Design, synthesis, and application of tartaric acid derived N-spiro quaternary ammonium salts as chiral phase-transfer catalysts

Article abstract of DOI:10.1039/c1ob06573d

A novel class of tartaric acid-derived N-spiro quaternary ammonium salts was synthesised starting from known TADDOLs. These compounds were found to catalyse the asymmetric α-alkylation of glycine Schiff bases with high enantioselectivities and in good yie

Full text of DOI:10.1039/c1ob06573d

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COMMUNICATION
Design, synthesis, and application of tartaric acid derived N-spiro quaternary
ammonium salts as chiral phase-transfer catalysts†‡
Mario Waser,* Katharina Gratzer, Richard Herchl and Norbert Mu¨ller
Received 14th September 2011, Accepted 14th October 2011
DOI: 10.1039/c1ob06573d
A novel class of tartaric acid-derived N-spiro quaternary
ammonium salts was synthesised starting from known TAD-
DOLs. These compounds were found to catalyse the asym-
metric a-alkylation of glycine Schiff bases with high enantios-
electivities and in good yields.
as both enantiomers are readily available in ample quantities.
Although Shibasaki et al. have demonstrated the high potential of
tartaric acid-derived bidentate PTCs,11 others were less successful
in their attempts to synthesize powerful tartaric acid-derived
catalytically active quaternary ammonium salts.13
Considering the high potential of tartaric acid-derived TAD-
DOLs (2) as chiral ligands in (transition-) metal catalysis,15 we
targeted the use of TADDOLs as starting materials for the
synthesis of a new class of quaternary ammonium salts. Inspired by
Maruoka’s success using axially-chiral C2-symmetric binaphthyl
based N-spiro quaternary ammonium ions,1,9,10 and keeping in
mind that TADDOLs represent a unique moiety with electronic
and steric properties different from other chiral motives, we
inferred that the centro-chiral C2-symmetric N-spiro ammonium
compounds 3 would be interesting targets with respect to the
development of novel chiral PTCs (Scheme 1).
The use of chiral phase-transfer catalysts (PTCs) for asymmet-
ric reactions has attracted considerable interest over the last
three decades.1 Among the different catalytically active struc-
tural motives like crown ethers, ammonium salts, and phospho-
nium salts, chiral quaternary ammonium salts have found the
most widespread applications.1 Following the seminal reports
of Wynberg2 and a group of Merck scientists3 describing the
successful use of chiral quaternary ammonium salts for asym-
metric epoxide formation2 or methylation of a phenylindanone
derivative,3 cinchona-based PTCs have been thoroughly investi-
gated in the 1990s.4–6 Due to their high catalytic potential and
broad application scope, these catalysts still belong to the most
commonly employed and most powerful PTCs as shown in several
recent reports.7,8
In 1999, Maruoka et al. introduced C2-symmetric binaphthyl-
based spiro ammonium salts as chiral PTCs.9 These Maruoka
catalysts proved to be very efficient even at low catalyst loadings
(<1 mol%) for a variety of asymmetric transformations.1,9,10 In
addition, also Shibasaki’s tartaric acid-derived bidentate PTCs11
and Lygo’s spirocyclic catalysts12 were found to be highly efficient
in asymmetric catalysis.
Scheme 1 Targeted tartaric acid-based C2-symmetric PTCs.
