Enantioselective Rhodium-Catalyzed Dimerization of ω-Allenyl Carboxylic Acids: Straightforward Synthesis of C2-Symmetric Macrodiolides

Article abstract of DOI:10.1002/anie.201803369

Herein, we report on the first enantioselective and atom-efficient catalytic one-step dimerization method to selectively transform ω-allenyl carboxylic acids into C₂-symmetric 14- to 28-membered bismacrolactones (macrodiolides). This convenient asymmetric access serves as an attractive route towards multiple naturally occuring homodimeric macrocyclic scaffolds and demonstrates excellent efficiency to construct the complex, symmetric core structures. By utilizing a rhodium catalyst with a modified chiral cyclopentylidene-diop ligand, the desired diolides were obtained in good to high yields, high diastereoselectivity, and excellent enantioselectivity.

Full text of DOI:10.1002/anie.201803369

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Accepted Article
Title: Enantioselective Rhodium-Catalyzed Dimerization of ω-Allenyl
Carboxylic Acids: Straightforward Synthesis of C2-Symmetric
Macrodiolides
Authors: Bernhard Breit and Philip Steib
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201803369
Angew. Chem. 10.1002/ange.201803369
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http://dx.doi.org/10.1002/ange.201803369

10.1002/anie.201803369
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Enantioselective Rhodium-Catalyzed Dimerization of ω-Allenyl
Carboxylic Acids: Straightforward Synthesis of C2-Symmetric
Macrodiolides
Philip Steib and Bernhard Breit*
Abstract: Herein, we report on the first enantioselective and atom-
efficient, catalytic one-step dimerization methodology to selectively
transform ω-allenyl carboxylic acids into C2-symmetric, 14- to 28-
membered bismacrolactones (macrodiolides). This convenient
asymmetric access serves as an attractive route towards multiple
naturally occuring homodimeric, macrocyclic scaffolds and
demonstrates the excellent efficiency to construct the complex,
symmetric core structures. Utilizing a rhodium catalyst with a
modified chiral cyclopentylidene-diop ligand, the desired diolides
were obtained in good to high yields, high diastereo- and excellent
enantioselectivity.
pronucleophiles,[15] to allenes and alkynes in an inter-, as well as
intramolecular manner to form branched allylic products.
In recent decades, dimeric structures of polyketide origin
have gained increasing scientific attention, as they show a
manifold of unique structural features and a great potential to
constitute
a large number of novel medicinally relevant
substances.[1,2] Aside from unsymmetrical, heterogeneous
dimers, a group of complex C2-symmetrical oxacyclic diolides
comprise a large number of biologically active compounds
(Scheme 1). In this spectrum, immuno-suppressives,[3a]
antibiotics,[3b] anthelmintics,[3c] herbicides and fungicides,[3d,e] as
well as active agents against cancer,[3f] HIV and the tropical
disease malaria can be found.[3g,h] As a consequence these
compounds have gained great interest as synthetic targets.[4]
By theory, this C2-symmetry element should allow for a
highly convergent dimerization strategy of an appropriate
monomer. However, known synthetic strategies towards diolides
follow more linear approaches, which result in multistep
synthesis, with the need for orthogonally protected building
blocks and/or previously implemented stereogenic centers.[5]
Today, the most frequently applied method to construct
macrolactones and diolides is the lactonization of the
corresponding seco acid with stoichiometric amounts of coupling
reagents.[6] However, only a few examples using the convergent
direct dimerization strategy have been developed, such as a
Scheme 1: Selected examples of biologically active diolides in nature,
common synthetic strategies and the concept of this report.
However, when attempting the formation of lactones of the
medium size range, dimeric diolides were observed as major
products.[14b] This let us speculate whether such a rhodium-
catalyzed dimerization reaction of allenyl-carboxylates could be
developed towards
a
general enantioselective catalytic
macrodiolide synthesis.[16]
We herein report such a general method for the enantio-,
diastereo- as well as regioselective rhodium-catalyzed
dimerization of allenyl-carboxylic acids for the formation of C2-
symmetric macrodiolides.
one-pot double
