Resolution of 1-n-butyl-3-methyl-3-phospholene 1-oxide with TADDOL derivatives and calcium salts of O,O'-dibenzoyl-(2R,3R)- or O,O'-di-p-toluoyl- (2R,3R)-tartaric acid

Article abstract of DOI:10.1002/chir.22293

The resolution methods applying (-)-(4R,5R)-4,5-bis(diphenylhydroxymethyl)- 2,2-dimethyldioxolane ("TADDOL"), (-)-(2R,3R)-α,α, α',α'-tetraphenyl-1,4-dioxaspiro[4.5]decan-2,3-dimethanol ("spiro-TADDOL"), as well as the acidic and neutral Ca²⁺ sa

Full text of DOI:10.1002/chir.22293

CHIRALITY 26:174–182 (2014)
Resolution of 1-n-Butyl-3-Methyl-3-Phospholene 1-Oxide With
TADDOL Derivatives and Calcium Salts of O,O’-Dibenzoyl-(2R,3R)- or
O,O’-di-p-Toluoyl-(2R,3R)-tartaric Acid
PÉTER BAGI,1 ANDRÁS FEKETE,1 MIHÁLY KÁLLAY,2,3 DÓRA HESSZ,4 MIKLÓS KUBINYI,3,4 TAMÁS HOLCZBAUER,5
1
MÁTYÁS CZUGLER,5 ELEMÉR FOGASSY,1 AND GYÖRGY KEGLEVICH
*
1Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, Budapest, Hungary
2MTA-BME Lendület Quantum Chemistry Research Group at the
3Department of Physical Chemistry and Material Science, Budapest University of Technology and Economics, Budapest, Hungary
4Institute of Molecular Pharmacology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary
5Institute of Organic Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary
ABSTRACT
dimethyldioxolane
The resolution methods applying (À)-(4R,5R)-4,5-bis(diphenylhydroxymethyl)-2,2-
(“TADDOL”),
(À)-(2R,3R)-α,α,α’,α’-tetraphenyl-1,4-dioxaspiro[4.5]decan-
2,3-dimethanol (“spiro-TADDOL”), as well as the acidic and neutral Ca2+ salts of (À)-O,O’-dibenzoyl-
and (À)-O,O’-di-p-toluoyl-(2R,3R)-tartaric acid were extended for the preparation of 1-n-butyl-3-
methyl-3-phospholene 1-oxide in optically active form. In one case, the intermediate diastereomeric
complex could be identified by single-crystal X-ray analysis. The absolute P-configuration of the
enantiomers of the phospholene oxide was also determined by comparing the experimentally
obtained and calculated CD spectra. Chirality 26:174–182, 2014. © 2014 Wiley Periodicals, Inc.
KEY WORDS: alkyl-3-phospholene 1-oxide; P-chirality; resolution methods; optical isomers;
X-ray crystallography; CD spectroscopy; absolute P-configuration
INTRODUCTION
The acidic Ca2+ salts of O,O’-dibenzoyl- and O,O’-di-p-toluoyl-
(2R,3R)-tartaric acid (4 and 5) were also as found suitable
resolving agents via diastereomeric coordinative complex forma-
tion.33,34 These resolution methods were also extended to
several phenyl-substituted 6-membered P-heterocycles.35
In this work, we studied the possibilities of the resolution of
1-n-butyl-3-methyl-3-phospholene 1-oxide (1) considering the
methods developed in our research group (Fig. 1). The abso-
lute P-configuration of the resulting enantiomers of n-butyl-3-
phospholene oxide (1) was determined by independent
methods.
The preparation of chiral phosphines in enantiopure form is of
great interest in organic chemistry, as the transition metal com-
plexes of these compounds may be applied as enantioselective
catalysts in various homogenous catalytic reactions.1,2
Since the first enantiomeric separation of compounds
having a nonsymmetrically substituted phosphorus atom by
Meisenheimer and Lichtenstadt,3 the preparation of optically
active P-stereogenic substances has been the subject of
continuing interest. The separation of optical isomers may
be based on the formation of covalent diastereomers, diaste-
reomeric salts, diastereomeric transition metal complexes,
and molecular complexes.4–6
There are several methods reported in the literature for the
resolution of phosphine oxides, but none of these methods
are of general use. The separation of enantiomers of several
secondary and tertiary phosphine oxides with a stereogenic
center either on the phosphorus atom or on the backbone
was accomplished via molecular complex formation with O,O’-
dibenzoyl-(2R,3R)-tartaric acid.7–15 In some special instances,
the bromocamphorsulfonic acid,3,16,17 camphorsulfonic acid,17
mandelic acid,18,19 2,2-dihydroxy-1,1-binaphthalene,18,20 as well
as the α-methylbenzylamine21 were also used successfully to
prepare optically active phosphine oxides.
Five-membered P-heterocycles, such as 1-substituted-3-
methyl-3-phospholene 1-oxides are important starting materials
for several five-, six-, seven-, and eight-membered deriva-
tives.22–25 Pietrusiewicz and co-workers reported several
methods for the preparation of the enantiomers of phospholene
oxides and their derivatives, but these methods are rather
special.26–29 Recently, our research group has developed effi-
cient resolution methods for the separation of the enantiomers
of 1-substituted-3-methyl-3-phospholene 1-oxides. The resolution
of the 3-phospholene oxides was accomplished via molecular
complex formation using TADDOL derivatives (2 and 3).30–32
© 2014 Wiley Periodicals, Inc.
MATERIALS AND METHODS
General
The 31P and 1H NMR spectra were taken on a Bruker AV-300 or DRX-
500 spectrometer operating at 121.5 and 300 or 202.4 and 500 MHz,
respectively.
