A flexible stereocontrolled synthesis of β-hydroxy-α-methyl esters: Application to the synthesis of stegobiol and serricorole

Article abstract of DOI:10.1055/s-1998-2052

β-Hydroxy-α-methyl esters have been obtained in a stereocontrolled manner and high enantiomeric and diastereomeric purity from commercially available methyl 3-oxopentanoate and methyl 3-oxobutanoate. The key step is file catalytic hydrogenation of the carbonyl group using (R)- or (S)-BINAP- Ru as chiral catalyst followed by asymmetric alkylation. Stegobiol and serricorole, components of the sex pheromone of the drugstore beetle, Stegobium paniceum (L.) and cigarette beetle, Lasioderma serricorne (F.), have been prepared from these chiral building blocks without the need for stoichiometric amounts of chiral auxiliaries.

Full text of DOI:10.1055/s-1998-2052

Papers
SYNTHESIS
386
b
a
A Flexible Stereocontrolled Synthesis of -Hydroxy- -methyl Esters:
Application to the Synthesis of Stegobiol and Serricorole
Pilar Gil,* Jesús Razkin, Alberto González
Departamento de Química Aplicada, Universidad Pública de Navarra, Campus Arrosadía, E-31006 Pamplona, Spain
Fax +34(48) 169565; E-mail: pgr@upna.es
Received 30 September 1997
Abstract: b-Hydroxy-a-methyl esters have been obtained in a
stereocontrolled manner and high enantiomeric and diastereomeric
purity from commercially available methyl 3-oxopentanoate and
methyl 3-oxobutanoate. The key step is the catalytic hydrogenation
of the carbonyl group using (R)- or (S)-BINAP-Ru as chiral catalyst
followed by asymmetric alkylation. Stegobiol and serricorole, com-
ponents of the sex pheromone of the drugstore beetle, Stegobium
paniceum (L.) and cigarette beetle, Lasioderma serricorne (F.),
have been prepared from these chiral building blocks without the
need for stoichiometric amounts of chiral auxiliaries.
and purified by column chromatography to afford 2a as a
single diastereomer in 69% yield; deprotection yielded
hydroxy ester 2b with 100% de. After O-silylation (89%)
and hydrolysis of the ester group (83%), pure (2S,3S)-
carboxylic acid 3 was obtained (Scheme 2). The configu-
ration at C-2 and C-3, which will turn into C-1¢and C-2¢,
respectively, in pheromone molecules, is very important
because it has been reported that the wrong stereoisomer
inhibits the action of stegobinone12 and stegobiol.13
Key words: catalytic chiral hydrogenation, (R)- and (S)-BINAP-
Ru, asymmetric alkylation, stegobiol, serricorole
The drugstore beetle, Stegobium paniceum, is a devastat-
ing pest that affects stored food and crops. One of the
components of the sex pheromone of this insect, stegobin-
one was isolated by Kuwahara et al.,1 and the other com-
ponent stegobiol was isolated by Kodama et al.2
Stegobinone has also been reported to be the attractant of
the furniture beetle, Anobium punctatum.3 Chuman et al.4
reported the isolation of serricorole and serricorone, two
components of the sex pheromone produced by females of
the cigarette beetle, Lasioderma serricorne, a serious pest
that damages cured tobacco leaves and dry foodstuffs.
Later, Imai et al.5 found that this insect also uses serri-
corone as oviposition deterrent.
Once the exact stereochemistry of stegobiol and stego-
binone was established,6 the first asymmetric synthesis of
these pheromones was achieved in 1986 by Mori et al.7
from enantiopure hydroxy esters of microbial origin. The
next synthesis via chiral boronic esters followed by aldol
condensation was reported in the 1990s by Matteson et
al.8 As for serricorole, Mori,s group9 applied the same ap-
proach used for stegobiol and Oppolzer et al.10 used chiral
sultams in an asymmetric aldol condensation to obtain the
target compound.
Scheme 1
During the course of our work on the synthesis of optical-
ly active pheromones, we recently described a stereose-
lective synthesis of sitophilate and sitophilure,11
aggregation pheromones for several species of Sitophilus
weevils, which devastate stored cereal grains. We now re-
port the synthesis of stegobiol, stegobinone, serricorole
and serricorone based on a common strategy for the prep-
aration of the key synthetic intermediates. Retrosynthetic
Reagents and conditions: i) a: 3,5-DNB acid, DCC, DMAP (69%); b:
KOH 1M, THF/MeOH, 0°C (96%); c: TBDMSCl, DMF, r.t. (89%);
analysis (Scheme 1) shows an oxo ester in each case which ii) KOH 3M, MeOH, reflux (83%).
upon disconnection leads to the three required synthetic
intermediates: a protected hydroxy acid 3 with anti-stere-
ochemistry, common to both pheromones, and two hy-
droxy ketones, 9 and 16, with relative syn-configuration.
The synthesis of carboxylic acid 3 (Scheme 2) started with
the hydroxy ester 1, intermediate in our synthesis of sito-
phi]ate, which was converted into its 3,5-dinitrobenzoate
Scheme 2
Using a similar strategy to that employed in the synthesis
of sitophilure,11 the preparation of hydroxy ketone 9
(Scheme 3) was achieved from oxo ester 4 (readily avail-
able through transesterification of commercial methyl 3-
oxopentanoate). The first step, key in the synthesis, was

April 1998
SYNTHESIS
387
the asymmetric hydrogenation of 4 using (R)-BINAP-Ru The third synthetic intermediate required, 16, was ob-
as catalyst.14 The reaction proceeded smoothly under 4
tained as shown in Scheme 4 starting from methyl 3-oxo-
bar in a simple hydrogenation apparatus and enantiopure
hydroxy ester 5 was obtained in 97% yield on 11 g scale.
The enantiomeric purity (≈100% ee) was determined by
chiral GC and the absolute configuration assigned by
comparison of optical rotation with the enantiomer.
Asymmetric alkylation afforded the anti-diastereoisomer
6 as the major product15a in almost quantitative yield. The
dianion of the new hydroxy ester 5 was generated with
LDA, in the presence of LiCl15b and using an excess of
BuLi.15c Mitsunobu inversion16 using 3,5-dinitrobenzoic
acid, triphenylphosphine and diethyl azodicarboxylate
(DEAD), afforded after purification by column chroma-
tography, 7a as a single diastereomer in 63% yield. Re-
moval of the dinitrobenzoate group from 7a yielded pure
7b. Protection of hydroxyl group in 7b with 3,4-dihydro-
2H-pyran (DHP) afforded 7c in 96% yield. Reduction of
7c with diisobutylaluminum hydride (DIBAL) converted
the ester group to the corresponding aldehyde in quantita-
tive yield at –100°C (as shown by GC). Due to its insta-
bility, the aldehyde was treated without further
purification with ethylmagnesium bromide to give 8 in
82% yield after column chromatography. The results in
Table 1 show the yield of reaction products formed, there-
by revealing the role of solvent in the DIBAL reduction.
