A new ligand containing a unique combination of backbone- and P-centered chirality: Synthesis, resolution and asymmetric catalysis using a chiral enantiopure 2,2'-biphospholene

Article abstract of DOI:10.1016/S0957-4166(99)00547-9

Enantiopure 2,2'-bi(1-phenyl-3,4-dimethyl-2,5-dihydro-1H-phosphole) has been synthesized and tested in the rhodium-catalyzed asymmetric hydrogenation of α-acetamidocinnamic acid. Enantioselectivities up to 75% have been achieved. The absolute configuration of the biphospholene was determined by X-ray diffraction methods on a crystalline tungsten carbonyl derivative. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(99)00547-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 10 (1999) 4701–4707
A new ligand containing a unique combination of backbone- and
P-centered chirality: synthesis, resolution and asymmetric
catalysis using a chiral enantiopure 2,20-biphospholene
Frank Bienewald, Louis Ricard, François Mercier and François Mathey ∗
Laboratoire ‘Hétéroéléments et Coordination’ UMR CNRS 7633, DCPH, Ecole Polytechnique, 91128 Palaiseau cedex,
France
Received 11 October 1999; accepted 26 November 1999
Abstract
Enantiopure 2,2’-bi(1-phenyl-3,4-dimethyl-2,5-dihydro-1H-phosphole) has been synthesized and tested in the
rhodium-catalyzed asymmetric hydrogenation of α-acetamidocinnamic acid. Enantioselectivities up to 75% have
been achieved. The absolute configuration of the biphospholene was determined by X-ray diffraction methods on
a crystalline tungsten carbonyl derivative. © 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
Chirality can be introduced into a ligand structure in many different ways.1 The most successful
concepts in the field of (di)phosphine ligand design are P-centered chirality,2,3 backbone chirality4 and
the introduction of chiral groups rendering the phosphorus atom non-stereogenic and chirotopic, as in the
phospholane-based ligands of the DuPHOS series.5
Our laboratory has recently synthesized ligands containing 2-substituted 3-phospholene skeletons.6
Their preparation has been facilitated by the discovery of a particularly straightforward access to a unique
C2-symmetric biphospholene structure, through the coupling of appropriately substituted phospholes
(Scheme 1).7,8
An unusual feature of these C2-symmetric ligands is the combination of two different types of chirality,
which are localized within the backbone and at the phosphorus atom. These ligands are more electron-rich
than the commonly used triarylphosphines and, being dialkylaryl- or trialkylphosphines, are comparable
with ligands of the DuPHOS/BPE series.5 Unlike DuPHOS, they have structures which should be
relatively easy to vary at the aryl moiety.
∗
Corresponding author. Fax: +33 (1) 6933-3990; e-mail: francois.mathey@polytechnique.fr
0957-4166/99/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00547-9
tetasy 3182

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Scheme 1.
2. Results and discussion
We employed the well-known palladium complex (+)-(R)-49 to separate the two enantiomers of
biphospholene 3. Complexation using 0.25 equivalents of complex 4 in dichloromethane at 0°C gave
a mixture containing the two diastereomeric complexes 5a/b in a ratio close to 1:1 (Scheme 2), along
with uncomplexed biphospholene 3. Hence, a kinetic resolution or enrichment of one enantiomer is not
feasible. As anticipated, complexation using half an equivalent of complex 4 cleanly gave the chelate
complexes 5a/b, as shown by 31P NMR spectra (two AB systems with doublets of 20 Hz coupling each
at 78.2, 76.3, 56.5, 54.6).
Scheme 2.
Unfortunately, attempts to separate the two diastereomers on silica (using CH2Cl2/EtOAc or
EtOAc/toluene mixtures) failed. Attempted crystallizations from several solvent mixtures, after anion
exchange with KPF6, were also unsuccessful.
Eventually, complexation of biphospholene 3 to 1 equivalent of palladium dimer 4 in THF was
attempted. The two diastereomeric bridged dinuclear palladium complexes 6a/b which were formed in
high yield showed broad singlets at 50.0 and 49.1 ppm in the 31P NMR spectra.

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4703
These two complexes were easily separated by flash chromatography on silica using toluene:EtOAc
(80:20) as eluent. Complex 6a (49.1 ppm) was eluted first. Decomplexation using NaCN in a biphasic
CH2Cl2/water mixture yielded pure samples of the two enantiomers (+)- and (−)-3, [α]D25=±125, as
colourless crystals.
In order to obtain a crystalline derivative for the determination of the absolute configuration, enantio-
pure (+)-3, derived from diastereomer 6b, was reacted with [(CO)5W(THF)]. (+)-(3)W(CO)4 could be
isolated as the only complex after recrystallization from toluene/CHCl3 as a crystalline solid, suitable for
X-ray structural analysis (Fig. 1).10 Its absolute configuration was shown to be (+)-(2R,20R).
Fig. 1.
The addition of a solution of ligand 3 to a suspension of [(COD)RhCl]2/KPF6 in methanol gave a
mixture of cationic complexes 7 (31P NMR: δ=77.8 ppm, JRh–P=147 Hz) and 8 (31P NMR: δ=78.9 ppm,
JRh–P=129 Hz) in a ratio close to 1:1 (Scheme 3).
Scheme 3.
Bis(diphosphine)rhodium complexes are not usually active hydrogenation catalysts, so complexation
to other rhodium precursors was tested to obtain higher yields of 7. Coordination using acidified (HBF4)
solutions of (acac)Rh(COD) in THF cleanly yielded catalyst precursor 7 (BF4 as anion).11 Compound 7