The enantiomeric excess (ee) values of the phospholene oxide 1 were
determined by chiral GC on an Agilent (Palo Alto, CA) 4890D instrument
equipped with a Supelco BETA DEX 120 column (30 m × 0.25 mm, 0.25
μm film, FID detector, nitrogen as carrier gas, injector 240°C, detector
300°C, head pressure: 10 psi, at 1:100 split ratio). Retention times of 1
by chiral gas chromatography (GC) (program: 2 min at 140°C, 20°C/
min to 175°C, followed by 1°C/min to 190°C, then kept at 190°C):
20.50 min for (R)-1 and 20.86 min for (S)-1.
Optical rotations were determined on a Perkin-Elmer (Boston, MA)
241 polarimeter.
*Correspondence to: György Keglevich, Department of Organic Chemistry
and Technology, Budapest University of Technology and Economics, 1521
Budapest, Hungary. E-mail: gkeglevich@mail.bme.hu
Received for publication 10 October 2013; Accepted 09 December 2013
DOI: 10.1002/chir.22293
Published online 8 February 2014 in Wiley Online Library
(wileyonlinelibrary.com).

RESOLUTION OF 1-N-BUTYL-3-METHYL-3-PHOSPHOLENE 1-OXIDE
175
Fig. 1. The n-butyl-3-phospholene oxide (1) and resolving agents [(À)-2-(À)-7] used in this study.
1-n-Butyl-3-methyl-3-phospholene 1-oxide (1),36 (À)-(4R,5R)-4,5-bis
Resolution of 1-n-Butyl-3-methyl-3-phospholene 1-Oxide
(diphenylhydroxymethyl)-2,2-dimethyldioxolane [(À)-2], (À)-(2R,3R)-
(1) With Spiro-TADDOL [(À)-3]
α,α,α’,α’-tetraphenyl-1,4-dioxaspiro[4.5]decan-2,3-dimethanol
[(À)-3]37
1-n-butyl-3-phospholene oxide (1) was resolved with spiro-TADDOL
[(À)-3] according to Representative Procedure A. The conditions and
the results are shown in Table 1, Entries 3–6.
and calcium hydrogen (À)-O,O’-dibezoyl-(2R,3R)-tartrate [(À)-4]33 were
synthesized as described earlier. (À)-O,O’-Dibezoyl- and (À)-O,O’-di-p-
toluoyl-(2R,3R)-tartaric acid were purchased from Aldrich Chemical (Mil-
waukee, WI).
Resolution of 1-n-Butyl-3-methyl-3-phospholene 1-Oxide
(1) With Calcium Hydrogen O,O’-Dibenzoyl-(2R,3R)-
tartrate [(À)-4] (Representative Procedure B)
Resolution of 1-n-Butyl-3-methyl-3-phospholene 1-Oxide
(1) With TADDOL [(À)-2] (Representative Procedure A)
0.15 g (0.90 mmol) of racemic 1-n-butyl-3-methyl-3-phospholene 1-oxide
(1) and 0.42 g (0.90 mmol) of TADDOL [(À)-2] was dissolved in 0.84 ml
of hot ethyl acetate, then 4.2 ml of hexane was added. Colorless crystal-
line diastereomeric complex (S)-1·(TADDOL)2 appeared immediately.
After standing at 26°C for 3 h, the crystals were separated by filtration
to give 0.32 g (65%) of (S)-1·(TADDOL)2 with a de of 26%. The diastereo-
meric complex (S)-1·(TADDOL)2 was purified further by two recrystalli-
zations from a mixture of 0.84 ml of ethyl acetate and 4.2 ml of hexane
to afford 0.14 g (28%) of the complex (S)-1·(TADDOL)2 with a de of
74%. The (S)-1-n-butyl-3-methyl-3-phospholene 1-oxide [(S)-1] was recov-
ered from the diastereomer by column chromatography (silica gel,
dichloromethane:methanol 97:3) to give 0.018 g (23%) of phospholene ox-
ide (S)-1 with an ee of 74%. [α]D25 = À12.1 (c 2.4, CHCl3). (Table 1, Entry
1). Resolution of 1-n-butyl-3-methyl-3-phospholene 1-oxide (1) with
TADDOL [(À)-2] was also performed in isopropyl alcohol. In this case,
the racemic 3-phospholene oxide 1 and the TADDOL [(À)-2] were
dissolved in hot isopropyl alcohol, and the corresponding diastereomeric
complexes precipitated by cooling the mixture to 26°C (Table 1, Entry 2).
To 0.17 g (0.22 mmol) of Ca(H-DBTA)2·(H2O)2 [(À)-4·(H2O)2] in 0.51 ml
of hot ethanol was added 0.15 g (0.88 mmol) of racemic 1-n-butyl-3-methyl-3-
phospholene 1-oxide (1) in 0.51 ml of acetonitrile. After the addition, the so-
lution was allowed to cool to 26°C, whereupon colorless crystals appeared.
