Kinetic resolution of homoaldols via catalytic asymmetric transacetalization

Article abstract of DOI:10.1021/ja108642s

The highly enantioselective kinetic resolution of homoaldols via a transacetalization reaction has been achieved. A novel phosphoric acid, STRIP, based on a spirocyclic 1,1′-spirobiindane backbone was designed and identified as a superior catalyst for this transformation. Remarkably, both secondary and tertiary homoaldols gave equally excellent results.

Full text of DOI:10.1021/ja108642s

Published on Web 11/18/2010
Kinetic Resolution of Homoaldols via Catalytic Asymmetric Transacetalization
†
†
ˇ
Ilija Coric´, Steffen Mu¨ller, and Benjamin List*
Max-Planck-Institut fu¨r Kohlenforschung, Kaiser-Wilhelm-Platz 1, D-45470 Mu¨lheim an der Ruhr, Germany
Received September 24, 2010; E-mail: list@mpi-muelheim.mpg.de
Table 1. Optimization of Reaction Conditions
Abstract: The highly enantioselective kinetic resolution of ho-
moaldols via a transacetalization reaction has been achieved. A
novel phosphoric acid, STRIP, based on a spirocyclic 1,1′-
spirobiindane backbone was designed and identified as a superior
catalyst for this transformation. Remarkably, both secondary and
tertiary homoaldols gave equally excellent results.
γ-Hydroxycarbonyl compounds, or homoaldols, represent a
versatile motif for organic synthesis that can be easily transformed
into a vast array of important chiral compounds such as γ-lactones,
tetrahydrofurans, pyrrolidines, and others. Consequently, various
homoenolate equivalents have been developed, but their use in
enantioselective homoaldol reactions invariably relies on stoichio-
metric chiral ligands or auxiliaries.1 Recently N-heterocyclic
carbenes opened up a new route for the organocatalytic generation
of homoenolates.2 However, their application in asymmetric ho-
moaldol reactions is still rather underdeveloped.3 Strategically
different approaches include catalytic enantioselective reduction of
γ-ketoesters4 and dynamic kinetic resolution of racemic γ-hy-
droxyamides using combined enzymatic and transition-metal ca-
talysis.5 Tertiary homoaldols, however, are not accessible by these
methods. We recently introduced a chiral Brønsted acid-catalyzed
asymmetric transacetalization reaction that generates chiral cyclic
acetals from the corresponding acyclic hydroxyacetals.6 We now
report a highly enantioselective kinetic resolution of homoaldol
acetals (rac-2) via a transacetalization reaction (Scheme 1) that is
catalyzed by STRIP (1e), which is a representative of an entirely
new class of phosphoric acid catalysts.7
a CH2Cl2 was used as the solvent.
structurally different Brønsted acids, we became interested in 1,1′-
spirobiindane as a platform for new phosphoric acid catalysts.10
Although the 1,1′-spirobiindane backbone is well-established in
metal catalysis,11 the corresponding phosphoric acids are largely
unknown.12 We expected these phosphoric acids to provide a
geometrically different and more rigid chiral pocket than their
BINOL-derived counterparts, offering new and potentially comple-
mentary tools for asymmetric Brønsted acid catalysis.
We initiated our studies on the kinetic resolution of homoaldols
by using secondary homoaldol rac-2a and BINOL-derived phos-
phoric acid catalyst 1a (TRIP),13 which was identified as the cat-
alyst of choice in our previous transacetalization studies.6 How-
ever, under identical conditions, only a moderate enantioselectivity
(er ) 25:75) of acetal 3a was obtained at 41% conversion (Table
1, entry 1). Other known phosphoric acid catalysts (1b-d) gave
only inferior results.
Scheme 1. Kinetic Resolution of Aldehyde Homoaldols
Remarkably, the novel spirocyclic TRIP-analogue STRIP [6,6′-
bis(2,4,6-triisopropylphenyl)-1,1′-spirobiindan-7,7′-diyl hydrogen
phosphate, 1e] provided excellent results. The STRIP-catalyzed
kinetic resolution of homoaldol rac-2a afforded cyclic acetal 3a
with an er of 95:5 and enantioenriched 2a with an er of 92:8 at
51% conversion (Table 1, entry 5). Further optimization identified
dichloromethane as the optimal solvent, resulting in higher reactivity
and increased enantioselectivity. At 55% conversion, both 3a and
2a were obtained in excellent enantiomeric ratios of 96.5:3.5 and
99:1, respectively (entry 6). Cyclic acetal 3a was obtained as the
cis diastereomer with a dr of 12:1. The minor trans diastereomer
5-epi-3a was obtained as a single enantiomer having the opposite
configuration at the alcohol-derived stereocenter.
Since the pioneering reports of Akiyama and Terada, BINOL-
derived phosphoric acids have become one of the cornerstones of
organocatalysis.8 However, the design of new chiral phosphoric
acids has mainly been limited to variations of the 3,3′-substituents
of the catalysts, with the notable exception of VAPOL hydrogen
phosphate.9 As a part of our interest in developing novel and
After establishing the optimal conditions, we set out to explore
the substrate scope. Importantly, racemic homoaldols rac-2 are
† These authors contributed equally.
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C O M M U N I C A T I O N S
Table 3. Kinetic Resolution of Tertiary Homoaldolsa
Table 2. Kinetic Resolution of Secondary Homoaldolsa
a Reactions were performed on a 0.1 mmol scale with molecular sieves
(50 mg). b The diastereomers were separable by column chromatography,
except for 3p-q. Only one enantiomer of the minor trans diastereomer
could be detected, except for 5-epi-3m (er 99.5:0.5), 5-epi-3p (er 99.5:0.5),
and 5-epi-3r (er 96.5:3.5).
