A chiral-anion generator: Application to catalytic desilylative kinetic resolution of silyl-protected secondary alcohols

Article abstract of DOI:10.1002/anie.201004777

Getting the grips on fluoride: Chiral hydroxy-terminated polyethers bearing a 3,3′-halogen-substituted chiral 1,1′-bi-2-naphthol (BINOL) unit manifest a new structural motif for chiral-anion generators. Their unique properties are revealed through highly enantioselective desilylative kinetic resolution of a variety of silyl-protected racemic alcohols with KF (see scheme).

Full text of DOI:10.1002/anie.201004777

Angewandte
Chemie
DOI: 10.1002/anie.201004777
Chiral Anions
A Chiral-Anion Generator: Application to Catalytic Desilylative
Kinetic Resolution of Silyl-Protected Secondary Alcohols**
Hailong Yan, Hyeong Bin Jang, Ji-Woong Lee, Hong Ki Kim, Soon Won Lee, Jung Woon Yang,
and Choong Eui Song*
Various important classes of organic reactions can be
conducted with fluoride anions as a catalyst or nucleophilic
reagent.[1] Although alkali-metal fluorides are a readily
available source of the fluoride ion, their applications are
limited, owing to their low solubilities in organic solvents. To
increase the solubility of alkali-metal salts, crown ethers are
frequently employed to generate a “naked” fluoride ion.[2]
Although this simple but innovative concept of crown ethers
has had a profound impact on science,[3] their application to
Scheme 1. New multifunctional promoters, bis(hydroxy) polyethers,
chemical reactions is limited, as they can only activate
fluorides (or, more generally, anions) as monofunctional
promoters.
generated by breaking an ether unit of crown ethers.
Recently, much effort has been made to develop efficient
multifunctional organocatalysts which enable cooperative
catalysis in an enzymelike manner.[4] In this context, we
wondered if bis(hydroxy) polyethers generated by breaking
an ether unit of crown ethers could serve as a new type of
multifunctional organic promoter in which 1) the ether
groups would act as a Lewis base toward K+, thus freeing
the counteranion and enhancing the solubility of the alkali-
metal salts, and 2) the terminal OH groups generated by
breaking the ether unit would be able to simultaneously
activate the electrophile by hydrogen bonding, thereby
stabilizing the transition state (Scheme 1).
Scheme 2. Chiral variants of bis(hydroxy) polyethers: very broadly
applicable chiral-anion generators.
On the basis of our hypothesis, we developed a remark-
ably powerful protocol for nucleophilic fluorination using
bis(hydroxy) polyethers such as tetraethylene glycol as a new
type of promoter.[5] We could also show that this type of
promoter can easily be modified to yield chiral variants
(Scheme 2); thus, the enantioselective desilylative kinetic
resolution of silyl ethers of racemic secondary alcohols with
KF using the chiral bis(hydroxy) polyether as an organo-
catalyst is in principle possible. We have now completed an
extensive screening of catalysts and report herein the highly
efficient desilylative kinetic resolution of various silyl-pro-
tected racemic alcohols, which constitutes a conceptually new
approach to the production of optically active silyl-protected
secondary alcohols.[6,7] The single-crystal X-ray structure of
the complex consisting of the catalyst and KF provides
detailed and interesting insight into the origin of the catalytic
activity and stereoselectivity.
To gain insight into the structure–activity relationship, we
synthesized a variety of chiral 1,1’-bi-2-naphthol (BINOL)-
based bis(hydroxy) polyethers and examined their catalytic
efficiency for the desilylative kinetic resolution of the
trimethylsilyl (TMS)-protected alcohol rac-1 as a model
substrate with KF (0.7 equiv) in the presence of the catalyst
(20 mol%) in 1,4-dioxane[8] at 208C. The results are summar-
ized in Table 1.
[*] H. Yan, H. B. Jang, J.-W. Lee,[+] H. K. Kim, Prof. Dr. S. W. Lee,
Prof. Dr. C. E. Song
Department of Chemistry, Sungkyunkwan University
Suwon 440-746 (Korea)
Fax: (+82)31-290-7075
E-mail: s1673@skku.edu
Prof. Dr. J. W. Yang, Prof. Dr. C. E. Song
Department of Energy Science, Sungkyunkwan University
Suwon 440-746 (Korea)
Quite surprisingly, as shown from the results in Table 1,
only those catalysts having halogen substituents at the 3,3’-
position on the BINOL group exhibited catalytic activity.
When catalysts having no halogen substituent at the 3,3’-
position, such as 3 and 4, were employed, no or only trace
conversion was observed (Table 1, entries 1 and 2). More
interestingly, a dramatic enhancement in both the activity and
enantioselectivity was observed when going from chlorine to
[+] Present address: Max-Planck-Institut fꢀr Kohlenforschung
45470 Mꢀlheim an der Ruhr (Germany)
[**] This work was supported by grants NRF-20090085824 (Basic
Science Research Program), NRF-20090094024 (Priority Research
Centers Program), R11-2005-008-00000-0 (SRC program), and R31-
2008-000-10029-0 (WCU program).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201004777.
Angew. Chem. Int. Ed. 2010, 49, 8915 –8917
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
8915

