Enantioselective Synthesis of anti -β-Hydroxy-α-amino Esters via an Organocatalyzed Decarboxylative Aldol Reaction

Article abstract of DOI:10.1055/s-0036-1588141

The first enantioselective decarboxylative aldol addition with α-amido-substituted malonic acid half oxyesters (MAHOs) is described. The combined use of a newly designed bifunctional sulfonamide catalyst with pentafluorobenzoic acid as an additive afforde

Full text of DOI:10.1055/s-0036-1588141

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Enantioselective Synthesis of anti-β-Hydroxy-α-amino Esters via
an Organocatalyzed Decarboxylative Aldol Reaction
Taryn March
O
O
O
OH
Akihiro Murata
catalyst (20 mol%)
C6F5CO2H (20 mol%)
Yusuke Kobayashi
Yoshiji Takemoto*
PhO
OH
N
PhO
R
MeO
O
O
NHFmoc
S
MeO
MeO
NHFmoc
CPME
10–15 °C
N
H
14 examples
23–99% yield
up to 95:5 er
up to 90:10 dr
N
Graduate School of Pharmaceutical Sciences, Kyoto University,
Yoshida, Sakyo-ku, 606-8501 Kyoto, Japan
takemoto@pharm.kyoto-u.ac.jp
O
R
H
catalyst
Received: 13.12.2016
Accepted: 09.01.2017
Published online: 03.02.2017
DOI: 10.1055/s-0036-1588141; Art ID: st-2016-b0841-c
found limited use7 due to the low acidity of the methylene
protons, MAHTs, which have considerably lower pKa value,
have proven good substrates in several organocatalyzed de-
carboxylative aldol-type reactions.8 Yet, these reactions all
rely on highly reactive electrophiles, namely isatins and tri-
fluoromethyl ketones, for good results, illustrating the rela-
tively poor reactivity of such substrates. Significant advanc-
es were made by Song and List,8g whose chiral sulfonamide
catalyst mediated the decarboxylative addition of MAHTs to
aldehydes in 73–94% ee and in yields of up to 96% for elec-
tron-deficient aldehydes, although reactions required a cat-
alyst loading of 30% and up to 96 hours for completion.
However, these examples all deal with unsubstituted
MAHTs and thus are limited to the creation of one new ste-
reocenter; simultaneously generating two new stereocen-
ters under high stereocontrol presents a huge additional
challenge.9
Despite the great potential of α-amido MAHOs for or-
ganic synthesis, their use in decarboxylative reactions is ra-
re, likely hindered by difficulties associated with their syn-
thesis and stability. To date, no method for the preparation
of α-amido MAHTs has been reported, and thus their reac-
tivity in such reactions is unknown. Therefore, there is
enormous room for innovation in this area regarding both
the synthesis and applications of these malonic acids.
During our preliminary studies into the decarboxlyative
aldol addition with MAHOs, a 1:1 ratio of highly reactive p-
nitrobenzaldehyde and N-Boc MAHO 1a were employed as
model substrates to screen a range of structurally diverse
bifunctional organocatalysts, including ureas, thioureas,
squaramides, benzothiadiazines, sulfonamides, and boronic
acids.10 After 48 hours in THF at room temperature, sulfon-
amide catalyst 3 (10 mol%) proved most effective, affording
the β-hydroxy-α-amino ester 4a in 45% yield and 66:34 er,
with 88:12 anti/syn ratio (Table 1, entry 1).
Abstract The first enantioselective decarboxylative aldol addition with
α-amido-substituted malonic acid half oxyesters (MAHOs) is described.
The combined use of a newly designed bifunctional sulfonamide cata-
lyst with pentafluorobenzoic acid as an additive afforded the β-hy-
droxy-α-amino acid derivatives in moderate to high yields and with high
enantioselectivities.
