Asymmetric synthesis of β′-amino-α,β-enones via addition of α,β-unsaturated ketone-derived enolates to chiral N-phosphonyl imines

Article abstract of DOI:10.1016/j.tetlet.2014.03.005

Efficient asymmetric Mannich addition reactions between α,β-unsaturated ketone derived enolates and N-phosphonyl imines were reported. These reactions could proceed smoothly for a variety of imine substrates with good (up to 96%) chemical yields and excellent diastereoselectivities (up to 98:2 dr). The method reported in this work provides an easy access to chiral β′-amino-α,β-enones.

Full text of DOI:10.1016/j.tetlet.2014.03.005

Tetrahedron Letters 55 (2014) 2476–2479
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Asymmetric synthesis of b0-amino-
of ,b-unsaturated ketone-derived enolates to chiral
N-phosphonyl imines
a,b-enones via addition
a
Yiwen Xiong a, Haibo Mei a,b, Jianlin Han a,b,c, , Guigen Li b,d, Yi Pan a,
⇑
⇑
a School of Chemistry and Chemical Engineering, State of Key Laboratory of Coordination, Nanjing University, Nanjing 210093, China
b Institute for Chemistry & BioMedical Sciences, Nanjing University, Nanjing 210093, China
c High-Tech Research Institute of Nanjing University, Changzhou 213164, China
d Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409-1061, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Efficient asymmetric Mannich addition reactions between a,b-unsaturated ketone derived enolates and
N-phosphonyl imines were reported. These reactions could proceed smoothly for a variety of imine sub-
strates with good (up to 96%) chemical yields and excellent diastereoselectivities (up to 98:2 dr). The
method reported in this work provides an easy access to chiral b0-amino-
a,b-enones.
Received 10 December 2013
Revised 25 February 2014
Accepted 2 March 2014
Available online 12 March 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
N-Phosphonyl imine
a
,b-Unsaturated ketone
Asymmetric Mannich reaction
b0-Amino-
,b-enones
a
Diastereoselectivity
Amino enone derivatives are one of the most important classes
of nitrogen-containing biological compounds.1 Their chemistry has
attracted a lot of attentions from organic chemists leading to dis-
covery and development of numerous useful compounds in the
fields of biological and medicinal chemistry.2 Among this type of
synthesis or some special examples. To the best of our knowledge,
only two asymmetric examples were reported until now, which
were zinc-promotes Mannich-type reaction of chiral aldimines
with 2-silyloxybutadienes18 and five-step conversion of cinna-
mates.19 So, the development of facile and efficient methodology
compounds, b0-amino-
a,b-enones take
a
particular important
for asymmetric preparation of b0-amino-
a,b-enones is still urgent
place.3 They belong to important organic synthetic intermediates
as they can be easily converted into the corresponding amino acid,4
pyrrolidine,5 thiazole,6 oxazole7 and many other multifunctional
compounds. They have also been served as ligand for the stereose-
lective synthesis of Mannich-type products.8 Furthermore, these
functional moieties were discovered as drug precursors, such as
antimicrobial molecules,9 Parkinson’s/Alzheimer’s disease inhibi-
tor10 and MTB (mycobacterium tuberculosis bacteria) inhibitor.11
In recent years, several representative methods have been doc-
and challenging. Phosphonyl imine chemistry has been studied in
our group for several years.20 This chiral phosphonyl auxiliary,
developed by our group has been successfully implied into many
asymmetric syntheses.21 Taking into account the importance of
b0-amino-
a,b-enones and our research interests in the chemistry
of phosphonyl imine, we, herein, reported a concise asymmetric
Mannich addition reaction of aryl-substituted enone derived eno-
lates with N-phosphonyl imine, giving b0-amino-
a,b-enones with
good yields and excellent diastereoselectivities (Scheme 1).
This asymmetric Mannich addition reaction was initially exam-
ined with (E)-4-phenylbut-3-en-2-one derived enolate and isopro-
pyl substituted chiral N-phosphonyl imine 1a (Table 1). According
to our previous reports,21 several common bases were examined
for the generation of ketone enolate and the following addition
reaction. LiHMDS performed best among these bases, achieving
61% yield and 92:8 diastereoselectivity after 24 h (entry 3, Table 1).
The other organic bases, such as n-BuLi, LDA, NaHMDS and KHMDS,
did not work at all, giving almost no desired product (entries 1, 2, 4
umented by chemists for the synthesis of b0-amino-
a,b-enones.
These methods included radical coupling with nitrones and nitrile
oxides,12 Horner–Wadsworth–Emmons olefination,13 Diels–Alder
reaction with various dienophiles,14 Baylis–Hillman reaction of
2-cycloocten-1-one,15 aziridine opening by aldehyde16 and so
on.17 However, most of these methods focused on symmetric
⇑
Corresponding authors. Tel.: +86 25 83686133; fax: +86 25 83593153.
E-mail addresses: hanjl@nju.edu.cn (J. Han), yipan@nju.edu.cn (Y. Pan).
http://dx.doi.org/10.1016/j.tetlet.2014.03.005
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

