Synthetic study of hetisine-type aconite alkaloids. Part 1: Preparation of tetracyclic intermediate containing the C14-C20 bond

Article abstract of DOI:10.1016/j.tet.2006.04.084

Full details for the total synthesis of (±)-nominine, a hetisine-type aconite alkaloid, are presented in three parts. Here (part 1), we describe the preparation of the key tetracyclic intermediate 6. Our palladium-catalyzed intramolecular α-arylation was adopted for preparation of the intermediate 4 with an angular formyl group. An acetal-ene reaction was then employed for C14-C20 bond formation to secure 6 from 5. The reaction mechanism of the acetal-ene reaction is discussed, and a method for removal of the 2-hydroxyethyl group from 6 is developed.

Full text of DOI:10.1016/j.tet.2006.04.084

Tetrahedron 62 (2006) 7056–7070
Synthetic study of hetisine-type aconite alkaloids. Part 1:
Preparation of tetracyclic intermediate containing the
C14–C20 bond
*
Hideaki Muratake and Mitsutaka Natsume
*
Research Foundation Itsuu Laboratory, 2-28-10 Tamagawa, Setagaya-ku, Tokyo 158-0094, Japan
Received 10 March 2006; accepted 12 April 2006
Available online 22 May 2006
Abstract—Full details for the total synthesis of (ꢀ)-nominine, a hetisine-type aconite alkaloid, are presented in three parts. Here (part 1), we
describe the preparation of the key tetracyclic intermediate 6. Our palladium-catalyzed intramolecular a-arylation was adopted for preparation
of the intermediate 4 with an angular formyl group. An acetal–ene reaction was then employed for C14–C20 bond formation to secure 6 from
5. The reaction mechanism of the acetal–ene reaction is discussed, and a method for removal of the 2-hydroxyethyl group from 6 is developed.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
1.1. The aconite alkaloids
from hetisine), not to mention total synthesis of a hetisan al-
kaloid, have remained unsuccessful since the structure of he-
tisine was first clarified by X-ray crystal-structure analysis in
1962.10 The heptacyclic hetisan skeleton is the most structur-
ally complex among the above five frameworks, and incorpo-
rates two additional bonds, N–C6 and C14–C20, relative to
the atidane skeleton, as exemplified by nominine, kobusine,
and pseudokobusine (Scheme 1). The synthetic difficulty of
the skeleton stems from the presence of these two bonds.
Aconitum, which has a beautiful blue-purple flower, is well-
known as a poisonous herb, which occasionally results in fa-
talities following accidental ingestion. The aconite alkaloids,
mainly contained in the tuberous root, have long been of in-
terest to researchers, because of both their pharmacological
activity and their structural complexity.1,2 Alkaloids with
similar structures have also been isolated from plants of the
species Delphinium, Consolida, Thalictrum, and Spiraea,
and these are included in the so-called aconite alkaloids.
Over 400 aconite alkaloids have so far been isolated and
structurally characterized.1,2
H
N
H N
H
H
H
H
N
H
H
H
H
Atidane
Veatchane
Cycloveatchane
The fundamental structural frameworks of these alkaloids
are generally classified into five skeletons, i.e., atidane,
veatchane, cycloveatchane, aconitane, and hetisan (Scheme
1). Extensive synthetic studies of these pharmacologically
important alkaloids for about 40 years have led to the total
synthesis of several alkaloids belonging to the first four of
the above five groups: atisine3 (atidane), veatchine4 (veatch-
ane), garryine5 (veatchane), napelline6 (cycloveatchane),
delphinine7 (aconitane), talatisamine8 (aconitane), and chas-
manine9 (aconitane). However, attempts to construct even
a simple hetisan skeleton (the name of which is derived
13
C
17
A
11
20
H
14
1
H
15
6
N
N
H
N 20
14
6
H
H
19
18
Aconitane
Hetisan
R
HO
HO
OH
N
HO
H
X
N
H
H
H
Nominine: R=X=H
Hetisine
Kobusine: R=OH, X=H
Pseudokobusine: R=X=OH
Keywords: Aconite; Alkaloid; a-Arylation; Palladium catalyst; Acetal–ene
reaction.
* Corresponding authors. Tel.: +81 3 3700 5492; fax: +81 3 3700 5431;
e-mail: hmuratake@itsuu.or.jp
Scheme 1. Five representative aconite skeletons and examples of hetisine-
type alkaloids.
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.04.084

H. Muratake, M. Natsume / Tetrahedron 62 (2006) 7056–7070
7057
1.2. Synthetic background
for large-scale preparation.20,21 Therefore, we prepared it
from 1-bromo-4-methoxy-2-methylbenzene (9) or 3-meth-
oxyphenylacetic acid (10) by modification of the method
of Ghatak20 or Meyers21 (Scheme 3), respectively. The cycli-
zation step of 3 to 4 was also improved for the large-scale
preparation.
Several years ago, we developed a novel palladium-catalyzed
intramolecular a-arylation of aliphatic ketone, formyl, and
nitro groups11 during the course of our synthetic studies of
duocarmycin SA analogs.12 As an application of this reac-
tion, we embarked on synthetic studies of the hetisine-type
aconite alkaloids. Our fundamental synthetic strategy was
to form the N–C6 and C14–C20 bonds at an early stage of
the synthetic route, because it would become more difficult
to connect them at a later stage, as these two bonds greatly re-
strict the molecular conformation. Thus, stereocontrol was
expected to be easier with early introduction of these two
bonds.
OMe
OMe
Br
R
R
9: R=H
11: R=Br
12: R=CN
10: R=COOH
16: R=CH2OH
a
b
c
d
e
f
g
h
13: R=COOEt
14: R=CH2OH
15: R=CH2OMs
2: R=CH2I
MeO
OHC
We first reported the preparation of the hexacyclic compound
1 lacking the C-ring of the hetisan skeleton, starting from
compound 2 by way of the intermediates 3–8 (Scheme
2).13 Our further synthetic efforts culminated in a total syn-
thesis of (ꢀ)-nominine (Scheme 1), the simplest hetisine-
type aconite alkaloid.14 In this and the next papers (parts 1
and 2), we present full details for the preparation of 1. In
part 3, we describe the total synthesis of (ꢀ)-nominine,
diverging from the intermediate 8. These three papers thus
describe the first synthesis of a hetisine-type aconite alkaloid.
Five synthetic investigations have been reported so far,
leading toward the total synthesis of this class of aconite
alkaloids.15–19
Br
6 steps
O
H
O
3
OMe
O
OHC
H
i
H
OMe
O
O
O
O
4
17: trans (α-H)
18: cis (β-H)
(cis/trans=3.4)
Scheme 3. Large-scale preparation of 2 and 4: (a) NBS, BPO, CCl4, Ref. 20;
(b) KCN, EtOH–H2O, 12 92%; (c) H2SO4, EtOH, 13 90%; (d) DIBAL-H,
CH2Cl2, 14 96%; (e) MsCl, Et3N, CH2Cl2, 15 99%; (f) NaI, acetone, 2
96%; (g) ClCOOMe, Et3N, THF, then NaBH4, THF–H2O, 16 95%; (h)
Br2, CHCl3, Ref. 21; (i) PdCl2(Ph3P)2, Cs2CO3, Ph3P, THF, 4 71%, 17
4%, 18 2%.
MeO
OHC
OMe
OMe
OHC
H
Br
Br
2.1.1. Preparationof1-bromo-2-(2-iodoethyl)-4-methoxy-
benzene (2). 1-Bromo-2-bromomethyl-4-methoxybenzene
(11), prepared from 9 according to the literature,20 was
treated with potassium cyanide (KCN) in ethanol–water
(EtOH–H2O) to afford 12 in 92% yield (Scheme 3).
Alcoholysis of 12 with sulfuric acid (H2SO4) in EtOH
afforded the ethyl ester 13 in 90% yield. Transformation
of 13 to 2 was carried out readily by (i) reduction with diiso-
butylaluminum hydride (DIBAL-H), (ii) methanesulfonyla-
tion of the resulting primary alcohol to form 15, and (iii)
iodination with sodium iodide (NaI) in acetone to give 2 in
yields of 96, 99, and 96%, respectively. Alternatively, com-
pound 14 was prepared from 10 as follows: reduction of
the carboxylic acid 10 to an alcohol 16 was carried out
with (i) methyl chloroformate (ClCOOMe), triethylamine
(Et3N), and (ii) sodium borohydride (NaBH4) in 95% yield,
and subsequent bromination according to the literature21
readily afforded the intermediate 14.
O
O
O
O
I
2
3
4
20
O
O
O
HO
O
14
OPiv
OAc
H
H
OPiv
H
H
O
O
5
6 (Part 1)
O
O
H
MOMO
OAc
MOMO
H
O
H
O
NC
7
8
(Part 3)
OBz
N
H
( )-Nominine
MOM=-CH2OMe
H
1 (Part 2)
Scheme 2. Outline of the preparation of 1 from 2.
2.1.2. Palladium-catalyzed cyclization of 3. Transforma-
tion of the above-obtained 2 to the precursor 3 was executed
according to the reported route in six steps.11c In our previ-
ous reports, 4 (cis/trans ¼ 4.2, the structure of the major cis
isomer had been established by the X-ray analysis11c) was
obtained by the treatment of 3 with dichlorobis(triphenyl-
phosphine)palladium(II) [PdCl2(Ph3P)2], cesium carbonate
(Cs2CO3) in tetrahydrofuran (THF) in 65% yield. On a larger
scale, however, precipitation of black palladium metal was
observed and the reaction ceased in mid-course. The reac-
tion proceeded reproducibly to completion in the presence
of triphenylphosphine [Ph3P, 0.2 equiv, PdCl2(Ph3P)2
2. Results and discussion
2.1. Preparation of tetracyclic intermediate 4
We have already reported in detail the preparation of com-
pound 4, starting from 2 via the precursor 3 by means of
a palladium-catalyzed intramolecular cyclization reaction
(Scheme 2).11b,c While the starting material 2 is a known
compound,21 the literature methods seemed inappropriate

7058
H. Muratake, M. Natsume / Tetrahedron 62 (2006) 7056–7070
(9 mol %), Cs2CO3 (1.6 equiv) in refluxing THF for 60 h on
a 32 mmol scale], though a longer reaction time was required
than in the case without the addition of Ph3P. Under these
conditions, the desired 4 (inseparable mixture of cis and
trans isomers in a ratio of cis/trans ¼ 3.4) was obtained in
71% yield, accompanied with by-products 17 (4%) and 18
(2%).
took place at C9 of 23 during the alkaline treatment, and
the resulting hydroperoxide 25 was attacked nucleophili-
cally by the enolate anion at C12 (hetisan numbering) to
yield 24. This was confirmed by the fact that on further ad-
dition of dimethyl sulfide (Me2S) to the alkaline treatment,
the g-hydroxy-a,b-enone 26 was obtained in 14% yield in
place of 24, in addition to 23 (58%) and recovered 22
(13%). Treatment of 22 with 1,8-diazabicyclo[5.4.0]undec-
7-ene (DBU) in benzene gave 25 (18%), 26 (19%), and re-
covered 22 (40%).22 To prove the structure, compound 26
was synthesized through an alterative approach, as follows.
Epoxidation of 22 was carried out with m-chloroperbenzoic
acid (m-CPBA) as usual, and then the resulting mixture was
treated with DBU to provide 26 (61%) along with its stereo-
isomer 27 (34%).
2.2. Transformation of 4 to 5
2.2.1. Transformation of 4 to the enone–diacetal 23.
Acetalization of 4 (cis/trans ¼ 3.4) with p-toluenesulfonic
acid (p-TsOH) and ethylene glycol in refluxing benzene af-
forded readily separable cis (19) and trans (20) diacetals in
61% and 34% yields, respectively (Scheme 4). An acid-
catalyzed equilibration was observed at the C5 position ad-
jacent to the original acetal group at C4, and the ratio of the
desired trans isomer 20 improved (19/20¼1.8). This equili-
bration was conveniently leveraged for the conversion of 19
to 20 by repeated acetalization of the isolated cis isomer 19
to give recovered 19 (61%) and 20 (35%). For the elabora-
tion of the anisole ring, the diacetal 20 was submitted to
Birch reduction with lithium (Li) metal in liq. ammonia
(NH3) and THF–EtOH to give the dihydro compound 21
in 92% yield. Brief exposure of 21 to 0.5% hydrochloric
acid (HCl) in THF–H2O (4:1) afforded the b,g-enone 22
(88%) along with the a,b-enone 23 (7%), the two acetal
groups being kept intact. The former was treated with
sodium methoxide (NaOMe) in methanol (MeOH) to yield
23 (55%) and an oxetane 24 (10%), accompanied with re-
covery of 22 (10%). It is likely that partial air oxidation
2.2.2. Preparation of 5 from 23. Reduction of the above-
obtained enone 23 with NaBH4 in the presence of cerium
chloride (CeCl3) was found to afford the desired b-allyl
alcohol 28 exclusively in 94% yield. The half height J value
1
(19 Hz) of H13 (hetisan numbering) in the H NMR spec-
trum of 28 implies an axial orientation, and this means that
the 13-hydroxy group must take equatorial b-configuration.
The reason why we need the b-allyl alcohol 28 is that the
stereochemistry of C8 accurately reflects that of the angular
C13 in the next two carbons (corresponding to C15 and
C16 of the hetisan skeleton) elongation at C13 by Claisen
rearrangement. Coordination of the oxygen atom of the 1,3-
dioxolanyl group at C10 to the cerium borohydride species
resulted in the desired one-sided reduction of the carbonyl
group from the a side to give 28, as depicted in Scheme 4.23
12
OMe
OMe
OMe
OMe
O
O
O
H
O
O
H
O
OHC
H
c
a
b
14
10
H
4
6
O
O
O
O
O
O
O
O
19
20
21
4
a
(cis/trans=3.4)
e
d
12
O
O
O
O
O
O
O
H
O
O
O
H
O
H
O
O
H
O
O
O
O
H
O
O
9
H
H
OH
OH
OOH
O
O
O
O
O
O
O
O
O
O
O
O
22
23
24
25
26
27
f
g
j
H3
Cl
Cl
13
OH
i
O
O
H
O
O
O
H
O
O
O
13
CeB
H
h
O
l
O
O
O
8
for 27
or k
H
H
H
H
H
H
R
OR
7
H
H
O
O
O
O
O
O
32: R=H
5: R=Piv
O
O
30
O
O
23
28
29: R=NMe2
or
m
31: R=OEt
Scheme 4. Transformation of 4 to 5: (a) (CH2OH)2, p-TsOH, benzene, 19 61% and 20 34% from 4; 19 61% and 20 35% from 19; (b) Li, EtOH, liq. NH3–THF, 21
92%; (c) 0.5% HCl, THF–H2O (4:1), 22 88%, 23 7%; (d) NaOMe, MeOH, 23 55%, 24 10%, recovery of 22 10%; (e) NaOMe, Me2S, MeOH, 23 58%, 26 14%,
recovery of 22 13%; (f) DBU, benzene, 25 18%, 26 19%, recovery of 22 40%; (g) m-CPBA, CH2Cl2, then DBU, benzene, 26 61%, 27 34%; (h) NaBH4,
CeCl3$7H2O, MeOH, 28 94%; (i) N,N-Dimethylacetamide dimethyl acetal, toluene, 160 ꢁC (sealed tube), 29 69%; (j) Ac2O, pyridine, CH2Cl2, 30 86%; (k)
MeC(OEt)3, t-BuCOOH, 160 ꢁC (sealed tube), 31 21%; (l) BH3$NH3, BuLi, THF, 32 94%. (m) Piv2O, Et3N, 4-DMAP, CH2Cl2, 5 98%.

