Total syntheses of plagiochins A and D, macrocyclic bis(bibenzyls), by Pd(0) catalyzed intramolecular Stille-Kelly reaction

Article abstract of DOI:10.3987/COM-00-S(I)26

Total syntheses of plagiochins A (1) and D (4), the former of which exhibits a significant neurotrophic activity, have been accomplished. The key 16-membered ring closure in 4 has been achieved directly from the dibromoperrottetin derivative (7) by Pd(0)

Full text of DOI:10.3987/COM-00-S(I)26

HETEROCYCLES, Vol. 54, No. 1, 2001, pp. 259 - 274, Received, 10th May, 2000
TOTAL SYNTHESES OF PLAGIOCHINS A AND D, MACROCYCLIC
BIS(BIBENZYLS), BY Pd(0) CATALYZED INTRAMOLECULAR STILLE-
KELLY REACTION1
Yoshiyasu Fukuyama,* Hideyuki Yaso, Takashi Mori, Hironobu Takahashi,
Hiroyuki Minami, and Mitsuaki Kodama
Faculty of Pharmaceutical Sciences, Tokushima Bunri University
180 Yamashiro-cho, Tokushima 770-8514, Japan
e-mail: fukuyama@ph.bunri-u.ac.jp
Abstract – Total syntheses of plagiochins A (1) and D (4), the former of which
exhibits a significant neurotrophic activity, have been accomplished. The key
16-membered ring closure in 4 has been achieved directly from the dibromoperrottetin
derivative (7) by Pd(0) catalyzed intramolecular Stille-Kelly reaction, whereas 1
has been synthesized from the dibromide (28) via the trimethylstannyl compounds
(29) and (30) by Pd(0) catalyzed intramolecular Stille reaction.
Macrocyclic bis(bibenzyls) are natural products occurring exclusively in liverwort species, and over 60
analogues are known up to date.2 Discovery of them can be mainly attributed to Prof. Asakawa and his
research group.3 Their novel structures and interesting biological activities (e.g. cytotoxicity4 and 5-
lipoxygenase inhibitor5) make them attractive targets for total synthesis.6 The cyclic bis(bibenzyls) are
further subdivided into three types 1, 2, and 3, which are made up of macrocyclic rings linked through
two biphenyl ether C-O bonds, biphenyl ether C-O and biaryl C-C bonds, and two biaryl C-C bonds,
OH
OH
O
O
R2
OH
O
MeO
OH
OH
R1
1 R1 = R2 = OH
5
2 R1 = H, R2 = OH
3 R1 = OH, R2 = H
4 R1 = R2 = H
Figure 1 Plagiochins A (1) ~ D (4) and marchantin A (5)

respectively. Two unsymmetrically substituted bis(bibenzyls) are presumably joined by oxidative phenol
C-O or C-C couplings, thus forming these unique macrocyclic structures. Representatives of the type 1
are 18-membered ring marchantin A (5) and 20-membered ring riccardin B isolated from Marchantia
polymorpha7 and Riccardia multifida,8 respectively, which have been already synthesized by us9 and two
other groups.10,11 Plagiochins A (1) ~ D (4) belonging to the type 2, isolated from Plagiochila acanthophylla,12
feature highly strained 16-membered ring system13 made up through biphenyl C-O ether and biaryl C-C
bonds. Among them, in particular, plagiochin A (1) has been found to exhibit significant neurotrophic
properties, e.g. promotion of neurite dendrites and network formation of neurons, and protection of
neuronal death in the cultures of rat cortical neurons.14 Their unique structural features and intriguing
biological activity have stimulated our interest in the type 2 cyclic bis(bibenzyls) so that we have recently
completed the synthesis of plagiochin D (4), the simplest number of the plagiochins.15 In this paper, we
report the full details of synthesis of plagiochin D (4), and the first synthesis of plagiochin A (1) having
the highest degree of oxidative stage among the plagiochins as well as neurotrophic property.
Synthesis of Plagiochin D (4)
The first synthesis of 4 reported by Nogradi et al.16 involved the Wurtz-type radical coupling at the
position b for the crucial macrocyclization as shown in Figure 2. However, all the procedures for the ring
formation at the position b including Nogradi's protocol suffered considerably poor yield.17 According to
the biosynthesis of marchantin A (5) proposed by Zenk et al.,18 perrottetin-type seco compounds19 such as
6 as shown in Figure 2 can be transformed into 4 by oxidative phenol couplings, but we failed our all
attempts to construct the biaryl C-C bond at the position a based on this approach utilizing the biomimetic
oxidative couplings. Hence, we turned our attention to employ intramolecular C-C cross coupling at the
OH
OR2
O
O
A
C
a
b
b
a
R1
R1
D
B
MeO
OH
MeO
O
OR2
6 R 1 = R2 = H
7 R 1 = Br, R2 = MOM
4
P(OMe)2
OBn
C
CHO
D
O
Br
Br
+
A
+
B
MeO
OBn
CHO
CO2Me
unit B (9)
unit C (10)
unit A (8)
Figure 2 Synthetic plan of plagiochin D (4)

position a in halogenated bis(bibenzyl) (7) by using transition metals.
According to the procedure used for the synthesis of marchantin A (5),9 dibromoperrottetin derivative (7),
a key precursor for the crucial C-C bond formation and macrocyclization, was prepared as follows
(Scheme 1). The unit A (8)9 and the phosphonate 9 readily derivable from o-bromo-m-methoxy-
benzaldehyde20 were effectively combined by Wardworth-Emmons reaction using sodium hydride, giving
rise to 11 in 94% yield. The ester group of 11 was reduced with lithium aluminum hydride to the hydroxy
group, which was then brominated with tetrabromomethane/triphenylphsophine followed by heating with
trimethyl phosphite to afford the phosphonate (12) in 81% yield. The Wardworth-Emmons reaction
between 10 and 12 smoothly proceeded to yield the bis(dibromostilbene) (13) in 89%. Next catalytic
hydrogenations of 13 were frustrated in the selective reduction of the double bonds by accompanying the
debromination. After several attempts, 13 was cleanly hydrogenated over PtO2 as catalyst and methylene
O
P(OMe)
2
OBn
CHO
O
Br
Br
a) – c)
86%
d)
+
94%
MeO
MeO
CHO
CO Me
2
9
8
OBn
OBn
O
O
CHO
Br
e), b), c)
81%
+
CO Me
2
P(OMe)
2
OBn
O
Br
Br
10
MeO
MeO
12
11
OBn
OMOM
O
O
d)
89%
f), g)
73%
Br
Br
Br
Br
MeO
OBn
MeO
OMOM
13
7
Reagents and conditions: a) NaBH , THF, 0˚C; b) CBr , Ph P, MeCN; c) P(OMe) , 90˚C
4
4
3
3
d) NaH, THF, 0˚C; e) LiAlH , THF, 0˚C; f) H , PtO , CH Cl ; g) NaH, MOMCl, DMF
4
2
2
2
2
Scheme 1 Preparation of dibromobis(bibenzyls) (7)

