Synthesis of P-chirogenic diarylphosphinoacetic acids and their proline derivatives for palladium-catalysed allylic alkylation reactions

Article abstract of DOI:10.1016/j.tetlet.2005.09.136

The synthesis of P-chirogenic diarylphosphinocarboxylic acids was achieved, from which a new class of amido- and amino-diphosphine ligands (PNP*) were derived, containing an L-proline backbone. The catalytic activities of the novel ligands were evaluated

Full text of DOI:10.1016/j.tetlet.2005.09.136

Tetrahedron
Letters
Tetrahedron Letters 46 (2005)8145–8148
Synthesis of P-chirogenic diarylphosphinoacetic acids and
their proline derivatives for palladium-catalysed allylic
alkylation reactions
Hubert Lam,a,ꢀ Peter N. Horton,b Michael B. Hursthouse,b
a,
David J. Aldousc and King Kuok (Mimi)Hii
*
aDepartment of Chemistry, King’s College, Strand, London, WC2R 2LS, UK
bEPSRC National X-Ray Crystallography Service, University of Southampton, Highfield, Southampton SO17, 1BJ, UK
cSanofi-Aventis Pharmaceuticals, 1041 Route 202-206, PO Box 6800, Bridgewater, NJ 08807-0800, USA
Received 28 June 2005; revised 19 September 2005; accepted 21 September 2005
Available online 10 October 2005
Abstract—The synthesis of P-chirogenic diarylphosphinocarboxylic acids was achieved, from which a new class of amido- and
amino-diphosphine ligands (PNP*)were derived, containing an L-proline backbone. The catalytic activities of the novel ligands were
evaluated in the palladium-catalysed allylic alkylation reaction of 1,3-diphenylpropenyl acetate.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
There are very few reports of non-C2 symmetrical phos-
phine ligands in asymmetric catalysis, especially those
containing more than one stereogenic centre.1
Figure 2. New classes of P-chirogenic ligands and their synthetic
precursors.
Previously, we have reported novel classes of unsymmet-
rical, aminodiphosphine ligands derived from L-proline
(Fig. 1), and their subsequent catalytic activity in the
asymmetric palladium-catalysed allylic alkylation reac-
by changing the nature of the nitrogen donor (1 vs 2),
the pendant donor atom (2 vs 4)and/or by the introduc-
tion of an additional stereogenic carbon (3 vs 4). Herein,
tion.2 In these studies, the pendant arm of the ligand
attached to the pyrrolidinyl nitrogen was modified either
we report the synthesis and comparative catalytic activ-
ities of a related series of amido- and amino-diphosphine
ligands 5 and 6 (Fig. 2), incorporating a stereogenic
phosphorus donor on the pendant arm.
2. Ligand synthesis
Adopting a convergent synthetic route previously estab-
lished in our laboratory,2 we envisaged that the ligands
could be prepared by the coupling between 7 and the P-
chiral phosphinocarboxylic acids 8. Although synthetic
methodologies for the preparation of P-chiral phosphi-
nocarboxylic acid–boranes have been extensively devel-
oped by Imamoto and co-workers,3 strategies to access
diarylphosphinoacetic acids such as 8 are rare.4 In this
Figure 1. Proline-derived amido- and amino-phosphine ligands.
Keywords: Chirogenic phosphine; PNP ligands; Palladium; Allylic
alkylation.
*
Corresponding author. Tel.: +44 20 75941142; fax: +44 20
75945804; e-mail: mimi.hii@imperial.ac.uk
ꢀ Present address: Department of Chemistry and Biochemistry, Florida
State University, 604 DLC, Tallahassee, FL 32306-4390, USA.
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.136

