Abstract
We report the development of a method to diastereoselectively access tetrasubstituted alkenes via nickel-catalyzed Suzuki-Miyaura cross-couplings of enol tosylates and boronic acid esters. Either diastereomeric product was selectively accessed from a mixture of enol tosylate starting material diastereomers in a convergent reaction by judicious choice of the ligand and reaction conditions. A similar protocol also enabled a divergent synthesis of each product isomer from diastereomerically pure enol tosylates. Notably, high-throughput optimization of the monophosphine ligands was guided by chemical space analysis of the kraken library to ensure a diverse selection of ligands was examined. Stereoelectronic analysis of the results provided insight into the requirements for reactive and selective ligands in this transformation. The synthetic utility of the optimized catalytic system was then probed in the stereoselective synthesis of various tetrasubstituted alkenes, with yields up to 94% and diastereomeric ratios up to 99:1 Z/E and 93:7 E/Z observed. Moreover, a detailed computational analysis and experimental mechanistic studies provided key insights into the nature of the underlying isomerization process impacting selectivity in the cross-coupling.
Highlights
While key progress in this field has been achieved by employing traditional olefination methods, these transformations often suffer from low atom-economy and poor stereoselectivity.[20,21,22,23]
The diastereo-convergent reaction is highlighted in this report due to its synthetic utility, as it obviates the need for stereoselective starting material preparation, which is challenging for the corresponding (Z)-configured enol tosylates.[47]
At the outset of the investigation, preliminary experimental data indicated that monophosphine ligands effectively promoted a nickel(0) cross-coupling of enol tosylate 1a and pinacol boronate 2a to access representative tetrasubstituted alkene diastereomers 3aa (Figure 2A, see SI for details)
Summary
Molecules with all-carbon tetrasubstituted alkene structural motifs, such as the estrogen receptor modulators tamoxifen and idoxifene,[1,2,3,4] amongst others (Figure 1A), have displayed significant biological activity and found widespread applications in the pharmaceutical industry.[5,6,7,8,9] their unique photoand electrochemical properties have rendered them useful for molecular switches[10,11] and material science.[12,13,14] Despite this rising demand, the stereoselective synthesis of tetrasubstituted alkenes has been a longstanding challenge and as a result only a few synthetic approaches have been reported in recent years.[15,16,17,18,19] While key progress in this field has been achieved by employing traditional olefination methods, these transformations often suffer from low atom-economy and poor stereoselectivity.[20,21,22,23] One of the most commonly applied synthetic strategies is the carbometalation of internal alkynes, followed by a metal-catalyzed cross-coupling.[24,25,26,27,28] This elegant approach has set the stage for a plethora of useful tetrasubstituted alkene syntheses, but is often associated with serious limitations regarding stereocontrol and functional group tolerance. We report a ligand-controlled Ni-catalyzed synthesis of stereodefined tetrasubstituted alkenes from either a single enol tosylate diastereomer in a stereodivergent process, or, alternatively, from a diastereomeric mixture of starting materials in a stereoconvergent manner (Figure 1C). The diastereo-convergent reaction is highlighted in this report due to its synthetic utility, as it obviates the need for stereoselective starting material preparation, which is challenging for the corresponding (Z)-configured enol tosylates.[47] An optimization study was designed4852 by using kraken, a computational database of >1500 phosphorus ligand descriptors, to identify a diverse set of phosphines to evaluate, which enabled the identification of reaction conditions for Ni-catalyzed Suzuki-Miyaura cross-coupling.5355. The unique mechanistic features of this catalytic transformation contrast the thermodynamic control of previously developed convergent cross-couplings for the synthesis of di- and trisubstituted alkenes, which typically proceed via metal-hydride catalyzed isomerizations.[56,57,58] Our mechanistic hypothesis is supported by a combination of DFT calculations and experimental insights to shed insight into the elusive isomerization step that has previously been observed in several cross-coupling reactions of alkenyl electrophiles.[46,53,59]
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