Homochiral C3-symmetric triols and triamines: Straightforward syntheses, and applications as chiral ligands

Article abstract of DOI:10.1055/s-2000-6255

Homochiral C₃-symmetric triols and triamines of varying steric demands have been made using an efficient one- or two-step procedure. The triols' use as ligands in organometallic complexes is explored briefly, as is the use of the titanium complex of one triol for asymmetric induction.

Full text of DOI:10.1055/s-2000-6255

PAPER
281
Homochiral C3-Symmetric Triols and Triamines: Straightforward Syntheses,
and Applications as Chiral Ligands
Susan K. Armstrong,*a Scott Clunasb
a Department of Chemistry, Joseph Black Building, University of Glasgow, Glasgow G12 8QQ, UK
Fax +44(141)3304888, E-mail: s.armstrong@chem.gla.ac.uk
b Department of Chemistry, University of Aberdeen, Meston Walk, Aberdeen AB24 3UE, UK
Received 17 August 1999; revised 30 September 1999
ed for the most part into the unlike diastereomer of the C3-
Abstract: Homochiral C3-symmetric triols and triamines of varying
symmetric product. Following purification, no trace of
steric demands have been made using an efficient one- or two-step
this minor diastereomer remains: the like isomers may
procedure. The triols’ use as ligands in organometallic complexes is
therefore be assumed to have extremely high enantiomer-
ic purity (e.g. RRR:SSS >13500:1 from starting material
of R:S = 96:4), by analogy with our triethers 2. We here
report our extension of this synthesis to more highly func-
tionalised species, including esters, amines and alcohols.
We describe some metal-binding properties of these novel
ligands, together with a preliminary exploration of their
potential for asymmetric induction.
explored briefly, as is the use of the titanium complex of one triol
for asymmetric induction.
Key words: C3-symmetric, homochiral, triols, triamines, asymmet-
ric induction, chiral organometallic complexes, ligands, tin
Introduction
In recent years, chiral systems showing C3 symmetry have
created interest and found application in several areas, in-
cluding molecular receptors,1 ion channel mimics,2 den-
drimers,3 organometallic ligands,1 and chromatographic
stationary phases.4 An excellent review has illustrated the
importance of C3 symmetry in asymmetric catalysis and
chiral recognition.1 C3-Symmetric tripodal ligands, which
in octahedral organometallic complexes render the re-
maining three co-ordination sites identical, have a major
contribution to make to asymmetric catalysis.
Br
R*O
R*OH, NaH,
Bu4NI
Br
OR*
50-75 %
1
2
Br
R*O
R*OH = menthol, borneol, isopinocampheol, etc.
Scheme 1
Chirality in C3-symmetric systems may be caused by
chiral centres in the starting materials, or by a twist in the
molecular structure. Chiral starting materials permit syn-
thesis in optically pure form, whereas resolution is neces-
sary when achiral starting materials give a structurally
twisted C3-symmetric product. Homochiral C3-symmetric
ligands frequently form hydrogen-bonded or organome-
tallic complexes with a twist axis, but as the twist chirality
generally follows the point chirality (unless the chiral cen-
tre is remote from the twist element5), the complexes are
generally homochiral with respect to both symmetry ele-
ments.6
Synthesis of C3-Symmetric Triols and Triethers
The central ring in our new compounds is benzene, chosen
for its conformational rigidity, its stability in many chem-
ical environments, and the availability of various suitably
functionalised derivatives. For this as for our earlier work,
the C3-symmetric starting material was 2,4,6-tris(bro-
momethyl)mesitylene (1), available commercially or by
our modification of the method of Závada et al.10,11 As
shown in Scheme 2, treatment of methyl (S)-lactate (3)
with one equivalent of sodium hydride followed by one
third of an equivalent of 2,4,6-tris(bromomethyl)mesityl-
ene (1) gave triester 4. This was then converted by treat-
ment with either methyl- or phenylmagnesium bromide to
the triols 5 and 6 respectively. We attempted to vary the
the steric demand of the ligand, and the length of the tether
between the central ring and the donor groups, but unfor-
tunately neither ethyl (S)-mandelate (7) nor methyl (S)-3-
hydroxy-2-methylpropionate (8) gave good results in the
coupling reactions. There is surprisingly little precedent
for reaction of either alcoholate with a benzylic electro-
phile.12
The homochiral C3-symmetric ligands so far reported al-
most all consist of three chiral arms radiating from a cen-
tral atom. By contrast, we were attracted by the extra
rigidity of ligands in which the three chiral arms radiate
from a ring, of which very few examples are known.7-9
We earlier reported the development of an efficient one-
step method (Scheme 1) for the preparation of homochiral
C3-symmetric triethers 2 consisting of three homochiral
arms radiating from a central benzene ring.10 An impor-
tant feature of this synthetic method was the large increase
in enantiomeric purity achieved by the synthesis. The cas-
es studied showed no detectable diastereoselectivity be-
tween the like and unlike isomers. The minor enantiomer
of the chiral starting material will therefore be incorporat-
Synthesis 2000, No. 2, 281–288 ISSN 0039-7881 © Thieme Stuttgart · New York

282
S. K. Armstrong, S. Clunas
PAPER
CO2Me
H
N
O
1. NaH
Ph
2. Bu4NI,
1 (0.33 equiv.)
Ph
O
O
CO2Me
1. NaH
2. Bu4NI,
1 (0.33 equiv.)
Ph
HO
CO2Me
62 %
O
3
NH
HO
NH
4
O
9
O
10
MeO2C
R
Ph
HN
7
Ph
excess
RMgBr
HO
CO2Et
R
OH
1. NaH
2. 1, Bu4NI
NMe2
O
O
Ph
no triester
formed
Ph
1. NaH
2. Bu4NI,
1 (0.33 equiv.)
R
Ph
O
R
O
N
N
1. NaH
2. 1, Bu4NI
OH
NMe2
HO
NMe2
53 %
O
11
8
O
R = Me, 5, 63 %
R = Ph, 6, 57 %
12
HO
R
CO2Me
Me2N
Ph
Ph
OH
R
Scheme 2
OH
N
Et3N,
1 (0.33 equiv.)
