PAMP ligand

H,H)-D PAMP-Rh complex, 95% ee Figure 3.27 a Chemical structure and 3D representation of l-DOPA b of the chiral ligands tested by Monsanto with their corresponding ee values cthe Rh complex used in the large-scale commercial process. 

LPS), monophosphoryl lipid A, and CpG DNA. These substances contain pathogen-associated molecular patterns (PAMPs) that are recognized by and stimulate cells of the immune system. Many of these substances, for example, LPS, have been discovered to act as ligands for Toll-like receptors (TLR). These receptors are expressed on APC, recognize highly conserved motifs on bacteria and viruses, and mediate APC activation. Vaccine developers are now focusing... 

N-acetylphenylalanine methyl ester during MAC hydrogenation in methanol solvent [C. R. Landis and J. Halpern, J. Am. Chem. Soc., 109 (1987) 1746]. The DI-PAMP coordinates to the rhodium through the phosphorus atoms and leaves plenty of space around the Rh cation for other molecules to bind and react. The unique feature of this system is that the chirality of the DIPAMP ligand induces the high stereoselectivity of the product molecules. An analogous nonchiral ligand on the Rh cation produces a catalyst that is not enantioselective. 

Shortly afterwards, we came up with our own chelating bisphosphane ligand, by dimerizing PAMP through another Mislow procedure. We called it DIPAMP, and chirality resided on the phosphorus atom. DIPAMP worked at about 95% ee in our L-dopa system and we quickly converted our commercial process to be able to use it. Part of our motivation to make a quick change was that DIPAMP was easier to make than CAMP, and, in addition, it was a nice, crystalline air-stable solid (Fig. 7). 

The catalyst precursor, 1, is air-stable which simplifies handling operations on a manufacturing scale. Despite these advantages, ligand synthesis is very difficult. After the initial preparation of menthylmethylphenylphosphinate (6), the (R)P-isorrier is separated by two fractional crystallizations (Fig. 6). The yield of (R,R)-DI-PAMP (8) is 18% based on 7 [9]. Another disadvantage is that the (R.R)-DIPAMP can racemize at 57 °C, which can be problematic since the last step is performed at 70 °C. Once the ligand is coordinated to rhodium, however, racemization is no longer a problem. 

The arylation of secondary phosphines 201 with ortho-aiy iodides, catalyzed by generated in situ complex Pda (dba>3 x CHQ3, containing chiral ligand Et,Et-FerroTANE 207 and LiBr, led to the formatiOTi of corresponding tertiary phosphines with enantioselectivity of 90% cc [ 132,137]. The palladium complex 209 also showed high enantioselectivity in arylation of secondary phosphines [131,132]. Some examples of arylation reaction of secondary phosphines with low ee were described. The asymmetric arylation of phosphine boranes with anisyl iodide, catalyzed by chiral complex of oxazoline phosphine 208, led to the formation of enantiomerically enriched tertiary phosphines 206 with 45% ee [134]. The Pd complex 210 of (R )-t-Bu-JOSlPHOS ligand catalyzed arylation of PH(Me)(Ph)(BH3) by o-anisyl iodide with the formation of PAMP-BH3 with 10% ee (Table 3) [112]. 

Moncarz JR, Brunker TJ, Jewett JC, Orchowski M, Glueck DS, Sommer RD, Lam K-C, Incarvito CD, Concolino TE, Ceccarelli C, Zakharov LN, Rheingold AL (2003) Palladium-catalyzed asymmetric phosphination. enantioselective synthesis of PAMP-BH3, ligand effects on catalysis, and direct observation of the stereochemistry of transmetalation and reductive elimination. Organometallics 22 3205-3221... 

Pizzano and co-workers also used the carboxylic acid derived from (5)-PAMP BH3 to prepare a P-stereogenic phosphine phosphite ligand (Scheme 4.36). 

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