Stereoselective approaches for the total synthesis of polyacetylenic (3R,8S)-falcarindiol

Article abstract of DOI:10.1055/s-2007-990944

The total synthesis of the polyacetylenic compound falcarindiol was achieved by two different routes from a common intermediate. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-990944

PAPER
A
Stereoselective Approaches for the Total Synthesis of Polyacetylenic
(3R,8S)-Falcarindiol
Total
S
ynthesis of
o
Polyacetylen
w
ic (3
R
,8
S
)
-Falcarin
r
diol avaram Sabitha,* Vangala Bhaskar, Ch. Srinivas Reddy, Jhillu S. Yadav
Organic Division I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 29 June 2007; revised 14 August 2007
activation of IKK and JAK in rat primary astrocytes.8 Fal-
carindiol (1) was also shown to exhibit antifungal activity9
towards Mycocentrospora acerina. Antimicrobial tests
showed growth inhibitory effects against Escherichia coli
DC2. The absolute configuration of falcarindiol (1) was
determined to be 3R,8S.10 Cai and co-workers11 reported
the first stereoselective synthesis of falcarindiol (1) from
L-tartaric acid and D-xylose.
In continuation of our studies on polyacetylenes,12 we
herein report two different strategies for the stereoselec-
tive synthesis of the polyacetylenic falcarindiol (1)
(Scheme 1). In route a, the synthesis of falcarindiol (1)
was achieved by coupling of enyne fragment 3 with the
acetylenic alcohol 4 by a Cadiot–Chodkiewicz reaction,
followed by conversion into the allylic alcohol. In route b,
enyne fragment 3 gave falcarindiol after a simple reaction
sequence via 6.
Abstract: The total synthesis of the polyacetylenic compound fal-
carindiol was achieved by two different routes from a common in-
termediate.
Key words: falcarindiol, anticancer activity, natural products,
alkynes, total synthesis
Falcarindiol (1) is a polyacetylenic natural product isolat-
ed from various umbelliferae1 species. It has been isolated
from Aegopodium podagraria L,2 and was later also iso-
lated from methanol extracts of Peucedanum praerup-
torum and Peucedanum japonicum, and showed
antimutagenic activity3a and an inhibitory effect on mam-
malian topoisomerase I activity.3b Falcarindiol (1) has
also been isolated from the tropical plant Dendropanax
arboreus and found to show anticancer activity.4 This
polyacetylenic compound is also found in carrot root.5 It
was also isolated from Anethum graveolens and showed
antibacterial activity.6 Novel antiproliferative falcarindiol
furanocoumarin ethers have been extracted from the root
of Angelica japonica.7 Falcarindiol (1) impairs the expres-
sion of inducible nitric oxide synthase by abrogating the
Accordingly, the synthesis of the left-hand side of the tar-
get molecule (as drawn in Scheme 1) began with heptyl
bromide (5) (Scheme 2). Coupling of 5 with propargyl al-
cohol gave acetylenic alcohol 7 in 65% yield. Partial re-
duction of the triple bond in compound 7 by the Lindlar
OH
HO
falcarindiol (1)
route b
route a
O
O
H
15C7
H15C7
O
TBSO
OH
TBSO
HO
6
2
O
O
HO
H15C7
Br
4
TBSO
3
Br
5
Scheme 1 Retrosynthetic analysis for the synthesis of falcarindiol (1)
SYNTHESIS 2008, No. x, pp 000A–000G
x
x.
x
x
.
2
0
0
7
Advanced online publication: xx.xx.2007
DOI: 10.1055/s-2007-990944; Art ID: Z16007SS
© Georg Thieme Verlag Stuttgart · New York

B
G. Sabitha et al.
PAPER
Br
+
OH
a
OH
OH
5
7
b
c
TMS
HO
8
9
d
e
Br
Br
Br
11
O
HO
HO
10
f
g
Br
3
TBSO
12
Scheme 2 Reagents and conditions: (a) Li/liquid NH3, Fe(NO3)3 (cat.), THF, –33 °C, 3 h, 65%; (b) H2, Lindlar cat., quinoline, EtOAc, r.t., 4
h, 90%; (c) 1. IBX, DMSO, CH2Cl2, 0 °C to r.t., 77%; 2. TMSC≡CH, n-BuLi, THF, –78 °C, 3 h, 89%; (d) NBS, AgNO3, acetone, r.t., 1 h, 87%;
(e) DMP, CH2Cl2, 0 °C to r.t., 1 h, 75%; (f) Me-(S)-CBS, BH3·SMe2, THF, –78 °C, 12 h, 70%; (g) TBSCl, imidazole, r.t., 2 h, 90%.
catalyst provided (Z)-allyl alcohol 8 in 90% yield. Oxida- The synthesis of the right-hand side fragment 4 of falcar-
tion of alcohol 8 by 2-iodoxybenzoic acid (IBX) afforded indiol (1; as drawn in Scheme 1) started with diethyl L-
an aldehyde, which, without isolation, was converted into (+)-tartrate [L-(+)-DET, 13] (Scheme 3). Diol 14 was pre-
1-(trimethylsilyl)alk-1-yn-3-ol 9 in 89% yield by treat- pared as previously described15 from diethyl L-(+)-tartrate
ment with (trimethylsilyl)acetylene in the presence of n- (13) by protection of the diol as the isopropylidene acetal
butyllithium in tetrahydrofuran at –78 °C for three hours followed by lithium aluminum hydride reduction of the
(Scheme 2).
carboxy groups (Scheme 3).
On treatment with N-bromosuccinimide and silver(I) ni- Desymmetrization of compound 14 could be achieved by
trate,13 compound 9 afforded 1-bromoalk-1-yne 10, which its conversion into the tert-butyldimethylsilyl ether 15 in
after oxidation provided ketone 11 (Scheme 2). The 81% yield (Scheme 3). Aldehyde 16 resulting from Swern
Corey–Bakshi–Shibata (CBS) enantioselective reduction oxidation proved to be unstable, and was immediately
of the carbonyl group of 11 was carried out with the bo- treated with a mixture of carbon tetrabromide and triphe-
rane–dimethyl sulfide complex in the presence of the nylphosphine to give dibromoalkene compound 17. The
commercially available Me-(S)-CBS reagent under stan- reaction of dibromoalkene 17 with three equivalents eth-
dard conditions,14 and provided alcohol 12 with the re- ylmagnesium bromide in tetrahydrofuran gave alkyne 18
quired stereochemistry at the hydroxy group (Scheme 2). in 78% yield (Scheme 3). Deprotection of the silyl group
The optical rotation and other spectral data of compound furnished fragment 4 (Scheme 3).
