Total synthesis of (-)-Cleistenolide

Article abstract of DOI:10.1021/jo1002642

(Figure Presented) The first total synthesis of Cleistenolide, a novel natural product recently isolated from the Annonaceae species Cleistochlamys kirkii Oliver, is described. The synthesis proceeds in six steps and 18% overall yield, starting from an enantiopure C2-symmetric building block and using a Sharpless epoxidation, a selective epoxide opening, and a ring-closing metathesis reaction.

Full text of DOI:10.1021/jo1002642

pubs.acs.org/joc
Total Synthesis of (-)-Cleistenolide
Bernd Schmidt,* Oliver Kunz, and Anne Biernat
Institut fuer Chemie, Organische Synthesechemie, Universitaet Potsdam, Karl-Liebknecht-Strasse 24-25,
D-14476 Golm, Germany
bernd.schmidt@uni-potsdam.de
Received February 12, 2010
The first total synthesis of Cleistenolide, a novel natural product recently isolated from the
Annonaceae species Cleistochlamys kirkii Oliver, is described. The synthesis proceeds in six steps
and 18% overall yield, starting from an enantiopure C2-symmetric building block and using a
Sharpless epoxidation, a selective epoxide opening, and a ring-closing metathesis reaction.
Introduction
Natural products and their semisynthetic derivatives are
traditionally important drugs, drug candidates, or lead
structures for novel drugs.1,2 The comparatively high success
rate for lead structures based on natural products is com-
monly attributed to the presence of privileged structures.3 In
particular, numerous antibacterial agents are derived from
natural sources, and the search for novel compounds, their
synthesis, and synthetic modification is an important task
which is further stimulated by the emergence of drug-resis-
tant bacteria strains.4
Cleistochlamys kirkii Oliver is an Annonaceae species occur-
ring in Tanzania and Mozambique.5 Extracts of this plant are
used in traditional medicine as a remedy for the treatment of
wound infections, rheumatism, and tuberculosis.6 Recently,
Nkunya et al. investigated the chemical composition of organic
extracts from fruits, leaves, and stem and root barks of C. kirkii
Oliver and discovered, apart from some known heptenolides,
two novel plant constituents, which were named cleistenolide
(1) and cleistodienol (2) (Figure 1).7
FIGURE 1. Novel natural products from C. kirkii.
authors. It was reasoned that these biological activities sub-
stantiate the effectiveness of the traditional use of C. kirkii
Oliver. Herein, we report the first total synthesis of cleisteno-
lide (1), starting from an enantiomerically pure mannitol-
derived compound. Our synthesis confirms the absolute con-
figuration assigned to (-)-cleistenolide.
Results and Discussion
We envisaged (R,R)-1,5-hexadiene-3,4-diol (3) as a starting
material, which was first synthesized from D-mannitol by Rama
Rao et al. in 1987.8 Later, an alternative procedure was described
by Burke et al.9,10 and a slight modification by us.11 A synthesis
of ent-3 from L-tartrate and its application in natural product
synthesis have also been published.12 Compound 3has been used
as a building block in the synthesis of natural products13-31 and
For cleistenolide, antibacterial activity against Staphy-
lococcus aureus and Bacillus anthracis, as well as antifungal
activity against Candida albicans, were reported by these
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DOI: 10.1021/jo1002642
r
Published on Web 03/11/2010
J. Org. Chem. 2010, 75, 2389–2394 2389
2010 American Chemical Society

Schmidt et al.
