A versatile intermediate for the preparation of C-functionalized azamacrocycles and application to the synthesis of the potent anti-HIV agent (±)JM2936

Full text of DOI:10.1021/jo951499w

J . Org. Chem. 1996, 61, 1519-1522
1519
A Ver sa tile In ter m ed ia te for th e
P r ep a r a tion of C-F u n ction a lized
Aza m a cr ocycles a n d Ap p lica tion to th e
Syn th esis of th e P oten t An ti-HIV Agen t
(()J M2936
Gary J . Bridger,*,† Renato T. Skerlj,†
Sreenivasan Padmanabhan,† and David Thornton‡
F igu r e 1.
J ohnson Matthey Pharmaceutical Research, 1401 King
Road, West Chester, Pennsylvania 19380 and J ohnson
Matthey Technology Centre, Blounts Court, Sonning
Common, Reading RG4 9NH, U.K.
tetra- and pentaazamacrocycles, cyclam is one of several
azamacrocyclic ring systems which have received con-
siderable recent attention for other biomedical applica-
tions such as NMR imaging,6 mimics of superoxide
dismutase,7 and diagnostic/therapeutic nuclear medi-
cine.8 From a synthetic standpoint, several groups have
prepared C-functionalized tetraazamacrocycles intended
as “bifunctional chelating agents” for nuclear medicine
applications. In order to covalently attach a radiometal
chelating agent to tumor-selective monoclonal antibodies
for cancer imaging, the azamacrocycle must be modified
on the periphery with a single protein reactive functional
group while maintaining the ligands necessary for strong
radiometal complexation. To this end, the cyclam ring
has been functionalized at nitrogen positions by N-
alkylation9 and at the 5- and 6-carbon positions by
macrocyclization reactions of linear tetraamines with
substituted R,â-unsaturated esters10,11 and malo-
nates.3a,11-15 The corresponding 2-carbon substituent can
be introduced into the cyclam ring by macrocyclization
of an ethylenediamine or amino acid synthon containing
the desired C-substituent.16,17 This approach has been
widely exemplified for the construction of C-functional-
ized [12]aneN4 macrocycles16,18 (using the identical pre-
cursor required for the construction of 2-substituted
Received August 14, 1995
In tr od u ction
Recently we reported the discovery of a novel series of
bis-tetraazamacrocycles, such as the bicyclam J M2763
(1) (Figure 1), that exhibit potent and selective inhibition
of human immunodeficiency virus type 1 (HIV-1) and
type 2 (HIV-2) replication with a unique mechanism of
action.1 In addition to high antiviral potency, dimers of
tetraazamacrocycles linked at a single nitrogen position
are particularly attractive drug candidates due to their
synthetic accessability. By modification of established
literature procedures2 we were able to prepare and report
the structure-activity relationship of an extensive series
of N-linked bis-tetraazamacrocycles in which the mac-
rocyclic ring size was varied from 12-16 members per
ring.3 As part of our ongoing efforts to understand the
structural features required for potent anti-HIV activity
in this class of compounds, we have investigated the
effect of connecting the 1,4,8,11-tetraazacyclotetradecane
([14]aneN4, cyclam) ring system(s) at carbon rather than
nitrogen positions,4 and this paper reports the synthetic
methodology we have used to achieve this goal exempli-
fied by the synthesis of (()J M2936 (2). To our knowl-
edge, J M2936 is also the first example of a bis-tet-
raazamacrocycle that is unsymmetrical due to the
nonidentical covalent connection of the rings at carbon
and nitrogen positions.5
(6) Lauffer, R. B. Chem. Rev. 1987, 87, 901.
(7) Riley, D. P.; Weiss, R. H. J . Am. Chem. Soc. 1994, 116, 387.
(8) Parker, D. Chem. Soc. Rev. 1990, 19, 271.
(9) (a) Franz, J .; Volkert, W. A.; Barefield, E. K.; Holmes, R. A. Nucl.
Med. Biol. 1987, 14, 569. (b) Smith-J ones, P. M.; Fridrich, R.; Kaden,
T. A.; Novak-Hofer, I.; Siebold, K.; Tschudin, D.; Maecke, H. R.
Bioconjugate Chem. 1991, 2, 415. (c) Stahl, W.; Kuhlmann, L.; Wiesner,
M.; Walch, A. Bioorg. Med. Chem. Lett. 1994, 4, 2597. (d) Stahl, W.;
Breipohl, G.; Kuhlmann, L.; Steinstrasser, A.; Gerhards, H. J .; Scholk-
ens, B. A. J . Med. Chem. 1995, 38, 2799.
(10) (a) Kimura, E.; Koike, T.; Takahashi, M. J . Chem. Soc., Chem.