The reaction of linear-aliphatic-substituted homoaldol rac-2i
illustrates a remarkable aspect of our reaction. As an additional
acetal stereocenter is created in the transacetalization, the high
catalyst control of its formation results in a partial parallel kinetic
resolution.14 Thus, even in cases where the enantiodifferentiation
of the starting material is not very pronounced, the less reactive
enantiomer is converted into the minor trans diastereomer. This
effect enabled us to obtain the major diastereomer of cyclic acetal
3i with an er of 96.5:3.5 and a perfect theoretical yield (50%) at
68% conversion (entry 9). For comparison, a simple kinetic
resolution would require a selectivity factor of 94 to achieve this
result. The STRIP-catalyzed kinetic resolution of homoaldols is also
extendable to other substrate classes: for example, homoaldols with
a cis double bond (rac-2j) or aromatic tether (rac-2k and rac-2l)
are also viable substrates (entries 10-12).
The exceptional results that STRIP delivered with secondary
homoaldols encouraged us to also explore the kinetic resolution of
tertiary homoaldols. Although chemical kinetic resolutions of
secondary alcohols have been well-studied,15 these methods are
generally not easily extendable to resolutions of tertiary alcohols,
and biocatalytic processes are also limited.16,17 The few nonenzy-
matic methods include chiral reagents18 and catalytic methods with
peptide-based catalysts19 and metal catalysts.20
a Reactions were performed on a 0.1 mmol scale with molecular
sieves (50 mg). b The diastereomers were separable by column
chromatography, except for 3j-l. Only one enantiomer of the minor
trans diastereomer could be detected, except for 5-epi-3h (er 97:3),
5-epi-3i (er 99.5:0.5), 5-epi-3k (er 71:29), and 5-epi-3l (er 83.5:16.5).
c Using 0.1 mol % of STRIP at a concentration of 0.1 M.
readily available from commercial materials in high yields in a
single step via the addition of an acetal-protected Grignard reagent
to aldehydes and ketones (Scheme 1).
Exploration of the substrate scope revealed that various secondary
homoaldols undergo a highly efficient kinetic resolution in the
presence of only 1 mol % of STRIP (Table 2). In most cases, both
cyclic acetal 3 and acetal homoaldol 2 were obtained with excellent
enantioselectivity. The nature of the aromatic substituent does not
seem to have a significant effect on the reaction, as various aromatic
substrates rac-2a-e and heteroaromatic substrate rac-2f underwent
superb kinetic resolutions (Table 2, entries 1-6). Homoaldols with
a vinyl or bulky aliphatic substituent behaved equally well (entries
7a and 8).
Remarkably, tertiary alcohols perform exceedingly well in our
asymmetric transacetalization, and STRIP-catalyzed resolution of
tertiary homoaldols rac-2m-r proceeded as efficiently as with
secondary homoaldols (Table 3). Both cyclic acetals 3m-r and
acyclic acetal homoaldols 2m-r, which possess valuable quaternary
stereocenters, were obtained with excellent enantioselectivity. The
kinetic resolution of substrates with sterically similar substituents
is remarkable. Highly efficient enantiodifferentiation between aryl
and bulky aliphatic groups (Table 3, entries 3-4) and even between
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Scheme 2. Utility of Cyclic Acetals 3
Scheme 3. Application in Natural Product Synthesis
aryl and benzyl groups (entry 5) was observed. Excellent results
were also obtained with substrate rac-2r bearing only aliphatic
substituents (entry 6). For comparison, a simple kinetic resolution
would have to operate at a selectivity factor of >300 to deliver the
product in 48% yield with 99:1 er.
Gratifyingly, the transacetalization reaction can be performed
even with a catalyst loading of only 0.1 mol % and a more
concentrated reaction mixture. For example, the kinetic resolution
of rac-2g proved to be equally effective under these conditions,
which resulted in almost identical enantiomeric ratios (Table 2, entry
7b).
of related transformations and applications of our new catalyst
class are ongoing.
Acknowledgment. Generous support by the Max-Planck-
Society, the DFG (Priority Program Organocatalysis SPP1179), and
the Fonds der Chemischen Industrie (award to B.L. and fellowship
to S.M.) is gratefully acknowledged. We thank our analytical
departments for excellent support.
Relative configurations of cyclic acetals 3a, 3k, 3l, and 3m were
determined by nuclear Overhauser effect spectroscopy (NOESY)
experiments. The absolute configuration of tetrahydrofuran 3a was
determined by comparison of the optical rotation of the γ-butyro-
lactone derivative obtained after Jones oxidation with the literature
value (see the Supporting Information). The configurations of other
secondary homoaldol products were assigned by analogy.
The acetal group in cyclic acetals can easily be modified, giving
access to a wide variety of products.21 To briefly demonstrate the
utility of our products, we performed the kinetic resolution of rac-
2c on a preparative scale (1.0 mmol) to obtain enantiomerically
enriched 2c and 3c in high yields and enantiomeric ratios (Scheme
2). Direct reduction of 3c led to tetrahydrofuran 4, whereas
hydrolysis of 3c liberated aldehyde homoaldol 5, which was readily
reduced to diol 6.
Supporting Information Available: Experimental procedures and
compound characterization. This material is available free of charge
via the Internet at http://pubs.acs.org.
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