Key words bifunctional organocatalyst, malonic acid half oxyester
(MAHO), cinchona alkaloid, sulfonamide, β-hydroxy-α-amino acid
anti-β-Hydroxy-α-amino acids form key components of
various natural products1 and are highly versatile synthons
for molecular synthesis. Stereoselective methods for their
synthesis include asymmetric ruthenium-catalysed hydro-
genation via dynamic kinetic resolution2 (DKR), rhodium-
catalysed multicomponent reactions,3 and aldol additions
mediated by metals4 or organocatalysts.5 Recently, Rouden
reported a metal-free decarboxylative aldol addition with
α-amino-substituted malonic acid half oxyesters (MAHOs).6
In the presence of an achiral tertiary amine base, the highly
reactive α-amido MAHOs underwent diastereoselective ad-
dition to various aldehydes, generating racemic products
with ≥100:1 anti/syn selectivity. Inspired by this result, we
sought to develop an enantioselective version as a continu-
ation of our research into bifunctional organocatalysis, and
herein present an overview of our research towards this
goal.
The use of MAHOs and malonic acid half thioesters
(MAHTs) as substrates exploits the ability of carboxylic ac-
ids to decompose via CO2 expulsion, allowing reactive eno-
late intermediates to be generated under almost neutral
conditions and with minimal waste. While MAHOs have
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

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Table 1 Investigation of MAHO Structure in the Decarboxylative Aldol Reaction with p-Nitrobenzaldehyde and Sulfonamide Catalyst 3
O
O
N
R1O
1a–h
OH
O
O
O
OH
NHR2
S
3 (10 mol%)
THF, rt, 48 h
N
R1O
H
N
NHR2
4a–h
NO2
p-O2NC6H4CHO
MeO
3
2
Entry
MAHO R1, R2
Product
Yield (%)a
anti/synb
erc
66:34
1
2
3
4
5
6
7
8
1a Et, Boc
1b Et, Bz
4a
4b
4c
4d
4e
4f
45
41
44
19
37
33
38
48
88:12
86:14
75:25
80:20
75:25
94:6
72:28
67:33
70:30
76:24
65:35
73:27
74:26
1c Et, o-F-C6H4C(O)
1d Et, Cbz
1e Et, Fmoc
1f Me, Bz
1g Ph, Bz
4g
4h
88:12
80:20
1h Ph, Fmoc
a Isolated yields of syn and anti isomers.
b Determined by 1H NMR analyses of crude reaction mixture.
c Determined by chiral HPLC analyses.
Using this catalyst in subsequent experiments to ex-
plore the MAHO structure (Table 1), Fmoc/Ph-protected 1h
was identified as the preferred MAHO substrate (48% yield,
74:26 er, 80:20 dr; Table 1, entry 8). Given the prevalence of
Fmoc protection in solid-phase peptide synthesis (SPPS)
and other synthetic applications, the ability to generate
these pre-protected products in a single step was an ideal
result. The choice of ester appeared to have less of an influ-
ence on reaction selectivity.
This N-Fmoc/OPh combination presented a problem for
large-scale synthesis of MAHO starting materials, however,
with the Fmoc group suffering from substantial decomposi-
tion in the rhodium-catalysed N–H insertion reaction pre-
viously used to synthesize our α-amido MAHOs. Further-
more, the base-labile phenyl ester is incompatible with
conditions typically employed for Fmoc protection. In a
new approach, we developed a novel direct protecting-
group exchange of a diphenylmethyl group for Fmoc under
hydrogenolysis conditions (Scheme 1).
By poisoning the palladium catalyst with 2,2′-bipyridyl,
the Ph2CH moiety was cleaved while leaving the Fmoc
group – which can be unstable under such conditions – in-
tact. The same methodology was also applied to the syn-
thesis of the corresponding MAHT 10, with the thioester
moiety having no detrimental effect on the catalyst. Both
substrates were ultimately prepared on a multigram scale
in excellent overall yield,10 and storage below 0 °C ensured
their stability for weeks or months. Both the synthesis of α-
amido MAHTs and this protecting group exchange are pre-
viously unreported in the literature.
