A synthesis-driven structure revision of 'plagiochin E', a highly bioactive bisbibenzyl

Article abstract of DOI:10.1055/s-0029-1217510

Recently, a bisbibenzyl named plagiochin E showing remarkable antifungal and antitumor activities was isolated from Marchantia polymorpha, a liverwort. The total synthesis of the proposed structure for plagiochin E and of two structurally and biosynthetic

Full text of DOI:10.1055/s-0029-1217510

1852
LETTER
A Synthesis-Driven Structure Revision of ‘Plagiochin E’, a Highly Bioactive
Bisbibenzyl
S
tructure Revision
n
of ‘Plagioch
d
in E’ reas Speicher,*a Matthias Groh,a Josef Zapp,b Anu Schaumlöffel,c Michael Knauer,c Gerhard Bringmannc
a
FR 8.1 Chemistry, Organic Chemistry, Saarland University, 66041 Saarbrücken, Germany
Fax +49(681)3022029; E-mail: anspeich@mx.uni-saarland.de
b
c
FR 8.2 Pharmacy, NMR Department, Saarland University, 66041 Saarbrücken, Germany
Institute of Organic Chemistry, University of Würzburg, Am Hubland, 97074 Würzburg, Germany
Received 9 March 2009
nate from two units of the bibenzyl lunularin (2), which
can be combined by several modes of O–C and/or C–C at-
tachment on the bases of phenol oxidation coupling to dif-
ferent subtypes like perrottetins, marchantins, riccardins,
Abstract: Recently, a bisbibenzyl named plagiochin E showing re-
markable antifungal and antitumor activities was isolated from
Marchantia polymorpha, a liverwort. The total synthesis of the pro-
posed structure for plagiochin E and of two structurally and biosyn-
thetically related bisbibenzyls and comparison of the NMR data of plagiochins, and isoplagiochins.2 The most common acy-
the synthetic compounds with those of the isolated bisbibenzyls ne-
cessitates a structure revision for plagiochin E. Exemplarily for this
clic precursor for cyclic bisbibenzyls with at least one
O–C connection is perrottetin E (3; Scheme 1). In total,
metabolite, the stereostructure was investigated, by racemate reso-
nine different cyclization products are possible starting
lution on a chiral Lux Cellulose-1 phase with HPLC-CD coupling
from 3 with respect to oxidative C–C coupling ortho and
and quantum chemical CD calculations, clearly assigning the P-
configuration for the faster and the M-configuration to the slower
enantiomer.
para to the hydroxyl groups. Four of them, compounds 4–
7 are shown in Scheme 1. They may, in principle, exhibit
the same NMR coupling pattern in the ‘upper’ part of the
molecule.
Key words: plagiochin E, bisbibenzyl, axially chiral biaryl, total
synthesis, natural products, circular dichroism
The distribution of the cyclic bisbibenzyls in liverworts,
their structure elucidation as well as biological activities
and total syntheses are well reviewed.1,3 In preceding pa-
pers, we reported on the synthesis of exemplified model
Bisbibenzyls are phenolic natural products that are found
exclusively in bryophytes.1 Biosynthetically, they origi-
OH
OH
OH
2
OH
6'
4'
1
4
H
1'
6
2'
C–C, only
C–O
+
OH
O
O H
O H
OH
OH
HO
1: isoplagiochin D
3: perrottetin E
C–C coupling
2 (two molecules of lunularin)
OH
HO
d
HO
OH
4'
HO
2'
OH
4
OH
6'
2'
b
OH
6
2
2
c
a
O
O
O
O
OH
OH
OH
OH
4: plagiochin E
5: plagiochin F
6: riccardin D
7: isoriccardin C
(proposed structure)
(not yet found in bryophytes)
Scheme 1
SYNLETT 2009, No. 11, pp 1852–1858
x
x
.x
x
.2
0
0
9
Advanced online publication: 16.06.2009
DOI: 10.1055/s-0029-1217510; Art ID: G06409ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Structure Revision of ‘Plagiochin E’
1853
compounds for some types of bisbibenzyls.4–6 Further- with the d–b fragment, 15 was converted into the phos-
more, we have investigated effects of axial chirality and phonium salt 16.
