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Enantioselective Isocyanoacetate Addition Reactions under Cooperative Base and Lewis Acid Catalysis

Final Report Summary - ENISOCOC (Enantioselective Isocyanoacetate Addition Reactions under Cooperative Base and Lewis Acid Catalysis)

Final Summary attached as pdf

ENISOCOC (FP7-PEOPLE-2010-IEF)
Dr. Irene Ortín Remón and Prof. Darren J. Dixon (University of Oxford)

1. INTRODUCTION: Cooperatively Catalysed Isocyanoacetate ketimine Mannich Reaction
2-Imidazolines form the structural core of many biologically active compounds,1 and are useful building blocks for the synthesis of cyclopalladated complexes, asymmetric catalysts and chiral solvating agents.2 In addition, through hydrolytic or reductive manipulation, these heterocycles are intermediates for the synthesis of biologically significant and highly versatile -diaminoacids.3 For these and other reasons, the asymmetric synthesis of 2-imidazolines has been the focus of a number of research groups in recent years. A direct route is the catalytic asymmetric Mannich-type addition / cyclization of isocyanoacetate pronucleophiles with imine electrophiles. Highly stereoselective examples using both metal-rich and metal-free catalysts have been reported using imines derived from aldehydes (aldimines).4 To date, however, there has been no report of the analogous but much more challenging reaction with the significantly less reactive ketone-derived imines (ketimines) despite its potential to provide a unique route to chiral 2-imidazolines possessing vicinal stereogenic centres, including a fully substituted -carbon.
Figure 1. Concept of the Catalytic Isocyanoacetate Ketimine Mannich Reaction.

2. OBJECTIVES OF THE PROJECT
Recently, we reported the highly enantio- and diastereoselective synthesis of oxazolines5 from isocyanoacetate pronucleophiles and aldehydes using cooperative combinations of cinchona-derived amino-phosphine precatalysts I and Ag(I) salts. This new binary catalyst system arose from a generally applicable design introduced by us to overcome poor reactivity profiles in numerous pronucleophile / electrophile addition reactions under bifunctional organocatalyst control. A true test of the capability of this flexible and tunable cooperative catalyst design was in attaining new reactivity and absolute and relative stereocontrol in reactions where previously there was no precedent. The catalytic asymmetric Mannich-type addition / cyclization of isocyanoacetate pronucleophiles I with ketimines II to afford imidazolines III indeed provided this opportunity and herein we wish to present our solution.
Figure 2. Concept of the Catalytic Isocyanoacetate Ketimine Mannich Reaction.

3. RESULTS
Proof of concept studies were performed on acetophenone-derived imine 3a bearing the N-diphenylphosphinoyl (DPP) protecting group. Such imines are readily prepared from the parent ketone and cleavage of the DPP group from the product imidazolines 4 was anticipated to be facile under mildly acidic conditions. The sterically demanding diphenylmethylisocyanoacetate 2a was chosen as the pro-nucleophilic component in alignment with our previous studies where stereocontrol correlated with the size of the ester substituent.

Table 1. Optimization studies.

entry precat MLn(mol %) R1 2 T (°C) solvent Time (h) 4 yield(%)[a] dr(t:c) [b] ee [c]
1 1a Ag2O (5) CH(Ph)2 2a r.t. CH2Cl2 48 h 4a 70 71:29 72
2 1a AuCl (10) CH(Ph)2 2a r.t. CH2Cl2 48 h 4a 20 14:86 2
3 1a CuCl (10) CH(Ph)2 2a r.t. CH2Cl2 48 h 4a 23 43:57 2
4 1a Ag2O (5) CH(Ph)2 2a r.t. TBME 24 h 4a 44 37:63 70
5 1a Ag2O (5) CH(Ph)2 2a r.t. EtOAc 24 h 4a 68 83:17 78
6 1a Ag2O (5) CH(Ph)2 2a –20 EtOAc 60 h 4a 70 84:16 83
7 1b Ag2O (5) CH(Ph)2 2a –20 EtOAc 60 h 4a 78 89:11 94
8 1a Ag2O (5) tBu 2b –20 EtOAc 60 h 4b 89 88:12 89
9 1a Ag2O (5) CH3 2c –20 EtOAc 60 h 4c 94 91:9 74
10 1a - CH(Ph)2 2a –20 EtOAc 120 h 4a 0 --- ---
11 - Ag2O (5) CH(Ph)2 2a –20 EtOAc 120 h 4a 83 18:82 0
[a] Combined yield of both diastereomers after FCC. [b] Diastereomeric ratio (dr) was determined by 1H NMR analysis of the crude reaction mixture. [c] Enantiomeric ratio (ee) of major diastereomer determined by chiral HPLC analysis after deprotection

