Temperature-Dependent Enantio- and Diastereodivergent Synthesis of Amino Acids with One or Multiple Chiral Centers

Article abstract of DOI:10.1021/acs.orglett.7b02296

A general and facile methodology for temperature-dependent enantiodivergent and diastereodivergent synthesis of amino acids with one or multiple chiral centers was developed. Camphor-based tricyclic iminolactones attack electrophiles from the endo face at low temperature (-78 to -40 °C) and from the exo face at high temperature (-10 to 25 °C).

Full text of DOI:10.1021/acs.orglett.7b02296

Letter
pubs.acs.org/OrgLett
Temperature-Dependent Enantio- and Diastereodivergent Synthesis
of Amino Acids with One or Multiple Chiral Centers
Shiming Fan, Shouxin Liu,* Sufang Zhu, Juan Feng, Zhiwei Zhang, and Jing Huang
State Key Laboratory Base, Hebei Laboratory of Molecular Chemistry for Drug, Hebei University of Science and Technology, No. 70
Yuhua East Road, Shijiazhuang 050018, China
S
* Supporting Information
ABSTRACT: A general and facile methodology for temper-
ature-dependent enantiodivergent and diastereodivergent syn-
thesis of amino acids with one or multiple chiral centers was
developed. Camphor-based tricyclic iminolactones attack
electrophiles from the endo face at low temperature (−78 to
−40 °C) and from the exo face at high temperature (−10 to 25
°C).
Scheme 1
tereodivergent reaction is an efficient way to access all
S
optically active stereoisomers of target chiral molecules,
which are highly important and valuable in drug discovery.1
Asymmetric catalysis is a powerful and practical method for
achieving stereodivergence.2 Enantiodivergent processes can be
achieved by selecting between a pair of enantiomeric catalysts.
However, diastereodivergent processes that generate chiral
molecules with multiple stereogenic centers in a single step are
much more challenging. A diastereochemical switch generally
requires the use of distinct chiral catalysts3 or ligands,4 the use of
stereodivergent dual catalysis,2d,5 the addition of different Lewis
acids,6 and change in structure of starting material.7 Recently, an
approach involving changing the reaction conditions, including
solvent and temperature,8 or using light9 to tune the functions of
a single catalyst for simply achieving enantio- and diastereodi-
vergence has been developed.
3a decreased, whereas exo-product 4a increased (Table 1, entries
2 and 3). At 25 °C, only the exo-product 4a was obtained (Table
1, entry 4). The attempt was also successful at 25 °C with KOt-Bu
as the base. Two stereoisomers of phenylalanine were obtained
after subsequent removal of the auxiliary. To evaluate the
generality of the reaction, alkylation of tricyclic iminolactones 1
and 2 with benzyl chloride, allyl bromide, and iodomethane were
conducted (Table 1, entries 5−12). All reactions yielded endo-
products using LDA as base at low temperature (−78 to −60
°C), whereas exo-products were obtained in good yield and
excellent dr (>99:1) using LDA or KOt-Bu as base at room
temperature. The results exhibit that the enantiodivergent
synthesis of (S)- and (R)-amino acids with one chiral center
can be realized using only one chiral auxiliary by varying reaction
temperature.
We conducted quantum chemical calculations to explain the
result of a stereoselective alkylation reaction controlled by
temperature. The geometries of products endo-3a and exo-4a
were optimized by Gaussian 03 at the B3LYP/6-31++g(d,p) level
without restriction. The results showed that the structure of exo-
4a was more stable than that of endo-3a, with an energy difference
Aside from asymmetric catalysis, using a chiral auxiliary is
another selection for stereodivergent synthesis.10 Xu’s group
developed a method for the preparation of optically active α-
amino acids by using hydroxycamphor as chiral auxiliary.11
Tricyclic iminolactone 1 or 2 prepared from glycine and chiral
auxiliary hydroxycamphor attacked electrophiles from the endo
face because of low steric hindrance. The synthesis of (S)-amino
acid used chiral auxiliary 3-hydroxycamphor, whereas the
synthesis of non-proteinogenic (R)-amino acid must use another
chiral auxiliary, 2-hydroxycamphor. Here, we investigated an
approach for changing the reaction temperature to realize
stereodivergent reaction using one chiral auxiliary for the
synthesis of amino acid stereoisomers with one or multiple
chiral centers (Scheme 1).
