Enantioselective Synthesis of (+)-Juvabione

Full text of DOI:10.1021/jo005516f

5072
J . Org. Chem. 2000, 65, 5072-5074
Sch em e 1
En a n tioselective Syn th esis of
(+)-J u va bion e
Eike J . Bergner and Gu¨nter Helmchen*
Organisch-Chemisches Institut der Universita¨t Heidelberg,
Im Neuenheimer Feld 270, D-69120 Heidelberg, Germany
en4@ix.urz.uni-heidelberg.de
Received May 19, 2000
In tr od u ction
In 1965 (+)-juvabione (1a , Figure 1) was discovered1
due to its high insect juvenile hormone activity.2 Out of
four stereoisomers, the (+)-(4R,1′R)-isomer displays the
highest biological activity.3 For a synthesis of pure
juvabione a high degree of diastereoselectivity is impor-
tant as separation of epi-juvabione, the C-1′ epimer, from
juvabione is difficult. While numerous syntheses of
racemic juvabione are recorded,4 the number of reports
on enantiomerically pure compound (EPC) syntheses of
(+)-juvabione is small: Ex-chiral-pool syntheses were
carried out using (+)-perillaldehyde or (+)-limonene as
starting materials.5 Asymmetric syntheses based on
enzyme controlled reductions (with yeast) were reported
by Mori et al.6 In a formal synthesis, Miles and Brinkman
used an auxiliary controlled alkylation of an organoman-
ganese compound as key step.7
synthesis of juvabione, by Mori.8 Both enantiomers of the
lactone are accessible in high yield and enantiomeric
purity via Pd-catalyzed asymmetric allylic alkylation of
cyclohexenyl acetate with malonates and a few subse-
quent steps.9 The relative configuration of the stereogenic
centers C-4 and C-1′ can be established by diastereose-
lective methylation of the enolate of lactone 2.8 As we
have shown by a synthesis of wine lactone,10 it is possible
to epimerize the center C-1′ via deprotonation-reproto-
nation with complete diastereoselectivity;11 i.e., epi-
juvabione is accessible via an analogous route.12 The
methoxycarbonyl group was introduced by Pd-catalyzed
allylic substitution with acyloxycarbonyl-malonate, a
synthetic equivalent of formiate introduced by Trost,13
and subsequent oxidative degradation and isomerization
of the double bond. In previous syntheses of juvabione,
elongation of the side chain of intermediate 7 required
numerous steps. We have now found an efficient solution
to this problem by Wittig olefination with a C5-ylide to
give a thioenolether and subsequent hydrolysis.
Realization of the plan outlined above is described in
Scheme 2. Methylation of 2 using Mori’s procedure8 gave
3 in 95% yield with diastereomeric purity of >99.9%. The
crucial palladium-catalyzed reaction of lactone 3 with
dimethyl sodio(pivaloyloxy)malonate as nucleophile, ob-
tained by treatment of ester 4b14 with NaH, was carried
out in 88% yield using 1 mol-% of palladium precomplex
and 1.5 mol-% of Ph2PCH2CH2PPh2 (dppe) as ligand
(THF, reflux). Diastereo- and regioselectivity of the allylic
substitution were very high; an isomer of 5 was not
found.15
F igu r e 1. Compounds with juvenile hormone activity isolated
from fir trees.
We now report an efficient synthesis of enantiomeri-
cally pure (+)-juvabione (1a ). Starting material is the
lactone 2 (Scheme 1) which was previously used in
syntheses of natural products by us and, for another
(1) Bowers, W. S.; Fales, H. M.; Thomson, M. J .; Uebel, E. C. Science
1966, 154, 1020-1021.
(2) Sla´ma, K.; Williams, C. M. Proc. Nat. Acad. Sci. U.S.A. 1965,
54, 411-414.