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separated as an orange, air sensitive oil upon evaporation of most of the solvent and addition of diethyl
ether. It solidified after several weeks.
Initial hydrogenations were performed using α-acetamidocinnamic acid 9 (Scheme 4). Results are
shown in Table 1.
Scheme 4.
Table 1
Asymmetric hydrogenation of α-acetamidocinnamic acid 9 using biphospholene rhodium complex 7
Under standard conditions (entry 1) the (2R,20R)-catalyst gave (R)-N-acetylphenylalanine in 69% ee.
Increasing the pressure to 40 atm had little effect upon selectivity (entry 2). However, the enantiomeric
excess could be increased slightly to 75% when lowering the temperature to 6°C (entry 3). The use of
solvents such as iPrOH or benzene gave selectivities of 59 and 40% ee, respectively (entries 4 and 5).
3. Conclusion
An enantiopure 2,20-biphospholene (3) having a unique combination of backbone and P-centered
chirality can be obtained through chromatographic separation of the diastereomeric palladium complexes
6a/b. Inital tests in the rhodium-catalyzed asymmetric hydrogenation of α-acetamidocinnamic acid have
shown good activity and enantioselectivities up to 75%.
We are currently synthesizing more ligands based on the 2,20-biphospholene scaffold and investigating
them in a range of processes. Further elaboration of this basic ligand structure is envisaged.
4. Experimental
4.1. General
NMR spectra were recorded on a Bruker AC 200 SY spectrometer operating at 200.13 MHz for 1H,
50.32 MHz for 13C and 81.01 MHz for 31P NMR. Chemical shifts are expressed in parts per million
(ppm) downfield from external tetramethylsilane (1H and 13C) and 85% aqueous H3PO4 (31P).

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Due to their sensitivity to air, all manipulations with the free ligand 3 and the corresponding rhodium
complex 7 were conducted with freshly degassed solvents under dry argon. In contrast, the apparently
air-stable palladium complexes 6a/b can be chromatographed without any precautions.
4.2. Synthesis and separation of the two diastereomeric complexes 6a and 6b
To a solution of 910 mg (2.4 mmol) 2,20-bi(1-phenyl-3,4-dimethyl-2,5-dihydro-1H-phosphole) 37
in 10 ml THF were added 1.4 g (2.4 mmol) bis{µ-chloro[(R)-N,N-dimethyl(α-methylbenzyl)amino-2-
C,N]palladium(II)} 49 and the solution was allowed to stir at room temperature for 15 min. Complete
formation of the two diastereomeric complexes can be monitored by 31P NMR ((THF): δ (ppm)=50.0,
49.1 (broader peak)). The solvent was removed in vacuo and the oily product was chromatographed on
silica (270 g). The diastereomer characterized by the broader peak in the 31P NMR at 49.1 ppm was
eluted first with toluene:EtOAc (80:20) as solvent (yield: 955 mg; 83%); that showing the less broad
peak at 50.0 ppm was eluted second with toluene:EtOAc (60:40) as solvent (yield: 820 mg; 76%).
1
Compound 6a: H NMR (CDCl3): δ (ppm)=7.70–7.60 (m, 2H), 7.35–7.10 (m, 3H), 6.85–6.50 (m,
4H), 4.80–4.55 (m, 1H), 3.95–3.75 (m, 1H), 3.70–3.45 (m, 1H), 2.87 (s, 3H), 2.80–2.65 (m, 1H), 2.64
(s, 3H), 2.31 (s, 3H), 1.68 (s, 3H), 1.51 (d, J=7 Hz, 3H). 13C NMR (CDCl3): δ (ppm)=153.5, 137.8 (d,
J=7 Hz), 134.8, 134.0, 132.3, 132.1, 132.0, 131.8, 130.2, 128.5, 128.4, 128.3, 126.1, 124.4, 122.4, 60.3,
52.4, 49.8, 45.2, 42.7, 42.0, 17.1, 17.0, 16.9, 16.7. 31P NMR (THF): δ (ppm)=49.1. [α]D25=−103 (c=1.0,
CHCl3).
1
Compound 6b: H NMR (CDCl3): δ (ppm)=7.85–6.50 (m, 9H), 4.70 (s, 1H), 4.15–3.90 (m, 1H),
3.71–3.45 (m, 1H), 2.87 (s, 3H), 2.80–2.65 (m, 1H), 2.60 (s, 3H), 2.31 (s, 3H), 1.70 (s, 3H), 1.51 (d,
J=6 Hz, 3H). 13C NMR (CDCl3): δ (ppm)=152.4, 149.4, 137.0 (t, J=6 Hz), 134.7–133.2 (m), 132.1 (t,
J=7 Hz), 131.9, 131.6, 128.3 (t, J=5 Hz), 126.0, 124.2, 122.7, 60.2, 52.2 (t, J=16 Hz), 49.0, 43.3, 42.4 (t,
J=17 Hz), 17.2 (t, J=5 Hz), 16.7 (t, J=4 Hz), 15.6. 31P NMR (THF): δ (ppm)=50.0. [α]D25=+82 (c=0.96,
CHCl3).
4.3. Decomplexation of 6a and 6b
To a solution of 410 mg (0.43 mmol) of complex 6b in 4 ml dichloromethane were added 2 ml of an
aqueous saturated NaCN solution. The mixture was shaken vigourously for 30 min, water (10 ml) was
added and the organic phase was separated. The aqueous phase was extracted twice with dichloromethane
(2 ml). The combined organic phases were dried over magnesium sulfate, filtered and the solvent was
removed in vacuo. The crude product was eluted over silica (2 g) with dichloromethane as solvent.
Evaporation of the solvent afforded 110 mg (0.29 mmol, 67% yield) of the ligand as a colourless solid.
1H NMR (CDCl3): δ (ppm)=7.50–7.22 (m, 5H, Ph), 3.30–2.85 (m, 2H, CH2), 2.60–2.45 (d, J=17 Hz, 1H,
CH), 1.84 (s, 3H, CH3), 1.84 (s, 3H, CH3). 13C NMR (CDCl3): δ (ppm)=142.3 (ψt, J=7 Hz, Cipso), 132.5
(s), 132.3 (s), 131.8, 131.6, 131.4, 128.3, 128.2, 128.1, 59.5 (ψt, J=10 Hz), 38.5, 17.0, 14.6. 31P NMR
(CH2Cl2): δ (ppm)=−25.5. (+)-(2R,20R)-3 [α]D25=+125 (c=0.71, CH2Cl2). From 6a: (−)-(2S,20S)-3
[α]D25=−125 (c=0.70, CH2Cl2).
4.4. Synthesis of tungsten complex ((+)-(R)-3)W(CO)4
A mixture of (CO)5W(THF) (prepared from 350 mg (1 mmol) W(CO)6 in 50 ml THF under
UV irradiation for 1.5 h) and 190 mg (0.5 mmol) diphosphine (+)-3 were stirred overnight at room

