Unique reactivity of α-alkoxy ginkgolide lactones to nucleophilic reagents: Preparation of new lactol derivatives

Article abstract of DOI:10.1246/bcsj.78.1843

It has been found that nucleophilic reagents, i.e., NaBH₄, Grignard reagents, and alkyl lithium, uniquely react with the α-alkoxy- or acyloxy-lactone moieties in ginkgolide and F-seco-ginkgolides to give rise to lactol derivatives. The reaction

Full text of DOI:10.1246/bcsj.78.1843

ꢀ 2005 The Chemical Society of Japan
Bull. Chem. Soc. Jpn., 78, 1843–1850 (2005) 1843
Unique Reactivity of ꢀ-Alkoxy Ginkgolide Lactones
to Nucleophilic Reagents: Preparation of New Lactol Derivatives
y
ꢀ;
ꢀ
ꢀ
Katsunori Tanaka, Marc Pimentel, Nina Berova, and Koji Nakanishi
Department of Chemistry, Columbia University, 3000 Broadway, New York, New York 10027, U. S. A.
Received April 25, 2005; E-mail: ktzenori@chem.sci.osaka-u.ac.jp
It has been found that nucleophilic reagents, i.e., NaBH4, Grignard reagents, and alkyl lithium, uniquely react with
the ꢀ-alkoxy- or acyloxy-lactone moieties in ginkgolide and F-seco-ginkgolides to give rise to lactol derivatives. The
reaction is rapid and stops at the lactol stage; the strong coordination of Na, Mg, and Li metals to the conformationally
rigid cage structure is involved in both the initiation and termination stages. The NaBH4 reduction of F-seco-ginkgolides
gives rise to an equilibrium mixture of ꢀ- and ꢁ-lactols, the separation of which becomes only possible after acylation by
p-phenylbenzoic acid. The resulting acyl-lactol stereogenic centers were elucidated by both NOE and the CD/FDCD
exciton chirality method utilizing the sterically hindered 7-hydroxyl. On the other hand, the alkylation of ginkgolide
B derivatives proceeds regio- and stereoselectively at the C-11 lactone group, resulting from the approach of Grignard
and alkyl lithium reagents to the convex face of the cage-shaped ginkgolide molecule. The additional new stereogenic
centers of the quaternary lactol hydroxyls have been determined by NOE. This facile alkylation protocol gives rise to a
deep-seated skeletal transformation of ginkgolides, resulting in a new class of ball-shaped heptacyclic ginkgolide deriv-
atives via ‘‘olefin/olefin’’ and ‘‘olefin/alkyne’’ ring-closing metathesis.
Ginkgolides from the Ginkgo biloba tree are diterpenes with
R1 R2 R3
O
a rigid cage structure consisting of six five-membered rings
and a unique t-Bu group (Fig. 1).1 Ginkgolides exhibit a vari-
ety of biological properties, one of the earliest recognized be-
ing their antagonist properties against the platelet activating
factor receptor (PAFR).2,3 Recently, it has been shown that
they are potent and selective antagonists of the inhibitory gly-
cine and GABAA receptors.4–6 In view of such attractive bio-
logical activities, a variety of ginkgolide analogs have been
prepared.7–19 So far, however, the preparation of ginkgolide
derivatives has been restricted to the functionalization of hy-
droxyl groups, i.e., selective acylation or alkylation of one of
the three hydroxyls in ginkgolide C.18
Another attractive approach is the modification and deep-
seated transformation of the ginkgolide cage skeleton. Exten-
sive degradation studies of native ginkgolides performed dur-
ing the course of structural determination20–26 gave rise to the
dilactone derivative 1 lacking ring F of the original ginkgo-
lides (see structure in Scheme 1). However, since neither the
biological activity nor the derivatization of F-seco-1 had been
explored, the current studies were performed in view of its at-
tractive truncated skeleton as a new template for the prepara-
tion of a new series of derivatives. During this study, unexpect-
edly, it was found that the ꢀ-alkoxy lactone moieties in 1 are
readily reduced by sodium borohydride (NaBH4) to produce
the corresponding lactols (Scheme 1).27 In this paper, we re-
port on the unique reactivity of nucleophilic reagents, such
as NaBH4, Grignard reagents, or alkyl lithium, towards the
ꢀ-alkoxy- or acyloxy-lactone moieties of ginkgolide and its
derivatives, leading to a new class of ginkgolide derivatives.
HO
O
Ginkgolide A
Ginkgolide B
Ginkgolide C
Ginkgolide J
Ginkgolide M
R1
H
OH
H
H
OH
OH
10
C
O
1
O
F
D
O
A
OH OH OH
OH OH
OH OH
B
7
3
Me
H
E
R3
H
R2
O
O
Fig. 1. Structure of five ginkgolides.
Results and Discussion
NaBH4 Reduction of F-seco-Ginkgolide and Ginkgolide
B Derivatives. The NaBH4 treatment (1 equivalent) of F-
seco-ginkgolide 1 quantitatively provided the C-13 and C-11
lactol derivatives 2 and 3 (Scheme 1). The reaction was com-
pleted within 5 min at room temperature, and interestingly,
none of the over-reduced dialcohols were obtained, even upon
exposure to excess NaBH4 and/or a prolonged reaction time. It
is to be noted that the ester groups in 1 were not reduced under
these conditions. The isolation and separation of lactol deriva-
tives 2 and 3 that exist as 1:1 equilibrium mixtures of lactol
hydroxy groups at both C-11 and C-13, became possible only
after acylation. Namely, a treatment of 2 and 3 with p-phenyl-
benzoic acid in the presence of EDC and DMAP gave 4–6 in a
ratio of 10:6:3, each isomer being readily separable by silica
gel TLC;28 the chemoselectivity ratio of reduction at C-13
and C-11 was thus 83:17 (see also Table 1). Under these con-
ditions, bis-lactol derivatives were obtained as less than 10%
of the products.
The stereochemistry of the 11- and two 13-p-phenyl-
benzoate, 4–6, were assigned from the following NOEs
(Scheme 2): 13-H/8-H and 13-H/12-H for 13ꢀ-benzoate 4,
13-H/3-H for 13ꢁ-benzoate derivative 5, and 2-H/11-H for 6.
y Present address: Department of Chemistry, Osaka University,
1-1 Machikaneyama, Toyonaka, Osaka 560-0043
Published on the web October 4, 2005; DOI 10.1246/bcsj.78.1843

1844 Bull. Chem. Soc. Jpn., 78, No. 10 (2005)
Unique Reactivity of Ginkgolide Lactones
O
O
HO 11
O11
MeO
13O
MeO
MeO
O
O
O
10
1) NaBH4
MeOH, rt
O
+
R =
MeO
O
3
4
O
O
R
OAc
Me 13
O
7
R
OAc
MeO
Me
OAc
O
O
O
HO
1
2
3
O
O
O
O
MeO
O
O
MeO
O
12
O
2) p-PhBzOH
EDC, DMAP, rt
MeO11
8
O
3
R
OAc
13 O
O
R
OAc
+
+
O
quant. from 1
O13
O
2
O
O
(4 : 5 : 6 = 10 : 6 : 3)
R
OAc
O
O
4
5
6
Scheme 1. Reduction of ꢀ-alkoxy lactones to lactols.
