Graphical Abstract



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Graphic 3. TG-DTA plot of complex (S)-16

Such as it was described before, the easy separation of the most active major complex (S)-16 was a very important feature to apply in a larger scale process. So, a series of cycles were run employing the same catalytic mixture (1:1 8-AgClO4), which was recovered and reused without any additional purification (Scheme 1 and Table 2). The reaction shown in Scheme 1 was performed on a 1 mmol scale on 6aa with a 10 mol% of catalyst to facilitate its manipulation and successive reutilization. In the cycles 1- 4 the enantioselectivity was higher than 99% ee keeping identical chemical yields (81-91%) (Table 2, entries 1-4). The fifth cycle also afforded the title product endo-12aa in high yield but with a slightly lower ee (98%) (Table 2, entry 5) due to the effect of the possible impurities contained in the catalyst. In all of the five cycles tested the endo:exo diastereoselectivity was higher than 98:2 according to 1H NMR experiments.

Table 2. Recycling experiments of 1:1 [(S)-Binap 8]:AgClO4 complex.

Cycle

Reaction (mmol)

(S)-6aa (mmol) a

Recovered Catalyst (%)

Yield (%)b

eeendo (%)c

1

1

0.100

95

91

>99

2

1

0.095d

93

89

>99

3

1

0.088d

92

91

>99

4

1

0.081d

90

90

99

5

1

0.073d

90

88

98


a Recovered after filtration of the crude reaction suspension and washed several times with toluene.

b Isolated yield of compound endo-12aa after recrystallization. The conversions were >99% and the endo:exo ratio were >98:2 in all of the essayed cycles.

c Determined by chiral HPLC (Daicel Chiralpak AS).

d Amount recovered from the previous cycle.

The existence of NLE was discarded when the reaction shown in the Scheme 1 was performed using different optical purities of the in situ generated major complex (S)-16 (Graphic 4). In this case, an almost linear behavior was observed and, in consequence, it was reasonable to assume that monomeric complexes can be the catalytically active species.





Graphic 4. NLE study of the model reaction catalyzed by the presumed major complex 16.

2.3. Scope of the 1,3-DC catalyzed by complexes (R)- and (S)-16.

The scope of the reaction employing different aryl- and ester groups at the iminoester structure with assorted dipolarophiles, was surveyed. Several ester and aryl groups were appropriate substituents in iminoglycinates 6 to perform efficiently the 1,3-DC with NMM 11 (Scheme 2 and Table 3).



Scheme 2. Reagents and conditions: i) (S)-Binap 8 (5 mol%), AgClO4 (5 mol%), base (5 mol%), toluene, rt, 16 h.




Table 3. 1.3-DC of iminoglycinates 6 and NMM 7.
















Product endo12

Entry



Ar

R

Base



Yield. (%)a

endo:exob

eeendo (%)c

1

6aa

Ph

Me

Et3N

12aa

90

>98:2

>99 (>99)d

2

6aa

Ph

Me

Et3N

12aae

90

>98:2

>99 (>99)d

3

6ab

Ph

Et

Et3N

12ab

78

90:10

90 (91)

4

6ac

Ph

Pri

Et3N

12ac

80

90:10

70 (72)

5

6ad

Ph

But

Et3N

12ad

81

75:25

92 (92)

6

6ba

2-naphthyl

Me

Et3N

12ba

89

>98:2

99 (>99)d

7

6bd

2-naphthyl

But

Et3N

12bd

87

95:5

92 (94)

8

6ca

2-CH3C6H4

Me

Et3N

12ca

85f

>98:2

70 (75)

9

6da

2-ClC6H4

Me

Et3N

12da

82f

>98:2

82 (85)

10

6da

2-ClC6H4

Me

Et3N

12da

82f,g

>98:2

82 (85)

11

6ea

4-CH3C6H4

Me

Et3N

12ea

88

>98:2

86 (88)d

12

6ea

4-CH3C6H4

Me

DBU

12ea

88

>98:2

99 (>99)d

13

6fa

4-(CH3O)C6H4

Me

Et3N

12fa

85

>98:2

80 (99)

14

6fa

4-(CH3O)C6H4

Me

Et3N

12fa

85g

>98:2

80 (99)

15

6fd

4-(CH3O)C6H4

But

Et3N

12fd

84

95:5

90 (91)

16

6ga

4-ClC6H4

Me

Et3N

12ga

87

>98:2

64 (65)

17

6ga

4-ClC6H4

Me

DBU

12ga

87g

>98:2

98 (99)

18

6gd

4-ClC6H4

But

Et3N

12gd

83

>98:2

80 (80)

19

6ha

2-thienyl

Me

Et3N

12ha

87

>98:2

90 (92)h

20

6ha

2-thienyl

Me

Et3N

12ha

87g

>98:2

90 (92)h

a Isolated yield after recrystallization.

b Determined by 1H-MNR.

c Determined by chiral HPLC (Chiralcel OD-H), in parenthesis the results of the recrystallized product..

d Determined by chiral HPLC (Chiralpak AS).

e Molecule (2R.3S.4S.5S) endo12aa obtained employing (R)-16.

f Purification by flash chromatography.

g Reaction performed with the recycled catalytic mixture.

h Determined by chiral HPLC (Chiralpak AD).


