Intermolecular Stereoselective Iridium-Catalyzed Allylic Alkylation: An Evolutionary Account

Abstract

Our lab has long been interested in the development of methods for the creation of enantioenriched all-carbon quaternary stereocenters. Historically, our interest has centered on palladium-catalyzed allylic alkylation, though recent efforts have moved to include the study of iridium catalysts. Whereas palladium catalysts enable the preparation of isolated stereocenters, the use of iridium catalysts allows for the direct construction of vicinal stereocenters via an enantio-, diastereo-, and regioselective allylic alkylation. This account details the evolution of our research program from inception, which focused on the first iridium-catalyzed allylic alkylation to prepare stereodyads containing a single quaternary center, to our most recent discovery that allows for the synthesis of vicinal quaternary centers.

Keywords: allylic alkylation; asymmetric catalysis; enantioselective; iridium; quaternary stereocenters; umpolung.

Figure 1

Stoltz group contributions to palladium-catalyzed allylic alkylation methodology and application in natural product total synthesis

Figure 2

Stereodyad-containing natural products as inspiration for the development of novel iridium-catalyzed allylic alkylation technology

Figure 3

Timeline for the development of iridium-catalyzed allylic alkylation prior to the Stoltz group’s entry into the field

Figure 4

Select examples of diverse product transformations of enantio- and diastereoselective iridium-catalyzed allylic alkylation products 51^{a a}Conditions: (a) pyrrolidine, AcOH, t-BuOMe, reflux, 95% yield. (b) Co₂(CO)₈, CH₂Cl₂, then Me₃NO×2H₂O, >20:1 dr, 99% yield. (c) HG-II (10 mol %), CH₂Cl₂, 40 °C, 96% yield. (d) i) allylmagnesium chloride, THF, −78 °C, 71% yield, ii) HG-II, CH₂Cl₂, 81% yield, iii) K₂OsO₄, NMO, THF/H₂O, 59% yield. (e) Me₃S(O)I, NaH, DMSO, 82% yield. (f) K₂OsO₄, NMO, THF/H₂O, 65% yield.

Figure 5

Iridium-catalyzed allylic alkylation strategies

Figure 6

Limitations in enantioselective iridium-catalyzed allylic alkylation prior to 2017

Figure 7

Enantioselective synthesis of acyclic α-quaternary esters 84 and amides 85

Figure 8

Product derivatizations of iridium-catalyzed allylic alkylation products 88 bearing vicinal all-carbon quaternary centers ^aConditions: (a) RhCl(PPh₃)₃, H₂ (balloon), benzene, 23 °C, 18 h, 92% yield. (b) O₃, pyridine, CH₂Cl₂, −78 °C, 4 min, 93% yield. (c) i. O₃, pyridine, CH₂Cl₂, −78 °C, 4 min, ii. p-TsOH, benzene, reflux, 18 h, 47% yield. (d) NaOH, EtOH/H₂O (1:1), 60 °C, 18 h, 38% yield. 1:11 dr. (e) i. O₃, MeOH,−78 °C, 0.5 h, ii. NaBH₄, 0 °C, 3 h, 65% yield, 1:2.5 dr.

Scheme 1

Enantio- and diastereoselective iridium-catalyzed allylic alkylation of cyclic nucleophiles 27, ^aReaction performed with (S,S_a)-L6 without LiBr.

Scheme 2

Iridium-catalyzed allylic alkylation/Cope rearrangement sequence

Scheme 3

Enantio- and diastereoselective Iridium-catalyzed allylic alkylation of acyclic nucleophiles 36

Scheme 4

Enantio- and diastereoselective iridium-catalyzed allylic alkylation reactions with crotyl chloride (46)

Scheme 5

First report of MAC reagent 65 in an asymmetric transition metal-catalyzed reaction

Scheme 6

Enantioselective synthesis of acyclic α-quaternary carboxylic acids 78

Scheme 7

Synthesis of vicinal all-carbon quaternary centers 88 via enantioselective iridium-catalyzed allylic alkylation