Enantioselective total synthesis of (-)-microcarpalide

Article abstract of DOI:10.1016/j.tet.2005.02.069

The enantioselective total synthesis of the actin-targeting metabolite (-)-microcarpalide is described. Key steps include ring-closing metathesis (RCM) for the final construction of the 10-membered lactone framework and stereoselective homologation of bor

Full text of DOI:10.1016/j.tet.2005.02.069

Tetrahedron 61 (2005) 4427–4436
Enantioselective total synthesis of (K)-microcarpalide
*
Paolo Davoli, Raffaele Fava, Stefania Morandi, Alberto Spaggiari and Fabio Prati
*
`
Dipartimento di Chimica, Universita di Modena e Reggio Emilia, via Campi 183, I-41100 Modena, Italy
Received 8 December 2004; revised 10 February 2005; accepted 24 February 2005
Available online 17 March 2005
Abstract—The enantioselective total synthesis of the actin-targeting metabolite (K)-microcarpalide is described. Key steps include ring-
closing metathesis (RCM) for the final construction of the 10-membered lactone framework and stereoselective homologation of boronic
esters for the insertion of all stereocentres with the desired absolute configuration. In particular, the acidic fragment was prepared in seven
steps from a suitable chiral bromomethane boronate by means of two sequential stereoselective homologations to install the two stereocentres
with the correct final R stereochemistry, employing (K)-pinanediol as the chiral director. Subsequent elaboration to the required C7
backbone entailed nucleophilic displacement with a vinyl Grignard reagent, oxidative cleavage of the boronic scaffold and protection–
deprotection manipulations. Interestingly, when the tribenzyloxy diene ester resulting from DCC-mediated coupling of the two key synthons
was subjected to RCM in the presence of Grubbs’ catalyst, the reaction proceeded stereoselectively to yield the desired trans oxecin-2-one,
albeit with poor conversion.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Actin-targeting small molecules are currently receiving an
increasing interest as potential lead structures for the
development of new therapeutic agents. The organization
of the actin cytoskeleton plays a prominent role in a variety
of processes such as cell shape change, cell migration and,
ultimately, tumor cell invasion and metastasis. Hence,
compounds that are capable of interfering with actin
dynamics may offer promising opportunities as novel
anticancer drugs.1
Microcarpalide (1) is a novel alkyl-substituted nonenolide
(Scheme 1) that was discovered from fermentation broths of
an unidentified endophytic fungus isolated from Ficus
microcarpa L. in the framework of a search campaign for
new secondary metabolites with anticytoskeletal activity.2
In particular, microcarpalide was found to display a
remarkable disrupting action on actin microfilaments,
while showing only weak toxicity to mammalian cells.2
By virtue of such a peculiar biological activity, the
apparently simple, but yet stereochemically demanding
macrocyclic structure of this new fungal metabolite has
aroused the interest of the chemical community, and a few
total syntheses have appeared accordingly.3–7
Keywords: Fungal metabolites; Nonenolides; Actin-targeting compounds;
Microfilament disrupting activity; Asymmetric homologation; Boronic
esters; Ring-closing metathesis.
*
Corresponding authors. Tel.: C39 59 2055056; fax: C39 59 373543
(F.P.); e-mail: prati.fabio@unimore.it
Scheme 1. Retrosynthetic disconnections.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.02.069

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P. Davoli et al. / Tetrahedron 61 (2005) 4427–4436
In the course of our previous total synthesis of micro-
carpalide, we had successfully exploited Matteson’s asym-
metric homologation8 to insert sequentially the two
stereocentres at positions 10 and 10 with the required S
absolute configuration, using (C)-pinanediol as the chiral
director.5 Along this line, we reasoned that the two
remaining stereocentres, namely 5R and 6R, could be also
installed likewise by an enantioselective approach
featuring the stereoselective homologation of suitable chiral
boronic esters, rather than from the chiral pool.3–6 Hence, a
modified retrosynthetic route was devised, as outlined in
Scheme 1.
Scheme 2. (a) n-BuLi, THF, K78 8C, then B(OMe)3, K78 8C, then TMSCl
or TMSBr, K78 8C/rt, then (1R,2R,3S,5R)-(K)-pinanediol, rt; (b) NaI,
acetone, rt (86%); (c) tert-butylacetate, LDA, THF, K78 8C.
Our synthetic strategy relied again on ring-closing meta-
thesis (RCM)9 for the final construction of the 10-membered
unsaturated macrocycle, owing to the inherently convergent
nature of this powerful transformation.10 Accordingly,
tactical disconnection of (K)-microcarpalide (1) into
subunits A5 and B was envisaged (Scheme 1).
readily synthesized in 73% overall yield by sequential
treatment of dibromomethane (2b) with n-BuLi, trimethyl-
borate16 and trimethylbromosilane† in THF at K78 8C,
followed by addition of (K)-pinanediol at rt.12,15 Formation
of the C–B bond was confirmed by a broad signal at 8.2 ppm
in the 13C NMR spectrum. In contrast, iodo analogue 3c was
obtained in 86% yield from 3a by halogen exchange with
sodium iodide in dry acetone (Scheme 2).12,17 The presence
of a new highfield signal (K22.8 ppm) in the 13C NMR
spectrum was suggestive of an iodine-bearing carbon
atom,18 which was confirmed by the correlation with the
CH2B protons in the COSY spectrum.
Retrosynthetically, the acidic fragment B can be ultimately
deconvoluted to chiral boronate E (Scheme 1), which is
easily obtained from the corresponding halobromomethane
and (K)-pinanediol that serves as the chiral auxiliary of
choice. In particular, chain elongation of E by means of a
suitable lithium enolate should firstly provide C3 boronic
ester D, which would then undergo two consecutive
stereoselective homologations in the presence of (dichloro-
methyl)lithium to afford a-chloro boronate C (Scheme 1).
The stereochemical outcome of both homologation
reactions would be controlled by (K)-pinanediol as the
chiral director, which would induce the desired R absolute
configuration at the newly inserted chlorine-bearing carbon
atoms. Nucleophilic displacement by a vinyl Grignard
reagent, followed by alkaline oxidative removal of the
boronic scaffold and protection–deprotection manipula-
tions, would finally result in the required C7 terminal alkene
B bearing two adjacent hydroxy groups in a threo fashion
with the correct R stereochemistry (Scheme 1).
For the assembly of the C3 unit, tert-butylacetate and
halomethaneboronates 3a–c were treated with LDA in THF
at K78 8C (Scheme 2).12 In the case of chloro derivative 3a,
only partial conversion was achieved and 2-[tert-butoxy-
carbonyl]ethaneboronate (4) was obtained in only 28%
yield, along with tert-butylacetoacetate as the main reaction
product arising from Claisen self-condensation of tert-
butylacetate.11 In contrast, most satisfactorily, reaction with
bromomethaneboronate 3b provided the displacement
product 4 in 75% yield, whereas a slightly lower yield
was observed with the iodo analogue 3c (65%).
2. Results and discussion
2.2. Asymmetric synthesis of the C7 fragment
2.1. Initial manouvre: synthesis of the C3 unit
With a substantial amount of C3 boronic ester 4 in hand, we
set sails for the acidic C7 fragment that was required for the
assembly of the diene ester to be subsequently used in the
RCM macrocyclization.
The enantioselective route to the C7 fragment B began with
the preparation of the appropriate chiral halomethane-
boronate 3 which was required to build up the C3 starting
unit by nucleophilic displacement with the lithium enolate
of tert-butylacetate.11,12 For the carboxylic group, in
particular, we envisaged that protection as a tert-butyl
ester would be appropriate, owing to its well-known
resistance to strongly basic environments such as those
that were planned to be encountered in all the subsequent
steps of our synthetic voyage, homologations included,11,13,14
and because of great ease of deprotection.
