Total synthesis of plakortone B

Article abstract of DOI:10.1002/chem.201000189

Plakortone B is a naturally occurring bicyclic[3.3.0]furanolactone compound with attractive bioactivities. Although the relative configuration of plakortone B's central core had been established by NMR spectroscopic methods, the absolute configuration of its four stereocenters remained unknown. In the present paper, all four possible isomers of plakortone B were synthesized and one of these molecules was found to be identical with the natural plakortone B on the basis of ¹H, ¹³C NMR spectra and specific rotation comparisons. Thus, the absolute configuration of the natural plakortone B was determined to be (35, 4S, 6R, 10R).

Full text of DOI:10.1002/chem.201000189

FULL PAPER
DOI: 10.1002/chem.201000189
Total Synthesis of Plakortone B
Xin-Gang Xie, Xun-Wei Wu, Hing-Ken Lee, Xiao-Shui Peng, and Henry N. C. Wong*[a]
Dedicated to the memory of Professor Xian Huang
Abstract: Plakortone B is a naturally
occurring bicyclic[3.3.0]furanolactone
known. In the present paper, all four
possible isomers of plakortone B were
synthesized and one of these molecules
was found to be identical with the nat-
ural plakortone B on the basis of 1H,
13C NMR spectra and specific rotation
comparisons. Thus, the absolute config-
uration of the natural plakortone B
was determined to be (3S,4S,6R,10R).
ACHTUNGTRENNUNG
compound with attractive bioactivities.
Although the relative configuration of
plakortone Bꢀs central core had been
established by NMR spectroscopic
methods, the absolute configuration of
its four stereocenters remained un-
Keywords: asymmetric synthesis ·
chirality · natural products · plakor-
tone B · structure elucidation
Introduction
theses, but the absolute configurations of the other three
plakortones (A, C, and F) still remain unknown.
Plakortones belong to a family of naturally occurring
bicyclicACHTUNGTRENNUNG[3.3.0]furanolactones isolated from the Caribbean
During our recent total synthesis of natural molecules
starting from substituted furans, we have developed an
sponges Plakortis halichondrioides (plakortones A–D)[1] and
Plakortis simplex (plakortones B–F)[2]. These compounds
are cardiac sacroplasmic reticulum Ca2+-pumping ATPase
activators that were found to be active at micromolar con-
centrations and relevant to the correction of cardiac muscle
relaxation abnormalities.[1–3] They also exhibit in vitro cyto-
toxic activity on a murine fibrosarcoma cell line and repre-
sent a new family of lead compounds with potential pharma-
cological interest.[2] The structures of the plakortone family
were established by NMR spectroscopic methods, and NOE
difference data provided the relative configurations of their
core structures. However, the absolute configurations of
their stereocenters were not revealed in the initial structure
elucidation.[1] Recently, the absolute configurations of pla-
kortones B,[4d] D,[4a,b] and E[4c] were established by total syn-
enantioselective route towards functionalized bicyclic-
AHCTUNGTRENNUNG
[3.3.0]furanolactones,[5] and as a result, were aware that this
key approach could also lead to plakortones. A program to-
wards the total synthesis of plakortone B was therefore initi-
ated in our laboratory. Due to the fact that the absolute con-
figuration of plakortone B was still unknown at the time we
began our synthetic work, our plan was to synthesize all
four possible isomers (Scheme 1) to confirm the absolute
configuration of the naturally occurring plakortone B by
comparison of their spectral and physical data.
[a] Dr. X.-G. Xie, Dr. X.-W. Wu, Dr. H.-K. Lee, Prof. Dr. X.-S. Peng,
Prof. Dr. H. N. C. Wong
Department of Chemistry, Centre of Novel Functional Molecules
Institute of Chinese Medicine and Institute of Molecular Technology
for Drug Discovery and Synthesis
The Chinese University of Hong Kong, Shatin
New Territories, Hong Kong SAR (China)
Fax : (+852)26096329
Since we were not aware of the absolute configuration of
plakortone B when we first started, we achieved and report-
ed an enantioselective route for the preparation of function-
E-mail: hncwong@cuhk.edu.hk
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000189.
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cule could be achieved by coupling the corresponding cen-
tral core and the side chain. Thus, two retrosynthetic discon-
nections were considered, generating ent-5[4a] and
6
(route A), and 7 and 8 (route B) as possible coupling com-
ponents (Scheme 2). Route A was based on a disconnection
Scheme 1. All four possible absolute configurations of plakortone B.
alized bicyclic lactones 3, 4, and 5 in 2002.[6] In the same
year, Kitching and Hayes reported an asymmetric total syn-
thesis of plakortone D, the absolute configuration of which
was assigned as (3S,4S,6S,10R).[4a] Based on the observations
that plakortone B was also isolated from the same natural
source[1,2] as well as on the total synthesis of plakortone B
by Semmelhack and co-workers,[4d] the absolute configura-
tion of plakortone B was also most likely to be
(3S,4S,6R,10R) (Scheme 1, compound 1). Therefore, com-
pound 5, which was previously prepared by us,[6a] might pos-
sess a central core that was an enantiomer of that of the nat-
ural plakortones. Herein, we report the total synthesis of
plakortone B and the determination of its absolute configu-
ration.
Results and Discussion
Scheme 2. Retrosynthetic analysis of compound 1.
