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promotes the reaction by transmetallation of the stannane
donor to an arguably more reactive organocopper species, the
phosphinite scavenges the released tin byproducts and hence
renders this transmetallation irreversible. As both reagents are
hardly basic and the conditions are fluoride free, this method
has been widely used by us and others for the preparation of
[61,64,65]
polyfunctionalized and/or polyunsaturated compounds.
It has also outperformed the venerable Suzuki–Miyaura cou-
[66,67]
pling on more than one occasion.
Despite its good track record, this procedure allowed the ex-
igent Stille coupling of 29 with 49 to be accomplished with
only 56% yield. Efforts to improve on this outcome by varying
the loadings and the ratio of the individual components were
to no avail. This optimization exercise was rendered difficult by
the fact that the crude product always seemed fairly clean by
TLC analysis and NMR spectroscopy. In any case, the result
itself was well reproducible in over 10 runs on different scales,
thus furnishing close to 1 gram of diyne 50 in readiness for
ring closure.
Scheme 6. a) Propyne, nBuLi, BF
10 mol%), tBuOOH (10 mol%), O
iPr NEt, DMSO, CH Cl , 08C, 86–89%; d) (i) 48, tBuLi, Et
3
·Et
2
O, THF, ꢀ788C, 87%; b) (nmp)
2
Co
·pyridine,
O, ꢀ788C, then ZnBr
(
2
(1 atm), iPrOH, 558C, 84%; c) SO
3
2
2
2
2
2
,
Et
Et
2
O, ꢀ358C ! 08C; (ii) (ꢀ)-N-methylephedrine/nBuLi, toluene, 08C; (iii) 46,
O, ꢀ208C, 80–85% (dr=95:5).
2
while the alkyne remained untouched, thus furnishing the
trans-disubstituted tetrahydrofuran 45 as the only detectable
isomer in consistently high yield. With regard to the catalyst,
best results were achieved with the “second generation” nmp
The crucial macrocyclization was achieved on exposure of
[28]
50 to 10/CH Cl2
in toluene at elevated temperature, al-
2
though the yield was somewhat variable (50–73%) depending
on the scale of the reaction. In contrast, the molybdenum alky-
[8e,l]
[27]
ligand for cobalt introduced by Pagenkopf and co-workers.
lidyne 9
was less effective because it gave substantial
With ample 45 in hand, the fragment synthesis was com-
amounts of an acyclic dimer as a byproduct. This outcome was
pleted by oxidation to the corresponding aldehyde followed
unexpected because 9 had proven superior to 10/CH Cl in
2
2
[
56]
by an N-methylephedrine-assisted addition of the dienylzinc
several challenging cases before (see also the model study
[
57]
[21a]
derivative derived from 48. However, this bromide turned
out to be surprisingly unstable and had to be prepared imme-
diately prior to use. Except for this caveat, the route to alcohol
shown above in Scheme 2).
However, this particular catalyst
seems to find its limitations with sterically hindered substrates
that might not be able to bind to the operative molybdenum
alkylidyne unit surrounded by three bulky triphenylsilanolate li-
47 is deemed satisfactory in that it is concise, selective and
[67]
high yielding. Moreover, addition of nucleophiles other than
the zinc reagent derived from 48 allow the side chain to be
modified with ease, which seems to account for much of the
bioactivity of the amphidinolides of this particular series (see
the Introduction section). This aspect is underlined by our ap-
proach to amphidinolide C (1) described below.
gands. To probe this aspect, the TES-group flanking one of
the alkynes in 50 was removed and the resulting slimmer
diyne 52 subjected to ring closure. In line with our expecta-
tions, complex 9 now allowed product 53 to be formed in up
to 70% yield, even though a high temperature was necessary
for the cyclization to proceed. From the organometallic view-
point, this outcome is remarkable: all alkyne metathesis cata-
lysts known to date are high-valent Schrock alkylidynes of
early transition metals and as such inherently nucleophilic at
The assembly phase and completion of the total synthesis
of amphidinolide F
[68]
the a-carbon atom.
The compatibility of 9 with a protic
Although only few steps remained to be accomplished at this
point, all strategic maneuvers were still ahead of us, including
the challenging ring-closing alkyne metathesis (RCAM) and the
largely unprecedented transannular alkyne hydration as the
cornerstones of the synthesis plan.
functional group is therefore noteworthy and has hardly any
precedent in the literature, except for a few cases from our
[67,69,70]
laboratory.
The NMR spectra of both cycloalkynes 51 and 53 feature
massive line broadening over the entire temperature range ac-
cessible to our spectrometer. At ꢀ208C or below, (at least) two
slowly interconverting conformers seem to be populated, but
no details could be deduced. Therefore it remained open
whether or not the C15ꢀOH group and the alkyne moiety
would be appropriately disposed for the projected transannu-
lar hydration reaction.
The critical assembly phase started with a Yamaguchi
esterification of acid 41 and alcohol 47 to give product 49
[
58]
without incident (Scheme 7).
Next, a Stille coupling with
iodide 29 was planned to set the conspicuous exo/endo diene
[
59]
motif.
We were apprehensive that this subunit might be
fragile and isomerization-prone; yet, our group had previously
developed a modified Stille protocol for particularly sensitive
It required a short screening to reduce this key transforma-
tion to practice. Although Hg(OTf) and PdCl had been suc-
[60,61]
compounds that was thought to meet the challenge.
addition to the mandatory palladium catalyst, this method
uses combination of copper thiophene-2-carboxylate
CuTC) and [Ph PO ][NBu ] as additives; while the former
In
2
2
cessful in our early model studies (see above), the application
of these catalysts to 53 resulted in decomposition of the pre-
cious material. In contrast, PtCl in Et O/H O seemed promising
a
[
62]
[63]
(
2
2
4
2
2
2
&
&
Chem. Eur. J. 2014, 20, 1 – 12
6
ꢂ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!