Synthesis and first applications of a new family of chiral monophosphine ligand: 2,5-diphenylphosphospholanes

Article abstract of DOI:10.1016/S0040-4020(02)00554-9

The cyclic phosphinic acid 1-hydroxy-1-r-oxo-2c,5-t-diphenylphospholane was synthesized and resolved into enantiomers through fractional crystallization of the quinine salts. The P-phenyl, P-methyl and P-benzyl tertiary phosphine oxides were obtained from

Full text of DOI:10.1016/S0040-4020(02)00554-9

TETRAHEDRON
Pergamon
Tetrahedron 58 (2002) 5895±5904
Synthesis and ®rst applications of a new family of chiral
monophosphine ligand: 2,5-diphenylphosphospholanes
a,²
Frederic Guillen, Michael Rivard, Martial Toffano, Jean-Yves Legros, Jean-Claude Daran
a
a
a
b
 Â
and Jean-Claude Fiauda,p
a
  Â
Laboratoire de Catalyse Moleculaire (ESA 8075), Institut de Chimie Moleculaire d'Orsay, Universite Paris-Sud,
Batiment 420, 91405 Orsay Cedex, France
bLaboratoire de Chimie de Coordination du CNRS (UPR 8241205) route de Narbonne, 31077 Toulouse Cedex, France
Received 15 April 2002; revised 27 May 2002; accepted 28 May 2002
AbstractÐThe cyclic phosphinic acid 1-hydroxy-1-r-oxo-2c,5-t-diphenylphospholane was synthesized and resolved into enantiomers
through fractional crystallization of the quinine salts. The P-phenyl, P-methyl and P-benzyl tertiary phosphine oxides were obtained
from the secondary phosphine oxide, reduction of the oxides afforded the corresponding tertiary P-phenyl and P-benzyl phosphines.
Hydrogenation of prochiral enamides were performed with Rh/(S,S)-1-1,2c,5-t-triphenylphospholane catalytic system. Methyl (Z)-N-acetyl
dehydrocinnamate was hydrogenated to give the N-acetyl phenylalaninate in 93% ee. q 2002 Published by Elsevier Science Ltd.
The elaboration of new chiral ligands is important for the
improvement of both reactivities and enantioselectivities
of transition metal-catalyzed asymmetric syntheses.
Phosphines are among the most widespread used ligands
in catalytic organometallic transformations.1 Owing to
their chelating properties, chiral diphosphines were the
most widely and successfully investigated in many reactions
such as Rh-, Ru-, Ir-catalyzed hydrogenation of ole®nic and
carbonyl compounds and Pd-catalyzed allylic substitutions
among others.
resolution of racemic secondary alcohols through acyl-
ation,12 in cycloaddition of dienoates with electron-de®cient
ole®ns13 and imines,14 and in g-addition reactions to acetyl-
enic esters.15
The chiral, 2,5-disubstituted phospholane framework, ®rst
synthesized by Burk,16 was the motif of the successful
diphosphine ligands DuPHOS [1,2-bis(2,5-dialkylphospho-
lanyl)-benzene], BPE [1,2-bis(2,5-dialkylphospholanyl)-
ethane] and related diphosphines. In those compounds, the
chiral 2,5-phospholane ring was built by a double substi-
tution of the stereochemically well-de®ned di-mesylates4a,16
or cyclic sulfates17 with dilithiated arylphosphide com-
pounds. The 2,5-dimethyl-1-phenylphospholane 1 showed
an interesting catalytic activity in acylation-mediated
resolution of secondary alcohols.12
It appears however that for some reactions, the suggested
turnover-determining or enantiodetermining step involve
complexes bearing a monodentate-P ligand. Indeed in
such reactions both reactivities and/or selectivities (enantio-,
regio-) displayed by diphosphines are often lower than with
monophosphines.2 This has been shown for Pd-catalyzed
hydrosilylation of ole®ns3 and 1,3-dienes,4 Pd-catalyzed
hydrovinylation,5 Pd-catalyzed allylation of organometal-
lics6 and stabilized carbanions7 with allylic carboxylates,
Pd-catalyzed reduction of allylic esters,8 1,4-hydroboration
of 1,3-eneynes,9 rhodium(I)-catalyzed hydrogenation of
2-acetamido cinnamate10 and nickel-catalyzed [21212]
cocyclization of triynes.11
However the above method does not permit the synthesis
of 2,5-diarylphospholanes, owing to the sensitivity of the
corresponding dimesylate or cyclic sulfate towards elimi-
nation in basic conditions. The synthesis of 2,5-diaryl-
phospholanes, whose steric, electronic and chelating
properties could be ®ne-tuned by varying the substitution
of the aryl rings, would be highly desirable. We reported yet
10 years ago the synthesis of the chiral 1,2-c,5-t-triphenyl-
phospholane 2a, through the resolution by chiral liquid
chromatography, then the reduction of the corresponding
oxide 3a.18 Since the resolution procedure of this phosphine
oxide was not practical on a preparative scale, we turned
to an other synthetic approach based on the synthesis and
resolution of the intermediate phospholanic acid 1-hydroxy-
r-1-oxo-c-2,t-5-diphenylphospholane (or trans-2,5-diphenyl-
phospholanic acid) 4.
Moreover, chiral basic monophosphines have been recog-
nized as useful asymmetric nucleophilic catalysts in kinetic
Keywords: phosphinic acid; phosphine; catalysis; enantioselection.
Corresponding author. Tel.: 133-1-69-15-7819; fax: 133-1-69-15-4680;
e-mail: ®aud@icmo.u-psud.fr
p
²
Á
Laboratoire de synthese de substances naturelles, Institut de Chimie
Moleculaire d'Orsay, Universite Paris-Sud, 91405 Orsay Cedex, France.
Â
Â
0040±4020/02/$ - see front matter q 2002 Published by Elsevier Science Ltd.
PII: S0040-4020(02)00554-9

5896
F. Guillen et al. / Tetrahedron 58 (2002) 5895±5904
Scheme 1. Synthesis of 1-aminophospholenes.
The present paper describes details for the preparation of a
set of new, enantiomerically pure 2,5-diphenylphospho-
lanes, including 1,2-c,5-t-triphenylphospholane 2a9 and
1-r-benzyl-2-c, 5-t-diphenylphospholane 2b.
acid.29 In this study, Polniaszek showed that the hydrolysis
of the intermediate chlorophospholenium salt afforded
mainly the trans isomer of the 2-alkyl-1-amino-1-oxo-
phospholene, and that the trans/cis ratio increased with
the steric bulk of the substituents to reach 100% for a
t-butyl substituent.
1. Synthesis and resolution of 1-hydroxy-1-r-oxo-2-c,5-t-
diphenylphospholane 4
We therefore devised a strategy for the synthesis of
1-hydroxy-1-r-oxo-2-c,5-t-diarylphospholanes based on
the McCormack reaction between the corresponding
1,4-diarylbutadiene and an aminophosphenium cation,
followed, after hydrogenation of the intermediate cis-phos-
pholene, by an isomerization step18 to give the trans-1-
amino-1-oxophospholene. Hydrolysis of the later
should give the desired trans-diarylphospholanic acid 4
(Scheme 2).
The target compound 1-hydroxy-1-r-oxo-2-c,5-t-diphenyl-
phospholane 4 has been previously described as a byproduct
in the reaction of the 1,4-diphenylbutane-1,4-dione with
diphenylphosphine.20 The low yield of phosphinic acid
along with the inconvenience of the reaction protocol
prompted us to devise a new synthesis of the phospholanic
acid 4.
Only a limited number of methods are known for the
preparation of cyclic phosphinic acids or derivatives. A
low-yielding method involved an intramolecular nucleo-
philic attack on a phosphonyl dichloride.21 Better yields
were obtained through the double Arbusov reaction between
bis (trimethylsilyloxy)phosphine (BTSP) and dielectro-
philes:22 2-methylphospholanic acid has been produced
using this route. However, on reaction with BTSP the
1,4-dibromo-1,4-diphenylbutane did not give in our hands
the desired 2,5-diphenylphospholanic acid, but elimination
products instead.
The reaction of diorganometallics with dichlorophosphites
has also been used for the synthesis of phospholanic acids.
Indeed, the reaction of the di-Grignard reagent from
1,4-dibromobutane or from 2,5-dibromohexane with ethyl
phosphorodichloridate afforded ethyl phospholanate23 or a
mixture of diastereoisomeric ethyl 2,5-dimethylphosphola-
nates,24 respectively. However, the di-Grignard or di-lithio
compound from 1,4-diaryl-1,4-dihalobutane are not readily
available.