However, considering the fact that asymmetric phase-transfer
catalysis using quaternary ammonium salts has been investigated
for three decades now, it is somewhat surprising that besides the
already mentioned privileged catalyst structures only a few other,
(most of them significantly less powerful) ammonium salt-based
PTCs have been reported so far.13,14
One of the main demands for novel catalysts is easy accessibility
from sufficiently available chiral starting materials. Tartaric acid
(1) has obtained a prominent position in asymmetric catalysis
Catalyst syntheses
The syntheses of TADDOL derivatives were carefully investigated
and described in the past, especially by the Seebach group.15,16
While different aryl substituents have to be introduced early in the
synthesis from 1, modifications of the hydroxyl groups are most
commonly achieved via conversion of 2 to dichloro compounds 4,
which can then be reacted with different nucleophiles.15–17
Initial experiments to develop a suitable synthesis route were
carried out using the dichloride 4a (Ar = Ph)16a as the starting
material. Subsequent carbon-chain elongation could be achieved
using TMSCN (2.5 eq.) in the presence of catalytic amounts of
SnCl4 (25%).18 With the dinitrile 5a in hand, conversion into the
sec-amine 6a was thought to be just a matter of standard functional
group manipulations. However, neither attempts to saponify 6a,
nor conversion into the corresponding dialdehyde upon treatment
Institute of Organic Chemistry, Johannes Kepler University Linz, Altenberg-
erstraße 69, 4040 Linz, Austria. E-mail: Mario.waser@jku.at; Fax: +43 732
2468 8747; Tel: +43 732 2468 8748
† This article is part of the joint ChemComm–Organic & Biomolecular
Chemistry ‘Organocatalysis’ web themed issue.
‡ Electronic supplementary information (ESI) available: Experimen-
tal procedures and characterisation of new compounds. See DOI:
10.1039/c1ob06573d
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The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 251–254 | 251
©

Table 1 Identification of the most active catalyst for the asymmetric a-alkylation of 7 and of the optimum reaction conditions
Entry
Cat.
Ar
Ph
Ya
Aa
Solvent
PhMe
Base
T/◦C
Yieldb (Conv.)c (%)
ee (%)d (Conf.)e
1
2
3
4
5
6
7
8
9
3aa
KOH (50%)
rt
-20
70 (~90)
55 (~70)
30 (~50)
35 (~50)
77 (~90)
47 (~60)
45 (~60)
65 (~80)
57 (~80)
21 (~30)
34 (S)
45 (S)
61 (S)
34 (S)
55 (S)
5 (S)
3ba
3ca
3da
3ea
3fa
3ga
3gb
3gc
4-tBu-Ph
4-F-Ph
3-Me-Ph
3,5-Me2-Ph
m-Biphenyl
p-Biphenyl
7 (S)
79 (S)
51 (S)
25 (R)
Ba
Ca
10
11
12
13
14
15
16
17f
18
19
20
21
22g
3ga
p-Biphenyl
Aa
PhMe
CH2Cl2
CsOH·H2O
-70
-70
-20
54 (~70)
35 (~50)
53 (~70)
71 (~90)
82 (>90)
69 (~80)
37 (~50)
33 (~50)
24 (~40)
61 (~75)
54 (~70)
81 (quant)
39 (S)
38 (R)
28 (R)
7 (S)
68 (S)
82 (S)
57 (S)
19 (S)
65 (S)
84 (S)
87 (S)
87 (S)
KOH (50%)
THF
PhF
benzene : PhMe (2 : 1)
NaOH (50%)
CsOH (50%)
KOH (50%)
benzene : PhMe (1 : 1)
PhMe
-35
a See Scheme 2. b Isolated yields. c Judged by 1H NMR or TLC of the crude product. d Determined by HPLC using a chiral stationary phase. e Determined
by comparison of the HPLC retention time and optical rotation with literature6,9 values. f Using 1% catalyst. g Using 3 eq. 8.
with DIBAL-H were feasible due to the low reactivity of 5a
(under harsher conditions partial decomposition but no product
formation was observed). Using LiAlH4 at room temperature
in different ethereal solvents also did not affect the cyano
groups, whereas a partial decomposition was observed at higher
temperatures. In addition, using other hydride donors (combined
with different additives) did not give any products either.
Surprisingly, upon refluxing 5a with an excess of LiAlH4 (10
eq.) in toluene for 2 h, full consumption of 5a was observed.