chloride as solvent, giving rise to the seco compound (7) in 73% yield after protecting the liberated
hydroxy groups as the MOM ethers. We are now in a position to employ key intramolecular aryl-aryl
cross coupling reactions for the construction of the 16-membered ring.
For the first of all, Ni(0) mediated intramolecular coupling21 which was recently utilized for the construction
of the 12-membered biaryl ring system in vancomysin22 as well as of the 17-membered biaryl ring
system23 was applied to the seco compounds (7) and (14) (Runs 1 and 2 in Table 1). Under Ni(0)
mediated coupling conditions, no cross coupling proceeded to solely give the recovery and/or the reduced
product (17).
OMOM
OR
O
O
R1
R2
MeO
OMOM
MeO
OR
18 R = MOM
4 R = H
7 R1 = R2 = Br
14 R1 = R2 = I
15 R1 = Br, R2 = SnMe3
16 R1 = SnMe3, R2 = Br
17 R1 = R2 = H
Scheme 2 Synthesis of plagiochin D (4)
Table 1 Intramolecular Cross Coupling Reaction of (7) by Transition Metals
Run
Reagent (equiv.)
Solvent
Temp (˚C)
Yield (%)
7
15 or 16
18
1*
2*
Ni(PPh3)2Cl2 (1.2)
Zn, PPh3
Ni(PPh3)4 (1.2)
DMF
DMF
160
160
100
100
-
-
0
0
O
B
3
(1.1)
toluene
120
100
-
0
O
2
Pd(PPh3)4 (0.05)
dppf (0.1)
KOAc (5.0)
4*
5
(Me3Sn)2 (1.1)
Pd(PPh3)4 (0.05)
(Me3Sn)2 (1.1)
Pd(PPh3)4 (0.05)
toluene
THF
120
60
45
41
9
17
0
10
*alsousing14.

On the other hand, the intramolecular Suzuki-Miyaura Pd(0) catalyzed reaction for 7 using
bis(pinacolate)diborane24 was also fruitless (Run 3). In contrast, the intramolecular version of Stille-Kelly
reaction25 led 7 to the crucial cross coupling (Run 4). A diluted solution of 7 was heated at 120˚C with
1.1 equivalent of hexamethylditin and 5 mol% tetrakis(triphenylphosphine)palladium in a sealed tube to
afford the cyclized product (18) in 17% yield along with a mixture of trimethylstannyl compounds (15)
and (16) (9%) and the recovered (7) (45%). The cyclization of the diiodide (14)26 under the same
conditions was comparable to that of 7, but no cross coupling reaction could be affected in other solvents
(THF, DMF and MeCN) except for toluene. The key intermediate for this ring closure can be regarded as
the isolated trimethylstannyl compounds (15) and (16). In fact, a diluted solution of 15 and 16 in toluene
was again heated at 120˚C with 5 mol% tetrakis(triphenylphosphine)palladium in a sealed tube, resulting
in the formation of the biaryl system (18) in 20% yield. Finally, removal of the MOM groups in 18 with
47% HBr in MeOH afforded plagiochin D (4) in 87% yield. Its spectral data were superimposable with
those of natural plagiochin D.
Synthesis of Plagiochin A (1)
As the intramolecular Stille-Kelly reaction was proved to be quite useful for the crucial 16-membered ring
formation at the position a in the plagiochins, we applied this methodology to our synthesis of neurotrophic
plagiochin A (1), the highest substitueted member of the plagiochins.
Ph
O
Ph
P(OMe)2
Br
O
CHO
D
O
O
Br
A
C
B
OBn
MeO
CHO
CO2Me
OBn
unit C (10)
unit D (19)
unit E (20)
Figure 3 Units required for synthesis of plagiochin A (1)
We need to prepare units D and E as shown in Figure 3, which are to be assembled with unit C (10),
according to similar sequence used for the synthesis of 4, to attain 1. Thus, the synthesis of 1 began with
the preparation of unit D (19) and unit E (20) as shown in Scheme 3. The diphenyl acetal (21) of methyl
gallate27 was coupled with p-bromobenzaldehyde under Ullmann condition (K2CO3 and CuO in pyridine
under reflux) to give rise to the unit D (19) in 80% yield. The unit E (20) was readily derived from
vanillin in five steps by the process as shown in Scheme 3. Thus the obtained 19 and 20 were coupled by
Wardwoth-Emmons reaction using sodium hydride in THF to afford 25 in 63% yield. The methyl ester
(25) was converted to the phosphonate (26) in 52% yield by LiAlH4 reduction and bromination with
thionyl bromide, followed by heating with trimethyl phosphite. The phosphonate (26) was again subjected

Ph
Ph
Ph
Ph
O
Br
O
O
O
HO
O
a)
+
80%
CHO
CO Me
CHO
CO Me
2
2
19
21
R
CHO
OBn
CHO
OBn
CHO
OH
Br
Br
b)
80%
c)
69%
d) – f)
63%
MeO
MeO
MeO
MeO
OBn
22
23
24 R = Br
20 R = P(O)(OMe)
2
Reagents and conditions: a) CuO, K CO , pyridine, 145˚C; b) BnBr, iPr NEt, DMF; c)
2
3
2
Br , AcONa, AcOH; d) NaBH , THF: e) CBr , PPh , MeCN; f) P(OMe) .
2
4
4
3
3
Scheme 3 Preparation of units D (19) and E (20)
to Wardworth-Emmons reaction with unit C (10), thereby giving rise to the key compound (27) having all
the benzene rings required for the synthesis of 1 in 76% yield. The double bonds in 27 were hydrogenated
over PtO2 in CH2Cl2 to yield the seco compound (28) in 47% yield after protecting the liberated hydroxy
groups as the MOM groups. Cross coupling of the dibromide (28) was attempted under the same
Stille-Kelly conditions successfully used for the direct ring closure of 7. In the case of 28, however, no
direct cyclization proceeded, but only metal exchanges took place to yield a mixture of the trimethylstannyl
compounds (29) and (30) in 44% yield. A diluted solution of a mixture of 29 and 30 in toluene was again
heated at 120˚C with 5 mol% tetrakis(triphenylphosphine)palladium in a sealed tube, thereby yielding the
cyclized product (31) in 31% yield. After all, the key macrocyclization of 28 was achieved by employing,
in turn, Stille-Kelly and Stille reactions. Deprotection of the MOM groups in 31 with 48% HBr afforded
1, which was identical in all respects with natural plagiochin A.
In conclusion, we have synthesized plagiochin D (4), the simplest member of the type 2 macrocyclic
bis(bibenzyls), by using an intramolecular Stille-Kelly reaction for the construction of the rigid 16-membered
biaryl ring system, and then have been succeeded in the first synthesis of the most biologically intriguing
plagiochin A (1) by applying the established methodology. Neurotrophic properties for plagiochin A will
be reported in due time.

