Junichiro Yamaguchi

CH Bond Functionalization: Emerging Synthetic Tools for Natural Products and Pharmaceuticals

The direct functionalization of C-H bonds in organic compounds has recently emerged as a powerful and ideal method for the formation of carbon-carbon and carbon-heteroatom bonds. This Review provides an overview of C-H bond functionalization strategies for the rapid synthesis of biologically active compounds such as natural products and pharmaceutical targets.

Nickel-Catalyzed C–H/C–O Coupling of Azoles with Phenol Derivatives

The first nickel-catalyzed C-H bond arylation of azoles with phenol derivatives is described. The new Ni(cod)(2)/dcype catalytic system is active for the coupling of various phenol derivatives such as esters, carbamates, carbonates, sulfamates, triflates, tosylates, and mesylates. With this C-H/C-O biaryl coupling, we synthesized a series of privileged 2-arylazoles, including biologically active alkaloids. Moreover, we demonstrated the utility of the present reaction for functionalizing estrone and quinine.

Nickel-Catalyzed Biaryl Coupling of Heteroarenes and Aryl Halides/Triflates

Ni-based catalytic systems for the arylation of heteroarenes with aryl halides and triflates have been established. Ni(OAc)(2)/bipy is a general catalyst for aryl bromides/iodides, and Ni(OAc)(2)/dppf is effective for aryl chlorides/triflates. Thiazole, benzothiazole, oxazole, benzoxazole, and benzimidazole are applicable as heteroarene coupling partners. A rapid synthesis of febuxostat, a drug for gout and hyperuricemia, is also demonstrated.

Decarbonylative C–H Coupling of Azoles and Aryl Esters: Unprecedented Nickel Catalysis and Application to the Synthesis of Muscoride A

A nickel-catalyzed decarbonylative C-H biaryl coupling of azoles and aryl esters is described. The newly developed catalytic system does not require the use of expensive metal catalysts or silver- or copper-based stoichiometric oxidants. We have successfully applied this new C-H arylation reaction to a convergent formal synthesis of muscoride A.

Oxidative Biaryl Coupling of Thiophenes and Thiazoles with Arylboronic Acids through Palladium Catalysis: Otherwise Difficult C4‐Selective CH Arylation Enabled by Boronic Acids

Heteroarenes equipped with aryl groups (heterobiaryls) are often found in biologically active compounds, organic materials, and pharmaceuticals. In recent years, the direct C H arylation of heteroarenes catalyzed by a transition-metal complex 2] has emerged as a practical alternative to the wellestablished Pd-catalyzed cross-coupling reactions. Although tremendous efforts in the synthetic community including our groups have culminated in a wealth of useful and highly active catalysts, considerable room remains for further investigations. In particular, the development of a unique catalytic system that can preferentially activate and arylate an otherwise less reactive C H bond on heteroarenes is critically important from both scientific and practical points of view. For example, the Pd-catalyzed arylation of C H bonds of thiophenes with haloarenes is known to occur preferentially at the positions a to the sulfur atom (C2 and/or C5) following the typical reactivity profile of the thiophene ring (Scheme 1, top reaction). 7] Except for very rare cases, 8] selective and preferential arylation at the positions b to the sulfur atom (C3 and/or C4) does not take place. This is also true for the arylation of thiazoles, and a catalytic system that can preferentially arylate the least reactive C4 positions has not been forthcoming. We herein report that the Pd-catalyzed oxidative C H arylation of thiophenes and thiazoles with arylboronic acids manifests the otherwise difficult C4 regioselectivity (Scheme 1, bottom reaction). The present finding is significant not only because the regioselective outcome is complementary to that of the arylation using haloarenes, but also because it demonstrates the remarkable mechanistic difference between these two seemingly related Pd-catalyzed direct arylation processes. In early experiments, we found that the C H arylation of 2-ethylthiophene (1a) with phenylboronic acid (2a) took place in the presence of 2,2,6,6-tetramethylpiperidine-N-oxyl radical (TEMPO), Pd(OAc)2, and 2,2’-bipyridyl (bipy) in 1,2-dichloroethane (DCE) at 80 8C (Table 1, entry 1). Very surprisingly, we identified 2-ethyl-4-phenylthiophene (3aa) to be the sole coupling product under these conditions (69% yield). The corresponding C5-phenylation product (4aa) was not identified. Based on these promising initial results we decided to further optimize the reaction conditions (Table 1). After we had found that the bipy is necessary for the reaction to occur (entry 2), we screened various nitrogen-based bidentate ligands such as bipy derivatives (L1–L3), phenanthrolines (L4–L6), and TMEDA (L7) in the reaction of 1a with 2a (entries 3–9). Although L4 and L6 were found to be equally effective ligands in terms of yield and regioselectivity, we selected bipy as the standard ligand for subsequent experiments in view of its efficiency, cost, and simplicity. With a,a,atrifluorotoluene as a solvent, a slightly higher yield (76 %) was obtained (entry 10) and the reaction also proceeded at lower temperatures, remarkably even at room temperature (entry 11). Replacing TEMPO with other oxidants such as p-benzoquinone, (diacetoxyiodo)benzene, and copper(II) chloride resulted in a much lower reaction efficiency (entries 12–14). Higher concentrations of 1a in a,a,atrifluorotoluene resulted in higher yields while the high regioselectivity was maintained (entries 15 and 16). Reducing the catalyst loading to 5 or 2 mol% Pd(OAc)2 led to a slight Scheme 1. Reagent-controlled regiodivergency in the Pd-catalyzed C H arylation of thiophenes and thiazoles.