After standing at 26°C for 24 h, the crystals were filtered off to give 0.17 g
(72%) of Ca[((S)-1)2(H-DBTA)2] with a de of 31%. The diastereomeric com-
plex was purified further by two digestions, by stirring the suspension of the
diastereomeric complex at 26°C in a mixture of 0.51 ml of ethanol, and 0.51
ml of acetonitrile for 24 h to afford 0.067 g (28%) of Ca[((S)-1)2(H-DBTA)2]
with a de of 76%. The phospholene oxide (S)-1 was recovered from the dia-
stereomeric complex by treatment of the 2 ml dichloromethane solution of
Ca[((S)-1)2(H-DBTA)2] with 2 ml of a 10% aqueous ammonia. The organic
layer was washed with 0.5 ml of water, dried (Na2SO4), and concentrated
to give 0.016 g (21%) of (S)-1-n-butyl-3-methyl-3-phospholene 1-oxide [(S)-1)]
with an ee of 76%. Resolution of 1-n-butyl-3-methyl-3-phospholene 1-oxide
(1) with Ca(H-DBTA)2 [(À)-4] was also performed in a mixture of ethanol
and ethyl-acetate. The conditions and the results are shown in Table 2,
Entries 1 and 2.
TABLE 1. Resolution of 1-n-butyl-3-methyl-3-phospholene 1-oxide (1) with TADDOL derivatives [(À)-2 and (À)-3]
,
,
,
Entry
Resolving agent
Eq.
Solventsa
Diastereomer complexb
Yieldc f (%)
eed f (%)
Se f (À)
Abs. Config.g
1
2
3
4
5
6
TADDOL
TADDOL
spiro-TADDOL
spiro-TADDOL
spiro-TADDOL
spiro-TADDOL
1
0.75
1
1
1
1
2×EtOAc/10×Hexane
6×iPrOH
2×EtOAc/10×Hexane
6×MeOH
6×EtOH
6×iPrOH
(1)(TADDOL)2
(65) 23
(44) 5
(83) 62
(75) 33
(80) 17
(86) 43
(26) 74
(41) 78
(54) 84
(51) 77
(28) 70
(62) 78
(0.17) 0.17
(0.18) 0.04
(0.45) 0.52
(0.38) 0.26
(0.22) 0.12
(0.53) 0.33
(S)
(S)
(S)
(R)
(R)
(S)
(1)2(TADDOL)3
(1)(spiro-TADDOL)2
(1)(spiro-TADDOL)2
(1)(spiro-TADDOL)2
(1)(spiro-TADDOL)2
aMixture of solvents for the crystallization and recrystallizations [ml of solvent/g of resolving agent].
bThe ratio of 1 and (À)-2 or (À)-3 was determined by 1H NMR.
cBased on the half of racemate 1 that is regarded to be 100% for each antipode.
dDetermined by chiral GC.
eResolving capability, also known as the Fogassy parameter (S = Y x ee).47
fResults obtained after the first crystallization are shown in parentheses, while results obtained after two recrystallizations are shown in boldface.
gThe absolute configuration of 1 was determined by X-ray analysis and CD spectroscopy.
Chirality DOI 10.1002/chir

176
BAGI ET AL.
complex [(S)-1·(spiro-TADDOL)2] was purified by three recrystallizations
Resolution of 1-n-Butyl-3-methyl-3-phospholene 1-Oxide
in a mixture of 4.4 ml of ethyl acetate and 22 ml of hexane. The (S)-1-n-bu-
tyl-3-methyl-3-phospholene 1-oxide [(S)-1] was recovered by column chro-
matography (silica gel, dichloromethane:methanol 97:3) to afford 0.19 g
(52%) of (S)-1 in an ee of 95%. The mother liquors of the crystallization and
recrystallizations were combined, and the solvent was evaporated to afford
1.3 g (61%) of a white powder as a 3:2 mixture of (R)-1 with an ee of 32%
and spiro-TADDOL [(À)-3]. 0.86 g (1.7 mmol) of spiro-TADDOL [(À)-3]
was added to this mixture and the resolution was performed in 10 ml of eth-
anol according to Representative Procedure A. The [(R)-1·(spiro-TADDOL)2]
complex was purified by three recrystallizations in 10 ml of ethanol and it
was decomposed by column chromatography (silica gel, dichloromethane:
methanol 97:3) to afford 0.04 g (11%) of (R)-1-n-butyl-3-methyl-3-phospholene
1-oxide [(R)-1] in an ee of 98%.
(1) With Calcium Hydrogen O,O’-di-p-Toluoyl-(2R,3R)-
tartrate [(À)-5] (Representative Procedure C)
To 0.18 g (0.45 mmol) of DPTTA·H2O in a mixture of 0.56 ml of ethanol
and 0.06 ml of water was added 0.013 g (0.23 mmol) of CaO, and the
mixture was heated to the boiling point until it became clear. 0.16 g
(0.91 mmol) of racemic 1-n-butyl-3-methyl-3-phospholene 1-oxide (1) in
0.56 ml of ethyl acetate was then added to the solution of the in situ
formed resolving agent Ca(H-DPTTA)2 [(À)-5]. After the addition, the solu-
tion was allowed to cool to 26°C, whereupon colorless crystals appeared.
After standing at 26°C for 24 h, the crystals were filtered off to give 0.18 g
(68%) of Ca[((S)-1)2(H-DPTTA)2] with a de of 38%. The diastereomeric
complex was purified further by two digestions, by stirring the suspension
of the diastereomeric complex at 26°C for 24 h in a mixture of 0.56 ml of
ethanol, 0.56 ml of ethyl acetate, and 0.06 ml of water to afford 0.13 g
(49%) Ca[((S)-1)2(H-DPTTA)2] with a de of 45%. The phospholene oxide
(S)-1 was recovered by treatment of the 2 ml dichloromethane solution of
the complex with 2 ml of 10% aqueous ammonia. The organic phase was
washed with 0.5 ml of water, dried (Na2SO4), and concentrated to give
0.034 g (44%) of (S)-1-n-butyl-3-methyl-3-phospholene 1-oxide [(S)-1] with
an ee of 45%. The resolution of 1-n-butyl-3-methyl-3-phospholene 1-oxide
(1) with Ca(H-DPTTA)2 [(À)-5] was accomplished in a mixture of ethanol
and water, or in a mixture of ethanol, acetonitrile, and water. The conditions
and the results are shown in Table 2, Entries 3–5.
