Deaminative and decarboxylative catalytic alkylation of amino acids with ketones

Article abstract of DOI:10.1002/anie.201307766

It cuts two ways: The cationic [Ru-H] complex catalyzes selective coupling of α- and β-amino acids with ketones to form α-alkylated ketone products. The reaction involves C-C and C-N bond cleavage which result in regio- and stereoselective alkylation using amino acids. A broad substrate scope and high functional-group tolerance is demonstrated. Copyright

Full text of DOI:10.1002/anie.201307766

Angewandte
Chemie
DOI: 10.1002/anie.201307766
Synthetic Methods
Deaminative and Decarboxylative Catalytic Alkylation of Amino
Acids with Ketones**
Nishantha Kalutharage and Chae S. Yi*
À
As one of the most important building blocks of living
organisms, a-amino acids constitute a highly attractive class of
bio-based reagents for the synthesis of complex organic
compounds.[1–4] Since amino acids are readily available from
biomass feedstock, using them as reagents would be highly
meritable from the viewpoint of replacing petrochemical-
based reagents and for designing renewable and sustainable
synthetic methods. While amino acids have been successfully
employed as the chiral scaffolds for metal catalysts[5–7] and as
organocatalysts,[8,9] they have not been widely utilized as
reagents in organic synthesis, in part because an efficient
C N cleavage methods for amino compounds. Our idea stems
from the recent discovery that a well-defined cationic
ruthenium hydride complex [(C6H6)(PCy3)(CO)RuH]+BF4
(1) is a selective catalyst for the dehydrative C H alkylation
À
À
reactions of alcohols.[23,24] Since the alkylation reaction is
driven by the formation of water, we surmized that the
analogous deaminative coupling reaction might be achievable
from using amino substrates. Herein, we disclose a highly
selective catalytic deaminative and decarboxylative coupling
reaction of amino acids with ketones. The catalytic coupling
À
À
method achieves direct C C and C N bond cleavage of
amino acid substrates, and exhibits high chemo- and regiose-
lectivity in forming the a-alkylated ketone products without
using any reactive reagents or protecting groups.
À
catalytic C N bond cleavage method for amino acids is not
À
available for associated C C coupling reactions. In this
regard, nature provides ample inspiration for effective
À
design on C N bond-cleavage methods for amines and
related nitrogen compounds.[10–15] Natural metalloenzymes
such as CYP450 and methane monooxygenases have been
found to mediate selective oxidative dealkylation of
amines.[10,11] In biochemical catabolic pathways, deamination
of a-amino acids is efficiently catalyzed by deaminase,
oxidase, and dehydrogenase enzymes.[12] N-Demethylation
of both DNA and mRNA has also been shown to be
intricately involved in gene regulating processes.[13–15]
To assess the feasibility of the deaminative coupling
reaction, we initially screened a number of ruthenium
catalysts for the coupling reaction of (S)-phenylglycine with
butanone under the reaction conditions stipulated in Equa-
tion (1). Among screened catalysts, the catalyst 1 shows
distinctively high activity in forming the coupling product 1-
phenyl-3-pentanone (2a; see Table S1 in the Supporting
Information). Moreover, the catalyst mediates highly regio-
selective alkylation to the sterically less demanding a-ketone
carbon atom in forming the product 2a. Following the
previously developed protocol for generating an active
ruthenium vinyl species,[25] we have been able to promote
the catalytic activity of 1 by adding a substoichiometric
amount of an alkene (10 mol%). We have also been able to
trap both ammonia and carbon dioxide byproducts by chemi-
cally converting them into isolable forms. Thus, carbon
dioxide is readily converted into BaCO3 (82% CO2), while
the treatment of the crude reaction mixture with HCl(aq) is
used to estimate the formation of ammonia (79% NH3) by
following a literature procedure.[26,27]
We surveyed the substrate scope of the coupling reaction
by using 1 (Table 1). In general, a-amino acids with both
aliphatic and aryl side chains readily react with ketones to
form the a-alkylated ketone products 2. The coupling of (S)-
phenylglycine with both 2- and 3-methylcyclohexanone result
in a highly diastereoselective formation of the a-alkylated
products 2i and 2j, respectively (entries 9 and 10). A number
of oxygen and nitrogen groups are tolerated in the coupling
with aryl-substituted ketone substrates (entries 11–17). The
coupling of an amino acid having a chiral substituent, l-
À
Designing catalytic C N bond-cleavage methods for
amines and related nitrogen compounds poses a challenging
problem in the field of homogeneous catalysis because of
À
a relatively strong C N bond strength and their tendency for
undergoing kinetically favored dehydrogenation and other
side reactions, as well as the potential for catalyst poisoning.