C3-symmetric ligands having nitrogen/oxygen mixed do-
nor sets have given interesting results in the past.6a,7 We
therefore treated (1R,2S)-ephedrine (9) and (1R,2S)-N-
methylephedrine (11) separately with one equivalent of
sodium hydride followed by one third of an equivalent of
2,4,6-tris(bromomethyl)mesitylene (1). The tertiary
amine 12 was obtained in good yield, but contains no
acidic donor group; the more interesting secondary amine
10 proved difficult to purify (Scheme 3). By carrying out
the reaction between (1R,2S)-ephedrine (9) and 2,4,6-
tris(bromomethyl)mesitylene (1) using triethylamine in-
stead of sodium hydride, tertiary amine triol 13 was pre-
pared, which proved amenable to purification. In the same
way, (S)-pyrrolidine-2-methanol (14) was treated with tri-
ethylamine and 2,4,6-tris(bromomethyl)mesitylene (1) to
give tertiary amine triol 15 (Scheme 3).
Ph
Ph
HN
OH
84 %
OH
9
N
13
HO
Ph
OH
N
Et3N,
1 (0.33 equiv.)
N
H
79 %
OH
OH
14
HO
N
15
Both H and 13C NMR spectroscopy showed that com-
1
Scheme 3
pounds 4, 5, 10, 12, 13 and 15 are C3-symmetric in solu-
1
tion. In the H NMR spectrum, all showed clearly the
diagnostic AB quartet centred at approximately d = 4.5,
attributable as in our earlier work10 to the diastereotopic
benzylic protons. Triol 6 gave more complex spectra in
O
Ph
O
1
both H and 13C NMR, indicative of lower symmetry in
O
the molecule. This may be attributed to intramolecular hy-
drogen bonding or to p-stacking among the benzene rings;
we are unable to define precisely why the symmetry is re-
duced in this somewhat crowded compound. The still
more crowded triketone 17, synthesised from tartrate-de-
rived keto alcohol 16 and 2,4,6-tris(bromomethyl)mesi-
tyl-ene (1), proved to be C3-symmetric in solution, so
simple steric crowding is an insufficient explanation for
the reduction in symmetry observed spectroscopically for
triol 6.
Ph
Ph
Ph
O
Ph Ph
1. NaH
2. Bu4NI,
1 (0.33 equiv.)
Ph
Ph
O
O
O
O
HO
O
O
58 %
O
O
Ph
O
Ph
16
Ph
Ph
17
O
O
Synthesis 2000, No. 2, 281–288 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Homochiral C3-Symmetric Triols and Triamines
283
ing an MM2 force field and molecular dynamics) that the
lowest energy conformation for isolated ligands of this
general type is one with two radiating chains above the
face of the central ring and one below it; this is also the
conformation we have previously observed for related
species in the solid state.10
Complexation Reactions of Homochiral C3-Symmet-
ric Triols
With homochiral C3-symmetric triols in hand, we could
now investigate their metal-binding properties. C3-sym-
metric ligands are of interest in the context of both tetra-
hedral and, in particular, octahedral metal complexes,
since the symmetry of the ligand is appropriate in each
case to that of the complex. We therefore chose to inves-
tigate complexation of ligands 5, 13 and 15 to tin, titani-
um, nickel and copper.
Our amino alcohol ligands 13 and 15 were investigated as
potential ligands for the divalent metal ions Ni2+ and Cu2+
using the procedure of Peacock and co-workers for com-
plexation of their C3-symmetric amino alcohols 18
(Scheme 4).7 One equivalent of our ligand (13 or 15) in
ethanolic solution was added to an ethanolic solution of
the hydrated metal nitrate. The ethanol was removed, and
the resulting green solid was redissolved in water. An
aqueous solution of ammonium hexafluorophosphate was
added to induce crystallisation. In the case of ligand 15
this protocol resulted in the formation of colourless crys-
tals. Their X-ray diffraction patterns at 296 and 123 K
were consistent with the composition (15)•3H+(PF6)2
(NO3).13 However, at both temperatures the finer structur-
al details were obscured by disorder of the pyrrolidine
rings and of one of the two independent PF6- anions.
Structure of the (15)•3H+ cation at 123 K as determined by X-ray cry-
stallography. Atoms are shown as spheres of arbitrary size. Severe
disorder affects particularly atoms C6-C9 and O1 and the positions
of these atoms are subject to large systematic errors.
Figure
2+
We therefore adopted a different strategy in screening our
ligands for metal complexation. Triol ligands 5 and 13
were treated separately in anhydrous deuterochloroform
with one equivalent of freshly prepared methyl- or phe-
nyltin trichloride and three equivalents of anhydrous tri-
ethylamine. The supernatant liquid (above precipitated
triethylammonium chloride) was analysed by 1H, 13C and
119Sn NMR spectroscopy. These showed clearly that the
trialkoxy tin complexes 19-21 had formed (Scheme 5).
OH
1. Ni(NO3)2,
EtOH
2. NH4PF6,
H2O
H
O
N
N
O
N
N
H
Ni
Ref. 7
O
H
N
HO
HO
N
18
[PF6]–
[NO3]–
1
OH
The formation of complex 21 was followed by H NMR
spectroscopy, and the presence of triethylamine shown to
be essential to complexation. The 119Sn chemical shift
data are unequivocal: complexes 19 and 20 come into res-
onance at -268 and -391 ppm respectively, while com-
plex 21 shows two signals, at -224 and -227 ppm
(relative to SnMe4). By constrast, the starting materials
gave signals at -18 ppm (MeSnCl3) and -61 ppm
(PhSnCl3). It is not unusual for alkyltin complexes of tri-
hydroxy ligands to give more than one peak in the 119Sn
NMR spectrum. Stannatrane complexes 22a-d, for exam-
ple, are reported to give three peaks, attributed to a tri-
meric structure in which each tin atom is hexacoordinate
and each occupies a different coordination sphere.14 These
trimeric structures decrease in stability with increasing
steric bulk at the metal (22a is most stable, 22d least stable
as the trimer), and the tert-butyl compound 22e is appar-
ently monomeric. Our rather bulky complexes 19 and 20,
giving single peaks in the 119Sn spectra, are apparently
2[PF6]–
[NO3]–
N
H
1. Ni(NO3)2, EtOH
2. NH4PF6, H2O
N
H
15
H
OH
HO
N
Scheme 4
The crystals were cubic in form, so that exact C3 symme-
try was imposed by the space group on both independent
hexafluorophosphate residues, on the nitrate anion, and on
the tris-ammonium cation. This cation consequently but
unexpectedly adopts a conformation (Figure) with all
three radiating chains on the same face of the central aro-
matic ring. We have shown by molecular modelling (us-
Synthesis 2000, No. 2, 281–288 ISSN 0039-7881 © Thieme Stuttgart · New York

284
S. K. Armstrong, S. Clunas
PAPER
monomeric, but we can obtain no direct proof of this ow- fore deduce that the titanium complex of our triol is acting
ing to the air-sensitive nature of the materials. The 1H and in a mechanistically similar manner to that described by
13C NMR spectra of the complexes were harder to inter- Seebach et al. for TADDOLate titantium complexes.17
pret than the 119Sn spectra, owing to considerable line This preliminary result, although showing low selectivity,
broadening. This was greatly reduced by obtaining spectra demonstrates that our C3-symmetric triols have potential
of complex 19 at 90°C in toluene-d8, enabling chemical for asymmetric induction in organic synthesis. We are
shifts and splitting patterns to be elucidated (see experi- pursuing this in several areas.
