Straightforward enantioselective synthesis of (+)-ancistrofuran

Article abstract of DOI:10.1016/j.tet.2005.07.087

This paper reports the straightforward enantioselective synthesis of (+)-ancistrofuran starting from a readily available enantiopure building block. A stereofacial directed diastereoselective addition of an organocerate for the installation of the require

Full text of DOI:10.1016/j.tet.2005.07.087

Tetrahedron 61 (2005) 9545–9549
Straightforward enantioselective synthesis of (C)-ancistrofuran
*
´
Elie Palombo, Gerard Audran and Honore Monti
´
´ ´ ´ ´ ´
Laboratoire de Reactivite Organique Selective, U.M.R. 6180 ‘Chirotechnologies: catalyse et biocatalyse’, Universite Paul Cezanne,
Aix-Marseille III, 13397 Marseille cedex 20, France
Received 8 June 2005; accepted 27 July 2005
Available online 11 August 2005
Abstract—This paper reports the straightforward enantioselective synthesis of (C)-ancistrofuran starting from a readily available
enantiopure building block. A stereofacial directed diastereoselective addition of an organocerate for the installation of the required
stereogenic center served as the key step. In addition, the efficient conversion of an intermediate hydroxy aldehyde to the one-carbon
homologated cyanide was developed. The sequence was achieved by the mild formation of a cyanohydrin and the subsequent one-pot two-
step Barton–McCombie double deoxygenation of the hydroxyl groups.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
oxabicyclo[3.2.1]octan-7-one, (C)-2, gave hydroxy lactone
(C)-3 in 89% yield, and protection of the created tertiary
alcohol with MOMCl (chloromethyl methyl ether) in the
presence of i-Pr2NEt9 afforded (K)-4 (92% yield). The
required stereochemistry of the addition was actually
established in the next step. Attempts to reduce the lactone
moiety in 4 to the corresponding aldehyde (lactol) using
1.2 equiv of DIBAL (diisobutylaluminum hydride) under
various conditions proved futile, giving a mixture of diol
and unreacted starting material, due to the uncontrolable
over-reduction. So, the desired product was obtained in two
steps.
Baker and co-workers1 isolated and identified ancistrofuran
(1, Fig. 1) as the major component in the defensive repellent
secretion used by the termite Ancistrotermes cavithorax
major soldiers against their common ant predators. Several
racemic syntheses of ancistrofuran have been reported.2–5
The only enantioselective synthesis was reported by Mori
and co-workers.6
We recently developed a concise synthetic pathway to
chiral, non-racemic oxo lactone 2 (8,8-dimethyl-6-oxabicy-
clo[3.2.1]octan-2,7-one) for the synthesis of karahana
lactone.7 In an effort to both probe the synthetic utility of
this potentially useful chiral building block and to develop
an efficient new synthetic route to (C)-ancistrofuran, we
designed an approach to this furanosesquiterpene. The key
steps utilize a stereofacial directed diastereoselective
addition of a methylcerium dichloride, and the conversion
of an intermediate hydroxy aldehyde to the one-carbon
homologated cyanide using the formation of a cyanohydrin,
followed by a double deoxygenation sequence of the
hydroxyl groups.
Convenient reduction of 4 with LiAlH4 (lithium aluminum
hydride) gave the diol (C)-5 in 98% yield and selective
oxidation of the primary alcohol function in 5 with sodium
hypochlorite, mediated by TEMPO (2,2,6,6-tetramethylpi-
peridinyl-1-oxy)10 afforded hydroxy aldehyde (C)-6 in
78% yield. X-ray crystallography analysis11 carried out on
the nicely crystalline diol (C)-5 indirectly proved the
proposed stereostructure for (C)-3 (Fig. 2).