ring strain in the macrocycles of the isoplagiochin type
The synthesis of the d–b fragment containing a protected
and an unprotected aldehyde moiety is shown in
(see 1), which are only C–C coupled.7,8
The plagiochins A–D (8–11) were isolated from Plagio- Scheme 3. The boronic ester 19 (fragment d) was pre-
chila fruticosa in 1987 (Figure 1).9 Total syntheses were pared starting from 4-bromo-3-methylanisol (17)21 and
published10–12 with the exception for plagiochin B. The submitted to a Suzuki coupling with the triflate 21, which
isolation of plagiochin E (4), however was described near- was prepared from o-vanillin (20).
ly 20 years later from Marchantia polymorpha (Chinese
Wittig reaction of 16 and 22 gave the stilbene 23
(Scheme 4). After hydrogenation and deprotection of the
aldehyde functionalities, the macrocyclization was
variation) and Asterella angusta through a bioassay-guid-
ed separation of the antifungal constituents.13,14
achieved under McMurry conditions, to give 25. Finally,
HO
R
compound 4 was obtained after hydrogenation and depro-
tection of the phenolic OH groups. The molecular formula
C28H24O4 was confirmed by HR-EI-MS [M+ peak at m/z =
424.1687 (calcd: 424.1675)]. Surprisingly, the spectro-
scopic data (see Tables 1 and 2) were significantly differ-
d
6'
1'
b
OMe
6
1
8: plagiochin A (R = OH)
9: plagiochin B (R = H )
c
a
HO
O
O
O
CHO
OH
CHO
c
a
14
HO
R
(i)
F
d
c
6'
(ii)
b
OMe
6
OH
OH
O
1
1'
OMe
12
OMe
10: plagiochin C (R = OH)
11: plagiochin D (R = H)
13
c
a
O
O
O
O
OH
CHO
(iii), (iv)
P+Ph3Br–
c
c
a
a
Figure 1
O
O
15
OMe
OMe
Interestingly, the conformational strain of 4 had been
computed before as a hypothetical oxidative cyclization
product of lunularin (2),2 but the compound had never
been isolated before from a natural source or even synthe-
16
Scheme 2 Reagents and conditions: (i) CH(OEt)3, tetrabutylammo-
nium tribromide, 1,3-propanediol, 65 °C, 12 h (91%); (ii) 14, K2CO3,
DMF, 160 °C, 20 h (93%); (iii) NaBH4, EtOH, 0 °C to r.t., 2 h (97%);
sized. The structure of plagiochin E (4) differs from that (iv) Ph3P·HBr, MeCN, reflux, 2 h (85%).
of 8–11 by a 6-2¢-coupling between rings d–b instead of a
MeO
MeO
(iii)
6-6¢-coupling. The biaryl connection b–d in 8–11 as well
d
MeO
d
as in 4 is o,o¢ relative to the two bisbibenzyl bridges, but
in 4, the OH group is also ortho to the biaryl axis.
O
d
Br
(i), (ii)
B
Br
O
Beside the antifungal activity against Candida albicans13–
16 the recently isolated substance exhibited reversal effect
on multidrug resistance in adriamycin-resistant K562/
A02 cells suggesting that 4 may be a potential candidate
for reversing drug resistance in cancer chemotherapy.17
The pharmacokinetics in rats were studied very recently
using an LC-tandem MS assay for the quantitation of pla-
giochin E and its main metabolite in rat plasma.18 Consid-
ering the still significantly growing interest in biological
activities of bisbibenzyls and other bryophyte
constituents19 we now report on our attempts for a short
and efficient total synthesis of the isolated ‘plagiochin E’
(4),13 resulting in a revision of its structure.
