Asymmetric Intramolecular Desymmetrization of meso-α,α′-Diazido Alcohols with Aryldiazoacetates: Assembly of Chiral C3 Fragments with Three Continuous Stereocenters

Article abstract of DOI:10.1021/acs.orglett.6b00570

The chiral Cu-complex-catalyzed intramolecular interception of meso-α,α′-diazido alcohols with aryldiazoacetates is explored. Most of the enantioenriched α-imino esters with three continuous stereocenters are produced with good to excellent yield and enantioselectivity, and a chiral pocket model is proposed for rationalization of the asymmetric desymmetrization.

Full text of DOI:10.1021/acs.orglett.6b00570

Letter
pubs.acs.org/OrgLett
Asymmetric Intramolecular Desymmetrization of meso-α,α′-Diazido
Alcohols with Aryldiazoacetates: Assembly of Chiral C Fragments
3
with Three Continuous Stereocenters
†
‡
,†
Jin-Bao Qiao, Yu-Ming Zhao, and Peiming Gu*
†Key Laboratory of Energy Sources & Engineering, State Key Laboratory Cultivation Base of Natural Gas Conversion and
Department of Chemistry, Ningxia University, Yinchuan 750021, China
‡
School of Chemistry & Chemical Engineering, Shaanxi Normal University, Xi’an 710119, China
*
S Supporting Information
ABSTRACT: The chiral Cu-complex-catalyzed intramolecu-
lar interception of meso-α,α′-diazido alcohols with aryldiazoa-
cetates is explored. Most of the enantioenriched α-imino esters
with three continuous stereocenters are produced with good to
excellent yield and enantioselectivity, and a chiral pocket
model is proposed for rationalization of the asymmetric
desymmetrization.
ighly functionalized 2-propanols, such as glycerol, α,α′-
H
diamino alcohols, and their derivatives, are very important
1
building blocks and conventional subunits of natural products,
2
lead compounds, and drugs in pharmaceutical research.
Asymmetric desymmetrization of glycerol offers practical
strategies for access to enantioenriched C fragments, but the
3
3
products are limited to the polyoxygenated propanes. The
optically active C scaffolds substituted with different functional
3
4
groups have been seldom addressed by the above method.
Recently, our group reported an intramolecular interception of
achiral 1,3-diazido-2-propanols with chiral Cu-carbenoids for
Figure 1. Representative pharmaceutical molecules with α,α′-diamino
alcohol units.
producing the C fragments with three different functional
3
groups (amino group, hydroxyl group, and azido group) at each
of the three carbons, which could be regarded as the potential
5
tion of the carbon frameworks with continuous stereocenters is
very challenging. The above facts stimulated us to initiate new
research on the asymmetric desymmetrization of meso-alkyl
bisazides. In this paper, we report the chiral Cu-complex-
catalyzed intramolecular reaction of meso-α,α′-diazido alcohols
precursors of chiral α,α′-diamino alcohols (Scheme 1). Further,
6
,7
this was the first report in which the interception reaction of
alkyl azides with carbenoids was directly applied in the
asymmetric synthesis.
with aryldiazoacetates to produce chiral C fragments with three
3
continuous stereocenters.
Scheme 1. Asymmetric Intramolecular Desymmetrization of
Achiral 1,3-Diazido-2-propanol
The meso substrates for asymmetric desymmetrization were
9
prepared from α,α′-dibromo ketones (see Supporting Informa-
tion for details). A representative four-step route for the synthesis
of 1a is outlined in Scheme 2. The preparation started from the
10
reduction of a known mixture of 5a and 6a, affording epoxide
a, epoxide 8a, and alcohol 9a. Structures of 7a, 8a, and 9a were
7
assigned by the products from the next step S 2 azidation.
