Chinese Chemical Letters  2017, Vol. 28 Issue (2): 213-217   PDF    
Enantioselective trapping of oxonium ylide intermediates by N-benzhydryl-α-imino ester: Synthesis of β-tetrasubstituted α-amino acids
Shi-Kun Jia, Yu-Bing Lei, Long-Long Song, Shun-Ying Liu, Wen-Hao Hu     
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Chemical Engineering, East China Normal University, Shanghai 200062, China
Abstract: A synergistic rhodium(II)/phosphoric acid catalyzed three component reaction of 3-diazooxindoles, alcohols and N-benzhydryl-α-imino ester is developed for the efficient construction of chiral β-alkoxy Cβ-tetrasubstituted α-amino acid derivatives in good yields and with excellent diastereoselectivities and high enantioselectivities. The synthetic application of the resulting products was illustrated by reducing with Pd/C under H2 atmosphere followed reacting with CSCl2 at room temperature to rapid afford 3-spirocyclic oxindole in a good yield with a chirality retainment. The three-component reaction is proposed to proceed through an electrophilic trapping of the oxonium ylides by N-benzhydryl-α-imino ester.
Key words: Three-component reaction     Oxonium ylide     N-Benzhydryl-α-imino ester     β-Tetrasubstituted α-amino acids     Chiral phosphoric acid    
1. Introduction

β-Oxa-quaternary a-amino acid derivatives are common and serviceable structural motifs in biologically active natural products and pharmaceuticals [1]. For instance, the ustiloxin and phomopsin families of natural products are potent microtubule depolymerizers [1a]. Furthermoresome quaternary β-substituteda-amino acids are incorporated into peptides to modulate secondary and tertiary structural conformations [2]. An array of elegant methods has been developed for the preparation of β-oxa-quaternary a-amino acid derivatives [3-5]. For example, Joullie´ and co-workers reported a method through ring opening of aziridines to synthesize these compounds [3]. Nevertheless, there has still been an increasing demand for the development of straightforward and convenient methods for the construction of chiral Cβ-tetrasubstituted a-amino acids and their derivatives.

Multi-component reactions (MCRs) are highly intriguing owing to significant advantages over traditional chemical synthesis on atom-and step-economy [6]. In recent years, our group has developed several novel multi-component reactions by trapping in situ generated active intermediates including oxonium ylides [7], ammonium ylides [8] and zwitterionic intermediates [9] with various electrophiles for the highly efficient construction of complex molecules.

As an active electrophile, a-imino esters have been widely used in direct [10], Lewis acid [11] or Brønsted acids [12] catalyzed Mannich-type additions to produce chiral amino acid derivatives. Wealsoemployeda-imino esters with Brønsted acids as catalysts to trap ammonium ylides to develop Mannich-type three-component reaction for the construction of β-amino Cβ-tetrasubstituted aamino acid derivatives with an excellent diastereoselectivity and enantioselectivity (Scheme 1, Eq. (1) ) [12c]. Very recently, we successfully established a four-component reaction using in situ generated a-imino esters to trap zwitterionic intermediates, in which a-amino acid derivatives bearing β-all carbon quaternary carbon centerwere efficiently provided in a rapid fashion (Scheme 1, Eq. (2) ) [12c]. However, there is a significant drawback of the above mentioned methods, as only N-aryl imino esters have been employed in all the cases. It has been extremely difficult to find compatible reaction conditions to remove the N-aryl protecting group from the three-component products maintaining the Cβ-tetrasubstituted functionalities unchanged, which thus limited the synthetic utility of these efficient methods. As a consequence, we turned our attention to N-benzhydryl a-imino ester which could be deprotected effortlessly under mild conditions. The challenges now are to address the reactivity compability of the relatively unreactive N-alkyl substituted a-imino ester and the active intermediates, and to achieve a diastereo-and enantioselective control of the reaction. Here, we report the first example of employing N-benzhydryl a-imino ester as an effective electrophile to trap oxonium ylide intermediate in situ generated from 3-diazooxindoles and alcohols under the co-catalytic system of rhodium(II)/chiral phosphoric acids. β-Alkoxy Cβ-tetrasubstituted a-amino acid derivatives were obtained in high yields and with an excellent diastereoselectivity and high enantioselectivity (Scheme 1, Eq. (3) ).

