Highly enantioselective amination reactions of fluorinated keto esters catalyzed by novel chiral guanidines derived from cinchona alkaloids

Article abstract of DOI:10.1002/adsc.201000562

Novel Cinchona alkaloid-derived guanidines catalyze stereoselective aminations of fluorinated keto esters, affording products with fluorine-containing quaternary stereogenic centers in excellent yields and with moderate to high enantioselectivities.

Full text of DOI:10.1002/adsc.201000562

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DOI: 10.1002/adsc.201000562
Highly Enantioselective Amination Reactions of Fluorinated
Keto Esters Catalyzed by Novel Chiral Guanidines Derived from
Cinchona Alkaloids
Xiao Han,a Fangrui Zhong,a,b and Yixin Lua,b,*
a
Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543, Republic of Singapore
Fax : (+65)-6779-1691; phone: (+65)-6516-1569; e-mail: chmlyx@nus.edu.sg
Medicinal Chemistry Program, Life Sciences Institute, National University of Singapore, Republic of Singapore
b
Received: July 16, 2010; Published online: October 26, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000562.
Abstract: Novel Cinchona alkaloid-derived guani-
dines catalyze stereoselective aminations of fluori-
nated keto esters, affording products with fluorine-
containing quaternary stereogenic centers in excel-
lent yields and with moderate to high enantioselec-
tivities.
Toru disclosed the dbfox-Ph/Ni(II) complex-catalyzed,
highly enantioselective fluorination of carbonyl com-
pounds. Subsequently, the same group described an
elegant desymmetrization-like fluorination of malo-
nates that was promoted by DNFOXD-Ph and
ZnACTHNUTRGNEUNG
(OAc)2.[7] In an interesting approach, the groups of
Stoltz, Nakamura, and Tunge investigated Pd(II)-
mediated decarboxylative allylation reactions to con-
struct fluorinated quaternary centers.[8]
Keywords: asymmetric amination; chiral guani-
dines; Cinchona alkaloids; fluorination substituent;
organocatalysis
In contrast to the widespread methods based on
transition metals, approaches employing organic cata-
lysts have received attention only in the past few
years.[9] Recently, organocatalytic approaches employ-
À
ing fluorinated substrates in asymmetric C C bond
Fluorine-containing molecules are very important in forming reactions have been demonstrated to be very
the pharmaceutical industry.[1] Fluorinated molecules useful in the synthesis of optically enriched fluorine-
often display distinctive characteristics compared to containing molecules.[10] By utilizing a-fluorinated-b-
their parent compounds, owing to the unique proper- keto esters as pronucleophiles, we achieved highly
À
ties of the fluorine atom and the resulting C F enantioselective organocatalytic Michael additions to
bond(s). Therefore, the asymmetric construction of nitroolefins[10a] and Mannich reactions with N-Boc-
fluorinated molecules has become a fascinating and imines.[10b] To further develop this synthetic methodol-
intensively investigated research area in organic syn- ogy to access structurally interesting and biologically
thesis.[2]
important fluorinated molecules, we became interest-
The catalytic synthesis of chiral fluorinated quater- ed in the direct amination of a-fluorinated-b-keto
nary carbon centers is a formidable synthetic chal- esters, since such reactions yield a-fluoro-a-amino
lenge, and a number of excellent approaches based on acids[11] possessing quaternary carbon centers. Al-
metal catalysis appeared in the literature recently. though asymmetric amination reactions of b-keto
Togni made the seminal discovery by utilizing Ti(IV)/ esters were well-explored in the literature, aminations
TADDOL complexes to achieve the catalytic enantio- of fluorinated substrates are rather limited.[12] Herein,
selective fluorination of b-keto esters in 2000.[3] So- we document a highly efficient enantioselective ami-
deoka and co-workers later developed the chiral pal- nation reaction of a-fluorinated-b-keto esters cata-
ladium(II)-bisphosphine-catalyzed
enantioselective lyzed by novel chiral guanidines derived from Cincho-
fluorination of b-keto esters, b-ketophosphonates, and na alkaloids.
N-Boc-protected oxindoles.[4] Similar palladium spe-
To effect the stereoselective amination reaction of
cies were employed by Kim et al. for the fluorination a-fluorinated b-keto esters, a bifunctional tertiary
of a-cyanoacetates.[5] By using bisoxazoline-copper(II) amine with a Brønsted acid moiety appears to be a
complexes, Ma and Cahard achieved the electrophilic good choice. We chose the amination reaction of a-
fluorination of b-keto esters.[6] Recently, Shibata and fluoro-b-keto ester 1a with di-tert-butyl azodicarboxy-
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Adv. Synth. Catal. 2010, 352, 2778 – 2782

