Synthesis of agarofuran antifeedants. Part 6: Enantioselective synthesis of a key decalinic intermediate

Article abstract of DOI:10.1016/S0957-4166(03)00132-0

The asymmetric synthesis of a template decalin precursor in the synthesis of polyhydroxylated agarofuran sesquiterpenes is described via a Lewis acid catalysed addition of furan to an activated cyclohexenone directed by an adjacent chiral ketal moiety.

Full text of DOI:10.1016/S0957-4166(03)00132-0

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 1153–1159
Synthesis of agarofuran antifeedants. Part 6: Enantioselective
synthesis of a key decalinic intermediateꢀ
Franc¸ois-Didier Boyer,a Thierry Prange´b and Paul-Henri Ducrota,*
aUnite´ de Phytopharmacie et Me´diateurs Chimiques, INRA, Route de Saint-Cyr, F-78026 Versailles Cedex, France
bChimie Structurale Biomole´culaire (UMR 7033 CNRS), 93017 Bobigny Cedex, France
Received 20 December 2002; revised 13 January 2003; accepted 4 February 2003
Abstract—The asymmetric synthesis of a template decalin precursor in the synthesis of polyhydroxylated agarofuran sesquiter-
penes is described via a Lewis acid catalysed addition of furan to an activated cyclohexenone directed by an adjacent chiral ketal
moiety. © 2003 Elsevier Science Ltd. All rights reserved.
Of the numerous diterpenic natural products isolated
from higher plants for their antifeedant activity on
insects, the esters of agarofuran sesquiterpenic polyols 1
represent a particularly interesting family of com-
pounds due to their structural diversity, numerous bio-
logical activities and abundance in the Celastraceae
family.1
also for accessing other natural terpenoids such as
clerodanes.5
According to our reported synthetic route to 2,4 the
first created stereogenic center of the molecule is gener-
ated during the 1,4-addition of furan to an a,b-unsatu-
rated b%-ketoester 3a, promoted by BF3·Et2O.
A number of synthetic strategies have been proposed
for the synthesis of the agarofuran backbone,2 which,
most of the time failed to lead to enantiospecific synthe-
ses. To our knowledge, the only reported work devoted
to the asymmetric synthesis of heavily hydroxylated
agarofurans, which are the most active compounds of
this family, comes from Spivey’s group.3 This enan-
tioselective approach is based on the desymmetrisation
of a symmetric decalinic precursor through asymmetric
epoxidation of a bis-allylic alcohol. Our own approach
to the synthesis of agarofuran polyols is also based on
the construction of a polyoxygenated decalinic precur-
sor 2 (Scheme 1). Due to the symmetry encountered in
the hydroxylation pattern of the sesquiterpenic back-
bone in most of the natural agarofurans, our precursor
has been designed to exhibit a similar pseudo-symmetry
and could also be regarded as the result of the desym-
metrisation of a naphthalene tetraone. An asymmetric
synthesis of this decalinic precursor would therefore be
valuable not only for the synthesis of agarofurans but
An asymmetric version of this reaction could be per-
formed either using a chiral Lewis acid and ketoester 3a
or asymmetric ketoesters 3b or 3c. Due to the distance
of the Lewis acid from the reactive center in the mech-
anism of this reaction, the first strategy seemed doomed
to failure. On the other hand, optically active ketoester
3d, incorporating a menthyl group had been used by
Lallemand et al.,6 leading to a diastereomeric excess of
70% for the furan addition. The third strategy, using
hydrobenzoin as a chiral protecting group for the car-
bonyl group adjacent to the reactive center, had also
been reported to be successful with nevertheless modest
to good diastereomeric excess in the case of a standard
ꢀ For Part V, see: Ref. 4d.
* Corresponding author. Tel.: 33-0-0130833641; fax: 33-0-130833119;
e-mail: ducrot@versailles.inra.fr
Scheme 1.
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00132-0

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F.-D. Boyer et al. / Tetrahedron: Asymmetry 14 (2003) 1153–1159
vinyl cuprate 1,4-addition, depending on the substitu-
tion of the starting ketoester.7
The second strategy using menthyl alcohol as the
source of chirality was tried but proved to be unsatis-
factory in this case due to difficulties encountered in the
preparation of the optically active ketoester 3b and also
in the further removal of the menthyl group through
either reduction or transesterification. Our aim was
therefore to apply the latter strategy, starting from
ketoester 3c, assuming that the 1,4-addition of the
furan would lead to better diastereoselectivities than
those obtained with vinyl cuprate.
