Model studies for a ring-closing metathesis approach to the bafilomycin macrolactone core from a 2,2-Dimethoxy tetraenic ester precursor

Article abstract of DOI:10.1002/ejoc.201300559

A ring-closing metathesis strategy is reported for the construction of the 16-membered macrolactone core of the bafilomycins. One decisive key feature is the presence of a 2,2-dimethoxyketal functionality at C-2 that provides the required flexibility to the tetraenic ester precursor, allowing the ring-closing metathesis reaction to take place. Three different model esters of increasing complexity were successfully subjected to the 1,3-diene-ene ring-closing metathesis reaction. The best promoter for the simplest esters was the Grubbs first-generation precatalyst. A Hoveyda-Grubbs-type trifluoromethylamido- containing precatalyst developed by Mauduit's group gave satisfactory results for the most complex ester. In all experiments, the 12-Z-configured isomer was obtained as the major product. Subsequent microwave-promoted methanol elimination was achieved on the simplest model compound using camphorsulfonic acid (CSA) as a catalyst. Under these conditions, a E to Z isomerization of the double bond at C-4, as well as ca. 50 % isomerization of the 12-Z double bond into the corresponding 12-E isomer, were observed. Thanks to the presence of a 2,2-dimethoxyketal functionality at C-2 of the ester precursors, models of the bafilomycin core were synthesized using a ring-closing metathesis strategy. An indenylidene Ru complex gave the best results for the ring-closing metathesis step on an advanced model ester. Finally, acid-catalysed elimination of MeOH yielded the required tetraenic macrolactone. Copyright

Full text of DOI:10.1002/ejoc.201300559

FULL PAPER
DOI: 10.1002/ejoc.201300559
Model Studies for a Ring-Closing Metathesis Approach to the Bafilomycin
Macrolactone Core from a 2,2-Dimethoxy Tetraenic Ester Precursor
Alice Chevalley,[a][‡] Joëlle Prunet,[b] Marc Mauduit,[c] and Jean-Pierre Férézou*[a]
Keywords: Natural products / Total synthesis / Cyclization / Macrocycles / Metathesis
A ring-closing metathesis strategy is reported for the con-
struction of the 16-membered macrolactone core of the bafil-
omycins. One decisive key feature is the presence of a 2,2-
dimethoxyketal functionality at C-2 that provides the re-
quired flexibility to the tetraenic ester precursor, allowing the
ring-closing metathesis reaction to take place. Three dif-
ferent model esters of increasing complexity were success-
fully subjected to the 1,3-diene-ene ring-closing metathesis
reaction. The best promoter for the simplest esters was the
Grubbs first-generation precatalyst. A Hoveyda–Grubbs-
type trifluoromethylamido-containing precatalyst developed
by Mauduit’s group gave satisfactory results for the most
complex ester. In all experiments, the 12-Z-configured iso-
mer was obtained as the major product. Subsequent micro-
wave-promoted methanol elimination was achieved on the
simplest model compound using camphorsulfonic acid (CSA)
as a catalyst. Under these conditions, a E to Z isomerization
of the double bond at C-4, as well as ca. 50% isomerization
of the 12-Z double bond into the corresponding 12-E isomer,
were observed.
derstanding of the regulation of V-ATPases, as well as in-
creasing knowledge about the diversity of the isoforms of
the different subunits of this enzymatic complex, make the
prospects for the development of specific inhibitors for
therapeutic purposes promising.[7]
Introduction
Bafilomycin A1 1 is a 16-membered macrolide first iso-
lated from the broth of Streptomyces griseus in 1984 by
Werner et al.[1] Its structure was confirmed in 1987 by X-
ray analysis.[2] Due to its potent specific inhibitory effect on
vacuolar-type proton-translocating ATPases (V-ATPases)
at the nanomolar level,[3] it was immediately recognized that
bafilomycin A1 had potential pharmaceutical applications
in combatting disorders involving the dysfunction of V-
ATPases. However, the ubiquity of V-ATPases precluded
rapid therapeutic applications of natural bafilomycin A1.
One of the first diseases to be targeted was osteoporosis,
and extensive structure–activity relationship studies led to
the identification of several optimized analogues, some of
which were patented.[4] Analogues such as SB-242784 from
GSK[5] or FR167356 from Fujisawa Pharmaceuticals[6] are
currently under clinical investigation. Today, increased un-
More recently, the bafilomycins have been the subject of
further research, due to their promising anticancer poten-
tial. New bafilomycin metabolites from Streptomyces sp.
strains of marine origin have been shown to act as potent
inhibitors of autophagy,[8] a catabolic process that repre-
sents an attractive target for cancer therapy.[9] Moreover, in
combination with other anticancer drugs, bafilomycin A1
has been shown to have potential anticancer properties.
[a] Laboratoire de Chimie des Procédés et Substances Naturelles,
ICMMO (UMR CNRS 8182), Bâtiment 410, Université Paris-
Sud,
91405 Orsay, France
E-mail: jean-pierre.ferezou@u-psud.fr
http://www.u-psud.fr/en/international.html
[b] WestCHEM, School of Chemistry, University of Glasgow, This has been demonstrated in combination with taxol for
Bcl-2/Bcl-xL-overexpressing malignancies.[10] In a similar
Joseph Black Building,
University Avenue, Glasgow G12 8QQ, UK
vein, in combination with anticancer drug Bortezomib, it
has been claimed that bafilomycin A1 can optimize some
cancer treatments.[11] A recent patent deals with a new
bafilomycin-like metabolite from Micromonospora sp. with
antiproliferative properties.[12] In addition to these potential
applications, bafilomycin A1 has been shown to have anti-
malarial activity.[13]
[c] Institut des Sciences Chimiques de Rennes, (UMR CNRS
6226), Ecole Nationale Supérieure de Chimie de Rennes,
Avenue du Général Leclerc, CS 50837, 35708 Rennes Cedex 7,
France
[‡] Current address: Chimie ParisTech (ENSCP), Laboratoire
Charles Friedel (UMR CNRS 7223), 11 rue Pierre et Marie
Curie, 75231 Paris Cedex 05, France
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300559.
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Its challenging structure and pharmaceutical potential
We therefore decided to test whether the increased flexi-
stimulate organic chemists to work towards the synthesis of bility at C-2 could be enough to enable cyclization to form
this molecule, as well as other plecomacrolide congeners. the bafilomycin macrolide ring by a ring-closing metathesis
Several total syntheses of 1 have been published since the strategy.[22] The overall strategy we initially adopted is sum-
pioneering work of Evans et al. in 1993.[14] These studies marized in Scheme 2. The key step would be the late forma-
were reviewed in 2005.[15] More recently, some more par- tion of the C-2 double bond of 5. This would take place
tial[16] or total syntheses[17] have been published.
after the RCM step that would transform tetraenic ester 7
In our group, work towards the synthesis of bafilomycin into 2,2-dimethoxy macrocycle 6. A simple Julia olefination
A1 had been undertaken previously. This approach was between sulfone 2 and aldehyde diene 10 would give C-1–
based on the synthesis of an intermediate seco ester by a C-12 acid subunit 8.
Stille cross-coupling reaction involving a classical C-12–C-
The convergence of this strategy is attractive from the
13 disconnection.[18] Due to the increasing importance of point of view of the synthesis of small libraries of bafilomy-
the ring-closing metathesis (RCM) reaction for the forma- cin analogues from a variety of alcohols 9 of increasing
tion of cyclic compounds Ϫ and especially macrocycles Ϫ structural complexity. As well as the simplest commercially
in the last decade,[19] it appeared to us that an alternative available 3-buten-1-ol (9a), two more ω-unsaturated
and more direct strategy involving RCM would give a more alcohols were tested: alcohol 9b, with an allylic methoxy
efficient alternative for the construction of the macrocyclic group that may have an influence on the outcome of the
core of the bafilomycins at the C-12–C-13 junction. We RCM step,[23] and the more complex alcohol 9c, which al-
were initially dissuaded from undertaking such an approach ready has the functional groups and stereogenic centres re-
when we became aware of the negative preliminary results quired for the synthesis of bafilomycin A1.
obtained by the Yang group in 2006.[20] These authors
failed in their attempt to construct the 16-membered
macrolactone core of the bafilomycins by RCM using an
analogous C-12–C-13 disconnection when the C-2–C-4
diene was already present in the polyenic ester precursor.
We thought that it would be possible to take advantage
of the strategy we had already developed for the synthesis
of C-1–C-11 subunit 4 via functionalized 2,2-dimethoxy-
ketal 3 according to Scheme 1. The presence of a tetrasub-
stituted centre at C-2 in 3 could facilitate the transforma-
tion into the macrolactone by RCM. This approach starts strategy described above for the construction of the bafilo-
from the easy to prepare, crystalline C4 sulfonyl ester 2.[21]
mycin 16-membered core.
In this paper, we report the results of our work using the
Scheme 1. Synthesis of the C-1–C-11 subunit of bafilomycins.[21] TMS = trimethylsilyl; TBS = tert-butyldimethylsilyl.
Scheme 2. Retrosynthesis of bafilomycin macrocycle model compounds.
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Model Studies on the Bafilomycin Macrolactone Core
of TMEDA, the syn Evans aldol product 15 was obtained
in 48% yield from 14 (dr = 15:1). The configuration of 9c
was deduced to be as shown based on literature precedent
for syn Evans condensation of the same propionyloxazolid-
inone 14 with an enantiopure α-methoxy aldehyde.[27] Com-
pound 15 was easily purified by chromatography. It was
transformed into TBS-mono-protected alcohol 9c by re-
duction with sodium borohydride[26] followed by selective
protection of the primary hydroxy group of the resulting
diol as a TBS ether (64% yield from 15).
Results and Discussion
Synthesis of Alcohols 9
For the sake of a convergent synthetic route, we chose to
prepare alcohols 9b and 9c from a common aldehyde 13.
We decided to synthesize 13 in enantiopure form in antici-
pation of the final synthetic project.
For the synthesis of intermediate aldehyde 13, we fol-
lowed a sequence described by Danishefsky in 2004 during
the synthesis of migrastatin, starting from (–)-dimethyl 2,3-
O-isopropylidene-l-tartrate (11; Scheme 3).[24] Reduction of
11 with DIBAL-H (diisobutylaluminium hydride), followed
by in situ addition of divinylzinc gave, after dimethyl ether
formation and acetonide deprotection, the expected prod-
Synthesis of the Tetraenic Ester RCM Precursors
A crucial step in the synthesis of acid intermediate 8 was
uct (i.e., 12) with a diastereomeric ratio of Ͼ9:1 (69% yield a Julia olefination between sulfone 2 and diene aldehyde 10.
over four steps).[25] Oxidative scission of 12 gave volatile Compound 10 was easily synthesized in three steps from
aldehyde 13, which was immediately used for the next steps known keto aldehyde 16, which was prepared by ozonolysis
without purification. Reduction of 13 with sodium boro- of 1-methylcyclohexene.[28] A Yamamoto olefination of 17
hydride gave enantioenriched alcohol 9b (37% yield from using allyldiphenylphosphine oxide followed by acid hydrol-
12).
ysis allowed the synthesis of 10 via 18 with a 9:1 E/Z stereo-
For the synthesis of hydroxy synthon 9c that is required selectivity (Scheme 4).[29] The subsequent condensation re-
for the bafilomycins, crude aldehyde 13 was subjected to a action between 2 and 10 proved to be more problematic
TiCl4-mediated syn Evans/Crimmins aldol condensation than expected. Although the starting aldehyde was com-
with enantiopure (R)-(–)-4-benzyl-3-propionyl-2-oxazolid- pletely consumed, separation of δ-lactone 19 from the ex-
inone (14).[26] As anticipated, in the presence of an excess cess of starting sulfone 2 proved to be particularly difficult,
Scheme 3. Reagents and conditions: a) i: DIBAL-H, toluene –78 °C; ii: vinylmagnesium bromide, ZnCl2, THF, room temp., 4 h; iii: NaH,
MeI, DMF, room temp., 2 h; iv: HCl (2 m), MeOH, reflux, 2 h; b) Pb(OAc)4, Na2CO3, CH2Cl2, 0 °C; c) NaBH4, Et2O; d) 14, TiCl4,
CH2Cl2, 0 °C, 5 min; TMEDA (tetramethylethylenediamine), 0 °C, 30 min, then crude 13, 0 °C, 1 h; e) i: NaBH4, THF/H2O overnight;
ii: TBSCl, DMAP (4-dimethylaminopyridine), Et3N, CH2Cl2, overnight.