Highly Enantioselective Amination Reactions of Fluorinated Keto Esters
Scheme 1. Amination reactions catalyzed by some known bifunctional catalysts.
late (DBAD) 2a as a model reaction, and the catalytic which have found widespread applications in asym-
effects of various bifunctional catalysts were exam- metric synthesis and catalysis, we therefore selected
ined (Scheme 1). Quinine-derived tertiary amine-thio- Cinchona alkaloids as structural motifs in our catalyst
urea catalyst 4 afforded the product in very low con- design. Guanidine-based organic molecules are re-
version and with a poor ee value.[13] Quinidine-derived markably versatile catalysts in a wide range of organic
sulfonamide[14] 5 was found to be completely ineffec- reactions,[17] and we envisioned that introduction of
tive. When tryptophan-derived tertiary amine-thiour- the guanidine moiety into Cinchona alkaloids may
ea catalyst 6[15] was employed, the desired product result in novel chiral guanidines. To test this hypothe-
was obtained in moderate yield and with modest sis, a number of guanidines (7–10) based on Cinchona
enantioselectivity. However, further optimizations of alkaloids were designed and prepared, as shown in
the reaction conditions did not lead to much improve- Scheme 2. It is anticipated that the guanidinium inter-
ment in stereoselectivity.
mediate generated upon deprotonation of keto esters
Given the ineffectiveness of the bifunctional terti- will form hydrogen bonding interactions with the keto
ary amine catalysts examined, we decided to design enolate, and such a structurally well-defined inter-
new catalysts to tackle this synthetic challenge. Cin- mediate complex may lead to a stereoselective amina-
chona alkaloids are privileged organic catalysts,[16] tion process.
Scheme 2. Novel guanidines derived from Cinchona alkaloids.
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Xiao Han et al.
COMMUNICATIONS
Table 1. Examination of novel guanidines in the amination
reactions of fluorinated 1a.[a]
Table 2. Guanidine 9-mediated asymmetric amination reac-
tion of various a-fluorinated b-keto esters.[a]
Entry R1/R2
t [h] Yield [%][b] ee [%][c]
Entry Cat. T [oC] Solvent t [h] Conv.[b] [%] ee[c] [%]
1
2
3
4
5
6
7
8
Ph/Me (3b)
Ph/Bn (3c)
p-NO2-C6H4/Et (3d) 20
p-Br-C6H4/Et (3e)
m-Br-C6H4/Et (3f)
p-Cl-C6H4/Et (3g)
p-Me-C6H4/Et (3h)
20
20
96
91
93
92
93
93
96
90
96
78
86
82
80
91
88
91
90
88
89
90
91
92
87
57
47
87
1
2
3
4
5
6
7
8
7
8
9
10
9
9
9
9
9
9
9
9
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
À50
À50
toluene
toluene
toluene
toluene
CH2Cl2 20
THF 24
CH3CN 20
ether 12
benzene 12
xylene 12
3
5
3
5
>99
>99
>99
>99
>99
50
>99
>99
>99
>99
>99
>99
70
71
73
73
50
60
21
69
66
71
87
90
20
20
20
72
p-OMe-C6H4/Et (3i) 48
9
2-naphthyl/Et (3j)
thiophenyl/Et (3k)
Me/Bn (3l)
i-Pr/Bn (3m)
t-Bu/Bn (3n)
72
72
96
96
96
9
10
11
12
13[d]
10
11
12[d]
toluene 12
toluene 20
[a]
The reactions were performed with 1a (0.05 mmol),
DBAD (0.05 mmol) and the catalyst (0.005 mmol) in the
solvent (0.5 mL) at the temperature specified.
Determined by H NMR analysis of the crude product.
The ee values were determined by chiral HPLC analysis.
[a]
The reactions were performed with ketoester
1
(0.05 mmol), DBAD (0.05 mmol) and 9 (0.005 mmol) in
the solvent specified (1.5 mL) at À508C.
Isolated yields.
The ee values were determined by chiral HPLC analysis.
The reaction was carried out at room temperature.
[b]
[c]
[d]
1
[b]
[c]
[d]