Initially, alkylation of tricyclic iminolactone 1 with benzyl
chloride was tested (Table 1, entries 1−4). The orientation of
iminolactone alkylation strongly depended on reaction temper-
ature. The reaction was endo alkylation when the reaction
temperature was −78 to −40 °C, and only endo-product 3a was
obtained. As temperature increased, the content of endo-product
Received: July 26, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02296
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Enantiodivergent Synthesis of (R)- and (S)-Amino
Acids
Scheme 2. Aldol Reaction of Tricyclic Iminolactones with
Aldehydes
We then probed the Michael addition of 1 or 2 with crotonate
esters and expected to prepare each stereoisomer of 3-methyl
glutamic acid after subsequent removal of the auxiliary. Initially,
the Michael addition of tricyclic iminolactone 1 to ethyl
crotonate was tested. The reaction did not deliver the desired
result with LDA as base at −78 °C (Table 2, entry 1). After
a
b
entry substrate
E
temp (°C)
product yield (%)
endo/exo
Table 2. Michael Addition of Tricyclic Iminolactone 1 to
Crotonate
1
2
1
1
1
1
1
1
1
1
2
2
2
2
a
a
a
a
b
b
c
c
a
a
b
b
−78 to − 40
−40
−20
25
3a
85
>99:1
3:2
3a+4a
3a+4a
4a
86
3
89
1:2
c
c
c
c
c
4
81, 76
89
<1:99
>99:1
<1:99
>99:1
<1:99
>99:1
<1:99
>99:1
<1:99
5
−78 to − 60
25
3b
6
4b
87, 84
72
7
−78 to − 60
25
3c
8
4c
68, 65
80
9
−78 to − 40
25
5a
10
11
12
6a
73, 72
82
−78 to − 60
25
5b
6b
78, 71
a
b
Yield of isolated alkylation product. Estimated by 1H NMR
temp
yield
a
b
entry
R
(°C)
base
LDA
adduct
(%)
dr
c
integrations. Yield using KOt-Bu as base.
1
2
3
4
5
6
7
8
9
Et
−78
−40
0
c
0
80
82
72
78
81
86
84
70
Et
LDA
LDA
LDA
LDA
LDA
LDA
LDA
11a + 13a
11a + 13a
11b + 13b
11c
82:18
38:62
90:10
>99:1
60:40
<1:99
<1:99
<1:99
(ΔG298K = 9.79 kJ/mol, ΔH298K = 10.38 kJ/mol) (Figure 1). This
finding was in good agreement with experimental results. The
Et
i-Pr
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
−40
−40
−20
0
11c + 13c
13c
25
13c
25
KOt-Bu
13c
a
b
Yield of isolated product. Estimated by 1H NMR integrations.
c
Reaction did not occur.
considering the low activity of ethyl crotonate, we attempted to
remedy the activity by increasing the reaction temperature.
Although the reaction proceeded smoothly in high yield at −40
and 0 °C, stereoselectivity was not ideal (Table 2, entries 2 and
3). Considering the strong steric effect of compound 1, the
stereoselectivity of Michael addition should be dependent on the
size of the ester group. Stereoselectivity was improved when
ethyl crotonate was replaced by isopropyl crotonate to perform
the Michael reaction. Furthermore, t-butyl crotonate was used to
run this reaction. As anticipated, the reaction only produced
endo-adduct (5S,14R)-11c in good yield (78%) and with
excellent stereoselectivities (dr >99:1) at −40 °C (Table 2,
entry 5). The absolute configuration of 11c was determined by
NOESY and further confirmed by hydrolysis to yield known
amino acids. As temperature increased successively, the addition
orientation was reversed from endo to exo. When the temperature
increased to 0 °C, the reaction was exo addition and yielded only
(5R,14R)-13c (dr >99:1) (Table 2, entry 7). The absolute
Figure 1. Calculated results of endo and exo reaction products.
alkylation proceeded from the endo face to furnish product 3a at
low temperature, which should be kinetically controlled. By
contrast, the reaction yielded a more stable exo-product 4a at
high temperature, which should be thermodynamically con-
trolled.
Next, stereodivergent synthesis of stereoisomers of non-
proteinogenic amino acids with two chiral centers was
performed. Aldol condensation of tricyclic iminolactones 1 and
2 with aldehydes was reported at −78 °C and yielded endo
addition product.11a In our test, the aldol condensation
orientation of tricyclic iminolactones 1 and 2 with isobutyl
aldehyde and benzaldehyde was reversed from endo to exo at −20
°C. However, further dehydration reactions of the products
occur easily at high temperature (Scheme 2).