Non-substituted methyl aryliminoglycinates 6, derived from benzaldehyde and 2-naphthalenecarbaldehyde, were the best substrates affording >99% ee (Table 3, entries 1, 2, and 6). In the example performed with catalytic complex (R)-16, the corresponding enantiomer (2S.3R.4R.5R)-endo-12aa was obtained (Table 3, entry 2). It was also demonstrated for these phenyl and 2-naphthyl derivatives that ethyl, isopropyl, and tert-butyl iminoglycinates were not suitable groups for obtaining the highest enantioselections (Table 3, entries 3, 4, 5, and 7). In these examples, it was also observed that larger amounts of the exo-diastereoisomer 12 were formed according to 1H NMR spectroscopy and chiral HPLC. More sterically hindered iminoglycinates derived from ortho-substituted aromatic aldehydes gave lower enantioselections (Table 3, entries 8 and 9), even working at 0 or 20 ºC and with other bases different to Et3N, such as DBU or DIEA. Using Et3N as base, the imines derived from electron-donating or electron-withdrawing para-substituted aromatic aldehydes shown a very similar tendency (Table 3, compare entries 11, 13, 14 and 16). In a few compounds the ee was increased after recrystallization of the previously purified sample endo-12fa (Table 3, entry 13), but in other situations the employment of DBU as base at 0 ºC resulted to be crucial in order to achieve excellent enantioselections of endo-12ea and endo-12ga (Table 3, entries 12 and 17). Unlike the results described from phenyl and naphthyl derivatives the terc-butyl esters were more effective than the corresponding methyl esters in those examples containing a para-substituted aromatic residue imino group (compare entries 13 and 15, 16 and 18 of Table 3). Heteroaromatic iminoglycinate bearing a 2-thienyl group furnished endo-cycloadduct 12ha with 92% ee after recrystallization (Table 3, entry 19). The recovery of the complex (S)-16 was successfully attempted in the examples recorded in entries 10, 14 and 20 of the Table 3 in 88-93% yield by simple filtration.
Next, sterically hindered α-substituted benzaldimino esters were tested as substrate in this 1,3-DC with NMM. Methyl benzylidenealaninate 18, methyl phenyliminophenylalaninate 19 and methyl 2‑thienyliminoleucinate 20 reacted with NMM under the same reaction conditions at room temperature for 48 h (Scheme 3). Cycloadducts endo-21-23 were diastereoselectivity obtained (>98:2 endo:exo ratio) and with good enantioselections (72-76% ee). However, compound endo-22 was obtained after recrystallization in 98% ee, and 58% yield (Scheme 3). The absolute configuration of the heterocycle (2R.3S.4S.5S) endo21 was determined X-ray diffraction analysis (Figure 4). 2-Thienyl derivatives endo-12ha and endo-23 can be considered as structurally related precursors of active inhibitors of the virus responsible of the hepatitis C 1 (Figure 1).Error: Reference source not foundi,21

Scheme 3. Reagents and conditions: i) (S)-Binap 8 (5 mol%), AgClO4 (5 mol%), Et3N (5 mol%), toluene, rt, 48 h.


Figure 4. ORTEP of cycloadduct endo-21.


Several maleimides were essayed employing the model reaction described in Scheme 1, that means benzyliminoglycinate 6aa, room temperature, (S)-8 (5 mol%), AgClO4(5 mol%) and Et3N (5 mol%) in toluene. N-Ethylmaleimide afforded similar results of endo-24 to the analogous obtained with NMM 7 after 8 h of reaction (Figure 5). Nevertheless, the bulkier N-phenylmaleimide (NPM) furnished lower ee (62%) of endo-25 and lower diastereoselectivity (90:10 endo:exo ratio) (Figure 5).

Figure 5. Products obtained from different N-substituted maleimides.


Monomethylated and dimethylated N-ethylmaleimides 26 and 29, respectively, were prepared22 and used as dipolarophiles. Non-symmetric maleimide 26 was an attractive reagent for studying how would be the regioselection of this process. When the reaction was completed cycloadducts 27 and 28 were obtained in a 44:56 ratio respectively. This ratio remained unaltered when the reaction was run at 0 or at –20 ºC, both in the presence of Et3N or DBU. In general, better enantioselection was achieved with DBU (84 and 89% ee) (Scheme 4). However, no reaction was observed when 3,4-dimethyl-N-ethylmaleimide 29 was allowed to react with imino ester 6aa.

Scheme 4. Reagents and conditions: i) (S)-Binap 8 (5 mol%), AgClO4 (5 mol%), Et3N (5 mol%), toluene, rt, 16 h.

Dipolarophiles different to maleimides were not appropriate for the particular requirements of this enantioselective 1,3‑DC catalyzed by the in situ generated complex (S)‑16 (Scheme 5 and Table 4). Acrylates 29, fumarates 30, maleate 31, and acrylonitrile 32 gave very high reaction conversions but the enantioselections never exceeded of the 36% ee (Table 4) maintaining the high endo:exo diastereoselection. Maleic anhydride, nitrostyrene, acrylamide and N-isopropylacrylamide did not react at all in spite of using DBU (10 mol%) as base or even other chiral ligands 9-11.
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