Enantioselective Synthesis of Pyrrole-Fused Piperazine and

Letter pubs.acs.org/acscatalysis

Enantioselective Synthesis of Pyrrole-Fused Piperazine and Piperazinone Derivatives via Ir-Catalyzed Asymmetric Allylic Amination Chun-Xiang Zhuo, Xiao Zhang, and Shu-Li You* State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China S Supporting Information *

ABSTRACT: Ir-catalyzed intramolecular asymmetric allylic amination reaction of pyrrole derivatives was achieved. The pyrrole-fused piperazine and piperazinone derivatives could be easily accessed from the pyrrole-tethered allylic carbonates in good yields and enantioselectivity (up to 98% ee).

KEYWORDS: allylic amination, asymmetric catalysis, iridium, piperazine, piperazinone, pyrrole

P

derivatives7c,e via the Ir-catalyzed asymmetric allylic dearomatization reactions and stereospecific migration reactions (path a, b, and c, Scheme 1).8 However, the R2 group on the pyrrole structural core was limited to electron-donating or electronneutral groups. By installing an electron-withdrawing group on the pyrrole core, our group recently reported the asymmetric

yrrole-fused piperazine and piperazinone derivatives represent one important class of natural products and pharmaceutical agents, which often display interesting biological activities.1 For instance, hanishin was found to be cytotoxic toward NSCLCN6 human nonsmall-cell lung carcinoma (IC50 9.7 μg/mL). Longamide B showed activity against African trypanosome (IC50 1.53 μg/mL); and longamide B methyl ester displayed cytotoxic activity against P-388 lymphocytic leukemia cells (ED50 30 μg/mL), respectively (Figure 1).2 Due to their potential application as

Scheme 1. Ir-Catalyzed Intramolecular Asymmetric Allylic Substitution Reaction of Pyrroles

Figure 1. Representative natural products containing pyrrole-fused piperazinone derivatives.

pharmaceuticals, efficient asymmetric syntheses of the above pyrrole-fused piperazine and piperazinone containing alkaloids are highly desirable.3−6 To date, the known procedures for the enantioselective construction of these pyrrole-fused piperazine and piperazinone derivatives are mainly limited to chiral pool strategy,4 Pd-catalyzed asymmetric allylic amination,5 and organocatalytic enantioselective aza-Michael addition reactions.6 As part of our ongoing efforts toward the enantioselective functionalization of pyrroles,7 we recently reported the efficient syntheses of spiro-2H-pyrrole7b,e and polycyclic pyrrole © XXXX American Chemical Society

Received: June 6, 2016 Revised: July 5, 2016

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ACS Catalysis

°C in THF, providing the pyrrole-fused piperazine product 3a in 81% yield and 98% ee (entry 6, Table 1). Under the optimized reaction conditions, various pyrrole tethered allylic carbonates 2b−i were explored to examine the generality of the process (Scheme 2). The reaction of allylic

allylic amination of pyrroles via the Ir/NHC catalytic system (path d, Scheme 1).5e However, the substrate scope was quite limited. Herein we describe the highly enantioselective construction of various pyrrole-fused piperazine and piperazinone derivatives via an easily accessible Ir/phosphoramidite catalytic system, providing a rapid access to the structural core of a series of natural products (path e, Scheme 1). The study was initiated by utilizing pyrrole tethered allylic carbonate (2a) as a model substrate to optimize the reaction conditions. In the presence of 2 mol % of [Ir(cod)Cl]2, 4 mol % of Feringa ligand 1a, and 1 equiv of Cs2CO3, the reaction of 2a in THF for 48 h led to the amination product 3a in 75% yield and 96% ee9−11 (entry 1, Table 1). Encouraged by these

Scheme 2. Reaction Substrate Scopea

Table 1. Optimization of the Reaction Conditionsa

entry

1

base

solvent

t (h)

yield (%)b

ee (%)c

1 2 3 4 5 6 7 8 9 10d 11 12 13 14e

1a 1a 1a 1a 1a 1b 1c 1d 1e 1f 1b 1b 1b 1b

Cs2CO3 Li2CO3 K3PO4 Et3N DBU DBU DBU DBU DBU DBU DBU DBU DBU DBU

THF THF THF THF THF THF THF THF THF THF DCM toluene dioxane dioxane

48 48 48 48 48 62 41 41 41 41 44 44 44 44

75 27 70 28 74 81 62 12 30 18 73 71 67 80

96 98 95 96 97 98 96 91 92 n.d. 56 94 95 95

a

Condition A: 2 mol % of [Ir(cod)Cl]2, 4 mol % of (S,S,Sa)-1b, 0.2 mmol of 2 and DBU in THF (2.0 mL); condition B: 2.5 mol % of [Ir(dbcot)Cl]2, 5 mol % of (S,S,Sa)-1b, 0.12 mmol of 2b, 0.18 mmol of DBU in THF (1.5 mL); condition C: 2 mol % of [Ir(cod)Cl]2, 4 mol % of (R,Ra)-1e, 0.2 mmol of 2 and DBU in THF (2.0 mL); condition D: 4 mol % of [Ir(cod)Cl]2, 8 mol % of (S,S,Sa)-1b, 0.2 mmol of 2 and Cs2CO3 in THF (2.0 mL). bIsolated yield. cDetermined by HPLC analysis. dFive mol % of [Ir(cod)Cl]2, 10 mol % of (S,S,Sa)-1b were used.

