The synthesis of an isopropyl substituted 1,4,7-triazacyclononane via an in situ sequential macrocyclisation method.

Article abstract of DOI:10.1039/b302887a

Using L-valine methyl ester hydrochloride as starting material, the synthesis of (2S)-2-isopropyl-1,4,7-trimethyl-1,4,7-triazacyclononane is described. Various standard Richman-Atkins cyclisation methods gave only poor yields in the key macrocyclisation step. Efficient macrocyclisation yields were, however, realised when an in situ sequential cyclisation method was developed.

Full text of DOI:10.1039/b302887a

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The synthesis of an isopropyl substituted 1,4,7-triazacyclononane
via an in situ sequential macrocyclisation method
Graham Stones, Gilles Argouarch,† Alan R. Kennedy, David C. Sherrington and
Colin L. Gibson*
Department of Pure & Applied Chemistry, University of Strathclyde, 295 Cathedral Street,
Glasgow, UK G1 1XL. E-mail: c.l.gibson@strath.ac.uk
Received 14th March 2003, Accepted 12th May 2003
First published as an Advance Article on the web 22nd May 2003
Using -valine methyl ester hydrochloride as starting material, the synthesis of (2S)-2-isopropyl-1,4,7-trimethyl-
1,4,7-triazacyclononane is described. Various standard Richman–Atkins cyclisation methods gave only poor yields
in the key macrocyclisation step. Efficient macrocyclisation yields were, however, realised when an in situ sequential
cyclisation method was developed.
Introduction
Currently, there is significant interest in the synthesis and
chemistry of polyazamacrocycles because of the ability of
these ligands to form kinetically and thermodynamically stable
metal ion complexes.1 The ability of 1,4,7-triazacyclononane 1a
together with N-alkyl derivatives 1b, and analogues thereof, to
stabilise high oxidation states of metal ions is particularly
noteworthy. The ability of ligands such as 1 to stabilise high
metal ion oxidation states has led to their use as biomimetics of
manganese enzymes including manganese catalyse and Photo-
system II.2 These biomimetic studies on 1b led Hage et al. to
develop manganese complexes of this macrocycle as catalysts
for low temperature bleaching with hydrogen peroxide.3
Hage et al. also used these manganese complexes as epoxid-
ation catalysts. Subsequently, there followed much interest in
the use of azamacrocycle derivatives of 1 in conjunction with
manganese ions as epoxidation catalysts. One drawback of the
use of macrocycle 1a and manganese() as an epoxidation sys-
tem is the pronounced catalyse activity resulting in the decom-
position of hydrogen peroxide. However, De Vos et al. have
developed a method for overcoming the problem of hydrogen
peroxide disproportionation by carrying out epoxidations at
0 ЊC in acetone.4 Subsequently, using complexes generated
in situ from manganese() and 1b both De Vos et al.5 and
Berkessel et al.6 have described stereoselective epoxidations of
unfunctionalised alkenes using hydrogen peroxide in the pres-
ence of oxalate or ascorbate co-additives. This considerable
interest led to the development of enantioselective epoxidations
being carried out using chiral non racemic analogues of 1b by
Beller et al.,7 Bolm et al.8,9 and ourselves.10
Fig. 1
The first reported synthesis of a chiral triazacyclononane
with a stereocentre on the ring annulus was the (R)-2-methyl-
1,4,7-triazacyclononane 2 by Mason and Peacock who investi-
gated the chiroptical properties of the cobalt() complex.11a
Their synthesis (Route A, Scheme 1) involved a Richman–
Atkins cyclisation19 of a 1,2-ditosamide 7a and tritosyl
diethanolamine 6 which afforded the tristosamide 8a. Sub-
sequent studies by Graham and Weatherburn showed that
Richman–Atkins cyclisation of racemic 1,2-ditosamide 7a and
tritosyl diethanolamine 6 in dimethyl sulfoxide only gave a 20%
yield of the tristosamide 8a in the macrocyclisation step.19 The
failure of Route A to afford efficient yields of macrocycle was
rationalised by Searle and Geue in the synthesis of tristosamide
8b in terms of inhibition of the first substitution step because
of steric and/or electronic factors from the bis anion of
bistosamide 7b.20
Despite the above interest in triazacyclononanes there are
few examples of the synthesis of chiral analogues where the
stereochemistry is directly associated with the macrocyclic ring
itself. At the outset of our studies only macrocycles 2,11 12 and
3
413 with one stereocentre on the macrocyclic ring had been
reported. Subsequently, triazacyclononanes possessing two
(C-2,314 and C-2,610,15,16) and three stereocentres9 on the
macrocyclic ring were reported. However, the synthesis of
chiral triazacyclononanes is far from trivial as evidenced from
our early studies in the area.17 In this context, we initially
focused on the synthesis of chiral monosubstituted triaza-
cyclononanes, even here there were obvious problems with the
synthesis of these molecules. Therefore, the challenge that we
set ourselves was the preparation of the novel sterically
demanding isopropyl substituted triazacyclononane 5 (Fig. 1).
Scheme 1
Failure of Route A to furnish efficient yields in the macro-
cyclisation step for both mono and unsubstituted macrocycles
led to the investigation of alternative disconnections. The
† Present address: UMR CNRS 6509, Organometalliques et Catalyse,
University de Rennes, Campus de Beaulieu, 35042 Rennes, France
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 3 5 7 – 2 3 6 3
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alternate approach (Route B, Scheme 1), first developed by Cox
et al. for the mono substituted macrocycle 8c, involved the
Richman–Atkins cyclisation of a tristosylate 10a with ethylene
glycol ditosylate 9.12 Such an approach afforded the macrocycle
8c in 71% yield while the method using 7c and 6 (Route A)
afforded only 35% yield. Subsequently, Koek et al. used Route
B in the synthesis of the racemic benzyl substituted azamacro-
cycle 8d from tristosamide 10b and bistosylate 9.13
With these observations in mind, we set about investigating
the preparation of the novel sterically demanding isopropyl
macrocycle 5 and its use as an epoxidation catalyst. In this
paper we describe our studies which showed that even using
approach B can be problematic and present a solution to this
problem.
