Preparation of optically active six-membered P-heterocycles: A 3-phosphabicyclo[3.1.0] hexane 3-oxide, a 1,2-dihydrophosphinine 1-oxide, and a 1,2,3,6-tetrahydrophosphinine 1-oxide

Article abstract of DOI:10.1002/hc.21080

The earlier described a 3-methyl-1-phenyl-3-phospholene 1-oxide (1) → 6,6-dichloro-1-methyl-3-phenyl-3-phosphabicyclo[3.1.0]hexane 3-oxide (2) → 4-chloro-1-phenyl-1,2-dihydrophosphinine 1-oxide (3) → 4-chloro-5-methyl-1- phenyl-1,2,3,6-tetrahydrophosphinine 1-oxide (4) reaction sequence was investigated from the point of view of preparing optically active intermediates/products (2-4). In principle, both the resolution of the corresponding racemic products and the transformation of the optically active starting materials are suitable approaches for the preparation of optically active six-membered P-heterocycles (2-4). Racemization occurred during the dichlorocyclopropanation reaction of (S)-3-methyl-1-phenyl-3-phospholene 1-oxide ((S)-1), but the thermolytic ring opening of (-)-2, and the selective reduction of α,β-double bond of (-)-3 did not cause the loss of optical activity. First in the literature, the resolution of a 3-phosphabicyclo[3.1.0] hexane 3-oxide (2) and a 1,2,3,6-tetrahydrophosphinine 1-oxide (4) was elaborated.

Full text of DOI:10.1002/hc.21080

Heteroatom Chemistry
Volume 24, Number 3, 2013
Preparation of Optically Active Six-Membered
P-Heterocycles: A 3-Phosphabicyclo[3.1.0]
hexane 3-oxide, a 1,2-Dihydrophosphinine
1-oxide, and a 1,2,3,6-Tetrahydrophosphinine
1-oxide
Pe´ter Bagi, Andrea Laki, and Gyo¨rgy Keglevich
Department of Organic Chemistry and Technology, Budapest University of Technology and
Economics, 1521 Budapest, Hungary
Received 5 September 2012; revised 21 December 2012
this article online at wileyonlinelibrary.com. DOI
ABSTRACT: The earlier described a 3-methyl-1-
10.1002/hc.21080
phenyl-3-phospholene 1-oxide (1) → 6,6-dichloro-
1-methyl-3-phenyl-3-phosphabicyclo[3.1.0]hexane
3-oxide (2) → 4-chloro-1-phenyl-1,2-dihydrophos-
phinine 1-oxide (3) → 4-chloro-5-methyl-1-phenyl-
INTRODUCTION
1,2,3,6-tetrahydrophosphinine 1-oxide (4) reaction
sequence was investigated from the point of view
of preparing optically active intermediates/products
(2–4). In principle, both the resolution of the corre-
sponding racemic products and the transformation
of the optically active starting materials are suitable
approaches for the preparation of optically active
six-membered P-heterocycles (2–4). Racemization oc-
curred during the dichlorocyclopropanation reaction
of (S)-3-methyl-1-phenyl-3-phospholene 1-oxide ((S)-
1), but the thermolytic ring opening of (−)-2, and the
selective reduction of α,β-double bond of (−)-3 did not
cause the loss of optical activity. First in the literature,
the resolution of a 3-phosphabicyclo[3.1.0]hexane
Optically active phosphine oxides form an impor-
tant class within organophosphorous compounds,
as they can be converted to the corresponding
phosphines that can be ligands in transition metal
complexes. Many optically active transition metal–
phosphine complexes are used as catalysts in enan-
tioselective homogeneous catalytic reactions, such
as hydrogenation and hydroformylation [1–3].
As optically active P-chiral compounds cannot
be found in the nature, the primary source of these
compounds is asymmetric synthesis or resolution
[4]. Several methods are reported for the resolution
of P-chiral compounds based on the formation of di-
asteromeric salts, molecular and coordination com-
plexes [5]. Chiral phosphonium salts can be resolved
by diastereomeric salt formation with the silver salts
of optically active acids [6]. The resolution of acyclic
phosphine oxides and phosphinates can be accom-
plished by molecular complex formation with 1,1ꢁ-
binaphthalene-2,2ꢁ-diol (BINOL) [7]. Several tran-
sition metal–chiral amine complexes were success-
fully used for the separation of the enantiomers of
chiral phosphines [8].
3-oxide (2) and
1-oxide (4) was elaborated. 2013 Wiley Periodicals,
a 1,2,3,6-tetrahydrophosphinine
ꢀC
Inc. Heteroatom Chem 24:179–186, 2013; View
Correspondence to: Gyo¨rgy Keglevich; e-mail: gkeglevich@
mail.bme.hu.
Contract grant sponsor: Hungarian Scientific and Research
Fund.
Contract grant number: OTKA K83118 and K104769.
ꢀC
2013 Wiley Periodicals, Inc.
179