Besides mainly unidentified decomposition products also 10% of
the sec-amine 6a could be isolated. After careful optimization of
the reaction conditions, it was found that refluxing a mixture of
5a and 20 eq. LiAlH4 in mesitylene for 30–45 min gave access
to 6a in 37% isolated yield. Although only modest in yield, the
reaction was found to be scalable to several grams, giving the key-
Scheme 2 Syntheses of azepane-based PTCs 3. a) SOCl2, Et3N, CH2Cl2,
intermediate 6a in sufficient quantities for further elaborations.
25 ◦C b) TMSCN, SnCl4, 25 ◦C, 47–63% (over two steps) c) LiAlH4,
The final quaternarization could be achieved upon refluxing with
mesitylene, reflux, 29–43% d) Br-Y-Br, K2CO3, CH3CN, reflux, 49–69%.
1,4-dibromobutane (CH3CN, K2CO3).
As depicted in Scheme 2, a variety of different aryl substituents
was introduced successfully. Noteworthy, whereas TADDOLs
with aryl groups having electronic properties similar to a phenyl
access to a small set of different quaternary ammonium bromides
3 in reasonable yields.19
group were easily converted into 6, more electron-rich as well
as more electron-poor aryl group containing ones failed as the
Application in asymmetric phase-transfer catalysis
corresponding dichlorides 4 could not be obtained. The different
amines 6 showed similar quaternarization behaviour as 6a, giving
Having developed a reliable route for the syntheses of C2-
symmetric N-spiro ammonium salts 3, we next evaluated the
252 | Org. Biomol. Chem., 2012, 10, 251–254
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catalytic potential of these compounds in the asymmetric a-
alkylation of the glycine ester benzophenone Schiff base 7 with
benzylbromide (8).
benzylbromide (8) we next carried out a short screening of
different electrophiles to examine the scope of this protocol. We
were glad to find that other electrophiles were tolerated well,
giving the corresponding products in good yields and reasonable
enantioselectivities (Table 2).
In conclusion, a series of novel C2-symmetric tartaric acid-
derived N-spiro quaternary ammonium salts has been successfully
synthesized. The catalytic potential of these compounds in the
asymmetric a-alkylation of glycine Schiff base strongly depends
on their aryl substituent and on the reaction conditions. Under
optimised conditions, the a-alkylated products could be obtained
in good yields and up to 93% ee. Further optimizations of the
catalyst structures are currently undertaken and will be reported
in due course.
Using the L-1 derived ammonium bromides 3aa–3ga the best-
suited aryl substituent was identified first (Table 1, entries 1–8). All
reactions were carried out for 20 h under biphasic conditions using
10 mol% catalyst, 25 eq. KOH, and similar dilution. As expected,
the choice of the aryl group was crucial not only with respect
to enantioselectivity, but also with respect to the reaction rate.
Having identified the p-biphenyl containing 3ga as the best among
the tested catalysts (entry 8), we next investigated the ammonium
bromides 3gb and 3gc (entries 9 and 10). Whereas the o-xylene-
derived catalyst 3gb gave a reduced enantiomeric excess of 51%, the
naphthyl-based 3gc was found to favour the oppositely configured
(R)-9, albeit in low yield and low ee only.
With the ammonium bromide 3ga as the most promising among
the so far synthesized PTCs we next screened different reaction
conditions (entries 11–22 give a representative overview about the
most significant results obtained hereby). Interestingly, the use
of CH2Cl2 gave (R)-9 predominantly (entries 12, 13), whereas
no stereodifferentiation could be achieved in THF (entry 14).
In addition, liquid–liquid biphasic conditions were found to be
superior over liquid–solid ones (entry 8 vs. 11). Besides a strong
solvent effect, the choice of the base was also found to be crucial
(entries 18,19). Lowering the catalyst amount to 1 mol% resulted
in a reduced ee and yield (entry 17). Finally, we found that carrying
out the reaction with an excess of electrophile in the presence of 10
mol% 3ga at -35 ◦C presents a good compromise to obtain (S)-9
in good yield and satisfactory enantioselectivity in a reasonably
short reaction time (entry 22). In addition, the catalyst could be
recovered (>85%) and reused several times without negatively
affecting its efficiency.