involves the reaction of ethylene glycol ditosylate 9 with the bis
sodium salt of a suitable tosamide derivative. Alternatively, the
caesium salt formed in situ from the tosamide and caesium car-
bonate can be used. Slow addition of the electrophilic tosylate
ester to the sodium or caesium salt in DMF at 80 ЊC generally
gives the macrocycle. However, all such approaches using bis-
tosamide 16 proved to be very inefficient with low yields of the
macrocycle 17 being formed together with decomposition and
polymeric products. It was speculated that the isopropyl group
in tristosamide 16 was detrimental to the cyclisation by inhibit-
ing the reactivity of the adjacent tosamide anion. This steric
hindrance would result in the less hindered tosamide anion of
dianion 18 displacing one O-tosyl ester group in ethylene glycol
ditosylate 9 to give the mono substitution product 19 (Scheme
3). The low yield of cyclisation product 17 suggested that the
intramolecular cyclisation of 19 was hindered, probably by the
C-2 isopropyl group. Consequently, a less sterically demanding
pathway from 19 may involve intermolecular substitution to
give the dimer 20. The dimeric product 20 could then react
further to give oligomeric and/or polymeric products.
Results and discussion
Our exploratory studies in this area with racemic 1,2-ditos-
amide 7a and tritosyl diethanolamine 6 confirmed the observ-
ations of Graham and Weatherburn19 in that Route A was not
a synthetically viable approach. In this case, macrocyclisation
was carried out in DMF and gave racemic 8a in only 10–15%
yield as impure material.
Thus, the synthesis of isopropyl substituted macrocycle 5 was
investigated based on the approach of Cox et al. for 3.12 In this
context, -valine methyl ester hydrochloride 11 was reacted neat
with ethylene diamine which afforded the amide 12 (89%)
(Scheme 2). Reduction of the amide 12 with borane–THF com-
plex followed by acid hydrolysis proved to be problematic with
only low yields of the triamine 13 being isolated. Therefore, an
alternative sequential procedure was developed for the prepar-
ation of a protected form of the triamine 13. This alternative
sequence involved initial reaction of amide 12 with 4-toluene-
sulfonyl chloride in pyridine which afforded the bistosamide
14 in 71% yield. Reduction of bistosamide 14 with borane–
dimethyl sulfide complex followed by acid hydrolysis gave the
hydrochloride salt 15 (63%). Protection of the central nitrogen
in 15 was accomplished by reaction with 4-toluenesulfonyl
chloride in pyridine which smoothly afforded the tristosamide
16 (72%).
Scheme 3 Reagents and conditions: i, 2 equiv. NaH, DMF, 60 ЊC; ii, 9.
In order that the problems of decomposition and/or oligo-
merisation via 19 could be avoided it was decided to try a
sequential cyclisation process. Accordingly, the bistosamide 14
was reacted with one equivalent of sodium hydride in DMF to
form the monosodium salt 21 followed by reaction with ethyl-
ene glycol ditosylate 9 (Scheme 4). This happily afforded the
mono alkylated product 22 which had alkylated at the least
hindered tosamide function. Subsequent treatment of 22 with
a further equivalent of sodium hydride in DMF afforded the
piperazine 23 rather than macrocyclisation. The piperazine 23
was a consequence of the amide nitrogen in the sodium salt of
Scheme
2
Reagents and conditions: i, (CH2NH2)2, 120 ЊC;
ii, H3BؒSMe2, THF, ∆; iii, 6 M HCl, ∆; iv, TsCl, pyr; v, 2 equiv. NaH, 9,
DMF, 80 ЊC; vi, CsCO3, 9, DMF, 80 ЊC.
The planned synthesis of macrocycle 5 required the
macrocyclisation of tristosamide 16 using a Richman–Atkins
cyclisation. In general, the Richman–Atkins macrocyclisation18
Scheme 4 Reagents and conditions: i, 1 equiv. NaH, DMF, 0 ЊC; ii, 9,
RT; iii, 1 equiv. NaH, DMF, 80 ЊC.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 3 5 7 – 2 3 6 3
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22 participating in the nucleophilic ring closure. Ourselves10
and Watkinson and co-workers16 had observed analogous
problems of a central nucleophilic nitrogen participating in
attempted macrocyclisations for the preparation of disubsti-
tuted systems. The solution to this problem required a
reduction of the nucleophilicity of the amide nitrogen in 22.
Accordingly, a sequential in situ alkylation and cyclisation
protocol was developed. Thus, tristosamide 16 was treated with
one equivalent of sodium hydride in DMF at 0 ЊC followed by
the addition of ethylene glycol ditosylate 9 (Scheme 5). Presum-
ably, this afforded the mono alkylated product 24. Slow addi-
tion of the final equivalent of sodium hydride was carried out
and this afforded the desired macrocycle 17 in a welcome 78%
yield.
isopropyl group. Only the third tosyl group furthest from the
isopropyl, is on the same face as it. All three N centers show
considerable deviations from planarity (N1, N2 and N3 lie
Ϫ0.320, 0.211 and Ϫ 0.104 Å respectively from the planes
defined by the atoms bonded to them). The tosylate on N3
(adjacent to isopropyl) is twisted so that the phenyl ring
lies over one face of the 9-membered ring whilst the other
tosyl groups point away from the main body of the molecule.
(Ct–N3–S3–C24 is 2.8Њ, where Ct is the 9-membered rings
centroid and C24 is the ipso C atom whilst the equivalent
torsions for the other tosyl groups are 140.5 and 175.5Њ). Sur-
prisingly for a structure with no obviously strong inter-
molecular contacts, there are large channels running parallel
to the crystallographic c direction. Careful examination of
electron-density syntheses showed no evidence for the presence
of disordered solvent in these.
The remaining sequence for the preparation of 5 required
the detosylation of 17 followed by N-methylation. Using the
detosylation conditions of Weatherburn and Graham of
hydrobromic acid in acetic acid afforded the mono 25 and bis-
tosamide 26 derivatives in 28 and 47% yields, respectively.
Complete detosylation was achieved with lithium in ammonia
reduction of 17 which afforded the deprotected macrocycle 27
as the hydrochloride salt (53%). Subsequent, Eschweiler–Clarke
N-methylation of the freebase of 27, formed in situ, gave the
required isopropyl macrocycle 5 in 72% yield.