Because the natural plakortone B was most likely to have
(3S,4S,6R,10R) absolute configuration, compound 1 was
chosen as our first synthetic target. According to the conver-
gent synthetic strategy, we envisioned that the target mole-
of the C7=C8 double bond and involved an addition–elimi-
nation strategy, which had been successfully applied in the
total synthesis of plakortone D.[4a] Route B was based on a
ꢀ
disconnection of the C8 C9 single bond and was expected
to be realized by a Suzuki coupling reaction.[7] It should be
noted at this point that only the approach based on route B
gave pure compound 1 successfully, and that the approach
based on route A only provided a mixture of compound 1
and its C7=C8 Z isomer.
Abstract in Chinese:
Retrosynthetic analysis of compound 1: As can be seen in
Scheme 2, ent-5,[4a] 7 (the central core), 6, and 8 (the side
chain) would be the potential precursors after the corre-
sponding disconnection of compound 1 (route A or B). The
required ent-5 is then derived from bicyclic lactone 9 by a
series of functional group interconversions. For the prepara-
tion of 9, we anticipated that the bicyclicACHTUNGTREN[NGNU 3.3.0] framework
could be established from butenolide 10 through an intra-
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Total Synthesis of Plakortone B
FULL PAPER
molecular Michael addition and a transesterification reac-
tion.[5b] Butenolide 10 can, in turn, be derived from tertiary
alcohol 11, which has previously been prepared by us.[8]
Iodide 7 can be obtained by a diastereoselective hydrostan-
nylation reaction followed by an iodination reaction from
the related alkyne, which was derived from the crucial pre-
cursor ent-5. The synthesis of side chains 6 and 8 was realiz-
ed by a standard procedure (see the Supporting Informa-
tion).[9]
With the optically pure tertiary alcohol 11 in hand, we
then started to synthesize the key intermediate butenolide
10 (Scheme 4). Protection of the tertiary alcohol 11, fol-
Construction of the central core ent-5: Our synthetic pro-
gram for the preparation of the core ent-5 required chiral al-
cohol 11 as a precursor. A highly diastereoselective prepara-
tion of alcohol 11 is depicted in Scheme 3.[8] Thus, when
Scheme 4. Synthesis of butenolide 10. a) Me3SiCl, imidazole, 4-dimethyl-
aminopyridine (DMAP), DMF, 08C, 0.5 h, 95%; b) nBuLi (2.2 equiv),
THF, ꢀ258C, 0.5 h, then Me3SiCl (1.05 equiv), ꢀ788C, 0.5 h, 80%;
c) i) 80% AcOH (aq.), 238C, 24 h; ii) tBuMe2SiCl, imidazole, DMAP,
THF, 238C, 0.5 h; iii) 2,2-dimethoxypropane, p-toluenesulfonic acid (cat.),
THF, reflux, 5 h; iv) nBu4NF (1.0 equiv), THF, 238C, 3 h, 63% over 4
steps; d) i) (COCl)2, DMSO, CH2Cl2, ꢀ788C, 1 h, then Et3N, ꢀ78!238C,
0.5 h; ii) EtMgBr, THF, 08C, 0.5 h; iii) pyridinium dichromate (PDC),
Scheme 3. Preparation of optically pure starting materials 11 and 15.
4 ꢂ molecular sieves, CH2Cl2, 238C, 24 h, 75% over
3 steps;
e) Me3SiCCH, nBuLi, THF, 08C, 86%; f) nBu4NF, THF, ꢀ108C, 20 min,
90%; (g) CH3CO3H, NaOAc, CH2Cl2, 238C, 24 h, 80%; h) Lindlarꢀs cata-
lyst, quinoline, H2, MeOH, 238C, 24 h, 95%; i) p-toluenesulfonic acid
(20 equiv), MeCN, 238C, 72 h, 80%.
ketone 12, which was prepared from d-mannitol, was treated
with 3-lithiofuran (13), according to Cramꢀs chelation con-
trol rule,[10] the nucleophile would preferentially attack from
the less-hindered b-side, providing (2R,3R)-syn-alcohol 11 as
the major product and (2R,3S)-anti-alcohol 15 as the minor
product; the diastereoselectivity ratio was 5:1. In a similar
manner, when ketone 14, which was also derived from d-
mannitol, was treated with a Grignard reagent (EtMgBr),
(2R,3S)-anti-alcohol 15 was produced preferentially and the
diastereoselectivity ratio was as high as 9:1. Compound 15
was previously employed by us to synthesize bicyclic lactone
5 in one of our programs.[6a] In this way, alcohols 11 and 15
were both derived from enantiopure (+)-2,3-O-isopropyli-
dene-d-glyceraldehyde,[11] the absolute R configuration of
our synthesized central cores could accordingly be estab-
lished on the basis of this stereogenic center.
lowed by highly regiospecific silylation reaction, gave ether
16 in a high yield.[5b] After conversion of 16 into 17 by a gen-
eral routine,[6a] the resulting primary alcohol 17 was convert-
ed into ketone 18 by a sequence of Swern oxidation,[12]
EtMgBr addition, and PDC oxidation. Alcohol 19 was then
prepared by a highly diastereoselective addition of trime-
thylsilylalkynyllithium to ketone 18, followed by a regiose-
lective desilylation. 2,4-Disubstituted furan 19 was converted
into butenolide 20 by a peracetic acid oxidation established
by Kuwajima and Urabe.[13] Butenolide 20 was partially hy-
drogenated over Lindlarꢀs catalyst[14] to afford alkene 21,
which was deprotected to afford the required butenolide 10.