(3) (a) Manville, J . F.; Bock, K.; von Rudloff, E. Phytochemistry 1977,
16, 1967-1971. (b) Numata, A.; Hokimoto, K.; Takemura, T.; Matsu-
naga, S.; Morita, R. Chem. Pharm. Bull. 1983, 31, 436-442. (c) Kawai,
K.; Takahashi, C.; Miyamoto, T.; Numata, A.; Iwabuchi, H.; Yoshikura,
M. Phytochemistry 1993, 32, 331-334. (d) Kawai, K.; Takahashi, C.;
Takada, T.; Numata, A. Phytochemistry 1993, 32, 1163-1165. (e)
Manville, J . F.; Greguss, L.; Sla´ma, K.; von Rudloff, E. Collect. Czech.
Chem. Commun. 1977, 42, 3658-3666.
(8) Nagano, E.; Mori, K. Biosci. Biotech. Biochem. 1992, 56, 1589-
1591.
(9) Review: Helmchen, G. J . Organomet. Chem. 1999, 576, 203-214.
(10) Bergner, E. J .; Helmchen, G. Eur. J . Org. Chem. 2000, 419-
423.
(11) Bartlett, P. A.; Pizzo, C. F. J . Org. Chem. 1981, 46, 3896-3900.
(12) Epimerization of 3 was carried out by deprotonation with LDA
at -78 °C and reprotonation with CH2(COOtBu)2 with diastereoselec-
tivity of 96: 4. After flash chromatography epi-3 was obtained in 70%
yield with diastereomeric purity >99.9%.
(13) (a) Trost, B. M.; Shi, Z. J . Am. Chem. Soc. 1996, 118, 3037-
3038. (b) Trost, B. M.; Kallander, L. S. J . Org. Chem. 1999, 64, 5427-
5435.
(4) Heathcock, C. H.; Graham, S. L.; Pirrung, M. C.; Plavac, F.;
White, T. C. In Total Synthesis of Natural Products; ApSimon, J ., Ed.;
Wiley: New York, 1983; Vol. 5, p 1.
(5) (a) Farges, G.; Veschambre, H. Bull. Soc. Chim. Fr. 1973, 11,
3172-3174. (b) Trost, B. M. Tamaru, Y. J . Am. Chem. Soc. 1977, 99,
3101-3113. (c) Pawson, B. A.; Cheng, H.-C.; Gurbaxani, S.; Saucy, G.
J . Am. Chem. Soc. 1977, 99, 336-343. (d) Craveiro, A. A.; Viera, I. G.
P. J . Braz. Chem. 1992, 124-126. (e) Fuganti, C.; Serra, S. J . Chem.
Soc., Perkin Trans. 1 2000, 97-101.
(6) Watanabe, H.; Shimizu, H.; Mori, K. Synthesis 1994, 1249-1254.
(7) Miles, W. H.; Brinkman, H. R. Tetrahedron Lett. 1992, 33, 589-
592.
(14) Bergner, E. J . Diplomarbeit 1997, Universita¨t Heidelberg.
(15) Under otherwise equal reaction conditions, the reaction with
dimethyl acetoxymalonate (4a ) resulted in 50% cleavage of the acetoxy
group; at room temperature after a reaction time of 24 h, the
substitution product (66%) was still accompanied by the deacetylation
product (10%). This side reaction does not occur with ester 4b.
10.1021/jo005516f CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/19/2000

Notes
J . Org. Chem., Vol. 65, No. 16, 2000 5073
Sch em e 2a
favorably with previous syntheses of (+)-juvabione (1a )
(nine steps, total yield 0.9%,8 10 steps, total yield 2.5%).6
The superior result is mainly due to the more efficient
buildup of the side chain. The bicyclic lactone 2 was
prepared from racemic (()-2-cyclohexen-1-yl acetate in
a five-step synthesis with an overall yield of 47% as
previously reported.10
Exp er im en ta l Section
Gen er a l Meth od s. Melting points and boiling points are
uncorrected. TLC: Machery-Nagel Polygram Sil G/UV precoated
sheets, treatment with I2 and/or aqueous KMnO4 solution for
visualization. For flash chromatography ICN Kieselgel S (0.032-
0.063 mm) was used. 1H and 13C NMR spectra were recorded
on a Bruker AC 300 spectrometer [300.13 MHz (1H), 75.46 MHz
(
13C), CDCl3]. Optical rotations were determined with a Perkin-
Elmer 241 Polarimeter. Reactions in dry solvents were carried
out under an argon atmosphere. Pd(OAc)2 was purchased from
Aldrich; (CH3S)2 and dppe were purchased from Fluka.
