Convenient formation of 4-hydroxyalk-2-en-1-one functionality via a Knoevenagel-type carbon chain elongation reaction of aldehyde with 1-arylsulfinylalkan-2-one

Article abstract of DOI:10.1021/jo001323g

A highly functionalized four-carbon unit, 4-hydroxyalk-2-en-1-one functionality [R²CH(OH)CH= CHCOR¹], was conveniently prepared by a reaction of an aldehyde (R²CH₂CHO) with a 1-(arylsulfinyl)alkan-2-one [ArS(O)CH₂COR¹] in the presence of diethylamine (Knoevenagel condition). Other functional groups, such as carbonyl and hydroxy groups, in both of the alkyl chains (R¹, R²) did not prevent this reaction. This reaction was used to conveniently prepare (±)-(11E)-13-hydroxy-10-oxooctadec-11-enoic acid (14), having cytotoxic activity, and its analogues from undec-10-enoic acid in good yield.

Full text of DOI:10.1021/jo001323g

1228
J . Org. Chem. 2001, 66, 1228-1232
Con ven ien t F or m a tion of 4-Hyd r oxya lk -2-en -1-on e F u n ction a lity
via A Kn oeven a gel-typ e Ca r bon Ch a in Elon ga tion Rea ction of
Ald eh yd e w ith 1-Ar ylsu lfin yla lk a n -2-on e
J unzo Nokami,* Kazuhide Kataoka, Kazuhiro Shiraishi, Masahiro Osafune,
Iqbal Hussain, and Shin-ichi Sumida
Department of Applied Chemistry, Faculty of Engineering, Okayama University of Science, 1-1 Ridai-cho,
Okayama 700-0005, J apan
nogami@dac.ous.ac.jp
Received September 5, 2000
A highly functionalized four-carbon unit, 4-hydroxyalk-2-en-1-one functionality [R2CH(OH)CHd
CHCOR1], was conveniently prepared by a reaction of an aldehyde (R2CH2CHO) with a 1-(aryl-
sulfinyl)alkan-2-one [ArS(O)CH2COR1] in the presence of diethylamine (Knoevenagel condition).
Other functional groups, such as carbonyl and hydroxy groups, in both of the alkyl chains (R1, R2)
did not prevent this reaction. This reaction was used to conveniently prepare (()-(11E)-13-hydroxy-
10-oxooctadec-11-enoic acid (14), having cytotoxic activity, and its analogues from undec-10-enoic
acid in good yield.
In tr od u ction
ployed for organic syntheses.5 This is a useful functional-
ity which occurs in the structure of some biologically
attractive natural products, especially macrolides such
as brefeldin A.5a,b
The construction of the carbon skeleton through car-
bon-carbon (C-C) bond formation and the functional-
ization of an appropriate carbon atom to form functional
groups are essential in organic synthesis. Subsequently,
in many approaches to C-C bond formation, a variety
of carbon-nucleophiles have been reacted with various
carbonyl compounds (aldehydes and ketones). Among
those, the Knoevenagel reaction1 of aldehydes using
active methylene compounds with a secondary amine are
useful tools for convenient carbon chain elongation along
with functionalization of the aldehyde to give R,â-
unsaturated carbonyls or nitriles.
Among the reactions utilizing sulfinyl-activated me-
thylene compounds, we are also very interested in the
reaction of 1-arylsulfinylalkan-2-one 5 with aldehydes,
because it is capable of introducing more than two
carbons into the carbon chain of an aldehyde to give a
wide variety of 4-hydroxyalk-2-en-1-ones [R2CH(OH)CHd
CHCOR1] with various substituents (R1), rather than 1
and 3.6 Here, we examine further the reaction of 5 with
aldehydes in the synthesis of highly functionalized
compounds having the 4-hydroxyalk-2-en-1-one unit 6.
In the early 1980s, we discovered that a Knoevenagel-
type reaction of aldehydes and ketones with 2-arylsulfi-
nylacetonitrile 1 gave a highly functionalized four-carbon
unit, 4-hydroxyalk-2-enenitrile 2, in high yield.2 This
reaction is interesting in organic synthesis, because it
gives a highly functionalized four-carbon (C4) unit from
normal aldehydes or ketones with two-carbon elongation
of the carbonyls similar to a Horner-Wadsworth-
Emmons (HWE) reaction.3 However, unlike the HWE
reaction, the C4 unit can be obtained without using an
R-hydroxyaldehyde or its synthetic equivalent, such as
an R-triorganosilyloxyaldehyde. Similar reactions of alkyl
2-arylsulfinyl acetates 3 with aldehydes to give alkyl
4-hydroxyalk-2-enoates 4 were also reported4 and em-
Resu lts a n d Discu ssion
Various â-keto sulfoxides (1-arylsulfinylalkan-2-ones)
5 were conveniently prepared by employing well-known
methods as follows (Figure 3):
(1) Oxidation of the corresponding sulfide (â-keto
sulfide) 7a ,b to sulfoxide 5a ,b, with mCPBA.
(2) Reaction of dianion 8 derived from 5a ,b with
alkylhalides and aldehyde to 5c,d and 5e, respectively.7
(3) Reaction of arylsulfinylcarbanion8 9 with carboxylic
ester to 5f-i.
(4) Oxidation of â-hydroxy sulfide 10 to â-hydroxy
sulfoxide 11 via transition metal-catalyzed oxidation with
hydrogen peroxide9,10a or tert-butyl hydroperoxide,10b-d or
(1) (a) J ones, G. Org. Reactions 1967, 15, 204-599. (b) Tietze, L.;
Beifuss, J . Comprehensive Organic Synthesis; Trost, B. M. Ed.;
Pergamon: 1991; Vol. 2, pp 341-394.
(2) Nokami, J .; Mandai, T.; Imakura, Y.; Nishiuchi, K.; Kawada, M.;
Wakabayashi, S. Tetrahedron Lett. 1981, 22, 4489-4490. Ono, T.;
Tamaoka, T.; Yuasa, Y.; Matsuda, T.; Nokami, J .; Wakabayashi, S. J .
