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Asymmetric Catalytic Aza-Henry Reactions Leading to 1 2-Diamines and 1 2-Diaminocarboxylic Acids.

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Angewandte
Chemie
Aza-Henry Reactions
Asymmetric Catalytic Aza-Henry Reactions Leading to
1,2-Diamines and 1,2-Diaminocarboxylic Acids
Bernhard Westermann*
Dedicated to Prof. Dr. Dieter Seebach
on the occasion of his 65th birthday
Keywords:
asymmetric syntheses ¥ aza-Henry reactions ¥
diamines ¥ Lewis acids ¥ Mannich reactions
The aldol reaction, known for its remarkable diastereo- and enantioselectivity, initiated quantum leaps in the
development of stereoselective synthesis. In this context the question frequently asked–™Does it work with
compounds having CN rather than
CO double bonds∫–has been answered extensively in recent years.[1] A
variety of synthetic procedures have
been devised to carry out the Mannich
and related reactions stereoselectively.
Despite all these improvements one
major gap remained, namely, the diastereoselective, asymmetric synthesis of
vicinal diamines. This class of compounds is of particular interest owing
to their broad utility, which ranges from
application as antitumor reagents to
employment as ligands in stereoselective organic synthesis.[2, 3]
Not surprisingly, a number of methods have been developed for the synthesis of products with these functional
units. Most of these procedures rely on
™chiral-pool∫ compounds and/or chiral
auxiliaries for stereocontrol. These approaches have several considerable
drawbacks: the stereochemistry of the
products is restricted by the limited
accessibility of starting materials (often
only one stereoisomer), and chiral auxiliaries, although often recyclable, may
be required in equimolar amounts.
[*] Priv.-Doz. Dr. B. Westermann
Faculty of Natural Sciences, University of
Paderborn
33095 Paderborn (Germany)
Fax: (þ 49) 5251-603-245
E-mail: bw@fb13n.uni-paderborn.de
Angew. Chem. Int. Ed. 2003, 42, 151 ± 153
Organometallic
methodologies
with potential catalytic variations
are known, but often they are
hampered by very narrow substrate-specificity or have limited
application for the synthesis of
chiral,
nonracemic
products.
B‰ckvall et al. described the aminopalladation of (E)-alkenes 1
and subsequent oxidation in the
presence of amines which provided racemic syn-diamines 2
(Scheme 1).[4, 5] Another attractive
synthesis of 1,2-diamines is based Scheme 2. Diastereoselective synthesis of 1,2-diaon the derivatization of 1,2-diols mines by means of an aza-Henry reaction (Tf ¼ triand 1,2-amino alcohols, which are triflate, CAN ¼ ceric ammonium nitrate).
provided by the Sharpless asymmetric dihydroxylation and aminohydroxylation of olefins, respective- diamines 8 could be obtained in high
ly.[6]
yields and with good diastereoselectivVery recently, Anderson et al. re- ities (Scheme 2).
In preliminary studies imines 4 and
ported an interesting synthesis of 1,2diamines.[7] First, an aza-Henry reaction nitroalkanes 6 were allowed to react in
(alternatively, nitro-Mannich reaction, the presence of Br˘nsted acids. More
i.e. addition of nitronates 6 to imines 5) recently the reaction was found to be
provided b-nitroamines 7. To avoid ret- catalyzed by Lewis acids like BF3 and
ro-addition, these intermediates were Sc(OTf)3.[8] Thus, the stage was set for
then reduced with SmI2, and the vicinal developing the catalytic, asymmetric
variants of this sequence–goals
addressed and achieved by the
research groups led by Shibasaki
and J˘rgensen.
Shibasaki et al. investigated the
aza-Henry reaction conducted with
the heterodimetallic catalyst 9,
which
they
had
developed
(Scheme 3).[9, 10] Since 9 shows concomitantly Br˘nsted-basic and
Lewis-acidic behavior, both the
Scheme 1. Diamination of alkenes via an aminoalkelectrophile and the nucleophile
yl-palladium intermediate (m-CPBA ¼ meta-chlorocan be activated. Complexes of this
perbenzoic acid).
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1433-7851/03/4202-0151 $ 20.00+.50/0
151
Highlights
OtBu
K
O
O
Al
O
O
Li
9
NO2
O
PPh2 R 11 9, (20 mol %)
N
Ar
CH2Cl2, – 40 °C
H
HN
R
Ar
10
12
a) SmI2,
THF, MeOH
O
PPh2
NO2
H2N
R
Ar
b) HCl, MeOH
then NaOH
NH2
13
Scheme 3. Asymmetric aza-Henry reaction
with the heterodimetallic complex 9.
type can be considered mimics of the
aldolase type II enzymes (Zn as cofactor) and have given excellent results as
catalysts in aldol, Strecker, and Reissert
reactions.[11]
For high selectivities it appears mandatory to include anchor groups (P¼O
bonds), which provide additional complexation and orientation in these heterodimetallic complexes (Scheme 4).
