Total synthesis of iso- and bongkrekic acids: Natural antibiotics displaying potent antiapoptotic properties

Article abstract of DOI:10.1002/chem.201002380

For over five decades, owing to their antiapoptotic activities, bongkrekic and isobongkrekic acids have generated interest from the scientific community. Here, we disclose full details of our investigation into the synthesis of isobongkrekic acid, which culminated in its first preparation and features various palladium-catalysed cross-couplings and Takai olefination reactions. Access to bongkrekic acid is also reported by this route. These syntheses involve the preparation and use of new general building blocks which could find wider applications. Iso-bong: A versatile first synthesis of isobongkrekic acid (IBA) has been developed. Key steps include three different palladium cross-couplings and an asymmetric homopropargylation. In-depth synthetic studies reveal the challenges faced in generating the right geometry of each diene.

Full text of DOI:10.1002/chem.201002380

FULL PAPER
DOI: 10.1002/chem.201002380
Total Synthesis of Iso- and Bongkrekic Acids: Natural Antibiotics Displaying
Potent Antiapoptotic Properties
Antoine FranÅais,* Antonio Leyva-Pꢀrez, Gorka Etxebarria-Jardi, Javier PeÇa, and
Steven V. Ley*[a]
Abstract: For over five decades, owing to their antiapoptotic activities, bongkrekic
and isobongkrekic acids have generated interest from the scientific community.
Here, we disclose full details of our investigation into the synthesis of isobongkrek-
ic acid, which culminated in its first preparation and features various palladium-
catalysed cross-couplings and Takai olefination reactions. Access to bongkrekic
acid is also reported by this route. These syntheses involve the preparation and
use of new general building blocks which could find wider applications.
Keywords: anti-apoptotic · natural
products palladium cross-cou-
plings · total synthesis
·
Introduction
Isobongkrekic acid (IBA) (1) and its more well known
isomer bongkrekic acid (BA) (2) (Scheme 1) are poisonous
antibiotics produced by Pseudomonas cocovenenans (or also
called Burkholderia gladioli). Their names come from an In-
donesian equivalent of tofu called tempeh bongkrꢀk. When
prepared from contaminated coconuts this dish can cause
food poisoning, and from 1951 to 1990 these intoxications
caused nearly 1000 deaths in central Java.[1] The origin of
this fatal response has been attributed to the presence of
bongkrekic derivatives and toxoflavin.[2] The sale of tempeh
bongkrꢀk is now prohibited by law in Indonesia.
Scheme 1. Isobongkrekic (1) and bongkrekic (2) acids.
earlier this year, biosynthetic studies revealed that BA was a
polyketide-derived with b-branches and terminal carboxy-
lates both derived from acetate.[10]
To date, there have been four reported total syntheses of
BA, the first by Corey and Tramontano in 1984.[11] Some 20
years later, Shindo, Shishido and co-workers devised a
second route which was not without its problems.[12] Dissatis-
fied by this approach, these two authors recently published
two different second generation syntheses in considerably
improved overall yields reaching 6.5[13] and 13.7%.[14] We
too became interested in this area and recently described
the first total synthesis of IBA as well as the shortest route
to BA reported so far.[15] Here, we describe our full investi-
gations into the syntheses of these two natural products.
BA and IBA were isolated in 1934[3] and 1976,[4] and the
structure of BA elucidated between 1970 and 1973.[5] BA
was determined to be an inhibitor of adenine nucleotide
translocase (ANT), which mediates the ADP/ATP exchange
in mitochondria.[6] IBA showed the same properties, albeit
to a lesser extent.[7] These particular effects on mitochondria
have been shown to delay the programmed cell death.[8] As
a result, bongkrekic derivatives have become general tools
in the elucidation of apoptosis mechanisms, appearing in
more than 700 publications.[9] Still a contemporary topic,
Synthetic plan: Our main objective, which distinguished our
synthesis from others, was to directly target the trimethyles-
ter of IBA [IBAMe3 (3)]; the advantage being the presumed
stability of the intermediate esters which would avoid labo-
rious sequences of protection/deprotection along the route.
The risk of this strategy lies in the final saponification which
might result in a loss of stereogenic integrity.
[a] Dr. A. FranÅais, Dr. A. Leyva-Pꢁrez, Dr. G. Etxebarria-Jardi, J. PeÇa,
Prof. Dr. S. V. Ley
Department of Chemistry, University of Cambridge
Lensfield Road, Cambridge, CB2 1EW Cambridge (UK)
Fax : (+44)1223-336-442
E-mail: svl1000@cam.ac.uk
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201002380.
Chem. Eur. J. 2011, 17, 329 – 343
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329

Based on this approach, it was expected that Sonogashira
coupling[16] between vinyl iodide 4 and alkyne 5 and subse-
quent cis-reduction of the acetylenic bond would provide ef-
ficient access to IBAMe3 (3) (Scheme 2). Several routes to
these two fragments were investigated.
Scheme 4. Initial retrosynthesis for fragment 5.
over four steps on 10 g scale (Scheme 5). Using Wittig–
Stork conditions,[20] ketone 13 was converted selectively to
vinyl iodide 6b, which participated in the anticipated Heck
reaction. Although undesired minor isomers were also ob-
tained, column chromatography provided good quality Z,E-
diene 10 but in moderate overall yield.
Scheme 2. Central disconnection of IBA 1.
Results and Discussion
Synthesis of the acetylene fragment 5
Plan A: The initial approach to acetylene 5 was to use func-
tionalised butanediacetal (BDA)-protected 1,2-diols 6[17]
that could be further elaborated by palladium-catalysed
cross-coupling reactions. This method has been previously
developed within our group (Scheme 3)[18] and exemplified
in the synthesis of (ꢀ)-epi-pyriculol.[19] Thus, we sought to
construct the Z,E-diene 10 through the Heck cross-coupling
of partners 11 and 6b (Scheme 4). Fragment 5 would arise
from diene 10 following BDA deprotection and an appropri-
ate alkynylation process.
Scheme 5. Synthesis of intermediate 10. a) Ph3P+CH2I·Iꢀ, NaHMDS,
THF, ꢀ78 to 08C, 3 h, 68% (Z/E 8:1); b) H2CC(Me)CO2Me 11a,
[Pd2dba3]/PACHTNUGTRNEG(UN tBu)3, Cy2NMe, toluene, 908C, 15 min, 100% (Z/E 70:30).
NaHMDS=sodium bis(trimethylsilyl) amide, THF=tetrahydrofuran.
Following our previously published procedures,[17,18] d-
mannitol (12) was converted to the ketone 13 in 25% yield
Next, the BDA protecting group was removed under
acidic conditions and the primary alcohol of the correspond-
ing diol was selectively tosylated to give 14 (Scheme 6).[21]
To avoid any racemisation, the free secondary hydroxyl was
methylated under non-basic conditions using Meerweinꢃs
salt.[22] Subsequent nucleophilic displacement of the tosylate
by lithium acetylide ethylenediamine complex was attempt-
ed under typical conditions.[23] Unfortunately, all attempts
failed and only isomers of ketone 15 were isolated, presuma-
bly as a result of an elimination process transiting through
the corresponding enol methyl ether. Alternatively, secon-
dary alcohol 14 was transformed to epoxide 16[24] and then
rapidly submitted to modified Yamaguchi ring-opening con-
ditions using BF3·THF.[25] Although complete addition was
achieved, the regioselectivity of the reaction was again dis-
appointingly low favouring undesired primary alcohol 18
over compound 17 in a ratio of 2.5:1.
Scheme 3. Pd-catalysed cross-coupling reactions performed on two differ-
ent vinyl iodide BDA-protected 1,2-diols 6a and 6b. a) o-TolB(OH)2, Pd-
ACHTUNGTRENNUNG
At this point therefore two clear difficulties had arisen
namely the synthesis of the Z,E-diene and installation of the
homopropargylic alcohol in 17. Further issues arose when
scaling up the Heck reaction where a poorer 1:1 ratio of
E,Z isomers was obtained. We therefore concluded that
A
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
termined by GC-MS). S-Phos=2-dicyclohexylphosphino-2’,6’-dimethoxy-
biphenyl, dppf=1,1’-bis(diphenylphosphino)ferrocene, dba=dibenzyl-
ACHTUNGTRENNUNGideneacetone.
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Total Synthesis of Iso- and Bongkrekic Acids
FULL PAPER
Scheme 8. Synthesis of boronic ester 19. a) NaH, CHI3, Et2O, 45 8C, 24 h;
b) KOH, EtOH/H2O 4:1, reflux, 24 h, 58% over 2 steps; c) H2SO4
(conc.), MeOH, reflux, 15 h, 94%; d) 24, [PdCl
DMSO, 808C, 2.5 h, 84%.
2ACHTUNGTREN(UNGN dppf)]·CH2Cl2, KOAc,
verted selectively to Z-vinyl iodide 26 again using the
Wittig–Stork conditions[20] in multigram quantities and in
69% yield over the two steps (Scheme 9). With the two
fragments in hand, we turned our attention to finding suita-
ble conditions for the proposed Suzuki–Miyaura coupling.[28]
As reported in several syntheses, including those containing
highly substituted dienes,[29] Kishiꢃs modified conditions
using thallous ethoxide would provide our best chance of
success.[30] In the event, the reaction was stereospecific with
complete formation of the desired Z,E-diene 27 in good
yield (geometry confirmed by NOE studies). Moreover, by
comparison to the previous Heck strategy, this reaction was
reliable and reproducible on gram scale affording significant
quantities of pure diene 27. Subsequent TBDPS deprotec-
tion with TBAF[31] and Dess–Martin oxidation[32] gave the
fully conjugated aldehyde 28 (Scheme 9).
Scheme 6. Alkynylation issues. a) HCl (2n), H2O, THF, reflux, 2 h,
quant.; b) TsCl, 2,4,6-collidine, CH2Cl2, RT, 24 h, 69%; c) Proton
Sponge, Meerweinꢃs salt, CH2Cl2, RT, 24 h, 60%; d) HCCLi/ethylenedi-
ACHTUNGTRENNUNGamine, DMSO, RT, 1 h, 75%; e) iPr2NEt, CH3CN, 658C, 15 h, 55%; f)
Me3SiCCH, nBuLi, BF3·THF, THF, ꢀ788C, 30 min, 85% conv. (17/18
1:2.5). DMSO=dimethylsulfoxide.
route was not robust enough to deliver the quantities of ma-
terial necessary to progress the synthesis further.
Plan B: A new strategy was investigated based upon two
critical bond construction events: a) the formation of the
Z,E-diene using a Suzuki–Miyaura coupling was expected to
be more selective, and b) a direct asymmetric homopropar-
gylation reaction would install the required stereogenic
centre (Scheme 7). Accordingly the two coupling partners,
boronic ester 19 and a synthetic equivalent for vinyl iodide
20, were prepared by straightforward methods.
At this stage, several options were available to append
the homopropargylic side chain in an enantioselective fash-
ion. We were initially attracted by the impressive yields and
enantiomeric ratios described with Soderquistꢃs asymmetric
allenyl borane 34[33] and by Denmarkꢃs allenyl stannane pro-
cedure using chiral phosphoramide ligand 35.[34] Unfortu-
nately, neither of these worked well in our particular situa-
tion owing to the instability of aldehyde 28. Nevertheless,
applying the mild conditions reported by Singaram,[35] using
indium metal to mediate reactivity in the presence of chiral
aminoalcohol 30, the homopropargylation occurs to give 29
in good yield (91%) and an acceptable 82:18 enantiomeric
ratio (e.r.) in favour of the desired product. We expected
that we could improve this ratio by a variety of methods
however in the end we opted to use the chemical kinetic res-
olution method reported by Fu et al.[36] Selective acylation
of the unwanted enantiomer using acetic anhydride in the
presence of the appropriate chiral iron 4-dimethylaminopyr-
idine complex (in this case 33)[37] provided 29 in an upgrad-
ed ratio of 95:5, which was deemed acceptable for the next
Scheme 7. Revised retrosynthesis for fragment 5.
Diethyl 2-methylmalonate (22) was transformed via a
known sequence of iodination and elimination/decarboxyla-
tion into vinyl iodide 23.[26] After formation of the corre-
sponding methyl ester under acidic conditions, a palladium-
catalysed iodine/boronic ester exchange was performed in
84% yield (Scheme 8). This route was reproducible on
larger scale and gave access to several grams of the stable
boronic ester 19.[27]
1
steps. All enantiomeric ratios were determined by H and
19F NMR analysis of the corresponding Mosher ester 31
(Scheme 9).[33] At this stage, we faced the task of methylat-
ing secondary alcohol 29 without epimerising the C17 ster-
eocentre or isomerising the Z,E-diene. Several procedures
were investigated without success, including Ag2O/MeI,[38]
diazomethane derivatives[39] or Meerweinꢃs salt in the pres-
ence of excess of Proton Sponge.[22] Ultimately, we found
The next component was obtained from hydroxyacetone
25, which was protected as its TBDPS ether and then con-
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331

A. FranÅais, S. V. Ley et al.
Scheme 10. Initial retrosynthesis for fragment 4.
verted in good yield and in one-pot to vinyl iodide 37. This
procedure was scalable and afforded multigram quantities of
the desired product.
