Radical cyclization in heterocycle synthesis. 12. Sulfanyl radical addition-addition-cyclization (SRAAC) of unbranched diynes and its application to the synthesis of A-ring fragment of 1 α,25-dihydroxyvitamin d3

Article abstract of DOI:10.1248/cpb.49.213

Sulfanyl radical addition-addition-cyclization (SRAAC) of unbranched diynes proceeded smoothly to give cyclized exo-olefins, while the sulfanyl radical addition-cyclization-addition (SRACA) of diynes having a quaternary carbon gave cyclized endo-olefins. This method was successfully applied to the synthesis of A-ring fragment of 1 α,25-dihydroxyvitamin D₃.

Full text of DOI:10.1248/cpb.49.213

February 2001
Chem. Pharm. Bull. 49(2) 213—224 (2001)
213
Radical Cyclization in Heterocycle Synthesis. 12.1) Sulfanyl Radical
Addition–Addition–Cyclization (SRAAC) of Unbranched Diynes and
Its Application to the Synthesis of A-Ring Fragment of
a
1 ,25-Dihydroxyvitamin D3
Okiko MIYATA, Emi NAKAJIMA, and Takeaki NAITO*
Kobe Pharmaceutical University, Motoyamakita, Higashinada, Kobe 658–8558, Japan.
Received September 25, 2000; accepted October 24, 2000
Sulfanyl radical addition–addition–cyclization (SRAAC) of unbranched diynes proceeded smoothly to give
cyclized exo-olefins, while the sulfanyl radical addition–cyclization–addition (SRACA) of diynes having a quater-
nary carbon gave cyclized endo-olefins. This method was successfully applied to the synthesis of A-ring fragment
of 1a,25-dihydroxyvitamin D3.
Key words sulfanyl radical; addition–addition–cyclization; diyne; alkylidenecyclopentane; alkylidenecyclohexane; vitamin D
Radical cyclization is a useful method for the preparation ther a quaternary carbon or a heteroatom, sulfanyl radical ad-
of various cyclic compounds.1) Recently, this method in dition–cyclization–addition (SRACA) occurred to give endo-
which carbon centered radical species are generated by the olefin 3. In the case of longer carbon chain, 1 (nϭ2, XϭCH2,
addition reaction of a radical to a multiple bond has drawn C(COOMe)2) gave exo-olefin 2 as the major product, while 1
the attention of synthetic chemists because of its several ad- (nϭ2, XϭNSO2Ar) gave a complex mixture. Synthetic util-
vantages, such as readily available starting substrate and for- ity of newly found SRAAC has been proved by a novel syn-
mation of functionalized products. The synthetic utility of thesis of A-ring fragment 5 of 1a,25-dihydroxyvitamin D3
this type of approach using diene and enyne systems has (1a,25-(OH)2D3).
been partially shown.2,3) To our knowledge, there have been
only a few papers published on the radical cyclization of Results and Discussion
diynes,4) which requires drastic conditions for successful rad-
SRAAC and SRACA to Diynes We first investigated
ical cyclization. Furthermore, diynes 1 (XϭC(COOMe)2) the radical cyclization of the readily available diynes 6a—
having a quaternary carbon have been employed as sub- d7,8) (Chart 2, Table 1). A solution containing thiophenol (1
strates, because the cyclization reaction is facilitated by the eq) and 2,2Ј-azobisisobutyronitrile (AIBN) (0.5 eq) in ben-
Thorpe–Ingold effect and reactive rotamer effect.5) Un- zene was added dropwise to a solution of an unbranched
branched diyne 1 (XϭCH2) has been reported to yield no cy- diyne, 1,6-heptadiyne (6a) in boiling benzene while stirring
clized product but only an acyclic adduct.4a,6) We found that under nitrogen. The solution was then refluxed for a further
the sulfanyl radical-induced cyclization of unbranched diyne 2 h and separation of the crude product gave the cyclic prod-
1 (XϭCH2) proceeded smoothly by employing 2 eq of ucts 7a (E:Zϭ 10 : 1) and 8a in 21 and 19% yields, respec-
thiophenol under mild conditions to give cyclized product 2 tively, along with the recovered volatile starting material 6a
as the major product in moderate yield (Chart 1). Addition- and acyclic adduct 10a as a mixture of (E)- and (Z)-isomers
ally, we disclosed that the feasibility of the sulfanyl radical (entry 1). 10a was also obtained but in 17% yield by radical
addition and/or cyclization is dependent upon the structure of reaction of 6a using 2,2Ј-azobis(2,4-dimethyl-4-methoxy-
the substrates. In the case of unbranched 1,6-heptadiyne 1 valeronitrile) (V-70)9) as radical initiator at room tempera-
(nϭ1, XϭCH2), sulfanyl radical addition–addition–cycliza- ture. When 2 eq of thiophenol was used in the presence of
tion (SRAAC) proceeded smoothly to give cyclized product AIBN, the reaction proceeded smoothly to give the exo-olefin
2 having an exo-olefin as the major product, while in the case 7a (E : Zϭ8 : 1) having two sulfanyl groups in 70% yield as
of 1,6-heptadiyne 1 (nϭ1, XϭC(COOMe)2, NTs) having ei- the major product (entry 2). On the other hand, the branched
Chart 1
To whom correspondence should be addressed. e-mail: taknaito@kobepharma-u.ac.jp
© 2001 Pharmaceutical Society of Japan

214
Vol. 49, No. 2
Chart 2
Table 1. Sulfanyl Radical Addition–Cyclization Reaction of 1,6-Diynes
Yield (%)
Entry
Substrate
PhSH (eq)
Total
7
8
9
10
1
2
3
4
5
6a
6a
6b
6c
6d
1
2
2
2
2
53
96
96
92
57
21 (E : Zϭ10 : 1)
70 (E : Zϭ 8 : 1)
—
20 (only Z)
10 (only Z)
19
26
86
55
28
—
—
10
17
19
13
—
—
—
—
diyne 6b having a quaternary carbon afforded the endo-olefin favored conformer 6A, due to the steric repulsion between
8b10) in 86% yield along with a small amount of thiophene the substituents on the X group and the alkyne part. There-
9b11a) and with no detection of exo-olefin 7b (entry 3). Thus, fore, addition of a sulfanyl radical to alkynes 6b, c followed
it is interesting to note that radical cyclization of unbranched by cyclization of the resulting vinyl radical F gave the diene
diyne 6a gave the exo-olefin 7a as the major product, while H, which underwent 1,4-radical addition of thiophenol to
branched diyne 6b provided the endo-olefin 8b. Radical ad- give 8. Doubly cyclized thiophene 9 would be obtained via
dition–cyclization of diynes 6c and 6d having a heteroatom intramolecular SHi reaction4b) of vinyl radical G on the
(XϭNSO2Ar or O) as the X group, gave the endo-olefins 8c phenylsulfanyl group.
and 8d as the major product in 55 and 28% yields, respec-
tively. In both cases, exo-olefins 7c, d (Z-isomer) and thio- then extended the sulfanyl radical addition–cyclization to 1,7-
phenes 9c, d4b,11b) were obtained as shown in Table 1. octadiynes 12a—c7,12) (Chart 4, Table 2) and 1,8-nonadiyne
After successful cyclization of 1,6-heptadiynes 6a—d, we
In order to explain the reaction pathway to these products, (17)7) (Chart 5). It is known2 f ) that cyclization of 6-heptenyl
we examined the equilibration between the exo- and endo- radical proceeds about 40 times slower than that of the corre-
products as well as a radical reaction of acyclic adduct 10a. sponding hexenyl radical. Cyclization of 12a proceeded
Under the radical reaction conditions, no equilibration be- smoothly to give the desired exo-product 13a (E : Zϭ5 : 2) in
tween 7a and 8a was observed and acyclic adduct 10a gave 69% yield. Radical reaction of 12b having a quarternary car-
exclusively 7a with no detection of two compounds, 8a and bon gave the exo-olefin 14b as the major product (entry 1).
9a. Therefore, we propose a plausible reaction pathway as However, 12c having heteroatom gave a complex mixture of
shown in Chart 3. Since unbranched diyne 6a would exist products from which (E)-exo-olefins 13c and (Z)-exo-14c,
normally in a stable zig-zag conformer 6A, the hydrogen and endo-olefin 15c were isolated in 3, 9, and 25% yields, re-
transfer from thiophenol to the resulting vinyl radical C, spectively (entry 2). To improve the yields of 13c and 14c,
formed from diyne 6a (XϭCH2) by the addition of a sulfanyl we examined the reaction procedure shown in entry 3. Ac-
radical, occurs to give the adduct 10 in preference to in- cording to the reaction pathway for 7 shown in Chart 3, when
tramolecular cyclization of C. As a next step, a sulfanyl radi- excess thiophenol (hydrogen donor) is present in a reaction
cal attacks another terminal alkyne in 10 to give vinyl radical mixture, the hydrogen transfer from thiophenol to the corre-
D. The vinyl radical D is less stable than cyclized radical E, sponding vinyl radical (C type in Chart 3), formed from 12c
which is stabilized by an adjacent sulfanyl group. Therefore, would proceed smoothly to give the adduct (10 type in Chart
since the equilibrium between D and E favors radical E, the 3) in preference to intramolecular cyclization of the vinyl
formation of cyclized exo-olefin 7 is preferable to that of the radical (C type in Chart 3). Finally, the adduct would be con-
adduct 11. On the other hand, diynes 6b, c having either a verted into the desired products 13c and 14c via the sulfanyl
quaternary carbon or a heteroatom (XϭC(COOMe)2 or radical addition to terminal alkyne followed by vinyl radical
NSO2Ar) would exist preferentially in a conformer 6B which cyclization. Thus, it is expected that SRAAC reaction would
is suitable for intramolecular cyclization compared to the less be preferable to SRACA reaction under the reaction condi-

February 2001
215
Chart 3
Chart 4
Table 2. Sulfanyl Radical Addition–Cyclization Reaction of 1,7-Diynes
Yield (%)
Entry
Substrate
Total
13
14
15
16
1
12b
12c
12c
87
72
56
6 (only E) 32 (only E)
3 (only E) 9 (only Z)
14 (only E) 25 (only Z)
14
25
17
20
33
0
2
3a)
Chart 5
a) Addition of PhSH (1 eq) and AIBN (0.5 eq) to a mixture of PhSH (1 eq) and 12c.
metrical isomers as a result of addition of thiophenol to the
alkynyl group (Chart 5).
tions. A mixture of thiophenol (1 eq) and AIBN was added to
a refluxing solution of 12c and thiophenol (1 eq) in benzene
to give exo-olefins 13c and 14c as the major product moni-
toring no formation of acyclic adduct 16 (entry 3). Under the
reaction conditions, no equilibration between 14c and 15c
was observed.
