Asymmetric organocatalytic synthesis of tertiary azomethyl alcohols: key intermediates towards azoxy compounds and α-hydroxy-β-amino esters

Article abstract of DOI:10.1039/c7ob00308k

A series of peracylated glycosamine-derived thioureas have been synthesized and their behavior as bifunctional organocatalysts has been tested in the enantioselective nucleophilic addition of formaldehyde tert-butyl hydrazone to aliphatic α-keto esters fo

Full text of DOI:10.1039/c7ob00308k

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Chem., 2017, DOI: 10.1039/C7OB00308K.
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OrgaPnleicas&e BdoionmootlaedcjuulsatrmCahregimnsistry
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DOI: 10.1039/C7OB00308K
Journal Name
ARTICLE
Asymmetric organocatalytic synthesis of tertiary azomethyl
alcohols: key intermediates towards azoxy compounds and α-
hydroxy-β-amino esters
Received 00th January 20xx,
Accepted 00th January 20xx
José A. Carmona,a Gonzalo de Gonzalo,b Inmaculada Serrano,b Ana M. Crespo-Peña,a Michal
DOI: 10.1039/x0xx00000x
Šimek,a David Monge,*,b Rosario Fernández*,b and José M. Lassaletta*,a
www.rsc.org/
A
series of peracylated glycosamine-derived thioureas has been synthesized and its behavior as bifunctional
organocatalysts has been tested in the enantioselective nucleophilic addition of formaldehyde tert-butyl hydrazone to
aliphatic α-keto esters for the synthesis of tertiary azomethyl alcohols. Using the 1,3,4,6-tetra-O-acetyl-2-amino-2-deoxy-
β-D-glucosamine derived 3,5-bis-(trifluoromethyl)phenyl thiourea the reaction could be accomplished with high yields (75-
98%) and moderate enantioselectivities (50-64% ee). Subsequent high-yielding and razemization-free tranformations of
both aromatic- and aliphatic-substituted diazene products in one pot fashion provides a direct entry to valuable azoxy
compounds and α-hydroxy-β-amino esters.
O
N
O
CF3
O
Introduction
HO
N
S
Chiral non-racemic tertiary alcohols and derivatives bearing
aryl or alkyl substituents at the stereogenic center are
recurrent scaffolds in many bioactive molecules. The selected
examples shown in Figure 1 include lactones Campothecin1
and Tripranavir,2 β-amino alcohol derivative SSR-241586,3
Voriconazole,4 and 2-substituted α-hydroxy-β-amino acids
(isoserines) which are present in several taxoid-based
anticancer agents.5 The increasing interest in known or
predicted biological properties exerted by 2-alkyl or 2-aryl
OH
O
HN
O
O
N
O
Ph
Tripranavir
Camptothecin
N
NMe2
F
N
N
O
HO
O
N
N
N
O
F
N
N
substituted
isoserine
fragments,
for
example
in
Ph
conformationally restricted peptidomimetics,6 contrast,
however, with the narrow palette of available methodologies
for the asymmetric synthesis of suitable precursors for such
molecules.7 Therefore, there is a strong interest in the
introduction of molecular diversity based on functionalized
tertiary alcohols. One straightforward approach relies on the
asymmetric nucleophilic addition to ketones and derivatives.8
During years, we have extensively investigated the nucleophilic
reactivity of formaldehyde N,N-dialkyl hydrazones for the
stereoselective introduction of single-carbon functional groups
into several electrophilic substrates.9
Cl
Cl
F
Voriconazole
SSR 241586
R2O
O
OH
O
R1
Ph
NH
O
O
O
OBz
OH
OAc
R
OH
Taxoids
Figure 1. Bioactive tertiary alcohols and derivatives.
More recently, we have also exploited the superior
performance of formaldehyde tert-butyl hydrazone (1)10 in
combination with organocalytic activations.11 The asymmetric
nucleophilic addition of 1 to aryl-substituted di-carbonyl
compounds such as α-keto esters 2 (Scheme 1, A)10a isatins,10c
and related bidentate electrophiles such as α-keto
phosphonates10d using BINAM-bis-urea as the organocatalyst
provides densely functionalized azomethyl carbinols (formally
hetero-carbonyl-ene products), which could be further
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ARTICLE
Journal Name
tBu
N
View Article Online
DOI: 10.1039/C7OB00308K
Results and discussion
A
tBu
O
N
Synthesis of alkyl-substituted azomethyl alcohols 3
NH
Cat.
+
HO
N
COOEt
Preliminary experiments towards alkyl-substituted adducts 3
were performed with commercially available ethyl 3-methyl-2-
oxobutanoate (2a) as model substrate (Table 1). At room
temperature, the reaction of 1 with 2a afforded the azomethyl
alcohol 3a at a reasonable rate (85% conversion after 2 h in
toluene (entry 1). Cooling to –15 °C strongly decelerated the
uncatalyzed reaction (entry 2), while a significant acceleration
by the Schreiner`s thiourea I (10 mol%) was observed at this
COOEt
H
H
R
R
2
1
3
CF3
Bifunctional
catalysis
O
N
H
N
H
F3C
H
N
Dual activation
CF3
H
H
N
Table 1. Screening of organocatalysts in the model reaction.a
O
O
O
H
Z
tBu
R
tBu
F3C
N
N
N
O
N
Cat. (10 mol%)
Toluene
NH
N
+
HO
CO2Et
CO2Et
3a
H
H
2a
This work
B
1
tBu
NH
tBu
N
tBu
N
O
Cat.
X
S
N
N
N
O
+
ArF
ArF
ArF
HO
R
HO
R
R
COOEt
N
N
H
N
N
H
H
H
H
H
H
H
2: R = Alkyl
N
N
1
COOEt
COOEt
I
ArF
4
3
X
NHPG
II X = S
III X = O
S
HO
R
ArF
N
H
N
tBu
S
H
COOEt
OH
5
N
IV
Ph
N
N
Scheme 1. Synthesis of aryl- and alkyl-substituted azomethyl tertiary alcohols 3:
a route to biologically relevant azoxy compounds 4 and α-hydroxy-β-amino
esters 5.
H
H
O
N
S
ArF
VII
HO
N
H
N
transformed into enantioenriched tertiary α-aryl α-hydroxy
aldehydes and derivatives thereof. In the originally proposed
working model, a bifunctional behaviour by the organocatalyst
results in the activation of both the hydrazone (via NH–
O=Chydrogen bonds) and the di-oxygenated electrophile
(using a second urea unit as multiple H-bond donor), while the
stereochemical outcome is explained by the relative bulkiness
of the aromatic group, oriented away from the more crowded
inner region of this ternary complex. In spite of the
experimental support collected for this model when ethyl
phenyl glyoxylate was used as the substrate,10a preliminary
experiments performed with aliphatic derivatives revealed a
poorer enantioselectivity, suggesting a priori that any kind of
π–π interactions might contribute to the stabilization of the
transition state.
H
N
tBu
tBu
V
AcO
AcO
AcO
tBu
S
O
S
ArF
N
ArF
N
N
H
N
N
H
H
H
Ph
O
OAc
VIII
VI
ArF = 3,5-(CF3)2C6H3
Entry
1
2
3
4
5
6
7
8
Cat.
none
none
I
T (°C)
rt
t (h)
2
Conv. (%)b ee (%)c,d
85
30
>95
66
>95
>95
85
87
41
>95
-
-
-
–15
–15
–15
–15
–15
–15
–15
–15
–15
48
48
48
48
48
48
48
67
43
II
III
IV
V
VI
VII
VIII
40 (S)
72 (R)
10 (R)
14 (R)
16 (S)
60 (R)
22 (S)
Aiming to expand the scope and applicability of azomethyl
tertiary alcohols 3, we report herein on the use of novel
saccharide-based
organocatalysts
for
accessing
enantiomerically enriched alkyl-substituted products and their
subsequent one pot transformations into azoxymethyl alcohols
4 and α-hydroxy-β-amino esters 5 (Scheme 1, B).
9
10
aReactions performed employing 2a (0.3 mmol), 1 (0.6 mmol) in toluene [1M].
bDetermined by 1H-NMR. cDetermined by chiral GC. dIn parentheses, absolute
configuration of the major enantiomer.
2 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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Journal Name
ARTICLE
O
R
temperature (>95% conversion, 48 h, entry 3). Therefore, we
explored the behavior of diverse bifunctional H-bonding
organocatalysts under these reaction conditions (entries 4-
10).∫ As observed for aryl-substituted α-keto esters, (R)-
BINAM-derived bis-urea III proved to be a superior catalyst
than its bis-thiourea analogue II (entry 5 vs 4), affording (R)-3a
in full conversion and 72% ee. The divergent stereochemical
outcome observed for these two catalysts is in agreement with
different activation modes operating in each case and the
major (R) absolute configuration provided by bis-urea III is
consistent with the dual activation mode proposed for the
aromatic substrates (see model in Scheme 1). Bifunctional 3,5-
bis(trifluoromethyl)phenyl-substituted thioureas bearing cis-1-
amino-2-indanol (IV), trans-1,2-diaminocyclohexane (V) and
tert-leucine (VI) chiral fragments afforded acceptable
activation levels, albeit with low enantioselections (entries 6-
8). The Jacobsen-type catalyst VII showed a higher selectivity
(60% ee) but lower activity (41% conversion, 67 h, entry 9),
probably due to its reduced acidity associated with the lack of
View Article Online
DOI: 10.1039/C7OB00308K
O
R
R
O
O
O
O
R
1
2
O
O
X
O
HN
H-bond donor
H-bond acceptor
HN
ArF
R = Alkyl, aryl; X = O, S
Figure 2. Hexosamine-derived (thio)ureas design.
organocatalysis.15 These compounds were synthesized in good
overall yields according to the general strategy depicted in
Scheme 2. First, commercially available hexosamine
D-glucosamine (6a) and D-galactosamine (6b)]
were efficiently converted into 1,3,4,6-tetra-O-acyl-β-
glycosamine hydrochlorides 8-10 following a three step
procedure: a) amine protection employing p-anisaldehyde; b)
standard esterifications; and c) removal of p-
methoxybenzylidene group with HCl in acetone. Subsequently,
the in situ generated free glycosamines were reacted with 3,5-
bis-(trifluoromethyl)phenyl isocyanate or thiocyanate, to
afford the corresponding urea IX and thioureas X-XIII in good
overall yields (71-95%).
hydrochlorides [
D
-
electron-poor aryl groups.12 Finally, multifunctional
D-glucose-
derived thiourea VIII was tested and the results revealed a
slightly superior catalytic activity, reaching full conversion in a
cleaner reaction, albeit in a low enantioselectivity (entry 10).
