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Synthesis of (±)-terpendole E a

a

b

a

Takaaki Teranishi , Tetsuro Murokawa , Masaru Enomoto & Shigefumi Kuwahara a

Laboratory of Applied Bioorganic Chemistry, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan b

Biomaterial Engineering Research Group, Bioproduction Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Sapporo, Japan Published online: 03 Sep 2014.

Click for updates To cite this article: Takaaki Teranishi, Tetsuro Murokawa, Masaru Enomoto & Shigefumi Kuwahara (2015) Synthesis of (±)terpendole E, Bioscience, Biotechnology, and Biochemistry, 79:1, 11-15, DOI: 10.1080/09168451.2014.955455 To link to this article: http://dx.doi.org/10.1080/09168451.2014.955455

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Bioscience, Biotechnology, and Biochemistry, 2015 Vol. 79, No. 1, 11–15

Synthesis of (±)-terpendole E Takaaki Teranishi1, Tetsuro Murokawa1, Masaru Enomoto2 and Shigefumi Kuwahara1,* 1

Laboratory of Applied Bioorganic Chemistry, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan; 2Biomaterial Engineering Research Group, Bioproduction Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Sapporo, Japan Received July 2, 2014; accepted July 28, 2014

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http://dx.doi.org/10.1080/09168451.2014.955455

The first synthesis of the racemate of terpendole E, a specific inhibitor of the mitotic kinesin Eg5, has been achieved from a known tricyclic dihydroxy ketone by a 13-step sequence that involves diastereoselective installation of its C3 quaternary stereocenter via a cyclopropyl ketone intermediate and Pd-mediated two-step construction of the indole ring moiety as the key transformations. Key words:

terpendole; indole diterpene; antimitotic; kinesin spindle protein; total synthesis

Terpendole E (1), originally isolated from the fungus Albophoma yamanashiensis (syn. Chaunopycnis alba) as a week ACAT (acyl-CoA: cholesterol acyltransferase) inhibitor,1) has been gaining increasing attention from cancer researchers since its rediscovery by Osada and co-workers as the first natural inhibitor of the mitotic kinesin Eg5 (also called kinesin spindle protein, KSP) (Fig. 1).2) This hexacyclic indole diterpene specifically arrests cell-division cycle at the M phase by inhibiting Eg5 which is a member of the kinesin-5 (BimC) family of motor proteins and plays essential roles in centrosome separation and formation of bipolar mitotic spindles.3) Furthermore, terpendole E (1) does not affect microtubule integrity in interphase, and thereby is expected as a promising lead for the development of anticancer drugs with fewer side effects than conventional antimitotic agents such as vinblastine and taxol that directly target tubulins. The biosynthetic pathway of some indole diterpenes was also elucidated by the Osada group through isolation and analysis of the terpendole E biosynthetic gene cluster, and the overproduction of 1 could be successfully realized by gene knockout of TerP, an enzyme responsible for the conversion of terpendole E into a downstream intermediate.4) Quite recently, Usui and co-workers revealed that terpendole E (1) and its 11-keto congener (11-ketopaspaline) inhibited several Eg5 mutants that are resistant to unnatural Eg5 inhibitors (STLC and GSK-1) with the same extent of inhibition against wild-type Eg5.3)

The challenging molecular architecture of 1 as well as its attractive pharmacological profiles prompted synthetic efforts toward 1, which led to the synthesis of 16-epi-terpendole E by Giannis and co-workers and a tricyclic right-hand moiety of 1 by the Oikawa group.5,6) We have also addressed the total synthesis of terpendole E, and recently succeeded in a diastereoselective synthesis of (±)-3 from known Wieland– Miescher ketone analog (±)-2.7,8) In this article, we describe the first synthesis of terpendole E as its racemate from (±)-3.

