Direct asymmetric anti-Mannich-type reactions catalyzed by a designed amino acid

Article abstract of DOI:10.1021/ja056984f

The development of catalysts for Mannich-type reactions that afford anti-products with excellent diastereo- and enantioselectivities under mild conditions and low catalyst loadings (1-5 mol %) is reported. Based on principles gained from the study of (S)-

Full text of DOI:10.1021/ja056984f

Published on Web 01/04/2006
Direct Asymmetric anti-Mannich-Type Reactions Catalyzed by a Designed
Amino Acid
Susumu Mitsumori,† Haile Zhang,† Paul Ha-Yeon Cheong,§ K. N. Houk,*,§ Fujie Tanaka,*,† and
Carlos F. Barbas, III*,†
The Skaggs Institute for Chemical Biology and the Departments of Chemistry and Molecular Biology, The Scripps
Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, and Department of Chemistry and
Biochemistry, UniVersity of California, Los Angeles, California 90095-1569
Received October 13, 2005; E-mail: carlos@scripps.edu; ftanaka@scripps.edu; houk@chem.ucla.edu
Scheme 1
Direct catalytic asymmetric Mannich reactions are highly effec-
tive carbon-carbon bond-forming reactions that are used for the
preparation of enantiomerically enriched amino acids, amino
alcohols, and their derivatives.1-7 Because of the utility of these
types of synthons, the demand for Mannich reactions that selectively
afford anti- or syn-products with high enantioselectivities is high.
syn-Selective, direct, catalytic, asymmetric Mannich reactions are
now common and have been performed using Zr-,1a Zn-,1b-d or
Cu-derived1e catalysts, Brønsted acids,2 cinchona alkaloids,3 phase-
transfer catalysts,4 and proline and related organocatalysts.5,6
Scheme 2
Enantioselective anti-Mannich reactions are, however, considerably
rarer.1a-c,7 Even a non-asymmetric anti selective Mannich reaction
would be of interest.8 Thus, the development of effective enanti-
oselective anti-Mannich catalysts is a challenge in contemporary
asymmetric synthesis. Here we present our studies regarding a
solution to this problem and disclose the design, synthesis, and
evaluation of amino acid catalyst 1 as a highly diastereo- and
enantioselective anti-Mannich catalyst for reactions involving
unmodified aldehydes (Scheme 1).
In the reaction of unmodified aldehydes with N-p-methoxyphenyl
(PMP) protected imines catalyzed by the natural amino acid (S)-
proline, (2S,3S)-syn-amino aldehydes are obtained with high
enantioselectivities6 (Scheme 1). Although reactions involving some
pyrrolidine derivatives afford anti-diastereomers as their major
products, the enantioselectivities obtained with these organocatalysts
are moderate.6 To design catalysts that provide anti-products with
high levels of enantioselectivities, we revisited the key factors that
control the diastereo- and enantioselectivities of (S)-proline-
catalyzed reactions6,9 (Scheme 2 left). Four considerations are
key: (1) (E)-Enamine intermediates predominate. (2) The s-trans
conformation of the (E)-enamine reacts in the C-C bond-forming
transition state. The s-cis conformation results in steric interaction
between the enamine and the substituent at the 2-position of the
pyrrolidine ring. (3) C-C bond formation occurs at the re face of
the enamine intermediate. This facial selection is controlled by
proton-transfer from the carboxylic acid to the imine nitrogen. (4)
The enamine attacks the si face of the (E)-imine. The facial
selectivity of the imine is also controlled by the proton transfer
that increases the electrophilicity of the imine.
(see point 2 above). This substituent can presumably be any
functional group that cannot initiate proton transfer to the imine.
The acid functionality was then placed at the distal 3-position of
the ring, to affect control of enamine and imine face selection in
the transition state (see points 3 and 4). To avoid steric interactions
between the substituent at the 5-position of the new catalyst and
the imine in the transition state, the substituents at 3- and 5-positions
should be in the trans configuration.
On the basis of these considerations, a new catalyst (3R,5R)-5-
methyl-3-pyrrolidinecarboxylic acid (RR35, 1) was designed. The
major transition state of the Mannich reaction catalyzed by 1 is
presented in Scheme 2 (right). Computational studies of the
1-catalyzed reaction of propionaldehyde and N-PMP-protected
R-imino methyl glyoxylate using HF/6-31G* level of theory10 were
used to test our design prior to synthesis. The catalyst was predicted
to give 95:5 anti:syn diastereoselectivity and ∼98% ee for the
formation of the (2S,3R)-product (Table 1, entry 1).
The stereoselective formation of the anti-products necessitates
a reversal in the facial selectivity of either the enamine or the imine,
compared to the proline-catalyzed reactions. A pyrrolidine derivative
bearing substituents at 2- and 4-positions (or at 3- and 5-positions)
(Scheme 2, right) was hypothesized to be an anti-Mannich catalyst.
The steric features of a substituent at the 5-position of the
pyrrolidine can be used to fix the conformation of the enamine
† The Scripps Research Institute.
§ University of California, Los Angeles.
