Bifurcated, modular syntheses of chiral annulet triazacyclononanes.

Article abstract of DOI:10.1039/b310492c

Three chiral 2,6-disubstituted tri-N-methyl azamacrocycles have been prepared by modular methods. These macrocycles were accessed from three chiral 1,4,7-triazaheptanes intermediates that were prepared by two independent routes. The first of these routes

Full text of DOI:10.1039/b310492c

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Bifurcated, modular syntheses of chiral annulet triazacyclononanes
Gilles Argouarch,† Graham Stones, Colin L. Gibson,* Alan R. Kennedy and
David C. Sherrington
Department of Pure & Applied Chemistry, University of Strathclyde, 295 Cathedral Street,
Glasgow, UK G1 1XL. E-mail: c.l.gibson@strath.ac.uk
Received 1st September 2003, Accepted 13th October 2003
First published as an Advance Article on the web 6th November 2003
Three chiral 2,6-disubstituted tri-N-methyl azamacrocycles have been prepared by modular methods. These
macrocycles were accessed from three chiral 1,4,7-triazaheptanes intermediates that were prepared by two
independent routes. The first of these routes involved the benzylamine opening of chiral tosyl aziridines followed
by debenzylation but was problematic on solubility grounds. A second, more effective, route was developed which
avoided debenzylation by using ammonia in the nucleophilic opening of chiral tosyl aziridines.
Introduction
The continued interest in the synthesis of 1,4,7-triazacyclo-
nonane derivatives is maintained by the use of transition metal
complexes of these azamacrocycles to catalyse a variety of
processes. Transition metal complexes of 1,4,7-triazacyclo-
nonane derivatives have been investigated as biomimetics of
manganese catalase,1,2 Photosystem II,1,3 and hemocyanin.4
These metal complexes have also been used to catalyse organic
transformations such as the hydrolytic cleavage of RNA,5
DNA6 and peptides7 as well as the oxidation of sulfides,8
alcohols,9 alkanes10 and alkenes.11 In particular, the epoxid-
ation of alkenes has generated considerable interest and
stereoselective12 as well as enantioselective processes have been
described using chiral analogues of 1,4,7-triazacyclononane by
Beller et al.,13 Bolm et al.14,15 and ourselves.16
Despite the great interest in triazacyclononanes and their
synthesis, the preparation of chiral variants where the stereo-
chemistry is associated with the carbon backbone are less
common. Thus, chiral triazacyclononanes with one,17 two
(C-2,3)18 and three15 stereocentres on the macrocyclic ring,
have been prepared. Recently, ourselves (1a–c),16 Kim et al.
(1e)19 and Watkinson and co-workers (1b,d)20 have reported the
preparation of 2,6-disubstituted triazacyclononanes 1a–e.
These three independent reports utilised the Richman–Atkins
cyclisation of chiral 4-substituted 1,7-ditosyl-1,4,7-triaza-
heptanes 2a–e with ethylene glycol ditosylate 3 in the key
macrocyclisation step (Scheme 1). The key intermediate 4-
substituted 1,7-ditosyl-1,4,7-triazaheptanes 2a–e were prepared
from 1,7-ditosyl-1,4,7-triazaheptanes 2f–h which, in turn, were
accessed by nitrogen based nucleophilic opening of the chiral
tosyl aziridines e.g. 4 (Scheme 2). While Kim et al. used azide
opening of chiral tosyl aziridine 4, we and Watkinson and
co-workers opted to use benzylamine. In our hands, the
subsequent debenzylation of 2i–k and analogues was problem-
atic because of solubility problems. Herein, we report full
experimental details of our syntheses of azamacrocycles 1a–c
and their detosylation and N-methylation from our previous
communication.16 In addition, an alternative route of choice,
avoiding the debenzylation problems involving the opening of
chiral tosyl aziridines with ammonia is described. In some
cases, this alternative route leads to improved overall yields in
comparison with the use of benzylamine aziridine opening and
subsequent debenzylation.
Scheme 1 Reagents and conditions: CsCO3, DMF, 80 ЊC or NaH,
DMF.
Scheme 2 Reagents and conditions: i, NaN3; ii, H2, Pd–C, MeOH;
iii, 4; iv, 0.5 equiv. BnNH2, MeOH; v, H2, Pd(OH)2, MeOH.
Results and discussion
The synthesis of chiral azamacrocycles 1a–c began with the
conversion of alaninol 5a and valinol 5b into the known tosyl
aziridines 621 and 422 via tosylation and cyclisation through
a modification of the method of Moberg and co-workers
(Scheme 3).23 It had been shown that sulfonamide aziridines
could be opened with primary amines to give bis(adducts)
under the appropriate conditions.22a,24 This nucleophilic attack
generally occurs at the least substituted carbon. Thus, reaction
of tosyl aziridines 6 and 4 with 0.5 of an equivalent of benzyl-
amine in methanol afforded the bis(adducts) 2i and 2j in 86 and
67%, respectively.25,26 Alternatively, treatment of tosyl aziridine
6 with excess benzylamine in methanol at room temperature
afforded the mono adduct 7 in 85% yield. Concomitantly with
our communication,16 Watkinson and co-workers25 reported a
similar approach to the mono adduct 7 (56%) and analogues
† Present address: UMR CNRS 6509, Organometalliques et Catalyse,
University de Rennes, Campus de Beaulieu, 35042 Rennes, France.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 4 0 8 – 4 4 1 7
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
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opened tosyl aziridines.22a,27 Accordingly, treatment of tosyl
aziridine 6 with ammonia saturated methanol at 0 ЊC afforded
the mono adduct 9a in 95% yield (Scheme 4). Subsequent reac-
tion of 9a with tosyl aziridine 6 in toluene at reflux provided an
alternative route to 2f in 61% yield (51.1% overall from 5a).
Analogously, ammonia opening of tosyl aziridine 4 afforded
the mono adduct 9b in 89% which then reacted with tosyl
aziridine 4 to provide 2g in 56% (44.9% overall from 5b).22a,27
The non-symmetric amine 2h was accessed by reaction of mono
adduct 9a with tosyl aziridine 4 in 88% yield (73.7% overall
from 5a). These alternative routes to the amines 2f–h via the
mono adducts 9 (Scheme 4) were the methods of choice as there
were no solubility issues making the syntheses much easier.
Moreover, the route using ammonia opening of aziridine was
significantly more efficient than the route using benzylamine
(Scheme 3) in the case of 2h (70.3 vs. 13.5 % overall from 5a).
Scheme 4 Reagents and conditions: i, NH3, MeOH, 0 ЊC; ii, 4 or 6,
C6H4CH3, ∆.
With effective routes to the secondary amine tosamides 2f–h
in hand we turned our attention to facilitating macrocyclisation
which required suppressing the nucleophilicity of the central
amine function. In Richman–Atkins macrocyclisations,28,29
the amino functionalities are commonly protected as their
sulfonamide derivatives. Accordingly, treatment of amines 2f–h
with tosyl chloride in pyridine furnished the fully protected
tristosamides 1a–c (Scheme 5).
Richman–Atkins cyclisations to form aza crowns generally
involve the reaction of the dianion of a bissulfonamide with a
bistosylate ester in anhydrous DMF. The sodium dianion of the
bissulfonamide is commonly prepared prior to cyclisation with
sodium hydride in DMF or sodium ethoxide in ethanol.28,29
Alternatively, the caesium salt can be generated in situ using
caesium carbonate in DMF. We have generally found that the
use of sodium hydride in DMF is a more effective procedure
to carry out the macrocyclisations to afford C-substituted 1,4,7-
triazacyclononane tristosamides.30 Therefore, macrocyclisation
of the tristosamides 2a–c with sodium hydride in DMF
with ethylene glycol ditosylate 3 smoothly afforded the triaza-
cyclononane tristosamides 1a–c in over 70% yield.
The subsequent steps from tristosamides 1a–c required the
removal of the N-tosyl protecting groups and subsequent
N-alkylation. N-Tosyl groups have been removed from C-alkyl
substituted triazacyclononanes by three popular deprotection
procedures. Thus, Mason et al. and Weatherburn et al. have
used hydrobromic acid in glacial acetic acid at reflux to depro-
tect a C-methyl substituted triazacyclononane tristosamide.17a,d
However, we have found that this method gives incomplete
deprotection of C-alkyl triazacyclononane tristosamides,
forming instead a mixture of mono and bistosamide macro-
cycles.30 Alternatively, Parker and co-workers have removed the
tosyl protecting groups in a 2-(4-benzamidobutyl)-1,4,7-triaza-
cyclononane tristosamide by lithium in ammonia or by heating
in concentrated sulfuric acid.17e We have found that the lithium
in ammonia reductive deprotection to be very efficient in the
case of C-alkyl macrocycles.30 Accordingly, lithium in ammonia
detosylation of tosamides 1a–c provided the free amines 10a–c.
In the case of 10b and 10c the process was reasonably efficient
with the formation of products in 66 and 87% yield, respect-
Scheme 3 Reagents and conditions: i, TsCl, pyr; ii, NaH, THF; iii, 0.5
equiv. BnNH2, MeOH; iv, excess BnNH2, MeOH; v, 6 MeOH; vi, H2,
Pd(OH)2, MeOH or H2, Pd–C, AcOH; vii, H2, Pd(OH)2, MeOH–
CH2Cl2; viii, 3 M HCl, MeOH.
using acetonitrile at reflux. The subsequent reaction of mono
adducts such as 7 with alternative tosyl aziridines was an
attractive prospect because it might allow a divergent approach
to C1 symmetric chiral precursors. Accordingly, reaction of
mono adduct 7 with tosyl aziridine 4 in methanol afforded the
non-symmetrical bis(adduct) 2k in 45% yield.
Ourselves and Watkinson and co-workers have shown that
2i16 and 2j,20 respectively, are not appropriate substrates for
Richman–Atkins cyclisation because of nucleophilic inter-
ference by the benzyl protected amine. Accordingly, hydro-
genolytic removal of the benzyl group from 2i and 2j using
palladium hydroxide in methanol afforded the free amines 2f
and 2g in 86 (65.2% overall from 5a) and 71% yield (42.9%
overall from 5b), respectively. However, solubility problems
were experienced in these debenzylation procedures. Indeed, in
larger scale (ca. 1 g) debenzylation of 2g, solubility problems
were acute and required the addition of dichloromethane as
co-solvent which afforded the novel imidazolidine 8 in 78%
yield. Subsequent, acid hydrolysis of imidazolidine 8 afforded
an alternative synthesis of amine 2g (43.3% overall yield from
5b). These solubility issues were severe for the debenzylation of
2k and this deprotection was unsuccessful using palladium
hydroxide in methanol. This process was achieved using
palladium on charcoal with acetic acid as the solvent which
afforded the non symmetric amine 2h in 40% yield (13.5%
overall from 5a).