Table 1. Reduction Ratio at ꢀ-Alkoxy or Acyloxy LactonesaÞ
OpPhBz
11
O
O
O
R1
R1
O
11
O
R1
10
O
R =
MeO
1) NaBH4
MeOH, rt
2) p-PhBzOH
+
O
Me
O
4
R2
R
O
R
13
R2
O
O
R2
13
R
7
O
pPhBzO
O
O
C13-lactol
C11-lactol
Reduction at
C13:C11
BXn
O
Subs.
R1
R2
O
H
Me
O
11
1
15
16
OMe
OAc
OAc
OAc
83:17
O
10
50:50
O
13 O
O
R
OAc
OMe OSiEt3 80:20
17
a) Each reaction was performed using 1 equivalent of NaBH4 at room temperature for 5 min. The
reaction mixtures were directly acylated by p-phenylbenzoic acid and the products were analyzed
1
by H NMR. None of over-reduced diols were observed.
The configuration of the main isomer 4, resulting from
MMFF94s method, predicted negative CD exciton chirality,
while a similar analysis of the diastereomeric 13ꢁ-lactol deriv-
ative would give rise to a positive exciton chirality. The struc-
ture of the main lactol acylate 12 was thus determined to
possess the 13ꢀ-lactol hydroxyl.31
NaBH4 reduction of the F-seco-ginkgolide derivative 1, was
also supported by a cross metathesis-CD/FDCD exciton chi-
rality protocol,29–31 which was performed on the similar deriv-
ative 12, obtained by a similar NaBH4 reduction of the 7-cin-
namoyl-F-seco-ginkgolide 9 (Scheme 2).31 Thus, the lactone
groups at C-11 and C-13 in 9, with the sterically hindered 7-
OH acylated with the cinnamate chromophore via cross me-
tathesis,32,33 were smoothly reduced by NaBH4 to give the cor-
responding lactols 10 and 11 as four diastereoisomers in quan-
titative yield. An inseparable equilibrium mixture of 10 and 11
was continuously acylated by p-phenylbenzoic acid in the
presence of EDC and DMAP to provide 12 as the main diaster-
eoisomer, which was readily separable from the other isomers
by silica-gel chromatography.
Our studies revealed that the ginkgolide ꢀ-alkoxyl lactones
are converted smoothly, selectively, and quantitatively into
lactols, by reacting with 1 equivalent NaBH4 at room temper-
ature for a few minutes. In contrast, it is well known that the
reduction of lactones or esters by NaBH4 requires a large ex-
cess of the reagent, i.e., exceeding 20 equivalents, and/or rel-
atively high reaction temperatures.34–37 For example, our con-
trol experiment showed that the lactone without ꢀ-alkoxyls,
i.e., Corey lactone (Fig. 2)29 is not reduced under the condition
employed in Scheme 1. Furthermore, when such reduction of
lactones proceeds, in most cases the products are the diols re-
sulting from over-reduction of the intermediary lactols, as is
the case of polyhydroxylated sugar lactones. It has been report-
ed that the electron-withdrawing ꢀ-oxygen or coordinating
CD and FDCD of the main isomer 12 show negative exciton
coupling between the cinnamate and p-phenylbenzoate chro-
mophores, with an amplitude of ACD ¼ ꢁ51. A conformation-
al analysis of 13ꢀ-lactol hydroxyl isomer 12 by MC/

K. Tanaka et al.
Bull. Chem. Soc. Jpn., 78, No. 10 (2005) 1845
O
O
O
MeO
MeO
O
O
O
O
12
MeO
11
O
O
2
O
3
8
O
O
O
MeO
13 O
O
O
MeO
OAc
O
MeO
OAc
Me
13O
Me
Me
O
O
O
OAc
: proton
: NOE
4
5
6
O11
O
O11
O
MeO
MeO
O
1)
2)
iPr2NEt quant.
Cl
NaBH4
MeOH, rt
O
O
O
O
N
N
Me13
7
O
MeO
Me 13
OH
7
MeO
Cl
O
O
O
O
Ru CHPh
O
Cl
60%
PCy3
7
8
9
O11
MeO
O
HO
O
O
11
O
MeO
O
MeO
O
MeO
8
O
13
O
O
p-PhBzOH
Me
O
O
+
O
O
O
EDC, DMAP
quant. for 2 steps
13
O
MeO
O
O
MeO
O
Me
O
O
Me
HO
O
O
Major isomer: 12
+
Major: 10
Minor: 11
Other two isomers
CD (10-6 M)
291 nm, ∆ε −33
263 nm, ∆ε +18
FDCD (10-8 M)
Scheme 2. Stereochemical analysis of reduction products 4–6 and 12.
O
H
O11
O
XnB
O
MeO
O
10
11
O
O
Me
1) NaBH4
MeOH
10
3
O
4
O
4
13O
7
R
O
O
OAc
O
OAc
13 O
R
1
O
O
BXn
R =
MeO
H
13
Me
(X = H or OMe)
Fig. 2. Structure of Corey lactone.
O
O
XnB
O
MeO
O
O11
O
functionalities linked to the carbonyl groups, e.g. ꢀ-amino
acids, accelerate the NaBH4 reduction.35,38,39 An unique reac-
tivity of ginkgolide lactones is therefore most likely caused by
the presence of suitably arranged C-4 and C-10 ꢀ-oxygen,
which are rigidly fixed in the ginkgolide cage skeleton
(Scheme 3). Namely, NaBH4 (or its methoxylated reagents,
NaBHx(OMe)4ꢁx) presumably coordinates tightly with the
lactone carbonyls and ꢀ-oxygens to yield a complex such as
13 that could accelerate the nucleophilic attack of the hydride
towards the lactone carbonyl, which in turn is activated by the
alkoxyl inductive effect. The preferred reduction of the 13-
lactone (C-13:C-11 = 83:17) is most likely to be due to the
stronger coordination of NaBH4 to this carbonyl. In addition,
the obtained lactol hydroxyl and ꢀ-alkoxyl could form strong
borate complexes, such as 14a and 14b, which might stabilize
the reaction intermediates and prevent further reduction, a phe-
Me
10
H+
4
+
+
2
3
13 O
O
OAc
R
O
OAc
R
BXn
O
O
14a
14b
Scheme 3. Possible mechanism of ꢀ-alkoxy lactones to lactols.
nomenon similar to the well-known partial reduction of lac-
tones by diisobutylaluminum hydride (DIBAL) at low temper-
ꢂ
ature, i.e., ꢁ78 C. Corsano and Piancatelli have also found
that glycidic lactones (ꢀ-epoxy lactones) are readily reduced
to glycidic lactols by NaBH4, although the latter are gradually
reduced further to diols by prolonged reaction periods.40 Note
that the DIBAL reduction of 1 leads to a mixture of products;
the mild NaBH4 reduction is thus an efficient alternative lead-
ing to the ꢀ-alkoxy lactol derivatives.

