Dimeric TADDOL Phosphoramidites in Asymmetric Catalysis: Domino Deracemization and Cyclopropanation of Sulfonium Ylides

Article abstract of DOI:10.1002/anie.201503851

A gold-catalyzed asymmetric cyclopropanation of unactivated olefins with sulfonium ylides in the presence of a bimetallic catalyst with a novel dimeric TADDOL-phosphoramidite ligand is reported. This transformation allows a rare gold-catalyzed dynamic deracemization of chiral racemic substrates, where the same catalyst is responsible for several synergistic tasks in solution. The products are useful building blocks in synthesis and enable expeditious access to natural products.

Full text of DOI:10.1002/anie.201503851

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201503851
German Edition: DOI: 10.1002/ange.201503851
Enantioselective Synthesis
Dimeric TADDOL Phosphoramidites in Asymmetric Catalysis:
Domino Deracemization and Cyclopropanation of Sulfonium Ylides**
Sebastian Klimczyk, Antonio Misale, Xueliang Huang, and Nuno Maulide*
Abstract: A gold-catalyzed asymmetric cyclopropanation of
unactivated olefins with sulfonium ylides in the presence of
a bimetallic catalyst with a novel dimeric TADDOL-phos-
phoramidite ligand is reported. This transformation allows
a rare gold-catalyzed dynamic deracemization of chiral
racemic substrates, where the same catalyst is responsible for
several synergistic tasks in solution. The products are useful
building blocks in synthesis and enable expeditious access to
natural products.
sulfonium ylides that proceeds through alkene activation.[9,10]
Herein, we report an enantioselective intramolecular cyclo-
propanation of allylic esters through a synergistic effect in
a bimetallic, dimeric catalyst framework.[11] In this process, an
unusual and highly efficient deracemization takes place,
whereby the same catalyst engages in two distinct, coopera-
tive catalytic cycles and which results in a domino catalytic
asymmetric transformation (Scheme 1).
T
he deracemization of chiral and racemic starting materials
by a given asymmetric reaction is one of the most valuable
transformations in enantioselective organic synthesis. This is
evident by the rise to prominence of kinetic resolutions and
their powerful dynamic variants (DKR and DYKAT). The
latter alternatives offer the possibility of quantitatively trans-
forming both enantiomers of a racemic mixture into a new,
optically pure product, effectively lifting the 50% theoretical
yield limitation of the former.[1–4] Recently, much interest has
been devoted to synergistic asymmetric catalysis, where two
catalysts (and two catalytic cycles) work in concert to create
new bonds in an enantioselective fashion. Several examples
are known to operate according to this principle, such as
dihydrofolate reductase,[5] dual transition-metal catalysis,[6] or
Scheme 1. Gold-catalyzed deracemization of allylic esters.
the combination of a transition metal and organocatalyst.[7]
A
Scheme 2 depicts a survey of various chiral gold(I)
complexes used for the asymmetric cyclopropanation of
substrate 1a (for a detailed screening, see the Supporting
Information). As shown, the class of TADDOL-derived
phosphoramidites L13–L16, first employed in gold catalysis
by Fürstner and co-workers,[12] gave the highest reactivity
(enabling full conversion within a few hours) and good
enantiomeric ratios.[13] Interestingly, other phosphoramidites
such as SIPHOS-PE L6 or the well-known BINOL deriva-
tives L7 and L8[14] showed only sluggish conversion along with
poor enantioselectivity. In this initial survey, the best enan-
tiomeric ratio of 81:19 was observed when 4-(tert-butyl)-
phenyl was employed as the aryl substituent in the TADDOL
backbone (cf. L15). Further manipulations of the backbone
did not lead to any increase in enantioselectivity, and attempts
involving chiral counterion strategies[15] led to a shutdown of
reactivity (see the Supporting Information for further details).
In sharp contrast, the new dimeric ligand L17 afforded the
desired bicyclopropane 2 in an excellent enantiomeric ratio of
90:10 with a catalyst loading of only 2.5 mol%.
