Diversity-oriented synthesis of amino acids using chiral enolates

Article abstract of DOI:10.1016/j.tetlet.2011.08.052

We report a facile diversity oriented synthesis of α- and β-amino acids, by utilizing the pluripotent α-methylene group in a chiral bicyclic lactam as our key point of transformation.

Full text of DOI:10.1016/j.tetlet.2011.08.052

Tetrahedron Letters 52 (2011) 5585–5588
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Tetrahedron Letters
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Diversity-oriented synthesis of amino acids using chiral enolates
Subhabrata Sen a, , Siva R. Kamma a, Venkata R. Potti a, Y.L.N. Murthy b, , Avinash B. Chaudhary a
⇑
a GVK Bioscience, 28A IDA Nacharam, Hyderabad, India
b Department of Chemistry, Food, Drugs and Water, College of Science and Technology, Andhra University, Vishakhapatnam, India
a r t i c l e i n f o
a b s t r a c t
Article history:
We report a facile diversity oriented synthesis of
a- and b-amino acids, by utilizing the pluripotent
Received 11 July 2011
Revised 4 August 2011
Accepted 8 August 2011
Available online 18 August 2011
a-methylene group in a chiral bicyclic lactam as our key point of transformation.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Diversity oriented synthesis
a-Amino acid
b-Amino acid
Mannich reaction
Pluripotent functional group
Diversity-oriented synthesis (DOS) is a facile synthetic method-
ology used toward the synthesis of compounds with structural
diversity.1 This is usually achieved by stereochemical and skeletal
modification of the central moiety. There are mainly two strategies
utilized in DOS to impart skeletal diversity, either on the basis of
reagent (reagent-based approach) or the substrate (the substrate-
based approach). In the reagent based approach, skeletal versatility
is achieved a) either by applying a heavily functionalized motif,
bearing various functionalities which, are transformed by several
reagents, or b) identifying a functional group that can participate
in various transformations with different reagents (pluripotent)
(Fig. 1).2 Hence identifying such pluripotent functional groups and
their subsequent reaction will be a valuable addition to this meth-
odology. Such diversity imparting chemistry which incorporates
rapid structural versatility to the products (which in turn can be
further transformed), could be utilized. Herein, we report the
Chiral oxazolines have been extensively utilized toward the
asymmetric synthesis of dialkylacetic and propanoic acids,
alkylbutyrolactones and valerolactones, by base mediated (nBuLi,
LDA etc.) alkylation of the methylene group a
- to the oxazolines.5
It is also used toward the synthesis of b-amino acids and several
heterocycles.6 Herein we report a novel diversity oriented synthe-
sis of a- and b-amino acid derivatives from same chiral oxazoline,
in high yields and moderate stereoselectivity. The fact that we have
identified a scaffold which can be tailored to different classes of
amino acids for the first time, is an important highlight of the
Letter.
Oxazoline 1 is prepared efficiently by condensation of methyl
imidate with R-phenylglycinol in 99% ee.7 We envision aldimine
based Mannich reaction of 1 as a suitable method for the generation
of appropriate intermediates (b-amino acid surrogates) which in
turn can be converted to b-amino acid derivatives. In order to opti-
mize the conditions we selected N-benzylbenzaldimine as the react-
ing intermediate. After exploring reactions with several bases at
ꢀ78 °C (Table 1), we observed 2.5 equiv LDA as the most efficient
protocol for the generation of the desired b-amino acid derivative
2 (entry 6). Reactions with LHMDS, KHMDS and NaHMDS resulted
in extremely poor yield (entries 2, 3, and 4). LDA with LiCl as an addi-
tive (entry 5), does not really impart any more efficiency than LDA
itself. However 1 equivalent of LDA (entry 1) was not good enough
to obtain a decent yield and diastereoselectivity. Finally the hydro-
lysis of oxazoline to ester, was straightforward with 6 N HCl under
refluxing condition to generate the ester 8.
development of DOS for the synthesis of a- and b-amino acids from
1 (Meyer’s oxazolidine), by implementing reagent based approach
(Fig. 2).2
a- And b-amino acids and their derivatives are essential syn-
thetic building blocks in organic synthesis and essay an important
role in pharmaceutical research.3 Hence the synthesis of these ami-
no acids (natural and unnatural) continues to be the focus of in-
tense investigation. There have been several enolate based and
organo catalytic syntheses of a
- and b-amino acids.4
⇑
Corresponding author. Tel.: +91 40 66281529; fax: +91 40 27152999.
E-mail addresses: organic6@hotmail.com, subhabrata.sen@gvkbio.com (S. Sen),
murthyyln@yahoo.co.in (Y.L.N. Murthy).
With the condition for Mannich optimized, we embarked on
investigating the generic nature of the reaction. Hence we reacted
1 with different types of aldimines (viz. aryl and heteroaryl). To our
Tel.: +91 0891 2844 686.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.052