As depicted in our synthetic plan, elaboration of aldehyde
(C)-6 to compound (C)-8 next required deoxygenation of
2. Results and discussion
As shown in Scheme 1, fully stereoselective addition of
methylcerium dichloride8 to (1S,5S)-8,8-dimethyl-2-oxo-6-
Keywords: Ancistrofuran; Natural products; Enantioselective synthesis;
One-carbon homologation.
*
Corresponding author. Tel./fax: C33 4 9128 8862;
e-mail: g.audran@univ.u-3mrs.fr
Figure 1.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.07.087

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E. Palombo et al. / Tetrahedron 61 (2005) 9545–9549
Scheme 2. Reagents and conditions: (a) (i) 3-bromofuran (3 equiv), n-BuLi
(3 equiv), Et2O, K78 8C, 30 min; (ii) hexane (hexane/etherZ4:1), (C)-8,
K78 to K45 8C, then K45 8C, 15 h; (b) 35% aq HCl (4.4 equiv), MeOH,
12 h, rt, 56% two steps; (c) LiHBEt3 (2 equiv), THF, 12 h, K78 8C to rt,
95%; (d) p-TsCl (4 equiv), pyridine, 72 h, rt, 75%.
The main shortcoming of the use of 3-lithiofuran as a
precursor is that very low temperatures must be maintained
throughout the reaction. Indeed, temperatures exceeding
K40 8C during the course of reagent generation and use
result in isomerisation to the more thermodynamically
stable 2-lithiofuran.14 Unfortunately, in the present work,
the addition reaction upon (C)-8 was sluggish at low
temperature. As a result, reactions were rigorously
conducted at K45 8C so that the addition process was
over in a few hours, while minimizing isomerisation. While
studying the nucleophilic addition, we also observed that
solvent effects were crucial for the outcome of the reaction.
Due to the acidity of the hydrogens in the a-carbon atom,
enolisable nitriles such as (C)-8 may be deprotonated by
organolithium reagents if the latter are employed in polar
solvents.15 Effectively, in our attempts, the addition of
3 equiv of 3-lithiofuran16 to nitrile (C)-8 in ether as a
solvent and subsequent acidification (HCl, MeOH) afforded
the expected hydroxy ketone (K)-9 in only 24% yield after
15 h at K45 8C, a substantial amount of the deprotected
starting material (ca. 35%) being recovered.17 Following the
same conditions, reaction performed in hexane–ether (4/1)
gave complete conversion, and afforded pure (K)-9 in 56%
yield after column chromatography. At this stage conver-
sion of (K)-9 into (C)-1 was carried out according to the
procedure developed by Baker and co-workers for the
synthesis of racemic 1.4,5 The crystalline hydroxy ketone
(K)-9 was reduced with lithium triethylhydroborate to give
diol 10, contaminated with ca. 5% of its epimer at the newly
generated chiral center. Treatment of 10 with p-toluene-
sulfonyl chloride in pyridine gave crude 1, which was
purified by silica gel column chromatography, then
preparative HPLC (see Section 4), to give pure (C)-
ancistrofuran (1) whose IR and 1H NMR spectroscopic data
were identical with those reported.6 The high optical purity
of (C)-1 (eeO98%) was verified by analytical chiral HPLC
[(S,S)-Whelk-O1, 250!4.6 mm; solvent: n-hexane–isopro-
panol (95/5), 1 mL/min].
Scheme 1. Reagents and conditions: (a) dried CeCl3 (3 equiv), MeLi
(3 equiv), THF, 12 h, K78 8C to rt, 89%; (b) MOMCl (7 equiv), i-Pr2NEt
(7.7 equiv), CH2Cl2, 48 h, rt, 92%; (c) LiAlH4 (2 equiv), Et2O, 3 h, rt, 98%;
(d) TEMPO (0.07 equiv), KBr (0.15 equiv), Bu4NCClK (0.06 equiv),
NaOCl (2.6 equiv), NaHCO3/brine, CH2Cl2, 0 8C, 78%; (e) KCN
(25 equiv), AcOH (32.5 equiv), EtOH, 12 h, rt, 80%; (f) PhOCSCl
(4 equiv), DMAP (8 equiv), CH2Cl2, 12 h, rt, then (g) Bu3SnH (4 equiv),
cat. AIBN, toluene, 1 h, reflux, 60% two steps.
