Total synthesis of (+)-neomarinone

Article abstract of DOI:10.1002/chem.200802021

The first total synthesis of (+)-neomarinone has been achieved by following a concise and convergent route using methyl (R)-lactate and (R)-3-methylcyclohexanone as chiral building blocks. Key steps of the synthesis are the stereocontrolled formation of the two quaternary stereocenters by diastereoselective 1,4-conjugate addition and enolate alkylation reactions, and the construction of the furanonaphthoquinone skeleton by regioselective Diels-Alder reaction between a 1,3-bis(trimethylsilyloxy)-1,3-diene and a bromoquinone. The synthesis proves the relative and absolute stereochemistry of natural neomarinone.

Full text of DOI:10.1002/chem.200802021

DOI: 10.1002/chem.200802021
Total Synthesis of (+)-Neomarinone
Miguel PeÇa-Lꢀpez, M. Montserrat Martꢁnez, Luis A. Sarandeses,* and
Josꢂ Pꢂrez Sestelo*[a]
Abstract: The first total synthesis of (+)-neomarinone has been achieved by fol-
lowing a concise and convergent route using methyl (R)-lactate and (R)-3-methyl-
cyclohexanone as chiral building blocks. Key steps of the synthesis are the stereo-
controlled formation of the two quaternary stereocenters by diastereoselective 1,4-
conjugate addition and enolate alkylation reactions, and the construction of the
furanonaphthoquinone skeleton by regioselective Diels–Alder reaction between a
1,3-bis(trimethylsilyloxy)-1,3-diene and a bromoquinone. The synthesis proves the
relative and absolute stereochemistry of natural neomarinone.
Keywords: alkylations · asymmetric
synthesis
·
cuprate additions
·
Diels–Alder reaction
products
·
natural
Introduction
Neomarinone (1, Figure 1), a marine natural product isolat-
ed from the fermentation broth of actinomycetes (strain
#CNH-099), displays in vitro cytotoxicity (IC50 =8 mgmLÀ1)
against HCT-116 colon carcinoma, an interesting value of
IC50 =10 mm in the NCI-60 panel cell lines of cancer, and
moderate antibiotic activity.[1] Neomarinone is a hybrid com-
pound of mixed polyketide–terpenoid origin (meroterpe-
noid)[2] that belongs to a small group of prenylated naphtho-
quinones, including the antibiotics furaquinocins[3] and mari-
none,[4] with a wide range of biological effects.[5] In particu-
lar, neomarinone features a dihydroxylated furanonaphtho-
Figure 1. Neomarinone, furaquinocins, and marinone.
quinone core linked to a ramified sesquiterpenoid side chain
with four stereogenic centers, two of which are quaternary.
The structural determination of neomarinone was made
difficult by the presence of five methyl groups with a
narrow range of NMR chemical shifts. In fact, the initially
proposed structure was revised in 2003 after an elegant
study of its biosynthesis, followed by extensive 2D NMR
spectroscopic analysis.[6] In this revision, the stereochemistry
of the methyl groups in the cyclohexene unit was assigned
as cis, based on chemical correlation with the natural prod-
ucts ageline A[7] and subersine,[8] while the relative stereo-
chemistry of the methyl groups at the furan ring was as-
signed as cis by chemical comparison with (À)-furaquinocin
C and (+)-3-epifuraquinocin C (Figure 1, R1 =R2 =R3 =
H).[9] However, the configuration of the cyclohexene ring
relative to the furan residue could not be unequivocally de-
termined. Herein, we report the first total synthesis of ACHTUNGTRENNUNG(+)-
neomarinone, which proves the relative and absolute stereo-
chemistry of the natural product.
[a] M. PeÇa-Lꢀpez, Dr. M. M. Martꢁnez, Prof. Dr. L. A. Sarandeses,
Prof. Dr. J. Pꢂrez Sestelo
Departamento de Quꢁmica Fundamental
Universidade da CoruÇa
Campus Zapateira, s/n; 15071A CoruÇa (Spain)
Fax : (+34)34-981-167-065
E-mail: qfsarandeses@udc.es
Results and Discussion
sestelo@udc.es
The synthesis of neomarinone was envisaged by construction
of the furanonaphthoquinone core by a regioselective Diels–
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200802021.
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FULL PAPER
Alder reaction between bromoquinone 2[10] and the inner-
outer ring 1,3-bis(trimethylsilyloxy)-1,3-diene 3, which con-
tains the furan ring functionalized with the side chain of
neoACHTUNGTRENNUNGmarinone (Scheme 1). Silyloxydienes are highly reactive
dienes in Diels–Alder reactions and we have shown that
inner-outer ring 1,3-silyloxydienes are particularly useful for
the synthesis of a wide variety of polycyclic structures.[11]
The synthesis of the 1,3-silyloxydiene was proposed from
the 1,3-dicarbonyl compound 4, prepared by a diastereose-
lective conjugate addition of an organometallic reagent de-
rived from iodide 5 to the enantiomerically pure a,b-unsatu-
rated lactone 6. For the enantioselective synthesis of iodide
5, we devised a sequence starting from commercially avail-
able (R)-3-methylcyclohexanone with formation of the qua-
ternary stereocenter through stereoselective sequential eno-
late alkylation reactions.
Scheme 2. Enantioselective synthesis of lactone 6.
stereoisomers. Further reaction of 13 with LDA and ethyl
bromoacetate at À788C afforded stereoselectively the a,a-
disubstituted ketone 14 in 60% yield as a single diastereo-
1
isomer, as determined by H NMR spectroscopy. The acid–
base hydrolysis of 14 produced, after purification by recrys-
tallization, the hemiketal 15 in 88% yield. The relative ste-
reochemistry of the methyl groups in 15 was first assigned
cis by NOESY experiments and confirmed by X-ray analy-
sis.[18] As expected, the enolate alkylation reaction takes
place trans to the C-3 methyl group. Interestingly, the enan-
tiopure hemiketal 15 was converted to the vinyltriflate 16 by
reaction with LDA (2.2 equiv) and PhNTf2 (1.1 equiv),[19]
and the carboxylic acid group transformed into the methyl
ester 17 by treatment with MeI/K2CO3 (83% overall yield).
Subsequent palladium-catalyzed reaction of Me3In
(0.5 equiv) with vinyltriflate 17 afforded the cross-coupling
product 18 in 93% yield.[20] The reduction of the ester 18
with LiAlH4 (87% yield) and reaction of the resulting alco-
hol 19 with PPh3 and I2 gave the desired iodide 5 in 97%
yield. Following this synthetic sequence, the enantiomeri-
cally pure iodide 5 was prepared from (R)-3-methylcyclo-
hexanone in 25% overall yield (nine steps).[21]
Scheme 1. Retrosynthetic analysis for neomarinone.
