Total synthesis of (-)-microcarpalide, a novel microfilament disrupting metabolite

Article abstract of DOI:10.1039/b308709c

The stereoselective total synthesis of (-)-microcarpalide, a recently discovered 10-membered lactone of fungal origin displaying a remarkable disrupting action on actin microfilaments, was accomplished by using ring-closing metathesis (RCM) as the key step for the formation of the medium-sized ring. The diene ester required for the macrocyclization reaction was assembled via DCC-mediated esterification of two suitable partners, each bearing a terminal alkene group. The alcohol fragment was synthesized from n-bromohexane through a seven-step sequence entailing two consecutive stereoselective homologations of chiral boronic esters as strategic transformations for the sequential insertion of the two stereocentres with the final S absolute configuration, using (+)-pinanediol as the chiral director; final elaboration to the desired C₁₁ framework envisaged treatment with an allyl Grignard reagent and oxidative cleavage of the boronic scaffold. In contrast, the acidic fragment was prepared in ten steps from D-tartaric acid, whose C₄ backbone was elongated to the required C₇ skeleton by means of two distinct Swern-Wittig oxidation-homologation sequences.

Full text of DOI:10.1039/b308709c

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Total synthesis of (؊)-microcarpalide, a novel microfilament
disrupting metabolite†
Paolo Davoli,* Alberto Spaggiari, Luca Castagnetti and Fabio Prati*
Dipartimento di Chimica, Università di Modena e Reggio Emilia, via Campi 183, I-41100
Modena, Italy. E-mail: davoli.chemistry@unimo.it; prati.fabio@unimo.it
Received 25th July 2003, Accepted 15th October 2003
First published as an Advance Article on the web 6th November 2003
The stereoselective total synthesis of (Ϫ)-microcarpalide, a recently discovered 10-membered lactone of fungal origin
displaying a remarkable disrupting action on actin microfilaments, was accomplished by using ring-closing
metathesis (RCM) as the key step for the formation of the medium-sized ring. The diene ester required for the
macrocyclization reaction was assembled via DCC-mediated esterification of two suitable partners, each bearing a
terminal alkene group. The alcohol fragment was synthesized from n-bromohexane through a seven-step sequence
entailing two consecutive stereoselective homologations of chiral boronic esters as strategic transformations for the
sequential insertion of the two stereocentres with the final S absolute configuration, using (ϩ)-pinanediol as the
chiral director; final elaboration to the desired C11 framework envisaged treatment with an allyl Grignard reagent and
oxidative cleavage of the boronic scaffold. In contrast, the acidic fragment was prepared in ten steps from -tartaric
acid, whose C4 backbone was elongated to the required C7 skeleton by means of two distinct Swern–Wittig
oxidation–homologation sequences.
relationship studies, we decided to challenge its total synthesis.
Introduction
In this respect, aiming also at shedding light on the mechanism
Secondary metabolites from endophytic fungi have been
of action of this novel fungal metabolite, the synthetic route
receiving a great deal of attention in recent years, and a number
ought to be versatile enough to allow the preparation of
of peculiar structures with specific bioactivities have been
analogues thereof. With this in mind, the retrosynthetic
approach outlined in Scheme 1 was devised.
discovered so far.1,2
Along this line, microcarpalide (1) has been recently char-
acterised as a new secondary metabolite produced by an endo-
phytic fungus (as yet unidentified) isolated from the bark of the
tropical tree Ficus microcarpa L.3 Bioassay-guided purification
of fermentation broths using immunofluorescence microscopy
to test anticytoskeletal activity led to the isolation of a new
substance displaying a remarkable disrupting action on actin
microfilaments, to which the structure 1 was assigned (Fig. 1).3
Fig. 1
Microcarpalide represents a novel alkyl-substituted noneno-
lide structurally related to a family of phytotoxins such as
achaetolide,4 pinolidoxin,5 lethalotoxin,6 putaminoxins7 and
herbarumins,8 from which it differs in the hydroxylation pattern
and the double bond position within the 10-membered lactone,
as well as in the longer side chain at C-10. At concentrations of
0.5–1 µg mLϪ1, microcarpalide was found to disrupt actin
microfilaments in approximately 50% of A-10 cells (from rat
smooth muscle);3 moreover, it displayed a weak cytotoxicity to
mammalian cells,3 thus making it an attractive tool for studying
Scheme 1 Retrosynthetic analysis.
cell motility and metastasis, and a potential lead structure to
develop new anticancer drugs.
Owing to such a peculiar biological activity and attracted by
the structural potential of microcarpalide for structure–activity
Firstly, the macrocyclic framework of microcarpalide was
retrosynthetically disassembled into fragments and
A
B
(Scheme 1) by means of two key disconnections, namely a
ring-closing metathesis (RCM)9 for the construction of the
oxecin ring, and an esterification reaction for assembling the
two alkene fragments. Both fragments contain two stereogenic
† Electronic supplementary information (ESI) available: 1H and 13C
NMR spectra of synthetic microcarpalide (1). See http://www.rsc.org/
suppdata/ob/b3/b308709c/
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 3 8 – 4 7
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
38

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carbon atoms and bear a terminal alkene group that is required
for the RCM macrocyclization.
Fragment A represents a dihydroxy substituted 1-undecene
with S absolute configuration at both adjacent stereocentres
(C-10 and C-1Ј in 1) and can be ultimately disconnected to the
C6 alkyl boronic acid (Scheme 1). In fact, boronic ester chem-
istry provides a highly stereoselective method for the sequential
insertion of stereocentres into the C–B bond.10 In particular,
chain elongation by means of two strategic stereoselective
homologations of the corresponding (ϩ)-pinanediol ester
would allow installation of the C-1Ј and C-10 atoms with the
desired stereochemistry under the guide of the same chiral
director, thus affording chloro derivative C. Final insertion of
the allylic appendage via SN2 displacement and oxidative
removal of the boronic ester would then lead to the required
C11 skeleton of A, providing at the same time the free
hydroxy group at C-10 to be used for the coupling reaction with
partner B.
Fragment B is a 4,5-disubstituted 6-heptenoic acid bearing
two contiguous hydroxy groups in a threo fashion, whose R
absolute configurations can be matched by the pattern dis-
played by -tartaric acid. Retrosynthetically, the C7 backbone
was traced back to a suitably protected -threitol D (Scheme 1)
by use of two different Swern–Wittig oxidation–homologation
sequences (each one with an appropriate phosphorus ylide),
which would allow chain elongation at both termini of the C4
chiral synthon D. In turn, threitol derivative D can be easily
prepared from -tartaric acid, as reported in the literature for
the -enantiomer.
Scheme 2 Synthesis of fragment A. Reagents and conditions: a. Mg,
Et2O, reflux, then trimethyl borate, Ϫ78 ЊC rt, 72%; b. (1S,2S,3R,
5S)-(ϩ)-pinanediol, Et2O, rt, 71%; c. (dichloromethyl)lithium, THF,
Ϫ100 ЊC rt, 64%; d. benzyl alcohol, n-BuLi, THF, Ϫ78 ЊC rt,
then reflux, 70%; e. (dichloromethyl)lithium, ZnCl2, THF, Ϫ100 ЊC
rt, 61%; f. allylmagnesium bromide, THF, Ϫ78 ЊC rt, 74%; g. H2O2,
NaOH, THF, 0 ЊC 45 ЊC, 90%.
Results and discussion
Synthesis of fragment A
For our synthesis we envisaged using the stereoselective
homologation of chiral boronic esters developed by Matteson
and coworkers10 to install the two adjacent stereocentres
with the required S absolute configuration. In particular,
(ϩ)-pinanediol was chosen as the chiral auxiliary to direct the
stereochemical outcome of the homologation reaction; in fact,
the (ϩ) isomer is known to induce the S configuration when
used as the chiral director.10,11
assigned to 1-chloroheptaneboronate 5. Subsequently, exposure
to a solution of (benzyloxy)lithium (prepared by titration
of benzyl alcohol with n-butyllithium in the presence of 1,10-
phenanthroline as indicator) in THF resulted in the SN2 nucleo-
philic displacement of the chlorine atom,11 thus affording the
corresponding 1-benzyloxy derivative 6 in 70% yield (Scheme
2). Compound 6 bears a protected hydroxy group with R
absolute configuration,14 which corresponds to the desired 1ЈS
stereochemistry in 1. More interestingly, benzyl ether 6 could
be also obtained directly from 4 through a one-pot procedure
that avoided the isolation of the α-chloroboronic ester 5 and,
gratifyingly, proceeded with higher overall yield (55%).
By close analogy, the second asymmetric centre was intro-
duced sequentially through stereoselective homologation of
α-benzyloxy boronic ester 6. Addition of (dichloromethyl)-
lithium at Ϫ100 ЊC in THF,13 followed by treatment with zinc
chloride (1 M solution in Et2O)10 provided 2-benzyloxy-1-
chloroboronate 7 in good yield (61%) (Scheme 2). In the
absence of zinc chloride, the homologation reaction was found
to display incomplete conversion and proceeded in lower yield,
albeit with excellent diastereoselectivity. In contrast, addition
of zinc chloride resulted in better conversions and yield, with-
out affecting d.e. NMR spectroscopy confirmed the insertion of
a new carbon atom (δH 3.65 ppm, doublet; δC 46.1 ppm, broad
signal due to the C–B bond) and the Hendo proton was used
again as diastereotopic marker to assess d.e., which was found
to be greater than 98%. By use of the same chiral director, the S
absolute configuration was installed.
The synthetic approach to fragment A commenced from
commercially available n-bromohexane (2), which was
converted into the corresponding Grignard derivative; reaction
between n-hexylmagnesium bromide and trimethyl borate in
diethyl ether at Ϫ78 ЊC, followed by acidic work-up, furnished
boronic acid 3 on a multigram scale in 72% yield (Scheme 2);12
acid 3 undergoes spontaneous dehydration to form the
corresponding trimeric boroxine, as shown by MS analysis.
