Total Synthesis of Putative Chagosensine

Article abstract of DOI:10.1002/anie.201808937

The marine macrolide chagosensine is the only natural product known to date that embodies a Z,Z-configured chloro-1,3-diene unit. This distinguishing substructure was prepared by a sequence of palladium-catalyzed 1,2-distannation of an alkyne precursor, regioselective Stille cross-coupling at the terminus of the resulting bisstannyl alkene with an elaborated alkenyl iodide, followed by chloro-destannation of the remaining internal site. The preparation of the required substrates centered on cobalt-catalyzed oxidative cyclization reactions of hydroxylated olefin precursors, which allowed the 2,5-trans-disubstituted tetrahydrofuran rings, embedded into each building block, to be formed with excellent selectivity. The highly strained macrolactone could ultimately be closed under forcing Yamaguchi conditions. Comparison of the spectral data of the synthetic sample with those of authentic chagosensine methyl ester confirmed that the structure of this intriguing compound has been mis-assigned by the isolation team.

Full text of DOI:10.1002/anie.201808937

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Accepted Article
Title: Total Synthesis of Putative Chagosensine
Authors: Alois Fürstner, Marc Heinrich, John J. Murphy, Marina K. Ilg,
Aurelien Letort, Jakub Flasz, and Petra Philipps
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201808937
Angew. Chem. 10.1002/ange.201808937
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Angewandte Chemie International Edition
10.1002/anie.201808937
Total Synthesis of Putative Chagosensine
[
+]
[+]
[+]
Marc Heinrich, John J. Murphy, Marina K. Ilg, Aurélien Letort, Jakub Flasz, Petra Philipps, and
*
Alois Fürstner
th
Dedicated to Prof. Manfred T. Reetz on the occasion of his 75 birthday
Abstract: The marine macrolide chagosensine is the only natural product known to date that
embodies a Z,Z-configured chloro-1,3-diene unit. This distinguishing substructure was prepared by a
sequence of palladium catalyzed 1,2-distannation of an alkyne precursor, regioselective Stille cross
coupling at the terminus of the resulting bisstannyl alkene with an elaborated alkenyl iodide, followed
by chloro-destannation of the remaining internal site. The preparation of the required substrates
centered on cobalt catalyzed oxidative cyclization reactions of hydroxylated olefin precursors, which
allowed the 2,5-trans-disubstituted tetrahydrofuran rings embedded into each building block to be
formed with excellent selectivity. The highly strained macrolactone could ultimately be closed under
forcing Yamaguchi conditions. Comparison of the spectral data of the synthetic sample with those of
authentic chagosensine methyl ester proved that the structure of this intriguing compound has been
mis-assigned by the isolation team.
Marine sponges often host highly diverse microbial communities. These symbiotic life forms are
arguably amongst the most prolific sources of bioactive secondary metabolites with, in part,
1
unprecedented molecular architectures. A striking example is chagosensine, a highly adorned
macrolide isolated from specimens of the calcareous sponge Leucetta chagosensis collected off the
*
M. Heinrich, Dr. J. J. Murphy, Dr. M. K. Ilg, Dr. A. Letort, Dr. J. Flasz, P. Philipps, Prof. A. Fürstner
Max-Planck-Institut für Kohlenforschung
4
5470 Mülheim/Ruhr (Germany)
Email: fuerstner@kofo.mpg.de
[
+]
These authors contributed equally to this work
Supporting Information and the ORCID Identification Number(s) of the author(s) of this article can be found
under ##########
1
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2
Eilat coastline in the Gulf of Aqaba. The proposed structure 1, which was elucidated by
spectroscopic means and degradation experiments, is noteworthy for the remarkably dense array of
1
1 stereogenic centers decorating the carbon perimeter; moreover, two 2,5-trans-disubstituted
tetrahydrofuran rings confer considerable strain onto the encircling 16-membered macrocyclic core.
The arguably most salient feature, however, is the (Z,Z)-configured chloro-1,3-diene motif, which  to
the best of our knowledge  is unprecedented in nature.
