Biomimetic synthesis of acid-sensitive (-)- and (+)-caparrapi oxides, (-)- and (+)-8-epicaparrapi oxides, and (+)-dysifragin induced by artificial cyclases

Article abstract of DOI:10.1016/j.bmc.2005.04.029

Asymmetric total syntheses of acid-sensitive (-)- and (+)-caparrapi oxides (1) and (+)-8-epicaparrapi oxide (2) from farnesol (10) are achieved using Sharpless-Katsuki epoxidation and Lewis acid-assisted chiral Bronsted acid (chiral LBA)-induced polyene cyclization as key steps. The relative configuration of (+)-dysifragin (4) is determined by a single-crystal X-ray diffraction and its total synthesis is accomplished by the diastereoselective epoxidation of (+)-1. Furthermore, (-)-1 can be directly synthesized from (S)-nerolidol (3) and (R)-LBA with 88% ds by reagent control, which overcame substrate control, while (-)-2 is obtained from (R)-3 and (R)-LBA with >99% ds by the double asymmetric induction.

Full text of DOI:10.1016/j.bmc.2005.04.029

Bioorganic & Medicinal Chemistry 13 (2005) 5055–5065
Biomimetic synthesis of acid-sensitive (ꢀ)- and
(+)-caparrapi oxides, (ꢀ)- and (+)-8-epicaparrapi oxides, and
(+)-dysifragin induced by artificial cyclases
Muhammet Uyanik,a Kazuaki Ishiharaa,* and Hisashi Yamamotob,*
aGraduate School of Engineering, Nagoya University, Furo-cho, Chikusa, Nagoya 464-8603, Japan
bDepartment of Chemistry, The University of Chicago, 5735 S. Ellis Avenue, Chicago, IL 60637, USA
Received 14 March 2005; accepted 12 April 2005
Available online 4 May 2005
Dedicated to Professor Koji Nakanishi in honor of his receipt of the Tetrahedron Prize.
Abstract—Asymmetric total syntheses of acid-sensitive (ꢀ)- and (+)-caparrapi oxides (1) and (+)-8-epicaparrapi oxide (2) from far-
nesol (10) are achieved using Sharpless–Katsuki epoxidation and Lewis acid-assisted chiral Brønsted acid (chiral LBA)-induced
polyene cyclization as key steps. The relative configuration of (+)-dysifragin (4) is determined by a single-crystal X-ray diffraction
and its total synthesis is accomplished by the diastereoselective epoxidation of (+)-1. Furthermore, (ꢀ)-1 can be directly synthesized
from (S)-nerolidol (3) and (R)-LBA with 88% ds by reagent control, which overcame substrate control, while (ꢀ)-2 is obtained from
(R)-3 and (R)-LBA with >99% ds by the double asymmetric induction.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
O
O
O
H
Natural bicyclic sesquiterpene ethers such as
(5S,8S,10S)-(ꢀ)- and (5R,8R,10R)-(+)-caparrapi oxides
(1)1,2 and 8-epicaparrapi oxide (2)3 can be formally de-
rived by biomimetic proton-induced cyclization of (S)-
(+)- or (R)-(ꢀ)-nerolidol (3) (Scheme 1). Compounds
(ꢀ)-1 has been isolated from the neutral fraction of
the essential oil of Ocotea caparrapi Nates (Dugand).1
On the other hand, (+)-1 and (+)-dysifragin (4) have
been isolated from the sponge Dysidea fragilis Montagu
(family Dysideidae).2 However, the absolute and relative
stereochemistry of (+)-4 has not been determined. 8-
Epicaparrapi oxide 2 has been isolated as a minor con-
stituent of the defense secretion of the termite Amitermes
evuncifer.3 Unfortunately, it has not yet been confirmed
whether the absolute configuration of natural product 2
by analogy to (3R,5R,8S,10R)-(+)-3b-bromo-8-epica-
parrapi oxide4 is (5R,8S,10R)-(+). According to Zefirov
and co-workers, the cyclization of ( )-3 induced by
(+)-4
H
O
10
H+-cyclase
?
5
8
(R)-3
(+)-1
H+-cyclase
?
O
O
H
(–)-1
H
H+-cyclase
?
O
O
(+)-2
(S)-3
Scheme 1. Formal biosynthetic routes for bicyclic and tricyclic
sesquiterpene ethers 1, 2, and 4.
5 equiv of HSO3F gives ( )-2 diastereoselectively (via
substrate control).5 However, there have been no suc-
cessful examples of the diastereoselective cyclization of
( )-3 to ( )-1. Kametani and co-workers obtained a
1:1 diastereomeric mixture of ( )-1 and ( )-2 through
the cyclization of b-hydroxy phenylselenide derived
from 10,11-epoxynerolidol induced by 5.7 equiv of
Keywords: Biomimetic synthesis; Caparrapi oxides; 8-Epicaparrapi
oxide; Dysifragin.
*
Corresponding authors. Tel.: +81 52 789 3331; fax: +81 52 789 3222
(K.I.); tel.: +1 773 702 5059; fax: +1 773 702 0805 (H.Y.); e-mail
addresses: ishihara@cc.nagoya-u.ac.jp; yamamoto@uchicago.edu
0968-0896/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2005.04.029

5056
M. Uyanik et al. / Bioorg. Med. Chem. 13 (2005) 5055–5065
tion of ( )-3 bearing an acid-sensitive allylic hydroxy
group gave a complex reaction mixture, and the desired
trans-fused 2-oxabicyclo[4.4.0]decanes were obtained in
less than 10% yield as a 37:63 mixture of ( )-1 and
( )-2, which were stable under the reaction conditions.
This diastereomeric ratio is due to substrate control:
transition-state assembly TS-B is more favorable than
transition-state assembly TS-A due to the steric differ-
ence between 3-vinyl group and 3-methyl group of ( )-
3 (Fig. 2). When (R)-5 was used as a Brønsted acid in-
stead of 6, a 9:91 mixture of (ꢀ)-1 (91% ee) and (ꢀ)-2
(78% ee) was obtained in 32% yield (entry 3). This result
indicates that (+)-2 and (ꢀ)-2 were obtained from (S)-3
and (R)-3 with 55% and >99% diastereoselectivity,
respectively. In the former case, low diastereoselectivity
was observed due to the mismatch in asymmetric induc-
tion between substrate control and reagent control. In
the latter case, high diastereoselectivity was observed
due to the double asymmetric induction of substrate
control and reagent control. The use of toluene in place
of CH2Cl2 lowered the chemical yield of 1 and 2, but
raised their enantioselectivities to 97% ee and 90% ee.
Notably, (ꢀ)-1 was obtained from (S)-3 with 88% dia-
stereoselectivity due to reagent control, which overcame
substrate control. The activated proton in (R)-5ÆSnCl4
preferentially attacked the si-face of the terminal isopre-
nyl group because the OH/p interaction between (R)-
5ÆSnCl4 and 3 in the initial protonation step should be
stronger in less polar solvents like toluene.7f
O
O
F
O
O
F
SnCl4
SnCl4
H
H
OMe
OMe
(R)-5•SnCl4
(S)-5•SnCl4
Figure 1. Artificial cyclases that are available in both enantiomeric
forms.
CF3CO2H.6 To concisely synthesize (+)-1 and (ꢀ)-1
through the polyene cyclization of (R)-3 and (S)-3,
respectively, asymmetric control with artificial cyclases
should be able to overcome substrate control, and both
enantiomers of artificial cyclases should be readily
available.
Recently, we demonstrated that Lewis acid-assisted chi-
ral Brønsted acids (chiral LBAs) prepared in situ from
chiral alcohols and tin(IV) chloride were highly effective
as artificial cyclases for the enantioselective biomimetic
cyclization of polyprenoids.7 For example, tri-, tetra-,
and pentacyclic terpenoids bearing a chroman skeleton
give products with up to 91% ee by enantioselective
cyclization of the corresponding 2-(polyprenyl)phenol
derivatives induced by chiral catechol derivative 5ÆSnCl4
(Fig. 1).7f We describe here a concise total synthesis of
acid-sensitive bicyclic sesquiterpenes (ꢀ)-1, (+)-1, and
(+)-2 based on a biomimetic pathway induced by the
chiral LBAs (R)-5ÆSnCl4 and (S)-5ÆSnCl4 and the diaste-
reoselective transformation from (+)-1 to (+)-4.8 The
absolute stereochemical structure of (+)-4 was estab-
lished by 13C NMR spectroscopic method and X-ray
diffraction.
To improve the chemical yield of 1 or 2 ( )-(E)-3,7,11-
trimethyl-6,10-dodecadiene-1,3-diol derivatives 7a–f,
which were less acid-sensitive than ( )-3, were examined
as substrates for cyclization with (R)-5ÆSnCl4 (Table 2).
Although the cyclizations of 1,3-diol 7a and 1-tert-butyl-
diphenylsilyl ether 7b were carried out in the presence of
2 equiv of (R)-5ÆSnCl4 in toluene at ꢀ78 ꢁC for 1 day, no
desired bicyclic ethers were obtained, probably due to
H
H
O
O
H
H
2. Results and discussion
Me
Me
Me
First, the diastereoselective cyclization of ( )-3, which
was obtained commercially, was examined with 1 equiv
of the achiral LBA, 2-methoxyphenol (6)ÆSnCl4, in
dichloromethane at ꢀ78 ꢁC (Table 1, entry 1). Cycliza-
TS-A (favored)
TS-B (disfavored)
Figure 2. Two transition-state assemblies TS-A and TS-B in the
proton-induced cyclization of ( )-3.
Table 1. Double asymmetric induction in the cyclization of ( )-3 with (R)-5ÆSnCl4
(S)-3
(–)-1
+
+
(+)-2
ArOH•SnCl4 (1 equiv)
+
+
+
solvent, –78 ˚C, 1 day
(+)-1
(–)-2
(R)-3
Entry
ArOH
Solvent
Yield
[%]a 1 + 2
Ratiob
Ratio 1:2
Ee
[%] (rotn.) 1,2
From
(S)-3 (ꢀ)-1:(+)-2
37:63
From
(R)-3 (+)-1:(ꢀ)-2
37:63
(+)-1:(ꢀ)-1:(+)-2:(ꢀ)-2
18.5:18.5:31.5:31.5
1
2
3
4
6c
6c
CH2Cl2
Toluene
CH2Cl2
Toluene
<10
0
37:63
—
—
—
—
0.4:8.2:9.9:81.5
0.4:27.5:3.7:68.4
—
45:55
88:12
—
<1:>99
<1:>99
(R)-5
(R)-5
32
13
9:91
28:32
91 (ꢀ), 78 (ꢀ)
97 (ꢀ), 90 (ꢀ)
a Isolated yield.
b The ratio was determined by GC analysis (PEG and b-DM columns).
c 2-Methoxyphenol (6).

