Enantio- and diastereoselective catalytic mannich-type reaction of a glycine schiff base using a chiral two-center phase-transfer catalyst

Article abstract of DOI:10.1002/anie.200500927

(Chemical Equation Presented) Optically active α,β-diamino acids are prepared under asymmetric phase-transfer reaction conditions from a glycine Schiff base and N-protected imines with a tartrate-derived diammonium salt (TaDiAS) as the phase-transfer cata

Full text of DOI:10.1002/anie.200500927

Communications
Various methods for the preparation of optically active a,b-
diamino acid derivatives have been reported.Almost all of
them, however, require the use of stoichiometric amounts of
chiral sources.One common method involves the displace-
ment of the hydroxy group of serine derivatives with an azide
moiety followed by reduction of the azide group,[1,4] and
another is the addition of glycine ester derivatives to chiral N-
sulfinyl imines.[5,6] Jørgensen and co-workers reported an
efficient catalytic method that relies on the aza-Henry
reaction of silyl nitronates with imines.[7] The catalytic
asymmetric synthesis of chiral serine derivatives by the
Sharpless asymmetric aminohydroxylation reaction is another
useful method.[8] Recently, more direct and atom-econom-
ically favorable methods using a Mannich-type reaction of a
glycine Schiff base with imines were reported by Jørgensen
and co-workers[9] and Maruoka and co-workers.[10] Although
these methods are highly enantioselective, there is still much
room for improvement.For example, the removal of para-
toluenesulfonate (tosyl) groups is difficult in the method of
Jørgensen and co-workers, and low substrate generality is a
problem in the method of Maruoka and co-workers.Both
methods are also only moderately diastereoselective.Herein,
we report a new direct method to access a variety of optically
active syn-a,b-diamino acid derivatives by a Mannich-type
reaction of a glycine Schiff base that uses a new chiral two-
center phase-transfer catalyst.The selection of the imine-
protecting group was pivotal to achieving high diastereose-
lectivity (up to 99:1).Moreover, the usefulness of the
obtained products was successfully demonstrated by their
transformation into a tripeptide and the key intermediate of
CP-99,994 through chemoselective deprotection of the N-
diphenylmethylene and N-tert-butoxycarbonyl (Boc) protect-
ing groups.
Phase-Transfer Catalysis
Enantio- and Diastereoselective Catalytic
Mannich-Type Reaction of a Glycine Schiff Base
Using a Chiral Two-Center Phase-Transfer
Catalyst**
Akihiro Okada, Tomoyuki Shibuguchi,
Takashi Ohshima,* Hyuma Masu, Kentaro Yamaguchi,
and Masakatsu Shibasaki*
To develop efficient methods for the synthesis of a,b-
diamino acid derivatives, we used Mannich protocols under
asymmetric phase-transfer reaction conditions because of the
preparative advantages of the phase-transfer process, such as
simple procedures and mild conditions.[11] Recently, we
developed the tartrate-derived diammonium salt (TaDiAS)
1, which efficiently catalyzes asymmetric phase-transfer
alkylations and Michael reactions of a glycine Schiff base 2.[12]
a,b-Diamino acids are key structural components in mole-
cules such as peptides and b-lactam antibiotics and in
medicinally relevant compounds;[1,2] for example, 2,3-diami-
no-3-phenylpropanoic acid is used as an advanced alternative
to the side chain of taxol to improve its water solubility.[3]
[*] A. Okada, T. Shibuguchi, Dr. T. Ohshima, Prof. Dr. M. Shibasaki
Graduate School of Pharmaceutical Sciences
The University of Tokyo
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
Fax: (+81)3-5684-5206
E-mail: ohshima@chem.es.osaka-u.ac.jp
mshibasa@mol.f.u-tokyo.ac.jp
Dr. H. Masu, Prof. Dr. K. Yamaguchi
Faculty of Pharmaceutical Sciences at Kagawa Campus
