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Published in final edited form as: Science. 2024 Nov 7;386(6722):641–646. doi: 10.1126/science.adp2425

Total synthesis of (−)-cylindrocyclophane A facilitated by C–H functionalization

Aaron T Bosse 1, Liam R Hunt 2,†, Camila A Suarez 1,2,†, Tyler D Casselman 2, Elizabeth L Goldstein 2, Austin C Wright 2, Hojoon Park 3, Scott C Virgil 2, Jin-Quan Yu 3, Brian M Stoltz 2,*, Huw M L Davies 1,*
PMCID: PMC11648813  NIHMSID: NIHMS2036796  PMID: 39509484

Abstract

(–)-Cylindrocyclophane A is a 22-membered C2-symmetric [7.7]paracyclophane bearing, bisresorcinol functionality and six stereocenters. Herein, we report a strategy to (–)-cylindrocyclophane A that employs ten C–H functionalization reactions, resulting in a streamlined synthesis with remarkable enantioselectivity and efficiency (17 steps). The use of chiral dirhodium tetracarboxylate catalysis enabled the C–H functionalization of primary and secondary positions which was complemented by palladium-catalyzed C(sp2)–C(sp2) cross couplings; resulting in the rapid formation of the macrocyclic core and all stereocenters with high regio-, diastereo-, and enantioselectivity. Finally, the use of a late-stage palladium-catalyzed four-fold C(sp2)–H acetoxylation installed the bis-resorcinol moieties. Ultimately, this research exemplifies how multi-laboratory collaborations can produce substantial modernizations of complex total synthesis endeavors.

One-Sentence Summary:

The asymmetric total synthesis of (-)-cylindrocyclophane A facilitated by C-H functionalization.

C–H functionalization has become an increasingly viable and accessible strategy over the recent years which has led to its amplified use toward more challenging bond constructions in complex settings (1–3). Instead of relying on the established approach of a series of functional group transformations, the key focus becomes the strategic and site-selective functionalization of the traditionally unactivated C–H bonds. Many highly effective methods have been developed for selective C–H functionalization, relying on different tactics, such as the use of directing groups, radical transformations, and catalyst-controlled group transfer reactions (4–8).

To date, C–H functionalization has been used as a critical transformation in a number of total syntheses, often employed as a late-stage diversification strategy or used to achieve a key disconnection which was not previously achievable (9–12). For example, the Li and Lei groups’ total synthesis of (–)-Incarviatone A demonstrates an impressive illustration of sequential C–H functionalization reactions conducted (13). As members of the NSF Center for Selective C–H Functionalization (CCHF) and the Catalysis Innovation Consortium (CIC), we have been exploring ways to combine the development of powerful C–H functionalization synthetic methods alongside their application in total synthesis (14–17). Our goal has been to demonstrate how the utilization of C–H functionalization can provide diverse routes toward challenging natural products, and fully alter the manner in which we conceptualize making architecturally and stereochemically complex targets. Herein we illustrate our application of asymmetric, catalyst-controlled C–H functionalization to total synthesis, a strategy yielding challenging bond formations with high regio-, diastereo- and enantioselectivity derived from the stereoelectronic precision of specialized transition-metal catalyzed systems.

The target compound is the [7.7]paracyclophane natural product, (–)-cylindrocyclophane A (1, Fig. 1), a compound that has garnered extensive synthetic interest due to its unique molecular architecture (18–25). The previous syntheses of 1 applied venerable chemical transformations such as the olefin metathesis, Horner–Wadsworth–Emmons reaction, and Ramberg–Bäcklund cyclodimerization strategies to construct the macrocycle and several other well-known transformations to forge each stereocenter (Fig. 1A, Fig. S6–S10), whereas this effort employs the application of C–H functionalization methodology developed in our groups to tackle these C–C and C–O bond formations. Our approach is quite distinct from the previous syntheses because it centers on catalyst-controlled asymmetric C–H functionalization (Fig 1B). In our previous study, we reported a method that asymmetrically forges C–C bonds via the C–H functionalization of distal, unactivated methylene sites utilizing 1,2,2-triphenylcyclopropane carboxylate (TPCP) ligands specifically in our Rh2(2-Cl-5-Br)TPCP4 catalyst and demonstrated its utility to generate a simplified [7.7]paracyclophane model. (26, 27)

Fig. 1. Strategies toward (–)-cylindrocyclophane A.