X-Ray Measurements
X-ray quality crystals of the diastereomeric complex 1:spiro-TADDOL
1:1 were grown from the saturated ethyl acetate solution of 252 mg
(1.46 mmol) of (S)-1-n-butyl-3-methyl-3-phospholene 1-oxide [(S)-1] and
7.4 mg (0.015 mmol) of spiro-TADDOL [(À)-3].
A selected single colorless prism crystal (0.15 × 0.2 × 0.4 mm) of 1: spiro-
TADDOL 1:1 was mounted on a Rigaku R-AXIS RAPID diffractometer (graph-
ite monochromator Mo-Kα radiation, λ = 0.71075 Å). Data collection was
performed at room temperature (T = 295(2) K). Crystal data for 1 : spiro-
TADDOL 1:1 = C43H51O5P, triclinic, space group P1, a = 9.4378(7) Å, b =
10.0316(9) Å, c = 20.3550(17) Å, a = 83.320(2), b = 82.798(2), g = 89.034(2), V
= 1899.0(3) Å3, T = 295(2) K, Z = 2, Dx = 1.187 Mg/m3, μ = 0.116 mm–1. The
initial structure model was obtained by SHELXS-97,38 completed by successive
difference Fourier syntheses and refined to convergence by SHELXL-97,38 R1
= 0.0669 and wR2 = 0.1567 for 5644 [I>2( I)] and R1 = 0.1064 and wR2 = 0.1816
for all (8968) intensity data. Refined absolute structure parameter x = 0.08(19).39
Relevant X-ray diffraction and model information have been deposited at the
Cambridge Crystallographic Data Centre under deposition number CCDC
965242. Copies of these data can be obtained free of charge upon application
to CCDC (12 Union Road, Cambridge CB2 1EZ, UK; fax: 00 44 (0) 1223
336033 or e-mail: deposit@ccdc.cam.ac.uk).
Resolution of 1-n-Butyl-3-methyl-3-phospholene 1-Oxide (1)
With Calcium O,O’-di-Benzoyl-(2R,3R)-tartrate and Calcium
O,O’-di-p-Toluoyl-(2R,3R)-tartrate [(À)-6 and (À)-7]
1-n-Butyl-3-phospholene oxide (1) was resolved with Ca(DBTA) and
Ca(DPTTA) [(À)-6 and (À)-7] according to Representative Procedure
C. Ca(DBTA) and Ca(DPTTA) [(À)-6 and (À)-7] were formed by the
reaction of a 1:1 mixture of CaO and DBTA or DPTTA. The conditions
and the results are shown in Table 3.
Complete Resolution Process for
1-n-Butyl-3-methyl-3-phospholene 1-Oxide (1) With
Spiro-TADDOL [(À)-3]
CD Measurements
The (S)-1-n-butyl-3-methyl-3-phospholene 1-oxide [(S)-1] was obtained by
the resolution of 0.75 g (4.3 mmol) of racemic 1 with 2.2 g (4.3 mmol) of
spiro-TADDOL [(À)-3] in a mixture of 4.4 ml of ethyl acetate and 22 ml of
hexane according to Representative Procedure A. The diastereomereic
The UV absorption and CD spectra were measured in acetonitrile
solution. The UV spectra were recorded on an Agilent 8453 diode array
spectrometer and the CD spectra were obtained with a Jasco J-810
spectropolarimeter.
TABLE 2. Resolution of 1-n-butyl-3-methyl-3-phospholene 1-oxide (1) with 0.25 equivalent of Ca(H-DBTA)2 or Ca(H-DPTTA)2
[(À)-4 or (À)-5]
Entry
Resolving agent
Solventsa
Diastereomer complexb
Yieldc,f (%)
eed,f (%)
Se,f (À)
Abs. Config.g
1
2
3
4
5
Ca(H-DBTA)2
Ca(H-DBTA)2
Ca(H-DPTTA)2
Ca(H-DPTTA)2
Ca(H-DPTTA)2
3×EtOAc/3×EtOH
3×MeCN/3×EtOH
3×EtOAc/3×EtOH/10%H2O
6×EtOH/10%H2O
3×MeCN/3×EtOH/10%H2O
Ca(1)2(H-DBTA)2
Ca(1)2(H-DBTA)2
Ca(1)2(H-DPTTA)2
Ca(1)2(H-DPTTA)2
Ca(1)2(H-DPTTA)2
(67) 14
(72) 21
(68) 44
(65) 27
(55) 21
(6) 13
(0.04) 0.02
(0.22) 0.16
(0.26) 0.20
(0.40) 0.21
(0.21) 0.13
(R)
(S)
(S)
(S)
(S)
(31) 76
(38) 45
(61) 77
(38) 62
See Table 1 for footnotes.
TABLE 3. Resolution of 1-n-butyl-3-methyl-3-phospholene 1-oxide (1) with Ca(DBTA) or Ca(DPTTA) [(À)-6 or (À)-7]
Resolving
agent
Diastereomer
complexb
Yieldc,f
(%)
Abs.
Entry
Eq.