Esterification with the chiral auxiliary (ϩ)-pinanediol in dry
Et2O at rt readily afforded the corresponding boronate 4 (71%
yield).10 The presence of a carbon–boron bond was confirmed
on the basis of the 13C NMR spectrum displaying a diagnostic
broad signal at 10.5 ppm for C-1, which could be detected
only in highly concentrated samples. Chiral boronate 4 is an
air-stable liquid that can be easily handled and stored over time
on the lab shelf.10 Hence, the stage was set to exploit Matteson’s
asymmetric homologation for inserting the first stereocentre.
Addition of in situ-generated (dichloromethyl)lithium to chiral
boronic ester 4 at Ϫ100 ЊC in THF13 provided α-chloro deriv-
ative 5 in good yield (64%) and high diastereoisomeric excess
(d.e. ≥ 98%) (Scheme 2). The presence of a new signal at 3.48
ppm in the 1H NMR spectrum indicated the successful
insertion of a chlorine-bearing carbon atom into the C–B bond
of 4, whereas the diastereoselectivity of the homologation was
determined by means of the diagnostic signal of the Hendo
proton of the pinanyl moiety (1.19 ppm, doublet).11 Since
(ϩ)-pinanediol is reported to direct the formation of (S)-α-
chloroboronic esters,10,11 the S absolute configuration could be
The desired C11 backbone of fragment A was then con-
structed by exploiting the ease of reaction of α-halo boronic
esters with C-nucleophiles, namely Grignard reagents.10 In the
case of 1-chlorooctaneboronate 7, an allylic appendage was
required for such a purpose. Accordingly, a solution of 7 in
THF was reacted with allylmagnesium bromide at Ϫ78 ЊC,
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 3 8 – 4 7
39

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Scheme 3 Synthesis of fragment B. Reagents and conditions: a. 2,2-dimethoxypropane, p-TsOH, reflux, 91%; b. LAH, Et2O, reflux, 87%;
c. TBDMSCl, NaH, THF, 91%; d. Swern oxidation (oxalyl chloride–DMSO, CH2Cl2, triethylamine, Ϫ70 ЊC), 90%; e. (ethoxy-
carbonylmethylene)triphenylphosphorane, DMF, rt, 94%; f. H2, Pd/C, EtOH, rt, 99%; g. TBAF, THF, rt, 82%; h. Swern oxidation (oxalyl chloride–
DMSO, CH2Cl2, triethylamine, Ϫ72 ЊC), 76%; i. methyltriphenylphosphonium bromide, n-BuLi, THF, Ϫ20 ЊC
rt, 42%; j. KOH, THF–MeOH–
water, rt, 81%.
affording compound 8 in 74% yield (Scheme 2). Since nucleo-
philic displacements on α-chloroboronates are known to occur
with SN2 mechanism,14 alkene 8 has opposite configuration at
the boron-bearing C atom with respect to 7 (even though the
same S chiral descriptor is used for priority reasons). Hence,
boronic ester 8 already features the two adjacent asymmetric
centres with the correct final stereochemistry required by 1.
Finally, oxidative removal of the boronic scaffold by treatment
with basic hydrogen peroxide in THF,10,11,15 which is reported to
occur with retention of configuration,16 yielded the desired
alcohol 9 (90%) with S,S absolute configuration (Scheme 2),
thus releasing the free hydroxy function required for the
coupling reaction with fragment B and meanwhile retaining the
benzylic protection at the adjacent position (the C-1Ј-to-be in 1)
to be cleaved off only at the end of the overall sequence.
treatment with triethylamine,20–22 gave aldehyde 18 (76%) which
was immediately homologated with methylenetriphenyl-
phosphorane in THF at Ϫ20 ЊC to provide 6-heptenoate
derivative 19 in 42% yield (Scheme 3).25 Batty and Crich used
buffered pyridinium chlorochromate (PCC) oxidation to
prepare the (4S,5R) enantiomer of the -threitol-derived
aldehyde 18 in order to avoid migration of the isopropylidene
group to the 5,6 site, which they experienced on the erythro
analogue using other oxidation methods, including Swern’s.25
In contrast, however, we did not observe any 5,6-isopropylidene
shift during Swern oxidation of either alcohol 13 or 17, and
both could be converted into the desired aldehyde 14 and 18,
respectively. Saponification of the ester 19 with KOH in THF–
MeOH–water (2 : 2 : 1) afforded the desired free acid 20 in 81%
yield,25 which was directly employed for the next coupling step
with alcohol 9.
Synthesis of fragment B
Completion of the total synthesis
For the preparation of the acidic partner B, we devised using
-tartaric acid as the starting chiral synthon, to which a number
of transformations described in the literature for the corre-
sponding -enantiomer were applied.
Firstly, -(Ϫ)-tartaric acid (10) was refluxed with 2,2-dimeth-
oxypropane in the presence of p-toluenesulfonic acid to yield
the corresponding dimethyl ester acetonide 11 in excellent yield
(Scheme 3).17 Subsequent lithium aluminium hydride reduction
in diethyl ether gave -(Ϫ)-threitol acetonide 12 (87% yield),18
which was treated with sodium hydride in THF and reacted
with tert-butyldimethylsilyl chloride at rt to afford the mono-
silylated derivative 13 on a multigram scale in excellent yield
(91%) (Scheme 3).19
Alcohol 13 was oxidised to aldehyde 14 under Swern
conditions at Ϫ70 ЊC;20–22 1H NMR analysis of the crude
residue revealed the presence of the diagnostic proton at
9.78 ppm as a doublet, thus confirming the identity of the
product, which was used without further purification for the
next Wittig reaction. Homologation of 14 with (ethoxycarb-
onylmethylene)triphenylphosphorane in anhydrous DMF at
rt22 smoothly afforded alkene 15 as an 85 : 15 trans–cis mixture
in 85% combined yield (over two steps) (Scheme 3); separation
of the geometric isomers was not required since the newly
formed double bond was to be hydrogenated in the following
step. Catalytic hydrogenation of alkene 15 with 10% palladium
on charcoal in ethanol under H2 atmosphere furnished hexano-
ate 16 in quantitative yield.23 Subsequently, removal of the
TBDMS protecting group with tetra-n-butylammonium fluor-
ide in dry THF at rt24 provided alcohol 17 in excellent yield
(82%), thus releasing the hydroxy function at C-6 to be used for
the final chain elongation, yet again by means of a Swern–
Wittig sequence. Oxidation of 17 in the presence of oxalyl
chloride–DMSO in dry CH2Cl2 at Ϫ72 ЊC, followed by
With the two alkene partners in hand, assembly of the dienic
substrate for the crucial macrocyclization reaction via ring-
closing metathesis (RCM)9 was performed by coupling alcohol
9 to acid 20 with DCC in the presence of DMAP in diethyl
ether at rt, to give ester 21 in 85% yield (Scheme 4). A highly-
diluted solution (0.45 mM) of diene 21 in anhydrous degassed
dichloromethane was then refluxed for 48 h under argon
atmosphere in the presence of Grubbs’ catalyst I (17 mol %)
(Fig. 2),9 to afford the 10-membered lactone 22 in excellent
yield (92%) as a mixture of two geometric isomers in a 67 : 33
E–Z-ratio (Scheme 4). The desired trans-oxecin (E)-22 could be
separated by column chromatography from the cis-analogue
(Z)-22; the stereochemistry of the newly formed double bond
was unambiguously assigned by comparison of the J7–8 coup-
ling constants (15.6 against 10.3 Hz, respectively).
The same stereoselectivity in the RCM cyclization has been
also reported by Marco and coworkers in the course of the first
total synthesis of microcarpalide,26 by using a closely related
diene ester that only differed in the protection at 1Ј-OH,
whereas formation of the unwanted (Z)-olefin resulted
upon exposure to second-generation Grubbs’ catalyst II
(Fig. 2).
The lack of stereocontrol in the synthesis of medium-sized
rings by RCM has been repeatedly addressed in the literature
(for leading references, see ref. 27) and still represents a major
drawback of this reaction. Mixtures of (E) and (Z) cyclo-
alkenes are usually formed and, in addition, 8- to 11-membered
rings are sensitive to the reverse process (ROM or ROMP)
because of their intrinsic ring strain.27 Therefore, a reliable and
general method of controlling the geometry of the newly
formed double bond in RCM macrocyclizations has been called
for. In this respect, second-generation Grubbs’ catalyst II is
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 3 8 – 4 7
40

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In contrast, the most recent total synthesis of microcarpalide
by Gurjar et al. featured an RCM reaction with Grubbs’
catalyst I which proceeded with excellent stereoselectivity
(10 : 1), yielding almost exclusively the required (E)-alkene
from a diene ester similar to 21, except for the presence of two
benzyl groups protecting the hydroxyls at positions 5 and 6, as
well as for a methoxyethoxymethyl substituent at 1Ј-OH.30
Hence, the nature of the diene substrate that is subjected to the
RCM reaction, and especially of its appendages, seems to play
an important role in determining the stereochemical outcome
of the metathetic process, at least for 10-membered lactones,
thus making it difficult to draw up general rules for controlling
selectivity in RCM reactions, even within a given catalyst.
