Enantioselective synthesis of α-fluorinated β-amino acid derivatives by an asymmetric mannich reaction and selective deacylation/ decarboxylation reactions

Article abstract of DOI:10.1002/chem.200902830

A study was conducted to demonstrate enantioselective synthesis of α-fluorinated β-amino acid (AA) derivatives by an asymmetric Mannich reaction and selective deacylation or decarboxylation reactions. Better yield was obtained from the Mannich reaction be

Full text of DOI:10.1002/chem.200902830

COMMUNICATION
DOI: 10.1002/chem.200902830
Enantioselective Synthesis of a-Fluorinated b-Amino Acid
Derivatives by an Asymmetric Mannich Reaction and Selective
Deacylation/Decarboxylation Reactions
Yuanhang Pan,[a] Yujun Zhao,[a] Ting Ma,[a] Yuanyong Yang,[a] Hongjun Liu,[a]
Zhiyong Jiang,*[b] and Choon-Hong Tan*[a]
Powerful probes for revealing the workings of biological
systems can be prepared through the judicious replacement
rare despite these developments. Furthermore, the synthetic
route to a-fluorinated b-amino acids (a-F-b-AAs), particu-
larly those containing chiral quaternary a-carbon center, is
virtually unexplored.[10]
of hydrogen atoms with fluorine.[1] The C F bond has a sig-
À
nificant effect on the reactivity, stability, and bioavailability
of molecules.[2] Thus, there is a strong demand for a wider
availability of versatile fluorine-containing building blocks;
enantiopure ones are particularly in demand.[3] The fluori-
nated amino acids[4] (F-AAs) impart unique properties when
they were used in the modification of peptides and proteins
in protein engineering. They are also ideal intermediates for
drug-discovery programs and have found their way into
drugs like Vaniqa (antineoplastic agent).[1] Fluorinated a-
amino acids[5] (F-a-AAs) are also well known as irreversible
inhibitors of pyridoxal phosphate-dependent enzymes. Con-
versely, much less is known about fluorinated b-amino acids
(F-b-AAs).[5b,6]
Recently, we reported the bicyclic, guanidine-catalyzed[11]
À
formation of asymmetric C F bonds using a-fluoro-b-ke-
toesters as fluorocarbon nucleophiles in highly enantio- and
diastereoselective conjugate-addition and Mannich reac-
tions.[11d] Such a-fluoro-b-ketoesters have also recently been
exploited by the groups of Lu,[12] Maruoka,[13] and others.[14]
Catalytic enantioselective nucleophilic fluorination is not
common, and the other successful example is the use of 1-
fluoroACHTNUTRGNEbNUG is(phenylsulfonyl)methane (FBSM). Shibata, Toru,
and co-workers have reported the use of this fluorocarbon
nucleophile in palladium-catalyzed, allylic-replacement,[15a]
Mannich-type,[15b] and Michael reactions with a,b-unsaturat-
ed ketones.[15c] This fluoronucleophile was also used by Pra-
kash, Olah, and co-workers in Mitsunobu[16a] and Michael
addition to chalcones.[16b]
As they are potential precursors for b-lactams, various
strategies for the stereoselective synthesis of b-AAs have
been reported.[6,7] Among these, the most robust and power-
ful method is attributed to the asymmetric Mannich reac-
tion, of which several organocatalytic versions have been de-
veloped over the past few years.[8,9] However, the synthesis
of F-b-AAs by using asymmetric Mannich reactions is still
In our preliminary studies, we obtained excellent yield
from the Mannich reaction between a-fluoro-b-ketoester 1a
and N-ethoxycarbonyl imine 2a, although the enantio- and
diastereoselectivities were moderate (Table 1, entry 1). Our
experiences with bicyclic, guanidine-catalyzed, asymmetric
reactions allowed us to predict that the catalyst system
would respond well to changes in the steric properties of the
substrates. Hence, we changed the N-ethoxycarbonyl imine
2a to N-tert-butyloxycarbonyl (Boc) imine 2b. The diaste-
reoselectivity increased slightly, but the enantiomeric excess
(ee) value decreased (Table 1, entry 2). We then worked on
the a-fluoro-b-ketoester, and replaced the ester moiety with
oxazolidinone, as it has an additional opportunity for hydro-
gen bonding due to the additional carbonyl groups. The
lower reactivity of b-keto acetyloxazolidinone 1b meant
that the reaction with N-Boc imine 2b had to be carried out
at room temperature; a moderate ee value was obtained,
but the diastereoselectivity was lost (Table 1, entry 3). How-
[a] Y. Pan, Y. Zhao, T. Ma, Y. Yang, H. Liu, Prof. Dr. C.-H. Tan
Department of Chemistry, National University of Singapore
3 Science Drive 3, Singapore 117543 (Singapore)
Fax : (+65)6779-1691
E-mail: chmtanch@nus.edu.sg
[b] Prof. Dr. Z. Jiang
Provincial Key Laboratory of Natural Medicine
and Immuno-Engineering, Henan University
Jinming Campus, Kaifeng, Henan, 475004 (P.R. China)
Fax : (+86)0378-2864665
E-mail: chmjzy@henu.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200902830.
Chem. Eur. J. 2010, 16, 779 – 782
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
779