Thus, for substrate 7c, dichloromethane was the solvent of
choice because when DIBAL in THF was used, only pri-
mary alcohol 7d was detected as the reaction product. In
the last step, oxidation of secondary alcohol 8 with sodi-
um hypochlorite under mild conditions17 yielded only
the ketone 9 (69%) as the main product due to the cleav-
age of tetrahydropyranyl (THP) group under the acidic
(HCl) workup conditions. Alternatively, Swern
oxidation18 of 8 followed by deprotection afforded 9 in a
butanoate (10). The sequence was similar to the previous
one, but with two modifications compared to the bulkier
ester 4. First, the alkylation step yielded hydroxy ester 12
in a higher diastereomeric excess (92%) and second, when
the protected ester 13c was treated with DIBAL in dichlo-
romethane, in contrast to that of 7c, the corresponding pri-
mary alcohol was the main reaction product (see Table 1).
Based on these results, the methyl ester 13c was treated
with LiAlH4 to give the primary alcohol 14, which was
oxidized to the intermediate aldehyde, then reacted with
ethylmagnesium bromide to give 15 in 73% yield. Thus in
this case an additional step was required to obtain the sec-
ondary alcohol 15. For the last step, oxidation to hydroxy
ketone 16, the results were similar to the other case.
slightly higher yield (76%) (Scheme 3). However, the Reagents and conditions: i) H2, (R)-BINAP-Ru, 4 atm, 75°C (97%);
ii) LDA,LiCl then MeI, –30°C (>99%); iii) a) Mitsunobu (74%), b)
deprot. (85%); c) DHP (95%); iv) LAH, Et2O, 0°C (94%); v ) Swern,
then EtMgBr (73%), vi) NaOCl, TEMPO (65%); vii) Swern, then PP-
TS, MeOH, reflux (75%).
lower yield of the first procedure is compensated by
much shorter reaction time and milder reaction condi-
tions.
Scheme 4
Table 1. Reduction of Esters 7c and 13c with DIBALa
Substrate
Solvent
Aldehydeb,c
Yield (%)
Alcoholb,c
Yield (%)
7c
7c
7c
13c
13c
CH2Cl2
THF
Hexane
CH2Cl2
THF
100
0
75
33
0
0
100
25
66
100
a 1.5 equiv at –l00°C for 1 h.
b The structures of intermediate aldehyde and the final reduction prod-
uct alcohol are not depicted in Schemes 3 and 4.
c Yield determined by GC.
Reagents and conditions: i) H2, (R)-BINAP-Ru, 4 atm, 75°C (97%);
ii) LDA,LiCl then MeI, –30°C (>99%); iii) a) Mitsunobu (63%), b)
deprot. (91%); c) DHP (96%); iv) DIBAL(CH2Cl2), then EtMgBr
(82%); v) NaOCl, TEMPO (69%); vi) Swern oxidation, then PPTS,
MeOH, reflux (76%).
In all cases, 13C NMR was a very helpful tool to follow the
course of the alkylation step and to assign the relative
stereochemistry of b-hydroxy-a-methyl esters. Table 2
shows the chemical shift values for diastereomeric com-
pounds 2b and 7b. There is an upfield shift of the carbons
Scheme 3

388
Papers
SYNTHESIS
in the syn-isomer as compared with those of the anti-iso- respectively. The synthesis starts with commercially
mer. This shift is smaller for methine carbons than for the available and cheap materials and the chiral catalyst was
other two in agreement with the literature data for other b- used in a substrate/catalyst ratio of 2100, making the
hydroxycarbonyl compounds.19
present method suitable to large scale preparation.
Table 2. 13C NMR Chemical Shift Values for Diastereomeric b-Hy-
droxy-a-methyl-Esters
Solvents were dried by distillation from drying agents as follows:THF,
Et2O (Na-benzophenone); benzene, toluene (Na); CH2Cl2, hexane
(P2O5); MeOH, EtOH (Mg).Column chromatography was performed
by using 230–400 mesh silica gel. 1H and 13C NMR spectra were re-
corded in CDCl3 solutions on a Varian Gemini 200. GC analysis was
conducted in a Shimazu GC-l4B, equipped with a FID detector using
He as carrier gas; capillary columns were used: TRB-1 (30 m´
0.25 mm) and b-DEX 110 (30 m ´ 0.25 mm). Elemental analyses were
performed in a Carlo Erba EA 1108 Analyzer. IR spectra were recorded
on a Nicolet 510M FT-IR as films or KBr pellets. Optical rotations
were measured using a JASCO-DIP-370 polarimeter. Hydrogenations
were conducted in a Parr 3911 shaker-type hydrogenation apparatus.
Product
13C NMR (CDCl3/TMS), d
CH
C–OH
CH3
2b (anti)
7b (syn)
45.11
44.32
74.68
73.05
14.69
11.08
Once the three building blocks containing all stereo-
centers in the correct configuration required for the target
pheromones have been obtained, we proceeded to esterify
3 with 16 and 9 to obtain the oxo esters 17 and 18, respec-
tively (Scheme 5). Thus, activation of carboxylic acid 3
with 2,6-dichlorobenzoyl chloride7 and then reaction with
the corresponding hydroxy ketone, furnished 17 or 18 in
83% and 86% respectively after purification by column
chromatography. The next step, synthesis of the dihydro-
pyranone ring, was accomplished by Ti-mediated cycliza-
tion.10 After removal of TBDMS group with aqueous HF
and purification, stegobiol and serricorole were obtained
in 62% and 64% yield, respectively. Optical rotation val-
ues were in agreement with reported data.8a,10a These
pheromones were easily converted to pure stegobinone
and serricorone in a single oxidation step, and the analyt-
ical and spectral data were also in accord with litera-
ture.7b,9
1-Ethylpropyl (2S,3S)-3-(3,5-Dinitrobenzoyloxy)-2-methylpen-
tanoate (2a):
A solution of 111 (6.87 g, 32 mmol), 1,3-dicyclohexylcarbodiimide
(DCC) (8.65 g, 42 mmol) and 4-dimethylaminopyridine (DMAP)
(0.61 g, 5 mmol) in anhyd CH2Cl2 (90 mL) was cooled to 0°C and 3,5-
dinitrobenzoic acid (8.92 g, 42 mmol) was added. The mixture was
stirred overnight at r.t., diluted with Et2O (180 mL) and the stirring
was continued for 1 h. The solid formed was filtered and the solvent
removed to yield the crude product which after column chromatogra-
phy on silica gel with hexane/EtOAc (15:1) as eluent afforded 8.8 g
(69%) of pure 2a as a white solid; mp 71–73°C; [a]D24 +23.4 (c = 1,
CHCl3).
IR (KBr): n = 1729 (C=O), 1551,1347 cm–1 (NO2).
1H NMR: d = 0.69–0.82 (2 t, J = 7.2 Hz, 6 H), 0.92 (t, J = 7.4 Hz, 3
H), 1.19 (d, J = 7.1 Hz, 3 H), 1.47 (qnt, J = 7.1 Hz, 4 H), 1,64–1.94
(m, 2 H), 2.90 (qnt, J = 7.2 Hz, 1 H), 4.65 (qnt, J = 6.2 Hz, 1 H), 5.34
(dt, J = 7.3 and 4.4 Hz, 1 H), 9.02 (d, J = 2.1 Hz, 2 H), 9.11 (t, J =
2.1 Hz, 1 H).
13C NMR: d = 9.34, 9.64, 13.67, 24.29, 26.43, 43.21, 77.20, 78.82,
122.33*, 129.28*, 133.87*, 148.54*, 161.79*, 172.87 (* DNB).