mental section). Similar temperature effects have been at-
tributed in the past to alkyl chain flexing,15 which
explanation seems appropriate to our complexes also.
13
Ti(OPri)4
Such flexing, occuring slowly at room temperature, may
MeO
also account for the presence of two 119Sn signals in the
spectrum of complex 21; alternatively, a dimeric structure
involving two tin atoms in different coordination spheres
cannot be ruled out.
CF3
OH
O
[complex]
R*COCl
PhCHO
Ph
O
Ph
Et2Zn
Ti(OPri)4
23
89-93 %
24
Scheme 6
N
N
RSnCl3
N
H
H
Starting materials were used as supplied by the manufacturers with-
out further purification unless indicated. 2,4,6-Tris(bromometh-
yl)mesitylene (1) was purchased from Aldrich, or made according
to the procedure in our earlier paper.10 THF was dried by distillation
under N2 from CaH2 and LiAlH4 using Ph3CH as indicator. Other
solvents were dried when necessary over molecular sieves (4Å). Pe-
troleum ether used had bp 40-60°C. Reactions involving air-sensi-
tive reagents were carried out under nitrogen in oven-dried
glassware using standard Schlenk techniques. Melting point deter-
minations were carried out using a Kofler hot-stage microscope and
are uncorrected. IR spectra were obtained as KBr disks on an ATI
Mattson Genesis series FTIR instrument. 1H NMR spectra were ob-
tained at 250 MHz in CDCl3 and 13C NMR spectra at 62.5 MHz in
CDCl3 on a Bruker AC 250 with a Tecmag data station. Chemical
shifts are given in ppm relative to TMS or CHCl3. Coupling con-
stants in 1H NMR spectra are given in Hz, and assignments in 13C
NMR spectra are made on the basis of DEPT-135 experiments.
Mass spectra were obtained on either a Finnigan Masslab Navigator
(low resolution) or a Jeol JMS 700 instrument (high resolution),
running in CI, EI or FAB mode.
13
Ph
H
Ph
Et3N, CDCl3
O
O
O
Ph
Sn
R
H
R = Me, 19
R = Ph, 20
O
O
O
MeSnCl3
5
Et3N, CDCl3
O
O
O
Sn
21
Me
22a, R = Me
22b, R = Et
22c, R = n-Bu
22d, R = Ph
22e, R = t-Bu
N
O
Sn
O
O
R
Scheme 5
(S)-1,3,5-Tris(1-methoxycarbonylethoxymethylene)-2,4,6-tri-
methylbenzene (4)
NaH (360 mg, 7.5 mmol, 50% dispersion in oil) was added with
cooling to a solution of methyl (S)-lactate (3; 782 mg, 7.5 mmol) in
anhyd THF (20 mL), and the mixture was stirred for 30 min before
the catalyst Bu4NI (280 mg, 0.75 mmol) and 1,3,5-tris(bromometh-
yl)mesitylene (1; 1.00 g, 2.5 mmol) were added. The mixture was
stirred at r.t. overnight, then filtered and the solvent removed under
In order to investigate the potential of our new ligands for
asymmetric induction, titanium complexes were made by
treating ligands 5, 13 and 15 with one equivalent of titani-
um tetraisopropoxide in toluene, followed after an hour by
exposure to high vacuum. NMR analysis at this stage reduced pressure. The residue was separated by gravity chromato-
graphy using Et2O/petroleum ether (1:1). to give the triester 4 as a
low melting amorphous white solid (0.73 g, 62%); mp 69-71°C.
showed increased complexity and considerable line
1
broadening in both H and 13C spectra, suggesting metal
1H NMR: d = 4.72 (3 H, d, Jα,β = 10.4 Hz, 3 ArCHαHβ), 4.43 (3 H,
d, Jβ,α = 10.4 Hz, 3 ArCHαHβ), 4.02 (3 H, q, J =6.7 Hz, 3 CH), 3.75
(9 H, s, 3 CO2CH3), 2.40 (9 H, s, 3 ArCH3), 1.37 (9 H, d, J = 6.7 Hz,
3 CH3).
13C NMR: d = 173.9 (CO2CH3), 139.0 (Carom), 132.1 (Carom), 74.2
(CH), 67.0 (ArCH2), 51.9 (CO2CH3), 18.9 (CHCH3), 15.5 (ArCH3).
complexation but precluding detailed structural analysis.
The presumed complex arising from ligand 13 and titani-
um tetraisopropoxide was treated with benzaldehyde at
room temperature for half an hour, followed by diethyl-
zinc at -10°C, then at 0°C for 48 h. Analysis of the result-
ing 1-phenylpropanol 23 via the Mosher’s esters 24 re-
vealed a racemic mixture; however, if an extra ten
equivalents of Ti(Opr-i)4 were added with the benzalde-
hyde and the reaction and analysis carried out as before
(Scheme 6), the resulting alcohol showed a 10% enantio-
meric excess in favour of the R-enantiomer.16 We there-
IR: n = 2987, 2955, 2913, 2895 (CH, alkyl), 1743 (C=O), 1449,
1372 (CH, alkyl), 1267, 1209, 1142 cm-1 (C-O, alkyl).