M. Uyanik et al. / Bioorg. Med. Chem. 13 (2005) 5055–5065
Table 2. Double asymmetric induction in the cyclization of ( )-7 with (R)-5ÆSnCl4
5057
RO
RO
RO
(R)-5•SnCl4
(2 equiv)
O
O
O
H
+
solvent
–78 °C, 1 day
H
H
(–)-8a–f
(–)-9a–f
( )-7a–f
Entry
R, 7
Solvent
Yield (%)a 8 + 9
Ratiob (+)-8:(ꢀ)-8:(+)-9:(ꢀ)-9
—
Ratio 8:9
Ee (%) (ꢀ)-8, (ꢀ)-9
—
1
2
3
4
5
6
7
8
9
H, 7a
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
CH2Cl2
PrCl
0
0
—
—
Sit-BuPh2, 7b
COi-Bu, 7c
CO(CH2)2Ph, 7d
COPh, 7e
COBn, 7f
—
—
—
—
0
—
16
21
29
78
41
65
3.7:49.3:4.5:42.5
5.8:49.2:4.0:41.0
4.0:58.0:3.4:34.6
8.5:38.5:8.7:44.3
3.1:48.9:2.6:45.4
4.0:40.0:5.0:51.0
53:47
55:45
62:38
47:53
52:48
44:56
86, 81
79, 82
87, 82
64, 67
88, 89
82, 82
COBn, 7f
COBn, 7f
COBn, 7f
CH2Cl2–PrClc
a Isolated yield.
b The ratio was determined by GC (PEG column) and HPLC analyses (AD-H columns).
c A 1:1 (v/v) mixed solvent.
the tight bidentate-chelation between the substrates and
SnCl4 (entries 1 and 2). This undesirable chelation dis-
turbs not only the generation of (R)-5ÆSnCl4 but also
the internal nucleophilic attack of the 3-hydroxy group
in the final step of the cyclization of 7.9 In the course
of screening various protecting groups for the 1-hydroxy
group of 7a, we found that 1-acylates such as 1-benzoate
7e and 1-phenylacetate 7f were effective for the cycliza-
tion of 7 and gave trans-fused 2-oxabicyclo[4.4.0]-
decanes 8 and 9 (entries 5–9). Interestingly, aliphatic
esters such as isovalerate 7c were inert under the same
reaction conditions (entry 3), and 3-phenylpropionate
7d was less reactive than 7e and 7f (entry 4). These
experimental data suggest the existence of some attrac-
tive interaction between Sn(IV) and a phenyl group of
7e and 7f.9 The cyclization of ( )-7f with (R)-5ÆSnCl4
gave a 62:38 mixture of (ꢀ)-7f (87% ee) and (ꢀ)-8f
(82% ee) in 29% yield (entry 6). Judging from the enanti-
oselectivity and chemical yield of 8 and 9, ( )-7f gave
slightly better results than ( )-7e (entry 5 vs entry 6).
Next, the solvent effect was investigated in the cycliza-
tion of ( )-7f with (R)-5ÆSnCl4 (entries 6–8): the enantio-
selectivity was higher in the order CH2Cl2 ꢁ
toluene < chloropropane, while the chemical yield of 8
and 9 increased in the order toluene < chloropro-
pane ꢁ CH2Cl2. Thus, chloropropane was superior to
toluene with respect to both enantioselectivity and reac-
tivity. Finally, when a 1:1 mixed solvent of chloropro-
pane and CH2Cl2 was used, a 44:56 mixture of (ꢀ)-8f
(82% ee) and (ꢀ)-9f (82% ee) was obtained in 65% yield
(entry 9). These experimental results indicate that the
substrate control of 7 is relatively lower than that of 3
because of little difference in the thermodynamic stabil-
ities of 8 and 9 (Table 1 vs Table 2). Fortunately, 8f and
9f were easily separable by column chromatography on
silica gel. In contrast, it was difficult to separate 1 and 2
without any chemical modification.6
from farnesol (10) in three steps (Scheme 2): (a) Sharp-
less–Katsuki epoxidation of 10 to (2S,3S)-(ꢀ)-epoxy-
farnesol (11) with 90% ee,11 (b) regioselective reduction
of (ꢀ)-11 to (S)-7a (>99% regioselectivity) with Red-
Alꢂ (65% sodium bis(2-methoxyethoxy)aluminum hy-
dride in toluene),12 and (c) regioselective acylation of
(S)-7a with phenylacetyl chloride to (S)-7f (>99%
regioselectivity).13
The asymmetric cyclization of (S)-7f induced by 2 equiv
of (R)-5ÆSnCl4 gave an 81:19 mixture of (ꢀ)-8f (>99%
ee) and (+)-9f (21% ee) in 74% yield. On the other hand,
the asymmetric cyclization of (S)-7f induced by 2 equiv
of (S)-5ÆSnCl4 gave a 14:86 mixture of (ꢀ)-8f (27% ee)
and (+)-9f (98% ee) in 73% yield. These experimental re-
sults indicate that the substrate control of 7f was much
lower than the reagent control by 5ÆSnCl4. Optically
pure (ꢀ)-8f and (+)-9f were easily separated by column
chromatography on silica gel (Scheme 3).
Optically pure (ꢀ)-caparrapi oxide 1 was obtained in
92% overall yield from (ꢀ)-8f in three steps (Scheme
4): hydrolysis of (ꢀ)-8f to (ꢀ)-8a under basic conditions
and subsequent Grieco elimination to (ꢀ)-1 through
alkyl o-nitrophenyl selenide 12.14 In the same manner,
(+)-8-epicaparrapi oxide 2 (98% ee) was obtained in
HO
HO
O
(5 mol%), (+)-DIPT (7.5 mol%)
TBHP (1.5 equiv)
Ti(Oi -Pr)4
MS 4A, CH2Cl2
–50~–45
(95%)
HO
°C, 2 h
(–)-11 (90% ee)
10
BnCO2
Red-Al® (1.5 equiv)
toluene
O
O
H
BnCOCl
H
collidine
CH2Cl2
(98%)
Compound (S)-7f had to be prepared to synthesize (ꢀ)-
8f, which is a synthetic precursor of (ꢀ)-caparrapi oxide
1.10 (S)-7f was prepared with 90% ee in 91% overall yield
(S)-7a (90% ee)
(S)-7f (90% ee)
(98%)
Scheme 2. Preparation of (S)-7f.

5058
M. Uyanik et al. / Bioorg. Med. Chem. 13 (2005) 5055–5065
NO2
SeCN
(–)-8f
>99% ee
c. c.
81
(R)-5•SnCl4 (2 equiv)
to
1 M LiOH
19
PrCl–CH2Cl2=1:1
–80 ˚C, 2 days
(74%)
(–)-8a
(>99% ee)
(–)-8f
(>99% ee)
MeOH
1 h, 0 ˚C
(>99%)
Bu3P, THF, rt
(96%)
(+)-9f
21% ee
(S)-7f
90% ee
NO2
(–)-8f
27% ee
H2O2
THF
O
Se
c. c.
(S)-5•SnCl4 (2 equiv)
14
to
86
(–)-1
(>99% ee)
PrCl–CH2Cl2=1:1
–80 ˚C, 2 days
(73%)
0 ˚C to rt, 1 day
(96%)
H
(+)-9f
98% ee
12 (>99% ee)
NO2
C. C. = column chromatography on silica gel
SeCN
Scheme 3. Diastereoselective preparation of (ꢀ)-8f and (+)-9f from
(S)-7f.
1 M LiOH
(+)-9a
(>99% ee)
(+)-9f
(98% ee)
MeOH
1 h, 0 ˚C
(>99%)
Bu3P, THF, rt
(96%)
NO2
91% overall yield from (+)-9d: (a) hydrolysis of (+)-9f to
(+)-9a (>99%), (b) o-nitrophenylselenylation of 9a
(96%), and (c) oxidative elimination of 13 to (+)-3
(95%).
H2O2
THF
O
Se
(+)-2
(98% ee)
0 ˚C to rt, 1 day
(95%)
H
13 (98% ee)
(+)-Caparrapi oxide 1 and its epoxide, (+)-dysifragin 4,
have been isolated from the sponge Dysidea fragilis
Montagu.2 However, the absolute and relative stereo-
chemistry of (+)-4 is not determined. To elucidate the
structure of (+)-4, it was necessary to synthesize diaste-
reomeric epoxides of (+)-1 in enantiomerically pure
form. Diastereoselective epoxidation of (+)-1, which
was synthesized from (+)-11 as above, was examined
with various oxidants. The representative results are
shown in Table 3. In most cases, unfortunately, the dia-
stereomer of (+)-4, (+)-14, was obtained as a major
product. However, two diastereomers were easily sepa-
Scheme 4. Synthetic transformation from (ꢀ)-1 and (+)-2 to (ꢀ)-8f
and (+)-9f using Griecoꢀs method.14
rated by flash column chromatography on silica gel. Per-
oxytrifluoroacetic acid prepared from urea hydrogen
peroxide and trifluoroacetic anhydride in situ gave the
best result: (+)-4 was obtained with 50% ds (entry 1).
1H NMR, 13C NMR, and IR spectra and absolute val-
ues of the specific rotation for synthetic product (+)-4
and for natural dysifragin2 were nearly identical. Based
on the Rodriguezꢀ 13C NMR method for the determina-
Table 3. Diastereoselective epoxidation of (+)-1
16
OH
OH
7
OH
9'
LiAlH4
O
(7.5 equiv)
O
O
O
14
Et2O
3'
12
rt, 3 h
H
H
H
H
13C NMR
C(12) δ 34.8
C(16) δ 19.8
13C NMR
C(3') δ 34.4
C(9') δ 21.7
(+)-4
15
95%
17
Oxidant
(+)-1
+
16
OH
OH
7
OH
9'
LiAlH4
(7.5 equiv)
O
O
O
O
14
3'
12
Et2O
rt, 3 h
H
H
H
H
(+)-14
13C NMR
C(12) δ 29.3
C(16) δ 23.8
13C NMR
C(3') δ 29.4
C(9') δ 24.2
16
18
80%
Entry Oxidant (equiv)
Additives (equiv)
Solvent
Temp (ꢁC), time (h) Yield (%)a (+)-4 + (ꢀ)-14 Ratiob (+)-4:(ꢀ)-14
H2O2Æ(H2N)2CO (10)
1a
2
K2HPO4 (8.8)
—
CH2Cl2
CH2Cl2
23, 3
97
96
70
50:50
45:55
37:63
(CF3CO)2O (2.5)
mCPBA (1.5)
Oxone (5)
23, 24
3b
Na2CO3 (5)
EtOAc–water 23, 16
Pyridine 23, 72
Acetone (10)
MeReO3 (0.015)
3-Cyanopyridine (0.3)
4c
H2O2 (4)
95
35:65
a Ref. 18.
b Ref. 19.
c Ref. 20.