The closest relatives of chagosensine are the members of the haterumalide and biselide families
3,4
which are derived from organisms as different as sponges, ascidians, or even terrestrial bacteria;
this variety of source organisms highlights the uncertainty as to the actual producer(s) of these
secondary metabolites. In structural terms, compounds 2, 3 and relatives are distinguished by a
skipped rather than conjugated chlorodiene unit embedded into a molecular framework that is
overall less complex than that of 1. The comparison with chagosensine would be incomplete,
however, without noticing some stereochemical subtleties: the “northern” tetrahydrofuran rings of 1
5,6
and 2/3 are ostensibly enantiomeric, whereas the adjacent hydroxylated chiral center on the side
chain seems to have the same absolute configuration throughout. Yet, said chagosensine sector finds
7
stereochemical correspondence in isolaulimalide (4), while the “southern” trans-tetrahydrofuran
8,9
ring flanked by an anti-diol unit is also prominently featured in amphidinolide C (5) and F.
Members of the haterumalide estate exhibit considerable cytotoxicity against various human cancer
cell lines, while esterification of the carboxylate terminus or oxidation at C20 (biselide series) reduces
2
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3
their acute toxicity for brine shrimp. This encouraging profile attests to the notion that chlorine-
10
containing small molecules often exhibit favorable biological properties and is certainly one of the
reasons for the numerous studies on compounds of this series, culminating in several total
11,12,13,14,15,16,17
syntheses.
In striking contrast, chagosensine remained unappreciated, perhaps because
2
no biodata were reported by the isolation team. This largely disproportional level of attention seems
unjustified in view of the truly unique constitution of 1 and the arguably much higher synthetic
challenge posed by this particular target. We now present an interim report on our work in this field,
which paved a way to putative chagosensine yet showed that the originally assigned structure
mandates major revision; to this end, a conceptually new approach to chlorodienes had to be
developed which is based on the preparation and serial manipulation of bis(metalated) building
blocks.
Scheme 1. Strategic considerations; M = metal or metalloid; X = halogen
Various scenarios for an efficient and stereoselective formation of the distinguishing Z,Z-chlorodiene
18,19
entity of 1 were considered at the outset of the project.
The ultimately successful pathway was
predicated on the strategies summarized in Scheme 1, all of which converge to the same substrate F.
Of these routes, chloroboration seemed ideal as it would afford a fragment of type C amenable to
cross coupling with an appropriate reaction partner of type H. This tantalizing option, however, could
not be reduced to practice even with simple model compounds because the necessary propargylic
20,21

OR substituent did not survive under the chosen conditions.
Likewise, attempted cis-
22
carbochlorination or dichlorination to give fragments of type B were to no avail. Promising hits,
3
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10.1002/anie.201808937
23,24
however, were obtained with a sequential strategy commencing with metal catalyzed diboration
25,26,27
28
or distannation
of the substrate. It seemed reasonable to expect that the terminal and hence
sterically more accessible CM bond in E could be selectively engaged in cross coupling, whereas the
remaining internal CM unit in the resulting product D should lend itself to subsequent chloro-
demetalation with retention of configuration. In fact, the site-selective Suzuki coupling of 1,2-
29
bisborylalkenes had previously been accomplished with a set of simple coupling partners. In line
with this literature precedent, we managed to obtain the model compound 9 in appreciable yield
30
(
Scheme 2). However, chlorodeboration under standard conditions proved incompatible with the
31
silyl ether protecting group but required assistance by stoichiometric [Ph PAuCl]. Encouraged by
3
this result, we went on to engage the much more elaborate building blocks 14 and 15 in the same
32
maneuver. Unfortunately, the site-selective cross coupling was accompanied by substantial proto-
deboration; truly problematic, however, was the chlorodeboration of 16a (X = BPin) which furnished
rather complex mixtures even in the presence of the gold promoter.
