Article pubs.acs.org/joc
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
Catalytic Enantioselective Synthesis of a Pyrrolizidine−AlkaloidInspired Compound Collection with Antiplasmodial Activity Zhi-Jun Jia,†,‡ Hiroshi Takayama,† Yushi Futamura,§ Harumi Aono,§ Jonathan O. Bauer,∥ Carsten Strohmann,∥ Andrey P. Antonchick,*,†,‡ Hiroyuki Osada,§ and Herbert Waldmann*,†,‡ †
Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany Chemical Biology, Faculty of Chemistry and Chemical Biology, Technical University Dortmund, Otto-Hahn-Strasse 4a, 44227 Dortmund, Germany § Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science,2-1 Hirosawa,Wako-shi, Saitama 351-0198, Japan ∥ Inorganic Chemistry, Faculty of Chemistry and Chemical Biology, Technical University Dortmund, Otto-Hahn-Strasse 6, 44227 Dortmund, Germany ‡
S Supporting Information *
ABSTRACT: A novel enantioselective approach to the synthesis of a compound collection inspired by natural pyrrolizidine alkaloids was developed, employing an enantioselectively catalyzed 1,3-dipolar cycloaddition as the key step. The cycloadducts were obtained with excellent enantio- and diastereoselectivity. Biological evaluation of the resulting compound collection revealed that the compound class has multiple bioactivities, including activity against Plasmodium falciparum 3D7 and inhibition of Hedgehog signaling.
■
INTRODUCTION Biology oriented synthesis (BIOS) employs biological relevance as key parameter in the selection of scaffolds for the synthesis of compound collections.1 Natural products (NPs) bind to multiple proteins in their biosynthesis and for the modulation of complex biological systems. The underlying scaffolds of NPs define biologically relevant starting points selected by evolution from vast chemical structure space. Therefore, compound collections inspired by natural product structure are expected to yield modulators of different biological processes.2 In particular, NPs and analogues thereof have proven to be efficient tools in the study of signal transduction processes, often with relevance to the establishment of disease.2,3 For instance, the Hedgehog signaling pathway is a major regulator of developmental processes and is involved in the establishment of basal cell carcinoma and medulloblastoma.4 Small molecule modulators have yielded insight into the biology of hedgehog signaling, and a Hedgehog pathway inhibitor is in clinical use.4 In addition, NPs have been widely applied in the treatment of infectious diseases caused by bacteria, viruses, parasites, and fungi. Among the most representative are artemisinin and its analogues as the current gold-standard therapy against malaria caused by the most pathogenic Plasmodium falciparum.5 However, the development of multidrug resistance against antimalarial drugs even including artemisinin highlights the need to explore new chemical diversity particularly inspired by NPs.6 Since natural product scaffolds and compound collections inspired by them typically are structurally complex and embody multiple stereogenic centers, the development of efficient methods for © XXXX American Chemical Society
their enantioselective synthesis is at the heart of BIOS and of chemical biology and medicinal chemistry research in general. Bi- and tricyclic pyrrolizidine alkaloids are a large group of NPs endowed with multiple bioactivities including insecticidal and cancerogenic modes of action (Figure 1).7 Their synthesis
Figure 1. Representative natural products with pyrrolizidine scaffold.
often employs multistep reaction sequences which so far have not given rise to chiral pyrrolizidine−alkaloid-inspired compound collections.7a,8 Herein, we report a general enantioselective catalytic strategy for functionalized pyrrolizidine scaffold synthesis and the evaluation of a compound collection synthesized thereby in a cell-based assay monitoring signaling through the Hedgehog pathway and in assays determining antiproliferative activities against cancer cell lines, bacteria, fungi, and P. falciparum. Special Issue: Synthesis of Antibiotics and Related Molecules Received: December 19, 2017
A
DOI: 10.1021/acs.joc.7b03202 J. Org. Chem. XXXX, XXX, XXX−XXX
Article
The Journal of Organic Chemistry For the enantioselective synthesis of a pyrrolizidine scaffold inspired compound collection we envisaged employing a strategy involving an asymmetric 1,3-dipolar cycloaddition of azomethine ylides and various olefins followed by a subsequent intramolecular lactamization (Scheme 1).9−11 If cyclic dipolar-
Table 1. Optimization of Reaction Conditions for 1,3Dipolar Cycloaddition of 1a with 2aa
Scheme 1. Retrosynthetic Proposal for the Compound Collection
ophiles were employed, tricyclic pyrrolizidine-3-ones should be obtained from pyrrolidinylpropionic acid esters through intramolecular lactam formation. The required functionalized pyrrolidinylpropionic acid esters could be obtained by asymmetric [3 + 2] cycloaddition of appropriate dipolarophiles and azomethine ylides from N-alkylidene glutamic acid esters.