Scheme 3.
The stabilisation of this conformation, where the furan
ring is in an axial position allowed us to explain the
subsequent stereoselective formation of the cis-decalin
products 10 and 11 in the aldol cyclisation.4c The
presence of the asymmetric ketal moiety, however,
induces the formation of two different conformers A
and B for ketoester 3c. Therefore, we had to allow a
conformational equilibrium to take place for 3c
between both conformers A and B depicted in Fig. 1.
Indeed, the more energetic conformer B, which never-
theless allows better steric differentiation between both
faces of the molecule is that which explains the forma-
tion of the desired isomer 8. Conformer A, in which the
phenyl groups of the hydrobenzoin moiety are interact-
ing less with the rest of the molecule does not lead to a
good steric differentiation of both faces of the molecule
and would be responsible for the formation of the
undesired isomer 9. Therefore, lowering the reaction
temperature would decrease the yield, and also perhaps
the diastereomeric excess of the reaction (Table 1, entry
4). The results of our optimisations are summarised in
Table 1. The best one (entry 6) was obtained when the
reaction was started at −78°C and the temperature then
slowly increased to −60°C and further maintained at
−60°C for 1 h. Quenching at −60°C with saturated
aqueous sodium bicarbonate solution was then
achieved and this procedure finally resulted in the com-
plete disappearance of the starting material and forma-
tion of the desired isomer 8 with 84% de.
1,4-Cyclohexanedione 4 was first carefully reduced to
the corresponding hydroxy ketone (NaBH4 0.25 equiv.
mol, −20°C, 60%). The free carbonyl group was subse-
quently protected using either (S,S)- or (R,R)-
hydrobenzoin, affording, after pyridine buffered
Dess–Martin periodinane oxidation, optically active
ketone 6. According to our previously reported work,
ketoester 3c was thereafter obtained in three steps via
ketoester 7. Ketoester (−)-3c ([h]D −48.8) was obtained
from (S,S)-hydrobenzoin, while (+)-3c ([h]D +49.8) was
derived from (R,R)-hydrobenzoin (Scheme 2).
Scheme 2.
The key step in our synthesis was the 1,4-addition of
furan to 3c (Scheme 3). The most critical factor encoun-
tered was the temperature of the reaction. Using
ketoester 3a as the starting material we have demon-
strated in our previous reports that furan approach is
pseudoaxial, anti to the axial oxygen of the ketal group,
leading to a unique conformer in which steric interac-
tions between the furan and the ketal are minimised.
Figure 1.
Subsequent dimethyldioxirane (DMDO)8 mediated oxi-
dative ring opening of the furan on a mixture of 8 and
9 yielded, as expected from our previous work,4c
a
mixture of the isomeric decalins 10 and 11 (Scheme 4),
which were further transformed to their corresponding
silyl ethers 12 and 13. Flash chromatography on silica

F.-D. Boyer et al. / Tetrahedron: Asymmetry 14 (2003) 1153–1159
1155
Table 1.
Conditions
Ratio [3/(8+9)]a
% dea
1
2
3
4
5
6
−78°C to rt (1 h)
0/100
67/33
0/100
20/80
0/100
0/100
40
57
71
64
74
84
quenchedb at rt
−60°C (2 h)
quenchedb at −60°C
−78°C (3 h), then −50°C (30 min)
quenchedb at −50°C
−78°C (4 h)
quenchedb at −78°C
−78°C (4 h), then −50°C (2 h), −5°C (2 h)
quenchedb at −5°C
−78°C (4 h), then −60°C (1 h)
quenchedb at −60°C
a Determined by 1H NMR analysis of the crude product.
b Quenched with saturated aqueous sodium bicarbonate solution.
Scheme 4.
gel allowed their separation. The major desired isomer
13 was thereby obtained in 26% overall yield from
ketoester (−)-3c (four steps). The configuration of the
stereogenic centres, first assumed from the mechanistic
considerations described above, was unambiguously
confirmed by X-ray analysis of 13 (Fig. 2).9
from (−)-3c, while (+)-2 ([h]D +93.4) was obtained either
from (+)-3c.
These results will allow the enantiospecific synthesis of
furano-agarofuran4c and pyrano-agarofurans4d sesquiter-
penes using our reported procedures. Although the
diastereoselectivity obtained in the 1,4-addition reaction
using the chiral hydrobenzoin ketal is not complete, the
use of more sterically hindered diols would probably not
give better results due to the conformational equilibrium
that has to take place during this reaction. More hindered
ketals would eventually prevent this equilibrium from
occurring and therefore lower not only the yield but
presumably also the diastereoselectivity of the reaction
as observed in our case when the reaction was performed
at lower temperature.