2-(2,2-Dim eth yl-p r op ion yloxy)m a lon ic Acid Dim eth yl
Ester (4b). A solution of 2,2-dimethylpropanoic acid (11.2 g, 110
mmol) in dry DMF (50 mL) was added to a suspension of NaH
(2.640 g, 110 mmol) in dry DMF (250 mL) under vigorous stirring
at room temperature. After 30 min stirring brommalonic acid
dimethylester (21.0 g, 100 mmol) was added slowly. The reaction
mixture was further stirred at room temperature for 12 h and
then poured into H2O (400 mL). The resultant mixture was
extracted with diethyl ether and the organic layer was dried over
Na2SO4 and concentrated in vacuo. The crude product was
purified by distillation under reduced pressure (bp 85-87 °C/
1.0 mbar) to give 20.24 g (87%) of 4b as colorless liquid: 1H NMR
(CDCl3) δ ) 1.23 [s, 9H, C(CH3)3], 3.78 (s, 6H, O-CH3), 5.46 [s,
1H, CH(CO)2]; 13C NMR (CDCl3) δ ) 26.6 [q, C(CH3)3], 38.5 [s,
C(CH3)3], 52.9 (q, O-CH3), 71.1 [d, CH(CO)2], 164.8 [s, CH(CO)2],
176.7 [s, O)C-C(CH3)3]. Anal. Calcd for C10H16O6 (232.23): C,
51.72; H, 6.95. Found: C, 51.59; H, 7.10.
The carboxylic acid 5 was reduced with lithium alu-
minum hydride to give the water soluble, crystalline
tetraol 6 in 72% yield. Workup using the procedure of
Mihailovic16 required thorough extraction of aluminum
salts with THF as otherwise the alcohol 6 was obtained
in low yield. Treatment of tetraol 6 with periodate,
esterification of the resultant carboxylic acid with diaz-
omethane and subsequent base-catalyzed isomerization
of the double bond gave ester 7 in 54% yield over three
steps.
(+)-2-[4-[(S)-1-Ca r boxyeth yl]-(1S,4R)-cycloh ex-2-en yl]-2-
(2,2-d im eth ylp r op ion yloxy)m a lon ic Acid Dim eth yl Ester
[(+)-(5)]. A suspension of Pd(OAc)2 (74.0 mg, 0.33 mmol) and
1,2-bis(diphenylphosphino)ethane (197 mg, 0.50 mmol) in dry
THF (40 mL) was stirred at room temperature for 2 h under an
argon atmosphere until a clear, yellow solution resulted, and
(+)-3 (7.82 g, 51.4 mmol, > 99.9% ee) was added to give solution
A. Sodium hydride (95%, 2.00 g, 87.0 mmol) was suspended in
dry THF (130 mL) and ester 4b (23.85 g, 103.0 mmol) was added.
