Letter pubs.acs.org/acscatalysis
Chemo- and Site-Selective Alkyl and Aryl Azide Reductions with Heterogeneous Nanoparticle Catalysts Venkatareddy Udumula,†,§ S. Hadi Nazari,†,§ Scott R. Burt,† Madher N. Alfindee,‡ and David J. Michaelis*,† †
Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah 84602, United States Department of Chemistry and Biochemistry, Utah State University, Logan, Utah 84322, United States
‡
S Supporting Information *
ABSTRACT: Site-selective modification of bioactive natural products is an effective approach to generating new leads for drug discovery. Herein, we show that heterogeneous nanoparticle catalysts enable site-selective monoreduction of polyazide substrates for the generation of aminoglycoside antibiotic derivatives. The nanoparticle catalysts are highly chemoselective for reduction of alkyl and aryl azides under mild conditions and in the presence of a variety of easily reduced functional groups. High regioselectivity for monoazide reduction is shown to favor reduction of the least sterically hindered azide. We hypothesize that the observed selectivity is derived from the greater ability of less-hindered azide groups to interact with the surface of the nanoparticle catalyst. These results are complementary to previous Staudinger reduction methods that report a preference for selective reduction of electronically activated azides. KEYWORDS: nanoparticle, azide, reductions, site-selective, catalysis, aminoglycosides
S
The development of nanoparticle catalysts for organic synthesis has recently emerged as an effective strategy for generating highly reactive, robust (high TON), and recyclable heterogeneous catalysts.11 One hallmark of nanoparticle catalysis is the ability to develop reactive heterogeneous catalysts where product selectivity (e.g., regioselectivity, diastereoselectivity, and enantioselectivity) can be controlled by varying the structure of the stabilizing ligands or polymer supports.12 Kobayashi,13 Toste,14 and others11d,15 have recently reported enantioselective transformations where chiral phosphine supporting ligands are thought to modify the surface of the nanoparticle catalyst and induce asymmetry. Our laboratory has demonstrated that the reactivity and chemoselectivity of Ru−Co bimetallic nanoparticles in nitroarene reductions can be optimized by modification of the supporting polymer structure.16 During the course of our studies on nanoparticle-catalyzed nitroarene reductions, we found that the reduction of aryl azide 1 could occur with high chemoselectivity in the presence of an easily reduced nitro functional group to give product 2 (Scheme 1). This exceptional selectivity for azide reduction under mild conditions suggested to us the potential utility of our nanoparticles for chemoselective late-stage azide reductions in the presence of other sensitive functionality.17 To date, chemoselective azide reductions with nanoparticle catalysts
ite-selective modification of polyfunctional natural products is an important avenue for generating synthetic analogues of existing bioactive molecules.1 This pursuit toward natural product derivatives is particularly imperative in the field of antibiotic research where multidrug-resistant bacteria represent the most significant threat to human health in the coming decades.2 Several methods toward site-selective derivatization of antibiotics have been developed and used in the context of polyol natural product diversification, including site-selective acylation and lipidation,3 phosphorylation,4 halogenation,5 and thiocarbonylation.6 One significant example of site-selective polyol functionalization was reported by Miller and co-workers for selective lipidation of vancomycin, where polypeptide-based acylation catalysts achieve site selectivity via catalyst control (see Figure 1a).3e Site-selective amine modification represents an equally attractive strategy for derivatization of polyamine natural products, especially in the context of aminoglycoside antibiotics.7 Because of the prevalence of azides in synthetic routes toward polyamines, site-selective azide reduction is one potential approach to selective amine functionalization.8−10 The Wong and Chang groups have reported selective reduction of polyazido derivatives of neamine en route to aminoglycoside antibiotics (Figure 1b).7 These studies demonstrate that high selectivity with phosphine reductants (Staudinger reduction) led to selective reduction of the most electronically activated (electron-deficient) azide. In this report, we describe highly chemoselective heterogeneous nanoparticle catalysts that enable site-selective reduction of the least hindered azide in polyazido substrates as a complementary method for siteselective azide reductions in antibiotic synthesis (Figure 1c). © 2016 American Chemical Society
Received: April 29, 2016 Revised: June 2, 2016 Published: June 6, 2016 4423
DOI: 10.1021/acscatal.6b01217 ACS Catal. 2016, 6, 4423−4427
Letter
ACS Catalysis Table 1. Optimization of Azide Reduction
entrya
conditions
1 2 3 4 5 6 7 8c
standard no Ru catalyst no NH2NH2·H2O 3 mol % Ru nanocatalyst 1 mol % Ru nanocatalyst 2 equiv NH2NH2·H2O 1.5 equiv NH2NH2·H2O 2 mol % Ru−Co nanocatalyst
time 1 24 24 1 3 1.4 2 2
h h h h h h h h
yieldb (%) 98 0 0 99 94 97 98 98
a
Reactions run using 0.4 mmol 3, 3 mol % ruthenium catalyst (0.41 mmol/g in polystyrene), and 3 equiv hydrazine hydrate in 1 mL EtOH, unless otherwise noted. bIsolated yield. cRun with 2 equiv NH2NH2·H2O.