Anal. calcd. for C18H24N2O8: C, 54.54; H, 6.10; N, 7.07. Found: C,
54.51; H, 6.15; N, 7.03.
1-Ethylpropyl (2S,3S)-3-Hydroxy-2-methylpentanoate (2b):
To a solution of 2a (2.2 g, 5.6 mmol) in THF/MeOH (15 mL,1:1) was
slowly added an aq solution of 1M KOH (5 mL) at 0°C. The purple
solution was stirred for 2 h and then quenched with satd aq NH4Cl
soln. The aqueous layer was extracted with Et2O, the organic layer
washed with brine, dried (MgSO4) and concentrated in vacuo to give
a liquid which was purified by distillation yielding 1.1 g (96%) of 2b
as a colorless liquid; bp 96–98°C/1 Torr; [a]D21 +6.1 (c = 1.02,
CHCl3) {Lit20 [a]D21 + 6.0 (c = 1.04, CHCl3)}.
IR (Neat): n = 3465 (OH), 1725 cm–1 (C=O).
1H NMR: d = 0.83 (t, J = 7.4 Hz, 6 H), 0.93 (t, J = 7.4 Hz, 3 H), 1.17
(d, J = 7.2 Hz, 3 H), 1.31–1.63 (m, 6 H), 2.48 (qnt, J = 7.2 Hz, 1 H),
2.79 (d, J = 7 Hz, 1 H), 3.35–3.62 (m, 1 H), 4.74 (qnt, J = 6.2 Hz, 1
H).
Reagents and conditions: i) 2,6-dichlorobenzoyl chloride, Et3N, then
16 and DMAP (83%); ii) TiCl4, i-Pr2EtN, –10°C, then HF aq., 0°C;
iii) Swern; iv) as i) but cmpound 9 (86%).
13C NMR: d = 9.74, 10.05, 14.69, 26.61, 27.75, 45.11, 74.68, 76.97,
176.0.
Scheme 5
1-Ethylpropyl (2S,3S)-3-tert-Butyldimethylsilyloxy-2-methylpen-
tanoate (2c):
In summary, the method reported here provides a highly
stereoselective route to b-hydroxy-a-methyl esters and
derivatives, an alternative to asymmetric aldol condensa-
tion. As illustrated in Scheme 6, this procedure allows
versatile access to any of the four stereoisomers in a pre-
dictable way and high enantio- and diastereomeric purity.
The key step is catalytic asymmetric hydrogenation using
(R)- or (S)-BINAP which lead to (R)- or (S)-hydroxy ester,
Imidazole (0.8 g, 12 mmol) and tert-butyldimethylsilyl chloride (TB-
DMSCl, 1.13 g, 7.5 mmol) were added to a stirred solution of 2b
(1.1 g, 5.34 mmol) in anhyd DMF (10 mL). The mixture was stirred
overnight at r.t. and then poured into ice-water and extracted with
Et2O (4 ´ 25 mL). The Et2O solution was washed with H2O and brine,
dried (MgSO4) and concentrated. The residue was distilled to give 1.5
g (89%) of 2c as a colorless liquid; bp 108–110 °C/1 Torr; [a]D21 +17.2
(c = 1, CHCl3) {Lit20 [a]D19 +17.3 (c = 1.07, CHCl3)}.
IR (Neat): n = 1735 cm–1 (C=O).

April 1998
SYNTHESIS
389
Scheme 6
1H NMR: d = 0.01 (s, 3 H), 0.02 (s, 3 H), 0.84 (s, 9H, t, J = 7.5 Hz,
9H), 1.05 (d, J = 7.3 Hz, 3 H), 1.31–1.61 (m, 4 H), 2.59 (dq, J = 7.1
and 5.7 Hz, 1 H), 3.90 (q, J = 5.5 Hz, 1 H), 4.69 (qnt, J = 6.1 Hz, 1 H).
13C NMR: d = –4.69*, –4.51*, 9.44, 9.57, 11.57, 18.10*, 25.75*,
25.85*, 26.20, 26.28, 45.34, 74.26, 76.23, 174.25 (* TBDMS).
After flushing several times with H2, this was pressurized to 4 bar.
The mixture was heated at 75°C for 8 h with magnetic stirring and
continuous H2 supply. After cooling, the excess H2 was removed and
the apparatus disassembled. The orange solution was concentrated
and the residue purified by distillation to afford 11.14 g (97%) of 5 as
a colorless liquid. GC: capillary column: b-DEX 110, temp. 120°C,
Rt 24.52 min., single peak (determined as acetate derivative); bp
72–74°C /0.9 Torr; [a]D22 –26.91 (c = 0.53, CHCl3).
(2S,3S)-3-tert-Butyldimethylsilyloxy-2-methylpentanoic Acid (3):
To a solution of 2c (2.1 g, 6.6 mmol) in MeOH (30 mL) was slowly
added an aq solution of 3 M KOH (9 mL) and the mixture was stirred
under reflux for 36 h. The mixture was concentrated, diluted with
H2O (25 mL), and extracted with Et2O (2´20 mL). The aqueous
phase was acidified with AcOH to pH 5 and extracted with Et2O (3 ´
20 mL). Evaporation of Et2O afforded a liquid which upon distillation
yielded 1.35 g (83%) of 3; bp 144–146°C/1.1 Torr; [a]D24 +13.0 (c =
1.3, CHCl3) {Lit10a [a]DD22 +13.08 (c = 1.36, CHCl3)}.
IR (Neat): n = 3450 (OH), 1733 cm–1 (C=O).
1H NMR: d = 0.77 (t, J = 7.5 Hz, 6 H), 0.85 (t, J = 7.4 Hz, 3 H),
1.30–1.57 (m, 6 H), 2.29 (dd, J = 16.1 and 8.3 Hz, 1 H), 2.41 (dd, J =
16.1 and 4.0 Hz, 1 H), 3.23 (d, J = 4.1 Hz, 1 H), 3.72–3.93 (m, 1 H),
4.69 (qnt, J = 6.2 Hz, 1 H).
13C NMR: d = 9.56, 9.81, 26.37, 29.41, 41.15, 69.30, 77.00, 172.70.
IR (Neat): n = 3500–2500 (OH), 1711 cm–1 (C=O).
1H NMR: d = 0.02 (s, 3 H), 0.04 (s, 3 H), 0.85 (s, 9H, t, J = 7.3 Hz, 3
H), 1.09 (d, J = 7.0 Hz, 3 H), 1.50 (dq, J = 7.5 and 5.3 Hz, 2 H), 2.63
(qnt, J = 6.8 Hz, 1 H), 3.87 (q, J = 6.1 Hz, 1 H), 11.6 (br s, 1 H).
13C NMR: d = –4.94*, –4.38*, 8.65, 12.41, 18.05*, 25.79*, 26.15,
44.83, 74.46, 181.01 (* TBDMS).