Programmed synthesis of arylthiazoles through sequential C–H couplings

A programmed synthesis of privileged arylthiazoles via sequential C–H couplings catalyzed by palladium or nickel catalysts has been accomplished. This versatile protocol can supply all possible arylthiazole substitution patterns (2-aryl, 4-aryl, 5-aryl, 2,4-diaryl, 2,5-diaryl, 4,5-diaryl, and 2,4,5-triaryl) from an unfunctionalized thiazole platform by 11 distinct synthetic routes. We have generated over 150 arylthiazoles by using this methodology. We have applied this method to the rapid synthesis of fatostatin (SREBP inhibitor), and the gram-scale synthesis of triarylthiazoles has been demonstrated.

Synthesis of Dragmacidin D via Direct C–H Couplings

Dragmacidin D, an emerging biologically active marine natural product, has attracted attention as a lead compound for treating Parkinsons and Alzheimers diseases. Prominent structural features of this compound are the two indole-pyrazinone bonds and the presence of a polar aminoimidazole unit. We have established a concise total synthesis of dragmacidin D using direct C-H coupling reactions. Methodological developments include (i) Pd-catalyzed thiophene-indole C-H/C-I coupling, (ii) Pd-catalyzed indole-pyrazine N-oxide C-H/C-H coupling, and (iii) acid-catalyzed indole-pyrazinone C-H/C-H coupling. These regioselective catalytic C-H couplings enabled us to rapidly assemble simple building blocks to construct the core structure of dragmacidin D in a step-economical fashion.

