Synthesis and biological activity of enantiomeric pairs of 5-(alk-2-enyl)thiolactomycin and 5-[(E)-cycloalk-2-enylidenemethyl] thiolactomycin congeners

Article abstract of DOI:10.1248/cpb.57.920

The title compounds were synthesized by the efficient route previously explored for the synthesis of enantiomeric pairs of thiolactomycin and its 3-demethyl derivative. These studies were carried out to prove the flexibility of the previously explored synthetic route to natural thiolactomycin (TLM) 1 and to examine the structure-activity relationship on the 5-position of 1. While all of the synthesized congeners lacked in vitro antibacterial activity, these studies led us to find 5-(alk-2-enyl)-TLM (ent-4d) which exhibits mammalian type I fatty acid synthase (FAS) inhibitory activity equal to that of C75, a potent inhibitor reported previously. It was also found that 5-[(E)-cycloalk-2- enylidenemethyl]-TLM (ent-5c) exhibited slightly less potent mammalian type I FAS inhibitory activity than C75.

Full text of DOI:10.1248/cpb.57.920

920
Chem. Pharm. Bull. 57(9) 920—936 (2009)
Vol. 57, No. 9
Synthesis and Biological Activity of Enantiomeric Pairs of 5-(Alk-2-
enyl)thiolactomycin and 5-[(E)-Cycloalk-2-
enylidenemethyl]thiolactomycin Congeners1,2)
b
Kohei OHATA ,a and Shiro TERASHIMA
*
a Discovery Research Laboratories, Kyorin Pharmaceutical Co., Ltd.; 2399–1 Nogi, Nogi-machi, Shimotsuga, Tochigi
329–0114, Japan: and b Sagami Chemical Research Center; 2743–1 Hayakawa, Ayase, Kanagawa 252–1193, Japan.
Received March 9, 2009; accepted July 1, 2009; published online July 1, 2009
The title compounds were synthesized by the efficient route previously explored for the synthesis of enan-
tiomeric pairs of thiolactomycin and its 3-demethyl derivative. These studies were carried out to prove the flexi-
bility of the previously explored synthetic route to natural thiolactomycin (TLM) 1 and to examine the struc-
ture–activity relationship on the 5-position of 1. While all of the synthesized congeners lacked in vitro antibacter-
ial activity, these studies led us to find 5-(alk-2-enyl)-TLM (ent-4d) which exhibits mammalian type I fatty acid
synthase (FAS) inhibitory activity equal to that of C75, a potent inhibitor reported previously. It was also found
that 5-[(E)-cycloalk-2-enylidenemethyl]-TLM (ent-5c) exhibited slightly less potent mammalian type I FAS in-
hibitory activity than C75.
Key words thiolactomycin; type I fatty acid synthase inhibitor; 5-(alk-2-enyl)thiolactomycin; 5-[(E)-cycloalk-2-enylidene-
methyl]thiolactomycin
(R)-(ꢀ)-Thiolactomycin (TLM, 1), a thiolactone antibiotic 2) in addition to that of 1 and 2. From the biological activity
isolated from a soil bacterium, Nocardia sp.,3) shows moder- assay carried out using 1, ent-1, 2 and ent-2, it was evident
ate in vitro activity against a number of pathogens, including that the in vitro antibacterial and type I FAS inhibitory activ-
Gram-positive and Gram-negative bacteria,4,5) Mycobac- ity of TLM congeners can be cleanly separated by changing
terium tuberculosis6,7) and malaria parasites8,9) (Fig. 1). Ac- not only the structure at the C3-position but also the absolute
cording to published reports,10—13) 1 exhibits inhibitory activ- configuration of the side chain at the C5-position.1,27) In the
ity against bacterial and plant type II fatty acid synthase course of our continuing studies on the synthesis and biologi-
(FAS) but not mammalian type I FAS. In studies done in cal activity of 1 and its congeners from the viewpoint of me-
greater detail, 1 appeared to act by inhibiting b-ketoacyl-acyl dicinal chemistry, we paid attention to the effects of the
carrier protein synthases.6,11,14) These inhibitory activities are structure and absolute configuration of the side chain at the
thought to explain the antibacterial and antiparasitical prop- C5-position of 1 on in vitro antibacterial and mammalian type
erties observed for 1. Interestingly, Townsend and colleagues I FAS inhibitory activity. Therefore, enantiomeric pairs of 5-
recently disclosed that 1 and its derivatives also show in- (alk-2-enyl)thiolactomycins [5-(alk-2-enyl)-TLMs] and their
hibitory activity against mammalian type I FAS.15) Syntheses 3-demethyl congeners [3-demethyl-5-(alk-2-enyl)-TLMs] (3,
and screenings of various structural types of TLM congeners ent-3, 4, ent-4) were designed so that we could learn exten-
have been reported 6—9,15—21) because these compounds seem sively about the structure–activity relationships of the C5-po-
to constitute promising drug candidates, with hitherto unex- sition of 1. We also focused our attention on the conforma-
plored modes of action, for the treatment of cancer, obesity, tional effects of the isoprenoid 1,3-diene moiety at the C5-po-
and infectious diseases. However, probably due to the lack of sition of 1 on in vitro antibacterial and mammalian type I
an efficient synthetic route,22—25) very few studies have ex- FAS inhibitory activity. Accordingly, we next targeted the
amined biological activity by utilizing optically active com- synthesis of enantiomeric pairs of 5-[(E)-cycloalk-2-enyli-
pounds.16)
denemethyl]thiolactomycins {5-[(E)-cycloalk-2-enylidene-
We recently reported an efficient total synthesis of 1 and methyl]-TLMs} and their 3-demethyl congeners {5-[(E)-cy-
its 3-demethyl congener (3-demethyl-TLM, 2) by employing cloalk-2-enylidenemethyl]-3-demethyl-TLMs} (5, ent-5, 6,
a novel deconjugative asymmetric a-sulfenylation of the ent-6) bearing six- to eight-membered rings.28) In these com-
chiral 3-(a,b,g,d-unsaturated-acyl)oxazolidin-2-one with a pounds, the isoprenoid 1,3-diene moiety present in 1 is
methanethiosulfonate as a key step.26,27) The flexibility of the clearly locked into an s-trans configuration as a consequence
explored synthetic route has been realized by the expeditious of their involvement in a ring system. We also expected that
synthesis of (S)-TLM (ent-1) and (S)-3-demethyl-TLM (ent- the successful synthesis of enantiomeric pairs of 3, 4, 5 and 6
Fig. 1. Structures of (R)-(ꢀ)-Thiolactomycin (1) and Its 3-Demethyl Congener (2), 5-(Alk-2-enyl)thiolactomycins and Their 3-Demethyl Congeners (3, 4),
5-[(E)-Cycloalk-2-enylidenemethyl]thiolactomycins and Their 3-Demethyl Congeners (5, 6) and C75
© 2009 Pharmaceutical Society of Japan
∗ To whom correspondence should be addressed. e-mail: kouhei.oohata@mb.kyorin-pharm.co.jp

September 2009
921
Table 1. Deconjugative Asymmetric a-Sulfenylation of the (S)-N-Acyloxazolidin-2-one 9b with S-3,3-Dimethoxypropyl Thiosulfonate 10
Yield of the a-sulfenylated products
Run
Base
Additive (eq)
Yield of 25b (%)a)
11b (%)
24b (%)
1
2
3
NaHMDS
NaHMDS
KHMDS
HMPA (4)
None
None
24
61
74
19
5
6
25
13
8
a) These samples were mixures of the two diastereoisomers. The ratio of the diastereomers was ca. 6 : 1—1 : 1 by 1H-NMR analysis.
might further substantiate the flexibility and efficiency of our trophilic agent with the functional group readily trans-
synthetic scheme previously developed for 1 and its con- formable into a thiol. 10 was prepared starting with 3-bromo-
gener. We wish to report here the details of synthesis of propionaldehyde dimethylacetal according to our previously
enantiomeric pairs of 3, 4, 5 and 6 and the in vitro antibacter- reported procedure.26,27) First, to secure the deconjugative
ial and mammalian type I FAS inhibitory activity of these asymmetric a-sulfenylation of 9 with 10, the sulfenylation
pairs. The results clearly disclosed novel aspects of the struc- was examined by using 9b as a model substrate and by em-
ture–activity relationships of the C5-position of TLM and led ploying various disilazide bases in a manner similar to that
us to explore ent-3-demethyl-5-(alk-2-enyl)-TLM (ent-4d) for the synthesis of 1 (Table 1). We found that the deconjuga-
and ent-5-[(E)-cycloalk-2-enylidenemethyl]-TLM (ent-5c). tive asymmetric a-sulfenylation of 9b took place smooth-
The former congener ent-4d exhibited mammalian type I ly by making use of potassium bis(trimethylsilyl)amide
FAS inhibitory activity equal to that of C75, a potent in- (KHMDS) as a base in the absence of hexamethylphospho-
hibitor previously revealed,15,29) and twice that of ent-2 previ- ramide (HMPA), providing the a-sulfenylated compound
ously reported.26,27) The latter congener ent-5c showed type I 11b in a stereoselective and regioselective manner along with
FAS inhibitory activity that was a little less potent than that the other a-sulfenylated product, 24b diastereomeric to 11b,
of C75 and a little more potent than that of ent-2. All the and the g-sulfenylated product, 25b (Table 1, run 3). In our
congeners synthesized in these studies were found to com- previous synthesis of 1,26,27) the deconjugative asymmetric a-
pletely lack in vitro antibacterial activity.
sulfenylation was effected using sodium bis(trimethylsilyl)-
amide (NaHMDS) in the presence of HMPA. However, unex-
pectedly, when 9b was treated under the same conditions
Results and Discussion
Synthesis of 5-Vinylthiolactomycins [5-(Alk-2-enyl)- (Table 1, run 1), the sulfenylation was found to occur in a
TLMs], Their 3-Demethyl Congeners [3-Demethyl-5-(alk- lower yield along with a lower diastereo- and regioselectivity.
2-enyl)-TLMs] and Their Enantiomers Following the The sulfenylation of 9a, c—f also showed a low selectivity
synthetic scheme previously established,26) we commenc- similar to that of 9b. It was anticipated that the stereo and/or
ed the synthesis of (R)-5-(alk-2-enyl)-TLMs and (R)-3- electronic difference between the dienolate derived from 9b
demethyl-5-(alk-2-enyl)-TLMs (3a—f, 4a—f) (Chart 1). and the trienolate I (Fig. 2) presumed to be involved in the
Among a,b-unsaturated carboxylic acids 8a—f used as the synthesis of 1 might make the transition state of sulfenylation
starting materials for the synthesis of 3a—f and 4a—f, 8a— different even under the same condition (Table 1, run 1).
c were commercially available while 8d—f were prepared Thus it was presumed that the reaction condition used for the
from the corresponding aldehydes 7d—f by a sequential synthesis of 1 would not be directly applied to the sulfenyla-
Horner–Wadsworth–Emmons reaction and alkaline hydroly- tion of 9b. Therefore, the sulfenylation of 9b was next exam-
sis in a method similar to that previously reported.26,27) 8a—f ined in the absence of HMPA in order to improve the di-
were transformed into (S)-N-acyloxazolidin-2-ones 9a—f by astereo- and regioselectivity (Table 1, run 2). Gratifyingly,
first treating them with pivaloyl chloride, and the resulting both diastereoselectivity of 11b against 24b and the regiose-
mixed anhydrides were allowed to react with (S)-4-benzylox- lectivity of 11b against 25b were dramatically improved.
azolidin-2-one.30) The preliminarily successful synthesis of Moreover, KHMDS was more effective than NaHMDS to
known ent-3b22) by the use of (R)-4-benzyloxazolidin-2-one further increase the chemical yield and regioselectivity, af-
as a chiral source allowed us to select (S)-4-benzyloxazo- fording 11b, 24b and 25b in 74%, 6% and 8% yields, respec-
lidin-2-one as a chiral auxiliary for the synthesis of 3a—f tively (Table 1, run 3). Separation of 11b, 24b and 25b was
and 4a—f (vide infra).
accomplished by flash column chromatography. While 25b
With 9a—f in hand, we next examined the electrophilic was always obtained as a mixture of the two diastereomers,
deconjugative asymmetric a-sulfenylation using S-3,3- their separation was not attempted. The other (S)-N-acyloxa-
dimethoxypropyl thiosulfonate 10 as a sulfenylating agent, zolidin-2-one 9a, c—f were subjected to the same conditions
which constitutes the key synthetic step. Based on our previ- as those optimized using 9b, producing the a-sulfenylated
ous results,26,27) we expected 10 to be as an excellent elec- compounds 11a, c—f in the yields shown in Chart 1 along

922
Vol. 57, No. 9
(a) (EtO)2P(O)CHMeCO2Et, tBuOLi, hexane, rt, then 10% NaOH aq., EtOH, 50 °C, 92% for 8d, 100% for 8e, 100% for 8f; (b) tBuCOCl, Et3N, THF, ꢂ15 °C, then LiCl, (S)-4-
benzyoxazolidin-2-one, rt 83% for 9a, 96% for 9b, 90% for 9c, 87% for 9d, 96% for 9e, 93% for 9f; (c) KHMDS, THF, ꢂ78 °C, then S-3,3-dimethoxypropyl methanethiosulfonate
(10), ꢂ78 to 0 °C, 18% for 11a, 74% for 11b (see Table 1), 60% for 11c, 50% for 11d, 61% for 11e, 51% for 11f; (d) Ti(OiPr)4, BnOH, 70 °C, 82% for 12a, 88% for 12b, 95% for
12c, 96% for 12d, 89% for 12e, 85% for 12f; (e) 6% HCl aq., THF, rt, 98% for 13a, 98% for 13b, 98% for 13c, 93% for 13d, 66% for 13e, 76% for 13f; (f) Cs2CO3, EtOH, 4 °C,
then CH3CH2COCl or CH3COCl, Et3N, CH2Cl2, 4 °C, 81% for 14a, 74% for 14b, 50% for 14c, 61% for 14d, 62% for 14e, 50% for 14f, 69% for 15a, 68% for 15b, 52% for 15c,
73% for 15d, 48% for 15e, 36% for 15f; (g) LiHMDS, THF, ꢂ78 °C-rt, 70% for 3a, 74% for 3b, 65% for 3c, 64% for 3d, 64% for 3e, 33% for 3f, 86% for 4a, 89% for 4b, 89% for
4c,77% for 4d, 87% for 4e, 76% for 4f.
Chart 1. Synthesis of 5-(Alk-2-enyl)thiolactomycins and Their 3-Demethyl Congeners (3, 4)
with the corresponding diastereomers 24a, c—f.
The absolute stereochemistry of the 2ꢁ-position of 11b was
rigorously assigned to have the (R)-configuration based on
the preliminarily successful synthesis of known ent-3b22)
from ent-11b. The 1H-NMR spectra of 11a, c—f which were
quite similar to that of 11b, clearly supported that 11a, c—f
bear the same (R)-configuration as that of 11b.31) Based on
these preliminary results, (S)-4-benzyloxazolidin-2-one was
Fig. 2. Plausible Transition State (II) of Deconjugative Asymmetric a-
employed as a chiral auxiliary for preparing 3 and 4 instead
Sulfenylation of 9 in the Absence of HMPA Compared with That (I) of Cor-
responding Intermediate to 1 in the Presence of HMPA
of its (R)-enantiomer (vide supra).
Unlike the previous case, in which (R)-N-acyloxazolidin-
2-one derived from (R)-4-benzyloxazolidin-2-one provided
the (R)-a-sulfenylated product by way of the non-chelated activity, the synthesis of enantiomeric pairs of 5-[(E)-
(E)-trienolate (I),26,27) the deconjugative asymmetric a- cycloalk-2-enylidenemethyl]-TLMs 5a—c and their 3-
sulfenylation of (S)-N-acyloxazolidin-2-one 9a—f prepared demethyl congeners 6a—c was examined by employing a,b-
from (S)-4-benzyloxazolidin-2-one gave the (R)-sulfenylated unsaturated carboxylic acids 17a—c as starting materials in a
products 11a—f. The latter reaction, carried out in the ab- method similar to that for the synthesis of 3 and 4 described
sence of HMPA, was expected to proceed through the in 2.2. Compounds 17a—c were prepared from a,b-unsatu-
chelated (E)-dienolate (II) due to the absence of HMPA with rated aldehydes 16a—c by a sequential Horner–Wadsworth–
the sterically less hindered a face approach of 10 (Fig. 2).
Emmons reaction and alkaline hydrolysis (Chart 2). 16a was
As shown in Chart 1, the a-sulfenylated products 11a—f commercially available, and 16b, c were prepared from 1-ni-
were transformed into benzyl esters 12a—f by imide-ester tromethylcycloheptene34) and Nꢁ-cyclooctylidene-4-methyl-
exchange using titanium benzyloxide [Ti(OBn)4].32,33) Acidic benzenesulfonohydrazide,35) respectively, according to the re-
hydrolysis of the dimethyl acetal moieties in 12a—f pro- ported procedures.34,35) Activation of 17a—c with pivaloyl
duced aldehydes 13a—f. The retro-Michael reaction of chloride followed by treatment of the formed mixed anhy-
13a—f using cesium carbonate (Cs2CO3) as a base and sub- drides with (R)-4-benzyloxazolidin-2-one afforded (R)-N-
sequent treatments of the resulting cesium thiolates with pro- acyloxazolidin-2-ones 18a—c. In this case, (R)-4-benzyloxa-
pionyl or acetyl chloride, provided a-acylthio esters 14a—f zolidin-2-one was selected as a chiral source by taking ac-
or 15a—f. According to the reported protocol,23) the Dieck- count not only of the reaction conditions for deconjugative
mann condensation of 14a—f and 15a—f using lithium asymmetric a-sulfenylation but also the absolute configura-
bis(trimethylsilyl)amide (LiHMDS) as a base furnished (R)- tion of the a-sulfenylated product (vide infra).
5-(alk-2-enyl)-TLM and their 3-demethyl congeners 3a—f
With 18a—c in hand, we attempted the key deconjugative
and 4a—f. Using the identical synthetic scheme as described asymmetric a-sulfenylation by employing the conditions
above, the enantiomers of 3a—f and 4a—f (ent-3a—f, ent- used for the sulfenylation reaction of the corresponding syn-
4a—f) were synthesized from ent-9a—f prepared from 8a—f thetic intermediate of 1.26,27) Thus, treatments of 18a with
and (R)-4-benzyloxazolidin-2-one.
3,3-dimethoxypropyl methanethiosulfonate 10 using NaH-
Synthesis of 5-[(E)-Cycloalk-2-enylidenemethyl] Thio- MDS as a base in the presence of HMPA led to the decon-
lactomycins {5-[(E)-Cycloalk-2-enylidenemethyl]-TLMs}, jugative asymmetric a-sulfenylation, giving rise to the a-
Their 3-Demethyl Congeners {5-[(E)-Cycloalk-2-enyli- sulfenylated product 19a highly diastereoselectively and in
denemethyl]-3-demethyl-TLMs} and Their Enantiomers excellent yield (Table 2, run 1).36) However, efficient sulfeny-
Next, in order to elucidate the relationship between the flexi- lation reactions of 18b, c were not effective under the same
bility of the C5-isoprenoid 1,3-diene moiety and biological conditions as those for 18a (Table 2, run 2, 4). It was antici-

September 2009
923
(a) (EtO)2P(O)CHMeCO2Et, tBuOLi, hexane, rt, then 10% NaOH aq., EtOH, 50 °C, 88% for 17a, 59% for 17b, 81% for 17c; (b) tBuCOCl, Et3N, THF, ꢂ15 °C, then LiCl, (R)-
4-benzyloxazolidin-2-one, rt, 81% for 18a, 78% for 18b, 71% for 18c; (c) see Table 2; (d) Ti(OiPr)4, BnOH, 70 °C, 76% for 20a, 69% for 20b, 87% for 20c; (e) 6% HCl aq., THF,
rt, 87% for 21a, 92% for 21b, 96% for 21c; (f) Cs2CO3, EtOH, 4 °C, then CH3CH2COCl or CH3COCl, Et3N, CH2Cl2, 4 °C, 66% for 22a, 68% for 22b, 73% for 22c, 68% for 23a,
63% for 23b, 67% for 23c; (g) LiHMDS, THF, ꢂ78 °C-rt, 84% for 5a, 89% for 5b, 66% for 5c, 99% for 6a, 64% for 6b, 46% for 6c.
Chart 2. Synthesis of 5-[(E)-Cycloalk-2-enylidenemethyl]thiolactomycins and Their 3-Demethyl Congeners (5, 6)
Table 2. Deconjugative Asymmetric a-Sulfenylation of the N-Acyloxazolidin-2-one 18a—c with S-3,3-Dimethoxypropyl Thiosulfonate 10
Yield of the a-sulfenylated products
Run
Substrate
Base (eq)
Additive (eq)
19ꢀ26ꢀ27 (%)
Ratio of 19 : 26 : 27a)a
1
2
3
4
5
18a (nꢃ1)
18b (nꢃ2)
18b (nꢃ2)
18c (nꢃ3)
18c (nꢃ3)
NaHMDS (1.1)
NaHMDS (1.1)
NaHMDS (2)
NaHMDS (1.1)
KHMDS (1.0)
HMPA (4)
HMPA (4)
HMPA (8)
HMPA (4)
92
35
64
ꢄ13
68
12 : 2 : 1
11 : 1 : 4
14 : 1 : 4
—
12 : 1 : 1
b)
18-Crown-6 (1.0)
a) Isomer ratio of 19, 26 to 27 was determined by the 1H-NMR spectrum and/or HPLC of the mixture. b) Isomer ratio of 19, 26 to 27 was not determined because this sam-
ple contained several impurities.
pated that the abstraction of the e-protons of 18b and 18c 19a—c and 26a—c were observed between olefinic C-3ꢁH
might be more difficult than that of 18a because of steric and C-5ꢁH. On the other hand, the structures of the 27a—c
and/or electronic differences between 18b, c and 18a, and were assigned by the NOESY spectra observed between C-
that the trienolates derived from 18b, c were more unstable 3ꢁH and C-9ꢁH, and not between C-3ꢁH and C-5ꢁH. The ab-
than that produced from 18a. Accordingly, the amount of solute stereochemistries of newly created asymmetric centers
base and the use of other additive were next examined. Thus, for 19a—c were assigned to have an (R)-configuration by
1
the sulfenylation of 18b produced the a-sulfenylated com- comparing their H-NMR spectra with that of the corre-
pound 19b in 64% yield even if the increased amounts of sponding a-sulfenylated product for the synthesis of 1 (vide
base and HMPA were used (Table 2, run 3). As for the supra).26,38) A plausible mechanism of deconjugative asym-
sulfenylating reaction of 18c, it was found to give a lower metric a-sulfenylation of 18 was anticipated to be very simi-
yield of 19c under conditions similar to those for 18a, b. Ex- lar to that proposed for the synthesis of 1 because HMPA or
perimentation revealed that the use of KHMDS (1.0 eq) as a 18-crown-6 was used as an additive in these reactions (see,
base in the presence of 18-crown-6 was more effective, giv- Fig. 2, I).
ing rise to 19c in a highly diastereoselective manner in a 68%
Following the same synthetic scheme as previously de-
yield (Table 2, run 5). In the deconjugative asymmetric a- scribed for the preparation of 3a—f and 4a—f, (R)-5-[(E)-
sulfenylation of 18a—c, we always observed the formation cycloalk-2-enylidenemethyl]-TLMs 5a—c and their 3-
of small amounts of the a-sulfenylated products 26a—c di- demethyl congeners 6a—c were readily prepared from the a-
astereomeric to 19a—c and the a-sulfenylated products sulfenylated products 19a—c isolated in pure states by
27a—c bearing a (Z)-configuration. The formation ratios of HPLC separation. Thus, as shown in Chart 2, the sequential
19a—c, 26a—c to 27a—c estimated by the 1H-NMR spectra imide-ester exchange of 19a—c, acidic hydrolysis of 20a—c,
and/or HPLC analyses are summarized in Table 2.37) Pure retro-Michael reaction of 21a—c, acylation with propionyl
samples of 19a—c were obtained by sequential separation or acetyl chloride and Dieckmann condensation of 22a—c
with column chromatography and HPLC.
and 23a—c furnished 5a—c and 6a—c, respectively. By the
The structures of 19a—c, 26a—c, and 27a—c were rigor- same synthetic scheme, the enantiomers of 5a—c and 6a—c
1
ously determined by their H-NMR spectra. Thus, the nu- (ent-5a—c, ent-6a—c) were prepared from ent-19a—c ob-
clear Overhauser effect spectroscopy (NOESY) spectra of tained from 17a—c and (S)-4-benzyloxazolidin-2-one.

