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.

C-H bond functionalization: emerging synthetic tools for natural products and pharmaceuticals

C-H bonds are ubiquitous in organic compounds. It would, therefore, appear that direct functionalization of substrates by activation of C-H bonds would eliminate the multiple steps and limitations associated with the preparation of functionalized starting materials. Regioselectivity is an important issue because organic molecules can contain a wide variety of C-H bonds. The use of a directing group can largely overcome the issue of regiocontrol by allowing the catalyst to come into proximity with the targeted C-H bonds. A wide variety of functional groups have been evaluated for use as directing groups in the transformation of C-H bonds. In 2005, Daugulis reported the arylation of unactivated C(sp(3))-H bonds by using 8-aminoquinoline and picolinamide as bidentate directing groups, with Pd(OAc)2 as the catalyst. Encouraged by these promising results, a number of transformations of C-H bonds have since been developed by using systems based on bidentate directing groups. In this Review, recent advances in this area are discussed.

Catalytic Functionalization of C(sp2) ? H and C(sp3) ? H Bonds by Using Bidentate Directing Groups

This Review summarizes the advancements in Pd-catalyzed C(sp3)–H activation via various redox manifolds, including Pd(0)/Pd(II), Pd(II)/Pd(IV), and Pd(II)/Pd(0). While few examples have been reported in the activation of alkane C–H bonds, many C(sp3)–H activation/C–C and C–heteroatom bond forming reactions have been developed by the use of directing group strategies to control regioselectivity and build structural patterns for synthetic chemistry. A number of mono- and bidentate ligands have also proven to be effective for accelerating C(sp3)–H activation directed by weakly coordinating auxiliaries, which provides great opportunities to control reactivity and selectivity (including enantioselectivity) in Pd-catalyzed C–H functionalization reactions.

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Palladium-Catalyzed Transformations of Alkyl C-H Bonds.

A mean-field phase diagram for conformationally symmetric diblock melts using the standard Gaussian polymer model is presented. Our calculation, which traverses the weak- to strong-segregation regimes, is free of traditional approximations. Regions of stability are determined for disordered (DIS) melts and for ordered structures including lamellae (L), hexagonally packed cylinders (H), body-centered cubic spheres (QIm3m), close-packed spheres (CPS), and the bicontinuous cubic network with Ia3d symmetry (QIa3d). The CPS phase exists in narrow regions along the order−disorder transition for χN ≥ 17.67. Results suggest that the QIa3d phase is not stable above χN ∼ 60. Along the L/QIa3d phase boundaries, a hexagonally perforated lamellar (HPL) phase is found to be nearly stable. Our results for the bicontinuous Pn3m cubic (QPn3m) phase, known as the OBDD, indicate that it is an unstable structure in diblock melts. Earlier approximation schemes used to examine mean-field behavior are reviewed, and compa...

Unifying Weak- and Strong-Segregation Block Copolymer Theories

Transition metal-catalyzed direct functionalization of C–H bonds is one of the key emerging strategies that is currently attracting tremendous attention with the aim to provide alternative environmentally friendly and efficient ways for the construction of C–C and C–hetero bonds. In particular, the strategy involving regioselective C–H activation assisted by various functional groups shows high potential, and significant achievements have been made in both the development of novel reactions and the mechanistic study. In this review, we attempt to give an overview of the development of utilizing the functionalities as directing groups. The discussion is directed towards the use of different functional groups as directing groups for the construction of C–C and C–hetero bonds via C–H activation using various transition metal catalysts. The synthetic applications and mechanistic features of these transformations will be discussed, and the review is organized on the basis of the type of directing groups and the type of bond being formed or the catalyst.

Transition metal-catalyzed C–H bond functionalizations by the use of diverse directing groups

In this critical review, the strategic and economic benefits of C–H functionalization logic will be analyzed through the critical lens of total synthesis. In order to illustrate the dramatically simplifying effects this type of logic can potentially have on synthetic planning, we take the reader through a series of case studies in which it has already been successfully applied. In the first section, a chronological look at key historical syntheses will be examined, leading into modern day examples. In the second section, our own experience with applying and executing synthesis with a C–H functionalization “mindset” will be discussed (114 references).

C–H functionalization logic in total synthesis

A strategy for the construction of unsymmetrical cyclobutanes using C–H functionalization logic is demonstrated in the total synthesis of piperarborenine B and piperarborenine D (reported structure). These syntheses feature a new preparation of cis-cyclobutane dicarboxylates from commercially available coumalate starting materials and a divergent approach to the controlled cis or trans installation of the two distinct aryl rings found in the natural products using the first example of cyclobutane C–H arylation. The structure of piperarborenine D is reassigned to a head-to-head dimer, which was synthesized using an intramolecular [2+2] photocycloaddition strategy.