Results and discussion Scheme 1 outlines our retrosynthetic analysis of (±)-1. On the basis of our previous synthetic studies on indole terpenoid natural products,9,10) the alkaloid was dissected into o-stannylated aniline segment 4 and tetracyclic enol triflate segment 5 with the intention of connecting the two segments by the Stille coupling reaction. The installation of the C3 quaternary stereocenter of 5 and simultaneous construction of its enol triflate portion would be achievable by reductive cleavage of the cyclopropane ring of 6 with an appropriate alkali metal followed by in situ trapping of the resulting enolate intermediate with a triflating agent. The diastereoselective formation of the cyclopropyl ketone 6 would be realized from 7 via stereoselective reduction of the ketone functionality and subsequent hydroxydirected cyclopropanation of the resulting allylic alcohol. The tetracyclic enone 7 would readily be obtainable from (±)-3. The preparation of key intermediate 6′ (bis-TBSprotected form of 6) began with the silylation of the two hydroxy groups in (±)-3 to afford 8 according to the literature procedure (Scheme 2).5) Alkylation of the bis-TBS ether 8 with bromide 9 followed by chemoselective hydrolysis of the enol ether moiety of the resulting product gave phosphonate 10 as an epimeric mixture at the C16 position.11) Subjection of the mixture to the intramolecular Horner–Wadsworth–Emmons

*Corresponding author. Email: [email protected] Abbreviations: TBSOTf, t-butyldimethylsilyl trifluoromethanesulfonate; TsOH, p-toluenesulfonic acid; LDA, lithium diisopropylamide; HMPA, hexamethylphosphoramide; TBAF, tetra-n-butylammonium fluoride. © 2014 Japan Society for Bioscience, Biotechnology, and Agrochemistry

12

T. Teranishi et al. H OH

16

11

H

N H

H

1

O

OH OH

O

ref 7 O O

O

12 steps 30%

H O H (±)-3

(±)-2

OH

Fig. 1. Structures of terpendole E (1) and our key synthetic intermediate (±)-3 previously prepared from known enone (±)-2.

H 1

SnR

OR3 3

+

(±)-1

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TfO

3

H

NHR2 4

5

H

O

OR3

H OR3

O H 6

H

O

O

OR1

O H O H (±)-3

Scheme 1.

OR3

H

OH

(OCOCF3)2 in DMSO at 60 °C in the presence of NaOAc according to our previously developed protocol.9,10,16) Finally, removal of the TBS-protecting groups with TBAF and then the Boc group under Wensbo’s conditions17) furnished (±)-1 in 63% yield for the two steps. The 1H and 13C NMR spectra of (±)-1 were identical with those of natural terpendole E. In conclusion, the first synthesis of terpendole E (1) as its racemate was accomplished from (±)-3 by the 13-step sequence (13% overall yield) involving the diastereoselective installation of the C3 stereocenter via the hydroxy-directed Simmons–Smith cyclopropanation of the allylic alcohol 11 coupled with the dissolving metal reduction of the cyclopropyl ketone 6′ and the Pd-mediated two-step indole ring formation from 5′ to 14. Our efforts toward the enantioselective synthesis of 1 and structurally related indole terpenoids using optically pure 2,18,19) as the starting material, are now in progress and will be reported in due course.

H OH 7

H

O

OR1

Experimental IR spectra were recorded by a Jasco FT/IR-4100 spectrometer using an ATR (ZnSe) attachment. NMR spectra were recorded with TMS as an internal standard in CDCl3 by a Varian MR-400 spectrometer (400 MHz for 1H and 100 MHz for 13C) unless otherwise stated. Optical rotation values were measured with a Jasco P-2200 polarimeter. Mass spectra were obtained with a Jeol JMS-700 spectrometer operated in the FAB mode. Merck silica gel 60 (63–200 μm) or Kanto Kagaku silica gel 60 N (neutral, 100–210 μm) was used for column chromatography. Solvents for reactions were distilled prior to use: THF from Na and benzophenone; CH2Cl2, DMSO and HMPA from CaH2.

Retrosynthetic analysis of (±)-1 leading to (±)-3.

olefination effected a stereoconvergent cyclization to give cyclopentenone derivative 7′ as a single diastereomer in 43% overall yield from 8. Reduction of 7′ with ® L-Selectride proceeded highly stereoselectively, delivering allylic alcohol 11 with an α-oriented hydroxy group, which was then exposed to hydroxy-directed Simmons–Smith cyclopropanation to provide 12.12,13) Finally, the Parikh–Doerinng oxidation of the cyclopropyl alcohol 12 furnished 6′ in 64% yield for the three steps from 7′. With the cyclopropyl ketone intermediate 6′ in hand, we set about the final stage of the synthesis of (±)-1 (Scheme 3). Reduction of 6′ with sodium naphthalenide in THF in the presence of t-BuOH as a proton source and subsequent trapping of the resulting enolate intermediate with Comins’ reagent gave the desired enol triflate 5′ with the stereochemistry at the C3 and C4 contiguous quaternary carbons correctly installed.9,10) The Stille coupling reaction of 5′ with tin reagent 4′ under Corey’s conditions afforded 1314,15); the two-step conversion of 6′ into 13 proceeded quite efficiently, providing 13 in an excellent overall yield of 95%. The oxidative indole ring formation from 13 to 14 was achieved in 91% yield by treating 13 with Pd