12 were in agreement with the reported data.11 Next, pro-
Finally, coupling of bromoacetylene 3 with alkyne 4 by
tection of the secondary hydroxy group as the tert-bu-
tyldimethylsilyl ether provided 3 (Scheme 2).
the Cadiot–Chodkiewicz procedure at 0 °C provided di-
:
O
O
b
a
L-(+)-DET
O
O
d
OH
OTBS
HO
c
HO
13
14
15
O
O
O
O
OTBS
OTBS
OTBS
Br
O
O
18
Br
17
O
16
OH
e
O
O
4
Scheme 3 Reagents and conditions: (a) TBSCl, imidazole, r.t., 2 h, 81%; (b) (COCl)2, DMSO, CH2Cl2, Et3N, –78 °C, 1 h, 81%; (c) Ph3P,
CBr4, CH2Cl2, –10 °C, 1 h, 75%; (d) EtMgBr, THF, 0 °C to r.t., 1 h, 78%; (e) TBAF, THF, r.t., 1 h, 81%.
Synthesis 2008, No. x, A–G © Thieme Stuttgart · New York

PAPER
Total Synthesis of Polyacetylenic (3R,8S)-Falcarindio
C
O
a
b
+
3
4
O
TBSO
HO
2
OH
O
c
( )5
( )5
O
TBSO
TBSO
20
I
19
d
1
Scheme 4 Reagents and conditions: (a) NH2OH·HCl, 70% aq EtNH2, CuCl, H2O, MeOH, 0 °C to r.t., 2 h, 64%; (b) Ph3P, I2, toluene, 0 °C to
r.t., 45 min, 90%; (c) Zn, NaI, EtOH, reflux, 3–4 h, 75%; (d) TBAF, 0 °C to r.t., 1 h, 75%.
b
OH
a
+
Br
H15C7
21
H15C7
OH
TBSO
TBSO
TBSO
3
c
CO2Et
OH
H15C7
H15C7
TBSO
23
22
O
d
e
( )5
OH
TBSO
6
OH
f
( )5
1
TBSO
20
Scheme 5 Reagents and conditions: (a) NH2OH·HCl, 70% aq EtNH2, CuCl, H2O, MeOH, 0 °C to r.t., 2 h, 62%; (b) 1. IBX, DMSO, CH2Cl2,
0 °C, 2 h, 82%; 2. Ph3P=CHCO2Et, CH2Cl2, 6 h, r.t., 84%; (c) DIBAL-H, CH2Cl2, –10 °C, 3 h, 82%; (d) 4 Å MS, (+)-DET, Ti(Oi-Pr)4,
cumenehydroperoxide, CH2Cl2, –25 °C, 5–6 h, 78%; (e) 1. Ph3P, I2, toluene, 0 °C to r.t., 45 min, 90%. 2. Zn, NaI, EtOH, reflux, 3–4 h, 75%;
(f) TBAF, 0 °C to r.t., 1 h, 87%.
acetylenic product 2 in 64% yield (Scheme 4). Subse- hol 6 was converted into the corresponding iodide, the
quently, conversion of the primary hydroxy group in 2 treatment of which with activated zinc in ethanol afforded
into an iodo group gave 19 in 90% yield. Reaction of io- 20, which, upon deprotection of the tert-butyldimethylsi-
dide 19 with activated zinc in refluxing ethanol resulted in lyl group, provided falcarindiol (1) (Scheme 5). The data
a facile elimination to afford allylic alcohol 20. Deprotec- of the compound thus obtained are in full agreement with
tion of the tert-butyldimethylsilyl group led to the target those of the synthetic compound 1 obtained from route a.
molecule, falcarindiol (1) (Scheme 4). The optical rota-
In conclusion, we have achieved the synthesis of falcarin-
1
tion and H and 13C NMR spectroscopic data of the syn-
diol (1) by two routes from a common intermediate.
thesized 1 were in agreement with the reported data of the
natural product.10
Reactions were conducted under N2 in anhyd solvents such as
In route b (cf. Scheme 1), compound 3 was coupled with
propargylic alcohol to provide diacetylenic alcohol 21 in
62% yield (Scheme 5). Oxidation with 2-iodoxybenzoic
acid (IBX) yielded an aldehyde, which underwent a Wit-
tig reaction with a stable two-carbon ylide to furnish the
corresponding ester 22 in 84% yield. Subsequently, 22
was reduced to its corresponding allyl alcohol 23, in 82%
yield, by diisobutylaluminum hydride in dichloromethane
at –10 °C (Scheme 5). Sharpless epoxidation of allylic al-
cohol 23 in the presence of natural tartrate provided the
desired epoxy alcohol 6 in 78% yield. The primary alco-
CH2Cl2, THF, CCl4, benzene, and EtOAc. All reactions were mon-
itored by TLC (silica-coated plates, visualizing under UV light).
Light petroleum (bp 60–80 °C) was used. Yields refer to chromato-
graphically and spectroscopically (1H and 13C NMR) homogeneous
material. Air-sensitive reagents were transferred by syringe or can-
nula. Evaporation of solvents was performed at reduced pressure on
a Buchi rotary evaporator. 1H and 13C NMR spectra of samples in
CDCl3 were recorded on Varian FT-200 MHz (Gemini) and Bruker
UXNMR FT-300 MHz (Avance) spectrometers. Chemical shifts d
are reported relative to TMS (d = 0.0) as internal standard. Mass
spectra were recorded under EI conditions at 70 eV on an LC-MSD
(Agilent technologies) spectrometer. Column chromatography was
Synthesis 2008, No. x, A–G © Thieme Stuttgart · New York

D
G. Sabitha et al.
PAPER
performed on silica gel (60–120 mesh) supplied by Acme Chemical
Co., India. TLC was performed on Merck 60 F-254 silica gel plates.
Optical rotations were measured with a JASCO DIP-370 polarime-
ter at 20 °C.
Yield: 4.4 g (89%).
