Total Synthesis of Epothilones

Storer RI, Takemoto T, Jackson PS, Brown DS, Baxendale IR, Ley SV (2004) Multi-step application of immobilized reagents and scavengers a total synthesis of epothilone C. Chem Eur J 10 2529-2547... 

Grieco in the total synthesis of (—)-epothilone B 134 used a rhodium-catalyzed hydroboration as a key step in the synthesis of the macrocyclic ring (Figure 15).141 Completion of the synthesis of the C(3)-C(12) fragment was carried out using a rhodium-catalyzed hydroboration as the key step. 

Total Synthesis of Epothilones Via Ring-Closing Metathesis. 75... 

Using a similar C12,C 13 disconnection approach, Schinzer et al. also achieved a total synthesis of epothilone A (4) [16]. The key step involved a highly selective aldol reaction between ketone 27 and aldehyde 10 to afford exclusively alcohol 28 with the correct C6,C7 stereochemistry (Scheme 6). Further elaboration led to triene 29, which underwent RCM using ruthenium initiator 3 in dichloromethane at 25°C, to afford macrocyles 30 in high yield (94%). Although no selectivity was observed (Z E=1 1), deprotection and epoxidation of the desired Z-isomer (30a) completed the total synthesis [16]. 

The greater reactivity of terminal olefins compared to their more hindered di-and tri-substituted counterparts became evident in the model studies (Sect. 2.2.1) and in the total synthesis of epothilones A, B and E (Sects. 2.2.2-2.2.4). Suitably positioned disubstituted olefins can, however, participate in RCM reactions employing the molybdenum initiator 1 [19], and this is demonstrated in the total synthesis of epothilone B (5) (Sect. 2.2.3). As expected this transformation proved impossible using the ruthenium complex 3. 

Scheme 12. Shibasaki utilizes a Al-catalyzed asymmetric CN addition to aldehydes and a La-catalyzed asymmetric aldol in the total synthesis of epothilone A (2000).

D. Sawada, M. Shibasaki Enantioselective Total Synthesis of Epothilone A Using Multifunctional Asymmetric Catalyses , Angew. Chem, Int. Ed Engl 2000,39,209-213. 

Scheme 2.1 Bond construction strategies for total synthesis of epothilone A and B.

A second key component of our practical total synthesis of epothilone B includes a B-alkyl Suzuki merger, Scheme 2.8, which successfully occurs between the previously described vinyl iodide [34] 66 and tricarbonyl 65. With the coupling step accomplished, the resultant TBS protecting group could be hydrolyzed to afford the requisite C15-hydroxy ester 67. 

Total synthesis of complex (macrocyclic) natural products using fast and flexible strategies and diversity-oriented synthesis of natural product-like macrocycles are important research topics in our laboratory. The following sections describe the total synthesis of epothilone D and epothilone D5 analogues, DOS of cyclopeptide alkaloid analogues, of biaryl ether macrocycles, and of steroid/peptide hybrid macrocycles, respectively. 

Recently, Hofle and Reichenbach also described the isolation of some further components of the epothilone family [93]. One of these was epothilone D5 (Fig. 14), which differs from epothilone D by the presence of an additional unsaturation between C8 and C9. Since this double bond is inherent to our synthesis of epothilone D, we also decided to pursue the total synthesis of epothilone D5 and its diastereomers. 

Highly diastereoselective dioxirane epoxidations have been widely employed in organic synthesis. For example, in the total synthesis of epothilone B, an important antitumor agent , the required epoxide was obtained in good yield and diastereoselectivity by DMD oxidation (equation 7) . ... 

Carreira and co-workers (138) successfully applied the Mg(II) ion-mediated nitrile oxide cycloaddition method to the total synthesis of epothilones A and B (Scheme 11.36). The key step in the synthesis was a hydroxyl-directed syn-selective nitrile oxide cycloaddition using a phosphorus-functionalized aliphatic nitrile oxide. This cycloaddition step served not only to introduce a heterocycle-substituted appendage into the skeleton of the epothilones, but also to assemble two... 