8146
H. Lam et al. / Tetrahedron Letters 46 (2005) 8145–8148
Scheme 1. Preparation of optically active diarylmethylphosphine–
boranes 9a–c: Reagents and conditions: (i)PhP(NEt 2)2, PhMe, (ii)
BH3ÆSMe2, (iii)ArLi, À40 ꢁC, THF; then H2O, (iv)MeOH, H 2SO4, (v)
MeLi then H2O.
project, we have designed a synthetic route to these pre-
Figure 3. ORTEP representation of the molecular structure of 10a,
determined by X-ray crystallography. Aromatic hydrogens omitted for
clarity.
´
cursors. Based on a synthetic method pioneered by Juge
et al.,5 successive stepwise chemo- and stereo-selective
displacements of an ephedrine chiral auxiliary from a
P-centre afforded three diarylmethylphosphine–borane
adducts (S)-9a–c in good yields and excellent enantio-
purities (Scheme 1).
Deprotonation of the methylphosphine–boranes 9 with
sec-BuLi at À78 ꢁC, followed by trapping with carbon
dioxide at À40 ꢁC, furnished P-chiral phosphinocarb-
oxylic acid–boranes 10a–c as white crystalline solids
after acidic work up (Scheme 2).
Scheme 3. Preparation of P-chiral amido- and amino-diphosphines:
Reagents and conditions: (i)( SP)-8, DMAP, EDC, CH2Cl2, rt, 24 h
(48–51%); (ii) BH3ÆTHF; (iii)Et 2NH, Raney Ni, MeOH, reflux (50–
60% over two steps).
The identity and absolute configuration (SP)of the
phosphinocarboxylic acid borane 10a were established
unequivocally by X-ray crystallography (Fig. 3).
The borane protecting group could be removed, with
retention of configuration, by treatment with trifluoro-
acetic acid, to provide a new class of phosphinocarboxylic
acid (PO)ligands 8a–c, which were subsequently coupled
with (S)-(À)-2-(diphenylphosphino)methylpyrrolidine,
7, to afford the unsymmetrical amidodiphosphine ligands
5a–c (Scheme 3). These amidodiphosphines displayed
restricted rotation about the amide bond, giving rise to
unequal rotamer populations.6 Perhaps unsurprisingly,
the distribution of the rotamers was dependent on the
substitution of the pendant chirogenic phosphorus donor
group, increasing in the following order: 1 (4.3:1)> 5c
(3.5:1)> 5b (1.8:1)> 5a (1.1:1).
taneously achieved using BH3ÆTHF, furnishing triborane
adducts. Removal of the protecting groups from the
P- and N-donor atoms was carried out in a one-pot pro-
cedure, using Raney Ni (cat.), Et2NH and methanol,2b
yielding the aminodiphosphine ligands 6a–c as oils. Sin-
gle sets of NMR resonances (31P, 1H and 13C)confirmed
that phosphines 5 and 6 were obtained as single
diastereomers.
3. Catalytic studies
A number of phosphinocarboxylic acids have been
employed in Pd-catalysed asymmetric allylic alkylation
(AAA)reactions with good effect, but none of them
contained a stereogenic phosphorus.7
Finally, reduction of the amide functionality and protec-
tion of the trivalent N- and P-donors were simul-
To obtain a direct comparison, optimal conditions
established in our previous work2b were employed to
assess the catalytic performance of the P-chirogenic
ligands 5, 6 and 8 in the Pd-catalysed AAA of 1,3-diphen-
ylpropenyl acetate with dimethyl malonate (Scheme 4,
Table 1).
Using the P-chirogenic phosphinocarboxylic acids 8a
and 8c, good conversion and enantioselectivity were
obtained at ambient temperature (entries 1 and 2). The
Scheme 2. Preparation of P-chiral phosphinocarboxylic acids:
Reagents and conditions: (i)(a) sec-BuLi, À78 ꢁC, (b)CO 2, À40 ꢁC,
(c)H 3O+ (55–60%); (ii) (a) TFA, 0 ꢁC, (b)aq NaOH (90–92%).

