The catalytic asymmetric acetalization

Article abstract of DOI:10.1002/anie.201300120

In straitened circumstances: In an asymmetric version of the acid-catalyzed acetalization of aldehydes, a novel member of the chiral confined Bronsted acid family significantly outperformed previously established catalysts, providing cyclic acetals with e

Full text of DOI:10.1002/anie.201300120

Angewandte
Chemie
DOI: 10.1002/anie.201300120
Acetals
The Catalytic Asymmetric Acetalization**
ˇ
´
Ji Hye Kim, Ilija Coric, Sreekumar Vellalath, and Benjamin List*
The Brønsted acid catalyzed acetalization of aldehydes with
Table 1: Catalyst discovery.
alcohols is one of the most common transformations in
organic synthesis and yet catalytic asymmetric versions, until
today, have been entirely unknown [Eq. (1)].[1] The advent of
Entry
Catalyst
(mol%)
t[a]
Conv. [%]
e.r.
1
2
3
4
5
6
7
8
4a (10)
5 (10)
4b (10)
6 (10)
7 d
7 d
7 d
7 d
7 d
7 d
2 h
2 h
7 d
3 h
20 h
22 h
4 d
48 h
48 h
66
19
50
31
66.5:33.5
79:21
52.5: 47.5
51.5:48.5
79:21
asymmetric Brønsted acid catalysis has recently enabled the
enantioselective generation of chiral N,N-, N,O-, and N,S-
acetals, either from imines or directly from aldehydes.[2,3] The
success of these reactions is based on the well-established
ability of chiral phosphoric acids to direct the enantioselective
addition of nucleophiles to imines.[3] However, the corre-
sponding enantioselective additions to oxocarbenium ion
intermediates, which are required for obtaining O,O-acetals,
are much less developed.[4] Although acetals are among the
most common stereocenters in organic molecules,[5] there are
only few examples of their catalytic asymmetric synthesis.[6,7]
We have recently reported that chiral Brønsted acids catalyze
intramolecular asymmetric transacetalizations and
spiroacetalizations generating chiral acetals with
high enantioselectivity.[8,9] However, although our
laboratory has pursued the direct asymmetric acetal-
ization of aldehydes with alcohols for many years now,
and has investigated numerous chiral Brønsted acid
catalysts, unfortunately, very little success towards this
goal has been encountered. Here we report that a new
member of our recently developed class of chiral
confined Brønsted acids finally enables this elusive
transformation with excellent selectivity and scope.
The summary of our investigations towards asym-
7a (10)
7b (10)
7c (10)
7d (10)
7e (10)
7 f (10)
7g (10)
7g (5)
7h (5)
7i (5)
66
<5
>99
>99
91
>99
>99
>99
>99
>99
>99
–
71:29
41.5:58.5
81:19
84.5:15.5
90:10
90.5:9.5
93.5:6.5
95:5
9
10
11
12
13
14
15[b]
7i (5)
95.5:4.5
[a] d=day. [b] 2 equiv of 2a, 10 mg of molecular sieves, 0.1m concen-
tration.
metric acetalization with diol 1a and aldehyde 2a is
given in Table 1. A catalytic amount of TRIP (4a;
Scheme 1), one of the most successful phosphoric acid
catalysts,[10,3f] catalyzes the reaction at room temper-
ature giving cyclic acetal 3a with an e.r. (enantiomeric
Scheme 1. Catalysts 4–7.
ratio) of 66.5:33.5 and 66% conversion after 7 days
(Table 1, entry 1). The recently developed spirocyclic
analogue STRIP (5), which proved to be superior to TRIP on
several occasions, gave a slightly improved e.r. of 79:21, but
displayed lower reactivity (Table 1, entry 2).[8b] Catalysts 4b
and 6, which provided excellent results for the related N,N-
and N,O-acetalizations of aldehydes,[2e,f] did not give any
improvement (Table 1, entries 3 and 4). This striking failure
of some of the most successful phosphoric acid catalysts
illustrates the general difficulty of dealing with oxocarbenium
ion intermediates in Brønsted acid catalysis.