Treatment of (E)-22 with titanium tetrachloride in CH2Cl2 at
0 ЊC30–31 (Scheme 4) resulted in the simultaneous removal of
both protective groups, affording a single product whose
spectral data matched perfectly those reported by Hemscheidt3
for the natural compound. Like natural microcarpalide, when
dissolved in acetonitrile synthetic 1 appears as a mixture of two
slowly interconverting conformers in a 76 : 24 ratio, as deter-
mined from the 1H NMR spectrum by using signals which
displayed suitable separation, namely those for H-10 (4.84 ppm
for the major conformer and 4.63 ppm for the minor one) and,
in addition, 5-OH (3.09 and 3.19 ppm, respectively). This
conformer ratio is identical to the 3.5 : 1 value described in the
literature for the natural 1 in the same solvent.3
At present, only two total syntheses of microcarpalide have
been disclosed in the literature so far.26,30 Like ours, both rely on
the construction of the 10-membered skeleton by means of a
ring-closing metathesis (RCM) macrocyclization using Grubbs’
catalyst I as the crucial step, thus requiring the synthesis of
two alkene partners, namely A and B (Scheme 1). Subunit B
was always prepared from the chiral pool, by starting either
from -tartaric acid26 or -mannose;30 the latter, however,
required a cumbersome and unduly lengthy sequence, thus
making the tartrate-derived one more attractive and applicable,
even though a more straightforward and, possibly, enantio-
selective approach would be desirable for future developments.
As far as partner A is concerned, it was previously synthesized
by means of diastereoselective addition of an allyltin reagent to
an (R)-glycidol-derived aldehyde as the key step26 or, later,30
through asymmetric dihydroxylation of a suitable alkene
precursor, followed by a long sequence of transformations. In
contrast, here a completely different and original route to
fragment A was followed, which fully exploited the stereo-
selective homologation of chiral boronic esters10 as a powerful
tool to introduce sequentially stereocentres with high
diastereoselectivity and desired absolute stereochemistry by use
of the same chiral auxiliary.
Scheme 4 Completion of the total synthesis. Reagents and conditions:
i., DCC, DMAP, Et2O, rt, 85%; ii., Grubbs’ catalyst I, CH2Cl2, reflux,
92%; iii., TiCl4, CH2Cl2, 0 ЊC, 66%.
Fig.
2
Catalysts for ring-closing metathesis (RCM): I Grubbs’
catalyst; II 2nd generation Grubbs’ catalyst; III Fürstner’s catalyst.
known to favour the formation of the thermodynamically more
stable (Z)-isomers.27
Within 10-membered lactones, for instance, in the total
synthesis of pinolidoxin by Liu and Kozmin, the presence of
an acetonide group spanning the two hydroxy functions in
positions α and β to one of the alkene appendages was found
to result in the stereoselective formation of the undesired (Z)-
olefin in the key RCM step with catalyst II, whereas removal of
the acetonide prior to metathetic ring closure determined a loss
of stereocontrol in double bond formation.28 Similarly, but
opposite in sense, excellent stereoselectivity in RCM was
reported by Fürstner’s group in the course of their recent total
synthesis of herbarumins and pinolidoxin,27 a family of phyto-
toxic nonenolides related to 1, by using the newly developed
ruthenium indenylidene catalyst III29 (Fig. 2). In particular,
the stereocontrol of the key RCM macrocyclization was suc-
cessfully reversed by simply switching to ruthenium complex
III, resulting in the selective formation of the desired (E)-
oxecin in a 10 : 1 ratio with the (Z)-isomer, which, in contrast,
was formed exclusively when carbene II was employed as the
catalyst.27
Prompted by such promising performances, we also exposed
diene 21 to a catalytic amount of Fürstner’s complex III,29
under similar reaction conditions. Although compound 21 was
successfully metathesized to lactone 22, unfortunately the
reaction afforded a mixture of (E) and (Z) isomers in about
2 : 1 ratio, respectively, as determined on the basis of 1H NMR
analysis, by using the signal belonging to H-7 [for (E)-olefin:
5.32 ppm, doublet of doublets; for (Z): 5.50 ppm, triplet] as
diagnostic marker.
Conclusions
In summary, a new stereoselective total synthesis of the micro-
filament disrupting agent microcarpalide (1), a secondary
metabolite produced by an endophytic fungus, has been
accomplished. Formation of the required 10-membered lactone
was achieved by means of ring-closing metathesis (RCM) of
a suitable diene ester that was assembled by coupling the
two advanced fragments A and B (i.e. 9 and 20, respectively).
Fragment A has been synthesized in 7 steps from n-bromo-
hexane through two consecutive stereoselective homologations
of chiral boronic esters 4 and 6 as key transformations, which
allowed the sequential introduction of the two asymmetric
centres with the final S absolute configuration, using (ϩ)-
pinanediol as the chiral auxiliary. Final elaboration entailed
insertion of the allylic appendage on derivative 7 by nucleo-
philic displacement of the chlorine atom, followed by oxidative
removal of the boronic scaffold to reveal alcohol 9. In turn,
fragment B has been prepared in 10 steps from -(Ϫ)-tartaric
acid. The required C7 backbone of 20 has been constructed
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 3 8 – 4 7
41

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from the C4 starting synthon using two different Swern–Wittig
oxidation–homologation sequences as key steps, each one with
a suitable phosphorus ylide. Hence, -tartrate-derived mono-
silylated threitol 13 was oxidized and homologated to afford
alkene 15, which was hydrogenated and exposed to TBAF, thus
revealing alcohol 17. Swern oxidation and Wittig methylenation
furnished ester 19, whose saponification yielded 6-heptenoic
acid 20. Completion of the total synthesis entailed a DCC-
mediated coupling between partners 9 and 20, followed by
RCM using Grubbs’ catalyst I, providing the desired 10-mem-
bered macrocyclic framework with good stereoselectivity
(67 : 33 E–Z) and excellent yield. Finally, cleavage of protective
groups afforded a single product whose spectroscopic proper-
ties were identical with those of the natural compound 1.
With a view to future structure–activity relationship (SAR)
studies, the synthetic route to 1 herein disclosed appears flexible
enough to allow the preparation of microcarpalide analogues,
by simply varying the starting materials and/or the chiral
director employed. In particular, our total synthesis features an
original enantioselective approach to fragment A that allows
the asymmetric insertion of suitably labelled atoms in specific
positions by means of Matteson’s stereoselective homolo-
gation, thus making available labelled derivatives which could
be of value for shedding light on the mechanism of action of
this novel fungal metabolite endowed with such a peculiar
biological activity. Further applications of this methodology
toward the preparation of analogues for SAR studies are being
currently pursued in our laboratory and will be reported in due
course.
about 50 min. In a separate flask, trimethyl borate (1.41 mL,
12.10 mmol) was dissolved in the same solvent (8 mL), and the
milky solution of n-hexylmagnesium bromide was slowly added
via syringe at Ϫ78 ЊC under mechanical stirring and Ar atmos-
phere over 10 min, washing with a further 2 mL of ether; during
addition, the temperature rose and was carefully maintained
below Ϫ60 ЊC. The reaction mixture was stirred overnight and
left to cool to rt, affording a light yellowish precipitate. After
dilution with Et2O (20 mL), the mixture was cooled at 0 ЊC and
10% aqueous sulfuric acid (12 mL) was added dropwise; the
clear solution thus obtained was warmed and stirred for 20 min
at rt. The yellow ethereal phase was separated and the aqueous
layer extracted with ether (3 × 12 mL); the white emulsion that
formed initially upon separation was subjected to the same
extraction protocol. The organic phases were pooled, washed
with water and brine, and dried over MgSO4. Filtration and
concentration in vacuo afforded the title compound 3 (5.69 g,
72%) as a white solid (mp 68–71 ЊC) (lit.12,32,33 88–90 ЊC) which
was used as such in the following step without further
purification. 1H NMR (200 MHz, as the corresponding borox-
ine): δ 0.79–1.00 (5H, m, CH2B and CH3), 1.22–1.53 (8H, m,
4 × CH2). 13C NMR: δ 14.3, 23.0, 25.9, 30.0, 32.0 (CH2B not
seen). MS, m/z (as boroxine): 336 (Mϩ, 75%), 306 (26), 278 (20),
265 (80), 250 (5), 195 (56), 167 (30), 84 (100), 69 (35), 55 (60).
[Found: C, 64.3; H, 11.6. C18H39B3O3 (boroxine) requires: C,
64.4; H, 11.7%].
(؉)-Pinanediol hexaneboronate (4). Boronic acid 3 (920 mg,
7.08 mmol) was dissolved in anhydrous diethyl ether (10 mL)
and stirred at rt in the presence of (1S,2S,3R,5S)-(ϩ)-
pinanediol (1.21 g, 7.08 mmol), which was added portionwise
over 1 h 15 min, until TLC analysis (light petroleum–ethyl
acetate 80 : 20) showed no disappearance of the pinanediol
itself. After rotary evaporation under reduced pressure, the
desired ester 4 was separated from the unreacted pinanediol by
means of column chromatography (light petroleum–ethyl acet-
ate 80 : 20), affording 1.002 g (71%) of a colourless oil (bp 80
ЊC, 0.09 mbar), [α]D ϩ20.9 (c 0.90). 1H NMR (200 MHz):
δ 0.78–0.95 (8H, m, 3 × H-6, 2 × CH2B and pinanyl CH3), 1.15
(1H, d, J 12.3, pinanyl Hendo), 1.24–1.56 (14H, m, H-2 to H-5
and 2 × pinanyl CH3), 1.80–2.45 (5H, m, pinanyl protons), 4.27
(1H, dd, J 8.6, 1.8, pinanyl CHOB). 13C NMR: δ 10.5 (m,
BCH2), 14.4, 22.9, 24.3, 24.5, 26.8, 27.5, 29.1, 30.1, 32.0, 32.5,
36.0, 38.5, 40.0, 51.8, 77.9, 85.6. MS, m/z: 264 (Mϩ, 11%), 249
(48), 235 (3), 223 (26), 195 (67), 181 (20), 168 (59), 134 (69), 109
(31), 83 (90), 67 (100), 55 (95). (Found: C, 72.7; H, 11.0.
C16H29BO2 requires: C, 72.7; H, 11.1%).
