Asymmetric synthesis using catalysts containing multiple stereogenic centres and a trans-1,2-diaminocyclohexane core; Reversal of predominant enantioselectivity upon N-alkylation

Article abstract of DOI:10.1016/j.tet.2004.11.030

N-Methylation of ligands containing a trans-1,2-diaminocyclohexane core and multiple stereogenic centres is shown to provide the product of the opposite configuration in significant enantiomeric excess, in the addition of diethylzinc to aldehydes. Some of

Full text of DOI:10.1016/j.tet.2004.11.030

Tetrahedron 61 (2005) 1269–1279
Asymmetric synthesis using catalysts containing multiple
stereogenic centres and a trans-1,2-diaminocyclohexane core;
reversal of predominant enantioselectivity upon N-alkylation
*
Alexander J. A. Cobb and Charles M. Marson
Department of Chemistry, University College London, Christopher Ingold Laboratories, 20 Gordon Street, London WC1H OAJ, UK
Received 2 September 2004; revised 15 October 2004; accepted 11 November 2004
Available online 8 December 2004
Abstract—N-Methylation of ligands containing a trans-1,2-diaminocyclohexane core and multiple stereogenic centres is shown to provide
the product of the opposite configuration in significant enantiomeric excess, in the addition of diethylzinc to aldehydes. Some of the ligands
were effective in an asymmetric Michael addition.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Catalytic asymmetric formation of carbon–carbon bonds is
a field of continuing importance in organic synthesis.1
Ligands derived from a b-amino alcohol or a vicinal
diamine are commonly found in catalysts, especially in the
asymmetric addition of organometallic reagents to carbonyl
compounds. In particular, the b-amino alcohol moiety has
found extensive use as a ligand in the asymmetric addition
of dialkylzincs to carbonyl compounds,2–4 and mechanistic
features have been thoroughly examined.3 Catalysts
incorporating a trans-1,2-diaminocyclohexane core have
Figure 1.
also found much use for asymmetric additions to carbonyl
compounds.5 For a ligand based upon either a b-amino
alcohol or a vicinal diamine, the co-ordination geometry is
Recently, our research has shown that catalysts with up to
reasonably well understood, leading in a number of cases to
four co-ordinating sites and at least as many possible
plausible models for the catalytic processes. In contrast,
coordinating atoms permit asymmetric hydrogenation of
catalysts prepared from ligands that contain multiple
carbonyl compounds; moreover, in several instances,
stereocentres have been studied much less. Representative
catalysts 16 and 27 (Fig. 1) were constructed from two
N-benzylation of the terminal amino groups resulted in
reversal of the absolute configuration of the major product.8
ephedrine units linked, respectively, by an alkyl or
In our search for new catalysts for asymmetric carbon–
alkylarylalkyl chain. In the addition of diethylzinc to
carbon bond formation that contain multiple co-ordinating
sites and stereogenic centres, a catalyst containing both a
benzaldehyde, ligands 1a and 2 afforded (R)-1-phenyl-
propan-1-ol in 32 and 85% ee, respectively;6 ligand 2
afforded the (S)-enantiomer in 80% ee.7 Additional possi-
trans-1,2-diaminocyclohexane subunit and b-amino alcohol
moiety was shown to be effective in the asymmetric addition
bilities for intramolecular coordination of related com-
of diethylzinc to aromatic aldehydes.9 These ligands possess
pounds could widen the scope of catalytic asymmetric
an extended array of up to six chiral centres. The
processes.
preparation, further reactions and reversal, upon N-methyl-
ation, of the predominant enantioselection induced by such
Keywords: Amine ligands; Catalysis; Asymmetric synthesis; Carbonyl
catalysts is here described.
alkylation; Michael addition.
* Corresponding author. Tel.: C44 20 7679 4712; fax: C44 20 7679 7463;
e-mail: c.m.marson@ucl.ac.uk
The unadorned ligands 4 and 5 incorporating bis(b-
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.11.030

1270
A. J. A. Cobb, C. M. Marson / Tetrahedron 61 (2005) 1269–1279
aminoalcohol) moieties were prepared according to
Scheme 1. (1R,2R)-(K)-1,2-Diaminocyclohexane 310 was
dialkylated with 2-bromoethanol (water, reflux, 12 h) to
give diol 4 (30%).11 N,N0-Dimethylation of diol 4 to give the
tertiary amino diol 5 (95%) was achieved using formal-
dehyde and formic acid in an Eschweiler–Clarke
procedure,12 but modified by addition of the hydrogen
donor sodium formate.13 The introduction of additional
chiral centres on the b-aminoalcohol unit was found to be
achieved satisfactorily by acylation followed by reduction.
Activation of the requisite enantiomer of mandelic acid with
dicyclohexylcarbodiimide (DCC) in the presence of
N-hydroxysuccinimide followed by addition of the diamine
3 afforded ligands 6 and 9 in respective yields of 56% and
50%.14 Reduction of amides 6 and 9 with Me2S$BH3 gave
the secondary amines 7 (32%) and 10 (25%) respectively.15
Those amines were also subjected to Eschweiler–Clarke
N,N0-dimethylation in the above manner to give the
corresponding tertiary amines 8 and 1116 in quantitative
yields.
the diamine 3. Reduction of amides 12 and 15 gave the
secondary amines 13 (99%) and 16 (65%) respectively.15
Those amines were also subjected to Eschweiler–Clarke
N,N0-dimethylation in the manner described above to give
the corresponding tertiary amines 14 (63%) and 17 (74%).
Since each of the above ligands possesses C2 symmetry, it
was of interest to prepare ligands with a trans-
diaminocyclohexane core that are not C2-symmetric,
because of the presence of N-substituents of opposite
configuration to each other. A stepwise synthesis was
required and proceeded by reaction of diamine 3 with (R)-
(K)-2-hydroxy-3-methylbutyric acid activated by carbonyl-
diimidazole in the presence of 1-hydroxybenzotriazole
to give the amide 18 followed by subsequent reaction with
(S)-(C)-2-hydroxy-3-methylbutyric acid and carbonyl-
diimidazole in the presence of 1-hydroxybenzotriazole to
give the diamide 19 (42%). Reduction of 19 with Me2S$BH3
afforded the diamine 20 (40%) which underwent N,N0-
dimethylation with formaldehyde and formic acid to give
the tetraamine 21 in 55% yield.
To provide a contrast to the planarity of the phenyl
substituents in the ligands 6–11, isopropyl-substituted
systems were also prepared (Scheme 2). Ligands 12 and
15, (89% and 92%, respectively) were prepared by
activation of the requisite enantiomer of 2-hydroxy-3-
methylbutyric acid with carbonyldiimidazole in the pre-
sence of 1-hydroxybenzotriazole, followed by addition of
Lastly, amino alcohols containing six chiral centres were
obtained by heating diamine 3 with cyclohexene oxide to
give diamino diol 22 (30%) which was also reacted with
formaldehyde and formic acid in the presence of sodium
formate to give quantitatively the corresponding tertiary
diamino diol 23.9 The relative configuration of each
stereocentre in diamino diol 22 was established by X-ray
Scheme 1. Reagents and conditions. (i) 2-Bromoethanol (2 mol equiv), reflux in water; (ii) 37% HCHO (20 mol equiv), 96% HCOOH (53 equiv), HCOONa
(10 mol%); (iii) (S)-(C)-mandelic acid (2.2 mol equiv), DCC (2.2 mol equiv), N-hydroxysuccinimide (2.2 mol equiv), THF; (iv) Me2S$BH3 (6 mol equiv),
Et2O$BF3 (14 mol equiv), THF.