924
Vol. 57, No. 9
Table 3. In Vitro Mammalian Type I FAS Inhibitory Activity of Enantiomeric Pairs of TLM and Its Congeners (1, ent-1, 2, ent-2, 3a—f, ent-3a—f, 4a—f,
ent-4a—f, 5a—c, ent-5a—c, 6a—c, ent-6a—c).
Mammalian type I
Mammalian type I
Compound
FAS inhibitory activity,
Compound
FAS inhibitory activity,
IC50 (mg/ml) HepG2 14
C
IC50 (mg/ml) HepG2 14
C
TLM (1)
ent-1
2
ꢅ80
43.7
ꢅ80
19.0
ꢅ80
ꢅ80
ꢅ80
70.1
72.3
37.1
72.1
ꢅ80
57.5
47.0
40.3
18.9
41.5
20.0
41.6
8.8
R2ꢃnBu 3e (91% ee)
ent-3e (89% ee)
4e (91% ee)
ent-4e (88% ee)
R2ꢃnHex 3f (94% ee)
ent-3f (84% ee)
4f (91% ee)
33.7
19.9
18.6
21.0
57.0
34.8
20.1
38.7
ꢅ80
ꢅ80
57.0
18.9
25.4
14.9
13.3
22.6
41.8
11.6
19.5
24.6
ent-2
R2ꢃH 3a (ꢅ90% ee)
ent-3a (ꢅ90% ee)
4a (ꢅ90% ee)
ent-4a (ꢅ90% ee)
R2ꢃMe 3b (ꢅ99% ee)
ent-3b (ꢅ99% ee)
4b (ꢅ99% ee)
ent-4b (ꢅ99% ee)
R2ꢃEt 3c (ꢅ90% ee)
ent-3c (ꢅ90% ee)
4c (ꢅ99% ee)
ent-4c (ꢅ99% ee)
R2ꢃnPr 3d (ꢅ90% ee)
ent-3d (ꢅ90% ee)
4d (ꢅ99% ee)
ent-4f (87% ee)
nꢃ1
nꢃ2
nꢃ3
5a (ꢅ99% ee)
ent-5a (ꢅ99% ee)
6a (ꢅ99% ee)
ent-6a (ꢅ99% ee)
5b (ꢅ99% ee)
ent-5b (ꢅ99% ee)
6b (ꢅ99% ee)
ent-6b (ꢅ99% ee)
5c (ꢅ99% ee)
ent-5c (ꢅ99% ee)
6c (ꢅ99% ee)
ent-6c (ꢅ99% ee)
ent-4d (ꢅ99% ee)
C75a)
7.4
a) See Fig. 1.
Antibacterial Activity and Type I FAS Inhibitory Ac- apparent for ent-4a—f. In addition, it was found that, as the
tivity of Enantiomeric Pairs of TLM Congeners After C5-alkenyl side chain becomes longer, the absolute configu-
3a—f, ent-3a—f, 4a—f, ent-4a—f, 5a—c, ent-5a—c, 6a—c ration renders less effect on type I FAS inhibitory activity
and ent-6a—c were synthesized,39) their in vitro antibacterial (see the cases for R2ꢃnPr, nBu and nHex). More potent type
activities against various strains of bacteria40) and their in- I FAS inhibitory activity was clearly shown by ent-5b, 6b
hibitory activities against mammalian type I FAS41) were and ent-5c. The activity of the most potent ent-5c was a little
evaluated similarly to those for 1, 2 and their enantiomers less than that of C75 and almost twice that of ent-2.26,27)
ent-1 and ent-2.1,27) Unlike the case in previous reports,1,25) However, it appeared that locking the s-trans configuration of
all the tested compounds lacked in vitro antibacterial activity isoprenoid the 1,3-diene moiety as a consequence of the in-
against all the tested strains of bacteria even though 3a—f, volvement in a ring system obviously decreased the tendency
4a—f, 5a—c and 6a—c bear the same (R)-configurations as to separate the biological activity due to the difference in the
1 and 2. Therefore, the results on the inhibitory activity absolute configuration at the C5-position as previously shown
against only mammalian type I FAS are summarized in Table for 1, ent-1, 2 and ent-2.1,27)
3 along with those for 1, ent-1, 2, ent-2 and C75, a potent in-
hibitor against type I FAS so far reported.15,29)
Conclusion
As for mammalian type I FAS inhibitory activity, 14 com-
In summary, we have succeeded in synthesizing 12 enan-
pounds—ent-4c, ent-3d, ent-4d, ent-3e, 4e, ent-4e and 4f, tiomeric pairs of 5-(alk-2-enyl)-TLMs (3a—f, ent-3a—f,
each of which has a vinyl moiety at the C5-position, and ent- 4a—f, ent-4a—f) and six enantiomeric pairs of 5-[(E)-cy-
6a, ent-5b, 6b, ent-6b, ent-5c, 6c and ent-6c, whose iso- cloalk-2-enylidenemethyl]-TLMs (5, ent-5, 6, ent-6) by em-
prenoid 1,3-diene moieties are involved in a ring system— ploying our efficient synthetic route previously explored for
were found to exhibit mammalian type I FAS inhibitory ac- the total synthesis of TLM (1), 3-demethyl congener (2), and
tivity at levels equal to or more potent than that recorded for their enantiomers (ent-1, ent-2).The examination of in vitro
ent-2. Especially, the inhibitory activity of ent-4d was almost antibacterial activity revealed that the free-rotational iso-
equal to that of C75 and more than twice that of previously prenoid 1,3-diene moiety and the (R)-configuration at the C5-
synthesized ent-2.26,27) Summing up the results for 5-(alk-2- position are essential for 1 and its congeners to exhibit in
enyl)-TLMs and their 3-demethyl congeners shown in Table vitro antibacterial activity. As for mammalian type I FAS in-
3, it might be concluded that, in general, the (S)-enantiomers hibitory activity, (S)-3-demethyl-TLM (ent-4d) exhibited a
show more potent type I FAS inhibitory activity than the cor- level of inhibitory activity against mammalian type I FAS
responding (R)-enantiomers (see the cases for R2ꢃEt and that was almost equal to that of C75, a potent inhibitor previ-
nPr) and that the activity of C3-demethyl congeners is higher ously reported and more than twice that of previously synthe-
than that of the corresponding C3-methyl compounds (see the sized ent-2.11,12) 5-[(E)-Cycloalk-2-enylidenemethyl]-TLM
cases for R2ꢃEt, nPr and nBu). As for the length of the C5- (ent-5c), in which the isoprenoid 1,3-diene moiety is locked
alkenyl moiety, type I FAS inhibitory activity seems to grad- into an s-trans configuration as a consequence of its involve-
ually increase until the number of carbon atoms reaches 5, ment in a ring system, was found to exhibit slightly less in-
above which it slightly decreases. This tendency was most hibitory activity than C75 and almost twice that of the previ-

September 2009
925
same manner as described for the preparation of 8d, afforded 8f (10.75 g,
100%) as a mixture of (E,Z) isomer (E/Zꢃ8 : 1). This sample was directly
used for the next acylation without separation of (E)- and (Z)-isomer. 1H-
NMR (400 MHz, CDCl3) d: 0.89 (3H, t, Jꢃ7.3 Hz), 1.20—1.49 (10H, m),
1.84 (24/9H, d, Jꢃ1.2 Hz), 1.91 (3/9H, d, Jꢃ1.2 Hz), 2.20 (16/9H, q,
Jꢃ7.3 Hz), 2.51 (2/9H, qd, Jꢃ7.3, 1.2 Hz), 6.09 (1/9H, td, Jꢃ7.3, 1.2 Hz),
6.92 (8/9H, td, Jꢃ7.3, 1.2 Hz). IR (neat) cmꢂ1: 1688, 1644. MS (EIꢀ) m/z:
184 (Mꢀ). HR-MS (EIꢀ) m/z: 184.1489 (Calcd for C11H20O2 (Mꢀ):
184.1463).
ously reported ent-2. Results of the biological activity col-
lected in these studies should be useful for future attempts to
design novel thiolactomycin congeners that might show more
prominent and clinically useful activity than 1.
Experimental
General All melting points were determined with a Yanaco MP-500
melting point apparatus and are uncorrected. Measurements of optical rota-
tions were carried out using a JASCO P-1020 automatic digital polarimeter.
Infrared spectra were recorded with a JASCO FT/IR-5300 spectrometer or a
(S,E)-4-Benzyl-3-(2-methylpent-2-enoyl)oxazolidin-2-one (9b) and Its
Enantiomer (ent-9b) (a) Preparation of 9b: To a solution of (E)-2-
methylpent-2-enoic acid (1.14 g, 9.79 mmol) and Et3N (3.0 ml, 21.5 mmol)
in THF (50 ml), pivaloyl chloride (1.65 ml, 9.98 mmol) was added dropwise
at ꢂ15 °C, and the resulting mixture was stirred at the same temperature for
15 min. Lithium chloride (500 mg, 11.8 mmol) and (S)-4-benzyloxazolidin-
2-one (2.10 g, 11.6 mmol) were added to the mixture at the same tempera-
ture, and the stirring was continued for 13 h at room temperature. After
quenching the reaction by adding saturated aqueous ammonium chloride so-
lution (30 ml), the mixture was extracted with AcOEt (30 mlꢇ3). The or-
ganic extracts were combined, washed with saturated aqueous sodium hy-
drogen carbonate solution (50 ml) and brine (50 ml), dried over anhydrous
Na2SO4, filtered, and then concentrated in vacuo. Flash column chromatog-
raphy (hexane/AcOEtꢃ5 : 1) of the residue gave 9b (2.56 g, 96%) as a color-
1
Perkin-Elmer spectrum 100 spectrometer. H-NMR spectra were measured
with a JEOL JNM-ECA-400 (400 MHz) spectrometer. Measurements of
13C-NMR spectra were carried out using a JEOL JNM-ECA-400 (100 MHz)
spectrometer. The chemical shifts are expressed in parts per million (d
value) downfield from tetramethylsilane, using tetramethylsilane (dꢃ0)
and/or residual solvents such as chloroform (dꢃ7.26) as an internal stan-
dard. Splitting patterns are indicated as s, singlet; d, doublet; t, triplet; q,
quartet; m, multiplet; br, broad peak. Measurements of mass spectra were
performed with a JEOL JMS-SX102X mass spectrometer. Data for elemen-
tal analyses are within ꢆ0.3% of the theoretical values, and were determined
by a Yanaco CHN-corder MT-6. Unless otherwise noted, all the experiments
were carried out using anhydrous solvents under an atmosphere of argon.
less oil. [a]D26 ꢀ94.7 (cꢃ1.0, MeOH). H-NMR (400 MHz, CDCl3) d: 1.06
1
Throughout this study, Merck precoated TLC plates (Silica gel 60 F254
,
(3H, t, Jꢃ7.3 Hz), 1.90 (3H, s), 2.22 (2H, quintet, Jꢃ7.3 Hz), 2.83 (1H, dd,
Jꢃ13.4, 9.2 Hz), 3.35 (1H, dd, Jꢃ13.4, 3.7 Hz), 4.15 (1H, dd, Jꢃ9.2,
3.7 Hz), 4.25 (1H, t, Jꢃ9.2 Hz), 4.67—4.75 (1H, m), 6.08 (1H, td, Jꢃ7.3,
1.2 Hz), 7.19—7.35 (5H, m). IR (neat) cmꢂ1: 1788, 1680. MS (EIꢀ) m/z:
273 (Mꢀ). HR-MS (EIꢀ) m/z: 273.1354 (Calcd for C16H19NO3 (Mꢀ):
273.1365).
(b) Preparation of ent-9b: Compound ent-9b (2.61 g, 96%) was prepared
as a colorless oil from (E)-2-methylpent-2-enoic acid (1.14 g, 9.99 mmol)
and (R)-4-benzyloxazolidin-2-one (2.10 g, 11.6 mmol) in the same manner
as described in (a). [a]D25 ꢂ94.1 (cꢃ1.0, MeOH). 1H-NMR, IR and MS
spectra of this sample were identical to those described in (a). HR-MS (EIꢀ)
m/z: 273.1388 (Calcd for C16H19NO3 (Mꢀ): 273.1365).
(S,E)-4-Benzyl-3-(2-methylbut-2-enoyl)oxazolidin-2-one (9a) and Its
Enantiomer (ent-9a) (a) Preparation of 9a: Treatments of tiglic acid
(2.00 g, 19.6 mmol) in a manner similar to that described for the preparation
of 9b, afforded 9a (4.23 g, 83%) as a colorless crystals. mp 84.7—85.2 °C
(diisopropyl ether). [a]D23 ꢀ106 (cꢃ1.0, MeOH). 1H-NMR (400 MHz,
CDCl3) d: 1.81 (3H, d, Jꢃ7.9 Hz), 1.91 (3H, s), 2.81 (1H, dd, Jꢃ13.4,
9.2 Hz), 3.35 (1H, dd, Jꢃ13.4, 3.1 Hz), 4.15 (1H, dd, Jꢃ9.2, 5.5 Hz), 4.24
(1H, t, Jꢃ9.2 Hz), 4.67—4.75 (1H, m), 6.21 (1H, qd, Jꢃ7.9, 1.2 Hz), 7.19—
7.36 (5H, m). IR (KBr) cmꢂ1: 1788, 1682. MS (EIꢀ) m/z: 259 (Mꢀ). Anal.
Calcd for C15H17NO3: C, 69.48; H, 6.61; N, 5.40. Found: C, 69.36; H, 6.60;
N, 5.39.
(b) Preparation of ent-9a: Compound ent-9a (2.39 g, 94%) was prepared
as a colorless crystals from tiglic acid (1.00 g, 9.79 mmol) and (R)-4-benzy-
loxazolidin-2-one (2.10 g, 11.9 mmol) in the same manner as described in
(a). mp 85.0—86.0 °C (diisopropyl ether). [a]D24 ꢂ102 (cꢃ1.1, MeOH). 1H-
NMR, IR and MS spectra of this sample were identical to those described in
(a). Anal. Calcd for C15H17NO3: C, 69.48; H, 6.61; N, 5.40. Found: C, 69.44;
H, 6.66; N, 5.30.
0.25 mm) were used for thin layer chromatographic (TLC) analysis, and all
the spots were visualized using UV light followed by coloring with phospho-
molybdic acid or anisaldehyde. Silica gel 60N (40—50 mm, neutral; Kanto
Chemical Co., Inc., Tokyo, Japan) or Chromatorex® NH DM2035 (200—
350 mesh; Fuji Silysia Chemical, Ltd., Aichi, Japan) was used for the flash
column chromatography. Analytical and preparative HPLC was carried out
using an apparatus equipped with a Hitachi L-7405 UV–vis detector, a Hi-
tachi L-7100 HPLC pump, a Hitachi D-7500 chromato integrator, a GL Sci-
ences UV702 UV–vis detector, a GL Sciences PU716 HPLC pump, and a
CO705 column oven. The following abbreviations are used for solvents and
reagents: ethanol (EtOH), methanol (MeOH), sodium sulfate (Na2SO4),
ethyl acetate (AcOEt), dichloromethane (CH2Cl2), chloroform (CHCl3), t-
butyl methyl ether (MTBE), tetrahydrofuran (THF), triethylamine (Et3N).
(E)-2-Methylhept-2-enoic Acid (8d) To a solution of triethyl 2-phos-
phonopropionate (5.5 ml, 24.8 mmol) in hexane (50 ml), lithium tert-butox-
ide (1.0 mol/l solution in hexane, 27.0 ml, 27.0 mmol) was added dropwise
at room temperature, and the resulting mixture was stirred at the same tem-
perature for 30 min. Pentanal (2.6 ml, 24.2 mmol) was added dropwise to the
mixture at 0 °C, and the resulting mixture was stirred at room temperature
for 30 min. After quenching the reaction by adding water (100 ml), the mix-
ture was extracted with hexane (100 mlꢇ3). The combined organic extracts
were dried over anhydrous Na2SO4, filtered, and then concentrated in vacuo.
The residue was dissolved in ethanol (50 ml), and 10% sodium hydroxide
(40 ml) was added to the ethanolic solution. The resulting mixture was
heated at 50 °C for 18 h with stirring. After cooling, the reaction mixture
was washed with hexane (50 mlꢇ3). The aqueous layer was made acidic (pH
1) by adding 2 mol/l HCl and extracted with AcOEt (50 mlꢇ2). The organic
extracts were combined, washed with brine (30 ml), dried over anhydrous
Na2SO4, filtered, and then concentrated in vacuo. Flash column chromatog-
raphy (hexane/AcOEtꢃ4 : 1) of the residue gave oily 8d (3.16 g, 92%) as a
mixture of (E,Z) isomer (E/Zꢃ8 : 1). This sample was directly used for the
next acylation without separation of (E)- and (Z)-isomer. 1H-NMR
(400 MHz, CDCl3) d: 0.92 (3H, t, Jꢃ7.3 Hz), 1.25—1.49 (4H, m), 1.84
(24/9H, d, Jꢃ1.2 Hz), 1.92 (3/9H, d, Jꢃ1.2 Hz), 2.20 (16/9H, q, Jꢃ7.3 Hz),
2.52 (2/9H, q, Jꢃ7.3 Hz), 6.09 (1/9H, td, Jꢃ7.3, 1.2 Hz), 6.91 (8/9H, td,
Jꢃ7.3, 1.2 Hz). IR (neat) cmꢂ1: 1688, 1644. MS (EIꢀ) m/z: 142 (Mꢀ). HR-
MS (EIꢀ) m/z: 142.0957 (Calcd for C8H14O2 (Mꢀ): 142.0994).
(S,E)-4-Benzyl-3-(2-methylhex-2-enoyl)oxazolidin-2-one (9c) and Its
Enantiomer (ent-9c) (a) Preparation of 9c: Treatments of (E)-2-methyl-
hex-2-enoic acid (1.5 ml, 11.9 mmol) in a manner similar to that described
for the preparation of 9b, afforded 9c (3.08 g, 90%) as a colorless crystals.
mp 42.2—42.7 °C (diisopropyl ether–hexane). [a]D23 ꢀ94.1 (cꢃ1.0, MeOH).
1H-NMR (400 MHz, CDCl3) d: 0.96 (3H, t, Jꢃ7.3 Hz), 1.49 (2H, q,
Jꢃ7.3 Hz), 1.91 (3H, s), 2.18 (2H, q, Jꢃ7.3 Hz), 2.83 (1H, dd, Jꢃ13.5,
9.8 Hz), 3.35 (1H, dd, Jꢃ13.5, 3.1 Hz), 4.15 (1H, dd, Jꢃ8.6, 5.5 Hz), 4.25
(1H, t, Jꢃ8.6 Hz), 4.66—4.76 (1H, m), 6.10 (1H, t, Jꢃ7.3 Hz), 7.19—7.35
(5H, m). IR (KBr) cmꢂ1: 1790, 1680. MS (EIꢀ) m/z: 287 (Mꢀ). Anal. Calcd
for C17H21NO3: C, 71.06; H, 7.37; N, 4.87. Found: C, 70.98; H, 7.37; N,
4.85.
(E)-2-Methyloct-2-enoic Acid (8e) Treatments of n-hexanal (5.8 ml,
45.1 mmol) with triethyl 2-phosphonopropionate (12.0 g, 49.4 mmol) in a
manner similar to that described for the preparation of 8d, afforded 8e
(6.48 g, 92%) as a mixture of (E,Z) isomer (E/Zꢃ8 : 1). This sample was di-
rectly used for the next acylation without separation of (E)- and (Z)-isomer.
1H-NMR (400 MHz, CDCl3) d: 0.86—0.91 (3H, m), 1.26—1.50 (6H, m),
1.84 (24/9H, d, Jꢃ1.2 Hz), 1.92 (3/9H, q, Jꢃ1.2 Hz), 2.20 (16/9H, q,
Jꢃ7.3 Hz), 2.51 (2/9H, qd, Jꢃ7.3, 1.2 Hz), 6.09 (1/9H, td, Jꢃ7.3, 1.2 Hz),
6.91 (8/9H, td, Jꢃ7.3, 1.2 Hz). IR (neat) cmꢂ1: 1688, 1644. MS (EIꢀ) m/z:
156 (Mꢀ). HR-MS (EIꢀ) m/z: 156.1144 (Calcd for C9H16O2 (Mꢀ):
156.1150).
(b) Preparation of ent-9c: Compound ent-9c (2.28 g, 100%) was prepared
as
a colorless crystals from (E)-2-methylhex-2-enoic acid (1.1 ml,
7.84 mmol) and (R)-4-benzyloxazolidin-2-one (1.68 g, 9.48 mmol) in the
same manner as described in (a). mp 42.0—42.5 °C (diisopropyl
1
ether–hexane). [a]D24 ꢂ91.8 (cꢃ0.9, MeOH). H-NMR, IR and MS spectra
of this sample were identical to those described in (a). Anal. Calcd for
C17H21NO3: C, 71.06; H, 7.37; N, 4.87. Found: C, 70.81; H, 7.31; N, 4.83.
(S,E)-4-Benzyl-3-(2-methylhept-2-enoyl)oxazolidin-2-one (9d) and Its
(E)-2-Methyldec-2-enoic Acid (8f) Treatments of n-octanal (9.0 ml,
54.7 mmol) with triethyl 2-phosphonopropionate (14.0 g, 57.6 mmol) in the