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Total Synthesis and Structural Revision of the Piperarborenines via Sequential Cyclobutane C - H Arylation

A new and general strategy for the synthesis of sequence-defined polymers is described that employs relay metathesis to promote the ring opening polymerization of unstrained macrocyclic structures. Central to this approach is the development of a small molecule “polymerization trigger” which when coupled with a diverse range of sequence-defined units allows for the controlled, directional synthesis of sequence controlled polymers.

A General Approach to Sequence-Controlled Polymers Using Macrocyclic Ring Opening Metathesis Polymerization

Our laboratory recently reported the synthesis of the pseudodimeric cyclobutane natural products piperarborenine B (1, Figure 1A) and piperarborenine D (proposed structure, 2) through a sequential cyclobutane C–H arylation strategy.[1,2] This led to both the concise preparation of these molecules (6–7 steps) and the structural reassignment of piperarborenine D (revised structure, 3). While the piperarborenines are the simplest examples of heterodimeric cyclobutane natural products isolated from pepper plants, a number of other heterodimers have been isolated, which all arise from a formal [2+2] cycloaddition of piperine-like monomers (4) with varying oxidation states and chain lengths.[3] Looking to extend our C–H functionalization strategy to more complex members of the family, our attention turned to the pipercyclobutanamides (5 and 6).



Figure 1

Selected heterodimeric cyclobutane natural products and retrosynthesis of pipercyclobutanamide A (5)



The pipercyclobutanamides were first isolated by Fujiwara and coworkers in 2001 from the fruits of the black pepper plant, Piper nigrum, though no biological activity was reported at that time.[3a] In 2006, Tezuka and coworkers reisolated pipercyclobutanamide A (5) and demonstrated a selective inhibition of cytochrome P450 2D6 (CYP2D6).[3c] These heterodimers represent a greater synthetic challenge than the piperarborenines (1,3) due to the presence of four different substituents on the cyclobutane ring. Both of these natural products contain an unusual cis unsaturated amide, and pipercyclobutanamide A (5) and B (6) contain styrene and styryl diene motifs, respectively. Viewing these molecules as an opportunity to develop cyclobutane C–H olefination chemistry, a synthetic strategy was devised and the retrosynthetic analysis of pipercyclobutanamide A (5) is shown in Figure 1B. First, the cis-alkene is transformed into an aldehyde through a stereocontrolled olefination reaction. The aldehyde could then be deconstructed to a directing group (DG) and the amide into a methyl ester using standard functional group manipulations to provide intermediate 7. Applying the strategy developed for the piperarborenines, this intermediate could be prepared through a series of epimerizations and sp3 C–H functionalizations on a desymmetrized cyclobutane dicarboxylate 8.

The direct olefination of sp2 C–H bonds has been known since the seminal work of Fujiwara and Moritani in the late 1960’s,[4] but few examples exist for the direct olefination of unactivated sp3 C–H bonds.[5] During a study towards the teleocidin natural products, Sames coupled an unactivated methyl group with a vinyl boronic acid, though the sequence proceeded through a discretely isolated palladacycle.[5e] The first catalytic example was reported in 2010 by Yu and coworkers.[5a] A highly electron-deficient anilide directing group was employed to couple acrylate derivatives directly to unactivated methyl and cyclopropyl C–H bonds. Chen and coworkers later reported the coupling of cyclic vinyl iodides with methylene C–H bonds using Daugulis’ picolinamide directing group under palladium catalysis.[5d] Encouraged by this result in particular, a styrenyl iodide was chosen as the first coupling partner to examine for the synthesis of pipercyclobutanamide A (5).[6]

Investigations started with the preparation of the requisite cyclobutane starting material 12 (Scheme 1). Applying the methodology developed previously for the piperarborenine natural products, methyl coumalate (9) underwent photochemical 4π electrocyclization at reduced temperature to give photopyrone 10.[7] This unstable intermediate was immediately hydrogenated and coupled to 8-aminoquinoline[8] in a single operation to give the desired C–H olefination precursor (12) in 54% overall yield. The olefination reaction was initially studied with (2-iodovinyl)benzene as a model coupling partner. The use of conditions originally developed for monoarylation (hexafluoroisopropanol (HFIP) as solvent and pivalic acid) resulted in low conversion and significant amounts of decomposition. Switching the solvent to toluene improved the reaction considerably to give bis-olefinated cyclobutane 13 as the major product in 50% isolated yield. This is in contrast to our previous work on the piperarborenines in which an epimerization event was required to allow for an efficient second C–H functionalization on the cyclobutane ring. The reason for this direct bis-olefination is unclear, but it may simply be that the vinyl iodide is smaller than the aryl iodide, leading to a more facile second reaction. Furthermore, 13 is an all-cis-cyclobutane that is quite strained and, to our knowledge, there are no other general methods for the controlled construction of this stereochemical array on a cyclobutane.



Scheme 1

Total synthesis of the proposed structure of pipercyclobutanamide A (5). Reagents and conditions: a) 450-W Hanovia lamp, Pyrex filter, DCM, 15 °C, 96 h; then H2, Pt/C, 4 h; then 8-aminoquinoline (1.2 equiv), EDC (1.2 equiv), 0 to 23 °C, ...