They can be present in the catalyst itself,
in the substrate, or in an additive to the
reaction mixture. In the case of the azaHenry reaction this unit is found in
substrate 10 (Scheme 3). Under optimized conditions 12 could be obtained
in 90 % yield (syn:anti > 6:1) with an
enantiomeric excess of > 80 %. Among
the disadvantages are the limited number of suitable nitronates 11 available
O
N
O
O
N
Ar
PPh2
O
O
Al
H
R2
NC
N
O
Ph2P
Al
O O
SiMe3
R1
O
PPh2
Scheme 4. The P¼O bond aids in the complexation and orientation of electrophiles and
nucleophiles.
152
(erythro:threo > 25:1) and high enantioselectivities (> 95 % ee for the erythro
product).
This limitation can be overcome and
the reaction can be conducted at room
temperature when amines (NEt3 has
been the amine of choice) are added to
the less reactive nitro compounds. The
resulting stereoselectivities and yields
are generally very high (erythro:threo
> 92:8; > 93 % ee for the erythro product, > 80 % ee for the threo product;
60±87 % yield) when Lewis acids 18 a or
18 b are used. All these features make
this sequence amenable to
technical applications. Decreasing the temperature
NO2
()
4
O
to 0 8C, which is easily
OTBS
O
PPh2
9, (20 mol %)
accomplished, increased
HN
PPh2
14
N
selectivities but prolonged
Ph
OTBS
CH2Cl2, – 40 °C
Ph
90 %, d.r. = 6:1 (anti)
reaction times (1 d at
NO2
15
16
20 8C, 5 d at 0 8C). The
solvent used (CH2Cl2)
HN
does not need further purification and drying, and
HN
inert gas atmosphere can
OMe
17
be avoided. The only critical point is the addition
Scheme 5. Synthesis of CP-99 994 (17) in which an aza-Henry
sequence of the reaction
reaction is the key step (TBS ¼ tert-butyldimethylsilyl).
partners.
In these studies the
of this type of simultaneous Lewis- ligands in the Lewis acids, C2-symmetacidic/Br˘nsted-basic activity in the op- rical modified bisoxazolines, have
timization of catalysts by either combi- proved to be superior to their BINOLnatorial or evolutional approaches may and TADDOL-derived congeners. The
lead to very powerful catalysts for aza- copper(i) salts employed can be copper
Henry reactions.
triflate and even copper bromide deThe breakthrough in terms of han- spite its decreased Lewis acidity. The
dling, substrate variety, and practicability was achieved by J˘rgensen et al.
R' R'
(Scheme 6).[13, 14] They showed that apO
O
plication of C2-symmetrical chiral Lewis
R
R
N
N
acids 18 a and 18 b (20 mol %) to the
Ph
Ph
Cu
addition of nitronates to imines can
18
(Xn)2
afford aza-Henry products 21 with high
18a: R = Ph, R' = H, Xn = OTf
diastereo- and enantioselectivities. Af18b: R = H, R' = Me, Xn = OTf
ter reduction of the nitro moiety in 21
very valuable building blocks like a,b18a (20 mol %)
PMB
NO2 THF, –100 °C
N
diaminocarboxylic acids 22 can be ob+
18b (20 mol %)
Et
H
CO2Et
tained (Scheme 6). If silylated nitroNEt3, 20 °C
nates are employed, addition of base is
19
20
not necessary. Under these reaction
PMB
NH2
HN
conditions the aza-Henry adducts 21
CO2Et
O 2N
H2, Raney-Ni
are stable and can be isolated. Owing
Et
CO2Et
NH2
Et
to the high reactivity of the silylated
21
22
nitronates, the reaction proceeds uncatalyzed even at 78 8C. Reaction tem- Scheme 6. Lewis acids with modified bisoxaperatures of 100 8C were required to zoline ligands in aza-Henry reactions
achieve
high
diastereoselectivities (PMB ¼ p-methoxybenzyl; Tf ¼ triflate).
