Emergent synthetic methods for the modular advancement of sp3-rich fragments

Abstract

Fragment-based drug discovery is an important and increasingly reliable technology for the delivery of clinical candidates. Notably, however, sp³-rich fragments are a largely untapped resource in molecular discovery, in part due to the lack of general and suitably robust chemical methods available to aid their development into higher affinity lead and drug compounds. This Perspective describes the challenges associated with developing sp³-rich fragments, and succinctly highlights recent advances in C(sp³)-H functionalisations of high potential value towards advancing fragment hits by 'growing' functionalised rings and chains from unconventional, carbon-centred vectors.

Fig. 1. Methods for fragment elaboration. (a) Conventional elaboration exploiting heteroatom-centred vectors; (b) unconventional elaboration by C(sp³)–H functionalisations (focus of this Perspective).

Fig. 2. Functionalisation types highlighted in this Perspective.

Scheme 1. Photoredox-mediated Minisci-type coupling of α-amino radicals with electron-deficient hetaryl rings. *55 : 45 rr (regiomeric ratio).

Scheme 2. Arylations α- to alicyclic heteroatoms, mediated by a decatungstate photocatalyst. Unless otherwise stated, rr (regiomeric ratio) and dr are >95 : 5.

Scheme 3. Rh-catalysed arylation of nitrogenous heterocycles.

Scheme 4. Pd-catalysed directed C(sp³)–H arylations of alicyclic amines. (a) Original procedure developed by Sanford; (b) next generation protocol by Li, Dechanstreiter, and Dandapandi, incorporating ligand L2, and demonstrating substantial scope with respect to the aryl iodide coupling partner.

Scheme 5. Pd-catalysed directed C(sp³)–H α-arylations distal to alicyclic carboxylic acids.

Scheme 6. Pd-catalysed directed γ- and δ-C(sp³)–H arylations (panels a and b, respectively) using transient directing groups. *Boc protection sequence: (1) 2 M HCl, THF; (2) 10 M NaOH; Boc₂O.

Scheme 7. Pd-catalysed directed β-C(sp³)–H arylations of alcohols using an O–N tethered directing group.

Scheme 8. Pd-catalysed directed γ-C(sp³)–H arylations of alcohols using an O-tethered directing group. (a) γ-Arylation of alcohols without active β-C–H bonds; (b) γ-arylation of alcohols with active β-C–H bonds. Ar^F = 2,3,5,6-tetrafluoro-4-(trifluoromethyl) phenyl.

Scheme 9. Alkylations α- to alicyclic heteroatoms using a Ir/quinuclidine/Ni catalyst system.^a50 eq. of cyclic ether used in the reaction.

Scheme 10. Benzophenone/Cu-catalysed coupling of alkyl radicals and electron deficient alkenes.

Scheme 11. Cross-dehydrogenative couplings between saturated heterocycles and benzophenone imines.^a5.0 eq. heteroaliphatic donor used.

Scheme 12. Photocatalysed coupling of α-amino radicals with benzaldehydes and aryl ketones.

Scheme 13. Ir-catalysed α-C(sp³)–H alkylation of saturated azacycles with alkenes. ^aIsomerises to give the linear product.

Scheme 14. Quinone-mediated oxidation of primary amines followed by addition of nucleophiles, furnishing primary α-tertiary amines. Conditions for Grignard addition: RMgX or RLi (6.0 eq.), TMEDA (1.0 eq.), 0–25 °C, 1–24 h.

Scheme 15. Photocatalysed alkylation–lactamisation of primary amines.

Scheme 16. Ir- and Ni-photocatalysed δ-C(sp³)–H alkylation of trifluoroacetamides.

Fig. 3. A “thought experiment” showing how known sp³-rich fragment hits might be structurally advanced using methodologies highlighted in this Perspective. “S#” refers to the specific scheme number in this manuscript for the transformation shown. For brevity, protecting group manipulation strategies are not shown. PG = protecting group.

Max J. Caplin

Daniel J. Foley