Upon stirring at room temperature a clear, colorless solution
resulted which was transferred into solution A. The reaction
mixture was heated at reflux for 3 h. After cooling, 6 N HCl
(100 mL) was added, and the mixture was extracted repeatedly
with diethyl ether (5 × 200 mL). The organic layer was dried
over Na2SO4 and concentrated in vacuo. Flash chromatography
on silica gel (40 × 5 cm) using petroleum ether/ethyl acetate
Build-up of the side chain via a Wittig-Horner olefi-
nation required access to aldehyde 8. Oxidation of alcohol
7 using the Dess-Martin method gave an excellent result
(yield of 87%).17 Application of the Swern method18 led
to up to 50% epimerization at CR of the aldehyde. For
the chain elongation of 8 a method developed by Warren
et al.19 was employed; this method is a Wittig-Horner
reaction of a lithium derivative of a (methylthio)alky-
lphosphine oxide with an aldehyde to give an alkenyl
sulfide which is hydrolyzed to a ketone. For the present
application, the new reagent 10 was required, which was
prepared in 68% yield by reaction of the known phosphine
oxide 9 with (CH3S)2 using a procedure of Warren et al.20
Phosphine oxide 10 was treated with n-BuLi at -78 °C
to give the lithium derivative which was reacted with
aldehyde 8. The resultant crude alkenyl sulfide 11 was
hydrolyzed with aqueous perchloric acid. Flash chroma-
tography gave pure (+)-juvabione (1a ) in 50% yield (from
aldehyde 8) and pure epi-juvabione (1b) in 3% yield.21
9:1 (0.5% HOAc) as eluent gave 5 (17.41 g, 88%) as a colorless,
1
viscous oil: [R]20 ) +26.7 (c 2.8, CHCl3, >99.9% ee); H NMR
D
(CDCl3) δ 1.15 (d, J ) 6.4 Hz, 3 H, CH3CH), 1.23 [s, 9 H,
C(CH3)3], 1.55-173 (m, 4H, CH2), 2.34-2.41 (m, 2 H, CHCHCH3),
2.93 (mc, 1 H, OCCHCHd), 3.75 (s, 6 H, OCH3), 5.63-5.66 (m,
1 H, dCH), 5.76-5.80 (m, 1 H, dCH), 9.5-11.2 (bs, COOH); 13
C
NMR (CDCl3) δ 14.8 (q, CH3), 20.1 (t, CH2), 22.6 (t, CH2), 26.8
[q, C(CH3)3], 36.2 (d, CHCHCH3), 38.7 [s, C(CH3)3], 41.6 (d,
OCCHCHd), 43.5 (d, CHCHCH3), 52.7, 52.8 (2q, OCH3), 83.6
[s, OC(COOCH3)2], 125.8 (d, dCH), 132.3 (d, dCH), 166.5 (s, 2
COOCH3), 177.1 [s, O)CC(CH3)3], 181.9 (s, COOH). Anal. Calcd
for C19H28O8 (384.43): C, 59.36; H, 7.34. Found: C, 59.38; H
7.34.
(+)-J uvabione (1a ) displayed an optical rotation of [R]25
D
) +66.9 (c 2.57, C6H6, > 99.9 % ee) which is in good
agreement with values previously reported, [R]25
)
D
+62.7 (c 0.45, C6H6)8 and [R]25 ) +64.5 (c 0.57, C6H6).5c
D
In conclusion, our synthesis starting from 2 requires
nine steps and provides a total yield of 14%. It compares
(16) Micovic, V. M.; Mihailovic, M. L. J . Org. Chem. 1953, 18, 1190-
1200.
(17) (a) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4155-
4156. (b) Dess, D. B.; Martin, J . C. J . Am. Chem. Soc. 1991, 113, 7277-
7287.
(18) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651-1660.
(19) Grayson, J . I.; Warren, S. J . Chem. Soc., Perkin Trans. 1 1977,
2263-2272.
(20) (a) Buss, A. D.; Warren, S. J . Chem. Soc., Perkin Trans. 1 1985,
2307-2325. (b) Zell, R. Helv. Chim. Acta 1979, 62, 474-480.
(21) In addition, [(methylthio)alkyl]phosphonic acid esters were used
as acylanion equivalents (Corey, E. J .; Shulman, J . I. J . Org. Chem.
1970, 35, 777-790). The lithium derivative of [3-methyl-1-(methylthio)-
butyl)-phosphonic acid diethyl ester gave incomplete conversion and
side products. One of the side reactions was transesterification of the
methyl to the ethyl ester. Accordingly, [3-methyl-1-(methylthio)-butyl]-
phosphonic acid dimethyl ester was probed. The alkenyl sulfide 11 was
obtained in 40% yield. One of the reasons for the low yield was
incomplete deprotonatiom of the phosphonate with s-BuLi as demon-
strated by quenching with D2O.

