Total synthesis of Amaryllidaceae alkaloids, (+)-vittatine and (+)-haemanthamine, starting from d-glucose

Article abstract of DOI:10.1016/j.tet.2007.05.041

The stereoselective total synthesis of (+)-vittatine 1 and (+)-haemanthamine 2 starting from d-glucose is described. The cyclohexene ring in 1 was prepared in an optically active form from d-glucose using Ferrier's carbocyclization reaction, and the criti

Full text of DOI:10.1016/j.tet.2007.05.041

Tetrahedron 63 (2007) 6977–6989
Total synthesis of Amaryllidaceae alkaloids, (D)-vittatine
and (D)-haemanthamine, starting from D-glucose
Masahiro Bohno,a Kazuteru Sugie,a Hidetoshi Imase,a Yusralina Binti Yusof,a
Takeshi Oishib and Noritaka Chidaa,
*
aDepartment of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi,
Kohoku-ku, Yokohama 223-8522, Japan
bSchool of Medicine, Keio University, 4-1-1 Hiyoshi, Kohoku-ku, Yokohama 223-8521, Japan
Received 5 April 2007; revised 10 May 2007; accepted 10 May 2007
Available online 17 May 2007
This paper is dedicated to the memory of the late Professor Yoshihiko Ito, who passed away on December 23, 2006
Abstract—The stereoselective total synthesis of (+)-vittatine 1 and (+)-haemanthamine 2 starting from D-glucose is described. The cyclo-
hexene ring in 1 was prepared in an optically active form from D-glucose using Ferrier’s carbocyclization reaction, and the critical quaternary
carbon was stereoselectively generated via chirality transfer by the Claisen rearrangement of cyclohexenol 6. The hexahydroindole skeleton
was effectively constructed by the intramolecular aminomercuration–demercuration of 14, followed by Chugaev reaction to provide 16.
Finally, Pictet–Spengler reaction completed the first chiral synthesis of (+)-vittatine 1. On the other hand, the a-hydroxylation of the ester
5 stereoselectively proceeded to give a-hydroxy ester 19, to which was introduced an amino function to provide 4. A similar transformation
of 4, as employed in the synthesis of vittatine, furnished (+)-haemanthamine 2.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
aminomercuration–demercuration, followed by Chugaev
reaction.
The alkaloids of the Amaryllidaceae family are composed
of over 100 structurally interesting bases and have stimu-
lated organic chemists due to their architectural diversity
as well as their biological activities.1 Among them, the
crinine-type alkaloids, which have the 5,10b-ethanophe-
nanthridine skeleton as the core structure, represented by
haemanthidine, pretazettine, and tazettine, have received
considerable attention, since they have been reported to
possess antiviral, anticancer, and other interesting activities
(Fig. 1).2 Although a number of synthetic approaches for
the crinine-type alkaloids have been developed,3,4 reports
of the chiral syntheses of these natural products are rather
limited.5 Since these alkaloids are expected to show a
wide range of biological activities, it is important to estab-
lish a chiral and effective synthetic route to these com-
pounds from readily available materials. In this paper, we
report the first chiral synthesis of (+)-vittatine6 1 and (+)-
haemanthamine7 2 starting from D-glucose,8 in which the
quaternary carbons in 1 and 2 were stereoselectively gener-
ated by Claisen rearrangement, and the hexahydroindole
skeleton was effectively constructed by intramolecular
2. Results and discussion
2.1. Retrosynthesis
Our retrosynthetic analysis of (+)-vittatine 1 suggested that
hexahydroindole 3 would be a promising intermediate for
the total synthesis (Fig. 2). The bicyclic skeleton in 3 was
expected to be constructed by the intramolecular amino-
mercuration9 of cyclohexene derivative 4, followed by
introduction of the carbon–carbon double bond, exploiting
the hydroxy group at C-1 (vittatine numbering). The pre-
cursor of 4, ester 5, was planned to be stereoselectively
prepared by Claisen rearrangement10 of cyclohexenol deriv-
ative 6. The cyclohexenol 6, in turn, was envisioned to be
synthesized from cyclohexenone 7, which is the known
compound11 prepared in optically pure form starting from
D-glucose utilizing Ferrier’s carbocyclization12 as the key
transformation.
On the other hand, if one could introduce a hydroxy group
into the a-position of an ester function (C-11, vittatine num-
bering) in 5 in a stereoselectivemanner, the resulting product,
hydroxyester would be converted into 9, which is expected
to yield haemanthamine 2 via hexahydroindole 8.
Keywords: Amaryllidaceae alkaloids; Vittatine; Haemanthamine; Claisen
rearrangement; Aminomercuration; Chugaev reaction.
* Corresponding author. Tel./fax: +81 45 566 1573; e-mail: chida@applc.
keio.ac.jp
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.05.041

6978
M. Bohno et al. / Tetrahedron 63 (2007) 6977–6989
Ph
O
O
O
O
O
8
O
O
O
3
9
7
O
BnO
MgBr
O
8 steps
(38%)
6a
10
OH
1
6
THF
–100 °C
(92%)
HO
OMe
R
2
11
11
N
12
OH
10
OTBS
3
N
5
HO
MeO
4
7
H
H
O
O
R = H: (+)-haemanthamine 2
(+)-vittatine 1
O
R = OH: haemanthidine
O
OBn
OBn
PCC
O
O
O
O
MS4Å
OH
CH2Cl2
rt
TBSO
TBSO
OH
O
TBSO
O
12
O
OH
11
O
O
N
N
MeO
MeO
O
O
Me
H
Me
H
OBn
OBn
NaBH4
CeCl3•7H2O
tazettine
pretazettine
4
1
+
6
MeOH–CH2Cl2
(1 : 1)
6
1
2
TBSO
Figure 1. Structures of some representative crinine-type alkaloids.
–78 °C
OH
13
OH
6
(68% from 11)
2.2. Preparation of the common intermediate, ester 5
(7% from 11)
8.4%
The synthesis of ester 5 commenced from the known
(4R,6S)-6-benzyloxy-4-(tert-butyldimethylsilyloxy)-2-cyclo-
hexenone11 7, prepared from commercially available methyl
4,6-O-benzylidene-a-D-glucopyranoside 10 utilizing the
catalytic Ferrier’s carbocyclization12c as the key transforma-
tion in a total of eight steps with a 38% overall yield (Scheme
1). The reaction of 7 with 3,4-(methylenedioxy)phenyl-
magnesium bromide at ꢀ100 ꢁC gave 1,2-adduct 11 as a dia-
stereomeric mixture (ca. 3:1) in a 92% yield. The oxidation
H
H
TBS
HO
7.6%
6
J
J
J
J
1,6 = 7.9 Hz
O
4
5ax,6 = 12.2 Hz
5eq,6 = 3.7 Hz
4,5ax = 9.5 Hz
:
observed
NOE
OBn
1
Ar
2
H
Heq
5
H
(enhancement %)
Hax
15 ~%
6.6%
Scheme 1.
˚
of 11 with PCC in the presence of molecular sieves, 4 A
˚
˚
(MS4A) afforded cyclohexenone 12, which was reduced
orthoacetate and MS4A in the presence of a catalytic amount
of propionic acid in a sealed tube at 130 ꢁC) successfully
afforded the rearranged product 5 in a 60% yield along
with the recovered starting material 6 (10% yield). However,
the reproducibility of the reaction was found to be rather
poor, and the yields of the rearranged product 6 sometimes
dropped to 35–50% when the reaction was carried out on
a larger scale (over 1 mmol scale). After some attempts, it
was found that the employment of 2-nitorophenol as the
acid catalyst15 produced an improvement in both the
under the conditions of Luche13 at ꢀ78 ꢁC to give cyclo-
hexenol 6 and its epimeric alcohol 13 in 68 and 7% isolated
yields from 11, respectively. The observed coupling constants
in 6 (J1,6¼7.9 Hz) and 13 (J1,6¼3.7 Hz) as well as the NOE
experiments in 6 supported their assigned configurations.
With the chiral cyclohexenol 6 in hand, the crucial Claisen
rearrangement was then investigated (Scheme 2). The con-
ventional Johnson–Claisen rearrangement10c,14 of 6 (triethyl
O
O
O
O
HO
1
2
1
1
O
O
NHBoc
N
O
TBSO
TBSO
O
Boc
H
OBn
4
3
BnO
CO Et
11
TBSO
2
O
OH
6
O
TBSO
O
O
5
OTES
HO
OTES
OBn
2
NHBoc
O
N
MeO
MeO
Boc
H
D-glucose
TBSO
9
8
7
Figure 2. Retrosynthetic analysis of (+)-vittatine 1 and (+)-haemanthamine 2. TBS¼–SiMe2(t-Bu), Boc¼–C(O)O(t-Bu), TES¼–SiEt3, and Bn¼–CH2Ph.

M. Bohno et al. / Tetrahedron 63 (2007) 6977–6989
6979
chemical yields and reproducibilities and gave 5 in a 71%
yield. The use of 2,4-dinitorophenol,16 meanwhile resulted
in the decomposition of the substrate. The observed coupling
constants and NOEs in 5 clearly supported the assigned
structure; especially the observed NOE between a methylene
group at C-2 and H-60 clearly revealed that the newly formed
quaternary carbon in 5 has an (S)-configuration.
reported for natural (+)-vittatine6b {mp 207–208 ꢁC; [a]2D5
+26 (c 0.50, CHCl3)}.
O
O
TsNHBoc
Ph3P
BnO
DIBAL-H
EtO2CN=NCO2Et
5
CH2OH
toluene
–78 °C
(97%)
THF
rt
TBSO
(98%)
O
O
14
O
O
O
O
CH3C(OEt)3
BnO
5'
6
2-nitrophenol
130 °C, 24 h
(71%)
CO2Et
6'
4'
2
BnO
Na, C10H10
HO
TBSO
THF
–40 °C
(77%)
N(Ts)Boc
5.8%
5
NHBoc
9.4%
TBSO
TBSO
15
J
5'ax,6' = 12.4 Hz
5'eq,6' = 2.7 Hz
4',5'ax = 9.0 Hz
4',5'eq = 6.3 Hz
4
H
H
H
H
O
J
J
J
5.9%
2.5%
6'
CH2PH
O
O
4'
Heq
11.3%
CO2Et
2
TBSO
5.9%
Hg(OCOCF3)2
THF, rt
NaH, CS2
then MeI
5'
H
HO
H
:
Hax
observed
then NaBH4
THF
O
NOE
aq. NaOH–H2O
N
TBSO
(enhancement %)
rt
O
Boc
H
(75%)
16
Scheme 2.
O
O
O
O
2.3. Total synthesis of (D)-vittatine
MeS
O
The reduction of the ester function in 5 with DIBAL-H
cleanly gave primary alcohol 14 in a 97% yield (Scheme
3), to which was introduced an amino functionality by
Mitsunobu amination with NH(Ts)(Boc)17 as a nucleophile
to afford 15 in a 98% yield. The treatment of 15 with
Na-naphthalene18 in THF at ꢀ40 ꢁC removed N-Ts as well
as the O-benzyl groups to give 4 in a 77% yield. The con-
struction of the perhydroindole skeleton was successfully
achieved by the intramolecular aminomercuration–demer-
curation of 4 to provide 16 in a 75% yield. Interestingly,
the presence of the Boc protecting group was essential for
the cyclization; when this reaction was carried out with
the corresponding primary amine (with no Boc group), no
cyclized product was obtained. Next, the introduction of
the requisite carbon–carbon double bond between C-1 and
C-2 was investigated. Initially, the hydroxy group in 16
was converted into the sulfonyl esters and the resulting
O-sulfonyl derivatives (OMs and OTs) were treated with
base (DBU or t-BuOK). However, under these reaction
conditions, only the decomposition of the substrates was
observed. To our delight, Chugaev reaction was found to
give good results. Thus, the hydroxy group in 16 was trans-
formed into the xanthate ester to afford 17 (97% yield), and
this was heated at 160 ꢁC in the presence of potassium
carbonate to provide 3 in an 80% yield from 16. Deprotec-
tion of the N-Boc group by the action of BF3$OEt2 gave
18 (78% yield, starting material 3 was recovered in 14%
yield). Finally, the exposure of 18 to the Pictet–Spengler
reaction conditions3b generated the ethano-bridge between
N(1) and C(60), and induced the deprotection of the O-
TBS group to furnish (+)-vittatine 1 in a 51% yield. The
1H NMR data were completely identical to those for (ꢀ)-
crinine [enantiomer of (+)-vittatine] reported by Pearson,3c
and the physical properties of 1 showed good agreement
{mp 205–207 ꢁC; [a]D22 +28 (c 0.20, CHCl3)} with those
160 °C
K2CO3
S
N
TBSO
N
TBSO
1,2-dichlorobenzene
Boc
H
O
Boc
H
(80% from 16)
3
17
O
O
O
5'
6'
BF3•OEt2
MS4Å
3
formalin
1
6
CH2Cl2
(78%)
6M aq. HCl
MeOH
7
N
N
H
HO
TBSO
H
H
50 °C
(recovered 3: 14%)
vittatine 1
18
(51%)
Scheme 3. Ts¼–SO2C6H4(p-Me).
2.4. Total synthesis of (D)-haemanthamine
Having established the new synthetic pathways to (+)-
vittatine 1 from D-glucose, we next turned our attention to
the synthesis of (+)-haemanthamine 2. For this purpose,
the introduction of a hydroxy function at C-2 (C-11 in
vittatine numbering) of the ester 5 was first investigated.
The selected results of the hydroxylation of an enolate de-
rived from 5 with various oxidants19 are listed in Table 1,
which showed that (i) the generation of the ester enolates
required a higher (0 ꢁC) temperature, and LiHMDS was
the base of choice (entries 1–4), (ii) reaction of the lithium
enolate with the (+)-Davis reagent19b at 0 ꢁC gave good re-
sults and provided the desired 19 in moderate yield (entry
6), and (iii) regardless of types of oxidants, (R)-alcohol 19
was obtained as the major product (entries 6, 8, and 9). As
a result, the desired product 19 was obtained in a 68% yield
based on the recovered starting material, under the condi-
tions noted in entry 6. Although the configuration at C-20
could not be determined at this stage, the successful

