Synthesis of (4R,9Z)-9-octadecen-4-olide, the female sex pheromone of Janus integer, and its enantiomer

Article abstract of DOI:10.1002/ejoc.200300634

Enantiomer separation of (±)-8-fert-butyldiphenylsilyloxy-1-octyn-3- ol was achieved by lipase-mediated asymmetric acetylation. The resolved (R)-alkynol was converted into (4R,9Z)-9-octadecen-4-olide, which was identical with the female sex pheromone of the currant stem girdler (Janus integer). The absolute configuration of the natural pheromone was thus established as R. (4S,9Z)-9-Octadecen-4-olide was also synthesized, and found to be pheromonally inhibitory. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200300634

FULL PAPER
Synthesis of (4R,9Z)-9-Octadecen-4-olide, the Female Sex Pheromone of
Janus integer, and Its Enantiomer[‡]
[a]
[b]
´
Chie Shibata and Kenji Mori*
Keywords: Configuration determination / Lactones / Lipases / Pheromones
Enantiomer separation of ( )-8-tert-butyldiphenylsilyloxy-1-
octyn-3-ol was achieved by lipase-mediated asymmetric
acetylation. The resolved (R)-alkynol was converted into
(4R,9Z)-9-octadecen-4-olide, which was identical with the fe-
male sex pheromone of the currant stem girdler (Janus inte-
ger). The absolute configuration of the natural pheromone
was thus established as R. (4S,9Z)-9-Octadecen-4-olide was
also synthesized, and found to be pheromonally inhibitory.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
As to the key optical resolution, we proposed to employ
biocatalysis.[4] As early as 1978, we attempted to use biocat-
alysis for the preparation of optically active acetylenic al-
cohols.[5] Asymmetric hydrolysis of the corresponding acet-
ates of (Ϯ)-acetylenic alcohols with Bacillus subtilis var.
Introduction
´
In 2001 Cosse et al. isolated and identified (Z)-9-octa-
decen-4-olide (1, Scheme 1) as a female-specific and
antennally active compound from the currant stem girdler,
Janus integer Norton (Hymenoptera: Cephidae), which is
an occasional pest of red currant in North America.[1] They
synthesized (Ϯ)-1, whose sex pheromone properties were
demonstrated by field experiments, and showed that the
natural 1 contained only a single enantiomer as analyzed
by GC on a chiral stationary phase.[1] In order to clarify
the absolute configuration of the natural pheromone, we
undertook the synthesis of both enantiomers of 1 with un-
ambiguous stereochemistry. This paper describes the syn-
thesis of (R)- and (S)-1, the former of which was proved to
be the natural pheromone by GC comparison and field bi-
oassay.
Scheme 1 shows our retrosynthetic analysis of (R)-1. The
(Z)-double bond at C-9 of (R)-1 can be constructed by (Z)-
selective olefination[2] between Wittig reagent A and lac-
tonic aldehyde (R)-B. The aldehyde (R)-B may be obtained
by oxidation of the hydroxy lactone (R)-C. The key inter-
mediate in the preparation of (R)-C is the acetylenic alcohol
(R)-D, which is available by optical resolution of (Ϯ)-D. The
acetylenic alcohol (Ϯ)-D can be prepared by ethynylation
of the known aldehyde E.[3]
[‡]
Pheromone Synthesis, CCXXIII. Part CCXXII: K. Mori,
Biosci. Biotechnol. Biochem. 2003, 67, 2224Ϫ2231.
[a]
Department of Applied Biological Chemistry, the University
of Tokyo,
Yayoi 1-1-1, Bunkyo-ku, Tokyo 113Ϫ8657, Japan
[b]
Insect Pheromone and Traps Division, Fuji Flavor Co., Ltd.
Midorigaoka 3-5-8, Hamura-City, Tokyo 205Ϫ8503, Japan
Fax: (internat.) ϩ81-42-555-7920
Scheme 1. Structure and retrosynthetic analysis of the female sex
pheromone (R)-1 of Janus integer
Eur. J. Org. Chem. 2004, 1083Ϫ1088
DOI: 10.1002/ejoc.200300634
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1083

C. Shibata, K. Mori
FULL PAPER
Niger, however, was not highly enantioselective.[5] At pre- (ϩ)-4 with 82% ee even after a single acetylation in vinyl
sent, an appropriate lipase for asymmetric acetylation of acetate.
(Ϯ)-acetylenic alcohols can be selected from commercially
Other promising but less satisfactory enzymes were lipase
available lipases. Accordingly, we decided to adopt a biocat- PS-C and lipase AK-20. However, the acetylations took
alytic approach, although there are several good methods[6] place much more sluggishly with these two enzymes. As
for chemical asymmetric synthesis of optically active D.
mentioned by Burgess,[7] we also experienced unfavorable
resolution in the case of some simpler 1-alkyn-3-ols. Success
in the case of (Ϯ)-4 was presumably due to the presence of
an extremely bulky tert-butyldiphenylsilyl (TBDPS) group
at the terminal position of the alkyl group to make possible
a better fit of (Ϫ)-4 with the active site of lipase AH-S.
In a preparative-scale experiment, the enzymatic acetylation
with vinyl acetate and lipase AH-S was repeated three times
to give (ϩ)-4 (96% ee) in 29% yield and the acetylated prod-
uct 5, which was treated with potassium carbonate in meth-
anol to give (Ϫ)-4 (93% ee) in 24% yield.