Download:
Scheme1. Electrophilic trapping of active intermediates by α-imino esters.

2. Experimental

1H NMR and 13C NMR spectra were recorded on Brucker Asend 400 MHz spectrometers. ESI-HRMS spectra were recorded on a Waters Micromass Q-TOF micro Synapt High Definition Mass Spectrometer. Enantiomeric ratio (er) was determined by HPLC analysis on Chiralpak IA columns. The spectral data and spectra of all the compounds are presented in the Supporting information. Commercial grade solvents were dried and redistilled before use. All other reagents were purchased from commercial sources and used without further purification.

General procedure for the preparation of racemic products: A mixture of Rh2(OAc)4 (0.002mmol), substituted alcohols 1 (0.3mmol), imine 3 (0.2mmol), 5 (10 mol%), and 4Å MS (100 mg) in 2 mL of CH2Cl2 under an argon atmosphere was cooled to 0 ℃. Diazo compound 2 (0.3mmol) in 1 mL of CH2Cl2 was then added over 1 h via a syringe pump. After completion of the addition, the reactionmixture was stirred for another 0.5 h, then filtrated and evaporated in vacuo to give the crude product. The crude products was purified by flash chromatography on silica gel (EtOAc/light petroleum ether = 1:25 ~ 1:10) to give the pure product.

3. Results and discussion

3, 3-Disubstituted oxindoles are privileged structural motifs in many biologically active molecules [13]. We decided to perform our three-component reaction of 3-diazooxindole, benzyl alcohol and N-benzhydryl a-imino ester, aiming to synthesize the Cβ-tetrasubstituted a-amino acid derivatives bearing an oxindole framework. A previously established synergistic catalytic system of the Rh2(OAc)4 and phosphoric acid (PPA) was employed to catalyze the reaction. To our delight, the desired threecomponent product 4a was obtained in 61% yield and with >95:5 diastereoselectivity (Table 1, entry 1) at 0 ℃. According to our previous experience on activing imines using chiral BINOLderived phosphoric acid, we evaluated a series of chiral BINOLderived PPA catalysts 5a-g (Fig. 1) to develop the enantioselective version of this reaction. Among them, (R)-3, 30-bis(2, 4, 6-triisopropylphenyl)-binol phosphoric acid 5e gave the best result, yielding 4a in 72% yield and with >95:5 dr and 93:7 er. (Table 1, entries 2-7) . With 1 mol% Rh2(OAc)4 and 10 mol% 5e, the effects of solvent and temperature were further investigated and CH2Cl2 (DCM) was found the best solvent (Table 1, entry 5 vs. entries 8-10) . Increasing or decreasing the reaction temperature caused reduced yields of 4a and a relatively lower stereoselectivities (Table 1, entries 11 and 12) .

Table 1
Optimization of the reaction conditions.a

Download:
Figure 1. Structures of catalysts.

With the optimized reaction conditions in hand, the substrate scope of this transformation was investigated. Several substituted benzyl alcohols were first examined, and for all substituted benzyl alcohols being tested, the desired three-component products 4a-e (Fig. 2) were obtained in moderate to good yields and with excellent diastereoselectivities (>95:5 for all cases). o-Tolylmethanol gave the corresponding product 4e in a 95:5 er. Other alcohols including heterocyclic substituted alcohols were employed to give comparable results (Fig. 2, 4f-j). Next, the generality for 3-diazooxindoles was tested. Using o-tolylmethanol, substituents on C5, C6 positions of N-benzyl 3-diazooxindoles also gave the desired products in good yields with excellent diastereoselectivities and high to excellent enantioselectivities (4k-p). The highest er value of 98:2 was obtained by using N-methyl 3-diazooxindoles (4q-u). Replacing the N-benzyl substituent of 3-diazooxindole to N-Bz caused sharply reduced yield and er value (4v vs. 4e). The absolute configuration of the three-component product was unambiguously determined as (2R, 3S) by X-ray analysis of 4c. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre (CCDC 1438793) via www.ccdc.cam.ac.uk/data_request/cif.