IR (neat): 3337, 3021, 2958, 2826, 2856, 2172, 1654, 1461, 1249,
1031, 968, 844, 759, 699 cm–1.
1H NMR (CDCl3, 300 MHz): d = 0.17 (s, 9 H), 0.89 (t, J = 6.7 Hz,
3 H), 1.28 (br s, 8 H), 1.39 (t, J = 6.7 Hz, 2 H), 1.67 (br s, 1 H), 2.12
(q, J = 6.7 Hz, 2 H), 5.05 (d, J = 6.7 Hz, 1 H), 5.44–5.59 (m, 2 H).
Dec-2-yn-1-ol (7)
Propargyl alcohol (10.0 g, 178.57 mmol) in anhyd THF (50 mL)
was added to a stirred suspension of LiNH2 [prepared in situ from
Li metal (7.49 g) in liquid NH3 (300 mL) in the presence of
Fe(NO3)3 (cat.)] at –78 °C over 15 min, and the resulting gray mix-
ture was stirred for another 1 h. 1-Bromoheptane (5; 38.35 g, 214.24
mmol) in anhyd THF (50 mL) was added dropwise to the mixture,
which was stirred for another 6 h at the same temperature. The mix-
ture was quenched with solid NH4Cl (15 g), and then the excess
NH3 was allowed to evaporate. The residue was dissolved in H2O
(50 mL) and the mixture was filtered through a small pad of Celite.
The filtrate was extracted with EtOAc (4 × 50 mL). The organic lay-
ers were combined, washed with H2O (50 mL) and brine (2 × 20
mL), and dried (Na2SO4). The solvent was removed under reduced
pressure and the residue was purified by column chromatography
(silica gel, hexane–EtOAc, 9:1).
MS (EI, 70 eV): m/z = 275 [M+ + Na].
(Z)-1-Bromododec-4-en-1-yn-3-ol (10)
A soln of 9 (4.0 g, 15.86 mmol) in acetone (40 mL) was treated with
NBS (2.82 g, 15.86 mmol) and AgNO3 (200 mg) at r.t. After 1 h, the
mixture was poured into ice-cooled H2O and the precipitated solid
was collected by filtration and washed with EtOAc. The resulting
filtrate was washed with brine (2 × 20 mL) and dried (Na2SO4).
Evaporation of the solvent followed by column chromatography
(silica gel, hexane–EtOAc, 9:1) afforded 10.
Yield: 3.2 g (84%).
IR (neat): 3379, 3021, 2924, 2854, 2211, 1725, 1648, 1631, 1460,
1377, 1253, 1031, 967, 754, 678 cm–1.
1H NMR (CDCl3, 200 MHz): d = 0.89 (t, J = 6.8 Hz, 3 H), 1.18–1.50
(m, 10 H), 1.81 (br s, 1 H), 2.00–2.20 (m, 2 H), 5.11 (d, J = 7.0 Hz,
1 H), 5.41–5.64 (m, 2 H).
Yield: 22.5 g (65%); pale yellow liquid.
IR (neat): 3334, 2928, 2857, 2225, 1670, 1456, 1227, 1136, 1012,
972 cm–1.
1H NMR (CDCl3, 300 MHz): d = 0.89 (t, J = 6.7 Hz, 3 H), 1.23–1.43
(m, 9 H), 1.50 (m, 2 H), 2.19 (t, J = 2.26 Hz, 2 H), 4.20 (m, 2 H).
ESI-MS: m/z = 282 [M+ + Na].
(Z)-1-Bromododec-4-en-1-yn-3-one (11)
MS (EI, 70 eV): m/z = 155 [M+ + 1].
A soln of 10 (3.0 g, 12.14 mmol) in anhyd CH2Cl2 (15 mL) was add-
ed over 15 min to a stirred soln of DMP (6.18 g, 14.57 mmol) in an-
hyd CH2Cl2 (5 mL). After 60 min, the homogeneous mixture was
diluted with CH2Cl2 (20 mL) and poured into cold sat. NaHCO3 (10
mL) and 20% aq Na2S2O3 (10 mL). The combined organic layer was
washed with aq NaHCO3 (2 × 10 mL) and brine (2 × 10 mL) and
dried (Na2SO4). The solvents were evaporated under reduced pres-
sure. The residue was purified by column chromatography (silica
gel, hexane–EtOAc, 9:1).
(Z)-Dec-2-en-1-ol (8)
The Lindlar catalyst (Pd/BaSO4) (1.0 g) was added to a soln of 7
(10.0 g, 64.93 mmol) in anhyd EtOAc (50 mL), and the mixture was
stirred at r.t. under a H2 atmosphere for 4 h. Then the mixture was
filtered and washed with EtOAc (3 × 60 mL), and the filtrate was
concentrated under reduced pressure and purified by column chro-
matography (silica gel, PE–EtOAc, 9:1).
Yield: 9.2 g (90%); colorless liquid.
IR (neat): 3326, 3014, 2925, 2855, 1655, 1461, 1030 cm–1.
Yield: 2.55 g (86%); colorless oil.
IR (neat): 2925, 2854, 2183, 1644, 1460, 1245, 974 cm–1.
1H NMR (CDCl3, 300 MHz): d = 0.89 (t, J = 6.7 Hz, 3 H), 1.18–1.44
(m, 10 H), 2.06 (q, J = 6.7 Hz, 2 H), 4.14 (d, J = 6.0 Hz, 2 H), 5.43–
5.64 (m, 2 H).
1H NMR (CDCl3, 200 MHz): d = 0.89 (t, J = 6.7 Hz, 3 H), 1.13–1.68
(br s, 10 H), 2.20–2.38 (m, 1 H), 2.56–2.73 (m, 2 H), 6.03–6.36 (m,
2 H).
MS (EI, 70 eV): m/z = 179 [M+ + Na].
MS (EI, 70 eV): m/z = 257 [M+].
(Z)-1-(Trimethylsilyl)dodec-4-en-1-yn-3-ol (9)
(3S,4Z)-1-Bromododec-4-en-1-yn-3-ol (12)
A soln of 8 (5.0 g, 32.04 mmol) in anhyd CH2Cl2 (20 mL) was added
to an ice-cooled soln of IBX (17.94 g, 64.10 mmol) in DMSO (15.0
mL). The mixture was stirred at r.t. for 2 h and then filtered through
a Celite pad and washed with Et2O (2 × 50 mL). The combined or-
ganic filtrates were washed with H2O (2 × 50 mL) and brine (2 × 50
mL), dried (Na2SO4), and concentrated in vacuo. The crude product
was purified by column chromatography (silica gel, PE–EtOAc,
9:1); this gave the aldehyde as an unstable viscous liquid, which
was directly used for the next reaction.