1-Ethylpropyl (2R,3R)-3-Hydroxy-2-methylpentanoate (6):
To a suspension of LiCl (6.78 g, 160 mmol) in anhyd THF (40 mL),
was added diisopropylamine (9.5 mL, 66.4 mmol). After cooling at
–78°C, a 2.5 M solution of BuLi in hexane (26.6 mL, 66.4 mmol) was
added dropwise under N2. After stirring for 1 h at 0°C, the LDA so-
lution was cooled to –78°C and compound 5 (5 g, 26.56 mmol) in
THF (15 mL) was added dropwise. The mixture was then stirred at
–30°C for 2 h. Another portion of BuLi (26.6 mL, 66.4 mmol) was
added at –78°C and the mixture was allowed to react for 2 h at –30°C.
The dianion thus formed was cooled to –78°C and MeI (8.5 mL,
133 mmol) in THF (6 mL) was added keeping the mixture at –30°C
for 1.5 d in a freezer. The reaction was quenched with satd aq NH4Cl
solution. After usual workup, 5.3 g of 6 was obtained. GC analysis
showed that conversion was >99% and diastereomeric excess 80%;
capillary column: TRB-1, temp. 120°C, Rt 7.91 min (anti), Rt
8.07 min (syn).
1-Ethylpropyl (R)-3-Hydroxypentanoate (5):
Following the procedure used for its enantiomer,11 a 25 mL flask was
charged with benzeneruthenium(II) chloride dimer (6.9 mg,
0.0137 mmol), (R)-BINAP21 (18 mg, 0.029 mmol) and anhyd DMF
(1 mL) under N2. The resulting suspension was stirred at 100°C for
10 min, DMF was then eliminated under vacuum yielding a reddish
solid which was taken up in anhyd MeOH (10 mL). The solution was
transferred to a previously degassed 250 mL Parr bottle containing 4
(11.35 g, 0.061 mol) and MeOH (20 mL). The bottle, provided with a
heating mantle, was assembled in the Parr hydrogenation apparatus.

390
Papers
SYNTHESIS
1-Ethylpropyl (2R,3S)-2-Methyl-3-(3,5-dinitrobenzoyloxy)pen- (4S,5S)-5-Tetrahydropyranyloxy-4-methylheptan-3-ol (8):
tanoate (7a): Following the above mentioned procedure, 7c (2.3 g, 8 mmol) was re-
A mixture of 6 (5.1 g, 25.8 mmol), Ph3P (13.66 g, 51.5 mmol), and acted with 1M DIBAL solution in CH2Cl2 (12 mL, 12 mmol), and af-
3,5-dinitrobenzoic acid (11.05 g, 51.5 mmol) in anhyd THF (90 mL) ter workup, gave 1.76 g (quantitative yield by GC) of the
was stirred and cooled to 0°C under N2. To the mixture was added corresponding aldhehyde that was used for the next step without fur-
dropwise DEAD (8.1 mL, 51.5 mmol) and stirred for 2 d at r.t. The ther purification. To a solution of the aldehyde (1.76 g) in Et2O
reaction was monitored by observing changes in color: yellow, blue- (20 mL) was added dropwise a 1M solution of EtMgBr in THF (16
greenish, dark blue, red, orange and finally yellow again. Hexane mL, 16 mmol) at –15°C and the mixture was stirred for 15 min., and
(60 mL) and Et2O (20 mL) were added to the mixture, and stirring then quenched with aq sat. NH4Cl solution. After workup, the liquid
was continued for 1 h. After filtration and concentration of the filtrate obtained was purified by chromatography to give 1.52 g (82%) of 8;
in vacuo, the residue was chromatographed on silica gel. Elution with bp 109–111°C/0.9 Torr; [a]D22 –14.5 (c = 1.05, CHCl3).
hexane/EtOAc (15:1) afforded 6.5 g (63%) of 7a as a single diastere- IR (Neat): n = 3454 cm–1 (OH).
omer; mp 34–35°C; [a]D24 +6.66 (c = 1.12, CHCl3) { Lit20 [a]D22 +6.61 1H NMR: d = 0.55–0.86 (m, 9 H), 1.10–1.76 (m, 11 H, 6 H, THP),
(c = 1.01, CHCl3)}.
2.95 (br s, 1 H), 3.20–3.60 (m, 3 H, 1 H, THP), 3.60–3.85 (m, 1 H,
THP), 4.35–4.62 (m, 1 H, THP).
IR (KBr): n = 1730 (C=O), 1547,1341 cm–1 (NO2).
1H NMR: d = 0.78 (t, J = 7.3 Hz, 6 H), 0.92 (t, J = 7.4 Hz, 3 H), 1.23
(d, J = 7.1 Hz, 3 H), 1.48 (qnt, J = 7.1 Hz, 4 H), 1.67–l.87 (m, 2 H),
2.82 (dq, J = 7.1 and 5.5 Hz, 1 H), 4.67 (qnt, J = 6.1 Hz, 1 H), 5.38
(dt, J = 5.7 and 5.4 Hz, 1 H), 9.05 (d, J = 2.1 Hz, 2 H), 9.14 (t, J =
2.1 Hz, 1 H).
(4R,5S)-5-Hydroxy-4-methylheptan-3-one (9):
Method A: To a solution of 8 (0.65 g, 2.82 mmol) and 2,2,6,6-tetra-
methyl-1-piperidinyloxy free radical (TEMPO, 5 mg, 0.03 mmol) in
CH2Cl2 (10 mL) was added a solution of KBr (36 mg, 0.3 mmol) in
H2O (1 mL). The mixture was cooled to 0°C and vigorously stirred.
Then a 1.16 M aq NaOCl solution (17 mL, 19.72 mmol, pH 9.5) was
added. After 20 min., the organic phase was separated and the aque-
ous phase extracted with CH2Cl2. The organic extract was washed
with 6% aq HCl (25 mL) containing KI (0.4 g) by stirring the biphasic
system for 20 min. The organic phase was treated with (2 ´ 30 mL)
of 10% aq Na2S2O3, then with H2O, and dried (Na2SO4). The residue
obtained after evaporation of the solvent was purified by column
chromatography (hexane/EtOAc, 10:1) to furnish 0.28 g (69%) of 9.
GC: capillary column TRB-1, temp. 120°C, Rt 3.32 min (single
peak); bp 59–61°C/0.9 Torr; [a]D22 –27.2 (c = 1.5, Et2O) {Lit22:
[a]D20 –26.7 (c = 1.52, Et2O)}.
13C NMR: d = 9.56, 9.96, 12.39, 24.94, 26.28, 42.97, 77.24, 78.42,
122.26*, 129.27*, 133.81*, 148.48*, 161.83*, 172.90 (* DNB).
Anal. calcd. for C18H24N2O8 C, 54.54; H, 6.10; N, 7.07. Found: C,
54.50; H, 6.14; N, 7.04.
1-Ethylpropyl (2R,3S)-3-Hydroxy-2-methylpentanoate (7b):
Removal of DNB group was done using the procedure as described
for 2b. Thus, from 7a (7.57 g, 19.1 mmol), 3.53 g (91%) of 7b was
obtained as a single diastereomer; bp 105–107°C/1.1 Torr; [a]D24
+4.16 (c = 1.5, CHCl3) {Lit20 [a]D24 +4.1 (c = 1.46, CHCl3)}.
IR (Neat): n = 3484 (OH), 1719 cm–1 (C =O).