Initially, a silver oxide (5 mol%) / cinchonine-derived amino-phosphine 1a (20 mol%) catalyst system was examined in dichloromethane as solvent at room temperature. A 2:1 ratio of precatalyst to metal ion ratio was chosen to minimize any competing background reaction.5 Pleasingly the trans-imidazoline product, (4S,5R)-4a, was obtained with significant diastereo- and enantiocontrol (Table 1, entry 1; 71:29 dr, 72% ee). A metal6,7 salt screen confirmed silver (rather than gold or copper) to be the best match for 1a (Table 1, entries 1-3). A solvent survey revealed ethyl acetate as the preferred choice in terms of both diastereo- and enantiocontrol (Table 1, entries 1, 4 and 5). Lowering the temperature of the reaction to ¬–20 °C was found to be beneficial for enantioselectivity (Table 1, entry 6; 84:16 dr, 83% ee) and employment of pseudoenantiomeric 1b in lieu of 1a afforded the enantiomeric product (4R,5S)-4a, as expected, but pleasingly with enhanced enantio- and diastereoselectivity (Table 1, entry 7; 89:11 dr, 94% ee). The bulky tert-butylisocyanoacetate was also reactive and afforded the major trans-imidazoline product (4S,5R)-4b in better yield and enantioselectivity (Table 1, entry 8; 89% yield, 88:12 dr, 89% ee). In contrast, use of methyl isocyanoacetate 2c resulted in diminished enantioselectivity for the major trans-diastereomer (4S,5R)-4c (Table 1, entry 9; 94 % yield, 91:9 dr, 74% ee). Finally, control experiments confirmed the importance of the combination of both silver salt and aminophosphine precatalyst; without the silver salt there was no reaction (Table 1, entry 10); without the precatalyst, enantiocontrol was (naturally) absent, the reaction was significantly slower and diastereoselectivity in favour of the cis-diastereomer predominated (Table 1, entry 11, 18:82 dr).
With the optimized reaction conditions established, the scope of the reaction was assessed by probing changes to both the aryl and alkyl groups of the ketimine in reactions with bulky isocyanoacetates 2a and 2b (Table 2).
With tert-butylisocyanoacetate pronucleophile 2b in the presence of cinchonidine-derived amino phosphine precatalyst 1b, good to excellent diastereoselectivities and excellent enantioselectivities (94-99% ee) were observed for DPP-protected para-substituted arylmethyl ketimines possessing both electron-withdrawing and electron-releasing groups (Table 2, entries 2-6). With the same set of electrophiles under the control of cinchonine-derived amino phosphine precatalyst 1a enantiomeric imidazoline products were obtained as anticipated but the magnitude of the enantioselectivity was diminished across the series. Importantly, ethyl phenyl ketone-derived imine 3f was also an excellent substrate and afforded the trans-imidazoline product 4h in high yield and good diastereoselectivity (Table 2, entry 7). With catalyst 1b the major trans-diastereomer was obtained with an excellent ee of 97% whereas the antipode was afforded with 82% ee using precatalyst 1a.