Scheme 2. Model studies: a) B (pin) , Pt(PPh ) (3 mol%), DMF, 80°C, 75%; b) 8, [(dppf)PdCl ] (3
2
2
3 4
2
mol%), K PO , aq. THF, reflux, 69%; c) (i) Ph PAuCl, Cs CO , iPrOH, 3Å MS, 50°C; (ii) NCS, RT, 75%; d)
3
4
3
2
3
CuCl , NaHCO , EtOH/H O, 60°C, 75%; e) (Bu Sn) , [(tBuNC) PdCl ] (10 mol%), THF, 85%; f) 8,
2
3
2
3
2
2
2
Pd(PPh ) (20 mol%), CuTC, [Ph PO ][NBu ], DMF, 59%; g) CuCl , 2,6-lutidine, THF, 74%; h) Pd (dba)
3
4
2
2
4
2
2
3
4
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(
10 mol%), Ph As (40 mol%), Ag O, THF/H O, 32% (16a) + 52% (16b); i) Ph PAuCl, Cs CO , MeOH, 3Å
3
2
2
3
2
3
MS, 50°C, then NCS, RT; dba = dibenzylideneacetone; dppf = 1,1'-bis(diphenylphosphino)ferrocene;
MS = molecular sieves; NCS = N-chlorosuccinimide; pin = pinacolato; TC = thiophene-2-carboxylate
Therefore we turned our attention to serial distannation/Stille coupling/chloro-destannation since
the inherently higher reactivity of the CSn bond almost certainly facilitates the last step of the
33
sequence; in fact, previous work from our group provides encouraging precedent for the chloro-
34,35
25-
destannation of elaborate compounds.
Since alkyne 1,2-distannation is also known to be facile,
27
the projected gambit seemed promising too. Strikingly, however, site-selective Stille reactions of
36
1
,2-bistannylalkenes are essentially unknown: the only documented examples employed simple
hypervalent aryliodonium salts as the electrophilic partner, whereas attempted use of iodobenzene
37,38
furnished complex mixtures.
This caveat notwithstanding, we were able to attain proof-of-
concept through coupling of 11 with 8 and subsequent chloro-destannation of product 12 thus
formed; some competing side reactions in the cross coupling step, however, forecasted the need for
careful optimization of the conditions.
5
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Scheme 3. a) H , Pd/BaSO (5 mol%), quinoline (10 mol%), MeOH, 65%; b) tBuOOH, Ti(OiPr) (5
2
4
4
mol%), (+)-DET (6 mol%), CH Cl , 20°C, 74% (90% ee); c) TBSCl, imidazole, DMAP (5 mol%), CH Cl ,
2
2
2
2
0
=
°C  RT, 96%; d) allylmagnesium chloride, CuI (15 mol%), THF, 25°C, 77% (pure regioisomer, ratio
10:1); e) Co(nmp) (10 mol%), tBuOOH (10 mol%), O (1 atm), iPrOH, 55°C, 79%; f) [SO pyridine],
2
2
3
(
iPr) NEt, DMSO, CH Cl , 25°C; g) (F CCH O) P(=O)CH COOMe, KHMDS, 18-crown-6, THF, 78°C 
2
2
2
3
2
2
2
RT, Z:E = 12:1, 63% (of pure Z-isomer, over two steps); h) K OsO 2(H O) (6 mol%), (DHQD) PYR (3
2
4
2
2
mol%), K CO , K Fe(CN) , MeSO NH , tBuOH/H O (1:1), 0°C, dr = 5:1, 67% (of pure isomer); i) 2,2-
2
3
3
6
2
2
2
dimethoxypropane, pTsOH (5 mol%), 89%; j) LiAlH , THF, 0°C  RT, 95%; k) [SO pyridine], (iPr) NEt,
4
3
2
DMSO, CH Cl , 25°C; l) [Ph PCH I]I, NaHMDS, HMPA, THF, 78°C, Z:E  20:1, 67% (of pure Z-isomer,
2
2
3
2
over two steps); m) HFpyridine, pyridine, THF, quant.; n) TEMPO (30 mol%), BAIB, aq. MeCN, 98%; o)
-(trimethylsilyl)ethanol, EDCI, DMAP (20 mol%), CH Cl , 71% (+ 7% of epimer, see Text); BAIB =
2
2
2
bis(acetoxy)iodobenzene; DET = diethyl tartrate; DMAP = 4-(dimethylamino)pyridine; EDCI = N-ethyl-
N′-(3-dimethylaminopropyl)carbodiimide hydrochloride; HMDS = hexamethyldisilazide; TBS = tert-
butyldimethylsilyl; TEMPO = 2,2,6,6-tetramethylpiperidine 1-oxyl radical; Ts = p-toluenesulfonyl
As this issue was deemed manageable, we ventured into the preparation of the required building