Total Synthesis of Palau’amine

Polycyclic dimeric pyrrole-imidazole alkaloids such as palau’amine (1, Figure 1),1 axinellamine A (2),2 and massadine chloride (3)3 possess daunting structural and physical attributes, including nine or more nitrogen atoms, eight contiguous stereogenic centers, reactive (hemi)aminal moieties, oxidation-prone pyrroles, and highly polar, non-crystalline morphologies. Their unique structures have been the focus of numerous publications from many groups worldwide, and have led to notable advances in synthetic methodology.4 Among the more complex members of this class, only the axinellamines (e.g. 2)5 and the massadines (e.g. 3)6 have succumbed to total synthesis, aided by the invention of a highly chemoselective and controllable late-stage oxidation reaction. Figure 1 Selected pyrrole-imidazole alkaloids, and retrosynthetic analysis of palau’amine (1). Ar = 2-(4,5-dibromopyrrole). In contrast to its siblings (2 and 3), palau’amine (1) possesses a unique chemical challenge: one of the pyrrole-amide sidechains is embedded in an exquisite, hexacyclic core architecture which contains a highly strained trans-azabicyclo[3.3.0]octane substructure (unprecedented among natural products). This is undoubtedly a central reason why the synthesis of palau’amine (1) has thus far eluded organic chemists despite the dozens of Ph.D. theses7 and studies towards publications8 that have appeared since its isolation in 1993 and structural reassignment in 2007.1 Many well-founded and logical plans to secure the idiosyncratic trans-5,5 core of 1 in our laboratory resulted in unfortunate empirical realities. Presumably, the high degree of strain implicit in the hexacyclic architecture thwarted all attempts at a biomimetic closure (N14-C10 and N1-C6 simultaneously)4 or a stepwise closure (N14-C10 followed by N1-C6).9 The lessons learned during those initial attempts inspired an alternative strategy that ultimately led to the total synthesis of 1 presented herein. As depicted in Figure 1, our retrosynthetic analysis relied upon a speculation that hypothetical macrocycle 4, dubbed “macro-palau’amine”, would be a kinetically stable isomer of the natural product core found in 1. It was predicted that an irreversible transannular ring-chain tautomerization would convert 4 into its consitutional isomer 1 via a dynamic equilibrium involving amidine tautomer 4′. Handheld molecular models suggested that 4 might adopt a folded conformation wherein N14 and C10 would be in close proximity to facilitate such a ring closure. A conceptually related late-stage shift of topology between constitutional isomers through dynamic equilibration was a key design element of our recent synthesis of the kapakahines.10 As with 1, “macro palau’amine” (4) exhibits a high level of strain and was believed to be accessible via macrolactamization of the diamine derived from diazide 5. This intermediate was envisioned to arise from the SNAr of a pyrrole (or surrogate thereof) to the bromo-aminoimidazole 6. The total synthesis of 1, outlined in Scheme 1, commences with the readily-available cyclopentane core 7, an intermediate enlisted in the synthesis of the massadines and available in 19 steps from commercially available materials in 1% overall yield.6 Treatment of 7 with aqueous TFA unveiled aminoguanidine 8, which was directly converted in unprotected form to the hemiaminal 10 in 64% isolated yield (along with 17% recovered 8, 130 mg scale)11 using silver(II)-picolinate (9). It is notable that this oxidation reaction takes place with precise regioselectivity – no oxidation of the primary amine is observed under these acidic reaction conditions. Construction of the remaining 2-aminoimidazole took place in 65% yield (251 mg scale)11 to afford 11 using cyanamide in brine (sat. aq. NaCl), a solvent that minimizes displacement of the highly labile chlorine atom.3,6 Subsequent bromination using Br2 in a 1:1 mixture of TFA:TFAA delivered the desired 2-amino-4-bromoimidazole 6 in 54% yield (150 mg scale).11 The introduction of the pyrrole moiety proved challenging, as standard conditions to couple amines to aryl halides using transition metal catalysis failed to produce any detectible amounts of product (even on the Boc-shielded 2-amino-4-bromoimidazole derivatives). In principle, the inherent ambiphilicity of the 2-aminoimidazole could lend itself to a unique reactivity pattern, one that would allow for uncatalyzed nucleophilic attack on the 2-amino-4-bromoimidazole as a possible direct route to the