Scheme 9. Synthesis of fragment 5. a) TBDPSCl, Et3N, DMAP, CH2Cl2,
08C to RT, 15 h; b) Ph3P+CH2I Iꢀ, NaHMDS, THF, ꢀ788C to RT, 4 h,
69% over 2 steps; c) 19, [PdACHTNUGTRNENUG(PPh3)4], TlOEt, THF/H2O 3:1, RT, 1 h,
91%; d) TBAF, THF, RT, 1 h, 99%; e) Dess–Martin periodinane,
CH2Cl2, 08C to RT, 1 h, quant.; f) 21, 30, In, THF, ꢀ788C to RT, 24 h,
93%, e.r. 82:18; g) Ac2O, 33 (cat.), Et3N, tert-amyl alcohol, 08C, 48 h,
81%, e.r. 95:5; h) 32, DMAP, THF, RT, 16 h, 82%; i) MeOTf, 2,6-di-tert-
butylpyridine, CH2Cl2, 608C, 15 h, 88%. TBDPSCl=tert-butyldiphenylsi-
Scheme 11. Synthesis of fragment 37. a) TBDPSCl, DBU, DMF, ꢀ508C,
30 min, 70%; b) SO3·pyridine, iPr2NEt, CH2Cl2, DMSO, 08C, 1 h, quant.;
c) CrCl2, CHI3, THF, 08C to RT, 3 h, 45%; d) TPAP, NMO, CH2Cl2, 4 ꢄ
MS, RT, 15 min, then CrCl2, CHI3, THF, RT, 1.5 h, 65%. DBU=1,8-
ACHTUNGTRENNUNGlyl chloride, DMAP=4-dimethylaminopyridine, TBAF=tetra-n-butylam-
monium fluoride, MeOTf=methyl trifluoromethanesulfonate.
diazabicycloACTHNUTRGNEUG[N 5.4.0]undec-7-ene, DMF=N,N-dimethylformamide, TPAP=
tetra-n-propylammonium perruthenate, NMO=N-methylmorpholine N-
oxide, MS=molecular sieves.
that treatment of alcohol 29 with methyl triflate and a hin-
dered base[40] cleanly afforded methyl ether 5 in 88% yield
without any isomerisation. In conclusion, acetylenic coupling
partner 5 was obtained in 12 steps overall (Scheme 9).
We now reached the crucial stage of how best to install
the geometry of the terminal 1,3-diene which distinguishes
IBA 1 from BA 2. The first and most straightforward option
was a Heck coupling reaction. Few examples in the litera-
ture have described the formation of hindered 1,3-dienes via
Heck reactions,[45] and coupling vinyl iodides with non-acti-
vated 1,2-substituted alkenes, such as diester 36a, appeared
to be particularly challenging. Several conditions, including
those detailed by Fu,[46] Jung[47] and Roglans,[48] were unsuc-
cessfully screened to couple dimethyl glutaconate 36a and
vinyl iodide 37. Eventually, conditions described by Buch-
wald[49] proved to be the most suitable for our substrate
giving a separable mixture of isomers 41a and 41b (4:1
ratio) in 30% yield (Scheme 12). Unfortunately, the yield
for this transformation dropped to 18% on scaling to quan-
tities greater than one gram.
Dissatisfied by these results, we elected to investigate the
Stille–Migita coupling.[50] Consequently, a stereoselective
synthesis of stannane 36b was achieved based on Piers hy-
drostannylation process (Scheme 13).[51] 3-Butyn-1-ol (42)
was protected as its TBS ether and the corresponding lithi-
um acetylide added to methyl chloroformate giving multi-
gram quantities of ester 43.[52] At this stage, it was planned
Synthesis of the vinyl iodide fragment 4
First challenge: The elaboration of the 1,3-diene: We first
considered a chiral pool approach to install the chiral centre
at C6 using the commercially available diol 39 (Scheme 10).
Vinyl iodide fragment 4 should then be obtained from the
logical assembly of fragments 36a (or 36b), 37 and 38 via a
palladium-catalysed cross-coupling, a Takai reaction and
subsequent elaboration.
Synthesis of the central vinyl iodide 37 commenced with
the low-temperature monosilylation of chiral diol 39
(Scheme 11).[41] Oxidation of alcohol 40 to the correspond-
ing aldehyde under Parikh–Doering conditions[42] followed
by Takai olefination[43] afforded vinyl iodide 37 in moderate
yield. Unfortunately, this procedure was irreproducible on
larger scale due to instability of the intermediate aldehyde.
Drawing inspiration from our work describing a one-pot
TPAP oxidation–Wittig olefination sequence,[44] a related
one-pot oxidation–Takai homologation was studied. After
minimal experimentation, alcohol 40 was successfully con-
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Total Synthesis of Iso- and Bongkrekic Acids
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Scheme 13. Synthesis of stannane 36b. a) TBSCl, imidazole, CH2Cl2, 08C
to RT, 3 h; b) ClCO2Me, nBuLi (in hexanes), THF, ꢀ408C to 08C, 2 h,
80% over 2 steps; c) iPr2NH, Bu3SnH, nBuLi, CuSPh, THF/MeOH, 08C
to ꢀ1008C to 08C, 4 h, 85%; d) H2CrO4, acetone, 08C, 10 min, 68%; e)
TMSCHN2, CH2Cl2/MeOH, 40 min, quant.; f) PPTS, MeOH, RT, 15 h,
92%; g) several oxidation methods, failed. TBSCl=tert-butyldimethylsil-
yl chloride, TMSCHN2 =trimethylsilyldiazomethane, PPTS=pyridinium
para-toluenesulfonate.
Scheme 12. Heck cross-coupling. a) PdACHTNUGTRNE(UNG OAc)2, Bu4NBr, Cy2NMe, DMF,
1408C, 1 h, 24% of 41a, 6% of 41b.
to perform the key hydrostannylation with diester 46 in
order to minimize the hazardous manipulation of the stan-
nane derivatives. After a successful deprotection, the corre-
sponding alcohol was subjected to many different oxidation
procedures: Swern,[53] TPAP/NMO,[54] TEMPO,[55] Dess–
Martin,[32] PCC,[56] and Jones[57] oxidation. None of these af-
forded the desired oxidised product and led to degradation
or to the corresponding allenyl aldehyde 45. Consequently,
the stereo- and regioselective hydrostannylation was per-
formed on the alkyne 43. Again, several methods of silyl de-
protection and oxidation were screened. Surprisingly, this
was eventually and smoothly achieved in one step under
Jonesꢃ conditions affording the corresponding carboxylic
acid[58] which was subsequently esterified with trimethylsilyl-
diazomethane.[59] Stannane 36b was then obtained on a
gram scale by this reliable five-step sequence in an overall
yield of 46%.
this method E,E-diene 41a could be isolated in an accepta-
ble 60% yield.
With effective access to the E,E-diene secured it was nec-
essary to verify the stereochemical integrity of the methyl
group. Diene 41a was deprotected with methanolic HCl[31]
(TBAF led to decomposition) and the resulting alcohol 47
was converted to Mosher ester 48.[33] Based on 1H and
19F NMR analysis, an e.r. of >95:5 was determined. Com-
forted by this observation, alcohol 47 was quantitatively oxi-
dised under Dess–Martin conditions[32] to the corresponding
aldehyde 49, ready for further homologation (Scheme 14).
Second challenge: a long elongation: In compliance with
our initial strategy (Scheme 10), the partner 38 for the Takai
coupling was obtained from butanediol 50 by a sequence of
a monoprotection, TPAP oxidation and transformation of
the aldehyde 25 to gem-diiodide 38 using Sternhellꢃs proto-
The coupling of fragments 37 and 36b via the Stille–
Migita reaction for hindered dienes was investigated using
three different procedures (Table 1, entries 1–3).[60,61] Fꢅrst-
nerꢃs
conditions,[61]
which
employ a phosphonate salt as a
tin scavenger, were the most
promising (entry 3). Modifica-
tion of the catalyst loading
(entry 4) and reaction time
(entry 5) allowed the coupling
to proceed in an encouraging
75% yield. Unfortunately, the
reaction always delivered a 3:2
mixture of isomers 41a and
41b; however, these could be
readily separated by conven-
tional chromatography. Surpris-
ingly, the E,E-diene was less
thermodynamically stable than
expected (this might also ac-
count for the stability and ge-
ometry of BA found in the
nature). On larger scale, the ad-
dition of triethylamine at the
end of the reaction (entry 6)
proved to be the most efficient
and convenient way to obtain
Table 1. Results of the Stille–Migita coupling between fragments 37 and 36b.
Entry Pd cat. [mol%]
Additives
Conditions
RT, 16 h
Yield [%] 41a and
41b
41a/41b
ratio[a]
1[60a]
2[60b]
3[61]
4
[(CH3CN)2PdCl2]
(10 mol%)
–
–
<10[b]
50[b]
50[b]
62[b]
75[b]
80[c]
–
CuTC
08C!RT,
1 h
RT, 2 h
1:1
3:2
3:2
3:2
3:1
[Pd
[Pd
[Pd
[Pd
U
CuTC
Ph2PO2NBu4
CuTC
Ph2PO2NBu4
CuTC
Ph2PO2NBu4
CuTC
RT, 2 h
RT, 1 h
RT, 1 h
5
ACHTUNGTRENNUNG
6
ACHTUNGTRENNUNG
Ph2PO2NBu4
[a] Calculated from isolated yields of the two products. [b] Performed on 0.3 mmol. [c] Performed on 1.3 mmol
an equilibrium 3:1 mixture. By and subsequent treatment with Et3N, RT, 30 min. CuTC=copper thiophene-2-carboxylate
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A. FranÅais, S. V. Ley et al.
in excess, this linker allows direct elongation of both termi-
ni.
Linker fragment 55 was obtained efficiently following the
double Schwartz dihydrozirconation and in situ iodinolysis[67]
of 1,5-hexadiyne 57 (Scheme 18).
Scheme 14. Synthesis of aldehyde 49. a) HCl 1.25m in MeOH, RT,
quant.; b) 32, DMAP, THF, RT, 16 h, 86%; c) Dess–Martin periodinane,
08C to RT, CH2Cl2, quant.
col (Scheme 15).[62] The low yield obtained in the last step
was consistent with those previously reported.[62] It is note-
worthy that the yield for the oxidation was significantly im-
proved (63 to 97%) by employing freshly prepared TPAP.[63]
Scheme 17. Second retrosynthesis for fragment 4.
Scheme 18. Synthesis of linker 55. a) Cp2ZrHCl, I2, THF, 408C, 10 min,
84%.
Scheme 15. Synthesis of gem-diodide 38. a) TBDPSCl, iPr2NEt, CH2Cl2,
RT, 2 h, quant.; b) TPAP (cat), NMO, CH2Cl2, RT, 1 h, 97%; c)
H2NNH2, H2O, 0 8C, 45 min, then I2, Et3N, CH2Cl2, 5 min, 36%.
Next, the synthesis of alkyl iodide 63 commenced with the
TBDPS protection of Roche ester 58 followed by DIBAL-
H reduction of the ester to aldehyde 59 (Scheme 19). Alde-
hyde 59 was then converted to E-vinyl iodide 56 using a
Takai olefination. Under the Stille–Migita coupling condi-
tions developed during our first approach, E,E-diene 60 was
isolated in a similar 61% yield. Surprisingly, and in contrast
to our initial route, TBDPS deprotection proceeded smooth-
ly and without any degradation using TBAF.[31] However,
subsequent iodination of the resulting alcohol[68] gave the
alkyl iodide 63 in only 30% yield. This disappointing result
was partly explained by a side reaction which resulted in the
formation of the two conjugated 1,3,5-trienes 62a and 62b.
Despite this problem and with alkyl iodide 63 in hand, the
Negishi coupling with bis-vinyl iodide 55 was attempted.
Unfortunately, none of the conditions[69] screened provided
the desired vinyl iodide fragment 4. We were therefore
forced to consider a new route, which also necessitated the
preparation of a new linker fragment.
Next, the Takai reaction[64] between aldehyde 49 and gem-
diiodide 38 was performed in a highly stereoselective fash-
ion with relative ease. Triene 53 was TBDPS deprotected
and oxidised under Dess–Martin conditions. Aldehyde 54
was converted to E-vinyl iodide 4 using a second Takai reac-
tion (Scheme 16).[43] In summary, the coupling fragment 4
was obtained in 17 steps (12 steps longest linear sequence)
and 8.5% overall yield.
Although this result was acceptable, a shorter route based
2
ꢀ
on a C
(sp ) C
(sp3) Negishi coupling[65] using bis(vininyl
iodide) 55[66] was also investigated (Scheme 17). When used
The bidirectional coupling partner 64 was designed in
order to overcome the synthetic issues of the previous route
(Scheme 20). This promising new triiodide coupling unit,
with its orthogonal reactivity, should allow us to install the
unsymmetrical hexa-1,5-diene fragment (a common subunit
to a number of natural products)[70] in an efficient and inter-
esting manner and was expected to find application in other
syntheses.
Pentynyl alcohol 65 was transformed selectively into the
corresponding E-vinyl iodide (Scheme 21).[71] Following un-
successful attempts with TPAP/NMO[54] and Swern[53] condi-
Scheme 16. Synthesis of vinyl iodide fragment 4. a) CrCl2, THF, RT, 15 h,
61%; b) HCl 1.25m in MeOH, RT, 85%; c) Dess–Martin periodinane,
CH2Cl2, RT, 4 h; d) CrCl2, CHI3, THF, 08C to RT, 3 h, 69% over 2 steps.
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Total Synthesis of Iso- and Bongkrekic Acids
FULL PAPER
Scheme 22. Completion of vinyl iodide fragment 4. a) CrCl2, THF, RT,
4.5 h, 79%.