MS: m/z (%) = 468 (M+, 12), 207 (C12H15O3, 2), 191 (C12H15O2, 6),
175 (C12H15O, 9), 157 (MH33+, 100).
Anal. calcd for C24H36O9: C, 61.5; H, 7.7. Found: C, 61.8; H, 7.5.
Synthesis 2000, No. 2, 281–288 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Homochiral C3-Symmetric Triols and Triamines
285
(S)-1,3,5-Tris(2-hydroxy-2-methylbut-3-oxymethylene)-2,4,6-
trimethylbenzene (5)
and the solvent removed under reduced pressure. The residue was
purified by column chromatography eluting with CH2Cl2/MeOH/
NH3 (80:19:1) to yield the triamine 10, which was identified by 1H
NMR, but could not be fully purified.
1H NMR: d = 7.40-7.25 (15 H, m, 3 C6H5), 4.43 (3 H, d, Jα,β = 10.4
Hz, ArCHαHβ), 4.27 (3 H, d, partially obscured, ArCHαHβ), 4.26 (3
H, d, partially obscured, 3 OCH), 3.44-3.32 (3 H, m, 3 NH), 2.75-
2.70 (3 H, m, 3 NCH), 2.29 (9 H, s, 3 ArCH3), 2.21 (9 H, s, 3 NCH3),
1.07 (9 H, d, J = 6.4 Hz, 3 CH3).
Methylmagnesium bromide (4.3 mL, 3.0 M in Et2O, 12.9 mmol)
was added dropwise to a solution of the triester 4 (450 mg, 0.96
mmol) in anhyd Et2O (30 mL). The mixture was heated to reflux for
4 h then allowed to cool and stirred at r.t. for 16 h. The mixture was
cooled to 0°C and satd aq NH4Cl solution (10 mL) was added drop-
wise. The resulting layers were separated and the aqueous layer was
extracted with Et2O (3 î 30 mL). The organic phases were com-
bined and washed with satd aq NaCl solution (20 mL), dried
(MgSO4) and the solvent removed under reduced pressure. The
crude product could be purified either by recrystallising from Et2O
or by column chromatography (Rf 0.45, EtOAc/hexane, 3:2) to
yield the triol 5 as white needles (281 mg, 63%); mp 130-132°C.
1H NMR: d = 4.72 (3 H, d, Jα,β = 10.1 Hz, ArCHαHβ), 4.39 (3 H, d,
Jβ,α = 10.1 Hz, ArCHαHβ), 3.38 (3 H, q, J = 6.4 Hz, 3 CH), 2.44 (9
H, s, 3 ArCH3), 1.24 (9 H, d, J = 6.4 Hz, 3 CH3), 1.19 (9 H, s, 3 CH3),
1.11 (9 H, s, 3 CH3).
13C NMR: d = 138.3, 133.1 (Carom), 82.3 (CH), 72.7 (COH), 66.0
(ArCH2), 26.2 (CH3), 23.6 (CH3), 15.8 (ArCH3), 13.8 (CH3).
(1R,2S)-1,3,5-Tris(2-N,N-Dimethylamino-1-phenylprop-1-
oxymethylene)-2,4,6-trimethylbenzene (12)
NaH (0.36 g, 7.5 mmol, 50% dispersion in oil) was added with cool-
ing to a solution of (1R,2S)-(-)-methylephedrine (11; 1.35 g, 7.5
mmol) in THF (20 mL), and the mixture stirred for 30 min before
the catalyst Bu4NI (0.28 g, 0.75 mmol) and the tribromide 1 (1.00 g,
2.5 mmol) were added. The mixture was heated to reflux overnight,
filtered and the solvent removed under reduced pressure. The resi-
due was purified by column chromatography eluting with CH2Cl2/
MeOH/NH3 (90:9:1, Rf 0.7) to yield the triamine 12 as a viscous oil
which slowly crystallised on standing (0.92 g, 53%); mp 100-
102°C.
IR: n = 3384 (OH), 2981, 2932, 2880 (CH, alkyl), 1459, 1383,
1367, 1331 (C-OH), 1171, 1097, 1073 cm-1 (C-O)
MS: m/z (%) = 492 (M+ + Na, 10), 207 (C12H15O3, 6), 191
(C12H15O2, 9), 175 (C12H15O, 29), 157 (MH33+, 100), 144 (C11H12,
55).
1H NMR: d = 7.38-7.25 (15 H, m, 3 C6H5), 4.75 (3 H, d, J = 6.4 Hz,
OCH), 4.33 (3 H, d, Jα,β = 10.5 Hz, ArCHαHβ), 4.24 (3 H, d, Jβ,α
=
10.5 Hz, ArCHαHβ), 2.81 (3 H, quin, J = 6.4 Hz, 3 NCH), 2.21 [18
H, s, 3 N(CH3)2], 2.15(9 H, s, 3 ArCH3), 1.72 (9 H, d, J = 6.8 Hz, 3
CH3).
Anal. calcd for C27H48O6: C, 69.2; H, 10.3. Found: C, 69.4; H, 10.2.
13C NMR: d = 141.9, 138.4, 132.8 (Carom), 128.2, 127.5 (CHarom),
84.5 (OCH), 66.1 (ArCH2), 64.5 (NCH), 41.2 [N(CH3)2], 15.8
(ArCH3), 8.22 (CH3).
(S)-1,3,5-Tris(1,1-diphenyl-1-hydroxyprop-2-oxymethylene)-
2,4,6-trimethylbenzene (6)
Phenylmagnesium bromide (4.8 mL, 3.0 M in Et2O, 14 mmol) was
added dropwise to a solution of the triester 4 (500 mg, 1.07 mmol)
in anhyd Et2O (30 mL). The mixture was heated to reflux for 16 h,
cooled to 0°C and satd aq NH4Cl solution (10 mL) was added drop-
wise. The resulting layers were separated and the aqueous layer was
extracted with Et2O (3 î 30 mL). The combined organic phases
were washed with satd aq NaCl solution (20 mL), dried (MgSO4)
and the solvent removed under reduced pressure. The crude product
was purified by column chromatography (Rf 0.4, EtOAc/hexane,
1:4) to yield the triol 6 as colourless needles (482 mg, 57%); mp
90-92°C.