In addition, the absolute configuration of alkene 21 was es-
tablished by X-ray crystallographic analysis.[33] With the aid
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H. N. C. Wong et al.
of the known R configuration of 12, the absolute configura-
tions of the two new stereocenters formed in the previous
reaction sequence were also confirmed.
Butenolide 10 was converted into bicyclic lactone 9 by an
intramolecular Michael addition followed by transesterifica-
tion[5b] in 50% overall yield, together with the formation of
the spirocyclic compound 22 in 28% yield (Scheme 5).
Scheme 6. Synthesis of core structure ent-5. a) tBuMe2SiCl, imidazole,
DMAP, DMF, 238C, 24 h, 90%; b) OsO4 (0.1 equiv), N-methylmorpho-
line N-oxide (NMO) (6.0 equiv), Me2CO/H2O (v/v=4:1), 1 week, 238C;
c) 2,2-dimethoxypropane (4 equiv), p-toluenesulfonic acid (cat.), THF,
238C, 24 h, 76% over 2 steps; d) NaH, THF, 08C, 10 min; then CS2, 08C,
10 min; then MeI, 08C, 30 min, 83%; e) nBu3SnH (10 equiv), 2,2’-azobis-
isobutyronitrile (AIBN) (cat.), benzene, reflux, 2 h, 90%; f) nBu4NF,
THF, 238C, 90%; g) Dess–Martin periodinane, CH2Cl2, 238C, 24 h;
Scheme 5. Synthesis of bicyclic lactone 9. a) i) Et3N (100 equiv), toluene,
reflux, 24 h; ii) 3n HCl (aq.), 238C, 48 h, 50% for 9 and 28% for 22;
b) 1,5-diazabicyclo
72 h, 90%.
ACHTUNGTRENNUNG[5.4.0]undec-5-ene (DBU) (0.1 equiv), toluene, reflux,
h) [RhClACHTNUGTRNEUG(N PPh3)3] (1.1 equiv), p-xylene, reflux, 60 h, 80% over 2 steps;
i) 80% AcOH (aq.), 238C, 48 h; j) NaIO4 (2 equiv), H2O, CH2Cl2, 238C,
30 min; k) NaBH4, EtOH, 238C, 70% over 3 steps; l) i) diisobutylalu-
minum hydride (DIBAL-H), CH2Cl2, ꢀ788C, 3 h; ii) MeOH, p-toluene-
sulfonic acid (cat.), THF, 238C, overnight, 70% over 2 steps.
Compound 22 was one of the two possible products (22
and 23) resulting from the intramolecular Michael addition
reaction of 10. Interestingly, we found that compound 22
could be completely transformed into 9 when DBU was
used. It was assumed that butenolide 10 was obtained initial-
ly by a retro-Michael addition reaction of compound 22
when treated with DBU. Then 10 was transformed into the
desired bicyclic lactone 9 through the same sequence as
before. We presumed that the intramolecular Michael addi-
tion and the subsequent transesterification could be con-
ducted in one pot by using DBU as a base. Further study
showed that DBU could indeed readily promote this trans-
formation, and bicyclic lactone 9 was obtained in 90% yield
directly from butenolide 10 by using a catalytic amount of
DBU in toluene upon heating to reflux for 72 h.
Bicyclic lactone 9 was transformed into the core ent-5 by
the sequence of reactions depicted in Scheme 6. After selec-
tive protection of the primary hydroxyl group of 9, an
osmium-catalyzed dihydroxylation[15] followed by protection
with acetone, provided the desired secondary alcohol 24. A
Barton deoxygenation reaction[16] of 24 led to the formation
of 25. It is interesting to iterate that at this point in the syn-
thetic sequence the secondary alcohol, with its R configura-
tion originating from d-mannitol, had served its role in guid-
ing the introduction of the other stereocenters, and was thus
removed. Subsequently, desilylation, Dess–Martin periodi-
nane oxidation,[17] and a reductive decarbonylation with Wil-
kinsonꢀs reagent,[18]converted 25 into 26. After deprotection,
oxidative cleavage[19] of the unmasked 1,2-dihydroxyl group,
followed by NaBH4-mediated reduction, provided ent-5. An-
alytical data for synthetic ent-5 were in good agreement
with the reported 1H and 13C NMR spectra and specific rota-
tion.[4a] To tolerate the subsequent reaction conditions
during the connection of the central core and the side chain,
ketal 27 was prepared from ent-5 by partial reduction of the
lactone group, followed by the formation of the cyclic ketal.
