Pummerer-type cyclization

The asymmetric version of an intramolecular Pummerer-type cyclization is quite useful for the synthesis of optically active heterocyclic compounds. Only a few examples of these types of reactions have been reported, and the ee yields were low. An example of an asymmetric intramolecular Pummerer cyclization was reported... 

The mechanism of penicillin biosynthesis from the Arnstein tripeptide, 8-(L-a-aminoadipoyl)-L-cysteinyl-D-valine (ACV), has been extensively studied and reviewed by many chemists. Most of the biosynthetic mechanisms have been ascertained by Baldwin and Bradley using an excellent enzymatic technique.55 However, the first step in the biosynthesis of penicillin, conversion of the Arnstein tripeptide to a cis-P-lactam intermediate, is still a fascinating mechanistic problem. Although Baldwin et al. recently proposed a mechanism involving an iron-bound thioaldehyde formation route via a Pummerer-type cyclization, the intermediate for this mechanism has not been identified. The mechanism of selective formation of the cw-P-lactam ring is still also unknown (Fig. 39).56 These types of biomimetic reactions have been chemically studied. An example of an unsuccessful intramolecular Pummerer cyclization of the sulfoxide involving a cysteine moiety under standard Pummerer conditions was reported by Wolfe et al.57 Although Kaneko reported the conversion of the very simple 3-phenylsulfinyl propionamide into a P-lactam with TMSOTf/triethylamine,58 a successful biomimetic synthesis of... 

P-lactams from Arnstein tripeptide derivatives had not yet been carried out (Fig. 40). The intramolecular Pummerer-type cyclization of the closely related (fi)-Am-stein tripeptide analogues with SKA predominantly gave the cw-P-lactams and the (S)-Arnstein tripeptide analogues gave a mixture of cis and trans P-lactams.59a It is noteworthy that cw-P-lactams were preferentially obtained from the (/ )-substrate considering the fact that the 3-amino-P-lactam moiety of naturally occurring... 

Kita, Y., Shibata, N., Kawano, N., Tohjo, T., Fujimori, C., Matsumoto, K., Fujita, S. Highly asymmetric Pummerer-type cyclization of chiral, non-racemic -amido sulfoxides. J. Chem. Soc., Perkin Trans. 1 1995, 2405-2410. 

Chiral indole-2-sulfoxides have been employed by Feldman and Karatjas for asymmetric spirooxindole synthesis [70]. In one example, treatment of 115 with triflic anhydride initiated a Pummerer-type cyclization of the silyl enol ether side chain onto C3 (Scheme 30). Sequential hydrolysis of the resulting thioimidate intermediate with aqueous HgCl2 afforded the spirocyclohexanone functionalized oxindole 116 in modest yield and enantioselectivity at —78°C (33, 67% ee). Improved selectivity (58, 86% ee) was observed at lower reaction temperature (-110°C). 

Tamura and coworkers studied Pummerer-type cationic cyclizations including a variant that led to a 3-pyrrolin-2-one (Scheme 33 1981 TL4301). Treatment of the a-sulfonylamide 162 with trifluoroacetic anhydride led to the formation of 3-pyrrohn-2-one 164 and pyrrolidinone 165 following a Pummerer-type reaction manifold that includes the cation intermediate 163. 

The Pummerer rearrangement has been employed in tandem with other reactions to enable complex transformations to be carried out efficiently and in a one-pot manner. Studies of these have been reported mainly by Padwa who has utilized such transformations in the syntheses of natural products. A particularly intriguing cascade sequence involving the Pummerer rearrangement was employed in the synthesis of the alkaloid jamtine, 57. " Padwa et al. synthesized the bromo-enamide 55 in a 4 1 (Z/ ) mixture of isomers. Treatment of the isomeric mixture with camphorsulfonic acid caused the the sulfoxide to undergo a Pummerer/Mannich ion cyclization, which was then followed by a spontaneous Pictet-Spengler reaction to furnish the isoquinoline core. Although a 5 2 1 1 mixture of diastereoisomers was obtained, the desired diastereoisomer 56 was formed preferentially. This was attributed to a 4 r-Nazarov-type conrotatory electrocyclisation which controls the direction of closure from the a-acylthionium ion intermediate. 

In addition, this type of aromatic ring activation by the SET oxidation strategy using hypervalent iodine reagents was utilized for the total synthesis of a sulfur-containing pyrroloiminoquinone alkaloid, ( )-makaluvamine F [119-121]. The reaction for the construction of the a-amino dihydrobenzothiophene part involved the efficient cyclization of the benzyl thioether. Hypervalent iodine reagent was iteratively utihzed for the successive oxidative transformation, that is, the azidation at the a-position of the sulfur group of the dihydrobenzothiophene via a Pummerer-like mechanism (Scheme 24). 

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