Completion of the synthesis
We hoped now that the effort invested in the preparation of
fragments 4 and 5 would be rewarded by their successful
union via Sonogashira coupling[16] (Table 2). Firstly, applica-
tion of Hoye conditions[72] employing [Pd
ACHTNUGTRNEUNG(PPh3)4] resulted in
only 18% of the desired coupled products with 50% recov-
ery of vinyl iodide 4 (entry 1). By increasing the stoichiome-
try of the catalyst, copper source and base, total conversion
was achieved and the desired enynes 67/68 could be isolated
in a 53% yield (entry 2). Unfortunately, the reaction was ac-
companied by the significant formation of dimer 69 resulting
from a Glaser coupling.[73] This type of side reaction normal-
ly occurs in presence of O2 and consequently, the reaction
Scheme 19. Attempted synthesis of vinyl iodide fragment 4 via Negishi
coupling. a) TBDPSCl, imidazole, 08C to RT, 1 h, 99%; b) DIBAL-H,
Et2O, ꢀ788C, 1 h, 70%; c) CrCl2, CHI3, THF, 08C to RT, 2 h, 80%; d)
36b, [PdACHTUNGTRENNUNG(PPh3)4], CuTC, Ph2PO2NBu4, DMF, RT, 30 min, then Et3N, RT,
1 h, 61%; e) TBAF, THF, 08C to RT, 1 h, 96%; f) PPh3, I2, imidazole,
CH2Cl2, 508C, 15 h, 62a/b: 50% and 63: 37%; g) 55, ZnCl2, tBuLi, [Pd-
(PPh3)4], Et2O, ꢀ788C to RT, 15 h, failed. DIBAL-H=diisobutylalumini-
um hydride.
was performed in degassed THF with [PdCl2ACHTNUGTRENUNG(PPh3)2] as cata-
lyst. The yield in Glaser product was decreased as was the
conversion to Sonogashira product 67/68 (entry 3). Finally,
by using the base as solvent[74] the dimer product was signifi-
cantly decreased from the product mixture (entry 4). This
resulted in a reliable 74% yield of eneynes 67/68. Further-
more, the ratio between the two separable isomers was 3:1
in favour of the desired 67. Unfortunately, the Glaser dimer
69 was inseparable from 67. As a result, the global mixture
of 67, 68 and 69 was carried through the next synthesis step.
In their synthesis of BA (2), Corey and Tramontano[11] re-
ported the chemoselective cis-reduction of the alkyne func-
tion by Lindlar hydrogenation.[75] However, in our hands,
the reaction required high catalyst loading and H2 pressures,
which frequently led to unpredictable and significant over-
reduction. We therefore choose the Avignon–Tropis–Bol-
land[76] method, as this had successfully been applied to our
synthesis of (ꢀ)-valilactone.[77] Pleasingly, the reaction pro-
ceeded in almost quantitative yield and the two isomers
IBAMe3 (3) and BAMe3 (70) were readily separated for an-
alytical purposes (Scheme 23). However, the 4:1 mixture
was used directly in the final hydrolysis experiments as
some double bond isomerisation was also expected under
these conditions.
Scheme 20. Final retrosynthesis for fragment 4.
tions, the primary alcohol was efficiently oxidised with
PCC.[56] Then, aldehyde 66 was converted to triiodide 64
under the Sternhell conditions.[62] Importantly, this sequence
was reproducible on gram scale and afforded reasonably
clean and stable material to proceed the synthesis.
At last, the Takai coupling[64] between fragments 49 and
64 gave E-vinyl iodide 4 selectively and in good yield
(Scheme 22). In summary, this final route afforded key cou-
pling fragment 4 in a scalable and reliable fashion with an
overall yield of 20.8% after 14 steps (9 steps longest linear
sequence).
For this final hydrolysis of the trimethylester substrates
we screened various hydroxide sources (Table 3).
Firstly, and following the work of Corey,[11] the use of
nBu4NOH was investigated. Unfortunately, a very complex
and inseparable mixture was obtained and no IBA (1) or
BA (2) could be detected (entry 1). Next, we used LiOH in
a H2O/THF mixture (entries 2 and 3)[78] and promisingly,
traces of the desired products were observed. Further inves-
tigation of LiOH in another biphasic H2O/DME mixture[79]
Scheme 21. Synthesis of triiodide 64. a) DIBAL-H, THF, ꢀ208C to RT,
15 h then I2, ꢀ788C to RT, 30 min, 56%; b) PCC, CH2Cl2, 08C, 6 h, 95%;
c) NH2NH2·H2O, RT, 1 h then Et3N, I2, RT, 10 min, 40%. PCC=pyridini-
um chlorochromate.
Chem. Eur. J. 2011, 17, 329 – 343
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335

A. FranÅais, S. V. Ley et al.
Table 2. Results of the Sonogashira coupling between fragments 4 and 5.
resisted isomerisation even
under these drastic conditions.
They were isolated in accepta-
ble yields and better ratios
using either aqueous KOH
(entry 5) or aqueous LiOH
(entry 6). Revisiting the promis-
ing biphasic H2O/DME condi-
tions but with KOH as a base
afforded pure IBA (1) and BA
(2) in 35 and 17% yield, respec-
tively, our best result so far
(entry 7).
Fortunately, also, separation
of the isomers was achievable
using preparative TLC. Finally,
however, it was important to
check for any epimerization of
the C6 and C17 stereocentres
arising from these harsh condi-
tions. Both IBA (1) and BA (2)
were reconverted separately
and quantitatively to their cor-
Entry
1[72]
Pd cat. [mol%]
[Pd(PPh3)4] (10 mol%)
Additives
Conditions[a]
Yield [%] 67/68[b] (% of recov. 4)
G
CuI (0.2 equiv)
Et3N (5 equiv)
CuI (1.2 equiv)
Et3N (10 equiv)
CuI (1.2 equiv)
Et3N (5 equiv)
CuI (0.2 equiv)
Et3N (solvent)
THF, RT, 16 h
18 (SM: 50)
2
[Pd
[PdCl
[PdCl2A
R
THF, RT, 5 h
THF,[c] RT, 5 h
Et3N, RT, 2.5 h
53
3
A
U
38 (SM: 20)
74
4[74]
A
CHTUNGTRENNUNG
[a] Performed on 0.07 mmol of 4 with 1.5 equiv of 5. [b] Estimated by 1H NMR from the mixture with dimer
69 [c] Degassed THF. SM=starting vinyl iodide 4.
responding
trimethylester
IBAMe3 (3) and BAMe3 (70)
(Scheme 24),[59] and both gave
analytical data including optical
rotation in accord with the orig-
inal substrates prior to their
saponification.
Table 3. Results towards IBA (1) and BA (2).
Whilst our synthetic materi-
als are in complete accordance
with the spectroscopic data pre-
sented in the literature, data
discrepancies do occur in the
optical rotational measurements
for IBA (1). For completeness,
we have summarised this data
in Table 4. Firstly, we observe
that all optical rotation data
arising from synthetic materials
match for the BA (2) series.
However, significant deviation
(both in sign and magnitude) is
evident when comparing these
data to that of the isolation
chemists.[80] In the original iso-
lation publications key analyses
were performed at very low
Entry
Base
Conditions[a]
Yield [%] 1/2[b]
1[11]
2[78]
3
nBu4NOH (5 equiv) 0.5m
LiOH (5 equiv) 1m
H2O/MeOH 1:1, 08C ! RT, 24 h
H2O/THF 1:1, 08C ! RT, 24 h
H2O/THF 1:1, 08C ! RT, 24 h
H2O/DME 1:4, RT, 1 h
H2O, 1008C, 48 h
–
incomplete
traces
31:23
31:12
24:14
35:17
LiOH (45 equiv) 1m
LiOH (100 equiv) 1m
KOH (100 equiv) 2m
LiOH (100 equiv) 2m
KOH (100 equiv) 0.2m
4[79]
5[4]
6
H2O, 1008C, 5 h
H2O/DME 1:4 RT, 8 h
7
[a] Performed on 0.4 mmol of starting 4:1 mixture. [b] Calculated from isolated yields of the two products.
DME=1,2-dimethoxyethane.
provided 1 and 2 in a combined 54% yield (entry 4). Re-
grettably, the initial 4:1 mixture degraded under these con-
ditions to a 3:2 mixture of 1/2; however, a 23% yield of BA
(2) was deemed acceptable in comparison to previous results
and when considering the sensitivity of the substrate.
During the isolation of IBA, Vignais and co-workers[4] ach-
ieved interconversion between the two natural products 1
and 2 using aqueous KOH at 1008C. In our hands, 1 and 2
concentrations and in aqueous or partially alcoholic sol-
vents. We suggest that this is both unnecessary and inappro-
priate[81] and leads us to believe that the natural products
might have been isolated as various carboxylate salts. This
could explain the differences between our measured optical
rotation values and those presented in the literature.
336
www.chemeurj.org
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 329 – 343

Total Synthesis of Iso- and Bongkrekic Acids
FULL PAPER
polarimeter with the sample temperature maintained at 258C. Concentra-
tion of the sample is quoted in units of 0.01 gcmꢀ3 1H NMR spectra
.
were recorded at room temperature on Bruker Avance TXI-700 cryop-
robe (700 MHz), DRX-600 (600 MHz), and DPX-400 (400 MHz, CDCl3)
spectrometers as solution in deuterated chloroform. The chemical shift d
are reported in ppm relative to tetramethylsilane. Residual CHCl3 (dH =
7.26 ppm, singlet) was used as an internal standard. The multiplicity of
signals is designated by the following abbreviations: s, singlet, brs, broad
singlet, d, doublet, bd, broad doublet, t, triplet, q, quartet, quint, quintet,
sex, sextet, m, multiplet. Coupling constants, J, are reported in Hertz
(Hz). 13C NMR spectra were recorded at 100 or 125 MHz on Bruker
DPX-400 or Bruker Avance DPX-500 cryoprobe instruments, respective-
ly. Spectra were recorded as dilute solution in deuterated chloroform,
with chemical shifts reported relative to residual CHCl3 (dC =77 ppm,
triplet). NMR spectra were assigned using information ascertained from
DEPT, COSY, HMBC, HMQC and NOE experiments. In order to facili-
Scheme 23. Synthesis of IBAMe3 3. a) Zn
3 + 70: 99%, ratio 3/70: 4:1.
ACHTUNGTRENUN(GN CuAg), MeOH/H2O 1:1, 658C,
tate
a straightforward comparison between data, NMR assignments
follow the standard numbering of the natural product (cf. Scheme 1). IR
spectra were recorded on a Perkin–Elmer Spectrum I FTIR spectrome-
ter. The samples were prepared as thin films. Only selected absorbances
(nmax) are reported in cmꢀ1. High resolution mass spectra (HRMS) were
obtained on a Water LCT Premier spectrometer with micromass MS soft-
ware using electrospray ionisation (ESI). Flash chromatography was car-
ried out using silica gel Breckland 60 (0.040–0.063). Florisil refers to 200–
300 mesh Florisil (BDH). Celite refers to Fluka Celite 545 coarse. Ana-
lytical and preparative TLCs were performed on a 0.25 mm thickness
plates pre-coated with Merck Kieselgel 60 F254 silica gel. TLC were vi-
sualised under UV (254 nm) and by oxidative staining with aqueous
acidic ammonium molybdateACHTNUTRGNE(NUG VII) solution. All intermediates and final
Scheme 24. Re-esterification of IBA and BA. a) TMSCHN2, CH2Cl2/
MeOH 5:1, quant.
compounds were stored under argon at ꢀ208C.
Boronic ester 19: To a solution of carboxylic acid 23[26] (8.0 g, 37.7 mmol)
in MeOH (24 mL) at RT was added concentrated H2SO4 (0.8 mL). The
reaction was stirred for 15 h at 1008C before removal of volatiles under
vacuum. Crude was dissolved in CH2Cl2 (30 mL) and reaction was
quenched with a saturated aqueous solution of NaHCO3. The aqueous
layer was extracted with CH2Cl2 (3ꢆ50 mL). The combined organic ex-
tracts were dried over MgSO4, filtered and concentrated under vacuum
to give the corresponding methyl ester as a brown oil (8 g, 94%). Rf =0.8
Table 4. Specific rotation values [a]D25
.
References
BA (2)
BAMe3 (70)
IBA (1)
IBAMe3 (3)
Corey[11]
–
+80
+81.5
+87.1
–
–
–
–
–
–
–
Shindo[13]
ꢀ51.3
ꢀ51.9
+105
ꢀ47.2
Shishido[14]
natural products[4b,82]
this work
1
+93.8
+55.5
+27.8
+110
(PE/Et2O 4:1); H NMR (400 MHz, CDCl3): d = 7.80 (d, J=1.0 Hz, 1H,
+81.2
H20), 3.76 (s, 3H, OCH3 ester), 2.07 ppm (d, J=1.0 Hz, 1H, H5’);
13C NMR (100 MHz, CDCl3): d = 164.3 (C22), 139.5 (C21), 98.6 (C20),
52.4 (OCH3 ester), 20.3 ppm (C5’); IR (film): nmax = 2952, 2923, 2854,
1717, 1601, 1435, 1380, 1289, 1215, 1098, 948, 836, 726, 683 cmꢀ1; HRMS
(ESI+): m/z: calcd for C5H7O2INa: 248.9388; found: 248.9391 [M+Na]+
.
