Application of the Heck reaction in the synthesis of macrocycles derived from amino alcohols

Article abstract of DOI:10.1055/s-2006-947328

A double Heck reaction is the key step in a straightforward and versatile synthesis of nitrogen-rich macrocycles, including one which X-ray crystallography has revealed forms a tube-like structure. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-947328

LETTER
2929
Application of the Heck Reaction in the Synthesis of Macrocycles Derived from
Amino Alcohols
Heck
R
eaction
u
inthe Synth
s
esis of
M
a
a
Department of Chemistry, Imperial College London, South Kensington Campus, London SW7 2AY, UK
Fax +44(207)5945804; E-mail: s.gibson@imperial.ac.uk
b
Department of Chemical Crystallography, Imperial College London, South Kensington Campus, London SW7 2AY, UK
Received 22 February 2006
Abstract: A double Heck reaction is the key step in a straightfor-
ward and versatile synthesis of nitrogen-rich macrocycles, includ-
ing one which X-ray crystallography has revealed forms a tube-like
structure.
O
N
Bn
O
I
7
Key words: amino alcohols, asymmetric synthesis, Heck reaction,
macrocycles, palladium
Pd(OAc)2 (10 mol%), n-Bu4NCl
NaHCO3, DMF (0.05 M)
110 °C, 16 h
The synthesis, structure and physical properties of macro-
cycles have fascinated chemists for many years.1 Their
inherent properties make them useful in areas as diverse
as ion transport across membranes, development of new
antibiotics, and catalysis.2 Examples drawn from the sub-
set of non-peptidic amino acid derived macrocycles in-
clude the natural product K-13 1 (Figure 1), which is an
inhibitor of the zinc metalloproteinase angiotensin I con-
verting enzyme,3 the marine sponge-derived jaspamide
(2), the Li+ complex of which has been used to model the
cation–p-interactions acknowledged to be important in
protein–DNA complexes,4 the synthetic adamantyl-rich
macrocycle 3, which has been shown to be capable of
transporting Na+ across a lipid bilayer,5 the synthetic
valine derivative 4, which forms a gel containing right-
hand twisted ribbons several micrometers long in organic
solvents,6 the synthetic tetraamide 5, which exhibits
surprisingly good enantioselectivity towards dipeptides
given the mimimal amount of chirality incorporated into
its structure,7 and the pyridine-containing macrocycle 6,
which self-assembles into a supramolecular structure
containing two tubes.8
N
Bn
O
O
O
O
Bn
N
8
17% yield
+
N
Bn
O
O
O
O
NBn
BnN
O
O
9
12% yield
As a result of our ongoing interest in the use of the Heck
reaction to make medium and large rings,9 we recently
developed a synthesis of non-racemic chiral macrocycles
based on Heck substrates typified by structure 7
(Scheme 1).10
Scheme 1
cules in which the ester linkages have been replaced by
amide linkages, e.g. structure 10 (Figure 2), and to replace
the benzene rings with heterocycles such as pyrrole as
illustrated in structure 11. The synthesis of 10 and 11, and
related proline-containing macrocycles, together with an
X-ray crystallographic analysis of one of the macrocycles
are reported here.
Under standard Heck conditions, macrocycles formed by
either two or three ‘head-to-tail’ coupling reactions (8 and
9 in this example) were formed.
In order to increase the number of sites for potential inter-
actions with guests, and to increase the hydrogen bonding
capacity of the macrocycles, we decided to target mole-
The synthesis of the Heck substrate 16, which it was pro-
posed would provide target macrocycle 10, began with a
reductive amination reaction between 4-iodobenzalde-
hyde, readily available in two steps from commercially
available 4-iodobenzoic acid,11 and (S)-valinol, obtained
by reduction of commercially available (S)-valine
SYNLETT 2006, No. 18, pp 2929–2934
0
3
.1
1
.2
0
0
6
Advanced online publication: 04.08.2006
DOI: 10.1055/s-2006-947328; Art ID: S02006ST
© Georg Thieme Verlag Stuttgart · New York

