Organocatalysis in conjugate amine additions. Synthesis of β-amino acid derivatives

Article abstract of DOI:10.1021/ja071739c

Conjugate addition of O-protected hydroxylamines to pyrazole-derived enoates proceeds with high efficiency and enantioselectivity when chiral thioureas are used as activators. A wide variety of substrates undergo conjugate amine addition providing access to enantioenriched β-amino acid derivatives. Structural requirements for the optimal thiourea catalyst have been established, and the results suggest that it operates as a bifunctional catalyst. Copyright

Full text of DOI:10.1021/ja071739c

Published on Web 06/07/2007
Organocatalysis in Conjugate Amine Additions. Synthesis of â-Amino Acid
Derivatives
Mukund P. Sibi* and Kennosuke Itoh
Department of Chemistry, North Dakota State UniVersity, Fargo, North Dakota 58105
Received March 12, 2007; E-mail: mukund.sibi@ndsu.edu
Organocatalysis is an area of intense investigation.1 Spectacular
Scheme 1
advances have been made in the past decade using organocatalysts
to prepare chiral building blocks. In this context, enamine and
iminium ion intermediates derived from chiral amines as well as
substrate and/or reagent activation through hydrogen bonds have
been employed in enantioselective transformations.2 In a majority
of reactions of the latter class, a thiourea motif has played a key
role.3 Conjugate addition of nitrogen nucleophiles to unsaturated
carboxylic acid derivatives provides rapid access to â-amino acids,
an important class of compounds.4 There are reported examples of
conjugate nitrogen nucleophile addition using organocatalysts.5
However, H-bond activation has played a limited role in enanti-
oselective conjugate addition of heteroatom nucleophiles.6 In
continuation of our program on the synthesis of â-amino acids,7
we have been interested in the development of simple and novel
organocatalysts which in combination with appropriate acyclic
systems would allow for the introduction of heteroatom nucleophiles
(Scheme 1). This work describes a highly efficient conjugate
hydroxylamine addition to enoates that proceed with high levels
of enantioselectivity using a bifunctional organocatalyst.8
Table 1. Evaluation of Solvent and Templates in Conjugate
Amine Additionsa
Our experiments began with the addition of O-benzylhydroxy-
lamine to pyrazole crotonate 5a, a template with properly positioned
hydrogen bond acceptors for activation by the readily available
chiral thiourea catalyst 6a.9 Reaction optimization involved variation
of solvent, additive, and template.10 Results from these experiments
are shown in Table 1. A stoichiometric amount of the chiral thiourea
was used in these experiments. Conjugate amine addition to 5a in
a variety of common organic solvents was slow, and the level of
enantioselectivity was poor (entries 1-4). Non-hydrogen bonding
solvents, such as methylene chloride, toluene, and trifluorotoluene,
were better (entry 5-7). Of these solvents, the reaction in
trifluorotoluene was the fastest, and the ee for the product was the
highest (entry 7). The use of MS 4 Å as an additive led to
improvements in chemical yields but not selectivity (compare entry
5 with 8; 6 with 9; 7 with 10). Cooling the reaction to 0 °C while
using the optimal trifluorotoluene as a solvent led to a substantial
improvement in selectivity (compare entry 10 with 11). The effect
of the pyrazole substituent on reactivity and selectivity was
evaluated (entries 12-15). Although the reactions were faster with
templates 5b-d, the levels of enantioselectivity were lower than
that with 5a.
Having a reasonable set of conditions at hand, we varied the
organocatalyst to understand the importance of bifunctionality,
stereochemistry, and structural rigidity on reactivity and selectivity
in amine additions. These reactions were performed at room
temperature with 5a as the substrate, trifluorotoluene as the solvent,
a stoichiometric amount of the chiral activator, and MS 4 Å as the
additive. Results from these experiments are shown in Chart 1. The
urea catalyst 6b was less effective in comparison to the thiourea
catalyst 6a with respect to both reactivity and selectivity. Replace-
ment of the bistrifluoromethylphenyl group (6a) with tetrafluo-
entry
substrate
solvent
additive
product
time, h
% yieldb
% eec
1
2
3
4
5
6
7
8
9
10
11d
12
13
14
15
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5b
5c
5c
5d
CH3CN
THF
Et2O
t-BuOH/THF
CH2Cl2
toluene
CF3C6H5
CH2Cl2
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7b
7c
7c
7d
216
216
216
168
192
192
48
192
192
24
41
43
58
61
61
68
76
75
73
75
82
85
76
76
72
-4
10
0
43
54
71
48
53
71
87
61
42
45
31
MS 4 Å
MS 4 Å
MS 4 Å
MS 4 Å
MS 4 Å
toluene
CF3C6H5
CF3C6H5
CF3C6H5
CF3C6H5
CF3C6H5
CF3C6H5
72
24
24
14
MS 4 Å
MS 4 Å
12
a For details of the reaction conditions see Supporting Information.
