Expedient synthesis of chiral 1,2- and 1,4-diamines: Protecting group dependent regioselectivity in direct organocatalytic asymmetric Mannich reactions

Article abstract of DOI:10.1021/ol060980d

Organocatalytic asymmetric Mannich reaction of protected amino ketones with imines in the presence of an L-proline-derived tetrazole catalyst afforded diamines with excellent yields and enantioselectivities of up to 99%. The amino ketone protecting group

Full text of DOI:10.1021/ol060980d

ORGANIC
LETTERS
2006
Vol. 8, No. 13
2839-2842
Expedient Synthesis of Chiral 1,2- and
1,4-Diamines: Protecting Group
Dependent Regioselectivity in Direct
Organocatalytic Asymmetric Mannich
Reactions
Naidu S. Chowdari, Moballigh Ahmad, Klaus Albertshofer, 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
carlos@scripps.edu
Received April 24, 2006
ABSTRACT
Organocatalytic asymmetric Mannich reaction of protected amino ketones with imines in the presence of an
L-proline-derived tetrazole catalyst
afforded diamines with excellent yields and enantioselectivities of up to 99%. The amino ketone protecting group controlled the regioselectivity
of the reaction providing access to chiral 1,2-diamines from azido ketones and 1,4-diamines from phthalimido ketones.
Chiral diamines are important building blocks for the
synthesis of pharmaceuticals and are motifs frequently
encountered in natural products.1 For example, chiral eth-
ylenediamine derivatives are used in the preparation of cis-
platin analogues employed in cancer therapy.2 As synthetic
tools, chiral diamines are used extensively as chiral auxil-
iaries and catalysts.3 Despite their significance, the asym-
metric synthesis of diamines is not straightforward. Chiral
diamines are most frequently synthesized from diols or
aziridines1 or by addition of glycine ester enolates to imines.4
The direct reductive coupling of imines has also been
reported, but this approach is limited to the preparation of
symmetrical vicinal diamines and has low stereoselectivity.5
Thus, more direct and efficient routes are needed for the
synthesis of this significant class of compounds.
In recent years, organocatalysis has emerged as a powerful
tool for asymmetric aldol,6 Mannich,7 Michael,8 Diels-
Alder,9 amination,10 oxidation,11 halogenation,12 Robinson
annulation,13 and multicomponent reactions.14 Although
hydroxy ketones have been employed in organocatalysis,6b,7j,8c
use of amino ketones has not yet been reported. Amino
ketones are not stable; therefore, we envisioned use of azido
ketones and protected amino ketones as surrogates for amino
ketones. We previously used amino aldehydes in direct
(4) (a) Bernardi, L.; Gothelf, A. S.; Hazell, R. G.; Jorgensen, K. A. J.
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37, 2580.
(2) Reedijk, J. Chem. Commun. 1996, 801.
(3) Whitesell, J. K. Chem. ReV. 1989, 89, 1581.
10.1021/ol060980d CCC: $33.50
© 2006 American Chemical Society
Published on Web 06/02/2006

