Total synthesis and evaluation of the actin-binding properties of microcarpalide and a focused library of analogues

Article abstract of DOI:10.1002/chem.200601370

A comparative investigation shows that hydroxylated 10-membered lactones modeled around the fungal metabolites microcarpalide (1) and pinolidoxin (2) are endowed with selective actin-binding properties. Although less potent than the marine natural product

Full text of DOI:10.1002/chem.200601370

DOI: 10.1002/chem.200601370
Total Synthesis and Evaluation of the Actin-Binding Properties of
Microcarpalide and a Focused Library of Analogues
Alois Fürstner,*[a] Takashi Nagano,[a] Christoph Müller,[a] Günter Seidel,[a] and
Oliver Müller[b]
Abstract: A comparative investigation
shows that hydroxylated 10-membered
lactones modeled around the fungal
metabolites microcarpalide (1) and pi-
nolidoxin (2) are endowed with selec-
tive actin-binding properties. Although
less potent than the marine natural
product latrunculin A, which repre-
sents the standard in the field, noneno-
lides of this type are significantly less
toxic and accommodate substantial
structural editing. Most notable is the
fact that even an intramolecular trans-
esterification with formation of a hy-
droxylated butanolide skeleton does
not annihilate their microfilament dis-
rupting capacity. This finding calls for a
reinvestigation of the biological profile
of other fungal metabolites that
embody a similar motif. Microcarpalide
(1) serving as the calibration point for
this comparative study was prepared
by total synthesis based on ring-closing
metathesis (RCM) as the key step. The
chosen route favorably compares to
previous approaches to this target and
provides further support for the notion
that the (E,Z)-configuration of
a
medium-sized cycloalkene can be con-
trolled by proper choice of the catalyst
as previously outlined by our group. 9-
epi-Microcarpalide 26 and furanone 27
as representative examples of the “nat-
ural productlike” compounds investi-
gated herein have been characterized
by crystal structure analysis.
Keywords:
actin
·
lactones
·
medium-sized rings · metathesis ·
natural products
Introduction
Bioassay-guided fractionation of the culture broth of an un-
identified endophytic fungus hosted by a Ficus microcarpa
L. plant in Hawaii led to the isolation of microcarpalide
(1).[1] This nonenolide showed antimicrofilament activity at
a concentration of ꢀ5 mgmLꢁ1, leading to a 50–75% loss of
the regular actin cytoskeleton in A-10 (rat smooth muscle)
cells. Thereby, the reported cytotoxicity of 1 is remarkably
low, with IC50 values for the KB- and LoVo cancer cell lines
being as high as 50 and 90 mgmLꢁ1, respectively.[1] This very
significant difference in the bioactivity thresholds recom-
mends microcarpalide as a potential lead structure en route
to selective, nontoxic antiactin agents[2] for use in chemical
biology, medicinal chemistry, and crop protection. Actin is
[a] Prof. A. Fürstner, Dr. T. Nagano, Dipl.-Chem. C. Müller,
Ing. G. Seidel
the most abundant protein in eukaryotic cells; it determines
their shape and mechanical properties, effects cell locomo-
tion, is responsible for strength development in muscles, and
enables motility processes as fundamental as cytokinesis as
well as exo- and endocytosis.[3]
Max-Planck-Institut für Kohlenforschung
45470 Mülheim/Ruhr (Germany)
Fax : (+49)208-306-2994
E-mail: fuerstner@mpi-muelheim.mpg.de
[b] O. Müller
As part of our ongoing program on the identification, syn-
thesis, chemical modification, and biological evaluation of
Max-Planck-Institut für Molekulare Physiologie
44227 Dortmund (Germany)
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FULL PAPER
actin-binding small molecules,[4–6] we chose this particular
medium-sized lactone as the starting point for further inves-
tigations. Our interest was reinforced by the resemblance of
1 to other nonenolides of fungal origin previously prepared
in this laboratory (structures 2–4).[7,8] Pinolidoxin 2[9] and
the closely related herbarumins 3 and 4[10] are promising
phytotoxic agents interfering with the defense metabolism
of higher plants; they consist of a similar (E)-configured
nonenolide skeleton decorated with hydroxyl groups and a
hydrophobic appendage.[11] Therefore, it seemed appropriate
to investigate if 2–4 and selected derivatives thereof also ex-
hibit any appreciable microfilament disrupting capacity and,
if so, to compare their efficacy with that of microcarpalide
(1) as the lead compound in this series.
Our approach to herbarumin and pinolidoxin was based
on ring-closing olefin metathesis (RCM) for the formation
of the strained 10-membered ring.[12] During this synthesis
campaign we were able to show that the proper choice of
catalyst determines the stereochemical outcome of the cycli-
zation reaction in a predictable fashion.[8,13] Specifically, the
use of the first-generation ruthenium carbene complexes
5[14] or 6[15] provided the desired (E)-alkenes with good to
Scheme 1. a) l-Dicyclohexyl tartrate, TiACTHER(UNG OiPr)4, tBuOOH, MS 4 Š,
CH2Cl2, 40% (of theoretical 50%, ee=98%); b) TBSOTf, 2,6-lutidine,
CH2Cl2, 08C, quant.; c) pentylmagnesium bromide, CuBr·SMe2, THF,
ꢁ78!ꢁ58C, 80%; d) MOMCl, (iPr)2NEt, catalytic DMAP, CH2Cl2,
85%; e) TBAF, THF, 84%. TBS=tert-butyldimethylsilyl; MOM=me-
thoxymethyl; DMAP=4-dimethylaminopyridine; TBAF=tetrabutylam-
monium fluoride.
(Scheme 2).[24] Exploiting the inherent preference of osmyla-
tion reactions for more electron-rich olefins, the internal
double bond of 15 reacted preferentially in the subsequent
excellent selectivity, whereas a second-generation catalyst,
such as 7,[16] engenders an equilibration process leading to
the thermodynamically more stable (Z)-isomers. This con-
cept of “catalyst control”[8] was later successfully extended
to a variety of other medium-sized ring derivatives,[17–19] in-
cluding microcarpalide itself.[20,21] To gain access to sufficient
quantities of this lead compound for the planned microfila-
ment assays, it, therefore, sufficed to develop a novel and
practical route to the required diene substrate, whereas the
final steps of the total synthesis could gravitate toward this
validated catalyst-controlled RCM methodology.
Scheme 2. a) MeC
b) AD-mix-b, MeSO2NH2, tBuOH/H2O, 5 8C; c) catalytic pTsOH,
MeOH, 54% (over two steps, ee=99%); d) Me2C(OMe)2, catalytic
ACHTRE(UNG OEt)3, propionic acid cat., reflux, cf. reference [24c];
AHCTREUNG
pTsOH, MeOH; e) KOH, MeOH, 93% (over two steps).
To this end, allyic alcohol 8 underwent a Sharpless kinetic
resolution, furnishing multigram quantities of the epoxyalco-
hol 9 in excellent optical purity (ee=98%) (Scheme 1).[22,23]
Temporary protection of the OH group as a TBS-ether fol-
lowed by copper-mediated opening of the oxirane ring in 10
with pentylmagnesium bromide gave alcohol 11, which was
converted into product 13 by two routine manipulations.
The required acid segment 20 was accessible from cheap
divinyl carbinol 14, which was transformed on a large scale
asymmetric Sharpless dihydroxylation.[25] The undesired ter-
minal diol byproduct 17 could be conveniently removed
after the crude reaction mixture had been treated with cata-
lytic amounts of p-toluenesulfonic acid in methanol, which
converted 16 into lactone 18 but left diol 17 untouched; be-
cause of the large difference in the polarity of these com-
pounds, they can be easily separated by flash chromatogra-
phy. Treatment of lactone 18 with acetone dimethylacetal in
methanol under slightly acidic conditions resulted in con-
into 15 by
a standard Johnson–Claisen rearrangement
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A. Fürstner et al.
comitant ring opening and acetal formation. Saponification
of the resulting ester 19 under standard conditions furnished
the required acid 20 in good overall yield.
Esterification of 13 and 20 with inversion of configura-
tion[27] at the alcoholic center set the correct stereochemistry
for the synthesis of 1 (Scheme 3). In line with our expecta-
annular proximity of the substituents on the 10-membered
frame and likely driven by the release of ring strain. A simi-
lar result was observed in the epimeric series (vide infra).
Esterification of 13 and 20 with retention of configuration
opened access to 9-epi-microcarpalide 26 (Scheme 4). The
Scheme 4. a) DCC, catalytic DMAP, CH2Cl2, 84%; b) catalyst
5
(20 mol%), CH2Cl2 (0.001m), reflux, 85% (E only); c) HSCH2CH2SH,
BF3·Et2O, CH2Cl2, 08C, 62%; d) catalyst 7 (20 mol%), 94% (E:Z 1.1:1);
e) HSCH2CH2SH, BF3·Et2O, CH2Cl2, 08C, 24%.
Scheme 3. a) DEAD, PPh3, 60%; b) catalyst
(0.001m), reflux, 72% (E:Z 2.3:1); c) HSCH2CH2SH, BF3·Et2O, CH2Cl2,
08C, 74%; d) catalyst
(20 mol%), 66% (+traces of (E)-22);[18a]
5 (20 mol%), CH2Cl2
7
e) HSCH2CH2SH, BF3·Et2O, CH2Cl2, 08C, 32%. DEAD=(Z)-1,2-dia-
zene-dicarboxylate
concept of “kinetic versus thermodynamic control” previ-
ously introduced by our group[8,13,17] could also be imposed
upon the ring closure of the resulting diene 24. Thus, the use
of complex 5 as the catalyst furnished (E)-25 exclusively,
whereas the second generation ruthenium carbene 7, under
otherwise identical conditions, led to the formation of ap-
preciable amounts of (Z)-25. In line with the results outlined
above, the cleavage of the acetal groups with ethane-1,2-di-
thiol and BF3·Et2O[21a] engendered a trans-lactonization of
(Z)-25 to furnanone 27, whereas the 10-membered ring re-
mained intact in the (E)-series. The structures assigned to 9-
epi-microcarpalide 26 and the ring-contracted isomer 27
were confirmed by single-crystal structure analysis (Fig-
ures 1 and 2).
tions,[8,13,17,20] treatment of the resulting diene 21 with cata-
lytic amounts of the ruthenium carbene complex 5 in dilute
CH2Cl2 solution resulted in an effective cyclization of the
10-membered ring, delivering (E)-22 as the major product;
in contrast, the use of catalyst 7 gave (Z)-22 exclusively.