1846 Bull. Chem. Soc. Jpn., 78, No. 10 (2005)
Unique Reactivity of Ginkgolide Lactones
We further examined the substituent effects on NaBH4 re-
duction at C-7 and C-10 of 1 (Table 1). Interestingly, when
the C-10 methoxy substituent of 1 (R1 substituent) was re-
placed by the acetoxyl group in 15, the reduction ratio at C-
11 carbonyl increased (C-13:C-11 = 50:50), possibly due to
better coordination of NaBH4 with the ꢀ-acetoxy lactone moi-
ety, which increases the reactivity at C-11 carbonyl (see struc-
ture 17). In contrast, a NaBH4 treatment of 16, in which the 7-
acetoxyl group in 1 (R2 substituent) was replaced by the bulk-
ier triethylsiloxy group, provided a C-11 to C-13 lactol ratio
similar to that obtained for 1 (C-13:C-11 = 80:20), indicating
that the remote C-7 substituents exert no steric and/or elec-
tronic influence.
The method was further applied to the natural ginkgolides
(Scheme 4). 10-O-Benzylated ginkgolide B (18), the most po-
tent ginkgolide antagonist against the PAF receptor,1 was read-
ily reduced by NaBH4 to give the C-11 lactol derivative as the
major product, which was separated from the minor C-13 lac-
tol by acylation with p-phenylbenzoic acid (regioselectivity at
C-11:C-13 lactones = 10:1). It is noted that the reduction did
not proceed at the C-15 lactone, which lacks a ꢀ-alkoxyl func-
tion. The high regioselectivity at the C-11 lactone over the C-
13 lactone, observed in this cage-shaped natural ginkgolide
case, is most likely due to the steric hindrance around the C-
13 lactone posed by an additional F-ring, so that the NaBH4
reagent is not readily accessible. The phenylbenzoate deriva-
tive was then converted into the corresponding lactol by meth-
anolysis with K2CO3 in 91% yield. Similarly, the methanolysis
of p-phenylbenzoate derivatives, obtained according to
Scheme 1 and Table 1, readily yielded an equilibrium mixture
of the corresponding lactols. The efficient NaBH4 reduction of
1, 15, and 16 thus provided a variety of ginkgolide lactols and
their diastereomeric acylates, leading to a total of 25 acylated
or alkylated derivatives at 7- and 10-hydroxyl.
Alkylation of Ginkgolide B: Preparation of New Class of
Ginkgolide Derivatives. Since we observed an enhanced re-
activity of ginkgolide ꢀ-alkoxyl lactone towards the hydride
ion, we further examined the reaction with other nucleophiles,
i.e., Grignard reagent and alkyllithium reagents (Scheme 5).
We chose 10-O-benzylated ginkgolide B 18 as a substrate
O
O
O11
O
OH
O11
O
O11
1) NaBH4
O
O
O
O
K2CO3
MeOH, rt
15
2) p-PhBzOH
O
O
O
OH
O
O
15
EDC, DMAP
Me
OH
OH
13 O
O
O
O
HO
65 %
Me
91 %
Me
13 O
18
HO
HO
O
O
O
Scheme 4. Synthesis of ginkgolide B lactol derivative.
O
M
11
O
O
O
R
O
O
O
O
RMgBr or RLi
O
15
O
10
Me
MO
THF, 0°C
10 min
OM
11O
OH
O
Me
13
O
O
HO
O
O
18
HO
R
11
O
H
H
HO
O
M
O
O
10
O
O
O
O
O
O
H+
R
O
10
O
H12
11O
Me
MO
OH
O
OM
OH
Me
O
Me
HO
O
HO
O
O
O
O
O
O
19-23
C11-lactol
NOE correlations
19
reagent
R
entry
yield (%) product
1
2
MgBr
86
50
19
20
MeMgBr
Me
Ph
3
4
5
PhMgBr
55
50
58
21
22
23
n-BuLi
n-Bu
CO2Et
CO2Et
Li
Scheme 5. Alkylation of 10-O-benzylated ginkgolide B derivatives. Each reaction was performed using 3 equivalents of RMgBr or
ꢂ
RLi at 0 C for 10 min. None of the over alkylated products at C-13 and/or C-15 were observed.

K. Tanaka et al.
Bull. Chem. Soc. Jpn., 78, No. 10 (2005) 1847
O
PCy3
O
HO
Cl
11
O
O
Ru CHPh
O
O
O
10
11
11
10 O
O
O
OH
Cl
10
O
MgCl
THF
H
O
PCy3
O
Me
O
OH
15
OH
O
74 %
OH
HO
O
Me
O
13 O
O
HO
Me
86 %
HO
O
O
O
24
25
26
N
N
O
HO
11
O
Cl
OH
O
Ru CHPh
O 11
O
11O
10
10
10 O
Cl
MgCl
O
15
O
O
PCy3
H
O
O
O
OH
O
OH
THF
56 %
36 %
O
OH
Me
O
Me
13 O
HO
HO
Me
O
HO
O
O
27
28
29
O
O
Scheme 6. Preparation of new class of ginkgolide B analogs.
for this alkylation trial. Note that the reaction of 18 with three
equivalents of allyl Grignard reagent in THF for 10 min at 0
ꢂC, regio- and stereoselectively provided C-11 quaternary lac-
tol 19 in 86% yield as a single isomer (Scheme 5, Entry 1).
Furthermore, the reaction of 18 with methylmagnesium bro-
mide (Entry 2), phenylmagnesium bromide (Entry 3), n-butyl-
lithium (Entry 4), and propargyllithium reagent (Entry 5), sim-
ilarly provided the corresponding C-11 lactols, 20–23, in 50–
58% yields, respectively. For Entries 2–5, the unreacted start-
ing materials were recovered under the same alkylation condi-
tion as for Entry 1, which led to a slight decrease of the prod-
uct yields.
These alkylations also proceeded preferentially at the C-11
lactone carrying the ꢀ-alkoxyl, the regioselectivity of which is
similar to that of NaBH4 reduction (Scheme 4). Furthermore,
bis-alkylated products, resulting from the opening of lactol in-
to the keto-alcohol, followed by the alkylation of ketone, were
not observed. We could not observe any alkylated products in
the control substrate, Corey lactone, under identical conditions
(Fig. 2). These results indicate that the strong coordination of
Mg and Li metals to the conformationally rigid ginkgolide
cage structure is also important for alkylation, in both the
initiation and termination stages; it involves a reaction mech-
anism similar to the NaBH4 reduction, as proposed in
Scheme 3. Therefore, the alkylation of ginkgolide C-11
lactone by the ester-containing propargyllithium reagent
(Scheme 5, Entry 5), also becomes possible without self-con-
densation of the reagent under these mild conditions.
tives (Scheme 6). Thus, the allylation of 10-O-allylated gink-
golide B 24, regio- and stereoselectively provided bis-allyl
derivative 25 in 86% yield, while the alkylation of 10-O-pro-
pargylated ginkgolide 27 similarly yielded 28 in 56% yield.
