Catalytic enantioselective electrophilic aminations of acyclic α-alkyl β-carbonyl nucleophiles

Article abstract of DOI:10.1055/s-0029-1217334

Highly enantioselective aminations of acyclic α-alkyl β-keto thioesters and trifluoroethyl α-methyl α-cyanoacetate (12) with as low as 0.05 mol% of a bifunctional cinchona alkaloid catalyst were established. This ability to afford high enantioselectivity

Full text of DOI:10.1055/s-0029-1217334

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Synlett. Author manuscript; available in PMC 2011 February 16.
Published in final edited form as:
Synlett. 2009 June ; 10: 1685–1689. doi:10.1055/s-0029-1217334.
Catalytic Enantioselective Electrophilic Aminations of Acyclic α-
Alkyl β-Carbonyl Nucleophilies
Xiaofeng Liu, Bingfeng Sun, and Li Deng
Department of Chemistry, Brandeis University, 415 South St., Waltham, MA 02454-9110, USA,
Fax +01 781 736 2516; E-mail: deng@brandeis.edu
Abstract
Highly enantioselective aminations of acyclic α-alkyl β-keto thioesters and trifluoroethyl α-methyl
α-cyanoacetate (12) with as low as 0.05 mol % of a bifunctional cinchona alkaloid catalyst were
established. This ability to afford highly enantioselectivity for the amination of α-alkyl β-carbonyl
compounds renders the 6′-OH cinchona alkaloid-catalyzed amination applicable for the
enantioselective synthesis of acyclic chiral compounds bearing N-substituted quaternary
stereocenters. The synthetic application of this reaction is illustrated in a concise asymmetric
synthesis of α-methylserine, a key intermediate previously utilized in the total synthesis of a small
molecule immunomodulator, conagenin.
Keywords
bifunctional catalysis; asymmetric organocatalysis; cinchona alkaloids; chiral amines; quaternary
stereocenters
Biologically interesting compounds often contain nitrogen-substituted quaternary
stereocenters. Thus, the construction of these quaternary stereocenters continues to attract
great interests from synthetic chemists. Most of the catalytic asymmetric methods have been
focused on enantioselective C-C bond forming reactions with nitrogen-containing prochiral
1,2
starting materials, as exemplified by enantioselective Strecker reactions and electrophilic
3,4
alkylations of glycine derivatives . On the other hand, catalytic enantioselective C-N bond
5
6
forming electrophilic aminations with metallic and organic catalysts recently emerged as
another promising approach for the creation of N-substituted quaternary stereocenters. Bi-
6b
6a
functional cinchona alkaloids 1 and 2 have been identified by us and Jørgensen ,
respectively, to be highly effective and general catalysts for the amination of αaryl α-
cyanoacetates (Figure 1). Importantly, the ready accessibility of catalysts 1 from both
quinidine and quinine allows these catalysts to provide facile access to both enantiomers of
the amination product. In this paper we wish to document our recent progress in realizing
highly enantioselective aminations of cyclic and acyclic α-alkyl β-carbonyl nucleophiles
with 1.
Our initial attempts to expand the scope of the 1-catalyzed amination began with an
investigation of the reaction of α-substituted β-ketoesters 3 and dibenzyl azodicarboxylate
(4a) in toluene in the presence of 1.
As summarized in Table 1, aminations of cyclic β-ketoesters 3a and 3b proceeded cleanly to
furnish the the corresponding amination products in excellent yield and enantioselectivity
Correspondence to: Li Deng.

