Kinetic resolution of secondary alcohols by the combination of a chiral Br?nsted acid, DABCO, and acetyl chloride

Article abstract of DOI:10.1021/ol301373x

An efficient and simple protocol for the kinetic resolution of secondary alcohols is presented. The new system is based on a combination of chiral Br?nsted acid, DABCO, and acetyl chloride and gives various enantioenriched alcohols with selectivity factors up to 105.

Full text of DOI:10.1021/ol301373x

ORGANIC
LETTERS
2012
Vol. 14, No. 13
3486–3489
Kinetic Resolution of Secondary Alcohols
by the Combination of a Chiral Brønsted
Acid, DABCO, and Acetyl Chloride
Hiroki Mandai,* Kyouta Murota, Koichi Mitsudo, and Seiji Suga*
Division of Chemistry and Biochemistry, Graduate School of Natural Science and Technology,
Okayama University, 3-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan
mandai@cc.okayama-u.ac.jp; suga@cc.okayama-u.ac.jp
Received May 27, 2012
ABSTRACT
An efficient and simple protocol for the kinetic resolution of secondary alcohols is presented. The new system is based on a combination of chiral
Brønsted acid, DABCO, and acetyl chloride and gives various enantioenriched alcohols with selectivity factors up to 105.
Over the past two decades, the kinetic resolution of
secondary alcohols through the use of nonenzymatic
methods has become an important transformation. Many
researchers in this field have focused on the development
of nucleophilic catalysts with high catalytic activity and
enantioselectivity.1 In such a reaction, the catalyst is
evaluated in terms of the Kagan’s equation, which gives
the stereoselectivity factor (s).2 In general, a catalyst with
an s factor greater than 20 is considered to be synthetically
useful.3 Meanwhile, chiralBrønstedacidshave been widely
used in asymmetric reactions4 since the pioneering studies
by Akiyama5 and Terada6 in 2004. Although chiral
Brønsted acids have been used in the dynamic kinetic re-
solution of azlactones through acyl transfer7 and in the kinetic
resolution of homoaldols through transacetalyzation,8 to the
best of our knowledge, there are no examples of the kinetic
resolution of secondary alcohols through the use of a simple
acetylating reagent in the presence of a chiral Brønsted acid. In
this communication, we report the kinetic resolution of
secondary alcohols by the combination of a chiral Brønsted
acid, DABCO, and acetyl chloride.
First, we sought to identify reaction systems in which a
chiral Brønsted acid increased the reaction rate and ex-
hibited the selectivity. Acetyl chloride and acetic anhydride
are commonly used as acylating reagents in combination
with organic bases such as pyridine. Acetyl chloride is a
less-reactive acylating reagent than acetic anhydride be-
causeofthedifferenceinthe structureof the ion pairaswell
(1) For a recent review of nucleophilic catalysts in asymmetric
transformations, see: (a) Taylor, J. E.; Bull, S. D.; Williams, J. M. J.
Chem. Soc. Rev. 2012, 41, 2109. (b) Krasnov, V. P.; Gruzdev, D. A.;
Levit, G. L. Eur. J. Org. Chem. 2012, 1471. (c) Pellissier, H. Adv. Synth.
€
Catal. 2011, 353, 1613. (d) Muller, C. E.; Schreiner, P. R. Angew. Chem.,
Int. Ed. 2011, 50, 6012. (e) Wurz, R. P. Chem. Rev. 2007, 107, 5570.
(2) Kagan, H. B.; Fiaud, J. C. Kinetic resolution. In Topics in
Stereochemistry; John Wiley & Sons, Inc.: 1988; p 249.
(3) For selected examples of the kinetic resolution of secondary
alcohols by a nucleophilic catalyst with s > 20, see: (a) Li, X.; Jiang,
H.; Uffman, E. W.; Guo, L.; Zhang, Y.; Yang, X.; Birman, V. B. J. Org.
Chem. 2012, 77, 1722. (b) Birman, V. B.; Li, X. Org. Lett. 2008, 10, 1115.
(c) Birman, V. B.; Li, X. Org. Lett. 2006, 8, 1351. (d) Miller, S. J. Acc.
Chem. Res. 2004, 37, 601. (e) Ishihara, K.; Kosugi, Y.; Akakura, M.
J. Am. Chem. Soc. 2004, 126, 12212. (f) Bellemin-Laponnaz, S.;
Tweddell, J.; Ruble, J. C.; Breitling, F. M.; Fu, G. C. Chem. Commun.
2000, 1009. (g) Sano, T.; Imai, K.; Ohashi, K.; Oriyama, T. Chem. Lett.
1999, 28, 265. (h) Vedejs, E.; Chen, X. J. Am. Chem. Soc. 1996, 118, 1809.
(i) Ruble, J. C.; Latham, H. A.; Fu, G. C. J. Am. Chem. Soc. 1997, 119,
1492.
(4) For a recent review of chiral Brønsted acid catalysts, see: (a)
Terada, M. Curr. Org. Chem. 2011, 15, 2227. (b) Rueping, M.; Nachtsheim,
B. J.; Ieawsuwan, W.; Atodiresei, I. Angew. Chem., Int. Ed. 2011, 50, 6706.
(c) Terada, M. Bull. Chem. Soc. Jpn. 2010, 83, 101. (d) Terada, M. Synthesis
2010, 1929. (e) Kampen, D.; Reisinger, C. M.; List, B. Top. Curr. Chem.
2010, 291, 395. (f) Akiyama, T. Chem. Rev. 2007, 107, 5744. (g) Akiyama,
T.; Itoh, J.; Fuchibe, K. Adv. Synth. Catal. 2006, 348, 999. (h) Terada, M.
Chem. Commun. 2008, 4097.
(5) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem.,
Int. Ed. 2004, 43, 1566.
(6) Uraguchi, D.; Terada, M. J. Am. Chem. Soc. 2004, 126, 5356.
(7) (a) Lu, G.; Birman, V. B. Org. Lett. 2011, 13, 356. (b) Wang, C.;
Luo, H.-W.; Gong, L.-Z. Synlett 2011, 992.
ꢀ
ꢁ
€
(8) Coric, I.; Muller, S.; List, B. J. Am. Chem. Soc. 2010, 132, 17370.
r
10.1021/ol301373x
Published on Web 06/26/2012
2012 American Chemical Society