Fig. 1

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(A) Reported synthetic strategies of cylindrocyclophane A. (B) Our C–H functionalization-based synthetic strategy.

Herein, we report six C–C and four C–O bonds of (–)-cylindrocyclophane A generated via ten C–H functionalizations with exquisite site- and stereoselectivity made possible by rhodium- and palladium-catalyzed processes originating from within the CCHF. Although catalytic amounts of these precious metals are required in these key transformations, related palladium-catalyzed processes are widely used in industry (28), and we have previously demonstrated that dirhodium-catalyzed C–H functionalizations can be conducted efficiently with loadings as low as 0.0005 mol% (29).

Synthetic plan.

By incorporating C–H functionalization logic into our retrosynthetic analysis of (–)-cylindrocyclophane A (1), we considered that we could effect several unusual transformations to rapidly simplify the molecule (Fig. 2). We posited that 1 could be derived from bis-amide 2 by addition of an appropriate nucleophile into each Weinreb amide. We envisioned introducing the 2,6-resorcinol functionality at a late-stage via four-fold Weinreb amide directed C–H acetoxylation of paracyclophane 3, reducing the complexity and modulating the reactivity of the aryl groups. The acetates at C1 and benzylic amide at C7 of macrocycle 3 could be traced back to an orthogonally protected macrocyclic tetra-ester 4. We identified that rhodium(II)-catalyzed secondary C(sp3)–H functionalizations could set the vicinal stereocenters in the natural product as well as serve as the linchpin strategy for C–C bond construction and macrocyclization. These transformations could reveal diazoester 5, which could be prepared via a palladium-catalyzed C–H functionalization of a diazoacetate with aryl halide 6. Finally, we anticipated that aryl halide 6 could arise from the enantioselective rhodium(II)-catalyzed primary C–H functionalization of a synthetic equivalent of hexane with a donor-acceptor rhodium-carbenoid derived catalytically from an aryl diazoacetate.

Fig. 2. Retrosynthesis of (-)-cylindrocyclophane A.

Fig. 2

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Asymmetric C–H Functionalization.

We initiated our synthesis with a selective primary C–H functionalization of known aryl diazoacetate 7 and trans-2-hexene 8 (Fig. 3A) (15, 26). We were pleased to find that the reaction proceeded with excellent regio- and enantioselectivity using the sterically hindered Rh2(R-p-PhTPCP)4 catalyst (Fig. 3B), designed to favor reactions at less crowded C–H bonds, affording 9 in respectable yield and excellent enantioselectivity at C20 (73% yield, 96% ee) (26–31). Hydrogenation of trans-olefin 9 was performed using Crabtree’s catalyst, affording iodide 10 in quantitative yield (32, 33). Attempts to directly access 10 via functionalization of n-hexane produced inseparable mixtures from primary and secondary C–H functionalization reactions. We then turned our attention to the C–H functionalization sequence to construct the [7.7]paracyclophane framework (Fig. 3A) which was also guided by our earlier work in synthesizing the model macrocycle (26). Subjecting iodide 10 to a palladium-catalyzed C(sp2)–C(sp2) cross-coupling with diazoester 11 smoothly delivered the aryl diazoacetate 12 via C–H functionalization of the acetate.

Fig. 3. Synthesis of the [7.7]paracyclophane framework.

Fig. 3

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(A) Detailed forward synthesis of a direct cyclodimerization and sequential C–H functionalization approach to construct the cylindrocyclophane core. (B) Structures of the asymmetric catalysts used to enable selective primary and secondary C–H functionalizations.

