Epothilone B synthesis

Schinzer then performed the same reaction with a-chiral aldehyde 17. Remarkably, this reaction provided again a single isomer 18 with the natural epothilone configuration in 49% yield [19]. The fully functionalized aldehyde 19 from Schinzer s epothilone B synthesis was also used in the same aldol process. However, a 10 1 mixture of diastereomers was obtained with the correct stereochemistry as the major product 20 [20]. In the meantime, Schinzer s chiral enolate 15 has been used extensively by other groups in academia [21] and in the pharmaceutical industry to synthesize a large number of analogues [22]. Most of the examples with highly func-... 

Some additional examples are given in Scheme 8.6. The electrophiles that have been used successfully include iodine (Entries 2 and 3) and cyanogen chloride (Entry 4). The adducts can undergo conjugate addition (Entry 5), alkylation (Entry 6), or epoxide ring opening (Entries 7 and 8). The latter reaction is an early step of a synthesis of epothilone B. 

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. 

With the C12,C13 disconnection producing an effective solution to the synthesis of epothilone A (4), it would seem likely that the metathesis approach could be extended readily to the preparation of epothilone B (5). However, installation of the desired C12 methyl group requires ring-closure of a diene precursor in which one of the olefins is disubstituted. Recently, such reactions have been shown to be problematic for Grubbs initiator 3 but more successful with Schrock s molybdenum initiator 1 [19]. Consistent with these reports, Danishefsky demonstrated that triene 38 would not undergo RCM with 3, whereas 1 was effective in promoting the transformation of 38 into a 1 1 mixture of 39a and 39b in good yield [14b] (Scheme 8). 

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. 

The Wittig reaction was employed to fuse diene 49 and aldehyde 50, in the final stages of the stereoselective synthesis of epothilone B, a macrocyclic compound with potential antifungal properties (equation 31)49. 

Scheme 2.6 Late generation synthesis of desoxy epothilone B and epothilone B. The key steps in this total synthesis are a stereospecific aldol reaction, B-alkyl Suzuki coupling, and stereoselective Noyori reaction.

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. 

After extensive developmental studies, [35] the final crucial element in our most recent synthesis of epothilone B involves an asymmetric catalytic reduction of the C3 ketone of 67 proceeding via a modified Noyori procedure (Scheme 2.8, 67—>68). In the event, Noyori reduction of ketone 67 afforded the desired diol 68 with excellent diasteresdectivity (>95 5). The ability to successftdly control the desired C3 stereochemistry of the late stage intermediate 68 permitted us to introduce the Cl-C7 fragment into the synthesis as an achiral building block. 

One example of the successful use of a macroaldolization was described by Danishefsky et al. in their early synthesis of epothilone B [49]. Another one by us is reported below [50]. 

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) . ... 

Epinephrine, chemiluminescence, 647 6-Epiplakortolide E, synthesis, 256, 257 Epithelial cells, ozone effects, 612 Epothilone B, dioxirane epoxidation synthesis, 1145... 

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>,... 

An unusual enolate of the 3-triethylsilyl-pro-tected 1,3,5-tricarbonyl compound 69 was applied to aldehyde 70 by Danishefsky et al., forming aldol 71 in 74 % yield and with a 5.5 1.0 ratio - remarkable considering that in this case no double stereodifferentiation improves the induction [10, 52J. A systematic study with different aldehydes revealed that an interaction between the double bond and the carbonyl group of the aldehyde is superior to minimization of steric hindrance in the transition state, thus leading to the desired C7-C8 anti relationship [53]. Later in the synthesis of epothilone B, in Danishefsky s approach, the triethylsilyl group was removed and the C3 ketone converted to the desired C3 alcohol by enantioselective catalytic Noyori reduction [10]. 

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. 

During the highly stereoselective total synthesis of epothilone B by J.D. White and co-workers, the stereochemistry of the alcohol portion of the macrolactone was established by applying Davis oxaziridine oxidation of a sodium enolate. The sodium enolate was generated from the corresponding chiral oxazolidinone derivative, which upon oxidation gave 71% yield of a-hydroxylated compound. 

The total synthesis of the microtubule stabilizing antitumor drug epothilone B was achieved by J. Mulzer et al. who cyclized the 16-membered macrocycle using the Keck macroiactonization. ... 

The final step in J. Mulzer s total syntheses of epothilones B and D was the oxidation of the C12-C13 double bond of epothilone D via a highly diastereoselective Priiezhaev reaction to obtain epothilone B. The same mCPBA oxidation endgame was chosen by R. E. Taylor et al. in the total synthesis of these two natural products. ... 

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