Total synthesis of (-)-flustramine B via one-pot intramolecular ullmann coupling and claisen rearrangement

Article abstract of DOI:10.3987/COM-08-S(D)49

Total synthesis of (-)-flustramine B was achieved via one-pot intramolecular Ullmann coupling and Claisen rearrangement. A striking feature of this method of synthesis is that the sequential intramolecular Ullmann coupling and Claisen rearrangement reactions proceeds with concomitant deprotection of the methoxymethyl (MOM) group to afford spirocyclic oxindole with perfect asymmetric transmission in good overall yield.

Full text of DOI:10.3987/COM-08-S(D)49

HETEROCYCLES, Vol. 79, 2009
805
HETEROCYCLES, Vol. 79, 2009, pp. 805 - 820. © The Japan Institute of Heterocyclic Chemistry
Received, 30th September, 2008, Accepted, 17th November, 2008, Published online, 20th November, 2008.
DOI: 10.3987/COM-08-S(D)49
TOTAL SYNTHESIS OF (–)-FLUSTRAMINE B VIA ONE-POT
INTRAMOLECULAR ULLMANN COUPLING AND CLAISEN
REARRANGEMENT
Tomohiro Hirano, Kanako Iwakiri, Hiroshi Miyamoto, Atsuo Nakazaki, and
Susumu Kobayashi*
Faculty of Pharmaceutical Sciences, Tokyo University of Science (RIKADAI)
2641 Yamazaki, Noda-shi, Chiba 278-8510, Japan. kobayash@rs.noda.tus.ac.jp
Abstract – Total synthesis of (–)-flustramine B was achieved via one-pot
intramolecular Ullmann coupling and Claisen rearrangement. A striking feature
of this method of synthesis is that the sequential intramolecular Ullmann coupling
and Claisen rearrangement reactions proceeds with concomitant deprotection of
the methoxymethyl (MOM) group to afford spirocyclic oxindole with perfect
asymmetric transmission in good overall yield.
INTRODUCTION
(–)-Flustramine B (1), isolated from the marine bryozoan flustra foliacea,1 is an example of
pyrrolidinoindoline alkaloids with a prenyl group at the C-3a quaternary carbon center (Figure 1).
Although (–)-1 has a simple scaffold structure, it displays interesting biological activity; for example, it
exhibits muscle-relaxant activity both in vivo and in vitro.2 Some natural compounds related to (–)-1, such
as debromoflustramine B1c and pseudophrynaminol,3 have been reported to show butyrylcholinesterase
inhibition activity4 and an antibacterial activity,5 respectively. Because of their structural features and the
important biological activities exhibited by them, pyrrolidinoindoline alkaloids have attracted
considerable attention, and a number of studies on the total synthesis of a series of pyrrolidinoindoline
alkaloids have been reported.6
Recently, we developed an efficient approach for the synthesis of spirocyclic oxindoles via one-pot
intramolecular Ullmann coupling and Claisen rearrangement (Scheme 1).7 This sequential reaction
proceeds in the following two steps: (1) intramolecular Ullmann coupling of 2-iodoindole (A) bearing an
allyl alcohol moiety in the presence of catalytic amount of CuCl and 2-aminopyridine in a 2-equiv
solution of NaOMe to yield a pyranoindole intermediate (B) and (2) subsequent thermal Claisen

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rearrangement of B to afford spirocyclic oxindole (C). In order to demonstrate the synthetic utility of the
obtained spirocyclic oxindole, we used it in the total synthesis of racemic debromoflustramine B.6e In this
paper, we describe the asymmetric total synthesis of flustramine B by carrying out our previously
developed method using enantioenriched 2-iodoindole bearing a 6-bromo group.
OH
3a
N
N
6
Me
Me
N
N
H
H
Br
N
Me
N
H
H
(–)-flustramine B (1)
debromoflustramine B
pseudophrynaminol
Figure 1. Structures of selected flustramines with a prenyl group at C-3a
R
R
HO
CuCl, NaOMe
2-aminopyridine
heat
R
O
I
O
N
N
N
intramolecular
Claisen
P
P
P
Ullmann coupling
rearrangement
2-iodoindole A
pyranoindole B
spirocyclic
oxindole C
Scheme 1. One-pot intramolecular Ullmann coupling and Claisen rearrangement of 2-iodoindole A
bearing an allyl alcohol moiety
RESULTS AND DISCUSSION
The synthetic strategy of (–)-flustramine B (1) is depicted in Scheme 2. According to literature,6a (–)-1
can be synthesized from the known amide 16, which in turn can be derived from keto carboxylic acid 12
using conventional transformations. Enantioenriched spirocyclic oxindole 11 could be a potential
precursor of keto carboxylic acid 12 after oxidative cleavage. We believe that the asymmetryic quaternary
carbon center located at C-3a in 11 could be controlled by selecting one-pot intramolecular Ullmann
coupling and Claisen rearrangement as the key reactions, which causes an asymmetric transmission of the
tertiary alcohol of 2-iodoindole 10. However, the Ullmann coupling of 10 may occur intermolecularly
because of the presence of the aryl bromide in 10, which is a potential reactive site; this is different from
the structure of the debromo analogue used in the synthesis of debromoflustramine B.6e The deprotection
of the MOM group in oxindoles should be carried out at a particular step once the one-pot intramolecular

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807
Ullmann coupling and Claisen rearrangement are complete.8 The iodo-desilylation of 9 should be carried
out in a mild medium because of the acid-labile nature of the tertiary allylic alcohol present in its
side-chain. The 2-silylindole 9 can be synthesized by the Larock indole synthesis9 of monobrominated
o-iodoaniline 4 and silyl acetylene 7, which possesses an indispensable chiral center and is a derivative of
(–)-linalool. o-Iodoaniline 4 can be prepared from commercially available o-nitroaniline.
O
O
NHMe
N
CO2H
O
Me
N
N
H
Br
Br
O
N
Br
H
16
12
(–)-flustramine B (1)
I
Larock
indole
syntehsis
R'O
Br
NH2
Ullmann &
Claisen
4
+
R
O
N
N
TMSO
Br
Br
MOM
P
9 (R = TMS, R' = TMS)
10 (R = I, R' = H)
11 (P = H)
TMS
7
Scheme 2. Synthetic strategy of (–)-flustramine B (1)
The synthetic route to enantioenriched spirocyclic oxindole 11 is summarized in Scheme 3. We first
prepared the iodoaniline derivative 4 from o-nitroaniline. Regioselective monobromination of
o-nitroaniline was achieved using aq. HBr and aq. H2O2 in MeOH, which afforded 2 in 75% yield.10 The
bromoaniline 2 was then converted into iodonitrobenzene 3 through a diazoarene under conventional
conditions.11 Refluxing of 3 with Fe in AcOH-EtOH led to the formation of the desired brominated
iodoaniline 4 in excellent yield.12
Silyl acetylene 7 bearing a chiral center, which is the other reactant required for the Larock indole
synthesis, was prepared from (–)-linalool by the following three steps. First, the ozonolysis of (–)-linalool
(98% ee) at –78 °C in CH2Cl2 and pyridine and then the addition of Me2S gave lactol 5 in moderate
yield.13 Lactol 5 was then treated with Ohira-Bestmann reagent 1814 to produce hydroxyacetylene 6 in