ˇ
´
[*] J. H. Kim, I. Coric, Dr. S. Vellalath, Prof. Dr. B. List
Max-Planck-Institut fꢀr Kohlenforschung
Kaiser-Wilhelm-Platz 1, 45470 Mꢀlheim an der Ruhr (Germany)
E-mail: list@kofo.mpg.de
[**] We thank H. Schucht for crystal structure analyses. Generous
support from the Max Planck Society and the European Research
Council (Advanced Grant “High Performance Lewis Acid Organo-
catalysis, HIPOCAT”) is gratefully acknowledged.
Recently, our group has developed a new generation of
stronger Brønsted acids, based on a C2-symmetric imidodi-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201300120.
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!

.
Angewandte
Communications
phosphate anion.[9a,11,12] The architecture of these catalysts
enables the construction of chiral confined Brønsted acids
with extremely sterically demanding chiral environments. We
hypothesized that in such a surrounding, a putative oxocar-
benium ion intermediate could be geometrically restrained.
This would result in a reduction of transition-state diversity,
leading to an increased enantioselectivity. However, testing
our previously reported confined acids 7a,b for the acetaliza-
tion reaction did not result in an improvement of the
enantioselectivity and reactivity (Table 1, entries 5 and 6).
We reasoned that the chiral environment created by
imidodiphosphoric acids 7a,b might be either too sterically
demanding or of inappropriate geometrical shape to effi-
ciently support the transition state of the acetalization.
However, our design of the imidodiphosphoric acids enables
the construction of very diverse chiral environments. Owing
to the presence of four substituents R, the steric demand of
the active site remains very high even with less sterically
demanding substituents. In comparison, with phosphoric acids
that possess only two substituents, these are often required to
be very bulky, limiting the choice of the substituent and
consequently the geometrical variability of the chiral environ-
ment.
We tested several imidodiphosphoric acid catalysts 7c–
i with a variety of substituents R. Catalysts 7c and 7d with
electron-withdrawing 3,5-(CF3)2C6H3 and C6F5 substituents
were especially active, giving full conversion in two hours,
although with low enantioselectivity (Table 1, entries 7 and
8). Catalysts 7e–g with various substitution patterns all gave
improved enantioselectivity and reactivity compared to
catalysts 4a,b, 5, 6, and 7a,b (Table 1, entries 9–11). The
striking differences in the reactivity and selectivity between
catalysts 7a,b and 7e, compared to catalysts 7 f,g emphasize
the structural versatility of the active sites available with our
confined acids. For example, while catalyst 7 f with p-biphenyl
substituents provided full conversion in 3 h, catalyst 7b was
almost completely inactive. Presumably, the four 9-anthra-
cenyl substituents in 7b completely block access of the
substrates to the active site. To our delight, confined
imidodiphosphoric acid 7g with the unsymmetrical 1-naph-
thyl substituent gave a promising enantiomeric ratio of 90:10
and allowed for lower catalyst loading (Table 1, entries 11 and
12).[12] Focusing on nonsymmetric substituents R, we next
tested the o-isopropylphenyl-substituted catalyst 7h, which
further improved the enantioselectivity (Table 1, entry 13).
Based on modeling studies, we expected that an extra
substituent in the 4- or 5-position on the 2-iPr-phenyl group
might provide a more rigid catalyst structure by increasing the
steric interaction between different substituents. Gratifyingly,
catalyst 7i, which was prepared from the natural product
thymol, enabled a highly enantioselective reaction giving
acetal 3a with an enantiomeric ratio of 95.5:4.5 (Table 1,
entries 14 and 15).
Table 2: Asymmetric acetalization of aliphatic aldehydes.
Entry T, t[a]
Product
Yield [%] e.r.
