With the optimized reaction conditions in hand, we next
examined the scope of aldimines and 1,3-dicarbonyl com-
pounds (Table 2). Fortunately, with the use of 1 mol% of
6·(11a)2, 10a was obtained in 91% yield with 90% ee. Un-
der these optimized conditions, N-Boc-Mannich product
H
N
R
R
R
Scheme 2 Dynamics of BINSA 6–ammonium salts in situ
Table 1 Screening of BINSA 6–Pyridinium Salts
hydroxide in hexamethylphosphoramide after optimiza-
tion of the reaction conditions. After protonation by ion-
exchange, compound (R)-6 could be prepared, in >10-
gram scale, in 51% yield over five steps from (R)-BINOL,
or in 82% yield in one step from commercially available
dithiol (R)-7.
Cbz
Cbz
6 (5 mol%)
amine (0–15 mol%)
NH
(R)
N
O
O
Ac
+
Ph
Ph
H
CH2Cl2, 0 °C, 30 min
Ac
9a (1.1 equiv)
8a
10a
amine, yield, and enantioselectivity
As a probe reaction,3a,14 we examined the catalytic enanti-
oselective direct Mannich-type reaction between N-Cbz-
phenylaldimine 8a and acetylacetone (9a) in dichlo-
romethane at 0 °C for 30 minutes. The enantioselectivity
of 10a was low (17% ee) when 5 mol% of 6 was used
without amines (Table 1). However, we found that 6–
achiral amine combined salts as chiral Brønsted acid–base
catalysts prepared in situ were effective (Scheme 1,
Figure 1, type a). The preliminary results with 6 (5
mol%)–amines (10 mol%) suggested that pyridines with
weak Brønsted basicity would be better Brønsted bases.
Even then, the use of pyridine, 2-phenylpyridine, or 2,6-
none
N
Ph
N
81%, 17% ee
8%, 5% ee
(10 mol%)
11%, 10% ee
(10 mol%)
t-Bu
N
t-Bu
N
Ph
N
Ph
11a
19%, 0% ee
(10 mol%)
32%, 76% ee
(10 mol%)
83%, 34% ee (2.5 mol%)
82%, 84% ee (5 mol%)
74%, 92% ee (10 mol%)
68%, 86% ee (15 mol%)
Synthesis 2010, No. 22, 3785–3801 © Thieme Stuttgart · New York

3788
M. Hatano, K. Ishihara
FEATURE ARTICLE
10b was obtained in 99% yield with 84% ee. From 9a and
a variety of N-Cbz-arylaldimines bearing electron-donat-
ing or electron-withdrawing groups in the aryl moiety, the
corresponding adducts 10c–h were obtained in high to ex-
cellent yields (92–>99%) and with high enantioselectivi-
ties (89–98% ee). When other diketones such as heptane-
3,5-dione and 1,3-diphenylpropane-1,3-dione were react-
ed with 8a, the corresponding adducts 10i and 10j were
obtained with 95% ee and 84% ee, respectively. More-
over, a cyclic 1,3-diketone could also be used, and the cor-
responding adduct 10k with a quaternary carbon center
was obtained in 98% yield with a syn/anti diastereomer
ratio of 83:17 and high enantioselectivity (91% ee, syn).
+
6
Ar
N
Ar
(5 mol%)
Cbz
H
O
O
O
N
11 (10 mol%)
+
N
O
Ph
CH2Cl2, 0 °C, 30 min
8a (1.5 equiv)
12
Cbz
NH
Cbz
Ph
O
O
NH
NaOMe
MeOH, 0 °C, 30 min
CO2Me
Ph
N
O
Ac
13
with 11a (Ar = Ph):
Ac
14, 62%
86% (dr = 53:47), 48% ee
with 11b (Ar = 2,4,6-Me3C6H2):
81% (dr = 60:40), 92% ee
Table 2 BINSA 6–Pyridinium Salt Catalysis
Scheme 4 Reaction of ketoamide 12
R1
R1
H
6 (1 mol%)
NH
O
O
N
O
O
In this reaction, BINSA (6) was found to be a highly ef-
fective chiral Brønsted acid that could be combined with
an achiral Brønsted base (Scheme 1, Figure 1, type a).
Combination of the achiral bulky 2,6-diarylpyridine 11
with 6 circumvented the trouble of having to build bulky
substituents at the 3,3¢-positions as is normally required
with analogous binaphthyl phosphoric acid catalysts. We
believe that BINSA should be a powerful chiral auxiliary
like BINOL, BINAP [2,2¢-bis(diphenylphosphino)-1,1¢-
binaphthalene], BINAM (2,2¢-diamino-1,1¢-binaphtha-
lene), etc., and could open a new frontier in acid–base
chemistry in asymmetric catalyses. In fact, we and other
research groups later developed BINSA derivatives and
their asymmetric catalyses, and we suspect that BINSA
catalysis will be developed further.15
11a (2 mol%)
+
Ar
R2
R2
R2
Ar
CH2Cl2, 0 °C, 30 min
R2
8
9 (1.1 equiv)
10
product, yield, and enantioselectivity
Cbz
NH
Cbz
Cbz
Ph
Boc
Ph
NH
NH
NH
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
10a
10b
10c
99%, 96% ee
10d
91%, 90% ee
99%, 84% ee
99%, 89% ee
Cbz
Cbz
Cbz
NH
NH
Ac
NH
Ac
Ac
Ac
Br
Ac
Ac
MeO
Cbz
10e
10f
10g
95%, 96% ee
92%, 98% ee
99%, 96% ee
3
Lithium(I) Binaphtholate Salts16
Cbz
NH
Cbz
NH
Cbz
NH
NH
O
O
O
Ac
Ph
Et Ph
Ph
A chiral Li(I)–BINOLate salt is one of the simplest acid–
base bifunctional catalysts.17 In landmark work, Kagan
and Holmes developed the trimethylsilylcyanation of al-
dehydes with the use of anhydrous chiral Li(I)–BINOLate
salts.18 Later, we reported that aqueous or alcoholic Li(I)–
BINOLate salts showed dramatically improved catalytic
activity as Lewis acid–Lewis base catalysts for trimethyl-
silylcyanation by activating both the aldehyde and cyan-
otrimethylsilane.19 Moreover, an interesting changeover
of the stereochemistry of the products was observed with
aqueous or alcoholic catalysts in place of anhydrous cata-
lysts. In the further study of Li(I)–BINOLate salts based
on the strong basicity of naphtholate oxygen, Li(I)–
BINOLate salts should be good Lewis acid–Brønsted base
catalysts, which activate both the substrate and the acidic
pronucleophile (Scheme 1, Figure 1, type b).
Ph
Ac
S
Ac
O
Et
O
Ph
10h
98%, 98% ee
10i
10j
10k
95%, 95% ee
>99%, 84% ee
98% (syn/anti = 83:17)
91% ee (syn)
A suitable chiral ammonium salt was easily tailor-made
for a ketoester equivalent such as 3-acetoacetyloxazoli-
din-2-one (12) (Scheme 4). The chiral ammonium salt
6·(11a)2, which was optimized for the previous reaction,
was not effective, and the desired product 13 was obtained
in 86% yield with low diastereo- and enantioselectivities.
In contrast, the enantioselectivity of 13 increased to 92%
ee when 2,6-dimesitylpyridine (11b) was used in place of
11a. In this way, the use of tailor-made salts 6·(11)2 made
it possible to avoid preparing single-molecule catalysts in
advance and offered a quick solution to this type of opti- By taking advantage of studies on Li(I)–BINOLate-cata-
mization problem. Note that compound 13 was easily lyzed trimethylsilylcyanation, we found that the mono-
transformed to b-amino carbonyl compound 14 via depro- lithium salt of 3,3¢-Ar2-BINOL in the presence of tert-
tection of the oxazolidinone moiety without loss of enan- butyl alcohol was effective. In particular, 3,3¢-(3,4,5-
tioselectivity.
F3C6H2)2-BINOL (15) was the most promising, and we
performed a direct Mannich-type reaction between N-Boc
Synthesis 2010, No. 22, 3785–3801 © Thieme Stuttgart · New York

FEATURE ARTICLE
Asymmetric Direct Mannich-Type Catalysis
3789
OTMS
OTMS
CN
Table 3 Reaction of Acyclic 1,3-Dicarbonyl Compounds
O
Li(I) salt catalysts
+
+
TMSCN
Ar
CN
Ar
(R)
(S)
Ar
H
15 (5 mol%)
Boc
O
NH
n-BuLi (5 mol%)
Boc
H
O
O
N
t-BuOH (10 mol%)
R1
O
O
Ar
+
OLi
OH
R1
(1.1 equiv)
diketone, ketoester
ketoamide, ketothioester
Product, yield, diastereoselectivity, and enantioselectivity
R2
H
O
Ar
Li(ROH)n
toluene, –78 °C, 2 h
R2
8
H
anhydrous Li(I) catalyst
[to give (R)-products]
aqueous or alcoholic Li(I) catalyst
[to give (S)-products]
Boc
Ph
Boc
Ph
Boc
Ph
Scheme 5 Trimethylsilylcyanation of aldehydes by Li(I)–BINOLates
O
NH
H
NH
H
NH
Ac
Ac
Et
CO2Et
CO2Me
Ac
aldimines and some 1,3-dicarbonyl compounds. In sum-
mary, an interesting changeover of both the diastereo-
selectivity and absolute stereochemistry was observed
between the acyclic 1,3-dicarbonyl compound 16a and the
cyclic compound 16b (Scheme 6). syn-Product 17b was
obtained from cyclic pronucleophiles while anti-product
17a was obtained from acyclic pronucleophiles.
10b, >99%
17c, 97%
syn/anti = 5:95
85% ee (anti)
17d, 97%
82% ee
syn/anti = 10:90
86% ee (anti)
Boc
Boc
NH
Ac
H
NH
Ac
Ph
H
O
MeO
O
NMe2
SEt
17f, 97%
17e, 93%
15 (5 mol%)
syn/anti = 4:99
84% ee (anti)
syn/anti = 9:91
97% ee (anti)
Boc
O
NH
n-BuLi (5 mol%)
Boc
H
O
O
N
t-BuOH (10 mol%)
Ph
+
OEt
Ph
toluene, –78 °C, 2 h
CO2Et
Next, we investigated cyclic 1,3-dicarbonyl compounds
(Table 4). For methyl 2-oxocyclohexanecarboxylate
(16c), a variety of aryl aldimines with an electron-
withdrawing group or an electron-donating group and
heteroaryl aldimines were acceptable. The reactions
proceeded smoothly in toluene at –78 °C within two hours
in the presence of 2.5 mol% of the catalyst. The desired
products were obtained in high yields with high syn-dia-
stereoselectivities (syn/anti 88:12–97:3) and high enan-
tioselectivities (87–95% ee). One mol% of the catalyst
was still effective, and 17g was obtained in 97% yield
with high diastereo- and enantioselectivity. Since the ob-
served TOF was 284 h–1 (71% yield at 3 min for 17g), the
high reactivity of this catalyst is quite unlike those of other
conventional catalysts.1–3 Moreover, another advantage is
that inexpensive lithium hydroxide can be used as a lithi-
um precursor in place of n-butyllithium/tert-butyl alcohol
in the synthesis of 17g.