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HETEROCYCLES, Vol. 79, 2009
71% yield. Finally, the hydroxy group and acetylene terminus in 6 were protected by TMS groups, and
the distillation of 6 (67 °C/3 mmHg) afforded the desired silyl acetylene 7 in 92% yield.
NH2
NH2
NO2
I
I
a
b, c
d
NO2
Br
Br
NO2
Br
NH2
o-nitroaniline
2
3
4
RO
O
O
e
f
O
HO
HO
P(OMe)2
R
N2
18
5
(–)-Linalool
(98% ee)
6 (R = H)
7 (R = TMS)
g
TMSO
HO
h
j, k
l
4
+
7
TMS
I
O
N
N
N
Br
Br
Br
R
MOM
H
8 (R = H)
9 (R = MOM)
10
11
i
Scheme 3. Reagents and conditions: (a) aq. HBr, aq. H2O2, MeOH, 0 °C→rt, 75%; (b) BF3·OEt2,
t-BuONO, THF, –30 °C; (c) KI, I2, rt, 88% (2 steps); (d) Fe, AcOH-EtOH, reflux, 91%; (e) O3, then Me2S,
CH2Cl2-pyridine, –78 °C, 66%; (f) 18, K2CO3, MeOH, rt, 71%; (g) n-BuLi, THF, –78 °C, then TMSCl,
–78 °C→rt, 92%; (h) Pd(OAc)2, PPh3, LiCl, K2CO3, DMF, 100 °C, 57%; (i) NaH, MOMCl, THF-DMF,
0 °C, 97%; (j) NIS, CH2Cl2, reflux; (k) TBAF, THF, 0 °C, 94% (2 steps); (l) CuCl, 2-aminopyridine,
NaOMe-MeOH, triglyme, 100 °C, 69%.
The Larock indole synthesis using iodoaniline derivative 4 and silyl acetylene 7 was performed under
typical conditions (LiCl, K2CO3, PPh3, Pd(OAc)2 in DMF at 100 °C) to afford the corresponding
2-silylindole 9 in 57% yield. The resulting silyl indole 8 was protected by a MOM group and its
iodo-desilylation was then examined. A solution of 1.2 equiv of ICl in CH2Cl2 was carefully added to
silyl indole 9 at –78 °C, which resulted in the formation of the dispensable 2-iodoindole 10 in moderate
yield (59%) after carrying out the deprotection of the TMS group on the tertiary alcohol. In contrast,
when 8 was treated with a solution of 1.05 equiv of NIS in CH2Cl2 at rt and warmed in a gentle reflux, the
yield of 10 improved significantly (94% yield of the two steps). 2-Iodoindole 10 was then subjected to the
key transformation reactions under the conditions specified by in our previous study to give the

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809
corresponding spirocyclic oxindole 11 in 69% yield; deiodinated indole was also produced in trace
amounts (6%). The formation of the corresponding intermolecular Ullmann adduct, 6-methoxy
spirocyclic oxindole, was not observed. Interestingly, this reaction involves not only the expected
intramolecular Ullmann coupling and Claisen rearrangement but also the deprotection of the MOM group
under basic conditions.15 The chiral HPLC analysis of the known debromo spirocyclic oxindole7a derived
from 11 revealed that 11 had an enantiomeric excess of 98%. This enantiomeric excess of the product
indicates that both intramolecular Ullmann coupling and Claisen rearrangement reactions were
stereospecific through a boat-like transition, as shown in Scheme 4.
OH
I
O
N
Br
N
H
Br
deprotection
Br
MOM
10
11
intramolecular
Ullmann
coupling
Claisen
rearrangement
O
O
O
Br
Br
N
N
N
Me
Me
Me
MOM
MOM
MOM
Scheme 4. Possible transition state of Claisen rearrangement
Scheme 5 summarizes the final transformation of the obtained spirocyclic oxindole 11 into
(–)-flustramine B (1) by our previously reported method6e but with a few modifications. The oxidative
cleavage of the cyclohexene ring in spirocyclic oxindole 11 occurred smoothly in the presence of a
catalytic amount of OsO4 with N-methyl morpholine N-oxide (NMO) as the co-oxidant; the resulting diol
was treated with NaIO4 to give ketoaldehyde. The addition of ketoaldehyde to a buffered solution of
16
NaClO2 afforded keto carboxylic acid 12 in good overall yield (84% from 11). The ketone carbonyl
group in 12 was converted into an exo-olefin by using the Wittig reaction in excess amount of
triphenylphosphonium methylide. The resulting alkene was then subjected to acid-catalyzed isomerization
using H2SO4 and MgSO4 to obtain carboxylic acid 14 bearing the desired prenyl group at C-3a.
Prenylations of this carboxylic acid and amide resulted in the formation of the corresponding ester 15