O
O
O
O
Me
18
19
17
MeO
MeO
OMe
b
OMe
d
TfO
HO
b
(iv)
19
b
(v)
OHC
OHC
OHC
O
O
20
21
22
Scheme 3 Reagents and conditions: (i) NBS (2 equiv), AIBN, CCl4,
hn, reflux, 24 h, then aq CaCO3, reflux, 18 h (72%) see ref.;22 (ii)
CH(OEt)3, tetrabutylammonium tribromide, 1,3-propanediol, 65 °C,
12 h (93%); (iii) n-BuLi, THF, –78 °C, 30 min, then B(OMe)3 at
–78 °C to r.t., then pinacol, MgSO4, CH2Cl2, r.t., 12 h (70%); (iv)
Tf2O, pyridine, 0 °C to r.t., 2 h (90%); (v) 19, Pd(PPh3)4, PhMe–EtOH–
The c–a fragment 154 was now obtained by a more
straightforward sequence20 (Scheme 2) starting from iso-
vanillin (12). For the Wittig coupling of the c–a fragment 2 M Na2CO3, reflux, 16 h (91%).
Synlett 2009, No. 11, 1852–1858 © Thieme Stuttgart · New York

1854
A. Speicher et al.
LETTER
MeO
MeO
MeO
OMe
d
b
TfO
(i)
(ii)
O
21
18
(i)
(ii), (iii)
B
+
16
22
O
O
O
O
O
CHO
O
O
26
27
OMe
O
d
23
OMe
(iii)
b
OMe
16
(iv)
26 + 27
MeO
MeO
MeO
MeO
OHC
O
O
28
(iv)
CHO
(v), (vi)
OMe
CHO
OMe
4
OMe
(v), (vi)
OMe
(vii)
O
CHO
O
O
O
O
O
O
CHO
OMe
OMe
OMe
25
24
Scheme 4 Reagents and conditions: (i) 16 (1.5 equiv), K2CO3, 18-
crown-6, CH2Cl2, reflux, 24 h (87%); (ii) Pd/C (5%), 3 bar H2, Et3N,
EtOAc, r.t., 24 h (95%); (iii) 2 M HCl–THF (1:1), r.t., 12 h (94%); (iv)
TiCl3(DME)2, Zn, DME, reflux, 30 h (23%) see ref.;23 (v) Pd/C (5%),
10 bar H2, EtOAc, r.t., 24 h (98%); (vi) BBr3 (10 equiv), CH2Cl2,
–78 °C to r.t. over 5 h, then 10 h at r.t. (68%).
O
29
OMe
30
OH
OMe
OH
OMe
ent from those reported in the literature for the isolated
bisbibenzyl with the proposed structure of plagiochin E.13
(viii), (ix)
The structure of the synthesized compound 4 was verified
by further NMR experiments (H,H COSY, C,H COSY,
HMBC, NOESY). We suppose that the isolated ‘pla-
giochin E’ might be a related bisbibenzyl also derived by
ortho- or para-selective phenol coupling from the acyclic
perrottetin E (3). The possible isomers with a similar sub-
stitution pattern (1,2,3-trisubstitution and 1,2,4-trisubsti-
tution) in the d–b fragment are shown in Scheme 1. The
structural relationship is most obvious for 4 and 5 with re-
spect to the ‘2-6’ substitution pattern in contrast to the ‘2-
4’ connection in 6 and 7 with two OH groups ortho to the
biaryl axis. From these, compound 5 (we now call it pla-
giochin F) has not been isolated or synthesized yet (but
nevertheless calculated, see ref. 2) and should be an alter-
native candidate for the compound described by Niu et
al.13
O
O
OH
OMe
31
5
Scheme 5 Synthesis of plagiochin F (5). Reagents and conditions:
(i) n-BuLi, THF, –78 °C, 30 min, then B(OMe)3, –78 °C to r.t., then
2 M HCl, isolation of the boronic acid, then pinacol, MgSO4, CH2Cl2,
r.t., 12 h; (42%); (ii) CH(OEt)3, tetrabutylammonium tribromide, 1,3-
propanediol, 65 °C, 12 h (95%); (iii) Pd(PPh3)4, PhMe–EtOH–2 M
Na2CO3, reflux, 16 h (67%); (iv) 16 (1.5 equiv), K2CO3, 18-crown-6,
CH2Cl2, reflux, 24 h (93%); (v) Pd/C (5%), 3 bar H2, Et3N, EtOAc,
r.t., 24 h (97%); (vi) 2 M HCl–THF (1:1), r.t., 12 h (97%); (vii)
TiCl3(DME)2, Zn, DME, reflux, 30 h (21%) see ref.;23 (viii) Pd/C
(5%), 10 bar H2, EtOAc, r.t., 24 h (98%); (ix) BBr3 (10 equiv),
CH2Cl2, –78 °C to r.t. over 5 h, then 10 h at r.t. (66%).
