The synthesis of chiral annulet 1,4,7-triazacyclononanes

Article abstract of DOI:10.1016/S0040-4039(02)00705-0

Novel and flexible routes for the synthesis of chiral ring annulet 2,6-disubstituted 1,4,7-trimethyl-1,4,7-triazamacrocycles are described. Efficient macrocyclisations were realised provided that chiral analogues of N,N-bis-[2-(toluene-sulfonylamino)ethyl]-toluene-4-sulfonamide were used as the nucleophilic components. Complexes prepared, in situ, from these 2,6-disubstituted 1,4,7-trimethyl-1,4,7-triazamacrocycles and manganese(II) catalysed the asymmetric epoxidation of styrene with hydrogen peroxide.

Full text of DOI:10.1016/S0040-4039(02)00705-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3795–3798
The synthesis of chiral annulet 1,4,7-triazacyclononanes
Gilles Argouarch,† Colin L. Gibson,* Graham Stones and David C. Sherrington
Department of Pure & Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, UK
Received 4 March 2002; revised 26 March 2002; accepted 10 April 2002
Abstract—Novel and flexible routes for the synthesis of chiral ring annulet 2,6-disubstituted 1,4,7-trimethyl-1,4,7-triazamacrocy-
cles are described. Efficient macrocyclisations were realised provided that chiral analogues of N,N-bis-[2-(toluene-sulfonyl-
amino)ethyl]-toluene-4-sulfonamide were used as the nucleophilic components. Complexes prepared, in situ, from these
2,6-disubstituted 1,4,7-trimethyl-1,4,7-triazamacrocycles and manganese(II) catalysed the asymmetric epoxidation of styrene with
hydrogen peroxide. © 2002 Elsevier Science Ltd. All rights reserved.
The azamacrocycle 1,4,7-triazacyclononane 1a and its
N-alkylated analogues e.g. 1b have rich and diverse
chelationchemistries. Thisisbecausethereisanenormous
thermodynamic and kinetic stability of the amine–metal
fragment regardless of the oxidation state and dn configu-
ration of the central metal ion.1 Thus, the metal complexes
that have been observed include Mn(II–V), Fe(II),
Fe(III), Ru(II–IV andVI), Co(III), Cu(II) andZn(II). The
ability of the triazacyclononanes 1 to stabilise high
oxidation states of metal ions, in particular manganese,
has led to the development of such complexes as oxidation
catalysts. In this context, the epoxidation of unfunction-
alised alkenes using hydrogen peroxide as the terminal
oxidant is particularly noteworthy. Overcoming the prob-
lems of hydrogen peroxide disproportionation by these
manganese complexes has resulted in the development of
effectivestereospecificepoxidationprotocols.2 Enantiose-
lective epoxidations have also been carried out with
managanese complexes bearing chiral analogues of 1b.3
Despite this rich array of chemistry, there are few
examples of the synthesis of chiral triazacyclononanes
where the stereochemistry is directly on the macro-
cyclic ring. Indeed, at the outset of our studies only
triazacyclononanes with one stereocentre on the
macrocyclic ring had been recorded.4 Recently, triaza-
cyclononanes possessing two (at C-2,35 and C-2,66)
and three stereogenic centres (C-2,5,8)3b on the
macrocycle have been reported.
As part of a continuing programme of chiral ligand
evolution we wished to develop flexible syntheses of
chiral analogues of 1 carrying two stereogenic centres
on the annulus. The desire was to place the ring
stereocentres close to the metal chelation centres
(nitrogen) to maximise the transfer of stereochemical
information to any chelated metal. In this letter we
describe the effective synthesis of such triazacy-
clononanes possessing C2 and C1 symmetry.
b
OTs
Ts
R
a
HN
N
N
NTs
H
OTs
OTs
Disconnection B
Disconnection A
TsN
R
N
TsN
HN
NTs
H
a
Ts
R
OTs
b
1a R = H
2
3
1b R = Me
Figure 1. Possible disconnections of macrocycles 1.
Keywords: asymmetric synthesis; epoxidation; polyamines.
* Corresponding author. Tel.: +44 (0)141 548 2796; fax: +44 (0)141 548 4246; e-mail: c.l.gibson@strath.ac.uk
† Present address: UMR CNRS 6509, Organome´talliques et Catalyse, Universite´ de Rennes 1, Campus de Beaulieu, 35042 Rennes, France.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00705-0

