An optimised synthetic approach to a chiral derivatising agent and the utilisation of a dimerisation reaction in the synthesis of a novel C2-symmetric diphosphine ligand

Article abstract of DOI:10.1016/j.tetasy.2007.02.014

We report an optimised synthetic approach to the chiral derivatising agent (5R)-methyl-1-(chloromethyl)-2-pyrrolidinone. In addition, the observation of an unwanted dimerisation product is turned to our advantage by providing a method for the synthesis of a new class of C2-symmetric chiral diphosphine.

Full text of DOI:10.1016/j.tetasy.2007.02.014

Tetrahedron: Asymmetry 18 (2007) 664–670
An optimised synthetic approach to a chiral derivatising agent
and the utilisation of a dimerisation reaction in the synthesis of a
novel C2-symmetric diphosphine ligand
Glynn D. Williams,a Charles E. Wade,b Guy J. Clarksonc and Martin Willsa,*
aAsymmetric Catalysis Group, Department of Chemistry, Warwick University, Coventry CV4 7AL, UK
bGlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Herts SG1 2NY, UK
cX-ray Crystallographic Unit, Department of Chemistry, Warwick University, Coventry CV4 7AL, UK
Received 9 February 2007; accepted 19 February 2007
Available online 19 March 2007
Abstract—We report an optimised synthetic approach to the chiral derivatising agent (5R)-methyl-1-(chloromethyl)-2-pyrrolidinone. In
addition, the observation of an unwanted dimerisation product is turned to our advantage by providing a method for the synthesis of a
new class of C2-symmetric chiral diphosphine.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
SOCl2, EtOH
82%
EtO
HO
O
O
N
H
During the course of a project directed towards the asym-
metric synthesis of cyclic amines via C@N reduction,1 we
required reagent 1 for its use as a chiral derivatising
agent.2–5 This compound was originally prepared by the
cyclisation and esterification of glutamic acid in refluxing
ethanol with an acid catalyst.2 Attempts to replicate this
procedure gave the desired ester in low yield. It was found
that intermediate 2 was more easily accessed from pyroglu-
tamic acid 3 using the method described by Silverman
(Scheme 1).6
N
H
3
O
O
2
i) NaBH4, H2O
TsO
NaI, HSnBu3, AIBN.
75%
ii) TsCl, KOH, CHCl3
O
N
H
45%
4
TMSCl
(CH2O)n
O
O
O
O
N
N
N
N
H
62%
Cl
2. Results and discussion
6
1
5
We have developed an optimised route to 1; pyroglutamic
acid 3 was suspended in ethanol and thionyl chloride added
dropwise. Removal of the solvent in vacuo and reduced
pressure distillation gave ethyl ester 2 in 82% yield. Ester
2 was reduced to the primary alcohol using sodium boro-
hydride in water following the method of Smith et al.2
The solution was then concentrated to approximately half
of the original volume and a biphasic mixture prepared by
adding chloroform, KOH, TsCl and the phase transfer cat-
Scheme 1. Synthesis of chloromethyl amide 1.
alyst tetra-n-butylammonium hydrogen sulfate. After vig-
orous stirring, tosylate 4 could be isolated in 45% yield
for the two steps. The tosyl group was converted to the io-
dide by an in situ Finkelstein reaction and radical removal
of the iodide using tributyltin hydride to give lactam 5 in
75% yield after distillation.
Chloromethylation was carried out by heating 5 in TMSCl
and para-formaldehyde at 50 ꢁC to give 1 in 62% yield after
distillation.
*
Corresponding author. Tel.: +44 24 7652 3260; fax: +44 24 7652 4112;
e-mail: m.wills@warwick.ac.uk
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.02.014

G. D. Williams et al. / Tetrahedron: Asymmetry 18 (2007) 664–670
665
During the course of this work, we made an unexpected
observation: Smith’s original procedure required the heat-
ing of 5, TMSCl and para-formaldehyde at reflux;2 but in
our hands this led to a single product with a singlet at
4.83 ppm, which appeared to integrate to one proton. It
was suspected that the chloromethylated product 1 was
reacting with lactam 5 to dimerise the lactam through a
methylene bridge; the singlet at 4.83 ppm was assigned as
the methylene CH2.
In 1980, Rigo and co-workers7a reported the synthesis of
diacid 11 from glutamic acid 12 and trioxane in nitrobenz-
ene at 150 ꢁC. We attempted to follow this procedure but
only recovered small amounts of diacid 11, coupled with
the arduous task of steam distilling off the nitrobenzene
made this procedure unappealing (Scheme 3).
O
O
O
O
PhNO2, TsOH
OH
O
HO
The compound was crystalline and a single crystal was
grown for X-ray crystallographic analysis, the structure
was confirmed as 6 (Fig. 1).
N
N
NH2
O
O
O
O
12
OH
HO
11
Scheme 3. One pot approach to dimer.
A successful approach to 7 is shown in Scheme 4. It was dis-
covered that heating pyroglutamic acid 3 and trioxane to-
gether without solvent at 190 ꢁC resulted in the formation
of the desired diacid as a white crystalline solid in 95% yield.