blocks. The southern sector 25 was prepared by adaptation of a literature route directed towards
39
amphidinolide C (Scheme 3). Specifically, Sharpless epoxidation of Z-crotyl alcohol (18) followed by
regioselective opening of the derived epoxide 19 with allylmagnesium chloride in the presence of CuI
as the catalyst worked nicely on scale. In line with our expectation, the oxidative Mukaiyama
40
cyclization of the resulting unsaturated alcohol 20 turned out to be exquisitely selective and high
41
yielding when using Co(nmp) as the catalyst, furnishing multigram quantities of the required 2,5-
2
trans-configured tetrahydrofuran derivative 21. In contrast, the seemingly trivial oxidation of 21 to
42
the corresponding aldehyde proved delicate: Only a modified Parikh-Doering oxidation using
SO pyridine]/DMSO in combination with (iPr) NEt rather than Et N prevented epimerization of the
[
3
2
3
nascent aldehyde from occurring. The crude product was immediately subjected to Still-Gennari
43
olefination, which afforded 22 (Z/E = 12:1). Ligand-controlled Sharpless dihydroxylation of the
44
major isomer closely followed the literature precedent in terms of yield and selectivity. The
resulting diol was converted into acetal 23; this protecting group was chosen not least because the
6
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10.1002/anie.201808937
isolation team had managed to convert a sample of authentic chagosensine methyl ester into the
2
corresponding isopropylidene acetal. The further elaboration of 23 involved routine adjustment of
45
the oxidation state followed by Stork/Zhao olefination, which was highly selective (Z:E  20:1) and
46
productive as long as HMPA was used as additive. Finally, the silyl ether terminus of 24 was
transformed into the corresponding 2-(trimethylsilyl)ethyl ester 25 as surrogate of the acid
47
functionality to be engaged in the projected macrolactonization. This route proved robust and
scalable, furnishing the southern building block 25 in 5.2% overall yield over the 15 steps of the
longest linear sequence.
Scheme 4. a) ethylene glycol, (EtO) CH, camphorsulfonic acid (5 mol%), CH Cl , 98%; b) O , Sudan red,
3
2
2
3
CH Cl , then Me S, 78°C  RT, 97%; c) Pd(OAc) (4 mol%), diethyl allyl phosphate, NaHCO , THF,
2
2
2
2
3
8
6°C, 58%; d) 36, Bu BOTf, Et N, CH Cl , 78°C  10°C, dr = 12:1, 80% (pure isomer); e) MOMCl,
2
3
2
2
TBAI (1 mol%), (iPr) NEt, CH Cl , 0°C, quant.; f) LiBH (OH), Et O, 0°C  RT, 88%; g) [SO pyridine],
2
2
2
3
2
3
(
iPr) NEt, DMSO, CH Cl , 30°C  10°C, quant.; h) MgBr (OEt ), allyltrimethylsilane, CH Cl , 0°C 
2
2
2
2
2
2
2
RT, dr = 14:1, 92% (pure isomer); i) TBSOTf, 2,6-lutidine, CH Cl , 0°C, 88%; j) DDQ, CH Cl /pH 7.4
2
2
2
2
buffer (1:1), 50°C, 70%; k) Co(nmp) (10 mol%), tBuOOH (10 mol%), O (1 atm), iPrOH, 55°C, dr 
2
2
2
0:1, 69% (pure isomer); l) [SO pyridine], (iPr) NEt, DMSO, CH Cl , 30°C  20°C; m)
3
2
2
2
7
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trimethylsilylacetylene, Zn(OTf) , ()-N-methylephedrine, (iPr) NEt, toluene, dr = 11:1, 65% (over two
2
2
steps); n) K CO , MeOH, 85%; o) (Bu Sn) , [(tBuNC) PdCl ] (10 mol%), THF, 93%; DDQ = 2,3-dichloro-
2
3
3
2
2
2
5
,6-dicyano-1,4-benzoquinone; MOM = methoxymethyl; TBAI = tetra-n-butylammonium iodide; Tf =
trifluoromethanesulfonyl
The northern domain of chagosensine was secured starting from (S)-citronellal (26) (Scheme 4).