The performance exhibited by catalyst VIII suggests that the
carbohydrate unit might serve as a bulky-electron-withdrawing
group,13 increasing the acidity of thiourea and affording
additional interactions with mono-alkyl hydrazone 1 via NH–
O=C bonding (similar to that proposed in the BINAM-bis-urea)
to the ester carbonyl groups. Considering this hypothesis, and
the enormous modulation possibilities of carbohydrates as
chiral scaffolds14 we decided to synthesize and evaluate a
Next, the new set of saccharide-based organocatalysts were
tested in the model reaction (Table 2). To our delight, D-per-
acetylated glucosamine-derived organocatalysts IX and X were
more selective than VIII (entries 1-3), being thiourea X more
active than urea IX, and affording (S)-3a in full conversion and
a higher enantioselectivity (58% ee, entry 3). It is convenient to
remark that, in contrast with catalysts II/III, good H-bond
acceptor functionalities (the carbonyl groups) are available in
both cases, so that the better performance of X can be
small
library
of
per-acylated
hexosamine-derived
organocatalysts placing a (thio)urea group at the C2 position
(Figure 2). To the best of our knowledge, (thio)ureas with this
alternative design have not been evaluated in asymmetric
OCOR
OCOR
OH
OCOR
ROCO
O
ROCO
HO
HO
i)
iii)
iv)
ROCO
ROCO
O
O
O
ii)
ROCO
OCOR
ROCO
OCOR
X
OH
N
OCOR
NH2.HCl
HN
NH2.HCl
8a(GlcN): R = Me (72%)a
8b(GalN): R = Me (64%)a
9a(GlcN): R = Ph (61%)a
10a(GlcN): R = tBu (54%)a
6a (GlcN)
6b (GalN)
HN
ArF
IX-XIII
7
OMe
OAc
O
OBz
OAc
OAc
OPiv
O
AcO
AcO
BzO
AcO
AcO
AcO
PivO
O
O
O
OAc
BzO
OBz
S
AcO
OAc
O
OAc
S
PivO
OPiv
HN
S
HN
HN
HN
HN
S
HN
HN
HN
HN
HN
ArF
ArF
ArF
ArF
ArF
XII (84%)
IX (74%)
X (84%)
XI (71%)
XIII (95%)
Scheme 2. Synthesis of hexosamine-based (thio)ureas. a) p-anisaldehyde, aq. NaOH; b) O-Acylations; c) aq. HCl, acetone. *3-step (6→8) yields. d) ArFNCX, Et3N, CH2Cl2.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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Table 2. Screening of saccharide-based organocatalysts.a
Table 3. Organocatalytic additions of 1 to alkyl-substituted α-keto esters 2.a
View Article Online
DOI: 10.1039/C7OB00308K
tBu
N
tBu
tBu
tBu
NH
tBu
O
N
N
O
Cat. (10 mol%)
N
N
N
N
NH
or
Cat. (10 mol%)
+
+
N
R
CO2Et
HO
HO
R
HO
Toluene
−15 °C
CO2Et
Solvent, −15 °C
H
H
2
CO2Et
(S)-3a
1
CO2Et
(S)-3
R
CO2Et
(R)-3
H
H
43 h
2a
1
Entry
1
2
3
4
5
6
7
2
R
iPr
Cat.
III
X
III
X
III
X
III
X
III
X
III
X
III
X
3
Yield (%)b
74
ee (%)
Entry
1
2
3
4
5
6
7
8
Cat.
VIII
IX
X
XI
XII
XIII
X
Solvent
Conv. (%)b
>95
ee (%)c
22
42
58
8
24
rac
58
34
2a
2a
2b
2b
2c
2c
2d
2d
2e
2e
2f
(R)-3a
(S)-3a
(R)-3b
(S)-3b
(R)-3c
(S)-3c
(R)-3d
(S)-3d
(R)-3e
(S)-3e
(R)-3f
(S)-3f
(R)-3g
(S)-3g
c 72
58c
49c
62c
16d
45d
16e
63e
50d
56d
14e
64e
42e
64e
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
iPr
98
75
85
62
85
60
90
80
88
88
86
14
65
>95
>95
85
Me
Me
n-Pr
n-Pr
n-C6H13
n-C6H13
Bn
78
Trifluorotoluene
TBME
86
30
70
60
8
X
X
X
9f
9
10
n-Hexane
CH2Cl2
48
54
10f
11
12
13g
14g
Bn
Ph(CH2)2
Ph(CH2)2
tBu
aReactions performed employing 2a (0.3 mmol) and 1 (0.6 mmol). bDetermined
2f
2g
2g
by 1H-NMR. cDetermined by chiral GC.
tBu
20
explained by the higher acidity of the thiourea moiety.
Notably,
selectivity within the series (entry 4). The stereoelectronic
influence by different acyl groups was analyzed employing
catalyst XII (per-benzoylated) and XIII (per-pivaloylated).
aReactions performed employing 2 (0.6 mmol), 1 (1.2 mmol) for 48 h (III) or 43 h
(X). bIsolated yield. cDetermined by chiral GC. dDetermined by chiral HPLC.
eDetermined by chiral HPLC of its corresponding azoxymethyl alcohol 4. fReaction
performed at –45 °C for 24 h. gReaction performed at 0 °C for 72 h.
D-galactosamine derivative XI induced the lower
Acceptable levels of activation, albeit low enantioselectivies, The versatility of the N-tert-butyldiazenylmethylene group is in
were observed in both cases (entries 5 and 6). Finally, poorer good part attributed to its equivalence with the formyl group.
conversions and/or enantioselectivities were observed in Thus, representative azomethyl alcohols 3c,e were
solvents such as trifluorotoluene (entry 8), tert-butyl methyl transformed into aldehydes 12c,e via a tautomerization–
ether (TBME, entry 8), n-hexane (entry 9) or CH2Cl2 (entry 10). hydrolysis sequence accomplished by simple treatment with
Thus, the model reaction revealed BINAM bis-urea III and
D
-
HCl in a biphasic H2O/Et2O medium (Scheme 3). Crude
glucosamine derivative X as the most selective and active aldehydes 12 did not resist chromatographic purifications but
organocatalysts, respectively. Consequently, the scope of the were isolated with a high degree of purity (>90%, estimated by
reaction with a range of alkyl-substituted α-keto esters was 1H-NMR). These intermediates were treated with Bu4NBH4 to
then explored employing both organocatalysts. The collected yield diols 13c,e in satisfactory overall yields. The absolute (S)
data (Table 3) indicates that the expected products (R)-3 were configuration of adducts 3c,e (stereochemistry induced by X)
obtained with acceptable yields (60-88%) when catalyst III was was determined by chemical correlation of diols 13c,e.16 The
used, although the enantioselectivities were highly dependent absolute configuration of other adducts 3 and derivatives
on the alkyl substituents (entries 1, 3, 5, 7, 9 and 11), dropping thereof was assigned by analogy assuming a uniform reaction
i
for those α-keto esters bearing linear alkyl chains [3a, R = Pr pathway [(S) induced by X and (R) induced by III].
n
(72% ee); 3b, R = Me (49% ee); 3c, R = Pr (16% ee); 3d, R =
nHex (16% ee); 3e,R = Bn (50% ee); 3f, R = CH2CH2Ph (14%
tBu
HO
N
ee)].¶ On the other hand, faster and cleaner reactions
"One-pot"
HO
N
catalyzed by X afforded products (S)-3 in good to excellent
yields (75-98%) and moderate enantioselectivities (50-64% ee),
without significant variations depending on the alkyl chain
structures (entries 2, 4, 6, 8, 10 and 12). Substrate 2e carrying
a benzyl substituent reacted much faster, reaching completion
in shorter times (24 h), even at –45 °C. In this case, both
organocatalysts provided similar ee's (above 50% ee, entries 9
and 10). As limitation, a poorer reactivity was observed for
tBu-substituted α-keto ester 2g (entries 13 and 14). Even at 0
°C for prolonged reaction times, (S)-3g was obtained with 20%
yield and 64% ee in presence of catalyst X.
HO
R
R
CO2Et
(S)-13c: R = Pr (43%)
(S)-13e: R = Bn (63%)
CO2Et
3c, 3e
HCl (aq)/ Et2O
Bu4NBH4
tBu
NH
O
HO
R
N
HO
CO2Et
12
R
CO2Et
11
Scheme 3. Synthesis of optically active diols (S)-13.
4 | J. Name., 2012, 00, 1-3
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Synthesis of azoxymethyl alcohols 4
ARTICLE
OMe
OH
O
View Article Online
O
N
The azoxy-containing natural products17 constitute a small but
growing family of compounds with varied biological activities,
the common structural feature of which is the presence of an
azoxy group (N=N→O). Compounds in this family include the
antitumour agent valanimycin, the carcinogen elaiomycin, the
antifungal agents maniwamycin A and azoxybacilin, and the
nematocidal compounds jietacins A and B, among others
(Figure 3). The increasing interest in this class of bioactive
compounds, however, contrasts with the lack of available
reactions for the direct introduction of azoxy groups. In this
context, oxidation of diazenes is a reasonably straightforward
methodology, although the control of regioselectivity usually
appears as an issue to overcome.18 Previous studies performed
in our laboratories,10c,d however, revealed that the N-
oxidationtakes place selectively at the most hindered tert-
butyl substituted nitrogen atom in similar derivatives.