The reaction was worked up by distilling off excess trioxane,
cooling to room temperature, crushing the solid to a fine
powder and then washing the powder in a sintered funnel
with EtOAc to remove any remaining trioxane (Scheme
4). It should be noted that the synthesis of 11 through the
use of aqueous formaldehyde has also been reported.7e
Figure 1. X-ray crystallographic structure of 6.
In view of this result we decided to investigate the use of
the dimerisation of 5 to give 6 in the preparation of novel
diphosphine ligands from this reaction.7 The diphosphine
we wished to investigate was compound 7, which we
thought we may be able to prepare from ditosylate 8. It
was anticipated that 8 could be formed from the reaction
of 4 with para-formaldehyde and TMSCl (Scheme 2).
190 oC, 95%
O
O
O
O
O
N
N
N
H
HO
O
O
O
O
3
11
OH
HO
O
O
O
O
O
O
NaBH4
H2O
EtOH
4
TsOH
N
N
N
N
N
N
83%
O
99%
O
7
8
13
OEt
EtO
PPh2
Ph2P
OTs
TsO
Scheme 2. Retrosynthesis of diphosphine 7.
O
O
O
O
KPPh2
THF
Tosylate 4 was a product of the synthesis of the chiral
derivitising agent 1 and when treated with TMSCl and
para-formaldehyde appeared to form the chloromethylated
adduct 9 but failed to form the desired dimer 8. Excessive
heating to try and drive the reaction resulted in decompo-
sition of intermediate 8.
N
N
N
N
65%
RO
Ph2P
OR
PPh2
14 R=H
8 R=Ts
7
NaH, TsCl
DMF, 61%
Scheme 4. Synthetic approach to diphosphine 7.
O
O
N
Cl
NH
To confirm the structure of 11, single crystals were grown
for X-ray crystallographic analysis (Fig. 2).
9
10
OTs
OH
The crystal data showed that 11 formed an interesting sec-
ondary structure in the solid state, connected by the hydro-
gen bonding of the acid OH and the amide C@O to form
H-bonded strands (Fig. 3).
Attempts were also made to dimerise ester 2 and alcohol 10
but these only resulted in decomposition products.

666
G. D. Williams et al. / Tetrahedron: Asymmetry 18 (2007) 664–670
of all the water to leave diol 14 as a white moisture sensitive
solid in 99% yield.
Diol 14 was converted to ditosylate 8 by treatment with
NaH in DMF followed by tosyl chloride at 0 ꢁC. After
aqueous work-up, the tosylate could be crystallised from
EtOAc/hexanes in 61% yield. Ditosylate 8 was treated with
two equivalents of potassium diphenylphosphine in THF
at ꢀ78 ꢁC. A 50:50 mixture of EtOAc/hexanes was added
to the crude reaction mixture and the resulting slurry fil-
tered through a short path of silica. Removal of the solvent
gave a white oil which on trituration with diethyl ether
gave diphosphine 7 as a white solid in 65% yield.
The structure of 7 was confirmed by X-ray crystallographic
analysis of the phosphine oxide, which was generated by air
oxidation, in a quantitative yield (Fig. 4).
Figure 2. X-ray crystallographic structure of 11.
Figure 4. X-ray crystallographic structure of 7 dioxide.
3. Conclusion
In conclusion, a novel bidentate phosphine ligand has been
prepared from pyroglutamic acid in five steps and in 31%
overall yield. Ruthenium and rhodium complexes were pre-
pared using this ligand and tested for activity in the hydro-
genation of acetophenone. Unfortunately, the complexes
gave poor results for this substrate, possibly due to the insta-
bility of the complexes under the reaction conditions.
Ligand 7 is currently being investigated in other transition
metal mediated reactions and the results will be reported
in due course.
Figure 3. Extended structure of 11.
4. Experimental
4.1. General
The diagram in Figure 3 shows the hydrogen bonded net-
work running parallel to the X-axis of the cell formed by
the carboxylic acid dimer. The H-bonded strands run in
opposite directions. These also form a hydrogen bonded
network with adjacent strands (not illustrated).
1
The H NMR, 13C NMR and 31P NMR spectra were re-
corded at 300, 75 and 121 MHz, respectively, using CDCl3
as a solvent, and were reported in ppm relative to CHCl3 (d
1
7.26) for H NMR and relative to the central CDCl3 reso-
Diacid 11 was converted to diester 13 by refluxing in EtOH
with a catalytic amount of p-TsOH overnight; removal of
the solvent gave a white crystalline solid which could be
recrystallised from EtOAc/hexanes to give pure 13 in
83% yield. Diester 13 was reduced to diol 14 by NaBH4
in water. The inorganics were precipitated by the addition
of acetone and filtered off. Removal of the water in vacuo
to approximately a third of the volume and the addition of
further acetone precipitated more solids that were filtered
off. This procedure was repeated once more before removal
nance (d 77.00) for 13C NMR. Flash chromatography(FC)
was carried out with silicagel 60 (230–400 mesh). All sol-
vents and commercially available chemicals, including ami-
no acid precursors were used as received.
4.2. Synthesis of ethyl-(2S)-5-oxopyrrolidine 2
To a suspension of (S)-pyroglutamic acid 3 (50.0 g,
0.39 mol) in EtOH (650 mL) was added dropwise SOCl2

G. D. Williams et al. / Tetrahedron: Asymmetry 18 (2007) 664–670
667
(45.7 g, 28 mL, 0.39 mol). The resulting solution was stir-
red for 1 h, neutralised (pH 7) with saturated NaHCO3
and extracted with CHCl3 (3 · 250 mL). The combined
organics were dried (Na2SO4) and the solvent was removed
under reduced pressure to give a green oil which was puri-
fied by reduced pressure distillation to afford ethyl-(2S)-5-
purified by flash column chromatography (SiO2, DCM–
MeOH, 100:0!90:10) to afford (5R)-5-methylpyrrolidin-
22
2-one 5 (4.2 g, 75%) as a colourless oil; ½aꢁD = +15.8 (c
22
0.023, EtOH) [lit.2 ½aꢁD = +16.0 (c 1, EtOH)]; mmax (neat)/
cmꢀ1 3217, 2965, 1677 and 1274; dH (400 MHz; CDCl3;
Me4Si) 6.83 (1H, br s, NH), 3.78 (1H, quintet, J 7.0,
CH), 2.40–2.19 (3H, m, COCH2CHaHb), 1.70–1.59 (1H,
m, COCH2CHaHb), and 1.22 (3H, t, J 7.0, CH3);
(75 MHz; CDCl3) 178.4 (Cq), 49.9 (CH), 30.5 (CH2), 28.8
(CH2) and 21.9 (CH3); m/z (EI+) 100 (60%) and 84 (100).
oxopyrrolidine 2 (49.1 g, 82%) as a white solid; mp 49–
22
51 ꢁC (lit.8 54–55 ꢁC); ½aꢁD = ꢀ6.8 (c 0.03, EtOH) [lit.8
22
½aꢁD = ꢀ7.1 (c 0.06, EtOH)]; (found: C, 53.42; H, 7.06;
N, 8.94. C7H11NO3 requires C, 53.49; H, 7.05; N, 8.91);
mmax (neat)/cmꢀ1 3206, 2982, 2341, 1742 and 1693; dH
(300 MHz; CDCl3; Me4Si) 7.23 (1H, br s, NH), 4.29–4.17
(1H, m, CH) 4.24 (2H, q, J 7.0, OCH2), 2.52–2.32 (3H,
m, COCH2CHaHb), 2.27–2.15 (1H, m, COCH2CHaHb)
and 1.31 (3H, t, J 7.0, CH3); dC (75 MHz; CDCl3) 178.7
(Cq), 172.5 (Cq), 61.9 (CH2), 55.9 (CH), 29.7 (CH2), 25.1
(CH2) and 14.5 (CH3); m/z (EI) 157.0740 (C7H11NO3
requires 157.0738) 158 (5%), 84 (100) and 56 (10).
4.5. Preparation of (5R)-methyl-1-(chloromethyl)-2-pyrrol-
idinone 1
To a solution of (5R)-5-methylpyrrolidin-2-one 5 (0.65 g,
6.6 mmol) in TMSCl (3 mL) was added para-formaldehyde
(0.22 g, 6.8 mmol), the resulting suspension was heated to
50 ꢁC for 2 h. Excess TMSCl was removed under reduced
pressure to give the crude product which was purified by
bulb-to-bulb distillation to afford (5R)-methyl-1-(chloro-
methyl)-2-pyrrolidinone 1 as a colourless oil (0.59 g,
4.3. Synthesis of [(2S)-5-oxopyrrolidin-2-yl]methyl-4-meth-
ylbenzenesulfonate 4 (adapted from Smith et al.2)
22
22
61%); ½aꢁD = +106.9 (c 0.021, CHCl3) [lit.2 ½aꢁD = +109.9
(c 0.032, CHCl3)]; mmax (neat)/cmꢀ1 2970, 1701, 1386 and
1255; dH (400 MHz; CDCl3) 5.61 (1H, d, J 10.4, ClCHaHb),
4.87 (1H, d, J 10.4, ClCHaHb), 3.86 (1H, sex, J 7.0, CH),
2.49–2.22 (3H, m, COCH2CHaHb), 1.67–1.37 (1H, m,
COCH2CHaHb) and 1.32 (3H, d, J 7.0, CH3); dC
(100 MHz; CDCl3) 176.1 (Cq), 52.4 (CH), 51.7 (CH2),
30.6 (CH2), 27.2 (CH2) and 19.7 (CH3); m/z (EI+)
147.0469 (C6H10NO35Cl requires 147.0451) 147 (3%), 132
(13%), 112 (100%) and 84 (35%).
To a solution of ethyl-(2S)-5-oxopyrrolidine 2 (15.7 g,
100.0 mmol) in water (50 mL) was added dropwise a solu-
tion of NaBH4 (2.2 g, 58.0 mmol) in water (50 mL) over a
period of 30 min. The resulting solution was warmed to rt
and stirred for a further 1 h. Acetone (10 mL) was added
dropwise at 0 ꢁC and stirred for 30 min. The reaction was
concentrated to ca. 40 mL, KOH (7.0 g, 125.0 mmol), TsCl
(19.1 g, 100.0 mmol), Bu4NSO4 (1 g, 2.94 mmol) and
CHCl3 (150 mL) were added and the reaction stirred vigor-
ously for 18 h. The phases were separated and the aqueous
phase extracted with DCM (3 · 100 mL). The combined
organics were dried (Na2SO4) and the solvent was removed
in vacuo to give a white solid which was recrystallised from
hot toluene to afford [(2S)-5-oxopyrrolidin-2-yl]methyl-4-
4.6. Synthesis of (5R)-5-methyl-1-{[(2R)-2-methyl-5-oxo-
pyrrolidin-1-yl]methylpyrrolidin-2-one 6
Procedure. Colourless crystalline plates; mp 110–112 ꢁC;
22
methylbenzenesulfonate 4 (12 g, 45%) as fine white needles;
½aꢁD = +207.7 (c 0.48, CHCl3); (found: C, 62.86; H, 8.60;
22
mp 126–128 ꢁC (lit.2 129–130 ꢁC); ½aꢁD = ꢀ6.5 (c 0.013,
22
N, 13.16. C11H18N2O2 requires C, 62.83; H, 8.63; N,
13.32); mmax (neat)/cmꢀ1 3356, 2964, 2861, 2358, 1677 and
1370; dH (300 MHz; CDCl3; Me4Si) 4.83 (2H, s, NCH2N),
3.56 (2H, sextet, J 6.2, 2 · CH3CH), 2.40–2.29 (4H, m,
2 · COCH2), 2.19–2.10 (2H, m, 2 · CHCHaHb), 1.68–
1.58 (2H, m, 2 · CH2CHaHb) and 1.31 (6H, d, J 6.2,
2 · CH3); dC (100 MHz; CDCl3) 176.1 (Cq), 52.6 (CH),
44.3 (CH2), 30.4 (CH2), 26.9 (CH2) and 19.9 (CH3); m/z
(EI+) 210.1368 (C11H18N2O2 requires 210.1368) 210
(27%), 112 (77%), 111 (100%), 98 (52%) and 83 (37%).
EtOH) [lit.2 ½aꢁD = ꢀ7.1 (c 1, EtOH)]; (found: C, 53.42;
H, 7.06; N, 8.94. C7H11NO3 requires C, 53.49; H, 7.05;
N, 8.91); mmax (neat)/cmꢀ1 3206, 2982, 2341, 1742 and
1693; dH (300 MHz; CDCl3; Me4Si) 7.80 (2H, d, J 8.5,
AA0 of AA0BB0 ArH), 7.38 (2H, d, J 8.5, AA0 of AA0BB0
ArH), 6.19 (1H, br s, NH), 4.05 (1H, dd, J 9.5 and 3.5,
OCHaHb), 3.97–3.86 (2H, m, OCHaHb + NCH), 2.48
(3H, s, CH3), 2.29–2.21 (3H, m, COCH2CHaHb) and
1.85–1.75 (1H, m, COCH2CHaHb); dC (100 MHz; CDCl3)
178.2 (Cq), 145.8 (Cq), 132.8 (Cq), 130.5 (CH), 128.3
(CH), 72.4 (CH2), 53.0 (CH), 29.6 (CH2), 23.2 (CH2) and
22.1 (CH3); m/z (EI+) 269.0739 (C12H15NO4S requires
269.0722) 270 (10%), 239 (20) and 84 (100).
4.7. Synthesis of L-(+)-1,10-methylenebis[5-oxo-2-pyrrol-
idinecarboxylic acid] 11
L-(+)-Pyroglutamic acid 3 (25.0 g, 0.19 mol) and trioxane
(17.4 g, 0.19 mol) were heated to 180 ꢁC for 3 h. Excess tri-
oxane was removed by distillation and the mixture was
then cooled to rt. The white solid was crushed to a fine
powder and washed with AcOH (20 mL) and EtOAc
(50 mL) to afford L-(+)-1,10-methylenebis[5-oxo-2-pyrrol-
idinecarboxylic acid 11 (25.0 g, 95%) as a fine white powder;
mp 290–295 ꢁC (decomp., water) (lit.7a 312 ꢁC, decomp.);
4.4. Synthesis of (5R)-5-methylpyrrolidin-2-one 5
To a solution of [(2S)-5-oxopyrrolidin-2-yl]methyl-4-meth-
ylbenzenesulfonate 4 (18.0 g, 67.2 mmol), NaI (19.8 g,
134.2 mmol), tributyltin hydride (21.0 g, 19.2 mL,
72.0 mmol) in DME (600 mL) was added AIBN (0.1 g,
0.61 mmol). The mixture was heated at reflux for 12 h
and cooled to rt. The white precipitate was filtered off
and washed with Et2O (2 · 300 mL) and the filtrate concen-
trated under reduced pressure to give a green oil which was
22
22
½aꢁD = +104.0 (c 0.022, H2O) [lit.7a ½aꢁD = +105.7 (c
0.009, H2O)]; (found: C, 48.80; H, 5.23; N, 10.41.
C11H14N2O6 requires C, 48.89; H, 5.22; N, 10.37); mmax

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G. D. Williams et al. / Tetrahedron: Asymmetry 18 (2007) 664–670
(neat)/cmꢀ1 2980, 2359, 1732, 1629 and 1158; dH
(300 MHz; DMSO) 13.10 (2H, br s, 2 · CO2H), 4.70 (2H,
s, NCH2N), 4.12–4.02 (2H, m, 2 · NCH), 2.37–2.20 (6H,
m, 2 · COCH2CHaHb) and 1.94–1.85 (2H, m, CHCHaHb);
dC (75 MHz; DMSO) 176.1 (Cq), 173.5 (Cq), 57.5
(CH), 46.8 (CH2), 29.1 (CH2) and 22.6 (CH2); m/z
(EI+) 271.0929 (C11H15N2O6 requires 271.0930), 271
(100%).
4.10. Synthesis of L-(+)-1,10-methylenebis[toluene-4-sulfonic
acid (S)-5-oxo-pyrrolidin-2-ylmethyl ester] 8
To a cooled (0 ꢁC) stirred suspension of washed (hexanes)
NaH (0.29 g, 12.1 mmol) in DMF (14 mL) was added a
solution of L-(+)-1,10-methylenebis[5-hydroxymethyl-2-
pyrrolidinone] 14 (1.4 g, 5.8 mmol) in DMF (14 mL). The
resulting suspension was stirred for 1 h at 0 ꢁC before tolu-
ene-4-sulfonyl chloride (2.3 g, 12.1 mmol) was added in
small portions over a period of 2 h. The reaction was
quenched by the addition of water (10 mL) and extracted
with EtOAc (4 · 25 mL). The combined organics were
washed with water (2 · 10 mL) and brine (10 mL), dried
(NaSO4) and the solvent removed in vacuo to afford a yel-
low oil. The crude was purified by flash column chromato-
graphy (SiO2, EtOAc–MeOH, 95:5) to give L-(+)-1,10-
methylenebis[toluene-4-sulfonic acid (S)-5-oxo-pyrrolidin-
4.8. Synthesis of L-(+)-1,10-methylenebis[5-oxo-2-pyrrol-
idinecarboxylic acid ethyl ester] 13
L-(+)-1,10-Methylenebis[5-oxo-2-pyrrolidinecarboxylic acid
11 (5.0 g, 18.5 mmol) and p-TsOH (0.1 g, 0.6 mmol) were
suspended in EtOH (50 mL) and heated at reflux for
16 h. The solution was cooled to rt and the solvent re-
moved under reduced pressure, the crude was redissolved
in DCM (100 mL) and washed with saturated NaHCO3
(20 mL), dried over Na2SO4 and the solvent removed under
reduced pressure to afford L-(+)-1,10-methylenebis[5-oxo-
2-pyrrolidinecarboxylic acid ethyl ester] 13 (5.0 g, 83%) as
a white solid; mp 112–114 ꢁC (toluene) (lit.9 117 ꢁC);
2-ylmethyl ester] 8 as a white crystalline solid; mp 116–
22
117 ꢁC (toluene); ½aꢁD = +52.6 (c 0.0204, EtOH); (found:
C, 54.47; H, 5.48; N, 5.09. C15H22N2O6 requires C, 54.53;
H, 5.49; N, 5.09); mmax (neat)/cmꢀ1 2923, 1698, 1356,
1171, 951 and 856; dH (300 MHz; CDCl3; Me4Si) 7.78
(4H, AA0 of AA0BB0 J 8.2, ArH), 7.38 (4H, BB0 of AA0BB0
J 8.2, ArH), 4.42 (2H, dd, J 11.1, 3.4, 2 · OCHaHb), 4.38
(2H, s, NCH2N), 4.01 (2H, dd, J 10.9, 2.0, 2 · OCHaHb),
3.76–3.70 (2H, m, 2 · NCH), 2.46 (6H, s, 2 · CH3) and
2.49–1.90 (8H, m, 2 · CH2CH2); dC (75 MHz; CDCl3)
176.8 (Cq), 145.8 (Cq), 132.7 (Cq), 130.5 (CH), 128.3
(CH) 68.6 (CH2), 55.7 (CH), 44.7 (CH2), 29.8 (CH2), 22.1
(CH3) and 21.4 (CH2); m/z (EI+) 551.1506 (C25H31N2O8S2
requires 551.1522) 550 (20%), 364 (19), 281 (100), 205 (25),
154 (35) and 90 (54).
22
22
½aꢁD = +52.7 (c 0.0204, EtOH) (lit.9 ½aꢁD = +55.6); (found:
C, 55.15; H, 6.76; N, 8.42. C15H22N2O6 requires C, 55.21;
H, 6.79; N, 8.58); mmax (neat)/cmꢀ1 2986, 2360, 1738,
1692, 1196 and 1033; dH (300 MHz; CDCl3; Me4Si) 4.82
(2H, s, NCH2N), 4.39 (2H, dd, J 5.4 and 2.6, 2 · NCH),
4.25 (4H, q, J 7.2, 2 · OCH2CH3), 2.45–2.31 20 (6H, m,
2 · COCH2CHaHb), 2.14–2.06 (2H, m, 2 · CHCHaHb)
and 1.32 (6H, t, J 7.3, 2 · OCH2CH3); dC (75 MHz;
CDCl3) 176.3 (Cq), 171.6 (Cq), 61.6 (CH2), 59.2 (CH),
48.3 (CH2), 28.9 (CH2), 23.0 (CH2) and 14.1 (CH3); m/z
(EI+) 326 (100%), 252 (45) and 169 (50).
4.11. Synthesis of L-(+)-1,10-Methylenebis[5-diphenyl-
phosphino-2-pyrrolidinone] 7
4.9. Synthesis of L-(+)-1,10-methylenebis[5-hydroxymethyl-
2-pyrrolidinone] 14
To a stirred solution of L-(+)-1,10-methylenebis[toluene-4-
sulfonic acid (S)-5-oxo-pyrrolidin-2-ylmethyl ester]
8
To a stirred solution of L-(+)-1,10-methylenebis[5-oxo-2-
pyrrolidine carboxylic acid ethyl ester] 13 (13.5 g,
41.4 mmol) in EtOH/water (135 mL/13.5 mL) was added
NaBH4 (4.72 g, 124 mmol) in 1 portion. The suspension
was stirred for 12 h, cooled to 0 ꢁC, acetone (100 mL)
was added and stirred for a further 2 h. The white solids
were filtered off and washed with cold EtOH (50 mL).
The filtrate was reduced by half under reduced pressure
and acetone (50 mL) added to the residue. The white pre-
cipitate was filtered off and washed with cold EtOH
(25 mL). The filtrate was evaporated under reduced pres-
sure to afford L-(+)-1,10-methylenebis[5-hydroxymethyl-2-
(1.28 g, 2.3 mmol) in THF was added dropwise a 0.5 mol
solution potassium diphenylphosphine (1.56 g, 13.9 ml,
6.9 mmol) in THF. The reaction was stirred for 1 h, diluted
with EtOAc–hexanes (50:50, 10 mL) and filtered through a
pad of silica. The solvent was removed under reduced pres-
sure to give a colourless oil, which was triturated with Et2O
to give a white solid. This was washed with Et2O (2 · 5 mL)
to afford L-(+)-1,10-methylenebis[5-diphenylphosphino-2-
pyrrolidinone] 7 (0.86 g, 65%) as a white powder; mp
22
158–160 ꢁC; ½aꢁD = +83.6 (c 0.031, EtOH); mmax (neat)/
cmꢀ1 3064, 2928, 1683, 1377 and 737; dH (300 MHz;
CDCl3; Me4Si) 7.53–7.30 (20H, m, 20 · ArH), 4.76 (2H,
s, NCH2N), 3.26–3.14 (2H, m, 2 · NCH), 2.98 (2H, dt, J
13.0, 3.2, 2 · PCHaHb), 2.43 (2H, ddd, J 15.3, 9.8 and
5.7, 2 · PCHaHb) and 2.20–1.82 (8H, m, 2 · CH2CH2);
dC (75 MHz; CDCl3) 175.2 (Cq), 137.7 (Cq, d, J 11.0),
136.2 (Cq, J 12.6), 133.1 (CH, d, J 20.1), 132.3 (CH, d, J
19.0), 128.9 (CH), 128.6 (CH), 128.4 (CH, d, J 1.7), 128.3
(CH, d, J 1.6), 53.5 (CH, d, J 20.1), 43.4 (CH2), 31.7
(CH2, d, J 14.4), 30.0 (CH2, d, J 2.2) and 24.6 (CH2, d, J
10.9); dP (121.51 MHz; CDCl3) ꢀ24.86; m/z (EI+)
577.2169 (C25H35N2O2P2 requires 577.2174), 578 (20%),
393 (40), 377 (45), 296 (100) and 183 (60).
pyrrolidinone] 14 (9.9 g, 99%) as
a colourless oil;
22
½aꢁD = +91.3 (c 0.0145, H2O); mmax (neat)/cmꢀ1 3329,
1657, 1410 and 1212; dH (300 MHz; D2O) 4.75 (2H, s,
NCH2N), 3.81 (2H, dd, J 12.6 and 3.4, 2 · OCHaHb),
3.62–3.56 (2H, m, 2 · NCH), 3.50 (2H, dd, J 12.6 and 2.5
2 · OCHaHb), 2.48–2.25 (4H, m, 2 · COCH2), 2.14–2.00
(2H, m, 2 · CHCHaHb) and 1.91–1.80 (2H, m,
2 · CHCHaHb); dC (100 MHz; D2O) 179.9 (Cq), 60.3
(CH2), 57.9 (CH), 45.0 (CH2), 30.2 (CH2) and 20.2
(CH2); m/z (EI+) 243.1344 (C11H19N2O4 requires
243.1344), 243 (20%).

G. D. Williams et al. / Tetrahedron: Asymmetry 18 (2007) 664–670
669
4.12. X-ray crystallographic data for 6
successful refinement. The structure was solved by direct
methods using SHELXS (Sheldrick, 1990) (TREF) with
additional light atoms found by Fourier methods. Hydro-
gen atoms were added at calculated positions and refined
using a riding model with freely rotating methyl groups.
Anisotropic displacement parameters were used for all
non-H atoms; H-atoms were given isotropic displacement
parameters equal to 1.2 (or 1.5 for methyl hydrogen atoms)
times the equivalent isotropic displacement parameter of
the atom to which the H-atom is attached. The chirality
was established from the known chirality of the compound
but the anomalous scattering was insufficiently large for
this to be checked independently. Floating origin con-
straints were generated automatically. R1 [For 1758
reflections with I > 2r(I)] = 0.0407, wR2 = 0.0832. Data/
restraints/parameters 2407/1/179. Extinction coefficient
0.006(3). Note: The asymmetric unit contains a dicarbox-
ylic acid. This forms hydrogen bonded ribbons (shown in
Fig. 3) which run parallel to the a axis of the cell. There
are close contacts between these ribbons. Refinement used
SHELXTL.10
C11H18N2O2, M = 210.27, Tetragonal, space group
P4(3)2(1)2, a = 6.8307(4), b = 6.8307(4), c = 24.495(2) A,
a = 90ꢁ, b = 90ꢁ, c = 90ꢁ, U = 1142.89(13) A (by least
˚
3
˚
squares refinement on 2637 reflection positions), T =
180(2) K, k = 0.71073 A, Z = 4, D(cal) = 1.222 g/cm3,
F(000) = 456. l(MoK-a) = 0.085 mmꢀ1. Crystal charac-
ter: colourless block. Crystal dimensions 0.22 · 0.12 ·
0.08 mm. Data collection and processing: Siemens SMART
(Siemens, 1994) three-circle system with CCD area detec-
tor. The crystal was held at 180(2) K with the Oxford Cryo-
system Cryostream Cooler (Cosier and Glazer, 1986).
Maximum theta was 25.00ꢁ. The hkl ranges were ꢀ7/8,
ꢀ5/8, ꢀ29/28. 5817 reflections measured, 1006 unique
[R(int) = 0.1100]. Absorption correction by semi-empirical
from equivalents; minimum and maximum transmission
factors: 0.53; 0.96. No crystal decay. Structure analysis
and refinement: Systematic absences indicated either space
group P4(3)2(1)2 or P4(1)2(1)2. The former was chosen
on the basis of intensity statistics and shown to be correct
by successful refinement. The structure was solved by direct
methods using SHELXS (Sheldrick, 1990) (TREF) with
additional light atoms found by Fourier methods. Hydro-
gen atoms were added at calculated positions and refined
using a riding model with freely rotating methyl groups.
Anisotropic displacement parameters were used for all
non-H atoms; H-atoms were given isotropic displacement
parameters equal to 1.2 (or 1.5 for methyl hydrogen
atoms) times the equivalent isotropic displacement para-
meter of the atom to which the H-atom is attached. The
chirality was established from the known chirality of the
compound but the anomalous scattering was insufficiently
large for this to be checked independently. C7 of the
molecule lies on the two-fold axis (4a) so there is only
half a molecule in the asymmetric unit and so four
molecules per cell. R1 [For 767 reflections with
I > 2r(I)] = 0.0673, wR2 = 0.1225. Data/restraints/para-
meters 1006/0/71. Extinction coefficient 0.066(9). Refine-
ment used SHELXTL.10
4.14. X-ray crystallographic data for 7
The asymmetric unit contains the compound as the bis
phosphine oxide. The unit cell contains four such mole-
cules. C35H36N2O4P2, M = 610.60, orthorhombic, space
group P2(1)2(1)2(1), a = 8.5543(11), b = 18.463(2), c =
3
˚
˚
19.916(3) A, a = 90ꢁ, b = 90ꢁ, c = 90ꢁ, U = 3145.5(7) A
(by least squares refinement on 7415 reflection positions),
T = 180(2) K, k = 0.71073 A, Z = 4, D(cal) = 1.289
˚
g/cm3, F(000) = 1288. l(MoK-a) = 0.180 mmꢀ1. Crystal
character: colourless block. Crystal dimensions 0.22 ·
0.20 · 0.06 mm. Data collection and processing: Siemens
SMART (Siemens, 1994) three-circle system with CCD
area detector. The crystal was held at 180(2) K with the
Oxford Cryosystem Cryostream Cooler (Cosier and Gla-
zer, 1986). Maximum theta was 28.87ꢁ. The hkl ranges
were ꢀ11/10, ꢀ23/23, ꢀ25/23. 20,277 reflections measured,
7572 unique [R(int) = 0.0744]. Absorption correction by
semi-empirical from equivalents; minimum and maximum
transmission factors: 0.63; 0.96. No crystal decay. Structure
analysis and refinement: Systematic absences indicated
space group P2(1)2(1)2(1) and shown to be correct by suc-
cessful refinement. The structure was solved by direct
methods using SHELXS (Sheldrick, 1990) (TREF) with
additional light atoms found by Fourier methods. Hydro-
gen atoms were added at calculated positions and refined
using a riding model with freely rotating methyl groups.
Anisotropic displacement parameters were used for all
non-H atoms; H-atoms were given isotropic displacement
parameters equal to 1.2 (or 1.5 for methyl hydrogen atoms)
times the equivalent isotropic displacement parameter of
the atom to which the H-atom is attached. The chirality
was established from the known chirality of the compound
and checked by refinement of a delta-f00 multiplier. Abso-
lute structure parameter x = ꢀ0.02(13). R1 [For 4680
reflections with I > 2r(I)] = 0.0769, wR2 = 0.1639. Data/re-
straints/parameters 7572/0/389. Extinction coefficient
0.0017(6). Largest difference Fourier peak and hole 0.380
and ꢀ0.451 e Aꢀ3. Refinement used SHELXTL.10
4.13. X-ray crystallographic data for 1111
C11H14N2O6, M = 270.24, monoclinic, space group P2(1),
˚
a = 7.9622(8), b = 9.1728(12), c = 9.1731(12) A, a = 90ꢁ,
3
˚
b = 112.952(4)ꢁ, c = 90ꢁ, U = 616.92(13) A (by least
squares refinement on 2893 reflection positions), T =
180(2) K, k = 0.71073 A, Z = 2, D(cal) = 1.455 g/cm3,
˚
F(000) = 284. l(MoK-a) = 0.120 mmꢀ1
. Crystal char-
acter: colourless block. Crystal dimensions 0.38 · 0.20 ·
0.14 mm. Data collection and processing: Siemens SMART
(Siemens, 1994) three-circle system with CCD area detec-
tor. The crystal was held at 180(2) K with the Oxford Cryo-
system Cryostream Cooler (Cosier and Glazer, 1986).
Maximum theta was 28.76ꢁ. The hkl ranges were ꢀ10/9,
ꢀ10/12, ꢀ11/12. 3928 reflections measured, 2407 unique
[R(int) = 0.0379]. Absorption correction by semi-empirical
from equivalents; minimum and maximum transmission
factors: 0.55; 0.96. No crystal decay. Structure analysis
and refinement: Systematic absences indicated space group
P2(1) or P2(1)/m. The former was chosen because of the
known chirality of the system and shown to be correct by

670
G. D. Williams et al. / Tetrahedron: Asymmetry 18 (2007) 664–670
2. Smith, M. B.; Dembofsky, B. T.; Son, Y. C. Org. Chem. 1994,
59, 1719–1725.
3. Latypov, S. K.; Riguera, R.; Smith, M. B.; Polivkova, J. J.
Org. Chem. 1998, 63, 8682–8688.
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1641–1648.
5. Chen, P.; Suh, D.-J.; Smith, M. B. J. Chem. Soc., Perkin
Trans. 1 1995, 1317–1322.
Additional material for all X-ray analyses available from
the Cambridge Crystallographic Data Centre comprises
H-atom coordinates, thermal parameters and the remain-
ing bond lengths and angles. The following crystal
structures have been deposited at the Cambridge Crystallo-
graphic Data Centre: CCDC 636611 (6); CCDC 636612
(11); CCDC 636613 (7).
6. Silverman, R. B.; Levy, M. A. J. Org. Chem. 1980, 45, 815–
818.
Acknowledgments
7. (a) Miquel, C.; Pigache, P.; Rigo, B. J. Heterocycl. Chem.
1980, 17, 1447–1453; (b) Cauliez, P.; Rigo, B.; Fasseur, D.;
Couturier, D. J. Heterocycl. Chem. 1991, 28, 1143–1146; (c)
Rigo, B.; Lelier, J. P.; Kolocouris, N. Synth. Commun. 1986,
16, 1587–1591; (d) Rigo, B.; De Quillarcq, J.; Fossaert, E.;
Kolocouris, N. J. Heterocycl. Chem. 1984, 21, 1393–1396; (e)
Stark, J. B.; Goodman, A. E. J. Am. Chem. Soc. 1952, 74,
4966–4967.
We thank the EPSRC and GlaxoSmithKline for generous
financial support of this project through the provision of
an industrial CASE award (to G.D.W.). We acknowledge
the use of the EPSRC Chemical Database Service at Dares-
bury,12 J. C. Bickerton of the Warwick MS service and Dr.
B. Stein of the Swansea EPSRC MS service for analyses of
certain compounds.
8. Khim, S.-K.; Cederstrom, E.; Ferri, D. C.; Marinano, P. S.
Tetrahedron 1996, 52, 3195–3222.
9. Kanao, S. Chem. Abstr. 1952, 46, 11044.
10. Sheldrick, G. M. SHELXTL ver 5.1, 1997, Bruker Analytical
X-ray Systems, Madison, Wis. USA.
11. The X-ray crystallographic structure of this compound has
been reported: Jones, F. T.; Palmer, K. J.; Black, D. R. Anal.
Chem. 1953, 25, 1929–1930.
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