17a
8b
16a
(1.1 equiv)
>99% (syn/anti = 4:96)
91% ee (anti)
15 (5 mol%)
n-BuLi (5 mol%)
t-BuOH (10 mol%)
Boc
O
O
NH
Boc
O
N
OEt
+
Ph
EtO2C
Ph
H
toluene, –78 °C, 2 h
17b
16b
(1.1 equiv)
8b
96% (syn/anti = 96:4)
97% ee (syn)
F
F
F
OH
OH
F
F
15
F
To demonstrate the synthetic utility of this approach, the
obtained adduct 17g (90% ee) was transformed to the use-
ful spiro-b-lactam 18 (Scheme 7). Diastereoselective re-
duction of 17g by sodium borohydride was conducted,
followed by deprotection of the amino moiety by trifluo-
roacetic acid and protection of the alcohol with tert-
butyldimethylsilyl chloride. Subsequent cyclization by
treatment with lithium diisopropylamide gave spiro-b-
lactam 18 with three consecutive chiral carbon centers in
a highly diastereo- and enantioselective manner.
Scheme 6 Reaction of acyclic and cyclic ketoesters with a chiral
Li(I)–BINOLate salt
First, we explored the scope of the diastereo- and enantio-
selective direct Mannich-type reaction with a class of
acyclic 1,3-dicarbonyl compounds by using 15 (5 mol%),
n-butyllithium (5 mol%), and tert-butyl alcohol (10 mol%)
in toluene at –78 °C for two hours (Table 3). A diketone,
ketoesters, ketoamide, and ketothioester gave the corre-
sponding products 10b, 17c–f with high enantioselectivi-
ties (82–97% ee). Notably, anti-products 17c–f were
selectively obtained from acyclic reagents without
epimerization at the a-tertiary carbon center. These results
are valuable since previous catalysts often gave syn/anti
mixtures, or the stereochemistry has not yet been deter-
mined.
Moreover, from an S-heterocyclic ketoester 16d, the de-
sired adduct 17o was obtained in 90% yield with a syn/
anti ratio of 88:12 with 93% ee (syn) (Scheme 8). Subse-
quent reduction by sodium borohydride and desulfuriza-
tion with Raney nickel gave the valuable acyclic b-amino
Synthesis 2010, No. 22, 3785–3801 © Thieme Stuttgart · New York

3790
M. Hatano, K. Ishihara
FEATURE ARTICLE
Boc
Table 4 syn-Enantioselective Reaction
O
S
NH
O
15 (5 mol%)
Boc
H
CO2Me
N
n-BuLi (5 mol%)
Ph
Boc
Ar
+
15 (2.5 mol%)
O
Boc
H
NH
O
t-BuOH (10 mol%)
toluene, –78 °C, 2 h
MeO2C
N
Ph
n-BuLi (2.5 mol%)
CO2Me
S
+
17o, 90%
Ar
t-BuOH (5 mol%)
16d (1.1 equiv)
8b
MeO2C
syn/anti = 88:12
93% ee (syn)
toluene, –78 °C, 2 h
17 (syn)
16c (1.1 equiv)
8
Boc
Boc
product, yield, diastereoselectivity, and enantioselectivity
Raney Ni
H2 (1 bar)
NH OH
NH OH
NaBH4
Boc
Boc
Ph
Ph
NH
O
NH
MeOH
THF–EtOH
0 °C, 0.5 h
O
MeO2C
MeO2C
reflux, 4 h
S
Ph
MeO2C
19, 78%, 93% ee
(single diastereomer)
>99% conv.
(84% dr)
MeO2C
17g
17h
98% (71% for 3 min; TOF = 284 h–1
syn/anti = 88:12, 91% ee (syn)
)
93%, syn/anti = 88:12
93% ee (syn)
Scheme 8 Transformation to an acyclic b-aminodicarbonyl com-
pound
[97%, syn/anti = 90:10, 84% ee (syn)]a
[96%, syn/anti = 92:8, 90% ee (syn)]b
O
15 (5 mol%)
Boc
H
N
n-BuLi (5 mol%)
Boc
Boc
Boc
CO2Me
+
NH
NH
NH
O
O
O
ROH (10 mol%)
Ph
MeO
Cl
toluene, –78 °C, 2 h
16e (1.1 equiv)
8b
MeO2C
MeO2C
17k
94%, syn/anti = 96:4
90% ee (syn)
MeO2C
Boc
Ph
Boc
Ph
O
O
NH
NH
17i
17j
93%, syn/anti = 88:12
93% ee (syn)
95%, syn/anti = 96:4
95% ee (syn)
+
MeO2C
syn-17p
t-BuOH: >99%, syn/anti = 52:48, 90% ee (syn), 97% ee (anti)
3,5-xylenol : 95%, syn/anti = 61:39, 43% ee (syn), 93% ee (anti)
MeO2C
anti-17p
Boc
NH
Boc
Boc
NH
NH
O
O
O
O
S
MeO2C
MeO2C
MeO2C
Scheme 9 Reaction of a ketoester with a five-membered ring
17l
17m
17n
96%, syn/anti = 91:9
91% ee (syn)
>99%, syn/anti = 95:5
87% ee (syn)
>99%, syn/anti = 97:3
95% ee (syn)
As shown in Tables 3 and 4 and Scheme 9, anti-products
were generally obtained from acyclic pronucleophiles,
while syn-products were generally obtained from cyclic
pronucleophiles. Opposite absolute configurations at the
amino-carbon center were observed among these syn- and
anti-products. These results, which are shown in Figure 2,
strongly suggest that the syn- and anti-isomers were ob-
tained thorough different reaction pathways, based mainly
on structural and/or conformational differences and the
acidity of 1,3-dicarbonyl compounds. In particular, cyclic
ketoester 16e with a five-membered ring has an interme-
diate nature, related to its conformation and acidity,6,20
among the 1,3-dicarbonyl compounds that were exam-
ined. Since 16c and 16e should exhibit six- and five-
membered ring chelation, respectively, 16c would be
more likely to chelate the lithium(I) center than 16e, even
though these compounds have similar pKa values.
a 15 (1 mol%), n-BuLi (1 mol%), t-BuOH (2 mol%).
b LiOH (2.5 mol%) was used in place of n-BuLi and t-BuOH.
Boc
NH
O
1) NaBH4, THF–EtOH, 0 °C
2) CF3CO2H, CH2Cl2, r.t.
Ph
MeO2C
3) TBSCl, imidazole, DMF, r.t.
17g (90% ee)
O
OTBS
NH2 OTBS
LDA
HN
Ph
THF, –40 °C
MeO2C
Ph
18, 90% ee
Scheme 7 Transformation to a spiro-b-lactam
carbonyl compound 19 with three consecutive chiral car-
Two major mechanisms can be considered (Figure 3). On
one hand, the aldimine would be activated by the Lewis
acidic lithium(I) center (path A). On the other hand, the
pronucleophile would be activated as a lithium enolate
(path B). In both paths, the addition of tert-butyl alcohol
would promote the dissociation to a monomeric precursor,
Li(I)–BINOLate·(t-BuOH)n. Since a more acidic acyclic
1,3-dicarbonyl compound would have a rather flexible
conformation, activation of the aldimine on the lithium(I)
center would be likely (path A). In path A, alcohols (t-
BuOH or 3,5-xylenol) would still coordinate to the lithi-
um(I) center, which would not strongly affect the enantio-
selectivity even in the case of 16e (Scheme 9, anti-17p).
bons involving a methyl-substituted quaternary center.
In place of 16c with a six-membered ring, when 16e with
a five-membered ring was used, a mixture of syn- and
anti-isomers was obtained at a low diastereomeric ratio of
52:48, with high enantioselectivities (90% ee and 97% ee,
respectively) (Scheme 9). Very interestingly, we also
found that the syn- and anti-isomers 17p showed different
absolute configurations at the amino-carbon center. More-
over, when 3,5-xylenol was used in place of tert-butyl al-
cohol, 17p was obtained in a similar diastereoselectivity
(syn/anti = 61:39), and the enantioselectivity of syn-17p
decreased significantly to 43% ee.
Synthesis 2010, No. 22, 3785–3801 © Thieme Stuttgart · New York

FEATURE ARTICLE
Asymmetric Direct Mannich-Type Catalysis
3791
conformationally
F
path A:
O
O
O
O
O
O
O
O
flexible
F
OMe
Boc
Ar
H
OMe
O
OMe
O
NH
O
O
F
RO
Ln
16e
16c
Li
O
O
RO2C
N
more acidic
8.94
acidity:
H
anti
O
(pKa, ref. 20)
10.67
12.00
12.04
F
more chelatable
conformation:
product:
F
F
F
F
Boc
Boc
path B:
NH
O
O
NH
F
H
O
Ph
MeO2C
Ph
MeO2C
O
Li
N
O
Boc
Ar
NH
O
O
O
syn-17g
syn-17p
OR
O
H
+
RO2C
Boc
Ph
Boc
Ph
F
Boc
O
NH
NH
NH
syn
Ac
H
conformationally
rigid
F
Ac
F
Ph
MeO2C
CO2Me
Ac
Figure 4 Possible transition states (L = t-BuOH)
anti-17q
anti-17c
10b
Figure 2 Relation of stereochemistry
4
Magnesium(II) Binaphtholate Salts21
In sharp contrast, a less acidic cyclic 1,3-dicarbonyl com-
pound would be preferentially activated as a lithium eno-
late since the conformationally rigid structure could
promote chelation to the lithium(I) center (path B).