(2S*,4R*,4aS*,4bR*,6aS*,9bS*,11aS*)-4-[(tert-Butyldimethylsilyl)oxy]-2-{2-[(tert-butyldimethylsilyl)oxy]propan-2-yl}-4a,9b-dimethyl-3,4,4a,4b,5,6,6a,7,9b,10,11, 11a-dodecahydroindeno[5,4-f]chromen-8(2H)-one (7′). To a stirred solution of LDA [prepared by treating a solution of i-Pr2NH (120 μL, 0.856 mmol) in THF (0.5 mL) with n-BuLi (1.6 M in hexane, 0.5 mL, 0.80 mmol) at 0 °C] a solution of 8 (209 mg, 0.388 mmol) in THF (3.4 mL) at 0 °C under a nitrogen atmosphere was added. After 75 min, a solution of 9 (166 mg, 0.606 mmol) and HPMA (0.2 mL, 1.15 mmol) in THF (2.0 mL) was added at −78 °C, and the resulting mixture was gradually warmed to room temperature. After 5 h, the mixture was quenched with saturated aq NH4Cl at 0 °C and extracted with EtOAc. The extract was washed with brine, dried (MgSO4) and concentrated in vacuo to give an oil, which was taken up in acetone (5 mL). To the solution 1 M aq HCl (1.5 mL) was added at 0 °C while stirring, and the resulting mixture was gradually warmed to room temperature. After 11 h, the mixture was quenched with solid K2CO3 (230 mg) at 0 °C, concentrated in vacuo and then extracted with EtOAc. The extract was successively washed with water and brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc = 1:2) to give 10 (208 mg) and

Synthesis of (±)-terpendole E

13

OTBS a, b (±)-3

c, d

O

H

(ref 5)

H 8

H OTBS

O

O

OTBS O

16

OTBS

O

(MeO)2P O e

H H

10

H H

7'

O

OTBS

HO OTBS

HO

g

H

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12

H

11

H H

O

OTBS h

O

OTBS

H OTBS

O O (MeO)2P

OTBS

H

OTBS f

H

O

OMe

H Br

H

6'

9

O

OTBS

Scheme 2. Preparation of 6′. Notes: Reagents and conditions: (a) TBSOTf, 2,6-lutidine, CH2Cl2, rt, 35 min; (b) TsOH·H2O, MeOH, THF, 0 °C, 3 h, 89% (two steps); (c) LDA, 9, THF, HMPA, −78 °C to rt, 5 h; (d) aq HCl, Me2CO, 0 °C to rt, 11 h; (e) Cs2CO3, THF, 50 °C, 23 h, 43% (three steps); (f) LiBH(s-Bu)3, THF, −78 to −40 °C, 3 h; (g) CH2I2, Et2Zn, CH2Cl2, 0 °C to rt, 3 h; (h) SO3·Py, DMSO, Et3 N, CH2Cl2, 0 °C to rt, 3.5 h, 63% (three steps).

