Enantioselective synthesis of α-oxy amides via Umpolung Amide Synthesis

Article abstract of DOI:10.1021/ja306225u

α-Oxy amides are prepared through enantioselective synthesis using a sequence beginning with a Henry addition of bromonitromethane to aldehydes and finishing with Umpolung Amide Synthesis (UmAS). Key to high enantioselection is the finding that ortho-iodo

Full text of DOI:10.1021/ja306225u

Communication
pubs.acs.org/JACS
Enantioselective Synthesis of α‑Oxy Amides via Umpolung Amide
Synthesis
Matthew W. Leighty, Bo Shen, and Jeffrey N. Johnston*
Department of Chemistry and Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37235,
United States
S
* Supporting Information
low selectivity.12 Furthermore, the use of active ester inter-
ABSTRACT: α-Oxy amides are prepared through enantio-
selective synthesis using a sequence beginning with a Henry
addition of bromonitromethane to aldehydes and finishing
with Umpolung Amide Synthesis (UmAS). Key to high
enantioselection is the finding that ortho-iodo benzoic acid
salts of the chiral copper(II) bis(oxazoline) catalyst deliver
both diastereomers of the Henry adduct with high enantio-
meric excess, homochiral at the oxygen-bearing carbon.
Overall, this approach to α-oxy amides provides an innovative
complement to alternatives that focus almost entirely on the
enantioselective synthesis of α-oxy carboxylic acids.
mediates to prepare α-oxy amides also provides a potential
epimerization pathway. In this context, we wondered whether
Umpolung Amide Synthesis (UmAS)13,14 might be leveraged to
eliminate the functional group manipulation step common to
carboxylic acid intermediates, while providing new opportunities
for enantioselective catalysis in the first transformation. The
latter could also stimulate innovative approaches to the enantio-
selective preparation of the β-oxy-α-bromonitroalkane donors.
The recent demonstration that UmAS can be used to prepare
isotopically labeled amides provides additional versatility to this
strategic shift.14 We report herein the use of bromonitromethane
as a carbonyl dianion synthon to achieve a fully convergent,
enantioselective synthesis of α-oxy amides.
Examination of established methods15,16 for the Henry addi-
tion with commercial bromonitromethane produced the desired
adduct in only moderate enantiomeric excess.17 For example, use
of indenyl bis(oxazoline) ligand L1 with copper(II) acetate in
ethanol furnished the adduct as a mixture of diastereomers in 53/
44% ee, respectively (Table 1, entry 1). The favored enantiomers
of each diastereomer are homochiral at the benzylic carbon and,
therefore, converge to the same α-oxy amide during the UmAS
step (vide infra). Alternative ligands provided some increase in
enantioselection, ultimately to the 87/89% ee level when using
tert-butyl bis(oxazoline) L6 (Table 1, entry 6). A slight but
reproducible solvent effect was also detected, leading to the use
of isopropyl alcohol to achieve 91/90% ee (Table 1, cf. entries 6−8).
Although this catalyst system worked well for ortho-substituted
aldehyde substrates, a decrease in enantioselection was observed
for meta- and para-substituted aldehydes. Therefore, additional
refinement to the catalyst was undertaken. In addition, it was
determined that MOM-protection of the alcohol18 prior to a
chromatographic step provided configurationally stable donors
by restricting the possibility of a retro-Henry reaction.
he α-oxy amide functional motif is common to numerous
T
biologically active natural products, with vitamin B5
(pantothenic acid)1 and mandelamide among the most prominent.
α-Oxy amides are also effective chelating ligands, and in this role
have been used for metal-centered catalysis.2 These examples are
chiral at the oxygen-substituted carbon, and preparative methods
have focused almost entirely on enantioselective α-oxy acid
synthesis, followed by standard condensative amide synthesis.3
For example, cyanohydrin synthesis is leveraged in this manner
(Figure 1, path A), with the earliest examples relying on a
Further refinement was achieved by following the hypothesis
that the counterion may affect the structure of the substrate-
bound catalyst.19 Although our attempts to crystallize the chiral
complex have been uniformly unsuccessful, the copper(II)
carboxylate complexes are bimetallic in nature, with bridging
carboxylates and solvent bound at the terminal position.20 Use of
a pivalate counterion provided some improvement (86/89% ee)
over the use of acetate (82/84% ee) (Table 2, entries 1, 3). Benzoate
also resulted in increased selectivity (88/91% ee) (Table 2, entry 2).
ortho-Methyl benzoate did not improve selectivity, a finding similar
Figure 1. Comparison of conventional α-oxy amide synthesis
approaches to the Henry/UmAS method used in this work.
resolution of racemic α-hydroxy acids prior to amide formation.
