Macrocyclic tethers

The first total synthesis of three naturally occurring cyclophane derivatives belonging to the turriane family of natural products was also described by A. Furstner et al These natural products have a sterically hindered biaryl moiety and saturated as well as unsaturated macrocyclic tethers. Stereoselective entry to this class of compounds is possible using RCAM followed by Lindlar reduction of the resulting cycloalkynes. 

REMP, the acronym for ring expansion metathesis polymerisation is a special case of ROMP, where the growing polymer chain stays attached to the catalyst at both ends nntil a macrocycle is released. This requires that the active carbene be tethered... 

One of the most convenient of these tether-directed functionalization strategies exploits the macrocyclization of C60 with bismalonate derivatives in a double Bingel reaction.156,571 With the exception of the cis-1 bisaddition product, all possible bisaddition patterns have been obtained by this macrocyclization reaction (Figure 13). As a general... 

With the bulky metallo-organic Pd(II) catalyst 98, on the other hand, selective formation of 99 was possible here functional groups are tolerated that would react with an Ag(I) catalyst (for example, terminal alkynes, alkyl chlorides, alkyl bromides and alkyl iodides) [59]. With l,n-diallenyl diketones (100), easily accessible by a bidirectional synthesis, up to 52-membered macrocycles (101) could be prepared in an end-group differentiating intramolecular reaction (Scheme 15.26) [60], For ring sizes lager than 12 only the E-diastereomer is formed overall yields of the macrocydes varied between 17 and 38%. Only with tethers shorter than 11 carbon atoms could the Z-diastereomer of the products be observed, a stereoisomer unknown from the intermolecular dimerization reactions of 96. 

With R = CR R C02Me and R = (CH2)3+ OH, the obtained 5-iminooxazolines 42a could be converted into macrocyclodepsipeptides of type 46 as shown in Fig. 16. Saponification of the ester with KOH in Me0H/H20 followed by protonation of the exocychc imine and attack of the neighboring carboxyl oxygen led to the formation of spirolactone 48. Attack of the tethered OH and fragmentation generated the desired 14-, 15-, and 16-membered macrocycles in 27-54% yield [155]. 

This difficulty has been circumvented by the introduction of a modified concept [100]. Here, flexible alkyl chains are used as tethers that are incorporated in macrocyclic cyclo-[n]-malonates. In this way, the regioselectivity is not based on steric preorganization but on the avoidance of unequal strain in the alkyl chains. This has very important consequences for the symmetry of the product addition pattern and dictates selection rules (1) Cyclo-[n]-malonates containing alkyl chains... 

Epoxide 96 was prepared such that photolytic conversion to the carbonyl ylide could be followed by an intramolecular cycloaddition with the tethered pendant olefin. However, photolysis of epoxide 96 led only to the formation of the regio-isomer 97 and the aldehyde 98 with no evidence of the corresponding cycloadduct. It was presumed that 97 arose from the ylide by thermal recyclization to the epoxide while 98 could form through the loss of a carbene from the ylide. The failure of the tethered alkene to undergo cycloaddition may have resulted from a poor trajectory for the cycloaddition. An extended analogue (99) allowed greater flexibility for the dipolarophile to adopt any number of conformations. Photolysis of epoxide 99 did lead to formation of the macrocyclic adduct 100, albeit in modest yields. 

Nitrenium ions have been applied to the synthesis of macrocycles and other medicinally interesting compounds. The most successful reactions have been in cases where the nitrenium ion is covalently tethered to its intended target. Further efforts aimed at modulating the selectivity of these intermediates would increase their synthetic utility. 

A similar reaction sequence occurs when the corresponding dication containing the macrocycle 9-aneNS2 is treated with an excess of KO Bu or KOH [Eq. (15)]. Even a suitably designed non-macrocyclic precursor can generate a tethered arene, as shown in Eq. (16).80... 

Hirsch and co-workers last year introduced a new concept for the tether-directed multifunctionalization of Cgo> with the use of cyclo-[n]-octylmalonates such as 34 (Figure 11) [50], As a result of the identical spacer lengths in these macrocycles, only bis- and tris-adducts with rotational symmetry are formed. The reaction of cyclo-[3]-octylmalonate (34) with Cgo leads to the e,e,e isomer 35 with high regioselectivity and excellent yield (94%). Additionally, 6% of... 

With the bis-malonate 56 containing a vra-disubstituted DB18C6 tether, the regioselectivity of the macrocyclization of C70 via double Bingel cyclopropanation... 

As expected, the amount of shape-persistent macrocycle in the crude reaction product depends strongly on the length of the covalent tether (Scheme 6.15)... 

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