the hydroxyl substituent and conversion of the aldehyde
function to the one-carbon homologated cyanide. This could
be conveniently combined without resorting to specific
additional steps, with the aid of a cyanohydrin. Thus, the
cyanohydrin 7 was prepared from aldehyde (C)-6 (KCN,
AcOH) as a mixture of diastereomers in 80% yield. Barton–
McCombie12 double deoxygenation of the two hydroxyl
moieties of 7 was achieved in an one-pot two-step process
via the corresponding thionocarbonate ester derivatives
which were reduced smoothly with tri-n-butyltin to provide
the target molecule (C)-8 in 60% yield for the two steps.
With the desired nitrile (C)-8 in hand, the introduction of
the furan group was addressed using 3-lithiofuran13
(Scheme 2).
3. Conclusions
To sum up, we presented a straightforward enantioselective
Figure 2. ORTEP view of (C)-5.

E. Palombo et al. / Tetrahedron 61 (2005) 9545–9549
9547
synthesis of (C)-ancistrofuran with the aid of a provisional
hydroxyl group, a diastereofacial selectivity and a specific
homologation sequence as the key steps. The target
molecule was prepared from a versatile enantiopure
building block by an 11-step sequence in 12.5% overall
yield. We believe that our strategy compares favourably
with the one described6 as far as number of steps,
stereoselectivity and chemical yields are concerned. In
addition, the enantiomer (K)-ancistrofuran can be syn-
thesized from the available ent-27 following the reaction
sequence detailed above.
at 0 8C, diisopropyl ethylamine (8.75 mL, 50.2 mmol) and
chloromethyl methyl ether (3.50 mL, 46.1 mmol). After
48 h at rt, the reaction mixture was diluted with CH2Cl2 and
the organic layer was washed with water. The aqueous
washes were back-extracted and the combined organic
layers were successively washed with 1 M HCl, saturated
solution of NaHCO3 and brine. The organic layer was dried,
filtered and concentrated to afford after purification by
column chromatography 1.37 g (92% yield) of pure (K)-4
as a solid; mpZ77 8C. [a]2D5 K14.2 (c 1.0, CHCl3). IR
(KBr): n 1766, 1153, 1048 cmK1 1H NMR (300 MHz,
.
CDCl3): d 4.71 and 4.53 (AB, JZ7.2 Hz, 2H), 4.24 (br d,
JZ4.5 Hz, 1H), 3.32 (s, 3H), 2.26 (br s, 1H), 2.05–1.76 (m,
3H), 1.55 (m, 1H), 1.32 (s, 3H), 1.28 (s, 3H), 1.06 (s, 3H).
13C NMR (75 MHz, CDCl3): d 177.4 (C), 90.9 (CH2), 85.2
(CH), 75.2 (C), 57.4 (CH), 55.6 (CH3), 42.0 (C), 30.1 (CH2),
28.0 (CH3), 25.3 (CH3), 22.2 (CH2), 21.2 (CH3). Anal.
Calcd for C12H20O4: C, 63.14; H, 8.83. Found: C, 62.99; H,
8.81.
4. Experimental
4.1. General
1H and 13C NMR spectra were recorded in CDCl3 at
300 MHz. Infrared spectra were measured as films or KBr
pellets on an FT-IR spectrometer. Optical rotations were
measured on a digital polarimeter at 25 8C with a Na lamp.
Melting points were uncorrected. Routine monitoring of
reactions was performed using Merck Silica gel 60 F254,
aluminum supported TLC plates. Column chromatography
was performed with Silica gel 60 (230–400 mesh) and
gradients pentane/ether as eluent, unless otherwise stated.