For the synthesis of enantiopure a,b-unsaturated lactone
6, we planned a short synthetic sequence from commercial
methyl (R)-lactate. Protection of the hydroxyl group as the
TBS ether followed by ester reduction with DIBAL gave
the aldehyde 7 in 79% overall yield (Scheme 2).[12] TiCl4-
catalyzed Knoevenagel condensation[13] of 7 with ethyl ace-
toacetate gave the a,b-unsaturated 1,3-carbonyl compound 8
in 72% yield as a mixture of stereoisomers (Z/E 75:25).[14]
Conjugate addition of lithium dimethylcuprate to (Z,E)-8
afforded 9 in 97% yield, and cleavage of the TBS ether with
TBAF at reflux produced the lactone 10 in excellent yield as
a mixture of stereoisomers at C-2 and C-3. The reaction of
10 with NaH and phenylselenyl chloride at 08C gave the sel-
enide 11 as a diastereomeric mixture in 94% yield. Finally,
the reaction of 11 with hydrogen peroxide (30% aq) at 08C
afforded the desired enone 6 in 87% yield (Scheme 2).[15,16]
Starting from commercially available (R)-methylcyclohex-
anone, the first step in the enantioselective synthesis of
iodide 5 was the preparation of the a-N-methylanilino-
methylene derivative 12[17] to perform the enolate alkylation
reactions in regio- and stereoselective fashion (Scheme 3).
Treatment of 12 with LDA and MeI at 08C produced the
methylated ketone 13[17] as a 1:5 (cis/trans) mixture of dia-
With the enantiomerically pure enone 6 and iodide 5 in
hand, we proceeded to assemble both fragments of neomari-
none by stereoselective 1,4-cuprate addition. In this endeav-
or, we first tried the conjugate addition of the Gilman cup-
rate (R2CuLi), prepared by halogen-metal exchange of
iodide 5 (2 equiv) with tBuLi and addition of CuI, to enone
6 at low temperature. Under these conditions, the conjugate
addition product 4 was obtained in 56% yield as a mixture
of C-2 acetyl epimers and the enol–lactone tautomer. In an
effort to improve the atom economy of the reaction, we also
tested the possibility of preparing hetero- or mixed cuprates.
It was found that the reaction of iodide 5 (1 equiv) with
tBuLi at À788C, followed by addition of a solution of
copper cyanide (1 equiv) and triACTHNUTRGNEUGN(n-butyl)phosphine, and fur-
ther reaction with 6 at À788C, afforded 4 in 52% yield
(Scheme 4). It is important to note that, although the yields
are comparable, the latter procedure consumes half of the
starting iodide.
The stereochemistry of the quaternary stereocenter gener-
ated in the cuprate addition was studied in the O-acetylated
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J. Pꢂrez Sestelo, L. A. Sarandeses et al.
Scheme 3. Enantioselective synthesis of iodide 5.
product 20 obtained by reaction of 1,3-dicarbonyl compound
sion of 4 in 21 involves several steps: 1) formation of the si-
lyloxydiene, 2) Diels–Alder reaction, 3) silyl enol ether hy-
drolysis, 4) trimethylsilyloxy elimination and, 5) aromatiza-
tion.
6
with acetic anhydride in pyridine at reflux (95%,
1
Scheme 4). The H NMR analysis of the acetylated product
showed a single stereoisomer at C-3, and the relative stereo-
chemistry of the b and g methyl groups at the lactone was
assigned as cis on the basis of nuclear Overhauser NMR ex-
periments. This result confirms that the stereoselectivity of
the cuprate addition reaction takes place trans to the g-
methyl group.
The last step in the synthesis was the cleavage of methyl
ether in the 1,4-benzoquinone. Initial attempts using Lewis
acids,[22] under different reaction conditions, led to decompo-
sition of the starting material. Alternatively, the consider-
ation of the methyl ether in the quinoid system as part of a
vinylogous ester prompted us to attempt the hydrolysis. Un-
fortunately, the reaction of 21 with 1m NaOH or KOH[23] at
RT for 24 h did not afford any reaction product, and heating
at 608C led to decomposition. Interestingly, acid hydrolysis
with HCl (37%)[10b] cleaved the methyl ether in 21, albeit
with isomerization of the double bond at the cyclohexene
and epimerization of the methyl group at the furan. Gratify-
ingly, treatment of 21 with HClO4 (70% aq)[24] at RT for
24 h led to a smooth reaction that afforded neomarinone (1)
in an excellent 76% yield. Synthetic neomarinone was iden-
tical in all respects (1H and 13C NMR, MS, UV, IR, TLC and
HPLC) to the natural compound. Additionally, the optical
rotation measured ([a]2D0 = +88.3 (c=0.2 in MeOH)) was
coincident in sign and value with that reported in the litera-
ture ([a]2D0 = +86 (c=0.5 in MeOH)).[1]
Scheme 4. Diastereoselective conjugate addition.
Once the 1,3-dicarbonyl compound 4 had been prepared,
the next step was the formation of the corresponding 1,3-
bisACHTUNGTRENNUNG(silyloxy)-1,3-diene and the Diels–Alder reaction with
bromoquinone 2 (Scheme 5). The preparation of the 1,3-
bis(trimethylsilyloxy)-1,3-diene 3 was attempted by sequen-
tial treatment of 4 with LDA (1.1 equiv) and TMSCl
(1.5 equiv). Unfortunately, the diene 3 proved to be very
sensitive to hydrolysis and all attempts to isolate this com-
pound failed. For this reason we decided to carry out the
diene formation and Diels–Alder reaction in one pot. In this
case, addition of bromoquinone 2[10] at room temperature to
a reaction vessel containing the solution of diene 3 led to an
exothermic reaction, and the methyl ether of neomarinone
21 was isolated in 54% yield after 12 h. Overall, the conver-
Scheme 5. Synthesis of neomarinone.
