A Formal Total Synthesis of Epothilone A:  Enantioselective Preparation of the C1−C6 and C7−C12 Fragments<sup>1</sup>

Taylor, Richard E.; Galvin, Gabriel M.; Hilfiker, Kerry A.; Chen, Yue

doi:10.1021/jo981461u

Cited by 30 publications

(7 citation statements)

References 20 publications

(18 reference statements)

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“…[ α ]$\rm{_{D}^{20}}$ =9.1° ( c =0.98, CHCl 3 ); 1 H NMR (CD 2 Cl 2 , 300 MHz): δ =4.06 (dd, J =2.6, 11.7 Hz, 1 H), 3.94 (dt, J =2.7, 11.9 Hz, 1 H), 3.84 (m, 1 H), 2.51 (q, J =7.2 Hz, 2 H), 1.62 (m, 1 H), 1.41 (s, 3 H), 1.34 (m, 1 H), 1.30 (s, 3 H), 1.11 (s, 3 H), 1.06 (s, 3 H), 0.98 (t, J =7.2 Hz, 3 H); 13 C NMR (CD 2 Cl 2 , 75 MHz): δ =215.2, 98.6, 74.3, 60.2, 50.9, 31.7, 29.9, 25.7, 21.3, 19.1, 19.0, 8.1; MS (EI): m / z (%): 215 (1), 199 (13), 156 (17), 139 (13), 127 (5), 115 (30), 99 (10), 83 (44), 71 (7), 57 (100), 43 (51), 29 (31), 55 (15); IR: ν =2975, 2939, 2877, 1706, 1467, 1381, 1372, 1273, 1198, 1105, 971, 855, 764 cm −1 ; HR‐MS (C 12 H 22 O 3 ): calcd 215.1647, found 215.1646. The analytical data are in agreement with those previously reported in the literature 51, 68…”

Section: Methodssupporting

confidence: 92%

Alkyne Metathesis: Development of a Novel Molybdenum-Based Catalyst System and Its Application to the Total Synthesis of Epothilone A and C

2001

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Sterically hindered molybdenum(III) amido complexes of the general type [Mo[(tBu)(Ar)N]3] (1), upon treatment with CH2Cl2 or other halogen donors, have been converted into highly effective catalysts for all kinds of alkyne metathesis reactions. Although the actual nature of the propagating species formed in situ is still elusive, halogen transfer to the Mo center of 1 plays a decisive role in the activation of such precatalysts. It was possible to isolate and characterize by X-ray crystallography some of the resulting molybdenum halide derivatives such as 15, 16 and 20 which themselves were shown to be catalytically active. Numerous applications illustrate the performance of the catalytic system 1/CH2Cl2 which operates under mild conditions and tolerates an array of polar functional groups. The wide scope allows the method to be implemented into the total synthesis of sensitive and polyfunctional natural products. Most notable among them is a concise entry into the potent anticancer agents epothilone A (86) and C (88). The macrolide core of these targets is forged by ring closing alkyne metathesis (RCAM) of diyne 113, followed by Lindlar hydrogenation of cycloalkyne 114 thus formed. Since this strategy opens a stereoselective entry into (Z)-alkene 115, the approach is inherently more efficient than previous syntheses based on conventional RCM.

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Section: Methodssupporting

confidence: 92%

Alkyne Metathesis: Development of a Novel Molybdenum-Based Catalyst System and Its Application to the Total Synthesis of Epothilone A and C

2001

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“…The connectivity analysis which guides our synthetic strategy is outlined in Figure . Similar to our approach to epothilone A, we chose a convergent route which has assembled the 16-membered macrolide from three fragments of similar complexity. Simplification of epothilone D was considered through three strategic disconnections.…”

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confidence: 99%

Total Synthesis of Epothilones B and D

Taylor

Chen

2001

Org. Lett.

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“…Significantly, they have been reported to be much more active against cell lines exhibiting multidrug resistance 57. Taylor et al have recently published an elegant, formal total synthesis of epothilone A 58. In this work the authors used the cross‐linked crystals of Pseudomonas (now Burkholderia ) cepacia lipase (ChiroCLEC‐PC) to resolve a key alcohol intermediate 13 by selective acylation with vinyl acetate in tert ‐butyl methyl ether.…”

Section: Applicationsmentioning

confidence: 99%

Protein Crystals as Novel Catalytic Materials

Margolin¹,

Navia²

2001

Angew. Chem. Int. Ed.

270

258

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In this era of molecular biology, protein crystallization is often considered to be a necessary first step in obtaining structural information through X‐ray diffraction analysis. In a different light, protein crystals can also be thought of as materials, whose chemical and physical properties make them broadly attractive and useful across a larger spectrum of disciplines. The full potential of these protein crystalline materials has been severely restricted in practice, however, both by their inherent fragility, and by strongly held skepticism concerning their routine and predictable growth, formulation, and practical application. Fortunately, these problems have turned out to be solvable. A systematic exploration of the biophysics and biochemistry of protein crystallization has shown that one can dependably create new protein crystalline materials more or less at will. In turn, these crystals can be readily strengthened, both chemically and mechanically, to make them suitable for practical commercialization. Today, these novel materials are used as industrial catalysts on a commercial scale, in bioremediation and “green chemistry” applications, and in enantioselective chromatography of pharmaceuticals and fine chemicals. In the near future, their utility will expand, to include the purification of protein drugs, formulation of direct protein therapeutics, and development of adjuvant‐less vaccines.

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A Formal Total Synthesis of Epothilone A: Enantioselective Preparation of the C1−C6 and C7−C12 Fragments¹

Cited by 30 publications

References 20 publications

Alkyne Metathesis: Development of a Novel Molybdenum-Based Catalyst System and Its Application to the Total Synthesis of Epothilone A and C

Alkyne Metathesis: Development of a Novel Molybdenum-Based Catalyst System and Its Application to the Total Synthesis of Epothilone A and C

Total Synthesis of Epothilones B and D

Protein Crystals as Novel Catalytic Materials

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A Formal Total Synthesis of Epothilone A: Enantioselective Preparation of the C1−C6 and C7−C12 Fragments1

Cited by 30 publications

References 20 publications

Alkyne Metathesis: Development of a Novel Molybdenum-Based Catalyst System and Its Application to the Total Synthesis of Epothilone A and C

Alkyne Metathesis: Development of a Novel Molybdenum-Based Catalyst System and Its Application to the Total Synthesis of Epothilone A and C

Total Synthesis of Epothilones B and D

Protein Crystals as Novel Catalytic Materials

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Product

Resources

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A Formal Total Synthesis of Epothilone A: Enantioselective Preparation of the C1−C6 and C7−C12 Fragments¹