Cyclization macro

Dendrimers 5-8 were obtained by taking advantage of the versatile regiose-lective reaction developed in the group of Diederich [24], which led to macro-cyclic bis-adducts of Cgg by a cyclization reaction at the C sphere with bis-mal-onate derivatives in a double Bingel cyclopropanation [25]. Reaction of the dendritic malonates with Cgg, I2, and l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in toluene at room temperature afforded the corresponding cyclization products 5-8 (Fig. 2). The relative position of the two cyclopropane rings in 5-8 on the Cgo core was determined based on the molecular symmetry deduced from the and NMR spectra (Cs) as well as on their UV/Vis spectra. It is well estabhshed... 

Scheme 3.21. Domino radical macro-cyclization/transannular-cyclization procedure for the synthesis of the taxane skeleton.

The synthesis of the disaccharide subunit 85 of tricolorin A, a cytotoxic resin glycoside isolated from lpomoea tricolor, provides a unique opportunity to compare the efficiency of an RCM-based macro cyclization reaction with that of a more conventional macrolactonization strategy. Furthermore, this specific target molecule challenges the compatibility of the catalysts with various functional groups. 

Prior to the synthesis of the epothilones, the use of RCM for the preparation of macrolactones had received little attention [5]. In part, this could be attributed to the generally held assumption that only conformational biased precursors would undergo cyclization. Although several examples of macro-RCM had been reported, notably by Pandit [9],Hoveyda [10] andFurstner [11], preparation of the densely functionalized 16-membered lactone core of the epothilones was not a trivial undertaking. Preliminary studies focused on the preparation and cyclization of model substrates in order to assess the viability of the RCM approach and to provide precedent for subsequent, more ambitious, synthetic endeavors. 

Since Pedersen s original work on the use of cations to template the formation of crown ethers [18-20], a large number of different templating agents for macro-cyclization reactions have been reported. While the initial work concentrated on the use of metal cations, further developments demonstrated that species with hydrogen bonding donor or acceptor properties could be equally useful to template the synthesis of macrocyclic molecules. 

Challenging applications in the field of macrocyclic furans have been investigated. The major synthetic advantage is the cyclization to the furan after the macro-cyclization. This will avoid a problematic ring closure to macrocycles (to 1,3-furano-phanes) with a furan substrate ( furan latest strategy ). Test substrates demonstrated the viability of this concept [50], as shown below for the synthesis of the [8]furano-phane 91 from the macrocyclic ketone 90 (Scheme 15.22) [39]. 

Many natural products are constrained by macrocyclic motifs, which are often essenhal for natural products to possess the desired biological properties. In the biosynthesis of macrocyclic NRPs and PKs, linear peptides or PKs are often mac-rocyclized by a TE domain located at the C-terminal of multi-modular synthases. For example, in the biosynthesis of the antibiotic tyrocidine A (Tyc A), a linear enzyme-bound decapephde, which is transferred from the last carrier protein (or thiolahon) domain of the Tyc A synthase, is cyclized by an intramolecular Sn2 reachon between the N-terminal amine nucleophile and the C-terminal ester, which is covalently linked to serine residual in the TE domain prior to macro-cyclization (Scheme 7.9) ([35] and references therein). 

MRS/acyclic stereoselection macro-cyclization by Stille coupling Nicolaou 2000A... 

Arylboronic acids esterified with support-bound 1,2-diols undergo Suzuki reaction with aryl iodides, whereby biaryls are released into solution (Entry 13, Table 3.46). This technique has also been used to prepare (3-turn mimetics by simultaneous macro-cyclization and cleavage from the support [766]. Alternatively, the C-B bond of a resin-bound boronate may be converted to a C-H bond by treatment with aqueous silver ammonium nitrate (Entry 14, Table 3.46). 

The entropically enhanced cycloaddition rate of an intramolecular cycloaddition permits alkenyl nitrile oxides to cyclize in the presence of free amino groups, in contrast to intermolecular reactions. Since nitrile oxides have a wide spectrum of possible intermolecular reactions, they also react well in macro-cyclic cyclizations. 