Therefore, we decided to explore the use of different oxidizing
reagents for the regioselective N-oxidation of compounds 3
leading to azoxy compunds 4 (Table 4). Azomethyl alcohol 3a
toluene/CH2Cl2 mixture (full conversion in 4 hours) or
DOI: 10.1039/C7OB00308K
N
CO2H
N
N
NH2
Azoxybacilin
Elaiomicyn
O
N
N
N
O
OH
N
CO2H
O
Valanimycin hydrate
Maniwamycin A
HO
O
HO
O
N
N
HO
OH
O
Cycasin
Figure 3. Bioactive molecules containing an azoxy moiety.
magnesium
monoperoxyphthalate
(MMPP)
in
a
toluene/MeOH mixture (full conversion in 1 hour). It was
found out that elimination of toluene after the addition step
facilitates the isolation of product 4a in excellent yield (98%
Table 4. One-pot synthesis of azoxymethyl alcohols 4.a
tBu
N
tBu
N
tBu
NH
O
N
O
N
Cat.
MMPP
MeOH
N
+
HO
R
HO
R
Toluene
T
R
CO2Et
H
H
COOEt
tBu
COOEt
2
1
3
4
tBu
tBu
N
tBu
N
tBu
tBu
N
N
N
N
N
N
N
O
N
N
O
O
O
N
O
O
HO
HO
(S)-4f
N
HO
HO
HO
HO
COOEt
(S)-4d
COOEt
COOEt
(S)-4a
COOEt
(S)-4c
Me
COOEt
COOEt
tBu
(S)-4b
(S)-4e
tBu
N
tBu
N
tBu
N
tBu
N
N
N
O
N
N
O
O
N
O
O
HO
HO
HO
HO
HO
COOEt
COOEt
COOEt
COOEt
COOEt
(R)-4l
Cl
S
NC
F
F
(R)-4h
(R)-4i
T (°C)
(R)-4k
(R)-4j
Cl
Entry
1
2
3
4
2
Cat.
X
X
X
X
t (h)b
4
Yield (%)c
98
ee (%)d
57
61
49
63
58
64
89
88
86
90
85
2a
2b
2c
2d
2e
2f
2g
2h
2i
−15
−15
−15
−15
−45
−15
−30
−45
−45
−45
−30
43
43
43
43
24
43
48
7
(S)-4a
(S)-4b
(S)-4c
(S)-4d
(S)-4e
(S)-4f
(R)-4h
(R)-4i
(R)-4j
(R)-4k
(R)-4l
77
78
84
88
77
80
90
83
5
X
X
6
7e
8f
III
III
III
III
III
9
10
11
9
6
72
2j
2k
82
79
aReactions performed employing 2 (0.6 mmol), 1 (1.2 mmol) and Cat. (10 mol%) at the temperature and for the time indicated. bReaction time of the first step.
cIsolated yield. dDetermined by chiral HPLC.
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Table 5. Synthesis of α-hydroxy-β-amino esters 5.a
overall, 2-steps), with total regioselectivity and without
racemization. Performing the addition with catalyst X in
toluene at –15/–45 °C, followed by the optimized oxidation
protocol, alkyl-substituted azoxymethyl alcohols (S)-4a-f were
synthesized in good overall yields (77-98% over 2-steps) and
moderate enantioselectivities (50-64% ee), consistent with
those measured in their parent azomethyl alcohols 3 (entries
1-6). In the aromatic series, (R)-BINAM bis-urea III was used at
lower temperatures (–30/–45 °C) for the first step to yield aryl-
/heteroaryl-substituted azoxymethyl alcohols (R)-4g-k with
several substitution patterns (entries 7-11) in high yields (79-
90%) and enantioselectivities (85-90% ee).
View Article Online
DOI: 10.1039/C7OB00308K
Entry
2
Cat. T (°C) t (h)b
5
Yield (%)c
49
ee (%)d
61
1
2
3
4
5
6
7
8
9
2a
2c
2d
2e
2f
2h
2i
2j
2k
2l
X
X
X
X
X
III
III
III
III
III
−15
−15
−15
−45
−15
−30
−45
−45
−45
−30
43 (S)-5a
43 (S)-5c
43 (S)-5d
24 (S)-5e
40
50
45
41
51
46
46
44
55
61
51
62
90
90
84
93
43
(S)-5f
48 (R)-5h
7
9
6
(R)-5i
(R)-5j
(R)-5k
(R)-5l
10
72
41
84
aReactions performed employing 2 (0.6 mmol), 1 (1.2 mmol) and Cat. (10 mol%)
at the temperature and for the time indicated. bReaction time of the first step.
cIsolated yield. dDetermined by chiral HPLC.
Synthesis of α-hydroxy-β-amino esters 5
Azomethyl alcohols 3 proved to be also suitable precursors for
quaternary α-hydroxy-β-amino acids (isoserines). The required
transformation of the N-tert-butyldiazenylmethylene group of
3 into the aminomethyl group in 5 was accomplished via a
CH2Cl2,‡ afforded (S)-5a in a satisfactory overall yield (49%, 4
steps) and enantioselectivity consistent with the azomethyl
alcohol precursor (S)-3a (entry 1, Table 5).
Employing organocatalysts X or III for the asymmetric
functionalization of alkyl- or aryl-substituted α-keto esters
followed by the above discussed protocol in a pseudo one pot
fashion, gave the targeted α-hydroxy-β-amino esters 5 in
satisfactory overall yields (41-51%) and moderate to good
enantiomeric excesses (Table 5).
one-pot
tautomerization/hydrolysis/reductive
amination
sequence, as depicted in Scheme 4. Treatment of
enantiomerically enriched diazene (S)-3a, with HCl in a
biphasic H2O/Et2O medium, followed by simple L–L extractions
afforded crude α-hydroxy aldehyde (S)-12a with a high degree
of purity. Subsequent reductive amination using p-anisidine
(PMPNH2) and sodium cyanoborohydride (NaCNBH3) in
tBu
Conclusions
NHPMP
NH
O
"One pot"
HO
R
N
In summary, readily available per-acetylated β-D-glucosamine
thiourea X appears as a competent organocatalyst for the
asymmetric nucleophilic addition of formaldehyde tert-butyl
hydrazone 1 to α-keto esters 2. Compared to previously
established BINAM bis-urea III catalysts, these new family of
bifunctional thioureas shows a fair catalytic activity and a
complementary scope, enabling the obtention of aliphatic
tertiary azomethyl alcohols 3 with high yields and moderate
enantioselectivities. Both aromatic- and aliphatic-substituted
products 3 have been employed as key precursors for the
synthesis of biologically relevant azoxy compounds 4 and α-
hydroxy-β-amino esters 5.
+
R
CO2Et
CO2Et
H
H
5
1
2
Toluene, T
Cat.
PMPNH2, NaCNBH3
tBu
tBu
N
O
N
NH
HO
R
N
HCl (aq)/Et2O
HO
R
HO
R
CO2Et
12
CO2Et
CO2Et
11
3
NHPMP
NHPMP
HO
NHPMP
CO2Et
NHPMP
HO
HO
HO
Ph
Experimental
CO2Et
CO2Et
CO2Et
Spectra were recorded at [1H NMR (300, 400 or 500 MHz); 13C NMR
(75, 100 or 125 MHz); 19F NMR (470.6 MHz)] with the solvent peak
(S)-5c
(S)-5e
(S)-5a
(S)-5d
NHPMP
CO2Et
1
used as the internal reference (7.26 and 77.0 ppm for H and 13C
NHPMP
NHPMP
HO
HO
Ph
HO
respectively). Column chromatography was performed on silica gel
(Merck Kieselgel 60). Analytical TLC was performed on aluminium
backed plates (1.5 × 5 cm) pre-coated (0.25 mm) with silica gel
(Merck, Silica Gel 60 F254). Compounds were visualized by
exposure to UV light or by dipping the plates in solutions of KMnO4,
vainilline or phosphomolibdic acid stains followed by heating.
Melting points were recorded in a metal block and are uncorrected.
Unless otherwise noted, analytical grade solvents and commercially
available reagents were used without further purification.
Formaldehyde tert-butyl hydrazone 1,20 organocatalysts II-IV21 and
CO2Et
(R)-5h
Ph
CO2Et
NHPMP
CO2Et
NC
(S)-5f
HO
(R)-5i
NHPMP
NHPMP
CO2Et
HO
HO
CO2Et
Cl
S
F
F
Cl
(R)-5l
(R)-5j
(R)-5k
Scheme 4. Synthesis of α-hydroxy-β-amino esters 5.
6 | J. Name., 2012, 00, 1-3
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not commercially available α-keto esters 222 were synthesized 9a: White solid (8.9 g, 61%), M.P. = 202-204 °C. 1H NVMieRw A(5rti0c0le OMnHlinze,
DOI: 10.1039/C7OB00308K
according to literature procedures.
CD3OD) δ 8.18 (dd, J = 8.1, 1.0 Hz, 2H), 7.98 (td, J = 8.3, 1.4 Hz, 4H),
7.85 (dd, J = 7.9, 1.0 Hz, 2H), 7.71 (t, J = 10.0 Hz, 1H), 7.60-7.52 (m,
6H), 7.42 (td, J = 8.0, 2.1 Hz, 4H), 7.36 (t, J = 8.2 Hz, 2H), 6.38 (d, J =
Synthesis of saccharide-based organocatalysts
VIII: 3,5-Bis(trifluoromethyl)phenyl isothiocyanate (151 µL, 0.8 10.0 Hz, 1H), 5.93 (t, J = 10.0 Hz, 1H), 5.80 (t, J = 10.0 Hz, 1H), 4.65-
mmol) was added to a solution of 2,3,4,6-tetra-O-acetyl-β-D- 4.64 (m, 1H), 4.49-4.40 (m, 2H), 4.17 (dd, J = 10.2, 8.9 Hz, 1H). 13C
glucopyranosylamine23 (256 mg, 0.7 mmol) in CH2Cl2 (10 mL). The NMR (125 MHz, CDCl3) δ 167.6, 167.4, 166.7, 165.7, 135.5, 135.0,
reaction mixture was stirred for 20 h at rt and the solvent was 134.9, 134.5, 131.4, 131.0, 130.7, 129.9, 129.6, 129.6, 129.5, 92.8,
removed in vacuo. Flash chromatography (Et2O/n-hexane/CH2Cl2 74.2, 73.2, 70.4, 63.6, 54.8. HRMS: m/z calculated for
5:1:1) afforded VIII (243 mg, 56%) as a white solid. M.P. = 68-70 °C. [C34H30NO9Cl]+: 596.6100; found: 596.6110.
