Modified strategy to synthesise the macrocidin A side chain

Scheme 3.30 Synthetic plan to synthesise 340 via allylic alcohol 353 applying a SeO2 mediated allylic oxidation strategy^212–214 based upon the work of Kempf et al.²¹¹ and unsuccessful experiments to convert 352 or 354 into allylic alcohols 355 or 356

3.1.4.5 Modified strategy to synthesise the macrocidin A side chain

The next strategy was a combination of the strategies of Barnickel¹⁵² and Christen.¹⁰¹ In order to circumvent the problems with the methyl ester during stereoselective methylation, the new strategy should involve straight forward protecting group chemistry. Scheme 3.31 outlines this process, starting with

compound 119. The alcohol should be protected and the methyl ester reduced to allylic alcohol 357. From there, 357 should be reacted with a protecting group orthogonal to the first one to give 358. Then, the first alcohol should be deprotected and oxidised to carboxylic acid 359. Again the Evans auxiliary should be used to introduce the methyl group in two steps and to yield 360.

Scheme 3.31 Synthetic plan to synthesise intermediate side chain 360

The selection of the right protecting groups was essential for the success of this route. Therefore, two parallel pathways were pursued, with two different protecting group patterns.

In the beginning, alcohol 119 was protected by applying the THP- or the TBS-protecting group (scheme 3.32).¹⁷²

Scheme 3.32 THP- (A) and TBS-protection (B) of 119, subsequent DIBAL-H reduction and Ac-protection of allylic alcohols 363 and 364²¹⁵

Well known literature procedures gave desired compounds 361¹⁷¹ and 362, before both were reduced to the respective allylic alcohols 363 and 364 using DIBAL-H^152,216. For the protection of liberated allylic alcohols 363 and 364, the acetyl (Ac) group was chosen, because it should be stable under THP- and TBS-cleavage conditions. The protection to 365 and 366 proceeded as planned using acetic anhydride (Ac2O) and DMAP in pyridine (scheme 3.32).²¹⁵

The following steps involved the removal of the THP-/TBS-protecting group to form 367 and the oxidation of the liberated alcohol to carboxylic acid 368. Standard THP-deprotection conditions employing p-TosOH in MeOH²¹⁷ gave two products in a ratio of 1:1. By NMR-spectroscopy, one was identified as desired product 367 and the other as its cis isomer. Somehow, the reaction conditions triggered the isomerisation of the double bond. Finally, clean THP-deprotection was achieved by reaction with AcOH in THF and H2O (scheme 3.33).¹⁷⁰ In parallel experiments, TBS-compound 366 was deprotected using TBAF to synthesise 367 (scheme 3.33).¹⁸⁴

Scheme 3.33 Generation of alcohol 367 via THP- (A) and TBS-deprotection (B) of 365 and 366 respectively^170,184 and two-step oxidation of 367 to carboxylic acid 368^107,195

The next task was the transformation of the liberated alcohol moiety of 367 into carboxylic acid 368 by oxidation. Once again, the one-step procedure applying PDC produced negative results, giving a mixture of the respective aldehyde and acid 368 in low yields. However, the two-step procedure succeeded in preparing 368 in mediocre yields of 50% over two steps (scheme 3.33). PCC oxidation¹⁹⁵ furnished the respective aldehyde and Pinnick oxidation^106,107 carboxylic acid 368.

Then, the same procedure as before was applied to facilitate the reaction between 368 and Evans auxiliary 289,^178,179 generating product 369 in a superb yield of 95%

(scheme 3.34). With 369 in hand, the stereoselective methylation was conducted as

before (scheme 3.34).^178,179 Although methylated compound 370 was isolated, next to a large amount of unreacted educt, only low stereoinduction was detected. In addition, deprotected compound was isolated, giving rise to the fact that the Ac-group was too labile.

Scheme 3.34 Coupling of Evans auxiliary 289 with Ac-protected compound 368^178,179 and stereoselective methylation attempt of 369

Due to the presumption that the instability of the Ac-protecting group could exhibit a disrupting effect on the stereoselective methylation, a new protecting group strategy was developed. The PMB-protecting group should be used instead of the Ac-group. It should not be susceptible to a nucleophilic attack by the enolate involved in the methylation process.

For this reason, the whole sequence was replicated using the PMB-protecting group (scheme 3.35). Starting from compound 364, two methods for the PMB-protection were tested. The first one applied para-methoxybenzyl chloride (PMBCl) with NaH and catalytic amounts of tetrabutylammonium iodide (TBAI)²¹⁸ and the second one PMB-trichloroacetimidate and PPTS.²¹⁹ The latter proved superior in producing 371, because of the high yields and easy purification.

From there the next four steps were performed according to the same protocols presented before (scheme 3.35). TBS-deprotection¹⁸⁴ of 371 to 372 was followed by a two-step oxidation via aldehyde 373 to carboxylic acid 374. In this case the oxidation to aldehyde 373 was conducted by rapid Swern oxidation²²⁰ due to the

higher crude yields (96%). The coupling of 374 with Evans auxiliary 289 lead to precursor 375.

Next, the stereoselective methylation was tested using standard conditions.^178,179 Scheme 3.35 shows that the synthesis of 376 worked according to plan. From GC measurements the de of the reaction was calculated to be 88% and as a by-product about 20% of unreacted starting material was reisolated.

Scheme 3.35 Preparation of side chain 375, incorporating the PMB-protecting group, for the subsequent stereoselective methylation

3.1.4.6 Outlook

The main question that remains to be addressed is when to introduce the epoxide.

The finalisation of the side chain should incorporate PMB-deprotection to liberate allylic alcohol 344 to achieve good enantioselectivity when performing the epoxidation. Then, either the epoxidation should be carried out followed by oxidative auxiliary cleavage or vice versa to give intermediate 345 (scheme 3.26). After Protection of the alcohol and 3-acylation with tetramic acid 116 should give 341 (see chapter 3.1.4.2, scheme 3.25). The last steps to synthesise macrocidin A (5) would

involve bromination of the liberated allylic alcohol to 342, Pd-mediated macro-cyclisation and deprotection.

3.2 Contributions to the synthesis of torrubiellone D