In situ epoxidations were carried out using macrocycle 5 by
application of the stereoselective method of Berkessel and
Sklorz6 involving manganese() acetate with an ascorbate/
ascorbic acid co-ligand system. In the case of dodecene, a
36% yield of the racemic epoxide was obtained while for
styrene, a 31% yield of (R)-styrene oxide was isolated with a
16% ee.
Conclusions
The synthesis of (2S)-2-isopropyl-1,4,7-trimethyl-1,4,7-triaza-
cyclononane was carried out in 7 steps and 8.5% overall yield
from -valine methyl ester hydrochloride. Standard Richman–
Atkins cyclisation procedures gave only low yields of the
macrocyclisation product. This inefficient cyclisation was attri-
buted to a detrimental steric hindrance of the 2-isopropyl sub-
stituted nucleophilic component in the macrocyclisation step.
Consequently, a sequential in situ macrocyclisation method was
developed which gave a cyclisation yield of 78%. The macro-
cycle was used as a ligand in the in situ epoxidation of alkenes
with manganese() and hydrogen peroxide in the presence of an
ascorbate/ascorbic acid co-ligand system.
Scheme 5 Reagents and conditions: i, 1 equiv. NaH, DMF, 0 ЊC; ii, 9,
RT; iii, Slow addn of 1 equiv. NaH, 80 ЊC; iv, HBr-AcOH, ∆, 48 h; v, Li,
NH3, EtOH, THF; vi, HCO2H, HCHO.
The spectral properties of 17 were in full accord with the
structure, however, the crystalline nature of 17 allowed both the
stereochemistry and the absolute structure to be confirmed
unequivocally by single crystal X-ray diffraction. The solid-
state structure (Fig. 2) indicated that as expected the isopropyl
group adopts a pseudo-equatorial position on the ring. The
ring puckering is dominated by the three sp2 N centers. These
are oriented so that two have the same directionality (N1 and
N3 in the crystal structure) and hold their substituent tosyl
groups on the opposite face of the 9-membered ring from the
Experimental
Instrumentation
Melting points were determined on a Reichert 7905 hot stage
and are uncorrected. Specific rotations were measured at 20 ЊC
in a 1 cm3 cell with a pathlength of 10 cm using a Perkin-Elmer
341 polarimeter. Specific rotations were measured at 20 ЊC, the
values are given in 10Ϫ1 deg cm2 gϪ1 and the concentrations are
quoted in g 100 cmϪ3. 1H-NMR spectra were recorded on
Bruker WM-250, JEOL 270, or Bruker AMX-400 spectro-
meters in the indicated solvents operating at 250, 270 or
400 MHz, respectively. 13C-NMR spectra were obtained on the
same instruments operating at 62.89, 67.80, and 100 MHz,
respectively. The following abbreviations were used: s, singlet; d,
doublet; t, triplet; q, quartet; m, multiplet; dd, doublet of doub-
lets; dq, doublet of quartets; sep, septet. Coupling constants
were recorded in Hz. Infra red (IR) spectra were recorded on a
Nicolet Impact 400D FTIR spectrometer either as liquid films
or as KBr discs. Mass spectra were recorded on a JEOL JMS
AX505 spectrometer at Strathclyde or at the EPSRC National
Fig. 2 Molecular structure of 17 with 40% displacement ellipsoids.
H atoms have been omitted for clarity.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 3 5 7 – 2 3 6 3
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Mass Spectrometry service, Swansea. Microanalyses were
performed by the microanalytical service at Strathclyde. HPLC
analysis of styrene oxide was performed using an Applied
Chromatography Systems (ACS) Model 351 isocratic pump in
conjunction with a Daicel Chiralcel OD column (250 × 4.6 mm)
with 0.25% propanol in hexane (1 cm3 minϪ1) as the eluant. The
peaks were detected with an ACS Model 750/12 UV detector set
at 254 nm and an ACS Chiramonitor. The data were collected
on a Viglen computer fitted with a SUMMIT data card and the
chromatograms were integrated using COMUS SUMMIT
software.
(Ar–C), 137.0 (Ar–C), 143.8 (Ar–C), 144.2 (Ar–C), 171.8
(C᎐O).
᎐
4-Methyl-N-{2-[(2S )-3-methyl-2-{[(4-methylphenyl)sulfonyl]-
amino}butylamino]ethyl}benzenesulfonamide 15. To a solution
of (2S)-3-methyl-2-{[(4-methylphenyl)sulfonyl]amino}-N-(2-
{[(4-methylphenyl)sulfonyl]amino}ethyl)butanamide 14 (1.80 g,
3.80 mmol) in THF (25 cm3) was added borane–dimethyl sul-
fide complex (1.10 cm3, 11.40 mmol). The reaction was heated
to reflux for 24 h. On cooling, the reaction was quenched with
methanol (20 cm3) and the volatiles were evaporated under
reduced pressure. To the resulting residue was added 2 M HCl
(25 cm3) and the system was heated to reflux for a further 24 h.
On cooling the resulting aqueous solution was extracted with
dichloromethane (×2, 25 cm3). The combined organic extracts
were dried (Na2SO4), filtered and evaporated to afford a pale
yellow oil which subsequently solidified to give a colourless
solid. Recrystallisation from EtOAc afforded the titled com-
pound as colourless crystals (1.2 g. 2.4 mmol, 63%); mp 147–
149 ЊC; Found C, 51.6; H, 6.6; N, 8.4; S, 13.2; Cl, 7.1; MHϩ
454.1850. C21H32O4S2N3Cl requires: C, 51.6; H, 6.4; N, 8.6; S,
13.0; Cl, 7.3%; 454.1841. [α]D Ϫ26.1 (c = 1, CHCl3). υmax(KBr,
cmϪ1) 3272 (s, NHTs), 3200–2600 (br, NϩH(Cl)), 2964 (s, CH),
2880 (s, CH), 2790 (s, CH), 1325 (s, SO2NH), 1175 (s, SO2NH);
δH (400 MHz, CDCl3) 0.67 (m, 6H, –CH3), 1.72 (m, 1H,
CH(CH3)2), 2.21 (br, 1H, NH ), 2.37 (s, 3H, –C6H4–CH3), 2.39
(s, 3H, –C6H4–CH3), 3.13 (m, 2H, CH2Nϩ), 3.38 (m, 2H,
CH2NTs), 3.40 (m, 2H, CH2Nϩ), 3.56 (m, 1H, CHNTs), 7.27
(m, 4H, –C6H4–CH3), 7.80 (d, J 8.2, 2H, –C6H4–CH3), 7.87 (d,
J 8.2, 2H, –C6H4–CH3), 8.75 (br, 1H, NH ); δC (100 MHz,
CDCl3) 18.6, 18.7 (–CH3), 21.7 (–C6H4–CH3), 21.8 (–C6H4–
CH3), 30.5 (CH(CH3)2), 42.7 (NCH2), 48.3 (NCH2), 49.7
(TsNCH2), 59.1 (TsNCH), 127.3 (2 × Ar–CH), 127.6 (2 ×
Ar–CH), 129.9 (4 × Ar–CH), 136.5 (Ar–C), 137.2 (Ar–C),
138.2 (Ar–C), 143.5 (Ar–C).