Table 2. Scope of the reaction.

entry[a] Ar R2 2 4 yield (%)[b] dr[c],[c] t:c ee [d]
1 Ph CH3 2a a 70(78) 84:16(89:11) 94(83)
2 Ph CH3 2b b 92(89) 99:1(88:12) 96(89)
3 p-NO2Ph CH3 2b d 87(89) 8:2(99:1) 95(73)
4 p-ClPh CH3 2b e 96(80) 96:4(95:5) 93(79)
5 p-CH3Ph CH3 2b f 78(88) 9:1(96:4) 98(75)
6 p-OCH3Ph CH3 2b g 87(81) 75:25(94:6) 99(70)
7 Ph Et 2b h 85(89) 88:12(97:3) 97(82)
8 p-NO2Ph CH3 2a i 97(88) 6:4(86:14) 88(75)
9 p-ClPh CH3 2a j 83(81) 86:14(94:6) 97(89)
10 p-CH3Ph CH3 2a k 96(89) 95:5(91:9) 96(88)
11 p-OCH3Ph CH3 2a l 96(84) 73:27(88:12) 98(88)
12 Ph Et 2a m 80(93) 81:19(88:12) 90(58)
13 m-OCH3Ph CH3 2a n 82(72) 74:26(75:25) 96(96)
14 o-OCH3Ph CH3 2a o 96(79) 8:2(77:23) 97(96)
15 p-Ph-Ph CH3 2a p 97(88) 9:1(82:18) 97(85)
16 o-BrPh CH3 2a q 97(74) 99:1(99:1) 96(89)
17 p-BrPh CH3 2a r 98(84) 78:22(82:18) 94(88)
18 o-FPh CH3 2a s 95(98) 84:16(8:2) 96(86)
19 p-FPh CH3 2a t 95(74) 83:17(91:9) 96(91)
20 3,5-(CF3)2Ph CH3 2a u 81(91) 78:22(83:17) 86(75)
21 3,4-Cl2Ph CH3 2a v 84(91) 85:15(86:14) 95(84)
[a] The data in parentheses refer to reactions performed with precatalyst 1a. [b] Combined yield of both diastereomers after flash column chromatography. [c] Diastereomeric ratio (dr) was determined by 1H NMR analysis of the crude reaction mixture. [d] Enantiomeric ratio (ee) of the major diastereomer determined by chiral HPLC analysis after DPP removal.

Using diphenylmethylisocyanoacetate pronucleophile 2a a wide range of ketimines with various electron-donating and electron-withdrawing substituents in ortho, meta and para positions were good substrates. As with the tert-butylisocyanoacetate pronucleophile, enantioselectivities for the major trans-diastereoisomer with precatalyst lb were superior (typically between 5-15 ee percentage points) to those obtained with precatalyst 1a and ranged from 88% ee with p-nitrophenylmethyl ketimine (table 2, entry 8) to 98% ee with DPP-protected p-methoxyphenylmethylketimine (table 2, entry 11). DPP-protected phenylethyl ketimine was reactive and gave the reaction product 4m in 80% yield, 81:19 dr and in 90% ee for the major trans-diastereoisomer under the control of 1b. In total 14 substrates proved effective, giving rise to excellent enantio- and good diastereoselectivities for the trans-diastereomers when amino phosphine precatalyst 1b was used with silver oxide (Table 2, entries 8-21).
Although 20 mol% loading of the precatalyst was found to be convenient for assessing substrate scope, in a further demonstration of the practicability of this reaction precatalyst 1b loading was reduced from 20 mol% to 10 mol%, 5 mol% and 1 mol% at –20 °C (Table 3, entries 1-3). The observed diastereo- and enantioselectivities, were comparable to those obtained at 20 mol% loading, however the reaction speeds became prohibitively slow. In order to reduce the reaction time, the temperature was increased to 0 °C. Pleasingly this was possible without significant detriment to either enantio- or diastereocontrol (Table 3, entries 4-6).

Table 3. Catalyst loading studies.

entry 1b (mol%) Ag2O(mol%) T(ºC) time(h) yield(%)[a] dr[b]t:c ee[c]
1 10 2.5 –20 60 87 94:6 96
2 5 1.25 –20 120 78 93:7 96
3 1 0.25 –20 160 77 92:8 95
4 10 2.5 0 24 89 89:11 95
5 5 1.25 0 60 87 86:14 93
6 1 0.25 0 60 58 87:13 94
[a] Combined yield of both diastereomers after FCC. [b] The dr was determined by 1H NMR analysis of the crude. [c] The ee of major diastereomer determined by chiral HPLC analysis after deprotection.