2930
S. E. Gibson et al.
LETTER
OH
OH
O
O
O
O
HN
O
Br
H
N
N
O
O
N
HN
H
H
HOOC
O
N
1
NH
OH
O
2
O
O
O
NH
HN
O
O
O
N
N
H
H
NH
O
HN
O
O
O
Ph
3
H
H
N
N
N
H
N
H
N
O
O
O
O
NH
HN
5
4
O
O
O
O
O
N
O
N
R
MeO
H
H
OMe
H
O
O
O
N
N
O
N
O
R
N
N
O
O
O
O
H
H
O
O
R
N
R
N
O
O
O
H
H
6
O
O
O
N
R
R
N
N
R
O
O
O
N
O
H
H
R
O
O
R
N
R
R
H
N
O
O
O
N
O
O
N
O
H
N
H
O
O
O
N
N
O
O
O
H
N
O
O
O
R
H
Figure 1
(Scheme 2).12 Amino alcohol 12 was isolated as a pale substrate 16, was achieved using a Mitsunobu reaction.13
yellow oil, and the secondary amine was subsequently Diethyl azodicarboxylate (DEAD) was added to a stirred
protected as its benzyl derivative 13.
solution of triphenylphosphine in THF at low tempera-
ture, followed by a THF solution of 13. Diphenyl phos-
phoryl azide was then added followed, after 24 hours, by
The replacement of the oxygen functionality in 13 with a
nitrogen functionality, the key step in the synthesis of
N
N
N
Bn
Bn
Bn
O
HN
HN
N
O
Bn
O
O
O
O
Bn
O
NH
NH
O
N
Bn
N
Bn
Bn
N
N
8
10
11
Figure 2
Synlett 2006, No. 18, 2929–2934 © Thieme Stuttgart · New York

LETTER
Heck Reaction in the Synthesis of Macrocycles
2931
31% yield of the desired macrocycle 10, which was fully
characterized by standard spectroscopic techniques and
elemental analysis.16 A doublet at d = 7.33 ppm in the 1H
NMR spectrum of 10, attributed to the vinylic benzylic
hydrogen, indicated a successful cyclization. The geo-
metry of the double bond was assigned as E from the
coupling constant between the two vinylic hydrogens
(J = 15.6 Hz).
OH
CHO
1) (S)-valinol, MgSO4
N
H
2) NaBH4
I
I
12
92% yield
K2CO3, BnBr,
18-crown-6
1) PPh3/DEAD
OH
N
Bn
2) 13
3) (PhO)2P(O)N3
4) H2O
Encouraged by this success, the effect of replacing valinol
with prolinol was examined. Use of prolinol was intended
not only to probe the effect of the use of a relatively
constrained amino acid skeleton on the synthesis of the
macrocycle, but also to start to test the flexibility of our
approach to non-racemic chiral macrocycles with respect
to the amino acid-derived component. Reductive amina-
tion of 4-iodobenzaldehyde with (S)-prolinol, obtained by
reduction of commercially available (S)-proline,17 gave
the amino alcohol 17 (Scheme 3). Conversion of the alco-
hol to the azide 18, reduction to the amine 19, and acyla-
tion to the acrylamide 20 all proceeded smoothly in the
presence of the tertiary amine derived from proline. Final-
ly, the Heck reaction of acylamide 20 afforded the desired
macrocycle 21 in 40% yield. Macrocycle 21 was fully
characterized and its structure was confirmed by X-ray
crystallographic analysis (Figure 3).
I
13
65% yield
acryloyl
chloride
PPh3,
H2O
N3
NH2
N
N
Bn
Bn
I
DIPEA
I
14
15
87% yield
85% yield
Pd(OAc)2
(10 mol%)
n-Bu4NCl
(1 equiv)
N
H
Bn
N
HN
N
O
Bn
O
NaHCO3
(2.5 equiv)
DMF, 110 °C,
16 h
I
O
NH
16
Bn
N
87% yield
1) (S)-prolinol,
MgSO4
CHO
1) PPh3/DEAD
N
10
31% yield
2) NaBH4
I
I
2) 17
3) (PhO)2P(O)N3
4) H2O
OH
Scheme 2
17
92% yield
distilled water. After a further hour of stirring, work-up of
the product mixture gave an 87% yield of azide 14. The
ease and reliability of this procedure facilitated the syn-
thesis of multi-gram amounts of 14.
