Allylboration Reaction - ACS Publications - American

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Multicomponent Hetero-[4 + 2] Cycloaddition/Allylboration Reaction: From Natural Product Synthesis to Drug Discovery Dennis G. Hall,* Taras Rybak, and Tristan Verdelet Department of Chemistry, University of Alberta, 4-010 Centennial Centre for Interdisciplinary Science, Edmonton, Alberta, Canada, T6G 2G2 CONSPECTUS: Multicomponent reactions (MCR), transformations employing three or more simple substrates in a single and highly atom-economical operation, are very attractive in both natural product synthesis and diversityoriented synthesis of druglike molecules. Several popular multicomponent reactions were designed by combining two well-established individual reactions that utilize mutually compatible substrates. In this regard, it is not surprising that the merging of two reactions deemed as workhorses of stereoselective synthesis, the Diels−Alder cycloaddition and carbonyl allylboration, would produce a powerful and highly versatile tandem MCR process. The idea of using 1,3-dienylboronates in [4 + 2] cycloadditions as a means to produce cyclic allylic boronates was first reported by Vaultier and Hoffmann in 1987. In their seminal study, a 1-boronodiene was reacted with electron-poor alkenes, and the intermediate cycloadducts were isolated and added to aldehydes in a separate step leading to αhydroxyalkylated carbocycles via a highly diastereoselective allylboration reaction. The one-pot three-component variant was realized in 1999 by Lallemand and co-workers, and soon after groups led by Hall and Carboni reported heterocyclic variants of the tandem [4 + 2] cycloaddition/allylboration to prepare α-hydroxyalkylated piperidine and pyran containing compounds, respectively. These classes of heterocycles are ubiquitous in Nature and are important components of pharmaceuticals. This Account summarizes the development and evolution of this powerful multicomponent reaction for accessing nonaromatic heterocycles and its many applications in natural products synthesis and drug discovery. The aza[4 + 2]cycloaddition/ allylboration MCR was first optimized in our laboratory using 4-boronylhydrazonobutadienes and N-substituted maleimides, and it was exploited in the preparation of combinatorial libraries of polysubstituted imidopiperidines that feature as many as four elements of chemical diversity. Biological screening of these druglike imidopiperidine libraries unveiled promising bioactive agents such as A12B4C3, the first reported inhibitor of the human DNA repair enzyme, polynucleotide kinase-phosphatase (hPNKP). Related applications of this MCR in target-oriented synthesis also led to total syntheses of palustrine alkaloids. The inverse electron-demand oxa[4 + 2] cycloaddition/allyboration variant can take advantage of Jacobsen’s chiral Cr(III)salen catalyst, affording a rare example of catalytic enantioselective MCR, one that provides a rapid access to α-hydroxyalkyl dihydropyrans in high enantio- and diastereoselectivity. This process exploits 3-boronoacrolein pinacolate as the heterodiene with ethyl vinyl ether or various 2-substituted enol ethers, along with a wide variety of aldehydes in the allylation stage. This versatile methodology was deployed in total syntheses of thiomarinol antibiotics, goniodiol and its derivatives, and the complex anticancer macrolide palmerolide A. More recent work from our laboratory centered on the regio- and stereoselective Suzuki− Miyaura cross-coupling of the dihydropyranyl boronates, thus providing a glimpse of the potential for new multicomponent variants that merge hetero[4 + 2] cycloadditions of 1-borylated heterodienes with transition metal-catalyzed transformations. This stereoselective MCR strategy holds great promise for provoking continuing applications in complex molecule synthesis and drug discovery, and is likely to inspire new and innovative MCR-based approaches to nonaromatic heterocycles.

1. INTRODUCTION Multicomponent reactions (MCR) employ three or more substrates to provide new products with optimal change in structure and functionality in a single highly atom-economical operation.1 They are attractive tools in both natural product synthesis 2 and diversity-oriented synthesis of druglike molecules.3 Several popular multicomponent reactions were designed by combining well-established individual reactions that utilize mutually compatible substrates. In this regard, it is not surprising that combining two reactions deemed as workhorses of stereoselective synthesis, the Diels−Alder cycloaddition and carbonyl allylboration,4 would produce a © 2016 American Chemical Society

powerful and versatile tandem MCR process. The use of 1,3dienylboronates in [4 + 2] cycloadditions was first reported by Vaultier and Hoffmann in 1987.5 In their seminal study, boronodiene 1 was reacted with maleic anhydride or maleimides (Scheme 1). The cycloadducts 2 were isolated, followed by C−B bond oxidation to afford secondary alcohols 3. Alternatively, addition of aldehydes to the cyclic allylboronates 2, in a separate step, led to α-hydroxyalkylated carbocycles 4 via a highly diastereoselective nucleophilic Received: August 3, 2016 Published: October 18, 2016 2489

DOI: 10.1021/acs.accounts.6b00403 Acc. Chem. Res. 2016, 49, 2489−2500

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Accounts of Chemical Research Scheme 1. Vaultier−Hoffmann Tandem [4 + 2] Cycloaddition/Allylboration Reaction

Scheme 3. Original [4 + 2] Cycloaddition/Allylboration Reaction by Vaultier and Hoffmann5

allylation. The first one-pot three-component variant was realized by Lallemand and co-workers in 1999.6 Soon after, groups led by Hall and Carboni reported heterocyclic variants of the tandem [4 + 2] cycloaddition/allylboration to prepare α-hydroxyalkylated piperidine and pyran compounds, respectively (Scheme 2).7,8 This Account summarizes the develop-

stereochemistry by NMR spectroscopy. The use of Lewis acids was only briefly examined as a means to facilitate the [4 + 2] cycloaddition.9 Electronically activated 1-borylated butadienes were explored with mixed success.10 Control of absolute stereochemistry is a challenging issue with the [4 + 2] cycloaddition step; use of a tartrate ester provided enantiomeric excess no higher than 70% ee.11 Alternatively, cyclohexadienylboronates were generated by way of cobaltcatalyzed diene-alkyne cycloaddition, and a 71% ee was obtained with a chiral ligand.12 Along with 2-borylated butadienes, 1-borylated butadienes were also employed in a number of other types of multicomponent processes.13

Scheme 2. General Scheme for the Tandem Hetero-[4 + 2] Cycloaddition/Allylboration Reaction