Total synthesis of compound 1 based on retrosynthetic anal-
ysis route A: With the central core ent-5 (Scheme 7) and
side chains 28–30[20] (for the synthesis of 28–30, see the Sup-
porting Information) in hand, we turned our attention to
their connection. After a number of unsuccessful experi-
ments (Wittig olefination,[21] Julia–Kocienski olefination,[9]
etc.), we realized that these failures were mainly due to the
exceedingly severe steric hindrance caused by the two com-
ponents. We then tried other conditions and finally found an
effective addition–elimination strategy (Scheme 7). Thus,
when aldehyde 31 (prepared from alcohol 27 by Swern oxi-
dation)[12] was treated with the organolithium reagent
formed from 28 by using the method devised by Yus and co-
workers,[22] the two components were linked together to give
a mixture of diastereomeric alcohols 32. Compound 33 was
obtained after Jones oxidation,[23] and subsequent selective
reduction of the carbonyl group in 33 with NaBH4 gave al-
cohol 34. Several dehydration methods were investigated
(sulfurane reagent,[24a] MsCl/Et3N,[24b,c] MsCl/pyridine,[24d]
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Total Synthesis of Plakortone B
FULL PAPER
Scheme 8. Total synthesis of 1. a) i) tBuMe2SiCl, imidazole, DMF, 238C,
1 h; ii) LiAlH4, THF, 08C, 0.5 h; iii) NaH, THF, 08C, 0.5 h, then BnBr,
reflux, 1.5 h; iv) nBu4NF, THF, 12 h, 238C, 58% over
4 steps;
b) i) (COCl)2, DMSO, CH2Cl2, ꢀ788C, 1 h, then Et3N, ꢀ78!238C, 0.5 h;
ii) Bestmannꢀs reagent, K2CO3, MeOH, 238C, 24 h, 60% over 2 steps;
c) i) Me3SiCl, imidazole, DMAP (cat.), DMF, 238C, 0.5 h; ii) nBuLi,
MeOTf, THF, ꢀ788C, 1 h; iii) nBu4NF, THF, 238C, 5 min, 84% over 3
Scheme 7. a) (COCl)2, DMSO, CH2Cl2, ꢀ788C, 1 h, then Et3N, ꢀ78!
238C, 0.5 h, 75%; b) Li (10 equiv), 4,4’-di(tert-butyl)-1,1’-biphenyl
(DTBB) (0.2 equiv), 28, then 31, ꢀ788C, THF, 3 h; c) Jones reagent,
Me2CO, 08C, 4 h, 30% over 2 steps; d) NaBH4, EtOH, 238C, 1 h, 85%;
e) Burgess reagent, toluene, reflux, 20 h, 60%.
steps; d) i) [PdCl2ACHTUNGTRNEG(UN PPh3)2], nBu3SnH, n-hexane, 238C, 2 h; ii) I2, CH2Cl2,
08C, 5 min, 60% over 2 steps; e) i) 37, tBuLi, Et2O, ꢀ788C, 5 min; ii) 9-
methoxy-9-borabicyclo
[3.3.1]nonane (9-OMe-BBN), THF, ꢀ788C,
10 min, then warm to 238C, 1 h; iii) 3n K3PO4 (aq.), 3 min; then iv) 35,
[PdCl2A
AHCTUNGTRENNUNG
C
MsCl/tBuOK, POCl3/pyridine,[24e] and p-toluenesulfonic
acid[24f]), but all proved to be unsuccessful. Gratifyingly,
when the dehydration reaction was conducted with the Bur-
gess reagent,[24g,h] the alkene product was obtained, however,
it was formed as a mixture of two chromatographically in-
0.5 h; g) PDC, DMF, 238C, 20 h, 60% over 3 steps.
terminal alkyne 39 by a sequence of Swern oxidation[12] and
an application of Ohira–Bestmannꢀs modification of Sey-
ferth–Gilbert homologation reaction.[29] Temporary protec-
tion of the tertiary hydroxyl group in 39 with a trimethylsilyl
group, methylation, followed by removal of the protecting
group, furnished alkyne 36 in 84% overall yield. Palladium-
catalyzed hydrostannylation reactions are efficient,[30] and
hexane was recently reported to inhibit the competitive
stannane dimerization in coupling reactions.[30c] In light of
these findings, hexane and several palladium catalysts were
tested to optimize the hydrostannylation reaction of alkyne
36. As a result of these investigations, we found that the
yield could be upgraded to 80% in the presence of catalytic
ꢀ
separable C7 C8 E and Z isomers in a ratio of 2:1, as con-
firmed by 1H NMR spectroscopy and GC–MS.[25] We at-
tempted to isomerize this mixture with the hope of obtain-
ing pure E-compound,[26] unfortunately, the isomeric ratio
remained unchanged in all trials.
Total synthesis of compound 1 based on retrosynthetic anal-
ysis route B: Because route A failed to provide pure com-
pound 1, we abandoned this approach and turned to
route B. In this approach, we required 7 (the central core)
and 8 (the side chain) as the potential Suzuki coupling pre-
cursors (Scheme 2). In practice, alkenyl iodide 35 was uti-
lized in place of 7 due to the steric hindrance of the very
compact central core, as well as the need to tolerate many
harsh reaction conditions (Scheme 8). Iodide 35 could be
obtained by a diastereoselective hydrostannylation reaction
followed by an iodination reaction from the related alkyne
36, which was derived from the crucial precursor ent-5.
[PdCl2ACTHNUGTRNE(UNG PPh3)2]. In this case, the diastereoselectivity was also
very high and the desired stannyl compound was obtained
as the only product. After iodination, the key alkenyl iodide
35 was obtained.
With the central core 35 and side chain 37 (see the Sup-
porting Information) in hand, the Suzuki coupling reaction
was performed to link the two partners together;[7] this
smoothly provided the desired coupling compound as the
only product. After debenzylation and PDC-mediated oxi-
dative cyclization, compound 1 was obtained in a pure form.
We were pleased to find that no isomerization reaction oc-
curred at either the C7=C8 or the C11=C12 double bonds
during the three-step route. The coupling constant between
H-11 and H-12 was 15.3 Hz, indicating the trans stereochem-
Construction of the core 35 and total synthesis of compound
1: Alkenyl iodide 35 was synthesized from ent-5 by the
chemical operations depicted in Scheme 8,[27] whereas the
crucial boronic acid 8 could be formed in situ from iodide
37.[28] After conversion of ent-5 into 38 by a standard proce-
dure, the resulting monocyclic alcohol 38 was converted into
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H. N. C. Wong et al.
istry of the C11=C12 disubstituted double bond. The cou-
pling constant between H-19 (d, J=1.4 Hz, 3H) and H-7 (q,
J=1.4 Hz, 1H) also led to the assignment of E stereochem-
istry to the C7=C8 trisubstituted double bond. Further infor-
mation obtained from NMR spectroscopy of compound 1
helped to establish the structure of compound 1 (Scheme 8).