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S. Sen et al. / Tetrahedron Letters 52 (2011) 5585–5588
X
Pluripotent
functional
group
Y
Z
Different Reagents
Diverse
Molecular
skeleton
Figure 1. The reagent based approach.
Table 2
Mannich reaction and hydrolysis
Entry
AAS
Yieldc (%)
deb (%)
Amino esters
Yield (%)
eeb (%)
1
2
3
4
5
6
2
3
82
73
77
–
–
70
90
90
85
–
–
80
8
9
10
–
11
12
43
68
71
62
–
88
90
90
80
–
N
O
4
5a
6
1
7
52
pluripotent
a
b
c
functional
Unable to isolate pure compound.
By HPLC.
By chiral HPLC (CHIRAL PAK AD, 4.6 ꢃ 250 mm, 5
group
lm).
Figure 2. Chiral auxiliaries with pluripotent functional group.
for the final hydrolysis as crude. The absolute configuration of
Table 1
the b-amino acid derivatives as depicted here, was determined
Investigation of Mannich reaction conditions and final hydrolysis
25
589
by comparing the SOR of 8 (SOR: ½
a
ꢁ
ꢀ6.1500° (MeOH, c 0.1)
HO
(as a representative example) with a literature value of a Boc-
NH.HCl
Ph
derivative of the same ester .8
N
OEt
H2N
Ph
For
nitrooxazoline derivative 13. In-turn it can be alkylated followed
by hydrolysis to generate the desired -amino ester. To that direc-
a-amino acid derivatives we envision the synthesis of chiral
O
1
Refer
a
Table 1
tion, we reacted chiral oxazoline 1 with n-propylnitrate (n-prop-
ONO2) to generate the corresponding nitro-derivative 13.
6N HCl
Reflux
Ph
Ph
Ph
N
O
Lithiating the resulting intermediate with LDA at ꢀ78 °C fol-
lowed by 3-methylbenzyl bromide, failed to generate the desired
derivative 15. On further investigation with various bases (LDA,
LHMDS, NaHMDS, KHMDS, NaH and NaOMe), in their different
stoichiometric ratios and at different temperatures (0, ꢀ10, ꢀ40
and ꢀ78 °C) we observed, absolutely no reactivity of 13. The 1H
NMR spectra of 13 revealed that the compound exists mostly in
its dipolar structure 14 (Scheme 1). This may be due to the pres-
ence of the highly electron withdrawing –NO2 and the imidate
adjacent to the central methylene protons. IR and UV spectra of
the compound also corroborates the same.9 In the 1H NMR we ob-
served a broad singlet at 9–10 ppm (characteristic of the immoni-
um ion). The proton adjacent to the –NO2 appeared as a singlet at
ꢂ6.7 ppm (Scheme 1).
BnHN
BnHN
O
O
2
8
Entry
Base
Eq
T (°C)
Yielda
deb
Yielda
eec
1
2
3
4
5
6
LDA
1
1
1
1
1
2.5
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
40%
36%
12%
14%
34%
67%
90%
90%
—
—
—
—
—
—
58%
—
—
—
—
—
90%
LHMDS
NaHMDS
KHMDS
LDA/LiCl
LDA
—
88%
90%
a
b
c
Isolated yield.
By HPLC.
Chiral HPLC (CHIRAL PAK AD, 4.6X 250 mm, 5 lm).
Consequently we decided to reverse the sequence and alkylate
the oxazoline first, followed by nitration. Initial reaction with
3-methyl benzylbromide and 1 equiv LDA at ꢀ78 °C to rt provided
clean alkylation by TLC. The reaction mixture was further cooled
to ꢀ78 °C and was treated with LDA followed by n-propyl nitrate.
To our satisfaction the desired nitro-intermediate was formed in
good yields and with moderate de. Encouraged by this result, we
reacted, quite a few alkyl halides with the chiral oxazoline 1,
followed by nitration with n-propylnitrate and LDA (Table 3). The
general yields range from 45–76% (entry 1–8) with excellent de
(>95%, entries 1–8). The relative configuration of the nitrooxazolines
(15–22) as depicted in the Schemes and Tables was predicted, by the
help of Meyers’ hypothesis on the mode of substitution on chiral
satisfaction all the aldimines we used, successfully underwent
Mannich reaction with good yields and decent de (Table 2). To ob-
tain the b-amino acid derivatives these intermediates generated
from Mannich reaction, were hydrolyzed with 6 N HCl. The yield
of the final ester, over two steps ranged anywhere from 43% to
70%. We observed that the ee of the amino ester was same as that
of the intermediate (amino acid surrogate), hence it suggests no
epimerization during the hydrolysis. We also executed the Man-
nich reaction with N-benzyl-isopropaldimine (entry 5). However
to our dismay, there was only 5% product conversion in LCMS. Also
the pyridyl intermediate 5 (entry 4), could not be purified (as it
was decomposing in the chromatography column) and was used