These isomeric lactones were then deprotected with ethane-
1,2-dithiol and BF3·Et2O, following a literature protocol.[21a]
Under these conditions, compound (E)-22 afforded (ꢁ)-mi-
crocarpalide 1 in 74% yield as a colorless syrup, the analyti-
cal and spectroscopic properties of which matched those of
the natural product in every respect.[1,20,21] Its (Z)-configured
analogue (Z)-22, however, reacted much less cleanly. More-
over, careful examination of the NMR spectroscopic and
MS data of the resulting major product showed that a lac-
tone interconversion had occurred, resulting in the forma-
tion of butanolide 23. This reaction is enabled by the trans-
The preparation of a suitable collection of pinolidoxin an-
alogues for biological testing largely followed the previously
established route to the parent compound 2;[8] however, the
synthesis of the required acid segment 32 was improved
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Microcarpalide
FULL PAPER
Figure 1. Molecular crystal structure of 9-epi-microcarpalide 26 in the
solid state. Anisotropic displacement parameters are drawn at the 50%
probability level.
Figure 2. Molecular crystal structure of butanolide 27 in the solid state.
Anisotropic displacement parameters are drawn at the 50% probability
level.
over prior art (Scheme 5). Formation of the (E)-cycloalkene
35 from diene 34 was ensured by the use of the ruthenium
indenylidene complex 6[15,28,29] as a readily available and
cheap substitute for the classical Grubbs catalyst 5. Com-
pound 35 thus obtained was then transformed into the
parent nonenolide 2, the corresponding ether 36, as well as
several esters of different polarity (38–40).
Figure 3. Fluorescence micrographs (250”) of NIH/3T3 fibroblast cells
allowing a direct comparison of the microfilament disrupting activity of
microcarpalide and related compounds. The actin filament is stained with
fluorescence-marked phalloidin, the nuclei with 2-(4-amidinophenyl)-6-
indolecarbamidine hydrochloride (DAPI). I: untreated cells; II: after in-
cubation with 1 (5 mm); III: after incubation with 2 (5 mm); IV: after incu-
bation with 27 (5 mm).
Evaluation of the actin-binding properties: Microcarpalide
1, its epimer 26, the corresponding butanolides 23 and 27,
the naturally occurring nonenolides herbarumin 4 and pino-
lidoxin 2, synthetic 7,8-bis-epi-pinolidoxin 41,[8] as well as
the collection of newly prepared derivatives 36–40 described
above, underwent a standardized assay allowing the effect
of small molecules on the actin cytoskeleton to be deter-
mined.
Specifically, NIH/3T3 fibroblasts were incubated with
DMSO solutions of the respective compounds at different
concentrations and the induced morphological changes were
visualized by staining the actin cytoskeleton of the cells with
fluorescene-marked phalloidin. In parallel, the number of
living cells were counted after an incubation time of 24 h as
an estimate for the toxicity of the compounds at a given
concentration.
for the entire series, except for 38 and 41 which were only
marginally active at this concentration. As can be seen from
Figure 3 (micrograph III), pinolidoxin 2 elicits a similar or
even stronger response than 1. Particularly noteworthy, how-
ever, is our finding that even the rearranged products 23
and 27 remain functional and exhibit an appreciable potency
(Figure 3, micrograph IV). This result shows that an intact
10-membered frame is not necessary to induce severe actin
malformation and raises the question whether other butano-
lides might share this particular biological profile. Potential
candidates are the sapinofuranones 44 and 45:[31] much like
microcarpalide and pinolidoxin, these compounds are secon-
dary metabolites of a phytopathogenic fungus that instigates
a wide range of disease symptoms of conifers and causes
In accordance with the published data for the A-10 cell
line,[1] incubation of the NIH/3T3 fibroblasts with microcar-
palide (1) at a 5 mm concentration resulted in clearly detect-
able actin microfilament disruption (Figure 3, micrograph
II). Importantly, however, similar potencies were observed
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A. Fürstner et al.
43,[4,5,32] the compounds investi-
gated herein are less effective
microfilament
disrupting
agents. However, they have the
bonus of being much less toxic
than 42; only for 39 was the
number of living cells reduced
to approximately 40% after
24 h of treatment. In all other
cases investigated, the entire fi-
broblast cell population contin-
ues to grow and metabolize
even upon incubation with
10 mm of the respective agent.
This finding corroborates the
significant differential between
antimicrofilament activity and
cytotoxicity previously noted
for the parent compound 1,[1]
and shows that this favorable
profile is retained throughout a
sizable number of analogues.
Conclusion
The first comparative investiga-
tion of the actin-binding prop-
erties of microcarpalide (1) and
other naturally occurring none-
nolides is reported. Although
their effects on actin are less
pronounced than those of the
latrunculins, which represent
the standard in the field,[4,32]
their toxicity index is more fa-
vorable. Moreover, it is demon-
Scheme 5. a) Hydrolytic kinetic resolution, cf. reference [30]; b) p-MeOC6H4CHACTHER(UNG OMe)2, camphorsulfonic acid
(10%), CH2Cl2, 59%; c) DIBAL-H, toluene, 08C!RT, 83 % (+17% of regioisomer); d) i) (COCl)2, DMSO,
Et3N, CH2Cl2, ꢁ788C!RT; ii) NaClO2, NaH2PO4, 2-methyl-2-butene, tBuOH/H2O, quant.; e) 2,4,6-trichloro-
benzoyl chloride, Et3N, catalytic DMAP, toluene, then alcohol 33, 89%; f) complex 6 (10 mol%), CH2Cl2,
reflux, 77% (+18% of Z isomer); g) HCl (1m), MeOH/H2O, 60 8C, 87%; h) DDQ, CH2Cl2, 90%; i) carboxylic
acid, 2,4,6-trichlorobenzoyl chloride, Et3N, catalytic DMAP, toluene, then alcohol 37; j) HCl (1m), MeOH/
H2O, 60 8C, 94% (38), 86% (39), 94% (40). DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone; DIBAL-H=
diisobutylaluminum hydride.
considerable damage in Pinus plantations around the world.
Not only is their structural resemblance to 23 and 27 strik-
ing, but it is also noteworthy that they exist in both enantio-
meric forms in nature, although in different fungal strains.[31]
Compared with the well-known actin-binding macrolides
latrunculin A (42) and its equipotent synthetic congener
strated that the basic nonenolide frame accommodates sig-
nificant structural changes without noticeable alterations of
the microfilament disrupting capacity. Therefore microcar-
palide and its at least equipotent congener pinolidoxin (2)
constitute validated leads in the quest for nontoxic actin-
binding agents. Most remarkable with regard to structure/ac-
tivity relationships is the finding that even the rearrange-
ment of the medium-sized lactone to a butanolide scaffold,
as found in compounds 23 and 27, does not engender loss of
bioactivity. As the latter skeleton is readily accessible by
more direct routes, an evaluation of this new hit is warrant-
ed and should be straightforward. It also remains to be seen
if closely related butanolides produced by other phytopatho-
genic fungi, such as the sapinofuranones, are endowed with
similar actin-disrupting properties.
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Microcarpalide
FULL PAPER
(c=1.02 in CHCl3); 1H NMR (400 MHz, CDCl3): d=5.80 (ddt, J=17.3,
8.7, 5.3 Hz, 1H), 5.07–4.97 (m, 2H), 4.75 (d, J=6.7 Hz, 1H), 4.58 (d, J=
6.6 Hz, 1H), 3.67 (ddd, J=8.3, 5.7, 3.3 Hz, 1H), 3.49–3.46 (m, 1H), 3.35
(s, 3H), 2.36–2.12 (m, 2H), 1.50–1.40 (m, 3H), 1.25–1.21 (m, 7H), 0.85–
0.83 (m, 12H), 0.06 (s, 3H), 0.04 ppm (s, 3H); 13C NMR (100 MHz,
CDCl3): d=135.8, 116.7, 96.2, 80.2, 74.3, 55.8, 37.6, 31.9, 30.7, 29.4, 29.4,
25.9, 25.9, 25.9, 22.6, 18.1, 14.1, ꢁ4.4, ꢁ4.5 ppm; IR (film): n˜ =3077, 2955,
2929, 2857, 2822, 1642, 1472, 1464, 1361, 1255, 1152, 1102, 1040, 915, 836,
776 cmꢁ1; MS (EI): m/z (%): 303 (8), 287 (13), 257 (67), 225 (5), 201 (26),
185 (83), 159 (14), 129 (15), 119 (27), 89 (70), 73 (75), 45 (100); HRMS
(EI): m/z: calcd for C19H40O3Si+Na: 367.2639 [M++Na]; found:
367.2637; elemental analysis calcd (%) for C19H40O3Si: C 66.22, H 11.70;
found: C 66.18, H 11.64.
Experimental Section
General methods: All reactions were carried out in flame-dried glassware
under Ar. The solvents were purified by distillation over the drying
agents indicated and were transferred under Ar: THF, Et2O, 1,4-dioxane
(Mg/anthracene), CH2Cl2 (P4O10), MeCN, Et3N, pyridine (CaH2), MeOH
(Mg), DMF (Desmodur, dibutyltin dilaurate), hexane, toluene (Na/K).