Before we completed the total synthesis of compound 1,
Semmelhack and co-workers reported a total synthesis of
compound 1 based on a similar disconnection strategy.[4d]
They claimed that their synthetic compound 1 had the same
absolute configuration as that of the naturally occurring mo-
lecular plakortone B, based on 1H and 13C NMR spectral
data comparison and analysis.[4d,31] However, we found that
our synthetic compound 1 exhibited a different 1H NMR
spectrum to that obtained by Semmelhack et al., especially
for the H-7 and H-11 proton resonances at d=5.00–
5.08 ppm. Although the spectral data of our synthetic com-
All four possible isomers of plakortone B were synthe-
sized so that a comparison of their NMR spectral data with
1
those of the natural plakortone B could be made.[1] All H
and 13C NMR spectra and specific rotation data are included
in the Supporting Information, with the most crucial data
summarized in Table 1. As can be seen, the four synthetic
samples can be divided into two pairs of enantiomers (1 and
ent-1 cf. 2 and ent-2). Although the differences in their
NMR spectra were generally very small, there were consid-
erable differences in the chemical shifts of the H-3, H-7, and
H-11 proton resonances, and the differences were more dis-
tinct at d=5.00–5.08 ppm when comparing the 1H NMR
spectra directly. We were fortunate to obtain a copy of the
original 1H NMR spectrum of the natural plakortone B.[2]
1
Whereas the H NMR spectra of our synthetic compounds 1
and ent-1 showed good agreement with that of the natural
1
plakortone B, the H NMR spectra of compounds 2 and ent-
1
pound 1 was in better agreement with the H and 13C NMR
2 exhibited significant differences (see the Supporting Infor-
mation for details). It is therefore clear that 2 and ent-2 are
not related to the natural plakortone B. Because the specific
rotation [a]2D5 of the natural plakortone B (ꢀ9.2, c=0.72 in
CHCl3)[1] differed from that of ent-1 ([a]2D0 =+15.5, c=0.28
in CHCl3), this enantiomer could also be excluded. Only
1H NMR spectrum and specific rotation ([a]2D0 =ꢀ16.0, c=
0.39 in CHCl3) of 1 fit closely with those of the natural pla-
kortone B.[32] These results further confirm that 1 possesses
a structure that is identical to that of the natural plakorto-
ne B, so the absolute configuration of naturally occurring
plakortone B can be assigned as (3S,4S,6R,10R).
spectral data of the natural plakortone B,[1] we did not wish
to come to a premature conclusion regarding the configura-
tion of the natural product, and this promoted us to synthe-
size the other three possible isomers of plakortone B [com-
parisons are summarized in the Supporting Information and
in Table 1 (see below)].
Total synthesis of isomers of plakortone B (ent-1, 2 and ent-
2) and the determination of its absolute configuration: With
the two central cores (35 and ent-35) and two side chains
(37 and ent-37) (for the detailed preparation of ent-35 and
ent-37, see the Supporting Information) available, the other
three possible isomers of plakortone B were synthesized
through similar sequences: Suzuki coupling, debenzylation,
and oxidative cyclization reactions. All reactions proceeded
smoothly to give the other three compounds (ent-1, 2 and
ent-2) in high yields (Scheme 9).
Conclusion
We have synthesized all four possible isomers of plakorto-
ne B. The absolute configuration of natural plakortone B
can now be assigned as (3S,4S,6R,10R) on the basis of spec-
troscopic and specific rotation comparisons.
Experimental Section
All nonaqueous reactions were carried out by using oven-dried glassware
under a positive pressure of dry nitrogen unless otherwise noted. All re-
agents and solvents were reagent grade. Further purifications and drying
by standard methods were used when necessary. Except as indicated oth-
erwise, reactions were magnetically stirred and monitored by thin-layer
chromatography (TLC) using Merck Silica Gel 60 F254 plates and visual-
ized by fluorescence quenching under UV light. In addition, compounds
on TLC plates were visualized with a spray of 5% w/v dodecamolybdo-
phosphoric acid in ethanol, with subsequent heating. Chromatographic
purification of products (flash chromatography) was performed on E.
Scheme 9. Total synthesis the other three isomers of plakortone B (ent-1,
2 and ent-2). a) i) 37 or ent-37, tBuLi, Et2O, ꢀ788C, 5 min; ii) 9-BBN-
OMe, THF, ꢀ788C, 10 min, then warm to 238C, 1 h; iii) 3n K3PO4 (aq.),
3 min; iv) 35 or ent-35, [PdCl2ACHTNUGTRNE(UGN dppf)2]·CH2Cl2, DMF, 238C, 20 h; b) Na/
NH3 (liq.), THF, ꢀ788C, 0.5 h; c) PDC, DMF, 238C, 20 h, 55%-60% in 3
steps.
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Chem. Eur. J. 2010, 16, 6933 – 6941

Total Synthesis of Plakortone B
FULL PAPER
Table 1. Specific rotation values and selected 1H NMR spectral data for all four possible absolute structures of plakortone B and those of the natural
product.