Tokushima Bunri University
Shido, Sanuki-city, Kagawa 769-2193 (Japan)
We initially examined a Mannich-type reaction of 2 using
N-diphenylphosphinoyl (dpp) imine 3a as an electrophile
because the dpp group can be readily removed under mild
conditions.[13] Under phase-transfer conditions using TaDiAS
1b, which is a suitable catalyst for asymmetric phase-transfer
Michael reactions,[12] and fluorobenzene and cesium carbon-
ate were determined to be the best solvent and base,
respectively; this reaction afforded the desired Mannich
[**] This work was supported by RFTF, a Grant-in-Aid for the Encour-
agement of Young Scientists (A), and a Grant-in-Aid for Specially
Promoted Research from the Japanese Society for the Promotion of
Science (JSPS) and the Ministry of Education, Culture, Sports,
Science, and Technology (MEXT).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200500927
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Angewandte
Chemie
product 4a in high yield (95%) and moderate selectivity (syn/
anti = 77:23, 51% ee; Table 1, entry 1).[14] Various N-pro-
tected imines were screened under the optimized conditions
(Table 1, entries 2–5).Although the reaction did not proceed
Table 1: Catalytic asymmetric Mannich-type reaction with various N-
protected imines 3.
Figure 1. Crystal structure of (S,S)-TaDiAS (1a). a) Top view and
b) side view.
Entry Imine 3 R2
T [8C] t [h] Yield [%] d.r.
[syn/anti][a]
ee [%][b]
1
2
3
4
5
3a
3b
3c
3d
3e
dpp
CHPh2 RT
CH2Ph RT
Boc
tosyl
4
2
72
72
2
95
77:33
51
acetal side chains, especially to the C2 and C3 positions
(Figure 1b).
n.r.[c]
n.r.[c]
quant
In the reaction, the enolate of 2 was expected to be
replaced with the BF4ꢀ ion and form a tight complex with the
cationic centers of 1.Therefore, we assumed that longer or
more sterically congested acetal substituents would prevent
an unfavorable approach by the imines to the enolate of 2.On
the basis of this hypothesis, the substituent effects of the
acetal moiety were examined (Table 2).[15] As expected, the
4
RT
>95:5
70:30
53
0
2.5 97
[a] Determined by HPLC analysis. [b] The ee value of the syn product was
determined by HPLC analysis. [c] n.r.=no reaction.
when diphenylmethyl imine 3b (Table 1, entry 2) and benzyl
imine 3c (Table 1, entry 3) were used, N-Boc imine 3d
(Table 1, entry 4) gave the product 4d in quantitative yield
with high diastereoselectivity (syn/anti = > 95:5) and moder-
ate enantioselectivity (53% ee).These results suggested that
the electron-withdrawing imine-protecting group plays an
important role in the reactivity.On the other hand, the N-
tosyl imine was less reactive and produced a low enantiose-
lectivity (Table 1, entry 5).Thus, we chose the N-Boc imine
3d as a substrate for further investigation because of these
results and the fact that a Boc protecting group can be readily
removed.
Table 2: Optimization of the catalyst structure for the asymmetric
Mannich-type reaction.
We next examined the structure of the catalyst to improve
enantioselectivity.We had previously synthesized a variety of
TaDiAS salts 1, and they had been examined in catalytic
asymmetric phase-transfer alkylations and Michael reactions.
However, rational design of the catalyst was still difficult
because of the lack of conformational information about 1,
except for preliminary computational analysis that suggested
the formation of a tight ion complex between the two cation
centers in 1 and the enolate of 2.Thus, on the basis of the
above analysis, we performed a conformational investigation
of 1.Although no useful information was obtained by NMR
spectroscopy, the structure of 1a was determined by X-ray
crystallographic analysis.A tetrafluoroborate anion is situ-
ated very close to each of the ammonium units, thus creating
an attractive C2-symmetrical chiral environment (Figure 1).
