Structure investigations of (ent)-cladospolide d by de novo synthesis and kinetic and thermodynamic isomerization

Article abstract of DOI:10.1055/s-0029-1217606

The de novo asymmetric synthesis of cladospolides B and C and (ent)-cladospolide D has been achieved from achiral non-1-yne. The 11-13-step route relies upon a Noyori reduction and a KAPA promoted alkyne zipper reaction to relay an achiral functionality a

Full text of DOI:10.1055/s-0029-1217606

PAPER
2847
Structure Investigations of (ent)-Cladospolide D by De Novo Synthesis and
Kinetic and Thermodynamic Isomerization
S
tructure Investiga
a
tions of
(
en
l
t
)
-Clad
a
ospolide
D
n Xing, John H. Penn,* George A. O’Doherty*
Department of Chemistry, West Virginia University, Morgantown, WV 26506, USA
Fax +1(304)2934904; E-mail: George.ODoherty@mail.wvu.edu
Received 21 May 2009
OH
OH
OH
OH
Abstract: The de novo asymmetric synthesis of cladospolides B
and C and (ent)-cladospolide D has been achieved from achiral non-
1-yne. The 11–13-step route relies upon a Noyori reduction and a
HO
O
OH
O
O
KAPA promoted alkyne zipper reaction to relay an achiral function-
ality across a nine-carbon fragment and to enable the installation of
a dienoate functionality. A diastereo- and regioselective Sharpless
O
O
O
dihydroxylation of a dienoate installed the remaining stereochemis-
try. The de novo asymmetric route allowed for the asymmetric syn-
thesis of three members of the cladospolide natural products and
correctly established the structure for cladospolide D.
cladospolide A
(1)
cladospolide B
(2)
cladospolide C
(3)
Key words: cladospolides B–D, asymmetric synthesis, natural
product synthesis, E/Z-alkene isomerization
O
O
OH
O
cladospolide D
(4)
In an interesting synergistic relationship between parasite
and host, the Cladosporium species produce secondary
metabolites that can regulate the host plant’s growth.1
This growth regulation is believed to occur via the inhibi-
tion of gibberellin biosynthesis.1c Structurally these fun-
gal products/plant pheromones are made up of a group
of diastereomeric twelve-membered macrolactone diols,
which differ in stereochemistry at the C4/C5 diol and C2/C3
double bond stereochemistry (Figure 1).1 These
stereochemical differences affect the biological activity.
For instance, cladospolides A–C inhibit the shoot elonga-
tion in rice seedlings,1c whereas, cladospolides A and B
have the opposite effect on the root growth of lettuce seed-
lings.1b
Figure 1 Cladospolides A–D
not been correctly determined.5 At issue was the stereo-
chemical assignment of the C2–C3 double bond, which
was solely based on a 13.5 Hz vicinal coupling constant
for the purported trans-enoate C=C bond.1d
Using asymmetric synthesis of all the possible diastereo-
mers and the comparison of optical rotation data, we as-
signed the absolute and relative stereochemistry for
cladospolide D (Figure 2).3c This work resulted in a cor-
rection of the initially assigned C2–C3 double bond ste-
reochemistry, which the first synthesis of cladospolide D,
by Hou, initially confirmed the structure as E-isomer 6.5
Unfortunately, this synthetic study missed a facile E/Z-
double bond isomerization and, thus, they actually pre-
pared the Z-isomer of cladospolide D (4), although they
reported it as (E)-cladospolide D (6). Herein, we report
the full account of our synthetic studies toward the suc-
cessful synthesis of cladospolide B/C and the (ent)-clado-
spolide D, which includes our study of the E/Z-double
These three natural products, cladospolides A–C,2–4 are
produced by the same and related organisms and it was
initially suggested that they should share the same C11
carbinol stereochemistry, which biosynthetically would
be formed earliest in the fatty acid biosynthetic pathway.
The relative stereochemistry for the cladospolides A–C
have been confirmed by several total syntheses, although
it should be noted that questions remain around clado-
spolide B, where the different signs of rotation were found
for the same absolute stereoisomer for synthetic clado-
spolide B by Banwell and us.2–4
OH
O
OH
O
In contrast to the plant pheromone activity of cladospolide
A–C, cladospolide D possesses antimicrobial activity
with IC50 values of 0.1 and 29 mg/mL against M. racemo-
sus and P. oryzae, respectively.1d Until our work, the ab-
solute and relative stereochemistry of cladospolide D had
O
O
OH
O
O
O
O
O
purported
cladospolide D
(5)
natural
(Z)-cladospolide D
(4)
(E)-cladospolide D
(6)
SYNTHESIS 2009, No. 17, pp 2847–2854
x
x.
x
x
.
2
0
0
9
Advanced online publication: 10.07.2009
DOI: 10.1055/s-0029-1217606; Art ID: C01609SS
© Georg Thieme Verlag Stuttgart · New York
Figure 2 (E/Z)-Cladospolide D

2848
Y. Xing et al.
PAPER
bond isomerization of cladospolides and their diastereo- give an ynoate, which by means of the Rychnovsky vari-
mers.
ant of the Trost ynoate to dienoate isomerization (Ph3P/
PhOH) was cleanly converted into (E,E)-dienoate 15 in
good yields (90%) and stereoselectivity.7 Dienoate 15 was
subjected to Sharpless asymmetric dihydroxylation condi-
tions [2% OsO4, 4% (DHQD)2PHAL] to give diol 9 in ap-
proximately 82% yield and as a single diastereomer.6
Similarly, dienoate 15 was dihydroxylated with the pseu-
doenantiomeric reagent [2% OsO4, 4% (DHQ)2PHAL] to
give diol 10 in approximately 80% yield and as a single
diastereomer (Scheme 2).
At the outset of this project, we had reservations regarding
the assignment of double bond stereochemistry for pur-
ported cladospolide D (5). Accordingly, our retrosynthet-
ic analysis (Scheme 1) envisioned that (Z)-cladospolide D
(4) could be prepared from cladospolide B (2) or its bis-
epimer 7. Similarly, (E)-cladospolide D (6) could be pre-
pared from cladospolide C (3) or its bis-epimer 8. In turn,
cladospolides B and C (2 and 3) and their bis-epimers 7
and 8 could come from the lactonization reactions of diols
9 and 10. Diols 9 and 10 could come from the diastereo- With all the sp3 stereocenters established for the clado-
selective and regioselective dihydroxylation,6 diene con- spolides, we turned to the assembly of the macrocycle
jugation,7 alkyne zipper isomerization,8 and Noyori (Scheme 3). To our delight this occurred with a small
asymmetric reduction of ynone 11,9 which could be pre- amount of double bond isomerization. Thus exposing diol
pared from commercially available non-1-yne (12).