926
Vol. 57, No. 9
Enantiomer (ent-9d) (a) Preparation of 9d: Treatments of 8d [an 8 : 1
mixture of the (E)- and (Z)-isomer] (1.20 g, 8.44 mmol) in a manner similar
to that described for the preparation of 9b, afforded oily 9d (2.21 g, 87%) as
8%), all as an oil.
Compound 11b: [a]D27 ꢀ54.8 (cꢃ0.6, MeOH). 1H-NMR (400 MHz,
CDCl3) d: 1.74 (3H, dd, Jꢃ6.1, 1.8 Hz), 1.79 (3H, s), 1.82—1.90 (2H, m),
a mixture of (E,Z) isomer (E/Zꢃ16 : 1). [a]D28 ꢀ80.9 (cꢃ1.1, MeOH). 1H- 2.50—2.64 (2H, m), 2.72 (1H, dd, Jꢃ13.4, 10.4 Hz), 3.315 (3H, s), 3.318
NMR (400 MHz, CDCl3) d: 0.92 (3H, t, Jꢃ7.3 Hz), 1.32—1.50 (4H, m),
(3H, s), 3.30—3.36 (1H, m), 4.09—4.20 (2H, m), 4.47 (1H, t, Jꢃ6.1 Hz),
1.91 (3H, d, Jꢃ1.2 Hz), 2.20 (2H, q, Jꢃ7.3 Hz), 2.83 (1H, dd, Jꢃ13.4, 4.66—4.72 (1H, m), 5.53 (1H, qd, Jꢃ6.1, 15.9 Hz), 5.83 (1H, qd, Jꢃ1.8,
9.2 Hz), 3.35 (15/16H, dd, Jꢃ13.4, 3.7 Hz), 3.41 (1/16H, dd, Jꢃ13.4, 15.9 Hz), 7.23—7.36 (5H, m). IR (neat) cmꢂ1: 1790, 1680. MS (CIꢀ) m/z:
3.7 Hz), 4.05—4.18 (1H, m), 4.25 (1H, t, Jꢃ8.6 Hz), 4.67—4.75 (1H, m),
376 {[(MꢂCH3O)ꢀH]ꢀ}. HR-MS (CIꢀ) m/z: 376.1551 (Calcd for
5.55 (1/16H, td, Jꢃ7.3, 1.2 Hz), 6.10 (15/16H, td, Jꢃ7.3, 1.2 Hz), 7.19— C20H26NO4S {[(MꢂCH3O)ꢀH]ꢀ}: 376.1583).
7.36 (5H, m). IR (neat) cmꢂ1: 1788, 1682. MS (EIꢀ) m/z: 301 (Mꢀ). HR-MS
(EIꢀ) m/z: 301.1661 (Calcd for C18H23NO3 (Mꢀ): 301.1678).
Compound 24b: [a]D25 ꢀ146 (cꢃ0.3, MeOH). 1H-NMR (400 MHz,
CDCl3) d: 1.73 (3H, dd, Jꢃ6.1, 1.2 Hz), 1.79—1.87 (5H, m), 2.44—2.63
(2H, m), 2.78 (1H, dd, Jꢃ13.4, 9.8 Hz), 3.26—3.34 (7H, m), 4.09—4.24
(2H, m), 4.47 (1H, t, Jꢃ6.1 Hz), 4.66—4.76 (1H, m), 5.49 (1H, qd, Jꢃ6.1,
(b) Preparation of ent-9d: Compound ent-9d (1.00 g, 89%, colorless oil)
was prepared as a mixture of (E,Z) isomer (E/Zꢃ19 : 1) from 8d [an 8 : 1
mixture of the (E)- and (Z)-isomer] (530 mg, 3.73 mmol) and (R)-4-benzy- 15.9 Hz), 5.82 (1H, qd, Jꢃ1.2, 15.9 Hz), 7.20—7.36 (5H, m). IR (ATR)
loxazolidin-2-one (745 mg, 4.12 mmol) in the same manner as described in
cmꢂ1: 1785, 1677. MS (CIꢀ) m/z: 408 [(MꢀH)ꢀ]. HR-MS (CIꢀ) m/z:
(a). [a]D24 ꢂ82.0 (cꢃ1.0, MeOH). 1H-NMR, IR and MS spectra of this sam- 408.1840 (Calcd for C21H30NO5S [(MꢀH)ꢀ]: 408.1845).
ple were identical to those described in (a). HR-MS (EIꢀ) m/z: 301.1698
Compound 25b (a Mixture of Two Diastereomers): H-NMR (400 MHz,
1
(Calcd for C18H23NO3 (Mꢀ): 301.1678).
CDCl3) d: 1.26 (3H, t, Jꢃ6.7 Hz), 1.51—1.58 (2H, m), 1.95 (3H, d,
(S,E)-4-Benzyl-3-(2-methyloct-2-enoyl)oxazolidin-2-one (9e) and Its Jꢃ1.2 Hz), 2.49—2.67 (2H, m), 2.84 (1H, dd, Jꢃ13.4, 9.2 Hz), 3.29—3.39
Enantiomer (ent-9e) (a) Preparation of 9e: Treatments of 8e [a 8 : 1 mix- (7H, m), 3.71—3.82 (1H, m), 4.08—4.20 (1H, m), 4.26 (1H, t, Jꢃ9.2 Hz),
ture of the (E)- and (Z)-isomer] (9.70 g, 62.1 mmol) in a manner similar to 4.45—4.54 (1H, m), 4.65—4.76 (1H, m), 5.83 (1H, qd, Jꢃ1.2, 10.4 Hz),
that described for the preparation of 9b, afforded oily 9e (18.7 g, 96%) as a
7.11—7.41 (5H, m). IR (ATR) cmꢂ1: 1782, 1678. MS (EIꢀ) m/z: 407 (Mꢀ).
mixture of (E,Z) isomer (E/Zꢃ8 : 1). [a]D18 ꢀ80.9 (cꢃ0.5, MeOH). 1H-NMR HR-MS (EIꢀ) m/z: 407.1744 (Calcd for C21H29NO5S (Mꢀ): 407.1766). Di-
(400 MHz, CDCl3) d: 0.90 (3H, t, Jꢃ7.3 Hz), 1.24—1.50 (6H, m), 1.90 (3H, astereomer ratio was determined by HPLC analysis.
d, Jꢃ1.2 Hz), 2.19 (16/9H, q, Jꢃ7.3 Hz), 2.50 (2/9H, q, Jꢃ7.3 Hz), 2.83
(1H, dd, Jꢃ13.5, 9.2 Hz), 3.35 (8/9H, dd, Jꢃ13.5, 3.7 Hz), 3.41 (1/9H, dd,
(b) Preparation of ent-11b: Compound ent-11b (1.67 g, 56%) was pre-
pared as a colorless oil from ent-9b (900 mg, 3.01 mmol) in the same man-
Jꢃ13.5, 3.7 Hz), 4.08—4.18 (1H, m), 4.24 (1H, t, Jꢃ8.6 Hz), 4.67—4.75 ner as described in (a).42) [a]D25 ꢂ53.6 (cꢃ0.8, MeOH). 1H-NMR, IR and
(1H, m), 5.55 (1/9H, td, Jꢃ7.3, 1.2 Hz), 6.10 (8/9H, td, Jꢃ7.3, 1.2 Hz), MS spectra of this sample were identical to those described in (a). HR-MS
7.19—7.36 (5H, m). IR (neat) cmꢂ1: 1790, 1682. MS (EIꢀ) m/z: 315 (Mꢀ).
HR-MS (EIꢀ) m/z: 315.1830 (Calcd for C19H25NO3 (Mꢀ): 315.1834).
(b) Preparation of ent-9e: Compound ent-9e (10.5 g, 81%, colorless oil)
was prepared as a mixture of (E,Z) isomer (E/Zꢃ16 : 1) from 8e [a 8 : 1 mix-
(EIꢀ) m/z: 407.1722 (Calcd for C21H29NO5S (Mꢀ): 407.1766).
Deconjugative Asymmetric a-Sulfenylation of (S)- and (R)-4-Benzyl-
3-(2-methylbut-2-enoyl)oxazolidin-2-one (9a, ent-9a). (S)-4-Benzyl-3-
[(R)-2-(3,3-dimethoxypropylthio)-2-methylbut-3-enoyl]oxazolidin-2-one
ture of the (E)- and (Z)-isomer] (6.48 g, 41.5 mmol) and (R)-4-benzyloxazo- (11a) and Its Enantiomer (ent-11a) (a) Preparation of 11a: Treatments of
lidin-2-one (8.26 g, 45.7 mmol) in the same manner as described in (a). [a]D18
9a (4.10 g, 15.8 mmol) in a manner similar to that described for the prepara-
1
ꢂ84.6 (cꢃ0.5, MeOH). H-NMR, IR and MS spectra of this sample were tion of 11b, afforded 11a (1.14 g, 18%) as a colorless oil.42) [a]D27 ꢀ52.1
identical to those described in (a). HR-MS (EIꢀ) m/z: 315.1816 (Calcd for
(cꢃ0.5, MeOH). 1H-NMR (400 MHz, CDCl3) d: 1.81 (3H, s), 1.82—1.90
(2H, m), 2.51—2.62 (2H, m), 2.72 (1H, dd, Jꢃ12.8, 11.0 Hz), 3.317 (3H, s),
C19H25NO3 (Mꢀ): 315.1834).
(S,E)-4-Benzyl-3-(2-methyldec-2-enoyl)oxazolidin-2-one (9f) and Its 3.321 (3H, s), 3.32—3.38 (1H, m), 4.09—4.21 (2H, m), 4.47 (1H, t,
Enantiomer (ent-9f) (a) Preparation of 9f: Treatments of 8f [an 8 : 1 mix- Jꢃ5.5 Hz), 4.70 (1H, m), 5.06 (1H, d, Jꢃ17.1 Hz), 5.18 (1H, d, Jꢃ11.0 Hz),
ture of the (E)- and (Z)-isomer] (10.7 g, 58.1 mmol) in a manner similar to 6.18 (1H, dd, Jꢃ17.1, 11.0 Hz), 7.23—7.37 (5H, m). IR (neat) cmꢂ1: 1790,
that described for the preparation of 9b, afforded oily 9f (18.6 g, 93%) as a
1680. MS (CIꢀ) m/z: 362 {[(MꢂCH3O)ꢀH]ꢀ}. HR-MS (CIꢀ) m/z:
mixture of (E,Z) isomer (E/Zꢃ18 : 1). [a]D19 ꢀ69.3 (cꢃ0.9, MeOH). 1H- 362.1459 (Calcd for C19H24NO4S {[(MꢂCH3O)ꢀH]ꢀ}: 362.1426).
NMR (400 MHz, CDCl3) d: 0.89 (3H, t, Jꢃ7.3 Hz), 1.23—1.50 (10H, m),
1.90 (3H, s), 2.19 (36/19H, q, Jꢃ7.3 Hz), 2.50 (2/19H, q, Jꢃ7.3 Hz), 2.82
(b) Preparation of ent-11a: Compound ent-11a (1.09 g, 16%) was pre-
pared as a colorless oil from ent-9a (4.56 g, 17.6 mmol) in the same manner
(1H, dd, Jꢃ13.5, 9.2 Hz), 3.35 (1H, dd, Jꢃ13.5, 3.7 Hz, 18/19H), 3.45 (dd, as described in (a).42) [a]D27 ꢂ55.4 (cꢃ1.1, MeOH). 1H-NMR, IR and MS
Jꢃ13.5, 3.7 Hz, 1/19H), 4.08—4.18 (m, 1H), 4.24 (t, Jꢃ8.6 Hz), 4.67—4.75 spectra of this sample were identical to those described in (a). HR-MS (EIꢀ)
(1H, m), 5.55 (1/19H, td, Jꢃ7.3, 1.2 Hz), 6.10 (18/19H, td, Jꢃ7.3, 1.2 Hz), m/z: 393.1606 (Calcd for C20H27NO5S (Mꢀ): 393.1610).
7.19—7.36 (1H, m). IR (neat) cmꢂ1: 1790, 1682. MS (EIꢀ) m/z: 343 (Mꢀ).
HR-MS (EIꢀ) m/z: 343.2172 (Calcd for C21H29NO3 (Mꢀ): 343.2147).
(b) Preparation of ent-9f: Compound ent-9f (12.2 g, 85% colorless oil)
was prepared as a mixture of (E,Z) isomer (E/Zꢃ16 : 1) from 8f [an 8 : 1
Deconjugative Asymmetric a-Sulfenylation of (S,E)- and (R,E)-4-Ben-
zyl-3-(2-methylhex-2-enoyl)oxazolidin-2-one (9c, ent-9c). (S)-4-Benzyl-3-
[(R,E)-2-(3,3-dimethoxypropylthio)-2-methylhex-3-enoyl]oxazolidin-2-
one (11c) and Its Enantiomer (ent-11c) (a) Preparation of 11c: Treat-
mixture of the (E)- and (Z)-isomer] (7.72 g, 41.9 mmol) and (R)-4-benzylox- ments of 9c (2.01 g, 6.99 mmol) in a manner similar to that described for the
azolidin-2-one (8.33 g, 48.0 mmol) in the same manner as described in (a).
preparation of 11b, afforded 11c (1.78 g, 60%) as a colorless oil.42) [a]D27
ꢀ54.1 (cꢃ0.7, MeOH). 1H-NMR (400 MHz, CDCl3) d: 0.99 (3H, t,
Jꢃ7.9 Hz), 1.80 (3H, s), 1.82—1.90 (2H, m), 2.04—2.13 (2H, m), 2.50—
2.65 (2H, m), 2.71 (1H, dd, Jꢃ13.4, 10.4 Hz), 3.317 (3H, s), 3.321 (3H, s),
3.30—3.37 (1H, m), 4.10—4.19 (2H, m), 4.47 (1H, t, Jꢃ5.5 Hz), 4.65—
4.73 (1H, m), 5.52 (1H, td, Jꢃ6.7 15.9 Hz), 5.80 (1H, td, Jꢃ1.8, 15.9 Hz),
1
[a]D18 ꢂ75.3 (cꢃ1.1, MeOH). H-NMR, IR and MS spectra of this sample
were identical to those described in (a). HR-MS (EIꢀ) m/z: 343.2147 (Calcd
for C21H29NO3 (Mꢀ): 343.2147).
Deconjugative Asymmetric a-Sulfenylation of (S,E)- and (R,E)-4-Ben-
zyl-3-(2-methylpent-2-enoyl)oxazolidin-2-one (9b, ent-9b). (S)-4-Benzyl-
3-[(R,E)-2-(3,3-dimethoxypropylthio)-2-methylpent-3-enoyl]oxazolidin- 7.23—7.37 (5H, m). IR (neat) cmꢂ1: 1790, 1680. MS (CIꢀ) m/z: 390
2-one (11b), Its (S,E)-Diastereomer (24b), (S)-4-Benzyl-3-[(RS,E)-4-(3,3- {[(MꢂCH3O)ꢀH]ꢀ}. HR-MS (CIꢀ) m/z: 390.1740 (Calcd for C21H28NO4S
dimethoxypropylthio)-2-methylpent-2-enoyl]oxazolidin-2-one (25b) and {[(MꢂCH3O)ꢀH]ꢀ}: 390.1739).
Their Enantiomers (ent-11b, ent-24b, ent-25b) (a) Preparation of 11b,
24b and 25b: To a solution of 9b (110 mg, 0.402 mmol) in THF (2.0 ml),
KHMDS (0.5 mol/l solution in toluene, 0.96 ml, 0.48 mmol) was added
dropwise at ꢂ78 °C, and the resulting mixture was stirred at the same tem-
perature for 30 min. A solution of 10 (130 mg, 0.607 mmol) in THF (0.4 ml)
was added to the reaction mixture at the same temperature, and the result-
(b) Preparation of ent-11c: Compound ent-11c (1.77 g, 71%) was pre-
pared as a colorless oil from ent-9c (1.70 g, 5.92 mmol) in the same manner
as described in (a).42) [a]D26 ꢂ55.5 (cꢃ1.0, MeOH). 1H-NMR, IR and MS
spectra of this sample were identical to those described in (a). HR-MS (EIꢀ)
m/z: 421.1889 (Calcd for C22H31NO5S (Mꢀ): 421.1923).
Deconjugative Asymmetric a-Sulfenylation of (S,E)- and (R,E)-4-Ben-
ing mixture was allowed to slowly warm to 0 °C. After quenching the zyl-3-(2-methylhept-2-enoyl)oxazolidin-2-one (9d, ent-9d). (S)-4-Benzyl-
reaction by adding saturated aqueous ammonium chloride solution (10 ml),
3-[(R,E)-2-(3,3-dimethoxypropylthio)-2-methylhept-3-enoyl]oxazolidin-
the mixture was extracted with AcOEt (10 mlꢇ3). The organic extracts 2-one (11d) and Its Enantiomer (ent-11d) (a) Preparation of 11d: Treat-
were combined, washed with brine (10 ml), dried over anhydrous Na2SO4,
ments of 9d (2.19 g, 7.27 mmol) in a manner similar to that described for the
filtered, and then concentrated in vacuo. Flash column chromatography preparation of 11b, afforded 11d (1.59 g, 50%) as a colorless oil.42) [a]D27
(hexane/AcOEtꢃ4 : 1) of the residue gave 11b (121 mg, 74%), its (2ꢁS)-di- ꢀ50.6 (cꢃ1.0, MeOH). 1H-NMR (400 MHz, CDCl3) d: 0.89 (3H, t,
astereomer 24b (10 mg, 6%) and the g-sulfenylated product 25b (13 mg,
Jꢃ7.3 Hz), 1.39 (2H, q, Jꢃ7.3 Hz), 1.80 (3H, s), 1.82—1.91 (2H, m),

September 2009
927
(R)-Benzyl 2-(3,3-Dimethoxypropylthio)-2-methylbut-3-enoate (12a)
and Its Enantiomer (ent-12a) (a) Preparation of 12a: Treatments of 11a
(1.13 g, 2.87 mmol) in a manner similar to that described for the preparation
of 12b, afforded 12a (766 mg, 82%) as a colorless oil. [a]D28 ꢀ3.3 (cꢃ0.8,
2.00—2.09 (2H, m), 2.50—2.65 (2H, m), 2.70 (1H, dd, Jꢃ13.4, 10.4 Hz),
3.315 (3H, s), 3.320 (3H, s), 3.30—3.37 (1H, m), 4.09—4.20 (2H, m), 4.47
(1H, t, Jꢃ5.5 Hz), 4.66—4.72 (1H, m), 5.49 (1H, td, Jꢃ7.3, 15.9 Hz), 5.80
(1H, td, Jꢃ1.2, 15.9 Hz), 7.23—7.37 (5H, m). IR (neat) cmꢂ1: 1792, 1680.
MS (EIꢀ) m/z: 435 (Mꢀ). HR-MS (EIꢀ) m/z: 435.2063 (Calcd for
C23H33NO5S (Mꢀ): 435.2079).
(b) Preparation of ent-11d: Compound ent-11d (659 mg, 54%) was pre-
pared as a colorless oil from ent-9d (850 mg, 2.82 mmol) in the same man-
ner as described in (a).42) [a]D27 ꢂ49.6 (cꢃ1.1, MeOH). 1H-NMR, IR and
MS spectra of this sample were identical to those described in (a). HR-MS
(CIꢀ) m/z: 404.1943 (Calcd for C22H30NO4S {[(MꢂCH3O)ꢀH]ꢀ}:
404.1896).
Deconjugative Asymmetric a-Sulfenylation of (S,E)- and (R,E)-4-Ben-
zyl-3-(2-methyloct-2-enoyl)oxazolidin-2-one (9e, ent-9e). (S)-4-Benzyl-3-
[(R,E)-2-(3,3-dimethoxypropylthio)-2-methyloct-3-enoyl]oxazolidin-2-
one (11e) and Its Enantiomer (ent-11e) (a) Preparation of 11e: Treat-
ments of 9e (12.6 g, 40.0 mmol) in a manner similar to that described for the
preparation of 11b afforded 11e (10.9 g, 61%) as a colorless oil.42) [a]D19
ꢀ46.0 (cꢃ0.5, MeOH). 1H-NMR (400 MHz, CDCl3) d: 0.89 (3H, t,
Jꢃ7.3 Hz), 1.24—1.36 (4H, m), 1.80 (3H, s), 1.81—1.92 (2H, m), 2.07 (2H,
q, Jꢃ6.1 Hz), 2.54—2.65 (2H, m), 2.70 (1H, dd, Jꢃ13.4, 10.4 Hz), 3.315
(3H, s), 3.320 (3H, s), 3.32—3.37 (1H, m), 4.09—4.18 (2H, m), 4.47 (1H, t,
Jꢃ6.1 Hz), 4.65—4.74 (1H, m), 5.49 (1H, td, Jꢃ6.7, 15.9 Hz), 5.80 (1H, td,
Jꢃ1.2, 15.9 Hz), 7.24—7.36 (5H, m). IR (neat) cmꢂ1: 1792, 1680. MS (CIꢀ)
m/z: 450 [(MꢀH)ꢀ]. HR-MS (CIꢀ) m/z: 450.2304 (Calcd for C24H36NO5S
[(MꢀH)ꢀ]: 450.2314).
1
CHCl3). H-NMR (400 MHz, CDCl3) d: 1.62 (3H, s), 1.75—1.82 (2H, m),
2.50—2.63 (2H, m), 3.29 (6H, s), 4.38 (1H, t, Jꢃ6.1 Hz), 5.19 (2H, s), 5.23
(1H, d, Jꢃ11.1 Hz), 5.27 (1H, d, Jꢃ17.7 Hz), 6.14 (1H, dd, Jꢃ17.7,
11.1 Hz), 7.30—7.38 (5H, m). IR (neat) cmꢂ1: 1728. MS (EIꢀ) m/z: 324
(Mꢀ). HR-MS (EIꢀ) m/z: 324.1424 (Calcd for C17H24O4S (Mꢀ): 324.1395).
(b) Preparation of ent-12a: Compound ent-12a (794 mg, 92%) was pre-
pared as a colorless oil from ent-11a (1.05 g, 2.67 mmol) in the same manner
as described in (a). [a]D27 ꢂ3.9 (cꢃ0.7, CHCl3). 1H-NMR, IR and MS spec-
tra of this sample were identical to those described in (a). HR-MS (CIꢀ) m/z:
293.1241 (Calcd for C16H21O3S {[(MꢂCH3O)ꢀH]ꢀ}: 293.1211).
(R,E)-Benzyl 2-(3,3-Dimethoxypropylthio)-2-methylhex-3-enoate (12c)
and Its Enantiomer (ent-12c) (a) Preparation of 12c: Treatments of 11c
(1.77 g, 4.20 mmol) in a manner similar to that described for the preparation
of 12b, afforded 12c (1.40 g, 95%) as a colorless oil. [a]D26 ꢀ3.6 (cꢃ1.0,
1
CHCl3). H-NMR (400 MHz, CDCl3) d: 0.99 (3H, t, Jꢃ7.9 Hz), 1.61 (3H,
s), 1.76—1.82 (2H, m), 2.07—2.13 (2H, m), 2.48—2.62 (2H, m), 3.29 (6H,
s), 4.38 (1H, t, Jꢃ5.5 Hz), 5.18 (2H, s), 5.68—5.79 (2H, m), 7.30—7.38
(5H, m). IR (neat) cmꢂ1: 1728. MS (EIꢀ) m/z: 352 (Mꢀ). HR-MS (EIꢀ) m/z:
352.1727 (Calcd for C19H28O4S (Mꢀ): 352.1708).
(b) Preparation of ent-12c: Compound ent-12c (1.42 g, 97%) was pre-
pared as a colorless oil from ent-11c (1.75 g, 4.15 mmol) in the same manner
as described in (a). [a]D27 ꢂ2.9 (cꢃ1.0, CHCl3). 1H-NMR, IR and MS spec-
tra of this sample were identical to those described in (a). HR-MS (CIꢀ) m/z:
321.1513 (Calcd for C18H25O3S {[(MꢂCH3O)ꢀH]ꢀ}: 321.1524).
(b) Preparation of ent-11e: Compound ent-11e (4.57 g, 80%) was pre-
pared as a colorless oil from ent-9e (4.00 g, 12.7 mmol) in the same manner
as described in (a).42) [a]D19 ꢂ49.9 (cꢃ0.6, MeOH). 1H-NMR, IR and MS
spectra of this sample were identical to those described in (a). HR-MS (CIꢀ)
m/z: 450.2319 (Calcd for C24H36NO5S [(MꢀH)ꢀ]: 450.2314).
(R,E)-Benzyl 2-(3,3-Dimethoxypropylthio)-2-methylhept-3-enoate
(12d) and Its Enantiomer (ent-12d) (a) Preparation of 12d: Treatments
of 11d (1.35 g, 3.11 mmol) in a manner similar to that described for the
preparation of 12b, afforded 12d (1.10 g, 96%) as a colorless oil. [a]D28 ꢀ3.1
(cꢃ0.8, CHCl3). 1H-NMR (400 MHz, CDCl3) d: 0.88 (3H, t, Jꢃ7.3 Hz),
1.39 (2H, q, Jꢃ7.3 Hz), 1.61 (3H, s), 1.74—1.81 (2H, m), 2.01—2.08 (2H,
m), 2.49—2.62 (2H, m), 3.29 (6H, s), 4.37 (1H, t, Jꢃ5.5 Hz), 5.18 (2H, s),
5.66 (1H, td, Jꢃ15.9, 6.7 Hz), 5.76 (1H, d, Jꢃ15.3 Hz), 7.30—7.39 (5H, m).
IR (neat) cmꢂ1: 1728. MS (CIꢀ) m/z: 335 {[(MꢂCH3O)ꢀH]ꢀ}. HR-MS
(EIꢀ) m/z: 335.1695 (Calcd for C19H27O3S {[(MꢂCH3O)ꢀH]ꢀ}: 335.1681).
(b) Preparation of ent-12d: Compound ent-12d (498 mg, 95%) was pre-
pared as a colorless oil from ent-11d (625 mg, 1.43 mmol) in the same man-
Deconjugative Asymmetric a-Sulfenylation of (S,E)- and (R,E)-4-Ben-
zyl-3-(2-methyldec-2-enoyl)oxazolidin-2-one (9f, ent-9f). (S)-4-Benzyl-3-
[(R,E)-2-(3,3-dimethoxypropylthio)-2-methyldec-3-enoyl]oxazolidin-2-
one (11f) and Its Enantiomer (ent-11f) (a) Preparation of 11f: Treat-
ments of 9f (13.7 g, 40.0 mmol) in a manner similar to that described for the
preparation of 11b afforded 11f (9.77 g, 51%) as a colorless oil.42) [a]D19
ꢀ41.4 (cꢃ0.5, MeOH). 1H-NMR (400 MHz, CDCl3) d: 0.87 (3H, t,
Jꢃ6.7 Hz), 1.24—1.37 (8H, m), 1.80 (3H, s), 1.80—1.90 (2H, m), 2.02—
2.10 (2H, m), 2.50—2.65 (2H, m), 2.70 (1H, dd, Jꢃ13.4, 10.4 Hz), 3.315
(3H, s), 3.318 (3H, s), 3.30—3.37 (1H, m), 4.08—4.18 (2H, m), 4.47 (1H, t,
Jꢃ5.5 Hz), 4.65—4.72 (1H, m), 5.48 (1H, td, Jꢃ6.7, 15.9 Hz), 5.80 (1H, td,
Jꢃ1.2, 15.9 Hz), 7.23—7.36 (5H, m). IR (neat) cmꢂ1: 1792, 1680. MS (CIꢀ)
m/z: 478 [(MꢀH)ꢀ]. HR-MS (CIꢀ) m/z: 478.2617 (Calcd for C26H40NO5S
[(MꢀH)ꢀ]: 478.2627.
1
ner as described in (a). [a]D28 ꢂ2.5 (cꢃ0.8, CHCl3). H-NMR, IR and MS
spectra of this sample were identical to those described in (a). HR-MS (CIꢀ)
m/z: 335.1678 (Calcd for C19H27O3S {[(MꢂCH3O)ꢀH]ꢀ}: 335.1681).
(R,E)-Benzyl 2-(3,3-Dimethoxypropylthio)-2-methyloct-3-enoate (12e)
and Its Enantiomer (ent-12e) (a) Preparation of 12e: Treatments of 11e
(10.7 g, 23.8 mmol) in a manner similar to that described for the preparation
of 12b, afforded 12e (8.03 g, 89%) as a colorless oil. [a]D21 ꢀ1.9 (cꢃ1.0,
CHCl3). 1H-NMR (400 MHz, CDCl3) d: 0.88 (3H, t, Jꢃ7.3 Hz), 1.24—1.37
(4H, m), 1.60 (3H, s), 1.78 (2H, td, Jꢃ7.3, 6.1 Hz), 2.07 (2H, q, Jꢃ6.1 Hz),
2.49—2.62 (2H, m), 3.29 (6H, s), 4.37 (1H, t, Jꢃ6.1 Hz), 5.18 (2H, s), 5.66
(1H, td, Jꢃ6.7, 15.9 Hz), 5.75 (1H, d, Jꢃ15.9 Hz), 7.30—7.39 (5H, m). IR
(neat) cmꢂ1: 1728. MS (CIꢀ) m/z: 381 [(MꢀH)ꢀ]. HR-MS (CIꢀ) m/z:
381.2067 (Calcd for C21H33O4S [(MꢀH)ꢀ]: 381.2100).
(b) Preparation of ent-11f: Compound ent-11f (3.44 g, 59%) was prepared
as a colorless oil from ent-9f (4.23 g, 12.3 mmol) in the same manner as de-
scribed in (a).42) [a]D19 ꢂ47.4 (cꢃ0.6, MeOH). 1H-NMR, IR and MS spectra
of this sample were identical to those described in (a). HR-MS (CIꢀ) m/z:
478.2620 (Calcd for C26H40NO5S [(MꢀH)ꢀ]: 478.2627).
(R,E)-Benzyl 2-(3,3-Dimethoxypropylthio)-2-methylpent-3-enoate
(12b) and Its Enantiomer (ent-12b) (a) Preparation of 12b: To benzyl al-
cohol (14.0 ml, 135 mmol), titanium isopropoxide (2.0 ml, 6.78 mmol) was
added and the resulting mixture was stirred at room temperature for 5 h
under a reduced pressure (0.5—1.0 mmHg). The mixture was added to 11b
(1.65 g, 4.05 mmol), and the whole was stirred at 70 °C for 16 h. After cool-
ing, the mixture was diluted with CH2Cl2 (40 ml) and the reaction was
quenched by adding 1 mol/l HCl (10 ml). The insoluble materials which ap-
peared were removed by filtration through a pad of Celite and washed with
CH2Cl2. The filtrates were combined, diluted with H2O (20 ml) and extracted
with CH2Cl2 (25 mlꢇ3). The organic extracts were combined, washed with
brine (25 ml), dried over anhydrous Na2SO4, filtered, and then concentrated
in vacuo. Flash column chromatography (hexane/AcOEtꢃ10 : 1) of the
residue gave 12b (1.21 g, 88%) as a colorless oil. [a]D26 ꢀ6.1 (cꢃ1.1,
(b) Preparation of ent-12e: Compound ent-12e (3.11 g, 92%) was pre-
pared as a colorless oil from ent-11e (4.00 g, 8.90 mmol) in the same manner
as described in (a). [a]D21 ꢂ2.8 (cꢃ1.0, CHCl3). 1H-NMR, IR and MS spec-
tra of this sample were identical to those described in (a). HR-MS (CIꢀ) m/z:
381.2059 (Calcd for C21H33O4S [(MꢀH)ꢀ]: 381.2100).
(R,E)-Benzyl 2-(3,3-Dimethoxypropylthio)-2-methyldec-3-enoate (12f)
and Its Enantiomer (ent-12f) (a) Preparation of 12f: Treatments of 11f
(9.60 g, 20.1 mmol) in a manner similar to that described for the preparation
of 12b, afforded 12f (7.00 g, 85%) as a colorless oil. [a]D21 ꢀ2.0 (cꢃ1.0,
CHCl3). 1H-NMR (400 MHz, CDCl3) d: 0.88 (3H, t, Jꢃ6.7 Hz), 1.24—1.37
(8H, m), 1.61 (3H, s), 1.78 (2H, td, Jꢃ7.3, 6.7 Hz), 2.06 (2H, q, Jꢃ6.7 Hz),
2.48—2.62 (2H, m), 3.29 (6H, s), 4.37 (1H, t, Jꢃ5.5 Hz), 5.18 (2H, s), 5.63
(1H, td, Jꢃ6.7, 15.3 Hz), 5.75 (1H, d, Jꢃ15.3 Hz), 7.31—7.39 (5H, m). IR
(neat) cmꢂ1: 1728. MS (CIꢀ) m/z: 409 [(MꢀH)ꢀ]. HR-MS (CIꢀ) m/z:
409.2408 (Calcd for C23H37O4S [(MꢀH)ꢀ]: 409.2413).
1
CHCl3). H-NMR (400 MHz, CDCl3) d: 1.61 (3H, s), 1.72—1.80 (5H, m),
2.48—2.62 (2H, m), 3.29 (6H, s), 4.37 (1H, t, Jꢃ6.1 Hz), 5.16 (1H, d,
Jꢃ12.8 Hz), 5.20 (1H, d, Jꢃ12.8 Hz), 5.65—5.82 (2H, m), 7.30—7.38 (5H,
m). IR (neat) cmꢂ1: 1728. MS (EIꢀ) m/z: 338 (Mꢀ). HR-MS (EIꢀ) m/z:
338.1542 (Calcd for C18H26O4S (Mꢀ): 338.1552).
(b) Preparation of ent-12f: Compound ent-12f (2.69 g, 98%) was prepared
as a colorless oil from ent-11f (3.20 g, 6.70 mmol) in the same manner as de-
(b) Preparation of ent-12b: Compound ent-12b (780 mg, 94%) was pre-
pared as a colorless oil from ent-11b (1.00 g, 2.45 mmol) in the same man-
1
scribed in (a). [a]D26 ꢂ2.5 (cꢃ1.1, CHCl3). H-NMR, IR and MS spectra of
this sample were identical to those described in (a). HR-MS (CIꢀ) m/z:
409.2403 (Calcd for C23H37O4S [(MꢀH)ꢀ]: 409.2413).
1
ner as described in (a). [a]D27 ꢂ6.5 (cꢃ1.1, CHCl3). H-NMR, IR and MS
spectra of this sample were identical to those described in (a). HR-MS (EIꢀ)
m/z: 338.1573 (Calcd for C18H26O4S (Mꢀ): 338.1552).
(R,E)-Benzyl 2-Methyl-2-(3-oxopropylthio)pent-3-enoate (13b) and Its

