Direct catalytic asymmetric anti-selective Mannich-type reactions

Article abstract of DOI:10.1039/b602221a

The simple chiral pyrrolidine catalyzed asymmetric anti-selective Mannich-type reaction is presented; the reaction gives the corresponding amino acid derivatives with 10:1->19:1 dr and 97-99% ee. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b602221a

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COMMUNICATION
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Direct catalytic asymmetric anti-selective Mannich-type reactions{
Ismail Ibrahem and Armando Co´rdova*
Received (in Cambridge, UK) 14th February 2006, Accepted 28th February 2006
First published as an Advance Article on the web 15th March 2006
DOI: 10.1039/b602221a
(Fig. 1) and thus change the stereochemical outcome of the
reaction and make it anti-selective. To test this we investigated the
chiral pyrrolidine-catalyzed Mannich-type reaction between ethyl
N-p-methoxyphenyl (PMP)-protected a-iminoglyoxylate and iso-
valeraldehyde 2a (eqn (1)). We found that several bulky pyrrolidine
derivatives catalyzed the reaction with moderate to good anti-
selectivity. To our delight we found that the readily available
TMS-protected a,a-diphenyl-2-pyrrolidinemethanol14 (diphenyl-
prolinol, 1) catalyzed the direct catalytic asymmetric Mannich-
type reaction with high anti- and enantioselectivity and the
corresponding b-formyl-a-amino acid 3a was furnished in 56%
yield with .19 : 1 dr (anti : syn) and 92% ee.
The simple chiral pyrrolidine catalyzed asymmetric anti-
selective Mannich-type reaction is presented; the reaction gives
the corresponding amino acid derivatives with 10 : 12.19 : 1 dr
and 97–99% ee.
The development of direct catalytic Mannich reactions has
received considered attention in recent years.1 It is used for the
enantioselective synthesis of amino acids, b-lactams, amino sugars,
imino sugars and amino alcohols.1–12 The synthetic utility of these
products have created a demand for catalytic highly enantioselec-
tive Mannich reactions that are either syn- or anti-selective.2
Several catalysts have been developed for the catalysis of syn-
selective direct asymmetric Mannich reactions. For instance,
organometallic La-,3 Zn-,4 Cu-5 and In-complexes6 catalyze the
reaction with excellent syn- and enantioselectivity. Moreover,
organocatalysts such as Brønsted acids,7 chincona alkaloids,8
proline and its derivatives,9 proline tetrazoles,10 and amino acids
catalyze11 the direct Mannich reaction with high syn- and
enantioselectivity. However, there are only a few examples of
anti-selective direct catalytic asymmetric Mannich-type reactions.12
Thus, the development of direct catalytic asymmetric anti-selective
Mannich reactions is important and challenging.13 Herein, we
report a highly anti- and enantioselective Mannich-type reaction
with aldehydes as nucleophiles that is catalyzed by a simple
diphenylprolinol derivative.
ð1Þ
Encouraged by this result, we performed a solvent screen with
protected diphenylprolinol 1 as the catalyst (Table 1).
The reaction proceeded smoothly with high anti- and enantio-
selectivity in all the solvents tested. The highest enantioselectivity
was obtained in CHCl3 and CH3CN. Notably, the reaction was
highly stereoselective in water: the amino acid derivative 3a was
formed with 12 : 1 dr and 98% ee. In fact, this is the first example
of a direct catalytic asymmetric Mannich-type reaction in water.
Based on the results from the solvent screen we chose to investigate
the chiral pyrrolidine 1 catalyzed anti-selective reaction between
different aldehydes and N-PMP-protected a-iminoglyoxylate in
CHCl3 and CH3CN (Table 2).
In the proline, hydroxyproline and proline tetrazole-catalyzed
Manich reactions, the Si-facial attack on the imine with a trans
configuration by the Si-face of the chiral enamine gives the
corresponding Mannich product with a syn relative configuration
(Fig. 1).9,10 However, we believed that efficient shielding of the Si-
face of the chiral enamine by the employment of a bulky chiral
amine catalyst would switch the facial selectivity of the reaction
Table 1 Solvent screen for the direct catalytic asymmetric anti-
selective formation of 2a
Time Temp. Yield
(%)a
ee
Entry Solvent
(h)
(uC)
drb
(%)c
1
2
3
4
5
6
7
a
t-BuOH: H2O-1:1 16
rt
rt
rt
4
rt
rt
4
35
50
56
68
43
32
35
.19 : 1 96
.19 : 1 99
.19 : 1 92
.19 : 1 98
14 : 1 88