M. Uyanik et al. / Bioorg. Med. Chem. 13 (2005) 5055–5065
5059
achiral and chiral substrates: (ꢀ)-caparrapi oxide 1
and (+)-8-epicaparrapi oxide 2 could be diastereoselec-
tively synthesized from (S)-7f by the reagent control of
(R)-5ÆSnCl4 and (S)-5ÆSnCl4, respectively, regardless of
the chirality of (S)-7f. Furthermore, in the cyclization
of ( )-3 induced by (R)-5ÆSnCl4, (ꢀ)-1 was diastereose-
lectively obtained from (S)-3 by reagent control, which
overcame substrate control, while (ꢀ)-2 was highly dia-
stereoselectively obtained from (R)-3 by the double
asymmetric induction of substrate control and reagent
control. (+)-Dysifragin 4 was synthesized from (+)-1
in high yield and its structure was fully determined by
X-ray diffraction.
Figure 3. X-ray diffraction of (+)-4.
4. Experimental
4.1. General methods
tion of C(14) configuration of 8,13-epoxylabdane-7,
14-diols, 17 and 18,16 the relative stereochemistries of
(+)-4 and (+)-14 were presumed by 13C NMR spectral
analysis of 15 and 16, which were transformed from
(+)-4 and (+)-14, respectively, by the regioselective
reductive cleavage using lithium aluminum hydride
(Table 3): the C(30) and C(90) chemical shifts of 15 were
analogous to the C(12) and C(16) chemical shifts of 17,
while the C(30) and C(90) chemical shifts of 16 were
analogous to the C(12) and C(16) chemical shifts of 18.
Infrared (IR) spectra were recorded on a JASCO FT/IR
460 plus spectrometer. H NMR spectra were measured
1
on a Varian Gemini-2000 (300 MHz) or Varian INO-
VA-500 (500 MHz) spectrometer at ambient tempera-
ture. Data were recorded as follows: chemical shift in
parts per million from internal tetramethylsilane on
the d scale, multiplicity (s = singlet; d = doublet; t =
triplet; m = multiplet), coupling constant (hertz),
integration, and assignment. 13C NMR spectra were
measured on a Varian Gemini-2000 (75 MHz) or Varian
INOVA-500 (125 MHz) spectrometer. Chemical shifts
were recorded in parts per million from the solvent
resonance employed as the internal standard (deutero-
chloroform at 77.00 ppm). High-performance liquid
chromatography (HPLC) analysis was conducted using
Shimadzu LC-10 AD coupled diode array-detector
SPD-MA-10A-VP and chiral column of Daicel CHI-
RALCEL OD-H (4.6 mm · 25 cm) or Daicel CHIR-
ALPAK AD-H (4.6 mm · 25 cm). Optical rotations
were measured on a JASCO DIP-1000 digital polarime-
ter. GC analysis was performed with Shimadzu 17A
instruments using PEG (0.25 mm · 25 m). All experi-
ments were carried out under an atmosphere of dry
nitrogen. For thin-layer chromatography (TLC) analy-
sis throughout this work, Merck precoated TLC plates
(silica gel 60 GF254 0.25 mm) were used. The products
were purified by column chromatography on silica gel
(E. Merck Art. 9385). High resolution mass spectral
analysis (HRMS) was performed at Chemical Instru-
ment Center, Nagoya University. In experiments that
required dry solvent, ether and tetrahydrofuran
(THF) were purchased from Aldrich or Wako as the
Fortunately, the relative stereochemical structure of (+)-
4 was determined by its X-ray diffraction (Fig. 3), and it
was ascertained that the Rodriguezꢀ 13C NMR method16
was also useful for determination of analogous chemical
structures like dysifragin.
Unnatural diastereomer (+)-14 could be transformed
to (+)-4 with three steps in 81% yield according to the
Prietoꢀs method17 (Scheme 5): the treatment of 14 with
cesium propionates as the epoxide-cleaving agent gave
a 2:1 molar mixture of regioisomeric propionates, 19
and 20, that was mesylated and methanolyzed to
produce the inverted epoxide (+)-4. Thus, (+)-4 was
obtained in 88% over all yield from (+)-1.
3. Conclusions
In summary, we have demonstrated that the chiral LBA
5ÆSnCl4 is an artificial cyclase that is useful for both
O
O
CsO
OH
O
(10 equiv)
O
O
˚
AcOH (2 equiv)
ꢁanhydrousꢀ and stored over 4 A molecular sieves. Hex-
+
(+)-14
O
OH
ane, toluene, 1-chloropropane, and dichloromethane
were freshly distilled from calcium hydride. Tin(IV)
chloride was distilled under nitrogen. Other simple
chemicals were analytical-grade and obtained
commercially.
18-crown-6
(6 equiv)
toluene
H
H
O
reflux, 3 days
92%
19
20
2 : 1
1. MsCl (2 equiv)
i-Pr2EtN (2.7 equiv)
–10~ 0 ˚C, 3 h
4.2. Preparation of chiral catechol derivatives (chiral BA
of (S)-5 and (R)-5)7f
(+)-4
2. K2CO3 (0.4 equiv)
MeOH, rt, 12 h
88% (2 steps)
Chiral catechols (S)- and (R)-5 were prepared from (R)-
BINOL and (S)-BINOL, respectively.
Scheme 5. Inversion from (+)-14 to (+)-4.

5060
M. Uyanik et al. / Bioorg. Med. Chem. 13 (2005) 5055–5065
4.3. Diastereoselective cyclization of trans-nerolidol
induced by chiral LBA 5ÆSnCl4 (Table 1)
concentrated. The residue was through pipette column
on silica gel to give MTPA ester of epoxyfarnesol
(90% ee). TLC (hexane–EtOAc, 4:1) Rf = 0.46; 1H
NMR analysis focused on the M or AB part of the
To a solution of chiral catechol (R)-5 (154 mg,
0.30 mmol) or 2-methoxyphenol (6, 33 mL, 0.30 mmol)
in toluene or CH2Cl2 (6 mL) was added a 1 M solution
of tin(IV) chloride in hexane (for toluene as reaction sol-
vent) or CH2Cl2 (for CH2Cl2 as reaction solvent)
(300 mL, 0.30 mmol) under N2 at room temperature,
and the mixture was stirred for 5 min. After the solution
was cooled to ꢀ78 ꢁC, trans-nerolidol (85 mL,
0.30 mmol) was added dropwise. The reaction mixture
was stirred for 1 day, quenched with saturated aqueous
NaHCO3, and extracted with ether. The combined
organic layers were dried over anhydrous MgSO4 and
concentrated. The crude product was purified by column
chromatography on silica gel (eluent: hexane–
ether = 50:1–30:1) to give bicyclic compounds contain-
ing a small amount of unknown products. Compounds
1 and 2 could not be separated by column chromatogra-
phy on silica gel.6 See Table 1 in the paper for yield of
bicyclic compounds.
1
ABM pattern, H NMR (C6D6, 300 MHz) d 0.97 (s,
3H), 1.22–1.45 (m, 2H), 1.50 (s, 3H), 1.56 (s, 3H), 1.68
(s, 3H), 1.90–2.20 (m, 8H), 2.74 (dd, J = 4.5, 7.2 Hz,
1H, M part of ABM pattern, major diastereomer, while
appearing of minor diastereomer at d 2.84), 3.43 (s, 3H),
4. 04 (dd, J = 7.2, 12.0 Hz, 1H, A part of ABM pattern,
major diastereomer, while appearing of minor diastereo-
mer at d 3.87), 4.18 (dd, J = 4.5, 12.0 Hz, 1H, B part of
ABM pattern, major diastereomer, while appearing of
minor diastereomer at d 3.91), 5.08 (t, J = 7.2 Hz, 1H),
5.21 (t, J = 7.2 Hz, 1H), 7.00–7.13 (m, 3H), 7.71 (d,
J = 7.8 Hz, 2H).
4.4.2. (S)-3,7,11-Trimethyl-6,10-dodecadiene-1,3-diol (7a).12
A 100-mL flask was charged with (ꢀ)-11 (1.458 g,
6.12 mmol) and dry toluene (17 mL). The mixture was
stirred under N2 at 0 ꢁC during the addition of Red-
Alꢂ (Kanto, 65% sodium bis(2-methoxyethoxy)alumi-
num hydride in toluene, 1.95 mL, 6.50 mmol). The reac-
tion was allowed to warm to room temperature, over
3 h, at which time TLC analysis of an acidified sample
disclosed the formation of single polar product. The
reaction was cooled to 0 ꢁC and quenched by addition
of 2-propanol (2 mL). Acidification with 5% aqueous
HCl was followed by phase separation and washing
the organic layer with water and brine and drying over
anhydrous MgSO4. The residue was purified by column
chromatography on silica gel (eluent: hexane–ethyl ace-
tate = 2:1) to give 7a (1.440 g, 5.99 mmol, 98% yield) as
colorless oil. TLC (hexane–EtOAc, 1:1) Rf = 0.16; IR
(film) 3550–3150, 2973, 2929, 2858, 1436, 1379, 1110,
4.4. Total synthesis of (5S,8S,10S)-(ꢀ)-caparrapi oxide
(1) and (5R,8S,10R)-(+)-epicaparrapi oxide (2) from
farnesol (10)
4.4.1. (2S,3S)-(ꢀ)-Epoxyfarnesol (11).11b,d A mixture of
˚
powdered, activated 4 A molecular sieves (20 mg),
and CH2Cl2 (1 mL) was cooled to ꢀ20 ꢁC. L-(+)-Diiso-
propyl tartrate (L-(+)-DIPT, 18 mg, 0.075 mmol,
Aldrich) and Ti(Oi-Pr)4 (14 mg, 15 mL, 0.05 mmol, dis-
tilled) were added sequentially. After the mixture was
cooled to ꢀ50 ꢁC, TBHP (400 mL, 1.50 mmol, 3.74 M
in toluene) was added and the resulting mixture was stir-
red for 30 min, whereupon freshly distilled trans, trans-
farnesol (222 mg, 1.00 mmol) was added. Stirring was
maintained for 2 h at ꢀ50 to ꢀ45 ꢁC. Diluted with
10% aqueous tartaric acid solution (5 mL) and stirred
at same temperature for further 30 min, and the reaction
mixture was allowed to warm to room temperature and
the stirring was continued for 1 h. Extracted with
CH2Cl2 (3 · 10 mL) and washed with water, dried over
anhydrous Na2SO4 and concentrated. To a residual oil
in ether (10 mL) was added aqueous 1 M NaOH
(3 mL) and the mixture was stirred at 0 ꢁC for 30 min.
