BoPhoz Ligands for Asymmetric Catalysis

Neil Boaz opened the conference with a presentation on work carried out at Eastman on the synthesis and uses of the BoPhoz ligands.  These ligands are similar to the Josiphos ligands developed at Ciba (now Solvias), but the remote phosphorous atom is attached via an amino-phosphorus linkage.  The ligands (1) are prepared from the commercially available Ugi amine (2) which is available from ferrocene in 4 steps (see Scheme 1).

Scheme 1
In the original synthesis the enantiomers of the Ugi amine were separated by resolution with tartaric acid, but this method was found to be low yielding and not robust on scale up, so the biocatalytic route using a kinetic resolution of the ferrocene alcohols was used to separate the enantiomers.  The Rhodium complexes of these ligands have been found to give excellent ee’s and conversions in the hydrogenation of enamides (eq 1), substituted itaconates (eq 2) and a–keto esters (eq 3) with high substrate to catalyst ratios (2500:1 – 10,000:1) and very high catalyst turnover rates (~30,000-50,000h^-1).

Photochemistry - New Light on an Old Problem
In a presentation given by Malcolm Berry of GlaxoSmithKline at Scientific Update’s one day Symposium on Novel Technologies for Future Manufacture of Fine Chemicals, the emphasis was on the potential of the technology.  The group at GSK have concentrated on redesigning the photo-reactor to incorporate modern lasers or systems used in water purification.  They have applied the technology to two projects.

For the photocyclisation below, it was found that UV light was required to isomerise the compound (1) and a rapid acid catalysed cyclisation then took place.

In the early stages of the project, when unpurified (1) was used, no additional acid was required for the cyclisation.  When purified (1) was used, the photoisomerisation took place, but would not cyclise until an acid catalyst was added.

The process was scaled up and kilogram quantities of (2) were produced.

In the second example, the target was to produce a technical synthesis of compound (5) suitable for making 4,000 kg per annum, with a long term expectation of 20,000 kg per annum.  The intended synthetic route required a key cyclisation step of the propynyl ether (3).

Originally a tin induced radical cyclisation of 3 to 4 had been used but a photochemical cyclisation of the type published by Cossy (Tet. Lett, 1994, 35, 8161) was expected to be more environmentally friendly.

A prototype continuous reactor was used to produce 600g/per day (equivalent to 180 kg/annum).

Small scale continuous photolysis was also used to perform the novel cyclisation below.

GSK believe that these methods have tremendous potential and have set up a collaboration with University of Bristol (Andrew Orr-Ewing and Kevin Booker-Milburn).  GSK’s funding has helped to found the University of Bristol Centre for Applied Photochemistry.