To this end, we devised applying two subsequent stereo-
selective homologations on chiral boronic ester 4 to install
the two contiguous stereocentres with the required R
absolute configuration, by analogy to the preparation of
the alcoholic C11 fragment performed in the course of our
previous total synthesis.5 In the present case, however, (K)-
pinanediol had to be used as the chiral director for the
homologation reaction, since it is reported to induce the R
absolute configuration at the newly formed stereocentre.8,13
Initial experiments were focused on exploring the perform-
ance of different halogen derivatives (3a–c) in the reaction
with tert-butylacetate in the presence of LDA (Scheme 2).11,12
Chloro derivative 3a was prepared from bromochloro-
methane (2a) according to a literature procedure.15 By close
analogy, pinanediol bromomethaneboronate (3b) was
Addition of in situ-generated (dichloromethyl)lithium to
chiral tert-butoxycarbonyl boronate 4 at K100 8C in THF,19
† When trimethylchlorosilane was used instead,15 products 3a and 3b were
formed in a 1:1 ratio.

P. Davoli et al. / Tetrahedron 61 (2005) 4427–4436
4429
Scheme 3. (a) (Dichloromethyl)lithium, ZnCl2, THF, K100 8C/rt; (b) benzyl alcohol, n-BuLi, THF, K78 8C/rt, then reflux (44% over two steps); (c)
(dichloromethyl)lithium, ZnCl2, THF, K100 8C/rt; (d) vinylmagnesium bromide, THF, K78 8C/rt (32% over two steps); (e) H2O2, NaOH, THF, 0 8C/
45 8C (89%); (f) NaH, DMF, PhCH2Br, K35 8C/K10 8C (48%).
followed by treatment with zinc chloride (1 M solution in
diethyl ether),8,14 resulted in chain extension to a-chloro
derivative 5 in 66% yield and diastereoisomeric excess
greater than 98% (Scheme 3). Successful insertion of a Cl-
bearing carbon atom into the carbon–boron bond was
confirmed by a broad resonance at 43.7 ppm in the 13C
NMR spectrum; in addition, a doublet of doublets at
vinylmagnesium bromide in THF at K78 8C, to afford
1-vinylbutaneboronate 8 in 33% yield (Scheme 3). Yet
again, the homologation–substitution sequence gave higher
yields when performed on boronic ester 6 as a one-pot
procedure (32% total yield over two steps), which avoided
purification of the a-chloro intermediate 7. Likewise,
unreacted 6 did not affect the outcome of the nucleophilic
displacement with the vinyl Grignard reagent, but care had
to be taken to remove all zinc salts during homologation
workup before moving to the substitution reaction. Dia-
stereoisomerically pure alkene 8 already bears the two
contiguous stereocentres with the correct final R,R absolute
configuration required by (K)-microcarpalide.
1
3.51 ppm accounting for the H-1 proton featured in the H
NMR spectrum. The diastereoselectivity of the homologa-
tion was determined by using the Hendo proton of the pinanyl
moiety (1.17 ppm, doublet) as diagnostic marker,13 as
already reported.5 Since (K)-pinanediol is known to direct
stereoselectively the formation of (R)-a-chloroboronic
esters,8,13 the R absolute configuration could be assigned
to 1-chloropropaneboronate 5. Most conveniently, isolation
and purification of chloro derivative 5 could be avoided, and
the subsequent nucleophilic displacement with (benzyl-
oxy)lithium at K78 8C in THF5 was actually carried out via
a one-pot homologation–substitution sequence, which
afforded 1-benzyloxy derivative 6 in 44% overall yield
from 4 (Scheme 3). The presence of a small quantity of
unreacted 4 did not have any detrimental effect during the
reaction on crude a-chloroboronic ester 5. Boronate 6
features a benzyl-protected hydroxy function with S
absolute configuration,20 which corresponds to the desired
5R stereochemistry in the target metabolite.2
Having successfully played its role as chiral director, the
boronic scaffold was removed by exposure to alkaline
hydrogen peroxide in THF,8,13,21 which revealed the
masked hydroxy function thus providing alcohol 9 in 89%
yield (Scheme 3). Since the reaction is well known to
occur with retention of configuration, the same R,R
stereochemistry could be also assigned to allylic
alcohol 9.
Protection of the released hydroxy group in 9 as a benzyl
ether was deemed the most convenient one, since the same
protecting group was already in place and therefore both
could be removed together later in the synthetic sequence.
Furthermore, no apparent functional group incompatibility
with the subsequent key RCM was to be feared, since
successful formation of a closely related 10-membered
lactone had been reported in the presence of benzyloxy
substituents both at the a and b positions to one of the
metathesizing olefinic side chains.4 Careful treatment of
5-hydroxyhept-6-enoic ester 9 with a stoichometric amount
of sodium hydride in DMF at K35 8C in the presence of
benzyl bromide provided the desired ether 10 in 48% yield
(Scheme 3), along with the free acid 11 (Scheme 4) and the
undesired benzyl ester in 16 and 7% yield, respectively.
When NaH was used in slight excess (1.3 equiv) at rt
instead,22 the product yield dropped to 2%, and formation of
unidentified by-products occurred. The tert-butyl protection
The synthetic route continued with the sequential insertion
of the second stereocentre, which was installed again by
means of Matteson’s asymmetric homologation. Exposure
of boronic ester 6 to (dichloromethyl)lithium at K100 8C in
THF,19 followed by zinc chloride (1 M in Et2O),8 resulted in
the formation of 2-benzyloxy-1-chlorobutaneboronate 7 in
52% yield (Scheme 3). Despite the use of zinc chloride,
which is usually employed to improve yield5,13 and
diastereoselectivity,13 the homologation displayed only
incomplete conversion (70% by NMR), although the
diastereoselectivity was excellent (d.e.R98%).
Completion of the desired C7 framework of the acidic
fragment was achieved by treating compound 7 with

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P. Davoli et al. / Tetrahedron 61 (2005) 4427–4436
bearing the desired trans geometry at the newly formed
double bond (Scheme 4), and no cis analogue could be
detected. The doublet of doublet at 5.69 ppm in the 1H NMR
spectrum displaying a coupling constant JH-7,H-8Z15.7 Hz
allowed us to assign the E stereochemistry to 14 beyond any
shadow of doubt.
Excellent stereoselectivity in the formation of the required
trans macrolactone by means of RCM has been reported in
the course of the recent total synthesis of (K)-micro-
carpalide by Gurjar et al., using a diene ester nearly identical
to 13, except for the methoxyethoxymethyl (MEM)
protecting group at 10–OH.4 When compared to their 67%
yield, however, our poor conversion, even over a longer
reaction time, is puzzling. Admittedly, in fact, such a
discrepancy within so closely related metathesizing sub-
strates is difficult to explain, especially in the absence of any
inherent functional incompatibility to RCM. In contrast,
metathetic ring closure of similar dienes bearing an
acetonide group spanning O-5 and O-6 was reported to
proceed uneventfully in excellent yield and comparable
selectivity, regardless of the hydroxyl protection at C-10 as
MOM3 or benzyl ether.5 In those cases, however, the
conformational constraint intrinsic to the acetonide protec-
tion might have favoured alignment of the two alkene
appendages in a cyclisation-friendly conformation, as
suggested by Fu¨rstner et al. on similar systems leading to
nonenolides.23 However, such a predisposition toward
metathetic ring closure can be also attained by means of
acyclic constraints.9a,e For instance, the nature of protecting
groups at neighbouring allylic and homoallylic hydroxy
functions was found to be decisive for the successful
formation of 10-membered carbocycles by RCM.24
Similarly, fine tuning of the protection at the allylic
position was required to construct the framework of
herbarumin III, a fungal nonenolide, by ring-closing
metathesis, either with Grubbs’ first or second generation
catalyst.25
Scheme 4. (a) TFA, CH2Cl2, rt (100%); (b) DCC, DMAP, CH2Cl2, rt
(66%); (c) Grubbs’ catalyst, CH2Cl2, reflux (61%; 43% conversion);
(d) TiCl4, CH2Cl2, 0 8C (58%).
at the carboxylic group clearly revealed limitations and it is
tempting to speculate that the moderate yields observed in
the course of the two homologation-substitution sequences
might be explained by the occurrence of such a deprotection
in stronger basic environments, despite the very low
temperature.