Ph
Ph
O
O
O
O
Ph
P(OMe)2
Br
Ph
O
1) LiAlH4, THF
2) SOBr2, benzene
3) P(OMe)3
O
O
NaH, THF
63%
CO2 Me
+
52%
MeO
Br
CHO
CO2Me
OBn
20
19
MeO
OBn
25
Ph
O
Ph
Ph
Ph
O
O
O
O
O
1) H2, PtO2
CH2Cl2
CHO
Br
NaH, THF
76%
+
2) MOMCl, NaH
DMF
P(OMe)2
Br
Br
OBn
O
Br
47%
10
MeO
OBn
MeO
OBn
OBn
26
27
OMOM
OMOM
OMOM
OMOM
O
O
5 mol% Pd(PPh3 )4
5 mol% Pd(PPh3 )4
2 eq. (Me3Sn)2
Br
Br
toluene, 120˚C
R1
toluene, 120˚C
R2
44%
31%
MeO
OM OM
MeO
OMOM
OMOM
28
OMOM
29 R1 = Br, R2 = SnMe3
30 R1 = SnMe3 , R2 = Br
OMOM
OMOM
OH
O
O
OH
48% HBr,MeOH
71%
Me O
OMOM
MeO
OH
OMOM
31
OH
1
Scheme 4 Synthesis of plagiochin A (1)

EXPERIMENTAL
Melting points were determined on a Yanagimoto MPJ-2 micro melting-point apparatus and were
1
uncorrected. IR spectra were on a JASCO FT-IR 5300 spectrophtometer. H NMR spectra were recorded
on Varian Gemini-200 and Unity-200, and JEOL ECP-400 instruments in CDCl3 solution with TMS as an
internal standard. MS spectra were measured on a JEOL AX-500 spectrometer. Thin-layer chromatography
was performed on Merck Kiselgel 60F254 precoated silica gel plates, and spots were visualized by irradiation
with UV (254 nm) and/ or by spraying with Ce2(SO4)3-H2SO4 followed by heating. Column chromatography
was performed with silica gel (Wakogel C-300).
THF was distilled from sodium-benzophenone and other solvents were distilled from calcium hydride.
Dimethyl [(2-bromo-5-methoxyphenyl)methyl]phosphonate (9). To a solution of 2-bromo-5-methoxy-
benzaldehyde (4.72 g, 21.8 mmol) in THF (20 mL) was slowly added NaBH4 (990 mg, 26.2 mmol) at
0˚C. After being stirred for 4 h, the reaction mixture was diluted with water and extracted with EtOAc.
The combined organic layers were washed successively with water and brine, dried over MgSO4 and
concentrated in vacuo. The residue was dissolved in MeCN (50 mL). To this solution was added
triphenylphosphine (11.4 g, 43.6 mmol) and CBr4 (14.4 g, 43.6 mmol). The mixture was stirred at rt
overnight, and then concentrated in vacuo to leave the residue, which was chromatographed on silica gel
(200 g) with hexane-EtOAc (3:1) to afford 2-bromo-5-methoxybenzylbromide (5.42 g, 89%) as colorless
needles (mp 88˚C). A mixture of this dibromide (5 g , 17.9 mmol) and trimethyl phosphite (7 mL) was
heated at 90˚C with stirring for 2 h. After being cooled to rt, the reaction mixture was directly
chromatographed on silica gel (240 g) with EtOAc to give unit B (9) (5.34 g, 97%) as a colorless oil: IR
1600, 1580, 1480 cm-1;1H NMR (200 MHz) δ 3.38 (2H, d, J = 22.2 Hz), 3.69 (3H, s), 3.75 (3H, s), 3.79
(3H, s), 6.70 (1H, m), 7.00 (1H, s), 7.45 (1H, m); EIMS m/z (rel. int.) 310 (M+, 4), 308 (M+, 4), 229
(100); HRMS (EI) calcd for C10H14O4BrP 307.9813, found: 307.9788.
Methyl 3-(4-formylphenoxy)-4-benzyloxybenzoate (8). A mixture of methyl 3-hydroxy-4-benzoate
(1.5 g, 5.64 mmol), p-bromobenzaldehyde (1.26 g, 6.78 mmol), anhydrous K2CO3 (1.56 g, 11.3 mmol)
and anhydrous pyridine (30 mL) was heated with stirring at 90˚C for 10 min. To this solution was added
cupric oxide (1.14 g, 14.1 mmol). The reaction mixture was vigorously stirred at 145˚C for 2 days. After
being cooled to rt, the reaction solution was filtered, and concentrated in vacuo to leave the residue.
CH2Cl2 was added to the residue. The obtained organic layer was washed successively with saturated
Cu(NO3)2, saturated NaHCO3, and brine, dried (MgSO4) and concentrated in vacuo to give the residue
(6.0 g), which was chromatographed on silica gel (240 g) with CH2Cl2-hexane (3:1) to afford 8 (1.42 g,
81%) as yellow color prisms: mp 94˚C (MeOH); IR 1715, 1610, 1600, 1580 cm-1; FABMS m/z 385 (M+ +
Na), 363 (M+ + 1); 1H NMR (200 MHz) δ 3.89 (3H, s), 5.11 (2H, s), 7.00 (2H, d, J = 8.8 Hz), 7.09 (2H,
d, J = 8.4 Hz), 7.10 (1H, d, J = 8.8 Hz), 7.25 (3H, m), 7.83 (2H, d, J = 8.8 Hz), 7.84 (1H, d, J = 1.8 Hz),
7.92 (1H, dd, J = 8.8, 1.8 Hz), 9.92 (1H, s); HRMS (FAB) calcd for C22H19O5 363.1233, found: 363.1248;
Anal. Cacld for C22H18O5: C, 72.93; H, 4.97. Found: C, 72.85; H, 5.13.