H. Lam et al. / Tetrahedron Letters 46 (2005) 8145–8148
8147
presented. The cooperative effects between C- and P-ste-
reogenic centres will be examined in our future work.
Acknowledgements
Scheme 4. Palladium-catalysed allylic alkylation.
This work was performed at Kingꢁs College London as
part of H.L.ꢁs PhD research. The authors wish to thank
Aventis Pharmaceuticals and Kingꢁs College, London,
for studentship support, and Johnson Matthey plc, for
the provision of palladium salts.
Table 1. Pd-catalysed asymmetric allylic alkylation (AAA)of 1,3-
diphenylpropenyl acetatea
b
Entry
Ligand
T (ꢁC)
t (h)Conv. (%)
ee/% (R/S)c
1d
2d
3
4
5
6
7
8
9
8a
8c
1
rt
rt
0
0
0
0
0
0
0
0
24
24
24
48
24
24
2
24
24
24
100
100
100
—
100
100
100
100
100
100
63 (R)
81 (R)
82 (S)
—
71 (S)
27 (S)
80 (S)
37 (S)
23 (S)
12 (R)
Supplementary data
5a
5b
5c
2
Experimental procedures and characterisation data are
available on-line. Crystallographic data (excluding
structure factors)for compound 8a have been deposited
with the Cambridge Crystallographic Data Centre as
supplementary publication number CCDC 276442.
Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2
1EZ, UK [fax: +44 (0)1223 336033 or e-mail: deposit@
ccdc.cam.ac.uk]. Supplementary data associated with
this article can be found, in the online version, at doi:
10.1016/j.tetlet.2005.09.136.
6a
6b
6c
10
a Typical reaction conditions: see Ref. 8. Reaction times were
unoptimised.
b Determined by 1H NMR.
c Determined by chiral HPLC.
d Ligand:metal ratio = 1:1.
naphthyl-substituted ligand afforded good enantioselec-
tivity (81%)in favour of the R-enantiomer.
References and notes
In comparison, the amido- and amino-diphosphine
ligands 5 and 6 yielded the S-enantiomer as the major
product (entries 3–10), except for the P-anisyl amido-
diphosphine 5a, which did not induce any catalytic
activity at 0 ꢁC (entry 4).
1. (a)Barbaro, P.; Bianchini, C.; Giambastiani, G.; Togni, A.
Chem. Commun. 2002, 2672–2673; (b)Deerenberg, S.;
Kamer, P. C. J.; van Leuween, P. W. N. M. Organomet-
allics 2000, 19, 2065–2072; (c)Tang, W.; Wang, W.; Zhang,
X. Angew Chem., Int. Ed. 2003, 42, 943–946; (d)Carmi-
chael, D.; Doucet, H.; Brown, J. M. Chem. Commun. 1999,
261–262; (e)Burgess, K.; Ohlmeyer, M. J.; Whitmire, K. H.
Organometallics 1992, 11, 3588–3600.
2. (a)Cheng, X.; Hii, K. K. Tetrahedron: Asymmetry 2003, 14,
2045–2052; (b)Lam, H.; Cheng, X.; Steed, J. W.; Aldous,
D. J.; Hii, K. K. Tetrahedron Lett. 2002, 43, 5875–5877.
3. (a)Danjo, H.; Higuchi, M.; Yada, M.; Imamoto, T.
Tetrahedron Lett. 2004, 45, 603–606; (b)Ohashi, A.;
Kikuchi, K.; Yasutake, M.; Imamoto, T. Eur. J. Org.
Chem. 2002, 15, 2535–2546; (c)Ohashi, A.; Imamoto, T.
Tetrahedron Lett. 2001, 42, 1099–1101; (d)Ohashi, A.;
Imamoto, T. Org. Lett. 2001, 3, 373–375.
Cooperative effects between the ligand backbone and
P-stereogenic centre have been previously observed
in several asymmetric catalytic processes, including
allylic alkylation, hydroboration, hydroformylation and
hydrogenation reactions.1b–e In the present case, the
introduction of the chirogenic P-donor in the pendant
arm led to a decrease in the ee value. Replacement of
the phenyl group of ligand 1 (entry 3)by ortho-substi-
tuted aryl groups (5a–b)or by a naphthyl moiety ( 6c)
seemed to decrease the enantioselectivity of the reaction
(entries 4–6), and a similar trend was observed for
ligands 6a–c (entries 7–10). Considering that the phos-
phinocarboxylic acids induce the formation of the oppo-
site enantiomer (entries 1 and 2), we hypothesise that the
beneficial effect induced by the chiral pyrrolidine back-
bone may be negated by the P-chiral pendant arm, play-
ing an anti-cooperative effect. In the case of ligand 6c,
the stereoinduction imposed by the former is over-rid-
den by that of the stereogenic phosphorus centre.
4. Diarylphosphinoacetic acid–borane complex has been
prepared by kinetic resolution of the corresponding men-
thyl esters Imamoto, T.; Oshiki, T.; Onozawa, T.; Kusum-
oto, T.; Sato, K. J. Am. Chem. Soc. 1990, 112, 5244–5252.
´
ˆ
5. Juge, S.; Stephan, M.; Laffitte, J. A.; Genet, J. P. Tetra-
hedron Lett. 1990, 31, 6357–6360.
6. For example, four singlets were observed in the 31P NMR
spectrum of phosphine 1, at À13.7 (minor), À20.4 (minor),
À17.3 (major)and À20.9 (major)ppm. Variable tempera-
ture 31P NMR experiments revealed that these resonances
coalesce at a temperature of 378 K, giving two broad
singlets at À15.8 (PB)and À19.0 (PA).
7. (a)Inoue, H.; Nagaoka, Y.; Tomioka, K. J. Org. Chem.
2002, 67, 5864–5867; (b)You, S. L.; Luo, Y. M.; Deng, W.
P.; Hou, X. L.; Dai, L. X. J. Organomet. Chem. 2001, 637,
4. Conclusion
In this letter, new mixed-donor unsymmetrical proline-
derived amido- and amino-phosphines were prepared
from P-chirogenic phosphinocarboxylic acids. Prelimin-
ary asymmetric catalytic results of these ligands were
845–849; (c)Knu hl, G.; Sennhenn, P.; Helmchen, G. J.
¨
Chem. Soc., Chem. Commun. 1995, 1845–1846; (d)Yama-
zaki, A.; Morimoto, T.; Achiwa, K. Tetrahedron: Asym-
metry 1993, 4, 2287–2290; (e)Okada, Y.; Minami, T.;