9 to acid-catalyzed acetonide formation/TBS deprotection
conditions gave the desired seco-acid, which when ex-
posed to the Yamaguchi lactonization conditions11 gave a
6:1 mixture of cladospolide C (3) (36%) and its double
bond isomer 7 (6%), after trifluoroacetic acid promoted
acetonide deprotection. Following a virtually identical
macrocyclization protocol, diol 10 was converted into a
similar mixture of cladospolide B (2) (6%) and its double
bond isomer 8 (34%).
HO
O
HO
O
OH
OH
O
O
4,5-bis-epi-
cladospolide B (7)
cladospolide B (2)
OH
cladospolide D (4)
OH
With the construction of the required four stereoisomeric
macrolactone diols, we turned our attention to the synthe-
sis and structural proof of cladospolide D. This began with
the investigation of the selective oxidation of the allylic
alcohol in cladospolide C (3) (Scheme 4). Unfortunately,
several oxidants (e.g., MnO2 and Dess–Martin periodi-
nane) lead to oxidative diol cleavage to give a dialdehyde
product. In our grahamimycin A synthesis, we had previ-
ously found that the enone functionality could be installed
by a stoichiometric 2,2,6,6-tetramethylpiperidin-1-yloxy
(TEMPO) oxidation of the allylic alcohol in colletodiol,
without the need for selective protection.6c Unfortunately,
when we applied these same conditions to the clado-
spolides, only products of double oxidation were ob-
tained. For instance, when we exposed cladospolide C (3)
and its C-4,5-bis-epimer 8 to the catalytic TEMPO oxida-
tion conditions [TEMPO (1 mol%), trichloroisocyanuric
acid (1 equiv)]12 only diketone 16 was observed. When
only one equivalent of co-oxidant was used [TEMPO (1
mol%), trichloroisocyanuric acid (0.33 equiv)] low yields
of 16 and starting material were observed. Similarly, cla-
dospolide B (2) and its C-4,5-bis-epimer 7 reacted under
the TEMPO oxidation conditions to give diketone 17.
Thus, we turned to a selective protection/oxidation/depro-
tection sequence.
OH
OH
O
O
O
O
4,5-bis-epi-
cladospolide C (8)
cladospolide C (3)
OTBS
OH
O
OEt
OH
9
2, 3, 7, 8
OTBS
OH
O
OEt
H
OH
10
O
11
12
6
Scheme 1 Retrosynthetic analysis
Lithiation of commercially available non-1-yne (12) and
alkylation with acetaldehyde gave racemic propargylic al-
cohol rac-13 (69%, two steps). Propargylic oxidation of
rac-13 with manganese dioxide gave the ynone 11. Expo-
sure of the ynone 11 to our modified Noyori conditions9
provided an excellent yield (85%) of propargyl alcohol 13
with high enantiomeric purity (>96% ee). Exposure of 13
to potassium 3-aminopropylamine reagent (KAPA) readi-
ly isomerized it to the terminal undecynol,8 which was
protected as its tert-butyldimethylsilyl ether (TBSCl/imi-
dazole, DMF) in good overall yield (82%) and with no
loss of enantiomeric purity (>96% ee).10 The terminal
alkyne 14 was carboxylated (n-BuLi/ClCO2Et, 83%) to
Because the absolute stereochemistry of cladospolide D
was not known and we had our doubts about the assigned
olefin geometry, we decided to perform the protection/
oxidation/deprotection sequence on both cladospolide B
(2) and C (3) as well as their 4,5-bis-epimers 7 and 8. Due
to the exploratory nature of these studies, no effort was
made to maximize the regioselectivity in the protection
step. Rather a regio-unselective TBS-protection was cho-
sen for simplicity’s sake (i.e., no bis-protection was ob-
Synthesis 2009, No. 17, 2847–2854 © Thieme Stuttgart · New York

PAPER
Structure Investigations of (ent)-Cladospolide D
2849
O
O
OH
H
1) n-BuLi then
Noyori*
H
6
2) MnO2, THF
69%
85%
11
13
12
6
6
1) n-BuLi
then ClCO2Et
H
OTBS
1) KAPA
TBSO
O
2) TBSCl
82%
OEt
2) PhOH, Ph3P
75%
7
5
14
15
TBSO
OH
OTBS
O
O
AD-mix-β*
OEt
OEt
OEt
OEt
82%
5
5
OH
OH
9
15
15
TBSO
OH
OTBS
O
O
AD-mix-α*
80%
5
5
10
Ts
N
Ph
Ph
Ru
N
H
Noyori (R,R)
Scheme 2 Synthesis of diols. Reagents and conditions: Noyori* = Noyori (R,R) (0.2 mol%), HCO2H/Et3N (5:4); AC-mix-b* = 1% OsO4, 5%
(DHQD)2PHAL, K3Fe(CN)6, K2CO3, MeSO2NH2, t-BuOH–H2O (1:1); AD-mix-a* = 1% OsO4, 5% (DHQ)2PHAL, K3Fe(CN)6, K2CO3,
MeSO2NH2, t-BuOH–H2O (1:1).
served and the minor regioisomer could be recycled). to improved regioselectivity in the TBS protection (2:1).13
This, in turn, helped with the assignment of the regioiso- Of the four enones produced, only 21 had spectral data
mers.
that matched cladospolide D,1d although the rotation was
opposite in sign. The spectral data for this Z-enone also
matched the data report by Hou for his synthetic clado-
spolide D, although it was assigned as the enantiomer of
the E-isomer 19 (6). Therefore, we concluded that a hid-
den alkene isomerization reaction must have occurred
during the Hou synthesis.