With adequate MAHO in hand, and having previously
narrowed down the preferred catalyst type, a range of aryl
sulfonamides bearing chiral amine substituents were
screened in the decarboxylative aldol reaction between
MAHO 1h and p-O2NC6H4CHO (2).10 Cinchona alkaloid de-
rivatives were clearly superior to other chiral amines, while
the presence of an ortho substituent on the sulfonamide
aryl ring proved essential for high enantio- and diastereose-
lectivity. Trimethoxyphenyl catalyst 11 ultimately gave the
best results, affording the product 13c in 70% yield, 90:10
er, and 72:18 anti/syn ratio. Despite extensive modelling,
synthesis, and screening of aryl sulfonamides with diverse
o-, m-, and p-substituents, a direct relationship between se-
O
O
1. LiHMDS, THF
–78 °C, 1 h
O
PhX
OtBu
NCPh2
Ph2CN
OtBu
2. PhXCOCl
–78 °C, 20 min
5
6, X = O
7, X = S
2) Fmoc-Cl (1.15 equiv)
H2 (balloon), THF
1) Pd/C (10% w/w)
2,2'-bipyridyl (0.5 equiv)
O
O
O
O
TFA, CH2Cl2
PhX
OtBu
PhX
OH
NHFmoc
0° C to rt
NHFmoc
1h, X = O: 91%
10, X = S: 92%
8, X = O: 92% from iminoglycine
9, X = S: 96% from iminoglycine
Scheme 1 Preparation of MAHO 1h and MAHT 10
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

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lectivity and either steric size or electronic effects was not
observed, which made further refinement of catalyst struc-
ture difficult.
substrates, such as o-O2NC6H4CHO, which went from 34%
with 1.5 equivalents of MAHO to 76%. Gratifyingly, no re-
duction in enantio- or diastereoselectivities were observed
– in fact, er and dr generally increased slightly.10
Cinchona alkaloid conformations are known to be high-
ly dependent on solvent and temperature,11 and optimal
orientation of the catalyst’s quinoline and quinuclidine
rings in the transition state is crucial for selective position-
ing of substrates via hydrogen bonding. Ethereal solvents,
which interact strongly with the catalyst and substrates,
were found to give the best results; performing the model
reaction in cyclopentyl methyl ether (CPME) at room tem-
perature afforded the product in 84% yield, 89:11 er, and
81:19 dr. The absence of strong hydrogen-bonding net-
works, as with chlorinated or hydrocarbon solvents, led to a
reduction in selectivity and yields, with only 28% of prod-
uct obtained in toluene.10
Exploring the scope of the reaction under these newly
optimised conditions, a series of aldehydes were treated
with MAHO 1h in the presence of catalyst 11 and C6F5COOH
(20 mol%). The results can be seen in Table 2. Aldehydes
bearing electron-withdrawing groups such as NO2 (Table 2,
entries 1–3) and CN (Table 2, entry 5) reacted rapidly, af-
fording the β-hydroxy-α-amino esters in yields of between
90–99%. Of these, o-O2NC6H4CHO was notably slower to re-
act due to steric hindrance, but gave the highest er of all
substrates (95:5, with 86:14 dr). p-Br and o-Cl benzalde-
hydes gave yields of only 68% (Table 2, entry 4) and 60% (Ta-
ble 2, entry 8), respectively, reflecting their decreased elec-
trophilicity, and in the case of the latter, steric hindrance. In
all these examples, the er was typically ≥ 91:9, and the dr ≥
83:17.
As expected, reactions with poor electrophiles suffered
from competing glycine formation, with m-anisaldehyde
and benzaldehyde giving yields of only 41% (Table 2, entry
9) and 46% (Table 2, entry 10), respectively, even after pro-
longed reaction times and at increased concentration. The
enantioselectivity also fell, with an er of 87:13 in both cas-
es. 2-Naphthaldehyde gave a similar result (Table 2, entry
12; 49%, 89:11 er, 84:16 dr), while the highly deactivated p-
anisaldehyde failed to give any product after two days. The
alkene cinnamaldehyde proved compatible with the amine
organocatalyst, and despite giving the product in only 36%
yield due to low reactivity, the er was an excellent 94:6 (Ta-
ble 2, entry 11, 81:19 dr). The decarboxylative aldol reac-
tion was also applicable to heterocyclic aldehydes with
varying results: 3-Thiophenecarboxaldehyde was slow to
react, and gave a poor 23% yield, with 84:16 er and 83:17 dr
(Table 2, entry 13), while reaction with 5-bromo-2-furalde-
hyde was complete after 20 hours, affording the product in
62% yield, 85:15 er and 81:19 dr (Table 2, entry 14). The di-
minished stereoselectivity of these two reactions is perhaps
a result of undesirable coordination between the heteroat-
om of the aldehydes and the catalyst and/or MAHO.
