Novel N,O-Cu(OAc)₂ complex catalysed diastereo- and enantioselective 1,4-addition of glycine derivatives to alkylidene malonates

Abstract

Newly developed chiral N,O-Cu(OAc)₂ complexes were found to catalyse the diastereo- and enantioselective 1,4-addition of glycine derivatives to alkylidene malonates to afford 3-aryl glutamic acids derivatives in good yields (82–98%) and high stereoselectivities (up to 83% for anti and 90% for syn adducts, respectively). High optical purity anti adducts (up to 99% ee) can be obtained after simple recrystallisation, and their conversion to free 3-aryl glutamic acids was demonstrated by a representative example, chlorpheg, via a one pot process in 72% yield.

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Introduction

The synthesis of optically active (un)natural α-amino acid derivatives is of great importance in current organic synthesis, especially in the post-genomic era.¹Glutamic acid and its β-substituted derivatives are biologically important α-amino acid derivatives because they work not only as essential components of peptides and proteins but also as signal mediators.² For example, chlorpheg,³3-p-chlorophenyl glutamic acid, is a selective L-homocysteic acid (HCA) uptake inhibitor, which selectively enhances the excitatory, depolarising activities of l-HCA on amphibian and mammalian central nervous system neurons. Among the most efficient synthetic methods of β-substituted glutamic acid derivatives are diastereoselective⁴ or catalytic⁵1,4-additions of glycine derivatives to α,β-unsaturated esters or amides. Kobayashi and co-workers reported the first example of alkaline earth metal calcium-catalysed diastereo- and enantioselective 1,4-additions of glycine derivatives to β-alkyl-α,β-unsaturated esters,⁶ 3-alkyl glutamic acid derivatives were prepared in excellent yields with up to 99% ee. It was shown that a tert-butylphenylmethylene glycine tert-butyl ester was the best substrate in terms of product distribution and selectivity. When less sterically hindered diphenylene glycine tert-butyl ester was employed a useful [3 + 2] cycloaddition reaction predominated to afford chiral multi-substituted pyrrolidines rather than 1,4-addition adducts. Furthermore, Kobayashi and co-workers have used this methodology to perform important transformations of nitroalkenes and enolate protonation.⁷ Nevertheless, the application of such a catalytic methodology to the synthesis of 3-aryl glutamic acid derivatives remains unreported.

Results and discussion

To-date, a great challenge for organic synthesis is the preparation of biologically relevant 3-aryl glutamic acid derivativesviacatalytic, diastero- and enantioselective 1,4-addition protocols. On the other hand, alkylidene malonates serve as excellent Michael acceptors and have been successfully employed in a variety of 1,4-addition reactions.^5e,8 To the best of our knowledge, catalytic enantioselective 1,4-addition of alkylidene malonates 1 to glycine ester derivatives 2 have not yet been reported.

Consequently, we envisaged that such catalytic enantioselective 1,4-additions may provide a practical approach for the production of valuable optically pure 3-aryl glutamic acid derivatives. In the course of developing new catalytic systems for asymmetric reactions we designed and synthesised a series of new 1,3-dihydroimidazole based N,O-bidentate ligands 4–8,⁹ which we envisioned as new chiral ligands for asymmetric transition metal catalysis. Herein, catalytic asymmetric 1,4-addition reactions of glycine derivatives to various alkylidene malonates to afford 3-aryl glutamic acid derivatives, under control of new N,O ligands, in good to high diasteroselectivities and enantioselectivities is presented (Scheme 1).

Scheme 1 Catalytic asymmetric 1,4-addition of glycine Schiff bases 2 to alkylidene malonates 1.

Initially, we examined N,O ligand 4 in the reaction of methyl cinnamate with glycine methyl ester 2a in the presence of 11 mol% of ligand and 10 mol% of Cu(OAc)₂ in THF at room temperature, unfortunately no reaction was observed, perhaps due to the relatively low reactivity of methyl cinnamate. Considering the stronger electrophilicity of alkylidene malonates over methyl cinnamate, dimethyl p-chlorobenzylidene malonate 1a was next used in a reaction with glycine methyl ester 2a under the same conditions. Pleasingly, the desired 1,4-adduct 3aa was obtained in 33% yield with moderate diastereo- and enantioselectivity (Table 1, entry 1, anti/syn = 85/15, 50% ee for anti adduct). Moreover, the addition of a catalytic amount of KO^tBu (10 mol%) was found to facilitate the reaction to afford 3aa in 85% yield with higher enantioselectivity (Table 1, entry 2, anti/syn = 91/9, 71% ee for anti adduct). At 0 °C the enantiomeric excess of 3aa could be further increased to 75% at the expense of yield under otherwise identical conditions (Table 1, entry 3). Screening solvents revealed THF to be optimal of those tried, in terms of both yield and enantioselectivity (Table 1, entries 4–8). Next, a series of Lewis acids were screened using 11 mol% of 4 and 10 mol% of KO^tBu at room temperature in THF. Copper salts with stronger Lewis acidity, such as Cu(OTf)₂ and CuCl₂ were found to be inactive for this reaction (Table 1, entries 12–15). Other metal Lewis acids such as NiCl₂·2H₂O, Ni(OAc)₂·4H₂O, Zn(OAc)₂·2H₂O were completely inactive either (Table 1, entries 9–11). Silver acetate allowed the reaction to proceed smoothly to afford the desired product 3aa in 80% yield, albeit with low enantiomeric excess (Table 1, entry 16, 26% ee for anti adduct). Screening bases suggested that variation does not change the enantioselectivity but does affect the yield, as such KO^tBu was selected as the optimal base. Since increasing the amount of KO^tBu to 20 mol% only increased the yield of product slightly without changing the enantioselectivity of corresponding product (Table 1, entry 2 versus 22) 10 mol% of KO^tBu was chosen as the optimal loading for further study.

