Tetrahydropyran-Based Hybrid Dipeptides as Asymmetric Catalysts for Michael Addition of Aldehydes to β-Nitrostyrenes

Article abstract of DOI:10.1002/adsc.201601193

A new series of hybrid dipeptide-like organocatalysts based on pyranoid ?- or ζ-amino acids and proline have been prepared for the asymmetric Michael addition of aldehydes to β-nitrostyrenes. The reaction proceeds under mild conditions to afford a wide ra

Full text of DOI:10.1002/adsc.201601193

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DOI: 10.1002/adsc.201601193
Tetrahydropyran-Based Hybrid Dipeptides as Asymmetric
Catalysts for Michael Addition of Aldehydes to b-Nitrostyrenes
Jorge Borges-Gonzꢀlez,a Andrꢁs Feher-Voelger,a Fernando Pinacho Crisꢂstomo,a,b
Ezequiel Q. Morales,a and Tomꢀs Martꢃna,b,*
a
Instituto de Productos Naturales y Agrobiologꢃa-CSIC, Avda. Astrofꢃsico Francisco Sꢀnchez, 3, 38206 La Laguna, S/C de
Tenerife, Spain
Fax : (+34)-922-260-135; e-mail: tmartin@ipna.csic.es
Instituto Universitario de Bio-Orgꢀnica “Antonio Gonzꢀlez”, CIBICAN, Avda. Astrofꢃsico Francisco Sꢀnchez, 2, 38206
b
La Laguna, S/C de Tenerife, Spain
Received: November 16, 2016; Revised: December 21, 2016; Published online: && &&, 0000
Supporting information for this article can be found under: http://dx.doi.org/10.1002/adsc.201601193.
Abstract: A new series of hybrid dipeptide-like or-
ganocatalysts based on pyranoid e- or z-amino acids
and proline have been prepared for the asymmetric
Michael addition of aldehydes to b-nitrostyrenes.
The reaction proceeds under mild conditions to
afford a wide range of g-nitroaldehydes with up to
98% yield and up to 96% ee. These dipeptides are
bifunctional organocatalysts, with a proline at the
N-terminus and a carboxylic acid at the C-terminus.
The tetrahydropyran unit embedded in the e- or z-
amino acid induces a well-defined conformation
that is responsible for the catalysis. These dipep-
amino acid, providing a fine tuning of the catalytic
properties.[4,5] Particularly interesting are the results
obtained by Wennemers and co-workers with tripepti-
dic catalysts of the type Pro-Pro-Asp/Glu, which over-
come some limitations of the organocatalytic version
of this Michael addition: high catalyst load, use of ad-
ditives and excess of aldehydes, and formation of
side-products by homo-aldol reactions. These tripep-
AHCTUNGTREGtNNUN ides feature a proline at the N-terminus (for enamine
formation) and a carboxylic acid at the C-terminus
(for nitronate protonation) which are at the right dis-
tance due to a well-defined b-turn conformation in-
duced by the d-Pro-Pro motif (Figure 1a).[6] Replace-
ment of the structural motif which induces a close
proximity between the proline residue and the car-
boxylic acid has been used by some research groups
to design new organocatalysts.[7] Recently, the Matile
ACHTUNGTRENNUNGtides represent a new type of organocatalyst with
a large number of possibilities to modulate their re-
activity and selectivity.
Keywords: aldehydes; asymmetric catalysis; Mi-
chael addition; organocatalysis; peptides
One of the most important and broadly utilized reac-
tions to form asymmetric C–C bonds in organic syn-
thesis is the Michael addition.[1] In this regard, orga-
nocatalysis has become an attractive alternative to
metal-based catalysts. Since the first report on the or-
ganocatalytic asymmetric Michael addition of alde-
hydes to nitroolefins,[2] huge progress has been made,
especially in developing more selective and efficient
pyrrolidine-type catalysts.[3] In the last few years,
short peptides or peptidomimetics have attracted the
attention of several research groups, due to their abili-
ty to mimic some enzymatic features such as high se-
lectivity and reactivity under mild reaction conditions.
Moreover, short peptides offer many sites for struc-
Figure 1. (a) Tripeptides found by Wennemers and co-work-
ers. (b) Dipeptides designed based on pyranoid sugar e- and
tural and functional diversity compared to a single z-amino acids.