Ligand 15, which is then protonated via lithium enoliza-
tion, would activate the aldimine through hydrogen bond-
ing. However, 3,5-xylenol (pKa = 10.1), which is more
acidic than tert-butyl alcohol (pKa = 15.3), might compete
with 15 (pKa = 7.2) and could trigger a nonselective path-
way, particularly in the case of 16e (Scheme 9, syn-
17p).20 Therefore, we conjectured that syn-isomers would
be obtained via path B, while anti-isomers would be ob-
tained via path A (Figure 4). In path A, a pronucleophile
would be activated by coordination with a Brønsted basic
naphtholate oxygen, followed by attack of the lithium-
coordinated aldimine on the re-face. In path B, the ald-
imine would be activated on a resulting Brønsted acidic
naphthol proton, and the lithium enolate would attack the
aldimine on the si-face.
As shown in Section 3, we developed chiral Li(I)–
BINOLate salts as effective acid–base catalysts for direct
Mannich-type reactions with 1,3-diketones, 1,3-ketoesters,
1,3-ketoamides, and 1,3-ketothioesters. However, mal-
onates could not be used even in the active lithium(I) ca-
talysis (Scheme 10). Among 1,3-dicarbonyl compounds,
the inherent difficulty of the direct Mannich-type reaction
with malonates is due to their weak acidity and stronger
chelation to the metal center without the generation of an
activated metal enolate.6 To overcome these problems, we
next examined a cooperative acid–base catalyst with diva-
lent group II elements instead of lithium(I). An uncom-
mon but easily prepared chiral Mg(II)–BINOLate salt22 is
particularly attractive (Scheme 1, Figure 1, type b). It
should have enough Brønsted basicity to generate the
magnesium(II) enolate in situ without the release of
BINOL, as shown in Figure 5. Therefore, when this coop-
erative acid–base Mg(II) salt catalyst activates both ald-
imine and malonate, a divalent magnesium(II) center
would be firmly bound to both BINOL and malonate
through ionic and coordinate bonds. As expected, Mg(II)–
BINOLate effectively catalyzed the reaction of N-Boc
aldimine 8b with dimethyl malonate (20a), and the corre-
sponding product 21a was obtained in 98% yield with
92% ee when 5 mol% each of BINOL and dibutylmagne-
sium were used in the presence of magnesium sulfate as a
drying reagent in toluene at –40 °C for six hours
(Scheme 10).
path A:
O
Ar2
O
H
Ar2
O
H
H
O
O
O
O
t-Bu
Boc
H
H
O
N
t-Bu
Li
H
Li
Boc
H
O
O
N
H
Ar1
Ar2
Ar2
Ar1
Boc
H
path B:
N
Ar2
O
Ar2
R
O
R
Ar1
H
Li
H
H
Li
O
Boc
O
(R)-BINOL (5 mol%)
O
O
O
O
NH
Boc
H
O
O
N
MX (5–10 mol%)
+
Ph
OMe
OMe
O
N
O
O
MeO
OMe toluene, –40 °C, 6 h
Ph
H
Ar2
Ar2
O
Boc
H
20a (1.1 equiv)
8b
21a
Ar1
n-BuLi (5 mol%) + t-BuOH (10 mol%): 98%, 0% ee
n-Bu2Mg (5 mol%) (MgSO4): 98%, 92% ee
Figure 3 Possible reaction pathways
Scheme 10 Catalysis by Li(I)– or Mg(II)–BINOLate salts
Synthesis 2010, No. 22, 3785–3801 © Thieme Stuttgart · New York

3792
M. Hatano, K. Ishihara
FEATURE ARTICLE
sium(II) center, and this may prevent generation of the ac-
tive catalyst.
OR1
R2
OR1
H
O
O
O
O
Mg
We next explored the scope of malonates (Table 6). Not
only dimethyl malonate (20a) but also dipropyl malonate,
dibenzyl malonate, and diallyl malonate could be used
successfully, and the corresponding products 21i–k were
obtained from 8b in almost quantitative yields with 88–
92% ee. The reactions of dimethyl a-halomalonates were
also examined. Although dimethyl 2-fluoromalonate gave
the corresponding adduct 21l with moderate enantioselec-
tivity (50% ee), the reactions of dimethyl 2-chloro-
malonate and dimethyl 2-bromomalonate proceeded
smoothly with the formation of a chiral quaternary carbon
center, and the desired a-halo-b-amino esters 21m and
21n, respectively, were obtained in high yields (92–
>99%) and with high enantioselectivities (96–97% ee).
The reaction proceeded smoothly even in the presence of
2.5 mol% of BINOL and 3.75 mol% of dibutylmagne-
sium, and a-bromo-b-amino ester 21n was obtained in
87% yield with 94% ee.
Figure 5 Expected Mg(II)–malonate BINOLate salts in situ
Interestingly, modification of the skeleton of BINOL
(e.g., substitution at the 3,3¢-positions, etc.) gave the
Mannich adducts in low reactivity and/or low enantiose-
lectivity. Therefore, to our delight, we selected simple and
inexpensive non-modified BINOL itself for subsequent
experiments. We further found that the reactions could
proceed at a more practical temperature such as –20 °C for
three hours without any loss of enantioselectivity
(Table 5). With regard to the protecting group in the N-
moiety of aldimines, tert-butoxycarbonyl (Boc) showed
better enantioselectivity than benzyoxycarbonyl (Cbz). A
variety products 21c–e of aryl aldimines with an electron-
withdrawing or electron-donating group and products
21f–h of heteroaryl aldimines were obtained in high
yields and with high enantioselectivities. In the case of the
3,4-dimethoxyphenyl-substituted aldimine, an optimal
1:1 ratio of BINOL/Bu2Mg (5 mol% each) provided the
product 21e in moderate yield (55%). Interestingly, how-
ever, a slight excess of dibutylmagnesium (7.5 mol%) to
BINOL (5 mol%) improved the yield and enantioselectiv-
ity (91% with 90% ee). A chelatable moiety such as an
ortho-dimethoxy group may partially ligate the magne-
To evaluate the tolerance of this catalyst, a 2-gram-scale
(5 mmol) synthesis of 21n was examined in the reaction
of 8b with dimethyl 2-bromomalonate (Scheme 11). The
reaction proceeded smoothly with the use of 5 mol% each
of BINOL and dibutylmagnesium in toluene at –20 °C for
Table 6 Scope of Malonates 20
(R)-BINOL (5 mol%)
Boc
n-Bu2Mg (5 mol%)
Boc
O
NH
O
O
O
N
+
OR1
R1O
OR1
toluene, MgSO4
–20 °C, 3 h
Ph
R2
OR1
Ph
H
R2
Table 5 Reaction of Dimethyl Malonate (20a)
8b
20 (1.1 equiv)
21
product, yield, and enantioselectivity
R1
(R)-BINOL (5 mol%)
O
NH
O
R1
H
Boc
Ph
Boc
Ph
Boc
O
O
n-Bu2Mg (5 mol%)
N
O
O
O
NH
NH
NH
O
+
Ar
OMe
OMe
toluene, MgSO4
–20 °C, 3 h
MeO
OMe
Ar
On-Pr
On-Pr
OBn Ph
OAllyl
O
O
OBn
OAllyl
21k
8
20a (1.1 equiv)
21
21i
99%, 92% ee
21j
99%, 91% ee
product, yield, and enantioselectivity
98%, 88% ee
Boc
Boc
Ph
Cbz
Ph
NH
Boc
Boc
Boc
NH
NH
O
F
O
O
NH
NH
NH
O
CO2Me
CO2Me
CO2Me
Ph
OMe
Ph
OMe
Ph
OMe
CO2Me
Cl
Br
CO2Me
21a
CO2Me
21b
98%, 81% ee
Cl
O
OMe
O
OMe
OMe
21c
>99%, 92% ee
98%, 93% ee
21l
>99%, 50% eea
21m
>99%, 97% ee
21n
92%, 96% ee
[87%, 94% ee]b
Cbz
Cbz
NH
NH
CO2Me
MeO
CO2Me
a Yield and enantioselectivity when BINOL (10 mol%) and Bu2Mg
(10 mol%) were used.
CO2Me
CO2Me
MeO
b Yield and enantioselectivity when BINOL (2.5 mol%) and Bu2Mg
(3.75 mol%) were used.
21d
94%, 87% ee
21e
55%, 87% ee
[91%, 90% ee]a
Boc
Boc
Boc
(R)-BINOL (5 mol%)
Boc
O
NH
NH
NH
NH
Boc
H
O
O
n-Bu2Mg (5 mol%)
N
CO2Me
CO2Me
CO2Me
+
O
Ph
OMe
N
MeO
OMe
Br
toluene, MgSO4
–20 °C, 4 h
S
Ph
CO2Me
CO2Me
CO2Me
21h
>99%, 89% ee
Br
O
OMe
21f
>99%, 90% ee
21g
8b (5 mmol)
(5.5 mmol)
21n, 2.07 g
>99%, 95% ee
>99%, 99% ee
a BINOL (5 mol%), Bu2Mg (7.5 mol%).
Scheme 11 Catalytic gram-scale synthesis
Synthesis 2010, No. 22, 3785–3801 © Thieme Stuttgart · New York

FEATURE ARTICLE
Asymmetric Direct Mannich-Type Catalysis
3793
four hours, and the desired product 21n was obtained in state with the tetrahedral magnesium(II) center by a
quantitative yield (2.07 g) with 99% ee.
Brønsted acid–Brønsted base system TS-24 might be
more favored due to the reasonably saturated coordination
sites, while other transition states, TS-25 and TS-26, have
a vacant site on the magnesium(II) center. TS-24 would
smoothly release the product after carbon–carbon bond
formation followed by protonation, and regenerate the
Mg(II)–BINOLate salt. However, in contrast to our ex-
pectation, we can not completely deny the presence of
other dimeric, trimeric, or oligomeric magnesium(II)
complexes in the transition states.
With regard to the utility of the resulting Mannich prod-
uct, we transformed 21a (92% ee) to the corresponding b-
lactam 23 (Scheme 12).23 Without any loss of enantiose-
lectivity (92% ee), b-phenyl-substituted b-lactam 23 was
obtained in 71% yield in three steps via the decarboxyla-
tion of 21a and subsequent cyclization of the synthetically
useful optically active b-amino ester 22 by treatment with
lithium diisopropylamide.