1H NMR: d = 7.55-7.50 (6 H, m, ArH), 7.44-7.40 (6 H, m, ArH),
7.25-7.11 (18 H, m, ArH), 4.52-4.48 (6 H, m, 3 CH and Ar-
CHαHβ), 4.29-4.24 (3 H, m, ArCHαHβ), 1.85, 1.77, 1.76 (9 H,
3 x s, 3 ArCH3), 1.12 (9 H, d, J = 5.8 Hz, 3 CH3).
13C NMR: d = 146.9, 146.8, 144.2, 138.8, 138.7, 132.3, 132.3
(Carom), 128.1, 128.0, 126.6, 125.9, 125.5 (CHarom), 80.0 (COH),
78.6, 78.5, 78.3 (CH), 65.9 (ArCH2), 15.0 (ArCH3), 14.9 (ArCH3),
13.5 (CH3).
IR: n = 3083, 3064, 3030 (CH, aromatic), 2968, 2932, 2906, 2867,
2822 (CH, alkyl), 1493, 1472, 1454 (CH, alkyl), 1269, 1187, 1132
(C-O), 761, 746 cm-1 (CH, aromatic).
MS: m/z = 694 (MH+, 100%), 516 (MH+ - C11H16NO, 55), 354
(MH+ - C22H32N2O, 10), 338 (MH+ - C22H32N2O2, 38), 176 (MH+
- C33H48N3O2, 33), 160 (MH+ - C33H48N3O3, 64).
HRMS (FAB): m/z calcd for C45H64N3O3 (M++H): 694.4948.
Found: 694.4955.
(1R,2S)-1,3,5-Tris[2-N-methylamino-1-phenylprop-1-oxymeth-
ylene]-2,4,6-trimethylbenzene (13)
(1R,2S)-(-)-Ephedrine (9; 1.24 g, 7.5 mmol) and Et3N (0.76 g, 7.51
mmol) were added to a solution of the tribromide 1 (1.00 g, 2.50
mmol) in chlorobenzene (10 mL). The mixture was stirred at r.t. for
1 h. The resulting precipitate was removed by filtration and the sol-
vent removed from the filtrate under reduced pressure at 100°C. The
residue was purified by column chromatography eluting with
CH2Cl2/MeOH/NH3 (90:9:1, Rf 0.5) to give the triol 13 as white
needles (1.36 g, 84%); mp 70-72°C.
IR: n = 3477 (OH), 3087, 3057, 3025 (CH, aromatic), 2977, 2932,
2909, 2897, 2784 (CH, alkyl), 1492, 1449 (CH, alkyl), 1373, 1316
(C-OH), 1172, 1093, 1041, 1032(C-O), 700 cm-1 (CH, aromatic).
MS: m/z (%) = 863 (M+ + Na, 8), 368 (80), 272 (55), 157 (70), 133
1H NMR: d = 7.25-7.11 (15 H, m, 3 C6H5), 4.58 (3 H, d, J = 6.1 Hz,
OCH), 3.91 (3 H, d, Jα,β = 13.1 Hz, ArCHαHβ), 3.71 (3 H, d, Jβ,α
=
13.1 Hz, ArCHαHβ), 2.86 (3 H, dq, J = 6.2, 6.6 Hz, 3 NCH), 2.17 (9
H, s, 3 NCH3), 2.05 (9 H, s, 3 ArCH3), 1.12 (9 H, d, J = 7.0 Hz, 3
CH3).
13C NMR: d = 142.9, 137.5, 133.2 (Carom), 127.8, 126.7, 126.4
(CHarom), 74.7 (OCH), 60.2 (CH2), 53.7 (NCH), 36.9 (NCH3), 16.3
(ArCH3), 10.0 (CH3).
(100).
HRMS (FAB): m/z calcd for C57H60NaO6 (M+ + Na): 863.4287.
Found: 863.4279.
(1R,2S)-1,3,5-Tris(2-N-methylamino-1-phenylprop-1-oxymeth-
ylene)-2,4,6-trimethylbenzene (10)
IR: n = 3420 (OH), 3027 (CH, aromatic), 2963, 2920, 2870 (CH,
alkyl), 1451 (CH, alkyl), 1383, 1354, 1264 (C-O), 760, 710 cm-1
(CH, aromatic).
NaH (360 mg, 7.5 mmol, 50% dispersion in oil) was added with
cooling to a solution of (1R,2S)-(-)-ephedrine (9; 1.24 g, 7.5 mmol)
in anhyd THF (20 mL) and the mixture stirred for 30 min. before the
catalyst Bu4NI (280 mg, 0.75 mmol) and the tribromide 1 (1.0 g, 2.5
mmol) were added. The mixture was stirred at r.t. overnight, filtered
MS: m/z (%) = 651 (M+, 100), 634 (M+ - OH, 20), 487 (M+
-
C10H14NO, 49), 323 (M+ - C20H28N2O2, 61), 155 (37).
Synthesis 2000, No. 2, 281–288 ISSN 0039-7881 © Thieme Stuttgart · New York

286
S. K. Armstrong, S. Clunas
PAPER
1,3,5-Tris[(2,2-dimethyl-4-phenylcarbonyl-1,3-dioxolan-5-
HRMS (FAB): m/z calcd for C42H58N3O3 (M+ + H): 652.4478.
Found: 652.4479.
yl)diphenylmethoxy]methylene-2,4,6-trimethylmesitylene (17)
NaH (25 mg, 0.52 mmol, 50% dispersion in oil) was added with
cooling to a solution of the keto alcohol 16 (200 mg, 0.515 mmol)
in anhyd THF (20 mL) and the mixture stirred for 30 min before the
catalyst Bu4NI (19 mg, 0.051 mmol) and the tribromide 1 (68 mg,
0.17 mmol) were added. The mixture was stirred at r.t. overnight,
filtered and the solvent removed under vacuum. The crude product
was purified by column chromatography (Et2O/petroleum ether,
4:7, Rf 0.4) to yield the triketone 17 as white needles (132 mg, 58%).