Microanalyzes were performed at our University. Unless
otherwise stated, the solutions were dried over magnesium
sulfate and evaporated in a rotary evaporator under reduced
pressure.
4.1.3. (1S,3R,4S)-3-Hydroxymethyl-4-methoxymethoxy-
2,2,4-trimethyl-cyclohexanol ((C)-5). A solution of (K)-4
(1.20 g, 5.26 mmol) in dry ether (30 mL) was slowly added
at 0 8C to a stirred slurry solution of LiAlH4 (400 mg,
10.5 mmol) in dry ether (10 mL). The reaction mixture was
allowed to rise to rt. After 3 h, Celite (10 g) and Na2-
SO4$10H2O (10 g) were added and the solution was stirred
for a further 1 h. The mixture was filtered through a pad of
MgSO4 and concentrated. Column chromatography of the
residue afforded 1.20 g (98% yield) of pure diol (C)-5 as
white crystals; mpZ86 8C. [a]2D5 C8.4 (c 1.0, CHCl3). IR
(KBr): n 3391, 1141, 1069 cmK1 1H NMR (300 MHz,
.
4.1.1. (1S,2S,5S)-2-Hydroxy-2,8,8-trimethyl-6-oxabicy-
clo[3.2.1]octan-7-one ((C)-3). Finely crushed Cerium(III)
chloride heptahydrate (8.65 g, 23.2 mmol) was placed in a
500 mL three-necked flask containing a stirring bar and
evacuated (ca. 0.1 Torr). The apparatus was heated at 80 8C
for 4 h, then the temperature was increased slowly to 140 8C
and maintained 5 h. The white solid was cooled to rt, the
apparatus was blanketed with argon, THF (26 mL) was
added and the mixture was stirred for 12 h. A 1.5 M solution
of methyllithium (15.5 mL, 23.2 mmol) was added drop-
wise at K78 8C to the resulting mixture. After 1 h at
K78 8C, a solution of (C)-2 (1.30 g, 7.73 mmol) in THF
(10 mL) was added dropwise and the reaction mixture was
allowed to rise to rt. After 12 h the reaction mixture was
diluted with ether, poured in an aqueous solution of NH4Cl
and extracted with ether. The organic extracts were
combined, washed with brine, dried, filtered and concen-
trated. Purification by column chromatography afforded
1.27 g (89% yield) of pure alcohol (C)-3 as white crystals;
mpZ95 8C. [a]2D5 C29.0 (c 1.0, CHCl3). IR (KBr): n 3397,
CDCl3): d 4.70 and 4.63 (AB, JZ7.4 Hz, 2H), 3.82 and 3.67
(br ABX, JZ11.0, 6.8 Hz, 2H), 3.31 (s, 3H), 3.30 (partially
overlapped m, 1H), 1.93–1.72 (m, 2H), 1.66–1.51 (m, 2H),
1.46–1.38 (m, 1H), 1.33 (s, 3H), 1.12 (s, 3H), 0.80 (br s,
3H). Anal. Calcd for C12H24O4: C, 62.04; H, 10.41. Found:
C, 62.35; H, 10.38.
4.1.4. (1S,3S,6S)-3-Hydroxy-6-methoxymethoxy-2,2,6-
trimethyl-cyclohexanecarbaldehyde ((C)-6). To a stirred
solution of (C)-5 (400 mg, 1.72 mmol) and 2,2,6,6-
tetramethylpiperidinyl-1-oxy (TEMPO, 29 mg, 0.127 mmol)
in CH2Cl2 (20 mL) was added a saturated aqueous solution
of sodium bicarbonate (4 mL) containing potassium
bromide (30 mg, 0.252 mmol) and tetrabutylammonium
chloride (29 mg, 0.104 mmol). To this cooled (0 8C) and
well stirred mixture was added dropwise 2 mL of aqueous
solution made of sodium hypochlorite (solution containing
ca. 9.6% chlorine, 2.75 mL, 4.47 mmol), a saturated sodium
bicarbonate solution (5 mL) and brine (11 mL). This
solution (2 mL) was added every hour until the total
consumption of the starting material monitored by TLC.