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Total Synthesis of (+)-Neomarinone
FULL PAPER
30 min stirring, a solution of 8 (E/Z 25:75, 1.00 g, 3.33 mmol) in Et2O
(8 mL) was added via cannula dropwise. After 15 minutes, the reaction
was quenched at 08C by addition of a few drops of saturated NH4Cl, and
extracted with Et2O (3ꢄ25 mL). The combined organic layer was washed
with brine (50 mL), dried, filtered and concentrated under reduced pres-
sure. The residue was purified by column chromatography (5% EtOAc/
hexanes) to give 9 (1.008 g, 3.16 mmol, 97%) as a mixture of stereoiso-
Conclusion
In summary, the first total synthesis of (+)-neomarinone has
been developed. The synthesis, which is concise and conver-
gent, is based in the construction of the furanonaphthoqui-
none skeleton by regioselective Diels–Alder reaction using
1
mers. H NMR (300 MHz, CDCl3, 258C): d=0.01 (s, 3H), 0.03+0.06 (2s,
a 1,3-bisACHTUNGTRENNUNG(silyloxy)-1,3-diene. The enantioselective synthesis
3H), 0.83+1.06 (2d, J=6.8 Hz, 3H), 0.89+0.90 (2s, 9H), 1.12+1.14
(2d, J=6.1 Hz, 3H), 1.26+1.28 (2t, J=7.3 Hz, 3H), 2.22+2.24 (2s, 3H),
2.35 (m, 1H), 3.57 (m, 1H), 3.86 (m, 1H), 4.17 ppm (m, 2H); 13C NMR
(75 MHz, CDCl3, 258C): d=À5.2, À4.9, À4.2, À4.0, 10.0, 11.4, 14.0, 14.1,
18.0, 18.1, 20.5, 21.4, 25.8, 25.9, 29.6, 29.7, 39.7, 40.0, 61.1, 61.2, 62.6, 63.4,
68.4, 69.1, 169.1, 169.3, 203.1, 203.8 ppm; IR (ATR): n˜ =3436, 2972, 2927,
2855, 2001, 1778, 1741 cmÀ1; MS (FAB, 3-NBA): m/z (%): 317 (8) [M+
+H], 316 (17) [M+], 169 (100); HRMS (FAB, 3-NBA): m/z: calcd for
C16H33O4Si: 317.2148 [M++H]; found: 317.2157.
was performed using methyl (R)-lactate and (R)-3-methylcy-
clohexanone as chiral building compounds. The two quater-
nary stereocenters were formed stereoselectively by 1,4-con-
jugate addition and enolate alkylation reactions.[25] The total
synthesis confirms the relative and absolute stereochemistry
of neomarinone.
(5R)-3-Acetyl-4,5-dimethyl-dihydrofuran-2(3H)-one (10): To a solution
of
9 (820 mg, 2.59 mmol) in THF (15 mL) at RT, TBAF (2.45 g,
Experimental Section
7.78 mmol) was added and the mixture was heated at reflux for 2 h.
After cooling to RT and evaporation of the solvent, the residue was dis-
solved in CH2Cl2 (30 mL) and the organic layer was washed with saturat-
ed NH4Cl (25 mL). The aqueous layer was extracted with CH2Cl2 (2ꢄ
20 mL) and the combined organic phase was dried, filtered and concen-
trated to give an oil which was purified by column chromatography
(20% EtOAc/hexanes), affording 10 (355 mg, 88%, 2.26 mmol, cis/trans
General methods: Unless otherwise is stated, all reactions were conduct-
ed in flame-dried glassware under a positive pressure of argon. Reaction
temperatures refer to external bath temperatures. Anhydrous solvents
were obtained by distillation from CaH2 (CH2Cl2 and pyridine) or from
the sodium/benzophenone (THF and Et2O). All other commercially
available reagents were used as received. Organic extracts were dried
over anhydrous MgSO4, filtered, and concentrated by using a rotary
evaporator at aspirator pressure (20–30 mmHg). TLC was effected on
silica gel 60 F254 (layer thickness 0.2 mm) and components were located
by observation under UV light and/or by treating the plates with a phos-
phomolybdic acid, or p-anisaldehyde reagent followed by heating.
Column chromatography was performed on silica gel (230–400 mesh).
NMR spectra were performed in a Bruker Avance 300 or Bruker Avance
500 spectrometers in CDCl3 using the residual solvent signal at d=
7.26 ppm (1H) or d=77.0 ppm (13C) as internal standard. DEPT was used
to assign carbon types. The low resolution electron-impact mass spectra
were measured on a Thermo Finnigan Trace MS spectrometer at 70 eV.
The high resolution mass spectra were measured on a Thermo Finnigan
MAT 95XP spectrometer. Infrared spectra were taken with a Bruker
Vector 22. Optical rotation values were determined at room temperature
in a JASCO DIP-1000 Digital polarimeter. IR spectra were taken with
ATR (“attenuated total reflectance”). Melting points are uncorrected.
1
39:61). Major isomer: H NMR (300 MHz, CDCl3, 258C): d=1.05 (d, J=
6.8 Hz, 3H), 1.29 (d, J=6.8 Hz, 3H), 2.42 (s, 3H), 3.06 (hexaplet, J=
6.8 Hz, 1H), 3.33 (d, J=6.8 Hz, 1H), 4.73 ppm (pentet, J=6.8 Hz, 1H);
13C NMR (75 MHz, CDCl3, 258C): d=13.3 (CH3), 15.7 (CH3), 29.7
(CH3), 34.9 (CH), 61.0 (CH), 78.7 (CH), 171.8 (C), 200.2 ppm (C); IR
(ATR): n˜ = 2977, 2931, 1760, 1714, 1651 cmÀ1; MS (FAB, 3-NBA): m/z
(%): 157 (23) [M++H], 156 (17) [M+], 154 (100); HRMS (FAB, 3-
NBA): m/z: calcd for C8H13O3: 157.0865 [M++H]; found: 157.0858.
Minor isomer: 1H NMR (300 MHz, CDCl3, 258C): d=1.12 (d, J=6.3 Hz,
3H), 1.43 (d, J=6.3 Hz, 3H), 2.45 (s, 3H), 2.59 (m, 1H), 3.37 (d, J=
6.8 Hz, 1H), 4.11 ppm (m, 1H).
AHCTUNGTERG(NNUN 4R,5R)-3-Acetyl-dihydro-4,5-dimethyl-3-(phenylselanyl)selenylfuran-
2(3H)-one (11): To a suspension of NaH (470 mg, 1.92 mmol) in THF
(10 mL) at 08C, a solution of 10 (200 mg, 1.28 mmol) in THF (4 mL) was
added dropwise via cannula, and the resulting mixture was stirred for
10 min at 08C and 1 h at RT. The reaction mixture was cooled at À808C
and a solution of PhSeCl (295 mg, 1.54 mmol) in THF (5 mL) was added
via cannula. After 1 h, the reaction was quenched by addition of a few
drops of saturated NH4Cl. The solvent was removed under reduced pres-
sure and the residue dissolved in Et2O (20 mL). The organic layer was
washed with saturated NaHCO3 and the aqueous layer extracted with
Et2O (3ꢄ20 mL). The combined organic phase was dried, filtered and
concentrated to give an oil which was purified by column chromatogra-
phy (10% EtOAc/hexanes), to afford the selenide 11 (375 mg,
1.20 mmol, 94%) as a 70:30 mixture of diastereoisomers as yellow oils.