N
acryloyl chloride
Et3N, DMAP
PPh3, H2O
N
I
I
N3
NH2
19
78% yield
Attempts to reduce azide 14 to its N-Boc-protected amine
using hydrogen gas in the presence of di-(tert-butyl)di-
carbonate (Boc2O) and Lindlar catalyst,14 or to amine 15
using lithium aluminiumhydride led to the return of un-
reacted starting material in the former case, and partial
loss of the iodine atom in the latter case. A Staudinger re-
action, used previously to convert an azido-glycoside into
the corresponding amino-glycoside in the presence of a 4-
iodobenzene substituent,15 however, proved to be success-
ful. Triphenylphosphine and distilled water were added to
a THF solution of azide 14, and the resulting mixture was
stirred at 50 °C for 16 hours, during which time the evo-
lution of nitrogen from the reaction flask was observed.
18
57% yield
N
Pd(OAc)2 (10 mol%)
n-Bu4NCl (1 equiv)
N
O
NH
O
I
O
HN
NaHCO3 (2.5 equiv)
DMF, 110 °C, 16 h
HN
20
72% yield
N
21
40% yield
Scheme 3
Work-up led to the isolation of amine 15; once again, the
ease and reliability of this procedure facilitated the syn-
thesis of multi-gram quantities of product.
In order to replace the benzene rings in macrocycles 10
and 21 with pyrroles, a suitable iodinated aldehyde was
required. Benzyl protection of commercially available
pyrrole 2-carbaldehyde was achieved using a literature
procedure18 to give pyrrole 22, which was subsequently
iodinated with [bis(trifluoroacetoxy)iodo]benzene and
iodine to give the novel derivative 23 (Scheme 4).
Installation of a suitable alkene partner for the Heck reac-
tion was easily achieved using acryloyl chloride and
diisopropylethylamine (DIPEA) to give acrylamide 16.
Subjecting this to Jeffery conditions for the Heck reaction,
followed by careful flash column chromatography gave a
Synlett 2006, No. 18, 2929–2934 © Thieme Stuttgart · New York

2932
S. E. Gibson et al.
LETTER
I
(CF3COO)2IPh
I2
NaH, BnBr
CHO
CHO
CHO
N
N
N
H
Bn
Bn
22
23
97% yield
62% yield
Scheme 4
I
I
1) (S)-valinol,
H
MgSO4
K2CO3, BnBr
18-crown-6
N
CHO
OH
N
N
Bn
2) NaBH4
Bn
23
24
98% yield
I
I
Bn
N
Bn
1) PPh3/DEAD (2 equiv)
N
N3
OH
N
N
Bn
2) 25
Bn
3) (PhO)2P(O)N3
4) H2O
26
95% yield
25
67% yield
I
acryloyl chloride
Et3N, DMAP
PPh3, H2O
Bn
N
NH2
N
Bn
27
92% yield
Pd(OAc)2
O
I
(10 mol%)
n-Bu4NCl
(1 equiv)
O
Bn
N
NH
N
N
Figure 3 Top: the stacking of the two independent macrocycles (A
and B) present in the crystals of 21. The geometries of the X–H···O
hydrogen bonds [X···O, H···O (Å), X–H···O (°)] are (a) X = N,
3.414(4), 2.57, 156; (b) X = N, 2.9472(18), 2.08, 162; (c) X = N,
3.111(2), 2.28, 154; (d) X = O, 2.751(3), 1.86, 169. Center: the
stacking of the two independent macrocycles (A and B) present in the
crystals of 21 viewed along the crystallographic a direction. Bottom:
the molecular structure of one (A) of the two independent macro-
cycles present in the crystals of 21.
N
H
Bn
NBn
BnN
Bn
Bn
NaHCO3
(2.5 equiv)
DMF, 110 °C,
16 h
N
28
50% yield
HN
O
11
35% yield
Scheme 5
crystals grown by slow evaporation of a dichlo-
romethane–hexane (2:1) mixture (Figure 3).19
The 2,4-relationship of the aldehyde and the iodine was
established from the typical coupling constant between
the hydrogens on carbons 3 and 5 of the pyrrole (J = 1.5
Hz).
