Truncated Cinchona alkaloids as catalysts in enantioselective monobenzoylation of meso-1,2-diols

Article abstract of DOI:10.1039/b808268e

Readily synthesised quincorine and quincoridine derived chiral diamines efficiently catalyse the asymmetric monobenzoylation of cyclic and acyclic meso-1,2-diols. The Royal Society of Chemistry.

Full text of DOI:10.1039/b808268e

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Truncated Cinchona alkaloids as catalysts in enantioselective
monobenzoylation of meso-1,2-diolsw
E. Peter Kundig,* Alvaro Enriquez Garcia, Thierry Lomberget, Pablo Perez Garcia
¨
and Patrick Romanens
Received (in Cambridge, UK) 15th May 2008, Accepted 17th June 2008
First published as an Advance Article on the web 2nd July 2008
DOI: 10.1039/b808268e
Readily synthesised quincorine and quincoridine derived chiral
diamines efficiently catalyse the asymmetric monobenzoylation
of cyclic and acyclic meso-1,2-diols.
Chiral diamines are widely used in organocatalytic, metal-
mediated and -catalysed asymmetric reactions.1 They are
accessible by asymmetric synthesis or from abundant natural
sources such as amino acids, ephedrine, and Cinchona alka-
loids, to name but a few. In this communication we report our
study on the desymmetrisation of meso-diols by the quin-
corine- and quincoridine-derived diamines 5 and 7.
Our interest in this field started with the search for a simple
and efficient method for the desymmetrisation of the meso-
complex 1 to give enantiomerically enriched 2. A number of
chiral acyl transfer catalysts have been successfully developed
in recent years for the desymmetrisation of meso-diols.2,3
Although not previously used for the desymmetrisation of
meso-1,4-diols, Oriyama’s proline derived catalyst 33 turned
out to be a good choice for the reaction in question
(Scheme 1).4 Assuming that the role of one amine function is
acyl activation, that of the second tertiary amine would be to
engage in hydrogen bonding to a hydroxy group and discri-
minate between the two enantiotopic alcohol moieties in 1,
thus setting up the system for stereoselective acyl delivery.
Pursuing this line of reasoning, we felt that other chiral
diamines incorporating a highly nucleophilic amine such as
the quinuclidine fragment may be good catalysts.
Scheme 1 Asymmetric acylation of the meso-diol 1.
In order to probe the scope of these acyl transfer catalysts
we extended the desymmetrisation from meso-1,4-diol com-
plexes to simple meso-1,2-diols. Cyclohexanediol 8 was se-
lected for checking conditions for this reaction. The reaction
proceeded readily in CH2Cl2 in the temperature range ꢀ60 1C
to 0 1C (Table 1, entries 1–3). Without the addition of catalyst,
only 20% of rac-9 was obtained after 22 h at ꢀ30 1C,
indicating a slow background reaction. (+)-9 was obtained
in excellent enantiomeric purity at ꢀ30 1C as seen in entry 2. A
drawback with CH2Cl2 as solvent was the competitive forma-
tion of the diacylation product 10. Part of this problem could
be tracked back to the low solubility of 8 in this solvent at low
temperatures. Lowering the concentration improved the result
only partially (entry 4). Competitive formation of 10 raises the
possibility of kinetic resolution. Indeed, as shown in Scheme 3,
this is the case. The product mixture obtained translates into a
Indeed the diamines 5 and 7, readily synthesised by reduc-
tive Eschweiler–Clark reaction and hydrogenation from the
precursor diamines 4 and 6 (Scheme 2), were excellently suited
for this task. Compounds 4 and 6 are accessible in a two step
sequence from quinine and quinidine, respectively.5z
Another advantage of 5 and 7 is their low molecular mass.
By stripping the alkaloids to the core function of the chiral
quinuclidine with a second amine function reduces the mole-
cular weight of the catalysts by 40%.
The two pseudo-enantiomeric diamine catalysts afforded 2
in ees of 95–99% (Scheme 1).4 The same reaction was also
applied equally successfully to [Cr(CO3)(5,8-dihydroxy-
tetralin)].6
Department of Organic Chemistry, University of Geneva, 30 Quai
Ernest Ansermet, 1211 Geneva 4, Switzerland.
E-mail: peter.kundig@chiorg.unige.ch; Fax: +41 22 379 3215;
Tel: +41 22 378 6093
w Electronic supplementary information (ESI) available: Synthesis
and spectral data of 5, 7, 9, 19–26 plus diacylated products. See
DOI: 10.1039/b808268e
Scheme 2 Access to the chiral acyl transfer catalysts 5 and 7.
Chem. Commun., 2008, 3519–3521 | 3519
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Table 1 Asymmetric benzoyl transfer to 1,2-cis-cyclohexanediol cat-
alysed by the chiral diamine 5
Table 2 Asymmetric benzoyl transfer to 1,2-diols catalysed by the
chiral diamine 5
Entry Solventa Catalyst T/ Conversionb Yieldb
eec
(+)-9 10
Yield
Entry Diol
Solvent Ratioa
Productb eec
(% yield) (%)
1C (%)
(+)-9
(%)
(%)
(%)
1
2
11 THF
1 : 93 : 6
EtOAc 3 : 95 : 2
19 (77)
19 (82)
92
90
1
2
CH2Cl2 5, 5%