Experimental
General
1H and 13C NMR spectra were recorded in CDCl3 solution
(unless otherwise noted) on a Bruker DPX 200 or AMQ 400
MHz spectrometer; chemical shifts are reported in δ values
from TMS as internal standard; coupling constants (J) are
given in Hz. For mass spectral determinations a Finnigan MAT
SSQ A and a Hewlett Packard HP5989A mass spectrometer
were used (EI, 70 eV). Elemental analyses were performed with
a Carlo Erba Elemental Analyzer 1110. Optical rotations were
recorded in chloroform (unless stated otherwise) at 20 ЊC on a
Perkin-Elmer 241 polarimeter and are in 10Ϫ1 deg cm2 gϪ1. All
organic solvents were dried and distilled by standard methods
prior to use and all reactions requiring anhydrous conditions
were carried out using oven-dried and argon-flushed glassware.
Chromatographic purification of compounds was performed
on silica gel (particle size 0.05–0.20 mm). Analytical TLC was
performed on pre-loaded (0.25 mm) glass supported silica gel
plates (Merck, Kieselgel 60, F254). Compounds were visualized
by exposure to UV light, I2 vapours and by dipping the plates in
1% Ce(SO4)2ؒ4H2O, 2.5% (NH4)Mo7O24ؒ4H2O in 10% sulfuric
acid followed by heating on a hot plate. (1S,2S,3R,5S)-(ϩ)-
Pinanediol and all other reagents were obtained from Aldrich.
Grubbs’ catalyst I was purchased from Strem Chemicals Ltd.,
(؉)-Pinanediol (1S )-1-chloroheptaneboronate (5). A solution
of anhydrous methylene chloride (183 µL, 2.85 mmol) in freshly
distilled dry THF (4 mL) was cooled at Ϫ100 ЊC and treated
with a 2.5 M solution of n-BuLi in hexanes (912 µL, 2.28 mmol)
under Ar flow and mechanical stirring; n-BuLi addition took
place over a 10 min period and the reaction mixture was then
stirred for an additional 30 min, carefully maintaining the tem-
perature below Ϫ100 ЊC. A white precipitate formed, which
slowly faded. Pinanediol ester 4 (500 mg, 1.90 mmol) was dis-
solved in THF (3 mL) and slowly added dropwise to the
(dichloromethyl)lithium solution at Ϫ100 ЊC. The reaction
mixture was stirred under argon atmosphere and allowed to
warm to rt overnight. After rotary evaporation, the residue
was diluted with light petroleum (100 mL) and treated with
saturated NH4Cl (25 mL). The aqueous phase was extracted
with light petroleum (2 × 50 mL), the combined organic phases
were dried over Na2SO4, filtered and concentrated under
reduced pressure. Column chromatography on SiO2 using light
petroleum–diethyl ether 97 : 3 as the eluant gave homologation
product 5 (380 mg, 64%) as a clear yellow liquid, [α]D ϩ27.3
(c 0.87). 1H NMR (200 MHz): δ 0.88–0.94 (6H, m, 3 × H-7 and
pinanyl CH3), 1.19 (1H, d, J 10.9, pinanyl Hendo), 1.24–1.56
whereas
dichloro(3-phenyl-1H-inden-1-ylidene)bis(tricyclo-
hexylphosphine)ruthenium() (Fürstner’s catalyst, III) was
prepared according to Fürstner et al.29
Synthesis of fragment A
Hexaneboronic acid (3)12,32,33. Activated magnesium turnings
(4.03 g, 16.58 mmol) were suspended in anhydrous diethyl ether
(5 mL) in a 100-mL two-necked round bottom flask equipped
with a reflux condenser and a dropping funnel. A portion
of neat 1-bromohexane (0.4 mL, 2.85 mmol) was added
straightaway along with a few crystals of I2 in order to initiate
the reaction. Once the mixture was refluxing, the remaining
halide (1.3 mL, 9.25 mmol) dissolved in Et2O (3 mL) was added
dropwise, and the reaction was kept under gentle reflux for
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 3 8 – 4 7
42

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(16H, m, H-2 to H-6 and 2 × pinanyl CH3), 1.80–2.45 (5H, m,
pinanyl protons), 3.48 (1H, dd, J 7.7, 6.8, H-1), 4.38 (1H, dd,
J 8.8, 2.0, pinanyl CHOB). 13C NMR: δ 14.4, 23.0, 24.3, 26.7,
27.4, 27.6, 28.8, 29.1, 31.8, 34.6, 35.7, 38.6, 39.8, 51.6, 78.9, 87.0
(ClCHB not seen). MS, m/z: 312 (Mϩ, 3%), 297 (4), 217 (32),
199 (40), 173 (36), 158 (43), 145 (100), 134 (98), 118 (78), 96
(52), 83 (70), 67 (54), 55 (57). (Found: C, 65.2; H, 9.7. C17H30-
BClO2 requires: C, 65.3; H, 9.7%).
(1H, d, J 12.0, CH2Ph), 7.20–7.45 (5H, m, arom). 13C NMR:
δ 14.4, 23.0, 24.3, 25.8, 26.7, 26.8, 28.8, 29.6, 32.1, 32.5, 35.6,
38.5, 39.8, 46.1 (br, CHCl), 51.6, 72.9, 78.9, 80.9, 87.2, 127.6,
128.1, 128.5, 139.0. MS, m/z: 324 ([M Ϫ PhCH2OH]ϩ, 30%), 309
(100), 293 (2), 247 (4), 147 (3), 133 (5), 119 (10), 91 (6). (Found:
C, 69.6; H, 8.9. C25H38BClO3 requires: C, 69.4; H, 8.8%).
(؉)-Pinanediol
(1S,1ЈS )-1-(1Ј-benzyloxy)heptylbut-3-
eneboronate (8). A 1 M solution of allylmagnesium bromide in
diethyl ether (1.88 mL, 1.88 mmol) was slowly added via syringe
over 10 min to a stirred solution of chloro derivative 7 (730 mg,
1.71 mmol) in anhydrous THF (20 mL) at Ϫ78 ЊC under Ar
flow. The mixture was warmed to rt overnight, and a white
precipitate began to form while the temperature was rising. The
yellow solution was then diluted with light petroleum (20 mL),
treated with saturated NH4Cl (20 mL) and the organic phase
was separated and dried over MgSO4. Filtration and concen-
tration in vacuo afforded an oily residue which was purified by
chromatography (light petroleum–diethyl ether 95 : 5) to give 8
as a pale yellow oil (575 mg, 74%), [α]D ϩ12.7 (c 4.4). 1H NMR
(200 MHz): δ 0.83 (3H, s, pinanyl CH3), 0.89 (3H, t, J 6.3,
H-7Ј), 1.20 (1H, d, J 10.1, pinanyl Hendo), 1.24–1.45 (16H, m,
H-2Ј to H-6Ј and 2 × pinanyl CH3), 1.50–2.40 (8H, m, H-1, H-2
and pinanyl protons), 3.58 (1H, q, J 5.5, H-1Ј), 4.26 (1H, dd,
J 8.8, 2.0, pinanyl CHOB), 4.53 (2H, AB system, J 11.2,
CH2Ph), 4.90–5.09 (2H, m, H-4), 5.88 (1H, ddt, J 16.9, 10.1,
6.5, H-3), 7.18–7.40 (5H, m, arom). 13C NMR: δ 14.4, 23.0,
24.4, 25.8, 26.7, 27.5, 29.1, 29.8, 31.7, 32.2, 33.1, 35.9, 38.5,
39.9, 51.6, 71.3, 78.0, 81.2, 85.8, 115.0, 127.4, 127.9, 128.4,
139.4, 139.7. The EIMS was unobtainable. (Found: C, 76.8; H,
9.8. C28H43BO3 requires: C, 76.7; H, 9.9%).
(؉)-Pinanediol (1R)-1-benzyloxyheptaneboronate (6). Benzyl
alcohol (759 µL, 7.34 mmol) was dissolved in anhydrous THF
(6 mL) in a 25-mL flask equipped with a dropping funnel and
a reflux condenser, and a few crystals of oven-dried (110 ЊC,
20 min) 1,10-phenanthroline were introduced. The solution was
cooled at Ϫ78 ЊC and a 2.5 M solution of n-BuLi in hexanes
(3.22 mL, 8.00 mmol) was added until the mixture turned dark
red. After stirring for 15 min at Ϫ78 ЊC and for an additional
5 min at rt under argon flow, chloro derivative 5 (2.081 g,
6.67 mmol) in 6 mL THF was slowly added via syringe to the
reaction flask at Ϫ78 ЊC. The pale yellow solution thus obtained
was allowed to warm to rt overnight under Ar atmosphere.
Complete conversion was reached after gentle refluxing of the
reaction mixture for 2 h. After dilution with Et2O (1 : 1 v/v with
respect to THF) and treatment with saturated NH4Cl (10 mL),
the organic phase was separated and the aqueous layer
extracted with ether (3 × 60 mL). The organic phases were
pooled, dried (Na2SO4), filtered and rotary evaporated in vacuo.
The residue was purified by chromatography (light petroleum–
diethyl ether 95 : 5), affording benzyloxy derivative 6 as a
fruit-scented bright yellow oil (1.75 g, 70%), [α]D ϩ4.8 (c 2.4). In
separate experiments, the title compound 6 was also prepared
on a gram scale directly from boronate 4 in a total 55% yield
(over two steps), following an improved one-pot procedure that
did not require isolation of the intermediate chloro derivative 5.
1H NMR (200 MHz): δ 0.86 (3H, s, pinanyl CH3), 0.89 (3H, t,
J 5.5, 3 × H-7), 1.17 (1H, d, J 10.8, pinanyl Hendo), 1.24–1.52
(16H, m, H-2 to H-6 and 2 × pinanyl CH3), 1.62–2.45 (5H, m,
pinanyl protons), 3.36 (1H, t, J 6.4, H-1), 4.33 (1H, dd, J 8.8,
2.0, pinanyl CHOB), 4.52 (1H, d, J 12.1, CH2Ph), 4.62 (1H, d,
J 12.1, CH2Ph), 7.19–7.42 (5H, m, arom). 13C NMR: δ 14.4,
23.0, 24.4, 26.9, 27.4, 29.1, 29.8, 31.8, 32.2, 35.8, 38.5, 39.9,
51.6, 68.3 (br, CHB), 72.5, 78.5, 86.5, 127.6, 128.2, 128.5, 139.6.