(E)-1-[4-(2-Benzyloxy-5-methoxycarbonylphenoxy)phenyl]-2-[2-bromo-5-methoxyphenyl]ethene
(11). A solution of 9 (1.5 g, 4.8 mmol) in THF (5 mL) was added to a suspension of 60% NaH (200 mg,
5.0 mmol) in THF (10 mL) at 0˚C. After 30 min at 0˚C, a solution of 8 (1.4 g, 4.5 mmol) in THF (5 mL)
was added over 30 min. After being stirred at rt overnight, the reaction mixture was poured into an
ice-water and extracted with EtOAc. The combined extracts were washed with water and brine, dried
(MgSO4) and concentrated in vacuo. The residue was chromatographed on silica gel (100 g) with
hexane-EtOAc (3:2) to afford 11 (2.26 g, 94%) as a yellow color amorphous material: IR 1715, 1590,
-1
1
1500 cm ; EIMS m/z (rel. int.) 546 (M+, 65), 544 (M+, 64), 374 (23), 256 (26); H NMR (200 MHz) δ
3.85 (3H, s), 3.87 (3H, s), 5.16 (2H, s), 6.71 (1H, dd, J = 8.8, 2.9 Hz), 6.92 – 7.52 (10H, m), 7.23 (1H, d, J
= 15.8 Hz), 7.48 (1H, d, J = 15.8 Hz), 7.77 (1H, d, J = 2.0 H z), 7.85 (1H, dd, J =8.8, 2.0 Hz); HRMS
(EI) calcd for C30H25O5Br 544.0886, found: 544.0848.
(E)-1-[[4-(2-Benzyloxy-5-dimethylphosphonomethyl)phenoxy]phenyl]-2-[2-bromo-5-
methoxyphenyl]ethene (12).
A solution of 11 (720 mg, 1.32 mmol) in THF (1 mL) was added to a
suspension of LiAlH4 (76 mg, 1.59 mmol) at 0˚C. After being stirred at rt overnight, EtOAc, water,
MgSO4and celite were successively added to the reaction mixture and filtered. The filtrate was concentrated
in vacuo to give the residue, which was dissolved in MeCN. To this solution were added triphenyl
phosphine (520 mg, 1.98 mmol), and CBr4 (657 mg, 1.98 mmol). The reaction mixture was stirred at rt
overnight and then concentrated in vacuo to give the residue, which was purified by chromatography on
silica gel (30 g) eluting with hexane-EtOAc (4:1) to afford the dibromide (620 mg). This was heated in
trimethyl phosphite (0.5 mL) at 90˚C for 2 h. The crude product obtained by the same work-up as
described in the preparation of 9 was chromatographed on silica gel (20 g) with EtOAc to yield 12 (651
mg, 81%) as a colorless oil. IR 1590, 1505 cm-1; EIMS m/z (rel. int.) 610 (M+, 100), 608 (M+, 95), 438
(68), 320 (29); 1H NMR (200 MHz) δ 3.09 (2H, d, J = 21.4 Hz), 3.65 (3H, s), 3.70 (3H, s), 3.84 (3H, s),
5.07 (2H, s), 6.71 (1H, dd, J = 8.8, 2.9 Hz), 6.92–7.51 (14H, m); HRMS (EI) calcd for C31H30O6BrP
608.0964, found: 608.0955.
2-Bromo-5-benzyloxybenzaledyde (10).
To a solution of 3-benzyloxybenzaldehyde (200 mg, 0.92
mmol) in acetic acid (6 mL) containing sodium acetate (200 mg) was added a solution of bromine (0.6
mL, 1.1 mmol) in acetic acid (2 mL) at 40˚C. After being stirred at 40˚C for 11 h, ether was added. The
solution was washed successively with 2M NaOH, water and brine, dried (MgSO4) and concentrated in
vacuo. The residue was chromatographed on silica gel (24 g) with hexane-EtOAc (4:1) to afford 10
-1
(184.8 mg, 68%) as a yellow color oil. IR 1695, 1590, 1485 cm ; EIMS m/z (rel. int.) 292 (M+, 17), 290
1
(M+, 17), 262 (33), 208 (23), 183 (27); H NMR (200 MHz) δ 5.09 (2H, s), 7.10 (1H, dd, J = 8.8, 3.2 Hz),
7.34–7.43 (5H, m), 7.51 (1H, d, J = 3.2 Hz), 7.53 (1H, d, J = 8.8 Hz), 10.30 (1H, s); HRMS (EI) calcd for
C14H11O2Br 289.9942, found: 289.9855.
Wardworth-Emmons reaction between 12 and 10.