Treatment of dibenzyloxy ester 10 with TFA at rt proceeded
without incident to afford the desired free acid 11 in
quantitative yield (Scheme 4).
Although it cannot be excluded a priori that even a remote
appendage might exert a dramatic effect in the formation of
10-membered macrocycles by RCM, this hypothesis
remains undoubtedly a topic for further investigations
which will have to be verified over a broader range of
substrates. In this respect, the influence of remote
substituents on the E/Z ratio in ring-closing metathesis has
been reported for larger ring systems, such as epothilones26
and salicylihalamides,27 which feature a 16- and 12-
membered lactone skeleton, respectively. Yet again, the
strong dependency of the metathetic process on the intimate
nature of the 1,u-diene substrate itself, and especially of its
appendages, either close or remote, is posing considerable
challenges at drawing up general and reliable guidelines for
controlling the formation of medium-sized rings by RCM,
even within a given ring size and catalyst.
2.3. Completion of the total synthesis
Having accomplished the stereoselective synthesis of the
required C7 acid 11, the stage was set to assemble the diene
ester for the key RCM macrocyclization. The appropriate
alcohol partner 12 had been already synthesized in our own
group through an enantioselective approach.5 Therefore,
acid 11 was coupled to alcohol 12 in the presence of DCC
and DMAP in methylene chloride at rt, to provide ester 13 in
66% yield (Scheme 4).
Exposure of diene ester 13 to Grubbs’ catalyst (22.5 mol%)
under high dilution (0.52 mM) in anhydrous degassed
dichloromethane under reflux9 afforded the expected
macrolactone 14 in 61% yield (Scheme 4), though,
regrettably, with poor conversion (43%), which could not
be improved by increasing the reaction time up to 140 h.
Much to our delight, however, the RCM macrocyclization
resulted in exclusive formation of (E)-oxecin-2-one 14
Completion of the total synthesis required cleavage of the
three benzyl groups protecting the hydroxy functions at
positions 5, 6 and 10. Accordingly, tribenzyl ether 14 was
treated with TiCl4 in dichloromethane at 0 8C5 to afford the
target metabolite (1) in 58% yield (Scheme 4). The product
had spectral properties in perfect agreement with those

P. Davoli et al. / Tetrahedron 61 (2005) 4427–4436
4431
reported in the literature for synthetic5 and natural
microcarpalide (1).2
4. Experimental
4.1. General
All solvents used were anhydrous, unless stated otherwise,
and all reactions requiring anhydrous conditions were
performed using oven-dried and argon-flushed glassware.
Anhydrous tetrahydrofuran and diethyl ether were prepared
by standard methods and freshly distilled over sodium
benzophenone ketyl prior to use. Dichloromethane and N,N-
dimethylformamide were dried according to standard
3. Conclusions and future prospects
To date, five different syntheses of microcarpalide are
available in the literature,3–7 although, for the sake of
stereochemical accuracy, four of them only have dealt with
the natural (K) enantiomer.3–5,7 In all cases except one,7 at
least one of the two key subunits was prepared from the
chiral pool.3–6 Ishigami and Kitahara, in constrast,
employed an original convergent approach that featured
two different Sharpless asymmetric dihydroxylations to
install the four stereocentres, and a Julia olefination
followed by Yamaguchi macrolactonization for the final
assembly of the oxecin-2-one scaffold.7
˚
procedures and stored upon 3 A molecular sieves. Acetone
was dried over potassium carbonate. (1R,2R,3S,5R)-(K)-
Pinanediol, dibromomethane, tert-butylacetate and all other
reagents were obtained from Aldrich. (K)-Pinanediol
chloromethaneboronate (3a) was prepared following the
procedure described by Strynadka and colleagues,15 except
for the replacement of chloroiodomethane with bromo-
chloromethane (2a) as the starting material. First generation
Grubbs’ catalyst [bis(tricyclohexylphosphine) benzylidine
ruthenium(IV) dichloride] was purchased from Strem Ltd
and maintained in a Schlenk flask under Ar atmosphere.
Chromatographic purification of compounds was carried out
on silica gel (60–200 mm). Details of analytical TLC have
been already described.5
In the present case, all four stereocentres have been installed
by asymmetric synthesis using (C)- or (K)-pinanediol as
chiral auxiliary during stereoselective homologations of
appropriate boronic esters. Final steps included DCC-
mediated coupling of the two chiral synthons (11 and 12)
bearing appropriate terminal alkene appendages, stereo-
selective ring-closing metathesis of the resulting diene ester
(13) and ultimate release of the three protected hydroxy
functions by treatment with titanium tetrachloride.
1H and 13C NMR spectra were recorded in CDCl3 solution
(except for 1, for which CD3CN was used)2,5 on a Bruker
DPX200 or Avance 400 spectrometer; chemical shifts (d)
are reported in ppm downfield from TMS as internal
standard (s singlet, d doublet, t triplet, q quartet, m multiplet,
br broad signal); coupling constants (J) are given in Hz
Two-dimensional NMR techniques (COSY, HMBC,
HSQC) were utilized to aid in the assignment of signals in
The enantioselective route herein disclosed represents a
flexible and convergent approach to microcarpalide and
analogues thereof, which should be of value in the
framework of SAR studies aiming at shedding light on the
mechanism of action of this peculiar fungal metabolite,
whose original endophytic producer has meanwhile been
lost.28 Moreover, the stepwise insertion of stereocenters by
means of Matteson’s asymmetric homologation would also
allow the introduction of suitably labelled atoms at defined
positions, a feature that could be appealing for future
biological studies.
13
1H and C spectra, in particular for 5,6,10-O,O,O-
tribenzylmicrocarpalide (14). IR spectra were recorded on
a Perkin–Elmer 1600 FTIR spectrophotometer; wave-
numbers (nmax) are in cmK1. For mass spectra determi-
nations a Finnigan MAT SSQ A and a Hewlett-Packard
HP5972 spectrometer were used (EI, 70 eV). Elemental
analyses were performed with a Carlo Erba Elemental
Analyzer mod. 1110. Optical rotations were measured in
chloroform at 20 8C with a Perkin–Elmer 241 polarimeter
and are expressed in 10K1 deg cm2 gK1; concentration (c) is
Microcarpalide (1) bears structural resemblance to a family
of phytotoxins such as herbarumins29 and pinolidoxin,30
with which it shares a common nonenolide architecture.
These fungal toxins interfere with the self-defense system in
plants and might, therefore, hold promise as lead com-
pounds for developing new herbicidal agents.23,31 Although
the phytotoxicity of microcarpalide has not been tested as
yet, it is tempting to suggest that a similar biological activity
might also occur.
in g 100 mLK1
.