Conclusion
The first total synthesis of isobongkrekic acid (1) has been
completed. This highly convergent route required only 13
steps from commercially available materials in the longest
linear sequence, required only 29 steps in total and afforded
(1) in 7.0% yield. We have also accessed bongkrekic acid
(2) in 4.7% yield, which compares favourably to recently
published syntheses.[83] Furthermore, the triiodide 64 has
been developed as a new and effective bidirectional cou-
pling partner that is of particular interest owing to its or-
thogonal reactivity. This linchpin component should find ap-
plication in other complex molecule syntheses where bis
skipped diene components appear as structural motifs.
To a solution of this methyl ester (2.96 g, 13.1 mmol, 1 equiv), bis(pinaco-
lato)diboron (6.65 g, 26.2 mmol, 2 equiv) and KOAc (2.57 g, 26.2 mmol,
2 equiv) in DMSO (45 mL) under argon at RT was added [PdCl2-
AHCTUNGTREGUN(NN dppf)]·CH2Cl2 (95 mg, 0.13 mmol, 10 mol%). The reaction was stirred
for 2.5 h at 808C. Then H2O (90 mL) was added and the aqueous layer
was extracted with Et2O (4ꢆ100 mL). The combined organic extracts
were dried over MgSO4, filtered and concentrated under vacuum. Purifi-
cation of the resulting crude brown solid by flash chromatography (PE/
Et2O 95:5) gave the pure boronic ester 19 as a colourless oil (2.5 g,
84%). Rf =0.65 (PE/Et2O 5:1); 1H NMR (400 MHz, CDCl3): d = 6.47
(d, J=0.7 Hz, 1H, H20), 3.70 (s, 3H, OCH3 ester), 2.10 (d, J=0.7 Hz,
1H, H5’), 1.24 ppm (s, 12H, CH3 pinacol); 13C NMR (100 MHz, CDCl3):
d = 168.2 (C22), 147.0 (C21), 127.0 (small brs, C20), 83.5 (2C, Cq pina-
col), 52.0 (OCH3 ester), 24.8 (4C, CH3 pinacol), 17.0 ppm (C5’); IR
(film): nmax = 2656, 2925, 2872, 2855, 1716, 1682, 16274, 1436, 1378, 1330,
1260, 1212, 1150, 1114, 1076, 1011, 962, 880, 831, 748, 673 cmꢀ1; HRMS
(ESI+): m/z: calcd for C11H19O4BNa: 249.1274; found: 248.9657
[M+Na]+.
Experimental Section
Vinyl iodide 26: To a solution of hydroxyacetone (2.8 mL, 36 mmol,
1 equiv), Et3N (6.1 mL, 44 mmol, 1.2 equiv) and DMAP (30 mg,
0.25 mmol, 0.7 mol%) in CH2Cl2 (15 mL) under argon at RT was added
dropwise TBDPSCl (9.4 mL, 36 mmol, 1 equiv). The reaction was stirred
for 15 h at RT and quenched afterwards with a saturated aqueous solu-
General methods: Solvents were freshly distilled before use. All non-
aqueous reactions were performed under an atmosphere of argon and
carried out using oven-dried glassware. PE=petroleum ether b.p. 40–
608C. Optical rotations were measured using a Perkin–Elmer model 343
Chem. Eur. J. 2011, 17, 329 – 343
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
337

A. FranÅais, S. V. Ley et al.
tion of NH4Cl. The aqueous layer was extracted with Et2O (2ꢆ80 mL).
The combined organic extracts were dried over MgSO4, filtered and con-
centrated under vacuum to give the expected silyl ether as a colourless
oil (11.42 g) clean enough to proceed the next step.
(536 mg, quant). Rf =0.6 (PE/Et2O 2:1); 1H NMR (400 MHz, CDCl3): d
= 10.40 (s, 1H, H17), 8.63 (d, J=12.6 Hz, 1H, H19), 7.20 (d, J=12.6 Hz,
1H, H20), 3.79 (s, 3H, OCH3 ester), 2.04 (s, 3H, H5’), 1.94 ppm (s, 3H,
H4’); 13C NMR (100 MHz, CDCl3): d= 190.4 (C17), 168.1 (C22), 139.8
(C18), 137.9 (C20), 133.2 (C21), 129.1 (C19), 52.3 (OCH3 ester), 17.2
(C4’), 12.6 ppm (C5’); HRMS (ESI+): m/z: calcd for C9H12O3Na:
191.0684; found: 191.6088 [M+Na]+.
To a solution of the Wittig–Stork salt[20,84] (23.2 g, 44 mmol, 1.2 equiv) in
THF (105 mL) under argon at RT was added dropwise a 1m solution of
NaHMDS (44 mL, 44 mmol, 1.2 equiv) in THF. After the reaction mix-
ture was stirred for 5 min to get complete solubilisation, the reaction was
cooled at ꢀ788C and a solution of the silyl ether (11.4 g, ca. 36 mmol,
1 equiv) in THF (55 mL) was added slowly. Then reaction was stirred for
45 min at ꢀ788C, 3 h at RT and quenched afterwards with a saturated
aqueous solution of NH4Cl. The aqueous layer was extracted with Et2O
(4ꢆ100 mL). The combined organic extracts were dried over MgSO4, fil-
tered and concentrated under vacuum. Purification of the resulting crude
brown oil by flash chromatography (PE/Et2O 100:0 ! 95:5) gave vinyl
iodide 26 as a yellow oil (10.78 g, 69% over 2 steps). Rf =0.85 (PE/Et2O
95:5); 1H NMR (400 MHz, CDCl3): d = 7.75–7.60 (m, 4H, Har), 7.48–
7.35 (m, 6H, Har), 5.87 (s, 1H, H19), 4.30 (s, 2H, H17), 2.00 (s, 3H, H4’),
1.07 ppm (s, 9H, CH3 (tBu)); 13C NMR (100 MHz, CDCl3): d = 146.4,
135.6, 133.4, 127.8 (12C, Car), 129.7 (C18), 72.7 (C19), 69.3 (C17), 26.9
(3C, CH3 (tBu)), 21.7 (C4’), 19.3 ppm (Cq (tBu)); IR (film): nmax = 3071,
3050, 2957, 2930, 2856, 1472, 1427, 1376, 1283, 1261, 1188, 1139, 1106,
1087, 1051, 1021, 953, 819, 737, 999, 669; HRMS (ESI+): m/z: calcd for
C20H25OSiINa;: 459.0617; found: 459.0604 [M+Na]+.
Alkyne 29: To a solution of indium (467 mg, 4.08 mmol, 2 equiv), chiral
aminoalcohol 30 (868 mg, 4.08 mmol, 2 equiv) and pyridine (330 mL,
4.08 mmol, 2 equiv) in THF (24.5 mL) under argon at RT was slowly
added propargyl bromide (450 mL, 4.08 mmol, 2 equiv). The cloudy sus-
pension was stirred for 30 min with formation of a coin of indium. Then,
more indium (233 mg, 2.04 mmol, 1 equiv) was added and the reaction
was cooled to ꢀ788C. A solution of aldehyde 28 (342 mg, 2.04 mmol,
1 equiv) in THF (5 mL) was added dropwise and the reaction was stirred
for 15 h at ꢀ788C then for 6 h during a slow warming to RT. The reaction
was quenched with an aqueous 1m solution of HCl (16 mL). The aqueous
layer was extracted with PE/Et2O 1:1 (2ꢆ60 mL). The combined organic
extracts were dried over MgSO4, filtered and concentrated under
vacuum. Purification of the resulting crude yellow oil by flash chromatog-
raphy (PE/Et2O 2:1) gave a 82:18 mixture enriched in enantiomer 29 as a
yellow oil (394 mg, 93%).
To a solution of this mixture of 29 (365 mg, 1.75 mmol, 1 equiv) and Et3N
(49 mL, 0.35 mmol, 0.2 equiv) in tert-amyl alcohol (3.5 mL) under air at-
mosphere at RT was added the DMAP iron catalyst 33 (58 mg,
0.09 mmol, 5 mol%). After sonication for 10 min to get a cloudy purple
solution, Ac2O was added slowly at 08C. Then, reaction was stirred for
48 h at 08C and finally quenched with MeOH (80 mL). Volatiles were re-
moved under vacuum. Purification of the resulting crude purple oil by
flash chromatography (PE/Et2O 7:3) gave a 95:5 enriched mixture of the
enantiomer 29 as a pale yellow oil (280 mg, 81%). Rf =0.4 (PE/Et2O
1:1); [a]D =ꢀ36.4 (c=0.55, CHCl3, 258C); 1H NMR (400 MHz, CDCl3):
d = 7.49 (d, J=12.0 Hz, 1H, H20), 6.25 (d, J=12.0 Hz, 1H, H19), 5.01
(d, J=7.9, 5.7 Hz, 1H, H17), 3.77 (s, 3H, OCH3 ester), 2.57 (ddd, J=
16.6, 7.9, 2.6 Hz, 1H, H16a), 2.43 (ddd, J=16.6, 5.7, 2.6 Hz, 1H, H16b),
2.08 (t, J=2.6 Hz, 1H, H14), 1.94 ppm (s, 6H, H4’ and H5’); 13C NMR
Diene 27: To a solution of vinyl iodide 26 (1.67 g, 3.84 mmol, 1 equiv)
and boronic ester 19 (1.3 g, 5.76 mmol, 1.5 equiv) in THF/H2O 3:1
(125 mL) under argon at RT was added [PdACHTNUTRGEN(UNG PPh3)4] (444 mg, 0.38 mmol,
10 mol%). The reaction was stirred for 5 min in the dark before adding
dropwise TlOEt (490 mL, 6.91 mmol, 1.8 equiv). After a 1 h stirring at
RT, more [PdACHTUNGTRENNUNG(PPh3)4] was added (222 mg, 0.19 mmol, 5 mol%) and reac-
tion was stirred for an additional hour still in the dark. Then, the result-
ing suspension was filtered through a pad of celite and rinsed with Et2O
(300 mL). The aqueous layer was extracted with Et2O (2ꢆ40 mL). The
combined organic extracts were dried over MgSO4, filtered and concen-
trated under vacuum. Purification of the resulting crude dark brown oil
by flash chromatography (PE/Et2O 97:3) gave diene 27 as a yellow oil
1
(1.44 g, 91%). Rf =0.3 (PE/Et2O 95:5); H NMR (400 MHz, CDCl3): d =
(100 MHz, CDCl3): d = 169.0 (C22), 145.5 (C21), 131.9 (C20), 127.0
7.86–7.65 (m, 4H, Har), 7.47–7.35 (m, 6H, Har), 7.32 (d, J=12.0 Hz, 1H,
H20), 6.16 (d, J=12.0 Hz, 1H, H19), 4.40 (s, 2H, H17), 3.70 (s, 3H,
OCH3 ester), 2.00 (s, 3H, H5’), 1.92 (s, 3H, H4’), 1.07 ppm (s, 9H, CH3
(C18), 123.4 (C19), 80.2 (C15), 71.3 (C14), 68.2 (C17), 51.9 (OCH3 ester),
26.1 (C16), 18.8 (C4’), 12.4 ppm (C5’); IR (film): nmax = 3447, 3306, 2951,
1697, 1635, 1603, 1436, 1389, 1322, 1255, 1209, 1112, 1044, 1012, 913, 752,
731 cmꢀ1; HRMS (ESI+): m/z: calcd for C12H16O3Na: 231.0997; found:
231.1007 [M+Na]+.
(tBu)); 13C NMR (100 MHz, CDCl3): d
= 169.1 (C22), 145.5 (C18),
135.6, 135.5, 133.4, 129.8, 129.7, 127.8 (12C, Car), 133.1 (C20), 125.6
(C21), 121.8 (C19), 63.0 (C17), 51.6 (OCH3 ester), 26.8 (3C, CH3 (tBu)),
22.4 (C4’), 19.3 (Cq (tBu)), 12.3 ppm (C5’); IR (film): nmax = 3051, 2931,
1894, 2857, 1706, 1640, 1604, 1428, 1377, 1325, 1254, 1199, 1109, 1073,
1027, 957, 941, 823, 807, 739, 700 cmꢀ1; HRMS (ESI+): m/z: calcd for
C25H33O3Si: 409.2193; found: 409.2190 [M+H]+.
