Synthesis and structural analysis of dehydrophenylalanine cyclophanes

Article abstract of DOI:10.1039/b205752m

The syntheses and structures of three cyclophanes containing two (Z)-dehydrophenylalanine residues are reported; the length of the tethers between the two amino acid residues is easily altered and changing this parameter has a significant effect on the so

Full text of DOI:10.1039/b205752m

Synthesis and structural analysis of dehydrophenylalanine cyclophanes
Susan E. Gibson (née Thomas),*a Jerome O. Jones,a S. Barret Kalindjian,b Jamie D. Knight,a
Jonathan W. Steeda and Matthew J. Tozer†b
a Department of Chemistry, King’s College London, Strand, London, UK WC2R 2LS.
E-mail: susan.gibson@kcl.ac.uk
b James Black Foundation, 68 Half Moon Lane, London, UK SE24 9JE
Received (in Cambridge, UK) 13th June 2002, Accepted 24th July 2002
First published as an Advance Article on the web 5th August 2002
The syntheses and structures of three cyclophanes contain-
ing two (Z)-dehydrophenylalanine residues are reported; the
length of the tethers between the two amino acid residues is
easily altered and changing this parameter has a significant
effect on the solid state structures of the cyclophanes.
protocol with serine methyl ester. Crystallisation of the
reductive amination products from hexane–diethyl ether pro-
vided analytically pure samples of 4a–c uncontaminated with
any branched products.‡ Protection of the amine of 4 with
Boc2O followed by tosylation of the alcohol and a subsequent
elimination reaction gave Heck substrates 5a–c with the desired
dehydroalanine residue connected to a remote p-iodoarene by
hydrocarbon chains containing 4, 6 and 10 carbon atoms.
Application of Heck reaction conditions to substrates 5a–c gave
The intermolecular Heck coupling of haloarenes and dehy-
droalanine derivatives, in which carbon–carbon bond formation
occurs at the b-carbon of the dehydroalanine derivative to give
(Z)-dehydrophenylalanine derivatives, is well established;1
recent applications of this powerful reaction include its use in
the synthesis of phenyltrisalanine, a new trifunctional amino
acid,2 and in the creation of a chiral dendrimer based on
aromatic bis- and tris-amino acids.3 A study of the Heck
coupling of o-haloarenes tethered to dehydroalanine derivatives
revealed that the intramolecular version of this reaction could be
used to generate (Z)-dehydrophenylalanine residues embedded
in seven-, eight- and nine-membered rings.4 The products of the
cyclisations were subsequently converted into the new con-
formationally constrained phenylalanine analogues, Sic, Hic
and Nic5 and these amino acids have been used in studies of
CCK2 receptor antagonists.6
There is currently considerable interest in the properties and
applications of cyclophanes7 and, more generally, in the control
of molecular architecture and crystal engineering.8 In view of
this, we wish to report herein a synthesis of cyclophanes
containing two (Z)-dehydrophenylalanine residues that is
designed to allow the distance between the two amino acid
residues to be easily varied; one of the key steps of the synthesis
involves Heck coupling between p-iodoarenes tethered to
dehydroalanine derivatives and the outcome of this reaction
represents a new type of haloarene–dehydroalanine coupling
reaction.
The initial step in the synthesis is the one that provides
flexibility with respect to the positioning of the two amino acid
residues. It is based on a literature Heck reaction9 between
haloarenes and w-hydroxyalkenes that forms w-arylaldehydes
by a mechanism that involves palladium hydride-catalysed
migration of the expected Heck product alkene along the
hydrocarbon chain to generate an enol that subsequently
tautomerises to the product aldehyde. Although many w-
hydroxyalkenes are commercially available, for the purposes of
this study we selected the 4-, 6- and 10-carbon units 1a–c for
reaction with 1,4-diiodobenzene, in the anticipation that these
three chain lengths might provide significantly different final
products. Reaction of 1a–c with 1,4-di-iodobenzene (Scheme 1)
provided the desired aldehydes 2a–c albeit contaminated at
levels of 13–23% with the branched isomers 3a–c, produced by
carbon-carbon formation at the internal carbon atom of the
alkenes 1a–c. Experience revealed that the branched isomers
were most easily removed at the end of the next step, and so, the
mixtures were carried forward into the next stage of the
synthesis.
In order to introduce the desired dehydroalanine residue, the
mixtures of 2 and 3 were subjected to a reductive amination
† Current address: Medivir UK Ltd, Peterhouse Technology Park, 100
Fulbourn Road, Cambridge CB1 9PT.
Scheme 1
1938
CHEM. COMMUN., 2002, 1938–1939
This journal is © The Royal Society of Chemistry 2002