1H NMR: d – 0.74 (t, J = 7.5 Hz, 6 H), 0.83 (t, J = 7.3 Hz, 3 H), 1.05
(d, J = 7.2 Hz, 3 H), 1.22–1.53 (m, 6 H), 2.38 (dq, J = 7.1 and 4.4 Hz,
1 H), 2.92 (d, J = 4.8 Hz, 1 H), 3.56–3.72 (m, 1 H), 4.64 (qnt, J = 6.2
Hz, 1 H).
IR (Neat): n = 3466 (OH), 1706 cm–1 (C=O).
1H NMR: d = 0.83 (t, J = 7.4 Hz, 3 H), 0.93 (t, J = 7.3 Hz, 3 H), 1.01
(d, J = 7.1 Hz, 3 H), 1.18–1.45 (m, 2 H), 2.31–2.58 (m, 3 H), 2.99 (br
s, 1 H), 3.60–3.75 (m, 1 H).
13C NMR: d = 9.38, 10.17, 11.08, 26.27, 26.85, 44.32, 73.05, 76.57,
175.71.
13C NMR: d = 7.30, 10.05, 10.23, 26.86, 34.90, 49.53, 72.55, 216.01.
Method B: To a cooled (–70°C) and stirred solution of oxalyl chloride
(0.3 mL, 3.46 mmol) in anhyd CH2Cl2 (6 mL) was added dropwise a
solution of DMSO (0.3 mL, 4.32 mmol) and the mixture was stirred
for 20 min. Then a solution of 8 (0.4 g, 1.73 mmol) in CH2Cl2 (4 mL)
was added dropwise. The mixture was kept for 1.5 h at –70°C, then i-
Pr2EtN (1.5 mL, 8.65 mmol) was added and the stirring was contin-
ued for 20 more min. The mixture was allowed to warm to 0°C, stirred
for 20 min at this temp. and partitioned between a mixture of H2O (20
mL) and benzene/Et2O (4:1, 25 mL). The organic layer was washed
with brine, dried (MgSO4) and concentrated in vacuo to yield 0.43 g
of a yellowish liquid. This was taken up in anhyd MeOH (5 mL), then
pyridinium p-toluenesulfonate (PPTS, 0.1 g, 0.4 mmol) was added
and the mixture was refluxed for 3 h. After usual workup, a liquid was
obtained which upon purification by column chromatography, afford-
ed 0.19 g (76%) of 9 as a colorless liquid and identical physical and
spectroscopic data as mentioned above.
1-Ethylpropyl
tanoate (7c):
(2R,3S)-3-Tetrahydropyranyloxy-2-methylpen-
Protection of hydroxyl group as tetrahydropyranyl ether was accom-
plished by reacting 7b (1.7 g, 8.40 mmol) with DHP (1.61 mL,
16.32 mmol) in the presence of PPTS as a catalyst. Compound 7c was
obtained in 96% yield as a colorless liquid; bp 148–150°C/1.4 Torr;
[a]D22 –14.80 (c = 1, CHCl3).
IR (Neat): n = 1731 cm–1 (C =O).
1H NMR: d = 0.60–0.85 (m, 9H), 0.93–1.10 (2 d, J = 7.1 Hz, 3 H),
1.23–1.73 (m, 12 H, 6 H, THP), 2.40–2.57 (m, 1 H), 3.21–3.37 (m, 1
H, THP), 3.58–3.83 (m, 2 H, 1 H, THP), 4.49 (t, J = 3.3 Hz, 1 H,
THP), 4.58 (qnt, J = 6.1 Hz, 1 H).
13C NMR: d = 8.62, 9.27, 9.57, 11.68, 13.30, 19.41*, 19.65*, 23.56*,
25.24, 25.72*, 25.99, 30.65*, 30.71*, 42.45, 43.42, 62.05*, 62.37*,
75.93, 76.06, 77.54, 79.84, 96.66*, 99.08*, 174.19 (* THP).
(2S,3S)-3-Tetrahydropyranyloxy-2-methylpentan-1-ol (7d):
A solution of 7c (1.97 g, 6.88 mmol) in anhyd Et2O (20 mL) was
cooled to –100°C and a 1M THF solution of DIBAL (21 mL,
21 mmol) was added dropwise. The mixture was stirred for 1 h and
then MeOH (4 mL) was added. The mixture was allowed to warm to
r.t. and poured into a sat. solution of Rochelle salts. After stirring for
1 h, the aqueous layer was extracted with Et2O, the organic layer was
dried (MgSO4) and the solvent removed to give after distillation 1.2 g
(86%) of 7d as a colorless liquid; bp 122–124°C/1.3 Torr; [a]D24 +8.9
(c = 1, CHCl3).
Methyl (R)-3-Hydroxybutanoate (11):
Prepared as described for 5 by hydrogenation of 10 (28 g, 0.24 mol)
using (R)-BINAP (71 mg, 0.115 mmol). After workup and purifica-
tion by distillation, 27.7 g (97%) of 11 was obtained; bp 34–36°C/
0.9 Torr; [a]D25 –23.5 (neat) { Lit14c [a]D25 –23.1/–23.6 (neat)}.
IR (Neat): n = 3440 (OH), 1735 cm–1 (C =O).
1H NMR: d = 1.08 (d, J = 6.2 Hz, 3 H), 2.32 (d, J = 6.6 Hz, 2 H), 3.30
(br s, 1 H), 3.55 (s, 3 H), 4.05 (sext, J = 6.3 Hz, 1 H).
13C NMR: d = 22.38, 42.65, 51.40, 63.95, 172.65.
IR (Neat): n = 3438 cm–1 (OH).
1H NMR: d = 0.68–1.00 (m, 6 H), 1.25–1.99 (m, 9 H, 6 H, THP),
3.32–3.94 (m, 6 H, 2 H, THP), 4.39–4.66 (m, 1 H, THP).
13C NMR: d = 9.83, 10.62, 10.87, 11.73, 20.13*, 21.72*, 24.02,
24.96*, 25.23 *, 25.51, 31.24*, 31.51*, 36.81, 37.68, 63.10*, 64.89*,
65.44, 65.56, 78.77, 81.43, 98.65*, 101.10* (* THP).
Methyl (2R,3R)-3-Hydroxy-2-methylbutanoate (12):
Under the same conditions described for 6, asymmetric alkylation of
11 (5.1 g, 43 mmol) afforded 5.7 g (quant. yield) of 12 (92% de) as
shown by GC: capillary column TRB-1, temp. 80°C, Rt 3.81 min (an-
ti), Rt 3.98 min (syn).

April 1998
SYNTHESIS
(4R,5S)-5-Hydroxy-4-methylhexan-3-one (16):
Analogous to the preparation of compound 9, oxidation of 15 was
done by two different methods.
391
Methyl (2R,3S)-2-Methyl-3-(3,5-dinitrobenzoyloxy)butanoate (13a):
As described for compound 7a, Mitsunobu inversion of 12 (5.7 g,
43 mmol) with Ph3P (22.82 g, 86 mmol), 3,5-dinitrobenzoic acid
(18.46 g, 86 mmol) and DEAD (13.53 mL, 86 mmol) yielded, after
purification, 10.44 g (74%) of 13a as a white solid. GC: capillary col-
umn TRB-1, temp. 250°C, Rt 5.11 min. (single peak), mp 67–68°C;
[a]D23 +12.9 (c = 1, CHCl3).