conceptual alternative would involve a finely tuned “super-
ligand” able to accompany and assist the same metal during
two (or more) different, asymmetric transformations.[8]
Recently, our group described a gold(I)-catalyzed intra-
molecular cyclopropanation of unactivated olefins with
[*] Dr. S. Klimczyk, Dr. A. Misale, Prof. Dr. N. Maulide
University of Vienna, Faculty of Chemistry
Institute of Organic Chemistry
Währinger Strasse 38, 1090 Vienna (Austria)
E-mail: nuno.maulide@univie.ac.at
Prof. Dr. X. Huang
State Key Laboratory of Structural Chemistry
Fujian Institute of Research on the Structure of Matter
Chinese Academy of Sciences
Yangqiao West Road 155, Fuzhou, Fujian 350002 (China)
[**] Generous support of this research by the DFG (Grants MA 4861/4-
1 and 4-2) and the ERC (StG FLATOUT) is acknowledged. We also
thank the University of Vienna and Max-Planck-Institut für Kohlen-
forschung, where parts of this research were carried out. We further
thank A. Roller (University Vienna) for X-ray analysis, S. Knittl-
Franck (University Vienna) for the preparation of starting materials,
and E. Macoratti (University Vienna) for assistance with chiral
HPLC analysis.
Particularly appealing from the outset was the prospect of
employing substrates that carry branched allyl groups. We
were aware that several substrates, such as methyl-substituted
3a, were themselves chiral (racemic) compounds. Much to
our surprise, subjecting rac-3a to the asymmetric cyclopropa-
nation conditions with the dimeric ligand L17 led to the
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201503851.
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clearly suggests a dynamic deracemization (rather than
a simple kinetic resolution) process. Furthermore, the use of
“linear” isomer 3b (which is not a chiral compound;
Scheme 3b) delivers the same cyclopropane 4a, with levels
of stereoselectivity nearly identical to those observed for the
“branched” isomer rac-3a.
The results depicted in Scheme 3c further show how the
double-bond geometry of the substrate is inconsequential (cf.
the E and Z isomers 3c and 3d). Thus, it is possible to use
starting materials with low geometrical purity (or even
regioisomer mixtures) to produce diastereomerically pure,
enantioenriched cyclopropanes,
a
significant synthetic
advantage of this method. Variation in the length of the side
chain is well tolerated in terminal or internal positions of the
allylic tether (cf. 3e and rac-3 f, Scheme 3d). Ketoester-
derived sulfonium ylide 3g also delivers the desired bicyclo-
propane product 4e in excellent selectivity.
The highly enantioselective transformations portrayed in
Scheme 3 are remarkable as they constitute, to the best of our
knowledge, unique examples of deracemizations promoted by
gold catalysis.
The unique regio-, diastereo-, and enantioconvergence of
this cyclopropanation reaction suggest the transient existence
of a common intermediate and motivate us to propose the
mechanism depicted in Scheme 4.[10] We believe that the
Scheme 2. Ligand screening for the asymmetric cyclopropanation of
1a. Unless specified, AgX=AgSbF6.
Scheme 4. Proposed mechanism of the dynamic deracemizing cyclo-
propanation.
substrate isomers must interconvert at a rate higher than that
of the cyclopropanation reaction. The racemization of chiral
racemic starting materials such as rac-3a is ensured by their
dynamic conversion into the achiral, linear allylic isomers (cf.
the equilibrium 5Ð6Ðent-5).[16] Such an equilibrium would
also account for the observed possibility of employing both
isomeric forms (5 or 6), including double-bond isomers (i.e.
(E)- or (Z)-6), of the starting material at will, and constitutes
an interesting racemization mechanism with potential for
further applications.
We propose that the catalyst subsequently selects for
those isomers carrying a terminal olefin appendage and
effectively achieves highly enantioselective chiral recognition
of only one enantiomer within the pair 5/ent-5, thereby
cyclopropanating that stereoisomer with very high diastereo-
selection.[17–19]
Scheme 3. Dynamic deracemization reactions promoted by L17.
cyclopropane product 4a as a single diastereoisomer with an
enantiomeric ratio of 96:4 (Scheme 3a). This result is all the
more striking as the product is obtained in a 72% yield, which
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Here, the ability of the same gold catalyst to catalyze both
domino allylic isomerization and cyclopropanation
a
sequence in high cooperativity with high regio-, diastereo-,
and enantioselectivity is unprecedented.
A key structural feature of ligand L17 is the presence of
two phosphorus donor atoms. Under the reaction conditions
each phosphorus atoms coordinates to one gold center in
what is, effectively, a bimetallic species. This raises the
question of whether the second metallic center has any
noteworthy beneficial effect on the cyclopropanation reac-
tion. The monomeric catalyst containing L15 leads to
a reduced enantioselectivity (e.r. 87:13) in the cyclopropana-
tion of rac-3a (Scheme 5). Strikingly, monometallic
Scheme 6. Substrate scope of the Au-catalyzed asymmetric cyclopro-
panation of sulfonium ylides. All the reported yields and e.r. values
refer to pure isolated material. [a] Reaction performed with L17·(AuCl)2
(5 mol%) and AgNTf2 (10 mol%). [b] Recrystallization afforded the
compound as enantiopure crystals, see the Supporting Information.
decreased to 0.62 mol% with no loss in yield or enantiose-
lectivity (see the Supporting Information for details).
