Advancing the Logic of Chemical Synthesis: C-H Activation as Strategic and Tactical Disconnections for C-C Bond Construction

Abstract

The design of synthetic routes by retrosynthetic logic is decisively influenced by the transformations available. Transition-metal-catalyzed C-H activation has emerged as a powerful strategy for C-C bond formation, with myriad methods developed for diverse substrates and coupling partners. However, its uptake in total synthesis has been tepid, partially due to their apparent synthetic intractability, as well as a lack of comprehensive guidelines for implementation. This Review addresses these issues and offers a guide to identify retrosynthetic opportunities to generate C-C bonds by C-H activation processes. By comparing total syntheses accomplished using traditional approaches and recent C-H activation methods, this Review demonstrates how C-H activation enabled C-C bond construction has led to more efficient retrosynthetic strategies, as well as the execution of previously unattainable tactical maneuvers. Finally, shortcomings of existing processes are highlighted; this Review illustrates how some highlighted total syntheses can be further economized by adopting next-generation ligand-enabled approaches.

Keywords: C−H activation; C−H functionalization; catalysis; total synthesis; transition metals.

Figure 1.

(A) A brief history of the evolution of organic synthesis from Wöhler’s total synthesis of urea (1) to the landmark total synthesis of vitamin B₁₂ by Woodward and Eschenmoser; (B) Application of the newly conceptualized Woodward-Hoffmann rules enabled Nicolaou to access the endiandric acids (6)

Figure 2.

Two examples of total syntheses uniquely enabled by transition-metal catalyzed processes: (A) a palladium-catalyzed cascade cyclization forms the scaffold for (+)-lysergol (7, Werz); (B) a ruthenium-catalyzed cascade ring closing metathesis generates the scaffold for morphine (8, Smith). HG-II: Hoveyda-Grubbs Second Generation Catalyst

Figure 3.

Overview of C–C bond formation via transition-metal catalyzed C–H activation and two examples on how they can offer a conceptually orthogonal approach towards organic synthesis: (A) via C(sp²)–H activation and (B) via β-C(sp³)–H activation

Figure 4.

A summary of the two general strategies for the site-selective formation of C–C bonds via transition metal-catalyzed C–H activation process for arenes: (A) directed approaches,^[24] or (B) in combination with norbornene-mediated palladation relay^[29,30]

Figure 5.

A summary of various direct C–C bond forming reactions via C–H activation processes for a representative class of N-heterocycles: pyrroles,^[52] indoles,^[–b] pyridines^[,–h,54] and quinolines^{[, ,–g,i]}

Figure 6.

General approach for reconceiving C(sp²)–C bond disconnection via a C(sp²)–H activation, with key considerations outlined

Figure 7.

Overview of the strategies to effect site-selective C(sp³)–H activation to form C–C bonds

Figure 8.

General approach for reconceiving C(sp³)–C bond disconnection via a C(sp³)–H activation approach, distinguishing between the polar reactivities with distance-guided factors that characterize C–H activation processes.

Figure 9.

Comparison between a canonical synthetic approach towards saturated heterocycle via a C–X bond disconnection, as compared with an alternative, uncanonical approach via C–C disconnection

Figure 10.

Key findings to help broaden substrate and coupling scope of future C–H activation transformations

Figure 11.

Contrasting canonical approaches for transition metal-catalyzed C–H activation to an ideal process by harnessing native functionalities

Scheme 1.

Fürstner’s approach towards the total synthesis of dictyodendrin B (9) (2005): (A) retrosynthesis of dictyodendrin B; (B) forward synthesis

Scheme 2.

An illustration of a structurally-obvious approach towards dictyodendrin B (9) as reported by Gaunt (2015): (A) retrosynthesis, (B) forward synthesis

Scheme 3.

Historical approaches taken towards the lamellarins

Scheme 4.