4.1.1. (K)-Pinanediol bromomethaneboronate (3b).
Commercially available dibromomethane (2.03 mL,
29.08 mmol) and freshly distilled trimethyl borate
(2.81 mL, 25.10 mmol) were dissolved in THF (20 mL) in
a 4-necked 100-mL flask equipped with two dropping
funnels and a mechanical stirrer, and cooled to K78 8C.
n-Butyllithium (2.5 M solution in hexanes, 10.5 mL,
26.25 mmol) was slowly added dropwise under Ar flow
over a 40 min period, using additional THF (5 mL) for
washing. After stirring for 1 h, bromotrimethylsilane
(3.84 mL, 29.09 mmol) was introduced, washing with
THF (5 mL). Formation of a white precipitate occurred.
The suspension was left to warm to rt overnight, and an
orange–yellow clear solution was obtained. A solution of
(1R,2R,3S,5R)-(K)-pinanediol (4.5 g, 26.43 mmol) in dry
THF (17 mL) was then added at rt under Ar flow and left to
react for 1 h. The reaction mixture was partitioned between
Furthermore, a number of 10-membered lactones of
polyketide biosynthetic origin are currently being isolated
from a variety of fungal species,32 endophytic fungi
included,33 and it is likely that these organisms might well
harbour a much greater chemical diversity in this respect.
Most interestingly, these fungal nonenolides are endowed
with the most diverse biological activities, and might,
therefore, represent a promising class of future lead
structures for a variety of applications. Yet again, design
and synthesis of analogues should be of great value to gain
some insight into structure-activity relationships within this
fascinating family of fungal metabolites.

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P. Davoli et al. / Tetrahedron 61 (2005) 4427–4436
ethyl acetate (230 mL) and water (50 mL) and phases were
separated. The aqueous layer was extracted with ethyl
acetate (3!30 mL) and the pooled organic phases were
dried (Na2SO4). After filtration and concentration in vacuo,
the crude liquid was purified by chromatography with
light petroleum/ethyl acetate 70:30, affording bromo-
methaneboronate 3b as a pale yellow oil (5.017 g, 73%
yield), [a]DZK22.5 (c 2.8, CHCl3). 1H NMR (200 MHz): d
0.80 (3H, s, pinanyl CH3), 1.16 (1H, d, JZ11.0 Hz, pinanyl
Hendo), 1.25 (3H, s, pinanyl CH3), 1.37 (3H, s, pinanyl CH3),
1.71–2.39 (5H, m, pinanyl protons), 2.57 (2H, s, CH2Br),
4.32 (1H, dd, JZ8.7, 1.8 Hz, CHOB). 13C NMR: d 8.2 (br,
CB), 23.9, 26.2, 27.0, 28.4, 35.2, 38.2, 39.3, 51.2, 78.5, 86.7.
IR (neat): nmax 1242, 1340, 1416. MS, m/z: 272–274 (1:1,
MC, 11), 257–259 (1:1, 32), 231 (33), 216–218 (1:1, 30),
203–205 (1:1, 52), 189 (25), 176 (26), 152 (25), 134 (74),
119 (30), 109 (30), 96 (80), 83 (100), 81 (66), 67 (62), 55
(51%). Anal. Calcd for C11H18BBrO2: C, 48.40; H, 6.65.
Found: C, 48.48; H, 6.71.
partitioned between light petroleum (100 mL) and satd
NH4Cl (180 mL). The aqueous layer was extracted with
light petroleum (2!85 mL) and the combined organic
phases were washed with brine (50 mL), dried over Na2SO4,
filtered and concentrated under reduced pressure to give a
syrupy orange liquid. After chromatographic purification
using light petroleum/diethyl ether 80:20 as the eluant, the
title compound 4 (4.254 g, 75% yield) was obtained as a
dense pale yellow oil, [a]DZK17.5 (c 1.0, CHCl3).
Following the same procedure, the title compound could
be also prepared from halomethaneboronates 3a and 3c,
albeit in lower yield (28% and 65%, respectively). When 3a
was used, tert-butylacetoacetate was also recovered11 after
column chromatography in addition to the unreacted
substrate. 1H NMR (200 MHz): d 0.72 (3H, s, pinanyl
CH3), 1.03 (2H, t, JZ7.5 Hz, H-1), 1.19 (1H, d, JZ10.8 Hz,
pinanyl Hendo), 1.29 (3H, s, pinanyl CH3), 1.37 (3H, s,
pinanyl CH3), 1.44 (9H, s, t-Bu), 1.70–2.30 (5H, m, pinanyl
protons), 2.36 (2H, t, JZ7.5 Hz, H-2), 4.27 (1H, dd, JZ8.7,
2.0 Hz, pinanyl CHOB). 13C NMR: d 6.8 (br, CB), 25.3,
27.7, 28.5, 29.5, 29.9, 31.4, 36.8, 39.5, 40.9, 52.7, 79.2,
81.1, 86.9, 175.0. IR (neat): nmax 1150, 1390, 1731. MS,
m/z: 252 ([MK56]C, 2), 235 (1), 210 (0.4), 196 (0.7), 181
(27), 167 (10), 154 (22), 135 (50), 119 (13), 109 (25), 99
(46), 93 (49), 83 (41), 67 (28), 57 (100), 55 (41), 43 (26%).
Anal. Calcd for C17H29BO4: C, 66.25; H, 9.48. Found: C,
66.31; H, 9.40.
4.1.2. (K)-Pinanediol iodomethaneboronate (3c). A
solution of (K)-pinanediol chloromethaneboronate (3a)15
(1.01 g, 4.42 mmol) in dry acetone (7 mL) was added
dropwise at rt over 5 min to a stirred solution of sodium
iodide in acetone (14 mL). The flask was wrapped in
aluminium foil to protect from light. Formation of a white
powdery precipitate was observed. After 3 h, the dark
yellow suspension was repeatedly centrifuged and the clear
solution was pipetted off, washing the residual solid with
diethyl ether. The pooled organic phases were evaporated to
dryness, partitioned between satd Na2S2O5 (15 mL) and
diethyl ether (50 mL), and the organic layer was washed
with brine (10 mL) and water (10 mL). After drying over
Na2SO4 and filtration, the solvent was evaporated under
reduced pressure to afford iodo derivative 3c (1.223 g, 86%
yield) as a dense yellow liquid which turned brown upon
prolonged exposure to light. [a]DZK23.6 (c 3.2, CHCl3).
1H NMR (200 MHz): d 0.88 (3H, s, pinanyl CH3), 1.28 (1H,
d, JZ10.5 Hz, pinanyl Hendo), 1.33 (3H, s, pinanyl CH3),
1.43 (3H, s, pinanyl CH3), 1.85K2.00 (2H, m, pinanyl
protons), 2.12 (1H, t, JZ5.1 Hz, pinanyl proton), 2.24 (2H,
s, CH2I), 2.25–2.56 (2H, m, pinanyl protons), 4.40 (1H, dd,
JZ8.8, 2.0 Hz, CHOB). 13C NMR: d K22.8 (br, ICB), 25.3,
27.7, 28.4, 29.7, 36.7, 39.8, 40.7, 52.8, 79.9, 87.9. IR (neat):
nmax 1241, 1380. MS, m/z: 320 (MC, 66), 305 (64), 291 (5),
277 (30), 265 (58), 251 (98), 224 (92), 193 (3), 179 (14), 152
(33), 134 (79), 127 (19), 124 (43), 96 (52), 83 (100), 67 (89),
55 (73%). Anal. Calcd for C11H18BIO2: C, 41.29; H, 5.67.