Solventsa
eed,f (%)
Se,f (À)
Config.g
1
2
3
4
CaDBTA
0.5
0.5
3×MeCN/3×EtOH/10%H2O Ca(1)(DBTA)
3×EtOAc/3×EtOH/10%H2O Ca(1)(DPTTA)
Ca5(1)2(DPTTA)5
1.25 3×MeCN/3×EtOH/10%H2O Ca5(1)2(DPTTA)5
(25) 11*
(41) 12
(79) 48
(80) 3
(58) 75* (0.14) 0.08*
(51) 55
(44) 75
(56) 56
(S)
(S)
(S)
(S)
CaDPTTA
CaDPTTA
CaDPTTA
(0.21) 0.07
(0.34) 0.36
(0.44) 0.02
1.25 6×EtOH/10%H2O
See Table 1 for footnotes.
*Diastereomeric complex was purified with one recrystallization.
Chirality DOI 10.1002/chir

RESOLUTION OF 1-N-BUTYL-3-METHYL-3-PHOSPHOLENE 1-OXIDE
177
Theoretical Calculations
The composition of the diastereomers was determined by 1H
NMR. This depended on the resolving agent [(À)-2 or (À)-3]
and the solvent used. In all but one instance, diastereomers
obtained contained the n-butyl-3-phospholene oxide (1) and
the TADDOL derivatives [(À)-2 or (À)-3] in a ratio of 1:2 (Ta-
ble 1, Entries 1 and 3–6). The resolution of n-butyl-phospholene
oxide 1 with TADDOL [(À)-2] in isopropyl alcohol afforded a
diastereomer of (1)2·[(À)-2]3 (Table 1, Entry 2). In the case
of all resolution experiments, the half equivalent methodol-
ogy46 was followed; hence, considering the composition of the
diastereomeric complexes, 0.75-1 equivalents of the resolving
agents [(À)-2 or (À)-3] were used (Table 1).
Quantum chemical calculations at the Density Functional Theory
(DFT) level choosing the PBE0 functional40,41 and the 6-311++G** basis
set were performed. Vertical excitation energies, as well as oscillator
and rotator strengths (in the velocity gauge) were calculated using the
time-dependent DFT method42 with the same functional and basis set.
Since the absorption and CD spectra were measured in acetonitrile, all
the DFT calculations were performed invoking the polarized continuum
model43 with acetonitrile as the solvent. All calculations were carried
out with the Gaussian 09 package.44
RESULTS AND DISCUSSION
Resolution of 1-n-Butyl-3-methyl-3-phospholene 1-Oxide
(1) With TADDOL Derivatives [(À)-2 and (À)-3]
The diastereomeric complexes obtained were analyzed by
chiral GC after regenerating the 3-phospholene oxide (1)
from the sample of the corresponding diastereomer by pre-
parative thin-layer chromatography (TLC) using silica gel
and 3% of methanol in dichloromethane as eluent. The ee
values were in the range of 26–62% after crystallization. The
enantiomeric purity increased significantly to 70–84% after
two recrystallizations (Table 1).
The resolution of 3-phospholene oxide 1 was attempted
with TADDOL and spiro-TADDOL [(À)-2 and (À)-3] in dif-
ferent solvents. Results of the successful resolutions leading
to crystalline diastereomers are summarized in Table 1.
Following the resolution method developed in our research
group,30,31 the resolution of 1-n-butyl-3-methyl-3-phospholene
1-oxide (1) was attempted first with TADDOL derivatives
[(À)-2 and (À)-3] in a mixture of ethyl-acetate and hexane.
According to this procedure, the mixture of racemic 3-
phospholene 1-oxide (1) and TADDOL or spiro-TADDOL
[(À)-2 or (À)-3, respectively] was dissolved in hot ethyl ace-
tate. The corresponding diastereomeric complex precipitated
after the addition of hexane to the mixture.
Previously, it was established in our research group that
the replacement of ethyl acetate by other solvents may
influence the efficiency of the resolutions of the aryl-, alkyl-,
and alkoxy-substituted-3-phospholene oxides with TADDOL
derivatives [(À)-2 and (À)-3].45 Hence, the resolution of the
3-phospholene oxide (1) with TADDOL derivatives [(À)-2
or (À)-3] was also attempted using methanol, ethanol, and
isopropyl alcohol as the solvent. In these cases, the mixtures
of the racemic 3-phospholene oxide (1) and TADDOL deriva-
tives [(À)-2 or (À)-3] were dissolved in hot alcohol, the mix-
tures were cooled to 26°C, whereupon crystalline
diastereomeric complex appeared (Scheme 1).
It was found that the resolving agent [(À)-2 or (À)-3] and
the solvent used influenced the efficiency of the resolution,
as well as the enantiomer of the 3-phospholene oxide (1)
incorporated in the diastereomeric complex. The highest
resolving capability (S = 0.52) was achieved with spiro-
TADDOL [(À)-3] in ethyl acetate and hexane (Table 1, Entry
3). Generally, a decrease in resolving capability (S) was
observed, when different alcohols were used as the solvent
instead of a mixture of ethyl acetate and hexane. However,
it is noteworthy that in a few instances the use of different
solvents with the same resolving agent [(À)-2 or (À)-3]
led to complex formation with different enantiomers of the
3-phospholene oxide (1). Resolution with spiro-TADDOL
[(À)-3] in isopropyl alcohol or in a mixture of ethyl acetate
and hexane afforded (S)-n-butyl-3-methyl-3-phospholene 1-
oxide [(S)-1], while the resolution in methanol or in ethanol led
to the other antipode [(R)-1] (Table 1, Entries 3 and 6 or 4 and 5).