Exposure of cladospolide C (3) to the three-step TBS
monoprotection/Dess–Martin oxidation/hydrogen fluo-
ride deprotection gave a 27% yield of enone 18
(Scheme 5). Cladospolide B (2) and its 4,5-bis-epimer 7
gave the corresponding enones 21 and 20, respectively,
with similar yields for this three-step sequence. The low
yield for these sequences was due to the poor regioselec- Consequently, we decided to investigate the isomerization
tivity (1:2 against) in the TBS-protection step. In contrast, of the olefin 19. When enone 19 was irradiated with UV
when the 4,5-bis-epimer 8 was exposed to the same three- light (300 nm) with and without iodine, a 1:1 ratio of 19
step sequence a higher yield of enone 19 was obtained due and (ent)-cladospolide D (21) was found along with a sig-
OH
MeO OMe
1)
p-TSA
TBSO
OH
O
HO
O
OH
2) LiOH
OH
OEt
O
3) Yamaguchi*
+
O
5
OH
4) TFA
9
O
4,5-bis-epi-
cladospolide B (7)
cladospolide C (3)
36%
6%
OH
MeO OMe
1)
p-TSA
TBSO
OH
O
HO
O
OH
2) LiOH
OH
OEt
O
+
3) Yamaguchi*
5
OH
O
4) TFA
O
10
4,5-bis-epi-
cladospolide C (8)
34%
cladospolide B (2)
6%
Scheme 3 Synthesis of cladospolide B and C and isomers. Reagents and conditions: Yamaguchi* = 2,4,6-trichlorobenzoyl chloride, DMAP.
Synthesis 2009, No. 17, 2847–2854 © Thieme Stuttgart · New York

2850
Y. Xing et al.
PAPER
OH
OH
OH
OH
O
O
TEMPO*
TEMPO*
67%
65%
O
O
O
O
O
O
4,5-bis-epi-
cladospolide C (8)
cladospolide C (3)
16
TEMPO*
TEMPO*
HO
O
HO
O
OH
O
OH
O
O
86%
85%
O
O
O
17
4,5-bis-epi-
cladospolide B (7)
cladospolide B (2)
Scheme 4 Diol oxidations. Reagents and conditions: TEMPO* = TEMPO, trichloroisocyanuric acid.
OTBS
O
OH
OH
OH
O
1) TBSCl
pyrex filter
300 nm hv
2) DMP
O
O
OTBS
3) 5% HF
in MeCN
O
O
O
O
(1:1.3)
27%
O
O
O
18
22
cladospolide C (3)
23
OTBS
O
pyrex filter
300 nm hv
OH
OH
O
1) TBSCl
2) DMP
3) 5% HF
in MeCN
54%
O
O
OTBS
O
OH
(1:2)
O
O
O
O
25
24
O
O
4,5-bis-epi-
cladospolide C (8)
Scheme 6 Photoequilibration
19
1) TBSCl
Z-isomer 23 being slightly favored. When we irradiated
benzene-d6 solutions of 24 and 25 under identical condi-
tions a photoequilibrium (Z/E, 2:1) was established,
which slightly favored the Z-isomer 25 (Scheme 6).
HO
O
2) DMP
3) 5% HF
in MeCN
27%
O
OH
O
OH
O
O
4,5-bis-epi-
cladospolide B (7)
20
The photoisomerization gave photoequilibria and not true
Keq, hence, we decided to isomerize the enones under io-
dine radical conditions. We exposed pure benzene-d6 so-
lutions of 22 and 23 to a catalytic amount of iodine under
thermal and photochemical conditions (Scheme 7). Under
these conditions, both solutions rapidly (<1 h) reached
equilibrium (Keq = 4, Z/E) with the Z-isomer being more
stable. When we turned to the E/Z-isomers of the natural
cladospolide D diastereomer, we found a much greater
difference in stability. When the same isomerization was
preformed with pure solutions of 24 and 25 the equilibri-
um was reached much more quickly and the equilibrium
achieved was in even greater preference for the Z-isomer
25 (Keq >20, Z/E). Therefore, we concluded that the driv-
ing force and barrier to isomerization of the cladospolide
D diastereomer 25 is quite strong.
1) TBSCl
O
HO
O
2) DMP
3) 5% HF
in MeCN
23%
O
OH
OH
O
(ent)-cladospolide D (21)
O
cladospolide B (2)
Scheme 5 Synthesis of cladospolide D and diastereomers
nificant amount of photodegradation products. While this
isomerization explained the problem with Hou’s assign-
ment of cladospolide D, the photochemical isomerization
reaction was not clean enough to be consistent with his re-
ported yield. Similarly byproducts were also observed,
when we explored the photoisomerization of 18 and 20.
However, much cleaner isomerization reactions were ob-
served for the TBS-protected enones, 22, 23, 24, and 25
(Scheme 6).
For comparison, we decided to study the double bond
isomerization between cladospolide C (3) and its 4,5-bis-
epimer 8 using the same equilibration condition
(Scheme 8). This study showed that no strong thermody-
namic preference for the Z-isomers could be found. For
When we irradiated benzene-d6 solutions of pure 22 and
23 for 24 hours with 300-nm light through a Pyrex filter,
a photoequilibrium (Z/E, 1.3:1) was established with the
Synthesis 2009, No. 17, 2847–2854 © Thieme Stuttgart · New York

PAPER
Structure Investigations of (ent)-Cladospolide D
2851
OTBS
O
OTBS
O
OTBS
OH
pyrex filter
300 nm hv, I2
DMP
95%
HF/Py
86%
O
O
OTBS
Keq = 4
O
O
O
O
O
O
O
23
22
26
24
OTBS
O
pyrex filter
300 nm hv, I2
HF (5 mol%)
in MeCN
87%
O
O
O
O
OH
O
OTBS
O
OTBS
Keq > 20
O
O
O
O
O
25
(ent)-cladospolide D (21)
25
24
Scheme 7 Photochemical equilibrium
OTBS
O
1) pyrex filter
300 nm hv, I2
O
O
OH
example, when cladospolide C (3) and its double bond
isomer 7 were isomerized under radical iodine conditions
(24 h irradiation with I2), we found equal amounts of 3 and
7 (Keq = 1). In contrast, we were not able to reach to full
equilibrium for the isomerization of 4,5-bis-epi-clado-
spolide C (8) to cladospolide B (2), but we could bracket
the equilibrium constant to be between 0.3 and 6
(Scheme 8), suggesting that the C4 carbonyl in clado-
spolide D has a strong effect on the E/Z-stability.
2) HF (5 mol%)
in MeCN
86%
O
O
O
(ent)-cladospolide D (21)
24
Scheme 9 Improved approaches to cladospolide D
tation was opposite in sign ([a]D –58 vs +56 in MeOH).