Macro carbocyclic rings can be constructed by cyclization of nitrile oxides derived from oj-nitro-l-al-kenes (Scheme 22). If the intervening bridge is not longer than seven atoms, only fused bicyclic products are obtained. Thus, the nitrile oxide derived from nitro compound (75a) is cyclized in 44% yield to the 5,9-fused bicyclic isoxazoline (76a).38 10-Nitro-l-decene (75b) also cyclized to (76b) in unspecified yield.39 It should be noted that these results go counter to the usual regiochemistry of an intermolecular nitrile oxide cycloaddition where the five-substituted isoxazoline is usually,27 although not always,40 heavily preferred from reaction of a terminal alkene. Thus, geometric constraints have won out over the normal electronic control. 

The implementation of this methodology for a synthesis of advanced macro-cyclic precursors of antitumor antibiotics lankacidins, which posses a carbocyclic structure, has been reported by Thomas [77]. In such a route, Scheme 13, one of the key steps is the ring opening of the (3-lactam nucleus in 30 by methanol, assisted by KCN, to give the corresponding (3-amino ester intermediate 31. The latter, upon cyclization and protecting group manipulation, renders 32, which on subsequent elaboration affords lankacidin C. 

Figure 7.9 Example of a reacting primary chain (a) and possible reactions of a macro reactive center (b) (1) propagation (2) crosslinking (3) cyclization ur.db = unreacted double bond r.db = reacted double bond.

The search for alternatives to the stepwise addition of new addends to a mono-, bis-, or tris-adduct of Cr,o for the preparation of highly functionalized fullerenes has been a challenge since the beginning of fullerene chemistry. Here we present the principal approaches introduced to control the regiochemistry of multiple additions to fullerenes by the use of tethered addend systems. The tethered macro-cyclization method proved to be a major breakthrough and has provided relatively facile access to otherwise strongly disfavored addition patterns. 

The average extension of the n + 1 chain atoms in space can be reduced by changing their connectivity. A conceptually simple means by which this reduction can be obtained is by the introduction of a covalent bond that links the two ends of the chain. This macro-cyclization leads to a reduction in (s2) that, in the case of large unperturbed chains, is a factor of 1/2 J27 ... 

The rational synthesis of 12c is shown in Scheme 5.17. The starting monoloop di-urea 15 is prepared in the conventional way analogous to Scheme 5.9 by macro-cyclization of the di-Boc derivative with an activated bisurethane under dilution conditions, followed by deprotection and acylation [50]. Although 15 belongs to the... 

Hisaeda and coworkers subsequently reported radical (macro)cyclizations of oo-bromoalkyl acrylates 300 catalyzed by modified vitamin B12 301a under photo-lytic conditions (Fig. 71) [334], The active Co(I) catalyst is generated by electroreduction at platinum cathodes and subsequently substitutes the halide in 300. The resulting organocobalt(III) intermediate was characterized by UV and MS techniques in the dark. Photolysis triggers 6-endo, 10-endo, or 16-endo cyclizations affording the products 302 in 95, 15, and 43% yield, respectively. The reaction was inhibited by addition of the radical trap PBN 303 and the derived radical adducts were detected by ESR-spectroscopy. 

Another independent intramolecular approach to cyclophanes was based on a macro-cyclization [74]. 

After solvent removal from the mother solution of re-precipitated copolymer 1 (Table 18), a semi-crystalline compound with the molecular mass equal —1100 was obtained [96, 97], The product of intramolecular cyclization of 1,7-divinyl-1,7-dimethylocta-phenylcyclohexasiloxane and 1,3-dihyd-ridetetramethyldisiloxane of the following structure only may display the current molecular mass because divinylorganocyclohexasiloxane of the tram-structure participates in formation of macro-molecular chain. 

For the construction of the 16-membered M(4-6)-macrocycle, special attention had to be directed to the correct arrangement of the chloro-substituent at ring 6. The SfjAr macro-cyclization gave the cyclization product diaste-reoselectively (d.r. = 5 1) in favor of the desired... 

Similar methodology was employed to the synthesis of more complex polycyclic ring system, as shown in Scheme 32 <1997TL9069>. The initial alkenyl radical 54, formed by an intramolecular radical 13-< 4t>-dig macro-cyclization, initiated a radical cascade reaction by first reacting at the a-position of the furan ring. 

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