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.
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.
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).
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
, the corresponding enantiomer (2S
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 1
H 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 Et3
N, such as DBU or DIEA. Using Et3
N 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
(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
(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
with 92% ee
after recrystallization (Table 3, entry 19). The recovery of the complex (S
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
were diastereoselectivity obtained (>98:2 endo
ratio) and with good enantioselections (72-76% ee
). However, compound endo
was obtained after recrystallization in 98% ee
, and 58% yield (Scheme 3). The absolute configuration of the heterocycle (2R
was determined X-ray diffraction analysis (Figure 4). 2-Thienyl derivatives endo
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
(5 mol%), AgClO4
(5 mol%) and Et3
N (5 mol%) in toluene. N
-Ethylmaleimide afforded similar results of endo
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
and lower diastereoselectivity (90:10 endo
ratio) (Figure 5).
Figure 5. Products obtained from different N-substituted maleimides.
Monomethylated and dimethylated N
, 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
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 Et3
N 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
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.