Table 1 1,4-Addition of 2a to 1a in the presence of N,O-ligand 4

Entry	Metal salts	Bases	Solvent	Yield (%)^a	anti : syn^b	ee^c/(anti : syn)
a Isolated yields, N.P. means no product observed (TLC analysis). b Ratio determined by HPLC. c Determined by HPLC.
1	Cu(OAc)2	—	THF	33	85 : 15	50/—
2	Cu(OAc)2	KO^tBu(10%)	THF	87	91 : 9	71/26
3	Cu(OAc)2	KO^tBu(10%)	THF(0 °C)	65	91 : 9	75/—
4	Cu(OAc)2	KO^tBu(10%)	Toluene	30	73 : 27	51/86
5	Cu(OAc)2	KO^tBu(10%)	CH2Cl2	28	52 : 48	20/81
6	Cu(OAc)2	KO^tBu(10%)	CH3CN	Trace	—	—
7	Cu(OAc)2	KO^tBu(10%)	Et2O	57	89 : 11	59/10
8	Cu(OAc)2	KO^tBu(10%)	Dioxane	80	89 : 11	67/26
9	NiCl2·6H2O	KO^tBu(10%)	THF	NP	—	—
10	Ni(OAc)2·4H2O	KO^tBu(10%)	THF	NP	—	—
11	Zn(OAc)2·2H2O	KO^tBu(10%)	THF	NP	—	—
12	Cu(OTf)2	KO^tBu(10%)	THF	Trace	—	—
13	CuCl2	KO^tBu(10%)	THF	Trace	—	—
14	Cu(ClO4)2·6H2O	KO^tBu(10%)	THF	Trace	—	—
15	Cu(acac)2·2H2O	KO^tBu(10%)	THF	Trace	—	—
16	AgOAc	KO^tBu(10%)	THF	80	79 : 21	26/0
17	Cu(OAc)2	NaHMDS(10%)	THF	91	89 : 11	63/19
18	Cu(OAc)2	PS (10%)	THF	50	89 : 11	67/23
19	Cu(OAc)2	CsCO3(10%)	THF	46	92 : 8	69/27
20	Cu(OAc)2	Et3N(10%)	THF	56	90 : 10	68/—
21	Cu(OAc)2	KO^tBu(5%)	THF	57	89 : 11	71/23
22	Cu(OAc)2	KO^tBu(20%)	THF	93	90 : 10	69/25

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The effect of variation in the ester moieties (R¹ and R²) was next probed, the results are summarised in Table 2. For both R¹ and R², the smallest group employed gave the optimal yield and enantioselectivity of corresponding 1,4-addition product (Table 2, entry 1, 71% ee, and anti : syn = 91 : 9). The diastereoselectivity was dramatically increased to 99 : 1 when the methyl ester group was replaced by a t-butyl ester, however yield and enantioselectivity were moderate (Table 2, entry 3). Substrate 1c, with an isopropyl ester, was found to be inactive for this catalytic system due to unconfirmed steric hindrance between isopropyl group and the catalytic complex.

Table 2 Optimisation of ester moiety R¹ and R² of both 1 and 2^a

Entry	R^1	R^2	Yield (%)	anti : syn	ee (anti : syn)
a All reactions performed at room temperature, with THF as solvent, using 11 mol% of ligand 4, 10 mol% of Cu(OAc)2 and 10 mol% of KO^tBu.
1	Me	Me	87	91 : 9	71/26
2	Me	Et	74	89 : 11	68/29
3	Me	t-Bu	27	>99 : 1	55/—
4	Me	Ph	65	89 : 11	51/7
5	Et	Me	68	91 : 9	67/27
6	i-Pr	Me	Trace	—	—

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Next, a series of N,O-ligands 5–8 were examined under the optimal reaction condition, the results are summarised in Table 3. It was found that the enantioselectivity of the 1,4-addition adduct was increased to 81% ee and 87% ee for both the anti and syn isomer when N,O-ligand 7, bearing two stereogenic centres on imidazole ring, was employed. Two other known oxazoline based N,O-ligands 9¹⁰ and 10¹¹ also gave the 1,4-addition adduct, with lower diastereoselectivities and low enantioselectivities (Table 3, entries 6 and 7). Commercially available bisoxazoline ligand 11 delivered the desired product in moderate yields and diastereoselectivity, in close to racemic form (Table 3, entry 8).