Mosher ester 31: To a solution of alkyne 29 (20 mg, 0.106 mmol, 1 equiv)
in THF (0.8 mL) under argon at RT were added DMAP (16 mg,
0.122 mmol, 1.1 equiv) and acyl chloride 32 (25 mL, 0.122 mmol,
1.1 equiv). The reaction was stirred for 15 h at RT and volatiles were re-
moved under vacuum. Purification of the resulting crude on preparative
TLC (PE/Et2O 3:2) gave a 95:5 enriched mixture of the diastereoisomer
31 as a colourless oil (37 mg, 82%). Rf =0.65 (PE/Et2O 2:1); 1H NMR
(400 MHz, CDCl3): d = 7.58 (d, J=11.8 Hz, 1H, H20), 7.54–7.47 (m,
2H, Har), 7.45–7.33 (m, 3H, Har), 6.36 (d, J=11.8 Hz, 1H, H19), 6.19 (t,
J=7.0 Hz, 1H, H17), 3.78 (s, 3H, OCH3 ester), 3.52 (s, 3H, OCH3 ether),
2.72 (ddd, J=16.8, 7.0, 2.6 Hz, 1H, H16a), 2.57 (ddd, J=16.8, 7.0, 2.6 Hz,
1H, H16b), 1.96 (s, 3H, H5’), 1.95 (t, J=2.6 Hz, 1H, H14), 1.90 ppm (s,
3H, H4’); 13C NMR (100 MHz, CDCl3): d = 168.7, 165.6 (C22 and C=O
Mosher ester), 139.4 (C21), 131.9, 129.7, 128.4, 127.6 (6C, Car), 131.4
(C20), 128.5 (C18), 125.8 (C19), 123.2 (q, J=286.8 Hz, 1C, CF3), 84.7 (q,
J=27.8 Hz, 1C, C-CF3), 78.2 (C15), 72.4 (C17), 71.4 (C14), 55.4 (OCH3
ether), 52.0 (OCH3 ester), 23.1 (C16), 19.3 (C4’), 12.6 ppm); 19F NMR
Aldehyde 28: To a solution of diene 27 (1.3 g, 3.19 mmol, 1 equiv) in
THF (33 mL) under argon at 08C was added dropwise a 1m solution of
TBAF (6.4 mL, 6.37 mmol, 12 equiv) in THF. The reaction was stirred for
1 h at 08C and quenched afterwards with a saturated aqueous solution of
NH4Cl. The aqueous layer was extracted with Et2O (2ꢆ40 mL). The
combined organic extracts were dried over MgSO4, filtered and concen-
trated under vacuum. Purification of the resulting crude yellow oil by
flash chromatography (PE/Et2O 1:1) gave the corresponding primary al-
cohol as a yellow oil (540 mg, 99%). Rf =0.2 (PE/Et2O 2:1); 1H NMR
(400 MHz, CDCl3): d
= 7.47 (d, J=12.0 Hz, 1H, H20), 6.21 (d, J=
12.0 Hz, 1H, H19), 4.34 (brs, 2H, H17), 3.74 (s, 3H, OCH3 ester), 1.98 (s,
3H, H5’), 1.92 ppm (s, 3H, H4’); 13C NMR (100 MHz, CDCl3): d = 169.2
(C22), 145.3 (C18), 132.8 (C20), 126.3 (C21), 122.8 (C19), 61.5 (C17),
51.8 (OCH3 ester), 22.3 (C4’), 12.6 ppm (C5’); HRMS (ESI+): m/z:
calcd for C9H14O3Na: 193.0841; found: 193.0839 [M+Na]+.
(500 MHz, CDCl3): d
= 71.72 ppm; HRMS (ESI+): m/z: calcd for
C22H23O5F3Na: 447.1395; found: 447.1390 [M+Na]+.
Acetylene fragment 5: To a solution of alkyne 29 (260 mg, 1.25 mmol,
1 equiv) and 2,6-tert-butylpyridine (840 mL, 3.75 mmol, 3 equiv) in
CH2Cl2 (9 mL) under argon at 08C was added dropwise MeOTf (420 mL,
3.75 mmol, 3 equiv). The reaction was stirred for 15 h at 608C and vola-
tiles were removed under vacuum. Purification of the resulting crude
orange oil by flash chromatography (PE/Et2O 9:1) gave the pure acety-
lene fragment 5 as a yellow oil (244 mg, 88%). Rf =0.7 (PE/Et2O 1:1);
To a solution of this alcohol (540 mg, 3.19 mmol, 1 equiv) in CH2Cl2
(23 mL) under argon at 08C was added Dess–Martin periodinane (1.62 g,
3.83 mmol, 1.2 equiv). The reaction was stirred for 1 h at RT and cooled
at 08C before addition of PE (25 mL). The white suspension is then fil-
tered through a pad of silica (PE/Et2O 1:1 (300 mL)). The volatiles were
removed under vacuum to give the expected aldehyde 28 as a yellow oil
338
www.chemeurj.org
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 329 – 343

Total Synthesis of Iso- and Bongkrekic Acids
FULL PAPER
[a]D =+26.8 (c=2.0, CHCl3, 258C); 1H NMR (400 MHz, CDCl3): d =
7.55 (d, J=12.0 Hz, 1H, H20), 6.42 (d, J=12.0 Hz, 1H, H19), 4.50 (t, J=
7.0 Hz, 1H, H17), 3.77 (s, 3H, OCH3 ester), 3.26 (s, 3H, OCH3 ether),
2.60 (ddd, J=16.7, 7.0, 2.6 Hz, 1H, H16a), 2.41 (ddd, J=16.7, 7.0, 2.6 Hz,
1H, H16b), 1.98 (t, J=2.6 Hz, 1H, H14), 1.95 (s, 3H, H5’), 1.86 ppm (s,
3H, H4’); 13C NMR (100 MHz, CDCl3): d = 167.2 (C22), 143.9 (C21),
132.1 (C20), 126.9 (C18), 125.7 (C19), 80.2 (C15), 76.9 (C17), 70.2 (C14),
56.7 (OCH3 ether), 51.9 (OCH3 ester), 23.9 (C16), 18.5 (C4’), 12.4 ppm
(C5’); IR (film): nmax = 3306, 2928, 2824, 1705, 1636, 1601, 1436, 1378,
1316, 1257, 1218, 1096, 1019, 913, 751, 731 cmꢀ1; HRMS (ESI+): m/z:
calcd for C13H18O3Na: 245.1148; found: 245.1149 [M+Na]+.
(tBu)), ꢀ5.3 ppm (2C, Si-CH3); IR (film): nmax = 3316, 2956, 2930, 2886,
2858, 1763, 1722, 1464, 1472, 1253, 1102, 1060, 1006, 915, 834, 775,
663 cmꢀ1
.
To a solution of this silyl ether (7.5 g, ca. 33 mmol, 1 equiv) in THF
(54 mL) under argon at ꢀ408C was added a 1.6m solution of nBuLi in
hexanes (22.7 mL, 36.3 mmol, 1.1 equiv). After stirring for 30 min at
ꢀ58C, methylchloroformate was added and the reaction was stirred 1.5 h
at RT. Then, the reaction was hydrolysed with an aqueous solution satu-
rated in NH4Cl and the aqueous layer was extracted with Et2O (3ꢆ
100 mL). The combined organic extracts were dried over MgSO4, filtered
and concentrated under vacuum. Purification of the resulting dark brown
oil by flash chromatography (PE/Et2O 95:5) gave the pure alkyne 43 as a
yellow oil (6.39 g, 80% over 2 steps). Rf =0.55 (PE/Et2O 95:5); 1H NMR
(400 MHz, CDCl3): d = 3.78 (t, J=6.9 Hz, 2H, H2’), 3.76 (s, 3H, OCH3
ester), 2.55 (t, J=6.9 Hz, 1H, H1’), 0.90 (s, 9H, CH3 (tBu)), 0.08 ppm (s,
6H, Si-CH3); 13C NMR (100 MHz, CDCl3): d = 154.1 (C1), 86.8 (C3),
73.7 (C2), 60.7 (C2’), 52.6 (OCH3 ester), 25.8 (3C, CH3 (tBu)), 23.1 (C1’),
Alcohol 40: To a solution of the chiral diol 39 (2.5 g, 24 mmol, 1 equiv)
and TBDPSCl (6.5 mL, 25 mmol, 1.05 equiv) in DMF (96 mL) under
argon at ꢀ508C was added DBU (5.1 mL, 34 mmol, 1.5 equiv). The reac-
tion was stirred for 30 min at ꢀ508C before addition of EtOAc (150 mL).
The organic layer was successively washed by a saturated aqueous solu-
tion of NH4Cl and a saturated aqueous solution of NaHCO3. Then, the
organic layer was dried over MgSO4, filtered and concentrated under
vacuum. Purification of the resulting crude colourless oil by flash chro-
matography (PE/Et2O 5:1) gave the pure alcohol 40 as a colourless oil
(5.75 g, 70%). Rf =0.25 (PE/Et2O 4:1); [a]D =ꢀ5.4 (c=1.0, CHCl3,
258C); 1H NMR (400 MHz, CDCl3): d = 7.77–7.71 (m, 4H, Har), 7.51–
7.36 (m, 6H, Har), 3.82–3.66 (m, 2H, H8), 3.56–3.44 (m, 2H, H5), 2.38
(brs, 1H, OH), 1.93–1.81 (m, 1H, H6), 1.75–1.59 (m, 1H, H7a), 1.57–1.44
(m, 1H, H7b), 0.91 ppm (d, J=6.8 Hz, 3H, H3’); 13C NMR (100 MHz,
CDCl3): d = 135.6, 133.5, 129.7, 127.7 (12C; Car), 68.3 (C5), 62.5 (C8),
36.8 (C7), 33.9 (C6), 26.9 (3C, CH3 (tBu)), 19.2 (Cq (tBu)), 17.1 ppm
(C3’); IR (film): nmax = 3344, 3071, 2957, 2930, 2858, 1472, 1428, 1389,
1361, 1106, 1086, 1041, 997, 822, 736, 699, 688 cmꢀ1; HRMS (ESI+): m/z:
calcd for C21H31O2Si: 343.2093; found: 343.2101 [M+H]+.
18.3 (1C, Cq (tBu)), ꢀ5.4 ppm (2C, Si-CH3); IR (film): nmax
= 2955,
2930, 2885, 2858, 2246, 1718, 1463, 1472, 1435, 1389, 1249, 1106, 1075,
1006, 909, 835, 812, 776, 752, 664 cmꢀ1; HRMS (ESI+): m/z: calcd for
C12H23O3Si: 243.1416; found: 243.1368 [M+H]+.
Stannane 44: To a solution of iPr2NH (10.9 mL, 77.8 mmol, 2.3 equiv) in
THF (110 mL) under argon at 08C were sequentially added a 1.6m solu-
tion of nBuLi in hexanes (44.4 mL, 66.6 mmol, 2 equiv) and Bu3SnH
(20 g, 66.6 mmol, 2 equiv). After cooling at ꢀ208C, CuSPh (11.5 g,
66.6 mmol, 2 equiv) was added in four portions and reaction was stirred
for 20 min. To the reaction cooled at ꢀ1008C WERE added via a cannu-
la a cold (ꢀ408C) solution of alkyne 43 (8.06 g, 33.3 mmol, 1 equiv) in
THF (54 mL) and MeOH (2.3 mL). Then, the reaction was stirred for 3 h
at ꢀ788C before addition of MeOH (8 mL) and warming to RT. Subse-
quently, the reaction was poured in H2O (300 mL). The aqueous layer
was extracted with Et2O (2ꢆ250 mL). The combined organic extracts
were dried over MgSO4, filtered and concentrated under vacuum. Purifi-
cation of the resulting crude dark brown oil by flash chromatography
(PE/Et2O 100:0 ! 97:3) gave the pure stannane 44 as an orange oil
(15.1 g, 85%). Rf =0.75 (PE/Et2O 98:2); 1H NMR (400 MHz, CDCl3): d
= 6.01 (s, 1H, H2), 3.70 (s, 3H, OCH3 ester), 3.67 (t, J=7.1 Hz, 2H,
H2’), 3.11 (t, J=7.1 Hz, 2H, H1’), 1.54–1.44 (m, 6H, CH2 (nBu)), 1.32
(sex, J=7.3 Hz, 6H, CH2 (nBu)), 0.97 (t, J=8.2 Hz, 6H, Sn-CH2), 0.90 (t,
J=7.3 Hz, 9H, CH3 (nBu)), 0.89 (s, 9H, CH3 (tBu)), 0.06 ppm (s, 6H, Si-
CH3); 13C NMR (100 MHz, CDCl3): d = 169.8 (C1), 164.4 (C3), 129.3
(C2), 62.6 (C2’), 50.8 (OCH3 ester), 38.8 (C1’), 29.0 (3C, CH2 (nBu)),
27.4 (3C, CH2 (nBu)), 26.0 (3C, CH3 (tBu)), 18.4 (1C, Cq (tBu)), 13.6
(3C, CH3 (nBu)), 10.1 (3C, Sn-CH2), ꢀ5.2 ppm (2C, Si-CH3); IR (film):
nmax = 2954, 2927, 2856, 1709, 1598, 1463, 1435, 1330, 1252, 1213, 1194,
1182, 1090, 1049, 1005, 835, 774, 665 cmꢀ1; HRMS (ESI+): m/z: calcd for
C24H51O3SiSn: 535.2629; found: 535.2672 [M+H]+.
Vinyl iodide 37: To a solution of alcohol 40 (2 g, 5.84 mmol, 1 equiv),
NMO (718 mg, 6.13 mmol, 1.05 equiv) and MS 4 ꢄ (1.2 g) in CH2Cl2
(12 mL) under argon at RT was added freshly prepared TPAP (205 mg,
0.58 mmol, 10 mol%). The reaction was stirred for 15 min at RT and vol-
atiles were removed under vacuum. THF (20 mL) and chloroform
(5.75 g, 14.6 mmol, 2.5 equiv) were added to the resulting black slurry.
