189453-10-9

Basic information

• Product Name: Epothilone D
• Synonyms: Oxacyclohexadec-13-ene-2,6-dione, 4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-(1E)-1-methyl-2-(2-methyl-4-thiazolyl)ethenyl-, (4S,7R,8S,9S,13Z,16S)-;Oxacyclohexadec-13-ene-2,6-dione, 4,8-dihydroxy-5,5,7,9,13-pentamethyl -16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-, (4S-(4R*,7S,8R*,9R*,1 3Z,16R*(E)))-;(3S,7S,14S,15S,16R)-3,15-Dihydroxy-2,2,10,14,16-pentamethyl-7-[1-(2-methyl-1,3-thiazol-4-yl)prop-1-en-2-yl]-6-oxacyclohexadec-9-ene-1,5-dione;Epothilone D;Desoxyepothilone B;(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-5,5,7,9,13-pentaMethyl-16-[(1E)-1-Methyl-2-(2-Methyl-4-thiazolyl)ethenyl]oxacyclohexadec-13-ene-2,6-dione;12,13-Desoxyepothilone B;Epo D
• CAS NO: 189453-10-9
• Molecular Formula: C₂₇H₄₁NO₅S
• Molecular Weight: 491.68
• Product Categories: Inhibitors;Chiral Reagents;Intermediates & Fine Chemicals;Pharmaceuticals;Sulfur & Selenium Compounds;Anti-cancer&immunity
• Mol File: 189453-10-9.mol
• Article Data: 36

Chemical Properties

• Melting Point: 63-66°C
• Boiling Point: 663.658 °C at 760 mmHg
• Flash Point: 355.168 °C
• Appearance: /
• Density: 1.085 g/cm³
• Vapor Pressure: 1.62E-18mmHg at 25°C
• Refractive Index: 1.522
• Storage Temp.: -20°C Freezer
• Solubility: Soluble in DMSO
• PKA: 13.47±0.70(Predicted)
• CAS DataBase Reference: Epothilone D(CAS DataBase Reference)
• NIST Chemistry Reference: Epothilone D(189453-10-9)
• EPA Substance Registry System: Epothilone D(189453-10-9)

Safety Data

• Hazardous Substances Data: 189453-10-9(Hazardous Substances Data)

Usage

Description

Epothilones are microtubule-stabilizing agents with potential anti-neoplastic actions. They are natural macrolides that have high potency in both taxane-sensitive and taxane-resistant models. Epothilone D is a desoxy form of epothilone B (Item No. 10924) that inhibits the growth of a variety of cancer cells both in vitro (IC50 values range from 0.97 to 21 nM) and in mice. Epothilone D is brain penetrant and reduces neurodegeneration in aged tau transgenic mice. Effects include improved axonal transport, decreased tau neuropathology, and reduced hippocampal neuron loss. Epothilone D also rescues microtubule defects and attenuates nigrostriatal degeneration in a mouse model of Parkinson’s disease.

Chemical Properties

White Foam

Uses

Different sources of media describe the Uses of 189453-10-9 differently. You can refer to the following data:
1. Epothilones are polyketide natural products that inhibit cancer cells by a mechanism similar to paclitaxel, and also are effective against paclitaxel-resistant tumours. Epothilone D is in phase I clinical testing of in patients with advanced solid tumours. Epothilone D is a cytotoxic macrolide that stabilises malignant cells' microtubules and arrests mitosis, a characteristic it shares with other epothilones. They bind to the same hepatic sites as does paclitaxel (Taxol) in a 1:1 stoichiometric ratio of a, b-tubulin heterodimers.
2. Epothilones are polyketide natural products that inhibit cancer cells by a mechanism similar to paclitaxel, and also are effective against paclitaxel-resistant tumours. Epothilone D is in phase I clinical testing of in patients with advanced solid tumours. Epothilone D is a cytotoxic macrolide that stabilises malignant cells'' microtubules and arrests mitosis, a characteristic it shares with other epothilones. They bind to the same hepatic sites as does paclitaxel (Taxol) in a 1:1 stoichiometric ratio of a, b-tubulin heterodimers.

Definition

ChEBI: An epithilone that is epithilone C in which the hydrogen at position 13 of the oxacyclohexadec-13-ene-2,6-dione macrocycle has been replaced by a methyl group.

in vitro

epothilone d is a more potent microtubule stabilizer in vitro than epothilone a or b. in vitro, epothilone d showed potent cytotoxicity in a panel of human tumor cell lines, with similar potency to paclitaxel. it also showed definite advantage over paclitaxel in drug-resistant cell lines, and retained its cytotoxicity against a multidrug resistant cell line over-expressing p-glycoprotein [1].

in vivo

in vivo, antitumor efficacy of epothilone d has been observed in both paclitaxel sensitive and resistant xenografts, as well as certain multidrug resistant xenografts including a doxorubinresistant ccrf-cem leukemic cell xenograft [1].

IC 50

2.9 nm for mcf-7 cell line; 2.7 nm for kb-31 cell line; 9.5 nm for ccrf-cem cell line

references

[1] konner j, grisham rn, park j, o'connor oa, cropp g, johnson r, hannah al, hensley ml, sabbatini p, mironov s, danishefsky s, hyman d, spriggs dr, dupont j, aghajanian c. phase i clinical, pharmacokinetic, and pharmacodynamic study of kos-862 (epothilone d) in patients with advanced solid tumors and lymphoma. invest new drugs. 2012 dec;30(6):2294-302. doi: 10.1007/s10637-011-9765-7.

InChI:InChI=1/C27H41NO5S/c1-16-9-8-10-17(2)25(31)19(4)26(32)27(6,7)23(29)14-24(30)33-22(12-11-16)18(3)13-21-15-34-20(5)28-21/h11,13,15,17,19,22-23,25,29,31H,8-10,12,14H2,1-7H3/b16-11-,18-13+/t17-,19+,22?,23-,25-/m0/s1

Synthetic route

12,13-deoxy-3-(triethylsilyloxy)epothilone B (241129-41-9) → epothilone D (189453-10-9)

Conditions	Yield
With pyridine hydrogenfluoride In tetrahydrofuran	98%
With pyridine hydrogenfluoride In tetrahydrofuran at 0℃; for 5h;	91%

(4S,7R,8S,9S,13Z,16S)-4,8-bis{[tert-butyl(dimethyl)silyl]oxy}-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxacyclohexadec-13-ene-2,6-dione (189453-35-8) → epothilone D (189453-10-9)

Conditions	Yield
With pyridine hydrogenfluoride In tetrahydrofuran at 20℃; for 36h;	96%
With pyridine; pyridine hydrogenfluoride In tetrahydrofuran at 0 - 20℃; for 36h;	96%
With pyridine hydrogenfluoride In tetrahydrofuran	92%

(13Z,4S,7R,8S,9S,16S)-4-(tert-butyldimethylsilyloxy)-8-hydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methylthiazol-4-yl)vinyl]oxacyclohexadec-13-ene-2,6-dione (219823-99-1) → epothilone D (189453-10-9)

Conditions	Yield
With pyridine hydrogenfluoride In tetrahydrofuran at 20℃; for 16h;	95%
With trifluoroacetic acid In dichloromethane at 0℃; for 1.5h;	69%

(Z)-(4S,6R,7S,8S,9S,16S)-8-(tert-Butyl-dimethyl-silanyloxy)-4,6-dihydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-thiazol-4-yl)-vinyl]-oxacyclohexadec-13-en-2-one (189453-51-8) → epothilone D (189453-10-9)

Conditions	Yield
With pyridine hydrogenfluoride In tetrahydrofuran at 0 - 20℃; for 2h; desilylation;	92%
Multi-step reaction with 3 steps 1: 89 percent / 2,6-lutidine / CH2Cl2 / -30 °C 2: 67 percent / Dess-Martin periodinane / CH2Cl2 / Ambient temperature 3: 80 percent / HF*pyridine / tetrahydrofuran / Ambient temperature View Scheme

Carbonic acid (Z)-(4S,7R,8S,9S,16S)-4-hydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-thiazol-4-yl)-vinyl]-2,6-dioxo-oxacyclohexadec-13-en-8-yl ester 2,2,2-trichloro-ethyl ester (380605-94-7) → epothilone D (189453-10-9)

Conditions	Yield
With ammonium chloride; zinc In methanol Heating;	92%

(E)-9,10-dehydro-12,13-desoxyepothilone B (350493-61-7) → epothilone D (189453-10-9)

Conditions	Yield
With TrisNHNH2; triethylamine In 1,2-dichloro-ethane at 50℃; for 7h;	91%
With TrisNHNH2; triethylamine In 1,2-dichloro-ethane at 50℃; for 7h;	91%
With potassium diazodicarboxylate; acetic acid In 1,2-dichloro-ethane at 45℃;	60%

10,11-didehydroepothilone D (371979-40-7) → epothilone D (189453-10-9)

Conditions	Yield
With potassium diazodicarboxylate; acetic acid In dichloromethane Heating;	86%

epothilone B (152044-54-7) → epothilone D (189453-10-9)

Conditions	Yield
With n-butyllithium; tungsten(VI) chloride In tetrahydrofuran deoxygenation;	78%