6980
M. Bohno et al. / Tetrahedron 63 (2007) 6977–6989
Table 1. Hydroxylation of the enolate of 5a
The reduction of the major hydroxy ester 19 with LiBH4 in
the presence of B(OMe)320 gave diol 21 (90% yield, Scheme
5), whose primary hydroxy group was selectively tosylated
to afford 22 in an 88% yield. The treatment of 22 with
Bu4NF deprotected O-TBS group as well as induced the
intramolecular SN2 reaction to provide epoxide 23 in a
93% yield (82% from 21). The minor diastereomer 20 could
also be converted into 23. Reduction of the ester function in
20 and subsequent selective acylation with benzoyl chloride
gave benzoate 25 (86% yield from 20). The remaining alco-
hol function in 25 was mesylated to afford 26, whose treat-
ment with Bu4NF, followed by treatment with MeONa
cleanly afforded epoxide 23 in a 76% yield from 25.
Entry Base
Temp 1 Oxidant Temp 2
(ꢁC)
Yieldb (%)
(ꢁC)
19
20
5
1
2
3
4
5
6
7
8
9
LiHMDS ꢀ78
(+)-DRc ꢀ78
0
16d
11d
7d
0
95
67
65
84
66
44
54
52
0
LiHMDS
NaHMDS
KHMDS
LiHMDS
LiHMDS
NaHMDS
LiHMDS
LiHMDS
0
0
0
0
0
0
0
0
(+)-DR
(+)-DR
(+)-DR
(+)-DR
(+)-DR
(+)-DR
(ꢀ)-DRe
ꢀ78
ꢀ78
ꢀ78
ꢀ40
0
15
38
12
27
38
2
4
7
5
9
0
0
0
f
O2
a
Reaction conditions: compound 5 (1.0 equiv) in THF was treated with
base (3.0 equiv) at the temperature shown in Temp 1 for 45 min. To this
solution was added a solution of oxidant (1.5 equiv) in THF dropwise at
the temperature shown in Temp 2, and the mixture was stirred at Temp
2 for 45 min.
O
O
O
O
b
c
d
LiBH4
Isolated yield after chromatographic purification.
(MeO)3B
Bu4NF
(+)-Davis reagent: [(1S)-(10-camphorsulfonyl)oxaziridine].
Combined yields of 19 and 20. Compound 19 was the major product but
the ratio of 19 to 20 was not determined.
(ꢀ)-Davis reagent: [(1R)-(10-camphorsulfonyl)oxaziridine].
O2 gas (excess amount) was introduced to the reaction mixture containing
P(OEt)3 (2.0 equiv).
BnO
BnO
19
OH
OR
THF
0 °C
THF
O
(93%)
e
f
(90%)
TBSO
HO
TsCl, Et3N
21 R = H
22 R = Ts
23
CH2Cl2
0 °C
Bu4NF, THF
then
(88%)
(98%)
conversion of 19 into haemanthamine 2 (vide infra) un-
ambiguously confirmed the (R)-configuration of the newly
formed hydroxy group in 19. The stereoselective forma-
tion of (R)-alcohol 19 might be accounted for by the steric
factor.
MeONa, MeOH
O
O
O
O
LiBH4
MsCl
(MeO)3B
BnO
DMAP
BnO
20
OH
OR
OMs
THF
0 °C
pyridine
(78%)
In the two plausible transition structures (5a and 5b,
Scheme 4) where three of four substituents on a cyclohexene
ring are in the equatorial positions, electrophilic attack of
the oxidant would occur from the upper face (foreside) of
the enolate to give 19 via 5a and 20 via 5b, since the lower
side (backside) of the enolate is hindered by the benzyloxy
group at C-6. In 5b, there would be non-bonded interactions
between an axial hydrogen at C-6 and the enolate oxygen
attached to C-10. Due to the sterically disfavored interactions
in 5b, the transition structure 5a would become more favored
one, thus affording 19 as the major product.
(99%)
TBSO
TBSO
BzO
26
BzCl
24 R = H
pyridine
0 °C
25 R = Bz
(87%)
Scheme 5. Bz¼–COPh and Ms¼–SO2Me.
With the epoxide 23 possessing the proper functionalities
and stereochemistry in hand, the final transformation to 2
was explored. The hydroxy group in 23 was methylated to
give 27 (92% yield, Scheme 6), which was reacted with so-
dium azide to afford primary azide 28 in a 79% yield. Selec-
tive hydrogenolysis of the azide function in 28 with the
Lindler catalyst in the presence of Boc2O21 provided carba-
mate 29, whose O-benzyl group was removed by the treat-
ment with sodium-naphthalene to give 9 in an 80% yield
from 28. The intramolecular aminomercuration–demercura-
tion of 9 successfully afforded perhydroindole 30 in a 53%
yield. The hydroxy group at C-4 in 30 was anticipated to
show a lower reactivity than that at C-3 due to the steric con-
gestion. Indeed, the reaction of 30 with TESCl afforded 3-O-
TES derivative 31 in a 67% isolated yield. To introduce the
carbon–carbon double bond between the C-4 and C-5,
Chugaev reaction was attempted. Thus, the same reaction
sequence as employed for the synthesis of vittatine (xanthate
ester formation followed by pyrolysis) was applied to 31
to give, after treatment with Boc2O and K2CO3, hexahy-
droindole 33 in a 66% yield from 31. During the pyrolysis
of 32, unexpected deprotection of the N-Boc group, which
has not been observed in Chugaev reaction of 17, took place.
Protection of a secondary amine group with the Boc group
was required for the purification of 33, since it was difficult
O
O
O
O
LiHMDS, THF
0 °C
BnO
BnO
5
OH
OH
R
S
+
then
2'
2'
(+)-Davis reagent
THF, 0 °C
CO2Et
1'
CO2Et
1'
TBSO
19
20
(4%)
(38%)
(recovered 5: 44%)
Et
O
OLi
1'
C
H
H
H
6
6
CH2Ph
H
CH2Ph
H
H
O
O
"O"
OLi
>
2'
C
2'
1
4
TBSO
4
1'
TBSO
"O"
OEt
O
O
5a
5b
20
O
O
19
Scheme 4.

M. Bohno et al. / Tetrahedron 63 (2007) 6977–6989
6981
to isolate the amine in pure form from the polar by-products.
Finally, Pictet–Spengler reaction of 33 cleanly provided (+)-
quaternary carbons, and aminomercuration–demercuration
followed by Chugaev reaction is a useful reaction sequence
for the construction of hexahydroindole skeletons, that are
frequently found in Amaryllidaceae alkaloids.
1
haemanthamine 2 in a quantitative yield. The H and 13C
NMR data of the synthetic 2 were fully identical to those
of natural (+)-haemanthamine, that had been kindly pro-
vided by Professor Takayama, and the physical properties
of 2 {mp 199–202 ꢁC; [a]D25 +41 (c 0.62, CHCl3)} showed
good agreement with those of natural (+)-haemanthamine
{mp 200–202 ꢁC; [a]D24 +42 (c 0.34, CHCl3)}.22
4. Experimental
4.1. General
Melting points were determined on a Mitamura–Riken
micro hot stage and were not corrected. Optical rotations
were recorded using a sodium lamp (589 nm) with a JASCO
DIP-370 instrument with 1-dm tube and values of [a]D are
recorded in units of 10ꢀ1 deg cm2 gꢀ1. Infrared (IR) spectra
O
O
O
O
NaN3
MeI
BnO
BnO
NH4Cl
NaH
OH
23
MeOH
50 °C
(79%)
O
THF
1
(92%)
were measured with a JASCO FT/IR-200 spectrometer. H
MeO
MeO
N3
NMR spectra were recorded at 300 MHz on a JEOL Lambda
300 or on a Varian MVX-300 spectrometers for solutions in
CDCl3, unless otherwise noted. Chemical shifts are reported
as d values in parts per million. Abbreviations used are:
br (broad peak), s (singlet), d (doublet), t (triplet), q (quartet),
and m (complex multiplet). 13C NMR spectra were recorded
at 75 MHz on a JEOL Lambda 300 spectrometer for solu-
tions in CDCl3, unless otherwise noted. Chemical shifts
are reported as d values in parts per milion. Mass spectra
are measured by a JEOL GC Mate spectrometer with
EI (70 eV) or FAB mode. Organic extracts were dried over
solid anhydrous Na2SO4 and concentrated below 40 ꢁC
under reduced pressure. Column chromatography was car-
ried out with silica gel (Merck Kieselgel 60 F254, 230–400
mesh) for purification. Preparative TLC (PLC) was per-
formed with Merck PLC plate (Kieselgel 60 F254, 0.5 mm
thickness).
27
28
O
O
O
O
Hg(OCOCF3)2
THF, rt
RO
H2, (Boc)2O
Lindler cat.
OH
HO
OH
then NaBH4
aq. NaOH–H2O
rt
EtOAc
4
3
(99%)
MeO
NHBoc
N
MeO
Boc
(53%)
H
Na, C10H10
29 R = Bn
9 R = H
30
THF
–30 °C
(81%)
O
O
TESCl
NaH, CS2
then MeI
HO
OTES
Et3N, DMAP
THF
CH2Cl2
(67%)
(98%)
N
MeO
Boc
H
31
4.1.1. Total synthesis of (D)-vittatine.
4.1.1.1. (1S,4R,6S)-1-(Benzo[1,3]dioxol-5-yl)-6-benzyl-
oxy-4-(tert-butyldimethylsilyloxy)-2-cyclohexen-1-ol and
its (1R)-isomer (11). To a solution of (4R,6S)-6-benzyl-
O
O
O
O
160 °C
K2CO3
711
1)
oxy-4-(tert-butyldimethylsilyloxy)-2-cyclohexenone
OTES
MeS
O
OTES
1,2-dichlorobenzene
(6.53 g, 19.6 mmol) in THF (320 mL) was slowly added
0.328 mol Lꢀ1 solution of 3,4-(methylenedioxy)phenyl-
magnesium bromide in THF (177 mL, 58.1 mmol) at
ꢀ100 ꢁC under Ar. After being stirred at ꢀ100 ꢁC for 1 h,
the reaction was quenched by the addition of saturated
aqueous NH4Cl solution at ꢀ100 ꢁC. The mixture was di-
luted with EtOAc and washed successively with saturated
aqueous NaHCO3 solution and brine, and then dried.
Removal of the solvent gave a residue, which was purified
by column chromatography (silica gel, 200 g, EtOAc/
hexanes¼1/7 as eluent) to afford first, minor isomer of 11
(2.03 g, 23%) as a colorless syrup: [a]2D3 ꢀ75 (c 0.81,
4
5
S
2)
(Boc)2O
K2CO3
N
N
MeO
MeO
Boc
H
32
Boc
H
MeOH
(66%)
33
O
O
OH
N
formalin
6M aq. HCl
MeOH
MeO
H
50 °C
(100%)
(+)-haemanthamine 2
1
CHCl3); IR (neat) 3530 cmꢀ1; H NMR d 0.12 (6H, s),
Scheme 6.
0.93 (9H, s), 1.94–2.15 (2H, m), 3.29 (1H, s), 3.58 (1H,
dd, J¼3.4 and 11.0 Hz), 4.28 (1H, d, J¼11.7 Hz), 4.36
(1H, m), 4.44 (1H, d, J¼11.7 Hz), 5.64 (1H, dd, J¼10.0
and 2.0 Hz), 5.87 (1H, br d, J¼10.0 Hz), 5.97 (2H, s), 6.78
(1H, dd, J¼0.7 and 7.6 Hz), 6.88 (1H, dd, J¼2.0 and
7.6 Hz), 6.90 (1H, s), and 7.09–7.30 (5H, m); 13C NMR
(75 MHz) d ꢀ4.65, ꢀ4.56, 18.2, 25.8, 33.8, 67.1, 71.8,
78.0, 79.3, 101.0, 106.7, 107.7, 119.0, 127.7, 127.8, 128.2,
131.0, 134.2, 137.7, 139.7, 146.5, and 147.5; HRMS
(FAB) m/z calcd for C26H35O5Si (M+H)+ 455.2254, found
455.2242.
3. Conclusion
In this study, a new synthesis route to (+)-vittatine and (+)-
haemanthamine starting from D-glucose was established.
This synthesis demonstrated that the methodology involving
Claisen rearrangement on the chiral cyclohexenol derived
from D-glucose by way of the catalytic Ferrier0s carbocycli-
zation is effective for the stereoselective generation of