MS, m/z: 384 (Mϩ, 4%), 297 (6), 235 (7), 135 (61), 107 (25),
97 (43), 91 (100), 69 (17), 55 (43). (Found: C, 74.8; H, 9.6.
C24H37BO3 requires: C, 75.0; H, 9.7%).
(4S,5S )-5-Benzyloxyundec-1-en-4-ol (9). Allyl boronate 8 (50
mg, 0.11 mmol) was dissolved in THF (2 mL) and treated with
a 2.2 M solution of NaOH (152 µL, 0.34 mmol) at 0 ЊC for 10
min under magnetic stirring. 35% Hydrogen peroxide (34 µL,
0.30 mmol) was added at 0 ЊC and the mixture was stirred for 15
min, during which a yellow precipitate formed. The reaction
was then warmed to 45 ЊC and the milky solution stirred for an
additional 1.5 h, until TLC analysis (light petroleum–diethyl
ether 95 : 5) showed disappearance of the starting material.
After addition of diethyl ether (15 mL) and water (5 mL), the
organic layer was separated and dried over MgSO4. Purification
of the bright yellow residue obtained upon filtration and rotary
evaporation was achieved by column chromatography, using
light petroleum–diethyl ether 70 : 30 as the eluant, thus afford-
ing the title compound 9 as a colourless liquid (39 mg, 90%),
[α]D ϩ17.8 (c 1.5), which upon refrigeration slowly crystallised
(؉)-Pinanediol (1S,2S )-2-benzyloxy-1-chlorooctaneboronate
(7). By close analogy to the synthesis of 5 reported above,
(dichloromethyl)lithium was prepared by treatment of di-
chloromethane (158 µL, 2.46 mmol) in THF (4 mL) with
n-BuLi (2.5 M solution in hexanes, 676 µL, 1.64 mmol) at Ϫ100
ЊC. Benzyl ether 6 (591 mg, 1.54 mmol) in THF (4 mL) was
then added to such a mixture at Ϫ100 ЊC, and after 5 min a
1 M solution of ZnCl2 in diethyl ether (923 µL, 0.92 mmol)
was slowly dropped in. The reaction was stirred under Ar
atmosphere and left to warm to rt overnight. The clear and
colourless solution thus obtained was concentrated under
reduced pressure, diluted with light petroleum (40 mL) and
treated with saturated NH4Cl (10 mL). After separation of the
organic layer, the aqueous phase was extracted with light
petroleum (3 × 15 mL), and the organic phases were pooled,
dried over MgSO4, filtered and rotary evaporated. After
chromatographic purification (light petroleum–diethyl ether
95 : 5), the title compound 7 was obtained as a pale yellow
1
in transparent needles. H NMR (200 MHz): δ 0.90 (3H, t,
J 6.7, H-11), 1.22–1.81 (10H, m, H-6 to H-10), 2.15–2.45 (3H,
m, OH and H-3), 3.34 (1H, q, J 5.5, H-5), 3.56–3.72 (1H, m,
H-4), 4.52 (1H, d, J 11.3, CH2Ph), 4.67 (1H, d, J 11.3, CH2Ph),
5.04–5.16 (2H, m, H-1), 5.87 (1H, ddt, J 17.6, 9.6, 7.0, H-2),
7.24–7.40 (5H, m, arom). 13C NMR: δ 14.4, 22.9, 25.5, 29.9,
30.6, 32.1, 38.5, 72.4, 72.8, 81.8, 117.6, 128.1, 128.2, 128.8,
135.4, 140.1. MS, m/z (as the corresponding TMS ether, by
treatment in situ with neat MSTFA at 70 ЊC for 1 h): 333
([M Ϫ 15]ϩ, 0.5%), 307 (5), 241 (0.6), 205 (6), 152 (6), 143 (44),
91 (100), 73 (29). (Found: C, 78.2; H, 10.1. C18H28O2 requires:
C, 78.2; H, 10.2%).
Synthesis of fragment B
Dimethyl 2,3-O-isopropylidene-D-(؉)-tartrate (11). The title
compound was prepared in 91% yield on a 50-g scale from
commercial -(Ϫ)-tartaric acid (10) according to Carmack and
Kelley;17 [α]D ϩ42.0 (neat) [lit.,17 (-isomer) Ϫ49.4].
1
liquid (374 mg, 61%), [α]D ϩ7.7 (c 2.3). H NMR (200 MHz):
δ 0.83–0.95 (6H, m, 3 × H-8 and pinanyl CH3), 1.17 (1H, d,
J 10.8, pinanyl Hendo), 1.27–1.48 (16H, m, H-3 to H-7 and
2 × pinanyl CH3), 1.60–2.45 (5H, m, pinanyl protons), 3.65
(1H, d, J 6.5, H-1), 3.81 (1H, dt, J 5.3, 6.5, H-2), 4.38 (1H, dd,
J 8.8, 2.0, pinanyl CHOB), 4.62 (1H, d, J 12.0, CH2Ph), 4.72
2,3-O-Isopropylidene-D-(؊)-threitol (12)34. LAH (10.11 g,
0.266 mol) was slurried in dry ether (100 mL) and refluxed for
30 min. Dimethyl 2,3-O-isopropylidene--(ϩ)-tartrate (11)
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 3 8 – 4 7
43

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(28.742 g, 0.132 mol) was dissolved in dry ether (130 mL) and
slowly added at rt under vigorous magnetic stirring. The
reaction mixture was refluxed for about 3 h and stirred at rt
overnight. After cooling with ice, ethyl acetate (12 mL) was
carefully added dropwise, followed by water (10 mL,
cautiously!), 4 M NaOH (10 mL) and, again, water (30 mL);
the suspension was stirred until gas release ceased and the
conspicuous ivory precipitate which had settled down was
filtered off, washing with abundant ether. The filter cake was
extracted thoroughly and repeatedly with ether in a Soxhlet
apparatus, and the pooled ethereal extracts were dried
(MgSO4), filtered and concentrated in vacuo. Claisen distillation
of the residue afforded -threitol derivative 12 (18.6 g, 87%) as
a pale yellow dense oil, bp 94–96 ЊC (0.7 mmHg), [α]D Ϫ2.1
(c 2.6) (lit.,34 Ϫ3.1), which crystallised upon freezing. 1H NMR
(200 MHz): δ 1.36 (6H, s, 2 × CH3), 3.40 (2 × 1H, br, 2 × OH ),
3.67 (4H, br, 2 × CH2), 3.89 (2H, m, 2 × CH ). 13C NMR: δ 27.3,
62.6, 78.8, 109.6. MS, m/z (as the corresponding bisTMS ether,
by derivatisation in situ with neat MSTFA at 100 ЊC for 3.5 h):
307 ([M ϩ 1]ϩ, 0.07%), 291 (90), 231 (22), 216 (36), 203 (40), 185
(18), 145 (60), 131 (69), 117 (58), 103 (88), 73 (100), 59 (14), 43
(11). (Found: C, 51.9; H, 8.8. C7H14O4 requires: C, 51.8; H,
8.7%).
After being repeatedly treated with anhydrous toluene and
rotary evaporated in order to remove azeotropically any trace
of water left, this crude material was directly used in the next
step. 1H NMR (200 MHz): δ 0.08 (3H, s, tBuMe2Si), 0.09 (3H, s,
tBuMe2Si), 0.91 (9H, s, 3 × tBuMe2Si), 1.41 (3H, s, Me2C), 1.42
(3H, s, Me2C), 3.66–4.16 (3H, m, CHCH2 and CH2), 4.33 (1H,
dd, J 7.2, 1.6, CHCHO), 9.78 (1H, d, J 1.6, CHO). MS, m/z: 259
([M Ϫ 15]ϩ, 4.9%), 245 (9.5), 217 (13), 199 (4.2), 187 (7.2), 171
(4.0), 159 (50), 145 (6.7), 131 (60), 117 (100), 101 (60), 89 (16),
75 (75), 59 (25), 43 (18).
(2E,4R,5R)- and (2Z,4R,5R)-6-(tert-Butyldimethylsilyloxy)-
4,5-(isopropylidenedioxy)hex-2-enoic acid ethyl ester (15). The
crude aldehyde 14 (1.189 g, 4.33 mmol) was dissolved in
anhydrous DMF (36 mL) and (ethoxycarbonylmethylene)-
triphenylphosphorane (4.448 g, 12.77 mmol) was added
portionwise at rt. The mixture was stirred overnight, poured in
350 mL water and thoroughly extracted with light petroleum
(5 × 150 mL). After drying over MgSO4, filtration and evapor-
ation under reduced pressure, the residue was purified by silica
gel chromatography using light petroleum–diethyl ether 70 : 30
as the eluant, to afford the title alkene 15 in an 85 : 15 trans–cis
mixture (as determined by GC-MS analysis) as a light yellow
liquid (1.402 g, 94%). (Found: C, 59.5; H, 9.5. C17H32O5Si
requires: C, 59.3; H, 9.4%).
