Enantioselective Rhodium-Catalyzed Atom-Economical Macrolactonization

Article abstract of DOI:10.1002/anie.201604301

A highly attractive route toward macrolactones, which form the cyclic scaffold of a multitude of diverse natural compounds, is described. Although many chemical approaches to this structural motif have been explored, an asymmetric variant of the cyclization is unprecedented. Herein we present an enantioselective macrolactonization through an intramolecular atom-economical rhodium-catalyzed coupling of ω-allenyl-substituted carboxylic acids. The use of a modified diop ligand, chiral DTBM-diop, led to high enantioselectivity (up to 93 % ee). The reaction tolerated a large variety of functionalities, including α,β-unsaturated carboxylic acids and depsipeptides, and provided the desired macrocycles with very high enantio- and diastereoselectivity.

Full text of DOI:10.1002/anie.201604301

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201604301
German Edition: DOI: 10.1002/ange.201604301
Asymmetric Catalysis
Enantioselective Rhodium-Catalyzed Atom-Economical
Macrolactonization
Stephanie Ganss and Bernhard Breit*
Abstract: A highly attractive route toward macrolactones,
which form the cyclic scaffold of a multitude of diverse natural
compounds, is described. Although many chemical approaches
to this structural motif have been explored, an asymmetric
variant of the cyclization is unprecedented. Herein we present
an enantioselective macrolactonization through an intramo-
lecular atom-economical rhodium-catalyzed coupling of w-
allenyl-substituted carboxylic acids. The use of a modified diop
ligand, chiral DTBM-diop, led to high enantioselectivity (up to
93% ee). The reaction tolerated a large variety of function-
alities, including a,b-unsaturated carboxylic acids and depsi-
peptides, and provided the desired macrocycles with very high
enantio- and diastereoselectivity.
M
acrocyclic natural products are captivating owing to their
often complex molecular architecture of a large ring com-
bined with a broad diversity of functional groups and high
stereochemical complexity.[1] In particular, macrocyclic scaf-
folds of the macrolactone family are present in numerous
natural compounds[2] exhibiting intriguing fungicidal and
insecticidal bioactivity,[3] as well as olfactory[4] and medicinal
properties (Scheme 1).[5]
Scheme 1. Selected examples of naturally occurring macrolactones.
formation have great potential as a powerful new strategy to
form macrolactones.[15]
In 2006, White and co-workers reported an elegant and
general procedure for the macrolactonization of w-alkenyl-
Over the past decades, many different methods have been
developed to close macrocyclic ring systems,[1c,2] for example,
ring-closing metathesis,[6] Diels–Alder macrocyclization,[7]
intramolecular cross-coupling,[8] metal-catalyzed coupling
reactions,[9] and Horner–Wadsworth–Emmons-type olefina-
tion reactions.[10] However, the macrolactonization of w-seco
acids by activation of either the acid or the alcohol moiety still
remains the most prevalent method with a variety of reliable
and high-yielding procedures.[2] Unfortunately, these proce-
dures are rather unattractive in terms of the modern demands
for resource efficiency in organic synthesis with regard to step
economy,[11] redox economy,[12] atom economy,[13] and pro-
tecting-group-free synthesis.[14] Furthermore, the often harsh
and basic conditions lead to isomerization, double-bond
migration, and epimerization.[2] Additionally, the introduction
of the required stereochemical information during the ring
closure would render a preceding installation step unneces-
sary. Hence, the development of improved access toward
(macro-)lactones remains a highly challenging and active
substituted carboxylic acids through a sulfoxide-promoted
[16]
À
palladium-catalyzed allylic C H oxidation. However, the
use of more than a stoichiometric amount of an external
oxidant is mandatory for this cyclization, the enantio- and
diastereoselectivity of which can to date not be controlled by
the catalyst. Intramolecular transition-metal-catalyzed addi-
tion reactions of carboxylic acids to multiple bonds are well-
known[17] and represent a new approach to (macro-)lactoni-
zation. In fact, the asymmetric intramolecular hydrooxycar-
bonylation of w-allenyl-substituted carboxylic acids was
reported most recently by Toste and co-workers,[18] who
used a bifunctional heterogeneous molecular gold catalyst,
and by Lipshutz and co-workers,[19] who employed a micellar
gold catalyst. Another iridium-catalyzed asymmetric lactoni-
zation of alkenyl-substituted carboxylic acids was reported by
Nagamoto and Nishimura.[20] Each reaction type proceeded
with mostly high enantioselectivity but was limited to g- and
d-lactones.