7-[(1E)-1-methyl-2-(2-methyl(1,3-thiazol-4-yl))vinyl]-(3S,7S,14S,15S,16R)-3,15-dihydroxy-2,2,10,14,16-pentamethyl-6-oxacyclohexadeca-9,12-diene-1,5-dione (220889-57-6) → epothilone D (189453-10-9)

Conditions	Yield
With trisylhydrazine; triethylamine In diethyl ether at 39℃;	71%
With trisylhydrazine; triethylamine In 1,2-dichloro-ethane at 50℃; for 18h;	70%
With potassium diazodicarboxylate; acetic acid In dichloromethane for 24h; Heating;	52%
With potassium diazodicarboxylate; acetic acid In dichloromethane for 25h; Heating;	52%

(Z)-(4S,7R,8S,9S,16S)-4,8-Bis-(tert-butyl-dimethyl-silanyloxy)-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-thiazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dione (204195-20-0) → epothilone D (189453-10-9) + E-epothilone D (189453-40-5)

Conditions	Yield
With pyridine hydrogenfluoride In tetrahydrofuran at 20℃; for 1.5h; desilylation;
With trifluoroacetic acid In dichloromethane at 0 - 20℃;
With pyridine; hydrogen fluoride In tetrahydrofuran at 20℃;

(3S,6R,7S,8S,12Z,15S,16E)-3-(tert-butyldimethylsilyloxy)-7-hydroxy-15-(2-trimethylsilylethoxymethoxy)-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxoheptadeca-12,16-dienoic acid (823789-81-7) → epothilone D (189453-10-9)

Conditions

Yield

Multi-step reaction with 7 steps 1.1: pyridine / CH2Cl2 / 1 h / 0 °C 2.1: CH2Cl2 / 5 h / 20 °C 3.1: 0.67 g / acetic acid / tetrahydrofuran; H2O / 3 h / 0 °C 4.1: 72 percent / magnesium bromide; nitromethane; 1-butanethiol / diethyl ether / 1 h / 20 °C 5.1: 2,4,6-trichlorobenzoyl chloride; triethylamine / tetrahydrofuran / 1 h / 0 °C 5.2: 0.14 g / DMAP / toluene; tetrahydrofuran / 4 h / 20 °C 6.1: 92 percent / zinc; ammonium chloride / methanol / 0.33 h / Heating 7.1: 95 percent / hydrogen fluoride-pyridine / tetrahydrofuran / 16 h / 20 °C View Scheme

(12Z,16E)-(3S,6R,7S,8S,15S)-3-(tert-Butyl-dimethyl-silanyloxy)-15-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-thiazol-4-yl)-5-oxo-7-(2,2,2-trichloro-ethoxycarbonyloxy)-heptadeca-12,16-dienoic acid (380605-92-5) → epothilone D (189453-10-9)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: 2,4,6-trichlorobenzoyl chloride; triethylamine / tetrahydrofuran / 1 h / 0 °C 1.2: 0.14 g / DMAP / toluene; tetrahydrofuran / 4 h / 20 °C 2.1: 92 percent / zinc; ammonium chloride / methanol / 0.33 h / Heating 3.1: 95 percent / hydrogen fluoride-pyridine / tetrahydrofuran / 16 h / 20 °C View Scheme

C45H85NO7SSi3 → epothilone D (189453-10-9)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: CH2Cl2 / 5 h / 20 °C 2.1: 0.67 g / acetic acid / tetrahydrofuran; H2O / 3 h / 0 °C 3.1: 72 percent / magnesium bromide; nitromethane; 1-butanethiol / diethyl ether / 1 h / 20 °C 4.1: 2,4,6-trichlorobenzoyl chloride; triethylamine / tetrahydrofuran / 1 h / 0 °C 4.2: 0.14 g / DMAP / toluene; tetrahydrofuran / 4 h / 20 °C 5.1: 92 percent / zinc; ammonium chloride / methanol / 0.33 h / Heating 6.1: 95 percent / hydrogen fluoride-pyridine / tetrahydrofuran / 16 h / 20 °C View Scheme

(3S,6R,7S,8S,12Z,15S,16E)-3-(tert-butyldimethylsilyloxy)-7-[(2,2,2-trichloroethoxycarbonyl)oxy]-15-(2-trimethylsilylethoxymethoxy)-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxoheptadeca-12,16-dienoic acid (823789-87-3) → epothilone D (189453-10-9)

Conditions

Yield

Multi-step reaction with 4 steps 1.1: 72 percent / magnesium bromide; nitromethane; 1-butanethiol / diethyl ether / 1 h / 20 °C 2.1: 2,4,6-trichlorobenzoyl chloride; triethylamine / tetrahydrofuran / 1 h / 0 °C 2.2: 0.14 g / DMAP / toluene; tetrahydrofuran / 4 h / 20 °C 3.1: 92 percent / zinc; ammonium chloride / methanol / 0.33 h / Heating 4.1: 95 percent / hydrogen fluoride-pyridine / tetrahydrofuran / 16 h / 20 °C View Scheme

C48H86Cl3NO9SSi3 → epothilone D (189453-10-9)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: 0.67 g / acetic acid / tetrahydrofuran; H2O / 3 h / 0 °C 2.1: 72 percent / magnesium bromide; nitromethane; 1-butanethiol / diethyl ether / 1 h / 20 °C 3.1: 2,4,6-trichlorobenzoyl chloride; triethylamine / tetrahydrofuran / 1 h / 0 °C 3.2: 0.14 g / DMAP / toluene; tetrahydrofuran / 4 h / 20 °C 4.1: 92 percent / zinc; ammonium chloride / methanol / 0.33 h / Heating 5.1: 95 percent / hydrogen fluoride-pyridine / tetrahydrofuran / 16 h / 20 °C View Scheme

4-(hydroxymethyl)-2-methylthiazole (76632-23-0) → epothilone D (189453-10-9)

Conditions

Yield

Multi-step reaction with 13 steps 1.1: 85 percent / Ph3P; CBr4 / CCl4 / 3 h / 20 °C 2.1: 86 percent / 3 h / 160 °C 3.1: n-butyllithium / tetrahydrofuran; hexane / 1 h / -78 °C 3.2: 86 percent / tetrahydrofuran; hexane / 12 h / -78 - 20 °C 4.1: (1R)-(+)-pinene; BH3*DMS / tetrahydrofuran / 0.5 h / 20 °C 4.2: 78 percent / lithium hydroxide; sodium perborate / tetrahydrofuran; H2O / 2 h / 20 °C 5.1: 94 percent / oxalyl chloride; DMSO; triethylamine / CH2Cl2 / -78 - 0 °C 6.1: diisopropylamine; n-butyllithium / tetrahydrofuran; hexane / 1.25 h / -78 - -40 °C 6.2: 59 percent / ZnCl2 / tetrahydrofuran; hexane; diethyl ether / 0.25 h / -78 °C 7.1: pyridine / CH2Cl2 / 1 h / 0 °C 8.1: CH2Cl2 / 5 h / 20 °C 9.1: 0.67 g / acetic acid / tetrahydrofuran; H2O / 3 h / 0 °C 10.1: 72 percent / magnesium bromide; nitromethane; 1-butanethiol / diethyl ether / 1 h / 20 °C 11.1: 2,4,6-trichlorobenzoyl chloride; triethylamine / tetrahydrofuran / 1 h / 0 °C 11.2: 0.14 g / DMAP / toluene; tetrahydrofuran / 4 h / 20 °C 12.1: 92 percent / zinc; ammonium chloride / methanol / 0.33 h / Heating 13.1: 95 percent / hydrogen fluoride-pyridine / tetrahydrofuran / 16 h / 20 °C View Scheme

4-(chloromethyl)-2-methyl-1,3-thiazole (39238-07-8) → epothilone D (189453-10-9)

