Lewis acid-promoted cyclization of heteroatom-substituted enynes.

Article abstract of DOI:10.1039/b307194d

Lewis acid-promoted cyclizations of heteroatom-substituted enynes have been examined. The reaction of enynes and bearing silicon substituents on an alkyne afforded the halogenated five-membered gamma-lactones and gamma-lactams as the main products. The reaction of substrates and having 2-phosphonoacrylate instead of malonate also gave halogenated five-membered cyclic compounds and as the major products. The cyclized products are highly substituted and potentially useful for further synthetic transformations.

Full text of DOI:10.1039/b307194d

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Lewis acid-promoted cyclization of heteroatom-substituted enynes
Shoko Yamazaki,*a Kuriko Yamadaa and Kagetoshi Yamamotob
a Department of Chemistry, Nara University of Education, Takabatake-cho, Nara 630-8528,
Japan. E-mail: yamazaks@nara-edu.ac.jp
b Department of Chemistry, Graduate School of Science, Osaka University,
1-1 Machikaneyama, Toyonaka, Osaka 560-0043, Japan
Received 26th June 2003, Accepted 10th November 2003
First published as an Advance Article on the web 8th December 2003
Lewis acid-promoted cyclizations of heteroatom-substituted enynes have been examined. The reaction of enynes 3
and 7 bearing silicon substituents on an alkyne afforded the halogenated five-membered γ-lactones 4 and γ-lactams 8
as the main products. The reaction of substrates 15 and 16 having 2-phosphonoacrylate instead of malonate also
gave halogenated five-membered cyclic compounds 17 and 18 as the major products. The cyclized products are highly
substituted and potentially useful for further synthetic transformations.
Introduction
Lewis acids are important catalysts in modern organic reac-
tions,1 and Lewis acid-promoted reactions have been exten-
sively utilized for various ring forming reactions.2 However,
very few examples of Lewis acid-promoted cyclizations of
enynes have been reported so far.3 Recently, we reported a
Lewis acid-promoted intramolecular C–C bond forming reac-
(2)
prepared by the reaction of diethyl ketomalonate with the
corresponding (triphenylphosphoranylidene)acetates (eqn. (3)).
The corresponding (triphenylphosphoranylidene)acetates were
prepared from the reaction of propargyl (triphenylphosphor-
anylidene)acetate, n-BuLi, and t-butylchlorodimethylsilane,
chlorotriisopropylsilane or t-butylchlorodiphenylsilane.
tion to give halogenated five-membered cyclic compounds as
shown in eqn. (1).4
(1)
As part of our efforts to demonstrate the scope and limit-
ations of this Lewis acid-promoted enyne cyclization, hetero-
atom substituted substrates are attractive, due to further
synthetic utility of the products. It is also of mechanistic inter-
est to examine the effect of substituents on the acetylene and
malonate moieties. Enynes 3 bearing silicon substituents on the
alkyne are expected to have different reactivity to alkyl or aryl
acetylenes, since a vinyl cation intermediate is involved in the
previously proposed mechanism.5,4 Phosphonate groups are
expected to have high reactivity, comparable to malonate
groups.6 The synthetic potential for compounds bearing hetero-
atoms such as silicon and phosphorus is also well recognized.7,8
In this paper, we disclose the results of our investigations into
heteroatom substituent effects on Lewis acid-promoted enyne
cyclization.
(3)
The reaction of trimethylsilylalkynyl substrate 3a in the
presence of FeCl3
(1.2 equivalents) in CH2Cl2 at room temper-
ature and subsequent treatment with water gave the chlorinated
γ-lactone 4a in 66% yield along with hydrated compound 5a in
13% yield (eqn. (4)). The reaction of t-butyldimethylsilyl sub-
strate 3b also proceeded similarly. The γ-lactone products 4a–b
have Z-olefin structure stereoselectively. The stereochemistry of
4a–b was determined by the NOEs observed between SiMe3 or
t
Results and discussion
SiMe2 Bu and CH–CH(CO2Et)2. The main products 4a–b are
the same type of products as the products 2 shown in eqn. (1).
On the other hand, the reaction of 3c–d did not give the
cyclized products but hydrated compounds 5c–d, probably
because of steric hindrance. The reaction of 3b–d in the pres-
ence of ZnBr2 did not proceed and the reaction of 3a in the
presence of ZnBr2 gave only the hydrated compounds 5a in 23%
yield along with the recovered starting material 3a (69%). The
formation of hydrated products 5a–d is presumed to result from
adventitious water in situ.4 Thus, silylalkynyl enynes have lower
A. Silicon-substituted enynes
Enynes 3 bearing silicon substituents on the alkyne were
expected to have different reactivity to alkyl or aryl acetylenes
due to the electropositive character of silicon towards carbon
and possible β-silicon stabilization.5 Enyne 3a was prepared by
hydrolysis of t-butyl diethyl ethenetricarboxylate and sub-
sequent reaction with 3-(trimethylsilyl)-2-propyn-1-ol in the
presence of DEAD and PPh3 (eqn. (2)). Enynes 3b–d were
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 2 5 7 – 2 6 4
257

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9 was prepared by the reaction of diethyl ketomalonate with
4-(trimethylsilyl)-2-butynyl (triphenylphosphoranylidene)acetate
(eqn. (8)). 4-(Trimethylsilyl)-2-butynyl (triphenylphosphoranyl-
idene)acetate was prepared from the reaction of propargyl
(triphenylphosphoranylidene)acetate, n-BuLi, and (iodomethyl)-
trimethylsilane. Reaction of 9 in the presence of FeCl3 and
ZnBr2 at room temperature and subsequent treatment with
water gave allene-substituted γ-lactone 10, in 55% and 73%
yields, respectively (eqn. (9)). The structure of 10 was proven by
spectroscopic means. Allene γ-lactone 10 showed characteristic
IR absorptions at 1974 and 1779 cmϪ1 and 13C NMR at 199.5
ppm. Compound 10 was unstable to silica gel column chrom-
atography and partially transformed to the conjugated diene 11.4
Compound 10 could be purified without isomerization by
preparative reverse-phase column chromatography (Cosmosil
75C18PREP, CH3CN–H2O). Treatment of 10 with triethyl-
amine gave 11 in 85% yield.
(4)
reactivity towards five-membered ring formation probably due
to both electronic and steric reasons. Other ring size formation
was not observed.
Treatment of chlorolactones 4a–b with Et3N or Al2O3 gave
6a–b by isomerization and dehydrochlorination, as previously
obtained for aryl and alkyl substrates (eqn. (5)). The silicon
substituted exomethylenic dienes may be useful Diels–Alder
substrates leading to polycyclic compounds.3b,9
(8)
(5)
Trimethylsilylalkynyl amide enyne
7 was prepared by
hydrolysis of t-butyl diethyl ethenetricarboxylate and subse-
quent reaction with N-methyl-N-[3-(trimethylsilyl)-2-propynyl]-
amine in the presence of triethylamine, HOBt and WSC
(eqn. (6)). Reaction of TMS-substituted amide enyne 7 with
FeCl3 in CH2Cl2 proceeded at room temperature to give the
chlorinated γ-lactam 8-Cl in 65% yield (eqn. (7)). Zinc bromide
promoted reactions also gave the brominated γ-lactam 8-Br in
lower yield (23%). The γ-lactam products 8-Cl and 8-Br have
Z-olefin stereochemistry, which was determined by the NOEs
between SiMe3 and CH–CH(CO2Et)2.
(9)
Cyclization of substrates 12 and 13 was also examined. 12
and 13 were prepared by the reaction of diethyl ketomalonate
with the corresponding (triphenylphosphoranylidene)acetates,
which were prepared from the reaction of 3-butynyl (triphenyl-
phosphoranylidene)acetate, n-BuLi, and chlorotrimethylsilane
or (iodomethyl)trimethysilane (eqn. (10)). Reactions of both 12
and 13 with FeCl3 gave recovered starting material along with
trace amounts of unidentified product. Reactions with ZnBr2
gave only recovered starting material. Six-membered ring
formation was not an efficient process, although β-silicon
stabilization is expected.