A Stille type coupling strategy has been utilised to complete a total synthesis of epothilone E. The vinyl iodide 30 and the thiazole stannane 31 were coupled to give the macrolactone 32 which is a precursor to natural epithilone E. The thiazole stannane 31 was prepared from 4-bromo-2-hydroxymethylthiazole via treatment of the lithiated protected 4-bromO 2-hydroxymethylthiazole with tributylstannyl chloride. This Stille coupling approach was also used to prepare a range of epothilone B analogues <99BMC665>,... 

The natural products epothilone A and B are structurally different from taxol but have similar anticancer activity. Significantly, they have been reported to be much more active against cell lines exhibiting multiple-drug resistance [26], Taylor and co-workers at the University of Notre Dame have recently published an elegant, formal total synthesis of epothilone A [27], In this work, the authors used the CLC form of Burkholderia cepacia (formerly Pseudomonas cepacia) lipase (ChiroCLEC -PC) to resolve a key alcohol intermediate by selective acylation with vinyl acetate in /-butyl methyl ether (Fig. 6). The enantioselectivity was >20 1 at 47% conversion and efficiently provided gram quantities of the desired (R) alcohol. Since the unreacted (S) alcohol can easily be epimerized by a simple oxidation-reduction sequence and the catalyst reused without significant loss in activity, the method is ideally suited for scale-up. 

RE Taylor, GM Galvin, KA Hilfiker, Y Chen. A formal total synthesis of epothilone A enantioselective preparation of the C1-C6 and C7-C12 fragments. J Org Chem 63 9580-9583, 1998. 

Scheme 2. Total synthesis of epothilon A on solid-phase by Nicolaou et al.

Epothilone A (2) is a natural product that exhibits taxoterelike anticancer activity. A new synthesis of the ketoacid 6, a common C1-C6 fragment used in the total synthesis of epothilone A, was accomplished by directed aldol reaction of acetone with the aldehyde 34 (Scheme 2.3c). The aldol reaction of acetone with the aldehyde 3 in the presence of D-proline proceeded smoothly to furnish the expected aldol product (4) in 75% yield and with greater than 99% ee. Intramolecular aldol reaction of the hydroxy ketone 4 in the presence of pyrrolidine gave the cyclohexenone 5 in good yield. Protection of the alcohol as a TBS ether followed by oxidation of the alkene then produced the desired ketoacid (6). 

In the total synthesis of epothilone E and other C20-derivatives, substituted thiazole (and other aromatics) have been coupled according to Stille s method to the macrocyclic vinyl iodide 74 obtained with selective RCM, leaving the vinyl iodide unaffected (Scheme 13) [18, 19]. The 2-substituted 4-trialkylstannyl-thiazoles 77 were synthesized from 2,4-dibromothiazolc 75 in five steps, as shown in Scheme 14. 

Sinha SC, Barbas CF 111, Lemer, RA. The antibody catalysis route to tbe total synthesis of epothilones. Proc. Natl. Acad. Sci. U.S.A. 1998 95(25) 14603-14608. 

Sinha SC, Sun J, Miller GP, Wartmann M, Lemer RA. Catalytic antibody route to tbe naturally occurring epotbilones total synthesis of epothilones A-F. Chem. Eur. J. 2001 7(8) 1691—1702. Haga N, Takayanagi H. Mechanisms of the photochemical rearrangement of diphenyl ethers. J. Oig. Chem. 1996 61(2) 735—745. Dickerson TJ, Tremblay MR, Hoffman TZ, Ruiz Dl, Janda KD. Catalysis of the photo-Fries reaction antibody-mediated stabi-hzation of high eneigy states. J. Am. Chem. Soc. 2003 125(50) 15395-15401. 

During the total synthesis of epothilone B, J.D. White et al. used the modified Castro-Stephens reaction instead of a Wittig reaction for the coupling of two important subunits (A B) to avoid strongly basic conditions. 

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