Conditions	Yield
Multi-step reaction with 12 steps 1.1: 86 percent / 6 h / 160 °C 2.1: n-butyllithium / tetrahydrofuran; hexane / 1 h / -78 °C 2.2: 86 percent / tetrahydrofuran; hexane / 12 h / -78 - 20 °C 3.1: (1R)-(+)-pinene; BH3*DMS / tetrahydrofuran / 0.5 h / 20 °C 3.2: 78 percent / lithium hydroxide; sodium perborate / tetrahydrofuran; H2O / 2 h / 20 °C 4.1: 94 percent / oxalyl chloride; DMSO; triethylamine / CH2Cl2 / -78 - 0 °C 5.1: diisopropylamine; n-butyllithium / tetrahydrofuran; hexane / 1.25 h / -78 - -40 °C 5.2: 59 percent / ZnCl2 / tetrahydrofuran; hexane; diethyl ether / 0.25 h / -78 °C 6.1: pyridine / CH2Cl2 / 1 h / 0 °C 7.1: CH2Cl2 / 5 h / 20 °C 8.1: 0.67 g / acetic acid / tetrahydrofuran; H2O / 3 h / 0 °C 9.1: 72 percent / magnesium bromide; nitromethane; 1-butanethiol / diethyl ether / 1 h / 20 °C 10.1: 2,4,6-trichlorobenzoyl chloride; triethylamine / tetrahydrofuran / 1 h / 0 °C 10.2: 0.14 g / DMAP / toluene; tetrahydrofuran / 4 h / 20 °C 11.1: 92 percent / zinc; ammonium chloride / methanol / 0.33 h / Heating 12.1: 95 percent / hydrogen fluoride-pyridine / tetrahydrofuran / 16 h / 20 °C View Scheme
Multi-step reaction with 11 steps 1.1: 84 percent / 2 h / 165 °C 2.1: tBuOK / tetrahydrofuran 2.2: 75 percent / tetrahydrofuran / 4 h / -30 - 20 °C 3.1: AcOH; H2O / tetrahydrofuran / 24 h / 20 °C 4.1: NaBH4 / methanol 5.1: CBr4; PPh3 / acetonitrile / 0 °C 5.2: 91 percent / 2,6-di-tert-butyl-4-methylpyridine / acetonitrile / -40 °C 6.1: tetrahydrofuran / -78 °C 7.1: LiHMDS / tetrahydrofuran / -78 °C 7.2: 80 percent / tetrahydrofuran 8.1: TMSOTf; collidine / CH2Cl2 / 1 h / 0 °C 8.2: 85 percent / nBu4NF / tetrahydrofuran 9.1: 2,4,6-trichlorobenzoyl chloride; Et3N / tetrahydrofuran / 1 h / 20 °C 9.2: 60 percent / DMAP / toluene / 80 °C 10.1: 86 percent / TFA / CH2Cl2 / 0 °C 11.1: 71 percent / 2,4,6-triisopropylbenzenesulfonyl hydrazide; Et3N / diethyl ether / 39 °C View Scheme
Multi-step reaction with 18 steps 1.1: 97 percent / benzene / 8 h / Heating 2.1: 10.95 g / LiHMDS / tetrahydrofuran / 0.67 h / 55 °C 3.1: oxalyl chloride; DMSO; DIPEA / CH2Cl2 / -78 - 20 °C 4.1: KHMDS; 18-crown-6 / tetrahydrofuran / 0.25 h 4.2: 5.45 g / tetrahydrofuran / 0.5 h / -78 °C 5.1: 98 percent / DIBALH / tetrahydrofuran; heptane / 2.5 h / 0 °C 6.1: Ph3P; imidazole; I2 / acetonitrile; diethyl ether / 1 h / 20 °C 7.1: 18-crown-6; KHMDS / tetrahydrofuran / 1 h / -78 °C 7.2: 93 percent / tetrahydrofuran / 1 h / -78 °C 8.1: 65 percent / Na2HPO4; Na-Hg amalgam / methanol; tetrahydrofuran / -15 - 20 °C 9.1: 99 percent / CSA / methanol; CH2Cl2 / 5 h / 0 - 10 °C 10.1: Dess-Martin periodinane; pyridine / CH2Cl2 / 4 h / 20 °C 11.1: LDA / tetrahydrofuran / 1 h / -78 - -35 °C 11.2: tetrahydrofuran / 1.5 h / -95 - -80 °C 12.1: 99 percent / 2,6-lutidine / CH2Cl2 / 3 h / 0 °C 13.1: 87 percent / CSA / methanol; CH2Cl2 / 4 h / 0 °C 14.1: Dess-Martin periodinane; Py / CH2Cl2 / 2 h / 20 °C 15.1: 380 mg / NaClO2; NaH2PO4 / 2-methyl-propan-2-ol; various solvent(s); H2O / 3 h 16.1: 55 percent / TBAF / tetrahydrofuran / 10 h / 20 °C 17.1: 69 percent / N-ethyl-N'-(3-(dimethylamino)propyl)carbodiimide *HCl; DMAP; DMAP*HCl / CHCl3 / 17 h / Heating 18.1: 96 percent / HF*Py; Py / tetrahydrofuran / 36 h / 0 - 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: 4 h / Reflux 2.1: potassium hexamethylsilazane / tetrahydrofuran / 0.25 h / 0 °C 2.2: 2 h / -78 - -20 °C 3.1: trifluoroacetic acid / dichloromethane / 1 h / 0 °C View Scheme

ethyl 2-methylthiazole-4-carboxylate (6436-59-5) → epothilone D (189453-10-9)

Conditions	Yield
Multi-step reaction with 14 steps 1.1: 84 percent / LiAlH4 / diethyl ether / 3 h / -78 °C 2.1: 85 percent / Ph3P; CBr4 / CCl4 / 3 h / 20 °C 3.1: 86 percent / 3 h / 160 °C 4.1: n-butyllithium / tetrahydrofuran; hexane / 1 h / -78 °C 4.2: 86 percent / tetrahydrofuran; hexane / 12 h / -78 - 20 °C 5.1: (1R)-(+)-pinene; BH3*DMS / tetrahydrofuran / 0.5 h / 20 °C 5.2: 78 percent / lithium hydroxide; sodium perborate / tetrahydrofuran; H2O / 2 h / 20 °C 6.1: 94 percent / oxalyl chloride; DMSO; triethylamine / CH2Cl2 / -78 - 0 °C 7.1: diisopropylamine; n-butyllithium / tetrahydrofuran; hexane / 1.25 h / -78 - -40 °C 7.2: 59 percent / ZnCl2 / tetrahydrofuran; hexane; diethyl ether / 0.25 h / -78 °C 8.1: pyridine / CH2Cl2 / 1 h / 0 °C 9.1: CH2Cl2 / 5 h / 20 °C 10.1: 0.67 g / acetic acid / tetrahydrofuran; H2O / 3 h / 0 °C 11.1: 72 percent / magnesium bromide; nitromethane; 1-butanethiol / diethyl ether / 1 h / 20 °C 12.1: 2,4,6-trichlorobenzoyl chloride; triethylamine / tetrahydrofuran / 1 h / 0 °C 12.2: 0.14 g / DMAP / toluene; tetrahydrofuran / 4 h / 20 °C 13.1: 92 percent / zinc; ammonium chloride / methanol / 0.33 h / Heating 14.1: 95 percent / hydrogen fluoride-pyridine / tetrahydrofuran / 16 h / 20 °C View Scheme
Multi-step reaction with 23 steps 1: 90 percent / DIBAL / CH2Cl2 / 1 h / -78 °C 2: 98 percent / benzene / 2 h / Heating 3: 74 percent / diethyl ether; pentane / 1 h / -100 °C 4: 99 percent / imidazole / dimethylformamide / 1) 0 deg C, 45 min, 2) 25 deg C, 2.5 h 5: 95 percent / 4-methylmorpholine N-oxide, OsO4 / tetrahydrofuran; 2-methyl-propan-2-ol; H2O / 1) 0 deg C, 2.5 h, 2) 25 deg C, 12 h 6: 98 percent / Pb(OAc)4 / ethyl acetate / 0.25 h / 0 °C 7: 95 percent / benzene / 3 h / Heating 8: 98 percent / DIBAL / tetrahydrofuran; CH2Cl2 / 3 h / -78 °C 9: 83 percent / Ph3P, CCl4 / 24 h / 100 °C 10: 99 percent / LiEt3BH / tetrahydrofuran / 1 h / 0 °C 11: 91 percent / 9-BBN / tetrahydrofuran / 2 h / 0 °C 12: 92 percent / I2, imidazole, Ph3P / diethyl ether; acetonitrile / 0.5 h / 0 °C 13: 1) LDA / 1) THF, 0 deg C, 8 h, 2) THF, -100 deg C -> -20 deg C, 10 h 14: 80 percent / monoperoxyphthalic acid magnesium salt / methanol / 1 h / 0 °C 15: 82 percent / DIBAL / toluene / 1 h / -78 °C 16: 1) LDA / 1) THF, -78 deg C, 15 min; -78 deg C -> -40 deg C, 1 h, 2) THF, -78 deg C, 15 min 17: 96 percent / 2,6-lutidine / CH2Cl2 / 2 h / 0 °C 18: 85 percent / camphorsulfonic acid / CH2Cl2; methanol / 0.5 h / 0 - 25 °C 19: 1) (COCl)2, DMSO, 2) Et3N / 1) CH2Cl2, -78 deg C, 30 min, 2) CH2Cl2, -78 deg C -> 0 deg C, 30 min 20: 90 percent / NaClO2, isobutylene, NaH2PO4 / 2-methyl-propan-2-ol; H2O; tetrahydrofuran / 1 h / Ambient temperature 21: 73 percent / TBAF / tetrahydrofuran / 8 h / 25 °C 22: 1) Et3N, 2,4,6-trichlorobenzoyl chloride, 2) 4-DMAP / 1) THF, 25 deg C, 15 min, 2) toluene, 25 deg C, 12 h 23: 91 percent / CF3CO2H / CH2Cl2 / 1) -20 deg C -> 0 deg C, 2) 0 deg C, 1 h View Scheme

diethyl (2-methyl-1,3-thiazol-4-yl)methylphosphonate (63928-37-0) → epothilone D (189453-10-9)