Commun. 1985, 385. (b) Kimura, E.; Shionoya, M.; Okamoto, M.; Nada,
H. J . Am. Chem. Soc. 1988, 110, 3679 and references therein.
(11) Morphy, R. J .; Parker, D.; Alexander, R.; Bains, A.; Carne, A.
F.; Eaton, M. A. W.; Harrison, A.; Millican, A.; Phipps, A.; Rhind, S.
K.; Titmas, R.; Weatherby, D. J . Chem. Soc., Chem. Commun. 1988,
156.
(12) Tabushi, I.; Taniguchi, Y.; Kato, H. Tetrahedron Lett. 1977, 12,
1049.
(13) (a) Moi, M. K.; Meares, C. F.; McCall, M. J .; Cole, W. C.;
DeNardo, S. J . Anal. Biochem. 1985, 148, 249. (b) Deshpande, S. V.;
DeNardo, S. J .; Meares, C. F.; McCall, M. J .; Adams, G. P.; Moi, M.
K.; DeNardo, G. L. J . Nucl. Med. 1988, 29, 217.
Ba ck gr ou n d
Due to the high kinetic stability exhibited by lan-
thanide, transition metal, and radiometal complexes of
* Author to whom correspondence should be addressed. Tel:(610)-
648-8026; Fax:(610)-648-8448; E-mail: bridggj@matthey. com.
† J ohnson Matthey Pharmaceutical Research.
‡ J ohnson Matthey Technology Centre.
(1) De Clercq, E.; Yamamoto, N.; Pauwels, R.; Baba, M.; Schols, D.;
Nakashima, H.; Balzarini, J .; Debyser, Z.; Murrer, B. A.; Schwartz,
D.; Thornton, D.; Bridger, G.; Fricker, S.; Henson, G.; Abrams, M.;
Picker, D. Proc. Natl. Acad. Sci. U.S.A. 1992, 89, 5286.
(2) For leading references see (a) Kruper, W. J .; Rudolf, P. R.;
Langhoff, C. A. J . Org. Chem. 1993, 58, 3869 (b) Bernhardt, P. V.;
Lawrance, G. A. Coord. Chem. Rev. 1990, 104, 297. (c) Kaden, T. A.
Top. Curr. Chem. 1984, 121, 157.
(3) (a) Bridger, G.; Skerlj, R.; Thornton, D.; Padmanabhan, S.;
Martellucci, S.; Henson, G.; Abrams, M.; Yamamoto, N.; De Vreese,
K.; Pauwels, R.; De Clercq, E. J . Med. Chem. 1995, 38, 366. (b) Bridger,
G. J .; Skerlj, R. T.; Padmanabhan, S.; Martellucci, S. A.; Henson, G.
W.; Abrams, M. J .; J oao, H. C.; Witvrouw, M.; De Vreese, K.; Pauwels,
R.; De Clercq, E. J . Med. Chem. 1996, 39, 109.
(4) In fact, the anti-HIV activity of bis-cyclams was serendipitously
discovered due to the presence of a 1.5-3% impurity of d,l-2,2′-bicyclam
in a commercially available sample of cyclam prepared by a nickel-
template synthesis. See Barefield, E. K.; Chueng, D.; Van Derveer, D.
G.; Wagner, F. J . Chem. Soc., Chem. Commun. 1981, 302.
(5) For a survey of bis-macrocyclic ligands see Sessler, J . L.; Sibert,
J . W. Tetrahedron 1993, 49, 8727.
(14) Takenouchi, K.; Watanabe, K.; Kato, Y.; Koike, T.; Kimura, E.
J . Org. Chem. 1993, 58, 1955.
(15) For the synthesis of 6,6′-bicyclam dimers and related ligands/
transition metal complexes, see (a) Fabbrizzi, L.; Forlini, F.; Perotti,
A.; Seghi, B. Inorg. Chem. 1984, 23, 807. (b) Fabbrizzi, L.; Montagna,
L.; Poggi, A.; Kaden, T. A.; Siegfried, L. C. J . Chem. Soc., Dalton Trans.
1987, 2631. (c) Dumas, S.; Lastra, E.; Hegedus, L. S. J . Am. Chem.
Soc. 1995, 117, 3368. (d) Inouye, Y.; Kanamori, T.; Yoshida, T.; Bu,
X.; Shionoya, M.; Koike, T.; Kimura, E. Biol. Pharm. Bull. 1994, 17,
243. (e) Mochizuki, K.; Gotoh, H.; Suwabe, M.; Sakakibara, T. Bull.
Chem. Soc. J pn. 1991, 64, 1750. (f) Mochizuki, K.; Higashiya, S.;
Uyama, M.; Kimura, T. J . Chem. Soc., Chem. Commun. 1994, 2673.