À
field. Transition-metal-catalyzed reactions for C O bond
Our research group is interested in the atom-economical
rhodium-catalyzed addition of pronucleophiles to alkynes[21]
and allenes.[22] In this context, a hydrooxycarbonylation to
form branched allylic esters[21b] was developed and serves as
an attractive alternative to allylic substitution[23a–c] and allylic
oxidation[23d,e] for the synthesis of valuable allylic intermedi-
ate structures.[24] When the achiral ligand DPEphos was used,
a broad range of racemic branched allylic esters were
obtained. This system was also performed in an intramolec-
[*] S. Ganss, Prof. Dr. B. Breit
Institut fꢀr Organische Chemie, Albert-Ludwigs-Universitꢁt Freiburg
Albertstrasse 21, 79104 Freiburg im Breisgau (Germany)
E-mail: bernhard.breit@chemie.uni-freiburg.de
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201604301.
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Table 1: Screening of different diop derivatives in the rhodium-catalyzed
macrolactonization.
ular manner to provide a racemic atom-economical (macro)-
lactonization method.[25] However, a general atom-econom-
ical and enantioselective macrolactonization based on tran-
sition-metal catalysis remains unknown.
Thorough investigations of the mechanism provided
evidence that this transformation proceeds via an intermedi-
ate allene.[26] In fact, we were able to report a general
intermolecular hydrooxycarbonylation of allenes with (À)-
diop ((À)-L1).[22a] The branched allylic esters with various
functionalities were obtained not just in high yields but also
with excellent enantioselectivity. These results encouraged us
to investigate the potential of this reaction for the first
enantioselective and atom-economical macrolactonization by
the intramolecular addition of carboxylic acids to terminal
allenes (Scheme 2).
Entry[a]
Ligand
Combined yield [%][b]
ee [%][d]
(ML/EL/DL)[c]
1[e]
2
3
4
5
6
7
(+)-diop (L1)
(+)-diop (L1)
85 (90:4:6)
81 (86:6:8)
69 (88:6:6)
<5
8 (76:–:24)
86 (80:9:11)
76 (82:8:10)
74 (R)
85 (R)
86 (S)
85 (S)
84 (S)
91 (S)
91 (R)
(À)-Cp-diop (L4)
(À)-Cy-diop (L5)
(À)-DM-diop (L2)
(À)-DTBM-diop (L3)
(+)-DTBM-diop (L3)
[a] Reaction conditions: [Rh(cod)acac] (9.0 mol%), ligand (9.0 mol%),
1 (0.5 mmol), DCE (0.01m), room temperature, 24 h. [b] Combined yield
of the product mixture. [c] Product ratio determined by 1H NMR
spectroscopy. [d] The ee value was determined by GC on a chiral
stationary phase. [e] The reaction was performed with [{Rh(cod)Cl}2]
(4.5 mol%). acac=acetylacetonate, cod=1,5-cyclooctadiene,
DCE=1,2-dichloroethane.
Scheme 2. General reaction scheme for the rhodium-catalyzed intra-
molecular asymmetric coupling of carboxylic acids with terminal
allenes.