6982
M. Bohno et al. / Tetrahedron 63 (2007) 6977–6989
Further elution gave a major isomer of 11 as a colorless
syrup (6.10 g, 68%): [a]D23 +144 (c 0.23, CHCl3); IR (neat)
6.1, and 12.2 Hz), 3.64 (1H, ddd, J¼3.7, 7.9, and 12.2 Hz),
4.28 (1H, m), 4.42 (2H, s), 4.70 (1H, m), 5.84 (1H, br dd,
J¼1.7 and 1.7 Hz), 5.96 (2H, s), 6.74–6.86 (3H, m), 7.10–
7.16 (2H, m), and 7.20–7.30 (3H, m); 13C NMR d ꢀ4.6,
ꢀ4.4, 18.1, 25.8, 36.3, 69.1, 73.3, 73.9, 74.2, 100.9, 107.4,
107.9, 120.4, 127.6, 128.0, 128.2, 128.5, 132.8, 137.9,
140.0, 146.9, and 147.4; HRMS (FAB) m/z calcd for
C26H35O5Si (M+H)+, 455.2254, found 455.2259; HRMS
(EI) m/z calcd for C26H34O5Si, M+, 454.2176, found
454.2177.
1
3430 cmꢀ1; H NMR (300 MHz) d 0.00 and 0.02 (each
3H, 2s), 0.82 (9H, s), 1.51 (1H, ddd, J¼9.5, 12.7, and
12.9 Hz), 2.00 (1H, m), 2.11 (1H, br s), 3.57 (1H, dd,
J¼3.2 and 12.9 Hz), 4.31 (1H, m), 4.68 (2H, s), 5.44 (1H,
dd, J¼1.7 and 10.0 Hz), 5.73 (1H, d, J¼10.0 Hz), 5.88
(2H, s), 6.72 (1H, d, J¼8.3 Hz), 6.93 (1H, dd, J¼1.7 and
8.3 Hz), 7.06 (1H, d, J¼1.7 Hz), and 7.18–7.28 (5H, m);
13C NMR d ꢀ4.65, ꢀ4.56, 18.1, 25.8, 36.0, 68.0, 72.4,
78.0, 80.2, 101.0, 107.2, 109.0, 121.7, 127.52, 127.55,
128.4, 131.6, 132.7, 134.9, 138.7, 146.9, and 147.2;
HRMS (FAB) m/z calcd for C26H35O5Si (M+H)+,
455.2254, found 455.2269. Anal. Calcd for C26H34O5Si:
C, 68.69; H, 7.54. Found: C, 68.47; H, 7.42.
Further elution gave 13 (0.17 g, 7% yield from 11) as a color-
less syrup: [a]1D9 ꢀ42 (c 0.35, CHCl3); IR (neat) 3460–3550,
1
1505 cmꢀ1; H NMR d 0.13 and 0.14 (each 3H, 2s), 0.93
(9H, s), 2.08 (1H, m), 2.25 (1H, ddd, J¼9.8, 11.9, and
11.9 Hz), 2.72 (1H, br d, J¼1.2 Hz), 3.82 (1H, ddd, J¼3.7,
3.7, and 11.9 Hz), 4.14 (1H, m), 4.33 and 4.42 (each 1H,
2d, J¼11.3 Hz), 4.63 (1H, ddd, J¼1.7, 6.1, and 9.8 Hz),
5.96 (2H, s), 6.05 (1H, dd, J¼1.7 and 5.9 Hz), 6.77 (1H, d,
J¼8.5 Hz), 6.87–6.91 (2H, m), 7.05–7.09 (2H, m), and
7.20–7.30 (3H, m); 13C NMR d ꢀ4.8, ꢀ4.5, 18.1, 25.8,
30.8, 66.3, 68.3, 68.6, 73.1, 101.0, 107.8, 108.0, 120.7,
125.7, 127.5, 127.9, 128.2, 133.0, 138.1, 144.2, 147.1, and
147.4; HRMS (EI) m/z calcd for C26H34O5Si, M+,
454.2176, found 454.2178.
4.1.1.2. (4S,6R)-3-(Benzo[1,3]dioxol-5-yl)-4-benzyl-
oxy-6-(tert-butyldimethylsilyloxy)-2-cyclohexen-1-one
(12). To a solution of the major isomer of 11 (1.93 g,
4.24 mmol) in CH2Cl2 (150 mL) were added pyridinium
˚
chlorochromate (3.57 g, 16.5 mmol) and MS4A (7.5 g),
and the reaction mixture was stirred at room temperature
for 30 min. Removal of the solvent gave a residue, which
was suspended in Et2O and the insoluble material was
removed by filtration through a pad of Celite. The filtrate
was concentrated to give crude ketone 12 (1.93 g), which
was used for next reaction without further purification.
The similar treatment of the minor isomer of 11 (0.63 g,
1.39 mmol) also afforded crude 12 (0.62 g). A small amount
of 12 was purified by column chromatography (silica gel,
EtOAc/hexanes¼1/7 as eluent) and used as an analytical
sample: mp 131.5–132.5 ꢁC; [a]D24 ꢀ142 (c 0.78, CHCl3);
4.1.1.4. [(1S,4R,6S)-1-(Benzo[1,3]dioxol-5-yl)-6-ben-
zyloxy-4-(tert-butyldimethylsilyloxy)-2-cyclohexen-1-yl]-
acetic acid ethyl ester (5). To a solution of 6 (350 mg,
0.768 mmol) in triethyl orthoacetate (48 mL) were added
˚
2-nitorophenol (90.8 mg, 0.656 mmol) and MS4A
(150 mg) under Ar at room temperature. The mixture was
stirred at 130 ꢁC for 24 h in a sealed tube. The reaction mix-
ture was filtrated through a pad of Celite and the filtrate was
washed successively with saturated aqueous NaHCO3 solu-
tion and brine, and then dried. Removal of the solvent gave
a residue, which was purified by column chromatography
(silica gel, 20 g, toluene/hexanes¼1/1 as eluent) to afford
5 (289.6 mg, 71%) as a colorless syrup: [a]2D2 ꢀ45 (c 0.89,
IR (neat) 1680, 1595 cmꢀ1 1H NMR d 0.08 and 0.19
;
(each 3H, 2s), 0.92 (9H, s), 2.29 (1H, ddd, J¼10.2, 13.2,
and 13.2 Hz), 2.71 (1H, ddd, J¼5.1, 5.1, and 13.2 Hz),
4.25 (1H, dd, J¼5.1 and 13.2 Hz), 4.45 (1H, d,
J¼11.2 Hz), 4.49 (1H, d, J¼11.2 Hz), 4.91 (1H, br dd,
J¼5.1 and 10.2 Hz), 5.98 (2H, s), 6.15 (1H, br s), 6.79
(1H, d, J¼8.0 Hz), 6.88 (1H, s), 6.94 (1H, d, J¼8.0 Hz),
7.13 (2H, m), and 7.23–7.29 (3H, m); 13C NMR d ꢀ5.41,
ꢀ4.38, 18.5, 25.8, 38.1, 69.5, 72.5, 72.9, 101.4, 107.7,
108.2, 121.7, 125.5, 127.9, 128.1, 128.4, 130.3, 137.1,
147.8, 148.8, 160.1, and 197.6; HRMS (FAB) m/z calcd
for C26H33O5Si (M+H)+, 453.2097, found 453.2091. Anal.
Calcd for C26H32O5Si: C, 68.99; H, 7.13. Found: C, 68.77;
H, 7.10.
1
CHCl3); IR (neat) 1730 cmꢀ1; H NMR d ꢀ0.03 and 0.00
(each 3H, 2s), 0.81 (9H, s), 1.06 (3H, t, J¼7.0 Hz), 1.34
(1H, ddd, J¼9.0, 12.4, and 12.4 Hz), 1.92 (1H, ddd,
J¼2.7, 6.3, and 12.4 Hz), 2.74 and 2.81 (each 1H, 2d,
J¼14.4 Hz), 3.64 (1H, dd, J¼2.7 and 12.4 Hz), 3.91 (2H,
q, J¼7.0 Hz), 4.25 (1H, dd, J¼6.3 and 9.0 Hz), 4.42 and
4.60 (each 1H, 2d, J¼11.7 Hz), 5.63 and 5.78 (each 1H,
2d, J¼10.2 Hz), 5.83 (2H, s), 6.66 (1H, d, J¼8.0 Hz), 6.84
(1H, dd, J¼1.7 and 8.0 Hz), 6.94 (1H, d, J¼1.7 Hz), and
7.15–7.30 (5H, m); 13C NMR d ꢀ4.62, ꢀ4.56, 14.1, 18.1,
25.8, 33.1, 42.1, 47.4, 60.0, 68.4, 71.3, 77.5, 100.8, 107.0,
110.3, 123.2, 127.5, 127.6, 128.3, 131.1, 132.8, 134.2,
138.6, 146.1, 146.9, and 171.2; HRMS (FAB) m/z calcd
for C30H41O6Si (M+H)+, 525.2672, found 525.2672. Anal.
Calcd for C30H40O6Si: C, 68.67; H, 7.68. Found: C, 68.63;
H, 7.82.
4.1.1.3. (1R,4S,6R)-3-(Benzo[1,3]dioxol-5-yl)-4-benzyl-
oxy-6-(tert-butyldimethylsilyloxy)-2-cyclohexen-1-ol (6)
and its (1S)-isomer (13). To a mixture of crude ketone 12
(2.55 g, 5.63 mmol) in MeOH (50 mL) and CH2Cl2
(75 mL) were added CeCl3$7H2O (3.07 g, 8.24 mmol) and
NaBH4 (218 mg, 5.76 mmol) at ꢀ78 ꢁC, and the mixture
was stirred at ꢀ78 ꢁC for 30 min. The reaction mixture
was diluted with H2O and products were extracted with
EtOAc. The organic layer was washed with brine, and then
dried. Removal of the solvent gave a residue, which was
purified by column chromatography (silica gel, 120 g,
EtOAc/hexanes¼1/10 as eluent) to afford 6 (1.87 g, 68%
overall yield from 11) as a colorless syrup: [a]1D9 ꢀ65
4.1.1.5. 2-[(1S,4R,6S)-1-(Benzo[1,3]dioxol-5-yl)-6-benz-
yloxy-4-(tert-butyldimethylsilyloxy)-2-cyclohexen-1-yl]-
ethanol (14). To a solution of 5 (578 mg, 1.10 mmol) in
toluene (29 mL) was added diisobutylaluminum hydride
(1.0 mol Lꢀ1 solution in toluene, 2.40 mL, 2.40 mmol) at
0 ꢁC, and the mixture was stirred at 0 ꢁC for 40 min. The
mixture was quenched by the addition of H2O and extracted
1
(c 0.67, CHCl3); IR (neat) 3440, 1505 cmꢀ1; H NMR d
0.14 (6H, s), 0.94 (9H, s), 1.89 (1H, ddd, J¼9.5, 12.2, and
12.2 Hz), 2.29 (1H, br d, J¼3.4 Hz), 2.39 (1H, ddd, J¼3.7,