À
As a result, only a few catalytic C N bond cleavage methods
have been developed over the years, and the most notable
examples include: the deaminative coupling of arylamines,[16]
arene–alkyne coupling of arylamides,[17] and dealkylation and
deallylation reactions of amines.[18–21] A broadly applicable
À
catalytic C N bond-cleavage method is essential not only for
efficient utilization of bio-derived nitrogen compounds in
organic synthesis, but also for designing cost-effective and
environmentally sustainable synthesis and reforming process
for biomass nitrogen feedstock.[22]
Inspired by natureꢀs ability to promote selective deami-
nation processes, we have been searching for novel catalytic
[*] N. Kalutharage, Prof. Dr. C. S. Yi
Department of Chemistry, Marquette University
Milwaukee, WI 53201-1881 (USA)
E-mail: chae.yi@marquette.edu
[**] Financial support from the US National Science of Foundation
(CHE-1011891 and CHE-1358439) is gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201307766.
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Table 1: Deaminative and decarboxylative coupling of a-amino acids with
isoleucine, with 4-methoxyacetophenone directly forms
an optically active product (+)-2u (entry 21). Protected
a-amino acids having oxygenated side chains such as l-
serine and l-aspartic acid derivatives smoothly afford
the coupling products 2y and 2z, respectively
(entries 25 and 26). In most cases, racemic d,l-amino
acids can be used without any significant change in the
product yields, but a secondary amino acid, l-proline,
does not yield any coupling products. We also com-
pared the analogous coupling of aliphatic and benzylic
amines with ketones, and in these cases, similar
alkylation products are formed but with considerably
lower yield because of the formation of imine and other
side products resulting from the homocoupling of
amines. To the best of our knowledge, the catalytic
method represents a unique set of examples on using
bio-based amino acids as the alkylating agent for the
ketones.[a]
Entry Amino acid Ketone
Product(s)
t
Yield
[h] [%][b]
1
2
R=H
R=Et
2a
2b
12 90
12 88
3
4
5
6
X=H, R=H
2c
2d
2e
2 f
12 79
12 90
X=OMe, R=H
X=OMe, R=Me
X=H, R=Ph
8
8
80
76
7
8
n=1
n=2
2g
2h
8
8
95
89
À
C C coupling reaction.
In an effort to extend its synthetic utility, we next
inspected the coupling reaction of b-amino acids with
ketones (Table 2). In the coupling of (S)-3-amino-2-
methylpropanoic acid with aryl-substituted ketones, the
n-propyl group is regioselectively alkylated to form the
coupling products 3a–f (entries 1–6). The coupling
reaction with 2-phenylcyclohexanone leads to the
diastereoselective formation of 3g (entry 7). In con-
trast, a modestly diastereoselective formation of the
ethylated product 3h is observed from the coupling of
3-aminopropanoic acid with 2-phenylcyclohexanone
(entry 9). Generally, the coupling reaction with
branched b-amino acids is quite sluggish, thus leading
to the decomposition products predominantly. Despite
such difficulties, we have been able to effect the
coupling reaction of the branched b-amino acids such
as 3-aminobutanoic acid and 3-amino-3-phenylpropa-
noic acid with acetophenone and indanone substrates
to form the alkylated products 3i–k (entries 10–12).
To further demonstrate synthetic versatility of the
catalytic coupling method, we employed a number of
bioactive ketone substrates to probe chemo- and
stereoselectivity patterns on the alkylation products
(Table 3). The alkylation of cholesterol (which readily
undergoes alcohol dehydrogenation under the reaction
conditions) and trans-androsterone with (S)-phenyl-
glycine occurs in a highly regio- and stereoselective
manner to give the anti-selective alkylation products,
(+)-4a and (+)-4b, respectively. In contrast, the cis-
fused deoxycholic acid benzyl ester with (S)-phenyl-
glycine leads to the syn-selective alkylation product
(+)-4c.