The optimization process was performed for the conver-
sion of the model substrate hexadeca-14,15-dienoic acid (1)
into the 15-membered macrolactone 2. In first reactivity
assays, we reevaluated the previously reported conditions and
optimized the different reaction parameters. The preliminary
optimal results were obtained at room temperature with
[{Rh(cod)Cl}2] and (+)-diop ((+)-L1) in DCE at a 0.01m
substrate concentration (Table 1, entry 1), which gave the R-
configured macrolactone 2.[27,28] Besides the desired product
lactone ML, the formation of the endo- and exocyclic enol
lactones EL as well as the corresponding diolide DL was
observed. Further screening of different rhodium precursors
revealed [Rh(cod)acac] as a suitable alternative catalyst,
which improved the ee value of 2 to 85% (Table 1, entry 2).[29]
To further improve the enantioselectivity, we tested different
privileged ligands. Since ligands containing a diop-analogue
backbone still proved to be the most suitable for the reaction,
various diop derivatives were tested with either an altered
acetal backbone (Table 1, entries 3 and 4) or varying aromatic
moieties with different steric and electronic properties
(entries 5–7). To our delight, product 2 was obtained with
high enantioselectivity (91% ee) with DTBM-diop (L3).
Having optimized the reaction conditions, we turned our
focus to the scope of the reaction for the synthesis of
macrolactones with different ring sizes, from a medium-sized
13-membered lactone up to a large 21-membered macro-
lactone (Scheme 3). All targeted macrolactones, 2–6, were
obtained in good yield and with good ee values of up to 93%.
To demonstrate the potential of this procedure for more
complex systems, we examined various functionalized w-
allenyl-substituted carboxylic acid substrates (Scheme 4). We
found that aromatic acids can be used, as exemplified by the
synthesis of the benzolactones 7 and 8, which were formed in
good yield with 89 and 85% ee, respectively. With the
synthesis of the dimethyl-substituted macrolactone 9, the
tolerance of a second ester functionality could be proved, thus
opening up the possibility of forming symmetrical and
unsymmetrical diolides. Under common basic macrolactoni-
zation conditions, the isomerization or migration of the
alkene of a,b-unsaturated carboxylic acids is a frequently
occurring problem.[2] Fortunately, the cyclization to 10 and 11
proceeded successfully with retention of the alkene config-
uration, and both products were obtained with 93% ee.
Next, we were curious to investigate the diastereoselec-
tivity of the macrolactonization of substrates with inherent
stereochemical information. We first examined the cyclization
of the linear precursors 12 and 13, containing a chiral amino
acid moiety, with racemic DTBM-diop to assess the diaste-
reoselectivity in terms of substrate control (Table 2, entries 1
and 4). A certain degree of diastereoselectivity in favor of the
S,S-configured products was observed. At this point, the
assignment of the configuration of the formed diastereomers
was confirmed by X-ray crystallographic analysis of (S,S)-14
and (S,R)-14.[28] We were pleased to observe almost perfect
diastereoselectivity in the formation of the alanine- and
phenylalanine-containing macrolactones 14 and 15 when
ligands (À)- and (+)-L3 were used.
2
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Table 2: Synthesis of depsipeptides 14 and 15 through the intramolec-
ular rhodium-catalyzed addition of carboxylic acids to allenes.[a]
Entry[a]
R
Ligand
Combined yield [%][b]
d.r.[c]
((S,S)-ML/(S,R)-ML/EL)[c]
1[b]
2[c]
3[c]
4[b]
5[c]
6[c]
Me
Me
Me
Bn
Bn
Bn
rac-L3
(À)-L3
(+)-L3
rac-L3
(À)-L3
(+)-L3
72 (53:19:28)
99 (83:7:10)
56 (0:60:40)
70 (39:20:41)
82 (53:5:42)
59 (3:73:23)
73:27
92:8
0:100
66:34
91:9
4:96
[a] Reaction conditions: [Rh(cod)acac] (9.0 mol%), (+)-L3 (9.0 mol%),
substrate (0.5 mmol), DCE (0.01m), room temperature, 24 h. [b] Com-
bined yield of the product mixture. [c] Diastereomeric ratio determined
by 1H NMR spectroscopy. Bn=benzyl.