Flash chromatography: Merck silica gel 60 (230–400 mesh). NMR spectra
were recorded on a Bruker DPX 300 or AV 400 spectrometer in the sol-
vents indicated; chemical shifts (d) are given in ppm relative to TMS,
coupling constants (J) in Hz. The solvent signals were used as references
and the chemical shifts converted to the TMS scale (CDCl3: dC =
77.0 ppm; residual CHCl3 in CDCl3: dH =7.24 ppm; CD2Cl2: dC =
53.8 ppm; residual CH2Cl2 in CD2Cl2: dH =5.32 ppm). IR: Nicolet FT-
7199 spectrometer, wavenumbers (l) in cmꢁ1. MS (EI): Finnigan MAT
8200 (70 eV), ESIMS: Finnigan MAT 95, accurate mass determinations:
Bruker APEX III FT-MS (7 T magnet). Melting points: Büchi melting
point apparatus B-540 (corrected). Elemental analyses: H. Kolbe, Mül-
heim/Ruhr. All commercially available compounds (Fluka, Lancaster, Al-
drich) were used as received.
AHCTRE(UNG 4R,5S)-5-(Methoxymethoxy)-1-undecen-4-ol (13): A solution of com-
pound 12 (357 mg, 1.04 mmol) and TBAF (1m in THF, 1.25 mL,
1.25 mmol) in THF (3 mL) was stirred for 24 h. For work up, the solution
was partitioned between water (5 mL) and EtOAc (5 mL), the combined
organic layers were washed with brine, dried (MgSO4), and evaporated,
and the residue was purified by flash chromatography (hexanes/EtOAc
10:1) to give product 13 as a colorless liquid (202 mg, 84%). [a]2D0 =+
21.58 (c=0.98 in CHCl3); 1H NMR (400 MHz, CDCl3): d=5.90 (tdd, J=
17.2, 10.2, 7.0 Hz, 1H), 5.16–5.09 (m, 2H), 4.75 (d, J=6.8 Hz, 1H), 4.65
(d, J=6.9 Hz, 1H), 3.69–3.65 (m, 1H), 3.57–3.53 (m, 1H), 3.43 (s, 3H),
2.77 (brs, 1H), 2.27–2.20 (m, 2H), 1.59–1.43 (m, 3H), 1.33–1.24 (m, 7H),
0.89 ppm (t, J=6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=135.5,
117.2, 97.3, 83.5, 72.4, 55.8, 36.4, 31.8, 30.4, 29.3, 25.8, 22.6, 14.1 ppm; IR
(film): n˜ =3460, 3076, 2930, 1642, 1212, 1152, 1100, 1037, 916 cmꢁ1; MS
(EI): m/z (%): 199 (0.3), 189 (3), 185 (5), 157 (14), 115 (9), 97 (13), 71
(14), 55 (16), 45 (100); HRMS (EI): m/z: calcd for C13H26O3 +Na:
253.1774 [M++Na]; found: 253.1773; elemental analysis calcd (%) for
C13H26O3: C 67.79, H 11.38; found: C 67.86, H 11.43.
tert-ButylACHTREUNG(dimethyl)({(1R)-1-[(2S)-oxiranyl]-3-butenyl}oxy)silane (10): A
solution of 2,6-lutidine (1.55 g, 14.5 mmol) and TBS-OTf (3.06 g,
11.6 mmol) in CH2Cl2 (5 mL) was added dropwise to a solution of alcohol
9 (1.04 g, 7.24 mmol)[22] in CH2Cl2 (10 mL) at 08C. After stirring for
5 min, the reaction was quenched with water, the mixture was repeatedly
extracted with EtOAc, the combined organic layers were washed with
brine and dried over MgSO4, and the solvent was evaporated. The resi-
due was purified by flash chromatography (hexanes/EtOAc 30:1) to give
product 10 as a colorless liquid (1.64 g, quant.). [a]2D0 =ꢁ27.48 (c=1.08 in
CHCl3); 1H NMR (400 MHz, CDCl3): d=5.87 (tdd, J=17.2, 10.2, 7.2 Hz,
1H), 5.14–5.07 (m, 2H), 3.63 (dd, J=11.1, 4.9 Hz, 1H), 2.91 (dt, J=4.3,
2.7 Hz, 1H), 2.69 (ddd, J=8.1, 5.4, 3.3 Hz, 2H), 2.43–2.28 (m, 2H), 0.88
(s, 9H), 0.05 (s, 3H), 0.04 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=
134.2, 117.4, 71.0, 54.3, 44.9, 40.0, 25.8, 25.8, 25.7, 18.2, ꢁ4.5, ꢁ4.8 ppm;
IR (film): n˜ =3078, 2956, 2930, 2858, 1642, 1473, 1253, 1111, 999, 914,
837, 777 cmꢁ1; MS (EI): m/z (%): 187 (14), 171 (7), 141 (24), 129 (23),
115 (14), 101 (32), 99 (23), 75 (100), 73 (79), 59 (27); elemental analysis
calcd (%) for C12H24O2Si: C 63.10, H 10.59; found: C 63.18, H 10.52.
Ethyl 4,6-heptadienoate (15): Ethyl formiate (22.55 g, 0.3 mol) was added
to a solution of vinylmagnesium bromide (1m in THF, 800 mL, 0.8 mol)
at 108C and the resulting mixture was stirred for 16 h at ambient temper-
ature once the addition was complete. The reaction was quenched with
aq HCl (2m, 300 mL), the aqueous phase was extracted with Et2O (3”
300 mL), the combined organic layers were dried (Na2SO4), and the sol-
vent was distilled off by using a Vigreux column. Triethyl orthoacetate
(239 g, 1.5 mol) and propionic acid (0.8 mL, 10.8 mmol) were added to a
solution of the resulting crude divinyl carbinol 14 in benzene (200 mL)
and the resulting mixture was refluxed for 16 h. For work up, the solvent
was distilled off at ambient pressure followed by removal of most of the
residual triethyl orthoacetate under reduced pressure (12 mbar). The resi-
due (ca. 75–80% pure by GC) was then purified by fractional distillation
using a 50 cm column under reduced pressure to give ester 15 in analyti-
cally pure form (>99%, GC) as a colorless liquid (13.2 g, 29%); b.p. 73–
748C (10 mbar). The analytical data are in accord with those previously
reported in the literature.[24] 1H NMR (300 MHz, CDCl3): d=6.24 (dt, J=
17, 10 Hz, 1H), 6.04 (dd, J=15, 10 Hz, 1H), 5.70–5.60 (m, 1H), 5.06 (d,
J=17 Hz, 1H), 4.94 (d, J=10 Hz, 1H), 4.09 (q, J=7.2 Hz, 2H), 2.37 (m,
4H), 1.21 ppm (t, J=7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=172.7,
136.7, 132.5, 131.8, 115.5, 60.2, 33.7, 27.7, 14.1 ppm; MS (EI): m/z (%):
154 (59) [M+], 117 (19), 109 (29), 81 (100), 80 (73), 79 (64), 67 (99), 61
(16), 53 (15), 41 (42), 29 (37).
ACHTREUNG(4R,5S)-4-{[tert-ButylACHTREUNG(dimethyl)silyl]oxy}-1-undecen-5-ol (11): CuBr·Me2S
(4.43 g, 21.5 mmol) was added to a solution of pentylmagnesium bromide
(2m in Et2O, 10.8 mL, 21.5 mmol) at ꢁ788C and the resulting mixture
was stirred at that temperature for 15 min. A solution of oxirane 10
(1.64 g, 7.18 mmol) in THF (30 mL) was introduced and the mixture was
stirred at ꢁ208C for 30 min and at ꢁ58C for 19 h. The reaction was then
quenched with aq saturated NH4Cl, the aqueous phase was extracted
with EtOAc (3”20 mL), the combined organic layers were washed with
brine, dried (MgSO4), and evaporated. Purification of the residue by
flash chromatography (hexanes/EtOAc 20:1) gave product 11 as a color-
less liquid (1.72 g, 80%). [a]2D0 =ꢁ0.98 (c=1.13 in CHCl3); 1H NMR
(400 MHz, CDCl3): d=5.83 (tdd, J=17.2, 10.2, 7.2 Hz, 1H), 5.10–5.02,
(m, 2H), 3.65 (ddd, J=9.0, 6.4, 4.0 Hz, 1H), 3.61–3.51 (m, 1H), 2.35–2.16
(m, 2H), 2.10 (br s, 1H), 1.52–1.47 (m, 1H), 1.41 (dd, J=13.4, 6.7 Hz,
2H), 1.35–1.26 (m, 6H), 0.92–0.87 (m, 13H), 0.07 ppm (s, 6H); 13C NMR
(100 MHz, CDCl3): d=135.6, 116.8, 75.1, 74.6, 35.9, 31.9, 31.8, 29.4, 26.1,
25.9 (2C), 25.8, 22.6, 18.1, 14.1, ꢁ4.3, ꢁ4.5 ppm; IR (film): n˜ = 3578,
3462, 3077, 2955, 2929, 2858, 1642, 1471, 1463, 1361, 1256, 1083, 1005,
913, 837, 776, 676 cmꢁ1; MS (EI): m/z (%): 285 (1), 259 (8), 243 (84), 225
(5), 199 (5), 185 (70), 145 (41), 129 (13), 95 (32), 75 (100), 67 (18);
HRMS (ESI-pos): m/z: calcd for C17H36O2Si+Na: 323.2377 [M++Na];
found: 323.2376; elemental analysis calcd (%) for C17H36O2Si: C 76.94, H
12.07; found: C 76.78, H 12.15.
(5R)-5-[(1R)-1-Hydroxy-2-propenyl]dihydro-2(3H)furanone (18): Ester
15 (2.00 g, 13.0 mmol) was added to a cooled (58C) solution of AD-mix-b
(18.2 g) and methanesulfonamide (1.23 g, 13.0 mmol) in tBuOH/H2O
(1:1, 120 mL) and the resulting mixture was stirred at that temperature
for 4 h. For work up, Na2SO3 (19.7 g, 156 mmol) was added in solid form
and stirring was continued for 1 h at 58C and for 2 h at ambient tempera-
ture. Enough water was then added to dissolve all salts, the resulting
aqueous phase was extracted with EtOAc (3”50 mL), and the combined
organic layers were washed with brine, dried (MgSO4), and evaporated.