M. Bohno et al. / Tetrahedron 63 (2007) 6977–6989
6983
with EtOAc. The organic layer was washed successively
with saturated aqueous NaHCO3 solution and brine, and
then dried. Removal of the solvent gave a residue, which
was purified by column chromatography (silica gel, 15 g,
EtOAc/hexanes¼1/6 as eluent) to afford 14 (515 mg, 97%)
as a colorless syrup: [a]2D2 ꢀ23 (c 0.82, CHCl3); IR (neat)
as eluent) to afford 4 (10.3 mg, 77%) as a colorless syrup:
[a]2D2 ꢀ23 (c 0.82, CHCl3); IR (neat) 3400, 1695, 1505,
1
1490 cmꢀ1; H NMR d 0.07 and 0.09 (each 3H, 2s), 0.88
(9H, s), 1.42 (9H, s), 1.58 (1H, ddd, J¼7.8, 10.5, and
12.4 Hz), 1.9–2.2 (2H, m), 2.10 (1H, m), 2.96 (1H, m),
3.08 (1H, m), 3.72 (1H, m), 4.36 (1H, m), 4.48 (1H, br s),
5.74 (1H, d, J¼10.2 Hz), 5.88 (1H, dd, J¼2.7 and
10.2 Hz), 5.94 (2H, d, J¼1.7 Hz), 6.79 (1H, d, J¼8.3 Hz),
6.86 (1H, dd, J¼1.4 and 8.3 Hz), and 6.93 (1H, d,
J¼1.4 Hz); 13C NMR d ꢀ4.72, 18.1, 22.6, 25.8, 28.4, 36.6
(2C), 38.0, 48.0, 67.0, 71.4, 79.2, 101.0, 107.8, 109.4,
122.3, 131.1, 132.1, 134.2, 146.3, 147.7, 155.8, and 158.9;
HRMS (FAB) m/z calcd for C26H42NO6Si (M+H)+,
492.2781, found 492.2780. Anal. Calcd for C26H41NO6Si:
C, 63.51; H, 8.40. Found: C, 63.43; H, 8.44.
1
3375 cmꢀ1; H NMR d ꢀ0.03 and ꢀ0.01 (each 3H, 2s),
0.80 (9H, s), 1.31 (1H, dd, J¼12.5 and 12.5 Hz), 1.92 (2H,
m), 2.10 (1H, ddd, J¼6.1, 8.0, and 14.0 Hz), 3.30–3.44
(3H, m), 4.22 (1H, m), 4.33 and 4.59 (each 1H, d,
J¼11.9 Hz), 5.51 (1H, dd, J¼1.5 and 10.0 Hz), 5.70 (1H,
d, J¼10.0 Hz), 5.84 (2H, s), 6.65 (1H, d, J¼7.5 Hz), 6.88
(1H, dd, J¼1.5 and 7.5 Hz), 6.96 (1H, d, J¼1.5 Hz), 7.15–
7.30 (5H, m); 13C NMR d ꢀ4.57, ꢀ4.48, 18.2, 25.9, 33.0,
40.6, 47.6, 59.6, 68.6, 71.1, 77.9, 100.8, 107.0, 110.5,
123.4, 127.6, 127.9, 128.4, 131.7, 132.7, 134.9, 138.6,
146.1, and 147.0; HRMS (FAB) m/z calcd for C28H39O5Si
(M+H)+, 483.2567, found 483.2568.
4.1.1.8. tert-Butyl (3aR,4S,6S,7aS)-3a-(benzo[1,3]di-
oxol-5-yl)-6-(tert-butyldimethylsilyloxy)-4-hydroxyocta-
hydroindole-1-carboxylate (16). A solution of 4 (295 mg,
0.601 mmol) in THF (20 mL) was degassed by freeze–
pump–thaw (FPT) cycles, which was added to a solution
of Hg(OCOCF3)2 (462 mg, 1.08 mmol) in THF (10 mL, de-
gassed by FPT cycles) via a cannula at room temperature.
After being stirred at room temperature for 22 h, to the mix-
ture was added a solution of NaBH4 (45 mg, 1.20 mmol) and
NaOH (48 mg, 1.20 mmol) in MeOH (2.4 mL, degassed by
FPT cycles) at room temperature, and the resulting mixture
was stirred for 10 min at room temperature. The insoluble
material was removed by filtration through a pad of Celite.
The filtrate was concentrated to give a residue, which was
purified by column chromatography (silica gel, 20 g,
EtOAc/hexanes¼1/5 as eluent) to afford 16 (221 mg, 75%)
as a colorless syrup: [a]D20 ꢀ17.5 (c 0.98, CHCl3); IR (neat)
4.1.1.6. tert-Butyl 2-[(1S,4R,6S)-1-(benzo[1,3]dioxol-5-
yl)-6-benzyloxy-4-(tert-butyldimethylsilyloxy)-2-cyclo-
hexen-1-yl]ethyl-(4-toluenesulfonyl)carbamate (15). To
a solution of 14 (806 mg, 1.67 mmol) in THF (20 mL) under
Ar were added N-(tert-butoxycarbonyl)-p-toluenesulfon-
amide (681 mg, 2.5 mmol), diethyl azodicarboxylate
(527 mg, 3.35 mmol), and triphenyl phosphine (1.32 g,
5.02 mmol) at room temperature. After being stirred for
1 h at room temperature, the reaction mixture was diluted
with EtOAc and washed successively with saturated aqueous
NaHCO3 solution and brine, and then dried. Removal of the
solvent gave a residue, which was purified by column chro-
matography (silica gel, 40 g, EtOAc/hexanes¼1/7 as eluent)
to afford 15 (1.21 g, 98%) as a colorless syrup: [a]2D4 ꢀ27 (c
1
1
0.85, CHCl3); IR (neat) 1730, 1600 cmꢀ1; H NMR d 0.08
3490, 1695, 1410 cmꢀ1; H NMR (CDCl3, 300 MHz, at
and 0.10 (each 3H, 2s), 0.91 (9H, s), 1.34 (9H, s), 1.44
(1H, ddd, J¼9.3, 12.2, and 12.2 Hz), 2.03 (1H, ddd,
J¼2.0, 6.1, and 12.2 Hz), 2.19 (1H, ddd, J¼4.2, 11.9, and
11.9 Hz), 2.41 (3H, s), 2.55 (1H, ddd, J¼6.8, 11.9, and
11.9 Hz), 3.53 (1H, dd, J¼2.0 and 12.2 Hz), 3.64–3.86
(2H, m), 4.35 (1H, dd, J¼6.1 and 9.3 Hz), 4.58 and 4.71
(each 1H, 2d, J¼11.7 Hz), 5.75 and 5.88 (each 1H, 2d,
J¼10.5 Hz), 5.92 (2H, d, J¼2.1 Hz), 6.76 and 6.98 (each
1H, 2d, J¼8.31 Hz), 7.12 (1H, s), 7.23–7.40 (7H, m), and
7.74 (2H, d, J¼8.3 Hz); 13C NMR d ꢀ4.66, ꢀ4.57, 18.1,
25.8, 27.8, 33.1, 37.3, 43.5, 47.5, 68.5, 71.4, 78.1, 84.0,
100.7, 106.9, 110.6, 123.5, 127.3, 127.6, 127.7, 128.2,
129.1, 130.7, 133.0, 134.0, 137.3, 138.5, 143.9, 146.1,
147.0, and 150.7; HRMS (FAB) m/z calcd for
C40H54NO8SSi (M+H)+, 735.3261, found 735.3269.
50 ꢁC) d 0.12 and 0.16 (each 3H, 2s), 0.90 (9H, s), 1.40–
1.60 (1H, m), 1.52 (9H, s), 1.90–2.02 (2H, m), 2.05–2.22
(2H, m), 2.28–2.46 (1H, br s), 2.99 (1H, m), 3.29 (1H, m),
3.76 (1H, br d, J¼9.5 Hz), 4.18 (1H, br d, J¼9.5 Hz), 4.27
(1H, br s), 4.67 (1H, m), 5.92 (2H, d, J¼3.03 Hz), and
13
6.73–6.85 (3H, m); C NMR (CDCl3, 75 MHz, at 50 ꢁC)
d ꢀ5.3, ꢀ4.8, 18.0, 25.7, 28.7, 33.9 (br), 34.5, 35.9, 43.0
(br), 53.2, 54.0, 68.7, 72.1, 79.3, 100.9, 107.2, 108.0,
119.3, 138.0, 145.8, 147.9, 154.1, and 160.1; HRMS
(FAB) m/z calcd for C26H42NO6Si (M+H)+, 492.2781, found
492.2777.
4.1.1.9. tert-Butyl (3aR,4S,6S,7aS)-3a-(benzo[1,3]-
dioxol-5-yl)-6-(tert-butyldimethylsilyloxy)-2,3,3a,6,7,7a-
hexahydro-1H-indole-1-carboxylate (3). To a solution of
16 (210 mg, 0.427 mmol) in THF (9.5 mL) were added
sodium hydride (60% in oil, 51.2 mg, 1.28 mmol) and imi-
dazole (2.9 mg, 0.04 mmol) at 0 ꢁC. After being stirred at
0 ꢁC for 30 min, to the mixture were added carbon disulfide
(0.194 mL, 3.20 mmol) and methyl iodide (0.053 mL,
0.854 mmol) at 0 ꢁC and the resulting mixture was stirred
at room temperature for 2 h. The mixture was diluted with
EtOAc, washed with brine, and then dried. Removal of the
solvent gave a residue, which was purified by column chro-
matography (silica gel, 18 g, EtOAc/hexanes¼1/5 as eluent)
to afford xanthate ester 17 (241 mg, 97%) as a colorless
4.1.1.7. tert-Butyl 2-[(1S,4R,6S)-1-(benzo[1,3]dioxol-
5-yl)-4-(tert-butyldimethylsilyloxy)-6-hydroxy-2-cyclo-
hexen-1-yl]ethylcarbamate (4). A mixture of Na (37.5 mg,
1.63 mmol) and naphthalene (209 mg, 1.63 mmol) in THF
(1.5 mL) was sonicated with ultrasound at room temperature
for 15 min and the resulting suspension was cooled to
ꢀ40 ꢁC. To this suspension was added a solution of 15
(20.0 mg, 0.027 mmol) in THF (3.5 mL) at ꢀ40 ꢁC via a can-
nula. The reaction mixture was stirred at ꢀ40 ꢁC for 1.5 h,
and then quenched with H2O. The mixture was diluted
with EtOAc, washed successively with brine, and then dried.
Removal of the solvent gave a residue, which was purified by
column chromatography (silica gel, 5 g, EtOAc/hexanes¼1/4
syrup: IR (neat) 1695, 1590 cmꢀ1 1H NMR (CDCl3,
;
300 MHz, at 45 ꢁC) d 0.50 and 0.84 (each 3H, 2s), 0.89
(9H, s), 1.46–1.55 (1H, m), 1.49 (9H, s), 1.93–2.31 (5H,