Am. Chem. Soc. 1984, 106, 7890-7893. Nokami, J .; Mandai, T.;
Nishimura, A.; Takeda, T.; Wakabayashi, S.; Kunieda, N. Tetrahedron
Lett. 1986, 27, 5109-5112.
(3) Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863-927.
(4) (a) Cass, Q. B.; J axa-Chamiec, A. A.; Sammes, P. G.; J . C. S.,
Chem. Commun. 1981, 1248-1250. (b) Tanikaga, R.; Nozaki, K.;
Tanaka, K.; Kaji, A. Chem. Lett. 1982, 1703-1706. (c) Tanikaga, R.;
Nozaki, K.; Tamura, T.; Kaji, A. Synthesis 1983, 134-135.
(5) (a) Corey, E. J .; Carpino, P. Tetrahedron Lett. 1990, 31, 7555-
7558. (b) Nokami, J ., Ohkura, M.; Dan-oh, Y.; Sakamoto, Y. Tetrahe-
dron Lett. 1991, 32, 2409-2412. (c) Nokami, J .; Taniguchi, T.; Gomyo,
S.; Kakihara, T. Chem. Lett. 1994, 1103-1106.
(6) Nokami, J .; Nishimura, A.; Sunami, M. Wakabayashi, S. Tetra-
hedron Lett. 1987, 28, 649-650.
(7) (a) Grieco, P. A.; Pogonowski, C. S. J . Org. Chem. 1974, 39, 732-
734. (b) Kuwajima, I.; Iwasawa, H. Tetrahedron Lett. 1974, 107-110.
(8) Tsuchihashi, G.; Iriuchijima, S.; Ishibashi, M. Tetrahedron Lett.
1972, 4605-4608.
(9) Watanabe, Y.; Numata, T.; Oae, S. Synthesis 1981, 204-206.
10.1021/jo001323g CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/31/2001

Formation of 4-Hydroxyalk-2-en-1-one Functionality
J . Org. Chem., Vol. 66, No. 4, 2001 1229
F igu r e 4. Reactivity of 12 to 6c.
The â-keto sulfoxides 5a -j obtained using the methods
1-4 were treated with aldehydes and diethylamine (in
the presence or absence of a small amount of acetic acid)
in propanenitrile to give 4-hydroxy-2-alkenones 6a -l. In
the presence of acetic acid, 6 was obtained in a shorter
reaction time, thus giving a higher yield than that in the
absence of acetic acid. This may be due to an acceleration
of the dehydration step in the Knoevenagel reaction by
the acid catalyst. The results are summarized in Table
1.12 The results for 5j are discussed later in the synthesis
of the fatty acid 14.
F igu r e 1. Two-carbon elongation of aldehydes by Knoevena-
gel reaction with sulfinyl-activated methylene compounds 1
and 3.
Although the reaction of 1-arylsulfinylpropan-2-one
5a ,b with hexanal and citronellal gave the corresponding
5-hydroxyalk-4-en-2-one 6a and 6b in good yield (entries
1-3), the reaction with cyclohexanecarboxaldehyde gave
the desired 6c in very poor yield (18%) together with its
precursor 12 (35%), although 5b was recovered in 31%
(entry 4). This may have been caused by the remarkably
slow rate of migration of the double bond from Râ (12) to
âγ (13) due to a lower acidity of the methine proton at
the γ-position of the sulfinyl group compared with that
in other cases (Figure 4).
F igu r e 2. More than two carbons elongation of aldehydes by
â-keto sulfoxides 5.
Carbonyl (ketone and ester) functionalities in both
â-keto sulfoxide (R1) and aldehyde (R2) did not prevent
the desired reaction (entries 5, 6, 11, and 14). Reaction
of the compound having the free hydroxy group 5e also
gave the desired product 6h without protection of the
hydroxy group (entry 9). Some protecting groups, such
as tert-butyldimethylsilyloxy13 in 5h and ketal (2,2-
ethylenedioxy) in 5i, were stable under the reaction
conditions (entries 12 and 13).
We employed this reaction in the synthesis of the
biologically attractive natural compound (fatty acid) from
undec-10-enoic acid (15) as shown below.
Syn th esis of (()-(11E)-13-Hyd r oxy-10-oxoocta d ec-
11-en oic Acid (14).14 (()-(11E)-13-Hydroxy-10-oxoocta-
dec-11-enoic acid (14) was discovered in corn extract and
was shown to be a stronger cytotoxic fatty acid than
linoleic acid.15 A retrosynthetic study of 14 based on our
reaction suggested that undec-10-enoic acid (15) could
be useful for this synthesis. That is, the terminal olefin
will be easily convertible into 1-arylthioalkan-2-ol via 1,2-
epoxide or 1,2-diol and then to â-keto sulfoxide. The
synthesis of 14 was carried out as follows.
F igu r e 3. Synthetic methods for various â-keto sulfoxides 5.
Undec-10-enoic acid (15) was converted to the corre-
sponding 10,11-epoxy ester 16 by mCPBA-oxidation of
via conventional oxidation with mCPBA, followed by an
improved Swern’s oxidation11 of â-hydroxy sulfoxide 11
to 5j.
(12) Note that all of the reactions in the tables were not completely
optimized. It is well-known that aldehydes are not very stable,
especially in the case of R-methylene aldehyde, due to the high
reactivities under basic and acidic conditions, at high temperature
(undesired reactions such as aldol and/or Cannizzaro reactions take
place very easily). Therefore, we had to choose the reaction conditions
carefully to obtain the desired product in high yield. This means that
the complete consumption of 5 did not always allow for the best yield
and sometimes gave a large amount of byproducts due to side reactions
of the aldehyde over the long reaction time, which resulted in a low
yield by contamination of inseparable byproducts and decomposition
of the desired product.