1H NMR (500 MHz, CDCl3) δ 8.62 (s, 1H), 7.94 (s, 2H), 7.61 (s, 1H),
10a: White solid (6.9 g, 54%), M.P. = 205-207 °C. 1H NMR (500 MHz,
7.03 (d, J = 10.0 Hz, 1H), 5.73 (t, J = 5.0 Hz, 1H), 5.38 (t, J = 10.0 Hz,
CD3OD) δ 5.93 (d, J = 10.0 Hz, 1H), 5.45 (t, J = 10.0 Hz, 1H), 5.18 (t, J
= 10.0 Hz, 1H), 4.14 (d, J = 5.0 Hz, 2H), 4.08-4.04 (m, 1H), 3.69 (t, J =
5.0 Hz, 1H), 1.27 (s, 9H), 1.22 (s, 9H), 1.19 (s, 9H), 1.18 (s, 9H). 13C
NMR (125 MHz, CD3OD) δ 179.3, 178.8, 177.9, 177.4, 92.0, 74.0,
72.7, 69.3, 62.5, 54.4, 40.1, 40.0, 39.9, 39.8, 27.5, 27.4, 27.2. HRMS:
m/z calculated for [C26H46NO9Cl]+: 516.6525; found: 516.6529.
1H), 5.21 (t, J = 10.0 Hz, 1H), 5.09 (t, J = 10.0 Hz, 1H), 4.71 (dd, J =
10.0, 5.0 Hz, 1H), 3.99 (d, J = 10.0 Hz, 1H), 3.93-3.89 (m, 1H), 2.09 (s,
3H), 2.06 (s, 6H), 2.03 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 182.4,
172.3, 171.1, 170.2, 169.5, 139.1, 131.6 (q, J = 34.0 Hz), 124.3 (q, J =
262.0 Hz), 124.2, 119.0 (t, J = 2.5 Hz), 82.8, 75.5, 73.7, 70.9, 68.7,
62.5, 21.1, 20.7, 20.6, 20.5. HRMS: m/z calculated for
20
[C23H24F6N2O9SNa]+: 641.0999; found: 641.1002. [α]D = +22.6 (c
General procedure for the synthesis of hexosamine-derived
(thio)ureas IX-XIII
1.0, CHCl3).
General procedure for the synthesis of hexosamine-derived amine
hydrochlorides 8-10
Et3N (0.7 mL, 5.3 mmol) and 3,5-bis(trifluoromethyl)phenyl
isocyanate or isothiocyanate (2.4 mmol) were sequentially added to
a solution of amine hydrochloride 8-10 (2.2 mmol) in CH2Cl2 (10 mL)
at room temperature. Reaction mixture was stirred for 24 h. Solvent
was removed in vacuo and the obtained solid was purified by flash
chromatography (Et2O/n-hexane/CH2Cl2 5:1:1) to afford the desired
(thio)urea.
p-Anisaldehyde (2.8 mL, 36.6 mmol) was added to a solution of D-
hexosamine hydrochloride 6a,b (5 g, 23.2 mmol) in NaOH aq. (1M,
25 mL) at 0 °C. The mixture was stirred for 3̴ h until a crystalline
solid was formed, which was then filtered and washed with cold
H2O (2x50 mL), EtOH (50 mL) and Et2O (50 mL). The crude imine
intermediates were directly subjected to O-acylation reactions to
afford per-O-acylated imines 7. O-acetylation: Acetic anhydride
(16.8 mL, 118 mmol) was added to a solution of the crude imine
(5.9 g, 19.8 mmol) in pyridine (17.6 mL, 218 mmol) at 0 °C. The
1
IX: White solid (981 mg, 74%), M.P. = 194-196 °C. H NMR (400
MHz, CDCl3) δ 7.82 (s, 2H), 7.50 (s, 2H), 5.87 (d, J = 8.6 Hz, 1H), 5.42
(d, J = 8.6 Hz, 1H), 5.31 (t, J = 9.8 Hz, 1H), 5.16 (t, J = 9.8 Hz, 1H),
4.30 (dd, J = 12.5, 4.0 Hz, 1H), 4.19-4.15 (m, 2H), 3.97-3.93 (m, 1H),
2.15 (s, 3H), 2.10 (s, 3H), 2.08 (s, 3H), 2.06 (s, 3H). 13C NMR (100
MHz, CDCl3) δ 171.8, 170.8, 169.8, 169.4, 153.9, 140.1, 132.2 (q, J =
33.1 Hz), 120.9 (q, J = 271.2 Hz), 118.6, 116.3, 92.8, 72.7, 72.6, 68.0,
61.7, 54.2, 20.9, 20.7, 20.6, 20.5. HRMS: m/z calculated for
[C23H24F6N2O10Na]+: 625.4310; found: 625.4320. [α]D20 = +9.2 (c 1.0,
CHCl3).
reaction mixture was allowed to reach rt and stirred for ̴24 h. An
ice-H2O (50 mL) mixture was added and the resulting solid was
filtered, washed with cold H2O (2 × 30 mL) and recrystallized from
EtOH. O-benzoylation: Et3N (30.4 mL, 217.8 mmol) and benzoyl
chloride (20.7 mL, 178.2 mmol) were added to a solution of the
crude imine (5.9 g, 19.8 mmol) in CH2Cl2 (150 mL) at 0 °C. The
reaction mixture was allowed to warm to rt, stirred for
̴24 h,
washed with NaHCO3 (4 × 30 mL) and concentrated to dryness. O-
pivaloylation: Et3N (30.4 mL, 217.8 mmol) and pivaloyl chloride
(26.8 mL, 218 mmol) were added to a solution of the crude imine
(5.9 g, 19.8 mmol) in CH2Cl2 (150 mL) at 60 °C. The reaction mixture
1
X: White solid (1.1 g, 84%), M.P. = 64-66 °C. H NMR (500 MHz,
CDCl3) δ 8.40 (s, 1H), 7.91 (s, 2H), 7.69 (s, 1H), 6.32 (br s, 1H), 5.81
(d, J = 8.5 Hz, 1H), 5.26-5.22 (m, 2H), 5.12 (br s, 1H), 4.28 (dd, J =
12.5, 4.5 Hz, 1H), 4.16 (dd, J = 12.5, 2.5 Hz, 1H), 3.89-3.86 (m, 1H),
2.15 (s, 3H), 2.10 (s, 3H), 2.07 (s, 3H), 2.04 (s, 3H). 13C NMR (125
MHz, CDCl3) δ 182.1, 171.8, 170.8, 169.7, 169.4, 139.2, 132.5 (q, J =
33.3 Hz), 124.1 (q, J = 271.3 Hz), 122.9, 119.4, 92.9, 72.9, 72.8, 67.8,
61.7, 57.7, 20.9, 20.7, 20.7, 20.5. HRMS: m/z calculated for
[C23H24F6N2O9SNa]+: 641.1004; found: 641.1015. [α]D20 = −1.6 (c 1.0,
CHCl3).
was stirred for
̴24 h, washed with NaHCO3 (4 × 30 mL) and
concentrated to dryness.
Imine hydrolysis: HCl (5M, 5 mL) was added to a solution of per-
acylated imine 7 (17.8 mmol) in acetone (40 mL) at 0 °C. The
reaction was stirred for 2 h, concentrated to dryness and the
resulting residue was washed with cold Et2O (2x50 mL) to afford O-
acyl amine hydrochlorides 8-10.
XI: White solid (966 mg, 71%), M.P. = 68-70 °C. 1H NMR (500 MHz,
CDCl3) δ 8.34 (s, 1H), 7.91 (s, 2H), 7.68 (s, 1H), 6.52 (br s, 1H), 5.83
(d, J = 8.1 Hz, 1H), 5.42 (s, 1H), 5.22 (d, J = 9.0 Hz, 1H), 5.08 (br s,
1H), 4.20-4.15 (m, 3H), 2.21 (s, 3H), 2.16 (s, 3H), 2.05 (s, 3H), 2.03 (s,
3H). 13C NMR (125 MHz, CDCl3) δ 182.5, 171.4, 170.9, 170.6, 169.9,
139.2, 132.7 (q, J = 34.0 Hz), 124.1 (q, J = 244.0 Hz), 123.9, 119.5,
8a: White solid (6.4 g, 72%). Characterization data is in agreement
with a literature report.24
8b: White solid (5.7 g, 64%). Characterization data is in agreement
with a literature report.25
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93.5, 72.2, 71.0, 66.6, 61.6, 55.0, 21.1, 20.9, 20.8, 20.8. HRMS: m/z He as mobile phase, τmajor = 17.3 min, τminor = 17.1 min, (62% ee)];
View Article Online
DOI: 10.1039/C7OB00308K
[α]D20 = –5.8 (c 1.0, CH2Cl2).
calculated for [C23H24F6N2O9SNa]+: 641.0999; found: 641.0989.
[α]D20 = +19.8 (c 1.0, CHCl3).
Ethyl (S,E)-2-[(tert-butyldiazenyl)methyl]-2-hydroxypentanoate [(S)-
3c]: Yelow oil (124 mg, 85%); 1H NMR (300 MHz, CDCl3) δ 4.25-4.15
(m, 2H), 4.10 (d, J = 13.0 Hz, 1H), 3.78 (d, J = 13.0 Hz, 1H), 3.39 (s,
1H), 1.84-1.46 (m, 4H), 1.25 (t, J = 7.0 Hz, 3H), 1.13 (s, 9H), 0.90 (t, J
= 7.0 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 175.0, 76.6, 75.0, 67.7,
61.6, 39.4, 26.7, 16.4, 14.2, 14.1. HRMS: m/z calculated for
[C12H25N2O3]+: 245.1860; found: 245.1862. The enantiomeric excess
was determined by HPLC using a Chiralpak AD-H column [hexane/i-
PrOH (98:2)]; flow rate 1 mL/min; τmajor = 6.7 min, τminor = 5.6 min
(45% ee); [α]D20 = +23.0 (c 0.6, CHCl3).