(2R,3R)-4-(tert-Butyldimethylsilyloxy)-2,3-(isopropylidene-
dioxy)butanol (13). Sodium hydride (0.66 g, 27.5 mmol; as 60%
dispersion in mineral oil) was added portionwise to a stirred
solution of -(Ϫ)-threitol acetonide 12 (4.006 g, 24.70 mmol) in
anhydrous THF (150 mL) cooled to 0 ЊC under Ar flow. When
(2E,4R,5R)-(15). 1H NMR (200 MHz): δ 0.07 (6H, s,
t
t
2 × BuMe2Si), 0.90 (9H, s, 3 × Me2 BuSi), 1.29 (3H, t, J 7.1,
CH2CH3), 1.42 (6H, s, 2 × Me2C), 3.69–3.86 (3H, m, H-5 and 2
× H-6), 4.20 (2H, q, J 7.1, CH2CH3), 4.45–4.56 (1H, m, H-4),
6.12 (1H, dd, J 15.7, 1.6, H-2), 6.94 (1H, dd, J 15.7, 5.1, H-3).
13C NMR: δ Ϫ4.13, Ϫ4.07, 15.6, 19.6, 27.2, 28.1, 28.3, 61.8,
64.1, 79.2, 82.1, 111.2, 123.3, 146.0, 176.7. MS, m/z: 329
([M Ϫ 15]ϩ, 13%), 299 (7.3), 281 (5.9), 241 (4.0), 229 (100), 199
(20), 183 (34), 155 (34), 117 (36), 109 (51), 89 (41), 84 (29), 75
(74), 59 (21), 43 (18).
effervescence ceased,
a solution of tert-butyldimethylsilyl
chloride (4.105 g, 27.2 mmol) in dry THF (50 mL) was slowly
added dropwise to the slurry at rt and stirred vigorously over-
night under Ar atmosphere. The milky mixture was poured in
water (120 mL), the yellow clear organic phase was separated
and the aqueous layer extracted with ethyl acetate (3 × 50 mL).
The organic phases were combined, washed with water (100
mL), dried (MgSO4) and rotary evaporated, giving a yellow
residue which was chromatographed on silica gel (light petrol-
eum–ethyl acetate from 90 : 10 to 50 : 50) to afford the desired
monosilylated alcohol 13 (6.21 g, 91%) as a lemon yellow oil,
[α]D Ϫ16.1 (c 3.2) [lit.,19,21 (2S,3S) ϩ16.1;19 ϩ15.321]. 1H NMR
(200 MHz): δ 0.06 (6H, s, 2 × tBuMe2Si), 0.88 (9H, s,
3 × tBuMe2Si), 1.37 (3H, s, Me2C), 1.39 (3H, s, Me2C), 2.55 (1H,
t, J 6.0, OH ), 3.60 (6H, m, 2 × CH and 2 × CH2). 13C NMR:
δ Ϫ4.19, Ϫ4.16, 19.6, 27.2, 28.2, 28.4, 64.1, 65.1, 79.4, 81.4,
110.4. MS, m/z: 275 ([M Ϫ 1]ϩ, 0.07%), 261 (17), 245 (2.8), 219
(14), 201 (3.5), 187 (4.6), 173 (5.6), 161 (44), 143 (20), 131 (100),
117 (43), 105 (16), 89 (14), 75 (96), 59 (41), 43 (18). (Found: C,
56.4; H, 10.3. C13H28O4Si requires: C, 56.5; H, 10.2%).
(2Z,4R,5R)-(15). 1H NMR (200 MHz): δ 0.057 (3H, s,
tBuMe2Si), 0.061 (3H, s, tBuMe2Si), 0.88 (9H, s, 3 × tBuMe2Si),
1.28 (3H, t, J 7.1, CH2CH3), 1.43 (6H, s, 2 × Me2C), 3.69–3.86
(3H, m, H-5 and 2 × H-6), 4.17 (2H, q, J 7.1, CH2CH3), 4.76–
4.84 (1H, m, H-4), 5.91 (1H, dd, J 11.7, 1.0, H-2), 6.18 (1H, dd,
J 11.7, 8.6, H-3). 13C NMR: δ Ϫ4.0, 27.3, 28.4, 28.5, 61.7, 65.2,
75.0, 83.6, 111.3, 124.2, 146.9, (C᎐O not seen). MS, m/z: 329
᎐
([M Ϫ 15]ϩ, 4.3%), 287 (26), 269 (24), 241 (17), 229 (91), 199
(9.2), 183 (68), 155 (34), 117 (52), 109 (100), 89 (15), 84 (23),
75 (62), 59 (20), 43 (18).
(4R,5R)-6-(tert-Butyldimethylsilyloxy)-4,5-(isopropylidene-
dioxy)hexanoic acid ethyl ester (16). Alkene 15 (1.321 g, 3.84
mmol) was dissolved in absolute EtOH (20 mL) and stirred
overnight with 10% wt. dry Pd on C (200 mg) at rt under H2
balloon pressure. The reaction mixture was passed through a
short Celite plug, washing with diethyl ether and EtOH, and the
resulting clear solution was evaporated to dryness to afford 16
as a colourless liquid (1.31 g, 99%) which was used as such for
the next reaction. For analysis, a small sample was purified by
silica gel chromatography, using light petroleum–diethyl ether
(2S,3R)-4-(tert-Butyldimethylsilyloxy)-2,3-(isopropylidene-
dioxy)butanal (14). Oxalyl chloride (588 µL, 6.84 mmol) was
dissolved in dry CH2Cl2 (13 mL) in a three-necked 100-mL
round bottom flask equipped with two dropping funnels and a
bubbler, and treated at Ϫ80 ЊC with a solution of anhydrous
DMSO (970 µL, 13.68 mmol) in CH2Cl2 (4.5 mL), which was
added dropwise over 15 min. The milky solution thus obtained
was stirred at Ϫ72 ЊC under Ar flow for an additional 30 min.
Alcohol 13 (1.716 g, 6.22 mmol) was dissolved in dry CH2Cl2
(8 mL) and slowly added at Ϫ70 ЊC over a 15 min period. After
stirring at Ϫ60 ЊC for a further 40 min, freshly distilled
anhydrous triethylamine (4.33 mL, 31.08 mmol) was added,
and the reaction mixture was stirred for 15 min at the same
temperature. The cold bath was then removed, the mixture
allowed to warm to rt and poured in 30 mL water. The lower
organic layer was separated and the aqueous phase extracted
with CH2Cl2 (3 × 20 mL); the pooled organic layers were
washed with saturated NH4Cl, satd. NaHCO3 and brine (60 mL
each), and dried over Na2SO4. After filtration and concen-
tration in vacuo a yellow sticky oil was obtained (1.53 g, 90%).
1
80 : 20 as the eluant; [α]D ϩ5.9 (c 1.5). H NMR (200 MHz):
t
t
δ 0.07 (6H, s, 2 × BuMe2Si), 0.89 (9H, s, 3 × BuMe2Si), 1.25
(3H, t, J 7.1, CH2CH3), 1.36 (3H, s, Me2C), 1.38 (3H, s, Me2C),
1.75–2.14 (2H, m, 2 × H-3), 2.34–2.60 (2H, m, 2 × H-2), 3.63–
3.82 (3H, m, H-4 and 2 × H-6), 3.85–3.95 (1H, m, H-5), 4.13
(2H, q, J 7.1, CH2CH3). 13C NMR: δ Ϫ4.12, Ϫ4.06, 15.6, 19.7,
27.2, 28.3, 28.8, 28.9, 32.1, 61.6, 65.0, 79.3, 82.2, 110.0, 174.6.
MS, m/z: 345 ([M Ϫ 1]ϩ, 0.1%), 331 (36), 301 (13), 289 (33), 271
(36), 243 (42), 231 (90), 185 (100), 157 (35), 143 (73), 111 (93),
83 (27), 75 (48), 59 (15), 43 (12). (Found: C, 59.2; H, 10.1.
C17H34O5Si requires: C, 58.9; H, 9.9%).
(4R,5R)-6-Hydroxy-4,5-(isopropylidenedioxy)hexanoic acid
ethyl ester (17). Silylated alcohol 16 (1.26 g, 3.64 mmol) was
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 3 8 – 4 7
44

View Article Online
dissolved in anhydrous THF (10 mL) and treated with a solu-
tion of tetra-n-butylammonium fluoride (1.142 g, 4.37 mmol) in
6 mL THF at rt under magnetic stirring and Ar atmosphere.
After 5 h the solvent was rotary evaporated, the yellowish
residue dissolved in ethyl acetate (15 mL) and washed with
water (15 mL). The aqueous layer was extracted with EtOAc
(15 mL) and the pooled organic phases were dried (Na2SO4)
and filtered. Concentration in vacuo followed by chromato-
graphy on silica gel (light petroleum–diethyl ether, from 70 : 30
to 40 : 60) yielded free alcohol 17 as a pale yellow oil (689 mg,
petroleum–diethyl ether 70 : 30 and finally 60 : 40) to afford the
title alkene 19 (181 mg, 42%) as a yellow liquid, [α]D ϩ0.7
1
(c 0.8). [lit.,25 (4S,5S) 0]. H NMR (200 MHz): δ 1.26 (3H, t,
J 7.1, CH2CH3), 1.41 (6H, s, 2 × Me2C), 1.73–2.06 (2H, m,
2 × H-3), 2.33–2.61 (2H, m, 2 × H-2), 3.70 (1H, dt, J 8.2, 3.9,
H-4), 4.01 (1H, ddt, J 8.2, 7.2, 0.8, H-5), 4.14 (2H, q, J 7.1,
CH CH ), 5.27 (1H, ddd, J 10.1, 1.5, 0.8, CH᎐CH ), 5.38 (1H,
᎐
2
3
2
ddd, J 17.1, 1.5, 0.8, CH᎐CH ), 5.81 (1H, ddd, J 17.1, 10.1, 7.2,
᎐
2
CH᎐CH ). 13C NMR: δ 15.6, 28.2, 28.3, 28.6, 32.0, 61.8, 80.9,
᎐
2
83.8, 110.2, 120.6, 136.4, 174.5. MS, m/z: 213 ([M Ϫ 15]ϩ, 21%),
195 (0.6), 171 (9.9), 125 (100), 115 (5.5), 98 (66), 83 (34), 69 (32),
55 (21), 43 (61). (Found: C, 63.2; H, 8.7. C12H20O4 requires: C,
63.1; H, 8.8%).