esterification,[8a,b] double SAKURAI allylation,[9] double SUZUKI or
STILLE cross-coupling and alkyne
metathesis.[10a,b;11]
MITSUNOBU
reaction,[7] double trans-
Nevertheless, direct enantioselective diolide formation ideally
employing catalyst control remains unknown.
Building upon prior experiences of allene/carboxylic acid
addition reactions from our group,[14a,b] we started optimization
by using undeca-9,10-dienoic acid (9g) as model substrate.
Employing [Rh(cod)Cl]2 and diop (L1) at room temperature in
DCE at a 0.01 M substrate concentration (Table 1, entry 1) with
a reaction time of 48 h a good yield of the macrodiolide dimer
was obtained albeit only in poor diastereoselectivity. The latter
could be significantly improved by lowering the reaction
temperature (Table 1, entry 1-4). Best results balancing yield
and diastereoselectivity were obtained at 0 °C (Table 1, entry 2).
A further screening of ligands proved the cyclopentylidene-
modified Cp-diop L2 as most suitable.[17] The increased activity
of this catalyst system allowed to lower the catalyst loading for
the reaction at 0 °C (Table 1, entry 6).
Transition metal catalyzed C-O bond formation could target
this issue next to modern demands for resource efficiency and
has been investigated throughout the past years in our
group.[12,13] Thus, our research has developed methods for
coupling carboxylic acids,[14a,b,c] next to other diverse
[*]
Ph. Steib, Prof. Dr. B. Breit
Institut für Organische Chemie, Albert-Ludwigs-Universität Freiburg
Albertstr. 21, 79104 Freiburg im Breisgau (Germany)
E-mail: bernhard.breit@chemie.uni-freiburg.de
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Table 1: Screening of diop derivatives at different temperatures.
Table 2: Synthesis of unfunctionalized 14- to 22-membered diolides by
rhodium-catalyzed dimerization of ω-allenyl carboxylic acids.
Entry
Ligand[a]
T [°C]
Yield [%][b]
d.r. (syn:anti)[c]
1
diop (L1)
r.t.
0
70
67
26
19
84
67
57:43
78:22
81:19
81:19
63:37
80:20
2[d]
3[d,e]
4[d,f]
5
diop (L1)
diop (L1)
-5
-10
r.t.
0
diop (L1)
Cp-diop (L2)
Cp-diop (L2)
6[g]
[a] Combined, isolated yield of diolides. [b] Ratio determined by 1H NMR of
vinyl-H atoms. [c] Determined by HPLC on a chiral phase. [d] 10 mol%
Cs2CO3 were added.
[a] Chiral variants of all ligands were used. [b] Isolated yield.
[c] Diastereomeric ratio determined by 1H NMR of the vinylic signals.
[d] 5.0 mol% [Rh(cod)Cl]2 and 10 mol% of ligand were used. [e] 64%
conversion. [f] 47% conversion. [g] 3.0 mol% [Rh(cod)Cl]2 and 6.0 mol%
ligand were used. DCE=1,2-dichloroethane. cod=1,5-cyclooctadiene.
Table 3: Synthesis of terephthalic and isoterephthalic acid derived 22- to 26-
membered diolides by rhodium-catalyzed dimerization of ω-allenyl carboxylic
acids.
With these conditions at hand, our focus turned to the scope
of the reaction. We started by investigating ω-allenyl carboxylic
acids with saturated carbon chain spacers of different
lengths.[18,19]
Indeed,
14-
to
22-membered
aliphatic
macrodiolides D1-D5 were obtained in moderate to high yields,
good diastereoselectivities and excellent enantioselectivities up
to >99% ee (Table 2).[20] The very high enantioselectivities of the
syn-diastereomers relate to the statistical asymmetric
amplification, known as the HOREAU principle.[21] Erosion of the
stereogenic center over time was excluded. When aiming at
larger, aliphatic ring sizes, we found increasing evidence that
diolide formation competes with the formation of higher
oligomers. When attempting to prepare 24-membered diolides
the corresponding 12-membered monolactone became the
major product.[14g]
Next, the dimerization of conformationally more restricted
ω-allenyl benzoic acid derivatives with either an ortho-, meta-
and para-substitution pattern was studied. The reaction of the
para-substituted allenyl acid 12e (Table 3, n=1) produced a
rather strained diolide D6 (see crystal structure of D6).[22] In this
case the addition of Cs2CO3 as a co-catalyst was found to be
beneficial to achieve full conversion. Accordingly, using a
substrate with elongated alkyl chain providing increased
conformational flexibility furnished a higher yield for diolide
formation D7. Good yields from 67 to 76% were obtained for the
meta-substituted products D8 and D9. In every case
enantioselectivities were excellent. However, the ortho-
substituted phthalic ester derivative reacted in