A solution of 12 (490 mg, 0.82 mmol) in THF (2 mL) was added to a suspension of 60% NaH (60 mg,
1.50 mmol) in THF (4 mL) at 0˚C. After 30 min at 0˚C, a solution of 10 (226 mg, 0.74 mmol) in THF (2
mL) was added over 30 min. After being stirred at rt overnight, the reaction mixture was poured into an
ice-water and extracted with EtOAc. The combined extracts were washed with water and brine, dried
(MgSO4) and concentrated in vacuo. The crude product obtained by the same work-up as described in the
preparation of 11 was chromatographed on silica gel (60 g) with hexane-CHCl3 (1:1) to yield 13 (560 mg,
-1
89%) as a colorless amorphous powder. IR 1590, 1500 cm ; EIMS m/z (rel. int.) 776 (M+, 23), 774 (M+,
63), 772 (M+, 19), 604 (17), 432 (10); 1H NMR (200 MHz) δ 3.84 (3H, s), 5.08 (2H, s), 5.11 (2H, s),
6.68–7.53 (27H, m); HRMS (EI) calcd for C43H34O4Br2 772.0824, found: 772.0804.
Hydrogenation of 13.
A solution of 13 (195 mg, 0.25 mmol) in CH2Cl2 (6 mL) was hydrogenated
over PtO2 (80 mg) under atmospheric pressure at rt. The catalyst was filtered off, and the filtrate was
concentrated in vacuo. The residue was chromatographed on silica gel (20 g) with CHCl3-EtOAc (9:1) to
afford the reduced product, which was dissolved in DMF (2 mL). This solution was added to a solution
of 60% NaH (48 mg, 1.2 mmol) at 0˚C under argon. After being stirred at 0˚C for 30 min, chloromethyl
methyl ether (0.1 mL, 1.2 mmol) was added. The reaction mixture was stirred at rt for 14 h. The reaction
mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed
with brine, dried (MgSO4) and concentrated in vacuo. The residue was chromatographed on silica gel (6
g) with CHCl3-hexane (9:1) to afford 7 (125 mg, 74%) as a colorless oil. IR 1574, 1508 cm-1; EIMS m/z
1
(rel. int.) 688 (M+, 50), 686 (M+, 90), 684 (M+, 47), 485 (42), 425 (100), 211 (50); H NMR (200 MHz) δ
2.82 - 2.98 (8H, m), 3.43 (3H, s), 3.44 (3H, s), 3.74 (3H, s), 5.09 (2H, s), 5.14 (2H, s), 6.64 (1H, dd, J =
8.4, 2.9 Hz), 6.71 (1H, d, J = 2.9 Hz), 6.76 (1H, dd, J = 8.4, 2.9 Hz), 6.78 - 6.89 (4H, m), 6.94 (1H, dd, J
= 8.4, 2.0 Hz), 7.12 (1H, d, J = 1.8 Hz), 7.16 (1H, d, J = 1.1 Hz), 7.40 (1H, d, J = 8.4 Hz), 7.42 (1H, d, J =
8.8 Hz); 13C NMR (50 MHz) δ 35.1, 35.2, 38.4, 38.6, 55.3, 55.9, 56.1, 94.4, 95.5, 113.2, 114.8, 115.8,
116.1, 117.8, 118.3, 121.2, 124.5, 129.5, 133.2, 133.3, 135.4, 136.2, 141.7, 141.8, 146.1, 146.9, 156.2,
156.5, 158.8; HRMS (EI) calcd for C33H34O6Br2 684.0710, found: 684.0722.
Intramolecular Stille-Kelly reaction of 7. To a solution of 7 (50 mg, 0.073 mmol) in toluene (10 mL)
was added hexamethylditin (26 mg, 0.08 mmol) and tetrakis(triphenylphosphine)palladium (4.2 mg,
0.0037 mmol). The reaction mixture in a sealed tube was heated at 120˚C for 24 h. After being filtered
and concentrated in vacuo, the crude product was purified by prep. TLC (hexane-EtOAc, 2:1) to yield 18
(7 mg, 17%), a mixture of 15 and 16 (2.7 mg, 9%) and the recovery 7 (11.7 mg, 45%) as a colorless oil,
respectively. 18: IR 1606, 1504, 1224, 1153 cm-1; EIMS m/z (rel. int.) 526 (M+, 100), 449 (12), 225 (49);
1H NMR (400 MHz) δ 2.10 (1H, m), 2.87–2.91 (3H, m), 3.05–3.12 (4H, m), 3.45 (3H, s), 3.57 (3H, s),
3.89 (3H, s), 5.12 (2H, s), 5.27 (2H, s), 5.30 (1H, d, J = 1.8 Hz), 6.68–6.78 (5H, m), 6.84 (1H, d, J = 8.3
Hz), 6.95 (3H, m), 7.02 (1H, d, J = 8.3 Hz), 7.03 (1H, d, J = 8.3 Hz), 7.21 (1H, d, J = 2.4 Hz); HRMS (EI)
calcd for C33H34O6 526.2355, found: 526.2364.
15 and 16: EIMS m/z (rel. int.) 754 (M+, 20).

Intramolecular Stille reaction of 15 and 16. To a solution of 15 and 16 (13.0 mg, 0.016 mmol) in
toluene (2 mL) was added tetrakis(triphenylphosphine)palladium (0.5 mg). The reaction mixture in a
sealed tube was heated at 120˚C for 12 h. After being filtered and concentrated, the obtained product was
subjected to prep. TLC (hexane-EtOAc, 2:1) to afford 18 (3 mg, 20%).
Plagiochin D (4). A solution of 18 (1.8 mg, 0.034 mmol) in methanol (1 mL) containing one drop of
48% HBr was stirred at 50˚C for 15 min. The reaction mixture was concentrated in vacuo to give the
residue, which was purified by prep. TLC (hexane-EtOAc, 2:1) to afford plagiochin D (4) (1.3 mg, 87%)
as a colorless oil. Its spectral data shown below were identical with those of natural plagiochin D.
-1
IR 3404, 1604, 1228 cm ; EIMS m/z (rel. int.) 438 (M+, 100), 332 (11), 225 (53), 213 (38); 1H NMR (400
MHz) δ 2.16 (1H, m), 2.71–3.05 (7H, m), 3.82 (3H, s), 4.58 (1H, s), 5.17 (1H, d, J = 1.8 Hz), 5.39 (1H,
s), 6.45 (1H, d, J = 2.6 Hz), 6.56 (1H, dd, J = 8.4, 2.6 Hz), 6.63 (1H, dd, J = 8.4, 2.7 Hz), 6.65 (1H, dd, J
= 8.1, 1.8 Hz), 6.67 (1H, dd, J = 8.8, 2.6 Hz), 6.75 (1H, d, J = 8.1 Hz), 6.83 (1H, d, J = 8.4 Hz), 6.85 (1H,
dd, J = 8.4, 2.6 Hz), 6.90 (1H, dd, J = 8.4, 2.6 Hz), 7.01 (1H, d, J = 8.8 Hz), 7.11 (1H, d, J = 2.6 Hz);
HRMS (EI) calcd for C29H26O4 438.1797, found: 438.1763.
Methyl 4,5-diphenylmethylenedioxy-3-(4-formylphenoxy)benzoate (19).
According to the same
procedure used for the preparation of 8, 19 (2.94 g, 80%) was prepared from 21 (1.5 g, 5.64 mmol),
p-bromobenzaldehyde (1.26 g, 6.78 mmol), anhydrous K2CO3 (1.56 g, 11.3 mmol), cupric oxide (1.14 g,
14.1 mmol) and pyridine (30 mL). 19: IR 1720, 1700, 1600, 1590, 1505 cm-1; EIMS m/z (rel. int.) 452
(M+, 73), 375 (100), 331 (16), 165 (20); 1H NMR (200 MHz) δ 3.87 (3H, s), 7.04 (2H, d, J = 8.8 Hz),
7.32–7.59 (12H, m), 7.83 (2H, d, J = 8.8 Hz), 9.95 (1H, s); HRMS (EI) calcd for C28H20O6 452.1259,
found: 452.1248.
3-Methoxy-4-phenylmethoxybenzaldehyde (22).
To a cooled (0˚C) solution of vanillin (10.0 g, 65.7
mmol) in DMF (30 mL) was successively added N,N-diisopropylethylamine (11.5 mL, 65.7 mmol) and
benzyl bromide (7.8 mL, 65.7 mmol). After being stirred at rt overnight, the reaction mixture was diluted
with water and extracted with ether. The combined organic layers were washed with brine, dried
(MgSO4) and concentrated in vacuo. The residue was chromatographed on silica gel (420 g) with
hexane-EtOAc (2:1) to afford 22 (13.0 g, 80%) as colorless plates: mp 63˚C (MeOH); IR 1680, 1590,
1
1510 cm-1; EIMS m/z (rel. int.) 242 (M+, 58), 91 (100); H NMR (200 MHz) δ 3.93 (3H, s), 5.23 (2H, s),
6.97 (1H, d, J = 8.2 Hz), 7.30–7.46 (7H, m), 9.82 (1H, s); HRMS (EI) calcd for C15H14O3 242.0943,
found: 242.0923.
2-Bromo-5-methoxy-4-benzyloxybenzaldehyde (23). To a solution of 22 (1.1 g, 4.55 mmol) in acetic
acid (11 mL) containing sodium acetate (1.1 g) was added bromine (0.58 mL, 11.4 mmol). The reaction
mixture was stirred at 40˚C for 11 h. After being cooled to rt, ether was added. The solution was washed
with 2M NaOH, water and brine, dried (MgSO4) and concentrated in vacuo. The residue was

