Selective formation of a trisubstituted alkene motif by trans-Hydrostannation/Stille coupling: Application to the total synthesis and late-Stage modification of 5,6-Dihydrocineromycin B

Article abstract of DOI:10.1002/anie.201501608

Countless natural products of polyketide origin have an E-configured 2-methyl-but-2-en-1-ol substructure. An unconventional entry into this important motif was developed as part of a concise total synthesis of 5,6-dihydrocineromycin B. The choice of this particular target was inspired by a recent study, which suggested that the cineromycin family of antibiotics might have overlooked lead qualities, although our biodata do not necessarily support this view. The new approach consists of a sequence of alkyne metathesis followed by a hydroxy-directed trans-hydrostannation and a largely unprecedented methyl-Stille coupling. The excellent yield and remarkable selectivity with which the signature trisubstituted alkene site of the target was procured is noteworthy considering the rather poor outcome of a classical ring-closing metathesis reaction. Moreover, the unorthodox ruthenium-catalyzed trans-hydrostannation is shown to be a versatile handle for diversity-oriented synthesis. Directed although indirect: The antibiotic dihydrocineromyin B is one of countless natural products featuring an E-configured 2-methylbut-2-en-1-ol substructure (see picture, RCAM=ring-closing alkyne metathesis). The key step in the synthesis was a ruthenium-catalyzed hydroxy-directed trans-hydrostannation of an alkyne. The method is efficient, broadly applicable, and suited to late-stage diversification.

Full text of DOI:10.1002/anie.201501608

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201501608
German Edition: DOI: 10.1002/ange.201501608
Alkyne Metathesis
Selective Formation of a Trisubstituted Alkene Motif by trans-
Hydrostannation/Stille Coupling: Application to the Total Synthesis
and Late-Stage Modification of 5,6-Dihydrocineromycin B**
Stephan M. Rummelt, Johannes Preindl, Heiko Sommer, and Alois Fꢀrstner*
Abstract: Countless natural products of polyketide origin have
an E-configured 2-methyl-but-2-en-1-ol substructure. An
unconventional entry into this important motif was developed
as part of a concise total synthesis of 5,6-dihydrocineromy-
cin B. The choice of this particular target was inspired by
a recent study, which suggested that the cineromycin family of
antibiotics might have overlooked lead qualities, although our
biodata do not necessarily support this view. The new approach
consists of a sequence of alkyne metathesis followed by
a hydroxy-directed trans-hydrostannation and a largely unpre-
cedented methyl-Stille coupling. The excellent yield and
remarkable selectivity with which the signature trisubstituted
alkene site of the target was procured is noteworthy considering
the rather poor outcome of a classical ring-closing metathesis
Scheme 1. Structures of albocycline (1), cineromycin B (2), and 5,6-
dihydrocinermycin B (3), together with a retrosynthetic disconnection
of the latter. DTS=diverted total synthesis.
reaction. Moreover, the unorthodox ruthenium-catalyzed
trans-hydrostannation is shown to be a versatile handle for
diversity-oriented synthesis.
[
1,2]
[3]
A
lbocycline (ingramycin, 1)
and cineromycin B (2) are
occurring but rare sister compound 5,6-dihydrocineromycin B
[9]
the parent compounds of a class of antibiotics which consist of
bare 14-membered macrolactone rings devoid of any
appended sugar residues (Scheme 1). Although the biolog-
ical spectrum of these macrolides was judged (too) narrow,
a recent report calls for a re-evaluation. Specifically, 1 was
reported to inhibit the growth of methicillin-resistant Staph-
yllococcus aureus (MRSA) with a potency similar to that of
(3) was deemed a sensible starting point, as it lacks the
doubly allylic environment about the C7-OR substituent and
is, therefore, expected to be chemically more robust. Like the
[
4]
[
10,11]
parent macrolides themselves,
targeted by total synthesis in the past, but no relevant biodata
were disclosed.
3 had already been
[
5]
[
12–14]
Therefore, a fresh approach was planned
with the intention to secure a good material supply, resolve
some previously unmet selectivity issues, and enable late-
stage modifications by diverted total synthesis (DTS) for
[
6–8]
vancomycin, the drug of last resort.
This finding insinuates
that the cineromycins might be overlooked lead structures in
the quest for anti-infective agents against resistant bacterial
strains of utmost clinically significance.
More detailed investigations, including a broader screen-
ing campaign, will be necessary to validate this aspect. Since
[
15]
biological testing.
These objectives were met by an unconventional
8
,9
approach to the trisubstituted D -alkene subunit of 3
(Scheme 1). Ring-closing olefin metathesis (RCM) had
previously been used to forge the macrocycle at this particular
site, but was found inefficient (40%) despite the high loading
of the second-generation Grubbs catalyst and the forcing
1
and 2 are fairly labile, an important issue to be addressed
concerns the stability of the scaffold. To this end, the naturally
[
14,16,17]
[
+]
[+]
[+]
conditions (25 mol%, 48 h, refluxing CH Cl ).