Conditions	Yield
Multi-step reaction with 11 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 1 h / -78 °C 1.2: 86 percent / tetrahydrofuran; hexane / 12 h / -78 - 20 °C 2.1: (1R)-(+)-pinene; BH3*DMS / tetrahydrofuran / 0.5 h / 20 °C 2.2: 78 percent / lithium hydroxide; sodium perborate / tetrahydrofuran; H2O / 2 h / 20 °C 3.1: 94 percent / oxalyl chloride; DMSO; triethylamine / CH2Cl2 / -78 - 0 °C 4.1: diisopropylamine; n-butyllithium / tetrahydrofuran; hexane / 1.25 h / -78 - -40 °C 4.2: 59 percent / ZnCl2 / tetrahydrofuran; hexane; diethyl ether / 0.25 h / -78 °C 5.1: pyridine / CH2Cl2 / 1 h / 0 °C 6.1: CH2Cl2 / 5 h / 20 °C 7.1: 0.67 g / acetic acid / tetrahydrofuran; H2O / 3 h / 0 °C 8.1: 72 percent / magnesium bromide; nitromethane; 1-butanethiol / diethyl ether / 1 h / 20 °C 9.1: 2,4,6-trichlorobenzoyl chloride; triethylamine / tetrahydrofuran / 1 h / 0 °C 9.2: 0.14 g / DMAP / toluene; tetrahydrofuran / 4 h / 20 °C 10.1: 92 percent / zinc; ammonium chloride / methanol / 0.33 h / Heating 11.1: 95 percent / hydrogen fluoride-pyridine / tetrahydrofuran / 16 h / 20 °C View Scheme
Multi-step reaction with 10 steps 1.1: tBuOK / tetrahydrofuran 1.2: 75 percent / tetrahydrofuran / 4 h / -30 - 20 °C 2.1: AcOH; H2O / tetrahydrofuran / 24 h / 20 °C 3.1: NaBH4 / methanol 4.1: CBr4; PPh3 / acetonitrile / 0 °C 4.2: 91 percent / 2,6-di-tert-butyl-4-methylpyridine / acetonitrile / -40 °C 5.1: tetrahydrofuran / -78 °C 6.1: LiHMDS / tetrahydrofuran / -78 °C 6.2: 80 percent / tetrahydrofuran 7.1: TMSOTf; collidine / CH2Cl2 / 1 h / 0 °C 7.2: 85 percent / nBu4NF / tetrahydrofuran 8.1: 2,4,6-trichlorobenzoyl chloride; Et3N / tetrahydrofuran / 1 h / 20 °C 8.2: 60 percent / DMAP / toluene / 80 °C 9.1: 86 percent / TFA / CH2Cl2 / 0 °C 10.1: 71 percent / 2,4,6-triisopropylbenzenesulfonyl hydrazide; Et3N / diethyl ether / 39 °C View Scheme
Multi-step reaction with 11 steps 1: 74 percent / n-BuLi 2: DIBAL-H 3: Dess-Martin periodinane 4: 67 percent / Li(i-Pr)2N / -78 °C 5: 79 percent / Cl2CHCO2H 6: Dess-Martin periodinane 7: NaClO2 8: MgBr2; n-BuSH; K2CO3 9: 62 percent / 2,4,6-trichlorobenzoyl chloride; DMAP 10: 91 percent / CF3CO2H / CH2Cl2 View Scheme

2,2-dimethyl-3-oxopentanal (106921-60-2) → epothilone D (189453-10-9)

Conditions	Yield
Multi-step reaction with 11 steps 1.1: 88 percent / Bu2BOTf; DIPEA / CH2Cl2 / 1 h / -78 °C 2.1: 95 percent / 2,6-lutidine / CH2Cl2 / 1 h / 0 °C 3.1: 76 percent / lithium hydroxide; hydrogen peroxide / tetrahydrofuran; H2O / 4 h / 20 °C 4.1: diisopropylamine; n-butyllithium / tetrahydrofuran; hexane / 1.25 h / -78 - -40 °C 4.2: 59 percent / ZnCl2 / tetrahydrofuran; hexane; diethyl ether / 0.25 h / -78 °C 5.1: pyridine / CH2Cl2 / 1 h / 0 °C 6.1: CH2Cl2 / 5 h / 20 °C 7.1: 0.67 g / acetic acid / tetrahydrofuran; H2O / 3 h / 0 °C 8.1: 72 percent / magnesium bromide; nitromethane; 1-butanethiol / diethyl ether / 1 h / 20 °C 9.1: 2,4,6-trichlorobenzoyl chloride; triethylamine / tetrahydrofuran / 1 h / 0 °C 9.2: 0.14 g / DMAP / toluene; tetrahydrofuran / 4 h / 20 °C 10.1: 92 percent / zinc; ammonium chloride / methanol / 0.33 h / Heating 11.1: 95 percent / hydrogen fluoride-pyridine / tetrahydrofuran / 16 h / 20 °C View Scheme
Multi-step reaction with 14 steps 1.1: 68 percent / (-)-Ipc2BOMe / diethyl ether / -100 °C 2.1: i-Pr2NH; n-BuLi / tetrahydrofuran; hexane / 0.83 h / -78 °C 2.2: 61 percent / tetrahydrofuran; hexane / 0.5 h / -78 °C 3.1: 89 percent / Et3N / CH2Cl2 / 0.75 h / 0 °C 4.1: OsO4; NaIO4 / tetrahydrofuran; H2O / 18 h 5.1: NaClO2; NaH2PO4; 2-methyl-2-butene / 2-methyl-propan-2-ol; H2O / 1 h 6.1: 502 mg / methanol; benzene; hexane / 0.75 h 7.1: 92 percent / H2 / Pd/C / ethanol / 0.75 h 8.1: 99 percent / TPAP; NMO / CH2Cl2 / 1 h 9.1: hexamethyldisilazane; n-BuLi / tetrahydrofuran; hexane / -78 - -30 °C 9.2: 82 percent / tetrahydrofuran; hexane / 70 h / -78 - 20 °C 10.1: 66 percent / aq. NaOH / propan-2-ol / 16 h / 45 °C 11.1: 89 percent / TBAF / tetrahydrofuran / 16 h / 0 - 25 °C 12.1: 1,3,5-Cl3C6H2COCl; Et3N / tetrahydrofuran / 0.75 h / 0 °C 12.2: 63 percent / DMAP / toluene; tetrahydrofuran / 4.5 h / 75 °C 13.1: 83 percent / TFA / CH2Cl2 / 4.5 h / 0 °C 14.1: 52 percent / KO2CN=NCO2K; AcOH / CH2Cl2 / 25 h / Heating View Scheme
Multi-step reaction with 16 steps 1.1: 68 percent / (-)-Ipc2BOMe / diethyl ether / -100 °C 2.1: i-Pr2NH; n-BuLi / tetrahydrofuran; hexane / 0.83 h / -78 °C 2.2: 61 percent / tetrahydrofuran; hexane / 0.5 h / -78 °C 3.1: 89 percent / Et3N / CH2Cl2 / 0.75 h / 0 °C 4.1: OsO4; NaIO4 / tetrahydrofuran; H2O / 18 h 5.1: NaClO2; NaH2PO4; 2-methyl-2-butene / 2-methyl-propan-2-ol; H2O / 1 h 6.1: 502 mg / methanol; benzene; hexane / 0.75 h 7.1: 92 percent / H2 / Pd/C / ethanol / 0.75 h 8.1: 99 percent / TPAP; NMO / CH2Cl2 / 1 h 9.1: t-BuOK / tetrahydrofuran / 5 h / -78 °C 9.2: 80 percent / tetrahydrofuran / 12 h / -78 °C 10.1: CuI; Et3N / diethyl ether; dimethylformamide / 20 °C 10.2: 60 percent / diethyl ether; dimethylformamide / 18 h / 20 °C 11.1: 68 percent / H2; Pb(OAc)2 / Pd/CaCO3 / hexane / 28 h / 20 °C 12.1: 66 percent / aq. NaOH / propan-2-ol / 16 h / 45 °C 13.1: 89 percent / TBAF / tetrahydrofuran / 16 h / 0 - 25 °C 14.1: 1,3,5-Cl3C6H2COCl; Et3N / tetrahydrofuran / 0.75 h / 0 °C 14.2: 63 percent / DMAP / toluene; tetrahydrofuran / 4.5 h / 75 °C 15.1: 83 percent / TFA / CH2Cl2 / 4.5 h / 0 °C 16.1: 52 percent / KO2CN=NCO2K; AcOH / CH2Cl2 / 25 h / Heating View Scheme
Multi-step reaction with 6 steps 1.1: Bu2BOTf; DIPEA / CH2Cl2 / -78 - 0 °C 1.2: 70 percent / Raney Ni / acetone / 0.75 h / 60 °C 2.1: 2,6-lutidine / CH2Cl2 / 0 - 20 °C 2.2: LiOH; H2O2 / tetrahydrofuran; H2O / 20 °C 3.1: 2,4,6-Cl3C6H2COCl; TEA; DMAP / tetrahydrofuran; toluene / 1 h / 20 °C 4.1: 95 percent / HF / pyridine; CH2Cl2 / 20 °C 5.1: 92 percent / Zn; aq. NH4Cl / methanol / Heating View Scheme
Multi-step reaction with 13 steps 1: 74 percent / diethyl ether / 0.5 h / -100 °C 2: 98 percent / 2,6-lutidine / CH2Cl2 / 0.75 h / -78 °C 3: 1) O3, 2) PPh3 / 1) CH2Cl2, -78 deg C, 30 min, 2) Ch2Cl2, -78 deg C -> room temperature; room temperature, 1 h 4: lithium tri-tert-butoxyaluminohydride / tetrahydrofuran / 1) -78 deg C, 5 min, 2) 0 deg C, 15 min 5: 1.26 g / Et3N, 4-DMAP / CH2Cl2 / 1) 0 deg C, 2 h, 2) 25 deg C, 10 h 6: 1) LDA / 1) THF, -78 deg C, 15 min; -78 deg C -> -40 deg C, 1 h, 2) THF, -78 deg C, 15 min 7: 96 percent / 2,6-lutidine / CH2Cl2 / 2 h / 0 °C 8: 85 percent / camphorsulfonic acid / CH2Cl2; methanol / 0.5 h / 0 - 25 °C 9: 1) (COCl)2, DMSO, 2) Et3N / 1) CH2Cl2, -78 deg C, 30 min, 2) CH2Cl2, -78 deg C -> 0 deg C, 30 min 10: 90 percent / NaClO2, isobutylene, NaH2PO4 / 2-methyl-propan-2-ol; H2O; tetrahydrofuran / 1 h / Ambient temperature 11: 73 percent / TBAF / tetrahydrofuran / 8 h / 25 °C 12: 1) Et3N, 2,4,6-trichlorobenzoyl chloride, 2) 4-DMAP / 1) THF, 25 deg C, 15 min, 2) toluene, 25 deg C, 12 h 13: 91 percent / CF3CO2H / CH2Cl2 / 1) -20 deg C -> 0 deg C, 2) 0 deg C, 1 h View Scheme