well the earlier reported 624 and 725 with the isolated ‘pla-
giochin E’,13 we suggest that the isolated compound may
be riccardin D (6). It should be noted that the published
NMR data of 624 and 413 were obtained in different sol-
vents.
It furthermore seemed rewarding to synthesize the as yet
unknown bisbibenzyl 5. The accomplished synthesis is
similar to that of 4 and is depicted in Scheme 5.
The HR-EI-MS showed the M+ peak at m/z = 424.1690
(calcd for C28H24O4: 424.1675). The structure of 5 was
ensured by different NMR experiments (H,H COSY, C,H
COSY, HMBC, NOESY). Again, the spectroscopical data
(see Tables 1 and 2) of the synthesized compound 5 also
showed significant deviations from those reported for the
isolated ‘plagiochin E’.13 Considering these results, we
now are able to exclude the structures 4 and 5 for the iso-
lated compound. Finally, comparing the spectroscopic
data of the four bisbibenzyls namely synthetic 4 and 5 as
So, as our next attempt for the structure elucidation of the
isolated bisbibenzyl, we decided to synthesize 6. In this
reaction sequence, the c–a phosphonium salt 16 was used
again and based on the building block 21 a new d–b frag-
ment 35 was synthesized. For the cyclization of this less
strained bisbibenzyl we used an intramolecular Wittig
reaction. The complete synthetic pathway is shown in
Schemes 6 and 7.
Synlett 2009, No. 11, 1852–1858 © Thieme Stuttgart · New York

LETTER
Structure Revision of ‘Plagiochin E’
1855
Table 1 1H NMR Data of Synthetic Compounds 4–6 (Figure 2; d in ppm)
500 MHz, acetone-d6
H–C(2)
4
5
6
6.61 (d, J = 2.4 Hz)
8.15 (br s)
–
6.32 (d, J = 1.8 Hz)
HO–C(3)
H–C(4)
7.37 (br s)
7.68 (br s)
–
6.66 (dd, J = 7.9, 2.4 Hz)
6.81 (d, J = 7.9 Hz)
–
6.73 (d, J = 7.9 Hz)
H–C(5)
7.00 (dd, J = 7.9, 7.6 Hz)
6.59 (d, J = 7.6 Hz)
6.84 (d, J = 8.0 Hz)
H–C(6)
6.31 (dd, J = 7.9, 1.8 Hz)
CH2(7)
3.08–3.15 (m), 1.93–2.00 (m)
2.79–2.85 (m), 2.69–2.75 (m)
5.30 (d, J = 2.1 Hz)
6.74 (d, J = 8.2 Hz)
6.64 (dd, J = 8.2, 2.1 Hz)
–
2.80–2.85 (m), 1.90–1.95 (m)
2.81–2.84 (m), 2.73–2.79 (m)
5.30 (d, J = 2.1 Hz)
2.71–2.67 (m), 2.63–2.56 (m)
2.71–2.68 (m), 2.71–2.68 (m)
5.45 (d, J = 2.0 Hz)
6.85 (d, J = 8.0 Hz)
6.72 (dd, J = 8.0, 2.0 Hz)
–
CH2(8)
H–C(10)
H–C(13)
H–C(14)
H–C(2¢)
6.72 (d, J = 7.9 Hz)
6.65 (dd, J = 7.9, 2.1 Hz)
7.23 (d, J = 2.1 Hz)
HO–C(3¢)
H–C(4¢)
7.50 (br s)
8.23 (br s)
7.15 (br s)
6.73 (d, J = 7.6 Hz)
7.21 (dd, J = 7.9, 7.6 Hz)