1
2
RT, 2 d
86
82
96:4
RT, 4 d
95:5
3
4
5
508C, 10 d
RT, 4 d
93
83
75
94.5:5.5
94.5:5.5
93.5:6.5
RT, 4 d
6
7
8
9
RT, 4 d
508C, 6 d
RT, 2 d
RT, 2 d
86
83
93
86
91.5:8.5
96.5:3.5
95.5:4.5
97.5:2.5
10
11
08C, 22 h
72
72
99.8:0.2
99:1
RT, 3 d
12
RT, 10 d
82
99.5:0.5
[a] d=day.
still good but slightly lower enantioselectivities (Table 2,
entries 4–6). We next investigated the applicability of this
catalytic system to other classes of diols. Gratifyingly, with
a simple aliphatic 1,3-diol (3-methylbutane-1,3-diol, 1b), the
enantioselectivity was even higher and enantiomeric ratios
between 95.5:4.5 and 97.5:2.5 could be obtained (Table 2,
entries 7–9). Encouraged by these results we next tackled the
acetalization with a 1,2-diol to access five-membered acetals.
Acetalization of isovaleraldehyde with 2-methylpropane-1,2-
diol (1c) proceeded with exceptional enantioselectivity giving
product 3j with an e.r. of 99.8:0.2 at 08C (Table 2, entry 10).
Linear and a-branched aldehydes could be employed with
equal success in the reaction (Table 2, entries 11 and 12),
although lower reactivity was observed with the branched
aldehyde.
Although our asymmetric acetalization reaction could be
performed with aliphatic aldehydes very efficiently, aromatic
aldehydes present an additional challenge as these are more
sensitive towards acid-catalyzed racemization under the
reaction conditions. Gratifyingly, catalyst 7i enabled the
asymmetric acetalization of benzaldehyde with 1,2-diol 1c
giving the five-membered acetal 3m in 89% yield with an e.r.
of 95.5:4.5 (Table 3, entry 1). Encouraged by this result, we
Having established satisfactory conditions, we set out to
explore the generality of the reaction (Table 2). Placing
chloro or nitro substituents on the aromatic ring of the diol
does not significantly affect the enantioselectivity, although
with the nitro-substituted diol the reactivity was significantly
lower (Table 2, entries 2 and 3). Different aldehydes afforded
2
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Table 3: Asymmetric acetalization of aromatic aldehydes.
Entry
1
T, t[a]
Product
Yield [%]
89
e.r.
RT, 2 d
95.5:4.5
2
3
RT, 62 h
RT, 42 h
79
74
98:2
96:4
Scheme 2. Plausible mechanism.
4a
4b
RT, 5 d
508C, 4 d
65
85
98.5:1.5
95:5
formation of hemiacetal intermediate A. Protonation of its
OH moiety by the catalyst results in the expulsion of a water
molecule and formation of the crucial oxocarbenium ion
intermediate B. The chiral imidodiphosphate counteranion
provides a chiral environment for the oxocarbenium cation,[13]
and functions as a base that directs the nucleophilic attack of
the second alcohol moiety to the si face of the oxocarbenium
ion furnishing the S-configured cyclic acetal.
Based on initial mechanistic studies we believe that
alternative pathways proceeding through tertiary-alcohol-
and phenol-derived oxocarbenium ions are less probable. We
have prepared racemic methyl acetal derivatives of the
proposed hemiacetal intermediates A (OMe instead of
OH), as alternative precursors for oxocarbenium ions B1
and B2. When treated with catalyst 7i these gave enantiose-
lectivities that are very similar to those obtained in the direct
acetalization reactions. In contrast, the acetal precursors for
the tertiary-alcohol- and phenol-derived oxocarbenium ions
gave different results (see the Supporting Information for
details).
In summary, we have developed the first catalytic
asymmetric acetalization of aldehydes. We demonstrate that
imidodiphosphoric acids are an excellent platform for the
construction of Brønsted acids with structurally versatile
confined chiral microenvironments. A novel Brønsted acid,
7i, readily available from natural thymol, drastically outper-
forms known catalysts and delivered acetals with excellent
enantioselectivity. Several practical applications of our meth-
odology, for example in kinetic resolutions, can be envisioned.
Also, selective substitution reactions at the acetal stereogenic
center with preservation of enantiopurity are appealing.
Further exploration of the asymmetric acetalization and
confined chiral Brønsted acid catalysts is in progress in our
laboratories.