As to the absolute configuration of the recovered (ϩ)-4,
it was assumed to be (R) according to the empirical rule
proposed by Burgess and Johnson.[7] This was verified by
converting (Ϫ)-4 to (Ϫ)-3-octanol with known (R) con-
figuration.[8] (Ϫ)-Alcohol 4 of 70% ee was used for this
experiment, and benzylated to furnish 6. Removal of the
TBDPS protective group of 6 was followed by tosylation
of the resulting alcohol 7. Reduction of tosylate 8 with
lithium aluminum hydride gave 9,[9] hydrogenolysis of
which furnished (R)-(Ϫ)-3-octanol (10). Accordingly, the
(S) configuration was assigned to 5, (Ϫ)-4, 6, 7, 8 and 9,
and the recovered (ϩ)-acetylenic alcohol 4 was (R)-4, as
expected.
Results and Discussion
As shown in Scheme 2, the first stage of the synthesis was
the preparation of (Ϯ)-4, its lipase-catalyzed asymmetric
acetylation to give the recovered 4 and the acetylated 5, and
determination of the absolute configuration of the acetyl-
ated 5 as (S) by its conversion into a compound with known
stereochemistry such as (R)-3-octanol (10). 1,6-Hexanediol
(2) was converted into the known aldehyde 3 (ϭ E) accord-
ing to the procedure described by Posner and Johnson.[3]
Addition of lithium acetylide ethylenediamine complex to 3
gave 8-tert-butyldiphenylsilyloxy-1-octyn-3-ol, (Ϯ)-4.
Scheme 3 summarizes the conversion of the alkynyl al-
cohol 4 to the desired lactone 1. The free hydroxy group of
(R)-4 was first protected as the tert-butyldimethysilyl (TBS)
ether to give (R)-11. Treatment of (R)-11 with butyllithium
and methyl chloroformate furnished acetylenic ester (R)-12.
This ester was hydrogenated over Adams’ platinum oxide
to afford saturated ester (R)-13. Fortunately, no appreciable
hydrogenolysis of the CϪO bond at C-4 took place. Depro-
tection of the two silyl protective groups of (R)-13 was
achieved with tetrabutylammonium fluoride (TBAF) to
give a mixture of hydroxy ester (R)-14 and hydroxy lactone
(R)-15. The mixture was subjected to alkaline hydrolysis
with potassium hydroxide, and the resulting potassium salt
of the hydroxy acid was acidified with hydrochloric acid
to give hydroxy lactone (R)-15. Oxidation of (R)-15 with
pyridinium chlorochromate (PCC) afforded lactonic alde-
hyde (R)-16.
Scheme 2. Lipase-catalyzed asymmetric acetylation of (Ϯ)-4, and
determination of the absolute configuration of the acetylated (S)-
5
by
its
conversion
into
(R)-10:
reagents.
(a)
HCϵCLi·H2N(CH2)2NH2, THF (62%); (b) Lipase AH-S (Am-
ano), CH2ϭCHOAc; SiO2 chromatography [3 times, 29% for (R)-
4]; (c) K2CO3, MeOH (24%, 2 steps ϫ 2 times); (d) NaH, BnBr,
THF, DMF (85%); (e) TBAF, THF (81%); (f) TsCl, C5H5N,
DMAP, CH2Cl2 (89%); (g) LiAlH4, THF (quant.); (h) H2, 5% Pd-
C, EtOH (33%)
Finally, Wittig reaction of (R)-16 with (triphenyl)non-
ylenephosphorane under Bestmann’s salt-free conditions[2]
furnished (4R,9Z)-9-octadecen-4-olide (1), [α]2D6 ϭ ϩ24 (c ϭ
0.50, CHCl3). It showed IR, 1H and 13C NMR spectral
properties and elemental analytical data in good agreement
Burgess and Jennings previously reported that asymmet- with the expected structure 1. In particular, its mass spec-
ric acetylation of 1-octyn-3-ol with lipases was not favor- trum was identical to the published spectrum of the natural
´
able to resolution, giving recovered (R)-1-octyn-3-ol of only 1. Dr. A. Cosse kindly carried out the GC analysis of (R)-
23% ee.[7] Nevertheless, we screened various lipases available 1 under the reported conditions with a β-DEX 225 col-
in our laboratory (mainly Amano lipases) with the hope of umn,[1] and proved it to be highly pure (95.9% ee; E/Z ϭ
achieving better resolution. Table 1 summarizes the results. 1.6:98.4). More importantly, he found (R)-1 to be the nat-
Fortunately, lipase AH-S (Amano) afforded the recovered urally occurring enantiomer. The overall yield of (R)-1 was
1084
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Eur. J. Org. Chem. 2004, 1083Ϫ1088

Synthesis of (4R,9Z)-9-Octadecen-4-olide and Its Enantiomer
Table 1. Screening of enzymes for asymmetric acetylation of (Ϯ)-4
FULL PAPER
Entry[a]
Enzyme[b]
Reaction time (h)
Enantiomeric purity (% ee) of (ϩ)-4[c]
1
2
3
4
5
6
7
8
9
Lipase AH-S
Lipase AH
Lipase PS
Lipase PS-C
Lipase PS-D
Lipase MY
Lipase AF-2
Lipase AK-20
Lipase FAD-15
22
244
246
101
77
197
197
76
82
15
no reaction
71
45
20
no reaction
69
9
197
[a]
[b]
All the reactions were carried out at room temperature (20Ϫ22 °C) employing neat vinyl acetate as the acetyl donor. Enzymes were
mainly the generous gift of Amano Enzyme Inc. Determined by HPLC analysis on Chiralcel-OD (see Exp. Sect.).
