Resolution of diols via catalytic asymmetric acetalization

Article abstract of DOI:10.1021/ja512481d

A highly enantioselective kinetic resolution of diols via asymmetric acetalization has been achieved using a chiral confined imidodiphosphoric acid catalyst. The reaction is highly efficient for the resolution of tertiary alcohols, giving selectivity factors of up to >300. Remarkably, even in cases where the selectivity factors are only moderate, highly enantioenriched diols are obtained via a stereodivergent resolution to diastereomeric acetals.

Full text of DOI:10.1021/ja512481d

Communication
pubs.acs.org/JACS
Resolution of Diols via Catalytic Asymmetric Acetalization
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Ji Hye Kim, Ilija Coric, Chiara Palumbo, and Benjamin List*
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Max-Planck-Institut fur Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mulheim an der Ruhr, Germany
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̈
S
* Supporting Information
Scheme 1. Resolution of Diols via Asymmetric Acetalization
ABSTRACT: A highly enantioselective kinetic resolution
of diols via asymmetric acetalization has been achieved
using a chiral confined imidodiphosphoric acid catalyst.
The reaction is highly efficient for the resolution of tertiary
alcohols, giving selectivity factors of up to >300.
Remarkably, even in cases where the selectivity factors
are only moderate, highly enantioenriched diols are
obtained via a stereodivergent resolution to diastereomeric
acetals.
cyclic acetal 4a in 50% isolated yield with an er of 98.5:1.5 and a
diastereomeric ratio (dr) of 58:1 (Table 1, entry 1). Exploration
of different aldehydes revealed that efficient kinetic resolution of
diol rac-2a can be achieved in the presence of only 1−2 mol%
of 1a to give a variety of 1,3-dioxolanes 4 with excellent
enantioselectivities and diastereoselectivities (Table 1). Replac-
ing isovaleraldehyde with less bulky n-pentanal or acetaldehyde
resulted in still high selectivity factors of 64 and 39, respectively
(entries 2 and 3). Increased steric bulk at the α-position of
isobutyraldehyde resulted in a higher selectivity factor of 79,
although a higher catalyst loading was required (entry 4). When
even more sterically demanding pivalaldehyde was used, the
reaction did not proceed at all (entry 5). Considering that the use
of isovaleraldehyde, which is bulkier than linear aldehydes and at
the same time less bulky than α-trisubstituted aldehydes, resulted
in the highest selectivity factor, we wondered if increasing
the bulkiness at the β-position could be beneficial. Indeed,
3,3-dimethylbutyraldehyde gave an excellent selectivity factor of
122 (entry 6). However, because of its significantly lower
reactivity, we used isovaleraldehyde for examining the diol scope
of the acetalization.
A variety of diols with substituted aromatic rings was tested for
the kinetic resolution (Table 2, entries 1−6). By placing chloro-,
methoxy-, or methyl-substituents at the para-position of the
aromatic ring of the diol, we obtained very high selectivity
factors from 64 to 99 with 2−3 mol% of the catalyst (Table 2,
entries 1−3). Kinetic resolutions employing diols with meta- or
ortho-substituents proceeded with increased enantioselectivity
compared to those bearing para-substitution (entries 4 and 5);
excellent selectivity factors of 110 and 135 were obtained in these
cases. 2-Naphthyl-substituted diol rac-2l gave a superb kinetic
resolution with a selectivity factor of 389 (entry 6). 1,2-Diol 2l
was isolated in 45% yield, with an er of 98.5:1.5, while 1,3-
dioxolane 4l was obtained with er over 99.5:0.5, and a dr of 93:1,
in 44% isolated yield. Encouraged by these results, we next
explored the possibility of replacing the methyl group with other
substituents. Gratifyingly, the reaction of ethyl-substituted diol
nantiomerically pure diols are common in natural products
E
and are valuable synthetic building blocks,1 Their synthesis
has attracted much attention and still constitutes an important
challenge. Next to the Sharpless dihydroxylation of olefins,2
other methods have been developed, such as epoxide opening,3
asymmetric hydrogenation of α-hydroxyketones,4 α-oxyamination/
reduction of carbonyls,5 diboration/oxidation of alkenes,6 and
others.7 However, synthetic approaches capable of delivering
diols with tertiary alcohol stereocenters with high enantio-
selectivity are much less common.2c,7d,e Since racemic diols are
readily accessible, kinetic resolution can be an attractive alternative
strategy for the preparation of enantioenriched diols.8 Methods for
kinetic resolution of diols via asymmetric acylation and silylation
are known,9 but they have been rarely applied to tertiary diols.9j
Next to ester and silyl groups, acetals are particularly useful
protecting groups for alcohols, with complementary stability and
deprotection conditions. Nevertheless, processes for the kinetic
resolution of alcohols via acetal formation are still in their
infancy, with asymmetric acetalization reactions being developed