In addition to the high yields and stereoselectivities, the advantage of our described method lies in the simple and efficient synthetic manipulation of the direct Mannich products into desirable building blocks and motifs. Protecting group-free 2-imidazolines were obtained by the efficient cleavage of the diphenylphosphoryl group8 using a 1.0 M solution of HCl in dichloromethane at room temperature (Table 4, entries 1-21). The deprotection was effected without compromise to either diastereo- or enantiopurity. Importantly, the absolute stereochemistry of the imidazolines was confirmed by single crystal X-ray analysis of 5w, a N-4-bromophenylsulphonyl derivative of 5r.

Figure 3. X-Ray of compound 5w (see attached document)

Furthermore, treatment of the unprotected 2-imidazoline 5a with a 50% aqueous solution of potassium hydroxide gave -diaminoacid9 6a without compromising stereochemistry (Scheme 2, Eq (1)). To probe the relative configuration of the -diaminoacid, the 1,2-diamine of compounds 5q and 5s were transformed into the cyclic urea derivatives 7q and 7s using excess Boc2O and DMAP (Scheme 2, Eq (2)). Absolute stereochemistry was confirmed by single crystal X-Ray analysis of 7q.

For more challenging, we decided to study the synthesis of imidazolines with two contiguous quaternaries stereocenters. A variety of aromatic ketimines, including heteroaromatic ketimines proved effective, giving rise to excellent enantio- and diastereoselectivities for trans diastereomers (entries 1-12, table 4), aliphatic ketimines were also well tolerated giving the best result in terms of enantioselectivity (entry 13, table 4). When cyclic ketimines were used, imidazolines including a spiro function were obtained in good enantioselectivity and excellent diastereoselectivity (entries 14-16, table 4). In order to generalize the reaction, it was performed with bulkiers aryl and alkyl groups in the side chain of the isocyanate. In this study, was observed that ethyl and bencyl group were well-tolerated giving same range values in terms of diastereoselectivity and slightly lower enantioselectivities than the alanine analogue (entries 17-22, table 4). In the other hand, with phenyl group cis diastereomer was obtained as the major one, and enantiselectivity dropped to 77 (entry 23, table 4).

Table 4. Scope of the reaction.

entry precat MLn R1 R2 Ar T(ºC) Solvent Time(h) Yield(%) Dr(t:c) [a] Ee [b]
1 1d Ag2O tBu CH3 p-Ph-Ph -20 EtOAc 60 h 60 / 88 100:0 88
2 1d Ag2O tBu CH3 p-F-Ph -20 EtOAc 60 h 99 / 84 100:0 89
3 1d Ag2O tBu CH3 o-F-Ph -20 EtOAc 60 h 95 / 62 100:0 88
4 1d Ag2O tBu CH3 p-Cl-Ph -20 EtOAc 60 h 94 / 71 100:0 86
5 1d Ag2O tBu CH3 p-NO2-Ph -20 EtOAc 60 h 84 / 79 100:0 72
6 1d Ag2O tBu CH3 p-Br-Ph -20 EtOAc 60 h 89 / 74 97:3 86
7 1d Ag2O tBu CH3 p-OCH3-Ph -20 EtOAc 60 h 91 / 75 100:0 90
8 1d Ag2O tBu CH3 o-OCH3-Ph -20 EtOAc 60 h 30 / 67 100:0 85
9 1d Ag2O tBu CH3 3-pyridinyl -20 EtOAc 60 h 80 / 85 100:0 85
10 1d Ag2O tBu CH3 2-pyridinyl -20 EtOAc 60 h 92 / 67 100:0 86
11 1d Ag2O tBu CH3 2-furyl -20 EtOAc 60 h 87 / 84 100:0 88
12 1d Ag2O tBu CH3 2-tiophenyl -20 EtOAc 60 h 40 / 89 100:0 83
13 1d Ag2O tBu CH3 Cyclohexyl 0 EtOAc 60 h 64 / 76 100:0 98
14 1d Ag2O tBu CH3 -20 EtOAc 60 h 67 / 94 100:0 75
15 1d Ag2O tBu CH3 -20 EtOAc 60 h 96 / 92 100:0 81
16 1d Ag2O tBu CH3 -20 EtOAc 60 h 98 / 77 100:0 84
17 1d Ag2O CH3 Bn Ph -20 EtOAc 60 h 80 / 75 98:2 81
18 1d Ag2O iPr Bn Ph -20 EtOAc 60 h 92 / 78 98:2 71
19 1d Ag2O tBu Bn Ph -20 EtOAc 60 h 75 / 86 100:0 80
20 1d Ag2O Bn Et Ph -20 EtOAc 60 h 89 / 84 99:1 84
21 1d Ag2O iPr Et Ph -20 EtOAc 60 h 80 / 84 100:0 84
22 1d Ag2O tBu Et Ph -20 EtOAc 60 h 75 / 79 100:0 90
23 1d Ag2O CH3 Ph Ph -20 EtOAc 60 h 62 / 92 18:82 77
[a] Diastereomer ratio (Dr) was determined by 1H NMR analysis.; [b] Determined by chiral HPLC analysis after conversion to N-deprotected-2-imidazoline.