A 1.0 M soln of BH3·SMe2 in THF (5.8 mL, 2 equiv) was added to
a 1.0 M soln of (S)-Me-CBS-oxazaborolidine in THF (0.46 mL,
1.55 mmol) at –78 °C under N2, and the mixture was stirred for 30
min. A soln of 11 (1.0 g, 3.89 mmol) in THF (5.0 mL) was added
dropwise, and the mixture was stirred for 12 h at –78 °C. The reac-
tion was quenched by the addition of MeOH (4 mL) and the mixture
was allowed to warm to r.t. The mixture was diluted with H2O (5
mL), the two phases were separated, and the aqueous layer was ex-
tracted with CH2Cl2 (3 × 20 mL). The combined organic fractions
were washed with H2O (1 × 15 mL), dried (MgSO4), and concen-
trated under reduced pressure. The residue was purified by column
chromatography (silica gel, hexane–EtOAc, 8:2).
Yield: 3.8 g (77%).
A 1.5 M soln of n-BuLi in hexane (15.58 mL, mmol) was added to
a soln of (trimethylsilyl)acetylene (2.28 g, 23.36 mmol) in anhyd
THF (6 mL) at –78 °C under N2. The mixture was stirred for 2 h and
then a soln of the aldehyde (3.0 g, 19.48 mmol) in anhyd THF (10
mL) was added slowly. The soln was stirred at –78 °C for 3 h and
then quenched with sat. aq NH4Cl. The organic phase was separated
and the aqueous phase was extracted with EtOAc (2 × 15 mL). The
combined organic phases were washed with brine (2 × 50 mL) and
dried (Na2SO4). The crude product was purified by column chroma-
tography (silica gel, hexane–EtOAc, 9:1).
Yield: 0.700 g (70%); colorless liquid; [a]D25 +78.1 (c 1.0, CHCl3).
IR (neat): 3379, 2924, 2854, 2211, 1725, 1648, 1631, 1460, 1377,
1253, 1031, 967, 754, 678 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.89 (t, J = 6.8 Hz, 3 H), 1.18–1.50
(m, 10 H), 1.81 (br s, 1 H), 2.00–2.20 (m, 2 H), 5.11 (d, J = 7.0 Hz,
1 H), 5.41–5.64 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 133.5, 128.3, 80.1, 58.7, 44.9, 31.6,
29.2, 29.1, 29.0, 27.4, 22.5, 14.0.
Synthesis 2008, No. x, A–G © Thieme Stuttgart · New York

PAPER
Total Synthesis of Polyacetylenic (3R,8S)-Falcarindio
E
ESI-MS: m/z = 282 [M+ + Na].
tert-Butyl{[(4S,5S)-5-ethynyl-2,2-dimethyl-1,3-dioxolan-4-
yl]methoxy}dimethylsilane (18)
[(1S,2Z)-1-(2-Bromoethynyl)dec-2-enyloxy](tert-butyl)dimeth-
ylsilane (3)
A freshly prepared soln of EtMgBr [from EtBr (4.19 mL) and Mg
(1.34 g)] was added to a stirred soln of 17 (4 g, 9.36 mmol) in anhyd
THF (30 mL) at 0 °C, and stirring was continued for 10 min at 0 °C
and 1 h at r.t. Sat. aq NH4Cl (10 mL) was added to the mixture,
which was then extracted with EtOAc (3 × 50 mL). The extract was
washed with H2O (2 × 20 mL) and brine (2 × 20 mL), dried, and
concentrated under reduced pressure. Column chromatography (sil-
ica gel, hexane–EtOAc, 8:2) of the crude product gave 18.
TBSCl (0.95 g, 6.31 mmol) was added portionwise to a stirred soln
of 12 (1.3 g, 5.26 mmol) and imidazole (0.716 g, 10.52 mmol) in an-
hyd CH2Cl2 (15 mL) at 0 °C. The mixture was stirred at r.t. for 2 h
and then quenched with H2O. The CH2Cl2 layer was separated and
the aqueous layer was extracted with additional CH2Cl2 (2 × 30
mL). The combined organic layers were washed with H2O (2 × 10
mL) and brine (2 × 10 mL) and dried (Na2SO4). The solvent was re-
moved in vacuo and the residue was purified by column chromatog-
raphy (silica gel, hexane–EtOAc, 9:1).
Yield: 1.95 g (78%); [a]D25 –11.9 (c 2.64, CHCl3).
IR (neat): 3307, 2988, 2930, 2858, 2250, 1464, 1253, 1058, 837,
777, 670 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.10 (s, 6 H), 0.92 (s, 9 H), 1.40,
1.48 (2 s, 6 H), 2.45 (d, J = 1.9 Hz, 1 H), 3.70 (d, J = 3.8 Hz, 2 H),
4.03–4.19 (m, 1 H), 4.55 (dd, J = 6.7 Hz, 1 H).
Yield: 1.7 g (90%); colorless liquid; [a]D25 +67.0 (c 0.5, CHCl3).
IR (neat): 3444, 2928, 2857, 2210, 1696, 1631, 1464, 1386, 1253,
1075, 838, 778, 676 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.10 (s, 3 H), 0.13 (s, 3 H), 0.85–
0.93 (s, 12 H), 1.18–1.47 (br s, 10 H), 2.06 (q, J = 6.7 Hz, 2 H), 5.09
(d, J = 6.7 Hz, 1 H), 5.36–5.50 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 131.3, 129.8, 80.6, 59.8, 44.0, 31.7,
29.6, 29.2, 29.1, 29.0, 27.5, 25.6, 22.5, 14.0.
MS (EI, 70 eV): m/z = 293 [M+ + Na].