Protic additives had little effect on reaction stereoselec-
tivity but produced a notable increase in yields. This cata-
lytic effect was largely independent of additive acidity, ster-
ics, or electronic properties, with pentafluorobenzoic acid
1
ultimately selected due to ease of use. H NMR studies in
THF-d8 showed marked changes in catalyst shape following
additive addition, but ultimately failed to elucidate the ex-
act mechanistic role of the additive.
Both dr and er were improved by lowering the concen-
tration from 0.1 M to 0.05 M; yields suffered considerably
at 0.025 M due to decarboxylation–protonation of the
MAHO, which competes with the aldol reaction pathway to
give the corresponding glycine derivative. Performing the
addition at 15 °C helps to mitigate this unproductive side
reaction, however, yields with poorly reactive aldehydes
still suffer as a result of byproduct formation. Given the su-
perior reactivity of MAHTs with these substrates, it was
postulated that their reaction with poor electrophiles may
be faster, giving higher yields. While reactions with 10 were
significantly faster, the higher instability of α-amido
MAHTs also led to a greater rate of byproduct formation.
Furthermore – and quite unexpectedly – stereocontrol was
almost nonexistent, even at 0 °C (52:48 er and 45:55 dr), a
result that was repeated with other organocatalysts tested.
Variations in solvent and temperature did not lead to im-
provements, and thus the application of MAHTs to this re-
action was not further pursued.
For determination of the absolute stereochemistry, β-
hydroxy-α-amino ester ent-4h was transesterified to the
methyl ester under mild conditions12 (Scheme 2). After sep-
aration of the anti isomer (78% ee), the Fmoc group was re-
moved and the amine reprotected with BzCl to give benzoyl
derivative ent-4f. Comparison of optical rotation data to
known amino ester ent-4f2c established the configuration of
our β-hydroxy-α-amino esters as R,R.
In an effort to counter byproduct formation and low
yields, reaction stoichiometry was then adjusted in favour
of excess aldehyde, which should increase the likelihood of
aldol addition vs. MAHO protonation. Using 5–10 equiva-
lents of the inexpensive and readily available aldehydes im-
proved yields substantially, particularly with less reactive
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Table 2 Scope of Decarboxylative Aldol Reaction between 1h and Various Aldehydes, Mediated by Sulfonamide Catalyst 11
N
11 (20 mol%)
MeO
O
OH
O
O
O
O
C6F5CO2H (12) (20 mol%)
S
MeO
MeO
N
RCHO
PhO
FmocHN
13a–m
R
PhO
OH
NHFmoc
1h (1 equiv)
H
CPME, 10–15 °C
N
11
Entry
R
RCHO (equiv)
Conc. (M)
Time (h)
Product
Yield (%)a
anti/synb
erc
95:5
1
2
o-O2NC6H4
m-O2NC6H4
p-O2NC6H4
p-BrC6H4
10
10
10
10
10
10
10
5
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.1
16
16
3
13a
13b
ent-4h
13c
13d
13e
13f
90
99
95
68
95
73
trace
60
41
46
36
49
23
62
86:14
89:11
88:12
85:15
89:11
88:12
–
93:7
89:11
92:8
93:7
93:7d
–
3
4
18
16
16
48
20
72
65
65
48
72
20
5
p-NCC6H4
p-F3CC6H4
p-MeOC6H4
o-ClC6H4
6
7
8
13g
13h
13i
90:10
83:17
88:12
81:19
84:16
83:17
81:19
91:9
87:13
87:13
94:6
89:11
84:16
85:15
9
m-MeOC6H4
Ph
5
0.1
10
11
12
13
14
10
10
10
5
0.1
CH=CHPh
2-naphthyl
3-thienyl
0.1
13j
0.1
13k
13l
0.1
5-Br-2-furyl
5
0.1
13m
a Isolated yields of syn and anti isomers.
b Determined by 1H NMR analyses of crude reaction mixture.
c Determined by chiral HPLC analyses.
d Determined after conversion into the methyl ester.
further advances in the area of organocatalyzed decarbox-
ylative reactions and sustainable catalysis, and is an area we
continue to pursue as part of our research theme.