N
The previous asymmetric desymmetrization affords α-imino
Treatment of epoxide 7a with NaN afforded an unsymmetric
3
esters with good to excellent yield and enantioselectivity, but the
5
diazido alcohol, which could not be used for further trans-
formation. Azidation of 8a and 9a gave the same meso-diazido
alcohol 11a. The two different diazido alcohols could be easily
recognized by NMR analysis. Only one structure could be
products possess only one stereocenter. The α,α′-diamino
alcohol units present in the active molecules generally have
several continuous asymmetric carbons. For example, α,α′-
2a,b
diamino alcohol I is used as the HIV-1 protease inhibitor, and
8
streptomycin II is applied clinically for treatment of tuberculosis
(
Figure 1). Both of these important compounds contain the C3
Received: February 29, 2016
fragments with continuous stereocenters. Generally, construc-
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00570
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Organic Letters
Letter
Scheme 2. Preparation of meso Substrate 1a
Table 1. Optimization of Reaction Conditions for the
Asymmetric Desymmetrization of 1a
a
assigned for the unsymmetric diazido alcohol, then the
configuration of epoxide 7a was ascertained. The setting
structure for 11a was supported by X-ray analysis of the ultimate
desymmetrization product. Thereafter, the precursors of 11a,
epoxide 8a, and alcohol 9a were firmly identified. Esterification of
temp
time
(h)
yield
b
c
entry L*
[M]
(°C)
(%)
ee (%)
d
1
2
3a
3a
3a
3a
3b
3c
3d
3e
3f
CuPF (MeCN)4
25
25
25
25
25
25
25
25
25
25
25
25
10
10
5
31
99
−70
6
FeCl2
NiCl2
PdCl2
d
11a with phenylacetic acid followed by diazo transfer reaction
3
80
80
27
20
36
14
14
92
4
trace
trace
98
−60
d
successfully gave the desired meso substrate 1a with 92% yield in
two steps.
With 1a in hand, screening experiments of chiral catalysts for
the asymmetric desymmetrization reaction were undertaken
4
−70
d
5
CuPF (MeCN)4
−78
6
d
6
CuPF (MeCN)4
99
−90
6
d
7
CuPF (MeCN)4
99
−86
6
(
Table 1). Initially, the previous chiral Cu complex for
8
CuPF (MeCN)4
99
26
6
desymmetrization of the achiral 1,3-diazido-2-propanol, pre-
9
CuPF (MeCN)4
99
0
6
pared in situ from CuPF (MeCN) , ligand 3a, and sodium
10
11
12
13
14
15
16
3g
3h
3i
CuPF (MeCN)4
86
84
93
91
97
93
96
92
6
4
6
tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (NaBARF), was
used for the meso substrate. The larger and noncoordinating ion
CuPF (MeCN)4
93
6
CuPF (MeCN)4
5
98
6
−
BARF was found to be good for the enantioselectivity of the
3h
3i
CuPF (MeCN)4
15
21
64
72
92
94
6
desymmetrization reaction in our previous paper. The α-imino
ester 2a was obtained in nearly quantitative yield, but the
enantioselectivity (70% ee) was unsatisfactory (Table 1, entry 1).
Replacement of Cu with other metals also encountered failures
CuPF (MeCN)4
6
3h
3i
CuPF (MeCN)4
90
6
CuPF (MeCN)4
5
77
6
a
Reaction conditions: CuPF (MeCN) (0.0025 mmol), ligand (0.0030
6
4
(
Table 1, entries 2−4), resulting in trace 2a with lower
mmol), and NaBARF (0.0030 mmol) were mixed in solvent (0.4 mL)
for 2 h at 25 °C; then diazo phenylacetate 1a (0.05 mmol) in solvent
(0.4 mL) was added, and the reaction mixture was stirred at the
enantioselectivity at room temperature.
We then switched our attention to the extensive modification
of bisoxazoline ligand 3a to obtain better enantioselectivity and
yield. Good results were observed when the size of two
substituents that were attached to the carbon linker of the
bisoxazoline ligand was enlarged (Table 1, entries 5−7). The α-
imino ester 2a was obtained with 90% ee and 99% yield in the
presence of ligand 3c/Cu complex. Ligands 3e and 3f were
prepared by modification of the substituent at bisoxazoline units
of ligand 3c, but after evaluation, both failed to give better
enantioselectivity. The more exciting results were achieved with
the ligands 3h and 3i possessing two phenyl groups at each of the
oxazoline rings, which were prepared through alkylation of the
b
conditions mentioned above. Isolated yield after purification.
c
d
Determined by chiral HPLC. Opposite enantioselectivity.
stereocontrol (2f). Naphthalene analogue 2g was also produced
with good control of stereochemistry. Further evaluation of the
two R groups of the α,α′-diazido alcohol unit revealed that
excellent enantioselectivity could be observed when they were
aryl groups with electron-withdrawing substituents (2h−2j).
The effect of electron-donating groups on this aryl ring was not
investigated due to the failure of substrate preparation. If the two
R groups of α,α′-diazido alcohol were alkyl groups, such as
methyl or benzyl, the enantioselectivity was decreased (2k−2l).