5074 J . Org. Chem., Vol. 65, No. 16, 2000
Notes
(+)-2-(4-[(S)-2-Hyd r oxym eth yleth yl]-(1S,4R)-cycloh ex-2-
en yl(p r op a n e-1,2,3-tr iol [(+)-6]. A solution of 5 (3.69 g, 9.60
mmol, >99.9% ee) in dry THF (15 mL) was added dropwise to a
stirred, cold (0 °C) suspension of lithium aluminum hydride (3.65
g, 96.1 mmol) in dry THF (70 mL). The reaction mixture was
heated at reflux for 5 h. After cooling, the mixture was diluted
with diethyl ether (200 mL) and cooled to 0 °C. Then water (3.7
mL), NaOH (3.7 mL, c ) 15%), and water (11 mL)16 were added
slowly with vigorous stirring. After further stirring for 12 h, the
white precipitate of aluminum salts was filtered off and washed
with THF extracted twice with boiling THF (100 mL). The THF
solutions were combined, dried over Na2SO4, filtered, and
concentrated in vacuo. Recrystallization from acetone/n-hexane
(m, 1 H, P-CH), 7.43-7.54 (m, 6 H, Ar-H), 7.79-7.91 (m, 4 H,
Ar-H); 13C NMR (CDCl3) δ 14.2 (q, SCH3), 20.7 [q, CH(CH3)2],
23.4 [q, CH(CH3)2], 24.8 [d, CH(CH3)2], 35.4 (t, CH2), 40.9 (dd, J
) 71.5 Hz, P-CH), 128.3, 128.4, 128.5, 128.6, 131.1, 131.2, 131.5,
131.6, 131.7 (Ar-C); 31P NMR (CDCl3) δ 33.3. Anal. Calcd for
C
18H23OPS (245.32): C, 67.87; H, 7.28; P, 9.79; S, 10.08.
Found: C, 67.77; H, 7.23; P, 9.73; S, 9.90.
(+)-(4R)-[(S)-Meth yl-2-oxo-eth yl]-cycloh ex-1-en eca r box-
ylic Acid Meth yl Ester [(+)-8]. A solution of 7 (397 mg, 2.00
mmol, >99.9% ee) in CH2Cl2 (5 mL) was added to a suspension
of Dess-Martin periodinane (933 mg, 2.2 mmol) in CH2Cl2 (10
mL). After the mixture was stirred at room temperature for 45
min, a mixture of Na2S2O3 (4 g) and saturated NaHCO3 solution
(15 mL) was added and the reaction mixture was stirred for 20
min. The organic layer was separated, and the aqueous layer
was extracted with diethyl ether. The organic layer was dried
over Na2SO4 and concentrated in vacuo. Flash chromatography
on silica gel (25 × 3 cm) using petroleum ether/ethyl acetate
yielded 1.59 g (72%) of 6 as white solid: mp 95-97 °C; [R]20
)
D
+9.57 (c 3.8, CH3OH, >99.9% ee); 1H NMR (CDCl3) δ 0.92 (d, J
) 6.9 Hz, 3 H, CH3), 1.50-1.70 (m, 5 H, CHCH3, CH2CH2), 2.01-
2.15 (mc, 1 H, OCCHCHd), 2.44 (mc, 1 H, CHCHCH3), 3.42 (dd,
J ) 10.7, 6.6 Hz, 1 H, CH2CHCH3), 3.55-3.65 [m, 5 H, CH2-
CHCH3, C(CH2OH)2], 5.74-5.84 (m, 2 H, HCdCH); 13C NMR
(CDCl3) δ 14.9 (q, CH3), 21.7, 24.4 (t, CH2-CH2), 37.1 [d, CHC-
(CH2OH)2], 40.2 (d, CHCHCH3), 41.2 (d, CHCHCH3), 64.9, 65.3
[t, C(CH2OH)2], 66.4 (t, H3CCHCH2OH), 77.0 [s, C(CH2OH)2],
128.6 (d, dCH), 133.5 (d, dCH). Anal. Calcd for C12H22O4
(230.30): C, 62.58; H, 9.63. Found: C, 62.38; H, 9.93.