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having three prenyl groups in 18% yield in three steps. Treatment of the prenyl ester 15 with aq. MeNH2
in MeOH gave N-methyl amide 16 in 67% yield.
O
CO2H
CO2H
a-c
d
e
O
O
O
N
N
N
Br
Br
Br
H
H
H
11
12
13
O
O
CO2H
O
f
g
O
NHMe
O
O
N
N
N
Br
Br
Br
H
14
15
16
O
h
i
N
N
Me
Me
N
N
H
H
Br
Br
17
1
Scheme 5. Reagents and conditions: (a) OsO4, NMO, acetone-H2O, rt; (b) NaIO4, THF-H2O, rt; (c)
NaClO2, NaH2PO4·2H2O, 2-methyl-2-butene, t-BuOH-H2O-THF, rt, 84% (3 steps); (d) Ph3PCH3Br,
n-BuLi, THF, –25 °C→rt; (e) H2SO4, then MgSO4, 1,4-dioxane, 60 °C; (f) prenyl bromide, K2CO3,
acetone, reflux, 18% (for 3 steps); (g) aq. MeNH2, MeOH, rt, 67%; (h) AlH3·EtNMe2, THF, –20 °C, 96%;
(i) AlH3·EtNMe2, THF, rt, 93%.
To complete the synthesis of 1 from N-methyl amide 16, we used the method reported by Kawasaki and
co-workers.6a First, we attempted the direct conversion of 16 to 1 using 5 equiv of AlH3·EtNMe2 between
–15 °C and rt. However, this resulted in the formation of a mixture of amide 16 and desired 1.17 Thus, the
following reductions were carried out stepwise. The addition of amide 16 to 5 equiv of AlH3·EtNMe2 at
–20 °C afforded (–)-flustramide B (17) in 96% yield as a single diastereomer. The resultant 17 was

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811
treated with 1.5 equiv of AlH3·EtNMe2 at rt to reduce the unreacted lactum carbonyl group, and
(–)-flustramine B (1) was obtained in 93% yield. The 1H and 13C NMR spectra and the specific rotation of
1 synthesized by our method were consistent with those of the corresponding naturally occurring
compounds1c and of that synthesized by a previous method.6a
In conclusion, we have achieved total synthesis of (–)-flustramine B via sequential intramolecular
Ullmann coupling and Claisen rearrangement, which spirocyclic oxindole without a loss of its
stereochemical integrity. This approach offers a potentially useful synthetic route to pyrrolidinoindoline
alkaloids bearing a prenyl group at C-3a.
EXPERIMENTAL
1
13
General Techniques. H and C NMR spectra were recorded on a JEOL JNM-LD400 spectrometer
operating at either 400 MHz (1H) or 100 MHz (13C). Chemical shifts are reported in δ units and are
referenced to the solvent, i.e., 7.26/77.1 for CDCl3. Multiplicities are indicated as: br (broadened), s
(singlet), d (doublet), t (triplet), q (quartet), quint (quintet), sept (septet), or m (multiplet). Coupling
constants (J) are reported in Hertz (Hz). Infrared spectra were recorded on a Jasco FT-IR410 spectrometer.
Melting points were recorded on a Yanaco MP-3S. Electrospray ionization mass spectra were recorded on
an Applied Biosystems API QSTAR pulsar i as high resolution, using poly(ethylene glycol) as internal
standard. Thin-layer chromatography (TLC) was performed on silica gel 60 F254 (Merck 1.05715.0009)
plates. Flash column chromatography was performed on a PSQ100B silica gel (Fuji Silysia Co., Ltd.,
Japan) or on a Silica gel 60 N (63-210 µm; Kanto Chemical Co., Inc., Japan) and PSQ100B was usually
used. THF and Et2O were purchased from Wako Pure Chemical Industries Ltd. in anhydrous grade.
CH2Cl2 was distilled from CaH2 immediately before use. Diisopropylethylamine, pyridine, and
triethylamine were distilled from CaH2 and stored over KOH. Toluene and DMF were distilled from
CaH2 and stored over activated MS 4A. Triglyme was distilled from LiAlH4 and stored over activated MS
4A. All moisture sensitive reactions were performed under a static argon atmosphere in oven-dried of
flame-dried glassware.
4-Bromo-2-nitroaniline (2). This compound was synthesized according to literature.10 To a solution of
o-nitroaniline (6.2 g, 45 mmol) in MeOH (92 mL) was cooled to 0 °C and 47% aq. HBr (15.5 g, 90
mmol) was added slowly, and 30% aq. H2O2 (5.1 mL, 45 mmol) was added dropwise. The reaction
mixture was left at rt for 21 h. The resulting mixture was concentrated under reduced pressure. The
residue was added water and then extracted three times with AcOEt. The combined organic layer was

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washed brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was
purified two times by silica gel column chromatography (hexane/AcOEt = 9:1) to afford 2 (7.34 g, 75%
1
yield) as an orange solid. Rf 0.42 (hexane/AcOEt = 2:1); H NMR (400 MHz, CDCl3) δ 8.28 (d, J = 2.2
13
Hz, 1H), 7.43 (dd, J = 8.8, 2.2 Hz, 1H), 6.73 (d, J = 8.8 Hz, 1H), 6.08 (br, 2H); C NMR (100 MHz,
CDCl3) δ 143.6, 138.5, 132.4, 128.3, 120.4, 107.8.
4-Bromo-1-iodo-2-nitrobenzene (3). This compound was synthesized according to literature with a
slight modification.11 BF3·OEt2 (16 mL, 126 mmol) was cooled –30 °C, and added dropwise a solution of
2 in dry THF (100 mL). The mixture was stirred for 10 min and added to dropwise a solution of
t-BuONO (13 mL, 111 mmol) in THF (80 mL). The reaction mixture was allowed to warm to −10 °C at
which time 160 mL of diethyl ether was added and mixture was allowed to stir at rt for 1 h until a pale
solid precipitated. The solid was filtered and washed with ether to afford a pale solid which was then
slowly added KI (7.1 g, 42.6 mmol), I2 (5.4 g, 21.3 mmol) and MeCN (120 mL). The reaction mixture
was stirred at rt for 1 h 15 min. After addition of a saturated aqueous solution of Na2S2O3 (250 mL), the
mixture was extracted two times with CH2Cl2. The combined organic layer was dried over Na2SO4,
filtered, and concentrated under reduced pressure to afford 3 (8.61 g, 88% yield for the two steps) as a
yellow solid. Rf 0.78 (hexane/AcOEt = 2:1); 1H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 2.2, 1H), 7.89 (d,
13
J = 8.3, 1H), 7.40 (dd, J = 8.5, 2.2 Hz, 1H); C NMR (100 MHz, CDCl3), δ 153.4, 142.9, 136.4, 128.4,
122.6, 84.3.
5-Bromo-2-iodoaniline (4). This compound was synthesized according to literature with a slight
modification.12 To a mixture of 3 (8.36 g, 25.3 mmol) and Fe (6.13 g, 108 mmol) in AcOH (45 mL) and
EtOH (45 mL) was refluxed for 1 h 15 min. The mixture was cooled to rt. After addition of a saturated
aqueous solution of NaHCO3 (200 mL), the mixture was extracted four times with Et2O. The combined
organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (hexane/AcOEt = 19:1) to afford 4 (6.89 g, 91% yield) as a
cream solid. Rf 0.57 (hexane/AcOEt = 4:1); 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 8.3 Hz, 1H), 6.88
13
(d, J = 2.2 Hz, 1H), 6.60 (dd, J = 8.3, 2.2 Hz, 1H), 4.14 (br, 2H); C NMR (100 MHz, CDCl3) δ 147.9,
139.8, 123.0, 122.7, 117.0, 81.9.
Lactol 5. This reaction was carried out according to literatures.13 A solution of (R)-(−)-linalool (11.8 mL,
66.1 mmol, 98% ee) in CH2Cl2 (540 mL) and pyridine (16 mL) was stirred and cooled to −78 °C. Ozone
was bubbled through the reaction mixture for 6 h at that temperature. After purging with O2 and addition
of Me2S (14.6 mL), the solution was allowed to warm slowly to rt overnight. The resulting mixture was

