Access to Î±,Î³-Diamino Diacid Derivatives via Organocatalytic

Letter Cite This: Org. Lett. 2018, 20, 7080−7084

pubs.acs.org/OrgLett

Access to α,γ-Diamino Diacid Derivatives via Organocatalytic Asymmetric 1,4-Addition of Azlactones and Dehydroalanines Junxian Yang,† Wangsheng Sun,*,† Zeyuan He,† Changjun Yu,† Guangjun Bao,† Yiping Li,† Yuyang Liu,† Liang Hong,*,‡ and Rui Wang*,† †

Org. Lett. 2018.20:7080-7084. Downloaded from pubs.acs.org by KAOHSIUNG MEDICAL UNIV on 11/16/18. For personal use only.

School of Life Sciences, Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, China ‡ School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China S Supporting Information *

ABSTRACT: A convenient and functional-group-tolerant organocatalytic asymmetric 1,4-addition of azlactones and dehydroalanine is disclosed. The reaction is used for the first synthesis of chiral α,γ-diamino diacid derivatives with nonadjacent stereogenic centers in moderate to high yields, with excellent diastereo- and enantioselectivities, under the catalysis of a chiral thiourea catalyst. In addition, the reaction could be conducted in gram-scale, and the products of the reaction could be readily converted to various α,γ-diamino diacid derivatives, α,γ-diamino dialcohols, and modified peptides with nonproteinogenic amino acid residues.

onproteinogenic amino acids not only are frequently encountered in a large number of naturally occurring, artificial, biological, or pharmaceutical compounds, proteins, peptidomimetic foldamers, and materials, but also possess significant biological activities themselves.1 For example, L-γcarboxyglutamic acid (L-Gla) has been found in several vertebrate calcium-binding proteins such as osteocalcin and contryphan as well as some neuroactive peptides such as conantoxin GV and conantoxin T.2 SYM2081 and (S)-CCGIV and its analogues show potent activity as N-methyl-Daspartate (NMDA) receptor agonists (Figure 1).3 On the other hand, preprepared diamino diacids have recently been employed as an alternative tool in the therapeutically useful

N

stapled cyclic peptide construction.4 These diamino diacids usually contain a disulfide bond or thioether, which are prone to degradation in the physiological environment and result in structural distortion and loss of activity.5 Therefore, it is highly desirable to develop an efficient and practical diastereoselective approach to diamino diacids without a disulfide bond or thioether. We have recently devoted much effort in the construction and application of chiral nonproteinogenic amino acids for analgesic peptide modification.6 In the course of our research, we found that the direct enantioselective construction of chiral diamino diacids is still surprisingly underdeveloped. Taking into account that both azlactones7,8 and masked dehydroalanines (Dha)9 are good precursors for the construction of amino acids, we realized that the integration of both substrates into one molecule with concomitant control of the stereochemistry might give direct access to chiral α,γ-diamino diacids. Although the catalytic asymmetric addition of azlactones to enals,7g,l enones,7i,m,u vinyl sulfones7n−p and nitroalkenes7h,w have been well developed, and the utilization of Dha as electrophiles has not been reported, mainly due to the less electrophilic Dha.

Figure 1. Representative examples of nonproteinogenic amino acids.

Received: September 20, 2018 Published: November 6, 2018

© 2018 American Chemical Society

7080

DOI: 10.1021/acs.orglett.8b03020 Org. Lett. 2018, 20, 7080−7084

Letter

Organic Letters Table 1. Optimization of the Reactiona

Inspired by the study of Chiba (Scheme 1)9e and our recent study on azlactones,8 we proposed that the reaction of Scheme 1. Proposition for Construction of α,γ-Diamino Diacid Derivatives