Communications
Table 1: Catalyst screening for desilylative kinetic resolution of rac-1 with
KF.
Entry
Catalyst
Conv.
[%]
ee of
s[b]
(S)-1[a]
Figure 1. ORTEP structure of a dimeric form of the complex of
KF-(R)-6.[10]
1
2
3
4
5
6
7
8
(S)-3 (X=H, n=1, R=H)
(S)-4 (X=Ph, n=1, R=H)
(S)-5 (X=Cl, n=1, R=H)
(R)-6 (X=Br, n=1, R=H)
(R)-7 (X=Br, n=0, R=H)
(R)-8 (X=Br, n=2, R=H)
(R)-9 (X=Br, n=1, R=Me)
(S)-10 (X=I, n=1, R=H)
8
n.d.
–
11
93[c]
6[c]
–
n.d.
–
1.5
21
1.3
–
n.r.
43.5
56
state, thus resulting in the observed enhanced enantioselec-
tivity.[11]
Having established that the iodine-substituted catalyst 10
is the optimum catalyst, we explored the scope of the
substrate using (S)-10 as the catalyst. As shown in
Scheme 3, an array of O-TMS-protected secondary aryl
30
n.r.
n.r.
55.5
–
97
–
29
[a] After deprotection of the TMS group, the enantiomeric excess of the
resulting alcohol was determined by HPLC analysis. [b] The selectivity
factors (s) are the averages of two runs. [c] The product has the
R configuration. n.r.=no reaction, n.d.=not determined.
iodine (Table 1, entries 3, 4, and 8). Thus, the best selectivity
factor (s = 29) was obtained when the 3,3’-iodo-substituted
chiral BINOL catalyst 10 was employed (Table 1, entry 8). As
expected, it was also observed that the terminal free hydroxy
group at the 2’,2’-position of the BINOL backbone plays an
essential role in maintaining the superior catalytic perfor-
mance of the multifunctional catalyst.[9] When the reaction
was carried out using a catalyst in which the 2’,2’-hydroxy
groups are methylated, no reaction was observed (Table 1,
entry 7). Finally, the ether chain length was also shown to play
a crucial role in the performance of the catalyst, which, as
would be expected, is responsible for the formation of a
suitable chiral coordination cage with KF. The catalyst having
three ether units (-(OCH2CH2)3-); n = 1) was shown to be a
more effective catalyst in terms of the s factor than the other
catalysts bearing longer (n = 2) or shorter (n = 0) ether units
(compare the results in Table 1, entries 4, 5, and 6).
Fortunately, we were able to obtain the single-crystal X-
ray structure of the dimeric form of the complex of KF and 6,
which provides detailed insight into the origin of the catalytic
activity and stereoselectivity (Figure 1).[10] According to the
X-ray structure, the Lewis basic halogen substituents (bro-
mine in this case) at the 3,3’-positions of the BINOL unit
interact strongly with the potassium ion as a counterpart of
the Lewis base, thereby reducing the Coulombic interaction
between K+ and FÀ ions. Thus, we attributed the higher
activity and stereoselectivity of 10 (X = I) than of 5 (X = Cl)
and 6 (X = Br) to the greater polarizability of the iodine atom,
which allows it to more strongly coordinate to the potassium
cation. In addition to this strong coordination of the iodine
atom to the potassium cation, the steric size of the former
might also influence the chiral environment of the transition
Scheme 3. Scope of the reaction. After deprotection of the TMS group of
the remaining substrates, the enantiomeric excess of the resulting
alcohols was determined by HPLC analysis. The selectivity factors (s) are
the averages of two runs; see the Supporting Information for details.
8916
www.angewandte.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 8915 –8917