Major isomer: 1H NMR (300 MHz, CDCl3, 258C): d=0.95 (d, J=7.3 Hz,
3H), 1.37 (d, J=6.3 Hz, 3H), 2.42 (s, 3H), 3.13 (m, 1H), 5.11 (m, 1H),
7.29–7.48 (m, 3H), 7.52–7.68 ppm (m, 2H); 13C NMR (75 MHz, CDCl3,
258C): d=9.8, 12.2, 15.2, 16.1, 26.6, 28.9, 39.3, 42.1, 61.5, 75.8, 125.5,
129.4, 129.5, 129.7, 130.7, 136.1, 137.6, 171.1, 172.2, 197.8, 199.6 ppm; IR
(ATR): n˜ =3366, 3057, 2976, 2924, 2853, 2042, 1759, 1695 cmÀ1; MS
(FAB, 3-NBA): m/z (%): 313 (100) [M++H], 312 (28) [M+]; HRMS
(FAB, 3-NBA): m/z: calcd for C14H17O3Se: 313.0343 [M++H]; found:
313.0354. Minor isomer: 1H NMR (300 MHz, CDCl3, 258C): d=1.25 (d,
J=7.3 Hz, 3H), 1.45 (d, J=6.3 Hz, 3H), 2.39 (s, 3H), 2.52 (m, 1H), 4.54
(m, 1H), 7.34–7.48 (m, 3H), 7.57–7.68 ppm (m, 2H).
Ethyl (R)-2-acetyl-4-(tert-butyldimethylsilyl)oxypent-2-enoate (8): To a
cold solution of TiCl4 (4.09 mL, 37.18 mmol) in CCl4 (5 mL) at À788C, a
solution of aldehyde 7 (1.75 g, 9.29 mmol) in THF (10 mL), ethyl aceto-
ACHTUNGTRENNUNGacetate (2.37 mL, 18.59 mmol) and pyridine (1.46 mL, 27.89 mmol) in
THF (5 mL) were successively added via cannula. Alter 12 h, the reaction
mixture was poured on ice and extracted with Et2O (2ꢄ150 mL). The
combined organic phase was washed with brine (200 mL) and saturated
NaHCO3 (200 mL), dried, filtered and concentrated in vacuo, to give an
oil which was purified by column chromatography (5% EtOAc/hexanes)
to afford
8
(2.01 g, 6.7 mmol, 72%, E/Z 25:75). (Z)-8: 1H NMR
(300 MHz, CDCl3, 258C): d=0.05 (s, 3H), 0.06 (s, 3H), 0.88 (s, 9H), 1.30
(d, J=6.7 Hz, 3H), 1.34 (t, J=7.2 Hz, 3H), 2.34 (s, 3H), 4.32 (q, J=
6.7 Hz, 3H), 4.69 (dq, J=8.3, 6.7 Hz, 1H), 6.71 ppm (d, J=8.3 Hz, 1H);
13C NMR (75 MHz, CDCl3, 258C): d=À4.9 (CH3), À4.7 (CH3), 14.1
(CH3), 18.1 (C), 23.5 (CH3), 25.7 (3ꢄCH3), 26.9 (CH3), 61.3 (CH2), 66.4
(CH), 133.7 (C), 150.9 (CH), 165.7 (C), 195.4 ppm (C); IR (ATR): n˜ =
2955, 2930, 2896, 2857, 1727, 1700, 1629 cmÀ1; MS (FAB, 3-NBA): m/z
(%): 301 (72) [M++H], 255 (25) [M+ÀC2H5O], 243 (100), 169 (29) [M+
ÀC4H9SiO]; HRMS (FAB, 3-NBA): m/z: calcd for C15H29O4Si: 301.1830
1
[M++H]; found: 301.1831. (E)-8: H NMR (300 MHz, CDCl3, 258C): d=
0.03 (s, 3H), 0.05 (s, 3H), 0.88 (s, 9H), 1.30 (d, J=6.7 Hz, 3H), 1.32 (t,
J=7.3 Hz, 3H), 2.34 (s, 3H), 4.26 (q, J=6.7 Hz, 3H), 4.64 (m, 1H),
6.84 ppm (d, J=7.8 Hz, 1H).
(R)-3-Acetyl-4,5-dimethylfuran-2(5H)-one (6): To a solution of selenide
11 (219 mg, 0.704 mmol) in CH2Cl2 (5 mL) at 08C, H2O2 (200 mL, 30%)
was added. After 10 minutes, the reaction mixture was stirred at RT for
40 min. Then, H2O (20 mL) was added and the aqueous layer was ex-
tracted with CH2Cl2 (2ꢄ15 mL). The combined organic phase was dried
(MgSO4), filtered and concentrated to give 6 (159 mg, 1.03 mmol, 87%)
Ethyl (R)-2-acetyl-4-(tert-butyldimethylsilyl)oxy-3-methylpentanoate (9):
To cold suspension of CuI (1.27 g, 6.65 mmol) in Et2O (15 mL) at 08C, a
solution of MeLi in Et2O (10.8 mL, 1.23m, 13.31 mmol) was added. After
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J. Pꢂrez Sestelo, L. A. Sarandeses et al.
as a clear liquid. [a]D =À3.4 (c=0.8 in MeOH); 1H NMR (300 MHz,
CDCl3, 258C): d=1.50 (d, J=7.0 Hz, 3H), 2.38 (s, 3H), 2.57 (s, 3H),
4.91 ppm (q, J=7.0 Hz, 1H); 13C NMR (75 MHz, CDCl3, 258C): d=14.0
(CH3), 17.6 (CH3), 30.1 (CH3), 79.3 (CH), 124.7 (C), 170.2 (C), 177.6 (C),
195.1 ppm (C); IR (ATR): n˜ =2928, 2255, 1750, 1688, 1632 cmÀ1; MS
(FAB, NPOE): m/z (%): 155 (16) [M++H], 140 (100), 111 (21) [M+
ÀC2H3O]; HRMS (FAB, NPOE): m/z: calcd for C8H11O3: 155.0703 [M+
+H]; found: 155.0702.
ÀC2H3O2], 96 (100); HRMS (EI): m/z: calcd for C9H12O3F3S: 257.0432
[M+ÀC2H3O2]; found: 257.0454.