(S)-3-((tert-butyldimethylsilyl)oxy)-4,4-dimethyl-5-oxoheptanoic acid (187283-45-0) → epothilone D (189453-10-9)

Conditions	Yield
Multi-step reaction with 8 steps 1.1: diisopropylamine; n-butyllithium / tetrahydrofuran; hexane / 1.25 h / -78 - -40 °C 1.2: 59 percent / ZnCl2 / tetrahydrofuran; hexane; diethyl ether / 0.25 h / -78 °C 2.1: pyridine / CH2Cl2 / 1 h / 0 °C 3.1: CH2Cl2 / 5 h / 20 °C 4.1: 0.67 g / acetic acid / tetrahydrofuran; H2O / 3 h / 0 °C 5.1: 72 percent / magnesium bromide; nitromethane; 1-butanethiol / diethyl ether / 1 h / 20 °C 6.1: 2,4,6-trichlorobenzoyl chloride; triethylamine / tetrahydrofuran / 1 h / 0 °C 6.2: 0.14 g / DMAP / toluene; tetrahydrofuran / 4 h / 20 °C 7.1: 92 percent / zinc; ammonium chloride / methanol / 0.33 h / Heating 8.1: 95 percent / hydrogen fluoride-pyridine / tetrahydrofuran / 16 h / 20 °C View Scheme
Multi-step reaction with 4 steps 1: 2,4,6-Cl3C6H2COCl; TEA; DMAP / tetrahydrofuran; toluene / 1 h / 20 °C 2: 95 percent / HF / pyridine; CH2Cl2 / 20 °C 3: 92 percent / Zn; aq. NH4Cl / methanol / Heating View Scheme
Multi-step reaction with 5 steps 1.1: titanium tetrachloride / dichloromethane / 0.08 h / -78 °C / Inert atmosphere 1.2: 1 h / -78 °C / Inert atmosphere 1.3: 3 h / -78 - 20 °C / Inert atmosphere 2.1: 2,6-dimethylpyridine / dichloromethane / 0 - 20 °C / Inert atmosphere 3.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 0.17 h / 20 °C / Inert atmosphere 4.1: 2,4,6-trichlorobenzoyl chloride; triethylamine / tetrahydrofuran / 0.67 h / 0 °C / Inert atmosphere 4.2: 20 °C / Inert atmosphere 5.1: trifluoroacetic acid / dichloromethane / 0.75 h / 0 °C / Inert atmosphere View Scheme
Multi-step reaction with 5 steps 1.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 2 h / 20 °C / Inert atmosphere 2.1: titanium tetrachloride; N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h / -78 °C / Inert atmosphere 2.2: 15 h / -12 °C / Inert atmosphere 3.1: 2,6-dimethylpyridine / dichloromethane / 5 h / -45 - 20 °C / Inert atmosphere 4.1: Hoveyda-Grubbs catalyst second generation / 1,2-dichloro-ethane / 4 h / 80 °C / Inert atmosphere 5.1: trifluoroacetic acid / dichloromethane / 2 h / -20 - 0 °C / Inert atmosphere View Scheme
Multi-step reaction with 6 steps 1: phenyltrimethylammonium tribromide / tetrahydrofuran / 1.25 h / 0 - 20 °C 2: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 18 h / 0 - 20 °C / Inert atmosphere 3: (1S)-10-camphorsulfonic acid / dichloromethane; methanol / 2.5 h / 0 °C 4: triethylamine; sulfur trioxide pyridine complex; dimethyl sulfoxide / dichloromethane / 1 h / 0 °C / Inert atmosphere 5: lithium iodide; chromium dichloride / tetrahydrofuran / 3.33 h / 20 °C / Inert atmosphere 6: trifluoroacetic acid / dichloromethane / 1.5 h / 0 °C View Scheme

(-)-(2R,3S,5Z)-2-(4-methoxybenzyloxy)-6,10-dimethylundeca-5,10-dien-3-ol (380605-86-7) → epothilone D (189453-10-9)

Conditions	Yield
Multi-step reaction with 14 steps 1.1: 92 percent / DIPEA / CH2Cl2 / 6 h / 20 °C 2.1: 91 percent / 2,3-dichloro-5,6-dicyano-1,4-benzoquinone / CH2Cl2; H2O / 3 h / 20 °C 3.1: 85 percent / oxalyl chloride; DMSO; triethylamine / CH2Cl2 / -78 - 0 °C 4.1: n-butyllithium / tetrahydrofuran; hexane / 1 h / -78 °C 4.2: 86 percent / tetrahydrofuran; hexane / 12 h / -78 - 20 °C 5.1: (1R)-(+)-pinene; BH3*DMS / tetrahydrofuran / 0.5 h / 20 °C 5.2: 78 percent / lithium hydroxide; sodium perborate / tetrahydrofuran; H2O / 2 h / 20 °C 6.1: 94 percent / oxalyl chloride; DMSO; triethylamine / CH2Cl2 / -78 - 0 °C 7.1: diisopropylamine; n-butyllithium / tetrahydrofuran; hexane / 1.25 h / -78 - -40 °C 7.2: 59 percent / ZnCl2 / tetrahydrofuran; hexane; diethyl ether / 0.25 h / -78 °C 8.1: pyridine / CH2Cl2 / 1 h / 0 °C 9.1: CH2Cl2 / 5 h / 20 °C 10.1: 0.67 g / acetic acid / tetrahydrofuran; H2O / 3 h / 0 °C 11.1: 72 percent / magnesium bromide; nitromethane; 1-butanethiol / diethyl ether / 1 h / 20 °C 12.1: 2,4,6-trichlorobenzoyl chloride; triethylamine / tetrahydrofuran / 1 h / 0 °C 12.2: 0.14 g / DMAP / toluene; tetrahydrofuran / 4 h / 20 °C 13.1: 92 percent / zinc; ammonium chloride / methanol / 0.33 h / Heating 14.1: 95 percent / hydrogen fluoride-pyridine / tetrahydrofuran / 16 h / 20 °C View Scheme
Multi-step reaction with 10 steps 1: 92 percent / DIPEA; DCM / 0 °C 2: 88 percent / DDQ / H2O 3: 85 percent / DMSO; (COCl)2; DCM / triethylamine / -78 °C 4: 72 percent / n-BuLi / tetrahydrofuran 5: (i-PC)2BH; aq. sodium borate / tetrahydrofuran / 0.5 h 6: 92 percent / DMSO; (COCl)2; NEt3 / CH2Cl2 / -78 °C 7: 2,4,6-Cl3C6H2COCl; TEA; DMAP / tetrahydrofuran; toluene / 1 h / 20 °C 8: 95 percent / HF / pyridine; CH2Cl2 / 20 °C 9: 92 percent / Zn; aq. NH4Cl / methanol / Heating View Scheme

(Z)-(S)-6,10-Dimethyl-3-(2-trimethylsilanyl-ethoxymethoxy)-undeca-5,10-dien-2-one (380605-89-0) → epothilone D (189453-10-9)