928
Vol. 57, No. 9
Enantiomer (ent-13b) (a) Preparation of 13b: To a solution of 12b
pared as a colorless oil from ent-12e (2.90 g, 7.62 mmol) in the same manner
(1.19 g, 3.52 mmol) in THF (18 ml), 6% HCl (6.0 ml) was added at room
as described in (a).43) 1H-NMR, IR and MS spectra of this sample were iden-
temperature, and the resulting mixture was stirred at the same temperature tical to those described in (a). HR-MS (EIꢀ) m/z: 334.1634 (Calcd for
for 6 h. After quenching the reaction by adding saturated aqueous sodium
hydrogen carbonate (30 ml) under cooling in an ice bath, the mixture was
C19H26O3S (Mꢀ): 334.1603).
(R,E)-Benzyl 2-Methyl-2-(3-oxopropylthio)dec-3-enoate (13f) and Its
extracted with AcOEt (15 mlꢇ3). The organic extracts were combined, Enantiomer (ent-13f) (a) Preparation of 13f: Treatments of 12f (6.85 g,
washed with brine (20 ml), dried over anhydrous Na2SO4, filtered, and then 16.8 mmol) in a manner similar to that described for the preparation of 13b,
concentrated in vacuo. Flash column chromatography (hexane/AcOEtꢃ7 : 1) afforded 13f (4.62 g, 76%) as a colorless oil.43) 1H-NMR (400 MHz, CDCl3)
of the residue gave 13b (1.01 g, 98%) as a colorless oil. [a]D27 ꢀ1.2 (cꢃ0.9, d: 0.88 (3H, t, Jꢃ7.3 Hz), 1.25—1.55 (8H, m,), 1.61 (3H, s), 2.03—2.09
THF). 1H-NMR (400 MHz, CDCl3) d: 1.61 (3H, s), 1.74 (3H, d, Jꢃ5.5 Hz),
2.57 (2H, t, Jꢃ7.3 Hz), 2.71—2.85 (2H, m), 5.16 (1H, d, Jꢃ12.8 Hz), 5.21
(2H, m), 2.57 (2H, td, Jꢃ7.3, 1.2 Hz), 2.71—2.85 (2H, m), 5.18 (1H, d,
Jꢃ12.2 Hz), 5.21 (1H, d, Jꢃ12.2 Hz), 5.63—5.75 (2H, m), 7.30—7.39 (5H,
(1H, d, Jꢃ12.8 Hz), 5.66—5.80 (2H, m), 7.31—7.39 (5H, m), 9.62 (1H, s). m), 9.62 (1H, d, Jꢃ1.2 Hz). IR (neat) cmꢂ1: 1713. MS (EIꢀ) m/z: 362 (Mꢀ).
IR (neat) cmꢂ1: 1726. MS (CIꢀ) m/z: 293 [(MꢀH)ꢀ]. HR-MS (CIꢀ) m/z: HR-MS (EIꢀ) m/z: 362.1891 (Calcd for C21H30O3S (Mꢀ): 362.1916).
293.1210 (Calcd for C16H21O3S [(MꢀH)ꢀ]: 293.1211).
(b) Preparation of ent-13f: Compound ent-13f (2.01 g, 88%) was prepared
(b) Preparation of ent-13b: Compound ent-13b (630 mg, 98%) was pre- as a colorless oil from ent-12f (2.57 g, 6.29 mmol) in the same manner as de-
pared as a colorless oil from ent-12b (743 mg, 2.20 mmol) in the same man-
scribed in (a).43) 1H-NMR, IR and MS spectra of this sample were identical
ner as described in (a). [a]D26 ꢂ4.7 (cꢃ0.9, THF). 1H-NMR, IR and MS
to those described in (a). HR-MS (EIꢀ) m/z: 362.1887 (Calcd for C21H30O3S
spectra of this sample were identical to those described in (a). HR-MS (EIꢀ) (Mꢀ): 362.1916).
m/z: 292.1122 (Calcd for C16H20O3S (Mꢀ): 292.1133).
(R,E)-Benzyl 2-Methyl-2-(propionylthio)pent-3-enoate (14b) and Its
(R)-Benzyl 2-Methyl-2-(3-oxopropylthio)but-3-enoate (13a) and Its Enantiomer (ent-14b) (a) Preparation of 14b: To a suspension of Cs2CO3
Enantiomer (ent-13a) (a) Preparation of 13a: Treatments of 12a (750 mg,
2.31 mmol) in a manner similar to those described for the preparation of 13b 1.37 mmol) in EtOH (34 ml) was added dropwise at 4 °C, and the resulting
afforded 13a (631 mg, 98%) as a colorless oil. [a]D21 ꢂ2.0 (cꢃ0.8, toluene).
mixture was stirred at the same temperature for 20 min. The reaction mix-
1H-NMR (400 MHz, CDCl3) d: 1.62 (3H, s), 2.58 (2H, td, Jꢃ6.7, 1.2 Hz), ture was poured into a mixture of saturated aqueous ammonium chloride so-
2.74—2.86 (2H, m), 5.19 (1H, d, Jꢃ12.8 Hz), 5.22 (1H, d, Jꢃ12.8 Hz), 5.25 lution and 1 mol/l HCl (3 : 1, 120 ml), and the aqueous mixture was extracted
(2.30 g, 7.06 mmol) in EtOH (105 ml), a solution of 13b (400 mg,
(1H, d, Jꢃ10.4 Hz), 5.28 (1H, d, Jꢃ17.1 Hz,), 6.11 (1H, dd, Jꢃ17.1, with Et2O (20 mlꢇ3). The organic extracts were combined, dried over anhy-
10.4 Hz), 7.31—7.40 (5H, m), 9.63 (1H, s). IR (neat) cmꢂ1: 1724. MS (CIꢀ) drous Na2SO4, filtered, and then concentrated in vacuo. The residue was di-
m/z: 279 [(MꢀH)ꢀ]. HR-MS (CIꢀ) m/z: 279.1021 (Calcd for C15H19O3S luted with CH2Cl2 (7 ml). Et3N (0.3 ml, 2.15 mmol) and propionyl chloride
[(MꢀH)ꢀ]: 279.1055).
(0.13 ml, 1.46 mmol) were added dropwise to the resulting CH2Cl2 solution
(b) Preparation of ent-13a: Compound ent-13a (621 mg, 93%) was pre- at 4 °C, and the mixture was stirred at the same temperature for 30 min.
pared as a colorless oil from ent-12a (780 mg, 2.40 mmol) in the same man-
After quenching the reaction by adding saturated aqueous ammonium chlo-
ride solution (30 ml), the mixture was extracted with CH2Cl2 (20 mlꢇ3). The
1
ner as described in (a). [a]D26 ꢀ2.2 (cꢃ0.5, toluene). H-NMR, IR and MS
spectra of this sample were identical to those described in (a). HR-MS (CIꢀ) organic extracts were combined, washed with brine (20 ml), dried over anhy-
m/z: 279.1046 (Calcd for C15H19O3S [(MꢀH)ꢀ]: 279.1055).
(R,E)-Benzyl 2-Methyl-2-(3-oxopropylthio)hex-3-enoate (13c) and Its matography (hexane/AcOEtꢃ20 : 1) of the residue gave 14b (295 mg, 74%)
Enantiomer (ent-13c) (a) Preparation of 13c: Treatments of 12c (1.34 g,
as a colorless oil. [a]D26 ꢀ38.0 (cꢃ0.4, CHCl3). 1H-NMR (400 MHz, CDCl3)
drous Na2SO4, filtered, and then concentrated in vacuo. Flash column chro-
3.80 mmol) in a manner similar to that described for the preparation of 13b, d: 1.10 (3H, t, Jꢃ7.3 Hz), 1.70 (3H, d, Jꢃ5.5 Hz), 1.75 (3H, s), 2.48 (2H, q,
afforded 13c (1.14 g, 98%) as a colorless oil.43) 1H-NMR (400 MHz, CDCl3) Jꢃ7.3 Hz), 5.15 (1H, d, Jꢃ12.2 Hz), 5.19 (1H, d, Jꢃ12.2 Hz), 5.60—5.80
d: 1.00 (3H, t, Jꢃ7.3 Hz), 1.61 (3H, s), 2.06—2.14 (2H, m), 2.58 (2H, td, (2H, m), 7.30—7.36 (5H, m). IR (neat) cmꢂ1: 1738, 1691. MS (CIꢀ) m/z:
Jꢃ7.3, 1.2 Hz), 2.71—2.85 (2H, m), 5.17 (1H, d, Jꢃ12.2 Hz), 5.21 (1H, d, 293 [(MꢀH)ꢀ]. HR-MS (CIꢀ) m/z: 293.1201 (Calcd for C16H21O3S
Jꢃ12.2 Hz), 5.71—5.74 (2H, m), 7.30—7.40 (5H, m,), 9.63 (1H, s). IR [(MꢀH)ꢀ]: 293.1211).
(neat) cmꢂ1: 1726. MS (CIꢀ) m/z: 307 [(MꢀH)ꢀ]. HR-MS (CIꢀ) m/z:
307.1325 (Calcd for C17H23O3S [(MꢀH)ꢀ]: 307.1368).
(b) Preparation of ent-14b: Compound ent-14b (241 mg, 86%) was pre-
pared as a colorless oil from ent-13b (281 mg, 0.961 mmol) in the same
1
(b) Preparation of ent-13c: Compound ent-13c (1.01 g, 97%) was pre- manner as described in (a). [a]D27 ꢂ30.3 (cꢃ0.4, CHCl3). H-NMR, IR and
pared as a colorless oil from ent-12c (1.20 g, 3.41 mmol) in the same manner
MS spectra of this sample were identical to those described in (a). HR-MS
as described in (a).43) 1H-NMR, IR and MS spectra of this sample were iden- (CIꢀ) m/z: 293.1249 (Calcd for C16H21O3S [(MꢀH)ꢀ]: 293.1211).
tical to those described in (a). HR-MS (CIꢀ) m/z: 307.1334 (Calcd for
C17H23O3S [(MꢀH)ꢀ]: 307.1368).
(R)-Benzyl 2-Methyl-2-(propionylthio)but-3-enoate (14a) and Its
Enantiomer (ent-14a) (a) Preparation of 14a: Treatments of 13a (240 mg,
(R,E)-Benzyl 2-Methyl-2-(3-oxopropylthio)hept-3-enoate (13d) and Its 1.06 mmol) in a manner similar to that described for the preparation of 14b,
Enantiomer (ent-13d) (a) Preparation of 13d: Treatments of 12d (992 mg,
afforded 14a (240 mg, 81%) as a colorless oil. [a]D30 ꢀ39.3 (cꢃ0.5, CHCl3).
2.71 mmol) in a manner similar to that described for the preparation of 13b, 1H-NMR (400 MHz, CDCl3) d: 1.11 (3H, t, Jꢃ7.3 Hz), 1.75 (3H, s), 2.49
afforded 13d (811 mg, 93%) as a colorless oil. [a]D28 ꢀ2.4 (cꢃ0.6, toluene).
1H-NMR (400 MHz, CDCl3) d: 0.88 (3H, t, Jꢃ7.3 Hz), 1.39 (2H, d,
(2H, q, Jꢃ7.3 Hz), 5.18 (2H, s), 5.25 (1H, d, Jꢃ11.0 Hz), 5.32 (1H, d,
Jꢃ17.1 Hz), 6.13 (1H, dd, Jꢃ17.1, 11.0 Hz), 7.28—7.38 (5H, m). IR (neat)
Jꢃ7.3 Hz), 1.61 (3H, s), 2.05 (2H, q, Jꢃ6.7 Hz), 2.57 (2H, td, Jꢃ6.7, cmꢂ1: 1738, 1693. MS (CIꢀ) m/z: 279 [(MꢀH)ꢀ]. HR-MS (CIꢀ) m/z:
1.2 Hz), 2.71—2.85 (2H, m), 5.17 (1H, d, Jꢃ12.2 Hz), 5.20 (1H, d, 279.1065 (Calcd for C15H19O3S [(MꢀH)ꢀ]: 279.1055).
Jꢃ12.2 Hz), 5.64—5.76 (2H, m), 7.32—7.38 (5H, m), 9.62 (1H, d,
Jꢃ1.2 Hz). IR (neat) cmꢂ1: 1726. MS (CIꢀ) m/z: 321 [(MꢀH)ꢀ]. HR-MS
(CIꢀ) m/z: 321.1498 (Calcd for C18H25O3S [(MꢀH)ꢀ]: 321.1524).
(b) Preparation of ent-14a: Compound ent-14a (227 mg, 73%) was pre-
pared as a colorless oil from ent-13a (310 mg, 1.11 mmol) in the same man-
1
ner as described in (a). [a]D30 ꢂ34.7 (cꢃ0.5, CHCl3). H-NMR, IR and MS
(b) Preparation of ent-13d: Compound ent-13d (389 mg, 92%) was pre- spectra of this sample were identical to those described in (a). HR-MS (CIꢀ)
pared as a colorless oil from ent-12d (485 mg, 1.32 mmol) in the same man-
m/z: 279.1065 (Calcd for C15H19O3S [(MꢀH)ꢀ]: 279.1055).
1
ner as described in (a). [a]D27 ꢂ2.6 (cꢃ0.6, toluene). H-NMR, IR and MS
(R,E)-Benzyl 2-Methyl-2-(propionylthio)hex-3-enoate (14c) and Its
spectra of this sample were identical to those described in (a). HR-MS (CIꢀ) Enantiomer (ent-14c) (a) Preparation of 14c: Treatments of 13c (468 mg,
m/z: 321.1552 (Calcd for C18H25O3S [(MꢀH)ꢀ]: 321.1524).
(R,E)-Benzyl 2-Methyl-2-(3-oxopropylthio)oct-3-enoate (13e) and Its afforded 14c (232 mg, 50%) as a colorless oil. [a]D27 ꢀ33.1 (cꢃ0.6, CHCl3).
Enantiomer (ent-13e) (a) Preparation of 13e: Treatments of 12e (7.67 g,
1H-NMR (400 MHz, CDCl3) d: 0.96 (3H, t, Jꢃ7.3 Hz), 1.11 (3H, t,
1.53 mmol) in a manner similar to that described for the preparation of 14b,
20.2 mmol) in a manner similar to that described for the preparation of 13b, Jꢃ7.3 Hz), 1.76 (3H, s), 2.00—2.10 (2H, m), 2.50 (2H, q, Jꢃ7.3 Hz), 5.17
afforded 13e (4.43 g, 66%) as a colorless oil.43) 1H-NMR (400 MHz, CDCl3) (2H, s), 5.62 (1H, td, Jꢃ1.2, 15.9 Hz), 5.77 (1H, td, Jꢃ6.1, 15.9 Hz), 7.29—
d: 0.89 (3H, t, Jꢃ7.3 Hz), 1.24—1.40 (4H, m), 1.61 (3H, s), 2.07 (2H, q, 7.36 (5H, m). IR (neat) cmꢂ1: 1738, 1692. MS (CIꢀ) m/z: 307 [(MꢀH)ꢀ].
Jꢃ6.7 Hz), 2.58 (2H, td, Jꢃ7.3, 1.2 Hz), 2.72—2.85 (2H, m), 5.17 (1H, d, HR-MS (CIꢀ) m/z: 307.1328 (Calcd for C17H23O3S [(MꢀH)ꢀ]: 307.1368).
Jꢃ12.2 Hz), 5.21 (1H, d, Jꢃ12.2 Hz), 5.67 (1H, td, Jꢃ6.1, 15.9 Hz), 5.73
(1H, d, Jꢃ15.9 Hz), 7.32—7.38 (5H, m), 9.63 (1H, d, Jꢃ1.2 Hz). IR (neat)
cmꢂ1: 1715. MS (EIꢀ) m/z: 334 (Mꢀ). HR-MS (EIꢀ) m/z: 334.1593 (Calcd
for C19H26O3S (Mꢀ): 334.1603.
(b) Preparation of ent-14c: Compound ent-14c (209 mg, 60%) was pre-
pared as a colorless oil from ent-13c (349 mg, 1.14 mmol) in the same man-
1
ner as described in (a). [a]D28 ꢂ25.1 (cꢃ0.6, CHCl3). H-NMR, IR and MS
spectra of this sample were identical to those described in (a). HR-MS (CIꢀ)
(b) Preparation of ent-13e: Compound ent-13e (2.55 g, 100%) was pre- m/z: 307.1354 (Calcd for C17H23O3S [(MꢀH)ꢀ]: 307.1368).