The proximately situated two unsaturated moieties, stereo-
selectively introduced at the C-ring of ginkgolide B, can be
utilized for constructing additional seven-membered ring sys-
tems via the olefin/olefin and olefin/alkyne ring-closure me-
tathesis. A ruthenium-catalyzed olefin/olefin metathesis41 of
25 in the presence of the first generation Grubbs’ catalyst, suc-
cessfully provided new ball-shaped heptacyclic ginkgolide 26
in 74% yield. On the other hand, the olefin/alkyne metathe-
sis42 attempted on 28, in the presence of the first generation
catalyst, only resulted in a recovery of the starting material,
even under THF reflux conditions. After optimization of the
conditions, regioselective olefin/acetylene metathesis was fi-
nally achieved in 36% yield in the presence of the more reac-
tive Grubbs’ second-generation catalyst43–45 in THF at room
temperature. Under this condition, compound 28 also partici-
pated in self-condensation by cross metathesis between olefins
and/or alkyne moieties in 28, leading to a decrease in the yield
of 29. Note that the presence of the diene moiety in 29, created
during olefin/acetylene metathesis, can be further utilized for
functionalization of this intriguing molecule, i.e., Diels–Alder
reaction, which enhances the diversity of this new class of
ginkgolide analogs.
Conclusion
The configuration of the new C-11 stereogenic center in 19
was determined from the NOEs of allyl protons with 12-H and
with t-butyl protons (Scheme 5). The quaternary stereogenic
centers at C-11 of other alkylation products, 20–23, were also
found to possess the same configuration as that of 19, deter-
In summary, the unique reactivity of the ginkgolide ꢀ-
protected hydroxy lactones toward nucleophilic reagents,
Grignard and alkyllithium reagents, and even the mild NaBH4
reducing reagent was observed. The reaction selectively pro-
vides lactol derivatives, presumably through strong coordina-
tion with the conformationally fixed ꢀ-protected hydroxyl
functionalities. Namely, the restricted reduction of ꢀ-protected
hydroxy lactones to ꢀ-lactols, instead of ring-opening to diols,
originates in the unique ginkgolide cage structure carrying crit-
ically positioned oxygen atoms. This leads to a new series of
ginkgolide derivatives, the biological evaluation of which will
be performed.
1
mined through a comparison of their characteristic H NMR
(Experimental Section). As shown in Scheme 5, the highly
ꢀ-selective alkylation is rationalized by the preferred approach
of alkyl nucleophiles from the convex face of the cage-shaped
ginkgolide molecule, in which the ꢀ-alkoxyl lactone carbonyl
is simultaneously activated for a nucleophilic attack by the
metal coordination.
The regio- and stereoselective alkylation of ꢀ-alkoxyl lac-
tone led to a deep-seated skeletal transformation of the ginkgo-
lide skeleton, yielding a new class of ginkgolide lactol deriva-
Experimental
Materials and General Procedures. Anhydrous dichloro-

1848 Bull. Chem. Soc. Jpn., 78, No. 10 (2005)
Unique Reactivity of Ginkgolide Lactones
methane was dried and distilled from CaH2. Unless otherwise not-
ed, materials were obtained from a commercial supplier and were
used without further purification. All reactions were performed in
pre-dried glassware under Ar unless noted. Purification was per-
formed either by column chromatography using ICN silica gel
(32–63 mesh) or by preparative TLC using silica gel plate, 60
F-254, 0.25 mm, E. Merck. 1H NMR spectra were obtained on
Bruker DMX 300 or 400 MHz spectrometers and are reported
in parts per million (ppm) relative to TMS (ꢂ), with coupling con-
stants (J) in hertz (Hz). Low- and high-resolution FAB mass spec-
tra were measured on a JEOL JMS-DX303 HF mass spectrometer
using a glycerol matrix and Xe ionizing gas. UV–vis spectra were
recorded on a Perkin-Elmer Lambda 40 spectrophotometer, and
reported as ꢃmax [nm] ("max [L molꢁ1 cmꢁ1]). The CD spectra
were recorded on a JASCO-810 spectrophotometer. The CD
spectra were measured in millidegrees and normarized into
ꢀ"max [L molꢁ1 cmꢁ1].
General Procedure of NaBH4 Reduction of Ginkgolide De-
rivatives: Preparation of Ginkgolide Lactol Benzoates. To a
solution of ginkgolide derivatives (ca. 0.05 mmol) in MeOH (1
mL) was added NaBH4 (1 equivalent) at room temperature, and
the mixture was stirred for 5 min. The reaction mixture was direct-
ly subjected to rapid chromatography on silica gel (50% ethyl ace-
tate in hexane) to afford the corresponding lactol derivatives. To a
solution of the lactol mixture obtained as mentioned above in di-
chloromethane (1 mL) was added p-phenylbenzoic acid (2 equiv-
alents), EDC (2.2 equivalents), and DMAP (2.2 equivalents) at
room temperature, and the mixture was stirred for 12 h. The reac-
tion mixture was concentrated in vacuo to give crude products,
which were purified by preparative thin-layer chromatography
on silica gel to afford the lactol p-phenylbenzoate derivatives.
F-seco-Ginkgolide C-13 ꢀ-Lactol p-Phenylbenzoate (4):
1H NMR (300 MHz, CDCl3) ꢂ 1.11 (s, 9H), 1.15 (d, 3H, J ¼
7:2 Hz), 1.77–1.98 (m, 2H), 2.07 (s, 3H), 2.21–2.28 (m, 1H),
2.57 (d, 1H, J ¼ 12:3 Hz), 2.69–2.80 (m, 1H), 2.93–3.05 (m,
2H), 3.59 (s, 3H), 3.77 (s, 3H), 4.47 (d, 1H, J ¼ 3:3 Hz), 4.58
(s, 1H), 5.14 (dd, 1H, J ¼ 12:3, 3.3 Hz), 5.87 (s, 1H), 6.44 (s,
1H), 7.36–7.48 (m, 3H), 7.61 (d, 2H, J ¼ 7:2 Hz), 7.68 (d, 2H,
J ¼ 8:4 Hz), 8.09 (d, 2H, J ¼ 8:4 Hz); HRFABMS calcd for
C37H43O11 ½M þ Hꢃþ 663.2805, found 663.2813.
