Configurationally stable propeller-like triarylphosphine and triarylphosphine oxide

Article abstract of DOI:10.1039/b709655k

Configurationally stable, propeller-like triarylphosphine and triarylphosphine oxide can be synthesized; a chiral scaffold based on Lissoclinum-cyclopeptides linked via three peptide bonds with a triphenylphosphine and triphenylphosphine oxide moiety, respectively, prevents effectively epimerization at the chiral phosphorus atom. The Royal Society of Chemistry.

Full text of DOI:10.1039/b709655k

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Configurationally stable propeller-like triarylphosphine and
triarylphosphine oxide{
a
Aron Pinte´r, Gebhard Haberhauer,* Isabella Hyla-Kryspin and Stefan Grimme*
a
b
b
´
Received (in Cambridge, UK) 27th June 2007, Accepted 25th July 2007
First published as an Advance Article on the web 13th August 2007
DOI: 10.1039/b709655k
Configurationally stable, propeller-like triarylphosphine and
triarylphosphine oxide can be synthesized; a chiral scaffold
based on Lissoclinum-cyclopeptides linked via three peptide
bonds with a triphenylphosphine and triphenylphosphine oxide
moiety, respectively, prevents effectively epimerization at the
chiral phosphorus atom.
Triphenylphosphine and triphenylphosphine oxide are valuable
reagents, additives or ligands in synthetic chemistry.1 Both
Scheme 1
molecules adopt propeller-like C3-symmetrical conformations,
thus minimizing intramolecular non-bonding repulsive interactions
between their phenyl rings, and therefore are helically chiral
substrates. However, organic compounds of this type, having the
general chemical structure Ar3Z (Z = N, P, PO), are regarded as
achiral, since fast inversion of helicity occurs even at ambient
temperature.2 For this reason, in chemical reactions where the
transfer of chirality is essential, phosphines3 or phosphine oxides
having an axial chirality, such as BINAP4 and BINAP-dioxide,5
are predominantly used. Numerous approaches to C3-symmetrical,
conformationally stable triphenylphosphines or triphenylphos-
phine oxides have already been undertaken; examples are the
introduction of substituents with chiral centers in ortho- or para-
positions,6 the utilization of chiral counterions7 or the introduction
of bulky substituents8 at the propeller blade aromatics for
enhancing the barrier of racemization at the phosphorus atom.
Although diastereospecific control over the helicity of triphenyl-
phosphine metal complexes is well known,9 these methods
generally failed in the case of triarylphosphine and triarylphos-
phine oxide derivatives as free ligands. The only example for a
stereochemically pure triarylphosphine oxide is a trisindolylphos-
phine oxide, where the stereochemical stability is the result of the
immense steric demand of the indolyl substituents.10
to be stabilized to such an extent that only this is adopted at
room temperature (1 in Scheme 1). As chiral scaffold we chose the
trisoxazole system 2, which resembles the naturally occurring
Lissoclinum-cyclopeptide Westiellamide.12
The desired triphenylphosphine oxide 1b was obtained by
cyclization of the chiral scaffold 9, having three amino functions as
coupling sites, with the tricarboxylic acid chloride 5 (Scheme 2).
The latter compound is available in three steps starting from
Recently we have shown that cyclic peptides can successfully be
used as templates for the chirality transfer of C3-symmetrical
compounds.11 Assuming that this concept is generally applicable,
we decided to try and synthesize a triphenylphosphine derivative
bound to a chiral, cyclic peptide scaffold. This scaffold should
cause one of the possible configurations at the phosphorus centre
aInstitut fu¨r Organische Chemie, Fachbereich Chemie, Universita¨t
Duisburg-Essen, Universita¨tsstraße 5, D-45117 Essen, Germany.
E-mail: gebhard.haberhauer@uni-due.de; Fax: +49 (0) 201 1834252
bOrganisch-Chemisches Institut, Westfa¨lische Wilhelms-Universita¨t,
Corrensstrasse 40, D-48149 Mu¨nster, Germany.
E-mail: grimmes@uni-muenster.de; Fax: +49 (0) 251 8336515
{ Electronic supplementary information (ESI) available: Experimental
details, calculated molecular structures of (P1)-1, atomic distances and
dihedral angles of 1 obtained from NMR experiments and calculated
values. See DOI: 10.1039/b709655k
Scheme 2 Reagents and conditions: (a) iPrMgCl, PBr3, THF, 278 uC A
RT, 54%; (b) HCl–AcOEt, quant.; (c) SOCl2, D, quant.; (d)
PhtNCH2COCl, KOtBu, THF, then 2 M HCl–H2O, 260 uC, 72%; (e)
Boc–L–Val–OH, iBuOCOCl, NMM, THF, 220 uC A RT, 65%; (f) PPh3,
Et3N, C2Cl6, CH2Cl2, RT, 52%; (g) Pd(OH)2/C, H2, MeOH, 98%; (h)
HCl, AcOEt, 98%; (i) PyBOP, iPr2NEt, DMF, RT, 32%; (j)
NH2NH2?H2O, Boc2O, THF–CH2Cl2–EtOH; (k) HCl, Et2O, RT, 90%
(2 steps); (l) 5, Et3N, CH2Cl2, RT, 20%; (m) HSiCl3, benzene, D, 78%.
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Chem. Commun., 2007, 3711–3713 | 3711