Given the modularity of this sequential C–H functionalization strategy, a monoarylation reaction could take place, followed by an olefination reaction to reach the end goal. When the standard monoarylation conditions were applied to reaction of cyclobutane 12 with 1-iodo-3,4-methylenedioxybenzene, poor conversion was observed due to methylenedioxy ring (3,4-dimethoxyiodobenzene as a coupling partner performed well). Pivalic acid proved to be an effective additive, and when the reaction was performed in tBuOH at high concentration, an acceptable monoarylation yield was obtained (54%, 1.00g scale). Due to the facile double olefination observed in the preparation of 13, monoarylated 14 was directly subjected to the C–H olefination reaction with styrenyl iodide 15. Optimizing the reaction was straightforward, employing catalytic Pd(OAc)2 in the presence of 1.5 equivalents of AgOAc with toluene as the solvent gave all-cis-cyclobutane 16 in 59% yield (480 mg scale). Pivalic acid as an additive retarded the reaction rate, and protic solvents such as t-BuOH or HFIP were inferior, giving low conversion or substantial decomposition, respectively.

With the sequential functionalization product (16) in hand, the relative stereochemistry needed to be altered to the all-trans configuration found in the natural product. This was anticipated to be a facile process given the strained nature of the all-cis stereochemistry and the thermodynamically downhill path to the desired all-trans product. Experimentally, this was verified through the use of two equivalents of sodium methoxide with C-1 epimerization occurring rapidly at room temperature (< 1 min). Upon warming the reaction mixture to 45 °C, the methyl ester (C-3) epimerizes over two hours and fully hydrolyzes after the addition of aqueous sodium hydroxide to give acid 18. Without further purification, 18 was treated with excess DIBAL to transform the aminoquinoline directing group directly into an aldehyde. By employing the free carboxylic acid in this reaction, the correct oxidation state found in the natural product is maintained with the carboxylate anion acting as an innate protecting group.[9] Additionally, the direct reduction of secondary amides with DIBAL has limited precedent, and the success of this reaction is likely the result of the chelating nature of the aminoquinoline motif.[10] Furthermore, this presents a new method for the cleavage of this amide directing group that avoids the extremes of pH and heat, expanding the synthetic utility of the Daugulis methodology if found to be general. Moving forward with the crude reaction product 19, piperidine was used as both a base and a coupling partner in the reaction with T3P® (propylphosphonic anhydride) to provide amide 20 in 40–45% isolated yield over 3 steps (114 – 386 mg scale).

To complete the synthesis of pipercyclobutanamide A (5), only an olefination reaction remained. This was accomplished through the use of Ando’s methodology for cis-selective unsaturated amide synthesis.[11] Treatment of aldehyde 20 with the Ando phosphonate (21) in the presence of tBuOK resulted in a ca. 5:1 cis:trans mixture of easily separable olefin isomers, giving the desired pipercyclobutanamide A (5) in 80% isolated yield (100 mg scale). Unfortunately, the 1H and 13C NMR data did not match the spectrum reported for the natural product.[12]

The concise synthesis of the proposed structure of pipercyclobutanamide A (5) further demonstrates the power of C–H functionalization logic in synthesis to provide substantial amounts of complex cyclobutanes (7 steps, 5 chromatographic purifications, 5% overall yield, >100 mg prepared). The sequence features mostly skeleton-forming transforms, is protecting-group-free,[13] and has only one concession step (DIBAL reduction) leading to an ideality of 85%.[14] Salient features of the synthesis include: (1) the first example of C–H olefination on an unactivated cyclobutane ring; (2) stereocontrolled access to highly strained all-cis cyclobutanes; (3) direct conversion of aminoquinoline amides directly to aldehydes; and (4) the use of a carboxylate anion as an “innate protecting group” in an amide reduction.

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Sequential C sp 3H Arylation and Olefination: Total Synthesis of the Proposed Structure of Pipercyclobutanamide A

The application of C–H functionalization logic to target-oriented synthesis provides an exciting new venue for the development of new and useful strategies in organic chemistry. In this article, C–H functionalization reactions are explored as an alternative approach to access pseudodimeric cyclobutane natural products, such as the dictazole and the piperarborenine families. The use of these strategies in a variety of complex settings highlights the subtle geometric, steric, and electronic effects at play in the auxiliary guided C–H functionalization of cyclobutanes.

Will R. Gutekunst

Papers

C–H functionalization logic in total synthesis

Total Synthesis and Structural Revision of the Piperarborenines via Sequential Cyclobutane C - H Arylation

A General Approach to Sequence-Controlled Polymers Using Macrocyclic Ring Opening Metathesis Polymerization

Sequential C sp 3H Arylation and Olefination: Total Synthesis of the Proposed Structure of Pipercyclobutanamide A

Applications of C-H functionalization logic to cyclobutane synthesis.