(g) Kajiwara, T.; Yamaguchi, T.; Kido, H.; Kawabata, S.; Kuroda, R.;
Ito, T. Inorg. Chem. 1993, 32, 4990. (h) Mountford, H. S.; Spreer, L.
O.; Otvos, J . W.; Calvin, M.; Brewer, K. J .; Richter, M.; Scott, B. Inorg.
Chem. 1992, 31, 718.
(16) McMurray, T. J .; Brechbiel, M.; Kumar, K.; Gansow, O. A.
Bioconjugate Chem. 1992, 3, 108.
0022-3263/96/1961-1519$12.00/0 © 1996 American Chemical Society

1520 J . Org. Chem., Vol. 61, No. 4, 1996
Notes
Sch em e 1
cyclams) in which the key macrocyclization step is the
aminolysis of esters or reaction of deprotonated tosyla-
mides with bis-electrophiles (the Richman-Atkins cy-
clization19 ).
However, these collective routes suffer from at least
one of several disadvantages: (a) the reported (protected)
functional groups chosen for incorporation are only
compatible with a small number of post-macrocyclization
functional group transformations; (b) the macrocycliza-
tion reaction is low yielding; and (c) each azamacrocycle
is constructed with a fixed carbon substituent connecting
the functional group to the azamacrocyclic ring, thus
limiting the opportunities for divergency of the side chain
from a single macrocyclic intermediate. From our per-
spective, it was desirable to incorporate a versatile
functional group directly upon the carbon backbone which
is stable to the macrocyclization conditions, and is also
capable of C-C bond forming reactions on the fully-
constructed azamacrocyclic ring. Based on the reports
of Burrows20 and Guglielmetti21 on the synthesis of
C-functionalized cyclams, in conjunction with our own
experience with the synthesis of azamacrocycles,3 the
Richman-Atkins cyclization methodology remains one
of the most efficient methods for construction of azamac-
rocyclic rings and has the added advantage that the
p-toluenesulfonamido group is stable to a wide variety
of post-macrocyclization reaction conditions. We herein
report that all of our compatibilty requirements were
satisfied by the incorporation of a C-appended, N-
methoxy-N-methylamide (Weinreb amide22 ) within an
ethylenediamine synthon which not only withstands the
deprotonated tosylamide macrocyclization conditions but
also serves as a convenient and versatile carbonyl
equivalent for further structural modification on the
azamacrocyclic (cyclam) ring.
to the Weinreb’s amide 5 by reaction with N,O-dimeth-
ylhydroxylamine hydrochloride in CH2Cl2 in the presence
of Et3N (overall yield 81% from 4). The left-hand
precursor 9 of the azamacrocycle 10a was obtained in a
straightforward manner in three steps from ethylenedi-
aminedipropionic acid (6) in an overall 76% yield. To-
sylation of 6 (under identical conditions to 3) gave the
diacid 7 which was reduced with BH3‚THF giving the diol
8. Derivatization of 8 with methanesulfonyl chloride
under standard conditions gave the dimesylate 9. Mac-
rocyclization to give 10a was accomplished by a modified
Richman-Atkins procedure: dropwise addition of a DMF
solution of 9 to a solution of 5 in DMF (final concentration
Resu lts a n d Discu ssion
The convergent synthesis of the requisite fully pro-
tected 2-(N-methoxy-N-methylcarboxamido)cyclam de-
rivative 10a was accomplished in six steps from com-
mercially available amino acids as illustrated in Scheme
1. Tosylation of 2,3-diaminopropionic acid (3) in dioxane/
H2O in the presence of sodium hydroxide gave the acid
(4) in 93% yield. Reaction of 4 with excess oxalyl chloride
in CH2Cl2 and a small volume of DMF gave the corre-
sponding acid chloride which was immediately converted
23
0.022 M) containing excess Cs2CO3 maintained at a
temperature of 65 °C gave the fully protected azamac-
rocycle 10a in a 70% isolated yield following purification
by column chromatography on silica gel. Under these
reaction conditions, we saw no evidence for formation of
the N-methylamide of 10a (or 5), a byproduct observed
by a number of groups when certain N-methoxy-N-
methylamides were reacted with hindered and/or highly
basic nucleophiles.24
The cyclam derivative 10a undergoes chelation con-
trolled nucleophilic addition reactions with good specific-
ity characteristic of N-methoxy-N-methylamides.25 For
example, addition of 3.5 equiv of methyllithium to a
solution of 10a in THF at -78 °C followed by quenching
the reaction mixture with water gave the methyl ketone
10b in 76% isolated yield.26 Alternatively, the amide 10a
can be reduced with 1.5 equiv of LiAlH4 (or DIBAL-H)
(17) For alternative approaches that introduce two alkyl or aryl
groups at the 2,10 or 2,3 positions of the cyclam ring, see (a) Wagler,
T. R.; Fang, Y.; Burrows, C. J . J . Org. Chem. 1989, 54, 1584. (b) Kise,
N.; Oike, H.; Okazaki, E.; Yoshimoto, M.; Shono, T. J . Org. Chem. 1995,
60, 3980 and references therein.