J ¼ 4:4 Hz), 5.25 (dd, 1H, J ¼ 12:8, 4.4 Hz), 5.94 (dd, 1H,
J ¼ 11:8, 1.2 Hz), 5.95 (s, 1H), 6.14 (dd, 1H, J ¼ 17:3, 10.4
Hz), 6.47 (dd, 1H, J ¼ 17:3, 1.2 Hz); HRFABMS calcd for
C25H33O10 ½M þ Hꢃþ 493.2074, found 493.2085.
F-seco-Ginkgolide Cinnamate Derivative (9): 1H NMR (400
MHz, CDCl3) ꢂ 1.12 (s, 9H), 1.22 (d, 3H, J ¼ 7:1 Hz), 1.85–2.07
(m, 3H), 2.16 (d, 1H, J ¼ 12:9 Hz), 2.56–2.64 (m, 2H), 2.83–2.90
(m, 1H), 3.73 (s, 3H), 3.77 (s, 3H), 4.54 (s, 1H), 4.71 (d, 1H, J ¼
4:4 Hz), 5.33 (dd, 1H, J ¼ 12:8, 4.2 Hz), 5.97 (s, 1H), 6.45 (d, 1H,
J ¼ 16:0 Hz), 7.40–7.41 (m, 3H), 7.51–7.55 (m, 2H), 7.73 (d, 1H,
J ¼ 16:0 Hz).
F-seco-Ginkgolide p-Phenylbenzoate Cinnamate Derivative
(12): 1H NMR (400 MHz, CDCl3) ꢂ 1.15 (s, 9H), 1.85–1.97 (m,
2H), 2.27–2.31 (m, 1H), 2.67 (d, 1H, J ¼ 11:2 Hz), 2.75–2.79 (m,
1H), 2.96–3.07 (m, 2H), 3.60 (s, 3H), 3.76 (s, 3H), 4.54 (d, 1H,
J ¼ 3:5 Hz), 4.62 (s, 1H), 5.34 (dd, 1H, J ¼ 12:4, 3.5 Hz), 5.92
(s, 1H), 6.44 (d, 1H, J ¼ 16:0 Hz), 6.49 (s, 1H), 7.36–7.71 (m,
13H), 8.10 (d, 2H, J ¼ 8:5 Hz); HRFABMS calcd for C44H46O11
½Mꢃþ 789.2677, found 789.2684.
10-O-Benzylated Ginkgolide C-11 ꢀ-Lactol p-Phenyl-
benzoate: 1H NMR (300 MHz, CDCl3) ꢂ 1.20 (s, 9H), 1.28
(d, 3H, J ¼ 6:9 Hz), 1.93–1.96 (m, 2H), 2.24–2.35 (m, 1H),
2.76 (s, 1H, C3-OH), 3.00 (d, 1H, J ¼ 3:0 Hz, C10-OH), 3.54
(q, 1H, J ¼ 6:9 Hz), 4.43 (dd, 1H, J ¼ 8:1, 3.3 Hz), 4.52 (d,
1H, J ¼ 9:6 Hz), 4.58 (d, 1H, J ¼ 7:8 Hz), 4.69 (d, 1H, J ¼ 9:9
Hz), 5.04 (d, 1H, J ¼ 2:4 Hz), 5.36 (d, 1H, J ¼ 3:0 Hz), 6.00
(s, 1H), 6.73 (d, 1H, J ¼ 2:4 Hz), 7.30–7.34 (m, 2H), 7.37–7.53
(m, 6H), 7.63–7.66 (m, 2H), 7.73 (d, 2H, J ¼ 8:4 Hz), 8.10 (d,
2H, J ¼ 8:4 Hz); HRFABMS calcd for C40H41O11 ½M þ Hꢃþ
697.2649, found 697.2659.
General Procedure of Alkylation of Ginkgolide Derivatives
by Grignard and Alkyllithium Reagents. To a solution of
ginkgolide derivatives (ca. 0.05 mmol) in THF (1 mL) was added
a 1–2 M solution of Grignard or alkyllithium reagents (3–4 equiv-
alents) in THF (ether) at 0 ꢂC. After the mixture was stirred for 10
min at this temperature, a H2O and saturated aqueous NH4Cl solu-
tion was added, and the resulting mixture was extracted with ethyl
acetate. The organic layers were combined, washed with brine,
dried over Na2SO4, filtered and concentrated in vacuo to give
the crude product. Column chromatography on silica gel (gradual-
ly 33% to 40% ethyl acetate in hexane) gave the corresponding
mono-alkylated product as a white solid.
Allylated Product of 10-O-Benzylated Ginkgolide B (19):
1H NMR (400 MHz, CDCl3) ꢂ 1.13 (s, 9H), 1.26 (d, 3H, J ¼
7:1 Hz), 1.86 (dd, 1H, J ¼ 13:3, 3.8 Hz), 1.95 (dd, 1H,
J ¼ 14:4, 4.0 Hz), 2.23 (dd, 1H, J ¼ 13:0, 4.0 Hz), 2.45 (d, 1H,
J ¼ 3:8 Hz), 2.61–2.76 (m, 3H) including 2.70 (s, 1H), 3.54 (q,
1H, J ¼ 7:1 Hz), 4.34 (d, 1H, J ¼ 8:9 Hz), 4.52 (d, 1H, J ¼ 8:1
Hz), 4.65 (s, 1H), 4.83 (d, 1H, J ¼ 8:9 Hz), 5.22 (d, 1H, J ¼
3:7 Hz), 5.32 (d, 1H, J ¼ 17:2 Hz), 5.43 (d, 1H, J ¼ 10:3 Hz),
5.51 (s, 1H), 5.64 (dd, 1H, J ¼ 8:1, 3.8 Hz), 5.90–6.01 (m, 1H),
7.31–7.42 (m, 5H); HRFABMS calcd for C30H35O9 ½M ꢁ H2O þ
Hꢃþ 539.2281, found 539.2300.
F-seco-Ginkgolide C-13 ꢁ-Lactol p-Phenylbenzoate (5):
1H NMR (300 MHz, CDCl3) ꢂ 1.05 (s, 9H), 1.24 (d, 3H, J ¼
7:2 Hz), 1.74–1.98 (m, 3H), 2.00 (s, 3H), 2.37–2.46 (m, 1H),
2.85–2.96 (m, 2H), 3.06 (d, 1H, J ¼ 12:3 Hz), 3.63 (s, 3H),
3.73 (s, 3H), 4.50 (s, 1H), 4.54 (d, 1H, J ¼ 6:0 Hz), 5.01 (dd,
1H, J ¼ 12:3, 6.0 Hz), 6.04 (s, 1H), 6.36 (s, 1H), 7.40–7.52 (m,
3H), 7.65 (d, 2H, J ¼ 7:2 Hz), 7.70 (d, 2H, J ¼ 8:4 Hz), 8.18
(d, 2H, J ¼ 8:4 Hz); HRFABMS calcd for C37H43O11 ½M þ Hꢃþ
663.2805, found 663.2810.