The reaction mixture was diluted with CH2Cl2 and the
phases were separated. The aqueous phase was extracted
with CH2Cl2 and the combined extracts were washed with
brine, dried, filtered and concentrated. Purification by silica
gel column chromatography afforded 309 mg (78% yield) of
pure aldehyde (C)-6 as an oil. [a]2D5 C43.0 (c 1.0, CHCl3).
1
1763, 1148, 1054 cmK1. H NMR (300 MHz, CDCl3): d
4.27 (br d, JZ4.7 Hz, 1H), 2.13 (br s, 1H), 2.07 (dddd, JZ
14.5, 11.6, 7.4, 0.6 Hz, 1H), 1.94 (s, OH), 1.87–1.77 (m,
1H), 1.72–1.65 (m, 2H), 1.35 (s, 3H), 1.33 (s, 3H), 1.07 (s,
3H). 13C NMR (75 MHz, CDCl3): d 177.9 (C), 85.5 (CH),
70.4 (C), 59.5 (CH), 42.2 (C), 31.9 (CH2), 30.6 (CH3), 27.9
(CH3), 22.1 (CH2), 21.5 (CH3). Anal. Calcd for C10H16O3:
C, 65.20; H, 8.75. Found: C, 64.88; H, 8.79.
IR (film): n 3384, 2829, 1713, 1157 cmK1 1H NMR
.
4.1.2. (1S,2S,5S)-2-Methoxymethoxy-2,8,8-trimethyl-6-
oxabicyclo[3.2.1]octan-7-one ((K)-4). To a stirred solution
of (C)-3 (1.20 g, 6.51 mmol) in CH2Cl2 (25 mL) was added
(300 MHz, CDCl3): d 9.82 (d, JZ4.9 Hz, 1H), 4.74 and 4.62
(AB, JZ7.3 Hz, 2H), 3.48 (br dd, JZ5.8, 3.1 Hz, 1H), 3.34
(s, 3H), 2.33 (d, JZ4.9 Hz, 1H), 2.06 (ddt, JZ13.0, 9.6,

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E. Palombo et al. / Tetrahedron 61 (2005) 9545–9549
3.0 Hz, 1H), 1.88 (ddd, JZ13.8, 10.4, 3.6 Hz, 1H), 1.29 (s,
3H), 1.15 (s, 3H), 0.97 (s, 3H). 13C NMR (75 MHz, CDCl3):
d 205.1 (CH), 89.9 (CH2), 75.7 (C), 74.4 (CH), 65.2 (CH),
55.3 (CH3), 38.1 (C), 31.5 (CH2), 28.4 (CH3), 26.2 (CH2),
24.1 (CH3), 22.2 (CH3). Anal. Calcd for C12H22O4: C,
62.58; H, 9.63. Found: C, 62.86; H, 9.59.
stirred for 10 min before addition of a solution of (C)-8
(184 mg, 0.82 mmol) in hexane (7 mL). The mixture was
allowed to rise slowly to K45 8C and maintained at the
same temperature over 15 h. The reaction mixture was
quenched with a saturated aqueous solution of NH4Cl
(10 mL) and the aqueous phase was extracted with AcOEt.
The combined extracts were washed with water, dried,
filtered and concentrated. To the crude residue in absolute
MeOH (10 mL) was added concentrated HCl solution (35%
wt in water, 0.35 mL) at 0 8C. The solution was allowed to
rise to rt and then stirred overnight. The reaction mixture
was diluted in ether, poured into a saturated solution of
NaHCO3, and the aqueous layer was extracted with ether.