September 2009
929
(R,E)-Benzyl 2-Methyl-2-(propionylthio)hept-3-enoate (14d) and Its
Enantiomer (ent-14d) (a) Preparation of 14d: Treatments of 13d (400 mg,
(R,E)-Benzyl 2-Methyl-2-(acetylthio)hex-3-enoate (15c) and Its Enan-
tiomer (ent-15c) (a) Preparation of 15c: Treatments of 13c (468 mg,
1.25 mmol) in a manner similar to that described for the preparation of 14b, 1.53 mmol) in a manner similar to that described for the preparation of 15b,
afforded 14d (244 mg, 61%) as a colorless oil. [a]D27 ꢀ28.2 (cꢃ0.5, CHCl3).
afforded 15c (234 mg, 52%) as a colorless oil. [a]D28 ꢀ20.7 (cꢃ0.6, CHCl3).
1H-NMR (400 MHz, CDCl3) d: 0.85 (3H, t, Jꢃ7.9 Hz), 1.11 (3H, t,
1H-NMR (400 MHz, CDCl3) d: 0.95 (3H, t, Jꢃ7.3 Hz), 1.76 (3H, s), 2.00—
Jꢃ7.3 Hz), 1.36 (2H, d, Jꢃ7.3 Hz), 1.76 (3H, s), 1.96—2.06 (2H, m), 2.48 2.10 (2H, m), 2.25 (3H, s), 5.15 (1H, d, Jꢃ12.2 Hz), 5.19 (1H, d,
(2H, q, Jꢃ7.9 Hz), 5.17 (2H, s), 5.63 (1H, d, Jꢃ15.9 Hz), 5.72 (1H, td,
Jꢃ12.2 Hz), 5.61 (1H, td, Jꢃ1.2, 15.3 Hz), 5.77 (1H, td, Jꢃ6.1, 15.3 Hz),
Jꢃ6.1, 15.9 Hz), 7.30—7.36 (5H, m). IR (neat) cmꢂ1: 1738, 1694. MS (CIꢀ) 7.28—7.36 (5H, m). IR (neat) cmꢂ1: 1738, 1692. MS (CIꢀ) m/z: 293
m/z: 321 [(MꢀH)ꢀ]. HR-MS (CIꢀ) m/z: 321.1518 (Calcd for C18H25O3S [(MꢀH)ꢀ]. HR-MS (CIꢀ) m/z: 293.1172 (Calcd for C16H21O3S [(MꢀH)ꢀ]:
[(MꢀH)ꢀ]: 321.1524).
293.1211).
(b) Preparation of ent-14d: Compound ent-14d (240 mg, 60%) was pre-
pared as a colorless oil from ent-13d (400 mg, 1.25 mmol) in the same man-
(b) Preparation of ent-15c: Compound ent-15c (289 mg, 75%) was pre-
pared as a colorless oil from ent-13c (401 mg, 1.31 mmol) in the same man-
ner as described in (a). [a]D26 ꢂ29.5 (cꢃ0.5, CHCl3). H-NMR, IR and MS
ner as described in (a). [a]D28 ꢂ21.4 (cꢃ0.6, CHCl3). H-NMR, IR and MS
1
1
spectra of this sample were identical to those described in (a). HR-MS (CIꢀ) spectra of this sample were identical to those described in (a). HR-MS (CIꢀ)
m/z: 321.1491 (Calcd for C18H25O3S [(MꢀH)ꢀ]: 321.1524).
m/z: 293.1212 (Calcd for C16H21O3S [(MꢀH)ꢀ]: 293.1211).
(R,E)-Benzyl 2-Methyl-2-(propionylthio)oct-3-enoate (14e) and Its
Enantiomer (ent-14e) (a) Preparation of 14e: Treatments of 13e (1.40 g,
(R,E)-Benzyl 2-Methyl-2-(acetylthio)hept-3-enoate (15d) and Its
Enantiomer (ent-15d) (a) Preparation of 15d: Treatments of 13d (390 mg,
4.19 mmol) in a manner similar to that described for the preparation of 14b, 1.22 mmol) in a manner similar to that described for the preparation of 15b,
afforded 14e (875 mg, 62%) as a colorless oil. [a]D27 ꢀ34.5 (cꢃ1.1, CHCl3).
afforded 15d (274 mg, 73%) as a colorless oil. [a]D21 ꢀ19.2 (cꢃ0.7, CHCl3).
1H-NMR (400 MHz, CDCl3) d: 0.88 (3H, t, Jꢃ7.3 Hz), 1.11 (3H, t,
1H-NMR(CDCl3) d: 0.85 (3H, t, Jꢃ7.3 Hz), 1.36 (2H, d, Jꢃ7.3 Hz), 1.76
Jꢃ7.3 Hz), 1.20—1.36 (4H, m), 1.76 (3H, s), 1.97—2.07 (2H, m), 2.50 (2H, (3H, s), 1.96—2.06 (2H, m), 2.25 (3H, s), 5.15 (1H, d, Jꢃ12.2 Hz), 5.20
q, Jꢃ7.3 Hz), 5.17 (2H, s), 5.63 (1H, d, Jꢃ15.9 Hz), 5.72 (1H, td, Jꢃ6.7, (1H, d, Jꢃ12.2 Hz), 5.63 (1H, d, Jꢃ15.3 Hz), 5.72 (1H, td, Jꢃ15.3, 6.7 Hz),
15.9 Hz), 7.29—7.38 (5H, m). IR (neat) cmꢂ1: 1738, 1694. MS (EIꢀ) m/z:
7.29—7.36 (5H, m). IR (neat) cmꢂ1: 1738, 1692. MS (CIꢀ) m/z: 307
334 (Mꢀ). HR-MS (EIꢀ) m/z: 334.1580 (Calcd for C19H26O3S (Mꢀ): [(MꢀH)ꢀ]. HR-MS (CIꢀ) m/z: 307.1344 (Calcd for C17H23O3S [(MꢀH)ꢀ]:
334.1603).
307.1368).
(b) Preparation of ent-14e: Compound ent-14e (759 mg, 76%) was pre-
pared as a colorless oil from ent-13e (1.00 g, 2.99 mmol) in the same manner
as described in (a). [a]D27 ꢂ33.9 (cꢃ1.1, CHCl3). 1H-NMR, IR and MS spec-
(b) Preparation of ent-15d: Compound ent-15d (252 mg, 66%) was pre-
pared as a colorless oil from ent-13d (400 mg, 1.25 mmol) in the same man-
1
ner as described in (a). [a]D21 ꢂ16.2 (cꢃ0.7, CHCl3). H-NMR, IR and MS
tra of this sample were identical to those described in (a). HR-MS (CIꢀ) m/z: spectra of this sample were identical to those described in (a). HR-MS (CIꢀ)
334.1572 (Calcd for C19H26O3S (Mꢀ): 334.1603.
m/z: 307.1338 (Calcd for C17H23O3S [(MꢀH)ꢀ]: 307.1368).
(R,E)-Benzyl 2-Methyl-2-(propionylthio)dec-3-enoate (14f) and Its
Enantiomer (ent-14f) (a) Preparation of 14f: Treatments of 13f (1.40 g,
(R,E)-Benzyl 2-Methyl-2-(acetylthio)oct-3-enoate (15e) and Its Enan-
tiomer (ent-15e) (a) Preparation of 15e: Treatments of 13e (2.94 g,
3.86 mmol) in a manner similar to that described for the preparation of 14b, 8.79 mmol) in a manner similar to that described for the preparation of 15b,
afforded 14f (697 mg, 50%) as a colorless oil. [a]D27 ꢀ38.9 (cꢃ0.5, CHCl3).
afforded 15e (1.35 g, 48%) as a colorless oil. [a]D27 ꢀ24.6 (cꢃ1.0, CHCl3).
1H-NMR (400 MHz, CDCl3) d: 0.87 (3H, t, Jꢃ7.3 Hz), 1.11 (3H, t,
1H-NMR (400 MHz, CDCl3) d: 0.88 (3H, t, Jꢃ6.7 Hz), 1.22—1.36 (4H, m),
Jꢃ7.3 Hz), 1.20—1.40 (8H, m), 1.76 (3H, s), 1.97—2.06 (2H, m), 2.48 (2H, 1.76 (3H, s), 2.04 (2H, q, Jꢃ6.7 Hz), 2.25 (3H, s), 5.15 (1H, d, Jꢃ12.2 Hz),
q, Jꢃ7.3 Hz), 5.17 (2H, s), 5.63 (1H, d, Jꢃ15.3 Hz), 5.73 (1H, td, Jꢃ6.1, 5.20 (1H, d, Jꢃ12.2 Hz), 5.62 (1H, d, Jꢃ15.9 Hz), 5.72 (1H, td, Jꢃ15.9,
15.3 Hz), 7.30—7.37 (5H, m). IR (neat) cmꢂ1: 1740, 1694. MS (EIꢀ) m/z:
6.7 Hz), 7.29—7.37 (5H, m). IR (neat) cmꢂ1: 1738, 1694. MS (EIꢀ) m/z:
362 (Mꢀ). HR-MS (EIꢀ) m/z: 362.1895 (Calcd for C21H30O3S (Mꢀ): 320 (Mꢀ). HR-MS (EIꢀ) m/z: 320.1479 (Calcd for C18H24O3S (Mꢀ):
362.1916).
320.1446).
(b) Preparation of ent-14f: Compound ent-14f (806 mg, 90%) was pre-
pared as a colorless oil from ent-13f (900 mg, 2.48 mmol) in the same man-
(b) Preparation of ent-15e: Compound ent-15e (359 mg, 37%) was pre-
pared as a colorless oil from ent-13e (1.00 g, 2.99 mmol) in the same manner
as described in (a). [a]D27 ꢂ25.9 (cꢃ1.0, CHCl3). 1H-NMR, IR and MS spec-
1
ner as described in (a). [a]D27 ꢂ35.6 (cꢃ1.0, CHCl3). H-NMR, IR and MS
spectra of this sample were identical to those described in (a). HR-MS (EIꢀ) tra of this sample were identical to those described in (a). HR-MS (CIꢀ) m/z:
m/z: 362.1887 (Calcd for C21H30O3S (Mꢀ): 362.1916).
320.1480 (Calcd for C18H24O3S (Mꢀ): 320.1446).
(R,E)-Benzyl 2-Methyl-2-(acetylthio)pent-3-enoate (15b) and Its
Enantiomer (ent-15b) (a) Preparation of 15b: Treatments of 13b (448 mg,
(R,E)-Benzyl 2-Methyl-2-(acetylthio)dec-3-enoate (15f) and Its Enan-
tiomer (ent-15f) (a) Preparation of 15f: Treatments of 13f (3.05 g,
1.53 mmol) in a manner similar to that described for the preparation of 14b 8.41 mmol) in a manner similar to that described for the preparation of 15b,
from 13b using acetyl chloride (0.11 ml, 1.52 mmol) in place of propionyl afforded 15f (1.06 g, 36%) as a colorless oil. [a]D27 ꢀ21.2 (cꢃ1.0, CHCl3).
chloride, afforded 15b (288 mg, 68%) as a colorless oil. [a]D27 ꢀ25.9 1H-NMR (400 MHz, CDCl3) d: 0.87 (3H, t, Jꢃ6.7 Hz), 1.20—1.38 (8H, m),
(cꢃ1.0, CHCl3). 1H-NMR (400 MHz, CDCl3) d: 1.70 (3H, d, Jꢃ5.5 Hz),
1.75 (3H, s), 2.25 (3H, s), 5.15 (1H, d, Jꢃ12.2 Hz), 5.20 (1H, d, Jꢃ12.2 Hz),
1.76 (3H, s), 1.97—2.05 (2H, m), 2.24 (3H, s), 5.15 (1H, d, Jꢃ12.2 Hz),
5.20 (1H, d, Jꢃ12.2 Hz), 5.62 (1H, d, Jꢃ15.3 Hz), 5.73 (1H, td, Jꢃ15.3,
5.65—5.80 (2H, m), 7.31—7.37 (5H, m). IR (neat) cmꢂ1: 1738, 1692. MS 6.7 Hz), 7.29—7.40 (5H, m). IR (neat) cmꢂ1: 1740, 1694. MS (EIꢀ) m/z:
(CIꢀ) m/z: 279 [(MꢀH)ꢀ]. HR-MS (CIꢀ) m/z: 279.1035 (Calcd for
C15H19O3S [(MꢀH)ꢀ]: 279.1055).
348 (Mꢀ). HR-MS (EIꢀ) m/z: 348.1745 (Calcd for C20H28O3S (Mꢀ):
348.1759).
(b) Preparation of ent-15b: Compound ent-15b (165 mg, 52%) was pre-
pared as a colorless oil from ent-13b (330 mg, 1.13 mmol) in the same man-
(b) Preparation of ent-15f: Compound ent-15f (803 mg, 83%) was pre-
pared as a colorless oil from ent-13f (1.00 g, 2.76 mmol) in the same manner
as described in (a). [a]D27 ꢂ29.5 (cꢃ1.0, CHCl3). 1H-NMR, IR and MS spec-
1
ner as described in (a). [a]D27 ꢂ20.1 (cꢃ1.0, CHCl3). H-NMR, IR and MS
spectra of this sample were identical to those described in (a). HR-MS (CIꢀ) tra of this sample were identical to those described in (a). HR-MS (CIꢀ) m/z:
m/z: 279.1052 (Calcd for C15H19O3S [(MꢀH)ꢀ]: 279.1055).
348.1715 (Calcd for C20H28O3S (Mꢀ): 348.1759).
(R)-Benzyl 2-Methyl-2-(acethylthio)but-3-enoate (15a) and Its Enan-
tiomer (ent-15a) (a) Preparation of 15a: Treatments of 13a (310 mg,
(R,E)-4-Hydroxy-3,5-dimethyl-5-(prop-1-enyl)thiophen-2(5H)-one
(3b) and Its Enantiomer (ent-3b) (a) Preparation of 3b: To a solution of
1.11 mmol) in a manner similar to that described for the preparation of 15b, 14b (289 mg, 0.988 mmol) in THF (49 ml), LiHMDS (1.0 mol/l solution in
afforded 15a (203 mg, 69%) as a colorless oil. [a]D29 ꢀ32.5 (cꢃ0.6, CHCl3). THF, 2.5 ml, 2.5 mmol) was added dropwise at ꢂ78 °C, and the resulting
1H-NMR (400 MHz, CDCl3) d: 1.75 (3H, s), 2.26 (3H, s), 5.18 (2H, s), 5.24 mixture was allowed to slowly warm to room temperature over 3.5 h. The
(1H, d, Jꢃ10.4 Hz), 5.32 (1H, d, Jꢃ17.1 Hz), 6.13 (1H, dd, Jꢃ17.1,
mixture was poured into a solution of 1 mol/l HCl (40 ml), and the aqueous
10.4 Hz), 7.29—7.39 (5H, m). IR (neat) cmꢂ1: 1738, 1693. MS (CIꢀ) m/z: mixture was extracted with Et2O (40 mlꢇ3). The organic extracts were com-
265 [(MꢀH)ꢀ]. HR-MS (CIꢀ) m/z: 265.0935 (Calcd for C14H17O3S bined, dried over anhydrous Na2SO4, filtered, and then concentrated in
[(MꢀH)ꢀ]: 265.0898).
vacuo. The residue was added to a saturated aqueous sodium hydrogen car-
(b) Preparation of ent-15a: Compound ent-15a (215 mg, 75%) was pre- bonate solution (20 ml). The aqueous mixture was washed with Et2O
pared as a colorless oil from ent-13a (300 mg, 1.08 mmol) in the same man-
(20 mlꢇ2), then made acidic (pH1) by adding 1 mol/l HCl. The resulting
aqueous mixture was extracted with Et2O (20 mlꢇ2) and AcOEt (20 mlꢇ2).
1
ner as described in (a). [a]D30 ꢂ32.7 (cꢃ0.6, CHCl3). H-NMR, IR and MS
spectra of this sample were identical to those described in (a). HR-MS (CIꢀ) The organic extracts were combined, dried over anhydrous Na2SO4, filtered,
m/z: 265.0934 (Calcd for C14H17O3S [(MꢀH)ꢀ]: 265.0898).
and then concentrated in vacuo to give 3b (134 mg, 74%) as a colorless pow-

930
Vol. 57, No. 9
der. mp 128—131 °C (diisopropyl ether–cyclohexane). [a]D26 ꢀ55.1 (cꢃ0.3,
MeOH) [ref. 22, [a]D ꢀ44 (cꢃ0.7, MeOH)]. The optical purity of 3b ob-
tained here was determined to be ꢅ99% ee by HPLC analysis with a chiral
column [Daicel Chiralpak AS f0.46 cmꢇ25 cm, hexane/2-propanol/TFAꢃ
as a colorless crystals from ent-14d (230 mg, 0.718 mmol) in the same man-
ner as described in (a). mp 70—73 °C (heptane–diisopropyl ether). [a]D25
ꢂ43.1 (cꢃ0.3, MeOH). The optical purity of ent-3d was calculated to be
1
ꢅ90% ee similar to that for 3d. H-NMR, 13C-NMR, IR and MS spectra of
this sample were identical to those described in (a). HR-MS (EIꢀ) m/z:
212.0883 (Calcd for C11H16O2S (Mꢀ): 212.0871).
1
90 : 10 : 0.1, flow rate 1.0 ml/min; tR 10.5 min (3b), 14.4 min (ent-3b)]. H-
NMR (400 MHz, CD3OD) d: 1.63 (3H, s), 1.72 (3H, s), 1.74 (3H, d,
Jꢃ1.8 Hz), 5.57 (1H, dd, Jꢃ15.3, 1.8 Hz), 5.78 (1H, qd, Jꢃ6.6, 15.3 Hz).
13C-NMR (100 MHz, CD3OD) d: 7.7, 17.9, 24.4, 58.4, 109.9, 127.9, 132.6,
182.6, 197.4. IR (KBr) cmꢂ1: 1605. MS (EIꢀ) m/z: 184 (Mꢀ). HR-MS (EIꢀ)
m/z: 184.0539 (Calcd for C9H12O2S (Mꢀ): 184.0558).
(b) Preparation of ent-3b: Compound ent-3b (57 mg, 39%) was prepared
as a colorless powder from ent-14b (230 mg, 0.787 mmol) in the same man-
ner as described in (a). mp 130—134.5 °C (diisopropyl ether–cyclohexane).
[a]D26 ꢂ53.8 (cꢃ0.3, MeOH) [ref. 22, [a]D ꢂ53.7 (cꢃ0.7, MeOH)]. The op-
tical purity of ent-3b prepared here was estimated to be ꢅ99% ee using a
method similar to that described in (a). 1H-NMR, 13C-NMR, IR and MS
spectra of this sample were identical to those described in (a). HR-MS (EIꢀ)
m/z: 184.0597 (Calcd for C9H12O2S (Mꢀ): 184.0558).
(R,E)-5-(Hex-1-enyl)-4-hydroxy-3,5-dimethylthiophen-2(5H)-one (3e)
and Its Enantiomer (ent-3e) (a) Preparation of 3e: Treatments of 14e
(800 mg, 2.39 mmol) in a manner similar to that described for the prepara-
tion of 3b, afforded 3e (346 mg, 64%) as a colorless oil. [a]D25 ꢀ69.1
(cꢃ0.9, MeOH). The optical purity of 3e obtained here was determined
to be 91% ee by HPLC analysis with a chiral column [Daicel Chiralcel
OD-H f0.46 cmꢇ25 cm, hexane/2-propanol/TFAꢃ98 : 2 : 0.1, flow rate
0.35 ml/min; tR 23.0 min (3e), 25.8 min (ent-3e)]. 1H-NMR (400 MHz,
CD3OD) d: 0.91 (3H, t, Jꢃ7.3 Hz), 1.26—1.42 (4H, m), 1.68 (3H, s), 1.73
(3H, s), 2.05—2.12 (2H, m), 5.55 (1H, td, Jꢃ1.2, 15.9 Hz), 5.76 (1H, td,
Jꢃ6.7, 15.9 Hz). 13C-NMR (100 MHz, CD3OD) d: 7.7, 14.2, 23.2, 24.5,
32.4, 33.0, 58.3, 110.1, 131.4, 131.8, 181.9, 197.4. IR (neat) cmꢂ1: 1705,
1616. MS (EIꢀ) m/z: 226 (Mꢀ). HR-MS (EIꢀ) m/z: 226.1070 (Calcd for
C12H18O2S (Mꢀ): 226.1028).
(R)-4-Hydroxy-3,5-dimethyl-5-vinylthiophen-2(5H)-one (3a) and Its
Enantiomer (ent-3a) (a) Preparation of 3a: Treatments of 14a (231 mg,
0.830 mmol) in a manner similar to that described for the preparation of 3b,
afforded 3a (99 mg, 70%) as a colorless powder. mp 114—116 °C (diiso-
propyl ether). [a]D25 ꢀ42.1 (cꢃ0.3, MeOH). While the optical purity of 3a
could not be determined by HPLC analysis, it was calculated to be ꢅ90% ee
based on the diastereomeric excess of the corresponding 11a which had
(b) Preparation of ent-3e: Compound ent-3e (165 mg, 49%) was prepared
as a colorless oil from ent-14e (500 mg, 1.50 mmol) in the same manner as
described in (a). [a]D19 ꢂ66.9 (cꢃ0.8, MeOH). The optical purity of ent-3e
prepared here was estimated to be 89% ee using a method similar to that de-
1
scribed in (a). H-NMR, 13C-NMR, IR and MS spectra of this sample were
identical to those described in (a). HR-MS (EIꢀ) m/z: 226.0986 (Calcd for
C12H18O2S (Mꢀ): 226.1028).
1
been determined as ꢅ90% de by the H-NMR spectra of 11a and its (2ꢁS)-
diastereomer. 1H-NMR (400 MHz, CD3OD) d: 1.68 (3H, s), 1.75 (3H, s),
5.22 (1H, d, Jꢃ10.4 Hz), 5.34 (1H, d, Jꢃ17.1 Hz), 5.95 (1H, dd, Jꢃ17.1,
10.4 Hz). 13C-NMR (100 MHz, CD3OD) d: 7.7, 23.6, 58.5, 110.3, 116.0,
139.8, 181.6, 197.0. IR (KBr) cmꢂ1: 1597. MS (EIꢀ) m/z: 170 (Mꢀ). HR-
MS (EIꢀ) m/z: 170.0384 (Calcd for C8H10O2S (Mꢀ): 170.0402).
(R,E)-4-Hydroxy-3,5-dimethyl-5-(oct-1-enyl)thiophen-2(5H)-one (3f)
and Its Enantiomer (ent-3f) (a) Preparation of 3f: Treatments of 14f
(670 mg, 1.85 mmol) in a manner similar to that described for the prepara-
tion of 3b, afforded 3f (155 mg, 33%) as a colorless oil. [a]D21 ꢀ57.2 (cꢃ1.1,
MeOH). The optical purity of 3f obtained here was determined to be
94% ee by HPLC analysis with a chiral column [Daicel Chiralpak
AS-H f0.46 cmꢇ25 cm, hexane/2-propanol/TFAꢃ95 : 5 : 0.1, flow rate
0.45 ml/min; tR 12.1 min (3f), 16.1 min (ent-3f)]. 1H-NMR (400 MHz,
CD3OD) d: 0.90 (3H, t, Jꢃ7.3 Hz), 1.22—1.42 (8H, m), 1.68 (3H, s), 1.73
(3H, s), 2.05—2.12 (2H, m), 5.55 (1H, td, Jꢃ1.2, 15.3 Hz), 5.76 (1H, td,
Jꢃ7.3, 15.3 Hz). 13C-NMR (100 MHz, CD3OD) d: 7.7, 14.4, 23.7, 24.5,
(b) Preparation of ent-3a: Compound ent-3a (89 mg, 67%) was prepared
as a colorless powder from ent-14a (218 mg, 0.783 mmol) in the same man-
ner as described in (a). mp 111—114 °C (diisopropyl ether). [a]D25 ꢂ38.2
(cꢃ0.3, MeOH). The optical purity of ent-3a was calculated to be ꢅ90% ee
similar to that for 3a. 1H-NMR, 13C-NMR, IR and MS spectra of this sample
were identical to those described in (a). HR-MS (EIꢀ) m/z: 170.0384 (Calcd
for C8H10O2S (Mꢀ): 170.0402).
(R,E)-5-(But-1-enyl)-4-hydroxy-3,5-dimethylthiophen-2(5H)-one (3c)
and Its Enantiomer (ent-3c) (a) Preparation of 3c: Treatments of 14c
(222 mg, 0.724 mmol) in a manner similar to that described for the prepara-
tion of 3b, afforded 3c (94 mg, 65%) as a colorless powder. mp 103.5—
105 °C (cyclohexane). [a]D23 ꢀ52.1 (cꢃ0.3, MeOH). While the optical pu-
rity of 3c could not be determined by HPLC analysis, it was calculated to be
ꢅ90% ee based on the diastereomeric excess of the corresponding 11c
which had been determined as ꢅ90% de by the 1H-NMR spectra of 11c and
its (2ꢁS)-diastereomer. 1H-NMR (400 MHz, CD3OD) d: 1.01 (3H, t,
Jꢃ7.3 Hz), 1.67 (3H, s), 1.73 (3H, s), 2.04—2.14 (2H, m), 5.55 (1H, td,
Jꢃ1.2, 15.3 Hz), 5.81 (1H, td, Jꢃ6.1, 15.3 Hz). 13C-NMR (100 MHz,
CD3OD) d: 7.7, 13.7, 24.5, 26.4, 58.3, 109.9, 130.6, 134.6, 182.5, 197.4. IR
(KBr) cmꢂ1: 1616. MS (EIꢀ) m/z: 198 (Mꢀ). HR-MS (EIꢀ) m/z: 198.0681
(Calcd for C10H14O2S (Mꢀ): 198.0715).
(b) Preparation of ent-3c: Compound ent-3c (90 mg, 70%) was prepared
as a colorless powder from ent-14c (200 mg, 0.653 mmol) in the same man-
ner as described in (a). mp 104—105.5 °C (cyclohexane). [a]D22 ꢂ48.6
(cꢃ0.3, MeOH). The optical purity of ent-3c was calculated to be ꢅ90% ee
similar to that for 3c. 1H-NMR, 13C-NMR, IR and MS spectra of this sample
were identical to those described in (a). HR-MS (EIꢀ) m/z: 198.0681 (Calcd
for C10H14O2S (Mꢀ): 198.0715).
(R,E)-4-Hydroxy-3,5-dimethyl-5-(pent-1-enyl)thiophen-2(5H)-one (3d)
and Its Enantiomer (ent-3d) (a) Preparation of 3d: Treatments of 14d
(234 mg, 0.730 mmol) in a manner similar to that described for the prepara-
tion of 3b, afforded 3d (99 mg, 64%) as a colorless crystals. mp 71—73 °C
(heptane–diisopropyl ether). [a]D25 ꢀ48.0 (cꢃ0.3, MeOH). While the optical
purity of 3d could not be determined by HPLC analysis, it was calculated to
be ꢅ90% ee based on the diastereomeric excess of the corresponding 11d
which had been determined as ꢅ90% de by the 1H-NMR spectra of 11d
and its (2ꢁS)-diastereomer. 1H-NMR (400 MHz, CD3OD) d: 0.91 (3H, t,
Jꢃ7.3 Hz), 1.42 (2H, q, Jꢃ7.3 Hz), 1.67 (3H, s), 1.73 (3H, s), 2.06 (2H, q,
Jꢃ7.3 Hz), 5.56 (1H, d, Jꢃ15.9 Hz,), 5.76 (1H, td, Jꢃ7.3, 15.9 Hz). 13C-
NMR (100 MHz, CD3OD) d: 7.7, 13.9, 23.3, 24.5, 35.4, 58.4, 109.8, 131.8,
132.9, 182.7, 197.4. IR (KBr) cmꢂ1: 1618. MS (EIꢀ) m/z: 212 (Mꢀ). HR-
MS (EIꢀ) m/z: 212.0875 (Calcd for C11H16O2S (Mꢀ): 212.0871).
29.8, 30.1, 32.8, 58.3, 110.1, 131.5, 133.2, 181.9, 197.4. IR (neat) cmꢂ1
:
1707, 1615. MS (EIꢀ) m/z: 254 (Mꢀ). HR-MS (EIꢀ) m/z: 254.1329 (Calcd
for C14H22O2S (Mꢀ): 254.1341).
(b) Preparation of ent-3f: Compound ent-3f (92 mg, 26%) was prepared as
a colorless oil from ent-14f (500 mg, 1.38 mmol) in the same manner as de-
scribed in (a). [a]D20 ꢂ54.5 (cꢃ0.9, MeOH). The optical purity of ent-3f pre-
pared here was estimated to be 84% ee using a method similar to that de-
1
scribed in (a). H-NMR, 13C-NMR, IR and MS spectra of this sample were
identical to those described in (a). HR-MS (EIꢀ) m/z: 254.1383 (Calcd for
C14H22O2S (Mꢀ): 254.1341).
(R,E)-4-Hydroxy-5-methyl-5-(prop-1-enyl)thiophen-2(5H)-one
(4b)
and Its Enantiomer (ent-4b) (a) Preparation of 4b: Treatments of 15b
(273 mg, 0.981 mmol) in a similar manner to that described for the prepara-
tion of 3b, gave 4b (148 mg, 89%) as a colorless powder. mp 97—98.5 °C
(hexane–AcOEt). [a]D25 ꢀ10.1 (cꢃ0.3, MeOH). The optical purity of 4b
prepared here was determined to be ꢅ99% ee by HPLC analysis with a chi-
ral column [Daicel Chiralcel IA f0.46 cmꢇ25 cm, hexane/2-propanol/
TFAꢃ98 : 2 : 0.1, flow rate 0.7 ml/min; tR 18.0 min (4b) and 19.5 min (ent-
4b)]. 1H-NMR (400 MHz, CD3OD) d: 1.72 (3H, d, Jꢃ1.2 Hz), 1.74 (3H, s),
5.63 (1H, dd, Jꢃ15.3, 1.2 Hz), 5.76—5.86 (1H, m). 13C-NMR (400 MHz,
CD3OD) d: 17.9, 24.9, 60.8, 127.7, 132.5, 189.6, 197.1. IR (KBr) cmꢂ1
:
1607. MS (EIꢀ) m/z: 170(Mꢀ). HR-MS (EIꢀ) m/z: 170.0380 (Calcd for
C8H10O2S (Mꢀ): 170.0402).
(b) Preparation of ent-4b: Compound ent-4b (54 mg, 88%) was prepared
as a colorless powder from ent-15b (100 mg, 0.359 mmol) in the same man-
ner as described in (a). mp 96—98.5 °C (hexane–AcOEt). [a]D25 ꢂ8.4
(cꢃ0.3, MeOH). The optical purity of ent-4b prepared here was estimated to
1
be ꢅ99% ee using a method similar to that described in (a). H-NMR, 13C-
NMR, IR and MS spectra of this sample were identical to those described in
(a). HR-MS (EIꢀ) m/z: 170.0377 (Calcd for C8H10O2S (Mꢀ): 170.0402).
(R)-4-Hydroxy-5-methyl-5-vinylthiophen-2(5H)-one (4a) and Its
Enantiomer (ent-4a) (a) Preparation of 4a: Treatments of 15a (192 mg,
0.726 mmol) in a manner similar to that described for the preparation of 3b,
afforded 4a (98 mg, 86%) as a colorless powder. mp 73—75 °C (cyclo-
hexane–diisopropyl ether). [a]D25 ꢀ23.3 (cꢃ0.3, MeOH). While the optical
purity of 4a could not be determined by HPLC analysis, it was calculated to
(b) Preparation of ent-3d: Compound ent-3d (115 mg, 75%) was prepared