H. Muratake, M. Natsume / Tetrahedron 62 (2006) 7056–7070
7059
O
O
H
O
H
O
HO
HO
NMe2
O
H
O
OH
p-TsOH
BF3·OEt2
or HCl
HO
H
H
H
H
H
O
O
R
O
O
H
O
O
O
O
O
O
O
(Table 1)
29: R=NMe2
31: R=OEt
33
34
O
H
O
O
H
O
H
HO
HO
p-TsOH, acetone
O
OPiv
BF3·OEt2
or SnCl
(Table 2)
or
H
OH
p-TsOH,
OPiv
4
HO
O
O
X
X
6: X,X=O (Table 2)
39: X,X=OCH2CH2O, 70%
5
35 (Table 1)
O
O
HO
O
HO
OH
O
O
H
OPiv
OPiv
PivO
X
H
H
H
H
O
H
H
H
OPiv
H
H
O
NMe2
X
O
O
4% NOE
41 3%
X
X
38: X,X=O (Table 2)
40: X,X=OCH2CH2O, 5%
36 (Table 1)
37 (Table 2)
Scheme 5. Acetal–ene reaction of 29, 31, and 5.
Then 28 was exposed to N,N-dimethylacetamide dimethyl
acetal in toluene at 160 ꢁC (sealed tube) to obtain the acet-
amide 29 in 69% yield.24 An inseparable mixture of dehy-
drated dienes was formed as by-products. Of the two
dienes, the D7,8 and D13,14 isomer 30 was formed exclusively
on acetylation of 28 with acetic anhydride (Ac2O) in pyri-
dine by spontaneous elimination of acetic acid from the in-
termediary allyl acetate. Usual Claisen reaction with ethyl
orthoacetate and pivalic acid afforded only 21% yield of
31. As the next acetal–ene reaction of 29 was subject to a se-
rious side reaction due to the side chain at C8 (vide infra), the
amide 29 was reduced with the reagent prepared in situ from
n-butyllithium (n-BuLi) and borane–ammonia complex
(BH3$NH3) to provide 32 in 94% yield.25 The alcohol 32
was protected as the pivaloate with pivalic anhydride
(Piv2O) and Et3N in the presence of 4-dimethylaminopyri-
dine (4-DMAP) to afford 5 in 98% yield. The bulky pivaloyl
protecting group was selected to prevent the side reaction in
the next acetal–ene reaction. Pivaloylation with pivaloyl
chloride (PivCl) and Et3N is much faster than that with
Piv2O, but it occasionally afforded an intractable mixture,
especially on large-scale reaction, probably due to ring
opening of the dioxolane ring at C4 to form (2-pivaloyl-
oxy)ethyl enol ether.
2.3. Formation of the C14–C20 bond
2.3.1. Acetal–ene reaction of 29, 31, and 5. First, the
substrate 29 was subjected to the acetal–ene reaction26
(Scheme 5). A dichloromethane (CH2Cl2) solution of 29
was treated with boron trifluoride diethyl etherate
(BF3$OEt2) at ꢂ18 ꢁC to provide the expected compound
33 in only 21% yield, along with the pentacyclic lactone 34
in 72% yield as a by-product after reacetalization of the par-
tially deprotected4-carbonylgroup (Table 1, run d). Since the
employment of CH2Cl2 as the reaction solvent resulted in the
desired 33 being a minor product, we looked for other reac-
tion solvents in order to improve the yield of 33 (Table 1).
Among the solvents tested, toluene was found to be the
best, giving 33 (41%) and 34 (48%) (run b). The reaction tem-
perature also affected the yield, and reaction at ꢂ18 ꢁC (run
b) gave the best yield of 33 among runs b, f, and g. A less polar
solvent, cyclohexene–PhCH3 (6:1) resulted in a lower yield
of 33 with a new by-product 35 in 10% yield. The acetal–
ene reaction of the ester 31 under the best conditions for 29
gave no desired compound corresponding to 33, but only
34 in 66% yield (run i). Treatment of 29 with dilute HCl
also afforded the lactone 34 in 64% yield, together with a
ketone 36 in 26% (run h).
Table 1. Acetal–ene reaction of 29, 31 to form 33, 34, 35, 36 (Scheme 5)
Run
Substrate
Acid
Solvent
Temp (ꢁC)
Time (h)
2
Yield (%)
33
34
35
36
a
29
BF3$OEt2
ꢂ18
18
63
10
—
(6:1)
-PhCH3
b
c
d
e
f
g
ha
i
29
29
29
29
29
29
29
31
BF3$OEt2
BF3$OEt2
BF3$OEt2
BF3$OEt2
BF3$OEt2
BF3$OEt2
0.5% HCl
BF3$OEt2
PhCH3
ꢂ18
ꢂ18
ꢂ18
ꢂ18
ꢂ80 to ꢂ40
19
0
ꢂ18
2
3
2
2
4
1
1
2
41
14
21
—
16
28
—
—
48
69
72
77
62
42
64
66
—
—
—
—
—
—
—
—
—
—
—
—
—
—
26
—
ClCH2CH2Cl
CH2Cl2
CH3NO2
PhCH3
PhH
THF–H2O (4:1)
PhCH3
a
Products were separated without reacetalization with ethylene glycol and p-TsOH.

7060
H. Muratake, M. Natsume / Tetrahedron 62 (2006) 7056–7070
Judging from the above result that even an ester group cy-
clized to form the lactone 34, it seemed possible that not
only the alcohol 32 but also its acetate would give the corre-
sponding cyclized products in their acetal–ene reactions.
Therefore, as mentioned in Section 2.2, we selected a bulky
pivaloyl group to protect the alcohol 32, affording 5, which
was subjected to the acetal–ene reaction under a variety of re-
action conditions (Table 2). The products were, this time, pu-
rified after deprotection of the C4 acetal group by treatment
with p-TsOH in acetone. When the reaction was carried out
in toluene at below ꢂ18 ꢁC, we obtained compound 6 in
a good yield of 66% (runs d, e). Careful separation of the re-
action products of run d provided two more compounds, 37
(3%) and 38 (3%), as by-products. The ene reaction under
the conditions of run d followed by reacetalization as above
provided 39 (70%), together with 40 (5%) and 41 (3%).
and 31, intramolecular cyclization occurs to form the lactone
34 by way of the intermediary cation D. On the contrary, this
cyclization is not able to occur from C, derived from 5,
because the bulkiness of the pivaloyl group prevents the
cyclization and results in retro-ene reaction to afford 6 even-
tually, by way of A and B. The stereochemistry of 33 was
born out by the fact that 4% NOE enhancement was
observed at H20 (d 4.44, d, J¼6.5 Hz) on irradiation at H14
1
(d 2.91, ddd, J¼7, 6.5, 1.5 Hz) in the H NMR spectrum.
Analogously, observation of the NOE enhancement between
two protons of 34 at d 3.85 (d, J¼3 Hz) and at d 4.26 (d,
J¼4 Hz) supports the structure; they were assigned to the
two protons on the carbons bearing the (2-hydroxyethyl)oxy
group and the lactone O atom, respectively. The IR spectrum
of 34 (nmax¼1767 cmꢂ1) is also consistent with the 5-mem-
bered lactone structure.
Table 2. Acetal–ene reaction of 5 to form 6
Partial cyclization from the intermediate B from 29 gives rise
)
to the by-product 35, whose IR spectrum (nmax¼1719 cmꢂ1
Run Lewis acid Solvent
Temp (ꢁC)
Time (h) 6 (%)
is consistent with the 6-membered lactone structure.
Formation of the cis isomer 37 is attributable to enolization
brought about by coordination of the C4 acetal or carbonyl
group to BF3. A sequence of reactions on 6, coordination
of the oxygen at C20 to BF3 followed by cyclization from
D12,13 to C20 in 3-exo-trig mode, and deprotonation from
C11 provides an explanation for the formation of the by-
products 38 and 40. Compound 41, obtained in a small
amount, is a by-product generated by trapping of the interme-
diary cation of the 6-endo-trig route with water at quenching
of the reaction. The orientation of the secondary hydroxy
group of 41 was determined by the fact that there is a 4%
NOE enhancement between the two protons on the carbons
bearing oxygen in the bicyclo[2.2.2]octane framework, as
depicted in Scheme 5.
a
b
c
d
e
f
BF3$OEt2
BF3$OEt2
BF3$OEt2
BF3$OEt2
BF3$OEt2
BF3$OEt2
SnCl4
CH2Cl2
ClCH2CH2Cl ꢂ18
ꢂ18
2
55
50
55
66a
66
59
45
2
2
1
2
CS2
ꢂ18
PhCH3
PhCH3
PhCH3
PhCH3
ꢂ18
ꢂ70 to ꢂ50
ꢂ18
0.17
2
g
ꢂ18
a
By-products 37 (3%) and 38 (3%) were also isolated.
2.3.2. Reaction mechanism of the acetal–ene reaction.
The reaction mechanism for the acetal–ene reaction is con-
sidered to be as follows. Coordination of the dioxolane oxy-
gen at C10 (hetisan numbering) of 29, 31, and 5 to BF3 gives
rise to an intermediate A, in which the oxonium cation is
arrayed so as to circumvent the steric congestion between
the two 1,3-diaxial substituents at C4 and C8, as depicted
in A (Scheme 6). Nucleophilic attack from the olefin to
the oxonium cation takes place in two different modes,
5-exo-trig and 6-endo-trig, giving intermediates B and C,
respectively. These reaction paths can explain the S* stereo-
chemistry of C20 in B and the corresponding carbon in C.
Deprotonation from C12 of B affords 33 from 29 and 6
from 5. In the case of C, on the other hand, there are no elim-
inable protons to form an olefin, because the two carbons ly-
ing adjacent to the cation are a tertiary bridgehead carbon
and a quaternary carbon. Therefore, when the intermediate
C carrying a nucleophilic C8 side chain is derived from 29
2.3.3. Suitability of 2-hydroxyethyl group to protect the
C20 hydroxy group and model study for its removal.
The above acetal–ene reaction furnished the desired tetracy-
clic products 33, 6, and 39 with a 2-hydroxyethyl protecting
group at the C20 hydroxy group. The ene reaction proceeds,
needless to say, starting from an aldehyde as well as an ace-
tal. However, this protecting group plays a critical role in the
total synthesis of (ꢀ)-nominine in the following respects. (1)
The compound without a protecting group on the C20
hydroxy group is in danger of undergoing C14–C20 bond
fission through the retro-ene reaction. In addition, it would
O
O 20
BF3
35 (for 29)
H 12
BF3
BF3
O
HO
14
O
:
O
O
14
O
R
H
H
H
H
R
O
20S*O
H
H
X
R
H
X
X
H
O
O
O
33: R=CONMe2; X,X=O(CH2)2O
6: R=CH2OPiv; X,X=O
O
O
B
X =N Me2, O Et
29: R=CONMe2
31: R=COOEt
5: R=CH2OPiv
D
BF3
39: R=OCH2Piv; X,X=O(CH2)2O
37, 38, 40 (for 5)
5-exo-trig
BF3
O
O BF3
O
HO
for 29, 31
O
F3B
O
O
6-endo-trig
BF3
O
H
O
H
O
H
R
H
H
H
O
O
O
10
R
O
R
O
O
H2O
8
34
O
41
4 O
C
C
A
for 5
Scheme 6. Reaction mechanism of the acetal–ene reaction to form the C14–C20 bond.