Notable direct approaches to α-oxy amide synthesis include the
Passerini reaction4−7 and its variants,8 as well as α-keto amide
reduction9,10 and biocatalysis of cyanohydrin hydrolysis,11 but
these often exhibit a narrow substrate scope and/or suffer from
Received: June 29, 2012
Published: September 11, 2012
© 2012 American Chemical Society
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Journal of the American Chemical Society
Communication
to selectivity (Table 2, entries 8−11). The effect was maximal for
both diastereomeric adducts when preparing the chiral catalyst
from copper(II) ortho-iodo benzoic acid.
Table 1. Enantioselective Henry Addition of
Bromonitromethane: Explorative Studies Using Chiral
a
Copper(II) Complexes
The tert-butyl bis(oxazoline)/Cu(oI-Bz)2 combination in iso-
propanol was evaluated against a selection of aldehydes (Table 3).
Since aldehydes are both plentiful and relatively inexpensive, it
was gratifying that most cases examined provided high levels of
enantioselection. The Henry protocol exhibited a broad tolerance for
aromatic aldehydes bearing a variety of substituents. Benzaldehyde
and similar substrates delivered the MOM-protected addition
products (3a−c) with high ee and yield (Table 3, entries 1−3).
Electron-donating substituents provided products with similar ee
but with slightly depressed yields (56−64%) (Table 3, entries 4−5).
Electron-withdrawing substituents at the para-position improved
this to as high as 96% ee and 75% yield (Table 3, entries 6 and 7).
Meta-substituted aryl aldehydes were converted to the correspond-
ing α-bromo nitroalkanes with moderate yield and good enantio-
selection (Table 3, entries 8−9), although 2-naphthaldehyde suf-
fered slightly (85% ee, Table 3, entry 10). Ortho-substituted
aldehydes led to adducts with high ee and did not exhibit decreased
reactivity (Table 3, entries 11−14), even when the substituent
was a competent chelating Lewis base. Aliphatic aldehydes
(Table 3, entries 15−16) delivered adducts in only moderate
yield, but it was difficult to attribute a cause since their volatility
hindered accurate measurements of conversion. However,
selectivity for these additions was high. Finally, our investigation
included several heteroaromatic aldehydes. Thiophene bearing
an aldehyde at the 3-position led to the adduct in good ee and
moderate yield (Table 3, entry 17), reflecting poor conversion.
Nitrogen heterocycles also appeared to suffer from incomplete
conversion, but a high ee was observed for a protected 2-pyrrole
(97/95% ee for 3r, Table 3, entry 18). The analogous indole
delivered adduct 3s with moderate selectivity (82/86% ee, Table 3,
entry 19).
b
c
entry
ligand
solvent
conv. (%)
ee (%)
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L6
L6
L6
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
MeOH
iPrOH
90
97
94
95
94
95
94
95
53/44
70/50
74/60
66/14
76/81
87/89
76/81
91/90
a
All reactions were conducted using aldehyde (1 equiv), 5 mol %
Cu(OAc)2·H2O, 5.5 mol % ligand, and bromonitromethane (10 equiv)
in solvent (0.5 M). Conversion based on H NMR analysis of crude
reaction mixtures. Enantiomeric excesses determined by chiral HPLC
using an IA column (Chiral Technologies). Values shown correspond
to each diastereomer (eed1/eed2).
b
1
c
Table 2. Enantioselective Henry Reaction: Effect of Cu(II)
a
Counteranion on Enantioselection
Table 3 provides details related to the subsequent UmAS step.
Enantioenriched (99% ee) α-methyl benzyl amine was used to
provide confirmation that the diastereomers 3 are homochiral at
the benzylic carbon and remained enriched throughout the
three-step sequence (Henry/MOM protection/UmAS). In each
case, the coupling proceeded in moderate to good yield, providing
the α-oxy amide (4) as a single diastereomer. This outcome is
consistent with the mechanism of UmAS, which does not provide a
pathway for epimerization at the carbon α to the carbonyl.13,14
This approach was applied to the preparation of LY411575,21,22
a potent γ-secretase inhibitor developed for the treatment of
Alzheimer’s disease (Scheme 1). Although several preparations
of this peptidic small molecule have been reported,23 the difluoro
mandelic acid is prepared as the racemate and coupled. The
diastereomers that result are separated chromatographically.
Using the chemistry described above, the mandelamide precursor
was prepared in 52% yield and 91/92% ee. Subsequent coupling to
alanine isopropyl ester was followed by hydrolysis of the ester.