The synthesis of 2 was then completed through hydro-
genation of the D6,7 double bond (14), regio- and stereose-
lective reduction of the carbonyl group at C-5 (15) and
deprotection of the carbonyl group at C-4. This last step
was performed by hydrogenolysis (H2, Pd(OH)2/C 10%,
AcOEt), while other methods yielded only large amounts
of degradation products or untouched starting material.
This reaction sequence afforded 2 in 10% yield from
ketoester 3c. Keto alcohol (−)-2 ([h]D −89.6) was derived

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F.-D. Boyer et al. / Tetrahedron: Asymmetry 14 (2003) 1153–1159
R10–10C (DCI or DEI) or linked to a Varian 3300 GC.
Ionization was obtained either by electronic impact (EI)
or chemical ionization with ammonia (CI, NH3). Mass
spectral data are reported as m/z. Optical rotations were
measured on a Perkin–Elmer 241 polarimeter in a 1-dm
cell. Infrared spectra (IR) were obtained on a Nicolet
Avatar 320 FT-IR and are reported in terms of fre-
quency of absorption (w, cm−1). Microanalyses were
performed by Institut de Chimie des Substances
Naturelles, Microanalytical Laboratory, Gif sur Yvette,
France. All reactions were monitored by thin layer
chromatography (TLC) carried out on E Merck Ref
5554 precoated silica gel 60F 254 plates. Visualization
was accomplished with UV light then 7–10% ethanolic
phosphomolybdic acid solution and KMnO4 solution
were used as developing agents followed by heating.
Tetrahydrofuran (THF) was distilled from sodium ben-
zophenone, dichloromethane (CH2Cl2) from CaH2. The
synthesis has been performed with the both enant-
iomeric hydrobenzoin ((1R,2R)-(+)-1,2-diphenyl-1,2-
ethanediol;
((1S,2S)-(−)-1,2-diphenyl-1,2-ethanediol)
purchased from Acros Organics 98+%. For the optical
rotations, the notation (R,R) and (S,S) refers to the
compound with the (R,R) auxiliary and (S,S),
respectively.
1.2. Synthesis of acetal 5
To a solution of (1S,2S)-(+)-1,2-diphenyl-1,2-ethanediol
(1.085 g, 5.07 mmol) and of keto alcohol derived from
the standard NaBH4 reduction of diketone 4 (555 mg,
4.86 mmol, 1 equiv.) in benzene (75 mL) was added
under argon PTSA (100 mg, 0.54 mmol). The reaction
mixture was warmed under azeotropic distillation
(Dean–Stark) for 3.5 h, cooled to room temperature, and
diluted with Et2O (150 mL). The resultant solution was
washed with aqueous saturated sodium bicarbonate
solution (40 mL), brine (40 mL), dried (MgSO4) and
concentrated under reduced pressure. The residue was
purified by chromatography on silica gel (EtOAc/cyclo-
hexane, 20:80) to give 1.45 g (4.6 mmol, 96%) of acetal
5 as a white solid. Mp 97–98°C (MeOH), (R,R): [h]D
+47.6 (c 1.76, CHCl3); (S,S): [h]D −41.35 (c 1.18,
CHCl3). 1H NMR: l 7.34–7.12 (m, 10H), 4.78 (d, J=7.0
Hz, 1H), 4.77 (d, J=7.0 Hz, 1H), 3.90–3.80 (m, 1H),
2.25–1.72 (m, 9H). 13C NMR: l 136.9 (s), 128.5 (d),
128.4 (d), 128.1 (d), 127.9 (d), 127.0 (d), 126.8 (d), 126.7
(d), 109.2 (s), 85.3 (d), 79.1 (d), 33.2 (t), 33.0 (t), 32.0 (t),
31.9 (t). GC analysis (MDN5S, 0.32 mm id.×30 m,
180–300°C, 8°C/min), retention time 11.55 min. CI/NH3
MS m/z 328 ([M+NH4]+, 2.5), 311 (MH+, 16), 293
(MH+−H2O, 1), 214 (100), 204 (72). IR (neat, cm−1):
3365, 3089, 3063, 3032, 2937, 1604, 1496, 1453, 1365,
1104. Anal. calcd for C20H22O3 (MW 280.29): C, 77.39;
H, 7.14. Found: C, 77.21; H, 7.22%.