The X-ray analysis of crystals of 21 revealed the presence
of two independent macrocycles (A and B) in the asym-
metric unit, and one disordered water molecule per pair of
macrocycles.
Reductive amination of aldehyde 23 with (S)-valinol and
(S)-prolinol proceeded smoothly to give alcohols 24 and
29 (Schemes 5 and 6), and conversion of the alcohols into
Heck substrates 28 and 32 was achieved using the meth-
odology developed for the benzene-containing substrates.
Gratifyingly, the head-to-tail Heck reactions worked well
in both cases to give macrocycles 11 and 33 in 35% and
39% yield, respectively.
The two macrocycles have noticeably different conforma-
tions,20 though in each case the aryl–alkenyl–amide
‘sides’21 are significantly inclined to each other (by ca.
54° in molecule A, and ca. 43° in molecule B) giving rise
to an overall trough-like conformation. The two indepen-
dent molecules are linked by a pair of N–H···O hydrogen
bonds from the N–H atoms of macrocycle B to the carbo-
nyl oxygen atoms of macrocycle A (interactions b and c).
In order to start to probe the structures of the macrocycles
made in this study, an X-ray crystallographic analysis of
benzene-containing macrocycle 21 was performed on
Synlett 2006, No. 18, 2929–2934 © Thieme Stuttgart · New York

LETTER
Heck Reaction in the Synthesis of Macrocycles
2933
I
References and Notes
1) (S)-prolinol,
MgSO4
I
1) PPh3/DEAD
2) 29
(1) For recent reviews on macrocyclic chemistry, see:
N
CHO
N
(a) Arico, F.; Chang, T.; Cantrill, S. J.; Khan, S. I.; Stoddart,
J. F. Chem. Eur. J. 2005, 11, 4655. (b) Bowman-James, K.
Acc. Chem. Res. 2005, 38, 671. (c) Schalley, C. A.;
Wielandt, T.; Brüggemann, J.; Vögtle, F. Top. Curr. Chem.
2004, 248, 141. (d) Wessjohann, L. A.; Ruijter, E. Top.
Curr. Chem. 2005, 243, 137. (e) Botta, B.; Cassani, M.;
D’Acquarica, I.; Misiti, D.; Subissati, D.; Delle Monache, G.
Curr. Org. Chem. 2005, 9, 337 . For recent reviews on the
synthetic challenges represented by macrocycles, see:
(f) Blankenstein, J.; Zhu, J. P. Eur. J. Org. Chem. 2005,
1949. (g) Bonaga, L. V. R.; Zhang, H. C.; Moretto, A. F.;
Ye, H.; Gauthier, D. A.; Li, J.; Leo, G. C.; Maryanoff, B. E.
J. Am. Chem. Soc. 2005, 127, 3473. (h) Beletskaya, I. P.;
Bessmertnykh, A. G.; Averin, A. D.; Denat, F.; Guilard, R.
Eur. J. Org. Chem. 2005, 281. (i) Schalley, C. A.; Reckien,
W.; Peyerimhoff, S.; Baytekin, B.; Vögtle, F. Chem. Eur. J.
2004, 10, 4777. (j) Barrett, A. G. M.; Hennessy, A. J.; Le
Vezouet, R.; Procopiou, P. A.; Seale, P. W.; Stefaniak, S.;
Upton, R. J.; White, A. J. P.; Williams, D. J. J. Org. Chem.
2004, 69, 1028.
N
2) NaBH4
OH 3) (PhO)2P(O)N3
4) H2O
Bn
Bn
23
29
70% yield
PPh3
(2 equiv),
H2O
I
I
acryloyl chloride
(10 equiv)
N
N
N
N
N3 THF, 50 °C,
20 h
Et3N, DMAP
NH2
Bn
Bn
30
31
63% yield
93% yield
Pd(OAc)2
(10 mol%)
n-Bu4NCl
(1 equiv)
I
N
N
NH
NaHCO3
(2.5 equiv)
DMF, 110 °C,
16 h
Bn
(2) For a review of applications of non-peptidic macrocycles
derived from amino acids, see: Gibson, S. E.; Lecci, C.
Angew. Chem. Int. Ed. 2005, 45, 1364.
