Graphical Abstract


Enantioselective synthesis of polysubstituted prolines by Binap-silver-catalyzed 1.3-dipolar cycloadditions



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Enantioselective synthesis of polysubstituted prolines by Binap-silver-catalyzed 1.3-dipolar cycloadditions

Carmen Nájera,a M. de Gracia Retamosa,a José M. Sansano,a

Abel de Cózar,b Fernando P. Cossíoc


a Departamento de Química Orgánica e Instituto de Síntesis Orgánica (ISO), Facultad de Ciencias

Universidad de Alicante, Apartado 99, 03080 Alicante, Spain.

b Area de Química Orgánica, Universidad de Castilla-La Mancha, E-13071 Ciudad Real, Spain.

c Departamento de Química Orgánica I, Facultad de Química, Universidad del País Vasco – Euskal Herriko Unibertsitatea, P. K. 1072, E-20018 San Sebastián-Donostia, Spain.

Dedicated to Prof. José M. Saá on the occasion of his 60th birthday

Abstract—. The enantioselective 1,3-dipolar cycloaddition reaction of stabilized azomethine ylides, generated from iminoesters, with maleimides was efficiently achieved by intermediacy of an equimolar mixture of chiral (R)- or (S)-Binap and AgClO4. The high stability of the titled catalytic metal-complex to light exposure and its insolubility in toluene made possible its recovery and reutilization in other new process. In order to get a better understanding of the behaviour of these chiral catalysts, we have carried out DFT1 calculations demonstrating the experimentally observed endo-selectivity through a very asynchronous transition state. © 2017 Elsevier Science. All rights reserved.
Keywords: 1.3-Dipolar cycloaddition/azomethine ylides/iminoesters/Binap/silver/prolines


1. Introduction
Proline is singular among the genetically encoded α‑amino acids (α‑AA) due to the rigidity conferred by its pyrrolidine ring, which leads to a steric hindrance particularity useful in the design of biologically active peptides,1 including the proline rich amphipathic cell-penetrating peptides.2 The substitution on the pyrrolidine heterocycle opens new perspectives formed on these two mentioned areas, especially in structure-activity relationships studies of the newly generated peptides.Error: Reference source not found Restriction of the conformational space not only concerns proline or its derivative itself but also the preceding residue. The substituent attached in position 2 of the heterocycle (α-methylation) is widely used to stabilize helical conformation of peptides, as well as some type I β‑trans arrangements. However, the substitution in position 3 has not been so studied and the results are not so predictable. Substituted prolines at the 4-position can be considered as a constrained analogues of homocysteine

glutamate, homoarginine and homoserine depending on the nature of the functional group used as substituent. These 4-substituted surrogates, together with prolines incorporating a substituent in position 5 use to stabilize type VI β‑turns conformations and favor the preference of the CV-exo-puckering in the peptide.Error: Reference source not found



The proline derived structures themselves have been employed as organocatalyst3 in many useful transformations and also as potent drugs. For example, antiviral agents 1, active against hepatitis C virus,4 kainoids 2 with neuro-excitatory activity or as insecticides,5 neuroexcitotoxin ()-dysibetaine 3.6 Hydroxyprolines 4 and 5 are crucial in collagen catabolism, and for stabilization of protocollagens and glycoproteins in plants and animals,7 respectively, etc.



Figure 1. Some biologically active proline derivatives.
The synthesis of enantioenriched substituted prolines8 can be achieved by several routes, as for example, starting from prolines or proline derivatives, and through C-N or C-C bond forming cyclizations. These routes operate under a diastereoselective key step included in a large synthetic sequence. Since 2002, several fascinating enantioselective syntheses of substituted prolines through 1.3-dipolar cycloaddition9 (1,3-DC) of azomethine ylides and electron poor alkenes have been developed by several groups.10 The simultaneous formation of the new three or four stereocentres of the resulting pyrrolidine can be achieved using chiral complexes of silver,11 copper,12 zinc,13 nickel,14 calcium,15 or chiral organocatalysts,16 the metal-catalyzed reaction being the most efficient and reliable route. Particularly, the most elevated endo:exo diastereoselectivities and enantioselectivities were obtained with mono- or bidentate chiral ligands AgI or CuI complexes.
The combination of (S)-Binap-AgOAc showed low ee in 1,3-DC using dipoles derived from iminoesters and dimethyl maleate (up to 13% ee) in the first efficient silver-catalyzed enantioselective 1,3-DC,Error: Reference source not founda or phenyl vinyl sulfone (up to 26% ee),Error: Reference source not founde,i as dipolarophiles. In our group, we have used the Binap ligand17 and AgClO4 to generate active catalysts in the 1,3-DC using N‑methylmaleimide (NMM) and iminoesters.Error: Reference source not foundh In this work, we will describe the scope of this reaction as well as the study of another diphosphines as well as the origin of the elevated enantioselection and endo-diastereoselectivity.
2. Results and discussion
2.1. Optimization of the reaction conditions.