(6)
(7)
B. Phosphonoacrylate enynes
2-Phosphonoacrylates are expected to have high reactivity
like methylenemalonate esters, since they are isoelectronic
analogues of methylenemalonates.6 The phosphonate substi-
tuted products have potential biological utility in addition to
synthetic utility.11,8 Substrates 15 and 16 having 2-phosphono-
acrylate instead of malonate were examined. Substrates 15
and 16 were prepared using 4-t-butyl 1-ethyl (E)-2-(diethoxy-
phosphoryl)-2-butenedioate 14 as shown in eqns. (11) and (12);
thus, hydrolysis of 14 by trifluoroacetic acid and subsequent
reaction with 1-phenyl-1-propyn-3-ol or N-methyl-N-(phenyl-
propargyl)amine gave 15 and 16, respectively.
Next, the reaction of propargylsilane enyne 9 was examined.
Propargylsilane 9 was expected to have high reactivity and
undergo facile cyclization by β-silicon cation stabilization.10
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 2 5 7 – 2 6 4
258

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In summary, Lewis acid-promoted cyclizations of hetero-
atom-substituted enynes have been examined. The reaction
of enynes 3 and 7 bearing silicon substituents on an alkyne
afforded the halogenated five-membered γ-lactones 4 and
γ-lactams 8 as the main products. The reaction of substrates 15
and 16 having 2-phosphonoacrylate instead of malonate also
gave the halogenated five-membered cyclic compounds 17
and 18 as the major products. The cyclized products are highly
functionalized by such as silyl and phosphonate groups and are
suitable for further elaboration.
(10)
Experimental
General methods
Melting points are uncorrected. IR spectra were recorded in the
1
FT-mode. H NMR spectra were recorded at 400 MHz. 13C
NMR spectra were recorded at 100.6 MHz. Chemical shifts are
reported in ppm relative to Me4Si or residual nondeuterated
solvent. 13C multiplicities were determined by DEPT and
HSQC. Mass spectra were recorded at an ionizing voltage of
70 eV by EI or FAB. All reactions were carried out under a
nitrogen atmosphere.
1,1-Diethyl 2-[3Ј-(trimethylsilyl)prop-2Ј-ynyl] ethene-1,1,2-
tricarboxylate (3a)
To a solution of 1,1-diethyl 2-hydrogen ethenetricarboxylate
(358 mg, 1.66 mmol) (prepared from 2-t-butyl 1,1-diethyl
ethenetricarboxylate upon treatment with CF3CO2H)13 in ether
(1.7 mL) were added diethyl azodicarboxylate 40% in toluene
(0.65 mL, 1.66 mmol), PPh3 (434 mg, 1.66 mmol) and 3-(tri-
methylsilyl)-2-propyn-1-ol (0.37 mL, 318 mg, 2.48 mmol) at
room temperature. The reaction mixture was stirred for 18 h.
After removal of the solvent under reduced pressure, the resi-
due was purified by column chromatography over silica gel with
hexane–ether (1 : 2) as eluent to give 3a (325 mg, 60%).
(11)
(12)
1
The reaction of 15 in the presence of FeCl3 or ZnBr2
(1.2 equivalents) in CH2Cl2 at room temperature gave the halo-
genated five-membered cyclic compounds 17 in 32–49% yield
as the major products (eqn. (13)).12 The reaction of the amide
enyne having a 2-phosphonoacrylate 16 in the presence of
FeCl3 or ZnBr2 in CH2Cl2 at room temperature gave the halo-
genated five-membered cyclic compounds 18 in 65–74% yield
(eqn. (14)).12 The products 17 and 18 have Z-olefin structure
stereoselectively. The stereochemistry of 17 and 18 was deter-
mined by the NOEs observed between Ph and CH–CH(CO2Et)-
(PO(OEt)2) and are the same as the malonate products 2 shown
in eqn. (1).
3a: Rf = 0.8 (hexane–ether = 1 : 2). Colorless oil; H NMR
(400 MHz, CDCl3) δ (ppm) 0.179 (s, 9H), 1.32 (t, J = 7.1 Hz,
3H), 1.35 (t, J = 7.1 Hz, 3H), 4.30 (q, J = 7.1 Hz, 2H), 4.38 (q,
J = 7.1 Hz, 2H), 4.78 (s, 2H), 6.90 (s, 1H); 13C NMR (100.6
MHz, CDCl3) δ (ppm) Ϫ0.31 (CH3), 14.00 (CH3), 14.04 (CH3),
53.96 (CH2), 62.29 (CH2), 62.68 (CH2), 93.29 (C), 97.79 (C),
129.05 (CH), 139.81 (C), 162.16 (C), 162.85 (C), 164.09 (C); IR
(neat) 2984, 2968, 2190, 1734, 1653, 1373, 1344, 1253, 1166,
1067, 849 cmϪ1; MS (EI) m/z 326; exact mass Mϩ 326.1178
(calcd for C15H22O6Si 326.1186).
Preparation of 3b
To a solution of propargyl (triphenylphosphoranylidene)-
acetate (3.87 g, 10.8 mmol) in THF (100 mL) was added 1.6 M
n-BuLi hexane solution (8.3 mL, 13.0 mmol) dropwise at
Ϫ78 ЊC. The mixture was stirred for 1 h, then t-butylchloro-
dimethylsilane (1.95 g, 13.0 mmol) was added. The reaction
mixture was allowed to warm to room temperature and stirred
overnight. Water was added and the mixture was extracted with
dichloromethane. The organic phase was dried (Na2SO4), and
evaporated in vacuo to give crude 3-(t-butyldimethylsilyl)prop-
2-ynyl (triphenylphosphoranylidene)acetate. To an ice–water-
cooled solution of diethyl ketomalonate (1.65 mL, 1.88 g, 10.8
mmol) in benzene (21 mL) was added (t-butyldimethylsilyl)-
propargyl (triphenylphosphoranylidene)acetate (10.8 mmol)
above prepared. The mixture was allowed to warm to room
temperature and stirred overnight. The benzene was evapor-
ated, and ether was added. The precipitate was removed by
filtration. The filtrate was concentrated and the residue was
purified by column chromatography over silica gel eluting with
hexane–ether (1 : 2) to give 3b (2.10 g, 53%).
(13)
(14)
Thus, the phosphonoacrylate moiety provides the reactive
acceptor site for enyne cyclization similar to the malonate
moiety. The phosphonate substituted cyclized products should
be useful for further synthetic transformations.
3b (Rf = 0.8 (hexane–ether = 1 : 2)): Pale yellow oil; 1H NMR
(400 MHz, CDCl3) δ (ppm) 0.112 (s, 6H), 0.928 (s, 9H), 1.32
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 2 5 7 – 2 6 4
259

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(t, J = 7.1 Hz, 3H), 1.35 (t, J = 7.1 Hz, 3H), 4.30 (q, J = 7.1 Hz,
2H), 4.38 (q, J = 7.1 Hz, 2H), 4.79 (s, 2H), 6.89 (s, 1H); 13C
NMR (100.6 MHz, CDCl3) δ (ppm) Ϫ4.79 (CH3), 14.00 (CH3),
14.03 (CH3), 16.52 (C), 26.05 (CH3), 54.00 (CH2), 62.28 (CH2),
62.69 (CH2), 91.65 (C), 98.41 (C), 129.06 (CH), 139.81 (C),
162.18 (C), 162.85 (C), 164.11 (C); IR (neat) 2958, 2934, 2862,
2190, 1734, 1653, 1473, 1371, 1344, 1257, 1164, 1067 cmϪ1; MS
(FAB) m/z 369 (M ϩ H)ϩ; exact mass (M ϩ H)ϩ 369.1755 (calcd
for C18H29O6Si 369.1733).