We speculated that the radical reaction of 1,7-octadiynes
12a—c would take place by a similar reaction pathway to the
case of formation of the 5-membered ring described in Chart
3 (Chart 6). The exo-products 13a—c and 14b, c were ob-
tained via either route I or IЈ by SRAAC reaction. The major
reaction pathway would be route I that involves addition of
sulfanyl radical to one of two alkynes which is less close to
1,8-Nonadiyne (17) did not undergo cyclization, but the
adduct 18 was obtained quantitatively as a mixture of geo-

216
Vol. 49, No. 2
Chart 6
Chart 7
the X-group and therefore sterically less hindered. On the min D3 Based on the results shown in the previous chapter,
other hand, SRACA reaction of 12b, c gave the endo-prod- we undertook the synthesis of A-ring fragment of 1a,25-di-
ucts 15b, c via route II. In the case of diester, the 1,7-oc- hydroxyvitamin D3. Since the discovery of 1a,25-dihydroxy-
tadiyne 12b gave a mixture of 13b, 14b and 15b with pre- vitamin D3 as the active metabolite of vitamin D, many syn-
dominant formation of exo-products 13b and 14b compared thetic efforts have been made in this area.13) Basic strate-
to endo-product 15b.
gies14) for the construction of 1a,25-dihydroxyvitamin D3
The result is quite contrary to the radical reaction of 1,6- mostly involve the coupling reaction of an A-ring precursor
heptadiyne 6b which afforded the endo-product 8b as the 22 with the CD-ring part 23 of the vitamin D skeleton (Chart
major product as shown in Table 1. It is suggested that the 7). On the basis of Lythgoe’s synthesis14c,d) of vitamin D3, a
radical cyclization of 1,7-octadiynes proceeds more slowly Hoffman-La Roche group14e, f ) achieved the synthesis of
than that of 1,6-heptadiynes.
1a,25-dihydroxyvitamin D3 using 22 as a useful precursor of
a
Synthesis of A-Ring Fragment of 1 ,25-Dihydroxyvita- A-ring synthon. We investigated the synthesis of 21, a known

February 2001
217
Chart 8
precursor14e, f ) of 22 using sulfanyl radical addition–cycliza-
tion of the diyne 19 as the key reaction.
We employed the diynes 31a, b as the chiral substrate for
radical addition–cyclization (Chart 8). 31a, b were prepared
from 3-buten-1-ol (24) as follows. According to the reported
procedure,15) the alcohol 24 was converted into the aldehyde
26 via protection of the hydroxy group in 24, asymmetric di-
hydroxylation of the resulting olefin with AD-mix-a, mono-
tosylation of the diol, transformation of the tosylate into the
Fig. 1. NOE Correlations of Compounds 34a, b
epoxide, introduction of acetylene unit, benzyloxymethyla- These stereostructures were deduced from comparison of the
tion, deprotection of the hydroxy group, and oxidation of the 1H-NMR spectra with those of 35a and 36a, respectively. On
alcohol. Addition of lithium acetylide to the aldehyde 26 the other hand, the attempted radical cyclization of 32 was
gave a 1 : 2 mixture of the diynes 27 and 28 in 92% com- unsuccessful and many uncharacterized products were
bined yield. Desilylation of 27 and 28 with potassium car- formed. We are unable at this time to offer an explanation of
bonate afforded 29 and 30, respectively. The diyne 29 also the influence of stereochemistry at 3-position on the radical
was prepared from 28 in 93% yield by epimerization of the cyclization.
hydroxyl group under Mitsunobu conditions. Furthermore,
The stereostructures of 34a, b were deduced from compar-
1
silylation of 29 and 30 with tert-butyldimethylsilyl trifluo- ison of the H-NMR spectra with those of the related com-
romethanesulfonate (TBSOTf) gave 31a and 32, respectively. pounds16) and nuclear Overhanser effect (NOE) correlations
Disilyl ether 31b was prepared from 29 via removal of the as shown in Fig. 1. Both the stereostructures at 1-position
benzyloxymethyl (BOM) group followed by silylation of the and geometry of olefin 35a were hardly discernible from the
resulting diol 33. The configurations of 31a, b were eventu- spectral analysis.
ally deduced from analysis including nuclear Overhauser en-
We next examined conversion of the main product 34b
hancement and exchange spectroscopy (NOESY) of the H- into the A-ring synthon 40 (Chart 10). Oxidation of 34b at
NMR spectra of the cyclized products 34a, b (Fig. 1).
0 °C with m-chloroperbenzoic acid (mCPBA) gave the sul-
1
We next investigated the sulfanyl radical addition–cycliza- foxide 37, which was then subjected to pyrolysis to give the
tion of substrates 31a, b and 32 (Chart 9, Table 3). Sulfanyl dienylsulfoxide 38.
radical addition–cyclization of 31a in the presence of thio-
In order to introduce an alkoxycarbonyl group17) at a-posi-
phenol and AIBN gave a separable mixture of 34a, 35a, and tion, we started to investigate the model study using 42 as
36a in combined 37% yield (entry 1). Similarly, 31b under- substrate, prepared from 13a via pyrolytic elimination of the
went the radical cyclization to give 34b and an inseparable corresponding sulfoxide (Chart 11, Table 4). Treatment of 42
mixture of 35b and 36b in combined 66% yield (entry 2). with methyllithium at Ϫ78 °C followed by acylation with

218
Vol. 49, No. 2
Chart 9
Table 3. Sulfanyl Radical Addition–Cyclization Reaction of 31a, b
Yield (%)
Entry
Substrate
Total
37
34
19
38
35
36
1
2
31a
31b
15
3
66
28
Chart 10
Chart 11
Table 4. Introduction of Alkoxycarbonyl Group
Base
Yield (%)
Temp.
(°C)
Timea)
(min)
Entry
Electrophile
R
(1.5 eq)
43
44
45
46
1
2
3
4
5
6
MeLi
MeLi
LDA
tert-BiLi
MeLi
MeLi
ClCOOMe
ClCOOMe
ClCOOMe
ClCOOMe
ClCOOMe
ClCOOEt
Me
Me
Me
Me
Me
Et
Ϫ78
Ϫ100
Ϫ100
Ϫ100
Ϫ100
Ϫ100
30
30
30
30
15
15
6
29
—
—
36
49
9
7
—
—
18
13
—
—
—
—
3
—
—
—
16
—
—
b)
—
a) Reaction time on lithiation of 42 with base before addition of electrophile. b) Recovery of 42.
methyl chloroformate gave the desired products 43a and 44a tempted acylation using lithium diisopropylamide (LDA) as
in low yields (entry 1). Lowering the temperature from Ϫ78 base was unsuccessful and the substrate 42 was mostly re-
to Ϫ100 °C improved the yield (36%) (entry 2). The at- covered (entry 3). Lithiation of 42 with tert-butyllithium fol-

February 2001
219
1.78—1.86 (1H, m), 2.00—2.07 (1H, m), 2.36—2.50 (2H, m), 2.75—2.82
(1H, m), 2.91 (1H, dd, Jϭ12.5, 9 Hz), 3.21 (1H, dd, Jϭ12.5, 5 Hz), 6.13
(1H, br q, Jϭ2 Hz), 7.15—7.20 (2H), 7.25—7.36 (8H) (each m). NOE was
observed between methylene-H (d 2.91, 3.21) and olefinic-H (d 6.13)
in NOESY spectroscopy. HRMS m/z: 312.1020 (Calcd for C19H20S2:
lowed by acylation gave tert-butyl sulfoxide 46 in low yield,
which would be formed as the result of attack of tert-butyl-
lithium on both sulfur atom and vinyl proton. Unfortunately,
43a and 44a could not be detected in the reaction mixture
(entry 4). When the reaction time for lithiation of 42 with 312.1006).
(Z)-[[[2-[(Phenylthio)methyl]cyclopentylidene]methyl]thio]benzene [(Z)-
methyl lithium was shortened from 30 min to 15 min, the de-
sired products 43a and 44a were obtained in 54% combined
yield (entry 5). When ethyl cyanoformate was used as acylat-
ing reagent, the yield of these two products was improved
(62%) (entry 6).
7a]: A yellow oil. 1H-NMR (500 MHz, CDCl3) d: 1.60—1.69 (1H, m),
1.74—1.83 (1H, m), 1.88—1.94 (2H, m), 2.39—2.53 (2H, m), 2.71 (1H, dd,
Jϭ13, 6 Hz), 3.00—3.07 (1H, m), 3.48 (1H, dd, Jϭ13, 3.5 Hz), 6.09 (1H, br
q, Jϭ2 Hz), 7.13—7.20 (2H), 7.24—7.31 (6H), 7.40—7.43 (2H) (each m).
NOE was observed between methylene-H (d 2.71, 3.48) and ArH (d 7.40—
7.43) in NOESY spectroscopy. HRMS m/z: 312.1020 (Calcd for C19H20S2:
312.1006).
Based on the preliminary experimental results, we next ex-
amined the acylation of vinyl sulfoxide 38 under the best
conditions shown in entry 6 of Table 4 (Chart 10). The de-
sired product 39 was obtained in 61% yield and in 2.4 : 1
ratio of (E)- and (Z)-isomers. Desulfurization of (E)-isomer
39 was achieved by Theobald’s method.18) (E)-39 was treated
with tert-butyllithium at Ϫ100 °C to give a 2.3 : 1 mixture of
the (Z)- and (E)-a,b-unsaturated esters 40 along with tert-
butyl phenylsulfoxide 41. To improve the yield of the desired
product 40, we examined desulfurization under different con-
ditions; however, no other reactions than Theobald’s method
gave this product.19) It is known14 f ) that (E)-isomer 40 is pho-
tochemically convertible to (Z)-40 in good yield, which is the
1,2-Bis[(phenylthio)methyl]cyclopentene (8a): A yellow oil. 1H-NMR
(300 MHz, CDCl3) d: 1.79 (2H, quint., Jϭ7.5 Hz), 2.44 (4H, t, Jϭ7.5 Hz),
3.34 (4H, br s), 7.16—7.33 (10H, m). HRMS m/z: 312.0999 (Calcd for
C19H20S2: 312.1006).
(E/Z)-1-Phenylthio-1-hepten-6-yne (10a): A yellow oil. 1H-NMR (300
MHz, CDCl3) d: 1.67 (2H, quint., Jϭ7.5 Hz), 1.96—2.00 (1H, m), 2.21—
2.42 (4H, m), 5.80 (1/2H, dt, Jϭ9, 7 Hz), 5.94 (1/2H, dt, Jϭ14.5, 7 Hz),
6.17—6.28 (1H, m), 7.16—7.53 (5H, m). HRMS m/z: 202.0821 (Calcd for
C13H14S: 202.0816).
Dimethyl 3,4-Bis[(phenylthio)methyl]-3-cyclopentene-1,1-dicarboxylate
(8b): A yellow oil. 1H-NMR (300 MHz, CDCl3) d: 3.12 (4H, br s), 3.18 (4H,
br s), 3.72 (6H, s), 7.18—7.38 (10H, m). IR (CHCl3) cmϪ1: 1740 (COO).
HRMS m/z: 428.1129 (Calcd for C23H24O4S2: 428.1116).