Scheme 4. Reagents and conditions: a) MeOH, pTsA (cat.), room temp., 30 min; b) allyldiphenylphosphine oxide, BuLi, THF/HMPA
(hexamethylphosphoramide), –78 °C, 30 min, then room temp., 2 h, 70%. c) H2O/HCO2H, room temp., overnight; d) 2 (5 equiv.), LDA,
THF, –78 °C, 5 min, –55 °C, 40 min, then 10 (THF), –78 °C, 25 min, then 0 °C, 20 min.
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as these compounds had the same polarity. Unfortunately, gin of the batch of amalgam used (see Experimental Sec-
all attempts to crystallize the remaining sulfone from the tion). For instance, a crude mixture of 22a/22b (ca. 1:1 ra-
crude reaction product mixture failed. Moreover, a variable tio) was directly subjected to an esterification reaction with
amount of enaminone 20 was produced in this reaction, alcohol 9a under Steglich conditions to give a mixture of
arising from the undesired addition of oxidized LDA (lith- esters 23a/23b (70% yield from 21). Also, compound 24 was
ium diisopropylamide) onto the ester functionality of sulf- obtained in 49% yield starting from 22a.
one 2.[30]
At this stage, when necessary, an IBX oxidation of the
Despite much effort, this route proved to be unfeasible 10-hydroxy derivatives allowed their easy conversion into
from a practical point of view. We therefore decided to de- the corresponding 10-keto compounds (exemplified for
velop a slightly less convergent route to the required tetra- 23b). Subsequent Yamamoto olefination of keto esters 23a
enic ester precursors of the RCM reaction by carrying out or 24a as described above delivered tetraenic model com-
the stereoselective Yamamoto condensation with allyldi- pounds 25 and 26 in 63 and 31% yields, respectively.
phenylphosphine oxide after the Julia condensation reac-
This approach was ineffective in the case of bulky sec-
tion. The results are shown in Scheme 5. Direct condensa- ondary alcohol 9c, required for the synthesis of the bafilo-
tion of sulfone 2 with ketoaldehyde 16 led, after aqueous mycins. Steglich conditions failed to give the expected ester
hydrogenosulfite quenching and chromatography, to 10-oxo (i.e., 28). Two modifications led to the formation of re-
δ-lactone 21 as a 1:1 mixture of diastereomers in 55% yield. quired ester. The esterification reaction was achieved under
Reductive elimination with Na/Hg led to the formation of Yamaguchi–Yonemitsu lactone formation conditions in the
the expected acid (i.e., 22) with an excellent E/Z stereoselec- presence of 2,4,6-trichlorobenzoyl chloride and an excess of
tivity in the formation of the trisubstituted double bond DMAP.[32] Moreover, in contrast to the Steglich reactions
(E/Z Ͼ 95:5).[31] However, a variable mixture of ketoacid described above, it proved to be necessary to purify acids
22a and hydroxyacid 22b was formed, depending on the ori- 22 before carrying out the esterification reaction, probably
Scheme 5. Reagents and conditions: a) 2, LDA, THF, –78 °C, 5 min, then –55 °C, 40 min, ketoaldehyde 16, –78 °C, 25 min, then 0 °C,
20 min; b) Na/Hg (6%), NaHCO3, THF/MeOH, –40 °C; c) 9a or 9b, EDC, DMAP, CH2Cl2, room temp., overnight; d) IBX (2-iodoxyben-
zoic acid), DMSO, THF, room temp., overnight; e) allyldiphenylphosphine oxide, BuLi, THF/HMPA, –78 °C, then room temp., 2 h;
f) TMSCHN2, MeOH/Et2O, 25 min, room temp.; g) IBX, DMSO, THF, room temp., overnight; h) i: KOH (10% aq.), reflux, 2 h; ii: 2,4,6-
trichlorobenzoyl chloride, DMAP (3 equiv.), Et3N, toluene, 9c, room temp., 30 h; i) allyl diphenylphosphine oxide, BuLi, THF/HMPA,
–78 °C then room temp., 2 h.
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Model Studies on the Bafilomycin Macrolactone Core
to remove the interfering residual phenylsulfinic acid still we tested the Grubbs I first-generation,[33] Grubbs II sec-
present in the crude product of the reductive elimination ond-generation,[34] and Hoveyda–Grubbs[35] precatalysts,
reaction. Treatment of the crude acid mixture 22a/22b with and the results are summarized in Scheme 6. In all cases,
diazomethane followed by IBX oxidation led to methyl keto the starting material had been consumed when the reaction
ester 27a. Subsequent alkaline hydrolysis of 27a followed by was stopped. In the first experiments, significant degrada-
esterification under Yamaguchi–Yonemitsu conditions gave tion occurred upon direct evaporation of the reaction mix-
keto ester 28 in 63% yield. Yamamoto olefination as de- ture. Better results were obtained by adding activated char-
scribed above gave tetraene 29 in good yield as a single coal at the end of the reaction before removal of the sol-
enantiopure 4E,10E stereoisomer.
vent.[36] All subsequent RCM reactions were carried out
with this post-reaction activated charcoal treatment. Under
these conditions, the best results for 25 were obtained using
the Grubbs I precatalyst at room temp., and compound 30
was formed in 66% yield. 14-Methoxy analogue 31 was ob-
RCM Reactions
With tetraenic esters 25, 26, and 29 in hand, we turned tained in 51% yield from 26, as a 9:1 mixture of Z/E iso-
to the RCM reactions. With the simplest esters 25 and 26, mers at C-12.
Scheme 6. RCM reactions with tetraenic esters 25 and 26.
Scheme 7. RCM reactions with tetraenic ester 29.
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The Z isomers were greatly predominant when the reac- tained with an acceptable level of degradation (with two
tions were run at room temperature, and often they were successive additions of 10 mol-% of the precatalyst). Con-
the only products detectable by 1H NMR spectroscopic sidering the Z/E selectivity at the C-12 double bond, al-
analysis of the crude product mixtures. When the Grubbs I though the preliminary RCM reactions described above for
precatalyst was used at reflux temperature, 20% of the E the simpler model compounds 25 and 26 led to the exclusive
isomer of 30 was formed. Various attempts to improve the formation of the Z isomer (the unnatural isomer), it clearly
formation of the E isomer by further treatment of the Z appeared that although increasing the bulk of the alcohol
isomer with Grubbs II or Hoveyda–Grubbs precatalysts did subunit in 29 had a deleterious effect on the kinetics of the
not alter the Z/E ratio or led to different levels of degrada- reaction (10% conversion with the Grubbs I precatalyst), it
tion products.
had a favourable effect on the E-selectivity for the forma-
We next turned to the RCM reaction of the more com- tion of the C-12 double bond. The E/Z ratios obtained var-
plex ester 29 (Scheme 7). When this compound was heated ied from 3:7 with precatalyst 35 to 1:1 with the Grubbs I
at reflux for 16 h in CH2Cl2 in the presence of the Grubbs precatalyst.
I precatalyst, macrolactone 32 was formed as a ca. 1:1 mix-
At this point, it was important to test the remaining cru-
ture of Z and E isomers, but the conversion was low. Under cial MeOH elimination reaction at C-2 to validate the syn-
more drastic conditions (increased catalyst loading or tem- thetic approach to the bafilomycin core. A similar elimi-
perature), the reaction mixture became more complex, and nation reaction had been already tested successfully in these
the amount of degradation products increased. We decided laboratories during a previous synthesis of a C-1–C-11 bafi-
to test Mauduit’s modified Hoveyda–Grubbs ruthenium lomycin precursor, using camphorsulfonic acid in refluxing
precatalysts M71-SIMes (33) and M71-SIPr (34),[37] as well benzene. It must be pointed out that these conditions only
as the new phosphine-based parent carbene complex M71- led to the expected elimination product (with the required
PCy3 (35). Precatalyst 35 was prepared in one step from the Z configuration) when the free seco acid was used; no elimi-
known Ru-indenylidene complex, RuCl2(PCy3)2(Ind) nation occurred when the corresponding esters were
(36),[38] by exchange with 2,2,2-trifluoro-N-(4-isopropoxy- tested.[39] As the present RCM approach to the bafilomy-
3-vinylphenyl)acetamide (37) according to Scheme 8.
cins would require the elimination of MeOH to occur after
Of all the precatalysts tested for the formation of 32, the formation of the macrolide core, we decided to test the
M71-PCy3 (35) gave the best result. A 48% yield was ob- elimination reaction with 2,2-dimethoxy ester 38, which we
anticipated would be a reasonable model for our purposes.
The most significant results are summarized in Scheme 9.
Under various conventional thermal conditions, either in
toluene, or in methanol as described by the group of Tera-
shima,[40] no reaction occurred (Scheme 9, entries 1 and 2).
The triflate conditions for the synthesis of enol ethers from
acetals developed by Gassman et al. also failed (Scheme 9,
entry 3; DIPEA = diisopropylethylamine).[41] We next
turned to microwave irradiation.[42] Microwave -promoted
trifluoroacetic acid (TFA) conditions adapted from Naka-
bayashi et al.[43] led to partial degradation of the starting
Scheme 8. Synthesis of M71-PCy3 (35).
Scheme 9. Model studies for the MeOH elimination.
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Model Studies on the Bafilomycin Macrolactone Core
Scheme 10. MeOH elimination reaction on macrolactone 30.
material (i.e., 38; Scheme 9, entry 4). When camphorsulf- predominantly had a 12-Z configuration, and this stereo-
onic acid was used at 150 °C, slow conversion into the de- isomer can be assumed to be the kinetic product.
sired diene (i.e., 39) was observed (Scheme 9, entry 5). The
In 2009, during the course of this study, Dai’s group used
best results g followed by a 2 h period of irradiation a strategy similar to ours to carry out the first synthesis
(Scheme 9, entry 6). Compound 38 was completely and of the macrocyclic core of the bafilomycins using an RCM
cleanly converted into diene 39, which was formed in 67% strategy.[46] These authors used an ester precursor with a
yield as a single product, which was deduced from literature vicinal diol functionality at C-2–C-3 to bring the flexibility
data to have the expected Z configuration.[44]
necessary for the formation of the macrolide. In their study,
These conditions were then tested on pure 12-Z-config- the RCM cyclization using the Grubbs second-generation
ured 16-membered macrolactone 30. After some experi- precatalyst led to the formation of the bafilomycin macro-
mentation, in the presence of 15 mol-% CSA in toluene at cycle in 89% yield and with a 12Z/12E ratio of 82:18. Thus,
150 °C under microwave irradiation, the expected elimi- in both cases tested so far, either by us or by Dai’s group,
nation of MeOH took place quantitatively to give an in- the formation of the 12-Z isomer is favoured in the forma-
separable mixture of tetraenic products 40, with only traces tion of trienic macrolide precursors of the bafilomycins by
of decomposition products (Scheme 10).
