Esters macrolactonization

Lipases also catalyze the intramolecular transesterification (lactonization) of hydroxy esters. Macrolactonization of a racemic hydroxy ester in the presence of PSL provided the corresponding (R)-lactone (Figure 6.22). This compound is the naturally occurring enantiomer of the pheromone produced by the merchant grain beetle [70]. Chemical macrolactonizations require high dilution to minimize... 

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. 

In order to overcome the problem, the inverse strategy was followed. Chromium-Reformatsky reaction between 76-derived C8 aldehyde and a 68-derived ester afforded all four possible C6,C7-diastereomers, which can be independently processed to epothilone D5 diastereomers (including the natural one) by the macrolactonization route. 

Although RCM gives brilliant results for the synthesis of medium-ring carbo-cycles, it is also effective for the synthesis of macrocyclic lactone as shown in Eqs. (6.25)-(6.27). Prior to RCM, macrolactonization was the most common method for the synthesis of macrocyclic lactone. However, we can now obtain the desired macrocyclic lactone from diene having an ester moiety in a chain by RCM followed by hydrogenation ... 

Bryostatins are a unique family of emerging cancer chemotherapeutic candidates isolated from marine bryozoa [457], They were first discovered in the bryozoan Bugula neritina, but problems with supply of sufficient quantities of this natural product hampered the study of this interesting group of marine metabolites for many years. Although the biochemical basis for their therapeutic activity is not known, these macrolactones exhibit high affinities for PKC isoenzymes, compete for the phorbol ester binding site on PKC and stimulate kinase activity in vivo and in vitro. Bryostatin 1, Fig. (54), one member of this family, is a PKC modulator in a variety of tumor systems [458,459], Bryostatin 1 is currently in phase II... 

Synthesis of 12- and 13-membered sulfur-containing lactones by homolytic macrocyclization of mercaptoacetic esters and alkynes has been investigated [95S307]. Reaction of the mercaptoester 245 with alkynes using triethyl borane radical initiation gave the macrolactones 247 and 248 in low yield [95TL2293], Remote asymmetric induction is observed during the cyclization. 

From Equation 6.19 it follows that the lower the concentration of the activated acid, the higher the selectivity with which the lactone is produced versus the acyclic ester, oligo- and polyesters. Macrolactones are therefore produced in very dilute (< 1 pmol/L) solutions. 

Macrolactonization. This acetylene reacts selectively with the carboxyl group of an (o-hydroxy carboxylic acid (2) to form a stable hydroxy enol ester 3. Addition of 10-camphorsulfonic acid or mercury(II) trifluoroacctate results in lactonization to macrolactones (4). 

Macrolactonization. The usually difficult lactonization to ll-membcred pyrroli-zidine dilactones can be achieved by use of a trimethylsilylethyl ester (8, 510-511) and activation of the lo-hydroxyl group by mesylation. Thus treatment of 1 with (C4H,)4N F in acetonitrile at 30° liberates the carboxyl group with spontaneous cyclization to the diastereomer 2, the methoxymethyl ether of dZ-crispatine. ... 

Table 7 Formation of macrolactones from a,/3-unsaturated esters catalyzed by (4a)...

The last step of this problem is the final cleavage of the two remaining secondary TBS-ethers. This is accomplished by HF-pyridine in THF and addition of hexafluorosilic acid. This significantly facilitates the cleavage of both TBS-ethers in terms of reaction time and yield. Furthermore, the reaction becomes less sensitive to the quality of the HF-pyridine batches. The conditions used are mild enough to allow the presence of acetals, esters and epoxides. Therefore the macrolactone is stable under these conditions, because the pH of hexafluorosilic acid is nearly the same as a solution of HF. Product 19 is itself an epothilone D analogue. 

---