Macrocyclic compounds allylation

The intramolecular allylation of soft carbon nucleophiles with allylic acetates as a good cyclization method has been extensively applied to syntheses of various three, four, five and six-membered rings, and medium and macrocyclic compounds[44]. Only a few typical examples of the cyclizations are treated among numerous applications. 

Intramolecular allylation offers a useful synthetic method for macrocyclic compounds. An application to the synthesis of humulene (83) by the cycliza-... 

Lewis-acid promoted cyclizations of allylic stannanes have been successfully employed to prepare macrocyclic compounds. An enantioenriched a-oxygenated allylic stannane led to a 14-membered cembrane precursor in high yield with excellent diastereoselectivity (Eq. 64) [80]. 

Intramolecular attacks of jr-allyl Pd complexes or of aryl palladium intermediates have been applied to the synthesis of cyclic systems in fact, this type of reaction appears to be particularly interesting for the preparation of macrocyclic compounds. 

Intramolecular allylation has proved extremely useful in the synthesis of macrocyclic compounds. In 1977, Nozaski and co-workers reported the first example in the synthesis of humulene 31. Intramolecular Tsuji-Trost allylation provided key intermediate 30 in moderate yield. 

Chemical Properties.—Thietan is a useful starting material in the synthesis of macrocyclic compounds the first step in the sequence is the reaction of thietan with allyl bromide to give an 85% yield of allyl 3-bromopropyl sulphide. When cis- and tra j-3-ethyl-2-propylthietan were irradiated in the presence of mercury vapour they gave but-l-ene and cis- and tm 5-hept-3-ene. At low F. Sannicolo, Ann. Chim. (Italy), 1973, 63, 825. 

An example of the efficient formation of an electron-deficient double bond by RCM was disclosed by a Japanese group in a novel total synthesis of the macrosphelides A (209) and B (208) (Scheme 41) [100]. When the PMB-pro-tected compound 204 was examined as a metathesis substrate, the ring closure did not proceed at all in dichloromethane using catalysts A or C. When the reaction was carried out using equimolar amounts of catalyst C in refluxing 1,2-dichloroethane, the cyclized product 205 was obtained in 65% yield after 5 days. On the other hand, the free allylic alcohol 206 reacted smoothly at room temperature leading to the desired macrocycle 207 in improved yield. 

Other Pd cross-coupling reactions such as Heck [52] and Suzuki [53] reactions have also been used for macrocyclizations. The main drawback for Pd catalyzed macrocylization is the yield, that is often somewhat disappointing if compared with other established methods. Also, the introduction of the required coupling components (e.g., trialkyltin group, vinylic iodide) can be difficult in some compounds. In other cases, Pd-catalyzed side reactions such as double bond migration or allylic activation can occur. 

The obvious disconnection in cyclopeptide alkaloids and indeed the strategy employed in most total syntheses of this type of compound is the formation of the aryl ether bond. Many groups chose to form the macrocyclic aryl ether by S Ar reaction. We decided to follow the inverse strategy, i.e., displacement of an allylic leaving group by a phenolate. In case of the natural cyclopeptide alkaloids, this would involve activation of yS-hydroxy-a-amino acids, which is likely to be accompanied by extensive elimination. Elimination is not possible when a-methylene- -hydroxy acids are used. Additionally, the double bond activates the leaving group and provides a handle for a possible later side chain attachment. 

Various cyclic compounds from three-membered rings to macrocycles have been prepared by intramolecular allylation. A typical example of this cyclization is the reaction of the monoacetate of 1,4-butenediol derivative 91 with the active methylene compound 92, which afforded the allylic alcohol 93. The three-membered chrysantemic acid derivatives 94 and 95 were then prepared after acetylation of 93, followed by Pd-catalysed intramolecular allylation [53],... 

The MALDI-TOF monitored SP preparation of lysobactin, a natural cyclopeptide antibiotic, on PS resin bearing the Rink amine linker 1.6 has been reported (141). The SPS scheme is shown in Fig. 1.21. The classical peptide coupling steps, the allyl deprotection (see Section 1.3.5), and the macrocyclization step were all monitored by MALDI-TOF, and the purity of the products was also determined using this technique. The presence of small impurities in compounds 1.56-1.61 was easily detected, and the reaction conditions for the key deprotection of 1.59 and cyclization of 1.60 were rapidly optimized. A total yield of 15% was obtained after HPLC purification of released 1.62 (lysobactin). 

Lewis acid-catalyzed allylation is widely used for incorporation of aUyl moieties in the total synthesis of biologically active and pharmaceutically important compounds. Magnesium bromide-catalyzed allylation has been used in the total synthesis of pamamycin-607 (Scheme 12.6) [22] and the convergent synthesis of the C1-C21 macrocyclic segment of apoptolidin (Scheme 12.6) [23]. 

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