1
82%), [α]D ϩ24.8 (c 1.1) [lit.,21,25 (4S,5S) Ϫ24.1;25 Ϫ19.521]. H
NMR (200 MHz): δ 1.26 (3H, t, J 7.1, CH2CH3), 1.39 (3H, s,
Me2C), 1.40 (3H, s, Me2C), 1.70–2.06 (2H, m, 2 × H-3), 2.10
(1H, t, J 5.4, OH ), 2.42 (1H, ddd, J 16.4, 8.2, 7.0, H-2), 2.54
(1H, ddd, J 16.4, 8.4, 6.7, H-2), 3.59–3.68 (1H, m, H-5),
3.70–3.85 (2H, m, 2 × H-6), 3.91 (1H, dt, J 3.8, 7.9, H-4), 4.14
(2H, q, J 7.1, CH2CH3). 13C NMR: δ 15.5, 28.4, 28.6, 29.4, 32.0,
61.8, 63.3, 77.6, 82.4, 110.3, 174.6. MS, m/z: 217 ([M Ϫ 15]ϩ,
62%), 187 (7.3), 171 (8.9), 156 (7.0), 143 (23), 129 (40), 115 (45),
111 (67), 101 (22), 83 (44), 59 (100). (Found: C, 56.8; H, 8.9.
C11H20O5 requires: C, 56.9; H, 8.7%).
(4R,5R)-4,5-(Isopropylidenedioxy)hept-6-enoic acid (20). The
ester 19 (166 mg, 0.728 mmol) was dissolved in 8 mL THF–
MeOH (1 : 1) and treated with aqueous KOH (248 mg in 2 mL)
at rt under magnetic stirring. After 2.5 h TLC (diethyl ether–
light petroleum 80 : 20) showed disappearance of the starting
material. The pale yellow reaction mixture was poured in a
separating funnel with water and diethyl ether (80 mL each),
and the pH was adjusted to 4–5 with 10% HCl. The aqueous
layer was further extracted with ether (3 × 20 mL) and the
pooled organic phases were washed with water (2 × 100 mL)
and brine (100 mL), dried over Na2SO4 and filtered. Finally,
rotary evaporation afforded the desired free acid 20 as a sticky
greenish oil (118 mg, 81%), which was used as such for the next
DCC-mediated coupling step. 1H NMR (200 MHz): δ 1.41 (6H,
s, 2 × Me2C), 1.70–2.06 (2H, m, 2 × H-3), 2.39–2.68 (2H, m, 2 ×
H-2), 3.72 (1H, dt, J 8.1, 3.9, H-4), 4.02 (1H, dd, J 8.1, 7.3,
(4R,5S )-4,5-(Isopropylidenedioxy)-6-oxohexanoic acid ethyl
ester (18). By analogy to the preparation of aldehyde 14
described above, a solution of DMSO (404 µL, 5.70 mmol) in
anhydrous CH2Cl2 (2 mL) was carefully added dropwise under
Ar flow over a 3 min period to a stirred solution of oxalyl
chloride (245 µL, 2.85 mmol) in the same solvent (5.5 mL)
cooled at Ϫ76 ЊC. The mixture was allowed to react for 30 min
at the same temperature, until a milky turbid appearance was
observed. Thereafter, alcohol 17 (601 mg, 2.59 mmol) was
dissolved in dry CH2Cl2 (3.5 mL) and slowly added at Ϫ72 ЊC to
the white mixture over a 15 min period. After stirring for 1 h at
Ϫ65 ЊC under Ar flow, anhydrous triethylamine (1.8 mL, 12.95
mmol) was added dropwise at Ϫ61 ЊC. The reaction mixture
was stirred for 15 min at the same temperature, left to warm to
rt over 2 h and poured into 15 mL water. The whitish clear
bottom phase was separated from the aqueous layer, which was
extracted with CH2Cl2 (3 × 15 mL); the organic phases were
combined, washed with 1 M HCl (50 mL), saturated NaHCO3
(50 mL) and brine (50 mL), dried (Na2SO4), filtered and evap-
orated under reduced pressure to give the crude aldehyde 18 as
a lemon yellow thick oil (455 mg, 76%), which was used for the
next Wittig reaction without further purification, except for
repeated treatments with anhydrous toluene followed by rotary
evaporation. 1H NMR (200 MHz): δ 1.26 (3H, t, J 7.1,
CH2CH3), 1.39 (3H, s, Me2C), 1.41 (3H, s, Me2C), 1.81–2.14
(2H, m, 2 × H-3), 2.38–2.60 (2H, m, 2 × H-2), 3.63–3.93 (1H,
m, H-4), 3.98 (1H, dd, J 7.5, 2.1, CHCHO), 4.14 (2H, q, J 7.1,
CH2CH3), 9.74 (1H, d, J 2.1, CHO). MS, m/z: 215 ([M Ϫ 15]ϩ,
32%), 201 (13), 185 (30), 143 (70), 127 (33), 115 (100), 99 (26),
85 (50), 59 (23), 43 (70).
H-5), 5.27 (1H, ddd, J 10.2, 1.5, 0.8, CH᎐CH ), 5.38 (1H, ddd,
᎐
2
J 17.2, 1.5, 0.9, CH᎐CH ), 5.81 (1H, ddd, J 17.2, 10.2, 7.3,
᎐
2
CH᎐CH ). 13C NMR: δ 26.5, 26.9, 27.1, 30.3, 79.4, 82.4, 108.9,
᎐
2
119.1, 135.0, 178.7. MS, m/z: 200 (Mϩ, 0.1%), 185 (64), 167
(1.4), 144 (5.1), 125 (100), 98 (93), 83 (57), 69 (47), 55 (28), 43
(84). (Found: C, 60.2; H, 7.8. C10H16O4 requires: C, 60.0; H,
8.0%).
DCC-mediated coupling and final steps of the total synthesis
(4R,5R)-4,5-(Isopropylidenedioxy)hept-6-enoic
acid,
(1ЈS,1ЉS )-1Ј-(1Љ-benzyloxyheptyl)-3Ј-butenyl ester (21). A solu-
tion of acid 20 (118 mg, 0.590 mmol) in 1.5 mL anhydrous ether
was added dropwise to alcohol 9 (165 mg, 0.598 mmol) in dry
ether (2 mL), and DCC (122 mg, 0.590 mmol) was added at rt,
along with DMAP (7 mg, 0.057 mmol). After stirring for 5.5 h,
the white precipitate was filtered off and the yellow clear solu-
tion evaporated to dryness. The turbid yellow oil was chroma-
tographed on silica gel with light petroleum–diethyl ether 95 : 5
to afford ester 21 as a liquid (205 mg, 85%), [α]D Ϫ1.9 (c 4.2),
1
along with 19 mg of unreacted 9. H NMR (200 MHz): δ 0.89
(3H, t, J 6.5, 3 × H-7Љ), 1.26 (8H, br m, H-3Љ to H-6Љ), 1.39 (3H,
s, Me2C), 1.41 (3H, s, Me2C), 1.44–1.62 (2H, m, 2 × H-2Љ),
1.72–2.07 (2H, m, 2 × H-3), 2.17–2.62 (4H, m, 2 × H-2 and 2 ×
H-2Ј), 3.45 (1H, dt, J 7.1, 4.5, H-1Љ), 3.69 (1H, dt, J 8.1, 3.9, H-
4), 4.00 (1H, dd, J 8.1, 7.2, H-5), 4.60 (2H, s, CH2Ph), 4.97–5.18
(3H, m, H-1Ј and 2 × H-4Ј), 5.25 (1H, ddd, J 10.2, 1.5, 0.8,
H-7), 5.38 (1H, ddd, J 17.1, 1.5, 0.9, H-7), 5.63–5.79 (1H, m,
H-3Ј), 5.80 (1H, ddd, J 17.1, 10.2, 7.2, H-6), 7.23–7.40 (5H, m,
arom). 13C NMR: δ 14.0, 22.5, 25.5, 26.9, 27.2, 29.3, 29.9, 30.8,
31.7, 34.4, 72.4, 73.5, 79.0, 82.4, 108.8, 117.5, 118.9, 127.6,
127.8, 128.3, 134.1, 135.1, 138.5, 172.6. MS, m/z: 458 (Mϩ,
0.4%), 443 (0.8), 361 (0.8), 294 (11), 275 (3.5), 259 (5.6), 223
(3.8), 205 (11), 183 (6.8), 143 (9.7), 125 (70), 98 (35), 91 (100), 83
(10), 69 (9.2), 55 (9.0), 43 (12). (Found: C, 73.4; H, 9.1.
C28H42O5 requires: C, 73.3; H, 9.2%).
(4R,5R)-4,5-(Isopropylidenedioxy)hept-6-enoic acid ethyl
ester (19). Methyltriphenylphosphonium bromide (1.837 g, 5.14
mmol) was slurried in 45 mL freshly distilled anhydrous THF.
The white suspension was cooled to Ϫ23 ЊC and n-butyllithium
(1.2 mL of a 2.5 M solution in hexanes) was added over 2 min
under Ar flow and magnetic stirring. The bright yellow mixture
was vigorously stirred and allowed to warm to rt for 1 h 40 min;
gas bubbles were observed to develop and a white solid to settle.