recovered 8 (42.5 mg). To a stirred solution of 10, just obtained (208 mg, 0.296 mmol) in THF (14 mL), Cs2CO3 (405 mg, 1.24 mmol) was added at 50 °C under a nitrogen atmosphere. After 23 h, the mixture was quenched with water at 0 °C and extracted with EtOAc and then with CH2Cl2. The combined extracts were successively washed with water and brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc = 11:1) to give 96.9 mg (43% from 8) of 7′. 1H NMR (400 MHz) δ: −0.02 (3H, s), 0.06 (6H, s), 0.09 (3H, s), 0.85 (9H, s), 0.86 (9H, s), 0.90 (3H, s), 1.00–1.11 (1H, m), 1.17 (3H, s), 1.20 (3H, s), 1.21 (3H, s), 1.46–1.74 (8H, m), 1.82 (1H, td, J = 13.4, 2.0 Hz), 1.94 (1H, d, J = 18.6 Hz), 2.17–2.25 (1H, m), 2.54 (1H, dd, J = 18.6, 6.4 Hz), 2.86–2.94 (1H, m), 3.42 (1H, dd, J = 11.9, 2.1 Hz), 3.53 (1H, br t, J = 7.2 Hz), 3.76 (1H, br s), 5.67 (1H, s); 13C NMR (100 MHz) δ: −5.0, −3.6, −2.12, −2.10, 13.7, 18.11, 18.14, 19.5, 20.4, 24.0, 25.1, 25.9 (3C), 26.0 (3C), 27.4, 29.0, 34.9, 35.3, 38.2, 39.8, 41.8, 42.4, 44.2, 71.1, 74.7, 76.3, 79.3, 121.4, 194.3, 209.7; HRMS (FAB) m/z: calcd. for C33H61O4Si2, 577.4108; found, 577.4106 ([M + H]+). (2aS*,3aR*,3bS*,5aS*,7S*,9R*,9aS*,9bR*,11aS*)-9[(tert-Butyldimethylsilyl)oxy]-7-{2-[(tert-butyldimethylsilyl)oxy]propan-2-yl}-3b,9a-dimethyltetradecahydrocyclopropa[3,3a]indeno[5,4-f]chromen-2(1H)-one (6′). To a stirred solution of 7′ (150 mg, 0.259 mmol) in

H

H OTBS

O

a

OTBS

TfO

3 4

H 6'

H

O

OTBS

H 5'

H

O

OTBS

b H OTBS H

NHBoc

H OTBS

c 13

H

O

OTBS

H

N Boc 14

H

O

OTBS d, e

H OH

SnMe3 NHBoc 4'

N H

H (±)-1

H

O

OH

Scheme 3. Completion of the synthesis of (±)-1. Notes: Reagents and conditions: (a) Na/C10H8, t-BuOH, THF, −78 °C, 1 h, then isoprene, Comins’ reagent, HMPA, −78 °C to rt, 3 h; (b) 4′, Pd(PPh3)4, CuCl, LiCl, DMSO, CH2Cl2, 50 °C 2 h, 95% (two steps); (c) Pd(OCOCF3)2, NaOAc, DMSO, 60 °C, 28 h, 91%; (d) TBAF, THF, 55 °C, 27 h; and (e) SiO2, 100 °C, 4 h, ca. 12 kPa, 63% (two steps).

