Bifunctional Br?nsted Base Catalyzed Mannich Reaction of β-Alkoxy α-Keto Amides: Stereocontrolled Entry to Functionalized Amino Diols

Article abstract of DOI:10.1002/chem.201802550

The potential of β-alkoxy α-keto amides as pronucleophiles in the enantioselective Mannich type reaction with p-nosyl imines is presented. The proper combination of β-alkoxy α-keto amides and a squaramide-based Br?nsted base catalyst produced highly enantioenriched Mannich adducts, which may be transformed into functionalized amino diols.

Full text of DOI:10.1002/chem.201802550

A Journal of
Accepted Article
Title: Bifunctional Brønsted Base Catalyzed Mannich Reaction of ß-
Alkoxy α-Keto Amides: Stereocontrolled Entry to Functionalized
Amino Diols
Authors: Claudio Palomo, Rosa López, Iñaki Bastida, and Haizea
Echave
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Bifunctional Brønsted Base Catalyzed Mannich Reaction of -
Alkoxy -Keto Amides: Stereocontrolled Entry to Functionalized
Amino Diols
Haizea Echave, Iñaki Bastida, Rosa López and Claudio Palomo*[a]
The potential of -alkoxy -keto amides as pronucleophiles in the
enantioselective Mannich type reaction with p-nosyl imines is
presented. The proper combination of -alkoxy -keto amides and a
squaramide-based Brønsted base catalyst produced highly
enantioenriched Mannich adducts which may be transformed into
functionalized amino diols.
would give loss of one of the stereogenic centers generated
during the reaction. [8, 9d-e]
A common feature of enantiopure compounds possessing
therapeutic potential, is their dense functionalization containing
numerous and frequently contiguous stereogenic centers, being
linear polyols[1] and amino polyols[2] some of the most frequent
fragments contained in this class of molecules. -Hydroxyketones
are traditionally the pronucleophiles of choice in direct asymmetric
and catalytic aldol[3] and Mannich[4] reactions to assemble 1,2-
diols and 1,2-amino alcohols which, after subsequent
stereoselective reduction of the ketone moiety, afford the
corresponding enantioenriched fragments with three contiguous
stereogenic centers. In contrast, -hydroxy-1,2-dicarbonyl
compounds that present extra reactive centers and offer the
opportunity for the construction of highly functionalized moieties
have been much less explored (Scheme 1a). The inherent high
reactivity of the dicarbonyl function against nucleophilic 1,2-
additions has hampered their use as pronucleophiles[5] until recent
times, in which the progress in selective activation modes has
enabled to enhance their nucleophilic character towards cross-
condensation instead of self-condensation.[6] Most examples
employ piruvates and belong to the Michael type reaction, for
which metallo- and organocatalytic approaches have been
described,[7] whereas the aldol[8] and Mannich-type reactions[9]
have been scarcely examined. Trying to fill this gap, we have
recently described the first direct enantioselective cross-aldol
reaction of -alkoxy-keto amides with aldehydes catalyzed by a
bifunctional Brønsted base (Scheme 1b).[10] We now document
the first direct Mannich-type reaction of these -alkoxy -keto
amides which further proves their utility as efficient pronucleophile
partners and provides an entrance to highly versatile
enantioenriched amino polyols.
Scheme 1. Polyols and amino polyols construction by direct catalytic aldol and
Mannich reactions.
Initially, we evaluated the reaction of -keto amides 1a and 1b
with different N-protected imines in the presence of several
bifunctional Brønsted base catalysts (Table 1). The experiments
soon revealed nosyl[11] protected imines to be the most suitable
azometines for this Mannich reaction. Nevertheless, to our
disappointment, ureidopeptide-based Brønsted base catalysts,
which were the most effective in promoting the parent
stereoselective aldol reaction,[10] displayed poor control over the
reaction selectivity; the addition of either -ketoamide 1a or 1b to
nosyl imines, promoted by catalysts C1 and C2, afforded the
corresponding Mannich adducts in generally good conversion and
high diastereoselectivity but poor enantioselectivities regardless
the reaction temperature (entries 5-8). Likewise, the thiourea
catalysts C3[12] and C4[13] provided poor enantiocontrol in the
reaction of 1a with imine 7a (entries 9, 10). However, cyclization
of the Mannich adducts was not observed under the described
reaction conditions. We were gratified to find out that squaramide
based Cinchona bases[14] (catalysts C5-C9) provided high
conversions and higher stereoselectivities, being the best result
achieved with catalyst C8 which produced the Mannich adduct
One problem associated with adducts from aldol and Mannich
reactions with -keto esters is their high tendency to cyclize and
produce isotetronic acids and pyrrolones, respectively, which
[a]
Dr. H. Echave, I. Bastida, Dr. R. López, Prof. Dr. C. Palomo
Departamento de Química Orgánica I, Facultad de Química
Universidad del País Vasco, Manuel de Lardizabal 3, 20018 San
Sebastián (Spain)
E-mail: claudio.palomo@ehu.eus
Supporting information for this article is given via a link at the end of
the document
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10a with a 97:3 diasteromeric ratio and 92% ee for the major
diastereomer (entry 14).