Then, this solution was slowly added via cannula under argon to a solu-
tion of CrCl2 (5.39 g, 43.8 mmol, 7.5 equiv) in THF (20 mL). The reaction
was stirred for 1.5 h at RT and quenched with H2O (100 mL). Subse-
quently, the aqueous layer was extracted with Et2O (3ꢆ100 mL). The
combined organic extracts were dried over MgSO4, filtered and concen-
trated under vacuum. Purification of the resulting crude black oil by
flash chromatography (PE/Et2O 99:1) gave the pure vinyl iodide 37 as an
orange oil (1.76 g, 65%). Rf =0.8 (PE/Et2O 98:2); [a]D =+9.1 (c=1.0,
1
CHCl3, 258C); H NMR (400 MHz, CDCl3): d = 7.75–7.63 (m, 4H, Har),
7.47–7.33 (m, 6H, Har), 6.38 (dd, J=14.4, 8.2 Hz, 1H, H5), 5.93 (d, J=
14.4 Hz, 1H, H4), 3.67 (t, J=5.8 Hz, 2H, H8), 2.49–2.41 (m, 1H, H6),
1.61–1.51 (m, 2H, H7), 1.06 (s, 9H, CH3 (tBu)), 0.97 ppm (d, J=7.7 Hz,
3H, H3’); 13C NMR (100 MHz, CDCl3): d = 151.7 (C5), 135.5, 133.9,
129.6, 127.7 (12C, Car), 73.7 (C4), 61.4 (C8), 38.7 (C7), 37.2 (C6), 26.9
(3C, CH3 (tBu)), 19.6 (C3’), 19.2 ppm (Cq (tBu)); IR (film): nmax = 3070,
3049, 2958, 2930, 2857, 1731, 1603, 1590, 1472, 1462, 1427, 1389, 1361,
1259, 1172, 1105, 1007, 998, 986, 948, 897, 822, 736, 699, 688 cmꢀ1; HRMS
(ESI+): m/z: calcd for C22H29O1Si1I1Na: 487.0924; found: 487.0920
[M+Na]+.
Stannane 36b: To a solution of stannane 44 (2.7 g, 5.07 mmol, 1 equiv) in
acetone (14.3 mL) at 08C was slowly added a freshly made and pre-
cooled at 08C solution of Jones reagent (1.52 g of CrO3 in 3.4 mL of H2O
and 1.4 mL of concentrated H2SO4, 15.21 mmol, 3 equiv). The reaction
was stirred for 10 min at 08C before addition of H2O (15 mL) and Et2O
(30 mL). Subsequently, the aqueous layer was extracted with Et2O (2ꢆ
30 mL). The combined organic extracts were dried over MgSO4, filtered
and concentrated under vacuum. Purification of the resulting brown oil
by flash chromatography (PE/Et2O 5:1) gave the pure corresponding car-
boxylic acid as a yellow oil (1.27 g, 68%). Rf =0.35 (PE/Et2O 4:1);
1H NMR (400 MHz, CDCl3): d = 6.18 (s, 1H, H2), 3.95 (s, 2H, H1’),
3.75 (s, 3H, OCH3 ester), 1.56–1.42 (m, 6H, CH2 (Bu)), 1.31 (sex, J=
7.3 Hz, 6H, CH2 (Bu)), 1.00 (t, J=8.2 Hz, 6H, Sn-CH2), 0.89 ppm (t, J=
7.3 Hz, 9H, CH3 (Bu)); 13C NMR (100 MHz, CDCl3): d = 174.8 (C2’),
165.5 (C3), 164.9 (C1), 130.3 (C2), 51.5 (OCH3 ester), 40.2 (C1’), 28.9
(3C, CH2 (Bu)), 27.3 (3C, CH2 (Bu)), 13.6 (3C, CH3 (Bu)), 10.6 ppm (3C,
Sn-CH2); HRMS (ESI+): m/z: calcd for C18H35O4Sn [M+H]+: 435.1557;
found: 435.1621. To a solution of this carboxylic acid (880 mg, 2.03 mmol,
1 equiv) in MeOH (0.8 mL) and CH2Cl2 (3.3 mL) at 08C was added a 2m
solution of TMSCHN2 in Et2O (1.22 mL, 2.44 mmol, 1.2 equiv). The reac-
tion was stirred at 08C for 40 min before removal of volatile under
Alkyne 43: To a solution of but-3-yn-1-ol 42 (2.5 mL, 33 mmol, 1 equiv)
and imidazole (4.5 g, 66 mmol, 2 equiv) in CH2Cl2 (15 mL) under argon
at 08C was added via cannula a solution of TBSCl (6.5 g, 43 mmol,
1.3 equiv) in CH2Cl2 (20 mL). After stirring for 3 h at RT, the reaction
was hydrolysed with a saturated aqueous solution of NH4Cl and the
aqueous layer was extracted with CH2Cl2 (2ꢆ100 mL). The combined or-
ganic extracts were dried over MgSO4, filtered and concentrated under
vacuum to give a crude yellow oil of the corresponding silyl ether (7.5 g)
directly engaged in the following step. Rf =0.8 (PE/Et2O 95:5); 1H NMR
(400 MHz, CDCl3): d = 3.74 (t, J=7.1 Hz, 2H, H2’), 3.99 (dt, J=7.1,
2.6 Hz, 2H, H1’), 1.95 (t, J=2.6 Hz, 1H, H2), 0.90 (s, 9H, CH3 (tBu)),
0.07 ppm (s, 6H, Si-CH3); 13C NMR (100 MHz, CDCl3): d = 81.5 (C3),
69.3 (C2), 61.8 (C2’), 25.9 (3C, CH3 (tBu)), 22.9 (C1’), 18.3 (1C, Cq
Chem. Eur. J. 2011, 17, 329 – 343
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
339

A. FranÅais, S. V. Ley et al.
vacuum. Purification of the resulting crude yellow oil by flash chromatog-
Mosher ester 48: To a solution of alcohol 47 (5 mg, 0.020 mmol, 1 equiv)
in THF (0.2 mL) under argon at RT were added DMAP (3 mg,
0.024 mmol, 1.1 equiv) and acyl chloride 32 (5 mL, 0.024 mmol, 1.1 equiv).
The reaction was stirred for 15 h at RT and volatiles were removed under
vacuum. Purification of the resulting crude on preparative TLC (PE/
Et2O 3:2) gave a 95:5 enriched mixture of the diastereoisomer 48 as a
white solid (8 mg, 86%). Rf =0.55 (PE/Et2O 1:1); 1H NMR (400 MHz,
CDCl3): d = 7.57–7.45 (m, 2H, Har), 7.45–7.36 (m, 3H), 6.03 (d, J=
15.7 Hz, 1H, H4), 5.87 (s, 1H, H2), 5.86 (dd, J=15.7, 8.2 Hz, 1H, H5),
4.36–4.16 (m, 2H, H8), 3.97 (d, J=16.2 Hz, 1H, H1a’), 3.91 (d, J=
16.2 Hz, 1H, H1b’), 3.72 (s, 3H, OCH3 ester), 3.68 (s, 3H, OCH3 ester),
3.54 (s, 3H, OCH3 ether), 2.40–2.29 (m, 1H, H6), 1.84–1.63 (m, 2H, H7),
raphy (PE/Et2O 95:5) gave the pure stannane 36b as a pale yellow oil
1
(910 mg, quant). Rf =0.55 (PE/Et2O 9:1); H NMR (400 MHz, CDCl3): d
= 6.11 (s, 1H, H2), 4.01 (s, 2H, H1’), 3.70 (s, 3H, OCH3 ester), 3.61 (s,
3H, OCH3 ester), 1.56–1.39 (m, 6H, CH2 (Bu)), 1.31 (sex, J=7.3 Hz, 6H,
CH2 (Bu)), 0.97 (t, J=8.2 Hz, 6H, Sn-CH2), 0.89 ppm (t, J=7.3 Hz, 9H,
CH3 (Bu)); 13C NMR (100 MHz, CDCl3): d = 172.3 (C2’), 164.8 (C3),
164.5 (C1), 129.8 (C2), 51.9, 51.0 (2C, OCH3 ester), 39.1 (C1’), 28.9 (3C,
CH2 (Bu)), 27.3 (3C, CH2 (Bu)), 13.7 (3C, CH3 (Bu)), 10.7 ppm (3C, Sn-
CH2); IR (film): nmax = 2955, 2924, 2872, 2853, 1733, 1715, 1599, 1457,
1435, 1377, 1325, 1250, 1195, 1163, 1072, 1002, 865, 690, 672 cmꢀ1; HRMS
(ESI+): m/z: calcd for C19H36O4SnNa: 471.1533; found: 471.1559
[M+Na]+.
1.04 ppm (d, J=6.7 Hz, 3H, H3’); 13C NMR (100 MHz, CDCl3
d =
170.7, 169.9, 165.7, 166.4 (3C, C1, C2’ and C=O Mosher ester), 147.6
(C3), 141.3 (C5), 132.3, 129.7, 128.5, 127.9, 127.3 (6C, Car), 131.6 (C4),
120.2 (C2), 123.3 (q, J=286.9 Hz, 1C, CF3), 84.5 (q, J=27.6 Hz, 1C, C-
CF3), 64.4 (C8), 55.4 (OCH3 ether), 52.1, 51.3 (2C, OCH3 ester), 34.9
(C7), 34.1 (C6), 33.2 (C1’), 20.1 ppm (C3’); 19F NMR (500 MHz, CDCl3):
Dienes 41a and 41b: To a solution of vinyl iodide 37 (592 mg, 1.27 mmol,
1 equiv) and stannane 36b (737 mg, 1.78 mmol, 1.4 equiv) in DMF under
argon at RT were added Ph2PO2NBu4 (812 mg, 1.78 mmol, 1.4 equiv),
[PdACHTUNGTRENNUNG(PPh3)4] (73 mg, 0.06 mmol, 5 mol%) and CuTC (190 mg, 1.00 mmol,
0.8 equiv). The reaction was stirred for 1 h at RT and then Et3N (7 mL)
was added. After stirring for 30 min at RT, H2O (15 mL) and Et2O
(15 mL) were added and the resulting orange suspension was filtered
through a pad of Celite (eluent: Et2O (100 mL)). The aqueous layer was
extracted with Et2O (2ꢆ20 mL). The combined organic extracts were
dried over MgSO4, filtered and concentrated under vacuum. Purification
of the resulting crude orange oil by flash chromatography (PE/Et2O 9:1)
gave the pure diene 41a as a yellow oil (375 mg, 60%) and the pure
diene 41b as a yellow oil (125 mg, 20%). Data for 41a: Rf =0.1 (PE/
Et2O 9:1); [a]D =+4.0 (c=1.0, CHCl3, 258C); 1H NMR (400 MHz,
CDCl3): d = 7.71–7.60 (m, 4H, Har), 7.47–7.33 (m, 6H, Har), 6.09 (d, J=
16.0 Hz, 1H, H4), 5.92 (dd, J=16.0, 7.5 Hz, 1H, H5), 5.86 (s, 1H, H2),
3.92 (s, 2H, H1’), 3.72 (s, 3H, OCH3 ester), 3.65 (t, J=7.5 Hz, 2H, H8),
3.64 (s, 3H, OCH3 ester), 2.60–2.42 (m, 1H, H6), 1.66–1.52 (m, 2H, H7),
1.05 (s, 9H, CH3 (tBu)), 1.01 ppm (d, J=7.5 Hz, 3H, H3’); 13C NMR
(100 MHz, CDCl3): d = 171.1 (C2’), 167.5 (C1), 148.6 (C3), 143.7 (C5),
135.9, 131.0, 130.0, 128.0 (13C, 12 Car and C4), 119.9 (C2), 62.0 (C8), 52.4,
51.6 (2C, OCH3 ester), 39.6 (C7), 34.1 (C6), 33.5 (C1’), 27.3 (3C, CH3
(tBu)), 20.4 (Cq (tBu)), 19.6 ppm (C3’); IR (film): nmax = 2952, 2931,
2858, 1741, 1713, 1636, 1615, 1429, 1324, 1261, 1192, 1154, 1106, 1008,
823, 738, 701, 688 cmꢀ1; HRMS (ESI+): m/z: calcd for C29H38O5SiNa:
517.2386; found: 517.2385 [M+Na]+. Data for 41b: Rf =0.15 (PE/Et2O
d
=
ꢀ71.71 ppm; HRMS (ESI+): m/z: calcd for C23H27O7F3Na:
495.1607; found: 495.1606 [M+Na]+.
Aldehyde 49: To a solution of alcohol 47 (180 mg, 0.70 mmol, 1 equiv) in
CH2Cl2 (5 mL) under argon at 08C was added Dess–Martin periodinane
(358 mg, 0.84 mmol, 1.2 equiv). The reaction was stirred 1 h at RT and
cooled at 08C before addition of PE (5 mL). The white suspension is
then filtered through a pad of silica (PE/Et2O 1:1 (200 mL)). The vola-
tiles were removed under vacuum to give the expected aldehyde 49 as a
yellow oil (180 mg, quant.) clean enough to proceed the next step. Rf =
0.2 (PE/Et2O 9:1); 1H NMR (400 MHz, CDCl3): d = 9.70 (t, J=1.8 Hz,
1H, H8), 6.14 (d, J=15.9 Hz, 1H, H4), 5.99 (dd, J=15.9, 7.2 Hz, 1H,
H5), 5.90 (s, 1H, H2), 3.93 (brs, 2H, H1’), 3.69 (s, 3H, OCH3 ester), 3.67
(s, 3H, OCH3 ester), 2.95–2.82 (m, 1H, H6), 2.50 (ddd, J=16.8, 6.7,
1.8 Hz, 1H, H7a), 2.43 (ddd, J=16.8, 7.0, 1.8 Hz, 1H, H7b), 1.11 ppm (d,
J=6.8 Hz, 3H, H3’); 13C NMR (100 MHz, CDCl3): d = 201.0 (C8), 170.6
(C2’), 166.8 (C1), 147.5 (C3), 140.7 (C5), 131.1 (C4), 120.5 (C2), 52.0,
51.3 (2C, OCH3 ester), 50.0 (C7), 33.1 (C1’), 31.7 (C6), 19.8 ppm (C3’);
HRMS (ESI+): m/z: calcd for C13H18O5Na: 277.1052; found: 277.1057
[M+Na]+.