Figure 2. X-Ray structure of 13.
1. Experimental
1.1. General remarks
Melting points, recorded on a Buchi 510 are uncor-
rected. NMR data (1H: 300 MHz; 13C: 75.5 MHz) are
recorded on a VARIAN Gemini 300 instrument. All
NMR spectra were recorded in deuteriochloroform
(CDCl3). Chemical shifts are reported in l ppm relative
to CHCl3 (CDCl3) as internal reference: 7.27 ppm for 1H
(77.14 ppm for 13C). Coupling constants (J) are given in
hertz (Hz). Multiplicities are recorded as s (singlet), d
(doublet), t (triplet), q (quadruplet), m (multiplet) and br
(broad). Mass spectra (MS) were obtained on a Nermag
1.3. Synthesis of ketone 6
To a solution of 5 (650 mg, 2.10 mmol) in CH2Cl2 (34
mL) and 34 drops of pyridine at 0°C was added drop-
wise under argon Dess–Martin’s periodinane (13.7 mL,
4.8 mmol, 15% solution in CH2Cl2) and the resultant
mixture was stirred for 18 h at 0°C and poured into a
stirred saturated aqueous solution (Na2S2O3/NaHCO3

F.-D. Boyer et al. / Tetrahedron: Asymmetry 14 (2003) 1153–1159
1157
1:1, 60 mL). The aqueous layer was extracted with
dichloromethane (2×50 mL), the combined organic lay-
ers were washed with brine (50 mL), dried (MgSO4) and
the solvent was evaporated under reduced pressure. The
residue was purified by chromatography on silica gel
(EtOAc/cyclohexane, 10:90 to 20:80) to give 570 mg of
6 (1.85 mmol, 88%) as a white solid. Mp 73–74°C
(EtOAc/cyclohexane), (R,R): [h]D +52.2 (c 2.28,
interval) and stirred for 1 h until complete decoloration
of the reaction mixture. The resultant mixture was
diluted with water (40 mL) and the organic layer sepa-
rated. The separated organic layer was washed with
aqueous saturated sodium bicarbonate solution (40
mL), brine (40 mL), dried (MgSO4) and concentrated in
vacuo to give 1.45 g of 3c (3.98 mmol, 99%) as a
colorless oil used in the next step without further
purification. (R,R): [h]D +49.8 (c 1.23, CHCl3); (S,S):
1
CHCl3); (S,S): [h]D −56.1 (c 1.15, CHCl3). H NMR: l
1
[h]D −48.8 (c 1.15, CHCl3). H NMR: l 7.45–7.19 (m,
7.37–7.24 (m, 10H), 4.86 (s, 2H), 2.70–2.62 (m, 4H),
2.38–2.34 (m, 4H). 13C NMR: l 210.0 (s), 136.2s), 128.6
(d), 126.7 (d), 107.9 (s), 85.6 (d), 38.2 (t), 35.3 (t). GC
analysis (MDN5S, 0.32 mm id.×30 m, 180–300°C, 8°C/
min), retention time 10.90 min. CI/NH3 MS m/z 326
([M+NH4]+, 100), 309 (MH+, 10), 214 (70), 202 (90). IR
(neat, cm−1): 3089, 3063, 3032, 2956, 2894, 1717, 1497,
1455, 1213, 1131.
10H), 4.88 (d, J=9.7 Hz, 1H), 4.80 (d, J=9.7 Hz, 1H),
3.84 (s, 3H), 2.88–2.34 (m, 2H), 2.31–2.22 (m, 2H). 13C
NMR: l 193.6 (s), 164.5 (s), 149.7 (d), 135.2 (s), 134.9
(s), 133.1 (s), 128.9 (d), 128.8 (d), 128.7 (d), 128.5 (d),
126.75 (d), 126.69 (d), 104.1 (s), 86.0 (d), 85.4 (d), 52.6
(q), 36.2 (t), 33.9 (t). GC analysis (MDN5S, 0.32 mm
id.×30 m, 180–300°C, 10°C/min), retention time 14.56
min. CI/NH3 MS m/z 382 ([M+NH4]+, 20), 365 (MH+,
50), 258 (100). IR (neat, cm−1): 3089, 3064, 3034, 2951,
2896, 1745, 1719, 1692, 1653, 1435, 1353, 1260, 1126.