Direct Cyclodimerization.

With aryl diazoacetate 12 in hand we were poised to investigate the cyclodimerization. Overcoming initially disappointing results, we were ecstatic to find that treating aryl diazoacetate 12 with Rh2(R-2-Cl-5-BrTPCP) delivered macrocycle 15 in a 10 respectable yield, given the complexity of the transformations (19% yield, 6:1 dr, Fig. 3 and S3). The absolute and relative configuration of the macrocyclic tetra-ester 15 was confirmed by x-ray diffraction analysis. This remarkable one-pot reaction assembles the [7,7]paracyclophane core of the natural product along with four new stereocenters in a single step. The direct cyclodimerization of diazoacetate 12 had limitations, in particular material throughput and the need for HPLC purification, which further limited throughput.

Stepwise Macrocyclization.

To complete the synthesis, we preferred to develop a strategy with higher material throughput and developed a stepwise approach to assemble macrocycle 15 building off our published model study (27). Treatment of diazoacetate 12 with Rh2(R-2-Cl-5-BrTPCP)4 and three equivalents of 10 generated aryl iodide 13 with excellent stereo- and regiocontrol to generate the C1–C2 stereodiad (68% yield, 19:1 dr). There is remarkably high regioselectivity in this unusual transformation for the most sterically accessible and electronically-stabilized C–H bond (>20:1 rr) and affords the product in high diastereoselectivity and satisfactory yield (68% yield, 19:1 dr).

The bis-arene intermediate 13 was subjected to another palladium-catalyzed cross-coupling by C–H functionalization and afforded the macrocyclization precursor 14. To our delight, the macrocyclization proceeded efficiently to generate the second stereodiad of C14–C15 upon treatment of diazoester 14 with Rh2(R-2-Cl-5-BrTPCP)4 (70% yield, 8:1 dr). The lower overall diastereoselectivity for the macrocyclization compared to the formation of aryl iodide 13 is due to Horeau’s effect, in which imperfect asymmetric induction generates diastereomeric rather than enantiomeric mixtures. To our delight, using the stepwise sequence enabled the preparation of >1.2 mmol of macrocycle 15 in a single pass. Additionally, we were pleased to find that at this scale macrocycle 15 could be isolated as a single diastereomer by recrystallization from the crude reaction mixture.

Our synthesis of macrocycle 15 via either a sequence of the direct cyclodimerization (12% yield over 4 steps) or stepwise macrocyclization (23% yield over 6 steps) from aryl diazoacetate 7 allowed for the efficient construction of the macrocyclic core and six stereocenters en route to the target. This approach of establishing the core macrocycle of the natural product relatively early in the synthesis is distinct from previous approaches, and we note that for the purposes of material throughput the stepwise route was used to continue the total synthesis.

With the macrocyclic framework in hand, the trichloroethyl esters of the macrocycle 15 were chemoselectively converted to the bis-Weinreb amide 16 (Fig. 4) (34). The remaining trifluoroethyl esters were then hydrolyzed to afford the bis-carboxylic acid 17, which was subjected to photocatalytic decarboxylative acetoxylation to deliver bis-benzylic acetate 3 (35). At this stage, we were poised to conduct the final, C–H functionalization reaction in the synthesis, namely a tetra-C(sp2)–H acetoxylation of macrocycle 3, a transformation only made possible by the conditions developed in the Yu group employing 5-(trifluoromethyl)pyridine-3-sulfonic acid ligand (36–38). In a single transformation, amide-directed tetra-C(sp2)–H oxidation of 3 delivered macrocycle 2 in 60% yield. This final linchpin transformation signified the completion of all the desired C–H functionalization steps toward the natural product.

Fig. 4. Final C–H functionalizations toward (–)-cylindrocyclophane A.

Fig. 4

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Completion of the synthesis.

