Scalable Route to Chiral Phosphoramidites

The chiral copper-catalyzed conjugate addition is a well-developed methodology to create asymmetric C-C bonds. Many efforts have been dedicated to design efficient systems and identifying highly efficient ligands. Among the most proficient ligands, the ones possessing a bis-phenol or a bis-naphthol moiety are the most prominent. Herein we describe a scalable convenient route that can afford phosphoramidites in excellent yield. Figure 1. General structure and application of phosphoramidites


Introduction
The engagement of chiral phosphoramidites as ligands in enantioselective copper-catalyzed conjugate carbon-carbon bond formation using organozinc reagents has become an essential tool in the hands of a synthetic chemist (Ferringa, 2000).A series of chiral ligands have been prepared, particularly the preparation of ligand 3 has been described in the literature (Vuagnoux-d'Augustin et al;2007) and is shown in Scheme 1.This ligand was used in the copper mediated asymmetry-inducing step in a production of taxadienone (Mendoza et al., 2012).However, during the process optimization route of taxadienone (Krasutsky et al., 2015) a substantial quantity of this intermediate was required and thus it was highly desirable to develop a method for preparation of ligand 3 that minimized the purification efforts as well as improved the overall yield of the product.The process described within this paper eliminated the silica gel chromatography step and provided a more convenient and efficient approach to chiral phosphoramidites.

Results and Discussion
Since bis-phenol 2 was not commercially available, a convenient route to make it was also desired.Although compound 2 is known in the literature (Neelamegam et al., 2010) a simple purification method was essential to obtain high quality material.Complete conversion of 1 to 2 was observed when 1.2 eq. of persulfate was used.The reported purification procedure using silica column purification did not purge closely eluting impurities.Instead, we found that the product can be crystallized from MTBE/heptanes in 60% yield.Scheme 1. Preparation of bis-phenol 2 and corresponding phosphoramidite ligand 3.
The second reaction, formation of phosphoramidite 3, was reported to proceed in THF (Vuagnoux-d'Augustin et al;2007).However, the reaction was plagued by the precipitation of salts and incomplete conversion.As a result, the decision was made to run the reaction in dichloromethane instead of THF.This change allowed the reaction to exist as a homogeneous solution.The order of addition was also investigated.When phosphorus trichloride was reacted with the bis-phenol 2 prior to the chiral amine addition, the reaction required substantial additional time due to the decreased reactivity of bis-phenoxy phosphino-chloride intermediate.Conversely, when the amine was added prior to the addition of bis-phenol 2, the desired product was formed in 2 hours and was isolated in 86% yield (the optimal stoichiometric ratio was found to be chiral amine:PCl3:bis-phenol 2 0.95:1:1).An alumina plug was used for the purification.The reaction was scaled up to 10 g of the chiral amine to give a quantitative yield of phosphoramidite 3. Encouraged with this result, we extended this strategy to prepare bis-naphthyl phosphoramidite 5 (Scheme 2).This catalyst was found to be useful for iridium catalyzed amination of allylic carbonates (Leitner et al., 2004).Scheme 2. Preparation of bis-naphthyl phosphoramidite 5.
The reaction proceeded as expected and the ligand 5 was obtained in quantitative yield.This result demonstrated the overall usefulness of this methodology.

Experimental
Chemical materials, solvents, and reagents were reagent grade and were used without further purification unless otherwise noted.Reaction progress was monitored using analytical thin-layer chromatography (TLC) on 0.25-mm Merck F-254 silica gel glass plates.Visualization was achieved by UV light (254 nm). 1 H NMR, 13 C NMR and 31 P spectra were recorded with a Bruker AVANCE 500 MHz spectrometer; chemical shifts were reported in parts per million (δ) using TMS as the internal standard with coupling constants (J) reported in hertz (Hz).

Conclusion
Herein we described a useful procedure to prepare chiral phosphoramidites in excellent yield.The process described within this paper eliminated the silica gel chromatography step and provided a more convenient and efficient procedure to chiral phosphoramidites.