14

T. Teranishi et al.

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®

THF (4.6 mL) L-Selectride (1.0 M in THF, 0.7 mL, 0.7 mmol) was added at −78 °C under a nitrogen atmosphere, and the resulting mixture was gradually warmed to −40 °C. After 3 h, the mixture was quenched with saturated aq NH4Cl at 0 °C and extracted with EtOAc. The extract was successively washed with water and brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc = 11:1) to give 11 (124 mg), which was then dissolved in CH2Cl2 (1.5 mL). To a stirred solution of CH2I2 (50 μL, 0.62 mmol) in CH2Cl2 (1.2 mL) were successively added Et2Zn (1.0 M in hexane, 0.5 mL, 0.5 mmol) and the solution of 11 prepared above at 0 °C under a nitrogen atmosphere, and the resulting mixture was gradually warmed to room temperature. After 3 h, the mixture was quenched with saturated aq NH4Cl at 0 °C and extracted with EtOAc. The extract was successively washed with water and brine, dried (MgSO4) and concentrated in vacuo to give an oil, which was taken up in CH2Cl2 (4.0 mL). To the solution, Et3N (0.4 mL, 2.88 mmol), DMSO (0.2 mL, 2.82 mmol) and SO3·Py (290 mg, 1.82 mmol) were successively added at 0 °C under a nitrogen atmosphere, and the resulting mixture was gradually warmed to room temperature. After 3.5 h, the mixture was quenched with saturated aq NH4Cl at 0 °C and extracted with EtOAc. The extract was successively washed with water and brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc = 20:1) to give 97.4 mg (63% from 7′) of 6′. 1H NMR (400 MHz) δ: 0.05 (3H, s), 0.07 (3H, s), 0.08 (3H, s), 0.09 (3H, s), 0.82 (3H, s), 0.84 (9H, s), 0.85–0.93 (2H, m), 0.95 (9H, s), 1.10 (1H, td, J = 12.7, 3.6 Hz), 1.16 (3H, s), 1.20 (3H, s), 1.21 (3H, s), 1.24–1.47 (3H, m), 1.47–1.64 (4H, m), 1.74–1.96 (6H, m), 2.57–2.67 (1H, m), 3.42 (1H, dd, J = 12.0, 2.5 Hz), 3.50 (1H, dd, J = 11.7, 4.3 Hz), 3.77 (1H, br s); 13C NMR (100 MHz) δ: −5.2, −3.4, −2.1 (2C), 13.1, 13.9, 18.1, 18.2, 20.7, 21.1, 23.8, 25.1, 25.9 (3C), 26.0 (3C), 27.4, 29.1 (2C), 31.2, 31.5, 35.1, 36.1, 37.8, 41.2, 44.1, 48.8, 71.0, 74.8, 76.6, 79.3, 213.8; HRMS (FAB) m/z: calcd. for C34H62O4Si2Na, 613.4085; found, 613.4083 ([M + Na]+). tert-Butyl [2-((2S*,4R*,4aS*,4bR*,6aS*,9aR*,9bS*,11aS*)-4-[(tert-butyldimethylsilyl)oxy]-2-{2-[(tertbutyldimethylsilyl)oxy]propan-2-yl}-4a,9a,9b-trimethyl2,3,4,4a,4b,5,6,6a,7,9a,9b,10,11,11a-tetradecahydroindeno[5,4-f]chromen-8-yl)phenyl]carbamate (13). To a stirred solution of 6′ (61.2 mg, 0.104 mmol) and t-BuOH (3.0 μL, 0.031 mmol) in THF (2.5 mL), a solution of sodium naphthalenide (0.65 M in THF, 0.8 mL, 0.33 mmol) was added dropwise at −78 °C under a nitrogen atmosphere, and the resulting mixture was stirred for 1 h. To the mixture, isoprene (0.2 mL) and a solution of 2-[N,N-bis(trifluoromethylsulfonyl) amino]-5-chloropyridine (163 mg, 0.414 mmol) and HMPA (0.1 mL, 0.575 mmol) in THF (0.8 mL) were successively added. The mixture was gradually warmed to 0 °C over 3 h before being quenched with saturated aq NH4Cl, and extracted with Et2O. The extract was successively washed with water and brine, dried