Conditions	Yield
Multi-step reaction with 11 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 1 h / -78 °C 1.2: 86 percent / tetrahydrofuran; hexane / 12 h / -78 - 20 °C 2.1: (1R)-(+)-pinene; BH3*DMS / tetrahydrofuran / 0.5 h / 20 °C 2.2: 78 percent / lithium hydroxide; sodium perborate / tetrahydrofuran; H2O / 2 h / 20 °C 3.1: 94 percent / oxalyl chloride; DMSO; triethylamine / CH2Cl2 / -78 - 0 °C 4.1: diisopropylamine; n-butyllithium / tetrahydrofuran; hexane / 1.25 h / -78 - -40 °C 4.2: 59 percent / ZnCl2 / tetrahydrofuran; hexane; diethyl ether / 0.25 h / -78 °C 5.1: pyridine / CH2Cl2 / 1 h / 0 °C 6.1: CH2Cl2 / 5 h / 20 °C 7.1: 0.67 g / acetic acid / tetrahydrofuran; H2O / 3 h / 0 °C 8.1: 72 percent / magnesium bromide; nitromethane; 1-butanethiol / diethyl ether / 1 h / 20 °C 9.1: 2,4,6-trichlorobenzoyl chloride; triethylamine / tetrahydrofuran / 1 h / 0 °C 9.2: 0.14 g / DMAP / toluene; tetrahydrofuran / 4 h / 20 °C 10.1: 92 percent / zinc; ammonium chloride / methanol / 0.33 h / Heating 11.1: 95 percent / hydrogen fluoride-pyridine / tetrahydrofuran / 16 h / 20 °C View Scheme
Multi-step reaction with 7 steps 1: 72 percent / n-BuLi / tetrahydrofuran 2: (i-PC)2BH; aq. sodium borate / tetrahydrofuran / 0.5 h 3: 92 percent / DMSO; (COCl)2; NEt3 / CH2Cl2 / -78 °C 4: 2,4,6-Cl3C6H2COCl; TEA; DMAP / tetrahydrofuran; toluene / 1 h / 20 °C 5: 95 percent / HF / pyridine; CH2Cl2 / 20 °C 6: 92 percent / Zn; aq. NH4Cl / methanol / Heating View Scheme

(Z)-(2R,3S)-6,10-Dimethyl-3-(2-trimethylsilanyl-ethoxymethoxy)-undeca-5,10-dien-2-ol (380605-88-9) → epothilone D (189453-10-9)

Conditions	Yield
Multi-step reaction with 12 steps 1.1: 85 percent / oxalyl chloride; DMSO; triethylamine / CH2Cl2 / -78 - 0 °C 2.1: n-butyllithium / tetrahydrofuran; hexane / 1 h / -78 °C 2.2: 86 percent / tetrahydrofuran; hexane / 12 h / -78 - 20 °C 3.1: (1R)-(+)-pinene; BH3*DMS / tetrahydrofuran / 0.5 h / 20 °C 3.2: 78 percent / lithium hydroxide; sodium perborate / tetrahydrofuran; H2O / 2 h / 20 °C 4.1: 94 percent / oxalyl chloride; DMSO; triethylamine / CH2Cl2 / -78 - 0 °C 5.1: diisopropylamine; n-butyllithium / tetrahydrofuran; hexane / 1.25 h / -78 - -40 °C 5.2: 59 percent / ZnCl2 / tetrahydrofuran; hexane; diethyl ether / 0.25 h / -78 °C 6.1: pyridine / CH2Cl2 / 1 h / 0 °C 7.1: CH2Cl2 / 5 h / 20 °C 8.1: 0.67 g / acetic acid / tetrahydrofuran; H2O / 3 h / 0 °C 9.1: 72 percent / magnesium bromide; nitromethane; 1-butanethiol / diethyl ether / 1 h / 20 °C 10.1: 2,4,6-trichlorobenzoyl chloride; triethylamine / tetrahydrofuran / 1 h / 0 °C 10.2: 0.14 g / DMAP / toluene; tetrahydrofuran / 4 h / 20 °C 11.1: 92 percent / zinc; ammonium chloride / methanol / 0.33 h / Heating 12.1: 95 percent / hydrogen fluoride-pyridine / tetrahydrofuran / 16 h / 20 °C View Scheme
Multi-step reaction with 8 steps 1: 85 percent / DMSO; (COCl)2; DCM / triethylamine / -78 °C 2: 72 percent / n-BuLi / tetrahydrofuran 3: (i-PC)2BH; aq. sodium borate / tetrahydrofuran / 0.5 h 4: 92 percent / DMSO; (COCl)2; NEt3 / CH2Cl2 / -78 °C 5: 2,4,6-Cl3C6H2COCl; TEA; DMAP / tetrahydrofuran; toluene / 1 h / 20 °C 6: 95 percent / HF / pyridine; CH2Cl2 / 20 °C 7: 92 percent / Zn; aq. NH4Cl / methanol / Heating View Scheme

(2-{1-[1-(4-methoxy-benzyloxy)-ethyl]-4,8-dimethyl-nona-3,8-dienyloxymethoxy}-ethyl)-trimethyl-silane (380605-87-8) → epothilone D (189453-10-9)

Conditions	Yield
Multi-step reaction with 13 steps 1.1: 91 percent / 2,3-dichloro-5,6-dicyano-1,4-benzoquinone / CH2Cl2; H2O / 3 h / 20 °C 2.1: 85 percent / oxalyl chloride; DMSO; triethylamine / CH2Cl2 / -78 - 0 °C 3.1: n-butyllithium / tetrahydrofuran; hexane / 1 h / -78 °C 3.2: 86 percent / tetrahydrofuran; hexane / 12 h / -78 - 20 °C 4.1: (1R)-(+)-pinene; BH3*DMS / tetrahydrofuran / 0.5 h / 20 °C 4.2: 78 percent / lithium hydroxide; sodium perborate / tetrahydrofuran; H2O / 2 h / 20 °C 5.1: 94 percent / oxalyl chloride; DMSO; triethylamine / CH2Cl2 / -78 - 0 °C 6.1: diisopropylamine; n-butyllithium / tetrahydrofuran; hexane / 1.25 h / -78 - -40 °C 6.2: 59 percent / ZnCl2 / tetrahydrofuran; hexane; diethyl ether / 0.25 h / -78 °C 7.1: pyridine / CH2Cl2 / 1 h / 0 °C 8.1: CH2Cl2 / 5 h / 20 °C 9.1: 0.67 g / acetic acid / tetrahydrofuran; H2O / 3 h / 0 °C 10.1: 72 percent / magnesium bromide; nitromethane; 1-butanethiol / diethyl ether / 1 h / 20 °C 11.1: 2,4,6-trichlorobenzoyl chloride; triethylamine / tetrahydrofuran / 1 h / 0 °C 11.2: 0.14 g / DMAP / toluene; tetrahydrofuran / 4 h / 20 °C 12.1: 92 percent / zinc; ammonium chloride / methanol / 0.33 h / Heating 13.1: 95 percent / hydrogen fluoride-pyridine / tetrahydrofuran / 16 h / 20 °C View Scheme
Multi-step reaction with 9 steps 1: 88 percent / DDQ / H2O 2: 85 percent / DMSO; (COCl)2; DCM / triethylamine / -78 °C 3: 72 percent / n-BuLi / tetrahydrofuran 4: (i-PC)2BH; aq. sodium borate / tetrahydrofuran / 0.5 h 5: 92 percent / DMSO; (COCl)2; NEt3 / CH2Cl2 / -78 °C 6: 2,4,6-Cl3C6H2COCl; TEA; DMAP / tetrahydrofuran; toluene / 1 h / 20 °C 7: 95 percent / HF / pyridine; CH2Cl2 / 20 °C 8: 92 percent / Zn; aq. NH4Cl / methanol / Heating View Scheme

2-methyl-4-[2,6,10-trimethyl-3-(2-trimethylsilanyl-ethoxymethoxy)-undeca-1,5,10-trienyl]-thiazole (380605-90-3) → epothilone D (189453-10-9)

Conditions	Yield
Multi-step reaction with 10 steps 1.1: (1R)-(+)-pinene; BH3*DMS / tetrahydrofuran / 0.5 h / 20 °C 1.2: 78 percent / lithium hydroxide; sodium perborate / tetrahydrofuran; H2O / 2 h / 20 °C 2.1: 94 percent / oxalyl chloride; DMSO; triethylamine / CH2Cl2 / -78 - 0 °C 3.1: diisopropylamine; n-butyllithium / tetrahydrofuran; hexane / 1.25 h / -78 - -40 °C 3.2: 59 percent / ZnCl2 / tetrahydrofuran; hexane; diethyl ether / 0.25 h / -78 °C 4.1: pyridine / CH2Cl2 / 1 h / 0 °C 5.1: CH2Cl2 / 5 h / 20 °C 6.1: 0.67 g / acetic acid / tetrahydrofuran; H2O / 3 h / 0 °C 7.1: 72 percent / magnesium bromide; nitromethane; 1-butanethiol / diethyl ether / 1 h / 20 °C 8.1: 2,4,6-trichlorobenzoyl chloride; triethylamine / tetrahydrofuran / 1 h / 0 °C 8.2: 0.14 g / DMAP / toluene; tetrahydrofuran / 4 h / 20 °C 9.1: 92 percent / zinc; ammonium chloride / methanol / 0.33 h / Heating 10.1: 95 percent / hydrogen fluoride-pyridine / tetrahydrofuran / 16 h / 20 °C View Scheme
Multi-step reaction with 6 steps 1: (i-PC)2BH; aq. sodium borate / tetrahydrofuran / 0.5 h 2: 92 percent / DMSO; (COCl)2; NEt3 / CH2Cl2 / -78 °C 3: 2,4,6-Cl3C6H2COCl; TEA; DMAP / tetrahydrofuran; toluene / 1 h / 20 °C 4: 95 percent / HF / pyridine; CH2Cl2 / 20 °C 5: 92 percent / Zn; aq. NH4Cl / methanol / Heating View Scheme