Dimethyl 4H-Cyclopenta[c]thiophene-5,5(6H)-dicarboxylate (9b)11a)
:
1
key intermediate for the synthesis of 1a,25-dihydroxyvita- Pale yellow crystals. mp 79—81 °C (Et2O). H-NMR (300 MHz, CDCl3) d:
3.35 (4H, br s), 3.71 (6H, s), 6.81 (2H, s). IR (CHCl3) cmϪ1: 1734 (COO).
min D3. The physical and spectral data of the (Z)-ester 40
([a]D22 Ϫ38.1° (cϭ0.11, Et2O)) were identical with those
HRMS m/z: 240.0479 (Calcd for C11H12O4S: 240.0456). Anal. Calcd for
C11H12O4S: C, 54.99; H, 5.03. Found: C, 54.87; H, 4.96.
(Z)-1-(Phenylsulfonyl)-4-[(phenylthio)methyl]-3-[(phenylthio)methyli-
([a]D25 Ϫ36.9° (cϭ0.3, Et2O)) of the authentic sample re-
ported in the literature.14 f ) Since (Z)-40 had previously been
converted into 1a,25-dihydroxyvitamin D3 via reduction of
the ester, transformation into phosphine oxide, Wittig reac-
tion, and finally deprotection, the present method provides a
new synthesis of 1a,25-dihydroxyvitamin D3.
dene]-pyrrolidine [(Z)-7c]: A yellow oil. 1H-NMR (500 MHz, CDCl3) d:
2.79 (1H, dd, Jϭ13, 9 Hz), 2.87—2.94 (1H, m), 3.08 (1H, dd, Jϭ13, 5.5
Hz), 3.32 (1H, dd, Jϭ10, 5 Hz), 3.47 (1H, dd, Jϭ10, 7 Hz), 3.90 (1H, ddd,
Jϭ15, 2.5, 1.5 Hz), 3.93 (1H, ddd, Jϭ15, 2.5, 2 Hz), 6.13 (1H, td, Jϭ2, 1.5
Hz), 7.19—7.31 (10H), 7.52—7.56 (2H), 7.59—7.64 (1H), 7.82—7.85 (2H)
(each m). NOE was observed between methylene-H (d 3.08) and olefinic-H
(d 6.13) in NOESY spectroscopy. 13C-NMR (125 MHz, CDCl3) d: 37.29,
43.29, 50.92, 52.81, 117.57, 126.74, 126.94, 127.81, 129.16, 129.19, 129.20,
130.02, 132.99, 134.97, 135.09, 139.90. HRMS m/z: 453.0884 (Calcd for
C24H23NO2S3: 453.0891).
In conclusion, we have developed for the first time
SRAAC of unbranched diynes. In the case of unbranched
1,6-heptadiyne, SRAAC proceeded smoothly to give the cy-
clized product having an exo-olefin as the major product.
Similarly, in the case of 6-membered ring formation, the exo-
olefin was obtained as a major product. Furthermore, we
achieved the synthesis of A-ring fragment of 1a,25-dihy-
droxyvitamin D3 (1a,25-(OH)2D3) via the route involving
SRAAC of diyne 31b.
1-(Phenylsulfonyl)-3,4-bis[(phenylthio)methyl]-2,5-dihydro-1H-pyrrole
(8c): Pale yellow crystals. mp 94—95°C (Et2O). 1H-NMR (300 MHz,
CDCl3) d: 2.97 (4H, br s), 4.15 (4H, br s), 7.06—7.27 (10H), 7.54—7.68
(3H), 7.81—7.87 (2H) (each m). IR (CHCl3) cmϪ1: 1348, 1166 (NSO2).
HRMS m/z: 453.0886 (Calcd for C24H23NO2S3: 453.0891). Anal. Calcd for
C24H23NO2S3: C, 63.54; H, 5.11; N, 3.09. Found: C, 63.54; H, 5.10; N, 3.04.
5-(Phenylsulfonyl)-5,6-dihydro-4H-thieno[3,4-c]pyrrole (9c)4b): Pale yel-
low crystals. mp 141—143 °C (Et2O) [lit.4b) mp 136—137°C]. 1H-NMR
(200 MHz, CDCl3) d: 4.41 (4H, br s), 6.89 (2H, s), 7.44—7.64 (3H), 7.83—
Experimental
General Melting points are uncorrected. 1H- and 13C-NMR spectra 7.92 (2H) (each m). IR (CHCl3) cmϪ1: 1350, 1170 (NSO2). HRMS m/z:
were recorded at 200, 300, or 500 MHz and at 50 or 125 MHz, respectively. 265.0231 (Calcd for C12H11NO2S2: 265.0231). Anal. Calcd for
IR spectra were recorded using FTIR apparatus. The data without special C12H11NO2S2: C, 54.32; H, 4.18; N, 5.28. Found: C, 54.30; H, 4.18; N, 5.15.
peaks in IR spectra are not shown here. Mass spectra were obtained by
(Z)-Tetrahydro-4-[(phenylthio)methyl]-3-[(phenylthio)methylidene]furan
electron-impact ionization (EI) method. Flash column chromatography was [(Z)-7d]: A yellow oil. 1H-NMR (500 MHz, CDCl3) d: 2.96—3.02 (2H, m),
preformed using E. Merck Kieselgel 60 (230—400 mesh). Medium-pressure 3.14—3.20 (1H, m), 3.87 (1H, dd, Jϭ9, 4 Hz), 4.04 (1H, dd, Jϭ9, 5.5 Hz),
column chromatography was performed using Lober größe B (E. Merck 4.41 (1H, br dd, Jϭ14.5, 2 Hz), 4.46 (1H, ddd, Jϭ14.5, 2, 1.5 Hz), 6.21 (1H,
310-25, Lichroprep Si60). Short column chromatography was undertaken on td, Jϭ2, 1.5 Hz), 7.19—7.38 (10H, m). NOE was observed between methyl-
a short glass filter using E. Merck Kieselgel 60 (230—400) under reduced ene-H (d 3.14-3.20) and olefinic-H (d 6.21) in NOESY spectroscopy. 13C-
pressure.
NMR (125 MHz, CDCl3) d: 37.16, 44.38, 70.53, 73.32, 113.97, 126.51,
Sulfanyl Radical Reaction of Diynes 6a—d (Table 1) To a boiling so- 126.55, 128.79, 129.06, 129.09, 129.12, 129.80, 135.65, 135.74, 145.55.
lution of the diynes 6a—d7) (1 mmol) in benzene (10 ml) was added a solu- HRMS m/z: 314.0809 (Calcd for C18H18OS2: 314.0799).
tion of thiophenol (1—2 mmol) and AIBN (0.5 mmol) in benzene (10—
3,4-Bis[(phenylthio)methyl]-2,5-dihydrofuran (8d): Yellow crystals. mp
20 ml) under nitrogen atmosphere by a syringe pump (3—5 ml/h) over 2 h. 78—79°C (Et2O). 1H-NMR (300 MHz, CDCl3) d: 3.27 (4H, br s), 4.65 (4H,
After being heated at reflux for a further 4 h, the reaction mixture was neu- br s), 7.17—7.34 (10H, m). HRMS m/z: 314.0792 (Calcd for C18H18OS2:
tralized with 5% KOH and extracted with CHCl3. The organic phase was 314.0799). Anal. Calcd for C18H18OS2: C, 68.75; H, 5.77. Found: C, 68.54;
washed with H2O, dried over MgSO4, and concentrated under reduced pres- H, 5.71.
sure. Purification of the residue by medium-pressure column chromatogra-
phy (hexane/AcOEt) afforded the cyclized compounds 7, 8, 9, and the
adduct 10 as shown in Table 1.
1H,3H-Thieno[3,4-c]furan (9d)11b): A yellow oil. 1H-NMR (200 MHz,
CDCl3) d: 4.83 (4H, br s), 6.84 (2H, s). HRMS m/z: 126.0137 (Calcd for
C6H6OS: 126.0139).
(E)-[[[2-[(Phenylthio)methyl]cyclopentylidene]methyl]thio]benzene [(E)-
Sulfanyl Radical Reaction of Diyne 6a Using V-70 To a solution of
7a]: A yellow oil. 1H-NMR (500 MHz, CDCl3) d: 1.57—1.71 (2H, m), diyne 6a (0.14 ml, 1.09 mmol) in benzene (5 ml) was added at room temper-

220
Vol. 49, No. 2
ature a solution of thiophenol (0.11 ml, 1.09 mmol) and V-70 (168 mg, 0.55 sure. Purification of the residue by medium-pressure column chromatogra-
mmol) in benzene (5 ml) under nitrogen atmosphere by a syringe pump (3 phy (hexane) afforded 13c (25.5 mg, 14%), 14c (46.6 mg, 25%), and 15c
ml/h) over 1.7 h. After being stirred at room temperature for another hour, (31.5 mg, 17%).
the reaction mixture was neutralized with 5% KOH and extracted with
(E/Z)-[[[2-[(Phenylthio)methyl]cyclohexylidene]methyl]thio]benzene
CHCl3. The organic phase was washed with H2O, dried over MgSO4, and (13a): 13a was formed as a 5 : 2 mixture of E/Z-isomers but a major product,
concentrated under reduced pressure. Purification of the residue by medium- (E)-13a was isolated by repeated purification by medium-pressure column
pressure column chromatography (hexane) afforded 10a (37 mg, 17%), 8a chromatography (hexane).
(17 mg, 5%) and (E)-7a (6.8 mg, 2%). The adduct 10a was obtained as a
1 : 1 mixture of E/Z-isomers.
(E)-[[[2-[(Phenylthio)methyl]cyclohexylidene]methyl]thio]benzene [(E)-
13a]: A yellow oil. 1H-NMR (500 MHz, CDCl3) d: 1.52—1.72 (4H), 1.85—
Sulfanyl Radical Reaction of Adduct 10a To a boiling solution of 10a 1.92 (2H) (each m), 2.33—2.45 (2H, m), 2.51 (1H, br quint., Jϭ6 Hz), 3.02
(25 mg, 0.12 mmol) in benzene (3 ml) under nitrogen atmosphere was added (1H, dd, Jϭ13, 7 Hz), 3.22 (1H, dd, Jϭ13, 7.5 Hz), 5.95 (1H, br s), 7.14—
a solution of thiophenol (0.03 ml, 0.12 mmol) and AIBN (10 mg, 0.06 mmol) 7.38 (10H, m). NOE was observed between methylene-H (d 3.02, 3.22) and
in benzene (3 ml) by a syringe pump (2 ml/h) over 1.5 h. After the reaction olefinic-H (d 5.95) in NOESY spectroscopy. IR (CHCl3) cmϪ1: 1350, 1170
mixture was heated at reflux for an hour more, the reaction mixture was neu- (NSO2). HRMS m/z: 326.1161 (Calcd for C20H22S2: 326.1163). (Z)-13a was
1
1
tralized with 5% KOH and extracted with CHCl3. The organic phase was characterized by H-NMR spectrum of a mixture of E/Z-isomers. H-NMR
washed with H2O, dried over MgSO4, and concentrated under reduced pres- (300 MHz, CDCl3) d: 3.10 (1H, dd, Jϭ13, 9 Hz), 3.15 (1H, dd, Jϭ13, 7 Hz),
sure. Purification of the residue by medium-pressure column chromatogra- 6.00 (1H, br s), 7.14—7.38 (10H, m).
phy (hexane) afforded 7a (21 mg, 55%) as a 2 : 1 mixture of E/Z-isomers.