Coupling of the resulting acid and amine 9 followed by MOM
deprotection delivered LY411575 as a single stereoisomer, for
which all analytical data (NMR, optical rotation) matched those
reported in the literature.
b
c
entry
CuII source
yield (%)
ee (%)
1
Cu(OAc)2·H2O
Cu(Bz)2·H2O
Cu(Piv)2·H2O
84
80
84
85
78
46
70
59
85
70
73
82/84
88/91
86/89
84/88
87/90
86/89
79/83
90/92
90/94
2
3
4
Cu(oMe-Bz)2·H2O
Cu(pF-Bz)2·H2O
Cu(pCl-Bz)2·H2O
Cu(oF-Bz)2·H2O
Cu(oCl-Bz)2·H2O
Cu(oBr-Bz)2·H2O
Cu(oI-Bz)2·H2O
Cu(oOMe-Bz)2·H2O
5
6
7
8
9
10
11
93/94
91/91
a
All reactions were conducted using aldehyde (1 equiv, 0.3 M in
iPrOH), 10 mol % Cu(II) complex, 10 mol % (S,S)-tBuBOX (L6), and
b
bromonitromethane (10 equiv). Isolated yield (two steps).
Enantiomeric excess determined by chiral HPLC using an AD-H
c
In summary, a new approach to α-oxy amides has been
developed using a three-step sequence: enantioselective Henry
addition, protection, and umpolung amide synthesis. An inter-
esting counterion effect was used to improve the enantioselectivity
of bromonitromethane addition using the Evans bis(oxazoline)−
copper(II) system, for which an ortho-iodo benzoate salt provided
substantial improvement. The selectivity achieved in the Henry
column (Chiral Technologies). Values shown correspond to each
diastereomer (eed1/eed2). See Supporting Information for complete
details.
to the use of para-fluoro, para-chloro, and ortho-fluoro benzoic
acid derivatives (Table 2, entries 4−7). However, ortho-halo and
ortho-methoxy benzoates did provide significant improvements
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Table 3. Enantioselective Synthesis of MOM-Protected α-Bromonitroalkanes and Their Use in UmAS
a
b
c
d
c
entry
R
3
ee (%)
yield (%)
4
yield(%)
1
2
3
4
5
6
7
8
9
C6H5
a
92/92
91/91
93/85
96/91
91/86
93/96
92/93
92/93
95/95
85/84
99/99
95/96
96/99
99/99
99/99
89/92
90/92
97/95
82/86
62
81
85
64
56
66
75
73
62
66
77
78
74
72
a
61
60
56
56
54
55
62
55
57
65
56
56
57
69
53
46
48
57
53
pMeC6H4
pPhC6H4
b
c
d
e
f
b
c
d
e
f
pMeOC6H4
pMeSC6H4
pFC6H4
pF3CC6H4
mBrC6H4
mMeOC6H4
2C10H7
oMeC6H4
oBrC6H4
g
h
i
g
h
i
e
10
j
j
11
12
13
14
15
16
17
18
19
k
l
k
l
oMeOC6H4
oMOMOC6H4
C6H11
m
n
o
p
q
r
m
n
o
p
q
r
f
45
PhCH2CH2
3thiophene
N-Ts-2pyrrole
N-Ts-3indole
47
50
51
43
s
s
a
i
All reactions were conducted using aldehyde (1 equiv, 0.3 M in PrOH), 10 mol % Cu(oI-Bz)2·H2O, 10.5 mol % (S,S)-tBuBOX (L6), and
b
bromonitromethane (10 equiv) at 0 °C. Determined by chiral HPLC using chiral stationary phase. Values shown correspond to each diastereomer
(eed1/eed2). Isolated yield. All reactions were conducted using bromonitroalkane (1 equiv), H2O (5 equiv), (S)-α-Me-benzylamine (1.2 equiv),
K2CO3 (2 equiv), and NIS (1 equiv) in DME (0.2 M). Amide isolated in 11:1 dr. Conducted at room temperature.
c
d
e
f
Scheme 1. Preparation of LY411575 Using the Enantioselective Mandelamide Synthesis
step is then translated through the UmAS step to prepare
stereoisomerically pure α-oxy amides. Conceptually, this is one
of the few approaches to chiral nonracemic α-oxy amides that
avoids the ubiquitous α-oxy carboxylic acid intermediate, one
that can suffer epimerization en route to amide derivatives.
AUTHOR INFORMATION
■
Corresponding Author
jeffrey.n.johnston@vanderbilt.edu
Notes
The authors declare no competing financial interest.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and spectroscopic data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
ACKNOWLEDGMENTS
S
■
Research reported in this publication was supported by the
National Institute of General Medical Sciences of the National
Institutes of Health under Award Number R01 GM 063557.
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