Boc
BINOL is simple, readily available in bulk quantities, and
inexpensive. Therefore, this Mg(II)–BINOLate salt cata-
lyst should be extremely practical in academic and indus-
trial process chemistry. In particular, the smooth
conversion within 3–4 hours at –20 °C with a catalyst
loading of 2.5–5 mol% of the Mg(II)–BINOLate salt is
outstanding, and this result is in sharp contrast to the reac-
tions with previous catalysts, which often require 10–20
mol% loading and a longer reaction time (sometimes >12
h).1–3
O
NH
1) 6 M HCl
O
NH2
100 °C, 1.5 h
Ph
OMe
OMe
2) MeOH
r.t., 36 h
Ph
OMe
O
21a, 92% ee
22, 91%
O
LDA (3 equiv)
THF, –78 °C, 24 h
HN
Ph
23, 78%, 92% ee
Scheme 12 b-Lactam synthesis
Although a further mechanistic investigation of the actual
catalysts should be necessary to determine which cooper-
ative acid–base system is more favored (Brønsted acid–
Brønsted base or Lewis acid–Brønsted base), we show a
working model for the possible transition states in
Figure 6. We assumed that some monomeric magne-
sium(II) pathways can explain the favored carbon–carbon
bond formation on the re-face. In particular, the transition
5
Chiral Calcium(II) Phosphate Salts and
Chiral Phosphoric Acids24
On one hand, since Akiyama et al.25 and Terada et al.3a,14
independently reported chiral phosphoric acid catalysts
derived from 3,3¢-disubstituted BINOL, these have be-
come recognized as some of the most useful organocata-
lysts.26 However, BINOL-derived phosphoric acids are
readily neutralized to adventitious metal salts such as al-
kali or alkaline earth metal salts by purification on silica
gel. Some researchers have focused on the possibility of
metal contaminants in phosphoric acids. Ding et al. re-
ported that HCl-washed phosphoric acid improved cata-
lytic activity in the Baeyer–Villiger reaction.27 Moreover,
Rueping et al. excluded calcium phosphate as a potential
active catalyst in their organocatalytic carbonyl-ene reac-
tion.28
O
O
re
N
H
H
O
OR1
R2
Mg
O
O
O
OR1
TS-24
Brønsted acid–Brønsted base [tetrahedral Mg(II)]
–
On the other hand, metal phosphates ([Mn+][(RO)2PO2 ]n)
have traditionally been of great value in asymmetric catal-
yses.29,30 In particular, in pioneering works, Alper et al. re-
ported the enantioselective hydrocarboxylation of olefins
catalyzed by palladium(II) phosphates (Scheme 13),29a
and Inanaga et al. later reported the hetero-Diels–Alder
reaction catalyzed by rare earth metal phosphates
(Scheme 14).29b,c Based on the bifunctional chemistry be-
O
OR1
R2
H
O
O
Mg
OR1
re
Ln
O
N
O
H
O
TS-25
Lewis acid–Brønsted base [tetrahedral Mg(II)]
–
tween acid (Mn+) and base [(RO)2PO2 ], replacement of
the acidic proton (H+) of phosphoric acids [(RO)2PO2H]
with a metal cation (Mn+) should affect the coordination/
activation of both the substrates and reagents (Scheme 1,
Figure 1, type c). We have developed a catalytic enantio-
selective trimethylsilylcyanation with the use of chiral
lithium(I) phosphate as a bifunctional Lewis acid–Lewis
base salt catalyst (Scheme 15).31 Similarly, a well-
designed chiral metal phosphate, which should act as a bi-
functional Lewis acid–Brønsted base salt catalyst, is sig-
O
O
H
re
O
H
N
OR1
R2
O
Mg
O
O
Ln
OR1
TS-26
Lewis acid–Brønsted base [octahedral Mg(II)]
Figure 6 Possible transition states 24–26 with monomeric magne-
sium(II) [Ln = vacant site or solvent]
Synthesis 2010, No. 22, 3785–3801 © Thieme Stuttgart · New York

3794
M. Hatano, K. Ishihara
FEATURE ARTICLE
kali or alkaline earth metal phosphates might activate 1,3-
dicarbonyl compounds more effectively than the corre-
sponding phosphoric acids due to their stronger Brønsted
basicity (Figure 7). In preliminary experiments, the
Mannich-type reaction of 8b with 9a was examined using
alkali or alkaline earth metal salts of 27a (Table 7). While
lithium(I), sodium (I), magnesium(II), and strontium(II)
salt catalysts gave disappointing results (entries 1–3 and
5), the calcium(II) salt catalyst Ca[27a]2 promoted the re-
action, and (R)-10b was obtained in >99% yield with 92%
ee in dichloromethane at room temperature (entry 4). In-
terestingly, this result with Ca[27a]2 was compatible with
Terada’s result using silica gel purified H[27a], which we
nearly reproduced ourselves (entry 6). However, with
HCl-washed H[27a], poor and opposite enantioselectivity
[27% ee, (S)-configuration] was observed for 10b (entry
7). In this context, we were prompted to re-evaluate
whether metal-free, pure phosphoric acid is the actual ac-
tive catalyst for the direct Mannich-type reaction. During
further investigation in the absence of calcium(II), we
found that the enantioselectivity was improved with steri-
cally demanding HCl-washed H[27b] in place of HCl-
washed H[27a] (entry 8). In particular, a remarkable sol-
vent effect was observed when toluene was used, and (S)-
10b was obtained in quantitative yield with 93% ee at –30
°C (entry 9).
O
O
O
P
OH
(5 mol%)
PdCl2 (13 mol%)
CO2H
CuCl2 (25 mol%), O2
+
+
H2O
CO
THF, HCl (aq), r.t., 18 h
i-Bu
i-Bu
89%, 83% ee
Scheme 13
O
O
O
P
Yb
3
O
(10 mol%)
O
O
OSiMe3
2,6-lutidine (10 mol%)
+
Ph
O
Ph
H
OMe
CH2Cl2, r.t., 16 h
94%, 89% ee
Scheme 14
Ph
O
O
P
OLi
O
Table 7 Screening of Catalysts
(10 mol%)
Me3SiO CN
O
Ph
Boc
+
Me3SiCN
Boc
NH
Ph
N
O
O
catalyst (2–5 mol%)
CH2Cl2, r.t., 1 h
Ph
toluene, –40 °C, 12 h
+
Ac
96%, 86% ee
*
Ph
Ph
H
Ac
Scheme 15
9a (1.1 equiv)
8b
10b
catalyst:
nificantly attractive for us to promote enantioselective
direct Mannich-type reactions of aldimines with 1,3-di-
carbonyl compounds (Figure 7).
Ar
M[27a]n (Ar = 4-(2-naphthyl)C6H4
O
O
M = H, Li, Na, Mg, Ca, Sr)
P
O
M
O
M[27b]n (Ar = 9-anthryl, M = H, Ca)
H-Nu
δ–
Brønsted base
n
O
O
O
Ar
δ+
P
[M]
Lewis acid
(Li, Na, Mg, Ca, Sr)
O
Entry Catalyst (mol%)
Yield (%) ee (%) (config)
1
Li[27a] (5)
99
88
11 (S)
9 (S)
Figure 7 Chiral metal phosphates as bifunctional salt catalysts
2
Na[27a] (5)
3
Mg[27a]2 (2.5)
>99
>99
>99
86
43 (R)
92 (R)
59 (R)
92 (R)
27 (S)
49 (S)
93 (S)
In this context, we recognized the significance of the acid-
ic purification (e.g., treatment with aq HCl) of chiral phos-
phoric acids to obtain a metal-free, pure organocatalyst.
Moreover, both metal-free chiral phosphoric acid H[27b]
and chiral calcium phosphate Ca[27a]2 catalyzed the
enantioselective direct Mannich-type reactions of ald-
imines with 1,3-dicarbonyl compounds. The presence of
small amounts of metal contaminants in ‘purified’ phos-
phoric acid may trigger unexpected excellent results or
may invalidate these evaluations.
4
Ca[27a]2 (2.5)
5
Sr[27a]2 (2.5)
6a
7
silica gel purified H[27a] (2)
HCl-washed H[27a] (2)
HCl-washed H[27b] (5)
HCl-washed H[27b] (5)
88
8
>99
>99
9b
a Original data by Terada: 99% yield and 95% ee (R) (see ref. 3a).
The enantioselective direct Mannich-type reaction of aldi-
mine 8b with acetylacetone (9a) catalyzed by H[27a] was b 8b (1.2 equiv), 9a (1 equiv), toluene, –30 °C, 12 h.
first developed by Terada et al.3a,14 We envisioned that al-
Synthesis 2010, No. 22, 3785–3801 © Thieme Stuttgart · New York

FEATURE ARTICLE
Asymmetric Direct Mannich-Type Catalysis
3795
During the catalyst screening, we found that silica gel pu-
rified H[27a] and HCl-washed H[27a] gave different H
Table 8 anti-Selective Catalysis with a Chiral Phosphoric Acid
1
NMR spectra in DMSO-d6. However, lithium(I), sodi-
um(I), magnesium(II), calcium(II), and strontium(II) salts
1
showed the same H NMR spectra as silica gel purified
H[27a]. In the FAB-LRMS analysis of silica gel purified
H[27a], two major m/z peaks at 775 and 791 and two mi-
nor m/z peaks at 1529 and 1543 were observed, which in-
dicate [H[27a] + Na]+, [Ca[27a]]+, [2 (H[27a]) + Na]+,
and [Ca[27a]2]+, respectively. Therefore, silica gel puri-
fied H[27a] involved at least sodium(I) and calcium(II)
salts.32 We emphasize that aqueous hydrochloric acid
treatment of silica gel purified material is essential for ob-
taining metal-free, pure phosphoric acid for efficient orga-
nocatalysis.
