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Abstract

Epothilone D, a microtubule-stabilizing macrolide, is an attractive synthetic target molecule as a potential anti-cancer drug candidate. As part of our ongoing synthetic studies of this natural product, this paper describes the synthesis of the thiazole-containing northern segment of epothilone D via an E-selective bromomethylenation and a Ni/Cr-mediated cross-coupling reaction.

Keywords

epothilone D macrolide microtubule stabilizer anti-cancer Alzheimer’s disease

Epothilones are 16-membered macrolides isolated from the myxobacterium Sorangium cellulosum that have been identified as microtubule-stabilizing agents (Figure 1).^1
-3 Accordingly, they have attracted the attention of numerous researchers aiming to develop new anti-cancer drugs based on the structures of epothilones.^4

-7

Figure 1

Structures of epothilones A-D.

Their complex molecular architectures contain a thiazole ring and allow for a diverse range of synthetic strategies, and several successful total syntheses have been accomplished to date.⁸

Among these natural products, epothilone D (4) has recently attracted considerable attention as a potential therapeutic agent for Alzheimer’s disease owing to its neuroprotective effects.^9

-13

Intrigued by its molecular structure and promising biological activities, we decided to undertake a synthetic study of epothilone D. In this communication, we report the synthesis of a thiazole-containing northern segment of epothilone D.

Our retrosynthetic analysis of epothilone D is outlined in Scheme 1. Epothilone D was retrosynthetically divided into the northern and southern segments (5 and 6, respectively). The thiazole-containing segment 5 could be synthesized via a Ni/Cr-mediated cross-coupling reaction¹⁴ between vinyl bromide 7 and aldehyde 8. A challenge in the synthesis of 7 is stereoselective construction of the trisubstituted olefin moiety. To this end, vinyl bromide 7 could be prepared from a bromoacrylate derivative, which could be stereoselectively obtained via a Horner-Wadsworth-Emmons (HWE) reaction between the known aldehyde 9 ¹⁵ and the Still-Gennari-type phosphonate reagent 10 that was previously developed in our group.^16

-19 Aldehyde 8 could be synthesized from 3-butyn-1-ol (11).

Scheme 1

Retrosynthetic analysis of epothilone D (4).

Our synthesis commenced with the preparation of vinyl bromide 7. The known aldehyde 9, prepared as previously reported,¹⁵ was subjected to the HWE reaction with phosphonate reagent 10 ^16

-19 (Table 1). The standard conditions employing a combination of t-BuOK and 18-crown-6^16

-19 afforded the desired acrylate derivative 12 in 73% yield with moderate stereoselectivity (E:Z = 5:1) (entry 1). Increasing the number of equivalents of 18-crown-6 affected neither the yield nor the stereoselectivity (entry 2). With lithium bis(trimethylsilyl)amide (LHMDS) as the base, the stereoselectivity was higher than that with t-BuOK, despite requiring a prolonged reaction time (entry 3). With LHMDS at 0°C, the reaction reached completion in 30 minutes, although the stereoselectivity was still unsatisfactory (entry 4). To our delight, sodium bis(trimethylsilyl)amide (NaHMDS) afforded excellent yield and stereoselectivity of the desired product (entry 5).

Table 1

Horner-Wadsworth-Emmons Reaction Between 9 and 10.


Entry	Base	18-Crown-6 (equiv)	Time	Temp. (°C)	Yield (%)	E:Z^a,b
1	t-BuOK	1.3	30 min	−78	73	5:1
2	t-BuOK	5.0	30 min	−78	71	5:1
3	LHMDS	None	24 h	−78	73	10:1
4	LHMDS	None	30 min	0	78	5:1
5	NaHMDS	None	30 min	−78	85	25:1

The E:Z ratio was determined via ¹H NMR analysis of the crude product.

The stereochemistries of the products were determined by downﬁeld shift of the olefinic proton signal of (Z)-12 compared to that of (E)-12 in the ¹H NMR spectra.