(10) Many methods have been developed for asymmetric oxidation
of sulfides to optical active sulfoxides, in which hydrogen peroxide or
tert-butyl hydroperoxide was used as an oxidant with a catalytic
amount of chiral transition metal (Mn, Ti, Mo) complexes, for ex-
ample: H2O2: (a) Palucki, M.; Hanson, P.; J acobsen E. N. Tetrahedron
Lett. 1992, 33, 7111-7114. t-BuOOH: (b) Kagan, H. B.; Pitchen, P.
Tetrahedron Lett. 1984, 25, 1049-1052. (c) Pitchen, P.; Dun˜ach, E.;
Deshmukh, M. N.; Kagan, H. B. J . Am. Chem. Soc. 1984, 106, 8188-
8193. (d) Komatsu, N.; Hashizume, M.; Sugita, T.; Uemura, S. J . Org.
Chem. 1993, 58, 4529-4533.
(13) Nokami, J .; Taniguchi, T.; Ogawa, Y. Chem. Lett. 1995, 43-
44.
(11) Mancuso, A. J .; Huang, S.-L.; Swern, D. J . Org. Chem. 1978,
43, 2480-2482.
(14) Preliminary report: Nokami, J .; Osafune, M.; Shiraishi, K.;
Sumida, S.; Imai, N. J . Chem. Soc., Perkin Trans. 1 1997, 2947-2948.

1230 J . Org. Chem., Vol. 66, No. 4, 2001
Ta ble 1. F or m a tion of 4-h yd r oxy-2-a lk en on e Un it by Rea ction of 5 w ith Ald eh yd es 7a
Nokami et al.
a
All reactions were performed with 5 (0.5-1.0 mmol), aldehyde (2.0 equiv), diethylamine (2.0 equiv), and acetic acid (0.5 equiv) in
propanitrile, unless otherwise noted. 3-(4-Chlorophenylsulfinyl)-4-cyclohexylbut-3-en-2-one 12 was obtained in 34% yield. c Reaction
b
was performed in the absence of acetic acid.
Sch em e 1a -g
the ester. Treatment of 16 with thiol and a base (K2CO3)
in acetone gave the â-hydroxy sulfide 10a quantitatively.
The â-hydroxy sulfide 10a was converted to sulfoxide 11a
by mCPBA-oxidation and then to the corresponding
â-keto sulfoxide 5j by Swern’s oxidation using an excess
amount (20 equiv) of dimethyl sulfoxide.16 Isopropyl 10-
oxo-11-(phenylsulfinyl)undecanoate (5j) was allowed to
react with heptanal (2 equiv) in the presence of diethy-
lamine (2 equiv) and acetic acid (0.5 equiv) in propaneni-
trile at 70 °C for 2 h to give isopropyl 13-hydroxy-10-
oxooctadec-11-enoate (6m ) in 76% yield. Hydrolysis of the
ester 6m was carried out enzymatically by lipase PS
(from Pseudomonas cepacia, Amano) in THF/phosphate
buffer (1/8 v/v) to give the acid (()-14, which was fully
characterized by spectral data, e.g., IR spectra due to the
carboxy group (COOH: 3500-2700 and 1709 cm-1) and
1H and 13C NMR of the carbon skeleton (disappearance
of the isopropyl group from 6m ).As shown above, this
synthesis was very convenient, because undec-10-enoic
acid (15) is inexpensive, and all of the reactions used here
are very common and easy to handle. The total yield of
14 from 15 (seven steps) was 42%. Moreover, its ana-
logues 6n -q were easily prepared by the reaction of 5j
with various aldehydes (Table 2).
a
b
d
PriOH, H+. mCPBA. c PhSH, K2CO3. mCPBA. e (COCl)2,
DMSO (20 equiv), Et3N. f Heptanal, Et2NH. g Lipase PS, phosphate
buffer.
Ta ble 2. Rea ction of 5j w ith Va r iou s Ald eh yd es in th e
P r esen ce of Dieth yla m in e a n d Acetic Acid a ,b
Exp er im en ta l Section
1
Gen er a l Meth od s. H NMR (300 MHz) and 13C NMR (75
a
b
The reaction was performed in propionitrile at 70 °C. The
MHZ) spectra were obtained CDCl3 unless noted otherwise.
High-resolution mass spectra were obtained in the Analysis
values in the parentheses show the result in the absence of acetic
acid. c R1 ) (CH2)8CO2Pri in 6 [R2CH(OH)CHdCHCOR1].
Center of our university. Elemental analyses were performed
in our laboratory. Tetrahydrofuran (THF) and diethyl ether
were distilled from benzophenone ketyl. Acetonitrile and
propanenitrile were dried over phosphorus pentoxide and
stored. Diethylamine and diisopropylamine were distilled from
calcium hydride and stored over molecular sieves. Methanol
and ethanol were distilled from Mg(OMe)2 and Mg(OEt)2,
respectively. Commercially available reagents were used
without further purification.
Rea ction of â-Keto Su lfoxid es 5 w ith Ald eh yd es in th e
P r esen ce of Dieth yla m in e
Rea ction of 1-(P h en ylsu lfin yl)p r op a n -2-on e (5a ) w ith
Hexa n a l to 5-Hyd r oxyn on -3-en -2-on e (6a ). To a solution
of 5a (100 mg, 0.55 mmol), diethylamine (94 µL, 1.10 mmol),
(15) (a) Kuga, H.; Ejima, A.; Mitui, I.; Sato, K.; Ishihara, N.; Fukuda,
K.; Saito, F.; Uenakai, K. Biosci. Biotech. Biochem. 1993, 57, 1020-
1021. (b) Hayashi, Y.; Ishihara, N.; Takahashi, M.; Fujii, E.; Uenakai,
K.; Masada, S.; Ichimoto, I. Biosci. Biotech. Biochem. 1996, 60, 1115-
1117. (c) Enantioselective syntheses of R- and S-14 and their lactones
R- and S-10-oxo-11(E)-octadecen-13-olide from linoleic acid via soybean
lipoxygenase oxidation have been reported, in which it was also
described that their in vitro cytotoxic activities (IC50 values against
tumorial cell P388) were scarcely affected by their configurations;
Matsushita, Y.; Sugamoto, K.; Nakama, T.; Matsui, T.; Hayashi, Y.;
Uenakai, K. Tetrahedron Lett. 1997, 38, 6055-6058. (d) More recently,
synthesis of S-14 was reported; Sharma, A.; Chattopadhya, S. Enan-
tiomer 1998, 3, 225-229.