Method A: From 15 (0.25 g, 1.16 mmol), TEMPO (2 mg,
0.018 mmol), KBr (21 mg, 0.18 mmol), 1.2 M NaOCl (6.6 mL,
8 mmol), 6% HCl (20 mL), KI (0.32 g). After column chromatogra-
phy, 98 mg (65%) of 16 was obtained; bp 50–52°C/1.4 Torr; [a]D21
–30.0 (c = 1.31, Et2O) {Lit7b [a]D21 –30.2 (c = 1.43, Et2O)}.
IR (Neat): n = 3423 (OH), 1708 cm–1 (C=O).
IR (KBr) : n = 1746, 1725 (C=O), 1549, 1347 cm–1 (NO2).
1H NMR: d = 1.27 (d, J = 7.2 Hz, 3 H), 1.41 (d, J = 6.5 Hz, 3 H), 2.83
(dq, J = 7.1 and 5.4 Hz, 1 H), 3.69 (s, 3 H), 5.46 (dq, J = 6.4 and 5.4
Hz, 1 H), 9.07 (d, J = 2.1 Hz, 2 H), 9.17 (t, J = 2.1 Hz, 1 H).
13C NMR: d = 12.23, 17.30, 43.95, 51.97, 73.80, 122.20*, 129.20*,
133.80*, 148.41*, 161.45*, 173.28 (* DNB).
1H NMR: d – 0.95 (t, J = 7.2 Hz, 3 H), 1.04 (d, J = 7.5 Hz, 3 H), 1.05
(d, J = 6.0 Hz, 3 H), 2.34–2.60 (m, 3 H), 3.07 (br s, 1 H), 3.89–4.07
(m, 1 H).
13C NMR: d – 7.59, 10.60, 20.10, 35.39, 51.17, 67.44, 216.37.
Method B: From 15 (0.25 g, 1.16 mmol), oxalyl chloride (0.2 mL,
2.31 mmol), DMSO (0.2 mL, 2.88 mmol), i-Pr2EtN (1 mL,
5.77 mmol), and PPTS (50 mg, 0.2 mmol), 113 mg (75%) of 16 was
obtained.
Anal. calcd. for C13H14N2O8: C, 47.86; H, 4.32; N, 8.59. Found: C,
47.87; H, 4.30; N, 8.61.
Methyl (2R,3S)-3-Hydroxy-2-methylbutanoate (13b):
To a solution of 13a (3 g, 9.19 mmol) in THF/MeOH (25 mL, 4:1)
was added a solution of KOH (0.132 g, 2 mmol) in MeOH (6 mL).
After stirring the mixture for 2 h at 0°C, usual workup and purifica-
tion afforded 1.03 g (85%) of 13b, GC: column TRB-1, temp. 80°C,
Rt 3.98 min (single peak); bp 115–117°C/18 Torr; [a]D25 –13.6 (c =
0.5, MeOH) {Lit23 [a]D25 –13.4 (c = 0.51, MeOH)}.
(1¢S,2¢R)-1¢,2¢-Dimethyl-3¢-oxopentyl (2S,3S)-3-tert-Butyldimeth-
ylsilyloxy-2-methylpentanoate (17):
To a mixture of 3 (0.25 g, 1 mmol) and Et3N (0.16 mL, 1.1 mmol) in
anhyd THF (8 mL) was added 2,6-dichlorobenzoyl chloride
(0.15 mL, 1.1 mmol) under a N2 atmosphere. The mixture was stirred
overnight at r.t. After filtration and removal of the solvent, the residue
was dissolved in anhyd benzene (6 mL). To the mixture were added a
solution of 16 (0.1 g, 0.77 mmol) in anhyd benzene (2 mL) and
DMAP (0.104 g, 0.85 mmol) in benzene (2 mL). The resulting mix-
ture was stirred for 6 h at 0°C and then overnight at r.t. lt was diluted
with Et2O (20 mL), washed with 1M HCl, H2O, aq NaHCO3, brine,
dried (MgSO4) and concentrated in vacuo. The residue was purified
by chromatography on silica gel (hexane/EtOAc, 50:1) to give 0.23 g
(83%) of 17 as a colorless liquid.
IR (Neat): n = 3469 (OH), 1738 cm–1 (C = O).
1H NMR d = 0.92 (d, J = 2.3 Hz, 3 H), 0.95 (d, J = 3.2 Hz, 3 H), 2.24
(dq, J = 7.1 and 5.2 Hz, 1 H), 3.30 (d, J = 5.3 Hz, 1 H), 3.45 (s, 3 H),
3.76 (sext, J = 5.6 Hz, 1 H).
13C NMR: d = 11.31, 19.93, 45.77, 51.19, 67.74, 175.50.
Methyl (2R,3S)-3-Tetrahydropyranyloxy-2-methylbutanoate (13c):
As described for 7c, DHP protection of 13b (2 g, 15.14 mmol) yielded
13c (3.1 g, 95%); bp 91–93°C/1 Torr; [a]D22 +12.1 (c = 1, CHCl3).
IR (Neat): n = 1740 cm–1 (C=O).
1H NMR: d = 1.02 (pseudo t, J = 6.8 Hz, 3 H), 1.08–1.13 (2d, J =
2.9 Hz, 3 H), 1.26–1.73 (m, 6 H, THP), 2.41 (qnt, J = 6.6 Hz, 1 H),
3.24–3.44 (m, 1 H, THP), 3.54 (d, J = 2.2 Hz, 3 H), 3.60–3.99 (m, 2
H, 1 H, THP), 4.45–4.62 (2t, J = 3.2 Hz, 1 H, THP).
IR (Neat): n = 1735 (C=O, ester), 1718 cm–1 (C=O, ketone).
1H NMR: d = 0.01 (s, 3 H), 0.02 (s, 3 H), 0.83 (s, 9H, t, J = 7.3 Hz, 3
H), 0.90–1.20 (m, 12 H), 1.28–1.51 (m, 2 H), 2.36–2.78 (m, 4 H), 3.84
(dq, J = 5.9, 1.2 Hz, 1 H), 5.09 (qnt, J = 6.1 Hz, 1 H).
13C NMR: d = 12.09, 12.45, 16.79, 19.15*, 19.58, 19.71*, 25.30*,
25.37*, 30.72*, 45.21, 45.80, 51.25, 61.80*, 62.52*, 71.28, 75.42,
94.69*, 99.74*, 174.72, 174.79 (* THP).
13C NMR: d = –4.68*, –4.50*, 7.66, 9.40, 11.32, 12.29, 17.72*,
25.65, 25.83*, 35.62, 45.43, 50.44, 71.00, 74.18, 173.52, 211.69
(* TBDMS).
(2S,3S)-2-Methyl-3-tetrahydropyranyloxybutan-1-ol (14):
To a cooled solution (0°C) of LiAlH4 (0.6 g, 15.72 mmol) in anhyd
Et2O (20 mL) was added dropwise a solution of 13c (1.7 g,
7.86 mmol) in Et2O (10 ml). The mixture was stirred for 2 h at 0°C
and then H2O was added (1 mL) followed by 1M NaOH (1 mL) and
stirring was continued for 2 more hours. After filtration and washing
with Et2O, the organic layer was dried (MgSO4) and evaporated
yielding a liquid which upon distillation afforded 1.4 g (94%) of 14;
bp 115–117°C/1.4 Torr; [a]D22 +30.5 (c = 1, CHCl3).