[c]
Scheme 3. Synthesis of the enantiomers of (Z)-9-octadecen-4-olide (1): reagents: (a) TBSCl, imidazole, DMF (94%); (b) BuLi, ClCO2Me,
˚
THF (94%), (c) H2, PtO2, hexane (89%), (d) TBAF, THF; (e) 1) KOH, MeOH, H2O; 2) dil. HCl (79%; 3 steps); (f) PCC, 4-A molecular
sieves, CH2Cl2 (68%); (g) Me(CH2)8PPh3Br, NaHMDS, hexane, THF, Ϫ100 °C (68%)
5.1% based on 3 (nine steps). Similarly (S)-1 (94.9% ee; natural pheromone by GC comparison. Lipase AH-S was
E/Z ϭ 1.6:98.4), [α]2D5 ϭ Ϫ23 (c ϭ 1.00, CHCl3), was synthe- found to be an appropriate enzyme for asymmetric acety-
sized from (S)-4 in 6.7% overall yield (10 steps).
lation of the acetylenic alcohol (S)-4. Field bioassay of the
In conclusion, both the enantiomers of (Z)-9-octadecen- enantiomers of 1 in the USA revealed (R)-1 to be phero-
4-olide (1) were synthesized, and (R)-1 was identical to the monally active, while (S)-1 was found to be a pheromone
Eur. J. Org. Chem. 2004, 1083Ϫ1088
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C. Shibata, K. Mori
FULL PAPER
OD 4.6 mm ϫ 25 cm; solvent: hexane/ethanol, 90:1; flow rate:
0.45 mL/min; detection at 254 nm); tR 36.1 min (98.2%) [(S)-4: tR
39.5 min (1.8%)]. (S)-4: n2D6 ϭ 1.5166. [α]2D6 ϭ ϩ0.5 (c ϭ 1.12,
CHCl3). C24H32O2Si (380.6): calcd. C 75.74, H 8.47; found C 75.52,
H 8.53. Its IR and NMR spectra were identical to those of (Ϯ)-4.
Following the same procedure as for the analysis of (R)-4, enanti-
omeric purity of (S)-4 was determined as 93.4% ee. tR 39.5 min
(95.7%) [(R)-4: tR 36.7 min (3.2%)].
inhibitor, making (Ϯ)-1 only ca. 10% as active as (R)-1. It
should be added that Bohlmann and Abraham reported in
1979 the isolation of (Ϫ)-9-octadecen-4-olide [(S)-1] from
the aerial parts of a South African plant, Helichrysum hypo-
1
cepharum (Compositae).[10] Their H NMR spectroscopic
data for (Ϫ)-1 coincided with ours. The plant thus produces
the opposite (S)-enantiomer of the (R)-pheromone [(R)-1]
of Janus integer.
(S)-3-Benzyloxy-8-tert-butyldiphenylsilyloxy-1-octyne [(S)-6]: NaH
(60% suspension in mineral oil, 30 mg, 0.94 mmol) was added to a
stirred and ice-cooled solution of (S)-4 (70% ee, 190 mg,
0.50 mmol) in THF (3 mL) and N,N-dimethylformamide (DMF,
1 mL). Benzyl bromide (169 mg, 0.98 mmol) was then added drop-
wise to the mixture at 0 °C. After stirring for 3 h at room tempera-
ture, the mixture was poured into water, and extracted with EtOAc.
The combined organic phases were successively washed with brine,
dried with MgSO4, and concentrated in vacuo. The residue was
chromatographed on silica gel (6.0 g, hexane/EtOAc, 40:1) to give
200 mg (85%) of (S)-6 as a colorless oil, n2D5 ϭ 1.5177. [α]2D5 ϭ Ϫ40
(c ϭ 0.91, CHCl3). IR (film): ν˜max. ϭ 3305 (w, CϵCϪH), 1110 (s,
SiϪO) cmϪ1. 1H NMR (300 MHz, CDCl3): δ ϭ 1.01 (s, 9 H, tBu),
1.34Ϫ1.54 (m, 6 H, 2-H, 3-H, 4-H), 1.56Ϫ1.80 (m, 2 H, 5-H), 2.46
(d, J ϭ 2.1 Hz, 1 H, 8-H), 3.64 (t, J ϭ 6.3 Hz, 2 H, 1-H), 4.05 (dt,
J ϭ 2.1, 4.5 Hz, 1 H, 6-H), 4.49 (d, J ϭ 11 Hz, 1 H, OCH2Ph),
4.80 (d, J ϭ 11 Hz, 1 H, OCH2Ph), 7.34Ϫ7.42 (m, 9 H, OCH2Ph,
TBDPS), 7.64Ϫ7.67 (m, 4 H, TBDPS) ppm. C31H38O2Si (470.7):
calcd. C 79.10, H 8.14; found C 78.80, H 8.34.
Experimental Section
1
General Remarks: IR: Jasco FT/IR-460 Plus. H NMR: Jeol EX-
90A (90 MHz), JNM-AL300 (300 MHz), JNM-LA400 (400 MHz)
or JNM-LA500 (500 MHz), with CHCl3 at δ ϭ 7.26 ppm used as
the internal standard. 13C NMR: JNM-LA400 (100 MHz), with
CHCl3 at δ ϭ 77.0 ppm used as the internal standard. MS: Hitachi
M-80B. Refractive index (nD): Atago DMT-1 refractometer. Op-
tical rotation: Jasco DIP-1000 polarimeter.
(؎)-8-tert-Butyldiphenylsilyloxy-1-octyn-3-ol [(؎)-4]: A solution of
(Ϯ)-3[3] (11.5 g, 32.5 mmol) in dry THF (120 mL) was added to a
stirred suspension of 90% HCϵCLi·H2N(CH2)2NH2 (16.6 g,
162 mmol) in dry THF (150 mL) at room temperature under argon.