Fig. 1 The stereochemical outcome of the (S)-proline direct asymmetric
catalyzed Mannich reaction and a plausible bulky chiral amine catalyzed
Mannich-type reaction.
CH3CN
CHCl3
CHCl3
Toluene
EtOH
17
16
24
16
16
16
.19 : 1 82
12 : 1 98
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm
University, Sweden. E-mail: acordova1a@netscape.net;
acordova@organ.su.se; Fax: + 46 8 15 49 08; Tel: +46 8 162479
{ Electronic supplementary information (ESI) available: experimental
procedures. See DOI: 10.1039/b602221a
H2O
Isolated yield of the pure products after silica-gel chromatography.
Anti:syn ratio as determined by NMR analyses. Determined by
b
c
chiral-phase HPLC analyses. PMP 5 p-methoxyphenyl.
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Table 2 Direct catalytic anti-selective asymmetric Mannich-type
reactions
Fig. 2 Proposed transition state for the protected diarylprolinol
catalyzed direct asymmetric anti-selective Mannich-type reaction.
Time Yield
Cond. Prod (h) (%)a
ee
Entry R
drb
(%)c
contributes to the stabilization of the Si-facial attack on the
electrophile.16
1
2
3
4
5
6
7
a
i-Pr
A
A
A
B
3a
3b
3c
3c
3d
3e
3a
24
18
14
17
16
16
16
68
63
.19 : 1
.19 : 1
98
99
n-pent
Me
Me
CH2OBn A
CH2Ph
i-Pr
45 (35)d 14 : 1 (15 : 1)d 99 (90)d
In summary, we have developed a highly anti- and enantio-
selective direct catalytic asymmetric Mannich-type reaction. The
asymmetric Mannich-type reactions are catalyzed by simple
diphenyl- and di(2-naphthyl)prolinol derivatives that are prepared
in one step and furnish amino acid derivatives in high yields with
14 : 12.19 : 1 dr and up to 99% ee. The reaction is also highly
stereoselective in water (90–98% ee). Further studies on the
development of direct catalytic anti-selective Mannich reactions
and their application in catalytic asymmetric domino- and tandem-
reactions are ongoing.
75
15 : 1
99
67 (30)d 14 : 1 (10 : 1)d 97 (90)d
A
A
67
45e
19 : 1
.19 : 1e
99
99e
Isolated yield of the pure products after silica-gel chromatography.
Syn:anti ratio as determined by NMR analyses. Determined by
b
c
d
chiral-phase HPLC analyses. Reaction performed in H2O at 4 uC,
1 h reaction time. Bn 5 benzyl, PMP 5 p-methoxyphenyl. TMS
protected di(2-naphthyl)prolinol (10 mol%) was used as the catalyst.
A 5 CHCl3, 4 uC. B 5 CH3CN, 4 uC.
e
We gratefully acknowledge the Swedish National Research
Council, Carl-Trygger Foundation, Lars-Hierta Foundation and
Medivir AB for financial support.
The diphenylprolinol 1-catalyzed direct Mannich-type reactions
were highly enantioselective and amino acid derivatives 3 were
isolated in moderate to high yields with 97–99% ee. The reactions
were highly anti-selective (14 : 12.19 : 1). For instance, a-amino
acid 3e was furnished in 67% yield with 19 : 1 dr and 99% ee.
Moreover, the chiral amine-catalyzed asymmetric reaction with
a-benzyloxyacetaldehyde as the donor was highly stereoselective
and gave 3d in 67% yield with 14 : 1 dr and 97% ee. Amino sugar
3d with an anti-configuration is an important chiral synthon and
can be used in the de novo synthesis of C-6 amino- and
iminosugars.9l Thus, the catalytic asymmetric anti-selective
Mannich-type reaction opens up the possibility of synthesizing
all the different diastereomers of amino and imino sugar
derivatives. We also investigated the organocatalytic asymmetric
Mannich-type reactions in water with aldehydes 2 as nucleophiles.
The reactions were very fast due to the hydrophobic effect15 and
the product together with the starting imine formed an organic
precipitate within 1 h, which upon isolation gave the correspond-
ing products 3 with high enantioselectivity (90–98% ee) but low
conversion (,40%). Moreover, TMS protected di(2-naphthyl)pro-
linol catalyzed the asymmetric Mannich reaction with excellent
anti- and enantioselectivity to give 3a with .19 : 1 dr and 99% ee.
The absolute stereochemistry of the Mannich products was
established by comparison with the epimerized (2S,3S)-syn-3a and
3d Mannich products obtained by (S)-proline catalysis.9g,i,l Hence,
(S)-diphenylprolinol 1 catalyzed the asymmetric formation of
(2S,3R)-amino acid derivatives 3. The stereochemical outcome of
the reaction was explained by the proposed transition state I
(Fig. 2). Thus, attack on the Si-face of the imine with a trans-
configuration by the Re-face of the chiral enamine gives the amino
acid derivative 3.
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