Zn4(OCOCF3)6O
O
OH
O
OH
(14) (cat.)
PhO
Fmoc
MeO
Fmoc
MeOH
60 °C, 24 h
51%
N
N
NO2
NO2
H
H
15
ent-4h (78% ee)
Acknowledgment
2. BzCl, Et3N
DMF, 0 °C, 1 h
44%
1. Pyrrolidine,
DMF, rt, 30 min
47%
We gratefully acknowledged a Grant-in-Aid for Scientific Research
(YT) on Innovative Areas ‘Advanced Molecular Transformations by Or-
ganocatalysts’ from MEXT, Japan. T.M. acknowledges a JSPS Postdoc-
toral Fellowship for Foreign Researchers.
O
OH
O
OH
MeO
MeO
NHBz
ent-4f, 91% ee
[α]D18 −95.8 (c 0.57, CHCl3)2c
NO2
NHBz
NO2
ent-4f (78% ee)
[α]D20 −81.1 (c 0.30, CHCl3)
Supporting Information
Scheme 2 Determination of the absolute configuration
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588141.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
In conclusion, we have developed the first reported en-
antio- and diastereoselective decarboxylative aldol addition
reaction between α-amido MAHOs and aldehydes for the
synthesis of anti-β-hydroxy-α-amino esters. Our novel bi-
functional organocatalyst facilitated reactions in moderate
to excellent yield with electron-deficient aldehydes and
with high selectivity. While results were less impressive
with deactivated aldehydes, this work promises to lead to
References and Notes
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T. March et al.
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Synlett
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To a stirred solution of 1h (0.05 mmol) in dry CPME (0.5–1.0
mL) at 10–15 °C, was added o-nitrobenzaldehyde (37.8 mg, 0.25
mmol), catalyst 11 (5.2 mg, 20 mol%), and pentafluorobenzoic
acid (2.1 mg, 20 mol%). The mixture was stirred at the same
temperature for 48 h, before being directly purified by silica gel
column chromatography (hexane–EtOAc) to give the anti-β-
hydroxy-α-amino acid 13a.
Phenyl (2S,3S)-2-[(9H-Fluoren-9-yl)methoxycarbonyl] amino-
3-hydroxy-3-(2-nitrophenyl)propanoate (13a)
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1H NMR (400 MHz, CDCl3): δ = 8.03 (d, J = 6.4 Hz, 1 H), 7.91–7.90
(m, 1 H), 7.75 (d, J = 6.4 Hz, 2 H), 7.66 (t, J = 6.2 Hz, 1 H), 7.55–
7.47 (m, 3 H), 7.40–7.34 (m, 5 H), 7.30–7.21 (m, 3 H), 7.00 (d, J =
6.0 Hz, 2 H), 5.85–5.80 (m, 2 H), 5.02–4.99 (m, 1 H), 4.24–4.34
(m, 2 H), 4.19–4.15 (m, 1 H), 3.69 (bs, 1 H). 13C NMR (100 MHz,
CDCl3): δ = 168.9, 156.1, 150.0, 147.8, 143.5, 141.2, 135.2, 133.7,
129.5, 129.4, 129.1, 127.7, 127.1, 126.2, 125.0, 124.8, 121.1,
119.9, 70.4, 67.4, 59.4, 46.9. IR (ATR): 3401, 1763, 1703, 1522
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cm–1 Na]+:
. ESI-HRMS: m/z calcd for C30H24N2NaO7 [M +
547.1476; found: 547.1464. HPLC [Chiralpak AD, hexane–2-
PrOH = 80:20, 0.8 mL/min, λ = 254 nm]: tR (major) = 34.1 min;
tR (minor) = 24.7 min.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E