Download:
Figure 2. Sturctures of products 4a-v. For all cases, d.r.(syn:anti) >20:1.

For the reaction mechanism of 3-diazooxindole involved multicomponent reaction, Gong and co-workers [14] reported a stepwise insertion/addition pathway in the three-component reaction of 3-diazooxindole, indole and nitroalkenes. To verify the current reaction proceeds with the stepwise or a concerted reaction pathway, control experiments were performed. Two-component O-H insertion product 6a was isolated and then treated with N-benzhydryl-a-imino ester 3a under the otherwise identical reaction conditions of the current three-component reaction, no 4a was observed (For details, see the Supporting information). This control experiment excluded the possibility that this threecomponent reaction proceeded through a stepwise O-H insertion/ Mannich addition pathway. A plausible reaction pathway was proposed in Scheme 2. Firstly, benzyl alcohol 1a and 3-diazooxindole 2a formed an active oxonium ylide or its enolate form catalyzed by Rh2(OAc)4. Electrophilic trapping of the active intermediate by chiral PPAs activated imines afforded the trapping products 4. The observed stereochemistry for this three-component reaction can be rationalized by an interaction model proposed by Simon and Goodman [15], which was used to explain the stereochemical outcome of this Mannich-type addition in the presence of chiral PPAs.

Download:
Scheme2. Plausible reaction pathway.

To achieve the synthetic application of the product, 4a with 99% ee was obtained by recrystalition in 74% yield and used for the next investigation. Under standard hydrogenation conditions, the benzyl substitude of alcohol and benzhydryl group of the product was easily removed, affording β-hydroxy-a-amino ester 7a possessing a primary amine unit with 99% ee in 78% yield. 3-Spirocyclic oxindole 8a was then subsequently obtained by reacting CSCl2 in a good yield and chirality retainment (Scheme 3) . Oxindole frameworks bearing a spirocyclic quaternary stereocenter at the C3 position as a kind of β-alkoxy Cβ-tetrasubstituted a-amino acid derivatives, such as spirobrassinin and methoxyspirobrassinin, always show potent antimicrobial, antitumor, and oviposition-stimulantbiological activities [16], which is not easily prepared by traditional method.

Download:
Scheme3. Synthetic application of 4a.

4. Conclusion

In summary, we have developed an efficient method for the construction of β-alkoxy Cβ- tetrasubstituted a-amino acid derivatives in good yields and with high diastereoselectivities and excellent enantioselectivities though a three-component reaction of benzyl alcohol, 3-diazooxindoles and N-benzhydryla-imino ester. Removal of N-benzhydryl protecting group can be easily achieved to give free amino acids, which facilitate the further functionalization of the resulting products. This transformation is proposed to proceed via an electrophilic trapping of oxonium ylide with the imino ester.

Acknowledgments

We greatly thank NSFC (No. 21332003) , STCSM (No.15ZR1411000) and Stake Key Laboratory of Advanced Technology for Materials Synthesis and Processing (2015-KF-11) for financial support.