We
metathesis
[
*] M. Sc. S. M. Rummelt, M. Sc. J. Preindl, M. Sc. H. Sommer,
Prof. A. Fꢀrstner
Max-Planck-Institut fꢀr Kohlenforschung
2
2
conjectured
that
ring-closing
alkyne
[
18,19]
(RCAM)
might provide a more favorable and predict-
4
5470 Mꢀlheim/Ruhr (Germany)
able solution, as long as the resulting cycloalkyne B could be
elaborated into a methyl-branched E-alkene. The ruthenium-
catalyzed trans-hydrostannation recently described by our
E-mail: fuerstner@kofo.mpg.de
+
[
] These authors contributed equally to this work.
[
20,21]
[
**] Generous financial support by the MPG is gratefully acknowledged.
We thank J. Rust and Prof. C. W. Lehmann for solving the X-ray
structure, the Analytical Departments of our Institute for excellent
support, Dr. J. Herrmann and Prof. R. Mꢀller, Helmholtz Institute for
Pharmaceutical Research Saarland, Saarbrꢀcken, for the biological
data, and Umicore AG & Ko KG, Hanau, for a generous gift of noble
metal salts.
group was thought to pave the way.
This reaction is
distinguished by an unorthodox stereochemical course and
shows excellent levels of regioselectivity when applied to
unprotected propargyl alcohol derivatives. By virtue of
a massive directing effect exerted by the protic site, the
R Sn group is delivered to the proximal C atom of the alkyne
3
unit with high fidelity. This pattern should bring an a-
alkenylstannane of type A into reach, which might then be
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201501608.
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
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1
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.
Angewandte
Communications
elaborated to the targeted natural product 3 by Stille
[22]
coupling. At the same time, the interim trialkyltin residue
provides a handle for late-stage modifications other than
methylation (A!E); in the present context, it might allow
the first structure/activity relationships to be probed with
little extra synthetic effort. In any case, the proposed strategy
is expected to be of more general interest, since E-configured
2
-methyl-but-2-en-1-ol motifs feature prominently in count-
less natural products of polyketide origin (Scheme 2).
Scheme 3. Reagents and conditions (the scales refer to the single
largest batches): a) O , CH Cl , ꢀ788C, then Me S, RT; b) NaOCl,
3
2
2
2
H O , NaH PO , tBuOH/H O (2:1), 80% (over both steps, 15 g
2
2
2
4
2
scale); c) I , MeCN, 73% (3.2 g scale); d) Bu SnH, benzene, reflux,
2
3
8
8% (3.7 g scale); e) CCl , PPh , THF, reflux; f) MeLi, [Cu(acac) ]
4
3
2
(
10 mol%), Et O, 08C, 74% (over both steps, 1.1 g scale); g) TESCl,
2
imidazole, DMAP (5 mol%), CH Cl , 99%, (5.9 g scale); h) O , CH Cl ,
2
2
3
2
2
pyridine, ꢀ788C, then Me S, RT, 77%, (5.8 g scale); i) propyne, Zn-
2
(
OTf) , (ꢀ)-N-methylephedrine, Et N, toluene, RT, then 10, 94% (3.9 g
2
3
scale, d.r.>20:1); j) TBSCl, imidazole, CH Cl , quant. (4.2 g scale),
2
2
k) O , CH Cl , ꢀ788C, then Me S, RT, 67% (5.6 g scale);
3
2
2
2
l) (EtO) P(O)CH COOH, TMEDA, DBU, Zn(OTf) , THF, 08C!RT,
2
2
2
8
0% (3.3 g scale); m) 8, DCC, DMAP, CH Cl , 08C, 84% (2 g scale).
2 2
acac=acetylacetonato, DBU=1,8-diazabicyclo[5.4.0]undec-7-ene,
DCC=dicyclohexylcarbodiimide, DMAP=4-dimethylaminopyridine,
TBS=tert-butyldimethylsilyl, TES=triethylsilyl, Tf=trifluoromethane-
sulfonyl, TMEDA=N,N,N’,N’-tetramethylethylenediamine.
[
12,13]
Scheme 2. Small selection of structurally diverse natural products
comprising one or more E-configured 2-methyl-but-2-en-1-ol subunits
setting the critical stereocenter at C7;
the excellent
outcome of the asymmetric propynylation (d.r. > 20:1) there-
fore constitutes a notable distinction. The resulting product 11
was readily elaborated into the acid segment 12; of the
necessary operations, the zinc-promoted variant of the
Horner–Wadsworth—Emmons olefination is probably most
noteworthy as it delivers an unprotected carboxylic acid right
away. Esterification with alcohol 8 then furnished diyne 13
in readiness for ring closure.