7.28 (d, J = 7.9 Hz)
2.97–3.00 (m), 2.54–2.60 (m)
3.23–3.29 (m), 3.00–3.03 (m)
7.05 (m)
6.66 (dd, J = 8.2, 2.4 Hz)
6.89 (d, J = 8.2 Hz)
6.79 (dd, J = 8.0, 1.3 Hz)
7.21 (dd, J = 8.0, 7.8 Hz)
6.99 (dd, J = 7.8, 1.3 Hz)
2.94–2.89 (m), 2.82–2.75 (m)
2.96–2.90 (m), 2.96–2.90 (m)
6.92 (br m)
H–C(5¢)
H–C(6¢)
–
CH2(7¢)
3.12–3.16 (m), 2.43–2.49 (m)
3.18–3.24 (m), 3.01–3.05 (m)
7.08 (dd, J = 8.2, 2.1 Hz)
6.77 (dd, J = 8.2, 2.4 Hz)
6.70 (dd, J = 8.2, 2.4 Hz)
7.05 (dd, J = 8.2, 2.1 Hz)
CH2(8¢)
H–C(10¢)a
H–C(11¢)a
H–C(13¢)a
H–C(14¢)a
6.82 (m)
6.77 (br m)
6.65 (m)
6.77 (br m)
7.04 (m)
7.02 (br m)
a Signals of H–C(10¢)/H–C(14¢) and H–C(11¢)/H–C(13¢) interchangeable.
The HR-EI-MS showed the M+ peak at m/z = 424.1659 ly mirror-imaged CD curves (Figure 3). Comparison of
(calcd for C28H24O4: 424.1675) and different NMR exper- these experimental CD spectra with those predicted
iments (H,H COSY, C,H COSY, HMBC, NOESY) were for the two enantiomers of 4 by quantum chemical
used to verify the structure of 6. The spectroscopical data TD-B2PLYP/SV(P)//B3LYP/6-31G*28 CD calculations29
matched those published for the isolated riccardin D (6)24
MeOOC
(solvent CDCl3) as well as those for the isolated ‘pla-
HO
(iii), (iv)
(i), (ii)
d
giochin E’13 (solvent acetone-d6).
d
I
I
In contrast to some bisbibenzyls possessing two C–C ax-
es, like, e.g., isoplagiochin C, which we have shown to be
configurationally stable and whose absolute configuration
we have established,7 no stereochemical investigations
have as yet been reported for bisbibenzyls with an ether
bridge and a C–C linkage. With the racemic synthetic ma-
terial in hands, the stereostructures of such oxygen-
bridged bisbibenzyls were investigated, exemplarily for
the authentic plagiochin E (4). Resolution of 4 into its two
atropo-enantiomers26 clearly evidenced that 4 is a chiral,
configurationally stable compound. Subsequent online
circular dichroism (CD) measurements of the resulting
peaks by LC-CD27 in the stopped-flow mode gave perfect-
OMe
OMe
32
33
MeO
OHC
THPO
THPO
d
d
21
b
B(OH)2
(v)
OMe
OMe
34
35
Scheme 6 Reagents and conditions: (i) 2 M NaOH, r.t., 24 h (85%);
(ii) excess SOCl2, reflux, 2 h, then NaBH4, dioxane, reflux, 2 h (77%);
(iii) dihydropyran, TsOH, CH2Cl2, r.t., 16 h (76%); (iv) n-BuLi, THF,
–78 °C, 30 min, then B(OMe)3, –78 °C to r.t., then sat. KH2PO4
(80%); (v) 21, Pd(PPh3)4, PhMe–EtOH–2 M Na2CO3, reflux, 16 h
(69%).