References
[1] (a) J.S. Grimley, A.M. Sawayama, H. Tanaka, et al., The enantioselective synthesis of Phomopsin B, Angew. Chem. Int. Ed. 46(2007) 8157-8159;(b) S. Fustero, M. Sánchez-Roselló, V. Rodrigo, et al., Solution-, solid-phase, and fluorous synthesis of β,β-difluorinated cyclic quaternary α-amino acid derivatives:a comparative study, Chem. Eur. J. 14(2008) 7019-7029;(c) S. Yamazaki, M. Takebayashi, K. Miyazaki, Zn(OTf)2-catalyzed reactions of ethenetricarboxylates with 2-aminobenzaldehydes leading to tetrahydroquinoline derivatives, J. Org. Chem. 75(2010) 1188-1196;(d) Q. Zhang, M. Cheng, X. Hu, B.G. Li, J.X. Ji, Gold-catalyzed three-component tandem process:an efficient and facile assembly of complex butenolides from alkynes, amines, and glyoxylic acid, J. Am. Chem. Soc. 132(2010) 7256-7257.
[2] F. Formaggio, C. Baldini, V. Moretto, Preferred conformations of peptides containing tert-leucine, a stericallydemanding, lipophilic α-amino acid with a quaternary side-chain Cβ atom. Chem. Eur. J. 11 (2005) 2395–2404. DOI:10.1002/(ISSN)1521-3765
[3] E.M. Forbeck, C.D. Evans, J.A. Gilleran, P. Li, M.M. Joullie, A regio- and stereoselective approach to quaternary centers from chiral trisubstituted aziridines, J. Am. Chem. Soc. 129(2007) 14463-14469.
[4] M. Mae, H. Amii, K. Uneyama, First synthesis of 3, 3-difluoroserine and cysteine derivatives via Mg(0)-promoted selective C-F bond cleavage of trifluoromethylimines. Tetrahedron Lett. 41 (2000) 7893–7896. DOI:10.1016/S0040-4039(00)01350-2
[5] (a) M. Duca, D.J. Maloney, M. Lodder, B. Wang, S.M. Hecht, Synthesis of bisaminoacylated pdCpAs and tandemly activated transfer RNAs, Bioorg. Med. Chem. 15(2007) 4629-4642;(b) W. Qian, J.E. Park, K.S. Lee, T.R. Burke Jr., Effects on polo-like kinase 1 polo-box domain binding affinities of peptides incurred by structural variation at the phosphoamino acid position, Bioorg. Med. Chem. 21(2013) 3996-4003.
[6] (a) D.J. Ramón, M. Yus, Asymmetric multicomponent reactions (AMCRs):the new frontier, Angew. Chem. Int. Ed. 44(2005) 1602-1634;(b) C. de Graaff, E. Ruijter, R.V.A. Orru, Recent developments in asymmetric multicomponent reactions, Chem. Soc. Rev. 41(2012) 3969-4009;(c) P.K. Maji, R.U. Islam, S.K. Bera, Recent progress in metal assisted multicomponent synthesis of heterocycles, Heterocycles 89(2014) 869-962;(d) S.B. Dongare, H.V. Chavan, P.S. Bhale, et al., A catalyst-and solvent-free multicomponent synthesis of 7-azagramine analogues via a Mannich type reaction, Chin. Chem. Lett. 27(2016) 99-103.
[7] (a) H. Huang, X. Guo, W. Hu, Efficient trapping of oxonium ylides with imines:a highly diastereoselective three-component reaction for the synthesis of β-amino-α-hydroxyesters with quaternary stereocenters, Angew. Chem. Int. Ed. 46(2007) 1337-1339;(b) W. Hu, X. Xu, J. Zhou, et al., Cooperative catalysis with chiral Brønsted acidRh2(OAc)4:highly enantioselective three-component reactions of diazo compounds with alcohols and imines, J. Am. Chem. Soc. 130(2008) 7782-7783;(c) X. Zhang, H. Huang, X. Guo, et al., Catalytic enantioselective tapping of an alcoholic oxonium ylide with aldehydes:RhII/ZrIV-co-catalyzed three-component reactions of aryl diazoacetates, benzyl alcohol, and aldehydes, Angew. Chem. Int. Ed. 