O
O
O
P
OH
Boc
Ar
NH
O
O
Boc
O
O
H[27b] (5 mol%)
toluene, –30 °C, 24 h
N
*
R1
+
R1
R3
R2
R3
Ar
H
R2
diketone, ketoester
ketolactone, ketothioester
8
(1.2 equiv)
Based on the preliminary results in Table 7, we thorough-
ly investigated metal-free phosphoric acid catalysis with
HCl-washed H[27b] in toluene at –30 °C for 24 h
(Table 8). Acyclic a-substituted 1,3-diketones smoothly
gave the Mannich adducts 10b,l–n with high enantiose-
lectivities (92–95% ee). Cyclic 1,3-diketones and b-keto-
esters also gave the corresponding products 10o,17g,p–r)
with both high diastereoselectivities and high enantiose-
lectivities (syn/anti, <10:>90, 95–98% ee. anti-Products
were selectively obtained by H[27b]-catalysis, while syn-
products were selectively obtained by 15/n-BuLi/t-BuOH-
catalysis (see Section 3). Remarkably, a-fluoro- and
a-chloro-b-ketoesters also gave anti-diastereomers with
high enantioselectivities as the major products (17s–u,
92–98% ee). A ketolactone and another functionalized
b-ketoester, such as ethyl 4,4,4-trichloroacetoacetate also
gave anti-adducts 28 and 29, respectively, as the major di-
astereomer with high enantioselectivities. Overall, these
anti-diastereomers obtained in Table 8 are valuable, since
conventional catalysts gave the syn-diastereomers as ma-
jor products.1–3 Furthermore, when S-aryl thioacetoace-
tate was used, the adducts 30a and 30b were obtained in
>99% yield with 82–86% ee. Unfortunately, however, re-
actions with thiomalonates did not proceed, and com-
pounds 31a and 31b were scarcely obtained by H[27b]
catalysis.
product, yield, diastereoselectivity, and enantioselectivity
Boc
Ph
Boc
Ph
Boc
Ph
Boc
NH
NH
NH
NH
Ac
Ac
Cl
Ac
Ac
Ac
Ac
Ac
Ac
10b, >99%
10l, >99%
10m, 92%
10n,a 97%
95% ee
93% ee
92% ee
94% ee
Boc
Boc
Boc
O
O
NH
NH
O
NH
Ph
Ph
MeO
MeO2C
Ac
MeO2C
17q,a 97%
syn/anti = 5:95
96% ee (anti)
10o, >99%
syn/anti = 10:90
95% ee (anti)
17o, >99%
syn/anti = 7:93
96% ee (anti)
Boc
NH
Boc
Boc
O
NH
NH
O
Ac
Ph
Ph
MeO2C
Ph
F
OEt
MeO2C
O
17r,a >99%
syn/anti = 2:98
95% ee (anti)
17s,a,b 88%
syn/anti = 18:82
83% ee/92% ee
17g, >99%
syn/anti = <1:>99
98% ee (anti)
Boc
NH
Boc
NH
Boc
NH
Ac
Ac
Ac
Ph
Cl
Ph
Cl
O
O
O
OMe
Br
O
OMe
17t,a >99%
syn/anti = 32:68
89% ee/98% ee
17u,a 98%
syn/anti = 27:73
83% ee/97% ee
28, >99%
syn/anti = 26:74
75% ee/91% ee
We discuss here a possible mechanism for H[27b] cataly-
sis. The unprecedented highly anti-selective catalysis is
considered to proceed via cyclic transition states, since the
H[27b] catalyst can activate both the aldimine and the 1,3-
dicarbonyl compound in a synclinal conformation
(Figure 8). The coordination of the aldimine to H[27b] is
sterically controlled as illustrated in TS-32 and TS-33,
due to steric repulsion between the 9-anthryl moiety of
H[27b] and the aryl moiety of the aldimine. The bulky
tert-butyl moiety in N-Boc, which should show signifi-
cant repulsion with the 1,3-dicarbonyl compound, would
be directed to inside the catalyst cavity. However, this re-
pulsion can be partially reduced by rotation of the ester
substitution (R1) of the aldimine in favored TS-32, while
the ketone moiety cannot inherently turn away in disfa-
vored TS-33. In TS-32, a pronucleophile would be acti-
vated by coordination with the Brønsted basic P=O
Boc
Boc
Boc
NH
O
O
NH
O
NH
Ac
Ac
Ph
CCl3
OEt
Ph
Ph
SPh
O
S(2,6-Xyl)
30a, >99%
dr = 68:32
81% ee/85% ee
30b,c >99%
dr = 62:38
29, >99%
dr = 70:30
91% ee/85% ee
85% ee/88% ee
Boc
Boc
NH
O
NH
O
Ph
SPh
Ph
S(2,6-Xyl)
O
SPh
O
S(2,6-Xyl)
31a,a trace
31b,a,c trace
a 1.5 equiv of 8 was used.
b Temperature was –20 °C.
c 2,6-Xyl = 2,6-Me2C6H3.
Synthesis 2010, No. 22, 3785–3801 © Thieme Stuttgart · New York

3796
M. Hatano, K. Ishihara
FEATURE ARTICLE
Table 9 Catalysis with a Chiral Calcium Phosphatea
moiety, followed by attack to the Brønsted acid (i.e., pro-
ton) coordinated aldimine on the si-face to give the anti-
product.
Boc
Ar
NH
O
O
Boc
H
O
O
Ca[27a]2 (2.5 mol%)
N
R1
SR2
+
R1
SR2
CH2Cl2, r.t., 1 h
Ar
(1.1 equiv)
8
ketothioester
thiomalonate
Boc
Ar1
O
NH
O
O
O
O
R1
O
P
R1
O
R2
R3
anti
(major)
N
si
H
O
O
H
O
R2
H
O
n
R3
O
O
O
O
O
TS-32 (favored)
O
Ca
P
P
O
O
H
O
Boc
Ar1
H
O
O
NH
O
R3
O
P
R1
R2
R3
O
N
si
H
O
O
n
H
O
R2
H
syn
(minor)
O
O
Ca[27a]2
R1
product, yield, diastereoselectivity, and enantioselectivity
TS-33 (disfavored)
Boc
Ph
Boc
Ph
NH
NH
Figure 8 Proposed transition states 32 and 33 for H[27b] catalysis
Ac
Ac
O
SPh
Next, we investigated the scope of the enantioselective di-
rect Mannich-type reaction with 1,3-dicarbonyl com-
pounds under the optimized conditions for Ca[27a]2
(Table 9). As a result, we found that b-ketothioesters33
were suitable pronucleophiles. The Mannich-type reac-
tion of 8b with S-phenyl thioacetoacetate proceeded
smoothly afforded the desired product 30a in >99% yield
with 90% ee. S-2,6-Xylyl thioacetoacetate also provided
the corresponding products 30b–h with better enantiose-
lectivities (90–98% ee) in the reaction of aldimines with
Me, MeO, Cl, and Br substitution with 0.5–2.5 mol% of
Ca[27a]2. To our great delight, S-2,6-xylyl thiomalonate
could be used in the presence of 2.5 mol% of Ca[27a]2,
and the corresponding adducts 31b–d were obtained in
high yields and with high enantioselectivities (91–95%
ee). This catalysis with thiomalonates by Ca[27a]2 was in
sharp contrast to that by H[27b], since the Brønsted basic-
ity of H[27b] was not sufficient to promote the reactions
through the activation of less acidic pronucleophiles.
O
S(2,6-Xyl)
30a, >99%, 90% ee
30b, >99%, 94% ee
[0.5 mol%: >99%, 98% ee]
Boc
NH
Boc
NH
Ac
Ac
O
S(2,6-Xyl)
MeO
O
S(2,6-Xyl)
30c, >99%, 94% ee
30d, 94%, 92% ee
Boc
NH
Boc
NH
Ac
Ac
Cl
O
S(2,6-Xyl)
Br
O
S(2,6-Xyl)
30e, 90%, 90% ee
30f, >99%, 91% ee
Boc
NH
Boc
NH
Ac
Ac
S
O
S(2,6-Xyl)
O
S(2,6-Xyl)
30g, 88%, 97% ee
30h, >99%, 96% ee
Boc
Boc
NH
O
NH
O
As noted above, H[27b] and Ca[27a]2 catalysts made it
possible to establish the first practical reaction of b-keto-
thioesters and thiomalonates. Remarkably, a change in the
absolute configuration of the amino stereocenter of the
products was observed with H[27b] (Table 8) vs. with
Ca[27a]2 (Table 9). Interestingly, these catalyses offer
enantiodivergence with the same absolute configuration
of the catalysts.
Ph
S(2,6-Xyl)
S(2,6-Xyl)
S(2,6-Xyl)
S(2,6-Xyl)
O
MeO
O
31c, 81%, 91% ee
31b, 94%, 95% ee
Boc
NH
O
O
S(2,6-Xyl)
Br
S(2,6-Xyl)
We next demonstrated the synthetic utility of b-keto-
thioesters and thiomalonates. Thiomalonate 31b was
readily transformed to malonate 21a without racemization
by treatment with silver trifluoroacetate and methanol in
tetrahydrofuran at 50 °C (Scheme 16).
31d, 89%, 95% ee
a 2,6-Xyl = 2,6-Me2C6H3.
Synthesis 2010, No. 22, 3785–3801 © Thieme Stuttgart · New York

FEATURE ARTICLE
Asymmetric Direct Mannich-Type Catalysis
3797
Boc
would be highly sterically hindered by the four 4-(b-naph-
thyl)C6H4 moieties, and a half-pipe-like chiral groove was
formed around the calcium(II) center (Figure 9). There-
fore, a sterically less-hindered cyclic transition state (TS-
37) would be favored in Ca[27a]2 catalysis, and a pronu-
cleophile activated by the Brønsted basic P=O moiety
would attack the aldimine activated by the Lewis acidic
calcium(II) center on the re-face to give the R-product.
Boc
Ph
NH
O
O
NH
CO2Me
CF3CO2Ag, MeOH
THF, 50 °C, 12 h
Ph
S(2,6-Xyl)
S(2,6-Xyl)
CO2Me
21a, >99%, 95% ee
31b, 95% ee
Scheme 16 Decarboxylation of thiomalonate 31b
The decarboxylations of b-ketoesters and malonates
would be difficult since harsh basic conditions are often
required. In fact, a common decarboxylation with lithium
hydroxide for 17c gave a complex mixture with a signifi-
cant loss of enantioselectivity (34, 13% yield and 69%
ee). In sharp contrast, compound 30b was converted into
b-amino ketone 34, which is also difficult to obtain direct-
ly from 8b and acetone,34 with palladium(II)/formic acid
catalysis35 (Scheme 17).