S. Sen et al. / Tetrahedron Letters 52 (2011) 5585–5588
5587
LDA, -78oC
+HN
H
O
n-propyl nitrate
N
O
N
O
NO2-
O2N
Scheme 1. Dipolar structure of chiral nitro oxazoline.
Table 3
oxazolines. It proposesthe absolute configuration of thefinal acid (in
our case ester) by the mode of introduction of new functionalities
into the chiral oxazoline. Thus, if the group of lower priority
(Cahn-Ingold-Prelog rule) is introduced first, the ester will have S
configuration, while if the group of higher priority is introduced first,
the ester will have R configuration.5 Finally, we selected few of the
intermediates as representative examples for the final conversion
to the amino esters. However efforts toward reduction of the nitro
to amine were disappointing, as we observed only the imine reduced
oxazolidine intermediate 27 (several hydrogenation conditions and
chemical reduction with Zn–AcOH; Sn–AcOH, Fe–HCl were tried).
Alternatively we hydrolyzed the oxazoline to the nitro ester
Synthesis of a-amino acid derivatives
Entry
AAS
Yielda (%)
deb (%)
Amino esters
Yielda (%)
eec (%)
1
2
3
4
6
7
8
9
15
16
17
18
19
20
21
22
54
87
56
72
86
78
66
66
99
99
99
95
99
95
98
98
23
24
–
–
–
–
–
25
43
68
–
–
–
–
–
79
90
90
–
–
–
–
–
82
a
Isolated yield.
Determined by HPLC.
Determined by chiral HPLC (CHIRAL PAK AD, 4.6 ꢃ 250 mm, 5
b
c
lm).
Ph
O
R1
O
R
H2N
O
H2N
O
NHBn
OH
NH.HCl
OEt
3-amino ester
β
R = Ph,
α
8
-amino ester
R1 = 4-fluorobenzyl,
24
R = 4,5-dichlorophenyl,
9
10
R1 = 4-methoxybenzyl,
R1 = 3-methylbenzyl,
25
R = 4-methoxyphenyl,
23
R = 3-pyridyl,
11
R = 2-furyl,
12
Ph
N
Ph
R1
O2N
α
-amino acid surrogates
O
N
Ph
R1 = 3-methylbenzyl, 15
R1 = 4-fluorobenzyl, 16
R1 = phenethyl, 17
R1= Methyl, 18
1
N
R
O
3-amino acid surrogates
O
β
R1 = p-benzyloxybenzyl, 19
R1 = Benzyl, 20
R = Ph,
2
NHBn
R = 4,5-dichlorophenyl,
3
R1 = Allyl, 21
R = 4-methoxyphenyl,
4
R1X
R1 = 4-Methoxybenzyl, 22
R = 2-furyl,
7
RC(H)=NBn
RONO2
Scheme 2. Reaction cycle for
a- and b-amino acid.

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S. Sen et al. / Tetrahedron Letters 52 (2011) 5585–5588
LDA, -78°C, RX
LDA, -78°C, i-pro. NO2
NO2
N
N
Ph
Ph
X1
O
O
1
NO2
-
15 22
X1
CO2Me
H2-Pd/C, EtOH
-
23a 25a
H2-Pd/C, EtOH
NO2
NH2
H
N
N
Ph
Ph
X1
NH2
X1
O
O
X1
27
26
CO2Me
Identified in LCMS (never isolated)
-
23 25
Scheme 3. Synthesis of
a-amino esters.
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(23a–25a), followed by reduction of NO2- to NH2, via Pd-C hydroge-
nation at atmospheric pressure of H2.
However, during hydrolysis we observed substantial epimeriza-
tion (extent of loss of ee ꢂ10–20%) of nitro oxazolines 15, 16 and 22
to the corresponding ester 23a–25a (Scheme 3). Hence the ee of the
final
In this Letter we have exhibited an efficient example of diversity
oriented synthesis of and b-amino acid derivatives (Scheme 2).
We have utilized the versatility of chiral bicyclic lactam and the
pluripotency of the -methylene group present in it. We are pres-
ently optimizing the conditions for an effective conversion of the
-amino acid surrogates to the final derivatives without decrease
a-amino esters reduced to the range of 80–90% (Table 3).
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The authors thank GVKBioscience for the financial support.
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9. Refer the IR and UV spectra in the experimental.