HETEROCYCLES, Vol. 79, 2009
813
washed successively with brine, aq. CuSO4, brine, and water. And then organic layer was dried over
Na2SO4, filtered, and concentrated under reduced pressure. The residue purified by silica gel
chromatography (hexane/AcOEt = 90:10 → 85/15 → 75/25) to afford lactol 5 (5.56 g, 66% yield) as a
light yellow oil. Rf 0.29 (hexane/AcOEt = 3:1).
(R)-3-Methyl-1-hepten-6-yn-3-ol (6). To a suspension of lactol 5 and K2CO3 (62.3 g, 451 mmol) in
MeOH (700 mL) was added a solution of diazophosphonate (32.1 g, 167 mmol) in MeOH (50 mL) via a
cannula, and then the reaction mixture was stirred at rt for 33 h. The resulting mixture was filtrated, and
concentrated under reduced pressure. The residue was diluted with brine. The mixture was extracted with
ether. The combined organic layer was dried over MgSO4, filtered, and concentrated under reduce
pressure. The residue purified by fractional distillation (53 °C/6 mmHg) to afford 6 (9.7 g, 71% yield) as
a colorless oil. Rf 0.47 (hexane/AcOEt = 3:1); 1H NMR (400 MHz, CDCl3) δ 5.87 (dd, J = 17.4, 10.8 Hz,
1H), 5.24 (dd, J = 17.4, 1.2 Hz, 1H), 5.09 (dd, J = 10.8, 1.2 Hz, 1H), 2.33-2.19 (m, 3H), 1.98 (t, J = 2.7
13
Hz, 1H), 1.83 (ddd, J = 13.8, 9.0, 7.1 Hz, 1H), 1.76 (ddd, J = 13.8, 9.3, 6.1 Hz, 1H), 1.29 (s, 3H); C
NMR (100 MHz, CDCl3) δ 143.9, 112.4, 84.6, 72.8, 68.5, 40.3, 27.8, 13.2; IR (neat, cm−1) 3420, 2118,
1638; HRMS (EI) calcd for C8H12O: 124.0888, found: 124.0882; [α]D24 −2.47 (c 1.14, CHCl3).
Silylacetylene 7. To a solution of 6 (14.7 g, 118 mmol) in dry THF (237 mL) was added dropwise n-BuLi
(2.66 M in hexane, 102 mL, 272 mmol) at −78 °C. After the mixture was stirred for 1 h at that
temperature, TMSCl (34.5 mL, 272 mmol) was then added dropwise. The reaction mixture was stirred for
3 h at −78 °C, and then allowed to warm slowly to rt over 9 h. The mixture was added to saturated
aqueous NaHCO3, the resulting mixture was extracted with hexane. The organic layer was dried over
MgSO4, filtered, and concentrated under reduced pressure. The residue purified by fractional distillation
1
(67 °C/3 mmHg) to afford 7 (29.2 g, 92% yield) as a colorless oil. Rf 0.89 (hexane/AcOEt = 10:1); H
NMR (400 MHz, CDCl3) δ 5.80 (dd, J = 17.3, 10.7 Hz, 1H), 5.12 (dd, J = 17.3, 1.5 Hz, 1H), 5.01 (dd, J =
10.7, 1.5 Hz, 1H), 2.27 (ddd, J = 16.7, 9.8, 6.4 Hz, 1H), 2.20 (ddd, J = 16.7, 9.5, 6.6 Hz, 1H), 1.79-1.68
13
(m, 2H), 1.31 (s, 3H), 0.134 (s, 9H), 0.106 (s, 9H); C NMR (100 MHz, CDCl3) δ 144.4, 112.3, 108.0,
83.6, 75.1, 42.3, 27.1, 14.6, 2.25, 0.01; IR (neat, cm−1) 2176, 1251, 841; HRMS (EI) calcd for
C14H28OSi2: 268.1679, found: 268.1684; [α]D23 −4.04 (c 1.57, CHCl3).
2-Silylindole 8. To a solution of o-iodoaniline 4 (8.31 g, 27.9 mmol) and silylacetylene 7 (12 g, 44.7
mmol) in DMF (140 mL) was successively added dry LiCl (1.18 g, 27.9 mmol) and K2CO3 (9.63 g, 69.9
mmol), PPh3 (366 mg, 1.39 mmol), and Pd(OAc)2 (341 mg, 1.39 mmol). Argon was bubbled through the
resulting mixture for 15 min at rt, and then the reaction mixture was stirred vigorously at 100 °C for 8.5 h.