H. Muratake, M. Natsume / Tetrahedron 62 (2006) 7056–7070
7061
be difficult to protect the hydroxy group on C20 because of
steric hindrance. In the case of the compounds 33, 6, and 39,
the 2-hydroxyethyl group (originated from ethylene glycol)
conveniently protected the hydroxy group. (2) As the 2-hy-
droxyethyl group is an extremely stable protecting group,
provided the terminal primary hydroxy group is protected
appropriately, it can readily tolerate a variety of reaction
conditions encountered in the subsequent synthetic route.
(3) The 2-hydroxyethyl group can be removed with ease
by bromination followed by mild reduction with zinc in
alcohol–H2O.
of the azabicyclo ring preferably at a later stage of the total
synthesis. Thus, we directed our attention to functionaliza-
tion of C11, C6, or the side chain at C8. Here, we describe
an attempt to functionalize C11 of 33 by allylic oxidation.
A number of aconite alkaloids, such as kobusine and pseudo-
kobusine, carry an oxygen function (carbonyl or hydroxy
group) at C11 (Scheme 1). To begin with, allylic oxidation
of 42 was examined (Scheme 7). Chromium trioxide
(CrO3, 12 equiv) oxidation in the presence of 3,5-dimethyl-
pyrazole28 gave favorable results, giving 45 and 46 in 28%
yield each, along with a recovery of 42 in 29% yield.
Further excess of the oxidizing reagent caused a significant
drop in the yields. Although the oxidation did not afford
the desired product 45 in satisfactory yield and the regio-
isomeric enone 46 was obtained in the same amount, some
alkaloids such as hetisine and spirasine IV have an oxygen
function at this position, C13.1,2
We confirmed these features by means of the following model
reactions with compound 33 (Scheme 7). Compound 33 was
readily brominated with carbon tetrabromide (CBr4) and
Ph3P to afford 42 in 87% yield. Then smooth removal of
the 2-bromoethyl group was carried out by exposure of 42
to zinc (Zn) in refluxing 2-propanol–H2O (14:1) with ammo-
nium chloride (NH4Cl) to afford 43 in the high yield of 94%.
Taking into consideration the prospective construction of the
azabicyclo ring system of the hetisan framework, we tried to
protect this hydroxy group with an acyl group, such as acetyl,
methanesulfonyl, or trifluoromethanesulfonyl. However,
these trials resulted in a recovery of 43 due to the steric con-
gestion around the hydroxy group. Oxidation of 43 with
Dess–Martin periodinane27 provided 44 in a good yield.
The above reductive deprotection of the hydroxy group at
C20 was carried out for 45 and 46. The sole product from
45 was a saturated keto–alcohol 47: the enone group was in-
compatiblewith the reductive conditions. The enone–alcohol
48 was produced from 46, but compound 50, corresponding
to 47 and the debrominated product 49, were also isolated.
Thus, it proved complicated to functionalize C11 of 33.
However, some clues were obtained for functionalization
of C11 and for C-ring formation by the connection of C12
and the side chain at C8.
Y1
Y2
O
X
b
R
R
H
H
H
H
In part 2, we will describe some attempts at C-ring formation
and the functionalization of C6 for the construction of the
pyrrolidine ring, leading to the synthesis of a hexacyclic
compound 1 lacking the C-ring of the hetisan skeleton.
O
O
O
O
R=CONMe2
33: X=OH
42: X=Br
43: Y1=OH, Y2=H
44: Y1,Y2=O
c
a
d
O
O
O
O
Br
Br
3. Conclusion
R
R
H
H
H
H
In summary, we have synthesized the tetracyclic synthetic
intermediates 33, 6, and 39 for hetisine-type aconite alka-
loids, utilizing the following key reactions: (i) palladium-
catalyzed intramolecular a-arylation at the formyl group
(3/4), and (ii) acetal–ene reaction to form the C14–C20
bond (29/33, 5/6, 5/39). This was a substantial step
toward the first total synthesis of hetisine-type aconite
alkaloids. In the subsequent papers, we report further efforts
toward this goal.
O
O
O
O
45
46
b
b
O
O
O
R
O
HO
H
HO
H
ZO
H
R
R
H
H
H
O
O
O
O
O
48: Z=H
49: Z=Et
50
47
Scheme 7. Model deprotection of the 2-hydroxyethyl group and allylic
oxidation of 33: (a) Br4C, Ph3P, CH2Cl2, 42 87%; (b) Zn, NH4Cl, 2-
PrOH-H2O (14:1), 43 94% from 42; 47 89% from 45; 48 49%, 49 9%, 50
39% from 46; (c) Dess–Martin periodinane, CH2Cl2, 44 92%; (d) CrO3,
3,5-dimethylpyrazole, 45 28%, 46 28%, recovery of 42 29%.
4. Experimental
Melting points were determined on a Yanagimoto micro-
melting point apparatus (hot plate), and are not corrected.
MS and high-resolution MS (HRMS) were recorded on
a Hitachi M-80B spectrometer in a gas chromatography
(GC) or direct inlet (DI) mode at an ionizing voltage of
70 eV, and figures in parentheses indicate the relative inten-
sities. IR spectra were measured on a Hitachi 215 or
Shimadzu IR-460 spectrophotometer. 1H NMR spectra
were obtained on a Varian Mercury 300 (300 MHz) in
CDCl3 unless otherwise specified and coupling constants (J
values) are rounded to the nearest 0.5 Hz. 13C NMR spectra
were measured on a Varian Mercury 300 (75 MHz) in
2.4. Further transformation from the acetal–ene
reaction products
With the desired compounds 33, 6, and 39 in hand, we next
examined further transformation toward the hetisan skele-
ton, including nominine. The basicity of the nitrogen on
the azabicyclo ring system is so strong that it would be trou-
blesome to carry on the synthesis employing the intermedi-
ates bearing the ring system. So we envisioned construction

7062
H. Muratake, M. Natsume / Tetrahedron 62 (2006) 7056–7070
CDCl3 and 13C multiplicities are shown in parentheses as
CH3 (primary), CH2 (secondary), CH (tertiary), and C (qua-
ternary). The NMR signals were assigned using proton de-
coupling techniques, as well as gCOSY, DEPT, gHSQC,
containing NH4Cl solid with efficient stirring to decompose
an excess reagent. The mixture was dredged with Celite
(200 g) and the whole was filtered through a Celite bed
in vacuo. The filtered Celite was washed thoroughly with
CH2Cl2. Usual work-up and separation by SiO2 column
chromatography [120 g, benzene–hexane (19:1)] gave 14
(7.74 g, 96%) as a colorless oil. GC–HRMS Calcd for
C9H11BrO2: 231.9923, 229.9942. Found: 231.9923,
229.9926. GC–MS m/z: 232, 230 (M+, 51, 53), 201, 199
(58, 56), 150 (72), 121 (100), 91 (51), 77 (65), 51 (55), 31
(74). 1H NMR d: 2.95 (2H, t, J¼6.5 Hz), 3.76 (3H, s), 3.82
(2H, t, J¼6.5 Hz), 7.76 (1H, br s, OH), 6.64 (1H, dd, J¼9,
3 Hz), 6.82 (1H, d, J¼3 Hz), 7.40 (1H, d, J¼9 Hz). 13C
NMR d: 39.4 (CH2), 55.3 (CH3), 61.8 (CH2), 113.5 (CH,
C4), 114.8 (C, C2), 116.7 (CH, C6), 133.1 (CH, C3),
138.6 (C, C1), 158.6 (C, C5).
1
gHMBC, and/or NOESY spectra. Some characteristic H
and 13C NMR signals were selected and assigned as HX
and CX, respectively, where X represents hetisan carbon
numbering. Column chromatography was conducted on
silica gel (SiO2, Fuji Davison BW 200), and the weight of
SiO2 and the eluting solvent is indicated in parentheses.
Preparative TLC (PTLC) was carried out on glass plates
(20ꢃ20 cm) coated with Merck Silica gel 60PF254 (0.8 mm
thick) unless otherwise specified, and the developing solvent
is indicated in parentheses. Usual work-up refers to washing
of the organic layers with water or brine, drying over anhy-
drous Na2SO4, and evaporating off the solvents under re-
duced pressure. Tetrahydrofuran (THF) was distilled from
sodium/benzophenone ketyl prior to use.
4.1.4. 2-Bromo-5-methoxyphenethyl methanesulfonate
(15). A solution of MsCl (2.85 ml, 36.8 mmol) in CH2Cl2
(5 ml) was added dropwise to a cooled (ꢂ20 ꢁC) solution
of 14 (7.74 g, 33.5 mmol) and Et3N (6.06 ml, 43.6 mmol)
in CH2Cl2 (45 ml) and the mixture was stirred for 1 h under
an Ar atmosphere. Saturated NaHCO3–H2O was added and
the whole was extracted with CH2Cl2. The organic layer was
washed with saturated CuSO4–H2O and then with saturated
NaHCO3–H2O. Usual work-up and purification by SiO2 col-
umn chromatography [100 g, hexane–EtOAc (5:2)] gave 15
(10.27 g, 99%) as a colorless syrup. DI-HRMS Calcd for
C10H13BrO4S: 309.9698, 307.9717. Found: 309.9684,
307.9692. DI-MS m/z: 310, 308 (M+, 21, 23), 214, 212
4.1. Large-scale preparation of 2 and 4 (Scheme 3)
4.1.1. (2-Bromo-5-methoxy)phenylacetonitrile (12). KCN
(7.48 g, 0.115 mol) was added to a solution of 1121 (7.48 g,
36.7 mmol) in EtOH (30 ml) and H2O (15 ml) and the mix-
ture was refluxed with stirring for 5 h. After having been
cooled, the mixture was extracted with EtOAc. Usual
work-up followed by recrystallization provided 12 (5.58 g,
92%) as colorless prisms, mp 54–55 ꢁC (Et2O–hexane).
Anal. Calcd for C9H8BrNO: C, 47.81; H, 3.57; Br, 35.35;
N, 6.20. Found: C, 47.66; H, 3.56; Br, 35.34; N, 6.21. GC–
HRMS Calcd for C9H8BrNO: 226.9770, 224.9789. Found:
226.9780, 224.9814. GC–MS m/z: 227, 225 (M+, 100, 95),
212, 210 (12, 13), 184, 182 (28, 30), 146 (34), 116 (23),
1
(90, 100), 201, 199 (18, 19), 79 (33), 51 (22). H NMR
d: 2.91 (3H, s), 3.16 (2H, t, J¼7 Hz), 3.78 (3H, s), 4.44
(2H, t, J¼7 Hz), 6.70 (1H, dd, J¼9, 3 Hz), 6.84 (1H, d,
J¼3 Hz), 7.43 (1H, d, J¼9 Hz). 13C NMR d: 36.0 (CH2),
37.2 (CH3), 55.4 (CH3), 68.3 (CH2), 114.4 (CH), 114.5
(C), 116.9 (CH), 133.3 (CH), 136.2 (C), 158.8 (C).
1
103 (41), 76 (26), 63 (25). IR (KBr) cmꢂ1: 2240. H NMR
d: 3.80 (2H, s), 3.82 (3H, s), 6.77 (1H, dd, J¼9, 3 Hz), 7.07
(1H, d, J¼3 Hz), 7.47 (1H, d, J¼9 Hz). 13C NMR d: 24.9
(CH2), 55.5 (CH3), 113.5 (C, C2), 115.2 (CH, C6), 115.4
(CH, C4), 116.7 (C, CN), 130.5 (C, C1), 133.4 (CH, C3),
159.1 (C, C5).
4.1.5. 1-Bromo-2-(2-iodoethyl)-4-methoxybenzene (2).
NaI (7.48 g, 49.9 mmol) was added to a solution of 15
(10.27 g, 33.2 mmol) in acetone (120 ml) and the mixture
was refluxed with stirring for 8 h. After the mixture had
been cooled in an ice bath, H2O was added and the whole
was extracted with EtOAc. Usual work-up and separation
by SiO2 column chromatography [100 g, hexane–EtOAc
(99.9:0.1)] yielded 2 (10.91 g, 96%) as a colorless syrup.
The product 2 is a known compound.20 GC–HRMS Calcd
for C9H10BrIO: 341.8942, 339.8962. Found: 341.8930,
339.8954. GC–MS m/z: 342, 340 (M+, 42, 44), 215, 213
(77, 79), 134 (100), 91 (42), 63 (48). 1H NMR d: 3.21–3.29
(2H, m), 3.31–3.39 (2H, m), 3.79 (3H, s), 6.70 (1H, dd,
J¼9, 3 Hz), 6.79 (1H, d, J¼3 Hz), 7.42 (1H, d, J¼9 Hz).
13C NMR d: 3.0 (CH2, CH2I), 40.7 (CH2), 55.4 (CH3),
114.0 (CH), 114.2 (C), 116.2 (CH), 133.3 (CH), 140.5 (C,
C1), 158.7 (C).
4.1.2. Ethyl (2-bromo-5-methoxy)phenylacetate (13). A
solution of 12 (13.54 g, 59.9 mmol) in EtOH (40 ml) and
concd H2SO4 (16.0 ml, 0.300 mol) was stirred under reflux
for 6 h. The mixturewas cooled in an ice bath and was diluted
with H2O. Extraction with EtOAc, washing with saturated
NaHCO3–H2O, usual work-up, and distillation afforded
13 (14.71 g, 90%) as a colorless oil, bp 174–176 ꢁC/
13 mmHg. GC–HRMS Calcd for C11H13BrO3: 274.0028,
272.0048. Found: 274.0032, 272.0050. GC–MS m/z: 274,
272 (M+, 13, 12), 201, 199 (46, 48), 193 (50), 165 (100),
1
77 (31), 51 (27). IR (neat) cmꢂ1: 1737. H NMR d: 1.26
(3H, t, J¼7 Hz), 3.73 (2H, s), 3.77 (3H, s), 4.18 (2H, q,
J¼7 Hz), 6.70 (1H, dd, J¼9, 3 Hz), 6.84 (1H, d, J¼3 Hz),
7.43 (1H, d, J¼9 Hz). 13C NMR d: 14.2 (CH3), 41.8 (CH2),
55.3 (CH3), 60.9 (CH2), 114.3 (CH), 115.2 (C), 116.9
(CH), 133.0 (CH), 134.9 (C, C1), 158.6 (C), 170.1 (C).
4.1.6. 2-(3-Methoxyphenyl)ethanol (16). A solution of
methyl chloroformate (24.5 ml, 0.317 mol) in THF (50 ml)
was added slowly to a cooled (ꢂ20 ꢁC) solution of 3-
methoxyphenylacetic acid (50.0 g, 0.301 mol) and Et3N
(44.5 ml, 0.320 mol) in THF (400 ml) and the mixture was
stirred at ꢂ20 ꢁC for 1 h. The precipitate was filtered under
reduced pressure and the filtered salt was washed with THF
(50 ml). The combined THF solution was added to a slurry
4.1.3. 2-(2-Bromo-5-methoxyphenyl)ethanol (14).
DIBAL-H (0.94 M in hexane, 93.0 ml, 87.4 mmol) was
added dropwise to a cooled (ꢂ78 ꢁC) solution of 13
(9.50 g, 34.8 mmol) in CH2Cl2 (120 ml) under an Ar atmo-
sphere, and the mixture was stirred at ꢂ78 to ꢂ8 ꢁC for 3 h.
The mixture was slowly poured into saturated NH4Cl–H2O