F-seco-Ginkgolide C-11 ꢀ-Lactol p-Phenylbenzoate (6):
1H NMR (300 MHz, CDCl3) ꢂ 1.16 (s, 9H), 1.23 (d, 3H, J ¼
6:9 Hz), 1.91–1.95 (m, 1H), 2.05–2.13 (m, 3H), 2.13 (s, 3H),
2.51–2.66 (m, 2H), 2.90–3.01 (m, 1H), 3.40 (s, 3H), 3.72 (s,
3H), 4.66 (d, 1H, J ¼ 7:2 Hz), 4.67 (s, 1H), 5.12 (dd, 1H,
J ¼ 12:9, 4.5 Hz), 5.95 (s, 1H), 6.58 (d, 1H, J ¼ 3:3 Hz), 7.40–
7.52 (m, 3H), 7.63 (d, 2H, J ¼ 7:2 Hz), 7.71 (d, 2H, J ¼ 8:4
Hz), 8.10 (d, 2H, J ¼ 8:4 Hz); HRFABMS calcd for C37H43O11
½M þ Hꢃþ 663.2805, found 663.2816.
Methylated Product of 10-O-Benzylated Ginkgolide B (20):
1H NMR (400 MHz, CDCl3) ꢂ 1.14 (s, 9H), 1.27 (d, 3H, J ¼ 7:2
Hz), 1.83 (ddd, 1H, J ¼ 13:4, 13.4, 4.9 Hz), 1.98 (dd, 1H,
J ¼ 14:4, 4.4 Hz), 2.25 (dd, 1H, J ¼ 13:0, 4.4 Hz), 2.42 (d, 1H,
J ¼ 3:9 Hz), 2.56 (s, 1H), 3.53 (q, 1H, J ¼ 7:2 Hz), 3.62 (s,
1H), 4.37 (d, 1H, J ¼ 8:9 Hz), 4.53 (d, 1H, J ¼ 8:1 Hz), 4.62
(s, 1H), 4.84 (d, 1H, J ¼ 8:9 Hz), 5.21 (d, 1H, J ¼ 3:7 Hz),
5.52 (s, 1H), 5.61 (dd, 1H, J ¼ 8:2, 3.9 Hz), 7.30–7.42 (m, 5H);
HRFABMS calcd for C28H35O10 ½M þ Hꢃþ 531.2230, found
Acryloylated Derivative of F-seco-Ginkgolide (7): 1H NMR
(400 MHz, CDCl3) ꢂ 1.10 (s, 9H), 1.21 (d, 3H, J ¼ 7:2 Hz), 1.84–
2.05 (m, 3H), 2.13 (d, 1H, J ¼ 12:8 Hz), 2.54–2.63 (m, 2H), 2.82–
2.89 (m, 1H), 3.73 (s, 3H), 3.76 (s, 3H), 4.53 (s, 1H), 4.68 (d, 1H,

K. Tanaka et al.
Bull. Chem. Soc. Jpn., 78, No. 10 (2005) 1849
531.2242.
(s, 9H), 1.27 (d, 3H, J ¼ 7:1 Hz), 1.78–1.90 (m, 2H), 2.26 (dd,
1H, J ¼ 11:9, 2.7 Hz), 2.35 (dd, 1H, J ¼ 15:6, 9.0 Hz), 2.42 (s,
1H), 2.72 (s, 1H), 3.07 (ddd, 1H, J ¼ 15:6, 3.1, 3.1 Hz), 3.34
(d, 1H, J ¼ 3:1 Hz), 3.49 (q, 1H, J ¼ 7:0 Hz), 4.31 (brd, 1H, J ¼
17:7 Hz), 4.53 (dd, 1H, J ¼ 8:2, 3.1 Hz), 4.62–4.71 (m, 3H), 5.39
(d, 1H, J ¼ 3:5 Hz), 5.49 (dd, 1H, J ¼ 11:7, 2.4 Hz), 5.58–5.65
(m, 1H), 5.84 (s, 1H); HRFABMS calcd for C24H31O10 ½M þ
Hꢃþ 479.1917, found 479.1928.
Phenylated Product of 10-O-Benzylated Ginkgolide B (21):
1H NMR (400 MHz, CDCl3) ꢂ 1.09 (s, 9H), 1.25 (d, 3H, J ¼ 7:2
Hz), 1.83 (ddd, 1H, J ¼ 14:0, 14.0, 3.9 Hz), 2.04 (dd, 1H,
J ¼ 13:6, 4.6 Hz), 2.25 (dd, 1H, J ¼ 13:4, 4.4 Hz), 2.45 (d, 1H,
J ¼ 4:0 Hz), 2.64 (s, 1H), 3.60 (q, 1H, J ¼ 7:2 Hz), 4.05 (d,
1H, J ¼ 9:3 Hz), 4.28 (s, 1H), 4.58 (d, 1H, J ¼ 8:1 Hz), 4.77
(s, 1H), 4.81 (d, 1H, J ¼ 9:4 Hz), 5.24 (d, 1H, J ¼ 3:6 Hz),
5.79 (s, 1H), 5.88 (dd, 1H, J ¼ 8:1, 4.0 Hz), 7.34–7.47 (m, 8H),
7.65 (d, 2H, J ¼ 7:8 Hz); HRFABMS calcd for C33H35O9 ½M ꢁ
H2O þ Hꢃþ 575.2281, found 575.2287.
Ring-Closing Metathesis of 28. To a solution of 28 (14 mg,
27.7 mmol) in dichloromethane (3.0 mL) were added Grubbs’ sec-
ond-generation ruthenium catalyst (4.71 mg, 5.55 mmol) at room
temperature; the mixture was stirred at this temperature for 30
min. The reaction mixture was concentrated in vacuo to give
the crude product, which was purified by column chromatography
on silica gel (ethyl acetate in hexane, gradually from 25% to 50%)
n-Butylated Product of 10-O-Benzylated Ginkgolide B (22):
1H NMR (400 MHz, CDCl3) ꢂ 0.98 (t, 3H, J ¼ 7:0 Hz), 1.14 (s,
9H), 1.26 (d, 3H, J ¼ 7:1 Hz), 1.41–1.68 (m, 6H), 1.79–1.88
(m, 1H), 1.95 (dd, 1H, J ¼ 14:3, 3.8 Hz), 2.24 (dd, 1H,
J ¼ 13:0, 4.0 Hz), 2.47 (d, 1H, J ¼ 3:8 Hz), 2.58 (s, 1H), 3.54
(q, 1H, J ¼ 7:1 Hz), 3.57 (s, 1H), 4.35 (d, 1H, J ¼ 8:9 Hz),
4.52 (d, 1H, J ¼ 8:2 Hz), 4.61 (s, 1H), 4.81 (d, 1H, J ¼ 8:9
Hz), 5.22 (d, 1H, J ¼ 3:6 Hz), 5.49 (s, 1H), 5.62 (dd, 1H,
J ¼ 8:2, 3.8 Hz), 7.31 (dd, 1H, J ¼ 7:0, 1.7 Hz), 7.38–7.44 (m,
1H), 7.49 (dd, 1H, J ¼ 7:4, 7.4 Hz), 7.60 (dd, 1H, J ¼ 7:4, 7.4
Hz), 7.81 (d, 1H, J ¼ 7:0 Hz); HRFABMS calcd for C31H40O10Na
½M þ Naꢃþ 595.2519, found 595.2542.