(16) Although the same result was obtained when more than 20
equiv of DMSO was used, the use of less than 15 equiv of DMSO gave
a TLC detectable amount of the corresponding â-keto sulfide.

Formation of 4-Hydroxyalk-2-en-1-one Functionality
J . Org. Chem., Vol. 66, No. 4, 2001 1231
and acetic acid (16 µL, 0.28 mmol) in propanenitrile (5 mL)
was added hexanal (99 µL, 1.10 mmol) under nitrogen at room
temperature. The reaction mixture was stirred for 6 h and then
diluted with ethyl acetate (or chloroform). The mixture was
washed with brine, dried, and concentrated under reduced
pressure. The residue was column chromatographed on silica
gel to give the oil 6a (70 mg, 82%): 1H NMR δ 0.92 (t, J ) 7.0
Hz, 3H), 1.30-1.46 (m, 4H), 1.56-1.68 (m, 2H), 1.75 (br, 1H),
2.28 (s, 3H), 4.28-4.37 (m, 1H), 6.27 (dd, J ) 16.0, 1.6 Hz,
1H), 6.77 (dd, J ) 16.0, 5.2 Hz, 1H); 13C NMR δ 14.0, 22.6,
27.3, 36.4, 71.1, 129.0, 149.6, 199.1; IR (neat) 3432, 2958, 2932,
2861, 1676, 1630, 981 cm-1. Anal. Calcd for C9H16O2: C, 69.19;
H, 10.32. Found: C, 69.44; H, 10.57.
1-P h en yl-5-h yd r oxyn on -3-en -2-on e (6i): 1H NMR δ 0.90
(t, J ) 7.3 Hz, 3H), 1.26-1.39 (m, 4H), 1.52-1.66 (m, 2H),
1.55 (br, 1H), 3.85 (s, 2H), 4.25-4.33 (m, 1H), 6.35 (dd, J )
15.8, 1.5 Hz, 1H), 6.87 (dd, J ) 15.8, 4.9 Hz, 1H), 7.19-7.37
(m, 5H); 13C NMR δ 14.3, 22.9, 27.7, 36.7, 48.5, 71.6, 127.3,
127.4, 129.1, 129.8, 134.6, 149.6, 197.9; IR (neat) 3423, 3063,
2957, 2932, 2871, 2860, 1686, 1629, 984 cm-1; HMRS (EI) calcd
for C13H20O2 232.1463, found 232.1468.
Meth yl 9-h yd r oxy-6-oxotr id ec-7-en oa te (6j): 1H NMR δ
0.92 (t, J ) 6.8 Hz, 3H), 1.28-1.44 (m, 4H), 1.59 (br, 1H), 1.58-
1.65 (m, 6H), 2.34 (t, J ) 6.9 Hz, 2H), 2.59 (t, J ) 6.8 Hz, 2H),
3.67 (s, 3H), 4.27-4.36 (m, 1H), 6.30 (dd, J ) 15.9, 1.7 Hz,
1H), 6.80 (dd, J ) 15.9, 4.9 Hz, 1H); 13C NMR δ 13.8, 22.4,
23.3, 24.3, 27.3, 33.7, 36.3, 40.0, 51.4, 71.0, 127.7, 148.3, 173.9,
200.2; IR (neat) 3446, 2956, 2935, 2875, 1735, 1676, 1633, 986
cm-1. Anal. Calcd for C14H24O4: C, 65.60; H, 9.44. Found: C,
65.89; H, 9.68.
6,10-Dim eth yl-5-h yd r oxyu n d eca -3,9-d ien -2-on e (6b): 1H
NMR δ 0.91 and 0.94 (d, J ) 6.9 Hz for δ 0.91, d, J ) 6.8 Hz
for δ 0.94, 3H), 1.12-1.19 (m, 2H), 1.43-1.81 (m, 2H), 1.61 (s,
3H), 1.69 (s, 3H), 1.88-2.14 (m, 2H), 2.28 (s, 3H), 4.22 and
4.27 (m, 1H), 5.04-5.13 (m, 1H), 6.30 (d, J ) 16.0 Hz, 1H),
6.77 (dd, J ) 16.0, 4.9 Hz, 1H); 13C NMR δ 14.4, 15.3, 18.0,
25.8, 25.9, 26.0, 27.7, 32.5, 33.2, 38.4, 38.7, 74.7, 75.5, 124.5,
130.0, 130.4, 132.1, 148.2, 149.0, 199.0; IR (neat) 3448, 2966,
2925, 2877, 2857, 1674, 1630, 983, 829 cm-1; HMRS (EI) calcd
for C13H22O2 210.1620, found 210.1609.
2-(ter t-Bu tyld im eth ylsilyloxy)-9-h yd r oxytr id ec-6-en -5-
1
on e (6k ): H NMR δ 0.03 (s, 3H), 0.04 (s, 3H), 0.88 (s, 9H),
0.89 (t, J ) 6.5 Hz, 3H), 1.14 (d, J ) 6.1 Hz, 3H), 1.24-1.36
(m, 8H), 1.54-1.84 (br, 1H), 1.75 (m, 2H), 2.54-2.70 (m, 2H),
3.79-3.90 (m, 1H), 4.26-4.37 (m, 1H), 6.30 (dd, J ) 15.9, 1.6
Hz, 1H), 6.79 (dd, J ) 15.9, 5.0 Hz, 1H); 13C NMR δ -4.8, -4.5,
13.9, 18.0, 22.5, 23.7, 24.9, 25.8, 31.6, 33.3, 36.6, 67.5, 71.1,
127.9, 148.0, 200.7; IR (neat) 3431, 2956, 2930, 2858, 1669,
1633, 1471, 986 cm-1; HMRS (EI) calcd for C19H38O3Si,
342.2592, found 342.2636.