5
6
7
508C, 6 d
608C, 7 d
RT, 52 h
83
79
77
99.5:0.5
97.5:2.5
96.5:3.5
[a] d=day.
next tested a variety of aromatic aldehydes. Acetals 3n–p with
substituents in either p- or m-positions on the phenyl ring
could be obtained with excellent enantioselectivity (Table 3,
entries 2–4). With disubstituted benzaldehydes 3q,r equally
excellent enantiomeric ratios of 99.5:0.5 and 97.5:2.5 were
obtained, even at slightly elevated reaction temperatures
(Table 3, entries 5 and 6). Likewise, the asymmetric acetali-
zation of 6-bromo-2-naphthaldehyde proceeded with a high
enantiomeric ratio of 96.5:3.5 (Table 3, entry 7). The absolute
configurations of acetals 3 f and 3s were determined to be S
by single-crystal X-ray analysis (Figure 1). The configurations
of other products were assigned by analogy.
A proposed mechanism for our asymmetric acetalization
is shown in Scheme 2. Initially, the reversible addition of the
primary alcohol moiety of the diol to the aldehyde leads to the
Received: January 7, 2013
Published online: && &&, &&&&
Keywords: acetalization · acetals · asymmetric catalysis ·
.
confined Brønsted acids · organocatalysis
[1] For an attempt using metal catalysis see: P. Barbaro, C.
Bianchini, W. Oberhauser, A. Togni, J. Mol. Catal. A 1999,
145, 139.
Figure 1. Crystal structures of acetals 3 f and 3s (ellipsoids at the 50%
probability level).[14]
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

.
Angewandte
Communications
[2] a) G. B. Rowland, H. Zhang, E. B. Rowland, S. Chennamadha-
vuni, Y. Wang, J. C. Antilla, J. Am. Chem. Soc. 2005, 127, 15696;
b) Y. Liang, E. B. Rowland, G. B. Rowland, J. A. Perman, J. C.
Antilla, Chem. Commun. 2007, 4477; c) G. Li, F. R. Fronczek,
J. C. Antilla, J. Am. Chem. Soc. 2008, 130, 12216; d) G. K. Ingle,
M. G. Mormino, L. Wojtas, J. C. Antilla, Org. Lett. 2011, 13,
4822; e) X. Cheng, S. Vellalath, R. Goddard, B. List, J. Am.
98, 261; Angew. Chem. Int. Ed. Engl. 1986, 25, 274; b) H.
Frauenrath, S. Reim, A. Wiesner, Tetrahedron: Asymmetry 1998,
9, 1103; c) S. D. Burke, N. Mꢀller, C. M. Beaudry, Org. Lett.
1999, 1, 1827; d) S. J. Fletcher, C. M. Rayner, Tetrahedron Lett.
1999, 40, 7139; e) G. S. Weatherhead, J. H. Houser, J. G. Ford,
J. Y. Jamieson, R. R. Schrock, A. H. Hoveyda, Tetrahedron Lett.
2000, 41, 9553; f) A. H. Hoveyda, R. R. Schrock, Chem. Eur. J.
2001, 7, 945.
ˇ
´
Chem. Soc. 2008, 130, 15786; f) S. Vellalath, I. Coric, B. List,
Angew. Chem. 2010, 122, 9943; Angew. Chem. Int. Ed. 2010, 49,
9749; g) M. Rueping, A. P. Antonchick, E. Sugiono, K. Gre-
nader, Angew. Chem. 2009, 121, 925; Angew. Chem. Int. Ed.
2009, 48, 908.
ˇ
´
[8] a) I. Coric, S. Vellalath, B. List, J. Am. Chem. Soc. 2010, 132,
ˇ
´
8536; b) I. Coric, S. Mꢀller, B. List, J. Am. Chem. Soc. 2010, 132,
17370.
ˇ
ˇ
´
´
[9] a) I. Coric, B. List, Nature 2012, 483, 315; b) I. Coric, S. Vellalath,
S. Mꢀller, X. Cheng, B. List, Top. Organomet. Chem. 2013, 44,
165; For subsequent report on asymmetric spiroacetalization,
see: c) Z. Sun, G. A. Winschel, A. Borovika, P. Nagorny, J. Am.
Chem. Soc. 2012, 134, 8074.