b Isolated yield. c Chiral HPLC analysis. d Reaction at 0 °C.
rophenyl group (6c) led to improvement in chemical yield but the
selectivity was much lower. The stereochemistry of the aminoin-
danol subunit had a significant impact with trans configured 6d
providing markedly lower selectivity than cis configured 6a. The
hydroxyl group on aminoindanol was important for reactivity and
selectivity, as compound 6e lacking the hydroxyl group gave modest
yield and nearly racemic product. Reactions with ligands 6f-i
clearly demonstrated the requirement for rigidity of the ligand
architecture.
We then evaluated the effect of catalyst loading and amine
structure on reactivity and selectivity and these results are shown
9
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J. AM. CHEM. SOC. 2007, 129, 8064-8065
10.1021/ja071739c CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Chart 1
Figure 1. Stereochemical model.
affording the products with high enantioselectivity (entries 4-7).
Compound 5j gave the product in high yield and 98% ee, even
when using 30 mol % of the thiourea catalyst (entry 8). Cinnamate
5i was less reactive and gave the product in low yield and selectivity
(entry 9). We have previously shown that the conjugate addition
products can be readily converted to â-amino acids.7 Overall, there
is good substrate scope for the addition of amines to pyrazole
derived enoates using a thiourea catalyst, providing access to a
variety of â-amino acid derivatives in high selectivity.
A working model for the conjugate amine addition is shown in
Figure 1. The model is consistent with the observed absolute
stereochemistry for the conjugate addition product (S)-7a and the
structural requirements for the chiral urea as shown in Chart 1.
The differential reactivity with ligands 6a and 6d suggests that
intramolecular delivery of the nucleophile is likely. Our results also
indicate that the pyrazole template plays a crucial role in providing
H-bond acceptor sites for better organization and hence higher levels
of selectivity in these organocatalysis reactions.
Table 2. Effect of Catalytic Loading and Nature of the Amine in
Additions to 5a
entry
amine R1
mol % 6a
time, h
product
% yielda
% eeb
1c
2c
3c
4c
5d
6d
Bn
Bn
Bn
Bn
Ph2CH
TBDMS
100
80
50
30
100
100
24
60
96
168
96
120
7a
7a
7a
7a
7aa
7bb
75
80
78
63
86
82
71
71
70
71
89
94
Acknowledgment. We thank NSF (Grant CHE-0316203) for
funding and L. Stanley and J. Zimmerman for helpful discussions.
Supporting Information Available: Characterization data for
compounds 5-16 and experimental procedures. This material is
available free of charge via the Internet at http://pubs.acs.org.
a Isolated yield. b Chiral HPLC. c Reaction at room temperature. d Reac-
tion at 0 °C.
References
(1) (a) Berkessel, A.; Gro¨ger, H. Asymmetric Organocatalysis; Wiley-VCH:
Weinheim, Germany, 2005. (b) Akiyama, T.; Itoh, J.; Fuchibe, K. Adv.
Synth. Catal. 2006, 348, 999.
Table 3. Breadth and Scope Experiments
(2) For recent reviews see: (a) Lelais, G.; MacMillan, D. W. C. Aldrichimica
Acta 2006, 39, 79. (b) List, B. Chem. Commun. 2006, 819. (c) Dalko, P.
I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138.
(3) For reviews see; (a) Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int.
Ed. 2006, 45, 1520. (b) Connon, S. J. Chem.sEur. J. 2006, 12, 5419. (c)
Takemoto, Y. Org. Biomol. Chem. 2005, 3, 4299.
entry
R
R1
time, h
product
% yielda
% eeb
(4) For recent reviews see: (a) Liu, M.; Sibi, M. P. Tetrahedron 2002, 58,
7991. (b) Xu, L.-W.; Xia, C.-G. Eur. J. Org. Chem. 2005, 633.
