We thank the Swedish Natural Research Council, the
Crafoord Foundation and the Royal Physiographic Society in
Lund for financial support.
Notes and references
‡
Abbreviations: PyAOP = [7-azabenzotriazol-1-yloxytris(pyrrolidino)-
phosphonium hexafluorophosphate]; Hünig’s base = N,N-diisopropyethyl-
amine (DIEA), EDC = 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide
hydrochloride, HOBt = 1-hydroxybenzotriazole hydrate, HATU = O-
(7-azabenzotriazol-1-yl)-N,N,NA,NA-tetramethyluronium hexafluorophos-
phate.
§
Compounds 1b and 2 were characterised by 1H and 13C NMR
spectroscopy (400 MHz, 298 K) and by mass spectroscopy (FAB). NOESY
1
experiment was used to make individual H NMR assignment. Polarimetric
measurements were performed at 20 °C.
4
Preparation of 1b. Compound 1a (1.0 g, 1.27 mmol) was dissolved in
MeOH (50 mL), Pd/C (50 mg) was added and the mixture was hydrogenated
at 1 atm overnight. After removal of the catalyst by filtration through Celite,
1
2
1
3
b was obtained as an amorphous white powder (0.48 g, 99%). mp
21
07.0–208.8 °C.
n
max(KBr)/cm
674.1. H NMR (300 MHz, CD OD) d 6.81 (s, 3H), 3.97 (dd, J = 8.5 Hz,
H), 3.51 (s, 9H), 2.87 (dd, J = 7.2 Hz, 6H). 13C NMR (75 MHz, CD
OD)
+16.3° (c 0.55, MeOH). HRMS
3409.9(NH), 2962.5, 1743.5(CO),
1
3
3
d 171.5, 137.9, 131.9, 55.9, 54.3, 37.8. [a]
D
Fig. 2 NOESY spectrum of 2 in CDCl
3
.
+
+
(FAB + H ) calculated for C18
27 3 6
H N O 381.1900. Found 382.1967 [M +
H].
Preparation of 2. A solution of Kemp’s triacid (0.033 g, 0.13 mmol),
PyAOP (0.20 g, 0.38 mmol) and DIEA (65 mL, 0.38 mmol) in DMF (10 mL)
was added, via a syringe pump, to a solution of 1b (0.050 g, 0.13 mmol) and
DIEA (65 mL, 0.38 mmol) in DMF (90 mL), over 10 h. The reaction mixture
was stirred for an additional 12 h at rt. The solvent was then removed under
reduced pressure and the residue was dissolved in diethyl ether (20 mL).
The organic phase was washed with 1 M HCl (10 3 10 mL) in order to
remove remaining PyAOP. The volume of the organic phase was reduced
at 2.62 ppm (Ja,b = 6.9 Hz). One of these protons (at 3.48 ppm)
presented a weak NOESY correlation to the a-proton, (Fig. 2).
This observation supported the H-bonding in the MM3-model.
As seen in Fig. 1, the a- and gauche b-protons are positioned
2.36 Å apart. These protons are located near the extension of the
aromatic plane, i.e. in the down-field shift region, as can be seen
1
in Fig. 1. The effect was confirmed by H NMR. The anti
relation between the two b-protons was expressed by the large
and the crude product was chromatographed (CH
0.5) to give 2 as a semi-solid (7 mg, 8%). nmax(KBr)/cm 3379.1(NHCO),
2 2 f
Cl –MeOH 30:1, R =
21
1
geminal coupling constant (Jb–b = 15.7 Hz). The signal
1
2
954.7, 1895.2, 1743.5(CO), 1643.2, 1535.2. H NMR (400 MHz, CDCl
d 6.91 (s, 3H), 6.73 (d, J = 10.2 Hz, 3H), 5.27 (ddd, JHa–Hb = 6.9 Hz,
Ha–NH = 10.2 Hz, 3H), 3.78 (s, 9H), 3.48 (dd, J = 6.9 Hz, 3H), 2.83 (d,
J = 15.8 Hz, 3H), 2.62 (dd, J = 7.3 Hz, 3H), 1.15 (s, 9H), 0.89 (d, J = 15.6
3
)
originating from the methylene protons in Kemp’s acid itself
appeared at 2.54 ppm, while the corresponding proton reso-
nance in 2 appeared as two different doublets, one at 2.83 ppm
and the other at 0.89 ppm, with a large geminal coupling
constant of 15.7 Hz. NOESY experiments revealed that the
equatorially positioned protons (the signal at 2.83 ppm)
presented a NOE enhancement effect to NHCO (Fig. 2). No
such effect was observed for the axial protons (0.89 ppm). This
observation also supports the H-bonding shown in the MM3-
model. As seen in Fig. 1, the NH–Ha distance is only 2.0 Å. The
array of NH…ONC hydrogen bonds closes the cage, thus
hindering guest molecules to enter. Moreover, the space
available inside the cage is probably too small to accommodate
a guest particle. This was estimated by MM37 energy
minimization of an imaginary inclusion complexes between a
hydrogen or helium atom and the cage, which resulted in ca.
J
13
Hz, 3H). C NMR (100 MHz, CDCl
2.2, 43.6, 40.9, 37.2, 35.9. [a] 23.4° (c 0.35, MeOH). HRMS (FAB +
Na ) calculated for C30H39N O Na 608.2584. Found 608.2588 [M
Na].
3
) d 176.0, 172.2, 135.3, 129.6, 52.4,
5
D
+
+
3
9
+
1
A. Ritzén and T. Frejd, Chem. Commun., 1999, 2, 207; A. Ritzén and T.
Frejd, Eur. J. Org. Chem., 2000, 22, 3771.
2
3
D. S. Kemp and K. S. Petrakis, J. Org. Chem., 1981, 46, 5140.
(a) J. Rebek Jr., L. Marshall, R. Wolak, K. Parris, M. Killoran, B. Askew,
D. Nemeth and N. Islam, J. Am. Chem. Soc., 1985, 107, 7476; (b) F. M.
Menger, P. A. Chicklo and M. J. Sherrod, Tetrahedron Lett., 1989,
30(50), 6943; (c) P. Thuéry, M. Neirlich, B. W. Baldwin, Y. Aoki and T.
Hirose, J. Chem. Soc., Perkin Trans. 2, 1999, 2077.
2
1
4 A. Ritzén, B. Basu, A. Wållberg and T. Frejd, Tetrahedron: Asymmetry,
998, 9, 3491.
R. A. Pascal Jr., J. Spergel and D. van Engen, Tetrahedron Lett., 1986,
7(35), 4099.
8
kcal mol higher energy of both complexes as compared to
1
the empty cage.
5
6
The protruding carboxylate groups of 2 may be used as
attachment points for various structures via ester- or amide
bonds. Compound 2 would then serve as a core of dendritic
structures. Synthetic work in this direction as well as molecular
recognition studies are in progress.
2
T. L. Chan, Y. X. Cui, T. C. W. Mak, R. J. Wang and H. N. C. Wong,
J. Crystallogr. Spectrosc. Res., 1991, 21, 297.
7 MacMimic3, InStar Software AB, Ideon Research Park, SE-223 70 Lund,
Sweden.
Chem. Commun., 2001, 1088–1089
1089