A. J. A. Cobb, C. M. Marson / Tetrahedron 61 (2005) 1269–1279
1271
Scheme 2. Reagents and conditions. (i) (R)-(K)-2-Hydroxy-3-methylbutyric acid (2.2 mol equiv), carbonyldiimidazole (1.5 mol equiv), 1-hydroxybenzo-
triazole (0.14 mol equiv), THF; (ii) Me2S$BH3 (5.5 mol equiv), Et2O$BF3 (4 mol equiv), THF; (iii) 37% HCHO, 90% HCOOH, HCOONa (10 mol%);
(iv) (R)-(K)-2-hydroxy-3-methylbutyric acid (0.5 mol equiv), carbonyldiimidazole (0.86 mol equiv), 1-hydroxybenzotriazole (0.1 mol equiv), THF; (v) (S)-
(C)-2-hydroxy-3-methylbutyric acid (2.2 mol equiv), carbonyldiimidazole (1.5 mol equiv), 1-hydroxybenzotriazole (0.35 mol equiv), THF (vi) 37% HCHO,
90% HCOOH.
crystallography performed on the racemic modification.17
A
investigating the addition of diethylzinc to aldehydes.2,19
This is considered as a yardstick for the efficiency and
enantioselectivity of a catalyst, since the rate of the reaction
in the absence of a catalyst is low but markedly increased in
the presence of a suitable catalyst.3,20 The unadorned
ligands as catalysts 4 and 5 did not provide 1-phenylpropan-
1-ol in either acceptable yield or enantiomeric excess
(Table 1). However, all of the catalysts studied containing
appended stereogenic centres (compounds 7, 8, 10, 11, 22
and 23) showed appreciable catalysis and in some cases
afforded the secondary alcohols in high ee, showing that
single diastereoisomer was also obtained from the reaction
of (1R,2R)-(K)-1,2-diaminocyclohexane with cyclohexene
oxide, as had been found in a previous study using the
racemic diamine.17 Such directed stereochemical control is
presumably assisted by hydrogen bonding networks and has
features in common with adducts formed from the co-
crystallisation of enantiopure 1,2-diaminocyclohexane with
cyclohexane-1,2-diols (Scheme 3).18
Some of the new ligands were evaluated as catalysts by

1272
A. J. A. Cobb, C. M. Marson / Tetrahedron 61 (2005) 1269–1279
Scheme 3. Reagents and conditions. (i) Cyclohexene oxide (3 mol equiv), EtOH, reflux; (ii) 37% HCHO, 96% HCOOH, HCOONa.
Table 1. Reaction of aldehydes with diethylzinc in toluenea
Entry
Ligand
Aldehyde
Temperature (8C)
Yield (%)b
ee (%)c
Configuration
1
2
3
4
5
6
7
8
4
5
7
8
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
PhCH]CHCHO
p-MeO$C6H4CHO
p-MeO$C6H4CHO
2-Naphthaldehyde
K30
K30
K30
K30
K30
K30
K30
K30
0
30
0
8
(S)
—
—
23
54
45
16
80
92
64
75
72
56
52
60
40
55
42
51
50
25
99
68
41
74
18
95
(R)
(S)
(S)
(R)
(R)
(S)
(R)
(S)
(R)
(R)
(S)
(R)
10
11
22
23
22
23
22
22
23
22
9
10
11
12
13
14
0
K30
K30
K30
0
a In the presence of the trans-1,2-diaminocyclohexane ligand (10 mol%), and 2.2 equiv of diethylzinc. Reactions were maintained at K30 or 0 8C for 4 h, then
allowed to warm to 20 8C over a further 12 h.
b Yields were determined by 1H NMR spectrometry.
c Enantiomeric excesses and absolute configurations of the alcohols were determined using a Chiralcel OD column.24
ligands with multiple stereogenic centres can indeed
participate as catalysts in asymmetric carbon–carbon bond
formation.
amine ligand. Conversely, for pair 10 and 11, which possess
the (S)-configuration at the carbinol carbon atom, the
N-methylated derivative 11 favours induction of the
(R)-enantiomer (entries 5 and 6). In previous work, N,N-
dimethylation led to reversal of enantioselectivity but in
only low ee’s using secondary amine ligands.21,22 Accord-
ingly, it is noteworthy that the secondary amine catalyst
22 affords 80% ee (Table 1, entry 7). While the
N-methylated catalysts 8, 11 and 23 all give greater amounts
of (S)-1-phenylpropan-1-ol, the effect is greatest with ligand
23, containing six stereogenic centres. Using 23 and 2-
naphthaldehyde, the aryl alcohol was not detected, pre-
sumably because of steric hindrance of approach to the
In all pairs of compounds studied (i.e., the secondary amines
and their corresponding N-methylated derivatives), a
reversal was observed in the configuration of the major
enantiomer. The configuration at the carbinol carbon atom
has a pronounced effect upon the asymmetric induction, and
where it is (R), as for pairs 7 and 8 (Table 1, entries 3 and 4),
and for pairs 22 and 23 (entries 7 and 8, 9 and 10, 12 and 13)
the N-methylated derivative favours induction of the (S)-
enantiomer, as compared with the corresponding secondary
Scheme 4.

A. J. A. Cobb, C. M. Marson / Tetrahedron 61 (2005) 1269–1279
1273
catalyst. Using a trans-1,2-diaminocyclohexane as part of a
salen ligand, ee’s of 30–70% were obtained for the addition
of diethylzinc to benzaldehyde;23 ligands such as 22
compare favourably, and show that systems based on a
trans-1,2-diaminocyclohexane but with additional chirality
can deliver significantly high ee’s in the enantioselective
addition to carbonyl compounds (Scheme 4).
observed for both the phenyl-substituted series (8 and 11),
and the isopropyl series (14 and 17), indicating that similar
complexation features regarding secondary and tertiary
(N-methylated) amine ligands are likely to operate for
Michael additions as well as for 1,2-additions to carbonyl
compounds.
These results show that introduction of new chiral centres at
the b-amino alcohol carbon atoms of the diamino diol 4 can
lead to improved ee’s, and that catalysts with multiple
stereogenic centres can lead to significant asymmetric
induction in carbon–carbon bond-forming reactions. A
cyclohexane backbone, as in 22 and 23, gave the highest
ee’s of those catalysts studied, as well as providing the
products of the opposite configuration in high enantiomeric
excess, simply by N,N0-dimethylation of the ligand.27
The absolute configurations obtained with catalysts 22 and
23 might be accounted for by a catalyst with a pocket
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) would be consistent with
previous models.19,25 For ligand 22, the bulk at nitrogen is
sufficiently small to allow the aryl ring to reside nearby,
leading to the attack of the aldehyde on its Re-face.
Conversely, for 23, the bulk of the N-methyl group is
deemed to hinder location of the aryl group as above, so
leading to Si-face addition and predominantly the (S)-1-
arylpropan-1-ol.
2. Experimental
2.1. General
Melting points were determined on a microscope hot-stage
apparatus and are uncorrected. Infrared spectra were
recorded on a Perkin–Elmer PE-983 spectrophotometer.
Optical rotations were measured at 20 8C. Unless otherwise
stated, 1H and 13C NMR spectra were recorded on a
Bruker AC300 instrument operating at 300 and 75 MHz,
respectively; chemical shifts are reported in d (ppm) relative
to the internal reference (tetramethylsilane or deuterio-
chloroform). Thin-layer chromatography was performed on
Merck 0.2 mm aluminium-backed silica gel 60 F254 plates
and visualized using alkaline KMnO4 spray or by ultraviolet
light. Flash column chromatography was performed using
Merck 0.040–0.063 mm, 230–400 mesh silica gel. Micro-
analytical data were obtained on a Perkin–Elmer 2400 CHN
In view of the use of tetradentate amino alcohols as ligands
in the asymmetric Michael addition26 of diethylzinc to
chalcone, the efficacy of some of the diamino diol ligands
was briefly examined (Scheme 5). Ligand 8 (Table 2) was
found to be significantly better than 14, again showing that
the stereogenic centre at the carbinol carbon atom plays a
major role. In the isopropyl substituted series, ligand 14
(corresponding to 8) gave a somewhat higher ee than the
diastereoisomer 17, but no asymmetric induction was
observed using ligand 21, containing opposite stereo-
chemistries at the carbinol position. Again, a (modest)
reversal in the configuration of the major enantiomer was
Scheme 5.