1-(3-Oxo-1-bu ten yl)cycloh exa n ol (6c) a n d 3-(4-Ch lor o-
p h en ylsu lfin yl)-4-cycloh exylbu t-3-en -2-on e (12). 6c: 1H
NMR δ 1.20-1.36 (m, 2H), 1.50-1.72 (m, 8H), 1.60 (br, 1H),
2.28 (s, 3H), 6.31 (d, J ) 16.0 Hz, 1H), 6.84 (d, J ) 16.0 Hz,
1H); 13C NMR δ 21.4, 25.1, 27.5, 36.9, 71.5, 127.0, 153.7, 199.2;
IR (neat) 3427, 2933, 2857, 1674, 1625, 984 cm-1; HMRS (EI)
calcd for C10H16O2 168.1150, found 168.1102.
2,2-Eth ylen ed ioxy-8-h yd r oxyu n d ec-6-en -5-on e (6l): 1H
NMR δ 0.91 (t, J ) 7.0 Hz, 3H), 1.33 (s, 3H), 1.28-1.44 (m,
4H), 1.53-1.71 (m, 2H), 1.70 (br, 1H), 2.02 (t, J ) 7.7 Hz, 2H),
2.67 (t, J ) 7.7 Hz, 2H), 3.88-3.99 (m, 4H), 4.28-4.36 (m, 1H),
6.31 (dd, J ) 15.9, 1.6 Hz, 1H), 6.81 (dd, J ) 15.9, 5.0 Hz,
1H); 13C NMR δ 14.3, 22.9, 24.3, 27.7, 33.2, 35.5, 36.7, 65.0,
71.5, 109.7, 128.3, 148.5, 200.4; IR (neat) 3444, 2957, 2934,
2873, 1668, 1633, 1134, 1091, 1051, 984 cm-1; HMRS (EI) calcd
for C14H24O4 256.1675, found 256.1689.
12: 1H NMR (400 MHz) δ 1.15-1.43 (m, 6H), 1.60-1.83 (m,
4H), 2.27 (s, 3H), 2.85-2.90 (m, 1H); 6.78 (d, J ) 10.4 Hz,
1H), 7.38-7.45 (m, 2H), 7.55-7.62 (m, 2H); IR (neat) 2929,
2853, 1692, 1662, 1052, 822 cm-1
.
5-Hyd r oxytr id ec-3-en e-2,8-d ion e (6d ): 1H NMR δ 0.89
(t, J ) 6.9 Hz, 3H), 1.21-1.38 (m, 4H), 1.52-1.63 (m, 2H),
1.74-1.87 (m, 1H), 1.93-2.04 (m, 1H), 2.28 (s, 3H), 2.43 (t, J
) 7.5 Hz, 2H), 4.35-4.43 (m, 1H), 6.31 (dd, J ) 15.9, 1.8 Hz,
1H), 6.74 (dd, J ) 15.9, 4.7 Hz, 1H); 13C NMR δ 14.2, 22.7,
23.6, 27.7, 30.1, 31.6, 38.5, 43.2, 70.3, 129.4, 149.3, 199.2, 212.3;
IR (neat) 3428, 2956, 2931, 2872, 2861, 1709, 1676, 1633, 982
cm-1; HMRS (EI) calcd for C13H22O3 226.1569, found 226.1598.
Meth yl 9-h yd r oxy-12-oxotr id ec-10-en oa te (6e): 1H NMR
δ 1.28-1.36 (m, 4H), 1.55-1.66 (m, 4H), 1.85 (br, 1H), 2.28 (s,
3H), 2.31 (t, J ) 7.2 Hz, 2H), 3.67 (s, 3H), 4.29-4.37 (m, 1H),
6.27 (dd, J ) 16.0, 1.5 Hz, 1H), 6.77 (dd, J ) 16.0, 5.0 Hz,
1H); 13C NMR δ 25.1, 25.5, 27.6, 29.3, 29.5, 34.3, 36.9, 51.8,
71.3, 129.2, 149.8, 174.7, 199.2; IR (neat) 3448, 2932, 2857,
1736, 1677, 1631, 982 cm-1; HMRS (EI) calcd for C14H24O4
256.1675, found 256.1674.
Syn th esis of (()-(11E)-13-Hyd r oxy-10-oxoocta d ec-11-
en oic Acid (14) fr om Un d ec-10-en oic Acid (15)
Isopr opyl 10-Hydr oxy-11-ph en ylth iou n decan oate (10a).
Undec-10-enoic acid (15) was treated with 2-propanol in the
presence of a catalytic amount of p-toluenesulfonic acid in
refluxing benzene with azeotropical removal of water to give
isopropyl undec-10-enoate. A solution of mCPBA (9 g; ca. 80%,
42 mmol) in dichloromethane (70 mL) was added to a solution
of the ester (4.0 g, 17.6 mmol) in dichloromethane (100 mL)
at 0 °C. After stirring at room temperature for 5 h, saturated
aqueous sodium thiosulfate (3 mL) was then added at 0 °C.
The reaction mixture was washed with saturated aqueous
sodium hydrogencarbonate (100 mL) and brine, dried, and
concentrated to give isopropyl 10,11-epoxyundecanoate (16)
(100% yield): 1H NMR δ 1.23 (d, J ) 6.3 Hz, 6H), 1.31-1.62
(m, 12H), 2.28 (t, J ) 7.5 Hz, 2H), 2.60 (ddd, J ) 5.0, 4.0, 2.7
Hz, 2H), 2.90 (m, 1H), 5.00 (m, 1H); 13C NMR δ 22.4 (× 2),
25.5, 26.5, 29.6, 29.7, 29.9 (× 2), 33.0, 35.2, 47.6, 52.9, 67.8,
173.9; IR (neat) 2980, 2930, 2856, 1732, 1467, 1374, 1258,
5-Hyd r oxyp en ta d ec-6-en -8-on e (6f): 1H NMR δ 0.86-
0.94 (m, 6H), 1.27-1.45 (m, 14H), 1.57-1.62 (m, 3H), 2.55 (t,
J ) 7.4 Hz, 2H), 4.27-4.35 (m, 1H), 6.30 (dd, J ) 15.8, 1.6
Hz, 1H), 6.79 (dd, J ) 15.8, 4.8 Hz, 1H); 13C NMR δ 14.3, 14.4,
22.9, 23.0, 24.5, 27.8, 29.4, 29.6, 32.0, 36.8, 41.1, 71.6, 128.3,
148.5, 201.5; IR (neat) 3435, 2957, 2929, 2858, 1670, 1632, 983
cm-1; HMRS (EI) calcd for C15H28O2 240.2089, found 240.2089.