1.4. Synthesis of b-ketoester 7
To a suspension of NaH (8.5 g, 95% powder, 39.11
mmol) in anhydrous THF (6 mL) under argon was
added successively freshly distilled anhydrous dimethyl
carbonate (12 mL, 142 mmol) and a solution of 6 (1.6
g, 5.19 mmol) in anhydrous THF (6 mL). After the
addition was complete, the mixture was heated under
reflux for 4 h. The resultant brownish mixture was
cooled to 0°C and 1% acetic acid aqueous solution (10
mL) was added. The organic layer was separated and
the aqueous phase was further extracted with Et2O
(3×30 mL). The combined organic layers were washed
with aqueous saturated sodium bicarbonate solution
(30 mL), brine (30 mL), dried (MgSO4) and concen-
trated in vacuo to give a crude material which was
purified by chromatography on silica gel (EtOAc/cyclo-
hexane, 10:90) to give 1.5 g of 7 (4.01 mmol, 78%) as a
colorless oil. (R,R): [h]D +70.0 (c 1.18, CHCl3); (S,S):
1.6. Furan 8/9
To a solution of 3c (1.67 g, 4.57 mmol) in CH2Cl2 (35
mL) at −78°C was added dropwise under argon freshly
distilled furan (6 mL, 31.25 mol) and BF3·Et2O (0.3 mL,
3.26 mmol). After the addition was completed, the
resultant solution was stirred for 4 h at −78°C then
warmed slowly to −60°C (30 min) stirred at this temper-
ature for 30 min and aqueous saturated sodium bicar-
bonate solution (22 mL) added. The resultant mixture
was warmed to room temperature and the organic layer
separated. The aqueous phase was extracted with CH2Cl2
(2×50 mL) and the combined organic phases washed with
brine (50 mL), dried (MgSO4) and concentrated under
reduced pressure. The crude product was purified by
chromatography on silica gel (EtOAc/cyclohexane 20:80)
to give 1.46 g of 8/9 (3.36 mmol, 73%) as a colorless oil.
(R,R) for a mixture of diastereomers (de=84%): [h]D
+168.6 (c 1.46, CHCl3); (S,S) for a mixture of
diastereomers (de=74%): [h]D −143.6 (c 1.09, CHCl3).
Major diastereomer 1H NMR: l 12.48 (s, 1H), 7.37–7.26
(m, 11H), 6.35 (dd, J=3.1, 1.7 Hz, 1H), 6.16 (d, J=3.1
Hz, 1H), 5.02 (d, J=8.6 Hz, 1H), 4.89 (d, J=8.6 Hz, 1H),
4.41 (s, 1H), 3.72 (s, 3H), 2.85–2.62 (m, 2H), 2.24–2.02
(m, 4H). 13C NMR: l 172.2 (s), 172.0 (s), 154.6 (s), 141.6
(d), 136.3 s), 136.2 (s), 128.1 (d), 126.5 (d), 126.4 (d), 126.3
(d), 109.8 (d), 108.4 (s), 107.3 (d), 97.1 (s), 85.2 (d), 85.0
(d), 51.3 (q), 42.6 (d), 27.8 (t), 27.4 (t). CI/NH3 MS m/z
450 ([M+NH4]+, 20), 433 (MH+, 25), 254 (30), 237 (35),
180 (100). IR (neat, cm−1): 3089, 3063, 3031, 2951, 1747,
1719, 1692, 1653, 1616, 1497, 1442, 1352, 1261.
1
[h]D −65.0 (c 1.62, CHCl3). H NMR: l 12.18 (s, 1H),
7.32–7.19 (m, 10H), 4.82 (d, J=8.5 Hz, 1H), 4.77 (d,
J=8.5 Hz, 1H), 3.78 (s, 3H), 2.80 (s, 2H), 2.72–2.58 (m,
2H), 2.18–2.11 (m, 2H). 13C NMR: l 172.6 (s), 171.3
(s), 136.4 (s), 136.3 (s), 128.6 (d), 126.9 (d), 126.8 (d),
108.0 (s), 95.4 (d), 85.8 (d), 51.7 (q), 34.1 (t), 31.9 (t),
28.0 (t). GC analysis (MDN5S, 0.32 mm id.×30 m,
180–300°C, 10°C/min), retention time 12.86 min. CI/
NH3 MS m/z 384 ([M+NH4]+, 15), 367 (MH+, 5), 260
(30), 214 (40), 180 (100). IR (neat, cm−1): 3089, 3063,
3031, 2951, 2887, 1746, 1719, 1658, 1617, 1442, 1288,
1231, 1126.