9:1 as eluent gave (+)-8 (342 mg, 87%) as a colorless oil: [R]21
D
) +121.8 (c 2.57, CHCl3, >99.9% ee); 1H NMR (CDCl3) δ 1.09
(d, J ) 7.1 Hz, 3 H, CCH3), 1.26-1.40 (m, 1 H, CH2), 1.66-1.80
(m, 1 H, CH2), 1.90-2.48 (m, 6 H, CH2, CHCHCH3, CHCH3),
3.71 (s, 3 H, OCH3), 6.91-6.93 (m, 1 H, CdCH), 9.66-9.67 (m,
1 H, HCdO); 13C NMR (CDCl3) δ 10.1 (q, CCH3), 24.1 (t, CH2),
24.6 (t, CH2), 30.0 (t, CH2), 33.3 (d, CHCHCH3), 50.3 (d, HCCH3),
51.6 (q, OCH3), 130.2 (s, CdCH), 138.2 (s, CdCH), 167.6 (s,
COOCH3), 204.6 (d, HCdO). Anal. Calcd for C11H16O3 (196.25):
C, 67.32; H, 8.22. Found: C, 67.03; H, 8.12.
(+)-(4R)-4-[(S)-2-Hyd r oxy-1-m eth yleth yl]cycloh ex-1-en e-
ca r boxylic Acid Meth yl Ester [(+)-7]. A solution of 6 (991
mg, 4.3 mmol, >99.9% ee) in water (40 mL) was added to a
solution of NaIO4 (2.76 g, 13.0 mmol) in water (20 mL). The
mixture was stirred for 2 h at room temperature and then
acidified with 6 N HCl. The resultant suspension was repeatedly
extracted with diethyl ether. The organic layer was dried over
Na2SO4 and concentrated in vacuo to give a yellow oil. This was
dissolved in diethyl ether (20 mL) and treated with a ethereal
solution of diazomethane until the yellow color persisted. The
solvent was removed and the residue was dissolved in methanol
(4 mL) and the solution added to a solution of NaOMe in
methanol (5 mL). After stirring for 1.5 h at room temperature,
water was added and the mixture was extracted with diethyl
ether. The organic layer was dried over Na2SO4 and concentrated
in vacuo. Flash chromatography on silica gel (20 × 3 cm) using
petroleum ether/ethyl acetate 9:1 as eluent gave 7 (460 mg, 54%)
(+)-(4R)-[(S)-1,5-Dim et h yl-3-oxo-h exyl]cycloh ex-1-en e-
ca r boxylic Acid Meth yl Ester [(+)-J u va bion e] [(+)-1a ]. A
solution of n-butyllithium (1.1 mL, 1.8 mmol, c ) 1.6 M in
n-hexane) was added slowly to a cooled solution (-78 °C) of 621
mg (1.95 mmol) of 10 in dry THF (10 mL). After being stirred
for 90 min, the mixture was allowed to warm to room temper-
ature and added dropwise to a cooled solution (-78 °C) of 294
mg (1.5 mmol, >99.9% ee) of the aldehyde 8 in dry THF (10 mL).
The reaction mixture was stirred at -78 °C for 6 h treated with
sadt. NH4Cl solution (40 mL) and extracted with CH2Cl2. The
organic layer was dried over Na2SO4 and concentrated in vacuo.
