Catalytic enantioselective synthesis of α,β-diamino acid derivatives

Article abstract of DOI:10.1021/ja9034494

(Chemical Equation Presented) Highly enantio- and diastereoselective organocatalytic Mannich additions of α-isothiocyanato imides to sulfonyl imines are reported. Enantiomerically enriched syn-α,β-diamino acid derivatives can be obtained in excellent yiel

Full text of DOI:10.1021/ja9034494

Published on Web 07/31/2009
Catalytic Enantioselective Synthesis of r,ꢀ-Diamino Acid Derivatives
Le Li, Madhu Ganesh, and Daniel Seidel*
Department of Chemistry and Chemical Biology, Rutgers, The State UniVersity of New Jersey,
Piscataway, New Jersey 08854
Received April 29, 2009; E-mail: seidel@rutchem.rutgers.edu
Table 1. Evaluation of Catalysts and Protecting Groupsa
Vicinal diamines are important structural motifs that have been
incorporated into chiral auxiliaries, catalysts, and ligands.1 R,ꢀ-
Diamino acids and their derivatives are part of many biologically
active natural products and synthetic materials.2 Here we report a
convenient method for the highly enantio- and diastereoselective
preparation of syn-R,ꢀ-diamino acid derivatives. Our approach relies
on Mannich reactions between R-isothiocyanato imides and sulfonyl
imines (eq 1) using readily available organocatalysts at relatively
low catalyst loadings and ambient temperature.
Various diastereoselective methods for the synthesis of R,ꢀ-
diamino acid derivatives have been reported.3 Catalytic enantiose-
lective approaches have focused on Mannich reactions of glycine
imines4 or nitro esters5 with various imines. Catalytic enantiose-
lective Mannich reactions of nitroalkanes or silyl nitronates with
R-imino esters have also been reported.6 In addition, R-isocyano
esters7 and azlactones8 have been employed as glycine equivalents
in Mannich reactions. Willis and co-workers have recently used
the R-isothiocyanato imide 1b in highly enantioselective aldol and
Mannich reactions.9,10 Using a chiral magnesium complex derived
from DBFox, products such as 2b were obtained with high levels
of enantioselectivity favoring the anti product.9b
entry
catalyst
sm
Pg
time [h]
yield [%]b
dr [%]c
ee [%]d
1e
3
4
5
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Bs
Ts
Bs
Ns
Ts
Ts
Ts
72
72
72
72
72
72
72
48
15
18
42
17
1.5
72
10
5.5
72
72
72
49
33
27
31
22
35
29
81
94
96
95
94
95
92
95
95
80
62
79
94:06
90:10
87:13
-56
-31
-56
60
84
95
96
-61
98
98
95
98
98
97
97
97
55
2e
3e
4e
7b
7c
7d
7e
3
7d
7e
7f
7g
7d
7df
7df
7df
6a
6b
7a
>95:05
>95:05
>95:05
>95:05
91:09
>95:05
>95:05
>95:05
>95:05
>95:05
>95:05
>95:05
>95:05
92:08
5e
6e
Based on our recent success in using R-isothiocyanato imide 1a
in catalytic enantioselective aldol reactions employing catalyst 3,11
we sought to expand this methodology to the use of imines. A
reaction of 1a with the tosyl imine derived from benzaldehyde was
incomplete after 3 days when using 5 mol % of catalyst 3. Product
2a was obtained in modest enantioselectivity and yield but with
good diastereoselectivity favoring the syn- diastereomer (Table 1,
entry 1). Subsequently, other readily available organocatalysts12-14
were evaluated. To our delight, the quinidine derived bifunctional
catalyst 7d, pioneered by Deng,14b provided product 2a in excellent
enantio- and diastereoselectivity (entry 6). However, a low reaction
rate was observed. Interestingly, significant rate acceleration was
achieved by using the unsubstituted R-isothiocyanato imide 1b in
place of 1a (entry 9). It was found that product 2b shows a lower
solubility in toluene as compared to 2a, limiting the possibility of
product inhibition. This should serve at least in part to explain the
faster reaction rates observed with this substrate. The nature of the
acyl group on catalyst 7 was found to have little effect on the ee
and dr of the product, with more electron-withdrawing groups
resulting in lower reaction rates (entries 9-12).
7e
8
9
10
11
12
13
14e
15
16
17e
18e
19e
93:07
94:06
50
52
a Reactions were performed at rt on a 0.2 mmol scale in anhydrous
toluene (0.1 M) using 2 equiv of imine. Reactions were run to full
conversion as judged by TLC analysis. The ee’s were determined by
HPLC analysis of the ester derivatives. b Combined yield of both
diastereomers. c trans:cis, determined by 1H NMR. d trans isomer. e The
reaction is incomplete. f Run with 1 mol % catalyst loading.
group allowed for complete conversion in only 5.5 h with 1 mol
% of catalyst 7d (entry 16). Control experiments with structurally
related quinidine derivatives showed that a free hydroxyl group on
the quinoline ring is important for both reactivity and selectivity