1.5. Synthesis of a,b-unsaturated b-ketoester 3c
To a solution of phenylselenyl chloride (802 mg, 4.18
mmol) in anhydrous CH2Cl2 (14.7 mL) at 0°C was
added dropwise anhydrous pyridine (0.34 mL). After 15
min, a solution of ketoester 7 (1.5 g, 4.01 mmol) in
anhydrous CH2Cl2 (12 mL) was added dropwise to the
orange solution, the resultant solution was stirred for
18 h at room temperature and diluted with CH2Cl2 (88
mL). A 1N HCl aqueous solution (8.8 mL) was added
to the mixture and the organic layer was separated and
cooled to −5°C. Hydrogen peroxide (30 wt% in water)
(1.36 mL) was added dropwise in four portions (15 min
1.7. Synthesis of aldol 10/11
To a solution of furan 8/9 (1.44 g, 3.31 mmol) in
acetone (55 mL) under argon at −10°C was added
dropwise a acetone solution of dimethyldioxirane8 (56.2
mL). After the addition was completed, the resultant
solution was stirred at 0°C for 1 h, dried at room
temperature for 2 h on MgSO4 and concentrated under
reduced pressure. The crude product was purified by
chromatography on silica gel (EtOAc/cyclohexane
40:60) to give 820 mg of 10/11 (1.80 mmol, 54%) as a

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F.-D. Boyer et al. / Tetrahedron: Asymmetry 14 (2003) 1153–1159
colorless oil. Major isomer: 1H NMR: l=7.35–7.30
(m, 7H), 7.18–7.05 (m, 4H), 6.03 (ddd, J=10.4, 2.7,
0.8 Hz, 1H), 5.78 (d, J=9.9 Hz, 1H, OH), 4.76 (d,
J=8.9 Hz, 1H), 4.68–4.64 (m, 1H), 4.49 (d, J=8.9
Hz, 1H), 3.96 (s, 1H), 3.80 (s, 3H), 3.36 (td, J=14.8,
5.7 Hz, 1H), 2.72 (ddd, J=14.6, 4.4, 3.1 Hz, 1H),
2.61 (ddd, J=14.8, 5.7, 3.1 Hz, 1H), 2.37 (td, J=
14.6, 4.4 Hz, 1H). 13C NMR: l=202.0 (s), 191.9 (s),
171.4 (s), 154.7 (d), 135.6 (s), 134.2 (s), 128.9 (d),
128.7 (d), 128.5 (d), 127.5 (d), 127.4 (d), 127.2–126.3
(d), 107.4 (s), 87.9 (d), 85.1 (d), 68.9 (d), 68.7 (s),
57.1 (d), 53.5 (q), 36.7 (t), 35.1 (t).
1.9. Synthesis of diketone 14
A solution of enone 12 (490 mg, 0.87 mmol) in
methanol (30 mL) was hydrogenated for 4 h under
atmospheric pressure in the presence of 10% palla-
dium on charcoal (40 mg). The suspension was
filtered through Celite and the resultant solution con-
centrated under reduced pressure. The residue was
purified by chromatography on silica gel (EtOAc/
cyclohexane, 10:90) to give 420 mg (0.74 mmol, 85%)
of 14 as a white solid. Mp 188–189°C (CHCl3).
1
(R,R): [h]D −3.47 (c 1.64, CHCl3). H NMR: l 7.36–
7.28 (m, 8H), 7.12–7.07 (m, 2H), 4.78 (dd, J=6.3, 2.2
Hz, 1H), 4.73 (d, J=8.6 Hz, 1H), 4.61 (d, J=8.6 Hz,
1H), 4.44 (s, 1H), 3.75 (s, 3H), 2.79 (t, J=7.0 Hz,
1H), 2.58–2.18 (m, 7H), 0.86 (s, 9H), 0.11 (s, 3H),
0.05 (s, 3H). 13C NMR: l 206.3 (s), 204.1 (s), 168.9
(s), 136.3 (s), 134.9 (s), 128.8 (d), 128.6 (d), 128.4 (d),
128.5 (d), 127.5 (d), 126.7 (d), 126.4 (d), 108.0 (s),
86.8 (d), 85.4 (d), 69.6 (d), 66.5 (s), 56.7 (d), 53.4 (q),
36.1 (t), 35.3 (t), 31.9 (t), 27.1 (t), 25.6 (q), 17.9 (s),
−4.4 (q), −5.2 (q). CI/NH3 MS m/z 582 ([M+NH4]+,
100), 565 (MH+, 10), 548 (15), 386 (20), 369 (25), 299
(60), 214 (60). IR (neat, cm−1): 3063, 3032, 2953,
2929, 2891, 2856, 1718, 1605, 1455, 1225.