The above problems with solubility in the debenzylations of
benzylamines 2i–k forced us to re-evaluate routes to amines
2f–h. The use of ammonia to open tosyl aziridines can yield
mixtures of mono, bis and tris(adducts).23,26 However, Taylor
and co-workers have developed a two step process for the
selective preparation of bis(adducts) via the mono ammonia
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 4 0 8 – 4 4 1 7
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Fig. 1 Chem3D representation of the molecular structure of 11e with
only the key hydrogen atoms included for clarity.
Unexpectedly, this material was the dihydrobromide salt 11e
rather than the anticipated trihydrobromide salt. The dihydro-
bromide salt 11e results from protonation of the less sterically
encumbered N1 and N4 while N7, adjacent to the isopropyl
group remains as the free base.
Conclusions
Two independent and modular routes have been developed for
the syntheses of chiral 1,4,7-triazaheptanes as intermediates
in the preparation of chiral 1,4,7-triazamacrocycles. The first
modular route to 1,4,7-triazaheptanes involved the benzyl-
amine nucleophilic opening of chiral tosyl aziridines followed
by hydrogenolytic debenzylation. Solubility problems in the
debenzylation step were overcome by developing an alternate
route that avoided the need for this deprotection step. These
more amenable routes involved the nucleophilic opening of
chiral tosyl aziridines with ammonia, which led, in some cases,
to increased efficiencies. The highly modular nature of these
routes readily allowed the preparation of C2 symmetric and
dissymmetric 1,4,7-triazaheptanes. These key intermediates
were then used in the preparation of three chiral 2,6-disubsti-
tuted 1,4,7-trimethyl triazamacrocycles in 8–9 steps overall and
12.77–29.9% overall yields.
Scheme 5 Reagents and conditions: i, TsCl, Pyr; ii, 3, NaH, DMF,
80 ЊC; iii, Li, NH3, EtOH; iv, CH2O, HCO2H, ∆.
ively. The deprotection of the dimethyl substituted macrocycle
1a was achieved in a disappointing yield of 13% and was
a function of the water solubility of triamine 10a. The C2
symmetric macrocycles 10a and 10b were additionally charac-
terised as their respective hydrochloride salts 10d and 10e while
the non-symmetric macrocycle 1c was also characterised as the
hydrobromide salt 10f. The use of sulfuric acid deprotection
was investigated in the case of deprotection of the non-
symmetric macrocycle 1c which afforded a lower yield of the
free amine 10c (63%).
The final step in our syntheses required the N-methylation of
macrocycles 10a–c. After a brief model study of the methyl-
ation of 1,4,7-triazacyclononane using butyllithium and methyl
iodide31 (45%) or Eschweiler–Clarke (82%)32 it was decided
to use the later N-methylation procedure on the grounds of
efficiency and purity of the product. Furthermore, the use of
Eschweiler–Clarke N-methylation proved to be particularly
advantageous in the case of dimethyl macrocycle 10a. In this
case simply taking the crude aqueous extract after lithium in
ammonia detosylation of 1a and subjecting it to these N-methy-
lation conditions afforded the dimethyl macrocycle 11a in 44%
over two steps. As water solubility was not an issue with 10b
and 10c, Eschweiler–Clarke N-methylation of the isolated
macrocycles gave the requisite novel macrocycles 11b and 11c in
66 and 90% yields, respectively. The N-methyl macrocycles 11a
and 11c were additionally characterised as their salts 11d and
11e, respectively. The crystalline nature of hydrobromide salt
11e allowed an X-ray analysis to be carried out and allowed
both the stereochemistry and the absolute structure to be
confirmed unequivocally by single crystal diffraction (Fig. 1).
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 . The [α]D values are given in 10Ϫ1 deg cm2 gϪ1
1
and the concentrations are given in g/100 cm3. H-nmr spectra
were recorded on Bruker WM-250, Jeol 270, or Bruker
AMX-400 spectrometers 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 doublets; 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, KBr discs or as a 1–2% solution (CCl4).
Mass spectra were recorded on a Jeol JMS AX505 spectrometer
at Strathclyde or at the EPSRC National Mass Spectrometry
service, Swansea. Microanalyses were performed by the
microanalytical service at Strathclyde.
General methods
Anhydrous reactions were carried out under an atmosphere of
nitrogen in oven dried glassware (140 ЊC). Anhydrous solvents
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 4 0 8 – 4 4 1 7
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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.33 using silica gel (230–400 mesh).
an analogous fashion to 2i using (2S)-2-isopropyl-1-[(4-
methylphenyl)sulfonyl]aziridine 4 (2.2 g, 14.2 mmol) and
benzylamine (492 mg, 4.60 mmol). Purification by column
chromatography on silica (hexane : ethyl acetate 2 : 1) followed
by recrystallisation (hexane : dichloromethane 2 : 1) afforded a
colourless solid (1.8 g, 3.08 mmol, 67%); mp 123–125 ЊC (lit.25
135–136 ЊC); Found MHϩ m/z 586.2773; Calculated for
C31H43O4S2N3 m/z 586.2773; [α]D Ϫ12.2 (c = 1.00, CHCl3) (lit.25
Ϫ37.6 (c = 0.5, CHCl3)); νmax (KBr, cmϪ1) 3266 (s, NHTs), 3034
(w, C6H4), 2966 (s, CH), 2927 (m, CH), 2876 (w, CH), 1325
(s, SO2NH), 1160 (s, SO2NH); δH (400 MHz, CDCl3) 0.65 (d,
J 8.2, 6H, –CH3), 0.67 (d, J 7.0, 6H, –CH3), 1.89 (m, 2H,
CH(CH3)2), 2.30 (d, J 5.7, 2H, CH2N), 2.34 (d, J 5.7, 2H,
CH2N), 2.41 (s, 6H, –C6H4–CH3) 2.48 (m, 2H, NCH2), 3.47 (m,
2H, TsNHCH ), 7.23 (m, 5H, –C6H5) 7.28 (m, 4H, –C6H4–CH3),
7.81 (d, J 8.3, 4H, –C6H4–CH3); δC (100 MHz, CDCl3) 17.5
(–CH3), 18.0 (–CH3), 21.7 (2 × –C6H4–CH3), 29.9 (CH(CH3)2),
54.3 (2 × NCH2), 56.2 (NCH2), 58.6 (2 × TsNCH), 127.1
(2 × Ar–CH), 127.4 (2 × Ar–CH), 128.5 (2 × Ar–CH), 129.6
(2 × Ar–CH), 129.7 (2 × Ar–CH), 137.9 (2 × Ar–C), 139.0
(2 × Ar–C), 143.1 (Ar–C).
Experimental procedures
(2S )-2-Methyl-1-[(4-methylphenyl)sulfonyl]aziridine 6. Using
(S)-alaninol 5a and the method of Moberg and co-workers,23
the title compound was obtained as an off white solid (4.4 g,
20.8 mmol, 88%); mp 60–62 ЊC (lit.21 mp 58–59 ЊC); Found C,
56.87; H, 6.1; N, 6.61; S, 15.48%; MHϩ m/z 212.0736; Calcu-
lated for C10H14NO2: C, 56.85; H, 6.2; N, 6.63; S, 15.17%; m/z
212.0659; [α]D ϩ30.3 (c = 1.02, CHCl3) (lit.21 ϩ29.6 (c = 1.02,
CHCl3)); νmax (KBr, cmϪ1) 3049 (w, C6H4), 2962 (s, CH), 2928
(m, CH), 2873 (w, CH), 1319 (s, SO2NH), 1159 (s, SO2NH);
δH (400 MHz, CDCl3) 1.26 (d, J 5.6, 3H, –CH3), 2.02 (d, J 5.8,
1H, TsNCH2), 2.45 (s, 3H, –C6H4–CH3), 2.62 (d, J 7.0, 1H,
TsNCH2), 2.82 (m, 1H, TsNCH ), 7.34 (d, J 8.0, 2H, –C6H4–
CH3), 7.82 (d, J 8.0, 2H, –C6H4–CH3); δC (100 MHz, CDCl3)
17.0 (–CH3), 21.8 (–C6H4–CH3), 35.0 (TsNCH2), 36.1
(TsNCH), 128.0 (Ar–CH), 129.9 (Ar–CH), 136.6 (Ar–C),
144.6 (Ar–C).
N-[(1S )-2-(Benzylamino)-1-methylethyl]-4-methylbenzene-
sulfonamide 7. To a solution of (2S)-2-methyl-1-[(4-methyl-
phenyl)sulfonyl]aziridine 6 (422 mg, 2 mmol) in methanol (10
cm3) was added benzylamine (1 g, 9.34 mmol). The solution was
stirred for 2 days at room temperature, upon completion of this
period the solvent was evaporated. Purification by column
chromatography on silica (hexane : EtOAc from 1 : 4) afforded
a colourless oil (542 mg, 1.70 mmol, 85%); Found C, 63.72; H,
6.91; N, 9.2; S, 10.18%; MHϩ m/z 319.1482; Calculated for
C17H22O2SN2 C, 64.12; H, 6.69; N, 8.8; S, 10.07%; m/z 319.1480;
[α]D ϩ2.6 (c = 0.70, CHCl3) (lit.25 Ϫ4.8 (c = 0.5, CHCl3)); νmax
(CCl4, cmϪ1) 3710–3460 (bw, NH), 3460–3130 (s, SO2NH),
3080, 3060, 3030 (all s, ArH), 2975, 2930, 2870, 2850 (all s, CH),
1600, 1490, 1450 (all s, Ar), 1320 (s, SO2N), 1150 (s, SO2N),
1095 (s), 820 (s), 740 (s), 700 (s); δH (250 MHz, CDCl3) 1.06 (d,
J 6.5, 3H, –CH3), 2.36 (s, 3H, –C6H4–CH3), 2.38–2.57 (m, 2H,
NCH2), 3.23 (m, 1H, TsNHCH ), 3.53 (s, 2H, NCH2), 7.15–7.32
(m, 7H, ArH ), 7.70 (d, J 8, 2H, –C6H4–CH3); δC (100 MHz,
CDCl3) 20.0 (–CH3), 21.9 (–C6H4–CH3), 49.2 (NCH2), 53.6
(NCH2), 54.1 (2 × TsNCH), 127.6 (Ar–CH), 127.7 (Ar–CH),
128.4 (Ar–CH), 128.9 (Ar–CH), 130.1 (Ar–CH), 138.0
(Ar–C), 140.2 (Ar–C), 143.7 (Ar–C).
(2S )-2-Isopropyl-1-[(4-methylphenyl)sulfonyl]aziridine
4.