Methyl 2-[(1S,6R)-1,6-dimethyl-2-(trifluoromethylsulfonyloxy)cyclohex-
2-enyl]-acetate (17): To a solution of 16 (160 mg, 0.506 mmol) in DMF
(10 mL), was added MeI (63 mL, 1.01 mmol) and K2CO3 (0.140 g,
1.01 mmol). After stirring overnight at RT, water (10 mL) was added and
extracted with Et2O (3ꢄ15 mL). The combined organic phase was
washed with brine (20 mL), dried, filtered and concentrated to reduced
pressure, to give an oil which was purified by column chromatography
(20% Et2O/hexanes) to afford 17 (160 mg, 0.62 mmol, 95%) as a color-
less oil. [a]2D0 =+2.1 (c=0.40 in MeOH); 1H NMR (300 MHz, CDCl3,
258C): d=0.97 (d, J=6.9 Hz, 3H), 1.08 (s, 3H), 1.47–1.63 (m, 2H), 2.02–
2.14 (m, 1H), 2.17–2.23 (m, 2H), 2.47 (d, J=15.1 Hz, 1H), 2.60 (d, J=
15.1 Hz, 1H), 3.66 (s, 3H), 5.79 (t, J=4.1 Hz, 1H); 13C NMR (75 MHz,
CDCl3, 258C): d=15.5 (CH3), 19.6 (CH3), 23.2 (CH2), 25.9 (CH2), 35.3
(CH), 40.2 (CH2), 41.1 (C), 51.4 (CH3), 116.7 (CH), 120.4 (C), 153.2 (C),
170.9 (C); IR (ATR): n˜ =2928, 2854, 2359, 2208, 2172, 2085, 2018, 1971,
1943 cmÀ1; MS (EI): m/z (%): 257 (4) [M+ÀC3H5O2], 149 (100); HRMS
(EI): m/z: calcd for C9H12O3F3S: 257.0446 [M+ÀC3H5O2]; found:
257.0454.
Ethyl 2-[(1S,6R,Z)-1,6-dimethyl-3-[[methyl
oxocyclohexyl]acetate (14): To cold solution of LDA (0.68 mL,
1.41 mmol) in THF (10 mL) at À788C, solution of 13 (0.312 g,
ACHTUNGTNER(NUNG phenyl)amino]methylene]-2-
a
a
1.28 mmol) in THF (5 mL) was added dropwise. After 20 min stirring,
ethyl bromoacetate (0.50 mL, 4.48 mmol) was added via syringe over a
10 min period and the reaction mixture was slowly allowed to reach RT.
The solvent was evaporated under reduced pressure and the residue was
partitioned between saturated NaHCO3 (15 mL), H2O (15 mL) and Et2O
(15 mL). The aqueous phase was extracted and the combined organic ex-
tracts were washed with brine (25 mL), dried, filtered and concentrated
in vacuo. The residue was purified by column chromatography (50%
Et2O/hexanes) to give 14 (251 mg, 0.760 mmol, 60%) as an orange oil.
1H NMR (300 MHz, CDCl3, 258C): d=0.90 (d, J=6.9 Hz, 3H), 1.02 (s,
3H), 1.25 (t, J=7.3 Hz, 3H), 1.42–1.53 (m, 2H), 2.05–2.25 (m, 3H), 2.40
(d, J=16.6 Hz, 1H), 3.14 (d, J=16.6 Hz, 1H), 3.42 (s, 3H), 4.05–4.17 (m,
2H), 7.03–7.10 (m, 3H), 7.29–7.34 (m, 2H), 7.54 ppm (s, 1H); 13C NMR
(75 MHz, CDCl3, 258C): d=14.2 (CH3), 16.3 (CH3), 19.7 (CH3), 26.6
(CH2), 27.6 (CH2), 34.2 (CH3), 41.7 (CH2), 42.3 (CH), 48.1 (C), 59.9
(CH2), 111.2 (C), 120.9 (CH), 123.6 (CH), 128.8 (CH), 145.4 (CH), 146.1
(C), 172.1 (C), 203.2 ppm (C); IR (ATR): n˜ =3383, 2961, 2927, 2324,
1730, 1652, 1598 cmÀ1; MS (EI): m/z (%): 330 (3) [M++1], 329 (16) [M+
], 284 (13) [M+ÀC2H5O], 242 (19) [M+ÀC4H7O2]; HRMS (EI): m/z:
calcd for C20H27NO3: 329.1985 [M+]; found: 329.1986.
Methyl 2-[(1S,6R)-1,2,6-trimethylcyclohex-2-enyl]acetate (18): To a cold
solution of InCl3 (44 mg, 0.20 mmol) in THF (5 mL) at À788C, a solution
of MeLi in Et2O (0.39 mL, 1.6m, 0.61 mmol) was slowly added via syringe
for a 15 min period. The reaction mixture was allowed to reach RT and a
solution of 17 (135 mg, 0.41 mmol) and [PdACTHNUGTRNEG(UN PPh3)2Cl2] (29 mg,
0.04 mmol) in THF (6 mL) was added via cannula. The resulting mixture
was heated at reflux overnight, cooled, the solvent removed in the evapo-
rator at reduced pressure. The residue was dissolved in Et2O (20 mL)
and the organic phase successively washed with satd. NH4Cl (20 mL),
satd. NaHCO3 (20 mL) and brine (20 mL), dried, filtered and concentrat-
ed to give an oil which was purified by column chromatography (10%
Et2O/hexanes) to afford 18 (74 mg, 0.38 mmol, 93%) as an oil. [a]D25
=
(3aS,4R,7aR)-Hexahydro-7a-hydroxy-3a,4-dimethylbenzofuran-2(3H)-
one (15): A solution of 14 (248 mg, 3.34 mmol) in HCl (10 mL, 10%) was
heated at reflux for 45 minutes. The mixture was cooled and extracted
with Et2O (3ꢄ10 mL). The organic layer was concentrated at reduced
volume and treated with a solution of NaOH (10 mL, 2n) at reflux for
1 h. The mixture was cooled, acidified with HCl (10%) and extracted
with Et2O (3ꢄ15 mL). The combined organic phase was washed with
brine (20 mL), dried, filtered and concentrated in vacuo. Purification by
column chromatography (50% Et2O/hexanes) afforded 15 (122 mg,
0.66 mmol, 88%) as a white solid. M.p. 107–1088C; [a]2D5 =À24.8 (c=0.5
in MeOH); 1H NMR (300 MHz, CDCl3, 258C): d=0.89 (d, J=6.6 Hz,
3H), 1.06 (s, 3H), 1.10–1.26 (m, 2H), 1.37–1.57 (m, 2H), 1.64–1.75 (m,
2H), 2.03–2.08 (m, 1H), 2.36 (d, J=16.6 Hz, 1H), 2.66 ppm (d, J=
16.6 Hz, 1H); 13C NMR (75 MHz, CDCl3, 258C): d=11.6 (CH3), 16.4
(CH3), 21.8 (CH2), 29.0 (CH2), 32.4 (CH2), 37.3 (CH), 41.2 (CH2), 46.1
(C), 108.2 (C), 176.9 ppm (C); IR (ATR): n˜ =3333, 2960, 2948, 2872,
+30 (c=0.5 in MeOH); 1H NMR (300 MHz, CDCl3, 258C): d=0.92 (d,
J=6.8 Hz, 3H), 0.97 (s, 3H), 1.36–1.49 (m, 1H), 1.52–1.61 (m, 1H), 1.71
(s, 3H), 1.84–2.02 (m, 3H), 2.43 (d, J=14.3 Hz, 1H), 2.52 (d, J=14.3 Hz,
1H), 3.64 (s, 3H), 5.42 ppm (brs, 1H); 13C NMR (75 MHz, CDCl3,
258C): d=15.9 (CH3), 19.4 (CH3), 20.9 (CH3), 24.5 (CH2), 26.8 (CH2),
34.5 (CH), 40.5 (C), 41.7 (CH2), 51.1 (CH3), 123.5 (CH), 138.3 (C),
172.4 ppm (C); IR (ATR): n˜ =2923, 1734, 1435, 1377, 1316, 1281 cmÀ1
;
MS (EI): m/z (%): 196 (8) [M+], 123 (55) [M+ÀC3H5O2], 122 (100);
HRMS (EI): m/z: calcd for C12H20O2: 196.1458 [M+]; found: 196.1450.