as the basicity of the counteranion (acetate vs chloride) in
the N-acetylpyridinium salts (Figure 1).9
Table 1. Screening of Various Aminesa
Figure 1. N-Acetylpyridinium salt intermediates.
We envisioned that it may be possible to activate the
slow reaction system by the introduction of a chiral
Brønsted acid, which would change the reactivity of the
ion pair and also provide a chiral environment. Hence, we
first examined the kinetic resolution of a racemic second-
ary alcohol (1a) with the use of 0.5 equiv of acetyl chloride
and a variety of bases in the presence of a chiral phosphoric
acid 3a as a potential chiral Brønsted acid (Table 1).
Pyridine derivatives, and other organic bases, showed
very similar s-factors (s = 1.1ꢀ3.4, entries 1ꢀ8). Surpris-
ingly, a fairly good result could be achieved when DABCO
was used as a base (s = 9.4, entry 9).10 Further explora-
tions with DABCO-related structures were performed
(entries 10ꢀ14). Quinuclidine, which has one less nitrogen
than DABCO, gave a much lower s-factor (s = 1.6, entry
10). Disconnection of one bridgehead carbon in DABCO,
1,4-dimethyl piperazine, also resulted in a low s-factor
(s = 2.1, entry 11). 1-Methyl piperidine and 1-methyl
morpholine as well as the acyclic 1,2-diamine also
gave results that were inferior to those with DABCO
(s = 1.4ꢀ2.4, entries 12ꢀ14). Based on these results, two
nitrogens and the rigid bicyclic framework are essential
and should greatly contribute to the high s-factor.
Next, a series of chiral phosphoric acids as a Brønsted
acid catalyst were tested in an attempt to increase the
s-factor. As shown in Table 2, a change in the catalyst from
3a to 3b or 3c dramatically decreased the s-factor, indicat-
ing that the size of the o-substituent on the phenyl ring (R)
significantly influenced the selectivity (entries 1ꢀ3). The
catalysts bearing a 2,4,6-trisubstituted phenyl group 3d
and 3e showed almost the same s-factor as the correspond-
ing 2,4-disubstituted catalysts (entry 4 vs 3, entry 5 vs 1).
The catalyst 3f, 4-MeOC6H4- and 4-CF3C6H4-substituted
catalysts 3g and 3h, and 3,5-di-CF3C6H3-substituted cat-
alyst 3i showed unsatisfactory results (s = 1.0ꢀ1.5, entries
6ꢀ9). The catalysts 3j and 3k, which are often used in
various asymmetric transformations, were also inferior to
3e (s = 1.1ꢀ3.2, entries 10 and 11). According to the results
of catalyst screening, 3e appeared to be the best catalyst for
the kinetic resolution of rac-1a.
a The reactions were performed on 0.2 mmol scale under Ar. b Conver-
sions were determined by 1H NMR analysis of the unpurified reaction
mixture. c Determined by HPLC; see the Supporting Information. d The
absolute configurations were assigned to be (R)-1a and (S)-2a.
The effects of the solvent and the concentration of the
substrate were also investigated (Table 3). The reaction in
toluene, CH2Cl2, MeCN, and THF gave moderate to high
selectivity (s = 5.5ꢀ10, entries 1ꢀ4). In contrast, the
reactions in various acyclic ethers as solvents more effi-
ciently promoted the kinetic resolution of rac-1a with high
selectivities (s = 8.5ꢀ14, entries 5ꢀ7). The conversion was
improved when 0.6 equiv of acetyl chloride and 0.65 equiv
of DABCO were used (45% conv.; s = 18; entry 8). In all
cases, the reaction mixture became heterogeneous when
acetyl chloride was added to a mixture11 of 5 mol % of 3e
and DABCO before the addition of the rac-alcohol.
According to this observation, we thought that it might
be important to increase the amount of solvent so that any
insoluble material could be effectively dissolved. As ex-
pected, a lower concentration of substrate improved the
s-factor (s = 29, entry 9). At the same concentration, the
(9) (a) Kattnig, E.; Albert, M. Org. Lett. 2004, 6, 945. (b) Spivey, A. C.;
€
Arseniyadis, S. Angew. Chem., Int. Ed. 2004, 43, 5436. (c) Hofle, G.; Steglich,
€
W.; Vorbruggen, H. Angew. Chem., Int. Ed. Engl. 1978, 17, 569.
(10) The combination of acetyl chloride and DABCO for the non
enantioselective esterification reaction under a solvent-free system has
been reported; see: Hajipour, A. R.; Mazloumi, G. Synth. Commun.
2002, 32, 23.
Org. Lett., Vol. 14, No. 13, 2012
3487