Table 2. Reaction of chalcone with diethylzinc in toluenea
Entry
Ligand
Yield (%)b
ee (%)c
Configuration
1
2
3
4
5
8
72
68
63
70
61
37
10
13
8
(R)
(S)
(R)
(S)
—
11
14
17
21
0
a Reactions were conducted at K30 8C with 16 mol% of Ni(acac)2 and 16 mol% of ligand.
b Yields were determined by 1H NMR spectrometry.
c Absolute configurations of the conjugate ketone were determined by HPLC analysis using a Chiralcel OD column.24

1274
A. J. A. Cobb, C. M. Marson / Tetrahedron 61 (2005) 1269–1279
elemental analyser. Mass spectra were obtained on a
VG7070H mass spectrometer with Finigan Incos II. All
solvents were reagent grade and, where necessary, were
purified and dried by standard methods. Evaporation refers
to the removal of solvent under reduced pressure.
(CH2CH2CHN). HRMS (EI): calcd for C22H26N2O4 (MC)
382.1893, found 382.1889.
2.1.3. (1R,2R)-(C)-N,N0-Bis(ethan-(1-(R)-phenyl)-1-ol)-
trans-1,2-diaminocyclohexane (7). To an oven-dried,
25 mL pear-shaped flask with an inlet capped with a septum
and containing a stirrer bar (1 cm length) was attached a 40
Vigreux column. At the top of the column was placed a
distillation arm with a small condenser. Between the
condenser and a 10 mL receiver flask was an outlet
connected to nitrogen through a mercury bubbler. The
whole system was flushed with nitrogen and the pear-shaped
flask was charged with a solution of amide 6 (0.235 g,
0.62 mmol) in dry THF (5 mL). To this solution was added
boron trifluoride etherate (0.312 mL, 8.61 mmol); the
mixture was then heated to reflux until it became clear.
Borane–dimethyl sulfide complex in THF (1.84 mL, 2 M,
3.69 mmol) was then added carefully over 15 min. The
liberated dimethyl sulfide and ether were distilled and
collected. After 18 h at reflux, the remaining solution was
allowed to cool to room temperature and the solvent
carefully removed by connecting the outlet for nitrogen to a
vacuum pump. The residual amine–boron trifluoride com-
plex was cooled to 0 8C and hydrochloric acid (10 mL, 6 M)
was added dropwise for the first few mL; CAUTION: the
initial reaction is very vigorous! The acidified solution was
heated at reflux for 1 h to ensure complete hydrolysis. The
solution was then allowed to cool to 20 8C and the non-basic
components removed by extraction with diethyl ether (3!
15 mL). The aqueous layer was made alkaline by addition of
aqueous sodium hydroxide (6 M, CAUTION) to pH 12 and
was then extracted with diethyl ether (3!15 mL). The
combined organic layers were dried (MgSO4), filtered, and
evaporated to give a clear oil that was purified by flash
column chromatography (1:19 methanol/chloroform) to
give amine 7 (71 mg, 32%) as a clear oil; [a]DZC1.87
(cZ1.55, CHCl3); IR (film) 3618 (br), 3149, 1645,
The following compounds were prepared according to
literature procedures: (1R,2R)-(K)-trans-1,2-diamino-
cyclohexane;10 (1S,2S)-(C)-trans-1,2-diaminocyclo-
hexane; (R)-(K)-2-hydroxy-3-methylbutyric acid;28 (S)-
(C)-2-hydroxy-3-methylbutyric acid;28 (1R,2R)-(K)-N,N0-
bis-(1-hydroxyethyl)-trans-diaminocyclohexane.29
2.1.1. (1R,2R)-(K)-N,N0-Dimethyl-N,N0-bis(1-hydro-
xyethyl)-trans-diaminocyclohexane (5). (1R,2R)-(K)-
N,N0-Bis-(1-hydroxyethyl)-trans-diaminocyclohexane
(0.40 g, 2.0 mmol) was dissolved in formaldehyde (3.3 mL,
37% w/v, 41 mmol,) and formic acid (4.2 mL, 96% v/v,
107 mmol) and the resulting solution heated to 90 8C.
Sodium formate (14 mg, 0.20 mmol) was then added and
the mixture was kept stirring at 90 8C for 16 h. The solution
was then was cooled to room temperature and made
alkaline, with cooling, to pH 12 with aqueous sodium
hydroxide (2 M). The mixture was extracted with diethyl
ether (3!20 mL) and the combined organic layers were
dried (MgSO4), filtered and evaporated to give amine 5
(0.43 g, 95%) as a clear oil; [a]DZK32.8 (cZ0.01,
1
CHCl3); IR (film) 3628 (br), 2886, 1123 cmK1; H NMR
(CDCl3) d 5.63 (2H, br, OH), 3.68 (4H, m, CH2OH), 3.58
(2H, m, CHN), 2.84 (4H, m, CH2N), 2.41 (6H, s, Me), 2.07–
1.20 (8H, m, CH2CH2CHN); 13C NMR (CDCl3) d 64.4
(CH2OH), 53.3 (CH2N), 40.7 (CHN), 35.9 (Me), 23.5
(CH2CHN), 21.6 (CH2CH2CHN). HRMS (EI): calcd for
C12H27N2O2 (MHC) 231.2073, found 231.2081.
2.1.2. (1R,2R)-(C)-N,N0-Bis(a-hydroxy-(S)-phenyl)-
acetamido-trans-1,2-diaminocyclohexane (6). L-Mandelic
acid (11.7 g, 77 mmol) and N-hydroxysuccinimide (8.86 g,
77 mmol) were added to a stirred solution of (1R,2R)-(K)-
trans-1,2-diaminocyclohexane (4.0 g, 35 mmol) in THF
(100 mL) and the resulting mixture was stirred for 30 min at
20 8C. To this solution was added 1,3-dicyclohexylcarbo-
diimide (15.9 g, 77 mmol) in portions over 10 min and the
resulting mixture was stirred for 48 h at 20 8C. Saturated
aqueous sodium hydrogen carbonate (50 mL) was then
added and the aqueous layer was extracted with ethyl
acetate (3!50 mL). The combined organic layers were
dried (MgSO4), filtered and evaporated to give an off-white
solid that was purified by flash column chromatography (7:3
ethyl acetate/petroleum ether). Any residual urea by-
product is removed in the first few fractions and is visible
by its precipitation within the fraction solvent. Evaporation
of the required fractions gave a white solid that was
recrystallized from the elution solvent to give amide 6
(7.4 g, 56%) as white plates, mp 158–160 8C; [a]DZC28.7
(cZ1, CHCl3) cmK1; IR (CHCl3) 3185 (br), 1645, 1535,
1
1580 cmK1; H NMR (CDCl3) d 7.48 (10H, m, phenyl),
4.97 (2H, m, CHOH), 3.48 (2H, br, CHOH), 3.22 (2H, m,
CHNH), 2.70 (4H, m, CH2NH), 2.15–1.25 (8H, m,
CH2CH2CHNH); 13C NMR (CDCl3, 75 MHz) d 142.9
(ipso-phenyl), 128.7 (o-phenyl), 127.8 (m-phenyl), 126.3
(p-phenyl), 74.7 (CHOH), 64.3 (CH2NH), 56.5 (CHNH),
33.4 (CH2CHNH), 25.6 (CH2CH2CHNH). HRMS (EI):
calcd for C22H31N2O2 (MHC) 355.2377, found 355.2386.