Scheme 2. Synthesis of the trans-diarylphospholanic acid 4.
We found that the reaction of the commercially available
(N,N-dimethylamino)dichlorophosphine with 1,4-diphenyl-
butadiene in the presence of aluminium trichloride afforded,
after hydrolysis, the desired meso 1-(N,N-dimethylamino)-
1-r-oxo-2-t,5-t-diphenylphosphol-3-ene 5 as the sole dia-
stereomer. The carbon±carbon double bond of 5 was then
catalytically hydrogenated over Pd on carbon to give the
corresponding meso 1-(N,N-dimethylamino)-1-r-oxo-2-t,5-
t-diphenylphospholane 6 (Scheme 3).
More recently, cyclic phosphinates could be obtained
through RCM of diallylphosphinates.25 The reaction is
however sensitive to the steric crowding of the substrates
and the yields are reduced when using a-P-substituted
phosphinates.
Isomerization of 6 into the more stable trans isomer 7 took
place readily with a catalytic amount of methyllithium;
More interestingly, phospholanes may result from hydro-
genation of phospholenes obtained by McCormack cyclo-
addition reaction between 1,3-dienes and P(III) reagents, i.e.
dihalophosphines,26 2-ethyldichlorophosphite27 or phos-
phenium cations.28 Aminochlorophosphenium ions react
with dienes below room temperature to give the correspond-
ing 1-amino-1-oxophospholene (Scheme 1).
Polniaszek used this latter strategy for the synthesis of
2-alkyl substituted phospholanic acids: hydrogenation
of the 1-amino-1-oxophospholene followed by hydrolysis
of the P±N bond gave access to the desired phospholanic
Scheme 3. Synthesis of the 1-(N,N-dimethylamino)-1-r-oxo-2-t,5-t-diphe-
nylphospholane 6.

F. Guillen et al. / Tetrahedron 58 (2002) 5895±5904
5897
Figure 1. Molecular view of 1-hydroxy-1-oxo-2,5-trans-diphenylphospho-
lane 4.
Scheme 4. Isomerization of 1-(N,N-dimethylamino)-1-r-oxo-2-t,5-t-diphe-
nylphospholane 6.
however careful monitoring of the reaction is needed to
minimize the formation of the even more stable cis isomer
8 (Scheme 4). More conveniently, the use of an excess
sodium methoxide in methanol afforded only the trans
isomer 7.
Each molecule of phosphinic acid interacts with a neigbour
Ê
through a strong hydrogen bond (O(1)±H(1) 1.04 A;
Ê
H(1)´´´O(2) 1.43 A; O(1)´´´O(2) 2.45 A; O(1)±H(1)´´´O(2)
Ê
È
167.48) to form helicoõdal catemer chain parallel to the b
axis (Fig. 2). The distances within the phospholane ring are
identical within experimental errors to related structures.31
The stereochemistries of the compounds 5 and 6 were
assigned according to Polniaszek,23 whereas the 2,5-trans
relationship in compound 7 is clearly indicated by the loss
of the symmetry plane in 13C NMR. Moreover, the com-
parison of the chemical shifts of the benzylic protons in
compounds 6±8 shows the characteristic deshielding of
the protons in 1,2-cis relationship with the oxygen of the
PvO bond (dˆ3.45±3.65 ppm) in compound 6 as
compared to the trans proton in compounds 7 and 8
(dˆ3.20±3.40 ppm). Subsequent acid-hydrolysis of the
resulting phosphinamide 7 delivered the 1-hydroxy-r-1-
oxo-c-2,t-5-diphenylphospholane 4, which was readily
resolved by fractional crystallization of its diastereomeric
quinine salts from methanol. Both enantiomers of 4 could
thus be obtained in high enantiomeric purity (.99% ee)
(Scheme 5).
Scheme 5. Synthesis and resolution of 1-hydroxy-r-1-oxo-c-2,t-5-diphenyl-
phospholane 4.
È
Figure 2. Helicoõdal catemer chain in 4.
It is then anticipated that in solution, the phosphinic acid
molecules could associate through this type of hydrogen-
bonding, resulting in reduced solubility of this material.
The phosphinic acid 4 is indeed only sparingly soluble in
THF, dichloromethane and more soluble in methanol.
The enantiomeric purity could be checked by analysis
(chiral HPLC) of the corresponding methyl phosphinate
10, obtained by reaction of the phosphinic acid 4 with
diazomethane or trimetylsilyldiazomethane.
2. X-Ray crystal structure of 1-hydroxy-1-oxo-2,5-trans-
diphenylphospholane 4
3. Synthesis of the 1-oxo-2-c,5-t-diphenylphospholanes
The functionalization at the phosphorus atom by an alkyl or
aryl group may be carried out either by electrophilic or
nucleophilic substitution. The substitution of phosphinic
acid derivatives by organometals (mainly organolithium
and Grignard reagents) has been widely used for the syn-
thesis of phosphine oxides,32 especially P-chiral tertiary
phosphine oxides.33 However Polniaszeck showed that
phospholanates are mostly inactive toward Grignard
reagents.29 On comparison of the behavior of phosphinoyl
chlorides and carboxylic chlorides towards organometals
The crystal data was collected using a Stoe IPDS diffracto-
meter operating at 180(2) K. Intensities were collected with
graphite monochromatized Mo Ka radiation (lˆ0.71073),
using a q scan technique. Cell parameters were re®ned
using 8000 selected re¯ections.
A molecular view with atom labeling scheme is shown
in Fig. 1. The molecule has a twisted conformation with
30
Ê
puckering parameters Qˆ0.455 A, Fˆ2101.9(2)8.

5898
F. Guillen et al. / Tetrahedron 58 (2002) 5895±5904
through reduction of phosphinates followed by reaction
with alkyl halides.36 Treatment of methyl phosphinate 10
successively with Red-Al, then methyl iodide gave either
the methyl phospholanyl oxide 3c or the dimethyl phos-
phonium 11, according to the reaction conditions used
(Scheme 7).
1-r-Oxo-1-benzyl-2-c,5-t-diphenylphospholane 3b could
be obtained from the secondary phosphine oxide 12 by
deprotonation with butyllithium followed by treatment
with benzyl bromide. Better results were obtained with
the anion produced in situ by LiAlH(OtBu)4 reduction of
the phosphinoyl chloride 9 (Scheme 8). Treatment of the
chloride 9 with SmI2 and benzyl chloride (the SmI2-
promoted coupling of alkyl halides and chlorophosphi-
nites)37 gave less satisfactory results.
Scheme 6. Synthesis of the tertiary phosphine oxide via nucleophilic substi-
tution.
A second way for the production of phospholanyl oxide 3a
is shown in Scheme 9. Palladium-catalyzed coupling of the
secondary phosphine oxide 12 with phenyl iodide afforded
3a in good yield.
(for which a number of organometals have been reported),34
one could anticipate that the reaction of the phosphinic
chloride 9 with a phenyl organometallic reagent would
produce the corresponding tertiary phosphine oxide. Care
should be taken however not to use too basic organometallic
reagents in order to avoid epimerization at the stereogenic
carbons atoms of the phospholane ring. In that respect
should the use of organolithiums being precluded. However,
neither the Grignard reagents nor the less basic ceric
organometallics35 succeeded in the clean substitution of
the chloride atom of 9. Phenyl copper and lithium dimethyl
cuprate were successful in producing the corresponding
phosphine oxide 3a and 3c, respectively, in satisfactory
yields (Scheme 6).
Scheme 9. Synthesis of 3a via a Pd-catalyzed coupling reaction.
4. Synthesis of the 2-c,5-t-diphenylphospholanes
A number of procedures have been tried to reduce the phos-
phine oxides to phosphines. Reduction of the oxides into
phospholanes was carried out according to Imamoto.38
Treatment of the phosphine oxides 3a and b with methyl
tri¯ate, followed by LiAlH4 afforded the phosphines 2a and
b, respectively, and quantitatively (Scheme 10).
Preparation of tertiary phosphine oxides has been reported
Scheme 7. Alkylation of the 1-methoxy-l-oxo-2,5-trans-diphenylphospho-
lane.
Scheme 10. Reduction of the tertiary phosphine oxides.
5. Enantioselective reduction of ole®nic compounds
Preliminary results19 indicated that triphenylphospholane 2a
could induce asymmetry (84%) in the rhodium-catalyzed
hydrogenation of N-acetyl dehydrocinnamic ester 13. We
report now that the asymmetric induction can reach 93%
using the same catalytic system, when the catalyst precursor
is prepared under rigorous exclusion of oxygen (Scheme
11).