9
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J. AM. CHEM. SOC. 2006, 128, 1040-1041
10.1021/ja056984f CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 1. RR35 (1)-Catalyzed Mannich-Type Reactionsa
Scheme 4
time
(h)
yield
(%)
drb
eec
(%)
changes to 82:18 anti:syn dr and 92% ee when transition states
with the unmethylated catalyst are located. This unmethylated
catalyst was also tested in an actual reaction, for the case where
R1 ) i-Pr. This derivative afforded (2R,3S)-anti-3 in 95:5 anti:syn
dr and 93% ee, which is a drop of ∼0.6 kcal/mol from the
1-catalyzed reaction with the same substrate (Table 1, entry 3).
An efficient organocatalyst RR35 (1) for anti-Mannich-type
reactions has been developed.14 This catalyst has been demonstrated
to be useful for the synthesis of amino acid derivatives with
excellent anti-diastereoselective control and high enantioselectivities
under mild conditions. Further studies on the full scope of this
Mannich catalyst, computational studies, and other reactions
catalyzed by it and its derivatives will be reported soon.
entry
R1
R2
product
anti:syn
1d
2
3
Me
Me
i-Pr
n-Bu
n-Bu
n-Bu
Me
Et
Et
Et
Et
Et
Et
Et
i-Pr
i-Pr
-
1
3
0.5
1
2
3
3
1
-
2
3
4
4
4
5
6
7
8
-
70
85
54
71
57
80
72
92
85
95:5
94:6
98:2
97:3
97:3
97:3
97:3
96:4
97:3
96:4
98
>99e
99
99
99
>99
>99
>97
98
4
5f,g
6f,h
7
n-Pent
CH2CHdCH2
i-Pr
8i
9
10
n-Pent
1
>99
a Typical conditions: To a solution of N-PMP-protected R-imino ester
(0.25 mmol, 1 equiv) and aldehyde (0.5 mmol, 2 equiv) in anhydrous DMSO
(2.5 mL), catalyst RR35 (1) (0.0125 mmol, 0.05 equiv, 5 mol % to the
imine) was added and the mixture was stirred at room temperature. b The
diastereomeric ratio (dr) was determined by 1H NMR. c The ee of the
(2S,3R)-anti-product was determined by chiral-phase HPLC analysis.
d Indicates computational predictions using methods described in the text.
e The ee was determined by HPLC analysis of the corresponding oxime
prepared with O-benzylhydroxylamine. f The reaction was performed in a
doubled scale. g Catalyst 1 (2 mol %) was used. h Catalyst 1 (1 mol %)
was used. i The reaction was performed with doubled concentration for each
reactant and catalyst 1.
Acknowledgment. This study was supported by The Skaggs
Institute for Chemical Biology and the National Institute of General
Medical Sciences, National Institutes of Health (GM36700 to
K.N.H.).
Supporting Information Available: Experimental procedures and
spectral and chromatographic data. This material is availablefree of
charge via the Internet at http://pubs.acs.org.
Scheme 3 a
References
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a (a) Known procedures (see Supporting Information); (b) (i) MsCl, Et3N,
(ii) LiBHEt3, (iii) TBAF, 94% (3 steps); (c) TsCl, pyridine, 58%; (d)
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RR35 (1)11 was synthesized (Scheme 3), and Mannich reactions
involving a variety of unmodified aldehydes were studied (Table
1). In accord with the design principles and in quantitative
agreement with the computational predictions, the reactions cata-
lyzed by 1 afforded anti-amino aldehyde products in excellent
diastereo- and enantioselectivities.12 With 5 mol % catalyst loading,
the reaction rates with catalyst 1 were approximately 2- to 3-fold
faster than the corresponding proline-catalyzed reactions that afford
the syn-products. The high catalytic efficiency of 1 allowed the
reactions to be catalyzed with only 1 or 2 mol % to afford the
desired products in reasonable yields within a few hours (Table 1,
entries 5 and 6).
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Imidazole isomerization13 of the anti-3 product obtained from
the 1-catalyzed reaction and of the (2S,3S)-syn-3 product obtained
from the (S)-proline-catalyzed reaction6 confirmed that the major
anti-product generated from the 1-catalyzed reaction had a (2S,3R)
configuration. (Scheme 4).
The relative contributions of the carboxylic acid and methyl
group of 1 in directing the stereochemical outcome of the reaction
were assessed. Computational studies involving the derivative
lacking the 5-methyl group, (S)-3-pyrrolidinecarboxylic acid,
indicate that the methyl group contributes ∼1 kcal/mol toward the
anti-diastereoselectivity. That is, the result in entry 1 of Table 1
(10) HF/6-31G* was used for rapid computation of the stereoselectivity.
(11) For racemic, cis and trans mixtures of this compound, see: Juaristi, E.;
Quintana, D.; Lamatsch, B.; Seebach, D. J. Org. Chem. 1991, 56, 2553.
(12) DMSO provided the best anti selectivity and enantioselectivity of the
solvents tested for the RR35-catalyzed Mannich reaction to afford anti-3.
Reactions in DMF (anti:syn ) 97:3, 97% ee), CH3CN (96:4, 96% ee),
EtOAc (94:6, 96% ee), and dioxane (97:3, 95% ee) were as efficient with
respect to reaction rate as in DMSO.
(13) Ward, D. E.; Sales, M.; Sasmal, P. J. Org. Chem. 2004, 69, 4808.
(14) After submission of this paper, another anti-Mannich catalyst has been
reported. Kano, T.; Yamaguchi, Y.; Tokuda, O.; Maruoka, K. J. Am. Chem.
Soc. 2005, 127, 16408.
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