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M. Bohno et al. / Tetrahedron 63 (2007) 6977–6989
m), 2.29 (3H, s), 3.25–3.45 (2H, m), 4.05 (1H, m), 4.50 (1H,
dd, J¼5.9 and 5.9 Hz), 5.93 (2H, s), 6.03 (1H, dd, J¼5.6 and
5.6 Hz), 6.75 (1H, d, J¼8.3 Hz), 6.83 (1H, d, J¼8.3 Hz), and
(37 wt % solution in water, 0.9 mL). After being stirred at
room temperature for 5 min, 6 mol Lꢀ1 aqueous HCl
(1.9 mL) was added to the mixture. The resulting mixture
was stirred at 50 ꢁC for 15 h, and then made basic with solid
potassium carbonate. The products were extracted with
CHCl3 and the organic layer was washed successively with
saturated aqueous NaHCO3 solution and brine, and then
dried. Removal of the solvent gave a residue, which was pu-
rified by column chromatography (silica gel, 2 g, MeOH/
CHCl3¼1/5 as eluent) to give (+)-vittatine (27.3 mg, 51%)
as a colorless solid: mp 205–207 ꢁC (lit.6b 207–208 ꢁC);
[a]2D2 +28 (c 0.46, CHCl3) [lit.6b [a]D25 +26 (c 0.5, CHCl3)];
13
6.86 (1H, s); C NMR (CDCl3, 75 MHz, at 45 ꢁC) d ꢀ4.9
(2C), 18.18, 18.24, 25.9, 28.6, 34.1, 34.3, 35.9, 43.6, 52.0,
57.7 (br), 65.7, 79.7, 81.2, 101.0, 107.8, 108.1, 120.4,
135.4, 146.2, 147.7, 154.5, and 214.9; HRMS (FAB) m/z
calcd for C28H44NO6S2Si (M+H)+, 582.2379, found
582.2372.
To a solution of the xanthate ester 17 (241 mg) in 1,2-dichlo-
robenzene (15.5 mL) was added potassium carbonate
(85.8 mg, 0.414 mmol), and the mixture was stirred at
160 ꢁC for 16 h under Ar. After cooling, the reaction mixture
was diluted with EtOAc, washed successively with saturated
aqueous NaHCO3 solution and brine, and then dried.
Removal of the solvent gave a residue, which was purified
by column chromatography (silica gel, 7 g, EtOAc/
hexanes¼1/7 as eluent) to afford 3 (160 mg, 82%) as a color-
less syrup: [a]2D2 +99 (c 0.69, CHCl3); IR (neat) 1695,
IR (neat) 3300, 2900, 1485, 1235, 1040, 935, 750 cmꢀ1
;
1H NMR d 1.75 (1H, ddd, J¼3.9, 13.6, and 13.6 Hz), 1.94
(1H, ddd, J¼6.1, 10.7, and 12.3 Hz), 2.06 (1H, br d,
J¼13.6 Hz), 2.20 (1H, ddd, J¼4.4, 9.0, and 12.3 Hz), 2.93
(1H, ddd, J¼6.1, 9.0, and 13.2 Hz), 3.35–3.50 (2H, m),
3.81 (1H, d, J¼16.6 Hz), 4.36 (1H, m), 4.44 (1H, d,
J¼16.6 Hz), 5.89 and 5.91 (each 1H, 2br s), 5.97 (1H, dd,
J¼5.1 and 9.9 Hz), 6.49 (1H, s), 6.58 (1H, d, J¼9.9 Hz),
and 6.85 (1H, s); (in C5D5N) d 1.85 (1H, ddd, J¼4.1, 13.4,
and 13.4 Hz), 1.95 (1H, ddd, J¼5.9, 9.3, and 9.9 Hz), 2.14
(1H, ddd, J¼5.1, 8.6, and 9.3 Hz), 2.31 (1H, br d,
J¼13.4 Hz), 2.88 (1H, ddd, J¼5.9, 8.6, and 13.9 Hz), 3.42
(1H, ddd, J¼5.1, 9.9, and 13.9 Hz), 3.75–3.85 (1H, m),
3.80 and 4.40 (each 1H, 2d, J¼16.8 Hz), 4.54 (1H, m),
5.97 (2H, br s), 6.17 (1H, dd, J¼5.4 and 10.0 Hz), 6.51
(1H, s), 6.65 (1H, d, J¼10.0 Hz), and 7.05 (1H, s); 13C
NMR d 32.5, 43.8, 44.3, 53.4, 61.9, 63.0, 63.7, 100.8,
102.9, 106.9, 125.4, 127.8, 131.5, 137.9, 145.9, and 146.3;
(in C5D5N) d 33.4, 44.3, 44.4, 53.5, 62.2, 63.30, 63.34,
100.8, 103.2, 107.0, 126.7, 129.1, 130.7, 139.0, 145.8, and
146.2; HRMS (FAB) m/z calcd for C16H18NO3 (M+H)+,
272.1287, found 272.1300.
1
1490 cmꢀ1; H NMR (CDCl3, 300 MHz, at 45 ꢁC) d 0.09
and 0.10 (each 3H, 2s), 0.91 (9H, s), 1.40–1.55 (10H, m),
1.65 (1H, m), 1.81 (1H, br dd, J¼5.1 and 11.7 Hz), 2.32
(1H, m), 3.21 (1H, m), 3.72 (1H, m), 3.93 (1H, br s), 4.28
(1H, br s), 5.48 and 5.91 (each 1H, d, J¼10.2 Hz), 5.94
(2H, s), 6.76 (1H, d, J¼8.0 Hz), 6.89 (1H, dd, J¼1.71 and
8.0 Hz), and 6.95 (1H, d, J¼1.71 Hz); 13C NMR (CDCl3,
75 MHz, at 45 ꢁC) d ꢀ4.54, 18.2, 26.0, 28.6, 32.4 (br),
36.0 (br), 45.7, 50.7 (br), 62.3, 64.1, 79.4 (br), 101.1,
107.6, 108.0, 120.2, 131.9 (br), 133.0 (br), 137.6, 146.3,
and 147.9 (a carbonyl carbon of Boc group could not be
detected due to broadening of the signal); HRMS (FAB)
m/z calcd for C26H40NO5Si (M+H)+, 474.2676, found
474.2667. Anal. Calcd for C26H39NO5Si: C, 65.93; H,
8.30. Found: C, 65.98; H, 8.31.
4.1.2. Total synthesis of (D)-haemanthamine.
4.1.1.10. (3aR,6S,7aS)-3a-(Benzo[1,3]dioxol-5-yl)-6-
(tert-butyldimethylsilyloxy)-2,3,3a,6,7,7a-hexahydro-1H-
indole (18). To a solution of 3 (120 mg, 0.254 mmol) in
4.1.2.1. (2R)-[(1R,4R,6S)-1-(Benzo[1,3]dioxol-5-yl)-6-
benzyloxy-4-(tert-butyldimethylsilyloxy)-2-cyclohexen-1-
yl]-2-hydroxyacetic acid ethyl ester (19) and its (2S)-iso-
mer (20). To a solution of 5 (101 mg, 0.192 mmol) in THF
(3.0 mL) at 0 ꢁC under Ar was added LiHMDS (1.0 M solu-
tion in THF, 0.580 mL, 0.580 mmol), and the mixture was
stirred at 0 ꢁC for 45 min. To this solution was added a solu-
tion of (1S)-(+)-(10-camphorsulfonyl)oxaziridine [(+)-Davis
reagent, 66.2 mg, 0.289 mmol] in THF (1.2 mL) at 0 ꢁC via
a cannula, and the mixture was stirred at 0 ꢁC for 45 min.
The reaction was quenched by the addition of saturated
aqueous NH4Cl solution at 0 ꢁC. The reaction mixture was
diluted with EtOAc and washed with brine, and then dried.
Removal of the solvent left a residue, which was purified
by column chromatography (silica gel, 7 g, EtOAc/
hexanes¼1/15 as eluent) to afford first, starting material 5
(44.8 mg, 44%). Further elution gave 19 (39.1 mg, 38%)
as a colorless syrup: [a]2D5 ꢀ66 (c 0.97, CHCl3); IR (neat)
˚
CH2Cl2 (10 mL) were added MS4A (30 mg) and BF3$Et2O
(0.0483 mL, 0.381 mmol) at room temperature. The reaction
mixture was stirred at room temperature for 4 h. The mixture
was diluted with CHCl3, washed with brine, and then dried.
Removal of the solvent gave a residue, which was purified by
column chromatography (silica gel, 2 g, EtOAc/hexanes¼1/7
then MeOH/CHCl3¼1/7 as eluents) to afford 18 (77 mg,
78%) as a colorless syrup: [a]2D1 +41 (c 0.12, CHCl3); IR
1
(neat) 3300–3400, 1485 cmꢀ1; H NMR d 0.09 and 0.11
(each 3H, 2s), 0.90 (9H, s), 1.65 (1H, ddd, J¼3.2, 9.3, and
13.4 Hz), 1.96 (1H, ddd, J¼6.6, 6.6, and 13.1 Hz), 2.05
(1H, ddd, J¼5.1, 5.1, and 13.4 Hz), 2.40 (1H, ddd, J¼7.1,
7.1, and 13.1 Hz), 3.14 (2H, m), 3.42 (1H, m), 4.49 (1H,
m, J¼5.1 and 9.3 Hz), 5.58 (1H, d, J¼10.2 Hz), 5.83 (1H,
br d, J¼10.2 Hz), 5.94 (2H, s), 6.75 (1H, d, J¼8.0 Hz),
6.86 (1H, dd, J¼1.71 and 8.0 Hz), and 6.92 (1H, d,
J¼1.71 Hz); 13C NMR d ꢀ4.56, ꢀ4.51, 18.2, 25.9,
32.9, 40.0, 45.6, 49.6, 63.7, 64.6, 101.0, 107.6, 107.8,
120.0, 131.3, 133.1, 139.2, 145.9, and 147.7; HRMS
(FAB) m/z calcd for C21H32NO3Si (M+H)+, 374.2151, found
374.2150. Further elution gave recovered 3 (16.8 mg, 14%).
1
3500, 1725 cmꢀ1; H NMR d 0.04 and 0.07 (each 3H, 2s),
0.85–0.90 (12H, m), 1.42 (1H, ddd, J¼9.9, 12.5, and
12.5 Hz), 2.03 (1H, dddd, J¼2.4, 2.4, 6.3, and 12.5 Hz),
2.75 (1H, d, J¼8.0 Hz), 3.80–3.99 (2H, m), 4.08 (1H, dd,
J¼2.4 and 12.5 Hz), 4.34 (1H, dddd, J¼1.7, 2.4, 6.3, and
9.9 Hz), 4.59 and 4.72 (each 1H, 2d, J¼11.6 Hz), 4.76
(1H, d, J¼8.0 Hz), 5.68 (1H, dd, J¼1.7 and 10.2 Hz), 5.92
(2H, s), 5.97 (1H, ddd, J¼2.4, 2.4, and 10.2 Hz), 6.71 (1H,
d, J¼8.4 Hz), 6.94 (1H, dd, J¼1.8 and 8.4 Hz), 7.14 (1H,
4.1.1.11. (D)-Vittatine (1). To a solution of 18 (76.7 mg,
0.199 mmol) in MeOH (0.5 mL) was added formaldehyde