Found: C, 41.33; H, 5.51.
4.1.4. (K)-Pinanediol (1R)-3-[tert-butoxycarbonyl]-1-
chloropropaneboronate (5). A solution of methylene
chloride (260 mL, 4.06 mmol) in THF (5 mL) was cooled
at K100 8C and treated with a 2.5 M solution of
n-butyllithium in hexanes (930 mL, 2.32 mmol) under Ar
flow and mechanical stirring. After 55 min, the solution of
boronate 4 (618 mg, 2.02 mmol) in THF (6 mL) was added
dropwise at K100 8C over a 20 min period and the flask was
warmed to K78 8C. Zinc chloride (1 M solution in diethyl
ether, 3.6 mL, 3.64 mmol) was then added during a 20 min
period, washing with THF (2 mL), and the reaction mixture
was left to stir at rt for 22 h. After dilution with light
petroleum (70 mL), the mixture was washed repeatedly with
water (5!35 mL) and concentrated in vacuo. The residue
was dissolved again in light petroleum (50 mL) and washed
with water (2!25 mL) for complete removal of zinc salts.
The organic phase was dried (Na2SO4), filtered and
concentrated in vacuo. Chromatographic purification of
the crude residue with light petroleum/ethyl acetate 80:20
afforded the desired product 5 in 90% purity (by NMR) as a
dense pale yellow oil (520 mg, 66% yield), [a]DZK26.1 (c
4.6), whilst unreacted substrate 4 accounted for the
remainder 10%. 1H NMR (200 MHz): d 0.84 (3H, s, pinanyl
CH3), 1.17 (1H, d, JZ10.9 Hz, pinanyl Hendo), 1.29 (3H, s,
pinanyl CH3), 1.42 (3H, s, pinanyl CH3), 1.44 (9H, s, t-Bu),
1.84–2.58 (9H, m, 5 pinanyl protons, 2!H-2, 2!H-3), 3.51
(1H, dd, JZ9.0, 5.4 Hz, H-1), 4.36 (1H, dd, JZ8.7, 1.8 Hz,
pinanyl CHOB). 13C NMR: d 25.2, 27.6, 28.3, 29.4, 29.7,
30.6, 34.2, 36.5, 39.5, 40.7, 43.7 (br, ClCHB), 52.5, 79.8,
81.5, 87.9, 173.3. MS, m/z: 300–302 (3:1, [MK56]C, 2),
285–287 (3:1, 1), 256–258 (3:1, 0.5), 249 (0.5), 231–233
(3:1, 26), 215 (2), 204 (10), 179 (4), 161 (11), 149 (11), 135
(69), 109 (22), 99 (64), 93 (45), 83 (31), 67 (30), 57 (100),
55 (39), 44 (6%).
4.1.3. (K)-Pinanediol 2-[tert-butoxycarbonyl]ethane-
boronate (4). In a four-necked 100-mL flask, (K)-
pinanediol bromomethaneboronate (3b) (5.017 g,
18.38 mmol) and tert-butyl acetate (2.97 mL, 22.06 mmol)
were dissolved in freshly distilled THF (23 mL) and cooled
to K78 8C. In a separate flask, fresh LDA was prepared by
treating diisopropylamine (3.09 mL, 22.06 mmol) with
n-butyllithium (2.5 M solution in hexanes, 8.1 mL,
20.22 mmol) in THF (11 mL) at K78 8C, followed by
gradual warming to rt over 1 h. The LDA solution thus
formed was slowly added via syringe at K78 8C under
magnetic stirring and Ar flow over a 30 min period. After
leaving to warm to rt overnight, the reaction mixture was

P. Davoli et al. / Tetrahedron 61 (2005) 4427–4436
4433
4.1.5. (K)-Pinanediol (1S)-1-benzyloxy-3-[tert-butoxy-
carbonyl]propaneboronate (6). A solution of boronate 4
(2.11 g, 6.85 mmol) in THF (7 mL) was slowly added at
K100 8C over 15 min to a mechanically stirred solution of
(dichloromethyl)lithium prepared from CH2Cl2 (882 mL,
13.76 mmol) and n-BuLi (2.5 M solution in hexanes,
3.2 mL, 8 mmol) in THF (8 mL) at K100 8C, by close
analogy to the procedure reported above. Subsequently, a
1 M solution of ZnCl2 in diethyl ether (12.3 mL,
12.3 mmol) was added at K78 8C over a 20 min period,
washing with THF (3 mL), and the mixture was left to stir at
rt. After 18 h the reaction mixture was diluted with light
petroleum (70 mL), washed with water (4!35 mL),
evaporated to dryness, dissolved in fresh light petroleum
(50 mL) and re-washed with water (4!25 mL). The organic
layer was dried over Na2SO4, filtered and concentrated in
vacuo to yield chloro boronate 5 as a yellow liquid (2.24 g)
which was used without further purification. In a separate
50-mL flask equipped with a reflux condenser, benzyl
alcohol (671 mL, 6.48 mmol) was dissolved in THF (3 mL)
and titrated with a 2.5 M solution of n-BuLi in hexanes
(2.8 mL, 7.0 mmol) at K78 8C under magnetic stirring and
Ar flow in the presence of a few crystals of oven-dried
(110 8C, 2 h) 1,10-phenanthroline as indicator, until the
colour turned dark red. The mixture was then stirred at
K78 8C for 15 min and briefly warmed to rt for 5 min.
Subsequently, a solution of crude 5 (2.24 g) in THF (7 mL)
was slowly dropped in at K78 8C, whereupon the solution
turned lemon yellow in colour. After leaving to warm to rt
overnight, the reaction mixture was heated under reflux for
2 h under Ar atmosphere until TLC showed disappearance
of the homologation product 5. The mixture was then
partitioned between light petroleum (45 mL) and satd
NH4Cl (45 mL), phases were separated and the aqueous
layer was extracted with diethyl ether (3!35 mL). The
combined organic phases were dried (Na2SO4), filtered and
evaporated under reduced pressure to give a viscous dark
yellow oil. Chromatographic purification with light
petroleum/diethyl ether 90:10 as the eluant afforded the
title compound 6 as a dense bright yellow oil (1.304 g, 44%
added dropwise over 20 min to the (dichloromethyl)lithium
solution at K100 8C, under mechanical stirring and Ar flow.
The reaction mixture was then warmed to K78 8C and
ZnCl2 (1 M solution in Et2O, 1.66 mL, 1.66 mmol) was
introduced. After leaving to warm to rt overnight, the
mixture was diluted with light petroleum (200 mL) washed
with water (4!100 mL), evaporated to dryness, dissolved
again in fresh light petroleum (130 mL) and thoroughly
washed with water (4!80 mL). The organic layer was dried
(Na2SO4), filtered and concentrated under reduced pressure
to afford a dense dark yellow oil (532 mg, 52% yield),
[a]DZK5.6 (c 2.1), which was used as such for the next
step. In addition to the desired homologation product (7),
NMR analysis revealed also the presence of 30% of
1
unreacted substrate. H NMR (200 MHz): d 0.85 (3H, s,
pinanyl CH3), 1.22 (1H, d, JZ10.8 Hz, pinanyl Hendo), 1.30
(3H, s, pinanyl CH3), 1.41 (3H, s, pinanyl CH3), 1.44 (9H, s,
t-Bu), 1.84–2.43 (7H, m, 5 pinanyl protons and 2!H-3),
2.35 (2H, t, JZ7.4 Hz, H-4), 3.63 (1H, d, JZ6.6 Hz, H-1),
3.83 (1H, ddd, JZ7.4, 6.6, 4.7 Hz, H-2), 4.38 (1H, dd, JZ
8.6, 2.0 Hz, pinanyl CHOB), 4.60 (1H, d, JZ11.2 Hz,
CH2Ph), 4.72 (1H, d, JZ11.2 Hz, CH2Ph), 7.25–7.40 (5H,
m, arom). 13C NMR: d 25.3, 27.7, 28.4, 28.9, 29.5, 29.8,
32.8, 36.6, 39.6, 40.7, 46.2 (br, ClCHB), 52.6, 74.1, 80.0,
80.9, 81.6, 88.3, 129.0, 129.2, 129.7, 139.7, 173.9. The
EI-MS was unobtainable.