[(4S,5S)-5-Ethynyl-2,2-dimethyl-1,3-dioxolan-4-yl]methanol
(4)
A 1 M soln of TBAF in THF (1.71 mL, 5.92 mmol) was added to a
soln of 18 (1.6 g, 5.92 mmol) in THF (15 mL) at 0 °C. The mixture
was stirred at r.t. for 1 h. After completion of the reaction, the mix-
ture was diluted with Et2O (30 mL). The combined organic layers
were washed with sat. aq NaCl (2 × 10 mL), dried (Na2SO4), and
concentrated under reduced pressure. The crude product was puri-
fied by column chromatography (silica gel, hexane–EtOAc, 7:3).
ESI-MS: m/z = 373 [M+ + 1].
tert-Butyl{[(4S,5S)-5-(2,2-dibromovinyl)-2,2-dimethyl-1,3-di-
oxolan-4-yl]methoxy}dimethylsilane (17)
A 500-mL two-necked round-bottom flask equipped with a magnet-
ic stirring bar, septum, and N2 inlet was charged with oxalyl chlo-
ride (6.29 mL, 72.44 mmol) and anhyd CH2Cl2 (50 mL). The soln
was cooled to –78 °C and then DMSO (10.25 mL, 144.87 mmol) in
anhyd CH2Cl2 (40 mL) was added dropwise. The soln was stirred
for 1 h at –78 °C and then 15 (10 g, 36.23 mmol) in CH2Cl2 was add-
ed by syringe over 5 min. The resulting white suspension was aged
for 1 h at –78 °C, and then Et3N (21.95 mL, 216.83 mmol) was add-
ed. The mixture was stirred for 15 min at –78 °C, warmed to –30 °C
over 1 h, and then quenched by the addition of 0.5 M aq NaHSO4
(100 mL). The combined organic layers were washed with H2O (2
× 100 mL) and brine (2 × 50 mL), dried (Na2SO4), and concentrated.
The yellow oil was purified by flash column chromatography (silica
gel, hexane–EtOAc, 7:3); this gave an unstable viscous liquid.
Yield: 0.750 g (81%); colorless liquid; [a]D25 –19.2 (c 1.0, CHCl3).
IR (neat): 3431, 3307, 2985, 2938, 2858, 2245, 1464, 1253, 1058
cm–1.
1H NMR (300 MHz, CDCl3): d = 1.42, 1.48 (2 s, 6 H), 2.12 (br s, 1
H), 2.47 (d, J = 2.2 Hz, 1 H), 3.63 (dd, J = 12.0, 3.7 Hz, 1 H), 3.85
(dd, J = 3.0, 1.5 Hz, 1 H), 4.09–4.16 (m, 1 H), 4.54 (dd, J = 7.5, 2.2
Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 110.6, 80.8, 80.5, 78.4, 69.8, 63.7,
25.8, 25.0.
MS (EI, 70 eV): m/z = 157 [M+ + 1].
Yield: 9.92 g (81%).
{(4S,5S)-5-[(5S,6Z)-5-(tert-Butyldimethylsiloxy)tetradec-6-ene-
1,3-diynyl]-2,2-dimethyl-1,3-dioxolan-4-yl}methanol (2)
A round-bottom flask was charged with a soln of NH2OH·HCl
(0.076 mg, 1.1 mmol) in H2O (0.8 mL), 70% aq EtNH2 (3.0 mL),
CuCl (0.0137 mg, 0.14 mmol), and MeOH (10 mL). Air was com-
pletely replaced by N2. Alkyne 4 (0.648 mg, 4.15 mmol) in MeOH
(3 mL) was added in one portion to the stirring mixture at 0 °C, and
then 3 (1.0 g, 2.77 mmol) in MeOH (3 mL) was added over 10 min
to the resulting yellow suspension, while the temperature was main-
tained at 0 °C. The mixture was stirred at r.t. for 2 h, and then the
reaction was quenched with sat. aq NH4Cl (5 mL), and the mixture
was extracted with Et2O (3 × 20 mL). The Et2O layer was washed
with brine (2 × 10 mL), dried (Na2SO4), and concentrated under
vacuum. The residue was purified by column chromatography (sil-
ica gel, hexane–EtOAc, 7:3).
A soln of PPh3 (19.14 g, 72.96 mmol) in anhyd CH2Cl2 (50 mL) was
added dropwise to a stirred soln of CBr4 (12.10 g, 36.49 mmol) in
anhyd CH2Cl2 (150 mL) under N2 at –10 °C. An intense yellow col-
or developed, which darkened after 30 min at this temperature.
Then a soln of 16 (5.0 g, 18.24 mmol) and Et3N (2.3 mL) in anhyd
CH2Cl2 (100 mL) was added at the same temperature. After stirring
at –10 °C for 60 min, the mixture was allowed to warm to 0 °C.
Then the mixture was warmed to r.t., concentrated to 150 mL, and
poured into hexane (600 mL). The mixture was filtered through a
Celite pad and the solid was washed with cold Et2O (3 × 60 mL).
The filtrate was concentrated under reduced pressure. The product
was purified by flash column chromatography (silica gel, hexane–
EtOAc, 9:1).
Yield: 5.9 g (75%); [a]D25 –5.9 (c 0.5, CHCl3).
Yield: 0.800 g (64%); colorless liquid; [a]D25 +118.6 (c 1.0, CHCl3).
IR (neat): 2986, 2930, 2858, 1624, 1463, 1377, 1252, 1072, 781,
675 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.07 (s, 6 H), 0.90 (s, 9 H), 1.40,
1.47 (2 s, 6 H), 3.70–3.80 (m, 3 H), 4.56 (d, J = 7.5 Hz, 1 H), 6.45
(d, J = 8.3 Hz, 1 H).
IR (neat): 3448, 2928, 2856, 2151, 1651, 1464, 1378, 1253, 1216,
1160, 1063, 839, 778, 671 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.10 (s, 3 H), 0.13 (s, 3 H), 0.89
(br s, 12 H), 1.16–1.52 (br s, 16 H), 2.06 (q, J = 6.2 Hz, 2 H), 3.50–
3.72 (m, 1 H), 3.86 (d, J = 12.5 Hz, 1 H), 4.15 (q, J = 3.1 Hz, 1 H),
4.63 (d, J = 7.8 Hz, 1 H), 5.13 (d, J = 6.1 Hz, 1 H), 5.35–5.53 (m, 2
H).
MS (EI, 70 eV): m/z = 431 [M+ + 1].