H. Muratake, M. Natsume / Tetrahedron 62 (2006) 7056–7070
7063
of NaBH4 (57.2 g, 1.51 mol) in H2O (300 ml) and the mix-
ture was stirred at 0–24 ꢁC for 40 h. Another portion of
NaBH4 (11.5 g, 0.303 mol) was added and the resulting mix-
ture was further stirred for 24 h. The mixture was gradually
poured into saturated NH4Cl–H2O and the whole was
extracted with CH2Cl2. Distillation afforded 16 (43.6 g,
96%) as a colorless oil (bp: 135–140 ꢁC/10 mmHg). The
compound 16 was prepared in the literature20 by treatment
of 3-methoxyphenylacetic acid with NaBH4 and I2 in 89%
yield, and is also available from Aldrich Chemical Co.
(bp: 141–143 ꢁC/12 mmHg).
m), 5.80 (1H, s), 6.60 (1H, d, J¼2.5 Hz), 6.63 (1H, dd,
J¼8.5, 2.5 Hz), 7.29 (1H, d, J¼8.5 Hz). 13C NMR d: 16.7
(CH2, C6), 19.7 (CH2, C2), 29.4 (CH2, C7), 33.9 (CH2,
C1), 35.6 (CH2, C3), 44.8 (C, C10), 49.0 (CH, C5), 54.9
(CH3), 64.1 (CH2), 64.4 (CH2), 64.9 (CH2), 65.6 (CH2),
105.0 (CH), 110.3 (CH, C12), 112.6 (CH), 128.1 (C), 128.3
(CH), 131.6 (C, C9), 139.4 (C, C8), 157.4 (C). Under the
same conditions, 19 (920 mg, 2.66 mmol) was acetalized to
give 20 (323 mg, 35%) and recovered 19 (561 mg, 61%).
4.2.2. Birch reduction of 20 to form 21. Li (7.89 g,
1.13 mol)wasaddedinsmallportionsduring2.5 htoacooled
(ꢂ78 ꢁC) solution of 20 (6.50 g, 18.8 mmol) in liq. NH3 (ca.
150 ml), THF (80 ml), and EtOH (80 ml) with efficient stir-
ring by a mechanical stirrer. After the addition completed,
stirring was continued for 3 h. Solid NH4Cl (10.0 g) was
slowly added and the cooling bath was removed. Stirring
was further continued at room temperature with trapping
evaporating NH3 with concd HCl and ice. Saturated
NH4Cl–H2O was added and the mixture was filtered through
a Celite bed, and the Celite was washed with CHCl3.
Extraction with CHCl3 followed by usual work-up afforded
crystalline material, which was purified by recrystallization
and SiO2 column chromatography [hexane–EtOAc (8:1)]
to yield 21 (5.99 g, 92%) as colorless prisms, mp 167–
168.5 ꢁC (CH2Cl2–hexane). Anal. Calcd for C20H28O5: C,
68.94; H, 8.10. Found: C, 68.73; H, 8.07. GC–HRMS
Calcd for C20H28O5: 348.1935. Found: 348.1923. GC–MS
m/z: 348 (M+, 4), 275 (35), 213 (10), 99 (100), 73 (38), 55
(12), 45 (18). IR (KBr) cmꢂ1: 1697, 1663. 1H NMR d: 1.17
(1H, ddd, J¼13, 13, 4.5 Hz, H1), 1.43 (1H, ddd, J¼13, 13,
5 Hz, H3), 1.59–2.04 (8H, m), 2.45 (1H, dddd, J¼13, 3, 3,
1.5 Hz, H1), 2.60 (2H, dd, J¼7.5, 7 Hz, H14), 2.74–3.04
(2H, m, H11), 3.54 (3H, s), 3.61–4.11 (8H, m), 4.60 (1H,
dd, J¼4, 3.5 Hz, H12), 5.66 (1H, s). 13C NMR d: 16.4
(CH2), 19.6 (CH2), 28.0 (CH2, C11), 30.2 (CH2), 32.3
(CH2), 34.3 (CH2, C14), 35.6 (CH2), 44.8 (C, C10), 49.5
(CH), 53.6 (CH3), 63.6 (CH2), 64.3 (CH2), 65.1 (CH2),
65.5 (CH2), 90.9 (CH, C12), 105.5 (CH), 110.3 (C, C4),
127.4 (C, C9), 127.9 (C), 151.8 (C, C13).
4.1.7. Improved Pd cyclization of 3 to form 4 and by-prod-
ucts 17, 18. A slurry of 3 (12.24 g, 32.0 mmol), PdCl2(Ph3P)2
(2.00 g, 2.85 mmol), Cs2CO3 (16.70 g, 51.2 mmol), and
Ph3P (1.67 g, 6.37 mmol) in THF (200 ml) was refluxed
with vigorous stirring under an Ar atmosphere for 60 h.
After the mixture had been cooled, saturated NH4Cl–H2O
was added and the mixture was extracted with EtOAc.
Usual work-up followed by purification by SiO2 column
chromatography (250 g, benzene) and PTLC provided 4
(6.83 g, 71%, cis/trans ¼ 3.4), 17 (61 mg, 4%), and 18
(29 mg, 2%) in order of increasing polarity. Spectral data
of the three products and single crystal X-ray analysis data
of cis-4 have already been reported.11c
4.2. Transformation of 4 to 5 (Scheme 4)
4.2.1. Acetalization of 4 to form 19 and 20. Ethylene glycol
(2.50 ml, 44.9 mmol) and p-TsOH$H2O (160 mg, 0.842 mmol)
were added to a solution of 4 (2.68 g, 8.87 mmol, cis/
trans ¼ 3.4) in benzene (40 ml), and the mixture was refluxed
with stirring for 6 h with a Dean–Stark apparatus. After
the mixture had been cooled in an ice bath, saturated
NaHCO3–H2O was added and the whole was extracted
with EtOAc. Usual work-up and subsequent SiO2 column
chromatography [80 g, hexane–EtOAc (14:1w9:1)] afforded
20 (1.05 g, 34%) and 19 (1.87 g, 61%) in order of increasing
polarity. 19: Colorless prisms, mp 99–100 ꢁC (CH2Cl2–hex-
ane). Anal. Calcd for C20H26O5: C, 69.34; H, 7.57. Found: C,
69.18; H, 7.53. GC–HRMS Calcd for C20H26O5: 346.1779.
Found: 346.1781. GC–MS m/z: 346 (M+, 1), 273 (17), 99
4.2.3. Hydrolysis of vinyl ether 21 to form 22 and 23.
HCl–H2O (2.5%, 5.0 ml) was added to a cooled (0 ꢁC) solu-
tion of 21 (590 mg, 1.70 mmol) in THF (20 ml) and the mix-
ture was stirred at the temperature for 1.5 h. Saturated
NaHCO3–H2O was added and the mixture was extracted
with CH2Cl2. Usual work-up and separation by SiO2 column
chromatography [25 g, hexane–EtOAc (4:1w1:1)] afforded
22 (497 mg, 88%) and 23 (41 mg, 7%) in order of increasing
polarity. 22: Colorless prisms, mp 142–144 ꢁC (CH2Cl2–
hexane). Anal. Calcd for C19H26O5: C, 68.24; H, 7.84.
Found: C, 68.18; H, 7.82. GC–HRMS Calcd for C19H26O5:
334.1779. Found: 334.1772. GC–MS m/z: 334 (M+, 1), 261
(2), 199 (1), 99 (22), 73 (100), 55 (7), 45 (11). IR (CHCl3)
1
(100), 73 (28), 55 (9), 45 (10). H NMR d: 1.41–1.56 (2H,
m), 1.60–1.75 (2H, m), 1.77–1.94 (2H, m), 2.04–2.19 (2H,
m), 2.27 (1H, dd, J¼5.5, 5.5 Hz, H5), 2.75 (1H, ddd, J¼17,
6.5, 6.5 Hz, H7), 2.88 (1H, ddd, J¼17, 7.5, 7.5 Hz, H7),
3.52–3.62 (1H, m), 3.68–3.97 (7H, m), 3.76 (3H, s), 5.24
(1H, s), 6.58 (1H, d, J¼3 Hz), 6.68 (1H, dd, J¼9, 3 Hz),
7.41 (1H, d, J¼9 Hz). 13C NMR d: 19.0 (CH2, C6), 19.2
(CH2, C3), 28.6 (CH2, C7), 28.8 (CH2, C1), 33.7 (CH2,
C2), 43.2 (CH, C5), 45.4 (C, C10), 54.8 (CH3), 64.0 (CH2),
64.5 (CH2), 65.0 (CH2), 65.1 (CH2), 107.7 (CH), 111.2
(ꢃ2, CH and C, C4 and C12), 112.8 (CH, C14), 128.3 (CH,
C11), 129.8 (C), 140.2 (C, C8), 157.1 (C). 20: Colorless
needles, mp 108–109 ꢁC (CH2Cl2–hexane). Anal. Calcd for
C20H26O5: C, 69.34; H, 7.57. Found: C, 69.25; H, 7.52.
GC–HRMS Calcd for C20H26O5: 346.1779. Found:
346.1783. GC–MS m/z: 346 (M+, 1), 273 (18), 99 (100), 73
1
cmꢂ1: 1713. H NMR d: 1.15 (1H, ddd, J¼13, 13, 4.5 Hz,
H1), 1.44 (1H, ddd, J¼13, 13, 5.5 Hz, H3), 1.60–1.80 (4H,
m), 1.82–2.05 (4H, m), ca. 2.26–2.48 (3H, m), 2.50 (1H,
dddd, J¼13, 3, 3, 1 Hz, H1), 2.64–2.74 (1H, m), 2.72 (1H,
d, J¼21 Hz, H14), 2.82 (1H, d, J¼21 Hz, H14), 3.65–4.10
(8H, m), 5.56 (1H, s). 13C NMR d: 16.4 (CH2), 19.5 (CH2),
26.1 (CH2, C12), 30.5 (CH2), 32.1 (CH2), 35.6 (CH2), 39.4
(CH2), 45.0 (C), 45.1 (CH2, C14), 49.7 (CH), 63.4 (CH2),
64.3 (CH2), 65.3 (CH2), 65.5 (CH2), 105.2 (CH), 110.0 (C),
1
(29), 55 (10), 45 (9). H NMR d: 1.31 (1H, ddd, J¼13.5,
13.5, 4 Hz, H1), 1.42–1.55 (1H, m), 1.66–1.97 (5H, m),
2.10–2.27 (1H, m), 2.67–2.78 (1H, m, dioxolane proton, an-
isotropy), 2.76–2.99 (3H, m), 3.50–3.64 (3H, m), 3.77 (3H,
s), 3.82–3.92 (1H, m), 3.94–4.03 (2H, m), 4.06–4.16 (1H,

7064
H. Muratake, M. Natsume / Tetrahedron 62 (2006) 7056–7070
128.9 (C), 131.7 (C), 211.9 (C). 23: Colorless prisms, mp
172–173 ꢁC (CH2Cl2–hexane). Anal. Calcd for C19H26O5:
C, 68.24; H, 7.84. Found: C, 67.78; H, 7.71. GC–HRMS
Calcd for C19H26O5: 334.1779. Found: 334.1782. GC–MS
m/z: 334 (M+, 10), 289 (4), 261 (4), 99 (21), 73 (100), 55
60.3 mmol) in benzene (2.5 ml) was refluxed with stirring
for 4 h. Addition of H2O, extraction with EtOAc, successive
washing with CuSO4–H2O and saturated NaHCO3–H2O,
and PTLC [benzene–EtOAc (4:1)] gave recovered 22
(4 mg, 40%), 25 (2 mg, 18%), and 26 (2 mg, 19%) in order
of increasing polarity. 25: Colorless glass. DI-HRMS Calcd
for C19H26O7: 366.1677. Found: 366.1695. DI-MS m/z: 366
(M+, 2), 350 (3), 293 (3), 277 (3), 251 (4), 99 (62), 73 (100),
55 (17), 45 (25). IR (CHCl3) cmꢂ1: 1653. 1H NMR d: 1.43
(1H, ddd, J¼12.5, 12.5, 5.5 Hz, H1), 1.49–1.92 (6H, m),
2.17 (1H, br d, J¼12.5 Hz, H1), 2.24–2.89 (7H, m), 3.64–
4.03 (8H, m), 5.52 (1H, s), 5.95 (1H, d, J¼2 Hz, H14),
7.59 (1H, br s, OOH).
1
(8), 45 (15). IR (CHCl3) cmꢂ1: 1652, 1611. H NMR d:
1.03–1.14 (1H, m), 1.40–1.52 (1H, m), 1.53–1.69 (2H, m),
1.72 (1H, dd, J¼13, 3 Hz, H5), 1.75–1.96 (3H, m), 1.99–
2.21 (4H, m), 2.29–2.47 (2H, m), 2.54 (1H, br dddd, J¼13,
3, 3, 1.5 Hz, H1), 2.64 (1H, br ddd, J¼17, 5, 1.5 Hz, H7),
3.66–4.05 (8H, m), 5.46 (1H, s), 5.73 (1H, br s, H14). 13C
NMR d: 19.0 (CH2), 19.6 (CH2), 23.4 (CH2), 34.15 (CH2),
34.18 (CH2), 35.6 (CH2), 38.2 (CH2), 44.9 (C), 49.7 (CH,
C9), 51.4 (CH), 62.8 (CH2), 64.2 (CH2), 64.6 (CH2), 65.5
(CH2), 104.9 (CH), 109.6 (C), 122.5 (CH, C14), 168.1 (C,
C8), 199.8 (C).
4.2.7. Alternative preparation of 26 and 27 by m-CPBA
oxidation of 22. m-CPBA (26 mg, 0.151 mmol) was added
to a solution of 22 (18 mg, 53.9 mmol) in CH2Cl2 (3 ml)
and the mixture was stirred at 0 ꢁC for 1 h, and at 20 ꢁC for
2.5 h. Saturated Na2S2O3–H2O and saturated NaHCO3–
H2O were added and the whole was extracted with CH2Cl2.
Usual work-up and rough separation by PTLC [hexane–
EtOAc (1:1)] afforded a mixture of products (20 mg), which
were treated with DBU (40 ml, 0.292 mmol) in refluxing
benzene (3 ml) for 30 min. The same work-up as in Section
4.2.5 and purification by PTLC [1.5% MeOH–CH2Cl2] fur-
nished 26 (11.5 mg, 61%) and 27 (6.5 mg, 34%) in order of
decreasing polarity. 27: Colorless prisms, mp 194–196 ꢁC
(CH2Cl2–hexane). Anal. Calcd for C19H26O6: C, 65.12; H,
7.48. Found: C, 64.85; H, 7.38. DI-HRMS Calcd for
C19H26O6: 350.1728. Found: 350.1724. DI-MS m/z: 350
(M+, 3), 260 (2), 133 (7), 99 (100), 73 (23), 55 (11), 45
4.2.4. NaOMe treatment of 22. NaOMe (150 mg,
2.78 mmol) was added to a cooled (0 ꢁC) slurry of 22
(305 mg, 0.913 mmol) in MeOH (15 ml) and the mixture
was stirred at 0 ꢁC for 0.5 h and at 18 ꢁC for 16 h. Saturated
NH4Cl–H2O was added and the whole was extracted with
CH2Cl2. Usual work-up followed by PTLC [benzene–
EtOAc (5:1)] gave recovered 22 (30 mg, 10%), 23 (169 mg,
55%), and an oxetane 24 (31 mg, 10%) in order of in-
creasing polarity. 24: Colorless glass. DI-HRMS Calcd
for C19H24O6: 348.1571. Found: 348.1557. DI-MS m/z:
348 (M+, 2), 257 (5), 99 (100), 73 (75), 55 (11), 45 (20). IR
(CHCl3) cmꢂ1: 1651. 1H NMR d: 1.52–1.71 (2H, m), 1.75–
1.92 (3H, m), 2.04–2.17 (2H, m), 2.21–2.42 (4H, m), 2.71
(1H, ddd, J¼18.5, 13, 7 Hz, H7), 2.86 (1H, dd, J¼12, 6 Hz,
H5), 3.40–3.54 (1H, m), 3.63–3.87 (4H, m), 3.91–4.01 (2H,
m), 4.03–4.14 (1H, m), 5.20 (1H, d, J¼7 Hz, H12), 5.51
(1H, s), 5.52 (1H, s, H14). 13C NMR d: 19.9 (CH2), 24.8
(CH2), 28.9 (CH2), 29.0 (CH2), 32.9 (CH2), 36.0 (CH2),
45.9 (C), 50.2 (CH), 62.7 (CH2), 63.5 (CH2), 64.4 (CH2),
65.9 (CH2), 88.0 (C, C9), 95.0 (CH, C12), 103.9 (CH),
106.9 (CH, C14), 110.0 (C, C4), 164.5 (C, C8), 199.1 (C).
1
(14). IR (CHCl3) cmꢂ1: 1665, 1620. H NMR d: 1.34 (1H,
ddd, J¼12.5, 12.5, 5 Hz, H1), 1.45–1.71 (4H, m), 1.77–
2.02 (3H, m), 2.03 (1H, dddd, J¼13, 13, 4.5, 1.5 Hz, H12),
2.17 (1H, ddd, J¼13, 4.5, 2.5 Hz, H12), 2.19–2.39 (3H, m),
2.90 (1H, ddd, J¼17, 13, 4.5 Hz, H11), 3.32 (1H, dddd,
J¼15.5, 12, 7, 2.5 Hz, H7), 3.76–3.87 (2H, m), 3.89–4.07
(5H, m), 4.08–4.17 (1H, m), 4.55 (1H, d, J¼1.5 Hz, OH),
5.53 (1H, s). 13C NMR d: 18.1 (CH2, C6), 19.7 (CH2, C2),
28.3 (CH2), 31.5 (CH2), 33.2 (CH2, C12), 34.0 (CH2, C11),
35.7 (CH2), 44.4 (CH, C5), 46.7 (C), 62.6 (CH2), 64.2
(CH2), 65.0 (CH2), 65.7 (CH2), 74.9 (C, C9), 106.1 (CH),
110.0 (C), 126.6 (CH), 166.4 (C, C8), 199.4 (C).
4.2.5. NaOMe treatment of 22 in the presence of Me2S.
NaOMe (40 mg, 0.741 mmol) was added to a cooled (0 ꢁC)
slurry of 22 (210 mg, 0.629 mmol) and Me2S (0.23 ml,
3.14 mmol) in MeOH (8 ml) and the mixture was stirred at
0 ꢁC for 0.5 h and at 18 ꢁC for 14 h. The same work-up as
above afforded recovered 22 (28 mg, 13%), 23 (122 mg,
58%), and 26 (31 mg, 14%) in order of increasing polarity.
26: Colorless needles, mp 234–235 ꢁC (CH2Cl2–hexane).
Anal. Calcd for C19H26O6: C, 65.12; H, 7.48. Found: C,
64.75; H, 7.35. DI-HRMS Calcd for C19H26O6: 350.1728.
Found: 350.1737. DI-MS m/z: 350 (M+, 8), 288 (11), 260
(11), 165 (11), 99 (100), 73 (83), 55 (19), 45 (35). IR
(CHCl3) cmꢂ1: 1660. 1H NMR d: 1.39–1.51 (1H, m), 1.57–
1.91 (6H, m), 1.97–2.05 (1H, m), 2.12–2.18 (1H, m), 2.16
(1H, br s, OH), 2.26–2.69 (6H, m), 3.67–4.04 (8H, m), 5.51
(1H, s), 5.66 (1H, br d, J¼2 Hz, H14). 13C NMR d: 19.1
(CH2), 19.3 (CH2), 26.3 (CH2), 30.0 (CH2), 31.2 (CH2),
33.5 (CH2, C12), 35.3 (CH2), 43.8 (CH), 48.9 (C, C10),
62.7 (CH2), 64.0 (CH2), 64.3 (CH2), 65.5 (CH2), 71.5 (C,
C9), 104.0 (CH), 110.6 (C), 122.9 (CH, C14), 165.2 (C,
C8), 199.3 (C, C13).
4.2.8. Reduction of 23 to form allylalcohol 28. CeCl7$H2O
(408 mg, 1.10 mmol) and NaBH4 (43 mg, 1.13 mmol) were
added to a cooled (0 ꢁC) solution of 23 (330 mg,
0.988 mmol) in MeOH (25 ml) and the mixture was stirred
at that temperature for 30 min. Quenching by successive ad-
dition of saturated NH4Cl–H2O and saturated NaHCO3–H2O
followed by extraction with CH2Cl2, usual work-up, and
PTLC [benzene–EtOAc (2:1)] provided 28 as colorless
prisms, mp 191–192 ꢁC (CH2Cl2–hexane). Anal. Calcd for
C19H28O5$1/4H2O: C, 66.93; H, 8.43. Found: C, 67.08; H,
8.37. DI-HRMS Calcd for C19H28O5: 336.1935. Found:
336.1936. DI-MS m/z: 336 (M+, 1), 318 (8), 184 (22), 99
1
(100), 73 (98), 45 (28). H NMR d: 0.93–1.05 (1H, m),
1.11–1.28 (1H, m), 1.38–1.50 (1H, m), 1.55–1.94 (10H, m,
including OH), ca. 2.01–2.14 (1H, m), ca. 2.12–2.25 (1H,
m), 2.41 (1H, ddd, J¼15, 3, 3 Hz, H7), 2.46 (1H, br dddd,
J¼13, 3, 3, 1.5 Hz, H1), 3.65–3.73 (1H, m), 3.77–3.96 (6H,
m), 3.97–4.03 (1H, m), 4.14–4.23 (1H, m, W1/2¼19 Hz,
H13), 5.21–5.25 (1H, m, W1/2¼5.5 Hz, H14), 5.45 (1H, s).
4.2.6. DBU treatment of 22 to form hydroperoxide 25 and
26. A solution of 22 (10 mg, 29.9 mmol) and DBU (9 ml,

