Will R. Gutekunst

Total synthesis and structural revision of the piperarborenines via sequential cyclobutane C-H arylation.

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.

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

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.

Applications of C–H Functionalization Logic to Cyclobutane Synthesis

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.

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

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.

Guided desaturation of unactivated aliphatics

The excision of hydrogen from an aliphatic carbon chain to produce an isolated olefin (desaturation) without overoxidation is one of the most impressive and powerful biosynthetic transformations for which there are no simple and mild laboratory substitutes. The versatility of olefins and the range of reactions they undergo are unsurpassed in functional group space. Thus, the conversion of a relatively inert aliphatic system into its unsaturated counterpart could open new possibilities in retrosynthesis. In this article, the invention of a directing group to achieve such a transformation under mild, operationally simple, metal-free conditions is outlined. This ‘portable desaturase’ (TzoCl) is a bench-stable, commercial entity (Aldrich, catalogue number L510092) that is facile to install on alcohol and amine functionalities to ultimately effect remote desaturation, while leaving behind a synthetically useful tosyl group. A bench-stable, aryl sulfonyl triazene is described that can be appended to alcohols or amines and used as a directing group to effect remote desaturation of unactivated aliphatics to produce olefins. The reaction is mild, operationally simple, requires no added metals and produces unsaturated tosylates or tosylamides available for further functionalization.

A Versatile and Scalable Strategy to Discrete Oligomers.

A versatile strategy is reported for the multigram synthesis of discrete oligomers from commercially available monomer families, e.g., acrylates, styrenics, and siloxanes. Central to this strategy is the identification of reproducible procedures for the separation of oligomer mixtures using automated flash chromatography systems with the effectiveness of this approach demonstrated through the multigram preparation of discrete oligomer libraries (Đ = 1.0). Synthetic availability, coupled with accurate structural control, allows these functional building blocks to be harnessed for both fundamental studies as well as targeted technological applications.

End group modification of poly(acrylates) obtained via ATRP: a user guide

The versatile and high yielding functionalization of polymer end groups is a critical tool for controlling material properties and/or for successful post polymerization reactions. In this report, bromine-terminated poly(methyl acrylate) derivatives are used as a model system for identifying conditions leading to quantitative transformation of the end group. A wide range of small molecules and associated reactions for the introduction of specific acidic, basic, hydrophilic or hydrophobic functionality are described. Analysis by SEC, 1H NMR and MALDI-ToF-MS provides evidence for full conversion of the end group. The user-friendly nature of these procedures serve as a powerful strategy for the synthesis of end functionalized polymers.

Direct access to functional (Meth)acrylate copolymers through transesterification with lithium alkoxides

A straightforward and efficient synthetic method that transforms poly(methyl methacrylate) (PMMA) into value-added materials is presented. Specifically, PMMA is modified by transesterification to produce a variety of functional copolymers from a single starting material. Key to the reaction is the use of lithium alkoxides, prepared by treatment of primary alcohols with LDA, to displace the methyl esters. Under optimized conditions, up to 65% functionalization was achieved and copolymers containing alkyl, alkene, alkyne, benzyl, and (poly)ether side groups could be prepared. The versatility of this protocol was further demonstrated through the functionalization of both PMMA homo and block copolymers obtained through either radical polymerization (traditional and controlled) or anionic procedures. The scope of this strategy was illustrated by extension to a range of architectures and polymer backbones.

Controlled Formation and Binding Selectivity of Discrete Oligo(methyl methacrylate) Stereocomplexes

The triple-helix stereocomplex of poly(methyl methacrylate) (PMMA) is a unique example of a multistranded synthetic helix that has significant utility and promise in materials science and nanotechnology. To gain a fundamental understanding of the underlying assembly process, discrete stereoregular oligomer libraries were prepared by combining stereospecific polymerization techniques with automated flash chromatography purification. Stereocomplex assembly of these discrete building blocks enabled the identification of (1) the minimum degree of polymerization required for the stereocomplex formation and (2) the dependence of the helix crystallization mode on the length of assembling precursors. More significantly, our experiments resolved binding selectivity between helical strands with similar molecular weights. This presents new opportunities for the development of next-generation polymeric materials based on a triple-helix motif.

Relay Conjugation of Living Metathesis Polymers

The covalent coupling of complex macromolecules is a modern challenge in both chemistry and biology. The development of efficient and chemoselective methods for polymer coupling and functionalization are increasingly important for designing new advanced materials and interfacing with biochemical systems. Herein, we present a new strategy to directly conjugate living polymers prepared using ring-opening metathesis polymerization (ROMP) to both small molecules and synthetic macromolecules. Central to this methodology is a terminal alkyne that serves as a directing group to promote a rapid, intramolecular reaction with an otherwise unreactive olefin. This highly chemoselective relay conjugation is compatible with a range of monomer families and uses a bench-stable enyne motif that can be easily introduced to functional targets. The rapid rate of the conjugation reaction paves the way for greatly streamlined construction of complex macromolecular systems derived from metathesis polymerization techniques without the need for specialized equipment.