Hence, structure 21 must be the enantiomer of clado-
spolide D and the structure should be revised to structure
4 as shown in Figure 1.
OH
pyrex filter
300 nm hv, I2
HO
O
In conclusion, a short and enantioselective synthesis of
(ent)-cladospolide D has been developed, which clears up
any ambiguities with its structural assignment. This struc-
tural proof involved the synthesis of all the possible ste-
reoisomers of cladospolide D as well as another two
members of this family of natural products, cladospolides
B and C. This de novo asymmetric approach used two re-
mote catalytic asymmetric reactions (Noyori reduction
and Sharpless asymmetric dihydroxylation) to establish
its asymmetry, therefore, this synthesis is also a formal
synthesis of the natural stereoisomer of cladospolide D.
This de novo route to the cladospolides compares favor-
ably (i.e., fewer steps and greater overall efficiency) to the
previous routes from chiral starting materials. In addition,
this route enabled the study of the C2–C3 alkene isomer-
ization that was of central importance to the structural
proof of cladospolide D.
OH
OH
Keq = 1
O
O
O
4,5-bis-epi-
cladospolide B (7)
cladospolide C (3)
OH
pyrex filter
300 nm hv, I2
HO
O
OH
OH
O
0.3 < Keq < 6
O
O
4,5-bis-epi-
cladospolide C (8)
cladospolide B (2)
Scheme 8 Photochemical equilibrium
With the knowledge of the structure of the desired target
molecule, we next sought an improved synthesis of clado-
spolide D (Scheme 9). We returned to the trans-diol 8,
which could be regioselectively protected to give 26 in
good yield. Dess–Martin oxidation of 26 cleanly gave
enone 24. At this stage photochemical isomerization of 24
cleanly gave the previously prepared Z-isomer 25 in near
quantitative yield (>95%). Interestingly, when 24 was
treated with the conditions used by Hou (HF/Py), instead
of our preferred conditions (5% HF/MeCN), clean double
bond isomerization occurred to give 25. As before, TBS-
deprotection with 5% hydrogen fluoride in acetonitrile oc-
1H and 13C NMR spectra were recorded on 600 M or 270 M NMR
spectrometers. Chemical shifts are reported relative to CDCl3 (d =
7.26) or CD3OD (d = 3.31) for 1H, and CDCl3 (d = 77.0) or CD3OD
(d = 49.15) for 13C. Optical rotations were measured with a digital
polarimeter in the solvent specified. IR spectra were obtained on a
FT-IR spectrophotometer. Melting points are uncorrected. Rf values
were obtained by elution of TLC plate in the stated solvent ratios
(v/v). Toluene, Et2O, THF, CH2Cl2, and Et3N were dried by passing
through activated alumina column with argon gas pressure. Com-
mercial reagents were used without purification unless otherwise
curred to give g-keto-enoate 21. Synthetic 21 material was noted. Air and/or moisture-sensitive reactions were carried out un-
spectroscopically (1H NMR, 13C NMR, IR, and MS) iden-
der an atmosphere of argon using oven/flamed-dried glassware and
standard syringe/septa techniques. Only new procedures are report-
tical with natural cladospolide D, although the optical ro-
ed in this experimental section.
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Y. Xing et al.
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(R,E)-12-Methyloxacyclododec-3-ene-2,5,6-trione (16)
(6S,12R,Z)-6-Hydroxy-12-methyloxacyclododec-3-ene-2,5-di-
one [(ent)-Cladospolide D, 21]
From diol 3: A soln of diol 3 (6 mg, 0.026 mmol) and trichloroiso-
cyanuric acid (6.1 mg, 0.026 mmol) in Et2O (0.3 mL) was stirred at
–30 °C, then TEMPO was added in one portion. The mixture was
stirred for 60 min and then quenched with sat. Na2CO3. The organic
layer was separated and the aqueous layer was extracted with Et2O.
The combined organic layers were washed with brine, dried
(Na2SO4), filtered, and concentrated. Chromatography (silica gel)
gave 16 (3.8 mg, 67%) as a colorless oil.
To a soln of 24 (1.0 mg) in benzene-d6 (3.0 mL), I2 (0.1 mg) was
added, the soln was irradiated with 300-nm UV light through a Pyr-
ex filter for 20 min; chromatography gave double bond isomer 25
(0.95 mg, 95%). To a plastic flask was added 25 (5 mg, 0.015
mmol), MeCN (0.1 mL), and 5% HF in MeCN (17 mL) at r.t. The
mixture was stirred for 2 h and then Et2O was added to dilute the
soln. The mixture was washed with NaHCO3, extracted with
EtOAc, dried (Na2SO4), and evaporated under reduced pressure to
leave the crude product, which was then purified using flash chro-
matography (silica gel) to give 21 (3 mg, 87%) as a colorless oil;
Rf = 0.36 (30% Et2O–hexane).
From diol 8: A soln of diol 8 (12 mg, 0.052 mmol) and trichloroiso-
cyanuric acid (12.3 mg, 0.053 mmol) in Et2O (0.5 mL) was stirred
at –30 °C, then TEMPO was added in one portion. The mixture was
stirred for 60 min and then quenched with sat. Na2CO3. The organic
layer was separated and the aqueous layer was extracted with Et2O.
The combined organic layers were washed with brine, dried
(Na2SO4), filtered, and concentrated. Chromatography (silica gel)
gave 16 (7.6 mg, 65%) as a colorless oil.
[a]D25 –57 (c 0.1, CH2Cl2).
IR (thin film): 3467, 2936, 1720, 1224, 1167, 1083 cm–1.
1H NMR (600 MHz, CDCl3): d = 6.40 (d, J = 13.2 Hz, 1 H), 6.31 (d,
J = 13.2 Hz, 1 H), 5.22 (dqd, J = 9.0, 6.0, 6.0 Hz, 1 H), 4.66 (ddd,
J = 8.4, 6.0, 5.4 Hz, 1 H), 3.16 (d, J = 6.0 Hz, 1 H), 1.95 (m, 1 H),
1.72–1.18 (m, 9 H), 1.30 (d, J = 6.0 Hz, 3 H).
Rf = 0.67 (hexane–EtOAc, 7:3). 1H spectra shows a mixture of dike-
tone 16 and its hydride.
[a]D20 –2 (c 0.1, MeOH).