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group took advantage of this bifunctional strategy to
As a proof of concept, we screened the catalytic
prepare anion-p catalysts.[8] Another building block properties of all these dipeptides for a representative
that offers huge possibilities for structural modulation 1,4-addition between trans-nitrostyrene and propanal
are the carbohydrates. Therefore, the combination of (Table 1). All reactions were performed with the tri-
both chiral building blocks is particularly promising fluoroacetic acid (TFA) salts of the dipeptides, the
for the development of new organocatalysts with corresponding equivalent of N-methylmorpholine
many possibilities to be modulated.
(NMM) to neutralize the ammonium salt, and
With this aim in mind, sugar amino acid units 3 equivalents of propanal for each equivalent of trans-
(SAAs) were considered as an optimal choice to be nitrostyrene.[15]
incorporated into the peptide backbones to provide
Generally, catalysts 5–8 with the proline residue at-
new peptides with organocatalytic properties. Carbo- tached near the tetrahydropyran ring provided better
hydrate-based prolinamides have been used in devel- diastereo- and enantioselectivities (Table 1, entries 5–
opment of new organocatalysts.[9] However, to the 8) than those catalysts 1–4 with the proline furthest
best of our knowledge, SAAs have never been intro- from the tetrahydropyran ring (Table 1, entries 1–4).
duced as part of the peptidic backbones to obtain Moreover, both enantiomers could be obtained by re-
peptidic catalysts. Herein, we report for the first time placing l-Pro with d-Pro.
the synthesis and application of new hybrid dipeptides
In order to check the influence of the tetrahydro-
as organocatalysts, whose conformations are con- pyran ring in the reaction outcome, an analogue lack-
trolled by pyranoid e- or z-amino acid carbohydrate ing the carbohydrate moiety (e.g., 9) was also synthe-
derivatives (Figure 1).
sized and screened. The dipeptide 9 afforded poor di-
SAAs are hybrid scaffolds that combine elements astereo- and enantioselectivity (Table 1, entry 9).
from carbohydrates and amino acids in their structure. These initial results confirmed the convenience of the
Among the several advantageous features displayed tetrahydropyran unit in providing the geometric re-
by SAAs for catalyst design, worthy of special men- quirements and conformational constraints for the
tion are the controllable and partially predictable con- achieved stereoselectivity.
formational restriction and the possibility to precisely
Under the preliminary conditions screened
modulate their chemical functionality and stereo- (Table 1, entries 1–9) catalyst 6a gave the best results,
chemistry. SAAs have been employed as useful pep- although with moderate diastereo- and enantioselec-
tide building blocks. Thus, diverse types of furanoid[10] tivity. In order to improve the catalyst performance,
and pyranoid[11] a-, b-, g- and d-SAAs have been de- new reaction conditions were also investigated
scribed as conformational constrained scaffolds. Previ- (Table 1, entries 10–17). From these experiments, it is
ous works from our group showed that the tetrahy- possible to recognize the importance of the fine
dropyran units bound by C-2 and C-3 positions (in- tuning of the ratio between the protic solvent and the
stead of the more common C-2 and C-6 binding) dis- low polar solvent.[16] Additionally, the catalyst load
play inherent conformational preferences in some (Table 1, entries 13 and 14) and reaction concentra-
macrooligolides and chiral receptors,[12] and this struc- tion (Table 1, entries 15–17) were also studied. In
tural topology was later extended to the synthesis of order to verify the importance of the conformation
cyclopeptides with well-defined and modulated con- stability of the tetrahydropyran subunit that provides
formations.[13]
the methoxy group at the C-4 equatorial position, cat-
Taking this into account, we decided to use pyra- alyst 6b, which lacks the methoxy group, was synthe-
noid sugar e-amino acid units to obtain hybrid dipep- sized. The reaction catalyzed by 6b was much slower
tides, which displayed a proline motif for the enamine and showed slightly worse diastereo- and enantiose-
formation, and a carboxylic acid for the protonation lectivity than the reaction performed by dipeptide 6a
of the iminium nitronate. Moreover, we introduced (Table 1, entry 18). The optimal conditions for 6a
a methoxy group at the C-4 equatorial position of the were achieved using 3% of catalyst load in 0.3% of i-
tetrahydropyran ring as an additional appendix for PrOH in DCM at 0.25M concentration (Table 1,
conformational control (Figure 1). For that purpose, entry 19). In light of these findings, we can emphasize
we used four sugar e-amino acid units, and all of them that our catalysts can work in very low polar media,
were coupled with both l- and d-proline to obtain 8 side-product formation is negligible, and no additives
new dipeptides. The tetrahydropyran-based e-amino are needed for catalysis. Considering the improve-
acids are easily obtained in a few steps from the com- ments obtained in the catalytic properties by Wenne-
mercially available tri-O-acetyl-d-galactal and tri-O- mersꢅs group when the catalyst H-d-Pro-Pro-Asp-NH2
acetyl-d-glucal.[14] Dipeptides were prepared by solu- was homologated to H-d-Pro-Pro-Glu-NH2,[6c,e] we
tion-phase coupling of the tert-butyl ester of the sugar decided to homologate the catalysts 5–8 by changing
e-amino acids with N-Boc-l- and d-prolines. Further the sugar e-amino acids for sugar z-amino acids. Thus,
deprotection with TFA afforded the dipeptides as we obtained a new set of catalysts 10–13.[14] This new
TFA salts (Table 1).