It was very interesting that when the two alkyl groups were
locked as a cyclopentane ring, the enantioselectivity was excellent
(2m). Here, we would like to emphasize the fact that α-imino
ester 2l could be regarded as a precursor of the analogue of HIV-1
protease inhibitor mentioned above (Figure 1). The previous
substrate, achiral 1n, was reinvestigated with the new Cu
complex, affording 2n with a disappointing enantioselectivity
(82% ee).
Furthermore, a 2 g scale reaction of 1i was carried out,
producing the imino ester 2i with 97% ee in 87% yield. The yield
of the gram-scale reaction decreased a bit, while the
enantioselectivity was more excellent. The absolute configu-
ration of the newly generated stereocenter substituted by the
ester group was assigned as R, and the structure of α-imino ester
11
commercially available bisoxazoline 3g. After careful opti-
mization, the best enantioselectivity (97% ee) was observed with
bisoxazoline 3h at 10 °C in CHCl , and it should be noted that
3
the product showed absolute configuration opposite of that from
the reaction catalyzed by ligands 3a−3f.
12
With the optimal ligand 3h, we next examined the scope of
substrates, and the results are presented in Scheme 3. The
conversion of phenyldiazoacetate 1a to enantioenriched 2a was
re-examined at 0.25 mmol scale, and the product was obtained
with 99% yield, though the enantioselectivity (96% ee) dropped
slightly. The meso substrates 1b−1m were successfully converted
to the cyclic α-imino esters 2b−2m with excellent yields. It
seemed that electron-withdrawing groups on the aromatic ring
would slightly affect the enantioselectivity (2a−2d), while the
electron-donating group would have a negative impact on the
B
DOI: 10.1021/acs.orglett.6b00570
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Organic Letters
Letter
a
Scheme 3. Scope of the Aryldiazoacetates
Scheme 4. Desymmetrization of α-Diazo(aryl)acetates 1o and
1p
α-imino ester 2o was obtained in 68% yield with 63% ee, and 2p
was produced in 84% yield with only 41% ee.
A very reasonable process for the interception of alkyl azides
with carbenoids had been proposed by Lecourt and Micouin’s
7
b
group. A possible induction model for the asymmetric
desymmetrization reaction is outlined in Figure 3, which was
a
Conditions: CuPF (MeCN) (0.0125 mmol), ligand (0.015 mmol),
6
4
and NaBARF (0.015 mmol) were mixed in CHCl (1.0 mL) for 2 h at
3
2
5 °C; then diazo phenylacetate 1 (0.25 mmol) in solvent (1.0 mL)
Figure 3. Possible induction model for the desymmetrization.
was added, and the reaction mixture was stirred at 10 °C for 9 h.
2
h was confirmed by single-crystal X-ray crystallography (Figure
first reported in the Cu-complex-catalyzed N−H insertion
13
2).
reaction with diazoesters by Zhou and co-workers. They had
prepared several crystals of binuclear chiral spiro-bisoxazoline/
copper complexes and observed that the reactive copper center
was in a chiral pocket. In this paper, we employed the different
chiral bisoxazoline ligands, though we could not get the crystal of
the catalyst. The suggested chiral induction model could be
accounted for by the observed results here. For substrates 1a−
1
m, the bulky R group and α′-carbon substituent would point
back to the blocking wall in the model I-a (Figure 3), affording
the observed products. While the bulky groups faced the catalyst
wall in model I-b, which would severely restrict the formation of
α-imino esters with opposite enantioselectivity.
In summary, asymmetric intramolecular desymmetrization of
the meso-1,3-diazido-2-propanol derivatives by chiral Cu-
carbenoids has been addressed, producing enantioenriched α-
amino-α′-azido alcohols with three continuous stereocenters.
The chiral pocket model was applied for rationalization of the
conversion. Further research on this topic in our laboratory will
focus on the intermolecular enantioselective desymmetrization
of the meso-alkyl bisazides.
Figure 2. X-ray structure of imino ester 2h.
Finally, two more substrates, phenyldiazoacetates 1o and 1p,
were investigated to reveal the impact of relative configuration of
the hydroxyl group with the two azido groups (Scheme 4). The
comparability study revealed that these two substrates were not
very suitable for the asymmetric desymmetrization process. The
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b00570.
C
DOI: 10.1021/acs.orglett.6b00570
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Experimental procedures and spectroscopic data and
Letter
copies of NMR spectra for all new compounds (PDF)
X-ray crystallographic data for 2h (CIF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: gupm@nxu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (Nos. 21262024, 21202074), the Program
for New Century Excellent Talents in University (NCET-13-
0
874), and the Program for Leading Talents of Ningxia Province.
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Org. Lett. XXXX, XXX, XXX−XXX