M. Bohno et al. / Tetrahedron 63 (2007) 6977–6989
6985
d, J¼1.8 Hz), and 7.27–7.42 (5H, m); 13C NMR d ꢀ4.55,
ꢀ4.62, 13.5, 18.1, 25.8, 33.4, 53.6, 61.0, 68.6, 71.7, 72.9,
75.3, 100.7, 106.8, 111.4, 124.2, 126.8, 127.56, 127.67,
128.3, 131.9, 136.8, 138.5, 146.4, 146.5, and 173.6;
HRMS (EI) m/z calcd for C30H40O7Si, M+, 540.2543, found
540.2544.
layer was washed successively with 1 mol Lꢀ1 aqueous HCl
solution, saturated aqueous NaHCO3 solution, and brine,
and then dried. Removal of the solvent left a residue, which
was purified by column chromatography (silica gel, 20 g,
EtOAc/hexanes¼1/10 as eluent) to afford tosylate 22
1H NMR d 0.03 and 0.06 (each 3H, 2s), 0.87 (9H, s), 1.33
(1H, ddd, J¼9.9, 12.0, and 12.3 Hz), 1.99 (1H, dddd,
J¼1.4, 2.4, 6.5, and 12.0 Hz), 2.08 (1H, d, J¼5.1 Hz), 2.43
(3H, s), 3.84 (2H, m), 3.98 (1H, dd, J¼2.4 and 12.3 Hz),
4.33 (1H, dddd, J¼2.1, 2.1, 6.5, and 9.9 Hz), 4.41–4.49
(2H, m), 4.68 (1H, d, J¼11.9 Hz), 5.42 (1H, dd, J¼2.1,
and 10.4 Hz), 5.89–5.95 (3H, m), 6.67 (1H, d, J¼8.3 Hz),
6.79 (1H, dd, J¼1.8 and 8.3 Hz), 6.89 (1H, d, J¼1.8 Hz),
7.26–7.42 (7H, m), and 7.65–7.70 (2H, m); 13C NMR
d ꢀ4.6, ꢀ4.7, 18.3, 21.6, 25.8, 33.0, 52.5, 68.3, 71.3, 72.4,
72.9, 73.8, 100.9, 107.4, 110.2, 123.6, 126.6, 127.8, 127.9,
128.4, 129.8, 131.7, 132.4, 136.4, 138.4, 144.9, 146.6, and
147.2; HRMS (EI) m/z calcd for C35H44O8SSi, M+,
652.2526, found 652.2529.
(1.013 g, 88%) as a colorless syrup: IR (neat) 3540 cmꢀ1
;
Further elution afforded 20 (4.2 mg, 4%) as a colorless
syrup: [a]2D3 ꢀ30 (c 0.65, CHCl3); IR (neat) 3500,
1
1725 cmꢀ1; H NMR d 0.04 and 0.07 (each 3H, 2s), 0.87
(9H, s), 1.20 (3H, t, J¼7.1 Hz), 1.48 (1H, ddd, J¼9.9,
12.3, and 12.3 Hz), 2.05 (1H, dddd, J¼1.1, 2.7, 6.5, and
12.3 Hz), 2.80 (1H, d, J¼4.7 Hz), 4.00 (1H, dd, J¼2.7 and
12.3 Hz), 4.11–4.23 (2H, m), 4.27 (1H, dddd, J¼1.1, 1.5,
6.5, and 9.9 Hz), 4.50 and 4.67 (each 1H, 2d, J¼11.7 Hz),
4.91 (1H, d, J¼4.7 Hz), 5.78 (1H, dd, J¼1.5 and 10.2 Hz),
5.84 (1H, ddd, J¼1.1, 1.1, and 10.2 Hz), 5.94 (2H, s), 6.77
(1H, d, J¼8.1 Hz), 6.98 (1H, dd, J¼1.8 and 8.1 Hz), 7.13
(1H, d, J¼1.8 Hz), and 7.27–7.38 (5H, m); 13C NMR
d ꢀ4.5, ꢀ4.6, 14.2, 18.2, 25.8, 33.2, 53.7, 61.8, 68.3, 71.1,
73.3, 75.1, 100.9, 107.2, 110.8, 124.0, 127.4, 127.5, 127.6,
128.3, 132.0, 133.8, 138.5, 146.3, 147.0, and 173.1;
HRMS (EI) m/z calcd for C30H40O7Si, M+, 540.2543, found
540.2538.
To a solution of 22 (1.013 g) in THF (28 mL) was added
Bu4NF (1.0 M solution in THF, 4.94 mL, 4.94 mmol) at
0 ꢁC, and the mixture was stirred at room temperature for
11 h. The mixture was diluted with EtOAc and washed
successively with saturated aqueous NaHCO3 solution and
brine, and then dried. Removal of the solvent left a residue,
which was purified by column chromatography (silica gel,
15 g, EtOAc/hexanes¼2/5 as eluent) to afford 23 (530 mg,
93%, 82% from 21) as a colorless syrup: [a]2D6 +31 (c 0.89,
4.1.2.2. (2R)-2-[(1R,4R,6S)-1-(Benzo[1,3]dioxol-5-yl)-
6-benzyloxy-4-(tert-butyldimethylsilyloxy)-2-cyclohexen-
1-yl]-2-hydroxyethanol (21). To a solution of 19 (1.06 g,
1.96 mmol) and trimethyl borate (0.262 mL, 2.35 mmol) in
THF (32 mL) at 0 ꢁC was added LiBH4 (171 mg,
7.84 mmol). After being stirred at room temperature for
4 h, the reaction mixture was quenched by slow addition
of MeOH at 0 ꢁC. The mixture was diluted with EtOAc
and washed successively with saturated aqueous NaHCO3
solution and brine, and then dried. Removal of the solvent
left a residue, which was purified by column chromato-
graphy (silica gel, 30 g, EtOAc/hexanes¼1/3 as eluent) to
afford 21 (879 mg, 90%) as a colorless syrup: [a]2D7 ꢀ109
1
CHCl3); IR (neat) 3400 cmꢀ1; H NMR d 1.98 (1H, ddd,
J¼5.3, 7.5, and 13.5 Hz), 2.32 (1H, ddd, J¼2.1, 5.7, 13.5,
and 12.0 Hz), 2.51 (1H, dd, J¼3.0 and 4.2 Hz), 2.61 (1H,
br s), 2.70 (1H, dd, J¼3.9 and 4.2 Hz), 3.43 (1H, dd,
J¼3.0 and 3.9 Hz), 3.87 (1H, dd, J¼2.1 and 7.5 Hz), 4.23
(2H, m), 4.45 (1H, d, J¼11.4 Hz), 5.44 (1H, d,
J¼10.2 Hz), 5.95 and 5.96 (each 1H, 2d, J¼1.5 Hz), 6.14
(1H, dd, J¼3.8 and 10.2 Hz), 6.79 (1H, d, J¼8.4 Hz), 6.90
(1H, dd, J¼1.8 and 8.4 Hz), 6.98 (1H, d, J¼1.8 Hz), 7.09–
7.14 (2H, m), and 7.21–7.32 (3H, m); 13C NMR d 32.0,
43.2, 47.5, 55.7, 64.7, 72.0, 79.5, 101.0, 107.6, 109.1,
121.5, 125.6, 127.6, 127.7, 128.2, 133.7, 134.8, 137.7,
146.4, and 147.4; HRMS (EI) m/z calcd for C22H22O5, M+,
366.1467, found 366.1460. Anal. Calcd for C22H22O5: C,
72.12; H, 6.05. Found: C, 72.10; H, 6.09.
1
(c 1.08, CHCl3); IR (neat) 3430 cmꢀ1; H NMR d 0.05
and 0.08 (each 3H, 2s), 0.88 (9H, s), 1.40 (1H, ddd, J¼9.9,
12.6, and 12.6 Hz), 1.92 (2H, br s), 2.03 (1H, dddd, J¼1.5,
2.7, 6.5, and 12.6 Hz), 3.35–3.39 (2H, m), 3.98 (1H, dd,
J¼2.7 and 12.6 Hz), 4.30 (1H, dd, J¼5.0 and 7.4 Hz), 4.36
(1H, dddd, J¼2.0, 2.0, 6.5, and 9.9 Hz), 4.50 and 4.73
(each 1H, 2d, J¼11.9 Hz), 5.59 (1H, dd, J¼2.0 and
10.0 Hz), 5.91–5.97 (3H, m), 6.74 (1H, d, J¼8.4 Hz), 6.90
(1H, dd, J¼1.8 and 8.4 Hz), 7.04 (1H, d, J¼1.8 Hz), and
7.29–7.40 (5H, m); 13C NMR d ꢀ4.55, ꢀ4.61, 18.2, 25.8,
33.0, 52.3, 62.8, 68.5, 71.2, 73.4, 74.2, 100.9, 107.3,
110.5, 123.7, 127.6, 127.8, 128.0, 132.5, 136.0, 138.5,
146.4, and 147.1; HRMS (EI) m/z calcd for C28H38O6Si,
M+, 498.2438, found 498.2445. Anal. Calcd for
C28H38O6Si: C, 67.44; H, 7.68. Found: C, 67.15; H, 7.71.
4.1.2.4. (2S)-2-[(1R,4R,6S)-1-(Benzo[1,3]dioxol-5-yl)-
6-benzyloxy-4-(tert-butyldimethylsilyloxy)-2-cyclohexen-
1-yl]-2-hydroxyethanol (24). To a solution of 20 (62.4 mg,
0.115 mmol) and trimethyl borate (0.0193 mL, 0.173 mmol)
in THF (2 mL) at 0 ꢁC was added LiBH4 (10.0 mg,
0.462 mmol). After being stirred at room temperature for
3 h, the reaction mixture was quenched by slow addition
of MeOH at 0 ꢁC. The mixture was diluted with EtOAc
and washed successively with saturated aqueous NaHCO3
solution and brine, and then dried. Removal of the solvent
left a residue, which was purified by column chromato-
graphy (silica gel, 1.5 g, EtOAc/toluene¼1/4 as eluent) to
afford 24 (56.7 mg, 99%) as a colorless syrup: [a]2D8 ꢀ33
4.1.2.3. (1R,4R,5S)-4-(Benzo[1,3]dioxol-5-yl)-5-benzyl-
oxy-4-[(2R)-oxiran-2-yl]-2-cyclohexen-1-ol(23). Toasolu-
tion of 21 (879 mg, 1.76 mmol) in CH2Cl2 (44 mL) at 0 ꢁC
was added Et3N (1.06 mL, 7.05 mmol). After stirring at
0 ꢁC at 10 min, TsCl (672 mg, 3.52 mmol) was slowly added
to the reaction mixture at 0 ꢁC. After being stirred at 0 ꢁC for
30 min and then at room temperature for 3.5 h, to the reac-
tion mixture was added 1 mol Lꢀ1 aqueous HCl solution at
0 ꢁC. The products were extracted with EtOAc, and organic
1
(c 0.99, CHCl3); IR (neat) 3420 cmꢀ1; H NMR d 0.06
and 0.09 (each 3H, 2s), 0.89 (9H, s), 1.38 (1H, ddd, J¼9.9,
12.3, and 12.3 Hz), 1.95 (1H, br s), 2.06 (1H, ddd, J¼2.6,
6.5, and 12.3 Hz), 3.40 (2H, m), 3.53 (1H, dd, J¼2.6 and

6986
M. Bohno et al. / Tetrahedron 63 (2007) 6977–6989
12.3 Hz), 4.28 (1H, dddd, J¼1.8, 1.8, 6.5, and 9.9 Hz), 4.36–
4.44 (2H, m), 4.69 (1H, d, J¼11.7 Hz), 5.75 (1H, dd, J¼1.8
and 10.5 Hz), 5.85 (1H, dd, J¼1.8 and 10.5 Hz), 5.96 (2H,
s), 6.86 (1H, d, J¼8.1 Hz), 7.01 (1H, dd, J¼1.7 and
8.1 Hz), 7.16 (1H, d, J¼1.7 Hz), and 7.30–7.43 (5H, m);
13C NMR d ꢀ4.5, ꢀ4.6, 18.2, 25.8, 32.9, 52.5, 63.3, 68.4,
70.5, 74.2, 74.8, 101.0, 107.6, 110.6, 124.0, 127.9, 128.0,
128.5, 132.5, 133.4, 138.0, 146.5, and 147.5; HRMS (EI)
m/z calcd for C28H38O6Si, M+, 498.2438, found 498.2434.
J¼10.4 Hz), 5.96 and 5.97 (each 1H, 2d, J¼1.2 Hz), 6.82
(1H, d, J¼8.1 Hz), 7.11 (1H, dd, J¼1.8 and 8.1 Hz), and
7.14–8.16 (11H, m); 13C NMR d ꢀ4.6, ꢀ4.5, 18.2, 25.8,
33.0, 38.5, 52.2, 64.0, 68.2, 70.5, 74.7, 83.5, 101.1, 107.4,
111.0, 124.1, 126.8, 128.1 (2C), 128.4, 128.6, 129.5,
130.0, 132.6, 133.1, 135.1, 137.5, 146.7, 147.2, and 166.2;
HRMS (EI) m/z calcd for C36H44O9SSi, M+, 680.2475,
found 680.2485.
4.1.2.7. Conversion of mesylate (26) to epoxide (23). To
a solution of 26 (7.5 mg, 0.011 mmol) in THF (0.3 mL) at
0 ꢁC was added Bu4NF (1.0 M solution in THF, 0.022 mL,
0.022 mmol), and the mixture was stirred at room tempera-
ture for 2 h. To the mixture, MeOH (0.3 mL) and MeONa
(1.2 mg, 0.022 mmol) were added at room temperature.
After being stirred at room temperature for 3 h, the reaction
mixture was diluted with CHCl3 and washed successively
with 1 mol Lꢀ1 aqueous HCl solution, saturated aqueous
NaHCO3 solution, and brine, and then dried. Removal of
the solvent left a residue, which was purified by column
chromatography (silica gel, 0.5 g, EtOAc/hexanes¼1/2 as
eluent) to afford 23 (3.9 mg, 98%) as a colorless syrup.
The spectral and physical data were fully identical to those
of 23 prepared from 22.
4.1.2.5. (2S)-2-[(1R,4R,6S)-1-(Benzo[1,3]dioxol-5-yl)-
6-benzyloxy-4-(tert-butyldimethylsilyloxy)-2-cyclohexen-
1-yl]-2-hydroxyethyl benzoate (25). To a solution of 24
(8.1 mg, 0.0162 mmol) in pyridine (0.4 mL) at 0 ꢁC was
added benzoyl chloride (0.0028 mL, 0.0244 mmol), and the
reaction mixture was stirred at 0 ꢁC for 4.5 h. To the reaction
mixture was added aqueous saturated NaHCO3 solution at
0 ꢁC, and the products were extracted with EtOAc. The or-
ganic layer was washed successively with saturated aqueous
NaHCO3 solution and brine, and then dried. Removal of the
solvent left a residue, which was purified by column chroma-
tography (silica gel, 0.5 g, EtOAc/hexanes¼1/10 as eluent)
to afford 25 (8.5 mg, 87%) as a colorless syrup: [a]2D2 ꢀ1.5
(c 1.12, CHCl3); IR (neat) 3500, 1720 cmꢀ1 1H NMR
;
d 0.08 and 0.11 (each 3H, 2s), 0.91 (9H, s), 1.43 (1H, ddd,
J¼10.0, 12.3, and 12.3 Hz), 2.07 (1H, br s), 2.09 (1H,
dddd, J¼1.2, 2.4, 6.3, and 12.3 Hz), 3.71 (1H, dd, J¼2.4
and 12.3 Hz), 4.12 (1H, dd, J¼7.8 and 11.4 Hz), 4.23 (1H,
dd, J¼1.2 and 11.4 Hz), 4.34 (1H, dddd, J¼1.8, 1.8, 6.3,
and 10.0 Hz), 4.44 (1H, d, J¼11.9 Hz), 4.66 (1H, ddd,
J¼1.2, 1.2, and 7.8 Hz), 4.71 (1H, d, J¼11.9 Hz), 5.82
(1H, dd, J¼1.8 and 10.5 Hz), 5.91 (1H, ddd, J¼1.2, 1.8,
and 10.5 Hz), 5.96 (2H, s), 6.82 (1H, d, J¼7.8 Hz), 7.04
(1H, dd, J¼1.8 and 7.8 Hz), 7.14–7.21 (2H, m), and 7.26–
8.07 (9H, m); 13C NMR d ꢀ4.5, ꢀ4.6, 18.2, 25.8, 33.0,
52.9, 66.7, 68.3, 70.6, 72.3, 74.9, 101.0, 107.6, 110.7,
124.1, 127.3, 127.8, 127.9, 128.3, 128.4, 129.7, 129.9,
131.8, 133.0, 134.3, 138.0, 146.7, 147.5, and 166.7;
HRMS (EI) m/z calcd for C35H42O7Si, M+, 602.2707, found
602.2700.
4.1.2.8. 5-{(1R,4R,6S)-6-Bezyloxy-4-methoxy-1-[(2R)-
oxiran-2-yl]-2-cyclohexen-1-yl}-benzo[1,3]dioxole (27).
To a solution of 23 (83.3 mg, 0.227 mmol) in THF at 0 ꢁC
were added sodium hydride (60% in oil, 27.3 mg,
1.14 mmol) and methyl iodide (0.0425 mL, 0.682 mmol),
and the mixture was stirred at 0 ꢁC for 5 h. After addition
of MeOH (1 mL), the reaction mixture was diluted with
EtOAc and washed successively with 1 mol Lꢀ1 aqueous
HCl solution, saturated aqueous NaHCO3 solution, and
brine, and then dried. Removal of the solvent left a residue,
which was purified by column chromatography (silica gel,
4 g, EtOAc/hexanes¼1/8 as eluent) to afford 27 (79.2 mg,
92%) as a colorless syrup: [a]2D7 ꢀ94 (c 0.89, CHCl3); IR
(neat) 3400 cmꢀ1; 1H NMR d 1.50 (1H, ddd, J¼10.0, 12.0,
and 12.6 Hz), 2.30 (1H, dddd, J¼1.4, 2.7, 6.3, and
12.0 Hz), 2.64 (1H, dd, J¼3.2 and 4.4 Hz), 2.77 (1H, dd,
J¼4.1 and 4.4 Hz), 3.38 (3H, s), 3.70 (1H, dd, J¼3.2 and
4.1 Hz), 3.77 (1H, dd, J¼2.7 and 12.6 Hz), 3.97 (1H,
dddd, J¼1.4, 2.1, 6.3, and 10.0 Hz), 4.57 and 4.74 (each
1H, 2d, J¼11.7 Hz), 5.37 (1H, dd, J¼2.1 and 10.5 Hz),
5.93 (2H, s), 6.04 (1H, ddd, J¼1.4, 1.4, and 10.5 Hz), 6.75
(1H, d, J¼8.1 Hz), 6.92 (1H, dd, J¼1.8 and 8.1 Hz), 7.07
(1H, d, J¼1.8 Hz), and 7.26–7.40 (5H, m); 13C NMR
d 29.1, 44.0, 48.1, 55.8 (2C), 71.5, 75.6, 77.7, 100.9,
107.3, 110.2, 123.0, 127.47 (2C), 127.52, 128.3, 130.9,
133.1, 138.3, 146.5, and 147.1; HRMS (EI) m/z calcd for
C23H24O5, M+, 380.1624, found 380.1625. Anal. Calcd for
C23H24O5: C, 72.61; H, 6.36. Found: C, 72.53; H, 6.32.
4.1.2.6. (1S)-1-[(1R,4R,6S)-1-(Benzo[1,3]dioxol-5-yl)-
6-benzyloxy-4-(tert-butyldimethylsilyloxy)-2-cyclohexen-
1-yl]-2-(benzoyloxy)ethyl methanesulfonate (26). To a
solution of 25 (8.5 mg, 0.0141 mmol) in pyridine (0.3 mL)
at 0 ꢁC was added methanesulfonyl chloride (0.0044 mL,
0.0564 mmol), and the mixture was stirred at 0 ꢁC for
40 min. To the reaction mixture at 0 ꢁC was added 4-dime-
thylaminopyridine (1 mg) and the resulting mixture was
stirred at room temperature for 28 h. The mixture was di-
luted with EtOAc and washed successively with 1 mol Lꢀ1
aqueous HCl solution, saturated aqueous NaHCO3 solution,
and brine, and then dried. Removal of the solvent left a resi-
due, which was purified by column chromatography (silica
gel, 0.5 g, EtOAc/hexanes¼1/15 as eluent) to afford 26
(7.5 mg, 78%) as a colorless syrup: [a]2D6 ꢀ0.8 (c 0.86,
4.1.2.9.
(1R)-2-Azido-1-[(1R,4R,6S)-1-(benzo[1,3]-
dioxol-5-yl)-6-benzyloxy-4-methoxy-2-cyclohexen-1-yl]-
ethanol (28). A mixture of 27 (79.2 mg, 0.208 mmol), NaN3
(135 mg, 2.08 mmol), and NH4Cl (111 mg, 2.08 mmol) in
MeOH (2.4 mL) was stirred at 50 ꢁC for 48 h. The reaction
mixture was diluted with EtOAc and washed with brine, and
then dried. Removal of the solvent left a residue, which was
purified by column chromatography (silica gel, 3.5 g,
EtOAc/hexanes¼1/4 as eluent) to afford 28 (70.0 mg,
1
CHCl3); IR (neat) 1725, 1360 cmꢀ1; H NMR d 0.06 and
0.09 (each 3H, 2s), 0.89 (9H, s), 1.38 (1H, ddd, J¼9.9,
12.0, and 12.0 Hz), 2.11 (1H, dd, J¼6.5 and 12.0 Hz), 2.29
(3H, s), 3.64 (1H, dd, J¼2.3 and 12.0 Hz), 4.18–4.23 (2H,
m), 4.31 (1H, dddd, J¼1.8, 1.8, 6.5, and 9.9 Hz), 4.46 and
4.74 (each 1H, 2d, J¼12.2 Hz), 5.69 (1H, dd, J¼4.1 and
7.1 Hz), 5.83 (1H, dd, J¼1.8 and 10.4 Hz), 5.92 (1H, br d,

