A short enantioselective synthesis of the topoisomerase II inhibitor (+)-eleutherin

Article abstract of DOI:10.1055/s-2007-983841

A Hauser-Kraus annulation was used as a key step for the concise enantioselective synthesis of the topoisomerase II inhibitor (+)-eleutherin. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-983841

SHORT PAPER
2611
A Short Enantioselective Synthesis of the Topoisomerase II Inhibitor
(+)-Eleutherin
E
nantiosel
e
e
ctive Synt
n
hesis of (+)-
n
E
leutherin ifer S. Gibson, Olivier Andrey, Margaret A. Brimble*
Department of Chemistry, University of Auckland, 23 Symonds St., Auckland, New Zealand
E-mail: m.brimble@auckland.ac.nz
Received 18 May 2007
unsaturated ketone 4, followed by reductive methylation
of the resulting naphthoquinone (Scheme 1).
Abstract: A Hauser–Kraus annulation was used as a key step for
the concise enantioselective synthesis of the topoisomerase II inhib-
itor (+)-eleutherin.
Cyanophthalide 3 was readily prepared from 2-methoxy-
benzoic acid (5) by conversion to the corresponding N,N-
diethylbenzamide, followed by ortho-lithiation and
formylation, to afford ortho-formyl-N,N-diethylbenz-
amide 6.9 The latter benzamide 6 was then transformed
into cyanophthalide 3 following the method reported by
Yoshii et al.8 (Scheme 2).
Key Words: Hauser–Kraus annulation, (+)-eleutherin, pyrano-
naphthoquinone
Eleutherin 1, a member of the pyranonaphthoquinone
family of antibiotics, was first isolated in 1950 from the
bulb of Eleutherine americana.1 The pyranonaphtho-
quinone family of antibiotics display a wide range of bio-
logical activities and have been proposed to act as
bioactive alkylating agents.2 Additionally, (+)-eleutherin
(1) is a reversible inhibitor of topoisomerase II – a target
for many clinically useful anticancer agents.3
OMe
O
OMe
O
OMe
O
a, b
c, d
OH
NEt2
CHO
O
5
6
3
CN
Scheme 2 Reagents and conditions: (a) SOCl2 (2.2 equiv), toluene,
reflux, 2 h then Et2NH (3 equiv), Et2O, 1 h, 71%; (b) t-BuLi (1.05
equiv), TMEDA (1.05 equiv), THF, –78 °C, 90 min then DMF (20
equiv), 70%; (c) Me3SiCN (1.5 equiv), KCN (0.1 equiv), CH2Cl2,
0 °C, 90 min then r.t., 30 min; (d) AcOH, r.t., 18 h, 66% over 2 steps.
OMe OMe
O
OMe
O
Me
Me
OTBDPS
O
Me
Me
OMe
O
O
2
The electrophilic coupling partner for the Hauser–Kraus
annulation, a,b-unsaturated ketone 4, was synthesized
from commercially available, chiral non-racemic ester 7.
The hydroxyl group of 7 was protected as a tert-butyl-
diphenylsilyl (TBDPS) ether, with diisobutylaluminum
hydride (DIBAL-H) reduction of the ester and Horner–
Wadsworth–Emmons reaction of the resulting known al-
dehyde 810 with dimethyl 2-oxopropyl phosphonate, pro-
viding the desired enone 4 (Scheme 3).
(+)-eleutherin 1
OMe
O
Me
+
OTBDPS
Me
O
CN
3
4
Scheme 1
O
Several syntheses of racemic eleutherin and analogues
have been reported.4 The first enantioselective synthesis
of (+)-eleutherin 1 using (S)-mellein as a key intermediate
was recently reported by Donner et al.5 However, this syn-
thesis requires several steps to prepare (S)-mellein6 with a
further five steps required to access (+)-eleutherin 1.5
O
OH
O
OTBDPS
a, b
c
Me
OTBDPS
EtO
Me
H
Me
Me
7
8
4
Scheme 3 Reagents and conditions: (a) TBDPS-Cl (1.5 equiv), imi-
dazole (1.5 equiv), CH2Cl2, r.t., 18 h, 97%; (b) DIBAL-H (1.1 equiv),
toluene, –78 °C, 15 min, 79%; (c) dimethyl 2-oxopropyl phosphonate
(1.3 equiv), NaH (1.3 equiv), THF, –10 °C, 30 min then aldehyde 8 (1
equiv), 1 h, 75%.