2-[(1S,6R)-1,2,6-Trimethylcyclohex-2-enyl]ethanol (19): To a solution of
18 (216 mg, 1.10 mmol) in THF (12 mL) at 08C, a solution of LiAlH4 in
THF (3.3 mL, 1m, 3.30 mmol) was added via syringe. After 3 h, the sol-
vent was removed and the residue was dissolved in Et2O (15 mL) and the
resulting organic phase was washed with HCl (10 mL, 5%), and brine
(20 mL), dried, filtered and concentrated. The residue was purified by
column chromatography (40% Et2O/hexanes) to afford 19 (161 mg,
0.96 mmol, 87%) as an oil. [a]2D5 =+36.3 (c=0.44 in MeOH); 1H NMR
(300 MHz, CDCl3, 258C): d=0.89 (s, 3H), 0.91 (d, J=6.8 Hz, 3H), 1.26–
1.30 (m, 1H), 1.38–1.47 (m, 2H), 1.67 (broad s, 3H), 1.75 (t, J=7.6 Hz,
2H), 1.91–1.98 (m, 2H), 3.45–3.55 (m, 1H), 3.60–3.68 (m, 1H), 5.43 ppm
(brs, 1H); 13C NMR (75 MHz, CDCl3, 258C): d=16.0 (CH3), 19.3 (CH3),
21.0 (CH3), 25.4 (CH2), 26.9 (CH2), 34.2 (CH), 39.1 (CH2), 39.6 (C), 59.9
(CH2), 124.2 (CH), 139.4 ppm (C); IR (ATR): n˜ =3312, 2960, 2920, 2876,
2857, 2837, 1453, 1437, 1377 cmÀ1; MS (EI): m/z (%): 169 (4) [M++1],
168 (4) [M+], 123 (100) [M+ÀC2H5O]; HRMS (EI): m/z: calcd for
C11H20O: 168.1509 [M+]; found: 168.1505.
1737, 1724 cmÀ1 MS (EI): m/z (%): 184 (2) [M+], 125 (62) [M+
;
ÀC2H3O2], 96 (100); HRMS (EI): m/z: calcd for C10H16O3: 184.1094 [M+
]; found: 184.1094.
2-[(1S,2R)-1,2-Dimethyl-6-oxocyclohexyl]acetic acid (16): To a cold solu-
tion of LDA (2.52 mL, 4.20 mmol) in THF (6 mL) at À408C, a solution
of 15 (352 mg, 1.91 mmol) in THF (8 mL) was added. After 30 min, a so-
lution of PhNTf2 (0.75 g, 2.10 mmol) in THF (5 mL) was added dropwise
via syringe and allowed to reach RT in a 6 h period. The reaction was
quenched with few drops of MeOH and added over NH4Cl (20 mL, satd.
sol.). The aqueous layer was extracted with Et2O (3ꢄ20 mL), and the
combined organic extracts were washed with brine (25 mL), dried, fil-
tered and concentrated in vacuo. The residue was purified by column
chromatography (40% Et2O/hexanes) to afford 16 (523 mg, 2.03 mmol,
87%) as an oil. [a]2D5 =+36.7 (c=0.45 in MeOH); 1H NMR (300 MHz,
CDCl3, 258C): d=1.00 (d, J=7.1 Hz, 3H), 1.12 (s, 3H), 1.47–1.70 (m,
2H), 2.06–2.26 (m, 3H), 2.51 (d, J=15.2 Hz, 1H), 2.66 (d, J=15.2 Hz,
1H), 5.81 ppm (t, J=4.0 Hz, 1H); 13C NMR (75 MHz, CDCl3, 258C): d=
15.4 (CH3), 19.6 (CH3), 23.1 (CH2), 25.8 (CH2), 35.3 (CH), 40.1 (CH2),
41.0 (C), 117.1 (CH), 120.5 (C), 152.7 (C), 175.8 ppm (C); IR (ATR): n˜ =
3387, 2931, 2873, 2358, 1756, 1709 cmÀ1; MS (EI): m/z (%): 257 (12) [M+
AHCTUNGTERG(NNUN 5R,6S)-6-(2-Iodoethyl)-1,5,6-trimethylcyclohex-1-ene (5): To a solution
of 19 (154 mg, 0.915 mmol) in dry THF (15 mL) at RT, PPh3 (288 mg,
1.10 mmol), imidazole (125 mg, 1.83 mmol) and I2 (279 mg, 1.10 mmol)
were successively added. After 45 min, the reaction mixture was poured
in a separating funnel with Na2S2O3 (10 mL, satd. sol.). The aqueous
layer was extracted with Et2O (3ꢄ20 mL), and the combined organic
phase was washed with brine (20 mL), dried, filtered and concentrated to
give a residue which was purified by column chromatography (hexanes),
to afford 5 (247 mg, 0.89 mmol, 97%) as a colorless oil. [a]D =À3.4 (c=
0.8 in MeOH); 1H NMR (300 MHz, CDCl3, 258C): d=0.87 (s, 3H), 0.89
914
www.chemeurj.org
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 910 – 916

Total Synthesis of (+)-Neomarinone
FULL PAPER
(d, J=6.9 Hz, 3H), 1.40–1.51 (m, 2H), 1.58–1.72 (m, 4H), 1.91–1.96 (m,
2H), 2.09 (dd, J=8.5, 6.0 Hz, 2H), 2.83–2.92 (m, 1H), 3.07–3.16 (m, 1H),
5.48 ppm (brs, 1H); 13C NMR (75 MHz, CDCl3, 258C): d=1.2 (CH2),
15.9 (CH3), 19.1 (CH), 20.5 (CH3), 25.4 (CH2), 26.7 (CH2), 33.0 (CH3),
41.9 (CH2), 43.5 (C), 125.2 (CH), 138.0 ppm (C); IR (ATR): n˜ =3020,
2961, 2920, 2874, 2855, 2836 cmÀ1; MS (EI): m/z (%): 278 (49) [M+], 123
(100) [M+ÀC2H4I]; HRMS (EI): m/z: calcd for C11H19I: 278.0526 [M+];
found: 278.0516.