The resulting ester moiety of 12 was reduced using diisobutylaluminum hydride (DIBAL-H) to afford alcohol 13 in 77% yield (Scheme 2), which was subsequently converted to vinyl bromide 7 via a 2-step sequence comprising tosylation and hydride reduction (Table 2). Among the bases screened for the tosylation step (entries 1-4), only t-BuOK furnished the anticipated tosylate 14 (entry 4). The unstable tosylate 14 was immediately subjected to hydride reduction (entries 4 and 5) to deliver vinyl bromide 7 in 80% yield over 2 steps using LiHBEt₃ (entry 5).

Scheme 2

Synthesis of allyl alcohol 13.

Table 2

Conversion of Allyl Alcohol 13 to Vinyl Bromide 7.


Entry	Base	Hydride reagent	Yield (%) of 7 (2 steps)
1	n-BuLi	-	-
2	Pyridine	-	-
3	NaH	-	-
4	t-BuOK	LiAlH₄	41
5	t-BuOK	LiHBEt₃	80

Next, turning our attention to the coupling partner of 7, aldehyde 8 was synthesized as depicted in Scheme 3. Commercially available 3-butyn-1-ol (11) was protected as the tetrahydropyranyl (THP) ether to afford 15 in good yield,²⁰ and the terminal alkyne was then silylated to provide the dimethylphenylsilyl (DMPS)-protected 16 in 87% yield. Hydroalumination of 16 using DIBAL-H and subsequent bromination afforded vinyl bromide 17 in 66% yield. After replacement of the bromine group by a methyl group to give 18 (95%), removal of the THP group using p-TsOH in MeOH (19, 95%) was followed by Dess-Martin oxidation to furnish aldehyde 8 in 88% yield.

Scheme 3

Synthesis of aldehyde 8.

With 2 segments 7 and 8 in hand, we next attempted the Ni/Cr-mediated coupling reaction of these compounds (Scheme 4). In dimethyl sulfoxide (DMSO) solvent, the reaction proceeded to afford the desired allyl alcohol 5, albeit in low yield, which was attributed to homocoupling of the starting vinyl bromide 7.

Scheme 4

Ni/Cr-mediated coupling of 7 and 8.

In conclusion, we accomplished the synthesis of the thiazole-containing northern segment (5) of epothilone D in racemic form. This synthesis featured the stereoselective construction of the trisubstituted olefin moiety via an E-selective bromomethylenation with our previously developed reagent 10 and a Ni/Cr-mediated coupling reaction.

Studies toward the asymmetric synthesis of 5 and stereoselective preparation of the southern segment 6 are currently underway in our laboratory.

Experimental

¹H nuclear magnetic resonance (NMR) spectra were recorded on JEOL JNM-AL300 (300 MHz) instrument. The chemical shifts are expressed in ppm relative to tetramethylsilane (δ=0) as an internal standard (CDCl₃ solution). Splitting patterns are indicated as follows: s, singlet; d, doublet; t, triplet; q, quartet; quint, quintet; m, multiplet; and br, broad peak. ¹³C NMR spectra were recorded on JEOL JNM-AL400 (100 MHz) instrument. The chemical shifts are reported in ppm relative to the central line of the triplet at 77.0 ppm for CDCl₃. Infrared (IR) spectra were measured on a JASCO VALOR-III spectrometer and are reported in wavenumbers (cm⁻¹). Both low-resolution mass spectra (MS) and high-resolution mass spectra (HRMS) were obtained using JEOL JMS 700 (double-focusing mass spectrometer [DFMS], electron impact ionization [EI], or fast atom bombardment [FAB] mode) instrument with a direct inlet system. Column chromatography was performed on silica gel (40-100 mesh). Analytical thin-layer chromatography (TLC) was conducted using 0.25 mm silica gel 60 F plates.