0
91
77
74
62
75
89
93
68
89e
94
96
94
92
499
96
97
91
93
14
19
25
9
6
3
0
6
3
4
CH2Cl2 5, 5% ꢀ30 93
CH2Cl2 5, 5% ꢀ60 87
CH2Cl2 5, 5% ꢀ30 84
3
4d
5
THF
THF
THF
THF
5, 5% ꢀ30 95
5, 2% ꢀ60 96
5, 1% ꢀ60 68
7, 5% ꢀ30 95
3
4
12 THF 3 : 90 : 7
EtOAc 2 : 92 : 6
20 (83)
20 (87)
82
78
6
7
8
9
10
11
85
91e
92
EtOAc 5, 5% ꢀ30 97
EtOAc 5, 5% ꢀ60 100
EtOAc 5, 2% ꢀ60 98
97
97
5
6
13 THF 6 : 77 : 17 21 (77)
EtOAc 5 : 84 : 11 21 (84)
75
77
4
a
b
0.11 M in 8 unless otherwise noted. From 1H NMR spectra, ratios
c
of crude product. HPLC: Chiralcel OJ-H column, eluent: 95 : 5
d
e
hexane–iPrOH. 0.055 M in 8. Product (ꢀ)-9.
7
8
8
THF 4 : 93 : 3
EtOAc 4 : 91 : 5
9 (95)
9 (92)
93
97
9
10
14 THF 10 : 86 : 3 22 (76)
EtOAc 10 : 89 : 8 22 (79)
66
84
11
12
15 THF 5 : 91 : 4
EtOAc 5 : 92 : 3
23 (87)
23 (86)
72
77
Scheme 3 Kinetic resolution in the asymmetric acylation of rac 8.
13
14
16 THF
16 : 64 : 20 24 (64)
EtOAc 23 : 51 : 26 24 (51)
89
93
selectivity factor of S = 10.4.7 Kinetic resolution due to the
faster second acylation of the minor enantiomer thus contri-
butes to the high ee of (+)-9 in entries 2–3 in Table 1. Another
problem with CH2Cl2 is that it reacts with diamines 5 and 7 at
rt to give the corresponding chloromethylammonium chloride
salt by Menshutkin reaction,7 a consequence of the high
nucleophilicity associated to the quinuclidine core.8y
15
16
17 THF 13 : 75 : 12 25 (70)
EtOAc 17 : 70 : 13 25 (65)
45
83
We therefore investigated other solvents. Of the ones tested
(chloroform, dichloroethane, acetonitrile, acetone, tert-amyl
alcohol, diethyl ether, tetrahydrofuran (THF), dimethoxy-
ethane, dioxane, and ethyl acetate (EtOAc)),9 THF and
EtOAc performed better than CH2Cl2 and over-acylation
could be largely avoided (entries 5–7 and 9–11).
17
18
18 THF
24 : 71 : 5 26 (68)
26 (82)
34
13
EtOAc 8 : 85 : 7
a
Product ratio of starting diol : monobenzoylated product : diben-
b
zoylated product. Isolated pure monobenzoylated (+)-products.
c
The faster reactions in these solvents allowed the catalyst
loading to be lowered to 2% (entries 6 and 11). As previously
found4,6 and as also noted by Mizuta et al.2 with other Cinchona
alkaloid derived catalysts, the pseudo-enantiomeric quinidine-
derived catalysts (in our case 7) did not quite reach the same
level of performance as the quinine-derived catalysts (entry 6).
The optimised conditions established for 9 were then
applied to a number of other cyclic and acyclic diols (Table 2).
Cyclic and acyclic diols were efficiently desymmetrised with
good to excellent conversions and moderate to excellent
Determined by HPLC: Chiralcel OJ-H column, eluent: 95 : 5
hexane–iPrOH.
enantioselectivities (entries 1 to 18). In most cases, the amount
of dibenzoates in the final mixture was o10%. Substrates
incorporating phenyl groups afforded products with lower
selectivities (entries 13 to 18). In part this is due to their low
solubility at low temperature in the two solvents tested.
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In conclusion, the chiral diamines 5 and 7, derived from
Cinchona alkaloids and thus accessible from inexpensive
commercially available materials, efficiently desymmetrise
meso-1,2-diols. On screening conditions, THF or EtOAc
emerged as the best solvents, giving highly enantioenriched
monobenzoate at low temperature with low 2 mol% catalyst
loadings.
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M. Sadamori, T. Fujimoto and I. Yamamoto, Angew. Chem., Int.
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2003, 125, 2410; C. Mazet, V. Kohler and A. Pfaltz, Angew. Chem.,
Int. Ed., 2005, 44, 4888; D. Nakamura, K. Kakiuchi, K. Koga and
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3. T. Oriyama, K. Imai, T. Hosoya and T. Sano, Tetrahedron Lett.,
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Tetrahedron Lett., 1998, 39, 3529. Synthesis: G. Hu and A. Vasella,
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Notes and references
4. E. P. Kundig, T. Lomberget, R. Bragg, C. Poulard and
¨
G. Bernardinelli, Chem. Commun., 2004, 1548.
5. O. Schrake, M. H. Franz, R. Wartchow and H. M. R. Hoffmann,
Tetrahedron, 2000, 56, 4453; I. Neda, T. Kaukorat and C. G. Hrib,
Tetrahedron: Asymmetry, 2002, 13, 1327; H. M. R. Hoffmann and
J. Frackenphol, Eur. J. Org. Chem., 2004, 4293.
z 4 and 6 are also commercially available from Aldrich and from
Buchler GmbH, Braunschweig, Germany.
y When using diamines 5 and 7 as catalysts in CH2Cl2, the diamine
solution should be prepared and rapidly cooled to 4 ꢀ20 1C.
1. S. France, D. J. Guerin, S. J. Miller and T. Lectka, Chem. Rev.,
2003, 103, 2985; C. A. de Parrodi and E. Juaristi, Synlett, 2006,
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6. E. P. Kundig, A. Enrıquez Garcıa, T. Lomberget and
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A. K. Fischer, Eur. J. Org. Chem., 2003, 3784.
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