1.8. Synthesis of silyl ether 12
To a solution of aldol 10/11 (770 mg, 1.69 mmol) in
CH2Cl2 (11.4 mL) under argon at 0°C was added
dropwise 2,6-lutidine (0.97 mL, 9.70 mmol) and tert-
butyldimethylsilyl trifluoromethanesulfonate (1.2 mL,
5.47 mmol). The resulting solution was warmed to
room temperature and stirred for 1 h, then 1N
aqueous HCl (10 mL) was added. The organic phase
was separated and the aqueous phase extracted with
CH2Cl2 (2×20 mL). The combined organic layers were
washed with brine, dried (MgSO4) and concentrated
under reduced pressure. The crude product was
purified by chromatography on silica gel (EtOAc/
cyclohexane, 10:90) to give 625 mg of 12 (1.09 mmol,
65%) as a white solid and 55 mg of 13 (0.10 mmol,
6%) as a white solid. 12: Mp 84–85°C (hexane/
EtOAc). (R,R): [h]D +170.1 (c 1.43, CHCl3); (S,S):
[h]D −170.6 (c 0.85, CHCl3). 1H NMR: l 7.54–7.39
(m, 2H), 7.38–7.26 (m, 6H), 7.05–7.00 (m, 3H), 6.03
(d, J=10.1 Hz, 1H), 5.25 (d, J=4.8 Hz, 1H), 4.70 (d,
J=8.8 Hz, 1H), 4.62 (d, J=8.8 Hz, 1H), 4.39 (s, 1H),
3.79 (s, 3H), 2.89 (ddd, J=15.8, 12.6, 6.6 Hz, 1H),
2.68 (ddd, J=15.8, 6.6, 2.6 Hz, 1H), 2.49–2.25 (m,
2H), 0.85 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H). 13C
NMR: l 203.3 (s), 193.4 (s), 168.5 (s), 148.6 (d),
136.7 (s), 134.8 (s), 130.4 (d), 128.9 (d), 128.7 (d),
128.5 (d), 128.4 (d), 128.0 (d), 126.2 (d), 108.4 (s),
86.8 (d), 85.7 (d), 67.7 (s), 66.5 (d), 54.8 (d), 53.3 (q),
34.8 (t), 32.9 (t), 25.6 (q), 17.9 (s), −3.9 (q), −5.0 (q).
CI/NH3 MS m/z 580 ([M+NH4]+, 40), 563 (MH+, 10),
548 (7), 384 (20), 367 (15), 214 (40), 180 (30), 106
(100). IR (neat, cm−1): 3062, 3033, 2952, 2929, 2887,
2857, 1751, 1721, 1684, 1454, 1228.
1.10. Synthesis of alcohol 15
To a solution of diketone 14 (400 mg, 0.70 mmol) in
THF (12.8 mL) under argon at −70°C was added
dropwise lithium tri-tert-butoxyaluminohydride (3
mL, 3.0 mmol, 1 M solution in THF). The reaction
mixture was stirred for 2 h at −70°C, for 2 h at
−10°C and for 1.5 h at room temperature. The result-
ing solution was treated at 0°C with saturated
aqueous ammonium chloride solution (4 mL), filtered
on Celite, dried (MgSO4) and concentrated under
reduced pressure. The residue was purified by chro-
matography on silica gel (EtOAc/cyclohexane 10:90 to
20:80) to give 268 mg (0.47 mmol, 66%) of 15 as a
colorless oil. (R,R): [h]D −1.40 (c 0.84, CHCl3). 1H
NMR: l 7.35–7.25 (m, 8H), 7.20–7.17 (m, 2H), 4.82
(d, J=8.6 Hz, 1H), 4.77–4.73 (m, 2H), 4.42 (br s,
1H), 3.63 (s, 3H), 3.31 (s, 1H), 2.88–2.77 (m, 1H),
2.65–2.52 (m, 2H), 2.39 (d, J=2.2, 1H), 2.24–2.14 (m,
1H), 2.08–1.90 (m, 2H), 1.77–1.57 (m, 2H), 0.89 (s,
9H), 0.12 (s, 3H), 0.05 (s, 3H). 13C NMR: l 205.4
(s), 170.0 (s), 136.3 (s), 135.7 (s), 128.7 (d), 128.6 (d),
128.5 (d), 127.1 (d), 126.7 (d), 110.1 (s), 86.4 (d), 85.5
(d), 69.0 (d), 65.4 (d), 62.4 (s), 52.5 (q), 51.2 (d), 36.2
(t), 33.6 (t), 28.3 (t), 25.9 (q), 24.8 (t), 18.1 (s), −4.4
(q), −4.9 (q). CI/NH3 MS m/z 584 ([M+NH4]+, 50),
567 (MH+, 10), 388 (95), 214 (100). IR (neat, cm−1):
3519, 3088, 3065, 3032, 2949, 2928, 2894, 2854, 1737,
1716, 1605, 1684, 1454, 1247, 1121.