Synlett 2009, No. 11, 1852–1858 © Thieme Stuttgart · New York

1856
A. Speicher et al.
LETTER
Table 2 13C NMR Data of Synthetic Compounds 4–6 (d in ppm)
4
4
HO
HO
5
3
OH
6'
3
2
5
6
3'
4'
5'
4'
2'
3'
125 MHz, acetone-d6
C(1)
4
5
6
2
5'
OH
6
1
1
1'
6'
1'
2'
8'
143.07
114.10
157.45
112.31
133.27
127.56
31.28
141.25
127.67
155.41
113.60
128.38
118.43
33.00
142.67
117.90
155.06
121.14
133.70
121.21
38.48
8
8
7
7
7'
7'
14'
8'
9
14'
9
C(2)
10
11
14
13'
10
11
14
13'
9'
9'
C(3)
13
12
13
10'
10'
12'
12'
O
12
O
11'
11'
C(4)
OH
OH
4: "plagiochin E"
5: plagiochin F
C(5)
HO
2'
OH
4
3
3'
2
4'
5'
C(6)
1
7
C(7)
1'
7'
8
9
6'
6
5
C(8)
30.63
30.94
37.52
14'
8'
10
14
13'
9'
C(9)
133.61
116.89
151.14
144.41
113.60
122.00
140.25
129.26
155.55
116.49
128.25
120.71
36.34
133.29
116.54
151.01
144.44
116.46
113.41
141.61
115.90
157.22
122.04
133.39
128.10
36.01
133.57
117.81
148.35
145.34
116.69
122.79
145.01
126.06
155.59
113.87
129.39
122.57
35.69
11
13
10'
12'
12
O
11'
C(10)
C(11)
C(12)
C(13)
C(14)
C(1¢)
OH
6: riccardin D
Figure 2 Structural correlation of the NMR of compounds 4–6
MeO
MeO
THPO
(i)
(ii), (iii)
+
16
35
O
O
C(2¢)
C(3¢)
36
O
OMe
C(4¢)
MeO
MeO
C(5¢)
MeO
MeO
HO
C(6¢)
C(7¢)
CHO
OMe
(iv),(v)
C(8¢)
34.03
33.99
38.51
C(9¢)
141.27
124.85
131.17
156.65
130.85
123.24
141.15
124.75
131.13
156.40
130.84
123.22
141.33
123.12
130.05
154.36
130.32
122.85
O
O
37
OMe
HO
C(10¢)a
C(11¢)a
C(12¢)
C(13¢)a
C(14¢)a
38
OH
6: riccardin D
(vi), (vii)
revised structure
for "plagiochin E"
a Signals of C(10¢)/C(14¢) and C(11¢)/C(13¢) interchangeable.
O
OH
In summary, the isolated bisbibenzyl called ‘plagiochin E’
showing remarkable biological activities13–17 has been
proven to be riccardin D (6), the first total synthesis of
which has now been described. The two other synthesized
bisbibenzyls plagiochin E (4) and plagiochin F (5), al-
though supposed to exist in nature (based on energetic and
biosynthetic considerations), have never been isolated.2
The successful availability of 4 and 5 by our chemical
synthesis now permits testing of their biological activities.
Furthermore the stereostructure of a bisbibenzyl with an
Scheme 7 Reagents and conditions: (i) 16 (1.5 equiv), K2CO3, 18-
crown-6, CH2Cl2, reflux, 24 h (94%); (ii) Pd/C (5%), 3 bar H2, Et3N,
EtOAc, r.t., 24 h (99%); (iii) 2 M HCl–THF (1:1), r.t., 12 h (96%); (iv)
Ph3P·HBr, MeCN, reflux, 12 h, reflux, 16 h; (v) NaOMe, CH2Cl2, 24
h (68% 2 steps) see ref.;30 (vi) Pd/C (5%), 10 bar H2, EtOAc, r.t., 24
h (95%); (vii) BBr3 (10 equiv), CH2Cl2, –78 °C to r.t. over 5 h, then
10 h at r.t. (71%).
revealed the faster eluting peak A (tR = 17.3 min) to be P-
configured, and, thus, the slower eluting peak B (tR = 30.1
min) to have the M-configuration at the biaryl axis
(Figure 3).