The selected model reaction between methyl benzylideneiminoglycinate 6aa and NMM 7 was carried out in toluene at room temperature using 5 mol % of (S)-Binap 8 and 5 mol% of AgI salt as catalyst precursor (Scheme 1).


Scheme 1. Reagents and conditions: i) (S)-Diphosphine (5 mol%), AgI salt (5 mol%), Et3N (5 mol%), toluene, rt, 16 h.


The reaction run with the equimolar amount of both Binap 8 and silver(I) salts such as AgBF4, AgNO3, Ag2O, (5 mol%) gave poor results in terms of enantioselection and conversion (Table 1, entries 1-3). When AgOAc was used excellent results of the compound 6aa were obtained (Table 1, entry 4), but the crude reaction product was not as clean as in the case of AgClO4 does. AgOTf, and AgF were also tested obtaining in both cases, not reproducible results (Table 1, entries 5 and 6). However, reproducible results of a very clear crude 12aa product with excellent enantioselectivities (>99% ee), high endo-diastereoselectivity (>98/2) and 90% yield were achieved with AgClO4 (Table 1, entry 7). A 3 mol% of the catalytic complex also gave good enantioselections but the reaction time was too large (1.5 d, Table 1, entry 8). This AgClO4 was used rather than the corresponding monohydrate because the last one was more difficult to weight (Table 1, entry 9). Next, different ratios of Binap:AgClO4 were tested. Thus, when it was added a 2:1 mixture of Binap:AgClO4 (Table 1, entry 10) the percentage of the exo-cycloadduct was increased. When a 1:2 mixture was prepared in situ the product 12aa was obtained with a very low enantioselectivity (Table 1, entry 11). In summary, the equimolar Binap:AgClO4 was definitively the most efficient complex for this process (compare entries 7, 10, and 11).

The effect of the solvent was also important because almost racemic mixtures were obtained with diethyl ether, whilst dichloromethane and THF gave moderate enantioselections (<60% ee) of product 12aa.


Three additional diphosphines (9-11) were evaluated in this particular model reaction (Scheme 1). It is very well known that the improvements of the enantioselection promoted by diphosphines was associated to changes in the corresponding both dihedral and bite angles of the resulting chiral metal complex.18 Thus, equimolar mixtures of silver perchlorate and ligands 9, 10, and 11 (5 mol% each) afforded cycloadduct endo-12aa with very high conversions and excellent enatioselections (>99% ee) except in the example of the reaction product generated by intermediacy of the chiral complex 11, which was isolated with a 98% ee (Table 1, entries 12-14).

According to these data, the AgI complex formed with (R)- and (S)-Binap 8 exhibited almost identical enantiodiscrimination than the other complexes generated from more expensive chiral ligands 9-11. In addition, the resulting equimolar Binap-AgClO4 can be recovered more easily than the analogous complexes generated from diphosphines 9, 10, and 11.



The absolute configuration of the four stereocentres of known product endo-14aa (2S.3R.4R.5R) was confirmed by NOESY experiments and by comparison of the obtained data with the previous ones published in the literature.19


Table 1. Optimization of the reaction of iminoesters 6a with NMM.



















Product 12a




Entry

Iminoester 6

Ligand

AgI salt

No.

Yield (%)b

endo:exoc

ee (%)d

1

6aa

8

AgBF4

12aa

77

89:11

72

2

6aa

8

AgNO3

12aa

65

85:11

67

3

6aa

8

Ag2O

12aa

65

90:10

18

4

6aa

8

AgOAc

12aa

89

>98:2

99

5

6aa

8

AgOTf

12aa

88

90:10

99

6

6aa

8

AgF

12aa

81

90:10

98

7

6aa

8

AgClO4

12aa

90

>98:2

>99

8

6aa

8

AgClO4e

12aa

90

>98:2

>99

9

6aa

8

AgClO4·H2O

12aa

89

>98:2

99

10

6aa

8

AgClO4f

12aa

89

90:10

98

11

6aa

8

AgClO4g

12aa

91

90:10

<50

12

6aa

9

AgClO4

12aa

91

>98:2

>99

13

6aa

10

AgClO4

12aa

90

>98:2

>99

14

6aa

11

AgClO4

12aa

90

>98:2

98



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