Y. Xiong et al. / Tetrahedron Letters 55 (2014) 2476–2479
2477
Ph
Ph
Ph
N
Ph
N
O
N
N
1) LiHMDS, THF, -78 o
2) aq NH4Cl
C
P
P
O
NH
O
O
N
R
Ar
Ar
up to 96% chemical yields
up to 98:2 dr
R
Scheme 1. Asymmetric synthesis of b0-amino-
a,b-enones.
Table 1
Optimization of reaction conditionsa
Ph
N
Ph
N
Ph
N
Ph
P
O
N
O
N
1) base
P
+
O
NH
O
2) aq NH4Cl
Ph
Ph
2a
3a
1a
Entry
Base
T (°C)
Solvent
Time (h)
Yieldb (%)
Drc
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
n-BuLi
LDA
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ40
0
THF
THF
THF
THF
THF
THF
THF
THF
Toluene
Ether
2-MeTHF
THF
THF
THF
24
24
24
24
24
24
24
24
24
24
24
24
24
12
30
NR
<10
61
<10
Trace
NR
NR
NR
Trace
14
37
—
—
92:8
—
—
—
—
—
—
—
91:9
73:27
—
89:11
92:8
LiHMDS
NaHMDS
KHMDS
NaOMe
Cs2CO3
DBU
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
31
<10
49
ꢀ78
ꢀ78
THF
70
a
b
c
Reaction conditions: (E)-4-phenylbut-3-en-2-one 2a (0.4 mmol), base (0.3 mmol), imine (0.15 mmol), solvent (7 mL).
Isolated yields.
Determined by 31P NMR.
Table 2
Scope of chiral N-phosphonyl imines and enonesa
Ph
N
Ph
Ph
N
Ph
N
O
1) LiHMDS, THF, -78 o
30 h
C
N
P
P
+
O
NH
O
O
N
R
2) aq NH4Cl
Ar
Ar
R
2
1
3
Entry
Ar
R
Product
Yieldb (%)
Drc
1
2
3
4
5
6
7
8
9
10
11
12
13
C6H5
4-ClC6H4
2-FC6H4
3-FC6H4
4-FC6H4
1-Naphthyl
2-Naphthyl
4-CH3C6H4
4-CH3OC6H4
3-CF3C6H4
2-Furyl
C6H5
H
H
H
H
H
H
H
H
H
H
H
4-Cl
3-Cl
3a
3b
3c
3d
3e
3f
3g
3h
3i
70
68
84
93
90
96
70
77
82
93
94
74
71
92:8
96:4
94:6
98:2
96:4
96:4
89:11
96:4
96:4
98:2
91:9
93:7
97:3
3j
3k
3l
C6H5
3m
a
b
c
Reaction conditions: enone 2 (0.4 mmol), LiHMDS (0.3 mmol), imine 1 (0.15 mmol), THF (7.0 mL) at ꢀ78 °C.
Isolated yields.
Determined by 31P NMR.