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G. Argouarch et al. / Tetrahedron Letters 43 (2002) 3795–3798
At the outset we were aware that disconnection A (Fig.
1) would be problematic if the analogues of ditosylate 3
used were secondary.4b,7 Furthermore, using disconnec-
tion B (Fig. 1) generally results in low yields in the
macrocyclisation step (<30%).4c,5a Consequently, our
plan was to use disconnection A, but with a chiral
analogue of tristosamide 2.
using palladium on charcoal with acetic acid as the
solvent, this afforded the required amine 10c in 40%
yield. Indeed, solubility problems were severe in the
large scale (ca. 1 g) palladium hydroxide debenzylation
of 7b. In this case, addition of dichloromethane as a
co-solvent resulted in the efficient formation of the
novel imidazolidine 11. Subsequent hydrolysis in reflux-
ing 3N hydrochloric acid afforded the required amine
10b. The free amines 10a–c were uneventfully converted
into the tristosamides 12a–c using tosyl chloride in
pyridine.
Our synthesis of chiral triazacyclononanes began with
alaninol 4a and valinol 4b which were converted into
the tosylates 5a and 5b and hence the chiral tosyl
aziridines 6a8 and 6b.9 Ring opening9a,10 of the chiral
tosyl aziridines 6a and 6b with 0.5 equiv. of benzyl-
amine in methanol afforded the C2 symmetric bis-
tosamides 7a and 7b, respectively. Alternatively, ring
opening of chiral tosyl aziridine 6a with excess benzyl-
amine afforded the amino tosamide 8. Subsequent, ring
opening of aziridine 6b with amino tosamide 8 gave the
C1 symmetric bistosamide 7c (Scheme 1).
Having removed the nucleophilic amine functionality in
7a–c by conversion into the tosamides 12a–c, we were
in a position to investigate the Richman–Atkins cyclisa-
tions. As such, tosamides 12a–c smoothly underwent
Richman–Atkins cyclisation to afford the novel triaza-
cyclononanes 13a–c (Scheme 3). Detosylation of the
triazacyclononanes 13a–c was most effectively carried
out using lithium in ammonia reduction which provided
the free amino triazacyclononanes 14a–c. In the case of
amino triazacyclononane 14a, the isolated yield was
only 13% and was a function of the water solubility.
Simply taking the crude aqueous mixture and subject-
ing it to Eschweiler–Clarke12 methylation gave the
required unique trimethyl triazacyclononane 15a in
46% over two steps. Water solubility was not a problem
in the case of the triazacyclononanes 14b and 14c, these
could be efficiently isolated after the lithium–ammonia
reduction. In these cases subsequent Eschweiler–Clarke
N-methylation afforded the novel trimethyl triazacy-
clononanes 15a and 15b.
Armed with the bistosamides 7a–c, the Richman–
Atkins cyclisation was attempted.11 However, under
standard Richman–Atkins conditions with bistosamide
7a and ditosylate 3 no reaction took place, while with
more forcing conditions (120°C) the chiral piperazine 9
resulted (Scheme 2). The formation of piperazine 9 is a
result of nucleophilic attack of the central benzylic
amine on an electrophilic tosylate from ethylene glycol
ditosylate 3 followed by expulsion of a C-3 tosamide
unit either prior to or during cyclisation. Clearly, the
nucleophilicity of the central benzylic amine in 7 needed
to be lowered for successful Richman–Atkins cyclisa-
tions. Accordingly, hydrogenolytic removal of the ben-
zyl group from 7a and 7b was achieved using palladium
hydroxide to afford the free amines 10a and 10b9a in 86
and 71% yields, respectively. On the other hand, deben-
zylation of 7c was unsuccessful using palladium
hydroxide, probably because of the insolubility of 7c in
methanol. However, debenzylation of 7c was achieved
The catalytic activity of the chiral trimethyl triaza-
macrocycles 15 in the hydrogen peroxide epoxidation of
alkenes was investigated using in situ protocols. These
procedures utilised 0.16–0.2 mol% of the triazacy-
clononanes 15 and 0.1–0.13 mol% of manganese(II)
R
NH2
R
R
b
a
HO
TsO
NHTs
N
Ts
4a R = Me
4b R = iPr
5a R = Me 90%
5b R = iPr 92%
6a R = Me 98%
6b R = iPr 98%
d
c
(85%)
R1
NHTs
NHTs
BnN
e
BnN
BnN
H
NTs
H
(45%)
NHTs
NHTs
8
R2
iPr
7a R1 = R2 = Me 86%
7b R1 = R2 = iPr 67%
7c
Scheme 1. Reagents and conditions: (a) 2 equiv. TsCl, pyr.; (b) NaH, THF; (c) 0.5 equiv. BnNH2, MeOH, rt; (d) 6a, excess
BnNH2, MeOH, rt; (e) 6b, MeOH; rt.