family of compounds was screened using the same
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Table 1. Catalyst screening and optimization of the reaction conditions.
[c]
Entry[a] Catalyst mol% Solvent (M)
Time [h] Conversion and yields [%][b] syn:anti
ee [%][d]
1
2
3
4
5
6
7
8
1
2
3
4
5
6a
7
8
3
3
3
3
3
3
3
3
3
3
3
3
5
10
3
3
3
3
3
CHCl3:i-PrOH 9:1 (0.45 M)
CHCl3:i-PrOH 9:1 (0.45 M)
CHCl3:i-PrOH 9:1 (0.45 M)
CHCl3:i-PrOH 9:1 (0.45 M)
CHCl3:i-PrOH 9:1 (0.45 M)
CHCl3:i-PrOH 9:1 (0.45 M)
CHCl3:i-PrOH 9:1 (0.45 M)
CHCl3:i-PrOH 9:1 (0.45 M)
CHCl3:i-PrOH 9:1 (0.45 M)
EtOH (0.45 M)
22
22
22
22
22
22
22
22
8
23
23
23
16
16
24
5
quant. (97)
quant. (97)
quant. (98)
quant. (97)
94 (92)
99 (97)
98 (96)
77 (75)
2:1
3:1
2:1
4:1
5:1
11:1
5:1
6:1
2:1
7:1
5:1
8:1
5:1
69 (2R,3S)
42 (2S,3R)
47 (2R,3S)
57 (2S,3R)
80 (2R,3S)
84 (2S,3R)
73 (2R,3S)
73 (2S,3R)
58 (2R,3S)
42 (2S,3R)
87 (2S,3R)
89 (2S,3R)
81 (2S,3R)
79 (2S,3R)
85 (2S,3R)
87 (2S,3R)
87 (2S,3R)
86 (2S,3R)
88 (2S,3R)
9
9
quant. (96)
quant. (95)
92 (90)
10
11
12
13
14
15
16
17
18
19
6a
6a
6a
6a
6a
6a
6a
6a
6b
6a
CHCl3 (0.45 M)
CH2Cl2 (0.45 M)
77 (74)
CHCl3:i-PrOH 9:1 (0.45 M)
CHCl3:i-PrOH 9:1 (0.45 M)
CH2Cl2:i-PrOH 95:5 (0.45 M)
CH2Cl2:i-PrOH 95:5 (0.25 M)
CH2Cl2:i-PrOH 95:5 (0.10 M)
CH2Cl2:i-PrOH 95:5 (0.25 M)
quant. (98)
quant. (97)
90 (88)
85 (83)
59 (57)
4:1
14:1
14:1
12:1
12:1
10:1
5
24
61 (58)
85 (84)
CH2Cl2:i-PrOH 99.7:0.3 (0.25 M) 23
[a]
[b]
[c]
[d]
All reactions were carried out at 0.1 mmol scale.
1
Determined by H NMR spectroscopy of the reaction mixture. In parentheses isolated yields.
1
Determined by H NMR spectroscopy of the reaction mixture.