RCM.
Macrolactone 40 was obtained as a mixture of four ste-
Interestingly, under the microwave-activated acidic con-
reoisomers in a ca. 4:4:1:1 ratio.[45] Surprisingly, careful H ditions used for the methanol elimination reaction of
NMR spectroscopic analysis of this mixture (600 MHz) macrolactone 30 to give 40, partial isomerization of the 12-
showed important modifications of the stereochemistry of Z to the 12-E configured double bond was observed. It is
the double bonds at C-4 and C-12. First of all, the double possible, based on the results of the various unsuccessful
bond at C-4 had Z stereochemistry for the two major iso- isomerization attempts performed with trienic macrocycles
mers, indicating that a total inversion of the initial E config- 30–32 in the presence of different RCM precatalysts (see
uration obtained in the Julia olefination reaction had taken above), that the less rigid 2,2-dimethoxy intermediate lact-
place. Moreover, a ca. 50% isomerization of the 12-Z-con- ones are more thermodynamically stable when the double
figured double bond was observed when the reaction time bond at C-12 has a Z configuration. In contrast, the final
was extended to 2 h. One of the two major isomers (12-E) tetraenic macrolide 40, with a 12-E configuration, could be
showed a signal at δ = 6.52 ppm, J = 14.6 and 11.2 Hz in claimed to be the more stable isomer once the C-2–C-4
1
1
its H NMR spectrum. This observed acid-promoted isom- diene is installed, although the fact that we observed a con-
erization at C-12 could indicate that the thermodynamic comitant isomerization of the double bond at C-4 makes
stability of the final tetraenic macrolactone 12-E-40 could this less certain. Further studies are clearly required in two
be similarly greater than its 12-Z-configured isomer. Fur- directions: 1) to validate and optimize the 12-Z to 12-E
ther studies will be needed to explain the isomerization of equilibration as a possible stereochemical bias for the syn-
the double bond at C-4, although it is reasonable to claim thesis of the final tetraenic lactone; 2) to preserve the E-
that the mechanism of formation of the more stable isomer configuration of the initially formed double bond at C-4.
of the 2,4-diene could proceed via an intermediate allyl cat- In the bafilomycins, where a methyl substituent is present
ion.
at C-6 (which is not the case for model compound 30), it
seems reasonable to expect that the unwanted Z isomer
would be disfavoured, due to additional allylic strain.
We are currently working towards the application of this
approach to the synthesis of bafilomycins, with particular
attention being paid to the control of the stereochemistry
at C-12.
Conclusions
The approach reported here allows the formation of the
macrolactone core of the bafilomycins by RCM starting
from 2,2-dimethoxyketal ester precursors, using either
Grubbs I or PCy3-type ruthenium precatalysts. Grubbs
first-generation precatalyst, in the case of esters 25 and 26,
as well as the new phosphine-based M71-PCy3 (35), in the
Experimental Section
General Methods: 1H NMR spectra were recorded with Bruker
case of 29, gave the best results. The macrocyclic products DPX 250 (250 MHz), DRX-300 (300 MHz), AV-360 (360 MHz),
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Avance DPX 400 (400 MHz), or DRX B600 (600 MHz) instru-
ments. Molecular sieves and K2CO3 were added to stock deuterated
chloroform. The following abbreviations are used to describe peak
patterns: br. = broad, ap. = apparent, s = singlet, d = doublet, t =
triplet, q = quartet, quint = quintuplet, and m = multiplet. Cou-
pling constants (J) are reported in Hz to Ϯ0.5 Hz. 1H chemical
1,3-dioxolane-4,5-diyl]bis(prop-2-en-1-ol) (7.1 g, 89%) as a pale
yellow liquid. Rf 0.4 (petroleum ether/Et2O, 1:1). 1H NMR (CDCl3,
400 MHz): δ = 5.97 (ddd, J = 5.9, 10.5, 17.2 Hz, 2 H), 5.37 (br. d,
J = 17.2 Hz, 2 H), 5.27 (br. d, J = 10.5 Hz, 2 H), 4.15 (m, 2 H),
3.88 (br. d, J = 4.3 Hz, 2 H), 1.41 (s, 6 H) ppm. 13C NMR (CDCl3,
100.63 MHz): δ = 136.8, 117.2, 109.5, 81.7, 73.6, 26.9 ppm.
shifts are expressed in parts per million (ppm), and are referenced
The above diol (3.0 g, 14.0 mmol, 1.0 equiv.) was put into DMF
(50 mL), and the mixture was cooled to 0 °C. NaH (60wt.-% in
mineral oil, 1.2 g, 30.8 mmol, 2.2 equiv.) was added portionwise,
followed, after 10 min, by commercially sourced methyl iodide
(2.1 mL, 33.6 mmol, 2.4 equiv.). The resulting solution was allowed
to warm to room temp. It was stirred for a further 45 min, and
then NH4OH (2 n aq.) was added. Usual extraction with EtOAc
(washing with brine) gave, after evaporation, a crude product. This
material was dissolved in a mixture of MeOH (50 mL) and HCl
(2 n aq.; 15 mL). This solution was heated under reflux for 2.5 h,
then it was allowed to cool to room temp. and Na2CO3 (satd. aq.)
was added. Usual extraction with EtOAc followed by purification
of the crude extract by flash chromatography on silica gel (petro-
leum ether/EtOAc, 2:1) gave diol 12 (2.2 g, 77%) as a pale yellow
oil. Rf 0.3 (petroleum ether/Et2O, 1:1). [α]D = +30.9 (c = 1.8,
1
to the residual H signal of deuterochloroform (δ = 7.26 ppm). 13
C
chemical shifts are expressed in parts per million, and are refer-
enced to the central peak of deuterochloroform (δ = 77.00 ppm).
When measured, DEPT-135 experiments are described according
to + (primary and tertiary C atoms, positive signals) or – (second-
ary C atoms, negative signals). Infrared spectra were recorded with
a Perkin–Elmer Spectrum One FTIR instrument, using the thin
film method on NaCl plates, prepared from solutions in CH2Cl2.
Absorption maxima (ν) are reported in wavenumbers (cm–1). High-
˜
resolution mass spectra were recorded using electrospray ionization
(ESI) with a TSQ (Thermo Scientific 2009) mass spectrometer with
direct introduction. The quoted masses are accurate to Ϯ5 ppm.
Flash chromatography was performed using silica gel (Merck Ged-
uran Si60 40–63 μm) as the stationary phase. Analytical TLC was
performed on aluminium plates precoated with silica gel (Merck
silica gel, 60 F254), which were visualized by UV fluorescence when
applicable (λmax = 254 nm), and/or by staining with vanillin or p-
anisadehyde ethanolic sulfuric acid solutions followed by heating.
Tetrahydrofuran (THF) and diethyl ether (Et2O) were distilled from
sodium–benzophenone. All air- and/or water-sensitive reactions
were carried out under a nitrogen atmosphere using a dual mani-
fold high-vacuum line with dry, freshly distilled solvents, using
standard syringe–cannula/septa and purge-and-refill techniques.
All glassware was dried with a flameless heatgun and kept under
vacuum before use. Optical rotations were determined with a Per-
kin–Elmer 241-instrument operating at the D-line of Na, and are
reported as follows: [α]2D5 (concentration [g/100 mL], solvent). Ex-
cept for alcohols 9b and 9c, which were synthesized in an enantio-
pure form in anticipation of a future synthesis of bafilomycin ana-
logues, neither optical rotations nor enantiomeric excess determi-
nations were carried out for the compounds synthesized in this
model study. Ozonolysis reactions were carried out using a BMT
802 X ozone generator. Microwave-assisted reactions were carried
out using a CEM Discover apparatus. Sulfone 2 was prepared as
described previously.[21] (R)-(–)-4-Benzyl-3-propionyl-2-oxazolid-
inone (14) is commercially available, and was also prepared on a
multigram scale according to a published procedure.[47]
CHCl3), ref. +31.0 (c
=
1.77, CHCl3). 1H NMR (CDCl3,
400 MHz): δ = 5.75 (ddd, J = 7.0, 11.1, 16.6 Hz, 2 H), 5.34 (m, 4
H), 3.71 (m, 2 H), 3.82 (m, 2 H), 3.33 (s, 6 H, OCH3), 3.02 (br., 2
H, OH) ppm. 13C NMR (CDCl3, 100.63 MHz): δ = 135.2 (2 C),
119.2 (2 C), 84.7 (2 C), 71.3 (2 C), 57.2 (2 OCH3) ppm. IR
(CH Cl ): ν = 3448, 3078, 2982, 2937, 2904, 2824, 1740, 1643 cm–1.
˜
2
2
HRMS (DI, EI): calcd. for [C10H18O4]+ 202.1205; found 202.1207.
These data are in agreement with the literature.[24]
(S)-2-Methoxybut-3-en-1-ol (9b): Diol 12 (550.0 mg, 2.7 mmol,
1.0 equiv.) was put into dry Et2O (30 mL), and commercially
sourced Pb(OAc)4 (1.3 g, 2.8 mmol, 1.05 equiv.) and NaHCO3
(240.0 mg, 2.8 mmol, 1.05 equiv.) were added. The reaction mixture
was stirred for 5 min at 0 °C, then at room temperature for 25 min,
and then ethylene glycol (70.0 μL) was added. The mixture was
stirred rapidly for 5 min, then it was filtered through a Celite pad.
Et2O and brine were added to the filtrate. The organic phase was
decanted and combined with ethereal washings of the aqueous
phase (small volumes). The combined organic phases were dried
with MgSO4. Without evaporation of the solvent, the crude organic
phase containing aldehyde 13 was cooled to 0 °C, and NaBH4
(306.0 mg, 8.1 mmol, 1.5 equiv.) was added. The reaction mixture
was stirred at 0 °C until no starting material remained (about
30 min). Then water and Et2O were added slowly. The mixture was
extracted with Et2O, and the solvent was evaporated carefully in
vacuo (cooled water bath). The residue was purified by flash
chromatography on silica gel (pentane/Et2O, 4:1 to 1:1) to give vol-
atile alcohol 9b (125 mg, 37% over two steps). [α]D = +37.9 (c =
1.05, CHCl3), ref. for the corresponding (R) isomer = –41.4 (c =
1.05, CHCl3).[48] 1H NMR (CDCl3, 400 MHz): δ = 5.67 (ddd, J =
7.3, 10.3, 17.5 Hz, 1 H), 5.31 (dd, J = 7.6, 13.8 Hz, 2 H), 3.70 (m,
1 H), 3.55 (m, 2 H), 3.33 (s, 3 H, OCH3), 2.10 (br. s, 1 H, OH)
ppm. 13C NMR (CDCl3, 100.63 MHz): δ = 134.7, 119.2, 83.3, 65.2,
56.5 ppm. HRMS (DI, EI): calcd. for [C5H10O2 + Na]+ 125.0578;
found 125.0573.