R2
O
H
O
O
R1
O
N
O
O
Ca
O
H
O
O
P
P
O
O
O
Boc
NH
PdCl2(dppf) (10 mol%)
P(2-furyl)3 (25 mol%)
Boc
Ph
NH
Ac
Ph
Ac
CuI, HCO2H
O
S(2,6-Xyl)
DMF, 50 °C, 12 h
34, 95%, 90% ee
30b, 94% ee
Scheme 17 Decarboxylation of b-ketothioester 30b
TS-37 (favored)
The reduction of 31b with Raney nickel under hydrogen
(1 bar) gave chiral b-amino alcohol 35 in 90% yield with
95% ee (Scheme 18). Moreover, b-Boc-amino thioester
36 was obtained from 31d in 74% yield with 95% ee
through decarboxylation in dimethyl sulfoxide–water at
Figure 9 Proposed transition state for Ca[27a]2 catalysis
6
Conclusions
110 °C in the presence of sodium chloride (Scheme 19).36 In summary, we have developed a series of extremely ac-
tive and practical acid–base combined salt catalysts for
Boc
the catalytic asymmetric direct Mannich-type reaction be-
NH
O
Boc
Ph
tween aldimines and 1,3-dicarbonyl compounds. In par-
ticular, we designed several chiral BINOL-derived simple
salt catalysts, such as chiral pyridinium 1,1¢-binaphthyl-
2,2¢-disulfonates 1, chiral lithium(I) binaphtholates 2,
chiral magnesium(II) binaphtholate (3), chiral calcium(II)
phosphates 4, and chiral phosphoric acids 5. These cata-
lysts covered a wide range of 1,3-dicarbonyl compounds
with different reactivities [i.e., diketones, ketoesters, keto-
lactones, diesters (malonate), ketoamides, ketothioesters,
dithioesters (thiomalonates)] (Table 10). Pharmaceutical-
ly useful, optically active b-amino ketones, b-amino es-
NH
Raney Ni, H2 (1 bar)
Ph
S(2,6-Xyl)
S(2,6-Xyl)
OH
EtOH–Et2O
50 °C, 5 h
O
35, 90%, 95% ee
31b, 95% ee
Scheme 18 Transformation to b-amino alcohol 35
Boc
Boc
NaCl
NH
O
O
NH
O
DMSO–H2O
110 °C, 5 h
S(2,6-Xyl)
S(2,6-Xyl)
S(2,6-Xyl)
Br
Br
31d, 95% ee
36, 74%, 95% ee
Table 10 Summary
Scheme 19 Transformation to monothioester 36
1,3-Dicarbonyl compound
diketone
Suitable catalysts
Although the further investigation of calcium(II) catalysis
is necessary,37 Lewis acidic calcium bis(phosphate) salt
Ca[27a]2, which was generated in situ and found in the
FAB-HRMS analysis (m/z for [Ca[27a]2]+; calcd:
1543.3736; found: 1543.3749), might play a role. 31P
NMR analysis of Ca[27a]2 (CD2Cl2) showed a broad peak
at d = 0.05, which suggests an oligomeric structure. How-
ever, when 8b (1 equiv) and 9a (1.1 equiv) were added to
the solution of Ca[27a]2 (2.5 mol%), a new sharp singlet
was immediately observed at d = 4.55, which suggests a
monomeric structure for Ca[27a]2. The calcium(II) center
1, 2, 4, 5
2, 5
2, 5
3
ketoester
ketolactone
diester (malonate)
ketoamide
1, 2
2, 4
4
ketothioester
dithioester (thiomalonate)
Synthesis 2010, No. 22, 3785–3801 © Thieme Stuttgart · New York

3798
M. Hatano, K. Ishihara
FEATURE ARTICLE
–78 °C for 2 h. The mixture was diluted with 10% HCl–MeOH (1
mL) at –78 °C. After 10 min, H2O (5 mL) and EtOAc (15 mL) were
added. The organic phase was extracted with EtOAc (2 × 15 mL),
washed with brine (20 mL), and dried (Na2SO4). The organic phase
was concentrated under reduced pressure and the crude product was
purified by column chromatography (silica gel, n-hexane–EtOAc,
5:1–2:1) to give the desired product. The enantiomeric purity was
determined by the chiral HPLC analysis.
ters, b-lactams, etc. were efficiently synthesized and/or
transformed in high yield and with high stereoselectivity
through this method. Our salt catalysts are significantly
attractive for not only academic but also industrial use,
since they can be immediately prepared in situ from sim-
ple and inexpensive precursors and show extremely high
reactivity.
Chiral Magnesium(II)–Binaphtholate Salt Catalysis; General
Procedure
All reactions were carried out under a N2 atmosphere using standard
vacuum-line techniques and glassware that was flame-dried and
cooled under N2 before use. All anhyd solvents and reagents were
obtained from commercial sources and distilled before use. All re-
A well-dried pyrex Schlenk tube was charged with (R)-BINOL (7.1
mg, 0.025 mmol) and well-dried MgSO4 (100 mg) under N2. Tolu-
ene (3 mL) was added, and the suspension was stirred at –20 °C for
5 min. 1.0 M Bu2Mg in heptane (25.0 mL, 0.025 mmol) was added,
and the mixture was stirred at –20 °C for 5 min. Dialkyl malonate
(0.55 mmol) and aldimine (0.50 mmol) were added to the mixture.
After then, the mixture was stirred at –20 °C for 3 h. The mixture
was diluted with 10% HCl–MeOH (2 mL) at –20 °C. After 10 min,
H2O (10 mL) and EtOAc (20 mL) were added. The organic phase
was extracted with EtOAc (2 × 20 mL), washed with brine (20 mL),
and dried (Na2SO4). The organic phase was concentrated under re-
duced pressure and the crude product was purified by column chro-
matography (silica gel, n-hexane–EtOAc, 5:1–2:1) to give the
desired product. The enantiomeric purity was determined by the
chiral HPLC analysis.
1
agents were purchased and used without further purification. H
NMR spectra were measured on a Jeol ECS-400 (400 MHz) spec-
trometer at r.t. with the solvent resonance employed as the external
standard (TMS d = 0). 13C NMR spectra were measured on Jeol
ECS-400 (100 MHz) spectrometer with the solvent resonance em-
ployed as the internal standard (CDCl3 d = 77.1). 19F NMR spectra
were measured on a Jeol ECS-400 (376 MHz) spectrometer with the
solvent resonance employed as the internal standard (CF3C6H5 d =
–63.24). 31P NMR spectra were measured on a Jeol ECS-400 (161
MHz) spectrometer with the solvent resonance employed as the in-
ternal standard (H3PO4 d = 0). HRMS analyses were performed at
Chemical Instrument Center, Nagoya University (Jeol JMS-700).
IR spectra were recorded on a Jasco FT/IR 460 plus spectrophotom-
eter. HPLC analysis was conducted using Shimadzu LC-10 AD
coupled diode array-detector SPD-MA-10A-VP and chiral column
of Daicel Chiralcel, Chiralpak. TLC analysis throughout this work,
Merck TLC plates (silica gel 60G F254 0.25 mm) were used. The
products were purified by neutral column chromatography on silica
gel (Kanto Chemical Co., Inc. 37560). Visualization was accom-
plished by UV light (254 nm), anisaldehyde, KMnO4, and phos-
phomolybdic acid.
Preparation of Silica Gel Purified H[27a]
‘Silica gel purified H[27a]’ was prepared by the reported
procedure3a through silica gel column purification but without sub-
sequent treatment with aq HCl. ‘Silica gel purified H[27a]’ can be
stored in a cool dark place.
Preparation of HCl-Washed H[27a]
The EtOAc soln of ‘silica gel purified H[27a]’ was thoroughly
washed with aq 2 M HCl, and the organic phase was separated. Af-
ter volatiles were removed under reduced pressure (<7 mbar), ‘HCl-
washed H[27a]’ was obtained as a white solid that can be stored in
a cool dark place.
Catalysts, Mannich products, and their derivatives (6, 10, 11, 13–
15, 17–19, 21–23, 27, 30, 31, 34–36) have been fully characterized
in the corresponding references.7,16,21,24
Chiral BINSA–Pyridinium Salt Catalysis; General Procedure
A well-dried Pyrex Schlenk tube was charged with (R)-1,1¢-binaph-
thyl-2,2¢-disulfonic acid (BINSA, 6, 1.0 mg, 0.0025 mmol) and 2,6-
diarylpyridine (0.005 mmol) under N2. MeCN (2 mL) was added,
and the soln was stirred at r.t. for 15 min. The volatiles were re-
moved in vacuo, and well-dried MgSO4 (50 mg, 0.42 mmol) and
CH2Cl2 (1.5 mL) were added, and the suspension was stirred at r.t.
for 30 min. The mixture was cooled to 0 °C, aldimine (0.375 mmol)
in CH2Cl2 (0.5 mL) was added via a cannula, and 1,3-dicarbonyl
compound (0.25 mmol) in CH2Cl2 (0.5 mL) was then added over 1
h (a syringe pump is useful if available.). The resultant mixture was
then stirred at 0 °C for 30 min. Sat. aq NaHCO3 (10 mL) was poured
into the mixture, and the product was extracted with EtOAc (2 × 15
mL). The combined extracts were washed with brine (10 mL) and
dried (Na2SO4). The organic phase was concentrated under reduced
pressure and the crude product was purified by column chromatog-
raphy (silica gel, n-hexane–EtOAc, 5:1–2:1) to give the desired
product. The enantiomeric purity was determined by chiral HPLC.
Preparation of M[27a]n Salts
Catalysts M[27a]n were prepared in situ in a Pyrex Schlenk tube for
the Mannich reaction. To prepare M[27a]n (2.5–5 mol%) such as
Li[27a], Na[27a], Mg[27a]2, Ca[27a]2, and Sr[27a]2 in situ, Li(Oi-
Pr) (5 mol%), NaOMe (5 mol%), Mg(Ot-Bu)2 (2.5 mol%), Ca(Oi-
Pr)2 (2.5 mol%), and Sr(Oi-Pr)2 (2.5 mol%), respectively, were used
with ‘HCl-washed H[27a]’ (5 mol%) in CH2Cl2–MeOH (1:1, 2
mL), and the soln was stirred at r.t. for 30 min. The volatiles were
removed in vacuo, and then CH2Cl2 (2 mL) was added and removed
in vacuo again. This solvent-removal sequence was repeated two
additional times, and the desired M[27a]n was obtained as a white
solid. Catalysts M[27a]n were used for the Mannich reaction just af-
ter this in situ preparation.
Chiral Phosphoric Acid Catalysis; General Procedure
A well-dried Pyrex Schlenk tube was charged with (R)-3,3¢-bis(9-
anthracenyl)-1,1¢-binaphthyl phosphate (HCl-washed H[27b])
(17.5 mg, 0.025 mmol) and toluene (4 mL) under N2. The soln was
cooled to –30 °C, and aldimine (0.60 mmol) was added, and then
1,3-dicarbonyl compound (0.50 mmol) in toluene (1 mL) was added
over 1 h. After that, the resultant mixture was stirred at –30 °C for
24 h. Sat. aq NaHCO3 (10 mL) was poured into the mixture, and the
product was extracted with EtOAc (3 × 15 mL). The combined ex-
tracts were washed with brine (10 mL) and dried (Na2SO4). The or-
ganic phase was concentrated under reduced pressure and the crude
product was purified by column chromatography (silica gel, n-hex-
Chiral Lithium(I)–Binaphtholate Salt Catalysis; General Pro-
cedure
A well-dried Pyrex Schlenk tube was charged with (R)-3,3¢-(3,4,5-
F3C6H2)2-BINOL (15, 13.6 mg, 0.025 mmol) and t-BuOH (4.8 mL,
0.05 mmol) under N2. Toluene (5 mL) was added, and the soln was
stirred at –78 °C for 10 min. 1.5 M n-BuLi in n-hexane (16.7 mL,
0.025 mmol) was added, and the soln was stirred at –78 °C for 10
min. 1,3-Dicarbonyl compound (1.1 mmol) and aldimine (1 mmol)
were added to the soln. The resultant mixture was then stirred at
Synthesis 2010, No. 22, 3785–3801 © Thieme Stuttgart · New York

FEATURE ARTICLE
Asymmetric Direct Mannich-Type Catalysis
3799
ane–Et2O, 5:1–1:1) to give the desired product. The enantiomeric
purity was determined by chiral HPLC.