In order to postulate the catalyst activation code and to further understand the role of precatalyst 1d, we carried out modifications on 1d in the amide function and the phosphine group. During these studies, when free-amide function was changed to an ester function or N-methyl-amide no reaction was observed (entries 2 and 3, table 5); with this we can conclude that the presence of a hydrogen bond is essential for the reactivity. When phosphine group was removed, reaction was not observed neither (entry 4, table 5), however when an external source of phosphine was added in the reaction, imidazoline was observed but in lower yield and very poor enantioseletivity (entry 5, table 11); this indicates that the presence of phosphine in the pre-catalyst is very important for reactivity and enantioselectivity. Finally, the relative stereochemistry at C-8 and C-9 was investigated. For this purpose precatalys 5, with the inverted stereochemistry at C-9 (with respect to 1d) was prepared; notably, a very poor yield and poor enantioselectivity was observed (entry 6, table 5) probing that the relative orientation of chiral pocket between the bridgehead nitrogen and the amide has a very important role in terms of enantioselectivity and reactivity (figure 4).

Table 5. Catalyst activation code study.

entry precat MLn T (ºC) Solvent Time (h) Yield(%) Dr(t:c) [a] Ee [b]
1 1d Ag2O -20 EtOAc 60 h 88 100:0 75
2 2 Ag2O -20 EtOAc 96 h n.r. --- --
3 3 Ag2O -20 EtOAc 96 h n.r. --- --
4 4 Ag2O -20 EtOAc 72 h n.r. --- --
5 4+PPh3 Ag2O -20 EtOAc 72 h 40 100:0 6
6 5 Ag2O -20 EtOAc 72 h 5 100:0 30
[a] Diastereomer ratio (Dr) was determined by 1H NMR analysis.; [b] Determined by chiral HPLC analysis after conversion to N-deprotected-2-imidazoline.

Figure 4. Postulated catalyst activation code. (see attached document)

4. CONCLUSIONS
In conclusion, in this project we have developed an efficient and general, diastereo- and enantioselective method for the synthesis of highly functionalised 2-imidazolines, possessing a fully substituted -stereocenter through a Mannich type reaction of isocyanoacetate pronucleophiles and ketimines using a silver and aminophosphine binary and cooperative catalyst system. Furthermore, highly functionalised 2-imidazolines two contiguous quaternary centers have been achieved. We have also demonstrated that chiral unprotected 2-imidazolines and ,-diaminoacids can be easily obtained from the protected 2-imidazoline reaction products. Further investigations to extend this study to the asymmetric synthesis of oxazolines with at least one quaternary centers have been started and are underway.

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