(in the beginning only nitromethane),
the restriction to N-phosphinoylimines
10, and the large amount of catalyst
(20 mol %, which corresponds to
40 mol % chiral auxiliary). One point
in favor of this methodology is that
vicinal diamines 13 can be obtained
easily from 12 by reduction of the nitro
group and cleavage of the phosphinoyl
group. The effectiveness of this method
has been demonstrated recently in
the synthesis of the potent antagonist
of
substance P,
CP-99 994
(17,
Scheme 5).[12] Certainly consideration
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1433-7851/03/4202-0152 $ 20.00+.50/0
Angew. Chem. Int. Ed. 2003, 42, No. 2
Angewandte
Chemie
sole stipulation is that the protecting
group on the imine should be an electron-rich aryl group.
The high selectivity of the addition is
attributed to a Zimmerman±Traxler
transition state, in which both reaction
partners are coordinated at the chiral
Lewis acid. If one presumes a rapid
equilibration of the E and the Z forms of
the nitronate, transition state 23 (PG ¼
Me Me
O
N
tBu
O
CO2Et
Me
N
O
tBu
MeNO2, CH2Cl2, RT
92%, 92% = ee
HO
CO2Et
26
HO
H2N
Me
CO2Et
27
O
Cu
N
O
N
PG
Ph
Cu
Tf2
Scheme 7. Henry reactions giving a-hydroxy-baminocarboxylic acids 27.
O
N
Me
N
24
Me
Ph
25
20 mol%
Me
O2N
O
O
R
H
23
protecting group) is formed exclusively,
which explains the preferred formation
of the erythro product.
Finally, it should be pointed out that
this method can be applied to the
classical Henry reaction in which ethyl
pyruvate (24) is converted into the
corresponding hydroxyaminocarboxylic
acid 27 (Scheme 7). The quaternary
stereogenic center is generated with
high selectivity.[15]
Both approaches, that based on the
bifunctional Lewis acid catalyst and that
based on the copper-bisoxazolidine cat-
Angew. Chem. Int. Ed. 2003, 42, 151 ± 153
alyst, have bright prospects. Even in the
initial evaluation of these catalysts they
have proven to be most valuable for a
number of very interesting products.[16]
[1] K. Juhl, N. Gathergood, K. A. J˘rgensen, Angew. Chem. 2001, 113, 3083;
Angew. Chem. Int. Ed. 2001, 40, 2995,
and references therein.
[2] D. Lucet, T. Le Gall, C. Mioskowski,
Angew. Chem. 1998, 110, 2724; Angew.
Chem. Int. Ed. 1998, 37, 2581.
[3] C. T. Lowden, J. S. Mendoza, Tetrahedron Lett. 2002, 43, 979.
[4] J. E. B‰ckvall, Tetrahedron Lett. 1975,
2225.
[5] J. E. B‰ckvall, Tetrahedron Lett. 1978,
163.
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
[6] Asymmetric Dihydroxylations and Aminohydroxylations, C. Bolm, J. P. Hildebrand, K. Muniz in Catalytic Asymmetric Synthesis, 2nd ed. (Ed.: I. Ojima),
Wiley-VCH, 2000, p. 399, and references
therein.
[7] H. Adams, J. C. Anderson, S. Peace,
A. M. K. Pennell, J. Org. Chem. 1998,
63, 9932.
[8] J. C. Anderson, S. Peace, S. Pih, Synlett
2000, 850.
[9] K. Yamada, S. J. Harwood, H. Grˆger,
M. Shibasaki, Angew. Chem. 1999, 111,
3713; Angew. Chem. Int. Ed. 1999, 38,
3504.
[10] K. Yamada, G. Moll, M. Shibasaki,
Synlett 2001, 980.
[11] H. Grˆger, Chem. Eur. J. 2001, 7, 5247,
and references therein.
[12] N. Tsuritani, K. Yamada, N. Yoshikawa,
M. Shibasaki, Chem. Lett. 2002, 276.
[13] K. R. Knudsen, T. Risgaard, N. Nishiwaki, K. V. Gothelf, K. A. J˘rgensen, J.
Am. Chem. Soc. 2001, 123, 5843.
[14] N. Nishiwaki, K. R. Knudsen, K. V.
Gothelf, K. A. J˘rgensen, Angew.
Chem. 2001, 113, 3080; Angew. Chem.
Int. Ed. 2001, 40, 2992.
[15] C. Christensen, K. Juhl, R. G. Hazell,
K. A. J˘rgensen, J. Org. Chem. 2002, 67,
4875. A minireview on the construction
of quaternary stereocenters: J. Christoffers, Angew. Chem. 2001, 113, 4725;
Angew. Chem. Int. Ed. 2001, 40, 4591.
[16] Diastereoselective Henry reactions under high pressure: Y. Misumi, K. Matsumoto, Angew. Chem. 2002, 114, 1073;
Angew. Chem. Int. Ed. 2002, 41, 1031.
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