General methods
Anhydrous reactions were carried out under an atmosphere of
nitrogen in oven dried glassware (140 ЊC). Anhydrous solvents
were obtained using standard procedures: ethanol (Mg(OEt)2),
pyridine (predried over KOH, distilled from CaH2), THF
(K metal), toluene (Na metal) and triethylamine (CaH2). All
other reagents were used as supplied. Flash column chromato-
graphy was performed according to the procedure of Still
et al.21 using silica gel (230–400 mesh).
Experimental procedures
(2S )-2-Amino-N-(2-aminoethyl)-3-methylbutanamide 12. To
ethylene diamine (50 cm3, 747 mmol) at room temperature
under a nitrogen atmosphere was added, portionwise, methyl
(2S)-2-amino-3-methylbutanoate 1122 (1.00 g, 5.96 mmol) over
10 min. The homogeneous mixture was brought to 120 ЊC for
6 h. The resulting reaction mixture was allowed to cool to room
temperature and the volatiles were evaporated to afford the title
compound as a viscous yellow oil without purification, (840 mg,
5.30 mmol, 89%). Found: MHϩ 160.1445. C7H17N3O requires:
160.1372; [α]D ϩ6.8 (c = 0.22, methanol); υmax (liquid film, cmϪ1)
3350 (br, NH), 3293 (br, NH), 2959 (s, CH), 2920 (s, CH), 2850
(s, CH), 1649 (s, C᎐O); δ (250 MHz, CDCl ) 0.76 (d, J 6.8, 3H,
᎐
H
3
–CH3), 0.83 (d, J 6.8, 3H, –CH3), 2.24 (m, 1H, CH(CH3)2),
2.76 (m, 2H, –CH2NH2), 3.17 (m, 2H, –CH2NH2), 3.25 (m,
1H, NHCOCH ); δC (100 MHz, CDCl3) 15.0, 18.6 (–CH3),
29.8 (–CH(CH3)2), 40.8 (–CH2NH2), 43.9 (–CHNH2), 59.2
(CONHCH).
4-Methyl-N-((1S )-2-methyl-1-{[(4-methylphenyl)sulfonyl](2-
{[(4-methylphenyl)sulfonyl]amino}ethyl)amino]methyl}propyl)-
benzenesulfonamide 16. To a solution of 4-methyl-N-((1S)-2-
methyl-1-{[(4-methylphenyl)sulfonyl]amino}ethyl)amino]-
methyl}propyl)benzenesulfonamide hydrochloride 15 (1.50 g,
3.10 mmol) in pyridine (20 cm3) at 0 ЊC under a nitrogen atmos-
phere was added p-toluenesulfonyl chloride (583 mg, 3.10
mmol) in batches over 30 min. The orange solution was allowed
to come to room temperature and stirred for a further 6 h at
room temperature. The now black reaction mixture was
quenched with ice (∼100 g) and conc. HCl (25 cm3). This mix-
ture was extracted with dichloromethane (×2, 25 cm3), and the
combined organic extracts were dried (Na2SO4), filtered and
evaporated to afford a crude dark brown oil. Purification by
column chromatography on silica (hexane–EtOAc–CH2Cl2 3 : 2
: 5) afforded a light yellow solid which subsequently solidified to
a colourless solid (1.4 g, 2.23 mmol, 72%); mp 78–80 ЊC; Found:
C, 55.3; H, 5.9; N, 6.7; S, 15.6; MHϩ 608.1930. C28H37O6S3N3
requires: C, 55.3; H, 6.1; N, 6.9; S, 15.8%; 608.1923; [α]D Ϫ46.4
(c = 1, CHCl3). υmax(KBr, cmϪ1) 3284 (s, NHTs), 3059 (w, C6H4),
2962 (s, CH), 2910 (s, CH), 2875 (m, CH), 1331 (s, SO2NH),
1156 (s, SO2NH); δH (400 MHz, CDCl3) 0.78 (d, J 6.8, 3H,
–CH3), 0.82 (d, J 6.8, 3H, –CH3), 1.77 (m, 1H, CH(CH3)2),
2.39 (s, 3H, –C6H4–CH3), 2.46 (s, 6H, –C6H4–CH3), 2.55
(m, 2H, CH2NTs), 2.77 (m, 2H, CH2NTs), 3.64 (m, 2H,
CH2NTs), 3.67 (m, 1H, CH2NTs), 7.25 (d, J 8.1, 3H, –C6H4–
CH3), 7.34 (d, J 8.1, 3H, –C6H4–CH3), 7.71 (d, J 8.1, 1H,
–C6H4–CH3), 7.77 (d, J 8.1, 1H, –C6H4–CH3), 7.88 (d, J 8.1,
4H, –C6H4–CH3); δC (100 MHz, CDCl3) 18.4, 18.7 (–CH3), 21.6
(–C6H4–CH3), 21.8 (2× –C6H4–CH3), 31.1 (CH(CH3)2), 48.2
(TsNCH2), 48.8 (TsNCH2), 49.3 (TsNCH2), 58.7 (TsNCH),
127.2 (3× Ar–CH), 128.4 (3× Ar–CH), 129.8 (3× Ar–CH),
136.8 (3× Ar–CH), 138.0 (2× Ar–C), 143.5 (2× Ar–C), 145.2
(2× Ar–C).