Liu et al.
Page 2
with 1 mol % or less of 1 (entries 1–3). It is noteworthy that even with 0.1 mol % loading of
Q-1 the excellent yield and enantioselectivity remain uncompromised (entry 2). In stark
contrast, the amination of the less active acyclic β-ketoester 3c proceeded in less than 20%
conversion and afforded the product in very poor ee even when 10 mol % of QD-1 was
employed in the reaction (entry 4). A TLC analysis of the resulting reaction mixture
revealed that catalyst QD-1 was completely consumed. In light of the report by Jørgensen
7
and coworkers of a Fridel-Crafts amination of cuperidine with di-t-butyl diazocarboxylate,
we suspected that QD-1 might undergo decomposition via a similar Fridel-Crafts reaction
with dibenzyl azodicarboxylate (4a) in toluene. Indeed, QD-6 and QD-7 were isolated in
64% and 33% yield, respectively, from a reaction of QD-1 with 4a in toluene (Scheme 1).
We further examined QD-6 and QD-7 as catalysts for the amination of 3c with 4a. As
presented in Table 2, the former was found to be inactive while the latter afforded a reaction
of low enantioselectivity and poor conversion (entries 2 and 3, Table 2). It was noticed that
the poor results obtained from the QD-1-catalyzed amination of acyclic β-ketoester 3c
resembled those afforded by QD-7, which suggested that the rapid decomposition of catalyst
QD-1 to form QD-6 and QD-7 could be the cause of the observed poor enantioselectivity
and activity afforded by QD-1 for the amination of 3c.
These experimental results also enable us to formulate a hypothesis, as described in Scheme
2, regarding the possible origin of the dramatic difference between the QD-1-catalyzed
amination of cyclic-α-substituted β-ketoesters such as 3a–b and that of acyclic β-ketoesters
3c. In line with our proposed mechanism for 6′-OH cinchona alkaloid-catalyzed asymmetric
8
conjugate additions, we postulated that QD-1 activated the β-ketoesters 3 via the formation
of a hydrogen-bonding complex with the corresponding enol of 3 (e-3) (Scheme 2).
However, QD-1 could also exist in the solution as a dimmer (QD-1) and/or an oligomer
2
(QD-1) , in which the hydrogen-bonding interaction between the 6′-OH and the quinuclidine
n
nitrogen could activate the quinoline ring in QD-1 toward the Fridel-Crafts amination that
decomposed QD-1 to form QD-6 and QD-7. While β-ketoesters 3 could exist in both the
enol and the keto form, relative to the equilibrium between acyclic β-ketoester 3c and its
corresponding enol e-3c, the equilibrium with a cyclic β-ketoesters such as 3a should be
more favorably toward the enol e-3, which promoted the formation of the catalyst-substrate
complexes 8 and 9 and, consequently, disfavored the formation of dimmer (QD-1) or
2
oligomer (QD-1) . This in turn should suppress the catalyst decomposition while enhancing
n
the desirable enantioselective amination of 3.
Guided by this analysis we began to investigate the amination of acyclic β-ketothioesters 10.
We expected that 10, a class of acyclic β-carbonyl nucleophiles bearing a more acidic α-
9
protons relative to those of the acyclic β-ketoesters, might undergo the 1-catalyzed
enantioselective amination with significantly retarded catalyst decomposition. Accordingly,
a reaction of dibenzyl azodicarboxylate (4a) and S-phenyl 2-methyl-3-oxothiobutyrate 10a
11,12
with QD-1 in toluene was carried out at room temperature.
Gratifyingly, with 1.0 mol
% of Q-1, the reaction rapidly proceeded to completion in five minutes at root temperature
to afford 11a in 92% yield and 95% ee (entry 1, Table 3). It is noteworthy that both the yield
and enantioselectivity could be maintained at an excellent level even with only 0.05 mol %
of Q-1 (entry 2). To our knowledge, this is one of the lowest catalyst loading documented
for a highly enantioselective asymmetric reaction mediated by an organic catalyst. As
summarized in Table 3, highly enantioselective aminations could be accomplished with
1
various acyclic β-ketothioesters 10a–d. Importantly, variations of both the α-substituent (R )
2
and the ketone substituent (R ) were well tolerated by the catalysts. Moreover, the
introduction of additional functional groups into the α-substituent is also accepted by the
catalysts (entry 5). A cyclic β-ketothioester such as 10e was also found to be a good
substrate (entries 6–7).
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We previously reported that QD-1 promoted highly enantioselective aminations of various