We therefore envisaged a more efficient, alternate route to
(+)-eleutherin 1, proceeding via the intermediate naphtha-
lene 2, which we planned to access via a Hauser–Kraus
annulation7 of known cyanophthalide 38 with chiral a,b-
The key Hauser–Kraus annulation of cyanophthalide 3
with a,b-unsaturated ketone 4 was best carried out in di-
methyl sulfoxide, using potassium tert-butoxide as the
base. Reductive methylation of the crude naphthoquinone
using sodium dithionite under phase transfer conditions,
followed by addition of sodium hydroxide and dimethyl
SYNTHESIS 2007, No. 17, pp 2611–2613
x
x.
x
x
.
2
0
0
7
Advanced online publication: 08.08.2007
DOI: 10.1055/s-2007-983841; Art ID: P05907SS
© Georg Thieme Verlag Stuttgart · New York

2612
J. S. Gibson et al.
SHORT PAPER
O
OMe
OMe OMe
O
OMe OMe Me
O
a, b
c, d
e
1
3
Me
OTBDPS
Me
OTBDPS
O
(+)-eleutherin 1
O
+
Me
Me
4
3
CN
9
2
Me
OMe
OMe
Scheme 4 Reagents and conditions: (a) t-BuOK (1.1 equiv), DMSO, 15 min; (b) TBABr (0.1 equiv), Na2S2O4 (6 equiv), H2O, THF, 30 min
then NaOH (20 equiv), Me2SO4 (20 equiv), 2 h, 67% (2 steps); (c) TBAF (10 equiv), THF, r.t., 4 d; (d) TFA (3 equiv), HSiEt3 (3 equiv), CH2Cl2,
–78 °C → r.t., 56% (2 steps); (e) (NH4)2Ce(NO3)6 (3 equiv), MeCN, H2O, 80%.
1H NMR (400 MHz, CDCl3): d = 1.09 [s, 9 H, C(CH3)3], 1.14 (d,
sulfate, gave the desired naphthalene 2 in good yield
J = 6.0 Hz, 3 H, CHCH3), 2.21 (s, 3 H, C=OCH3), 2.37 (m, 2 H,
(Scheme 4). Silyl deprotection of naphthalene 2 using tet-
CH2), 4.04 (sext, J = 6.0 Hz, 1 H, CH), 6.01 (dt, J = 16.0, 1.3 Hz,
ra-n-butylammonium fluoride and subsequent treatment
1 H, =CH), 6.79 (dt, J = 16.0, 7.3 Hz, 1 H, =CH), 7.39–7.47 (m,
of the resulting hemiacetal with trifluoroacetic acid and
6 H, H-Ar), 7.69–7.71 (m, 4 H, H-Ar).
13C NMR (75 MHz, CDCl3): d = 19.2 (C-Si), 23.4 (CHCH3), 26.6
(C=OCH3), 26.9 [C(CH3)3], 42.3 (CH2), 68.5 (CH), 127.5 (CH-Ar),
triethylsilane, afforded benzo[g]isochromene 9 as a single
diastereoisomer, arising from pseudo-axial delivery of the
hydride as reported by Kraus et al.4g (Scheme 4).