(2S )-3-Methyl-2-{[(4-methylphenyl)sulfonyl]amino}-N-
(2-{[(4-methylphenyl)sulfonyl]amino}ethyl)butanamide 14. To a
solution of (2S)-2-amino-N-(2-aminoethyl)-3-methylbutan-
amide 12 (4.90 g, 30.70 mmol) in pyridine (70 cm3) at 0 ЊC under
a nitrogen atmosphere was added p-toluenesulfonyl chloride
(14.66 g, 76.9 mmol) in batches over 30 min. The orange solu-
tion was allowed to come to room temperature and stirred for a
further 6 h at room temperature. The black reaction mixture,
was quenched with ice (∼300 g) and conc. HCl (80 cm3). This
mixture was washed with dichloromethane (×2, 100 cm3), and
the combined organic extracts were dried (Na2SO4), filtered
and evaporated. The resulting brown red oil was crystallised
(methanol–water) to afford the title compound as colourless
needles (10.1 g, 21.7 mmol, 71%); mp 163–164 ЊC. Found: C,
53.9; H, 6.3; N, 9.0; S, 13.7: MHϩ 468.2016. C21H29O5S2N3
requires: C, 54.2; H, 6.2; N, 8.7; S, 13.7%: 468.1990. [α]D Ϫ34.5
(c = 1, CHCl3). υmax (KBr, cmϪ1) 3339 (s, NHTs), 3263 (s,
NHCO), 2962 (m, CH), 2929 (m, CH), 2877 (m, CH), 1655 (s,
C᎐O), 1328 (s, SO NH), 1159 (s, SO NH); δ (400 MHz,
᎐
2
2
H
CDCl3) 0.77 (d, J 6.8, 3H, –CH3), 0.80 (d, J 6.8, 3H, –CH3),
2.06 (m, 1H, CH(CH3)2), 2.44 (s, 3H, –C6H4–CH3), 2.46 (s, 3H,
–C6H4–CH3), 3.03 (m, 2H, –NCH2), 3.35 (m, 2H, TsNCH2),
3.51 (m, 1H, TsNCH ), 5.61 (s, 1H, CONH ), 5.7 (d, J 7.7,
1H, TsNH ), 6.96 (s,1H, TsNH ), 7.73–7.8 (m, 8H, –C6H4–
CH3); δC (100 MHz, CDCl3) 17.5 (–CH3), 19.3 (–CH3), 21.7
(2 × –C6H4–CH3), 31.0 (CH(CH3)2), 39.7 (TsNCH2–), 42.8
(CH2NHCO), 62.7 (COCHNTs), 127.3 (2 × Ar–CH), 127.7
(2 × Ar–CH), 129.9 (2 × Ar–CH), 130.1 (2× Ar–CH), 136.3
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 3 5 7 – 2 3 6 3
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{2-[((2S )-3-Methyl-2-{{(4-methylphenyl)sulfonyl]amino}-
butanoyl)amino]ethyl}[(4-methylphenyl)sulfonyl]amino}ethyl-4-
methylbenzene sulfonate 22. To a solution of (2S)-3-methyl-2-
{[(4-methylphenyl)sulfonyl]amino}-N-(2-{[(4-methylphenyl)-
sulfonyl]amino}ethyl)butanamide 14 (1.00 g, 2.10 mmol) in
DMF (10 cm3) at 0 ЊC was added a suspension of NaH (51 mg,
2.14 mmol) in DMF (2 cm3) over 1 h. The suspension was
allowed to come to room temperature and stirred for a further
1 h. Ethylene glycol ditosylate 9 (583 mg, 2.10 mmol) in DMF
(1 cm3) was added dropwise over 30 min to the solution. The
reaction was stirred overnight and at the completion of
this period the reaction was quenched by the addition of water
(10 cm3). The DMF was removed under reduced pressure
(12 mmHg) and the residue was dissolved in EtOAc (15 cm3).
The organic layer was washed with water (×2, 20 cm3), dried
(Na2SO4), filtered and evaporated to give a brown solid. Purifi-
cation by column chromatography on silica (hexane–EtOAc–
CH2Cl2 4 : 1 : 5) afforded a white solid (798 mg, 1.2 mmol,
57%); mp 132–134 ЊC; Found: C, 55.3; H, 5.9; N, 6.7; S, 15.6;
MHϩ 666.1953. C30H39O8S3N3 requires: C, 55.3; H, 6.1; N, 6.9;
S, 15.8%; 666.1977. [α]D Ϫ24.1 (c = 1, CHCl3). υmax(KBr, cmϪ1)
3334 (s, NHTs), 3254 (s, NHCO), 3080 (w, C6H4), 2960 (s, CH),
2920 (s, CH), 2810 (m, CH), 1649 (s, C᎐O), 1350 (s, SO NH),
1180 (s, SO2NH); δH (400 MHz, CDCl3) 0.82 (d, J 6.8, 3H,
–CH3), 0.90 (d, J 6.8, 3H, –CH3), 2.1 (m, 1H, CH(CH3)2),
2.26 (s, 3H, –C6H4–CH3), 2.37 (s, 3H, –C6H4–CH3), 2.47 (s,
3H, –C6H4–CH3), 3.01 (m, 2H, CH2N), 3.14 (m, 2H, CH2N),
3.28 (m, 2H, CH2NTs), 3.51 (d, J 4.7, 1H, CHNTs), 4.19
(m, 2H, CH2OTs), 5.32 (br, 1H, CONH), 7.25 (d, J 8.0,
2H, –C6H4–CH3), 7.32 (d, J 8.0, 2H, –C6H4–CH3), 7.38 (d,
J 8.3, 2H, –C6H4–CH3), 7.64 (d, J 8.3, 2H, –C6H4–CH3), 7.75
(d, J 8.3, 2H, –C6H4–CH3), 7.79 (d, J 8.3, 2H, –C6H4–CH3);
δC (100 MHz, CDCl3) 17.3, 19.3 (–CH3), 21.7 (3 × –C6H4–
CH3), 31.4 (CH(CH3)2), 38.8 (NCH2), 48.6 (TsNCH2), 49.5
(TsNCH2), 62.2 (TsNCH), 69.1 (TsOCH2), 127.4 (2× Ar–CH),
127.6 (2× Ar–CH), 128.1 (2 × Ar–CH), 129.2 (2 × Ar–CH),
130.2 (2 × Ar–CH), 132.4 (Ar–CH), 135.2 (Ar–CH), 137.0 (2×
Ar–C), 143.7 (2× Ar–C), 144.3 (Ar–C), 145.5 (Ar–C), 171.1
(2× Ar–CH), 130.2 (2× Ar–CH), 133.0 (Ar–C), 136.9 (Ar–C),
143.7 (Ar–C), 144.5 (Ar–C), 169.3 (C᎐O).