H. Muratake, M. Natsume / Tetrahedron 62 (2006) 7056–7070
7065
13C NMR d: 19.7 (CH2), 19.8 (CH2), 22.1 (CH2, C11), 33.9
(CH2), 34.3 (CH2), 34.5 (CH2), 35.8 (CH2), 44.4 (C), 48.9
(CH, C9), 52.8 (CH), 62.6 (CH2), 64.1 (CH2), 65.1 (CH2),
65.4 (CH2), 67.9 (CH, C13), 105.7 (CH), 110.0 (C), 122.3
(CH, C14), 141.3 (C, C8).
4.5 Hz, H1), 1.24 (3H, dd, J¼7, 7 Hz, OCH2CH3), 1.42–
1.94 (13H, m), 2.12 (1H, ddd, J¼13.5, 6.5, 6.5 Hz, H7),
2.29 (1H, d, J¼13.5 Hz, CH2COO), 2.51 (1H, d, J¼
13.5 Hz, CH2COO), 2.52 (1H, br d, J¼13 Hz, H1), 3.63–
4.04 (8H, m), 4.02–4.14 (2H, m, OCH2CH3), 5.34 (1H, s),
5.40 (1H, br d, J¼10 Hz, H14), 5.69 (1H, ddd, J¼10, 5,
2.5 Hz, H13). 13C NMR d: 14.3 (CH3), 16.8 (CH2), 20.0
(CH2), 20.6 (CH2), 23.6 (CH2), 34.1 (CH2), 35.9 (CH2),
37.6 (C), 38.4 (CH2), 43.8 (C), 49.5 (CH), 49.7 (CH2,
CH2COO), 50.4 (CH), 59.8 (CH2, OCH2CH3), 62.3 (CH2),
63.9 (CH2), 64.1 (CH2), 65.7 (CH2), 104.9 (CH), 110.4 (C),
126.4 (CH, C13), 136.1 (CH, C14), 171.8 (C).
4.2.9. Claisen rearrangement of 28 under neutral con-
ditions to form 29. A solution of 28 (500 mg, 1.49 mmol)
and N,N-dimethylacetamide dimethyl acetal (1.53 ml,
10.48 mmol) in toluene (20 ml) was heated with stirring at
160 ꢁC (bath temperature) in a sealed tube for 4 h. The vola-
tile materials were removed in vacuo and resulting residue
was purified by SiO2 column chromatography [25 g, benz-
ene–EtOAc (4:1)] to yield 29 (418 mg, 69%) as colorless
needles, mp 140.5–141.5 ꢁC (CH2Cl2–hexane). Anal.
Calcd for C23H35NO5: C, 68.12; H, 8.70; N, 3.45. Found:
C, 68.04; H, 8.62; N, 3.48. DI-HRMS Calcd for
C23H35NO5: 405.2513. Found: 405.2521. DI-MS m/z: 405
(M+, 4), 360 (6), 332 (20), 319 (15), 245 (56), 99 (82), 73
4.2.12. Reduction of acetamide 29 to form 32. n-BuLi
(1.5 M in hexane, 5.57 ml, 8.36 mmol) was added to a cooled
(0 ꢁC) slurry of BH3$NH3 (90%, 307 mg, 8.97 mmol) in THF
(12 ml) in a round bottom flask (300 ml). The mixture was
stirred under an Ar atmosphere at that temperature for
5 min and at 20 ꢁC for 10 min, and then was allowed to
cool again to 0 ꢁC. A THF (8 ml) solution of 29 (480 mg,
1.19 mmol) was added dropwise to this and the mixture
was stirred for 10 min. The cooling bath was removed and
the mixture was further stirred at 22 ꢁC for 19 h. After the
mixture had been cooled in an ice bath again, saturated
NH4Cl–H2O (25 ml) and NH4Cl powder (ca. 2 g) were grad-
ually added to this with efficient stirring. SiO2 (15 g) and
CH2Cl2 (30 ml) were further added and the whole was vigor-
ously stirred at 20 ꢁC for 3 h. The whole was filtered under
reduced pressure and filtered SiO2 was washed thoroughly
with CH2Cl2. Usual work-up followed by SiO2 column chro-
matography [30 g, 1% MeOH–CH2Cl2] yielded 32 (404 mg,
94%) as a colorless viscous syrup. DI-HRMS Calcd for
C21H32O5: 364.2248. Found: 364.2247. DI-MS m/z: 364
(M+, 6), 319 (27), 291 (17), 185 (6), 112 (21), 99 (99), 73
1
(100), 45 (34). IR (CHCl3) cmꢂ1: 1622. H NMR d: 1.09
(1H, ddd, J¼13, 13, 4.5 Hz, H1), 1.48 (1H, ddd, J¼13, 13,
5 Hz, H3), 1.52–2.02 (12H, m), 2.08–2.19 (1H, m), 2.32
(1H, d, J¼14 Hz, CH2CON), 2.51 (1H, br dddd, J¼13, 3,
3, 1 Hz, H1), 2.56 (1H, d, J¼14 Hz, CH2CON), 2.91 (3H,
s), 2.98 (3H, s), 3.65–4.07 (8H, m), 5.34 (1H, s), 5.45 (1H,
br dd, J¼10, 1.5 Hz, H14), 5.67 (1H, ddd, J¼10, 5, 2.5 Hz,
H13). 13C NMR d: 16.9 (CH2), 20.0 (CH2), 20.7 (CH2),
23.6 (CH2), 34.3 (CH2), 34.5 (CH3), 35.9 (CH2), 38.1 (C),
38.2 (CH2), 38.5 (CH3), 43.8 (C, C8), 46.2 (CH2,
CH2CON), 49.7 (CH), 50.6 (CH), 62.3 (CH2), 63.9 (CH2),
64.0 (CH2), 65.6 (CH2), 104.9 (CH), 110.5 (C), 126.3 (CH,
C13), 136.6 (CH, C14), 171.5 (C).
4.2.10. Acetylation of 28 to form diene 30. Ac2O (0.10 ml,
1.06 mmol) was added to a solution of 28 (5.5 mg,
16.4 mmol) and pyridine (0.30 ml, 3.71 mmol) in CH2Cl2
(1 ml) and the mixture was stirred at 20 ꢁC for 2 h.
Saturated NaHCO3–H2O was added and the whole was ex-
tracted with CH2Cl2. Usual work-up and PTLC [hexane–
CH2Cl2 (1:2)] gave 30 (4.5 mg, 86%) as a labile colorless
syrup. GC–HRMS Calcd for C19H26O4: 318.1830. Found:
318.1818. GC–MS m/z: 318 (M+, 8), 245 (11), 211 (10),
184 (24), 99 (84), 73 (100), 45 (35). 1H NMR d: 0.96–1.08
(1H, m), 1.41–1.71 (4H, m), 1.85–2.26 (8H, m), 2.59 (1H,
dddd, J¼13, 3, 3, 1.5 Hz, H1), 3.67–3.86 (4H, m), 3.90–
4.06 (4H, m), 5.43 (1H, s), 5.50–5.55 (1H, m, H7), 5.61–
5.69 (1H, m, H13), 5.99 (1H, dd, J¼9.5, 1.5 Hz, H14). 13C
NMR d: 19.6, 22.0, 24.1, 27.3, 35.4, 36.0, 41.9, 48.6, 48.7,
62.1, 64.1, 65.46, 65.52, 105.3, 109.9, 122.6, 126.4, 129.7,
136.0.
1
(100), 55 (21), 45 (46). H NMR d: 1.00 (1H, ddd, J¼13,
13, 4.5 Hz, H1), 1.31 (1H, ddd, J¼13.5, 13, 6.5 Hz, H7),
1.46 (1H, ddd, J¼13, 13, 5 Hz, H3), 1.48–1.81 (9H, m,
including OH), 1.81–2.01 (5H, m), 2.09 (1H, ddd, J¼13.5,
7, 7 Hz, H7), 2.53 (1H, dddd, J¼13, 3, 3, 1.5 Hz, H1), 3.66–
3.83 (4H, m), 3.87–3.97 (3H, m), 3.99–4.07 (1H, m), 5.33
(1H, s), 5.37 (1H, dd, J¼10, 1.5 Hz, H14), 5.70 (1H, ddd,
J¼10, 5, 2.5 Hz, H13). 13C NMR d: 16.7 (CH2), 20.0 (CH2),
21.0 (CH2), 26.4 (CH2), 34.2 (CH2), 36.0 (CH2), 36.9
(C, C8), 38.7 (CH2), 43.7 (C), 49.0 (CH2, CH2CH2OH),
49.3 (CH), 51.8 (CH), 59.9 (CH2, CH2CH2OH), 62.3 (CH2),
63.9 (CH2), 64.2 (CH2), 65.7 (CH2), 104.9 (CH), 110.4 (C),
126.4 (CH), 137.2 (CH).
4.2.13. Pivaloylation of 32 to form 5. Piv2O (1.22 ml,
6.02 mmol) was slowly added to a cooled (0 ꢁC) solution
of Et3N (3.30 ml, 23.7 mmol) in CH2Cl2 (3 ml) under an
Ar atmosphere and the mixture was stirred at that tempera-
ture for 15 min. The resulting solution was slowly added
dropwise to a cooled (ꢂ18 ꢁC) solution of 32 (560 mg,
1.54 mmol) and 4-DMAP (28 mg, 0.230 mmol) in CH2Cl2
(2 ml). The whole was stirred at ꢂ18 to 23 ꢁC for five days.
Saturated NaHCO3–H2O was added and the mixture was ex-
tracted with CH2Cl2. Usual work-up and SiO2 column chro-
matography [40 g, hexane–EtOAc (8:1)] afforded 5 (674 mg,
98%) as a colorless needles, mp 93–94 ꢁC (CH2Cl2–hexane).
Anal. Calcd for C26H40O6: C, 69.61; H, 8.99. Found: C,
69.40; H, 9.02. DI-HRMS Calcd for C26H40O6: 448.2823.
Found: 448.2832. DI-MS m/z: 448 (M+, 3), 403 (3), 375
4.2.11. Claisen rearrangement of 28 under acidic condi-
tions to form 31. A solution of 28 (20 mg, 59.5 mmol) and
pivalic acid (2 mg, 19.6 mmol) in triethyl orthoacetate
(1.50 ml, 8.19 mmol) was heated with stirring at 160 ꢁC
(bath temperature) in a sealed tube for 15 h. After the mixture
had been cooled, saturated NaHCO3–H2O was added and the
whole was extracted with CH2Cl2. Usual work-up and PTLC
[hexane–CH2Cl2 (1:1)] gave 31 (5 mg, 21%) as a colorless
syrup. DI-HRMS Calcd for C23H34O6: 406.2353. Found:
406.2342. DI-MS m/z: 406 (M+, 7), 361 (12), 344 (6), 333
(16), 319 (15), 245 (21), 99 (79), 73 (100), 45 (37). IR
(CHCl3) cmꢂ1: 1720. 1H NMR d: 1.03 (1H, ddd, J¼13, 13,