Another interesting fact is that the alkyl chains of the acetal
moiety snake up in a direction perpendicular to the dioxolane
ring.A previous examination of substituent effects in
asymmetric phase-transfer catalysis revealed that both aro-
matic and acetal moieties strongly affected enantioselectivity.
This unexpected substituent effect by the acetal moiety can be
understood from the proximity of the counteranions to the
Entry Cat. R3
T
t
Yield
[%]
d.r.
ee
1
[8C] [h]
[syn/anti][a] [%][b]
1
2
3
4
5
6
1a
1b
1c
1d
1e
1 f
H
Me
Ph
4
4
4
4
4
4
4
1
1
96
>95:5
58
59
62
57
60
48
65
82
quant >95:5
98:2
0.5 quant >95:5
0.5 quant
CH2Ph
4-tBuC6H4
2,4,6-Me3C6H2
4-FC6H4
4-FC6H4
0.5 quant
0.5 97
0.5 99
98:2
98:2
97:3
95:5
7
1g
1g
8[c]
ꢀ45 48
95
[a] Determined by HPLC analysis. [b] The ee value of the syn product was
determined by HPLC analysis. [c] Solvent was PhF/pentane (4:1).
introduction of an aromatic ring at the C2 positions of the
acetal side chains improved the enantioselectivity (Table 2,
entry 3).On the other hand, the introduction of a benzyl
group at C2, which results in an aromatic ring at the C3
position (Table 2, entry 4), and a bulky substituent at C2
(Table 2, entry 6) gave only moderate enantioselectivity.
Finally, the best results were obtained from the use of the 4-
fluorophenyl-substituted catalyst 1g (Table 2, entry 7), which
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suggests the possibility of p–p interactions.[16]
Performing the latter reaction at lower temper-
ature (ꢀ458C) further improved the enantio-
selectivity to 82% ee (Table 2, entry 8).
We examined the scope and limitations of
the reaction under the optimized conditions
using various N-Boc imines.As summarized in
Table 3, all the asymmetric Mannich-type reac-
tions proceeded in high yield with high diaster-
eoselectivity
(syn/anti = 95:5–99:1)
when
10 mol% of TaDiAS 1g was used with
Cs2CO3 in fluorobenzene.In terms of enantio-
selectivity, C-phenyl imine derivatives with an
electron-donating group at the 4-position were
suitable substrates (Table 3, entries 2 and 3).
On the other hand, 4-chlorophenyl and 2-
naphthyl substituents (Table 3, entries 7 and
8) were only moderately enantioselective.
Scheme 1. Syntheses of tripeptide 6 and the key intermediate 8 of CP-99,994. Reagents
and conditions: a) 0.5m citric acid, THF, RT; b) N-Cbz-gly, WSC, HOBt, CH2Cl2, 48C
(90% over 2 steps); c) 2n HCl, MeOH, RT; d) N-Boc-gly, WSC, HOBt, CH2Cl2, 48C
(92% over 2 steps); e) BnBr, K2CO3, THF, reflux; f) recrystallization from EtOAc/
hexane (42% over 3 steps, 99% ee); g) LiAlH4, 4!408C (91%); h) see ref. [19]
Cbz=carbobenzoxy, Bn=benzyl, gly=glycine, HOBt=1-hydroxybenzotriazole,
WSC=N-ethyl-N’-(3-dimethylaminopropyl)carbodiimide.
Table 3: Scope and limitations of catalytic an asymmetric Mannich-type reaction.
(Scheme 1, top).Highly chemoselective
deprotection of the N-diphenylmethylene
group of 4 f by aqueous citric acid, followed
by a subsequent peptide-coupling reaction
gave dipeptide 5.Next, the N-Boc group
was readily deprotected with a 2n solution
of HCl in methanol to afford, after another
peptide-coupling reaction, the optically
pure tripeptide 6 in good yield.Moreover,
the protected a,b-diamino ester 4d, which
was synthesized by using (R,R)-TaDiAS 1g,
was successfully converted into the key
intermediate 8[19] in an optically pure form
(Scheme 1, bottom).