(E)-Methyl 2-Bromo-3-(2-Methylthiazol-4-yl)Acrylate (12)

To a stirred solution of 10 (4.30 g, 10.8 mmol) in tetrahydrofuran (THF) (20 mL) was added NaHMDS (1.0 M solution in THF, 10.0 mL, 10.0 mmol) at −78°C. After stirring at the same temperature for 40 minutes, aldehyde 9 (1.15 g, 9.04 mmol) in THF (100 mL) precooled to −78°C was added to the reaction mixture and stirring was continued for 30 minutes. The reaction was quenched by the addition of saturated aqueous NH₄Cl (50 mL). The resulting mixture was extracted with EtOAc (100 mL, 3 times). The combined organic layers were washed with brine (100 mL), dried over MgSO₄, filtered, and concentrated in vacuo. The crude residue was purified via flash chromatography on silica gel (toluene/CH₂Cl₂, 5:1) to afford ester 12 (1.70 g, 85% yield) as a pale yellow solid.

Rf: 0.33 (toluene/CH₂Cl₂, 5:1).

IR (CHCl₃): 2953, 1732, 1434, 1359, 1224, 787 cm⁻¹.

¹H NMR (300 MHz, CDCl₃): 2.75 (3H, s), 3.90 (3H, s), 8.34 (1H, s), 8.46 (1H, s).

¹³C NMR (100 MHz, CDCl₃): 19.1, 52.9, 111.4, 119.7, 129.7, 149.0, 165.4, 165.5.

MS (EI, 70 eV): m/z = 263, 261 [M⁺].

HRMS-EI: m/z [M⁺] calcd for C₈H₈BrNO₂S: 260.9459; found: 260.9456.

(E)-2-Bromo-3-(2-Methylthiazol-4-yl)-2-Propen-1-Ol (13)

To a stirred solution of ester 12 (1.01 g, 3.85 mmol) in toluene (100 mL) was added DIBAL-H (1.0 M solution in toluene, 12 mL, 12 mmol) at −78°C. After stirring at the same temperature for 1 hour, the reaction mixture was warmed to 0°C and stirred for 1 hour. MeOH (10 mL) was added, and the mixture was stirred for 30 minutes. Saturated aqueous Rochelle salt (100 mL) was added and the resulting mixture was extracted with EtOAc (100 mL, 3 times). The combined organic layers were washed with brine (100 mL), dried over MgSO₄, filtered, and concentrated in vacuo. The crude residue was purified via flash chromatography on silica gel (hexane/EtOAc, 5:1) to afford alcohol 13 (694 mg, 77% yield) as a pale yellow oil.

Rf: 0.43 (hexane/EtOAc, 5:1).

IR (CHCl₃): 3232, 3019, 1508, 1189, 728 cm⁻¹.

¹H NMR (300 MHz, CDCl₃): 2.73 (3H, s), 4.65 (2H, d, J = 7.3 Hz), 5.96 (1H, t, J = 7.3 Hz), 6.94 (1H, s), 7.02 (1H, s).

¹³C NMR (100 MHz, CDCl₃): 19.1, 67.0, 118.0, 125.8, 128.6, 150.4, 167.1.

MS (EI, 70 eV): m/z = 235, 233 [M⁺].

HRMS-EI: m/z [M⁺] calcd for C₇H₈BrNOS: 232.9510; found: 232.9508.

(E)-2-Bromo-3-(2-Methylthiazole-4-yl)-2-Propene (7)

To a stirred solution of alcohol 13 (447 mg, 1.91 mmol) in THF (15 mL) was added t-BuOK (1.0 M solution in THF, 2.3 mL, 2.3 mmol) at −78°C. After stirring at the same temperature for 30 minutes, p-TsCl (437 mg, 2.3 mmol) was added, and stirring was continued for 10 minutes. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction was quenched by the addition of saturated aqueous NaHCO₃ (20 mL) and the resulting mixture was extracted with EtOAc (20 mL, 3 times). The combined organic layers were washed with brine (20 mL), dried over MgSO₄, filtered, and concentrated in vacuo. The crude residue was used for the next step without further purification.