This critical step was accomplished by the molybdenum
alkylidyne ate complex 21 endowed with triphenylsilanolate
ligands which is arguably one of the most active and selective
(
or immediate derivatives thereof).
(
S)-Citronellene (4) served as the entry point for the
preparation of the necessary alcohol building block
Scheme 3). Selective ozonolysis of the more highly substi-
[
30]
(
tuted double bond followed by oxidation of the resulting
aldehyde furnished multigram amounts of acid 5, which was
iodo-lactonized with iodine in MeCN at ambient temper-
[
23,24]
ature.
Reduction of the CꢀI bond preceded the con-
[
31,32]
version of the resulting lactone 6 into the required non-
alkyne metathesis catalysts known to date (Scheme 4).
terminal alkyne according to a procedure recently described
The reaction proceeded smoothly at ambient temperature to
afford the corresponding 14-membered cycloalkyne 14 in
excellent yield; this outcome is fully appreciated when
compared with the difficulties encountered in closing the
ring by RCM at the same site (see above). Next, the silyl
protecting groups were cleaved with HF·pyridine and the
[
25,26]
by our group.
To this end, 6 was treated with CCl /PPh3
4
and the resulting dichloro-olefin 7 treated with MeLi in the
presence of a catalytic amount of [Cu(acac) ] to cause
2
[
14]
a reductive alkylation with direct formation of the methyl-
capped acetylene derivative 8.
A practical synthesis of the acid segment started from
inexpensive (R)-linalool (9; Scheme 3). Protection with a TES
group followed by a selective ozonolysis gave aldehyde 10,
resulting diol 15 treated with Bu SnH in the presence of
3
[
33]
[Cp*RuCl ] (5 mol%) to give the expected a-alkenylstan-
2
n
[27]
nane 16, basically as a single isomer (a/b > 20:1, E/Z > 20:1).
It is also important to note that the transannular alkene,
which competes with the alkyne for coordination to the p-
affine ruthenium catalyst, did not interfere with the directed
trans-hydrostannation.
which was subjected to a Carreira reaction to set the missing
stereocenter while installing the alkyne handle for the
[28]
envisaged macrocyclization. Although the use of propyne
[
29]
has little precedent, the addition worked well on a multi-
gram scale. In this context, we recall that two of the three
reported syntheses of 3 failed to achieve any selectivity while
The gratifying outcome of this operationally simple but
exquisitely selective transformation is confidently ascribed to
2
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Angewandte
Chemie
[
40–42]
Stille coupling reactions to the current needs.
cally, the rapid sequential addition of CuTC (1.05 equiv)
and MeI (1.5 equiv) to a stirred solution of 16, [Pd(PPh ) ]
Specifi-
[
43]
3
4
[44]
(
5 mol%), and [Ph PO ][NBu ] (1.1 equiv)
in DMF at
2
2
4
ambient temperature gave 5,6-dihydrocineromycin (3) in
excellent yield. The present synthesis is shorter and consid-
erably more selective than any the previous ones; the data of
synthetic 3 thus formed are in accord with the literature
[9,12,13,45]
data.
The order of addition as well as the stoichiometry of the
reactants is important in the methyl-Stille reaction to ensure
full conversion but avoid competing protodestannation.
While this bias mandated careful optimization, it also
provided an unexpected opportunity. Thus, treatment of 16
with stoichiometric amounts of CuTC and [Ph PO ][NBu ] in
2
2
4
DMF followed by an aqueous work up furnished the
corresponding des-methyl derivative 17 as a first non-natural
analogue for screening purposes. This mild and essentially
neutral procedure compares favorably to other methods for
protodestannation, which usually employ a strong Brønsted
acid or a harsh nucleophilic additive (MeONa, CsF) and are
Scheme 4. Reagents and conditions (the scales refer to the single
largest batches): a) 14 (10 mol%), MS 5 ꢁ, toluene, 92% (800 mg
scale), b) HF·pyridine, THF, pyridine, 84% (545 mg scale); c) Bu SnH,
3
[
Cp*RuCl ] (5 mol%), CH Cl , 83% (336 mg scale); d) [Pd(PPh ) ]
2
n
2
2
3
4
(
5 mol%), [Ph PO ][NBu ], CuTC, MeI, DMF, 92% (286 mg scale), see
2 2 4
therefore limited in terms of their functional-group toler-
text; e) CuTC, [Ph PO ][NBu ], DMF, 78% (15 mg scale); f) CuCl ,
[46]
2
2
4
2
ance.