Scheme 4. Three-Component Variant by Six and Lallemand6

ment and evolution of this versatile MCR for accessing nonaromatic heterocycles and its many applications in natural products synthesis and drug discovery. Experimentally, the above [4 + 2] cycloaddition/allylboration chemistry was executed in a one-pot sequential manner where the aldehyde is added after completion of the [4 + 2] cycloaddition. A priori, the aldehyde would not be expected to interfere with the first step by reacting neither with the boronobutadiene or the dienophile. This idea was put to the test by Six and Lallemand, who reported the first application of the tandem [4 + 2] cycloaddition/allylboration as a formal MCR where all three reactants are present from the beginning.6 Thus, when diene 5 was heated with excess methyl acrylate and aldehyde 10 at 80 °C in a solventless mixture, the expected three-component adduct 11 was isolated in a modest yield (Scheme 4). Later, the Lallemand group demonstrated the power of this MCR strategy to forge the decalin core of the complex diterpene, clerodin 1 (15, Scheme 5).14 Upon heating together 4-borono-1,3-diene 12, methyl acrylate, and γbenzyloxy butanal (10), the α-hydroxyalkyl cyclohexene 13 was isolated as a single diastereomer, albeit in low yield. From 13, several transformations led to the advanced clerodan intermediate 14.

2. BACKGROUND: SYNTHESIS OF CARBOCYCLES BY [4 + 2] CYCLOADDITION/ALLYLBORATION In their original publication, Vaultier, Hoffmann, and coworkers prepared 3-methyl-1,3-butadienylboronates and examined their thermal [4 + 2] cycloaddition with various dienophiles.5 As examplified in Scheme 3, it was found that catechol dienylboronate 5 reacts with maleic anhydride and N-phenyl maleimide at 80 °C to give the desired cycloadduct 6 in high stereoselectivity. Acrylates required a higher temperature (100 °C). Following the [4 + 2] cycloaddition, the reaction vessel was allowed to cool to ambient temperature and an aldehyde was introduced. Adducts of maleic anhydride reacted at this temperature whereas cyclic allylic boronates derived from N-phenyl maleimide reacted at 60 °C. Thus, using benzaldehyde, product 8 was isolated in 69% yield as a single diastereomer consistent with the expected chairlike transition state (7).4 Notably, allylation products derived from cycloadducts of maleic anhydride underwent intramolecular transesterification to furnish a bicyclic lactone, such as 9, which allowed a proof of relative 2490


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Accounts of Chemical Research Scheme 5. Model Approach to Clerodin Using a ThreeComponent [4 + 2] Cycloaddition/Allylboration,14 by Lallemand and Co-Workers

Scheme 6. Multicomponent Aza[4 + 2] Cycloaddition/ Allylboration Reaction for the Preparation of Polysubstituted Imidopiperidines,7 by Hall and Co-Workers

3. SYNTHESIS OF PIPERIDINES BY AZA-[4 + 2] CYCLOADDITION/ALLYLBORATION 3.1. Reaction Development

Several biologically interesting alkaloids and azasugar analogues contain a piperidine ring flanked with a stereodefined hydroxyalkyl group at the α-position.15 Although many approaches were reported to access these β-aminoalcohol units, most require several linear steps to establish the correct stereochemistry prior to, or after ring closure.16 Hall and coworkers envisioned that a hetero[4 + 2] cycloaddition of the unprecedented 1-aza-4-borono-1,3-butadienes (17) with appropriate dienophiles could be followed by reaction of the allylboronate intermediate with added aldehydes, thus providing α-hydroxyalkyl dehydropiperidines in a single operation (Scheme 6).7 The required hydrazonodienes 17 were easily synthesized by acid-catalyzed condensation of 3-boronoacrolein 1617 with the desired hydrazines (Scheme 6). Optimization of this MCR was performed with 4-boropinacolyl-1-dimethylamino-1-azadiene, N-phenylmaleimide, and benzaldehyde to give bicyclic product 21a. Given that both steps were found to occur slowly at ambient temperature, a one-pot procedure was devised in which the three reagents are heated together in toluene at 80 °C. The most economical conditions to achieve full consumption of the heterodiene employed a 1:2:1 diene/ dienophile/aldehyde ratio and a reaction time of 72 h. The bicyclic adducts 21 were obtained in moderate yields following a basic aqueous workup to hydrolyze the resulting pinacol borate 20, and silica chromatography purification. Several combinations of representative substrates were explored to assess the generality of this MCR. Unsurprisingly, as seen with products 21a and 21b, the maleimide substituent (R3) can be varied liberally (Scheme 6). Most importantly, products 21f−h demonstrate that a wide range of aliphatic and aromatic aldehydes can be employed. As shown with products 21c−e, heterodienes made from both mono- and disubstituted phenylhydrazines, and hydrazides, are suitable substrates. In all cases, a single or highly predominant stereoisomer was observed by 1H NMR analysis of crude reaction products. Remarkably, it is even possible to bypass

the hydrazone preformation step (i.e., 16 to 17) and conduct the reaction as a four-component process directly by heating together 16, the hydrazine, maleimide and the allylboration aldehyde.18 This simpler procedure is made possible because of the high electrophilicity of 16, however, yields are inferior to that of the corresponding three-component variant. The imidopiperidine products are appealing toward combinatorial chemistry applications. Taking into account both hydrazone substituents in 17 (R1, R2), the three components of this simple MCR deliver four elements of diversity into the compact bicyclic scaffold of products 21. Moreover, as shown with the formation of 22 from 21b (Scheme 7), the corresponding saturated piperidines can be obtained following Raney nickel catalyzed hydrogenolysis of the hydrazine moiety. In complementary fashion, the double bond in 21b was selectively hydrogenated to provide 23. Xray crystal structure determination7 on the latter confirmed that the relative stereochemistry of α-hydroxyalkyl dehydropiperidine 21 mirrors that of the carbocyclic series.5 2491


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Accounts of Chemical Research

reduction. A total synthesis of methyl palustramate (31) was also reported using the same strategy and a novel hydrazine unit that allowed a chemoselective N−N bond cleavage to leave the alkene intact.22