7066
H. Muratake, M. Natsume / Tetrahedron 62 (2006) 7056–7070
(8), 319 (5), 99 (61), 73 (100), 57 (35), 45 (24), 41 (17). IR
(25), 318 (6), 113 (16), 112 (14), 99 (100), 86 (10), 55 (10),
1
1
(CHCl3) cmꢂ1: 1719. H NMR d: 1.01 (1H, ddd, J¼13.5,
45 (17). IR (CHCl3) cmꢂ1: 1767. H NMR d: 0.94–0.97
13, 4.5 Hz, H1), 1.18 (9H, s), 1.34 (1H, ddd, J¼13.5, 13.5,
6.5 Hz, H7), 1.47 (1H, ddd, J¼13, 13, 5 Hz, H3), 1.48–1.80
(8H, m), 1.81–2.00 (1H, m), 2.10 (1H, ddd, J¼13.5, 7,
7 Hz, H7), 2.53 (1H, br d, J¼13 Hz, H1), 3.66–3.84 (4H,
m), 3.87–3.97 (3H, m), 4.00–4.12 (3H, m), 5.31 (1H, br dd,
J¼9.5, 1.5 Hz, H14), 5.34 (1H, s), 5.70 (1H, ddd, J¼9.5, 5,
2.5 Hz, H13). 13C NMR d: 16.7 (CH2), 20.0 (CH2), 21.0
(CH2), 23.9 (CH2), 27.2 (CH3ꢃ3), 34.1 (CH2), 36.0 (CH2),
36.8 (C, C8), 38.6 (C, COCMe3), 38.7 (CH2), 43.8 (C),
44.1 (CH2, CH2CH2OPiv), 49.4 (CH), 51.5 (CH), 62.0
(CH2, CH2OPiv), 62.3 (CH2), 63.9 (CH2), 64.2 (CH2), 65.7
(CH2), 104.9 (CH), 110.4 (C), 126.4 (CH, C13), 136.4
(CH, C14), 178.4 (C).
(1H, m), 1.25–1.92 (13H, m), 2.04 (1H, ddddd, J¼14, 14,
14, 4, 4 Hz, H2), 2.28 (1H, d, J¼19 Hz, CH2COO), 2.29–
2.37 (2H, m), 2.69 (1H, d, J¼19 Hz, CH2COO), 3.33–3.41
(1H, m), 3.35 (1H, br s, OH), 3.61–3.79 (2H, m, sharpened
with D2O), 3.71–3.77 (1H, m), 3.81–3.89 (1H, m), 3.85
(1H, d, J¼3 Hz, H corresponding to H20), 3.90–4.03 (3H,
m), 4.26 (1H, d, J¼4 Hz, CHOCO). 13C NMR d: 9.8 (CH2,
C corresponding to C12), 15.3 (CH2, C corresponding to
C11), 17.1 (CH2, C6), 22.1 (CH2, C2), 31.9 (CH2, C1),
33.1 (CH, C corresponding to C13), 34.6 (CH2, C3), 37.9
(CH2, C7), 38.9 (C, C8), 40.6 (CH2, CH2COO), 40.9 (C,
C10), 47.4 (CH, C9), 50.5 (CH, C5), 61.9 (CH2, CH2OH),
64.2 (CH2), 65.4 (CH2), 70.6 (CH2, CH2CH2OH), 75.5
(CH, C corresponding to C20), 84.1 (CH, C corresponding
to C14), 110.1 (C, C4), 176.3 (C, COO). Another by-product
35 with polarity between 33 and 34 was obtained as a color-
less glass employing cyclohexene–toluene (6:1) as the reac-
tion solvent (run a). DI-HRMS Calcd for C21H30O6:
378.2041. Found: 378.2027. DI-MS m/z: 378 (M+, 5), 333
(42), 317 (4), 289 (2), 99 (100), 55 (13), 45 (20). IR
(CHCl3) cmꢂ1: 1719. 1H NMR d: 0.82–0.91 (1H, m), 1.07–
2.07 (12H, m), 2.23 (1H, d, J¼19.5 Hz, CH2COO), 2.24–
2.38 (2H, m), 2.47–2.58 (3H, m), 2.70 (1H, d, J¼19.5 Hz,
CH2COO), 3.58–3.65 (1H, m), 3.68–3.85 (4H, m), 3.89–
4.01 (3H, m), 4.58 (1H, br dd, J¼4.5, 4 Hz, H13), 4.68
(1H, d, J¼6.5 Hz, H20).
4.3. Acetal–ene reactions of 29, 31, and 5 (Scheme 5)
4.3.1. BF3 treatment of 29 and 31 to form 33 and 34 (35)
(Table 1). The procedure for Table 1, run b was described as
a representative example. BF3$OEt2 (105 ml, 0.828 mmol)
was added to a cooled (ꢂ18 ꢁC) solution of 29 (56 mg,
0.138 mmol) in toluene (5 ml) under an Ar atmosphere
with stirring. After stirring for 2 h at ꢂ18 ꢁC, saturated
NaHCO3–H2O (8 ml) and EtOAc (10 ml) were added and re-
sulting mixture was vigorously stirred for 2 h at an ambient
temperature. Extraction with EtOAc followed by usual
work-up gave a residue (66 mg). The residue was dissolved
in benzene (6 ml) and to this were added ethylene glycol
(0.40 ml, 7.18 mmol) and p-TsOH$H2O (4 mg, 21.1 mmol).
The mixture was stirred under reflux using a Dean–Stark ap-
paratus for 2 h. After the mixture had been cooled, saturated
NaHCO3–H2O was added and the whole was extracted with
CH2Cl2. Usual work-up and PTLC (1.8% MeOH–CH2Cl2)
afforded 33 (23 mg, 41%) and 34 (25 mg, 48%) in order of
decreasing polarity. 33: Colorless glass. DI-HRMS Calcd
for C23H35NO5: 405.2513. Found: 405.2522. DI-MS m/z:
405 (M+, 19), 360 (20), 343 (12), 318 (9), 273 (9), 257
(14), 99 (100), 87 (58), 72 (33), 55 (19), 45 (34). IR
(CHCl3) cmꢂ1: 1627. 1H NMR d: 1.06 (1H, ddd, J¼13, 12,
5 Hz, H1), 1.19–1.31 (1H, m), 1.46 (1H, br d, J¼5 Hz, H9),
1.50–1.80 (7H, m), 1.85–1.98 (1H, m), 2.07 (1H, br d,
J¼13 Hz, H1), 2.18 (1H, d, J¼15.5 Hz, CH2CON), 2.20
(1H, dddd, J¼19, 5, 2.5, 2.5 Hz, H11), 2.38 (1H, br d,
J¼19 Hz, H11), 2.48 (1H, d, J¼15.5 Hz, CH2CON), 2.89
(1H, br s, OH), 2.91 (1H, ddd, J¼7, 6.5, 1.5 Hz, H14), 2.93
(3H, s), 3.00 (3H, s), 3.38 (1H, ddd, J¼11, 6, 3.5 Hz), 3.57
(1H, ddd, J¼11, 6, 3 Hz), 3.62–3.76 [2H, m, changed with
D2O to 3.66 (1H, ddd, J¼12, 6, 3 Hz) and 3.72 (1H, ddd,
J¼12, 6, 3.5 Hz)], 3.74–3.86 (1H, m), 3.86–4.00 (3H, m),
4.44 (1H, d, J¼6.5 Hz, H20), 5.59 (1H, ddd, J¼9.5, 3,
2.5 Hz, H12), 5.70 (1H, dddd, J¼9.5, 7, 2, 1.5 Hz, H13).
13C NMR d: 18.3 (CH2, C6), 21.3 (CH2, C2), 27.1 (CH2,
C11), 28.8 (CH2, C1), 33.8 (CH2, C7), 34.8 (CH2, C3),
35.3 (CH3, NCH3), 37.4 (CH2, CH2CON), 37.8 (CH3,
NCH3), 43.6 (C, C8), 48.1 (CH, C14), 48.2 (C, C10), 50.5
(CH, C5), 54.5 (CH, C9), 62.2 (CH2, CH2OH), 63.9 (CH2),
65.4 (CH2), 69.6 (CH2, CH2CH2OH), 80.3 (CH, C20),
110.5 (C, C4), 125.7 (CH, C12), 128.7 (CH, C13), 172.5
(C, CON). 34: Colorless prisms, mp 206–207 ꢁC (CH2Cl2–
hexane). Anal. Calcd for C21H30O6: C, 66.64; H, 7.99.
Found: C, 66.36; H, 8.02. DI-HRMS Calcd for C21H30O6:
378.2041. Found: 378.2043. DI-MS m/z: 378 (M+, 3), 333
4.3.2. HCl treatment of 29 to form 34 and 36 (Table 1, run
h). HCl–H2O (2.5% 0.5 ml) was added to a cooled (0 ꢁC)
solution of 29 (30 mg, 74.1 mmol) in THF (2 ml) and the
mixture was stirred for 1 h. Saturated NaHCO3–H2O (5 ml)
and EtOAc (5 ml) were added and resulting mixture was vig-
orously stirred for 2 h at an ambient temperature. Extraction
with EtOAc followed by usual work-up and PTLC (0.8%
MeOH–CH2Cl2) afforded 34 (18 mg, 64%) and 36 (7 mg,
26%) in order of increasing polarity. 36: Colorless glass.
DI-HRMS Calcd for C21H31NO4: 361.2251. Found:
361.2264. DI-MS m/z: 361 (M+, 1), 333 (2), 288 (7), 274
(11), 261 (7), 246 (19), 218 (8), 201 (18), 91 (21), 87 (85),
73 (100), 45 (38). IR (CHCl3) cmꢂ1: 1704, 1631. 1H NMR
d: 1.19–1.39 (2H, m), 1.72 (1H, ddd, J¼13, 13, 4 Hz),
1.80–2.11 (8H, m), 2.14–2.24 (2H, m), 2.24 (1H, d,
J¼15 Hz), 2.29–2.45 (2H, m), 2.53 (1H, d, J¼15 Hz), 2.65
(1H, br ddd, J¼13, 3.5, 3.5 Hz, H1), 2.92 (3H, s), 2.99
(3H, s), 3.59–3.77 (3H, m), 3.96–4.06 (1H, m), 5.29 (1H,
s), 5.71 (1H, ddd, J¼10, 3.5, 2.5 Hz), 5.59 (1H, br d,
J¼10 Hz). 13C NMR d: 17.4 (CH2), 17.5 (CH2), 21.3
(CH2), 22.4 (CH2), 33.3 (CH2), 35.4 (CH3), 37.3 (C),
37.9 (CH2), 38.1 (CH3), 39.2 (CH2, C3), 45.3 (CH2),
45.9 (CH), 47.9 (C), 57.8 (CH, C5), 62.7 (CH2), 65.2
(CH2), 105.0 (CH), 129.5 (CH), 136.1 (CH), 170.8 (C),
209.8 (C, C4).
4.3.3. Acetal–ene reaction of 5 to form 6 (37, 38) (Table 2).
The procedure for Table 2, run d was described as a represen-
tative example. BF3$OEt2 (392 ml, 3.09 mmol) was added to
a cooled (ꢂ18 ꢁC) solution of 5 (231 mg, 0.516 mmol) in tol-
uene (10 ml) under an Ar atmosphere with stirring. After stir-
ring for 1 h at ꢂ18 ꢁC, saturated NaHCO3–H2O was added
and the mixture was extracted with CH2Cl2. After usual
work-up, obtained residue (260 mg) was dissolved in acetone