JOCArticle
SCHEME 1. Proposed Synthesis of Cleistenolide
SCHEME 2. Epoxidation of Allylic Alcohol 4
SCHEME 3. RCM of an Acrylate Derived from 8
non-natural carbohydrate analogues.32,33 Very recently, 3and its
derivatives were used as chiral ligands in rhodium-catalyzed
conjugate additions.34
Originally, we planned to desymmetrize diol 3 by mono-
acetylation and to convert the resulting monoacetate 4 via
stereoselective OH-directed epoxidation and acryloylation
to compound 5. As final steps of the sequence we envisaged a
nucleophilic epoxide opening with benzoate, acetylation of
the newly formed OH-group, and ring-closing olefin meta-
thesis for the formation of the C3-C4 double bond. Because
scrambling of labile functional groups or protecting groups,
such as esters or silyl ethers, upon nucleophilic cleavage of
proximal epoxides is often a problem,35 we thought it might
be advantageous to perform the RCM step prior to the
epoxide opening (Scheme 1).
mixture of epimers, using either VO(acac)2 or Sharpless
conditions (Scheme 2).37,38
Taking this disappointing result into account, we expected
that the use of a protecting group would be overall advanta-
geous. In a previous project, we used benzyl-protected
epoxide 8, which is, in contrast to 7, conveniently available
from the enantiomerically pure precursor via Sharpless
epoxidation in excellent yield and diastereoselectivity if
L-(þ)-DET is used as a ligand.11 Epoxide 8 was previously
synthesized from racemic starting material using Sharpless
conditions.39 Although we are aware of the difficulties
associated with the selective removal of a benzyl protecting
group in the presence of C-C-double bonds, we decided to
use this starting material to check the feasibility of the
subsequent steps (Scheme 3).
To our surprise, the envisaged stereoselective epoxidation
of allylic alcohol 436 proceeded only in poor yield and
unsatisfactory diastereoselectivity. Thus, the required epox-
ide 7 was obtained in approximately 40% yield as a 3:1
(14) Burke, S. D.; Voight, E. A. Org. Lett. 2001, 3, 237–240.
(15) Voight, E. A.; Rein, C.; Burke, S. D. Tetrahedron Lett. 2001, 42,
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2002, 4, 467–470.
(17) Voight, E. A.; Rein, C.; Burke, S. D. J. Org. Chem. 2002, 67, 8489–
8499.
Epoxide 8 was first converted to the required acrylate 9,
which was then subjected to the conditions of a metathesis
reaction using the second-generation precatalyst A.40-42
Complete consumption of the starting material was observed
after a few hours; however, we could not isolate the desired
lactone 10 in pure form and in preparatively useful yield due
to formation of an unidentified byproduct, which could not
be removed by chromatography or crystallization. NMR
spectroscopy revealed an unsaturated lactone structure for
this byproduct, and several signals in the ether/epoxide
range. It should be stated that the integrity of the starting
material 9 was checked immediately before the RCM step;
thus, the RCM conditions are apparently responsible for the
rather sluggish conversion of acrylate 9 into lactone 10.
These problems prompted us to reconsider the choice of
(18) Voight, E. A.; Seradj, H.; Roethle, P. A.; Burke, S. D. Org. Lett.
2004, 6, 4045–4048.
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SCHEME 4. Synthesis of (-)-Cleistenolide (1)
TABLE 1. Conditions for Epoxide Opening of 13
benzoic acid Pri2NEt
(equiv)
cat. B
(equiv) (mol %) 13a (%) 14a (%) 16a (%)
entry
1b,c
2c
1.1
1.1
2.2
2.2
4.0
1.1
1.1
1.1
1.1
2.0
5
5
5
n.d.
n.d.
n.d.
n.d.
20
33
53
47
53e
16
12
12
6
3c
4c
5d
aYields of isolated products. bReaction conducted in MTBE (0.2 mL/
mmol). cProduct composition determined after 76 h at 20 °C. dProduct
composition determined after 46 h at 20 °C. eYield of 14 based on
recovered starting material is 66%.