6b
α-aryl α-cyanoacetates. However, the enantioselectivity drastically deteriorated for the
amination with ethyl α-methyl α-cyanoacetate, an α-alkyl α-cyanoacetate, and furnished the
corresponding amination product in only 35% ee and in 75% yield. It is noteworthy that
Jorgensen and coworkers reported similarly low enantioselectivity (27% ee) for the
6a
amination of ethyl α-methyl α-cyanoacetate with isocuperidine (2) as the catalyst. Our
success in realizing highly enantioselective aminations of β-ketothioesters 10 suggested that
the 1-catalyzed asymmetric amination with an α-alkyl α-cyanoacetate bearing a more acidic
α-hydrogen, such as 2,2,2-trifluoroethyl α-methyl α-cyanoacetate (12), might occur with
improved enantioselectivity. To our delight, aminations of 12 and di-t-butyl
azodicarboxylate (4b) with Q- and QD-1 generated the desirable product 13 in 91% and
81% ee, respectively, and in virtually quantitative yield (Scheme 3).
After the expansion of the substrate scope described above, the 1-catalyzed enantioselective
amination has become applicable to acyclic α-alkyl β-carbonyl compounds. Consequently, it
provides a useful method for the asymmetric synthesis of acyclic chiral aliphatic compounds
containing N-substituted quaternary centers. Taking advantage of this new capacity of the 1-
catalyzed amination, we developed a concise synthesis of methyl (S)-α-methylserinate 16
(Scheme 3). Thisα,α-disubstituted amino acid was used as a key intermediate in a total
synthesis of conagenin 17, a small molecule immunomodulator that enhances the
10
proliferation and lymphokine production of activated T cells.
In conclusion, we have realized highly enantioselective aminations of acyclic α-alkyl β-keto-
thioesters and trifluoroethyl α-methyl α-cyanoacetate (12), thereby significantly expanded
the substrate scope of the 6′-OH cinchona alkaloid-catalyzed aminations. Consequently, as
illustrated in its application in the asymmetric synthesis of α-methylserine 16, this efficient
and operationally simple catalytic asymmetric amination could be applied to facilitate the
demanding but important task of constructing N-substituted quaternary stereocenters bearing
aliphatic substituents in acyclic compounds.
Acknowledgments
We gratefully acknowledge the financial support of NIH (GM-61591) and Daiso Inc.
References
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11. Experimental procedure for the asymmetric amination of 3 (or 10) with 4a catalyzed by Q-1: A
suspension of Q-1 in toluene (2.0 mL) was subjected to ultrasound until no chunky solid was
visible (c.a. 15 min). The resulting mixture was heated at 110 °C until a clear solution was formed
(10–15 min). While it was still hot, the solution was allowed to pass a cotton plug to remove any
trace amount of insoluble residue and then cooled to room temperature. Then 3 (or 10) (0.22
mmol, 1.1 eq) was added. This mixture was stirred at indicated temperature and a solution of 4a
(0.50 M, 0.40 mL, 0.20 mmol) was added dropwise in 5–10 min. The stirring was continued until
the color of the solution turned from yellow to colorless (or at indicated time) and the amination
product was isolated by flash chromatography separation.
12. Experimental procedure for the asymmetric amination of 3 (or 10) with 4a catalyzed by QD-1: To
a solution of 3 or 10 (0.22 mmol, 1.1 eq) and QD-1 in toluene (2.0 mL) at indicated temperature
under stirring, a solution of 4a in toluene (0.50 M, 0.40 mL, 0.20 mmol) was added dropwise in5–
10 min. The resulting reaction mixture was stirred until the color of the solution turned from
yellow to colorless (or at indicated time), and the aminationproduct was isolated by flash
chromatography.
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Figure 1.
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Scheme 1.
Amination of QD-1
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Scheme 2.
Proposed Reaction Pathways of Catalyst 1
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Scheme 3.
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Table 2
Amination of 3c with 4a Using Different Catalysts a
Entry
Catalyst
b
c
Conv. (%) / Time ee (%)
1
None
(back ground)
No product / 7d
N/A
2
3
4
QD-6
QD-7
QD-1
No product / 7d
14% / 7d
N/A
10
19% / 7d
17
a
b
c
Reaction was performed with 1.1 equiv of 3 and 1.0 equiv of 4a in toluene.
1
Conversions were determined by H NMR.
ee was determined using HPLC.
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