Dimethyl (E)-3-[(Phenylthio)methyl]-4-[(phenylthio)methylidene]-1,1-
Attempted Isomerization of E-exo-Olefin E-7a to endo-Olefin 8a cyclohexanedicarboxylate [(E)-13b]: A yellow oil. 1H-NMR (500 MHz,
under Radical Conditions A solution of (E)-7a (33.3 mg, 0.11 mmol), CDCl3) d: 3.07 (1H, dd, Jϭ12.5, 8.5 Hz), 3.16 (1H, dd, Jϭ12.5, 7 Hz), 3.73,
thiophenol (0.01 ml, 0.11 mmol) and AIBN (9 mg, 0.06 mmol) in benzene 3.75 (each 3H, s), 6.14 (1H, br s), 7.14—7.39 (10H, m). NOE was
(5 ml) was refluxed under nitrogen atmosphere for 6 h. The reaction mixture observed between methylene-H (d 3.07, 3.16) and olefinic-H (d 6.14)
was neutralized with 5% KOH and extracted with CHCl3. The organic phase in NOESY spectroscopy. IR (CHCl3) cmϪ1: 1731 (COO). HRMS m/z:
was washed with H2O, dried over MgSO4, and concentrated under reduced 442.1288 (Calcd for C24H26O4S2: 442.1273).
pressure. Purification of the residue by medium-pressure column chromatog-
raphy (hexane) afforded (E)-7a (21.3 mg, 64%) and (Z)-7a (2.3 mg, 7%). 8a cyclohexanedicarboxylate [(E)-14b]: A yellow oil. 1H-NMR (500 MHz,
could not be detected. CDCl3) d: 1.70 (1H, dtd, Jϭ14, 7, 4.5 Hz), 2.01 (1H, td, Jϭ9, 4.5 Hz), 2.08
Dimethyl (E)-4-[(Phenylthio)methyl]-3-[(phenylthio)methylidene]-1,1-
Attempted Isomerization of endo-Olefin 8a to E-exo-Olefin E-7a (1H, ddd, Jϭ14, 9, 4.5 Hz), 2.20 (1H, td, Jϭ9, 4.5 Hz), 2.48 (1H, br dd, Jϭ7,
under the Radical Conditions According to the procedure given for at- 4.5 Hz), 2.95, 3.00 (2H, ABq, Jϭ14 Hz), 2.98 (1H, dd, Jϭ12.5, 7 Hz), 3.21
tempted isomerization of (E)-7a, reaction of 8a (31 mg, 0.1 mmol) with (1H, dd, Jϭ12.5, 7 Hz), 3.70, 3.72 (each 3H, s), 6.09 (1H, br s), 7.16—7.35
thiophenol (0.01 ml, 0.1 mmol) in the presence of AIBN (8.2 mg, 0.05 (10H, m). NOE was observed between methylene-H (d 2.98, 3.21) and
mmol) recovered 8a (23.3 mg, 75%). (E)-7a could not be detected.
Dimethyl 3-Butynyl-2-propynylpropanedioate (12b) To a stirred sus- HRMS m/z: 442.1275 (Calcd for C24H26O4S2: 442.1273).
pension of NaH (60% in oil) (263 mg, 6.57 mmol) in tetrahydrofuran (THF) Dimethyl 3,4-Bis[(phenylthio)methyl]-3-cyclohexene-1,1-dicarboxylate
olefinic-H (d 6.09) in NOESY spectroscopy. IR (CHCl3) cmϪ1: 1732 (COO).
1
(6 ml) was added dropwise a solution of dimethyl 3-butynylpropanedioate (15b): A yellow oil. H-NMR (300 MHz, CDCl3) d: 2.14 (2H, t, Jϭ6 Hz),
(1.10 g, 5.97 mmol)10a,b) in THF (3 ml) under nitrogen atmosphere at room 2.25 (2H, br t, Jϭ6 Hz), 2.72 (2H, s), 3.26, 3.28 (each 2H, br s), 3.72 (6H, s),
temperature. After being stirred at the same temperature for 20 min, a solu- 7.16—7.35 (10H, m). IR (CHCl3) cmϪ1: 1732 (COO). HRMS m/z: 442.1275
tion of propargyl chloride (0.46 ml, 5.97 mmol) in THF (3 ml) was added (Calcd for C24H26O4S2: 442.1273).
dropwise to the reaction mixture at the same temperature. The reaction mix-
Dimethyl (E/Z)-2-[4-(Phenylthio)-3-butenyl]-2-propynylpropanedioate
ture was stirred at reflux temperature for 17 h, then diluted with saturated (16b): 16b was obtained as a 3 : 2 mixture of E/Z-isomers. A yellow oil. 1H-
aqueous NaHCO3 and extracted with Et2O. The organic phase was washed NMR (300 MHz, CDCl3) d: 2.01 (1H, t, Jϭ2.5 Hz), 2.05—2.52 (4H, m),
with H2O, dried over MgSO4, and concentrated under reduced pressure. Pu- 2.85 (6/5H, d, Jϭ2.5 Hz), 2.90 (4/5H, d, Jϭ2.5 Hz), 3.74 and 3.75 (each 3H,
rification of the residue by flash column chromatography (Et2O/petroleum s), 5.72—5.93 (1H, m), 6.20 (3/5H, br d, Jϭ15 Hz), 6.22 (2/5H, br d, Jϭ9
1
ether 4 : 1) afforded 12b (1.23 g, 92%) as a yellow oil. H-NMR (300 MHz, Hz), 7.10—7.38 (5H, m). IR (CHCl3) cmϪ1: 3309 (CϵCH). HRMS m/z:
CDCl3) d: 1.98 and 2.05 (each 1H, br t, Jϭ2.5 Hz), 2.20—2.28 (2H, m), 332.1090 (Calcd for C18H20O4S: 332.1082).
2.33—2.41 (2H, m), 2.88 (2H, d, Jϭ2.5 Hz), 3.77 (6H, s). IR (CHCl3) cmϪ1
:
(E)-1-[(4-Methylphenyl)sulfonyl]-3-[(phenylthio)methyl]-4-[(phenylthio)-
3308 (CϵCH), 1740 (COO). HRMS m/z: 222.0908 (Calcd for C12H14O4: methylidene]piperidine [(E)-13c]: A yellow oil. 1H-NMR (300 MHz, CDCl3)
222.0892).
d: 2.97 (3H, s), 2.64—2.79 (2H, m), 6.02 (1H, br s), 7.11—7.82 (14H, m).
N-(3-Butynyl)-4-methyl-N-(2-propynyl)benzenesulfonamide (12c) To IR (CHCl3) cmϪ1: 1353, 1161 (NSO2). HRMS m/z: 481.1213 (Calcd for
solution of the N-(2-propynyl)-p-toluenesulfonamide (1.76 g, 8.4 C26H27NO2S3: 481.1204).
a
mmol)12c,d) in THF (8 ml) was added 3-butyn-1-ol (1 ml, 12.5 mmol) and
(Z)-1-[(4-Methylphenyl)sulfonyl]-4-[(phenylthio)methyl]-3-[(phenylthio)-
triphenylphosphine (2.2 g, 8.4 mmol) under argon atmosphere at room tem- methylidene]piperidine [(Z)-14c]: A yellow oil. 1H-NMR (500 MHz, CDCl3)
perature. Then, diethyl azodicarboxylate (DEAD) (40% in toluene) was added d: 1.67 (1H, dtd, Jϭ12.5, 7.5, 3.5 Hz), 2.00 (1H, br ddd, Jϭ12.5, 8, 4 Hz),
dropwise. After being stirred for 2 h at room temperature, the solvent was 2.37—2.46 (1H, m), 2.42 (3H, s), 2.88 (1H, dd, Jϭ13, 8 Hz), 3.11 (1H, dd,
removed under reduced pressure and the residue was purified by flash col- Jϭ13, 6.5 Hz), 3.12 (1H, ddd, Jϭ12, 7.5, 4 Hz), 3.33 (1H, ddd, Jϭ12, 8, 3.5
umn chromatography (hexane/AcOEt 2 : 1) to afford 12c (1.86 g, 85%) as a Hz), 3.74 (1H, d, Jϭ13.5 Hz), 3.97 (1H, d, Jϭ13.5 Hz), 6.13 (1H, br s),
yellow oil. 1H-NMR (300 MHz, CDCl3) d: 2.01, 2.08 (each 1H, t, 7.15—7.35 (12H, m), 7.69 (2H, d, Jϭ8 Hz). NOE was observed between
Jϭ2.5 Hz), 2.43 (3H, s), 2.53 (2H, td, Jϭ7, 2.5 Hz), 3.34 (2H, t, Jϭ7 Hz), methylene-H (d 2.88, 3.11) and olefinic-H (d 6.13) in NOESY spectroscopy.
4.21 (2H, d, Jϭ2.5 Hz), 7.30, 7.74 (each 2H, br d, Jϭ8 Hz). IR (CHCl3) IR (CHCl3) cmϪ1: 1351, 1162 (NSO2). HRMS m/z: 481.1214 (Calcd for
cmϪ1: 3308 (CϵCH), 1350, 1161 (NSO2). HRMS m/z: 261.0828 (Calcd for C26H27NO2S3: 481.1204).
C14H15NO2S: 261.0823).
1,2,5,6-Tetrahydro-1-[(4-methylphenyl)sulfonyl]-3,4-bis[(phenylthio)-
Radical Cyclization of Diynes 12a—c (General Procedure) (Entries 1 methyl]pyridine (15c): A yellow oil. 1H-NMR (300 MHz, CDCl3) d: 2.32
and 2 in Table 2 and Chart 4) According to the procedure given for radi- (2H, br t, Jϭ5.5 Hz), 2.46 (3H, s), 3.16 (2H, t, Jϭ5.5 Hz), 3.19, 3.20 (each
cal reaction of 6a—d, the reaction of 12a—c (1 mmol) with thiophenol 2H, br s), 3.64 (2H, s), 7.11—7.76 (14H, m). IR (CHCl3) cmϪ1: 1343, 1162
(2 mmol) in the presence of AIBN (0.5 mmol) gave 13—15, and 16 as (NSO2). HRMS m/z: 481.1214 (Calcd for C26H27NO2S3: 481.1204).
shown in Table 2 and Chart 4.