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HETEROCYCLES, Vol. 79, 2009
After cooling to rt, the resulting mixture was filtered through a pad of Celite, and filtrate was concentrated
under reduced pressure. The residue was added a saturated aqueous solution of NH4Cl and H2O. The
mixture was extracted with hexane/AcOEt = 1:1 solvent, and organic layer was washed two times with
H2O, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The
residue was purified by silica gel chromatography (hexane/AcOEt = 20:1; hexane/diisopropyl ether =
50:1; hexane/toluene = 20:1) to afford 8 (6.93 g, 57% yield) as a light yellow solid. mp 60-61 °C; Rf 0.54
(hexane/AcOEt = 6:1); 1H NMR (400 MHz, CDCl3) δ 7.79 (br s, 1H), 7.48 (d, J = 1.7 Hz, 1H), 7.40 (d, J
= 8.3 Hz, 1H), 7.16 (dd, J = 8.4, 1.6 Hz, 1H), 5.99 (dd, J = 17.2, 10.6 Hz, 1H), 5.21 (dd, J = 17.3, 1.7 Hz,
1H), 5.09 (dd, J = 10.7, 1.5 Hz, 1H), 2.90-2.75 (m, 2H), 1.80-1.71 (m, 2H), 1.42 (s, 3H), 0.30 (s, 9H),
13
0.16 (s, 9H) C NMR (100 MHz, CDCl3) δ −0.7 (CH3), 2.6 (CH3), 20.3 (CH2), 26.9 (CH3), 45.9 (CH2),
75.8 (C), 112.2 (CH2), 113.7 (CH), 115.8 (C), 120.0 (CH), 122.2 (CH), 125.9 (C), 127.7 (C), 133.7 (C),
139.0 (C), 145.3 (CH); IR (KBr, cm−1) 3451, 2954, 1604, 1568, 1514, 1250, 1049, 840; HRMS (ESI)
calcd for C20H32NONaSi2Br: 460.1098, found: 460.1097; [α]D24 –0.233 (c 0.99, CHCl3).
N-MOM indole 9. To a suspension of NaH (55w%, 382 mg, 8.75 mmol) in THF (8.9 mL) and DMF (4.2
mL) at 0 °C was added dropwise a solution of 2-silylindole 8 (2.74 g, 6.25 mmol) in THF (12 mL) over
20 min. After the resulting mixture was stirred at that temperature for 1 h, MOMCl (0.55 mL, 7.19 mmol)
was added dropwise via syringe. The reaction mixture was stirred at 0 °C for 2 h, and H2O was added.
The resulting mixture was extracted with ether, and the organic layer was washed with brine, dried over
Na2SO4, filtrated, and concentrated under reduced pressure. The residue was purified by silica gel
chromatography (hexane/AcOEt = 95:1) to afford 9 (2.93 g, 97% yield) as a yellow oil. Rf 0.61
(hexane/AcOEt = 6:1); 1H NMR (400 MHz, CDCl3) δ 7.54 (d, J = 1.7 Hz, 1H), 7.38 (d, J = 8.3 Hz, 1H),
7.18 (dd, J = 8.4, 1.6 Hz, 1H), 5.99 (dd, J = 17.3, 10.7 Hz, 1H), 5.40 (s, 2H), 5.20 (dd, J = 17.3, 1.5 Hz,
1H), 5.09 (dd, J = 10.7, 1.5 Hz, 1H), 3.19 (s, 3H), 2.93-2.70 (m, 2H), 1.73 (br t, J = 8.6 Hz, 2H), 1.42 (s,
13
3H), 0.43 (s, 9H), 0.16 (s, 9H); C NMR (100 MHz, CDCl3); δ 1.2 (CH3), 2.6 (CH3), 20.0 (CH2), 26.8
(CH3), 46.0 (CH2), 55.5 (CH3), 75.8 (C), 75.9 (CH2), 112.2 (CH2), 112.4 (CH), 116.6 (C), 120.2 (CH),
122.6 (CH), 128.0 (C), 128.1 (C), 135.8 (C), 141.0 (C), 145.3 (CH); IR (neat, cm−1) 2954, 1595, 1566,
1249, 1052, 839; HRMS (ESI) calcd for C22H36NO2NaSi2Br: 504.1360, found: 504.1340; [α]D24 +1.21 (c
0.933, CHCl3).
2-Iodoindole 10. To a solution of 2-silylindole 9 (679 mg, 1.41 mmol) in CH2Cl2 (28 mL) was added NIS
(334 mg, 1.48 mmol). The reaction mixture was refluxed for 8 h in the dark. After the reaction mixture
was cooled to rt, a saturated aqueous solution of Na2S2O3 was then added. The resulting mixture was

