Building C(sp3)-rich complexity by combining cycloaddition and C-C cross-coupling reactions

Abstract

Prized for their ability to rapidly generate chemical complexity by building new ring systems and stereocentres¹, cycloaddition reactions have featured in numerous total syntheses² and are a key component in the education of chemistry students³. Similarly, carbon-carbon (C-C) cross-coupling methods are integral to synthesis because of their programmability, modularity and reliability⁴. Within the area of drug discovery, an overreliance on cross-coupling has led to a disproportionate representation of flat architectures that are rich in carbon atoms with orbitals hybridized in an sp² manner⁵. Despite the ability of cycloadditions to introduce multiple carbon sp³ centres in a single step, they are less used⁶. This is probably because of their lack of modularity, stemming from the idiosyncratic steric and electronic rules for each specific type of cycloaddition. Here we demonstrate a strategy for combining the optimal features of these two chemical transformations into one simple sequence, to enable the modular, enantioselective, scalable and programmable preparation of useful building blocks, natural products and lead scaffolds for drug discovery.

Extended Data Figure 1.

Complete substrate scope of [4+2] cycloaddtion/cross-couplings. See Supplementary Information for synthetic details. R¹,R² = (Het)Aryl, alkyl, alkenyl, alknnyl. X-ray structure data is available for compounds 11, 19, 23, 25, 28, 44, 45, 49,

Extended Data Figure 2.

Complete substrate scope of A [3+2], B [2+2] and C [2+1] sections. See Supplementary Information for synthetic details. R¹,R² = (Het)Aryl, alkyl, alkenyl, alknnyl. X-ray structure data is available for compounds C₂ and 65.

Figure 1.. Combining the logic of cycloaddition and C–C cross coupling.

A, Cylcoaddition and C–C cross coupling; B, Case study: retrosynthetic analysis of enantiopure building block 3; C, Maleic anhydride used as available and modular chiral dihalide surrogate.

Figure 2.. Substrate scope of combining cycloaddition and C–C cross coupling. A–D

The cycloaddition component is shown in black, the first cross coupling is shown in green and the 2^nd cross coupling is shown in blue. The yield and ee refer to the 2^nd cross coupling. Besides compound 89 (dr 8.5:1), excellent diastereoselectivity (dr >10:1) was observed in all cross couplings. See Extended Data Figures 1 and 2 for complete substrate scope and Supplementary Information for synthetic details. X-ray structure data is available for compounds 11, 19, 23, 25, 28, 65 and C₂. N = Negishi; S = Suzuki; K = Kumada cross-coupling; N= Boc, tert-butyloxycarbonyl; TIPS, triisopropylsilyl; Ts, tosyl;

Figure 3.. Applications of combining cycloaddition and C–C cross coupling.

A, gram-scale synthesis of (±)–epibatidine. B, asymmetric synthesis of asenapine (Saphris™). C, modular synthesis towards epothilone analogue fragement. D, synthesis of LEO Pharma key intermediate. E, synthesis of Eisai Pharmaceutical key intermediate. F, New chiral 2π synthons for cycloaddition: application to the modular asymmetric synthesis of EED protein-protein interaction inhibitor. Excellent diastereoselectivity (dr >10:1) was observed in all cross couplings. See Supplementary Information for full synthetic details and schemes. X-ray structure data is available for compounds 1, 107 and 118. Boc, tert-butyloxycarbonyl; Pin, pinacol group; TBDPS, tert-butyldiphenylsilyl; TBS, tert-butyldimethylsilyl; TCNHPI, tetrachloro-N-hydroxyphthalimide; THP, tetrahydropyranyl; TIPS, triisopropylsilyl; TMS, trimethylsilyl.