A-dehydroamino ester

Fig. 12.17 Agostic dihydride intermediate derived from a dehydroamino ester substrate.

Fig. 31.10 Comparison of rate (schematic) and enantioselec-tivity for mono- and bidentate phosphorus ligands on 1 mM scale, (a) a-Dehydroamino ester, 2 bar H2 (b) jS-dehydroami-no ester, 10 bar H2.

A type Ilac synthesis of functionalized pyrroles was developed that adapted the Larock indole synthesis <06OL5837>. For example, treatment of iodoacrylate 19 and trimethylsilylphenylacetylene 20 with palladium acetate led to the formation of pyrrole-2-carboxylate 21 with excellent regioselectivity. 19 was prepared by iodinating (N-iodosuccinimide) the corresponding commercially available dehydroamino ester. 

Table 2 Asymmetric hydrogenation of / ,/3-dimethyl a-dehydroamino acid esters...

A different variation on this theme has been developed by Ito, where the TRAP ligands (37) form a nine-membered metallocycle [157-162]. The ruthenium catalysts seem to function best at low pressures, but highly functionalized dehydroamino esters can be reduced with high degrees of asymmetric induction [157, 159-164], as well as indoles [165]. 

Several accounts have described (Z)-dehydroamino acid esters as being less active than the corresponding (F)-isomer [59c, 143-145]. In fact, Bruneau and Demonchaux reported that when reduction of an (E/Z)-mixture of 73 with Rh-Et-DuPhos in THF was not complete, only unreacted (Z)-73 was detected. These findings conflict, however, with results obtained in MeOH [56 d], where the ligand structure was also found to be significant to the relative reactivity of each stereoisomer. As for a-dehydroamino acid derivatives, preformed metal-diphosphine complexes generally perform in superior fashion to those prepared in situ [56d]. 

Many synthetic applications of Rh-catalyzed hydrogenation of a-dehydroamino acid derivatives have recently been explored (Scheme 26.2). Takahashi has reported a one-pot sequential enantioseiective hydrogenation utilizing a BINAP-Rh and a BINAP-Ru catalyst to synthesize 4-amino-3-hydroxy-5-phenylpentanoic acids in over 95% ee. The process involves a first step in which the dehydroami-no acid unit is hydrogenated with the BINAP-Rh catalyst, followed by hydrogenation of the / -keto ester unit with the BINAP-Ru catalyst [87]. A hindered pyridine substituted a-dehydroamino acid derivative has been hydrogenated by a... 

The hydrogenation of />,/>-disubsti tilled a-dehydroamino acids remains a relatively challenging problem. The Rh complexes of chiral ligands such as Cy-BisP [58a], MiniPhos [65], and unsymmetrical BisP 13 [67b] have shown high efficiencies for some / ,/ -disubstituted a-dehydroamino acid substrates. Some efficient examples of hydrogenation of / ,/1-dimethyl a-dehydroamino acid esters with different chiral phosphorus ligands are listed in Table 26.2. 

It transpires that most classes of monodentate ligands include members that are able to induce high enantioselectivity in the hydrogenation of the two benchmark substrates 52 a and 53 a. It is not clear whether their corresponding acids 52b and 53 b have been studied or, alternatively, if the authors decided not to include (disappointing) ee-values. For phosphoramidite MonoPhos (29 a), however, the ee-values are invariably excellent. Overall, the TOFs range from 50 to 170 IT1, but have not been optimized in most cases. Unfortunately, with one exception [87], the hydrogenation of dehydroamino esters in which R1 is a (functionalized) alkyl substituent has not been studied, probably because of their difficult accessibility. 

Figure 1.3. Catalytic hydrogenation of A-acylated dehydroamino esters via an unsatu-rated/dihydride mechanism the p substituents in the substrates are omitted for clarity [P-P = (i ,R)-DIPAMP, (i ,i )-CHIRAPHOS, or (R)-BINAP S = solvent or a weak ligand].

Several chiral phosphorous ligands with great structural diversity are effective for the rhodium-catalyzed hydrogenation of a-dehydroamino acid derivatives. Tab. 1.1 summarizes the asymmetric hydrogenation of (Z)-2-(acetamido)ciimamic acid, 2-(acetamido)acrylic acid, and their methyl ester derivatives. 

A further step was taken when first Halpern [28] and then Brown [29] were able to identify a further intermediate, the rhodium alkyl hydride formed by addition of dihydrogen to the enamide complex with transfer of a single hydride to the benzylic carbon. For the simple dppe complex studied by Halpern, the interpretation of the experiment was straightforward, but the intermediate derived from DIPAMP by Brown and Chaloner provided a major surprise only the disfavored minor diastereomer of the enamide complex was reactive towards H2. The major/minor equilibrium is so strongly biased towards the former below -50 °C that reaction with H2 is undetected. Only when the solvate complex is allowed to react with the dehydroamino acid derivative under H2, well below -50 °C (under which conditions up to 35% of the minor diastereomer is initially observed) is the alkyl hydride observed, concomitant with disappearance of that minor diastereomer. This reactive intermediate was characterized by its H-NMR (hydride), the distinctive P-NMR and by both heteronuclear coupling and chemical shifts in the C-NMR spectra of alkyl hydrides derived from singly and doubly labeled dehydroamino esters. 

---