O
32
33
27% yield
39% yield
(3) (a) For a synthesis of K-13 analogues, see: Cristau, P.; Vors,
J. P.; Zhu, J. Org. Lett. 2003, 5, 5575. (b) For a synthesis of
K-13, see: Boger, D. L.; Yohannes, D. J. Org. Chem. 1989,
54, 2498. (c) For fermentation, isolation and biological
properties, see: Kase, H.; Kaneko, M.; Yamada, K. J.
Antibiotics 1987, 40, 450.
Scheme 6
These pairs of macrocycles are then linked to neighbor-
ing, lattice translated, pairs by hydrogen bonds involving
the included water molecule, one of the N–H protons of
macrocycle A linking to the water molecule (interaction
a), and one of the water protons linking to one of the car-
bonyl oxygen atoms of macrocycle B (interaction d).22
This serves to form a continuous stack of macrocycles
along the crystallographic a direction, with the edges of
the macrocycles lined up so as to form a pseudo-tube.
(4) (a) Tabudravu, J. N.; Morris, L. A.; Milne, B. F.; Jaspars, M.
Org. Biomol. Chem. 2005, 3, 745. (b) Wintjens, R.; Liévin,
J.; Rooman, M.; Buisine, E. J. Mol. Biol. 2000, 302, 395.
(c) Cioca, D. P.; Kitano, K. Cell. Mol. Life Sci. 2002, 59,
1377. (d) Bubb, M. R.; Spector, I.; Beyer, B. B.; Fosen, K.
M. J. Biol. Chem. 2000, 275, 5163. (e) For a total synthesis
of jaspamide, see: Yoshiro, H.; Katsuyuki, Y.; Takefumi, M.
Heterocycles 1994, 39, 603.
(5) Ranganathan, D.; Samant, M. P.; Nagaraj, R.; Bikshapathy,
E. Tetrahedron Lett. 2002, 43, 5145.
In conclusion, macrocycles 10, 21, 11, and 33 have been
synthesized via a concise synthetic route, which is amena-
ble to variation via, for example, the use of other amino
alcohols, or 2- or 3-iodobenzaldehyde and derivatives of
other heterocycles. The X-ray crystallographic structure
of 21, in which hydrogen bonding leads to a continuous
stack of macrocycles is encouraging, and suggests that our
strategy of placing increased numbers of nitrogen atoms
in the structures to promote molecular interactions will
lead to a range of interesting properties that will mimic
more closely those found in naturally occurring macro-
cycles.
(6) (a) Becerril, J.; Burguete, M. I.; Escuder, B.; Luis, S. V.;
Miravet, J. F.; Querol, M. Chem. Commun. 2002, 738.
(b) Becerril, J.; Burguete, M. I.; Escuder, B.; Galindo, F.;
Gavara, R.; Miravet, J. F.; Luis, S. V.; Peris, G. Chem. Eur.
J. 2004, 10, 3879. (c) Becerril, J.; Escuder, B.; Miravet, J.
F.; Gavara, R.; Luis, S. V. Eur. J. Org. Chem. 2005, 481.
(7) Dowden, J.; Edwards, P. D.; Flack, S. S.; Kilburn, J. D.
Chem. Eur. J. 1999, 5, 79.
(8) Ranganathan, D.; Thomas, A.; Haridas, V.; Kurur, S.;
Madhusudanan, K. P.; Roy, R.; Kunwar, A. C.; Sarma, A. V.
S.; Vairamani, M.; Sarma, K. D. J. Org. Chem. 1999, 64,
3620.
(9) (a) Gibson, S. E.; Middleton, R. J. J. Chem. Soc., Chem.
Commun. 1995, 1743. (b) Gibson, S. E.; Guillo, N.; Tozer,
M. J. Chem. Commun. 1997, 637. (c) Gibson, S. E.; Guillo,
N.; Middleton, R. J.; Thuilliez, A.; Tozer, M. J. J. Chem.