The results of the asymmetric hydrogenation of dimethyl
itaconate 14 and itaconic acid 15 are indicated in Scheme
11. In every case hydrogenation took place at room
temperature, under atmospheric pressure of hydrogen at
Scheme 8. Syntheses of the 1-benzyl-1-r-oxo-2-c,5-t-triphenylphospholane
3b.

F. Guillen et al. / Tetrahedron 58 (2002) 5895±5904
5899
out on a Regis Pirkle(S,S)-Whelk-O1column or a Chiralcel
OD-H column.
All reactions were carried out in Schlenk tubes under an
argon atmosphere. All solvents were distilled from appro-
priate drying agents prior to use.
The crystal data was collected using a Stoe IPDS diffracto-
meter operating at 180(2) K. Intensities were collected with
graphite monochromatized Mo Ka radiation (lˆ0.71073),
using a q scan technique. Cell parameters were re®ned
using 8000 selected re¯ections.
The structure was solved by direct methods (SIR9739) and
re®ned by least-squares procedures on F2 using SHELXL-
97.40 All H atoms attached to carbon were introduced in
Ê
calculation in idealized positions (d(CH)ˆ0.96 A, d(OH)ˆ
Ê
0.82 A) and treated as riding models. The drawing of the
molecule (Fig. 1) was realized with the help of ORTEP3241
and the view of the hydrogen bond catemer (Fig. 2) with
CAMERON.42 Final re®nement allowed the fraction contri-
bution of the inverted enantiomer to vary (Bernardinelli and
Flack, 1985; Flack, 1983)43 the Flack's parameter quoted
being the re®ned value of this contribution. Crystallographic
data (excluding structure factors) have been deposited with
the Cambridge Crystallographic Data Centre as supplemen-
tary publication no. CCDC 171981. Copies of the data can
be obtained free of charge on application to the Director,
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax:
(144) 1223-336-033; e-mail: deposit@ccdc.cam.ac.uk).
Scheme 11. Catalytic asymmetric hydrogenation using 2a±Rh complex.
high rate (t1/2,15 min in all cases). The catalytic system
showed also good activity in the hydrogenation of
electron-rich N-acetyl enamides 16 and 17 (t1/2ˆ14 min
for 16); however for the cyclic enamide 16 the asymmetric
induction is poor.
7.1.1. 1-[(N,N)-Dimethylamino]-1-r-oxo-2-t,5-t-diphenyl-
phosphol-3-ene 5. N,N-dimethylaminophosphinodichlori-
dite (12 g, 82.2 mmol) was added to a stirred suspension
of aluminium chloride (10.4 g, 77.7 mmol) in 100 mL
anhydrous CH2Cl2 under argon. After 45 min, the greenish
solution was placed in an ice bath and a pre-cooled solution
of 1,4-diphenylbutadiene (15.4 g, 75 mmol) in 250 mL
anhydrous CH2Cl2 was slowly added. The reaction mixture
was then stirred at 08C under argon for 16 h, then poured in a
mixture of 400 mL of aqueous EDTA (0.2 M) and 200 mL
of an aqueous saturated solution of NaHCO3 cooled to 08C.
The biphasic mixture was then vigorously stirred for 4 h at
08C, then ®ltered on celite, decanted and the aqueous layer
extracted with CH2Cl2 (2£100 mL). The organic layers
were washed with saturated NaHCO3 (200 mL), 1M HCl
(200 mL) and brine (200 mL), then dried over MgSO4 and
concentrated under vacuum at room temperature. The
resulting yellow oil was triturated with ether (50 mL), and
the slightly yellowish precipitate of 1-[(N,N)-dimethyl-
6. Conclusion
A new chiral phospholane ligand has been developped. The
preliminary assays indicate that ligand 2a affords excellent
activity and enantioselectivity in Rh-catalyzed asymmetric
hydrogenation of trisubstituted acyclic enamides. Further
ligand modi®cations and applications in asymmetric
catalysis are currently underway.
7. Experimental
7.1. General procedures
NMR spectra were recorded on a Bruker AC 250 spectro-
meter at 250 MHz (1H), 62.9 MHz (13C) and 101.2 MHz
(31P). Chemical shifts (d) are reported in ppm relative to
amino]-1-r-oxo-2-t,5-t-diphenylphosphol-3-ene
(14.5 g)
collected by ®ltration. Partial concentration of the ether
solution, followed by cooling to 08C allowed the recovery
of an additional 2.0 g of product, for a total amount of 16.5 g
(55.6 mmol, 74%) that was used without further puri®cation
in the following step. A recrystallization from cold acetone/
hexane gave an analytical sample of phospholene 5 as white
crystals (mp 105±1158C, dec.). Anal. calcd for C18H20NOP
(297.33): C, 72.71; H, 6.78; P, 10.42. Found: C, 72.63; H,
1
internal tetramethylsilane for H and 13C and to external
85% H3PO4 for 31P. Carbon and phosphorus NMR spectra
were recorded with complete proton decoupling. Flash
column chromatography was performed using silica gel
Merck (0.04±0.063 mm). Optical rotations were recorded
at the sodium D line with a Perkin±Elmer 341polarimeter.
High-resolution mass spectra were obtained with a MAT 95
spectrometer.
1
7.45; P, 10.53. H NMR (250 MHz, CDCl3): dˆ7.35±7.10
(10H, m), 6.52 (2H, d, Jˆ29.3 Hz), 4.27 (2H, d, Jˆ
18.6 Hz), 1.85 (6H, d, Jˆ8.3 Hz). 13C NMR (62.9 MHz,
CDCl3): dˆ135.7 (d, Jˆ8.0 Hz), 130.6 (d, Jˆ16.7 Hz),
Analytical HPLC was performed with a single wavelength
UV detector (254 nm). Chiral analytical HPLC was carried

5900
F. Guillen et al. / Tetrahedron 58 (2002) 5895±5904
128.4 (d, Jˆ2.4 Hz), 127.0 (d, Jˆ4.8 Hz), 126.7 (d, Jˆ
2.8 Hz), 49.1(d, Jˆ71.9 Hz), 35.8 (d, Jˆ1.9 Hz). 31P
NMR (101.2 MHz, CDCl3): dˆ69.0.
C, 72.21; H, 7.39; P, 10.83. MS (El) m/z(rel. int.): 44 (7), 91
(14), 92 (15), 104 (base), 206 (23), 299 (M1z, 12). 1H NMR
(250 MHz, CDCl3): dˆ7.4±7.1(10H, m), 3.4±3.2 (2H, m),
2.63 (6H, d, Jˆ9.5 Hz), 2.45±2.25 (4H, m). 13C NMR
(62.9 MHz, CDCl3): dˆ137.5 (d, Jˆ6.2 Hz), 128.7 (d,
Jˆ5.5 Hz), 128.5 (d, Jˆ1.9 Hz), 126.5 (d, Jˆ2.1Hz), 41.4
(d, Jˆ78.0 Hz), 36.2 (d, Jˆ2.2 Hz), 29.4 (d, Jˆ11.9 Hz).
31P NMR (101.2 MHz, CDCl3): dˆ57.8.
7.1.2. 1-[(N,N)-Dimethylamino]-1-r-oxo-2-t,5-t-diphenyl-
phospholane 6. A pressure reactor was charged with
1-[(N,N)-dimethylamino]-1-r-oxo-2-t,5-t-diphenylphosphol-
3-ene 5 (16.08 g, 54.1 mmol), Pd±C (10%, 0.5 g) and
methanol (75 mL). The reactor was purged with hydrogen,
then pressurized to 50 bar of hydrogen. After 16 h, the reac-
tion mixture was ®ltered through celite and the solvent
removed in vacuo, giving 15.4 g of colorless oil, which
crystallized upon addition of ether. A recristallization in
an AcOEt/hexane mixture gave 14.9 g (50 mmol, 92%) of
1-[(N,N)-dimethylamino]-1-r-oxo-2-t,5-t-diphenylphospho-
lane 6 as colorless crystals (mp 114±1158C). Anal. calcd for
C18H22NOP (299.35): C, 72.22; H, 7.41; P, 10.35. Found: C,
72.04; H, 7.41; P, 10.39. MS (El) m/z (rel. int.): 77 (15), 91
(20), 104 (base), 206 (45), 299 (M1z, 47). 1H NMR
(250 MHz, CDCl3): dˆ7.3±7.0 (10H, m), 3.65±3.45 (2H,
m), 2.5±2.3 (4H, m), 1.75 (6H, d, Jˆ8.3 Hz). 13C NMR
(62.9 MHz, CDCl3): dˆ136.6 (d, Jˆ5.7 Hz), 128.1 (d,
Jˆ2.4 Hz), 126.6 (d, Jˆ5.0 Hz), 126.0 (d, Jˆ2.6 Hz), 45.3
(d, Jˆ72.7 Hz), 34.9 (d, Jˆ2.4 Hz), 26.4 (d, Jˆ13.1 Hz).