Scheme 3. Synthesis of unfunctionalized 13- to 21-membered macro-
lactones by the intramolecular rhodium-catalyzed addition of carboxylic
acids to allenes. Reaction conditions: [Rh(cod)acac] (9.0 mol%),
(+)-L3 (9.0 mol%), substrate (0.5 mmol), DCE (0.01m), room temper-
ature, 24 h. [a] Combined yield of the product mixture. [b] Product ratio
1
determined by H NMR spectroscopy. [c] The ee value was determined
by GC on a chiral stationary phase. [d] The ee value was determined by
HPLC on a chiral stationary phase.
acids with terminal allenes for the synthesis of enantiomer-
ically enriched macrolactones. This first direct enantioselec-
tive synthesis of macrolactones gives the desired products in
good yields with high enantio- and diastereoselectivity. The
presented conditions were applied to the formation of many
different ring sizes and a broad range of functionalities, in
particular, ester, amide, and olefinic groups. Future studies
will elucidate the potential for a general asymmetric homo-
dimerization strategy. Applications of this methodology in the
target-oriented synthesis of natural products are being
pursued in our laboratory.
Acknowledgements
This research was supported by the DFG and the Interna-
tional Research Training Group “Catalysts and Catalytic
Reactions for Organic Synthesis” (IRTG 1038). We thank
Umicore, BASF, and Wacker for generous gifts of chemicals.
Dr. Manfred Keller and Dr. Daniel Kratzert are acknowl-
edged for X-ray crystal-structure analysis. Nico Hçfflin is
acknowledged for his enduring, motivated, skillful technical
assistance.
Scheme 4. Synthesis of functionalized macrolactones by the intramo-
lecular rhodium-catalyzed addition of carboxylic acids to allenes.
Reaction conditions: [Rh(cod)acac] (9.0 mol%), (+)-L3 (9.0 mol%),
substrate (0.5 mmol), DCE (0.01m), room temperature, 24 h. [a] Com-
bined yield of the product mixture. [b] Product ratio determined by
1H NMR spectroscopy. [c] The ee value was determined by HPLC on
a chiral stationary phase. n.d.=not detected.
Keywords: asymmetric catalysis · hydrooxycarbonylation ·
In summary, we have described a highly atom-economical
rhodium-catalyzed intramolecular coupling of carboxylic
ligand design · macrolactonization · rhodium
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Angewandte
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Chemie
[26] U. Gellrich, A. Meißner, A. Steffani, M. Kꢂhny, H.-J. Drexler, D.
Heller, D. A. Plattner, B. Breit, J. Am. Chem. Soc. 2014, 136,
1097 – 1104.
[27] The absolute stereoconfiguration was assigned by the Mosher
ester analysis for secondary alcohols according to the Kakisawa
method: I. Ohtami, T. Kusumi, Y. Kashman, H. Kakisawa, J. Am.
Chem. Soc. 1991, 113, 4092 – 4096.
[29] The enantioselectivity of the reaction did not depend on the
reaction time. Additional proof of the stereochemical integrity
of the product was derived from treatment of the product with
the catalyst and both enantiomers of the ligand (see the
Supporting Information for further details).
Received: May 3, 2016
[28] See the Supporting Information for details.
Published online: && &&, &&&&
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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Angewandte
Communications
Chemie
Communications
Asymmetric Catalysis
S. Ganss, B. Breit*
&&&& — &&&&
Enantioselective Rhodium-Catalyzed
Atom-Economical Macrolactonization
Reaching for stars: An intramolecular
rhodium-catalyzed hydrooxycarbonyla-
tion of w-allenyl-substituted carboxylic
acids in the presence of a chiral phos-
phine ligand permitted the direct asym-
metric formation of macrolactones (see
scheme). The macrolactonization pro-
ceeded with good to high enantio- and
diastereoselectivity.
6
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ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!