Soc., Perkin. Trans. 1 1997, 447. (d) Gibson, S. E.; Guillo,
N.; Jones, J. O.; Buck, I. M.; Kalindjian, S. B.; Roberts, S.;
Tozer, M. J. Eur. J. Med. Chem. 2002, 37, 379. (e) Gibson,
S. E.; Jones, J. O.; Kalindjian, S. B.; Knight, J. D.; Steed, J.
W.; Tozer, M. J. Chem. Commun. 2002, 1938. (f) Gibson,
S. E.; Jones, J. O.; Kalindjian, S. B.; Knight, J. D.; Mainolfi,
N.; Rudd, M.; Steed, J. W.; Tozer, M. J.; Wright, P. T.
Tetrahedron 2004, 60, 6945.
Acknowledgment
The authors would like to thank the Engineering and Physical
Sciences Research Council (EPSRC) for a studentship (to CL).
Synlett 2006, No. 18, 2929–2934 © Thieme Stuttgart · New York

2934
S. E. Gibson et al.
LETTER
669.4185 [M + H+]. Anal. Calcd (%) for C44H52N4O2
(668.41): C, 79.00; H, 7.84; N, 8.38. Found: C, 78.94; H,
7.79; N, 8.28.
(10) (a) Gibson, S. E.; Mainolfi, N.; Kalindjian, S. B.; Wright, P.
T. Chem. Commun. 2003, 1568. (b) Gibson, S. E.; Mainolfi,
N.; Kalindjian, S. B.; Wright, P. T.; White, A. J. P. Chem.
Eur. J. 2005, 11, 69.
(11) Tan, D. S.; Foley, M. A.; Stockwell, B. R.; Shair, M. D.;
Schreiber, S. L. J. Am. Chem. Soc. 1999, 121, 9073.
(12) Meyers, A. I.; Dickman, D. A.; Bailey, T. R. J. Am. Chem.
Soc. 1985, 107, 7974.
(17) Wallén, E. A. A.; Christiaans, J. A. M.; Saario, S. M.;
Forsberg, M. M.; Venäläinen, J. I.; Paso, H. M.; Männisto,
P. T.; Gynther, J. Bioorg. Med. Chem. 2002, 10, 2199.
(18) Iwao, M.; Mahalanabis, K. K.; Watanabe, M.; De Silva, S.
O.; Snieckus, V. Tetrahedron 1983, 39, 1955.
(13) Stork, G.; Niu, D.; Fujimoto, A.; Koft, E. R.; Balkovec, J.
M.; Tata, J. R.; Dake, G. R. J. Am. Chem. Soc. 2001, 123,
3239.
(14) Reddy, P. G.; Pratap, T. V.; Kumar, G. D. K.; Mohanty, S.
K.; Baskaran, S. Eur. J. Org. Chem. 2002, 3740.
(15) Hanessian, S.; Zhan, L.; Bovey, R.; Saavedra, O. M.;
Juillerat-Jeanneret, L. J. Med. Chem. 2003, 46, 3600.
(16) Representative Heck Reaction:
(19) Crystal Data for 21.
C30H36N4O2·0.5H2O, M = 493.64, monoclinic, P21 (no. 4),
a = 11.5469 (5), b = 17.6488 (8), c = 13.8139 (6) Å,
b = 107.469 (4)°, V = 2685.3 (2) Å3, Z = 4 (two independent
molecules), Dc = 1.221 g cm–3, m(Cu-Ka) = 0.622 mm–1,
T = 173 K, colorless blocks, Oxford Diffraction Xcalibur PX
Ultra diffractometer; 9511 independent measured
reflections, F2 refinement, R1 = 0.033, wR2 = 0.079, 8661
independent observed absorption-corrected reflections [|Fo|
> 4s(|Fo|), 2qmax = 142°], 688 parameters. The absolute
structure of 21 was determined by a combination of R-factor
tests [R1+ = 0.0326, R1– = 0.0327] and by use of the Flack
parameter [x+ = +0.07 (13), x– = +0.93 (13)]. The included
water molecule is disordered over two positions, and though
the hydrogen atoms for the major (ca. 83%) occupancy site
were located from a DF map, this disorder means that they
must be treated with caution. Additionally, the presence of
more than one site for the water oxygen atom means that the
hydrogen bonds involving this included water can only be
taken as indicative. Whilst it is clear that the N(7) proton
hydrogen bonds to, and that the O(8¢) carbonyl oxygen
accepts a hydrogen bond from, a water molecule in this area,
exactly what the distances are, and whether both bonds are
ever present at the same time, are unknown. CCDC 290796.