The Z-configured counterpart 18 was also within
THF, 77% (42 mg scale); g) H (1 atm), Pd/BaSO , THF, pyridine,
2
4
reach by a routine Lindlar hydrogenation of the alkyne
precursor 15. As a further testimony of the flexibility of the
chosen approach, the tin residue was exchanged for a chloride
7
4% (20 mg scale); h) TBAF, THF, 97% (130 mg scale). Cp*=penta-
methylcyclopentadienyl, CuTC=copper thiophene-2-carboxylate,
TBAF=tetra-n-butylammonium fluoride.
[
47]
substituent upon treatment of 16 with CuCl2; NOE contacts
confirm that this transformation proceeded with retention of
the double-bond configuration to give 19 as the only product
in good chemical yield. Finally, a more profound structural
modification was procured on treatment of 14 with TBAF; by
virtue of the basic character of this reagent, the incipient diol
15 engages in a transannular oxa-Michael reaction to give the
bicyclic product 20. Its constitution was confirmed by single-
the cooperativity between the propargylic -OH group in the
[34]
substrate and the {Ru-Cl} unit of the catalyst. Structural as
well as spectroscopic data suggest that the chloride ligand
engages in hydrogen bonding, which aligns and locks the
alkyne within the coordination sphere of the catalyst. At the
same time, the incoming stannane
[48]
reagent is predisposed in a matching
crystal X-ray diffraction.
Figure 1 shows this unusual
orientation by an additional interligand
interaction between the {Ru-Cl} group
and the tin center; the resulting favor-
able array of type F is thought to warrant
the excellent regioselectivity of the ensu-
[
34]
ing trans-addition.
Although the conversion of 16 into 3 by a Stille reaction
with MeI (or an equivalent thereof) seemed straightforward,
[
35,36]
we were surprised to find hardly any precedent.
Instead,
indirect solutions prevail in the literature, in which an
alkenylstannane is first converted into the corresponding
iodide, which is then treated with a stoichiometric amount of
[
37]
Me CuLi
or cross-coupled with an appropriate methyl
2
[
38]
donor. Alternatively, transmetalation strategies were exer-
cised that rely on the initial transformation of the alkenyltin
species into a more reactive organolithium or organocopper
[
39]
Figure 1. Structure of compound 20 in the solid state; cineromycin
numbering scheme.
reagent which is then trapped with MeX. In the present
case, however, an organolithium intermediate is excluded by
the presence of the lactone group in 16, whereas a Sn!Cu
exchange mandates an excess of a cuprate reagent that might
endanger the Michael acceptor site of this elaborate substrate.
Gratifyingly though, such maneuvering was found to be
unnecessary: after some optimization, we were able to adapt
a procedure previously described by our group for demanding
scaffold incorporating a 1,5-trans-disubstituted pyrane ring,
which forces the C8ꢀC9 triple bond to bend away from
linearity (C7-C8-C9 167.48).
These analogues comprise deep-seated structural point
mutations, none of which could be instigated by derivatization
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
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.
Angewandte
Communications
[
15]
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To our dismay, however,
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different bacteria (including S. aureus) and one fungus.
These data suggest that the chemically vulnerable doubly
allylic alcohol substructure in the top region of the purport-
[
[49]
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5]
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doubt on the potential lead qualities of this macrolide, further
analogues need to be tested for a more informed conclusion.
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study outlines an effective way of grafting stereodefined
trisubstituted olefins (and related motifs) flanked by a hy-
droxy group, a structural pattern that is present in numerous
natural products. The chosen approach is based on the regio-
and stereoselective functionalization of an internal alkyne,
comprises only transformations of proven functional-group
tolerance, and therefore qualifies for late-stage applications;
it also represents the first implementation of a directed trans-
hydrostannation into target-oriented synthesis. At the same
time, the scope of the venerable Stille–Migita coupling was
expanded to encompass MeI as an electrophilic partner.
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shortly.
[
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2
[
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-
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Keywords: alkyne metathesis · cross-coupling ·
hydrostannation · natural products · ruthenium
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[
Received: February 18, 2015
Revised: March 10, 2015
Published online: && &&, &&&&
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Alkyne Metathesis
Directed although indirect: The antibiotic
dihydrocineromyin B is one of countless
natural products featuring an E-config-
ured 2-methyl-but-2-en-1-ol substructure
S. M. Rummelt, J. Preindl, H. Sommer,
A. Fꢁrstner*
&&&& — &&&&
(
see picture, RCAM=ring-closing alkyne
Selective Formation of a Trisubstituted
Alkene Motif by trans-Hydrostannation/
Stille Coupling: Application to the Total
Synthesis and Late-Stage Modification of
metathesis). The key step in the synthesis
was a ruthenium-catalyzed hydroxy-
directed trans-hydrostannation of an
alkyne. The method is efficient, broadly
applicable, and suited to late-stage
diversification.
5
,6-Dihydrocineromycin B
6
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These are not the final page numbers!