The phenomenon that TADDOL-derivatives [(À)-2 or (À)-3]
may form diastereomeric complexes with both antipodes of the
3-phospholene oxide (1) in different solvents allowed us to de-
velop resolution procedures to obtain both enantiomers from
racemic 1-n-butyl-3-methyl-3-phospholene 1-oxide (1).
In all cases, the diastereomers formed were filtered off
from the mother liquors after 3 h of crystallization. The diaste-
reomeric complexes were purified further by two recrystalli-
zations from the corresponding solvents. The 3-phospholene
oxide (1) was recovered from the corresponding diastereo-
mers by column chromatography using silica gel and 3% of
methanol in dichloromethane as the eluent.
Both enantiomers of 1-n-butyl-3-methyl-3-phospholene
1-oxide (1) could be prepared by resolution with spiro-
TADDOL [(À)-3] using either a mixture of ethyl acetate
and hexane, or ethanol. So the racemic n-butyl-3-
phospholene 1-oxide (1) was resolved with 1 equivalent
Scheme 1. General resolution procedure for racemic 3-phospholene oxide (1) using TADDOL derivatives [(À)-2 and (À)-3].
Chirality DOI 10.1002/chir

178
BAGI ET AL.
of spiro-TADDOL [(À)-3] in a mixture of ethyl acetate and
hexane to afford (À)-(S)-1-n-butyl-3-methyl-3-phospholene
1-oxide [(S)-1] with an ee of 95% and in a yield of 52%
after the purification of the diastereomeric complex
[(À)-1]·[(À)-3]2 by three recrystallizations and decomplexation
by column chromatography. To obtain the other antipode, the
mother liquors of the crystallization and recrystallizations were
combined, the solvent was evaporated to obtain a 2:3 mixture
of spiro-TADDOL [(À)-3] and (R)-n-butyl-3-phospholene 1-oxide
[(R)-1] with an ee of 32% and in a yield of 121% (based on the half
of racemic 1 that is regarded to be 100% for each antipode). To
this mixture a 0.65 equivalent of spiro-TADDOL [(À)-3] was
added to have 1.32 equivalent of spiro-TADDOL [(À)-3] in total,
and the resolution was accomplished in ethanol to afford (+)-(R)-
1-n-butyl-3-methyl-3-phospholene 1-oxide [(R)-1] with an ee of
98% and in a yield of 11% after the purification of the diastere-
omeric complex [(+)-1]·[(À)-3]2 by three recrystallizations and
the decomplexation by column chromatography (Scheme 2).
or (À)-5] (Scheme 3). The crystalline diastereomers were
filtrated off after 24 h. 1H NMR studies proved, that the composi-
tion of the diastereomeric complexes were Ca(1)2(H-DBTA)2 or
Ca(1)2(H-DPTTA)2. These diastereomers [Ca(1)2(H-DBTA)2 or
Ca(1)2(H-DPTTA)2] were purified further by two digestions
(i.e., stirring the crystals in the corresponding solvent at 26°C
for 24 h). The 3-phospholene oxide (1) was recovered by
treating the dichloromethane solution of the corresponding
complex Ca(1)2(H-DBTA)2 or Ca(1)2(H-DPTTA)2 with 10%
aqueous ammonia. The ee of the 3-phospholene enantiomers
(1) was determined by chiral GC.
In the case of the resolutions with Ca(H-DBTA)2 [(À)-4], the
enantiomer of the 3-phosphospholene oxide (1) incorporated in
the diastereomeric complex Ca(1)2(H-DBTA)2 was dependent
on the solvent used. The (R)- or the (S)-n-butyl-3-phospholene 1-
oxide [(R)-1 or (S)-1] could be obtained with Ca(H-DBTA)2 using
either a mixture of ethyl acetate and ethanol, or a mixture of ace-
tonitrile and ethanol, respectively (Table 2, Entries 1 and 2).
The highest ee and resolving capability (S) values obtained with
Ca(H-DBTA)2 or Ca(H-DPTTA)2 [(À)-4 or (À)-5] were 77%
and 0.21 after purification by two digestions (Table 2, Entry 4).
Considering the resolving capability (S), the application of
Ca(H-DPTTA)2 [(À)-5] seems to be more advantageous
than that of Ca(H-DBTA)2 [(À)-4] (Compare Table 2,
Entries 1–2 and 3–5).
Resolution of 1-n-Butyl-3-methyl-3-phospholene 1-Oxide
(1) With Calcium Hydrogen (À)-O,O’-Dibenzoyl- or
(À)-O,O’-di-p-Toluoyl-(2R,3R)-tartrate [(À)-4 or (À)-5]
The resolution of the 3-phospholene oxide (1) was also
attempted with the acidic Ca2+-salts of (À)-O,O’-dibenzoyl- or
(À)-O,O’-di-p-toluoyl-(2R,3R)-tartaric acid [(À)-4 or (À)-5].
The results are summarized in Table 2.
Ca(H-DBTA)2 [(À)-4] was prepared in advance as described
in our earlier studies,33,34 while Ca(H-DPTTA)2 [(À)-5] was al-
ways prepared in situ by the reaction of (À)-O,O’-di-p-toluoyl-
(2R,3R)-tartaric acid and CaO in a 10:1 mixture of ethanol and
water. The racemic 3-phospholene oxide (1) in ethanol, ethyl
acetate or acetonitrile was added to the hot ethanolic solution
of 0.25 equivalents of Ca(H-DBTA)2 or Ca(H-DPTTA)2 [(À)-4
Resolution of 1-n-Butyl-3-methyl-3-phospholene 1-Oxide
(1) With Calcium (À)-O,O’-Dibenzoyl- and (À)-O,O’-di-p-
Toluoyl-(2R,3R)-tartrate [(À)-6 and (À)-7]
Based on our earlier study,34 the resolution of n-butyl--3-
phospholene oxide (1) was also attempted with the neutral
Ca2+ salts of (À)-O,O’-dibenzoyl- and (À)-O,O’-di-p-toluoyl-
(2R,3R)-tartaric acid [(À)-6 and (À)-7], as these resolving
Scheme 2. The complete resolution process of 1-n-butyl-3-methyl-3-phospholene 1-oxide (1) with spiro-TADDOL (À)-3.