8-Hyd r oxyd od eca -1,6-d ien -5-on e (6g): 1H NMR δ 0.92 (t,
J ) 7.1 Hz, 3H), 1.26-1.46 (m, 4H), 1.54-1.70 (m, 2H), 1.74
(br, 1H), 2.38 (dt, J ) 6.5, 7.4 Hz, 2H), 2.67 (t, J ) 7.4 Hz,
2H), 4.29-4.37 (m, 1H), 4.99 (d, J ) 10.2 Hz, 1H), 5.84 (ddt,
J ) 17.1, 10.2, 6.5 Hz, 1H), 6.32 (dd, J ) 15.9, 1.6 Hz, 1H),
6.81 (dd, J ) 15.9, 5.0 Hz, 1H); 13C NMR δ 13.9, 22.5, 27.3,
27.9, 36.3, 39.6, 71.1, 115.2, 127.8, 137.0, 148.3, 199.9; IR (neat)
3435, 3079, 2958, 2932, 2861, 1667, 1634, 984 cm-1; HMRS
(EI) calcd for C12H20O2 196.1464, found 196.1442.
1181, 1110, 961-700, 834, 756 cm-1
.
To a suspension of finely powdered potassium carbonate
(3.84 g, 40 mmol) in acetone (30 mL) were added thiophenol
(0.93 mL, 10 mmol) and a solution of 16 (2.42 g, 10 mmol) in
acetone (15 mL) successively at 0 °C. After stirring at room
temperature for 7 h, the mixture was filtered to remove excess
potassium carbonate and concentrated. The resulting mixture
was diluted with ethyl acetate (50 mL), washed with brine,
dried (MgSO4), filtered, and concentrated under reduced
pressure to give crude 10a . Purification by column chroma-
tography on silica gel (EtOAc/hexane ) 1/5) afforded 10a as a
6,11-Dih yd r oxyh ep t-7-en -9-on e (6h ): 1H NMR δ 0.84-
0.91 (m, 6H), 1.25-1.45 (m, 14H), 1.50-1.75 (m, 4H), 1.70 (br,
1H), 2.65 (dd, J ) 17.5, 8.9 Hz, 1H), 2.78 (dd, J ) 17.5, 2.8
Hz, 1H), 3.12 (br, 1H), 4.03-4.13 (m, 1H), 4.28-4.38 (m, 1H),
1
colorless solid (3.03 g, 86%): mp 29-31 °C; H NMR δ 1.10
(d, J ) 6.2 Hz, 6H), 1.27-1.61 (m, 12H), 2.25 (t, J ) 7.5 Hz,
2H), 2.41 (br, 1H), 2.99 (ddd, J ) 13.7, 3.4, 8.8 Hz, 2H), 3.66
(m, 1H), 5.00 (m, 1H), 7.21-7.40 (m, 5H); 13C NMR δ 21.7 (×
2), 24.8, 25.5, 29.0, 29.1, 29.3, 34.5, 35.9, 41.9, 67.2, 69.2, 126.3,
128.9 (× 2), 129.7 (× 2), 135.4, 173.3; IR (Nujol mull) 3377,
1736, 1179, 1110, 761, 690 cm-1; HMRS (EI) calcd for
6.31 (d, J ) 15.9 Hz, 1H), 6.84 (dd, J ) 15.9, 5.0 Hz, 1H); 13
C
NMR δ 14.4, 14.4, 22.9, 23.0, 25.3, 25.8, 29.6, 32.0, 32.0, 32.1,
36.9, 47.1, 68.2, 71.4, 128.6, 150.0, 201.6; IR (neat) 3393, 2955,
2921, 2855, 1678, 1621, 997 cm-1; Anal. Calcd for C17H32O3:
C, 71.79; H, 11.34. Found: C, 71.52; H, 11.37.
C
20H32O3S 352.2074, found 352.2101.

1232 J . Org. Chem., Vol. 66, No. 4, 2001
Nokami et al.
Isop r op yl 10-Hyd r oxy-11-p h en ylsu lfin ylu n d eca n oa te
(11a ). To a solution of the â-hydroxy sulfide 10a (1.2 g, 3.16
mmol) in dichloromethane (20 mL) was added a solution of
mCPBA (0.68 g, 3.16 mmol) in 10 mL of dichloromethane at 0
°C. After stirring at 0 °C for an additional 1.5 h, the reaction
mixture was treated with saturated aqueous sodium thiosul-
fate (1 mL) and then saturated aqueous sodium hydrogencar-
bonate (20 mL). The organic phase was separated, and the
water phase was extracted with chloroform. The combined
extracts were washed with brine, dried (MgSO4), filtered, and
concentrated in vacuo. The crude product was purified by
chromatography on silica gel (EtOAc/hexane ) 1/2) to give 11a
2), 29.7, 29.8, 35.3, 41.3, 67.8, 68.1, 128.1, 149.4, 174.2, 201.7;
IR (CHCl3) 3448, 2980, 2931, 2856, 1727, 1663, 1635, 1466,
1374, 1109, 978, 755 cm-1. Anal. Calcd for C17H30O4: C, 68.42;
H, 10.13. Found: C, 68.55; H, 10.30.