the carboxamide function, offers several options for better
catalyst/substrate recognition as compared with common
catalysts such as C5. [16]
Table 1. Nitrogen protecting group in imine and catalyst screening for the
Mannich reaction of -keto amides.[a-d]
Having optimized the reaction conditions, we examined the scope
of the transformation with respect to the azomethine group. A
representative selection of N-p-nosyl imines was subjected to
treatment with 1a to afford Mannich adducts 10 in generally good
diastereo- and enantioselectivities.
Table 2. Mannich reaction scope of 1a with different N-p-nosyl imines 7.[a-f]
Ent
keto/Imine
Cat
T(ºC),t(h)
Conv(%)[b]
d.r. [c]
ee(%)[d]
1
2
1a/2
1a/3
C1
C1
C1
C1
C1
C1
C2
C2
C3
C4
C5
C6
C7
C8
C9
0,72
0,72
0
-
-
-
0
-
3
1a/4
20,120
20,120
20,15
20,15
20,17
60,45
20,15
20,15
20,15
20,15
20,15
20,15
20,15
80
85:15
-
34
-
4
1a/5
0
5
1a/6
71
82:18
94:6
93:7
99:1
94:4
95:5
94:6
87:13
95:5
97:3
90:10
28
30
30
40
48
48
88
64
92
92
80
6
1a/7a
1b/7a
1b/7a
1a/7a
1a/7a
1a/7a
1a/7a
1a/7a
1a/7a
1a/7a
>95
>95
90
7
8
9
>95
>95
>95
>95
>95
>95
>95
10
11
12
13
14
15
[a] Reactions conducted on a 0.2 mmol scale in 0.5 mL of CH2Cl2 (mol ratio
of -keto amide/imine, 1:1.5). [b] Determined by 1H NMR. [c] Determined by
1H NMR and corroborated by HPLC. [d] ee of the major diasteromer
determined by chiral HPLC.
[a] Reactions conducted on a 0.15 mmol scale in 1.5 mL of CHCl3 (mol ratio of
1a/7, 1:1.5 for aromatic imines; 1:3 for aliphatic imines). [b] Yield of the isolated
anti,syn adduct 11 after Mannich reaction and stereoselective reduction. [c] Syn,
anti ratio determined by 1H NMR spectroscopy and corroborated by HPLC for
the Mannich adducts 10 before reduction. [d] The ee value of the major
diasteromer (syn Mannich adduct), before reduction, was determined by chiral-
phase HPLC. [e] Mannich reaction carried out at 0 ºC. [f] Determined after
recrystallization of the corresponding anti,syn adduct.
The influence of solvent and temperature was evaluated using
catalyst C8 and, among the solvents, chloroform gave the best
results in the presence of molecular sieves; adduct 10a was
obtained with 99:1 diastereomeric ratio and 92% ee at 20 ºC.[15]
It is also worth of noting that catalysts C6-C9 belong to a new
modular subfamily of squaramides which, by simple fine tuning
Again, and most importantly, in none of these reactions was
formation of cyclized product observed thus enabling subsequent
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Table 3. Mannich reaction scope with different -alkoxy -keto amides.[a-d]
carbonyl reduction to produce amino diols in a concise simple way.
