Macrocyclic alkene

As recently demonstrated by Furstner and Langemann, higher yields of the disubstituted olefin 83 can be obtained under high dilution conditions using la as the catalyst. Our experiments clearly illustrate that synthesis of trisubstituted macrocyclic alkenes is more complicated than that of their disubstituted analogues. See Furstner A, Langemann K (1996) J Org Chem 61 3942... 

Some novel bicyclic pyrylium salts arise when a dicarboxylic acid derivative is used. For example, although decanedioyl chloride did not diacylate isobutene, possibly because of strain inherent in the expected product, 1,12-dodecanedioyl chloride gave a very low yield of the pyrylium salt (658) (62T1079). A dilute solution of the reactants in nitromethane was used in order to favour the intramolecular reaction. In a similar vein, a macrocyclic alkene, such as cyclododecene, undergoes diacylation to the bicyclic salt (659) (68TL4643), whilst... 

Ring-closing metathesis (RCM) of the 6,6 -diallyl ether afforded macrocyclic alkenes,314 which can be reduced (H2/Pd) to saturated compounds with simultaneous removal of all benzyl protecting groups (Scheme 35).68... 

In the reaction shown in Scheme 2.15, the selectivity could also depend on the solvent, as it is the case for 39, used for the preparation of the 17-membered diether 40 using catalyst Gl by Tori et al. in ether, the macrocyclic alkene is obtained as a 1 1 mixture of E- and Z-olefins, and in dichloromethane, the E-isomer of 40 is produced exclusively (Scheme 2.16) [31]. No rational explanation is given for the effect of solvent or temperature. 

The confomiational preferences and stereoselective reactions of a number of macrocyclic systems have been studied. The stereochemical results have been explained on the basis of the model of local conformer control. The epoxidation of a macrocyclic alkene containing the substitution pattern (21) provides a single epoxide having the stereochemistry (22). A macrocycle containing a l,S-diene system adepts the local confoimation (23) that is iree of torsional strain epoxidation of (23) from the less hindered side fiimishes the syn-diepoxide (24). The MCPBA epoxidations of the unsaturated macrocyclic lactones (25) and (2Q are stereoselective (equations 9 and 10). In the epoxidation of (26) six new chiral centres are introduced the reaction product is a 20 1 1 mixture of triepoxides. The tiiepoxide (27) is closely related to the C(9)-C(23) segment of monensin B. 

Audino M., Grice K., Alexander R., and Kagi R. I. (2002) Macrocyclic alkenes in crude oils from the algaenan of Botryococcus braunii. Org. Geochem. 33, 979-984. 

Functionalized macrocyclic alkenes can be synthesized by intramolecular Stille coupling using polymer-bound stannanes. The products are released during the coupling process. ... 

Martin s sulfurane is widely used for the production of cyclic alkenes. Surprisingly, it has seen limited use in the production of macrocyclic alkenes. In the penultimate step of Danishefsky s synthesis of aigialomycin (61), Martin s sulfurane reacts with homobenzylic alcohol 59 to provide conjugated alkene 60 in 90% yield.28 The subsequent global deprotection step completed the total synthesis. Xu was unable to generate a macrocyclic... 

Diphenyl phosphite-ester-aldehyde substrates (83) undergo a Z-selective intramolecular Homer-Wadsworth-Emmons (HWE) reaction to give macrocyclic ene-lactones (84). Terminal placement of the ester in the substrate gives a macrocyclic alkene with... 

Scheme 7.7 Post RCAM entry to stereodefined macrocyclic alkenes.

Since then, the metathesis reaction has been extended to other types of alkenes, viz. substituted alkenes, dienes and polyenes, and to alkynes. Of special interest is the metathesis of cycloalkenes. This gives rise to a ring enlargement resulting in macrocyclic compounds and eventually poly-... 

An obvious drawback in RCM-based synthesis of unsaturated macrocyclic natural compounds is the lack of control over the newly formed double bond. The products formed are usually obtained as mixture of ( /Z)-isomers with the (E)-isomer dominating in most cases. The best solution for this problem might be a sequence of RCAM followed by (E)- or (Z)-selective partial reduction. Until now, alkyne metathesis has remained in the shadow of alkene-based metathesis reactions. One of the reasons maybe the lack of commercially available catalysts for this type of reaction. When alkyne metathesis as a new synthetic tool was reviewed in early 1999 [184], there existed only a single report disclosed by Fiirstner s laboratory [185] on the RCAM-based conversion of functionalized diynes to triple-bonded 12- to 28-membered macrocycles with the concomitant expulsion of 2-butyne (cf Fig. 3a). These reactions were catalyzed by Schrock s tungsten-carbyne complex G. Since then, Furstner and coworkers have achieved a series of natural product syntheses, which seem to establish RCAM followed by partial reduction to (Z)- or (E)-cycloalkenes as a useful macrocyclization alternative to RCM. As work up to early 2000, including the development of alternative alkyne metathesis catalysts, is competently covered in Fiirstner s excellent review [2a], we will concentrate here only on the most recent natural product syntheses, which were all achieved by Fiirstner s team. 