Chirality DOI 10.1002/chir

RESOLUTION OF 1-N-BUTYL-3-METHYL-3-PHOSPHOLENE 1-OXIDE
179
Scheme 3. General resolution procedure for racemic 3-phospholene oxide (1) using Ca(H-DBTA)2 or Ca(H-DPTTA)2 [(À)-4 or (À)-5].
agents have also been found suitable for the resolution of some
3-phosholene oxides. The results of the successful resolutions
leading to crystalline diastereomers are summarized in Table 3.
In all instances, the Ca(DBTA) and Ca(DPTTA) [(À)-6 and
(À)-7] were prepared in situ by the reaction of a 1:1 ratio of
CaO and (À)-O,O’-dibenzoyl- or (À)-O,O’-di-p-toluoyl-
(2R,3R)-tartaric acid in a mixture of ethanol and water. To this
solution was added the racemic 3-phospholene oxide (1) in
ethanol, ethyl acetate, or acetonitrile. The crystalline diaste-
reomeric complexes formed were removed from the mother
liquor by filtration after 24 h. The diastereomers were puri-
fied by digestions. In one case, only one purification step
was applied, as the corresponding diastereomeric complex
may have dissolved completely during the second digestion
(Table 3, Entry 1) (Scheme 4).
Single-Crystal X-Ray Analysis of Diastereomeric Complex
[(S)-1]·(spiro-TADDOL)
X-ray quality crystals could only be grown by mixing spiro-
TADDOL [(À)-3] with a large excess of (S)-1-n-butyl-3-
methyl-3-phospholene 1-oxide [(S)-1] in ethyl acetate. The slow
evaporation of solvent afforded a single crystal incorporating
(S)-1-n-butyl-3-phospholene 1-oxide [(S)-1] and spiro-TADDOL
[(À)-3] in a ratio of 1:1, contrary to the diastereomeric complex
[(S)-1]·(spiro-TADDOL)2 obtained during the resolution experi-
ments by reacting the 1-n-butyl-3-phospholene 1-oxide (1) with
an equimolar amount of spiro-TADDOL [(À)-3] (Table 1, Entry 3).
The results from the crystal structure determination of the
1 : spiro-TADDOL 1:1 molecular associate (Fig. 2), apart from
revealing the respective molecular structures, as well as abso-
lute configurations of its components, also give an insight into
the mode of binding and the underlying physical phenomenon
of molecular recognition. The disordered alkyl tail on the
P-heterocycle (1) underlines the possibility of alternating
conformations of this moiety. This, apart from an obvious
entropic gain for these crystals, also indicates that the
phospholene rings do have some intrinsic pseudo-rotatory
ability. This kind of inherent disorder gives an indication as
to the origin of the relative low scattering power of the
crystals. The recognition of 1 is apparently facilitated by the
H-bridges. These, apart from the expected internal O—H … O
bridge lending some additional stiffness to the spiro-TADDOL
backbone bind the phospholene oxide O-acceptor to the
remaining OH of the master molecule, another classic recog-
nition motif of the TADDOL-type host molecules.
The composition of the diastereomeric complexes was
1
determined by H NMR. The ratio of the 3-phospholene oxide
(1) and the CaDBTA or CaDPTTA [(À)-6 or (À)-7] was 1:1 (Ta-
ble 3, Entries 1 and 2), but diastereomers with a ratio of 2:5 were
also formed (Table 3, Entries 3–4). In all instances, the (S)-n-bu-
tyl-3-phospholene oxide [(S)-1] was obtained by resolution with
CaDBTA or CaDPTTA [(À)-6 and (À)-7] (Table 3).
In all but one instance, using CaDBTA and CaDPTTA
[(À)-6 and (À)-7], the resolving capability (S) was in the range
of 0.02–0.08 after purification (Tables 3), which is lower than
the results obtained with the corresponding acidic Ca2+ salts
[(À)-4 and (À)-5] (Table 2). The difference in the resolving
capability (S) may be explained by the lower yields (3–12%)
obtained with CaDBTA and CaDPTTA [(À)-6 and (À)-7].
However, among the acidic and the neutral Ca2+-salts of the
(À)-O,O’-dibenzoyl- or (À)-O,O’-di-p-toluoyl-(2R,3R)-tartaric
acid [(À)-4 - (À)-7], the highest resolving capability (S = 0.36)
was obtained during the resolution of n-butyl-3-phospholene
oxide (1) with CaDPTTA in a mixture of ethanol and water
(Table 3, Entry 3).
CD Spectra of 1-n-Butyl-3-methyl-3-phospholene 1-Oxide
(1)
The UV absorption and CD spectra of the 1-n-butyl-3-
methyl-3-phospholene 1-oxide (1) were recorded (Table 4)
Scheme 4. General resolution procedure for racemic 3-phospholene oxide (1) using CaDBTA or CaDPTTA [(À)-6 or (À)-7].
Chirality DOI 10.1002/chir

180
BAGI ET AL.