Determined by chiral HPLC, Chiralpak IC-3, hexane:i-PrOH.
model reaction under the optimal conditions de- tries 5–7). In this case, the enantiomeric outcome of
scribed previously (Table 2). From the stereoselective the chiral g-nitroaldehydes can be switched by using
point of view, catalyst 11 afforded the best results the diastereomeric dipeptide 12 (Table 2, entries 3
(Table 2, entries 1–4). However, under these reaction and 7). Furthermore, in order to evaluate the impor-
conditions the catalyst 11 led to moderate yields. tance of the intramolecular carboxylic acid moiety in
Changing the solvent polarity, the catalyst load and the catalytic process, the carboxylic acid of catalyst 11
the reaction concentration improved the yields with- was transformed into an ester, resulting in a nearly in-
out affecting the enantiomeric excess (Table 2, en- active peptide 14 (Table 2, entry 8). This supports the
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Table 2. Catalyst screening and optimization of the reaction conditions.
[c]
Entry[a] Catalyst mol% Solvent (M)
Time [h] Conversion and yields [%][b] syn:anti
ee [%][d]
1
2
3
4
5
6
7
8
10
11
12
13
11
11
12
14
11
11
3
3
3
3
5
5
5
3
5
5
CH2Cl2:i-PrOH 99.7:0.3 (0.25 M) 69
CH2Cl2:i-PrOH 99.7:0.3 (0.25 M) 24
CH2Cl2:i-PrOH 99.7:0.3 (0.25 M) 42
CH2Cl2:i-PrOH 99.7:0.3 (0.25 M) 42
44 (41)
74 (72)
95 (93)
60 (57)
16:1
10:1
17:1
10:1
8:1
7:1
7:1
–
16:1
3:1
86 (2R,3S)
93 (2S,3R)
92 (2R,3S)
81 (2S,3R)
89 (2S,3R)
93 (2S,3R)
92 (2R,3S)
–
CH2Cl2 (0.25 M)
CH2Cl2 (0.1 M)
16
22
quant. (97)
quant. (98)
quant. (98)
7 (À)
CH2Cl2 (0.1 M)
20
CH2Cl2:i-PrOH 95:5 (0.25 M)
CH2Cl2 (0.1 M)
24
45
9[e]
10[f]
quant. (97)
98 (96)
94 (2S,3R)
94 (2S,3R)
CH2Cl2 (0.1 M)
>150
[a]
All reactions were carried out at 0.1 mmol scale.
[b]
[c]
[d]
[e]
[f]
1
Determined by H NMR spectroscopy of the reaction mixture. In parentheses isolated yields.
1
Determined by H NMR spectroscopy of the reaction mixture.
Determined by chiral HPLC, Chiralpak IC-3, hexane:i-PrOH.
The reaction was performed at 08C.
The reaction was performed at À208C.
idea that the catalysts behave as bifunctional catalysts aromatic substituents (Table 3, entries 11–12). Lower-
where the carboxylic acid moiety is placed in an ap- ing the temperature at 08C improved the syn:anti
propriate position to activate the nitrostyrene and to ratio from 4.8:1 to 23:1 (Table 3, entry 10), although
act as a proton donor that transfers a proton to the the reaction needed a longer time.
iminium nitronate intermediate.[6h] Additionally, dif-
To gain insights on the conformational equilibrium,
ferent temperatures were analyzed with the expecta- a theoretical conformational analysis was performed
tion of reaching higher enantiomeric ratios (Table 2, for dipeptides 11 and 12. Conformational search was
entries 9 and 10). Despite the better diastereoselectiv- done using mixed Torsional/Low Mode Conforma-
ity at 08C there was no remarkable improvement of tional Search[17] which has proved to be very useful on
the enantiomeric excess. At À208C the reaction pro- conformational searches of small peptides. It was used
ceeds slowly without any further improvement of the as implemented in Maestro/Macromodel (Schrçdinger
enantio- and diastereomeric outcome.