The crude aldehyde 18 (438 mg, 1.90 mmol) was dissolved in
dry THF (5 mL) and added dropwise over a 3 min period to the
yellow slurry at Ϫ20 ЊC and stirred for 30 min at the same
temperature. After 2 h at rt, the orange-yellow cloudy mixture
was poured in 200 mL diethyl ether and stirred for 5 min;
the white suspension thus formed was passed through a short
Celite pad and washed with abundant ether to obtain a clear
colourless solution. Concentration in vacuo provided a crude
residue which was purified by silica gel chromatography (light
(5R,6R,7E,10S )- and (5R,6R,7Z,10S )-10-[(1ЈS )-1Ј-Benzyl-
oxyheptyl]-5,6-isopropylidenedioxy-3,4,5,6,9,10-hexahydro-2H-
oxecin-2-one, (E-22 and Z-22). Ester 21 (50 mg, 0.109 mmol)
was dissolved in freshly distilled degassed anhydrous CH2Cl2
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 3 8 – 4 7
45

View Article Online
(230 mL) and Grubbs’ catalyst I was added (15.5 mg, 0.0188
mmol). The mixture was refluxed for 2 days under Ar flow until
TLC (light petroleum–diethyl ether 80 : 20) showed complete
disappearance of the starting material. Most of the solvent was
then distilled off and the concentrated solution left to stir at rt
for 2 h under air bubbling in order to decompose the catalyst.
Evaporation to dryness gave a brown residue which was
purified by chromatography on silica gel; slow elution with light
petroleum–diethyl ether mixtures (from 97 : 3 to 80 : 20)
allowed separation of the desired trans stereoisomer (E)-22 (29
mg) from cis derivative (Z)-22 (14 mg) (combined 92% yield).
(5R,6R,7E,10S)-22. [α]D Ϫ37.9 (c 3.0). 1H NMR (200 MHz):
δ 0.90 (3H, t, J 6.5, 3 × H-7Ј), 1.27 (8H, br envelope, H-3Ј to
H-6Ј), 1.41 (6H, s, 2 × Me2C), 1.51–1.80 (2H, m, 2 × H-2Ј),
1.87–2.71 (6H, m, 2 × H-3, H-4 and H-9), 3.47 (1H, m, H-1Ј),
3.64 (1H, m, H-5), 3.92 (1H, t, J 9.2, H-6), 4.56 (1H, d, J 11.6,
CH2Ph), 4.65 (1H, d, J 11.6, CH2Ph), 4.95 (1H, m, H-10), 5.32
(1H, dd, J 15.6, 9.2, H-7), 5.78 (1H, ddd, J 15.6, 11.0, 4.7, H-8),
7.29–7.40 (5H, m, arom). 13C NMR: δ 14.0, 22.5, 25.4, 25.6,
26.9, 27.1, 29.4, 29.7, 31.7, 34.2, 72.5, 73.4, 79.8, 80.4, 84.4,
108.8, 127.8, 127.9, 128.4, 129.2, 130.3, 138.2, 171.8. MS, m/z:
430 (Mϩ, 0.22%), 415 (0.33), 373 (0.60), 328 (1.1), 298 (0.71),
237 (3.3), 220 (1.8), 205 (4.3), 203 (7.0), 179 (1.8), 123 (6.2), 113
(14), 91 (100), 85 (23), 79 (6.2), 65 (3.1), 55 (5.5). (Found: C,
72.4; H, 9.0. C26H38O5 requires: C, 72.5; H, 8.9%).
J 11.3, 4.9, 3.3, H-10), 5.08 (1H, dd, J 15.7, 9.4, H-7 minor),
5.53 (1H, dddd, J 15.8, 10.3, 5.3, 2.2, H-8), 5.69 (1H, m, H-8
minor), 5.73 (1H, dd, J 15.8, 2.5, H-7). 13C NMR (100 MHz,
CD3CN; referenced to CD3CN at 118.26 ppm): δ 14.4 (C-7Ј),
23.3 (C-6Ј), 26.1 (C-3Ј), 26.5 (C-4), 29.3 (C-3), 30.0 (C-4Ј), 32.2
(C-9, minor conformer), 32.3 (C-5Ј, minor), 32.6 (C-5Ј), 33.9
(C-2Ј, minor), 34.3 (C-2Ј), 35.9 (C-3, minor), 36.7 (C-9), 72.5
(C-6), 72.9 (C-1Ј), 73.5 (C-5), 73.8 (C-1Ј, minor), 76.4 (C-10,
minor), 77.0 (C-5, minor), 79.5 (C-6, minor), 79.7 (C-10), 126.7
(C-8), 130.0 (C-8, minor), 133.8 (C-7, minor), 134.6 (C-7), 173.5
(C-2, minor), 176.4 (C-2) [see also electronic supporting
1
information (ESI) for original H and 13C NMR spectra of
synthetic 1]. MS, m/z: 301 ([M ϩ 1]ϩ, 1.4%), 283 (0.55), 265
(0.78), 198 (6.2), 180 (55), 162 (1.2), 151 (3.5), 141 (10), 129 (30),
113 (13), 110 (16), 95 (39), 84 (100), 73 (44), 70 (80), 55 (64).
(Found: C, 63.9; H, 9.2. C16H28O5 requires: C, 64.0; H, 9.4%).
Acknowledgements
We are grateful to the Università di Modena e Reggio Emilia
(“Progetto Giovani Ricercatori” to P.D.) for financial support.
Spectroscopic assistance from the staff at Centro Inter-
dipartimentale Grandi Strumenti (Università di Modena) has
been greatly appreciated throughout the project. We thank
Stefania Morandi and Chiara Danieli for critically examining
NMR assignments of pinanediol boronates. We are also
grateful to Dr Claudia Zucchi for kindly providing Fürstner’s
catalyst III.
1
(5R,6R,7Z,10S)-22. [α]D ϩ4.5 (c 1.6). H NMR (200 MHz):
δ 0.89 (3H, t, J 6.5, 3 × H-7Ј), 1.27 (8H, br envelope, H-3Ј to
H-6Ј), 1.40 (3H, s, Me2C), 1.42 (3H, s, Me2C), 1.50–1.77 (2H,
m, 2 × H-2Ј), 2.01–2.77 (6H, m, 2 × H-3, H-4 and H-9), 3.49
(1H, m, H-1Ј), 3.66 (1H, ddd, J 10.2, 9.5, 2.3, H-5), 4.52 (1H,
dd, J 9.5, 8.0, H-6), 4.58 (1H, d, J 11.6, CH2Ph), 4.66 (1H, d,
J 11.6, CH2Ph), 5.10 (1H, ddd, J 11.8, 4.4, 2.2, H-10), 5.50 (1H,
t, J 10.3, H-7), 5.74 (1H, dt, J 10.3, 7.0, H-8), 7.28–7.44 (5H, m,
arom). 13C NMR: δ 14.0, 22.5, 25.4, 26.8, 27.0, 29.3, 29.6, 30.5,
31.7, 32.1, 72.6, 72.8, 77.1, 79.7, 81.5, 107.6, 127.7, 128.4, 130.3,
130.9, 138.0, 176.6. MS, m/z: 430 (Mϩ, 0.69%), 415 (2.3), 373
(0.30), 328 (1.1), 298 (0.60), 265 (1.7), 237 (3.0), 220 (1.7), 205
(3.9), 203 (6.3), 179 (2.5), 123 (5.1), 113 (13), 91 (100), 85 (16),
79 (6.6), 65 (3.1), 55 (6.6). (Found: C, 72.7; H, 9.1. C26H38O5
requires: C, 72.5; H, 8.9%).
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(5R,6R,7E,10S )-5,6-Dihydroxy-10-[(1ЈS )-1Ј-hydroxyheptyl]-
3,4,5,6,9,10-hexahydro-2H-oxecin-2-one (microcarpalide, 1)3.
Titanium tetrachloride (66 µL, 0.605 mmol) in anhydrous
CH2Cl2 (0.5 mL) was slowly added dropwise over 10 min to a
stirred solution of trans derivative E-22 (26 mg, 0.0605 mmol)
in dry CH2Cl2 (2.5 mL) cooled to 0 ЊC. After 1.5 h the ochre-
yellow cloudy mixture was poured in water (5 mL), diluted with
CH2Cl2 (4 mL) and treated with satd. NaHCO3 (8 mL), brine
(5 mL) and EtOAc (15 mL) in a separating funnel. After
settling, the upper milky layer was discarded, whereas the clear
lower phase was separated, dried (Na2SO4), filtered and concen-
trated under reduced pressure; silica gel chromatography of
the crude residue using ethyl acetate as the eluant afforded
microcarpalide 1 as a beige oil (12 mg, 66%), [α]D Ϫ23.6 (c 1.0,
MeOH) (lit.,3 Ϫ22). NMR analysis clearly showed the presence
of two slowly interconverting conformers in a 76 : 24 ratio
(in CD3CN), which is identical to the value described in the
literature for the natural compound in the same solvent.3 1H
NMR (400 MHz, CD3CN; referenced to the residual proton at
1.96 ppm): δ 0.91 (3H, t, J 6.8, 3 × H-7Ј), 1.26–1.38 (8H, br
envelope, H-3Ј to H-6Ј), 1.41–1.47 (2H, br m, 2 × H-2Ј), 1.80
(1H, br dddd, H-4), 2.02 (1H, br ddd, H-4 minor conformer),
2.11–2.23 (3H, br m, H-3, H-4 and H-9), 2.27–2.34 (1H, br m,
H-9), 2.36 (1H, ddd, J 5.2, 2.7, 1.1, H-9 minor), 2.47–2.58 (1H,
m, H-3), 2.83 (1H, d, J 5.8, 1Ј-OH ), 2.86 (1H, d, J 6.4, 6-OH ),
3.09 (1H, d, J 4.1, 5-OH ), 3.19 (1H, d, J 3.2, 5-OH minor), 3.28
(1H, br dt, H-5 minor), 3.54–3.60 (1H, br m, H-1Ј), 3.64 (1H,
dt, J 3.1, 9.1, H-6 minor), 3.80 (1H, br m, H-5), 4.13 (1H, br m,
H-6), 4.63 (1H, ddd, J 8.4, 4.5, 2.7, H-10 minor), 4.84 (1H, ddd,
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 3 8 – 4 7
46

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O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 3 8 – 4 7
47