Acetalization followed by ozonolysis of the double bond furnished 27 and set the stage for a modified
Saegusa oxidation to give enal 28, which worked nicely on scale using Pd(OAc) as catalyst in
2
48
combination with diethyl allyl phosphate as the terminal oxidant. Parenthetically we note that this
sequence is a practical alternative to a literature route that required nine steps for the preparation of
49
the analogous dimethylacetal derivative. An auxiliary-controlled glycolate syn-aldol reaction then
50,51
gave 29 with high selectivity,
which was processed into aldehyde 30 by standard protecting
group- and oxidation state management. Its treatment with allyltrimethylsilane in the presence of
51
MgBr OEt as promotor set the all-syn stereotriad of product 31 (dr  14:1). This favorable
2
2
52
outcome is thought to reflect a 1,2-Cram chelate transition state, in which the directing effect of
the proximal benzyl ether outweighs the influence of the distal –OMOM group. To this end, two
equivalents of the magnesium salt had to be used to preclude internal competition of the
neighboring coordination sites for the Lewis-acid and hence avoid any ambiguity as to which donor
substituent steers the addition process.
Compound 31 was readily advanced into alcohol 32, which was subjected to yet another cobalt
40,41
catalyzed oxidative Mukaiyama cyclization.
Although this substrate comprises of two different
alkene moieties, the formation of the desired tetrahydrofuran derivative 33 was remarkably selective
in regio- as well as stereochemical terms (dr > 20:1, 33: (other isomers) > 12:1). Epimerization-free
oxidation of 33 was again best achieved via the modified Parikh-Doering protocol described above
using (iPr) NEt as the base. The resulting aldehyde, though labile, participated in a diastereoselective
2
53
Carreira alkynylation with trimethylsilylacetylene (dr = 11:1), although this reaction mandated
considerable optimization. The meticulous drying of all reagents and the addition of the aldehyde
54
51
partner in one portion to the mixture was key to success. With good amounts of 34 in hand, the
required building block representing the northern half of chagosensine was well within reach, since
8
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25
desilylation of the alkyne terminus of 34 and the subsequent palladium catalyzed distannation with
formation of 35 both worked exceedingly well. An overall yield of 7.6% over the 15 steps of this
sequence attests to the efficacy of the chosen route.
As expected, the premier implementation of a site-selective Stille coupling of a 1,2-bisstannane
derivative into target-oriented synthesis did indeed require careful optimization (Scheme 5). Best
results were obtained using copper-free procedures, as this additive evidently favors premature
destannation (cf. Scheme 2) and/or coupling at the internal position. Bulky phosphine ligands to the
55,56,57
palladium catalyst proved beneficial too,
most likely because they impart selectivity for CC-
bond formation at the sterically more accessible terminal CSn site of 35. At the same time, the
P(tBu) ligands disfavor competing homocoupling of the alkenyl iodide on steric grounds, which
3
nevertheless remained the most serious side reaction even when 25 was added slowly to the
55,58
mixture.
The use of LiCl as promotor and of [Ph PO ][NBu ] as effective tin scavenger also
2
2
4
59,60
improved the results.
These procedural modifications allowed us to obtain the desired diene
product 37 in well reproducible 50% yield on a > 100 mg scale (single largest batch).
Scheme 5. a) 25 (slow addition), (tBu P) Pd (15 mol%), [Ph PO ][NBu ], LiCl, NMP, 60°C, 50%; b)
3
2
2
2
4
CuCl , 2,6-lutidine, THF, 78%; c) TBAF(H O) , THF, 80%; d) 39, NaHCO , 1,2-dichloroethane, 80°C, 30%
2
2
3
3
(80% brsm); NMP = N-methyl-2-pyrrolidone; TBAF = tetra-n-butylammonium fluoride
9
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In view of the difficulties with chlorodeborylation encountered during the model studies (vide supra),
it was gratifying to find that the chloro-destannation of the densely functionalized derivative 37
proceeded smoothly with CuCl in THF under the conditions previously adapted by our group for
2
34,35
delicate cases;
importantly, the stereochemistry of the double bond was strictly preserved.
Treatment of the resulting Z,Z-chlorodiene with TBAF unveiled seco-acid 38 in readiness for
macrocyclization. Even though we had anticipated that the two 2,5-trans-disubstituted
tetrahydrofuran rings would impose considerable strain onto the emerging macrocycle and hence
render ring closure challenging, we had to learn that 38 did not engage in macrolactonization at all
61
when subjected to many of the standard protocols. Only a modified Mukaiyama lactonization
62,63
promoted by 39 afforded a distinct product in modest yield under forcing conditions;
surprisingly
though, detailed NMR analysis showed that the –OH group at C12 rather than the –OH group on the
THF-ring had reacted. The formation of a 12-membered macrocycle 40 comprising a single 2,5-trans-
disubstituted tetrahydrofuran ring is evidently easier than formation of the strained 16-membered
lactone of 1. This somewhat paradoxical outcome highlights the challenge posed by chagosensine.