13C NMR (150 MHz, CD3Cl): d = 203.5, 165.4, 133.3, 130.9, 73.5,
71.5, 33.2, 31.1, 23.0, 21.6, 21.5, 20.6.
IR (thin film): 3373, 2934, 1715, 1134, 1040, 987, 706 cm–1.
1H NMR (600 MHz, CDCl3): d = peaks associated with the dike-
tone: 6.87 (d, J = 15.6 Hz, 1 H), 6.36 (d, J = 15.6 Hz, 1 H), 5.05 (m,
1 H), 3.05 (ddd, J = 13.2, 7.8, 3.0 Hz, 1 H), 2.36 (ddd, J = 13.2,
12.0, 3.0 Hz, 1 H), 1.41 (d, J = 7.8 Hz, 3 H); peaks associated with
the hydrate: 7.00 (s, 2 H), 4.60 (m, 1 H), 4.14 (s, 1 H), 3.73 (s, 1 H),
2.69 (m, 1 H), 2.54 (m, 1 H), 1.41 (d, J = 6.6 Hz, 3 H), peaks asso-
ciated with the mixture: 1.67–1.54 (m).
HRMS (ESI): m/z [M + H]+ calcd for C12H19O4: 227.1278; found:
227.1278.
Photoequilibration of TBS-Protected (E)-5-bis-Cladospolide D
22 and TBS-Protected (Z)-5-bis-Cladospolide D 23
A soln of 22 (1.5 mg) in benzene-d6 (3.5 mL) was irradiated with
300-nm UV light through a Pyrex filter. After 24 h, a photoequilib-
rium (23/22, 1.3:1) was established with the Z-isomer 23 slightly fa-
vored; 22 and 23 could be separated by chromatography.
13C NMR (150 MHz, CD3Cl): d = diketone 16: 204.2, 195.6, 164.9,
136.6, 136.0, 75.5, 39.5, 34.8, 24.8, 23.4, 21.8, 20.8.
Pure 23 (1.0 mg) was irradiated in benzene-d6 (3.0 mL) soln with
300-nm UV light through a Pyrex filter, the same photoequilibrium
(23/22, 1.3:1) was established with the Z-isomer 23 slightly fa-
vored; 22 and 23 could be separated by chromatography.
HRMS (ESI): m/z [M + H]+ calcd for C12H17O4: 225.1121; found:
225.1122.
(R,Z)-12-Methyloxacyclododec-3-ene-2,5,6-trione (17)
From diol 7: A soln of diol 7 (6 mg, 0.026 mmol) and trichloroiso-
cyanuric acid (6.0 mg, 0.026 mmol) in Et2O (0.3 mL) was stirred at
–30 °C, then TEMPO was added in one portion. The mixture was
stirred for 40 min and then quenched with sat. Na2CO3. The organic
layer was separated and the aqueous layer was extracted with Et2O.
The combined organic layers were washed with brine, dried
(Na2SO4), filtered, and concentrated. Chromatography (silica gel)
gave 17 (5.0 mg, 86%) as a colorless oil.
(E)-O-(tert-Butyldimethylsilyl)-5-bis-cladospolide D (22)
Rf = 0.33 (10% Et2O–hexane).
[a]D25 –12 (c 0.5, CH2Cl2).
IR (thin film): 2931, 2858, 1721, 1463, 1251, 1078, 838, 779 cm–1.
1H NMR (600 MHz, CDCl3): d = 7.21 (d, J = 16.8 Hz, 1 H), 6.90 (d,
J = 16.8 Hz, 1 H), 4.89 (dqd, J = 7.8, 6.0, 4.8 Hz, 1 H), 4.41 (dd,
J = 6.0, 4.2 Hz, 1 H), 1.78–1.15 (m, 10 H), 1.34 (d, J = 6.0 Hz, 3 H),
0.91 (s, 9 H), 0.10 (s, 3 H), 0.07 (s, 3 H).
From diol 2: A soln of diol 2 (15 mg, 0.066 mmol) and trichloroiso-
cyanuric acid (15.3 mg, 0.066 mmol) in Et2O (0.6 mL) was stirred
at –30 °C, then TEMPO was added in one portion. The mixture was
stirred for 40 min and then quenched with sat. Na2CO3. The organic
layer was separated and the aqueous layer was extracted with Et2O.
The combined organic layers were washed with brine, dried
(Na2SO4), filtered, and concentrated. Chromatography (silica gel)
gave 17 (12 mg, 85%) as a colorless oil.
13C NMR (150 MHz, CD3Cl): d = 200.8, 166.8, 138.2, 131.3, 79.2,
75.3, 35.1, 34.1, 27.7, 25.8, 23.9, 20.6, 18.1, –4.79, –5.25.
HRMS (ESI): m/z [M + Na]+ calcd for C18H32O4SiNa: 363.1962;
found: 363.1964.
(Z)-O-(tert-Butyldimethylsilyl)-5-bis-cladospolide D (23)
Rf = 0.50 (10% Et2O–hexane).
Rf = 0.34 (hexane–EtOAc, 9:1).
[a]D25 +18 (c 0.4, CH2Cl2).
[a]D25 +2 (c 0.5, CH2Cl2).
IR (thin film): 2932, 2857, 1717, 1464, 1285, 1098, 838, 778 cm–1.
IR (thin film): 2931, 1710, 1377, 1284, 995 cm–1.
1H NMR (600 MHz, CDCl3): d = 6.78 (d, J = 12.6 Hz, 1 H), 5.95 (d,
J = 12.6 Hz, 1 H), 4.87 (dqd, J = 9.0, 6.0, 3.0 Hz, 1 H), 4.14 (dd,
J = 9.6, 3.0 Hz, 1 H), 1.84–1.24 (m, 10 H), 1.25 (d, J = 6.0 Hz, 3 H),
0.91 (s, 9 H), 0.09 (s, 6 H).
1H NMR (600 MHz, CDCl3): d = 6.49 (d, J = 12.6 Hz, 1 H), 6.29 (d,
J = 12.6 Hz, 1 H), 5.02 (dqd, J = 6.0, 6.0, 2.4 Hz, 1 H), 3.13 (ddd,
J = 15.6, 10.2, 2.4 Hz, 1 H), 2.44 (ddd, J = 15.6, 9.6, 2.4 Hz, 1 H),
1.98 (m, 1 H), 1.83 (m, 1 H), 1.59–1.61 (m, 6 H), 1.18 (d, J = 6.0
Hz, 3 H).