Scheme 7. Selective Hydrogenation of Imidopiperidine 21b7

3.3. Application to the Preparation and Screening of Libraries of Polysubstituted Piperidines

Multicomponent reactions provide rapid diversification of chemical space in the generation of libraries of small molecules for biological screening. Toward this end, Hall and co-workers exploited the tandem aza[4 + 2]cycloaddition/allylboration to access a wide variety of polysubstituted piperidines 21.18 As described in section 3.1, it was found that heterodienes 17 do not need to be preformed and isolated, making possible a four-component process in a single operation. From a selection of 23 hydrazines, 7 N-substituted maleimides and 75 possible aldehydes providing a large structural and functional diversity of 12 075 possible combinations, a random subset of 944 imidopiperidines 21 were synthesized via both three- and four-component procedures (Scheme 9). Reactions were

Scheme 8. Total Synthesis of Methyl Dihydropalustramate by Touré and Hall19

Scheme 9. Library of Polysubstituted Imidopiperidines by Hall and Co-Workers18

performed at 85 °C for 3 days, at a 0.1 mmol scale, in sets of 48 combinations using a parallel semiautomated synthesizer. After a simple workup, crude products were purified by reverse-phase HPLC using mass-based fraction collection. Due to a rigorous purification focused on product homogeneity, imidopiperidines 21 were isolated within a range of 10 to 30% yields that is lower than the yields obtained from individual procedures. A library subset of 244 compounds was evaluated against a panel of protein phosphatase enzymes and two library members exhibited a moderate inhibitory effect on tyrosine phosphatase MPTPB (32 and 33, Figure 1).18

3.2. Application to the Total Synthesis of Palustrine Alkaloids

The aza[4 + 2] cycloaddition/allylboration MCR was applied to the asymmetric synthesis of methyl (−)-dihydropalustramate (24),19 a degradation product of (−)-palustrine (Scheme 8).20 This synthesis featured the thermal reaction between 1dibenzylamino-1-aza-4-boronodiene (25), Waldner’s chiral dienophile 26,21 and propionaldehyde in toluene for 3 days. The MCR adduct 28 was isolated, through the intermediacy of cycloadduct 27, as a single regio- and diastereomer in good yield. Sulfinimide 28 was then treated with sodium hydroxide followed by acidification to afford the corresponding sulfinic acid intermediate (29), which fragmented in refluxing chloroform to give amide 30 in good yield through a retrosulfinyl-ene rearrangement. Completion of the synthesis of 24 featured a one-carbon homologation and the hydrogenolytic cleavage of the N−N bond with concomitant alkene

Figure 1. Imidopiperidine inhibitors of MPTPB phosphatase.18 2492


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Accounts of Chemical Research 3.4. Discovery of Promising Inhibitors of Human Polynucleotide Kinase/Phosphatase

Human polynucleotide kinase/phosphatase (hPNKP) is an enzyme involved in DNA repair that catalyzes phosphorylation of 5′-hydroxy- and dephosphorylation of 3′phosphateDNA termini.23 It has been shown that cells depleted in PNKP exhibit a lower survival rate than normal cells after exposure to genotoxic agents,24 suggesting that this enzyme is a potential target in cancer therapy. In search of inhibitors of hPNKP, Weinfeld and co-workers screened the imidopiperidine library described in section 3.3. To this end, a fluorescence-based assay monitoring the phosphatase activity of the enzyme was employed to uncover five promising library members.25 After further analyses, A12B4C3 (34, Figure 2) was identified as the best candidate with a low-micromolar IC50. Interestingly, 34 displayed only weak inhibition of the enzyme’s kinase function.

Figure 3. Radiosensitization of wild and PNKP depleted A549 lung carcinoma and MDA-MB-231 breast adenocarcinoma cells by A12B4C3 (34) after exposure to γ-radiation. Adapted from ref 25. Figure 2. Structure of PNKP inhibitor A12B4C3 (34).25,26

The specificity of imido-piperidine 34 for hPNKP was found to be quite remarkable. Its phosphatase inhibitory activity is significantly lower with other protein phosphatases (hAPTX, calcineurin and PP-1γ) and PNKP isolated from different species. Kinetic analysis of the binding behavior of 34 with the enzyme revealed that it does not prevent DNA from binding to hPNKP and thus acts as a noncompetitive inhibitor. Circular dichroism, UV difference spectroscopy and FRET studies imply that a conformational change occurs in the protein in the presence of inhibitor 34.26 Although the precise binding site of 34 has not been identified, studies using hPNKP mutants suggested that it interacts with the enzyme in proximity of Trp 402.26 Weinfeld and co-workers probed the aptitude of 34 to act as both a radio- and chemosensitizer of cancer cells.25,26 In a first assay, wild and PNKP-depleted A549 lung carcinoma and MDA-MB-231 breast adenocarcinoma cells were subjected to γ-radiation in the presence of 34 at non toxic concentration (1 μM). Dose− response curves for cell survival showed that the presence of the inhibitor almost doubled the radiosensitivity of both wild A549 and MDA-MB-231 cells at a level similar to that of PNKP-depleted cells in the drug’s absence (Figure 3). Moreover, 34 failed to sensitize PNKP-depleted cells, which supports the premise that PNKP is the cellular target of this inhibitor. Comparable responses were observed when 34 was tested on wild and PNKP-depleted A549 lung cancer cells subjected to the topoisomerase I inhibitor camphothecin, thus confirming that A12B4C3 can also act as a chemo-sensitizer.

Figure 4. Structure of JAK/STAT signaling inhibitor 3527

may have therapeutic potential for the treatment of human cancers displaying aberrent JAT/STAT signaling. Using a library of over 30,000 random chemotypes that included a few hundreds imidopiperidines 21, Cardona and co-workers identified three imidopiperidines that displayed antibacterial activity against Burkholderia cepacia complex (Bcc), a pathogen known to be difficult to eradicate in cystic fibrosis patients.28

4. SYNTHESIS OF PYRANS BY OXA-[4 + 2] CYCLOADDITION/ALLYLBORATION 4.1. Reaction Development

Myriad natural products contain substituted pyran units, of which, α-hydroxyalkyl pyrans are one of the most common motifs.29 These substances display a broad range of biological properties, including antibiotic and anticancer activity. Notable examples include simple natural products like 2-deoxy-KDO (36) and goniodiol (38), or more complex ones such as thiomarinol (39) and psymberin (40) (Figure 5). Based on the aza[4 + 2] cycloaddition/allylboration MCR described in the previous sections, it was envisioned that αhydroxyalkyl dihydropyrans could arise from the use of 3boronoacrolein esters in inverse electron-demand oxa[4 + 2] cycloaddition with enol ethers (Scheme 10). The racemic variant was demonstrated by the Carboni Group using Yb(fod)3 as catalyst.8 Soon after, the capability to employ

3.5. Other Biological Applications

Upon screening a small library of imidopiperidines 21, Baeg and co-workers found that compound 35 (Figure 4) affects JAK/STAT pathway signaling by inhibiting STAT3 phosphorylation in Hodgkin lymphoma L540 cells.27 Moreover, cells treated with 35 showed a decreased expression of persistently activated JAK3. This study suggested that imidopiperidine 35 2493


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Scheme 11. Scope of Aldehydes in the Oxa[4 + 2] Cycloaddition/Allylboration Reaction with 16,32 by Gao and Hall

Figure 5. Selected natural products containing the α-hydroxyalkyl pyran unit.