3H), 3.88 (d, J = 4.0 Hz, 1H), 3.89–3.91 (m, 1H), 4.15–4.38
(m, 4H), 4.91 (dd, J = 14.6, 2.1 Hz, 1H), 5.01 (dd, J = 14.6 Hz,
1.2 Hz, 1H). Selected NOEs are between δ 0.285, 0.367 and
3.88, δ 0.285, 0.367 and 3.89–3.91, δ 0.976 and 3.88, and δ 0.976
and 3.89–3.91; 13C NMR (100.6 MHz, CDCl3) δ (ppm) Ϫ4.48
(CH3), Ϫ4.15 (CH3), 13.93 (CH3), 13.96 (CH3), 17.50 (C), 27.22
(CH3), 42.86 (CH), 56.02 (CH), 62.22 (CH2), 62.57 (CH2), 72.55
(CH2), 133.52 (C), 145.18 (C), 166.18 (C), 166.90 (C), 174.96
(C); IR (neat) 2938, 2862, 1792, 1734, 1628, 1470, 1373, 1340,
1260, 1158, 1046, 837 cmϪ1; Mass (EI) m/z 404, 406; exact mass
Mϩ 404.1422 (calcd for C18H29O635ClSi 404.1422), 406.1380
(calcd for C18H29O637ClSi 406.1392).
5b (Yield 10%) (Rf = 0.6 (hexane–ether = 1 : 2)): Colorless oil;
1H NMR (400 MHz, CDCl3) δ (ppm) 0.113 (s, 6H), 0.931
(s, 9H), 1.29 (t, J = 7.1 Hz, 3H), 1.30 (t, J = 7.1 Hz, 3H), 3.53
(bs, 1H), 3.97 (d, J = 4.0 Hz, 1H), 4.22–4.31 (m, 4H), 4.76 (d,
J = 15.7 Hz, 1H), 4.76–4.79 (m, 1H), 4.86 (d, J = 15.7 Hz, 1H);
13C NMR (100.6 MHz, CDCl3) δ (ppm) Ϫ4.79 (CH3), 14.08
(CH3), 16.50 (C), 26.04 (CH3), 54.34 (CH2), 55.06 (CH), 62.15
(CH2), 62.18 (CH2), 69.78 (CH), 91.61 (C), 98.44 (C), 166.95
(C), 167.13 (C), 170.97 (C); IR (neat) 3494, 2958, 2934, 2864,
2188, 1748, 1480, 1373, 1036, 839, 828 cmϪ1; Mass (FAB) m/z
387 (M ϩ H)ϩ; exact mass (M ϩ H)ϩ 387.1853 (calcd for
C18H31O7Si 387.1839).
5c (Yield 20%) (Rf = 0.7 (hexane–ether = 1 : 2)): Colorless oil;
1H NMR (400 MHz, CDCl3) δ (ppm) 1.05 (bs, 21H), 1.27 (t,
J = 7.1 Hz, 3H), 1.29 (t, J = 7.1 Hz, 3H), 3.55 (d, J = 7.1 Hz,
1H), 3.95 (d, J = 4.1 Hz, 1H), 4.19–4.29 (m, 4H), 4.75 (dd,
J = 6.4, 4.1 Hz, 1H), 4.77 (d, J = 15.7 Hz, 1H), 4.87 (d,
J = 15.7 Hz, 1H); 13C NMR (100.6 MHz, CDCl3) δ (ppm) 11.08
(CH), 14.02 (CH3), 14.05 (CH3), 18.54 (CH3), 54.38 (CH2),
55.02 (CH), 62.09 (CH2), 62.14 (CH2), 69.76 (CH), 89.64 (C),
99.60 (C), 166.92 (C), 167.12 (C), 170.97 (C); IR (neat) 3480,
2946, 2868, 2186, 1750, 1464, 1373, 1180, 1036, 884 cmϪ1; Mass
(FAB) m/z 429 (M ϩ H)ϩ; exact mass (M ϩ H)ϩ 429.2312 (calcd
for C21H37O7Si 429.2309).
3c (Yield 22%) (Rf = 0.8 (hexane–ether = 1 : 2)): Pale
yellow oil; 1H NMR (400 MHz, CDCl3) δ (ppm) 1.05–1.06 (m,
21H), 1.32 (t, J = 7.1 Hz, 3H), 1.35 (t, J = 7.1 Hz, 3H), 4.30 (q,
J = 7.1 Hz, 2H), 4.38 (q, J = 7.1 Hz, 2H), 4.81 (s, 2H), 6.90 (s,
1H); 13C NMR (100.6 MHz, CDCl3) δ (ppm) 11.11 (CH), 12.33
(CH), 13.99 (CH3), 14.03 (CH3), 17.78 (CH3), 18.57 (CH3),
54.10 (CH2), 62.27 (CH2), 62.69 (CH2), 89.73 (C), 99.57 (C),
129.12 (CH), 139.77 (C), 162.20 (C), 162.87 (C), 164.12 (C); IR
(neat) 2946, 2868, 1730, 1464, 1344, 1259, 1164, 1067, 884 cmϪ1
;
MS (FAB) m/z 411 (M ϩ H)ϩ; exact mass (M ϩ H)ϩ 411.2186
(calcd for C21H35O6Si 411.2203).
3d (Yield 33%) (Rf = 0.8 (hexane–ether = 1 : 2)): Pale yellow
1
oil; H NMR (400 MHz, CDCl3) δ (ppm) 1.09 (s, 9H), 1.29
(t, J = 7.1 H, 3H), 1.33 (t, J = 7.1 Hz, 3H), 4.31 (q, J = 7.1 Hz,
2H), 4.35 (q, J = 7.1 Hz, 2H), 4.95 (s, 2H), 6.93 (s, 1H), 7.36–
7.41 (m, 6H), 7.75–7.78 (m, 4H); 13C NMR (100.6 MHz,
CDCl3) δ (ppm) 13.95 (CH3), 14.03 (CH3), 18.58 (C), 27.07
(CH3), 54.07 (CH2), 62.31 (CH2), 62.70 (CH2), 88.82 (C), 101.80
(C), 127.89 (CH), 128.92 (CH), 129.78 (CH), 132.58 (C), 135.63
(CH), 139.96 (C), 162.19 (C), 162.88 (C), 164.07 (C); IR (neat)
2962, 2934, 2862, 2190, 1734, 1653, 1473, 1431, 1253, 1164,
1112, 1067, 820 cmϪ1; MS (EI) m/z 435 (MϩϪ57); MS (FAB)
m/z 515 (M ϩ Na)ϩ; exact mass (M ϩ Na)ϩ 515.1863 (calcd for
C28H32O6SiNa 515.1866).
Typical cyclization procedure (eqn. (4))
To a solution of 3a (208 mg, 0.64 mmol) in dichloromethane
(1.5 ml) was added FeCl3 (119 mg, 0.73 mmol) at 0 ЊC. The
mixture was allowed to warm to room temperature and stirred
for 3 h. The reaction mixture was quenched by water and then
saturated aqueous NaHCO3. The mixture was extracted with
dichloromethane and the organic phase was dried (Na2SO4),
and evaporated in vacuo. The residue was purified by column
chromatography over silica gel eluting with hexane–ether (1 : 2)
to give 4a (152 mg, 66%) and 5a (27 mg, 13%).
5d (including a small amount of impurity) (Yield ca. 43%)
(Rf = 0.6 (hexane–ether = 1 : 2)): Colorless oil; H NMR (400
1
MHz, CDCl3) δ (ppm) 0.981 (s, 9H), 1.20–1.29 (m, 6H), 3.61 (d,
J = 7.3 Hz, 1H), 3.95–3.97 (m, 1H), 4.14–4.27 (m, 4H), 4.75–
4.78 (m, 1H), 4.86–4.87 (m, 2H), 7.35–7.44 (m, 6H), 7.67–7.69
(m, 4H); 13C NMR (100.6 MHz, CDCl3) δ (ppm) 13.95 (CH3),
13.99 (CH3), 14.02 (CH3), 18.45 (C), 25.34 (CH3), 54.02 (CH2),
55.11 (CH), 62.24 (CH2), 62.27 (CH2), 69.70 (CH), 88.97 (C),
89.02 (C), 99.66 (C), 99.69 (C), 127.77 (CH), 130.25 (CH),
133.14 (C), 133.18 (C), 134.49 (CH), 166.94 (C), 167.16 (C),
167.19 (C), 170.91 (C), 170.93 (C); IR (neat) 3500, 2960, 2936,
2862, 2190, 1744, 1475, 1373, 1270, 1181, 1035, 864 cmϪ1; Mass
(EI) m/z 510; exact mass Mϩ 510.2065 (calcd for C28H34O7Si
510.2074).