13C NMR (100 MHz, CDCl3): d = 27.6, 28.2 (3 C), 53.8, 58.6, 77.5,
80.4, 128.1 (2 C), 128.4, 128.8 (2 C), 135.8, 154.4, 166.7, 198.3.
Ethyl (S)-2-[(R)-(tert-Butoxycarbonylamino)(phenyl)methyl]-2-
fluoro-3-oxobutanoate (17s)
anti-Isomer (Major)
92% ee; HPLC (Daicel Chiralpak AD-H × 2, n-hexane–i-PrOH
20:1, 0.5 mL/min): tR = 60.2 [minor, (R,S)], 63.7 min [major, (S,R)].
Methyl (S)-2-[(R)-(4-Bromophenyl)(tert-butoxycarbonylami-
no)methyl]-2-chloro-3-oxobutanoate (17u)
Diastereomeric mixture; HPLC (Daicel Chiralpak AD-H × 3, n-
hexane–i-PrOH 95:5, 0.3 mL/min): anti-isomer (major) tR = 102.0
[major, (S,R)], 111.2 min [minor, (R,S)]; syn-isomer (minor)
tR = 84.6 [minor, (S,S)], 121.2 min [major, (R,R)].
[a]D26 –3.0 (c 1.2, CHCl3).
IR (syn/anti mixtures, neat): 3433, 2979, 2932, 1720, 1489, 1366,
IR (neat): 3372, 2980, 2935, 1758, 1733, 1704, 1497, 1367, 1255,
1164, 1016 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.09 (t, J = 7.2 Hz, 3 H), 1.38 (s,
9 H), 2.36 (d, J = 4.6 Hz, 3 H), 4.02–4.16 (m, 2 H), 5.41 (d, J = 9.2
Hz, 1 H), 5.68 (dd, J = 26.6, 10.1 Hz, 1 H), 7.28–7.39 (m, 5 H).
13C NMR (100 MHz, CDCl3): d = 13.7, 26.4, 28.1 (3 C), 57.0 (d,
JC–F = 19.1 Hz), 62.8, 80.5, 101.2 (d, JC–F = 204.0 Hz), 128.1 (2 C),
128.3, 128.5 (2 C), 135.9, 154.4, 164.0 (d, JC–F = 24.8 Hz), 199.6 (d,
JC–F = 25.7 Hz).
1245, 1166, 1011 cm–1.
HRMS (FAB+): m/z [M + Na]+ calcd for C17H21BrClNNaO5:
456.0189; found: 456.0184.
anti-Isomer (Major)
1H NMR (400 MHz, CDCl3): d = 1.39 (s, 9 H), 2.34 (s, 3 H), 3.76
(s, 3 H), 5.63 (d, J = 9.2 Hz, 1 H), 5.86 (d, J = 9.2 Hz, 1 H), 7.26 (d,
J = 8.7 Hz, 2 H), 7.44 (d, J = 8.7 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 27.5, 28.1 (3 C), 53.9, 57.9, 77.1,
80.4, 122.4, 130.6 (2 C), 131.2 (2 C), 135.3, 154.2, 166.1, 198.7.
19F NMR (376 MHz, CDCl3): d = –175.8.
HRMS (FAB+): m/z [M + Na]+ calcd for C18H24FNNaO5: 376.1536;
syn-Isomer (Minor)
found: 376.1536.
1H NMR (400 MHz, CDCl3): d = 1.39 (s, 9 H), 2.34 (s, 3 H), 3.78
(s, 3 H), 5.55 (d, J = 10.6 Hz, 1 H), 6.10 (d, J = 10.6 Hz, 1 H), 7.29
(d, J = 8.2 Hz, 2 H), 7.45 (d, J = 8.2 Hz, 2 H).
syn-Isomer (Minor)
83% ee; HPLC (Daicel Chiralpak AD-H × 2, n-hexane–i-PrOH
20:1, 0.5 mL/min): tR = 73.8 [minor, (S,S)], 107.3 min [major,
(R,R)].
[a]D26 –13.2 (c 1.3, CHCl3).
13C NMR (100 MHz, CDCl3): d = 27.5, 28.1 (3 C), 53.9, 58.1, 77.1,
80.6, 122.6, 130.6 (2 C), 131.2 (2 C), 134.9, 154.3, 166.5, 197.9.
tert-Butyl {(R)-[(R)-3-Acetyl-2-oxotetrahydrofuran-3-yl](phe-
nyl)methyl}carbamate (28)
Diastereomeric mixture.
IR (neat): 3364, 2979, 2934, 1756, 1733, 1498, 1367, 1248, 1165,
1065 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.31 (t, J = 7.1 Hz, 3 H), 1.39 (s,
9 H), 1.99 (d, J = 4.6 Hz, 3 H), 4.17–4.41 (m, 2 H), 5.50 (d, J = 10.1
Hz, 1 H), 5.67 (dd, J = 27.3, 10.3 Hz, 1 H), 7.28–7.34 (m, 5 H).
13C NMR (100 MHz, CDCl3): d = 13.9, 26.4, 28.1 (3 C), 56.9 (d,
JC–F = 19.1 Hz), 63.1, 80.3, 101.9 (d, JC–F = 203.1 Hz), 128.3 (2 C),
128.4, 128.6 (2 C), 135.6, 154.3, 164.3 (d, JC–F = 26.7 Hz), 199.9 (d,
JC–F = 28.6 Hz).
anti-Diastereomer (Major)
Pale yellow oil; Rf = 0.7 (n-hexane–EtOAc, 2:1); HPLC (OD-H × 2,
n-hexane–i-PrOH 4:1, 0.5 mL/min, 210 nm): tR = 20.1 (major), 35.2
min (minor).
IR (neat): 3368, 2978, 1769, 1713, 1366, 1160, 1023 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.30 (m, 1 H), 1.39 (s, 9 H), 2.07
(m, 1 H), 2.49 (s, 3 H), 2.89 (m, 1 H), 3.59 (m, 1 H), 5.10 (br, 1 H),
5.80 (br, 1 H), 7.20–7.42 (m, 5 H).
19F NMR (376 MHz, CDCl3): d = –175.2.
HRMS (FAB+): m/z [M + Na]+ calcd for C18H24FNNaO5: 376.1536;
13C NMR (100 MHz, CDCl3): d = 24.3, 25.5, 28.3, 56.4, 66.2, 67.0,
80.8, 127.3, 128.5, 128.9, 137.1, 154.6, 173.3, 201.1.
found: 376.1534.
Methyl (S)-2-[(R)-(tert-Butoxycarbonylamino)(phenyl)methyl]-
2-chloro-3-oxobutanoate (17t)
Diastereomeric mixture; HPLC (Daicel Chiralpak AD-H × 3, n-
hexane–i-PrOH 95:5, 0.3 mL/min): anti-isomer (major) tR = 91.0
[major, (S,R)], 97.0 min [minor, (R,S)], syn-isomer (minor)
tR = 77.4 [minor, (S,S)], 94.6 min [major, (R,R)].
HRMS (FAB+): m/z [M + Na]+ calcd for C18H23NNaO5: 356.1474;
found: 356.1476.
syn-Diastereomer (Minor)
Colorless solid; mp 145–146 °C; Rf = 0.45 (n-hexane–EtOAc, 2:1);
HPLC (OD-H × 2, n-hexane–i-PrOH 4:1, 0.5 mL/min, 210 nm):
tR = 27.9 (minor), 38.4 min (major).
1H NMR (400 MHz, CDCl3): d = 1.40 (s, 9 H), 2.15–2.50 (m, 2 H),
2.45 (s, 3 H), 3.69 (m, 1 H), 4.36 (m, 1 H), 5.30 (br, 1 H), 6.63 (br,
1 H), 7.25–7.45 (m, 5 H).
IR (syn/anti mixtures, neat): 3437, 2979, 1718, 1493, 1367, 1243,
1166, 1050 cm–1.
HRMS (FAB+): m/z [M + Na]+ calcd for C17H22ClNNaO5:
378.1084; found: 378.1083.
13C NMR (100 MHz, CDCl3): d = 26.2, 28.3, 29.9, 53.1, 65.6, 67.5,
anti-Isomer (Major)
80.3, 128.1, 128.9, 129.0, 137.1, 155.0, 175.9, 203.5.
1H NMR (400 MHz, CDCl3): d = 1.40 (s, 9 H), 2.34 (s, 3 H), 3.74
(s, 3 H), 5.68 (d, J = 9.2 Hz, 1 H), 5.87 (d, J = 9.2 Hz, 1 H), 7.27–
7.34 (m, 3 H), 7.34–7.42 (m, 2 H).
HRMS (FAB+): m/z [M + Na]+ calcd for C18H23NNaO5: 356.1474;
found: 356.1471.
13C NMR (100 MHz, CDCl3): d = 27.6, 28.2 (3 C), 53.8, 58.3, 77.8,
80.2, 128.1 (2 C), 128.3, 128.8 (2 C), 136.2, 154.3, 166.3, 198.9.
Ethyl 2-[(S)-(tert-Butoxycarbonylamino)(phenyl)methyl]-4,4,4-
trichloro-3-oxobutanoate (29)
Diastereomeric mixture; HPLC (Daicel Chiralpak AD-H × 2, n-
hexane–EtOH 40:1, 0.5 mL/min): major diastereomer tR = 30.7
(major), 40.4 min (minor); minor diastereomer tR = 36.7 (minor),
38.4 min (major).
syn-Isomer (Minor)
1H NMR (400 MHz, CDCl3): d = 1.40 (s, 9 H), 2.34 (s, 3 H), 3.77
(s, 3 H), 5.59 (d, J = 9.8 Hz, 1 H), 6.12 (d, J = 9.8 Hz, 1 H), 7.27–
7.34 (m, 3 H), 7.34–7.42 (m, 2 H).