4.1.7. (K)-Pinanediol (1R,2R)-2-benzyloxy-4-[tert-
butoxycarbonyl]-1-vinylbutaneboronate (8). Following
the same procedure reported above, (dichloromethyl)-
lithium was prepared by treating methylene chloride
(396 mL, 6.17 mmol) in THF (4 mL) with n-BuLi (2.5 M
solution in hexanes, 1.43 mL, 3.58 mmol) at K100 8C. A
solution of benzyloxy derivative 6 (1.317 g, 3.07 mmol) in
THF (7 mL) was added dropwise at K100 8C over a 15 min
period, and the temperature was raised to K78 8C. Zinc
chloride (1 M solution in Et2O, 5.5 mL, 5.5 mmol) was
introduced and the reaction mixture was left to warm to rt
overnight. Similarly as above, the mixture was diluted with
light petroleum (200 mL) washed with water (4!100 mL),
concentrated in vacuo, dissolved in fresh light petroleum
(70 mL) and washed again with water (4!50 mL). The
organic phase was dried over Na2SO4, filtered and
concentrated under reduced pressure to give crude a-chloro
derivative 7 as a dense bright yellow oil (1.256 g) which was
employed immediately for the substitution reaction without
further purification. Vinylmagnesium bromide (1 M
solution in THF, 3.2 mL, 3.2 mmol) was added dropwise
via syringe over 10 min to a stirred solution of crude 7 in
THF (20 mL) at K78 8C and the mixture was left to react
for 1 h at this temperature. After warming to rt overnight,
the reaction mixture was partitioned between light
petroleum (90 mL) and satd ammonium chloride (60 mL).
Phases were separated and the aqueous layer was extracted
with light petroleum (3!30 mL). The organic phases were
combined, dried (Na2SO4), filtered and concentrated in
vacuo to give a dark yellow residue. Purification by column
chromatography using light petroleum/diethyl ether
mixtures of increasing polarity (from 100 to 80:20) as
eluants, afforded vinyl derivative 8 as a bright yellow dense
liquid (459 mg) in 32% overall yield (over two steps),
1
yield over two steps), [a]DZK0.79 (c 1.2, CHCl3). H
NMR (200 MHz): d 0.84 (3H, s, pinanyl CH3), 1.15 (1H, d,
JZ10.7 Hz, pinanyl Hendo), 1.30 (3H, s, pinanyl CH3), 1.40
(3H, s, pinanyl CH3), 1.43 (9H, s, t-Bu), 1.84–2.38 (7H, m, 5
pinanyl protons and 2!H-2), 2.39 (2H, t, JZ7.7 Hz, H-3),
3.36 (1H, dd, JZ7.3, 5.9 Hz, H-1), 4.32 (1H, dd, JZ8.6,
1.8 Hz, pinanyl CHOB), 4.50 (1H, d, JZ11.9 Hz, CH2Ph),
4.61 (1H, d, JZ11.9 Hz, CH2Ph), 7.20–7.39 (5H, m, arom).
13C NMR: d 25.3, 27.9, 28.1, 28.4, 29.5, 30.0, 33.9, 36.7,
39.5, 40.9, 52.6, 67.9 (br, CHB), 73.6, 79.5, 81.3, 87.6,
128.7, 129.2, 129.6, 140.3, 174.4. IR (neat): nmax 698, 736,
1150, 1374, 1730. MS, m/z: 429 ([MC1]C, 2), 373 (3), 355
(9), 281 (11), 265 (7), 225 (2), 179 (2), 153 (27), 135 (59),
109 (13), 93 (25), 91 (100), 57 (27%). Anal. Calcd for
C25H37BO5: C, 70.10; H, 8.71. Found: C, 70.33; H, 8.55.
4.1.6. (K)-Pinanediol (1R,2R)-2-benzyloxy-4-[tert-
butoxycarbonyl]-1-chlorobutaneboronate (7). By close
analogy to the synthesis of 5, (dichloromethyl)lithium was
prepared by treatment of dichloromethane (195 mL,
3.04 mmol) in THF (6 mL) with n-BuLi (2.5 M solution
in hexanes, 0.7 mL, 1.75 mmol) at K100 8C. Benzyl ether 6
(648 mg, 1.51 mmol) was dissolved in THF (6 mL) and
1
[a]DZC3.8 (c 1.6, CHCl3). H NMR (200 MHz): d 0.82
(3H, s, pinanyl CH3), 1.13 (1H, d, JZ10.2 Hz, pinanyl

4434
P. Davoli et al. / Tetrahedron 61 (2005) 4427–4436
Hendo), 1.26 (3H, s, pinanyl CH3), 1.33 (3H, s, pinanyl CH3),
1.44 (9H, s, t-Bu), 1.74–2.42 (10H, m, 5 pinanyl protons,
H-1, 2!H-3 and 2!H-4), 3.74 (1H, ddd, JZ7.7, 6.6,
4.1 Hz, H-2), 4.26 (1H, dd, JZ8.7, 2.0 Hz, pinanyl CHOB),
4.52 (1H, d, JZ11.5 Hz, CH2Ph), 4.59 (1H, d, JZ11.5 Hz,
CH2Ph), 5.04 (1H, dd, JZ9.9, 2.0 Hz, CH]CH2), 5.10 (1H,
ddd, JZ17.1, 2.0, 0.8 Hz, CH]CH2), 5.84 (1H, dt, JZ
17.1, 9.9 Hz, CH]CH2), 7.20–7.36 (5H, m, arom). 13C
NMR: d 25.3, 27.6, 28.4, 29.0, 29.5, 29.9, 32.2, 36.7, 39.5,
40.8, 52.7, 72.4, 79.2, 80.7, 81.3, 87.1, 117.4, 128.6, 129.0,
129.5, 137.0, 140.2, 174.5 (CHB not seen). IR (neat): nmax
697, 736, 905, 992, 1152, 1636, 1730. MS, m/z: 469 ([MC
1]C, 0.4), 413 (0.3), 397 (0.7), 305 (1), 249 (5), 217 (2), 193
(54), 159 (12), 135 (18), 106 (26), 91 (100), 79 (10), 57
(16%). Anal. Calcd for C28H41BO5: C, 71.79; H, 8.82.
Found: C, 71.65; H, 9.01.
evaporation afforded a dark yellow crude residue which was
purified by chromatography on silica gel, eluting with light
petroleum/diethyl ether mixtures from 100 to 50:50. The
desired dibenzyl ether 10 was obtained (93 mg, 44% yield)
as a dense pale yellow oil, along with (4R,5R)-4,5-
dibenzyloxy-hept-6-enoic acid (11, 29 mg), (4R,5R)-4,5-
dibenzyloxy-hept-6-enoic acid benzyl ester (16 mg) and
unreacted 9 (13 mg). The undesired benzyl ester was
1
identified on the basis of H NMR spectroscopy only (data
not shown).