H. Muratake, M. Natsume / Tetrahedron 62 (2006) 7056–7070
7067
(10 ml) and to this was added p-TsOH$H2O (21 mg,
0.111 mmol) at 0 ꢁC. The mixture was stirred at 0 ꢁC for
10 min and at 19 ꢁC for 3.5 h. Saturated NaHCO3–H2O
was added and the whole was extracted with CH2Cl2. Usual
work-up and PTLC [hexane–EtOAc (2:1)] yielded crude 38
(12 mg), 6 (138 mg, 66%), and crude 37 (18 mg) in order
of increasing polarity. The crude 37 was further purified
by PTLC (0.3% MeOH–CH2Cl2) to give 37 (6 mg, 3%).
The crude-38 was also separated by PTLC [hexane-1,2-di-
methoxyethane (DME) (19:1)] to provide 38 (6 mg, 3%). 6:
Colorless glass. DI-HRMS Calcd for C24H36O5: 404.2561.
Found: 404.2569. DI-MS m/z: 404 (M+, 3), 369 (5), 302
(5), 275 (8), 240 (31), 91 (39), 73 (36), 57 (100), 45 (41),
(CH), 54.0 (CH), 62.2 (CH2), 124.3 (CH, C11), 125.7
(CH, C12), 178.3 (C), 212.4 (C).
4.3.4. Acetal–ene reaction, reacetalization of 5 to form 39,
40, and 41. The crude ene reaction product (592 mg) pre-
pared as above from 5 (582 mg, 1.30 mmol) and BF3$OEt2
(0.80 ml, 6.50 mmol) was dissolved in benzene (40 ml).
Ethylene glycol (3.60 ml, 64.6 mmol) and p-TsOH$H2O
(30 mg, 0.16 mmol) were added to the solution and the mix-
ture was heated under reflux for 1.5 h with Dean–Stark appa-
ratus. The same work-up as before followed by separation by
PTLC [benzene–EtOAc (8:1)] furnished crude-40 (42 mg),
39 (408 mg, 70%), and crude 41 (35 mg) in order of increas-
ing polarity. The crude-40 was purified by PTLC [hexane–
CH2Cl2 (1:1)] to yield 40 (25 mg, 3%). Crude 41 was also
separated by PTLC [benzene–EtOAc (3:1)] to afford 41
(18 mg, 3%). 39: Colorless glass. DI-HRMS Calcd for
C26H40O6: 448.2823. Found: 448.2831. DI-MS m/z: 448
(M+, 5), 403 (11), 386 (3), 363 (2), 319 (3), 285 (3), 284
(3), 257 (4), 112 (16), 99 (100), 57 (50), 45 (23), 41 (20).
1
41 (47). IR (CHCl3) cmꢂ1: 1717, 1705. H NMR d: 1.18
(9H, s), 1.45–1.98 (8H, m, including OH), 1.68 (1H, ddd,
J¼13.5, 8.5, 6 Hz, CH2CH2OPiv), 1.98–2.09 (1H, m), 2.04
(1H, ddd, J¼13, 5, 8.5, 6.5 Hz, CH2CH2OPiv), 2.21–2.36
(5H, m), 2.42 (1H, br d, J¼19 Hz, H11), 2.56 (1H, ddd,
J¼6.5, 6.5, 1.5 Hz, H14), 3.25 (1H, ddd, J¼9, 5, 4.5,
3 Hz, CH2CH2OH), 3.35 (1H, ddd, J¼9.5, 7.5, 3 Hz,
CH2CH2OH), 3.54–3.72 [2H, m, changed with D2O to
3.58 (1H, ddd, J¼11.5, 4.5, 3 Hz) and 3.66 (1H, ddd,
J¼11.5, 7.5, 3 Hz)], 3.62 (1H, d, J¼6.5 Hz, H20), 4.00
(1H, ddd, J¼11, 8.5, 6.5 Hz, CH2OPiv), 4.14 (1H, ddd,
J¼11, 8.5, 6 Hz, CH2OPiv), 5.60 (1H, ddd, J¼9.5, 3,
3 Hz, H12), 5.69 (1H, dddd, J¼9.5, 6.5, 2, 1.5 Hz, H13).
13C NMR d: 19.1 (CH2, C6), 25.6 (CH2, C2), 27.17
(CH3ꢃ3), 27.23 (CH2, C11), 28.6 (CH2, C1), 33.6 (CH2,
CH2CH2OPiv), 33.8 (CH2, C7), 38.6 (C, CMe3), 41.5
(CH2, C3), 42.6 (C, C8), 47.7 (CH, C14), 53.8 (CH, C9),
54.0 (C, C10), 56.5 (CH, C6), 62.0 (CH2, CH2OH), 62.5
(CH2, CH2OPiv), 69.8 (CH2, CH2CH2OH), 81.2 (CH,
C20), 126.2 (CH, C12), 126.9 (CH, C13), 178.4 (C), 212.1
(C). 37: Colorless glass. DI-HRMS Calcd for C24H36O5:
404.2561. Found: 404.2580. DI-MS m/z: 404 (M+, 3), 342
(16), 302 (8), 275 (14), 240 (28), 213 (39), 91 (37), 73
(32), 57 (100), 45 (49), 41 (48). IR (CHCl3) cmꢂ1: 1708.
1H NMR d: 1.18 (9H, s), 1.40–1.73 (6H, m), 1.41 (1H,
br d, J¼4.5 Hz, H9), 1.62 (1H, br s, OH), 1.98–2.42 (8H, m),
2.53 (1H, br d, J¼6 Hz, H5), 2.55 (1H, ddd, J¼7, 6,
1.5 Hz, H14), 3.41 (1H, ddd, J¼9.5, 5, 3.5 Hz), 3.46 (1H,
ddd, J¼9.5, 6.5, 3.5 Hz), 3.62–3.79 [2H, m, changed with
D2O to 3.66 (1H, ddd, J¼11.5, 5, 3.5 Hz) and 3.73 (1H,
ddd, J¼11.5, 6.5, 3.5 Hz)], 3.96 (1H, d, J¼6 Hz), 4.00
(1H, ddd, J¼10.5, 8, 6.5 Hz), 4.09 (1H, ddd, J¼10.5, 8.5,
6 Hz), 5.60 (1H, ddd, J¼9.5, 3, 3 Hz), 5.69 (1H, dddd,
J¼9.5, 7, 2, 1.5 Hz). 13C NMR d: 17.8 (CH2), 23.7 (CH2),
25.9 (CH2), 27.2 (CH3ꢃ3), 28.4 (CH2), 32.3 (CH2), 33.5
(CH2), 38.6 (C), 41.3 (CH2), 43.3 (ꢃ2, CH and C, C8 and
C9), 46.4 (CH), 53.1 (C), 57.3 (CH, C5), 61.9 (CH2), 62.4
(CH2), 70.3 (CH2), 87.6 (CH), 126.2 (CH), 126.7 (CH),
178.4 (C), 210.7 (C). 38: Colorless glass. DI-HRMS Calcd
for C22H30O3: 342.2193. Found: 342.2201. DI-MS m/z:
342 (M+, 2), 240 (56), 212 (20), 129 (25), 91 (31), 57
1
IR (CHCl3) cmꢂ1: 1711. H NMR d: 1.00–1.11 (1H, m),
1.17–1.28 (2H, m), 1.18 (9H, s), 1.51–1.89 (9H, m), 2.06
(1H, ddd, J¼13.5, 8.5, 6.5 Hz), 2.07 (1H, br d, J¼13.5 Hz,
H1), 2.18 (1H, dddd, J¼19, 5, 2.5, 2.5 Hz, H11), 2.36 (1H,
br d, J¼19 Hz, H11), 2.50 (1H, ddd, J¼6.5, 6, 1 Hz, H14),
2.85 (1H, t, J¼6.5 Hz, OH), 3.33–3.41 (1H, m), 3.51–3.59
(1H, m), 3.66–3.73 (2H, m), 3.77–3.87 (1H, m), 3.87–4.00
(3H, m), 4.00 (1H, ddd, J¼10.5, 8.5, 6.5 Hz), 4.13 (1H,
ddd, J¼10.5, 8.5, 6 Hz), 4.42 (1H, d, J¼6.5 Hz), 5.59 (1H,
br ddd, J¼9.5, 2.5, 2.5 Hz, H12), 5.66 (1H, br dd, J¼9.5,
6.5 Hz, H13). 13C NMR d: 18.3 (CH2), 21.2 (CH2), 26.9
(CH2), 27.2 (CH3ꢃ3), 28.8 (CH2), 33.5 (CH), 34.1 (CH2),
34.7 (CH2, C3), 38.5 (C), 42.3 (C), 47.6 (CH), 48.4 (C),
50.6 (CH, C5), 54.8 (CH), 62.3 (CH2), 62.6 (CH2), 63.9
(CH2), 65.4 (CH2), 69.7 (CH2), 80.6 (CH), 110.4 (C, C5),
125.9 (CH), 127.4 (CH), 178.4 (C). 40: Colorless glass.
DI-HRMS Calcd for C24H34O4: 386.2455. Found:
386.2460. DI-MS m/z: 386 (M+, 4), 284 (27), 257 (5), 195
(6), 99 (100), 57 (38), 41 (17). IR (CHCl3) cmꢂ1: 1712. 1H
NMR d: 0.82–0.96 (1H, m), 1.07 (1H, ddd, J¼7, 5, 1 Hz,
H14), 1.17 (9H, s), 1.19–1.82 (15H, m), 3.80–4.05 (6H,
m), 5.57 (1H, ddd, J¼8, 6.5, 2 Hz, H11), 6.08 (1H, ddd,
J¼8, 5.5, 1.5 Hz, H12). 13C NMR d: 16.1 (CH, C13), 18.8
(CH2), 19.1 (CH, C20), 20.4 (CH2), 24.2 (CH, C14), 27.2
(CH3ꢃ3), 29.8 (CH2), 32.6 (CH2), 32.9 (CH), 35.5 (CH2),
38.5 (C), 39.2 (C), 43.8 (C), 48.7 (CH), 54.0 (CH), 62.4
(CH2), 64.4 (CH2), 65.4 (CH2), 110.5 (C, C4), 123.8 (CH),
125.8 (CH), 178.4 (C). 41: Colorless glass. DI-HRMS
Calcd for C26H42O7: 466.2928. Found: 466.2924. DI-MS
m/z: 466 (M+, 2), 421 (18), 405 (2), 364 (11), 319 (7), 302
(6), 112 (30), 99 (100), 73 (16), 57 (84), 45 (15), 41 (21).
1
IR (CHCl3) cmꢂ1: 1713. H NMR d: 0.76 (1H, dd, J¼2.5,
2.5 Hz, H9), 0.80 (1H, ddd, J¼13, 13, 4.5 Hz, H1), 1.21–
1.41 (4H, m), 1.23 (9H, s), 1.41–1.89 (11H, m, including
secondary OH), 1.90–2.03 (2H, m), 2.33 (1H, br ddd,
J¼13, 3, 3 Hz, H1), 3.24 (1H, br dd, J¼5.5, 5.5 Hz, primary
OH), 3.35–3.44 (1H, m), 3.56–3.65 (2H, m), ca. 3.63–3.74
(3H, m), 3.79–3.99 (5H, m), 4.70 (1H, d, J¼2.5 Hz,
CHOH). 13C NMR d: 10.5 (CH2, C corresponding to C12),
14.8 (CH2, C corresponding to C11), 16.6 (CH2), 22.2
(CH2), 27.2 (CH3ꢃ3), 32.2 (CH2), 33.8 (CH, C correspond-
ing to C13), 34.9 (CH2), 35.0 (CH2), 36.9 (CH2), 37.1 (C),
39.1 (C), 40.6 (C), 46.7 (CH), 50.8 (CH), 59.9 (CH2), 61.9
1
(100), 41 (64). IR (CHCl3) cmꢂ1: 1709. H NMR d: 1.06–
1.15 (2H, m, H14 and H20), 1.18 (9H, s), 1.32–1.42 (1H,
m), 1.37–1.52 (2H, m), 1.52–1.73 (5H, m), 1.80–2.06 (3H,
m), 1.99 (1H, dd, J¼7, 1.5 Hz), 2.20–2.39 (3H, m), 3.94–
4.09 (2H, m), 5.67 (1H, ddd, J¼8, 7, 2 Hz, H11), 6.11
(1H, ddd, J¼8, 5.5, 1.5 Hz, H12). 13C NMR d: 16.4 (CH,
C13), 18.8 (CH, C20), 19.8 (CH2, C6), 23.7 (CH2, C2),
24.0 (CH, C14), 27.2 (CH3ꢃ3), 29.3 (CH2), 31.9 (CH2),
32.8 (CH2), 38.6 (C), 39.2 (C), 41.8 (CH2), 48.7 (C), 53.2