1
4a (Rf = 0.7 (hexane–ether = 1 : 2)): Colorless oil; H NMR
(400 MHz, CDCl3) δ (ppm) 0.329 (s, 9H), 1.27 (t, J = 7.1 Hz,
3H), 1.31 (t, J = 7.1 Hz, 3H), 3.85 (d, J = 4.6 Hz, 1H), 3.91–3.93
(m, 1H), 4.19–4.34 (m, 4H), 4.88 (dd, J = 14.6, 2.2 Hz, 1H), 4.95
(d, J = 14.6 Hz, 1H). Selected NOEs are between δ 1.27 and 3.85
and δ 1.27 and 3.91–3.93; 13C NMR (100.6 MHz, CDCl3)
δ (ppm) Ϫ1.03 (CH3), 13.97 (CH3), 14.04 (CH3), 42.80 (CH),
55.40 (CH), 62.32 (CH2), 62.61 (CH2), 72.14 (CH2), 134.04 (C),
143.47 (C), 166.08 (C), 166.77 (C), 174.78 (C); IR (neat) 2962,
1792, 1750, 1734, 1634, 1452, 1373, 1342, 1257, 1158, 1046, 845
cmϪ1; Mass (EI) m/z 362, 364; exact mass Mϩ 362.0974 (calcd
for C15H23O6SiCl 362.0952).
Conversion of 4a to 6a (eqn. (5))
(A) To a solution of 4a (86 mg, 0.24 mmol) in dichloromethane
(0.5 mL) was added triethylamine (59 µL, 42 mg, 0.42 mmol) at
room temperature. The mixture was stirred for 1 h. The reaction
mixture was concentrated in vacuo. The residue was extracted
with dichloromethane and the organic phase was washed with
saturated aqueous NaHCO3, dried (Na2SO4), and evaporated
in vacuo to give 6a quantitatively.
1
5a (Rf = 0.6 (hexane–ether = 1 : 2)): Colorless oil; H NMR
(400 MHz, CDCl3) δ (ppm) 0.173 (s, 9H), 1.29 (t, J = 7.1 Hz,
3H), 1.30 (t, J = 7.1 Hz, 3H), 3.53 (d, J = 7.1 Hz, 1H), 3.97 (d,
J = 4.1 Hz, 1H), 4.22–4.29 (m, 4H), 4.74 (d, J = 15.7 Hz, 1H),
4.77 (dd, J = 7.1, 4.1 Hz, 1H), 4.84 (d, J = 15.7 Hz, 1H); 13C
NMR (100.6 MHz, CDCl3) δ (ppm) Ϫ0.32 (CH3), 14.07 (CH3),
54.31 (CH2), 55.08 (CH), 62.15 (CH2), 62.18 (CH2), 69.78 (CH),
93.23 (C), 97.82 (C), 166.94 (C), 167.10 (C), 170.97 (C); IR
(B) Filtration of 4a (83 mg, 0.23 mmol) on Al2O3 containing
5% H2O by column (2.3 × 10 cm) eluting with hexane–ether
(1 : 2) yielded 6a (36 mg, 49%).
1
6a (Rf = 0.7, hexane–ether (1 : 2)): Colorless oil; H NMR
(400 MHz, CDCl3) δ (ppm) 0.183 (s, 9H), 1.33 (t, J = 7.1 Hz,
3H), 1.34 (t, J = 7.1 Hz, 3H), 4.32 (q, J = 7.1 Hz, 3H), 4.37 (q,
J = 7.1 Hz, 3H), 4.88 (d, J = 2.5 Hz, 2H), 7.13 (t, J = 2.5 Hz,
1H). Selected NOEs in the 2D-NOESY spectra were between
δ 0.183 and 4.88; 13C NMR (100.6 MHz, CDCl3) δ (ppm)
Ϫ0.879 (CH3), 13.86 (CH3), 13.92 (CH3), 62.59 (CH2), 70.60
(neat) 3488, 2966, 2190, 1748, 1734, 1253, 1180, 1036, 847 cmϪ1
;
Mass (EI) m/z 344 (Mϩ), 345 ((M ϩ H)ϩ).
4b (Yield 64%) (Rf = 0.8 (hexane–ether = 1 : 2)): Colorless oil;
1H NMR (400 MHz, CDCl3) δ (ppm) 0.285 (s, 3H), 0.367 (s,
3H), 0.976 (s, 9H), 1.25 (t, J = 7.2 Hz, 3H), 1.30 (t, J = 7.1 Hz,
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 2 5 7 – 2 6 4
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(CH2), 129.60 (C), 131.74 (C), 138.03 (CH), 140.89 (C), 162.62
(C), 164.17 (C), 168.01 (C); IR (neat) 2986, 2962, 1779, 1729,
1634, 1466, 1367, 1249, 1195, 1075, 1017, 859 cmϪ1; MS (EI)
m/z 326; exact mass Mϩ 326.1155 (calcd for C15H22O6Si
326.1186).
mixture was allowed to warm to room temperature and stirred
for 18 h. The reaction mixture was quenched by water and then
saturated aqueous NaHCO3. The mixture was extracted with
dichloromethane and the organic phase was washed with water,
dried (Na2SO4), and evaporated in vacuo. The residue was puri-
fied by column chromatography over silica gel eluting with
hexane–ether (1 : 2) to give 8-Br (26 mg, 23%).
1
6b (Yield 68%): Colorless oil; H NMR (400 MHz, CDCl3)
δ (ppm) 0.137 (s, 6H), 0.917 (s, 9H), 1.32 (t, J = 7.1 Hz,
3H), 1.34 (t, J = 7.1 Hz, 3H), 4.32 (q, J = 7.1 Hz, 2H), 4.37 (q,
J = 7.1 Hz, 2H), 4.88 (d, J = 2.5 Hz, 2H), 7.19 (t, J = 2.5 Hz,
1H). Selected NOEs in the 2D-NOESY spectra were between
δ 0.137 and 4.88 and δ 0.917 and 4.88; 13C NMR (100.6 MHz,
CDCl3) δ (ppm) Ϫ5.15 (CH3), 13.86 (CH3), 13.97 (CH3), 17.45
(C), 26.28 (CH3), 62.62 (CH2), 70.89 (CH2), 129.56 (C), 131.75
(C), 136.06 (CH), 141.74 (C), 162.60 (C), 164.19 (C), 167.98
(C); IR (neat) 2956, 2934, 2864, 1780, 1734, 1470, 1367, 1247,
1195, 1077, 841, 826 cmϪ1; MS (EI) m/z 368; exact mass Mϩ
368.1651 (calcd for C18H28O6Si 368.1655).
8-Br (Rf = 0.2 (hexane–ether = 1 : 2)): Colorless oil; 1H NMR
(400 MHz, CDCl3) δ (ppm) 0.342 (s, 9H), 1.24 (t, J = 7.1 Hz,
3H), 1.31 (t, J = 7.1 Hz, 3H), 2.93 (s, 3H), 3.79 (bs, 2H), 3.92 (d,
J = 15.7 Hz, 1H), 4.00 (d, J = 15.7, Hz, 1H), 4.19 (q, J = 7.1 Hz,
2H), 4.23–4.37 (m, 2H). Selected NOEs in the 2D-NOESY
spectra were between δ 0.342 and 3.79; 13C NMR (100.6 MHz,
CDCl3) δ (ppm) Ϫ0.241 (CH3), 14.02 (CH3), 14.17 (CH3), 29.45
(CH3), 46.17 (CH), 54.89 (CH), 58.63 (CH2), 61.71 (CH2), 62.21
(CH2), 127.28 (C), 144.97 (C), 166.98 (C), 167.10 (C), 171.78
(C); IR (neat) 2982, 1734, 1707, 1491, 1373, 1342, 1294, 1257,
1158, 1033, 845 cmϪ1; MS (EI) m/z 419, 421; exact mass Mϩ
419.0759 (calcd for C16H2679BrNO5Si 419.0764), 421.0745
(calcd for C16H2681BrNO5Si 421.0743).