(entries 17-19). In agreement with Deng’s findings,14b this suggests
a bifunctional role for catalyst 7d.
With the optimized reaction conditions in hand, a series of
different Bs protected imines was evaluated (Table 2). Electron-
rich and electron-poor aromatic imines with different substitution
patterns provide products in generally good yields and with high
levels of diastereo- and enantioselectivity (entries 1-13). Het-
eroaromatic and R,ꢀ-unsaturated imines are also viable substrates
We next focused on the use of other imine protecting groups.15
Remarkably, replacement of the tosyl group for the simpler
benzenesulfonyl (Bs) analogue resulted in a 10-fold rate increase
(compare entries 9 and 13). While subtle electronic effects can be
invoked to partially rationalize this dramatic rate acceleration, we
noted a marked solubility difference in the two products with 2c
being less soluble than 2b. This allowed for reduction of the catalyst
loading to 1 mol % while maintaining reasonable reaction rates
and without adverse effects on the stereoselectivity (entry 15).
Employment of the synthetically useful 4-nosyl (Ns) protecting
9
11648 J. AM. CHEM. SOC. 2009, 131, 11648–11649
10.1021/ja9034494 CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Scope of the Reactiona
Supporting Information Available: Experimental procedures and
characterization data, transformation of compound 9a to the corre-
sponding unprotected syn-R,ꢀ-diamino acid, and X-ray crystal structures
of 8h, 8o and the byproduct derived from 8q. This material is available
free of charge via the Internet at http://pubs.acs.org.
entry
R
product
time [h]
yield [%]b
drc
ee [%]
References
1
2
3
4
5
6
7
8
Ph
2c
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
8o
8p
8q
15
10
3
15
10
9
97
96
85
92
93
87
95
94
99
80
90
90
82
95
97
90
90
53
>95:05
>95:05
92:08
>95:05
>95:05
>95:05
>95:05
>95:05
>95:05
72:28
>95:05
>95:05
92:08
>95:05
81:19
98
99
93
98
97
99
99
97
97
91
98
99
95
97
92
95
89
91
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4-NO2-C6H4
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4-F-C6H4
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3-Br-C6H4
3-MeO-C6H4
2-Cl-C6H4
2-Me-C6H4
2-naphthyl
1-naphthyl
2-thienyl
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7
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48e
48e
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2-furyl
cinnamyl
CH2CH2Ph
n-Bu
12
44
40
48e
85:15
91:09
83:17
a Reactions were run at rt on a 1 mmol scale using 1.5 equiv of imine.
The ee’s were determined by HPLC analysis of the ester derivatives.
b Combined yield of both diastereomers. c trans:cis, determined by 1H
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typically less stable, these substrates are compatible with the current
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with an additional equivalent of imine.16
Table 3. Reactions with Lower Catalyst Loadinga
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entry
Ar
product
time [h]
yield [%]b
drc
ee [%]
1
2
3
4-Me-C6H4
3-MeO-C6H4
2-naphthyl
9a
9b
9c
20
24
48
90
92
87
95:05
91:09
92:08
98
97
94
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a See footnote a in Table 2. b See footnote b in Table 2. c See
footnote c in Table 2.
It was generally observed that reactions yielding more soluble
products (e.g., 8l) suffer from lower reaction rates. This is in
agreement with our hypothesis that rapid catalyst turnover is linked
to product precipitation. In an attempt to lower catalyst loadings
further, we evaluated several more reactive and less soluble N-nosyl
imines (Table 3). Gratifyingly, a catalyst loading of 0.25 mol %
can routinely be applied to these substrates. High levels of
stereoselectivity are preserved while reaction rates remain reasonable.
In summary, we have reported catalytic enantioselective Mannich
reactions of R-isothiocyanato imides with sulfonyl protected imines.
syn-R,ꢀ-Diamino acid derivatives can be obtained in a highly
diastereo- and enantioselective fashion using substrate/catalyst ratios
as high as 400:1. Product precipitation based approaches might offer
a general solution to achieving lower catalyst loadings in a variety
of different processes.
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Acknowledgment. Financial support from Rutgers, The State
University of New Jersey is gratefully acknowledged. We thank
Dr. Tom Emge for crystallographic analysis.
(15) Boc-protected imines gave inferior results.
(16) See the Supporting Information for details.
JA9034494
9
J. AM. CHEM. SOC. VOL. 131, NO. 33, 2009 11649