■
RESULTS AND DISCUSSION N-4-Bromobenzylideneglutamic acid dimethyl ester 1a and Nmethylmaleimide 2a were selected for the establishment of the asymmetric [3 + 2] cycloaddition (Table 1). Various silver(I), copper(I), and copper(II) salts in combination with chiral ligands were initially tested in the presence of a substoichiometric amount of base (Et3N, 20 mol %) in toluene or dichloromethane (Table 1, entries 1−9). In general, in dichloromethane as solvent the endo-cycloaddition proceeded in good yield and with high diastereoselectivity. In toluene, formation of product 3a was not observed. Only moderate enantioselectivity was achieved using silver(I) and copper(II) salts in the presence of chiral ligands 4−7. The best results with respect to yield, diastereoselectivity, and enantioselectivity for product 3a were obtained if Cu(CH3CN)4ClO4 (10 mol %) and (R)-Fesulphos 8 (12 mol %) (Table 1, entry 9) were employed. After further optimization, the catalyst loading could be reduced to 5 mol % of Cu(CH3CN)4ClO4 in the presence of 6 mol % of ligand 8 (Table 1, entry 10). The reduction of catalyst loading to 2 mol % of Cu(CH3CN)4ClO4 resulted in low chemical yield and enantiomeric excess (Table 1, entry 11). Thus, the optimal reaction conditions for the [3 + 2] cycloaddition included the use of Cu(CH3CN)4ClO4 (5 mol %) as catalyst, (R)-Fesulphos (6 mol %) as chiral ligand, and triethylamine (20 mol %) as base in dichloromethane at ambient temperature. The absolute configuration of the major endo-cycloproduct 3a was determined by single-crystal X-ray diffraction analysis.12 To rationalize the stereochemical course of the transformation, we propose the model shown in Scheme 2. First, complex A forms through coordination of the copper(I) salt with (R)-Fesulphos and imine 1. Subsequently, the deprotonation of complex A by triethylamine affords the azomethine ylide, which readily reacts with dipolarophile 2. The maleimide 2 approaches the copper(II)-coordinated azomethine ylide from the less-hindered face to avoid unfavorable steric interactions with the bulky tert-butyl group of ligand 8. The endo-approach is more favored than the exo transition state due to unfavorable steric interactions of maleimide 2 and the propionate group (R3) on the azomethine ylide. Therefore, endo-product 3 is formed with high selectivity.
entry
metal
L
solvent
time (h)
yield (%)
endo/ exo
ee (%)
1 2 3 4 5 6 7 8 9 10c 11d
AgOAc AgOTf Cu(OTf)2 AgOAc AgOTf Cu(OTf)2 AgOAc AgOAc CuClO4b CuClO4b CuClO4b
4 4 4 5 5 5 6 7 8 8 8
CH2Cl2 toluene CH2Cl2 CH2Cl2 toluene CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2
12 48 12 6 48 6 6 12 6 24 48
78
>20:1
26
71 77
>20:1 >20:1
32 58
70 69 65 82 82 51
>20:1 >20:1 >20:1 >20:1 >20:1 >20:1
65 56 28 95 95 8
a Reaction conditions for the [3 + 2] cycloaddition: 1a (1.0 equiv., 0.1 mmol), 2a (1.5 equiv) with Et3N (20 mol %) in solvent (0.1 M) at room temperature in the presence of 10 mol % salt and 12 mol % of the chiral ligand. bCuClO4 = Cu(CH3CN)4ClO4. c5 mol % of salt and 6 mol % of chiral ligand were used. d2 mol % of salt and 2.4 mol % of chiral ligand were used. L = ligand.
