DIPAMP synthesis

The most effective catalysts for enantioselective amino acid synthesis are coordination complexes of rhodium(I) with 1,5-cyclooctadiene (COD) and a chiral diphosphine such as (JR,jR)-l,2-bis(o-anisylphenylphosphino)ethane, the so-called DiPAMP ligand. The complex owes its chirality to the presence of the trisubstituted phosphorus atoms (Section 9.12). 

Perhaps the one major drawback with DIPAMP is the long synthetic sequence required for its preparation, though shorter and cheaper methods are now available [12]. The ligand continues to be a player for the synthesis of amino acid derivatives at scale, including L-Dopa, as mentioned above [12, 25, 27-29]. Its continued use is a testament to the power of the initial discoveries, as well as showing that a chemical catalyst can achieve selectivities only previously seen with enzymes. 

DIPAMP-Rh complex to give the corresponding chiral a-amino acid derivative in over 98% ee. The chiral product has been used for the synthesis of (S)-(-)-ac-romelobic acid [88]. Hydrogenation of a tetrahydropyrazine derivative catalyzed by a PHANEPHOS-Rh complex at -40"C gives an intermediate for the synthesis of Crixivan in 86% ee [82a]. Hydrogenation of another tetrahydropyrazine carboxamide derivative catalyzed by an (R)-BINAP-Rh catalyst leads to the chiral product in 99% ee [89]. 

A Rh-dipamp complex was later applied by NSC Technologies for the manufacture of several unnatural amino acids with good catalyst performances (ee 95-98%, TON 5000-20000) [30] and was also very selective but with low activity (ee 98%, TON 20) in a feasibility study for a synthesis of acromelobic acid by Abbott Laboratories [31]. 

Chapter 2 to 6 have introduced a variety of reactions such as asymmetric C-C bond formations (Chapters 2, 3, and 5), asymmetric oxidation reactions (Chapter 4), and asymmetric reduction reactions (Chapter 6). Such asymmetric reactions have been applied in several industrial processes, such as the asymmetric synthesis of l-DOPA, a drug for the treatment of Parkinson s disease, via Rh(DIPAMP)-catalyzed hydrogenation (Monsanto) the asymmetric synthesis of the cyclopropane component of cilastatin using a copper complex-catalyzed asymmetric cyclopropanation reaction (Sumitomo) and the industrial synthesis of menthol and citronellal through asymmetric isomerization of enamines and asymmetric hydrogenation reactions (Takasago). Now, the side chain of taxol can also be synthesized by several asymmetric approaches. 

Uemura, T., Zhang, X.Y., Matsumura, K., Sayo, N., Kumobayashi, H., Ohta, T., Nozaki, K. and Takaya, H. J. Org. Chem., 1996, 61, 5510 a classical example is the Monsanto synthesis of (l)-DOPA using ruthenium complexed with the diphosphine DIPAMP, see Classics in Total Synthesis, Nicolaou, K.C. and Sorensen, E.J. VCH, Weinheim, 1996. 

L-Dopa was produced industrially by Hoffrnann-LaRoche, using a modification of the Erlenmeyer synthesis for amino acids. In the 1960s, research at Monsanto focused on increasing the L-Dopa form rather than producing the racemic mixture. A team led by William S. Knowles (1917—) was successful in producing a rhodium-diphosphine catalyst called DiPamp that resulted in a 97.5% yield of L-Dopa when used in the Hoffrnann-LaRoche process. Knowles s work produced the first industrial asymmetric synthesis of a compound. Knowles was awarded the 2001 Nobel Prize in chemistry for his work. Work in the last decade has led to green chemistry synthesis processes of L-Dopa using benzene and catechol. 

Homogeneous asymmetric hydrogenation is a practical synthetic method (27). The DIPAMP-Rh-catalyzed reaction has been used for the commercial production of (S)-DOPA [(5)-3-(3,4-dihydroxy-phenyl) alanine] used to treat Parkinson s disease (Monsanto Co. and VES Isis-Chemie) (Scheme 12) (27, 28). (S)-Phenylalanine, a component of the nonnutritive sweetener aspartame, is also prepared by en-antioselective hydrogenation (Anic S.p.A. and Enichem Synthesis) (29). A cationic PNNP-Rh(nbd) complex appears to be the best catalyst for this purpose (15c) (see Scheme 5 in Chapter 1). 

As many endeavors in transition-metal catalysis, the design, synthesis and screening of chiral ligands have played a pivotal role in the development of the asymmetric allylic alkylation reaction. A series of C2-symmetric diphosphines such as DiPAMP, chiraphos, DIOP. and BINAP,... 

Catalytic asymmetric hydrogenation processes have been at the forefront of practical applications. Following the classical Monsanto s L-DOPA production using DiPAMP-Rh catalyst, BINAP-Ru catalysts have been used in the industrial synthesis of a P-lactam key intermediate to caibapenem antibiotics (Takasago Int. Corp.), 1,2-propanediol (50 tons/year),... 

The advantages and disadvantages of Rh(DIPAMP) are summarized in Table 12.1. The catalyst precursor, 13, is air-stable, which simplifies handling operations on a manufacturing scale. Despite these advantages, ligand synthesis is very difficult. After the initial preparation of menthylmethyl-phenylphosphinate (16), the (/f),-isomer is separated by two fractional crystallizations (Scheme... 

Other routes to A .A -DIPAMP (2) have been reported.2 31 At present, the most practical synthesis of DIPAMP involves the formation of a single diastereoisomer of 18 by the combination of PhP(NEt2) 2 and (-)-ephedrine followed by formation of the borane adduct (Scheme 12.3).29,32,33... 

The cost of the ligand and catalyst preparation can be critical in the decision to pursue technical transfer to manufacturing stage. Fortunately, the high reactivity of [Rh(COD)(/ ,/ -DIPAMP)]+BF4-(13) in most enamide reductions can offset the high price, low yield synthesis of DIPAMP. 

Rh(COD)(/ ,/ -DIPAMP)]+BF4- (13) has shown remarkable activity and enantioselectivity in the asymmetric hydrogenation of various enamides, enol acetates, and unsaturated olefins.20 26 For the past 20 years, 13 has been the premier asymmetric homogeneous catalyst for amino acid synthesis, but a new generation of catalysts based on novel bisphosphines (vide infra) has surpassed it in versatility. 

Fig. 6.21. Synthesis of L-DOPA with the cationic Rh-DiPAMP catalyst.

Reduction of the enamide double bond of a-(acylamino)acrylic acid 6.16 with Rh complex of diphosphine ligand DIPAMP (5.2) is an important step in the synthesis of L-DOPA (6.17), used for the treatment of Parkinson s disease. 

What is happening in stereochemical terms in this sequence of reactions What is the other product from the crystallisation from hexane The product is one enantiomer of a phosphine oxide. If you wanted the other enantiomer, what would you do Revision. This phosphine oxide is used in the synthesis of DIPAMP, the chiral ligand for asymmetric catalytic hydrogenation... 

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