Catalytic asymmetric transacetalization

Article abstract of DOI:10.1021/ja102753d

A catalytic enantioselective transacetalization has been developed. The chiral phosphoric acid TRIP was demonstrated to be an efficient and highly enantioselective catalyst for the activation of O, O-acetals. The reaction enables the asymmetric synthesis of acetals with the acetal carbon as the only stereogenic center.

Full text of DOI:10.1021/ja102753d

Published on Web 06/07/2010
Catalytic Asymmetric Transacetalization
ˇ
Ilija Coric´, Sreekumar Vellalath, and Benjamin List*
Max-Planck-Institut fu¨r Kohlenforschung, Kaiser-Wilhelm-Platz 1, D-45470, Mu¨lheim an der Ruhr, Germany
Received April 9, 2010; E-mail: list@mpi-muelheim.mpg.de
Table 1. Optimization of Reaction Conditionsa
Stereogenic acetals are ubiquitous in natural products, ranging
from simple carbohydrates to complex spiroketal polyketides.1
Controlling their relative and absolute configuration can be
extremely important. For example, starch and cellulose only vary
in the configuration at their anomeric acetal stereocenter.2 The
importance of chiral acetals is further illustrated by their occurrence
in a variety of chiral pharmaceuticals and their potential as
diastereocontrolling elements in organic synthesis.3,4 Nevertheless,
methods for the enantioselectiVe synthesis of stereogenic acetals
are very limited and usually based on chiral starting materials or
reagents.5 Catalytic enantioselective approaches employ enzymatic
resolutions or metal-catalyzed desymmetrizations, in which the
entry
catalyst
solvent
time
er
acetal carbon is not a reaction center.6 Only a single catalytic
asymmetric formation of acetals was previously achieved via a
metal-catalyzed hydroetherification of enol ethers.7 Here we report
a Brønsted acid catalyzed asymmetric transacetalization reaction
that furnishes chiral acetals with excellent enantioselectivity.
Recent advances in enantioselective Brønsted acid catalysis have
enabled the generation of chiral N,N- and N,O-acetals.8 The
enantiodifferentiation in these reactions is based on the ability of
chiral phosphoric acids to asymmetrically control the addition of
nucleophiles to imines.9 While related enantioselective additions
to oxocarbenium ion intermediates could potentially lead to chiral
O,O-acetals, this reactivity is much less explored.10 We have a long-
standing interest in catalytic asymmetric acetalizations and are now
focusing on the transacetalization reaction in which one alkoxy
group of an acetal is exchanged with another one (eq 1).
1b
2
3
4
5
1a
1a
1a
1a
1a
1a
1b
1c
CHCl3
CHCl3
toluene
hexane
benzene
CHCl3/benzene 1:1
CHCl3/benzene 1:1
CHCl3/benzene 1:1
benzene
6 h
4 h
2 h
1 h
2 h
76.0:24.0
91.0:9.0
87.0:13.0
71.0:29.0
90.0:10.0
91.5:8.5
22.0:78.0
82.0:18.0
94.5:5.5
6
7
3 h
<1 h
<1 h
48 h
8
9c
1a (1 mol %)
a Unless otherwise specified, reactions were performed on 0.025
mmol scale (0.1 M solution), 4 Å MS (10 mg) at room temperature.
b Without MS. c 0.025 M solution, 20 °C.
mixture gave a significant increase in enantioselectivity (entry 2).
This suggested that ethanol, which is formed during the reaction,
has a detrimental effect on the enantioselectivity. Additional solvent
and catalyst screenings (including acids 1b and 1c) left TRIP
remaining as the optimal catalyst. Remarkably, reducing both
catalyst loading and concentration improved the enantioselectivity
and an er of 94.5:5.5 was achieved with only 1 mol % of TRIP
(entry 9).