180 Bagi, Laki, and Keglevich
In the literature, only a few examples can be
found for the resolution of P-chiral phosphine oxides
without acidic or basic character via diastereomer
formation. These methods usually require the appli-
cation of expensive resolving agents (e.g., BINOL)[7]
or give the enantiomers in low enantiomeric excess
(ee). Recently, our research group developed a
resolution method for P-chiral cyclic phosphine
oxides, namely aryl-, alkyl-, and alkoxy-3-methyl-3-
phospholene 1-oxides, using cheap and easily avail-
able tartaric acid derivatives. Calcium hydrogen
(−)-O,Oꢁ-dibezoyl-(2R,3R)-tartarate [Ca(H-DBTA)2]
(5) and calcium hydrogen (−)-O,Oꢁ-di-p-tolyl-
(2R,3R)-tartarate [Ca(H-DPTTA)2] (6) were used for
the resolution of 3-phospholene oxides via diastere-
omeric coordination complex formation [9, 10].
The (4R,5R)-(−)-4,5-bis(diphenylhydroxymethyl)-
2,2-dimethyldioxolane (TADDOL) (7) and (2R,3R)-
(−)-α,α,αꢁ,αꢁ-tetraphenyl-1,4-dioxaspiro [4.5] decan-
2,3-dimethanol (spiro-TADDOL) (8) were also
found suitable for the resolution of phospholene
oxides based on diastereomeric molecular complex
formation [11, 12]. The resolution of a 3:1 mixture
of 3-methyl- and 5-methyl-4-chloro-1-phenyl-1,2-
dihydrophosphinine 1-oxides (3A and 3B) was also
accomplished with (−)-spiro-TADDOL (8) [13]. To
the best of our knowledge, these methods are the
only examples in the literature for the resolution
of P-chiral cyclic phosphine oxides with high ee
and good yield. Moreover, the methods developed
by us are not only efficient and practical in the
sense of simplicity and low cost, but may also be
of more general value. It seems to be probable that
our procedure may also be suitable for the optical
resolution of other phosphine oxides.
FIGURE 1 The P-heterocycles and resolving agents used
in our study.
In this paper, strategies for the preparation
of optically active six-membered P-heterocycles,
such as a 3-phosphabicyclo[3.1.0]hexane 3-oxide
(2), a 1,2-dihydrophosphinine 1-oxide (3A and
3B), and a 1,2,3,6-tetrahydrophosphinine 1-oxide
(4) are investigated. This work includes devel-
opment of suitable resolution methods for these
six-membered P-heterocycles (2–4) using [Ca(H-
DBTA)2] (5), (−)-[Ca(H-DPTTA)2] (6), TADDOL (7),
and spiro-TADDOL (8) as resolving agents (Fig. 1).
The question was whether the resolution should be
done in the starting material (1, 2, 3), or product
(2, 3, 4) stage to obtain optically active 2–4. It was
also investigated, if the optical activity is preserved
or racemization occurs during the individual steps
of the 1 → 2 → 3 → 4 reaction sequence.
RESULTS AND DISCUSSION
According to another synthesis strategy,
(1R,2S,5R)-(−)-menthol and (S)-(−)-α-phenylethy-
lamine were utilized as chiral building blocks to syn-
thesize an optically active 3-phospholene 1-oxide,
and a 3-phosphabicyclo[3.1.0]hexane 3-oxide [14].
Five-membered P-heterocycles are versatile
starting materials for six-membered P-heterocycles,
phosphinine derivatives. Dichlorocarbene addition
on the double bond of 3-methyl-1-phenyl-3-
phospholene 1-oxide (1) afforded 6,6-dichloro-
1-methyl-3-phenyl-3-phosphabicyclo[3.1.0]hexane
3-oxide (2) in a diastereoselective manner [15].
Thermolytic opening of the cyclopropane ring of
phosphabicyclohexane oxide 2 led to a 3:1 mixture
of the double bond isomers of 4-chloro-1-phenyl-
1,2-dihydrophosphinine 1-oxides (3A and 3B) [15].
The 3-methyl-1,2-dihydrophosphinine 1-oxide 3A
may be converted to the corresponding 1,2,3,6-
tetrahydrophosphinine 1-oxide (4) by selective
reduction of the α,β-double bond by borane [16].
First, we prepared the 1-phenyl-3-phospholene ox-
ide dichlorocarbene adduct (2) having the dichloro-
cyclopropane ring and the P=O function in posi-
tion trans in a racemic form as described earlier
using chloroform and 50% sodium hydroxide un-
der phase transfer catalytic conditions [15]. Then
we tried to resolve the phosphabicyclo[3.1.0]hexane
3-oxide (2) so obtained. To the solution of cal-
cium hydrogen (−)-O,Oꢁ-dibezoyl-(2R,3R)-tartarate
[Ca(H-DBTA)2] (5) in a 5:1 mixture of ethanol
and water, 4 equivalents of racemic phosphabicy-
clo[3.1.0]hexane 3-oxide 2 was added. After crys-
tallization at 26◦C, the precipitate was filtered off
to afford the corresponding complex Ca[(−)-2]2-
(H-DBTA)2. The coordination complex was further
purified by digestion: the crystalline complex was
stirred in a 10:1 mixture of ethanol–water at room
temperature. The complete dissolution of the crys-
tals was not necessary; the digestion was found
Heteroatom Chemistry DOI 10.1002/hc