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815
extracted two times with CH2Cl2, and the combined organic layer was dried over Na2SO4, filtrated, and
concentrated under reduced pressure to afford the crude iodide.
To a solution of the crude iodide in dry THF (28 mL) was added TBAF (1 M in THF, 2.4 mL, 2.8 mmol)
at 0 °C. After the reaction mixture was stirred for 8 h at 0 °C, a saturated aqueous solution of NaHCO3
was added. The resulting mixture was extracted two times with AcOEt and the combined organic layer
was dried over Na2SO4, filtrated, and concentrated under pressure. The residue was purified by silica gel
chromatography (hexane/AcOEt = 8:1) to afford 10 (618 mg, 94% yield) as a white solid. mp 69-72 °C;
1
Rf 0.46 (hexane/AcOEt = 2:1); H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 1.7 Hz, 1H), 7.38 (d, J = 8.3
Hz, 1H), 7.22 (dd, J = 8.3, 1.7 Hz, 1H), 6.03 (dd, J = 17.5, 10.9 Hz, 1H), 5.45 (s, 2H), 5.32 (dd, J = 17.3,
1.0 Hz, 1H), 5.16 (dd, J = 17.3, 1.0 Hz, 1H), 3.29 (s, 3H), 2.78 (ddd, J = 14.2, 10.8, 6.4 Hz, 1H), 2.73
(ddd, J = 14.2, 10.8, 6.4 Hz, 1H), 18.2 (ddd, J = 13.6, 10.8, 6.4 Hz, 1H), 1.75 (ddd, J = 13.6, 10.8, 6.4 Hz,
13
1H), 1.39 (s, 3H); C NMR (100 MHz, CDCl3) δ 21.9 (CH2), 28.0 (CH3), 42.0 (CH2), 55.9 (CH3), 73.1
(C), 77.3 (CH2), 86.1 (C), 112.2 (CH2), 113.1 (CH), 116.3 (C), 119.4 (CH), 123.1 (C), 123.5 (CH), 127.2
(C), 139.3 (C), 144.6 (CH); IR (KBr, cm−1) 3444, 2928, 1600, 1459, 1336, 1089, 916, 845, 804; HRMS
(ESI) calcd for C16H19NO2NaBrI: 485.9536, found: 485.9536; [α]D24 −10.87 (c 0.90, CHCl3).
Enantiomeric excess was determined by HPLC using a chiral column (DAICEL Chiralpak® AD-H;
hexane/i-PrOH = 98:2; flow rate 1.0 mL/min; oven 30 °C; 10 Rt = 39.0 min, enantiomer Rt = 33.4 min;
monitoring 254 nm; 98% ee). HRMS (ESI) calcd for 10 C16H19NO2NaBrI: 485.9536, found: 485.9526,
HRMS (ESI) calcd for enantiomer C16H19NO2NaBrI: 485.9536, found: 485.9516.
Spirocyclic oxindole 11. A dry two-necked round-bottomed flask was charged with CuCl (24 mg, 0.24
mmol), 2-aminopyridine (23 mg, 0.24 mmol) and small amount of triglyme. The flask was evacuated and
backfilled with argon. 2-Iodoindole 10 (564 mg, 1.2 mmol) in triglyme (24 mL) was added. After
bubbling with argon for 3 min, NaOMe solution in MeOH (25w/w%, 1.1 mL, 4.8 mmol) was added. The
reaction mixture was stirred vigorously at 100 °C for 26 h. After cooling to rt, the reaction mixture was
filtered through Celite, and filtrate was concentrated under reduced pressure. The residue was added a
saturated aqueous solution of NH4Cl and H2O. The mixture was extracted two times a solvent of
hexane/AcOEt = 5:1. The combined organic layer was washed three times with H2O, dried over Na2SO4,
filtered, and concentrated under reduced pressure. The residue purified by silica gel chromatography
(hexane/AcOEt = 8:1) to afford spirocyclic oxindole 11 (219 mg, 69% yield) as a white solid. mp
150-155 °C; Rf 0.39 (hexane/AcOEt = 2:1); 1H NMR (400 MHz, CDCl3) δ 8.08 (br s, 1H), 7.11 (dd, J =
7.9, 1.8 Hz, 1H) 7.08 (d, J = 1.7 Hz, 1H), 7.02 (d, J = 8.1 Hz, 1H), 5.55-5.54 (m, 1H), 2.26-2.59 (m, 1H),
2.20-2.19 (m, 2H), 2.07 (ddd, J = 12.4, 9.6, 7.6 Hz, 1H), 2.00-1.93 (m, 1H), 1.80 (s, 3H); 13C NMR (400
MHz, CDCl3) δ 23.5 (CH3), 26.5 (CH2), 29.5 (CH2), 31.9 (CH2), 46.1 (C), 112.9 (CH), 118.5 (CH), 121.1

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(C), 125.2 (CH), 125.6 (CH), 133.8 (C, 2 carbons), 141.1 (C), 182.6 (C); IR (KBr, cm−1) 3112, 2905,
2837, 1715, 1602, 1455, 1322, 1228, 806; HRMS (ESI) calcd for C14H14NONaBr: 314.0150, found:
314.0156; [α]D24 +132.3 (c 0.293, CHCl3).
Keto carboxylic acid 12. To a solution of spirocyclic oxindole 11 (457 mg, 1.56 mmol) in acetone (13
mL) and H2O (3 mL) was added OsO4 (2.35 mL, 0.02 M in t-BuOH, 0.047 mmol) and NMO (274 mg,
2.34 mmol). After the reaction mixture was stirred at rt for 4 h, a saturated aqueous solution of Na2S2O3
was added. The resulting mixture was extracted two times with AcOEt, and the combined organic layer
was dried over Na2SO4, filtrated, and concentrated under reduced pressure to afford the crude diol.
To the mixture of the crude diol in THF (14 mL) and H2O (14 mL) was added NaIO4 (1.3 g, 6.24 mmol).
After the reaction mixture was stirred at rt for 4 h, a saturated aqueous solution of Na2S2O3 was added.
The resulting mixture was extracted two times with AcOEt. The combined organic layer was dried over
Na2SO4, filtrated, and concentrated under reduced pressure to afford the crude ketoaldehyde.
To the solution of the crude ketoaldehyde in THF (10 mL), t-BuOH (20 mL), and H2O (20 mL) was
added 2-methy-2-butene (1.6 mL, 15.6 mmol) and NaH2PO4·2H2O (733 mg, 4.7 mmol) and NaClO2 (425
mg, 4.7 mmol). The reaction mixture was stirred at rt for 11 h. The resulting mixture was concentrated
under reduced pressure. The residue was diluted with 1 N HCl and extracted five times with CHCl3. The
combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The
residue purified by silica gel chromatography (hexane/AcOEt = 1:1 → CHCl3/MeOH = 6:1) to afford 12
1
(448 mg, 84% yield) as a white solid. mp 58-63 °C; Rf 0.36 (CHCl3/MeOH = 3:1); H NMR (400 MHz,
CDCl3) δ 9.45 (s 1H), 7.17 (dd, J = 7.8, 1.5 Hz, 1H), 7.06 (d, J = 1.5 Hz, 1H), 6.98 (d, J = 8.1 Hz), 3.03
13
(d, J = 16.6 Hz, 1H), 2.82 (d, J = 16.3 Hz, 1H), 2.31-2.23 (m, 1H), 2.05-1.91 (m, 3H), 1.98 (s, 3H); C
NMR (100 MHz, CDCl3) δ 29.9 (CH3), 31.2 (CH2), 37.3 (CH2), 40.9 (CH2), 49.3 (C), 114.0 (CH), 122.1
(C), 124.2 (CH), 125.8 (CH), 129.6 (C), 142.8 (C), 173.5 (C), 182.1 (C), 207.3 (C); IR (KBr, cm−1) 3263,
24
1717, 1611, 1482, 1187; HRMS (ESI) calcd for C14H14NO4NaBr: 361.9998, found: 362.0002; [α]D
−36.27 (c 0.46, CHCl3).
exo-Methylene 13. To a solution of methyltriphenylphosphonium bromide (1.76 g, 4.94 mmol), dried at
70-80 °C for 20 h under reduced pressure before use, in THF (12 mL) was added n-BuLi (2.95 mL, 1.59
M in hexane, 2.95 mmol) at −25 °C. After stirring at −25 °C for 1 h, a solution of 12 (160 mg, 0.47
mmol) in THF (4 mL) was added at −25 °C. After stirring at −25 °C for 7 h, the reaction mixture was
allowed to warm −5 °C and stirred for 15 h. The reaction mixture was allowed to warm rt and stirred for 4
h .The reaction mixture was added to a saturated aqueous NH4Cl and 1 N HCl. The resulting mixture was
extracted four times with CH2Cl2. The combined organic layer was dried over Na2SO4, filtered, and