᎐
(2S )-2-Isopropyl-1,4,7-tris[(4-methylphenyl)sulfonyl]-1,4,7-
triazacyclononane 17. To a solution of 4-methyl-N((1S)-2-
methyl-1-{[[(4-methylphenyl)sulfonyl](2-{[(4-methylphenyl)-
sulfonyl]amino}ethyl)amino]methyl}propyl)benzenesulfon-
amide 16 (1.00 g, 1.63 mmol) in DMF (10 cm3) at 0 ЊC was
added a suspension of washed NaH (39 mg, 1.63 mmol) in
DMF (1 cm3) over 30 min. The suspension was allowed to come
to room temperature and stirred for a further 1 h. Ethylene
glycol ditosylate 9 (603 mg, 1.63 mmol) in DMF (1 cm3) was
added dropwise over 30 min to the solution. The temperature
was raised to 80 ЊC and the final equivalent of NaH (39 mg,
1.63 mmol) in DMF (1 cm3) was added by slow addition over
2 h. The solution was maintained at 80 ЊC overnight and at com-
pletion was quenched by the addition of water (10 cm3). The
DMF was removed under reduced pressure (12 mmHg) and the
residue was dissolved in EtOAc (15 cm3). The organic layer was
washed with water (×2, 20 cm3), dried (Na2SO4), filtered and
evaporated to give a brown solid. Purification by column
chromatography on silica (hexane–EtOAc–CH2Cl2 4 : 1 : 5)
afforded a colourless solid (815 mg, 1.28 mmol, 78%); mp
178–180 ЊC; Found: MHϩ 634.2079. C30H39O6S3N3 requires:
634.2089; [α]D Ϫ34.4 (c = 1, CHCl3). υmax (KBr, cmϪ1) 3034 (w,
C6H4), 2918 (m, CH), 2910 (m, CH), 2850 (w, CH), 1338 (s,
SO2NH), 1158 (s, SO2NH); δH (400 MHz, CDCl3) 0.68 (d, J 6.7,
3H, –CH3), 1.05 (d, J 6.7, 3H, –CH3), 1.25 (m, 1H, CH(CH3)2),
2.39 (s, 3H, –C6H4–CH3), 2.43 (s, 3H, –C6H4–CH3), 2.44 (s, 3H,
–C6H4–CH3), 3.07 (m, 4H, CH2NTs), 3.47 (m, 4H, CH2NTs),
3.80 (m, 2H, CH2NTs), 4.36 (m, 1H, CHNTs), 7.3 (m, 6H,
–C6H4–CH3), 7.58 (d, J 8.0, 2H, –C6H4–CH3), 7.70 (d, J 8.0,
2H, –C6H4–CH3), 7.83 (d, J 8.0, 2H, –C6H4–CH3); δC (100
MHz, CDCl3) 20.6 (–CH3), 21.72 (3× –C6H4–CH3), 21.7
(CH(CH3)2), 46.1 (TsNCH2), 47.8 (TsNCH2), 46.3 (TsNCH2),
51.3 (TsNCH2), 52.1 (TsNCH2), 53.9 (TsNCH2), 127.5
(2 × Ar–CH), 128.0 (4 × Ar–CH), 128.1 (2 × Ar–CH), 130.1
(2 × Ar–CH), 130.2 (2 × Ar–CH), 143.5 (2 × Ar–C), 144.0
(2 × Ar–C), 144.3 (2 × Ar–C).
᎐
2
(C᎐O).
᎐
4-Methyl-N-[(1S )-2-methyl-1-({4-[(4-methylphenyl)sulfonyl]-
1-piperazinyl}carbonyl)propyl]benzenesulfonamide 23. NaH
(18 mg, 0.75 mmol) in DMF (1 cm3) was added dropwise to a
solution of {2-[((2S)-3-methyl-2-{{(4-methylphenyl)sulfonyl]-
amino}butanoyl)amino]ethyl}[(4-methylphenyl)sulfonyl]amino}-
ethyl-4-methylbenzene sulfonate 22 (500 mg, 0.75 mmol)
in DMF (8 cm3) at 80 ЊC. The resulting solution was stirred at
80 ЊC overnight. During this period the colour of the solution
changed from colourless to brown and at completion the reac-
tion was quenched by addition of water (10 cm3). The DMF
was removed under reduced pressure (12 mmHg) and the resi-
due was dissolved in EtOAc (15 cm3). The organic layer was
washed with water (×2, 20 cm3), dried (Na2SO4), filtered and
evaporated to give a brown solid. Purification by column
chromatography on silica (hexane–EtOAc–CH2Cl2 3 : 2 : 5)
afforded a colourless solid (192 mg, 0.39 mmol, 52%); mp 184–
185 ЊC; Found: MHϩ 494.1751; C23H31O5S2N3 requires:
494.1783; [α]D ϩ99.8 (c = 1, CHCl3). υmax(KBr, cmϪ1) 3285 (m,
NHTs), 3064 (w, C6H4), 2980 (m, CH), 2950 (m, CH), 2840 (m,
X-Ray crystallographic study of (2S )-2-isopropyl-1,4,7-tris-
[(4-methylphenyl)sulfonyl]-1,4,7-triazacyclononane 17‡. Colour-
less crystals of 17 were grown from ethyl acetate solution.
Crystal data for 17, C30H39N3O6S3; Measurements were made at
150 K on a colourless fragment cut from a larger crystal using
a Rigaku AFC7S diffractometer. Hexagonal, space group P65,
a = b = 19.555(3), c = 15.475(4) Å, V = 5125.2(17) Å3, Z = 6,
Mo-Kα radiation, λ = 0.71069 Å, µ = 0.260 mmϪ1. Final refine-
ment to convergence on F 2 gave R = 0.0460 (5086 obs. data
only), Rw = 0.1292 (all 7639 unique data) and GOF = 1.024.
Refinement of a Flack parameter to 0.00(8) indicates that the
absolute structure is as shown.