13: Mp 149–150°C (CHCl3). (R,R): [h]D −8.25 (c
1.09, CHCl3). 1H NMR: l 7.55–7.43 (m, 2H), 7.40–
7.32 (m, 3H), 7.27–7.24 (m, 3H), 7.10–7.02 (m, 2H),
6.89 (dd, J=10.3, 4.9 Hz, 1H), 6.06 (d, J=10.3 Hz,
1H), 5.16 (d, J=4.9 Hz, 1H), 4.61 (d, J=8.8 Hz,
1H), 4.55 (d, J=8.8 Hz, 1H), 4.12 (s, 1H), 3.69 (s,
3H), 2.99–2.79 (m, 2H), 2.64–2.58 (m, 1H), 2.38–2.33
(m, 1H), 0.86 (s, 9H), 0.14 (s, 3H), 0.10 (s, 3H). 13C
NMR: l 204.1 (s), 193.2 (s), 169.7 (s), 146.7 (d),
136.7 (s), 135.0 (s), 129.7 (d), 128.9 (d), 128.7 (d),
128.3 (d), 128.0 (d), 127.9 (d), 126.6 (d), 109.1 (s),
86.6 (d), 84.6 (d), 66.7 (d), 63.2 (s), 54.7 (d), 53.5 (q),
37.5 (t), 33.4 (t), 25.9 (q), 18.2 (s), −4.5 (q), −4.7 (q).
1.11. 4-(tert-Butyldimethylsilyl)oxy-1-hydroxy-5,8-
dioxo-octahydronaphthalene-4a-carboxylic acid methyl
ester, 2
A solution of alcohol 15 (248 mg, 0.437 mmol) in
EtOAc (27 mL) was hydrogenated for 18 h under
atmospheric pressure in the presence of 10% Pd(OH)2

F.-D. Boyer et al. / Tetrahedron: Asymmetry 14 (2003) 1153–1159
1159
on charcoal (40 mg). The suspension was filtered
through Celite and the resultant solution concentrated
under reduced pressure. The residue was purified by
chromatography on silica gel (EtOAc/cyclohexane,
10:90) to give 110 mg (0.297 mmol, 68%) of 2 as white
solid. Spectroscopic data have been reported:4c
(1S,4S,4aR,8aR) from (1R,2R)-(+)-1,2-diphenyl-1,2-
G.; Descoins, C.; Prange´, T.; Ducrot, P.-H. Eur. J. Org.
Chem. 2003, accepted; (d) Boyer, F.-D.; Descoins, C.;
Ducrot, P.-H. Eur. J. Org. Chem. 2003, accepted.
5. Merrit, A. T.; Ley, S. V. Nat. Prod. Rep. 1992, 9, 243–287.
6. Renard, P.-Y.; Poirel, C.; Lallemand, J.-Y. Tetrahedron:
Asymmetry 1995, 6, 105–106.
7. Konopelski, J. P.; Deng, H.; Schiemann, K.; Keane, J. M.;
Olmstead, M. M. Synlett 1998, 1105–1107.
8. Adam, W.; Bialas, J.; Hadjiarapoglou, L. Chem. Ber. 1991,
124, 2377.
ethanediol:
[h]D
+93.4
(c
1.22,
CHCl3);
(1R,4R,4aS,8aS) from (1S,2S)-(+)-1,2-diphenyl-1,2-
ethanediol: [h]D −89.6 (c 1.20, CHCl3).
9. X-Ray data for 13: Monoclinic, space group P21. Parame-
,
ters: a=12.646(3); b=19.171(5); c=13.630(4) A; i=
105.11(2)°. Z=8 (two independent molecules in a.u.). Data
References
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