8148
H. Lam et al. / Tetrahedron Letters 46 (2005) 8145–8148
Umezu, Y.; Nishikawa, S.; Mori, R.; Nakayama, Y.
Tetrahedron: Asymmetry 1991, 2, 667–682.
(200 mg, 1.5 mmol), N,O-bis(trimethylsilyl)acetamide (370
lL, 1.5 mmol)and KOAc (0.75 mg.) The reaction mixture
was stirred for 24–48 h. Satd aq NH4Cl solution (10 mL)
was added to the reaction mixture, before extraction with
diethyl ether (2 · 10 mL). The combined organic fractions
were dried over MgSO4, filtered, evaporated, and filtered
through a short plug of silica to afford a viscous oil.
Enantiomeric excess was determined by chiral HPLC using
a Chiralpak AD column.
8. General catalytic procedure:2 To [g3-C3H5PdCl]2 (5.5 mg,
30 lmol, 3 mol %)was added a solution of the correspond-
ing ligand (60 lmol)in DCM (5 mL.) The suspension was
degassed by three freeze-thaw cycles, then stirred at 50 ꢁC
for 2 h. The mixture was cooled to 0 ꢁC, before the addition
of a solution of (rac)trans-1,3-diphenylpropenyl acetate
(126 mg, 0.5 mmol)in DCM (5 mL,) dimethyl malonate