Isop r op yl 13-h yd r oxy-10-oxo-14-p h en ylt et r a d ec-11-
en oa te (6o): 1H NMR δ 1.22 (d, J ) 6.4 Hz, 6H), 1.29 (m,
8H), 1.59 (m, 4H), 1.84 (br, 1H), 2.25 (t, J ) 7.5 Hz, 2H), 2.52
(t, J ) 7.4 Hz, 2H), 2.88 (ddd, J ) 13.6, 8.1, 5.1 Hz, 2H), 4.53
(m, 1H), 5.00 (m, 1H), 6.30 (dd, J ) 15.9, 1.7 Hz, 1H), 6.83
(dd, J ) 15.9, 4.7 Hz, 1H), 7.28 (m, 5H); 13C NMR δ 21.8 (×
2), 24.0, 24.9, 28.9, 29.0 (× 2), 29.1, 34.6, 40.8, 43.3, 67.3, 71.8,
126.9, 128.3, 128.6 (× 2), 129.4 (× 2), 136.8, 146.5, 173.4, 200.6;
IR (CHCl3) 3448, 2980, 2931, 2856, 1727, 1663, 1635, 1455,
1370, 1109, 984, 751, 700 cm-1. Anal. Calcd for C23H34O4: C,
73.76; H, 9.15. Found: C, 74.09; H, 8.98.
Isop r op yl 13-h yd r oxy-10-oxoicos-11-en oa te (6p ): 1H
NMR δ 0.88 (t, J ) 6.6 Hz, 3H), 1.23 (d, J ) 6.4 Hz, 6H), 1.30
(m, 14H), 1.59 (m, 6H), 2.00 (br, 1H), 2.25 (t, J ) 7.5 Hz, 2H),
2.55 (t, J ) 7.4 Hz, 2H), 4.31 (ddt, J ) 5.5, 5.5, 1.5 Hz, 1H),
5.00 (m, 1H), 6.29 (dd, J ) 15.9, 1.5 Hz, 1H), 6.79 (dd, J )
15.9, 5.0 Hz, 1H); 13C NMR δ 14.0, 21.8 (× 2), 22.6, 24.0, 24.9,
25.2, 28.9, 29.0 (× 2), 29.1 (× 2), 29.4, 31.7, 34.6, 36.7, 40.7,
67.3, 71.2, 127.9, 147.9, 173.4, 200.8; IR (CHCl3) 3454, 2978,
2929, 2856, 1732, 1677, 1632, 1466, 1374, 1181, 1109, 981, 756
cm-1; Anal. Calcd for C23H42O4: C, 72.21; H, 11.07. Found: C,
72.38; H, 10.98.
1
as a colorless solid (1.12 g, 96%): mp 39-42 °C; H NMR δ
1.10 (d, J ) 6.3 Hz, 6H), 1.28-1.61 (m, 12H), 2.24 (dt, J )
7.4, 3.0 Hz, 2H), 2.68 (dd, J ) 13.5, 1.8 Hz, 0.5H), 2.80 (dd, J
) 13.0, 2.4 Hz, 0.5H), 2.96 (dd, J ) 13.0, 9.3 Hz, 0.5H), 3.06
(dd, J ) 13.5, 9.8 Hz, 0.5H), 3.90 (br, 1H), 4.15 (m, 0.5H), 4.32
(m, 0.5H), 5.00 (m, 0.5H), 7.53-7.66 (m, 5H); 13C NMR δ 21.8
(× 2), 24.9, 25.0, 28.9, 29.1, 29.2, 29.3, 34.6, 37.0, 37.1, 62.2,
62.6, 66.3, 67.3, 68.6, 123.8, 123.9, 129.3, 129.4, 130.9, 131.3,
143.0, 143.8, 173.3; IR (CHCl3) 3377, 3014, 2932, 2856, 1720,
1467, 1444, 1375, 1108, 1032, 691 cm-1; HMRS (EI) calcd for
C
20H32O4S 368.2023, found 368.2025.
Isop r op yl 10-Oxo-11-p h en ylsu lfin ylu n d eca n oa te (5j).
To a solution of oxalyl chloride (0.3 mL, 3.47 mmol) in
dichloromethane (16 mL) was added 4.5 mL (63.2 mmol) of
dimethyl sulfoxide (DMSO) at -60 °C. After 5 min, to the
stirred solution was added the â-hydroxy sulfoxide 11a (1.16
g, 3.16 mmol) in dichloromethane (5 mL) over 2 min, the
stirring was continued for an additional 1 h at -60 °C, and
then triethylamine (2.2 mL, 15.8 mmol) was added. Following
this, the temperature was slowly raised to room temperature
by removal of the cooling bath. The reaction mixture was
washed with water, and the water layer was extracted with
chloroform. The combined extracts were dried (MgSO4), fil-
tered, and concentrated in vacuo. Purification by chromatog-
raphy on silica gel (EtOAc/hexane ) 1/1) and recrystalization
from ether-hexane gave a colorless solid 5j (0.95 g, 82%): mp
Isop r op yl 14,18-d im eth yl-13-h yd r oxy-10-oxon on a d eca -
1
11,17-d ien oa te (6q): (mixture of diastereomers, ca. 1:1) H
NMR δ 0.90 (d, J ) 6.8 Hz, 3H), 0.93 (d, J ) 6.8 Hz, 3H), 1.23
(d, J ) 6.5 Hz, 6H), 1.30 (m, 8H), 1.60 (s, 3H), 1.69 (s, 3H),
2.00 (br, 1H), 2.00 (m, 1H), 2.25 (t, J ) 7.5 Hz, 2H), 2.55 (t, J
) 7.4 Hz, 2H), 4.20 (dt, J ) 5.2, 1.5 Hz, 0.5H), 4.26 (dt, J )
4.4, 1.6 Hz, 0.5H), 5.00 (m, 1H), 5.09 (m, 1H), 6.32 (dt, J )
15.9, 1.5 Hz, 1H), 6.80 (dd, J ) 15.9, 5.0 Hz, 1H); 13C NMR δ
14.0 and 15.0, 21.8 (× 2), 22.6, 24.1, 24.9, 25.5 and 25.6, 25.7,
28.96, 29.01, 29.11, 29.14, 32.1 and 32.8, 34.6, 38.0 and 38.4,
40.8, 67.3, 74.5 and 75.3, 124.1, 128.7 and 129.2, 131.8, 146.1
and 147.0, 173.4, 200.5; IR (CHCl3) 3446, 2965, 2930, 2856,
1
66-67 °C; H NMR δ 1.23 (d, J ) 6.3 Hz, 6H), 1.26-1.30 (m,
1731, 1668, 1633, 1456, 1375, 1181, 1109, 984, 824, 756 cm-1
.