Aldehyde 66: To
a 1m solution of DiBAL-H (100 mL, 100 mmol,
1
3.5 equiv) in hexanes under argon at ꢀ208C was added slowly pentynol
65 (3.7 mL, 40 mmol, 1 equiv). The reaction was stirred for 15 h at RT
before removal of volatiles under vacuum. The resultant colourless oil
was dissolved in THF (40 mL) and a solution of iodine (12.18 g, 48 mmol,
1.2 equiv) in THF (67 mL) was slowly added at ꢀ788C under argon.
Then the reaction was stirred for 20 min at ꢀ788C and warmed to RT.
Next, the brown solution was cautiously poured at 08C in a 2n solution
of HCl (17 mL) and more 2n HCl (13 mL) was carefully added. After
complete solubilisation of the aluminium salts, the aqueous layer was ex-
tracted with PE/Et2O 1:1 (2ꢆ100 mL). The combined organic extracts
were dried over MgSO4, filtered and concentrated under vacuum. Purifi-
cation of the resulting crude yellow oil by flash chromatography (PE/
Et2O 1:1) gave the pure corresponding vinyl iodide as a yellow oil
9:1); [a]D =ꢀ2.4 (c=1.27, CHCl3, 258C); H NMR (400 MHz, CDCl3): d
= 7.69–7.62 (m, 4H, Har), 7.53 (d, J=16.1 Hz, 1H, H4), 7.45–7.31 (m,
6H, Har), 6.01 (dd, J=16.1, 7.8 Hz, 1H, H5), 5.70 (s, 1H, H2), 3.71 (s,
3H, OCH3 ester), 3.66 (t, J=6.6 Hz, 2H, H8), 3.62 (s, 3H, OCH3 ester),
3.29 (brs, 2H, H1’), 2.63–2.53 (m, 1H, H6), 1.67 (q, J=6.6 Hz, 2H, H7),
1.05 (s, 9H, CH3 (tBu)), 1.04 ppm (d, J=7.0 Hz, 3H, H3’); 13C NMR
(100 MHz, CDCl3): d = 170.7 (C2’), 166.3 (C1), 147.1 (C3), 145.0 (C5),
135.6, 134.0, 129.6, 127.6 (12C, Car), 124.9 (C4), 118.4 (C2), 61.8 (C8),
52.1, 51.2 (2C, OCH3 ester), 40.4 (C1’), 39.3 (C7), 34.0 (C6), 26.9 (3C,
CH3 (tBu)), 20.0 (Cq (tBu)), 19.2 ppm (C3’); HRMS (ESI+): m/z: calcd
for C29H38O5SiNa: 517.2386; found: 517.2388 [M+Na]+.
Alcohol 47: To the diene 41a (100 mg, 0.20 mmol, 1 equiv) under argon
at 08C was added
a 1.25m solution of HCl in MeOH (2.42 mL,
1
(4.72 g, 56%). Rf =0.45 (PE/Et2O 2:3); H NMR (400 MHz, CDCl3): d =
3.03 mmol, 15 equiv). The reaction was stirred for 4 h during warming to
RT. Then, the reaction was neutralised with solid NaHCO3 (255 mg,
3.03 mmol, 15 equiv) and the volatiles were removed under vacuum. Pu-
rification of the resulting crude white solid by flash chromatography (PE/
Et2O 1:2) gave the pure alcohol 47 as a yellow oil (52 mg, quant.). Rf =
0.2 (PE/Et2O 1:2); [a]D =+29.7 (c=1.0, CHCl3, 258C); 1H NMR
(400 MHz, CDCl3): d = 6.10 (d, J=15.7 Hz, 1H, H4), 5.92 (dd, J=15.7,
8.1 Hz, 1H, H5), 5.85 (s, 1H, H2), 3.98 (d, J=16.2 Hz, 1H, H1a’), 3.85
(d, J=16.2 Hz, 1H, H1b’), 3.66 (s, 3H, OCH3 ester), 3.64 (s, 3H, OCH3
ester), 3.65–3.52 (m, 2H, H8), 2.47–2.36 (m, 1H, H6), 2.05–1.93 (brs, 1H,
OH), 1.64–1.50 (m, 2H, H7), 1.01 ppm (d, J=6.7 Hz, 3H, H3’); 13C NMR
(100 MHz, CDCl3): d = 171.2 (C2’), 167.4 (C1), 148.3 (C3), 143.5 (C5),
131.0 (C4), 120.1 (C2), 61.0 (C8), 52.4, 51.6 (2C, OCH3 ester), 39.7 (C7),
34.7 (C6), 33.4 (C1’), 20.6 ppm (C3’); IR (film): nmax = 3425, 2953, 1736,
1710, 1636, 1614, 1435, 1378, 1327, 1261, 1238, 1193, 1152, 1049, 1028,
6.53 (dt, J=14.4, 7.2 Hz, 1H, H12), 6.05 (d, J=14.4 Hz, 1H, H13), 3.72–
3.62 (m, 2H, H9), 2.17 (q, J=7.2 Hz, 2H, H11), 1.72–1.62 ppm (m, 2H,
H10); 13C NMR (100 MHz, CDCl3): d = 145.8 (C12), 75.0 (C13), 61.9
(C9), 32.3 (C11), 31.2 ppm (C10); IR (film): nmax = 3305, 3078, 2936,
2882, 1641, 1435, 1221, 1056, 994, 946, 911, 851 cmꢀ1. To a solution of this
vinyl iodide (2.9 g, 13.6 mmol, 1 equiv) and Celite (5.86 g) in CH2Cl2
under argon at 08C was added PCC (5.86 g, 27.2 mmol, 2 equiv). The re-
action was stirred at RT for 6 h and then was filtered through a pad of
silica using as eluent PE/Et2O 3:1 (400 mL). Volatiles were removed
under vacuum to give the aldehyde 66 as a yellow oil (2.72 g, 95%) clean
enough to proceed the next step. Rf =0.75 (PE/Et2O 3:2); 1H NMR
(400 MHz, CDCl3): d = 9.78 (s, 1H, H9), 6.52 (dt, J=14.4, 7.1 Hz, 1H,
H12), 6.12 (d, J=14.4 Hz, 1H, H13), 2.57 (t, J=7.1 Hz, 2H, H10),
2.39 ppm (q, J=7.1 Hz, 2H, H11); 13C NMR (100 MHz, CDCl3): d =
200.6 (C9), 143.9 (C12), 76.3 (C13), 42.2 (C10), 28.4 ppm (C11); IR
(film): nmax = 3052, 2927, 2826, 2723, 1723, 1607, 1409, 1389, 1211, 1176,
1003, 971, 917, 878, 834, 731 cmꢀ1
C13H20O5Na: 279.1208; found: 279.1216 [M+Na]+.
; HRMS (ESI+): m/z: calcd for
340
www.chemeurj.org
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 329 – 343

Total Synthesis of Iso- and Bongkrekic Acids
FULL PAPER
945, 856, 659 cmꢀ1; HRMS (ESI+): m/z: calcd for C5H7OINa: 232.9439;
found: 232.1700 [M+Na]+.
14.3, 7.2 Hz, 1H, H12), 5.40 (dt, J=15.2, 7.2 Hz, 1H, H9), 5.33 (dt, J=
15.2, 7.2 Hz, 1H, H8), 5.21 (ddd, J=10.7, 7.4, 7.2 Hz, 1H, H15), 4.34 (t,
J=7.2 Hz, 1H, H17), 3.97 (d, J=16.2 Hz, 1H, H1’a), 3.93 (d, J=16.2 Hz,
1H, H1’b), 3.75 (s, 3H, OCH3 ester), 3.70 (s, 3H, OCH3 ester), 3.69 (s,
3H, OCH3 ester), 3.21 (s, 3H, OCH3 ether), 2.58 (dt, J=14.7, 7.2 Hz,
1H, H16a), 2.37 (ddd, J=14.7, 7.4, 7.2 Hz, 1H, H16b), 2.32–2.26 (m, 1H,
H6), 2.15 (q, J=7.2 Hz, 2H, H11), 2.08 (q, J=7.2 Hz, 2H, H10), 2.06 (dt,
J=13.9, 7.2 Hz, 1H, H7a), 1.99 (dt, J=13.9, 7.2 Hz, 1H, H7b), 1.94 (s,
3H, H5’), 1.83 (s, 3H, H4’), 1.01 ppm (d, J=6.7 Hz, 3H, H3’); 13C NMR
(100 MHz, CDCl3): d = 170.7 (C2’), 169.1 (C22), 167.1 (C1), 148.2 (C3),
145.6 (C21), 143.3 (C5), 134.9 (C12), 132.2 (C20), 131.7 (C9), 130.6 (C4),
130.3 (C14), 128.1 (C8), 126.5 (C18), 125.7 (C13), 125.0 (C19), 124.4
(C15), 119.5 (C2), 78.4 (C17), 56.4 (OCH3 ether), 52.0, 51.8, 51.2 (3C,
OCH3 ester), 39.7 (C7), 37.4 (C6), 33.2 (C1’), 32.9 (C11), 32.3 (C10), 32.1
(C16), 19.3 (C3’), 18.7 (C4’), 12.3 ppm (C5’); HRMS (ESI+): m/z: calcd
for C31H44O7Na: 551.2985; found: 551.2997 [M+Na]+. Data for BAMe3
28: Colourless oil; Rf =0.50 (PE/Et2O 2:1); [a]D =+81.2 (c=0.25, CHCl3,
Triiodide 64: To aldehyde 66 (2 g, 9.53 mmol, 1 equiv) at 08C was added
hydrazine monohydrate (925 mL, 19.06 mmol, 2 equiv) and reaction was
stirred for 1 h at RT. Then, H2O (10 mL) and CH2Cl2 (10 mL) were
added and the aqueous layer was extracted 2 times with CH2Cl2 (2ꢆ
15 mL). The combined organic extracts were dried over MgSO4, filtered
and concentrated under vacuum. To this crude pale yellow oil at RT and
under argon were added Et3N (2.39 mL, 17.15 mmol, 1.8 equiv) and
iodine in 3 portions (2.66 g, 10.48 mmol, 1.1 equiv) and the reaction was
stirred for 10 min. After hydrolysis with a 25%/w aqueous solution of
Na2SO3 (60 mL), the aqueous layer was extracted with CH2Cl2 (2ꢆ
60 mL) and the combined organic extracts were dried over MgSO4, fil-
tered and concentrated under vacuum. Purification of the resulting crude
brown oil by flash chromatography (pure PE) gave the triiodide 64 as a
yellow oil (1.7 g, 40%). Rf =0.8 (PE/Et2O 99.5:0.5); 1H NMR (400 MHz,
CDCl3): d = 6.45 (dt, J=14.2, 7.2 Hz, 1H, H12), 6.16 (d, J=14.2 Hz,
1H, H13), 5.04 (t, J=6.6 Hz, 1H, H9), 2.45 (dt, J=7.2, 6.6 Hz, 2H, H10),
2.18 ppm (q, J=7.2 Hz, 2H, H11); 13C NMR (100 MHz, CDCl3): d =
142.3 (C12), 77.2 (C13), 46.1 (C10), 38.0 (C11), ꢀ28.4 ppm (C9); IR
(film): nmax = 3044, 2934, 2837, 1604, 1425, 1220, 1191, 1085, 939, 784,
732, 663 cmꢀ1; HRMS (ESI+): m/z: calcd for C5H7I3: 447.7676; found:
447.7670 [M]+.