Extracted with ether (3 · 10 mL), washed with NH4Cl
and brine, dried over anhydrous MgSO4, and concen-
trated. The crude product was purified by column chro-
matography on silica gel (eluent: hexane–ethyl
acetate = 4:1) to give 11 (226 mg, 0.95 mmol, 95% yield
1049 cmꢀ1 1H NMR (CDCl3, 300 MHz) d 1.26 (s,
;
3H), 1.54–1.71 (m, 3H), 1.60 (s, 3H), 1.63 (s, 3H), 1.68
(s, 3H), 1.81 (ddd, J = 4.8, 7.5, 15.0 Hz, 1H), 1.97–2.14
(m, 6H), 2.34 (br s, 1H), 2.78 (br s, 1H), 3.86–3.95 (m,
2H), 5.08 (t, J = 7.0 Hz, 1H), 5.15 (t, J = 7.0 Hz, 1H);
13C NMR (CDCl3, 75 MHz) d 15.6, 17.3, 22.3, 25.3,
26.1, 26.3, 39.4, 41.3, 42.0, 58.8, 72.9, 123.9, 124.0,
22.3
130.7, 134.6; ½aꢂ
0.80 (c 2.0, CHCl3) for 90% ee;
HRMS (FAB) m/z calcd for C15H28O2Na (M+Na)
D
263.1987, found 263.1980.
4.5. Selective silylation or acylation of 1-hydroxy group of
7a13
4.5.1. ( )-1-tert-Butyldimethylsiloxy-3,7,11-trimethyl-6,10-
dodecadiene-3-ol (7b). To a solution of 7a (1.010 g,
4.20 mmol) and imidazole (572 mg, 8.4 mmol) in N,N-
dimethylformamide (DMF, 8 mL) was added slowly
tert-butylchlorodiphenylsilane (1.196 mL, 4.60 mmol) in
DMF (2 mL) at room temperature. After stirring 3 h
at rt, quenched with water, extracted with hexane,
washed with brine, dried over anhydrous MgSO4, and
concentrated. The residue was purified by column chro-
matography on silica gel (eluent: hexane–ethyl ace-
tate = 10:1) to give 7b (2.01 g, 4.20 mmol, 100% yield) as
colorless oil. TLC (hexane–EtOAc, 4:1) Rf = 0.44; 1H
NMR (CDCl3, 300 MHz) d 1.06 (s, 9H), 1.24 (s, 3H),
1.50–1.85 (m, 4H), 1.60 (s, 6H), 1.68 (s, 3H), 1.94–2.12
1
with 90% ee). TLC (hexane–EtOAc, 2:1) Rf = 0.40; H
NMR (CDCl3, 300 MHz) d 1.31 (s, 3H), 1.45–1.75 (m,
2H), 1.61 (s, 6H), 1.68 (s, 3H), 1.95–2.14 (m, 7H), 2.99
(dd, J = 4.5, 6.6 Hz, 1H), 3.69 (ddd, J = 4.8, 6.6,
11.7 Hz, 1H), 3.81 (ddd, J = 4.5, 7.5, 11.7 Hz, 1H),
5.05–5.13 (m, 2H). Determination of the ee value of 11
via mosher ester: A mixture of 4-(dimethylamino)pyri-
dine (DMAP, 5 mg, 0.04 mmol) and Et3N (27 mL) in
CH2Cl2 (140 mL) was treated with 10 (9.8 mg,
0.04 mmol). Immediately, (+)-a-methoxy-a-(trifluoro-
methyl)phenylacetyl chloride (MTPACl, 8 mL) was
added. After 30 min, quenched with water, dried, and

M. Uyanik et al. / Bioorg. Med. Chem. 13 (2005) 5055–5065
5061
(m, 6H), 3.71 (s, OH), 3.92 (t, J = 7.2 Hz, 2H), 5.08–5.16
(m, 2H), 7.37–7.44 (m, 6H), 7.68–7.71 (m, 4H).
Rf = 0.23; IR (film) 3600–3250 (br, OH), 2972, 2928,
1
2858, 1714 (C@O), 1452, 1279, 1114 cmꢀ1; H NMR
(CDCl3, 300 MHz) d 1.29 (s, 3H), 1.50–1.70 (m, 2H),
1.60 (s, 3H), 1.62 (s, 3H), 1.68 (s, 3H), 1.79 (s, 1H),
1.96–2.15 (m, 8H), 4.50 (t, J = 7.0 Hz, 2H), 5.08 (t,
J = 7.0 Hz, 1H), 5.14 (t, J = 7.0 Hz, 1H), 7.43 (t,
J = 7.5 Hz, 2H), 7.56 (t, J = 7.5 Hz, 1H), 8.02 (d, J =
7.5 Hz, 2H); 13C NMR (CDCl3, 75 MHz) d 16.0, 17.7,
22.5, 25.7, 26.6, 27.0, 39.6, 39.8, 42.2, 61.7, 71.9, 123.9,
124.1, 128.3 (2C), 129.5 (2C), 130.2, 131.5, 132.9,
135.6, 166.6; HRMS (FAB) m/z calcd for C22H32O3Na
(M+Na) 367.2249, found 367.2245.
4.5.2. ( )-1-Isovaleryloxy-3,7,11-trimethyl-6,10-dodeca-
diene-3-ol (7c). To a solution of 7a (159 mg, 0.66 mmol),
2,4,6-collidine (114 mL, 0.86 mmol) in CH2Cl2 (1.3 mL)
at ꢀ78 ꢁC under N2 was added isovaleryl chloride
(105 mL, 0.86 mmol) dropwise and stirred for 5 h at
ꢀ78 ꢁC. Then 1 M HCl was poured into this mixture,
extracted with hexane (twice), washed with brine, dried
over anhydrous MgSO4, and concentrated. The residue
was purified by column chromatography on silica gel
(eluent: hexane–ethyl acetate = 10:1) to give 7c
(204 mg, 0.63 mmol, 95% yield) as colorless oil. TLC
(hexane–EtOAc, 4:1) Rf = 0.30; IR (film) 3600–3250
(br, OH), 2968, 2930, 2872, 1726 (C@O), 1523, 1436,
4.5.5. (S)-1-Phenylacetoxy-3,7,11-trimethyl-6,10-dodeca-
diene-3-ol (7f). To a solution of 7a (841 mg, 3.50 mmol),
2,4,6-collidine (604 mL, 4.55 mmol) in CH2Cl2 (7 mL) at
ꢀ78 ꢁC under N2 was added phenyl acetyl chloride
(602 mL, 4.55 mmol) dropwise and stirred for 5 h at
ꢀ78 ꢁC. Then 1 M HCl was poured into this mixture,
extracted with hexane (twice), washed with brine, dried
over anhydrous MgSO4, and concentrated. The residue
was purified by column chromatography on silica gel
(eluent: hexane–ethyl acetate = 10:1) to give 7f
(1.23 mg, 3.43 mmol, 98% yield) as colorless oil. TLC
(hexane–EtOAc, 4:1) Rf = 0.22; HPLC (two linear OD-
H columns, hexane–i-PrOH = 40:1, flow rate = 0.5 mL/
min) tR = 20.2 min for (S)-7f, 21.2 min for (R)-7f; IR
(film) 3650–3150 (br, OH), 2968, 2925, 2855, 1734
1385, 1296, 1120, 1049 cmꢀ1
;
1H NMR (CDCl3,
300 MHz) d 0.79 (d, J = 6.3 Hz, 3H), 1.06 (s, 3H),
1.34–1.39 (m, 2H), 1.44 (s, 3H), 1.46 (s, 3H), 1.52 (s,
3H), 1.67 (dt, J = 1.5, 6.9 Hz, 2H), 1.80–2.03 (m, 9H),
4.08 (t, J = 6.9 Hz, 2H), 4.90–5.01 (m, 2H); 13C NMR
(CDCl3, 75 MHz) d 15.9, 17.6, 22.3 (2C), 22.5, 25.6
(2C), 26.5, 26.8, 39.6, 39.7, 42.1, 43.4, 60.9, 71.7,
123.9, 124.1, 131.3, 135.4, 173.1; HRMS (FAB) m/z
calcd for C20H36O3Na (M+Na) 347.2562, found
347.2572.
4.5.3. ( )-1-(3-Phenylpropionyloxy)-3,7,11-trimethyl-6,10-
dodecadiene-3-ol (7d). To a solution of 7a (180 mg,
0.75 mmol), 2,4,6-collidine (130 mL, 0.98 mmol) in
CH2Cl2 (1.5 mL) at ꢀ78 ꢁC under N2 was added hydro-
cinnamoyl chloride (146 mL, 0.98 mmol) dropwise and
stirred for 5 h at ꢀ78 ꢁC. Then 1 M HCl was poured
into this mixture, extracted with hexane (twice), washed
with brine, dried over anhydrous MgSO4, and concen-
trated. The residue was purified by column chromato-
graphy on silica gel (eluent: hexane–ethyl acetate = 8:1)
to give 7d (265 mg, 0.71 mmol, 95% yield) as colorless
oil. TLC (hexane–EtOAc, 4:1) Rf = 0.28; IR (film)
3600–3250 (br, OH), 2972, 2928, 2863, 1728 (C@O),
1
(C@O), 1454, 1257, 1142, 757 cmꢀ1; H NMR (CDCl3,
300 MHz) d 1.17 (s, 3H), 1.45–1.53 (m, 2H), 1.60 (s,
3H), 1.61 (s, 3H), 1.68 (s, 3H), 1.81 (t, J = 6.9 Hz,
2H), 1.95–2.08 (m, 7H), 3.62 (s, 2H), 4.26 (t,
J = 6.9 Hz, 2H), 5.05–5.14 (m, 2H), 7.28–7.36 (m, 5H);
13C NMR (CDCl3, 75 MHz) d 15.9, 17.5, 22.4, 25.6,
26.5, 26.6, 39.5 (2C), 41.3, 41.9, 61.6, 71.5, 123.9,
124.1, 127.0, 128.4 (2C), 129.1 (2C), 131.2, 133.7,
135.3, 171.4; ½aꢂ
22.3
ꢀ1.7 (c 2.0, CHCl3) for 90% ee;
D
HRMS (FAB) m/z calcd for C23H34O3Na (M+Na)
381.2406, found 381.2409.