Carbonic acid (Z)-(4S,7R,8S,9S,16S)-4-(tert-butyl-dimethyl-silanyloxy)-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-thiazol-4-yl)-vinyl]-2,6-dioxo-oxacyclohexadec-13-en-8-yl ester 2,2,2-trichloro-ethyl ester (380605-93-6) → epothilone D (189453-10-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: 92 percent / zinc; ammonium chloride / methanol / 0.33 h / Heating 2: 95 percent / hydrogen fluoride-pyridine / tetrahydrofuran / 16 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1: 95 percent / HF / pyridine; CH2Cl2 / 20 °C 2: 92 percent / Zn; aq. NH4Cl / methanol / Heating View Scheme

(+)-(2S,6Z,9S,10E)-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-9-(2-trimethylsilylethoxymethoxy)undeca-6,10-dienal (380605-84-5) → epothilone D (189453-10-9)

Conditions	Yield
Multi-step reaction with 8 steps 1.1: diisopropylamine; n-butyllithium / tetrahydrofuran; hexane / 1.25 h / -78 - -40 °C 1.2: 59 percent / ZnCl2 / tetrahydrofuran; hexane; diethyl ether / 0.25 h / -78 °C 2.1: pyridine / CH2Cl2 / 1 h / 0 °C 3.1: CH2Cl2 / 5 h / 20 °C 4.1: 0.67 g / acetic acid / tetrahydrofuran; H2O / 3 h / 0 °C 5.1: 72 percent / magnesium bromide; nitromethane; 1-butanethiol / diethyl ether / 1 h / 20 °C 6.1: 2,4,6-trichlorobenzoyl chloride; triethylamine / tetrahydrofuran / 1 h / 0 °C 6.2: 0.14 g / DMAP / toluene; tetrahydrofuran / 4 h / 20 °C 7.1: 92 percent / zinc; ammonium chloride / methanol / 0.33 h / Heating 8.1: 95 percent / hydrogen fluoride-pyridine / tetrahydrofuran / 16 h / 20 °C View Scheme
Multi-step reaction with 8 steps 1: 67 percent / Li(i-Pr)2N / -78 °C 2: 79 percent / Cl2CHCO2H 3: Dess-Martin periodinane 4: NaClO2 5: MgBr2; n-BuSH; K2CO3 6: 62 percent / 2,4,6-trichlorobenzoyl chloride; DMAP 7: 91 percent / CF3CO2H / CH2Cl2 View Scheme
Multi-step reaction with 4 steps 1: 2,4,6-Cl3C6H2COCl; TEA; DMAP / tetrahydrofuran; toluene / 1 h / 20 °C 2: 95 percent / HF / pyridine; CH2Cl2 / 20 °C 3: 92 percent / Zn; aq. NH4Cl / methanol / Heating View Scheme
Multi-step reaction with 8 steps 1.1: lithium diisopropyl amide; n-butyllithium / tetrahydrofuran; hexane / 1.5 h / -78 - 40 °C 1.2: 0.03 h / -78 °C 2.1: 2,6-dimethylpyridine / dichloromethane / 6 h / 0 °C 3.1: dichloro-acetic acid / dichloromethane / 2 h / 20 °C 4.1: Dess-Martin periodane / dichloromethane / 0.5 h / 20 °C 5.1: sodium chlorite; sodium dihydrogenphosphate; 2,3-Dimethyl-2-butene / tetrahydrofuran; water; tert-butyl alcohol / 1 h / 20 °C 6.1: potassium carbonate; magnesium bromide ethyl etherate; n-butanethiol / diethyl ether / 2 h / 20 °C 7.1: triethylamine; 2,4,6-trichlorobenzoyl chloride / tetrahydrofuran / 0.75 h / 0 °C 7.2: 5 h / 75 °C 8.1: trifluoroacetic acid / dichloromethane / 6 h / 0 °C View Scheme

(2S,9S,6Z,10E)-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-9-(2-trimethylsilylethoxy)methoxyundeca-6,10-dien-1-ol (380605-91-4) → epothilone D (189453-10-9)

Conditions	Yield
Multi-step reaction with 9 steps 1.1: 94 percent / oxalyl chloride; DMSO; triethylamine / CH2Cl2 / -78 - 0 °C 2.1: diisopropylamine; n-butyllithium / tetrahydrofuran; hexane / 1.25 h / -78 - -40 °C 2.2: 59 percent / ZnCl2 / tetrahydrofuran; hexane; diethyl ether / 0.25 h / -78 °C 3.1: pyridine / CH2Cl2 / 1 h / 0 °C 4.1: CH2Cl2 / 5 h / 20 °C 5.1: 0.67 g / acetic acid / tetrahydrofuran; H2O / 3 h / 0 °C 6.1: 72 percent / magnesium bromide; nitromethane; 1-butanethiol / diethyl ether / 1 h / 20 °C 7.1: 2,4,6-trichlorobenzoyl chloride; triethylamine / tetrahydrofuran / 1 h / 0 °C 7.2: 0.14 g / DMAP / toluene; tetrahydrofuran / 4 h / 20 °C 8.1: 92 percent / zinc; ammonium chloride / methanol / 0.33 h / Heating 9.1: 95 percent / hydrogen fluoride-pyridine / tetrahydrofuran / 16 h / 20 °C View Scheme
Multi-step reaction with 9 steps 1: Dess-Martin periodinane 2: 67 percent / Li(i-Pr)2N / -78 °C 3: 79 percent / Cl2CHCO2H 4: Dess-Martin periodinane 5: NaClO2 6: MgBr2; n-BuSH; K2CO3 7: 62 percent / 2,4,6-trichlorobenzoyl chloride; DMAP 8: 91 percent / CF3CO2H / CH2Cl2 View Scheme
Multi-step reaction with 5 steps 1: 92 percent / DMSO; (COCl)2; NEt3 / CH2Cl2 / -78 °C 2: 2,4,6-Cl3C6H2COCl; TEA; DMAP / tetrahydrofuran; toluene / 1 h / 20 °C 3: 95 percent / HF / pyridine; CH2Cl2 / 20 °C 4: 92 percent / Zn; aq. NH4Cl / methanol / Heating View Scheme
Multi-step reaction with 9 steps 1.1: Dess-Martin periodane / dichloromethane / 0.5 h / 20 °C 2.1: lithium diisopropyl amide; n-butyllithium / tetrahydrofuran; hexane / 1.5 h / -78 - 40 °C 2.2: 0.03 h / -78 °C 3.1: 2,6-dimethylpyridine / dichloromethane / 6 h / 0 °C 4.1: dichloro-acetic acid / dichloromethane / 2 h / 20 °C 5.1: Dess-Martin periodane / dichloromethane / 0.5 h / 20 °C 6.1: sodium chlorite; sodium dihydrogenphosphate; 2,3-Dimethyl-2-butene / tetrahydrofuran; water; tert-butyl alcohol / 1 h / 20 °C 7.1: potassium carbonate; magnesium bromide ethyl etherate; n-butanethiol / diethyl ether / 2 h / 20 °C 8.1: triethylamine; 2,4,6-trichlorobenzoyl chloride / tetrahydrofuran / 0.75 h / 0 °C 8.2: 5 h / 75 °C 9.1: trifluoroacetic acid / dichloromethane / 6 h / 0 °C View Scheme

(3S)-3-[((tert-butyl)dimethylsilyl)oxy]-1-[(1S,5R)-10,10-dimethyl-3,3-dioxido-3-thia-4-azatricyclo[5.2.1.01.5]dec-4-yl]-4,4-dimethylheptan-1,5-dione (250679-52-8) → epothilone D (189453-10-9)

Conditions	Yield
Multi-step reaction with 9 steps 1.1: 76 percent / lithium hydroxide; hydrogen peroxide / tetrahydrofuran; H2O / 4 h / 20 °C 2.1: diisopropylamine; n-butyllithium / tetrahydrofuran; hexane / 1.25 h / -78 - -40 °C 2.2: 59 percent / ZnCl2 / tetrahydrofuran; hexane; diethyl ether / 0.25 h / -78 °C 3.1: pyridine / CH2Cl2 / 1 h / 0 °C 4.1: CH2Cl2 / 5 h / 20 °C 5.1: 0.67 g / acetic acid / tetrahydrofuran; H2O / 3 h / 0 °C 6.1: 72 percent / magnesium bromide; nitromethane; 1-butanethiol / diethyl ether / 1 h / 20 °C 7.1: 2,4,6-trichlorobenzoyl chloride; triethylamine / tetrahydrofuran / 1 h / 0 °C 7.2: 0.14 g / DMAP / toluene; tetrahydrofuran / 4 h / 20 °C 8.1: 92 percent / zinc; ammonium chloride / methanol / 0.33 h / Heating 9.1: 95 percent / hydrogen fluoride-pyridine / tetrahydrofuran / 16 h / 20 °C View Scheme
Multi-step reaction with 6 steps 1.1: lithium hydroxide monohydrate; dihydrogen peroxide / tetrahydrofuran; water / 24.5 h / 0 - 25 °C / Inert atmosphere 2.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 2 h / 20 °C / Inert atmosphere 3.1: titanium tetrachloride; N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h / -78 °C / Inert atmosphere 3.2: 15 h / -12 °C / Inert atmosphere 4.1: 2,6-dimethylpyridine / dichloromethane / 5 h / -45 - 20 °C / Inert atmosphere 5.1: Hoveyda-Grubbs catalyst second generation / 1,2-dichloro-ethane / 4 h / 80 °C / Inert atmosphere 6.1: trifluoroacetic acid / dichloromethane / 2 h / -20 - 0 °C / Inert atmosphere View Scheme

epothilone D (189453-10-9) → epothilone B (152044-54-7)