The residue was dissolved in MeOH (15 mL) before pTsOH (100 mg,
0.53 mmol) was introduced, and the resulting solution was stirred for 15 h
at ambient temperature. All volatile materials were then evaporated and
the crude product was purified by flash chromatography (hexanes/EtOAc
gradient) to give lactone 18 as a colorless liquid (994 mg, 54%). The ana-
Compound 12: A solution of alcohol 11 (1.72 g, 5.72 mmol), MOM-Cl
(1.38 g, 17.2 mmol), EtNACHTRE(UNG iPr)2 (2.22 g, 17.2 mmol) and DMAP (ca.
50 mg) in CH2Cl2 (15 mL) was stirred for 18 h. For work up, the solution
was partitioned between water and tert-butyl methyl ether, the combined
organic layers were washed with brine, dried (MgSO4), and evaporated,
and the residue was purified by flash chromatography (hexanes/EtOAc
20:1) to give product 12 as a colorless liquid (1.67 g, 85%). [a]2D0 =ꢁ35.38
Chem. Eur. J. 2007, 13, 1452 – 1462
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1457

A. Fürstner et al.
lytical and spectroscopic data agree with those published in the litera-
ture.[26] [a]D20 =ꢁ30.08 (c=1.03, CHCl3); 1H NMR (300 MHz, CDCl3): d=
5.90 (ddd, J=16.9, 10.5, 6.2 Hz, 1H), 5.38 (dd, J=33.1, 13.9 Hz, 2H),
4.48 (dt, J=7.3, 5.3 Hz, 1H), 4.19–4.15 (m, 1H), 2.68–2.48 (m, 2H), 2.28–
2.11 ppm (m, 3H); 13C NMR (100 MHz, CDCl3): d=177.2, 135.1, 118.3,
82.4, 74.6, 28.4, 23.5 ppm.
(104 mg, 84%). [a]2D0 =ꢁ17.08 (c=1.02, CHCl3); 1H NMR (400 MHz,
CDCl3): d=5.84–5.69 (m, 2H), 5.38 (dd, J=17.1, 1.2 Hz, 1H), 5.26 (dd,
J=10.3, 1.3 Hz, 1H), 5.11–5.02 (m, 3H), 4.72 (d, J=6.9 Hz, 1H), 4.60 (d,
J=6.9 Hz, 1H), 4.00 (dd, J=8.2, 7.5 Hz, 1H), 3.69 (dt, J=8.4, 3.7 Hz,
1H), 3.64 (dd, J=8.1, 3.2 Hz, 1H), 3.39 (s, 3H), 2.57–2.33 (m, 4H), 1.99–
1.91 (m, 1H), 1.85–1.76 (m, 1H), 1.56–1.47 (m, 3H), 1.41 (s, 3H), 1.40 (s,
3H), 1.33–1.29 (brm, 7H), 0.89 ppm (t, J=6.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=172.6, 135.0, 134.0, 119.2, 117.5, 108.8, 96.0, 82.5,
79.5, 77.8, 74.1, 55.8, 34.2, 31.8, 30.8, 30.6, 29.3, 27.2, 26.9, 26.8, 25.6, 22.6,
14.1 ppm; IR (film): n˜ =3080, 2954, 1737, 1644, 1379, 1371, 1241, 1166,
1101, 1069, 1038, 989, 920, 875 cmꢁ1; MS (EI): m/z (%): 397 (4), 283 (2),
229 (19), 183 (9), 125 (100), 98 (65), 45 (61); HRMS (EI): m/z: calcd for
C23H40O6 +Na: 435.2717 [M++Na]; found: 435.2717; elemental analysis
calcd (%) for C23H40O6: C 66.96, H 9.77; found: C 66.85, H 9.70.
3-[(4R,5R)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl]propanoic acid (20): A
solution of lactone 18 (994 mg, 6.99 mmol), 2,2-dimethoxypropane (8.5 g,
82 mmol), and pTsOH (150 mg, 0.79 mmol) in MeOH (10 mL) was stir-
red for 24 h at ambient temperature. The reaction was quenched with
water (10 mL) and the resulting aqueous phase was extracted with
EtOAc (3”20 mL). The combined organic layers were washed with
brine, dried (MgSO4), and evaporated to give crude methyl ester 19
which was used in the next step without further purification.
Ring-closing metathesis: preparation of the nonenolides 22: A solution
of diene 21 (300 mg, 0.73 mmol) in CH2Cl2 (18 mL) was added over 1 h
to a refluxing solution of complex 5 (120 mg, 0.15 mmol) in CH2Cl2
(710 mL) and reflux was continued for 24 h once the addition was com-
plete. For workup, all volatile materials were evaporated and the residue
was purified by flash chromatography (hexanes/EtOAc 10:1) to give (E)-
22 as a colorless syrup (139 mg, 50%) and (Z)-22 as a pale-yellow syrup
(61 mg, 22%).
Compound (E)-22:[20] [a]D20 =ꢁ31.28 (c=0.85, CHCl3); 1H NMR
(400 MHz, CDCl3): d=5.96–5.72 (m, 1H), 5.33 (dd, J=15.6, 9.2 Hz, 1H),
5.11–4.91 (m, 1H), 4.71 (d, J=7.0 Hz, 1H), 4.68 (d, J=7.0 Hz, 1H), 3.93
(t, J=8.8 Hz, 1H), 3.67–3.59 (m, 2H), 3.41 (s, 3H), 2.69–2.61 (m, 1H),
2.54 (dt, J=13.0, 4.4 Hz, 1H), 2.45–2.40 (m, 1H), 2.37–2.27 (m, 1H),
2.11–2.05 (m, 1H), 2.04–1.93 (m, 1H), 1.57 ppm (brs, 2H), 1.41 (s, 6H),
1.29 (brs, 8H), 0.89 (t, J=6.5 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=
171.7, 130.1, 129.3, 108.8, 96.4, 84.4, 79.8, 79.2, 73.5, 56.0, 34.2, 31.7, 30.8,
30.5, 29.4, 27.1, 26.9, 25.5, 25.3, 22.6, 14.1 ppm; IR (film): n˜ = 2931, 2859,
1732, 1666, 1447, 1379, 1237, 1166, 1066, 1040, 977, 919 cmꢁ1; MS (EI): m/
z (%): 384 (5) [M+], 352 (1), 327 (1), 282 (4), 237 (14), 157 (7), 139 (10),
123 (17), 110 (23), 85 (37), 79 (12), 45 (100); HRMS (EI): m/z: calcd for
C21H36O6 +Na: 407.2404 [M++Na]; found: 407.2407.
A solution of KOH (25% w/w in MeOH, 5 mL) was added to a solution
of crude 19 in MeOH (15 mL) and the resulting mixture was stirred for
3 d at ambient temperature. The solution was diluted with water (15 mL),
the aqueous phase was extracted with tert-butyl methyl ether (4”20 mL),
and the combined organic layers were discarded. The aqueous phase was
then acidified with aq HCl (3m) to pH ꢂ3, before it was extracted again
with tert-butyl methyl ether (5”15 mL). The combined organic layers
were washed with brine, dried (MgSO4), and evaporated to give acid 20
as pale yellow oil (1.30 g, 93% over both steps). [a]2D0 =+3.48 (c=0.89,
1
CHCl3); H NMR (300 MHz, CDCl3): d=5.81 (ddd, J=17.5, 10.2, 7.4 Hz,
1H), 5.38 (dd, J=17.1, 1.0 Hz, 1H), 5.28 (dd, J=10.3, 0.7 Hz, 1H), 4.04–
3.99 (m, 1H), 3.71 (dt, J=8.3, 3.7 Hz, 1H), 2.65–2.43 (m, 2H), 2.03–1.76
(m, 2H), 1.41 ppm (s, 6H); 13C NMR (100 MHz, CDCl3): d=178.7, 134.9,
119.3, 109.0, 82.4, 79.3, 30.4, 27.2, 27.0, 26.5 ppm; IR (film): n˜ =3086,
2987, 2935, 2875, 1739, 1712, 1380, 1372, 1242, 1167, 1114, 1069, 989, 934,
873 cmꢁ1; MS (EI): m/z (%): 200 (0.1) [M+], 185 (39), 167 (1), 144 (3),
125 (71), 98 (75), 83 (37), 69 (25), 55 (23), 43 (100); HRMS (EI): m/z:
calcd for C10H16O4: 199.0977; found: 199.0976; elemental analysis calcd
(%) for C10H16O4: C 59.98, H 8.05; found: C 59.70, H 8.11.
(1S)-1-[(1S)-1-(Methoxymethoxy)heptyl]-3-butenyl
methyl-5-vinyl-1,3-dioxolan-4-yl]propanoate (21):
3-[(4R,5R)-2,2-di-
PPh3 (92.0 mg,
Compound (Z)-22:[18a] [a]D20 =+20.28 (c=0.89, CHCl3); 1H NMR
(400 MHz, CDCl3): d=5.75 (dt, J=10.4, 7.0 Hz, 1H), 5.51 (t, J=10.3 Hz,
1H), 5.05 (ddd, J=11.9, 4.2, 2.0 Hz, 1H), 4.69 (s, 2H), 4.53–4.48 (m, 1H),
3.69–3.62 (m, 2H), 3.41 (s, 3H), 2.71–2.62 (m, 2H), 2.40–2.06 (m, 4H),
1.61–1.52 (m, 2H), 1.43 (s, 3H), 1.40 (s, 3H), 1.37–1.22 (br m, 8H),
0.88 ppm (t, J=6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=170.7,
130.9, 130.3, 107.7, 96.5, 81.4, 78.3, 76.7, 72.9, 55.9, 32.2, 31.7, 30.9, 29.4,
29.3, 28.2, 27.1, 26.9, 25.1, 22.6, 14.1 ppm; IR (film): n˜ =3020, 2932, 2858,
1737, 1661, 1379, 1369, 1242, 1179, 1100, 1056, 1031, 919, 885 cmꢁ1; MS
(EI): m/z (%): 384 (5) [M+], 369 (7), 282 (4), 265 (4), 252 (3), 237 (14),
220 (18), 199 (3), 179 (3), 157 (6), 110 (22), 85 (33), 45 (100); HRMS
(EI): m/z: calcd for C21H36O6 +Na: 407.2404 [M++Na]; found: 407.2405.