After stirring for 1.5 h at room temperature, the mixture was
poured into a saturated aqueous NaHCO3 solution and water, and
the resulting mixture was extracted with Et2O. The combined ex-
tract was successively washed with water and brine, dried with
MgSO4, and concentrated in vacuo. The residue was chromato-
graphed on silica gel (250 g, hexane/EtOAc, 20:1) to give 7.56 g of
(Ϯ)-4 (62%) as a colorless oil, n2D5 ϭ 1.5167. IR (film): ν˜max. ϭ 3395
(S)-6-Benzyloxy-7-octyn-1-ol [(S)-7]: A solution of TBAF in THF
(1.0 , 690 µL, 0.69 mmol) was added to a stirred and ice-cooled
solution of (S)-6 (250 mg, 0.53 mmol) in THF (3 mL). After stir-
ring for 12 h at room temperature, the mixture was poured into ice
water and extracted with EtOAc. The combined organic phases
were successively washed with brine, dried with MgSO4, and con-
centrated in vacuo. The residue was chromatographed on silica gel
(5.0 g, hexane/EtOAc, 10:1) to give 100 mg (81%) of (S)-7 as a col-
orless oil, n2D3 ϭ 1.5151. [α]2D6 ϭ Ϫ86 (c ϭ 1.00, CHCl3). IR (film):
(m, OϪH), 3305 (m, CϵCϪH), 1110(s, SiϪO) cmϪ1 1H NMR
.
(400 MHz, CDCl3): δ ϭ 1.04 (s, 9 H, TBDPS), 1.20Ϫ1.89 (m, 9 H,
4-H, 5-H, 6-H, 7-H, OH), 2.46 (d, J ϭ 1.5 Hz, 1 H, 1-H), 3.66 (t,
J ϭ 6.3 Hz, 2 H, 8-H), 4.35 (dt, J ϭ 1.5, 6.6 Hz, 1 H, 3-H),
7.26Ϫ7.44 (m, 6 H, TBDPS), 7.65Ϫ7.68 (m, 4 H, TBDPS) ppm.
C24H32O2Si (380.6): calcd. C 75.74, H 8.47; found C 75.64, H 8.82.
ν˜max. ϭ 3365 (s, OϪH), 3290 (w, CϵCϪH), 1070(s, SiϪO) cmϪ1
.
1H NMR (400 MHz, CDCl3): δ ϭ 1.37 (quintet, J ϭ 7.6 Hz, 2 H,
3-H), 1.47Ϫ1.60 (m, 4 H, 2-H, 4-H), 1.71Ϫ1.83 (m, 2 H, 5-H), 2.47
(d, J ϭ 1.5 Hz, 1 H, 8-H), 3.63 (q, J ϭ 6.1 Hz, 2 H, 1-H), 4.08 (dt,
J ϭ 6.4, 1.5 Hz, 1 H, 6-H), 4.50 (d, J ϭ 8.9 Hz, 1 H, OCH2Ph),
4.80 (d, J ϭ 8.9 Hz, 1 H, OCH2Ph), 7.28Ϫ7.36 (m, 5 H, OCH2Ph)
ppm. C15H20O2 (232.3): calcd. C 77.55, H 8.68; found C 77.26,
H 8.81.
(R)-8-tert-Butyldiphenylsilyloxy-1-octyn-3-ol [(R)-4] and (S)-8-tert-
Butyldiphenylsilyloxy-1-octyn-3-ol [(S)-4]: Lipase AH-S (2.00 g) was
added to a solution of (Ϯ)-4 (10.0 g, 26.4 mmol) in vinyl acetate
(600 mL), and the mixture was stirred for 22 h at room tempera-
ture. The enzyme was filtered off through a Celite pad and the
filtrate was concentrated in vacuo. The residue was chromato-
graphed on silica gel (200 g, hexane/EtOAc, 20:1) to give crude (R)-
4 (5.03 g, 50%) and (S)-6-acetoxy-1-tert-butyldiphenylsilyloxy-7-oc- (S)-6-Benzyloxy-7-octynyl Tosylate [(S)-8]: Pyridine (42 µL,
tyne [(S)-5] (5.45 g, 49%). The crude (R)-4 was acetylated according 0.53 mmol), DMAP (15 mg, 0.12 mmol) and TsCl (116 mg,
to this procedure twice more to give 2.94 g of (R)-4 [total for all
three times; 29% based on (Ϯ)-4] as a colorless oil. K2CO3 (2.67 g,
0.61 mmol) were added to a stirred and ice-cooled solution of (S)-
7 (75 mg, 0.32 mmol) in CH2Cl2 (2 mL). After stirring for 17 h at
19.4 mmol) was added to a solution of (S)-5 (5.45.g, 12.9 mmol) in 4 °C, the mixture was poured into water and extracted with EtOAc.
MeOH (50 mL). After stirring for 2 h at room temperature, the The combined organic phases were successively washed with 1 
mixture was poured into water and extracted with Et2O. The com- HCl, saturated aqueous NaHCO3 solution and brine, dried with
bined extract was successively washed with water and brine, dried
with MgSO4, and concentrated in vacuo. The residue was chroma-
tographed on silica gel (100 g, hexane/EtOAc, 20:1) to give 4.55 g
(93%) of (S)-4 as a colorless oil. This was resolved once more ac-
cording to the same procedure as that described for the enzymatic
resolution and methanolysis to give 2.40 g of (S)-4 [2 steps ϫ 2
times, 24%, based on (Ϯ)-4] as a colorless oil. (R)-4: n2D5 ϭ 1.5172.