Synthesis 2008, No. x, A–G © Thieme Stuttgart · New York

F
G. Sabitha et al.
PAPER
13C NMR (75 MHz, CDCl3): d = 132.1, 129.0, 110.9, 81.6, 80.7,
75.8, 70.8, 67.8, 66.7, 60.7, 59.4, 31.7, 29.2, 29.1, 29.0, 27.7, 26.6,
25.9, 25.6, 22.5, 14.0, –4.6.
1H NMR (200 MHz, CDCl3): d = 0.89 (t, J = 6.6 Hz, 3 H), 1.19–1.25
(br s, 10 H), 1.82–2.30 (m, 4 H), 4.95 (d, J = 5.3 Hz, 1 H), 5.13 (d,
J = 8.5 Hz, 1 H), 5.21 (dt, J = 9.7, 1.1 Hz, 1 H), 5.49 (dt, J = 16.9,
1.2 Hz, 1 H), 5.71–6.05 (m, 3 H).
13C NMR (75 MHz, CDCl3): d = 136.7, 133.7, 128.7, 116.4, 80.4,
78.4, 71.0, 68.4, 63.6, 58.6, 31.8, 29.6, 29.2, 29.1, 29.0, 22.6, 14.0.
MS (EI, 70 eV): m/z = 471 [M+ + Na].
tert-Butyl{(1S)-5-[(4S,5R)-5-(iodomethyl)-2,2-dimethyl-1,3-di-
oxolan-4-yl]-1-[(Z)-non-1-enyl]penta-2,4-diynyloxy}dimethyl-
silane (19)
MS (EI, 70 eV): m/z = 283 [M+ + Na].
Ph3P (1.77 g, 6.76 mmol), imidazole (0.37 g, 5.57 mmol), and I2
(0.84 g, 6.68 mmol) were added to a stirred soln of 2 (1.0 g, 2.22
mmol) in toluene (20 mL) at 0 °C. The mixture was stirred at r.t. for
45 min, and the solid that formed was collected by filtration and
washed with Et2O (2 × 20 mL). The filtrate was washed with 10%
aq Na2S2O3 (2 × 10 mL), H2O (2 × 10 mL), and brine (2 × 10 mL).
The organic layer was dried (Na2SO4), concentrated under reduced
pressure, and purified by column chromatography (silica gel, hex-
ane–EtOAc, 8:2).
(6S,7Z)-6-(tert-Butyldimethylsiloxy)pentadec-7-ene-2,4-diyn-1-
ol (21)
A round-bottom flask was charged with a soln of NH2OH·HCl
(0.076 mg, 1.1 mmol) in H2O (0.8 mL), 70% aq EtNH2 (3.0 mL),
CuCl (0.0137 mg, 0.14 mmol), and MeOH (10 mL). Air was com-
pletely replaced by N2. Propargylic alcohol (0.387 mg, 6.92 mmol)
in MeOH (3 mL) was added in one portion at 0 °C to the stirring
mixture, and then 3 (1.0 g, 2.77 mmol) in MeOH (3 mL) was added
over 10 min to the resulting yellow suspension, while the tempera-
ture was maintained at 0 °C. The mixture was stirred at r.t. for 2 h,
and then the reaction was quenched with sat. aq NH4Cl (5 mL) and
extracted with Et2O (3 × 15 mL). The Et2O layer was washed with
brine (2 × 10 mL), dried (Na2SO4), and concentrated under vacuum.
The residue was purified by column chromatography (silica gel,
hexane–EtOAc, 8:2).
Yield: 1.13 g (90%); colorless liquid.
IR (neat): 2955, 2928, 2856, 2250,1654, 1464, 1377, 1321, 1253,
1171, 1049, 965, 839, 779, 671 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.11 (s, 3 H), 0.13 (s, 3 H), 0.89
(br s, 12 H), 1.21–1.54 (m, 16 H), 2.06 (q, J = 6.0 Hz, 2 H), 3.21–
3.35 (m, 2 H), 4.05 (q, J = 6.0 Hz, 1 H), 4.50 (d, J = 6.7 Hz, 1 H),
5.13 (d, J = 6.7 Hz, 1 H), 5.44 (q, J = 3.0 Hz, 2 H).
Yield: 0.600 g (62%); colorless liquid.
IR (neat): 3447, 2927, 2855, 2250, 1637, 1464, 1253, 1027, 836,
775, 670 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.11, 0.13 (2 s, 6 H), 0.89 (br s, 12
H), 1.34–1.54 (m, 10 H), 2.07 (q, J = 6.7 Hz, 2 H), 4.31 (br s, 2 H),
5.14 (d, J = 6.7 Hz, 1 H), 5.38–5.50 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 132.1, 129.0, 111.7, 81.1, 80.3,
75.5, 71.5, 71.3, 67.7, 59.4, 31.7, 29.2, 29.1, 29.0, 27.7, 27.2, 26.3,
25.6, 22.6, 18.1, 14.0, –0.03, –4.54.
MS (EI, 70 eV): m/z = 581 [M+ + Na].
(3R,8S,9Z)-8-(tert-Butyldimethylsiloxy)heptadeca-1,9-diene-
4,6-diyn-3-ol (20)
A mixture of 19 (1.0 g, 27.2 mmol), NaI (0.53 g, 3.58 mmol), and
activated Zn dust (0.46 g, 7.16 mmol) in EtOH (10 mL) was re-
fluxed under N2 for 4 h. The solvent was removed under reduced
pressure and the residue was purified by column chromatography
(silica gel, hexane–EtOAc, 7:3).
MS (EI, 70 eV): m/z = 349 [M+ + 1].
Ethyl (2E,8S,9Z)-8-(tert-Butyldimethylsiloxy)heptadeca-2,9-di-
ene-4,6-diynoate (22)
A soln of 21 (1.5 g, 4.31 mmol) in anhyd CH2Cl2 (15 mL) was added
to an ice-cooled soln of IBX (2.41 g, 8.62 mmol) in DMSO (4.5
mL). The mixture was stirred at r.t. for 2 h and then filtered through
a Celite pad and washed with Et2O (3 × 20 mL). The combined or-
ganic filtrates were washed with H2O (2 × 20 mL) and brine (2 × 10
mL), dried (Na2SO4), and concentrated under vacuum. The crude
product was purified by column chromatography (silica gel, PE–
EtOAc, 9:1); this provided the aldehyde as an unstable viscous liq-
uid, which was directly used for the next reaction.
