Cyclative cleavage solid-phase synthesis

Cyclative Cleavage Strategies for the Solid-Phase Synthesis of Heterocycles and Natural Products... 

Solid-Phase Synthesis Terminated by Diketopiperazine Cyclative Cleavage (Scheme 1). The Fmoc-L-Trp resin (loading 0.5 mmol/g) is first deprotected with 20% piperidine in DMF for 20 min, and the resin washed and dried. The resin ( 1 g, 0.62 mmol/g) is shaken with benzaldehyde (0.63 ml, 10 molar equiv.) and trimethyl orthoformate (1.36 ml, 20 molar equiv.) in 7 ml CH2C12 overnight, followed by washing and drying to give resin 1. 

In the solid-phase synthesis of peptides with C-terminal Cys(Trt) residues attached via ester linkages to the resin, the Fmoc/tBu strategy with repetitive base treatments leads to epim-erization, which can be reduced by the use of DBU and shortened Fmoc-cleavage cycles, but is not fully suppressed.f 1 Concomitant (3-elimination and formation of (3-(l-piper-idyl)alanine is observed, although to a lesser extent than with the 5-(acetamidomethyl)t l or 5-(tert-butylsulfanyl) group. 

A newer method [26] switched to N-terminal (rather than C-terminal) attachment of the amino acid building blocks and to a base- (rather than an acid-) catalyzed cyclative cleavage strategy. In contrast to the first published method for the solid-phase synthesis of hydantoins [12], which relied on isocyanates for derivatiza-... 

Moreover, cyclative cleavage is an often used technique that has been developed into a powerful tool for traceless solid-phase synthesis. One example of particular... 

To complete this short treatment on solid-phase synthesis, let us be mention the efforts made by several groups to obtain methods that allow a cyclorelease (also called cyclative cleavage) of the macrocycle, in other words, the cyclization reaction and the release from the polymer support occur simultaneously. The methods developed so far involve the metathesis reaction (Fig. 15a) the Stille coupling (Fig. ISb) and sulfur ylides (Fig. 16a). 

For a review, see Ganesan, A., Cyclative cleavage strategies for the solid-phase synthesis of heterocycles and natural products, in Methods in Enzymology Combinatorial Chemistry, Part B, Morales, G.B. and Bunin, B.A., Fds., Academic Press, San Diego, CA, 2003, 369, 415. 

Bonnet, D. and Ganesan, A., Solid-phase synthesis of tetrahydro-beta-carbohnehydantoins via the N-acyliminium Pictet-Spengler reaction and cyclative cleavage, J. Comb. Chem., 4, 546, 2002. 

Knepper K, Ziegert RE, Brase S. Solid-phase synthesis of isoindolinones and naturally-occurring benzobutyrolactones (phthalides) using a cyclative-cleavage approach. Tetrahedron 2004 60 8591-8603. 

While the first examples of RCM on solid phase exploited the opportunity to simultaneously release the substrate from the resin, RCM without concomitant cleavage has been even more extensively used in solid-phase synthesis and has the advantage that the catalyst is recovered in the solution at the end of the catalytic cycle and thus unhindered to turn over. However, the proportion of cyclization... 

Fig. 19 Synthesis and cyclative cleavage of 2,4,6-trisubstituted pyrimidines using microwave-assisted solid-phase protocol. Reagents and conditions a DMF, camphorsul-phonic acid, MW 80 °C, 30 min, open vessel b EtONa, EtOH/THF (4/1), MW 130 °C, to min, closed vessel. Y = O, NEt2 R = Me, i-Pr R = Et R" = H, alkyl, cycloalkyl, aryl, benzyl R" = H, Me, Et...

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