[α]2D6 ϭ Ϫ0.5 (c ϭ 1.18, CHCl3). C24H32O2Si (380.6): calcd. C 75.74,
H 8.47; found C 75.50, H 8.69. Its IR and NMR spectra were
identical to those of (Ϯ)-4. The enantiomeric purity of (R)-4 was
estimated to be 96.4% ee by HPLC analysis (column: Chiralcel
MgSO4, and concentrated in vacuo. The residue was chromato-
graphed on silica gel (3.0 g, hexane/EtOAc, 30:1) to give 111 mg
(89%) of (S)-8 as a colorless oil, n2D3 ϭ 1.5178. [α]2D6 ϭ Ϫ52 (c ϭ
1.00, CHCl3). IR (film): ν˜max. ϭ 3285 (w, CϵCϪH), 1360 (s, Sϭ
O), 1175 (s, SϭO), 1070 (s, SiϪO) cmϪ1 1H NMR (300 MHz,
.
CDCl3): δ ϭ 1.30Ϫ1.73 (m, 8 H, 2-H, 3-H, 4-H, 5-H), 2.44 (s, 3
H, Ar-Me), 2.46 (d, J ϭ 2.1 Hz, 1 H, 8-H), 4.01 (t, J ϭ 6.6 Hz, 2
H, 1-H), 3.99Ϫ4.03 (m, 1 H, 6-H), 4.48 (d, J ϭ 12 Hz, 1 H,
OCH2Ph), 4.79 (d, J ϭ 12 Hz, 1 H, OCH2Ph), 7.32Ϫ7.34 (m, 7 H,
OCH2Ph, Ar-Me), 7.78 (d, J ϭ 8.4 Hz, 2 H, Ar-Me) ppm.
C22H26O4S2 (386.5): calcd. C 68.37, H 6.78; found C 68.26, H 6.86.
1086
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Synthesis of (4R,9Z)-9-Octadecen-4-olide and Its Enantiomer
FULL PAPER
(S)-3-Benzyloxy-1-octyne [(S)-9]: A solution of (S)-8 (100 mg,
0.26 mmol) in THF (2 mL) was added dropwise to a stirred and
ice-cooled suspension of LiAlH4 (39 mg, 1.03 mmol) in THF
(3 mL). After stirring under reflux for 0.5 h, the reaction mixture
was cooled to 0 °C. Water (0.1 mL), 15% aqueous NaOH solution
(0.1 mL) and water (0.1 mL) were added to the mixture, and it was
filtered through a Celite pad. The filtrate was concentrated in va-
cuo. The residue was chromatographed on silica gel (3.0 g, hexane/
1.5062. [α]2D6 ϭ ϩ10 (c ϭ 1.01, CHCl3). IR (film): ν˜max. ϭ 2235 (m,
1
CϵC), 1720 (CϭO), 1250 [s, C(ϭO)ϪO], 1110 cmϪ1 (s, SiϪO). H
NMR (300 MHz, CDCl3): δ ϭ 0.11 (s, 3 H, TBS), 0.15 (s, 3 H,
TBS), 0.91 (s, 9 H, TBS), 1.05 (s, 9 H, TBDPS), 1.24Ϫ1.70 (m, 6
H, 5-H, 6-H, 7-H, 8-H), 3.65 (t, J ϭ 6.3 Hz, 2 H, 9-H), 3.77 (s, 3
H, CO2Me), 4.43 (t, J ϭ 6.6 Hz, 1 H, 4-H), 7.35Ϫ7.42 (m, 6 H,
TBDPS), 7.65Ϫ7.68 (m, 4 H, TBDPS) ppm. C32H48O4Si2 (552.9):
calcd. C 69.51, H 8.75; found C 69.48, H 9.07. This was employed
in the next step without further purification.
EtOAc, 60:1) to give 56 mg (quant.) of (S)-9 as a colorless oil, n2D2
ϭ
1.4929. [α]2D3 ϭ Ϫ49 (c ϭ 0.55, CHCl3). IR (film): ν˜max. ϭ 3305 (w,
Methyl
(S)-4-tert-Butyldimethylsilyloxy-9-tert-butyldiphenylsilyl-
CϵCϪH), 1090 (s, CϪOϪC) cmϪ1. ref.[9] [α]2D5 ϭ Ϫ49.2 (c ϭ 0.9,
oxy-2-nonynoate [(S)-12]: Using the method described for the prep-
aration of (R)-12, (S)-11 (668 mg, 1.34 mmol) yielded 746 mg (qu-
ant.) of (S)-12 as a colorless oil, n2D5 ϭ 1.5082. [α]2D5 ϭ Ϫ19 (c ϭ
1.00, CHCl3). This value was not consistent with that of (R)-12.
The reason could not be clarified. C32H48O4Si2 (552.9): calcd. C
69.51, H 8.75; found C 69.45, H 8.75. Its IR and NMR spectra
were identical to those of (R)-12. This was employed in the next
step without further purification.
1
CHCl3). H NMR (300 MHz, CDCl3): δ ϭ 0.88 (t, J ϭ 7.2 Hz, 3
H, 8-H), 1.23Ϫ1.52 (m, 6 H, 5-H, 6-H, 7-H), 1.69Ϫ1.81 (m, 2 H,
4-H), 2.47 (d, J ϭ 2.1 Hz, 1 H, 1-H), 4.07 (dt, J ϭ 2.1, 6.6 Hz, 1
H, 3-H), 4.51 (d, J ϭ 12 Hz, 1 H, OCH2Ph) 4.81 (d, J ϭ 12 Hz, 1
H, OCH2Ph), 7.28Ϫ7.36 (m, 5 H, OCH2Ph) ppm. Its IR and NMR
spectra were identical to those in ref.[9] C15H20O (216.3): calcd. C
83.28, H 9.32; found C 83.15, H 9.54.