organocatalytic aldol reactions as an effective route to
â-hydroxy-R-amino acids.6j Here, we report direct, regio-
specific, asymmetric synthesis of 1,2- and 1,4-diamines based
on the Mannich reaction of imines with azido ketones and
with protected amino ketones, respectively.
We initially studied the Mannich reaction of N-p-meth-
oxyphenyl (N-PMP) protected R-imino ethyl glyoxylate with
azidobutanone using a catalytic amount of L-proline 1 (30
mol %) in dimethyl sulfoxide (DMSO) at room temperature.
The reaction was complete within 48 h and provided the
Mannich product in 84% yield with excellent enantio-
selectivity (>92% ee) albeit poor diastereoselectivity (syn/
anti ) 51:49) (Table 1, entry 1). At 4 °C in DMF, the
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J. Org. Chem. 2002, 67, 301. (d) Northrup, A. B.; MacMillan, D. W. C. J.
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Soc. 2003, 125, 5262. (g) Mase, N.; Tanaka, F.; Barbas, C. F., III. Angew.
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A.; Arvidsson, P. I. Tetrahedron: Asymmetry 2004, 15, 1831. (j)
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(k) Kofoed, J.; Nielsen, J.; Reymond, J.-L. Bioorg. Med. Chem. Lett. 2003,
13, 2445. (l) Chandrasekhar, S.; Narsihmulu, Ch.; Reddy, N. R.; Sultana,
S. S. Chem. Commun. 2004, 2450. (m) Berkessel, A.; Koch, B.; Lex, J.
AdV. Synth. Catal. 2004, 346, 1141 (n) Suri, J. T.; Ramachary, D. B.; Barbas,
C. F., III. Org. Lett. 2005, 7, 1383. (o) Mase, N.; Nakai, Y.; Ohara, N.;
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Table 1. Effect of Various Catalysts and Solvents on the
Organocatalytic Asymmetric Synthesis of 1,2-Azidoaminesa
time yield
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Tanaka, F.; Barbas, C. F., III. J. Am. Chem. Soc. 2006, 128, 1040. (l)
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Barbas, C. F., III. Tetrahedron Lett. 2001, 43, 7749 (n) Enders, D.; Grondal,
C.; Vrettou, M.; Raabe, G. Angew. Chem., Int. Ed. 2004, 44, 4079. (o)
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Soc. 2000, 122, 4243. (b) Ramachary, D. B.; Chowdari. N. S.; Barbas, C.
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entry catalyst
solvent
DMSO
DMF, 4 °C 187
IPA, 4 °C
DMSO
(h)
(%) syn/anti ee (syn/anti)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
1
1
1
2
3
3
3
3
3
3
3
3
3
3
3
48
84
82
80
80
93
90
92
88
90
80
93
84
80
76
83
51/49
92/8
89/11
56/44
94/6
82/18
91/9
84/16
91/9
92/98
96/99
99/99
79/69
98/70
75/88
97/65
85/86
97/90
99/99
90/43
72/45
91/22
89/16
73/44
24
24
4
6
39
6
40
24
120
72
31
95
48
DMSO
DMF
DMF, 4 °C
NMP
NMP, 4 °C
IPA, 4 °C
CH2Cl2
CH3CN
dioxane
toluene
[bmim]BF4
95/5
83/17
78/22
78/22
76/24
78/22
a ee was determined by chiral HPLC analysis. Syn/anti ratio was based
on 1H NMR. Stereochemistry was assigned on the basis of previous Mannich
reactions.7j
diastereoselectivity improved to 92:8, but the reaction
required 187 h to reach completion (entry 2). When 2-pro-
panol (IPA) was used the reactivity and enantioselectivity
were increased relative to the room-temperature reaction, but
diastereoselectivity was decreased (entry 3).
We then tested L-proline-derived sulfonamide 2 and
tetrazole 3 as catalysts; these catalysts are stronger acids than
proline and have been used previously in enamine-based
organocatalysis.6h,7g,15 The reaction rate was acceptable for
catalyst 2 (24 h for completion); however, diastereoselectivity
was poor (entry 4). Catalyst 3 performed very well with
respect to reaction time (4 h), diastereoselectivity (syn/anti
) 94/6), and enantioselectivity (98%) (entry 5). Catalyst 3
performed well in a variety of solvents (entries 5-15). Of
the solvents screened, DMSO was the best in terms of reac-
tion time, yield, and diastereo- and enantioselectivities. At
(15) For preparation of catalyst 2, see ref 6m: For catalyst 3, see:
Almquist, R. G.; Chao, W.-R.; White, C. J. J. Med. Chem. 1985, 28, 1067.
Franckevie`ius, V.; Knudsen, K. R.; Ladlow, M.; Longbottom, D. A.; Ley,
S. V. Synlett 2006, 6, 889.
2840
Org. Lett., Vol. 8, No. 13, 2006