Preparation of 7
N-Methyl-N-[(3-(trimethylsilyl)-2-propynyl)amine was pre-
pared by the reaction of 3-bromo-1-(trimethylsilyl)-1-propyne
and N-methylamine (colorless oil, bp. 44–48 ЊC/85 mmHg). To
a solution of 1,1-diethyl 2-hydrogen ethenetricarboxylate (139
mg, 0.64 mmol) (prepared from 2-t-butyl 1,1-diethyl ethene-
tricarboxylate upon treatment with CF3CO2H)13 in THF (1.3
mL) were added N-methyl-N-[3-(trimethylsilyl)-2-propynyl]-
amine (90.6 mg, 0.64 mmol), triethylamine (89 µl, 0.64 mmol),
HOBt (1-hydroxybenzotriazole) (196 mg, 1.3 mmol) and WSC
(1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochlor-
ide) (128 mg, 0.67 mmol) at 0 ЊC. The reaction mixture was
stirred for 1 h at 0 ЊC, allowed to warm to room temperature
and stirred for 16 h. After removal of the solvent under reduced
pressure, the residue was dissolved in CH2Cl2 and the organic
phase was washed with saturated aqueous NaHCO3 solution, 2
M aqueous citric acid, saturated aqueous NaHCO3 and water,
dried (Na2SO4), and evaporated in vacuo. The residue was
purified by column chromatography over silica gel eluting with
hexane–ether (1 : 2) to give 7 (88 mg, 32%).
Preparation of 9
9 was prepared by the reaction of diethyl ketomalonate with
4-(trimethylsilyl)-2-butynyl (triphenylphosphoranylidene)acetate
in the same manner as the preparation of 3b. 4-(Trimethylsilyl)-2-
butynyl (triphenylphosphoranylidene)acetate was prepared from
the reaction of propargyl (triphenylphosphoranylidene)acetate,
n-BuLi, and (iodomethyl)trimethylsilane.
9 (43%) (Rf = 0.8 (hexane–ether = 1 : 2)): Colorless oil;
1H NMR (400 MHz, CDCl3) δ (ppm) 0.098 (s, 9H), 1.32 (t,
J = 7.1 Hz, 3H), 1.35 (t, J = 7.1 Hz, 3H), 1.50 (t, J = 2.6 Hz,
2H), 4.30 (q, J = 7.1 Hz, 2H), 4.38 (q, J = 7.1 Hz, 2H), 4.77 (t,
J = 2.6 Hz, 2H), 6.89 (s, 1H); 13C NMR (100.6 MHz, CDCl3)
δ (ppm) Ϫ1.99 (CH3), 7.30 (CH2), 13.98 (CH3), 14.02 (CH3),
54.55 (CH2), 62.24 (CH2), 62.62 (CH2), 71.77 (C), 86.99 (C),
129.41 (CH), 139.56 (C), 162.26 (C), 163.09 (C), 164.20 (C); IR
(neat) 2986, 2964, 2230, 1740, 1734, 1653, 1373, 1346, 1253,
1180, 855 cmϪ1; MS (EI) m/z 340; exact mass Mϩ 340.1353
(calcd for C16H24O6Si 340.1342).
1
7 (Rf = 0.4 (hexane–ether = 1 : 2)): Colorless oil; H NMR
(400 MHz, CDCl3) (2 rotamers, ratio = 6 : 4) δ (ppm) 0.145 (s,
9 × 0.6H, major rotamer), 0.160 (s, 9 × 0.4H, minor rotamer),
1.28–1.33 (m, 6H), 3.04 (s, 3 × 0.4H), 3.10 (s, 3 × 0.6H), 4.09
(s, 2 × 0.4H), 4.28 (s, 2 × 0.6H), 4.26–4.34 (m, 4H), 7.31 (s,
1 × 0.6H), 7.34 (s, 1 × 0.4H); 13C NMR (100.6 MHz, CDCl3)
δ (ppm) Ϫ0.256 (CH3), Ϫ0.165 (CH3), 13.99 (CH3), 14.01
(CH3), 14.06 (CH3), 32.84 (CH3), 34.54 (CH3), 36.84 (CH2),
40.86 (CH2), 61.88 (CH2), 61.93 (CH2), 62.27 (CH2), 89.73 (C),
91.11 (C), 98.47 (C), 99.19 (C), 134.19 (CH), 134.47 (CH),
134.54 (C), 134.65 (C), 162.96 (C), 163.66 (C), 163.99 (C),
164.25 (C); IR (neat) 2966, 2182, 1734, 1655, 1406, 1375, 1255,
1069, 1027, 847 cmϪ1; MS (EI) m/z 339; exact mass Mϩ
339.1494 (calcd for C16H25NO5Si 339.1502).
8-Cl (Yield 65%) (Rf = 0.2 (hexane–ether = 1 : 2)): Colorless
oil; 1H NMR (400 MHz, CDCl3) δ (ppm) 0.323 (s, 9H), 1.24 (t,
J = 7.1 Hz, 3H), 1.31 (t, J = 7.1 Hz, 3H), 2.93 (d, J = 0.7 Hz,
3H), 3.76 (d, J = 4.9 Hz, 1H), 3.83 (bd, J = 4.9 Hz, 1H), 3.98
(dd, J = 15.5, 1.8 Hz, 1H), 4.09 (dd, J = 15.5, 1.5 Hz, 1H), 4.15–
4.37 (m, 4H). Selected NOEs in the 2D-NOESY spectra were
between δ 0.323 and 3.76 and δ 0.323 and 3.83; 13C NMR (100.6
MHz, CDCl3) δ (ppm) Ϫ0.870 (CH3), 14.02 (CH3), 14.15 (CH3),
29.50 (CH3), 45.10 (CH), 55.03 (CH), 55.39 (CH2), 61.68 (CH2),
62.18 (CH2), 133.97 (C), 142.73 (C), 167.05 (C), 167.10 (C),
171.65 (C); IR (neat) 2982, 1738, 1713, 1294, 1257, 1158, 845
cmϪ1; MS (EI) m/z 375; exact mass Mϩ 375.1284 (calcd for
C16H26ClNO5Si 375.1269).
Reaction of 9 with ZnBr2 (eqn. (9))
To a solution of 9 (132 mg, 0.39 mmol) in dichloromethane
(1.6 ml) was added ZnBr2 (101 mg, 0.45 mmol) at 0 ЊC. The
mixture was allowed to warm to room temperature and stirred
for 18 h. The reaction mixture was quenched by water and then
saturated aqueous NaHCO3. The mixture was extracted with
dichloromethane and the organic phase was washed with water,
dried (Na2SO4), and evaporated in vacuo. The residue was puri-
fied by reverse-phase column chromatography over Cosmosil
75C18-PREP eluting with CH3CN–H2O (6 : 4) to give 10
(76 mg, 73%).
1
10: Pale yellow oil; H NMR (400 MHz, CDCl3) δ (ppm)
1.288 (t, J = 7.1 Hz, 3H), 1.290 (t, J = 7.1 Hz, 3H), 3.92–3.97 (m,
2H), 4.17–4.35 (m, 4H), 4.85–4.97 (m, 2H), 5.05–5.10 (m, 2H);
13C NMR (100.6 MHz, CDCl3) δ (ppm) 14.03 (CH3), 41.22
(CH), 52.35 (CH), 62.00 (CH2), 62.26 (CH2), 67.87 (CH2), 76.58
(C), 82.93 (CH2), 95.80 (C), 166.91 (C), 166.96 (C), 174.49 (C),
199.55 (C); IR (neat) 2988, 1974, 1779, 1742, 1373, 1251, 1181,
1031 cmϪ1; MS (EI) m/z 268; exact mass Mϩ 268.0945 (calcd for
C13H16O6 268.0947).