fashion: The main product was found to be the 12-membered
monolactone M1, indicating that conformationally more
proximate orientation of the reacting functional groups induces
monolactone formation.
a different
[a] Combined, isolated yield of diolides. [b] Ratio determined by 1H NMR of
arylic-H atoms. [c] Determined by HPLC on a chiral phase. [d] 4.5 mol%
[Rh(cod)Cl]2, 9.0 mol% ligand and 10 mol% Cs2CO3 were used. [e] Syringe
pump technique was applied.
a
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Table 5: Catalyst control upon rhodium-catalyzed dimerization of an α-chiral
ω-allenyl carboxylic acid. Determination of the configuration of the three
possible diastereomers.
We also looked into the preparation of macrodiolides,
functionalized with several different heterocyclic systems. Such
heterocyclic diolides might serve as receptors for differently
]
charged ions and neutral molecules.[23 We were delighted to
see that thiophene- and indole-based substrates provided the
corresponding diolides D10 to D12 with good yields. Even basic,
potentially metal-coordinating pyridines (D13) were tolerated. In
addition
to
excellent
enantioselectivities,
improved
diastereoselectivities up to 90:10 were observed. Such pyridine-
containing macrocycles may become of use as attractive chiral
ligands in asymmetric homogeneous catalysis, with the feature
of being readily functionalized by modification of the vinyl group.
Table 4: Synthesis of diolides with divers heteroaryl-groups.
[a] Combined, isolated yield of diolides. [b] (−)-L2 was used. [c] (+)-L2 was
used. [d] Ratio determined by 1H NMR of arylic-H atoms after filtration through
silica. Non stereogenic H-Atoms are omitted for clarity regarding the ORTEP
drawings.
In conclusion, we herein developed a highly atom-efficient,
enantioselective, one-step rhodium-catalyzed dimerization
strategy of ω-allenyl carboxylic acids, furnishing C2-symmetrical
homodiolides and generating two stereogenic centers
concomitantly. Aside from good yields, the 14- to 28-membered
symmetric diolides were obtained in high diastereo- and
excellent enantioselectivity. This methodology represents a
valuable alternative over existing two-step seco acid coupling
procedures. Functionalization within the ring system and late
stage modification of the allylic moiety could grant a convenient
access to this important class of natural products and to a field
of new complexing macrocycles, chiral ligand classes as well as
interesting organic materials when polymerized.
[a] Combined, isolated yield of diolides. [b] Ratio determined by 1H NMR of
arylic-H atoms. [c] Determined by HPLC on a chiral phase.
Acknowledgements
Having managed to construct diolides enantioselectively, we
pursued with addressing the question whether catalyst control of
diastereoselectivity can be achieved using allenic caboylic acid
substrates with preexisting stereoinformation. To this aim, para-
substituted benzoic acid derived allene 12e was elongated with
a (S)-lactic acid moiety, providing the possibility to form three
diolidic diastereoisomers D14a-c (Table 5). Indeed, we were
This research was supported by the DFG. Dr. Stephanie Ganss is
acknowledged for her kind support and effort during the project.
Dr. Daniel Kratzert and Dr. Manfred Keller are acknowledged for
X-ray crystal structure analysis. Dr. Alexander M. Haydl is
acknowledged for fruitful discussions.
delighted
to
observe
perfect
catalyst
control
of
Keywords: asymmetric catalysis • macrolactones • diolide •
diastereoselectivity forming either of the C2-symmetric diolides
D14a and D14b, when employing (−)-L2 or (+)-L2 as chiral
ligands, respectively. Assignment of the configuration was
confirmed by X-ray analysis for the all-(S) diastereomer D14a
and the (S,R,S,R)-diastereomer D14b.
rhodium • allenes
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Philip Steib and Bernhard Breit*
Page No. – Page No.
Enantioselective Rhodium-Catalyzed
Dimerization of ω-Allenyl Carboxylic
Acids: Straightforward Synthesis of
C2-Symmetric Macrodiolides
.
A
highly atom-efficient, enantioselective, one-step rhodium-
catalyzed dimerization strategy of ω-allenyl carboxylic acids, furnishing
C2-symmetrical homodiolides, a structural motif found in numerous
natural products, has been developed. The method features high
enantioselectivies generating two stereogenic centers concomitantly.
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