13C NMR (150 MHz, CD3Cl): d = 204.3, 164.5, 140.4, 125.9, 78.8,
73.9, 31.9, 31.3, 27.1, 25.7, 20.7, 19.5, 19.3, 18.0, –4.80, –5.13.
13C NMR (150 MHz, CD3Cl): d = 199.1, 190.4, 163.8, 135.7, 129.6,
73.2, 34.6, 31.6, 26.5, 21.4, 21.0, 19.0.
HRMS (ESI): m/z [M + H]+ calcd for C18H32O4SiNa: 363.1962;
found: 363.1964.
HRMS (ESI): m/z [M + H]+ calcd for C12H17O4: 225.1121; found:
225.1122.
Synthesis 2009, No. 17, 2847–2854 © Thieme Stuttgart · New York

PAPER
Structure Investigations of (ent)-Cladospolide D
2853
Iodine-Promoted Photochemical Equilibration of TBS-Protect-
ed (E)-5-bis-Cladospolide D 22 and TBS-Protected (Z)-5-bis-
Cladospolide D 23
Pyrex filter. After 20 min, the same photochemical equilibrium
(Keq > 20, 25/24) was established with the Z-isomer 25 favored.
To a soln of 22 (1.5 mg) in benzene-d6 (3.5 mL), I2 (0.1 mg) was
added, the soln was irradiated with 300-nm UV light through a Pyr-
ex filter. After 50 min, a photochemical equilibrium (Keq = 4, 23/22)
was established with the Z-isomer 23 favored; 22 and 23 could be
separated by chromatography.
Iodine-Promoted Photochemical Equilibration of Cladospolide
C (3) and 4,5-bis-epi-Cladospolide B (7)
To a soln of 3 (1.0 mg) in benzene-d6 (3.0 mL), I2 (0.1 mg) was add-
ed, the soln was irradiated with 300-nm UV light through a Pyrex
filter. After 24 h, a photochemical equilibrium (Keq = 1, 3/7) was es-
tablished; 3 and 7 were separated by chromatography (silica gel,
50% Et2O–hexane).
To a soln of 23 (1.0 mg) in benzene-d6 (3.0 mL), I2 (0.1 mg) was
added, the soln was irradiated with 300-nm UV light through a Pyr-
ex filter. After 50 min, the same photochemical equilibrium
(Keq = 4, 23/22) was established with the Z-isomer 23 favored; 22
and 23 could be separated by chromatography.
To the other soln of 7 (1.0 mg) in benzene-d6 (3.0 mL), I2 (0.1 mg)
was added; the soln was irradiated with 300-nm UV light through a
Pyrex filter. After 24 h, the same photochemical equilibrium
(Keq = 1, 3/7) was established; 3 and 7 were separated by chroma-
tography (silica gel, 50% Et2O–hexane).
Photoequilibration of TBS-Protected (E)-Cladospolide D 24
and TBS-Protected (Z)-Cladospolide D 25
A soln of 24 (1.0 mg) in benzene-d6 (3.0 mL) was irradiated with
300-nm UV light through a Pyrex filter. After 24 h, a photoequilib-
rium (24/25, 1:2) was established with the Z-isomer 25 slightly fa-
vored; 24 and 25 could be separated by chromatography.
Cladospolide C (3)
Mp 91–92 °C; Rf = 0.27 (50% Et2O–hexane).
[a]D25 +53 (c 0.4, MeOH).
IR (thin film): 3415, 2940, 2864, 1705, 1650, 1460, 1258, 1035 cm–1.
When pure 25 (1.0 mg) was irradiated in benzene-d6 (3.0 mL) soln
with 300 nm UV light through a Pyrex filter, the same photo equi-
librium (24/25, 1:2) was established with the Z-isomer 25 slightly
favored; 24 and 25 could be separated by chromatography.
1H NMR (600 MHz, CDCl3): d = 6.81 (dd, J = 15.6, 9.0 Hz, 1 H),
6.05 (d, J = 15.6 Hz, 1 H), 4.98 (dqd, J = 8.4, 6.0, 1.8 Hz, 1 H), 3.98
(dd, J = 8.4, 7.8 Hz, 1 H), 3.57 (ddd, J = 7.8, 7.8, 1.8 Hz, 1 H), 1.30
(d, J = 6.0 Hz, 3 H) 1.69–1.11 (m, 10 H).
13C NMR (150 MHz, CD3Cl): d = 166.7, 145.3, 124.5, 77.5, 76.5,
74.3, 33.9, 32.1, 27.3, 24.5, 24.1, 20.8.
(E)-O-(tert-Butyldimethylsilyl)cladospolide D (24)
Rf = 0.64 (10% Et2O–hexane).
[a]D25 +31 (c 0.4, CH2Cl2).
HRMS (ESI): m/z [M + H]+ calcd for C12H21O4: 229.1434; found:
229.1435.
IR (thin film): 2932, 2858, 1723, 1464, 1254, 1095, 847, 779 cm–1.
1H NMR (600 MHz, CDCl3): d = 7.41 (d, J = 16.8 Hz, 1 H), 6.93 (d,
J = 16.8 Hz, 1 H), 4.63 (qdd, J = 6.0, 6.0, 6.0 Hz, 1 H), 4.34 (dd,
J = 6.0, 1.6 Hz, 1 H), 1.90–1.06 (m, 10 H), 1.34 (d, J = 6.0 Hz, 3 H),
0.92 (s, 9 H), 0.08 (s, 3 H), 0.07 (s, 3 H).
4,5-bis-epi-Cladospolide B (7)
Rf = 0.33 (50% Et2O–hexane).
[a]D25 –1 (c 0.2, MeOH).
IR (thin film): 3272, 2943, 2862, 1710, 1461, 1278, 1050 cm–1.
13C NMR (150 MHz, CD3Cl): d = 201.3, 167.5, 134.2, 132.0, 77.2,
74.9, 34.8, 34.2, 27.9, 25.7, 24.1, 21.4, 20.6, 18.1, –4.91, –4.90.