1H NMR: d = 7.49-7.07 (45 H, m, 9 C6H5), 5.73 (3 H, s, 3 CH), 5.19
(3 H, s, 3 CH), 4.53 (3 H, d, J = 11.9 Hz, 3 ArCHαHβ), 4.44 (3 H, d,
J = 11.6 Hz, 3 ArCHαHβ), 2.20 (9 H, s, 3 ArCH3), 1.41 (9 H, s, 3
CH3), 1.01 (9 H, s, 3 CH3).
(S)-1,3,5-Tris(2-hydroxymethylenepyrrolidin-1-ylmethylene)-
2,4,6-trimethylbenzene (15)
(S)-(+)-2-Pyrrolidinemethanol (14; 760 mg, 7.5 mmol) and Et3N
(0.76 g, 7.5 mmol) were added to a solution of the tribromide 1
(1.00 g, 2.5 mmol) in chlorobenzene (15 mL). The mixture was
stirred at r.t. overnight. The resulting precipitate was removed by
filtration and the solvent removed from the filtrate under reduced
pressure at 100°C. The residue was purified by column chromato-
graphy eluting with CH2Cl2/MeOH/NH3 (90:9:1, Rf 0.4) to give the
triol 15 as a white amorphous solid (911 mg, 79%); mp 116-118°C.
1H NMR: d = 3.90 (3 H, d, Jα,β = 12.8 Hz, ArCHαHβ), 3.71 (3 H, d,
Jβ,α = 12.8 Hz, ArCHαHβ), 3.23-3.09 (6 H, m, 3 CH2OH), 2.93-
2.87 (3 H, m, 3 NCHαHβ), 2.76-2.73 (3 H, m, 3 NCH), 2.52-2.43
(3 H, m, partially obscured, 3 NCHαHβ), 2.47 (9 H, s, 3 ArCH3),
1.98-1.89 (3 H, m, 3 CHαHβ), 1.78-1.64 (3 H, m, partially ob-
scured, 3 CHαHβ), 1.78-1.64 (6 H, m, partially obscured, 3 CH2).
MS: m/z = 1344 (M+ + Na), 973 (M+ - C25H23O3), 371 (C25H23O3),
469, 205.
HRMS (FAB): m/z calcd for C42H72NaO3 (M++Na): 1344.5959.
Found: 1344.5846.
13C NMR: d = 137.6, 134.8 (Carom), 65.6 (CH), 64.2 (CH2OH), 55.9
(NCH2), 54.1 (ArCH2), 29.5 (CH2), 24.9 (CH2), 18.2 (ArCH3).
Phenyltin Trichloride
SnCl4 (9.77 g, 37.5 mmol) was added under N2 to SnPh4 (5.34 g,
12.5 mmol). The mixture was heated at 180°C for 12 h and allowed
to cool to r.t. before being exposed to air for 10 min. The resulting
liquid was then distilled at 150°C/2 Torr via Kugelrohr to yield the
product as a colourless liquid (2.12 g, 56%).
IR: n = 3350 (OH), 2948, 2868, 2784 (CH, alkyl), 1457 (CH, alkyl),
1357, 1343 cm-1(COH).
MS: m/z (%) = 460 (MH+, 100), 443 (MH+ - OH, 27), 429 (MH+ -
CH2OH, 33), 360 (MH+ - C5H10NO, 33), 266 (30), 155 (41).
119Sn NMR: d = -61.4.
HRMS (FAB): m/z calcd for C27H46N3O3 (M+ + H): 460.3540.
Found: 460.3548.
Methyltin Complex of Ephedrine-Derived Triol 19
To a 5 mL round bottom flask purged with N2 and charged with the
ephedrine-derived triol 13 (40 mg, 0.061 mmol) and Et3N (19 mg,
0.19 mmol) in anhyd CDCl3 (0.5 mL) was added slowly MeSnCl3
(15 mg, 0.061 mmol). The mixture was left for 30 min during which
time a colourless precipitate formed. The liquid phase of the mix-
ture was transferred via syringe to an NMR tube for spectroscopic
analysis.
2,2-Dimethyl-4-phenylcarbonyl-5-diphenylmethanol-1,3-diox-
olane (16)
Phenylmagnesium bromide (27.1 mL, 3.0 M in Et2O, 81.4 mmol)
was added dropwise to a solution of dimethyl 2,3-O-isopropyl-
idene-L-tartrate (15.0 g, 68.8 mmol) in anhyd Et2O (100 mL). The
mixture was heated to reflux for 5 h, then allowed to cool and stirred
at r.t. overnight, cooled to 0°C and quenched carefully with satd aq
NH4Cl solution (200 mL). The resulting layers were separated and
the aqueous layer was washed with Et2O (3 î 100 mL). The organ-
ic phases were combined and washed with satd aq NaCl solution
(100 mL), dried (MgSO4) and the solvent removed under reduced
pressure. The remaining oil was distilled under reduced pressure to
remove the some of the unreacted tartrate. The residue was purified
by gravity column chromatography (Et2O/petroleum ether, 3:7) to
yield the crude keto alcohol 16 (Rf 0.5) which was then recrystal-
lised from EtOAc/hexane; white needles (0.42 g, 2%); mp 180-
182°C, and tetraphenyl TADDOL (Rf 0.45) as white cuboids (5.64
g, 18%). The remaining mixture of unreacted tartrate and 2,2-di-
methyl-4-methoxycarbonyl-5-diphenylmethanol-1,3-dioxolane
could not be adequately separated.
1H NMR: d = 7.79-6.92 (15 H, m, 3 C6H5), 5.85 (1 H, d, J = 6.4 Hz,
CH), 5.14 (1 H, d, J = 6.4 Hz, CH), 3.29 (1 H, s, OH), 1.51 (3 H, s,
CH3), 1.42 (3 H, s, CH3).
13C NMR: d = 196.9 (C=O), 145.3, 142.4, 135.5 (Carom), 133.3,
129.1, 128.2, 128.1, 127.4, 127.2, 127.1, 125.8 (CHarom), 112.2
[C(CH3)2]), 80.7(CH), 77.0 (C-OH), 76.2 (CH), 27.0 (CH3), 26.1
(CH3).
119Sn NMR: d = -267.8.
Phenyltin Complex of Ephedrine-Derived Triol 20
To a 5 mL round bottom flask purged with N2 and charged with the
ephedrine-derived triol 13 (40 mg, 0.061 mmol) and Et3N (19 mg,
0.19 mmol) in anhyd CDCl3 (0.5 mL) was added slowly PhSnCl3
(19 mg, 0.061 mmol). The mixture was left for 30 min during which
time a colourless precipitate formed. The liquid phase of the mix-
ture was transferred via syringe to an NMR tube for spectroscopic
analysis.