With the optimal reaction conditions identified, we investigated the substrate scope. In general, the asymmetric [3 + 2] cycloaddition tolerates a broad range of Schiff bases and dipolarophiles (Table 2). Schiff bases with electron-donating groups (Table 2, entries 2−5 and 11−14) or with electronwithdrawing groups (Table 2, entries 6, 15, and 16) reacted with maleimides 2a or 2b to give endo products 3 in good yields and with high enantiomeric excess. Schiff bases derived from heteroaromatic aldehydes and bulky aromatic aldehydes were compatible with the transformation and reacted with similar efficiency (Table 2, entries 7, 8, 17, and 18). Unfortunately, for Schiff bases obtained from aliphatic aldehydes (Table 2, entry 19), chemical yield and enantiomeric excess are low. Notably, Schiff bases derived from cinnamic aldehydes proceeded well with high enantioselectivity (Table 2, entries 9 and 20). Additionally, maleimides with methyl and phenyl groups could be employed without any decrease of reactivity and enantioselectivity (Table 2, entries 1 and 10). After investigation of the scope of the asymmetric cycloaddition, we explored the feasibility of intramolecular lactamization. Various methods for the straightforward formation of bicyclic lactams from cycloadducts 3 were tested, including heating activation with EDCI, acid, base, trimethylaluminum, or a combination of these conditions.13 The best B
DOI: 10.1021/acs.joc.7b03202 J. Org. Chem. XXXX, XXX, XXX−XXX
Article
The Journal of Organic Chemistry Scheme 2. Proposed Model for the Enantioselective [3 + 2] Cycloaddition
Table 3. Lactamization of [2 + 3] Cycloaddition Productsa
Table 2. Structural Variations at the Schiff Base and Maleimidea
endo/ exo
ee (%)
entry
R
R
time (h)
product
yield (%)
1 2 3 4 5 6 7 8 9
Ph p-MeOC6H4 p-MeC6H4 m-MeC6H4 o-MeC6H4 p-FC6H4 2-naphthyl 2-furanyl pNO2C6H4CH CH Ph p-MeOC6H4 p-MeC6H4 m-MeC6H4 o-MeC6H4 p-BrC6H4 o-FC6H4 2-naphthyl 2-furanyl (CH3)2CH pNO2C6H4CH CH
Me Me Me Me Me Me Me Me Me
18 18 18 18 18 18 18 18 24
3b 3c 3d 3e 3f 3g 3h 3i 3j
86 82 85 85 83 82 85 81 65
>20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1
99 99 99 99 99 97 91 99 99
Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph
18 18 18 18 18 18 18 18 18 24 24
3k 3l 3m 3n 3o 3p 3q 3r 3s 3t 3u
88 84 81 83 83 86 73 88 82 61 72
>20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1
99 97 96 99 96 98 92 97 94 43 99
10 11 12 13 14 15 16 17 18 19 20 a
1
2
entry b
1 2 3 4 5 6 7 8 9
R1
R2
product
yield (%)
p-BrC6H4 C6H5 p-MeC6H4 m-MeC6H4 o-MeC6H4 2-naphthyl p-MeOC6H4 p-BrC6H4 p-NO2C6H4CHCH
Me Me Me Me Me Me Ph Ph Ph
9a 9b 9d 9e 9f 9h 9l 9p 9u
91 93 89 90 88 92 92 95 88
a Reaction conditions: the solution of ester 3 (0.1 mmol) in 1 mL of a mixed solvent of toluene/AcOH (4:1) was refluxed for 90 min. bThe ee of 9a is 97%.
transformation by using AgOAc as catalyst, affording the corresponding racemic pyrrolidines and bicyclic pyrrolizidines in satisfactory yields.14 In total, a library of 119 compounds was obtained. Subsequent evaluation of the compounds in different biological settings resulted in the discovery of novel inhibitors of Hedgehog pathway signaling in mouse embryonic mesoderm fibroblast C3H10T1/2 cells14 with IC50 values