(2S,3R)-2,3-Dihydro-6-[(1¢S,2¢S)-2¢-hydroxy-1¢-methylbutyl]-
2,3,5-trimethyl-4H-pyran-4-one (Stegobiol):
A 1M soln of TiCl4 in CH2Cl2 (3.1 mL, 3.1 mmol) was added drop-
wise at –78°C to a mixture of 17 (0.22 g, 0.6 mmol) and i-Pr2EtN
(0.85 mL, 4.9 mmol) in CH2Cl2 (30 mL). The mixture was stirred at
–78°C for 1 h, then allowed to warm up to –10°C over 2 h and stirred
at that temperature for 20 h. Workup gave a liquid that was taken up
in MeCN (8 mL) and treated with 40% aq HF (10 drops) The mixture
was stirred at 0°C for 10 h, diluted with Et2O, washed with satd aq
NaHCO3 solution and dried (MgSO4). Column chromatography on
silica gel (hexane/Et2O, 2:1) gave pure stegobiol (85 mg, 62%); oil.
GC: column TRB-1, temp. 180°C, Rt 5.19 min. (single peak). [a]D23
–116±5 (c = 0.21, CHCl3) {Lit8a [a]D25 –118±7 (c = 0.107, CHCl3)}.
IR (Neat): n = 3432 (OH), 1661 (C=O), 1600 cm–1 (C=C).
IR (Neat): n = 3425 cm–1 (OH).
1H NMR: d – 0.70–0.77 (2d, J = 5.9Hz, 3 H), 1.0–1.14 (2d, J =
6.5 Hz, 3 H), 1.30–1.90 (m, 7 H, 6 H, THP), 2.99 (br s, 1 H),
3.30–3.65 (m, 3 H, 1 H, THP), 3.69–3.87 (m, 1 H, THP), 3.93 (dq, J
= 6.5, 3.3 Hz, 1 H), 4.38–4.65 (m, 1 H, THP).
13C NMR: d – 10.47, 12.07, 15.95, 17.31, 19.80*, 20.77*, 25.17*,
25.33 *, 30.97*, 31.27*, 39.37, 39.84, 62.70*, 64.18*, 64.90, 72.32,
76.55, 97.82*, 99.11* (* THP).
1H NMR: d = 0.97 (t, J = 7.3 Hz, 3 H), 1.00 (d, J = 7.3 Hz, 3 H), 1.15
(d, J = 7.1 Hz, 3 H), 1.29 (d, J = 5.6 Hz, 3 H), 1.33–1.62 (m, 2 H), 1.72
(s, 3 H), 1.91 (br s, 1 H), 2.34 (dq, J = 7.2 and 3.5 Hz, 1 H), 2.83 (qnt,
J = 6.9 Hz, 1 H), 3.46–3.62 (m, 1 H), 4.46 (dq, J = 6.6 and 3.4 Hz, 1 H).
13C NMR: d = 9.31, 9.51, 10.16, 14.81, 15.97, 28.30, 40.89, 43.71,
75.30, 76.59, 109.22, 172.60, 196.91.
(4S,5S)-5-Tetrahydropyranyloxy-4-methylhexan-3-ol (15):
Swern oxidation of 14 (1.69 g, 9 mmol), using oxalyl chloride
(1.76 mL, 20 mmol), DMSO (1.77 mL, 25 mmol), and i-Pr2EtN
(7.1 mL, 40 mmol), afforded 2.34 g of a liquid that was taken up in
Et2O (20 mL). Addition of a 1M THF soln of EtMgBr (20 mL), workup
and column chromatography (hexane/EtOAc, 12:1) afforded 1.42 g
(73%) of 15; bp 127–129 °C/1.4 Torr; [a]D22 –16.5 (c = 1.06, CHCl3).
IR (Neat): n = 3419 cm–1 (OH).
(2S,3R)-2,3-Dihydro-2,3,5-trimethyl-6-[(R)-1 -methyl-2 -oxobu-
tyl]-4H-pyran-4-one (Stegobinone):
¢
¢
Oxidation of stegobiol was done under Swern conditions. Stegobiol
(0.06 g, 0.25 mmol), oxalyl chloride (0.1 mL, 1 mmol), DMSO
(0.14 mL, 2 mmol), and i-Pr2EtN (0.4 mL, 2.2 mmol) gave after pu-
rification 45 mg (81%) of stegobinone; oil. GC: TRB-1, temp. 180°C,
Rt 4.73 min (single peak). [a]D23 –286±3 (c = 0.53, CHCl3) {Lit7b
[a]D23 –282±10 (c = 0.11, CHCl3)}.
1H NMR: d = 0.67–0.98 (m, 6 H), 1.08–1.80 (m, 11 H, 6 H, THP),
2.90 (br s, 1 H), 3.31–3.56 (m, 2 H, 1 H, THP), 3.56–3.97 (m, 3 H, 1
H, THP), 4.44–4.79 (m, 1 H, THP).
13C NMR: d = 5.11, 6.17, 10.64, 10.73, 17.23, 19.94*, 20.41*,
25.24*, 25.38*, 27.60, 27.95, 31.10*, 31.51*, 41.59, 42.30, 62.92*,
63.58*, 75.83, 76.69, 77.44, 81.63, 95.86*, 100.56* (* THP).
IR (Neat): n = 1720 (C=O), 1665 (C=O, a,b-unsaturated), 1663 cm–1
(C=C).

392
Papers
SYNTHESIS
1H NMR: d = 0.97–l.05 (d, J = 7.3 Hz, 3 H, t, J = 7.6 Hz, 3 H), 1.25
(d, J = 6.6 Hz, 3 H), 1.26 (d, J = 7.0 Hz, 3 H), 1.75 (s, 3 H), 2.24–2.50
(m, 3 H), 3.59 (q, J = 7.0 Hz, 1 H), 4.41 (dq, J = 6.6 and 3.6 Hz, 1 H).
13C NMR: d = 7.91, 9.46, 12.83, 15.73, 33.88, 43.67, 49.15, 77.12,
109.31, 168.77, 196.84, 207.31.
(1) a) Kuwahara, Y.; Fukami, H.; Ishii, S.; Matsumura, F.; Burkhol-
der, W. E. J.Chem. Ecol. 1975, 1, 413.
b) Kuwahara, Y.; Fukami, H.; Howard, R.; Ishii, S.; Matsumu-
ra, F.; Burkholder, W. E. Tetrahedron 1978, 34, 1769.
(2) Kodama, H.; Ono, M.; Kohno, M.; Ohnishi, A. J. Chem. Ecol.
1987, 13, 1871.
(3) White, P. R.; Birch, M. C. J. Chem. Ecol. 1987, 13, 1695.
(4) Chuman, T.; Mochizuki, K.; Kato, K.; Ono, M.; Okubo, A.
Agric. Biol. Chem. 1983, 47, 1413.