(2S )-2-Isopropyl-1-[(4-methylphenyl)sulfonyl]-1,4,7-triaza-
cyclononane 25 and (2S )-2-isopropyl-1,4-bis[(4-methylphenyl)-
sulfonyl]-1,4,7-triazacyclononane 26. To a solution of HBr
(48%, 1.6 cm3) and glacial acetic acid (0.9 cm3) was added (2S)-
2-isopropyl-1,4,7-tris[(4-methylphenyl)sulfonyl]-1,4,7-triaza-
cyclononane 17 (0.20 g, 0.32 mmol) to give a suspension. The
reaction was heated to reflux upon which the suspension dissol-
ved. The reaction was continued for a 48 h period. On comple-
tion, the reaction was cooled and ether (15 cm3) was added
to the reaction. The precipitate that formed was removed by
filtration. The supernatant was washed with 2 M NaOH (×2,
15 cm3), dried (Na2SO4), filtered and evaporated to give a
brown solid. Purification by column chromatography on silica
CH), 1639 (s, C᎐O), 1335 (s, SO NH), 1170 (s, SO NH); δ (400
᎐
2
2
H
MHz, CDCl3) 0.79 (d, J 6.7, 3H, –CH3), 0.95 (d, J 6.7, 3H,
–CH3), 1.72 (m, 1H, CH(CH3)2), 2.25 (s, 3H, –C6H4–CH3), 2.46
(s, 3H, –C6H4–CH3), 2.52 (m, 2H, CH2N), 2.7 (m, 2H, CH2N),
3.31 (m, 2H, CH2NTs), 3.46 (m, 2H, CH2NTs), 3.83 (m, 1H,
CHNTs), 7.05 (d, J 8.0, 2H, –C6H4–CH3), 7.38 (d, J 8.0, 2H,
–C6H4–CH3), 7.58 (d, J 8.2, 2H, –C6H4–CH3), 7.64 (d, J 8.2,
2H, –C6H4–CH3), δC (100 MHz, CDCl3) 16.8, 19.8 (–CH3), 21.5
(–C6H4–CH3), 21.7 (–C6H4–CH3), 31.5 (CH(CH3)2), 41.5
(NCH2), 45.0 (NCH2), 45.3 (TsNCH2), 45.7 (2× TsNCH2),
57.7 (TsNCH), 127.5 (2× Ar–CH), 127.9 (2× Ar–CH), 129.5
‡ CCDC reference numbers 206761. See http://www.rsc.org/suppdata/
ob/b3/b302887a/ for crystallographic data in .cif or other electronic
format.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 3 5 7 – 2 3 6 3
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(hexane–EtOAc–CH2Cl2 2 : 3 : 5) afforded two fractions. The
more mobile 26 as an off white solid (72 mg, 0.15 mmol, 47%);
mp 104–106 ЊC; Found: MHϩ 480.2009; C23H34O4S2N3 requires
480.1991; υmax (KBr, cmϪ1) 3323 (s, NH), 3052 (w, C6H4), 2964
(m, CH), 2848 (m, CH), 1325 (s, SO2NH), 1162 (s, SO2NH);
δH (400 MHz, CDCl3) 0.83 (d, J 7.0, 6H, CH3), 2.15 (m, 1H,
((CH3)2CH ), 2.27 (m, 4H, CH2N), 2.44 (s, 3H, –C6H4–CH3),
2.52 (s, 3H, –C6H4–CH3), 2.90 (m, 2H, CH2NTs), 3.12 (m, 1H,
CHaHbNTs), 3.28 (m, 2H, CH2NTs), 3.46 (m, 1H, CHaHbNTs),
3.75 (m, 1H, CHNTs), 5.16 (br, 1H, NH ), 7.24 (d, J 8.2, 2H,
–C6H4–CH3), 7.41 (d, J 8.2, 2H, –C6H4–CH3), 7.75 (d, J 8.2,
2H, –C6H4–CH3), 7.85 (d, J 8.2, 2H, –C6H4–CH3); δC (100
MHz, CDCl3) 16.6 (–CH3), 18.2 (–CH3), 21.7 (C6H4–CH3),
21.8 (C6H4–CH3), 29.3 ((CH3)2CH), 45.9 (2× NCH2), 52.2
(TsNCH2), 55.1 (TsNCH2), 55.0 (TsNCH2), 56.1 (TsNCH),
127.3 (2× Ar–CH), 127.9 (2× Ar–CH), 129.7 (2× Ar–CH),
130.0 (2× Ar–CH), 132.6 (Ar–C), 137.5 (Ar–C), 143.5 (Ar–C),
144.2 (Ar–C).
acidified (pH 1) with conc. HCl (1 cm3) and the volatiles were
removed under reduced pressure. The aqueous solution was
extracted with dichloromethane (×2, 10 cm3). The aqueous
phase was made basic (pH 14) by addition of solid NaOH
(∼500 mg). The basic solution was extracted with dichloro-
methane (×4, 10 cm3), and the combined organic phases were
dried (Na2SO4), filtered and evaporated to give a light brown oil
(98 mg, 0.46 mmol, 72%); Found: MHϩ 214.2286; C12H27N3
requires 214.2283. [α]D ϩ12.3 (c = 1, CHCl3); υmax(CCl4, cmϪ1)
2950 (m, CH), 2870 (m, CH); δH (400 MHz, CDCl3) 0.84 (d,
J 6.9, 3H, –CH3), 0.86 (d, J 6.9, 3H, –CH3), 1.66 (m, 1H,
CH(CH3)2), 2.31 (m, 2H, NCH2), 2.34 (s, 3H, NCH3), 2.35 (s,
3H, NCH3), 2.38 (s, 3H, NCH3), 2.58 (m, 4H, NCH2), 2.60 (m,
2H, NCH2) 2.72 (m, 2H, NCH2), 3.09 (m, H, NCH ); δC (100
MHz, CDCl3) 20.8 (–CH3), 21.2 (–CH3), 30.2 (CH(CH3)2),
37.8 (NCH3), 46.7 (NCH3), 47.6 (NCH3), 56.1 (NCH2), 56.3
(NCH2), 57.2 (NCH2), 57.3 (NCH2), 57.4 (NCH2), 69.2
(NCH).