obtained under Lewis- or Brønsted-acidic conditions. A first
success was achieved when the conditions described by
Khalafi-Nezhad et al.45 were used. These authors described
the cleavage of epoxides with benzoic acid catalyzed by
10 mol % of NBu4Br (TBAB) in acetonitrile. Application
of these conditions to our substrate 13 led to the recovery of
unreacted starting material. Therefore, the amount of TBAB
was gradually increased, and full conversion was achieved
with 2.0 equiv of TBAB. Unfortunately, numerous bypro-
ducts were formed, and only one defined product could be
isolated in 30% yield. A careful inspection of the 1H NMR
spectrum of this compound revealed that we did not obtain
the expected 14, but a regioisomer 16, which is obviously the
result of an intramolecular acrylate transfer. The next method
tested was inspired by work published by Jacobsen et al., who
used Co-salen complexes for the desymmetrization of meso-
epoxides with benzoic acid in the presence of Pri2NEt.46 To avoid
complications potentially arising from matched/mismatched
pairs, we did not use a chiral salen complex but the commercially
available achiral salcomine catalyst B, which has previously been
used for epoxide-opening reactions.47 The results obtained for
these experiments are summarized in Table 1. In the first
experiments (entry 1), small volumes of MTBE were used as a
solvent and 5 mol % of the cobalt catalyst B. Both the base and
the nucleophile, benzoic acid were used in a slight excess. TLC
revealed that no conversion occurred after 76 h, and upon
workup the starting material 13 was recovered unchanged.
In the following experiments the reaction was conducted in
the absence of any solvent under otherwise identical conditions.
The regioisomers 14 and 16 were obtained as a separable 2:1
mixture in a combined yield of 49% (entry 2). Increasing the
amount of benzoic acid to 2.2 equiv results in a significantly
improved yield of the desired 14 and a significantly improved
protecting groups and the order of steps. A route which was
eventually found to be viable is shown in Scheme 4.
Diol 3 was first protected as a TBS ether 11,43 which was
then subjected to the conditions of a Sharpless epoxida-
tion. As previously described for acetate 4 (Scheme 2), the
VO(acac)2-catalyzed epoxidation of 11 is very fast but
proceeds only with unsatisfactory stereoselectivity.44 By
using L-(þ)-DET in the Sharpless epoxidation the required
epoxide 1244 was obtained in good yield and excellent
selectivity (dr >19:1, 1H NMR spectroscopy), but the reac-
tion required rather long reaction times of up to 28 days.
Reducing the reaction time to 14 days provided the product
in a lower but still useful yield of 72%. The long reaction
times are somewhat surprising because the combination of
(R,R)-3 and L-(þ)-DET represents a matched pair. Fortu-
nately, the long reaction times are outweighed by the fact
that quantities of several grams of 12 are easily obtained per
batch. In the next step, the acrylate required for the RCM
step was introduced. We were aware of the potential pro-
blems resulting from this order of steps because the sub-
sequent nucleophilic epoxide cleavage with benzoic acid or a
benzoate might be hampered by a competing 1,4-addition or
inter- or intramolecular acrylate-transfer reactions. Never-
theless, we opted for this order of steps to minimize the
number of protecting group operations. The first attempts to
synthesize 14 from 13 and benzoic acid were indeed rather
discouraging. The use of Li-, Na-, K-, or Cs-benzoates in
solvents such as toluene, THF, DMF, or DMSO at various
temperatures resulted either in no conversion or in complete
decomposition of the starting material. Similar results were
(45) Khalafi-Nezhad, A.; Soltani Rad, M. N.; Khoshnood, A. Synthesis
2003, 2552–2558.
(43) Quinn, K. J.; Isaacs, A. K.; DeChristopher, B. A.; Szklarz, S. C.;
Arvary, R. A. Org. Lett. 2005, 7, 1243–1245.
(44) Schmidt, B.; Nave, S. Adv. Synth. Catal. 2006, 348, 531–537.
(46) Jacobsen, E. N.; Kakiuchi, F.; Konsler, R. G.; Larrow, J. F.;
Tokunaga, M. Tetrahedron Lett. 1997, 38, 773–776.
(47) Naeimi, H.; Moradian, M. Can. J. Chem. 2006, 84, 1575–1579.
J. Org. Chem. Vol. 75, No. 7, 2010 2391

Schmidt et al.