Release 2016-1)[18] using chloroform as solvent. The
Once we had achieved the optimum conditions for best force field (FF) to suite our molecules is
the best conversion and enantiomeric excess, the next OPLS3[19] among all implemented on MacroModel
step was to evaluate the scope of catalyst 11. We tried with all high quality torsion/bending/stretching pa-
a range of b-nitrostyrenes and aldehydes. High to ex- rameters. Charges were provided from the FF with an
cellent yields and stereoselectivities were obtained at extended cutoff. Conformers were minimized using
room temperature within 6–45 hours (Table 3). Better a truncated Newton conjugate gradient (TNCG)
stereoselectivities were observed when aldehydes method with gradient convergence within a 0.005
such as butanal and pentanal were used instead of threshold. To be sure to map all the conformational
propanal (Table 3, entries 1 and 2). A similar result space a 10000 maximum number of steps was the
was observed when hydrocinnamaldehyde was used limit within an energetic range of 21.0 kJmolÀ1
(Table 3, entry 3). Also, nitroolefins bearing electron- (5.02 kcalmolÀ1).
poor aromatic substituents were more reactive
The lowest-energy conformation of dipeptide 11
(Table 3, entries 4–10) than those with electron-rich displays a folded structure where both appendices, the
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Table 3. Substrate scope of conjugate addition reactions between aldehydes and b-nitrostyrenes catalyzed by dipeptide 11.
Entry[a]
1
Product
Time [h]
22
Conversion and yields [%][b]
quant. (97)
syn:anti[c]
ee [%] (2S,3R)[d]
29:1
95
2
22
quant. (98)
32:1
95
3
4
5
22
22
22
96 (93)
31:1
6.4:1
27:1
93
92
95
quant. (96)
95 (93)
6
7
6
6
98 (96)
97 (95)
7:1
93
92
8.7:1
8
22
quant. (97)
24:1
96
92
9
22
99 (97)
6.5:1
16
45
quant. (98)
quant. (97)
4.8:1
23:1
93
94[e]
10
11
22
45
98 (95)
88 (84)
4.7:1
3.5:1
92
91
12
[a]
All reactions were carried out at 0.1 mmol scale.
[b]
[c]
[d]
[e]
1
Determined by H NMR spectroscopy of the reaction mixture. In parentheses isolated yields.
1
Determined by H NMR spectroscopy of the reaction mixture.
Determined by chiral HPLC, Chiralpak IC-3, hexane:i-PrOH.
The reaction was performed at 08C.
proline residue and the carboxylic acid, are in close oxygen atom of the 3-oxypropanoic acid forms a 6-
contact. The proline N–H pointing to the C=O of the membered hydrogen-bonded pseudocycle (C6), which
carboxylic acid forms a 13-membered hydrogen- reduces the degree of freedom of the C-terminus (Fig-
bonded pseudocycle (C13), which helps to keep the ure 2a). Conversely, the lowest-energy conformation
folded geometry. A second intramolecular hydrogen of the dipeptide 12 shows an unfolded or more ex-
bond between the carboxylic acid O–H and the ether tended structure with both appendices far apart.
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Figure 3. (a) Lowest-energy conformation of the enamine of
11. (b) Lowest-energy conformation of the enamine of 12.
Clustering of representative conformers within 10 kJmolÀ1
from the global minimum just for visualization ease only of
the enamines of 11 (c) and 12 (d).
Figure 2. (a) Lowest-energy conformation of dipeptide 11.
(b) Lowest-energy conformation of dipeptide 12. Clustering
of representative conformers within 10 kJmolÀ1 from the
global minimum just for visualization ease only of dipepti-
des 11 (c) and 12 (d).
CHCl3, almost all the conformers of the enamine of
11 display similar folded structures (Figure 3c). None-
However, the intramolecular hydrogen bond between theless, in the case of the enamine of 12, different sets
the carboxylic acid O–H and the ether oxygen atom of conformers can be distinguished, mainly partially
of the 3-oxypropanoic acid is also present (Figure 2b). folded and folded structures. These differences are
Within a range of 21 kJmolÀ1 from the global mini- due to changes in the dihedral angle N–C–C–N of the
mum in CHCl3, almost all the conformers of dipeptide proline residue (Figure 3d).