47(2008) 6647-6649;(d) X. Guan, L. Yang, W. Hu, Cooperative catalysis in multicomponent reactions:highly enantioselective synthesis of γ-hydroxyketones with a quaternary carbon stereocenter, Angew. Chem. Int. Ed. 49(2010) 2190-2192;(e) X. Guo, W. Hu, Novel multicomponent reactions via trapping of protic onium ylides with electrophiles, Acc. Chem. Res. 46(2013) 2427-2440;(f) T. Shi, X. Guo, S. Teng, W. Hu, Pd(II)-catalyzed formal[4+1] cycloaddition reactions of diazoacetates and aryl propargyl alcohols to form 2,5-dihydrofurans, Chem. Commun. 51(2015) 15204-15207;(g) M. Tang, Y. Wu, Y. Liu, et al., One-pot enantioselective multi-component cascade reactions for synthesis of chiral functionalized hydro-epoxyisochromenes:a rapid access to molecular complexity, Acta Chim. Sin. 74(2016) 54-60.
[8] (a) J. Jiang, H.D. Xu, J.B. Xi, et al., Diastereoselectively switchable enantioselective trapping of carbamate ammonium ylides with imines, J. Am. Chem. Soc. 133(2011) 8428-8431;(b) C. Jing, D. Xing, Y. Qian, et al., Diversity-oriented three-component reactions of diazo compounds with anilines and 4-oxo-enoates, Angew. Chem. Int. Ed. 52(2013) 9289-9292;(c) C. Ma, D. Xing, C. Zhai, et al., Iron porphyrin-catalyzed three-component reaction of ethyl diazoacetate with aliphatic amines and β,γ-unsaturated α-keto esters, Org. Lett. 15(2013) 6140-6143;(d) C. Jing, D. Xing, W. Hu, Highly diastereoselective synthesis of 3-hydroxy-2, 2,3-trisubstituted indolines via intramolecular trapping of ammonium ylides with ketones, Chem. Commun. 50(2014) 951-953;(e) X. Ma, J. Jiang, S. Lv, et al., An ylide transformation of rhodium(I) carbene:enantioselective three-component reaction through trapping of rhodium(I)-associated ammonium ylides by β-nitroacrylates, Angew. Chem. Int. Ed. 53(2014) 13136-13139.
[9] (a) H. Qiu, M. Li, L.Q. Jiang, et al., Highly enantioselective trapping of zwitterionic intermediates by imines, Nat. Chem. 4(2012) 733-738;(b) D. Zhang, H. Qiu, L. Jiang, et al., Enantioselective palladium(II) phosphate catalyzed three-component reactions of pyrrole, diazoesters, and imines, Angew. Chem. Int. Ed. 52(2013) 13356-13360;(c) S. Jia, D. Xing, D. Zhang, W. Hu, Catalytic asymmetric functionalization of aromatic C-H bonds by electrophilic trapping of metal-carbene-induced zwitterionic intermediates, Angew. Chem. Int. Ed. 53(2014) 13098-13101;(d) D. Zhang, J. Zhou, Z. Kang, W. Hu, Bond cleavage, fragment modification and reassembly in enantioselective three-component reactions, Nat. Commun. 6(2015) 5801-5809;(e) M. Li, X. Guo, W. Jin, et al., An enantioselective three-component reaction of diazoacetates with indoles and enals by iridium/iminium co-catalysis, Chem. Commun. 52(2016) 2736-2739;(f) H. Qiu, D. Zhang, S.Y. Liu, et al., Asymmetric C-H functionalization of indoles via enantioselective protonation, Acta Chim. Sin. 70(2012) 2484-2488.