Compound 10: [a]DZC9.5 (c 1.7, CHCl3). 1H NMR
(200 MHz): d 1.45 (9H, s, t-Bu), 1.62–2.02 (2H, m, H-3),
2.20–2.46 (2H, m, H-2), 3.55 (1H, ddd, JZ9.2, 5.9, 3.7 Hz,
H-4), 3.92 (1H, dd, JZ7.4, 5.9 Hz, H-5), 4.43 (1H, d, JZ
12.0 Hz, CH2Ph), 4.57 (1H, d, JZ11.4 Hz, CH2Ph), 4.66
(1H, d, JZ12.0 Hz, CH2Ph), 4.78 (1H, d, JZ11.4 Hz,
CH2Ph), 5.28–5.38 (2H, m, H-7), 5.86 (1H, ddd, JZ16.2,
11.4, 7.4 Hz, H-6), 7.25–7.44 (10H, m, arom). 13C NMR: d
26.3, 28.1, 31.6, 70.6, 73.4, 80.0, 80.2, 82.7, 118.9, 127.45,
127.53, 127.7, 128.0, 128.3, 135.1, 138.5, 138.7, 172.9. IR
(neat): nmax 697, 734, 929, 997, 1072, 1165, 1455, 1497,
1734. MS, m/z: 339 ([MK57]C, 0.2), 249 (2), 232 (0.6), 193
(29), 181 (5), 143 (2), 125 (3), 101 (2), 92 (6), 91 (100), 85
(2), 65 (4), 57 (5%). Anal. Calcd for C25H32O4: C, 75.73; H,
8.13. Found: C, 75.94; H, 7.98.
4.1.8. (4R,5R)-4-Benzyloxy-5-hydroxyhept-6-enoic acid
tert-butyl ester (9). Vinyl boronate 8 (537 mg, 1.15 mmol)
was dissolved in THF (10 mL) and treated with sodium
hydroxide (2.2 M solution, 1.56 mL, 3.44 mmol) at 0 8C for
10 min under magnetic stirring. Upon addition of hydrogen
peroxide (35% w/w solution, 272 mL, 3.11 mmol) at 0 8C, a
white precipitate formed. After 15 min at 0 8C, the cloudy
solution was stirred at 45 8C for an additional 1 h until TLC
analysis (light petroleum/diethyl ether 50:50) revealed
disappearance of the starting boronate. The reaction mixture
was partitioned between diethyl ether (40 mL) and water
(20 mL), phases were separated and the aqueous layer was
extracted with diethyl ether (3!10 mL). The pooled
organic phases were dried over Na2SO4, filtered and
concentrated in vacuo. Purification of the thick yellow
residue by column chromatography, using light petroleum/
diethyl ether 70:30 as the eluant, afforded the title
compound 9 (313 mg, 89% yield) as a dense pale yellow
4.1.10. (4R,5R)-4,5-Dibenzyloxyhept-6-enoic acid (11).
tert-Butyl ester 10 (93 mg, 0.23 mmol) was dissolved in
dichloromethane (1 mL) and stirred at rt in the presence of
TFA (520 mL, 7.0 mmol), until disappearance on TLC (light
petroleum/diethyl ether 80:20) occurred. After 2 h the
reaction mixture was evaporated under reduced pressure
to afford the free acid 11 (80 mg, 100% yield) as a dense
light brown oil, [a]DZC9.7 (c 1.5, CHCl3), which was used
without further purification for the next DCC-mediated
1
oil, [a]DZC14.0 (c 1.6, CHCl3). H NMR (200 MHz): d
1
1.45 (9H, s, t-Bu), 1.73–2.06 (2H, m, H-3), 2.20–2.48 (1H,
br, CHOH), 2.36 (2H, t, JZ7.5 Hz, H-2), 3.44 (1H, m, H-4),
4.09 (1H, tt, JZ5.9, 1.4 Hz, H-5), 4.58 (1H, d, JZ11.3 Hz,
CH2Ph), 4.66 (1H, d, JZ11.3 Hz, CH2Ph), 5.24 (1H, dt, JZ
10.5, 1.4 Hz, H-7), 5.38 (1H, dt, JZ17.2, 1.4 Hz, H-7), 5.91
(1H, ddd, JZ17.2, 10.5, 5.9 Hz, H-6), 7.25–7.45 (5H, m,
arom). 13C NMR: d 25.8, 28.1, 31.0, 72.9, 74.3, 80.3, 81.1,
116.9, 127.8, 127.9, 128.5, 137.4, 138.1, 172.8. IR (neat):
nmax 698, 736, 923, 994, 1094, 1154, 1455, 1497, 1729,
3454 (br). MS, m/z: 306 (MC, 0.5), 305 (1), 265 (1), 249
(0.3), 232 (0.4), 214 (1), 193 (44), 173 (1), 155 (1), 129 (26),
91 (100), 73 (24), 57 (9), 41 (5%). Anal. Calcd for
C18H26O4: C, 70.56; H, 8.55. Found: C, 70.75; H, 8.48.
coupling reaction. H NMR (200 MHz): d 1.66–2.04 (2H,
m, H-3), 2.22–2.56 (2H, m, H-2), 3.57 (1H, ddd, JZ9.2, 5.8,
3.6 Hz, H-4), 3.95 (1H, dd, JZ7.4, 5.8 Hz, H-5), 4.42 (1H,
d, JZ11.9 Hz, CH2Ph), 4.56 (1H, d, JZ11.4 Hz, CH2Ph),
4.67 (1H, d, JZ11.9 Hz, CH2Ph), 4.78 (1H, d, JZ11.4 Hz,
CH2Ph), 5.29–5.39 (2H, m, H-7), 5.84 (1H, ddd, JZ16.4,
11.2, 7.4 Hz, H-6), 7.19–7.42 (10H, m, arom), 8.10–8.40
(1H, br, COOH). 13C NMR: d 25.9, 30.3, 70.6, 73.4, 79.9,
82.5, 119.2, 127.6, 127.7, 127.8, 128.1, 128.4, 134.9, 138.3,
179.8. IR (neat): nmax 698, 736, 931, 995, 1071, 1454, 1497,
1709, 3064 (br). MS, m/z (as the corresponding methyl ester,
obtained by treatment with diazomethane in diethyl ether):
354 (MC, 0.02), 263 (0.4), 246 (8), 207 (14), 157 (4), 140
(4), 115 (6), 91 (100), 65 (6). Anal. Calcd for C21H24O4: C,
74.09; H, 7.11. Found: C, 74.18; H, 7.02.
4.1.9. (4R,5R)-4,5-Dibenzyloxyhept-6-enoic acid tert-
butyl ester (10). Sodium hydride (60% suspension in
mineral oil, 22 mg, 0.55 mmol) was slurried in DMF
(1.1 mL) and added via syringe to a stirred solution of
alcohol 9 (162 mg, 0.53 mmol) and benzyl bromide (69 mL,
0.58 mmol) in DMF (0.8 mL) at K35 8C. Vigorous gas
release was observed. The reaction mixture was stirred at
K35 8C for 1 h 10 min, warmed to K20 8C during 1 h and
finally kept at K10 8C for an additional 1 h. After
quenching with cold water (10 mL), the mixture was
extracted with light petroleum (4!15 mL). The combined
organic phases were washed with water (10 mL) and brine
(10 mL), and dried over Na2SO4. Filtration and rotary
4.1.11. (4R,5R)-4,5-Dibenzyloxyhept-6-enoic acid,
(10S,100S)-10-(100-benzyloxyheptyl)-30-butenyl ester (13).