chromatographed on silica gel (24 g) with hexane-EtOAc (4:1) to afford 23 (999 mg, 69%) as colorless
-1
prisms: mp 98˚C (MeOH); IR 1670, 1580, 1495 cm ; EIMS m/z (rel. int.) 322 (M+, 32), 320 (M+, 33); 1H
NMR (200 MHz) δ 3.92 (3H, s), 5.20 (2H, s), 7.10 (1H, s), 7.36–7.45 (6H, m), 10.18 (1H, s); HRMS (EI)
calcd for C15H13BrO3 320.0048, found: 320.0051.
5-Bromo-4-bromomethyl-1-benzyloxy-2-methyloxybenzene (24). To a solution of 23 (5.77 g, 18.0
mmol) in THF (35 mL) was added NaBH4 (0.82 g, 21.6 mmol) at 0˚C. After being stirred for 4 h, the
reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were
washed with brine, dried (MgSO4) and concentrated in vacuo. The obtained crude alchohol was dissolved
in MeCH (40 mL), and then CBr4 (8.96 g, 27.0 mmol) and triphenylphosphine (7.1 g, 27.0 mmol) were
added. The reaction solution was stirred at rt overnight, and then concentrated in vacuo to leave the
residue, which was chromatographed on silica gel (180 g) with hexane-CHCl3 (1:1) to afford 24 (4.33 g,
63%) as white needles: mp 110˚C (from hexane-CHCl3); IR 1505, 1208, 1013 cm-1; EIMS m/z (rel. int.)
1
387 (M+, 5), 385 (M+, 9), 383 (M+, 5), 307 (22), 91 (100); H NMR (200 MHz) δ 3.88 (3H, s), 4.58 (2H,
s), 5.12 (2H, s), 6.95 (1H, s), 7.07 (1H, s), 7.35–7.42 (5H, m); Anal. Cacld for C15H14O2Br2: C, 46.66; H,
3.65. Found C, 46.80; H, 3.72.
Dimethyl 2-bromo-4-benzyloxy-5-methoxybenzylphosphonate (20). A mixture of 24 (100 mg, 0.26
mmol) and trimethylphosphite (1 mL) was stirred at 90˚C for 3 h. The reaction mixture was chromatographed
on silica gel (5 g) with EtOAc to give 20 (116.6 mg, 100%) as white needles: mp 69˚C (from hexane-CH2Cl2);
1
EIMS m/z (rel. int.) 416 (M+, 13), 414 (M+, 13), 335 (36), 109 (20); H NMR (200 MHz) δ 3.33 (2H, d, J
= 21.6 Hz), 3.68 (3H, s), 3.73 (3H, s), 3.87 (3H, s), 5.10 (2H, s), 7.00 (1H, d, J = 2.6 Hz), 7.07 (1H, s),
7.34–7.42 (5H, m); Anal. Cacld for C17H20O5BrP: C, 49.17; H, 4.86. Found: C, 49.26; H, 4.90.
(E)-1-[[4-(5-Methoxycarbonyl-2,3-diphenylmethylenedioxy)phenoxy]phenyl]-2-[2-bromo-4-
benzyloxy-5-methoxyphenyl]ethene (25). A solution of 20 (3.37 g, 8.15 mmol) in THF (10 mL) was
added to a suspension of 60% NaH (341.6 mg, 8.54 mmol) in THF (17 mL) at 0˚C. After 30 min at 0˚C, a
solution of 19 (2.94 g, 7.76 mmol) in THF (10 mL) was added over 30 min. After being stirred at rt
overnight, the reaction mixture was poured into an ice-water and extracted with EtOAc. The combined
extracts were washed with water and brine, dried (MgSO4) and concentrated in vacuo. The residue was
chromatographed on silica gel (200 g) with CHCl3 to afford 25 (3.18 g, 63%) as white prisms: mp 186˚C
(from hexane-CH2Cl2); IR 1718, 1504, 1207 cm-1; FABMS m/z 742 (M+), 740 (M+); 1H NMR (200 MHz)
δ 3.85 (3H, s), 3.95 (3H, s), 5.14 (2H, s), 6.67 (2H, d, J = 8.8 Hz), 7.10 (1H, s), 7.35–7.52 (21H, m);
HRMS (FAB) calcd. for C43H33O7Br 740.1410, found: 740.1425; Anal. Cacld for C43H33BrO7: C, 69.64;
H, 4.49. Found: C, 69.91; H, 4.50.
(E)-1-[[4-(5-Dimethylphosphonomethyl-2,3-diphenylmethylenedioxy)phenoxy]phenyl]-2-[2-bromo-