only very recently.10 High selectivity was previously achieved
only in the kinetic resolution of alcohols via intramolecular
transacetalization.10b Now we report that direct acetalization of
aldehydes with racemic diols provides an efficient method for the
kinetic resolution of diols possessing valuable tertiary alcohol
stereocenters. Furthermore, as the acetalization reaction creates
an additional stereocenter, a complementary stereodivergent
resolution of diols into two separable diastereoisomers is pos-
sible when the kinetic enantiomer differentiation is unsatisfactory
(Scheme 1).8b The method also enables access to enantio-
enriched 1,3-dioxolanes possessing two stereocenters, itself a
valuable motif.11
We initiated our studies using terminal diol rac-2a as a model
substrate and confined imidodiphosphoric acid catalyst 1a, which
has previously been identified as an excellent catalyst for
asymmetric acetalizations.10d Using 1 mol% of the catalyst and
isovaleraldehyde in toluene at 20 °C, kinetic resolution pro-
ceeded with a very high selectivity factor of 118, giving diol 2a in
46% isolated yield with an enantiomeric ratio (er) of 97.5:2.5 and
Received: December 8, 2014
© XXXX American Chemical Society
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DOI: 10.1021/ja512481d
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Table 1. Identification of Suitable Aldehydes for Kinetic Resolution
a
b
Theoretical conversion calculated from ee values of the product and the recovered starting material (see SI). Isolated yield on a 0.5 mmol scale.
c
d
e
Determined by HPLC analysis on a chiral stationary phase. Determined by GC analysis on a chiral stationary phase. For most minor
f
g
1
diastereomers er >99.5:0.5. Calculated from theoretical conversion and enantiomeric excess of enantioenriched diol (see SI). Determined by H
NMR analysis.
rac-2m proceeded with 2 mol% of 1a with a selectivity factor of
115 (entry 7). Interestingly, even the isopropyl-substituted diol
rac-2n exhibited an impressive selectivity factor of 372, with only
1 mol% of the catalyst (entry 8). It is rather remarkable that such
a high selectivity factor could be obtained with a diol that
possesses two similarly bulky substituents, phenyl and isopropyl.
The exceptional results with aryl,alkyl-substituted 1,2-diols
encouraged us to also explore the kinetic resolution of dialkyl-
substituted diols. Gratifyingly, the reaction of methyl,cyclohexyl-
substituted diol rac-2o proceeded with a selectivity factor of 23
(entry 9). With methyl,hexyl-substituted diol, the reaction still
proceeded with a reasonable selectivity factor of 9 (entry 10). Diol
2p could be isolated with a good er of 93:7 in 33% yield. Product
4p was obtained with an excellent er of 98.5:1.5 and a dr of 4:1.
This example further demonstrates how excellent stereocontrol of
the acetal stereocenter formation is accomplished by the catalyst
independently of the diol substrate. Good enantioselectivities of
dialkyl-substituted diols could be obtained at higher conversion,
even if the selectivity factor is not particularly high.
conversion of the rac-diol, as exemplified with rac-2p (s = 9) and
rac-2s (s = 1.6) (Scheme 2). Although the enantiomer
Scheme 2. Stereodivergent Access to Enantioenriched Diols
We next investigated the applicability of our catalytic system to
1,3-diols. Although the reactivity and selectivity declined slightly,
additional screening of conditions and use of the bulkier catalyst
1b resulted in good selectivity factors. With methyl,phenyl-
substituted 1,3-diol, a selectivity factor of 29 was achieved,
providing 1,3-diol 2q in 40% yield and excellent enantio-
selectivity, with an er of 99:1 (entry 11). A 1,3-diol with methyl
and naphthyl substituents afforded a still good but slightly lower
selectivity factor of 16 (entry 12).
We also examined whether diols with secondary alcohol
stereocenters, which are usually preferred substrates for other
kinetic resolutions,8,9 are suitable substrates for our catalytic
system. Disappointingly, almost no selectivity was observed for
the resolution of diol rac-2s (entry 13). However, an important
aspect of our acetalization reaction was revealed in this case.
Because of the exceptional enantiocontrol of our catalyst in
creating the acetal stereogenic center, the kinetic resolution is
applicable even to cases where the actual enantiomer differ-
entiation is poor. As the enantiomers are being converted into
two different diastereomers, the reaction can be run to full
differentiation is not satisfactory in these cases, excellent control
of the acetal stereocenter channels the two diol enantiomers into
two highly enantioenriched acetal diastereomers. These can be
separated by chromatography on silica gel. In the subsequent
deprotection step, enantioenriched diols (R)-2p, (S)-2p and
(R)-2s, (S)-2s could be obtained from the corresponding acetals
(Scheme 2). It is noteworthy that, from a single asymmetric
reaction using one configuration of catalyst, both enantiomers of
the diols rac-2p and rac-2s could be obtained with very high
enantiomeric ratios.