To a stirred solution of the crude tosylate 14 (749 mg) in THF (30 mL) at 0°C was added LiHBEt₃ (1.0 M solution in THF, 19 mL, 19 mmol), and the resulting solution was stirred for 1 hour. Saturated aqueous Rochelle salt (20 mL) was added and the resulting mixture was extracted with EtOAc (30 mL, 3 times). The combined organic layers were washed with brine (30 mL), dried over MgSO₄, filtered, and concentrated in vacuo. The crude residue was purified via flash chromatography on silica gel (hexane/EtOAc, 20:1) to afford vinyl bromide 7 (333 mg, 80% yield) as a pale yellow oil.

Rf: 0.44 (hexane/EtOAc, 5:1).

IR (CHCl₃): 2927, 1640, 1507, 1377, 1185, 788 cm⁻¹.

¹H NMR (300 MHz, CDCl₃): 2.70 (3H, s), 2.77 (3H, d, J = 1.3 Hz), 6.85 (1H, m), 6.91 (1H, s).

¹³C NMR (100 MHz, CDCl₃): 19.3, 30.3, 116.6, 125.1, 126.1, 151.5, 165.3.

MS (EI, 70 eV): m/z = 219, 217 [M⁺].

HRMS-EI: m/z [M⁺] calcd for C₇H₈BrNS: 216.9561; found: 216.9558.

4-(2-Tetrahydropyranoxy)-1-Butyne (15)

To a stirred solution of 3-butyn-1-ol (7.76 g, 111 mmol) in CH₂Cl₂ (100 mL) were added p-TsOH·H₂O (212 mg, 1.11 mmol) and 3,4-dihydro-2H-pyran (10.3 g, 122 mmol) at 0°C. After stirring at the same temperature for 15 minutes, the reaction mixture was allowed to warm to room temperature and stirred for 3 hours. MeOH (10 mL) was added and the mixture was stirred for 30 minutes. The reaction was quenched by the addition of saturated aqueous NaHCO₃ (50 mL) and the resulting mixture was extracted with CH₂Cl₂ (100 mL, 3 times). The combined organic layers were washed with brine (100 mL), dried over MgSO₄, filtered, and concentrated in vacuo. The crude residue was purified via flash chromatography on silica gel (hexane/EtOAc, 5:1) to afford THP ether 15 (15.4 g, 90% yield) as a colorless oil.

Rf: 0.43 (hexane/EtOAc, 5:1).

¹H NMR (300 MHz, CDCl₃): 1.24-1.83 (6H, m), 1.98 (1H, t, J = 2.7 Hz), 2.50 (2H, dt, J = 7.1, 2.7 Hz), 3.50-3.62 (2H, m), 3.80-3.93 (2H, m), 4.65 (1H, t, J = 2.9 Hz). The spectroscopic data for 15 were identical to those reported in the literature.²⁰

1-Dimethylphenylsilyl-4-(2-Tetrahydropyranoxy)-1-Butyne (16)

To a stirred solution of THP ether 15 (6.23 g, 40.7 mmol) in THF (200 mL) was added n-BuLi (1.64 M solution in n-hexane, 30.0 mL, 49.2 mmol) dropwise over 20 minutes at −78°C. After stirring at the same temperature for 30 minutes, chloro(dimethyl)phenylsilane (DMPSCl) (8.1 mL, 49 mmol) was added. The reaction mixture was stirred for 30 minutes, allowed to warm to room temperature, and stirred for an additional 2 hours. The reaction was quenched by the addition of water (100 mL) and the resulting mixture was extracted with EtOAc (100 mL, 3 times). The combined organic layers were washed with brine (100 mL), dried over MgSO₄, filtered, and concentrated in vacuo. The crude residue was purified via flash chromatography on silica gel (toluene) to afford THP ether 16 (10.2 g, 87% yield) as a pale yellow oil.

Rf: 0.29 (hexane/EtOAc, 10:1).

