Stille macrocyclization

Stille macrocyclization. Several macrocylic antibiotics contain a y-oxo-a, y3-unsaturated ester group. Macrolides of this type can be obtained by Stille intramolecular coupling.1 The substrates are available from Mitsunobu esterification of propriolic acid with an w-hydroxy ester followed by hydrostannylation to give /3-stannyl alkcnoates I as a 1 1 mixture of (Z)- and (E)-isomcrs. Selective saponification of the methyl ester... 

The Smith group has also achieved the total synthesis of rapamycin (2) and demethoxyrapamycin (Fig. 6). Their total synthesis of 2 features aldol reaction of acetylpipecolic acid and the C10-C20 segment, esterification with the C21-C42 segment, and final Stille macrocyclization at the C20 and C21 positions. 

Scheme 6.29 Differentiation of two terminal vinyl iodides in a Stille macrocyclization, forming a cyclic 1.3-diene [89].

It is interesting to note that although the first examples of template effects were observed in nitrogen macrocycles (see chapter 2) no template effect appears to operate in the synthesis of 72. Richman and Atkins note this in their original report . The authors replaced the sodium cation with tetramethylammonium cations and still obtained greater than 50% yield of tetra-N-tosyl-72. Shaw considered this problem and suggested that because of the bulky N-tosyl groups, .. . the loss of internal entropy on cyclization is small He offered this as an explanation for the apparent lack of a template effect in the cyclization. 

Intramolecular Pd(0)-catalyzed Stille reaction of organotin reagents with electrophiles leading to C—C a-bond formation in synthesis of heterocycles, particularly, macrocyclic lactones 99JCS(P1)1235. 

An intramolecular variant of the Stille coupling is suitable for the construction of macrocycles. An example is the ring-closing step to form a 14-membered lactone ring 8 in a synthesis of zearalenone as reported by Stille et al. ... 

The palladium-catalyzed cyclization of compound 138 amply demonstrates the utility of the Stille reaction as a macrocyclization method (see Scheme 37). This efficient ring closure is just one of many examples disclosed by J.E. Baldwin and his group at Oxford.58 Interestingly, compound 138 can be employed as a stereoisomeric mixture of vinylstannanes because both stereoisomers converge on the same cyclized product. To rationalize this result, it was suggested that the configuration of the vinylstannane moiety is conserved in the cyclization, but that the macrocycle resulting from the (Z)-vinylstannane stereoisomer isomerizes to the thermodynamically favored trans product under the reaction condi-... 

Scheme 37. Baldwin s approach to y-oxo-a,/ -unsaturated macrocycles by intramolecular Stille coupling.

An intramolecular palladium(o)-catalyzed cross-coupling of an aryl iodide with a trans vinylstannane is the penultimate maneuver in the Stille-Hegedus total synthesis of (S)-zearalenone (142) (see Scheme 38).59 In the event, exposure of compound 140 to Pd(PPh3)4 catalyst on a 20% cross-linked polystyrene support in refluxing toluene brings about the desired macrocyclization, affording the 14-membered macrolide 141 in 54% yield. Acid-induced hydrolysis of the two methoxyethoxymethyl (MEM) ethers completes the total synthesis of 142. 

Chemical transformations at the macroeyclic chromophorc of expanded porphyrins are still not known. The complexation behavior of expanded porphyrins is very different from that of nonexpanded porphinoid macrocycles. The coordination hole of the expanded porphyrins is often too big for the complexation of a single metal ion, so in fact two metal ions can be chelated. With some expanded porphyrins, anion binding is observable, a striking difference to the nonexpanded porphyrins. The complexation behavior and the host-guest chemistry of expanded porphyrins is a rapidly growing field of research. The work in this field has been reviewed. Ie f... 

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. 

Macrocyclic structures with three or six central metal atoms are still more rare and have been observed only for palladium(II) [63] and iron(II)/... 

In the previous Sections, the properties of acids and bases in macrocycles and other concave structures have been compared. A number of factors have been recognized which influence the acidity or basicity of an acid or base (i) hydrogen bonds, (ii) hindered solvation (exclusion of solvent), (iii) formation of tight ion pairs (high microacidity but low overall acidity), and (iv) Coulomb forces when poly anions are formed. A fifth influence, (v) steric hindrance, still has to be discussed. 

In this review, we tried to cover all the supramolecular species that maybe classified as rotaxane dendrimers. We classified them by their structures - where in dendrimer rotaxane-hke features are introduced. Several different types of macrocycles have been employed as a ring component in the templated synthesis of rotaxane dendrimers. While the synthesis of Type I and II rotaxanes dendrimers is relatively straightforward, that of well-defined Type III rotaxane dendrimers, particularly those of second and higher generations, is still challenging. 

The Stille reaction has been successfully applied to a number of macrocyclic ring closures.207 In a synthesis of amphidinolide A, the two major fragments were coupled via a selective Stille reaction, presumably governed by steric factors. After deprotection the ring was closed by coupling the second vinyl stannane group with an allylic acetate.208... 

It is appropriate to identify our approach to developing the present review in the context of the Co chapter in CCC(1987). The first-edition chapter on Co featured a focused discussion and tabulation of synthetic methods, and many of these basic methods are still employed in synthesis today. Consequently, to avoid repetition, there will be diminished description here where prior appropriate methods have been provided, and only newer developments featured. The last two decades feature the development of many mixed-donor and sophisticated multidentate and macrocyclic ligands, which found limited coverage in the previous edition, and these will be discussed in more detail herein. Reaction kinetics and mechanism were also described thoroughly in the previous edition. We shall not reiterate this material, since the core mechanisms of many reactions involving Co compounds are now adequately defined. 

A Mitsunobu process simultaneously coupled the enyne acid fragment 4 to /J-lactam 10 and inverted the CIO stereochemistry to the required (S)-configured ester 11 in 93% yield. A deprotection provided alcohol 12, the key /J-lactam-based macrolactonization substrate, which, under conditions similar to those reported by Palomo for intermolecular alcoholysis of /J-lactams (Ojima et al, 1992, 1993 Palomo et al, 1995), provided the desired core macrocycle 13 of PatA 13 (Hesse, 1991 Manhas et al, 1988 Wasserman, 1987). Subsequent Lindlar hydrogenation gave the required E, Z-dienoate. A Stille reaction and final deprotection cleanly provided (-)-PatA that was identical in all respects to the natural product (Romo etal, 1998 Rzasaef al, 1998). This first total synthesis confirmed the relative and absolute configuration of the natural product and paved the way for synthesis of derivatives for probing the mode of action of this natural product. 

C3-trifluoroacetamide 27 were synthesized by deprotection of Boc-macrocycle 15, followed by acylation, to give macrocycles 24 and 25. Subsequent Lindlar reduction and Stille reaction gave the C3-acylated derivatives 26 and 27. 

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