M. Bohno et al. / Tetrahedron 63 (2007) 6977–6989
6987
79%) as a colorless syrup: [a]2D6 ꢀ37 (c 1.01, CHCl3); IR
3420, 1690 cmꢀ1
;
1H NMR d 1.30–1.48 (1H, m), 1.42
(neat) 3430, 2100 cmꢀ1
;
1H NMR d 1.34 (1H, ddd,
(9H, s), 2.04–2.14 (2H, m), 3.01–3.20 (2H, m), 3.36 (3H,
s), 3.61 (1H, br s), 4.01 (1H, dddd, J¼1.9, 1.9, 6.3, and
9.6 Hz), 4.27 (1H, ddd, J¼2.7, 9.3, and 12.1 Hz), 4.36
(1H, dd, J¼5.7 and 11.7 Hz), 4.92 (1H, t, J¼5.9 Hz), 5.69
(1H, dd, J¼1.4 and 10.5 Hz), 5.94 and 5.95 (each 1H, 2d,
J¼1.5 Hz), 6.13 (1H, ddd, J¼1.9, 1.9, and 10.5 Hz), 6.78
(1H, d, J¼8.4 Hz), 6.90 (1H, dd, J¼1.4 and 8.4 Hz), and
7.03 (1H, d, J¼1.4 Hz); 13C NMR d 28.3, 33.2, 43.4, 53.5,
55.9, 67.4, 74.1, 75.7, 79.9, 101.0, 107.8, 110.0, 123.2,
128.9, 132.1 (2C), 146.6, 147.6, and 157.3; HRMS (FAB)
m/z calcd for C21H29NO7 (M+H)+, 407.1944, found
407.1944.
J¼10.4, 12.0, and 12.6 Hz), 1.75 (1H, d, J¼6.0 Hz), 2.25
(1H, dddd, J¼1.4, 2.7, 6.3, and 12.0 Hz), 3.03 (1H, dd,
J¼2.4 and 12.6 Hz), 3.15 (1H, dd, J¼9.3 and 12.6 Hz),
3.36 (3H, s), 3.95–4.03 (2H, m), 4.30 (1H, ddd, J¼2.4,
6.0, and 9.3 Hz), 4.46 and 4.76 (each 1H, 2d, J¼12.2 Hz),
5.68 (1H, dd, J¼1.5 and 10.5 Hz), 5.94 (2H, s), 6.12 (1H,
ddd, J¼1.4, 1.4, and 10.5 Hz), 6.74 (1H, d, J¼8.4 Hz),
6.85 (1H, dd, J¼2.1 and 8.4 Hz), 6.99 (1H, d, J¼2.1 Hz),
and 7.31–7.43 (5H, m); 13C NMR d 28.9, 52.9, 53.5, 55.7,
71.1, 72.3, 73.8, 76.0, 101.0, 107.5, 110.1, 123.5, 128.0,
128.6, 128.8, 132.1, 132.3, 138.3, 146.6, and 147.4;
HRMS (EI) m/z calcd for C23H25N3O5, M+, 423.1794, found
423.1790.
4.1.2.12. tert-Butyl (2R,3aR,4S,6S,7aS)-3a-(benzo[1,3]-
dioxol-5-yl)-2,4-dihydroxy-6-methoxyoctahydroindole-1-
carboxylate (30). A solution of 9 (21.2 mg, 0.0518 mmol)
in THF (0.7 mL) was degassed by freeze–pump–thaw
(FPT) cycles, which was added to a solution of Hg(O-
COCF3)2 (33.1 mg, 0.0777 mmol) in THF (1.4 mL, de-
gassed by FPT cycles) via a cannula under Ar. After being
stirred at room temperature for 120 h, to the mixture was
added a solution of NaBH4 (2.8 mg, 0.075 mmol) and
NaOH (3.0 mg, 0.075 mmol) in MeOH (0.15 mL, degassed
by FPT cycles) at room temperature, and the resulting mix-
ture was stirred for 10 min at room temperature. The insolu-
ble material was removed by filtration through a pad of
Celite. The filtrate was partially concentrated and diluted
with EtOAc, which was washed with brine, and then dried.
Removal of the solvent left a residue, which was purified
by preparative TLC (EtOAc/hexanes¼1/1) to afford 30
(11.2 mg, 53%) as a colorless syrup: [a]2D2 +18 (c 1.10,
4.1.2.10. tert-Butyl (2R)-2-[(1R,4R,6S)-1-(benzo[1,3]-
dioxol-5-yl)-6-benzyloxy-4-methoxy-2-cyclohexen-1-yl]-
2-hydroxyethylcarbamate (29). A mixture of Lindler
catalyst (140 mg) in EtOAc (1.5 mL) was stirred under an
atmospheric pressure of H2 at room temperature for 1 h.
To this mixture was added a solution of 28 (70.0 mg,
0.165 mmol) and di-tert-butyl dicarbonate (0.0760 mL,
0.331 mmol) in EtOAc (1.5 mL) via a cannula, and the
whole mixture was stirred under an atmospheric pressure
of H2 at room temperature for 5 h. The catalyst was removed
by filtration through a pad of Celite and the filtrate was con-
centrated to give a residue, which was purified by column
chromatography (silica gel, 2.5 g, EtOAc/hexanes¼1/2 as
eluent) to afford 29 (81.3 mg, 99%) as a colorless syrup:
[a]D25 ꢀ28 (c 1.10, CHCl3); IR (neat) 3390, 1690 cmꢀ1; 1H
NMR d 1.34 (1H, ddd, J¼10.5, 12.0, and 12.0 Hz), 1.43
(9H, s), 2.16–2.36 (1H, m), 2.85–3.11 (3H, m), 3.34 (3H,
s), 3.99 (1H, dddd, J¼2.0, 2.0, 6.5, and 9.9 Hz), 4.04 (1H,
m), 4.28 (1H, ddd, J¼2.3, 5.7, and 12.0 Hz), 4.53 (1H, d,
J¼11.7 Hz), 4.70–4.80 (2H, m), 5.75 (1H, br d,
J¼10.4 Hz), 5.92 (2H, s), 6.10 (1H, br d, J¼10.4 Hz), 6.72
(1H, d, J¼8.1 Hz), 6.88 (1H, dd, J¼1.8 and 8.1 Hz), 7.02
(1H, d, J¼1.8 Hz), and 7.26–7.40 (5H, m); 13C NMR
d 28.3, 29.1, 43.2, 53.2, 55.6, 71.4, 73.6, 74.7, 76.1, 79.8,
100.8, 107.3, 110.3, 123.6, 127.6, 127.7, 128.4, 129.3,
132.1, 132.7, 138.6, 146.4, 147.2, and 157.3; HRMS (EI)
m/z calcd for C28H35NO7, M+, 497.2414, found 497.2413.
Anal. Calcd for C28H35NO7: C, 67.59; H, 7.09. Found: C,
67.43; H, 7.06.
CHCl3); IR (neat) 3430, 1670 cmꢀ1; H NMR (DMSO-d6,
1
300 MHz, at 60 ꢁC) d 1.49 (9H, s), 1.70 (1H, ddd, J¼7.9,
7.9, and 12.9 Hz), 1.98 (1H, m), 2.22 (1H, ddd, J¼3.8, 3.8,
and 12.9 Hz), 2.36–2.49 (1H, m), 3.19 (1H, dd, J¼5.0 and
11.6 Hz), 3.34 (3H, s), 3.48 (1H, dd, J¼6.5 and 11.6 Hz),
3.61 (1H, m), 3.79 (1H, d, J¼5.7 Hz), 4.25–4.36 (2H, m),
4.43 (1H, ddd, J¼4.5, 5.0, and 6.5 Hz), 5.74 (1H, d,
J¼4.5 Hz), 6.02 and 6.03 (each 1H, 2d, J¼0.6 Hz), 6.83
(1H, d, J¼8.4 Hz), 6.99 (1H, dd, J¼1.8 and 8.4 Hz), and
7.15 (1H, d, J¼1.8 Hz); 13C NMR (DMSO-d6, 75 MHz, at
60 ꢁC) d 28.1, 30.9, 34.8, 51.9, 54.9, 55.2, 57.4, 67.8, 74.5,
76.9, 78.6, and 79.1 (rotameric pair), 100.6, 107.2, 108.7,
120.6, 136.1, 145.2, 146.8, and 153.6; HRMS (EI) m/z calcd
for C21H29NO7, M+, 407.1944, found 407.1950.
4.1.2.11. tert-Butyl (2R)-2-[(1R,4R,6S)-1-(benzo[1,3]-
dioxol-5-yl)-4-methoxy-6-hydroxy-2-cyclohexen-1-yl]-2-
hydroxyethylcarbamate (9). A mixture of Na (128 mg,
5.58 mmol) and naphthalene (718 mg, 5.58 mmol) in THF
(7.0 mL) was sonicated with ultrasound at room temperature
for 25 min and the resulting moss green suspension was
cooled to ꢀ30 ꢁC. To the mixture was added a solution of
29 (111 mg, 0.223 mmol) in THF (4.0 mL) at ꢀ30 ꢁC via
a cannula. The reaction mixture was stirred at ꢀ30 ꢁC for
2 h, and then quenched by slow addition of MeOH, followed
by addition of aqueous saturated NH4Cl solution at ꢀ30 ꢁC.
After being stirred at room temperature for 10 min, the reac-
tion mixture was diluted with EtOAc, and washed with brine,
and then dried. Removal of the solvent gave a residue, which
was purified by column chromatography (silica gel, 4 g,
EtOAc/toluene¼1/4 as eluent) to afford 9 (74.0 mg, 81%)
as a colorless syrup: [a]2D3 ꢀ14 (c 1.02, CHCl3); IR (neat)
Further elution gave the recovered starting material 9
(2.8 mg, 13%).
4.1.2.13. tert-Butyl (2R,3aR,4S,6S,7aS)-3a-(benzo[1,3]-
dioxol-5-yl)-4-hydroxy-6-methoxy-2-triethylsilyloxyocta-
hydroindole-1-carboxylate (31). To a solution of 30
(53.8 mg, 0.131 mmol) in CH2Cl2 (5.4 mL) at 0 ꢁC were
added Et3N (0.0494 mL, 0.329 mmol) and N,N-dimethyl-
aminopyridine (24.1 mg, 0.197 mmol), and the mixture
was stirred at 0 ꢁC for 40 min. To this solution, TESCl
(0.0662 mL, 0.394 mmol) was added dropwise at 0 ꢁC,
and the resulting mixture was stirred at 0 ꢁC for 2.5 h, and
then at room temperature for 12 h. To the reaction mixture
was added H2O, and the products were extracted with
EtOAc. The organic layer was washed successively with sat-
urated aqueous NaHCO3 solution and brine, and then dried.

