Syntheses of Novel Chiral Monophosphines, 2,5-Dialkyl-7-phenyl-7-phosphabicyclo- [2.2.1]heptanes, and Their Application in Highly Enantioselective Pd-Catalyzed Allylic Alkylations.

Design and synthesis of chiral phosphines have played a significant role in the development of transition metal catalyzed asymmetric reactions.1 Many excellent chiral bidentate phosphines such as DIPAMP,2 DIOP,3 Chiraphos,4 and BINAP5 have been developed for a variety of catalytic reactions. Recent additions to this family of ligands include the Duphos and BPE species of Burk and co-workers.6 The most significant characteristics of Duphos and BPE are (1) they contain several alkyl groups attached to the phosphine and thus are more electron rich than many related chiral arylphosphine ligands and (2) the steric environment can be varied by changing the substituents on the chiral carbon centers. Highly enantioselective reactions have been reported with these ligands.6 Despite these successes, one potential problem is the conformational flexibility that exists in these ligands which may limit their applicability to other types of reactions. It is well-known that rapid interconversion of the envelope and half-chair conformations can occur in five-membered rings. We now report new chiral phosphines with rigid fused bicyclic rings which do not possess the conformational flexibility associated with the five-membered rings present in the Duphos and BPE ligands (Figure 1). The rigid fused bicyclic [2.2.1] structure represents a new motif in chiral ligand design. Analogous to Burk’s systems, changes in the size of the R group on the ring system can modulate the asymmetric induction and high enantioselectivities can be achieved. Herein, we report the syntheses of chiral monophosphines with this fused bicyclic ring structure (Figure 2)7 and their application in Pd-catalyzed asymmetric allylic alkylations. The ligand synthesis depends on the availability of enantiomerically pure cyclic 1,4-diols. Halterman8 and Vollhardt9 have previously prepared chiral cyclopentadiene derivatives from the chiral diols.8,9 Halterman8 has synthesized chiral diols 1 and 2 from the inexpensive starting materials p-xylene and p-diisopropylbenzene, respectively. The synthesis employed Birch reduction,10 followed by asymmetric hydroboration11 and recrystallization to 100% ee. Conversion of the optically pure diols to the corresponding mesylates proceeds cleanly. Nucleophilic substitution by Li2PPh on the chiral dimesylates 3 and 4 generated the corresponding bicyclic phosphines, which were trapped by BH3‚THF to form the air-stable boron-protected monophosphines 5 and 6, respectively. Deprotection with a strong acid12 produces the desired products (7, (1R,2S,4R,5S)-(+)-2,5-dimethyl7-phenyl-7-phosphabicyclo[2.2.1]heptane; 8, (1R,2R,4R,5R)(+)-2,5-diisopropyl-7-phenyl-7-phosphabicyclo[2.2.1]heptane) in high yields.