0.35 mmol) was added to a solution of alcohol 13 (41.0 mg, 0.18 mmol)
and acid 20 (35.3 mg, 0.18 mmol) in toluene (1.5 mL), followed by the
dropwise addition of diethyl (Z)-1,2-diazene-dicarboxylate (DEAD,
61.4 mg, 0.35 mmol). After stirring for 1.5 h, additional PPh3 (46.0 mg,
0.18 mmol) and DEAD (30.7 mg, 0.18 mmol) were introduced and stir-
ring was continued for 18 h. A standard extractive workup followed by
flash chromatography (hexanes/EtOAc, 10:1) of the crude product fur-
nished ester 21 as a colorless liquid (43.6 mg, 60%).[20] [a]D20 =+4.28 (c=
1.02, CHCl3); 1H NMR (300 MHz, CDCl3): d=5.86–5.68 (m, 2H), 5.37
(brd, J=16.7 Hz, 1H), 5.26 (brd, J=10.4 Hz, 1H), 5.13–5.03 (m, 3H),
4.70 (d, J=6.9 Hz, 1H), 4.67 (d, J=6.9 Hz, 1H), 4.02–3.97 (m, 1H), 3.69
(dt, J=8.3, 3.8 Hz, 1H), 3.58 (dt, J=6.3, 4.3 Hz, 1H), 3.40 (s, 3H), 2.59–
2.28 (m, 4H), 2.01–1.75 (m, 2H), 1.52–1.47 (m, 2H), 1.41 (s, 3H), 1.39 (s,
3H), 1.35–1.27 (m, 8H), 0.88 ppm (t, J=6.5 Hz, 3H); 13C NMR (75 MHz,
CDCl3): d=172.6, 135.0, 133.9, 119.2, 117.7, 108.8, 96.6, 82.4, 79.5, 78.0,
73.6, 55.9, 34.7, 31.7, 30.7, 30.5, 29.4, 27.2, 26.9, 26.8, 25.3, 22.6, 14.1 ppm;
IR (film): n˜ =3080, 2931, 2859, 1737, 1644, 1379, 1370, 1241, 1165, 1103,
1069, 1039, 989, 920, 875 cmꢁ1; MS (EI): m/z (%): 397 (6), 283 (2), 253
(1), 229 (17), 213 (4), 183 (10), 143 (6), 125 (100), 113 (6), 98 (64), 45
(57); HRMS (EI): m/z: calcd for C23H40O6Na: 435.2717 [M++Na];
found: 435.2714; elemental analysis calcd (%) for C23H40O6: C 66.96, H
9.77; found C 66.87, H 9.81.
Nonenolide (E)-25: Prepared according to the procedure for the ring-
closing alkene metathesis described above, using diene 24 (80.0 mg,
0.19 mmol) and catalyst 5 (32 mg, 0.04 mmol); only traces of the (Z)-
isomer were formed which could be removed by flash chromatography
with hexanes/EtOAc 10:1 as the eluent; colorless liquid (63.5 mg, 85%).
[a]2D0 =+4.88 (c=0.94, CHCl3); 1H NMR (400 MHz, CDCl3): d=5.71
(ddd, J=15.5, 11.2, 4.4 Hz, 1H), 5.31 (dd, J=15.3, 9.6 Hz, 1H), 5.08 (dt,
J=11.4, 3.5 Hz, 1H), 4.75 (d, J=6.9 Hz, 1H), 4.68 (d, J=6.8 Hz, 1H),
3.94 (t, J=8.9 Hz, 1H), 3.70 (dt, J=8.0, 3.9 Hz, 1H), 3.53 (td, J=8.4,
3.2 Hz, 1H), 3.41 (s, 3H), 2.53–2.42 (m, 2H), 2.26–2.05 (m, 4H), 1.59–
1.46 (m, 3H), 1.41 (s, 3H), 1.40 (s, 3H), 1.29 (brm, 7H), 0.89 ppm (t, J=
6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=173.9, 135.1, 129.6, 108.0,
96.4, 82.4, 82.1, 77.8, 75.0, 55.9, 34.5, 32.2, 31.7, 31.2, 29.3, 27.2, 27.0, 27.0,
25.4, 22.6, 14.1 ppm; IR (film): n˜ =2932, 1733, 1669, 1378, 1367, 1239,
1212, 1181, 1152, 1066, 1043, 975, 920, 861 cmꢁ1; MS (EI): m/z (%): 384
(6) [M+], 369 (8), 382 (4), 365 (3), 237 (16), 220 (22), 157 (7), 139 (13),
110 (28), 85 (37), 45 (100); HRMS (EI): m/z: calcd for C21H36O6 +Na:
407.2404 [M++Na]; found: 407.2407; elemental analysis calcd (%) for
C21H36O6: C 65.60, H 9.44; found: C 65.48, H 9.38.
(1R)-1-[(1S)-1-(Methoxymethoxy)heptyl]-3-butenyl
methyl-5-vinyl-1,3-dioxolan-4-yl]propanoate (24):
3-[(4R,5R)-2,2-di-
solution of DCC
A
(92 mg, 0.5 mmol) in CH2Cl2 (2 mL) was added to a solution of alcohol
13 (69 mg, 0.3 mmol), acid 20 (90 mg, 0.4 mmol), and DMAP (ca. 5 mg)
and the resulting mixture was stirred at ambient temperature for 18 h.
CH2Cl2 (2 mL) was then added, the precipitates were filtered off through
a short pad of silica, and the filtrate was evaporated. The residue was sus-
pended in water (10 mL) and extracted with tert-butyl methyl ether (3”
15 mL), the combined organic phases were washed with brine, dried
(MgSO4), and evaporated, and the residue was purified by flash chroma-
tography (hexanes/EtOAc 10:1) to give ester 24 as a colorless liquid
Nonenolide (Z)-25: Prepared according to the procedure for the ring-
closing alkene metathesis described above, using diene 24 (104 mg,
1458
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 1452 – 1462

Microcarpalide
FULL PAPER
0.25 mmol) and catalyst 7 (43 mg, 0.05 mmol). Flash chromatography
(hexanes/EtOAc 10:1) of the crude product afforded (E)-25 (49 mg,
50%) and (Z)-25 (43 mg, 44%).
323.1829 [M++Na]; found: 323.1828; elemental analysis calcd (%) for
C16H28O5: C 63.97, H 9.40; found: C 64.11, H 9.49.
Furanone 27: Prepared as described above from lactone (Z)-25 (38 mg,
Compound (Z)-25: Pale yellow oil; [a]2D0 =+17.18 (c=1.01, CHCl3);
1H NMR (400 MHz, CDCl3): d=5.87 (dt, J=10.5, 7.3 Hz, 1H), 5.57 (t,
J=10.4 Hz, 1H), 4.96 (t, J=5.6 Hz, 1H), 4.68 (s, 2H), 4.25–4.21 (m, 1H),
3.86 (ddd, J=8.1, 4.8, 2.9 Hz, 1H), 3.65 (dd, J=11.2, 6.1 Hz, 1H), 3.41 (s,
3H), 2.76–2.63 (m, 2H), 2.43–2.34 (m, 2H), 2.18 (ddt, J=14.4, 11.6,
2.6 Hz, 1H), 2.07–1.99 (m, 1H), 1.55–1.49 (m, 2H), 1.42 (s, 3H), 1.41 (s,
3H), 1.38–1.24 (m, 8H), 0.88 ppm (t, J=6.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=171.7, 130.4, 129.2, 107.8, 96.3, 79.6, 76.3, 74.0,
73.4, 55.0, 31.7, 31.5, 29.4, 29.4, 27.2, 27.0, 25.6, 25.4, 24.4, 22.6, 14.1 ppm;
IR (film): n˜ = 3021, 2932, 1734, 1657, 1379, 1370, 1244, 1161, 1096, 1038,
933, 883 cmꢁ1; MS (EI): m/z (%): 384 ([M+] 9), 369 (12), 339 (2), 309 (3),
282 (8), 265 (7), 237 (27), 220 (39), 193 (5), 157 (10), 110 (40), 85 (47), 55
(18), 45 (100); HRMS (EI): m/z: calcd for C21H36O6 +Na: 407.2404 [M+
+Na]; found: 407.2404; elemental analysis calcd (%) for C21H36O6: C
65.60, H 9.44; found: C 65.46, H 9.38.
0.1 mmol) as a colorless solid (7 mg, 24%); crystals suitable for X-ray dif-
fraction analysis were grown from CH2Cl2. M.p.=104–1058C; [a]D20
=
ꢁ54.48 (c=0.31, MeOH); 1H NMR (400 MHz, CD3CN): d=5.77–5.70
(m, 1H), 5.62–5.57 (m, 1H), 4.45–4.39 (m, 2H), 3.56 (brd, J=2.6 Hz,
1H), 3.39 (brs, 2H), 3.03 (brd, J=2.9 Hz, 1H), 2.78 (brd, J=4.4 Hz,
1H), 2.48–2.42 (m, 2H), 2.38–2.18 (m, 2H), 2.12–1.97 (m, 2H), 1.57–1.41
(m, 2H), 1.36–1.18 (brm, 8H), 0.89 ppm (t, J=6.7 Hz, 3H); 13C NMR
(100 MHz, CD3CN): d=178.4, 132.4, 130.5, 83.5, 74.8, 74.4, 69.4, 33.2,
32.5, 31.4, 30.1, 28.9, 26.5, 24.3, 23.3, 14.3 ppm; IR (film): n˜ =3400, 2951,
2928, 1763, 1658, 1188, 1036 cmꢁ1; MS (EI): m/z (%): 282 (2), 264 (1),
215 (1), 197 (73), 186 (10), 179 (25), 167 (94), 138 (78), 122 (32), 95 (42),
85 (82), 79 (36), 67 (37), 55 (100), 43 (69); HRMS (EI): m/z: calcd for
C16H28O5 +Na: 323.1829 [M++Na]; found: 323.1829; elemental analysis
calcd (%) for C16H28O5: C 63.97, H 9.40; found: C 64.10, H 9.36.