258C); 1H NMR (700 MHz): d
= 7.51 (bd, J=15.7 Hz, 2H, H4 and
H20), 6.36 (d, J=11.8 Hz, 1H, H19), 6.26 (dd, J=15.1, 11.1 Hz, 1H,
H13), 6.05 (dd, J=16.1, 7.4 Hz, 1H, H5), 5.99 (t, J=11.1 Hz, 1H, H14),
5.69 (s, 1H, H2), 5.67 (dt, J=15.1, 7.1 Hz, 1H, H12), 5.41 (dt, J=15.2,
6.4 Hz, 1H, H9), 5.35 (dt, J=15.2, 7.0 Hz, 1H, H8), 5.21 (dt, J=11.1,
7.3 Hz, 1H, H15), 4.34 (t, J=7.3 Hz, 1H, H17), 3.75 (s, 3H, OCH3 ester),
3.71 (s, 3H, OCH3 ester), 3.68 (s, 3H, OCH3 ester), 3.33 (d, J=15.9 Hz,
1H, H1’a), 3.30 (d, J=15.9 Hz, 1H, H1’b), 3.21 (s, 3H, OCH3 ether), 2.58
(dt, J=14.8, 7.3 Hz, 1H, H16a), 2.38 (dt, J=14.8, 7.3 Hz, 1H, H16b),
2.38–2.32 (m, 1H, H6), 2.15 (q, J=7.1 Hz, 2H, H11), 2.08 (dt, J=7.1,
6.4 Hz, 2H, H10), 2.08–2.03 (m, 1H, H7a), 2.02–1.97 (m, 1H, H7b), 1.94
(s, 3H, H5’), 1.84 (s, 3H, H4’), 1.02 ppm (d, J=6.7 Hz, 3H, H3’);
13C NMR (125 MHz, CDCl3): d = 170.7 (C2’), 169.1 (C22), 166.3 (C1),
147.2 (C3), 145.5 (C21), 145.0 (C5), 135.0 (C12), 132.1 (C20), 131.5 (C9),
130.5 (C14), 128.2 (C8), 126.4 (C18), 125.6 (C13), 125.0 (C19), 124.6
(C4), 124.3 (C15), 118.3 (C2), 78.3 (C17), 56.4 (OCH3 ether), 52.2, 51.8,
51.1 (3C, OCH3 ester), 40.4 (C1’), 39.7 (C7), 37.5 (C6), 32.9 (C11), 32.4
Vinyl iodide 4: To a solution of CrCl2 (645 mg, 5.25 mmol, 7.5 equiv) in
THF (8 mL) under argon at RT was added a solution of aldehyde 49
(180 mg, 0.7 mmol, 1 equiv) and gem-diiodide
7 (950 mg, 2.1 mmol,
3 equiv) in THF (4 mL). The reaction was stirred at RT for 4.5 h. Then,
H2O (15 mL) and Et2O (15 mL) were added and the aqueous layer was
extracted with Et2O (2ꢆ20 mL). The combined organic extracts were
dried over MgSO4, filtered and concentrated under vacuum. Purification
of the resulting crude yellow oil by flash chromatography (PE/Et2O 9:1)
gave the pure vinyl iodide 4 as a yellow oil (238 mg, 79%). Rf =0.2 (PE/
Et2O 9:1); [a]D =+11.1 (c=1.2, CHCl3, 258C); 1H NMR (400 MHz,
CDCl3): d = 6.49 (dt, J=14.8, 6.6 Hz, 1H, H12), 6.10 (d, J=15.8 Hz,
1H, H4), 5.99 (d, J=14.8 Hz, 1H, H13), 5.98 (dd, J=15.8, 6.9 Hz, 1H,
H5), 5.90 (s, 1H, H2), 5.42–5.31 (m, 2H, H8 and H9), 3.98 (d, J=
16.3 Hz, 1H, H1’a), 3.93 (d, J=16.3 Hz, 1H, H1’b), 3.71 (s, 3H, OCH3
ester), 3.69 (s, 3H, OCH3 ester), 2.35–2.25 (m, 1H, H6), 2.22–1.97 (m,
6H, H7, H10 and H11), 1.02 ppm (d, J=6.7 Hz, 3H, H3’); 13C NMR
(100 MHz, CDCl3): d = 170.7 (C2’), 167.1 (C1), 148.2 (C3), 145.9 (C12),
143.2 (C5), 130.7 (C4), 130.4 (C9), 128.9 (C8), 119.6 (C2), 74.8 (C13),
52.0, 51.2 (2C, OCH3 ester), 39.7 (C7), 37.4 (C6), 35.9 (C11 or C10), 33.2
(C1’), 31.3 (C10 or C11), 19.4 ppm (C3’); IR (film): nmax = 2926, 1741,
(C10), 32.1 (C16), 19.2 (C3’), 18.6 (C4’), 12.3 ppm (C5’); IR (film): nmax
=
2952, 2692, 1742, 1711, 1636, 1603, 1435, 1377, 1258, 1232, 1155, 1096,
970, 863, 752 cmꢀ1; HRMS (ESI+): m/z: calcd for C31H44O7Na: 551.2985;
found: 551.2991 [M+Na]+.
Isobongkrekic acid IBA 1: To a 4:1 mixture of IBAMe3 3 and BAMe3 70
(25 mg, 47 mmol, 1 equiv) in DME (19 mL) was added a 1m solution of
KOH (4.7 mL, 4.7 mmol, 100 equiv) in H2O. The solution was stirred at
RT for 8 h and neutralised with 5 mL of aqueous 1n HCl. The aqueous
layer is extracted with Et2O (3ꢆ15 mL). The combined organic extracts
were dried over MgSO4, filtered and concentrated under vacuum. Purifi-
cation of the resulting crude yellow oil on preparative TLC (CH2Cl2/
MeOH/AcOH 97:3:0.5) furnished the pure desired IBA 1 (8 mg, 35%)
and the pure desired BA 2 (3.9 mg, 17%) as two white oily solids. Data
for IBA 1: White oily solid; Rf =0.25 (CHCl3/MeOH/AcOH 94:5:1);
[a]D =+55.5 (c=0.31, CHCl3, 258C); 1H NMR (700 MHz): d = 7.65 (d,
J=12.2 Hz, 1H, H20), 6.32 (d, J=12.2 Hz, 1H, H19), 6.26 (dd, J=14.8,
10.9 Hz, 1H, H13), 6.10 (d, J=15.8 Hz, 1H, H4), 6.05 (t, J=10.9 Hz, 1H,
H14), 5.97 (dd, J=15.8, 8.2 Hz, 1H, H5), 5.91 (s, 1H, H2), 5.72 (dt, J=
14.8, 7.4 Hz, 1H, H12), 5.45 (dt, J=10.9, 7.4 Hz, 1H, H15), 5.40–5.32 (m,
1H, H9), 5.29 (dt, J=15.3, 7.6 Hz, 1H, H8), 4.34 (d, J=16.7 Hz, 1H,
H1’a), 4.29 (dd, J=9.7, 3.8 Hz, 1H, H17), 3.77 (d, J=16.7 Hz, 1H, H1’b),
3.19 (s, 3H, OCH3), 2.36 (ddd, J=13.7, 9.7, 7.4 Hz, 1H, H16a), 2.34–2.27
(m, 1H, H6), 2.29 (ddd, J=13.7, 7.4, 3.8 Hz, 1H, H16b), 2.22–2.16 (m,
1H, H7a), 2.08 (q, J=7.4 Hz, 2H, H11), 2.05–1.98 (m, 2H, H10), 1.94 (s,
3H, H5’), 1.93–1.82 (m, 1H, H7b), 1.87 (s, 3H, H4’), 1.06 ppm (d, J=
6.7 Hz, 3H, H3’); 13C NMR (125 MHz, CDCl3): d = 177.4 (C2’), 174.6
(C22), 169.1 (C1), 149.6 (C3), 149.1 (C21), 144.4 (C5), 135.7 (C12), 134.4
(C20), 131.7 (C4), 131.1 (C14), 130.5 (C9), 127.7 (C8), 125.2 (C18), 125.0,
124.7 (2C, C13 and C15), 123.6 (C19), 118.7 (C2), 80.6 (C17), 57.0
(OCH3), 40.4 (C7), 38.4 (C6), 33.1 (C11), 32.9, 32.8 (2C, C1’ and C10),
32.6 (C16), 20.5 (C3’), 18.7 (C4’), 11.7 ppm (C5’); IR (film): nmax = 2926,
1683, 1631, 1614, 1420, 1268, 1203, 1094, 967, 947, 875, 737 cmꢀ1; HRMS
(ESI+): m/z: calcd for C28H38O7Na: 509.2516; found: 509.2515 [M+Na]+.
1714, 1637, 1615, 1435, 1378, 1325, 1262, 1193, 1157, 1026, 968 cmꢀ1
;
HRMS (ESI+): m/z: calcd for C18H26O4I: 433.0876; found: 433.0881
[M+H]+.
Trimethyl iso- and bongkrekate triesters IBAMe3 3 and BAMe3 70: To a
solution of vinyl iodide 4 (24 mg, 56 mmol, 1 equiv) in Et3N (1.7 mL)
were added successively CuI (2 mg, 11 mmol, 0.2 equiv) and [PdACTHUNTRGNE(UNG PPh3)4]
(4 mg, 6 mmol, 0.1 equiv) under argon at RT. Then a solution of alkyne 5
(16 mg, 72 mmol, 1.3 equiv) in Et3N was slowly added and the resulting
orange suspension was stirred for 4 h. Solvent was removed under
vacuum and the resulting oil was purified by a flash chromatography on
silica gel (toluene/acetone 95:5). 32 mg mixture of the two expected iso-
mers 67/68 and the Glaser dimer 69 were isolated. To a microwave sealed
tube containing this mixture, methanol (0.9 mL), water (0.9 mL) and Zn-
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
The slurry was filter through a pad of Celite and rinsed with Et2O. Vola-
tiles were removed under vacuum and the crude was purified on a prepa-
rative TLC (toluene/acetone 96:4) to give pure IBAMe3 3 (17.5 mg,
59%) and pure BAMe3 70 (4 mg, 14%) for a total yield of 73% over two
steps. Data for IBAMe3 3: Pale yellow oil; Rf =0.45 (PE/Et2O 2:1);
1
[a]D =+110.0 (c=0.15, CHCl3, 258C); H NMR (700 MHz): d = 7.51 (d,
J=12.0 Hz, 1H, H20), 6.36 (d, J=12.0 Hz, 1H, H19), 6.26 (dd, J=14.3,
11.3 Hz, 1H, H13), 6.09 (d, J=15.9 Hz, 1H, H4), 6.01–5.96 (m, 1H,
H14), 5.99 (dd, J=15.9, 7.7 Hz, 1H, H5), 5.89 (s, 1H, H2), 5.67 (dt, J=
Bongkrekic acid BA 2: To a 4:1 mixture of IBAMe3 3 and BAMe3 70
(25 mg, 47 mmol, 1 equiv) in DME (19 mL) was added a 1m solution of
Chem. Eur. J. 2011, 17, 329 – 343
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
341

A. FranÅais, S. V. Ley et al.
LiOH (4.7 mL, 4.7 mmol, 100 equiv) in H2O. The solution was stirred at
RT for 15 h and neutralised with 5 mL of an aqueous 1n HCl. The aque-
ous layer is extracted with Et2O (3ꢆ15 mL). The combined organic ex-
tracts were dried over MgSO4, filtered and concentrated under vacuum.
Purification of the resulting crude yellow oil on preparative TLC
(CH2Cl2/MeOH/AcOH: 97:3:0.5) furnished pure IBA 1 (8 mg, 31%) and
the pure desired BA 2 (3.9 mg, 23%) as two white oily solids. Data for
BA 2: White oily solid, Rf =0.35 (CHCl3/MeOH/AcOH 94:5:1); [a]D =
ꢀ47.2 (c=0.175, CHCl3, 258C); 1H NMR (700 MHz): d = 7.63 (d, J=
12.2 Hz, 1H, H20), 7.43 (d, J=16.0 Hz, 1H, H4), 6.34 (d, J=12.2 Hz,
1H, H19), 6.28 (dd, J=14.9, 11.1 Hz, 1H, H13), 6.05 (t, J=11.1 Hz, 1H,
H14), 6.00 (dd, J=16.0, 8.2 Hz, 1H, H5), 5.74 (dt, J=14.9, 6.6 Hz, 1H,
H12), 5.72 (s, 1H, H2), 5.41 (dt, J=15.3, 6.3 Hz, 1H, H9), 5.41–5.36 (m,
1H, H15), 5.34 (dt, J=15.3, 7.1 Hz, 1H, H8), 4.33 (dd, J=8.8, 5.0 Hz,
1H, H17), 3.46 (d, J=16.0 Hz, 1H, H1’a), 3.32 (d, J=16.0 Hz, 1H, H1’b),
3.21 (s, 3H, OCH3), 2.45 (ddd, J=13.7, 8.8, 7.9 Hz, 1H, H16a), 2.39–2.32
(m, 1H, H6), 2.27 (ddd, J=13.7, 9.0, 5.0 Hz, 1H, H16b), 2.21–2.15 (m,
1H, H7a), 2.12 (dt, J=9.6, 6.6 Hz, 2H, H11), 2.03 (dt, J=9.6, 6.3 Hz, 2H,
H10), 1.94 (s, 3H, H5’), 1.92–1.85 (m, 1H, H7b), 1.87 (s, 3H, H4’),
b) N. Zamzami, P. Marchetti, M. Castedo, T. Hirsch, S. A. Susin, B.
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1.07 ppm (d, J=6.7 Hz, 3H, H3’); 13C NMR (125 MHz, CDCl3): d
=
176.5 (C2’), 174.7 (C22), 169.7 (C1), 148.8 (C3), 148.6 (C21), 145.4 (C5),
135.9 (C12), 134.5 (C20), 131.5 (C9), 131.3 (C14), 128.1 (C8), 125.3 (C4),
125.1 (C18), 124.6 (C13), 124.3 (C15), 124.1 (C19), 118.0 (C2), 80.0
(C17), 56.8 (OCH3), 40.7 (C1’), 40.0 (C7), 38.8 (C6), 33.2 (C11), 32.5
(C10), 32.2 (C16), 20.5 (C3’), 18.6 (C4’), 11.7 ppm (C5’); HRMS (ESI+):
m/z: calcd for C28H39O7: 487.2696; found: 487.2695 [M+H]+.
Re-esterification procedure: To IBA 1 or BA 2 (5 mg, 10 mmol, 1 equiv)
in CH2Cl2 (200 mL) and MeOH (50 mmol) was added a 2m solution of
TMSCHN2 (25 mL, 50 mmol, 50 equiv) in Et2O. The solution was stirred
at RT for 40 min and volatiles were removed under vacuum. Purification
of the resulting crude yellow oil on preparative TLC (PE/Et2O 2:1) fur-
nished the pure desired IBAMe3 27 (5.4 mg, quant) or the pure desired
BAMe3 28 (5.4 mg, quant) as a colourless oil. Both products afforded
identical analytical data as the original substrates prior to their saponifi-
cation.
Acknowledgements
The authors are grateful to EPSRC (S.V.L., A.F. and A.L.P.), to le minis-
tꢀre franÅais des affaires ꢁtrangꢀres (A.F.) and to el Ministerio de Ciencia
ˇ
e Innovacion de Espana (G.E.J.). S.V.L. also acknowledges support from
the B.P. Endowment at Cambridge. The authors would like also to thank
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Published online: December 13, 2010
Chem. Eur. J. 2011, 17, 329 – 343
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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