carbonate containing an allyl group on the amine moiety (2b) in the tether gave the corresponding product (3b) in moderate yield and excellent ee with [Ir(cod)Cl]2 as the iridium precursor (68% yield, 98% ee). Simply switching the iridium precursor to [Ir(dbcot)Cl]2, which was introduced by Helmchen and co-workers13 in Ir-catalyzed allylic substitution reactions, the yield could be improved to 86% with preserved enantioselectivity (3b, Scheme 2). When the Boc-protected substrate (2c) and the all-carbon tethered pyrrole substrate (2d) were used, the reactions occurred smoothly in moderate ee, respectively, with 1b as the chiral ligand (86% ee for 3c, 78% ee for 3d). Interestingly, changing the chiral ligand to 1e, which could form an iridacycle with [Ir(cod)Cl]2 via a phenyl C(sp2)-H bond activation rather than a methyl C(sp3)-H bond activation in the Feringa type ligands,12b excellent ee could be obtained for both substrates (72−77% yield, 94−95% ee, 3c,d, Scheme 2). Substrates bearing an acetyl group (2e) or an ester group (2f−h) on the pyrrole core all reacted smoothly, affording the desired products 3e−h in good to excellent yields and excellent enantioselectivity (58−87% yield, 97−98% ee,

a

Reaction conditions: 2 mol % of [Ir(cod)Cl]2, 4 mol % of 1, 0.1 mmol of 2a and base in solvent (1.0 mL). bIsolated yield. cDetermined by HPLC analysis. dn.d. = not determined. eReaction was conducted at 80 °C.

results, further optimization of the reaction conditions was carried out. Various bases such as Li2CO3, K3PO4, Et3N, and DBU were screened (entries 2−5, Table 1), and DBU was found to be the optimal base for the reaction process. Catalysts generated from ligands 1b−1c could enable the asymmetric allylic amination reaction of 2a in good to excellent yields and enantioselectivity (62−81% yield, 96−98% ee, entries 6−7, Table 1). However, when ligands 1d−1f12 were tested, only low to moderate yields could be obtained (12−30% yield, entries 8−10, Table 1). Next, examination of solvents and reaction temperature (entries 11−14, Table 1) led to the optimal reaction conditions: 2 mol % of [Ir(cod)Cl]2, 4 mol % of Alexakis ligand 1b, and 1 equiv of DBU, 1 equiv of 2a at 50 5308

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ACS Catalysis 3e−h, Scheme 2). It is noteworthy that when the pyrrolecontaining amide substrate 2i was used, the reaction underwent smoothly, affording the pyrrole-fused piperazinone 3i in 78% yield and 96% ee (3i, Scheme 2). The structure and stereochemistry of the products were confirmed unambiguously by an X-ray crystallographic analysis of a crystal of enantiopure 3a.14 The absolute configuration was determined as S. In addition, the dibromo-substituted pyrrole containing amide substrate 2j was also tested in this reaction. To our disappointment, only moderate enantioselectivity could be obtained when 1b was used as the chiral ligand (67% ee, 3j, Scheme 3). Gratifyingly, by switching the chiral ligand to 1e,

In summary, we have achieved an Ir-catalyzed intramolecular asymmetric allylic amination reaction of pyrrole derivatives. The pyrrole-fused piperazine and piperazinone derivatives could be easily accessed from the pyrrole tethered allylic carbonates in good to excellent yields, excellent chemo- and enantioselectivity. Further investigations on the reaction scope and applications of the highly enantioenriched pyrrole-fused piperazine and piperazinone derivatives are currently under investigation in our laboratory.

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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/acscatal.6b01585. Experimental procedures and characterization data for all new compounds (PDF) Crystallographic data (CIF)

Scheme 3. Reaction Substrate ScopeBromopyrroleContaining Substratesa

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the National Basic Research Program of China (2016YFA0202900, 2015CB856600) and NSFC (21332009, 21421091) for generous financial support.

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a Reaction conditions: 2 mol % of [Ir(cod)Cl]2, 4 mol % of (R,Ra)-1e, 0.2 mmol of 2 and DBU in THF (2.0 mL). bIsolated yield. c Determined by HPLC analysis. dReaction conditions: 2 mol % of [Ir(cod)Cl]2, 4 mol % of (S,S,Sa)-1b, 0.2 mmol of 2 and Cs2CO3 in THF (2.0 mL). eReaction conditions: 4 mol % of [Ir(cod)Cl]2, 8 mol % of (S,Sa)-1f, 0.2 mmol of 2 and Cs2CO3 in THF (2.0 mL).

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the enantioselective control of the reaction could be improved to 93% ee (3j, Scheme 3).15 To our delight, when the pmethoxybenzyl (PMB)-group-protected substrate 2k was used, the reaction occurred smoothly, providing the dibromosubstituted pyrrole-fused piperazinone derivative 3k in 96% yield and 96% ee (3k, Scheme 3). The reaction conditions were also suitable for the monobromo-substituted pyrrole 2l (89% yield, 83% ee, 3l, Scheme 3). By using the sterically bulkier ligand 1f,12c,d the enantioselective control of the reaction could be improved to 91% ee (85% yield, 3l, Scheme 3). The products obtained here could be readily transformed to the natural products such as longamide B, longamide B methyl ester, cyclooroidin, and hanishin (Scheme 4), as reported in the literature.5d Scheme 4. Transformation of 3l to Natural Products

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