Conversion of 10 to 11 (eqn. (9))
To a solution of 10 (96 mg, 0.36 mmol) in dichloromethane
(1.0 mL) was added triethylamine (50 µL, 36 mg, 0.36 mmol) at
room temperature. The mixture was stirred for 30 min. The
reaction mixture was concentrated in vacuo. The residue was
extracted with dichloromethane and the organic phase was
washed with saturated aqueous NaHCO3, dried (Na2SO4), and
Reaction of 7 with ZnBr2 (eqn. (7))
To a solution of 7 (90.6 mg, 0.27 mmol) in dichloromethane
(0.6 ml) was added ZnBr2 (69 mg, 0.31 mmol) at 0 ЊC. The
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 2 5 7 – 2 6 4
261

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evaporated in vacuo to give 11 (82 mg, 85%). The data for 11
diphenyl diselenide (1.35 g, 4.3 mmol) in THF (3.4 mL) at room
temperature followed by further stirring for 10 min] was then
added. The mixture was stirred for 22 h at room temperature
and 1 M HCl and dichloromethane were added to the mixture.
The organic layer was separated, washed with saturated sodium
bicarbonate solution and dried (MgSO4). The solvent was
evaporated in vacuo. The residue was purified by column
chromatography over silica gel eluting with cyclohexane–ether
(1 : 4) to give the title compound (2.71 g, 77%) (Rf = 0.3 (cyclo-
hexane–ether = 1 : 2)): Colorless oil; 1H NMR (400 MHz,
CDCl3) δ (ppm) 1.25 (t, J = 7.1 Hz, 3H), 1.30–1.38 (m, 6H), 1.41
(s, 9H), 2.52 (dd, J = 17.5, 14.2 Hz, 1H), 3.14 (dd, J = 17.5,
7.2 Hz, 1H), 4.12–4.44 (m, 6H), 7.28–7.32 (m, 2H), 7.38–7.42
(m, 1H), 7.80–7.82 (m, 2H); 13C NMR (100.6 MHz, CDCl3)
δ (ppm) 13.94 (CH3), 16.43 (d, JCP = 6.1 Hz, CH3), 16.60
(d, JCP = 5.3 Hz, CH3), 28.02 (CH3), 38.20 (CH2), 47.98 (d,
JCP = 143 Hz, C), 62.24 (CH2), 63.31 (d, JCP = 7.6 Hz, CH2),
65.32 (d, JCP = 7.6 Hz, CH2), 81.29 (C), 126.48 (d, JCP = 1.5 Hz,
were in accord with the reported data.4
Preparation of 12 and 13
Compounds 12 and 13 were prepared by the reaction of diethyl
ketomalonate with 4-(trimethylsilyl)-3-butynyl and 5-(tri-
methylsilyl)-3-pentynyl (triphenylphosphoranylidene)acetates,
respectively, in the same manner as the preparation of 3b. The
(triphenylphosphoranylidene)acetates were prepared from the
reaction of 3-butynyl (triphenylphosphoranylidene)acetate and
chlorotrimethylsilane or (iodomethyl)trimethylsilane.
12 (Yield 25%) (Rf = 0.8 (hexane–ether = 1 : 2)): Colorless
oil; 1H NMR (400 MHz, CDCl3) δ (ppm) 0.141 (s, 9H), 1.31 (t,
J = 7.1 Hz, 3H), 1.35 (t, J = 7.1 Hz, 3H), 2.59 (t, J = 7.0 Hz,
2H), 4.27 (t, J = 7.0 Hz, 2H), 4.30 (q, J = 7.1 Hz, 2H), 4.37 (q,
J = 7.1 Hz, 2H), 6.87 (s, 1H); 13C NMR (100.6 MHz, CDCl3)
δ (ppm) 0.010 (CH3), 13.99 (CH3), 14.02 (CH3), 20.18 (CH2),
62.22 (CH2), 62.62 (CH2), 63.50 (CH2), 87.08 (C), 101.50 (C),
129.52 (CH), 139.55 (C), 162.26 (C), 163.38 (C), 164.23 (C); IR
(neat) 2966, 2182, 1734, 1255, 1180, 1067, 1025, 845 cmϪ1; MS
(EI) m/z 340; exact mass Mϩ 340.1353 (calcd for C16H24O6Si
340.1342).
C), 128.71 (CH), 129.87 (CH), 138.96 (CH), 168.34 (d, JCP
=
15.3 Hz, C), 168.69 (C); 31P NMR (CDCl3, 161.9 MHz) δ (ppm)
Ϫ0.545; IR (neat) 2984, 1734, 1369, 1255, 1154, 1023 cmϪ1; MS
(EI) m/z 494; exact mass Mϩ 494.0993 (calcd for C20H31O7PSe
494.0973).
13 (Yield 21%) (Rf = 0.7 (hexane–ether = 1 : 2)): Colorless oil;
1H NMR (400 MHz, CDCl3) δ (ppm) 0.076 (s, 9H), 1.32 (t,
J = 7.1 Hz, 3H), 1.35 (t, J = 7.1 Hz, 3H), 1.41 (t, J = 2.7 Hz, 2H),
2.49–2.54 (m, 2H), 4.23 (t, J = 7.0 Hz, 2H), 4.30 (q, J = 7.1 Hz,
2H), 4.37 (q, J = 7.1 Hz, 2H), 6.88 (s, 1H); 13C NMR (100.6
MHz, CDCl3) δ (ppm) Ϫ2.05 (CH3), 6.99 (CH2), 13.99 (CH3),
14.02 (CH3), 19.33 (CH2), 62.20 (CH2), 62.59 (CH2), 64.45
(CH2), 73.53 (C), 80.05 (C), 129.72 (CH), 139.40 (C), 162.29
(C), 163.45 (C), 164.29 (C); IR (neat) 2964, 1734, 1253, 1180,
1067, 853 cmϪ1; MS (EI) m/z 354; exact mass Mϩ 354.1491
(calcd for C17H26O6Si 354.1499).
4-t-butyl 1-ethyl (E )-2-(diethoxyphosphoryl)-2-butenedioate (14)
Water (2.3 mL) and hydrogen peroxide (30%, 2.0 mL, 59 mmol)
were added to a stirred solution of 4-t-butyl 1-ethyl 2-(diethoxy-
phosphoryl)-2-(phenylseleno)butanedioate (3.28 g, 6.64 mmol)
in dichloromethane (12 mL) at such a rate the temperature
remained above 30 ЊC. After being stirred for a further 1 h at
20 ЊC, the mixture was washed with saturated sodium bicarb-
onate solution and dried over MgSO4, and the solvent was
evaporated in vacuo to give the title compound (2.5 g, 100%):
1
Colorless oil; H NMR (400 MHz, CDCl3) δ (ppm) 1.31–1.38
(m, 9H), 1.49 (s, 9H), 4.12–4.22 (m, 4H), 4.33 (q, J = 7.1 Hz,
2H), 6.74 (d, J = 22.3 Hz, 1H). Selected NOEs in the 2D-
NOESY spectra were between δ 1.49 and 4.33; 13C NMR (100.6
MHz, CDCl3) δ (ppm) 14.00 (CH3), 16.26 (d, JCP = 6.9 Hz,
CH3), 27.96 (CH3), 62.03 (CH2), 63.38 (d, JCP = 5.3 Hz, CH2),
82.95 (C), 137.11 (d, JCP = 172 Hz, C), 137.83 (d, JCP = 6.9 Hz,
CH), 162.51 (d, JCP = 25.2 Hz, C), 164.63 (d, JCP = 11.4 Hz, C);
31P NMR (CDCl3, 161.9 MHz) δ (ppm) Ϫ9.619; IR (neat) 2986,
1734, 1628, 1371, 1257, 1154, 1021 cmϪ1; MS (EI) m/z 281
(Mϩ Ϫ 57).