Scheme 10. Design of a Three-Component Lewis AcidCatalyzed Inverse Electron-Demand Oxa[4 + 2] Cycloaddition/Allylboration

Moreover, it was found unnecessary to purify intermediate 42 and eliminate residual catalyst 41 when used only in a 1 mol % loading.32,33 Consequently, this oxa[4 + 2] cycloaddition/ allylboration sequence can be executed in a one-pot threecomponent procedure from 16 by simple addition of another aldehyde after completion of the cycloaddition stage. Simple aldehydes react at relatively low temperature (40 °C) in neat vinyl ethyl ether to afford α-hydroxybenzyl dihydropyran 45 as a single diastereomer, a result consistent with the usual cyclic transition structure (43, Scheme 11).32,33 Suitable aldehydes include aromatic ones with different electronic characteristics, and aliphatic (products 45b,c) as well as α,β-unsaturated aldehydes (45d,e) (Scheme 11). The resulting products were obtained in good to excellent yields and >95% ee. The possibility of using chiral α-substituted aldehydes is particularly attractive in the context of natural product synthesis. Using both enantiomers of aldehyde 46 as model substrate, it was found that the additions are subject to a strong reagent-controlling effect from allylboronate 42 (Scheme 12).33 Whereas (R)-configured aldehyde 46 reacts efficiently to give the diastereomerically pure Felkin-Anh adduct 47, the (S) isomer reacts at a slower rate, however giving the same configuration at the newly formed center. The

Jacobsen’s tridentate (Schiff base) chromium complex 41 as a chiral catalyst30 paved the way for a sequential catalytic enantioselective process,31 and a one-pot variant using lower catalyst loadings was realized in our laboratory (Scheme 11).32 The purity of the key substrate 3-boronoacrolein pinacolate (16), made in two steps from commercial 3,3-diethoxypropyne,17 was found to be very important. When freshly distilled 16, 5 mol % catalyst 41, and BaO or molecular sieves as dehydrating agent were stirred for 14 h at room temperature in neat ethyl vinyl ether, dihydropyran 42 was isolated with high enantioselectivity (Scheme 11). The exceptional reactivity of borylated heterodiene 16 made it possible to reduce the catalyst loading; both conversion and ee remained very high with as low as 0.3 mol % of 41.32,33 The surprising reactivity of heterodiene 16 was ascribed to additional stabilization through a 2-electrons-3-atoms center enabled by boron’s vacant orbital in the cycloaddition transition state.33 One initial concern was the distinct possibility that cyclic allylic boronate 42 could undergo an allylboration with aldehyde 16 at a rate faster than that of the heterocycloaddition, thus leading to the undesired “self-allylboration” product 44. In the event, it was found that the cycloadddition occurs smoothly at ambient temperature, whereas the allylboration step is slower and requires higher temperatures.

Scheme 12. Double-Diastereocontrolled Additions of 42 onto Chiral α-Siloxy Aldehydes,33 by Carboni and Hall

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isomers. When a 3:1 Z:E mixture of 1-ethoxypropene (56) was employed in a stoichiometric excess, a kinetic resolution operated where only the all-cis stereoisomer 57 from Z-56 was observed (Scheme 14, eq 2).33 In contrast, with the smaller Lewis acid Yb(fod)3, the corresponding 3:1 mixture of diastereomers 57 and 58 was isolated. This result may be rationalized by the significant size of complex 41, which induces unfavorable steric interactions with the substituent of E enol ethers at the transition state level (Figure 6).

matched process giving 47 was applied in the total synthesis of goniodiol (vide infra).34 A number of acyclic and cyclic enol ether derivatives were tested in the catalytic enantioselective cycloaddition with heterodiene 16 (Scheme 13).33 Vinyl acetate (49) failed to Scheme 13. Evaluation of Other Heterodienes33

react, highlighting the need for an alkoxy substituent. A 1substituted enol ether (50) did not provide the desired cycloadduct, however acyclic and cyclic 2-substituted enol ethers are suitable despite a lower reactivity. Whereas ethyl vinyl ether reacted with 16 in less than 2 h with 1 mol % of catalyst 41,32 enol ether 51 required over 5 h with 3 mol % of 41 (Scheme 14).35 Nonetheless, the all-cis endo adduct 53

Figure 6. Effect of catalyst 41 on the reactivity of isomeric 2substituted enol ethers.

Few heterodienes other than 16 were evaluated in this MCR. In one example, Carreaux and co-workers prepared a boron-substituted heterodendralene, 59, which was reacted with ethyl vinyl ether in the presence of Yb(fod)3 to afford dihydropyran derivative 60 (Scheme 15).36 As expected, 60

Scheme 14. Oxa[4 + 2] Cycloaddition of 16 with 2Substituted Enol Ethers33,35

Scheme 15. Application of Heterodendralene 59 in the Oxa[4 + 2] Cycloaddition/Allylboration,36 by Carreaux and Co-Workers

reacts with aldehydes to afford the secondary homoallylic alcohol product 61 in good yield, transmitting a new 1,3butadienyl unit in the process. The latter can subsequently add to electron-poor dienophiles, exemplified by N-phenylmaleimide, giving the tricylic product 62 of a normal Diels− Alder cycloaddition. 4.2. Application to the Synthesis of (5R,6S)-6-Acetoxy-5-hexadecanolide