A structurally-obvious and expedient approach towards lamellarin C and I as reported by Yamaguchi (27 and 28, 2014)

Scheme 5.

Historical approaches taken towards hongoquercin A (32) and related congeners^[68,69]

Scheme 6.

Structurally-obvious approach to the total synthesis of hongoquercin A (32). (A) Retrosynthesis of (+)-hongoquercin A and (B) Forward synthesis of hongoquercin A

Scheme 7.

Jacobson’s first synthesis of heptamethyl lithospermate (34, 1979)

Scheme 8.

Ellman’s asymmetric total synthesis of (+)-lithospermic acid (36, 2005)

Scheme 9.

Yu’s total synthesis of (+)-lithospermic acid (36, 2011)

Scheme 10.

(A) Overview of historical atropselective synthetic approaches towards the total synthesis of (+)-steganone (47) and (+)-isoschizandrin (48); (B) Shi’s formal synthesis of (+)-steganone and (+)-isoschizandrin as enabled by an atropselective C(sp²)–H alkynylation strategy (2018)

Scheme 11.

Suzuki’s total synthesis and stereochemical assignment of TAN-1085 (53, 2004); (A) Retrosynthetic analysis of TAN-1085 and (B) forward synthesis

Scheme 12.

(A) Leveraging axial-to-point chirality in the synthesis of TAN-1085 (2004); (B) Suzuki’s second-generation approach towards TAN-1085 via a point-to-axial chirality relay strategy (2009) (B) Shi’s approach towards TAN-1085 (2019) via an atropselective C–H olefination strategy

Scheme 13.

Past routes taken for the total syntheses of cyclobutane-containing natural products incarvillateine C (65, 2004) and dipiperamide A (66, 2005) by Kibayashi

Scheme 14.

Baran’s total synthesis of (A) the piperarborenines (67 and 68, 2011) and (B) putative pipercyclobutanamide A (69, 2012) as mediated by a sequential C–H functionalization strategy

Scheme 15.

Further applications of C–H activation methods for the synthesis of cyclobutene-containing natural products: (A) Fox’s enantioselective synthesis of piperarborenine B (67); (B) Reisman’s total synthesis of (+)-psiguadial B (77)

Scheme 16.

The Nicolaou total synthesis of (−)-epiccocin G and 8,8’-epi-entrostratin B (2011). (A) Retrosynthesis of (−)-epiccocin G; (B) Forward synthesis of (−)-epiccocin G (78) and 8,8’-epi-ent-rostratin B (79)

Scheme 17.

Baudoin’s total synthesis of (−)-epiccocin G (78) and (−)-rostratin A (87), employing a bidirectional C(sp³)–H activation-mediated cyclization as a key step (2019)

Scheme 18.

Summary of past synthetic strategies taken towards the total synthesis of podophyllotoxin (94)

Scheme 19.

Maimone’s six-step total synthesis of rac-podophyllotoxin via a late-stage C(sp³)–H arylation strategy (2014)

Scheme 20.

Summary of past synthetic strategies taken towards the total synthesis of (−)-quinine (99)

Scheme 21.

Maulide’s ten-step total synthesis of (−) and (+)-quinine (99), as well as various quinine analogues, enabled by C(sp³)–H arylation reaction (2018)

Scheme 22.

(A) A combination of weak-coordination and ligand acceleration enables a challenging desymmetrizing C(sp³)–H olefination. (B) A potentially more concise total synthesis of (−)-quinine, leveraging a weakly-directing triflimide motif as highlighted in (A)

Scheme 23.

(A) Methodology gaps for a potential four-step total synthesis of hongoquercin A. (B) Opportunities for more atom economical approach towards the synthesis of psiguadial B.

Scheme 24.

A potentially shorter enantioselective total synthesis of piperarborenine B (67) using a desymmetrizing C(sp²)–H activation transformation

Scheme 25.

Total synthesis and configurational assignment of delavatine A by Shen, Li, Zhang et al. (110)