0.23 mmol, 54%) as a brilliant yellow solid. M.p. > 2008C; [a]D =
1
+ 49.1(c=0.25 in MeOH); H NMR (500 MHz, CDCl3, 258C): d=0.80 (s,
3H), 0.81 (d, J=6.9 Hz, 3H), 1.25 (s, 3H), 1.27–1.43 (m, 4H), 1.45 (d, J=
6.5 Hz, 3H), 1.55 (s, 3H), 1.62–1.78 (m, 3H), 1.91–1.99 (m, 2H), 2.07 (s,
3H), 4.00 (s, 3H), 4.85 (q, J=6.5 Hz, 1H), 5.41 (brs, 1H), 6.73 (brs, 1H),
7.19 ppm (s, 1H); 13C NMR (125 MHz, CDCl3, 258C): d=9.4 (CH3), 15.3
(CH3), 15.9 (CH3), 19.1 (CH3), 20.2 (CH3), 21.2 (CH3), 25.6 (CH2), 27.0
(CH2), 31.1 (CH2), 31.6 (CH2), 33.3 (CH), 40.3 (C), 46.7 (C), 60.7 (CH3),
87.8 (CH), 108.9 (CH), 109.6 (C), 124.6 (CH), 128.0 (C), 133.3 (C), 134.0
(C), 139.1 (C), 156.7 (C), 156.8 (C), 161.2 (C), 181.2 (C), 184.0 ppm (C);
IR (ATR): n˜ =3310, 2922, 2852, 2359, 2325, 2051, 1981, 1666, 1627, 1572,
1291 cmÀ1; MS (FAB, 3-NBA): m/z (%): 439 (50) [M++H], 438 (10)
[M+], 154 (100); HRMS (FAB, 3-NBA): m/z: calcd for C27H35O5:
439.2479 [M++H]; found: 439.2490.
ACHTUNGTRENNUNG(4S,5R)-3-Acetyl-4,5-dimethyl-4-{2-[(1S,6R)-1,2,6-trimethylcyclohex-2-
enyl]ethyl}-dihydrofuran-2(3H)-one (4): To a solution of tBuLi (690 mL,
1.7m in pentane, 1.173 mmol) in Et2O (5 mL) at À788C, a solution of
iodide 5 (163 mg, 0.586 mmol) in Et2O (3 mL) was added dropwise via
cannula for 10 min. After 30 min, a clear solution of CuCN (58 mg,
0.65 mmol) and Bu3P (240 mL, 0.973 mmol) in Et2O (3 mL) was added
via cannula. The mixture was left for 1 h at À788C and slowly warmed
up to À408C during 1 h. Then, the reaction mixture was cooled to À788C
and a solution of 6 (110 mg, 0.704 mmol) in Et2O (4 mL) was added via
cannula. After 1 h, the reaction was quenched with few drops of metha-
nol and poured into a separating funnel with satd. NH4Cl (25 mL). The
mixture was extracted with Et2O (30 mL) and the organic phase was
washed with brine (25 mL), dried, filtered and concentrated, to give a
residue which was purified by column chromatography (20% EtOAc/
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
lution of 21 (10.9 mg, 0.031 mmol) in THF (3 mL) at RT, HClO4 (1.2 mL,
70% aq) was added. After 16 h, the solvent was removed, and the resi-
due dissolved in EtOAc (15 mL). The organic phase was washed with
H2O (20 mL) and brine (20 mL), dried, filtered and concentrated to give
a residue which was purified by column chromatography (30% EtOAc/
hexanes) to afford 1 (8 mg, 0.02 mmol, 76%) as a fine yellow solid. M.p.
>
2008C; [a]2D0 =+88.3 (c=0.2, MeOH); 1H NMR (500 MHz,
1
hexanes) to afford 4 (94 mg, 0.31 mmol, 52%) as a colorless oil. H NMR
[D6]DMSO, 258C): d=0.74 (s, 3H), 0.78 (d, J=6.8 Hz, 3H), 1.14 (s, 3H),
1.15–1.26 (m, 2H), 1.30 (d, J=6.5 Hz, 3H), 1.32–1.40 (m, 3H), 1.52 (s,
3H), 1.66–1.73 (m, 1H), 1.82 (s, 3H), 1.84–1.96 (m, 3H), 4.65 (q, J=
6.5 Hz, 1H), 5.36 (brs, 1H), 7.04 (s, 1H), 10.28 (brs, 1H), 10.71 ppm
(brs, 1H); 13C NMR (125 MHz, [D6]DMSO, 258C): d=8.6 (CH3), 15.1
(CH3), 15.7 (CH3), 18.8 (CH3), 19.7 (CH3), 20.9 (CH3), 25.1 (CH2), 26.6
(CH2), 30.5 (CH2), 31.0 (CH2), 32.8 (CH), 39.7 (C), 46.0 (C), 86.3 (CH),
107.9 (C), 107.9 (CH), 120.3 (C), 123.9 (CH), 127.3 (C), 131.6 (C), 138.9
(C), 153.7 (C), 157.7 (C), 159.9 (C), 180.4 (C), 182.7 ppm (C); IR (ATR):
n˜ =3295, 2923, 2853, 2360, 2324, 2164, 2050, 1981, 1655, 1629, 1566,
1297 cmÀ1; UV (MeOH) lmax =398, 318, 266, 216 nm; MS (FAB, 3-NBA):
m/z (%): 425 (20) [M++H], 424 (5) [M+], 137 (100); HRMS (FAB, 3-
NBA): m/z: calcd for C26H33O5: 425.2323 [M++H]; found: 425.2320.