refined using the programs SHELXS-9010 and SHELXL-97,11 respectively.
The program X-Seed12 was used as an interface to the SHELX programs,
and to prepare the figures. Final GOF = 1.278, R1 = 0.1500, wR2 =
0.2157, R indices based on 1970 reflections with I > 2s(I) (refinement on
F2), 222 parameters, 0 restraints. Lp and absorption corrections applied, m =
0.082 mm21. For 6b: C42H58N2O8, M = 718.90, colourless block, 0.25 3
¯
0.25 3 0.10 mm, triclinic, space group P1 (no. 2), a = 9.1007(7), b =
9.9502(7), c = 11.8468(8) Å, a = 74.339(5), b = 80.254(4), g =
81.103(4)°, V = 1011.31(13) Å3, Z = 1, Dc = 1.180 g cm23, F000 = 388,
KappaCCD, Mo-Ka radiation, l = 0.71073 Å, T = 120(2) K, 2qmax
=
49.6°, 5761 reflections collected, 3435 unique (Rint 0.0439). The
=
structure was solved and refined using the programs SHELXS-9010 and
SHELXL-97,11 respectively. The program X-Seed12 was used as an
interface to the SHELX programs, and to prepare the figures. Final GOF =
1.025, R1 = 0.0421, wR2 = 0.0968, R indices based on 2577 reflections
with I > 2s(I) (refinement on F2), 240 parameters, 0 restraints. Lp and
absorption corrections applied,
m
=
0.081 mm21
.
For 6c:
C
52H78.10Cl3.90N2O8.70, M = 1008.72, colourless plate, 0.20 3 0.15 3 0.10
¯
mm, triclinic, space group P1 (no. 2), a = 8.1987(4), b = 8.8260(6), c =
20.8707(13) Å, a = 101.52(4), b = 91.999(4), g = 113.079(3)°, V =
1350.58(14) Å3, Z = 1, Dc = 1.240 g cm23, F000 = 540, KappaCCD, Mo-
Ka radiation, l = 0.71073 Å, T = 100(2) K, 2qmax = 50.0°, 7441
reflections collected, 4708 unique (Rint = 0.0937). The structure was solved
and refined using the programs SHELXS-9010 and SHELXL-97,11
respectively. The program X-Seed12 was used as an interface to the SHELX
programs, and to prepare the figures. Final GOF = 1.106, R1 = 0.1299,
Fig. 1 ORTEP drawings for 6a, 6b and 6c. Hydrogen atoms are omitted for
clarity.
wR2
(refinement on F2), 302 parameters, 180 restraints. Lp and absorption
corrections applied, m = 0.268 mm21
General comment: Overall precision for compounds 6a and 6c is
relatively poor as a result of sample quality. The samples took the form of
small needles with a tendency towards twinning. Compound 6c included
disorder solvent of crystallisation modelled satisfactorily as a mixed site
containing 65% CHCl3 and 35% MeOH. Solvent atoms were treated
isotropically.
= 0.2724, R indices based on 3141 reflections with I > 2s(I)
products that were tentatively identified as cyclophanes 6a–c on
the basis of their spectroscopic and analytical data.
.
Crystallisation of 6a–c followed by X-ray crystallographic
analysis§ of the colourless crystals obtained confirmed the
structures of 6a–c and revealed that in the solid state, these
compounds adopt structures in which the (Z)-dehydrophenyla-
lanine residues have quite different spatial relationships to each
other (Fig. 1). Compounds 6a and 6b adopt an open AbarrelA
shaped structure that leaves a small cavity in the centre of the