pyrrole-acid intermediate 5. Scheme 1 Total synthesis of palau’amine (1). Counterions are CF3CO2− and are omitted for clarity. Reagents and conditions: a) TFA/H2O (1/1), 50 °C, 12 h, then silver(II)picolinate (2.4 equiv), TFA/H2O (1/9), 23 °C, 5 min, 64% + ... In the event, the nucleophilic pyrrole surrogate 1212 was reacted with 2-amino-4-bromoimidazole 6 buffered with AcOH, followed by treatment with TFA, to deliver the desired N-coupled pyrrole-2-carboxylic acid 5 in a one-pot operation in 44% yield (91 mg scale).11 Presumably, facile N–C bond formation is observed due to the high reactivity of its tautomeric amidine form (6′). This reaction appears to be general and its scope will be reported in the full account of this work. The pyrrole-forming step, mediated by TFA and traversing through oxonium 14, involves no less than five chemical transformations occurring in tandem to deliver 5. In preparation for the key macrolactamization step, the azide groups of 5 were reduced to afford highly polar diamine 15 (4.0 mg scale). The synthesis of “macro-palau’amine” 4 was effected using EDC and HOBt. Heating of the crude reaction mixture in TFA (70 °C) elicited the crucial transannular cyclization (presumably proceeding via amidine tautomer 4′) that fastened the remaining two stereocenters and cemented the hallmark trans-5,5 ring system to deliver palau’amine (1) in 17% overall yield from 5 (one-pot, average of 55% per operation) after repeated purification with reverse phase HPLC (spectroscopically identical to that reported for 1 with the exception of optical rotation).13 Optimization and mechanistic investigation of this final sequence (5 Π 1) is currently underway.9 The journey to 1 (25 steps from commercial material, 0.015% overall yield with current procedures)9 has led not only to useful strategies and methods, but also to an empirical demonstration of numerous guiding principles for synthesis design at the frontiers of chemical complexity.14 Over six years ago our lab embarked on the synthesis of dimeric pyrrole-imidazole alkaloids by methodically applying the logic of biosynthesis where appropriate during the syntheses of sceptrin, oxysceptrin, nakamuric acid, ageliferin, nagelamide, the axinellamines (e.g. 2), and the massadines (e.g. 3).5,6,15 The synthesis of 1 benefited from a tremendous amount of chemical reactivity learned during those endeavours. Our 2004 biosynthetic hypothesis15b led us to pursue the true structure of 1 prior to the realization of its revised structure.1 In an effort to apply redox economic principles16 to this chemical synthesis program, a late-stage, chemoselective, silver-mediated oxidation was invented to circumvent laborious routes to the key hemiaminal unit expressed in 1–3 (C–20, Figure 1). Cascade reactions were incorporated to rapidly assemble complexity (e.g. 6 Π 5 Π 1). Finally, innate reactivity was embraced so as to minimize the use of redundant and orthogonal protecting group operations,17 and instead maximize the discovery of interesting chemical reactivity such as the direct coupling of nucleophiles to unprotected 2-amino-4-bromoimidazoles. An enantioselective, scalable variant of the current synthesis, as well as a full account of this work will be forthcoming.

Isolation, structure, and reactivity of an arylnickel(II) pivalate complex in catalytic C-H/C-O biaryl coupling

We describe mechanistic studies of a C-H/C-O biaryl coupling of 1,3-azoles and aryl pivalates catalyzed by Ni(cod)2/dcype. This study not only supports a catalytic cycle consisting of C-O oxidative addition, C-H nickelation, and reductive elimination but also provides insight into the dramatic ligand effect in C-H/C-O coupling. We have achieved the first synthesis, isolation and structure elucidation of an arylnickel(II) pivalate, which is an intermediate in the catalytic cycle after oxidative addition of a C-O bond. Furthermore, kinetic studies and kinetic isotope effect investigations reveal that the C-H nickelation is the turnover-limiting step in the catalytic cycle.

Nickel‐Catalyzed α‐Arylation of Ketones with Phenol Derivatives

The nickel-catalyzed α-arylation of ketones with readily available phenol derivatives (esters and carbamates) provides access to useful α-arylketones. For this transformation, 3,4-bis(dicyclohexylphosphino)thiophene (dcypt) was identified as a new, enabling, air-stable ligand for this transformation. The intermediate of an assumed C-O oxidative addition was isolated and characterized by X-ray crystal-structure analysis.