B
DOI: 10.1021/acs.orglett.7b02296
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
configuration of 13c was confirmed by X-ray crystallography.
The attempt was also successful at room temperature whether
using LDA or KOt-Bu as base (Table 2, entries 8 and 9).
Distereomers 12c and 14c were not detected in the reaction.
This temperature-dependent asymmetric Michael addition was a
key procedure for accessing stereoisomers of 3-methyl glutamic
acid. Hydrolysis of two diastereomers 11c and 13c produced
optically pure (2S,3R)- and (2R,3R)-3-methyl glutamic acids.
To access the two other stereoisomers of 3-methyl glutamic
acid, the addition of tricyclic iminolactone 2 to ethyl crotonate
was performed. At −40 °C, the endo reaction proceeded and
generated a spirocyclic compound 15a containing four new
stereogenic centers as the major product (Table 3, entry 2),
new chiral centers were generated. Thus, it is difficult to obtain
optically pure products. The reaction was unsuccessful when
iminolactone 1 was treated with t-butyl tiglate in the presence of
LDA at −40 to 25 °C (Table 4, entry 1). Evidently, the
Table 4. Michael Addition of Tricyclic Iminolactone 1 to
Tiglate
Table 3. Michael Addition of Tricyclic Iminolactone 2 to
Crotonate
a
b
c
entry
R
temp (°C)
yield (%)
dr
1
2
3
4
5
6
7
8
t-Bu
−40 to 25
−40 to 25
−40 to − 20
25
0
0
Bn
4-NO2-Bn
0
4-NO2-Bn
71
86
0
37:32:31
43:35:22
3,5-di-CF3-Bn
2,6-di-Cl-Bn
2,6-di-Cl-Bn
2,6-di-Cl-Bn
25
−20
−10
25
d
67
75
85:15
e
10:90
a
b
c
R is the ester group of tiglate. Yield of isolated product. Estimated
d
e
1
by H NMR integrations. The ratio of 18/19 is 85:15. The ratio of
18/19 is 10:90.
temp
yield
a
endo/
b
entry
R
(°C)
base
LDA
adduct
(%)
exo
1
2
3
4
5
6
7
8
Et
−78
−40
0
c
eletrophilicity of CC in t-butyl tiglate decreased significantly
due to α-methyl of tiglate compared with t-butyl crotonate. To
improve the reactivity of CC, we applied a strategy of changing
the ester group and selected substituted benzyl tiglate as the
Michael reaction acceptor to rerun the reaction. The results
showed that the introduction of electron-withdrawing groups
from the benzene ring was available to increase the reactivity of
ester and resulted in a good yield. However, reaction stereo-
selectivity strongly depended on the position of the substitution
groups at the benzene ring and reaction temperature (Table 4,
entries 2−8). The o-position substituent was more favorable for
asymmetric Michael addition. Presumably, the stereoselectivity
should be affected by camphor and ester groups collectively. The
space distance of the o-position substituent and camphor is closer
than m- and p-substituents, which shows a stronger stereocontrol
effect. When 2,6-dichlorobenzyl tiglate reacted with iminolac-
tone 1, the reaction did not deliver the desired result at low
temperature (≤−20 °C) (Table 4, entry 6). As temperature
increased successively, two exo-Michael adducts 18 and 19 were
obtained. Notably, at −10 °C, the reaction produced
predominantly exo-Michael adduct 18 with a 18/19 ratio of
85:15, and the configuration of 18 is (5R,14R,15S) (Table 4,
entry 7); however, at 25 °C, the reaction predominantly yielded
another exo-Michael adduct 19 with a 18/19 ratio of 10:90, and
the configuration of 19 is (5R,14S,15R) (Table 4, entry 8). The
absolute configurations of products 18 and 19 were ascertained
by X-ray crystallography.12
Et
LDA
LDA
LDA
LDA
LDA
DBU
15a + 16a
15a + 16a
15a + 16a
15b
78
82
74
89
90
2:1
1:1.5
1:3
Et
Et
25
t-Bu
t-Bu
Et
−40
25
>99:1
>99:1
15b
−40
−40
c
Et
LiHMDS
b
15a + 16a
35
2:1
a
Yield of isolated product. Estimated by the yield of isolated product.