The combined extracts were washed with brine, dried,
filtered and concentrated. Column chromatography of the
residue gave 115 mg (56% yield for the two steps) of
compound (K)-9 as a white solid; mpZ94 8C. [a]2D5 K10.3
4.1.5. Hydroxy-(3-hydroxy-6-methoxymethoxy-2,2,6-tri-
methyl-cyclohexyl)-acetonitrile (7). This reaction must be
done in a well-ventilated hood. To a stirred suspension of
potassium cyanide (10.6 g, 163 mmol) in absolute ethanol
(50 mL) was added dropwise glacial acetic acid (12.1 mL,
212 mmol) under an argon atmosphere. After 1.5 h, a
solution of (C)-6 (1.50 g, 6.51 mmol) in absolute ethanol
(18 mL) was added dropwise at 0 8C, and the solution was
stirred at rt for 12 h. The reaction mixture was diluted with
ether, poured into water and extracted with ether. The
combined extracts were washed with brine, dried, filtered
and concentrated. Purification by column chromatography
gave 1.34 g (80% yield) of an inseparable mixture (1:2) of
1
(c 1.0, CHCl3). IR (KBr): n 3383, 1703, 1169 cmK1. H
NMR (300 MHz, CDCl3): d 8.09 (br s, 1H), 7.41 (br t, JZ
1.7 Hz, 1H), 6.76 (br dd, JZ1.7, 0.7 Hz, 1H), 2.90 and 2.76
(ABX, JZ16.8, 5.8, 4.7 Hz, 2H), 2.11 (br t, JZ5.2 Hz, 1H),
1.83–1.75 (m, 1H), 1.61–1.20 (m, 5H), 1.14 (s, 3H), 0.84 (s,
3H), 0.83 (s, 3H). 13C NMR (75 MHz, CDCl3): d 196.5 (C),
147.0 (CH), 144.1 (CH), 127.7 (C), 108.8 (CH), 73.0 (C),
51.9 (CH), 43.3 (CH2), 41.1 (CH2), 37.1 (CH2), 35.2 (C),
32.5 (CH3), 22.5 (CH3), 21.3 (CH3), 20.5 (CH2). Anal.
Calcd for C15H22O3: C, 71.97; H, 8.86. Found: C, 72.21; H,
8.89.
diastereomers 7. IR (film): n 3406, 2241, 1143, 1050 cmK1
.
1H NMR (300 MHz, CDCl3): d 4.89–4.82 (m, 1H, major
and minor), 4.75 and 4.65 (AB, JZ7.2 Hz, 2H, minor), 4.74
and 4.66 (AB, JZ7.5 Hz, 2H, major), 3.32 (s, 3H, major and
minor), 3.32 (m, 1H, major and minor), 1.90–1.42 (m, 5H,
major and minor), 1.52 (s, 3H, minor), 1.50 (s, 3H, major),
1.20 (s, 3H, minor), 1.19 (s, 6H, major), 1.02 (s, 3H, minor).
4.1.6. ((1S,2S)-2-Methoxymethoxy-2,6,6-trimethyl-cyclo-
hexyl)-acetonitrile ((C)-8). To a stirred solution of
cyanohydrin 7 (1.26 g, 4.90 mmol) in CH2Cl2 (40 mL)
was added at 0 8C DMAP (4.80 g, 39.2 mmol) and phenyl
chlorothionoformate (2.70 mL, 19.5 mmol) under an argon
atmosphere. After 12 h at rt, the reaction mixture was
poured into water and extracted with ether. The combined
organic extracts were washed with water, dried, filtered and
concentrated. Column chromatography of the residue
afforded 2.30 g of a diastereomeric mixture of phenoxy-
thiocarbonyl ester. To a stirred solution of ester (2.30 g,
4.34 mmol) in toluene (30 mL) was added tri-n-butyltin
hydride (4.60 mL, 17.1 mmol) and a catalytic amount of
AIBN in toluene (20 mL) under an argon atmosphere. The
reaction mixture was stirred under reflux for 1 h, cooled and
concentrated. The resulting oily residue was purified by
silica gel column chromatography to give 663 mg of pure
(C)-8 (60% yield for the two steps). [a]2D5 C4.7 (c 1.0,
4.1.8. (1S,2S)-2-((S)-2-Furan-3-yl-2-hydroxy-ethyl)-1,3,
3-trimethyl-cyclohexanol (10). To a stirred solution of
(K)-9 (100 mg, 0.40 mmol) in THF (15 mL), a 1 M THF
solution of lithium triethylhydridoborate (800 mL,
0.80 mmol) was added dropwise at K78 8C under an
argon atmosphere. The reaction mixture was stirred for a
further 3 h at K78 8C, then allowed to rise to rt. After 12 h,
the solution was poured into water and extracted with ether.