31P NMR (101.2 MHz, CDCl3): dˆ67.3.
7.1.6. One pot isomerization-hydrolysis of 6. Sodium
methoxide (11.3 g, 209 mmol) was added to a solution of
1-[(N,N)-dimethylamino]-1-r-oxo-2-t,5-t-diphenylphospho-
lane 5 (12.5 g, 41.8 mmol) in methanol (100 mL). The
resulting suspension was stirred at room temperature for
1h 15 min, at which time the GC analysis of an aliquot
showed 99% conversion into the trans isomer. The reaction
mixture was then poured into 250 mL of 6N aqueous HCl
and stirred for 4 h. The white precipitate was then collected
by ®ltration and recrystallized in methanol to give 10.6 g
(39 mmol, 93%) of racemic 1-hydroxy-1-oxo-2,5-trans-
diphenylphospholane 4 as a white crystalline solid (mp
227±2288C). Anal. calcd for C16H17O2P (272.27): C,
70.58; H, 6.29; P, 11.38. Found: C, 70.48; H, 6.33; P,
11.08. MS (El) m/z (rel. int.): 78 (21), 91 (20), 104 (base),
168 (7), 272 (M1z, 54). 1H NMR (250 MHz, CDCl3):
dˆ7.3±7.05 (10H, m), 4.5 (1H, large s), 3.2±3.0 (2H, m),
2.5±2.2 (2H, m), 2.1±1.9 (2H, m). 13C NMR (62.9 MHz,
CD3OD): dˆ138.0 (d, Jˆ5.7 Hz), 129.7 (d, Jˆ5.5 Hz),
129.5 (d, Jˆ1.9 Hz), 127.7 (d, Jˆ2.4 Hz), 47.0 (d, Jˆ
87.0 Hz), 30.2 (d, Jˆ11.9 Hz). 31P NMR (101.2 MHz,
CD3OD): dˆ66.0.
7.1.3. MeLi-mediated isomerization of 6. Methyllithium
(0.12 mL of a 1.6 M solution in hexane, 0.19 mmol) was
slowly added at room temperature to a stirred solution of
1-[(N,N)-dimethylamino]-1-r-oxo-2-t,5-t-diphenylphospho-
lane 6 (1.12 g, 3.75 mmol) in anhydrous THF (6 mL) under
argon. After 16 h at room temperature, the orange solution
was hydrolyzed with aqueous HCl (1M, 5 mL), extracted
with toluene (2£20 mL) and the organic layers washed with
water (10 mL), brine (10 mL), then dried over anhydrous
MgSO4 and the solvent removed in vacuo. A ¯ash chroma-
tography over silica gel (AcOEt/MeOH 95/5) afforded
0.81g (2.7 mmol, 72%) of 1-[( N,N)-dimethylamino]-1-r-
oxo-2-c,5-t-diphenylphospholane 7 as a white crystalline
solid. A similar reaction carried out with 5.0 g (16.7
mmol) of 6 and 0.52 mL (0.83 mmol) of MeLi in 20 mL
of anhydrous THF afforded, after silica gel column chroma-
tography, 3.05 g (10.2 mmol, 61%) of dl-7 and 1.71 g
(5.7 mmol, 34%) of meso-8.
7.1.7. Hydrolysis of 7. 48 mL (144 mmol) of a 3 M aqueous
HCl solution were slowly added at room temperature to a
solution of 1.16 g (3.88 mmol) of 1-[(N,N)-dimethylamino]-
1-r-oxo-2-c,5-t-diphenylphospholane 7 in 20 mL of ethanol.
After 16 h at room temperature, the cloudy solution was
made alkaline by careful addition of a 4 M aqueous NaOH
solution and extracted by 2£30 mL of dichloromethane. The
organic phase was discarded and the aqueous layer made
acidic by careful addition of concentrated HCl. The pre-
cipitated phospholanic acid extracted by 5£50 mL of
dichloromethane and the organic phase was washed withe
brine (50 mL), dried over anhydrous magnesium sulfate and
the solvent removed in vacuo to afford 0.88 g (3.23 mmol,
83%) of phospholanic acid dl-4 as a white solid.
7.1.4. 1-[(N,N)-Dimethylamino]-1-r-oxo-2-c,5-t-diphenyl-
phospholane 7. Mp 141±1428C. Anal. calcd for
C18H22NOP (299.35): C, 72.22; H, 7.41; P, 10.35. Found:
C, 72.41; H, 7.45; P, 10.97. MS (El) m/z (rel. int.): 44 (31),
7.1.8. Resolution of 1-hydroxy-1-oxo-2,5-trans-diphenyl-
phospholane 4. Racemic 1-hydroxy-1-oxo-2,5-trans-di-
phenylphospholane 4 (2.72 g, 10 mmol) was dissolved in
the minimum amount of re¯uxing methanol. Quinine
(3.25 g, 10 mmol) was then added; after cooling to room
temperature, the white precipitate was collected, dissolved
in dichloromethane, then decomposed with 100 mL of 2N
aqueous NaOH. After decantation, the organic layer was
washed with 2N NaOH solution (3£10 mL), then with
brine, dried over MgSO4 and the solvent was evaporated to
offered the quinine. The aqueous phase was collected and
treated with concentrate HCl solution to give the precipitated
phospholanic acid 4. Recrystallization in methanol afforded
1.18 g (4.34 mmol, 87% of the theoretical amount for one
enantiomer) of (S,S)-(2)-1-hydroxy-1-oxo-2,5-trans-di-
phenylphospholane 4 as white crystals (mp 269±2708C).
1
91(22), 104 (98), 206 (43), 256 (43), 299 (M 1z, base). H
NMR (250 MHz, CDCl3): dˆ7.35±7.1 (10H, m), 3.58 (1H,
ddd, Jˆ7.7, 12.1, 23.4 Hz), 3.24 (1H, dt, Jˆ7.1, 12.7 Hz),
2.6±2.0 (4H, m), 2.27 (6H, d, Jˆ8.8 Hz). 13C NMR (62.9
MHz, CDCl3): dˆ136.7 (d, Jˆ4.8 Hz), 136.0 (d, Jˆ
5.2 Hz), 128.5 (d, Jˆ5.2 Hz), 128.2 (d, Jˆ1.7 Hz), 128.1
(d, Jˆ2.1Hz), 126.9 (d, Jˆ5.2 Hz), 126.4 (d, Jˆ2.4 Hz),
126.2 (d, Jˆ2.6 Hz), 47.0 (d, Jˆ75.3 Hz), 42.1(d, Jˆ
78.0 Hz), 35.6 (d, Jˆ2.4 Hz), 29.4 (d, Jˆ11.9 Hz), 27.2
(d, Jˆ9.3 Hz). 31P NMR (101.2 MHz, CDCl3): dˆ59.9.
7.1.5. 1-[(N,N)-Dimethylamino]-1-r-oxo-2-c,5-c-diphenyl-
phospholane 8. Mp 153±1548C. Anal. calcd for
C18H22NOP (299.35): C, 72.22; H, 7.41; P, 10.35. Found:

F. Guillen et al. / Tetrahedron 58 (2002) 5895±5904
5901
[a]Dˆ2102.7 (cˆ0.6, CH2Cl2). The enantiomeric excess
was found to be .99.6% by chiral HPLC ((S,S)-Whelk
01, CH2Cl2/Hexane/MeOH 80/20/1) of the methyl ester
derivative 10.
of phosphinoyl chloride (S,S)-9, prepared as above from
2 g (7.34 mmol) of (S,S)-(2)-1-hydroxy-1-oxo-2,5-trans-
diphenylphospholane 4. The mixture was stirred for 1.15 h
at 2608C, whereas the solution turned deep yellow.