The more polar fraction gave yellow sticky solid 25 (29 mg,
0.09 mmol, 28%); mp 161–163 ЊC; Found: MHϩ 326.1923;
C16H28O2SN3 requires 326.1902. υmax(KBr, cmϪ1) 3356 (w, NH),
3068 (w, C6H4), 2958 (m, CH), 2872 (m, CH), 1326 (s, SO2NH),
1157 (s, SO2NH); δH (400 MHz, CDCl3) 0.86 (d, J 6.0, 3H,
CH3), 0.90 (d, J 6.0, 3H, CH3), 2.08 (m, 1H, ((CH3)2CH ), 2.12
(m, 4H, CH2N), 2.14 (m, 1H, CHaHbNTs), 2.27 (m, 1H, CHaHb-
NTs), 2.40 (s, 3H, –C6H4–CH3), 2.60 (m, 2H, CH2N), 2.79 (m,
2H, CH2NTs), 3.05 (m, 1H, CHNTs), 7.24 (d, J 8.2, 2H, –C6H4–
CH3), 7.41 (d, J 8.2, 2H, –C6H4–CH3), 7.31 (d, J 8.1, 2H,
–C6H4–CH3), 7.74 (d, J 8.1, 2H, –C6H4–CH3); δC (100 MHz,
CDCl3) 16.6 (CH3), 18.6 (CH3), 21.9 (–C6H4–CH3), 29.4
(NCH), 46.1 (NCH2), 46.5 (NCH2), 54.3 (NCH2), 55.1
(TsNCH2), 56.9 (TsNCH), 127.6 (2 × Ar–CH), 129.8 (2 ×
Ar–CH), 137.6 (Ar–C), 143.6 (Ar–C).
(2S )-2-Isopropyl-1,4,7-trimethyl-1,4,7-triazacyclononane tri-
hydrobromide. To a solution of (2S)-2-isopropyl-1,4,7-tri-
methyl-1,4,7-triazacyclononane 5 (98 mg, 0.46 mmol) in EtOH
(2 cm3) was added HBr (48%, 0.15 cm3) at room temperature
with rapid stirring. To this solution was added ether (10 cm3)
and the colourless precipitate that formed was removed by
filtration and dried under reduced pressure to give the hydro-
bromide salt (121 mg, 0.37 mmol, 80%); mp 118–120 ЊC;
Found: MHϩ 214.2273; C12H27N3 requires 214.2283; [α]D ϩ83.2
(c = 1, MeOH). υmax(KBr, cmϪ1) 3407 (s, NH, br), 2968 (m, CH),
2651 (m, CH); δH (400 MHz, D2O) 1.51 (d, J 6.7, 3H, –CH3),
1.66 (d, J 6.7, 3H, –CH3), 2.65 (m, 1H, CH(CH3)2), 3.26 (s, 3H,
NϩCH3), 3.64 (m, 3H, NϩCH3), 3.66 (m, 3H, NϩCH3), 4.02 (m,
4H, NϩCH2), 4.11 (m, 2H, NϩCH2), 4.28 (m, 2H, NϩCH2), 4.34
(m, 2H, NϩCH2), 4.48 (m, 1H, NϩCH ); δC (100 MHz, D2O)
19.8 (–CH3), 20.0 (–CH3), 29.1 (CH(CH3)2), 42.8 (NϩCH3),
45.8 (NϩCH3), 46.3 (NϩCH3), 54.4 (2× NϩCH2), 65.2
(3× NϩCH2), 69.5 (NϩCH).
(2S )-2-Isopropyl-1,4,7-triazacyclononane trihydrochloride 27.
To a solution of (2S)-2-isopropyl-1,4,7-tris[(4-methylphenyl)-
sulfonyl]-1,4,7-triazacyclononane 17 (350 mg, 0.55 mmol) in
THF (25 cm3) and EtOH (1.40 cm3, 30 mmol) was condensed
dry NH3 (150 cm3) at Ϫ78 ЊC. To this solution was added
lithium metal (189 mg, 27 mmol) in small portions to give an
intense blue color. The reaction mixture was allowed to warm
to room temperature overnight. Water was added (10 cm3) and
the solution was acidified (pH 1) with conc HCl (1 cm3). The
aqueous solution was extracted with dichloromethane (×2, 10
cm3). The aqueous phase was made basic (pH 14) by addition
of solid NaOH (∼500 mg). The basic solution was extracted
with dichloromethane (×4, 10 cm3), EtOAc (×2, 10 cm3) and the
combined organic phases were dried (Na2SO4), filtered and
evaporated to give light yellow oil (72 mg, 0.42 mmol, 76%). To
a solution of this oil (72 mg, 0.42 mmol) in EtOH (2 cm3) was
added conc. HCl (0.12 cm3) at room temperature with rapid
stirring. To this solution was added ether (10 cm3) and the
colourless precipitate that formed was removed by filtration
and dried under reduced pressure to give the hydrochloride
salt (89 mg, 0.29 mmol, 69%); mp 142–144 ЊC; Found: MHϩ
172.1813. C9H21N3 requires 172.1811; [α]D ϩ29.7 (c = 1,
MeOH). υmax(KBr, cmϪ1) 3440 (w, NH), 2957 (s, CH), 2762 (s,
CH); δH (400 MHz, D2O) 1.00 (d, J 6.8, 3H, –CH3), 1.08 (d,
J 6.8, 3H, –CH3), 1.94 (m, 2H, CH(CH3)2), 3.10 (m, 2H,
NHCH2), 3.41 (m, 6H, NHCH2), 3.63 (m, 1H, NHCH ); δC (100
MHz, D2O) 18.2 (–CH3), 19.0 (–CH3), 30.9 (CH(CH3)2), 41.5
(NHCH2), 41.8 (NHCH2), 43.1 (NHCH2), 43.1 (NHCH2), 46.1
(NHCH), 59.1 (NHCH).
Acknowledgements
We thank the EPSRC for funding through a ROPA award (to
G. A., grant GR/M52477) and studentship (to G.S.). We are
grateful to Professor A. Berkessel (Universität zu Köln) for
the unpublished full experimental procedure for their in situ
epoxidation protocol. We also thank Stuart Cook and Dr Terry
Lowdon (Hickson & Welch) for valuable discussions. We are
indebted to the EPSRC National Mass Spectrometry Service,
Swansea for running some mass spectra.
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O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 3 5 7 – 2 3 6 3
2362

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