¹H NMR (300 MHz, CDCl₃): 0.39 (6H, s), 1.51-1.72 (6H, m), 2.59 (2H, t, J = 7.1 Hz), 3.48-3.62 (2H, m), 3.82-3.90 (2H, m), 4.67 (1H, t, J = 3.3 Hz), 7.34-7.38 (3H, m), 7.61-7.65 (2H, m).

MS (FAB): m/z = 289 [M+H⁺].

(E)-1-Bromo-1-Dimethylphenylsilyl-4-(2-Tetrahydropyranyloxy)-1-Butene (17)

To a stirred solution of THP ether 16 (9.50 g, 32.9 mmol) in Et₂O (33 mL) was added DIBAL-H (1.04 M solution in n-hexane, 48.0 mL, 49.9 mmol) at 0°C. After stirring at the same temperature for 20 minutes, the reaction mixture was allowed to warm to room temperature and stirred for 40 hours. Et₂O (33 mL) and pyridine (6.6 mL, 82 mmol) were added and the reaction mixture was cooled to −78°C. Bromine (1.5 M solution in CH₂Cl₂, 33 mL, 51 mmol) was added dropwise and the stirring was continued for 1 hour. The reaction was quenched by the addition of 1 N NaOH (80 mL) and the mixture was extracted with EtOAc (200 mL, 3 times). The combined organic layers were successively washed with 1 N HCl (150 mL) and saturated aqueous NaHCO₃ (200 mL, twice), dried over MgSO₄, filtered, and concentrated in vacuo. The crude residue was purified via flash chromatography on silica gel (hexane/EtOAc, 10:1) to afford vinyl bromide 17 (8.00 g, 66% yield) as a colorless oil.

Rf: 0.31 (hexane/EtOAc, 10:1).

IR (CHCl₃): 2950, 1604, 1442, 1353, 1252, 1032 cm⁻¹.

¹H NMR (300 MHz, CDCl₃): 0.55 (6H, s), 1.52-1.83 (6H, m), 2.19 (2H, dt, J = 7.9, 6.6 Hz), 3.26 (1H, dt, J = 9.5, 6.6 Hz), 3.43-3.49 (1H, m), 3.62 (1H, dt, J = 9.7, 6.4 Hz), 3.74-3.80 (1H, m), 4.60 (1H, t, J = 3.1 Hz), 6.80 (1H, t, J = 7.9 Hz), 7.34-7.40 (3H, m), 7.57-7.61 (2H, m).

MS (EI, 70 eV): m/z = 370, 368 [M⁺].

HRMS-EI: m/z [M⁺] calcd for C₁₇H₂₅BrO₂Si: 368.0807; found: 368.0804.

(Z)-2-Dimethylphenylsilyl-5-(2-Tetrahydropyranyloxy)-2-Pentene (18)

To a stirred solution of vinyl bromide 17 (3.48 g, 9.42 mmol) in THF (100 mL) was added n-BuLi (1.64 M solution in n-hexane, 17.2 mL, 28.2 mmol) at −78°C. After stirring at the same temperature for 1 hour, MeI (2.1 mL, 34 mmol) was added and the resulting mixture was stirred for 6 hours. The reaction was quenched by the addition of MeOH (10 mL) and the resulting mixture was stirred for 2 hours. Saturated aqueous NH₄Cl (50 mL) was then added and the resulting mixture was extracted with EtOAc (100 mL, 3 times). The combined organic layers were washed with brine (100 mL), dried over MgSO₄, filtered, and concentrated in vacuo. The crude residue was purified via flash chromatography on silica gel (hexane/EtOAc, 10:1) to afford THP ether 18 (2.75 g, 95% yield) as a colorless oil.

Rf: 0.48 (hexane/EtOAc, 10:1).

IR (CHCl₃): 2952, 1619, 1428, 1251, 1031, 816, 702 cm⁻¹.

¹H NMR (300 MHz, CDCl₃): 0.40 (6H, s), 1.46-1.81 (6H, m), 2.29 (2H, q, J = 6.8 Hz), 3.26 (1H, dt, J = 9.5, 6.6 Hz), 3.43-3.49 (1H, m), 3.62 (1H, dt, J = 9.7, 6.4 Hz), 3.74-3.80 (1H, m), 4.60 (1H, t, J = 3.1 Hz), 6.80 (1H, t, J = 7.9 Hz), 7.34-7.40 (3H, m), 7.57-7.61 (2H, m).