The usefulness of the oxa[4 + 2] cycloaddition/allylboration MCR was first demonstrated in a concise total synthesis of (5R,6S)-6-acetoxy-5-hexadecanolide (37, Figure 5).32 This small gamma-lactone is the oviposition attractant pheromone of the female Culex mosquito37 capable of transmitting the West Nile virus. Thus, as described above, reaction between 16 and ethyl vinyl ether, affords cyclic allylboronate 42 in high enantioselectivity (96% ee) (Scheme 16). One-pot addition of undecanal to 42 and gentle heating led to the α-hydroxyalkyl dihydropyran 64 as a single diastereomer

formed cleanly as a single stereoisomer. Surprisingly, the allylboration step proved challenging. Compared to the simple adduct 42, which reacts with various aldehydes at 40−45 °C,33 much higher temperatures were needed for trisubstituted cyclic allylic boronates.33,35 In the putative allylboration transition state (54) leading to 55, the pyran ring adopts an unfavorable chairlike conformation with both pseudoaxial boronate and ethoxy substituents.33,35 Furthermore, the large size of catalyst 41 bears an impact on the reactivity of alkene 2495


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Accounts of Chemical Research Scheme 16. Total Synthesis of (5R,6S)-6-Acetoxy-5hexadecanolide (37) by Gao and Hall32

Scheme 17. Synthesis of (+)-8-Methoxygoniodiol by Carreaux and Carboni38

Scheme 18. Total Synthesis of Thiomarinol 39 by Gao and Hall35

consistent with the expected transition structure (63). To complete the synthesis of pheromone 37, hydrogenation of 64 and acetylation of the secondary alcohol of intermediate 65 by inversion of configuration afforded 66. Oxidation of the acetal led to the desired lactone 37 after only five steps from 16. 4.3. Application to the Synthesis of Goniodiol and 8-Methoxygoniodiol

Carreaux, Carboni and co-workers extended the application of the oxa[4 + 2]cycloaddition/allylboration to the use of chiral α-substituted aldehydes (cf., Scheme 12), with a convincing demonstration of utility featuring the synthesis of the cytotoxic antitumor natural product, goniodiol (38, Figure 5).34 A similar strategy was employed in a synthesis of 8methoxygoniodiol (70), a natural analogue of goniodiol (Scheme 17).38 To this end, use of (2R)-methoxy(phenyl)acetaldehyde (67) in the double-diastereoselective MCR led to product 68 as a single stereoisomer. Four more steps were needed to complete the synthesis of 70; first alcohol protection, followed by oxidation of the acetal to the corresponding lactone 69, then alkene migration and fluorodesilylation. A similar sequence was exploited in the syntheses of (+)-goniotriol, (−)-goniofupyrone, a (+)-altholactone,34 and (+)-iso-exo-brevocomin.39

total synthesis of a member (39, Figure 5)35 of the thiomarinol family of antibiotics related to the commercial topical antibacterial agent, mupirocin. The key MCR step of this synthesis aimed at preparing dihydropyran 76, and called for an isomerically pure Z-configured disubstituted enol ether (Scheme 18). It was not possible, however, to prepare isomerically pure (Z)-71. Instead a 3:1 Z/E mixture of 71 had to be employed in the [4 + 2] cycloaddition. Fortunately, as described in section 4.1, the large catalyst 41 promotes the cycloaddition of the requisite Z enol ether 71 faster than that of the corresponding E isomer, thus affording cyclic allylboronate 73 as the sole stereoisomer. The latter adds stereoselectively to unsaturated aldehyde 74 via transition structure 75 in a “one-pot” sequential process that delivers the

4.4. Application to the Synthesis of Thiomarinol Antibiotics

Hall and co-workers achieved a challenging example of the oxa[4 + 2]cycloaddition/allylboration MCR in their concise 2496


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Accounts of Chemical Research targeted product 76 in good yield. The remarkable selectivity of this MCR enabled an expedient enantiocontrolled synthesis of thiomarinol 39, which was completed in 13 steps and 22% overall yield from 16. Furthermore, rapid access to intermediates of type 76 subsequently allowed the design of a series of thiomarinol analogues that were evaluated for their antibacterial activity.40

Scheme 20. Retrosynthetic Strategy for Palmerolide A

4.5. Application to the Preparation of Libraries of Polyhydroxylated Pyrans

A small library of thiomarinol-inspired, trihydroxylated pyran analogues of type 78 was synthesized by exploiting the catalytic enantioselective MCR (Scheme 19).41 First, highly Scheme 19. Library of Polyhydroxylated Pyrans 78 by AlZoubi and Hall41

Scheme 21. Synthesis of Palmerolide Intermediate 85 Using the Oxa[4 + 2] Cycloaddition/Allylboration DoubleAdduct of Aldehyde 16,42 by Hall and Co-Workers

substituted α-hydroxyalkyl dihydropyrans 55 were assembled utilizing three different enol ethers (51) and a wide variety of aldehydes, such as aromatic, heteroaromatic, unsaturated and aliphatic ones. In the second operation, a mild and direct method for reducing the acetal unit was optimized to provide intermediate 77 without the need for protecting a nearby hydroxyl group. This procedure expedited the sequence, which was completed by a Upjohn dihydroxylation of the residual olefin of 77 to provide the desired library of trihydroxylated pyrans 78. The relative stereochemistry of the library compounds was confirmed by X-ray crystallography on one of the analogues. 4.6. Application to the Synthesis of Palmerolide A

In 2009, Hall and co-workers applied the oxa[4 + 2] cycloaddition/allylboration to a total synthesis of palmerolide A (79),42 a complex macrolide with selective antimelanoma activity.43 Construction of the “east” fragment 80 featured the chiral secondary boronate 81 as a key intermediate (Scheme 20). This synthetic strategy exploited the “self-allylboration” product 44 that was initially feared to form uncontrollably via

42 (cf. Scheme 11). In the event, use of excess aldehyde 16 did lead to the desired product 44 via allylic boronate 42 (Scheme 21). The secondary hydroxyl group of 44 was then acylated with 82 to give ester 83. This set the stage for a 2497


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Accounts of Chemical Research boron-Claisen-Ireland rearrangement of silyl enol ether 84 that produced chiral secondary alkylboronate 81 in high diastereoselectivity. Strategically, boronate 81 served as a masked alcohol, allowing a differentiation of the C10 and C11 hydroxyls of palmerolide for selective introduction of a C11 carbamate unit later in the synthesis. Thus, a stereoretentive oxidation of the B−C bond of 81 followed by methylation of the intermediate carboxylic acid afforded monoprotected diol 85. The East fragment of palmerolide was completed in 8 more steps that included a pyran ring opening and chain extension, with an ultimate coupling with the West hemisphere en route to a successful total synthesis. Of note, this synthesis featured the first borylated variant of a ClaisenIreland rearrangement.