Yield: 0.5 g (75%); pale yellow liquid; [a]D25 +120.6 (c 0.5, CHCl3).
IR (neat): 3391, 3024, 2928, 2856, 2150, 1646, 1465, 1315, 1254,
1078, 933, 837, 778, 672 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.10 (s, 3 H), 0.13 (s, 3 H), 0.89
(br s, 12 H), 1.28 (br s, 8 H), 1.35–1.44 (m, 2 H), 1.76 (br s, 1 H),
2.01–2.11 (m, 2 H), 4.89 (t, J = 5.0 Hz, 1 H), 5.14 (d, J = 6.2 Hz, 1
H), 5.23 (dt, J = 10.1, 1.1 Hz, 1 H), 5.40–5.47 (m, 2 H), 5.49 (t,
J = 1.1 Hz, 1 H), 5.85–5.99 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 135.9, 132.1, 129.2, 117.5, 80.7,
77.6, 70.6, 67.9, 63.5, 59.5, 31.7, 29.2, 29.1, 29.0, 27.7, 25.7, 22.6,
18.1, 14.0, –4.5.
Yield: 1.23 g (82%).
Ph3P=CHCO2Et (1.84 g, 5.28 mmol) was added to a soln of the
above aldehyde (1.2 g, 3.46 mmol) in anhyd CH2Cl2 (15 mL) and
the mixture was stirred for 6 h at r.t. The completion of the reaction
was monitored by TLC. The CH2Cl2 was removed under reduced
pressure, the residue was dissolved in Et2O, and PE was added. The
Ph3PO that had crystallized was removed by filtration and the fil-
trate was concentrated to dryness. The crude product was chromato-
graphed (silica gel, hexane–EtOAc, 9:1); this gave pure 22.
MS (EI, 70 eV): m/z = 397 [M+ + Na].
(3R,8S)-Falcarindiol (1)
Yield: 1.22 g (84%); colorless liquid; [a]D25 +89.2 (c 1.0, CHCl3).
A 1 M soln of TBAF in THF (0.34 mL, 1.20 mmol) was added to a
soln of 20 (0.450 g, 1.20 mmol) in THF (10 mL) at 0 °C. The mix-
ture was stirred at r.t. for 1 h. After completion of the reaction, the
mixture was treated with sat. aq NH4Cl (10 mL) and extracted with
EtOAc (3 × 20 mL). The combined organic layers were washed with
sat. aq NaCl (2 × 15 mL), dried (Na2SO4), and concentrated under
reduced pressure. The crude product was purified by column chro-
matography (silica gel, hexane–EtOAc, 6:4).
IR (neat): 2928, 2856, 2227, 1721, 1613, 1465, 1311, 1259, 1078,
957, 838 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.12 (s, 3 H), 0.14 (s, 3 H), 0.89
(br s, 12 H), 1.16–1.45 (m, 13 H), 2.01–2.12 (m, 2 H), 4.22 (q,
J = 7.5 Hz, 3 H), 5.24 (d, J = 6.7 Hz, 1 H), 5.43–5.52 (m, 2 H), 6.31
(d, J = 15.8 Hz, 1 H), 6.70–6.93 (m, 1 H).
25
Yield: 0.270 g (87%); pale yellow liquid; [a]D +278.6 (c 1.0,
13C NMR (75 MHz, CDCl3): d = 165.3, 133.1, 132.4, 128.9, 123.7,
86.8, 81.9, 68.9, 64.2, 60.9, 59.6, 31.7, 29.2, 29.1, 29.0, 27.7, 25.7,
22.6, 14.5, –4.5.
Et2O).
IR (neat): 3340, 3024, 2955, 2855, 2230, 2168, 1465, 1078, 933
cm–1.
MS (EI, 70 eV): m/z = 439 [M+ + Na].
Synthesis 2008, No. x, A–G © Thieme Stuttgart · New York

PAPER
Total Synthesis of Polyacetylenic (3R,8S)-Falcarindio
G
(2E,8S,9Z)-8-(tert-Butyldimethylsiloxy)heptadeca-2,9-diene-
4,6-diyn-1-ol (23)
washed with Et2O (2 × 20 mL), and the filtrate was washed with
10% aq Na2S2O3 (2 × 10 mL), H2O (2 × 10 mL), and brine (2 × 10
mL). The organic layer was dried (Na2SO4) and concentrated; this
gave the crude product as an unstable viscous liquid, which was di-
rectly used for the next reaction.
A 1.2 M soln of DIBAL-H in CH2Cl2 (5.97 mL) was added drop-
wise to a soln of 22 (1.2 g, 2.87 mmol) in CH2Cl2 (15 mL) at –10 °C.
The progress of the reaction was monitored by TLC. The reaction
was quenched with MeOH and sodium potassium tartrate and the
mixture was extracted with EtOAc (3 × 50 mL). The combined ex-
tracts were washed with brine (2 × 15 mL), dried (Na2SO4), filtered,
and concentrated under reduced pressure; this gave the crude prod-
uct, which was purified by chromatography (silica gel, PE–EtOAc,
8:2).
A mixture of the above product, NaI (0.69 g, 4.60 mmol), and acti-
vated Zn dust (0.50 g, 7.67 mmol) in EtOH (10 mL) was refluxed
under N2 for 3–4 h. The solvent was removed under reduced pres-
sure and the residue was purified by column chromatography (silica
gel, hexane–EtOAc, 7:3).
Yield: 0.43 g (76%); white liquid; [a]D25 +120.6 (c 0.5, CHCl3).
Yield: 880 mg (82%); [a]D25 +73.0 (c 0.5, CHCl3).
IR (neat): 3391, 3024, 2928, 2856, 2150, 1646, 1465, 1315, 1254,
1078, 933, 837, 778, 672 cm–1.
