Reversal of enantioselectivity using catalysts containing multiple stereogenic centres

Article abstract of DOI:10.1016/S0957-4166(01)00290-7

N-Methylation of ligands with multiple stereogenic centres is shown to provide the product of the opposite configuration in significant enantiomeric excess (e.e.), in the addition of diethylzinc to aldehydes. The catalysts possess stereogenic centres appe

Full text of DOI:10.1016/S0957-4166(01)00290-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 1547–1550
Reversal of enantioselectivity using catalysts containing multiple
stereogenic centres
Alexander J. A. Cobb and Charles M. Marson*
Department of Chemistry, University College London, Christopher Ingold Laboratories, 20 Gordon Street,
London WC1H 0AJ, UK
Received 31 May 2001; accepted 22 June 2001
Abstract—N-Methylation of ligands with multiple stereogenic centres is shown to provide the product of the opposite
configuration in significant enantiomeric excess (e.e.), in the addition of diethylzinc to aldehydes. The catalysts possess stereogenic
centres appended to a trans-1,2-cyclohexanediamine core. © 2001 Elsevier Science Ltd. All rights reserved.
Catalytic asymmetric formation of carbonꢀcarbon
bonds is a field of major contemporary interest in
organic synthesis.1 Within this area, the addition of
diethylzinc to aldehydes2 provides a yardstick for the
efficiency and enantioselectivity of a catalyst, since the
rate of the reaction in the absence of a catalyst is low
and catalytic effects can be substantial.3,4 The b-amino
alcohol moiety has been extensively studied as a ligand
in the asymmetric addition of dialkylzinc reagents to
carbonyl compounds,2b,4,5 and mechanistic features
have been thoroughly investigated.4 Such asymmetric
additions to carbonyl compounds have also used the
well studied trans-1,2-cyclohexanediamine systems as
catalysts.6 We sought to develop new catalysts that
include both a trans-1,2-diaminocyclohexyl subunit and
vicinal b-amino alcohol moieties, partly because few
ligands capable of tetradentate coordination are
known. These ligands possess an extended array of up
to six stereogenic centres (Scheme 1) and the predomi-
nant enantioselection they induce is shown to be
reversed upon N-methylation.7
The bis(b-aminoalcohol) catalysts were synthesised
according to Scheme 2. (1R,2R)-(−)-1,2-Diaminocyclo-
hexane8 was dialkylated with 2-bromoethanol (water,
reflux, 12 hours) to give 4a (30%),9 which was N,N%-
dimethylated using HCHO–HCOOH in an Eschweiler–
Clarke procedure,10 but in the presence of the hydrogen
donor sodium formate11 to give 4b (95%). That route
provided the unadorned basic ligand. Ligands 5 and 7
(56 and 50%, respectively), possessing additional stereo-
genic centres, were prepared by activation of the requi-
site enantiomer of mandelic acid with DCC in the
presence of N-hydroxysuccinimide and then reaction
with 3.12 Reduction13 of amides 5 and 7 gave the
secondary amines 6a (32%) and 8a (25%), respectively,
which were also subjected to Eschweiler–Clarke N,N%-
dimethylation in the above manner to give the tertiary
amines 6b and 8b14 quantitatively. Lastly, systems with
six stereogenic centres were obtained by heating 3 with
cyclohexene oxide to give 9a (30%), which was also
reacted with HCHO–HCOOH in the presence of
Scheme 1. Extended polyheteroatomic chiral systems as enantioselective catalysts.
* Corresponding author.
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00290-7

1548
A. J. A. Cobb, C. M. Marson / Tetrahedron: Asymmetry 12 (2001) 1547–1550
Scheme 2. Synthesis of trans-1,2-diaminocyclohexane catalysts with extended chiral systems. Reagents: (i) 2-bromoethanol (2 mol
equiv.), reflux in water; (ii) (S)-(+)-mandelic acid, DCC (2.5 mol equiv.), N-hydroxysuccinimide (2.5 mol equiv.), THF; (iii)
Me2S·BH3 (3.3 mol equiv.), Et2O·BF3 (4 mol equiv.), THF; (iv) 37% HCHO (2 mol equiv.), 90% HCOOH (3 mol equiv.); (v)
(R)-(−)-mandelic acid, DCC (2.5 mol equiv.), N-hydroxysuccinimide (2.5 mol equiv.), THF; (vi) cyclohexene oxide (3 mol equiv.),
EtOH, reflux.