119Sn NMR: d = -390.7.
Methyltin Complex of Lactate-Derived Triol (21)
To an NMR tube purged with N2 and charged with the lactate-de-
rived triol 5 (50 mg, 0.11 mmol) in anhyd CDCl3 (0.5 mL) was add-
ed slowly MeSnCl3 (26 mg, 0.11 mmol). The mixture was left for
1
30 min before H and 119Sn NMR analyses were carried out. Both
spectra indicated that no reaction had occurred. On the addition of
Et3N (32 mg, 0.32 mmol) a colourless precipitate formed. This was
removed by filtration and the filtrate was analysed by NMR.
119Sn NMR: d = -233.8, -227.0 (1:1).
IR: n = 3420 (OH), 2955, 2942, 2853 (CH, alkyl), 1685 (C=O),
1449, 1374 (COH), 1212, 1151, 1041 (C-O), 753, 690 cm-1 (CH,
arom).
MS: m/z (%) = 412 (M+ + Na, 8), 167 (100), 104 (80).
1-Phenylpropan-1-ol (23) (no excess of titanium tetraiso-
propoxide)
Titanium tetraisopropoxide (87 mg, 0.31 mmol) was added under
N2 to a solution of the ephedrine-derived triol 13 (200 mg, 0.31
mmol) in anhyd toluene (5 mL). The mixture was left for 1 h at r.t.
before being exposed to a high vacuum (1 Torr) for 30 min. Benzal-
dehyde (326 mg, 3.1 mmol) was then added to the mixture which
Anal. calcd for C25H24O4: C, 77.3; H, 6.2. Found: C, 77.0; H, 6.0.
Synthesis 2000, No. 2, 281–288 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Homochiral C3-Symmetric Triols and Triamines
287
-
was then allowed to stand at r.t. for a further 30 min. The mixture
was then cooled to -10°C before diethylzinc (9.2 mL, 1.0 M in tol-
uene, 9.2 mmol) was added and the mixture left to stand at 0°C for
48 h. The reaction was quenched with satd aq NH4Cl solution (2
mL) and acidified with dil HCl. The layers were separated and the
organic phase washed with satd aq Na2CO3 solution. The two layers
were again separated and the combined aqueous layers washed with
CH2Cl2 (3 î 10 mL). The combined organic phases were dried
(Na2SO4) and the solvent removed under reduced pressure to give
23 as a colourless oil (374 mg, 89%) which was recognised by its
1H NMR spectrum.
Formation of Crystals of 15•3H+2PF6- NO3
The pyrrolidine-derived triol 15 (200 mg, 0.44 mmol) in absolute
EtOH (2 mL) was added to a solution of Ni(NO3)2∑6H2O (152 mg,
0.44 mmol) in EtOH (2 mL). The solvent was removed under vac-
uum and the green solid was redissolved in H2O (5 mL). A solution
of NH4PF6 (212 mg, 1.3 mmol) in H2O (2 mL) was added to the
mixture which was left to stand overnight, after which time colour-
less crystals had formed. X-ray crystallographic analysis of a crystal
identified it as a mixture of the cation 15•3H+, one NO3 and two
-
PF6- counter ions.
Crystal Data for 15•3H+(PF6)2(NO3)
1H NMR: d = 7.35 -7.20 (5 H, m, C6H5), 4.55 (1 H, t, J = 6.3 Hz,
CH), 1.70 (2 H, dt, J = 6.4, 7.3 Hz, CH2), 0.92 (3 H, t, J = 7.3 Hz,
CH3). [Lit.18 d = 7.36-7.24 (5 H, m), 4.57 (1 H, t, J = 6.6 Hz), 1.86-
1.71 (2 H, m), 0.90 (3 H, t, J = 7.6 Hz).
C27H48F12N4O6P2, M = 814.63, cubic, space group P 21 3 (No. 198),
Z = 4. At 296 K a = 15.240(1) Å, V = 3540(1) Å3 and at 123 K
a = 15.090(1) Å, V = 3436(1) Å3. Disorder of the pyrrolidine resi-
dues and of a PF6- resulted in poor refinements (R = 0.09 for 1102
reflections with I > 2σ(I) at 296 K and R = 0.11 for 1220 reflections
at 123 K) with physically unreasonable bond lengths and anisotro-
pic displacement parameters for the C6-C9 and O1 atoms. Al-
though this disorder precludes detailed discussion of the crystal and
molecular structure the X-ray analyses, together with the its chemi-
cal history, establish the chemical composition of the sample and
the cation conformation.
1-Phenylpropan-1-ol (23) (with an excess of titanium tetraiso-
propoxide)
The experiment described directly above was repeated using the
same quantities of reagents, and extra Ti(i-PrO)4 (872 mg, 3.1
mmol) was added to the reaction mixture at the same time as the
benzaldehyde. Once again 1-phenylpropan-1-ol (23) was obtained
as a colourless oil (387 mg, 93%) which gave 1H NMR data identi-
cal to the previous experiment.
Acknowledgement
(R)-(-)-a-Methoxy-a-(trifluoromethyl)phenylacetyl Chloride
A mixture of (R)-(-)-a-methoxy-a-(trifluoromethyl)phenylacetic
acid (100 mg, 0.43 mmol) and SOCl2 (2 mL) was heated to relux for
4 h. The mixture was allowed to cool, and the excess of thionyl
chloride was removed under reduced pressure. The resulting acid
chloride was used without purification.
We are grateful to the EPSRC for a project studentship (supporting
SC), to Dr. James Wardell of the University of Aberdeen for help
and advice, particularly concerning tin chemistry, and to Mr. Tony
Ritchie of the University of Glasgow for obtaining mass spectral da-
ta. We gratefully acknowledge the assistance of Dr. Kenneth Muir
of the University of Glasgow, and of Dr. Alan Howie of the Univer-
sity of Aberdeen, with the X-ray analyses.