The final challenge to complete the synthesis would be the installation of the two propyl side chains. We envisioned that treatment of bis-Weinreb amide 2 with excess propyl Grignard would effect nucleophilic addition as well as global deacylation. Despite extensive efforts, the resulting diketone was impervious to deoxygenation (Fig. S4). The next approach centered around the reaction of macrocycle 2 with excess DIBAL (Fig. S5). Unfortunately, the reduction provided a complex mixture of products that could not be elaborated to the final natural product (1) in acceptable yield. We hypothesized the poor results were due to the in situ generation of phenoxides cyclizing onto the Weinreb amide; therefore, we elected to transform the phenolic acetates into methyl ethers.

We found that chemoselective deacylation of the phenolic acetates followed by methylation delivered tetra-methyl ether 18 (39). Treatment of macrocycle 18 with DIBAL reductively cleaved the remaining acetates and reduced both Weinreb amides to the corresponding aldehydes (40), which were directly subjected to a Wittig olefination to deliver bis-olefin 19 as a single set of alkene isomers (41). Finally, hydrogenation of bis-olefin 19 delivered (–)-tetra-O-methyl-cylindrocyclophane A (20), which was then demethylated using the vigorous conditions of Hoye and co-workers to afford (–)-cylindrocyclophane A (1) (20).

Overall, our synthesis involves either a shorter 17-step or more scalable 19-step sequence from commercial starting material utilizing ten C–H functionalization reactions that forge six C–C bonds, and four C–O bonds. Specifically, the route showcases four catalyst-controlled enantioselective and diastereoselective C–H functionalizations to generate all six stereogenic centers of the natural product, as well as two palladium-catalyzed C–H functionalizations of diazocarbonyl compounds, and four amide-directed C–H acetoxylations. The presented research exemplifies the power of multi-institutional collaboration and C–H functionalization as an enabling technology to selectively transform low-cost materials into highly functionalized and stereochemically-complex building blocks.

Supplementary Material

Supplementary Material

Acknowledgments:

This study was facilitated by constructive discussions within the NSF Center for Selective C–H Functionalization and the Catalysis Innovation Consortium. The authors thank Dr. John Bacsa (Emory University) and Dr. Michael Takase (Caltech) for X-ray structure determination, Dr. David VanderVelde (Caltech) for NMR expertise, and Dr. Mona Shahgholi and Jay Barbor (Caltech) for mass spectrometry assistance. We additionally thank Skylar Osler for assistance in GPC analysis. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the National Science Foundation.

Funding:

This work was supported by the National Science Foundation under the CCI Center for Selective C–H Functionalization (CHE-1700982). B.M.S.’s portion of the work was also supported by the NIH-NIGMS (R35GM145239), Heritage Medical Research Investigators Program, and Caltech. H.M.L.D.’s portion of this work was also supported by the National Science Foundation (CHE-1956154) and the NIH-NIGMS (R01GM099142). E.L.G was supported by the NSF GRFP. L.R.H was supported by the University of Auckland doctoral scholarship award.

Footnotes

Competing interests: HMLD is a named inventor on a patent entitled, Dirhodium Catalyst Compositions and Synthetic Processes Related Thereto (US 8.974.428. issued March 10, 2015). The other authors declare that they have no competing interests.

SUPPLEMENTARY MATERIALS

Materials and Methods

Figures S1 to S10

Tables S1 to S30

NMR Spectra

Reference (42)

Data and materials availability:

Crystallographic parameters for compounds 15, 17, 20, and 1 are available free of charge from the Cambridge Crystallographic Data Centre under CCDC 2364844, 2364845, 2364843, 2364846, respectively. Spectra, materials and methods, substrate and reagent details are available in the supplementary materials.

References and Notes

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Material
NIHMS2036796-supplement-Supplementary_Material.pdf (14.2MB, pdf)

Data Availability Statement

Crystallographic parameters for compounds 15, 17, 20, and 1 are available free of charge from the Cambridge Crystallographic Data Centre under CCDC 2364844, 2364845, 2364843, 2364846, respectively. Spectra, materials and methods, substrate and reagent details are available in the supplementary materials.

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