Thus far, chemists have been able to influence the stereoselectivity of macro-cyclic RCM through steric and electronic substrate features or by the choice of a catalyst with appropriate activity, but there still exists a lack of prediction over the stereochemistry of macrocyclic RCM. One of the most important extensions of the original metathesis reaction for the synthesis of stereochemi-cally defined (cyclo)alkenes is alkyne metathesis, followed by selective partial hydrogenation. 

With a-monosubstituted ylides the oxidation results in the formation of alkenes (by subsequent Wittig reaction on the intermediate aldehyde). A recent example of such synthesis is found in the preparation of all-(Z)-cyclododecate-traene by oxidation of the appropriate bis-ylide [33]. It must be pointed out that an approach of the same macrocycle based on ring closing metathesis was found ineffective. 

Based on information accrued during the stereochemical elucidation, macrolactone 85 was identified as a viable synthetic intermediate (Scheme 12). The authors were cognizant of the potential challenges that could arise. First, the required formation of a trisubstituted alkene in a projected Horner-Emmons macrocyclization was without strong precedent. Also, this strategy would necessitate a stereoselective reduction of the Cl5 ketone, which was predicted to be feasible based on MM2 calculations. 

Over the last decade, the chemistry of the carbon-carbon triple bond has experienced a vigorous resurgence [1]. Whereas construction of alkyne-con-taining systems had previously been a laborious process, the advent of new synthetic methodology based on organotransition metal complexes has revolutionized the field [2]. Specifically, palladium-catalyzed cross-coupling reactions between alkyne sp-carbon atoms and sp -carbon atoms of arenes and alkenes have allowed for rapid assembly of relatively complex structures [3]. In particular, the preparation of alkyne-rich macrocycles, the subject of this report, has benefited enormously from these recent advances. For the purpose of this review, we Emit the discussion to cychc systems which contain benzene and acetylene moieties only, henceforth referred to as phenylacetylene and phenyldiacetylene macrocycles (PAMs and PDMs, respectively). Not only have a wide... 

To mimic the square-pyramidal coordination of iron bleomycin, a series of iron (Il)complexes with pyridine-containing macrocycles 4 was synthesized and used for the epoxidation of alkenes with H2O2 (Scheme 4) [35]. These macrocycles bear an aminopropyl pendant arm and in presence of poorly coordinating acids like triflic acid a reversible dissociation of the arm is possible and the catalytic active species is formed. These complexes perform well in alkene epoxidations (66-89% yield with 90-98% selectivity in 5 min at room temperature). Furthermore, recyclable terpyridines 5 lead to highly active Fe -complexes, which show good to excellent results (up to 96% yield) for the epoxidation with oxone at room temperature (Scheme 4) [36]. 

A dinuclear iron(ll/Ill) complex bearing a hexadentate phenol ligand displayed moderate activity toward aziridination of alkenes with PhlNTs a large excess of alkene (2,000 equiv. vs PhlNTs) was required for good product yields (Scheme 22) [76]. It is noteworthy that complex 4 is active in the aziridination of aliphatic alkenes, affording higher product yields than copper (11) catalysts with tetradentate macrocyclic ligands [77]. 

Dioxygen is a cheap and ideal source of oxygen but it is very difficult to activate and there are relatively few examples of 02 oxidations catalyzed by zeolite-encapsulated complexes. Encapsulated CoPc is active for the oxidation of propene to aldehyde, whereas the free complex is inactive.104 A triple catalytic system, Pd(OAc)2, benzoquinone, and a metal macrocycle, was used to oxidize alkenes with molecular oxygen at room temperature.105 Zeolite-encapsulated FePc106-108 and CoSalophen (Scheme 7.5)107109 complexes were used as oxygen-activating catalysts. With the use of a Ru complex instead of Pd(OAc)2 in the triple catalytic system, primary alcohols can be oxidized selectively to aldehydes.110... 

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