1-Phenylpropan-1-yl (R)-(-)-a-Methoxy-a-(trifluorometh-
yl)phenyl Acetate (24)
(R)-(-)-a-Methoxy-a-(trifluoromethyl)phenylacetyl chloride (28
mg, 0.11 mmol) was added under N2 to a solution of each sample of
1-phenylpropan-1-ol (15 mg, 0.11 mmol) in anhyd CCl4 (5 drops)
and anhyd pyridine (5 drops). Each mixture was left to stand at r.t.
for 12 h, then H2O (1 mL) and Et2O (10 mL) were added. The layers
were separated, and the organic phase was washed with dil HCl (1
mL) and satd aq NaHCO3 solution and dried (MgSO4). The solvent
was removed under reduced pressure from each sample to give the
ester 24 as a colourless oil.
References
(1) Moberg, C. Angew. Chem. Int. Ed. 1998, 37, 248.
(2) See for example Burke, S. D.; O’Donnell, C. J.; Hans, J. J.;
Moon, C. W.; Ng, R. A.; Atkins, T. W.; Packard, G. K.
Tetrahedron Lett. 1997, 38, 2593.
(3) See for example:
Ashton, P. R.; Boyd, S. E.; Brown, C. L.; Jayaraman, N.;
Nepogodier, S. A.; Stoddart, J. F. Chem. Eur. J. 1996, 2, 1115.
(4) See for example:
Betschinger, F.; Libman, J.; Shanzer, A. J. Chromatog. A
1996, 746, 53.
(5) Weizman, H.; Libman, J.; Shanzer, A. J. Am. Chem. Soc.
1998, 120, 2188.
(S)-1-Phenylpropan-1-yl (R)-(-)-a-Methoxy-a-(trifluorometh-
yl)phenyl Acetate (S,R-24)
1H NMR: d = 7.42-7.20 (10 H, m, 2 C6H5), 5.93 (1 H, dd, J = 6.0,
7.9 Hz, CH), 3.56 (3 H, s, OCH3), 2.08-1.85 (2 H, m, CH2), 0.85 (3
H, t, J = 7.4 Hz, CH3) [Lit.17 d = 7.66-7.00 (10 H, m), 5.90 (1 H, dd,
J = 6.1, 7.7 Hz), 3.54 (3 H, q, J = 1.2 Hz), 2.10-1.75 (2 H, m), 0.83
(3 H, t, J = 7.3 Hz).
(6) See for example:
(a) Smith, G. T.; Mallinson, P. R.; Peacock, R. D.; Farrugia,
L. J.; Fallis, I. A.; Frampton, C. S.; Howard, J. A. K. J. Chem.
Soc., Chem. Commun. 1996, 525.
19F NMR: d = -73.2 [Lit.17 d = -72.2].
(b) Tor, Y.; Libman, J.; Shanzer, A.; Felder, C. E.; Lifson, S.
J. Am. Chem. Soc. 1992, 114, 6653.
(7) Fallis, I. A.; Farrugia, L. J.; Macdonald, N. M.; Peacock, R. D.
J. Chem. Soc., Dalton Trans. 1993, 2759.
(8) Clouston, L. L.; Spino, C.; Berg, D. J. Abstr. Pap. Am. Chem.
Soc. 1997, 213, 439-ORGN.
(9) Tor, Y.; Libman, J.; Shanzer, A.; Felder, C. E.; Lifson, S. J.
Am. Chem. Soc. 1992, 114, 6661.
(10) Armstrong, S. K.; Clunas, S.; Muir, K. W. Synthesis 1999,
993.
(11) Závada, J.; Pámkova, M.; Arnold, Z. Collect. Czech Chem.
Commun. 1976, 41, 1777.
(R)-1-Phenylpropan-1-yl (R)-(-)-a-Methoxy-a-(triflurometh-
yl)phenyl Acetate (R,R-24)
1H NMR: d = 7.42-7.20 (10 H, m, 2 C6H5), 5.84 (1 H, dd, J = 6.4,
7.6 Hz, CH), 3.43 (3 H, s, OCH3), 2.08-1.85 (2 H, m, CH2), 0.94 (3
H, t, J = 7.3 Hz, CH3) [Lit.17 d = 7.66-7.00 (10 H, m), 5.82 (1 H, dd,
J = 6.4, 7.6 Hz), 3.45 (3 H, q, J = 1.2 Hz), 2.10-1.75 (2 H, m), 0.93
(3 H, t, J = 7.3 Hz).
19F NMR: d = -72.9 [Lit.17 d = -71.9].
In the sample from the reaction with one equivalent of Ti(OPr-i)4,
the ratio of these signals was 1:1. In the sample from the reaction
with an excess of Ti(OPr-i)4, the ratio was 45:55 (SR:RR).
(12) See for example Tetrahedron Lett. 1988, 29, 4139.
(13) Muir, K.W.; Howie, R.A.; Fun, H.K.; Razak, I.A.,
unpublished results. Full crystallographic details have been
Synthesis 2000, No. 2, 281–288 ISSN 0039-7881 © Thieme Stuttgart · New York

288
S. K. Armstrong, S. Clunas
PAPER
deposited with the Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge CB2 1EZ, UK, from whom
further information about the structure can be obtained. Any
request should quote the deposition numbers 134344 and
134345.
(16) Takeushi, Y.; Itoh, N.; Kawahara, S.; Koizumi, T.
Tetrahedron 1993, 49, 1861.
(17) Seebach, D.; Platner, D. A.; Beck, A. K.; Wang, Y. M.;
Huniker, D. Helv. Chim. Acta 1992, 75, 2171.
(18) Uchiyama, M.; Kameda, M.; Mishima, O.; Yokoyama, N.;
Koike, M.; Kondo, Y.; Sakamoto, T. J. Am. Chem. Soc. 1998,
120, 4934.
(14) Jurkschat, K.; Mügge, C.; Tzschach, A.; Zschunke, A.;
Engelhardt, G.; Lippmaa, E.; Mägi, M.; Larin, M. F.;
Pestunovich, V. A.; Voronkov, M. G. J. Organomet. Chem.
1979, 171, 301.
(15) Zeldin, M.; Ochs, J. J. Organomet. Chem. 1975, 86, 369.
Article Identifier:
1437-210X,E;2000,0,02,0281,02888,ftx,en;P05099SS.pdf
Synthesis 2000, No. 2, 281–288 ISSN 0039-7881 © Thieme Stuttgart · New York