The microwave-assisted synthesis of a 2-carboxyphosphole

Article abstract of DOI:10.1016/j.tetlet.2008.01.075

Using a one-pot four-step reaction a readily available phospholide was converted efficiently to a 2-carboxyphosphole. This compound can be used as a building block for the synthesis of phosphole-containing peptides, where the phosphole can serve as a coor

Full text of DOI:10.1016/j.tetlet.2008.01.075

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Tetrahedron Letters 49 (2008) 1734–1737
The microwave-assisted synthesis of a 2-carboxyphosphole
Steven van Zutphen a,b,*, Guilhem Mora a, Vicente J. Margarit a, Xavier F. Le Goff a,
Duncan Carmichael a, Pascal Le Floch a
a Laboratoire ‘He´te´roe´le´ments et Coordination’, Ecole Polytechnique, CNRS, 91128 Palaiseau Cedex, France
b Corning SAS, Corning European Technology Center, 77210 Avon, France
Received 6 December 2007; revised 8 January 2008; accepted 17 January 2008
Available online 20 January 2008
Abstract
Using a one-pot four-step reaction a readily available phospholide was converted efficiently to a 2-carboxyphosphole. This compound
can be used as a building block for the synthesis of phosphole-containing peptides, where the phosphole can serve as a coordination site
for late transition metals and may affect the secondary structure of the peptide.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Phosphorus heterocycles; Sigmatropic rearrangement; P Ligands; Microwave-assisted synthesis
The coordination chemistry of phospholes with late
transition metals such as platinum, rhodium or palladium
has found widespread application in transition metal catal-
ysis.1–4 Our research is focussed on the development of new
biocompatible catalysts. To achieve this, we are trying to
incorporate phospholes into polypeptide chains. Such
non-natural polypeptides might find applications in highly
specialised, enantioselective catalysis of reactions quite
uncommon to native enzymes.5
Phospholes can be conveniently synthesised via the
McCormack synthesis involving the reaction of an aryldi-
halophosphine with a diene. This synthesis is however
not compatible with many functional group substituents.6
Functionality is, therefore, more conveniently introduced
through nucleophilic or electrophilic substitution reactions
at the P atom.7 Using a nucleophilic substitution reaction,
we recently synthesised the first phosphole-containing
amino-acid,8 and incorporated this into a cyclic decamer
whose coordination properties are under current
investigation.9
which is similar to the phospholane carboxylic acid
described by Kobayashi and co-workers,10,11 the five-mem-
bered ring of proline is replaced by the phosphole ring. The
rigid structure of this molecule, and the bulky phenyl group
on the 5-position, could make it a suitable turn-inducer in a
polypeptide12 whilst the lone-pair on the phosphorus
makes it a good ligand for late transition metal centres.
Ideally, it should be possible to integrate our phosphole
building block into a standard peptide synthesis. We, there-
fore, designed phosphole 1 (Fig. 1) to be compatible with
Fmoc-based peptide synthesis, where the building-blocks
possess a free acid functionality and an amine protected
by a base-labile protecting group (2).13 For a phosphole,
the synthetic equivalent of the deprotonated amine is the
phospholide anion. This anion can be masked conveniently
through alkylation with bromopropionitrile to give a stable
cyanoethyl phosphole.14 The phospholide can be regener-
ated with a strong base such as tBuOK at room tempera-
ture releasing acrylonitrile as the side-product.15
The one-pot, four-step synthesis of 7 from readily avail-
able 3, and its subsequent conversion to target compound
1, is detailed in Scheme 1. We recently reported on the
facile, large-scale synthesis of phospholide 3.16 On reaction
with Boc2O, this phospholide yields the expected phos-
phole 4, which shows a 31P NMR chemical shift at
As an extension of that Letter, we describe the synthesis
of a 2-carboxyphosphole inspired by proline. In this design,
*
Corresponding author. Tel.: +33 164 69 7024; fax: +33 164 69 7455.
E-mail address: vanzutphs@corning.com (S. van Zutphen).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.01.075