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TABLE 2. Optimization of RCM Conditions for Acrylate 14
entry
precatalyst A (mol %)
solvent
concn of 14a (mol/L)
T/°C
phenol (equiv)
time (h)
ratio 14:15b
yield of 15 (%)
1
2
3
4
5
5
5
5
10
5
toluene
C6F6
0.005
0.005
0.005
0.0025
0.002
0.004d
0.003d
110
80
110
40
110
60
70
none
none
0.5
0.5
0.5
16
16
3
4
3
2.5:1
>19:1
1.1:1
n.d.
n.d.
n.d.
n.d.
36
toluene
CH2Cl2
toluene
toluene
toluene
2.0:1
5
1:1.1
1:1.7
1:4.0
6c
0.5
0.5
6
6
56
75
7c
10
aInitial concentration of substrate 14, unless otherwise stated. bDetermined from the 1H NMR spectra of the crude reaction mixtures by integration of
baseline-separated signals. cSolutions of 14 and of precatalyst A in toluene were added to a solution of phenol in toluene at the appropriate temperature
over a period of 3 h; stirring was then continued for further 3 h. dConcentrations of 14 and 15 after completed addition: c = (n(14) þ n(15))/(total volume
of solvent).
SCHEME 5. Acrylate Migration under Desilylating Conditions
beneficial effect of high dilution in the ring-closing metath-
esis of acrylates was noted some time ago52 and was more
recently systematically investigated by us.53 Disappoint-
ingly, after 16 h in refluxing toluene a conversion of only
30% was observed (entry 1). Recently, Blechert et al.54 and
Grela et al.55 reported a promoting effect of hexafluoroben-
zene and other fluorinated aromatic hydrocarbons on olefin
metathesis reactions. We tried these conditions for the ring
closure of 14 but could not detect any conversion after 16 h at
80 °C (entry 2). In the next experiment, we returned to the
original conditions described in entry 1 and used 50 mol % of
phenol as a promoting additive (entry 3). With these condi-
tions, a significant improvement was observed: after just 3 h
a 1:1 ratio of starting material 14 and product 15 was
observed. The positive effect of phenol in difficult cross-
metathesis reactions was originally reported by Forman
et al.56 and recently exploited by us in ring-closing enyne
metathesis reactions.36 We tried to further improve the
reaction by using a lower initial substrate concentration
and a lower reaction temperature, in order to enhance the
catalyst lifetime, but this approach was not successful (entry
4). We then tested a higher catalyst loading of 10 mol %, in
combination with an initial substrate concentration of 2 ꢀ
10-3 M (entry 5). Remarkably, the result was virtually
identical with the one listed in entry 3: after 3 h, a conversion
of approximately 50% was observed, and the isolated yield
of 15 was 36%. Yields higher than 50% were eventually
obtained by using the promoting effect of phenol in combi-
nation with pseudo-high-dilution conditions and a reduced
reaction temperature for enhanced catalyst lifetime. In a first
experiment along these lines, a 4.6 ꢀ 10-3 M solution of
ratio of regioisomers (entry 3). Interestingly, virtually the same
result was obtained in the absence of the cobalt catalyst B, with
the isolated yield of the desired epoxide cleavage product 14
being only slightly lower (entry 4). Eventually, the best condi-
tions were found with 4.0 equiv of nucleophile and 2.0 equiv of
base in the absence of any solvent (entry 5). Under these
conditions, 53% of 14 was isolated, along with only minor
amounts of the regioisomer 16 and 20% of unreacted starting
material 13.