Conditions	Yield
With 3,3-dimethyldioxirane In dichloromethane at -50℃;	98%
With 3,3-dimethyldioxirane In dichloromethane; acetone at -78 - -50℃; for 2.5h; Epoxidation;	97%
With 3,3-dimethyldioxirane In dichloromethane at -35℃;	97%

t-butyldimethylsiyl triflate (69739-34-0) + epothilone D (189453-10-9) → (4S,7R,8S,9S,13Z,16S)-4,8-bis{[tert-butyl(dimethyl)silyl]oxy}-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxacyclohexadec-13-ene-2,6-dione (189453-35-8)

Conditions	Yield
With triethylamine In dichloromethane at -78℃;	85%
With 2,6-dimethylpyridine In dichloromethane at 0℃; silylation;

epothilone D (189453-10-9) → C27H42N2O5S

Conditions	Yield
With bis{rhodium[3,3'-(1,3-phenylene)bis(2,2-dimethylpropanoic acid)]}; O-(2,4-dinitrophenyl)hydroxylamine at 25℃; for 4h; Inert atmosphere;	70%

epothilone D (189453-10-9) → epothilone B (152044-54-7) + (1R,3S,7S,10R,11S,12S,16S)-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione

Conditions	Yield
With Oxone; 1,1,1-trifluoro-2-propanone; edetate disodium; sodium hydrogencarbonate In water; acetonitrile at 0℃;	A 69% B n/a
With 3,3-dimethyldioxirane In dichloromethane; acetone at -78 - -50℃;	A 53% B n/a
With 3-chloro-benzenecarboperoxoic acid In chloroform at -10 - 0℃; for 5h;	A 30% B n/a

epothilone D (189453-10-9) → (1S,3S,7S,10R,11S,12S,16R)-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[(1E)-1-(2-methyl-1,3-thiazol-4-yl)prop-1-en-2-yl]-4-oxa-17-azabicyclo[14.1.0]heptadecane-5,9-dione

Conditions	Yield
With bis{rhodium[3,3'-(1,3-phenylene)bis(2,2-dimethylpropanoic acid)]}; O-(2,4-dinitrophenyl)hydroxylamine In 2,2,2-trifluoroethanol at 25℃; for 4h; Inert atmosphere;	66%
With bis{rhodium[3,3'-(1,3-phenylene)bis(2,2-dimethylpropanoic acid)]}; O-(2,4-dinitrophenyl)hydroxylamine In 2,2,2-trifluoroethanol at 25℃; for 4h;	66%

Upstream product

• 189453-51-8 (Z)-(4S,6R,7S,8S,9S,16S)-8-(tert-Butyl-dimethyl-silanyloxy)-4,6-dihydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-thiazol-4-yl)-vinyl]-oxacyclohexadec-13-en-2-one 
• 56981-06-7 (2R,4aR,6S,8aS)-6-Methoxy-7-methyl-2-phenyl-4,4a,6,8a-tetrahydro-pyrano[3,2-d][1,3]dioxine 
• 193146-26-8 (3S,6R,7S,8S,12Z,15S,16E)-3,7-bis{[tert-butyl(dimethyl)silyl]oxy}-15-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxoheptadeca-12,16-dienoic acid 
• 68907-48-2 methyl 4,6-O-benzylidene-2-deoxy-2-C-methyl-3-O<(thiomethyl)-thiocarbonyl>-α-D-altro-pyranoside 
• 56981-07-8 methyl 2,3-dideoxy-2-c-methyl-α-D-erythro-hex-2-enooyranoside 
• 68907-47-1 methyl 4,6-O-benzylidene-2-deoxy-2-C-methyl-α-D-altro-pyranoside 
• 448210-62-6 (3S,6R,7S,8S)-4,4,6,8-Tetramethyl-5-oxo-7-(2,2,2-trichloro-ethoxycarbonyloxy)-3-triethylsilanyloxy-undec-10-enoic acid (Z)-(S)-4-methyl-1-[(E)-1-methyl-2-(2-methyl-thiazol-4-yl)-vinyl]-hexa-3,5-dienyl ester 
• 448210-70-6 (3S,6R,7S,8S)-3-Hydroxy-4,4,6,8-tetramethyl-5-oxo-7-(2,2,2-trichloro-ethoxycarbonyloxy)-undec-10-enoic acid (Z)-(S)-4-methyl-1-[(E)-1-methyl-2-(2-methyl-thiazol-4-yl)-vinyl]-hexa-3,5-dienyl ester 
• 448210-71-7 Carbonic acid (11E,13Z)-(4S,7R,8S,9S,16S)-4-hydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-thiazol-4-yl)-vinyl]-2,6-dioxo-oxacyclohexadeca-11,13-dien-8-yl ester 2,2,2-trichloro-ethyl ester 
• 448210-81-9 (11E,13Z)-(4S,7R,8S,9S,16S)-8-Hydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-thiazol-4-yl)-vinyl]-4-triethylsilanyloxy-oxacyclohexadeca-11,13-diene-2,6-dione 
• 448210-60-4 (3S,6R,7S,8S)-5-oxo-3-(triethylsilyloxy)-4,4,6,8-tetramethyl-7-(2,2,2-trichloroethoxycarbonyloxy)-10-undecenoic acid 
• 448210-58-0 4-((1E,5Z)-(S)-2,6-Dimethyl-3-triethylsilanyloxy-octa-1,5,7-trienyl)-2-methyl-thiazole 
• 448210-69-3 Acetic acid (Z)-(S)-4-methyl-1-[(E)-1-methyl-2-(2-methyl-thiazol-4-yl)-vinyl]-hexa-3,5-dienyl ester 
• 448210-59-1 (1E,5Z)-(S)-2,6-Dimethyl-1-(2-methyl-thiazol-4-yl)-octa-1,5,7-trien-3-ol 

Downstream Products

• 152044-54-7 epothilone B 
• 219989-84-1 ixabepilone 
• 247230-49-5 (1S,3S,7S,10R,11S,12S,16S)-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-((E)-1-(2-methylthiazol-4-yl)prop-1-en-2-yl)-4-oxabicyclo[14.1.0]heptadecane-5,9-dione 
• 189453-35-8 (4S,7R,8S,9S,13Z,16S,1'E)-4,8-di-tert-butyldimethylsilyloxy-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-methyl-1,3-thiazol-4-yl)-1-ethenyl]-1-oxa-13-cyclohexadecene-2,6-dione 

Relevant articles and documents

Epothilone D and its 9-Methyl analogues: Combinatorial syntheses, conformation, and biological activities

Epothilone D (Epo D) and its 9-Methyl conformational analogues were synthesized through a highly efficient combinatorial approach. The fragment E was synthesized in 11 total steps with 6 longest linear steps, and each aldehyde B was prepared via a 3-step sequence. Starting from the common precursor E and a suitable aldehydes B, each target molecule were obtained in only 4 steps. The 9-(S)-epo D and 9-(R)-epo D demonstrated significant difference in inhibition activities against cancer cell lines and in conformational analysis.

The Total Synthesis of Epothilone D as a Yardstick for Probing New Methodologies

Here, a concise and highly convergent synthesis of epothilone D was investigated, relying on fragments of equal complexity that could be prepared in gram scale quantities. The strategy to construct the fragments includes the use of a previously reported enantiospecific zinc-catalyzed cross-coupling of an α-hydroxy ester triflate with a Grignard reagent, the application of a hydroboration/boron–magnesium exchange sequence for the rapid construction of the Z-substituted trisubstituted double bond present in the natural product, and a Noyori-type hydrogenation to install the β-hydroxy ester moiety of the southern part. The key to success is the diastereoselective head-to-tail macrolactonization by an intramolecular addition of the corresponding ω-alkynyl-substituted carboxylic acids to construct a new stereocenter in the macrocyclic core structure in one single step.

Total synthesis of epothilone D: The nerol/macroaldolization approach

A highly convergent and stereocontrolled synthesis of epothilone D (4) is reported. Key features are a cheap and Z-selective synthesis of the northern half based on nerol and acetoacetate and chromium(II)-mediated Reformatsky reactions as a powerful tool for chemoselective asymmetric carbon-carbon bond formations, including an unusual stereospecific macroaldolization.