Scheme 22. Stereospecific, Regioselective Suzuki−Miyaura Cross-Coupling of Heterocyclic Allylic Boronates,44 by Hall and Co-Workers

4.7. Oxa-[4 + 2] Cycloaddition/Suzuki-Miyaura Cross-Coupling Sequence

Aside from α-hydroxyalkyl pyrans, other common pyran cores of bioactive molecules are the aryl and alkenyl 2- and 4substituted pyrans exemplified by the diarylheptanoids (−)-centrolobine (86) and diospongin B (87), as well as macrolides like (−)-zampanolide (88) and laulimalide (89) (Figure 7).

Scheme 23. Total Synthesis of Diospongin B by Rybak and Hall45

Figure 7. Selected natural products containing the 2- or 4-substituted aryl- or alkenyl-bound pyran unit.

As part of an effort to provide new methods to access these structures, Hall and co-workers recently achieved a regioselective and stereospecific Suzuki−Miyaura cross-coupling of piperidine- and pyran-derived allylboronates with aryl and alkenyl organobromides (Scheme 22A).44 The main challenges toward cross-coupling of optically enriched allylboronates 90 and 93 consisted not only in maintaining enantiomeric purity, but also in controlling the regioselectivity; two regioisomers may be produced from the C−C coupling at either the α- or γ-site of the allylboron unit. To this end, the authors optimized a catalyst-controlled divergent process leading to both regioisomers independently from a single cyclic allylboronate. Thus, coupling of 90 or 93 with a variety of aryl and alkenyl bromides provides the respective αfunctionalized regiosiomer 91 or 94 in up to 49:1 selectivity using a NHC or a triarylphosphine ligand, whereas the strong σ-donating and sterically hindered ligand XPhos favored the γregioisomers 92 and 95 with high stereochemical retention (Scheme 22A).44

Based on the successful cross-coupling of unsubstituted pyranyl allylic boronate 93, 2-ethoxy dihydropyranyl boronate 42 (the product of oxa[4 + 2]cycloaddition between 16 and ethyl vinyl ether), was investigated as a substrate in these C(sp2)−C(sp3) cross-couplings (Scheme 22B).45 In a similar ligand-dependent manner, the regiodivergent synthesis of αand γ-regioisomers 96 and 97 was successfully accomplished. This method was subsequently exploited in a synthesis of the 2498


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Accounts of Chemical Research natural product, diospongin B (87) (Scheme 23).45 Using the phenyl-coupled γ-regioisomer 98, diospongin B was completed in only five additional steps, allowing the authors to confirm a controversial reassessment of the absolute configuration of this natural product.

stages of this program, we thank the Natural Sciences and Engineering Research Council of Canada, the Alberta Cancer Board, and the Canadian Institutes for Health Research.

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(1) (a) Zhu, J., Wang, Q., Wang, M., Eds. Multicomponent Reactions in Organic Synthesis; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2015. (b) Cioc, R. C.; Ruijter, E.; Orru, R. V. A. Multicomponent Reactions: Advanced Tools for Sustainable Organic Synthesis. Green Chem. 2014, 16, 2958−2975. (2) Touré, B.; Hall, D. G. Natural Product Synthesis Using Multicomponent Reaction Strategies. Chem. Rev. 2009, 109, 4439− 4486. (3) Hulme, C.; Gore, V. Multi-component Reactions: Emerging Chemistry in Drug Discovery, from Xylocain to Crixivan. Curr. Med. Chem. 2003, 10, 51−80. (4) Lachance, H.; Hall, D. G. Allylboration of Carbonyl Compounds. Org. React. 2009, 73, 1−574. (5) Vaultier, M.; Truchet, F.; Carboni, B.; Hoffmann, R. W.; Denne, I. Diels-Alder Reactions of 1,3-Dienylboronates as a New Route to Functionalized Carbocycles. Tetrahedron Lett. 1987, 28, 4169−4172. (6) Six, Y.; Lallemand, J. Y. An Improvement to the Vaultier Tandem Sequence: a Practical Highly Stereoselective Threecomponent Reaction. Tetrahedron Lett. 1999, 40, 1295−1296. (7) (a) Tailor, J.; Hall, D. G. Tandem Aza[4 + 2]/Allylboration: a Novel Multicomponent Reaction for the Stereocontrolled Synthesis of α-Hydroxyalkyl Piperidine Derivatives. Org. Lett. 2000, 2, 3715− 3718. (b) Touré, B. B.; Hoveyda, H. R.; Tailor, J.; Ulaczyk-Lesanko, A.; Hall, D. G. A Three-Component Reaction for Diversity-Oriented Synthesis of Polysubstituted Piperidines: Solution and Solid-Phase Optimization of the First Tandem Aza[4 + 2]/Allylboration. Chem. Eur. J. 2003, 9, 466−474. (8) Deligny, M.; Carreaux, F.; Toupet, L.; Carboni, B. Efficient Asymmetric Synthesis of 2,6-Disubstituted 2H-Dihydropyrans via a Catalytic Hetero-Diels−Alder/Allylboration Sequence. Adv. Synth. Catal. 2003, 345, 1215−1219. (9) Renard, P.-Y.; Six, Y.; Lallemand, J.-Y. 1,3-Dienylboronates in Diels-Alder Reaction: Part III. Tetrahedron Lett. 1997, 38, 6589− 6590. (10) Gao, X.; Hall, D. G. New Electronically Enriched Boronobutadienes for the Synthesis of Hydroxylated Cyclohexenes via Tandem [4 + 2]/Allylboration. Tetrahedron Lett. 2003, 44, 2231− 2235. (11) Renard, P.-Y.; Lallemand, J.-Y. 1,3-Dienylboronates in DielsAlder Reactions: Part II. Tetrahedron: Asymmetry 1996, 7, 2523− 2524. (12) Hilt, G.; Hess, W.; Harms, K. Asymmetric Cobalt-Catalyzed Diels−Alder Reactions of a Boron-Functionalized 1,3-Diene with Alkynes and Allylboration with Aldehydes. Org. Lett. 2006, 8, 3287− 3290. (13) Eberlin, L.; Tripoteau, F.; Carreaux, F.; Whiting, A.; Carboni, B. Boron-Substituted 1,3-Dienes and Heterodienes as Key Elements in Multicomponent Processes. Beilstein J. Org. Chem. 2014, 10, 237− 250. (14) Lallemand, J.-Y.; Six, Y.; Ricard, L. A Concise Synthesis of an Advanced Clerodin Intermediate through a Vaultier Tandem Reaction. Eur. J. Org. Chem. 2002, 2002, 503−513. (15) Buckingham, J., Baggaley, K. H., Roberts, A. D., Szabo, L. F., Eds. Dictionary of Alkaloids, 2nd ed.; CRC Press Taylor & Francis Group: Boca Raton, London, and New York, 2010. (16) Reviews on the synthesis of piperidines: (a) Mateeva, N. N.; Winfield, L. L.; Redda, K. K. The Chemistry and Pharmacology of Tetrahydropyridines. Curr. Med. Chem. 2005, 12, 551−571. (b) Silva, E. M. P.; Varandas, P. A. M. M.; Silva, A. M. S. Developments in the Synthesis of 1,2-Dihydropyridines. Synthesis 2013, 45, 3053−3090. (17) Gravel, M.; Toure, B. B.; Hall, D. G. Practical Procedure for the Preparation of Functionalized (E)-Alkenylboronic Acids Includ-