11 display similar folded structures (Figure 2c). How-
The preferred diastereo- and enantioselectivity
ever, in the case of dipeptide 12 four different sets of could be explained by looking at the proposed transi-
conformers can be distinguished, folded and unfolded tion state model for this reaction (Figure 4).[21] For
structures (Figure 2d).
catalyst 11, the Re face of the trans-b-nitrostyrene ap-
According to the reaction mechanism proposed for proaches the Re face of the syn enamine via an acy-
these types of bifunctional catalysts, the product ste- clic synclinal transition state as described by See-
reochemistry is governed by an enamine structure bach.[22] This facilitates favorable electrostatic interac-
formed between the proline residue and the aldehy- tions between the developing iminium and nitronate
de.[6h] Therefore, a theoretical conformational analysis groups along with the carboxylic acid, which is point-
was performed also for the enamines of both dipepti- ing to the Re face of the syn enamine. The carboxylic
des 11 and 12. For the enamine of 11, the lowest- acid activates the Michael acceptor by a hydrogen
energy conformation displays a folded geometry even bond formation and later produces the protonation of
when the hydrogen bond between the proline N–H the iminium nitronate formed. This approach provides
and the carbonyl group from carboxylic acid is not the 2S,3R products and resembles the Sunojꢅs transi-
operating to form the 13-membered hydrogen-bonded tion state model described for the proline (Fig-
pseudocycle (C13). The enamine in this case leads to ure 4a).[23] Similarly, in catalyst 12, the Si face of the
a syn conformation (Figure 3a). On the other hand, trans-b-nitrostyrene approaches the Si face of the syn
the lowest-energy structure of the enamine of dipep- enamine to afford the 2R,3S products. In this case,
tide 12 exhibits also a syn conformation but a partially the carboxylic acid is pointing toward the Si face of
folded geometry with an intramolecular hydrogen the syn enamine (Figure 4b).
bond between the carboxylic acid O–H and the C=O
In conclusion, we have designed and prepared
of the proline residue forming a 12-membered hydro- a novel series of hybrid dipeptide-like organocatalysts
gen-bonded pseudocycle (C12) (Figure 3b). Within which efficiently promote asymmetric 1,4-additions of
a range of 21 kJmolÀ1 from the global minimum in aldehydes to b-nitrostyrenes. These catalysts combine
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Acknowledgements
This research was supported by the Spanish MINECO, cofi-
nanced by the European Regional Development Fund
(ERDF) (CTQ2014-59649-P). J. B-G. and A. F-V. thank the
Spanish MEC for an FPU fellowship. F. P. C. thanks the
CSIC for a JAE-doc contract, cofinanced by FSE.
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Figure 4. Proposed transition state model for catalysts 11 (a)
and 12 (b).
two highly-modulable building blocks: amino acids
and carbohydrates. The carbohydrate motif is embed-
ded in the e- or z-amino acids, which is coupled with
a proline to obtain the dipeptide. We also demonstrat-
ed the bifunctional behavior of these organocatalysts,
highlighting the importance of the tetrahydropyran
unit that provides a well-defined conformation allow-
ing the observed reactivity and stereoselectivity. The
present work also emphasizes how small structure
changes like homologation of the carboxylic acid
chain have significant effects on the catalyst per-
formance. The design of these new dipeptide-like or-
ganocatalysts offers huge possibilities to be modulat-
ed by easily changing substituents or stereochemistry
of the carbohydrate unit. Taking full advantage of the
modular nature of these dipeptides, we are currently
working to develop new catalysts with improved per-
formance and to extend them to other substrates and
reactions. Our progress will be published in due time.
Experimental Section
General Procedure
The aldehyde (3.0 equiv.) and the b-nitrostyrene (1.0 equiv.)
were added to a solution of dipeptide (0.03–0.05 equiv.) and
N-methylmorpholine (0.03–0.05 equiv.) in the solvent indi-
cated in the Tables. The reaction mixture was stirred until
TLC showed the end of the reaction. The solvents were re-
moved under vacuum and the crude was purified by a chro-
matography column with silica gel using mixtures of hexanes
and ethyl acetate as eluent.
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Tetrahydropyran-Based Hybrid Dipeptides as Asymmetric
Catalysts for Michael Addition of Aldehydes to b-
Nitrostyrenes
9
Adv. Synth. Catal. 2017, 359, 1 – 9
Jorge Borges-Gonzꢀlez, Andrꢁs Feher-Voelger,
Fernando Pinacho Crisꢂstomo, Ezequiel Q. Morales,
Tomꢀs Martꢃn*
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These are not the final page numbers!