Table 1. Highly enantioselective and diastereoselective Mannich reac-
Table 3. Highly enantioselective and diastereoselective reactions be-
tions of fluorocarbon nucleophiles 1a–c.
tween b-keto acyloxazolidinone 1d–g and N-Eoc imines.
2 [R2]
T [8C]
4
Yield [%][a]
dr[b]
ee [%][c]
1
R1
2
4
Yield [%][a]
dr[b]
ee [%][c]
1
1
2
3
4
1d
1d
1e
1 f
1 f
1 f
1g
nPr
nPr
PhCH2CH2
Bn
Bn
Bn
2e
2j
2j
2e
2 f
2j
2j
4m
4n
4o
4p
4q
4r
99
90
92
99
95
93
92
95:5
97:3
96:4
96:4
92:8
94:6
98:2
97
98
98
>99
95
98
1
2
3
4
5
1a
1a
1b
1c
1c
2a [Et]
À50
À50
RT
RT
RT
4a
4b
4c
4d
4e
99
90
92
85
96
9:1
10:1
1:1
4:1
96:4
84
71
83
95
98
2b [tBu]
2b [tBu]
2b [tBu]
2c [CEt3]
5
6
[a] Yield of isolated product. [b] Determined by HPLC analysis. [c] De-
termined by HPLC.
7[d]
(CH3)2C=CH
4s
97
[a] Yield of isolated product. [b] Determined by HPLC analysis. [c] De-
termined by HPLC. [d] Reaction time was 60 h.
ever, when b-keto acetyloxazolidinone 1c was used as the
donor with N-3-ethylpentan-3-yloxycarbonyl (Eoc) imine 2c
(both developed in our laboratory), we obtained adduct 4e
in excellent yields and excellent enantio- and diastereoselec-
tivities (Table 1, entry 5).
With the optimized conditions established, we evaluated
the performance of b-keto acetyloxazolidinone 1c with a
series of different N-Eoc imines in the presence of 10 mol%
of bicyclic guanidine catalyst 3 (Table 2). Excellent results
(up to 98:2 dr, up to 99% ee) were observed with imines
containing both electron-withdrawing and electron-donating
aryl groups. Different substituents on the aryl ring did not
affect the ee values and diastereoselectivities. b-Keto acylox-
azolidinones 1d–g, which contain different aliphatic chains,
were also investigated under the optimized conditions
(Table 3). Increasing the length of the donor did not greatly
affect either the enantio- or diastereoselectivities, but the re-
actions became more sluggish and required longer reaction
times. Interestingly, dimethyl-ene-keto acetyloxazolidinones
1g (Table 3, entry 7) also provided excellent results. The
presence of the additional double bond in adduct 4s should
allow ample opportunities for further functionalization.
FBSM was shown to be an excellent fluoronucleophile.
We prepared a-fluoro-b-sulfones 5a and 5b to determine
whether they are suitable for this reaction. Indeed, the Man-
nich reaction of 1-fluoro-1-(phenylsulfonyl)propan-2-one
(5a) gave an adduct with a high ee value and good diaste-
reoselectivity [Eq. (1)].
The preparation of a-fluoro-a,b-diamines, particularly one
that contains a quaternary fluorinated carbon, is an attrac-
tive
target.
a-Fluoro-a-nitro(phenylsulfonyl)methane
(FNSM; 5b) was previously shown to participate in Michael
reaction with good results.[16b] FNSM and N-Eoc imine 2j
underwent Mannich reaction smoothly at À508C to give
adduct 6b with a good ee value and diastereoselectivity
[Eq. (2)].
Table 2. Highly enantioselective and diastereoselective reactions be-
tween b-keto acetyloxazolidinone 1c and N-Eoc imines.
The ability of malonates and b-ketoesters to be decar-
boxylated via their corresponding acids under acidic condi-
tions after alkylation allows these reagents to be extremely
useful and form a significant portion of undergraduate
teaching on carbonyl chemistry. It is known that decarboxy-
lation occurs through a six-membered transition state with
the elimination of a molecule of carbon dioxide. It is, how-
ever, less well known that, under strongly basic conditions,
b-ketoesters undergo deacylation, with cleavage of the keto
side, in a retro-Claisen condensation fashion. The ability of
a,a-dichloro-b-keto esters to react with even relatively weak
nucleophiles under mild conditions to effect this deacylation
reaction has also been overlooked.[17]
2
R
4
Yield [%][a]
dr[b]
ee [%][c]
1
2
3
4
2d
2e
2 f
2g
2h
2i
4-F
4-Br
3-OMe
3-Cl
2-Napth
4-Cl
4 f
4g
4h
4i
4j
4k
4l
99
99
99
93
99
97
96
95:5
99:1
95:5
93:7
93:7
94:6
98:2
98
98
98
98
98
97
99
5
6[d]
7[d]
2j
4-OMe
Initially, we were searching for mild conditions to modify
the oxazolidinone moiety of the Mannich product. We
[a] Yield of isolated product. [b] Determined by HPLC analysis. [c] De-
termined by HPLC. [d] Toluene as solvent, RT. 48 h.
780
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Chem. Eur. J. 2010, 16, 779 – 782