(18) For leading references on the synthesis of [12]aneN4 ligands
functionalized on the carbon backbone for covalent attachment to
tumor selective monoclonal antibodies, see (a) Moi, M. K.; Meares, C.
F. J . Am. Chem. Soc. 1988, 110, 6266. (b) Renn, O.; Meares, C. F.
Bioconjugate Chem. 1992, 3, 563. (c) Cox, J . P. L.; J ankowski, K. J .;
Katusky, R.; Parker, D.; Beeley, N. R. A.; Boyce, B. A.; Eaton, M. A.
W.; Millar, K.; Millican, A. T.; Harrison, A.; Walker, C J . Chem. Soc.,
Chem. Commun. 1989, 797. (d) Cox, J . P. L.; Craig, A. S.; Helps, I. M.;
J ankowski, K. J .; Parker, D.; Eaton, M. A. W.; Millican, A. T.; Millar,
K.; Beeley, N. R. A.; Boyce, B. A. J . Chem. Soc. Perkin Trans. 1 1990,
2567. (e) Takenouchi, K.; Tabe, M.; Watanabe, K.; Hazato, A.; Kato,
Y.; Shionoya, M.; Koike, T.; Kimura, E. J . Org. Chem. 1993, 58, 6895.
(19) (a) Richman, J . E.; Atkins, T. J . J . Am. Chem. Soc. 1974, 96,
2268. (b) Atkins, T. J . Richman, J . E.; Oettle, W. F. Org. Synth. 1978,
58, 86.
(23) Vriesema, B. K.; Butler, J .; Kellogg, R. M. J . Org. Chem. 1984,
49, 110.
(24) (a) Graham, S. L.; Scholz, T. H. Tetrahedron Lett. 1990, 31,
6269. (b) Graham, S. L.; Scholz, T. H. J . Org. Chem. 1991, 56, 4260.
(c) Lubell, W. D.; J amison, T. F.; Rapoport, H. J . Org. Chem. 1990,
55, 3511. (d) Romo, D.; J ohnson, D. D.; Plamondon, L.; Miwa, T.;
Schreiber, S. L. J . Org. Chem. 1992, 57, 5060.
(20) Wagler, T. R; Burrows, C. J . J . Chem. Soc., Chem. Commun.
1987, 277.
(21) Benabdallah, T.; Guglielmetti, R. Helv. Chim. Acta. 1988, 71,
602.
(25) For a recent review of the applications of N-methoxy-N-methyl
amides see Sibi, M. P. Org. Prep. Proced. Int. 1993, 25, 15.
(22) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.

Notes
J . Org. Chem., Vol. 61, No. 4, 1996 1521
and 2,3-diaminopropionic acid monohydrochloride (3) were
obtained from TCI America (Portland, OR).
Sch em e 2
N,N-Bis(p-tolu en esu lfon yl)-N,N′-bis(2-ca r boxyeth yl)eth -
ylen ed ia m in e (7). In a three-necked round-bottomed flask
equipped with a pH electrode and a mechanical stirrer was
placed 6 (5.0 g, 18.0 mmol), dioxane (30 mL), and H2O (120 mL).
A dropping funnel containing 1 N NaOH was placed on the flask,
and the pH was adjusted by titration to pH 9 during which time
the mixture became homogeneous. An ice bath was placed under
the flask and solid p-toluenesulfonyl chloride (7.6 g, 39.7 mmol)
was added in small portions over 30 min with vigorous stirring.
The reaction mixture was maintained at pH 9 for 6 h by titration
with NaOH then more p-toluenesulfonyl chloride was added (1.5
g). Stirring was continued with pH monitoring for 3 h and then
stirred overnight while warming to room temperature during
which time the pH had dropped to pH 6 and product had
precipitated. NaOH was added until unreacted p-toluenesulfo-
nyl chloride alone remained suspended and was filtered off. The
pH of the filtrate was lowered to pH 4 with 1 N HCl and cooled
in an ice bath. The white solid which precipitated was collected
by filtration, washed with H2O, and dried giving 7 (8.10 g, 88%)
1
as a white solid; mp 204-205 °C; H NMR (CDCl3/MeOH-d4) δ
2.45 (6H, s), 2.62 (4H, t, J ) 7.2 Hz), 3.29 (4H, s), 3.42 (4H, t, J
) 7.2 Hz), 7.36 (4H, m), 7.73 (4H, m). Anal. Calcd for
C
22H28N2O8S2: C, 51.55; H, 5.52; N, 5.46. Found: C, 51.48; H,
5.53; N, 5.46.