7068
H. Muratake, M. Natsume / Tetrahedron 62 (2006) 7056–7070
(CH2), 64.3 (CH2), 65.4 (CH2), 70.2 (CH2), 74.6 (CH,
CHOH), 75.8 (CH), 110.4 (C), 177.8 (C).
Na2S2O3–H2O were added and the whole was extracted
with CH2Cl2. Usual work-up and separation by PTLC [hex-
ane–DME (3:2)] provided 44 (11 mg, 92%) as colorless
prisms, mp 195–196 ꢁC (CH2Cl2–hexane). Anal. Calcd for
C21H29NO4: C, 70.19; H, 8.13; N, 3.90. Found: C, 70.03;
H, 8.23; N, 3.94. DI-HRMS Calcd for C21H29NO4:
359.2095. Found: 359.2084. DI-MS m/z: 359 (M+, 3), 331
(27), 244 (21), 129 (27), 99 (100), 91 (24), 87 (67), 72
4.4. Model deprotection of 2-hydroxyethyl group and
allylic oxidation of 33 (Scheme 7)
4.4.1. Bromination of 33 to form 42. Ph3P (33 mg,
0.143 mmol) and CBr4 (33 mg, 99.4 mmol) were added to
a cooled (0 ꢁC) solution of 33 (20 mg, 49.4 mmol) in
CH2Cl2 (4 ml) and the mixture was stirred at 20 ꢁC for 1 h.
Saturated NaHCO3–H2O was added and the whole was
extracted with CH2Cl2. Usual work-up and PTLC [CH2Cl2–
EtOAc (19:1)] gave 42 (20 mg, 87%) as a colorless glass. DI-
HRMS Calcd for C23H34BrNO4: 469.1650, 467.1670.
Found: 469.1654, 467.1671. DI-MS m/z: 469, 467 (M+, 10,
10), 424, 422 (3, 2), 388 (16), 360 (23), 344 (8), 273 (11),
257 (11), 99 (100), 87 (67), 72 (27), 45 (28). IR (CHCl3)
1
(34), 55 (25), 45 (37). IR (CHCl3) cmꢂ1: 1727, 1635. H
NMR d: 1.25 (1H, ddd, J¼13, 13, 4 Hz), 1.34 (1H, ddd,
J¼13.5, 13.5, 4.5 Hz), 1.51–1.66 (2H, m), 1.69–1.92 (6H,
m), 2.09 (1H, br dd, J¼5.5, 3 Hz), 2.22–2.40 (3H, m), 2.47
(1H, d, J¼16 Hz), 2.52 (1H, d, J¼16 Hz), 2.94 (1H, dd,
J¼7.5, 2.5 Hz, H14), 2.94 (3H, s), 3.02 (3H, s), 3.73–3.81
(1H, m), 3.83–4.02 (3H, m), 5.70 (1H, ddd, J¼9.5, 3,
2.5 Hz), 5.80 (1H, dddd, J¼9.5, 7.5, 2, 1.5 Hz). 13C NMR
d: 19.5 (CH2), 20.0 (CH2), 26.1 (CH2), 29.8 (CH2), 34.0
(CH2), 34.8 (CH2), 35.4 (ꢃ2, CH3 and CH2), 37.8 (CH3),
41.1 (C), 51.1 (CH), 52.7 (CH), 54.9 (C, C10), 56.7 (CH,
C14), 64.0 (CH2), 66.0 (CH2), 109.2 (C), 126.8 (CH),
128.1 (CH), 171.5 (C), 211.7 (C, C20).
1
cmꢂ1: 1632. H NMR d: 1.02 (1H, ddd, J¼13, 13, 4 Hz,
H1), 1.22 (1H, ddd, J¼13.5, 12.5, 4 Hz, H3), 1.42 (1H, br
d, J¼5.5 Hz, H9), 1.50–1.79 (7H, m), 1.86–1.96 (1H, m),
2.04 (1H, br dddd, J¼13, 3, 3, 1.5 Hz, H1), 2.17 (1H, dddd,
J¼18, 5.5, 2.5, 2 Hz, H11), 2.36 (1H, br d, J¼18.5 Hz,
H11), 2.45 (1H, d, J¼15.5 Hz), 2.69 (1H, d, J¼15.5 Hz),
2.90 (1H, ddd, J¼6.5, 6.5, 1.5 Hz), 2.92 (3H, s), 3.00 (3H,
s), 3.38–3.54 (2H, m, CH2Br), 3.55–3.64 (1H, m), 3.67–
3.81 (2H, m), 3.85–3.98 (3H, m), 4.33 (1H, d, J¼6.5 Hz),
5.55 (1H, ddd, J¼9.5, 3, 2.5 Hz), 5.68 (1H, dddd, J¼9.5,
6.5, 2, 2 Hz). 13C NMR d: 18.2 (CH2), 21.0 (CH2), 27.0
(CH2), 28.7 (CH2), 30.4 (CH2, CH2Br), 33.9 (CH2), 34.9
(CH2), 35.3 (CH3), 37.5 (CH2), 37.8 (CH3), 43.7 (C), 48.3
(CH), 48.4 (C), 50.6 (CH), 54.6 (CH), 63.9 (CH2), 65.4
(CH2), 69.6 (CH2, CH2CH2Br), 81.3 (CH), 110.3 (C),
125.3 (CH), 129.0 (CH), 172.5 (C).
4.4.4. Oxidation of 42 with CrO3 and 3,5-dimethyl-
pyrazole. To a cooled (ꢂ18 ꢁC) slurry of CrO3 (49 mg,
0.490 mmol) in CH2Cl2 was added 3,5-dimethylpyrazole
(55 mg, 0.573 mmol) and the mixture was stirred for
15 min. A solution of 42 (19 mg, 40.6 mmol) in CH2Cl2
(2 ml) was added to this and the resulting mixture was stirred
at ꢂ18 to 27 ꢁC for 38 h. Saturated NaHCO3–H2O and
saturated Na2S2O3–H2O were added and the whole was
extracted with CH2Cl2. Usual work-up and separation by
PTLC (0.5% MeOH–CH2Cl2) provided recovery of 42
(5.5 mg, 29%) and a mixture of 45 and 46 (15 mg) in order
of increasing polarity. The latter was further purified by
PTLC [hexane–2-propanol (6:1)] and yielded 45 (5.5 mg,
28%) and 46 (5.5 mg, 28%) in order of decreasing polarity.
45: Colorless glass. DI-HRMS Calcd for C23H32BrNO5:
483.1443, 481.1463. Found: 483.1434, 481.1461. DI-MS
m/z: 483, 481 (M+, 6, 6), 402 (16), 397, 395 (6, 6), 271
(84), 109, 107 (17, 17), 99 (100), 87 (84), 72 (41), 55 (25),
4.4.2. Reductive deprotection of 42 to form 43. Zn dust
(252 mg, 3.85 mg atom) and NH4Cl (10 mg, 0.187 mmol)
were added to a solution of 42 (18 mg, 38.5 mmol) in 2-prop-
anol–H2O (14:1, 5 ml) and the mixture was refluxed with
stirring for 3 h. Saturated NH4Cl–H2O was added and the
whole was filtered under reduced pressure. Extraction with
CH2Cl2 followed by PTLC [hexane-DME (2:1)] afforded
43 (13 mg, 94%) as a colorless glass. DI-HRMS Calcd for
C21H34NO4: 361.2251. Found: 361.2240. DI-MS m/z: 361
(M+, 56), 332 (24), 316 (41), 274 (15), 245 (22), 183 (23),
99 (87), 87 (100), 72 (46), 55 (29), 45 (50). IR (CHCl3)
1
45 (32). IR (CHCl3) cmꢂ1: 1661, 1639. H NMR d: 1.20–
1.38 (3H, m), 1.47–1.82 (7H, m), 2.08 (1H, br dd, J¼1.5,
1.5 Hz, H9), 2.19 (1H, ddd, J¼13.5, 6.5, 2 Hz), 2.25 (1H,
d, J¼16 Hz), 2.57 (1H, d, J¼16 Hz), 2.89 (3H, s), 2.91
(3H, s), 3.39 (1H, dt, J¼10, 6.5 Hz), 3.45 (1H, dt, J¼10,
6.5 Hz), 3.72 (2H, dd, J¼6.5, 6.5 Hz), 3.76–3.85 (2H, m),
3.88–4.00 (3H, m), 4.66 (1H, d, J¼6.5 Hz), 6.11 (1H, dd,
J¼9.5, 1.5 Hz, H12), 7.16 (1H, dd, J¼9.5, 7.5 Hz, H13).
13C NMR d: 18.0 (CH2), 20.7 (CH2), 29.5 (CH2), 30.2
(CH2), 34.5 (CH2), 34.9 (CH2), 35.3 (CH3), 37.6 (CH3),
38.0 (CH2), 47.7 (C), 49.6 (CH), 50.0 (CH), 51.8 (C), 64.0
(CH2), 65.5 (CH2), 70.1 (CH2), 74.6 (CH, C9), 79.6 (CH,
C20), 109.6 (C), 129.4 (CH, C12), 153.7 (CH, C13), 170.8
(C), 202.0 (C, C11). 46: Colorless glass. DI-HRMS Calcd
for C23H32BrNO5: 483.1443, 481.1463. Found: 483.1418,
481.1461. DI-MS m/z: 483, 481 (M+, 13, 10), 402 (11),
374 (16), 358 (11), 271 (12), 109, 107 (14, 14), 99 (100),
87 (33), 72 (32), 55 (11), 45 (17). IR (CHCl3) cmꢂ1: 1677,
1
cmꢂ1: 1626. H NMR d: 1.09 (1H, ddd, J¼13, 13, 4 Hz),
1.23 (1H, ddd, J¼13, 12.5, 4 Hz), 1.51 (1H, br d, J¼5 Hz),
1.54–1.94 (9H, m), 2.12 (1H, br d, J¼11.5 Hz, OH), 2.28
(1H, dd, J¼19.5, 5 Hz), 2.38 (1H, br d, J¼19.5 Hz), 2.49
(1H, d, J¼15.5 Hz), 2.59 (1H, d, J¼15.5 Hz), 2.85–2.92
(1H, m), 2.93 (3H, s), 3.01 (3H, s), 3.73–3.81 (1H, m),
3.84–4.00 (3H, m), 4.70 (1H, br dd, J¼11.5, 7 Hz, changed
to d, J¼7 Hz with D2O, H20), 5.72–5.83 (2H, m). 13C NMR
d: 18.0 (CH2), 21.1 (CH2), 27.5 (CH2), 29.1 (CH2), 33.9
(CH2), 34.9 (CH2), 35.3 (CH3), 37.6 (CH2), 37.9 (CH3),
43.7 (C), 48.4 (C, C10), 50.0 (CH), 50.5 (CH, C14), 53.8
(CH), 63.9 (CH2), 65.5 (CH2), 72.6 (CH, C20), 110.1 (C),
128.6 (CH), 129.6 (CH), 172.4 (C).
1
1638. H NMR d: 1.19–1.89 (10H, m), 2.01 (1H, br d,
4.4.3. Dess–Martin oxidation of 43 to form 44. A solution
of 43 (12 mg, 33.2 mmol) and Dess–Martin periodinane
(70 mg, 0.165 mmol) in CH2Cl2 (4 ml) was refluxed with
stirring for 8 h. Saturated NaHCO3–H2O and saturated
J¼13 Hz), 2.32 (1H, d, J¼15.5 Hz), 2.39 (1H, d,
J¼15.5 Hz), 2.66 (1H, dd, J¼7, 1.5 Hz, H9), 2.89 (3H, s),
2.92 (3H, s), 3.18 (1H, ddd, J¼7, 1.5, 1.5 Hz, H14), 3.32
(2H, dd, J¼6.5, 6.5 Hz), 3.56 (1H, dt, J¼10.5, 6.5 Hz),

H. Muratake, M. Natsume / Tetrahedron 62 (2006) 7056–7070
7069
3.75 (1H, dt, J¼10.5, 6.5 Hz), 3.76–3.85 (1H, m), 3.88–4.01
(3H, m), 4.61 (1H, d, J¼7 Hz), 6.10 (1H, dd, J¼9.5, 1.5 Hz,
H12), 7.08 (1H, dd, J¼9.5, 7 Hz, H11). 13C NMR d: 17.9
(CH2), 20.7 (CH2), 29.7 (CH2), 29.9 (CH2), 33.9 (CH2),
35.0 (CH2), 35.3 (CH3), 36.3 (CH2), 37.7 (CH3), 49.4
(CH), 51.5 (C), 53.1 (C), 56.7 (CH, C9), 64.0 (CH2), 65.4
(CH2), 66.1 (CH, C14), 70.8 (CH2), 77.5 (CH), 109.7 (C),
131.1 (CH, C12), 151.1 (CH, C11), 170.8 (C), 200.4
(C, C13).
dd, J¼9.5, 7 Hz). 50: Colorless glass. DI-HRMS Calcd for
C21H31NO5: 377.2200. Found: 377.2197. DI-MS m/z: 377
(M+, 19), 332 (10), 192 (7), 168 (12), 99 (100), 87 (40), 72
1
(32), 55 (15), 46 (22). IR (CHCl3) cmꢂ1: 1701, 1640. H
NMR d: 1.23 (1H, ddd, J¼13.5, 13.5, 4.5 Hz), 1.32 (1H,
ddd, J¼13, 13, 4 Hz), 1.42–2.27 (14H, m, including OH),
2.08 (1H, d, J¼15.5 Hz), 2.30 (1H, d, J¼15.5 Hz), 2.67
(1H, ddd, J¼18, 10, 10 Hz, H12), 2.83 (1H, d, J¼7.5 Hz,
H14), 2.92 (3H, s), 2.96 (3H, s), 3.76–3.85 (1H, m), 3.86–
4.00 (3H, m), 4.94 (1H, br d, J¼7.5 Hz, H20). 13C NMR
d: 17.9 (CH2), 19.5 (CH2, C11), 20.9 (CH2), 27.7 (CH2),
33.3 (CH2), 34.8 (CH2), 35.4 (CH3), 36.2 (CH2, C12), 36.6
(CH2), 37.8 (CH3), 47.2 (C), 47.7 (C), 50.0 (CH), 52.5
(CH), 63.9 (CH2), 65.4 (CH2), 67.9 (CH, C14), 68.8 (CH,
C20), 110.1 (C), 170.4 (C), 212.4 (C).
4.4.5. Zn reduction of 45 to form 47. In a similar manner as
for the preparation of 43 from 42 (Section 4.4.2), 45 (6.5 mg,
13.5 mmol) was treated with Zn (220 mg, 3.36 mg atom) and
NH4Cl (11 mg, 0.206 mmol) for 3 h. The same work-up and
PTLC (2% MeOH–CH2Cl2) gave 47 (4.5 mg, 89%) as a col-
orless glass. DI-HRMS Calcd for C21H31NO5: 377.2200.
Found: 377.2209. DI-MS m/z: 377 (M+, 22), 332 (6), 276
(7), 180 (10), 99 (100), 87 (61), 72 (41), 55 (17), 46 (23),
Acknowledgements
1
45 (21). IR (CHCl3) cmꢂ1: 1689, 1640. H NMR d: 1.06–
1.21 (2H, m), 1.32 (1H, ddd, J¼12.5, 12.5, 5 Hz, H3),
1.46–1.74 (6H, m), 1.66 (1H, br s, OH), 1.75–1.84 (3H,
m), 2.15 (1H, d, J¼16.5 Hz), 2.15–2.32 (3H, m), 2.28 (1H,
d, J¼16.5 Hz), 2.64 (1H, ddd, J¼19, 10, 10 Hz, H12),
2.92 (3H, s), 2.94 (3H, s), 2.98–3.05 (1H, m), 3.77–3.85
(1H, m), 3.86–4.01 (3H, m), 4.95 (1H, br d, J¼7 Hz, H20).
13C NMR d: 17.9 (CH2), 20.8 (CH2), 20.9 (CH2, C13),
27.0 (CH2), 34.4 (CH2), 35.2 (CH2), 35.3 (CH3), 36.9
(CH2, C12), 37.6 (CH3), 38.5 (CH2), 45.5 (CH, C14), 46.3
(C), 48.7 (C), 49.7 (CH), 64.0 (CH2), 65.5 (CH2), 70.2
(CH), 74.2 (CH, C9), 109.7 (C), 170.2 (C), 215.0 (C).
The authors thank Shionogi & Co., Ltd, for elemental anal-
ysis. A part of this work was supported by a Grant-in-Aid for
Scientific Research from Japan Society for the Promotion of
Science (JSPS), which is gratefully acknowledged.
References and notes
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4.4.6. Zn reduction of 46 to form 48, 49, 50. In the same
manner as for the procedure of Section 4.4.5, 46 (6.5 mg,
13.5 mmol) was treated with Zn (220 mg, 3.36 mg atom)
and NH4Cl (11 mg, 0.206 mmol) for 4 h. The same work-
up and PTLC (2% MeOH–CH2Cl2) gave 48 (2.5 mg,
49%), 50 (2 mg, 39%), and 49 (0.5 mg, 9%) in order of de-
creasing polarity. 48: Colorless glass. DI-HRMS Calcd for
C21H29NO5: 375.2044. Found: 375.2057. DI-MS m/z: 375
(M+, 25), 347 (8), 330 (4), 289 (9), 271 (22), 227 (11), 99
(100), 87 (76), 72 (28), 45 (22). IR (CHCl3) cmꢂ1: 1675,
1
1634. H NMR d: 1.25–1.92 (11H, m, including OH), 2.12
(1H, br d, J¼13 Hz, H1), 2.34 (1H, d, J¼15.5 Hz), 2.41
(1H, d, J¼15.5 Hz), 2.71 (1H, br d, J¼7 Hz), 2.89 (3H, s),
2.92 (3H, s), 3.11 (1H, ddd, J¼7, 1.5, 1.5 Hz, H14), 3.77–
3.85 (1H, m), 3.87–3.98 (3H, m), 5.05 (1H, br d, J¼7 Hz,
H20), 6.12 (1H, dd, J¼9.5, 1.5 Hz), 7.14 (1H, dd, J¼9.5,
7 Hz). 13C NMR d: 17.8 (CH2), 20.9 (CH2), 29.6 (CH2),
33.9 (CH2), 35.1 (CH2), 35.3 (CH3), 36.3 (CH2), 37.7
(CH3), 49.5 (CH), 51.6 (C), 52.1 (C), 56.9 (CH), 64.1
(CH2), 65.4 (CH2), 68.2 (CH, C14), 69.3 (CH, C20), 109.7
(C), 170.9 (C), 130.9 (CH), 151.8 (CH), 201.5 (C). 49:
Colorless glass. DI-HRMS Calcd for C23H33NO5:
403.2357. Found: 403.2367. DI-MS m/z: 403 (M+, 25),
374 (15), 358 (7), 317 (21), 99 (100), 87 (22), 72 (33). IR
(CHCl3) cmꢂ1: 1672, 1633. 1H NMR d: 1.04 (3H, dd,
J¼7, 7 Hz, OCH2CH3), 1.20–1.88 (10H, m), 2.00 (1H,
br d, J¼13 Hz), 2.32 (1H, d, J¼15.5 Hz), 2.39 (1H,
d, J¼15.5 Hz), 2.64 (1H, br d, J¼7 Hz), 2.89 (3H, s),
2.92 (3H, s), 3.16 (1H, ddd, J¼7, 1.5, 1.5 Hz), 3.30 (1H,
dq, J¼9, 7 Hz, OCH2CH3), 3.49 (1H, dq, J¼9, 7 Hz,
OCH2CH3), 3.74–3.85 (1H, m), 3.87–3.99 (3H, m), 4.54
(1H, d, J¼7 Hz), 6.09 (1H, dd, J¼9.5, 1.5 Hz), 7.06 (1H,

7070
H. Muratake, M. Natsume / Tetrahedron 62 (2006) 7056–7070
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