September 2009
931
prepared here was estimated to be 88% ee using a method similar to that de-
be ꢅ90% ee based on the diastereomeric excess of the corresponding 11a
which had been determined as ꢅ90% de by the 1H-NMR spectra of 11a and
its (2ꢁS)-diastereomer. 1H-NMR (400 MHz, CD3OD) d: 1.77 (3H, s), 5.22
(1H, d, Jꢃ11.0 Hz), 5.37 (1H, d, Jꢃ17.1 Hz), 6.02 (1H, dd, Jꢃ17.1,
11.0 Hz). 13C-NMR (100 MHz, CD3OD) d: 24.2, 60.0, 115.9, 139.7, 189.1,
196.6. IR (KBr) cmꢂ1: 1605. MS (EIꢀ) m/z: 156 (Mꢀ). HR-MS (EIꢀ) m/z:
156.0242 (Calcd for C7H8O2S (Mꢀ): 156.0245.
(b) Preparation of ent-4a: Compound ent-4a (110 mg, 91%) was prepared
as a colorless powder from ent-15a (205 mg, 0.776 mmol) in the same man-
ner as described in (a). mp 73—75 °C (cyclohexane–diisopropyl ether).
[a]D25 ꢂ18.9 (cꢃ0.3, MeOH). The optical purity of ent-4a was calculated to
be ꢅ90% ee similar to the case for 4a. 1H-NMR, 13C-NMR, IR and MS
spectra of this sample were identical to those described in (a). HR-MS (EIꢀ)
m/z: 156.0240 (Calcd for C7H8O2S (Mꢀ): 156.0245).
(R,E)-5-(But-1-enyl)-4-hydroxy-5-methylthiophen-2(5H)-one (4c) and
Its Enantiomer (ent-4c) (a) Preparation of 4c: Treatments of 15c (224 mg,
0.766 mmol) in a manner similar to that described for the preparation of 3b,
afforded 4c (126 mg, 89%) as a colorless powder. mp 102—104 °C (cyclo-
hexane–diisopropyl ether). [a]D25 ꢀ9.2 (cꢃ0.3, MeOH). The optical purity
of 4c prepared here was determined to be ꢅ99% ee by HPLC analysis with
a chiral column [Daicel Chiralcel IA f0.46 cmꢇ25 cm, hexane/2-propanol/
TFAꢃ98 : 2 : 0.1, flow rate 0.5 ml/min; tR 21.1 min (4c), 23.3 min (ent-4c)].
1H-NMR (400 MHz, CD3OD) d: 1.01 (3H, t, Jꢃ7.3 Hz), 1.74 (3H, s),
2.05—2.14 (2H, m), 5.61 (1H, td, Jꢃ1.2, 15.9 Hz), 5.88 (1H, td, Jꢃ6.1,
15.9 Hz). 13C-NMR (100 MHz, CD3OD) d: 13.8, 25.0, 26.4, 60.7, 130.5,
134.5, 189.7, 197.1. IR (KBr) cmꢂ1: 1605. MS (EIꢀ) m/z: 210 (Mꢀ). HR-
MS (EIꢀ) m/z: 184.0553 (Calcd for C9H12O2S (Mꢀ): 184.0558).
(b) Preparation of ent-4c: Compound ent-4c (126 mg, 73%) was prepared
as a colorless powder from ent-15c (205 mg, 0.776 mmol) in the same man-
ner as described in (a). mp 105—107 °C (cyclohexane–diisopropyl ether).
[a]D25 ꢂ8.8 (cꢃ0.3, MeOH). The optical purity of ent-4c prepared here was
estimated to be ꢅ99% ee using a method similar to that described in (a). 1H-
NMR, 13C-NMR, IR and MS spectra of this sample were identical to those
described in (a). HR-MS (EIꢀ) m/z: 184.0521 (Calcd for C9H12O2S (Mꢀ):
184.0558).
1
scribed in (a). H-NMR, 13C-NMR, IR and MS spectra of this sample were
identical to those described in (a). HR-MS (CIꢀ) m/z: 213.0948 (Calcd for
C11H17O2S [(MꢀH)ꢀ]: 213.0949).
(R,E)-4-Hydroxy-5-methyl-5-(oct-1-enyl)thiophen-2(5H)-one (4f) and
Its Enantiomer (ent-4f) (a) Preparation of 4f: Treatments of 15f (1.00 g,
2.87 mmol) in a manner similar to those described for the preparation of 3b,
afforded 4f (526 mg, 76%) as a colorless oil. [a]D22 ꢀ78.7 (cꢃ0.8, CHCl3).
The optical purity of 4f prepared here was determined to be 91% ee by
HPLC analysis with a chiral column [Daicel Chiralcel OD-H f0.46 cmꢇ
25 cm, hexane/2-propanol/TFAꢃ98 : 2 : 0.1, flow rate 0.35 ml/min, tR
21.3 min (4f), 24.5 min (ent-4f)]. 1H-NMR (400 MHz, CD3OD) d: 0.90 (3H,
t, Jꢃ6.7 Hz), 1.22—1.42 (8H, m), 1.75 (3H, s), 2.08 (2H, qd, Jꢃ6.7,
1.2 Hz), 5.61 (1H, td, Jꢃ1.2, 15.3 Hz), 5.80 (1H, td, Jꢃ6.7, 15.3 Hz). 13C-
NMR (100 MHz, CD3OD) d: 14.4, 23.7, 24.9, 29.8, 30.1, 32.8, 33.3, 60.7,
131.4, 133.2, 189.1, 197.0. IR (neat) cmꢂ1: 1630, 1586. MS (EIꢀ) m/z: 240
(Mꢀ). HR-MS (EIꢀ) m/z: 240.1155 (Calcd for C13H20O2S (Mꢀ): 240.1184).
(b) Preparation of ent-4f: Compound ent-4f (306 mg, 89%) was prepared
as a colorless oil from ent-15f (500 mg, 1.43 mmol) in the same manner as
described in (a). [a]D22 ꢂ75.8 (cꢃ0.7, CHCl3). The optical purity of ent-4f
prepared here was estimated to be 87% ee using a method similar to that de-
1
scribed in (a). H-NMR, 13C-NMR, IR and MS spectra of this sample were
identical to those described in (a). HR-MS (EIꢀ) m/z: 240.1152 (Calcd for
C13H20O2S (Mꢀ): 240.1184).
Cyclohept-1-enecarbaldehyde (16b) To
a solution of 1-(nitro-
methyl)cyclohept-1-ene17) (1.86 g, 12.0 mmol) in MeOH (60 ml), sodium
methoxide (750 mg, 13.2 mmol) was added at room temperature, and the
resulting mixture was stirred at the same temperature for 30 min. Titani-
um(III) chloride (20% aqueous solution, 37.0 g, 48.0 mmol) was added to
the mixture at the same temperature, and the stirring was continued for 3 h at
room temperature. The reaction mixture was extracted with Et2O (30 mlꢇ5).
The organic extracts were combined, dried over anhydrous Na2SO4, filtered,
and then concentrated in vacuo. Flash column chromatography (hexane/
1
AcOEtꢃ10 : 1) of the residue gave 16b (1.14 g, 77%) as a colorless oil. H-
NMR (400 MHz, CDCl3) d: 1.46—1.54 (2H, m), 1.58—1.64 (2H, m),
1.76—1.84 (2H, m), 2.41—2.49 (4H, m), 6.87 (1H, t, Jꢃ6.4 Hz), 9.34 (1H,
s). IR (ATR) cmꢂ1: 1679, 1641. MS (EIꢀ) m/z: 124 (Mꢀ). HR-MS (EIꢀ) m/z:
124.0896 (Calcd for C8H12O (Mꢀ): 124.0888).
(R,E)-4-Hydroxy-5-methyl-5-(pent-1-enyl)thiophen-2(5H)-one
(4d)
and Its Enantiomer (ent-4d) (a) Preparation of 4d: Treatments of 15d
(260 mg, 0.849 mmol) in a manner similar to that described for the prepara-
tion of 3b, afforded 4d (129 mg, 77%) as a colorless powder. mp 90—92 °C
(cyclohexane–diisopropyl ether). [a]D25 ꢀ112 (cꢃ0.3, CHCl3). The optical
purity of 4d prepared here was determined to be ꢅ99% ee by HPLC analy-
sis with a chiral column [Daicel Chiralpak IA f0.46 cmꢇ25 cm, hexane/2-
propanol/TFAꢃ98 : 2 : 0.1, flow rate 0.5 ml/min; tR 19.6 min (4d), 21.2 min
(E)-Cyclooct-1-enecarbaldehyde (16c) To a stirred suspension of 4-
methylbenzenesulfonohydrazide (38.9 g, 198 mmol) and cyclooctanone
(25.0 g, 0.198 mmol) in MeOH (132 ml) was added conc. HCl (0.6 ml) at
room temperature and the resulting mixture was stirred at the same tempera-
ture for 2 h. The precipitates which appeared were collected by filtration and
dried in vacuo to afford Nꢁ-cyclooctylidene-4-methylbenzenesulfonohy-
drazide as a white solid (52.7 g, 91%). To a stirred suspension of Nꢁ-
cyclooctylidene-4-methylbenzenesulfonohydrazide (1.00 g, 3.40 mmol) in
TMEDA (13.6 ml), n-BuLi (1.6 mol/l in hexane, 4.9 ml, 7.84 mmol) was
added dropwise at ꢂ78 °C. After the resulting mixture was stirred at room
temperature for 30 min, DMF (1.3 ml, 16.8 mmol) was added at 4 °C. The re-
action mixture was stirred at room temperature for 2 h. After quenching the
reaction by adding water, the mixture was extracted with AcOEt (20 mlꢇ3).
The organic extracts were combined, washed with brine (20 ml), dried over
anhydrous Na2SO4, filtered, and then concentrated in vacuo. Flash column
chromatography (hexane/AcOEtꢃ20 : 1) of the residue gave 16c (370 mg,
79%) as a colorless oil. 1H-NMR (400 MHz, CDCl3) d: 1.40—1.58 (6H, m),
1.65—1.74 (2H, m), 2.40—2.50 (4H, m), 6.72 (1H, t, Jꢃ8.3 Hz), 9.41 (1H,
s). IR (ATR) cmꢂ1: 1681. MS (EIꢀ) m/z: 138 (Mꢀ). HR-MS (EIꢀ) m/z:
138.1043 (Calcd for C9H14O (Mꢀ): 138.1045).
1
(ent-4d)]. H-NMR (400 MHz, CD3OD) d: 1.01 (3H, t, Jꢃ7.3 Hz), 1.14—
1.27 (2H, m), 1.74 (3H, s), 1.82—1.90 (2H, m), 5.61 (1H, td, Jꢃ1.2,
15.9 Hz), 5.88 (1H, td, Jꢃ6.1, 15.9 Hz). 13C-NMR (100 MHz, CD3OD) d:
13.8, 23.3, 25.0, 35.4, 60.7, 131.7, 132.9, 189.4, 197.1. IR (KBr) cmꢂ1
:
1615. MS (CIꢀ) m/z: 199 [(MꢀH)ꢀ]. HR-MS (CIꢀ) m/z: 199.0820 (Calcd
for C10H15O2S [(MꢀH)ꢀ]: 199.0793).
(b) Preparation of ent-4d: Compound ent-4d (114 mg, 73%) was prepared
as a colorless powder from ent-15d (243 mg, 0.793 mmol) in the same man-
ner as described in (a). mp 90—92.5 °C (cyclohexane–diisopropyl ether).
[a]D21 ꢂ103 (cꢃ0.3, CHCl3). The optical purity of ent-4d prepared here was
estimated to be ꢅ99% ee using a method similar to that described in (a). 1H-
NMR, 13C-NMR, IR and MS spectra of this sample were identical to those
described in (a). HR-MS (CIꢀ) m/z: 199.0766 (Calcd for C10H15O2S
[(MꢀH)ꢀ]: 199.0793).
(R,E)-5-(Hex-1-enyl)-4-hydroxy-5-methylthiophen-2(5H)-one (4e) and
Its Enantiomer (ent-4e) (a) Preparation of 4e: Treatments of 15e (1.30 g,
4.06 mmol) in a manner similar to that described for the preparation of 3b,
afforded 4e (752 mg, 87%) as a colorless oil. [a]D22 ꢀ85.7 (cꢃ0.9, CHCl3).
The optical purity of 4e prepared here was determined to be 91% ee
(E)-3-Cyclohexenyl-2-methylacrylic acid (17a) Treatments of 16a
(2.90 ml, 24.9 mmol) and triethyl 2-phosphonopropionate (6.40 g,
26.3 mmol) in a manner similar to that described for the preparation of 8d,
afforded 17a (3.64 g, 88%) as a colorless crystals. mp 102—103 °C
(MeOHꢂH2O). 1H-NMR (400 MHz, CDCl3) d: 1.56—1.70 (4H, m), 2.02
by HPLC analysis with
a chiral column [Daicel Chiralcel OD-H
(3H, s), 2.16—2.30 (4H, m), 6.00 (1H, br s), 7.18 (1H, s). IR (KBr) cmꢂ1
:
f0.46 cmꢇ25 cm, hexane/2-propanol/TFAꢃ98 : 2 : 0.1, flow rate 0.35 ml/
1661. MS (EIꢀ) m/z: 166 (Mꢀ). HR-MS (EIꢀ) m/z: 166.1002 (Calcd for
C10H14O2 (Mꢀ): 166.0994).
1
min, tR 23.0 min (4e), 25.8 min (ent-4e)]. H-NMR (400 MHz, CD3OD) d:
0.91 (3H, t, Jꢃ7.3 Hz), 1.26—1.42 (4H, m), 1.75 (3H, s), 2.09 (2H, qd,
Jꢃ7.3, 1.2 Hz), 5.61 (1H, td, Jꢃ1.2, 15.3 Hz), 5.79 (1H, td, Jꢃ6.7, 15.3 Hz).
13C-NMR (100 MHz, CD3OD) d: 14.2, 23.1, 25.0, 32.4, 33.0, 60.7, 131.4,
133.1, 189.1, 197.0. IR (neat) cmꢂ1: 1624, 1586. MS (CIꢀ) m/z: 213
[(MꢀH)ꢀ]. HR-MS (CIꢀ) m/z: 213.0945 (Calcd for C11H17O2S [(MꢀH)ꢀ]:
213.0949).
(E)-3-Cycloheptenyl-2-methylacrylic Acid (17b) Treatments of 16b
(17.4 g, 140 mmol) and triethyl 2-phosphonopropionate (33.4 g, 137 mmol)
in a manner similar to that described for the preparation of 8d, afforded 17b
1
(15.0 g, 59%) as a colorless crystals. mp 102—103 °C (MeOHꢂH2O). H-
NMR (400 MHz, CDCl3) d: 1.50—1.59 (4H, m), 1.75—1.82 (2H, m), 1.97
(3H, d, Jꢃ1.2 Hz), 2.24—2.36 (4H, m), 6.06 (1H, t, Jꢃ6.7 Hz), 7.25 (1H, s).
IR (ATR) cmꢂ1: 1670 cmꢂ1. MS (CIꢀ) m/z: 181 [(MꢀH)ꢀ]. HR-MS (CIꢀ)
m/z: 181.1241 (Calcd for C11H17O2 [(MꢀH)ꢀ]: 181.1229).
(b) Preparation of ent-4e: Compound ent-4e (138 mg, 83%) was prepared
as a colorless oil from ent-15e (250 mg, 0.780 mmol) in the same manner as
described in (a). [a]D21 ꢂ85.5 (cꢃ0.7, CHCl3). The optical purity of ent-4e

932
(E)-3-[(E)-Cyclooctenyl]-2-methylacrylic Acid (17c) Treatments of
16c (6.91 g, 50.0 mmol) and triethyl 2-phosphonopropionate (13.4 g,
55.1 mmol) in a manner similar to that described for the preparation of 8d,
afforded 17c (7.81 g, 81%) as a colorless crystals. mp 61—62 °C (MeOHꢂ
H2O). 1H-NMR (400 MHz, CDCl3) d: 1.49—1.56 (8H, m), 2.01 (3H, d,
Jꢃ1.2 Hz), 2.20—2.38 (4H, m), 5.49 (1H, br s), 5.90 (1H, t, Jꢃ8.6 Hz), 7.17
(1H, s). IR (ATR) cmꢂ1: 1664. MS (CIꢀ) m/z: 195 [(MꢀH)ꢀ]. HR-MS (CIꢀ)
m/z: 195.1392 (Calcd for C12H19O2 [(MꢀH)ꢀ]: 195.1385).
Vol. 57, No. 9
trated in vacuo. Flash column chromatography (hexane/AcOEtꢃ4 : 1) of the
residue gave a mixture of 19a, 26a and 27a (1.70 g, 92%) as an oil.21) The
mixture of 19a, 26a and 27a (260 mg) was further separated by HPLC
[Daicel Chiralpak IC f2.0 cmꢇ25 cm, hexane/2-propanolꢃ85 : 15, flow
rate 8.0 ml/min, followed by Daicel Chiralpak IA f2.0 cmꢇ25 cm,
hexane/EtOHꢃ90 : 10, flow rate 10 ml/min. HPLC analyses of 19a, 26a and
compound 27a: Daicel Chiralpak IC f0.46 cmꢇ25 cm, hexane/2-
propanolꢃ85 : 15, flow rate 0.5 ml/min; tR 23.8 min (26a), 24.2 min (27a),
27.4 min (19a)] to give pure samples of 19a, 26a and 27a, all as an oil.
Compound 19a (209 mg): [a]D27 ꢂ265 (cꢃ1.0, MeOH). 1H-NMR
(400 MHz, CDCl3) d: 1.62 (2H, quintet, Jꢃ6.1 Hz), 1.82—1.89 (2H, m),
1.95 (3H, s), 1.96—2.10 (3H, m), 2.40—2.49 (1H, m), 2.59—2.66 (2H, m),
2.73 (1H, dd, Jꢃ13.1, 10.1 Hz), 3.31—3.38 (7H, m), 4.10—4.15 (2H, m),
4.49 (1H, t, Jꢃ5.5 Hz), 4.63—4.71 (1H, m), 5.44 (1H, s), 5.76 (1H, td,
Jꢃ10.4, 5.5 Hz), 6.03 (1H, d, Jꢃ10.4 Hz), 7.23—7.36 (5H, m). IR (ATR)
cmꢂ1: 1785, 1677 cmꢂ1. MS (CIꢀ) m/z: 460 [(MꢀH)ꢀ]. HR-MS (CIꢀ) m/z:
460.2173 (Calcd for C25H34NO5S [(MꢀH)ꢀ]: 460.2158).
(R,E)-4-Benzyl-3-(3-cyclohexenyl-2-methylacryloyl)oxazolidin-2-one
(18a) and Its Enantiomer (ent-18a) (a) Preparation of 18a: Treatments of
17a (3.00 g, 18.0 mmol) in a manner similar to that described for the prepa-
ration of 9b, afforded 18a (4.73 g, 81%) as a colorless crystals. mp 95—
96 °C (diisopropyl ether). [a]D25 ꢂ75.0 (cꢃ1.0, MeOH). 1H-NMR
(400 MHz, CDCl3) d: 1.56—1.71 (4H, m), 2.08 (3H, s), 2.15—2.21 (2H,
m), 2.24—2.31 (2H, m), 2.83 (1H, dd, Jꢃ13.5, 9.2 Hz), 3.35 (1H, dd,
Jꢃ13.5, 3.7 Hz), 4.15 (1H, dd, Jꢃ9.2, 5.5 Hz), 4.25 (1H, t, Jꢃ9.2 Hz),
4.68—4.76 (1H, m), 5.95 (1H, br s), 6.38 (1H, s), 7.19—7.35 (5H, m). IR
(KBr) cmꢂ1: 1792, 1663. MS (EIꢀ) m/z: 325 (Mꢀ). HR-MS (EIꢀ) m/z:
325.1691 (Calcd for C20H23NO3 (Mꢀ): 325.1678).
(b) Preparation of ent-18a: Compound ent-18a (2.07 g, 79%) was pre-
pared as a colorless crystals from 17a (1.41 g, 8.48 mmol) and (S)-4-benzy-
loxazolidin-2-one (1.71 g, 9.46 mmol) in the same manner as described in
(a). mp 95—97 °C (diisopropyl ether). [a]D25 ꢀ81.8 (cꢃ0.9, MeOH). 1H-
NMR, IR and MS spectra of this sample were identical to those described in
(a). HR-MS (EIꢀ) m/z: 325.1697 (Calcd for C20H23NO3 (Mꢀ): 325.1678).
(R,E)-4-Benzyl-3-(3-cycloheptenyl-2-methylacryloyl)oxazolidin-2-one
(18b) and Its Enantiomer (ent-18b) (a) Preparation of 18b: Treatments
of 17b (2.00 g, 11.1 mmol) in a manner similar to that described for the
preparation of 9b, afforded 18b (2.94 g, 78%) as a colorless crystals. mp
98—103 °C (diisopropyl ether). [a]D23 ꢂ62.7 (cꢃ0.3, MeOH). 1H-NMR
(400 MHz, CDCl3) d: 1.50—1.59 (4H, m), 1.74—1.82 (2H, m), 2.04 (3H, d,
Jꢃ1.8 Hz), 2.22—2.36 (4H, m), 2.82 (1H, dd, Jꢃ13.5, 9.2 Hz), 3.36 (1H,
dd, Jꢃ13.5, 3.1 Hz), 4.15 (1H, dd, Jꢃ9.2, 5.5 Hz), 4.25 (1H, t, Jꢃ7.9 Hz),
4.69—4.76 (1H, m), 6.06 (1H, t, Jꢃ6.7 Hz), 6.45 (1H, s), 7.19—7.36 (5H,
m). IR (KBr) cmꢂ1: 1792, 1667. MS (EIꢀ) m/z: 339 (Mꢀ). HR-MS (EIꢀ)
m/z: 339.1812 (Calcd for C21H25NO3 (Mꢀ): 339.1834).
Compound 26a (29 mg): [a]D28 ꢂ11.8 (cꢃ0.2, MeOH). 1H-NMR
(400 MHz, CDCl3) d: 1.55—1.71 (2H, m), 1.79—1.93 (5H, m), 2.01—2.32
(4H, m), 2.56—2.70 (3H, m), 3.32 (3H, s), 3.34 (3H, s), 3.38—3.46 (1H,
m), 4.06—4.15 (2H, m), 4.47 (1H, t, Jꢃ5.8 Hz), 4.63—4.71 (1H, m), 5.50
(1H, s), 5.71—5.81 (1H, m), 6.04 (1H, d, Jꢃ9.8 Hz), 7.24—7.38 (5H, m).
IR (ATR) cmꢂ1: 1786, 1672. MS (CIꢀ) m/z: 460 [(MꢀH)ꢀ]. HR-MS (CIꢀ)
m/z: 460.2146 (Calcd for C25H34NO5S [(MꢀH)ꢀ]: 460.2158).
Compound 27a (16 mg): [a]D23 ꢂ228 (cꢃ0.3, MeOH). 1H-NMR
(400 MHz, CDCl3) d: 1.56—1.68 (1H, m), 1.70—1.80 (1H, m), 1.82—1.90
(2H, m), 1.97 (3H, s), 2.06—2.13 (2H, m,), 2.24—2.32 (2H, m), 2.58—2.80
(3H, m), 3.30—3.38 (7H, m), 4.01 (1H, t, Jꢃ8.6 Hz), 4.19 (1H, dd, Jꢃ8.6,
1.2 Hz), 4.49 (1H, t, Jꢃ5.5 Hz), 4.58—4.63 (1H, m), 5.32 (1H, s), 5.79—
5.90 (1H, m), 6.04 (1H, d, Jꢃ10.4 Hz), 7.14—7.39 (5H, m). IR (ATR) cmꢂ1
:
1785, 1681. MS (CIꢀ) m/z: 460 [(MꢀH)ꢀ]. HR-MS (CIꢀ) m/z: 460.2146
(Calcd for C25H34NO5S [(MꢀH)ꢀ]: 460.2185).
(b) Preparation of ent-19a: Compound ent-19a (1.17 g, 51%) and two
types of by-products enantiomeric to 26a [ent-26a] (179 mg, 8%) and 27a
[ent-27a] (112 mg, 5%) were prepared all as a colorless oil from ent-18a
(1.63 g, 5.01 mmol) in the same manner as described in (a) after separation
by HPLC [Daicel Chiralpak IA f2.0 cmꢇ25 cm, hexane/EtOHꢃ90 : 10,
flow rate 20 ml/min. HPLC analyses of ent-19a, ent-26a and ent-27a: Daicel
Chiralpak IA f0.46 cmꢇ25 cm, hexane/EtOHꢃ90 : 10, flow rate 0.5 ml/min;
tR 18.4 min (ent-27a), 20.4 min (ent-26a), 25.3 min (ent-19a)]. ent-19a:
[a]D23 ꢀ298 (cꢃ1.0, MeOH). HR-MS (ESIꢀ) m/z: 428.18955 (Calcd for
C24H30NO4S {[(MꢂCH3OH)ꢀH]ꢀ}: 428.18955). 1H-NMR, IR and MS
spectra of these samples were identical to those described in (a).
Deconjugative Asymmetric a-Sulfenylation of (R,E)- and (S,E)-4-Ben-
zyl-3-(3-cycloheptenyl-2-methylacryloyl)oxazolidin-2-one (18b, ent-18b).
(R)-4-Benzyl-3-[(R,E)-3-(cyclohept-2-enylidene)-2-(3,3-dimethoxypropyl-
thio)-2-methylpropanoyl]oxazolidin-2-one (19b) and Its Enantiomer
(ent-19b) (a) Preparation of 19b: Treatments of 18b (2.80 g, 8.25 mmol) in
a manner similar to that described for the preparation of 19a, afforded 19b
(1.20 g, 31%) as a colorless oil after separation by HPLC [Daicel Chiralpak
IA f2.0 cmꢇ25 cm, hexane/EtOHꢃ91 : 9, flow rate 10 ml/min. HPLC analy-
sis of 19b: Daicel Chiralpak IA f0.46 cmꢇ25 cm, hexane/EtOHꢃ91 : 9,
flow rate 0.5 ml/min; tR 22.8 min]. [a]D27 ꢂ164 (cꢃ0.6, MeOH). 1H-NMR
(400 MHz, CDCl3) d: 1.54—1.73 (4H, m), 1.82—1.90 (2H, m), 1.96 (3H,
s), 2.20 (2H, q, Jꢃ5.1 Hz), 2.28—2.42 (2H, m), 2.58—2.69 (2H, m), 2.74
(1H, dd, Jꢃ13.1, 10.1 Hz), 3.31—3.37 (7H, m), 4.10—4.17 (2H, m), 4.49
(1H, t, Jꢃ5.8 Hz), 4.62—4.68 (1H, m), 5.56 (1H, s), 5.63—5.69 (1H, m),
6.01 (1H, d, Jꢃ12.2 Hz), 7.22—7.36 (5H, m). IR(ATR) cmꢂ1: 1784, 1679.
MS (CIꢀ) m/z: 474 [(MꢀH)ꢀ]. HR-MS (CIꢀ) m/z: 474.2286 (Calcd for
C26H36NO5S [(MꢀH)ꢀ]: 474.2314). Although the formation of two types of
the by-products 26b and 27b was observed similarly to the preparation of
19a, 26a and 27a, their isolation was not attempted.37)
(b) Preparation of ent-18b: Compound ent-18b (4.84 g, 86%) was pre-
pared as a colorless crystals from 17b (3.00 g, 16.6 mmol) and (S)-4-benzy-
loxazolidin-2-one (3.53 g, 19.5 mmol) in the same manner as described in
(a). mp 94—96 °C (diisopropyl ether). [a]D25 ꢀ70.5 (cꢃ0.3, MeOH). 1H-
NMR, IR and MS spectra of this sample were identical to those described in
(a). HR-MS (EIꢀ) m/z: 339.1846 (Calcd for C21H25NO3 (Mꢀ): 339.1834).
(R,E)-4-Benzyl-3-[(E)-3-cyclooctenyl-2-methylacryloyl]oxazolidin-2-
one (18c) and Its Enantiomer (ent-18c) (a) Preparation of 18c: Treat-
ments of 17c (2.31 g, 11.9 mmol) in a manner similar to that described for
the preparation of 9b, afforded 18c (3.00 g, 71%) as a colorless crystals. mp
91.5—93.0 °C (diisopropyl ether). [a]D28 ꢂ72.1 (cꢃ0.3, MeOH). 1H-NMR
(400 MHz, CDCl3) d: 1.44—1.63 (8H, m), 2.08 (3H, d, Jꢃ1.2 Hz), 2.19—
2.39 (4H, m), 2.84 (1H, dd, Jꢃ13.4, 9.2 Hz), 3.35 (1H, dd, Jꢃ13.4, 3.7 Hz),
4.15 (1H, dd, Jꢃ8.6, 5.8 Hz), 4.26 (1H, t, Jꢃ8.6 Hz), 4.69—4.77 (1H, m),
5.91 (1H, t, Jꢃ8.3Hz), 6.39 (1H, s), 7.19—7.36 (5H, m). IR (ATR) cmꢂ1
:
1790, 1669. MS (EIꢀ) m/z: 353 (Mꢀ). HR-MS (EIꢀ) m/z: 353.2030 (Calcd
for C22H27NO3 (Mꢀ): 353.1991).
(b) Preparation of ent-18c: Compound ent-18c (3.29 g, 65%) was pre-
pared as a colorless crystals from 17c (2.78 g, 14.3 mmol) and (S)-4-benzy-
loxazolidin-2-one (3.04 g, 16.8 mmol) in the same manner as described in
(a). mp 93.0—94.5 °C (diisopropyl ether). [a]D28 ꢀ70.0 (cꢃ0.3, MeOH). 1H-
NMR, IR and MS spectra of this sample were identical to those described in
(a). HR-MS (EIꢀ) m/z: 353.2030 (Calcd for C22H27NO3 (Mꢀ): 353.1991).
Deconjugative Asymmetric a-Sulfenylation of (R,E)- and (S,E)-4-Ben-
zyl-3-(3-cyclohexenyl-2-methylacryloyl)oxazolidin-2-one (18a, ent-18a).
(R)-4-Benzyl-3-[(R,E)-3-(cyclohex-2-enylidene)-2-(3,3-dimethoxypropyl-
thio)-2-methylpropanoyl]oxazolidin-2-one (19a), Its (S,E)-Diastereomer
(26a), (R,Z)-Isomer (27a) and Their Enantiomers (ent-19a, ent-26a, ent-
27a) (a) Preparation of 19a, 26a and 27a: To a solution of 18a (1.30 g,
4.00 mmol) and HMPA (2.8 ml, 16.1 mmol) in THF (20 ml), NaHMDS
(1.0 mol/l solution in THF, 4.4 ml, 4.40 mmol) was added dropwise at
ꢂ78 °C, and the resulting mixture was stirred at the same temperature for
30 min. A solution of 10 (1.14 g, 5.32 mmol) in THF (4 ml) was added to the
reaction mixture at the same temperature, and the resulting mixture was al-
lowed to slowly warm to 0 °C. After quenching the reaction by adding satu-
rated aqueous ammonium chloride solution (40 ml), the mixture was ex-
tracted with AcOEt (40 mlꢇ3). The organic extracts were combined, washed
with brine (40 ml), dried over anhydrous Na2SO4, filtered, and then concen-
(b) Preparation of ent-19b: Compound ent-19b (1.39 g, 36%) was pre-
pared from ent-18b (2.80 g, 8.25 mmol) as a colorless oil in the same
manner as described in (a) after separation by HPLC [Daicel Chiralpak
IC f2.0 cmꢇ25 cm, hexane/MTBE/AcOEt/EtOHꢃ88 : 7 : 3 : 2, flow rate
15 ml/min. HPLC analysis of ent-19b: Daicel Chiralpak IC f0.46 cmꢇ
25 cm, hexane/MTBE/AcOEt/EtOHꢃ88 : 7 : 3 : 2, flow rate 0.75 ml/min; tR
13.7 min]. [a]D26 ꢀ160 (cꢃ0.6, MeOH). HR-MS (CIꢀ) m/z: 474.2286 (Calcd
for C26H36NO5S [(MꢀH)ꢀ]: 474.2314). 1H-NMR, IR and MS spectra of this
sample were identical to those described in (a). Although the formation of
two types of the by-products ent-26b and ent-27b was anticipated similarly
to the case described in (a), their isolation was not attempted.
Deconjugative Asymmetric a-Sulfenylation of (R,E)- and (S,E)-4-Ben-