The reaction was quenched at 2608C with acetic acid
(2.5 mL), and after 5 min stirring at this temperature, the
colorless solution was treated in open air with 50 mL of a
1/1 mixture of a concentrated aqueous solution of ammonia
and saturated NH4Cl aqueous solution under vigorous
stirring. The mixture was diluted with dichloromethane
and allowed to heat to room temperature. The blue solution
was extracted with dichloromethane, the organic layer
washed with brine, dried over anhydrous magnesium
sulfate and concentrated. The white solid was subjected to
chromatographic puri®cation (dichloromethane/methanol,
95/5) on silica gel, to obtain 2.15 g (6.47 mmol, 88%) of a
white solid. A recrystallization from AcOEt/hexane gave
1.70 g (70% from 4) of (S,S)-(2)-1-r-oxo-1,2-c,5-t-tri-
phenylphospholane 3a, mp 202±2048C (racemic com-
pound: 171±1738C). The enantiomeric excess of 3a was
found to be .99.5% by chiral HPLC analysis (Chiralcel
OD-H, eluent hexane/iPrOH 3/1). [a]Dˆ2130 (MeOH,
cˆ1.01). Anal. calcd for C22H21OP (332.36): C, 79.25; H,
The ®ltrate was evaporated and decomposed following the
same procedure to give 1.15 g (4.23 mmol, 85% of the theo-
retical amount for one enantiomer) of (R,R)-(1)-1-hydroxy-
1-oxo-2,5-trans-diphenylphospholane 4 (.99.6% ee).
Crystal data for 4. C16H17O2P; Mrˆ272.27; monoclinic;
space group I2; aˆ11.3405(12), bˆ5.7054(5), cˆ
22.323(3) A, Vˆ1402.5(3) A , Zˆ4, rcalcdˆ1.289 g mm23
,
Ê
Ê 3
mˆ0.191 mm21
;
2umaxˆ52.38; re¯ections collected
unique used, 6977 2675(Rintˆ0.0276) 2613 (I.2s(I)); para-
meters re®ned, 176; R/wR2 (all data)ˆ0.0249/0.0660;
GOFˆ1.082; D/smaxˆ0.001; [Dr]minˆ[Dr]maxˆ20.18,
Ê 23
0.18 e A ; Flack's parameterˆ20.08(7).
7.1.9.
(R,R)-(1)-1-Methoxy-1-r-oxo-2-c,5-t-diphenyl-
phospholane 10. A solution of (R,R)-(1)-1-hydroxy-1-
oxo-2,5-trans-diphenylphospholane 4 (705 mg, 2.59 mmol)
in CH2Cl2 (50 mL) was treated at room temperature by a
solution of diazomethane in ether, until persistence of the
yellow color. The excess diazomethane was quenched by
acetic acid, and the resulting solution concentrated in vacuo,
to give 740 mg (2.58 mmol, 99%) of (R,R)-(1)-1-methoxy-
1-r-oxo-2-c,5-t-diphenylphospholane 10 as a white solid.
[a]Dˆ176.4 (CH2Cl2, cˆ1.03). MS (EI) m/z (rel. int.): 78
(26), 91 (20), 104 (base), 182 (14), 286 (M1z, 94). 1H NMR
(250 MHz, CDCl3): dˆ7.4±7.2 (10H, m), 3.5±3.3 (1H, m),
3.25±3.1 (1H, m), 3.14 (3H, d, Jˆ10.2 Hz), 2.6±2.4 (4H,
m). 13C NMR (62.9 MHz, CDCl3): dˆ136.1 (d, Jˆ4.6 Hz),
135.5 (d, Jˆ6.9 Hz), 128.7±128.4 (m), 127.9 (d, Jˆ4.7 Hz),
126.85 (d, Jˆ2.6 Hz), 126.8 (d, Jˆ2.4 Hz), 51.7 (d, Jˆ
7.4 Hz), 46.3 (d, Jˆ82.8 Hz), 44.9 (d, Jˆ87.4 Hz), 30.4
(d, Jˆ13.4 Hz), 27.7 (d, Jˆ11.6 Hz). 31P NMR (101.2
MHz, CDCl3): dˆ65.9.
1
6.44; P, 9.15. Found: C, 79.09; H, 6.61; P, 9.32. H NMR
(250 MHz, CDCl3): dˆ7.5±7.3 (2H, m), 7.3±7.1(8H, m),
6.9±6.1(5H, m), 3.83 (1H, ddd, Jˆ7.1, 12.9, 25.5 Hz), 3.48
(1H, dt, Jˆ12.9, 8.1 Hz), 2.75±2.4 (3H, m), 2.25±2.1 (1H,
m). 13C NMR (62.9 MHz, CDCl3): dˆ135.3 (d, Jˆ3.6 Hz),
135.7 (d, Jˆ5.5 Hz), 131.5 (d, Jˆ2.8 Hz), 131.1 (d, Jˆ
8.3 Hz), 130.6 (d, Jˆ88.9 Hz), 128.8 (d, Jˆ5.0 Hz), 128.6
(d, Jˆ1.9 Hz), 128.2 (d, Jˆ2.4 Hz), 128.0 (d, Jˆ11.4 Hz),
127.1 (d, Jˆ5.0 Hz), 127.0 (d, Jˆ2.1Hz), 126.3 (d, Jˆ
2.6 Hz), 51.0 (d, Jˆ61.5 Hz), 46.7 (d, Jˆ62.0 Hz), 31.5
(d, Jˆ7.4 Hz), 27.9 (d, Jˆ8.6 Hz). 31P NMR (101.2 MHz,
CDCl3): dˆ53.5. MS (EI) m/z (rel. int.): 78 (16), 91 (40),
104 (46), 206 (20), 227 (35), 228 (33), 332 (base, M1z).
7.1.12. (R,R)-(1)-1-Benzyl-1-r-oxo-2-c,5-t-diphenylphos-
pholane 3b. (R,R)-(1)-1-Chloro-1-r-oxo-2-c,5-t-diphenyl-
phospholane 9 (3.68 mmol, from 1g of ( R,R)-(1)-1-
hydroxy-1-oxo-2,5-t-diphenylphospholane 4) were sus-
pended in 30 mL of freshly distilled ether after sonication
and cooled at 08C. Lithium tri-ter-butoxyaluminohydride
(12 mmol, prepared from 455 mg (12 mmol) of lithium
aluminium hydride and 2.66 g (36 mmol) of t-butanol) in
suspension in ether were then added via cannula and the
mixture was allowed to reach room temperature. When
gas evolution had ceased, 1mL (8.5 mmol) of benzyl
bromide was added and the resulting mixture was stirred
overnight. After dilution with EtOAc/dichloromethane
(60/40), the mixture was hydrolyzed with aqueous 1N
HCl. The aqueous layer was extracted with EtOAc and the
combined organic layers were washed with aqueous satu-
rated K2CO3 then distilled water and dried over MgSO4.
Recrystallization from EtOAc/dichloromethane afforded
900 mg (2.60 mmol, 70%) of the phosphine oxide
(R,R)-(1)-3b as a white solid (mp 212±2168C). [a]Dˆ
133.6 (MeOH, cˆ1.02). 1H NMR (250 MHz, CDCl3):
dˆ7.45±7.35 (4H, m), 7.35±7.05 (7H, m), 7.05±6.95
(2H, d, Jˆ3 Hz), 6.85±6.75 (2H, d, Jˆ5.3 Hz), 3.8±3.6
(1H, m), 3.1±2.8 (2H, m), 2.6±2.4 (2H, m), 2.4±2.1 (2H,
m), 2.1±1.85 (1H, m). 13C NMR (62.9 MHz, CDCl3):
dˆ136.5 (d, Jˆ5.4 Hz), 136.2 (d, Jˆ3.6 Hz), 131.6 (d,
7.1.10. (S,S)-(2)-1-Chloro-1-r-oxo-2-c,5-t-diphenylphos-
pholane 9. A Schlenk tube was charged with (S,S)-(2)1-
hydroxy-1-oxo-2,5-trans-diphenylphospholane 4 (272 mg,
1mmol), then purged with argon. Anhydrous THF (5 mL)
was then added, and the resulting suspension cooled to 08C
in an ice bath. Oxalyl chloride (0.4 mL, 4 mmol) was then
slowly added. After 5 min, the ice bath was removed and
the stirring continued for 2 h. The THF and excess oxalyl
chloride were then removed under high vacuum, and the
1-chloro-1-r-oxo,2-c,5-t-diphenylphospholane obtained as
276 mg (0.95 mmol, 95%) of a white, moisture sensitive
1
solid. H NMR (250 MHz, CDCI3): dˆ7.4±7.1(10H, m),
3.9±3.6 (2H, m), 2.65±2.5 (1H, m), 2.45±2.15 (3H, m). 31P
NMR (101.2 MHz, CDCl3): dˆ80.3.