Preparation of Optically Active Six-Membered P-Heterocycles 181
TABLE 1 Preparation of Optically Active Six-Membered P-Heterocycles (2–4)
By optical resolution of the products
Entry
Product
Resolving Agent
Solvent
Yield (%)a
Enantiomeric Excess (%)b
Specific Rotation
1
2
3
4
5
6
2
2
2
3
4
4
(−)-Ca(H-DBTA)2
(−)-Ca(H-DPTTA)2
(−)-spiro-TADDOL
(−)-spiro-TADDOL
(−)-Ca(H-DPTTA)2
(−)-TADDOL
EtOH/water
EtOH/water
EtOAc/hexane
Acetone/hexane
EtOH/water
30
30
58
39
28
21
67
22
55
87
99
65
(−)
(+)
(+)
(−)
(+)
(−)
EtOAc/hexane
Starting from optically active substrate
Starting Material
Product
Enantiomeric
Excess (%)b
Specific
Rotation
Synthetic
Route
Yield
(%)a
Enantiomeric
Excess (%)b
Specific
Rotation
Entry
No.
No.
7
8
9
10
1
1
2
3
93
93
67
87
(−)
(−)
(−)
(−)
1→2 Method A
1→2 Method B
2→3
2
2
3
4
34
34
20
20
0
0
67
87
(+)
(−)
3→4
aYield of the enantiomers of the six-membered P-heterocycles (2–4) is based on the half of the racemate that is regarded to be 100% for each
antipode.
bEnantiomeric excess was determined by chiral HPLC.
sufficient for the separation of the diastereomeric
coordination complexes. The diastereomeric ex-
cess (de) of the Ca[(−)-2]2(H-DBTA)2 was 63% af-
ter first precipitation, and 67% after the diges-
tion. The phenyl-phosphabicyclo[3.1.0]hexane oxide
(−)-2 was recovered by treating the chloroform so-
lution of the complex with 10% aqueous ammo-
nia to afford (−)-2 with an ee of 67% in a yield of
30% (Scheme 1/(1); Table 1, entry 1). The resolu-
tion of racemic 2 was also accomplished with cal-
cium hydrogen (−)-O,Oꢁ-di-p-tolyl-(2R,3R)-tartarate
[Ca(H-DPTTA)2] (6) according to the procedure de-
scribed above, except that the resolving agent was
prepared in situ by the reaction of DPTTA and
half equivalent of CaO in a 10:1 mixture of ethanol
and water. The decomplexation of the Ca[(+)-2]2(H-
DPTTA)2 led to (+)-2 with an ee of 22% in a
yield of 30% (Table 1, entry 2). Interestingly, the
(−)-Ca(H-DBTA)2 (5) formed a coordination com-
plex with enantiomer (−)-2 whereas (−)-Ca-
(H-DPTTA)2 (6) preferred complex formation with
the other antipode [(+)-2]. Hence, both antipodes
of 2 could be prepared. The (−)-spiro-TADDOL (8)
could also be applied successfully for the resolu-
tion of racemic 2. During the resolution procedure,
hexane was added to the solution of racemic 2
and half equivalent of (−)-spiro-TADDOL (8) in hot
ethyl acetate, whereupon the molecular complex of
[(+)-2](spiro-TADDOL) precipitated. Column chro-
matography of the complex afforded (+)-2 with an
ee of 55% and yield of 58% (Scheme 1/(1); Table
1, entry 3). The resolution of racemic 2 was also
attempted with (−)-TADDOL (7), but in this case no
crystalline molecular complex was formed.
Then we tried to convert the (S)-antipode of 3-
phospholene oxide 1 to optically active 2 by dichloro-
carbene addition. The dichlorocarbene was gen-
erated under phase transfer catalytic conditions
from chloroform with aqueous sodium hydrox-
ide (method A; Table 1, entry 7) or from sodium
trichloroacetate (method B; Table 1, entry 8). As we
observed, racemization occurred in both cases. It re-
mains a question, if the racemization occurs in the
starting material (1), or the product stage (2).
On the basis of the above experiences, res-
olution is the only way for the preparation of
the optically active 6,6-dichloro-1-methyl-3-phenyl-
3-phosphabicyclo[3.1.0]hexane 3-oxide (2), as the
dichlorocarbane addition on the double bond of
optically active 3-methyl-1-phenyl-3-phospholene 1-
oxide (1) led to racemic 3-phosphabicyclo[3.1.0]-
hexane oxide (2). The resolution methods developed
were suitable for the preparation of both antipodes
of phosphabicyclo[3.1.0] hexane oxide (2).
Preparation of Optically Active 3-Methyl- and
5-Methyl-4-chloro-1-phenyl-1,2-
dihydrophosphinine 1-oxides (3A and 3B)
First the title product (3A and 3B) was prepared by
resolution, then by the thermolysis of the optically
active phospholene–dichlorocarbene adduct [(−)-2].
Heteroatom Chemistry DOI 10.1002/hc

