Syntheses of (−)-Epothilone B

Schinzer, Dieter; Bauer, Armin; Schieber, Jennifer

doi:10.1002/(sici)1521-3765(19990903)5:9<2492::aid-chem2492>3.0.co;2-r

Cited by 94 publications

(92 citation statements)

References 6 publications

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“…It should also be noted in this context that the optical rotation reported for carboxylic acid 3 by Nicolaou and co-workers ([a] D 16) [20] is of the wrong sign. The preparation of alkyl iodide 4 has previously been described by Schinzer and coworkers [19], except for a different approach to the synthesis of carboxylic acid 11 and the use of a valine-rather than phenylalanine-derived Evans auxiliary in the crucial methylation step [13 3 14, Scheme 3). Our own synthesis of this building block is closely related to Schinzer×s approach (Scheme 3).…”

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confidence: 85%

“…As for building block 3, the chemistry outlined in Scheme 3 allowed the synthesis of 4 on a multiple-hundred-g scale. The synthesis of building block 5 is based on the known alcohol 19 [19] as an advanced intermediate (Scheme 4). Swern oxidation of 19 provided aldehyde 20 in 85% yield, which was then converted into dibromo-olefin 21 via Corey-Fuchs reaction [25].…”

mentioning

confidence: 99%

“…Large-scale preparation of 13 was, thus, based on the reaction of the anion of (4S)-4-benzyloxazolidin-2-one with crude 12 (obtained by simple evaporation of the reaction mixture), which still provided 13 in a satisfactory 82% overall yield based on 11. The choice of (4S)-4-benzyloxazolidin-2-one rather than (4S)-4-isopropyloxazolidin-2-one [19] as the chiral auxiliary in the ensuing methylation step was primarily based on the lower price of the former, which, in the anticipated subsequent scale-up of the synthesis of 4, would be of significant importance. Methylation of the sodium enolate of 13 with MeI at À 788 furnished a 11 : 1 mixture of diastereoisomers (by reversed-phase HPLC) in favor of the desired 14 (91%).…”

mentioning

confidence: 99%

“…3). It is important to note that methylation of the (4S)-N-acyl-4-isopropyl oxazolidinone analogous to 13 as described by Schinzer and co-workers [19] likewise led to a ca. 11 : 1 mixture of diastereoisomers, which, in our hands, was again inseparable by silicagel chromatography in numerous solvent systems, including the one reported [19] to provide the diastereoisomerically pure methylation product.…”

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confidence: 99%

“…The first step in this assembly process involved reductive coupling between vinyl iodide 5 and the preformed zincate derived from 4 in the presence of a Pd 0 catalyst [19], which provided trans-olefin 23 in 69% yield. Treatment of 23 with 1.1 equiv.…”

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The Total Synthesis and Biological Assessment of trans-Epothilone A

Altmann

Bold

Caravatti

et al. 2002

HCA

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Dedicated to Professor Dieter Seebach on the occasion of his 65th birthdayThe total synthesis of (12S,13S)-trans-epothilone A (1a) was achieved based on two different convergent strategies. In a first-generation approach, construction of the C(11)ÀC(12) bond by Pd 0 -catalyzed Negishi-type coupling between the C(12)-to-C(15) trans-vinyl iodide 5 and the C(7)-to-C(11) alkyl iodide 4 preceded the (nonselective) formation of the C(6)ÀC(7) bond by aldol reaction between the C(7)-to-C(15) aldehyde 25 and the dianion derived from the C(1)-to-C(6) acid 3. The lack of selectivity in the aldol step was addressed in a second-generation approach, which involved construction of the C(6)ÀC(7) bond in a highly diastereoselective fashion through reaction between the acetonide-protected C(1)-to-C(6) diol 31 (−Schinzer×s ketone×) and the C(7)-to-C(11) aldehyde 30. As part of this strategy, the C(11)ÀC(12) bond was established subsequent to the critical aldol step and was based on B-alkyl Suzuki coupling between the C(1)-to-C(11) fragment 40 and C(12)-to-C(15) trans-vinyl iodide 5. Both approaches converged at the stage of the 3-O, 7-O-bis-TBS-protected seco acid 27, which was converted to trans-deoxyepothilone A (2) via Yamaguchi macrolactonization and subsequent deprotection. Stereoselective epoxidation of the trans C(12)ÀC(13) bond could be achieved by epoxidation with Oxone ¾ in the presence of the catalyst 1,2 : 4,5-di-O-isopropylidene-l-erythro-2,3-hexodiuro-2,6-pyranose (42a), which provided a 8 : 1 mixture of 1a and its (12R,13R)-epoxide isomer 1b in 27% yield (54% based on recovered starting material). The absolute configuration of 1a was established by X-ray crystallography. Compound 1a is at least equipotent with natural epothilone A in its ability to induce tubulin polymerization and to inhibit the growth of human cancer cell lines in vitro. In contrast, the biological activity of 1b is at least two orders of magnitude lower than that of epothilone A or 1a.Introduction. ± Epothilones A and B (Fig. 1) are the main representatives of a family of bacterial natural products that exhibit potent antiproliferative activity against a broad range of human cancer cell lines. First isolated in 1993 by Reichenbach, Hˆfle, and coworkers [1], these compounds were subsequently shown by Bollag et al. to be microtubule depolymerization inhibitors [2] and, thus, to inhibit human cancer cell growth by the same mechanism of action as the renowned anticancer drug Taxol ¾ (paclitaxel) [3]. At the time of this discovery, epothilones A and B, apart from paclitaxel and its analogs, were the only compounds recognized in the literature to act as microtubule-stabilizing agents 1 ). However, in distinct contrast to paclitaxel, epothilones were found to be equally effective in vitro against drug-sensitive and multidrug-resistant cell lines [2] [5 ± 7], which immediately suggested that epothilone-derived anticancer agents could eventually be useful for the treatment of drug-resistant tumors.