IR (neat): 3445, 2926, 2855, 2229, 1631, 1463, 1319, 1253, 1077,
946, 836, 776 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.10 (s, 3 H), 0.13 (s, 3 H), 0.89
(br s, 12 H), 1.28 (br s, 8 H), 1.35–1.44 (m, 2 H), 1.76 (br s, 1 H),
2.01–2.11 (m, 2 H), 4.89 (t, J = 5.0 Hz, 1 H), 5.14 (d, J = 6.2 Hz, 1
H), 5.23 (dt, J = 10.1, 1.1 Hz, 1 H), 5.40–5.47 (m, 2 H), 5.49 (t,
J = 1.1 Hz, 1 H), 5.85–5.99 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 135.9, 132.1, 129.2, 117.5, 80.7,
77.6, 70.6, 67.9, 63.5, 59.5, 31.7, 29.2, 29.1, 29.0, 27.7, 25.7, 22.6,
18.1, 14.0, –4.5, –4.7.
1H NMR (200 MHz, CDCl3): d = 0.12 (s, 3 H), 0.13 (s, 3 H), 0.89
(br s, 12 H), 1.18–1.45 (br s, 10 H), 1.55 (br s, 1 H), 2.06 (q, J = 5.8
Hz, 2 H), 4.24 (dd, J = 2.9, 1.9 Hz, 2 H), 5.21 (d, J = 6.8 Hz, 1 H),
5.40–5.56 (m, 2 H), 5.80 (d, J = 15.6 Hz, 1 H), 6.40 (dt, J = 15.6,
4.8 Hz, 1 H).
13C NMR (50 MHz, CDCl3): d = 145.3, 131.9, 129.3, 128.7, 82.8,
74.2, 68.7, 64.1, 62.6, 59.6, 31.7, 29.2, 29.1, 29.0, 27.7, 25.7, 22.6,
14.5, –4.5.
MS (EI, 70 eV): m/z = 397 [M+ + Na].
MS (EI, 70 eV): m/z = 397 [M+ + Na].
{(2S,3S)-3-[(5S,6Z)-5-(tert-Butyldimethylsiloxy)tetradec-6-ene-
1,3-diynyl]oxiran-2-yl}methanol (6)
Acknowledgment
V.B. thanks UGC, New Delhi for the award of a fellowship.
Anhyd CH2Cl2 (20 mL) was added to powdered, activated 4 Å MS
(80 mg), and the suspended mixture was cooled to –20 °C. L-(+)-
DIPT (10 mg, 0.45 mmol) and Ti(Oi-Pr)4 (12mg, 0.45 mmol) were
added to the stirring mixture, which was stirred for a further 30 min
at –20 °C. Allyl alcohol 23 (850 mg, 2.26 mmol) in anhyd CH2Cl2
(5 mL) was added and the resulting mixture was stirred for another
45 min at –20 °C. Cumenehydroperoxide (0.41 mL, 2.72 mmol)
was added and the mixture was stirred at the same temperature for
5–6 h. After completion of the reaction (monitored by TLC), the
mixture was warmed to 0 °C, quenched with H2O (0.1 mL), and
stirred for 1 h at 0 °C. Then 10% aq NaOH saturated with NaCl
(0.85 mL) was added, and the resulting mixture was stirred vigor-
ously for another 30 min at 0 °C. The resulting mixture was vacu-
um-filtered through Celite, and the filter cake was washed well with
CH2Cl2. The organic phase was separated and aqueous phase was
extracted with CH2Cl2 (3 × 15 mL); the combined organic phases
were washed with brine (2 × 5 mL) and dried (Na2SO4). Removal of
solvent under reduced pressure and purification by chromatography
(silica gel, hexane–EtOAc, 6:4) gave 6.
References
(1) (a) Bohlmann, F.; Burkhardt, T.; Zdero, C. Naturally
Occurring Acetylenes; Academic Press: London, 1973.
(b) Muir, A. D.; Cole, A. L. J.; Walker, J. R. L. Planta Med.
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(2) Kemp, M. S. Phytochemistry 1978, 17, 1002.
(3) (a) Miyazawa, M.; Shimamura, H.; Bhuva, R. C.; Nakamura,
S.-I.; Kameoka, H. J. Agric. Food Chem. 1996, 44, 3444.
(b) Lee, G.; Park, H.-G.; Choi, M.-L.; Young, H. K.; Yong,
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1979, 83, 463.
Yield: 690 mg (78%); viscous liquid; [a]D25 +129.6 (c 0.5, CHCl3).
IR (neat): 3414, 2927, 2856, 2229, 1742, 1652, 1463, 1382, 1312,
1254, 1076, 839, 779 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.10 (s, 3 H), 0.12 (s, 3 H), 0.89
(br s, 12 H), 1.17–1.46 (m, 10 H), 2.05 (m, 3 H), 3.30 (d, J = 1.5, 1
H), 3.48 (s, 1 H), 3.71 (d, J = 12.0 Hz, 1 H), 3.93 (d, J = 13.5 Hz, 1
H), 5.12 (d, J = 6.0 Hz, 1 H), 5.43 (d, J = 4.5 Hz, 2 H).
13C NMR (50 MHz, CDCl3): d = 132.2, 128.9, 79.9, 75.0, 68.6, 60.0,
59.8, 59.3, 47.2, 42.5, 31.6, 29.8, 29.1, 29.0, 27.6, 25.6, 22.5, 14.0,
–4.5.
(10) Lemmich, E. Phytochemistry 1981, 20, 1419.
(11) Zheng, G.; Lu, W.; Cai, J. J. Nat. Prod. 1999, 62, 626.
(12) Sabitha, G.; Reddy, C. S.; Yadav, J. S. Tetrahedron Lett.
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(13) Hofmeister, H.; Annen, K.; Laurent, H.; Wiechert, R.
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2005, 7, 5813. (b) Fiandanese, V.; Bottalico, D.;
Cardellicchio, C.; Marchese, G.; Punzi, A. Tetrahedron
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MS (EI, 70 eV): m/z = 391 [M+ + 1].
(3R,8S,9Z)-8-(tert-Butyldimethylsiloxy)heptadeca-1,9-diene-
4,6-diyn-3-ol (20)
Ph3P (1.2 g, 4.60 mmol), imidazole (0.26 g, 3.83 mmol), and I2
(0.84 g, 6.68 mmol) were added to a stirred soln of 6 (600 mg, 1.53
mmol) in toluene (10 mL) at 0 °C. The mixture was stirred at r.t. for
45 min. The solid that resulted was collected by filtration and
(15) Feit, P. W. J. Med. Chem. 1964, 7, 14.
Synthesis 2008, No. x, A–G © Thieme Stuttgart · New York