(3R,6R)-3,6-Dimethoxyocta-1,7-diene-4,5-diol (12): Anhydrous
ZnCl2 (20.1 g, 147.8 mmol, 3.9 equiv., dried three times by melting
under vacuum until constant mass) was dissolved in dry THF
(90 mL), and a commercially sourced solution of vinylmagnesium
bromide (1.0 m in THF; 271 mL, 271 mmol, 7.1 equiv.) was slowly
added. A dark green solution with some precipitate was formed.
(–)-Dimethyl 2,3-O-isopropylidene-l-tartrate 11 (8 g, 37.4 mmol,
1.0 equiv.) was dissolved in dry toluene (100 mL), the solution was
cooled to –78 °C, and DIBAL-H (1.0 m in toluene; 86 mL,
86 mmol, 2.3 equiv.) was added slowly. This mixture was stirred for
3 h at –78 °C, then the solution of divinylzinc was slowly added to
the aldehyde solution by cannula at –78 °C. After 30 min, the mix-
ture was allowed to warm to room temperature, and it was stirred
for a further 4 h. The reaction mixture was then cooled to 0 °C,
and NH4Cl (satd. aq.) and Rochelle salt solution (satd. aq., excess)
were added carefully. The mixture was stirred overnight. EtOAc
and brine were added, and usual extraction followed by purifica-
tion by flash chromatography on silica gel (petroleum ether/EtOAc,
4-Benzyl-3-[(2R,3R,4S)-3-hydroxy-4-methoxy-2-methylhex-5-enoyl]-
oxazolidin-2-one (15): A solution of crude aldehyde 13 was pre-
pared from diol 12 (2.5 g, 12.4 mmol, 1.0 equiv.) by oxidation with
Pb(OAc)4 (6.3 g, 12.9 mmol, 1.05 equiv.) as described above, except
that the final extraction was carried out with CH2Cl2, with no evap-
oration of the solvent. (R)-(–)-4-Benzyl-3-propionyl-2-oxazolid-
4:1 to 1:1) gave intermediate (1R,1ЈR)-1,1Ј-[(4R,5R)-2,2-dimethyl- inone 14 (2.8 g, 12.02 mmol, 0.5 equiv.) was dissolved in dry
8272
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 8265–8278

Model Studies on the Bafilomycin Macrolactone Core
CH2Cl2 (150 mL) at 0 °C, and commercially sourced TiCl4 (1.5 mL,
13.6 mmol, 0.55 equiv.) was added. The resulting solution was
stirred for 5 min. Distilled TMEDA (3.5 mL, 23.2 mmol,
0.94 equiv.) was added to this orange mixture, and the resulting
dark-brown mixture was stirred for 30 min at 0 °C. The CH2Cl2
solution of aldehyde 13 was then added by cannula. The reaction
mixture was stirred for 1 h at 0 °C, then NH4Cl (satd. aq.) was
added. Usual extraction was carried out to give a crude aldol prod-
uct (dr = 15:1 from 1H NMR spectroscopy). This material was
purified by flash chromatography on silica gel (EtOAc/petroleum
remove residual O3 until the solution become colourless. Then,
Me2S (1.2 mL, 16.6 mmol, 1.6 equiv.) was added at –78 °C. After
10 min, the mixture was allowed to warm to room temperature,
and it was stirred overnight under a well-ventilated hood. H2O and
CH2Cl2 were added. The usual work-up was carried out with
CH2Cl2. The organic phase was concentrated in vacuo using an
aqueous KOH trap. The residue was purified by flash chromatog-
raphy on silica gel (petroleum ether/Et2O, 3:2) to give 6-oxohept-
anal 16 (1.25 g, 94%) as a colourless liquid (stable for 1 month
1
at –20 °C). Rf 0.4 (petroleum ether/Et2O, 7:3). H NMR (CDCl3,
ether, 1:4 to 4:1) to give compound 15 (1.9 g, 48% from 14) as a
400 MHz): δ = 9.75 (t, J = 1.5 Hz, 1 H), 2.46–2.42 (m, 4 H), 2.12
1
pale yellow oil. [α]D = –38.9 (c = 1.7, CHCl3). H NMR (CDCl3, (s, 3 H), 1.60 (m, 4 H) ppm. 13C NMR (CDCl3, 100 MHz): δ =
400 MHz): δ = 7.34–7.19 (m, 5 H), 5.77 (ddd, J = 8.0, 10.3, 18.1 Hz, 208.4, 202.1, 43.6, 43.2, 29.9, 23.1, 21.5 ppm. IR (CH Cl ): ν =
˜
2
2
1 H), 5.32 (m, 2 H), 4.68 (ddd, J = 3.5, 6.9, 13.5 Hz, 1 H), 4.17
3418, 2944, 2729, 1710, 1411, 1363, 1161, 1086, 1000 cm–1. HRMS
(m, 2 H), 3.95 (m, 2 H), 3.54 (m, 1 H), 3.26 (s, 3 H, OCH3), 3.23 (DI, EI): calcd. for [C7H12O2]+ 128.0837; found 128.0839. These
(dd, J = 3.2, 13.4 Hz, 1 H), 2.93 (br. s, 1 H, OH), 2.79 (dd, J = 9.4,
13.4 Hz, 1 H), 1.33 (d, J = 6.5 Hz, 3 H) ppm. 13C NMR (CDCl3,
100.63 MHz; DEPT): δ = 176.4, 152.6, 135.4 (+), 135.0, 129.4 (+),
128.7 (+), 127.1 (+), 119.7 (–), 83.7 (+), 72.9 (+), 65.9 (–), 56.2 (+),
54.9 (+), 39.5 (+), 37.6 (–), 12.7 (+) ppm. HRMS (DI, EI): calcd.
for [C18H23NO5 + Na]+ 356.1474; found 356.1468.
data are in agreement with published ones.[49]
7,7-Dimethoxyheptan-2-one (17): A solution of crude 6-oxohept-
anal 16 (6.0 g, 46.8 mmol, 1.0 equiv.) prepared as described above
and pTsA (133.0 mg, 0.4 mmol, 0.01 equiv.) in MeOH (60 mL) was
stirred for 30 min at room temperature. NaHCO3 (5% aq.) was
added to this reaction mixture, and work-up was carried out with
(2S,3R,4S)-1-(tert-Butyldimethylsilyloxy)-4-methoxy-2-methyl- EtOAc. The crude material was purified by flash chromatography
hex-5-en-3-ol (9c): NaBH4 (930 mg, 24.6 mmol, 4.6 equiv.) was on silica gel (petroleum ether/EtOAc, 95:5) to give 17 (7.9 g, 82%)
added to a solution of oxazolidinone 15 (1.7 g, 5.3 mmol,
1.0 equiv.) in a mixture of THF/H2O (5:1; 70 mL) at 0 °C. The
mixture was stirred overnight at room temp., then HCl (2 n aq.)
was added, and stirring was continued for 5 min. Extraction as us-
ual with Et2O (washing with brine) followed by flash chromatog-
raphy (Et2O/pentane, 50:50 to 100:0) gave intermediate (2S,3R,4S)-
as a colourless liquid. Rf 0.5 (petroleum ether/Et2O, 7:3). 1H NMR
(CDCl3, 400 MHz): δ = 4.34 (t, J = 5.7 Hz, 1 H), 3.30 (s, 6 H),
2.42 (t, J = 7.4 Hz, 2 H), 2.12 (s, 3 H), 1.62–1.55 (m, 4 H), 1.35
(m, 2 H) ppm. 13C NMR (CDCl3, 100 MHz, DEPT): δ = 208.7,
104.4 (–), 52.8 (+, 2 C), 43.6 (+), 32.4 (+), 29.9 (–), 24.2 (+), 23.6
(+) ppm. IR (CH Cl ): ν = 2950, 1713, 1364, 1127, 1051 cm–1
.
˜
2
2
4-methoxy-2-methylhex-5-ene-1,3-diol (C-13–C-17 diol; 787 mg, HRMS (DI, EI): calcd. for [C9H18O3 + Na]+ 197.1154; found
1
83%) as a colourless oil. [α]D = +29.6 (c = 1.8, CHCl3). H NMR
(CDCl3, 400 MHz): δ = 5.90 (br. s, 2 H, exch. H), 5.76 (ddd, J =
8.0, 10.4, 17.1 Hz, 1 H), 5.39 (m, 2 H), 3.76–3.65 (m, 2 + 1 H),
3.55 (t, J = 7.5 Hz, 1 H), 3.29 (s, 3 H, OCH3), 2.0 (m, 1 H), 0.99
(d, J = 7.1 Hz, 3 H) ppm. 13C NMR (CDCl3, 100.63 MHz, DEPT):
δ = 135.7 (+), 120.7 (–), 84.1 (+), 74.7 (+), 67.2 (–), 56.4 (+), 35.9
197.1148.
(E)-6-Methylnona-6,8-dienal (10): Commercially sourced allyldi-
phenylphosphine oxide (5.4 g, 22.3 mmol, 2.3 equiv.; dried 3 times
by azeotropic distillation with toluene) was dissolved in dry THF
(1000 mL), and the mixture was cooled to –78 °C. Distilled HMPA
(6.7 mL, 38.8 mmol, 4.0 equiv.) and BuLi (1.3 m in hexanes;
175 mL, 22.3 mmol, 2.3 equiv.) were added with rapid stirring. The
resulting red solution was stirred for 30 min at –78 °C, then a solu-
tion of 17 (1.70 g, 9.7 mmol, 1.0 equiv.) in dry THF (10 mL) was
added dropwise by syringe. The reaction mixture was stirred for a
further 30 min at –78 °C, then at room temperature for 2 h. NH4Cl
(satd. aq.) was added. Usual extraction with EtOAc followed by
flash chromatography on silica gel (petroleum ether/Et2O, 98:2)
gave (E)-9,9-dimethoxy-4-methylnona-1,3-diene 18 (1.3 g, 68%; 9:1
mixture of E and Z isomers), as well as recovered starting material
(0.5 g, 29%). Data for 18: Rf 0.8 (9:1 petroleum ether/Et2O). 1H
(+), 10.5 (+) ppm. IR (CH Cl ): ν = 3395, 3079, 2969, 2935, 2881,
˜
2
2
2824, 1743, 1712, 1643 cm–1. HRMS (DI, EI): calcd. for [C8H16O3
+ Na]+ 183.0997; found 183.0992.