7.1.11. (S,S)-(2)-1-r-Oxo-1,2-c,5-t-triphenylphospholane
3a through organocuprate substitution of 9. To a Schlenk
tube containing a suspension of the CuBr±dimethylsul®de
complex (1.5 g, 7,3 mmol) in 20 mL THF and cooled to
2408C in an acetone/dry ice bath was added 7.4 mL
(7.4 mmol) of a 1M phenyllithium solution in ether. The
resulting yellow solution was stirred for 10 min (2408C),
then 5 min (08C). After cooling down to 2608C, the phenyl-
cuprous solution was added to a precooled (2608C) solution

5902
F. Guillen et al. / Tetrahedron 58 (2002) 5895±5904
Jˆ7.2 Hz), 130.3 (d, Jˆ5.3 Hz), 129.3 (d, Jˆ5.1Hz), 129.1
(d, Jˆ5.1Hz), 128.9 (d, Jˆ2.1Hz), 128.6 (d, Jˆ 1.5 Hz),
127.6 (d, Jˆ4.6 Hz), 127.4 (d, Jˆ2.6 Hz), 127.1 (d, Jˆ
2.6 Hz), 126.9 (d, Jˆ2 Hz), 49.8 (d, Jˆ57.6 Hz), 44.6
(d, Jˆ60.4 Hz), 36.4 (d, Jˆ56.4 Hz), 32.4 (d, Jˆ 7.5 Hz),
26.8 (d, Jˆ9.3 Hz). 31P NMR (101.2 MHz, CDCl3): dˆ
58.8. HRMS (EI) calcd for C23H23OP: 346.1487, found:
346.1482.
(MgSO4), concentrated to give 147 mg of a white solid. A
chromatographic puri®cation (silica gel, CH2Cl2/MeOH 95/
5) afforded 102 mg (0.26 mmol, 51%) of 11 as a white
1
powder. H NMR (250 MHz, CDCl3): dˆ7.6±7.45 (4H,
m), 7.4±7.2 (6H, m), 5.1±4.95 (2H, m), 2.9±2.7 (3H, m),
2.6±2.5 (1H, m), 1.74 (6H, d, Jˆ13.4 Hz). 13C NMR
(62.9 MHz, CDCl3): dˆ131.9 (d, Jˆ5.2 Hz), 129.4 (d,
Jˆ2.9 Hz), 128.5 (d, Jˆ5.2 Hz), 128.4 (d, Jˆ3.8 Hz), 42.8
(d, Jˆ46.5 Hz), 30.8 (d, Jˆ6.9 Hz), 7.4 (d, Jˆ48.2 Hz). 31P
NMR (101.2 MHz, CDCl3): dˆ47.3.
7.1.13. (S,S)-(2)-1-Methyl-1-r-oxo-2-c,5-t-diphenylphos-
pholane 3c. To a Schlenk tube containing a suspension of
the CuBr±dimethylsul®de complex (185 mg, 0.9 mmol) in
4 mL THF and cooled (2788C) in a bath was added 1.12 mL
(1.8 mmol) of a solution of 1.6 M methyllithium in ether.
The resulting yellow solution was stirred for 30 min
(2788C). The dimethylcuprate solution was added to a
precooled (2788C) solution of phosphinic acid chloride
(S,S)-9, prepared as above from 246 mg (0.9 mmol) of
(S,S)-(2)-1-hydroxy-1-oxo-2,5-trans-diphenylphospholane
4 and 0.4 mL of oxalyl chloride in 4 mL THF. The mixture
was stirred for 2 h at 2788C, whereas the solution turned
deep yellow. The reaction was quenched at 2788C with
acetic acid (0.2 mL), and after 5 min stirring at this tempera-
ture, the mixture was allowed to heat to room temperature.
The colorless solution was treated in open air with 10 mL
of a 1/9 mixture of a concentrated aqueous solution of
ammonia and saturated NH4Cl aqueous solution under
vigorous stirring. The blue solution was stirred for 15 min
then extracted with dichloromethane, and the organic layer
washed with brine, dried over anhydrous magnesium
sulfate and concentrated to give 191 mg of a white solid.
A recrystallization from AcOEt/hexane gave 169 mg
(0.63 mmol, 69%) of (S,S)-(2)-1-methyl-1-r-oxo-2-c,5-t-
diphenylphospholane 3c as slim needles, mp 160±1628C;
the ee was assayed to .98% through 31P NMR of the
compound in the presence of the chiral solvating agent
(R)-N-(1-phenylethyl)-3,5-dinitrophenylamide. [a]Dˆ267.5
(CHCl3, cˆ1.04). 1H NMR (250 MHz, CDCl3): dˆ7.4±7.2
(10H, m), 3.61 (1H, ddd, Jˆ25, 12.5, 7.2 Hz), 2.95 (1H, dt,
Jˆ12.9, 7.5 Hz), 2.65±2.25 (3H, m), 2.1±1.9 (1H, m), 1.14
(3H, d, Jˆ12.4 Hz). 13C NMR (62.9 MHz, CDCl3): dˆ
136.5 (d, Jˆ3.8 Hz), 136.0 (d, Jˆ5.2 Hz), 128.9 (d, Jˆ
2.6 Hz), 128.8 (d, Jˆ5.0 Hz), 128.6 (d, Jˆ1.9 Hz), 127.2
(d, Jˆ4.5 Hz), 127.0 (d, Jˆ2.4 Hz), 126.9 (d, Jˆ2.8 Hz),
49.5 (d, Jˆ60.8 Hz), 47.4 (d, Jˆ61.5 Hz), 31.9 (d, Jˆ
7.2 Hz), 27.3 (d, Jˆ8.8 Hz), 13.9 (d, Jˆ63.4 Hz). 31P
NMR (101.2 MHz, CDCl3): dˆ61.3 (63.1 in the presence
of (R)-N-(1-phenylethyl)-3,5-dinitrophenylamide). MS (EI)
m/z (rel. int.): 91 (60), 103 (44), 104 (61), 165 (70), 166 (70),
270 (M1z, base).
7.1.15. (S,S)-(2)-1-r-Oxo-2-c,5-t-diphenylphospholane
12. Method A. To a suspension obtained after sonication
of (S,S)-(2)-1-chloro-1-r-oxo-2-c,5-t-diphenylphospholane
9 (0.95 g, 3.68 mmol) in dry ether (50 mL) were added
portionwise 180 mg (4.73 mmol) of lithium aluminium
hydride. The reaction mixture turned yellow then purple
and ®nally gray. The suspension was stirred overnight
then hydrolyzed with 1N aqueous HCl. The aqueous layer
was extracted with EtOAc and the combined organic layers
washed with saturated K2CO3, water and dried over MgSO4.
The solvent was removed in vacuo and the phosphine oxide
12 was recovered almost quantitatively as a smelly white
solid.
Method B. To a suspension of anhydrous cerium chloride
(296 mg, 1.2 mmol) in 10 mL anhydrous THF was added at
room temperature a solution of (S,S)-(2)-9 prepared from
272 mg (1mmol) of phosphinic acid ( S,S)-(2)-4 dissolved
in 5 mL THF. After 0.5 h stirring, LiAlH4 (76 mg,
2.0 mmol) was added portionwise. The resulting mixture
was stirred for 20 min at room temperature, then hydrolyzed
with a minimum amount of water. The granular precipitate
was ®ltrated, the solvent removed in vacuo and the yellow
solid obtained dissolved in 20 mL toluene. To this solution
were added 0.23 mL (3.5 mmol) of 30% H2O2 diluted in
5 mL of water, and the biphasic mixture was stirred for
2 h at room temperature. After decantation, the organic
layer was thoroughly extracted with 6£10 ml of water,
dried over anhydrous magnesium sulfate et concentrated
in vacuo. Flash chromatography (eluent CH2Cl2/AcOEt
9/1then CH Cl2/MeOH 19/1) followed by a recrystalli-
2
zation in AcOEt/hexane afforded 146 mg (0.57 mmol,
57%) of (S,S)-(2)-1-r-oxo-2-c,5-t-diphenylphospholane 12
1
as a white solid. H NMR (250 MHz, CDCl3): dˆ7.5±7.0
(10H, m), 7.15 (1H, dq, Jˆ470, 2.9 Hz), 3.55 (1H, dddd,
Jˆ23.4, 11.8, 7.8, 3.9 Hz), 3.26 (1H, dtd, Jˆ12.3, 7.6,
2.9 Hz), 2.75±2.25 (3H, m), 2.1±1.85 (1H, m). 13C NMR
(62.9 MHz, CDCl3): dˆ136.2 (d, Jˆ3.3 Hz), 135.0 (d,
Jˆ6.0 Hz), 129.0 (d, Jˆ0.7 Hz), 128.9 (d, Jˆ2.6 Hz),
128.7 (d, Jˆ1.4 Hz), 127.3 (d, Jˆ5.9 Hz), 127.2 (d, Jˆ
2.9 Hz), 127.1 (d, Jˆ2.1Hz), 48.6 (d, Jˆ60.6 Hz), 45.3
(d, Jˆ59.8 Hz), 32.8 (d, Jˆ7.2 Hz), 28.4 (d, Jˆ11.0 Hz).