Acetal 30: A solution of diol 29 (1.40 g, 12.1 mmol),[30] p-methoxybenzal-
dehyde dimethyl acetal (4.40 g, 24.2 mmol) and camphorsulfonic acid
(279 mg, 1.20 mmol) in CH2Cl2 (40 mL) was refluxed for 14 h. The reac-
tion was quenched with Et3N before all volatiles were evaporated and
the residue was purified by flash chromatography (hexane/EtOAc 19:1)
to afford product 30 as a colorless liquid (1.67 g, 59%); mixture of diaste-
reomers (dr=57:43). 1H NMR (400 MHz, C6D6): d=7.51–7.46 (m, 4H),
6.80–6.76 (m, 4H), 5.92 (s, 1H of minor isomer), 5.77 (s, 1H of major
isomer), 5.73–5.62 (m, 2H), 4.99–4.91 (m, 4H), 3.97–3.83 (m, 3H), 3.71
(dd, J=7.5, 6.9 Hz, 1H of major isomer), 3.41 (dd, J=7.5, 6.9 Hz, 1H of
major isomer), 3.27 (dd, J=7.7, 7.0 Hz, 1H of minor isomer), 3.26 (s, 3H
of minor isomer), 3.25 (s, 3H of major isomer), 2.08–1.91 (m, 4H), 1.69–
1.56 (m, 2H), 1.43–1.22 ppm (m, 2H); 13C NMR (100 MHz, CD2Cl2; mix-
ture of isomers): d=161.3, 161.1, 138.8, 131.7, 131.1, 128.8, 128.6, 115.5,
114.3, 104.6, 103.7, 77.3, 76.7, 56.0, 33.7, 33.4, 30.8, 30.7 ppm; IR (film):
n˜ =3076, 2937, 1716, 1641, 1615, 1517, 1249, 1171, 1079, 1034, 915,
830 cmꢁ1; MS (EI): m/z (%): 234 (10), 233 (21), 135 (100), 121 (20), 108
(31), 81 (16), 77 (12), 41 (11); HRMS (EI): m/z: calcd for C14H18O3 +Na:
257.11481 [M++Na]; found 257.11483; elemental analysis calcd (%) for
C14H18O3: C 71.77, H 7.74; found C 71.86, H 7.70.
(ꢁ)-Microcarpalide (1): BF3·Et2O (51.4 mg, 0.36 mmol) and 1,2-ethane-
1,2-dithiol (136 mg, 1.45 mmol) were added to a solution of compound
(E)-22 (139 mg, 0.36 mmol) in CH2Cl2 (15 mL) at 08C. After stirring for
1.5 h, the reaction was quenched with saturated aq NaHCO3 (20 mL), the
organic phase was carefully extracted with EtOAc (3”20 mL), the com-
bined organic layers were washed with brine, dried (MgSO4), and evapo-
rated, and the residue was purified by flash chromatography (hexanes/
EtOAc 10:1!0:1) to give product
1 as a colorless oil (80.6 mg,
74%).[1,20,21] [a]D20 =ꢁ27.28 (c=0.83, MeOH); 1H NMR (400 MHz,
CD3CN; mixture of two conformers): d=5.70 (dd, J=15.8, 1.6 Hz, 1H),
5.55–5.47 (m, 1H), 4.81 (ddd, J=11.2, 4.3, 3.6 Hz, 1H), 4.11 (brs, 1H),
3.78 (brs, 1H), 3.55 (brm, 1H), 3.12 (brs, 1H), 2.86 (brm, 2H), 2.56–2.34
(m, 1H), 2.26–2.21 (m, 1H), 2.08–2.03 (m, 3H), 1.81–1.69 (m, 1H), 1.43
(brm, 2H), 1.29 (brm, 8H), 0.89 ppm (t, J=6.8 Hz, 3H); 13C NMR
(100 MHz, CD3CN; mixture of two conformers): d=176.3, 173.4, 134.4,
133.7, 129.9, 126.6, 79.4, 76.9, 76.4, 73.7, 72.7, 72.3, 36.6, 35.9, 34.1, 33.8,
32.5, 32.2, 32.1, 29.9, 26.4, 26.0, 23.3, 14.3 ppm; IR (film): n˜ = 3398, 3035,
2928, 1710, 1435, 1225, 1157, 1064, 983 cmꢁ1; MS (EI): m/z (%): 282 (1),
230 (1), 198 (3), 180 (38), 141 (7), 129 (20), 95 (23), 84 (73), 70 (100), 55
(48), 43 (49); HRMS (EI): m/z: calcd for C16H28O5 +Na: 323.1829 [M+
+Na]; found: 323.1828; elemental analysis calcd (%) for C16H28O5: C
63.97, H 9.40; found: C 63.88, H 9.37.
Alcohol 31: To a solution of compound 30 (1.06 g, 4.52 mmol) in toluene
(40 mL) was added DIBAL-H (1m in toluene, 9.0 mL, 9.0 mmol) at 08C.
The mixture was allowed to warm to room temperature over 3 h. The re-
action mixture was filtered through a short pad of silica to remove the
aluminum salts, the filtrate was adsorped on silica and the product eluted
with hexane/EtOAc (10:1!4:1) to give product 31 as a colorless liquid
Furanone 23: Prepared from compound (Z)-22 (77 mg, 0.2 mmol) by fol-
lowing the procedure described above; colorless oil (19 mg, 32%). [a]D20
=
+61.98 (c=0.95, MeOH); 1H NMR (400 MHz, CD3CN): d=5.55 (ddd,
J=10.3, 10.0, 7.1 Hz, 1H), 5.39 (t, J=10.6 Hz, 1H), 4.69 (ddd, J=11.6,
3.7, 1.7, 1H), 4.33 (t, J=9.4 Hz, 1H), 3.56–3.55 (m, 2H), 3.30 (brs, 1H),
3.19 (brs, 1H), 2.97 (brs, 1H), 2.69–2.60 (m, 1H), 2.57–2.51 (m, 1H),
2.18–2.04 (m, 3H), 1.79–1.72 (m, 1H), 1.42 (brm, 3H), 1.29 (brs, 7H),
0.88 ppm (t, J=6.2 Hz, 3H); 13C NMR (100 MHz, CD3CN): d=175.1,
133.3, 129.6, 76.1, 75.6, 72.9, 70.3, 34.2, 32.4, 31.0, 30.0, 29.9, 29.6, 26.2,
23.2, 14.3 ppm; IR (film): n˜ =3406, 3011, 2954, 2927, 2856, 1734, 1714,
1663, 1250, 1144, 1056 cmꢁ1; MS (EI): m/z (%): 300 (0.5) [M+], 282 (2),
264 (0.4), 215 (1), 197 (47), 179 (20), 167 (58), 150 (22), 138 (96), 122
(25), 110 (29), 95 (38), 85 (76), 55 (100), 43 (73); HRMS (EI): m/z: calcd
for C16H28O5 +Na: 323.1829 [M++Na]; found: 323.1831; elemental analy-
sis calcd (%) for C16H28O5: C 63.97, H 9.40; found: C 63.75, H 9.27.
1
(885 mg, 83%). H NMR (400 MHz, CDCl3): d=7.29 (d, J=8.6 Hz, 2H),
6.91 (d, J=8.6 Hz, 2H), 5.83 (ddt, J=17.1, 10.2, 6.6 Hz, 1H), 5.07–4.99
(m, 2H), 4.57 (d, J=11.2 Hz, 1H), 4.50 (d, J=11.2 Hz, 1H), 3.83 (s, 3H),
3.72 (dd, J=13.8, 5.8, 1H), 3.57–3.52 (m, 2H), 2.18–2.13 (m, 2H), 1.86
(br, 1H), 1.80–1.71 (m, 1H), 1.66–1.59 ppm (m, 1H); 13C NMR
(100 MHz, CDCl3): d=159.0, 137.8, 130.2, 129.0 (2C), 114.5, 113.6 (2C),
78.4, 70.9, 63.8, 54.9, 29.8, 29.2 ppm; IR (film): n˜ =3429, 2998, 2935, 1640,
1612, 1514, 1248, 1036, 99 8, 912, 822 cmꢁ1; MS (EI): m/z (%): 236 (1),
205 (9), 121 (100), 77 (5); HRMS (EI): m/z: calcd for C14H20O3 +Na:
259.13049 [M++Na]; found 259.13022. Small amounts of the regioisomer-
ic PMB-ether could be separated (178 mg, 17%), which showed the fol-
1
lowing spectroscopic properties: H NMR (400 MHz, CDCl3): d=7.10 (d,
J=8.6 Hz, 2H), 6.74 (d, J=8.6 Hz, 2H), 5.67 (ddt, J=17.1, 10.3, 6.6 Hz,
1H), 4.91–4.79 (m, 2H), 4.33 (s, 2H), 3.66 (m, 1H), 3.65 (s, 3H), 3.33
(dd, J=9.4, 3.1 Hz, 1H), 3.16 (dd, J=9.4, 7.8 Hz, 1H), 2.06–1.96 (m,
3H), 1.43–1.36 ppm (m, 2H); 13C NMR (100 MHz, CDCl3): d=159.0,
137.9, 129.7, 129.0 (2C), 114.5, 113.5 (2C), 73.8, 72.7, 69.5, 54.9, 32.0,
29.4 ppm; IR (film): n˜ =3452, 2999, 2934, 1640, 1612, 1586, 1514, 1248,
1092, 997, 912, 821 cmꢁ1; MS (EI): m/z (%): 236 (5), 137 (12), 122 (19),
121 (100), 77 (5); HRMS (EI): m/z: calcd for C14H20O3 +Na: 259.13047
[M++Na]; found 259.13023.
9-epi-Microcarpalide (26): Prepared as described above from lactone
(E)-25 (47 mg, 0.12 mmol) in the form of colorless crystals (23 mg, 62%).