Analogously, (S)-valinol 5b afforded the title compound as an
off white solid (3.3 g, 13.6 mmol, 90%); mp 85–87 ЊC (lit.27
75–77 ЊC); Found C, 60.5; H, 7.2; N, 5.8; S, 13.4%; MHϩ m/z
240.1051; Calculated for C12H27O2SN: C, 60.2; H, 7.2; N, 5.9; S,
13.4%; m/z 240.1058; [α]D ϩ15.9 (c = 0.95, CHCl3) (lit.27 ϩ12.2
(c = 1.2, CHCl3)); νmax (KBr, cmϪ1) 3049 (w, C6H4), 2962 (s, CH),
2928 (m, CH), 2873 (w, CH), 1319 (s, SO2NH), 1159 (s,
SO2NH); δH (400 MHz, CDCl3) 0.80 (d, J 6.7, 3H, –CH3), 0.90
(d, J 6.7, 3H, –CH3), 1.42 (m, 1H, CH(CH3)2), 2.10 (d, J 4.6,
1H, TsNCH2), 2.45 (s, 3H, –C6H4–CH3), 2.52 (m, 1H, TsNCH ),
2.61 (d, J 8.0, 1H, TsNCH2), 7.34 (d, J 8.0, 2H, –C6H4–CH3);
7.83 (d, J 8.0, 2H, –C6H4–CH3); δC (100 MHz, CDCl3) 19.2
(–CH3), 19.7 (–CH3), 21.8 (–C6H4–CH3), 30.3 (CH(CH3)2),
32.9 (TsNCH2), 46.4 (TsNCH2); 128.3 (Ar–CH), 129.7
(Ar–CH), 135.4 (Ar–C), 144.6 (Ar–C).
N-{(1S )-2-[Benzyl((2S )-{(4-methylphenyl)sulfonyl]amino}-
propyl)amino]-1-methylethyl}-4-methylbenzenesulfonamide 2i.
To a solution of (2S)-2-methyl-1-[(4-methylphenyl)sulfonyl]-
aziridine 6 (1.8 g, 8.53 mmol) in methanol (20 cm3) was added
benzylamine (456 mg, 4.26 mmol). The solution was stirred for
4 days at room temperature, upon completion of this period the
solvent was evaporated to give a crude brown solid. Purification
by column chromatography on silica (hexane : EtOAc from 2 : 1
to 1 : 1) afforded a colourless solid (1.94 g, 3.67 mmol, 86%);
mp 129 ЊC (lit. for hemi hydrate25 91–92 ЊC). Found C, 60.84;
H, 6.46; N, 7.74%; MHϩ m/z 530.2153; Calculated for
C27H35O4S2N3: C, 61.22; H, 6.66; N, 7.94%; m/z 530.2147; [α]D
Ϫ13.8 (c = 1.00, CHCl3) (lit. for hemi hydrate25 Ϫ43.2 (c = 0.5,
CHCl3)); νmax (KBr, cmϪ1) 3450–3100 (bm, NHTs), 3064 (w,
ArH), 3030 (w, ArH), 2970, 2930, 2820 (all w, CH), 1332 (s,
NSO2), 1162 (s, NSO2), 1094 (s), 815 (m, ArH); δH (250 MHz,
CDCl3) 0.91 (d, J 6.3, 6H, –CH3), 2.15–2.41 (m, 4H, NCH2),
2.33 (s, 6H, –C6H4–CH3), 3.08 (d, J 13.5, 1H, NCHaHb), 3.36
(m, 2H, NCH ), 3.47 (d, J 13.5, 1H, NCHaHb), 5.24 (bs, 2H,
SO2NH ), 7.02–7.05 (m, 2H, ArH ), 7.19–7.31 (m, 7H, ArH ),
7.76 (d, J 8.1, 4H, –C6H4–CH3); δC (100 MHz, CDCl3) 19.8
(–CH3), 21.6 (–C6H4CH3), 47.1 (NCH2), 57.9 (NCH2), 59.6
(TsNCH), 127.2, 127.4, 128.5, 129.3, 129.7 (all Ar–CH), 137.5,
138.1, 143.3 (all Ar–C).
N-{(1S )-2-[Benzyl((2S )-3-methyl-2-{[(4-methylphenyl)-
sulfonyl]amino}butyl)amino]-1-methylethyl}-4-methylbenzene-
sulfonamide 2k. To a solution of (2S)-2-isopropyl-1-[(4-
methylphenyl)sulfonyl]aziridine 4 (433 mg, 1.81 mmol) in
methanol (10 cm3) was added N-[(1S)-2-(benzylamino)-1-
methylethyl]-4-methylbenzenesulfonamide 7 (576 mg, 1.81
mmol). The solution was stirred for 4 days at RT and the
solvent was evaporated. The crude product was purified by
column chromatography on silica (hexane : EtOAc 3 : 1) to give
the unreacted aziridine 4 in a first fraction (206 mg, 0.86 mmol,
48%) and in a second fraction the title compound as a colour-
less solid (452 mg, 0.81 mmol, 45%); mp 143–145 ЊC; Found C,
62.54; H, 7.16; N, 7.39%; MHϩ m/z 558.2444; C29H39N3O4S2
requires C, 62.45; H, 7.05; N, 7.54%; m/z 558.2460; [α]D = Ϫ12.8
(c = 0.50, CHCl3); νmax (KBr, cmϪ1) 3270 (s, SO2NH), 3060 and
3030 (w, ArH), 2960 and 2930 (m, CH), 1600 (w, Ar), 1445 (s),
1320 (s, SO2N), 1160 (s, SO2N), 810 (m, ArH), 750 (m, ArH),
700 (m, ArH); δH (400 MHz, CDCl3) 0.64 (d, J 6.8, 3H, –CH3),
0.67 (d, J 6.9, 3H, –CH3), 1.04 (d, J 6.3, 3H, –CH3), 1.81 (m,
1H, CH(CH3)2), 2.27–2.32 (m, 2H, CH2N), 2.39 (s, 3H, –C6H4–
CH3), 2.42 (s, 3H, –C6H4–CH3), 2.43–2.49 (m, 2H, CH2N), 3.19
(d, J 13.3, 1H, CHaHbPh), 3.43 (m, 1H, TsNHCH ), 3.53 (m,
1H, TsNHCH ), 3.68 (d, J 13.3, 1H, CHaHbPh), 4.85 (bs, 1H,
TsNHCH), 5.48 (bs, 1H, TsNHCH), 7.16–7.30 (m, 9H, ArH ),
7.80–7.85 (m, 4H, ArH ); δC (100 MHz, CDCl3) 17.5 (–CH3),
((1S )-1-{[Benzyl((2S )-3-methyl-2-{[(4-methylphenyl)sulf-
onyl]amino}butyl)amino]methyl}-2-methylpropyl)-4-methyl-
benzenesulfonamide 2j. The title compound was obtained in
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 4 0 8 – 4 4 1 7
4411

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18.0 (–CH3), 20.0 (–CH3), 21.6 (–C6H4–CH3), 21.7 (–C6H4–
CH3), 30.1 (CH(CH3)2), 47.0 (NCH2), 54.6 (NCH2), 56.2
(NCH2), 58.3 (TsNCH), 59.7 (TsNCH), 127.1 (Ar–CH), 127.2
(Ar–CH), 127.4 (Ar–CH), 128.5 (Ar–CH), 129.5 (Ar–CH),
129.6 (Ar–CH), 129.7 (Ar–CH), 137.6 (Ar–C), 138.4 (Ar–C),
138.8 (Ar–C), 143.2 (Ar–C), 143.3 (Ar–C).
CH3); δC (100 MHz, CDCl3) 19.4 (–CH3), 21.6 (–CH3), 49.1
(NCH2), 54.1 (NCH), 127.2 (Ar–CH), 129.9 (Ar–CH), 137.9
(Ar–C), 143.4 (Ar–C).
Method (b), via ring opening of (2S)-2-methyl-1-[(4-
methylphenyl)sulfonyl]aziridine 6 with [(1S)-2-amino-1-methyl-
ethyl]-4-methylbenzenesulfonamide 9a. A solution of [(1S)-2-
amino-1-methylethyl]-4-methylbenzenesulfonamide 9a (1.5 g,
6.6 mmol) in anhydrous toluene (25 cm3) was heated to reflux
under an inert atmosphere. To this solution was added (2S)-2-
methyl-1-[(4-methylphenyl)sulfonyl]aziridine 6 (1.4 g, 6.6 mmol)
dropwise over a 2 h period. The reaction mixture was heated at
reflux temperature for an additional 48 h. On completion of
this period the toluene was removed under reduced pressure
and the residue was dissolved in dichloromethane (10 cm3). The
dichloromethane extract was washed with 3 M HCl (×2,
15 cm3) dried (Na2SO4), filtered and evaporated to give a light
brown solid. Purification by column chromatography on silica
(hexane : EtOAc : CH2Cl2 2 : 3 : 5) afforded a colourless solid
(1.9 g, 4.0 mmol, 60%) with identical spectroscopic data to that
recorded above.
[(1S )-2-Amino-1-methylethyl]-4-methylbenzenesulfonamide
9a. To a saturated solution of ammonia in methanol (300 cm3)
at 0 ЊC was added, dropwise, with stirring a solution of (2S)-2-
methyl-1-[(4-methylphenyl)sulfonyl]aziridine 6 (4.8 g, 22.77
mmol) in methanol (100 cm3) over a period of 2 h. Ammonia
was bubbled continuously through the reaction mixture during
addition and for 30 min after it was completed. The solution
flask was stoppered and allowed to stand for 24 h. The volatiles
were evaporated under reduced pressure to afford the title com-
pound as a colourless solid (4.95 g, 21.69 mmol, 95%) (toluene);
mp 128–130 ЊC; Found C, 52.8; H, 7.38; N, 12.17; S, 14.36%;
MHϩ m/z 229.0994; C10H16N2O2S requires C, 52.61; H, 7.06; N,
12.27; S, 14.04%; m/z 229.1011; [α]D 14.9 (c = 1, CHCl3); νmax
(KBr, cmϪ1) 3350 (s, NH2), 3290 (m, NHTs), 3055 (s, C6H4),
2980 (s, CH), 2878 (s, CH), 2626 (s, CH), 1600 (s), 1493 (s), 1457
(s), 1311 (s, SO2NH), 1156 (s, SO2NH), 1097 (s), 815 (s, C6H4);
δH (400 MHz, CDCl3) 0.99 (d, J 6.6, 3H, –CH3), 2,40 (s, 3H,
C6H4–CH3), 2.49 (dd, J 13, 6.97, 1H, CH2NH2), 2.66 (dd, J 13,
4.49, 1H, CH2NH2), 3.14–3.22 (m, 1H, CHNHTs), 7.27 (d,
J 7.98, 2H, –C6H4–CH3), 7.75 (d, J 7.98, 2H, –C6H4–CH3);
δC (100 MHz, CDCl3) 18.99 (–CH3), 21.64 (–C6H4–CH3),
47.31 (CH2NH2), 51.87 (TsNCH), 127.19 (2 × Ar–CH), 129.81
(2 × Ar–CH), 138.13 (Ar–C), 143.36 (Ar–C).