(E/Z)-4-Methyl-N-[(4-phenylthio)-3-butenyl]-N-(2-propynyl)benzenesul-
Procedure Involving Addition of PhSH to a Mixture of 12c and PhSH fonamide (16c): 16c was obtained as a 2 : 3 mixture of E/Z-isomers. A yel-
(Entry 3 in Table 2) To a boiling solution of 12c (100 mg, 0.38 mmol) and low oil. 1H-NMR (300 MHz, CDCl3) d: 2.04 (3/5H, t, Jϭ2.5 Hz), 2.07
thiophenol (0.04 ml, 0.38 mmol) in benzene (5 ml) under nitrogen atmos- (2/5H, t, Jϭ2.5 Hz), 2.43 (3H, s), 2.05—2.59 (2H, m), 3.30 (4/5H, br t, Jϭ7
phere was added a solution of thiophenol (0.04 ml, 0.38 mmol) and AIBN Hz), 3.40 (6/5H, br t, Jϭ7 Hz), 4.15 (4/5H, d, Jϭ2.5 Hz), 4.22 (6/5H, d,
(27.3 mg, 0.17 mmol) in benzene (5 ml) by a syringe pump (2 ml/h) over Jϭ2.5 Hz), 5.77—5.88 (1H, m), 6.26 (2/5H, dt, Jϭ14.5, 1 Hz), 6.32 (3/5H,
2.5 h. After being heated at reflux for a further 4 h, the reaction mixture was dt, Jϭ9, 1 Hz), 7.12—7.49 (7H), 7.70—7.78 (2H) (each m). IR (CHCl3)
neutralized with 5% KOH and extracted with CHCl3. The organic phase was cmϪ1: 3307 (CϵCH), 1349, 1161 (NSO2). HRMS m/z: 371.1022 (Calcd for
washed with H2O, dried over MgSO4, and concentrated under reduced pres- C20H21NO2S2: 371.1014).

February 2001
221
Attempted Isomerization of 14c to 15c under Radical Conditions the reaction mixture. After being stirred at the same temperature for 5 h, the
According to the procedure given for attempted isomerization of (E)-7a, re- solvent was removed under reduced pressure. To a solution of the residue in
action of (Z)-14c (29.8 mg, 0.06 mmol) with thiophenol (0.006 ml, 0.06 MeOH (2 ml) was added K2CO3 (276 mg, 2 mmol) under nitrogen atmos-
mmol) in the presence of AIBN (3.1 mg, 0.03 mmol) recovered the (Z)-14c
(22.1 mg, 74%). 15c could not be detected.
phere at room temperature. After being stirred at the same temperature for
30 min, the reaction mixture was diluted with H2O and was extracted with
Attempted Isomerization of 15c to 14c under Radical Conditions CHCl3. The organic phase was washed with H2O, dried over MgSO4, and
According to the procedure given for attempted isomerization of (E)-7a, re- concentrated under reduced pressure. Purification of the residue by medium-
action of 15c (78.6 mg, 0.16 mmol) with thiophenol (0.02 ml, 0.16 mmol) in
pressure column chromatography (hexane/AcOEt 3 : 1) afforded 29 (40.7
the presence of AIBN (8.3 mg, 0.08 mmol) recovered 15c (22.1 mg, 74%). mg, 93%) as a yellow oil which was identical with the sample prepared from
(Z)-14c could not be detected.
1,9-Bis(phenylthio)-1,8-nonadiene (18) According to the procedure
given for sulfanyl radical cyclization of 6a—d, reaction of 17 (100 mg, 0.83
27.
(3S,5R)-3-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-5-[(phenylmethoxy)-
methoxy]-1,7-octadiyne (31a) To a solution of 29 (27 mg, 0.11 mmol) and
mmol) with thiophenol (0.17 ml, 1.66 mmol) in the presence of AIBN (27.3 2,6-lutidine (0.025 ml, 0.21 mmol) in CH2Cl2 (2 ml) was added TBSOTf
mg, 0.17 mmol) gave exclusively 18 (278.7 mg, 99%) as a mixture of E/Z- (0.03 ml, 0.13 mmol) under nitrogen atmosphere at 0 °C. After being stirred
1
isomers. A yellow oil. H-NMR (300 MHz, CDCl3) d: 1.32—1.61 (6H, m), at the same temperature for 1 h, the reaction mixture was diluted with H2O
2.02—2.31 (4H, m), 5.76—6.03, 6.09—6.22 (each 2H, m), 7.12—7.36
(10H, m). HRMS m/z: 340.1318 (Calcd for C21H24S2: 340.1319).
and was extracted with CHCl3. The organic phase was washed with H2O,
dried over MgSO4, and concentrated under reduced pressure. Purification of
(3S,5R)- and (3R,5R)-1-(Trimethylsilyl)-5-[(phenylmethoxy)methoxy]- the residue by medium-pressure column chromatography (hexane/AcOEt
1,7-octadiyn-3-ols (27, 28) To a stirred solution of trimethylsilylacetylide 20 : 1) afforded 31a (38.9 mg, quant.) as a pale yellow oil. 1H-NMR (500
(1 ml, 7.07 mmol) in absolute THF (15 ml) was added n-BuLi (1.57 M in
MHz, CDCl3) d: 0.11 and 0.16 (each 3H, s), 0.90 (9H, s), 2.04 (1H, t,
hexane) (4.5 ml, 7.07 mmol) under nitrogen atmosphere at Ϫ40 °C. After Jϭ2.5 Hz), 2.01—2.10 (2H, m), 2.41 (1H, d, Jϭ2 Hz), 2.50 (1H, ddd,
being stirred at the same temperature for 15 min, a solution of 2615) Jϭ16.5, 4, 2.5 Hz), 2.66 (1H, ddd, Jϭ16.5, 6, 2.5 Hz), 3.90—3.95 (1H, m),
(547.3 mg, 2.36 mmol) in THF (15 ml) was added. The reaction mixture was 4.54—4.57 (1H, m), 4.58, 4.76 (2H, ABq, Jϭ12 Hz), 4.83, 4.86 (2H, ABq,
stirred at the same temperature for 30 min, diluted with saturated aqueous Jϭ7 Hz), 7.27—7.37 (5H, m). 13C-NMR (125 MHz, CDCl3) d: Ϫ1.97,
NH4Cl and extracted with CHCl3. The organic phase was washed with H2O,
Ϫ4.26, 18.13, 25.36, 25.81, 43.51, 59.28, 69.86, 70.50, 72.64, 73.46, 94.91,
dried over MgSO4, and concentrated under reduced pressure. Purification of 127.74, 127.95, 128.44, 137.70. IR (CHCl3) cmϪ1: 3307 (CϵCH). HRMS
the residue by flash column chromatography (hexane/AcOEt 3 : 1) afforded m/z: 372.2122 (Calcd for C22H32O3Si: 372.2119). [a]D20 Ϫ72.9° (cϭ0.95,
27 (239 mg, 31%) and 28 (478 mg, 61%).
CHCl3).
(3R,5R)-3-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-5-[(phenylmethoxy)-
27: A yellow oil. 1H-NMR (200 MHz, CDCl3) d: 0.17 (9H, s), 2.05 (1H, t,
Jϭ2.5 Hz), 1.93—2.20 (2H, m), 2.42—2.68 (2H, m), 2.88 (1H, dd, Jϭ6.5, methoxy]-1,7-octadiyne (32) According to the procedure given for the
0.5 Hz), 4.08—4.21 (1H, m), 4.56—4.68 (1H, m), 4.66, 4.69 (2H, ABq, silylation of 29, 30 (71.5 mg, 0.28 mmol) was treated with TBSOTf (0.08 ml,
Jϭ12 Hz), 4.87, 4.88 (2H, ABq, Jϭ7 Hz), 7.24—7.48 (5H, m). 13C-NMR 0.33 mmol) to afford 32 (103.1 mg, quant.) as a pale yellow oil. 1H-NMR
(50 MHz, CDCl3) d: Ϫ0.27, 24.68, 41.39, 59.69, 69.94, 70.59, 73.44, 80.12,
(500 MHz, CDCl3) d: 0.12, 0.15 (each 3H, s), 0.90 (9H, s), 2.03 (1H, t,
94.30, 106.14, 127.80, 128.38, 137.21. IR (CHCl3) cmϪ1: 3493 (OH), 3308 Jϭ2.5 Hz), 2.03 (1H, ddd, Jϭ13.5, 8, 4.5 Hz), 2.11 (1H, ddd, Jϭ13.5, 8, 6
(CϵCH). HRMS m/z: 330.1649 (Calcd for C19H26O3Si: 330.1651). [a]D22
Ϫ33.9° (cϭ1.23, CHCl3).
Hz), 2.42 (1H, dd, Jϭ2, 0.5 Hz), 2.50 (1H, ddd, Jϭ17, 4.5, 2.5 Hz), 2.66
(1H, ddd, Jϭ17, 6, 2.5 Hz), 4.03—4.09 (1H, m), 4.60 (1H, ddd, Jϭ8, 6, 2.5
28: A yellow oil. 1H-NMR (200 MHz, CDCl3) d: 0.17 (9H, s), 2.05 (1H, t, Hz), 4.64, 4.69 (2H, ABq, Jϭ12 Hz), 4.83, 4.87 (2H, ABq, Jϭ7.5 Hz),
Jϭ2.5 Hz), 1.97—2.27 (2H, m), 2.44 (1H, dd, Jϭ4.5, 2 Hz), 2.46—2.70 7.27—7.38 (5H, m). 13C-NMR (125 MHz, CDCl3) d: Ϫ5.06, Ϫ4.55, 18.17,
(2H, m), 3.95—4.08 (1H, m), 4.55—4.64 (1H, m), 4.64, 4.67 (2H, ABq,
24.80, 25.76, 42.81, 60.38, 69.80, 70.45, 72.91, 73.18, 94.09, 127.71,
Jϭ12 Hz), 4.83, 4.86 (2H, ABq, Jϭ7 Hz), 7.22—7.43 (5H, m). 13C-NMR 127.88, 128.42, 137.76. IR (CHCl3) cmϪ1: 3307 (CϵCH). HRMS m/z:
(50 MHz, CDCl3) d: Ϫ0.30, 24.59, 41.79, 60.75, 69.82, 70.58, 73.97, 80.16,
372.2110 (Calcd for C22H32O3Si: 372.2119). [a]D21 Ϫ86.1° (cϭ0.55, CHCl3).
(3S,5R)-1,7-Octadiyn-3,5-Diol (33) To a solution of 29 (546 mg, 2.12
89.87, 93.90, 105.86, 127.68, 127.79, 128.33, 137.37. IR (CHCl3) cmϪ1
:
3501 (OH), 3308 (CϵCH). HRMS m/z: 330.1657 (Calcd for C19H26O3Si: mmol) and thiophenol (0.44 ml, 4.34 mmol) in CH2Cl2 (5 ml) was added
330.1651). [a]D22 Ϫ32.1° (cϭ0.65, CHCl3).