4 °C, IPA, N,N-dimethylformamide (DMF), and N-methyl-
2-pyrrolidone (NMP) also provided good diastereo- and
enantioselectivity but required longer reaction times (24-
40 h). Reaction rates were relatively slow in CH2Cl2, CH3CN,
1,4-dioxane, toluene, and [1-butyl-3-methylimidazolium]BF4.
We also tested (S)-2-(methoxymethyl)pyrrolidine7m and (S)-
(+)-1-(2-pyrrolidinylmethyl)pyrrolidine/CF3CO2H,6g but these
catalysts provided product in negligible amounts.
from benzyloxyacetaldehyde to the carbohydrate-derived
aldehyde can be ascribed to increased steric hindrance with
the latter substrates. A one-pot reduction and butoxy-carbonyl
(Boc) protection of Mannich product 6 to provide differen-
tially protected 1,2-diamine 10 was achieved by using Pd/C
and Boc2O under hydrogen atmosphere (Scheme 1).16
Under these optimized conditions (catalyst 3 in DMSO),
we next studied three-component Mannich reactions using
different azidoketones and various aldehydes (Table 2). The
Scheme 1. Synthesis of Differentially Protected 1,2-Diamine
10
Table 2. Mannich Reactions for the Synthesis of Various
1,2-Azidoamines
Next we used phthalimidoacetone, a phthaloyl-protected
amino ketone, as donor (Table 3). Reaction of ethyl glyox-
alate imine in DMSO in the presence of catalyst 3 at room
temperature provided the Mannich product 11 in 86% yield
Table 3. Mannich Reactions for the Synthesis of Protected
1,4-Diamines
reaction with azidoacetone was complete within 30 min,
whereas azidoacetophenone reacted slowly and required 40
h for completion. These reactions also worked well with 10
mol % of catalyst as exemplified for azidoacetone; in this
case the product 5 was obtained in 1.5 h with 94% yield,
excellent diastereoselectivity (syn/anti ) 86/14), and enan-
tioselectivity (99%). Reaction with benzyloxyacetaldehyde-
and carbohydrate-derived aldehydes yielded the azidoamines
7-9 with protected hydroxyl and polyhydroxy functional-
ities. All of these products were obtained regiospecifically
with good diastereoselectivity (syn/anti ) 70/30 to 91/9) and
enantioselectivity (82-99% ee).
a (-) Represents opposite enantiomer obtained using D-proline-derived
tetrazole catalyst ent-3. b Diasteriomers are formed with 10:1 ratio.
The reaction with azidoacetophenone was very slow (40
h), most likely due to the conjugative stabilization of the
reactive enamine by the phenyl group. The decreasing
reactivity observed from azidoacetone to azidobutanone and
Org. Lett., Vol. 8, No. 13, 2006
2841