As the next step, we considered the cleavage of the TBS
group prior to the RCM step. We thought that this order
might be advantageous because OH-directing and activating
effects11,36,48-50 should facilitate the metathesis reaction. It
has, however, been previously described in the literature that
the cleavage of a TBS ether with an acetate in the vicinity can
result in the formation of regioisomeric alcohols due to
intramolecular acetyl group transfer.51 We checked the
chances of success for a desilylation in the presence of an
acrylate and a benzoate in the same molecule for compound
16: upon treatment with TBAF at 0 °C two products, most
likely regioisomers 17a and 17b, were obtained as an insepar-
able mixture. To verify the formation of 17b, the mixture was
subjected to the conditions of a ring-closing metathesis using
5 mol % of A. Only one product was isolated, which was
identified as the γ-butyrolactone 18 (Scheme 5).
phenol in toluene was preheated to 60 °C, and a 1.8 ꢀ 10-2
M
solution of 14 in toluene and a 0.9 ꢀ 10-3 M solution of
precatalyst A in toluene were simultaneously added over 3 h.
After the completed addition, the reaction temperature was
maintained for another 3 h. Under these conditions, corres-
ponding to an overall substrate concentration of 4 ꢀ 10-3
M
and a catalyst loading of 5 mol %, a conversion of ca. 65%
and a yield of 56% were obtained (entry 6). Finally, a
The chances to suppress the acrylate migration are rather
small, and we therefore decided to use the TBS-protected
diene 14 for the RCM reaction. This step required consider-
able optimization (Table 2). In a first attempt to obtain 15,
5 mol % of second-generation precatalyst A and an initial
substrate concentration of 5 ꢀ 10-3 M were used. The
€
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2392 J. Org. Chem. Vol. 75, No. 7, 2010

Schmidt et al.
JOCArticle
conversion of 80% and a preparatively useful yield of 75%
were obtained with a 2.3 ꢀ 10-3 M solution of phenol in
toluene, preheated to 70 °C, and simultaneous addition of a
DIPEA (2.3 mL, 13.4 mmol) was added 13 (2.00 g, 6.7 mmol). The
mixture was stirred at ambient temperature for 46 h. The reaction
was diluted with CH2Cl2 (25 mL) and quenched by addition of
water, and the aqueous layer was extracted three times with diethyl
ether (20 mL). The combined organic layers were washed with
NaHCO3 (aq) solution and with brine, dried with MgSO4, filtered,
and evaporated. The residue was purified by columm chromatog-
raphy on silica to give the title compound 14 (1.50 g, 53%), its regio-
isomer 16 (0.18 g, 6%), and unreacted starting material 13 (0.39 g,
20%). (2R,3R,4R)-3-(Acryloyloxy)-4-(tert-butyldimethylsilyloxy)-
2-hydroxyhex-5-enyl benzoate (14): [R]23D þ51.5 (c 1.56, CH2Cl2);
1H NMR (300 MHz, CDCl3) δ 8.06-8.01 (d, J = 7.7, 2H), 7.53
(t, J = 7.3, 1H), 7.41 (dd, J = 7.7, 7.3, 2H), 6.42 (dd, J = 17.3, 1.4,
1H), 6.09 (dd, J = 17.3, 10.4, 1H), 5.93 (ddd, J = 17.1, 10.5, 5.3,
1H), 5.84 (dd, J = 10.4, 1.4, 1H), 5.38 (ddd, J = 17.2, 1.5, 1.5, 1H),
5.28 (ddd, J = 10.5, 1.4, 1.4, 1H), 5.08 (dd, J = 7.8, 4.4, 1H), 4.56
(dddd, J = 5.4, 4.4, 1.5, 1.3, 1H), 4.51 (dd, J = 9.1, 4.7, 1H), 4.28
(dd, J = 9.1, 5.1, 1H), 4.28 (m, 1H), 3.64 (d, J = 1.4, 1H), 0.90
(s, 9H), 0.10 (s, 3H), 0.05 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
166.6 (0), 164.9 (0), 135.3 (1), 133.0 (1), 131.9 (2), 129.9 (0), 129.7
(1), 128.3 (1), 127.8 (1), 117.6 (2), 73.3 (1), 72.9 (1), 69.0 (1), 65.7
(2), 25.7 (3), 18.1 (0), -4.8 (3), -5.2 (3); IR (neat) ν3486 (bw), 2955
(w), 2930 (w), 2857 (w), 1723 (s), 1405 (m), 1255 (s); LRMS (ESI)
m/z 289 (100), 403 (60), 421 (Mþ þ H, 16); HRMS (ESI) calcd for
C22H33O6Siþ (Mþ þ H) 421.2046, found 421.2039. Anal. Calcd for
C22H32O6Si (420.57): C, 62.8; H, 7.7. Found: C, 62.6; H, 7.7.