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temperature. The solvent was removed in vacuo and the residue was chromatographed over silica with
hexane:dichloromethane 80:20, affording 300 mg (86%) of ((+)-(R)-3)W(CO)4 as white crystals. The
1
product was recrystallized from CDCl3:toluene 50:50. H NMR (CDCl3): δ (ppm)=7.70–7.55 (m, 2H,
Ph), 7.45–7.25 (m, 3H, Ph), 3.90–3.52 (m, 1H), 3.28–2.83 (m, 2H), 1.60 (s, 3H, CH3), 1.35 (s, 3H, CH3).
13C NMR (CDCl3): δ (ppm)=208.4 m, CO), 201.4 (m, CO), 136.6 (ψt, J=17 Hz), 131.8 (t, J=3 Hz),
130.8, 130.1, 129.7 (t, J=5 Hz), 128.6 (d, J=5Hz), 57.8 (t, J=22 Hz), 45.3 (m), 16.5 (d, J=5 Hz), 14.9 (d,
J=3 Hz). 31P NMR (CDCl3): δ (ppm)=52.2 (1JP–W=226 Hz). [α]D25=+246 (c=1.32, CDCl3).
4.5. Synthesis of rhodium complex 7
To a solution of 62 mg (0.2 mmol) (acetylacetonato)(1,5-cyclooctadiene)rhodium and 48 mg (0.3
mmol) tetrafluoroboric acid diethyl etherate in 2 ml THF was added a solution of 76 mg (0.2 mmol)
2,20-bi(1-phenyl-3,4-dimethyl-2,5-dihydro-1H-phosphole) 3 in 1 ml THF dropwise over a period of 5
min. After stirring for 30 min, most of the solvent was removed in vacuo and diethyl ether (2 ml) was
added to precipitate complex 7. The upper layer was decanted, the residue was again washed with 2 ml
diethyl ether and finally dried in vacuo. 31P NMR (THF): δ=78.4 ppm (d, JRh–P=146 Hz).
4.6. Hydrogenation of α-acetamidocinnamic acid 9
To a 0.2 molar solution of 410 mg (2 mmol) α-acetamidocinnamic acid 9 in freshly degassed methanol
was added 0.3–0.5 mol% of catalyst precursor 7. The solution was subsequently transferred by means
of a syringe into a hydrogenation bomb, previously purged three times with 7 atm hydrogen and stirred
under 7 atm hydrogen for the indicated time. The pressure was released and the solvent was removed in
vacuo. The conversion was determined from 1H NMR spectra of the crude product in d6-DMSO. A small
sample was converted into its methyl ester with trimethylsilyldiazomethane in hexane:2-propanol=90:10,
and the enantiomeric excess was determined by HPLC analysis using a Daicel column Chiralcel OD
(hexane:2-propanol=90:10, 1 ml/min; retention times: 9.7 min (R), 12.3 min (S)).
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