Scheme 5. Demonstration of the synergistic effect of the metal centers
in the dynamic deracemization of rac-3a.
The cyclopropane products reported herein are useful
synthetic intermediates in their own right (Scheme 7). For
example, derivative 4d could be subjected to ring opening
with an amine nucleophile in the presence of the mild Lewis
acid LiNTf2. An excess (2 equiv) of amine leads to the highly
functionalized lactam 10. The use of only 0.8 equiv of the
nucleophilic amine delivers the bicyclic product 11.[21] The
L17·AuCl, bearing only one gold center for the dinuclear
phosphoramidite ligand, performs in a virtually identical
fashion towards substrate rac-3a (e.r. 88:12). Instead, the
dinuclear gold catalyst L17·(AuCl)2 is singularly able to
promote the cyclopropanation with the highest enantioselec-
tion (e.r. 94:6), clearly demonstrating that a synergistic effect
is imparted by the second metal center.[20]
At this juncture, we further delineated the scope and
limitations of this reaction (Scheme 6). Sulfonium ylides
derived from malonates underwent cyclopropanation
smoothly in short reaction times (Scheme 6, 2a and 2b).
Furthermore, several ketoester-derived sulfonium ylides
delivered the corresponding cyclopropanes in good to excel-
lent yields, as did sulfonium ylides carrying aliphatic sub-
stituents (Scheme 6, 2c–2e) or electron-rich aromatic groups
(2 f–h and 2j). Heterocycle-bearing sulfonium ylides under-
went cyclopropanation and afforded the corresponding cyclo-
propanes in excellent yields with high enantioselectivities (2l
and 2m). Several cyclopropanes readily crystallized to afford
nearly enantiomerically pure substances (2 f,h,j,m). For
example, compound 2m was obtained in a 98:2 enantiomeric
ratio after crystallization, and the absolute configuration of
the product was determined by X-ray crystallography to be
(1S,5R). The cyclopropanation reaction could also be per-
formed on a gram scale and the catalyst loading further
Scheme 7. Elaboration of selected cyclopropane lactone products.
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such as 14.[22b–d]
The method reported herein also enables entry to the
asymmetric synthesis of butenolide natural products. For
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(Scheme 8). SmI2-mediated reductive cleavage of the cyclo-
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Scheme 8. Asymmetric synthesis of trans-(À)-cognac lactone 16.
propane followed by a Krapcho decarboxylation delivers the
enantioenriched natural product 16 in good yield.[23]
In summary, we have developed a gold-catalyzed asym-
metric cyclopropanation that delivers useful synthetic build-
ing blocks. Central to the realization of this endeavor was the
design of a dimeric TADDOL-phosphoramidite ligand in
a bimetallic gold catalyst, where the two metal centers work
synergistically to enhance the enantioselectivity. Notably, this
process is capable of achieving the dynamic deracemization of
chiral racemic substrates by means of a domino allylic
isomerization and enantio- as well as diastereoselective
cyclopropanation. The same catalyst is responsible for several
tasks in a process which, to the best of our knowledge,
constitutes a rare dynamic deracemization phenomenon in
gold catalysis.
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[16] For a related rearrangement, see N. Marion, R. Gealageas, S. P.
Nolan, Org. Lett. 2007, 9, 2653. In control experiments, we have
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gold catalyst and is independent of the ylide appendage. See the
Supporting Information for details.
[17] In support of this hypothesis, the enantiomeric ratio of the
product remains constant throughout the entire reaction and the
formed enantioenriched product does not racemize upon
exposure to the reaction conditions. See the Supporting Infor-
mation for details.
Keywords: cyclopropanation · deracemization ·
enantioselective synthesis · lactones · total synthesis
How to cite: Angew. Chem. Int. Ed. 2015, 54, 10365–10369
Angew. Chem. 2015, 127, 10507–10511
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[19] See NMR studies in the Supporting Information for details.
[20] More-detailed studies are underway to elucidate the true origin
of this unique phenomenon. For the preparation of mononuclear
complex L17·AuCl, see the Supporting Information.
[21] C. Lalli, A. Trabocchi, G. Menchi, A. Guarna, Synlett 2008, 189.
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Received: April 27, 2015
Revised: May 14, 2015
Published online: July 3, 2015
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