(MgSO4) and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/ EtOAc = 80:1) to give 5′ (74.1 mg), which was dissolved, together with 4′ (109 mg, 0.306 mmol), in CH2Cl2 (2.0 mL)/DMSO (4.0 mL). The solution was added dropwise to a stirred mixture of Pd(PPh3)4 (36.0 mg, 0.0312 mmol), CuCl (126 mg, 1.27 mmol) and LiCl (45.1 mg, 1.06 mmol) in DMSO (3.0 mL) at room temperature under an argon atmosphere. After being stirred at 50 °C for 2 h, the reaction mixture was quenched with brine and extracted with EtOAc. The extract was successively washed with water and brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc = 50:1) to give 75.5 mg (95% from 6′) of 13. 1H NMR (400 MHz) δ: 0.06 (3H, s), 0.09 (6H, s), 0.10 (3H, s), 0.84 (3H, s), 0.85 (9H, s), 0.96 (12H, s), 1.14 (3H s), 1.17 (3H, s), 1.21 (3H, s), 1.22–1.72 (9H, m), 1.50 (9H, s), 1.83 (1H, t, J = 13.1 Hz), 2.07 (1H, dd, J = 12.7, 2.1 Hz), 2.22 (1H, dd, J = 13.7, 6.3 Hz), 2.26–2.36 (1H, m), 2.49 (1H, dd, J = 13.7, 12.0 Hz), 3.45 (1H, dd, J = 11.7, 1.6 Hz), 3.51 (1H, dd, J = 11.1, 3.5 Hz), 3.77 (1H, br s), 5.97 (1H, s), 6.90 (1H, br s), 6.98 (1H, t, J = 7.5 Hz), 7.06 (1H, d, J = 7.5 Hz), 7.19 (1H, dd, J = 8.1, 7.5 Hz), 7.95 (1H, d, J = 8.1 Hz); 13C NMR (100 MHz) δ: −4.7, −3.8, −2.1 (2C), 13.2, 13.3, 18.1, 18.2, 19.6, 21.4, 24.5, 24.7, 25.1, 25.96 (3C), 26.04 (3C), 27.4, 28.3 (3C), 29.2, 31.8, 36.8, 38.5, 39.3, 41.2, 44.0, 56.8, 71.5, 74.9, 76.8, 79.2, 80.1, 119.4, 122.6, 127.1, 127.5, 128.5, 134.9, 139.2, 140.1, 152.9; HRMS (FAB) m/z: calcd. for C45H77O5NSi2Na, 790.5238; found, 790.5241 ([M + Na]+). tert-Butyl (2S*,4R*,4aS*,4bR*,6aS*,12bS*,12cS*,14aS*)-4-[(tert-butyldimethylsilyl)oxy]-2-{2-[(tertbutyldimethylsilyl)oxy]propan-2-yl}-4a,12b,12c-trimethyl-2,3,4,4a,4b,5,6,6a,7,12b,12c,13,14,14a-tetradecahydro-12H-chromeno[5′,6′:6,7]indeno[1,2-b] indole-12-carboxylate (14). To a stirred solution of 13 (18.8 mg, 0.0245 mmol) in DMSO (2.0 mL), NaOAc (95.7 mg, 1.17 mmol) and Pd(OCOCF3)2 (175 mg, 0.526 mmol) at room temperature were successively added under an argon atmosphere. After 16 h of stirring at 60 °C, additional NaOAc (42.6 mg, 0.519 mmol) and Pd(OCOCF3)2 (90.2 mg, 0.271 mmol) were added, and the resulting mixture was stirred for 12 h before being quenched with water at 0 °C. The mixture was extracted with a mixture of hexane/EtOAc (2:1), and the extract was successively washed with water and brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by preparative TLC (hexane/ EtOAc = 60:1) to give 17.1 mg (91%) of 14. 1H NMR (400 MHz) δ: 0.06 (3H, s), 0.09 (3H, s), 0.10 (6H, s), 0.81 (3H, s), 0.85 (9H, s), 0.96 (9H, s), 1.04 (3H, s), 1.17 (3H, s), 1.21 (3H, s), 1.39 (3H, s), 1.65 (9H, s), 1.27–1.34 (1H, m), 1.48–1.58 (4H, m), 1.58–1.70 (3H, m), 1.76–1.87 (2H, m), 2.15 (1H, dd, J = 12.8, 2.8 Hz), 2.32 (1H, dd, J = 13.4, 12.2 Hz), 2.55 (1H, dd, J = 13.4, 6.6 Hz), 2.77–2.87 (1H, m), 3.46 (1H, dd, J = 11.9, 2.1 Hz), 3.55 (1H, br t, J = 8.1 Hz), 3.78 (1H, br s), 7.14–7.20 (2H, m), 7.33–7.38 (1H, m), 7.76–7.81 (1H, m); 13C NMR (100 MHz) δ: −4.7,

Synthesis of (±)-terpendole E

−3.8, −2.11, −2.08, 12.8, 13.2, 18.1, 18.2, 20.5, 21.3, 24.7, 25.1, 25.3, 25.97 (3C), 26.04 (3C), 26.8, 27.5, 28.1 (3C), 29.2, 34.9, 37.2, 41.51, 41.53, 50.2, 56.6, 71.6, 74.8, 76.2, 78.9, 83.7, 114.2, 118.4, 122.1, 122.6, 126.3, 126.5, 140.2, 151.4, 151.8; HRMS (FAB) m/z: calcd. for C45H75O5NSi2Na, 788.5082; found, 788.5077 ([M + Na]+).

15

Acknowledgments We are grateful to Dr Osada, Dr Hirota and Dr Motoyama (RIKEN) for providing NMR spectra of terpendole E.