Absolute
configuration rotation
Specific
1H NMR [ppm]
H-11[b]
H-3
H-7[a]
H-12
H-19
natural
plakortone B mined
not deter-
[a]2D5 =ꢀ9.2
4.21 (dd, J=1.3,
5.1 Hz, 1H)
5.03 (q,
J=1.3 Hz,
1H)
5.03 (q,
J=1.4 Hz,
1H)
5.06 (ddt, J=1.5, 8.4, 5.36 (dt, J=6.3,
15.3 Hz, 1H) 15.3 Hz, 1H)
1.69 (d,
J=1.3 Hz,
3H)
1.69 (d,
J=1.4 Hz,
3H)
1.69 (d,
J=1.1 Hz,
3H)
1.69 (d,
J=1.7 Hz,
3H)
(c=0.72 in CHCl3)
1
3S,4S,6R,10R [a]2D0 =ꢀ16.0
4.21 (dd, J=1.1,
5.0 Hz, 1H)
5.06 (ddt, J=1.0, 8.4, 5.36 (dt, J=6.3,
(c=0.39 in CHCl3)
15.3 Hz, 1H)
15.3 Hz, 1H)
ent-1
2
3R,4R,6S,10S [a]2D0 =+15.5
4.21 (dd, J=1.2,
5.0 Hz, 1H)
5.03 (s, 1H)
5.06 (dd, J=7.8,
5.36 (dt, J=6.3,
(c=0.28 in CHCl3)
15.3 Hz, 1H)
15.3 Hz, 1H)
3S,4S,6R,10S
[a]2D0 =ꢀ30.1
4.19 (dd, J=1.5,
4.8 Hz, 1H)
5.04 (s, 1H)
5.05 (dd, J=8.8,
5.36 (dt, J=6.3,
(c=0.41 in CHCl3)
15.3 Hz, 1H)
15.2 Hz, 1H)
ent-2
3R,4R,6S,10R [a]2D0 =+29.5
(c=0.67 in CHCl3)
4.19 (dd, 1H, J=1.5, 5.04 (s, 1H)
4.8 Hz, 1H)
5.05 (dd, J=8.8,
5.36 (dt, J=6.3,
1.69 (d,
J=1.7 Hz,
3H)
15.3 Hz, 1H)
15.2 Hz, 1H)
[a] 1H NMR spectra of compounds 1, ent-1, 2 and ent-2 were recorded with a Bruker Avance III-400 spectrometer. Coupling constants J
ACHTNUTRGNE(NUG H19,H7) and J-
ACHTUNGTRENNUNG(H7,H19) of 1 were determined by 2D J-Resolved NMR spectroscopic analysis with an Avance Bruker 600 MHz spectrometer. Due perhaps to the reso-
lution of the NMR equipment used, H-7 of our synthetic samples (ent-1, 2 and ent-2) showed as a singlet in the 1H NMR spectra; the signal from H-19
gave a doublet. [b] For the same reason as stated in [a], H-11 of our synthetic samples (ent-1, 2 and ent-2) showed a ꢄddꢀ peak instead of a ꢄddtꢀ set.
Merck Silica Gel 60 (230–400 mesh). All evaporation of organic solvents
were carried out with a rotary evaporator. Yields refer to chromato-
graphically and spectroscopically pure compounds, unless otherwise
stated.
The obtained stannane compound was dissolved in CH2Cl2 (4 mL) and
cooled to 08C. I2 (50 mg, 0.196 mmol) was added and the resulting mix-
ture was stirred at 08C for 5–8 min then worked up by the addition of a
saturated aqueous solution of Na2S2O3 (3 mL) and extracted with diethyl
ether (3ꢃ10 mL). The combined organic layers were washed with brine
(10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure to give a residue that was purified by flash column
chromatography on silica gel (8 g, hexanes/ethyl acetate, 5:1) to give 35
(55 mg, 60% for the 2 steps) as an oil. Rf =0.20 (hexanes/ethyl acetate,
5:1); [a]2D0 =ꢀ19.3 (c=0.8 in CHCl3); 1H NMR (400 MHz, CDCl3, 258C,
TMS): d=7.25 ppm (m, 5H; ArH), 5.98 (s, 1H; =CH), 4.42 (s, 2H;
ArCH2), 3.56–3.63 (m, 2H; OCH2), 3.45–3.49 (m, 1H; OCH), 2.50 (s,
NMR spectra were recorded with a Bruker DRX300 spectrometer, a
Bruker Avance III 400 spectrometer or an Avance Bruker 600 MHz spec-
trometer. Chemical shifts (d) are reported in ppm with the solvent reso-
nance given relative to chloroform (d=7.26 ppm) or tetramethylsilane
(d=0.00 ppm) for 1H nuclei, and chloroform (d=77.0 ppm) for 13C
nuclei. Data are reported as follows: brs=broad singlet, s=singlet, d=
doublet, t=triplet, q=quartet, m=multiplet; coupling constants in Hz.
1H NMR measurements were carried out at RT in deuterated chloroform
unless otherwise stated. Mass spectra (EIMS and HRMS (ESI)) were ob-
tained with a HP 5989B spectrometer and determined at an ionizing volt-
age of 70 eV unless otherwise stated; relevant data are tabulated as m/z
values.