N,N′-Bis(p-tolu en esu lfon yl)-2,3-d ia m in op r op ion ic Acid
(4). In a similar manner, 3 (5.0 g, 0.036 mol) gave 4 (13.6 g,
93%) as a white solid: mp 227-228 °C dec; 1H NMR (DMSO-
d6) δ 2.37 (3H, s), 2.39 (3H, s), 2.61 (1H, m), 2.77 (1H, m), 3.82
(1H, m), 7.29-7.36 (4H, m), 7.51-7.61 (4H, m), 7.69 (1H, m),
8.99 (1H, d, J ) 9.0 Hz). Anal. Calcd for C17H20N2O6S2: C,
49.50; H, 4.89; N, 6.79. Found: C, 49.23; H, 4.86; N, 6.78.
N,N′-Bis(p-tolu en esu lfon yl)-N,N′-bis(3-h yd r oxyp r op yl)-
eth ylen ed ia m in e (8). To a stirred solution of 7 (25.0 g, 0.049
mol) in anhydrous THF (300 mL) under argon at 0 °C was added
BH3‚THF dropwise (Aldrich, 500 mL, 1.0 M solution in THF,
10 equiv), and the mixture was stirred overnight at room
temperature. The excess BH3‚THF was evaporated at reduced
pressure and the residue treated with 5% HCl giving a white
suspension. The pH of the mixture was adjused to pH 9 with 1
N NaOH and extracted with CH2Cl2 (3 × 200 mL). The organic
extracts were dried (MgSO4) and evaporated under reduced
pressure to give 8 (22.6 g, 96%) as a white solid: mp 134-135
in THF at -20 °C to give the aldehyde 11 (the corre-
sponding alcohol byproduct could not be detected in the
1H NMR of the crude 11) which was used for the
synthesis of (()J M2936 (2) as shown in Scheme 2. The
crude product 11 was homologated with (carbethoxy-
methylene)triphenylphosphorane (1.0 equiv) at room
temperature in CH2Cl2 to give a 86:14 (E:Z) mixture of
R,â-unsaturated esters 12 in 64% overall yield from 10a .
A two-step reduction of 12 with H2/Pd/C (to give the ester
13) followed by BH3‚THF gave the alcohol 14 which was
subsequently converted to the corresponding bromide 15
in 85% yield by reaction with CBr4/PPh3 in refluxing
benzene. To complete the synthesis of the desired bis-
tetraazamacrocycle, bromide 15 was reacted with 4,8,-
11-tris(p-toluenesulfonyl)-1,4,8,11-tetraazacyclotetrade-
cane (16)27 in refluxing CH3CN in the presence of excess
K2CO3 to give the heptatosyl protected dimer 17. Finally,
deprotection of the p-toluenesulfonamido groups by hy-
drolysis with 48% aqueous HBr/acetic acid at reflux gave
(()J M2936 (2) which precipitated from the reaction
mixture as the octahydrobromide salt.
In summary, we have presented a general and conve-
nient method for the introduction of substituents on the
carbon backbone of azamacrocycles via a Weinreb amide
attached to the periphery of a single macrocyclic inter-
mediate. Since the Weinreb amide is introduced into the
ring from an amino acid precursor, and nucleophilic
additions occur without loss of enantiomeric purity,25 this
method is also applicable to the synthesis of optically
pure azamacrocycles.
1
°C; H NMR (CDCl3) δ 1.79 (4H, m), 2.20 (1H, br s), 2.44 (6H,
s), 3.25 (4H, t, J ) 6.6 Hz), 3.30 (4H, s), 3.73 (4H, m), 7.33 (4H,
m), 7.69 (4H, m). Anal. Calcd for C22H32N2O6S2: C, 54.52; H,
6.65; N, 5.78. Found: C, 54.29; H, 6.59; N, 5.72.
N,N′-Bis(p -t olu en esu lfon yl)-N,N′-b is[[(m et h a n esu lfo-
n yl)oxy]p r op yl]eth ylen ed ia m in e (9). To a stirred suspension
of 8 (22.5 g, 0.047 mol) in CH2Cl2 (500 mL) containing Et3N (16.2
mL) was added methanesulfonyl chloride (7.91 mL, 2.2 equiv)
dropwise at 0 °C, and the mixture was allowed to warm to room
temperature overnight during which time it became yellow and
homogeneous. The solution was washed with saturated aqueous
NaHCO3 (3 × 100 mL) and brine (2 × 100 mL) and then dried
(MgSO4) and evaporated under reduced pressure. The solid
residue was recrystallized from EtOAc to give 9 (26.8 g, 90%)
1
as a white crystalline solid: mp 148-149 °C; H NMR (CDCl3)
δ 2.04 (4H, m), 2.45 (6H, s), 3.06 (6H, s), 3.23 (4H, t, J ) 6.9
Hz), 3.28 (4H, s), 4.30 (4H, t, J ) 5.7 Hz), 7.35 (4H, m), 7.69
(4H, m); DCI MS m/ z 641 (35, M), 391 (93), 295 (39), 235 (52),
157 (100). Anal. Calcd for C24H36N2O10S4: C, 44.98; H, 5.66;
N, 4.37. Found: C, 44.85; H, 5.63; N, 4.35.
