Synthetic studies on neomarinone: practical and efficient stereoselective synthesis of the side chain

Article abstract of DOI:10.1016/j.tetlet.2007.07.064

A practical and efficient stereoselective synthesis of the side chain of neomarinone is reported. The synthesis was achieved in six steps (41% overall yield) from 2-methyl-2-cyclohexenone. The key step is a novel stereoselective 1,4-conjugate addition/eno

Full text of DOI:10.1016/j.tetlet.2007.07.064

Tetrahedron Letters 48 (2007) 6493–6495
Synthetic studies on neomarinone: practical and
efficient stereoselective synthesis of the side chain
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*
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Rosa M. Suarez, M. Montserrat Martınez, Luis A. Sarandeses and Jose Perez Sestelo
Departamento de Quı´mica Fundamental, Universidade da Corun˜a, E-15071 A Corun˜a, Spain
Received 29 May 2007; revised 5 July 2007; accepted 10 July 2007
Available online 14 July 2007
Abstract—A practical and efficient stereoselective synthesis of the side chain of neomarinone is reported. The synthesis was achieved
in six steps (41% overall yield) from 2-methyl-2-cyclohexenone. The key step is a novel stereoselective 1,4-conjugate addition/enolate
alkylation by an epoxide-opening reaction.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Neomarinone (1, Fig. 1) is a marine natural product iso-
lated from the fermentation broth of actinomycetes
strain #CNH-099 by Fenical et al. in 2000.1 It belongs
to a small group of prenylated naphthoquinones, includ-
ing furaquinocin C (2)2 and marinone (3),3 with broad
antibiotic and anticancer activities.4 It displays moder-
ate in vitro cytotoxicity (IC50 = 8 mg/mL) against
HCT-116 colon carcinoma, a mean IC50 of 10 mM in
assays with the NCI-60 panel of cancer cell lines, and
moderate antibiotic activity. Structurally, neomarinone
is a meroterpenoid (hybrid compounds of mixed poly-
ketide-terpenoid origin)5 that has a naphthoquinone
unit linked to a ramified sesquiterpenoid side chain with
four stereogenic centers, two of them being quaternary.
The structural elucidation of neomarinone has proved
difficult due to the presence of five methyl groups in a
small range of NMR chemical shifts. Indeed, in the
initially proposed structure,1 the stereochemistry of the
methyl groups of the side chain was not determined.
In 2003, biosynthetic studies on neomarinone by Moore
et al. led to its structural revision, with correction of the
structure of the side chain (Fig. 1).6 The stereochemistry
of the methyl groups in the cyclohexenyl unit of neo-
marinone was assigned cis, based on chemical correla-
tion with the natural products ageline A7 and
subersine,8 which have the same cyclohexenyl unit with
cis and trans stereochemistry, respectively. The relative
stereochemistry of the methyl groups of the furan ring
was assigned by chemical comparison with (À)-furaqui-
nocin C and (+)-3-epifuraquinocin C.9 However, the
configuration of the methyl groups of the cyclohexenyl
ring relative to the methyl groups of the furyl residue
could not be unequivocally determined.
The retrosynthetic analysis for neomarinone is depicted
in Scheme 1. In this approach, the naphthofuranic skel-
eton would be obtained by a regioselective Diels–Alder
reaction between a bromoquinone (4, Scheme 1) and a
1,3-bis(trimethylsilyloxy)-1,3-diene (5) containing the
side chain; the quaternary stereocenter at the furyl ring
would then be formed by diastereoselective conjugate
addition of an organometallic reagent derived from
Figure 1. Neomarinone, furaquinocin C and marinone.
Keywords: Natural product synthesis; 1,4-Addition reactions; Enolate
alkylation reactions; Stereoselective synthesis.
*
Corresponding authors. Fax: +34 981 167 065 (J.S.); e-mail
addresses: qfsarand@udc.es; sestelo@udc.es
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.064