127.6 (CH-Ar), 129.6 (CH-Ar), 129.7 (CH-Ar), 133.4 (=CH), 133.9
(C-Ar), 134.1 (C-Ar), 138.8 (2 × CH-Ar), 144.8 (=CH), 198.5
Finally, oxidation of (1R,3S)-dimethyl benzo[g]iso-
chromene 9 with aqueous cerium(IV) ammonium nitrate,
gave (+)-eleutherin 1 {[a]D20 +335 (c 0.35, CH2Cl2); nat-
(C=O).
MS (CI): m/z (%) = 384 (4) [M + NH4]+, 367 (6) [M + H]+, 309 (72),
289 (41), 283 (52), 265 (100).
HRMS-CI: m/z [M + H]+ calcd for C23H31O2Si: 367.2093; found:
367.2096.
20
ural (+)-eleutherin1 [a]D +346 (c 1.01, CHCl3)}
(Scheme 4).
In conclusion, we have developed a concise, enantioselec-
tive synthesis of (+)-eleutherin 1 via a Hauser–Kraus an-
nulation of cyanophthalide 3 with a,b-unsaturated ketone
4.
(S)-1-{3-[2-(tert-Butyldiphenylsilyloxy)propyl]-1,4,8-tri-
methoxynaphthalen-2-yl}ethanone (2)
To a solution of t-BuOK (83 mg, 0.70 mmol) in DMSO (1 mL) was
added a solution of cyanophthalide 3 (120 mg, 0.63 mmol) in
DMSO (1 mL) followed by a solution of a,b-unsaturated ketone 4
(255 mg, 0.70 mmol) in DMSO (1.5 mL). The reaction mixture was
stirred for 15 min then diluted with Et2O (30 mL) and quenched by
addition of sat. NH4Cl (5 mL). The aqueous layer was extracted
with Et2O (3 × 10 mL). The combined organic extracts were dried
over anhydrous Na2SO4, filtered, concentrated in vacuo and the re-
sulting residue was taken up in THF (5 mL) and H2O (2 mL).
TBABr (0.1 equiv, 20 mg) was added, followed by a solution of so-
dium dithionate (662 mg, 6 equiv) in H2O (2 mL). The reaction mix-
ture was stirred for 30 min then a solution of NaOH (507 mg, 20
equiv) in H2O (3 mL) was added followed by dimethyl sulfate (1.21
mL, 20 equiv). The reaction mixture was stirred for 2 h then H2O
(20 mL) was added and the aqueous layer was extracted with EtOAc
(3 × 20 mL). The combined organic extracts were dried over anhy-
drous Na2SO4, filtered, concentrated in vacuo and the resulting res-
idue was purified by flash chromatography (hexane–EtOAc, 9:1) to
afford naphthalene 2.
All reactions were conducted in flame-dried or oven-dried glass-
ware under a dry nitrogen atmosphere unless otherwise noted. All
solvents were purified according to standard procedures where nec-
essary. Chemical reagents were used as purchased. Low-resolution
mass spectra were recorded on a VG-70SE mass spectrometer at a
nominal accelerating voltage of 70eV. Chemical ionisation (CI)
mass spectra were obtained with ammonia as the reagent gas. Fast
atom bombardment (FAB) mass spectra were obtained with 3-ni-
trobenzyl alcohol as the matrix. IR specta were obtained using a
Perkin–Elmer spectrum 1000 Fourier Transform Infrared spectro-
meter as a thin film between NaCl plates. TLC was carried out on
precoated silica plates (Merck Kieselgel 60F-254) and compounds
were visualised by UV fluorescence or by staining with alkaline po-
tassium permanganate solution or vanillin in methanolic sulfuric
acid and heating. NMR spectra were obtained using a Bruker DRX-
400 operating at either 400 MHz or 100 MHz or a Bruker Avance
300 spectrometer operating at either 300 MHz or 75 MHz. All
chemical shifts are given in parts per million (ppm) downfield from
TMS as internal standard (1H) or relative to CDCl3 (13C).
Yield: 241 mg (67%); oil; [a]D20 +12.1 (c 0.42, CHCl3).