1
to afford 29 (5.0 mg, 36%) as a white solid: H NMR (400 MHz,
CDCl3) ꢂ 1.13 (s, 9H), 1.27 (d, 3H, J ¼ 7:1 Hz), 1.79–1.93 (m,
2H), 2.29 (dd, 1H, J ¼ 12:1, 3.1 Hz), 2.37 (s, 1H), 2.44 (dd,
1H, J ¼ 15:2, 9.0 Hz), 2.68 (s, 1H), 3.12 (brd, 1H, J ¼ 15:1
Hz), 3.30 (d, 1H, J ¼ 3:1 Hz), 3.47 (q, 1H, J ¼ 7:0 Hz), 4.44
(brd, 1H, J ¼ 17:2 Hz), 4.53 (dd, 1H, J ¼ 8:2, 3.2 Hz), 4.62–
4.73 (m, 3H), 4.90 (d, 1H, J ¼ 17:9 Hz), 5.04 (d, 1H, J ¼ 11:3
Hz), 5.40 (d, 1H, J ¼ 3:7 Hz), 5.67 (brd, 1H, J ¼ 6:9 Hz),
5.84 (s, 1H), 6.17–6.27 (m, 1H); HRFABMS calcd for C26H31O9
½M ꢁ H2O þ Hꢃþ 487.1968, found 487.1964.
Propargylated Product of 10-O-Benzylated Ginkgolide B
(23): 1H NMR (400 MHz, CDCl3) ꢂ 1.17 (s, 9H), 1.26 (d, 3H,
J ¼ 6:9 Hz), 1.51 (t, 3H, J ¼ 7:0 Hz), 1.85 (ddd, 1H, J ¼ 13:7,
13.7, 4.1 Hz), 2.02 (dd, 1H, J ¼ 14:4, 4.4 Hz), 2.27 (dd, 1H,
J ¼ 13:5, 4.4 Hz), 2.30 (d, 1H, J ¼ 4:2 Hz), 2.58 (s, 1H), 3.46
(q, 1H, J ¼ 7:0 Hz), 4.24 (q, 2H, J ¼ 7:1 Hz), 4.33 (d, 1H, J ¼
9:0 Hz), 4.43 (d, 1H, J ¼ 9:0 Hz), 4.52 (d, 1H, J ¼ 8:1 Hz),
5.13 (s, 1H), 5.18 (s, 1H), 5.25 (d, 1H, J ¼ 3:8 Hz), 5.35 (dd,
1H, J ¼ 8:1, 4.1 Hz), 5.68 (s, 1H), 7.23–7.26 (m, 3H), 7.39–
7.41 (m, 2H); HRFABMS calcd for C32H37O12 ½M þ Hꢃþ
613.2285, found 613.2275.
Allylated Product of 10-O-Allylated Ginkgolide B (25):
1H NMR (400 MHz, CDCl3) ꢂ 1.07 (s, 9H), 1.26 (d, 3H, J ¼
7:1 Hz), 1.89–1.97 (m, 2H), 2.26 (dd, 1H, J ¼ 11:6, 2.6 Hz),
2.54 (dd, 1H, J ¼ 13:7, 8.6 Hz), 2.62 (dd, 1H, J ¼ 13:4, 6.1
Hz), 2.67 (s, 1H), 2.96 (d, 1H, J ¼ 3:8 Hz), 3.52 (q, 1H, J ¼
7:0 Hz), 3.88 (dd, 1H, J ¼ 10:5, 5.5 Hz), 3.94 (s, 1H), 4.34 (dd,
1H, J ¼ 10:4, 6.8 Hz), 4.48 (s, 1H), 4.61 (d, 1H, J ¼ 8:2 Hz),
5.27–5.42 (m, 5H), 5.66 (d, 1H, J ¼ 8:2, 3.8 Hz), 5.85–5.97 (m,
2H); HRFABMS calcd for C26H35O4 ½M þ Hꢃþ 507.2230, found
507.2235.
Allylated Product of 10-O-Propargylated Ginkgolide B
(28): 1H NMR (400 MHz, CDCl3) ꢂ 1.08 (s, 9H), 1.26 (d, 3H,
J ¼ 7:0 Hz), 1.61 (s, 1H), 1.91–1.97 (m, 2H), 2.26 (d, 1H, J ¼
8:8 Hz), 2.50–2.67 (m, 3H), 2.73 (s, 1H), 2.98 (d, 1H, J ¼ 3:8
Hz), 3.53 (q, 1H, J ¼ 7:0 Hz), 4.11–4.17 (m, 3H), 4.46 (dd, 1H,
J ¼ 14:4, 2.2 Hz), 4.57 (s, 1H), 4.64 (d, 1H, J ¼ 8:1 Hz), 5.29
(d, 1H, J ¼ 17:2 Hz), 5.35 (s, 1H), 5.39 (d, 1H, J ¼ 10:0 Hz),
5.49 (s, 1H), 5.66 (dd, 1H, J ¼ 8:1, 3.8 Hz), 5.84–5.92 (m, 1H);
FABMS calcd for C26H31O9 ½M ꢁ H2O þ Hꢃþ 487.19, found
487.18.
We are grateful to Dr. Hideki Ishii and Dr. Jaracz Stanislav,
Columbia University, for purifying ginkgolide B, and to Dr.
Gennaro Pescitelli, University of Pisa, for the molecular mod-
eling of 12. We acknowledge the Jasco Corporation for gener-
ously providing us with a new FDCD device, J-465. This re-
search is supported by the National Institutes of Health, NIH
Grant MH 068817 and GM 34509 (K.N. and N.B.). K.T. is
grateful to the JSPS Postdoctoral Fellowships for Research
Abroad.
References
1 K. Stromgaard and K. Nakanishi, Angew. Chem., Int. Ed.,
43, 1640 (2004).
2 P. Braquet, K. Drieu, and A. Etienne, Actual. Chim. Ther.,
13, 237 (1986).
3
P. Braquet, B. Spinnewyn, M. Braquet, R. H. Bourgain,
J. E. Taylor, A. Etienne, and K. Drieu, Blood Vessels, 16, 558
(1985).
4
E. L. Kondratskaya, P. V. Lishko, S. S. Chatterjee, and O.
A. Krishtal, Neurochem. Int., 40, 647 (2002).
E. L. Kondratskaya and O. A. Krishtal, Neurophysiology,
34, 155 (2002).