6494
R. M. Sua´rez et al. / Tetrahedron Letters 48 (2007) 6493–6495
During our investigation, we found that the reaction of
2-methyl-2-cyclohexenone (9)12 with lithium dimethyl
cuprate, followed by addition of ethylene oxide at low
temperature, afforded hemiketal 10 in 62% yield as a sin-
gle diastereoisomer as shown by 1H NMR (Scheme 3).13
The formation of 10 can be reasonably explained by the
cyclization of the intermediate c-hydroxyketone. The
relative stereochemistry of the methyl groups in 10 was
determined to be cis by NOESY experiments, demon-
strating that the enolate alkylation takes place anti to
the methyl group at b-position. This reaction is, to the
best of our knowledge, the first example of a tandem
conjugate addition–enolate alkylation reaction using
an epoxide as the electrophile.
In the next step, hemiketal 10, in equilibrium with the
corresponding c-hydroxyketone compound, was trans-
formed into silylether 11 by treatment with TBSCl
(1.5 equiv) and Et3N (1.2 equiv) in the presence of cata-
lytic amounts of DMAP (15%) in CH2Cl2 (75% yield).
For transformation of cyclohexanone 11 into 1-methyl-
cyclohexene 13, we considered the application of our
recently developed palladium-catalyzed cross-coupling
reaction of indium organometallics with alkenyl electro-
philes.14 Therefore, ketone 11 was transformed into a
vinyl triflate by treatment with KHMDS followed by
addition of PhNTf2, affording 12 in high yield (96%).15
The palladium-catalyzed cross-coupling reaction of 12
with trimethylindium (0.5 equiv) in the presence of cata-
lytic amounts of Pd(PPh3)2Cl2 (5 mol %) afforded the
coupling product 13 in quantitative yield. Finally, cleav-
age of silylether 13 with tetrabutylammonium fluoride
(3 equiv) at room temperature for 2 h gave the corre-
sponding alcohol that, without further purification,
was converted to the desired iodide 716 by treatment
with PPh3 and I2 in 98% yield.
Scheme 1. Retrosynthetic analysis for neomarinone.
iodide 7 to the a,b-unsaturated lactone 8. In this Letter,
we report a practical and efficient stereoselective synthe-
sis of iodide 7.
For stereoselective synthesis of iodide 7,10 we devised an
expedient synthetic procedure from 2-methyl-2-cyclo-
hexenone (9), using as key step for generating the chiral
centers, a stereoselective tandem conjugate addition/
enolate alkylation reaction with a C2 electrophile
(Scheme 2). The 1,4-addition of organometallic
reagents to a,b-unsaturated carbonyl systems followed
by enolate trapping with electrophiles constitutes an ele-
gant methodology for the preparation of functionalized
cycloketones and derivatives.11 Although in these tan-
dem reactions alkyl halides and aldehydes are the most
widely used electrophiles, we decided to explore the util-
ity of an epoxide such as ethylene oxide.
In summary, iodide 7, containing the cyclohexenyl unit
of the side chain of neomarinone, has been synthesized
in six steps from 2-methyl-2-cyclohexenone (41% overall
yield), a synthetic procedure that allows the preparation
of iodide 7 in a multigram scale. The key step of the syn-
thesis is a novel stereoselective tandem 1,4-conjugate
addition/enolate alkylation by an epoxide-opening reac-
Scheme 2. Retrosynthetic analysis for iodide 7.
Scheme 3. Synthesis of iodide 7.