12H), 1.47-1.62 (m, 4H), 2.25 (t, J ) 7.6 Hz, 2H), 2.39-2.54
(m, 2H), 3.82 (dd, J ) 37.8, 13.6 Hz, 2H), 5.00 (m, 1H), 7.53-
7.68 (m, 5H); 13C NMR δ 21.8 (× 2), 22.9, 24.9, 28.76, 28.94,
28.95, 29.04, 34.6, 45.0, 67.3, 68.1, 124.0 (× 2), 129.4 (× 2),
131.6, 143.0, 173.4, 201.7; IR (CHCl3) 2983, 2933, 2857, 1717,
1467, 1445, 1375, 1108, 1045, 690 cm-1; HMRS (EI) calcd for
Anal. Calcd for C24H42O4: C, 73.05; H, 10.73. Found: C, 73.29;
H, 10.68.
13-Hyd r oxy-10-oxoocta d ec-11-en oic Acid (14). To a
suspension of lipase PS (from Pseudomonas cepacia, 400 mg)
in THF (0.5 mL) and a phosphate buffer of pH 7.0 (4 mL) was
added the ester 6n (200 mg, 0.28 mmol). After stirring at room
temperature for 24 h, Selite 545 (2 g) was added to the mixture.
The insoluble materials were filtered off, and the filtrate was
acidified by hydrochloric acid (2 N, 3 mL) and then extracted
with chloroform twice. The combined extracts were dried
(MgSO4), filtered, and concentrated in vacuo to give a crude
solid. Recrystallization from chloroform-hexane gave 14 as a
white solid (145 mg, 82%): mp 58-60 °C [lit. 64 °C];15b 1H
NMR δ 0.89 (t, J ) 6.6 Hz, 3H), 1.30-1.63 (m, 21H), 2.34 (t,
J ) 7.4 Hz, 2H), 2.55 (t, J ) 7.4 Hz, 2H), 4.32 (m, 1H), 6.30
(dd, J ) 15.9, 1.4 Hz, 1H), 6.80 (dd, J ) 15.9, 5.10 Hz, 1H);
13C NMR δ 13.9, 22.5, 24.1, 24.6, 24.9, 28.8, 28.9, 29.0 (× 2),
31.6, 33.9, 36.6, 40.6, 71.2, 127.9, 148.0, 179.4, 201.2; IR
(CHCl3) 3400, 3019, 2932, 2858, 1709, 1674, 1632, 1466, 1410,
C
20H30O4S 366.1866, found 366.1856.
Isop r op yl 13-Hyd r oxy-10-oxoocta d ec-11-en oa te (6m ).
To a solution of the â-keto sulfoxide 5j (100 mg, 0.27 mmol) in
propanenitrile (5 mL) were added diethylamine (57 µL, 0.55
mmol), acetic acid (8 µL, 0.14 mmol), and heptanal (76 µL, 0.54
mmol) under nitrogen. After stirring for 2 h at 70 °C, the
mixture was cooled to 0 °C and diluted with chloroform and
washed with brine. The organic layer was separated, and the
water layer was extracted with chloroform. The combined
extracts were dried (MgSO4), filtered, and concentrated in
vacuo. The residual oil was purified by column chromatogra-
phy on silica gel (EtOAc/hexane)1/4) to give 6m as a pale
yellow oil (74 mg, 76%): 1H NMR δ 0.89 (t, J ) 6.6 Hz, 3H),
1.10 (d, J ) 6.3 Hz, 6H), 1.26-1.63 (m, 20H), 2.04 (br, 1H),
2.25 (t, J ) 7.5 Hz, 2H), 2.55 (t, J ) 7.4 Hz, 2H), 4.32 (m, 1H),
5.00 (m, 1H), 6.30 (dd, J ) 15.9, 1.4 Hz, 1H), 6.80 (dd, J )
15.9, 5.1 Hz, 1H); 13C NMR δ 14.0, 21.8 (× 2), 22.5, 24.1, 24.89,
24.92, 28.96, 29.0 (× 2), 29.1, 31.6, 34.6, 36.7, 40.7, 67.3, 71.3,
127.9, 147.8, 173.4, 200.8; IR (CHCl3) 3449, 2978, 2931, 2857,
1731, 1676, 1632, 1467, 1374, 1110, 754, 725 cm-1; HMRS (EI)
calcd for C21H38O4 354.5303, found 354.5321.
1143, 1079 cm-1
.
Ack n ow led gm en t. This study was financially sup-
ported by a Grant for Cooperative Research adminis-
tered by the J apan Private School Promotion Founda-
tion.
Isop r op yl 13-h yd r oxy-10-oxotetr a d ec-11-en oa te (6n ):
1H NMR δ 1.23 (d, J ) 6.2 Hz, 6H), 1.30 (m, 8H), 1.35 (d, J )
6.6 Hz, 3H), 1.60 (m, 4H), 2.00 (br, 1H), 2.25 (t, J ) 7.5 Hz,
2H), 2.55 (t, J ) 7.4 Hz, 2H), 4.502 (ddq, J ) 6.6, 4.8, 1.6 Hz,
1H), 5.00 (m, 1H), 6.29 (dd, J ) 15.9, 1.6 Hz, 1H), 6.79 (dd, J
) 15.9, 4.7 Hz, 1H); 13C NMR δ 22.5 (× 2), 22.4, 24.7, 29.6 (×
Su p p or tin g In for m a tion Ava ila ble: Spectroscopic data
(1H and 13C NMR, IR, HRMS, and elemental analysis) and
experimental details of â-keto sulfoxides 5a -i. This material
is available free of charge via the Internet at http://pubs.acs.org.
J O001323G