A concentration of 0.033M was used.
The effects of our novel guanidines 7–10 on the
amination reactions of fluorinated keto ester 1a were
investigated, and the results are summarized in
Table 1. We were delighted to find that the novel gua-
nidines 7–10 were in general very efficient, and the
products were formed quantitatively and with good
enantioselectivity (entries 1–4) . Different guanidines
seemed to offer little difference in inducing stereose-
lectivity, and 9 was chosen for further studies. A sol-
vent screening revealed that toluene was the best sol-
vent. The desired amination product could be ob-
tained quantitatively and with 90% ee under the opti-
mized reaction conditions (entry 12).
The scope of the asymmetric amination reactions of
fluorinated substrates was next examined (Table 2).
The reaction is applicable to different aryl keto esters,
and the desired products were obtained in very high
yields and with excellent enantioselectivities (en-
tries 1–10). In the case of aliphatic keto ester sub- Figure 1. ORTEP structure of 3e.
strates, the reactions proceeded with low reactivity
and moderate enantioselectivity (entry 11 and 12).
When tert-butyl keto ester was utilized, the reaction structural scaffolds, and applied such catalysts to the
had to be carried out at room temperature whereupon asymmetric amination reactions of a-fluorinated b-
good chemical yield and high enantioselectivity were keto esters. The desired aminated products with a flu-
attainable (entry 13). The absolute configuration of orine-containing quaternary center were obtained in
the amination product 3e was determined to be R excellent yields and with very high enantioselectivity.
based on X-ray crystallographic analysis (Figure 1).[18] This method may provide a practical entry for the
In summary, we have designed and prepared sever- preparation of biologically useful a-fluoro-a-amino
al novel chiral guanidines based on Cinchona alkaloid acid derivatives.[11] Moreover, the novel chiral guani-
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Highly Enantioselective Amination Reactions of Fluorinated Keto Esters
Takano, Y. Shimura, M. Sodeoka, J. Am. Chem. Soc.
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dines may find wide applications in other asymmetric
organic reactions. Investigations along these lines are
in progress in our laboratory, and will be reported in
due course.
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Experimental Section
Representative Procedure
Ethyl 2-fluoro-3-oxo-3-phenylpropanoate 1a (10.5 mg,
0.05 mmol) was added to a mixture of guanidine 9 (2.8 mg,
0.005 mmol) and di-tert-butyl azodicarboxylate 2a (11.5 mg,
0.05 mmol) in toluene (1.5 mL) in a sample vial. The vial
was then capped and the reaction mixture was stirred at
À508C for 20 h. Solvent was then removed and the residue
was purified by column chromatography on silica gel
(hexane: ethyl acetate=10:1 to 5: 1) to afford 3a as a white
solid; yield: 21 mg (95%). See Supporting Information for
1H and 13C NMR spectra; HR-MS: m/z=463.1843, calcd. for
C21H29FN2O7Na [M+Na]+: 463.1856. The ee value was 90%
[Chiralcel IC, l=254 nm, 10% i-PrOH/hexane, flow rate=
1.0 mLminÀ1]: tR (major)=16.1 min, tR (minor)=26.4 min.
Acknowledgements
We thank the National University of Singapore and the Min-
istry of Education (MOE) of Singapore (R-143-000-362-112)
for the generous financial support.
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