4-t-butyl 1-ethyl 2-(diethoxyphosphoryl)butanedioate
Sodium hydride (0.522 g, 60% dispersion in oil, 13.0 mmol,
washed 3 times with pentane) was suspended in THF (12.0
mL). After the mixture was cooled to 0 ЊC, triethyl phosphono-
acetate (2.69 g, 12.0 mmol) was added dropwise. After 1 h,
t-butyl bromoacetate (1.77 mL, 2.34 g, 12.0 mmol) was added,
and the mixture was stirred for 18 h at room temperature. The
mixture was extracted with ether and the ether extracts were
washed with 1 M hydrochloric acid and saturated sodium
chloride solution and dried (MgSO4). The solvent was evapor-
ated in vacuo. The residue was purified by column chromato-
graphy over silica gel eluting with hexane–ether (1 : 2) to give
Preparation of 15
1
To a solution of 1-ethyl 4-hydrogen (E)-2-(diethoxyphosphoryl)-
2-butenedioate (295 mg, 1.05 mmol) (prepared from 4-t-butyl
1-ethyl (E)-2-(diethoxyphosphoryl)-2-butenedioate upon treat-
ment with CF3CO2H) in CH2Cl2 (3.8 mL) were added 1-phenyl-
1-propyn-3-ol (131 mg, 0.98 mmol), WSC (202 mg, 1.05 mmol)
and DMAP (4-dimethylaminopyridine) (129 mg, 1.05 mmol) at
0 ЊC and stirred for 2 h. The reaction mixture was allowed to
warm to room temperature and stirred for 14 h. After removal
of the solvent under reduced pressure, the mixture was
extracted with ether, washed with saturated sodium bicarbonate
solution and dried over MgSO4. The solvent was evaporated
in vacuo and the residue was purified by column chromato-
graphy over silica gel with hexane–ether (1 : 2) as eluent to give
15 (68 mg, 16%). The yield could not be improved.
the title compound (3.52 g, 87%) (Rf = 0.1): Colorless oil; H
NMR (400 MHz, CDCl3) δ (ppm) 1.27–1.37 (m, 9H), 1.43 (s,
9H), 2.73 (ddd, J = 17.4, 9.1, 3.4 Hz, 1H), 2.99 (ddd, J = 17.4,
11.5, 6.9 Hz, 1H), 3.40 (ddd, J = 24.0, 11.5, 3.4 Hz, 1H), 4.11–
4.28 (m, 6H); 13C NMR (100.6 MHz, CDCl3) δ (ppm) 14.13
(CH3), 16.37 (d, JCP = 6.1 Hz, CH3), 16.43 (d, JCP = 5.3 Hz,
CH3), 28.04 (CH3), 32.58 (d, JCP = 3.1 Hz, CH2), 41.47 (d, JCP
=
131 Hz, CH), 61.71 (CH2), 62.93 (d, JCP = 6.9 Hz, CH2), 63.00
(d, JCP = 6.1 Hz, CH2), 81.48 (C), 168.38 (d, JCP = 5.3 Hz, C),
170.19 (d, JCP = 19.8 Hz, C); 31P NMR (CDCl3, 161.9 MHz)
δ (ppm) 1.826; IR (neat) 2984, 1734, 1371, 1255, 1154, 1023
cmϪ1; MS (EI) m/z 283 (Mϩ Ϫ 57).
4-t-butyl 1-ethyl 2-(diethoxyphosphoryl)-2-
(phenylseleno)butanedioate
15: (Rf = 0.2 (hexane–ether = 1 : 2)): Pale yellow oil; 1H NMR
(400 MHz, CDCl3) δ (ppm) 1.33 (t, J = 7.1 Hz, 3H), 1.35–1.38
(m, 6H), 4.14–4.24 (m, 4H), 4.35 (q, J = 7.1 Hz, 3H), 5.01
(s, 2H), 6.86 (d, J = 21.8 Hz, 1H), 7.29–7.36 (m, 3H), 7.44–7.46
(m, 2H); 13C NMR (100.6 MHz, CDCl3) δ (ppm) 13.97 (CH3),
16.24 (d, JCP = 6.1 Hz, CH3), 54.04 (CH2), 62.36 (CH2), 63.58 (d,
JCP = 5.3 Hz, CH2), 81.89 (C), 87.34 (C), 121.89 (C), 128.40
(CH), 129.02 (CH), 131.94 (CH), 134.45 (d, JCP = 6.9 Hz, CH),
139.79 (d, JCP = 170 Hz, C), 162.61 (d, JCP = 25.2 Hz, C), 164.31
Sodium hydride (0.503 g, 60% dispersion in oil, 12.6 mmol,
washed 3 times with pentane) was suspended in THF
(16.0 mL). After the mixture was cooled to 0 ЊC, 4-t-butyl
1-ethyl 2-(diethoxyphosphoryl)butanedioate (2.43 g, 7.2 mmol)
was added and the mixture was stirred for 2 h at room temper-
ature. Phenylselenyl bromide [8.6 mmol, prepared by adding
bromine (0.23 mL, 719 mg, 4.5 mmol) to a stirred solution of
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262

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(d, JCP = 11.4 Hz, C); 31P NMR (CDCl3, 161.9 MHz) δ (ppm)
Ϫ10.67; IR (neat) 2986, 1734, 1620, 1371, 1334, 1261, 1168,
1019 cmϪ1; MS (EI) m/z 350 ((M ϩ H)ϩ), 349 (Mϩ).
(t, J = 7.1 Hz, 3H), 1.26 (t, J = 7.1 Hz, 3H), 2.88 (dd, J = 28.1,
2.7 Hz, 1H), 2.99 (s, 3H), 3.59–3.69 (m, 1H), 3.80–3.90 (m, 1H),
4.00–4.29 (m, 7H), 7.35–7.46 (m, 5H). Selected NOEs are
between δ 2.88 and 7.35–7.46 and δ 4.00–4.29 and 7.35–7.46;
13C NMR (100.6 MHz, CDCl3) δ (ppm) 14.07 (CH3), 16.26 (d,
JCP = 6.9 Hz, CH3), 16.45 (d, JCP = 6.1 Hz, CH3), 29.70 (CH3),
43.78 (d, JCP = 1.5 Hz, CH), 44.41 (d, JCP = 132 Hz, CH), 54.56
Preparation of 16
16 was prepared by the reaction of 1-ethyl 4-hydrogen (E)-2-
(diethoxyphosphoryl)-2-butenedioate (prepared from 4-t-butyl
1-ethyl (E)-2-(diethoxyphosphoryl)-2-butenedioate upon treat-
ment with CF3CO2H) and N-methyl-N-(phenylpropargyl)-
amine14 in the same manner as the preparation of 7.
(CH2), 61.59 (CH2), 62.06 (d, JCP = 6.1 Hz, CH2), 63.92 (d, JCP
6.9 Hz, CH2), 126.91 (C), 128.26 (CH), 129.17 (CH), 129.42
(CH), 130.98 (d, JCP = 14.5 Hz, C), 136.76 (C), 166.92 (d, JCP
=
=
4.6 Hz, C), 174.65 (C); IR (KBr) 2988, 2930, 1740, 1713, 1257,
1170, 1033 cmϪ1; MS (EI) m/z 443; exact mass Mϩ 443.1314
(calcd for C20H27ClNO6P 443.1265); Anal. Calcd for C20H27-
ClNO6P: C 54.12; H, 6.13; N 3.16; Cl 7.99; Found: C, 54.02; H,
6.07; N 3.23; Cl 7.97%.