Although transacetalization reactions usually require relatively
strong Brønsted acid catalysts, we reasoned that an intramolecular
variant might be amenable to mild asymmetric Brønsted acid
catalysis. We envisioned that this design could potentially address
problems resulting from the reversibility of the reaction and product
racemization. As Brønsted acids generally activate acetals by
catalyzing the formation of an oxocarbenium ion intermediate, we
expected that a chiral counteranion would provide an asymmetric
environment for the subsequent alcohol attack.10,11
We began our investigation by studying the reaction of alcohol
2a to acetal 3a using Brønsted acid catalyst 1a (TRIP), with bulky
2,4,6-(iPr)3C6H2 substituents in 3,3′-positions.12 Several reports have
established TRIP as one of the more useful and general phosphoric
acid catalysts.13 With 5 mol % of (S)-TRIP in CHCl3, the
intramolecular transacetalization of substrate 2a proceeded with a
promising er of 76:24 (Table 1, entry 1). Gratifyingly, a prolonged
reaction time did not lead to any observable decrease in optical
purity, suggesting that, under the reaction conditions, the rates of
the reverse reaction and product racemization via an oxocarbenium
ion were not competitive. Adding molecular sieves to the reaction
Having established these optimized conditions, we set out to
explore the substrate scope. Substrates 2 were easily available in
one or two steps from commercial materials. In some cases neat
substrates 2 undergo a slow intramolecular transacetalization
spontaneously. However this can be avoided by storing the
substrates as solutions in diethyl ether or ethyl acetate and
evaporating the solvent shortly before the enantioselective transac-
etalization. Exploration of the substrate scope revealed that various
tertiary alcohols form five-membered cyclic acetals 3 in excellent
yields and with high enantiomeric ratios (Table 2). Interestingly,
aliphatic and aromatic substituents on the alcohol are tolerated
equally well. Both electron-rich and -poor aromatic substituents
are suitable. In the case of aliphatic substituents, increased bulkiness
led to higher enantioselectivity, with isopropyl substituted alcohol
3h giving the highest enantiomeric ratio of 98:2 (entry 8).
Intramolecular transacetalization can also be applied to the parallel
kinetic resolution of chiral tertiary alcohols. Acetal 3l, which
contains a quaternary carbon stereogenic center, was obtained from
the corresponding racemic alcohol precursor in excellent yield and
high enantioselectivity for both diastereomers (er 91:9 and er 96:4,
9
8536 J. AM. CHEM. SOC. 2010, 132, 8536–8537
10.1021/ja102753d  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Substrate Scope of the Enantioselective Intramolecular
assembly such as A might account for the selective activation of
the hydroxyl acetal. The hydroxyl moiety in the substrate serves
as a directing group and also increases the acidity of the phosphoric
acid through hydrogen bonding. Subsequent cyclization might
proceed through an oxocarbenium intermediate, in which the
phosphate anion provides a chiral environment through hydrogen
bonding interactions with the oxocarbenium ion moiety and the
hydroxyl group (B) or by a more SN2-like pathway (C).
Transacetalization Reactiona
In summary, we report the first catalytic enantioselective
intramolecular transacetalization reaction, furnishing chiral acetals
with the acetal carbon as the only stereogenic center. We are
unaware of previous reports on phosphoric acid catalyzed enanti-
oselective addition of nucleophiles to simple O,O-acetals. Further
studies of this novel transformation and similar processes are
currently underway in our laboratories.
Acknowledgment. We thank the Alexander von Humboldt
Foundation (fellowship for S.V.), the Max-Planck-Society, the DFG
(Priority Program Organocatalysis SPP1179), and the Fonds der
Chemischen Industrie (Award to B.L.).
Supporting Information Available: Experimental procedures,
compound characterization, and X-ray data for compound 3d. This
material is available free of charge via the Internet at http://pubs.acs.org.
References
(1) Aho, J. E.; Pihko, P. M.; Rissa, T. K. Chem. ReV. 2005, 105, 4406.
(2) Carey, F. A. Organic Chemistry, 6th ed.; McGraw-Hill: 2006.
(3) (a) Felix, W.; Rimbach, G.; Wengenroth, H. Arzneim.-Forsch. 1969, 19,
1860. (b) Mavragani, C. P.; Moutsopoulos, H. M. Clinic ReV. Allerg.
Immunol. 2007, 32, 287.
(4) (a) Seebach, D.; Sting, A. R.; Hoffmann, M. Angew. Chem., Int. Ed. Engl.
1996, 35, 2708. (b) Schmalz, H.-G.; Heꢀler, E.; Bats, J. W.; Du¨rner, G.
Tetrahedron Lett. 1994, 35, 4543. (c) Rehnberg, N.; Sundin, A.; Magnusson,
G. J. Org. Chem. 1990, 55, 5477. (d) Carreira, E. M.; Kvaerno, L. Classics
in StereoselectiVe Synthesis; Wiley-VCH: 2009.
(5) (a) Matsutani, H.; Ichikawa, S.; Yaruva, J.; Kasumoto, T.; Hiyama, T. J. Am.
Chem. Soc. 1997, 119, 4541. (b) Davies, S. G.; Correia, L. M. A. R. B.