Information about the reaction mecha-
nism is essential to improve the efficiency of
the catalyst, TaDiAS 1.Despite the value of
mechanistic investigations in catalyst devel-
opment, however, only limited mechanistic
studies on asymmetric phase-transfer catal-
ysis have been reported.[20] To gain insight
Entry
Imine 3
R4
T [8C]
t [h]
Yield [%]
d.r.
ee [%][b]
[syn/anti][a]
1
2[c]
3
3d
3 f
3g
3h
3i
3j
3k
3l
Ph
ꢀ30
ꢀ45
ꢀ40
ꢀ45
ꢀ20
ꢀ40
ꢀ20
ꢀ20
ꢀ40
ꢀ30
19
48
48
72
66
48
20
72
48
48
98
95
98
96
99
99
87
87
98
86
99:1
95:5
98:2
95:5
97:3
98:2
98:2
>95:5
98:2
98:2
70
4-OMe-C6H4
4-Me-C6H4
3-Me-C6H4
2-Me-C6H4
4-F-C6H4
4-Cl-C6H4
2-naphthyl
2-thiophenyl
82 (99)[d]
80
4[c]
5
70
68
72
58
60
80
66
6
7
8
9
3m
3n
=
10
(E)-PhCH CH2
[a] Determined by HPLC analysis. [b] The ee value of the syn product was determined by HPLC analysis.
[c] Solvent was PhF/pentane (4:1). [d] The ee value after a single recrystallization.
Although N-Boc C-aliphatic imines could not be applied
because of the difficulties in synthesizing them, the use of a,b-
unsaturated imines for the Mannich-type reaction followed by
hydrogenation is an alternative method (Table 3, entry 10).
Another beneficial feature of this process is that most of the
products were obtained as crystalline solids, and in fact a
single recrystallization of 4 f (82% ee) provided an optically
pure compound in 74% yield.Although the enantioselectivity
of the reaction was not very satisfactory, to the best of our
knowledge, this diastereoselectivity is the highest reported for
a catalytic Mannich-type reaction of a glycine Schiff base 2
with imines.
The synthetic utility of the resulting optically active a,b-
diamino acid derivatives was demonstrated by straightfor-
ward transformations into tripeptide 6 and key intermediate 8
for the synthesis of the selective and potent neurokinin
substance P antagonist (+)-CP-99,994[17–19] through deprotec-
tion of the N-diphenylmethylene and N-Boc groups
into the mechanism of this asymmetric phase-transfer cata-
lytic reaction, we performed initial rate kinetic studies.[21]
First-order dependency was observed for the glycine Schiff
base 2 and Cs2CO3, whereas the reaction rate had zero-order
dependency for the imine 3 and the catalyst 1.These results
indicated that the rate-determining step of the Mannich-type
reaction is deprotonation of 2 by Cs2CO3; unexpectedly, 1 was
not involved in this step.On the basis of these results, we
propose a catalytic cycle for the asymmetric Mannich-type
reaction (Scheme 2).Deprotonation of 2 by Cs2CO3 at the
interface between the liquid and solid phase followed by
counteranion exchange with the catalyst 1 gives complex
10.[22] An asymmetric C C bond-forming reaction of 10 with
ꢀ
the imine 3 gives the Mannich product 11.Finally, counter-
anion exchange between 11 and the resulting CsBF4 provides
12 and generates 1.The very low reaction efficiency that
results from the use of a catalytic amount of Cs2CO3 indicates
that the formation of 10 through direct deprotonation of 2 in
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quantitative yield) and syn-selective (up to 99:1) enantio- and
diastereoselective catalytic Mannich-type reaction of a gly-
cine Schiff base 2 with N-Boc imines 3 using the newly
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Received: March 14, 2005
Published online: June 14, 2005
Keywords: amino acids · asymmetric catalysis ·
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