XII: White solid (1.6 g, 84%), M.P. = 75-77 °C. 1H NMR (400 MHz,
CDCl3) δ 8.17 (d, J = 8.0 Hz, 2H), 8.09 (br s, 1H), 8.01 (d, J = 8.0 Hz,
2H), 7.91 (d, J = 8.0 Hz, 2H), 7.84 (d, J = 8.0 Hz, 2H), 7.58-7.50 (m,
6H), 7.43-7.32 (m, 8H), 7.22-7.10 (m, 1H), 6.89 (d, J = 7.1 Hz, 1H),
6.35 (d, J = 8.0 Hz, 1H), 5.87-5.78 (m, 2H), 5.67 (br s, 1H), 4.71 (d, J =
8.0 Hz, 1H), 4.60-4.40 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 182.3,
167.9, 166.4, 165.6, 165.5, 139.2, 134.3, 133.8, 133.4, 132.3 (q, J =
26.7 Hz), 130.7, 130.2, 130.0, 129.8, 129.6, 128.8, 128.8, 128.6,
128.6, 128.3, 124.7, 123.0 (q, J = 272.1 Hz), 119.2, 93.9, 73.8, 73.3,
69.7, 63.1, 58.1. HRMS: m/z calculated for [C43H32F6N2O9SNa]+:
889.1625; found: 889.1611. [α]D20 = –28.5 (c 0.5, CHCl3).
XIII: White solid (1.6 g, 95%), M.P. = 80-82 °C. 1H NMR (300 MHz,
CDCl3) δ 8.27 (br s, 1H), 7.79 (s, 2H), 7.72 (s, 1H), 6.4 (br s, 1H), 5.73
(d, J = 8.4 Hz, 1H), 5.27 (d, J = 9.1 Hz, 2H), 4.17 (d, J = 3.0 Hz, 2H),
3.89-3.86 (m, 1H), 2.04 (s, 1H), 1.22 (s, 9H), 1.22 (s, 9H), 1.17 (s, 9H),
1.15 (s, 9H). 13C NMR (75 MHz, CDCl3) δ 182.1, 180.1, 178.3, 176.5,
139.1, 133.3 (q, J = 33.0 Hz), 124.9, 122.8 (q, J = 271.0 Hz), 120.0,
93.2, 73.5, 72.7, 67.4, 61.8, 57.3, 39.3, 39.1, 39.1, 39.0, 27.3, 27.2,
27.2, 27.0. HRMS: m/z calculated for [C35H48F6N2O9SNa]+: 809.2877;
found: 809.2866. [α]D20 = +13.6 (c 1.0, CHCl3).
Ethyl (S,E)-2-[(tert-butyldiazenyl)methyl]-2-hydroxyoctanoate [(S)-
3d]: Yelow oil (155 mg, 90%); 1H NMR (400 MHz, CDCl3) δ 4.23 (q, J
= 7.2 Hz, 2H), 4.13 (d, J = 13.2 Hz, 1H), 3.80 (d, J = 13.2 Hz, 1H), 3.39
(s, 1H), 1.86-1.71 (m, 2H), 1.56-1.49 (m, 2H), 1.30-1.26 (m, 6H), 1.28
(t, J = 6.8 Hz, 3H), 1.16 (s, 9H), 0.87 (t, J = 6.4 Hz, 3H). 13C NMR (100
MHz, CDCl3) δ 175.3, 77.4, 75.3, 68.0, 61.9, 37.4, 31.8, 29.5, 26.9,
23.1, 22.7, 14.4, 14.2. HRMS: m/z calculated for [C15H30N2O3Na]+:
309.2149; found: 309.2142. The enantiomeric excess was
determined by HPLC of its corresponding azoxymethyl alcohol (S)-
4d; [α]D20 = +5.9 (c 1.0, CHCl3, 63% ee).
Ethyl
(S,E)-2-benzyl-3-(tert-butyldiazenyl)-2-hydroxypropanoate
[(S)-3e]: Yellow oil (154 mg, 88%): 1H NMR (300 MHz, CDCl3) δ 7.23-
7.13 (m, 5H), 4.21 (d, J = 13.2 Hz, 1H), 4.10 (qd, J = 7.1, 2.9 Hz, 2H),
3.77 (d, J = 13.2 Hz, 1H), 3.09 (d, J = 13.5 Hz, 1H), 3.01 (d, J = 13.5
Hz, 1H), 1.18 (t, J = 7.1 Hz, 3H), 1.09 (s, 9H). 13C NMR (75 MHz,
CDCl3) δ 174.2, 135.2, 130.4, 128.1, 127.0, 77.1, 74.6, 68.0, 61.9,
43.4, 26.8, 14.2. HRMS: m/z calculated for [C16H25O3N2]+: 293.1860;
found: 293.1851. The enantiomeric excess was determined by HPLC
General procedure for the catalytic enantioselective reactions of
tert-butyl hydrazone 1 with α-keto esters 2.
Formaldehyde tert-butyl hydrazone 1 (134 μL, 1.2 mmol) was added
to a solution of α-keto ester 2 (0.6 mmol) and catalyst X or III (0.06
mmol) in toluene (0.6 mL) at the specified temperature (Tables 3-5).
The mixture was stirred for the time specified (TLC monitoring).
Solvent was removed in vacuo. Flash chromatography
(Toluene/EtOAc) afforded the corresponding azomethyl alcohols 3.
using a Chiralpak OJ-H column [hexane:iPrOH (98:2)]; flow rate 1
27
mL/min; 30 °C, τmajor = 6.5 min, τminor = 7.2 min (56% ee); [α]D
−4.83 (c 0.4, CHCl3).
=
Ethyl
(S,E)-2-[(tert-butyldiazenyl)methyl]-2-hydroxy-3-methyl
1
Ethyl
(S,E)-2-[(tert-butyldiazenyl)methyl]-2-hydroxy-4-phenyl
butanoate [(S)-3a]: Yelow oil (144 mg, 98%); H NMR (400 MHz,
CDCl3) δ 4.23 (q, J = 6.8 Hz, 2H), 4.11 (d, J = 12.8 Hz, 1H), 3.85 (d, J =
12.8 Hz, 1H), 3.29 (s, 1H), 2.18-2.11 (m, 1H), 1.28 (t, J = 6.8 Hz, 3H),
1.15 (s, 9 H), 1.02 (d, J = 6.8 Hz, 3H,), 0.91 (d, J = 6.8 Hz, 3H). 13C
NMR (100 MHz, CDCl3) δ 175.2, 78.8, 73.7, 67.7, 61.7, 34.0, 26.6,
17.0, 16.1, 14.1. HRMS: m/z calculated for [C12H24N2O3]+: 244.3314;
found: 244.3318. The enantiomeric excess was determined by GC
[Chrompack CP7500, cyclodextrin-β, 225 m x 0.25 mm x 0.25 μm,
He as mobile phase, τmajor = 14.3 min, τminor = 13.8 min, (58% ee)];
[α]D20 = +17.8 (c 0.8, CH2Cl2).
butanoate [(S)-3f]: Yelow oil (158 mg, 86%); 1H NMR (400 MHz,
CDCl3) δ 7.28 (m, 3H), 7.19 (d, J = 7.2 Hz, 2H), 4.23 (q, J = 7.2 Hz,
2H), 4.17 (d, J = 13.2 Hz, 1H), 4.01 (br s, 1H), 3.80 (d, J = 13.2 Hz,
1H), 2.94-2.85 (m, 1H), 2.62-2.51 (m, 1H), 2.22-2.08 (m, 2H), 1.29 (t,
J = 7.2 Hz, 3H), 1.17 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 175.0,
141.4, 128.6, 128.4, 76.4, 75.1, 68.0, 61.9, 39.0, 29.5, 26.8, 14.3.
HRMS: m/z calculated for [C17H26N2O3Na]+: 329.1836; found:
329.1829. The enantiomeric excess was determined by HPLC of its
20
corresponding azoxymethyl alcohol (S)-4f; [α]D = +4.7 (c 1.0,
CHCl3, 64% ee).
Ethyl
(R,E)-2-[(tert-butyldiazenyl)methyl]-2-hydroxy-3-methyl
20
butanoate [(R)-3a]: Yelow oil (109 mg, 74%). [α]D = +21.1 (c 1.0,
CH2Cl2, 72% ee).
Ethyl
(S,E)-2-[(tert-butyldiazenyl)methyl]-2-hydroxy-3,3-dimethyl
butanoate [(S)-3g]: Yelow oil (31 mg, 20%); 1H NMR (400 MHz,
Ethyl
(S,E)-3-(tert-butyldiazenyl)-2-hydroxy-2-methylpropanoate CDCl3) δ 4.32 (d, J = 13.2 Hz, 1H), 4.31-4.22 (m, 2H), 3.77 (d, J = 13.1
[(S)-3b]: Yelow oil (110 mg, 85%); 1H NMR (400 MHz, CDCl3) δ 4.25- Hz, 1H), 3.46 (s, 1H), 1.30 (t, J = 7.2 Hz, 3H), 1.14 (s, 9H), 1.06 (s, 9H).
4.19 (m, 2H), 4.17 (d, J = 13.2 Hz, 1H), 3.83 (d, J = 13.2 Hz, 1H), 3.46 13C NMR (100 MHz, CDCl3) δ 175.1, 81.0, 70.9, 67.8, 61.7, 37.2, 26.8,
(s, 1H), 1.52 (s, 3 H), 1.28 (t, J = 7.2 Hz, 3H), 1.17 (s, 9 H). 13C NMR 25.7, 14.3. HRMS: m/z calculated for [C13H27N2O3]+: 259.2016;
(100 MHz, CDCl3) δ 175.3, 77.1, 75.2, 73.8, 61.7, 26.6, 23.9, 14.1. found: 259.2010. The enantiomeric excess was determined by HPLC
HRMS: m/z calculated for [C10H20N2O3]+: 216.1474; found: of its corresponding azoxymethyl alcohol (S)-4g using a Chiralpak
216.1468. The enantiomeric excess was determined by GC AD-H column [hexane/i-PrOH (80:20)]; flow rate 1 mL/min; τmajor
=
[Chrompack CP7500, cyclodextrin-β, 225 m x 0.25 mm x 0.25 μm, 4.5 min, τminor = 4.1 min (64% ee); [α]D20 = +2.9 (c 0.7, CHCl3).
8 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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ARTICLE
Chiralpak OJ-H column [hexane:iPrOH (98:2)]; flow rVaiteew A1rtimcleL/Omnliinne;
30 °C, τmajor = 13.6 min, τminor = 15.0 min (58% ee); [α]D
0.6, CHCl3).