molecules. In contrast 6c adopts a closed, linear structure in the
solid state in which cavity volume is minimised. It is anticipated
that the chemical and stereochemical properties of 6a–c will
prove to be significantly different.
Finally, structures 6a–c contain two elements of chirality and
the conformations identified in the solid state are meso
structures. Experiments designed to access the dl pair of a
smaller homologue in this series and separate the component
enantiomers are underway.
CCDC 188015, 188016 and 189757. See http://www.rsc.org/suppdata/
cc/b2/b205752m/ for crystallographic data in CIF or other electronic
format.
1 See, for example: (a) M. Cutolo, V. Fiandanese, F. Naso and O.
Sciacovelli, Tetrahedron Lett, 1983, 24, 4603; (b) A.-S. Carlström and
T. Frejd, Synthesis, 1989, 414; (c) A.-S. Carlström and T. Frejd, Acta
Chem. Scand., 1992, 46, 163.
2 A. Ritzen, B. Basu, A. Wallberg and T. Frejd, Tetrahedron: Asymmetry,
1998, 9, 3491.
3 A. Ritzen and T. Frejd, Chem. Commun., 1999, 207.
4 S. E. Gibson and R. J. Middleton, J. Chem. Soc., Chem. Commun., 1995,
1743.
5 (a) S. E. Gibson, N. Guillo, R. J. Middleton, A. Thuilliez and M. J.
Tozer, J. Chem. Soc., Perkin Trans. 1, 1997, 447; (b) S. E. Gibson, J. O.
Jones, R. McCague, M. J. Tozer and N. J. Whitcombe, Synlett, 1999,
954.
6 (a) S. E. Gibson, N. Guillo, S. B. Kalindjian and M. J. Tozer, Biorg.
Med. Chem. Lett, 1997, 7, 1289; (b) S. E. Gibson, N. Guillo, J. O. Jones,
I. M. Buck, S. B. Kalindjian, S. Roberts and M. J. Tozer, Eur. J. Med.
Chem., 2002, 37, 379.
7 J. Breitenbach, J. Boosfeld and F. Vögtle, in Comprehensive Supramo-
lecular Chemistry, ed. F. Vögtle, Pergamon, New York, 1996, vol. 2, pp.
29–67.
8 D. Braga, F. Grepioni and G. R. Desiraju, Chem. Rev., 1998, 98,
1375.
9 R. C. Larock, W.-Y. Leung and S. Stolz-Dunn, Tetrahedron Lett., 1989,
30, 6629.
The authors thank James Black Foundation for generous
studentship support (J. O. J.), the RSC for a Hickinbottom
Fellowship student bursary (J. O. J.), EPSRC for an Ear-Marked
studentship (J. D. K.) and EPSRC and King’s College London
for the provision of the X-ray diffractometer.
Notes and references
‡ The novel compounds 4a–c, 5a–c and 6a–c all gave satisfactory
spectroscopic (IR, 1H NMR, 13C NMR and low-resolution MS) and
microanalytical data.
§
Crystal data: for 6a : C19H25NO4, M = 331.40, 0.20 3 0.10 3 0.10
¯
mm, triclinic, space group P1 (no. 2), a = 9.068(2), b = 10.189(3), c =
11.317(3) Å, a = 68.324(15), b = 75.548(16), g = 77.333(15)°, V =
931.5(4) Å3, Z = 2, Dc = 1.182 g cm23, F000 = 356, KappaCCD, Mo-Ka
radiation, l = 0.71073 Å, T = 100(2)K, 2qmax = 50.0°, 4700 reflections
collected, 3015 unique (Rint = 0.1335). The structure was solved and
10 G. M. Sheldrick, Acta Crystallogr., Sect. A., 1990, 46, 467.
11 G. M. Sheldrick, SHELXL-97: University of Göttingen, 1997.
12 L. J. Barbour, XSeed, University of Missouri, Columbia, 1999.
CHEM. COMMUN., 2002, 1938–1939
1939