Synthesis of a-Fluorinated b-Amino Acid Derivatives
COMMUNICATION
These unexpected results pro-
vided us with an entry towards
the preparation of novel, chiral
a-fluorinated b-amino acid de-
rivatives.
In conclusion, we have devel-
oped a highly enantio- and dia-
stereoselective guanidine-cata-
lyzed Mannich reaction with a-
fluoro-b-keto acyloxazolidinone
as the fluorocarbon nucleophile.
a-Fluoro-b-amino acid deriva-
found that oxazolidinone can be converted to a methyl ester
easily by using potassium carbonate under mild conditions
without loss of ee value or diastereoselectivity [Eq. (3)].
When the amount of potassium carbonate was increased,
transesterification was followed by deacylation to yield the
a-fluoro-b-amino ester 7c [Eq. (4)]. A round of optimiza-
tion revealed that the use of ethanol at a lower reaction
temperature gave the best yield. The deacylation should
proceed by retro-Claisen condensation[18] to provide an eno-
late that undergoes diastereoselective protonation to give
the syn diastereoisomer as the major product (Scheme 1).
When sodium hydroxide was used, the oxazolidinone
moiety was converted to the carboxylate salt, which under-
went decarboxylation.[19] The enolate subsequently generat-
ed underwent protonation to give a 1:1 mixture of a-fluoro-
b-amino ketones 7d and 7e, which were separated by flash
chromatography [Eq. (5), Scheme 2]. The use of such mild
conditions for deacylation and decarboxylation is likely to
À
be due to the inductive effect of a neighboring C F bond.
Scheme 1. Preparation of a-fluoro-b-amino ester 7c by deacylation and
protonation reactions.
tives with chiral fluorinated
carbon were obtained through
selective deacylation or decar-
boxylation reactions. A transi-
ent enolate was obtained by
retro-Claisen or decarboxyla-
tion followed by protonation to
give enantiopure fluorinated
compounds. Such processes
constitute new strategies that
have not previously been re-
ported.
Experimental Section
Representative procedure: Synthesis
of 4e: N-3-Ethylpentan-3-yloxycar-
bonyl (Eoc) imine (2c; 24.7 mg,
Chem. Eur. J. 2010, 16, 779 – 782
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Scheme 2. Preparation of a-fluoro-b-ketones 7d and 7e by deacylation
and protonation reactions.
0.1 mmol, 2.0 equiv) and catalyst 3 (1.12 mg, 0.005 mmol, 0.1 equiv) were
dissolved in CH2Cl2 (0.5 mL), and the mixture was stirred at room tem-
perature for 10 min. Fluorocarbon nucleophile 1c (10.85 mg, 0.05 mmol,
1.0 equiv) was added, and this reaction mixture was stirred at room tem-
perature for 24 h. After complete consumption of 1c, the solvent was re-
moved in vacuo, and the crude product was directly loaded onto a short
silica gel column. Flash chromatography with hexane/ethyl acetate mix-
tures led to product 4e (22.2 mg, 96%) as colorless oil.
Acknowledgements
This work was supported by ARF grants (R-143-000-337-112 and R-143-
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Singapore.
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Keywords: decarboxylation · fluorocarbon nucleophiles ·
guanidine · Mannich reaction · retro-Claisen condensation
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Received: October 14, 2009
Published online: November 26, 2009
782
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