This diol (560.0 mg, 3.5 mmol, 1.0 equiv.) was dissolved in distilled
CH2Cl2 (30 mL), and distilled triethylamine (600 μL, 4.3 mmol,
1.24 equiv.), DMAP (30.0 mg, 0.2 mmol, 0.06 equiv.), and TBSCl
(580.0 mg, 3.9 mmol, 1.1 equiv.) were added. The reaction mixture
was stirred overnight at room temp. Then NH4Cl (satd. aq.) was
added, and extraction was carried out with Et2O. The crude mate-
rial was purified by flash chromatography on silica gel (pentane/
EtOAc, 100:0 to 40:60) to give mono-TBS ether 9c (740 mg, 77%) NMR (CDCl3, 400 MHz; E isomer reported): δ = 9.76 (s, 1 H),
as a colourless liquid. [α]D = +9.7 (c = 1.8, CHCl3). 1H NMR
(CDCl3, 400 MHz): δ = 5.78 (ddd, J = 7.7, 10.4, 17.2 Hz, 1 H),
5.36 (m, 2 H), 3.78–3.48 (m, 2 + 1 H), 3.52 (m, 1 H), 3.28 (s, 3 H),
3.06 (d, J = 2.5 Hz, 1 H, OH), 1.98 (dq, J = 2.8, 7.0 Hz, 1 H), 0.99
6.57 (td, J = 10.5, 16.8 Hz, 1 H), 5.85 (d, J = 10.9 Hz, 1 H), 5.08
(dd, J = 1.8, 16.8 Hz, 1 H), 4.98 (dd, J = 1.8, 10.2 Hz, 1 H), 4.36
(t, J = 5.7 Hz, 1 H), 3.31 (s, 6 H), 2.06 (t, J = 7.5 Hz, 2 H), 1.74
(s, 3 H), 1.60 (m, 2 H), 1.45 (m, 2 H), 1.34 (m, 2 H) ppm. 13C
(d, J = 7.0 Hz, 3 H), 0.88 (s, 9 H), 0.05 (s, 6 H) ppm. 13C NMR NMR (CDCl3, 100 MHz; E isomer reported): δ = 139.5, 133.4,
(CDCl3, 100.63 MHz, DEPT): δ = 136.1 (+), 119.3 (–), 83.7 (+),
75.5 (+), 68.3 (–), 56.3 (+), 35.5 (+), 25.9 (+), 18.2, 10.5 (+), –5.6
125.5, 114.5, 104.6, 52.6 (2 C), 39.7, 32.4, 27.6, 24.3, 16.5 ppm. IR
(CH Cl ): ν = 3086, 2939, 1648, 1463, 1126, 1073 cm–1. HRMS
˜
2
2
(+) ppm. IR (NaCl): ν = 3490, 3077, 2956, 2930, 2884, 2858, 1642,
(DI, EI): calcd. for [C12H22O2] 198.1620; found 198.1629.
˜
1472 cm–1. HRMS (DI, EI): calcd. for [C14H30O3Si + Na]+
297.1862; found 297.1856.
Distilled water (0.5 mL) and formic acid (0.5 mL) were added to
pure diene acetal 18 (200.0 mg, 1.1 mmol, 1.0 equiv.), and the mix-
ture was stirred at room temperature for 14 h. Then Et2O and
NaOH (5% aq.) were added. Usual work-up followed by rapid
flash chromatography on silica gel (petroleum ether/EtOAc, 99:1)
gave dienal 10 (133 mg, 87%) as a colourless liquid containing a
90:10 mixture of E and Z isomers (unstable compound). Rf 0.2 (1:1
6-Oxoheptanal (16): Methylcyclohexene (1.23 mL, 10.4 mmol,
1.0 equiv.) was put into CH2Cl2 (75 mL), MeOH (19 mL) was
added, and the mixture was cooled to –78 °C. A stream of O3 was
bubbled through the solution until a pale blue colour persisted
(about 1 h). A stream of N2 was bubbled through the solution to
Eur. J. Org. Chem. 2013, 8265–8278
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
8273

A. Chevalley, J. Prunet, M. Mauduit, J.-P. Férézou
FULL PAPER
petroleum ether/Et2O). H NMR (CDCl3, 400 MHz): δ = 9.76 (t,
1
5.3 Hz, 1 H), 3.33 (s, 6 H), 2.59 (s, 2 H), 2.42 (t, J = 2.4 Hz, 2 H),
J = 1.7 Hz, 1 H), 6.56 (td, J = 10.5, 16.5 Hz, 1 H), 5.84 (d, J = 2.15 (s, 3 H), 2.00 (q, J = 7.2, 14.3 Hz, 2 H), 1.66 (s, 3 H), 1.54 (m,
10.6 Hz, 1 H), 5.08 (dd, J = 1.8, 16.8 Hz, 1 H), 4.99 (dd, J = 1.8,
10.1 Hz, 1 H), 2.44 (dt, J = 1.7, 7.2 Hz, 2 H), 2.07 (t, J = 7.5 Hz,
2 H), 1.32 (m, 2 H) ppm. 13C NMR (CDCl3, 100 MHz, selected
significant signals): δ = 210.6, 170.5, 129.9, 128.9, 103.1, 68.4, 49.8,
2 H), 1.75 (s, 3 H), 1.62 (m, 2 H), 1.48 (m, 2 H) ppm. 13C NMR 43.4, 43.0, 29.8, 29.5, 28.6, 27.3, 22.9, 16.3, 14.0 ppm. This crude
(CDCl3, 100 MHz): δ = 202.4, 138.8, 133.2, 125.8, 114.8, 43.7, 39.4,
mixture was used directly in the next reaction.
27.2, 21.7, 16.5 ppm.
This reaction was repeated several times, and it was observed that
with commercially sourced Na/Hg amalgam (beads; 6%) alcohol
22b was not formed, probably due to this amalgam having a lower
reactivity than the amalgam we prepared ourselves.
3,3-Dimethoxy-5-methyl-6-(5-oxohexyl)-5-(phenylsulfonyl)tetra-
hydro-2H-pyran-2-one (21): BuLi (1.5 m in hexanes; 10.4 mL,
15.6 mmol, 2.9 equiv.) was added to freshly distilled diethylamine
(1.6 mL, 15.6 mmol, 2.9 equiv.) in dry THF (10 mL) at –78 °C. The
resulting mixture was stirred for 10 min at this temperature, and
then for 15 min at 0 °C. This cold basic solution was added by
cannula to a solution of sulfone 2 (5.1 g, 16.1 mmol, 3.0 equiv.;
dried three times by azeotropic distillation with toluene and under
high vacuum overnight) in dry THF (70 mL) at –78 °C. The reac-
tion mixture was stirred at –78 °C for 5 min, then at –55 °C for
40 min. The reaction mixture was then cooled to –78 °C and a solu-
tion of 6-oxoheptanal 16 (690.0 mg, 5.4 mmol, 1.0 equiv.) in dry
THF (5 mL, followed by a further 2 mL for rinsing) was added
dropwise. The mixture was stirred for 25 min at –78 °C. Then the
reaction mixture was allowed to warm to 0 °C, and after 20 min,
NaHSO4 (2 n aq.) and Et2O were added. Usual extraction with
Et2O followed by purification by flash chromatography on silica
gel (Et2O/petroleum ether, 70:30 to 95:5) gave, in order of elution,
starting sulfone 2 (3.2 g), and 21 (875 mg, 51%; 1:1 mixture of two
diastereomers) as a pale yellow oil. Rf 0.3 (petroleum ether/Et2O,
2:8).
(E)-But-3-enyl 2,2-Dimethoxy-4-methyl-10-oxoundec-4-enoate (23a)
and (E)-But-3-en-1-yl 10-Hydroxy-2,2-dimethoxy-4-methylundec-4-
enoate (23b): The crude ca. 1:1 mixture of 22a and 22b (50 mg, ca.
0.2 mmol, contaminated by some amount of phenylsulfinic acid)
prepared as described above was dissolved in CH2Cl2 (4 mL), and
3-buten-1-ol (9a; 57 μL, 0.4 mmol, 2.2 equiv.), DMAP (7.0 mg,
0.05 mmol, 0.3 equiv.), and 1-ethyl-3(3-dimethylaminopropyl)car-
bodiimide hydrochloride (EDC; 89.0 mg, 0.5 mmol, 2.5 equiv.)
were added at room temp. with rapid stirring. The resulting pale
orange solution was stirred overnight at room temperature, then
NaHSO4 (2 n aq.) and EtOAc were added (pH must be Ͻ4). Usual
extraction followed by silica gel flash chromatography (EtOAc/pe-
troleum ether, 20:80 to 60:40) gave, in order of elution, keto ester
23a (23 mg, 40% from 21), and hydroxy alcohol 23b (23 mg 40%
from 21).
Data for 23a, Rf 0.5 (petroleum ether/Et2O, 1:1). 1H NMR (CDCl3,
400 MHz): δ = 5.79 (tdd, J = 6.7, 10.2, 17.4 Hz, 1 H), 5.18 (t, J =
6.9 Hz, 1 H), 5.10 (m, 2 H), 4.16 (t, J = 6.9 Hz, 2 H), 3.27 (s, 6 H),
2.54 (s, 2 H), 2.44–2.37 (m, 4 H), 2.11 (s, 3 H), 1.95 (q, J = 7.4 Hz,
2 H), 1.62 (s, 3 H), 1.53 (quint, J = 7.6 Hz, 2 H), 1.30–1.23 (quint,
J = 7.5 Hz, 2 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 208.9,
168.7, 133.7, 129.5, 129.2, 117.4, 103.0, 64.4, 49.8 (2 C), 43.6, 43.3,
Data for the first diastereomer, pure aliquot fraction: 1H NMR
(CDCl3, 400 MHz): δ = 7.88–7.56 (m, 5 H), 4.61 (dd, J = 1.7,
11.3 Hz, 1 H), 3.31 (s, 3 H), 3.22 (s, 3 H), 2.71 (d, J = 15.4 Hz, 1
H), 2.47 (m, 2 H), 2.21 (m, 1 H), 2.15 (s, 3 H), 2.11 (d, J = 15.4 Hz,
1 H), 1.99 (m, 1 H), 1.68–1.60 (m, 4 H), 1.56 (s, 3 H) ppm. 13C
NMR (CDCl3, 100 MHz): δ = 208.5, 165.8, 137.0 134.4, 130.5,
129.3, 95.8, 81.7, 64.4 52.2, 49.0, 43.3, 39.2, 29.9, 29.6, 26.7, 23.0,
22.2 ppm.
32.9, 29.8, 29.1, 27.7, 23.5, 16.4 ppm. IR (CH Cl ): ν = 2941, 2991,
˜
2
2
2859, 1747, 1713, 1643, 1459, 1360, 1323, 1200, 1137, 1109 cm–1.
HRMS (DI, EI): calcd. for [C18H30O5]+ 326.2093; found 326.2093.
Data for 23b, Rf 0.3 (petroleum ether/Et2O, 1:1). 1H NMR (CDCl3,
400 MHz): δ = 5.80 (ddt, J = 6.7, 10.3, 17.0 Hz, 1 H), 5.20 (t, J =
6.7 Hz, 1 H), 5.10 (m, 2 H), 4.18 (t, J = 6.9 Hz, 2 H), 3.75 (m, 1
H), 3.27 (s, 6 H), 2.55 (s, 2 H), 2.43 (q, J = 6.9 Hz, 4 H), 1.96 (q,
J = 5.9 Hz, 4 H), 1.62 (s, 3 H), 1.42–1.30 (m, 6 H), 1.17 (d, J =
6.2 Hz, 3 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 168.8, 133.7,
129.7, 117.5, 103.0, 68.0, 64.3, 49.8 (2 C), 43.4, 39.3, 32.9, 29.5,
27.9, 25.3, 23.5, 16.4 ppm.
1
Data for the second diastereomer, pure aliquot fraction: H NMR
(CDCl3, 400 MHz): δ = 7.88–7.60 (m, 5 H), 4.84 (dd, J = 1.7,
11.3 Hz, 1 H), 3.24 (s, 3 H), 3.21 (d, J = 14.8 Hz, 1 H), 3.12 (s, 3
H), 2.92 (d, J = 14.8 Hz, 1 H), 2.45 (m, 2 H), 2.19 (m, 1 H), 2.13
(s, 3 H), 1.70–1.56 (m, 5 H), 1.50 (s, 3 H) ppm. 13C NMR (CDCl3,
100 MHz): δ = 208.4 165.4, 135.6, 134.5, 130.4, 129.1, 94.8 78.9
64.1, 50.5, 49.3, 43.2, 39.9, 30.0, 29.9, 25.5, 23.1, 16.7 ppm. IR
(CH Cl ): ν = 3057, 2945, 1773, 1717, 1639, 1448, 1362, 1316 cm–1.