Synlett 2009, No. 11, 1852–1858 © Thieme Stuttgart · New York

LETTER
Structure Revision of ‘Plagiochin E’
1857
(3) Asakawa, Y.; Toyota, M.; Tori, M.; Hashimoto, T.
Spectroscopy 2000, 14, 149.
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J. Org. Chem. 1998, 877.
(5) Speicher, A.; Backes, T.; Grosse, S. Tetrahedron 2005, 61,
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(23) General Procedure for the McMurry Macrocyclization:
A mixture of zinc dust (2.12 g, 32.4 mmol) and TiCl3(DME)2
(3.00 g, 8.76 mmol) in anhyd DME (80 mL) was heated to
reflux for 1.5 h under an argon atmosphere. A solution of the
dialdehyde (560 mg, 1.13 mmol) in anhyd DME (100 mL)
was added dropwise over 5 h. The black mixture was heated
to reflux for 48 h. After cooling to r.t. the reaction mixture
was filtered through a short pad of silica gel eluting with
EtOAc. The colorless filtrate was then concentrated and
purified by flash chromatography (silica gel; hexane–
EtOAc, 3:1).
Figure 3 Stereochemical assignment of the two enantiomers of 4, by
LC-CD coupling and quantum chemical CD calculations
ether bridge and a C–C linkage has been investigated for
the first time, here exemplarily for plagiochin E (4), by
online CD measurements and quantum chemical CD cal-
culations, thus permitting assignment of the absolute con-
figuration of the two enantiomers, (M)-4 and (P)-4.
(24) Toyota, M.; Nagashima, F.; Asakawa, J. Phytochemistry
1988, 27, 2603.
(25) Asakawa, Y.; Tori, M.; Takikawa, K.; Krishnamurty, H. G.;
Kanti Kar, S. Phytochemistry 1987, 26, 1811.
(26) Resolution of the enantiomers of 4 was carried out on a Lux
Cellulose-1 phase (4.6 mm × 250 mm, 5 mm, Phenomenex);
flow rate: 0.5 mL/min using an i-PrOH–n-hexane gradient
(20:80, 60:40 for 16.5 min, 95:5 for 9.5 min, 20:80 for 2 min,
20:80 for 12 min).
Acknowledgment
We thank the Deutsche Forschungsgemeinschaft for financial sup-
port (DFG, Sp 498/2-1 and DFG, Br 699/12).
(27) Bringmann, G.; Gulder, T. A. M.; Reichert, M.; Gulder, T.
Chirality 2008, 20, 628.
References and Notes
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G. E.; Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A.;
Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.;
Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi,
M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.;
(1) Asakawa, Y. In Progress in the Chemistry of Organic
Natural Products; Herz, E.; Kirby, G. W.; Moore, R. E.;
Steglich, W.; Tamm, C., Eds.; Springer: Vienna/New York,
1995, 5.
(2) Keserü, G. M.; Nógrádi, M. Phytochemistry 1992, 31, 1573.
Synlett 2009, No. 11, 1852–1858 © Thieme Stuttgart · New York

1858
A. Speicher et al.
LETTER
and Semi-Empirical Program Package, Version 2.6.35;
Universität Bonn: Germany, 2008. (c) Details of the
quantum chemical calculations will be published in a
comprehensive paper, including details about the use of the
method in comparison to other computational procedures.
(29) Bringmann, G.; Bruhn, T.; Maksimenka, K.; Hemberger, Y.
Eur. J. Org. Chem. 2009, 2717.
(30) A solution of 37 (2.50 g, 5.03 mmol) and Ph3P·HBr (1.81 g,
5.27 mmol) in MeCN (60 mL) was refluxed for 12 h. The
solvent was removed in vacuo and the crude phosphonium
salt was dissolved in anhyd CH2Cl2 (250 mL). This solution
was added dropwise over 6 h to a mixture of NaOMe (1.50
g, 27.8 mmol) in anhyd CH2Cl2 (350 mL), and stirring was
continued for 12 h. After filtration and evaporation of the
solvent the residue was purified by column chromatography
(silica gel, CH2Cl2) and 38 was obtained as a colorless solid
(1.60 g, 3.44 mmol, 68%).
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