Amino Acid-Derived Bifunctional Phosphines for Enantioselective Transformations

Abstract

Even though seminal reports on phosphine catalysis appeared in the 1960s, in the last few decades of the past century trivalent phosphines were viewed primarily as useful ligands for transition-metal-mediated processes. The 1990s saw revived interest in using phosphines in organic catalysis, but the key advances in asymmetric phosphine catalysis have all come within the past decade. The uniqueness of phosphine catalysis can be attributed to the high nucleophilicity of the phosphorus atom. In typical phosphine-catalyzed reactions, nucleophilic attacks of the phosphorus atom on electron-deficient multiple bonds create different reactive ylide-type intermediates. When such structurally diverse zwitterionic species react with a variety of suitable substrates, new reaction patterns are often discovered and a diverse array of reactions can be developed. In recent years, substantial progress has been made in the field of asymmetric phosphine catalysis; many new reactions have been discovered, and numerous enantioselective processes have been reported. However, we felt that powerful and versatile phosphine catalysts that can work for a wide range of asymmetric reactions are still lacking. We therefore set our goal to develop a family of easily derived phosphine catalysts that are efficient in asymmetric induction for a broad range of phosphine-mediated transformations. This Account describes our efforts in the past few years on the development of amino acid-based bifunctional phosphines and their applications to enantioselective processes. Building upon our previous success in primary-amine-mediated enamine catalysis, we first established that bifunctional phosphines could be readily prepared from amino acids. In most of our studies, we chose threonine as the key backbone for catalyst development, and threonine-based monoamino acid or dipeptide bifunctional phosphines have displayed remarkable stereochemical control. We began our investigations by demonstrating the usefulness of our phosphine catalysts in aza-Morita-Baylis-Hillman (aza-MBH) and MBH reactions. We then showed the great power of amino acid/dipeptide phosphines in a wide range of [3 + 2] annulation processes, including [3 + 2] cycloaddition of allenoates to acrylates/acrylamides, [3 + 2] annulation of imines with allenoates, and [3 + 2] cyclization employing MBH carbonates and activated alkenes. By utilizing α-substituted allenoates and activated alkenes, we developed an enantioselective [4 + 2] annulation to access functionalized cyclohexenes. We also devised a novel enantioselective [4 + 2] annulation process by using α-substituted allenones for the construction of 3,4-dihydropyrans. With the use of β'-acetate allenoate, a [4 + 1] annulation process has been designed to access chiral spiropyrazolones. Another array of reactions that make use of the basicity of zwitterionic phosphonium enolate intermediates have been successfully attained, including the first phosphine-catalyzed asymmetric Michael addition, enantioselective allylic substitution of MBH carbo...

Atroposelective Phosphoric Acid Catalyzed Three‐Component Cascade Reaction: Enantioselective Synthesis of Axially Chiral N‐Arylindoles

“…[6,15] Thus, to demonstrate the utility of this new axially chiral Narylindole scaffold, 4gva was reduced to the axially chiral monophosphine 10 with complete retention of enantiopurity (87 % ee)u sing HSiCl 3 (Scheme 5). [6,15] Thus, to demonstrate the utility of this new axially chiral Narylindole scaffold, 4gva was reduced to the axially chiral monophosphine 10 with complete retention of enantiopurity (87 % ee)u sing HSiCl 3 (Scheme 5).…”

Enantioselective γ‐Addition of Pyrazole and Imidazole Heterocycles to Allenoates Catalyzed by Chiral Phosphine

“…Over the past decade,e nantioselective phosphine-catalyzed g-addition reaction has emerged as an important transformation, [8] enabling the addition of av ariety of nucleophiles,s uch as oxygen, [9] carbon, [10] sulfur, [11] and basic nitrogen [12] nucleophiles,t oa llenoates in av ery straightforward manner. [13] However,abrief survey of the literature reveals that direct phosphine-catalyzed asymmetric N-g-additions of nitrogen heterocycles containing acidic NÀH bond are very rare.…”

“…[12a] To improve the E/ Z selectivity,wefurther optimized the reaction conditions by varying the additives (entries [5][6][7][8][9]. Indeed, the Fu group has reported the phosphine 4d-catalyzed asymmetric g-addition of nitrogen nucleophilies to allenoates.…”

Phosphine‐Catalyzed (3+2) Annulation of Isoindigos with Allenes: Enantioselective Formation of Two Vicinal Quaternary Stereogenic Centers

“…[6] We thus set our goal to develop enantioselective annulation reactions making use of tetrasubstituted alkenes as ar eaction partner, for the efficient construction of molecular architectures containing two contiguous all-carbon quaternary stereogenic centers. [9n-s] Given the importance of HPI alkaloids family,there clearly exists aneed to develop efficient catalytic asymmetric synthetic approaches for facile and versatile synthesis of these molecules and their structural analogues.I nc onnection to our disclosure of amino-acid-derived bifunctional phosphines and their applications in asymmetric synthesis, [10] we envisioned that the core bispyrrolidino [2,3-b]indoline structure in HPI alkaloids [11] may be conveniently constructed by employing an isoindigo,a sastarting substance,i nap hosphine-catalyzed (3+ +2) annulation with an allene.W hereas the idea of installing two vicinal all-carbon quaternary stereocenters at the C 3a and C 3a' through as ingle-step operation was very appealing to us,wewere mindful that tetrasubstituted alkenes are inherently sterically encumbered and have never been utilized in phosphine-catalyzed asymmetric (3+ +2) annulation processes.W er easoned that the two oxindole moieties may provide sufficient activation to the internally buried double bond, and the planar oxindole structures may be less sterically demanding and thus makes this otherwise extremely difficult reaction feasible.H erein, we document an unprecedented (3+ +2) annulation between isoindigos and allenes for highly enantioselective creation of structures containing two vicinal quaternary stereogenic centers. [7] In this context, we were attracted to dimeric and polymeric hexahydropyrroloindole (HPI) alkaloids, [8] as tructurally and biologically fascinating class of cyclotryptamine alkaloids with ac enterpiece bispyrrolidino- [2,3-b]indoline bearing two sterically congested adjacent allcarbon quaternary stereogenic centers at C 3a and C 3a' .Afew selected HPI alkaloids are illustrated in Scheme 2.…”