M.p.=104–1058C; [a]2D0 =+47.38 (c=0.51, MeOH); 1H NMR (400 MHz,
CD3CN): d=5.51 (ddd, J=15.5, 10.6, 5.0 Hz, 1H), 5.25 (dd, J=15.4,
9.7 Hz, 1H), 4.77 (ddd, J=11.3, 5.3, 3.3, 1H), 3.61–3.52 (m, 2H), 3.32–
3.27 (m, 3H), 2.93 (d, J=5.6 Hz, 1H), 2.46–2.39 (m, 2H), 2.12–1.98 (m,
2H), 1.92–1.82 (m, 2H), 1.54–1.44 (m, 2H), 1.35–1.29 (br m, 8H),
0.89 ppm (t, J=6.8 Hz, 3H); 13C NMR (100 MHz, CD3CN): d=175.9,
134.5, 133.2, 78.3, 77.7, 77.1, 72.7, 35.2, 34.0, 32.7, 32.4, 31.7, 30.0, 26.2,
23.2, 14.3 ppm; IR (film): n˜ =3398, 2929, 2857, 1730, 1710, 1666, 1431,
1383, 1239, 1149, 1057, 977 cmꢁ1; MS (EI): m/z (%): 301 (0.1) [M+], 282
(0.1), 213 (0.5), 198 (2), 180 (26), 141 (6), 129 (24), 95 (21), 84 (100), 70
(66), 55 (44), 43 (38); HRMS (EI): m/z: calcd for C16H28O5 +Na:
Carboxylic acid 32: Oxalyl chloride (0.26 mL, 3.0 mmol) was added drop-
wise to a solution of DMSO (0.43 mL, 6.0 mmol) in CH2Cl2 (10 mL) at
ꢁ788C and the resulting mixture was stirred for 15 min at that tempera-
ture. A solution of alcohol 31 (473 mg, 2.0 mmol) in CH2Cl2 (3 mL) was
Chem. Eur. J. 2007, 13, 1452 – 1462
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1459

A. Fürstner et al.
added and the resulting suspension was stirred for 45 min, at which point
Et3N (1.1 mL, 8.0 mmol) was introduced. The mixture was then allowed
to reach 08C over 3 h before it was quenched with saturated aq NH4Cl
(10 mL). The aqueous layer was repeatedly extracted with Et2O (3”
10 mL), the combined organic layers were washed with brine, dried over
Na2SO4, and evaporated.
(%): 404 (2), 283 (11), 137 (13), 121 (100), 95 (7), 77 (4); HRMS (EI): m/
z: calcd for C23H32O6 +Na: 427.20911 [M++Na]; found: 427.20906.
Compound 36:
A solution of (E)-35 (60 mg, 0.15 mmol) in MeOH
(5 mL), water (2.4 mL) and aq HCl (1m, 1 mL) was stirred at 608C for
1 h. The reaction mixture was neutralized with aq NaOH (1m) and the
organic solvents were evaporated. The remaining aqueous layer was ex-
tracted with EtOAc (3”10 mL), the combined organic layers were
washed with brine and dried over Na2SO4. Evaporation of the solvent fol-
lowed by purification of the residue by flash chromatography (hexane/
EtOAc 1:1) provided product 36 as a colorless syrup (49 mg, 87%).
1H NMR (400 MHz, CDCl3): d=7.20 (d, J=8.7 Hz, 2H), 6.82 (d, J=
8.7 Hz, 2H), 5.68 (d, J=15.7 Hz, 1H), 5.45–5.38 (m, 1H), 5.03 (dt, J=
9.5, 2.4 Hz, 1H), 4.60 (d, J=11.0 Hz, 1H), 4.38 (brm, 1H), 4.31 (d, J=
4.3 Hz, 1H), 3.89 (dd, J=5.2, 2.5 Hz, 1H), 3.74 (s, 3H), 3.56 (brs, 1H),
2.42–2.33 (m, 2H), 2.30 (brs, 1H), 2.04–1.81 (m, 4H), 1.62–1.56 (m, 1H),
1.36–1.18 ppm (m, 2H), 0.87 (t, J=7.4 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=174.6, 159.0, 131.9, 129.7, 128.7 (2C), 122.8, 113.5 (2C), 75.3,
73.0, 72.8, 71.7, 70.7, 54.9, 33.5, 31.0, 26.5, 17.8, 13.6 ppm; IR (film): n˜ =
3470, 2997, 2958, 1724, 1612, 1586, 1514, 1250, 1056, 821 cmꢁ1; MS (EI):
m/z (%): 364 (1), 278 (1), 137 (9), 121 (100), 113 (2), 77 (3), 55 (2);
HRMS (EI): m/z: calcd for C20H28O6 +Na: 387.17781 [M++Na]; found
387.17748.
The resulting crude aldehyde (481 mg, quant.) was dissolved in tBuOH
(15 mL). A solution of NaH2PO4 (380 mg, 3.2 mmol) in water (2.5 mL),
2-methyl-2-butene (1.1 mL) and NaClO2 (570 mg, 6.3 mmol) were succes-
sively added and the resulting mixture was stirred at room temperature
for 2.5 h. All volatile materials were removed under reduced pressure
and the residue was dissolved in CH2Cl2 (10 mL). The solution was dried
over Na2SO4 and the solvent was evaporated to give carboxylic acid 32
(504 mg, quant.) which could be used in the next step without further pu-
rification. The spectroscopic data of 32 are in full agreement with those
previously reported in the literature.[8]
Ester 34: Et3N (0.61 mL, 4.4 mmol) and 2,4,6-trichlorobenzoyl chloride
(0.32 mL, 2.0 mmol) were added to
a solution of acid 32 (504 mg,
2.0 mmol) in toluene (19 mL). The resulting suspension was stirred for
1.5 h before a solution of alcohol 33 (407 mg, 2.0 mmol)[8] and DMAP
(122 mg, 1.0 mmol) in toluene (11 mL) was introduced and the resulting
mixture was stirred at ambient temperature for 2 h. The precipitate
formed was filtered off through a pad of silica, the filtrate was evaporat-
ed, and the residue was purified by flash column chromatography
(hexane/EtOAc 19:1) to give ester 34 as a colorless oil (764 mg, 89%).
1H NMR (400 MHz, CDCl3): d=7.20 (d, J=8.7 Hz, 2H), 6.81 (d, J=
8.7 Hz, 2H), 5.81–5.64 (m, 2H), 5.31–5.13 (m, 2H), 4.98–4.89 (m, 2H),
4.57–4.53 (m, 2H), 4.21 (d, J=11.0 Hz, 1H), 4.14 (dd, J=7.5, 6.5 Hz,
1H), 3.81–3.78 (m, 1H), 3.73 (s, 3H), 2.15–2.07 (m, 2H), 1.76–1.71 (m,
2H), 1.67–1.56 (m, 2H), 1.42 (s, 3H), 1.31 (s, 3H), 1.29 (m, 3H),
0.85 ppm (t, J=7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=171.5,
159.1, 137.1, 132.8, 129.4, 129.2 (2C), 118.3, 115.0, 113.5 (2C), 108.4, 78.4,
77.7, 71.9, 71.6, 54.9, 33.0, 31.8, 29.2, 27.2, 26.6, 24.9, 17.5, 13.7 ppm; IR
(film): n˜ =3077, 1959, 1750, 1641, 1613, 1514, 1381, 1372, 124 9, 1214,
1109, 1037, 995, 927, 872, 822 cmꢁ1; MS (EI): m/z (%): 249 (11), 197 (27),
137 (14), 125 (14), 121 (100), 98 (22), 69 (11), 55 (12); HRMS (EI): m/z:
calcd for C25H36O6 +Na: 455.24041 [M++Na]; found 455.24074.
Compound 37: A solution of product 35 (80 mg, 0.20 mmol) and DDQ
(48 mg, 0.21 mmol) in CH2Cl2 (7.0 mL) and water (0.4 mL) was stirred
for 15 h at room temperature. For work up, all volatile materials were
evaporated and the residue was purified by flash chromatography
(hexane/EtOAc 9:1!6:1) to give alcohol 37 as a colorless syrup (51 mg,
90%). The analytical and spectroscopic data were in full agreement with
those previously reported in the literature.[8]
Product 38: Et3N (56 mL, 0.40 mmol) and 2,4,6-trichlorobenzoyl chloride
(28 mL, 0.18 mmol) were added to a solution of hexanoic acid (21 mg,
0.18 mmol) in toluene (2.0 mL) and the resulting suspension was stirred
for 1.5 h before a solution of alcohol 37 (51 mg, 0.18 mmol) and DMAP
(11 mg, 0.09 mmol) in toluene (1.0 mL) was introduced. Stirring was con-
tinued for 2 h, the precipitated salts were filtered off through a short pad
of silica, the filtrate was evaporated, and the residue was purified by
flash chromatography (hexane/EtOAc 19:1) to afford the corresponding
ester. This product was dissolved in MeOH (5 mL), water (2.4 mL), and
aq HCl (1m, 1 mL) and the resulting mixture was stirred at 608C for 1 h.
The reaction was then neutralized with aq NaOH (1m), the aqueous
layer was extracted with EtOAc (3”5 mL), the combined organic phases
were washed with brine and dried over anhydrous Na2SO4. The solvent
was evaporated and the residue purified by flash chromatography
(hexane/EtOAc 2:1) to give product 38 as a colorless syrup (58 mg,
94%). 1H NMR (400 MHz, CDCl3): d=5.58 (d, J=15.8 Hz, 1H), 5.48–
5.44 (m, 1H), 5.13 (dd, J=5.4, 1.6 Hz, 1H), 4.97 (dt, J=9.5, 2.6 Hz, 1H),
4.37 (m, 1H), 3.45–3.42 (m, 1H), 2.35–2.33 (m, 3H), 2.17–2.11 (m, 4H),
Nonenolide 35: A solution of diene 34 (543 mg, 1.26 mmol) and the
ruthenium catalyst 6 (120 mg, 0.13 mmol) in CH2Cl2 (700 mL) was re-
fluxed for 15 h. The reaction was quenched with ethyl vinyl ether
(1.8 mL) before the solvent was evaporated and the residue was purified
by flash chromatography (hexane/EtOAc 19:1) to afford (E)-35 (392 mg,
77%) and small amounts of the Z isomer (92 mg, 18%) as colorless
syrups each.