(2R,3R,4R)-2-(Acryloyloxy)-4-(tert-butyldimethylsilyloxy)-3-hydroxy-
hex-5-enyl benzoate (16): 1H NMR (500 MHz, CDCl3) δ 8.02-7.99
(2H), 7.54 (t, J = 7.5, 1H), 7.42 (dd, J = 7.5, 7.5, 2H), 6.43 (dd, J =
17.3, 1.3, 1H), 6.14 (dd, J = 17.3, 10.4, 1H), 5.94 (ddd, J = 17.4, 10.4,
7.3, 1H), 5.85 (dd, J = 10.5, 1.4, 1H), 5.27 (ddd, J = 17.3, 1.2, 1.2,
1H), 5.22 (ddd, J = 10.5, 1.2, 1.2, 1H), 5.20 (ddd, J = 7.9, 5.7, 2.7,
1H), 4.82 (dd, J= 12.2, 2.7, 1H), 4.57 (dd, J= 12.2, 5.7, 1H), 4.21 (dd,
J = 7.3, 3.3, 1H), 3.75 (ddd, J = 7.7, 7.7, 3.3, 1H), 2.71 (d, J = 7.6,
1H), 0.91 (s, 9H), 0.10 (s, 3H), 0.07 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 166.2 (0), 165.1 (0), 137.9 (1), 133.0 (1), 131.5 (2), 130.0 (0),
129.7 (1), 128.3 (1), 128.1 (1), 117.2 (2), 73.3 (1), 73.1 (1), 71.5 (1), 63.2
(2),25.8(3),18.1(0),-4.0 (3), -5.1 (3); IR (neat) ν1724(s),1404(m),
1254 (s), 834 (s); LRMS (ESI) m/z 217 (50), 289 (100), 421 (Mþ þ H,
41), 443 (Mþ þ Na, 38); HRMS (ESI) calcd for C22H33O6Siþ (Mþ þ
H) 421.2046, found 421.2057.
1.8 ꢀ 10-2 M solution of 14 in toluene and a 1.8ꢀ 10-3
M
solution of precatalyst A in toluene. This corresponds to a
total concentration of 3ꢀ 10-3 M and a catalyst loading of
10 mol % (entry 7).
Completion of the synthesis required desilylation of 15
and acetylation of the two secondary alcohols. This was most
conveniently achieved as a one-flask reaction in THF by
addition of TBAF and subsequently of acetic acid anhydride.
Notably, the desilylation/double acetylation proceeds in the
absence of additional base and gratifyingly without any
migration of the benzoyl group. Thus, analytically pure
(-)-cleistenolide (1) was obtained as a single regio- and
stereoisomer in a yield of 66%. Melting point, elemental
1
analysis, HRMS, IR, and H and 13C NMR data are in
accord with the structure assigned to cleistenolide and match
the values reported by Nkunya et al. for the material iso-
lated from the natural source.7 The only discrepancy was
discovered for the specific rotation: we observed in re-
peated measurements a value of [R]24D = -165 for synthetic
cleistenolide (1), whereas a significantly lower value of
[R]D=-63.5 was reported in the literature.7 However, as
both natural and synthetic cleistenolide are levorotatory,
we conclude that the absolute configuration assigned to
(-)-cleistenolide (Figure 1) is correct.