1454, 1383, 1046, 929 cmꢀ1
;
1H NMR (CDCl3,
4.6. General procedure for the diastereoselective cycliza-
tion of 6 induced by chiral LBA 5ÆSnCl4 (Table 2)
300 MHz) d 1.18 (s, 3H), 1.46–1.52 (m, 2H), 1.59 (s,
3H), 1.61 (s, 3H), 1.67 (s, 3H), 1.78 (dt, J = 2.1,
7.2 Hz, 2H), 1.96–2.07 (m, 7H), 2.61 (t, J = 7.8 Hz,
2H), 2.93 (t, J = 7.8 Hz, 2H), 4.23 (t, J = 6.9 Hz, 2H),
5.06–5.14 (m, 2H), 7.16–7.20 (m, 3H), 7.24–7.29 (m,
2H); 13C NMR (CDCl3, 75 MHz) d 15.9, 17.5, 22.4,
25.6 (2C), 26.5, 26.7, 30.8, 35.8, 39.5, 42.0, 61.2, 71.6,
123.9, 124.1, 126.1, 128.1 (2C), 128.3 (2C), 131.2,
135.3, 140.2, 172.8; HRMS (FAB) m/z calcd for
C24H36O3Na (M+Na) 395.2562, found 395.2576.
To a solution of chiral catechol (R)-5 (103 mg,
0.20 mmol) in toluene or CH2Cl2 or n-PrCl (2 mL) was
added a 1 M solution of tin(IV) chloride in hexane (for
toluene as reaction solvent) or CH2Cl2 (for CH2Cl2 or
n-PrCl as reaction solvent) (200 mL, 0.20 mmol) at room
temperature, and the mixture was stirred for 5 min. After
the solution was cooled to ꢀ78 ꢁC, 1.0 M solution of 7 in
toluene (for toluene as reaction solvent) or CH2Cl2 (for
CH2Cl2 or n-PrCl as reaction solvent) (100 mL,
0.10 mmol) was added dropwise. The reaction mixture
was stirred for 1 day, quenched with saturated aqueous
NaHCO3, and extracted with ether. The combined
organic phases were dried over anhydrous MgSO4
and concentrated. The crude product was purified by
column chromatography on silica gel (eluent: hexane–
ether = 10:1 ! 5:1 ! 2:1) to give bicyclic compounds,
chiral catechol, and monocyclic compounds. Further col-
umn chromatography (see below for conditions of each
compound) of bicyclics gave 8 and 9. Yields, ratio, and
enantioselectivity of bicyclics are described in Table 2.
4.5.4. ( )-1-Benzoxy-3,7,11-trimethyl-6,10-dodecadiene-
3-ol (7e). To a solution of 7a (240 mg, 1.0 mmol), pyri-
dine (105 mL, 1.3 mmol) in CH2Cl2 (2 mL) at ꢀ78 ꢁC
under N2 was added benzoyl chloride (151 mL,
1.3 mmol) dropwise and stirred for 10 h at ꢀ78 ꢁC. Then
1 M HCl was poured into this mixture, extracted with
hexane (twice), washed with brine, dried over anhydrous
MgSO4, and concentrated. The residue was purified by
column chromatography on silica gel (eluent: hexane–
ethyl acetate = 10:1) to give 7e (327 mg, 0.95 mmol,
95% yield) as colorless oil. TLC (hexane–EtOAc, 4:1)

5062
M. Uyanik et al. / Bioorg. Med. Chem. 13 (2005) 5055–5065
4.6.1. (20S,40aS,80aS)-(ꢀ)-2-(20,50,50,80a-Tetramethylocta-
hydrochromen-20-yl)ethyl 3-phenylpropionate (8d). TLC
(hexane–EtOAc, 4:1) Rf = 0.68; column chromatogra-
phy, hexane–Et2O = 20:1; HPLC (two linear AD-H col-
umns, hexane–i-PrOH = 250:1, flow rate = 0.5 mL/min)
tR = 45.1 min for (+)-8d, 47.2 min for (ꢀ)-8d; GC
(PEG, column temp 210 ꢁC, 120 kPa) tR = 54.3 min;
IR (film) 2992, 2938, 2868, 1725 (C@O), 1455, 1377,
0.89 (s, 3H), 1.14 (s, 3H), 1.17–1.80 (m, 19H), 1.25 (s,
3H), 2.05 (quintet, J = 7.5 Hz, 1H), 2.61 (t, J = 7.8 Hz,
2H), 2.95 (t, J = 7.8 Hz, 2H), 4.15–4.27 (m, 2H), 7.19–
7.21 (m, 3H), 7.28–7.32 (m, 2H); 13C NMR (CDCl3,
75 MHz) d 16.2, 20.2, 20.8, 23.1, 30.5, 31.0, 32.2, 33.5,
36.0, 38.1, 39.4, 41.4, 42.0, 53.5, 61.9, 72.3, 75.3, 126.2,
128.3 (2C), 128.5 (2C), 140.5, 173.0; HRMS (FAB) m/
z calcd for C24H36O3SeNa (M+Na) 395.2562, found
395.2576.
1
1134, 1101, 976 cmꢀ1; H NMR (CDCl3, 300 MHz) d
0.75 (s, 3H), 0.88 (s, 3H), 1.13–1.82 (m, 10H), 1.24 (s,
3H), 1.25 (s, 3H), 2.61 (t, J = 7.8 Hz, 2H), 2.94 (t,
J = 7.8 Hz, 2H), 4.18 (ddd, J = 6.3, 8.4, 11.1 Hz, 1H),
4.25 (ddd, J = 6.3, 8.7, 11.1 Hz, 1H), 7.19–7.21 (m,
3H), 7.28–7.31 (m, 2H); 13C NMR (CDCl3, 75 MHz) d
16.2, 20.0, 20.8, 23.5, 28.1, 30.9, 32.2, 33.4, 36.0,
36.9, 41.4, 41.5, 43.5, 54.1, 61.5, 72.1, 74.9, 126.2,
128.3 (2C), 128.4 (2C), 140.6, 173.1; HRMS (FAB)
m/z calcd for C24H36O3Na (M+Na) 395.2562, found
395.2576.
4.6.5. (20S,40aR,80aR)-(+)-2-(20,50,50,80a-Tetramethylocta-
hydrochromen-20-yl)ethyl Benzoate (9e). TLC (hexane–
Et2O–CH2Cl2, 12:1) Rf = 0.32; column chromatogra-
phy, hexane–Et2O = 20:1–15:1; HPLC (AD-H column,
hexane–i-PrOH = 200:1, flow rate = 1.0 mL/min) tR =
8.1 min for (ꢀ)-9e, 9.5 min for (+)-9e; GC (PEG, col-
umn temp 210 ꢁC, 210 kPa) tR = 34.4 min; 1H NMR
(CDCl3, 300 MHz) d 0.78 (s, 3H), 0.90 (s, 3H), 1.12–
1.70 (m, 10H), 1.23 (s, 3H), 1.32 (s, 3H), 1.84–1.95 (m,
2H), 2.17–2.30 (m, 1H), 4.40–4.51 (m, 2H), 7.43 (t,
J = 7.5 Hz, 2H), 7.55 (t, J = 7.5 Hz, 1H), 8.04 (dd,
J = 1.5, 7.5 Hz, 2H).
4.6.2. (20S,40aS,80aS)-(ꢀ)-2-(20,50,50,80a-Tetramethylocta-
hydrochromen-20-yl)ethyl benzoate (8e). TLC (hexane–
EtOAc, 12:1) Rf = 0.40; column chromatography,
hexane–Et2O = 25:1–20:1; HPLC (AD-H column, hex-
ane–i-PrOH = 200:1, flow rate = 1.0 mL/min) tR = 7.9
min for (+)-8e, 8.7 min for (ꢀ)-8e; GC (PEG, column
temp 210 ꢁC, 120 kPa) tR = 31.6 min; 1H NMR (CDCl3,
300 MHz) d 0.77 (s, 3H), 0.89 (s, 3H), 1.16–1.71 (m,
11H), 1.28 (s, 3H), 1.31 (s, 3H), 1.83 (ddd, J = 6.0, 8.4,
13.8 Hz, 1H), 1.94 (ddd, J = 6.0, 8.1, 13.2 Hz, 1H), 4.44
(ddd, J = 2.4, 6.0, 11.1 Hz, 1H), 4.50 (ddd, J = 1.8, 8.1,
11.1 Hz, 1H), 7.43 (t, J = 1.5, 7.5 Hz, 2H), 7.55 (dd,
J = 1.5, 7.5 Hz, 1H), 8.03 (dd, J = 1.5, 7.5 Hz, 2H).
4.6.6. (20S,40aR,80aR)-(+)-2-(20,50,50,80a-Tetramethylocta-
hydrochromen-20-yl)ethyl phenylacetate (9f). TLC
(hexane–Et2O–CH2Cl2, 4:1:1) Rf = 0.60; column chro-
matography, hexane–Et2O = 15:1–10:1; HPLC (AD-H
column, hexane–i-PrOH = 250:1, flow rate = 1.0 mL/
min) tR = 9.4 min for (ꢀ)-9f, 12.8 min for (+)-9f; GC
(PEG, column temp 210 ꢁC, 120 kPa) tR = 40.1 min;
1
IR (film) 2976, 2936, 1727, 1523, 1426, 1045 cmꢀ1; H
NMR (CDCl3, 300 MHz) d 0.76 (s, 3H), 0.88 (s, 3H),
1.11 (s, 3H), 1.12–1.82 (m, 12H), 1.24 (s, 3H), 2.05
(dd, J = 5.7, 8.1 Hz, 1H), 2.09 (dd, J = 6.0, 7.5 Hz,
1H), 3.60 (s, 2H), 4.15 (ddd, J = 6.6, 8.1, 11.1 Hz, 1H),
4.25 (ddd, J = 6.0, 8.4, 11.1 Hz, 1H), 7.24–7.35 (m,
5H); 13C NMR (CDCl3, 75 MHz) d 16.1, 20.1, 20.8,
23.1, 30.5, 32.2, 33.4, 37.9, 39.3, 41.4, 41.5, 42.0, 53.3,
4.6.3. (20S,40aS,80aS)-(ꢀ)-2-(20,50,50,80a-Tetramethylocta-
hydrochromen-20-yl)ethyl phenylacetate (8f). TLC (hex-
ane–EtOAc–CH2Cl2, 4:1:1) Rf = 0.62; column chromato-
graphy, hexane–Et2O = 15:1; HPLC (two linear AD-H
columns, hexane–i-PrOH = 250:1, flow rate = 0.5 mL/
min) tR = 39.7 min for (+)-8f, 41.2 min for (ꢀ)-8f; GC
(PEG, column temp 210 ꢁC, 120 kPa) tR = 39.0 min;
62.3, 72.2, 75.2, 127.0, 128.5 (2C), 129.3 (2C), 134.1,
171.6; ½aꢂ
23.4
23 (c 1.0, CHCl3) for 98% ee; HRMS
(FAB) m/z calcd for C23H34O3Na (M+Na) 381.2406,
found 381.2409.