2.1.4. (R,R)-(C)-N,N0-Dimethyl-N,N0-bis(ethan-(1-(R)-
phenyl)-1-ol)-trans-1,2-diaminocyclohexane (8). Amino
alcohol 7 (0.25 g, 0.65 mmol) was dissolved in aqueous
37% formaldehyde (1.2 mL, 15 mmol) and the resulting
solution stirred at 20 8C for 10 min. Aqueous 90% formic
acid (1.5 mL, 35 mmol) was then added and the mixture was
stirred and heated at 90 8C for 24 h. The mixture was then
cooled to 20 8C and made alkaline (pH 12) by addition of
aqueous sodium hydroxide (2 M) with constant cooling. The
aqueous layer was extracted with diethyl ether (2!25 mL)
and the combined organic layers were dried (MgSO4),
filtered and evaporated to give an oil that was purified by
flash column chromatography (1:19 methanol/chloroform)
to give amine 8 (0.26 g, quantitative) as a clear oil;
[a]DZK27.7 (cZ0.76, CHCl3); IR (film) 3520 (br),
1
1060 cmK1; H NMR (CDCl3) d 7.22 (10H, m, phenyl),
6.38 (2H, br, NH), 4.47 (2H, s, CHOH), 3.67 (2H, br, OH),
3.52 (2H, m, CHN), 1.80–1.10 (8H, m, CH2CH2CHN); 13
C
NMR (CDCl3) d 173.3 (C]O), 140.0 (ipso-phenyl), 129.2
(o-phenyl), 129.0 (m-phenyl), 127.1 (p-phenyl), 74.2
(CHOH), 54.2 (CHN), 34.3 (CH2CHN), 25.3
1
3061, 1645, 1511 cmK1; H NMR (CDCl3) d 7.35 (10H,
m, phenyl), 5.71 (2H, br, OH), 4.79 (2H, m, CHOH), 2.85

A. J. A. Cobb, C. M. Marson / Tetrahedron 61 (2005) 1269–1279
1275
(2H, m, CHN), 2.43 (4H, m, CH2N), 2.17 (6H, s, CH3),
1.75–1.05 (8H, m, CH2CH2CHN)); 13C NMR (CDCl3) d
143.8 (ipso-phenyl), 128.6 (o-phenyl), 127.4 (m-phenyl),
126.4 (p-phenyl), 70.6 (CHOH), 63.2 (CH2N and CHN),
37.4 (CH3), 25.9 (CH2CHN), 24.8 (CH2CH2CHN). HRMS
(EI): calcd for C24H35N2O2 (MHC) 383.2699, found
383.2692.
amine 11 (31 mg, quantitative) as a clear oil; [a]DZK111.6
(cZ0.57, CHCl3); IR (film) 3567, 2988, 1511, 1168 cmK1
;
1H NMR (CHCl3) d 7.31 (10H, m, phenyl), 7.51 (2H, br,
OH), 4.83 (2H, m, CHOH), 2.75 (2H, m, CHNH), 2.50–2.30
(10H, m, NCH3, NCH2, CHN), 2.02–1.80 (4H, CH2CHN),
1.10 (4H, m, CH2CH2CHN); 13C NMR (CDCl3) d 143.3
(ipso-phenyl), 128.9 (o-phenyl), 127.9 (m-phenyl), 126.6
(p-phenyl), 72.2 (CHOH), 65.0 (CH2N), 60.5 (CHN), 42.0
(NCH3), 26.0 (CH2CHN), 23.8 (CH2CH2CHN). FAB-MS
m/z 383 (MHC, 100%), 232 (17%). HRMS (EI): calcd for
C24H35N2O2 (MHC) 383.2701, found 383.2699.
2.1.5.
(1R,2R)-(C)-N,N0-(a-Hydroxy-(R)-phenyl)-
acetamido-trans-1,2-diaminocyclohexane (9). D-Mandelic
acid (11.7 g, 77 mmol) and N-hydroxysuccinimide (8.86 g,
77 mmol) were added to a stirred solution of (1R,2R)-(K)-
trans-1,2-diaminocyclohexane (4.0 g, 35 mmol) in THF
(100 mL) and the resulting mixture stirred for 30 min at
20 8C. To this solution was added 1,3-dicyclohexylcarbo-
diimide (15.9 g, 77 mmol) in portions over 10 min and the
resulting mixture was stirred for 48 h at 20 8C. The mixture
was worked up as described for 6, and after column
chromatography, evaporation of the required fractions gave
a white solid which was recrystallized from ethyl acetate.
The white plates so obtained were filtered and dried under
reduced pressure to give amide 9 (6.5 g, 50%) as plates, mp
173–174 8C; [a]DZC17.6 (cZ1, CHCl3); (CHCl3) 3184,
1645, 1534, 1059 cmK1; 1H NMR (CDCl3) d 7.12 (10H, m,
aryl), 4.88 (2H, br, NH), 4.72 (2H, s, CHOH), 3.48 (2H, m,
CHN), 1.65–1.00 (8H, m, CH2CH2CHN); 13C NMR
(CDCl3) d 174.1 (C]O), 139.6 (ipso-phenyl), 129.0
(o-phenyl), 128.7 (m-phenyl), 127.1 (p-phenyl), 74.4
(CHOH), 53.6 (CHN), 32.4 (CH2CHN), 25.0 (CH2CH2-
CHN); IR (KBr pellet) 3355, 2944, 2832, 1657 cmK1; FAB-
MS m/z 383 (MHC, 100%). HRMS (EI): calcd for
C22H26N2O4 (MC) 382.1893, found 382.1897.
2.1.8. (1R,2R)-(C)-N,N0-Bis-(1-hydroxy-1-(S)-isopropyl-
acetamido)-trans-1,2-diaminocyclohexane (12).
A
solution of carbonyldiimidazole (3.14 g, 19.4 mmol) in
dry THF (10 mL) was added to a stirred solution of (S)-(C)-
2-hydroxy-3-methylbutyric acid (2.0 g, 17.0 mmol) and
1-hydroxybenzotriazole (0.23 g, 1.7 mmol) in freshly dis-
tilled THF (60 mL) under an inert atmosphere at 20 8C, and
the mixture was stirred for 1 h. A solution of (1R,2R)-(K)-
trans-diaminocyclohexane (0.88 g, 0.77 mmol) in dry THF
(2 mL) was then added dropwise. The mixture was stirred at
20 8C for 24 h, then hydrochloric acid (50 mL, 1 M) as
added. The aqueous layer was extracted with diethyl ether
(3!25 mL) and the combined organic layers were dried
(MgSO4), filtered and evaporated to give an off-white solid
which was purified by flash column chromatography (4:1
ethyl acetate/40–60 8C petroleum ether). Evaporation of
the appropriate fractions gave a white solid that was
recrystallized from isopropanol to give amide 12 as white
needles (2.16 g, 89%), mp 197–198 8C; [a]DZC32.2 (cZ
1
1, MeOH); IR (CHCl3) 3592, 2859, 1602 cmK1; H NMR
(CD3OD) d 3.75 (2H, d, JZ3.5 Hz, CHOH), 3.68 (2H, m,
CHN), 2.01 (2H, m, CH3CHCH3), 2.00–1.75 (4H, m,
CH2CHN), 1.35 (4H, m, CH2CH2CHN), 0.97 (6H, d, JZ
7.0 Hz, CH3CHCH3), 0.83 (6H, d, JZ7.0 Hz, CH3CHCH3);
13C NMR (CH3OD) d 177.2 (C]O), 77.6 (CHOH), 54.2
(CHN), 33.7 (CH3CHCH3), 33.5 (CH2CHN), 26.1 (CH2-
CH2CHN), 20.1 (CH3CHCH3), 17.2 (CH3CHCH3); FAB-
MS m/z 315 (MHC, 100%), 215 (21%), 141 (23%), 98
(42%). Anal. calcd for C16H30N2O4: C, 61.10; H, 9.62; N,
8.91. Found: C, 61.09; H, 9.74; N, 8.85.
2.1.6. (1R,2R)-(K)-N,N0-Bis(ethan-(1-(S)-phenyl)-1-ol)-
trans-1,2-diaminocyclohexane (10). The procedure
described for amine 7 was followed using a solution of
amide 9 (0.404 g, 1.06 mmol) in dry THF (5 mL). To this
solution was added boron trifluoride etherate (0.153 mL,
4.22 mmol) and the solution was heated to reflux until it
became clear. Borane–dimethyl sulfide complex in THF
(1.17 mL, 2 M, 2.33 mmol) was then added carefully over
15 min. The subsequent steps, work-up and isolation as
described for amine 7 gave an oil that was purified by flash
column chromatography (1:19 methanol/chloroform) to
give amine 10 (94 mg, 25%) as a clear oil that solidified
on cooling to 4 8C; [a]DZK96.6 (cZ0.5, CHCl3); IR (film)
3626, 3090, 1650 cmK1; 1H NMR (CDCl3) d 7.30 (10H, m,
phenyl), 4.76 (2H, m, CHOH), 3.00–2.60 (6H, m, CH2NH
and CHNH), 2.25 (2H, m, NH), 2.05–1.20 (8H, m,
CH2CH2CHNH); 13C NMR (CDCl3) d 143.1 (ipso-phenyl),
128.8 (o-phenyl), 127.9 (m-phenyl), 126.4 (p-phenyl), 72.6
(CHOH), 60.8 (CH2NH), 54.4 (CHNH), 32.5 (CH2CHNH),
25.5 (CH2CH2CHNH). HRMS (EI): calcd for C22H30N2O2
(MHC) 355.2377, found, 355.2386.