4-Methyl-N-((1S )-2-methyl-1-{[((2S )-3-methyl-2{[(4-methyl-
phenyl)sulfonyl]amino}butyl)amino]methyl}propyl)benzenesulf-
onamide 2g. Method (a), via debenzylation of ((1S)-1-{[benzyl-
((2S)-3-methyl-2-{[(4-methylphenyl)sulfonyl]amino}butyl)-
amino]methyl}-2-methylpropyl)-4-methylbenzenesulfonamide 2j.
Debenzylation
of
((1S)-1-{[benzyl((2S)-3-methyl-2-{[(4-
methylphenyl)sulfonyl]amino}butyl)amino]methyl}-2-methyl-
propyl)-4-methylbenzenesulfonamide 2j (1 g, 1.79 mmol) in an
analogous fashion to the preparation of 2f followed by column
chromatography on silica (hexane : EtOAc : CH2Cl2 2 : 3 : 5)
gave the title compound as a colourless solid (695 mg, 1.4
mmol, 78%); mp 121–123 ЊC (lit.22a 121–122 ЊC); Found MHϩ
m/z 496.2317; C24H37O4S2N3 requires m/z 496.2304; [α]D Ϫ21.8
(c = 0.5, CHCl3) (lit.27 Ϫ17.0 (c = 1.1, CHCl3)); νmax (KBr, cmϪ1)
3289 (s, NHTs), 3230 (s, NH), 2957 (s, CH), 2810 (m, CH), 1322
(s, SO2NH), 1159 (s, SO2NH); δH (400 MHz, CDCl3) 0.65 (m,
12H, –CH3), 1.66 (m, 2H, CH(CH3)2), 2.33 (m, 2H, CH2NH),
2.41 (s, 6H, –C6H4–CH3), 2.45 (m, 2H, CH2NH), 3.02 (m, 2H,
CHNH), 4.96 (br, 1H, NH ), 7.29 (d, J 8.0, 4H, –C6H4–CH3),
7.76 (d, J 8.0, 4H, –C6H4–CH3); δC (100 MHz, CDCl3) 18.5
(–CH3), 18.7 (–CH3), 21.6 (2 × –C6H4–CH3), 30.4 (CH(CH3)2),
49.7 (2 × NCH2), 58.8 (2 × TsNCH), 127.2 (4 × Ar–CH), 129.8
(4 × Ar–CH), 138.4 (2 × Ar–C), 143.3 (2 × Ar–C).
Method (b), via hydrolysis of N-[(1S)-1-({(4S)-4-isopropyl-
3-[(4-methylphenyl)sulfonyl]imidazolidinyl}methyl)-2-methyl-
propyl]-4-methylbenzenesulfonamide 8. ((1S)-1-{[Benzyl((2S)-
3-methyl-2-{[(4-methylphenyl)sulfonyl]amino}butyl)amino]-
methyl}-2-methylpropyl)-4-methylbenzenesulfonamide 2j (3.0
g, 5.3 mmol) and Pd(OH)2 (285 mg, 10 mol% Pd) were placed in
MeOH (50 cm3) and dichloromethane (50 cm3) under 1 atm H2.
After 3 h there was no further uptake of hydrogen and the
reaction was stopped. The solvent was evaporated and the
crude material was purified by column chromatography on
silica (hexane : EtOAc : CH2Cl2 2 : 3 : 5) to afford N-[(1S)-
1-({(4S)-4-isopropyl-3-[(4-methylphenyl)sulfonyl]imidazol-
idinyl}methyl)-2-methylpropyl]-4-methylbenzenesulfonamide
8 as a colourless solid (1.8 g, 3.6 mmol, 68%); mp 110–111 ЊC;
Found MHϩ m/z 508.22816; C25H38O4S2N3 requires m/z
508.23038; [α]D = Ϫ31.0 (c = 1, CHCl3). νmax (KBr, cmϪ1) 3285 (s,
NHTs), 2969 (s, CH), 2823 (m, CH), 1342 (s, SO2NH), 1162 (s,
SO2NH); δH (400 MHz, CDCl3) 0.6 (d, J 6.9, 3H, –CH3), 0.65
(d, J 6.9, 3H, –CH3), 0.84 (d, J 6.7, 3H, –CH3), 0.65 (d, J 6.7,
3H, –CH3), 1.60 (m, 1H, CH(CH3)2), 2.01 (m, 1H, CH(CH3)2),
2.02 (m, 2H, CH2N), 2.41 (s, 6H, –C6H4–CH3), 2.47 (m, 2H,
CH2NTs), 2.83 (m, 1H, CHaHbNTs), 3.51 (m, 1H, CHaHbNTs),
3.62 (d, J 8.4, 1H, CHNTs), 4.0 (d, J 8.4, 1H, CHNTs), 7.29
(m, 4H, –C6H4–CH3), 7.76 (m, 4H, –C6H4–CH3); δC (100 MHz,
CDCl3) 16.50 (–CH3), 17.7 (–CH3), 17.9 (–CH3), 19.3 (–CH3),
29.0 (2 × –C6H4–CH3), 31.4 (CH(CH3)2), 53.4 (NCH2), 53.7
[(1S )-1-(Aminomethyl)-2-methylpropyl]-4-methylbenzene-
sulfonamide 9b. Compound 9b was prepared in an analogous
fashion to 9a using (2S)-2-isopropyl-1-[(4-methylphenyl)-
sulfonyl]aziridine 4 (1.4 g, 5.8 mmol) which afforded a colour-
less solid (1.35 g, 5.2 mmol, 89%); mp 85–87 ЊC (lit.22a 87–88
ЊC); Found MHϩ m/z 257.1334; C12H20O2SN2 requires m/z
257.1323; [α]D Ϫ15.9 (c = 1, CHCl3) (lit.22a ϩ12.0 c = 1, C6H6);
νmax (KBr, cmϪ1) 3396 (s, NH2), 3357 (s, NH2), 3297 (s, NHTs),
3070 (s, C6H4), 2959 (s, CH), 2873 (s, CH), 2778 (m, CH), 1311
(s, SO2NH), 1148 (s, SO2NH); δH (400 MHz, CDCl3) 0.79 (d,
J 6.9, 3H, –CH3), 0.81 (d, J 6.9, 3H, –CH3), 1.77 (m, 1H,
CH(CH3)2), 2.42 (s, 3H, –C6H4–CH3), 2.58 (dd, J 13.2, 4.7, 1H,
–CH2NH2), 2.67 (dd, J 13.2, 6.0, 1H, –CH2NH2), 2.96 (m,
1H, CHNHTs), 7.29 (d, J 8.0, 2H, –C6H4–CH3), 7.78 (d, J 8.0,
2H, –C6H4–CH3); δC (100 MHz, CDCl3) 18.7 (–CH3), 18.9
(–CH3), 30.0 (–C6H4–CH3), 30.4 (CH(CH3)2), 42.5 (CH2NH2)
61.2 (TsNCH), 127.2 (2 × Ar–CH), 129.7 (2 × Ar–CH), 138.4
(Ar–C), 143.3 (Ar–C).
4-Methyl-N-{(1S )-1-methyl-2-[((2S )-2-{[(4-methylphenyl)-
sulfonyl] amino]propyl)amino]ethyl}benzenesulfonamide 2f.
Method (a), via debenzylation of N-{(1S)-2-[benzyl((2S)-
{(4-methylphenyl)sulfonyl]amino}propyl)amino]-1-methyl-
ethyl}-4-methylbenzenesulfonamide 2i. N-{(1S)-2-[Benzyl((2S)-
{(4-methylphenyl)sulfonyl]amino}propyl)amino]-1-methyl-
ethyl}-4-methylbenzenesulfonamide 2i (1.62 g, 3.06 mmol) and
Pd(OH)2 (163 mg, 10 mol% Pd) in MeOH (30 cm3) under 1 atm
H2 at RT. After 1 h, the hydrogenation was complete and the
solvent was evaporated. Purification of the crude product on
silica (EtOAc) gave a colourless solid (1.15 g, 2.62 mmol, 86%);
mp 131ЊC; Found C, 54.56; H, 6.63; N, 9.46%; MHϩ m/z
440.1673; C20H29N3O4S2 requires C, 54.65; H, 6.65; N, 9.56%;
m/z 440.1678; [α]D = Ϫ15.4 (c = 1, CHCl3); νmax (KBr, cmϪ1)
3260 (s, SO2NH), 3060 and 3039 (w, ArH), 2970, 2930 and 2870
(all s, CH), 1600 (m, Ar), 1460 (s), 1440 (s), 1320 (s, SO2N),
1150 (s, SO2N), 820 (s, ArH); δH (400 MHz, CDCl3) 0.95 (d,
J 6.6, 6H, –CH3), 2.30–2.38 (m, 4H, –CH2NH), 2.40 (s, 6H,
–C6H4–CH3), 3.23 (m, 2H, –CHTsN), 5.20 (bs, 2H, TsNH ),
7.29 (d, J 7.9, 4H, –C6H4–CH3), 7.77 (d, J 7.9, 4H, –C6H4–
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 4 0 8 – 4 4 1 7
4412

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(NCH2), 57.4 (TsNCH), 63.8 (TsNCH) 71.5 (TsNCH2N),
127.3 (2 × Ar–CH), 127.9 (2 × Ar–CH), 129.8 (2 × Ar–CH),
129.9 (2 × Ar–CH), 135.3 (Ar–C), 137.9 (Ar–C), 143.5
(Ar–C), 143.9 (Ar–C).
(Ar–CH), 138.0 (Ar–C), 138.3 (Ar–C), 143.4 (Ar–C), 143.5
(Ar–C).