This work was supported by the Austrian Science Funds (FWF)
Project No. P22508-N17. The NMR-spectrometers used were co-
financed by the European Union in the context of the project
RERI-uasb, EFRE RU2-EU-124/100-2010 (ETC Austria-Czech
Republic 2007-2013).
Notes and references
1 For reviews about asymmetric phase-transfer catalysis: (a) K.
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(Eds: Y. Sasson, R. Neumann), Blackie Academic & Professional, Lon-
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2 R. Helder, J. C. Hummelen, R. W. P. M. Laane, J. S. Wiering and H.
Wynberg, Tetrahedron Lett., 1976, 17, 1831.
3 U. H. Dolling, P. Davis and E. J. J. Grabowski, J. Am. Chem. Soc., 1984,
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4 (a) M. J. O’Donnell, W. D. Bennett and S. Wu, J. Am. Chem. Soc., 1989,
111, 2353; (b) M. J. O’Donnell, S. Wu and J. C. Huffman, Tetrahedron,
1994, 50, 4507.
Having identified the most active catalyst and the optimum
reaction conditions for the asymmetric a-alkylation of 7 with
5 (a) B. Lygo and P. G. Wainwright, Tetrahedron Lett., 1997, 38, 8595;
(b) B. Lygo, J. Crosby and J. A. Peterson, Tetrahedron Lett., 1999, 40,
1385.
Table 2 Scope of the a-alkylation of 7 using different electrophiles
6 E. J. Corey, F. Xu and M. C. Noe, J. Am. Chem. Soc., 1997, 119, 12414.
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ee (%)b
Entry RBr
Electrophile
Product Yielda (%) (Conf.)c
1
2
PhCH2Br
8
10
9
11
81
83
87 (S)
76 (S)
10 (a) S. Shirakawa, K. Liu, H. Ito and K. Maruoka, Chem. Commun.,
2011, 47, 1515; (b) T. Kano, A. Yamamoto, S. Song and K. Maruoka,
Chem. Commun., 2011, 47, 4358; (c) Q. Lan, X. Wang, S. Shirakawa
and K. Maruoka, Org. Process Res. Dev., 2010, 14, 684.
11 (a) T. Shibuguchi, Y. Fukuta, Y. Akachi, A. Sekine, T. Ohshima and
M. Shibasaki, Tetrahedron Lett., 2002, 43, 9539; (b) A. Okada, T.
Shibuguchi, T. Ohshima, H. Masu, K. Yamaguchi and M. Shibasaki,
Angew. Chem., Int. Ed., 2005, 44, 4564.
3
4
5
6
12
14
16
18
13
15
17
19
80
79
79
71
85 (S)
80 (S)
93 (S)
78 (S)
12 B. Lygo, B. Allbutta and S. R. James, Tetrahedron Lett., 2003, 44,
5629.
13 (a) S. Arai, R. Tsuji and A. Nishida, Tetrahedron Lett., 2002, 43, 9535;
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14 (a) S. Kumar and U. Ramachandram, Tetrahedron, 2005, 61, 4141; (b) S.
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a Isolated yields b Determined by HPLC using a chiral stationary phase.
c Determined by comparison of the HPLC retention time and optical
rotation with literature values.6,9,20
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16 (a) D. Seebach, A. K. Beck, M. Hayakawa, G. Jaeschke, F. N. M.
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18 M. T. Reetz, I. Chatzhosifidis, H. Ku¨nzer and H. Mu¨ller-Starke,
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19 A detailed discussion of our efforts to synthesise these PTCs as well as
scope and limitations of the developed synthesis route will be reported
in a full paper in due course.
20 J. H. Lee, M. S. Yoo, J. H. Jung, S. Jew, H. Park and B. S. Jeong,
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254 | Org. Biomol. Chem., 2012, 10, 251–254
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