(R)-3-Octanol [(R)-10]: A solution of (S)-9 (57 mg, 0.26 mmol) in
EtOH (1 mL) was shaken under a H2 atmosphere in the presence
of 5% Pd-C (15 mg) for 21 h at room temperature. The catalyst was
removed by filtration through a Celite pad, and the filtrate was
concentrated in vacuo. The residue was chromatographed on silica
gel (5.0 g, hexane/EtOAc, 30:1) to give 11 mg (33%) of (R)-10 as a
colorless oil, n2D3 ϭ 1.4218 (ref.[8] n2D2 ϭ 1.4222). [α]2D2 ϭ Ϫ6.5 (c ϭ
0.15, CHCl3). [ref.[8] [α]2D2 ϭ Ϫ9.7 (c ϭ 0.93, CHCl3)]. Its IR and
NMR spectra were identical to those in ref.[8]
Methyl (R)-4-tert-Butyldimethylsilyloxy-9-tert-butyldiphenylsilyl-
oxy-2-nonanoate [(R)-13]: A solution of (R)-12 (92 mg, 0.17 mmol)
in hexane (1 mL) was shaken under a H2 atmosphere in the pres-
ence of PtO2 (1 mg) for 22 h at room temperature. The catalyst was
removed by filtration through a Celite pad, and the filtrate was
concentrated in vacuo. The residue was chromatographed on silica
gel (3.0 g, hexane/EtOAc, 75:1) to give 82 mg (89%) of (R)-13 as a
colorless oil, n2D6 ϭ 1.5064. [α]2D6 ϭ Ϫ5.4 (c ϭ 1.04, CHCl3). IR
(film): ν˜max. ϭ 1740 (s, CϭO), 1255 [s, C(ϭO)ϪO], 1110 (s, SiϪO)
1
(R)-3-tert-Butyldimethylsilyloxy-8-tert-butyldiphenylsilyloxy-1-oc-
tyne [(R)-11]: TBSCl (1.17 g, 7.77 mmol) was added to a stirred
and ice-cooled solution of (R)-4 (2.69 g, 7.07 mmol) and imidazole
(529 mg, 7.77 mmol) in DMF (30 mL). After stirring for 22 h at
room temperature, the mixture was poured into water and extracted
with Et2O. The combined extract was successively washed with
water and brine, dried with MgSO4, and concentrated in vacuo.
The residue was chromatographed on silica gel (100 g, hexane/
cmϪ1. H NMR (500 MHz, CDCl3): δ ϭ 0.41 (s, 3 H, TBS), 0.45
(s, 3 H, TBS), 0.89 (s, 9 H, TBS), 1.06 (s, 9 H, TBDPS), 1.26Ϫ1.81
(m, 10 H, 3-H, 5-H, 6-H, 7-H, 8-H), 2.29Ϫ2.39 (m, 2 H, 2-H), 3.66
(t, J ϭ 6.4 Hz, 2 H, 9-H) 3.68 (s, 3 H, CO2Me), 3.65Ϫ3.70 (m, 1
H, 4-H), 7.27Ϫ7.44 (m, 6 H, TBDPS), 7.67Ϫ7.69 (m, 4 H, TBDPS)
ppm. C32H52O4Si2 (556.9): calcd. C 69.01, H 9.41; found C 69.29,
H 9.62.
Methyl
(S)-4-tert-Butyldimethylsilyloxy-9-tert-butyldiphenylsilyl-
EtOAc, 50:1) to give 3.29 g (94%) of (R)-11 as a colorless oil, n2D6
ϭ
oxy-2-nonanoate [(S)-13]: Using the method described for the prep-
aration of (R)-13, (S)-12 (700 mg, 1.26 mmol) yielded 698 mg of
(S)-13 (99%) as a colorless oil, n2D3 ϭ 1.5063. [α]2D3 ϭ ϩ5.5 (c ϭ
0.20, CHCl3). C32H52O4Si2 (556.9): calcd. C 69.01, H 9.41; found
C 69.04, H 9.64. Its IR and NMR spectra were identical to those
of (R)-13.
1.5090. [α]2D6 ϭ ϩ19 (c ϭ 0.82, CHCl3). IR (film): ν˜max. ϭ 3310 (w,
CϵCϪH), 1110 (s, SiϪO) cmϪ1. 1H NMR (300 MHz, CDCl3): δ ϭ
0.11 (s, 3 H, TBS), 0.13 (s, 3 H, TBS), 0.90 (s, 9 H, TBS), 1.05 (s,
9 H, TBDPS), 1.41Ϫ1.68 (m, 8 H, 2-H, 3-H, 4-H, 5-H), 2.37 (d,
J ϭ 1.9 Hz, 1 H, 8-H), 3.66 (t, J ϭ 6.3 Hz, 2 H, 1-H), 4.32 (dt,
J ϭ 1.9, 6.4 Hz, 1 H, 6-H), 7.35Ϫ7.42 (m, 6 H, TBDPS), 7.65Ϫ7.68
(m, 4 H, TBDPS) ppm. C30H46O2Si2 (494.9): calcd. C 72.81, H
9.37; found C 73.08, H 9.63.
(R)-9-Hydroxy-4-nonanolide [(R)-15]: A solution of TBAF in THF
(1.0 , 5.39 mL, 5.39 mmol) was added to a stirred and ice-cooled
solution of (R)-13 (1.00 g 1.80 mmol) in THF (10 mL). After stir-
ring for 20 h at room temperature, the mixture was poured into ice
water and extracted with EtOAc. The combined extracts were
washed with brine, dried with MgSO4, and concentrated in vacuo
to give 800 mg of a crude mixture of (R)-14 and (R)-15 as a color-
less oil. This was employed in the next step without further purifi-
cation. A solution of KOH (151 mg, 2.70 mmol) in water (2 mL)
was added to a stirred and ice-cooled solution of the crude mixture
(S)-3-tert-Butyldimethylsilyloxy-8-tert-butyldiphenylsilyloxy-1-oc-
tyne [(S)-11]: Using the method described for the preparation of
(R)-11, (S)-4 (540 mg, 1.41 mmol) yielded 648 mg (quant.) of (S)-
11 as a colorless oil, n2D6 ϭ 1.5110. [α]2D6 ϭ Ϫ20 (c ϭ 1.01, CHCl3).