azlactones and Dha might be catalyzed by a bifunctional chiral thiourea catalyst10 via multihydrogen bond interaction. The reaction may starts as intermediate A, where the tertiary amine moiety of the catalyst acts as a base to activate the azlactones 1 via enolization;8a the thiourea moiety of the catalyst activates Dha 2 via multiple H-bond interaction. Intermediate A may immediately transforms to intermediate B via nucleophilic addition to effect subsequent protonation (Scheme 1).11 Nevertheless, the reaction is considered to be a great challenge as it requires the simultaneous control of two nonadjacent stereogenic centers. Herein, we report for the first time that the α,γ-diamino diacids with two nonadjacent stereogenic centers could be synthesized via the highly stereoselective conjugate addition of azlactones 1 to Dha 2. To demonstrate the feasibility of our proposition, we investigated the reaction of azlactone 1a with Dha 2a catalyzed by a chiral bifunctional thiourea 3a in toluene at room temperature.12 Fortunately, the reaction afforded the desired product in moderate conversion with satisfactory diastereoand enantioselectivities (Table 1, entry 1). Encouraged by these promising results, we examined a series of bifunctional H-bond donor catalysts and found that cat. 3c provided the best enantioselectivity (Table 1, entries 1−6). To gain better results, we changed azlactone 1a to 1b as the model substrate, and greatly improved enantioselectivity (91% ee) was observed, albeit with moderate conversion and diastereoselectivity (Table 1, entry 7). The 3 Å Molecular sieves (MS) were then added as an additive13 in the reaction under the catalysis of 3c to further promote the results of the reaction (Table 1, entry 8). A variety of solvents were also screened, and toluene was proven to be the most successful (Table 1, entries 8−16). To further improve the reaction, we changed Dha 2a to 2b as the model substrate, and significant improvement was observed, with 95% conversion, 87:13 dr,

entry

1

2

3

solvent

conv (%)b

4, drb

ee (%)c

1 2 3 4 5 6 7 8d 9d 10d 11d 12d 13d 14d 15d 16d 17d 18d,e

1a 1a 1a 1a 1a 1a 1b 1b 1b 1b 1b 1b 1b 1b 1b 1b 1b 1b

2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2b 2b

3a 3b 3c 3d 3e 3f 3c 3c 3c 3c 3c 3c 3c 3c 3c 3c 3c 3c

toluene toluene toluene toluene toluene toluene toluene toluene PhCl PhF PhCF3 Et2O THF DCE DCM CH3CN toluene toluene

65 68 45 64 70 63 54 63 55 52 50 80 60 35 50 20 95 90(82)f

80:20 87:13 70:30 50:50 86:14 80:20 77:23 78:22 80:20 80:20 80:20 70:30 70:30 82:18 70:30 50:50 87:13 91:9

69 37 74 29 7 61 91 95 83 79 75 63 94 84 80 5 96 98

a

Unless otherwise stated, the reaction was carried out on a 0.1 mmol sacle in 2 mL of solvent at room temperature with a ratio of 1/2/3 = 1.0:1.0:0.2 within 3 days. bDetermined by 1HNMR analysis of the crude reaction mixture. cDetermined by HPLC using a Chiralcel IC column. dOne-hundred milligrams of 3 Å MS was used in the reaction. eReaction was carried out at 0 °C with a ratio of 1b/2b/3c = 1.0:2.0:0.2 within 5 days. fYield of the isolated major product is given within the parentheses.

and 96% ee (Table 1, entry 17). When the reaction was carried out with a ratio of 1b/2b = 1.0:2.0 at 0 °C, the optimal results were obtained, with 82% isolated yield, 91:9 dr, and 98% ee (Table 1, entry 18). Having established the optimal reaction conditions, we then turned our attention to exploring the scope of the reaction. Satisfyingly, the reaction proceeded smoothly with a wide range of substrates (Scheme 2). We first examined the generality of the reaction by varying the azlactones 1. It exhibited that different substitutions on both C2 and C4 positions of azlactones had minor influence on the reaction. Azlactones with different aryl substitutions at the C2 position could participate in the reaction in moderate to high yields (63−93%), with excellent diastereo- (90:10−97:3 dr) and enantioselectivities (95−99% ee) (Scheme 2, 4a−4g). Various patterns of substitutions, regardless of alkyl or aryl, at C4 of azlactones showed good compatibility in the reaction, which 7081


Letter

Organic Letters Scheme 2. Scope of the Reactiona

a Unless otherwise stated, the reaction was carried out on a 0.1 mmol sacle in 2 mL toluene at 0 °C with a ratio of 1/2/3c = 1.0:2.0:0.2 in requisite time. The yield refers to the isolated yield of the major product. The dr was determined by 1HNMR analysis of the crude reaction mixture; ee was determined by HPLC using a Chiralcel IC column. bReaction was carried out at −40 °C. cTotal yield of the both diastereomers. dReaction was carried out at room temperature.