[3] a) T. Akiyama, J. Itoh, K. Yokota, K. Fuchibe, Angew. Chem.
2004, 116, 1592; Angew. Chem. Int. Ed. 2004, 43, 1566; b) D.
Uraguchi, M. Terada, J. Am. Chem. Soc. 2004, 126, 5356; c) T.
Akiyama, Chem. Rev. 2007, 107, 5744; d) M. Terada, Synthesis
2010, 1929; For discussions on the role of metal impurities see:
e) M. Hatano, K. Moriyama, T. Maki, K. Ishihara, Angew. Chem.
2010, 122, 3911; Angew. Chem. Int. Ed. 2010, 49, 3823; f) M.
Klussmann, L. Ratjen, S. Hoffmann, V. Wakchaure, R. Goddard,
B. List, Synlett 2010, 2189.
[10] a) S. Hoffmann, A. M. Seayad, B. List, Angew. Chem. 2005, 117,
7590; Angew. Chem. Int. Ed. 2005, 44, 7424; b) G. Adair, S.
Mukherjee, B. List, Aldrichimica Acta 2008, 41, 31.
ˇ
´
[11] S. Liao, I. Coric, Q. Wang, B. List, J. Am. Chem. Soc. 2012, 134,
10765.
[4] a) S. E. Reisman, A. G. Doyle, E. N. Jacobsen, J. Am. Chem. Soc.
2008, 130, 7198; b) M. Terada, H. Tanaka, K. Sorimachi, J. Am.
Chem. Soc. 2009, 131, 3430; c) Q.-W. Zhang, C.-A. Fan, H.-J.
Zhang, Y.-Q. Tu, Y.-M. Zhao, P. Gu, Z.-M. Chen, Angew. Chem.
2009, 121, 8724; Angew. Chem. Int. Ed. 2009, 48, 8572.
[12] For subsequent reports on the use of imidodiphosphoric acid
catalysts see: a) Y.-Y. Chen, Y.-J. Jiang, Y.-S. Fan, D. Sha, Q.
Wang, G. Zhang, L. Zheng, S. Zhang, Tetrahedron: Asymmetry
2012, 23, 904; b) K. Wu, Y.-J. Jiang, Y.-S. Fan, D. Sha, S. Zhang,
Chem. Eur. J. 2013, 19, 474.
[5] a) E. M. Carreira, L. Kvaerno, Classics in Stereoselective Syn-
thesis, Wiley-VCH, Weinheim, 2009; b) J. E. Aho, P. M. Pihko,
T. K. Rissa, Chem. Rev. 2005, 105, 4406.
[6] a) H. Nagano, T. Katsuki, Chem. Lett. 2002, 31, 782; b) Y.
Kawamura, Y. Kawano, T. Matsuda, Y. Ishitobi, T. Hosokawa, J.
Org. Chem. 2009, 74, 3048; c) S. Handa, L. M. Slaughter, Angew.
Chem. 2012, 124, 2966; Angew. Chem. Int. Ed. 2012, 51, 2912.
[7] For methods in which the acetal carbon is not the reaction
center, see: a) H. Frauenrath, T. Philipps, Angew. Chem. 1986,
[13] a) S. Mayer, B. List, Angew. Chem. 2006, 118, 4299; Angew.
Chem. Int. Ed. 2006, 45, 4193; b) M. Mahlau, B. List, Angew.
Chem. 2013, 125, 540; Angew. Chem. Int. Ed. 2013, 52, 518;
c) R. J. Phipps, G. L. Hamilton, F. D. Toste, Nat. Chem. 2012, 4,
603.
[14] CCDC 915231 (3 f) and 915232 (3s) contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
4
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Communications
Acetals
ˇ
´
J. H. Kim, I. Coric, S. Vellalath,
B. List*
&&&& — &&&&
The Catalytic Asymmetric Acetalization
In straitened circumstances: In an asym-
metric version of the acid-catalyzed ace-
talization of aldehydes, a novel member
of the chiral confined Brønsted acid
family significantly outperformed previ-
ously established catalysts, providing
cyclic acetals with excellent enantioselec-
tivity (see scheme; Ar=2-iPr-5-MeC6H3).
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!