D
IR (film) 2975, 2936, 1726, 1523, 1426, 1045 cmꢀ1
;
1H NMR (CDCl3, 300 MHz) d 0.75 (s, 3H), 0.87 (s,
3H), 1.07–1.60 (m, 11H), 1.22 (s, 3H), 1.24 (s, 3H),
1.66 (ddd, J = 6.3, 8.4, 13.8 Hz, 1H), 1.78 (ddd,
J = 6.3, 8.4, 13.8 Hz, 1H), 3.60 (s, 2H), 4.20 (ddd,
J = 6.3, 8.4, 11.1 Hz, 1H), 4.26 (ddd, J = 6.3, 8.7,
11.1 Hz, 1H), 7.23–7.24 (m, 5H); 13C NMR (CDCl3,
75 MHz) d 16.1, 20.7 (2C), 23.4, 28.0, 32.0 (2C), 36.7
4.6.7. (20S,40aS,80aS)-(ꢀ)-2-(20,50,50,80a-Tetramethyloc-
tahydrochromen-20-yl)ethanol (8a). To a solution of 8f
(100 mg, 0.58 mmol) in methanol (2 mL) at 0 ꢁC was
added 1 M aqueous LiOH (870 mL, 0.87 mmol). After
stirring for an additional 1 h poured into brine and
extracted with ether (twice). The combined organic
phases were dried over anhydrous MgSO4 and
concentrated. The crude product was through pipette
column on silica gel to give 8a (139 mg, 0.58 mmol,
100% yield) as colorless oil. TLC (hexane–EtOAc,
2.5:1) Rf = 0.37; IR (film) 3550–3250 (br, OH), 2975,
(2C), 41.4 (2C), 43.3, 54.0, 61.8, 72.0, 74.6, 126.9,
128.4 (2C), 129.7 (2C), 134.1, 171.7; ½aꢂ
22.8
ꢀ8.2 (c 1.0,
D
CHCl3) for >99% ee; HRMS (FAB) m/z calcd for
C23H34O3Na (M+Na) 381.2406, found 381.2409.
4.6.4. (20S,40aR,80aR)-(+)-2-(20,50,50,80a-Tetramethylocta-
hydrochromen-20-yl)ethyl 3-phenylpropionate (9d). TLC
(hexane–EtOAc, 4:1) Rf = 0.66; column chromato-
graphy, hexane–Et2O = 15:1; HPLC (AD-H column,
hexane–i-PrOH = 250:1, flow rate = 1.0 mL/min) tR =
9.8 min for (ꢀ)-9d, 14.0 min for (+)-9d; GC (PEG, col-
umn temp 210 ꢁC, 120 kPa) tR = 56.8 min; IR (film)
2982, 2938, 2870, 1726 (C@O), 1456, 1375, 1180, 1100,
2941, 2872, 1711, 1523, 1427, 1046, 929 cmꢀ1 1H
;
NMR (CDCl3, 300 MHz) d 0.77 (s, 3H), 0.90 (s,
3H), 1.21–1.75 (m, 13H), 1.29 (s, 3H), 1.32 (s, 3H),
3.72–3.88 (m, 2H), 4.04 (t, J = 5.0 Hz, OH); 13C
NMR (CDCl3, 75 MHz) d 16.1, 20.0, 20.8, 23.3,
27.6, 32.1, 33.4, 37.3, 41.3, 41.7, 45.8, 54.2, 59.7,
76.0, 76.1; ½aꢂ
23.4
ꢀ6.4 (c 1.0, CHCl3) for >99% ee;
D
HRMS (FAB) m/z calcd for C15H28O2Na (M+Na)
263.1987, found 263.1980.
1
974 cmꢀ1; H NMR (CDCl3, 300 MHz) d 0.77 (s, 3H),

M. Uyanik et al. / Bioorg. Med. Chem. 13 (2005) 5055–5065
5063
4.6.8. (20S,40aS,80aS)-(ꢀ)-o-Nitrophenyl-2-(20,50,50,80a-
75 MHz) d 15.6, 20.0, 20.5, 24.0, 28.8, 31.9, 33.7, 35.1,
23.1
tetramethyloctahydrochromen-20-yl)ethylselenide
(12).
41.5, 42.3, 44.0, 50.0, 60.0, 74.6, 75.5; ½aꢂ
29 (c 1.0,
CHCl3) for 98% ee; HRMS (FAB) m/z calcd for
D
To a stirring solution of 8a (166 mg, 0.69 mmol) and
o-nitrophenyl selenocyanate (384 mg, 1.73 mmol) in
dry THF (3 mL) under N2 at room temperature was
added tri-n-butylphosphine (427 mL, 1.73 mmol). After
stirring for 3 h, quenched with ethanol and concen-
trated. The crude product was purified by column chro-
matography on silica gel (eluent: hexane–ether = 15:1)
to give 12 (282 mg, 0.66 mmol, 96% yield) as yellow
oil. TLC (hexane–EtOAc, 4:1) Rf = 0.54; HPLC (OD-
H column, hexane–i-PrOH = 80:1, flow rate = 1.0 mL/
min) tR = 6.7 min for (+)-12, 8.0 min for (ꢀ)-13; IR
C15H28O2Na (M+Na) 263.1987, found 263.1978.
4.6.11. (20S,40aR,80aR)-(+)-o-Nitrophenyl-2-(20,50,50,80a-
tetramethyloctahydrochromen-20-yl)ethyl-selenide (13).
To a stirring solution of 9a (19.2 mg, 0.080 mmol) and
o-nitrophenyl selenocyanate (44.4 mg, 0.200 mmol) in
dry THF (1 mL) under N2 at room temperature was
added tri-n-butylphosphine (49 mL, 0.200 mmol). After
stirring for 3 h, quenched with ethanol and concen-
trated. The crude product was purified by column chro-
matography on silica gel (eluent: hexane–ether = 10:1)
to give 13 (32.4 mg, 0.076 mmol, 95% yield) as yellow
oil. TLC (hexane–EtOAc, 4:1) Rf = 0.48; IR (film)
(film) 2976, 2932, 1515, 1426, 1335, 1046, 929 cmꢀ1
;
1H NMR (CDCl3, 300 MHz) d 0.78 (s, 3H), 0.90 (s,
3H), 1.16–1.73 (m, 11H), 1.28 (s, 3H), 1.30 (s, 3H),
1.78 (ddd, J = 5.7, 10.8, 13.4 Hz, 1H), 1.87 (ddd,
J = 5.7, 11.1, 13.4 Hz, 1H), 2.97 (dt, J = 5.8, 12.4 Hz,
1H), 3.06 (dt, J = 5.8, 12.4 Hz, 1H), 7.30 (ddd, J = 1.2,
7.2, 8.2 Hz, 1H), 7.52 (ddd, J = 1.2, 7.2, 8.2 Hz, 1H),
7.74 (dd, J = 1.2, 8.2 Hz, 1H), 8.30 (dd, J = 1.2,
8.2 Hz, 1H); 13C NMR (CDCl3, 75 MHz) d 16.3, 20.1,
20.5, 20.8, 23.5, 27.4, 32.3, 33.5, 36.8, 41.5, 41.7, 44.5,
2977, 2932, 1520, 1425, 1335, 1046, 929 cmꢀ1 1H
;
NMR (CDCl3, 300 MHz) d 0.78 (s, 3H), 0.90 (s, 3H),
1.18–1.90 (m, 12H), 1.24 (s, 3H), 1.28 (s, 3H), 2.19
(ddd, J = 4.2, 12.0, 14.1 Hz, 1H), 2.96 (dt, J = 5.1,
10.6 Hz, 1H), 3.06 (dt, J = 3.9, 106 Hz, 1H), 7.31 (ddd,
J = 1.5, 6.9, 9.5 Hz, 1H), 7.52 (ddd, J = 1.5, 6.9,
9.5 Hz, 1H), 7.59 (dd, J = 1.5, 8.4 Hz, 1H), 8.31 (dd,
J = 1.5, 8.4 Hz, 1H); 13C NMR (CDCl3, 75 MHz) d 16.1,
20.2, 20.8, 21.3, 22.9, 30.0, 32.2, 33.5, 37.9, 38.9, 41.4,
54.3, 73.2, 75.0, 125.0, 126.4, 129.2, 133.5, 134.4;
½aꢂ
23.7
ꢀ9.0 (c 1.0, CHCl3) for >99% ee; HRMS (FAB)
D
m/z calcd for C21H31O3SeNa (M+Na) 448.1367, found
443.1383.
42.1, 53.3, 73.4, 75.4, 125.2, 126.4, 129.2, 133.6, 134.4;
29 (c 1.0, CHCl3) for 98% ee; HRMS (FAB) m/z
23.7
½aꢂ
D
calcd for C21H31O3SeNa (M+Na) 448.1367, found
448.1367.