(300 MHz, CDCl3, 258C): d=0.85–0.89 (m, 6H), 1.01–1.14 (m, 3H),
1.25–1.31 (m, 5H), 1.35–1.48 (m, 4H), 1.52–1.70 (m, 4H), 1.92–2.02 (m,
2H), 2.37 (s, 3H), 3.40+3.43 (2s, 1H), 4.31+4.39+4.73 (3q, J=6.5 Hz,
1H), 5.43 ppm (brs, 1H); IR (ATR): n˜ =3413, 2965, 1776, 1711,
1453 cmÀ1; MS (FAB, thioglycerol): m/z (%): 307 (22) [M++H], 123
(100); HRMS (FAB, thioglycerol): m/z: calcd for C19H31O3: 307.2268 [M+
+H]; found: 307.2253.
1-[(4S,5R)-4,5-Dimethyl-2-oxo-4-{2-[(1S,6R)-1,2,6-trimethylcyclohex-2-
enyl]ethyl}-dihydrofuran-3(2H)-ylidene]ethyl acetate (20): To a solution
of 4 (17 mg, 0.055 mmol) in CH2Cl2 (3 mL), pyridine (90 mL, 1.108 mmol)
and Ac2O (40 mL, 0.440 mmol) were added via syringe and the resulting
solution was heated at reflux for 12 h. The reaction mixture was cooled
and washed with satd. NH4Cl (5 mL) and brine (10 mL). The organic
phase was dried, filtered and concentrated to give a residue which was
purified by column chromatography (20% EtOAc/hexanes) to afford 20
(18 mg, 0.05 mmol, 95%) as a colorless oil. 1H NMR (500 MHz, CDCl3,
258C): d=0.87 (d, J=7.0 Hz, 3H), 0.88 (s, 3H), 1.14 (s, 3H), 1.28 (d, J=
6.5 Hz, 3H), 1.28–1.36 (m, 3H), 1.39–1.46 (m, 2H), 1.59 (s, 3H), 1.61–
1.70 (m, 2H), 1.96–2.00 (m, 2H), 2.22 (s, 3H), 2.46 (s, 3H), 4.30 (q, J=
6.5 Hz, 1H), 5.46 ppm (brs, 1H); 13C NMR (125 MHz, CDCl3, 258C): d=
15.9 (CH3), 16.4 (CH3), 18.1 (CH3), 19.0 (CH3), 19.6 (CH3), 21.0 (CH3),
21.1 (CH3), 25.5 (CH2), 26.9 (CH2), 30.4 (CH2), 32.9 (CH2), 33.2 (CH),
40.3 (C), 45.7 (C), 80.1 (CH), 122.0 (C), 124.9 (CH), 138.8 (C), 159.9 (C),
167.8 (C), 170.0 ppm (C); IR (ATR): n˜ =2922, 1763, 1749, 1672, 1446,
1372 cmÀ1; MS (FAB, 3-NBA): m/z (%): 349 (22) [M++H], 307 (75) [M+
ÀC2H3O], 123 (100); HRMS (FAB, 3-NBA): m/z: calcd for C21H33O4:
349.2373 [M++H]; found: 349.2375.
Acknowledgement
We are grateful to the Xunta de Galicia (PGIDIT05BTF10301PR) for fi-
nancial support. We thank Dr. M. Mar Real and Dr. Rosa M. Suꢅrez for
initial studies for this project. We also thank Prof. W. Fenical for provid-
ing us with a sample of natural neomarinone and Prof. A. B. Smith, III
for helpful discussions. M.P.L. and M.M.M. thank the Xunta de Galicia
for a predoctoral fellowship (Marꢁa Barbeito program) and a postdoctor-
al contract (Isidro Parga Pondal program), respectively.
ACHTUNGTRENNUNG
[1] I. H. Hardt, P. R. Jensen, W. Fenical, Tetrahedron Lett. 2000, 41,
2073–2076.
AHCTUNGTRENNUNG
To a cold solution of 4 (130 mg, 0.424 mmol) in THF (3 mL) at À788C, a
solution of LDA in THF (880 mL, 0.483m, 0.424 mmol) was added drop-
wise via syringe. After 20 minutes, freshly distilled TMSCl (80 mL,
0.636 mmol) was added and the reaction warmed at RT for 30 min. Then,
the reaction mixture was cooled at À788C and a solution of LDA
(880 mL, 0.483m in THF, 0.424 mmol) added via syringe over a 5 minutes
period. After 20 minutes, freshly distilled TMSCl (80 mL, 0.636 mmol)
was added via syringe, and the reaction mixture was allowed to reach RT
for 1 h. Then, a solution of the bromoquinone 2 (117 g, 0.509 mmol) in
THF (3 mL) was added to the previously prepared 1,3-bis(trimethylsilyl-
[2] T. J. Simpson, Top. Curr. Chem. 1998, 195, 1–48.
[3] a) M. Ishibashi, S. Funayama, Y. Anraku, K. Komiyama, S. Omura,
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miyama, S. Omura, J. Org. Chem. 1990, 55, 1132–1133.
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5, 4449–4452.
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1822.
ACHTUNGTRENNUNGoxy)-1,3-diene, dropwise via cannula. After 15 h, a catalytic amount of
TsOH was added, and the mixture stirred for 30 minutes. The solvent
was removed and the residue was dissolved in Et2O (10 mL). The organic
phase was washed with HCl (5%, 20 mL) and brine (20 mL), dried, fil-
tered and concentrated, to give a residue which was purified by column
chromatography (30% to 50% EtOAc/hexanes) to afford 21 (100 mg,
[8] J. Carroll, E. N. Jonsson, R. Ebel, M. S. Hartman, T. R. Holman, P.
Crews, J. Org. Chem. 2001, 66, 6847–6851.
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1995, 117, 10755–10756; b) A. B. Smith, J. Pꢂrez Sestelo, P. G.
Dormer, Heterocycles 2000, 52, 1315–1328.
Chem. Eur. J. 2009, 15, 910 – 916
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
915

J. Pꢂrez Sestelo, L. A. Sarandeses et al.
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Received: October 1, 2008
Published online: December 3, 2008
916
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