Angewandte
Chemie
chiral fluoride nucleophile, see: d) J. A. Kalow, A. G. Doyle,
J. Am. Chem. Soc. 2010, 132, 3268 – 3269.
[2] C. L. Liotta, H. P. Harris, J. Am. Chem. Soc. 1974, 96, 2250 –
2252.
alkyl carbinols can be kinetically resolved with good selec-
tivity factors, affording the enantioenriched O-TMS-pro-
tected secondary aryl alkyl carbinols with excellent ee
values. The TMS-protected aryl propargyl and aryl alkenyl
carbinols can also be easily accessed in excellent enantiose-
lectivities by desilylative kinetic resolution. To our knowl-
edge, this is the first successful catalytic example of the
desilylative kinetic resolution of the silyl ethers of racemic
secondary alcohols, which, as mentioned above, provides a
conceptually new approach to the production of optically
active silyl-protected secondary alcohols.[6,7]
The in situ generation of chiral fluorides, which can serve
as catalysts for a variety of asymmetric reactions, is one of the
most challenging problems in modern organic chemistry. We
developed a new structural motif for use as a chiral-anion
generator, composed of a bis(hydroxy) polyether bearing a
3,3’-halogen-substituted chiral BINOL unit, showing excel-
lent enantioselectivity (s up to 30, or greater than 97% ee for
the remaining substrate at 56% conversion) for the enantio-
selective desilylative kinetic resolution of a variety of silyl-
protected racemic alcohols with KF. The single-crystal X-ray
structure of the complex of the catalyst and KF provides
detailed insight into the origin of the catalytic activity and
enantioselectivity. This study can open up a new avenue of
research for chiral-fluoride-catalyzed asymmetric reac-
tions,[1b,c] which have vast synthetic potential but remain a
relatively undeveloped field. More generally, our results offer
a new concept for the molecular design of chiral-anion
generators as well as opportunities for the development of
related applications.
[3] C. J. Pedersen, Nobel Lecture, http://nobelprize.org/nobel_
prizes/chemistry/laureates/1987/pedersen-lecture.html.
[4] Cooperative catalysis using bifunctional organocatalysts: a) J.-A.
Ma, D. Cahard, Angew. Chem. 2004, 116, 4666 – 4683; Angew.
Chem. Int. Ed. 2004, 43, 4566 – 4583; b) C. Allemann, R.
Gordillo, F. R. Clemente, P. H.-Y. Cheong, K. N. Houk, Acc.
Chem. Res. 2004, 37, 558 – 569.
[5] In the presence of tetraethyleneglycol, the fluorination reactions
proceeded unprecedentedly fast and were completed within
1.5 h, affording the fluorinated product in quantitative yields.
Moreover, under microwave conditions, the reaction was
completed within a minute. In contrast to these results, in
organic solvents and even in the presence of crown ethers, the
fluorination reaction gave only 4% yield after the same reaction
time. J. W. Lee, H. Yan, H. B. Jang, H. K. Kim, S.-W. Park, S. Lee,
D. Y. Chi, C. E. Song, Angew. Chem. 2009, 121, 7819 – 7822;
Angew. Chem. Int. Ed. 2009, 48, 7683 – 7686.
[6] Reviews: a) S. Rendler, M. Oestreich, Angew. Chem. 2008, 120,
254 – 257; Angew. Chem. Int. Ed. 2008, 47, 248 – 250; b) A.
Weickgenannt, M. Mewald, M. Oestreich, Org. Biomol. Chem.
2010, 8, 1497 – 1504.
[7] Examples for organocatalytic enantioselective silylation of
alcohols: a) T. Isobe, K. Fukuda, Y. Araki, T. Ishikawa, Chem.
Commun. 2001, 243 – 244; b) Y. Zhao, J. Rodrigo, A. H. Hov-
eyda, M. L. Snapper, Nature 2006, 443, 67 – 70; c) Y. Zhao, A. W.
Mitra, A. H. Hoveyda, M. L. Snapper, Angew. Chem. 2007, 119,
8623 – 8626; Angew. Chem. Int. Ed. 2007, 46, 8471 – 8474; d) Y.
Zhao, A. H. Hoveyda, M. L. Snapper, Angew. Chem. 2009, 121,
555 – 558; Angew. Chem. Int. Ed. 2009, 48, 547 – 550.
[8] Other solvents were also screened for this reaction using the
catalyst 6, but its enantioselectivity with them was found to be
much inferior to that with dioxane: toluene (s = 3.9), Et2O (s =
2.5), THF (s = 6), CH3CN (s = 1.0), ClCH2CH2Cl (s = 4.7), and
CH2Cl2 (s = 10). For more experimental results, see Table S-2 in
the Supporting Information.
[9] This result is in agreement with our recent study on nucleophilic
fluorination reactions using bis(hydroxy) polyethers and KF.
[10] CCDC 777372 contains 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.
Received: August 1, 2010
Published online: October 6, 2010
Keywords: asymmetric catalysis · chirality · fluorides ·
.
kinetic resolution · polyethers
[1] For a general review, see: a) J. H. Clark, Chem. Rev. 1980, 80,
429 – 452; for reviews on chiral fluoride-catalyzed asymmetric
reactions, see: b) S. Shirakawa, T. Ooi, K. Maruoka in Asym-
metric Phase Transfer Catalysis (Ed.: K. Maruoka), Wiley-VCH,
Weinheim, 2008, chap. 9, pp. 189 – 206; c) T. Ooi, K. Maruoka,
Acc. Chem. Res. 2004, 37, 526 – 533; for a recent example of a
[11] To understand the effect of halogen substituents on the catalytic
activity and enantioselectivity in more detail and to explain the
observed sense of stereoselectivity, computational studies are
currently underway in our laboratory.
Angew. Chem. Int. Ed. 2010, 49, 8915 –8917
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
8917