and 64% ee as a single regioisomer. At 4 °C, ee’s were
improved: DMF gave 90% ee, whereas NMP provided 91%
ee. The p-nitrobenzaldehyde imine reaction was also studied
using three different solvents, and the highest ee (97%) was
obtained in NMP solvent at 4 °C. Using these optimized
conditions, we synthesized p-cyanophenyl- and phenyl-
substituted 1,4-diamines with good to excellent ee’s. Imines
flanked with electron- withdrawing groups present on their
aromatic rings are more reactive than benzaldehyde-PMP-
imine. A carbohydrate-based imine also reacted with
phthalimidoacetone to provide aza sugar 15 in 53% yield.
In contrast to our results using azidoketones that provided
vicinal diamine derivatives exclusively, phthalimidoacetone
provided only the 1,4-diamine derivatives. Upon selective
reduction, 11 should give hydroxyornithine, a constituent of
an antifungal peptide natural product (Scheme 2).17 Unlike
Figure 1. Proposed transition states.
reactivity is in accord with mechanisms of Mannich reactions
involving hydroxy ketone and dialkyl ketone donors.7j In the
case of phthalimidoketone, attack of the methyl group, rather
than the methylene group of the ketone, results in the
formation of the 1,4-diamine product through the enamine
with the less-substituted double bond (TS-2). Here the
competing enamine of TS-3 suffers due to steric hindrance.
In conclusion, we have demonstrated for the first time
direct asymmetric Mannich reactions of imines with varied
protected amino ketones to afford selective access to chiral
1,2- and 1,4-diamines with excellent yields and enantio-
selectivities. The identity of the protecting group controlled
the regioselectivity of the reaction and provided for the
synthesis for 1,2- and 1,4-diamines with azidoketones and
phthalimidoketones, respectively. The scope of the azido-
ketone Mannich reaction appears to be very broad, coupling
a wide range of azidoketones and imines. The product chiral
azidoketones prepared here are interesting substrates for
subsequent Click chemistry-based diversification.19 These
reactions can be performed under environmentally friendly
conditions without the requirements for an inert atmosphere
or for dry solvents and provide expedient access to this
significant class of molecules.
Scheme 2. Synthetic Route to Hydroxyornithine
results obtained using the tetrazole catalyst, with L-proline
1 as catalyst in NMP solvent at room temperature, phthal-
imidoacetone provided Mannich product 11 in trace amounts
accompanying the formation of cycloaddition product 16 with
59% isolated yield based on proline.18 Proline forms an
iminium with ethyl glyoxalate, generated from in situ
hydrolysis of glyoxalate imine. Decarboxylation of the
iminium species followed by [3 + 2] cycloaddition with ethyl
glyoxalate imine provided compound 16. Catalyst 2 also
provided Mannich product 11 in trace amounts.
Based on the regioselectivities of products, we propose
that the reaction occurs through the transition states shown
in Figure 1. The catalyst reacts with azido ketone to form
the enamine with the more highly substituted double bond,
and attack of the methylene group gives the 1,2-azidoamine
as the Mannich product (TS-1). Here deprotonation at the
R-carbon is facilitated by the enhanced acidity provided by
azide substitution and this enamine is thermodynamically
more stable than the enamine generated by deprotonation at
the other R-carbon based on resonance considerations. This
Acknowledgment. This study was supported in part by
the Skaggs Institute for Chemical Biology.
Supporting Information Available: Experimental pro-
cedures and analytical data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL060980D
(19) Demko, Z, P.; Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41,
2113.
(20) General Experimental Procedure for Mannich Reaction. To a
glass vial charged with aldehyde (0.5 mmol) and p-anisidine (0.5 mmol)
was added DMSO (1 mL). The solution was stirred at room temperature
until imine formation was complete as monitored by TLC (30-60 min).
Catalyst (30 mol %) and ketone (0.75 mmol) were added, and the reaction
was stirred at room temperature. After completion of the reaction as
monitored by TLC, half-saturated NH4Cl solution and ethyl acetate were
added with vigorous stirring, the layers were separated, and the organic
phase was washed with water. The combined organic phases were dried
(Na2SO4), concentrated, and purified by flash column chromatography (silica
gel, mixtures of hexanes/ethyl acetate) to afford the desired Mannich product.
(16) Saito, S.; Nakajima, H.; Inaba, M.; Moriwake, T. Tetrahedron Lett.
1989, 30, 837.
(17) Paintner, F. F.; Allmendinger, L.; Bauschke, G.; Klemann, P. Org.
Lett. 2005, 7, 1423.
(18) Although this type of cycloaddition product was not reported in
the Mannich reaction, cyclic products are reported in the literature using
two equivalents of aldehyde and proline. See: (a) Kano, T.; Takai, J.;
Tokuda, O.; Maruoka, K. Angew. Chem., Int. Ed. 2005, 44, 3055. (b) Orsini,
F.; Pelizzoni, F.; Forte, M.; Destro, R.; Gariboldi, P. Tetrahedron 1988,
44, 519.
2842
Org. Lett., Vol. 8, No. 13, 2006