(4S,5S)-5-Benzyloxyundec-1-en-4-ol (12)5 (37 mg,
0.134 mmol) was dissolved in methylene chloride
(3.5 mL) and added via syringe to a stirred solution of
acid 11 (48 mg, 0.141 mmol) in the same solvent (1 mL).
DCC (35 mg, 0.17 mmol) and DMAP (3 mg, 0.025 mmol)
were added at rt and the reaction mixture was stirred for
25 h. After removal of the white powdery precipitate, the
solvent was evaporated in vacuo and the crude residue was
purified by chromatography with light petroleum/diethyl

P. Davoli et al. / Tetrahedron 61 (2005) 4427–4436
4435
ether 90:10 to afford ester 13 as a dense pale yellow liquid
(53 mg, 66% yield), [a]DZC1.9 (c 1.4, CHCl3). H NMR
and treated at 0 8C with a solution of titanium tetrachloride
(53 mL, 0.484 mmol) in CH2Cl2 (0.5 mL). After stirring for
1 h, water (3 mL) was added to the turbid brown mixture.
The organic phase was separated and the aqueous layer was
extracted with CH2Cl2 (3!3 mL). The pooled organic
phases were washed with satd NaHCO3 (20 mL) and brine
(20 mL), and dried over Na2SO4. After filtration and
concentration in vacuo, the crude greenish-brown residue
was purified by column chromatography on silica gel using
AcOEt as the eluant, to afford a colourless viscous liquid
(7 mg, 58% yield) whose spectral properties matched
perfectly those reported in the literature for synthetic5 and
natural microcarpalide (1).2
1
(200 MHz): d 0.89 (3H, t, JZ6.5 Hz, H-700), 1.06–2.09
(12H, m, H-200 to H-600, H-3), 2.23–2.56 (4H, m, H-2 and
H-20), 3.41–3.64 (2H, m, H-4 and H-100), 3.92 (1H, dd, JZ
7.3, 6.0 Hz, H-5), 4.42 (1H, d, JZ12.0 Hz, CH2Ph), 4.54
(1H, d, JZ11.4 Hz, CH2Ph), 4.60 (2H, s, PhCH2OC-100),
4.65 (1H, d, JZ12.0 Hz, CH2Ph), 4.75 (1H, d, JZ11.4 Hz,
CH2Ph), 4.95–5.15 (3H, m, H-10 and 2!H-40), 5.25–5.37
(2H, m, H-7), 5.62–5.92 (2H, m, H-6 and H-30), 7.22–7.43
(15H, m, arom). 13C NMR: d 14.0, 22.6, 25.6, 26.3, 29.4,
29.9, 30.6, 31.7, 34.3, 70.6, 72.3, 73.2, 73.4, 79.0, 80.2,
82.6, 117.5, 119.0, 127.5, 127.6, 127.7, 127.8, 127.9, 128.3,
134.2, 135.1, 138.5, 138.56, 138.62, 173.1. IR (neat): nmax
734, 911, 930, 997, 1070, 1109, 1454, 1497, 1735, 2856,
2927, 3031, 3055. MS, m/z: 599 ([MC1]C, 0.4), 507 (0.5),
491 (0.3), 451 (5), 401 (2), 384 (1), 349 (1), 293 (2), 259 (9),
253 (5), 233 (3), 205 (2), 181 (30), 135 (5), 125 (8), 113 (6),
91 (100), 85 (16), 65 (5%). Anal. Calcd for C39H50O5: C,
78.22; H, 8.42. Found: C, 78.39; H, 8.47.
Acknowledgements
Financial support from MIUR (COFIN 2003) and
`
Universita di Modena e Reggio Emilia (‘Progetto Giovani
Ricercatori’ to P.D.) was greatly appreciated. Thanks are
due to Adriano Benedetti and Maria Cecilia Rossi (Centro
Interdipartimentale Grandi Strumenti) for spectroscopic
assistance throughout the project. We are indebted to
Stefano Baldini for preliminary experiments with halo-
methaneboronates 2a,c and to Prof. Thomas Hemscheidt
(Department of Chemistry, University of Hawai’i at Ma¯noa,
Honolulu) for kindly sharing with us unpublished infor-
mation about the endophytic fungal strain from which 12
was originally isolated. We also thank the Fondazione Cassa
di Risparmio di Modena for funding the purchase of the
400 MHz NMR spectrometer.
4.1.12. (5R,6R,7E,10S)-10-[(10S)-10-Benzyloxyheptyl]-
5,6-dibenzyloxy-3,4,5,6,9,10-hexahydro-2H-oxecin-2-
one (14). First generation Grubbs’ catalyst (22 mg,
0.027 mmol) was added to a solution of diene ester 13
(72 mg, 0.12 mmol) in freshly distilled degassed anhydrous
dichloromethane (230 mL) and the mixture was heated
under reflux under Ar flow. Air was then bubbled in under
vigorous magnetic stirring to favour catalyst decomposition
and the solvent was evaporated under reduced pressure,
affording a dark brown oily residue which was chromato-
graphed using light petroleum/diethyl ether mixtures of
increasing polarity (from 100 to 70:30) as eluants to provide
the title oxecine 14 (18 mg, 26% yield), [a]DZK28.8 (c
1
1.5, CHCl3), along with unreacted diene 13 (41 mg). H
NMR (400 MHz): d 0.93 (3H, t, JZ6.8 Hz, H-700), 1.22–1.52
(8H, br m, H-30 to H-60), 1.54–1.70 (2H, m, H-2 ), 2.01–2.17
(1H, m, H-4), 2.17–2.27 (1H, m, H-3), 2.27–2.39 (3H, m,
H-4 and 2!H-9), 2.60–2.72 (1H, m, H-3), 3.47–3.57 (1H,
m, H-10), 3.76 (1H, t, JZ5.4 Hz, H-5), 4.14 (1H, br d, JZ
4.9 Hz, H-6), 4.52 (1H, d, JZ11.9 Hz, PhCH2OC-5), 4.53
(1H, d, JZ12.4 Hz, PhCH2OC-6), 4.60 (1H, d, JZ11.9 Hz,
PhCH2OC-5), 4.66 (2H, AB system, PhCH2OC-10), 4.70
(1H, d, JZ12.4 Hz, PhCH2OC-6), 5.26 (1H, dt, JZ9.7,
4.8 Hz, H-10), 5.69 (1H, dd, JZ15.7, 1.9 Hz, H-7), 5.71–
5.80 (1H, m, H-8), 7.24–7.42 (15H, m, arom). 13C NMR
(1000MHz): d 14.0 (C-70), 22.6 (C-60), 23.7 (br, C-4), 250.4
(C-3 ), 28.9 (br, C-3), 29.4 (C-40), 30.7 (C-20), 31.8 (C-5 ),
35.9 (C-9), 71.3 (PhCH2OC-5), 71.5 (PhCH2OC-6), 72.6
(PhCH2OC-10), 76.4 (C-10), 77.3 (C-6), 78.3 (br, C-5), 79.7
(C-10), 126.6 (C-8), 127.2, 127.4, 127.5, 128.0, 128.33,
128.35, 128.40, 131.6 (C-7), 138.4, 138.6, 138.8, 175.3
(C-2). IR (neat): nmax 737, 978, 1027, 1072, 1120, 1148,
1222, 1274, 1377, 1454, 1496, 1737, 2856, 2932, 3030,
3064. MS, m/z: 571 ([MC1]C, !0.1), 378 (0.8), 287 (3),
253 (11), 244 (1), 205 (2), 181 (9), 160 (5), 113 (4), 91
(100), 85 (5), 65 (2%). Anal. Calcd for C37H46O5: C, 77.86;
H, 8.12. Found: C, 77.94; H, 8.21.
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