hydrate (entries 6 and 7), we found that reductions in the presence of 2 mol % ruthenium and 3 equiv hydrazine hydrate provided the most reproducible results over a wide range of substrates (entry 1). In contrast to our previous studies on nitroarene reductions, the use of mixed-metal Ru−Co nanoparticles did not improve the reactivity in this system (entry 8). With optimized reaction conditions in hand, we next explored the chemoselectivity of our catalysts for azide reductions in the presence of other easily reducible functional groups (Figure 2). Aromatic azides are chemoselectively Figure 1. Site-selective derivatization of antibiotics: (a) Vancomycin,3e (b) aminoglycosides antibiotics,7 and (c) current work.
Scheme 1. Chemoselective Azide Reduction
have focused almost exclusively on aromatic azides,18 which have limited synthetic utility, because aromatic azides are generally synthesized from the corresponding anilines. Herein, we show that polystyrene-supported ruthenium nanoparticles are highly chemoselective catalysts for the reduction of both aryl and alkyl azides. More importantly, we demonstrate that the nanoparticle catalysts provide high regioselectivity in latestage reductions of polyazides, where selectivity is principally governed by sterics. Our preliminary studies focused on the reduction of alkyl azides, because of their importance as synthetic intermediates en route to amines. Our polystyrene-supported ruthenium nanoparticles (∼2 nm particle size) were prepared in a single step from commercial materials via NaBH4 reduction of RuCl3 in the presence of polystyrene (see the Supporting Information). Under optimized reduction conditions, we found that olefin-containing alkyl azide 3 was readily converted to amine 4 with just 3 mol % Ru nanoparticles and 3 equiv of hydrazine hydrate (Table 1). Remarkably, this reduction occurred within just 1 h at room temperature and no reduction of the olefin was observed (entry 1). No product was observed in the absence of ruthenium catalyst (entry 2), or when the hydrazine was omitted (entry 3). While complete conversion to the primary amine could be obtained with as little as 1 mol % catalyst loading (entries 4 and 5) and 1.5 equiv hydrazine
Figure 2. Chemoselective reduction of aromatic azides.
reduced in the presence of numerous other functional groups, including aromatic halides (5a−5c), anilines (5d), phenols (5e), carboxylic acids (5f), ketones (5g), cyanides (5h), nitro groups (5i), and esters (5j). In addition, alkynes (5k) and alkenes (5l) were not reduced under our standard conditions. An aromatic bis(azide) substrate was also cleanly reduced in nearly quantitative yield to generate dianiline product 5m. In all cases, the product is isolated in exceptional purity without the need for chromatography. Polyfunctional alkyl azides are also readily reduced with high chemoselectivity under our standard conditions (Figure 3). Benzylic (6a−6c), allylic (6d), tertiary (6e), secondary (6f), and primary (4, 6g−6l) azides, including simple alkyl azides (6i) are all rapidly reduced to the corresponding amine with high chemoselectivity. The reduction reaction tolerates alkenes (4, 6d, 6h), alkynes (6c, 6j), benzyl (6k) and TBS ethers (6l), acetals (6g), and alcohols (6f). In all cases, products were obtained with >96% selectivity toward azide reduction. The 4424
DOI: 10.1021/acscatal.6b01217 ACS Catal. 2016, 6, 4423−4427
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ACS Catalysis Table 2. Regioselective Azide Reduction
entrya 1d 2 3 4 5 6 7e 8e,f 9g,h 10j
Figure 3. Chemoselective reduction of aliphatic azides.