˜
2
2
2-Methoxybut-3-enyl (E)-2,2-Dimethoxy-4-methyl-10-oxoundec-4-
enoate (24): Compound 22a (140.0 mg, 0.5 mmol, 1.0 equiv.) was
dissolved in CH2Cl2 (15 mL), and alcohol 9b (102.0 mg, 1.1 mmol,
2.2 equiv.), DMAP (18.9 mg, 0.1 mmol, 0.3 equiv.), and EDC
(246.6 mg, 1.3 mmol, 2.5 equiv.) were added with rapid stirring.
The resulting pale orange solution was stirred overnight at room
temp., and then NaHSO4 (2 n aq.) and EtOAc were added (pH
must be Ͻ4). Extraction with Et2O followed by purification by
flash chromatography on silica gel (Et2O/pentane, 20:80 to 60:40)
gave compound 24 (89 mg, 49%). Rf 0.3 (petroleum ether/Et2O,
1:1). 1H NMR (CDCl3, 400 MHz): δ = 5.70 (ddd, J = 7.2, 10.2,
17.4 Hz, 1 H), 5.32 (m, 2 H), 5.21 (t, J = 6.8 Hz, 1 H), 4.11 (d, J
= 5.4 Hz, 2 H), 3.86 (dd, J = 6.0, 11.8 Hz, 1 H), 3.31 (s, 3 H), 3.27
(s, 6 H), 2.55 (s, 2 H), 2.38 (t, J = 7.4 Hz, 2 H), 2.11 (s, 3 H), 1.95
(q, J = 7.1 Hz, 2 H), 1.62 (s, 3 H), 1.54 (quint, J = 7.6 Hz, 2 H),
1.28 (quint, J = 7.1 Hz, 2 H) ppm. 13C NMR (CDCl3, 100 MHz):
δ = 208.9, 168.6, 134.5, 129.4, 129.2, 119.2, 103.0, 80.1, 66.8, 56.6,
49.8 (2 C), 43.6, 43.3, 29.6, 29.1, 29.7, 23.5, 16.4 ppm. IR (CH2Cl2):
HRMS (DI, EI): calcd. for [C19H25O7S]+ ([M – CH3]+) 397.1321;
found 397.1317.
(E)-2,2-Dimethoxy-4-methyl-10-oxoundec-4-enoic Acid (22a and
22b): A mixture of methanol (7 mL) and dry THF (8 mL) was co-
oled to –40 °C, and Na/Hg (6 %; 2.8 g, 5.8 mmol, 10.0 equiv.,
freshly reduced in powder), NaHCO3 (490.0 mg, 5.8 mmol,
10.0 equiv.), and the diastereomeric mixture of δ-lactones 21
(240.0 mg, 0.6 mmol, 1.0 equiv.; dried twice by azeotropic distil-
lation with toluene) were added. The reaction mixture was stirred
at –40 °C for ca. 2 h until no starting material remained (TLC mon-
itoring: Et2O/petroleum ether, 9:1). Water and Et2O were then
slowly added, and the phases were separated. The aqueous phase
was then acidified until pH = 1 and extracted three times using the
salting out protocol with brine/Et2O. The latter organic phases
were combined, washed with brine, and concentrated to give a ca.
1:1 mixture of 22a and 22b, which were neither separated nor fully
1
characterized at this stage (175 mg) as a pale yellow oil. H NMR
(CDCl3, 400 MHz, selected significant signals): δ = 5.26 (t, J =
ν = 2939, 2859, 1748, 1715, 1454, 1360, 1323, 1284, 1200, 1137,
˜
8274
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 8265–8278

Model Studies on the Bafilomycin Macrolactone Core
1108 cm–1. HRMS (DI, EI): calcd. for [C19H32O6Na]+ 379.2097;
found 379.2091.
Data for 27a: Rf 0.5 (Et2O/pentane, 1:1). 1H NMR (CDCl3,
400 MHz): δ = 5.20 (t, J = 6.6 Hz, 1 H), 3.74 (s, 3 H), 3.29 (s, 6
H), 2.56 (s, 2 H), 2.40 (t, J = 7.4 Hz, 2 H), 2.13 (s, 3 H), 1.96 (q,
J = 7.2 Hz, 2 H), 1.63 (s, 3 H), 1.55 (m, J = 7.4 Hz, 3 H), 1.29 (m,
3 H) ppm. 13C NMR (CDCl3, 100 MHz, DEPT): δ = 208.9, 169.1,
129.3 (+), 128.9, 103.2, 52.0 (+), 49.8 (2 C, +), 43.5 (–), 43.4 (–),
29.7 (+), 29.0 (–), 27.6 (–), 23.3 (–), 16.2 (+) ppm. HRMS (DI, EI):
calcd. for [C15H26O5 + Na]+ 309.1678; found 309.1672.
But-3-enyl (4E,10E)-2,2-Dimethoxy-4,10-d~imethyltrideca-4,10,12-
trienoate (25): Commercially sourced allyldiphenylphosphine oxide
(49.0 mg, 0.20 mmol, 2.2 equiv.;, dried 3 times by azeotropic distil-
lation), freshly distilled HMPA (64 μL, 0.37 mmol, 4.0 equiv.), and
BuLi (1.1 m in hexanes; 176 μL, 0.13 mmol, 2.2 equiv.) were added
to dry THF (2 mL) at –78 °C with rapid stirring. The resulting red
solution was stirred for 10 min at –78 °C, and then a solution of
ketone 23a (30.0 mg, 0.09 mmol, 1.0 equiv.) in dry THF (1 mL) was
added. The reaction mixture was stirred for 10 min at –78 °C, then
at room temp. for 2 h, and then EtOAc and NH4Cl (satd. aq.) were
added. Usual extraction followed by flash chromatography on silica
gel (Et2O/petroleum ether, 40:60) gave tetraene 25 (20 mg, 63%, 9:1
mixture of E/Z isomers), and also recovered starting material
Data for 27b: Rf 0.2 (Et2O/pentane, 1:1). 1H NMR (CDCl3,
400 MHz): δ = 5.15 (t, J = 7.0 Hz, 1 H), 3.74 (m, 1 H), 3.70 (s, 3
H), 3.24 (s, 6 H), 2.51 (s, 2 H), 1.92 (m, 2 H), 1.58 (s, 3 H), 1.36–
1.24 (m, 6 H), 1.13 (d, J = 6.2 Hz, 3 H) ppm. 13C NMR (CDCl3,
100 MHz): δ = 169.1, 129.8 (+), 129.0, 103.3, 67.8 (+), 52.0 (+),
49.7 (2 C, +), 43.4 (–), 39.1 (–), 29.4 (–), 27.8 (–), 25.2 (–), 23.4 (+),
16.2 (+) ppm. HRMS (DI, EI): calcd. for [C15H28O5 + Na]+
311.1834; found 311.1831.
1
(10 mg, 33%). Data for 25: Rf 0.7 (petroleum ether/Et2O, 1:1). H
NMR (CDCl3, 400 MHz): δ = 6.56 (td, J = 10.5 Hz, 16.8 1 H),
5.84–5.73 (m, 2 H), 5.21 (t, J = 6.9 Hz, 1 H), 5.15–4.93 (m, 4 H),
4.17 (t, J = 6.5 Hz, 2 H), 3.28 (s, 6 H), 2.55 (s, 2 H), 2.42 (q, J =
6.0 Hz, 2 H), 2.02 (t, J = 7.6 Hz, 2 H), 1.96 (q, J = 7.2 Hz, 2 H),
1.73 (s, 3 H), 1.63 (s, 3 H), 1.43–1.35 (m, 4 H) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 168.7, 139.6, 133.7, 133.4, 129.7, 129.1,
125.4, 117.4, 114.4, 103.0, 64.4, 49.8 (2 C), 43.4, 39.7, 33.0, 29.2,
2-Iodoxybenzoic acid (218.0 mg, 0.8 mmol, 3.0 equiv.) was dis-
solved in DMSO (1 mL), and a solution of alcohol 27b (85.0 mg,
0.3 mmol, 1.0 equiv.) in dry THF (5 mL) was added at room tem-
perature. The reaction mixture was stirred overnight in the dark
at room temperature, then water (5 mL) was added. The resulting
mixture was stirred for 4 h, and a white precipitate was formed.
The mixture was then filtered through Celite (rinsing several times
with Et2O). Usual extraction of the filtrate with EtOAc followed
by flash chromatography on silica gel (EtOAc/petroleum ether,
20:80 to 60:40) gave keto ester 27a (68 mg, 81%). Spectroscopic
data were in agreement with those of 27a isolated as described
above.
27.9, 27.4, 16.5, 16.3 ppm. IR (CH Cl ): ν = 3064, 2956, 1727,
˜
2
2
1642, 1478, 1445, 1375, 1284, 1129 cm–1. HRMS (DI, EI): calcd.
for [C21H34O4]+ 350.2457; found 350.2461.
2-Methoxybut-3-enyl (4E,10E)-2,2-Dimethoxy-4,10-dimethyltri-
deca-4,10,12-trienoate (26): Commercially sourced allyldiphenyl-
phosphine oxide (31.0 mg, 0.12 mmol, 3.0 equiv.; dried 3 times by
azeotropic distillation), freshly distilled HMPA (29 μL, 0.17 mmol,
4.0 equiv.), and BuLi (2.2 m in hexanes; 67 μL, 0.14 mmol,
3.5 equiv.) were added to dry THF (5 mL) at –78 °C with rapid
stirring. After 10 min at –78 °C, the red solution was mixed with a
solution of ketone 24a (15.0 mg, 0.04 mmol, 1.0 equiv.) in dry THF
(1 mL). The reaction mixture was stirred for 10 min at –78 °C, then
at room temp. for 2 h. Extraction as described above followed by
purification by flash chromatography on silica gel (Et2O/petroleum
ether, 40:60) gave tetraene 26 (5 mg, 31%; 9:1 mixture of E/Z iso-
mers), and also recovered starting material (5 mg, 33%). Data for
26: Rf 0.7 (petroleum ether/Et2O, 1:1). 1H NMR (CDCl3,
400 MHz): δ = 6.56 (dt, J = 16.7, 10.3 Hz, 1 H), 5.83 (d, J =
11.0 Hz, 1 H), 5.68 (ddd, J = 7.3, 10.3, 17.4 Hz, 1 H), 5.34 (m, 2
H), 5.22 (t, J = 8.1 Hz, 1 H), 5.00 (m, 2 H), 4.12 (d, J = 5.6 Hz, 2
H), 3.86 (dd, J = 6.2, 12.4 Hz, 1 H), 3.32 (s, 3 H), 3.29 (s, 6 H),
2.57 (s, 2 H), 1.98 (m, 4 H), 1.74 (s, 3 H), 1.63 (s, 3 H), 1.30 (m, 4
H) ppm. 13C NMR (CDCl3, 100 MHz): δ = (no CO signal detected
due to bad signal to noise ratio), 168.7, 139.6, 134.3, 133.4, 129.8,
129.0, 125.4, 119.5, 114.5, 102.9, 82.2, 66.9, 56.9, 49.8 (2 C), 43.6,
39.8, 29.7, 27.9, 27.2, 16.6, 16.4 ppm. HRMS (DI, EI): calcd. for
[C22H36O5]+ 380.2563; found 380.2566.
