Chiral N-phosphonyl imine chemistry: Asymmetric synthesis of α,β-diamino esters by reacting phosphonyl imines with glycine enolates

Article abstract of DOI:10.1016/j.bmcl.2009.03.001

Chiral phosphonyl imines attached with N-isopropyl protection group were found to react with lithium glycine enolates under convenient conditions to give α,β-diamino esters. Thirteen examples have been examined in good to excellent chemical yields (85-97%

Full text of DOI:10.1016/j.bmcl.2009.03.001

Bioorganic & Medicinal Chemistry Letters 19 (2009) 3967–3969
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Bioorganic & Medicinal Chemistry Letters
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Chiral N-phosphonyl imine chemistry: Asymmetric synthesis of a,b-diamino
esters by reacting phosphonyl imines with glycine enolates
*
Teng Ai, Guigen Li
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:
Chiral phosphonyl imines attached with N-isopropyl protection group were found to react with lithium
glycine enolates under convenient conditions to give ,b-diamino esters. Thirteen examples have been
examined in good to excellent chemical yields (85–97%) diastereoselectivity (up to 99% de). By treating
with HBr at room temperature, the chiral auxiliary can be readily removed and recycled. The absolute
structure has been unambiguously determined by converting a product to a known sample.
Published by Elsevier Ltd.
Received 15 February 2009
Accepted 2 March 2009
Available online 5 March 2009
a
Dedicate to Professor Carlos F. Barbas on
occasion of his 2009 Tetrahedron Young
Investigator Award
Keywords:
Phosphoramide
N-phosphonyl imines
Glycine enolate
a,b-diamino ester
Vicinal diamino functionality is an important structural unit
existing in many biologically active compounds.1,2 For example,
chiral ,b-diamino acid derivatives bearing vicinal diamino frame-
tween 2.0 equiv of lithium glycine enolate and phosphonyl imines
bearing different N-protection groups (Table 1). The formation of
four diastereoisomers was clearly indicated by 31P NMR of the
crude reaction mixtures (Table 1, entries 1–5). Among the five pro-
tection groups, isopropyl group showed highest diastereoselectiv-
ity to give anti stereoisomer as major product (Table 1, entry 1).
To further optimize this reaction, several conditions were
examined by using different bases for enolate generation and
imine 1a as the electrophilic substrate (Table 2). Among the four
bases listed in Table 2, n-BuLi was found to be the best for the gen-
eration of metal enolates (Table 2, entry 7). Interestingly, the
potassium enolate generated by (Me3Si)2NK failed to react with
imine 1a (Table 2, entry 6). This observation could be attributed
to the poor activation of phosphonyl imine by potassium cation.
5.0 Equiv of lithium enolate was found to be necessary to
achieve higher diastereoselectivity and chemical yields (Table 2,
a
works are widely found in number of antibiotics and natural prod-
ucts.3 Several methods have been developed for the synthesis of
a,b-diamino acids and their derivatives including asymmetric
Mannich reaction,4 asymmetric aza-Henry reaction,5 aziridine ring
openings,6,7 imino-aldol reaction,8,9 etc. Among these known
methods, a direct diastereoseletive addition reaction between a
glycine equivalent and an imine is particularly attractive since
‘two stereogenic centers could be created in a single operation’.10
Very recently, we have established novel N-phosphoramide and
N-phosphonyl imine chemistry, and successfully utilized this
chemistry in many nucleopholic addition reactions, such as asym-
metric aza-Darzens reaction,11 asymmetric aza-Henry reaction,12
asymmetric Mannich reaction,13 asymmetric additions of allymag-
nesium bromides,14 asymmetric additions of Weinreb amide- and
malonate-derived enolates.15 In continuation of our studies on this
important chemistry, we would like to report the additions of lith-
ium glycine enolates onto chiral phosphonyl imines for the asym-
metric synthesis of chiral a,b-diamino esters (Scheme 1).
In our previous work,13 the N-protection group on imine auxil-
iary was found to be important in controlling diastereoselectivity
of addition reactions. Therefore, we first examined the reaction be-
* Corresponding author.
E-mail address: Guigen.Li@ttu.edu (G. Li).
Scheme 1. Additions of glycine enolate to N-phosphonyl imines.
0960-894X/$ - see front matter Published by Elsevier Ltd.
doi:10.1016/j.bmcl.2009.03.001

