Design and synthesis of a s-triazene based asymmetric organocatalyst and its application in enantioselective alkylation

Abstract

A very efficient chiral organocatalyst was prepared from the readily available cyanuric chloride. The asymmetric catalyst exhibited a highly enantioselective catalytic performance for the alkylation of a glycinate Schiff base, which provides a useful procedure for the enantioselective synthesis of structurally diverse natural and unnatural α-alkyl-α-amino acids.

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The development of enantioselective C–C bond formation is a topic of great interest in organic synthesis.¹ Recent advances highlight the benefits/significance of environmentally friendly and efficient catalysts for such enantioselective transformations. Among others, phase transfer catalysts (PTCs) are known to play a pivotal role in enantioselective modifications in organic synthesis. Within PTCs, several nitrogen and phosphorous containing quaternary centres are frequently used in chiral PTCs.² Such chiral PTCs have a broad spectrum of applications owing to their diverse catalytically active structural motifs and high catalytic potential.³ It is well acknowledged that chiral PTCs are non-metal containing environmentally friendly organocatalysts.⁴ Additionally, chiral PTCs have many advantages over homogeneous catalysts, due to their high catalytic potential and broad spectrum of applications.⁵ Use of cinchona alkaloid salts as catalysts has been reported under biphasic conditions initially for the enantioselective alkylation of a glycinate Schiff base by O’Donnell et al. in 1989.⁶ Subsequently, o-alkylation of the cinchona alkaloids afforded a higher enantiomeric excess.⁷ Later, chiral C₂-symmetric quaternary ammonium salts, a new PTC class, was introduced by Maruoka et al. in 1999 with a binaphthyl structure for alkylation of glycinate derivatives.⁸ Shortly after, the Maruoka catalysts were found to be very efficient for a variety of asymmetric transformations even at very low catalyst loadings (<1 mol%). In addition, Shibasaki’s tartaric acid-derived bidentate PTCs,⁹ Lygo’s spirocyclic catalysts¹⁰ and guanidine type catalysts¹¹ were found to be highly efficient in asymmetric synthesis. The novel chiral quaternary catalysts have drawn the attention of many scientists because of their easy accessibility from sufficiently available chiral starting materials. A literature survey reveals that guanidines and amidines as asymmetric organocatalysts have been reported for several synthetic applications in organic synthesis.^12–14 Indeed, guanidine group containing molecules more often form stabilized complex salts via parallel interactions including hydrogen bonding with anionic compounds.¹⁵

Our research group is highly active within the field of catalytic organic transformations and designing s-triazene based effective catalytic systems for the synthesis of biologically active molecules.¹⁶ We diversified our idea by targeting the use of s-triazene as starting material for the synthesis of a new class of quaternary ammonium salts. It is well documented that s-triazene shows excellent catalytic properties for organic transformation reactions such as C–C and C–N bond formations.¹⁷ A literature survey revealed that the nature of the guanidine and thiourea containing groups of the catalyst has a strong influence on its catalytic performance for the alkylation of α-amino acids.¹⁸ In view of various studies, we designed three different chiral PTCs based on s-triazine for the alkylation of prochiral substrate 3 to produce optically active α-amino acids in good yields. The overall syntheses of three different chiral PTCs are presented in Scheme 1. In the first step, the chloro group of s-triazene was substituted by chiral amine (s)-phenylethylamine to give compound 1, containing a guanidine type moiety. Then compound 1 was reacted with propargyl bromide to produce compound 2, which on further reaction with benzyl bromide in toluene yielded chiral quaternary ammonium salt sT1. After the successful synthesis of chiral PTC sT1, we further investigated the chemistry and designed two new catalysts, sT2 and sT3 shown in Scheme 1, based on pyrrolidine and piperidine containing quaternary salts. For the synthesis of chiral quaternary salts sT2 and sT3, compound 1 was reacted with 1,5-dibromopentane and 1,4-dibromobutane, respectively. The structures of the chiral quaternary salts were confirmed by ¹H and ¹³C NMR and mass spectrometry (see ESI†).

Scheme 1 Synthesis of chiral PTCs sT1, sT2 and sT3.

Herein, we show the enantioselective alkylation of a glycinate Schiff base using newly developed chiral catalysts sT1, sT2 and sT3 to produce optically active α-amino acids, which are frequently used in peptide and peptidomimetic synthesis.

Based on this, we began with the synthesis of prochiral substrate benzophenone imine glycinate 3 for the asymmetric alkylation study.¹⁹

To optimize the enantioselective potential of the synthesized quaternary salts in the asymmetric alkylations, we performed the alkylation with an excess of benzyl bromide as shown in Scheme 2. All reactions were carried out under biphasic conditions to get the maximum yield and high enantioselectivity, using a different mol% of catalyst and varying temperature ranges for the scope of C–C bond forming method.

Scheme 2 Optimization of catalysts.

It is observed that at room temperature with 2 mol% catalyst loading, the reaction to form the alkylated product showed lower enantioselectivity (Table 1, Entry 1). Subsequently, an increase of catalyst loading from 2 mol% to 5 and 10 mol% catalyst at room temperature resulted in an increase in enantioselectivity (Table 1, Entries 2 and 3). Further, lowering of the temperature from room temperature to −10 °C increased the enantioselectivity of the reaction as shown in Table 1. The reaction to form the alkylated product showed better enantioselectivity at 10 mol% catalyst loading (Table 1, Entries 3, 6, 9 and 12). The reaction was also performed in the liquid–solid state (Table 1, Entry 13) and showed poor enantioselectivity. Therefore the remaining two catalysts sT2 & sT3 were not evaluated in the liquid–solid phase.