IR (oil): 3069, 2931, 2856, 1701, 1616, 1588, 1571, 1459, 1421,
1369, 1335, 1266, 1109 cm–1.
(S,E)-6-(tert-Butyldiphenylsilyloxy)hept-3-en-2-one (4)
1H NMR (400 MHz, CDCl3): d = 1.01 [s, 9 H, C(CH3)3], 1.02 (d,
J = 5.8 Hz, 3 H, CHCH3), 2.49 (s, 3 H, C=OCH3), 2.84 (dd, J = 7.6,
13.0 Hz, 1 H, CHH), 3.56 (dd, J = 6.7, 13.0 Hz, 1 H, CHH), 3.73 (s,
3 H, OCH3), 3.77 (s, 3 H, OCH3), 4.05 (s, 3 H, OCH3), 4.33 (m, 1 H,
CH), 6.92 (d, J = 7.6 Hz, 1 H, H-Ar), 7.29–7.47 (m, 7 H, H-Ar),
7.58 (dd, J = 7.9, 1.3 Hz, 2 H, H-Ar), 7.64 (dd, J = 8.5, 0.1 Hz, 1 H,
H-Ar), 7.71 (dd, J = 6.0, 1.5 Hz, 2 H, H-Ar).
13C NMR (100 MHz, CDCl3): d = 19.1 (C-Si), 23.4 (CHCH3), 26.9
[C(CH3)3], 33.1 (C=OCH3), 37.2 (CH2), 56.0 (OCH3), 61.3 (OCH3),
63.7 (OCH3), 69.4 (CH), 105.9 (CH-Ar), 115.1 (CH-Ar), 119.4 (C-
Ar), 124.8 (C-Ar), 127.0 (CH-Ar),127.4 (2 × CH-Ar), 129.4
(2 × CH-Ar),131.4 (C-Ar), 134.3 (C-Ar), 134.7 (C-Ar), 135.2 (C-
Ar), 135.8 (CH-Ar), 135.9 (CH-Ar), 148.9 (C-Ar), 151.3 (C-Ar),
156.3 (C-Ar), 205.8 (C=O).
Dimethyl 2-oxopropylphosphonate (0.33 mL, 2.39 mmol) was add-
ed dropwise to a cooled (–10 °C) suspension of NaH (95 mg, 60%
w/w) in THF (10 mL). After 30 min, a solution of aldehyde 5 (600
mg, 1.84 mmol) in THF (10 mL) was added. The reaction mixture
was allowed to come to r.t., stirred for a further 1 h then quenched
by addition of sat. aq NH4Cl (10 mL). The aqueous layer was ex-
tracted with CH2Cl2 (3 × 20 mL) and the combined organic extracts
were dried over anhydrous Na2SO4, filtered and concentrated in
vacuo. The resulting residue was purified by flash chromatography
(hexane–EtOAc, 95:5) to afford a,b-unsaturated ketone 4.
Yield: 505 mg, (75%); oil; [a]D20 –40.3 (c 3.0, CH2Cl2).
IR (oil): 3071, 2961, 2930, 2857, 2894, 1698, 1675, 1630, 1427,
1389, 1361, 1253, 1111 cm–1.
Synthesis 2007, No. 17, 2611–2613 © Thieme Stuttgart · New York

SHORT PAPER
Enantioselective Synthesis of (+)-Eleutherin
2613
MS (FAB): m/z (%) = 557 (12) [M + H]+, 499 (50), 310 (87), 135
(100).
HRMS-FAB: m/z [M + H]+ calcd for C34H41O5Si: 557.2723; found:
557.2721.