31P NMR (101.2 MHz, CDCl3): dˆ54.5. MS (EI) m/z (rel.
int.): 78 (28), 91 (70), 104 (base), 117 (26), 134 (14), 152
(20), 256 (M1z, 45).
7.1.14. 1,1-Dimethyl-2,5-trans-diphenylphospholanium
iodide 11. To a solution of 1-methoxy-1-oxo-2,5-trans-
diphenylphospholane 10 (143 mg, 0.5 mmol) in 5 mL of
THF were added at 08C, 0.60 mL (2.1mmol) of a solution
of Red-Alw (3.5 M in toluene). The solution was stirred
for 15 min at 08C, then 1h at room temperature. To the
resulting bright yellow mixture cooled in an ice-bath iodo-
methane (0.5 mL, 8 mmol) was added. After 5 min, 20 mL
of an aqueous solution of sodium acetate (10 g L21) were
added, the mixture stirred for 30 min, the THF removed in
vacuo and the aqueous phase extracted with dichloro-
methane (4£50 mL). The organic phases were dried
7.1.16. (S,S)-(2)-3a Through palladium-catalyzed
coupling of (S,S)-12 with iodobenzene. Pd(dba)2 (30 mg,
0.05 mmol) and 1,3-bisdiphenylphosphinopropane (23 mg,
0.056 mmol) were placed in a Schlenk tube under an argon
atmosphere. Anhydrous DMF (2 mL) was added and the
solution was stirred for 15 min at room temperature. To

F. Guillen et al. / Tetrahedron 58 (2002) 5895±5904
5903
the yellow solution was added 134 mL (0.6 mmol) of iodo-
7.2. Rhodium-catalyzed asymmetric hydrogenation:
general method
benzene. After 15 min stirring, to the orange mixture was
added a solution of 350 mL (2 mmol) of diisopropylethyl-
amine and 178 mg (0.5 mmol) of 2,5-trans-diphenyl-
phospholane oxide 12 in 2 mL of anhydrous DMF. The
resulting solution was heated to 100±1058C for 16 h. The
solvent was then removed and the brown oil taken into
10 mL dichloromethane. The organic phase was washed
with 5% aqueous NaHCO3 (2£10 mL), brine (10 mL),
dried over MgSO4, and concentrated in vacuo. The brown
solid was subjected to chromatographic puri®cation
(dichloromethane/methanol 95/5), to obtain 131 mg
(0.395 mmol, 79%) of 1-r-oxo-1,2-c,5-t-triphenylphospho-
lane 3a.
A Schlenk tube placed in a glove box was charged with
(2)-2a (15.2 mg, 24 mmol) and bis(cyclooctadiene)-
rhodium tetra¯uoroborate (8.4 mg, 10 mmol). The tube
was then taken out of the glove box and charged with
10 mL of degassed, anhydrous methanol. The mixture was
stirred for 20 min, and the yellow solution obtained was
canulated into a Schlenk tube containing 2 mmol of the
chosen enamide under a hydrogen atmosphere. The uptake
of hydrogen began immediately upon stirring. After
completion of the reaction (no further hydrogen uptake),
the resulting solution was concentrated in vacuo, taken up
in dichloromethane (10 mL) and stirred with activated
carbon for 1.5 h. Filtration over celite and removal of the
solvent afforded the hydrogenated product. Enantiomeric
excesses were determined by chiral HPLC on a Chiralcel
OD-H column, with hexane/i-PrOH 9/1as eluent.
7.1.17. (S,S)-(2)-1-r-,2-c,5-t-Triphenylphospholane 2a.
To 665 mg (2 mmol) of phosphine oxide 3a dissolved in
10 mL of freshly distilled DME, 250 mL (2.2 mmol) of
methyl tri¯uoromethanesulfonate were added dropwise at
room temperature under an argon atmosphere. After 2 h,
the mixture was cooled down to 08C and 115 mg
(3 mmol) of lithium aluminium hydride were added. The
heterogeneous mixture was allowed to warm to room
temperature and stirred for additional 1.5 h. After hydrolysis
with a minimum amount of water, the mixture was ®ltered
under argon through Celite via cannula. The solvent was
removed in vacuo and the phospholane 2a was obtained
as a white solid and stored in a glove box without further
puri®cation. [a]Dˆ235.5 (CH2Cl2, cˆ0.85). 1H NMR
(250 MHz, CDCl3): dˆ7.4±7.2 (4H, m), 7.2±7.0 (9H, m),
6.87 (2H, d, Jˆ6.8 Hz), 4.04 (1H, dt, Jˆ10.8, 7.8 Hz), 3.8
(1H, ddd, Jˆ17.8, 12.0, 5.7 Hz), 2.8±2.7 (1H, m), 2.3±2.2
(2H, m), 2.15±2.0 (1H, m). 13C NMR (75.5 MHz, CDCl3):
dˆ144.6 (d, Jˆ18.9 Hz), 138.6 (s), 135.8 (d, Jˆ29.1Hz),
133.2 (d, Jˆ18.5 Hz), 128.6 (s), 128.1 (d, Jˆ30.9 Hz),
127.8±127.5 (m), 126.0 (d, Jˆ2.2 Hz), 125.4 (d, Jˆ
1.8 Hz), 48.8 (d, Jˆ17.4 Hz), 46.8 (d, Jˆ15.6 Hz), 36.6
(s), 32.7 (d, Jˆ3.6 Hz). 31P NMR (101.2 MHz, CDCl3):
dˆ21.3.
References
1. Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley:
New York, 1994.
2. Lagasse, F.; Kagan, H. B. Chem. Pharm. Bull. 2000, 48, 31 5±
324. Hayashi, T. J. Organometal. Chem. 1999, 576, 195±202.
3. Hayashi, T. Acta Chem. Scand. 1996, 50, 259 and references
cited therein.
4. Pedersen, H. L.; Johannsen, M. J. Chem. Soc., Chem.
Commun. 1999, 2517. Hayashi, T.; Han, J. W.; Takeda, A.;
Tang, J.; Nohmi, K.; Mukaide, K.; Tsuji, H.; Uozumi, Y. Adv.
Synth. Catal. 2001, 343, 279±283.
5. Rajanbabu, T. V.; Nomura, N.; Jin, J.; Radetich, B.; Park, H.;
Nandi, M. Chem. Eur. J. 1999, 5, 1963±1968.
6. Fiaud, J.-C.; Aribi-Zouioueche, L. J. Organometal. Chem.
1985, 295, 383±387.
7. Hayashi, T.; Kawatsura, M.; Uozumi, T. J. Chem. Soc., Chem.
Commun. 1997, 561. Hayashi, T.; Kawatsura, M.; Uozumi, Y.
J. Am. Chem. Soc. 1998, 120, 1681. Cheng, Z.; Jiang, Q.; Zhu,
G.; Xiao, D.; Cao, P.; Guo, C.; Zhang, X. J. Org. Chem. 1997,
62, 4521. Fuji, K.; Ohnishi, H.; Moriyama, S.; Tanaka, K.;
Kawabata, T.; Tsubaki, K. Synlett 2000, 351±352.
8. Tsuji, J.; Mandai, T. Synlett 1996, 1±24. Hayashi, T.;
Iwamura, H.; Naito, M.; Matsumoto, Y.; Uozumi, Y.; Miki,
M.; Yanagi, K. J. Am. Chem. Soc. 1994, 116, 775±775 and
references cited therein. Fuji, K.; Sakurai, M.; Tohkai, N.;
Kuroda, A.; Kawabata, T.; Fukazawa, Y.; Kinoshita, T.;
Tada, T. J. Chem. Soc., Chem. Commun. 1996, 1609. Fuji,
K.; Sakurai, M.; Kinoshita, T.; Tada, T.; Kuroda, A.;
Kawabata, T. Chem. Pharm. Bull. 1997, 45, 1524. Fuji, K.;
Sakurai, M.; Kinoshita, T.; Kawabata, T. Tetrahedron Lett.
1998, 39, 6323.
7.1.18.