2478
Y. Xiong et al. / Tetrahedron Letters 55 (2014) 2476–2479
O
solution in methanol and stirred at room temperature for 24 h
(Scheme 2). The corresponding free b0-amino-
,b-enone was then
Ph
N
Ph
a
O
NH
O
N
converted into its N-ethoxycarbonyl derivative by reaction with
diethyl carbonate to give compound 4a in an overall yield of 81%.
Then, the absolute configuration of the newly generated chiral cen-
ter was unambiguously assigned as S by comparison of the optical
rotation with those of known sample.19 The stereochemical assign-
ments of other products were made by analogy, based on similarity
of their chiroptical properties and NMR data.
a, b
P
Ph
Ph
O
NH
O
4a
Ph
Ph
81% yield
[α] = +4.9 (c = 0.66, CHCl3)
3a
[α]lit = +6.6 (c = 0.94, CHCl3)
On the basis of the above result, a six-membered chairlike tran-
sition state was suggested to explain the resulting stereoselectivity
(Scheme 3). This transition state model is similar to that of our pre-
vious chiral phosphonyl imine system.21a The lithium metal cation
connects with two reaction partners through oxygen atom and
nitrogen atom. This manner would be responsible for the excellent
control of diastereoselectivity of the system and resulting in S
configuration.
Scheme 2. Cleavage of chiral auxiliary: (a) HCl/MeOH, rt; (b) (EtO)2CO, Et3N, DCM.
and 5). DBU, NaOMe and Cs2CO3 were also not good choices for this
system (entries 6–8). Then, the solvent for this reaction was
investigated. THF was found to be the best choice, and the other
two solvents led to both decreased chemical yields (14% and 37%
for entries 10 and 11, respectively) and diastereoselectivities
(dr = 91:9 for entry 11). When the reaction was conducted in tolu-
ene, almost no desired product formed (entry 9). Both yields and
diastereoselectivities decreased dramatically when the reaction
temperature was increased (entries 12 and 13). Finally, the reac-
tion time was examined, and it was found that 30 h was needed
for the reaction (entries 14 and 15).
In summary, we have developed a facile asymmetric Mannich
reaction between enone enolates and chiral N-phosphonyl imines.
The reaction was found to tolerate a wide scope of imine substrates
with good chemical yields and high diastereoselectivities (up to
98:2 dr). This methodology provides an easy and efficient strategy
for the synthesis of chiral b0-amino-
a,b-enones. The chiral auxil-
iary, phosphonyl moiety can be easily cleaved under simple and
mild condition.
With optimized reaction condition in hand, the scope of
N-phosphonyl imines was then tested. As shown in Table 2, the
asymmetric reaction of lithium enolates with the chiral N-phos-
phonyl imines could proceed well, providing b0-amino-
a,b-enones
Acknowledgments
in good to excellent chemical yields (68–96%) and up to 98:2 dia-
stereoselectivities. Variation of the substituents on the aromatic
rings of imines did not show any obvious effect on reaction
efficiency. Both electron-withdrawing (entries 2–5 and 10) and
electron-donating group (entries 8 and 9) substituted aromatic
phosphonyl imine were found to be suitable substrates for this
reaction. Good to excellent diastereoselectivities were obtained
for all the examined cases, and the highest diastereoselectivity
was found in the cases of the imine substrates containing a
meta-substituted aromatic ring (98:2 dr, entries 3 and 10). Notably,
imines with a naphthyl ring 1f and 1g were also well tolerated in
this reaction and gave the target product in good yields and high
diastereoselectivities (entries 6 and 7). Especially for 1f, higher
chemical yield and better diastereoselectivity were found (96%
yield and 96:4 dr, entry 6). It was also found that the imine with
furyl group 1k worked well in the current reaction and gave struc-
turally interesting product 3k in 94% yield and 91:9 dr (entry 11).
We gratefully acknowledge the financial support from the
National Natural Science Foundation of China (No. 21102071)
and the Fundamental Research Funds for the Central Universities
(Nos. 1107020522 and 1082020502). The Jiangsu 333 program
(for Pan) and Changzhou Jin-Feng-Huang program (for Han) are
also acknowledged.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.03.
005.
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