¹³C NMR (100 MHz, CDCl₃): −0.4 (2C), 20.3, 26.0, 26.3, 31.5, 33.5, 62.9, 67.9, 99.4, 128.6 (2C), 129.2, 129.6 (2C), 135.6, 140.2, 140.9.

MS (EI, 70 eV): m/z = 304 [M⁺].

HRMS-EI: m/z [M⁺] calcd for C₁₈H₂₈O₂Si: 304.1859; found: 304.1862.

Anal. Calcd for C₁₈H₂₈O₂Si: C, 71.00; H, 9.27. Found: C, 71.19; H, 9.35.

(Z)-4-Dimethylphenylsilyl-3-Penten-1-ol (19)

To a stirred solution of THP ether 18 (1.79 g, 5.88 mmol) in MeOH (30 mL) was added p-TsOH·H₂O (56 mg, 0.29 mmol) at room temperature. After stirring for 1 hour, Et₃N (2.0 mL, 14 mmol) was added and the stirring was continued for 15 minutes. The resulting mixture was concentrated in vacuo. The crude residue was purified via flash chromatography on silica gel (hexane/EtOAc, 10:1) to afford alcohol 19 (1.23 g, 95% yield) as a colorless oil.

Rf: 0.37 (hexane/EtOAc, 3:1).

IR (CHCl₃): 3436, 2956, 1618, 1428, 1251 cm⁻¹.

¹H NMR (300 MHz, CDCl₃): 0.46 (6H, s), 1.77 (1H, br s), 1.90 (3H, t, J = 1.5 Hz), 2.26 (2H, q, J = 6.3 Hz), 3.51 (2H, t, J = 6.3 Hz), 6.14 (1H, tq, J = 6.3, 1.5 Hz), 7.38-7.40 (3H, m), 7.57‒7.59 (2H, m).

¹³C NMR (100 MHz, CDCl₃): −1.4 (2C), 25.2, 35.3, 62.2, 127.7 (2C), 128.8, 133.6 (2C), 136.0, 139.2, 139.5.

MS (EI, 70 eV): m/z = 220 [M⁺].

HRMS-EI: m/z [M⁺] calcd for C₁₃H₂₀OSi: 220.1283; found: 220.1280.

(Z)-4-Dimethylphenylsilyl-3-Pentenal (8)

To a stirred solution of alcohol 19 (74 mg, 0.34 mmol) in CH₂Cl₂ (3.0 mL) was added Dess-Martin periodinane (213 mg, 0.502 mmol) at room temperature. After stirring at the same temperature for 1.5 hours, the reaction was quenched by the addition of a mixture of saturated aqueous NaHCO₃ and 5% Na₂S₂O₃ (1:1, 16 mL). The resulting mixture was extracted with Et₂O (15 mL, 3 times). The combined organic layers were washed with brine (20 mL), dried over MgSO₄, filtered, and concentrated in vacuo. The crude residue was purified via flash chromatography on silica gel (hexane/EtOAc, 5:1) to afford aldehyde 8 (65 mg, 88% yield) as a pale yellow oil.

Rf: 0.44 (hexane/EtOAc, 5:1).

IR (CHCl₃): 2960, 1720, 1428, 1223, 1111, 769 cm⁻¹.

¹H NMR (300 MHz, CDCl₃): 0.40 (6H, s), 1.91 (3H, q, J = 1.3 Hz), 3.05 (2H, dquint, J = 7.5, 1.3 Hz), 6.22 (1H, tq, J = 7.5, 1.7 Hz), 7.31-7.39 (3H, m), 7.47-7.53 (2H, m), 9.45 (1H, t, J = 1.7 Hz).

