Synthesis of C₂‐Symmetric Bisphosphine Ligands from Tartaric Acid, and Their Performance in the Pd‐Catalyzed Asymmetric O‐Allylation of a Phenol

Abstract

Starting from tartaric acid derived chiral diols or dicarboxylic acid dichlorides with either a 2,2-dimethyl-1,3-dioxolane (Taddol) or a 2,3-dimethoxy-2,3-dimethyl-1,4-dioxane (Tatrol) core structure, and BH 3 -protected ortho-phosphanyl phenols, a set of fourteen new C 2 -symmetric diphosphine ligands was synthesized. In addition, three related ligands were obtained from ortho-diphenylphosphino-anilines. The fully characterized ligands were then tested in the Pd-cata-[a] 4316 C 2 -Symmetric Bisphosphine Ligands Figure 3. C 2 -symmetric ether-bridged bisphosphine ligands 23a-23j. Synthesis of Ester-Bridged Bisphosphine LigandsInitially, ester-bridged ligands 25 were synthesized by Steglich esterification [22] [DCC (N,NЈ-dicyclohexylcarbodiimide), DMAP (4-dimethylaminopyridine)] of dicarboxylic acids 24 with the BH 3 -protected phosphanyl-phenols 4, and subsequent borane deprotection with DABCO (Scheme 4). However, the desired ligands (i.e., 25) were obtained only in low yields by this method (Յ15 %). Fortunately, the synthesis could be significantly improved by treating protected phosphanyl-phenols 4 with diacid dichlorides 17 or 21 in the presence of an excess (10 equiv.) of DABCO to give the desired ligands (i.e., 25) directly in up to 50 % yield after chromatographic purification. The reactions only worked well with substrates with small ortho substituents (R = H, n-alkyl). Bulky substituents (R = phenyl, tert-butyl) in the position ortho to the hydroxy group in 4 were not tolerated Scheme 4. Synthesis of ester-bridged bisphosphine ligands 25, a: (i) DCC, 24, DMAP, DMF, room temp., (ii) DABCO, toluene, 50°C, b: DABCO (10 equiv.), 17 or 21, CH 2 Cl 2 , r.t.

Pd‐Catalyzed Asymmetric N‐Allylation of Amino Acid Esters with Exceptional Levels of Catalyst Control: Stereo‐Divergent Synthesis of ProM‐15 and Related Bicyclic Dipeptide Mimetics

“…However, the enantioselectivity was unsatisfactory (e.r.≤83:17) even upon lowering the temperature to −10 °C (entries 2–4). After screening a variety of other chiral ligands (see Table SI‐1 in the Supporting Information), we were pleased to find that some of the C 2 ‐symmetric chiral diphosphine ligands L2 – L8 , recently developed in our laboratory, gave superior results (Figure ).…”

The 15th Frank Warren Organic Chemistry Conference

“…In a continuation of the theme of developing environmentally benign methodologies in his third visit to the conference, Prof. Dr. Hans‐Joachim Knölker walked us through his progress in regioselective iron(III)‐catalyzed intermolecular oxidative coupling of diaryl amines, as well the iron(III)‐catalyzed Wacker type oxidations . Prof. Dr. Hans‐Günther Schmalz gave an account of his group's work in the development of modular chiral P , P ‐ligands, for the enantioselective synthesis of structurally complex marine natural products . Prof. Henok Kinfe used his keynote lecture to exhibit the utility of glycals in synthetic organic chemistry for the construction of complex bioactive heterocycles, while Prof. Gareth Arnott detailed the potential of inherently chiral calixarenes and his journey toward selective derivatization of these molecules .…”

A Short Enantioselective Synthesis of (S)-Levetiracetam through Direct Palladium-Catalyzed Asymmetric N-Allylation of Methyl 4-Aminobutyrate

“…8 Although the Stecko synthesis provides the target 1 with a respectable overall yield, its low step economy 9 reflects the difficulties associated with the direct introduction of suitably functionalized amines in asymmetric allylic substitution reactions. 10,11 Addressing this particular challenge, we recently succeeded in developing a powerful protocol for the Pd-catalyzed asymmetric N-allylation of -amino acid esters by employing a new class of tartaric acid-derived C 2 -symmetric chiral diphosphine ligands, such as (S,S)-iPr-MediPhos (L*), 12 which not only gave rise to high enantioselectivities, but also formed particularly active catalysts (Scheme 2). 7 Here, we describe an adaptation of this methodology in an exceedingly short and efficient synthesis of levetiracetam ( 1), according to the strategy outlined in Scheme 1.…”