5. CONCLUSION AND OUTLOOK Although the carbocyclic variant was initially reported in 1987, it is only in the past 15 years that heterocyclic aza- and oxa[4 + 2]cycloaddition/allylboration variants were developed and exploited in a wide variety of endeavors in target-oriented and diversity-oriented synthesis of piperidine and pyran derivatives. Few multicomponent reactions demonstrate this level of versatility. Indeed, the discovery of A12B4C3, the first reported inhibitor of the human DNA repair enzyme hPNKP, clearly highlights the value and importance of designing new multicomponent reactions to access new chemotypes for drug discovery applications. As recently demonstrated with a short enantioselective synthesis of diospongin B,45 merging hetero[4 + 2] cycloadditions with transition metal-catalyzed cross-coupling reactions may open further opportunities for designing new MCRs.

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REFERENCES

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest. Biographies Dennis G. Hall received his Ph.D. from Université de Sherbrooke in 1995, working under the supervision of Prof. Pierre Deslongchamps. After graduation, he spent two years as an NSERC Postdoctoral Fellow in the laboratory of Prof. Peter G. Schultz at U. C. Berkeley. In 1997, he initiated his independent academic career at the University of Alberta where he currently holds the Canada Research Chair in Organoboron Chemistry for Catalysis and Drug Discovery. Taras Rybak received his B.Sc. degree in chemistry in 2010, where he performed undergraduate research with Prof. Gary Dmitrienko. Afterwards, he earned his Ph.D. degree in chemistry in 2016 under the supervision of Prof. Dennis G. Hall at the University of Alberta. His Ph.D. research focused on the asymmetric preparation of polysubstituted pyrans towards the synthesis of biologically active compounds. Currently, he is a Research Scientist at Paraza Pharma Inc. in Montreal, Canada. Tristan Verdelet obtained his M.Sc. degree in chemistry in 2008 at the Université de Rennes (France) in the team of Prof. Bertrand Carboni. He then moved to the Université de Rouen where he received his Ph.D degree in 2012 under the supervision of Prof. Pierre-Yves Renard and Dr. Ludovic Jean. His work was focused on the synthesis of antidotes for treating people poisoned with organophosphorus warfare agents. He is currently working as a postdoctoral fellow in the team of Prof. Dennis G. Hall.

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ACKNOWLEDGMENTS D.G.H. is deeply indebted to all of his past co-workers, whose names can be found in the references, for their significant contributions to the projects described herein. Professor Michael Weinfeld (U. of Alberta Department of Oncology) is gratefully acknowledged for a longstanding collaboration on the hPKNP target. For generous financial support at various 2499