Table 3 Ligand screening (4–11) for the reaction of 1a and 2a^a

Entry	L	Yield (%)	anti : syn	ee (anti : syn)
a All reactions performed at room temperature, with THF as solvent, using 11 mol% of ligand 4, 10 mol% of Cu(OAc)2 and 10 mol% of KO^tBu.
1	4	87	91 : 9	71/26
2	5	85	90 : 10	66/19
3	6	73	56 : 44	36/54
4	7	86	87 : 13	81/87
5	8	60	91 : 9	70/60
6	9	61	80 : 20	31/5
7	10	71	80 : 20	−19/−15
8	11	49	79 : 21	7/rac

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Having established the optimal catalytic system, the scope and generality of substrates with regard to the aryl funtionality of alkylidene malonates was examined. As shown in Table 4, a wide array of arylidene malonates 1a–k derived from various of aromatic aldehydes, bearing electron-rich, -neutral and -deficient groups, reacted smoothly with glycine methyl ester 2a to afford the corresponding 1,4-adducts (3aa–3ka) in high yields (82–98%) with moderate diastero- (4 : 1 to 9 : 1) and good enantioselectivities (79–83% ee for anti adducts and 83–90% ee for syn) (Table 4, entries 1–9). It is apparent that both the position and electronic properties of the substituents on the phenyl ring have little influence on the reaction activity and stereoselectivity. Notably, heteroaromatic substrates 1l and 1m were also tolerated and gave the corresponding adducts in good yields and similar stereoselectivities (Table 4, entries 10 and 11). The enantiomeric excess of the anti isomer of 3aa, 3ea and 3ha were improved to >98% after a simple recrystallisation.

Table 4 Asymmetric 1,4-addition of 2 to 1 in the presence of N,O-ligand 7^a

Entry	R^1	Yield (%)	anti : syn	ee (anti : syn)
a KO^tBu is not need. b The reaction time was 24 h. c Data in parentheses were the ee of anti adduct after simple crystallisation.
1	p-Cl-Ph (1a)	86	87 : 13	81/87(98/—)^c
2	m-Cl-Ph (1d)	90	85 : 15	79/89
3	p-Br-Ph (1e)	98	87 : 13	81/88(98/—)^c
4	p-CF3-Ph (1f)	96	89 : 11	80/88
5^a^,^b	p-NO2-Ph (1g)	83	82 : 18	80/86
6	Ph (1h)	89	88 : 12	83/90(99/—)^c
7	p-Me-Ph (1i)	93	89 : 11	82/83
8	o-Me-Ph (1j)	82	82 : 18	80/90
9	p-OMe-Ph (1k)	82	87 : 13	81/86
10	2-furyl (1l)	93	82 : 18	81/86
11	3-pyridyl (1m)	88	80 : 20	78/80

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Transformation of 3aa was also conducted to afford selective L-homocysteic acid (HCA) uptake inhibitor chlorpheg (12) in 72% yield via the hydrolysis of esters, subsequent decarboxylation and hydrolysis of imine in one pot (Scheme 2).

Scheme 2 One pot imine and ester hydrolysis of 3aa to give Chlorpheg 12 in 72% yield.

The relative configuration of major adducts of 3 were assigned as the anti isomer by X-ray diffraction analysis of 3ha (see ESI)† and comparison of other spectroscopic data. The absolute configuration of 3 was established as (2R,3S) by comparing the optical rotation of 12 to that of literature precedents.¹²

Conclusions

In summary, the first highly efficient catalytic diastereo- and enantioselective 1,4-addition of glycine derivatives to alkylidene malonates in the presence of chiral N,O-Cu(OAc)₂ complexes to afford 3-aryl glutamic acids derivatives in good yields (82–98%) and high stereoselectivities (up to 83% for anti and 90% for syn adducts respectively) has been developed. High optical purity anti adducts were obtained after simple recrystallisation, and their conversion to free 3-aryl glutamic acids was demonstrated by a representative example, chlorpheg (12), via a one pot process in 72% yield. Further mechanistic studies and development of applications are now in progress.

Acknowledgements

WPD thanks financial support from the New Century Excellent Talents in University, the Ministry of Education, China (no. NCET-07-0283), the Shanghai Committee of Science and Technology (grant no. 06PJ14023) and “111” Project (no. B07023). JSF thanks ECUST for visiting Professorship, ERDF AWMII and the University of Birmingham for support. WPD and JSF thank the CAtalysis and Sensing for our Environment (CASE) network, and the CASE09 workshop at ECUST for networking opportunities.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: The synthetic procedures for N,O-ligands 4 and 7 along with corresponding spectral data; general experimental procedure, spectral data for all 1,4-addition adducts 3; X-ray analysis data of 3ha in CIF format is provided. CCDC reference number 795643. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c0cy00001a

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