e.e.’s with the secondary amine ligands.18,19 Thus, it is
sodium formate to give the corresponding tertiary
amine 9b quantitatively.
noteworthy that the secondary amine catalyst 9a
affords 80% e.e. (Table 1, entry 5). While the N-methyl-
ated catalysts 6b, 8b and 9b all give greater amounts of
(S)-1-phenylpropan-1-ol, the effect is greatest with 9b, a
catalyst with six stereogenic centres. However, with 9b
and 2-naphthaldehyde, there was no detectable yield of
the aryl alcohol, presumably because of steric hindrance
of approach to the catalyst. With a trans-1,2-diamino-
cyclohexane as part of a salen ligand, e.e.’s of 30–70%
were obtained for the addition of diethylzinc to benz-
aldehyde;20 our ligands 9 compare favourably, and
show that systems based on a trans-1,2-diaminocyclo-
hexane, but with extended chirality, can deliver signifi-
cantly high e.e.’s in the enantioselective addition to
carbonyl compounds. In contrast, the amines 4a and
4b, lacking additional chirality, did not give satisfactory
Only the racemic 9a has been prepared previously, and
the relative configuration was established by X-ray
crystallography.15 We also obtained only a single
diastereoisomer16 from the reaction of (1R,2R)-(−)-1,2-
diaminocyclohexane with cyclohexene oxide, as had
been found in a previous study using the racemic
diamine.15 Such directed stereochemical control during
the reaction, undoubtedly assisted by hydrogen bond-
ing networks, has features in common with adducts
formed from the co-crystallisation of enantiopure 1,2-
diaminocyclohexane with cyclohexane-1,2-diols.17
While N,N-dimethylation can lead to reversal of enan-
tioselectivity,18 previous work has described only low

A. J. A. Cobb, C. M. Marson / Tetrahedron: Asymmetry 12 (2001) 1547–1550
Table 1. Reaction of aldehydes with diethylzinc in toluenea
1549
Entry
Ligand
Aldehyde
Temp. (°C)
Yield (%)b
E.e. (%)c
Configuration
1
2
3
4
5
6
7
8
6a
6b
8a
8b
9a
9b
9a
9b
9a
9b
9a
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
−30
−30
−30
−30
−30
−30
0
40
55
42
51
50
25
99
68
74
18
95
23
54
45
16
80
92
64
75
56
52
60
(R)
(S)
(S)
(R)
(R)
(S)
(R)
(S)
(R)
(S)
(R)
0
9
10
11
p-MeO·C6H4CHO
p-MeO·C6H4CHO
2-Naphthaldehyde
−30
−30
0
a The trans-1,2-diaminocyclohexane ligand (10 mol%), and 2.2 equiv. of diethylzinc were used. Reactions were maintained at −30 or 0°C for 4 h,
then allowed to warm to 20°C over a subsequent period of 12 h.
b Yields were determined by 1H NMR spectroscopy.
c The absolute configurations of the alcohols were determined using a Chiralcel OD column.21
results (4a gave 30% of 2a in 8% e.e., but 4b gave no 2a).
and Physical Sciences Research Council is gratefully
acknowledged.
In asymmetric additions to aldehydes, the nature of the
N-substituent can substantially affect the enantioselec-
tivities. Thus, depending on the nature of the dialkyl
References
substituent,
N,N-dialkylnorephedrine
derivatives
afforded (S)-5-methylhexan-3-ol in e.e.s of 53–83%.4b
However, no reversal of e.e. was noted and a tertiary
amine was needed, as is often the case. The absolute
configurations obtained with catalysts 9a and 9b, as well
as the fact that 9b favours the (S)-configuration of
1-arylpropan-1-ol (compared with 9a) can be accounted
for by a model in which the aldehyde presents to the
pocket of the catalyst defined by the flanking wall of the
aminocyclohexanol ring and the basal plane that
includes two zinc and two oxygen atoms. Interaction of
the carbonyl group of the aldehyde with the zinc atom
coordinated to the diamine unit prior to alkyl transfer
from the other zinc atom (presumed to be bound to the
two oxygen atoms) has been previously postulated.2a,22
For 9a, the NH group is sufficiently small to allow the
aryl ring to reside nearby, leading to the attack of the
Re-face of the aldehyde. Conversely, for 9b, the bulk of
the N-methyl group is presumed to be sufficient to
hinder location of the aryl group as above, thereby
leading to addition to the Si-face and predominantly the
(S)-1-arylpropan-1-ol. However, further investigations
are needed before these tentative proposals can be fully
substantiated.