9
10
R=Me, R’=H
R=H, R’=Me
(Æ)-2i (>20:1 d.r.)
(Æ)-2j (>20:1 d.r.)
12 83
12 85
11
12
13
14
15
16
17
X=OMe, R=H
X=OMe, R=Me
X=H, R=H
X=Cl, R=H
X=CN, R=H
X=NH2, R=H
2k
2l
2m
2n
2o
2p
12 90
12 80
12 74
12 80
12 74
12 90
12 92
X=NC4H8O, R=H 2q
18
19
20
X=H, n=1
X=OMe, n=1
X=H, n=2
2r
2s
2t
8
8
8
90
92
89
21
(+)-2u
12 93
22
23
24
25
X=H, R=Me
X=H, R=iPr
X=OMe, R=Bn
X=OMe
R=CH2OBn
X=H
2v
2w
2x
2y
8
88
12 90
12 75
12 80
The alkylation of l-isoleucine with indanone leads
to a modestly diastereoselective formation of the
coupling product 4d (d.r. = 2:1). The coupling reaction
of (S)-phenylglycine with dihydro-b-ionone proceeds in
a regioselective fashion to give 4e, while the coupling of
l-tryptophan with 4-methoxyacetophenone yields the
coupling product 4 f, thus resulting from the dehydro-
genation of indole moiety. The regio- and diastereose-
lective formation of these alkylation products can
26
27
2z
10 75
12 95
R=CH2CH2CO2Me
X=H, R=CH2Cy
2aa
[a] Reaction conditions: amino acid (1.2 mmol), ketone (1.0 mmol), cyclo-
pentene (0.1 mmol), toluene (2 mL), 1 (3 mol%), 110–1208C. [b] Yield of
isolated product is based on the ketone substrate. The d.r. values were
1
determined by H NMR spectroscopy.
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Table 2: Deaminative and decarboxylative coupling of b-amino acids
Table 3: Catalytic coupling of a-amino acids with bioactive ketones.[a]
with ketones.[a]
Entry Amino acid
Ketone
Product(s)
t
Yield
[h] [%][b]
1
2
3
4
X=H, R=H
X=OMe, R=H 3b
X=H, R=Me
X=H, R=Ph
3a
12 80
12 85
3c
3d
8
8
78
90
5
6
n=1
n=2
3e
3 f
8
90
16 83
[a] Reaction conditions: amino acid (1.2 mmol), ketone (1.0 mmol),
cyclopentene (0.1 mmol), toluene (2 mL), 1 (3 mol%), 110–1208C.
Yields are those for the isolated product. The d.r. values were determined
by 1H NMR spectroscopy.
7
(Æ)-3g
12 90
(10:1 d.r.)
À
C H exchange. The extensive deuterium incorporation on the
8
9
2v
12 89
12 83
b-carbon atom can be interpreted as an amine–imine hydro-
genation/dehydrogenation of the amino acid substrate under
the reaction conditions. Second, the NMR technique reported
by Singleton and co-workers is used to measure the 12C/13C
kinetic isotope effect (KIE) from the coupling reaction of 4-
methoxyacetophenone with l-leucine [Eq. (3)].[28] The most
pronounced carbon KIE is observed for the b-carbon atom of
2k, when the 12C/13C ratio of the product at 96% conversion is
compared to that of the product obtained at a low conversion
(KIE on C3 = 1.024; average of 3 runs; see Table S2 in the
Supporting Information). The unique carbon KIE on the b-
(Æ)-3h
(3:2 d.r.)
10
11
X=OMe
X=H
3i
3j
12 81
12 78
À
carbon atom of 2k suggests that the C N bond cleavage is
intimately involved in the turnover limiting step of the
coupling reaction.
12
3k
12 80
[a] Reaction conditions: amino acid (1.2 mmol), ketone (1.0 mmol),
cyclopentene (0.1 mmol), toluene (2 mL), 1 (3 mol%), 110–1208C.