September 2009
933
zyl-3-(3-cyclooctenyl-2-methylacryloyl)oxazolidin-2-one (18c, ent-18c). m/z: 418 (Mꢀ). HR-MS (EIꢀ) m/z: 418.2159 (Calcd for C24H34O4S (Mꢀ):
(R)-4-Benzyl-3-[(R,E)-3-(cyclooct-2-enylidene)-2-(3,3-dimethoxypropyl- 418.2178).
thio)-2-methylpropanoyl]oxazolidin-2-one (19c) and Its Enantiomer
(ent-19c) (a) Preparation of 19c: Treatment of 18c (2.50 g, 7.07 mmol) in a
manner similar to that described for the preparation of 19a, afforded 19c
(b) Preparation of ent-20c: Compound ent-20c (998 mg, 89%) was pre-
pared as a colorless oil from ent-19c (1.30 g, 2.67 mmol) in the same manner
as described in (a). [a]D24 ꢂ15.0 (cꢃ0.5, CHCl3). 1H-NMR, IR and MS spec-
(1.72 g, 50%) as a colorless powder after separation by HPLC [Daicel Chi- tra of this sample were identical to those described in (a). HR-MS (EIꢀ) m/z:
ralpak IA f2.0 cmꢇ25 cm, hexane/MTBE/2-propanolꢃ80 : 10 : 10, flow rate
18 ml/min followed by Daicel Chiralpak IC f2.0 cmꢇ25 cm, hexane/2-
418.2171 (Calcd for C24H34O4S (Mꢀ): 418.2178).
(R,E)-Benzyl 3-(Cyclohex-2-enylidene)-2-methyl-2-(3-oxopropylthio)-
propanolꢃ75 : 25, flow rate 10 ml/min. HPLC analysis of 19c: Daicel Chi- propanoate (21a) and Its Enantiomer (ent-21a) (a) Preparation of 21a:
ralpak IA f0.46 cmꢇ25 cm, hexane/MTBE/2-propanolꢃ80 : 10 : 10, flow
Treatments of 20a (730 mg, 1.87 mmol) in a manner similar to that de-
rate 0.9 ml/min; tR 9.7 min: Daicel Chiralpak IC f0.46 cmꢇ25 cm, hexane/2- scribed for the preparation of 13b, afforded 21a (562 mg, 87%) as a color-
propanolꢃ75 : 25, flow rate 0.5 ml/min; tR 21.4 min]. mp 63—65.5 °C (cy- less oil. [a]D21 ꢀ44.8 (cꢃ0.6, CHCl3). 1H-NMR (400 MHz, CDCl3) d:
clohexane). [a]D25 ꢂ368 (cꢃ0.5, MeOH). 1H-NMR (400 MHz, CDCl3) d: 1.50—1.65 (2H, m), 1.65 (3H, s), 2.02—2.10 (2H, m), 2.14—2.23 (1H, m),
1.40—1.56 (5H, m), 1.65—1.78 (1H, m), 1.82—1.90 (2H, m), 1.98 (3H, s), 2.28—2.37 (1H, m), 2.57 (2H, td, Jꢃ6.7, 1.2 Hz), 2.75—2.87 (2H, m), 5.16
2.20—2.32 (1H, m), 2.40—2.70 (5H, m), 2.75 (1H, q, Jꢃ13.4 Hz), 3.27— (1H, d, Jꢃ12.2 Hz), 5.23 (1H, d, Jꢃ12.2 Hz), 5.47 (1H, s), 5.78—5.84 (1H,
3.37 (7H, m), 4.06—4.17 (2H, m), 4.48 (1H, t, Jꢃ5.5 Hz), 4.63—4.70 (1H, m), 6.01 (1H, d, Jꢃ9.8 Hz), 7.30—7.41 (5H, m), 9.62 (1H, d, Jꢃ1.2 Hz). IR
m), 5.46 (1H, td, Jꢃ12.2, 8.6 Hz), 5.64 (1H, s), 6.11 (1H, d, Jꢃ12.2 Hz),
(neat) cmꢂ1: 1725. MS (EIꢀ) m/z: 344 (Mꢀ). HR-MS (EIꢀ) m/z: 344.1424
7.22—7.36 (5H, m). IR (ATR) cmꢂ1: 1787, 1672. MS (EIꢀ) m/z: 487 (Mꢀ). (Calcd for C20H24O3S (Mꢀ): 344.1446).
HR-MS (EIꢀ) m/z: 487.2380 (Calcd for C27H37NO5S (Mꢀ): 487.2392). Al-
(b) Preparation of ent-21a: Compound ent-21a (494 mg, 82%) was pre-
though the formation of two types of the by-products 26c and 27c was ob- pared as a colorless oil from ent-20a (680 mg, 1.74 mmol) in the same man-
served similarly to the preparation of 19a, 26a and 27a, their isolation was ner as described in (a). [a]D26 ꢂ43.5 (cꢃ1.0, CHCl3). H-NMR, IR and MS
1
not attempted.37)
spectra of this sample were identical to those described in (a). HR-MS (EIꢀ)
(b) Preparation of ent-19c: Compound ent-19c (1.53 g, 44%) was pre- m/z: 344.1432 (Calcd for C20H24O3S (Mꢀ): 344.1446).
pared as a colorless powder from ent-18c (2.50 g, 7.07 mmol) in the same
(R,E)-Benzyl 3-(Cyclohept-2-enylidene)-2-methyl-2-(3-oxopropyl-
manner as described in (a) after separation by HPLC [Daicel Chiralpak IC thio)propanoate (21b) and Its Enantiomer (ent-21b) (a) Preparation of
f2.0 cmꢇ25 cm, hexane/MTBE/EtOHꢃ85 : 10 : 5, flow rate 15 ml/min.
HPLC analysis of ent-19c: Daicel Chiralpak IC f0.46 cmꢇ25 cm,
hexane/MTBE/EtOHꢃ85 : 10 : 5, flow rate 0.75 ml/min; tR 11.5 min]. mp
21b: Treatments of 20b (900 mg, 2.22 mmol) in a manner similar to that de-
scribed for the preparation of 13b, afforded 21b (733 mg, 92%) as a color-
less oil.43) 1H-NMR (400 MHz, CDCl3) d: 1.58—1.70 (7H, m), 2.18—2.24
63—65.5 °C (cyclohexane). [a]D26 ꢀ349 (cꢃ0.5, MeOH). HR-MS (EIꢀ) m/z: (2H, m), 2.33—2.40 (2H, m), 2.56 (2H, t, Jꢃ7.0 Hz), 2.76—2.88 (2H, m),
487.2368 (Calcd for C27H37NO5S (Mꢀ): 487.2392). 1H-NMR, IR and MS
spectra of this sample were identical to those described in (a). Although the
5.16 (1H, d, Jꢃ12.2 Hz), 5.23 (1H, d, Jꢃ12.2 Hz), 5.60 (1H, s), 5.67—5.73
(1H, m), 6.00 (1H, d, Jꢃ11.6 Hz), 7.30—7.40 (5H, m), 9.62 (1H, s). IR
formation of two types of the by-products ent-26c and ent-27c was antici- (ATR) cmꢂ1: 1718. MS (EIꢀ) m/z: 358 (Mꢀ). HR-MS (EIꢀ) m/z: 358.1635
pated similarly to the case described in (a), their isolation was not attempted.
(Calcd for C21H26O3S (Mꢀ): 358.1603).
(R,E)-Benzyl 3-(Cyclohex-2-enylidene)-2-(3,3-dimethoxypropylthio)-
(b) Preparation of ent-21b: Compound ent-21b (614 mg, 98%) was pre-
2-methylpropanoate (20a) and Its Enantiomer (ent-20a) (a) Preparation pared as a colorless oil from ent-20b (704 mg, 1.74 mmol) in the same man-
of 20a: Treatments of 19a (1.30 g, 2.83 mmol) in a manner similar to that
ner as described in (a).43) 1H-NMR, IR and MS spectra of this sample were
described for the preparation of 12b, afforded 20a (844 mg, 76%) as a color- identical to those described in (a). HR-MS (CIꢀ) m/z: 359.1662 (Calcd for
less oil. [a]D24 ꢀ26.1 (cꢃ1.0, CHCl3). 1H-NMR (400 MHz, CDCl3) d: C21H27O3S [(MꢀH)ꢀ]: 359.1681).
1.50—1.64 (2H, m), 1.65 (3H, s), 1.74—1.81 (2H, m), 2.02—2.10 (2H, m),
(R,E)-Benzyl 3-(Cyclooct-2-enylidene)-2-methyl-2-(3-oxopropylthio)-
2.15—2.38 (2H, m), 2.52—2.65 (2H, m), 3.28 (6H, s), 4.37 (1H, t, propanoate (21c) and Its Enantiomer (ent-21c) (a) Preparation of 21c:
Jꢃ5.5 Hz), 5.17 (1H, d, Jꢃ12.2 Hz), 5.21 (1H, d, Jꢃ12.2 Hz), 5.46 (1H, s),
5.76—5.82 (1H, m), 6.01 (1H, d, Jꢃ10.4 Hz), 7.31—7.40 (5H, m). IR
Treatments of 20c (978 mg, 2.34 mmol) in a manner similar to that described
for the preparation of 13b, afforded 21c (838 mg, 96%) as a colorless oil.
(ATR) cmꢂ1: 1721. MS (EIꢀ) m/z: 390 (Mꢀ). HR-MS (EIꢀ) m/z: 390.1889 [a]D28 ꢀ34.3 (cꢃ0.3, CHCl3). 1H-NMR (400 MHz, CDCl3) d: 1.46—1.68
(Calcd for C22H30O4S (Mꢀ): 390.1865).
(b) Preparation of ent-20a: Compound ent-20a (713 mg, 76%) was pre- (2H, m), 5.15 (1H, d, Jꢃ12.2 Hz), 5.22 (1H, d, Jꢃ12.2 Hz), 5.49 (1H, td,
(6H, m), 1.67 (3H, s), 2.30—2.46 (2H, m), 2.48—2.58 (4H, m), 2.76—2.86
pared as a colorless oil from ent-19a (1.10 g, 2.39 mmol) in the same manner
as described in (a). [a]D26 ꢂ24.9 (cꢃ1.0, CHCl3). 1H-NMR, IR and MS spec-
tra of this sample were identical to those described in (a). HR-MS (EIꢀ) m/z:
390.1826 (Calcd for C22H30O4S (Mꢀ): 390.1865).
Jꢃ9.6, 12.2 Hz), 5.69 (1H, s), 6.09 (1H, d, Jꢃ12.2 Hz), 7.30—7.40 (5H, m),
9.62 (1H, t, Jꢃ1.2 Hz). IR (ATR) cmꢂ1: 1720. MS (EIꢀ) m/z: 372 (Mꢀ).
HR-MS (EIꢀ) m/z: 372.1789 (Calcd for C22H28O3S (Mꢀ): 372.1759).
(b) Preparation of ent-21c: Compound ent-21c (776 mg, 96%) was pre-
(R,E)-Benzyl 3-(Cyclohept-2-enylidene)-2-(3,3-dimethoxypropylthio)- pared as a colorless oil from ent-20c (913 mg, 2.18 mmol) in the same man-
2-methylpropanoate (20b) and Its Enantiomer (ent-20b) (a) Preparation ner as described in (a). [a]D28 ꢂ25.1 (cꢃ0.3, CHCl3). H-NMR, IR and MS
1
of 20b: Treatments of 19b (1.60 g, 3.38 mmol) in a manner similar to that
described for the preparation of 12b, afforded 20b (936 mg, 69%) as a color-
less oil. [a]D25 ꢀ5.6 (cꢃ0.5, CHCl3). 1H-NMR (400 MHz, CDCl3) d: 1.56—
spectra of this sample were identical to those described in (a). HR-MS (CIꢀ)
m/z: 372.1754 (Calcd for C22H28O3S (Mꢀ): 372.1759).
(R,E)-Benzyl 3-(Cyclohex-2-enylidene)-2-methyl-2-(propionylthio)-
1.69 (4H, m), 1.66 (3H, s), 1.76—1.80 (2H, m), 2.19—2.24 (2H, m), 2.28— propanoate (22a) and Its Enantiomer (ent-22a) (a) Preparation of 22a:
2.42 (2H, m), 2.51—2.64 (2H, m), 3.30 (6H, s), 4.37 (1H, t, Jꢃ5.8 Hz), 5.16
Treatments of 21a (240 mg, 1.06 mmol) in a manner similar to that de-
(1H, d, Jꢃ12.2 Hz), 5.21 (1H, d, Jꢃ12.2 Hz), 5.60 (1H, s), 5.64—5.72 (1H, scribed for the preparation of 14b, afforded 22a (172 mg, 66%) as a color-
m), 6.00 (1H, d, Jꢃ12.8 Hz), 7.31—7.40 (5H, m). IR (ATR) cmꢂ1: 1722. less oil. [a]D23 ꢀ24.9 (cꢃ0.1, CHCl3). H-NMR (400 MHz, CDCl3) d: 1.10
1
MS (EIꢀ) m/z: 404 (Mꢀ). HR-MS (EIꢀ) m/z: 404.2023 (Calcd for C23H32O4S (3H, t, Jꢃ7.4 Hz), 1.50—1.61 (2H, m), 1.90 (3H, s), 2.01—2.06 (2H, m),
(Mꢀ): 404.2021).
2.24—2.34 (1H, m), 2.35—2.44 (1H, m), 2.49 (2H, q, Jꢃ7.4 Hz), 5.16 (1H,
(b) Preparation of ent-20b: Compound ent-20b (742 mg, 87%) was pre- d, Jꢃ12.8 Hz), 5.19 (1H, d, Jꢃ12.8 Hz), 5.41 (1H, s), 5.81 (1H, td, Jꢃ3.7,
pared as a colorless oil from ent-19b (1.00 g, 2.11 mmol) in the same man-
9.8 Hz), 5.95 (1H, td, Jꢃ3.0, 9.8 Hz), 7.28—7.38 (5H, m). IR (neat) cmꢂ1
1738, 1694. MS (EIꢀ) m/z: 344 (Mꢀ). HR-MS (EIꢀ) m/z: 344.1427 (Calcd
:
1
ner as described in (a). [a]D26 ꢂ5.4 (cꢃ0.5, CHCl3). H-NMR, IR and MS
spectra of this sample were identical to those described in (a). HR-MS (EIꢀ) for C20H24O3S (Mꢀ): 344.1446).
m/z: 404.2044 (Calcd for C23H32O4S (Mꢀ): 404.2021).
(b) Preparation of ent-22a: Compound ent-22a (163 mg, 68%) was pre-
(R,E)-Benzyl 3-(Cyclooct-2-enylidene)-2-(3,3-dimethoxypropylthio)-2- pared as a colorless oil from ent-21a (240 mg, 0.697 mmol) in the same
methylpropanoate (20c) and Its Enantiomer (ent-20c) (a) Preparation of manner as described in (a). [a]D23 ꢂ23.7 (cꢃ0.4, CHCl3). H-NMR, IR and
1
20c: Treatments of 19c (1.40 g, 2.87 mmol) in a manner similar to that de-
scribed for the preparation of 12b, afforded 20c (1.05 g, 87%) as a colorless
oil. [a]D24 ꢀ17.5 (cꢃ0.3, CHCl3). 1H-NMR (400 MHz, CDCl3) d: 1.49—
MS spectra of this sample were identical to those described in (a). HR-MS
(EIꢀ) m/z: 344.1451 (Calcd for C20H24O3S (Mꢀ): 344.1446).
(R,E)-Benzyl 3-(Cyclohept-2-enylidene)-2-methyl-2-(propionylthio)-
1.68 (6H, m), 1.66 (3H, s), 1.73—1.80 (2H, m), 2.30—2.44 (2H, m), 2.46— propanoate (22b) and Its Enantiomer (ent-22b) (a) Preparation of 22b:
2.64 (4H, m), 3.28 (6H, s), 4.37 (1H, t, Jꢃ5.8 Hz), 5.15 (1H, d, Jꢃ12.2 Hz),
Treatments of 21b (251 mg, 0.700 mmol) in a manner similar to that de-
5.20 (1H, d, Jꢃ12.2 Hz), 5.48 (1H, td, Jꢃ12.2, 9.6 Hz), 5.69 (1H, s), 6.09 scribed for the preparation of 14b afforded 22b (170 mg, 68%) as a colorless
(1H, d, Jꢃ12.2 Hz), 7.30—7.38 (5H, m). IR (ATR) cmꢂ1: 1722. MS (EIꢀ) oil. [a]D25 ꢀ14.5 (cꢃ0.6, CHCl3). H-NMR (400 MHz, CDCl3) d: 1.11 (3H,
1