Table 1 Screening of chiral catalysts for enantioselectivity

Entry	Temp. (°C)	50% base^a in water (w/v)	Catalyst	Mol% of catalyst	Yield^b (%)	ee^c (%)
a 50% KOH aqueous solution (5 g dissolved in water and made up to 10 mL KOH solution).b Experimental yield.c Determined by HPLC using a CHIRALCEL OD-H column.d Racemic mixture chromatogram shown in ESI S26.
1	rt	0.5 mL	sT1	2	74	22
2	rt	0.5 mL	sT1	5	76	28
3	rt	0.5 mL	sT1	10	76	46
4	10	0.5 mL	sT1	2	72	48
5	10	0.5 mL	sT1	5	68	52
6	10	0.5 mL	sT1	10	58	60
7	0	0.5 mL	sT1	2	74	48
8	0	0.5 mL	sT1	5	60	60
9	0	0.5 mL	sT1	10	85	70
10	−10	0.5 mL	sT1	2	53	72
11	−10	0.5 mL	sT1	5	58	76
12	−10	0.5 mL	sT1	10	90	82
13	−10	0.24 g pallets	sT1	10	40	50
14	−10	0.5 mL	sT2	2	59	26
15	−10	0.5 mL	sT2	5	70	38
16	−10	0.5 mL	sT2	10	65	39
17	−10	0.5 mL	sT3	2	58	28
18	−10	0.5 mL	sT3	5	68	50
19	−10	0.5 mL	sT3	10	68	38
20	−10	0.5 mL	—	—	52	rac^d

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Then, we investigated the effect of the other two chiral quaternary ammonium salts sT2 and sT3 (Table 1, Entries 14–19) under similar reaction conditions. It was noticed that piperidine and pyrrolidine derived catalysts sT2 and sT3, using 10 mol% at −10 °C, gave a reduced enantiomeric excess (ee) in comparison to N-alkyne and N-benzyl derived catalyst sT1. It is obvious from the analysis of Table 1 that the chiral ammonium salt sT1 was found to be the most promising PTC of all those tested. In conclusion, the reaction performed with an excess of electrophile in the presence of 10 mol% of sT1 at −10 °C was found to provide suitable conditions for the asymmetric alkylation of the glycinate Schiff base (Table 1, Entry 12). These optimized reaction conditions were used (Table 1, Entry 12) for the alkylation of glycinate Schiff base 3 with different electrophiles, followed by hydrolysis of the alkylated product 4 to get the corresponding products (5–14) with good enantioselectivity, given in Table 2.

Table 2 Scope of the α-alkylation of benzophenone glycinate Schiff base using different electrophiles

Entry	Electrophile^a (RBr)	Product	Time (h)	Yield^b (%)	ee^c (%)
a Reaction of prochiral substrate 3 with electrophiles.b Experimental yield.c Determined by HPLC using CHIRALCEL OD-H column.
1		5	3.5	75	95
2		6	3.5	85	89
3		7	4.5	90	82
4		8	6.0	67	81
5		9	4.5	55	75
6		10	5.5	85	85
7		11	5.5	80	77
8		12	4.5	76	68
9		13	4.5	90	83
10		14	4.5	85	90

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The possible role of the new catalyst in asymmetric synthesis is presented in Fig. 1. It is stipulated that the PTC’s (sT1) s-triazene nitrogen is hydrogen bonded with the hydrogen atom of the hydroxyl group of the E-enolate (glycinate Schiff base). s-Triazene forms a guanidine type moiety with a cationic nitrogen and stabilizes this complex. The benzylic groups of the catalyst lie in one plane which possibly coordinate to the phenyl rings of the benzophenone Schiff base through π–π interactions.²⁰ The hydrogen atom of the alkyne is then bonded with the nitrogen of the Schiff base to stabilize the transition state. Formation of this transition state allows the electrophile to attack the prochiral centre in a ‘trans’ direction to generate an asymmetric centre. Thus, the choice of benzyl group and alkyne group are crucial in designing newer catalysts with respect to enantioselectivity.

Fig. 1 Proposed transition state of catalyst with substrate 3.

Conclusions

In conclusion, we designed and synthesized new efficient s-triazene based N-quaternary ammonium salts sT1, sT2 and sT3 as phase transfer catalysts (PTCs) and used them to efficiently alkylate a glycinate Schiff base to produce natural and unnatural α-amino acids. The asymmetric catalytic potential of these compounds in the asymmetric α-alkylation of the glycinate Schiff base depends on their substituents and reaction conditions. Under optimized conditions, the α-alkylated products could be obtained in excellent yields and up to 95% ee. More enantioselective applications of the catalysts are in progress.

Acknowledgements

SKM and AKS are thankful to CSIR, India for providing fellowship. SKA acknowledges the University of Delhi for financial support. The authors are thankful to Dr Nisha Saxena for the manuscript preparation.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5ra11209e

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