C30H46O2Si2 (494.9): calcd. C 72.81, H 9.37; found C 72.78, H 9.47.
Its IR and NMR spectra were identical to those of (R)-11.
Methyl (R)-4-tert-Butyldimethylsilyloxy-9-tert-butyldiphenylsilyl-
oxy-2-nonynoate [(R)-12]: A solution of nBuLi in hexane (1.55 , of (R)-14 and (R)-15 (800 mg) in MeOH (10 mL). After stirring for
8.46 mL, 13.1 mmol) was added to a stirred and cooled solution of
(R)-11 (3.23 g, 6.53 mmol) in THF (30 mL) at Ϫ78 °C under argon.
After stirring for 30 min at Ϫ78 °C, ClCO2Me (1.01 mL,
30 min at room temperature, it was evaporated to remove MeOH
and brought to pH 2 with 3  HCl. The mixture was stirred at
room temperature for 2 h, and then extracted with Et2O. The com-
13.1 mmol) was added dropwise. The mixture was allowed to warm bined extracts were successively washed with saturated aqueous
to room temperature with stirring for 3 h. It was then quenched
with water and extracted with Et2O. The combined extracts were
washed with brine, dried with MgSO4, and concentrated in vacuo.
The residue was chromatographed on silica gel (100 g, hexane/
NaHCO3 solution and brine, dried with MgSO4, and concentrated
in vacuo. The residue was chromatographed on silica gel (50 g, hex-
ane/EtOAc, 10:1) to give 244 mg (2 steps, 79%) of (R)-15 as a color-
less oil, n2D6 ϭ 1.4680. [α]2D6 ϭ ϩ36 (c ϭ 1.08, CHCl3). IR (film):
EtOAc, 75:1) to give 3.38 g (94%) of (R)-12 as a colorless oil, n2D6
ϭ
ν˜max. ϭ 3405 (s, OϪH), 1760 (s, CϭO), 1190 [s, C(ϭO)ϪO] cmϪ1
.
Eur. J. Org. Chem. 2004, 1083Ϫ1088
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1087

C. Shibata, K. Mori
FULL PAPER
1H NMR (400 MHz, CDCl3): δ ϭ 1.25Ϫ1.90 (m, 10 H, 3-H, 5-H, CϪH), 2855 (s, CϪH), 1780 (s, CϭO), 1460 (m, CH2), 1385 (w,
6-H, 7-H, 8-H, OH), 2.33 (ddt, J ϭ 6.1, 7.3, 19.3 Hz, 1 H, 3-H), CϪH) 1350 (w, CϪH), 1175 [s, C(ϭO)ϪO), 1020 (w, CϪH), 915
1
2.54 (dd, J ϭ 7.3, 9.3 Hz, 2 H, 2-H), 3.65 (t, J ϭ 6.6 Hz, 2 H, 9-H),
(w, CϪH), 720 (w, CH2) cmϪ1. H NMR (500 MHz, CDCl3): δ ϭ
4.49 (quint, J ϭ 6.1 Hz, 1 H, 4-H) ppm. C9H16O3 (172.2): calcd. C 0.88 (t, J ϭ 7.0 Hz, 3 H, 18-H), 1.27Ϫ1.76 (m, 19 H, 3-H, 5-H, 6-
62.77, H 9.36; found C 62.65, H 9.09.
H, 7-H, 12-H, 13-H, 14-H, 15-H, 16-H, 17-H), 1.81Ϫ1.89 (m, 1 H,
3-H), 1.99Ϫ2.06 (m, 4 H, 8-H, 11-H), 2.32 (ddt, J ϭ 6.5, 7.5, 13 Hz,
1 H, 3-H), 2.53 (ddd, J ϭ 1.3, 7.5, 9.2 Hz, 2 H, 2-H), 4.48 (quint,
J ϭ 6.5 Hz, 1 H, 4-H), 5.35 (dtt, J ϭ 7.1, 12, 18 Hz, 2 H, 9-H, 10-
H) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 14.10, 14.11, 22.7,
24.9, 27.0, 27.2, 28.0, 28.9, 29.3, 29.4, 29.5, 29.7, 31.9, 35.5, 81.0,
129.1, 130.5, 177.3 ppm. MS (EI, 70 eV): m/z (%) ϭ 41 (94), 55
(93), 67 (100), 81 (100), 95 (79), 109 (44), 122 (30), 136 (44), 154
(30), 168 (12), 181 (7), 207 (7), 220 (17), 280 (40) [Mϩ] C18H32O2
(280.5): calcd. C 77.09, H 11.50; found C 77.21, H 11.42. The en-
antiomeric excess of (R)-1 was determined as 95.9% ee and the
(S)-9-Hydroxy-4-nonanolide [(S)-15]: Using the method described
for the preparation of (R)-15, (S)-13 (660 mg, 1.19 mmol) yielded
134 mg (2 steps, 66%) of (S)-15 as a colorless oil, n2D5 ϭ 1.4681.
[α]2D5 ϭ Ϫ36 (c ϭ 1.08, CHCl3). C9H16O3 (172.2): calcd. C 62.77,
H 9.36; found C 62.54, H 9.38. Its IR and NMR spectra were
identical to those of (R)-15.