General procedure for the synthesis of azoxymethyl alcohols 4.
27
DOI: 10.1039/C7=OB+010.53208(Kc
Following the general procedure for the catalytic enantioselective
reactions of hydrazone 1 (1.2 mmol) with α-keto esters 2 (0.6
mmol). After consumption of starting material, the solvent was [(S)-4f]: Yellow oil (150 mg, 77%). 1H NMR (400 MHz, CDCl3) δ 7.30-
removed in vacuo and the residue was dissolved in MeOH (2 mL), 7.21 (m, 3H), 7.15 (d, J = 6.8 Hz, 2H,), 4.14 (m, 2H), 3.65 (d, J = 18.0
cooled to 0 °C, and MMPP (1.48 g, 5 equiv.) was added. The Hz, 1H), 3.56 (d, J = 18.0 Hz, 1H), 3.54 (s, 1H), 2.84-2.80 (m, 1H),
reaction mixture was stirred until consumption of the azomethyl 2.54-2.45 (m, 1H), 2.11-2.03 (m, 2H), 1.48 (s, 9H), 1.22 (t, J = 6.8 Hz,
alcohol 3 (tlc monitoring, 2-3 h.), diluted with H2O (5 mL), extracted 3H). 13C NMR (100 MHz, CDCl3) δ 174.9, 141.4, 128.4, 126.0, 76.8,
with CH2Cl2 (3 × 10 mL), dried over Na2SO4 and concentrated in 76.0, 61.9, 60.1, 38.6, 29.6, 28.2, 14.3. HRMS: m/z calculated for
vacuo. The resulting residue was purified by flash chromatography [C17H26N2O4Na]+: 345.1785; found: 345.1780. The enantiomeric
(Toluene/EtOAc) to afford azoxymethyl alcohol 4.
excess was determined by HPLC using a Chiralpak AD-H column
[hexane/i-PrOH (80:20)]; flow rate 1 mL/min; τmajor = 6.1 min, τminor
= 5.6 min (64% ee); [α]D20 = +21.9 (c 1.0, CHCl3).
[(S)-4a]: Yellow oil (154 mg, 98%). 1H NMR (400 MHz, CDCl3) δ 4.22-
4.20 (m, 2H), 3.63 (d, J = 17.0 Hz, 1H), 3.59 (d, J = 17.0 Hz, 1H), 3.36
(s, 1H), 2.10-2.07 (m, 1H), 1.49 (s, 9H), 1.24 (t, J = 6.8 Hz, 3H), 1.00 [(R)-4h]: White solid (141 mg, 80%); M.P.: 100-102 °C. 1H NMR (400
(d, J = 6.8 Hz, 3H), 0.88 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3) MHz, CDCl3) δ 7.64 (d, J = 7.2 Hz, 2H), 7.44-7.26 (m, 3H), 4.31-4.17
δ 175.5, 78.6, 76.6, 61.7, 58.8, 33.8, 28.2, 17.2, 16.1, 14.3. HRMS: (m, 2H), 4.16 (d, J = 17.6 Hz, 1H), 3.98 (s, 1H), 3.81 (d, J = 17.6 Hz,
m/z calculated for [C12H24N2O4Na]+: 283.1628; found: 283.1623. The 1H), 1.53 (s, 9H), 1.25 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ
enantiomeric excess was determined by HPLC using a Chiralpak AD- 173.8, 139.4, 128.3, 128.2, 125.7, 77.2, 76.8, 62.4, 60.6, 28.2, 14.2.
H column [hexane/i-PrOH (98:2)]; flow rate 1 mL/min; τmajor = 10.4 HRMS: m/z calculated for [C15H22N2O4Na]+: 317.1472; found:
min, τminor = 9.9 min (57% ee); [α]D20 = +7.5 (c 1.0, CHCl3).
317.1468. The enantiomeric excess was determined by HPLC using a
[(S)-4b]: White solid (108 mg, 77%), M.P.: 97-99 °C. 1H NMR (500
Chiralpak AD-H column [hexane/i-PrOH (80:20)]; flow rate 1
20
mL/min; τmajor = 6.6 min, τminor = 7.6 min (89% ee); [α]D = +8.3 (c
1.0, CHCl3).
MHz, CDCl3) δ 4.24-4.13 (m, 2H), 3.64 (d, J = 15.0 Hz, 1H,), 3.49 (d, J
= 15.0 Hz, 1H), 3.44 (s, 1H), 1.48 (s, 9H), 1.46 (s, 3H), 1.22 (t, J = 5.0
Hz, 3H).13C NMR (125 MHz, CDCl3) δ 175.3, 76.6, 73.3, 61.7, 60.5, [(R)-4i]: Yellow oil (174 mg, 90%). 1H NMR (400 MHz, CDCl3) δ 7.78
28.1, 23.7, 14.1. HRMS: m/z calculated for [C10H21N2O4Na]+: (d, J = 8.0 Hz, 2H), 7.64 (d, J = 8.0 Hz, 2H), 4.29-4.16 (m, 2H), 4.12 (s,
255.1315; found: 255.1311. The enantiomeric excess was 1H), 4.08 (d, J = 18.0 Hz, 1H), 3.75 (d, J = 18.0 Hz, 1H), 1.49 (s, 9H),
determined by HPLC using a Chiralpak OJ column [hexane/i-PrOH 1.23 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 172.7, 144.6,
(98:2)]; flow rate 1 mL/min; τmajor = 11.5 min, τminor = 13.5 min (61% 132.1, 126.8, 118.5, 112.2, 77.1, 76.8, 63.0, 60.5, 28.2, 14.2. HRMS:
ee); [α]D20 = –3.5 (c 0.5, CHCl3).
m/z calculated for [C16H21N3O4Na]+: 342.1424; found: 342.1419. The
enantiomeric excess was determined by HPLC using a Chiralpak AD-
H column [hexane/i-PrOH (80:20)]; flow rate 1 mL/min; τmajor = 10.6
min, τminor = 11.6 min (88% ee); [α]D20 = +13.6 (c 1.3, CHCl3).
[(S)-4c]: Yellow oil (122 mg, 78%). 1H NMR (300 MHz, CDCl3) δ 4.27-
4.15 (m, 2H), 3.72 (d, J = 17.0 Hz, 1H), 3.61 (d, J = 17.0 Hz, 1H), 3.43
(s, 1H), 1.79-1.72 (m, 2H), 1.60-1.53 (m, 2H), 1.50 (s, 9H), 1.25 (t, J =
7.0 Hz, 3H), 0.92 (t, J = 7.3 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ [(R)-4j]: White solid (181 mg, 83%); M.P.: 102-104 °C. 1H NMR (400
175.2, 76.3, 61.7, 60.1, 39.1, 28.2, 16.6, 14.3, 14.1. HRMS: m/z MHz, CDCl3) δ 7.80 (s, 1H), 7.51 (d, J = 8.5 Hz, 1H), 7.45 (d, J = 8.5
calculated for [C12H24N2O4Na]: 283.1628; found: 283.1622. The Hz, 1H), 4.39-4.16 (m, 2H), 4.09 (s, 1H), 4.09 (d, J = 17.9 Hz, 1H),
enantiomeric excess was determined by HPLC using a Chiralpak AD- 3.77 (d, J = 17.9 Hz, 1H), 1.54 (s, 9H), 1.28 (t, J = 7.1 Hz, 3H). 13C
H column [hexane/i-PrOH (98:2)]; flow rate 1 mL/min; τmajor = 15.1 NMR (100 MHz, CDCl3) δ 173.0, 139.6, 132.6, 132.5, 130.3, 128.2,
min, τminor = 12.0 min (49% ee); [α]D20 = +15.5 (c 0.5, CHCl3).
125.4, 76.8, 76.5, 62.9, 60.5, 28.2, 14.2. HRMS: m/z calculated for
[C15H20Cl2N2O4Na]+: 385.0692; found: 385.0689. The enantiomeric
excess was determined by HPLC using a Chiralpak AD-H column
[hexane/i-PrOH (80:20)]; flow rate 1 mL/min; τmajor = 5.6 min, τminor
= 6.3 min (86% ee); [α]D20 = +12.3 (c 1.0, CHCl3).
1
[(S)-4d]: Yellow oil (152 mg, 84%). 1H NMR (400 MHz, CDCl3) δ 4.23-
4.12 (m, 2H), 3.60 (d, J = 18.0 Hz, 1H), 3.49 (d, J = 18.0 Hz, 1H), 3.41
(s, 1H), 1.73-1.69 (m, 2H), 1.56-1.49 (m, 2H), 1.47 (s, 9H), 1.27-1.19
(m, 9H), 0.83 (t, J = 5.6 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 175.2,
76.6, 76.3, 61.7, 60.1, 36.9, 31.6, 29.3, 28.1, 23.1, 22.5, 13.9, 14.3. [(R)-4k]: Yellowish oil (162 mg, 82%): H NMR (300 MHz, CDCl3) δ
HRMS: m/z calculated for [C15H30N2O4Na]+: 325.2098; found: 7.51 (td, J = 8.7, 6.3 Hz, 1H), 688-6.78 (m, 1H), 6.74 (ddd, J = 11.3,
325.2091. The enantiomeric excess was determined by HPLC using a 8.7, 2.6 Hz, 1H), 4.25-4.08 (m, 2H), 4.11 (s, 1H), 4.09 (d, J = 17.8 Hz,
Chiralpak AD-H column [hexane/i-PrOH (80:20)]; flow rate 1 1H), 3.96 (d, J = 17.8 Hz, 1H), 1.45 (s, 9H), 1.15 (t, J = 7.1 Hz, 3H). 13
C
20
mL/min; τmajor = 5.0 min, τminor = 4.3 min (63% ee); [α]D = +6.2 (c NMR (75 MHz, CDCl3) δ 173.0, 162.9 (dd, J = 250.2, 12.3 Hz), 160.4
1.0, CHCl3).