The reduction step performed on the crude reaction adducts 10
using K-Selectride provided anti,syn-amino diols 11 (Table 2) in
reasonable good yields upon isolation after the two steps and with
essentially complete stereoselectivity whilst using Et3B/NaBH4 the
opposite syn,syn- isomers could be obtained, vide infra. The
absolute configuration was determined for compound 11a by X-
ray single crystal structure and that of the remaining adducts was
established by assuming a uniform reaction mechanism.[17] As
data in Table 2 show, N-p-nosyl protected imines with electron
donating or withdrawing substituents were equally competent
reaction partners, apparently irrespective of the p- or m-
substitution pattern for adducts monosubstituted (11a-g) and
disubstituted (11i-k) in the aromatic ring, producing enantiomeric
excesses generally above 90%. Heteroaromatic imine such as 7l
also produced the corresponding adduct 11l with excellent
diastereoselectivity and high enantioselectivity. Nevertheless, o-
substitution considerably affected both diastereo- and
enantioselectivity of the reaction (adduct 11h). On the other hand,
reactions performed at 3 mmol scale showed no detrimental effect
on the stereochemical outcome (adduct 11a). In addition, when
catalyst loading was lowered to 5 mol% the reaction underwent
with identical levels of selectivity although longer reaction times
were required (adducts 11a, 11f and 11g). We also studied the
Mannich reaction between -keto amide 1a and a representative
selection of p-nosyl N-protected imines derived from aliphatic
aldehydes. Imines derived from -branched alkyl aldehydes
produced the corresponding adducts 11m and 11n in high
enantiomeric excesses and excellent diastereomeric ratios,
whereas the lower asymmetric induction exerted in the reaction
with linear imine 7o could be mitigated by recrystallization of the
corresponding anti,syn adduct 11o.
[a] Reactions conducted on a 0.15 mmol scale in 1.5 mL of CHCl3 (mol ratio of
1/7, 1:1.5 for aromatic imines; 1:3 for aliphatic imines). Yield of the syn adduct
after purification. [b] Syn,anti ratio determined by 1H NMR spectroscopy and
corroborated by HPLC. [c] The ee value of the major diasteromer (syn Mannich
adduct) was determined by chiral-phase HPLC. [d] Reaction carried out at -40
ºC.
the corresponding amino diol 21 in high yield.[18] An interesting
feature of nosyl protected amines is that they can be easily
transformed in secondary amines through alkylation followed by
deprotection.[19] Methylation of adduct 11a, and subsequent p-
nosyl cleavage, produced the corresponding secondary amine 22
in 50% overall yield. This approach highlights the structural
versatility of the catalytic Mannich reaction displayed, since the
nosyl group allows the access to either primary or secondary
amines. Also, the reduction of the amide group, carried out using
the borane tetrahydrofurancomplex[20] produced diamines 23 and
24 in good yields.
To further proof the efficacy of this protocol, differently substituted
-keto amides were subjected to Mannich reaction under the
previous conditions. Satisfactorily, variations on the substitution
of both the amide and alkoxy moieties (R and R1, respectively),
were compatible with the methodology and, as data in Table 3
show, results were consistently good. Diisopropyl -keto amide
1c reacted with both aromatic and aliphatic p-nosyl N-protected
imines to produce the corresponding Mannich adducts 12 and 13
with
high
diastereoselectivity
albeit
with
moderate
enantioselectivity for the aliphatic adduct 13. Interestingly, the
methodology resulted also compatible with morpholine derived -
keto amide 1d to produce the enantioenriched adducts 14-16.
Likewise, modification in the nature of the alkoxy moiety did not
substantially affect either reactivity or selectivity (adducts 17-19)
confirming the high versatility of the method.
As noted above, the stereochemical outcome of the
stereoselective reduction of the Mannich adducts, promoted by K-
Selectride, could be inverted (Scheme 2) to efficiently produce,
under treatment with Et3B/NaBH4,
a
12:88 mixture of
anti,syn:syn,syn diastereoisomers from which the major syn,syn
adduct 20 was isolated in 58% yield. On the other hand, the
cleavage of the p-nosyl protecting group was efficiently promoted
in the presence of thiophenol and potassium carbonate, to afford
Scheme 2. Elaboration of Mannich adducts into enantioenriched amino diols.