(R)-9-Oxo-4-nonanolide [(R)-16]: PCC (84 mg, 0.39 mmol) was ad-
ded to a stirred and ice-cooled suspension of powdered molecular
˚
sieves 4 A (20 mg) in a solution of (R)-15 (53 mg, 0.30 mmol) in
´
E/Z ratio was 1.6:98.4 by GC analysis (Dr. A. Cosse).
dry CH2Cl2 (1 mL). After stirring for 1.5 h at room temperature,
the mixture was diluted with Et2O and filtered through silica gel
(2 g), and the filtrate was concentrated in vacuo. The residue was
chromatographed on silica gel (1.0 g, hexane/EtOAc, 20:1) to give
36 mg (68%) of (R)-16 as a colorless oil, n2D6 ϭ 1.4749. [α]2D6 ϭ ϩ53
(c ϭ 0.64, CHCl3). IR (film): ν˜max. ϭ 2725 [m, C(ϭO)ϪH], 1770
(4S,9Z)-9-Octadecen-4-olide [(S)-1]: Using the method described
for the preparation of (R)-1, (S)-16 (39 mg, 0.29 mmol) yielded
55 mg (86%) of (S)-1 as a colorless oil, n2D6 ϭ 1.4681. [α]2D6 ϭ Ϫ23
(c ϭ 1.00, CHCl3). Its IR and NMR and MS spectra were identical
to those of (R)-1. C18H32O2 (280.5): calcd. C 77.09, H 11.50; found
C 76.82, H 11.79. The enantiomeric excess of (S)-1 was determined
as 94.9% ee and the E/Z ratio was 1.6:98.4 by GC analysis (Dr.
(s, CϭO), 1720 [C(ϭO)ϪH], 1180 [s, C(ϭO)ϪO] cmϪ1. H NMR
1
(500 MHz, CDCl3): δ ϭ 1.39Ϫ1.88 (m, 9 H, 3-H, 5-H, 6-H, 7-H,
8-H), 2.32 (ddt, J ϭ 6.7, 7.3, 20.2 Hz, 1 H, 3-H), 2.47 (dt, J ϭ 1.5,
7.5 Hz, 2 H, 9-H), 2.52 (dd, J ϭ 7.3, 9.5 Hz, 2 H, 2-H), 4.48 (quint.
like, J ϭ 6.7 Hz, 1 H, 4-H), 9.77 (t, J ϭ 1.5 Hz, 1 H, CHO). This
was employed in the next step without further purification.
´
A. Cosse).
Acknowledgments
(S)-9-Oxo-4-nonanolide [(S)-16]: Using the method described for
the preparation of (R)-16, (S)-15 (50 mg, 0.29 mmol) yielded 39 mg
(80%) of (S)-16 as a colorless oil, n2D6 ϭ 1.4659. [α]2D6 ϭ Ϫ41 (c ϭ
1.04, CHCl3). This value was not consistent with that of (R)-16.
The reason could not be clarified. Its IR and NMR spectra were
identical to those of (R)-16. This was employed in the next step
without further purification.
´
We thank Drs. R. J. Bartelt, A. Cosse and D. G. James (U.S. De-
partment of Agriculture) for discussion, bioassay and GC analysis
of 1 on a chiral stationary phase. Our thanks are due to Dr. Y.
Hirose (Amano Enzyme Inc.) for his generous supply of lipases.
[1]
´
A. A. Cosse, R. J. Bartelt, D. G. James, R. J. Petroski, J. Chem.
Ecol. 2001, 27, 1841Ϫ1851.
[2]
H. J. Bestmann, W. Stransky, O. Vostrowsky, Chem. Ber. 1976,
(4R,9Z)-9-Octadecen-4-olide [(R)-1]: A solution of NaN(SiMe3)2 in
toluene (1.0 , 8.09 mL, 8.09 mmol) was added to a stirred suspen-
sion of dry nonyltriphenylphosphonium bromide (5.22 g,
10.8 mmol) in dry hexane (50 mL) and the mixture was stirred and
refluxed for 3 h under argon. The resulting orange solution was
transferred to another flask through a cannula under argon, and
was added dropwise to a solution of (R)-16 (90 mg, 0.53 mmol) in
dry THF (2 mL) at Ϫ100 °C under argon. The reaction mixture
was allowed to warm to room temperature with stirring for 30 min,
then quenched with a saturated aqueous NH4Cl solution, and ex-
tracted with Et2O. The combined extracts were successively washed
with water and brine, dried with MgSO4, and concentrated in va-
cuo. The residue was chromatographed on silica gel (20 g, hexane/
109, 1694Ϫ1700.
[3]
[4]
G. H. Posner, N. Johnson, J. Org. Chem. 1994, 59, 7855Ϫ7861.
K. Mori, in Stereoselective Biocatalysis (Ed.: R. N. Patel), Mar-
cel Dekker, New York, 2000, 59Ϫ85.
K. Mori, H. Akao, Tetrahedron Lett. 1978, 4127Ϫ4130.
G. Procter, Asymmetric Synthesis, Oxford Univ. Press, Oxford,
1996, 156Ϫ169.
[5]
[6]
[7]
[8]
K. Burgess, L. D. Jennings, J. Am. Chem. Soc. 1991, 113,
6129Ϫ6139.
M. Fujiwhara, K. Mori, Agric. Biol. Chem. 1986, 50,
2925Ϫ2927.
J. S. Yadav, P. P. Maniyan, Synth. Commum. 1993, 23,
[9]
2731Ϫ2741.
[10]
F. Bohlmann, W.-R. Abraham, Phytochemistry 1979, 18,
1851Ϫ1853.
EtOAc, 40:1) to give 110 mg (68%) of (R)-1 as a colorless oil, n2D6
1.4706. [α]2D6 ϭ ϩ24 (c ϭ 0.50, CHCl3). IR (film): ν˜max. ϭ 2925 (s,
ϭ
Received October 8, 2003
1088
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 1083Ϫ1088