The organic extracts were combined, washed with brine,
dried, filtered and concentrated. Purification by column
chromatography of the residue afforded 96 mg (95% yield)
of 10 contaminated with ca. 5% of its epimer. This mixture
was used in the next steps without further purification. IR
(film): n 3362, 1158, 1029, 890 cmK1. 1H NMR (300 MHz,
CDCl3): d 7.36 (m, 2H), 6.34 (br t, JZ1.3 Hz, 1H), 4.99 (dd,
JZ6.8, 4.3 Hz, 1H), 2.02–1.73 (m, 3H), 1.58–1.30 (m, 6H),
1.23 (s, 3H), 0.81 (s, 3H), 0.78 (s, 3H). 13C NMR (75 MHz,
CDCl3): d 142.9 (CH), 139.0 (CH), 129.5 (C), 109.0 (CH),
73.6 (C), 65.9 (CH), 50.0 (CH), 44.1 (CH2), 41.8 (CH2),
35.0 (CH2), 33.9 (CH3), 32.8 (C), 23.5 (CH3), 21.4 (CH3),
20.3 (CH2).
1
CHCl3). IR (film): n 2253, 1246, 1167, 1054 cmK1. H
NMR (300 MHz, CDCl3): d 4.71 (s, 2H), 3.37 (s, 3H), 2.61
and 2.24 (ABX, JZ17.2, 7.0, 4.7 Hz, 2H), 1.84 (m, 2H),
1.65–1.24 (m, 5H), 1.16 (s, 3H), 1.08 (s, 3H), 0.88 (s, 3H).
13C NMR (75 MHz, CDCl3): d 121.4 (C), 89.9 (CH2), 78.2
(C), 55.4 (CH3), 52.3 (CH), 41.0 (CH2), 38.3 (CH2), 35.2
(C), 33.0 (CH3), 21.1 (CH3), 19.7 (CH3), 19.6 (CH2), 12.9
(CH2). Anal. Calcd for C13H23NO2: C, 69.29; H, 10.29.
Found: C, 69.60; H, 10.27.
4.1.9. (2R,3aS,7aS)-2-Furan-3-yl-4,4,7a-trimethyl-octa-
hydro-benzofuran, ancistrofuran ((C)-1). p-Toluenesul-
fonyl chloride (275 mg, 1.44 mmol) was added to a solution
of 10 (91 mg, 0.36 mmol) in pyridine (6 mL) at 0 8C and the
mixture was allowed to rise to rt. After stirring for 3 days,
the reaction mixture was poured into water and extracted
with ether. The combined organic extracts were washed
with 1 M HCl, saturated NaHCO3, brine, dried and
concentrated. The oily residue was purified by column
chromatography followed by preparative high performance
liquid chromatography (CHIRALCEL-OJ, 250!10 mm;
solvent: n-hexane–isopropanol (90/10), 4.5 mL/min;
4.1.7.