G. Argouarch et al. / Tetrahedron Letters 43 (2002) 3795–3798
3797
R1
Me
NHTs
a
BnN
NTs
BnN
32%
NHTs
R2
7a R1 = R2 = Me
7b R1 = R2 = iPr
7c R1 = Me R2 = iPr
9
b or c
40-86%
d 78%
Ts
R1
R1
iPr
N
NHTs
NHTs
NHTs
e
f
N
TsN
HN
NHTs
92%
72-89%
NHTs
iPr
R2
R2
11
10a R1 = R2 = Me
10b R1 = R2 = iPr
10c R1 = Me R2 = iPr
12a R1 = R2 = Me
12b R1 = R2 = iPr
12c R1 = Me R2 = iPr
Scheme 2. Reagents and conditions: (a) (i) NaH, THF, D; (ii) (CH2OTs)2, DMF, 120°C; (b) Pd(OH)2, H2, MeOH; (c) Pd–C, H2,
AcOH; (d) Pd(OH)2, H2, MeOH–CH2Cl2; (e) 3N HCl, D; (f) TsCl, pyr.
ions with, or without, an ascorbate co-ligand. Using
2,6-dimethyl macrocycle 15a failed to give any epoxida-
tion while the use of the diispropyl macrocycle 15b
afforded (R)-styrene epoxide 17 in 31% yield and 16%
ee. In the case of macrocycle 15c, (R)-styrene epoxide
17 was obtained in 15% yield and 23% ee (Scheme 4).
macrocyclic ring. The key development for effective and
efficient Richman–Atkins cyclisations involved the use
of the tristosamides 12a–c as the nucleophilic compo-
nents in the cyclisation. Failure to use tristosamides
12a–c led to no macrocyclisation or to low yields. The
tristosamides 12a–c were readily prepared by the ring
opening of chiral tosyl aziridines 6a and 6b with benzyl-
amine followed by appropriate functional group inter-
changes. The azamacrocyles 15a–c were used as ligands
in the enantioselective epoxidation of styrene 16, which
yielded (R)-styrene oxide 17 in up to 23% ee.
In summary, we have developed novel and flexible
routes for the synthesis of C2 and C1 symmetric 1,4,7-
trimethyl-1,4,7-triazamacrocycles 15a–c where the stere-
ochemical information resides directly on the
R1
R1
R1
Me
NH
NH
N
N
NTs
a
b
c
HN
Me N
10
TsN
72-75%
66-87%
46-90%
NTs
R2
R2
Me
R2
13a R1 = R2 = Me
13b R1 = R2 = iPr
13c R1 = Me R2 = iPr
14a R1 = R2 = Me
14b R1 = R2 = iPr
14c R1 = Me R2 = iPr
15a R1 = R2 = Me
15b R1 = R2 = iPr
15c R1 = Me R2 = iPr
Scheme 3. Reagents and conditions: (a) (i) NaH, THF, D; (ii) (CH2OTs)2, DMF, 80°C; (b) Li–NH3, EtOH; (c) HCO2H,
formaldehyde, D.
a or b
O
Ph
Ph
16
17
0-31%
16-23%ee
Scheme 4. Reagents and conditions: (a) 0.16 mol% of 15a or 15b, 0.1 mol% of aq. Mn(OAc)2, 0.21 mol% of aq. sodium ascorbate,
0.05 mol% of aq. ascorbic acid, 2 equiv. H2O2, CH3CN, CH3COCH3; (b) 0.2 mol% of 15c, 0.13 mol% of aq. MnSO4, 2 equiv.
H2O2, CH3CN, CH3COCH3.

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G. Argouarch et al. / Tetrahedron Letters 43 (2002) 3795–3798
A. S.; Helps, I. M.; Jankowski, K. J.; Parker, D.; Eaton,
Acknowledgements
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We thank the EPSRC for funding through a ROPA
award (to G.A., grant GR/M28477) and studentship (to
G.S.). We are grateful to Stuart Cook and Dr. Terry
Lowdon of Hickson & Welch for valuable discussions
and the supply of achiral materials and to Alison
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