Pseudodilution

Scheme 2.8 Palladium-catalyzed allylic substitution an example of pseudodilute conditions.

Many biologically active peptides are cyclic in nature, and the SPS of this class of peptides, exemplified by 2.7, has also received attention with several different strategies for the final cyclization. The phenomenon of pseudodilution on bead in which each resin site is essentially isolated from its neighbors favors the intramolecular cyclization reaction compared to the intermolecular dimerization, which occurs in solution even at high dilutions. The SPS of cyclic peptides has recently been covered in two excellent reviews (31, 32). The technique of cyclative cleavage via the N- or the C-terminus (see Section 1.2.7) has been used, as has anchoring through amino acid side chains with sequential cyclization and peptide release. 

Indeed, the first example of macrocyclization based on Ugi reaction was reported in 1979 from the group of Failli et al. [62]. Reaction of a TFA salt of H-Ala-Phe-Val-Gly-Leu-Met-OH (20), isobutyraldehyde and cyclohexyl isocyanide afforded the cyclohexapeptide 21 as a mixture of two separable diastereoisomers in 33% overall yield. Slow addition of 20 to the reaction mixture was applied to achieve the pseudodilution in order to minimize the oligomerization (Scheme 8). 

One of the most striking demonstrations of the Heck reaction on solid phase was an efficient macrocyclization reaction by Hauske et al. They cyclized the resin-bound species 19 under mild conditions and obtained products with high post-cleavage purity (Scheme 19). The efficiency of these reactions for a variety of structural modifications in the ring seems to suggest that the pseudodilution effects of site isolation on resin are important. 

It has been shown that cyclization can be conveniently performed while the peptide remains anchored to the solid support, thus taking advantage of the pseudodilution phenomenon, which favors intramolecular reactions over intermolecular side reactions. This chapter surveys the literature on the syntheses of cyclic peptides in which all steps have been carried out in the solid-phase mode. Other reviews of this subject have appeared [1,2]. 

Boc-Asp(OH)-OFm was attached to a methylbenzhydrylamine (MBHA)-resin, maintaining a low substitution level (0.4 mmol/g) in order to respect the pseudodilution principle unreacted amino groups were capped by acetylation. After elongation of the peptide chain by standard methods on an automatic synthesizer using the Boc/Bzl strategy and deprotection of the C-and A-termini with TFA and piperidine, respectively, cyclization was obtained by treatment with BOP (3 equiv.) and DIEA (6 equiv.) in NMP (2 h at room temperature, twice). HF cleavage yielded the desired cyclic product with an overall 10% yield after HPLC purification (Scheme 3). 

For a discussion of the pseudodilution effect reached with polymer-bound Pd° see [39 a, f] and references cited therein. 

Immobilisation prevents the benzyne intermediates from dimerisation and allows the alternative transformation which in solution is too slow to compete with dimerisation. Applications of functionalised polymers for monoprotection (many examples were contributed by Lezno, A"6.146-150 further examples see Refs. - SZ) or monoactivation of symmetrically difunctionalised molecules as well as their use to promote the formation of large rings are based on this site isolation or pseudodilution effect . ... 

When the concentrations of the target analytes in the sample exceed the upper limit of the linear range of the calibration curve, a dilution or pseudodilution step is mandatory in order to fit the vmknown concentration to this portion of the calibration curve, and hence to increase the precision of the measurements. A series of alternatives to the usual previous dilution of the sample have been developed in order to avoid the errors involved in a dilution step or in the weighing of small amounts of a solid. These alternatives are (1) using of a lower pervaporation temperature (2) changing the chemical conditions to a less favorable situation if a derivatization reaction is required, in order to reduce the yield of the monitored species (3) enlarging the air gap between the... 

Among the previously mentioned advantages of sohd-phase synthesis, the pseudodilution effect particularly affects the intramolecular variant of the Mizoroki-Heck reaction, commonly resulting in increased yields and leading to the most complex stractures obtained by Mizoroki-Heck reactions on solid phase. 

With selected aryne precursors it has been possible to demonstrate the intermediacy of free arynes in cyclojaddition reactions by other methods. The most convincing of these is the previously mentioned spectroscopic detection of benzyne (1) from the photolysis of phthaloyl peroxide (72) in an argon matrix at 8 K and its subsequent reaction with furan (146a) upon warming to give the adduct 148a. A conceptually similar technique is pseudodilution, in which... 

The techniqne of pseudodilution using palladium on a polymer support avoids a high level of dilution and leads to a more efficient macrocyclization but stereoselectivity is poor.f Scheme 10 depicts the formation of a 2 1 ratio of diastereomeric alkenes included in medium sized (n = 4) rings as well as a 4 1 ratio in the case of larger rings (n = 9). 

B.ii.c. Intramolecular Heck Reactions. The main advantage of intramolecular Heck reactions on solid support is the pseudodilution of the starting material leading to an increase of the yield. The first use of this was reported in 1995 for the synthesis of 20- to 24-membered macrocyclic ring systems (Scheme 3). ... 

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