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1H-NMR spectra of 1a and 1b confirm the assumption that
Table 1 Relative energies of the conformers of 1a and 1b calculated
with the TZVP basis set
only one diastereomer is present in solution. Furthermore, the
torsion angles ascertained from 3J coupling constants approve
both the rigidness of the triphenylphosphine moiety as well as the
preference of the P1-conformation.19
DE/kJ mol21
Method
P1
P2
M1
M2
1
BP86
BP86
B3LYP
SCS-MP2
1a
1b
1b
1b
0.0
0.0
0.0
0.0
51.4
51.5
56.6
73.3
19.3
19.0
24.1
55.0
40.2
35.6
33.7
37.1
A variable temperature H-NMR measurement as well as 2D-
NOESY experiments were carried out for 1b.20 VT-1H-NMR
measurements showed that there are no dynamic processes
occurring between 260 uC and +60 uC. The comparison of
H,H-distances in 1b from 2D-NOESY measurements with those of
the conformers calculated by BP86/TZVP shows that these are
only consistent with the P1-conformation. The short distances
between the amide hydrogen and one hydrogen of the adjacent
m-iodobenzoic acid tert-butyl ester. The chiral scaffold 9 could be
synthesized in a few steps from the imine 6. Reduction of the
triphenylphosphine oxide 1b with HSiCl3 afforded the triphenyl-
phosphine 1a.
˚
methylene group (2.3 A) on the one side and one aromatic proton
˚
(2.1 A) on the other side indicate that 1b is rigid and possesses no
In principle, the triphenyl derivatives 1 can adopt four different
conformations (P1, P2, M1 and M2): On the one side, the three
phenyl rings can be present in two opposite helicities (P- or
M-isomer), and on the other side, the amide bonds connecting the
chiral scaffold to the triphenylphosphine system can adopt two
different orientations. Viewing the molecule from the phosphorus
atom along the main C3-axis the hydrogen atoms of the three
amide bonds are pointing clockwise in the case of conformers (P2)-
1 and (M2)-1 and anticlockwise for isomers (P1)-1 and (M1)-1.
To evaluate the relative stabilities of the stereoisomers, quantum
chemical calculations were performed using the TURBOMOLE
program.13 The structures were determined by geometry optimiza-
tions at the DFT-level using the BP86-GGA functional.14 For all
calculations an AO-basis of triple-zeta quality with polarization
functions (TZVP)15 and the RI-approximation16 was used.
Applying other GGAs led to similar structures and similar relative
energies (deviation , 5 kJ mol21) of the diastereomers. The
structures optimized by BP86 were further used in single-point
calculations with B3LYP17 and SCS-MP218 methods, as well as for
the calculation of (vertical) electronic CD spectra. All calculations
reveal that the P1-isomers of 1a and 1b are strongly stabilized in
preference to the others (Table 1, Fig. 1). The high energy
differences between the P1-conformers and the other isomers
indicate that phosphine 1a as well as phosphine oxide 1b adopt
only the P1-conformation in solution at ambient temperature.
conformational flexibility.
Additionally, CD measurements were carried out to confirm
that only the diastereomer (P1)-1b is present in solution. Fig. 2
shows CD spectra of chiral scaffold 2 and of triphenylphosphine
oxide 1b. Compared to the CD spectrum of 2 the De-values of 1b
show a change of sign, as well as a substantial increase in intensity
by a factor of up to six. The new bands at 265, 249, 233 and
205 nm of 1b arise from the triphenylphosphine oxide chromo-
phore and support the stabilization of one conformation.
Furthermore, a CD spectrum was calculated for (P1)-1b by the
time-dependent DFT (TDDFT) method.21,22 To avoid artificial
excited electronic states with charge-transfer character, which often
appear for large molecules when using pure GGAs, TDDFT-
calculations were carried out by the BH-LYP hybrid functional23
with a HF-exchange fraction of 50%. This calculated spectrum is
also depicted in Fig. 2 showing an evident accordance between
experiment and theory.
In summary, we have demonstrated that it is possible to stabilize
one conformation of a propeller-like triphenylphosphine and
triphenylphosphine oxide by using a chiral scaffold based on
Lissoclinum-cyclopeptides. The facile synthesis of such systems via
combination of a chiral scaffold with an achiral phosphine allows
us to develop novel triarylphosphines and triarylphosphine oxides
and to investigate their applicability in catalysis and synthesis.
The authors thank the DFG and SFB 424 for financial support.
We are grateful to Dr Andreea Schuster and Dipl.-Ing. Heinz
Bandmann for many helpful discussions.
Fig. 1 Molecular structures of the energetically preferred conformer
(P1)-1a calculated at the BP86/TZVP level; all hydrogen atoms have been
omitted for clarity.
Fig. 2 CD spectra of peptide 2 (green) and of phosphine oxide 1b
[experimental: red; calculated at the TDDFT-BHLYP/TZVP//BP86/TZVP
level for isomer P1 (intensity scaling factor: 0.22): blue].
3712 | Chem. Commun., 2007, 3711–3713
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