R. M. Sua´rez et al. / Tetrahedron Letters 48 (2007) 6493–6495
6495
Alexakis, A. J. Org. Chem. 2006, 71, 5737–5742; (c)
Kitamura, M.; Miki, T.; Nakano, K.; Noyori, R. Tetra-
hedron Lett. 1996, 37, 5141–5144; (d) Boeckman, R. K., Jr.
J. Org. Chem. 1973, 38, 4450–4452.
tion. The synthesis of racemic iodide 7 should allow the
total synthesis of neomarinone and its diastereoisomers,
and should provide useful data for establishing the rela-
tive stereochemistry of the cis methyl groups of the
cyclohexane unit with respect to the cis methyl groups
of the furan ring, and the absolute configuration of
neomarinone.
12. Warnhoff, E. W.; Martin, D. G.; Johnson, W. S. Org.
Synth. Coll. 1963, 4, 162–166.
13. Experimental procedure: To a cooled solution of methyl
cuprate in Et2O (10 mL, 1 M) at 0 ꢁC, a solution of 2-
methyl-2-cyclohexenone (9, 1 g, 9.08 mmol) in Et2O
(9 mL) was added via cannula. After 1 h stirring, the
reaction mixture was cooled at À60 ꢁC and a freshly
prepared cooled solution (0 ꢁC) of ethylene oxide in Et2O
was added via cannula. The reaction mixture was slowly
warmed to room temperature in a 12 h period, quenched
by addition of NH4OH (30%):NH4Cl (satd. sol.) (2:1,
20 mL) and extracted with Et2O (3 · 25 mL). The com-
bined organic layer was washed with saturated aqueous
NH4Cl solution (50 mL) and brine (50 mL), dried
(MgSO4), filtered, and the solvent evaporated under
reduced pressure. The crude was purified by column
chromatography (15% EtOAc/hexanes) giving 960 mg of
hemiketal 10 as a white solid [62%, Rf = 0.25 (30%
EtOAc/hexanes)]. Mp 81–82 ꢁC. 1H NMR (300 MHz,
CDCl3) d 0.87 (d, J = 6.6 Hz, 3H), 0.97 (s, 3H), 1.07–1.23
(m, 1H), 1.38–1.66 (m, 4H), 1.84–1.89 (m, 1H), 1.90 (s,
3H), 1.93–2.00 (m, 1H), 3.89 (dd, J = 16.7, 8.5 Hz, 1H),
3.99 (dt, J = 9.3 3.0 Hz, 1H); 13C NMR (75 MHz, CDCl3)
d 12.8 (CH3), 16.7 (CH3), 22.6 (CH2), 29.8 (CH2), 33.0
(CH2), 34.6 (CH2), 35.5 (CH), 47.5 (C), 64.1 (CH2), 105.8
(C); IR (NaCl) 3401, 2959–2934, 915 cmÀ1; MS (EI,
70 eV) m/z 171 (M++H, 3), 170 (M+, 8), 153 (M+ÀOH,
56), 126 (M+ÀC2H4O, 33), 83 (100); HRMS (FAB) Calcd
for C10H19O2 171.1385 (M++H); found, 171.1379.
Acknowledgments
This research was supported by the Xunta de Galicia
(Spain, PGIDIT05BTF10301PR) and Ministerio de
´
Educacion y Ciencia (Spain, CTQ2006-06166). R.M.S.
´
thanks the Ministerio de Educacion y Ciencia for an
FPU fellowship and M.M.M. thanks Xunta de Galicia
for a research contract sponsored by the Isidro Parga
Pondal program.
References and notes
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16. Spectroscopic data for iodide 7: 1H NMR (300 MHz,
CDCl3) d 0.83 (s, 3 H), 0.89 (d, J = 6.9 Hz, 3H), 1.37–1.51
(m, 2H), 1.63 (br s, 3H), 1.91–1.96 (m, 2H), 2.09 (m, 2H),
2.88 (dt, J = 9.7, 7.3 Hz, 1H), 3.13 (dt, J = 9.3, 7.3 Hz,
1H), 5.48 (br s, 1H); 13C NMR (75 MHz, CDCl3) d 1.3
(CH2), 15.9 (CH3), 19.2 (CH), 20.5 (CH3), 25.4 (CH2),
26.7 (CH2), 33.1 (CH3), 41.9 (CH2), 43.5 (C), 125.2 (CH),
138.1 (C); IR (NaCl) 3019, 2963–2835, 1464, 1160,
´
9. Smith, A. B.; Perez Sestelo, J.; Dormer, P. G. J. Am.
Chem. Soc. 1995, 117, 10755–10756.
10. Iodide 7 had been prepared previously, although by a long
and impractical synthetic sequence: Asao, K.; Iio, H.;
Tokoroyama, T. Tetrahedron Lett. 1989, 30, 6401–6404.
11. For an exhaustive review of this type of reaction, see: (a)
Chapdelaine, M. J.; Hulce, M. Org. React. 1990, 38, 225–
653; For key references, see: (b) Rathgeb, X.; March, S.;
562 cmÀ1
;
MS (EI, 70 eV) m/z 278 (M+, 2), 123
(M+ÀC2H4I, 100); HRMS (EI) Calcd for C11H19I,
278.0532 (M+); found, 278.0521.