The diastereo- and enantioselectivity observed might be
consistent with a reaction model in which the Re face of the Z
enolate approaches the Re face of the N-protected imine (Figure
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1). For this model, we propose that the deprotonated nucleophile
binds to the H-bond network, and the protonated amine activates
the electrophile whilst orientates its approach during reaction.[21]
As evidence in favor of this assumption, we found that the
chemical shift of the ortho-ArH in C8 is affected[22] ( = + 0.06
ppm) by addition of 1 equivalent of -keto amide 1c, while
remains unaffected by addition of the imine 7a. Furthermore, the
singlet corresponding to the protons at the enolizable position in
1c splits into two peaks upon addition of C8. This effect suggests
catalyst C8 and the -keto amide interact strongly, so that the
homotopic protons in the achiral substrate become heterotopic
and distinguishable in the substrate-catalyst complex.
Acknowledgements
Finantial support was provided by the University of the Basque Country
UPV/EHU (UFI QOSYC 11/22), Basque Government (Grant No IT-628-13), and
Ministerio de Economía y Competitividad (MEC, Grant CTQ2016-78487-C2),
Spain, H. E. and I. B. thank G.V. for fellowships. We also thank SGiker
(UPV/EHU) for providing NMR, HRMS, and X-Ray resources.
Keywords: asymmetric catalysis • Brønsted bases • Mannich reaction •
organocatalysis • synthetic reactions
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Figure 1. Plausible reaction model and selected 1H NMR.
In summary, we report the first direct catalytic formal Mannich
reaction of -alkoxy -keto amides with p-nosyl N-protected
imines that provides a quick entry for construction of amino diols.
The newly developed squaramide-based Brønsted base catalyst
employed promoted the transient generation of -keto amide
enolates, regardless the substitution pattern at both the amide
and alkoxy moieties, which reacted with either aromatic and
aliphatic imines in a highly stereoselective fashion. The resulting
Mannich
adducts
upon
reduction
produced
highly
enantioenriched linear anti,syn- and syn,syn-amino diols
containing three contiguous stereogenic centers in an
unprecedented way.
Experimental Section
To a cooled solution of the corresponding α-keto amide 1 (1 equiv., 0.15 mmol)
squaramide-based catalyst C8 (0.02 equiv., 0.03 mmol) and molecular sieves
(pellets, 3Å, 0.1 g) in CHCl3 (1.5 mL) was added the corresponding imine 7 (1.5
equiv. for aromatic imines; 3 equiv. for aliphatic imines) at the indicated
temperature. The resulting solution was stirred at the same temperature until
complete disappearance of 1. The reaction mixture was quenched with HCl
0.1M (5 mL), the organic layer was washed with HCl 0.1M (3 x 5 mL), dried over
MgSO4, filtered and concentrated in vacuo to afford the corresponding crude
Mannich adduct. To a cooled solution of the corresponding crude Mannich
adduct in THF (1.5 mL) was added K-Selectride (1M THF, 3-4 equiv.) at –78 °C.
After stirring for 2 h, phosphate buffer pH=7 (0.5 mL) and EtOH (1.0 mL) were
successively added, followed by H2O2 (30% , 0.8 mL) five minutes later. The
reaction temperature was allowed to rise to room temperature and the mixture
was stirred for 10 additional min. Then, it was diluted with EtOAc (5 mL) and
water (5 mL). The aqueous phase was extracted with EtOAc (3 x 5 mL), the
organic layers were combined, dried over MgSO4, filtered and concentrated in
vacuo. The crude product was purified by flash column chromatography
(Hex/EtOAc) to afford the corresponding pure anti,syn compounds.
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529. For selected examples using organocatalysis, see: f) B. List, P.
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10.1002/chem.201802550
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[5]
[6]
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compounds,
such
as
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acid
and
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10.1002/chem.201802550
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Haizea Echave, Iñaki Bastida, Rosa
López and Claudio Palomo*
Page No. – Page No.
Bifunctional Brønsted Base Catalyzed
Mannich Reaction of -Alkoxy -Keto
Amides: Stereocontrolled Entry to
Functionalized Amino Diols
The enantioselective Mannich reaction of -alkoxy α‐keto amides with N-p-
nosyl protected imines was accomplished using squaramide‐based Brønsted
base catalysts. The reaction provides stereodefined syn‐amino alcohols which
are valuable precursors of highly functionalized linear amino diols containing
three contiguous stereocenters.
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