¹³C NMR (100 MHz, CDCl₃): −1.6 (2C), 25.3, 46.6, 128.1 (2C), 129.2, 131.8, 133.7 (2C), 138.5, 139.9, 199.9.

MS (EI, 70 eV): m/z = 218 [M⁺].

HRMS-EI: m/z [M⁺] calcd for C₁₃H₁₈OSi: 218.1127; found: 218.1129.

(1E,5Z)-6-Dimethylphenylsilyl-2-Methyl-1-(2-Methylthiazol-4-yl)-1,5-Heptadien-3-ol (5)

To a stirred solution of vinyl bromide 7 (63 mg, 0.29 mmol) and aldehyde 8 (30 mg, 0.14 mmol) in DMSO (3.0 mL) were added CrCl₂ (172 mg, 1.4 mmol) and NiCl₂ (2 mg, 0.02 mmol) at room temperature in a glove box. After stirring at the same temperature for 1 hour, the reaction was quenched by the addition of water (20 mL). The resulting mixture was extracted with Et₂O (20 mL, 3 times). The combined organic layers were washed with brine (20 mL), dried over MgSO₄, filtered, and concentrated in vacuo. The crude residue was purified via flash chromatography on silica gel (hexane/EtOAc, 5:1) to afford allyl alcohol 5 (6 mg, 12% yield) as a pale yellow oil.

Rf: 0.1 (hexane/EtOAc, 5:1).

IR (CHCl₃): 3341, 2929, 1617, 1508, 1428, 1210, 1110, 703 cm⁻¹.

¹H NMR (300 MHz, CDCl₃): 0.41 (6H, s), 1.26 (1H, br s), 1.86 (6H, s), 2.29 (2H, t, J = 7.1 Hz), 2.70 (3H, s), 4.04 (1H, t, J = 6.2 Hz), 6.14 (1H, t, J = 6.2 Hz), 6.43 (1H, s), 6.90 (1H, s), 7.26-7.35 (3H, m), 7.51-7.55 (2H, m).

¹³C NMR (100 MHz, CDCl₃): −1.3 (2C), 14.1, 19.2, 25.4, 37.9, 76.7, 115.5, 118.8, 127.9 (2C), 128.9, 133.7 (2C), 136.7, 139.3 (2C), 141.6, 152.8, 164.5.

MS (EI, 70 eV): m/z = 357 [M⁺].

HRMS-EI: m/z [M⁺] calcd for C₂₀H₂₇NOSSi: 357.1583; found: 357.1577.

Footnotes

Authors’ Note

This paper is dedicated to Professor Chiaki Kuroda on the occasion of his 65th birthday.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was partially supported by a grant from the Dementia Drug Resource Development Center, Project S1511016, the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan.

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Studies toward the Total Synthesis of Epothilone D: Synthesis of the Thiazole-Containing Northern Segment

Abstract

Keywords

Experimental

(E)-Methyl 2-Bromo-3-(2-Methylthiazol-4-yl)Acrylate (12)

(E)-2-Bromo-3-(2-Methylthiazol-4-yl)-2-Propen-1-Ol (13)

(E)-2-Bromo-3-(2-Methylthiazole-4-yl)-2-Propene (7)

4-(2-Tetrahydropyranoxy)-1-Butyne (15)

1-Dimethylphenylsilyl-4-(2-Tetrahydropyranoxy)-1-Butyne (16)

(E)-1-Bromo-1-Dimethylphenylsilyl-4-(2-Tetrahydropyranyloxy)-1-Butene (17)

(Z)-2-Dimethylphenylsilyl-5-(2-Tetrahydropyranyloxy)-2-Pentene (18)

(Z)-4-Dimethylphenylsilyl-3-Penten-1-ol (19)

(Z)-4-Dimethylphenylsilyl-3-Pentenal (8)

(1E,5Z)-6-Dimethylphenylsilyl-2-Methyl-1-(2-Methylthiazol-4-yl)-1,5-Heptadien-3-ol (5)

Footnotes

Authors’ Note

Declaration of Conflicting Interests

Funding

References