BF3·OEt2 (1.1 ml, 8.48 mmol) under nitrogen atmosphere at 0 °C. After
(3S,5R)-5-[(Phenylmethoxy)methoxy]-1,7-octadiyn-3-ol (29) To a being stirred at the same temperature for 17 h, the solvent was removed
stirred solution of 27 (202.2 mg, 0.61 mmol) in MeOH (6.1 ml) was added under reduced pressure and the residue was purified by medium-pressure
K2CO3 (305 mg, 2.2 mmol) under a nitrogen atmosphere at room tempera- column chromatography (hexane→hexane/AcOEt 2 : 1) to afford 33 (243
ture. After being stirred at the same temperature for 30 min, the reaction mg, 83%) as a yellow oil. 1H-NMR (300 MHz, CDCl3) d: 1.87 (2H, m), 2.09
mixture was diluted with H2O and extracted with CHCl3. The organic phase (1H, t, Jϭ2.5 Hz), 2.36—2.51 (2H, m), 2.52 (1H, d, Jϭ2 Hz), 2.60 (1H, br d,
was washed with H2O, dried over MgSO4, and concentrated under reduced Jϭ3 Hz), 3.04 (1H, br d, Jϭ5 Hz), 4.27—4.39 (1H, m), 4.65—4.74 (1H, m).
pressure. Purification of the residue by medium-pressure column chromatog- 13C-NMR (50 MHz, CDCl3) d: 27.30, 41.44, 60.18, 67.33, 71.10, 73.33,
raphy (hexane/AcOEt 3 : 1) afforded 29 (158.1 mg, quant.) as a yellow oil. 80.04, 83.97. IR (CHCl3) cmϪ1: 3452 (OH), 3306 (CϵCH). HRMS m/z:
1H-NMR (200 MHz, CDCl3) d: 2.04 (1H, t, Jϭ2.5 Hz), 1.95—2.22 (2H, m), 138.0671 (Calcd for C8H10O2: 138.0681). [a]D22 Ϫ88.7° (cϭ0.62, CHCl3).
2.47 (1H, d, Jϭ2 Hz), 2.42—2.67 (2H, m), 3.00 (1H, d, Jϭ7 Hz), 4.12—
(3S,5R)-3,5-Bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-1,7-octadiyne
4.25 (1H, m), 4.57—4.69 (1H, m), 4.67, 4.68 (2H, ABq, Jϭ12.5 Hz), 4.87, (31b) According to the procedure given for the silylation of 30, 33 (243
4.90 (2H, ABq, Jϭ7 Hz), 7.25—7.42 (m, 5H). 13C-NMR (50 MHz, CDCl3) mg, 1.76 mmol) was treated with TBSOTf (1 ml, 4.4 mmol) to afford 31b
1
d: 24.53, 41.18, 59.21, 70.04, 72.90, 73.23, 79.96, 84.33, 94.21, 127.80, (645 mg, quant.) as a pale yellow oil. H-NMR (200 MHz, CDCl3) d: 0.09,
128.39, 137.18. IR (CHCl3) cmϪ1: 3488 (OH), 3307 (CϵCH). HRMS m/z: 0.10, 0.15, 0.17 (each 3H, s), 0.89, 0.90 (each 9H, s), 1.81—2.14 (2H, m),
258.1256 (Calcd for C16H18O3: 258.1256). [a]D23 Ϫ55.7° (cϭ0.93, CHCl3).
1.99 (1H, t, Jϭ2.5 Hz), 2.38 (2H, dd, Jϭ6, 2.5 Hz), 2.42 (1H, d, Jϭ2 Hz),
(3R,5R)-5-[(Phenylmethoxy)methoxy]-1,7-octadiyn-3-ol (30) Accord- 3.94—4.08 (1H, m), 4.52 (1H, ddd, Jϭ8.5, 5, 2 Hz). 13C-NMR (50 MHz,
ing to the procedure given for the desilylation of 27, 28 (34.1 mg, 0.1 mmol) CDCl3) d: 17.93, 18.05, 25.73, 27.61, 46.07, 59.29, 67.27, 70.24, 72.75,
was treated with K2CO3 (50 mg, 0.36 mmol) to afford 30 (26.7 mg, quant.) as 80.89, 85.50. IR (CHCl3) cmϪ1: 3307 (CϵCH). HRMS m/z: 366.2419
a yellow oil. 1H-NMR (200 MHz, CDCl3) d: 2.05 (1H, t, Jϭ2.5 Hz), 1.98— (Calcd for C20H38O2Si2: 366.2410). [a]D20 Ϫ78.0° (cϭ1.16, CHCl3).
2.29 (2H, m), 2.47 (1H, d, Jϭ4.5 Hz), 2.50 (1H, d, Jϭ2.5 Hz), 2.44—2.69
Sulfanyl Radical Addition–Cyclization Reaction of 31a To a boiling
solution of the diyne 31a (43.2 mg, 0.12 mmol) in benzene (5 ml) under ni-
(2H, m), 3.98—4.12 (1H, m), 4.57—4.66 (1H, m), 4.65, 4.67 (2H, ABq,
Jϭ12 Hz), 4.84, 4.88 (2H, ABq, Jϭ7 Hz), 7.26—7.43 (5H, m). 13C-NMR trogen atmosphere was added a solution of thiophenol (0.016 ml, 0.15 mmol)
(50 MHz, CDCl3) d: 24.47, 41.70, 60.05, 69.83, 70.67, 73.35, 73.58, 80.04,
and AIBN (9.53 mg, 0.06 mmol) in benzene (5 ml) by a syringe pump
84.14, 93.75, 127.68, 127.76, 128.30, 137.30. IR (CHCl3) cmϪ1: 3490 (OH), (2 ml/h) over 2.5 h. After being heated at reflux for a further 3.5 h, the reac-
3307 (CϵCH). HRMS m/z: 258.1266 (Calcd for C16H18O3: 258.1256). [a]D22
Ϫ90.4° (cϭ0.74, CHCl3).
Mitsunobu Reaction of 28 To a stirred solution of 28 (55.1 mg, 0.17
tion mixture was neutralized with 5% KOH and extracted with CHCl3. The
organic phase was washed with H2O, dried over MgSO4, and concentrated
under reduced pressure. The repeated purification of the residue by medium-
mmol) in benzene (4 ml) was added benzoic acid (42.9 mg, 0.35 mmol) and pressure column chromatography (hexane→hexane/AcOEt 30 : 1) afforded
PPh3 (88.9 mg, 0.35 mmol) under nitrogen atmosphere at room temperature. 34a (13.1 mg, 19%), 35a (10.3 mg, 15%), and 36a (2 mg, 3%).
Then, DEAD (40% in toluene) (148 mg, 0.34 mmol) was added dropwise to
[2R-(1E,2a,3a,5b)]-[[[3-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-5-

222
Vol. 49, No. 2
[(phenylmethoxy)methoxy]-2-[(phenylthio)methyl]-cyclohexylidene]- residue by short column chromatography (hexane→hexane/AcOEt 5 : 1→
1
methyl]-thio]benzene (34a): A pale yellow oil. H-NMR (500 MHz, CDCl3) AcOEt) afforded 42 (418 mg, 26%) and 45 (167 mg, 10%).
1
d: Ϫ0.07, 0.03 (each 3H, s), 0.87 (9H, s), 1.81 (1H, ddd, Jϭ13, 9.5, 3 Hz),
1.97 (1H, br dt, Jϭ13, 4.5 Hz), 2.24 (1H, br dd, Jϭ13.5, 9.5 Hz), 2.45 (1H,
br td, Jϭ7, 4.5 Hz), 3.02 (1H, br dd, Jϭ13.5, 4.5 Hz), 3.04 (1H, dd, Jϭ13,
42: A colorless oil. H-NMR (500 MHz, CDCl3) d: 1.65—1.72 (1H, m),
1.72—1.87 (3H, m), 2.28—2.38 (2H, m), 2.64—2.70 (1H, m), 2.90—2.96
(1H, m), 4.78 (1H, dd, Jϭ2.5, 1 Hz), 4.92 (1H, br d, Jϭ1 Hz), 6.21 (1H, s),
7 Hz), 3.16 (1H, dd, Jϭ13, 7 Hz), 4.03 (1H, tt, Jϭ9.5, 4.5 Hz), 4.12 (1H, 7.43—7.54 (3H), 7.57—7.62 (2H) (each m). NOE were observed between
br td, Jϭ4.5, 3 Hz), 4.61 (2H, s), 4.77, 4.81 (2H, ABq, Jϭ7 Hz), 6.07 (1H, 4-Hax (d 1.65—1.72) and 6-Hax (d 2.64—2.70), and between olefinic-H (d
s), 7.15—7.35 (15H, m). NOE was observed between methylene-H (d 3.04,
4.92) adjacent to 2-position and olefinic-H (d 6.21) adjacent to 1-position in
3.16) and olefinic-H (d 6.07) in NOESY spectroscopy. 13C-NMR (125 MHz, NOESY spectroscopy. 13C-NMR (125 MHz, CDCl3) d: 26.07, 26.26, 30.92,
CDCl3) d: Ϫ4.83, Ϫ4.77, 17.98, 25.74, 33.73, 34.65, 37.07, 51.61, 69.40,
34.93, 111.70, 124.07, 129.26, 129.31, 130.46, 144.98, 147.67, 153.95. IR
70.67, 71.93, 92.90, 119.44, 125.77, 126.11, 127.61, 127.87, 128.18, 128.38, (CHCl3) cmϪ1: 1028 (SO). HRMS m/z: 232.0900 (Calcd for C14H16OS:
128.88, 128.99, 129.22, 136.27, 136.92, 137.88, 140.99. HRMS m/z: 232.0922).
1
592.2517 (Calcd for C34H44O3S2Si: 592.2501).
45: A colorless oil. H-NMR (500 MHz, CDCl3) d: 1.68—1.84 (4H, m),
2.28—2.51 (4H, m), 5.11 (1H, br s), 5.20 (1H, dd, Jϭ3, 1.5 Hz), 6.10 (1H,
s), 7.45—7.56 (3H), 7.65—7.68 (2H) (each m). NOE was observed between
olefinic-H (d 5.20) and ArH (d 7.45—7.56) in NOESY spectroscopy. 13C-
NMR (125 MHz, CDCl3) d: 27.04, 27.10, 36.36, 37.39, 48.09, 115.25,
[2S-(2a,4b,6x)]-[[[2-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-4-[(phenyl-
methoxy)methoxy]-6-[(phenylthio)methyl]cyclohexylidene]methyl]-
thio]benzene (35a): A pale yellow oil. 1H-NMR (500 MHz, CDCl3) d: 0.08,
0.14 (each 3H, s), 0.83 (9H, s), 2.26 (1H, br dd, Jϭ12.5, 3 Hz), 2.50 (1H,
br dd, Jϭ12.5, 3 Hz), 2.88—2.93 (2H, m), 3.23 (1H, br dd, Jϭ15, 4 Hz), 124.63, 129.15, 129.26, 129.66, 130.57, 144.35. IR (CHCl3) cmϪ1: 1020
3.26 (1H, br dd, Jϭ13, 7.5 Hz), 3.38 (1H, br dd, Jϭ13, 7.5 Hz), 4.18—4.26
(1H, m), 4.61, 4.62 (2H, ABq, Jϭ11.5 Hz), 4.81, 4.84 (2H, ABq, Jϭ7 Hz),
(SO). HRMS m/z: 232.0909 (Calcd for C14H16OS: 232.0922).