1
Compound (E)-35: H NMR (400 MHz, CDCl3; mixture of two conform-
ers): d=7.22–7.15 (m, 4H), 6.83–6.79 (m, 4H), 5.80–5.37 (m, 4H), 5.02–
4.86 (m, 2H), 4.70–4.59 (m, 4H), 4.48–4.23 (m, 2H), 4.07–3.89 (m, 4H),
3.74 (s, 3H of major conformer), 3.73 (s, 3H of minor conformer), 2.40–
2.20 (m, 2H), 2.09–1.50 (m, 10H), 1.47 (s, 3H of major conformer), 1.39
(s, 3H of minor conformer), 1.36–1.29 (m, major and minor conformer
overlapping, 7H), 0.88 (t, J=7.4 Hz, 3H of minor conformer), 0.87 (t, J=
7.4 Hz, 3H of major conformer); 13C NMR (100 MHz, CDCl3, mixture of
two conformers): d=174.8, 172.3, 159.1, 159.0, 132.0, 131.8, 129.8, 129.1,
128.8, 128.4, 127.1, 122.7, 113.5, 113.5, 108.7, 108.6, 78.0, 77.7, 77.6, 75.8,
75.7, 75.3, 71.6, 71.2, 71.1, 54.9, 33.8, 33.6, 31.6, 29.7, 28.2, 27.6, 26.8, 26.6,
25.8, 25.4, 24.9, 17.8, 17.6, 13.6, 13.6 ppm; IR (film): n˜ =2933, 1725, 1613,
1586, 1514, 1381, 1249, 1221, 1221, 1120, 1053, 822 cmꢁ1; MS (EI): m/z
(%): 404 (1), 283 (9), 225 (5), 121 (100), 95 (5), 77 (4); HRMS (EI): m/z:
calcd for C23H32O6 +Na: 427.20911 [M++Na]; found 427.20929.
Compound (Z)-35: 1H NMR (400 MHz, CDCl3): d=7.19 (d, J=8.6 Hz,
2H), 6.82 (d, J=8.6 Hz, 2H), 5.32 (m, 2H), 4.98–4.94 (m, 1H), 4.78–4.73
(m, 1H), 4.50 (d, J=11.2 Hz, 1H), 4.26–4.22 (m, 2H), 3.97 (t, J=3.4 Hz,
1H), 3.74 (s, 3H), 2.59 (m, 1H), 2.04–2.00 (m, 1H), 1.90–1.75 (m, 2H),
1.64–1.55 (m, 2H), 1.43 (s, 3H), 1.37 (m, 2H), 1.32 (m, 3H), 0.89 ppm (t,
J=7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=171.6, 159.1, 133.4,
129.3, 129.0 (2C), 127.6, 113.6 (2C), 109.8, 78.7, 76.1, 74.4, 72.8, 71.4,
54.9, 35.4, 32.6, 27.9, 25.5, 21.3, 17.8, 13.8 ppm; IR (film): n˜ =2959, 1737,
1612, 1514, 1381, 1370, 1250, 1082, 1042, 869, 827 cmꢁ1; MS (EI): m/z
1.90–1.61 (m, 4H), 1.50–1.40ACHTREU(NG m, 1H), 1.32–1.12 (m, 6H), 0.86 (t, J=
7.0 Hz, 3H), 0.82 ppm (t, J=7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d=172.2, 171.4, 132.0, 122.6, 73.1, 72.7, 71.0, 69.3, 33.8, 33.4, 30.8, 29.5,
27.0, 24.3, 22.0, 17.2, 13.5, 13.4 ppm; IR (film): n˜ =3460, 2959, 1740, 1258,
1078, 986 cmꢁ1; MS (EI): m/z (%): 426 (2), 323 (2), 285 (5), 244 (20), 183
(100), 141 (83), 124 (10), 113 (32), 86 (15), 71 (21), 57 (59), 55 (41), 43
(39), 41 (20), 29 (10); HRMS (EI): m/z: calcd for C18H30O6 +Na:
365.19346 [M++Na]; found: 365.19314.
Compound 39: Prepared analogously as a colorless syrup (53 mg, 86%).
1H NMR (400 MHz, CDCl3): d=5.58 (dd, J=15.8, 1.2 Hz, 1H), 5.48–5.40
(m, 1H), 5.14 (dd, J=5.5, 2.0 Hz, 1H), 4.96 (dt, J=9.6, 2.7 Hz, 1H), 4.37
(m, 1H), 3.43 (dd, J=9.8, 2.7 Hz, 1H), 2.38–2.27 (m, 3H), 2.18–1.17 (m,
27H), 0.82 (t, J=7.4 Hz, 3H), 0.81 ppm (t, J=6.6 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=172.3, 171.4, 132.0, 122.6, 73.1, 72.7, 71.0, 69.3,
33.8, 33.4, 31.5, 29.4, 29.2, 29.2, 29.1, 28.9 (2C), 28.7, 27.0, 24.7, 22.3, 17.2,
13.7, 13.5 ppm; IR (film): n˜ =3530, 3414, 3038, 2957, 1743, 1723, 1259,
1060 cmꢁ1; MS (EI): m/z (%): 342 (1), 257 (2), 141 (49), 113 (23), 99
(100), 86 (11), 71 (29), 67 (10), 57 (18), 55 (25), 43 (41), 41 (14), 29 (11);
HRMS (EI): m/z: calcd for C24H42O6 +Na: 449.28736 [M++Na]; found
449.28750.
1460
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 1452 – 1462

Microcarpalide
FULL PAPER
Compound 40: Prepared analogously as a colorless syrup (66 mg, 94%).
1H NMR (400 MHz, CDCl3): d=7.26–7.14 (m, 5H), 5.53–5.49 (m, 1H),
5.45–5.38 (m, 1H), 5.13 (dd, J=5.5, 1.8 Hz, 1H), 4.94 (dt, J=9.4, 2.5 Hz,
1H), 4.34 (m, 1H), 3.36 (dd, J=9.8, 2.6 Hz, 1H), 2.94 (t, J=7.8 Hz, 2H),
2.69 (t, J=7.8 Hz, 2H), 2.32–2.21 (m, 1H), 2.15–2.01 (m, 4H), 1.89–1.81
(m, 1H), 1.78–1.70 (m, 1H), 1.42–1.13 (m, 3H), 0.82 ppm (t, J=7.4 Hz,
3H); 13C NMR (100 MHz, CDCl3): d=171.3, 171.2, 139.8, 132.0, 128.2
(2C), 127.8 (2C), 126.1, 122.5, 72.9, 72.7, 71.0, 69.6, 35.1, 33.3, 30.5, 29.4,
26.9, 17.2, 13.5 ppm; IR (film): n˜ =3467, 3028, 2959, 1736, 1604, 1497,
1454, 1259, 1078, 1078, 752, 699 cmꢁ1; MS (EI): m/z (%): 376 (3), 291
(10), 244 (13), 141 (5 9), 133 (90), 113 (25), 105 (100), 91 (70), 86 (12), 70
(12), 67 (12), 55 (26), 41 (11); HRMS (EI): m/z: calcd for C21H28O6 +Na:
399.17781 [M++Na]; found 399.17811.
Springer, Berlin, 2003, pp. 511–523; e) G. Fenteany, S. Zhu, Curr.
Top. Med. Chem. 2003, 3, 593–616; f) M. A. Jordan, L. Wilson,
Curr. Opin. Cell Biol. 1998, 10, 123–130.
[4] a) A. Fürstner, D. Kirk, M. D. B. Fenster, C. Aꢂssa, D. De Souza, O.
Müller, Proc. Natl. Acad. Sci. USA 2005, 102, 8103–8108.
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X-ray crystal structure analysis of 9-epi-microcarpalide (26): Empirical
formula=C16H28O5; Mr =300.38 gmolꢁ1; colorless block; crystal size=
0.18”0.06”0.04 mm; orthorhombic; space group=P212121; a=5.2184(6),
b=7.4547(7), c=42.045(13) Š; V=1635.6(5) Š3; T=100 K; Z=4; 1calcd
=
1.220 gcmꢁ3; l=0.71073 Š, m(MoKa)=0.089 mmꢁ1; multiscan absorption
ACHTREUNG
correction; Nonius KappaCCD diffractometer; 5.15<q<33.09; 15611
measured reflections; 3044 independent reflections; 2748 reflections with
I>2s(I), Structure solved by direct methods and refined by full-matrix
least-squares against F2 to R1 =0.042 [I>2s(I)], wR2 =0.094; 203 param-
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ꢁ3
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tron density=+0.4/ꢁ0.2 eŠ
.
X-ray crystal structure analysis of butanolide 27: Empirical formula=
C16H28O5; Mr =300.38 gmolꢁ1; colorless plate; crystal size=0.18”0.06”
0.04 mm; orthorhombic; space group=P212121; a=5.13100(10), b=
6.0500(3), c=19.8385(3) Š; V=1633.75(5) Š3; T=100 K; Z=4; 1calcd
=
1.221 g·cm3; l=0.71073 Š; m(MoKa)=0.089 mmꢁ1; multiscan absorption
ACHTREUNG
correction; Nonius KappaCCD diffractometer; 3.27<q<33.18; 50586
measured reflections; 3557 independent reflections; 3241 reflections with
I>2s(I); structure solved by direct methods and refined by full-matrix
least-squares against F2 to R1 =0.043 [I>2s(I)], wR2 =0.099; 203 param-
eters; OH atoms refined other H atoms riding; S=1.095; residual elec-
ꢁ3
tron density=+0.3/ꢁ0.2 eŠ
.
CCDC-620214 and -620215 contain the supplementary crystallographic
data (excluding structure factors) for this paper. These data can be ob-
tained free of charge from the Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
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Acknowledgements
Generous financial support by the Max-Planck-Gesellschaft, the Chemi-
cal Genomics Center (CGC Initiative of the MPG), the Fonds der Chem-
ischen Industrie (stipend for C.M.), and the Merck Research Council is
gratefully acknowledged. We thank Dr. C. W. Lehmann and Dr. R. God-
dard for performing the crystal structure analyses, Dr. R. Mynott and his
team for expert NMR support, and Mr. D. Laurich for excellent technical
assistance.
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Received: September 24, 2006
Published online: November 24, 2006
1462
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Chem. Eur. J. 2007, 13, 1452 – 1462