1H NMR (300 MHz, CDCl3): d = 1.36 (d, J = 6.2 Hz, 3 H, CHCH3),
1.53 (d, J = 6.6 Hz, 3 H, CHCH3), 2.21 (ddd, J = 18.3, 10.2, 3.8 Hz,
1 H, CHaxH), 2.75 (dt, J = 18.3, 2.6 Hz, 1 H, CHHeq), 3.56 (ddq,
J = 10.2, 6.2, 2.5 Hz, 1 H, CH2CHCH3), 3.99 (s, 3 H, OCH3), 4.85
(m, 1 H, CHCH3), 7.27 (dd, J = 8.3, 1.0 Hz, 1 H, H-Ar), 7.63 (dd,
J = 8.3, 7.0 Hz, 1 H, H-Ar), 7.73 (dd, J = 7.0, 1.0 Hz, 1 H, H-Ar).
13C NMR (75 MHz, CDCl3): d = 20.8 (CHCH3), 21.3 (CHCH3),
29.9 (CH2), 56.5 (OCH3), 68.7 (CH), 70.3 (CH), 117.7 (CH-Ar),
119.0 (CH-Ar), 120.3 (C-Ar), 133.9 (C-Ar), 134.6 (CH-Ar), 139.9
(C-Ar), 148.7 (C-Ar), 159.4 (C-Ar), 183.8 (C=O), 184.1 (C=O).
(1R,3S)-5,9,10-Trimethoxy-1,3-dimethyl-3,4-dihydro-1H-ben-
zo[g]isochromene (9)
Naphthalene 2 (90 mg, 0.16 mmol) was taken up in anhydrous THF
(5 mL) and a solution of TBAF (10 equiv, 1.16 mmol, 422 mg) in
THF (4 mL) was added. The reaction mixture stirred under N2 at r.t.
for 4 d, then the reaction mixture was concentrated in vacuo and the
resulting residue flushed through a pad of silica (hexane–EtOAc,
1:1). The filtrate was concentrated in vacuo and the resulting oil was
taken up in anhydrous CH2Cl2 (5 mL) and cooled to –78 °C. TFA (3
equiv, 0.48 mmol, 0.04 mL) was added and the reaction mixture
was stirred for 15 min before addition of triethylsilane (3 equiv,
0.48 mmol, 0.08 mL). The reaction mixture was stirred at –78 °C
for 30 min then allowed to reach r.t. and stirred overnight. H2O (10
mL) was added and the aqueous layer was extracted with EtOAc
(3 × 20 mL). The combined organic extracts were dried over anhy-
drous Na2SO4, filtered, concentrated under vacuo and the resulting
residue was purified by flash chromatography (hexane–EtOAc, 7:3)
to afford isochromene 9.
MS (EI): m/z (%) = 272 (100) [M]+, 257 (78) [M – Me]+, 243 (52).
HRMS-EI: m/z [M]+ calcd for C16H16O4: 272.1048; found:
272.1050.
Acknowledgments
This work was supported by the Royal Society of New Zealand
Marsden fund. The authors would also like to thank Nicolas Scher-
rier and Kristof Seubert for preliminary studies.
References
Yield: 27 mg (56%); oil; [a]D20 +97.5 (c 1.1, CH2Cl2).
(1) Schmid, H.; Ebnöther, A.; Meijer, Th. M. Helv. Chim. Acta
1950, 224, 1751.
(2) Brimble, M. A.; Duncalf, L. J.; Narin, M. R. Nat. Prod. Rep.
1999, 16, 267; and references therein.
(3) Krishnan, P.; Bastow, K. F. Biochem. Pharm. 2000, 66,
1367.
IR (oil): 3444, 2970, 2934, 2840, 1781, 1738, 1618, 1595, 1571,
1447, 1372, 1335 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.43 (d, J = 6.2 Hz, 3 H, CHCH3),