2,3-Bis[(p-tolu en esu lfon yl)a m in o]-N-m eth oxy-N-m eth yl-
p r op a n a m id e (5). To a stirred suspension of 4 (8.0 g, 19.4
mmol) in anhydrous CH2Cl2 (200 mL) under argon at 0 °C was
added oxalyl chloride (Aldrich, 2 M solution in CH2Cl2, 97.0 mL)
dropwise followed by DMF (1.0 mL). The mixture was allowed
to warm to room temperature over 5 h during which time it
became orange and homogeneous. The excess oxalyl chloride
was evaporated under reduced pressure and anhydrous CH2Cl2
added (200 mL), and the mixture was evaporated once again.
This procedure was repeated three times and the residual oil
was then placed on a high-vacuum pump for 30 min giving a
yellow foam. Anhydrous CH2Cl2 (200 mL) was added once again
under argon with stirring, and the solution was cooled to 0 °C.
N,O-Dimethylhydroxylamine hydrochloride (Aldrich, 18.9 g, 10
Exp er im en ta l Section
Gen er a l. See reference 3 for general experimental proce-
dures. 1H NMR spectra were recorded at 300 MHz. The starting
materials, ethylenediaminedipropionic acid dihydrochloride (6)
(26) Although the p-toluenesulfonamido group is considered “un-
stable” with respect to alkyllithium and Grignard reagents, we have
found that a large excess of the reagent and elevated temperatures
are required for deprotection: See Greene, T. W.; Wuts, P. G. M.
Protective groups in organic synthesis, 2nd ed., J ohn Wiley & Sons,
1991. Similarly, the N-methyl amide of 10a was not observed, see
reference 24.
(27) Ciampolini, M.; Fabbrizzi, L.; Perotti, A.; Poggi, A.; Seghi, B.;
Zanobini, F. Inorg. Chem. 1987, 26, 3527.

1522 J . Org. Chem., Vol. 61, No. 4, 1996
Notes
equiv) was added in one portion followed by anhydrous Et3N
dropwise until all of the N,O-dimethylhydroxylamine hydro-
chloride had dissolved. The solution was then allowed to stir
overnight at room temperature during which time the orange
color had faded. The solvent was evaporated under reduced
pressure and the residue partitioned between EtOAc and
saturated aqueous NaHCO3, and the organic layer was sepa-
rated, dried (MgSO4), and evaporated under reduced pressure.
The solid white residue was dissolved in a minimum volume of
EtOAc and triturated with ether giving 5 (7.10 g, 81%) as a white
solid: mp 197-198 °C; 1H NMR (CDCl3) δ 2.41 (3H, s), 2.44 (3H,
s), 3.01 (4H, s overlapping m), 3.24 (1H, m), 3.46 (3H, s), 4.24
(1H, m), 5.09 (1H, m), 5.68 (1H, d, J ) 8.4 Hz), 7.26-7.32 (4H,
m), 7.66-7.73 (4H, m); DCI MS m/ z 456 (100, M), 302 (42), 172
(26). Anal. Calcd for C19H25N3O6S2: C, 50.09; H, 5.53; N, 9.22.
Found: C, 50.20; H, 5.50; N, 9.19.
2-(3-Hydr oxypr opyl)-1,4,8,11-tetr akis(p-tolu en esu lfon yl)-
1,4,8,11-tetr a a za cyclotetr a d eca n e (14). The white foam from
above was dissolved in anhydrous THF (50 mL) with stirring
under argon, and BH3‚THF (Aldrich, 1.0 M solution in THF, 5.0
equiv, 6.3 mL) was added. The mixture was heated to reflux
for 5 h and then allowed to cool and evaporated to dryness under
reduced pressure, and the residue was quenched with 5% HCl
(10 mL). The white suspension was made basic with 1 N NaOH
until pH 9 and then extracted with EtOAc (3 × 50 mL), the
combined organic extracts were dried (MgSO4) and evaporated
under reduced pressure, and the residue was purified by column
chromatography on silica gel (EtOAc/hexane, 7:3) giving 14 (820
mg, 90% from 12): mp 119-120 °C; 1H NMR (CDCl3) δ 1.26
(2H, br m), 1.75-2.04 (6H, br m), 2.44 (12H, s), 2.70-3.41 (15H,
br m), 3.46 (2H, m), 7.26-7.35 (8H, m), 7.63-7.75 (8H, m); FAB
MS m/ z 875 (100, M + H), 719 (80), 565 (32). Anal. Calcd for
2-(N-Meth oxy-N-m eth ylca r boxa m oyl)-1,4,8,11-tetr a k is-
(p-tolu en esu lfon yl)-1,4,8,11-tetr aazacyclotetr adecan e (10a).