readily achieved in high yield (91%, 1.17 g), with excellent diastereoselectivity (>20:1 dr) and enantioselectivity (98% ee) (Scheme 3a). Pleasingly, the product 4r could be transformed into various derivatives under different conditions. For instance, under the conditions of NaOMe (2.5 equiv) in MeOH, 4r could be transformed to diamino diacid ester 5 in high yield without any loss of enantioselectivity within 5 min, while similar results could be obtained under the conditions of K2CO3 (1 equiv) in MeOH in 12 h (Scheme 3b). Diamino diacid derivative 6 could be readily achieved in high yield with the preservation of stereointegrity in 12 h under an acidic condition with conc. HCl in CH3CN (Scheme 3c). In addition, a ring-open amide-bond formation of 4r and methyl glycinate could occur under a basic condition to furnish a protected dipeptide derivative 7 (Scheme 3d). When the products were treated with conc. HCl in CH3CN, with a subsequent treatment of TMSCHN2, diamino diacid esters 8 could be obtained in excellent yields. They could be further transformed into various compounds. For example, when 8a

provided the corresponding adducts in moderate to excellent yields (41−95%), with good to excellent diastereo- (84:16− 98:2 dr) and enantioselectivities (89−99% ee) (Scheme 2, 4h−4q). Dha 2 with different imide protecting groups were then surveyed, and a variety of dehydroalanine could be involved in the reaction, which afforded the adducts in high yields (75−98%), diastereoselectivities (78:22−98:2 dr), and enantioselectivities (96−99% ee) (Scheme 2, 4r−4z). It is particularly noteworthy that the reaction can be applied in the late-stage modification of peptides with Dha residues (Scheme 2, 4aa). In addition, the diastereomers of the products could be separated on a common silica gel column chromatography, which benefits this method a useful synthetic route. Moreover, the absolute configuration of the product 4r was determined unambiguously by X-ray crystallographic analysis, and those of other products were assigned by analogy. In line with the application of this method, we carried out some scalable and derivative studies. Under the optimized reaction conditions, the preparative scale synthesis of 4r was 7082


Letter

Organic Letters Scheme 3. Scale-Up Experiment and Transformation of the Product

Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

was reduced with NaBH4, deprotected with AcOH in conc. HCl, and reprotected with Boc2O in CH2Cl2, a diaminodialcohol 9 was provided with full retention of the optical purity (Scheme 3e). Interestingly, when 8b was treated with ethylenediamine, switchable reactions occurred under different conditions. Deprotection of 8b to 10 occurred at room temperature (Scheme 3f), while a deprotection−cyclization product 11 was furnished at 40 °C (Scheme 3g). 11 Could be easily transformed into 12 with more practical protection groups (Scheme 3h). In summary, a convenient and functional-group-tolerant organocatalytic asymmetric 1,4-addition of azlactones 1 and Dha 2 was furnished under the catalysis of a chiral thiourea catalyst in moderate to high yields (41−98%), with excellent diastereo- (78:22−98:2 dr) and enantioselectivities (89−99% ee). The products of the reaction were characterized as masked chiral α,γ-diamino diacid derivatives with nonadjacent stereogenic centers and protected peptides with nonproteinogenic amino acid residues. In addition, the reaction could be conducted in gram-scale, and the products of the reaction could be readily converted to various α,γ-diamino diacid derivatives, α,γ-diamino dialcohols, and modified peptides. The further application of this protocol in medicinal chemistry is still ongoing in our laboratory.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] *E-mail: [email protected] *E-mail: [email protected] ORCID

Wangsheng Sun: 0000-0001-5277-3329 Rui Wang: 0000-0002-4719-9921 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful for financial support from the NSFC (21502079, 21572278, 21432003), the Program for ChangJiang Scholars and Innovative Research Team in University (IRT_15R27), and the Fundamental Research Funds for the Central Universities (lzujbky-2018-95, lzujbky-2017-k11, lzujbky-2018-kb11).

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REFERENCES

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b03020. Experimental procedure, characterization data, NMR spectra (PDF) Accession Codes

CCDC 1566447 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, by e-mailing data_ [email protected], or by contacting The Cambridge 7083


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Organic Letters

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Access to Î±,Î³-Diamino Diacid Derivatives via Organocatalytic

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