Method (b), via ring opening of (2S)-2-isopropyl-1-[(4-
methylphenyl)sulfonyl]aziridine 4 with [(1S)-2-amino-1-methyl-
ethyl]-4-methylbenzenesulfonamide 9a. The title compound was
obtained in an analogous fashion to compound 2f using [(1S)-
2-amino-1-methylethyl]-4-methylbenzenesulfonamide 9a (1.458
g, 6.396 mmol) and (2S)-2-isopropyl-1-[(4-methylphenyl)-
sulfonyl]aziridine 4 (1.526 g, 6.38 mmol) and flash column
chromatography on silica (CH2Cl2 : MeOH 92 : 8) afforded a
colourless gum (2.621 g, 5.61 mmol, 88%); mp 30–32.5 ЊC;
Found MHϩ m/z 468.2018; C22H34N3O4S2 requires m/z
468.1991; [α]D = Ϫ10.2 (c = 1.01; CHCl3); νmax (CCl4, cmϪ1) 3275
(s, NH) 3064 and 3043 (w, ArH), 2965 (s, CH), 2933 (m, CH),
2878 (m, CH), 1463 (s), 1429 (s), 1326 (s, SO2NH), 1161 (s,
SO2NH), 815 (m, ArH); δH (400 MHz, CDCl3) 0.72 (d, J 6.9,
3H,–CH3), 0.75 (d, J 6.9, 3H,–CH3), 0.93 (d, J 6.5, 3H,–CH3),
1.66 (m, 1H, CH(CH3)2), 2.35 (m, 4H, –CH2NH), 2.40 (s, 6H,
–C6H4–CH3), 3.00 (m, 1H, CHNHTs), 3.21 (m, 1H, CHNHTs),
7.28 (m, 4H, –C6H4–CH3), 7.76 (m, 4H, –C6H4–CH3); δC (100
MHz, CDCl3) 18.4 (–CH3), 18.7 (–CH3), 19.5 (–CH3), 21.6
(2 × –C6H4–CH3), 30.5 (CH(CH3)2), 48.97 (NCH2), 49.4
(NCH2), 54.4 (TsNCH), 58.8 (TsNCH), 127.2 (Ar–CH),
127.3)Ar–CH), 129.8 (Ar–CH), 129.9 (Ar–CH), 138.0 (Ar–C),
138.4 (Ar–C), 143.4 (Ar–C), 143.4 (Ar–C).
To a solution of N-[(1S)-1-({(4S)-4-isopropyl-3-[(4-methyl-
phenyl)sulfonyl]imidazolidinyl}methyl)-2-methylpropyl]-4-
methylbenzenesulfonamide 8 (130 mg, 0.26 mmol) in methanol
(5 cm3) was added 3 M aqueous hydrochloric acid (5 cm3) and
the reaction was stirred for 7 h. The reaction was cooled to 0 ЊC
and neutralised to pH 10 with 2 M aqueous sodium hydroxide
and extracted with dichloromethane (×2, 10 cm3). The com-
bined organic extracts were concentrated under reduced
pressure and the residue taken up in ethanol (5 cm3). To the
resulting solution was added solid sodium hydroxide (256 mg,
6.4 mmol, 25 equiv.) and this mixture was heated to reflux for 22
h. At the completion of this period the volatiles were removed
under reduced pressure. The residue was suspended in water
(10 cm3) and this was acidified to pH 8 with 12 M aqueous
hydrochloric acid. The aqueous phase was extracted with di-
chloromethane (×3, 10 cm3) then dried (Na2SO4), filtered and
evaporated. Purification by column chromatography on silica
(hexane : EtOAc : CH2Cl2 2 : 3 : 5) gave 4-methyl-N-((1S)-2-
methyl-1-{[((2S)-3-methyl-2{[(4-methyl-
phenyl)sulfonyl]amino}butyl)amino]methyl}propyl)benzene-
sulfonamide 2g as a colourless solid (116.7 mg, 0.24 mmol,
92%); Found C, 58.25; H, 7.60; N, 8.25; S, 13.09%; MHϩ m/z
496.2295; C24H37N3O4S2 requires C, 58.15; H, 7.52; N, 8.48; S,
12.94%; m/z 496.2304. The remaining spectroscopic data was
identical to that recorded above.
Method (c), via ring opening of (2S)-2-isopropyl-1-[(4-
methylphenyl)sulfonyl]aziridine 4 with (1S)-1-(aminomethyl)-
2-methylpropyl]-4-methylbenzenesulfonamide 9b. The title
compound was obtained in an analogous fashion to the prepar-
ation of compound 2f using [(1S)-1-(aminomethyl)-2-methyl-
propyl]-4-methylbenzenesulfonamide 9b (1.3 g, 5 mmol) and
(2S)-2-isopropyl-1-[(4-methylphenyl)sulfonyl]aziridine 4 (1.2 g,
5 mmol) followed by purification by column chromatography
on silica (hexane : EtOAc : CH2Cl2 2 : 3 : 5) gave the title
compound as a white solid (1.4 g, 2.8 mmol, 56%) with spectro-
scopic data identical to that recorded above.
4-Methyl-N-{(1S )-1-methyl-2-[[(4-methylphenyl)sulfonyl]-
((2S )-2-{[(4-methylphenyl)sulfonyl]amino}propyl)amino]ethyl}-
benzenesulfonamide 2a. To a solution of 4-methyl-N-{(1S)-1-
methyl-2-[((2S)-2-{[(4-methylphenyl)sulfonyl]amino]propyl)-
amino]ethyl}benzenesulfonamide 2f (1.3 g, 2.8 mmol) in
pyridine (20 cm3) at 0 ЊC under a nitrogen atmosphere was
added p-toluenesulfonyl chloride (550 mg, 2.8 mmol) in batches
over 30 min. The orange solution was allowed to come to room
temperature and stirred for a further 6 h whereby the colour
changed from orange to red. The reaction was quenched with
ice (∼100 g) and conc. HCl (25 cm3). This mixture 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 chromato-
graphy on silica (hexane : EtOAc : CH2Cl2 4 : 1 : 5) afforded a
yellow solid (1.5 g, 2.5 mmol, 89%); mp 68–70 ЊC; Found C,
54.5; H, 5.9; N, 6.8%; MHϩ m/z 594.1760; C27H35O6S3N3
requires C, 54.6; H, 5.9; N, 7.1%; m/z 594.1766; [α]D Ϫ42.3
(c = 1, CHCl3); νmax (KBr, cmϪ1) 3275 (s, NHTs), 3034 (w, C6H4),
2977 (m, CH), 2926 (m, CH), 2874 (m, CH), 1331 (s, SO2NH),
1159 (s, SO2NH); δH (400 MHz, CDCl3) 0.96 (d, J 6.6, 6H,
–CH3), 2.46 (s, 6H, –C6H4–CH3), 2.48 (s, 3H, –C6H4–CH3), 2.84
(dd, J 14.8, 6.2, 2H, –CH2NTs), 3.16 (dd, J 14.8, 6.2, 2H,
–CH2NTs), 3.40 (m, 2H, –CHNHTs), 7.31 (d, J 8.3, 4H, –C6H4–
CH3), 7.36 (d, J 8.3, 2H, –C6H4–CH3), 7.69 (d, J 8.3, 2H,
–C6H4–CH3), 7.77 (d, J 8.3, 4H, –C6H4–CH3); δC (100 MHz,
CDCl3) 19.2 (2 × –CH3), 21.7 (–C6H4–CH3), 21.7 (2 × –C6H4–
CH3), 48.7 (2 × TsNCH2), 60.6 (2 × TsNCH), 127.3 (2 × Ar–
CH), 127.6 (4 × Ar–CH), 129.9 (4 × Ar–CH), 130.2 (4 × Ar–
CH), 135.21 (2 × Ar–C), 137.8 (2 × Ar–C), 143.7 (Ar–C),
144.3 (Ar–C).
4-Methyl-N-{(1S )-1-methyl-2-[((2S )-3-methyl-2-{[(4-methyl-
phenyl)sulfonyl]amino}butyl)amino]ethyl}benzenesulfonamide
2h. Method (a), via debenzylation of N-{(1S)-2-[benzyl((2S)-
3-methyl-2-{[(4-methylphenyl)sulfonyl]amino}butyl)amino]-1-
methylethyl}-4-methylbenzenesulfonamide
2k.
N-{(1S)-2-
[Benzyl((2S)-3-methyl-2-{[(4-methylphenyl)sulfonyl]amino}-
butyl)amino]-1-methylethyl}-4-methylbenzenesulfonamide 2k
(300 mg, 0.54 mmol) and palladium on charcoal (57 mg, 10
mol% Pd) in AcOH (5 cm3) were hydrogenated under 1 atm H2
at RT for 12 h. After evaporation of the solvent, the crude
product was filtered through a short pad of silica (EtOAc:
EtOH 1 : 1). After evaporation of the solvent, 2 M aqueous
sodium hydroxide was added to the amine which was then
extracted with EtOAc, washed with 2 M NaOH and brine, and
dried over MgSO4. Purification by flash column chromato-
graphy on silica (EtOAc) gave an oil (100 mg, 0.21 mmol, 40%);
Found MHϩ m/z 468.1981; Calculated for C22H34N3O4S2 m/z
461.1991; [α]D = Ϫ13.8 (c = 1.00; CHCl3); νmax (CCl4, cmϪ1) 3275
(s, NH), 3064 and 3043 (w, ArH). 2965 (s, CH), 2933 (m, CH),
2878 (m, CH), 1463 (s), 1492 (s), 1326 (s, SO2NH), 1161 (s,
SO2NH), 815 (m, ArH); δH (400 MHz, CDCl3) 0.74 (d, J 6.9,
3H, CH3), 0.76 (d, J 6.9, 3H, CH3), 0.96 (d, J 6.5, 3H, CH3),
1.67 (m, 1H, CH(CH3)2), 2.29–2.46 (m, 4H, CH2NH), 2.41 (s,
6H, –C6H4–CH3), 3.02 (m, 1H, CHNH), 3.22 (m, 1H, CHNH),
5.05 (bs, 2H, NH ), 7.28–7.32 (m, 4H, –C6H4–CH3), 7.75–7.78
(m, 4H, –C6H4–CH3); δC (100 MHz, CDCl3) 18.4 (–CH3), 18.7
(–CH3), 19.5 (–CH3), 21.6 (2 × –C6H4–CH3), 30.6 (CH(CH3)2),
49.0 (NCH2), 49.5 (NCH2), 54.4 (TsNCH), 58.9 (TsNCH),
127.2 (Ar–CH), 127.3)Ar–CH), 129.8 (Ar–CH), 129.9
4-Methyl-N-[(1S )-2-methyl-1-({((2S )-3-methyl-2-{[(4-
methylphenyl)sulfonyl]amino}butyl)[(4-methylphenyl)sulfonyl]-
amino}methyl)propyl]benzenesulfonamide 2b. Compound 2b
was prepared in an identical manner to 2a using 4-methyl-
N-((1S)-2-methyl-1-{[((2S)-3-methyl-2{[(4-methylphenyl)-
sulfonyl]amino}butyl)amino]methyl}propyl)benzenesulfon-
amide 2g (1.4 g, 2.8 mmol). Purification by column chromato-
graphy on silica (hexane : EtOAc : CH2Cl2 4 : 1 : 5) afforded a
yellow solid (1.5 g, 2.3 mmol, 82%); mp 209–211 ЊC (lit.20 mp
205–207 ЊC); Found C, 57.3; H, 6.7; N, 6.5; S, 14.8%; MHϩ m/z
650.2404; C31H43O6S3N3 requires C, 57.3; H, 6.8; N, 6.2; S,
14.7%; m/z 650.2405; [α]D Ϫ73.1 (c = 1, CHCl3) (lit.20 Ϫ30.4
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 4 0 8 – 4 4 1 7
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(c = 0.5, CHCl3)); νmax (KBr, cmϪ1) 3250 (s, NHTs), 3044 (w,
C6H4), 2961 (m, CH), 2928 (m, CH), 2874 (m, CH), 1325 (s,
SO2NH), 1162 (s, SO2NH); δH (400 MHz, CDCl3) 0.58 (d, J 6.9,
6H, –CH3), 0.74 (d, J 6.9, 6H, –CH3), 1.84 (m, 2H, CH(CH3)2),
2.42 (s, 6H, –C6H4–CH3), 2.46 (s, 3H, –C6H4–CH3), 3.01 (m,
4H, –CH2NHTs), 3.18 (m, 2H, –CHNHTs), 5.00 (d, J 8.0, 2H,
NHTs), 7.28 (d, J 8.0, 4H, –C6H4–CH3), 7.36 (d, J 8.0, 2H,
–C6H4–CH3), 7.67 (d, J 8.3, 2H, –C6H4–CH3), 7.74 (d, J 8.3,
4H, –C6H4–CH3); δC (100 MHz, CDCl3) 16.6 (2 × ϪCH3), 17.9
(2 × ϪCH3), 21.7 (3 × –C6H4–CH3), 28.5 (2 × CH(CH3)2),
51.0 (2 × TsNCH2), 57.2 (2 × TsNCH), 127.4 (2 × Ar–CH),
127.7 (3 × Ar–CH), 129.7 (3 × Ar–CH), 130.2 (3 × Ar–CH),
134.8 (2 × Ar–C) 137.7 (2 × Ar–C), 143.5 (2 × Ar–C).