1.70 (d, J = 6.3 Hz, 3 H, CHCH3), 2.62 (dd, J = 16.0, 10.9 Hz, 1 H,
CHH), 3.09 (ddd, J = 16.0, 1.9, 0.7 Hz, 1 H, CHH), 3.69 (m, 1 H,
CHCH3), 3.80 (s, 3 H, OCH3), 3.91 (s, 3 H, OCH3), 4.03 (s, 3 H,
OCH3), 5.28 (q, 3J = 6.3 Hz, 1 H, CHCH3), 6.86 (d, J = 8.0 Hz, 1 H,
H-Ar), 7.43 (t, J = 8.0 Hz, 1 H, H-Ar), 7.74 (dd, J = 8.0, 0.7 Hz,
1 H, H-Ar).
13C NMR (75 MHz, CDCl3): d = 21.6 (CHCH3), 23.2 (CHCH3),
31.7 (CH2), 56.0 (OCH3), 61.3 (OCH3), 61.7 (OCH3), 69.9 (CH),
71.4 (CH), 105.6 (CH-Ar), 114.5 (CH-Ar), 119.3 (C-Ar), 125.7 (C-
Ar), 126.1 (CH-Ar), 129.7 (C-Ar), 129.8 (C-Ar), 148.6 (C-Ar),
148.8 (C-Ar), 155.9 (C-Ar).
(4) (a) Schmid, H.; Eisenhuth, W. Helv. Chim. Acta 1958, 213,
2021. (b) Webb, A. D.; Harris, T. M. Tetrahedron Lett.
1977, 24, 2069. (c) Naruta, Y.; Uno, H.; Maruyama, K. J.
Chem. Soc., Chem. Commun. 1981, 1277. (d) Kometani, T.;
Yoshii, E. J. Chem. Soc., Perkin Trans. 1 1981, 1191.
(e) Kometani, T.; Yoshii, E. J. Chem. Soc., Perkin Trans. 1
1981, 1197. (f) Giles, R. G. F.; Green, I. R.; Hugo, V. I.;
Mitchell, P. R. K. J. Chem. Soc., Chem. Commun. 1983, 51.
(g) Giles, R. G. F.; Green, I. R.; Hugo, V. I.; Yorke, S. C.;
Mitchell, P. R. K. J. Chem. Soc., Perkin Trans. 1 1984,
2383. (h) Kraus, G. A.; Molina, M. T.; Walling, J. A. J.
Chem. Soc., Chem. Commun. 1986, 1568. (i) Uno, H. J.
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Uneda, T.; Tanmatsu, M.; Morikawa, O.; Konishi, H.
Tetrahedron Lett. 1998, 39, 7725.
MS (EI): m/z (%) = 302 (91) [M]+, 287 (100) [M – Me]+, 272 (24)
[M – 2 × Me]+), 257 (27) [M – 3 × Me]+.
HRMS-EI: m/z [M]+ calcd for C18H22O4: 302.1518; found:
302.1517.
(5) Teweirik, L. M.; Dimitriadis, C.; Donner, C. D.; Gill, M.;
Willems, B. Org. Biomol. Chem. 2006, 4, 3311.
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(+)-Eleutherin (1)
(1R,3S)-5,9,10-Trimethoxy-1,3-dimethyl-3,4-dihydro-1H-ben-
zo[g]isochromene (9; 90 mg, 0.30 mmol) was taken up in MeCN (7
mL) and a solution of cerium(IV) ammonium nitrate (490 mg, 0.90
mmol) in H2O (4 mL) was added. The reaction mixture was stirred
at r.t. for 1 h then H2O (10 mL) was added and the aqueous layer was
extracted with EtOAc (3 × 20 mL). The combined organic extracts
were dried over anhydrous Na2SO4, filtered, concentrated in vacuo
and the resulting residue was purified by flash chromatography
(hexane–EtOAc, 3:2) and then recrystallized from Et2O–EtOAc to
afford (+)-eleutherin 1.
(10) Garbaccio, R. M.; Stachel, S. J.; Baeschlin, D. K.;
Danishefsky, S. J. J. Am. Chem. Soc. 2001, 123, 10903.
Yield: 65 mg (80%); yellow needles; [a]D20 +335 (c 0.35, CH2Cl2).
Synthesis 2007, No. 17, 2611–2613 © Thieme Stuttgart · New York