Introduction of Alkoxycarbonyl Group to a-Position in 42 (Table 4).
5.10 (1H, br t, Jϭ3 Hz), 5.98 (1H, br s), 7.12—7.38 (15H, m). 13C-NMR [Table 4, Entry 5] To a solution of 42 (99 mg, 0.43 mmol) in THF (4.3 ml)
(125 MHz, CDCl3) d: Ϫ5.07, Ϫ4.65, 17.91, 25.76, 30.06, 36.59, 40.27,
41.68, 67.63, 69.37, 71.80, 93.22, 114.92, 126.14, 127.86, 128.43, 128.86,
was added MeLi (1.1 M solution in Et2O) (0.58 ml, 0.64 mmol) under nitro-
gen atmosphere at Ϫ100 °C. After being stirred at the same temperature for
128.91, 129.04, 129.46, 136.34, 136.65, 137.94, 145.60. HRMS m/z: 15 min, ClCOOMe (0.08 ml, 0.85 mmol) was added to the reaction mixture.
592.2513 (Calcd for C34H44O3S2Si: 592.2501). After further stirring at the same temperature for 15 min, the reaction mix-
[3S-(3a,5b)]-3-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-5-[(phenyl- ture was diluted with saturated aqueous NH4Cl and extracted with CHCl3.
methoxy)methoxy]-1,2-bis[(phenylthio)methyl]-1-cyclohexene (36a): A pale The organic phase was washed with H2O, dried over MgSO4, and concen-
1
yellow oil. H-NMR (500 MHz, CDCl3) d: 0.02, 0.08 (each 3H), 0.87 (9H, trated under reduced pressure. Purification of the residue by flash column
s), 1.68 (1H, ddd, Jϭ13, 11, 4 Hz), 2.00 (1H, br dd, Jϭ12, 9 Hz), 2.06 (1H, chromatography (hexane/AcOEt 2 : 1) afforded 43a (44 mg, 36%), 44a (22
br dtd, Jϭ13, 4, 1.5 Hz), 2.74 (1H, br dd, Jϭ12, 4 Hz), 2.95 (1H, d, mg, 18%) and 45 (3 mg, 3%).
Jϭ12.5 Hz), 3.15 (1H, d, Jϭ12.5 Hz), 3.39 (1H, d, Jϭ12.5 Hz), 3.43 (1H, d,
Methyl (E)-(2-Methylenecyclohexylidene)(phenylsulfinyl)acetate (43a):
Jϭ12.5 Hz), 4.06—4.12 (1H, m), 4.52 (1H, br t, Jϭ4 Hz), 4.63 (2H, s), 4.82, A pale yellow oil. 1H-NMR (200 MHz, CDCl3) d: 1.67—1.98 (4H, m), 2.40
4.83 (2H, ABq, Jϭ7 Hz), 7.20—7.38 (15H, m). 13C-NMR (125 MHz, (2H, br t, Jϭ6 Hz), 2.71—2.87 (1H, m), 2.88—3.06 (1H, m), 3.48 (3H, s),
CDCl3) d: Ϫ4.76, Ϫ4.42, 17.96, 25.81, 33.31, 35.18, 37.49, 38.49, 66.94,
69.33, 69.51, 93.09, 126.74, 127.15, 127.62, 127.85, 128.40, 128.76, 128.84,
131.15, 131.48, 132.13, 135.49, 136.18, 137.90, 141.05. HRMS m/z:
592.2508 (Calcd for C34H44O3S2Si: 592.2501).
4.85, 4.87 (each 1H, br s), 7.44—7.64 (5H, m). IR (CHCl3) cmϪ1: 1724
(COO). HRMS m/z: 290.0100 (Calcd for C16H18O3S: 290.0075).
Methyl (Z)-(2-Methylenecyclohexylidene)(phenylsulfinyl)acetate (44a): A
1
yellow oil. H-NMR (500 MHz, CDCl3) d: 1.71—1.81 (2H, m), 1.81—1.87
Sulfanyl Radical Addition–Cyclization Reaction of 31b According to (1H, m), 1.87—1.95 (1H, m), 2.28—2.43 (2H, m), 2.53—2.59 (1H, m),
the procedure given for the radical reaction of 31a, reaction of 31b (197 mg, 2.67—2.73 (1H, m), 3.43 (3H, s), 5.30 (1H, br d, Jϭ1 Hz), 5.34 (1H, br s),
0.54 mmol) with thiophenol (0.11 ml, 1.08 mmol) in the presence of AIBN 7.43—7.53 (3H), 7.58—7.60 (2H) (each m). NOE was observed between
(44 mg, 0.27 mmol) afforded 34b (120 mg, 38%) and the mixture of 35b and olefinic-H (d 5.34) and Ar-H (d 7.43—7.53) in NOESY spectroscopy.
36b (35b : 36bϭ1 : 1) (89 mg, 28%).
HRMS m/z: 290.0086 (Calcd for C16H18O3S: 290.0075).
[2R-(1E,2a,3a,5b)]-[[[3,5-Bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-2-
[Table 4, Entry 4] To a solution of 42 (31 mg, 0.13 mmol) in THF (2
ml) was added tert-BuLi (1.54 M solution in n-pentane) (0.12 ml, 0.19 mmol)
[(phenylthio)methyl]cyclohexylidene]methyl]thio]benzene (34b): A yellow
1
oil. H-NMR (500 MHz, CDCl3) d: 0.04, 0.05 (each 6H, s), 0.08 (18H, s), under nitrogen atmosphere at Ϫ100 °C. After being stirred at the same tem-
1.74 (1H, ddd, Jϭ13, 10, 3 Hz), 1.84 (1H, dt, Jϭ13, 3 Hz), 2.12 (1H, ddd, perature for 30 min, ClCOOMe (0.02 ml, 0.26 mmol) was added. The reac-
Jϭ13.5, 10, 1 Hz), 2.46 (1H, td, Jϭ7, 3 Hz), 2.92 (1H, ddd, Jϭ13.5, 4.5,
1 Hz), 3.04 (1H, dd, Jϭ13, 7 Hz), 3.12 (1H, dd, Jϭ13, 7 Hz), 4.02 (1H, tdd,
tion mixture was stirred at the same temperature for 15 min, diluted with sat-
urated aqueous NH4Cl, and extracted with CHCl3. The organic phase was
Jϭ10, 4.5, 3 Hz), 4.12 (1H, dd, Jϭ7, 3 Hz), 6.02 (1H, s), 7.11—7.34 (10H, washed with H2O, dried over MgSO4, and concentrated under reduced pres-
m). NOE was observed between methylene-H (d 3.04, 3.12) and olefinic-H sure. Purification of the residue by flash column chromatography (hexane/
(d 6.02) in NOESY spectroscopy. 13C-NMR (125 MHz, CDCl3) d: Ϫ4.88,
AcOEt 2 : 1) afforded methyl (E)-(2-methylenecyclohexylidene)[(1,1-di-
25.70, 25.88, 29.70, 34.72, 36.76, 51.48, 57.26, 70.78, 118.73, 125.59, methylethyl)sulfinyl]acetate (46) as a pale yellow oil. (5.6 mg, 16%). 1H-
126.04, 127.65, 128.03, 128.10, 128.81, 128.95, 129.17, 136.30, 137.21, NMR (200 MHz, CDCl3) d: 1.34 (9H, s), 1.52—1.88 (4H, m), 2.28—2.44
142.45. HRMS m/z: 586.2816 (Calcd for C32H50O2S2Si2: 586.2791). [a]D20
Ϫ46.7° (cϭ2.26, CHCl3).
(3H, m), 2.72—2.86 (1H, m), 3.70 (3H, s), 4.88, 4.90 (each 1H, br s). IR
(CHCl3) cmϪ1: 1727 (COO), 1037 (SO). HRMS m/z: 270.1260 (Calcd for
[2S-(2a,4b,6x)]-[[[2,4-Bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-6- C14H22O3S: 270.1290).
[(phenylthio)methyl]cyclohexylidene]methyl]thio]benzene (35b) and [3S-
(3a,5b)]-3,5-Bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-1,2-bis[(phenyl-
[Table 4, Entry 6] To a solution of 42 (215 mg, 0.93 mmol) in THF
(9 ml) was added MeLi (1.1 M solution in Et2O) (1.22 ml, 1.4 mmol) under
thio)methyl]-1-cyclohexene (36b): 1H-NMR (300 MHz) d: 2.52 (1/2H, m nitrogen atmosphere at Ϫ100 °C. After being stirred at the same temperature
(35b)), 2.58 (1/2H, m (35b)), 2.88 (1/2H, br d, Jϭ12 Hz (36b)), 3.15 (1/2H, for 15 min, NCCOOEt (0.18 ml, 1.86 mmol) was added. The reaction mix-
br d, Jϭ12 Hz (36b)), 3.37 (1/2H, br d, Jϭ12 Hz, (36b)), 3.41 (1/2H, br d, ture was further stirred at the same temperature for 15 min, diluted with sat-
Jϭ12 Hz (36b)), 4.02—4.12 (1/2H, m (36b)), 4.18—4.28 (1/2H, m (35b)),
4.51 (1/2H, br t, Jϭ3 Hz (36b)), 5.06 (1/2H, br t, Jϭ3 Hz (35b)), 5.96 (1/2H, washed with H2O, dried over MgSO4, and concentrated under reduced pres-
br s, (35b)). sure. Purification of the residue by flash column chromatography (hexane/
(E)- and (Z)-[[(2-Methylenecyclohexylidene)methyl]sulfinyl]benzenes AcOEt 2 : 1) afforded 43b (139 mg, 49%) and 44b (36 mg, 13%).
(42, 45) To a stirred solution of 13a (E : Zϭ5 : 2) (2.3 g, 7 mmol) in Ethyl (E)-(2-Methylenecyclohexylidene)(phenylsulfinyl)acetate (43b): A
urated aqueous NH4Cl, and extracted with CHCl3. The organic phase was
CH2Cl2 (70 ml) was added dropwise mCPBA (70%, assay) (3.47 g, 14 yellow oil. 1H-NMR (500 MHz, CDCl3) d: 1.04 (3H, t, Jϭ7 Hz), 1.69—1.77
mmol) in CH2Cl2 (140 ml) under nitrogen atmosphere at 0 °C. After being (1H, m), 1.77—1.97 (3H, m), 2.36—2.46 (2H, m), 2.78 (1H, ddd, Jϭ13.5,
stirred at the same temperature for 30 min, the reaction mixture was neutral- 9, 4.5 Hz), 2.98 (1H, br ddd, Jϭ13.5, 7, 4 Hz), 3.85—4.05 (2H, m), 4.86
ized with saturated aqueous NaHCO3 and extracted with CHCl3. The organic (2H, br s), 7.44—7.52 (3H), 7.78—7.61 (2H) (each m). NOE was observed
phase was washed with H2O, dried over MgSO4, and concentrated under re- between CH3 (d 1.04) and olefinic-H (d 4.86), and between 4-Hax (d 1.69—
duced pressure to give the crude sulfoxide. A solution of the crude sulfoxide 1.77) and 6-Hax (d 2.78) in NOESY spectroscopy. IR (CHCl3) cmϪ1
:
in toluene (130 ml) was heated at reflux under nitrogen atmosphere for 6 h. 1720 (COO), 1041 (SO). HRMS ms/z: 304.1138 (Calcd for C17H20O3S:
The solvent was removed under reduced pressure and purification of the 304.1133).