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817
concentrated under reduced pressure. The residue purified by silica gel chromatography (CHCl3/MeOH =
40:1 → 25:1 → 5:1; CHCl3/i-PrOH = 10:1) to afford 13 (~92 mg, ~57% yield) as a white solid; Rf 0.36
(CHCl3/MeOH = 5:1); 1H NMR (400 MHz, CDCl3) δ 8.68 (br s, 1H), 7.19 (dd, J = 7.8, 1.6 Hz, 1H), 7.08
(d, J = 1.6 Hz, 1H), 7.02 (d, J = 7.8 Hz, 1H), 4.65 (s, 1H), 4.56 (s, 1H), 3.05 (d, J = 16.1 Hz, 1H), 2.83 (d,
J = 16.1 Hz, 1H), 2.02-1.96 (m, 1H), 1.88-1.77 (m, 2H), 1.61-1.53 (m, 1H), 1.61 (s, 3H).
endo-Alkene 14. A solution of 13 (~92 mg, ~0.27 mmol) in 1,4-dioxane (2.7 mL) was added to H2SO4
(165 mg, 95%, 1.6 mmol). The mixture was stirred at 60 °C for 6 h and MgSO4 (920 mg, 10w/w based on
97) was added. After 10 h of additional stirring at 60 °C, the reaction mixture was cooled to rt and then
poured into ice water. This mixture was extracted four times with CHCl3 and the combined organic layer
was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (CHCl3/MeOH = 10:1) to afford 14 (~46.5 mg, ~50% yield) as a white
solid. Rf 0.36 (CHCl3/MeOH = 5:1); 1H NMR (400 MHz, CDCl3) δ 8.39 (br s, 1H), 7.15 (dd, J = 7.8, 1.6
Hz, 1H), 7.05 (d, J = 1.7 Hz, 1H), 7.00 (d, J = 8.0 Hz, 1H), 4.88 (t, J = 7.8 Hz, 1H), 3.04 (d, J = 16.6 Hz,
1H), 2.86 (d, J = 16.6 Hz, 1H), 2.42 (t, J = 7.8 Hz, 2H), 1.62 (s, 3H), 1.48 (s, 3H).
Prepnyl ester 15. To a solution of 14 (~50.4 mg, ~0.15 mmol) in acetone (3 mL) was added K2CO3 (243
mg, 1.76 mmol) and prenyl bromide (0.18 mL, 1.5 mmol). The reaction mixture was refluxed for 19 h.
After the reaction mixture was cooling to rt, the reaction mixture was filtered through a pad of Celite, and
filtrate was concentrated under reduced pressure. The residue was added AcOEt. The mixture was washed
two times with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (hexane/AcOEt = 30:1) to afford prenyl ester 15 (41
1
mg, 18% yield from keto carboxylic acid 12) as a colorless oil. Rf 0.55 (hexane/AcOEt = 3:1); H NMR
(400 MHz, CDCl3) δ 7.11 (dd, J = 7.8, 1.7 Hz, 1H), 7.01 (d, J = 7.8 Hz, 1H), 6.88 (d, J = 1.7 Hz, 1H),
5.10 (tt, J = 6.6, 1.3 Hz, 1H), 4.99 (tt, J = 7.3, 1.3 Hz, 1H), 4.80 (tt, J = 7.6, 1.3 Hz, 1H), 4.45 (dd, J =
15.6, 6.6 Hz, 1H), 4.39 (dd, J = 12.3, 7.3 Hz, 1H), 4.25 (dd, J = 12.3, 7.3 Hz, 1H), 4.12 (dd, J = 15.6, 6.6
Hz, 1H), 3.02 (d, J = 16.3, 1H), 2,85 (d, J = 16.3 Hz, 1H), 2.42 (dd, J = 14.4, 7.6 Hz, 1H), 2.37 (dd, J =
13
14.0, 8.0 Hz, 1H), 1.83 (s, 3H), 1.74 (s, 3H), 1.68 (s, 3H), 1.58 (s, 3H), 1.55 (s, 3H), 1.47 (s, 3H); C
NMR (100 MHz, CDCl3) δ 178.6 (C), 169.7 (C), 145.0 (C), 139.2 (C), 136.6 (C), 136.5 (C), 130.2 (C),
124.5 (CH), 124.1 (CH), 121.5 (C), 118.3 (CH), 118.0 (CH), 116.6 (CH), 111.9 (CH), 61.4 (CH2), 49.7
(C), 40.0 (CH2), 38.2 (CH2), 36.4 (CH2), 25.9 (CH3), 25.7 (CH3), 25.6 (CH3), 18.2 (CH3), 18.0 (CH3),
17.8 (CH3); IR (neat, cm−1) 2925, 1730, 1604, 1171, 594; HRMS (ESI) calcd for C25H32NO3NaBr:
496.1457, found: 496.1460; [α]D23 −11.9 (c 1.36, CHCl3).