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Accounts of Chemical Research ing the Unprecedented 1-Alkoxycarbonyl Derivatives. Org. Prep. Proced. Int. 2004, 36, 573−579. (18) Ulaczyk-Lesanko, A.; Pelletier, E.; Lee, M.; Prinz, H.; Waldmann, H.; Hall, D. G. Optimization of Three- and FourComponent Reactions for Polysubstituted Piperidines: Application to the Synthesis and Preliminary Biological Screening of a Prototype Library. J. Comb. Chem. 2007, 9, 695−703. (19) Touré, B. B.; Hall, D. G. Three-Component Sequential Aza[4 + 2] Cycloaddition/Allylboration/Retro-Sulfinyl-Ene Reaction: a New Stereocontrolled Entry to Palustrine Alkaloids and Other 2,6Disubstituted Piperidines. Angew. Chem., Int. Ed. 2004, 43, 2001− 2004. (20) Karrer, P.; Eugster, C. H. Ü ber ein Alkaloid aus Equisetum palustre. Helv. Chim. Acta 1948, 31, 1062−1066. (21) Waldner, A. Synthesis and Application of a Highly Efficient, Homochiral Dienophile. Tetrahedron Lett. 1989, 30, 3061−3064. (22) Touré, B. B.; Hall, D. G. Design of a Nonreductive Method for Chemoselective Cleavage of Hydrazines in the Presence of Unsaturations: Application to a Stereoconvergent Three-Component Synthesis of (−)-Methyl Palustramate. J. Org. Chem. 2004, 69, 8429−8436. (23) Weinfeld, M.; Mani, S. M.; Abdou, I.; Aceytuno, R. D.; Glover, J. N. M. Tidying Up Loose Ends: The Role of Polynucleotide Kinase/Phosphatase in DNA Strand Break Repair. Trends Biochem. Sci. 2011, 36, 262−271. (24) Rasouli-Nia, A.; Karimi-Busheri, F.; Weinfeld, M. Stable Down-Regulation of Human Polynucleotide Kinase Enhances Spontaneous Mutation Frequency and Sensitizes Cells to Genotoxic Agents. Proc. Natl. Acad. Sci. U. S. A. 2004, 101, 6905−6910. (25) Freschauf, G. K.; Karimi-Busheri, F.; Ulaczyk-Lesanko, A.; Mereniuk, T. R.; Ahrens, A.; Koshy, J. M.; Rasouli-Nia, A.; Pasarj, P.; Holmes, C. F. B.; Rininsland, F.; Hall, D. G.; Weinfeld, M. Identification of a Small Molecule Inhibitor of the Human DNA Repair Enzyme Polynucleotide Kinase/Phosphatase. Cancer Res. 2009, 69, 7739−7746. (26) Freschauf, G. K.; Mani, R. S.; Mereniuk, T. R.; Fanta, M.; Virgen, C. A.; Dianov, G. L.; Grassot, J.-M.; Hall, D. G.; Weinfeld, M. Mechanism of Action of an Imidopiperidine Inhibitor of Human Polynucleotide Kinase/Phosphatase. J. Biol. Chem. 2010, 285, 2351− 2360. (27) Kim, B. H.; Yin, C.-H.; Guo, Q.; Bach, E. A.; Lee, H.; Sandoval, C.; Jayabose, S.; Ulaczyk-Lesanko, A.; Hall, D. G.; Baeg, G.-H. A Small-Molecule Compound Identified Through a Cell-Based Screening Inhibits JAK/STAT Pathway Signaling in Human Cancer Cells. Mol. Cancer Ther. 2008, 7, 2672−2680. (28) Selin, C.; Stietz, M. S.; Blanchard, J. E.; Gehrke, S. S.; Bernard, S.; Hall, D. G.; Brown, E. M.; Cardona, S. T. A Pipeline for Screening Small Molecules with Growth Inhibitory Activity against Burkholderia cenocepacia. PLoS One 2015, 10, e0128587. (29) Perry, M. A.; Rychnovsky, S. D.; Sizemore, N. Synthesis of Saturated Tetrahydropyrans; Springer-Verlag: Berlin, 2014; Vol. 35. (30) Gademann, K.; Chavez, D. E.; Jacobsen, E. N. Highly Enantioselective Inverse-Electron-Demand Hetero-Diels−Alder Reactions of α,β-Unsaturated Aldehydes. Angew. Chem., Int. Ed. 2002, 41, 3059−3061. (31) Deligny, M.; Carreaux, F.; Carboni, B.; Toupet, L.; Dujardin, G. A Novel Diastereoselective Route to alpha-Hydroxyalkyl Dihydropyrans Using a Hetero Diels-Alder/Allylboration Sequence. Chem. Commun. 2003, 276−277. (32) Gao, X.; Hall, D. G. 3-Boronoacrolein as an Exceptional Heterodiene in the Highly Enantio- and Diastereoselective Cr(III)Catalyzed Three-Component [4 + 2]/Allylboration. J. Am. Chem. Soc. 2003, 125, 9308−9309. (33) Gao, X.; Hall, D. G.; Deligny, M.; Favre, A.; Carreaux, F.; Carboni, B. Catalytic Enantioselective Three-Component Hetero-[4 + 2] Cycloaddition/Allylboration Approach to α-Hydroxyalkyl Pyrans: Scope, Limitations, and Mechanistic Proposal. Chem. - Eur. J. 2006, 12, 3132−3142.

(34) Favre, A.; Carreaux, F.; Deligny, M.; Carboni, B. Stereoselective Synthesis of (+)-Goniodiol, (+)-Goniotriol, (−)-Goniofupyrone, and (+)-Altholactone Using a Catalytic Asymmetric HeteroDiels−Alder/Allylboration Approach. Eur. J. Org. Chem. 2008, 2008, 4900−4907. (35) Gao, X.; Hall, D. G. Catalytic Asymmetric Synthesis of a Potent Thiomarinol Antibiotic. J. Am. Chem. Soc. 2005, 127, 1628− 1629. (36) Tripoteau, F.; Verdelet, T.; Hercouet, A.; Carreaux, F.; Carboni, B. Boron- and Silicon-Substituted [3]-1-Heterodendralenes as Versatile Building Blocks for the Rapid Construction of Polycyclic Architectures. Chem. - Eur. J. 2011, 17, 13670−13675. (37) Laurence, B. R.; Pickett, J. A. J. Erythro-6-acetoxy-5hexadecanolide, the Major Component of a Mosquito Oviposition Attractant Pheromone. J. Chem. Soc., Chem. Commun. 1982, 59−60. (38) Carreaux, F.; Favre, A.; Carboni, B.; Rouaud, I.; Boustie, J. First Synthesis of (+)-8-Methoxygoniodiol and its Analogue, 8Deoxygoniodiol, Using a Three Component Strategy. Tetrahedron Lett. 2006, 47, 4545−4548. (39) Bouziane, A.; Régnier, T.; Carreaux, F.; Carboni, B.; Bruneau, C.; Renaud, J.-L. A New Access to the 6,8-Dioxabicyclo[3.2.1]octane Ring System Using a Three-Component Reaction: Enantioselective Synthesis of (+)-iso-exo-Brevicomin. Synlett 2010, 2010, 207−210. (40) Marion, O.; Gao, X.; Marcus, S.; Hall, D. G. Synthesis and Preliminary Antibacterial Evaluation of Simplified Thiomarinol Analogs. Bioorg. Med. Chem. 2009, 17, 1006−1017. (41) Al-Zoubi, R. M.; Hall, D. G. Catalytic Enantioselective Diversity-Oriented Synthesis of a Small Library of Polyhydroxylated Pyrans Inspired from Thiomarinol Antibiotics. Mol. Diversity 2014, 18, 701−719. (42) Penner, M. N.; Rauniyar, V.; Kaspar, L.; Hall, D. G. Catalytic Asymmetric Synthesis of Palmerolide A via Organoboron Methodology. J. Am. Chem. Soc. 2009, 131, 14216−14217. (43) Diyabalanage, T.; Amsler, C. D.; McClintock, J. B.; Baker, B. J. Palmerolide A, a Cytotoxic Macrolide from the Antarctic Tunicate Synoicum adareanum. J. Am. Chem. Soc. 2006, 128, 5630−5631. (44) Ding, J.; Rybak, T.; Hall, D. G. Synthesis of Chiral Heterocycles by Ligand-Controlled Regiodivergent and Enantiospecific Suzuki-Miyaura Cross-Coupling. Nat. Commun. 2014, 5, 5474. (45) Rybak, T.; Hall, D. G. Stereoselective and Regiodivergent Allylic Suzuki-Miyaura Cross-Coupling of 2-Ethoxydihydropyranyl Boronates: Synthesis and Confirmation of Absolute Stereochemistry of Diospongin B. Org. Lett. 2015, 17, 4156−4159.

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