(dd, J = 252.0, 11.9 Hz), 129.1 (dd, J = 9.8, 5.3 Hz), 123.4 (dd, J =
12.6, 3.9 Hz), 111.1 (dd, J = 21.0, 3.5 Hz), 104.6 (dd, J = 26.6, 25.6
1
[(S)-4e]: Yellowish oil (163 mg, 88%): H NMR (300 MHz, CDCl3) δ
7.34-7.21 (m, 5H), 4.33-4.07 (m, 2H), 3.80 (d, J = 18.0 Hz, 1H), 3.63
(d, J = 18.0 Hz, 1H), 3.14 (d, J = 17.3 Hz, 1H), 3.10 (d, J = 17.3 Hz, 1H),
1.53 (s, 9H), 1.25 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ
174.3, 135.2, 130.3, 128.2, 127.0, 76.8, 61.8, 59.7, 43.1, 28.2, 14.2.
HRMS: m/z calculated for [C16H24O4N2Na]+: 331.1628; found:
331.1621. The enantiomeric excess was determined by HPLC using a
Hz), 77.2, 74.9 (d, J = 2.0 Hz), 62.5, 58.3 (d, J = 3.6 Hz), 28.1, 14.0. 19
F
NMR (283 MHz, CDCl3) δ −107.49 (d, J = 8.7 Hz), −109.87 (d, J = 8.7
Hz). HRMS: m/z calculated for [C15H20O4N2F2Na]+: 353.1283; found:
353.1276. The enantiomeric excess was determined by HPLC using a
Chiralpak AD-H column [hexane:iPrOH (80:20)]; flow rate 1 mL/min;
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J. Name., 2013, 00, 1-3 | 9
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Organic & Biomolecular Chemistry
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Page 10 of 12
ARTICLE
Journal Name
30 °C, τmajor = 5.7 min, τminor = 6.7 min (90 % ee); [α]D27 = +2.5 (c 0.7, Ethyl (S)-2-hydroxy-2-{[(4-methoxyphenyl)amino]methyl} octanoate
View Article Online
1
[(S)-5d]: Yellowish oil (97 mg, 50%): H NDMORI: (1300.1003M9/HCz7,OCB0D0C3l03)8Kδ
6.73-6.64 (m, 2H), 6.61-6.54 (m, 2H), 4.20-3.99 (m, 2H), 3.67 (s, 3H),
3.43 (d, J = 12.3 Hz, 1H), 3.10 (d, J = 12.3 Hz, 1H), 1.74-1.55 (m, 2H),
1.49-1.33 (m, 1H), 1.27-1.13 (m, 9H), 1.12-0.94 (m, 1H) 0.80 (t, J =
6.7 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 175.7, 152.8, 141.8, 115.5,
114.7, 77.6, 62.2, 55.8, 52.9, 37.0, 31.6, 29.3, 23.1, 22.5, 14.2, 14.0.
HRMS: m/z calculated for [C18H30NO4]+: 324.2095; found: 324.2063.
The enantiomeric excess was determined by HPLC using a Chiralpak
AD-H column [hexane:iPrOH (80:20)]; flow rate 0.7 mL/min; 30 °C,
CHCl3).
1
[(R)-4l]: Yellowish oil (142 mg, 79%): H NMR (300 MHz, CDCl3) δ
7.20 (dd, J = 5.1, 1.2 Hz, 1H), 7.09 (dd, J = 3.6, 1.2 Hz, 1H), 6.92 (dd, J
= 5.1, 3.6 Hz, 1H), 4.30-4.09 (m, 2H), 4.18 (s, 1H), 4.02 (d, J = 18.0
Hz, 1H), 3.79 (d, J = 18.0 Hz, 1H), 1.46 (s, 9H), 1.20 (t, J = 7.1 Hz, 3H).
13C NMR (75 MHz, CDCl3) δ 172.9, 143.9, 127.1, 125.5, 124.7, 76.9,
76.1, 62.7, 61.4, 28.2, 14.2. HRMS: m/z calculated for
[C13H20O4N2NaS]+: 293.1860; found: 293.1851. The enantiomeric
excess was determined by HPLC using a Chiralpak AD-H column
[hexane:iPrOH (80:20)]; flow rate 1 mL/min; 30 °C, τmajor = 6.4 min,
τminor = 7.7 min (85% ee); [α]D27 = +3.8 (c 0.4, CHCl3).
27
τmajor = 10.9 min, τminor = 12.1 min (61% ee); [α]D = +7.4 (c 1.6,
CHCl3).
Ethyl
(S)-2-benzyl-2-hydroxy-3-[(4-methoxyphenyl)amino]
propanoate [(S)-5e]: Yellowish oil (89 mg, 45%): 1H NMR (300 MHz,
General procedure for the synthesis of α-hydroxy-β-amino esters
5
CDCl3) δ 7.36-7.22 (m, 5H), 6.84-6.77 (m, 2H), 6.70-6.64 (m, 2H),
Following the general procedure for the catalytic enantioselective 4.20-4.09 (m, 2H), 3.78 (s, 3H), 3.67 (d, J = 12.2 Hz, 1H), 3.48 (br s,
reactions of hydrazone 1 (1.2 mmol) with α-keto esters 2 (0.6 1H), 3.30 (d, J = 12.2 Hz, 1H), 3.13 (d, J = 13.6 Hz, 1H), 3.06 (d, J =
mmol). After consumption of starting material, the solvent was 13.6 Hz, 1H), 1.25 (t, J = 7.1 Hz, 3H).13C NMR (75 MHz, CDCl3) δ
removed in vacuo and the residue was dissolved in Et2O (5.5 mL), 174.6, 152.6, 142.2, 135.2, 130.1, 128.2, 127.1, 115.2, 114.8, 78.2,
cooled to 0 °C, and HCl (6 M, 2.5 mL) was added. The reaction 62.2, 55.8, 52.5, 43.1, 14.1. HRMS: m/z calculated for [C19H24O4N]+:
mixture was allowed to warm to rt, stirred for 2 h, and extracted 330.1700; found: 330.1691. The enantiomeric excess was
with Et2O (2 × 5 mL) and CH2Cl2 (2 × 5 mL). The combined organic determined by HPLC using a Chiralpak OJ-H column [hexane:iPrOH
layer was dried over Na2SO4 and concentrated in vacuo to afford α- (90:10)]; flow rate 1 mL/min; 30 °C, τmajor = 27.7 min, τminor = 29.9
min (51% ee); [α]D27 = +10.7 (c 1.5, CHCl3).
hydroxy aldehyde 12. p-Anisidine (121 mg, 0.9 mmol) and NaCNBH3
(88 mg, 1.4 mmol) were added to a solution of crude aldehyde in
Ethyl
(S)-2-hydroxy-2-{[(4-methoxyphenyl)amino]methyl}-4-
CH2Cl2 (3 mL) at room temperature. The reaction mixture was
stirred for 2-3 h, H2O was added and the mixture was extracted
with CH2Cl2 (3 × 5 mL). The combined organic layer was dried over
Na2SO4 and concentrated in vacuo. Flash chromatography
1
phenylbutanoate [(S)-5f]: Yellowish oil (84 mg, 41%): H NMR (400
MHz, CDCl3) δ 7.36-7.27 (m, 2H), 7.27-7.16 (m, 3H), 6.86-6.73 (m,
2H), 6.68-6.59 (m, 2H), 4.16 (qq, J = 10.7, 7.1 Hz, 2H), 3.77 (s, 3H),
3.71 (br s, 1H), 3.55 (d, J = 12.4 Hz, 1H), 3.24 (d, J = 12.3 Hz, 1H),
2.86 (ddd, J = 13.6, 10.9, 5.6 Hz, 1H), 2.50 (ddd, J = 13.6, 11.2, 5.8
Hz, 1H), 2.18-2.03 (m, 1H), 1.27 (t, J = 7.1 Hz, 1H). 13C NMR (100
MHz, CDCl3) δ 175.5, 152.6, 142.2, 141.3, 128.5, 128.4, 126.1, 115.2,
114.8, 77.4, 62.4, 55.8, 52.8, 38.6, 29.7, 14.2. HRMS: m/z calculated
for [C20H25NO4]+: 343.1856; found: 343.1847. The enantiomeric
excess was determined by HPLC using a Chiralpak AD-H column
[hexane:iPrOH (80:20)]; flow rate 1 mL/min; 30 °C, τmajor = 9.8 min,
τminor = 12.4 min (62% ee); [α]D23 = −6.3 (c 1.0, CHCl3).
(hexane/EtOAc)
afforded
the
corresponding
β-amino-α-
hydroxyester 5.
Ethyl
(S)-2-hydroxy-2-{[(4-methoxyphenyl)amino]methyl}-3-
methylbutanoate [(S)-5a]: Yellowish oil (83 mg, 49%):1H NMR (300
MHz, CDCl3) δ 6.73-6.63 (m, 2H), 6.60-6.48 (m, 2H), 4.22-3.98 (m,
2H), 3.66 (s, 3H), 3.44 (br s, 1H), 3.40 (d, J = 12.0 Hz, 1H), 3.18 (d, J =
12.0 Hz, 1H), 1.99 (hept, J = 6.8 Hz, 1H), 1.16 (t, J = 7.1 Hz, 3H), 0.92
(d, J = 6.8 Hz, 3H), 0.82 (d, J = 6.8 Hz, 3H). 13C NMR (75 MHz, CDCl3)
δ 175.9, 152.5, 142.5, 115.2, 114.7, 80.1, 62.1, 55.8, 50.7, 33.9,
17.3, 16.4, 14.6. HRMS: m/z calculated for [C15H24NO4]+: 282.1700;
found: 282.1693. The enantiomeric excess was determined by HPLC
Ethyl
(R)-2-hydroxy-3-[(4-methoxyphenyl)amino]-2-phenyl
propanoate [(R)-5h]: Yellowish oil (101 mg, 51%): 1H NMR (300
MHz, CDCl3) δ 7.67 (d, J = 7.6 Hz, 2H), 7.45-7.32 (m, 3H), 6.78 (d, J =
8.8 Hz, 2H), 6.68 (d, J = 8.8 Hz, 2H), 4.22 (q, J = 7.2 Hz, 2H), 4.19 (br
s, 1H)4.01 (d, J = 12.4 Hz, 1H), 3.75 (s, 3H), 3.39 (d, J = 12.4 Hz, 1H),
1.23 (t, J = 7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 174.2, 152.7,
142.2, 139.7, 128.5, 128.2, 125.5, 115.5, 114.8, 78.7, 62.8, 55.8,
53.4, 14.0. HRMS: m/z calculated for [C18H23NO4]+: 316.1543; found:
316.1540. The enantiomeric excess was determined by HPLC using a
Chiralpak AD-H column [hexane:iPrOH (80:20)]; flow rate 1 mL/min;
30 °C, τmajor = 16.2 min, τminor = 12.6 min (90% ee); [α]D20 = +11.7 (c
1.01, CHCl3).
using a Chiralpak AD-H column [hexane:iPrOH (80:20)]; flow rate 1
23
mL/min; 30 °C, τmajor = 7.7 min, τminor = 9.9 min (61% ee); [α]D
+4.5 (c 0.9, CHCl3).