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HETEROCYCLES, Vol. 79, 2009
Methyl amide 16. To a solution of prenyl ester 15 (20.4 mg, 0.043 mmol) in MeOH (0.5 mL) was added
40% aqueous MeNH2 (0.5 mL). The reaction mixture was stirred at rt for 35 h. The mixture was diluted
with AcOEt and the organic layer was washed two times with a saturated aqueous NH4Cl and one time
with brine, dried over Na2SO4, filtrated, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (hexane/AcOEt = 2:1 → CHCl3/MeOH = 12:1) to afford
methyl amide 16 (12.1 mg, 67% yield) as a white solid. mp 155-159 °C; Rf 0.45 (CHCl3/MeOH = 12:1);
1H NMR (400 MHz, CDCl3) δ 7.16 (dd, J = 7.8, 1.7 Hz, 1H), 7.09 (d, J = 7.8 Hz, 1H), 6.90 (d, J = 1.7 Hz,
1H), 5.99 (s, 1H), 5.06 (tt, J = 6.6, 1.3 Hz, 1H), 4.75 (tt, J = 7.6, 1.3 Hz, 1H), 4.39 (dd, J = 15.6, 6.6 Hz,
1H), 4.19 (dd, J = 15.6, 6.6 Hz, 1H), 2.80 (d, J = 14.9 Hz, 1H), 2.68 (d, J = 14.2 Hz, 1H), 2.65 (d, J = 4.9
13
Hz, 3H), 2.48 (d, J = 7.6 Hz, 2H), 1.82 (s, 3H), 1.73 (s, 3H), 1.57 (s, 3H), 1.46 (s, 3H); C NMR (100
MHz, CDCl3) δ 179.3 (C), 169.3 (C), 144.2 (C), 136.9 (C), 136.4 (C), 130.4 (C), 125.1 (CH), 124.6 (CH),
121.5 (C), 118.0 (CH), 116.7 (CH), 112.1 (CH), 50.5 (C), 42.2 (CH2), 38.2 (CH2), 36.0 (CH2), 26.2 (CH3),
25.8 (CH3), 25.7 (CH3), 18.2 (CH3), 18.0 (CH3); IR (KBr, cm−1) 3272, 3096, 2973, 2916, 1722, 1630,
1603, 1160; HRMS (ESI) calcd for C21H27N2O2NaBr: 441.1148, found: 441.1149; [α]D23 −14.34 (c 0.81,
CHCl3).
(−)-Flustramide B (17). To a solution of 16 (5.3 mg, 0.0126 mmol) in THF was added dropwise
AlH3·EtNMe2 (0.5 M in toluene, 0.13 mL, 0.065 mmol) at −20 °C. After the reaction mixture was stirred
for 40 min at −20 °C, THF-H2O (v/v = 1:1) was added dropwise. The resulting mixture was added to a
saturated aqueous NaHCO3, and extracted two times with AcOEt. The organic layer was dried over
Na2SO4, filtrated, and concentrated under reduced pressure. The residue was purified by silica gel column
chromatography (hexane/AcOEt = 2:1) to afford (−)-flustramide B (17) (4.9 mg, 96% yield) as a colorless
1
oil. Rf 0.37 (hexane/AcOEt = 1:3); H NMR (400 MHz, CDCl3) δ 6.85 (br s, 2H), 6.60 (br s, 1H),
5.20-5.16 (m, 1H), 4.98-4.91 (m, 1H), 4.72 (s, 1H), 3.96 (dd, J = 16.0, 6.3 Hz, 1H), 3.89 (dd, J = 15.9, 7.1
Hz, 1H), 2.87 (s, 3H), 2.64 (s, 2H), 2.37 (dd, J = 14.7, 7.8 Hz, 1H), 2.32 (dd, J = 15.0, 6.8 Hz, 1H), 1.75
(s, 3H), 1.74 (s, 3H), 1.70 (s, 3H), 1.56 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 172.8, 150.6, 136.1, 136.0,
134.3, 124.4, 122.2, 121.5, 120.1, 118.2, 111.7, 87.4, 49.6, 46.6, 41.7, 37.4, 28.0, 26.0, 25.7, 18.1(4),
18.1(3); IR (neat, cm−1) 2967, 2913, 1696, 1597, 668; HRMS (ESI) calcd for C21H27N2ONaBr: 425.1198,
found: 425.1205; [α]D23 −117.37 (c 0.30, CHCl3), [lit.,6a [α]D18 −116.1 (c 1.72, CHCl3)].
(−)-Flustramine B (1). To a solution of 17 (4.9 mg, 0.0117 mmol) in THF was added dropwise
AlH3·EtNMe2 (0.052 mL, 0.5 M in toluene, 0.026 mmol) at rt. After the reaction mixture was stirred at rt
for 10 min, THF-H2O (v/v = 1:1) was added dropwise. The resulting mixture was added to a saturated

HETEROCYCLES, Vol. 79, 2009
819
aqueous NaHCO3, and extracted two times with AcOEt. The organic layer was dried over Na2SO4,
filtrated, and concentrated under reduced pressure. The residue was purified by silica gel column
chromatography (hexane/AcOEt = 2:1) to afford (−)-flustramine B (1) (4.2 mg, 93% yield) as a colorless
oil. Rf 0.32 (hexane/AcOEt = 1:3); 1H NMR (400 MHz, CDCl3) δ 6.80 (d, J = 7.8 Hz, 1H), 6.73 (dd, J =
7.8, 1.7 Hz, 1H), 6.49 (d, J = 1.7 Hz, 1H), 5.14-5.11 (m, 1H), 4.95-4.91 (m, 1H), 4.28 (s, 1H), 3.88 (dd, J
= 16.1, 5.6 Hz, 1H), 3.79 (dd, J = 16.1, 7.3 Hz, 1H), 2.67 (ddd, J = 9.4, 6.6, 3.4 Hz, 1H), 2.55 (td, J = 9.3,
5.8 Hz, 1H), 2.47 (s, 3H), 2.83 (d, J = 7.6 Hz, 2H), 2.03 (ddd, J = 11.7, 9.0, 6.6 Hz, 1H), 1.86 (ddd, J =
13
12.0, 5.8, 3.4 Hz, 1H), 1.71 (br s, 6H), 1.65 (br s, 3H), 1.57 (br s, 3H); C NMR (100 MHz, CDCl3)
δ 153.1, 134.78, 134.76, 133.8, 124.0, 121.3, 120.7, 120.4, 119.9, 110.0, 91.6, 56.8, 52.8, 46.2, 39.0, 38.3,
38.1, 25.9, 25.7, 18.15, 18.09; IR (neat, cm−1) 2965, 2928, 2792, 1599, 1485, 915; HRMS (ESI) calcd for
23
18
C21H29N2Br+H: 389.1586, found: 389.1589; [α]D −115.3 (c 0.27, CHCl3), [lit.,6a [α]D −105.9 (c 0.77,
CHCl3)].
ACKNOWLEDGEMENTS
This work was supported by a Grant-Aid for Young Scientists (B) (KAKENHI 19790026) from the
Ministry of Education, Culture, Sports, Science and Technology of Japan, NOVARTIS Foundation
(Japan) for the Promotion of Science, and Chugai Pharmaceutical Co., Ltd (A.N.). We thank Takasago
International Corporation for a generous gift of (–)-linalool.
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15. The investigation of the scope and limitation of the present method of deprotection is currently being
carried out and its results will be described in due course.
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17. Kawasaki and co-workers have also reported a similar result in which the yield of 1 synthesized
using 5 equiv of AlH3·EtNMe2 at rt was low (34%).