A solution of the residue in 20 mL of diethyl ether was added to
aqueous HClO4 (35%, 20 mL,). After stirring for 2 h at room
temperature and neutralization with solid NaHCO3, the mixture
was extracted with diethyl ether and the organic layer dried over
Na2SO4. After concentration in vacuo flash chromatography on
silica gel (35 × 3 cm), using petroleum ether/ethyl acetate 98:2
as eluent, gave (+)-juvabione (1) (201 mg, 50%) as a colorless
oil: [R]25D ) +66.9 (c 2.57, C6H6, >99.9% ee) (lit.8 [R]D25 ) +62.7
(c 0.45, C6H6)); 1H NMR22 (CDCl3) δ 0.86 (d, J ) 6.8 Hz, 3 H,
1′-CH3), 0.89 [d, J ) 6.6 Hz, 3 H, CH(CH3)2], 0.90 [d, J ) 6.6
Hz, 3 H, CH(CH3)2], 1.12-1.20 (m, 1 H, CH2), 1.35-1.39 (m, 1
H, 4-H), 1.72-1.85 (m, 1 H, CH2), 1.90-2.46 [sh, 10 H, 1′-H,
CH(CH3)2, CH2], 3.67 (s, 3 H, OCH3), 6.89-6.91 (m, 1 H, Cd
CH); 13C NMR (CDCl3) δ 16.5 (q, 1′-CH3), 22.5 [q, CH(CH3)2],
22.6 [q, CH(CH3)2], 24.5 [d, CH(CH3)2], 24.7 (t, CH2), 24.8 (t,
CH2), 29.7 (t, dCHCH2), 32.6 (d, C-1′), 37.7 (d, C-4), 47.8 (t, C-2′),
51.4 (q, OCH3), 52.4 [t, CH2CH(CH3)], 130.1 (s, CdCH), 139.2
(d, CdCH), 167.7 (s, COOCH3), 210.4 (s, CH2COCH2).
as pale yellow oil: [R]20 ) +91.4 (c 2.96, CHCl3, >99.9% ee);
D
1H NMR (CDCl3) δ 0.89 (d, J ) 6.7 Hz, 3 H, HCCH3), 1.11-1.24
(m, 1 H, CH2), 1.48-1.62 (m, 2 H, CHCHCH3), 1.75-2.44 (m, 5
H, CH2), 3.47 (dd, J ) 10.6, 6.2 Hz, 1 H, CH2OH), 3.59 (dd, J )
10.6, 5.4 Hz, 1H, CH2OH), 3.67 (s, OCH3), 6.90-6.92 (m, 1H,
dCH); 13C NMR (CDCl3) δ 13.2 (q, CCH3), 24.3 (t, CH2), 24.4 (t,
CH2), 30.1 (t, CH2), 34.2 (d, CHCHCH3), 39.3 (d, CHCHCH3),
51.3 (q, OCH3), 65.7 (t, CH2OH), 129.9 (s, )CCOOCH3), 139.3
(d, dCH), 167.7 (s, COOCH3). Anal. Calcd for C11H18O3
(198.26): C, 66.64; H, 9.15. Found: C, 66.30; H, 9.28.
[3-Meth yl-1-(m eth ylth io)bu tyl]d ip h en ylp h osp h in e Ox-
id e (10). Under an argon atmosphere, a solution of (3-methyl-
butyl)diphenylphosphine oxide (4.50 g, 16.4 mmol) and freshly
distilled TMEDA (2.9 mL, 19.3 mmol) in dry THF (80 mL) was
cooled to -78 °C. Then n-butyllithium (12.7 mL, 19.4 mmol, c
) 1.6 M in n-hexane) was added slowly. The resultant orange
solution was stirred for 60 min and then treated at -78 °C with
a solution of dimethyl disulfide (1.70 mL 19.2 mmol) in dry THF
(15 mL). The resultant mixture was stirred for 60 min at -78
°C and allowed to warm to room temperature. Then 2 N NaOH
(90 mL) was added and the mixture was extracted with CH2-
Cl2. The organic layer was dried over Na2SO4 and concentrated
in vacuo. Recrystallization from ethyl acetate yielded 3.63 g
(68%) 10 as colorless needles: mp 144-145 °C; 1H NMR (CDCl3)
δ 0.87 [d, J ) 6.5 Hz, 3 H, CH(CH3)2], 0.90 [d, J ) 6.7 Hz, 3 H,
CH(CH3)2], 1.46-1.52 (m, 1 H, CH2), 1.76-1.77 (m, 1 H, CH2),
2.00 (s, 3 H, SCH3), 2.02-2.06 [m, 1 H, CH(CH3)2], 3.02-3.10
Ack n ow led gm en t. This work was supported by the
Deutsche Forschungsgemeinschaft (SFB 247) and the
Fonds der Chemischen Industrie. We thank Mrs. Olena
Tverskoy for skillful technical assistance.
J O005516F
(22) The assignment of the resonances is based on 1H-1H COSY,
HMQC and HMBC experiments.