1-Furan-3-yl-2-((1S,2S)-2-hydroxy-2,6,6-tri-
methyl-cyclohexyl)-ethanone ((K)-9). To a solution of
3-bromofuran (223 mL, 2.48 mmol) in ether (3 mL) was
added dropwise, at K78 8C, n-BuLi (1.6 M solution in
hexanes, 1.55 mL, 2.48 mmol) under an argon atmosphere
and the resulting solution was stirred at K78 8C for 1.5 h.
Hexane (3.5 mL) was added at K78 8C and the mixture was

E. Palombo et al. / Tetrahedron 61 (2005) 9545–9549
9549
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Paquette, L. A., Ed.; Encyclopedia of Reagents for Organic
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Reviews: (d) Imamoto, T. In Trost, B. M., Fleming, I., Eds.;
Comprehensive Organic Synthesis; Pergamon: Oxford, 1991;
Vol. 1, pp 231–250. (e) Molander, G. A. Chem. Rev. 1992, 92,
29–68.
detection at 230 nm) to give 63 mg (75% yield) of pure (C)-
1. [a]2D5 C8.1 (c 1, CHCl3). IR (film): n 1162, 1038,
1
991 cmK1. H NMR (300 MHz, CDCl3): d 7.36 (m, 2H),
6.37 (m, 1H), 4.91 (dd, JZ9.2, 6.9 Hz, 1H), 2.19 (ddd, JZ
11.7, 6.7, 5.4 Hz, 1H), 1.97–1.32 (m, 7H), 1.24–1.16 (m,
1H), 1.13 (s, 3H), 0.98 (s, 3H), 0.86 (s, 3H). 13C NMR
(75 MHz, CDCl3): d 143.1 (CH), 138.8 (CH), 129.3 (C),
109.1 (CH), 81.0 (C), 71.6 (CH), 57.4 (CH), 40.8 (CH2),
39.1 (CH2), 33.2 (CH3), 32.9 (CH2), 31.4 (C), 23.4 (CH3),
21.3 (CH2), 20.4 (CH3). Anal. Calcd for C15H22O2: C,
76.88; H, 9.46. Found: C, 77.09; H, 9.43.
9. Stork, G.; Takahashi, T. J. Am. Chem. Soc. 1977, 99,
1275–1276.
10. Siedlecka, R.; Skarzewski, J.; Miochowski, J. Tetrahedron
Lett. 1990, 31, 2177–2180.
Acknowledgements
11. Details of the X-ray structure can be obtained from the
Cambridge Crystallographic Data Centre: CCDC 271219.
12. Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin
Trans. 1 1975, 1574–1585.
We are thankful to Dr. R. Faure and Dr. M. Giorgi for NMR
and X-ray diffraction experiments. We thank P. Fournier for
the English language revision of the manuscript.
13. (a) Collins, M. A.; Tanis, S. P. In Paquette, L. A., Ed.;
Encyclopedia of Reagents for Organic Synthesis; Wiley:
Chichester, 1995; Vol. 5, pp 2989–2991. (b) Review: Hou,
X. L.; Cheung, H. Y.; Hon, T. Y.; Kwan, P. O.; Lo, T. H.;
Tong, S. Y.; Wong, H. N. C. Tetrahedron 1998, 54,
1955–2020.
References and notes
14. Bock, I.; Bornowski, H.; Ranft, A.; Theis, H. Tetrahedron
1990, 46, 1199–1210.
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16. Prepared from 3-bromofuran: Fukuyama, Y.; Kawashima, Y.;
Miwa, T.; Tokoroyama, T. Synthesis 1974, 443–444.
17. Nucleophilic addition of 3-lithiofuran upon enolisable nitriles
in ether as a solvent has been described. (a) Low temperature
(K60 8C) and low yield (17%): Liska, R. Heterocycles 2001,
55, 1475–1486. (b) Unusual temperature (K25 8C) and good
yield (70%): Sugimura, T.; Tai, A. Tetrahedron 1994, 50,
11647–11658.
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8. (a) Imamoto, T.; Kusumoto, T.; Tawarayama, Y.; Sugiura, Y.;