To a stirred solution of 5 (7.10 g, 0.0156 mol) and cesium
carbonate (12.72 g, 2.5 equiv) in anhydrous DMF (550 mL)
maintained at 65 °C (oil bath temperature) was added dropwise
a solution of 9 (10.0 g, 1.0 equiv) in DMF (150 mL) over 24 h
under argon. The mixture was allowed to stir at 65 °C for 48 h
and then allowed to cool and evaporated under reduced pressure.
The residue was partitioned between EtOAc and H2O, and the
organic layer was separated, washed exhaustively with brine,
dried (MgSO4), and evaporated under reduced pressure to give
the crude product as a white solid. Purification by column
chromatography on silica gel (EtOAc/hexane, 1:1) gave 10a (9.5
C
41H54N4S4O9: C, 56.22; H, 6.17; N, 6.40. Found: C, 56.17; H,
6.21; N, 6.32.
2-(3-Br om op r op yl)-1,4,8,11-tetr a k is(p-tolu en esu lfon yl)-
1,4,8,11-tetr a a za cyclotetr a d eca n e (15). 14 (600 mg, 0.69
mmol), triphenylphosphine (451 mg, 2.5 equiv), and carbon
tetrabromide (570 mg, 2.5 equiv) were heated to reflux in
benzene (50 mL) for 5.0 h and then allowed to cool and
evaporated under reduced pressure. The residue was purified
by column chromatography on silica gel (EtOAc/hexane, 1:1),
giving 15 (550 mg, 85%) as a white foamy solid: mp 116-117
°C; 1H NMR (CDCl3) δ 1.40 (2H, br m), 1.60-2.00 (6H, br m),
2.44 (12H, s), 2.90 (2H, m), 3.05-3.49 (15H, br m), 7.31-7.35
(8H, m), 7.63-7.75 (8H, m); FAB MS m/ z 939 (97, M81Br + H),
1
g, 70%) as a white foam: mp 108-109 °C; H NMR (CDCl3) δ
1.61-1.92 (2H, br m), 2.25 (2H, br m), 2.43-2.45 (12H, m), 2.85-
2.97 (4H, br m), 2.99 (3H, s), 3.04-3.50 (7H, br m), 3.52 (6H, s
overlapping m), 5.31 (1H, m), 7.26-7.40 (8H, m), 7.66-7.79 (8H,
m); 13C NMR (75 MHz, CDCl3) δ 21.42, 25.62, 29.76, 44.85, 47.57,
48.36, 49.06, 50.59, 56.90, 61.30, 127.34-127.89, 129.39-129.77,
133.53, 134.69, 135.30, 136.98, 143.51, 143.97, 166.79; FAB MS
m/ z 905 (35, M + H), 904 (56, M), 748 (100), 659 (100). Anal.
Calcd for C41H53N5O10S4: C, 54.42; H, 5.86; N, 7.74. Found: C,
54.42; H, 5.89; N, 7.68.
937 (87, M79Br + H), 783 (100), 627 (34). Anal. Calcd for C41H53
-
N4S4O8Br: C, 52.45; H, 5.65; N, 5.97. Found: C, 52.58; H, 5.72;
N, 5.85.
1′,4,4′,8,8′,11,11′-H ep t a k is(p -t olu en esu lfon yl)-1,2′-(1,3-
p r op a n ed iyl)bis(1,4,8,11-tetr a a za cyclotetr a d eca n e) (17).