16 (Yield 66%) (Rf = 0.4 (hexane–ether = 1 : 2)): Pale yellow
1
oil; H NMR (400 MHz, CDCl3) (2 rotamers, ratio = 6 : 4),
δ (ppm) 1.23–1.38 (m, 9H), 3.13 (s, 3 × 0.4H, minor rotamer),
3.14 (s, 3 × 0.6H, major rotamer), 4.15–4.32 (m, 6H), 4.29 (s,
2 × 0.4H), 4.51 (s, 2 × 0.6H), 7.28–7.50 (m, 6H); 13C NMR
(100.6 MHz, CDCl3) δ (ppm) 13.97 (CH3), 14.01 (CH3), 16.36
(d, JCP = 6.1 Hz, CH3), 32.51 (CH3), 34.69 (CH3), 36.51 (CH2),
40.75 (CH2), 61.99 (CH2), 62.06 (CH2), 63.33 (d, JCP = 5.3 Hz,
CH2), 82.33 (C), 82.97 (C), 84.44 (C), 85.53 (C), 122.08 (C),
122.52 (C), 128.40 (CH), 128.46 (CH), 128.62 (CH), 128.87
(CH), 131.44 (d, JCP = 179 Hz, C), 131.82 (CH), 131.84 (CH),
18-Br (Yield 65%)12 (Rf = 0.8 (ether–methanol = 4 : 1)): Pale
yellow crystals (hexane–EtOAc 1 : 1); mp 116–117 ЊC; 1H NMR
(400 MHz, CDCl3) δ (ppm) 1.13 (t, J = 7.0 Hz, 3H), 1.20 (t,
J = 7.0 Hz, 3H), 1.24 (t, J = 7.0 Hz, 3H), 2.84 (dd, J = 28.3, 2.8
Hz, 1H), 2.99 (s, 3H), 3.54–3.64 (m, 1H), 3.77–3.87 (m, 1H),
4.02–4.28 (m, 7H), 7.33–7.45 (m, 5H). Selected NOEs are
between δ 2.84 and 7.33–7.45 and δ 4.02–4.28 and 7.33–7.45;
13C NMR (100.6 MHz, CDCl3) δ (ppm) 14.10 (CH3), 16.26 (d,
JCP = 6.1 Hz, CH3), 16.44 (d, JCP = 5.3 Hz, CH3), 29.69 (CH3),
44.36 (d, JCP = 131 Hz, CH), 44.52 (d, JCP = 2.3 Hz, CH), 56.92
144.20 (d, JCP = 6.1 Hz, CH), 144.64 (CH), 163.77 (d, JCP
13.7 Hz, C), 164.79 (d, JCP = 21.4 Hz, C), 165.01 (d, JCP
=
=
22.1 Hz, C); 31P NMR (CDCl3, 161.9 MHz) δ (ppm) Ϫ8.960; IR
(neat) 2986, 1729, 1653, 1491, 1446, 1404, 1251, 1023 cmϪ1; MS
(EI) m/z 407; exact mass Mϩ 407.1477 (calcd for C20H26NO6P
407.1498).
(CH2), 61.62 (CH2), 62.05 (d, JCP = 6.1 Hz, CH2), 63.92 (d, JCP
6.1 Hz, CH2), 117.82 (C), 128.45 (CH), 129.21 (CH), 129.33
(CH), 133.94 (d, JCP = 14.5 Hz, C), 138.42 (C), 166.90 (d, JCP
=
=
4.6 Hz, C), 171.74 (C); IR (KBr) 2984, 1738, 1709, 1317, 1255,
1023 cmϪ1; MS (EI) m/z 487, 489; exact mass Mϩ 487.0784
(calcd for C20H27BrNO6P 487.0759); Anal. Calcd for C20H27-
ClNO6P: C 49.19; H, 5.57; N 2.87; Found: C, 49.04; H, 5.48; N
2.99%.
Reactions of 15 and 16
The cyclization reactions of 15 and 16 were carried out by
the above described procedures for preparation of 4a and 8-Br.
The reaction time was 3 h for FeCl3 and 18 h for ZnBr2.
17-Cl (a single stereoisomer, Yield 49%)12 (Rf = 0.5 (CH2Cl2–
ether = 1 : 1)): Colorless crystals (hexane–EtOAc 1 : 1); mp 129–
130 ЊC; 1H NMR (400 MHz, CDCl3) δ (ppm) 1.14 (td, J = 7.1,
0.7 Hz, 3H), 1.22 (t, J = 7.1 Hz, 3H), 1.26 (td, J = 7.1, 0.7 Hz,
3H), 2.93 (dd, J = 28.0, 2.7 Hz, 1H), 3.60–3.70 (m, 1H), 3.81–
3.91 (m, 1H), 4.06–4.32 (m, 5H), 4.99 (dd, J = 14.6, 2.4, 1H),
5.03 (dd, J = 14.6, 1.8 Hz, 1H), 7.39–7.49 (m, 5H). Selected
NOEs are between δ 2.93 and 7.39–7.49 and δ 4.06–4.32 and
7.39–7.49; 13C NMR (100.6 MHz, CDCl3) δ (ppm) 13.97 (CH3),
16.23 (d, JCP = 8.4 Hz, CH3), 16.30 (d, JCP = 6.1 Hz, CH3), 41.72
(d, JCP = 1.5 Hz, CH), 44.81 (d, JCP = 130 Hz, CH), 62.28 (CH2),
62.32 (d, JCP = 8.4 Hz, CH2), 64.15 (d, JCP = 6.9 Hz, CH2), 71.01
(CH2), 126.49 (C), 128.03 (CH), 129.32 (CH), 129.81 (CH),
132.10 (d, JCP = 13.7 Hz, C), 135.91 (C), 166.70 (d, JCP = 5.3 Hz,
C), 174.64 (C); 31P NMR (CDCl3, 161.9 MHz) δ (ppm) Ϫ1.992;
Acknowledgements
This work was supported by the Ministry of Education,
Culture, Sports, Science, and Technology of the Japanese
Government and partially supported by CREST of JST (Japan
Science and Technology Corporation).
References
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IR (KBr) 2992, 2940, 1787, 1731, 1251, 1205, 1172, 1054 cmϪ1
;
MS (EI) m/z 430; exact mass Mϩ 430.0967 (calcd for C19H24-
ClO7P 430.0948); Anal. Calcd for C19H24ClO7P: C 52.97; H,
5.62; Found: C, 52.74; H, 5.53%.
17-Br (Yield 32%)12 (Rf = 0.5 (CH2Cl2–ether = 1 : 1)): Color-
1
less crystals (hexane–EtOAc 1 : 1); mp 118–119 ЊC; H NMR
(400 MHz, CDCl3) δ (ppm) 1.13 (td, J = 7.1, 0.6 Hz, 3H),
1.23 (t, J = 7.1 Hz, 3H), 1.25 (td, J = 7.1, 0.7 Hz, 3H), 2.87 (dd,
J = 27.9, 2.8 Hz, 1H), 3.55–3.65 (m, 1H), 3.77–3.87 (m, 1H),
4.08–4.33 (m, 5H), 4.90–4.92 (m, 2H), 7.37–7.47 (m, 5H).
Selected NOEs are between δ 4.08–4.33 and 7.37–7.47; 13C
NMR (100.6 MHz, CDCl3) δ (ppm) 14.00 (CH3), 16.21 (d, JCP
=
6.1 Hz, CH3), 16.28 (d, JCP = 7.6 Hz, CH3), 42.51 (CH), 44.57
(d, JCP = 130 Hz, CH), 62.28 (CH2), 64.12 (d, JCP = 6.1 Hz,
CH2), 72.99 (CH2), 116.99 (C), 128.25 (CH), 129.35 (CH),
129.71 (CH), 130.01 (d, JCP = 14.5 Hz, C), 137.59 (C), 166.67
(C), 174.67 (C); IR (KBr) 2986, 2940, 1787, 1729, 1249, 1048,
1025 cmϪ1; MS (EI) m/z 474, 476; exact mass Mϩ 474.9696
(calcd for C19H24BrO7P 474.0443).
18-Cl (Yield 74%)12 (Rf = 0.8 (ether–methanol = 2 : 1)): Pale
yellow crystals (hexane–EtOAc 1 : 1); mp 119–121 ЊC; 1H NMR
(400 MHz, CDCl3) δ (ppm) 1.13 (td, J = 7.1, 0.5 Hz, 3H), 1.19
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 2 5 7 – 2 6 4
263

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(c) S. Yamazaki, T. Takada, T. Imanishi, Y. Moriguchi and
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12 The products 17 and 18 have two chiral centers. The major isolated
products 17 and 18 consist of almost single stereoisomers by NMR.
A trace amount of impurity or their diastereoisomers were included
in 17-Br, 18-Cl and 18-Br. Configuration at C3 in the ring and
CH(CO2Et)(PO(OEt)2) could not be assigned by spectral data.
Stereoselective protonation of the presumed intermediate enolate A
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10 For intramolecular reactions of propargyl silanes: (a) H. Hiemstra
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Logusch, in Handbook of Organophosphorus Chemistry, ed. R.
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13 T. R. Kelly, Tetrahedron Lett., 1973, 437.
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332.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 2 5 7 – 2 6 4
264