[b] Yield of isolated product is based on the ketone substrate. The d.r.
values were determined by 1H NMR spectroscopy.
readily be explained from imposing a sterically least hindered
ruthenium enolate species.
To further probe electronic effect of the ketone substrate,
a Hammett plot is constructed from the reaction of a series of
p-X-C6H4COMe (X = NH2, OCH3, CH3, H, Cl, CN) with l-
leucine [Eq. (4)]. A linear correlation from the relative rate
versus the Hammett sp is observed with a positive slope (1 =
+ 1.2 Æ 0.2; see Figure S2 in the Supporting Information).
Strong promotional effects by para-electron-withdrawing
groups suggests a substantial build-up of cationic character
on the a-carbon atom of the ketone substrate, and the results
can be explained by the formation of a cationic ruthenium
enolate species.
We performed the following experiments to gain mech-
anistic insights into the coupling reaction. First, the treatment
of C6D5COCD3 with l-leucine leads to substantial deuterium
incorporation at both a- and b-carbon atoms on the coupling
product [D]-2m [Eq. (2)]. The observed hydrogen–deuterium
exchange pattern is consistent with a facile keto–enol
tautomerization of the ketone substrate and the ortho-arene
To probe the deamination versus decarboxylation
sequence, we surveyed a number of different carbonyl
substrates with l-leucine. The trapped amide product 5 is
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À
KIE data provides support for the C N cleavage as the rate-
limiting step in leading to the formation of the alkylated
product 2. The regio- and stereoselective formation of the
alkylation product can be readily rationalized from the
preferential formation of the sterically least demanding
ruthenium enolate complex and an intramolecular addition
of the alkyl group. Finally, the extrusion of ammonia
byproduct provides the driving force for the regeneration of
the ruthenium enolate complex 6.
In summary, we have successfully developed a novel
catalytic alkylation method using readily available amino acid
substrates as a bio-based alkylation agent. The salient
features of the catalytic method are that it achieves direct
successfully obtained from the treatment of dihydrocoumarin
with l-leucine [Eq. (5)]. The selective formation of the amide
product 5 supports a preferential decarboxylation over the
deamination step for the amino acid substrate. Transition
metal catalyzed decarboxylative coupling methods have been
successfully employed for the synthesis of complex organic
molecules.[29]
À
À
C C and C N bond cleavage of biomass-derived amino acid
substrates, exhibits a broad range of substrate scope, as well as
high regio- and stereoselectivity, and it does not require any
reactive reagents or pre-functionalization of the substrates in
forming the a-alkylated ketone products.
Although details still remain to be established, we Experimental Section
General procedure for the coupling reaction of an amino acid with
propose a working mechanistic hypothesis for the coupling
reaction on the basis of these experimental results
(Scheme 1). We propose that the cationic ruthenium(II)
a ketone: In a glove box, the amino acid (1.2 mmol), ketone
(1.0 mmol), cyclopentene (0.1 mmol), and the Ru catalyst
1 (3 mol%) were dissolved in toluene (2 mL) in a 25 mL Schlenk
tube equipped with a Teflon stopcock and a magnetic stirring bar. The
tube was brought out of the glove box, and was stirred in an oil bath
set at 1208C for 6–12 h. The reaction tube was taken out of the oil
bath, and cooled to room temperature. After the tube was open to air,
the solution was filtered through a short silica gel column by eluting
with CH2Cl2 (10 mL), and the filtrate was analyzed by GC and GC-
MS. Analytically pure product was isolated by a simple column
chromatography on silica gel (280–400 mesh, hexanes/EtOAc = 40:1
to 1:1). The products were completely characterized by NMR
spectroscopy and GC-MS methods.
Received: September 4, 2013
Published online: October 31, 2013
Scheme 1. Plausible mechanistic pathway for the alkylation of a-amino
acid with 2-butanone.
Keywords: alkylation · amino acids · ketones · ruthenium ·
.
synthetic methods
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exchange pattern on the coupling product [D]-2m is consis-
tent with a facile and reversible enolization of the ketone
substrate via the ruthenium enolate species 6.[32] Late
transition metal/enolate complexes have been well known
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