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supporting

confidence: 85%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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The Total Synthesis and Biological Assessment of trans-Epothilone A

Altmann

Bold

Caravatti

et al. 2002

HCA

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Enantioselective Total Synthesis of Epothilone A Using Multifunctional Asymmetric Catalyses

Sawada

Shibasaki²

2000

Angewandte Chemie

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Epothilones (see Scheme 1 for epothilones A (1) and B (2)) show potent antitumor activity by binding and stabilizing microtubules in the same way as taxol, and they are promising drug candidates. Epothilones A and B were isolated from the groups with a dihedral angle of 608 between the two planes and in which both CO groups are cisoid (length of the PtÀPt bond 2.584 ). [7a] Other related, crystallographically characterized dinuclear platinum carbonyl species include [{PtCl(CO)(PtBu 2 Ph)} 2 ] [7b] and [{Pt(C 6 F 5 )(CO)(PPh 3 )} 2 ], [7c] which have dihedral angles of 70.18 and 78.68, and PtÀPt distances of 2.628 and 2.599(), respectively. Preliminary reports have also appeared for [{PtCl(CO)(PPh 3 )} 2 ] [8] and, in all cases, the carbonyl groups are cis and the two phosphanes are trans to the PtÀPt bond.It has been shown that there is no correlation of d(PtÀPt) with 1 J(Pt,Pt') in closely related dinuclear platinum complexes. [8] It is worth noting that 1 J(Pt,Pt') for 1 is 550.9 Hz, while the values for [{PtCl 2 (CO)} 2 ] 2À (5250 Hz) [9] and [{PtCl(CO)(PPh 3 )} 2 ] (760 Hz) [8] are widely different, although other related coupling constants are similar (see Table 1 and refs. [8, 9]).Prolonged evacuation of 1 results in disproportionation and formation of 2 through loss of CO [see Eq. (2)]. In this case, 13 C and 195 Pt NMR measurements on unenriched and 99 % 13 CO-enriched 2 show that there are two magnetically equivalent carbonyl groups per platinum with no 195 PtÀ 195 Pt coupling; 2 is thus a monomer. We presently favor a squareplanar platinum(ii) center with two CO ligands in a cis configuration, consistent with both IR and Raman measurements; the CO stretching frequencies are close to those for cis-[Pt(CO) 2 (SO 3 F) 2 ], [5b] but higher than those for cis-[Pt(CO) 2 Cl 2 ]. [10] It is difficult to be sure whether the other two coordination sites on platinum are occupied by a bidentate SO 4 2À or by two monodentate SO 4 2À /HSO 4 À groups since it is impossible to obtain any useful IR or Raman data in the sulfato region. However, when 1 is in concentrated H 2 SO 4 , it seems more probable that the other two sites are occupied by monodentate HSO 4 À groups as recently found for silver(i). [11] The discovery of 1 suggests that homoleptic cationic carbonyl complexes of late transition metals in low oxidation states can be formed in media which are less acidic than the superacids that have been used previously. We found that this unusual dinuclear platinum carbonyl complex, 1, exhibits high catalytic activity for the carbonylation of olefins; [12] future studies will investigate the detailed reaction mechanism of this catalytic activity and attempts will be made to obtain 1 as a crystalline salt. Experimental SectionStandard canula transfer techniques were used for all sample manipulations. NMR spectra were recorded in D 2 SO 4 at room temperature on a Bruker AMX 200. The 13 C chemical shifts were referenced to external tetramethylsilane (TMS), and 195 Pt chemical shifts were referenced to 42.8 MHz at s...

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