1H NMR (600 MHz, CDCl3): d = 6.12 (dd, J = 12.0, 8.4 Hz, 1 H),
6.05 (dd, J = 12.0, 1.2 Hz, 1 H), 5.10 (qdd, J = 6.0, 5.4, 3.0 Hz, 1
H), 4.97 (ddd, J = 8.4, 4.8, 1.2 Hz, 1 H), 3.87 (ddd, J = 9.0, 4.8, 3.0
Hz, 1 H), 2.04–1.35 (m, 10 H), 1.25 (d, J = 6.0 Hz, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C18H33O4Si: 341.2143; found:
341.2144.
13C NMR (150 MHz, CD3Cl): d = 166.7, 145.3, 124.5, 77.5, 76.5,
74.3, 33.9, 32.1, 27.3, 24.5, 24.1, 20.8.
(Z)-O-(tert-Butyldimethylsilyl)cladospolide D (25)
Rf = 0.37 (10% Et2O–hexane).
[a]D25 –80 (c 0.5, CH2Cl2).
HRMS (ESI): m/z [M + H]+ calcd for C12H21O4: 229.1434; found:
229.1435.
IR (thin film): 2931, 2860, 1726, 1464, 1251, 1164, 1119, 839, 778
cm–1.
Isomerization of Cladospolide B (2) and 4,5-bis-epi-Clado-
spolide C (8)
1H NMR (600 MHz, CDCl3): d = 6.73 (d, J = 12.6 Hz, 1 H), 6.23 (d,
J = 12.6 Hz, 1 H), 4.91 (dqd, J = 9.6, 6.0, 3.0 Hz, 1 H), 4.32 (dd,
J = 7.8, 4.2 Hz, 1 H), 1.93–1.26 (m, 10 H), 1.27 (d, J = 6.0 Hz, 3 H),
0.93 (s, 9 H), 0.11 (s, 3 H), 0.09 (s, 3 H).
To a soln of 8 (1.0 mg) in benzene-d6 (3.0 mL), I2 (0.1 mg) was add-
ed; the soln was irradiated with 300-nm UV light through a Pyrex
filter. After 24 h, a photochemical equilibrium (Keq = 0.3, 2/8) was
established; 8 and 2 were separated by chromatography (silica gel,
50% Et2O–hexane).
13C NMR (150 MHz, CD3Cl): d = 203.2, 166.3, 133.6, 130.6, 76.4,
73.9, 33.3, 330.5, 26.3, 25.8, 22.1, 21.2, 20.0, 18.1, –4.91, –5.07.
HRMS (ESI): m/z [M + H]+ calcd for C18H33O4Si: 341.2143; found:
341.2144.
To the other soln of 2 (1.0 mg) in benzene-d6 (3.0 mL), I2 (0.1 mg)
was added; the soln was irradiated with 300 nm UV light through a
Pyrex filter. After 24 h, a photochemical equilibrium (Keq = 6, 2/8)
was established; 8 and 2 were separated by chromatography (silica
gel, 50% Et2O–hexane).
Iodine-Promoted Photochemical Equilibration of TBS-Protect-
ed (E)-Cladospolide D 24 and TBS-Protected (Z)-Gladospolide
D 25
To a soln of 24 (1.0 mg) in benzene-d6 (3.0 mL), I2 (0.1 mg) was
added, the soln was irradiated with 300-nm UV light through a Pyr-
ex filter. After 20 min, a photochemical equilibrium (Keq > 20, 25/24)
was established with the Z-isomer 25 favored.
4,5-bis-epi-Cladospolide C (8)
Rf = 0.41 (50% Et2O–hexane).
[a]D25 –13 (c 0.1, MeOH).
IR (thin film): 3396, 2937, 2870, 1711, 1464, 1247, 1028 cm–1.
To the other soln of 25 (1.0 mg) in benzene-d6 (3.0 mL), I2 (0.1 mg)
was added, the soln was irradiated with 300-nm UV light through a
1H NMR (600 MHz, CDCl3): d = 6.94 (dd, J = 15.6, 6.0 Hz, 1 H),
6.12 (dd, J = 15.6, 1.2 Hz, 1 H), 4.96 (dqd, J = 6.6, 6.0, 3.0 Hz, 1
Synthesis 2009, No. 17, 2847–2854 © Thieme Stuttgart · New York

2854
Y. Xing et al.
PAPER
H), 4.12 (ddd, J = 7.2, 6.0, 1.2 Hz, 1 H), 3.32 (ddd, J = 9.6, 7.8, 1.8
Hz, 1 H), 1.74–1.20 (m, 10 H), 1.28 (d, J = 6.0 Hz, 3 H).
(3) For the synthesis of cladospolide B, see: (a) Pandey, S. K.;
Kumar, P. Tetrahedron Lett. 2005, 46, 6625. (b) Austin, K.
A. B.; Banwell, M. G.; Loong, D. T. J.; Rae, A. D.; Willis,
A. C. Org. Biomol. Chem. 2005, 3, 1081. (c) Xing, Y.;
O’Doherty, G. A. Org. Lett. 2009, 11, 1107.
13C NMR (150 MHz, CD3Cl): d = 167.2, 146.9, 122.5, 78.0, 77.8,
73.1, 33.2, 32.6, 28.3, 25.0, 22.8, 19.0.
HRMS (ESI): m/z [M + H]+ calcd for C12H20O4Na: 251.1254;
found: 251.1254.
(4) For the synthesis of cladospolide C, see ref. 3c and:
(a) Banwell, M. G.; Loong, D. T. J.; Willis, A. C. Aust. J.
Chem. 2005, 58, 511. (b) Chou, C.-Y.; Hou, D.-R. J. Org.
Chem. 2006, 71, 9887. (c) Sharma, G. V. M.; Reddy, K. L.;
Reddy, J. J. Tetrahedron Lett. 2006, 47, 6537. (d) Reddy,
C. R.; Rao, N. N. Tetrahedron Lett. 2009, 50, 2478.
(5) For the synthesis of cladospolide D, see ref. 3c and: Lu,
K.-J.; Chen, C.-H.; Hou, D.-R. Tetrahedron 2009, 65, 225.
(6) The regioselectivity of the asymmetric dihydroxylation of
dienoates has been studied by Sharpless and our group, see:
(a) Berker, H.; Soler, M. A.; Sharpless, K. B. Tetrahedron
1995, 51, 1345. (b) Zhang, Y.; O’Doherty, G. A.
Tetrahedron 2005, 61, 6337. For synthetic application of
this, see: (c) Hunter, T. J.; O’Doherty, G. A. Org. Lett. 2002,
4, 4447. (d) Guo, H.; Mortensen, M. S.; O’Doherty, G. A.