3968
T. Ai, G. Li / Bioorg. Med. Chem. Lett. 19 (2009) 3967–3969
Table 1
Table 3
Effects of protection groups on chiral auxiliarya
Asymmetric additions of phosphonyl iminesa
Entry
1
R
Imine
Ratiob
Yieldc (%)
85
Entry
R1
Ratiob
Yieldc (%)
H3C
H3C
1
2
3
4
5
6
7
8
Ph (1a)
100:1:0:5
100:0:0:7
100:5:0:11
100:5:0:8
100:0:3:5
100:0:0:12
100:0:4:5
100:6:0:11
100:1:0:10
100:7:4:11
100:0:0:12
100:0:0:17
100:4:0:10
93 (3)
1a
100:1:1:15
4-CH3 (2a)
4-OCH3 (2b)
4-OBn (2c)
2-Br (2d)
4-Br (2e)
2-Cl (2f)
4-Cl (2g)
4-F (2h)
4-CN (2i)
88 (3a)
85 (3b)
97 (3c)
89 (3d)
94 (3e)
87 (3f)
92 (3g)
90 (3h)
92 (3i)
97 (3j)
85 (3k)
88 (3l)
H3C
H3C
2
3
1b
1c
100:0:0:23
100:0:1:25
60
75
9
10
11
12
13
4
1d
1f
100:3:25:61
100:3:5:30
80
78
4-NO2 (2j)
Naphth-1-yl (2k)
Naphth-2-yl (2l)
5
a
Reaction condition: 0.1mmol imine, 0.5 mmol glycine ethyl ester, 0.55 mmol n-
BuLi.
b
c
Determined by 31P NMR.
a
Reaction condition: 0.10 mmol of imine, 0.20 mmol of glycine ethyl ester,
0.22 mmol of base.
Conversion yield, isomers not separated.
b
Determined by 31P NMR.
Conversion yield, isomers not separated.
c
entries 1–4, 7 and 8). The excess amount of glycine ethyl ester can
be easily recovered via column purification.
The solvent effect was also examined for this reaction. Tetrahy-
drofuran (THF) was proven to be the best solvent regarding both
chemical yields and diastereoselectivity. When Et2O was employed
as solvent, the reaction proceeded smoothly to give a similar yield
of 92%, but afforded a slightly lower diastereoselectivity (Table 2,
entry 7 and 9). For the cases of CH2Cl2 and toluene as solvents,
the diastereoselectivity and chemical yields were decreased (Table
2, entries 10 and 11).
Table 2
Optimization of reaction conditions
Based on the above optimized condition, we next examined the
scope of substrates by using several phosphonyl imines (2a–2l). All
thirteen cases were performed smoothly with good to excellent
chemical yields (85–97%). Both electron-donating (Table 3, entries
2–4) and electron-withdrawing (Table 3, entries 5–11) group-at-
tached phosphonyl imines were found to be suitable for this reac-
tion. When imines bearing ortho groups on their aromatic rings
were also used as substrates, slightly higher diastereoselectivites
were obtained (Table 3, entries 5–8).
The absolute configuration of product 3 was determined by
chemical conversions as shown in Scheme 2. Treatment of 3 with
aqueous HBr in methanol at room temperature for 12 hours fol-
lowed by neutralization with NaHCO3 gave (2S, 3S)-4 in 90% yield.
Further converting 4 to 5 was performed using carbonyl diimidaz-
ole and H-4, H-5 coupling constant of 9.6 Hz is consistent with cis
Entry
Base
Equiv
Solvent
Isomer ratioa
Yieldb (%)
1
2
3
4
5
6
7
8
LDA
LDA
LDA
LDA
LiHMDS
KHMDS
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
1.1
2.0
3.0
5.0
5.0
5.0
5.0
2.0
5.0
5.0
5.0
THF
THF
THF
THF
THF
THF
THF
THF
100:1:2:14
100:1:1:15
100:2:1:14
100:3:1:9
100:3:1:8
—
100:1:0:5
100:3:1:7
100:3:4:5
100:2:5:28
100:0:18:16
80
85
92
93
90
<10
93
90
92
88
85
9
10
11
Et2O
CH2Cl2
PhCH3
a
Determined by 31P NMR.
Conversion yield, isomers not separated.
b
Scheme 2. Determination of the absolute configurations of 3.

T. Ai, G. Li / Bioorg. Med. Chem. Lett. 19 (2009) 3967–3969
3969
configuration.10a,16 The optical rotation of 4 and coupling constant
of 5 reveals the absolute configuration of diamino product 3 is
shown as (2S, 3S).
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In summary, a new method has been developed for the asym-
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a-b diamino es-
ters in good yields and excellent diastereoselectivity. By changing
different N-protecting groups, the chiral N-phosphonyl imines
can be optimized to give better results for this reaction. The use
of excess amounts of enolates was found to be crucial to the suc-
cess of this synthesis.
Acknowledgment
6. For a review on aziridine chemistry, see: Tanner, D. Angew. Chem., Int. Ed. Engl.
1993, 33, 599–619.
Financial assistance from Robert A. Welch Foundation (D-1361)
is gratefully acknowledged.
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Supplementary data
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Supplementary data associated with this article can be found, in
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