3H; =CCH3), 2.28 ( s, 1H; OH), 1.95 (d, 3J
1.82 (d, 3J
(H,H)=13.2 Hz, 1H; CH), 1.83–1.89 (m, 2H; CH2), 1.50–1.59
(m, 1H; CH), 1.45–1.55 (m, 2H; CH2), 1.31–1.39 (m, 1H; CH), 0.86 (t,
3J(H,H)=6.8 Hz, 3H; CH3), 0.83 ppm (t, 3J
(H,H)=6.5 Hz, 3H; CH3);
ACHTUNGERTN(NUNG H,H)=13.2 Hz, 1H; CH),
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
13C NMR (100 MHz, CDCl3, 258C, TMS): d=146.1 (=CH), 137.9 (Bn),
128.6 (Bn), 127.9 (Bn), 127.8 (Bn), 96.3 (=CI), 86.2 (COH), 82.6
(COCH), 81.2 (CHOC), 73.3 (PhCH2), 67.4 (CH2OBn), 50.9 (CH2), 34.7
(CH2), 30.9 (CH2), 29.5 (CH3C=C), 29.3 (CH2), 9.1 (CH3), 8.8 ppm
(CH3); HRMS (ESI): m/z calcd for C20H29O3INa: 467.1054 [M+Na]+;
found: 467.1052.
Melting points were measured on a Reichert Microscope apparatus and
were uncorrected. Optical rotations were measured with a Perkin–Elmer
model 241 polarimeter operating at the sodium D line with a 100 mm
path-length cell operating at 208C, and are reported as follows: [a]TD con-
centration (g/100 mL), and solvent. X-ray data sets were obtained with a
P4 X-ray four circle diffractometer and analyzed with SHELXTL PLUS
(PC Version) unless otherwise stated.
Compound 1: Iodide 37 (50 mg, 0.21 mmol) was added to a 25 mL oven-
dried, two-necked, round-bottomed flask under an argon atmosphere. Di-
ethyl ether (3 mL) was added by using a syringe, and the resulting solu-
tion was cooled to ꢀ788C. tBuLi (0.4 mL, 1.5m in pentane, 0.6 mmol)
was added rapidly by using a syringe and the solution was stirred at
For full experiment details concerning all new compounds, see the Sup-
porting Information.
Vinyl iodide 35: Compound 36 (65 mg, 0.206 mmol) and [PdCl2ACTHNUTRGEN(UNG PPh3)2]
(0.01 mmol, 3 mg) were added to a 10 mL, argon-filled, two-necked,
round-bottomed flask equipped with a magnetic stirring bar. The flask
was evacuated and filled with argon three times, and then freshly distilled
ꢀ788C for 5 min, then 9-methoxy-9-borabicyclo
ACHTUNGERTN[NUNG 3.3.1]nonane (0.5 mL,
1m in THF, 0.5 mmol) was added by using a syringe followed by THF
(3 mL). The solution was stirred at ꢀ788C for 10 min, then slowly
warmed to 238C and stirred at that temperature for 1 h. An aqueous so-
lution of K3PO4 (0.17 mL, 3n, 0.51 mmol) was added followed by a solu-
tion of vinyl iodide 35 (23 mg, 0.065 mmol) in THF (1 mL), DMF (3 mL),
n-hexane (3 mL) was added by using
a syringe. Tributyltin hydride
(140 mL, 151 mg, 0.5 mmol) was added slowly (over about 10 min) by
using a syringe. The reaction was stirred at 238C for 1.5 h, then immedi-
ately transferred to a silica gel column (8 g) and rapidly eluted with hex-
and [PdCl2ACHTUNGRTNE(UNG dppf)2]·CH2Cl2 (0.006 mmol, 5 mg). The resulting black solu-
anes until the excess Bu3SnH/ACHTNUGTRNEU(GN Bu3Sn)2 was removed, followed by elution
with a mixture of hexanes and ethyl acetate (10:1) to obtain the stannane
compound as a colorless oil: Rf =0.23 (hexanes/ethyl acetate, 10:1).
tion was stirred at 238C for 16 h. Diethyl ether (10 mL) was added and
the mixture was transferred to a separating flask. Water (10 mL) was
added and the layers were separated. The aqueous layer was extracted
Chem. Eur. J. 2010, 16, 6933 – 6941
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6939

H. N. C. Wong et al.
with diethyl ether (3ꢃ10 mL). The combined organic extracts were
washed with water (2ꢃ10 mL) and brine (10 mL), dried over anhydrous
Na2SO4, and concentrated under reduced pressure to give a residue that
was purified by flash column chromatography on silica gel (8 g; hexanes/
ethyl acetate, 10:1) to give the coupling product as a colorless oil that
was used immediately in the following debenzylation reaction. Rf =0.25
(hexanes/ethyl acetate, 10:1).
to express our sincere gratitude to Professor Semmelhack for helpful dis-
cussions before this paper was submitted.
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A 50 mL three-necked, round-bottomed flask was equipped with a mag-
netic stirring bar and attached to a vacuum line, an oil bubbler, and a
tank of anhydrous ammonia. The flask was placed under vacuum, filled
with argon, and cooled to ꢀ788C. The argon flow was stopped and am-
monia flow was condensed. When 5–6 mL liquid ammonia condensed
into the flask, the ammonia flow was stopped, the tank and bubbler were
disconnected and the flask was placed under argon. Sodium (90 mg,
3.9 mmol) was cut into small pieces, washed quickly with anhydrous di-
ethyl ether to remove any residual oil, and added in portions to the flask
at ꢀ788C. The liquid turned a deep-blue color and was stirred at ꢀ788C
for 10 min until all of the sodium had been dissolved. A solution of the
above coupling product in THF (10 mL) was added by using a syringe
and the mixture was stirred at ꢀ788C (blue color persists) for 45 min.