(5) (a) Chen, Y. K.; Yoshida, M.; MacMillan, D. W. C. J. Am. Chem. Soc.
2006, 128, 9328. (b) Ibrahem, I.; Rios, R.; Vesely, J.; Zhao, G-L.; Cordova,
A. Chem. Commun. 2007, 849. (c) Diner, P.; Nielsen, M.; Marigo, M.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2007, 46, 1983. (d) Li, H.; Wang,
J.; Xie, H.; Zu, L.; Jiang, W.; Duesler, E. N.; Wang, W. Org. Lett. 2007,
9, 965. (e) Guerin, D. J.; Miller, S. J. J. Am Chem. Soc. 2002, 124, 2134.
(f) Takasu, K.; Maiti, S.; Ihara, M. Heterocycles 2003, 59, 51. (g) Wang,
J.; Li, H.; Zu, L.; Wang, W. Org. Lett. 2006, 8, 1391.
(6) For the addition of nonamine nucleophiles using organocatalysts see: (a)
Li, B.-J.; Jiang, L.; Liu, M.; Chen, Y.-C.; Ding, L-S.; Wu, Y. Synlett
2005, 603. (b) Wang, W.; Li, H.; Wang, J.; Zu, L. J. Am. Chem. Soc.
2006, 128, 10354.
1
2
3
4
5
6
Me 5a
Ph2CH
Ph2CH
TBDMS
Ph2CH
Ph2CH
Ph2CH
Ph2CH
Ph2CH
PhCH2
96
96
96
168
138
216
288
24
7aa
7e
7ee
7f
7g
7h
7i
86
50
42
92
84
68
59
98
19
89
94
90
91
88
90
89
98
67
CO2Et 5e
CO2Et 5e
Et 5f
n-Pr 5g
i-Pr 5h
c-C6H11 5i
CH2OPMP 5j
Ph 5k
7
8c
9d
7j
7k
72
a Isolated yield. b Chiral HPLC. c Reaction run using 30 mol% of 6a.
(7) Sibi, M. P.; Shay, J. J.; Liu, M.; Jasperse, C. P. J. Am. Chem. Soc. 1998,
d Reaction at room temperature.
120, 6615.
(8) For the use of amino indanol-derived thiourea in catalysis see: (a) Herrera,
R. P.; Sgarzani, V.; Bernardi, L.; Ricci, A. Angew. Chem., Int. Ed. 2005,
44, 6576. For examples of bifunctional organocatalysis see: (b) Wang,
B.; Wu, F.; Wang, Y.; Liu, X.; Deng, L. J. Am. Chem. Soc. 2007, 129,
768. (c) Inokuma, T.; Hoashi, Y.; Takemoto, Y J. Am. Chem. Soc. 2006,
128, 9413. (d) Yalalov, D. A.; Tsogoeva, S. B.; Schmatz, S. AdV. Synth.
Catal. 2006, 348, 826. (e) McCooey, S. H.; Connon, S. J. Angew. Chem.,
Int. Ed. 2005, 44, 6367. (f) Huang, H.; Jacobsen, E. N. J. Am. Chem.
Soc. 2006, 128, 7170. (g) Wang, J.; Li, H.; Zu, L.; Jiang, W.; Xie, H.;
Duan, W.; Wang, W. J. Am. Chem. Soc. 2006, 128, 12652.
(9) See Supporting Information for conditions and experimental details.
(10) We have screened other templates in conjugate amine additions. For
example, addition to oxazolidinone crotonate gave the addition product
in low yield and selectivity. These results will be reported in a full account.
in Table 2. Lowering the catalyst loading from 100 mol % to 30
mol % led to longer reaction times with no loss in enantioselectivity
for the product (entries 1-4). Changing the O-substituent on the
hydroxylamine from benzyl to benzhydryl to tert-butyldimethylsilyl
gave the products in good selectivity (entries 5 and 6).
Substrate scope in conjugate additions has been evaluated and
these results are shown in Table 3. Amine addition to crotonate 5a
was efficient yielding the product in high ee (entry 1). The fumarate
5e gave the addition product in modest yield but very high
selectivity (entries 2 and 3). Compounds with alkyl substituents
on the â-carbon were competent substrates in the conjugate addition
JA071739C
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J. AM. CHEM. SOC. VOL. 129, NO. 26, 2007 8065