2.1.9. (1R,2R)-(K)-N,N0-Bis(ethan-(1-(R)-isopropyl)-1-
ol)-trans-1,2-diaminocyclohexane (13). The procedure
described for amine 7 was followed using a solution of
amide 12 (0.10 g, 0.32 mmol) in dry THF (5 mL). To this
solution was added boron trifluoride etherate (0.16 mL,
1.27 mmol) and the solution was heated to reflux until it
became clear. Borane–dimethyl sulfide complex in THF
(3 mL, 2 M, 3.18 mmol) was then added carefully over a
period of 15 min. The subsequent steps, work-up and
isolation as described for amine 7 gave an oil that was
purified by flash column chromatography (1:49 methanol/
chloroform) to give amine 13 (90 mg, 99%) as a clear oil;
[a]DZK7.2; (cZ0.31, CHCl3); IR (film) 3202, 1556,
2.1.7. (1R,2R)-(K)-N,N0-Dimethyl-N,N0-bis(ethan-(1-(S)-
phenyl)-1-ol)-trans-1,2-diaminocyclohexane (11). Amino
alcohol 10 (30 mg, 0.085 mmol) was dissolved in aqueous
37% formaldehyde (1.4 mL, 19 mmol) and the resulting
solution stirred at 20 8C for 10 min. Aqueous 90% formic
acid (1.8 mL, 42 mmol) was then added and the mixture was
stirred and heated at 90 8C for 24 h. The mixture was
worked up and purified as described for amine 8 to give
1
1383 cmK1; H NMR (CDCl3) d 4.91 (2H, br, OH), 3.32
(2H, m, CHOH), 2.88 (4H, m, CH2NH), 2.16 (2H, m,
CHNH), 2.00–1.15 (8H, m, CH2CH2CHNH), 1.53 (2H, m,
CH3CHCH3), 0.87 (6H, d, JZ7.0 Hz, CH3CHCH3), 0.83
(6H, d, JZ7.0 Hz, CH3CHCH3); 13C NMR (CDCl3) d 76.7
(CHOH), 63.8 (CH2NH), 51.6 (CHNH), 32.8 (CH3CHCH3),
30.4 (CH2CHNH), 25.5 (CH2CH2CHNH), 19.1

1276
A. J. A. Cobb, C. M. Marson / Tetrahedron 61 (2005) 1269–1279
(CH3CHCH3), 18.7 (CH3CHCH3). HRMS (EI): calcd for
C16H35N2O2 (MHC) 287.2699, found 287.2710.
CH2CH2CHNH), 1.54 (2H, m, CH3CHCH3), 0.88 (6H, d,
JZ7.0 Hz, CH3CHCH3), 0.83 (6H, d, JZ7.0 Hz, CH3-
CHCH3); 13C NMR (CDCl3, 125 MHz) d 74.8 (CHOH),
60.9 (CH2NH), 49.9 (CHNH), 32.6 (CH3CHCH3), 32.4
(CH2CHNH), 25.5 (CH2CH2CHNH), 19.0 (CH3CHCH3),
18.6 (CH3CHCH3). HRMS (EI): calcd for C16H35N2O2
(MHC) 287.2699, found 287.2696.
2.1.10. (1R,2R)-(K)-N,N0-Dimethyl-N,N0-bis(ethan-(1-
(R)-isopropyl)-1-ol)-trans-1,2-diaminocyclohexane (14).
Amino alcohol 13 (29 mg, 0.10 mmol) was dissolved in
aqueous 37% formaldehyde (2.8 mL, 27 mmol) and the
resulting solution stirred at 20 8C for 10 min. Aqueous 90%
formic acid (2.0 mL, 35 mmol) was then added and the
mixture was stirred and heated at 90 8C for 24 h. The
mixture was worked up and purified as described for
amine 8 to give amine 14 (20 mg, 63%) as a clear oil;
[a]DZK42.8 (cZ1, CHCl3); IR (film) 3119, 1503,
2.1.13. (1R,2R)-(K)-N,N0-Dimethyl-N,N0-bis(ethan-(1-
(S)-isopropyl)-1-ol)-trans-1,2-diaminocyclohexane (17).
Amino alcohol 16 (46 mg, 0.16 mmol) was dissolved in
aqueous 37% formaldehyde (2.8 mL, 27 mmol) and the
resulting solution stirred at 20 8C for 10 min. Aqueous 90%
formic acid (3.6 mL, 63 mmol) was then added and the
mixture was stirred and heated at 90 8C for 24 h. The
mixture was worked up and purified as described for
amine 8 to give amine 17 (36 mg, 74%) as a clear oil;
[a]DZK67.3 (cZ1.8, CHCl3); IR (film) 3602, 3128, 1512,
1
1204 cmK1; H NMR (CDCl3) d 3.29 (2H, m, CHOH),
2.68 (2H, m, CHHN), 2.44 (2H, m, CHN), 2.26 (2H, m,
CHHN), 2.23 (6H, s, NCH3), 1.77–1.10 (8H, m, CH2CH2-
CHN), 1.55 (2H, m, CH3CHCH3), 0.97 (6H, d, JZ7.0 Hz,
CH3CHCH3), 0.89 (6H, d, JZ7.0 Hz, CH3CHCH3); 13C
NMR (CDCl3) d 72.1 (CHOH), 65.9 (CH2N), 59.2 (CHN),
35.5 (NCH3), 32.4 (CH3CHCH3), 25.5 (CH2CHN), 24.9
(CH2CH2CHN), 18.8 (CH3CHCH3), 18.4 (CH3CHCH3).
HRMS (EI): calcd for C18H39N2O2 (MHC) 315.3012, found
315.3009.
1
1206 cmK1; H NMR (CHCl3, 500 MHz) d 3.39 (2H, m,
CHOH), 2.40–2.29 (6H, m, CH2N and CHN), 2.14 (6H, s,
CH3N), 1.97–1.80 (4H, m, CHHCHHCHN), 1.55 (2H, m,
CH3CHCH3), 1.12 (4H, m, CHHCHHCHN), 0.89 (6H, d,
JZ7.0 Hz, CH3CHCH3), 0.85 (6H, d, JZ7.0 Hz, CH3-
CHCH3); 13C NMR (CDCl3, 125 MHz) d 73.6 (CHOH),
64.8 (CH2N), 54.8 (CHN), 32.3 (CH3CHCH3), 31.2
(NCH3), 25.8 (CH2CHN), 23.3 (CH2CH2CHN), 18.8 (CH3-
CHCH3), 18.5 (CH3CHCH3). HRMS (EI): calcd for
C18H39N2O2 (MHC) 315.3012, found 315.3016.