Scheme 6. a) CuCl , 2,6-lutidine, THF, 78%; b) MOMCl, TBAI, (iPr) NEt, 1,2-dichloroethane, 50°C, 92%;
2
2
c) TBAF(H O) , THF, 0°C  RT; d) 2,4,6-trichlorobenzoyl chloride, (iPr) NEt, THF, then DMAP,
2
3
2
toluene, reflux, 40% (43) + ca. 6% (epimer) + 13% (lactide); e) Me BBr, CH Cl , 78°C; f) NaClO ,
2
2
2
2
NaH PO , 2-methyl-2-butene, THF/tBuOH/H O (4:4:1), 0°C; g) CH N , CH Cl , 20% (over three steps)
2
4
2
2
2
2
2
Confronted with this impasse, the C12-OH group in 41 was protected as MOM-acetal prior to release
of the seco-acid (Scheme 6). Compound 42 thus formed did indeed allow macrolactone 43 to be
1
0
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closed, although very harsh conditions were necessary. While the modified Mukaiyama protocol
64
furnished only 27%, Yamaguchi lactonization in boiling toluene gave the desired compound in well
reproducible 40% yield after 20 h reaction time; trace amounts of an epimer (presumably at the C2
position) and 13% of the cyclic head-to-tail dimer (lactide) could be separated by flash
chromatography (see the Supporting Information). The spectroscopic analysis of 43 was impeded by
the presence of (at least) two signal sets, indicative of the presence of two distinct conformers, which
interconvert rapidly in solution. This spectral feature was unexpected since the isolation team had
2
not reported any such complication for acetonide derivatives of authentic chagosensine.
The concomitant cleavage of all four acetal units in 43 proceeded under mild conditions with freshly
65,66
prepared Me BBr,
whereas more common reagents led to degradation. At this stage, the only
2
remaining step for the completion of the total synthesis was the oxidation of the aldehyde to the
corresponding carboxylic acid, which should represent chagosensine. While the Pinnick oxidation per
67
se worked well, we found the resulting product to be unexpectedly fragile; several attempts at its
isolation resulted in decomposition. In the hope to impart higher stability, the crude acid 1  which
represents putative chagosensine prepared in 22 steps (longest linear sequence)  was treated with
diazomethane to give methyl ester 40; note that the isolated natural product had been treated
2
analogously during the isolation campaign and the data of the resulting ester are well documented.
Although not overly stable either synthetic 44 was manageable and could be fully characterized.
Unfortunately, its NMR spectra do not nearly match those of authentic chagosensine methyl ester:
the deviations are huge (see the SI), such that there is no doubt that the structure of this enticing
2,68,69
natural product has been mis-assigned by the isolation team.
In view of the stereochemical
variance reported in the literature for closely related macrolides (see above), it is conceivable that
the configuration attributed to the northern tetrahydrofuran ring is incorrect. The fact, however, that
the spectral mismatch is scattered over the entire molecular framework does certainly not allow us
to exclude other and/or additional mis-assignments at this point. Future work intends to narrow the
possible scenarios down, establish the correct structure of chagosensine, make meaningful amounts
of this unique macrolide available for biological profiling, and explore the opportunities provided by
the newly developed methodology for serial formation of functionalized dienes in more detail.
1
1
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Acknowledgements
Generous financial support by the MPG is gratefully acknowledged. We thank Mrs. Samira Speicher
for valuable assistance and the analytical departments of our Institute for the excellent cooperation
during the entire program.
For the Table of Contents
Unique: Chagosensine is the only natural product known to date comprising a Z,Z-configured chloro-
1
,3-diene unit. This distinguishing motif was obtained by serial alkyne 1,2-distannation, regioselective
Stille coupling and chloro-destannation. The recorded spectral data showed, however, that the
stereostructure of this marine macrolide had been mis-assigned by the isolation team.
Keywords: Chloroalkenes  Macrolides  Organotin Compounds  Stille Coupling  Total Synthesis
1
2
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