Reaction did not occur.
c
which could be hydrolyzed to form the spirocyclic amino acid, as
a proline derivative. The absolute configuration of 15a was
confirmed by X-ray crystallography. At 25 °C, optically pure exo-
Michael adduct 16a ((5S,14S)-isomer) was obtained as the
major product (Table 3, entry 4). Compared with the structure
of tricyclic iminolactone 1, the imine of 2 lacks the steric
hindrance protection of the methyl group at the bridgehead C8.
Thus, the intermediate carbanion C15 attacks imino C7 easily.
Another main reason for formation of compound 15 should be
that the orientation of addition keeps away from the cis-1,4
stereointeraction of methyl at C14 and the marked H of
intermediate 15 in boat configuration. To prevent cyclization,
ethyl crotonate was replaced with t-butyl crotonate to enhance
the steric hindrance effects of the ester group, but only spirocyclic
product 15b was obtained (Table 3, entries 5 and 6). From the
structure of product 15, the ester group R is far away from the
camphor structure. Thus, increasing the size of the ester group
cannot hinder the addition occurrence. Using LiHMDS and
DBU as bases of the reaction was also examined, but the attempts
were unsuccessful (Table 3, entries 7 and 8).
Products 9a, 11, 13, 15, 16a, 18, and 19 were hydrolyzed with
4−6 N HCl solution at 70 to 80 °C to obtain the corresponding
amino acids. Optically pure amino acids were obtained
successfully in good yields (>70%) and excellent enantiomeric
and/or diastereomeric excesses (>99% ee/de). The syntheses of
non-proteinogenic amino acids, including (2R,3R,4S)-3-methyl
glutamic acid 23, (2R,3S,4R)-3,4-dimethyl glutamic acid 24, and
(2R,3S,4S,5S)-multisubstituted proline 25, were first reported.
On the basis of the results of Michael reaction of tricyclic
iminolactone 1 with crotonate esters, we conducted the reaction
of tricyclic iminolactone 1 to tiglate. In principle, the Michael
reaction can form eight diastereoisomeric products, where three
C
DOI: 10.1021/acs.orglett.7b02296
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
The recovered chiral auxiliary was recycled to prepare tricyclic
iminolactone (Table 5).
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a
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entry
substrate
product
yield (%)
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[α]D
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7
9a
11
13
16a
18
19
15
20
21
22
23
24
25
26
79
82
76
79
72
81
86
2S,3S
+20
2S,3R
+21.8
−37.2
+37.8
−26.8
−30.5
−54.3
2R,3R
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a
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In summary, we developed a novel and practical method for
the enantiodivergent and diastereodivergent synthesis of amino
acid stereoisomers with one or multiple chiral centers. The
reaction orientation of tricyclic iminolactone is found to be
strongly dependent on reaction temperature. Highly stereo-
selective construction of multiple chiral centers was completed
by a diastereodivergent Michael addition in a single operation.
The structure of the ester group is another crucial factor that
influences the Michael reaction rate and stereoselectivity.
Extensions of this strategy with other chiral compounds are in
progress in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
(11) (a) Luo, Y.-C.; Zhang, H.-H.; Wang, Y.; Xu, P.-F. Acc. Chem. Res.
2010, 43, 1317−1330. (b) Xu, P.-F.; Chen, Y.-S.; Lin, S.-I.; Lu, T.-J. J.
Org. Chem. 2002, 67, 2309−2314. (c) Xu, P.-F.; Lu, T.-J. J. Org. Chem.
2003, 68, 658−661.
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b02296.
(12) CCDC-1548053 (8a), 1548054 (9a), 1402147 (13c), 1402221
(15a), 1402149 (18), and 1402148 (19) contain the supplementary
crystallographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
Synthetic procedures and NMR data (PDF)
X-ray data for compounds 8a, 9a, 13c, 15a, 18, 19 (ZIP)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: chsxliu@hotmail.com.
ORCID
Shouxin Liu: 0000-0003-4104-2971
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was from the National Basic Research Program
of China (2011CB512007, 2012CB723501), the National
Natural Science Foundation of China (30472074, 30873139),
the Hebei Natural Science Foundation (12966737D,
10276406D6), and the Department of Education of Hebei
Province Fund (QN2017065, BJ2017059).
D
DOI: 10.1021/acs.orglett.7b02296
Org. Lett. XXXX, XXX, XXX−XXX