Org. Lett. 2008, 10, 3149. (e) Ahmed, M. d. M.; Mortensen,
M. S.; O’Doherty, G. A. J. Org. Chem. 2006, 71, 7741.
(f) Ahmed, M. d. M.; O’Doherty, G. A. Tetrahedron Lett.
2005, 46, 3015. (g) Ahmed, M. d. M.; Berry, B. P.; Hunter,
T. J.; Tomcik, D. J.; O’Doherty, G. A. Org. Lett. 2005, 7,
745.
Cladospolide B (2)
Mp 108–109 °C; Rf = 0.57 (50% Et2O–hexane).
[a]D25 +24 (c 0.1, MeOH).
IR (thin film): 3345, 2934, 2865, 1707, 1461, 1280, 1046 cm–1.
1H NMR (600 MHz, CDCl3): d = 6.23 (dd, J = 12.0, 8.4 Hz, 1 H),
5.77 (dd, J = 12.0, 1.2 Hz, 1 H), 5.26 (ddd, J = 8.4, 4.2, 1.2 Hz, 1
H), 4.88 (dqd, J = 10.2, 6.0, 1.8 Hz, 1 H), 3.77 (ddd, J = 9.0, 4.2, 2.4
Hz, 1 H), 1.84–1.35 (m, 10 H), 1.28 (d, J = 6.0 Hz, 3 H).
13C NMR (150 MHz, CD3Cl): d = 165.8, 148.5, 121.9, 74.4, 73.9,
67.5, 32.0, 30.6, 25.7, 24.1, 21.3, 19.7.
HRMS (ESI): m/z [M + H]+ calcd for C12H21O4: 229.1434; found:
229.1435.
Acknowledgment
We are grateful to NSF (CHE-0749451) and the ACS-PRF (47094-
AC1) for the support of our research program and NSF-EPSCoR
(0314742) for a 600 MHz NMR at WVU.
(7) (a) Rychnovsky, S. D.; Kim, J. J. Org. Chem. 1994, 59,
2659. (b) Trost, B.; Kazmaier, U. J. Am. Chem. Soc. 1992,
114, 7933. For synthetic application of this, see: (c) Li, M.;
O’Doherty, G. A. Org. Lett. 2006, 8, 3987.
References
(8) (a) Brown, C. A.; Yamashita, A. J. Am. Chem. Soc. 1975, 97,
891. (b) Kimmel, T.; Becker, D. J. Org. Chem. 1984, 49,
2494. For synthetic application of this, see: (c) Hoye, R. C.;
Baigorria, A. S.; Danielson, M. E.; Pragman, A. A.;
Rajapakse, H. A. J. Org. Chem. 1999, 64, 2450. (d) Li, M.;
O’Doherty, G. A. Org. Lett. 2006, 8, 6087.
(9) For the Noyori reduction of ynones see: (a) Fujii, A.;
Hashiguchi, S.; Uematsu, N.; Ikariya, T.; Noyori, R. J. Am.
Chem. Soc. 1996, 118, 2521. (b) Noyori, R.; Ohkuma, T.
Angew. Chem. Int. Ed. 2001, 40, 40. For its use in
synthesis, see: (c) Guo, H.; O’Doherty, G. A. Org. Lett.
2005, 7, 3921.
(10) Trost, B. M.; Horne, D. B.; Woltering, M. J. Chem. Eur. J.
2006, 12, 6607.
(11) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi,
M. Bull. Chem. Soc. Jpn. 1979, 52, 1989.
(12) (a) Luca, L. D.; Giacomelli, G.; Porcheddu, A. Org. Lett.
2001, 3, 3041. (b) Ahmed, M. d. M.; Cui, H.; O’Doherty, G.
A. J. Org. Chem. 2006, 71, 6686.
(13) The double bond stereochemistry for four potential
diastereomers of cladospolide D 18–21 were conclusively
assigned by examination of the C2/C3 H–H coupling
constants (for the E-isomers, 18, J = 16.2 Hz; 19, J = 16.2
Hz; and for the Z-isomers 20, J = 13.2 Hz and 21, J = 13.2
Hz).
(1) (a) Hirota, A.; Isogai, A.; Sakai, H. Agric. Biol. Chem. 1981,
45, 799. (b) Hirota, A.; Sakai, H.; Isogai, A. Agric. Biol.
Chem. 1985, 49, 731. (c) Fujii, Y.; Fukuda, A.; Hamasaki,
T.; Ichimoto, I.; Nakajima, H. Phytochemistry 1995, 40,
1443. (d) Zhang, H.; Tomoda, H.; Tabata, N.; Miura, H.;
Namikoshi, M.; Yamaguchi, Y.; Masuma, R.; Omura, S.
J. Antibiot. 2001, 54, 635. (e) Hirota, A.; Sakai, H.; Isogai,
A.; Kitano, Y.; Ashida, T.; Hirota, H.; Takahashi, T. Agric.
Biol. Chem. 1985, 49, 903. (f) Hirota, H.; Hirota, A.; Sakai,
H.; Isogai, A.; Takahashi, T. Bull. Chem. Soc. Jpn. 1985, 58,
2147. (g) Smith, C. J.; Abbanat, D.; Bernan, V. S.; Maiese,
W. M.; Greenstein, M.; Jompa, J.; Tahir, A.; Ireland, C. M.
J. Nat. Prod. 2000, 63, 142.
(2) For the synthesis of cladospolide A, see: (a) Banwell, M.
G.; Loong, D. T. J. Org. Biomol. Chem. 2004, 2, 2050.
(b) Banwell, M. G.; Jolliffe, K. A.; Loong, D. T. J.; McRae,
K. J.; Vounatsos, F. J. Chem. Soc., Perkin Trans. 1 2002, 22.
(c) Solladie, G.; Almario, A. Tetrahedron: Asymmetry 1995,
6, 559. (d) Solladie, G.; Almario, A. Pure Appl. Chem. 1994,
66, 2159. (e) Ichimoto, I.; Sato, M.; Kirihata, M.; Ueda, H.
Chem. Express 1987, 2, 495. (f) Maemoto, S.; Mori, K.
Chem. Lett. 1987, 109. (g) Mori, K.; Maemoto, S. Liebigs
Ann. Chem. 1987, 863.
Synthesis 2009, No. 17, 2847–2854 © Thieme Stuttgart · New York