ruthenium nanoparticle catalyst can also be recovered and reused; the reduction of substrate 3 was conducted five consecutive times (95%−99% yield) with the same recycled catalyst and did not show any significant decrease in yield.19 The greatest potential of our catalyst lies in its ability to perform chemoselective reductions in the context of complex molecule synthesis (Figure 4). The azide reduction reaction
time 12 4 5 5 5 5 30 40 40 40
h h h h h h h h h h
polystyrene
temperature
8a:8bb
yield of 8ac (%)
4-H 4-H 4-H 4-CF3 4-OMe 4-tBu 4-H 4-H 4-H
−78 °C rt 0 °C to rt 0 °C to rt 0 °C to rt 0 °C to rt 0 °C to rt 0 °C to rt 0 °C to rt 0 °C to rt
1.9:1 3.0:1 3.3:1 1:2.4 1:1.7 1:20 3.3:1 5.1:1 7.9:1 4.5:1
54 60 76 28 22 5 70 62 79i 33
Reactions run with 0.2 mmol 6, 4 equiv NH2NH2·H2O, and 4 mol % Ru/PS catalyst in ethanol (0.06 M). bRatio determined by isolated yield of 8a and 8b. cIsolated yield. dRun with PMe3 (1.1 equiv) for 4 h; see ref 7. eSlow addition of NH2NH2·H2O over 1 h. fWith 3 mol % Ru/PS catalyst and 4 equiv NH2NH2·H2O. gWith 2 mol % Ru/PS catalyst and 3 equiv NH2NH2·H2O. hAddition of 1 equiv NH2NH2· H2O after 24 h. i8% recovered 6. jRun with 5% Ru on carbon (2 mol % Ru). a
9). This result is in contrast to commercially available ruthenium on carbon, which provided very low conversion and only moderate selectivity under the same conditions (entry 10). We next investigated site-selective azide reductions with an assortment of electronically and sterically diverse bis-azide substrates (Figure 5). Primary azides are reduced in moderate
Figure 4. Chemoselective azide reduction in biomolecule synthesis. Conditions for this synthesis are as described in Figure 3.
provides nearly quantitative yield and selectivity on many common biomolecules, including steroids (6m), nucleotide bases (6n), saccharides (6o), and amino acids (6p). In all cases, the product was obtained in pure form (>95%) after removal of the catalyst via filtration and without chromatography. Having established that both aryl and alkyl azides can be reduced with high chemoselectivity, we next sought to determine whether our catalyst could perform site-selective reductions in molecules containing multiple azide groups (Table 2). Using proline-derived bis-azide 7, we found that conditions previously optimized for regioselective azide reduction provided a 1.9:1 mixture of mono- and bis-reduction products and only a modest yield of 8a (entry 1). When our ruthenium nanoparticle catalyst was employed, the reaction proceeded with 3:1 selectivity in 60% yield (entry 2). If the reaction was initiated at 0 °C and allowed to stir at room temperature (rt) for 5 h, 76% of the desired product could be obtained (entry 3). When the electronic (entries 4 and 5) and steric (entry 6) properties of the supporting polymer were modified, lower product selectivity was observed. Optimizing the catalyst loading (entries 7−8) allowed us to obtain the mono reduction product in up to 5:1 selectivity. If an additional 1.0 equiv of hydrazine was added halfway through the reaction, conversion approached 100% and the desired product was obtained in high yield (79%) and very good selectivity (entry
Figure 5. Regioselective monoazide reduction. (a) Conditions: 2 mol % Ru/PS catalyst, 4 equiv NH2NH2·H2O in EtOH (0.13 M), 0 °C to rt, 6 h. Regioselectivity determined by 1H NMR analysis of the crude reaction mixture. Isolated yield. (b) Ratio of 11a:11b determined by isolated yield of each isomer.