2.1.11. (1R,2R)-(C)-N,N0-Bis-(1-hydroxy-1-(R)-iso-
propylacetamido)-trans-1,2-diaminocyclohexane (15). A
solution of carbonyldiimidazole (3.14 g, 19.4 mmol) in dry
THF was added to a stirred solution of (R)-(K)-2-hydroxy-
3-methylbutyric acid (3.42 g, 29.0 mol) and 1-hydroxy-
benzotriazole (0.46 g, 2.7 mmol) in freshly distilled THF
(70 mL) under an inert atmosphere at 20 8C, and the mixture
was stirred for 1 h. A solution of (1R,2R)-(K)-trans-
diaminocyclohexane (1.50 g, 13.1 mmol) in dry THF
(5 mL) was then added dropwise. The mixture was stirred
at 20 8C for 24 h followed by work-up and flash column
chromatography as described for 12. Evaporation of
the appropriate fractions gave a white solid that was
recrystallized from ethanol to give amide 15 as white
needles (3.78 g, 92%), mp 210–212 8C; [a]DZC51.7 (cZ
2.1.14. (1R,2R)-(C)-N-(a-Hydroxy-(R)-isopropylaceta-
mido)-trans-1,2-diaminocyclohexane (18). Carbonyldi-
imidazole (3.10 g, 19 mmol) was added in portions to a
stirred solution of (R)-(K)-2-hydroxy-3-methylbutyric acid
(1.30 g, 11 mmol) and 1-hydroxybenzotriazole (0.30 g,
2.2 mmol) in anhydrous THF (45 mL) under an inert
atmosphere at 20 8C, and the mixture was stirred for 1 h.
After this time, a solution of (1R,2R)-(K)-trans-1,2-
diaminocyclohexane (2.50 g, 22 mmol) in anhydrous tetra-
hydrofuran (5 mL) was added dropwise over 15 min. The
mixture was stirred at 20 8C for 16 h followed by
evaporation of the solvent and acidification of the residue
with hydrochloric acid (1 M) to pH 2. The aqueous layer
was washed with ethyl acetate (3!30 mL) and the
combined organic layers discarded. The remaining aqueous
layer was then made alkaline to pH 11 with aqueous sodium
hydroxide (1 M) and extracted with ethyl acetate (3!
30 mL). The combined organic layers were dried (MgSO4),
filtered and evaporated to give a white solid which was
recrystallized from isopropanol to give 18 as white plates
(0.14 g, 4%), mp 127–128 8C; [a]DZC83.3 (cZ0.5,
1
1, MeOH); IR (CHCl3) 3616, 2864, 1619 cmK1; H NMR
(CD3OD) d 3.84 (2H, d, JZ3.5 Hz, CHOH), 3.75 (2H, m,
CHN), 2.15 (2H, m, CH3CHCH3), 2.00–1.40 (8H, m,
CH2CH2CHN), 1.03 (6H, d, JZ7.0 Hz, CH3CHCH3), 0.87
(6H, d, JZ7.0 Hz, CH3CHCH3); 13C NMR (CDCl3) d 177.0
(C]O), 77.2 (CHOH), 54.1 (CHN), 33.8 (CH3CHCH3),
33.3 (CH2CHN), 26.2 (CH2CH2CHN), 20.1 (CH3CHCH3),
16.5 (CH3CHCH3). Anal. calcd for C16H30N2O4: C, 61.10;
H, 9.62; N, 8.91. Found: C, 61.14; H, 9.74; N, 8.82.
2.1.12. (1R,2R)-(K)-N,N0-Bis(ethan-(1-(S)-isopropyl)-1-
ol)-trans-1,2-diaminocyclohexane (16). The procedure
described for amine 7 was followed using a solution of
amide 15 (0.134 g, 0.43 mmol) in dry THF (5 mL). To this
solution was added boron trifluoride etherate (0.22 mL,
1.71 mmol) and the solution was heated to reflux until it
became clear. Borane–dimethyl sulfide complex in THF
(1.17 mL, 2 M, 2.33 mmol) was then added carefully over
15 min. The subsequent steps, work-up and isolation as
described for amine 7 (chromatography not required) gave
amine 16 (79 mg, 65%) as a clear oil; [a]DZK29.8 (cZ
1
CHCl3); IR (film) 3520 (br), 1683, 1469, 1183 cmK1; H
NMR (CDCl3, 500 MHz) d 6.64 (1H, m, NH), 3.96 (1H, d,
JZ4.0 Hz, CHOH), 3.64 (1H, m, CHNHCO), 2.99 (3H, br,
OH and NH2), 2.49 (1H, m, CHNH2), 2.13 (1H, m,
CH3CHCH3), 1.95–1.35 (8H, m, CH2CH2CHN), 1.04 (3H,
d, JZ7.0 Hz, CH3CHCH3), 0.89 (3H, d, JZ7.0 Hz, CH3-
CHCH3); 13C NMR (CDCl3, 125 MHz) d 174.5 (C]O),
76.3 (CHOH), 55.4 (CHNH), 54.3 (CHNH2), 35.7 (CH2-
CHNHCO), 32.7 (CH2CHNH2), 31.6 (CH3CHCH3), 25.0
(CH2CHN), 24.9 (CH2CH2CHN), 19.3 (CH3CHCH3), 15.8
(CH3CHCH3). FAB-MS m/z 215 (MHC, 100%). HRMS
(EI): calcd for C11H23N2O2 (MHC) 215.1760, found
215.1761.
1
0.04, CHCl3); IR (film) 3369, 3200, 1565, 1382 cmK1; H
NMR (CDCl3, 500 MHz) d 3.26 (2H, m, CHOH), 2.51 (4H,
m, CH2NH), 2.11 (2H, m, CHNH), 1.99–1.08 (8H, m,

A. J. A. Cobb, C. M. Marson / Tetrahedron 61 (2005) 1269–1279
1277
2.1.15. (1R,2R)-(C)-N-(a-Hydroxy-(R)-isopropylaceta-
mido)-N0-(a-hydroxy-(S)-isopropylacetamido)-trans-
1,2-diaminocyclohexane (19). A solution of 1,10-carbonyl-
diimidazole (36 mg, 0.22 mmol) in dry tetrahydrofuran
(2 mL) was added via a pressure-equilibrating dropping
funnel to a solution of (S)-(C)-2-hydroxy-3-methylbutyric
acid (26 mg, 0.22 mmol) and 1-hydroxybenzotriazole
hydrate (30 mg, 0.22 mmol) in dry tetrahydrofuran
(10 mL) under an inert atmosphere at 20 8C, and the
mixture was stirred for 1.5 h. A solution of amide 18
(40 mg, 0.19 mmol) in dry THF (2 mL) was then added
dropwise via a gas-tight syringe and the resulting solution
stirred for 16 h under an inert atmosphere at 20 8C. The
solution was then acidified with hydrochloric acid (20 mL,
1 M) and the aqueous layer extracted with ethyl acetate (3!
20 mL). The combined organic layers were dried (MgSO4),
filtered and evaporated to give an off-white solid that
was purified via flash chromatography (4:1 ethyl acetate/
40–60 8C petroleum ether) to give amide 19 as a white solid
(25 mg, 42%), mp 182 8C; [a]DZC5.3 (cZ0.5, MeOH); IR
0.17 mmol) was dissolved in aqueous 37% formaldehyde
(1.0 mL, 9.6 mmol) and the resulting solution stirred at
20 8C for 10 min. Aqueous 90% formic acid (1 mL,
17.5 mmol) was then added and the mixture was stirred
and heated at 90 8C for 24 h. The mixture was allowed to
cool to 20 8C and made alkaline (pH 12) by addition of
sodium hydroxide (2 M) with constant cooling. The aqueous
layer was extracted with diethyl ether (2!25 mL) and the
combined organic layers were dried (MgSO4), filtered and
evaporated to give amine 21 (30 mg, 55%) as a clear oil;
[a]DZK18.2 (cZ0.15, CHCl3); IR (film) 3482 (br), 1399,
1
1105 cmK1; H NMR (CDCl3, 500 MHz) d 3.40 (2H, m,
CHOH), 2.50–2.25 (6H, m, CH2N and CHN), 2.15 (6H, s,
CH3N), 1.95–1.25 (8H, m, CH2CH2CHNH), 1.60 (2H, m,
CH3CHCH3), 0.90 (3H, d, JZ7.0 Hz, CH3CHCH3), 0.88
(3H, d, JZ7.0 Hz, CH3CHCH3), 0.87 (3H, d, JZ7.0 Hz,
CH3CHCH3), 0.85 (3H, d, JZ7.0 Hz, CH3CHCH3). HRMS
(EI): calcd for C18H39N2O2 (MHC) 315.3012, found
315.3025.