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ing the products with the opposite configuration in high
e.e., simply by N,N%-dimethylation of the ligand.23
8. (1R,2R)-(−)-1,2-Diaminocyclohexane was obtained by
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Financial support (to A.J.A.C.) from the Engineering

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one portion and the resulting solution was stirred at 90°C
for 16 h. After this time, the solution was cooled to 20°C
and then basified, with cooling, to pH 12 with 2 M
aqueous sodium hydroxide. The aqueous layer was
washed with diethyl ether (3×20 mL) and the combined
organic layers were dried (MgSO4), filtered and evapo-
rated under reduced pressure to give a clear oil (0.58 g,
95%) that required no further purification; [h]D=+42.2 (c
12. All compounds gave satisfactory spectral data (1H and
13C NMR, IR and MS), and all new compounds gave
satisfactory analytical data or HRMS. Procedures for
acylation of 3 with (R)- and (S)-mandelic acid were
adapted from: Ho, P. T.; Ngu, K. J. Org. Chem. 1993, 58,
2313–2316.
1
0.53, CHCl3); H NMR l (CDCl3, 300 MHz) l 3.23 (2H,
13. Brown, H. C.; Narasimhan, S.; Choi, Y. M. Synthesis
1981, 996–997.
m, C1HOH), 2.45 (2H, m, C1%HNH), 2.30 (2H, m,
C2HNH), 2.09 (6H, s, CH3), 2.02 (2H, m), 1.86 (2H, m),
1.75–1.63 (8H, m), 1.64–1.18 (12H, m); 13C NMR
(CDCl3, 75 MHz) l 72.59, 67.77, 66.55, 34.00, 29.31,
28.78, 27.80, 26.57, 26.33, 24.87. HRMS calcd for
C20H38N2O2 (MH+) 339.3012. Found: 339.3009. FAB MS
(%) 339 (MH+, 100), 210 (22), 112 (19).
14. For a synthesis of 8b using (R)-(+)-styrene oxide, see:
Cross, R. J.; Farrugia, L. J.; Newman, P. D.; Peacock, R.
D.; Stirling, D. Inorg. Chem. 1999, 38, 1186–1192.
15. De Sousa, A. S.; Hancock, R. D.; Reibenspies, J. H. J.
Chem. Soc., Dalton Trans. 1997, 2831–2835.
16. (1R,2R)-N,N%-Bis((3S,4S)-4-hydroxycyclohexyl)-trans-
17. Hanessian, S.; Simard, M.; Roelens, S. J. Am. Chem. Soc.
1995, 117, 7630–7645.
1,2-diaminocyclohexane 9a. To
a stirred solution of
(1R,2R)-(−)-trans-1,2-diaminocyclohexane (4.80 g, 42.0
mmol) in anhydrous ethanol (100 mL) under an inert
atmosphere at 20°C was added cyclohexene oxide (17.3
mL, 171 mmol) via a pressure-equalising dropping funnel
over a period of 20 min. Upon complete addition, the
mixture was heated under reflux for 16 h. After this time,
the pale yellow solution was allowed to cool to 20°C,
whereupon the solvent was evaporated to give a brown
oil that was acidified to pH 2 with 2 M aqueous hydro-
chloric acid and the aqueous layer extracted with chloro-
form (2×50 mL) which was discarded. The aqueous layer
was then basified to pH 11 with 2 M aqueous sodium
hydroxide and the aqueous layer was again extracted
with chloroform (2×50 mL). The combined organic layers
were dried (MgSO4), filtered and evaporated. The result-
ing yellow–orange oil was subjected to purification by
18. Kimura, K.; Sugiyama, E.; Ishizuka, T.; Kunieda, T.
Tetrahedron Lett. 1992, 33, 3147–3150.
19. Delair, P.; Einhorn, C.; Einhorn, J.; Luche, J. L. Tetra-
hedron 1995, 51, 165–172.
20. Cozzi, P. G.; Papa, A.; Umani-Ronchi, A. Tetrahedron
Lett. 1996, 37, 4613–4616.