934
Vol. 57, No. 9
t, Jꢃ7.3 Hz), 1.59—1.70 (4H, m), 1.89 (3H, s), 2.13—2.24 (2H, m), 2.35— powder. mp 111—113 °C (cyclohexane). [a]D27 ꢀ128 (cꢃ0.3, MeOH). The
2.57 (4H, m), 5.17 (2H, s), 5.56 (1H, s), 5.68—5.73 (1H, m), 5.96 (1H, d, optical purity of 5a was calculated to be ꢅ99% ee based on the diastere-
Jꢃ11.6 Hz), 7.30—7.38 (5H, m). IR (ATR) cmꢂ1: 1734, 1690. MS (EIꢀ) omeric excess of the corresponding 19a which had been determined as
1
m/z: 358 (Mꢀ). HR-MS (EIꢀ) m/z: 358.1605 (Calcd for C21H26O3S (Mꢀ): ꢅ99% de by HPLC analysis. H-NMR (400 MHz, CD3OD) d: 1.56—1.68
358.1603).
(2H, m), 1.68 (3H, s), 1.77 (3H, s), 2.05—2.12 (2H, m), 2.12—2.22 (1H,
(b) Preparation of ent-22b: Compound ent-22b (158 mg, 53%) was pre- m), 2.26—2.35 (1H, m), 5.33 (1H, s), 5.85 (1H, td, Jꢃ4.3, 9.8 Hz), 6.02
pared as a colorless oil from ent-21b (300 mg, 0.837 mmol) in the same
(1H, td, Jꢃ1.8, 9.8 Hz). 13C-NMR (100 MHz, CD3OD) d: 7.7, 23.0, 26.1,
1
manner as described in (a). [a]D25 ꢂ19.4 (cꢃ0.6, CHCl3). H-NMR, IR and
26.2, 30.3, 56.5, 109.9, 125.6, 131.5, 131.8, 141.8, 183.4, 197.8. IR (KBr)
MS spectra of this sample were identical to those described in (a). HR-MS cmꢂ1: 1609. MS (EIꢀ) m/z: 236 (Mꢀ). HR-MS (EIꢀ) m/z: 236.0869 (Calcd
(CIꢀ) m/z: 359.1671 (Calcd for C21H27O3S [(MꢀH)ꢀ]: 359.1681).
for C13H16O2S (Mꢀ): 236.0871).
(R,E)-Benzyl 3-(Cyclooct-2-enylidene)-2-methyl-2-(propionylthio)-
(b) Preparation of ent-5a: Compound ent-5a (99 mg, 91%) was prepared
propanoate (22c) and Its Enantiomer (ent-22c) (a) Preparation of 22c: as a colorless powder from ent-22a (158 mg, 0.459 mmol) in the same man-
Treatments of 21c (335 mg, 0.899 mmol) in a manner similar to that de-
scribed for the preparation of 14b, afforded 22c (245 mg, 73%) as a color-
ner as described in (a). mp 107—112 °C (cyclohexane). [a]D25 ꢂ133 (cꢃ0.6,
MeOH). The optical purity of ent-5a was estimated to be ꢅ99% ee similarly
1
1
less oil. [a]D22 ꢀ11.0 (cꢃ0.3, CHCl3). H-NMR (400 MHz, CDCl3) d: 1.10
to case for 5a. H-NMR, 13C-NMR, IR and MS spectra of this sample were
(3H, t, Jꢃ7.6 Hz), 1.44—1.70 (6H, m), 1.90 (3H, s), 2.35—2.40 (2H, m), identical to those described in (a). HR-MS (EIꢀ) m/z: 236.0876 (Calcd for
2.46—2.52 (2H, m), 2.56—2.64 (2H, m), 5.17 (2H, s), 5.49 (1H, td, Jꢃ9.6, C13H16O2S (Mꢀ): 236.0871).
12.2 Hz), 5.66 (1H, s), 6.05 (1H, d, Jꢃ12.2 Hz), 7.29—7.37 (5H, m). IR
(ATR) cmꢂ1: 1734, 1690. MS (EIꢀ) m/z: 372 (Mꢀ). HR-MS (EIꢀ) m/z: phen-2(5H)-one (5b) and Its Enantiomer (ent-5b) (a) Preparation of 5b:
372.1791 (Calcd for C22H28O3S (Mꢀ): 372.1759).
Treatments of 22b (139 mg, 0.391 mmol) in a manner similar to that de-
(R,E)-5-(Cyclohept-2-enylidenemethyl)-4-hydroxy-3,5-dimethylthio-
(b) Preparation of ent-22c: Compound ent-22c (162 mg, 54%) was pre- scribed for the preparation of 3b, afforded 5b (81 mg, 89%) as a colorless
pared as a colorless oil from ent-21c (300 mg, 0.805 mmol) in the same
oil. [a]D27 ꢀ86.4 (cꢃ0.2, MeOH). The optical purity of 5b was calculated to
be ꢅ99% ee based on the diastereomeric excess of the corresponding 19b
1
manner as described in (a). [a]D22 ꢂ7.9 (cꢃ0.1, CHCl3). H-NMR, IR and
MS spectra of this sample were identical to those described in (a). HR-MS which had been determined as ꢅ99% de by HPLC analysis. 1H-NMR
(EIꢀ) m/z: 372.1791 (Calcd for C22H28O3S (Mꢀ): 372.1759).
(400 MHz, CD3OD) d: 1.66—1.75 (7H, m), 1.80 (3H, s), 2.20—2.28 (2H,
(R,E)-Benzyl 2-Acetylthio-3-(cyclohex-2-enylidene)-2-methypropano- m), 2.40—2.50 (2H, m), 5.51 (1H, s), 5.70—5.78 (1H, m), 6.02 (1H, d,
ate (23a) and Its Enantiomer (ent-23a) (a) Preparation of 23a: Treat- Jꢃ11.6 Hz). 13C-NMR (100 MHz, CD3OD) d: 7.7, 25.2, 26.5, 28.2, 29.0,
ments of 21a (290 mg, 0.842 mmol) in a manner similar to that described for
the preparation of 15b, afforded 23a (188 mg, 68%) as a colorless oil. [a]D28
30.6, 56.4, 110.0, 128.9, 134.1, 135.6, 146.1, 197.9. IR (ATR) cmꢂ1: 1603.
MS (EIꢀ) m/z: 250 (Mꢀ). HR-MS (EIꢀ) m/z: 250.1065 (Calcd for C14H18O2S
ꢀ20.4 (cꢃ1.0, CHCl3). 1H-NMR (400 MHz, CDCl3) d: 1.50—1.61 (2H, m), (Mꢀ): 250.1028).
1.90 (3H, s), 2.01—2.06 (2H, m), 2.24 (3H, s), 2.24—2.34 (1H, m), 2.37—
(b) Preparation of ent-5b: Compound ent-5b (97 mg, 96%) was prepared
as a colorless oil from ent-22b (145 mg, 0.404 mmol) in the same manner as
2.45 (1H, m), 5.18 (2H, s), 5.40 (1H, s), 5.82 (1H, td, Jꢃ4.3, 9.8 Hz), 5.95
(1H, td, Jꢃ1.3, 9.8 Hz), 7.28—7.38 (5H, m). IR (neat) cmꢂ1: 1738, 1692. described in (a). [a]D27 ꢂ92.9 (cꢃ0.2, MeOH). The optical purity of ent-5b
MS (EIꢀ) m/z: 330 (Mꢀ). HR-MS (EIꢀ) m/z: 330.1251 (Calcd for C19H22O3S
was estimated to be ꢅ99% ee similarly to case for 5b. 1H-NMR, 13C-NMR,
IR and MS spectra of this sample were identical to those described in (a).
(Mꢀ): 330.1290).
(b) Preparation of ent-23a: Compound ent-23a (148 mg, 65%) was pre- HR-MS (EIꢀ) m/z: 250.0998 (Calcd for C14H18O2S (Mꢀ): 250.1028).
pared as a colorless oil from ent-21a (238 mg, 0.691 mmol) in the same
(R,E)-5-(Cyclooct-2-enylidenemethyl)-4-hydroxy-3,5-dimethylthio-
phen-2(5H)-one (5c) and Its Enantiomer (ent-5c) (a) Preparation of 5c:
manner as described in (a). [a]D25 ꢂ19.2 (cꢃ0.3, CHCl3). H-NMR, IR and
1
MS spectra of this sample were identical to those described in (a). HR-MS Treatments of 22c (187 mg, 0.502 mmol) in a manner similar to that de-
(EIꢀ) m/z: 330.1310 (Calcd for C19H22O3S (Mꢀ): 330.1290).
scribed for the preparation of 3b, afforded 5c (88 mg, 66%) as a colorless
(R,E)-Benzyl 2-Acetylthio-3-(cyclohept-2-enylidene)-2-methypropan- powder. mp 112—116 °C (cyclohexane). [a]D27 ꢀ77.3 (cꢃ0.3, MeOH). The
oate (23b) and Its Enantiomer (ent-23b) (a) Preparation of 23b: Treat- optical purity of 5c was calculated to be ꢅ99% ee based on the diastere-
ments of 21b (251 mg, 0.700 mmol) in a manner similar to that described for
omeric excess of the corresponding 19c which had been determined as
ꢅ99% de by HPLC analysis. H-NMR (400 MHz, CD3OD) d: 1.50—1.70
the preparation of 15b, afforded 23b (152 mg, 63%) as a colorless oil. [a]D29
1
1
ꢀ4.7 (cꢃ0.1, CHCl3). H-NMR (400 MHz, CDCl3) d: 1.59—1.68 (4H, m), (6H, m), 1.68 (3H, s), 1.77 (3H, s), 2.30—2.40 (1H, m), 2.46—2.58 (3H,
1.89 (3H, s), 2.17—2.24 (2H, m), 2.25 (3H, s), 2.39—2.56 (2H, m), 5.16 m), 5.48—5.57 (2H, m), 6.11 (1H, d, Jꢃ11.6 Hz). 13C-NMR (100 MHz,
(1H, d, Jꢃ12.2 Hz), 5.19 (1H, d, Jꢃ12.2 Hz), 5.54 (1H, s), 5.68—5.74 (1H, CD3OD) d: 7.8, 23.8, 26.9, 27.1, 27.9, 28.6, 30.8, 56.3, 109.8, 129.1, 131.4,
m), 5.96 (1H, d, Jꢃ11.6 Hz), 7.30—7.36 (5H, m). IR (neat) cmꢂ1: 1738, 137.8, 146.2, 183.7, 197.7. IR (ATR) cmꢂ1: 1608. MS (EIꢀ) m/z: 264 (Mꢀ).
1692 MS (CIꢀ) m/z: 345 [(MꢀH)ꢀ]. HR-MS (CIꢀ) m/z: 345.15688 (Calcd
for C20H25O3S [(MꢀH)ꢀ]: 345.15245).
HR-MS (EIꢀ) m/z: 264.1173 (Calcd for C15H20O2S (Mꢀ): 264.1184.
(b) Preparation of ent-5c: Compound ent-5c (67 mg, 71%) was prepared
(b) Preparation of ent-23b: Compound ent-23b (143 mg, 36%) was pre- as a colorless powder from ent-22c (128 mg, 0.357 mmol) in the same man-
pared as a colorless oil from ent-21b (415 mg, 1.16 mmol) in the same man-
ner as described in (a). mp 113—115 °C (cyclohexane). [a]D27 ꢂ79.8 (cꢃ0.3,
1
ner as described in (a). [a]D25 ꢂ3.7 (cꢃ0.3, CHCl3). H-NMR, IR and MS
MeOH). The optical purity of ent-5c was estimated to be ꢅ99% ee similarly
spectra of this sample were identical to those described in (a). HR-MS (EIꢀ) to case for 5c. H-NMR, 13C-NMR, IR and MS spectra of this sample were
1
m/z: 344.1430 (Calcd for C20H24O3S (Mꢀ): 344.1446).
identical to those described in (a). HR-MS (EIꢀ) m/z: 264.1173 (Calcd for
(R,E)-Benzyl 2-Acetylthio-3-(cyclooct-2-enylidene)-2-methypro- C15H20O2S (Mꢀ): 264.1184).
panoate (23c) and Its Enantiomer (ent-23c) (a) Preparation of 23c:
Treatments of 21c (335 mg, 0.899 mmol) in a manner similar to that de-
(R,E)-5-(Cyclohex-2-enylidenemethyl)-4-hydroxy-5-methylthiophen-
2(5H)-one (6a) and Its Enantiomer (ent-6a) (a) Preparation of 6a: Treat-
scribed for the preparation of 15b, afforded 23c (217 mg, 67%) as a color- ments of 23a (171 mg, 0.726 mmol) in a manner similar to that described for
less oil. [a]D21 ꢀ7.3 (cꢃ0.3, CHCl3). 1H-NMR (400 MHz, CDCl3) d: 1.43— the preparation of 3b, afforded 6a (114 mg, 99%) as a colorless powder. mp
1.64 (6H, m), 1.90 (3H, s), 2.24 (3H, s), 2.38 (2H, q, Jꢃ7.1 Hz), 2.54—2.68 106—110 °C (cyclohexane). [a]D27 ꢀ138 (cꢃ0.2, MeOH). The optical purity
(2H, m), 5.15 (1H, d, Jꢃ12.2 Hz), 5.20 (1H, d, Jꢃ12.2 Hz), 5.49 (1H, td,
Jꢃ8.6, 12.2 Hz), 5.65 (1H, s), 6.05 (1H, d, Jꢃ12.2 Hz), 7.29—7.37 (5H, m).
IR (ATR) cmꢂ1: 1735, 1689. MS (EIꢀ) m/z: 358 (Mꢀ). HR-MS (EIꢀ) m/z:
358.1624 (Calcd for C21H26O3S (Mꢀ): 358.1603).
of 6a was calculated to be ꢅ99% ee based on the diastereomeric excess of
the corresponding 19a which had been determined as ꢅ99% de by HPLC
analysis. 1H-NMR (400 MHz, CD3OD) d: 1.60—1.72 (2H, m), 1.80 (3H, s),
2.06—2.13 (2H, m), 2.23—2.32 (1H, m), 2.36—2.46 (1H, m), 5.37 (1H, s),
(b) Preparation of ent-23c: Compound ent-23c (191 mg, 66%) was pre- 5.84 (1H, td, Jꢃ4.3, 9.8 Hz), 6.01 (1H, td, Jꢃ1.8, 9.8 Hz). 13C-NMR
pared as a colorless oil from ent-21c (300 mg, 0.805 mmol) in the same
(100 MHz, CD3OD) d: 23.0, 26.1, 26.6, 30.4, 58.9, 125.6, 131.4, 131.7,
1
manner as described in (a). [a]D28 ꢂ4.8 (cꢃ0.3, CHCl3). H-NMR, IR and
141.7, 190.3, 197.5. IR (KBr) cmꢂ1: 1603. MS (EIꢀ) m/z: 222 (Mꢀ). HR-
MS spectra of this sample were identical to those described in (a). HR-MS MS (EIꢀ) m/z: 222.0728 (Calcd for C12H14O2S (Mꢀ): 222.0715).
(EIꢀ) m/z: 358.1623 (Calcd for C21H26O3S (Mꢀ): 358.1603).
(b) Preparation of ent-6a: Compound ent-6a (61 mg, 63%) was prepared
(R,E)-5-(Cyclohex-2-enylidenemethyl)-4-hydroxy-3,5-dimethylthio- as a colorless powder from ent-23a (205 mg, 0.776 mmol) in the same man-
phen-2(5H)-one (5a) and Its Enantiomer (ent-5a) (a) Preparation of 5a:
Treatments of 22a (222 mg, 0.724 mmol) in a manner similar to that de-
scribed for the preparation of 3b, afforded 5a (85 mg, 84%) as a colorless
ner as described in (a). mp 105—107 °C (cyclohexane). [a]D27 ꢂ133 (cꢃ0.6,
MeOH). The optical purity of ent-6a was estimated to be ꢅ99% ee similarly
1
to the case for 6a. H-NMR, 13C-NMR, IR and MS spectra of this sample

September 2009
935
were identical to those described in (a). HR-MS (EIꢀ) m/z: 222.0742 (Calcd
for C12H14O2S (Mꢀ): 222.0715).
were carried out by Drs. M. Takei and M. Tsunoda of Kyorin Pharmaceuti-
cal Co., Ltd., to whom the authors’ thanks are due.
(R,E)-5-(Cyclohept-2-enylidenemethyl)-4-hydroxy-5-methylthiophen-
2(5H)-one (6b) and Its Enantiomer (ent-6b) (a) Preparation of 6b: Treat-
ments of 23b (144 mg, 0.418 mmol) in a manner similar to that described for
the preparation of 3b, afforded 6b (63 mg, 64%) as a colorless powder. mp
85—89 °C (cyclohexane). [a]D27 ꢀ137 (cꢃ0.2, MeOH). The optical purity of
6b was calculated to be ꢅ99% ee based on the diastereomeric excess of the
corresponding 19b which had been determined as ꢅ99% de by HPLC
analysis. 1H-NMR (400 MHz, CD3OD) d: 1.66—1.75 (4H, m), 1.80 (3H, s),
2.20—2.28 (2H, m), 2.40—2.50 (2H, m), 5.50 (1H, s), 5.70—5.78 (1H, m),
6.02 (1H, d, Jꢃ11.6 Hz). 13C-NMR (100 MHz, CD3OD) d: 26.7, 28.3, 29.0,
29.8, 30.8, 59.0, 116.8, 129.0, 134.0, 135.6, 145.9, 190.7, 197.6. IR (ATR)
cmꢂ1: 1600. MS (EIꢀ) m/z: 236 (Mꢀ). HR-MS (EIꢀ) m/z: 236.0918 (Calcd
for C13H16O2S (Mꢀ): 236.0871).
References and Notes
1) Ohata K., Terashima S., Bioorg. Med. Chem. Lett., 17, 4070—4074
(2007).
2) Ohata K., Terashima S., Bioorg. Med. Chem. Lett., 18, 5598—5600
(2008).
3) Oishi H., Noto T., Sasaki H., Suzuki K., Hayashi T., Okazaki H., Ando
K., Sawada M., J. Antibiot., 35, 391—395 (1982).
4) Noto T., Miyakawa S., Oishi H., Endo H., Okazaki H., J. Antibiot., 35,
401—410 (1982).
5) Miyakawa S., Suzuki K., Noto T., Harada Y., Okazaki H., J. Antibiot.,
35, 411—419 (1982).
6) Kremer L., Douglas J. D., Baulard A. R., Morehouse C., Guy M. R.,
Alland D., Dover L. G., Lakey J. H., Jacobs W. R., Brennan P. J., Min-
nikin D. E., Besra G. S., J. Biol. Chem., 275, 16857—16864 (2000).
7) Slayden R. A., Lee R. E., Armour J. W., Cooper A. M., Orme I. M.,
Brennan P. J., Besra G. S., Antimicrob. Agents Chemother., 40, 2813—
2819 (1996).
8) Waller R. F., Ralph S. A., Reed M. B., Su V., Douglas J. D., Minnikin
D. E., Cowman A. F., Besra G. S., McFadden G. I., Antimicrob. Agents
Chemother., 47, 297—301 (2003).
9) Jones S. M., Urch J. E., Brun R., Harwood J. L., Berry C., Gilber I. H.,
Bioorg. Med. Chem., 12, 683—692 (2004).
10) Jackowski S., Murphy C. M., Cronan J. E., Rock C. O., J. Biol. Chem.,
264, 7624—7629 (1989).
11) Price A. C., Choi K.-H., Heath R. J., Li Z., White S. W., Rock C. O., J.
Biol. Chem., 276, 6551—6559 (2001).
12) Hayashi T., Yamamoto O., Sasaki H., Kawaguchi A., Okazaki H.,
Biochem. Biophys. Res. Commun., 115, 1108—1113 (1983).
13) Nishida I., Kawaguchi A., Yamada M., J. Biochem. (Tokyo), 99,
1447—1454 (1986).
(b) Preparation of ent-6b: Compound ent-6b (73 mg, 74%) was prepared
as a colorless powder from ent-23b (205 mg, 0.776 mmol) in the same man-
ner as described in (a). mp 88—91 °C (cyclohexane). [a]D27 ꢂ128 (cꢃ0.2,
MeOH). The optical purity of ent-6b was estimated to be ꢅ99% ee similarly
1
to the case for 6b. H-NMR, 13C-NMR, IR and MS spectra of this sample
were identical to those described in (a). HR-MS (EIꢀ) m/z: 236.0893 (Calcd
for C13H16O2S (Mꢀ): 236.0871).
(R,E)-5-(Cyclooct-2-enylidenemethyl)-4-hydroxy-5-methylthiophen-
2(5H)-one (6c) and Its Enantiomer (ent-6c) (a) Preparation of 6c: Treat-
ments of 23c (162 mg, 0.452 mmol) in a manner similar to that described for
the preparation of 3b, afforded 6c (52 mg, 46%) as a colorless powder. mp
132—135 °C (cyclohexane). [a]D24 ꢀ75.3 (cꢃ0.3, MeOH). The optical pu-
rity of 6c was calculated to be ꢅ99% ee based on the diastereomeric excess
of the corresponding 19c which had been determined as ꢅ99% de by HPLC
1
analysis. H-NMR (400 MHz, CD3OD) d: 1.50—1.62 (4H, m), 1.64—1.74
(2H, m), 1.81 (3H, s), 2.30—2.40 (1H, m), 2.46—2.64 (3H, m), 5.48—5.56
(1H, m), 5.60 (1H, s), 6.11 (1H, d, Jꢃ11.6 Hz). 13C-NMR (100 MHz,
CD3OD) d: 23.9, 27.0, 27.3, 27.9, 28.8, 31.0, 58.9, 129.1, 131.3, 137.7,
145.9, 190.6, 197.5. IR (ATR) cmꢂ1: 1593. MS (EIꢀ) m/z: 250 (Mꢀ). HR-
MS (EIꢀ) m/z: 250.1007 (Calcd for C14H18O2S (Mꢀ): 250.1028).
14) Jones A. L., Herbert D., Rutter A. J., Dancer J. E., Harwood J. L.,
Biochem. J., 347, 205—209 (2000).
15) McFadden J. M., Medghalchi S. M., Thupari J. N., Pinn M. L., Vadla-
mudi A., Miller K. I., Kuhajda F. P., Townsend C. A., J. Med. Chem.,
48, 946—961 (2005).
16) Sakya S. M., Suarez-Contreras M., Dirlam J. P., O’Connell T. N.,
Hayashi S. F., Santoro S. L., Kamicker B. J., George D. M., Ziegler C.
B., Bioorg. Med. Chem. Lett., 11, 2751—2754 (2001).
17) Kim P., Zhang Y.-M., Shenoy G., Nguyen Q.-A., Boshoff H. I., Manju-
natha U. H., Goodwin M. B., Lonsdale J., Price A. C., Miller D. J.,
Duncan K., White S. W., Rock C. O., Barry C. E. III, Dowd C. S., J.
Med. Chem., 49, 159—171 (2006).
18) Senior S. J., Illarionov P. A., Gurcha S. S., Campbell I. B., Schaeffer
M. L., Minnikin D. E., Besra G. S., Bioorg. Med. Chem. Lett., 13,
3685—3688 (2003).
19) Senior S. J., Illarionov P. A., Gurcha S. S., Campbell I. B., Schaeffer
M. L., Minnikin D. E., Besra G. S., Bioorg. Med. Chem. Lett., 14,
373—376 (2004).
20) Kamal A., Shaik A. A., Sinha R., Yadav J. S., Arora S. K., Bioorg.
Med. Chem. Lett., 15, 1927—1929 (2005).
21) Jones S. M., Urch J. E., Kaiser M., Brun R., Harwood J. L., Berry C.,
Gilbert I. H., J. Med. Chem., 48, 5932—5941 (2005).
22) Chambers M. S., Thomas E. J., J. Chem. Soc., Perkin Trans. 1, 1997,
417—431 (1997).
23) McFadden J. M., Frehywot G. L., Townsend C. A., Org. Lett., 4,
3859—3862 (2002).
24) Toyama K., Tanchi T., Mase N., Yoda H., Takabe K., Tetrahedron Lett.,
47, 7163—7166 (2006).
(b) Preparation of ent-6c: Compound ent-6c (50 mg, 45%) was prepared
as a colorless powder from ent-23c (159 mg, 0.444 mmol) in the same man-
ner as described in (a). mp 134—136 °C (cyclohexane). [a]D23 ꢂ76.5 (cꢃ0.3,
MeOH). The optical purity of ent-6c was estimated to be ꢅ99% ee similarly
1
to the case for 6c. H-NMR, 13C-NMR, IR and MS spectra of this sample
were identical to those described in (a). HR-MS (EIꢀ) m/z: 250.1000 (Calcd
for C14H18O2S (Mꢀ): 250.1028).
Biological Assay In vitro antibacterial activity assay: The minimum in-
hibitory concentration (MIC) (mg/ml) was determined by the ager dilution
method22) with Muller-Hinton agar (Difco Laboratories, Detroit, MI,
U.S.A.). The MIC was defined as the lowest concentration of an antibacterial
agent that inhibited visible growth after incubation at 35 °C for 18 h.
In vitro inhibitory activity assay for mammalian type I fatty acid synthase:
Fatty acid synthesis was evaluated by measuring the incorporation of [1-14C]
acetate into cellular fatty acid as previously described23) with some modifi-
cation. Human HepG2 cells were seeded in a 12-well plate and cultured in
Dulbecco’s modified Eagle’s medium (DMEM) containing 10% fetal calf
serum supplemented with 100 U/ml penicillin and 100 mg/ml streptomycin
in a 5% CO2 atmosphere at 37 °C for 24 h. The medium was removed and
replaced with serum-free DMEM. After 24 h incubation, the cells were
treated with various concentrations of the test compound for 4 h in Krebs-
Ringer phosphate HEPES buffer (pH 7.4). [1-14C] acetate (0.4 uCi/ml;
56.5 mCi/mmol; Perkin-Elmer Inc., Norwalk, CT, U.S.A.) was added to the
medium, which was then incubated at 37 °C for 2 h. The metabolic reaction
was stopped by the addition of ethanolic KOH, and the samples were left at
80 °C for 2 h. After extracting nonsaponifiable lipids with petroleum ether,
the water-soluble residual layer was acidified to pH ꢄ1 by the addition of
HCl. Total fatty acids were extracted with petroleum ether, and the com-
bined organic extracts were dried and concentrated in vacuo. The residue
was dissolved with methanol and was transferred into a scintillaton vial. Ra-
dioactivity of total fatty acids was counted by a liquid scintillation counter
(Perkin-Elmer Inc.). IC50 values were calculated by the auto-analysis pro-
gram GraphPad Prism, version 4.00 (GraphPad Software Inc., La Jolla, CA,
U.S.A.).
25) Dormann K. L., Brückner R., Angew. Chem., Int. Ed., 46, 1160—1163
(2007).
26) Ohata K., Terashima S., Tetrahedron Lett., 47, 2787—2791 (2006).
27) Ohata K., Terashima S., Tetrahedron, 65, 2244—2253 (2009).
28) In addition to 5a—c, 6a—c and their enantiomers (ent-5a—c, ent-
6a—c), 5-[(E)-cyclopent-2-enylidenemethyl]-TLM, its 3-demethyl
congener and their enantiomers (5d, 6d, ent-5d, ent-6d) were designed
and their synthesis was attempted following the same synthetic scheme
shown in Chart 2. Although the scheme proceeded smoothly to the
stage of 20 (nꢃ0), aldehyde 21 (nꢃ0) derived from 20 (nꢃ0) was
found to be very unstable, probably due to facile isomerization to
the cyclopentadiene derivative and the subsequent intramolecular
Diels–Alder reaction (Ohata K. and Terashima S., unpublished re-
Acknowledgments We are grateful to Dr. T. Ishizaki of Kyorin Pharma-
ceutical Co., Ltd., for his extensive support and to Dr. Y. Fukuda of Kyorin
Pharmaceutical Co., Ltd., for his valuable suggestions and discussions. The
in vitro antibacterial and mammalian type I FAS inhibitory activity assays

936
Vol. 57, No. 9
sults).
19b; 5.62 ppm [(Me)(SR)C–CHꢃC] for the (S)-diastereomer of
19b (26b); 5.64 ppm [(Me)(SR)C–CHꢃC] for 19c; 5.72 ppm
[(Me)(SR)C–CHꢃC] for the (S)-diastereomer of 19c (26c); 5.72 ppm
[(Me)(SR)C–CHꢃC] for the synthetic intermediate of 1; 5.77 ppm
[(Me)(SR)C–CHꢃC] for the (S)-diastereomer of the synthetic inter-
mediate of 1.
29) Kuhajda F. P., Pizer E. S., Li J. N., Mani S., Frehywot G. L., Townsend
C. A., Proc. Natl. Acad. Sci. U.S.A., 97, 3450—3454 (2000).
39) The enantiomeric exesses of 3a—f, ent-3a—f, 4a—f, ent-4a—f, 5a—
c, ent-5a—c, 6a—c and ent-6a—c were shown in Table 3 and in Ex-
perimental.
40) Determination of MICs by agar dilution methods was performed ac-
cording to the guideline M7-A6 of the Clinical and Laboratory Stan-
dards Institute (2003).
41) Fatty acid synthesis was evaluated by measuring the incorporation of
[1-14C] acetate into cellular fatty acid as previously described with
some modifications. See, Murakami K., Tobe K., Ide T., Mochizuki T.,
Ohashi M., Akanuma Y., Yazaki Y., Kadowaki T., Diabetes, 47,
1841—1847 (1998).
42) Formation of two types of the by-products corresponding to 24b and
25b was observed, similar to the case described for the preparation of
11b, 24b and 25b from 9b.
30) Ho G. J., Mathre P. J., J. Org. Chem., 60, 2271—2273 (1995).
1
31) In H-NMR spectrum, the two olefinic protons of 11b showed larger
chemical shifts than 24b. The same relationships were also observed
for the chemical shift values of 11a, c—f and 24a, c—f.
32) Seebach D., Hungerbuhler E., Naef R., Schurrenberger P., Weidmann
B., Zuger M., Synthesis, 1982, 138—141 (1982).
33) Evans D. A., Britton T. C., Ellman J. A., Dorow R. L., J. Am. Chem.
Soc., 112, 4011—4030 (1990).
34) Tamura R., Sato M., Oda D., J. Org. Chem., 51, 4368—4375 (1986).
35) Naya A., Ishikawa M., Matsuda K., Ohwaki K., Saeki T., Noguchi K.,
Ohtake N., Bioorg. Med. Chem., 11, 875—884 (2003).
36) In the absence of HMPA, the deconjugative asymmetric a-sulfenyla-
tion of 19a did not take place at all.
37) Formation ratios of 19, 26 to 27 estimated by the H-NMR spectrum
and/or HPLC analysis are as follows: 19/26/27; 12 : 2 : 1 for
19a/26a/27a; 14 : 1 : 4 for 19b/26b/27b; 12 : 1 : 1 for 19c/26c/27c.
38) Some representative data are as follows: H-NMR (CDCl3): 5.44 ppm
43) Since the absolute optical rotation values for the enantiomeric pairs of
the oily compounds bearing an 3-oxopropylthio group were occasion-
ally found to be inconsistent, the [a]D a values for those compounds
were not included in this report. At present, the reason for the ob-
served inconsistency is unclear.
1
1
[(Me)(SR)C–CHꢃC] for 19a; 5.50 ppm [(Me)(SR)C–CHꢃC] for the
(S)-diastereomer of 19a (26a); 5.56 ppm [(Me)(SR)C–CHꢃC] for