To a solution of 15 (200 mg, 0.21 mmol) and 4,8,11-tris(p-
toluenesulfonyl)-1,4,8,11-tetraazacyclotetradecane27 (16, 141 mg,
1.0 equiv) in CH3CN (10 mL) was added anhydrous K2CO3 (58
mg, 2.0 equiv), and the mixture was heated to reflux with
stirring for 8 days under argon. The mixture was evaporated
under reduced pressure, and the crude product was purified by
column chromatography on silica gel (EtOAc/hexane, 6:4) to give
2-(2-Car beth oxyeth en yl)-1,4,8,11-tetr akis(p-tolu en esu lfo-
n yl)-1,4,8,11-tetr a a za cyclotetr a d eca n e (12). To a stirred
solution of 10a (1.50 g, 1.66 mmol) in THF (50 mL) under argon
at -20 °C was added LiAlH4 (Aldrich, 1.0 M solution in THF,
2.48 mL, 1.5 equiv) dropwise, and the mixture was stirred at
this temperature for 30 min and then quenched with 5% HCl
(10 mL). The mixture was extracted with EtOAc (3 × 50 mL),
and the combined extracts were washed with saturated aqueous
NaHCO3, dried (MgSO4), and evaporated under reduced pressure
to give 11 as a white foamy solid: 1H NMR (CDCl3) δ 1.72-
2.02 (4H, m), 2.44 (12H, m), 2.81-3.64 (12H, m), 4.18 (2H, dd,
J ) 15.7, 5.1 Hz), 4.40 (1H, t, J ) 5.1 Hz), 7.26-7.35 (8H, m),
7.60-7.78 (8H, m), 9.76 (1H, s). This was used without further
purification. The solid was dissolved in anhydrous CH2Cl2 (50
mL) under argon, (carbethoxymethylene)triphenylphosphorane
(Aldrich, 578 mg, 1.0 equiv) was added, and the mixture was
stirred overnight at room temperature. The solution was
evaporated under reduced pressure and purified directly by
column chromatography on silica gel (EtOAc/hexane, 1:1) giving
a white foamy solid identified by 1H NMR as an 86:14 (E:Z)
mixture of 12 (0.96 g, 64%): mp 110-111 °C; 1H NMR (CDCl3)
[trans-isomer] δ 1.29 (3H, t, J ) 6.9 Hz), 1.70-2.01 (4H, m),
2.41 (3H, m), 2.44 (9H, s), 3.04 (6H, br m), 3.20-3.45 (8H, br
m), 4.16 (2H, q, J ) 6.9 Hz), 4.40 (1H, m), 5.75 (1H, d, J ) 15.9
Hz), 6.85 (1H, dd, J ) 15.9, 8.1 Hz), 7.29-7.35 (8H, m), 7.65-
7.70 (8H, m); FAB MS m/ z 915 (63, M + H), 869 (27), 760 (100),
606 (52).
1
17 (200 mg, 62%) as a white foamy solid: mp 135-136 °C; H
NMR (CDCl3) δ 1.65 (6H, br m), 2.90 (6H, br m), 2.20 (2H, br
m), 2.42 (21H, br m), 2.50 (2H, br m), 2.80-3.61 (29H, br m),
7.26-7.32 (14H, m), 7.64-7.80 (14H, m); FAB MS m/ z 1519
(100, M + H), 1363 (31), 1209 (8). Anal. Calcd for C72H94
-
N8S7O14: C, 56.84; H, 6.18; N, 7.37. Found: C, 57.26; H, 6.39;
N, 7.06.
1,2′-(1,3-P r op a n ed iyl)bis(1,4,8,11-tetr a a za cyclotetr a d e-
ca n e) Octa h yd r obr om id e Dih yd r a te [(()J M2936, 2]. 17
(550 mg) was dissolved in a mixture of acetic acid and hydro-
bromic acid (Aldrich, 48% aqueous, 50 mL) (3:2) and heated to
reflux for 4 days during which time a white crystalline solid
precipitated. The mixture was allowed to cool, and the solid was
collected by filtration, washed with acetic acid and then ether,
and dried in vacuo to give 2 (275 mg, 70%) as a white powder:
1
mp 270-271 °C dec.; H NMR (D2O) δ 1.40 (2H, m), 1.50-1.95
(10H, br m), 2.60-2.80 (2H, m), 2.80-3.50 (31H, br m); FAB
MS m/ z 524 (89, MH + H81Br), 522 (100, MH + H79Br), 442
(68, M + H). Anal. Calcd for C23H52N8‚8HBr‚2H2O: C, 24.55;
H, 5.69; N, 9.96. Found: C, 24.57; H, 5.75; N, 9.64.
2-((2-Ca r beth oxyeth yl)-1,4,8,11-tetr a k is(p-tolu en esu lfo-
n yl)-1,4,8,11-tetr a a za cyclotetr a d eca n e (13). To a solution
of 12 (0.96 g) in EtOAc/MeOH (1:1, 60 mL) was added palladium
on carbon (Aldrich, 10%, 500 mg), and the mixture was hydro-
genated on a Parr apparatus at 50 psi for 48 h. The mixture
was filtered through Celite and evaporated under reduced
pressure, giving 13 as a white foam: 1H NMR (CDCl3) δ 1.23
(3H, t, J ) 7.2 Hz), 1.60-1.90 (6H, br m), 2.15 (2H, br m), 2.44
(12H, m), 2.80-3.60 (15H, br m), 4.05 (2H, q, J ) 7.2 Hz), 7.26-
7.34 (8H, m), 7.65-7.80 (8H, m). This was used directly in the
next step.
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
spectra for compounds 10b, 11, 12, and 13 (4 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
J O951499W