(3 × Ar–CH), 129.9 (3 × Ar–CH), 130.0 (3 × Ar–CH), 137.1
(2 × Ar–C), 143.6 (2 × Ar–C), 143.9 (2 × Ar–C).
(2S,6S )-2,6-Diisopropyl-1,4,7-tris[(4-methylphenyl)sulfonyl]-
1,4,7-triazacyclononane 1b. Compound 1b was prepared in an
identical manner to 1a from 4-methyl-N-[(1S)-2-methyl-1-
({((2S)-3-methyl-2-{[(4-methylphenyl)sulfonyl]amino}butyl)-
[(4-methylphenyl)sulfonyl]amino}methyl)propyl]benzene-
sulfonamide 2b (800 mg, 1.2 mmol) and washed sodium hydride
(103 mg, 2.5 mmol). Purification by column chromatography
on silica (hexane : EtOAc : CH2Cl2 4 : 1 : 5) afforded a colour-
less solid (514 mg, 0.87 mmol, 73%); mp 210–212 ЊC (lit.20 mp
214–215 ЊC); Found MHϩ m/z 676.2540; C33H46O6S3N3 requires
m/z 676.2549; [α]D = Ϫ76.1 (c = 1, CHCl3) (lit.20 [α]D = Ϫ7.4
(c = 0.5, CHCl3)); νmax (KBr, cmϪ1) 2972 (w, CH), 2880 (w, CH),
2720 (w, CH), 1338 (s, SO2NH), 1172 (s, SO2NH); δH (400 MHz,
CDCl3) 0.38 (br, 6H, –CH3), 0.88 (d, J 6.2, 6H, –CH3), 1.01 (m,
2H, CH(CH3)2), 2.40 (s, 6H, –C6H4–CH3), 2.47 (s, 3H, –C6H4–
CH3), 3.21 (m, 4H, –CH2NTs), 3.40 (m, 2H, –CHNTs), 3.66 (m,
4H, –CH2NTs), 3.78 (m, 2H, –CHNTs), 7.28 (d, J 8.0, 4H,
–C6H4–CH3), 7.37 (d, J 8.0, 2H, –C6H4–CH3), 7.73 (m, 6H,
–C6H4–CH3); δC (100 MHz, CDCl3) 20.2 (2 × –CH3), 20.6
(2 × –CH3), 21.6 (3 × –C6H4–CH3), 21.7 (2 × CH(CH3)2),
45.7 (4 × TsNCH2), 64.6 (2 × TsNCH), 127.7 (4 × Ar–CH),
128.2 (4 × Ar–CH), 129.8 (4 × Ar–CH), 129.9 (2 × Ar–C),
143.6 (2 × Ar–C), 144.1 (2 × Ar–C).
4-Methyl-N-((1S )-1-methyl-2-{((2S )-3-methyl-2-{[(4-methyl-
phenyl)sulfonyl]amino}butyl)[(4-methylphenyl)sulfonyl]amino}-
ethyl)benzenesulfonamide 2c. Compound 2c was prepared in an
identical manner to 2a using 4-methyl-N-{(1S)-1-methyl-2-
[((2S)-3-methyl-2-{[(4-methyl-phenyl)sulfonyl]amino}butyl)-
amino]ethyl}benzenesulfonamide 2h (1.916 mg, 4.1 mmol).
Purification by silica flash column chromatography (CH2Cl2 :
EtOAc 94 : 6) afforded a colourless solid (1.838 g, 2.96 mmol,
72%); mp 165–166 ЊC; Found C, 55.77; H, 6.12; N, 6.66; S,
15.65%; MHϩ m/z 622.2112; C29H40N3O6S3 requires C, 56.02;
H, 6.32; N, 6.76; S, 15.47%; m/z 622.2079; [α]D Ϫ67 (c = 0.505,
CHCl3); νmax (CCl4, cmϪ1) 3281 (w, NHTs), 2965, 2927 and 2873
(m, all CH), 1164 (w, SO2N), 908 (s), 739 (s); δH (400 MHz,
CDCl3) 0.51 (d, J 6.9, 3H, –CH3), 0.69 (d, J 6.9, 3H, –CH3),
0.95 (d, J 6.5, 3H, –CH3), 1.74 (m, 1H, CH(CH3)2), 2.39 (s, 3H,
–C6H4–CH3), 2.41 (s, 3H, –C6H4–CH3), 2.43 (s, 3H, –C6H4–
CH3), 2.70 (dd, J 14.9, 6.2, 1H, –CHHNHTs), 2.91 (dd, J 14.1,
6.2, 1H, –CHHNHTs), 3.12 (m, 3H, –CHNHTs), 3.35 (m, 1H,
–CHNHTs), 5.08 (d, J 6.2, 1H, NHTs), 5.44 (bs, 1H, NHTs),
7.27 (m, 6H, –C6H4–CH3), 7.69 (m, 12H, –C6H4–CH3);
δC (100 MHz, CDCl3) 16.15 (–CH3), 18.42 (–CH3), 19.43
(–CH3), 21.66 (2 × –C6H4–CH3), 21.70 (–C6H4–CH3) 28.25
(CH(CH3)2), 48.99 (TsNCH2), 51.50 (TsNCH2), 55.27
(TsNCH), 56.97 (TsNCH), 127.4, 127.37, 127.72, 129.82,
129.88 and 130.15 (all Ar–CH), 134.86, 137.55, 137.86 (all
Ar–C), 143.52, 143.69, 144.30 (all Ar–C).
(2S,6S )-2-Isopropyl-6-methyl-1,4,7-tris[(4-methylphenyl)-
sulfonyl]-1,4,7-triazacyclonane 1c. Compound 1c was prepared
in an identical manner to 1a from 4-methyl-N-((1S)-1-methyl-
2-{((2S)-3-methyl-2-{[(4-methylphenyl)sulfonyl]amino}butyl)-
[(4-methylphenyl)sulfonyl]amino}ethyl)benzenesulfonamide 2c
(820.6 mg, 1.32 mmol) and washed sodium hydride (108.6 mg,
2.71 mmol). Purification by column chromatography on silica
(EtOAc : CH2Cl2 2 : 98) afforded a colourless solid (618 mg,
0.955 mmol, 72%), an analytical sample was obtained by purifi-
cation on alumina (CH2Cl2) mp 105–106 ЊC; Found C, 57.14;
H, 6.40; N, 6.41; S, 15.15%; MHϩ m/z 648.2260; C31H41N3O6S3
requires C, 57.47; H, 6.38; N, 6.49; S, 14.85%; m/z 648.2236; [α]D
= 80.8 (c = 0.505 CHCl3)); νmax (KBr, cmϪ1) 3063 (w, ArH), 3029
(w, ArH), 2967 (m, CH), 1452 (m), 1392 (m), 1336 (s, SO2N),
1155 (s, SO2N), 1089 (s), 982 (s), 822 (m, ArH); δH (400 MHz,
CDCl3) 0.33 (d, J 6.8, 3H, –CH3), 0.63 (d, J 6.8, 3H, –CH3),
0.89 (d, J 6.5, 3H, –CH3), 1.47 (m, 1H, CH(CH3)2), 2.41 (s, 3H,
–C6H4–CH3), 2.43 (s, 3H, –C6H4–CH3), 2.47 (s, 3H, –C6H4–
CH3), 3.37 (m, 5H, 2 ×–CH2NTs ϩ –CHNTs), 3.72 (m, 4H, 2 ×
–CH2NHTs), 4.20 (bs, 1H, CHNTs), 7.29 (m, 4H, –C6H4–CH3),
7.36 (d, J 8, 2H, –C6H4–CH3), 7.67 (m, 4H, –C6H4–CH3), 7.76
(d, J 8, 2H, –C6H4–CH3); δC (100 MHz, CDCl3) 15.22 (–CH3),
20.19 (–CH3), 20.55 (–CH3), 21.66 (2 × –C6H4–CH3), 21.69
(–C6H4–CH3), 29.3 (CH(CH3)2), 44.60 (TsNCH2), 47.06
(TsNCH2), 53.81 (TsNCH2) 64.6 (2 × TsNCH), 127.23 (Ar–
CH), 127.63 (Ar–CH), 127.75 (Ar–CH), 129.81 (Ar–CH),
130.02 (Ar–CH), 137.18 (Ar–C), 143.60 (Ar–C), 143.75
(Ar–C), 143.88 (Ar–C).