(E)-[(2S,3R,4S)-1-(tert-Butyldimethylsilyloxy)-4-methoxy-2-meth-
ylhex-5-en-3-yl] 2,2-Dimethoxy-4-methyl-10-oxoundec-4-enoate
(28): KOH (10% aq.; 5 mL) was added to keto ester 27a (90.0 mg,
0.31 mmol). The reaction mixture was heated at reflux until no
more starting material remained (2 h). HCl (2 n aq.) was added to
the reaction mixture until the pH reached ca. 1. The aqueous phase
was saturated with NaCl, then extraction was carried out with Et2O
to give crude acid 22a (90 mg). Commercially sourced DMAP
(34.0 mg; 0.27 mmol, 3.0 equiv.) and then dry toluene (1 mL) were
added to this crude product (25.0 mg, 0.09 mmol, 1.0 equiv.; dried
by azeotropic distillations with toluene) at room temp. under N2.
The mixture was stirred for 5 min, then freshly distilled triethyl-
amine (50 μL, 0.37 mmol, 4.0 equiv.), commercially sourced 2,4,6-
trichlorobenzoyl chloride (43 μL, 0.27 mmol, 3.0 equiv.), and a
solution of alcohol 9c (76.0 mg; 0.27 mmol, 3.0 equiv.; dried by
azeotropic distillation 3 times with toluene) in toluene (1 mL) were
added. The resulting orange mixture was stirred for 30 h at room
temp., then Et2O and NaHCO3 (satd. aq.) were added. Extraction
was carried out with Et2O, and purification on silica gel (Et2O/
pentane, 10:90 to 50:50) gave, in order of elution, unconsumed
alcohol 9c, and keto ester 28 (30.0 mg, 63% over two steps) as a
1
pale yellow oil. H NMR (CDCl3, 400 MHz): δ = 5.76 (ddd, J =
7.8, 11.3, 16.8 Hz, 1 H), 5.26 (m, 2 H), 5.15 (t, J = 4.6 Hz, 1 H),
3.77 (dd, J = 4.4, 7.8 Hz, 1 H), 3.59–3.38 (m, 2 H + 1 H), 3.26 (s,
9 H), 2.58 (s, 2 H), 2.40 (t, J = 7.4 Hz, 2 H), 2.13 (s, 3 H), 1.96 (m,
2 H + 1 H), 1.62 (s, 3 H), 1.55 (m, 2 H), 1.30 (m, 2 H), 0.92 (d, J
= 6.9 Hz, 3 H), 0.88 (s, 9 H), 0.03 (s, 6 H) ppm. 13C NMR (CDCl3,
100 MHz, DEPT): δ = 209.0, 168.3, 134.6 (+), 129.1, 128.1 (+),
119.5 (–), 102.1, 82.8 (+), 76.1 (+), 65.4 (–), 56.3 (+), 49.9 (+), 49.7
(+), 43.7 (–), 42.5 (–), 36.4 (+), 29.8 (+), 29.0 (–), 27.8 (–), 25.9 (3
C, +), 23.6 (–), 18.2, 16.8 (+), 12.4 (+), –5.4 (2 C) ppm. HRMS
(DI, EI): calcd. for [C28H52O7Si + Na]+ 551.3380; found 551.3375.
Methyl (E)-2,2-Dimethoxy-4-methyl-10-oxoundec-4-enoate (27a):
The crude mixture of 22a and 22b (250.0 mg, ca. 1.0 equiv.; par-
tially contaminated with phenylsulfinic acid) prepared as described
above was dissolved in Et2O (10 mL) under N2 at room temp.
MeOH (2.5 mL) was added, and then commercially sourced (tri-
methylsilyl)diazomethane (2.0 m in Et2O; 1.2 mL, 2.5 equiv.) was
added slowly. Due to its toxicity, care was taken to use a well-
ventilated hood.[50] The yellow reaction mixture was stirred for
20 min, then it was evaporated under reduced pressure. The crude
product was purified by flash chromatography on silica gel (Et2O/
pentane, 20:80 to 80:20) to give keto ester 27a (75 mg) and hydroxy (4E,10E)-[(2S,3R,4S)-1-(tert-Butyldimethylsilyloxy)-4-methoxy-
ester 27b (75 mg; 57% combined yield).
2-methylhex-5-en-3-yl] 2,2-Dimethoxy-4,10-dimethyltrideca-4,10,12-
Eur. J. Org. Chem. 2013, 8265–8278
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
8275

A. Chevalley, J. Prunet, M. Mauduit, J.-P. Férézou
FULL PAPER
trienoate (29): Commercially sourced allyldiphenylphosphine oxide
(43.0 mg, 0.17 mmol, 3.0 equiv.; dried three times by toluene azeo-
tropic distillation), freshly distilled DMPU (21 μL, 0.17 mmol,
3.0 equiv.), and BuLi (2.1 m in hexanes; 84 μL, 0.17 mmol,
3.0 equiv.) were added to dry THF (5 mL) at –78 °C with rapid
stirring. This red solution was stirred for 10 min at –78 °C, and
then a solution of keto ester 28 (31.0 mg, 0.059 mmol, 1.0 equiv.)
in dry THF (1 mL) was added. The reaction mixture was stirred
for 10 min at –78 °C, then at room temp. for 2 h, and then EtOAc
and NH4Cl (satd. aq.) were added. Usual extraction with EtOAc
followed by purification by flash chromatography on silica gel
(Et2O/petroleum ether, 40:60) gave diene ester 29 (25 mg, 77%; 9:1
mixture of E/Z isomers), as well as recovered starting material 28
(5 mg, 16%). Data for 29: Rf 0.9 (petroleum ether/Et2O, 1:1). 1H
NMR (CDCl3, 400 MHz): δ = 6.56 (dt, J = 10.5, 16.7 Hz, 1 H),
5.76 (m, 2 H), 5.32 (m, 2 H), 5.15 (t, J = 4.7 Hz, 1 H), 5.00 (m, 2
(5E,11E,13E,15S)-3,3,15-Trimethoxy-5,11-dimethyloxacyclohexa-
deca-5,11,13-trien-2-one (31Z): Grubbs I precatalyst (1.0 mg,
0.003 mmol, 0.18 equiv.) was added to a solution of ester 26 (5 mg,
0.013 mmol, 1.0 equiv.) in degassed CH2Cl2 (80 mL), and the reac-
tion mixture was stirred at room temperature for 22 h. After this
time, TLC showed no remaining starting material. Activated char-
coal (50 mg) was added to the reaction mixture, which was then
stirred for 20 h at room temp. The mixture was filtered through a
Celite pad, rinsing with CH2Cl2. The solvent was evaporated in
vacuo, and the residue was purified by flash chromatography on
silica gel (Et2O/pentane, 0:100 to 50:50) to give macrolactone 31
(2.5 mg, 51%, 12Z/12E Ͼ95:5) as a mixture of unseparated iso-
mers, contaminated with starting material. Data for 31Z: Rf 0.9
(petroleum ether/Et2O, 1:1). 1H NMR (CDCl3, 400 MHz): δ = 6.38
(t, J = 10.8 Hz, 1 H), 5.85 (d, J = 10.8 Hz, 1 H), 5.26 (dd, J = 8.5,
11.2 Hz, 1 H), 5.17 (t, J = 6.9 Hz, 1 H), 4.41 (m, 1 H), 4.12 (d, J
H), 3.77 (dd, J = 4.4, 7.8 Hz, 1 H), 3.59–3.38 (m, 2 + 1 H), 3.29 = 5.6 Hz, 2 H), 3.32 (s, 3 H), 3.29 (s, 6 H), 2.57–2.51 (m, 2 H), 1.72
(s, 6 H), 3.28 (s, 3 H), 2.58 (s, 2 H), 2.06–1.95 (m, 5 H), 1.73 (s, 3
(s, 3 H), 1.70 (s, 3 H), 1.56–1.51 (m, 4 H), 1.33–1.25 (m, 4 H) ppm.
H), 1.63 (s, 3 H), 1.40–1.30 (m, 4 H), 0.94 (d, J = 6.9 Hz, 3 H),
HRMS (DI, EI): calcd. for [C20H32O5 + Na]+ 375.2147; found
0.88 (s, 9 H), 0.03 (s, 6 H) ppm. 13C NMR (CDCl3, 100 MHz, 375.2151.
DEPT): δ = 168.3, 139.8, 134.7 (+), 133.4 (+), 128.8, 128.6 (+),
(5E,11E,13E,15S,16R)-16-[(S)-1-(tert-Butyldimethylsilyloxy)-
125.3, 119.5 (–), 114.4 (–), 102.1, 82.8 (+), 76.1 (+), 65.4 (–), 56.4
(+), 49.9 (+), 49.7 (+), 42.6 (–), 39.7 (–), 36.4 (+), 29.2 (–), 27.9
(–), 27.5 (–), 25.9 (3 C, +), 18.2, 16.8 (+), 16.5 (+), 12.4 (+), –5.4
(2 C) ppm. HRMS (DI, EI): calcd. for [C31H56O6Si + Na]+
575.3744; found 575.3745.
propan-2-yl]-3,3,15-trimethoxy-5,11-dimethyloxacyclohexadeca-
5,11,13-trien-2-one (32Z): Precatalyst M71-PCy3 (35; 2 mg,
0.003 mmol, 0.1 equiv.) was added to a solution of ester 29 (15 mg,
0.03 mmol, 1 equiv.) in degassed CH2Cl2 (15 mL). The reaction
mixture was stirred for 22 h at room temperature. After this time,
TLC showed some remaining starting material. and Further M71-
PCy3 (35; 2 mg, 0.003 mmol, 0.1 equiv.) was then added to the reac-
tion mixture, which was then stirred for a further 22 h at room
temperature. Activated charcoal (50-fold excess w/w with respect to
the catalyst) was added to the reaction mixture. The mixture was
stirred for 20 h at room temp., then it was filtered through a Celite
pad, rinsing with CH2Cl2. The solvent was evaporated in vacuo,
and the residue was purified by flash chromatography on silica gel
(Et2O/pentane, 0:100 to 50:50) to give macrolactone 32 (7 mg,
48%) as a 7:3 mixture of Z and E isomers at C-12 (contaminated
with some starting material). Data for 32Z: Rf 0.9 (petroleum ether/
Et2O, 1:1). 1H NMR (CDCl3, 400 MHz, main signals for the major
12Z isomers reported): δ = 6.37 (t, J = 11.1 Hz, 1 H), 5.95 (d, J =
11.7 Hz, 1 H), 5.39 (t, J = 6.9 Hz, 1 H), 5.25 (dd, J = 8.3, 10.5 Hz,
1 H), 4.34–4.22 (m, 2 H), 3.47 (m, 2 H), 3.37 (s, 3 H), 3.30 (s, 6
H), 2.65–2.49 (m, 2 + 1 H), 2.06–1.95 (m, 4 H), 1.71 (s, 3 H), 1.55
(s, 3 H), 1.40–1.30 (m, 4 H), 1.02 (d, J = 6.9 Hz, 3 H), 0.84 (s, 9
H), 0.01 (s, 6 H) ppm. HRMS (DI, EI): calcd. for [C29H52O6Si +
Na]+ 547.3431; found 547.3425.