(5) Imai, T.; Kodama, H.; Chuman, T.; Kohno, M. J. Chem. Ecol.
1990, 16, 1237.
(6) a) Hoffman, R. W.; Ladner, W. Tetrahedron Lett. 1979, 4653.
b) Mori, K.; Ebata, T.; Sakakibara, M. Tetrahedron 1981, 37,
709.
c) Hoffman, R. W.; Ladner, W.; Steinbach, K.; Massa, W.;
Schmidt, R.; Snatzke; G. Chem. Ber. 1981, 114, 2786.
(7) a) Mori, K.; Ebata, T. Tetrahedron 1986, 42, 4685.
b) Mori, K.; Ebata, T. Tetrahedron 1986, 42, 4413.
(8) a) Matteson, D. S.; Man, H-W. J. Org. Chem. 1993, 58, 6545.
b) Matteson, D. S.; Man, H-W.; Ho, O. C. J. Am. Chem. Soc.
1996, 118, 4560.
(1¢S,2¢R)-1¢-Ethyl-2¢-methyl-3¢-oxopentyl (2S,3S)-3-tert-Bu-
tyldimethylsilyloxy-2-methylpentanoate (18):
Following the same procedure as for 17, acid 3 (0.66 g, 2.7 mmol),
2,6-dichlorobenzoyl chloride (0.4 mL, 2.8 mmol), Et3N (0.42 mL,
3 mmol), 9 (0.3 g, 2.1 mmol), and DMAP (0.28 g, 2.3 mmol) gave,
after purification by column chromatography on silica gel (hexane/
EtOAc, 50:1), 0.66 g (86%) of 18; oil.
IR (Neat): n = 1738 (C =O, ester), 1720 cm–1 (C=O, ketone).
1H NMR: d = –0.02 (s, 3 H), –0.01 (s, 3 H), 0.65–0.85 (s, 9H, m, 6 H),
0.94 (t, J = 7.2 Hz, 3 H), 1.00 (d, J = 7.0 Hz, 3 H), 1.01 (d, J = 7.2
Hz, 3 H), 1.22–l.63 (m, 4 H), 2.25–2.60 (m, 3 H), 2.69 (dq, J = 7.0
and 5.2 Hz, 1 H), 3.70–3.90 (m, 1 H), 5.04 (q, J = 6.1 Hz, 1 H).
13C NMR: d = –4.66*, –4.56*, 7.69, 9.81, 10.04, 11.07, 11.39,
18.06*, 25.10, 25.62, 25.82*, 35.06, 45.47, 48.82, 74.21, 74.94,
173.56, 211.40 (* TBDMS).
(9) Ebata, T.; Mori, K. Agric. Biol. Chem. 1987, 51, 2925.
(10) a) Oppolzer, W.; Rodriguez, I. Helv. Chim. Acta 1993, 76, 1275.
b) Oppolzer, W.; Rodriguez, I. ibid. 1993, 76, 1282.
(11) Razkin, J.; González, A.; Gil, P. Tetrahedron: Asymmetry 1996,
7, 3479.
(12) Kodama, H.; Mochizuki, K.; Kohno, M.; Ohnishi, A.; Kuwaha-
ra, Y. J. Chem. Ecol. 1987, 13, 1859.
(13) Ebata, T.; Mori, K. Agric. Biol. Chem. 1990, 54, 527.
(14) a) Noyori, R.; Ohkuma, T.; Kitamura, M.; Takaya, H.; Sayo, N.;
Kumobayashi, H.; Akutagawa, S. J. Am. Chem. Soc. 1987, 109,
5856.
(2S,3R)-2-Ethyl-2,3-dihydro-6-[(1¢S,2¢S)-2¢-hydroxy-1¢-methyl-
butyl]-3,5-dimethyl-4H-pyran-4-one (Serricorole):
As described for stegobiol, 18 (0.55 g, 1.5 mmol) was treated with i-
Pr2EtN (2.1 mL, 11.8 mmol) and TiCl4 (0.82 mL, 7.4 mmol), and then
deprotected with HF. Purification gave 0.22 g (64%) of serricorole;
oil. GC: TRB-1, temp. 180°C, Rt 5.25 min (single peak). [a]D22
–124±2 (c = 2.18, CHCl3) {Lit10a [a]D24–124 (c = 2.34, CHCl3)}.
IR (Neat): n = 3435 (OH), 1654 (C =O), 1598 cm–1 (C=C).
1H NMR: d = 0.85–1.00 (t, J = 7.1 Hz, 6 H, d, J = 7.1 Hz, 3 H), 1.14
(d, J = 7.0 Hz, 3 H), 1.27–1.64 (m, 3 H), 1.64–l.89 (s, 3 H, m, 1 H),
1.89–2.07 (m, 1 H), 2.32 (dq, J = 7.4 and 3.3 Hz, 1 H), 2.83 (qnt, J =
7.0 Hz, 1 H), 3.54 (br s, 1 H), 4.05–4.21 (m, 1 H).
b) Kitamura, M.; Tokunaga, M.; Ohkuma, T.; Noyori, R. Tetra-
hedron Lett. 1991, 32, 4163.
c) Kitamura, M.; Tokunaga, M.; Ohkuma, T.; Noyori, R. Org.
Synth. 1993, 71, 1.
13C NMR: d = 9.37, 9.63, 9.98, 10.15, 14.82, 23.45, 28.21, 41.05,
42.54, 75.29, 81.92, 109.29, 173.06, 197.31.
d) Noyori, R. Tetrahedron 1994, 50, 4259.
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68, 1373.
(16) a) Mitsunobu, O. Synthesis 1981, 1.
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(2S,3R)-2-Ethy1-2,3-dihydro-3,5-dimethyl-6-[(R)-1¢-methyl-2¢-
oxobutyl]-4H-pyran-4-one (Serricorone):
Oxidation of serricorole (0.22 g, 0.91 mmol) with oxalyl chloride
(0.17 mL, 2 mmol) and DMSO (0.18 mL, 2.5 mmol) in the presence
of i-Pr2EtN (0.8 mL, 4.5 mmol) yielded after purification 180 mg
(83%) of serricorone; oil. GC: TRB-1, temp. 180°C, Rt 5.79 min (sin-
gle peak); [a]D24 –272±3 (c = 0.47, CHCl3) {Lit9 [a]D24 –269±4 (c =
0.11, CHCl3)}.
IR (Neat): n = 1725 (C=O), 1669 (C=O, a,b-unsaturated), 1611 cm–1
(C=C).
1H NMR: d = 0.80–1.05 (t, J = 7.8 Hz, 3 H, d, J = 7.4 Hz, 3 H, t, J =
7.2 Hz, 3 H), 1.23 (d, J = 7.0 Hz, 3 H), 1.31–l.54 (m, 1 H), 1.60–1.85
(s, 3 H, m, 1 H), 2.19–2.45 (m, 3 H), 3.58 (q, J = 7.0 Hz, 1 H),
3.96–4.11 (m, 1 H).
13C NMR: d = 7.81, 9.41, 9.57, 9.78, 12.97, 23.34, 33.84, 42.63,
49.02, 82.47, 109.36, 169.12, 197.16, 207.15.
Financial support from Gobierno de Navarra (Orden Foral 497/93)
is gratefully acknowledged.