(CHCl3) 3601 (br), 1689, 1694, 1465 cmK1 1H NMR
;
2.1.18. (1R,2R)-N,N0-Bis((3S,4S)-4-hydroxycyclohexyl)-
trans-1,2-diaminocyclohexane (22). To a stirred solution
of (1R,2R)-(K)-trans-1,2-diaminocyclohexane (4.80 g,
42.0 mmol) in anhydrous ethanol (100 mL) under an inert
atmosphere at 20 8C was added cyclohexene oxide
(17.3 mL, 171 mmol) via a pressure-equilibrated dropping
funnel over a period of 20 min. Upon complete addition, the
mixture was heated at reflux for 16 h. After this time, the
pale yellow solution was allowed to cool to 20 8C where-
upon the solvent was evaporated to give a brown oil that was
acidified to pH 2 with 2 M hydrochloric acid and the
aqueous layer extracted with chloroform (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 resulting yellow-orange oil was subjected
to purification by 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 8C). On allowing
to cool, small glassy needles deposited which were
isolated and recrystallised from cyclohexane to give 22
(3.90 g, 30%), as small glassy needles, mp 129–130 8C;
[a]DZC11.2 (c 1, CHCl3); IR (film) nmax 3126, 2926, 2854,
(500 MHz, CDCl3) d 7.31 (1H, br, CHNH), 7.02 (1H, br,
CHNH), 3.92 (1H, d, JZ4.5 Hz, CHOH), 3.77 (1H, d, JZ
4.5 Hz, CHOH), 3.75 (2H, m, CHNH), 2.12 (1H, m,
CH3CHCH3), 1.91 (1H, m, CH3CHCH3), 1.89–1.35 (8H,
m, CH2CH2CHN), 0.99 (3H, d, JZ7.0 Hz, CH3CHCH3),
0.92 (3H, d, JZ7.0 Hz, CH3CHCH3), 0.79 (3H, d, JZ
7.0 Hz, CH3CHCH3), 0.77 (3H, d, JZ7.0 Hz, CH3CHCH3);
13C NMR (125 MHz, CDCl3) d 174.8 (C]O), 174.6
(C]O), 76.7 (CHOH), 76.0 (CHOH), 53.2 (CHNH), 52.7
(CHNH), 32.3 (CH2CHNH), 32.2 (CH2CHNH), 31.8 (CH3-
CHCH3), 31.4 (CH3CHCH3), 24.8 (CH2CH2CHN), 24.7
(CH2CH2CHN), 19.7 (CH3CHCH3), 19.4 (CH3CHCH3),
16.2 (CH3CHCH3), 15.8 (CH3CHCH3). HRMS (EI): calcd
for C16H31N2O4 (MHC) 315.2284, found 315.2273.
2.1.16. (1R,2R)-(K)-N-(Ethan-(1-(S)-isopropyl)-1-ol)-N0-
(ethan-(1-(R)-isopropyl)-1-ol)-trans-1,2-diamino-cyclo-
hexane (20). The procedure described for amine 7 was
followed using a solution of amide 19 (22 mg, 0.07 mmol)
in dry THF (2 mL). To this solution was added boron
trifluoride etherate (0.04 mL, 0.27 mmol) and the solution
was heated to reflux until it became clear. Borane–dimethyl
sulfide complex in THF (1.17 mL, 2 M, 2.33 mmol) was
then added carefully over 15 min. The subsequent steps,
work-up and isolation as described for amine 7 (chroma-
tography not required) gave amine 20 (8 mg, 40%) as a clear
oil; [a]DZK35.2 (cZ0.4, CHCl3); IR (film) 3321 (br),
1566, 1213 cmK1; 1H NMR (CDCl3, 500 MHz) d 3.27 (2H,
m, CHOH), 2.85–2.60 (2H, m, CH2NH), 2.50–2.25 (2H, m,
CH2NH), 2.10 (2H, m, CHNH), 1.56 (2H, m, CH3CHCH3),
2.00–1.15 (8H, m, CH2CH2CHNH), 0.90–0.82 (12H, m,
CH3CHCH3); 13C NMR (CDCl3, 125 MHz) d 76.3
(CHOH), 74.8 (CHOH), 61.4 (CH2NH), 59.7 (CH2NH),
51.1 (CHNH), 49.8 (CHNH), 32.6 (CH2CHNH), 32.3
(CH2CHNH), 31.3 (CH3CHCH3), 31.2 (CH3CHCH3), 25.4
(CH2CH2CHNH), 19.1 (CH3CHCH3), 19.0 (CH3CHCH3),
18.7 (CH3CHCH3), 18.6 (CH3CHCH3). HRMS (EI): calcd
for C16H35N2O2 (MHC) 287.2699, found 287.2694.
1
1446, 1369, 1105 cmK1; H NMR (CDCl3, 600 MHz) d
7.63 (2H, br, OH), 3.49 (2H, m, C1HOH), 2.43 (2H, m,
0
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) d
77.46, 65.58, 65.44, 35.25, 33.19, 32.57, 25.59, 25.46,
24.33. HRMS calcd for C18H35N2O2 (MHC) 311.2699.
Found: 311.2699. FAB MS (%) 311 (MHC, 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.
2.1.19.
(1R,2R)-N,N0-Dimethyl-N,N0-bis((3S,4S)-4-
hydroxycyclohexyl)-trans-1,2-diaminocyclohexane (23).
Diamine 22 (0.556 g, 1.80 mmol) was dissolved in formal-
dehyde (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 8C. Sodium formate (7.40 mmol, 0.50 g) was
then added in one portion and the resulting solution was
2.1.17. (1R,2R)-(K)-N,N0-Dimethyl-N-(ethan-(1-(S)-iso-
propyl)-1-ol)-N0-(ethan-(1-(R)-isopropyl)-1-ol)-trans-
1,2-diaminocyclohexane (21). Amino alcohol 20 (50 mg,

1278
A. J. A. Cobb, C. M. Marson / Tetrahedron 61 (2005) 1269–1279
stirred at 90 8C for 16 h. After this time, the solution was
cooled to 20 8C 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 evaporated under reduced pressure to give a clear
oil (0.58 g, 95%) that required no further purification;
[a]DZC42.2 (c 0.53, CHCl3); IR (film) nmax 3401, 1454,
2.1.24. (R)- or (S)-Ethylchalcone 27. Typical procedure.
Amino alcohol 8 (30.6 mg, 0.08 mmol, 8 mol%) and nickel
acetonylacetonate (18 mg, 0.07 mmol, 7 mol%) in freshly
distilled acetonitrile (2 mL) were heated at reflux under an
atmosphere of nitrogen with stirring for 1 h. The solution
was allowed to cool to 20 8C and a solution of chalcone
(208 mg, 1.0 mmol) in freshly distilled acetonitrile (5 mL)
was added. The mixture was cooled to K35 8C (cooling
bath) and a solution of diethylzinc in toluene (1.36 mL,
1.1 M, 1.5 mmol) was added cautiously whereupon an
immediate colour change from green to dark brown
occurred. After stirring at K30 8C for 16 h, the solution
was poured into hydrochloric acid (15 mL, 3 M) and the
aqueous layer extracted with dichloromethane (3!20 mL).
The combined organic layers were shaken with brine
(25 mL) and then dried (MgSO4), filtered and evaporated
to give crude 27 which was purified by flash column
1
1204, 1061 cmK1; H NMR d (CDCl3, 300 MHz) d 3.23
0
(2H, 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) d 72.59, 67.77, 66.55, 34.00, 29.31, 28.78, 27.80,
26.57, 26.33, 24.87. HRMS calcd for C20H38N2O2 (MHC)
339.3012. Found: 339.3009. FAB MS (%) 339 (MHC, 100),
210 (22), 112 (19).