6988
M. Bohno et al. / Tetrahedron 63 (2007) 6977–6989
Removal of the solvent left a residue, which was purified by
preparative TLC (EtOAc/toluene¼1/12) to afford 31
(45.7 mg, 67%) as a colorless syrup: [a]2D4 +27 (c 1.10,
(1H, br dd, J¼7.5 and 7.5 Hz), 5.91 (1H, br d, J¼10.4 Hz),
5.98 (2H, s), 6.14 (1H, br d, J¼10.4 Hz), 6.84–6.87 (2H,
m), and 7.07 (1H, s); 13C NMR (DMSO-d6, 75 MHz, at
60 ꢁC) d 4.4, 6.1, 26.7 (br), 28.0, 51.7, 53.2 (br), 55.0,
60.7, 71.9, 74.8 (br), 78.6 and 79.0 (rotameric pair), 100.7,
107.3, 107.5, 120.7, 127.9, 130.6, 135.4, 145.8, 147.4, and
153.4; HRMS (EI) m/z calcd for C27H41NO6Si, M+,
503.2703, found 507.2722.
1
CHCl3); IR (neat) 3510, 1690 cmꢀ1; H NMR (DMSO-d6,
300 MHz, at 60 ꢁC) d 0.55–0.65 (6H, m), 0.91 (9H, t,
J¼8.0 Hz), 1.43 (9H, s), 1.77 (1H, ddd, J¼6.8, 6.8,
and 13.2 Hz), 1.99 (1H, m), 2.15 (1H, ddd, J¼3.9, 3.9,
and 13.2 Hz), 2.18–2.27 (1H, m), 3.09 (1H, dd, J¼3.5 and
11.7 Hz), 3.27 (3H, s), 3.34 (1H, dd, J¼5.7 and 11.7 Hz),
3.53 (1H, d, J¼6.0 Hz), 3.56–3.64 (1H, m), 4.22–4.33
(2H, m), 4.51 (1H, dd, J¼3.5 and 5.7 Hz), 5.96 and 5.97
(each 1H, 2d, J¼1.1 Hz), 6.82 (1H, d, J¼8.3 Hz), 6.91
(1H, dd, J¼1.7 and 8.4 Hz), and 7.10 (1H, d, J¼1.7 Hz);
13C NMR (DMSO-d6, 75 MHz, at 60 ꢁC) d 4.1, 6.3, 28.1,
30.4, 34.9, 52.5, 55.2, 55.9, 56.5, 67.8, 74.4, 78.7, and
79.1 (rotameric pair), 78.8, 100.7, 107.4, 108.4, 120.5,
135.3, 145.3, 147.0, and 153.5; HRMS (EI) m/z calcd for
C27H43NO7Si, M+, 521.2809, found 521.2807.
4.1.2.15. (D)-Haemanthamine (2). To a solution of 33
(22.7 mg, 0.0451 mmol) in MeOH (1.2 mL) at room temper-
ature was added 6 mol Lꢀ1 aqueous HCl (2.4 mL), and the
mixture was stirred at room temperature for 45 min. To
this mixture, formaldehyde (37 wt % solution in water,
1.2 mL) was added, and the reaction mixture was stirred at
room temperature for 1 h and then at 50 ꢁC for 21 h. The
mixture was washed with Et2O and then made basic by
slow addition of solid potassium carbonate. The products
were extracted with CHCl3 and the organic layer was
washed with brine, and then dried. Removal of the solvent
gave a residue, which was purified by column chromato-
graphy (silica gel, 1 g, MeOH/CHCl3¼1/60 as eluent) to
give (+)-haemanthamine 2 (13.6 mg, 100%) as a crystalline
residue: mp 199–202 ꢁC (natural haemanthamine22 200–
202 ꢁC); [a]D25 +41 (c 0.62, CHCl3) [natural haemanth-
amine22 [a]D24 +42 (c 0.34, CHCl3)]; IR (neat) 3400, 2930,
4.1.2.14. tert-Butyl (2R,3aR,6S,7aS)-3a-(benzo[1,3]di-
oxol-5-yl)-6-methoxy-2-triethylsilyloxy-2,3,3a,6,7,7a-hexa-
hydro-1H-indole-1-carboxylate (33). To a solution of 31
(12.8 mg, 0.0245 mmol) in THF (0.6 mL) was added sodium
hydride (60% in oil, 1.8 mg, 0.074 mmol) at 0 ꢁC, and the
mixture was stirred at 0 ꢁC for 20 min. To the mixture at
0 ꢁC were added carbon disulfide (0.011 mL, 0.18 mmol),
and after being stirred at room temperature for 2 h, methyl
iodide (0.0030 mL, 0.048 mmol) was added. The resulting
mixture was stirred at room temperature for 5 h. The mixture
was diluted with EtOAc, washed with brine, and then dried.
Removal of the solvent gave a residue, which was purified
by column chromatography (silica gel, 0.5 g, EtOAc/
hexanes¼1/20 as eluent) to afford xanthate ester 32
1510, 1485 cmꢀ1 1H NMR d 1.97–2.06 (2H, m), 2.11
;
(1H, ddd, J¼1.8, 5.4, and 13.8 Hz), 3.25 (1H, dd, J¼3.3
and 14.1 Hz), 3.30–3.43 (2H, m), 3.36 (3H, s), 3.69 (1H,
d, J¼17.1 Hz), 3.86 (1H, ddd, J¼1.8, 4.0 and 4.7 Hz), 3.98
(1H, dd, J¼3.3 and 6.7 Hz), 4.32 (1H, d, J¼17.1 Hz), 5.88
and 5.89 (each 1H, 2br s), 6.36 (1H, dd, J¼4.7 and
10.2 Hz), 6.43 (1H, d, J¼10.2 Hz), 6.47 (1H, s), and 6.82
(1H, s); 13C NMR d 28.2, 50.0, 56.5, 61.3, 62.6, 63.5,
72.7, 80.1, 100.8, 103.3, 106.8, 126.7, 127.3, 131.8, 135.3,
146.1, and 146.4; HRMS (EI) m/z calcd for C17H19NO4,
M+, 301.1314, found 301.1316.
(14.8 mg, 98%) as a colorless syrup: IR (neat) 1690 cmꢀ1
;
1H NMR (300 MHz) d 0.62–0.72 (6H, m), 0.97 (9H, t,
J¼8.0 Hz), 1.45 (9H, s), 2.00–2.15 (m, 2H), 2.10 (3H, s),
2.20–2.30 (1H, m), 2.35–2.46 (1H, m), 3.04 (1H, dd,
J¼1.2 and 12.3 Hz), 3.18 (3H, s), 3.25 (1H, dd, J¼4.8 and
12.3 Hz), 3.62–3.68 (1H, m), 4.54 (1H, dd, J¼1.2 and
4.8 Hz), 4.61 (1H, dd, J¼5.9 and 10.1 Hz), 5.96 and 5.99
(each 1H, 2d, J¼0.9 Hz), 6.33 (1H, dd, J¼3.6 and 3.6 Hz),
6.69 (1H, dd, J¼2.1 and 8.3 Hz), 6.74 (1H, d, J¼2.1 Hz),
and 6.85 (1H, d, J¼8.1 Hz); HRMS (EI) m/z calcd for
C29H45NO7S2Si (M+H)+, 611.2407, found 611.2400.
Acknowledgements
We thank Professor Hiromitsu Takayama (Graduate School
of Pharmaceutical Sciences, Chiba University, Chiba, Japan)
for a generous gift of natural haemanthamine. We also thank
the Ministry of Education, Culture, Sports, Science, and
Technology, Japan (Grant-in-Aid for Scientific Research,
B15350027 and Grant-in-Aid for the 21st Century COE
program ‘KEIO LCC’) for financial assistance.
A mixture of xanthate ester 32 (14.8 mg) and potassium
carbonate (5.0 mg, 0.036 mmol) in 1,2-dichlorobenzene
(1.0 mL) in a sealed tube was stirred at 160 ꢁC for 12 h. After
cooling, the reaction mixture was concentrated to give a
residue, which was dissolved in MeOH (0.5 mL). To this
solution at room temperature were added potassium carbo-
nate (6.7 mg, 0.0484 mmol) and di-tert-butyl dicarbonate
(0.0083 mL, 0.036 mmol), and the mixture was stirred at
room temperature for 12 h. The reaction mixture was diluted
with EtOAc, and washed with brine, and then dried.
Removal of the solvent gave a residue, which was purified
by column chromatography (silica gel, 0.8 g, EtOAc/
hexanes¼1/25 as eluent) to afford 33 (8.0 mg, 66%) as a col-
orless syrup: [a]2D2 +67 (c 1.00, CHCl3); IR (neat)
References and notes
1. For reviews on Amaryllidaceae alkaloids, see: (a) Martin, S. F.
The Alkaloids; Brossi, A., Ed.; Academic: New York, NY,
1987; Vol. 30, pp 251–376; (b) Hoshino, O. The Alkaloids;
Cordell, G. A., Ed.; Academic: New York, NY, 1998; Vol. 51,
pp 323–424; (c) Jin, Z.; Li, Z.; Hyang, R. Nat. Prod. Rep.
2002, 19, 454–476; (d) Jin, Z. Nat. Prod. Rep. 2005, 22, 111–
126; (e) Tsuda, Y. Heterocycles 1978, 10, 555–595.
2. (a) Papas, T. S.; Sandhaus, L.; Chirigos, M. A.; Furusawa, E.
Biochem. Biophys. Res. Commun. 1973, 52, 88–92; (b)
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1690 cmꢀ1
;
1H NMR (DMSO-d6, 300 MHz, at 60 ꢁC)
d 0.31–0.51 (6H, m), 0.77 (9H, t, J¼7.8 Hz), 1.20–1.31
(1H, m), 1.43 (9H, s), 2.50–2.65 (1H, m), 2.85 (1H, m),
3.27 (3H, s), 3.63–3.80 (2H, m), 3.87–3.96 (1H, m), 4.63

M. Bohno et al. / Tetrahedron 63 (2007) 6977–6989
6989
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