NH4Cl (535 mg, 10 mmol) was added and the solution was stirred at
ꢀ788C until the blue color disappeared. The flask was opened to air and
warmed to 238C to allow ammonia to evaporate. Water (10 mL) and di-
ethyl ether (30 mL) were added, the organic layer was separated and the
aqueous layer was extracted with diethyl ether (3ꢃ10 mL). The com-
bined organic extracts were washed with water (10 mL) and brine
(10 mL), dried over anhydrous Na2SO4, and concentrated under reduced
pressure to give a residue that was purified by flash column chromatogra-
phy on silica gel (8 g; hexanes/ethyl acetate, 2:1) to afford the debenzyla-
tion product as a colorless oil, which was immediately used in the follow-
ing oxidative cyclization reaction: Rf =0.23 (hexanes/ethyl acetate, 2:1).
PDC (150 mg, 0.4 mmol) at 08C was added in one portion to a solution
of the debenzylation product in DMF (1.5 mL) and the reaction mixture
was stirred at 238C overnight. The mixture was diluted with diethyl ether
(30 mL) then washed with water (2ꢃ10 mL) and brine (10 mL). The or-
ganic phase was dried over anhydrous Na2SO4 and concentrated under
reduced pressure to give a residue that was purified by flash column
chromatography on silica gel (8 g; hexanes/diethyl ether, 10:1) to give
compound 1 as a colorless oil (13 mg, 60% over 3 steps). Rf =0.23 (hex-
anes/diethyl ether, 10:1). [a]2D0 =ꢀ16.0 (c=0.39 in CHCl3); 1H NMR
(400 MHz, CDCl3, 258C, TMS): d=5.36 (dt, 3J
=CH), 5.06 (ddt, 3J
3J(H,H)=1.4 Hz, 1H; =CH), 4.21 (dd, 3J
2.71 (dd, 3J(H,H)=5.1, 18.6 Hz, 1H; COCH), 2.64 (dd, 3J
18.6 Hz, 1H; COCH), 2.24 (d, 3J
(H,H)=13.7 Hz, 1H; CH), 2.14 (d,
3J
(H,H)=13.7 Hz, 1H; CH), 1.99–2.04 (m, 4H; 2CH, CH2), 1.82–1.87 (m,
1H; CH), 1.69 (d, J
1.32–1.38 (m, 1H; CH), 1.10–1.17 (m, 1H; CH), 0.96 (t, J
3H; CH3), 0.95 (t, 3J(H,H)=7.4 Hz, 3H; CH3), 0.86 (t, 3J
3H; CH3), 0.83 ppm (t, J
CDCl3, 258C, TMS): d=175.7 (C=O), 137.1 (=C), 132.7
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
3
ACHTUNGTRENNUNG(H,H)=1.4 Hz, 3H; CH3), 1.66–1.77 (m, 4H; 2CH2),
3
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
3
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
CH), 129.5 (=CH), 97.2 (COC=O), 86.9 (COCH), 79.5 (CHOC), 49.0
(CH2), 46.9 (CH2C=C), 42.6 (CHC=C), 36.7 (CH2C=O), 33.7 (CH2), 30.3
(CH2), 27.8 (CH2), 25.5 (CH2), 16.7 (CH3C=C), 14.0 (CH3), 11.5 (CH3),
8.7 (CH3), 8.3 ppm (CH3); HRMS (ESI): m/z [M+Na]+ calcd
C21H34O3Na: 357.24000; found: 357.24002.
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Acknowledgements
We thank the Area of Excellence Scheme established under the Univer-
sity Grants Committee of the Hong Kong SAR, China (Project No. AoE/
9-10/01) for financial support. A Direct Grant from the Chinese Universi-
ty of Hong Kong is also gratefully acknowledged. We also thank Prof. Er-
1
nesto Fattorusso for providing us with an authentic H NMR spectrum of
natural plakortone B for spectroscopic comparison. We would also like
[25] See the Supporting Information for details.
6940
www.chemeurj.org
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 6933 – 6941

Total Synthesis of Plakortone B
FULL PAPER
1
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with the authentic H NMR spectrum of 1 provided by Professor Er-
nesto Fattorusso.
[32] The specific rotation of our synthetic 1 [a]2D0 =ꢀ16.0 (c=0.39 in
CHCl3) does not quite agree with that of the naturally occurring pla-
kortone B [a]2D0 =ꢀ9.2 (c=0.72 in CHCl3). However, it is envisaged
that this difference between synthetic 1 and the natural plakorto-
ne B was acceptable because 1) synthetic 1 could fit the spectral
data of natural plakortone B; 2) the specific rotation value of syn-
thetic 1 is in good agreement with the value of its synthetic enantio-
mer ent-1 [a]2D0 =+15.5 (c=0.28 in CHCl3); and 3) the difference
might be due to the way these values were measured, for example,
purity, equipment, temperature, and concentration of the samples.
[33] CCDC-763045 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
[31] In his article, Professor Semmelhack did not report the specific rota-
tion of their synthetic 1, and the 1H NMR spectrum obtained by his
group showed a slight difference at d=5.00–5.08 ppm as compared
Received: January 23, 2010
Published online: April 29, 2010
Chem. Eur. J. 2010, 16, 6933 – 6941
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6941