S. van Zutphen et al. / Tetrahedron Letters 49 (2008) 1734–1737
1735
1 equiv Boc2O
in THF 1h
K
Δ
H
O
Ph
O
P
Ph
Ph
Ph
P
P
P
OH
O
O
O
3
CN
5
1
4
TFA in
CH2Cl2,
quantitative
1 equiv bromo-
O
O
O
tBuOCO2H
O
propionitrile
95%
Ph
Ph
P
Ph
P
P
K
or Boc2O
O
O
O
O
6
CN
7
8
Scheme 1. The four-step, one-pot synthesis of phosphole 7 and its transformation to target compound 1. Phosphole 8 is formed as a side-product when the
heating is not carried out in a microwave or excess Boc2O is used.
8.7 ppm. Heating the reaction mixture containing com-
pound 4 prompts a1,5 shift of the ester group, but neither
intermediate 5, nor the cyclodimer formed by a Diels–
Alder reaction with itself, were observed. Instead, the reac-
tion proceeded directly to phospholide 6, which shows a
31P NMR chemical shift at 104 ppm. This is probably
because tBuOCO2K, formed in situ in the first step of the
reaction, is effecting the deprotonation of 5 to yield 6.17
However, when refluxing the reaction mixture in an oil
bath a side-product 8, with a 31P NMR shift at 16.7 ppm,
was observed. This compound, which forms even when a
deficiency of Boc2O is employed, can be isolated as the only
product when the reaction is carried out using excess
Boc2O. We, therefore, reasoned that it must be formed
through a reaction of tBuOCO2H or Boc2O with phos-
pholide 6.
To avoid this problem, one could decide to isolate
phosphole 4 and then heat it in the presence of tBuOK
to yield the desired phospholide. In a more elegant one-
pot approach, side-product formation can be prevented
when the tBuOCO2K is decarboxylated to give tBuOK
and CO2 in situ. In this case, the tBuOK can act as the base
to deprotonate 5, but the reaction with phospholide 6 to
form a side-product cannot take place. We found that
when promoting the [1,5]-functional group shift under
microwave irradiation (300 W, 100 °C), phospholide 6
was the sole product, and side product 8 was not observed.
It appears that under these conditions the decarboxylation
takes place at the same time as the functional group shift.
Quenching phospholide 6 with bromopropionitrile gives
the expected phosphole 7 which shows a 31P NMR chemical
shift at 6.1 ppm. This phosphole is stable at room tempera-
ture and not particularly prone to air oxidation. After filtra-
tion through a short silica column, the product was treated
with TFA to give the target compound 1. Since compounds
1 and 7 may be oxidised by air over time they are best stored
and handled under nitrogen. Should the oxides, with 31P
NMR chemical shifts at 48.2 and 44.6 ppm, respectively,
form, they can easily be reconverted to the phospholes by
heating in CH2Cl2 with excess phenylsilane for several
hours,18 monitoring the progress of the reaction by 31P
NMR.
Single crystals of 1 suitable for X-ray analysis were
obtained by the slow evaporation of a methanol solution.
A displacement ellipsoid plot of a single molecule of 1 is
shown in Figure 2 and significant bond lengths are listed
in the corresponding legend. Crystal data and structural
refinement details are presented in the Supplementary data.
R2
R3
R1
COOH
CN
COOH
P
N
Fmoc
Fig. 2. Displacement ellipsoid plot (50%) of compound 1 CCDC 673227.
H omitted for clarity. Significant bond lengths: P(1)–C(2) 1.796(1), P(1)–
C(5) 1.800(1), C(2)–C(3) 1.367(2), C(3)–C(4) 1.471(2), C(4)–C(5)
1
2
3
1
2
R = Ph; R , R = Me
˚
Fig. 1. Phosphole 1 compared to N-Fmoc-proline 2.
1.364(2) A.

1736
S. van Zutphen et al. / Tetrahedron Letters 49 (2008) 1734–1737
tion.19,20 They also show platinum satellites (JPtP of
2855 Hz), which are quite typical for PEt3 and a relatively
small coupling of 2233 Hz for the phosphole.
i tBuOK
O
ii propionyl chloride
Ph
7
P
In summary, we have described the synthesis and chara-
cterisation of a 2-carboxyphosphole that is suitable for
introduction into the backbone of a polypeptide chain. A
substituted phosphole moiety in a polypeptide can have a
two-fold functionality. Firstly, the phosphorus lone pair
can coordinate to a transition metal. This was illustrated
by the coordination of several transition metal ions (Pd,
Pt, Ni and Au) to model compound 9. Secondly, and anal-
ogous to proline, the rigid structure of the phosphole ring
may serve as a folding element, introducing a secondary
structure in a polypeptide. Phosphole 1, therefore, opens
up possibilities for the synthesis of new, biocompatible
ligands for transition metal catalysts.
O
in THF, 93%
O
9
Scheme 2. Conversion of phosphole 7 to model compound 9.
Fmoc-based peptide synthesis involves the deprotection
of the Fmoc-protected amine followed by reaction with an
activated carboxylic acid. To test the suitability of com-
pound 1 for integration into a polypeptide, we studied its
reactivity under similar conditions. Unlike the Fmoc pro-
tection group, we found that the cyanoethyl moiety was
stable towards piperidine. It can however be cleaved with
a stronger base. For example, when 1 equiv of tBuOK
was added to 7 in THF at room temperature, phospholide
6 was rapidly observed by 31P NMR and the reaction was
complete within 10 min. Upon reaction with propionyl
chloride, product 9, with a 31P NMR chemical shift at
36.8 ppm, was readily isolated (Scheme 2). This compound
is a model for the phosphole integrated in a polypeptide,
containing a 1-carbonyl phosphole system as an amide
bond surrogate. A reaction between 6 and N-Boc glycine,
activated using isobutyl chloroformate in the presence
of N-methylmorpholine, gave a product with a similar
31P NMR chemical shift at 32.1 ppm. Unfortunately,
this product was not isolated due to stability problems
during purification. Although a strong base such as
tBuOK may cause racemisation of neighbouring amino
acids, these reactions demonstrate the compatibility of
Acknowledgement
The authors would like to thank the European Commu-
nity (Adventure-STREP Project No. 15471) as well as the
Ecole Polytechnique for financial support of this work.
Supplementary data
Experimental details and crystallographic tables for 1.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2008.01.075.
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