Stereoselective Installation of Five Contiguous Stereogenic Centers in a Double Aldol–Tishchenko Cascade and Evaluation of the Key Transition State through DFT Calculation

Abstract

The stereoselective formation of 5 contiguous chiral centers in a single pot reaction is demonstrated using an aldol, aldol–Tishchenko reaction of N - tert -butyl sulfinimines. One diastereoisomer (from 32 possibilities) predominates, and a series of cyclic and acyclic 3-amino-1,5-diol derivatives are synthesized in good yields (up to 80%) and excellent diastereoselectivities (up to >98:2 dr). Investigations support two reversible aldol steps, and multiple intermediates which are funnelled through a remarkably selective, irreversible, Tishchenko reduction, in a Curtin–Hammett phenomenon. DFT calculations using a disolvated (THF) model reveal the factors controlling stereoselectivity in the final irreversible Tishchenko step.

The Aldol‐Tishchenko Reaction of Butanone, Cyclobutanone and a 3‐Pentanone Derived Sulfinylimine and DFT Calculations of the Stereo‐determining Step

“…The crude product was purified by column chromatography on silica gel (4 : 1 hexane : EtOAc) to yield the title compound as a pale yellow oil (0.61 g, 35 %). Spectroscopic characteristics were consistent with previously reported data [31] Synthesis of butanone derived 3-amino-1,5-diol precursors: To a Schlenk tube under N 2 atmosphere containing diisopropylamine (1.2 equiv.) and anhydrous THF (5 mL/mmol of sulfinylimine) was added n-BuLi (1.26 M in hexanes, 1.1 equiv.)…”

“…Our previous calculations of related reactions show that the stereodetermining step is the intramolecular hydride transfer to reduce the imine to the corresponding amine. [30,31] This one transition state (TS) controls the stereochemistry at each newly formed carbon centre, as all previous steps are reversible. Thus, we compared the relative TS barriers for intramolecular hydride transfer to form different diastereomers.…”

“…This decision was based on the lowest-energy TSs observed for the cycloheptanone derived substrates. [31] For the butanone derived substrate, the second-lowest energy TS led to the product with opposite stereochemistry at the hydroxy group. The difference between the two lowest-energy TSs (TS1a and TS2a) was 1.7 kcal/mol.…”

“…[28][29][30] This was then further expanded to include a double aldol-Tishchenko reaction procedure, ultimately allowing access to highly enantio-and diastereomerically enriched 3-amino-1,5-diol derivatives (Scheme 1). [31] Herein, we describe further expansion of the double aldol-Tishchenko reaction of cyclic and acyclic chiral sulfinylimines, to include butanone, cyclobutanone and 3-pentanone derivatives. These highly functionalized compounds have great potential for synthetic utility, for example, as important medicinal scaffolds and effective chiral ligands, due to the number potential anchor-points present.…”

Stereocontrolled Construction of Acyclic Quaternary Carbon Centers via α-Hydroxymethylation of α-Branched N-tert-Butanesulfinyl Ketimines

“…We also examined the reactions of N - t BS imines derived from α,α-aryl,alkyl acetophenones, and we obtained both diastereomers of the corresponding hydroxymethylation products ( 3s / 3t and 3u / 3v ) with good diastereoselectivities (>20:1 dr) . These results indicate that, under our reaction conditions, the metalloenamine intermediate did not convert from geometric isomer Z to the thermodynamically preferred isomer E .…”