(2S,6S )-2,6-Dimethyl-1,4,7-tris[(4-methylphenyl)sulfonyl]-
1,4,7-triazacyclononane 1a. Hexane washed NaH (42 mg,
1.7 mmol) in DMF (1 cm3) was added to a solution of 4-methyl-
N-{(1S)-1-methyl-2-[[(4-methylphenyl)sulfonyl]((2S)-2-{[(4-
methylphenyl)
sulfonyl]amino}propyl)amino]ethyl}benzene-
sulfonamide 2a (500 mg, 0.84 mmol) in DMF (8 cm3) at room
temperature. The resulting solution was heated to 80 ЊC and a
solution of ethyleneglycol ditosylate 3 (343 mg, 0.92 mmol) in
DMF (2 cm3) was added dropwise over 1 h. During this period
the colour of the solution changed from brown to black. The
reaction was stirred overnight at 80 ЊC and at completion was
quenched by addition of water (10 cm3). The DMF was
removed under reduced pressure (12 mmHg) and the residue
dissolved in EtOAc (15 cm3). The organic layer was washed
with water (×2, 20 cm3), dried (Na2SO4), filtered and evapor-
ated to give a brown solid. Purification by column chromato-
graphy on silica (hexane : EtOAc : CH2Cl2 4 : 1 : 5) afforded a
colourless solid (374 mg, 0.60 mmol, 71%); mp 209–211 ЊC;
Found C, 56.0; H, 6.0; N, 6.5%; MHϩ m/z 620.1926;
C29H37O6S3N3 requires C, 56.2; H, 6.0; N, 6.8%; m/z 620.1923;
[α]D ϩ95.3 (c = 1, CHCl3); νmax (KBr, cmϪ1) 3064 (w, C6H4), 2924
(w, CH), 1335 (s, SO2NH), 1155 (s, SO2NH); δH (400 MHz,
CDCl3) 0.69 (d, J 6.5, 6H, –CH3), 2.43 (s, 6H, –C6H4–CH3),
2.46 (s, 3H, –C6H4–CH3), 3.24 (d, J 13.8, 2H, –CH2NTs), 3.52
(m, 6H, –CH2NTs), 4.15 (m, 2H, –CHNTs), 7.30 (d, 8.0, 4H,
–C6H4–CH3), 7.35 (d, J 8.0, 2H, –C6H4–CH3), 7.65 (d, J 8.3,
4H, –C6H4–CH3), 7.78 (d, J 8.3, 2H, –C6H4–CH3); δC (100
MHz, CDCl3) 14.9 (–CH3), 21.7 (3 × –C6H4–CH3), 45.6
(4 × TsNCH2), 53.8 (2 × TsNCH), 127.2 (3 × Ar–CH), 127.7
(2S,6S )-2,6-Dimethyl-1,4,7-triazacyclononane 10a. To
a
solution of (2S,6S)-2,6-dimethyl-1,4,7-tris[(4-methylphenyl)-
sulfonyl]-1,4,7-triazacyclononane 1a (912 mg, 1.5 mmol) in
THF (25 cm3) and EtOH (4.5 cm3, 80 mmol) was condensed dry
NH3 (200 cm3) at Ϫ78 ЊC. To this solution was added lithium
metal (514 mg, 74 mmol) in small portions to give an intense
blue colour. 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 aque-
ous 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
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 4 0 8 – 4 4 1 7
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evaporated to give a light yellow oil (38 mg, 0.24 mmol, 16%);
Found MHϩ m/z 158.1654; C8H19N3 requires m/z 158.1657; [α]D
ϩ41.3 (c = 1, CHCl3); νmax (CCl4, cmϪ1) 3291 (br, w, NH), 2872
(s, CH), 2809 (s, CH); δH (400 MHz, CDCl3) 1.13 (d, J 6.5, 6H,
–CH3), 2.69 (m, 2H, NHCH2), 2.95 (m, 6H, NHCH2), 3.01 (m,
2H, NHCH ), 3.51 (br, 3H, NH ); δC (100 MHz, CDCl3) 18.3
(2 × –CH3), 42.5 (2 × NHCH2), 50.7 (NHCH2), 51.9
(NHCH2), 53.6 (2 × NHCH).
(CH2N), 49.03 (CH2N), 49.55 (CH2N), 49.90 (CHN), 58.36
(CHN).
(2S,6S )-2-Isopropyl-6-methyl-1,4,7-triazacyclononane
tri-
hydrobromide 10f. To a stirred solution of (2S,6S)-2-isopropyl-
6-methyl-1,4,7-triazacyclonane 10c (38.6 mg, 0.209 mmol) in
ether (2 cm3) at 0 ЊC was added hydrobromic acid (48%, 0.1 cm3,
0.883 mmol) to give a tan coloured solid. The solid was washed
with ether (×3, 3 cm3) followed by azeotropic removal of water
by evaporation of added toluene (×4, 5 cm3). The residue was
twice precipitated from EtOH (1 cm3) by the addition of ether
(2 cm3) which gave a cream solid (58.9 mg, 0.138 mmol, 66%)
mp 195–198 ЊC; Found C, 27.03; H, 5.85; N, 9.02%; C10H25N3ؒ
3HBrؒH2O requires C, 26.93; H, 6.33; N, 9.42%; [α]D ϩ30.4
(c = 0.565, MeOH); νmax (KBr, cmϪ1) 3645–3200 (sbr, NH), 2961
(s, CH), 2766 (s), 2651 (s); δH (400 MHz, D2O) 0.99 (d, J 6.8,
3H, –CH3), 1.08 (d, J 6.8, 3H, –CH3), 1.33 (d, J 6.68, 3H,
–CH3), 1.97 (sep, J 6.8, 1H, CH(CH3)2), 3.02 (m, 2H,
2 × CHNH), 3.23–3.71 (m, 7H, 7 × CHNH), 3.91 (m, 1H,
CHNH); δC (100 MHz, D2O) 14.68 (–CH3), 18.31 (–CH3),
19.11 (–CH3), 30.87 (CH(CH3)2), 38.29 (CH2N), 42.75
(CH2N), 46.41 (CH2N), 46.86 (CH2N), 51.8 (CHN), 58.65
(CHN).
(2S,6S )-2,6-Dimethyl-1,4,7-triazacyclononane trihydrochlor-
ide 10d. To a solution of (2S,6S)-2,6-dimethyl-1,4,7-triazacyclo-
nonane 10a (38 mg, 0.14 mmol) in EtOH (2 cm3) was added
conc. HCl (0.08 cm3) at room temperature with rapid stirring.
To this solution was added ether (10 cm3) and the white precipi-
tate that formed was removed by filtration and dried under
reduced pressure to give the hydrochloride salt as a colourless
solid (49 mg, 0.19 mmol, 79%); mp 133–135 ЊC; Found MHϩ
m/z 158.1654; C8H19N3 requires m/z 158.1657; [α]D ϩ33.1 (c = 1,
MeOH); νmax (KBr, cmϪ1) 2963 (s, CH), 2871 (s, CH), 2805 (s,
CH); δH (400 MHz, CD3OD) 1.33 (d, J 6.6, 6H, –CH3), 2.94 (m,
2H, NHCH2), 3.19 (dd, J 14.6, 4.2 2H, NHCH2), 3.31 (m, 2H,
NHCH2), 3.47 (m, 2H, NHCH2), 3.68 (m, 2H, NHCH ); δC (100
MHz, CD3OD) 16.1 (–CH3), 17.8 (–CH3), 40.9 (2 × NHCH2),
51.6 (2 × NHCH2), 57.8 (2 × NHCH).
(2S,6S )-1,2,4,6,7-Pentamethyl-1,4,7-triazacyclononane 11a.
To a solution of (2S,6S)-2,6-dimethyl-1,4,7-tris[(4-methyl-
phenyl)sulfonyl]-1,4,7-triazacyclononane 1a (912 mg, 1.5
mmol) in THF (25 cm3) and EtOH (4.5 cm3, 80 mmol) was
condensed dry NH3 (200 cm3) at Ϫ78 ЊC. To this solution was
added lithium metal (512 mg, 74 mmol) in small portions to
give an intense blue colour. The reaction mixture was allowed
to warm to room temperature overnight. Water was added
(5 cm3) and the solution was acidified (pH 1) with conc. HCl
(1 cm3). The aqueous solution was extracted with dichloro-
methane (×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) and ethyl
acetate (×2, 10 cm3). The resulting aqueous solution was
acidified (pH 1) with conc. HCl (1 cm3) and the volatiles were
removed under reduced pressure (2 mmHg). This residue was
dissolved in H2O (1 cm3) and the solution was neutralised with
solid NaOH (168 mg). To this solution was added formalde-
hyde (37%, 1.1 cm3, 13.5 mmol) and formic acid (90%, 1.7 cm3,
30 mmol). The solution was heated to reflux (bath temp. 90 ЊC)
under a nitrogen atmosphere for 20 h. After cooling to room
temperature the reaction was 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 dichloromethane (×4, 10 cm3), and the com-
bined organic phases were dried (Na2SO4), filtered and evapor-
ated to give light brown oil (131 mg, 0.66 mmol, 44%); Found
MHϩ m/z 200.2121; C9H21N3 requires m/z 200.2127; [α]D ϩ42.3
(c = 1, CHCl3); νmax (CCl4, cmϪ1) 2966 (m, CH), 2777 (m, CH);
δH (400 MHz, CDCl3) 0.74 (d, J 6.1, 6H, –CH3), 2.05 (d, J 10.1,
2H, NCH2), 2.18 (m, 2H, NCH2), 2.31 (s, 9H, NCH3), 2.68 (d,
J 11.3, 2H, NCH2), 2.92 (m, 2H, NCH2), 2.96 (m, 2H, NCH );
δC (100 MHz, D2O) 11.6 (2 × –CH3), 41.3 (NCH3), 45.9
(NCH3), 51.3 (NCH3), 53.4 (2 × NCH2), 54.9 (2 × NCH2), 60.4
(2 × NCH).
(2S,6S )-2,6-Diisopropyl-1,4,7-triazacyclononane 10b. Com-
pound 10b was prepared in an identical fashion to 10a using
(2S,6S)-2,6-diisopropyl-1,4,7-tris[(4-methylphenyl)sulfonyl]-
1,4,7-triazacyclononane 1b (400 mg, 0.59 mmol), EtOH (1.8
cm3, 32 mmol) and lithium metal (206 mg, 29 mmol) to give a
light yellow oil (92 mg, 0.43 mmol, 72%); Found MHϩ m/z
214.2283; C12H27N3 requires m/z 214.2283; [α]D ϩ79.2 (c = 1,
CHCl3); νmax (CCl4, cmϪ1) 3316 (w, NH), 2958 (m, CH), 2871
(m, CH); δH (400 MHz, CDCl3) 0.88 (d, J 6.7, 6H, –CH3), 0.96
(d, J 6.7, 6H, –CH3), 1.56 (m, 2H, CH(CH3)2), 2.44 (m, 4H,
NHCH2), 2.64 (m, 2H, NHCH2), 2.76 (m, 2H, NHCH2), 3.01
(d, J 8.9, 2H, NHCH ), 3.25 (br, 3H, NH); δC (100 MHz,
CDCl3) 19.7 (2 × –CH3), 19.9 (2 × –CH3), 31.9 (2 ×
CH(CH3)2), 43.9 (2 × NHCH2), 48.7 (2 × NHCH2), 58.9
(2 × NHCH).