Based on our previous results,10d we propose that the
cyclization of an oxocarbenium intermediate is the enantio-
discriminating step in our reaction (Figure 1). The OH group at
the tertiary stereocenter is presumably hydrogen bonded to the
chiral imidodiphosphate anion, placing the alcohol stereocenter
in its close vicinity, which results in an efficient kinetic resolution
B
DOI: 10.1021/ja512481d
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Table 2. Diol Scope
a
b
Theoretical conversion calculated from ee values of the product and the recovered starting material (see SI). Isolated yield on a 0.5 mmol scale.
c
d
e
Determined by HPLC or GC analysis on a chiral stationary phase. For most minor diastereomers er ≥ 98:2. Calculated from theoretical
f
conversion and enantiomeric excess of enantioenriched diol (see SI). The reaction was performed at 0 °C.
factors up to >300.14 The reaction provides free enantioenriched
diols and acetal-protected diols with excellent enantio-
selectivities. 1,2-Diols possessing similar aliphatic substituents
at the tertiary alcohol stereocenter, which are hard to obtain by
other methods, can be resolved via separation of diastereomeric
acetal products. Further studies regarding the applications of
asymmetric acetalizations and our confined Brønsted acids are
ongoing.
Figure 1. Suggested pre-transition-state assembly explaining the
preferred cis-diastereomer selectivity.
in the cyclization step. Additional oxocarbenium C−H···anion
hydrogen bonding potentially further stabilizes the transition
state.12 The aldehyde alkyl chain and the larger alcohol substituent
both take pseudoequatorial positions in the five-membered
transition state, resulting in their cis relationship in the products.13
In summary, the first kinetic resolution of diols via asymmetric
acetalization reaction has been disclosed, achieving selectivity
ASSOCIATED CONTENT
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S
* Supporting Information
Experimental procedures and compound characterization.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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DOI: 10.1021/ja512481d
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
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(10) (a) Coric,
́
I.; Vellalath, S.; List, B. J. Am. Chem. Soc. 2010, 132,
AUTHOR INFORMATION
Corresponding Author
*list@kofo.mpg.de.
Notes
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̌
8536. (b) Coric, I.; Muller, S.; List, B. J. Am. Chem. Soc. 2010, 132,
17370. (c) Coric,
I.; Vellalath, S.; List, B. Angew. Chem., Int. Ed. 2013, 52, 4474. (e) Coric,
́
̈
̌
̌
́ ́
I.; List, B. Nature 2012, 483, 315. (d) Kim, J. H.; Coric,
̌
́
I.; Vellalath, S.; Muller, S.; Cheng, X.; List, B. Top. Organomet. Chem.
̈
2013, 44, 165. (f) Sun, Z. K.; Winschel, G. A.; Borovika, A.; Nagorny, P.
J. Am. Chem. Soc. 2012, 134, 8074. (g) Mensah, E.; Camasso, N.; Kaplan,
W.; Nagorny, P. Angew. Chem., Int. Ed. 2013, 52, 12932. (h) Handa, S.;
Slaughter, L. M. Angew. Chem., Int. Ed. 2012, 51, 2912. (i) Nagano, H.;
Katsuki, T. Chem. Lett. 2002, 31, 782. (j) Lim, W.; Kim, J.; Rhee, Y. H. J.
Am. Chem. Soc. 2014, 136, 13618. (k) Chen, Z.; Sun, J. Angew. Chem., Int.
Ed. 2013, 52, 13593.
(11) Chen, W.; Lin, L.; Cai, Y.; Xia, Y.; Cao, W.; Liu, X.; Feng, X. Chem.
Commun. 2014, 50, 2161.
(12) Terada, M.; Tanaka, H.; Sorimachi, K. J. Am. Chem. Soc. 2009,
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(13) Willy, W. E.; Binsch, G.; Eliel, E. L. J. Am. Chem. Soc. 1970, 92,
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(14) During the revision of this manuscript, a kinetic resolution of
amino alcohols via intermolecular acetalization of enol ethers has been
reported: Yamanaka, T.; Kondoh, A.; Terada, M.; J. Am. Chem. Soc.
2015, DOI: 10.1021/ja512238n.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We gratefully acknowledge generous support from the Max
Planck Society. C.P. is thankful to the Ministero dell’Istruzione,
dell’Universita e della Ricerca (MIUR), for a fellowship. We
̀
thank Natascha Wippich and Jutta Rosentreter for technical
assistance.
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DOI: 10.1021/ja512481d
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX