Synthesis and resolution of benzylisopropylphenylphosphine, a monodentate P-chiral ligand

Article abstract of DOI:10.1016/S0957-4166(00)00300-1

The synthesis of benzylisopropylphenylphosphine by reaction between the benzylphenylphosphide anion and isopropyl chloride and its subsequent resolution by means of an optically active palladium metallacycle is reported. The synthesis of the organometallic complex [Pd(η³-2-MeC₃H₄)Cl(PBn(i)PrPh)] is also described, as well as the assignment of the absolute configuration of the coordinated phosphine by mono- and bidimensional proton NMR spectra, using the homochiral palladacycle as a reference point. In order to estimate the height of the energy barrier corresponding to the rotation of the phosphine ligand around the Pd-P bond, several calculations were performed at the semiempirical PM3(tm) level. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00300-1

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 3335–3343
Synthesis and resolution of benzylisopropylphenylphosphine,
a monodentate P-chiral ligand
Joan Albert, Ramo´n Bosque, J. Magali Cadena, Jaume R. Granell,* Guillermo Muller*
and Juan Ignacio Ordinas
Departament de Qu´ımica Inorga`nica, Universitat de Barcelona, Diagonal 647, 08028 Barcelona, Spain
Received 29 June 2000; accepted 7 August 2000
Abstract
The synthesis of benzylisopropylphenylphosphine by reaction between the benzylphenylphosphide
anion and isopropyl chloride and its subsequent resolution by means of an optically active palladium
metallacycle is reported. The synthesis of the organometallic complex [Pd(h3-2-MeC3H4)Cl(PBniPrPh)] is
also described, as well as the assignment of the absolute configuration of the coordinated phosphine by
mono- and bidimensional proton NMR spectra, using the homochiral palladacycle as a reference point.
In order to estimate the height of the energy barrier corresponding to the rotation of the phosphine ligand
around the PdꢀP bond, several calculations were performed at the semiempirical PM3(tm) level. © 2000
Elsevier Science Ltd. All rights reserved.
1. Introduction
Transition metal complexes with chiral phosphines are used as catalysts in asymmetric
synthesis.1 Among the many chiral phosphines developed for application in asymmetric cataly-
sis, monodentate ligands possessing a stereogenic phosphorus atom are rare, even though
asymmetric induction is expected to be improved if the stereogenic center is close to the metal
atom in the catalyst.2
The asymmetric synthesis of some P-chiral phosphines, PR1R2R3, by using borane com-
pounds,3 via dynamic resolution of racemic tert-butylphenylphosphine with (−)-sparteine4 or by
using cyclometallated derivatives,5 has recently been published. The resolution of tert-
butylphenyl(4-bromophenyl)phosphine6 and benzylcyclohexylphenylphosphine7 has also been
reported. The use of P-chiral aminophosphine phosphinite ligands for the asymmetric hydro-
genation or hydroformylation reactions has recently been described.8 The catalytic results
showed the predominance of the P-center chirality over the carbon backbone effect.
* Corresponding authors. Fax: 34-934907725; e-mail: jgranell@kripto.qui.ub.es
0957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00300-1

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Following our work on the synthesis and resolution of chiral phosphines,7,9 we describe here
the synthesis of benzylisopropylphenylphosphine, its resolution by palladium metallacycles, and
the assignment of its absolute configuration by mono- and bidimensional proton NMR spectra.
2. Results and discussion
To the best of our knowledge, there is only one report on the synthesis of benzylisopropyl-
phenylphosphine. This is a preliminary communication without characterization data, in which
the authors describe the synthesis, with an enantiomeric excess of 20%, by reaction of iPrLi with
the phosphinite P(OCin)BnPh, where HOCin is the resolving agent cinchonine. This phosphinite
was previously obtained from PClBnPh and HOCin.10
van Doorn has published a study about the reductive cleavage of carbonꢀphosphorus bonds
with alkali metals and he reports that the cleavage of one PꢀCH2Ph bond of PBn2Ph is selective
if Li/THF is used. In contrast, the use of other reagents such as Na/NH3 causes the cleavage of
both benzyl groups.11 Bearing these results in mind and following the published methodology
for the synthesis of PBnCyPh,7 we have synthesized benzylisopropylphenylphosphine. After
stirring a mixture of dibenzylphenylphosphine and lithium metal in THF under a dry nitrogen
atmosphere at room temperature for 20 h, complete cleavage of one of the PꢀCH2 bonds of the
dibenzylphenylphosphine was accomplished, with the formation of the benzylphenylphosphide
anion. The 31P NMR spectrum, under nitrogen, illustrated the formation of this anion (l=−37.1
ppm) and was used to monitor the progress of the reaction. Isopropyl chloride was added after
removing the excess lithium, affording the racemic ( )-benzylisopropylphenylphosphine. Then a
saturated solution of NiCl2 in absolute ethanol was added, and the resulting solution was stirred
for 15 min and concentrated in vacuo to give dark red crystals of the paramagnetic complex
dichlorobis[( )-benzylisopropylphenylphosphine]nickel(II).
Benzylisopropylphenylphosphine is easily oxidized in air, but it can be stored for months as
a nickel complex. Moreover, the addition of a few drops of water to an organic solution of the
nickel complex affords the free phosphine. This strategy is also a way for the purification of this
ligand. This methodology was followed for the synthesis of the complex [Pd(h3-2-MeC3H4)Cl-
{( )-PBniPrPh)}]. The addition of a few drops of water to a THF solution of [NiCl2(PBniPrPh)2]
caused the decoordination of the phosphine. Then, the organic phase was separated and dried
and the addition of [Pd(m-Cl)(h3-2-MeC3H4)]2 led to the formation of 3, which was precipitated
in n-pentane. NMR data show that 3 occurs in two diastereomeric forms in a 5/4 ratio. Proton
NMR data of the allylic group were assigned by comparison with literature values.12 Unusually
high field shifts of Hc and Hd were observed, showing that these protons are in close proximity
to aromatic phosphine rings.
ortho-Palladated derivatives of optically active N-donor ligands are good resolving agents for
Lewis bases.13 The enantiomerically pure cyclopalladated dinuclear compound 4 was obtained
from the optically active amine as reported.9b Reaction of dimer 4 with the phosphine afforded
the mononuclear complex [PdCl(CꢀN)(PBniPrPh)] 5 as a 1/1 mixture of diastereomers. The high
field shift of the aromatic protons of the metallated group in 5 due to the aromatic rings of the
phosphine indicates the cis disposition of the phosphorus relative to the metallated carbon atom.
The chemical shift of the phosphorus confirms this arrangement,14 which is usual in cyclopalla-
dated compounds containing phosphines.15

J. Albert et al. / Tetrahedron: Asymmetry 11 (2000) 3335–3343
3337
Compound 5 (200 mg) was eluted at room temperature in a SiO2 column with CHCl3ꢀacetone
1
(100/3) as eluent. The fractions eluted (15 mL) were concentrated in vacuo and checked by H
NMR spectroscopy. The fractions of the enantiomerically pure compound (by 200 MHz 1H NMR
spectroscopy) were selected using H1 and H2 proton signals. The first diastereomer eluted 5% was
obtained in 54% yield (54 mg), with a d.e. higher than 95%, and the second diastereomer 5¦ was
obtained in 52% yield with 77% d.e.
The efficiency of cyclopalladated compounds derived from 1-(1-naphthyl)ethylamine as resolv-
ing agents has been related to the locked asymmetric envelope conformation of the metallacycle,
due to the fact that the methyl substituent of the stereogenic carbon atom adopts an axial
disposition to avoid the unfavorable interaction with H6 (see Scheme 1).16 The NOESY spectra
of both diastereomers of 5 showed that the methinic proton of the chiral carbon atom H7 had
strong negative off-diagonal peaks with H6 and H8 and, in contrast, the methyl protons of the
chiral carbon atom presented only strong NOE interaction with H9 and H7. These data confirmed
the axial disposition of this methyl group and the equatorial disposition of H7 in these complexes.17
Scheme 1. (i) Li, THF, room temperature, 20 h; (ii) isopropyl chloride, THF, 0°C, 10 min; (iii) NiCl2, THF/EtOH,
room temperature, 15 min; (iv) THF, D2O, room temperature, 30 min; (v) [NiCl2L2] (L=(PBnRPh), THF, room
temperature, 45 min
It has been demonstrated that NOE techniques16b,17,18 or the NMR chemical shift regularities19
can be used to determine the absolute configurations of coordinated chiral diphosphines. Dunina
et al.6 have recently extended these studies to the monodentate P-chiral ligand tert-butylphenyl(4-
bromophenyl)phosphine. These authors have shown that it is possible to assign the absolute
configuration of this phosphine by NMR techniques using the homochiral palladacycle as a
reference point.
We have re-examined the NMR data of diastereomers (RC,SP) and (RC,RP) of the cyclopalla-
dated complex 6, containing coordinated benzylcyclohexylphenylphosphine (see Scheme 1), in
order to check the possibility of assigning, by NMR techniques, the absolute configuration of
phosphorus in monodentate ligands PBnRPh, coordinated to optically active cyclopalladated
compounds. The absolute configuration of both diastereomers of complex 6 is known, as well as
the crystal structure of the compound (RC,SP)-[PdCl(C6H4CHMeNMe2)(PBnCyPh)].7 The crys-

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J. Albert et al. / Tetrahedron: Asymmetry 11 (2000) 3335–3343
tal structure of this complex shows the benzyl substituent of the phosphine widely separated
from the metallacycle and on the opposite side of the coordination plane in relation to the
methyl group of the chiral carbon atom. In addition, the cyclohexyl group of the phosphine is
oriented towards the chloro ligand and the phenyl group is located in the proximity of the
metallacycle (see Fig. 1).
Figure 1. Structure of (RC,SP)-[PdCl(C6H4CHMeNMe2)(PBnCyPh)]
The NOESY spectrum of (RC,SP)-6, in CDCl3 solution, showed that the H1 proton only
presented strong NOE interaction with the protons of the phosphine phenyl group (l=7.55
ppm). In contrast the NOESY spectrum of the diastereomer (RC,RP)-6, in CDCl3 solution,
showed that the H1 proton of this diastereomer only presented strong NOE interaction with two
of the cyclohexyl protons (l=2.18 and 1.66 ppm). It should also be noted that in no case was
NOE interaction between the benzylic protons of the phosphine and the protons of the
metallated ring observed. All these results show that the rotation around the PdꢀP bond is
rather restricted in these complexes, and that the structure of the main conformomer in solution
is similar to the structure determined by X-ray diffraction of (RC,SP)-
[PdCl(C6H4CHMeNMe2)(PBnCyPh)]. It is reasonable to assume that, in both diastereomers, the
benzyl group is separated from the metallacycle and it is located on the opposite side of the
coordination plane in relation to the methyl group of the chiral carbon atom, and the difference
between the two diastereomers would be the exchange of the positions of cyclohexyl and phenyl
groups. As a consequence, the NOESY spectra of such cyclometallated derivatives allow the
absolute configuration of the phosphine to be revealed. Furthermore, the chemical shift of the
H1 proton can also be used to propose the absolute configuration of the phosphine. In the NMR

J. Albert et al. / Tetrahedron: Asymmetry 11 (2000) 3335–3343
3339
spectrum of the (RC,SP)-diastereomer the signal of this proton is high field shifted (it appears at
l=6.05 ppm) in relation to the signal of this proton in the (RC,RP)-diastereomer (l=6.48 ppm),
as a consequence of the proximity of the phenyl group of the phosphine to the metallated ring.6
It is reasonable to assume that in diastereomers 5, containing the benzylisopropylphenylphos-
phine, the benzyl group is also placed away from the metallacycle in the major conformer and
that the most significant difference between the two diastereomers is the relative positions of the
isopropyl and phenyl groups. The NOESY spectrum of the first diastereomer eluted 5%, in CDCl3
solution, showed that the H1 proton only presented strong NOE interaction with the protons of
one of the methyl groups of the isopropyl fragment (l=1.35 ppm). The NOESY spectrum of the
second diastereomer eluted 5¦, in CDCl3 solution, showed that the H1 proton only presented
strong NOE interaction with the ortho-phenyl protons of the phosphine (l=7.30 ppm), and in
none of the diastereomers was NOE interaction between the benzylic protons of the phosphine
and the protons of the metallated ring observed. These data suggest the R and S configurations
for the phosphorus atom in the diastereomers 5% and 5¦, respectively. The high field shift of the
signal of the metallated ring proton H1 in the diastereomer 5¦ (l=6.02 ppm) in relation to the
signal of this proton in the diastereomer 5% (l=6.50 ppm) also agrees with the (RC,SP)
configuration proposed for 5¦.
In order to estimate the height of the energy barrier corresponding to the rotation of the
phosphine ligand around the PdꢀP bond, several calculations were performed on compound
(RC,SP)-6 at the semiempirical PM3(tm) level. The dihedral angle CmetꢀPdꢀPꢀCPh was increased
in 18° steps, for one complete rotation. One of the features of the PM3(tm) method is the trend
to overestimate the interactions between the metal and hydrogen atoms when the former has a
square-planar environment, thus giving rise to artificial geometry minima.20 This effect is
especially strong when the initial geometry is far from the equilibrium, as in the case of
conformational search. For this reason, no geometric optimization has been made. However, for
each value of the dihedral angle, a systematic conformer search was performed, rotating each of
the PꢀC bonds in increments of 120°. For the remaining parameters the experimental values
corresponding to the X-ray diffraction have been used. Only the most stable of the 27
conformations corresponding to each value of the dihedral angle have been taken into account.
According to the calculations, the most stable conformation corresponds to that determined
experimentally in the solid state. The height of the barrier — taken as the difference in heat of
formation between the minimum and the maximum energy systems — is 39.5 kcal/mol, which
is too high to allow for a free rotation of the phosphine at room temperature. All these results
confirm the information obtained in solution by means of NMR.
3. Experimental
1
1H NMR at 200 MHz were recorded on a Varian Gemini 200 spectrometer and H NMR at
500 MHz, 13C at 75.42 MHz and 31P{1H} at 101.26 MHz were recorded, respectively, on a
Varian VXR 500, a Varian 300 and a Bruker DRX 250 spectrometers. Chemical shifts (in ppm)
1
were measured relative to SiMe4 for H and to 85% H3PO4 for 31P. Microanalyses were
performed at the Institut de Qu´ımica Bio-Orga`nica de Barcelona and at the Serveis Cient´ıfico-
Te`cnics de la Universitat de Barcelona. Infrared spectra were recorded as KBr disks on a Nicolet
520 FT-IR spectrometer. The optical rotations of the complexes were determined in CHCl3 at
20°C using a Perkin–Elmer 241-MC polarimeter. Mass spectra were recorded on a Fisons

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J. Albert et al. / Tetrahedron: Asymmetry 11 (2000) 3335–3343
VG-Quattro spectrometer. The samples were introduced in a matrix of 2-nitrobenzyl alcohol for
FAB analysis and then subjected to bombardment with cesium atoms.
3.1. Materials and synthesis
All the reactions involving free phosphines were carried out using Schlenk techniques under
a nitrogen atmosphere. All solvents were dried and degassed by standard methods. Tetra-
hydrofuran and toluene were distilled over sodium–benzophenone, under nitrogen, before use.
All chemicals were of commercial grade and used as received. PBn2Ph and compounds 4 and 6
were prepared according to procedures described elsewhere.7,9b,21
3.1.1. Synthesis of ( )-benzylisopropylphenylphosphine, 1
Small pieces of lithium (0.080 g, 11.53 mmol) were added to a solution of dibenzylphenylphos-
phine (1.4 g, 4.82 mmol) in THF (30 mL), and the reaction mixture was stirred for 20 h at room
temperature. The excess of lithium was removed by decantation, the solution was cooled to 0°C
and isopropyl chloride (0.45 mL, 5.11 mmol) was added and the mixture was stirred for 10
minutes. Afterwards the reaction mixture was warmed to room temperature and was stirred for
a further 5 minutes. The resulting solution was cooled again to 0°C and was washed twice with
10 mL of an aqueous solution of ammonium chloride (15%), the organic layer was dried over
anhydrous Na2SO4, and concentrated in vacuo to afford ( )-benzylisopropylphenylphosphine as
an oil, which can be characterized by NMR spectroscopy. Characterization data: 31P{1H} NMR
1
(101.26 MHz, CDCl3): l=−1.65 s. H NMR (250 MHz, CDCl3): l=0.90 (dd, JHP=13.5 Hz,
JHH=6.9 Hz, 3H, MeCHP), 1.13 (dd, JHP=15.1 Hz, JHH=6.9 Hz, 3H, MeCHP), 1.98 (m, 1H,
HCP), 3.16 (d, 14.1 Hz, 1H, H2CP), 3.09 (d, 14.1 Hz, 1H, H2CP), 7.00–7.50 (m, 10H, aromatic).
13C NMR (75.4 MHz, CDCl3): l=19.18 (d, JPC=12.8 Hz, MeCHP), 19.57 (d, JPC=17.7 Hz,
MeCHP), 26.00 (d, JPC=11.0 Hz, HCP), 33.33 (d, JPC=17.1 Hz, H2CP), 125.48 (s, pBn), 128.06
(s, mBn), 128.30 (d, J=10.9 Hz, mPh), 128.97 (d, J=6.1 Hz, oBn), 129.08 (s, pPh), 133.45 (d,
J=18.9 Hz, oPh), 136.49 (d, J=14.3 Hz, ipsoPh), 138.28 (s, ipsoBn). GC-MS: 242 (M+).
3.1.2. Synthesis of [NiCl2(PBniPrPh)2], 2
For the synthesis of the coordination compound, a solution of NiCl2 (0.5 g, 2.1 mmol) in
absolute ethanol (10 mL) was added to a THF solution of ( )-benzylisopropylphenylphosphine,
and the resulting mixture was stirred for 15 minutes and then concentrated in vacuo. Dark red
crystals of the complex were obtained, filtered and dried. The yield of the global process was
55% (0.814 g). Anal. calcd (found) for C32H38Cl2NiP2: C, 62.58 (62.1); H, 6.24 (6.1). IR (KBr):
1488s, 1440s, 752s, 688s.
3.1.3. Synthesis of [Pd(p3-2-MeC3H4)Cl(( )-PBniPrPh)], 3
A few drops of deoxygenated water were added to a solution of [NiCl2(PBniPrPh)2] (0.293 g,
0.477 mmol) in THF (20 mL) and the mixture was stirred until the red color completely
disappeared (about 10 minutes). The aqueous phase was separated and the organic layer was
dried over anhydrous Na2SO4. The organic phase was separated and 0.180 g (0.457 mmol) of
[Pd(m-Cl)(h3-2-MeC3H4)]2 were added; the resulting suspension was stirred at room temperature
for 30 minutes. THF replaced n-pentane, and a yellow solid precipitated as a mixture of
diastereomers (in a ratio 5/4). The solid obtained, in 75% yield (300 mg), was filtered and dried

J. Albert et al. / Tetrahedron: Asymmetry 11 (2000) 3335–3343
3341
under vacuum. Characterization data: anal. calcd (found) for C20H26ClPPd: C, 54.69 (54.9); H,
5.97 (6.1). 31P{1H} NMR (101.26 MHz, CDCl3): l=38.65 s (major diastereomer) and 37.56 s
1
(minor diastereomer). H NMR (500 MHz, CDCl3); major isomer: l=0.99 (dd, JHP=15.5 Hz,
J=7.0 Hz, 3H, MeCHP), 1.22 (dd, JHP=17.7 Hz, JHH=7.0 Hz, 3H, MeCHP), 1.84 (s, 3H, Me),
2.03 (s, 1H, Hd), 2.47 (m, JHP=9.5 Hz, JHH=7.0, 1H, HCP), 2.98 (br s, 1H, Hc), 3.41 (d,
J
HP=10.0 Hz, 1H, Hb), 3.55 (m, JHP=14.0 Hz, JHH=8.0 Hz, 1H, H2CP), 3.62 (m, JHP=14.25
Hz, JHH=5.0 Hz, 1H, H2CP), 4.44 (d, JHP=6.75 Hz, 1H, Ha), 6.90–7.45 (m, 10H, aromatic);
minor isomer: 1.02 (dd, JHP=15.0 Hz, JHH=7.0 Hz, 3H, MeCHP), 1.32 (dd, JHP=18.0 Hz,
J
HH=7.0 Hz, 3H, MeCHP), 1.76 (s, 3H, Me), 2.42 (s, 1H, Hd), 2.52 (m, JHP=10.0 Hz, JHH=7.0
Hz, 1H, HCP), 2.92 (br s, 1H, Hc), 3.44 (d, JHP=9.5 Hz, 1H, Hb), 3.50 (dd, JHP=14.0 Hz,
HH=8.0 Hz, 1H, CH2), 3.60 (dd, JHP=14.25 Hz, JHH=4.5 Hz, 1H, CH2), 4.46 (d, JHP=6.5 Hz,
J
1H, Ha), 6.90–7.45 (m, 10H). 13C NMR (75.4 MHz, CDCl3): major isomer: l=18.0 (d, JCP=7.0
Hz, MeCHP), 18.8 (d, JCP=7.4 Hz, MeCHP), 23.0 (s, Me), 23.8 (d, JCP=21.9 Hz, HCP), 31.8
(d, JCP=17.0 Hz, H2CP), 55.8 (br s, C3), 78.1 (d, JCP=31.7 Hz, C1), 126.3 (d, JCP=3.0 Hz,
pBn), 127.9 (d, JCP=4.5 Hz, mPh), 128.0 (s, mBn), 129.8 (d, JCP=4.6 Hz, oBn), 130.5 (d,
JCP=2.4 Hz, pPh), 131.2 (d, JCP=5.2 Hz, C2), 133.4 (d, JCP=11.6 Hz, oPh), 135.1 (d, JCP=4.8
Hz, ipsoBn); minor isomer: 18.0 (d, JCP=7.0 Hz, MeCHP), 19.0 (d, JCP=8.0 Hz, MeCHP), 23.0
(s, Me), 24.1 (d, JCP=22.0 Hz, CHP), 31.7 (d, JCP=17.4 Hz, CH2P), 55.6 (br s, C3), 78.1 (d,
JCP=31.7 Hz, C1), 126.3 (d, JCP=2.8 Hz, pBn), 127.9 (d, JCP=4.5 Hz, mPh), 128.0 (s, mBn),
129.8 (d, JCP=4.7 Hz, oBn), 130.4 (d, JCP=2.1 Hz, pPh), 131.6 (d, JCP=5.2 Hz, C2), 133.4 (d,
JCP=11.9 Hz, oPh), 134.9 (d, JCP=5.5 Hz, ipsoBn). IR (KBr): 1433s, 1100s, 1026s, 773s, 745s,
697s.
3.1.4. Synthesis of 5
A suspension formed by 0.32 mmol (200 mg) of 4, 0.32 mmol (197 mg) of [NiCl2(PBniPrPh)2]
and 40 mL of THF was stirred at room temperature for 45 min and the resulting solution was
concentrated in vacuo. The solid obtained was eluted by SiO2 column chromatography with
CHCl3–acetone (100/5) as eluent. Compound 5 (1/1 mixture of diastereomers) was isolated as a
yellow solid in a 70% yield. Characterization data: 31P{1H} (101.26 MHz, CDCl3) l=45.2 s and
42.3 s. Anal. calcd (found) for C28H31ClNPPd: C, 60.66 (60.8); H, 5.63 (5.5); N, 2.52 (2.4).
MS-Positive FAB: 518 [(M−Cl)+].
3.1.5. Separation of diastereomers 5
Compound 5 (200 mg) was carefully eluted at room temperature in a SiO2 column (50 g of
SiO2) with CHCl3–acetone (100/3) as eluent. The fractions eluted (15 mL) were concentrated in
1
vacuo and checked by H NMR spectroscopy. The fractions of the optically pure compound
were chosen according to the aromatic proton signals. The diastereomer 5% was obtained in 54%
yield (54 mg), with a d.e. higher than 95%. Characterization data: 31P{1H} NMR (101.26 MHz,
1
CDCl3) l=42.3 s. H NMR (500 MHz, CDCl3): l=1.35 (dd, JHH=7.0 Hz, JHP=16 Hz, 3H,
MeCHP), 1.45 (dd, JHH=7.0 Hz, JPH=17 Hz, 3H, MeCHP), 1.95 (d, JHH=6.5 Hz, 3H, Me),
2.66 (m, 1H, HCP), 3.54 (m, 2H, JHH=14 Hz, JPH=10.5 Hz, H2CP and NH9), 3.86 (dd,
J
HH=13.5 Hz, JHP=10.5 Hz, 1H, H2CP), 4.06 (br, 1H, NH8), 5.20 (m, JHH=6.5 Hz, 1H, H7),
6.50 (dd, JHH=9 Hz, JPH=5.0 Hz, 1H, H1), 6.93 (d, JHH=9 Hz, 1H, H2), 7.01–7.07 (m, 5H,
aromatic), 7.18–7.29 (m, 3H, aromatic), 7.31–7.36 (m, 2H, aromatic), 7.40 (m, 2H, aromatic),
7.55 (d, JHH=7.5 Hz, 1H, H3), 7.63 (d, JHH=8.5 Hz, 1H, H6). Optical rotation: [h]2D0=−19.7
(c=1, CHCl3). The second diastereomer eluted 5¦ was obtained in 52% yield with 77% d.e.:

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J. Albert et al. / Tetrahedron: Asymmetry 11 (2000) 3335–3343
1
31P{1H} NMR (101.26 MHz, CDCl3) l=45.2, s. H NMR (500 MHz, CDCl3) l=0.9 (dd,
JHH=7.0 Hz, JHP=14 Hz, 3H, MeCHP), 1.4 (dd, JHH=6.8 Hz, JPH=18.6 Hz, 3H, MeCHP),
2.01 (d, JHH=6.2 Hz, 3H, Me), 2.83 (q, 1H, HCP), 3.51 (br, 1H, NH2), 3.63–3.88 (m, 2H,
H2CP), 3.95 (br s, 1H, NH2), 5.20 (q, JHH=6.2 Hz, 1H, H7), 6.02 (dd, JHH=8.8 Hz, JHP=5.6
Hz, 1H, H1), 6.74 (d, JHH=8.8 Hz, 1H, H2), 7.05–7.30 (m, 7H, aromatic), 7.35–7.40 (m, 3H,
aromatic), 7.43–7.64 (m, 4H, aromatic).
1H NMR data (500 MHz, CDCl3) of (RC,RP)-6. l=1.95 (d, JHH=6.5 Hz, 3H, Me), 1.25–2.35
(m, 11H, aliphatic), 3.54 (m, 1H, CH2), 3.56 (br, 1H, NH), 3.88 (m, 1H, CH2), 4.05 (br, 1H,
NH), 5.2 (m, JHH=5.5 Hz, 1H, HCMe), 6.48 (dd, JHH=9 Hz, JPH=5Hz, 1H, H1), 6.91 (m, 3H,
aromatic), 7.06 (m, 3H, aromatic), 7.10 (m, 2H, aromatic), 7.20–7.35 (m, 5H, aromatic), 7.50 (d,
J
HH=7.5 Hz, 1H, aromatic), 7.60 (d, JHH=8.5 Hz, 1H, aromatic).
3
1H NMR data (500 MHz, CDCl3) of (RC,SP)-6. l=1.98 (d, JHH=6.2 Hz, 3H, Me), 0.8–2.63
(m, 11H, aliphatic), 3.49–3.72 (br, 2H, NH, CH2), 3.85–3.98 (br, 2H, NH, CH2), 5.2 (m,
3
3JHH=5.6 Hz, 1H, HCMe), 6.05 (dd, JHH=8.6 Hz, JPH=5.2 Hz, 1H, H1), 6.70 (d, JHH=8.4
Hz, 1H, H2), 7.12–7.30 (m, 9H, aromatic), 7.46–7.64 (m, 5H, aromatic).
4. Computational details
The calculations were performed with the Spartan suite of programs.22 The PM3(tm)
method23,24 was used with the default parameters supplied by the program.
Acknowledgements
This work was supported by the DGICYT and by the Comissionat per a Universitats i
Recerca (project: 1999SGR 333545). J. M. C. thanks the Agencia Espan˜ola de Cooperacio´n
Internacional for a fellowship.
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