21. Hwang, C.-D.; Uang, B.-J. Tetrahedron: Asymmetry
1998, 9, 3979–3984. Representative conditions for the
addition of diethylzinc to aldehydes: (S)- and/or (R)-1-
phenylpropan-1-ol 2. Typical procedure. Ligand 9a (0.06
g, 0.20 mmol, 10 mol%) was dissolved with stirring in
freshly distilled toluene (9 mL) under an atmosphere of
nitrogen at 20°C. Freshly distilled benzaldehyde (0.20
mL, 2.0 mmol) was then injected by syringe and the
resulting solution stirred for 15 min. The mixture was
then cooled to −30°C (cooling bath) and a solution of
diethylzinc in toluene (1.1 M, 3.6 mL, 4 mmol) was
injected by syringe, ensuring that the tip of the needle was
below the surface of the solution. The mixture was stirred
at −30°C for 16 h. Aqueous hydrochloric acid solution (1
M, 10 mL) was added slowly (CAUTION: vigorous
reaction). The aqueous layer was extracted with diethyl
ether (2×20 mL) and the combined organic layers were
dried (MgSO4), filtered and evaporated under reduced
pressure to give a turbid oil that was further purified by
flash column chromatography (ethyl acetate, petroleum
ether 40–60°C, 3:17 v/v) to give a clear oil (0.135 mg,
flash
column
chromatography,
initially
with
methanol:chloroform (1:4 v/v), then followed by
methanol:chloroform (1:19 v/v) to give a clear oil that
was dissolved in hot petroleum ether (40–60°C). On
cooling, small glassy needles deposited which were iso-
lated and recrystallised from cyclohexane to give 9a as
small glassy needles (3.90 g, 30%), mp 129–130°C; IR
(thin film) wmax 3126, 2926, 2854, 1446, 1369, 1105 cm−1
;
1
[h]D=+11.2 (c 1, CHCl3); H NMR (CDCl3, 600 MHz) l
7.63 (2H, br, OH), 3.49 (2H, m, C1HOH), 2.43 (2H, m,
C1%HNH), 2.29 (2H, m, C2HNH), 2.01 (2H, m), 1.91 (2H,
m), 1.67 (6H, m), 1.64 (2H, m), 1.30–1.18 (10H, m), 0.99
(2H, m), 0.65 (2H, m); 13C NMR (CDCl3, 150 MHz) l
77.46, 65.58, 65.44, 35.25, 33.19, 32.57, 25.59, 25.46,
24.33. HRMS calcd for C18H35N2O2 (MH+) 311.2699.
Found: 311.2699. FAB MS (%) 311 (MH+, 100), 196 (52),
115 (42). Anal. calcd for C18H34N2O2 C, 69.62; H, 11.04;
N, 9.03. Found: C, 69.42; H, 11.14; N, 8.93%.
50%). Enantiomeric excess was determined using
a
Chiracel OD column. 1H NMR (CDCl3, 300 MHz) l
7.32 (5H, m, Ar-H), 4.56 (1H, t, J 7.3, CHOH), 2.43 (1H,
br, OH), 1.78 (2H, m, CH2), 1.43 (3H, t, J 7.3, CH3).
22. Corey, E. J.; Hannon, F. J. Tetrahedron Lett. 1987, 28,
5237–5240.
23. The 2-pyrrolidinylmethanol system provides a rare exam-
ple of an NH catalyst being active (36% e.e.) and the
corresponding (N-benzyl) tertiary amine affording pre-
dominantly the opposite enantiomer (82% e.e.): Yang, X.;
Shen, J.; Da, C.; Wang, R.; Choi, M. C. K.; Yang, L.;
Wong, K. Tetrahedron: Asymmetry 1999, 10, 133–138.
(1R,2R)-N,N%-Dimethyl-N,N%-bis((3S,4S)-4-hydroxycyclo-
hexyl)-trans-1,2-diaminocyclohexane 9b. Diamine 9a
(0.556 g, 1.80 mmol) was dissolved in formaldehyde (37%
by wt, 4.0 mmol, 6.0 mL) and formic acid (96% v/v, 0.22
mol, 7.8 mL) and the resulting solution heated to 90°C.
Sodium formate (7.40 mmol, 0.50 g) was then added in
.