Catalytic enantioselective addition of organometallics to unprotected carboxylic acids

Abstract

Conjugate addition of organometallics to carbonyl based Michael acceptors is a widely used method that allows the building of new carbon-carbon (C-C) bonds and the introduction of chirality in a single step. However, conjugate additions to the simplest Michael acceptors, namely unprotected, unsaturated carboxylic acids, are considered to be prohibited by the fact that acid-base reactions overpower any other type of reactivity, including nucleophilic addition. Here we describe a transient protecting group strategy that allows efficient catalytic asymmetric additions of organomagnesium reagents to unprotected α,β-unsaturated carboxylic acids. This unorthodox pathway is achieved by preventing the formation of unreactive carboxylate salts by means of a reactive intermediate, allowing modifications of the carbon chain to proceed unhindered, while the stereochemistry is controlled with a chiral copper catalyst. A wide variety of β-chiral carboxylic acids, obtained with excellent enantioselectivities and yields, can be further transformed into valuable molecules through for instance catalytic decarboxylative cross-coupling reactions.

Fig. 1

State of the art in conjugate additions to unsaturated carboxylic acids and potential value of addition products. a Fundamental problem that prevents the development of conjugate additions to unprotected unsaturated carboxylic acids: mixing of organometallics with carboxylic acids leads to an acid–base reaction, resulting in a carboxylate salt A nearly unreactive toward further reactions. b Overview of transformations of the carboxylic acid functional group leading to its chiral derivatives and new structural motives: carboxylic acids can undergo straightforward functionalization and decarboxylative cross-coupling reactions

Fig. 2

Reaction development. a Our approach, based on the use of Lewis acid to promote in situ formation of a transient intermediate B that can undergo conjugate addition of organometallic reagent. b Conjugate addition of EtMgBr to the substrate 1a in the absence of chiral catalyst with varying conditions. c Rationalization of the experimental data in entries 1–7 obtained for conjugate addition of EtMgBr in various conditions

Fig. 3

¹H NMR experiments carried out in CD₂Cl₂ at −55 °C using substrate 1b, tBuMe₂SiOTf and MeMgBr. a Crotonic acid 1b. b Mixture of 1b with 2.2 equiv. of tBuMe₂SiOTf. c Isolated pure tBuMe₂Si-ester of 1b. d Mixture of 1b with 2.2 equiv. of tBuMe₂SiOTf followed by addition of 1.0 equiv. of MeMgBr

Fig. 4

Scope of the substrate and Grignard reagent. ^aFor details see Supplementary Information. Isolated yields for all the products are shown. The absolute configuration of the products obtained with (R)-L4 or (R,R)-L5 as the ligands are opposite. ^bReaction conditions: 0.1 M of the substrate in tBuOMe with 5 mol% (R)-L4/CuBr·SMe₂ or in tBuOMe/toluene = 1/1 with 10 mol% (R,R)-L5/CuBr·SMe₂, 2–3 equiv. of Me₃SiOTf and RMgBr. ^cUsing 5 mol% (R,R)-L5/CuBr·SMe₂ as a catalyst in the same condition led to 1a with 93% ee. ^dUsing 5 mol% (R)-L4/CuBr·SMe₂ as a catalyst led to 2e with 57% ee. ^eThe reaction performed using 10 mol% of (R)-L4/CuBr·SMe₂. ^fThe reaction performed at −40 °C

Fig. 5

Synthetic utility of the process. a Ni-catalyzed decarboxylative alkylation and borylation of chiral acid 2k. b Ag-catalyzed decarboxylative bromination of product 3b. c Ag-catalyzed decarboxylative azidation of chiral acid 3h followed by click reaction. d Late-stage functionalization of a RXR antagonist 5a. e Effect of the different procedures on the structure of the final asymmetric conjugate addition of EtMgBr to the carboxylic acid substrate 1l. f Reported synthetic route to a potent 15-lipoxygenase-1-inhibitor 7a. g Synthesis of the derivative 7b in two steps using current methodology. h Synthesis of chiral acid 3c, which is a key intermediate of several natural products. i) HATU, NEt₃, NiCl₂·glyme, 4,4'-di-t-butyl-2,2'-dipyridyl, ZnEt₂, in DMF at RT; ii) N-hydroxyphthalimide, DCC, in CH₂Cl₂ at RT, 2h, then MgBr₂·OEt₂, NiCl₂·6H₂O, 4,4'-dimethoxy-2,2'-bipyridyl, [B₂pin₂Me]Li, in DMF, THF, at 0 °C 1 h ~ RT 1 h; iii) Ag(Phen)₂OTf, dibromoisocyanuric acid, in 1,2-dichloroethane at 60 °C; iv) AgF, K₂S₂O₈, MesSO₂N₃ in CH₃CN, H₂O, at 55 °C; v) phenylacetylene, CuTc, in toluene at RT; vi) CuBr·SMe₂, (R,R)-L2, Me₃SiOTf, MeMgBr, in tBuOMe:Toluene = 1:1, at −20 °C; vii) CuBr·SMe₂, (R)-L1, Me₃SiOTf, EtMgBr, in tBuOMe at −20 °C; viii) CuBr·SMe₂, (R)-L1, nBuLi, Me3SiOTf, EtMgBr, in tBuOMe at −78 °C 2 h ~ RT 16 h; ix) CuBr·SMe₂, (R)-L1, Me₃SiOTf, nHexMgBr, in tBuOMe at −78 °C; x) SOCl₂, DMF (1 drop), in CH₂Cl₂ at RT, 1 h, then ethyl 6-chloro-1H-indole-2-carboxylate, SnCl₄, in CH₂Cl₂, reflux; xi) CuBr·SMe₂, (S,S)-L2, Me₃SiOTf, MeMgBr, in tBuOMe:Toluene = 1:1 at −20 °C