Fig. 2. Ray tracing perspective view of the crystallographic asymmetric
unit of the 1 : spiro- TADDOL 2:2 molecular associate in atomic displacements
representation at the 25% probability level. H-bonds are marked in pale broken
lines, while all H atoms are omitted for the sake of visibility. Disordered
atomic positions of 1 n-butyl tails are visible at both independent molecules.
Absolute configurations are S for both 1 molecules and are all R for all chiral
centers of both spiro-TADDOL hosts.
Fig. 3. Optimized geometry for the lowest-energy conformer of (S)-1-ethyl-
3-methyl-3-phospholene 1-oxide [(S)-1]. Selected bond lengths (Å) and angles
(°) are as follows: P1-O1 1.510, P1-C1 1.836, C1-C2 1.501, C2-C3 1.339, C3-C4
1.492, C3-C5 1.508, C5-P1 1.833, P1-C6 1.819; C1-P1-C5 95, O1-P1-C6 114; O1-
P1-C6-C7 56, O1-P1-C1-C2 140.
and analyzed. To determine the absolute configuration of
the 3-phospholene 1-oxide (1), quantum chemical calculations
at the DFT level choosing the PBE0 functional and the
6-311++G** basis set were performed.
In our calculations, simplified model compounds were
considered. We modeled 1-n-butyl-3-methyl-3-phospholene
1-oxide (1) by 1-ethyl-3-methyl-3-phospholene 1-oxide (Fig. 3.).
This simplification significantly reduces the computation time,
but it is not expected to affect the assignment of absolute con-
figuration because the spectral properties of the compounds
in the UV-visible region are almost independent of the substitu-
ent. This is well justified by the fact that the measured spectrum
was in good agreement with that of the n-propyl-substituted de-
rivative available from our previous studies.31
First, a systematic conformation analysis was carried out
for the simplified molecule. Three low-energy conformers
were found for the model compound, which lie at ca. 5 kJ/mol
above the most stable one. These conformers were considered
in the subsequent calculations. The geometries for all of them
were optimized, and excitation energies and the transition mo-
ments were calculated. The theoretical UV absorption and CD
curves were obtained as superpositions of individual Gaussian
functions centered at the wavelengths of the theoretically calcu-
lated transitions and having heights proportional to the corre-
sponding calculated oscillator and rotator strengths,
respectively. The spectra of the individual conformers were
Boltzmann-weighted. The simulated spectra were normalized
so that the height of the dominating peak is identical to that of
the experimental spectra; beside this, the spectra were shifted
to the red so that the position of the most intense band of the ab-
sorption spectra was identical.
while the calculated and measured spectra are compared in
Fig. 4. The agreement of the experimental and theoretical ab-
sorption spectra of the compounds is satisfactory and justifies
the selection of the applied theoretical model. The sign of the
dominant features in the measured and computed CD spectra
are identical, thus the absolute configuration of the synthe-
sized compounds corresponds to that for the isomers
considered in the calculations.
The dominant features of the spectra could be assigned on
the basis of the theoretical calculations. The intense negative
band at 238 nm in the CD spectrum belongs to two close-lying
transitions, which can be described as excitations from the πC=C
and noxygen orbitals to low-lying diffuse virtual orbitals. These
transitions have low oscillator strengths, but high rotator
strengths, leading only to a weak absorption in the UV spec-
trum at the position of their intense signal in the CD spectrum.
CONCLUSIONS
Resolution procedures were elaborated for 1-n-butyl-3-methyl-
3-phospholene 1-oxide (1) using TADDOL-derivatives [(À)-2
and (À)-3], as well as acidic and neutral Ca2+-salts of the
(À)-O,O’-dibenzoyl- or (À)-O,O’-di-p-toluoyl-(2R,3R)-tartaric acid
[(À)-4 - (À)-7]. It was investigated how the solvents influence
the efficiency of the resolutions. Both antipodes of 1-n-butyl-3-
phospholene 1-oxide (1) were prepared with an ee >95% by
exploiting the different antipode preference of the
TADDOL-derivatives [(À)-2 and (À)-3] in different solvents.
The optimized geometry and selected geometrical parame-
ters for the most stable conformer are presented in Fig. 3,
TABLE 4. Observed UV and CD spectral bands of 1-n-butyl-3-methyl-3-phospholene 1-oxide (1)
UV spectra CD spectra
ε [dm3mol–1cm–1 Δε [dm3mol–1cm–1
]
λ [nm]
]
λ [nm]
1-n-butyl-3-methyl-3-phospholene 1-oxide (1)
191
216 (sh)
3200
1300
Negative Cotton effect
215
238
9.6
À8.3
Chirality DOI 10.1002/chir

RESOLUTION OF 1-N-BUTYL-3-METHYL-3-PHOSPHOLENE 1-OXIDE
181
Fig. 4. Calculated (dashed line) UV absorption (left) and CD (right) spectra of (S)-1-ethyl-3-methyl-3-phospholene 1-oxide together with the respective measured
(solid line) spectra of (À)-1-n-butyl-3-methyl-3-phospholene 1-oxide [(À)-1] in acetonitrile.
13. Takaya H, Mashima K, Koyano K, Yagi M, Kumobayashi H, Taketomi T,
The absolute configuration of 3-phospholene oxide enantio-
mer 1 was determined by X-ray crystallography and CD spec-
troscopy using quantum chemical calculations for the analysis
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ACKNOWLEDGMENTS
Contract grant sponsor: Hungarian Scientific Research Fund
(OTKA); Contract grant numbers: K83118, K104769, K108752,
and K75869.
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SUPPORTING INFORMATION
Additional supporting information may be found in the
online version of this article at the publisher’s web-site.
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Chirality DOI 10.1002/chir