1
chromatography; H NMR (CDCl3) d 7.93 (2H, m, o-aryl
2.1.20. (R)- or (S)-1-Phenylpropan-1-ol (25a). Represen-
tative procedure. Ligand 22 (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 8C. 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 K30 8C (cooling
bath) and a solution of diethylzinc in toluene (3.5 mL,
1.1 M, 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 K30 8C for 16 h. Aqueous hydro-
chloric acid (10 mL, 1 M) was then 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
to give a turbid oil that was purified by flash column
chromatography (3:17 ethyl acetate: 40–60 8C petroleum
ether) to give 25a (0.135 mg, 50%) as a clear oil; 1H NMR
(CDCl3) d 7.32 (5H, m, phenyl), 4.56 (1H, t, JZ7.5 Hz,
CHOH), 2.43 (1H, br, OH), 1.78 (2H, m, CH2), 1.43 (3H, t,
JZ7.5 Hz, CH3). Enantiomeric excess was determined on a
Chiralcel OD column (99:1 i-PrOH/hexane; 1 mL minK1 tR
20 min, tS 29 min).
ketone), 7.52 (3H, m, m and p-aryl ketone), 7.25 (5H, m,
phenyl-alkyl), 3.31 (3H, m, C(O)CH2CH), 1.75 (2H, m,
CH2CH3), 0.88 (3H, t, JZ7.0 Hz, CH2CH3). Enantiomeric
excess was determined on a Chiralcel OD column (0.2: 99.8,
i-PrOH/hexane, 1 mL minK1; tR 23 min, tS 18 min).
Acknowledgements
Financial support (studentship to A. J. A. C.) from the
Engineering and Physical Sciences Research Council is
gratefully acknowledged.
References and notes
1. (a) Noyori, R. Asymmetric Catalysis in Organic Synthesis;
Wiley: New York, 1994. (b) Corey, E. J.; Guzman-Perez, A.
Angew. Chem., Int. Ed. 1998, 37, 388–401.
2. (a) Soai, K.; Niwa, S. Chem. Rev. 1992, 92, 833–856. (b)
Knochel, P.; Singer, R. D. Chem. Rev. 1993, 93, 2117–2188.
3. (a) Kitamura, M.; Okada, S.; Suga, S.; Noyori, R. J. Am. Chem.
Soc. 1989, 111, 4028–4036. (b) Soai, K.; Yokoyama, S.;
Hayasaka, T. J. Org. Chem. 1991, 56, 4264–4268.
4. Jian, L. S.; Yaozhong, J.; Aiqiao, M. Tetrahedron: Asymmetry
1992, 3, 1467–1474.
2.1.21. (R)- or (S)-1-Phenylpent-1-en-3-ol (25b). 1H NMR
(CDCl3) d 7.12 (5H, m, aryl), 6.40 (1H, d, JZ16.0 Hz, aryl–
CHZCH), 5.92 (1H, dd, JZ16.0, 7.0 Hz, aryl–CHZCH),
4.08 (1H, m, CHOH), 1.80 (1H, br, OH), 1.51 (2H, m, CH2),
0.82 (3H, t, JZ7.5 Hz, CH3). Enantiomeric excess was
determined on a Chiralcel OD column (5:95 i-PrOH/hexane,
1 mL minK1; tR 12 min, tS 19 min).
5. Bennani, Y. L.; Hanessian, S. Chem. Rev. 1997, 97,
3161–3195.
6. Soai, K.; Nishi, M.; Ito, Y. Chem. Lett. 1987, 2405–2406.
´ ´ ´
7. Andres, J. M.; Martınez, M. A.; Pedrosa, R.; Perez-Encabo, A.
2.1.22. (R)- or (S)-1-p-Methoxyphenylpropan-1-ol (25c).
1H NMR (CDCl3) d 7.15–6.80 (4H, m, aryl), 4.71 (1H, t, JZ
7.0 Hz, CHOH), 3.79 (3H, s, CH3), 2.48 (1H, br, OH), 1.85
(2H, m, CH2), 0.92 (3H, t, JZ7.0 Hz, CH3). ee was
determined on a Chiralcel OD column (2.5: 97.5 i-PrOH/
hexane; 0.7 mL minK1; tR 33 min, tS 40 min).
Tetrahedron: Asymmetry 1994, 5, 67–72.
8. Marson, C. M.; Schwarz, I. Tetrahedron Lett. 2000, 41,
8999–9003.
9. Cobb, A. J. A.; Marson, C. M. Tetrahedron: Asymmetry 2001,
12, 1547–1550.
10. Larrow, J. F.; Jacobsen, E. N.; Gao, Y.; Hong, Y.; Nie, X.;
Zepp, C. M. J. Org. Chem. 1994, 59, 1939–1942.
11. Atoh, M.; Sørensen, H. O.; Andersen, P. Acta Chem. Scand.
1997, 51, 1169–1177.
1
2.1.23. (R)- or (S)-1-(a-Naphthyl)-1-propanol (25d). H
NMR (CDCl3) d 7.72 (7H, m, aryl), 5.35 (1H, t, JZ7.0 Hz,
CHOH), 2.31 (1H, br, OH), 1.99 (2H, m, CH2), 1.02 (3H, t,
JZ7.0 Hz, CH3). Enantiomeric excess was determined on a
12. Pine, S. H.; Sanchez, B. L. J. Org. Chem. 1971, 36, 829–832.
13. (a) Cantarelli, G. Farmaco Ed. Sci. 1970, 248–252. (b)
Rajagopal, S.; Spatola, A. F. J. Org. Chem. 1995, 60,
1347–1355.
Chiralcel OD column (4:96 i-PrOH/hexane, 0.5 mL minK1
tR 31 min, tS 27 min).
;

A. J. A. Cobb, C. M. Marson / Tetrahedron 61 (2005) 1269–1279
1279
14. 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.
23. Cozzi, P. G.; Papa, A.; Umani-Ronchi, A. Tetrahedron Lett.
1996, 37, 4613–4616.
24. Hwang, C-D. ; Uang, B.-J. Tetrahedron: Asymmetry 1998, 9,
3979–3984.
15. Brown, H. C.; Narasimhan, S.; Choi, Y. M. Synthesis 1981,
996–997.
25. Corey, E. J.; Hannon, F. J. Tetrahedron Lett. 1987, 28,
5237–5240.
16. For a synthesis of 11 using (R)-(C)-styrene oxide see: Cross,
R. J.; Farrugia, L. J.; Newman, P. D.; Peacock, R. D.; Stirling,
D. Inorg. Chem. 1999, 38, 1186–1192.
26. De Vries, A. H. M.; Imbos, R.; Feringa, B. L. Tetrahedron:
Asymmetry 1997, 8, 1467–1473.
17. De Sousa, A. S.; Hancock, R. D.; Reibenspies, J. H. J. Chem.
Soc., Dalton Trans. 1997, 2831–2835.
27. The 2-pyrrolidinylmethanol system affords a rare example of
an NH catalyst being active (36% ee) and the corresponding
(N-benzyl) tertiary amine affording predominantly the
opposite enantiomer (82% ee): Yang, X.; Shen, J.; Da, C.;
Wang, R.; Choi, M. C. K.; Yang, L.; Wong, K. Tetrahedron:
Asymmetry 1999, 10, 133–138.
18. Hanessian, S.; Simard, M.; Roelens, S. J. Am. Chem. Soc.
1995, 117, 7630–7645.
19. Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed. Engl. 1991,
30, 49–69.
20. (a) Oguni, N.; Omi, T.; Yamamoto, Y.; Nakamura, A. Chem.
Lett. 1983, 841–842. (b) Kitamura, M.; Suga, S.; Kawai, K.;
Noyori, R. J. Am. Chem. Soc. 1986, 108, 6071–6072.
21. Kimura, K.; Sugiyama, E.; Ishizuka, T.; Kunieda, T.
Tetrahedron Lett. 1992, 33, 3147–3150.
´
28. Li, W. R.; Ewing, W. R.; Harris, B. D.; Joullie, M. M. J. Am.
Chem. Soc. 1990, 112, 7659–7672.
29. Atoh, M.; Sørensen, H. O.; Anderson, P. Acta Chem. Scand.
1997, 51, 1169–1177.
22. Delair, P.; Einhorn, C.; Einhorn, J.; Luche, J. L. Tetrahedron
1995, 51, 165–172.