Table 2. Screening of Various Brønsted Acidsa
Table 3. Screening of Various Solvents and Concentrations of
Substratea
concn
(M)
time
(h)
temp
conv
(%)b
entry
solvent
(°C)
sc
1
toluene
CH2Cl2
MeCN
THF
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
15
15
15
15
15
15
15
15
0
0
0
0
0
0
0
0
21
21
31
5
10
2
6.4
5.8
5.5
13
3
4
entry
catalyst
conv (%)b
sc
5
TBME
i-Pr2O
Et2O
16
7
6
8.5
14
1
3a
3b
3c
3d
3e
3f
24
26
25
28
21
29
16
19
21
14
31
9.4
3.4
2.8
2.4
10
7
8d
22
45e
2
Et2O
18
3
4
9d
Et2O
Et2O
Et2O
Et2O
Et2O
0.07
0.07
0.07
0.07
0.07
15
15
15
5
0
40e
56e
11e
51e
49e
29
43
ꢀ
5
10d
11d,f
12d
13d
ꢀ20
ꢀ20
ꢀ20
ꢀ20
6
1.3
1.5
1.5
1.0
3.2
1.1
7
3g
3h
3i
54
52
8
1
9
a See footnote a of Table 1. b See footnote b of Table 1. c See footnote
c of Table 1. d 0.6 equiv of AcCl and 0.65 equiv of DABCO were used.
e Conversions were determined by HPLC using following equation
[conversion = eealcohol/(eealcohol þ eeester)]. f The reaction was carried
out in the absence of 3e.
10
11
3j
3k
a See footnote a of Table 1. b See footnote b of Table 1. c See footnote
c of Table 1.
reaction at a lower reaction temperature (ꢀ20 °C, 15 h)
showed s = 43 (entry 10). Without the Brønsted acid
catalyst 3e, the reaction with acetyl chloride and DABCO
afforded the ester in only 11% conversion after 15 h
(uncatalyzed reaction, entry 11). The s-factor improved
with a shorter reaction time because of the competing
uncatalyzed reaction was suppressed. The reaction for 5
h showed s = 54 with 51% conversion, and that for 1 h
showed s = 52 with 49% conversion (entries 12 and 13).
These experiments clearly indicate that Brønsted acid 3e
drastically accelerated the acetylation reaction with the
use of DABCO and acetyl chloride, which is otherwise
very slow.
The chiral Brønsted acid catalyzed kinetic resolution
could be performed with variousracemicalcohols(Figure2).
Phenyl- and naphthyl-based carbinols 1a, 1b, and 1c could
be efficiently resolved within 5 h with s = 30ꢀ54. The
propargylic alcohols 1d and 1e could also be used in the
kinetic resolution with s = 19ꢀ27, which is still a good
selectivity factor. In addition, the new system is compatible
with various functionalities. For example, the reaction of
thevinylalcohol1f, whichpossessesa silyl ether, and which
is an important intermediate for the synthesis of a
stagonolide series,12 proceeded with acceptable selectivity
(s = 11). The MoritaꢀBaylisꢀHillman adduct 1g could be
used in the reaction to give alcohol 1g and the ester 2g with
good selectivity (s = 19). Cyclic cis-alcohols bearing a
benzoate functionality could be used in the reaction and
gave the alcohol 1h and the diester 2h (s = 105) without the
migration and/or loss of benzoate. Our method gives
various enantioenriched alcohols within 5 h.
The mechanism of the chiral Brønsted acid catalyzed
kinetic resolution of racemic secondary alcohols is not yet
clear. As mentioned above, the reaction mixtures are
heterogeneous and there are some insoluble species that
might be in a complex equilibrium. Since a preliminary
spectroscopic investigation indicated that there are no
appreciable quantities of intermediates in the solution
phase, a small quantity of reactive species with high acyl-
transfer ability may be generated in the solution. Accord-
ing to the pKa value of the conjugate acid of DABCO,13
one of the two protons (pKa 2.97) is enormously dissoci-
able (Figure 3). We presume that such a dicationic inter-
mediate (4 or 5) involving chiral phosphate ion(s)14 would
be generated in the solution, and the characteristics of the
conjugate acid of DABCO suggest that intermediates 4
(12) (a) Giri, A. G.; Mondal, M. A.; Puranik, V. G.; Ramana, C. V.
Org. Biomol. Chem. 2010, 8, 398. (b) Jana, N.; Mahapatra, T.; Nanda, S.
Tetrahedron: Asymmetry 2009, 20, 2622.
(11) We thought that the salt of 3e and DABCO would form initially.
For pioneering studies on the use of a Brønsted acid and amine salt in
enantioselective transformation, see: (a) Wang, X.; Reisinger, C. M.;
List, B. J. Am. Chem. Soc. 2008, 130, 6070. (b) Wang, X.; List, B. Angew.
Chem., Int. Ed. 2008, 47, 1119. (c) Martin, N. J. A.; List, B. J. Am. Chem.
Soc. 2006, 128, 13368. (d) Mayer, S.; List, B. Angew. Chem., Int. Ed.
2006, 45, 4193.
ꢁ
(13) Benoit, R. L.; Lefebvre, D.; Frechette, M. Can. J. Chem. 1987,
65, 996.
(14) For an example of a chiral anion-directed approach to kinetic
resolution of secondary amines, see: De, C. K.; Klauber, E. G.; Seidel, D.
J. Am. Chem. Soc. 2009, 131, 17060.
3488
Org. Lett., Vol. 14, No. 13, 2012