5
6 L. Ivic, T. T. J. Sands, N. Fishkin, K. Nakanishi, A. R.
Kriegstein, and K. Stromgaard, J. Biol. Chem., 278, 49279 (2003).
7 J. R. Rapin, M. Zaibi, and K. Drieu, Drug Dev. Res., 45, 23
(1998).
Ring-Closing Metathesis of 25. To a solution of 25 (10 mg,
19.7 mmol) in THF (5.0 mL) were added Grubbs’ first-generation
ruthenium catalyst (3.25 mg, 3.95 mmol) at room temperature, and
the mixture was stirred at this temperature for 21 h. The reaction
mixture was concentrated in vacuo to give the crude product,
which was purified by column chromatography on silica gel (ethyl
acetate in hexane, gradually from 33% to 50%) to afford 26 (7.0
mg, 74%) as a white solid: 1H NMR (400 MHz, CDCl3) ꢂ 1.12
8
9
P. Braquet, Drugs Future, 12, 643 (1987).
P. Braquet, A. Esanu, E. Buisine, D. Hosford, C. Broquet,
and M. Koltai, Med. Res. Rev., 11, 295 (1991).
10 L. Hu, Z. Chen, and Y. Xie, J. Asian Nat. Prod. Res., 4,
219 (2001).
11 L. Hu, Z. Chen, Y. Xie, Y. Jiang, and H. Zhen, J. Asian
Nat. Prod. Res., 3, 103 (2000).
12 L. Hu, Z. Chen, Y. Xie, H. Jiang, and H. Zhen, Bioorg.

1850 Bull. Chem. Soc. Jpn., 78, No. 10 (2005)
Unique Reactivity of Ginkgolide Lactones
Med. Chem., 8, 1515 (2000).
13 E. J. Corey and A. V. Gavai, Tetrahedron Lett., 30, 6959
(1989).
30 K. Tanaka, G. Pescitelli, L. Di Bari, T. L. Xiao, K.
Nakanishi, D. W. Armstrong, and N. Berova, Org. Biomol. Chem.,
2, 48 (2004).
14 E. J. Corey and K. S. Rao, Tetrahedron Lett., 32, 4623
(1991).
31 K. Tanaka, G. Pescitelli, K. Nakanishi, and N. Berova,
Monatsh. Chem., 136, 367 (2005).
15 H. K. Park, S. K. Lee, P. U. Park, and W. J. Kwak,
in Sunkyong Industries Co., Ltd., S. Korea, Patent WO9306107
(1993).
16 P.-U. Park, S. Pyo, S.-K. Lee, J. H. Sung, W. J. Kwak,
H.-K. Park, Y.-B. Cho, G.-H. Ryu, and T. S. Kim, in Sunkyong
Industries Co., Ltd., S. Korea, Patent WO9518131 (1995).
17 K. Stromgaard, D. R. Saito, H. Shindou, S. Ishii, T.
Shimizu, and K. Nakanishi, J. Med. Chem., 45, 4038 (2002).
18 S. Jaracz, K. Stromgaard, and K. Nakanishi, J. Org. Chem.,
67, 4623 (2002).
19 S. Jaracz, K. Nakanishi, A. A. Jensen, and K. Stromgaard,
Chem.—Eur. J., 10, 1507 (2004).
20 M. Maruyama, A. Terahara, Y. Itagaki, and K. Nakanishi,
Tetrahedron Lett., 4, 299 (1967).
21 M. Maruyama, A. Terahara, Y. Itagaki, and K. Nakanishi,
Tetrahedron Lett., 4, 303 (1967).
22 M. Maruyama, A. Terahara, Y. Nakadaira, M. C. Woods,
and K. Nakanishi, Tetrahedron Lett., 4, 309 (1967).
23 M. Maruyama, A. Terahara, Y. Nakadaira, M. C. Woods,
Y. Takagi, and K. Nakanishi, Tetrahedron Lett., 4, 315 (1967).
24 M. C. Woods, I. Miura, Y. Nakadaira, A. Terahara, M.
Maruyama, and K. Nakanishi, Tetrahedron Lett., 4, 321 (1967).
25 K. Nakanishi, Pure Appl. Chem., 14, 89 (1967).
26 M. Maruyama and A. Terahara, ‘‘The Science Reports of
the Tohoku University,’’ (1967), Vol. L, p. 92.
27 K. Tanaka, K. D. Kester, N. Berova, and K. Nakanishi,
Tetrahedron Lett., 46, 531 (2005).
32 A. K. Chatterjee, T.-L. Choi, D. P. Sanders, and R. H.
Grubbs, J. Am. Chem. Soc., 125, 11360 (2003).
33 S. J. Connon and S. Blechert, Angew. Chem., Int. Ed., 42,
1900 (2003).
34 K. Soai, H. Oyamada, and A. Ookawa, Synth. Commun.,
12, 463 (1982).
35 A. G. M. Barrett, ‘‘Reduction of Carboxylic Acid Deriva-
tives to Alcohols, Ethers, and Amines,’’ Pergamon Press, London
(1991), Vol. 5, Chap. 6.2, pp. 235–257.
36 M. L. Wolfrom and H. B. Wood, J. Am. Chem. Soc., 73,
2933 (1951).
37 M. L. Wolfrom and K. Anno, J. Am. Chem. Soc., 74, 5583
(1952).
38 J. E. G. Barnett and P. W. Kent, J. Am. Chem. Soc., 85,
2743 (1963).
39 J. Mauger and A. Robert, J. Chem. Soc., Chem. Commun.,
1986, 395.
40 S. Corsano and G. Piancatelli, J. Chem. Soc., Chem. Com-
mun., 1971, 1106.
41 S.-Y. Han and S. Chang, ‘‘General Ring-Closing Metathe-
sis,’’ ed by R. H. Grubbs, Wiley-VCH, Weinheim (2003), Vol. 2,
pp. 5–127.
42 M. Mori, ‘‘Ene-Yne Metathesis,’’ ed by R. H. Grubbs,
Wiley-Vch, Weinheim (2003), Vol. 2, pp. 176–204.
43 A. K. Chatterjee, F. D. Toste, T.-L. Choi, and R. H.
Grubbs, Adv. Synth. Catal., 344, 634 (2002).
44 M. Scholl, S. Ding, C. W. Lee, and R. H. Grubbs, Org.
Lett., 1, 953 (1999).
28 E. J. Corey, S. M. Albonico, U. Koelliker, T. K. Schaaf,
and R. K. Varma, J. Am. Chem. Soc., 93, 1491 (1971).
29 K. Tanaka, K. Nakanishi, and N. Berova, J. Am. Chem.
Soc., 125, 10802 (2003).
45 M. Scholl, T. M. Trnka, J. P. Morgan, and R. H. Grubbs,
Tetrahedron Lett., 40, 2247 (1999).