selectivity over a series of more electronically activated benzylic azides (9a−9e). In addition, primary azides selectively reduce in the presence of alkyl secondary azides (8a, 9f). Aromatic azides are also reduced with modest preference over primary (9g) azides. Sterics appear to play an important role in selective azide reduction, as lysine bis-azide 10 reduced with moderate selectivity favoring reduction of the primary azido group (11a) (Figure 5b).20 This result is in stark contrast with a previous report demonstrating that, under Staudinger reduction 4425
DOI: 10.1021/acscatal.6b01217 ACS Catal. 2016, 6, 4423−4427
Letter
ACS Catalysis conditions, the electronically activated α-secondary azide (11b) was reduced preferentially to the less-hindered primary azide with ca. 15:1 selectivity.7a The high selectivity for primary azide reductions described above led us to investigate the reduction of saccharide bis-azide substrates that are common intermediates in the synthesis of aminosugars. Previous examples of site-selective azide reductions with aminosugars have demonstrated that electronically activated azides (proximal electron-withdrawing oxygen atoms) react preferentially under Staudinger reduction conditions.7 With our nanoparticle catalysts, α-D-gluco-pyranoside bis-azide reacted with nearly complete selectivity for the primary azide over the electronically activated secondary azide to provide product 12 in high yield (Figure 6). A bis-azide sugar containing an anomeric azide also reacted with preference for reduction of the more sterically available primary azide to give monoamine product 13.
Figure 6. Regioselective azide reduction in polysaccharides. Conditions: 4−7 mol % Ru/PS catalyst, 4−5 equiv NH2NH2·H2O in EtOH (0.13M), 0 °C to rt, 7−10 h, then Boc2O, rt, 12 h; isolated yield. Selectivity determined by 1H NMR analysis of the crude reaction mixture. Figure 7. Site-selective azide reduction in aminoglycoside antibiotic derivatives including (a) kanamycin tetraazide and (b) neamine tetraazide.
We next investigated the selectivity of our catalysts for siteselective azide reductions of aminoglycoside antibiotic derivatives. Kanamycin-derived tetraazide 14 underwent selective reduction of the primary azide to monoamine 15 in moderate yield (41%, 60% based on recovered starting material) (Figure 7a). This result is remarkable because all reported cases of selective azide reductions with aminoglycoside derivatives have provided selective reduction of the electronically activated secondary azides (in blue).7 However, our polystyrenesupported nanoparticles maintain a high preference for reduction of the sterically most accessible azide. The remainder of the mass in this reduction reaction is composed principally of bis- and tris-reduced products and not monoreduced isomers, confirming the high selectivity for initial reduction of the sterically most accessible azide. We also investigated the reduction of neamine tetraazide 16 and found that, under similar conditions employed for reduction of kanamycin derivative 14, a secondary azide was selectively reduced over the primary azide to give product 17 (Figure 7b). Importantly, the more sterically accessible secondary azide (shown in red) was reduced in preference to the electronically more activated azide (shown in blue). For this substrate, we hypothesize that the primary azide may be sterically less accessible due to conformation changes, or that a combination of electronic activation and low steric hindrance led to selective reduction of this secondary azide. In conclusion, we have demonstrated that polystyrenesupported nanoparticles are highly reactive and chemoselective heterogeneous catalysts for the hydrazine-mediated reduction of azides to amines. The heterogeneous nanoparticle catalysts are chemoselective for azide reduction in the presence of numerous easily reduced functional groups. The catalysts can also be easily recovered and recycled from the reaction mixture and crude products are obtained in high purity without
subsequent purification. Our nanoparticle catalysts also enable highly site-selective azide reductions of polyazides, including monoazide reductions of aminoglycoside antibiotic precursors. This alternative approach to selective azide reduction provides a practical and efficient method for site-selective derivatization of aminoglycoside antibiotics for analogue generation and drug discovery.
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ASSOCIATED CONTENT
* Supporting Information S
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acscatal.6b01217. Experimental procedures, characterization data for all new compounds, and STEM characterization data for nanoparticle catalysts (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Author Contributions §
These authors contributed equally.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank Brigham Young University for financial support. We thank Cheng-Wei Tom Chang for providing kanamycin tetraazide (14) and neamine tetraazide (16) derivatives. We thank Paul Minson for assistance in obtaining STEM characterization data. 4426
DOI: 10.1021/acscatal.6b01217 ACS Catal. 2016, 6, 4423−4427
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ACS Catalysis
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(b) Ahammed, S.; Saha, A.; Ranu, B. C. J. Org. Chem. 2011, 76, 7235− 7239. (19) When the reaction of 6f was halted at partial conversion over five consecutive recycles, the same partial conversion (47%−56% conversion, 1 h) was obtained for each run. See the Supporting Information. (20) Knouzi, N.; Vaultier, M.; Carrié, R. Bull. Soc. Chim. Fr. 1985, 5, 815−819.
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