(2S,6S )-2,6-Diisopropyl-1,4,7-triazacyclononane monohydro-
chloride 10e. Compound 10e was prepared in an analogous
fashion to 10d using (2S,6S)-2,6-diisopropyl-1,4,7-triazacyclo-
nonane 10b (92 mg, 0.43 mmol) to afford a colourless solid (98
mg, 0.39 mmol, 90%); mp 136–138 ЊC; Found MHϩ m/z
214.2283; C12H27N3 requires m/z 214.2283; [α]D ϩ58.7 (c = 1,
MeOH); νmax (KBr, cmϪ1) 3416 (w, NH); 2963 (s, CH), 2766 (s,
CH), 2650 (s, CH); δH (400 MHz, D2O) 0.94 (d, J 6.8, 6H,
–CH3), 1.99 (m, 2H, CH(CH3)2), 2.98 (m, 2H, NHCH2), 3.31
(m, 2H, NHCH2), 3.48 (m, 6H, NHCH2), 3.48 (m, 2H,
NHCH ); δC (100 M, D2O) 18.1 (2 × –CH3), 19.0 (2 × –CH3),
29.6 (2 × CH(CH3)2), 40.9 (2 × NHCH2), 45.5 (2 × NHCH2),
60.3 (2 × NHCH).
(2S,6S )-2-Isopropyl-6-methyl-1,4,7-triazacyclononane 10c.
Compound 10c was prepared in an analogous fashion to 10a
using(2S,6S)-2-isopropyl-6-methyl-1,4,7-tris[(4-methylphenyl)-
sulfonyl]-1,4,7-triazacyclonane 1c (559.7 mg, 0.865 mmol),
EtOH (2.74 cm3) and lithium wire (242.7 mg, 34.97 mmol) to
afford a light yellow oil (140.1 mg, 0.756 mmol, 87%); Found
MHϩ m/z 186.1968; C10H24N3 requires m/z 186.1970; νmax (liq.
film, cmϪ1) 3630–3055 (bm, NH), 2953 (s, CH), 2921 (s, CH),
2870 (s, CH), 1466 (m), 1370 (m), 1160 (m), 1121 (m); δH (400
MHz, CDCl3) 0.89 (d, J 6.7, 3H, –CH3), 0.95 (d, J 6.7, 3H,
–CH3), 1.01 (d, J 6.6, 3H, –CH3), 1.54 (sep, J 6.7, 1H,
CH(CH3)2), 2.20 (bs, 3H, 3 × NH ), 2.40 (m, 3H, 3 × CHN),
2.58 (m, 2H, 2 × CHN), 2.83 (m, 4H, 4 × CHN), 2.91 (m, 1H,
CHN); δC (100 MHz, CDCl3) 17.51 (–CH3), 19.36 (–CH3),
19.41 (–CH3), 31.94 (CH(CH3)2), 40.46 (CH2N), 44.85
(2S,6S )-1,2,4,6,7-Pentamethyl-1,4,7-triazacyclononane tri-
hydrochloride 11d. To a solution of (2S,6S)-1,2,4,6,7-penta-
methyl-1,4,7-triazacyclononane 11a (131 mg, 0.66 mmol) in
EtOH (2 cm3) was added conc. HCl (0.19 cm3) at room temper-
ature with rapid stirring. To this solution was added ether
(10 cm3) and the white precipitate that formed was removed by
filtration and dried under reduced pressure to give the hydro-
chloride salt (202 mg, 0.65 mmol, 98%); mp 181–183 ЊC; Found
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 4 0 8 – 4 4 1 7
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MHϩ m/z 200.2127; C12H27N3 requires m/z 200.2126; [α]D ϩ36.1
(c = 1, MeOH); νmax (KBr, cmϪ1) 3400 (s, NH, br), 2956 (m,
CH), 2814 (m, CH); δH (400 MHz, D2O) 1.25 (d, J 6.1, 6H,
–CH3), 2.71 (m, 3H, NCH3), 2.80 (m, 3H, NCH3), 2.94 (m, 3H,
NCH3), 3.04 (m, 6H, NCH2), 3.45 (m, 2H, NCH2), 3.76 (m, 2H,
NCH ), δC (100 MHz, D2O) 9.4 (–CH3), 11.1 (–CH3), 37.1
(NCH3), 41.8 (NCH3), 44.6 (NCH3), 45.5 (NCH2), 51.6
(NCH2), 53.0 (NCH2), 55.8 (NCH2), 58.9 (2 × NCH).
MeOH); νmax (CCl4, cmϪ1) 3625–3170 (bm, NHϩ), 3060 (s),
2995 (s, CH), 2980 (s, CH), 2910 (s, CH), 2900–2710 (bs), 1470
(s), 1383 (s), 1341 (s), 1050 (s), 1044 (s), 974 (s); δH (400 MHz,
D2O) 1.0 (d, J 5.8, 3H, –CH3), 1.18 (d, J 6.0, 3H, –CH3), 1.42 (d,
J 6.0, 3H, –CH3), 2.17 (m, 1H, CH(CH3)2), 2.70 (s, 3H, NCH3),
2.92 (m, 1H, NCH ), 3.06 (s, 3H, NCH3), 3.16 (s, 3H, NCH3),
3.25 (m, 3H, NCH ), 3.48 (m, 3H, NCH ), 3.74 (m, 1H, NCH ),
3.86 (m, 1H, NCH ), 4.08 (m, 1H, NCH ); δC (100 MHz, D2O)
9.60 (–CH3), 19.25 (–CH3), 21.45 (–CH3), 28.21 (CH(CH3)2),
36.30 (–CH3N), 42.25 (–CH3N), 44.55 (–CH3N), 47.68
(–CH2N), 52.02 (–CH2N), 55.58 (–CH2N), 57.35 (–CHN),
57.80 (–CHN), 58.37 (–CH2N), 59.57 (–CHN).
(2S,6S )-2,6-Diisopropyl-1,4,7-trimethyl-1,4,7-triazacyclo-
nonane 11b. A stirred solution of (2S,6S)-2,6-diisopropyl-1,4,7-
triazacyclononane 10b (91 mg, 0.42 mmol) and formaldehyde
(37%, 0.3 cm3, 3.9 mmol) and formic acid (90%, 0.4 cm3, 9.2
mmol) was heated to reflux (bath temp. 90 ЊC) under a nitrogen
atmosphere for 20 h. After cooling to room temperature the
reaction was acidified (pH 1) with conc. HCl (1 cm3) and the
volatiles were removed under reduced pressure (12 mmHg).
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), and the com-
bined organic phases were dried (Na2SO4), filtered and evapor-
ated to give light brown oil (73 mg, 0.28 mmol, 66%); Found
MHϩ m/z 256.2752; C15H33N3 requires m/z 256.2753; [α]D ϩ38.4
(c = 0.5, CHCl3); νmax (CCl4, cmϪ1) 2955 (m, CH), 2870 (m, CH);
δH (400 MHz, CDCl3) 0.86 (d, J 2.3, 6H, –CH3), 0.88 (d, J 2.3,
6H, –CH3), 1.64 (m, 2H, CH(CH3)2), 2.19 (m, 3H, NCH3), 2.33
(m, 3H, NCH3), 2.35 (m, 3H, NCH3), 2.40 (m, 4H, NCH3), 2.49
(s, 2H, NCH3), 2.64 (m, 2H, NCH2), 2.82 (m, 2H, NCH );
δC (100 MHz, CDCl3) 20.9 (2 × –CH3), 21.2 (2 × –CH3), 30.7
(2 × CH(CH3)2), 40.0 (2 × NCH3), 45.2 (NCH3), 46.1 (NCH2),
46.2 (NCH2), 52.0 (NCH2), 55.7 (NCH2), 67.2 (2 × NCH).
Crystal data for 11e
Measurements were made on a Nonius Kappa CCD diffract-
ometer at 150 K: C13H31Br2N3, orthorhombic, space group
P212121, a = 7.5110(2), b= 12.0412(5), c = 19.5980(7) Å,
V = 1772.47(11) Å3, Z = 4, MoKα radiation, λ = 0.71073 Å,
µ = 4.565 mmϪ1. Data were corrected for absorption with a
multi-scan method. Final refinement to convergence on F 2 and
with 177 parameters gave R = 0.0349 (3241 observed data),
Rw = 0.0685 (all 3844 unique reflections) and GOF = 1.039,
Flack parameter Ϫ0.030(11).
CCDC reference number 219446.
See http://www.rsc.org/suppdata/ob/b3/b310492c/ for crystal-
lographic data in CIF or other electronic format.
Acknowledgements
We thank the EPSRC for funding through a ROPA award (to
G. A., grant GR/M52477) and studentship (to G. S.). 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, and to the EPSRC National Crystallo-
graphy Service, University of Southampton, for data collection
on 11e.
(2S,6S )-2-Isopropyl-1,4,6,7-tetramethyl-1,4,7-triazacyclo-
nonane 11c. A stirred solution of (2S,6S)-2-isopropyl-6-methyl-
1,4,7-triazacyclononane 10c (133.1 mg, 0.718 mmol) and form-
aldehyde (37%, 0.5 cm3, 6.67 mmol) and formic acid (90%, 0.67
cm3, 15.59 mmol) was heated to reflux under a nitrogen atmos-
phere for 20 h. After cooling to 0 ЊC, the reaction was acidified
(pH 1) via the addition of 1 M aqueous HCl (5 cm3) and con-
centrated in vacuo (1 mmHg). The residue was dissolved in
water (15 cm3) and washed with ether (×3, 15 cm3) and then
basified (pH 14) by the addition of solid NaOH. The basic
aqueous solution was extracted with dichloromethane (×4, 15
cm3) and the combined organic extracts were dried (Na2SO4),
filtered and evaporated to afford a yellow oil (147.1 mg, 0.647
mmol, 90%); Found MHϩ m/z 228.2441; C13H29N3 requires
228.2439; νmax (liq. film, cmϪ1) 2954 (s), 2928 (s), 2870 (s, all
CH), 2835 (s), 2790 (s), 2765 (s), 1450 (m), 1363 (m); δH (400
MHz, CDCl3) 0.74 (d, J 6.4, 3H, –CH3), 0.79 (d, J 6.7, 6H,
–CH3), 1.57 (m, 1H, CH(CH3)2), 2.09 (m, 2H, CHN), 2.25 (m,
2H, CHN), 2.28 (s, 6H, NCH3), 2.41 (s, 3H, NCH3), 2.46
(m, 1H, CHN), 2.57 (m, 1H, CHN), 2.78 (m, 1H, CHN), 2.85
(m, 1H, CHN), 2.88 (m, 1H, CHN); δC (100 MHz, CDCl3)
12.51 (–CH3), 20.96 (–CH3), 21.25 (–CH3), 30.68 (CH(CH3)2),
41.95 (–CH3N), 45.67 (–CH3N), 50.24 (–CH3N), 54.39
(–CH2N), 56.30 (–CH2N), 56.5 (–CHN), 60.6 (–CH2N), 65.76
(–CHN).
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