4-benzyloxy-5-methoxyphenyl]ethene (26). A solution of 25 (3.18 g, 4.30 mmol) of THF (20 mL) was
added dropwise to a suspension of LiAlH4 (280 mg, 5.81 mmol) in THF (40 mL) at 0˚C. The reaction
mixture was stirred at rt for 12 h and then diluted with EtOAc. To this solution were added water, MgSO4
and celite. After the solid was filtered off, the filtrate was concentrated in vacuo to yield the alcohol (3.07
g, 100%). This alcohol (1.86 g, 2.79 mmol) was dissolved in benzene (60 mL). To this solution was
added thionyl bromide (0.19 mL, 2.79 mmol). The reaction mixture was stirred for 20 min, and then
poured into an ice-water. The benzene layer was washed with brine, dried (MgSO4) and concentrated in
vacuo to give the residue, to which trimethyl phsophite (0.99 mL, 8.37 mmol) was added. The reaction
mixture was stirred at 90˚C for 3 h, and then directly purified by chromatography on silica gel (70 g)
eluting with hexane-EtOAc (1:9) to afford 26 (1.05 g, 52%) as white powder: mp 159˚C (from hexane-
-1
CH2Cl2); IR 1601, 1504, 1263 cm ; EIMS m/z (rel. int.) 804 (M+, 5), 713 (7), 313 (13), 252 (40), 182
(51); 1H NMR (200 MHz)δ 3.03 (2H, d, J = 21.2 Hz), 3.66 (3H, s), 3.71 (3H, s), 3.95 (3H, s), 5.14 (2H,
s), 6.54 (1H, s), 6.73 (1H, s), 6.87–6.89 (2H, m), 6.96 (2H, d, J = 8.1 Hz), 7.10 (1H, s), 7.17 (1H, s),
7.26–7.52 (17H, m); Anal. Cacld for C44H38O8Br: C, 65.60; H, 4.75. Found: C, 66.02; H, 4.85.
Wardworth-Emmons reaction between 26 and 10. A solution of 26 (870 mg, 1.08 mmol) in THF (2
mL) was added to a suspension of 60% NaH (100 mg, 2.50 mmol) in THF (6 mL) at 0˚C. After 30 min at
0˚C, a solution of 2-bromo-5-benzyloxybenzaldehyde (530 mg, 1.82 mmol) in THF (2 mL) was added
over 30 min. After being stirred at rt for 12 h, the crude product obtained by the same work-up as
described in the preparation of 11 was chromatographed on silica gel (40 g) with hexane-CHCl3 (3:2) to
1
afford 27 (745 mg, 76%) as white powder: mp 189˚C (from hexane-CH2Cl2); IR 1599, 1504 cm-1; H
NMR (200 MHz) δ 3.95 (3H, s), 5.06 (2H, s), 5.14 (2H, s), 6.72–6.78 (2H, m), 6.87 (2H, d, J = 4.8 Hz),
6.97 (1H, d, J = 4.4 Hz), 7.03–7.04 (2H, m), 7.11 (1H, s), 7.17–7.19 (2H, m), 7.33–7.55 (22H, m).
Hydrogenation of 27.
A solution of 27 (585 mg, 0.60 mmol) in CH2Cl2 (12 mL) was hydrogenated
over PtO2 (150 mg) under atmospheric pressure at rt. After the catalyst was filtered off, the filtrate was
concentrated in vacuo to give the product (190 mg), which was dissolved in DMF (2 mL). To this
solution was added 60% NaH (154 mg, 4.0 mmol) at 0˚C. After being stirred for 30 min, chloromethyl
methyl ether (0.3 mL, 4.0 mmol) was added. The reaction mixture was stirred at rt for 14 h, and then
diluted with water, extracted with EtOAc. The combined organic layers were washed with water and
brine, dried (MgSO4) and concentrated in vacuo to give the residue, which was chromatographed on silica
gel (20 g) with hexane-EtOAc (2:1) to afford 28 (216.7 mg, 47%) as a colorless oil. IR 1587, 1504, 1155
1
cm-1; H NMR (200 MHz) δ 2.76–2.97 (8H, m), 3.44 (3H, s), 3.51 (3H, s), 3.52 (3H, s), 3.53 (3H, s), 3.79
(3H, s), 5.09 (2H, s), 5.11 (2H, s), 5.18 (2H, s), 5.20 (2H, s), 6.47 (1H, d, J = 1.9 Hz), 6.63 (1H, s),
6.73–6.80 (3H, m), 6.87 (2H, d, J = 8.6 Hz), 7.13 (2H, d, J = 8.6 Hz), 7.33 (1H, s), 7.49 (1H, d, J = 8.5
Hz); 13C NMR (50 MHz) δ 35.6, 35.7, 38.2 (x2), 55.9, 56.0, 56.2, 57.0, 94.5, 95.4, 95.7, 98.5, 112.1,
113.6, 114.3, 115.9, 116.1, 117.4, 118.3, 120.6, 129.6, 133.3, 134.6, 135.7, 137.7, 141.5, 145.3, 149.0,
149.9, 151.3, 155.8, 156.5.