Chem. Commun. 1996, 1803. (c) Spantulescu, M. D.; Boudreau, M. A.;
Vederas, J. C. Org. Lett. 2009, 11, 645. (d) Uchiyama, M.; Oka, M.; Harai,
S.; Ohta, A. Tetrahedron Lett. 2001, 42, 1931. (e) Rychnovsky, S. D.; Bax,
B. M. Tetrahedron Lett. 2000, 41, 3593.
(6) (a) Fletcher, S. J.; Rayner, C. M. Tetrahedron Lett. 1999, 40, 7139. (b)
Weatherhead, G. S.; Houser, J. H.; Ford, J. G.; Jamieson, J. Y.; Schrock,
R. R.; Hoveyda, A. H. Tetrahedron Lett. 2000, 41, 9553. (c) Hoveyda,
A. H.; Schrock, R. R. Chem.sEur. J. 2001, 7, 945. (d) Burke, S. D.; Mu¨ller,
N.; Beaudry, C. M. Org. Lett. 1999, 1, 1827. (e) Frauenrath, H.; Philipps,
T. Angew. Chem., Int. Ed. Engl. 1986, 25, 274. (f) Frauenrath, H.; Reim,
S.; Wiesner, A. Tetrahedron: Asymmetry 1998, 9, 1103.
(7) (a) Nagano, H.; Katsuki, T. Chem. Lett. 2002, 31, 782. For an attempt at
direct carbonyl acetalization, see: (b) Barbaro, P.; Bianchini, C.; Oberhauser,
W.; Togni, A. J. Mol. Catal. A 1999, 145, 139.
(8) (a) Rowland, G. B.; Zhang, H.; Rowland, E. B.; Chennamadhavuni, S.;
Wang, Y.; Antilla, J. C. J. Am. Chem. Soc. 2005, 127, 15696. (b) Liang,
Y.; Rowland, E. B.; Rowland, G. B.; Perman, J. A.; Antilla, J. C. Chem.
Commun. 2007, 4477. (c) Li, G.; Fronczek, F. R.; Antilla, J. C. J. Am.
Chem. Soc. 2008, 130, 12216. (d) Cheng, X.; Vellalath, S.; Goddard, R.;
List, B. J. Am. Chem. Soc. 2008, 130, 15786. (e) Rueping, M.; Antonchick,
A. P.; Sugiono, E.; Grenader, K. Angew. Chem., Int. Ed. 2009, 48, 908.
(9) (a) Terada, M. Chem. Commun. 2008, 4097. (b) Akiyama, T. Chem. ReV.
2007, 107, 5744.
a Unless otherwise specified, reactions were performed on 0.3 mmol
scale with molecular sieves (50 mg/0.1 mmol). All yields refer to
isolated yields. Enantiomeric ratios were determined by HPLC or GC
analysis on a chiral stationary phase. b Reaction performed on 0.9 mmol
scale. c Reaction time: 3e, 7 days; 3n, 4 days; 3o, 30 min. d For yield
determination see Supporting Information.
entry 12). The effect of the pre-existing stereogenic center on the
stereoselectivity appears to be small. Longer O-alkyl substituents
(ethyl vs n-propyl, entry 13) are well tolerated. Our reaction could
also be extended to a six-membered acetal (entry 14) and ones that
are derived from primary alcohols (entries 15 and 16). Products
3n, 3o, and 3p were formed in high yield but lower enantioselec-
tivity.
(10) (a) Reisman, S. E.; Doyle, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2008,
130, 7198. (b) Terada, M.; Tanaka, H.; Sorimachi, K. J. Am. Chem. Soc.
2009, 131, 3430. (c) Zhang, Q.-W.; Fan, C.-A.; Zhang, H.-J.; Tu, Y.-Q.;
Zhao, Y.-M.; Gu, P.; Chen, Z.-M. Angew. Chem., Int. Ed. 2009, 48, 8572.
(11) Mayer, S.; List, B. Angew. Chem., Int. Ed. 2006, 45, 4193.
(12) Hoffmann, S.; Seayad, A. M.; List, B. Angew. Chem., Int. Ed. 2005, 44,
7424.
The absolute configuration of acetal 3d was determined to be
(R) by single-crystal X-ray analysis. Configurations of other
products were assigned by analogy. Product 3d was obtained on a
0.9 mmol scale in 99% isolated yield and with an er of 97:3.
Regarding the mechanism of the reaction, we speculate that the
bifunctional character of the phosphoric acid is crucial for the
observed reactivity and enantioselectivity. A hydrogen bonded
(13) Adair, G.; Mukherjee, S.; List, B. Aldrichimica Acta 2008, 41, 31.
JA102753D
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J. AM. CHEM. SOC. VOL. 132, NO. 25, 2010 8537