Conclusions
In conclusion, we report the first total synthesis of the
recently discovered antibiotic and antifungal plant constitu-
ent (-)-cleistenolide. The synthesis was achieved in six steps
and 18% overall yield from (R,R)-hexa-1,5-diene-3,4-diol
(derived from D-mannitol) and confirms the assigned absolute
configuration. Key features of our route to (-)-cleistenolide are
the efficient utilization of the C2 symmetry of the starting
material, a Sharpless epoxidation, a selective epoxide opening
with benzoic acid, and a ring-closing metathesis reaction.
Optimized Procedure for the Synthesis of (R)-2-((2R,3R)-
3-(tert-Butyldimethylsilyloxy)-6-oxo-3,6-dihydro-2H-pyran-2-yl)-
2-hydroxyethyl Benzoate (15). A solution of phenol (37 mg, 0.39
mmol) in toluene (200 mL) was heated to 70 °C. Precatalyst A
(67mg, 10mol%) intoluene(50mL) and14 (330 mg, 0.78 mmol) in
toluene (50 mL) were added simultaneously over 3 h at 70 °C. The
solution was stirred for another 3 h at this temperature and then
cooled to ambient temperature, and the solvent was evaporated. The
residue was purified by columm chromatography on silica to give
the title compound 15 (230 mg, 75%) as a colorless solid: mp
118-120 °C; [R]23D -130.9 (c 0.34, CH2Cl2); 1H NMR (600 MHz,
CDCl3) δ 8.03 (dd, J = 8.4, 1.3, 2H), 7.56 (t, J = 7.4, 1H), 7.42
(dd, J = 7.8, 7.8, 2H), 6.93 (dd, J = 9.7, 5.8, 1H), 6.10 (d, J = 9.7,
1H), 4.83 (dd, J = 12.2, 2.3, 1H), 4.57 (dd, J = 12.1, 4.5, 1H), 4.47
(dd, J = 5.8, 2.3, 1H), 4.31 (m, 1H), 4.28 (dd, J = 9.2, 2.2, 1H), 3.14
(d, J = 4.1, 1H), 0.87 (s, 9H), 0.14 (s, 3H), 0.10 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 167.6 (0), 162.6 (0), 144.4 (1), 133.3 (1), 129.7
(1), 129.4 (0), 128.4 (1), 122.6 (1), 79.1 (1), 67.6 (1), 60.0 (1), 66.1 (2),
25.6 (3), 18.0 (0), -4.3 (3), -4.9 (3); IR (neat) ν 3533 (bw), 2927 (w),
2855 (w), 1704 (s), 1260 (m), 1120 (m), 1094 (m), 1064 (m); LRMS
(ESI) m/z 375 (12), 393 (Mþ þ H, 100); HRMS (ESI) calcd for
C20H29O6Siþ (Mþ þ H) 393.1733, found 393.1702. Anal. Calcd for
C20H28O6Si (392.54): C, 61.2; H, 7.2. Found: C, 61.0; H, 7.2.
(-)-Cleistenolide (1). To a solution of 15 (150 mg, 0.38 mmol)
in dry and degassed THF (10 mL) was added TBAF (133 mg,
0.42 mmol). The mixture was stirred at ambient temperature for
5 min, and then acetic anhydride (144 μL, 1.52 mmol) was
Experimental Section
(1R,2R)-2-(tert-Butyldimethylsilyloxy)-1-((R)-oxiran-2-yl)-
but-3-enyl Acrylate (13). To a solution of 12 (2.00 g, 8.2 mmol) in
CH2Cl2 (80 mL) were added DIPEA (7.6 mL, 24.6 mmol) and
acryloyl chloride (1.7 mL, 21.3 mmol) at 0 °C. The mixture was
allowed to warm to ambient temperature and stirred for 3 h. The
reaction was quenched by addition of water, and the aqueous layer
was extracted three times with diethyl ether (30 mL). The combined