(5E,11E,13Z)-3,3-Dimethoxy-5,11-dimethyloxacyclohexadeca-
5,11,13-trien-2-one (Z-30) and (5E,11E,13E)-3,3-Dimethoxy-5,11-
dimethyloxacyclohexadeca-5,11,13-trien-2-one (E-30): Typical con-
ditions for RCM experiments: Before use, CH2Cl2 was degassed
using a freeze–pump–thaw technique (4ϫ). Benzylidene-bis(tricy-
clohexylphosphine)dichlororuthenium (Grubbs I precatalyst;
34.0 mg, 0.023 mmol, 0.2 equiv.) was added to a solution of tetra-
enic ester 25 (40 mg, 0.11 mmol, 1.0 equiv.) in degassed CH2Cl2
(90 mL). The reaction mixture was stirred at room temperature for
16 h. After this time, TLC showed that all of the starting material
had been consumed. Activated charcoal (1.7 g, 50-fold excess w/w
with respect to the catalyst) was added to the reaction mixture,
which was then stirred for 20 h at room temp. The mixture was
filtered through a Celite pad (rinsing several times with CH2Cl2).
The solvent was evaporated under reduced pressure, and the resi-
due was purified by flash chromatography on silica gel (Et2O/pent-
ane, 0:100 to 50:50) to give macrolactone 30 (23 mg, 66%) as an
1
unseparated mixture of E and Z isomers (E/Z Ͼ 95:5 based on H
NMR spectroscopy). Rf 0.7 (pentane/Et2O, 7:3).
1
Data for Z-30 (major isomer): H NMR (CDCl3, 400 MHz): δ =
M71-PCy3 Complex 35: Ru indenylidene catalyst 36 (4.16 g,
4.51 mmol, 1 equiv.) and copper chloride (447 mg, 4.51 mmol,
1 equiv.) were dissolved in dry CH2Cl2 (90 mL), and 2,2,2-trifluoro-
N-(4-isopropoxy-3-vinylphenyl)acetamide 37 (1.23 g, 4.51 mmol,
1 equiv.) was added. The resulting mixture was stirred at 35 °C for
2 h 30 min. The volatiles were removed under reduced pressure,
pentane/acetone, 9:1 was added to the residue, and the resulting
mixture was filtered through a plug of Celite. The filtrate was con-
centrated in vacuo. Acetone was added to the residue, and the re-
sulting mixture was filtered through a plug of Celite. The filtrate
was concentrated in vacuo to give M71-PCy3 (35) as a brown
microcrystalline solid (2.27 g, 71%). 1H NMR (400 MHz, CDCl3):
δ = 17.29 (d, J = 4.5 Hz, 1 H), 8.00 (d, J = 2.5 Hz, 1 H), 7.91 (br.
6.35 (t, J = 10.8 Hz, 1 H), 5.99 (d, J = 10.8 Hz, 1 H), 5.38 (app q,
J = 8.2 Hz, 1 H), 5.16 (t, J = 6.4 Hz, 1 H), 3.93 (m, 2 H), 3.30 (s,
6 H), 2.54 (m, 4 H), 2.12 (m, 2 H), 2.00 (m, 2 H), 1.72, 1.69 (2 s,
2ϫ3 H), 1.55 (m, 2 H), 1.30 (m, 2 H) ppm. 13C NMR (CDCl3,
100 MHz, DEPT): δ = 168.8, 138.6, 130.0 (+), 129.4, 129.0 (+),
121.7 (+), 119.4 (+), 104.2, 64.6 (–), 50.0 (2 C, +), 44.0 (–), 37.0
(–), 27.0 (–), 26.9 (–), 26.8 (–), 17.2 (+), 16.5 (+) ppm. IR CH2Cl2):
ν = 2940, 2858, 1791, 1748, 1709, 1455, 1378, 1325, 1288, 1199,
˜
1139, 1099, 1063 cm–1. HRMS (DI, EI): calcd. for [C19H30O4]+
322.2144; found 322.2149.
1
Data for E-30 (minor isomer): H NMR spectral assignments de-
duced from spectra of mixtures containing different E/Z ratios. 1H
NMR (CDCl3, 400 MHz): δ = 6.26 (dd, J = 10.6, 16.0 Hz, 1 H), s, 1 H), 7.67 (dd, J = 8.9, 2.5 Hz, 1 H), 7.01 (d, J = 8.9 Hz, 1 H),
5.86 (d, J = 10.8 Hz, 1 H), 5.63–5.56 (m, 1 H), 5.22 (t, J = 6.4 Hz,
1 H), 4.33 (t, J = 5.3 Hz, 2 H), 3.25 (s, 6 H), 2.57 (s, 2 H), 2.47 (m,
2 H), 2.15 (m, 2 H), 1.99 (m, 2 H), 1.75 (s, 3 H), 1.65 (s, 3 H),
1.46–1.41 (m, 4 H) ppm.
5.22–5.13 (m, 1 H), 2.34–2.18 (m, 3 H), 2.00 (t, J = 8.5 Hz, 6 H),
1.84–1.66 (m, 20 H), 1.29–1.12 (m, 10 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 276.5, 154.7, 150.6, 143.8, 130.0, 121.0,
117.1, 114.8, 113.6, 76.1, 35.8 (3 C), 35.5 (3 C), 30.1 (3 C), 27.8 (3
8276
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 8265–8278

Model Studies on the Bafilomycin Macrolactone Core
C), 27. (3 C), 26.9, 26.2 (2 C), 22.0 (2 C) ppm. 19F NMR (376 MHz, NMR (CDCl3, 600 MHz, selective NOESY and TOCSY measure-
CDCl3): δ = –75.58 ppm. 31P NMR (162 MHz, CDCl3): δ = ments, signals for the two major isomers): δ = 7.02, 6.93 (2 s, 2ϫ1
5 8 . 8 4 p p m . H R M S ( M A L D I - T O F ) c a l c d . f o r
H, 2 3-H), 6.52 (dd, J = 14.6, 11.2 Hz, 1 H, E-40 12-H), 6.40 (dd,
J = 11.1 Hz, 1 H, Z-40 12-H), 6.32 (d, J = 11.7 Hz, 1 H, Z-40 11-
H), 5.91 (d, J = 11.1 Hz, 1 H, E-40 11-H), 5.57–5.49 (m, 2 H, E-
40 13-H and 1ϫ5-H), 5.44 (dd, J = 8.0, 8.0 Hz, 1 H, 1ϫ5-H), 5.35
(ddd, J = 9.8, 9.4, 8.6 Hz, 1 H, Z-40 13-H), 4.20 (m, 2ϫ2 H, 2 15-
H2), 3.68, 3.67 (2 s, 6 H, 2 OMe), 2.59 (m, 2 H, Z-40 14-H), 2.46
(ddd, J = 6.3, 6.0, 6.0 Hz, 2 H, E-40 14-H), 2.31 (m, 2 H, 9-H2),
2.25 (m, 2 H, 9-H2), 2.09 (m, 2 + 4 H, 2ϫ6-H2 and 1ϫH2), 2.01
(s, 6 H, 2 Me-C-4), 1.72, 1.71 (2 s, 2ϫ3 H, 2 Me-C-10), 1.61 (m,
6 H) ppm. HRMS (DI, EI): calcd. for [C18H26O3 + Na]+ 313.1780;
found 313.1778.
C30H4635Cl37ClF3NO2PRu [M]+ 713.1531; found 713.1712.
C
30H45Cl2F3NO2PRu (711.63): calcd. C 50.63, H 6.37, N 1.97;
found C 51.18, H 6.49, N 1.97, S 0.
Methyl 2,2-Dimethoxy-4-methylpent-4-enoate (38):[51] A solution of
LDA was prepared by dropwise addition of BuLi (2.1 m in hexanes;
3.7 mL, 4.9 mmol, 1.0 equiv.) to a stirred solution of freshly dis-
tilled diisopropylamine (692 μL, 4.9 mmol, 1.0 equiv.) in THF
(6 mL) at –78 °C, and the mixture was stirred for 15 min. A solu-
tion of methyl dimethoxyacetate (605 μL, 4.9 mmol, 1 equiv.) in
THF (6 mL) was added dropwise. The reaction mixture was stirred
for 15 min at –78 °C, and then for 10 min at 0 °C. Commercially
sourced 3-bromo-2-methylpropene (498 μL, 4.9 mmol, 1.0 equiv.)
was then added. The mixture was stirred for 20 min at 0 °C, then
it was allowed to warm to room temperature, and it was stirred for
a further 30 min. Water was added, and usual extraction was car-
ried out with EtOAc. The crude material was purified by flash
chromatography (EtOAc/petroleum ether, 20:80 to 50:50) to give 38
(699 mg, 75%), and also N,N-diisopropyl-2,2-dimethoxyacetamide
(80 mg, 8%) as a by-product.[52] Data for 38: 1H NMR (CDCl3,
400 MHz): δ = 4.82 (m, 2 H), 3.76 (s, 3 H), 3.29 (s, 6 H), 2.61 (s,
2 H), 1.75 (s, 3 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 161.9,
139.5, 114.9, 102.8, 52.2, 49.8 (2 C), 41.6, 22.9 ppm. HRMS (DI,
EI) Calc for [C9H16O4]+ 188.1049; found 188.1047.
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra for all reported compounds.
Acknowledgments
Ecole Polytechnique (Palaiseau, France) is gratefully acknowledged
for a PhD grant to A. C. Particular thanks are due to Omega Cat
Systems SARL for kindly providing precatalysts 33 and 34. Thanks
are also due to Jean-Pierre Baltaze at ICMMO for performing the
600 MHz NMR spectroscopic measurements.
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Methyl (Z)-2-Methoxy-4-methylpenta-2,4-dienoate (39): Cam-
phorsulfonic acid (22 mg, 0.05 equiv.) was added to acetal 36
(360 mg, 1.9 mmol, 1.0 equiv.) in dry toluene (3 mL) at room tem-
perature. The reaction mixture was stirred at 150 °C under 300 W
microwave irradiation. Every 2 h, the progress of the reaction was
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were added after 2 h and 4 h of reaction time (2ϫ 22 mg). After
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usual extraction with EtOAc followed by flash chromatography on
silica gel (EtOAc/petroleum ether, 10:90) gave dienoic ester 39
(201 mg, 67%). 1H NMR (CDCl3, 400 MHz): δ = 6.62 (s, 1 H),
5.27 (s, 1 H), 5.13 (s, 1 H), 3.80 (s, 3 H), 3.67 (s, 3 H), 2.05 (s, 3
H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 165.0, 144.7, 139.5,
126.6, 122.0, 60.1, 52.0, 21.5 ppm. HRMS (DI, EI) Calc for [4] a) Review: S. Gagliardi, M. Rees, C. Farina, Curr. Med. Chem.
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(5E,11E,13E)-3-Methoxy-5,11-dimethyloxacyclohexadeca-
3,5,11,13-tetraen-2-one (E-40) and (5E,11E,13Z)-3-Methoxy-5,11-
dimethyloxacyclohexadeca-3,5,11,13-tetraen-2-one (Z-40): Cam-
phorsulfonic acid (1 mg, 0.001 mmol, 0.05 equiv.) was added to
pure macrolactone Z-30 (10 mg, 0.03 mmol, 1 equiv.) in dry tolu-
ene (1 mL) at room temperature. The reaction mixture was stirred
at 150 °C under microwave irradiation (300 W) for 1 h. Then solid
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carried out with EtOAc. Analysis by NMR spectroscopy showed
no consumption of the starting material. The remaining major
starting macrolactone Z-30 was dissolved in dry toluene (1 mL),
and camphorsulfonic acid (2 mg, 0.02 mmol, 0.1 equiv.) was added.
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tion was carried out with EtOAc as before. The residue was purified
by flash chromatography on silica gel (Et2O/pentane, 0:100 to
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8277

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Received: April 17, 2013
Published Online: November 20, 2013
8278
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 8265–8278