(20) The most obvious conformational difference between
macrocycles A and B is the orientation of the two five-
membered C4N rings with respect to the macrocycle, and
Palladium(II) acetate (0.010 g, 0.043 mmol), NaHCO3
(0.091 g, 1.08 mmol) and tetra-n-butyl ammonium chloride
(0.120 g, 0.43 mmol) were added in one portion to a stirred
solution of alkene 16 (0.200 g, 0.43 mmol) in dry DMF (20
mL) and the resulting mixture was heated up to 110 °C and
stirred for 16 h. After cooling, the product mixture was
filtered over a short pad of Celite® and concentrated in
vacuo. Purification of the crude product by flash column
chromatography (SiO2; hexane–EtOAc, 10:0 to 4:6)
afforded 10 as a colorless crystalline solid (0.045 g, 31%).
Rf = 0.21 (SiO2; hexane–EtOAc, 5:5); mp 252–256 °C;
[a]D20 –177.0 [c 0. 11 (g/dL) in CH2Cl2]. IR (CH2Cl2): 3387
(N–H), 1664 (C=O), 1499 (C=C) cm–1. 1H NMR (400 MHz,
CDCl3): d = 1.01 (d, J = 6.7 Hz, 3 H, CH3CHCH3), 1.20 (d,
J = 6.7 Hz, 3 H, CH3CHCH3), 2.07–2.14 (m, 1 H,
CH3CHCH3), 2.34–2.39 (m, 1 H, NCHCH2), 2.79–2.85 (m,
1 H, CHHNHCO), 3.62 (d, J = 13.2 Hz, 1 H, ArCHHNH),
3.64 (d, J = 12.8 Hz, 1 H, ArCHHNH), 3.73 (d, J = 13.2 Hz,
1 H, ArCHHNH), 3.75 (m, 1 H, CHHNHCO), 4.03 (d,
J = 12.8 Hz, 1 H, ArCHHNH), 5.82 (d, J = 8.0 Hz, 1 H,
NHCO), 5.91 (d, J = 15.6 Hz, 1 H, NHCOCH=CHAr), 6.98
(d, J = 8.0 Hz, 2 H, ArH2,6), 7.33 (d, J = 15.6 Hz, 1 H,
NHCOCH=CHAr), 7.36–7.38 and 7.43–7.47 (m, 5 H,
NCH2PhH), 7.41 (d, J = 8.0 Hz, 2 H, ArH3,5) ppm. 13C NMR
(100 MHz, CDCl3): d = 20.2 (CH3CHCH3), 23.2
this difference can be described by considering the C(macro)
N–C–C(macro) torsion angles about the common bond
between the C4N ring and the macrocycle. For molecule A
these torsion angles are ca. –72° and –122° at N(1) and
N(18), respectively, whilst for molecule B the corresponding
angles are ca. –148° and –136°, respectively.
–
(CH3CHCH3), 28.8 (CH3CHCH3), 38.2 (CH2NHCO), 52.2
and 54.7 (ArCH2NH and PhCH2NH), 63.6 (NCHCH2),
120.8 (NHCOCH=CHAr), 127.4 (CPhH), 127.9 (CAr3,5H),
128.7 and 129.6 (CPhH), 129.7 (CAr2,6H), 134.1
(CArCH=CH), 139.0 (NHCOCH=CHAr), 140.3 and 141.9
(CArCH2N and CPhCH2N), 164.9 (NHCO) ppm. MS (FAB/
+): m/z (%): 669 (55) [M + H+], 334 (5) [M+/2]. HRMS
(FAB/+): m/z calcd for C44H53N4O2: 669.4169; found:
(21) These aryl–alkenyl–amide ‘sides’ are noticeably non-planar,
the constituent C9NO atoms being coplanar to within only
ca. 0.28 and 0.13 Å for the N(7) and N(24) units in molecule
A, and ca. 0.22 and 0.29 Å for the corresponding units in
molecule B.
(22) The water molecule is disordered over two positions, the
major (ca. 83%) occupancy orientation being shown in
Figure 3 and used for the hydrogen bonding geometries.
Synlett 2006, No. 18, 2929–2934 © Thieme Stuttgart · New York