organic layers were washed with NH4Cl (aq) solution and with
brine, dried with MgSO4, filtered, and evaporated. The residue was
purified by column chromatography to give 13 (2.25 g, 92%): [R]25
D
þ37.5 (c 1.07, CH2Cl2);1H NMR (300 MHz, CDCl3) δ6.40 (d, J =
17.3, 1H), 6.10 (dd, J = 17.3, 10.4, 1H), 5.86 (ddd, J = 17.5, 10.5,
5.9, 1H), 5.85 (d, J = 10.7, 1H), 5.32 (d, J = 17.2, 1H), 5.20 (d, J =
10.4, 1H), 4.82 (dd, J = 5.0, 5.0, 1H), 4.40 (dd, J = 5.4, 5.3, 1H),
3.17 (ddd, J = 7.0, 4.8, 3.2, 1H), 2.80-2.70 (2H), 0.90 (s, 9H), 0.10
(s, 3H), 0.05 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 165.0 (0), 136.4
(1), 131.3 (2), 128.1 (1), 116.9 (2), 74.6 (1), 73.2 (1), 49.5 (1), 45.13
(2), 25.7 (3), 18.0 (0), -4.6 (3), -5.1 (3); IR (neat) ν 2930 (w), 2857
(w), 1730 (w), 1183 (m); LRMS (ESI) m/z 227 (100), 299 (M - H,
10), 321 (M þ Na, 13); HRMS (ESI) calcd for C15H26NaO4Siþ
(Mþ þ Na) 321.1498, found 321.1505.
Optimized Procedure for the Epoxide-Opening Reaction of 13 with
Benzoic Acid. To a solution of benzoic acid (3.20 g, 26.8 mmol) in
J. Org. Chem. Vol. 75, No. 7, 2010 2393

Schmidt et al.
JOCArticle
added. The solution was stirred for 1 h at ambient tempera-
ture. The reaction was quenched by addition of water, and the
aqueous layer was extracted three times with diethyl ether
(10 mL). The combined organic layers were washed with NH4Cl
(aq) solution and with brine, dried with MgSO4, filtered, and
evaporated. The residue was purified by column chromato-
graphy to give (-)-cleistenolide (1) (90 mg, 66%) as a colorless
solid: mp 133-134 °C; [R]24D -164.6 (c 0.48, CH2Cl2); 1H NMR
(300 MHz, CDCl3) δ 8.01 (d, J = 7.7, 2H), 7.57 (t, J = 7.5, 1H),
7.44 (dd, J = 7.7, 7.4, 2H), 7.00 (dd, J = 9.7, 6.1, 1H), 6.29 (d,
J = 9.7, 1H), 5.51 (ddd, J = 9.6, 4.4, 2.4, 1H), 5.41 (dd, J = 6.1,
2.6, 1H), 4.93 (d, J = 12.5, 2.4, 1H), 4.80 (dd, J = 9.6, 2.7, 1H),
4.52 (dd, J = 12.5, 4.4, 1H), 2.08 (s, 3H), 2.04 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 169.8 (0), 169.4 (0), 165.9 (0), 161.0 (0), 139.7
(1), 133.2 (1), 129.6 (0), 129.6 (1), 128.5 (1), 125.3 (1), 75.5 (1),
67.7 (1), 62.0 (2), 59.7 (1), 20.6 (3), 20.4 (3); IR (neat) ν 2963 (w),
1725 (s), 1452 (m), 1372 (m), 1224 (s), 1099 (s), 1070 (s); LRMS
(ESI) m/z 139 (48), 241 (100), 303 (35), 363 (Mþ þ H, 61);
HRMS (ESI) calcd for C18H19O8þ (Mþ þ H) 363.1080, found
363.1093. Anal. Calcd for C18H18O8 (362.33): C, 59.7; H, 5.0.
Found: C, 59.4; H, 4.9.
Acknowledgment. This work was generously supported
by the Deutsche Forschungsgemeinschaft (DFG-grant
Schm 1095/6-1). We thank Evonik Oxeno for generous
donations of solvents.
Supporting Information Available: Experimental proce-
dures, analytical data, and copies of 1H and 13C NMR spectra
for all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
2394 J. Org. Chem. Vol. 75, No. 7, 2010