Latent electrophile

It is appropriate at this juncture to address some of the more useful transformations of 2,3-epoxy alcohols.913 A 2,3-epoxy alcohol such as compound 14 possesses two obvious electrophilic sites one at C-2, and the other at C-3. But in addition, C-l of a 2,3-epoxy alcohol also has latent electrophilic reactivity. For example, exposure of 14 to aqueous sodium hydroxide solution results in the formation of triol 19 in 79% yield (see Scheme 5). In this interesting transformation, hydroxide ion induces the establishment of an equilibrium between 2,3-epoxy-l-ol 14 and the isomeric 1,2-epoxy-3-ol 18. This reversible, base-induced epoxide migration reaction is a process known as the Payne rearrangement.14... 

The studies described above show that a quinone methide or its aza-analogue quinonimine methide incorporated as a latent electrophilic species into a cyclic lactone or lactam precursor can modify a second nucleophilic residue within the enzyme active site after formation of the acyl-enzyme. Very efficient suicide... 

Preparation of Copolymers Containing Both Electrophilic and Nucleophilic Groups. Our first implementation of this reaction scheme involved the preparation of a series of copolymers incorporating both a latent electrophile and an electron-rich aromatic moiety which, being phenolic, also provides access to swelling-free development in aqueous medium. The copolymers are prepared as shown in Figure 1 by copolymerization of 4-t-butyloxycarbonyloxy-styrene with 4-acetyloxymethyl-styrene. Although the reactivity ratios of these two monomers are different [11], our study of this system has confirmed that they copolymerize essentially in random fashion. 

It can be seen in Table 1 that the lithographic sensitivity of the copolymers blended with 10% sulfonium salt increases as the percentage of latent electrophile (vinylbenzyl acetate) units is increased,. For a 50/50 copolymer the lithographic sensitivity is approximately 0.5 mJ/cm2 with a very high contrast of over 4. It should be noted however that aqueous development is no longer possible for the 50/50 copolymer for which some isopropanol must be added to the aqueous base developer. 

Use of a Difunctional Crosslinker. An alternate approach to chemically amplified imaging through electrophilic aromatic substitution is shown in Figure 6 below. In this approach a polyfunctional low molecular weight latent electrophile is used in a three component system also including a photoactive triaryl sulfonium salt and a phenolic polymer. In this case again crosslinking of the polymer is observed upon... 

Acid-catalyzed condensation has been the primary and dominant foundation for aqueous base developable negative resist systems [354-363]. The first commercial chemical amplification resist was built on this mechanism. The condensation resists are typically three-component systems comprising a base soluble binder resin bearing reaction sites for crosslinking (phenolic resin), a radiation-sensitive acid generator, and an acid-sensitive latent electrophile... 

Other crosslinkers have been also extensively studied (Fig. 123). Benzyl acetate derivatives are such a latent electrophile, which yields a stable benzylic carbocation, releasing acetic acid, upon acid treatment. The carbocation undergoes electrophilic substitution reactions onto the electron-rich benzene ring and crosslinks the phenolic resin when the latent electrophile is multifunctional [366-370]. The crosslinker can be an additive or incorporated into a phe-... 

Aldehydes can methylolate phenols with an acid as a catalyst and therefore function as latent electrophiles in the negative resist design based on condensation (Fig. 125) [150]. The methylolated phenolic resin is expected to dissolve more slowly in aqueous base than its precursor resin and therefore this process could be exploited in negative imaging. Furthermore, the methylolated phenol can undergo further condensation with phenol. If the phenol is polymeric, the second reaction results in crosslinking, lowering the dissolution rate even further. 

In the above condensation resist designs, the phenolic resin offers a reaction site as well as base solubility. Self-condensation of polymeric furan derivatives has been utilized as an alternative crosslinking mechanism for aqueous base development (Fig. 126) [375]. The copolymer resist is based on poly[4-hydroxy-styrene-co-4-(3-furyl-3-hydroxypropyl)styrene], which was prepared by radical copolymerization of the acetyl-protected furan monomer with BOCST followed by base hydrolysis. The furan methanol residue, highly reactive toward electrophiles due to a mesomeric electron release from oxygen that facilitates the attack on the ring carbons, readily yields a stable carbocation upon acid treatment. Thus, the pendant furfuryl groups serve as both the latent electrophile and the nucleophile. Model reactions indicated that the furfuryl carbocation reacts more preferentially with the furan nucleus than the phenolic functionality. 

In contrast to other inactivators of dopamine /3-hydroxylase, p-cresol is unusual in that it does not contain a latent electrophile (Goodhart et al., 1987). Oxidation of the benzylic carbon occurs, as evidenced by production of 4-hydroxybenzyl alcohol as well as the corresponding aldehyde. Inactivation with radiolabeled p-cresol leads to substoichiometric modification of the enzyme, with the majority of the radiolabel distributed between four tryptic peptides (DeWolf et al., 1988). Analysis of two of the peptides indicates that they are of identical sequence, each containing modified tyrosine residues which differ in the structure of the p-cresol-amino acid adduct. A second pathway for inactivation is proposed which requires radical-mediated oxidation of the enzyme without incorporation of the inactivator. 

Thus, we focused on identifying a compound which contained only one active electrophile and a second latent electrophile, which would require orthogonal activation to couple to the phosphoryl moiety. We identified two potential options capable of this type of reactivity (Scheme 6) (1) alkylation with chloromethyl acetate, which occurred with high selectively for the N1 position, followed by treatment with B-bromocatechol borane to provide bromide 25 and (2) alkylation with (chloromethyl)(4-chlorophenyl)sulfide (26) to produce a mixture of 27 and 28. Activation of sulfur with chlorine resulted in conversion of 27 to chloromethyl intermediate 22. Both 22 and 25 readily converted to 21 upon treatment with 18. 

SCHEME 6 Options for stepwise introduction of prodrug by latent electrophile. 

Jung, H. H. and Floreancig, P. E. 2006. Gold-catalyzed heterocycle synthesis using homo-propargylic ethers as latent electrophiles. Org. Lett. 8 1949-1951. 

One way to increase selectivity and duration of action of enzyme inhibitors is to design a substrate with a latent electrophile, which becomes unmasked only after it reacts in the active site. This type of inhibition is referred to as suicide or mechanism-based inhibition (1-5) and is, in principle, extremely selective. 

This paper describes two new classes of organo-carbonate compounds which are designed to contain a choline or choline mimic to provide high affinity at the anionic site, and a latent electrophilic group that can be released by reaction at the esteratic site and then react with the serine hydroxyl or a proximal nucleophile. These two general types of inhibitors, aryl carbonates and enol carbonates, are illustrated in Figure 2. The proposed mechanism of inhibition of the aryl carbonate class of inhibitors, similar to that for the enol carbonates, is shown in Figure 3. 

Figure 5. Schematic representation of latent electrophiles that may be used in the development of cross-linking chemically amplified resists.

---