4.6.9. (5S,8S,10S)-(ꢀ)-Caparrapi oxide (1).1,2,15 To a
solution of 12 (276 mg, 0.65 mmol) in THF (15 mL)
was slowly added 30% aqueous hydrogen peroxide
(592 mL) at 0 ꢁC. Stirring was maintained for 1 day at
room temperature. Water was added, extracted with
ether (twice), washed with water, dried over anhydrous
MgSO4, and concentrated. The residue was purified by
column chromatography on silica gel (eluent: hexane–
ether = 10:1) to give 1 (139 mg, 0.625 mmol, 96% yield)
as colorless oil. TLC (hexane–EtOAc, 4:1) Rf = 0.45;
GC (PEG, column temp 60 ꢁC, 60 kPa) tR = 109.8 min;
GC (b-DM column, column temp 70 ꢁC, 70 kPa)
4.6.12. (5R,8S,10R)-(+)-Epicaparrapi oxide (2).4a,15 To
a solution of 13 (21.3 mg, 0.050 mmol) in THF (1 mL)
was slowly added 30% aqueous hydrogen peroxide
(46 mL) at 0 ꢁC. Stirring was maintained for 1 day at
room temperature. Water was added, extracted with
ether (twice), washed with water, dried over anhydrous
MgSO4, and concentrated. The residue was purified by
column chromatography on silica gel (eluent: hexane–
ether = 10:1) to give 2 (10.6 mg, 0.048 mmol, 96% yield)
as colorless oil. TLC (hexane–EtOAc, 4:1) Rf = 0.45;
GC (PEG, column temp 60 ꢁC, 60 kPa) tR = 114.4 min;
GC (b-DM column, column temp 80 ꢁC, 100 kPa)
tR = 61.1 min for (+)-2, tR = 66.6 min for (ꢀ)-2; 1H
NMR (CDCl3, 300 MHz) d 0.73 (s, 3H), 0.89 (s, 3H),
1.18–1.67 (m, 10H), 1.14 (s, 3H), 1.22 (s, 3H), 2.18–
2.28 (m, 1H), 4.91 (dd, J = 1.0, 11.1 Hz, 1H), 4.97 (dd,
J = 1.0, 18.0 Hz, 1H), 6.02 (dd, J = 11.1, 18.0 Hz, 1H);
1
tR = 104.9 min for (+)-1, tR = 108.6 min for (ꢀ)-1; H
NMR (CDCl3, 300 MHz) d 0.79 (s, 3H), 0.86 (s, 3H),
1.15–1.84 (m, 11H), 1.29 (s, 3H), 1.30 (s, 3H), 4.92
(dd, J = 1.5, 10.7 Hz, 1H), 5.15 (dd, J = 1.5, 17.4 Hz,
1H), 5.89 (dd, J = 10.7, 17.4 Hz, 1H); ½aꢂ
22.7
ꢀ19 (c
D
0.065, CHCl3) for >99% ee.
23.0
D
for 98% ee.
22.5
D
4.6.10. (20S,40aR,80aR)-(+)-2-(20,50,50,80a-Tetramethyl-
octahydrochromen-20-yl)ethanol (9a). To a solution of
9f (22 mg, 0.061 mmol) in methanol (1 mL) at 0 ꢁC
was added 1 M aqueous LiOH (92 mL, 0.092 mmol).
After stirring for an additional 1 h poured into brine
and extracted with ether (twice). The combined organic
phases were dried over anhydrous MgSO4 and concen-
trated. The crude product was through pipette column
on silica gel to give 9a (14.6 mg, 0.061 mmol, 100%
yield) as colorless oil. TLC (hexane–EtOAc, 2.5:1)
Rf = 0.20; IR (film) 3550–3250 (br, OH), 2976, 2941,
½aꢂ
43 (c 1.1, EtOH) and ½aꢂ
48 (c 1.0, CHCl3)
4.7. Diastereoselective epoxidation of (+)-1 with peroxy-
trifluoroacetic acid (Table 3, entry 1)
To a stirred mixture of urea hydrogen peroxide (144 mg,
1.5 mmol), potassium hydrogen phosphate (230 mg,
1.32 mmol) and (+)-1 (33 mg, 0.15 mmol) in CH2Cl2
(2 mL) was added trifluroacetic anhydride (54 mL,
0.38 mmol) dropwise at 0 ꢁC. The resulting mixture
was allowed to warm to room temperature and stirred
for additional 3 h. A saturated solution of sodium
hydrogen carbonate (1 mL) was added to neutralize
the acids present and an aqueous layer was then
extracted with CH2Cl2 (twice). The combined organic
1
2872, 1523, 1427, 1046, 926 cmꢀ1; H NMR (CDCl3,
300 MHz) d 0.67 (s, 3H), 0.74 (s, 3H), 1.00–1.60 (m,
11H), 1.11 (s, 3H), 1.17 (s, 3H), 1.76–1.90 (m, 2H),
3.23 (br s, OH), 3.60 (quintet, J = 5.1 Hz, 1H), 3.79
(ddd, J = 4.8, 9.0, 11.1 Hz, 1H); 13C NMR (CDCl3,

5064
M. Uyanik et al. / Bioorg. Med. Chem. 13 (2005) 5055–5065
layers were washed with water, dried over anhydrous
MgSO4, and concentrated under reduced pressure. The
residue was purified by column chromatography on
silica gel (eluent: hexane–diethyl ether = 15:1–10:1) to
give (+)-dysifragin (4, 17.5 mg, 0.073 mmol, 49% yield)
as amorphous solid and its (+)-epimer (14, 17.3 mg,
0.073 mmol, 49% yield) as amorphous solid,
respectively.
resulting mixture was filtered, dried over anhydrous
MgSO4, and concentrated. The residue was purified by
flash column chromatography on silica gel (eluent: hex-
ane–diethyl ether = 5:1) to give 15 (9 mg, 0.038 mmol,
95% yield) as colorless oil. TLC (hexane–EtOAc, 4:1)
1
Rf = 0.45; H NMR (CDCl3, 500 MHz) d 0.76 (s, 3H),
0.89 (s, 3H), 1.06 (d, J = 6.6 Hz, 1H), 1.15 (s, 3H),
1.20–1.66 (m, 11H), 1.27 (s, 3H), 2.76 (d, J = 5.1 Hz,
OH), 3.26–3.41 (m, 1H); For 13C NMR (CDCl3,
75 MHz), see Table 4.
4.7.1. (+)-Dysifragin (4).2 TLC (hexane–EtOAc, 4:1)
Rf = 0.55; IR (film) 2998, 2938, 2868, 1459, 1377,
1101 cmꢀ1
3H), 0.89 (s, 3H), 1.19–1.71 (m, 11H), 1.22 (s, 3H),
;
1H NMR (CDCl3, 500 MHz) d 0.78 (s,
4.7.4. (1S,20R,40aR,80aR)-1-(20,50,50,80a-Tetramethyloc-
tahydrochromen-20-yl)ethanol (16).16 To a solution of
(+)-14 (12 mg, 0.05 mmol) in Et2O (2 mL) was added
LiAlH4 (11 mg, 0.3 mmol) at 0 ꢁC, and allowed to warm
to room temperature. After being stirred for 3 h at the
same temperature, excess LiAlH4 was decomposed with
EtOAc, then with H2O at 0 ꢁC. Anhydrous Na2SO4 was
added and stirred for 30 min at room temperature. The
resulting mixture was filtered, dried over anhydrous
MgSO4, and concentrated. The residue was purified by
flash column chromatography on silica gel (eluent: hex-
ane–diethyl ether = 5:1) to give 16 (9.6 mg, 0.04 mmol,
80% yield) as colorless oil. TLC (hexane–EtOAc, 4:1)
1.28 (s, 3H), 2.65 (dd, J = 4.0, 5.5 Hz, 1H), 2.76 (dd,
J = 3.0, 5.5 Hz, 1H), 2.82 (dt, J = 3.0, 4.0 Hz, 1H); For
21.3
13C NMR (CDCl3, 125 MHz), see Table 4; ½aꢂ
13 (c
1.3, CHCl3) for 98% ee; HRMS (FAB) m/z calcd for
C23H34O3Na (M+Na) 261.1830, found 261.1833.
D
4.7.2. (+)-Epidysifragin (14). TLC (hexane–EtOAc, 4:1)
Rf = 0.49; IR (film) 2997, 2934, 2863, 1457, 1378, 1222,
1
1209, 1101 cmꢀ1; H NMR (CDCl3, 500 MHz) d 0.77
(s, 3H), 0.90 (s, 3H), 1.20–1.70 (m, 11H), 1.23 (s, 3H),
1.29 (s, 3H), 2.66 (dd, J = 4.0, 5.0 Hz, 1H), 2.71 (dd,
J = 3.0, 5.0 Hz, 1H), 2.87 (dt, J = 3.0, 4.0 Hz, 1H); For
1
Rf = 0.36; H NMR (CDCl3, 500 MHz) d 0.77 (s, 3H),
21.5
13C NMR (CDCl3, 125 MHz), see Table 4; ½aꢂ
15 (c
0.080, CHCl3) for 98% ee; HRMS (FAB) m/z calcd for
C23H34O3Na (M+Na) 261.1830, found 261.1827.
0.90 (s, 3H), 1.04 (d, J = 6.3 Hz, 1H), 1.10–1.82 (m,
11H), 1.20 (s, 3H), 1.32 (s, 3H), 3.05 (s, OH), 3.48
(ddd, J = 2.0, 6.9, 13.6 Hz, 1H); For 13C NMR (CDCl3,
75 MHz), see Table 4.
D
4.7.3. (1R,20R,40aR,80aR)-1-(20,50,50,80a-Tetramethyloc-
tahydrochromen-20-yl)ethanol (15).16 To a solution of
(+)-4 (10 mg, 0.04 mmol) in Et2O (2 mL) was added
LiAlH4 (11 mg, 0.3 mmol) at 0 ꢁC, and allowed to warm
to room temperature. After being stirred for 3 h at the
same temperature, excess LiAlH4 was decomposed with
EtOAc, then with H2O at 0 ꢁC. Anhydrous Na2SO4 was
added and stirred for 30 min at room temperature. The
4.7.5. X-ray crystallographic analysis of (+)-4. Com-
pound (+)-4 was crystallized without any solvents at
ꢀ25 ꢁC. Crystal data: C15H26O2, M = 238.36, crystal
dimensions 0.30 · .20 · 0.07 mm3, orthorhombic, space
group P212121 (#19), a = 6.9005 (19), b = 11.488 (3),
3
˚
˚
c = 17.729 (5) A, V = 1405.4 (7) A , Z = 4, Dc =
1.127 g/cm3, T = 223 K. X-ray crystallographic analysis
was performed with a Bruker SMART APEX CCD dif-
fractometer (graphite monochromator, MoKa radia-
˚
tion, k = 0.71073 A). The structure was solved by
Table 4. 13C chemical shifts (d) of (+)-4, (+)-14, 15, and 16
direct methods and expanded using Fourier techniques.