=
Ethyl
(S)-2-hydroxy-2-{[(4-methoxyphenyl)amino]methyl}
1
pentanoate [(S)-5c]: Yellow oil (67 mg, 40%). H NMR (300 MHz,
CDCl3) δ 6.75 (d, J = 9.0 Hz, 2H), 6.61 (d, J = 9.0 Hz, 2H), 4.26-4.08
(m, 2H), 3.74 (s, 3H), 3.57 (br s, 1H), 3.49 (d, J = 12.3 Hz, 2H), 3.15
(d, J = 12.3 Hz, 2H), 1.76-1.65 (m, 2H), 1.57-1.41 (m, 1H), 1.24 (t, J =
14.3 Hz, 3H), 1.20-1.07 (m, 1H), 0.92 (t, J = 7.3 Hz, 3H). 13C NMR (75
MHz, CDCl3) δ 175.7, 152.6, 142.1, 115.3, 114.8, 77.6, 62.1, 55.8,
52.7, 39.1, 16.6, 14.2, 14.1. HRMS: m/z calculated for [C15H23NO4]+:
282.1635; found: 282.1630. The enantiomeric excess was
determined by HPLC using a Chiralpak AD-H column [hexane/i-PrOH
(80:20)]; flow rate 1 mL/min; τmajor = 8.8 min, τminor = 11.5 min (55%
ee); [α]D20 = –4.9 (c 0.5, CHCl3).
Ethyl
(R)-2-(4-cyanophenyl)-2-hydroxy-3-[(4-methoxyphenyl)
amino]propanoate [(R)-5i]: Yellowish oil (94 mg, 46%): 1H NMR (300
MHz, CDCl3) δ 7.73 (d, J = 8.6 Hz, 2H), 7.59 (d, J = 8.6 Hz, 2H), 6.72-
6.66 (m, 2H), 6.64-6.55 (m, 2H), 4.13 (q, J = 7.1 Hz, 2H), 3.87 (d, J =
12.6 Hz, 1H), 3.66 (s, 3H), 3.28 (d, J = 12.6 Hz, 1H), 1.16 (t, J = 7.1 Hz,
3H). 13C NMR (75 MHz, CDCl3) δ 172.1, 151.9, 143.7, 140.6, 131.2,
10 | J. Name., 2012, 00, 1-3
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125.5, 117.5, 114.6, 113.8, 111.2, 77.5, 62.3, 54.7, 52.6, 13.0. added to a solution of crude aldehyde in CH Cl (3 mL) at room
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2
2
HRMS: m/z calculated for [C19H22N2O4]+: 341.1496; found: temperature. The reaction mixture was stirred for 2-3 h. Flash
DOI: 10.1039/C7OB00308K
chromatography (CH2Cl2/MeOH 97:3) afforded the pure diols 13.
341.1496. The enantiomeric excess was determined by HPLC using a
Chiralpak IB column [hexane:iPrOH (90:10)]; flow rate 1 mL/min; 30
°C, τmajor = 15.9 min, τminor = 14.2 min (90% ee); [α]D23 = +11.3 (c 1.2,
CHCl3).
Ethyl (S)-2-hydroxy-2-(hydroxymethyl)pentanoate [(S)-13c]: yellow
25
oil (45 mg, 43%). [α]D25 = −5.6 (c 1.7, CHCl3, 50% ee). Lit. [α]D
11.1 [c 4.0, CHCl3, 44% ee, (R)].16a
=
Ethyl
(R)-2-(3,4-dichlorophenyl)-2-hydroxy-3-[(4-methoxyphenyl)
Ethyl (S)-2-benzyl-2,3-dihydroxypropanoate [(S)-13e]: yellow oil (85
mg, 63%). [α]D25 = +9.8 (c 0.8, CHCl3, 60% ee). Lit. [α]D25 = +10.4 (c
0.9, CHCl3, 76% ee).16b
amino]propanoate [(R)-5j]: Yellow oil (106 mg, 46%). 1H NMR (400
MHz, CDCl3) δ 7.82 (d, J = 2.1 Hz, 1H), 7.54 (dd, J = 8.5, 2.1 Hz, 1H),
7.47 (d, J = 8.5 Hz, 1H), 6.83-6.77 (m, 2H), 6.73-6.66 (m, 2H), 4.27-
4.24 (m, 2H), 3.94 (d, J = 12.5 Hz, 1H), 3.77 (s, 3H), 3.36 (d, J = 12.5
Hz, 1H), 1.27 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 173.3,
152.9, 141.7, 139.8, 132.7, 132.5, 130.4, 127.9, 125.1, 115.6, 114.8,
78.0, 63.3, 55.8, 53.6, 14.0. HRMS: m/z calculated for
[C18H20NO4Cl2]+: 384.0764; found: 384.0757. The enantiomeric
excess was determined by HPLC using a Chiralpak AD-H column
[hexane/i-PrOH (80:20)]; flow rate 1 mL/min; τmajor = 11.6 min, τminor
= 10.3 min (84% ee); [α]D20 = +10.4 (c 0.5, CHCl3).
Acknowledgements
This work was supported by the Ministerio de Economía y
Competitividad of Spain (CTQ2016-76908-C2-1-P, CTQ2016-
76908-C2-2-P, contract RYC-2012-10014 for G. de G.),
European FEDER funds and the Junta de Andalucía (Grant
2012/FQM 1078 and fellowships for I.S. and J.A.C). D. M.
acknowledges the Universidad de Sevilla for a postdoctoral
contract.
Ethyl
(R)-2-(2,4-difluorophenyl)-2-hydroxy-3-[(4-methoxyphenyl)
amino]propanoate [(R)-5k]: Yellowish oil (93 mg, 44%): 1H NMR
(300 MHz, CDCl3) δ 7.55 (m, 1H), 6.87-6.79 (m, 1H), 6.79-6.73 (m,
1H), 6.73-6.67 (m, 2H), 6.65-6.58 (m, 2H), 4.12 (q, J = 7.1 Hz, 2H),
3.97 (d, J = 12.5 Hz, 1H), 3.47 (d, J = 12.5 Hz, 1H), 1.12 (t, J = 7.1 Hz,
3H). 13C NMR (75 MHz, CDCl3) δ 173.3, 162.9 (dd, J = 250.2, 12.2 Hz),
160.4 (dd, J = 250.9, 11.8 Hz), 153.0, 141.7, 128.9 (dd, J = 9.7, 5.5
Hz), 123.4 (dd, J = 12.7, 3.9 Hz), 115.6, 114.8, 111.3 (dd, J = 21.0, 3.5
Hz), 104.6 (dd, J = 26.6, 25.6 Hz), 75.8 (d, J = 2.5 Hz), 62.8, 55.8, 51.4
(d, J = 4.0 Hz), 13.9. 19F NMR (283 MHz, CDCl3) δ −108.39 (d, J = 8.5
Notes and references
∫ Reactions performed at lower temperatures resulted in longer
reaction times without improvement of the enantioselectivities.
Additionally, 1 M concentration of 2 was selected as the best
option: the enantioselectivities slightly dropped at higher
concentrations (2 M) while reactions performed at c = 0.5 M
required longer times without improvement of the
enantioselectivities.
¶ These results apparently indicates that the working model
depicted in Scheme 1 apply also to aliphatic derivatives, but a
smaller methylene group in primary alkyl chains may
accommodate better in the inner region of the catalyst resulting
in lower enantioselectivities.
Hz), −109.89 (d,
J = 8.5 Hz). HRMS: m/z calculated for
[C18H21F2NO4]+: 352.1355; found: 352.1350. The enantiomeric
excess was determined by HPLC using a Chiralpak IA column
[hexane:iPrOH (80:20)]; flow rate 1 mL/min; 30 °C, τmajor =9.6 min,
τminor = 12.6 min (93% ee); [α]D23 = +8.0 (c 1.0, CHCl3).
‡ Alternative reductive amination conditions (BnNH2 instead of
PMPNH2 or NaBH4 in MeOH/TFE medium) gave lower yields (5-
30%).
Ethyl (R)-2-hydroxy-3-[(4-methoxyphenyl)amino]-2-(thiophen-2-yl)
propanoate [(R)-5l]: Yellowish oil (79 mg, 41%): H NMR (300 MHz,
1
CDCl3) δ 7.20 (dd, J = 5.1, 1.2 Hz, 1H), 7.10 (dd, J = 3.6, 1.2 Hz, 1H),
6.93 (dd, J = 5.1, 3.6 Hz, 1H), 6.70 (d, J = 8.3 Hz, 2H), 6.59 (d, J = 8.3
Hz, 2H), 4.19-4.10 (m, 2H), 4.07 (d, J = 6.5 Hz, 1H), 3.66 (s, 3H), 3.38
(d, J = 6.5 Hz, 1H), 1.18 (t, J = 7.0 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ
173.2, 152.8, 144.1, 141.8, 127.2, 125.4, 124.4, 115.5, 114.6, 77.7,
63.1, 55.8, 54.5, 14.0. HRMS: m/z calculated for [C16H21NO4S]+:
322.1108; found: 322.1103. The enantiomeric excess was
determined by HPLC using a Chiralpak AD-H column [hexane:iPrOH
(80:20)]; flow rate 1 mL/min; 30 °C, τmajor = 19.2 min, τminor = 15.3
min (84% ee); [α]D23 = +11.8 (c 0.9, CHCl3).
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3
General procedure for the synthesis of diols 13
Following the general procedure for the catalytic enantioselective
reactions of hydrazone 1 (1.2 mmol) with α-keto esters 2 (0.6
mmol). After consumption of starting material, solvent was
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