Intramolecular Stille-Kelly reaction of 28. A mixture of 28 (50 mg, 0.062 mmol), hexamethylditin
(50 mg, 0.16 mmol) and tetrakis(triphenylphosphine)palladium (3.5 mg, 0.0031 mmol) in toluene (6 mL)
was heated in a sealed tube at 120˚C for 48 h. After the catalyst was filtered off, the reaction mixture was
concentrated in vacuo to give the residue, which was purified by prep. TLC (hexane-EtOAc, 1:1) to afford
a mixture of 29 and 30 (13 mg, 44%). A mixture of 29 and 30 was dissolved in toluene (2 mL) and then
tetrakis(triphenylphosphine)palladium (0.5 mg) was added under argon. This mixture was heated in a
sealed tube at 120˚C for 20 h and then was concentrated in vacuo to give the residue, which was purified
by prep. TLC (hexane-EtOAc, 2:1) to afford 31 (3 mg, 31%) as an oil. 1H NMR (200 MHz) δ 2.05 (1H,
m), 2.82–3.09 (7H, m), 3.44 (3H, s), 3.45 (3H, s), 3.53 (3H, s), 3.67 (3H, s), 4.01 (3H, s), 4.99 (1H, br s),
5.11 (2H, s), 5.15 (2H, d, J = 4.0 Hz), 5.21 (2H, d, J = 4.4 Hz), 5.23 (2H, s), 6.64 (1H, br s), 6.70-6.97
(6H, m), 6.95 (1H, s), 7.12 (1H, s); HRMS (FAB) calcd for C37H42O10 646.2778, found: 646.2801.
Plagiochin A (1). To a solution of 31 (2.4 mg) in MeOH (2 mL) was added one drop of 48% HBr. The
reaction mixture was stirred at 50˚C for 15 min, and then concentrated in vacuo to give the residue, which
was purified by prep. TLC (hexane-EtOAc, 1:1) to afford 1 (1.4 mg, 71%), which was identical in all
1
respects with natural plagiochin A. H NMR (400 MHz) δ 2.29–3.34 (1H, m), 2.81–3.15 (7H, m), 4.02
(3H, s), 4.56 (1H, s), 4.81 (1H, d, J = 1.5 Hz), 5.26 (2H, s), 5.45 (1H, s), 6.45 (1H, s), 6.47 (1H, d, J = 2.6
Hz), 6.62 (1H, dd, J = 8.4, 2.6 Hz), 6.70 (1H, dd, J = 8.4, 2.2 Hz), 6.73 (1H, dd, J = 8.4, 2.2 Hz), 6.76
(1H, s), 6.86 (1H, dd, J = 8.4, 2.2 Hz), 6.89 (1H, d, J = 8.4 Hz), 6.91 (1H, dd, J = 8.4, 2.2 Hz), 7.24 (1H,
s).
ACKNOWLEDGMENT
We wish to thank Prof. Y. Asakawa and Dr. T. Hashimoto, Tokushima Bunri University, for kind
donation of natural plagiochins A and D. This work is supported by the Science Research Promotion
Fund from the Promotion and Mutual Aid Corporation for Private Schools of Japan.
REFERENCES AND NOTES
1. Dedicated to Professor Shô Itô on the occasion of his 77th birthday.
2. Y. Asakawa, 'Progress in the Chemistry of Organic Natural Products,' Vol. 42, ed. by W. Hertz, H.
Grisebach, and G. W. Kirby, Springer, Wien, 1982, pp. 1 - 562.
3. Y. Asakawa, 'Progress in the Chemistry of Organic Natural Products,' Vol. 65, ed. by W. Hertz, G.
W. Kirby, R. E. Moor, W. Steglich, and C. Tamn, Springer, Wien, 1995, pp. 1 - 285.
4. Y. Asakawa, 'Bryophytes, Their Chemistry and Chemical Taxonomy,' ed. by H. D. Zinsmeister and
R. Mues, Oxford University Press, Oxford, 1990, p. 369.
5. Y. Asakawa, 'Bryophyte Development: Physiology and Biochemistry,' ed. by R. N. Chopra and S. C.

Bhatia, CRS press, Florida, 1990, p. 259.
6. G. M. Keserü and M. Nogradi, Nat. Prod. Rep., 1995, 12, 69; J. Gerencser, G. M. Keserü, I.
Macsari, M. Nogradi, M. Kajtar-Peredy, and A. Szöllösy, J. Org. Chem., 1997, 62, 3666.
7. M. Tori, M. Toyota, L. J. Harrison, K. Takigawa, and Y. Asakawa, Tetrahedron Lett., 1985, 26,
4735.
8. Y. Asakawa, M. Toyota, Z. Taira, T. Takemoto, and M. Kido, J. Org. Chem., 1983, 48, 2164.
9. M. Kodama, Y. Shiobara, H. Sumitomo, K. Matsumura, M. Tsukamoto, and C. Harada, Tetrahedron
Lett., 1985, 26, 877; M. Kodama, Y. Shiobara, H. Sumitomo, K. Matsumura, M. Tsukamoto, and C.
Harada, J. Org. Chem., 1987, 53, 72.
10. A. Gottsegen, M. Nogradi, B. Vermes, M. Kajtar-Peredy, and E. Bihatsi-Karsai, J. Chem. Soc.,
Perkin Trans. 1, 1990, 315.
11. M. Iyoda, M. Sakaitani, H. Otsuka, and M. Oda, Tetrahedron Lett., 1985, 26, 4777.
12. T. Hashimoto, M. Tori, Y. Asakawa, and Y. Fukazawa, Tetrahedron Lett., 1987, 28, 6925.
13. G. M. Keserü and M. Nogradi, Phytochemistry, 1992, 31, 1573.
14. Plagiochin A (1) shows significantly not only outgrowth promotion of neurons but also increase of
choline acetyltransferase activity in the cultures of fetal rat cortical neurons at 1–0.1 µM.
15. Y. Fukuyama, H. Yaso, K. Nakamura, and M. Kodama, Tetrahedron Lett., 1999, 40, 105.
16. G. M. Keserü, G. Mezey-Vandor, M. Nogradi, B. Vermes, and M. Kajtar-Peredy, Tetrahedron,
1992, 48, 913.
17. Y. Fukuyama, K. Nakamura, and M. Kodama, 112th Annual Meeting of Pharmaceutical Society of
Japan, Fukuoka, Japan, 1992, Abstracts 2, p. 78. The only way by which we could achieve the ring
closure at the position b involved the two step cyclization via a sulfur linkage by the Stevens
reaction. This procedure, however, had not been able to overcome poor yield (1%).
18. S. Friederich, U. H. Maier, B. Deus-Neumann, Y. Asakawa, and M. H. Zenk, Phytochemistry, 1999,
50, 589.
19. T. Hashimoto, H. Suzuki, M. Tori, and Y. Asakawa, Phytochemistry, 1991, 30, 1523.
20. I. Fleming and M. Woolias, J. Chem. Soc., Perkin Trans. 1, 1979, 829.
21. M. F. Semmelkack, P. Helquist, L. D. Jones, L. Keller, L. Mendelson, L. S. Ryono, J. G. Smith, and
R. D. Stauffer, J. Am. Chem. Soc., 1981, 103, 6460.
22. K. C. Nicolaou, X. -J. Chu, J. M. Tamanjulu, S. Natarajan, S. Bräse, F. Rübsam, and C. N. C.
Boddy, Angew. Chem., Int. Ed. Engl., 1997, 36, 1539.
23. A. -C. Carbonnelle, E. G. Zamora, R. Beugelmans, and G. Toussi, Tetrahedron Lett., 1998, 39,
4471.
24. T. Isiyama, M. Murata, and N. Miyaura, J. Org. Chem., 1995, 60, 7508.
25. J. K. Stille and B. L. Groh, J. Am. Chem. Soc., 1987, 109, 813; T. R. Kelly, Q. Li, and V. Bhushan,
Tetrahedron Lett., 1990, 31, 161.

26. The iodide (14) was readily prepared by the lithiation of 7 with n-BuLi, followed by quenching with
iodine at -78˚C.
27. L. Jurd, J. Am. Chem. Soc., 1959, 81, 4606.