Macrocyclics, selective formation

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. 

Brunelle, D. J., Boden, E. P. and Shannon, T. G., Remarkably selective formation of macrocyclic aromatic carbonates versatile new intermediates for the synthesis of aromatic polycarbonates, J. Am. Chem. Soc., 112,569 (1990). 

It should be stressed that there is not alwaysjustice in reseach evaluation. The selective formation of inclusion complexes by cyclodextrins (such as 11) was established by Cramer [6] at least 15 years earlier than that by crown ethers. However, cyclodextrin studies forming an independent branch of host-guest chemistry seem underestimated in spite of their considerably greater practical importance at present than that of other host macrocycles (crown ethers 17, calixarenes 18, etc.). Sometimes they are even totally neglected by discussing inclusion phenomena [7]. 

The control of alkene geometry in RCM reactions has been an area of intense research and interest since the process was first developed. While a general solution to this challenge has not yet been developed, intriguing observations of E Z control in macrocyclizations continue to be reported. For example, in the course of their studies on the synthesis of herbarumin I and II, Fiirstner and co-workers reported the selective formation of either of the two isomeric alkene products 16 or 17 via RCM of diene 15 <02JA7061> (Scheme 8). The diene 15 was transformed into the -alkene 17 using the ruthenium indenylidene catalyst (Fiirstner Metathesis Catalyst FMC, <01MI4811>) while use of the MC2 led to clean formation of the Z-isomer 16. 

The macrocycles (14)2 and (15) containing the phosphine oxide function have been prepared. Oxidation of (15) produces only the d,/-form (16) of the disulphoxide. This differs from the corresponding oxidation of the acyclic analogue (17) which gives all four possible stereoisomers of (18). It is suggested that the selective formation of (16) is due to the... 

Fig. 2 Efficient syntheses of macrocycles for concave reagents using thermodynamic control for macrocyclizations (a) Formation of concave 1,10-phenanthrolines 2 by ring-closing metathesis (b) selection of niacrocyclic diimines 7 from a dynamic combinatorial library with the help of transition metal ions as templates and subsequent reduction to 8. here formation of an 18-membered macrocycle by using Ca. ...

Scheme 22 Proposed mechanism for ring expansion and ring contraction with some selected cyclic and macrocyclic alkanes formation from cyclooctane metathesis. ROM ring-opening metathesis, RCM ring-closing metathesis. Iso double-bond isomerization...

As one of the earliest appUcatiOTis of RCM for macrocyclization in natural product synthesis, the Hoveyda group reported in 1995 that Schrock catalyst catalyzed Z-selective formation of the macrocycle in Fig. 24 as a single alkene stereoisomer, which is a late stage intermediate for the total synthesis of Fluvirucin B [54]. While the conformational control of the substrate was believed to be crucial for the selectivity, recent stodies showed that catalyst cmitrol also played a key role in the reaction outcome, as Ru-catalyzed RCM of a very similar substrate yielded a 1 1 mixture of Z E isomers [55]. 

Kendomycin (13) was isolated from different Streptomyces species, which showed potent antibacterial and cytostatic activities [36, 37]. Due to its challenging chemical structure and interesting biological profile, a number of impressive total syntheses have been accomplished [38]. However, all attempts to achieve 13,14-macrocyclization and formation of the desired 13,14- -olefin by alkene RCM were unsuccessful [39-41]. In 2009, Mulzer and coworkers described a novel approach to the total synthesis of kendomycin (13) via the selective alkene RCM at ClO-Cll as one of the key steps (Fig. 5) [42]. In this work, they demonstrated that RCM with Grubbs II catalyst smoothly facilitated ring closure to form the 10,ll- -olefin (15)... 

Shair and co-workers turned their attention to the regiochemical outcome of enyne-metathesis macrocyclizations, and they completed the biomimetic synthesis of a cytotoxic marine natural product (—)-longithorone A (204, Scheme 24.51). Biosynthetically, the natural product has been proposed originating from two [12]-paracyclophanes 205 and 206 by two Diels-Alder reactions, and thus, the authors applied enyne metathesis macrocyclization to the preparations of paracyclophanes 205 and 206. Both metathesis precmsors 208 and 210 were prepared from the common intermediate 207. The cyclization of enyne 208 in the presence of [Ru]-Ia (50mol%) in refluxing CH2CI2 under ethylene atmosphere proceeded with excellent atropdiastereoselectivity and -stereoselectivity. On the other hand, the macrocyclization of enyne 210 was less atropdiastereoselective (selective formation of the endocy-clic olefin ( /Z= 3.9 1). Nevertheless, the desired product 211 was obtained in 31% yield. In the absence of ethylene, neither macrocyclization of 208 nor 210 occurred. 

Bradshaw and his coworkers have listed several motivations for their explorations in this area. One objective of [the] research program is to prepare and study a series of multi-dentate compounds which resemble naturally occurring macrocyclic compounds . Further, Bradshaw and his coworkers have said that it is our hope that we can prepare macrocycles to mimic the selectivities of the naturally occurring cyclic antibiotics and thereby make available models for the investigation of biological cation transportation and selectivity processes . These workers have presented a number of comparisons with valinomy-cin . The other expressly stated goal of their research is to prepare molecules which will allow us to systematically examine the parameters which affect complex stability and to understand that stability in terms of AH and TAS values for complex formation . 

In 159 and 163-166 the tertiary amine function is coordinated to the boron atom and transmits the electronic change due to the ester formation to the chromophore. In 160-162 the boron atom is directly connected to the chromophore. After the complexation of the saccharide, the change of the charge transfer, e.g., for 159 [249-251], or the fluorescence bands, e.g., for 160-166 [252-255], can be measured and interpreted. The most selective binding of n-glucose has been achieved with host 164 that forms a 1 1 complex with a macrocyclic structure (Scheme 1). 

---