Synthesis 2010, No. 22, 3785–3801 © Thieme Stuttgart · New York

3800
M. Hatano, K. Ishihara
FEATURE ARTICLE
IR (syn/anti mixtures, neat): 3444, 2980, 1762, 1721, 1496, 1367,
Tsubogo, T.; Yamashita, Y.; Kobayashi, S. J. Org. Chem.
2010, 75, 963.
1250, 1168, 1084, 1027 cm–1.
(3) (a) Uraguchi, D.; Terada, M. J. Am. Chem. Soc. 2004, 126,
5356. (b) Lou, S.; Taoka, B. M.; Ting, A.; Schaus, S. E.
J. Am. Chem. Soc. 2005, 127, 11256. (c) Tillman, A. L.; Ye,
J.; Dixon, D. J. Chem. Commun. 2006, 1191. (d) Song, J.;
Wang, Y.; Deng, L. J. Am. Chem. Soc. 2006, 128, 6048.
(e) Fini, F.; Bernardi, L.; Herrera, R. P.; Pettersen, D.; Ricci,
A.; Sgarzani, V. Adv. Synth. Catal. 2006, 348, 2043.
(f) Song, J.; Shih, H.-W.; Deng, L. Org. Lett. 2007, 9, 603.
(g) Yamaoka, Y.; Miyabe, H.; Yasui, Y.; Takemoto, Y.
Synthesis 2007, 2571. (h) Takada, K.; Tanaka, S.;
Nagasawa, K. Synlett 2009, 1643. (i) Han, X.;
HRMS (FAB+): m/z [M + Na]+ calcd for C18H22Cl3NNaO5:
460.0461; found: 460.0451.
Major Diastereomer
1H NMR (400 MHz, CDCl3): d = 1.27 (t, J = 6.4 Hz, 3 H), 1.42 (s,
9 H), 4.28–4.44 (m, 2 H), 4.58–4.78 (m, 1 H), 5.53–5.70 (m, 1 H),
6.26 (d, J = 9.6 Hz, 1 H), 7.24–7.34 (m, 5 H).
13C NMR (100 MHz, CDCl3): d = 13.9, 28.2 (3 C), 55.2, 56.4, 62.7,
80.0, 95.7, 126.4 (2 C), 128.0, 128.6 (2 C), 138.1, 154.8, 165.7,
184.6.
Kwiatkowski, J.; Xue, F.; Huang, K.-W.; Lu, Y. Angew.
Chem. Int. Ed. 2009, 48, 7604. (j) Pan, Y.; Zhao, Y.; Ma, T.;
Yang, Y.; Liu, H.; Jiang, Z.; Tan, C.-H. Chem. Eur. J. 2010,
16, 779. (k) Lee, J. H.; Kim, D. Y. Synthesis 2010, 1860.
(4) For reviews in BINOL chemistry, see: (a) Chen, Y.; Yekta,
S.; Yudin, A. K. Chem. Rev. 2003, 103, 3155.
(b) Shibasaki, M.; Matsunaga, S. Chem. Soc. Rev. 2006, 35,
269. (c) Brunel, J. M. Chem. Rev. 2007, 107, PR1.
(5) For reviews in acid–base chemistry, see: (a) Kanai, M.;
Kato, N.; Ichikawa, E.; Shibasaki, M. Synlett 2005, 1491.
(b) Ishihara, K.; Sakakura, A.; Hatano, M. Synlett 2007, 686.
(6) The pKa value for 1,3-dicarbonyl compounds, see:
(a) Olmstead, W. N.; Bordwell, F. G. J. Org. Chem. 1980,
45, 3299. (b) Mori, K.; Oshiba, M.; Hara, T.; Mizugaki, T.;
Ebitani, K.; Kaneda, K. Tetrahedron Lett. 2005, 46, 4283.
(7) Hatano, M.; Maki, T.; Moriyama, K.; Arinobe, M.; Ishihara,
K. J. Am. Chem. Soc. 2008, 130, 16858.
(8) Achiral diarylammonium arenesulfonates for ester
condensation reactions, see: (a) Wakasugi, K.; Misaki, T.;
Yamada, K.; Tanabe, Y. Tetrahedron Lett. 2000, 41, 5249.
(b) Ishihara, K.; Nakagawa, S.; Sakakura, A. J. Am. Chem.
Soc. 2005, 127, 4168. (c) Sakakura, A.; Nakagawa, S.;
Ishihara, K. Tetrahedron 2006, 62, 422. (d) Sakakura, A.;
Watanabe, H.; Nakagawa, S.; Ishihara, K. Chem. Asian J.
2007, 2, 477.
(9) Asymmetric catalysis by ammonium sulfonates, see: aza-
Henry reactions: (a) Nugent, B. M.; Yoder, R. A.; Johnston,
J. N. J. Am. Chem. Soc. 2004, 126, 3418. Diels–Alder
reactions: (b) Ishihara, K.; Nakano, K. J. Am. Chem. Soc.
2005, 127, 10504. (c) Sakakura, A.; Suzuki, K.; Nakano, K.;
Ishihara, K. Org. Lett. 2006, 8, 2229. (d) Kano, T.; Tanaka,
Y.; Maruoka, K. Org. Lett. 2006, 8, 2687. [2+2]
Minor Diastereomer
1H NMR (400 MHz, CDCl3): d = 1.19 (t, J = 7.2 Hz, 3 H), 1.42 (s,
9 H), 4.28–4.44 (m, 2 H), 4.58–4.78 (m, 1 H), 5.53–5.70 (m, 1 H),
5.77 (d, J = 8.3 Hz, 1 H), 7.24–7.34 (m, 5 H).
13C NMR (100 MHz, CDCl3): d = 13.8, 28.2 (3 C), 55.0, 56.6, 60.4,
80.1, 95.5, 126.8 (2 C), 128.1, 128.7 (2 C), 138.5, 154.9, 165.9,
182.1.
Chiral Calcium(II) Phosphate Salt Catalysis; General Proce-
dure
A well-dried Pyrex Schlenk tube was charged with (R)-3,3¢-bis(4-
naphthalen-2-ylphenyl)-1,1¢-binaphthyl phosphate (HCl-washed
H[27a], 18.8 mg, 0.025 mmol) and Ca(Oi-Pr)2 (2.0 mg, 0.0125
mmol) under N2. CH2Cl2–MeOH (1:1, 2 mL) was added, and the
soln was stirred at r.t. for 30 min. The volatile solvents were then
removed in vacuo, and CH2Cl2 (2 mL) was added and removed in
vacuo again. This solvent-removal sequence was repeated two ad-
ditional times, and Ca[27a]2 was obtained in situ as a white solid.
CH2Cl2 (4 mL) was then added, and the soln was stirred at r.t. for 15
min. To the soln was added aldimine (0.50 mmol). 1,3-Dicarbonyl
compound (0.55 mmol) in CH2Cl2 (1.0 mL) was then added over 1
h (a syringe pump is useful if available.). The resultant mixture was
stirred at r.t. for 1 h. Sat. aq NH4Cl (10 mL) was poured into the
mixture, and the product was extracted with EtOAc (3 × 15 mL).
The combined extracts were washed with brine (10 mL) and dried
(Na2SO4). The organic phase was concentrated under reduced pres-
sure and the crude product was purified by column chromatography
(silica gel, n-hexane–Et2O, 5:1–1:1) to give the desired product.
The enantiomeric purity was determined by chiral HPLC.
Acknowledgment
Cycloadditions: (e) Ishihara, K.; Nakano, K. J. Am. Chem.
Soc. 2007, 129, 8930.
Financial support for this project was partially provided by JSPS.
KAKENHI (20245022), MEXT. KAKENHI (21750094,
21200033), and the Global COE Program of MEXT.
(10) Barber, H. J.; Smiles, S. J. Chem. Soc. 1928, 1141.
(11) List and co-workers reported asymmetric catalysis with
BINSA, where the enantioselectivities were 0–5% ee:
(a) Kampen, D.; Ladépêche, A.; Claßen, G.; List, B. Adv.
Synth. Catal. 2008, 350, 962. (b) Pan, S. C.; List, B. Chem.
Asian J. 2008, 3, 430.
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Synthesis 2010, No. 22, 3785–3801 © Thieme Stuttgart · New York

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Asymmetric Direct Mannich-Type Catalysis
3801
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(e) Hamilton, G. L.; Kang, E. J.; Mba, M.; Toste, F. D.
Science 2007, 317, 496.
(16) Hatano, M.; Horibe, T.; Ishihara, K. J. Am. Chem. Soc. 2010,
132, 56.
(17) Chiral Li(I)–BINOLate catalyses, see: (a) Schiffers, R.;
Kagan, H. B. Synlett 1997, 1175. (b) Loog, O.; Mäeorg, U.
Tetrahedron: Asymmetry 1999, 10, 2411. (c) Nakajima, M.;
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(30) For a review, and the references therein: Rueping, M.;
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(31) Hatano, M.; Ikeno, T.; Matsumura, T.; Torii, S.; Ishihara, K.
Adv. Synth. Catal. 2008, 350, 1776.
(32) After our publication of ref. 24, List and co-workers reported
their investigation of the metal impurities in ‘phosphoric
acid’. A trace-element analysis by ICP-OES revealed that
various alkali and alkaline earth metals were present as
major impurities in the order Ca > Na > Mg > Si >> other
metals. They warned that these impurities could impair the
catalytic activities of the expected ‘phosphoric acid’, such as
in asymmetric hydrogenation. Klussmann, M.; Ratjen, L.;
Hoffmann, S.; Wakchaure, V.; Goddard, R.; List, B. Synlett
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(18) Holmes, I. P.; Kagan, H. B. Tetrahedron Lett. 2000, 41,
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(19) Hatano, M.; Ikeno, T.; Miyamoto, T.; Ishihara, K. J. Am.
Chem. Soc. 2005, 127, 10776.
(20) pKa values, which were reported in SciFinder, were
calculated using Advanced Chemistry Development (ACD/
Labs) software V11.02 (1994-2010 ACD/Labs).
(21) Hatano, M.; Horibe, T.; Ishihara, K. Org. Lett. 2010, 12,
3502.
(22) Mg(II)–BINOLates have received little attention in
asymmetric catalysis, see: (a) Noyori, R.; Suga, S.; Kawai,
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Synthesis 2010, No. 22, 3785–3801 © Thieme Stuttgart · New York