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References (±)-Terpendole E [(±)-1]. To a stirred solution of 14 (19.1 mg, 0.0249 mmol) in THF (1.2 mL) TBAF (1.0 M in THF, 0.4 mL, 0.4 mmol) was added at room temperature under a nitrogen atmosphere. After 17 h of stirring at 55 °C, additional TBAF (1.0 M in THF, 0.2 mL, 0.2 mmol) was added, and the mixture was stirred for 10 h before being quenched with saturated aq NH4Cl at 0 °C. The mixture was extracted with EtOAc and the extract was washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by preparative TLC (hexane/EtOAc = 4:1) to give an oil (9.4 mg), which was then diluted with Et2O, mixed with SiO2 (Kanto Kagaku silica gel 60 N, 125 mg) and concentrated to dryness. The solid residue was heated at 100 °C for 4 h in vacuo (ca. 12 kPa) before being washed several times with EtOAc. The combined washings were concentrated in vacuo and the residue was purified by preparative TLC (hexane/EtOAc = 3:1) to give 6.9 mg (63%) of (±)-1. IR (ATR) νmax: 3433 (m), 2935 (s), 1292 (w), 1087 (m), 1041 (w), 741 (w); 1H NMR [400 MHz, (CD3)2SO] δ: 0.79 (3H, s), 0.96 (3H, s), 1.03 (3H, s), 1.05 (3H, s), 1.08 (3H, s), 1.18–1.30 (1H, m), 1.46 (1H, br d, J = 14.0 Hz), 1.52–1.73 (6H, m), 1.78 (1H, br t, J = 14.0 Hz), 1.85–1.91 (1H, m), 2.14 (1H, br d, J = 11.8 Hz), 2.23 (1H, dd, J = 12.5, 11.2 Hz), 2.55 (1H, dd, J = 13.0, 6.2 Hz), 2.60–2.69 (1H, m), 3.43 (1H, dd, J = 12.2, 1.8 Hz), 3.48 (1H, dd, J = 10.7, 3.7 Hz), 3.60 (1H, br s), 4.02 (1H, s, OH), 4.61 (1H, d, J = 3.6 Hz, OH), 6.88 (1H, t, J = 7.6 Hz), 6.92 (1H, t, J = 7.6 Hz), 7.25 (2H, d, J = 7.6 Hz), 10.56 (1H, s, NH); 13 C NMR [100 MHz, (CD3)2SO] δ: 13.2, 14.6, 19.4, 21.0, 24.3, 24.8, 25.0, 26.8, 27.2, 29.3, 32.2, 37.0, 39.2, 40.1, 48.6, 52.7, 68.4, 70.3, 77.0, 79.0, 111.8, 115.7, 117.6, 118.4, 119.2, 124.4, 140.2, 151.4; 1H NMR (400 MHz, CD3OD) δ: 0.90 (3H, s), 1.05 (3H, s), 1.15 (3H, s), 1.168 (3H, s), 1.174 (3H, s), 1.31–1.43 (1H, m), 1.53 (1H, br d, J = 13.9 Hz), 1.64–1.78 (4H, m), 1.79–1.90 (3H, m), 1.97 (1H, td, J = 13.9, 2.7 Hz), 2.22 (1H, dd, J = 12.7, 2.0 Hz), 2.28 (1H, dd, J = 12.7, 11.3 Hz), 2.60 (1H, dd, J = 13.2, 6.3 Hz), 2.72–2.81 (1H, m), 3.53–3.59 (2H, m), 3.76 (1H, br s), 6.91 (1H, t, J = 7.3 Hz), 6.94 (1H, t, J = 7.3 Hz), 7.27 (2H, d, J = 7.3 Hz); 13C NMR (100 MHz, CD3OD) δ: 13.9, 14.9, 20.2, 22.7, 25.4, 25.6, 25.8, 26.4, 28.4, 30.9, 33.8, 39.0, 41.0, 41.9, 50.3, 54.6, 70.9, 72.8, 79.1, 80.5, 112.6, 117.8, 118.7, 119.7, 120.6, 126.3, 142.1, 152.4; HRMS (FAB) m/z: calcd. for C28H40O3 N, 438.3008; found, 438.3005 ([M + H]+).

Supplemental material The supplemental material for this paper [NMR spectra of (±)-1] is available at http://dx.doi.org/10. 1080/09168451.2014.955455.

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Synthesis of (±)-terpendole E.

The first synthesis of the racemate of terpendole E, a specific inhibitor of the mitotic kinesin Eg5, has been achieved from a known tricyclic dihydro...
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