Figure 3. Plausible intermediates in the kinetic resolution.
species should be a dicationic fluorinating reagent possessing
bis chiral phosphates as counteranions related to 4 and 5.
In conclusion, we have presented an efficient method for
the kinetic resolution of a wide range of alcohols involving
aromatic carbinols, propargyl alcohols, vinyl alcohol, a
MoritaꢀBaylisꢀHillman adduct, and a cyclic cis-alcohol.
This process involves a practical procedure and proceeds
efficiently (33ꢀ56% conversion) and with exceptional
selectivity (s = 11ꢀ105). The present observations shed
light on a newaspectof bothacylation chemistry and chiral
Brønsted acid catalyzed reaction. Further investigations
on the mechanism of the kinetic resolution of secondary
alcohols by a combination of chiral Brønsted acid, DABCO,
and acetyl chloride are underway.
Figure 2. Substrate scope of the kinetic resolution of rac-
alcohols.
Acknowledgment. We are grateful to the SC-NMR
Laboratory of Okayama University for the measurement
of NMR spectra.
and/or 5 are highly reactive. Very recently, Toste and co-
workers reported the enantioselective fluorination of ole-
fins with the combination of a Selectfluor and a chiral
phosphate catalyst.15 They also proposed that the reactive
Supporting Information Available. Experimental pro-
cedures and spectral data for substrates and products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(15) (a) Rauniyar, V.; Lackner, A. D.; Hamilton, G. L.; Toste, F. D.
Science 2011, 334, 1681. (b) Phipps, R. J.; Hiramatsu, K.; Toste, F. D.
J. Am. Chem. Soc. 2012, 134, 8376.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 13, 2012
3489