[10] (a) B.M.Trost,L.R. Terrell,A direct catalyticasymmetricMannich-type reaction to syn-amino alcohols, J. Am. Chem. Soc. 125(2003) 338-339;(b) A. Cordova, W. Notz, G. Zhong, J.M. Betancort, C.F. Barbas, A highly enantioselective amino acid-catalyzed route to functionalized α-amino acids, J. Am. Chem. Soc. 124(2002) 1842-1843;(c) P. Ramaraju, N.A. Mir, D. Singh, et al., Enantioselective synthesis of N-PMP-1,2-dihydropyridines via formal[4+2] cycloaddition between aqueous glutaraldehyde and imines, Org. Lett. 17(2015) 5582-5585;(d) K. Nagata, Y. Kuga, A. Higashi, et al., Asymmetric synthesis and catalytic activity of 3-methyl-β-proline in enantioselective anti-Mannich-type reactions, J. Org. Chem. 78(2013) 7131-7136.
[11] (a) S. Kobayashi, R. Matsubara, Y. Nakamura, H. Kitagawa, M. Sugiura, Catalytic, asymmetric Mannich-type reactions of N-acylimino esters:reactivity, diastereoand enantioselectivity, and application to synthesis of N-acylated amino acid derivatives, J Am. Chem. Soc. 125(2003) 2507-2515;(b) D. Ferraris, B. Young, C. Cox, et al., Catalytic, enantioselective alkylation of α-imino esters:the synthesis of nonnatural α-amino acid derivatives, J. Am. Chem. Soc. 124(2002) 67-77;(c) L. Bernardi, A.S. Gothelf, R.G. Hazell, K.A. Jørgensen, Catalytic asymmetric Mannich reactions of glycine derivatives with imines. a new approach to optically active α,β-diamino acid derivatives, J. Org. Chem. 68(2003) 2583-2591.
[12] (a) S. Zhong, M. Nieger, A. Bihlmeier, M. Shi, S. Bräse, Asymmetric organocatalytic synthesis of 4,6-bis(1H-indole-3-yl)-piperidine-2 carboxylates, Org. Biomol. Chem. 12(2014) 3265-3270;(b) Y.P. He, Y.L. Du, S.W. Luo, L.Z. Gong, Asymmetric sp3 C-H functionalization via a chiral Brønsted acid-catalyzed redox reaction for the synthesis of cyclic aminals, Tetrahedron Lett. 52(2011) 7064-7066;(c) J. Jiang, X. Ma, S. Liu, et al., Enantioselective trapping of phosphoramidate ammonium ylides with imino esters for synthesis of 2,3-diaminosuccinic acid derivatives, Chem. Commun. 49(2013) 4238-4240;(d) Y. Qian, C. Jing, S. Liu, W. Hu, A highly enantioselective four-component reaction for the efficient construction of chiral β-hydroxy-α-amino acid derivatives, Chem. Commun. 49(2013) 2700-2702;(e) C. Jing, D. Xing, W. Hu, Catalytic asymmetric four-component reaction for the rapid construction of 3,3-disubstituted 3-Indol-3'-yloxindoles, Org. Lett. 17(2015) 4336-4339.
[13] (a) B.M. Trost, M.K. Brennan, Asymmetric syntheses of oxindole and indole spirocyclic alkaloid natural products, Synthesis 18(2009) 3003-3025;(b) C.V. Galliford, K.A. Schneidt, Pyrrolidinyl-spirooxindole natural products as inspirations for the development of potential therapeutic agents, Angew. Chem. Int. Ed. 46(2007) 8748-8758.
[14] D.F. Chen, F. Zhao, Y. Hu, L.Z. Gong, C-H functionalization/asymmetric Michael addition cascade enabled by relay catalysis:metal carbenoid used for C-C bond formation, Angew. Chem. Int. Ed. 53(2014) 10763-10767.
[15] L. Simón, J.M. Goodman, A model for the enantioselectivity of imine reactions catalyzed by BINOL-phosphoric acid catalysts, J. Org. Chem. 76(2011) 1775-1788.
[16] (a) X. Jiang, Y. Cao, Y. Wang, et al., A unique approach to the concise synthesis of highly optically active spirooxazolines and the discovery of a more potent oxindole-type phytoalexin analogue, J. Am. Chem. Soc. 132(2010) 15328-15333;(b) M. Suchy, P. Kutschy, K. Monde, et al., Synthesis, absolute configuration, and enantiomeric enrichment of a cruciferous oxindole phytoalexin, (S)-(-)-spirobrassinin, and its oxazoline analog, J. Org. Chem. 66(2001) 3940-3947.