February 2001
223
[lit.14 f ) [a]D25 Ϫ36.9° (cϭ0.3, EtOH)]. These spectral data are identical with
those reported.14 f )
Ethyl (Z)-(2-Methylenecyclohexylidene)(phenylsulfinyl)acetate (44b): A
yellow oil. 1H-NMR (200 MHz, CDCl3) d: 1.01 (3H, t, Jϭ7 Hz), 1.64—1.96
(4H, m), 2.18—2.47 (2H, m), 2.47—2.61 (2H, m), 3.80—4.00 (2H, m), 5.30
and 5.34 (each 1H, br s), 7.41—7.56 (3H), 7.56—7.66 (2H) (each, m). IR
(CHCl3) cmϪ1: 1720 (COO), 1043 (SO). HRMS m/z: 304.1129 (Calcd for
C17H20O3S: 304.1133).
Ethyl [3S-(1E,3a,5b)]-[3,5-Bis[[(1,1-dimethylethyl)dimethylsily]oxy]-2-
1
methylenecyclohexylidene]acetate [(E)-40]: A colorless oil. H-NMR (300
MHz, CDCl3) d: 0.06, 0.07 (each 6H, s), 0.87, 0.91 (each 9H, s), 1.27 (3H, t,
Jϭ7.5 Hz), 1.77 (1H, ddd, Jϭ12, 9, 2.5 Hz, 1.98 (1H, br d, Jϭ12 Hz), 2.66
(1H, br d, Jϭ14 Hz), 3.39 (1H, br d, Jϭ14 Hz), 4.09—4.16 (2H, m), 4.24—
4.27 (1H,), 4.56—4.60 (1H, m), 5.07, 5.09, 5.91 (each 1H, s). These spectral
data are identical with those reported.14 f )
[3S-(1E,3a,5b)]-[[[3,5-Bis[[(1,1-dimethylethyl)dimethylsily]oxy]-2-
methylenecyclohexylidene]methyl]sulfinyl]benzene (38) According to
the procedure given for the oxidation and subsequent pyrolysis of 13a, 34b
(132 mg, 0.23 mmol) was converted into 38 (42 mg, 37%) via disulfoxide 37.
[(1,1-Dimethylethyl)sulfinyl]benzene (41): A yellow oil. 1H-NMR (200
MHz, CDCl3) d: 1.18 (9H, s), 7.45—7.54 (3H), 7.54—7.67 (2H) (each m).
IR (CHCl3) cmϪ1: 1032 (SO). HRMS m/z: 182.0764 (Calcd for C10H14OS:
182.0765). These spectral data are identical with those reported.18)
1
A yellow oil. H-NMR (500 MHz, CDCl3) d: Ϫ0.09, 0.02, 0.08, 0.12 (each
3H, s), 0.81, 0.91 (each 9H, s), 0.83—1.91 (2H, m), 2.76—2.88 (2H, m),
4.28 (1H, ddd, Jϭ10.5, 6.5, 4 Hz), 4.51 (1H, br dd, J ϭ 6, 5 Hz), 5.00, 6.23
(each 1H, br s), 6.23 (1H, t, Jϭ1 Hz), 7.42—7.58 (5H, m). NOE was ob-
served between olefinic-H (d 5.00) adjacent to 1-position and olefinic-H (d
6.23) adjacent to 2-position in NOESY spectroscopy. 13C-NMR (50 MHz,
CDCl3) d: Ϫ5.26, Ϫ5.02, Ϫ4.09, 17.93, 18.02, 25.53, 25.69, 39.04, 43.43,
66.60, 70.45, 111.16, 123.94, 129.14, 130.32, 132.63, 144.78, 149.63. IR
(CHCl3) cmϪ1: 1085 (SO). HRMS m/z: 492.2546 (Calcd for C26H44O3SSi2:
492.2550). [a]D23 Ϫ6.0° (cϭ0.69, CHCl3).
Acknowledgements This work was supported in part by a Grant-in-Aid
for Scientific Research from the Ministry of Education, Science, Sports and
Culture, Japan and a research grant from the Science Research Promotion
Fund of the Japan Private School Promotion Foundation.
References and Notes
1) Part 11: Miyata O., Nishiguchi A., Ninomiya I., Aoe K., Okamura K.,
Naito T., J. Org. Chem., 65, 6922—6931 (2000).
Introduction of Ethoxycarbonyl Group to a-Position in 38 To a solu-
tion of 38 (34.5 mg, 0.07 mmol) in THF (0.7 ml) was added MeLi (1.1 M so-
lution in Et2O) (0.09 ml, 0.11 mmol) under nitrogen atmosphere at Ϫ100 °C.
After being stirred at the same temperature for 15 min, NCCOOEt (0.013
ml, 0.14 mmol) was added. The reaction mixture was stirred at the same
temperature for another 15 min, diluted with saturated aqueous NH4Cl and
extracted with CHCl3. The organic phase was washed with H2O, dried over
MgSO4, and concentrated under reduced pressure. Purification of the residue
by flash column chromatography (hexane/AcOEt 3 : 1) afforded (E)-39
(16.8 mg, 43%) and (Z)-39 (6.9 mg, 18%).
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Ethyl [3S-(1E,3a,5b)]-[3,5-Bis[[(1,1-dimethylethyl)dimethylsily]oxy]-2-
methylenecyclohexylidene](phenylsulfinyl)acetate [(E)-39]: A yellow solid.
1H-NMR (500 MHz, CDCl3) d: 0.02, 0.06, 0.09, 0.13 (each 3H, s), 0.88,
0.92 (each 9H, s), 1.05 (3H, t, Jϭ7 Hz), 1.77 (1H, ddd, Jϭ12, 9, 2.5 Hz),
2.03 (1H, dddd, Jϭ12, 6, 5, 1.5 Hz), 2.63 (1H, dd, Jϭ13.5, 3 Hz), 3.09 (1H,
ddd, Jϭ13.5, 5.5, 1.5 Hz), 3.93—4.06 (2H, m), 4.31—4.35 (1H, m), 4.61—
4.66 (1H, m), 4.96, 5.11 (each 1H, t, Jϭ1.5 Hz), 7.42—7.49 (3H), 7.55—
7.58 (2H) (each m). NOE was observed between 4-Hax (d 1.77) and 6-Hax
(d 2.63), and between Me (d 1.05) and olefinic-H (d 5.11) in NOESY spec-
troscopy. IR (CHCl3) cmϪ1: 1723 (COO), 1088 (SO). HRMS m/z: 564.2756
(Calcd for C29H48O5SSi2: 564.2761). [a]D22 Ϫ74.5° (cϭ0.80, CHCl3).
Ethyl [3S-(1Z,3a,5b)]-[3,5-Bis[[(1,1-dimethylethyl)dimethylsily]oxy]-2-
methylenecyclohexylidene](phenylsulfinyl)acetate [(Z)-39]: A pale yellow
oil. 1H-NMR (500 MHz, CDCl3) d: 0.00, 0.06, 0.07, 0.09 (each 3H, s), 0.86,
0.92 (each 9H, s), 0.93 (3H, t, Jϭ7 Hz), 1.73 (1H, dddd, Jϭ13, 11, 2.5,
2 Hz), 2.14 (1H, br dt, Jϭ13, 5 Hz), 2.35 (1H, dd, Jϭ13.5, 3 Hz), 3.02 (1H,
ddd, Jϭ13.5, 3.5, 2 H), 3.78—3.86 (1H, m), 3.88—3.98 (1H, m), 4.28—
4.32 (1H, m), 4.60—4.64 (1H, m), 5.59—5.61 (2H, m), 7.37—7.45 (3H),
7.57—7.55 (2H) (each m). NOE was observed between 4-Hax (d 1.73) and
6-Hax (d 2.35), and between olefinic-H (d 5.59—5.61) and Ar-H (d 7.37—
7.45) in NOESY spectroscopy. 13C-NMR (125 MHz, CDCl3) d: Ϫ5.29,
Ϫ4.87, Ϫ3.70, 14.02, 17.82, 25.54, 25.71, 32.19, 40.95, 61.98, 63.16, 65.51,
124.71, 127.14, 128.39, 128.73, 129.12, 130.59, 131.00, 132.44, 136.34. IR
(CHCl3) cmϪ1: 1718 (COO), 1085 (SO). HRMS m/z: 564.2773 (Calcd for
C29H48O5SSi2: 564.2761). [a]D24 Ϫ39.2° (cϭ0.74, CHCl3).
Desulfurization of (E)-39 To a solution of (E)-39 (15.7 mg, 0.03
mmol) in Et2O (1 ml) was added tert-BuLi (1.54 M in n-pentane) (0.04 ml,
0.05 mmol) under nitrogen atmosphere at Ϫ100 °C, and several seconds later
MeOH (1 ml) was added as described in the literature.18) The reaction mix-
ture was diluted with H2O and extracted with CHCl3. The organic phase was
washed with H2O, dried over MgSO4, and concentrated under reduced pres-
sure. The repeated purification of the residue by medium-pressure column
chromatography (hexane/AcOEt 50 : 1→hexane/AcOEt 7 : 1) afforded (Z)-
40 (1.6 mg, 13%), (E)-40 (0.7 mg, 6%), and 41 (5.2 mg, 52%).
Ethyl [3S-(1Z,3a,5b)]-[3,5-Bis[[(1,1-dimethylethyl)dimethylsily]oxy]-2-
methylenecyclohexylidene]acetate [(Z)-40]: A colorless oil. 1H-NMR (500
MHz, CDCl3) d: 0.03, 0.07 (each 6H, s), 0.85, 0.88 (each 9H, s), 1.21 (3H, t,
Jϭ7 Hz), 1.74 (1H, br ddd, Jϭ12, 9, 3 Hz), 1.91 (1H, br dt, Jϭ12, 5.5 Hz),
2.23 (1H, br dd, Jϭ13, 5.5 Hz), 2.40 (1H, br d, Jϭ13 Hz), 4.04—4.13 (2H,
m), 4.20—4.24 (1H, m), 4.51 (1H, br dd Jϭ9, 3 Hz), 5.00, 5.17 (each 1H,
br s), 5.61 (1H, s). 13C-NMR (125 MHz, CDCl3) d: Ϫ5.21, Ϫ4.91, 14.12,
18.03, 18.26, 25.71, 25.78, 44.68, 46.13, 59.74, 67.38, 70.88, 110.66,
117.67, 147.36, 152.93, 166.03. IR (CHCl3) cmϪ1: 1717 (COO). HRMS m/z:
440.2777 (Calcd for C23H44O4Si2: 440.2776). [a]D22 Ϫ38.1° (cϭ0.11, EtOH)
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