(S,S)-(2)-1-r-Benzyl-2-c,5-t-diphenylphospho-
lane 2b. To 1.8 g (5.2 mmol) of phosphine oxide 3b
dissolved in 7 mL of freshly distilled DME, 600 mL
(5.7 mmol) of methyl tri¯uoromethanesulfonate were
added dropwise at room temperature under an argon atmos-
phere. After 2 h, the mixture was cooled down to 08C and
500 mg (13 mmol) of lithium aluminium hydride were
added. The heterogeneous mixture was allowed to warm
to room temperature and stirred for additional 1.5 h. After
dilution with 25 mL of dry and degassed diethyl ether, the
mixture was ®ltered under argon through silica via cannula.
The solvent was removed in vacuo and the phospholane 2b
was obtained as a white solid and stored in a glove box
without further puri®cation. [a]Dˆ2197 (CDCl3, cˆ
1
1.12). H NMR (250 MHz, CDCl3): dˆ7.35±7.3 (4H, m),
9. Matsumoto, Y.; Naito, M.; Uozumi, Y.; Hayashi, T. J. Chem.
Soc., Chem. Commun. 1993, 1468.
7.2±7.0 (7H, m), 7.0 (2H, d, Jˆ7.9 Hz), 6.85 (2H, d,
Jˆ7.9 Hz), 3.8±3.6 (1H, m), 3.3±3.2 (1H, m), 2.65±2.3
(5H, m), 2.05±1.85 (1H, m). 13C NMR (62.9 MHz,
CDCl3): dˆ144.7 (d, Jˆ17 Hz), 139.3 (s), 138 (d, Jˆ
7.4 Hz), 129.7 (d, Jˆ6 Hz), 128.9±128.5 (m), 128.0±
127.7 (m), 126.3 (s), 126.0 (d, Jˆ4.8 Hz), 48.8 (d, Jˆ
18.5 Hz), 47.2 (d, Jˆ17 Hz), 36.5 (s), 32.3 (d, Jˆ32 Hz),
32.2 (s). 31P NMR (101.2 MHz, CDCl3): dˆ18.4.
10. Burk, M. J.; Feaster, J. E.; Harlow, R. L. Tetrahedron:
Asymmetry 1991, 2, 569±592. Claver, C.; Fernandez, E.;
Gillon, A.; Heslop, K.; Hyett, D.; Martorell, A.; Orpen,
A. G.; Pringle, P. G. Chem. Commun. 2000, 961±962.
11. Sato, Y.; Nishimata, T.; Mori, M. J. Org. Chem. 1994, 59,
6133±6135.
12. Vedejs, E.; Daugulis, O. J. Am. Chem. Soc. 1999, 121,

5904
F. Guillen et al. / Tetrahedron 58 (2002) 5895±5904
5813±5814. Vedejs, E.; Daugulis, O.; Diver, S. T. J. Org.
Chem. 1996, 61, 4300.
31. (a) Hocking, M. B.; Bushnell, G. W. Can. J. Chem. 1990, 68,
1021±1026. (b) Wieczorek, M. W.; Bujacz, G. D.; Bodalski,
R.; Quin, L. D. J. Chem. Crystallogr. 1994, 24, 431.
(c) Nieger, M.; Link, M.; Niecke, E. Z. Kristallogra®ya
1995, 210, 791±793. (d) Tissot, O.; Gouygou, M.; Daran,
J. C.; Balavoine, G. Acta Crystallogr. 1998, C54, 676±679.
32. Crofts, P. C. Organic Phosphorus Compounds; Kosolapoff,
G. M., Ed.; Wiley: New York, 1973; Vol. 6, pp 1±187.
33. Korpium, O.; Lewis, R. A.; Chickos, J.; Mislow, K. J. Am.
Chem. Soc. 1968, 90, 4842.
13. Zhang, C.; Lu, X. J. Org. Chem. 1995, 60, 2906±2908. Zhu,
G.; Chen, Z.; Jiang, Q.; Xiao, D.; Cao, P.; Zhang, X. J. Am.
Chem. Soc. 1997, 119, 3836.
14. Xu, Z.; Lu, X. F. Tetrahedron Lett. 1999, 40, 549±552.
15. Alvarez-Ibarra, C.; Csaky, A. G.; Gomez de la Oliva, C.
J. Org. Chem. 2000, 65, 3544±3547.
16. Burk, M. J.; Feaster, J. E.; Nugent, W. A.; Harlow, R. L. J. Am.
Chem. Soc. 1993, 115, 10125.
34. O'Neill, B. T. Comprehensive Organic Synthesis; Trost, B. M.,
Flemming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 1,
pp 397±458, Chapter 13. Dieter, R. K. Tetrahedron 1999,
55, 4177.
17. Holz, J.; Quirmbach, M.; Schmidt, U.; Heller, D.; StuÈrmer, R.;
Borner, A. J. Org. Chem. 1998, 63, 8031. Li, W.; Zhang, Z.;
Xiao, D.; Zhang, X. Tetrahedron Lett. 1999, 40, 6701.
18. Fiaud, J.-C.; Legros, J.-Y. Tetrahedron Lett. 1991, 32, 5089±
5092.
35. Imamoto, T.; Kusumoto, T.; Tawarayama, Y.; Sugiura, Y.;
Mita, T.; Hatanaka, Y.; Yokoyama, M. J. Org. Chem. 1984,
49, 3904. Fex, T.; Froborg, J.; Magnusson, G.; Thoren, S.
J. Org. Chem. 1976, 41, 3518±3520. Dalpozzo, R.; De
Nino, A.; Miele, D.; Tagarelli, A.; Bartoli, G. Eur. J. Org.
1999, 2299±2301.
19. Fiaud, J.-C.; Guillen, F. Tetrahedron Lett. 1999, 40, 1939±
2942.
20. Kalinov, S. M.; Rostovskaya, M. F.; Vysotskii, V. I. Zh.
Obshch. Khim. 1988, 58, 783 J. Gen. Chem. USSR (Engl.
Transl.) 1988, 58, 693.
36. Wetzel, R. B.; Kenyon, G. L. J. Org. Chem. 1974, 39, 1531±
1535.
21. Kosolapoff, G. M.; Struck, R. F. J. Chem. Soc. 1957, 3739.
22. Boyd, E. A.; Boyd, M. E. K.; Kerrigan, F. Tetrahedron Lett.
1996, 37, 5425±5426 and references cited herein.
Montchamp, J.-L.; Tian, F.; Frost, J. W. J. Org. Chem.
1995, 60, 6076±6081.
37. Sasaki, M.; Collin, J.; Kagan, H. B. Tetrahedron Lett. 1991,
32, 2493.
38. Imamoto, T. Org. Lett. 2001, 3, 87±90.
39. Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, G. L.;
Giacovazzo, C.; Guagliardi, A.; Moliterni, A. G. G.; Polidori,
G.; Spagn, R. SIR97 a program for automatic solution of
crystal structures by direct methods. J. Appl. Crystallogr.
1999, 32, 115.
23. Wong, S. C.; Carruthers, N. I.; Chan, T.-M. J. Chem. Res. (S)
1993, 268.
24. Polniaszek, R. P.; Foster, A. L. J. Org. Chem. 1991, 56, 3137±
3146.
25. Bujard, M.; Gouverneur, V.; Mioskowski, C. J. Org. Chem.
1999, 64, 2119±2123.
40. Sheldrick, G. M. SHELXL97: Program for Crystal Structure
È
Re®nement; University of Gottingen, Germany, 1997.
41. Farrugia, L. J. ORTEP-32 for Windows. J. Appl. Crystallogr.
1997, 30, 565.
26. Quin, L. D. The Heterocyclic Chemistry of Phoshorus; Wiley-
Interscience: New York, 1981; Chapter 2.
27. Hum, G.; Wooler, K.; Lee, J.; Taylor, S. D. Can. J. Chem.
2000, 78, 642±655.
42. Watkin, D. J.; Prout, C. K.; Pearce, L. J. CAMERON,
Chemical Crystallography Laboratory, University of Oxford,
Oxford, 1996.
28. Cowley, A. H.; Kemp, R. A.; Lasch, J. G.; Norman, N. C.;
Stewart, C. A. J. Am. Chem. Soc. 1983, 105, 7444. SooHoo,
C. K.; Baxter, S. G. J. Am. Chem. Soc. 1983, 105, 7443.
Polniaszek, R. P. J. Org. Chem. 1992, 57, 5189±5195.
29. Polniaszek, R. P. J. Org. Chem. 1992, 57, 5189±5195.
30. Cremer, D.; Pople, J. A. J. Am. Chem. Soc. 1975, 97, 1354±
1358.
43. (a) Bernardinelli, G.; Flack, H. D. Acta Crystallogr. 1985,
A41, 500±511. (b) Flack, H. D. Acta Crystallogr. 1983,
A39, 876±881.