Enantioselective syntheses, pyrrole

The indole and pyrrole rings are incorporated into many biologically active molecules. Therefore, the functionalization of indole and pyrrole cores via Michael-type additions has been discussed. This chapter especially focuses on studies of the last 10 years on catalyst systems, enantioselective synthesis and the design of natural products or biological active molecules as related to Michael additions of indole and pyrrole. 

A novel Pd-catalyzed asymmetric annulation was reported between 5-bromopyrrole-2-carboxylate esters and vinyl aziridines <07OL2357>. The resulting pyrrolopiperazinones such as 58 served as key intermediates in the enantioselective synthesis of longamide B and a number of other pyrrole alkaloids. 

Applying the strategy of direct coupling of pyrroles with carbonyl compounds, Baran et al. developed a short enantioselective synthesis of (5)-ketorolac, Syntex s analgesic and anti-inflammatory agent.The antipode of ketorolac is more potent and causes fewer side effects. 

The first enantioselective synthesis of pyrrolyl-substituted triarylmethanes 57 was reported using a novel organocatalyst 58.The scope of the reaction was broad as pyrrole 56 was allowed to react with a variety of differentially substituted aryl—indolyl 55 coupling partners to afford products of the form 57 in good to excellent yields with high enantiometric excess (ee) (14OL1096). 

Baran PS, Richter JM, Lin DW (2005) Direct coupling of pyrroles with carbonyl compounds short enantioselective synthesis of (S)-ketorolac. Angew Chem Int Ed 44 609-612... 

Furthermore, enantioselective additions of pyrroles to a,P-unsaturated 2-acyl imidazoles catalyzed by the same catalyst system have been accomplished (69-99%, 77-96% ee) [153]. Using this methodology, a short enantioselective synthesis of an alkaloid ( + )-heliotridane has been attained. This process was then extended to a one-pot asymmetric synthesis of 2-substituted indoles from 4,7-dihydroindoles. 

The Aspidosperma family of indole alkaloids has inspired many synthetic strategies for the construction of their pentacyclic framework of the parent compound aspidospermidine (366), since the initial clinical success of two derivatives, vinblastine (10) and vincristine, as anticancer agents. The alkaloids such as (-)-rhazinal (369) and (-)-rhazinilam (6) have been identified as novel leads for the development of new generation anticancer agents [10,11]. Bis-lactams (-)-leucunolam (370) and (-t-)-epi-leucunolam (371) have bio-genetic and structural relationships with these compounds [236]. Recently, enantioselective or racemic total syntheses of some of the these natural product were achieved. One successful synthesis was the preparation of the tricyclic ketone 365, an advanced intermediate in the synthesis of aspidospermidine (366), from pyrrole (1) (Scheme 76) [14]. The key step is the construction of the indolizidine 360, which represents the first example of the equivalent intramolecular Michael addition process [14,237,238]. The DIBAL-H mediated reduction product was subject to mesylation under the Crossland-... 

The first carbon addition to allenes catalyzed by gold was described by Hashmi and was the addition of furans to allenones, a reaction that is discussed as a conjugate addition to carbonyls. Then the annulation of 2-allenyl indoles was described (equation 111)and an enantioselective version was later developed for terminal allenes. Then Nelson described the cyclization of an N-substituted pyrrol in the synthesis of (—)-Rhazinilam (equation 112). In that case, gold notably improved the yields and selectivities obtained with Pd(II) or Ag(l), and gave complete retention of the chiral information of the allene. The most recent report is on the hydroarylations of allenes with gold-covered substituted benzenes as substrates. ""... 

An interesting enantioselective copper-catalyzed coupling of pyrroles 261 with isatins 260 was reported for the synthesis of 3-substituted-3-hydroxy-2-oxindoles 262. This reaction proceeds in moderate to high yield with high ee (140L3192). 

The hydroamination of alkynes is a highly atom-efficient approach to the synthesis of enamines and imines, as well as to the synthesis of A-heterocyclic compounds such as indoles and pyrroles, which are widely occurring functional groups in biologically active molecules. Also included in this section is the hydroamination of allenes and alkenes, as the reaction of these substrates with chiral bimetallic catalysts has been shown to yield the chiral amine products with high enantioselectivity. 

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