Three thousand six hundred and fifty one reflections
were independent and unique, and 2018 with I > 2r(I)
(2hmax = 29.09ꢁ) were used for the solution of the struc-
ture. The non-hydrogen atoms were refined anisotropi-
cally. R = 0.0544 and Rw = 0.1110.
OH
OH
9'
12'
9'
12'
9'
12'
9'
12'
O
O
8'
8'
8'
8'
O
O
O
O
7'
7'
7'
7'
1
1
1
1
1'
4'a
1'
4'a
1'
4'a
1'
4'a
8'a
8'a
8'a
8'a
2'
3'
2'
3'
2'
3'
2'
3'
2
2
2
2
6' 5'
6' 5'
6' 5'
6' 5'
4'
4'
4'
4'
H
H
H
H
11' 10'
11' 10'
11' 10'
11' 10'
(+)-4
(+)-14
15
16
C(n)
(+)-4 (+)-14 Dd((+)-4, 15
(+)-14)
16
Dd((+)-15,
(+)-16)
Crystallographic data have been deposited with
Cambridge Crystallographic Data Centre: Deposition
number CCDC 265385 for (+)-4. Copy of the data can
be obtained free of charge via http://www.ccdc.cam.
ac.uk/conts/retrieving.html (or from the Cambridge
Crystallographic Data Centre, 12, Union Road,
Cambridge, CB2 1EZ, UK; Fax: +44 1223 336033;
e-mail deposit@ccdc.cam.ac.uk).
C(1)
C(2)
C(20)
C(30)
C(40)
59.8
43.9
70.7
33.7
20.0
59.9
43.8
71.2
33.6
20.0
53.7
33.6
41.5
15.7
41.5
75.3
23.5
32.1
20.8
24.2
ꢀ0.1
+0.1
ꢀ0.5
+0.1
0
75.7 73.2 +2.5
16.3 15.3 +1.0
75.2 76.4 ꢀ1.2
34.4 29.4 +5.0
20.0 20.0
54.1 54.5 ꢀ0.4
33.4 33.4
0
C(40a) 53.0
ꢀ0.7
ꢀ0.1
ꢀ0.1
+0.2
ꢀ0.1
ꢀ0.3
+0.2
ꢀ0.1
0
C(50)
C(60)
C(70)
C(80)
33.5
41.4
15.9
41.4
0
41.5 41.4 +0.1
16.0 15.7 +0.3
4.7.6. Epoxide inversion from (+)-14 to (+)-4.17 Cesium
propionate (168 mg, 0.6 mmol) and 18-crown-6 (95 mg,
0.36 mmol) were added to the flask and removed mois-
tures under high-vacuum pressure (0.04 mmHg) while
stirring overnight. Dry toluene (4 mL) and freshly
distilled AcOH (7 mL, 0.12 mmol) were added to the
flask and the mixture was vigorously stirred. When the
41.7 41.7
0
C(80a) 75.0
C(90)
23.7
C(100) 32.0
C(110) 20.8
C(120) 24.6
75.1 75.8 ꢀ0.7
23.4 23.2 +0.2
32.1 32.1
20.8 20.8
0
0
+0.4
21.7 24.2 ꢀ2.5

M. Uyanik et al. / Bioorg. Med. Chem. 13 (2005) 5055–5065
5065
Bagrianskaya, I. Y.; Barkhash, V. A.; Shcherbukhin, V.
V.; Zefirov, N. S.; Perutskii, V. B.; Ungur, N. D.; Vlad, P.
F. J. Org. Chem. 1994, 59, 1509–1517.
solids dispersed, (+)-14 (14 mg, 0.06 mmol) was added,
and the resulting mixture was heated to reflux for
3 days. Poured in to aqueous NaHCO3 and extracted
with EtOAc (three times). The combined organic layers
were washed with water and brine, dried over anhydrous
MgSO4, and concentrated under reduced pressure. The
residue was through pipette column on silica gel to give
a mixture of regioisomeric propionates, 19 and 20 (2:1
on TLC, 17 mg, 0.055 mmol, 92% yield), and used next
step without further purification. Distilled MsCl (10 mL,
0.11 mmol) was added to a stirred solution of 19, 20,
N,N-diisopropylethylamine (26 lL, 0.15 mmol), and
DMAP (15 mg, 0.12 mmol) in CH2Cl2 was added drop-
wise at ꢀ10 ꢁC. The reaction mixture was stirred for
additional 3 h at ꢀ10 to 0 ꢁC, quenched with NH4Cl
(aq), and the aqueous layer was extracted with Et2O
(twice). The combined organic layer was washed with
water, dried over anhydrous MgSO4, concentrated,
and used in next step without further purification. To
a mixture of regioisomeric mesylates were added MeOH
(2.5 mL) and K2CO3 (4 mg, 0.022 mmol), and stirred for
12 h at room temperature. After the reaction was com-
pleted, the resultant mixture was passed through a
short-column chromatography on silica gel, and concen-
trated under reduced pressure. The residue was purified
on flash column chromatography on silica gel (eluent:
hexane–diethyl ether = 10:1) to give (+)-4 (11.5 mg,
0.048 mmol, 88% yield in two steps) as amorphous solid.
6. (a) Kametani, T. Tetrahedron Lett. 1981, 22, 3655–
3656; (b) Kametani, T.; Kurobe, H.; Nemoto, H.;
Fukumoto, K. J. Chem. Soc., Perkin Trans. 1 1982,
1085–1087.
7. (a) Ishihara, K.; Nakamura, S.; Yamamoto, H. J. Am.
Chem. Soc. 1999, 121, 4906–4907; (b) Nakamura, S.;
Ishihara, K.; Yamamoto, H. J. Am. Chem. Soc. 2000, 122,
8131–8140; (c) Ishihara, K.; Ishibashi, H.; Yamamoto, H.
J. Am. Chem. Soc. 2001, 123, 1505–1506; (d) Ishihara, K.;
Ishibashi, H.; Yamamoto, H. J. Am. Chem. Soc. 2002,
124, 3647–3655; (e) Kumazawa, K.; Ishihara, K.; Yamam-
oto, H. Org. Lett. 2004, 6, 2551–2554; (f) Ishibashi, H.;
Ishihara, K.; Yamamoto, H. J. Am. Chem. Soc. 2004, 126,
11122–11123.
8. Part of this work has been published as the following
preliminary communication: Muhammet, U.; Ishibashi,
H.; Ishihara, K.; Yamamoto, H. Org. Lett. 2005, 7, 1601–
1604.
9. Predictable chelation structures of 7 with SnCl4 are shown
below. Further studies to elucidate the existence of some
attractive interaction between Sn(IV) and a phenyl group
of 7e and 7f are currently in progress in our laboratory,
and our results will be reported in due course
R
O
O
Cl4Sn
O
O
H
O
Sn
H
Cl4
Undesirable chelation
Desirable chelation
Acknowledgments
10. For the asymmetric synthesis of (ꢀ)-1 from (ꢀ)-sclareol,
see: Barrero, A. F.; Alvarez-Manzaneda, E. J.; Chah-
Financial support for this project was provided by
SORST, Japan Science and Technology Agency (JST),
JSPS.KAKENHI (15205021), the Mitsubishi Founda-
tion, the Uehara Memorial Foundation, the Kowa Life
Science Foundation, and the 21st Century COE pro-
gram ꢁNature-Guided Materials Processingꢀ of MEXT.
We also acknowledge Dr. Manabu Hatano for the sin-
gle-crystal X-ray analysis.
´
boun, R.; Paiz, M. C. Tetrahedron Lett. 1998, 39, 9543–
9544.
11. (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980,
102, 5974–5976; (b) Kigoshi, H.; Ojika, M.; Shizuri, Y.;
Niwa, H.; Yamada, K. Tetrahedron 1986, 42, 3789–3792;
(c) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.;
Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987,
109, 5765–5780; (d) Dittmer, D. C.; Discordia, R. P.;
Zhang, Y.; Murphy, C. K.; Kumar, A.; Pepito, A. S.;
Wang, Y. J. Org. Chem. 1993, 58, 718–731.
12. (a) Viti, S. M. Tetrahedron Lett. 1982, 23, 4541–4544; (b)
Hyatt, J. A.; Kottas, G. S.; Effler, J. Org. Process Res.
Dev. 2002, 6, 782–787.
References and notes
1. For the isolation of (ꢀ)-1, see: (a) Appel, H. H.; Brooks,
C. J. W.; Campbell, M. M. Perf. Essent. Oil Rec. 1967,
776–781; (b) Brooks, C. J. W.; Campbell, M. M. Phyto-
chemistry 1969, 8, 215–218.
13. Ishihara, K.; Kurihara, H.; Yamamoto, H. J. Org. Chem.
1993, 58, 3791–3793.
14. Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem.
1976, 41, 1485–1486.
2. For the isolation of (+)-1, see: Shen, Y.-C.; Hsieh, P.-W.
Chin. Pharm. J. 1999, 51, 213–218.
15. Lomardi, P.; Cookson, R. C. Helv. Chim. Acta 1976, 59,
1158–1168.
3. For the isolation of natural product 2, see: (a) Wadhams,
L. J.; Baker, R.; Howse, P. E. Tetrahedron Lett. 1974,
1697–1700; (b) Baker, R.; Evans, D. A.; McDowell, P. G.
Tetrahedron Lett. 1978, 4073–4076.
16. Garcia-Alvarez, M. C.; Rodriguez, B. J. Org. Chem. 1981,
46, 1915.
17. Arbelo, D. O.; Prieto, J. A. Tetrahedron Lett. 2002, 43,
4111.
4. For the isolation of (+)-2, see: (a) Faulkner, D. J.
Phytochemistry 1976, 15, 1993–1994; (b) Kato, T.; Ishii,
K.; Ichinose, I.; Nakai, Y.; Kumagai, T. J. Chem. Soc.,
Chem. Commun. 1980, 1106–1109.
18. Cooper, M. S.; Heaney, H.; Newbold, A. J.; Sanderson,
W. R. Synlett 1990, 5, 533–535.
19. Hashimoto, N.; Kanda, A. Org. Process Res. Dev. 2002,
405–406.
5. For the diastereoselective cyclization of ( )-3 to ( )-2, see:
Polovinka, M. P.; Korchagina, D. V.; Gatilov, Y. V.;
20. Christophe, C.; Adolfsson, H.; Sharpless, K. B. Chem.
Commun. 1997, 3, 1565–1566.