182 Bagi, Laki, and Keglevich
the double bond isomers (3A and 3B) did not change
[13]. It was assumed that the sign of the rotation
for the two isomers (3A and 3B) is the same. The
phenomenon that chiral phosphine oxides with
similar P-neighborhood may have similar sign for
the optical rotation is studied by us by quantum
chemical calculations.
The thermolytic cyclopropane ring opening
of the optically active (−)-6,6-dichloro-1-methyl-
3-phenyl-3-phosphabicyclo[3.1.0]hexane
3-oxide
[(−)-2] with an ee of 67% took place without
racemization and afforded 3:1 mixture of
a
(+)-3-methyl and 5-methyl-4-chloro-1-phenyl-1,2-
dihydrophosphinine 1-oxides ((+)-3A and (+)-3B)
in 20% yield and with an ee of 67% for both double
bond isomers (Scheme 1/(2); Table 1, entry 9).
Both the thermolysis of optically active phos-
phabicyclo[3.1.0]hexane 3-oxide 2, and the reso-
lution of 1-phenyl-1,2-dihydrophosphinine 1-oxides
(3A and 3B) were found suitable for the prepara-
tion of optically active dihydrophosphinine oxides
3A and 3B. Considering green chemical and envi-
ronment friendly aspects, resolution in the start-
ing material stage is preferable. However, resolu-
tion in the product stage provides 1-phenyl-1,2-
dihydrophosphinine 1-oxides (3A and 3B) in a
higher ee.
Preparation of Optically Active 4-Chloro-1-
phenyl-5-methyl-1,2,3,6-tetrahydrophosphinine
1-Oxide (4)
The resolution of racemic 1-phenyl-1,2,3,6-
tetrahydrophosphinine 1-oxide (4) and the reduction
of optically active 3A were attempted to prepare
the enantiomers of 1,2,3,6-tetrahydrophosphinine
oxide 4.
Racemic 4 was resolved with (−)-Ca(H-DPTTA)2
(6) in a 10:1 mixture of ethanol–water as de-
scribed earlier. The purification of the Ca[(+)-4]2(H-
DPTTA)2 complex by two digestions in a 10:1 mix-
ture of ethanol–water followed by decomposition of
the diastereomer led to (+)-4 with an ee of 99% and
yield of 28% (Table 1, entry 5). The resolution of
racemic 4 with half equivalent of (−)-TADDOL (7) in
a 3:5 mixture of ethyl acetate and hexane led to (−)-4
with an ee of 65% and yield of 21% after purifica-
tion (Scheme 1/(5); Table 1, entry 6). The resolution
with (−)-Ca(H-DBTA)2 (5) and (−)-spiro-TADDOL
(8) was not successful, as no crystalline complex was
formed during the resolution attempt.
SCHEME 1 Preparation of optically active P-heterocycles.
The resolution of a 3:1 mixture of 3-methyl-
and 5-methyl-4-chloro-1-phenyl-1,2-dihydrophos-
phinine 1-oxides (3A and 3B) was accomplished
as described earlier with 0.5 equivalent of (−)-
spiro-TADDOL (8) affording (−)-3A and (−)-3B
with an ee of 87% and yield of 39% (Scheme 1/(3);
Table 1, entry 4). During the resolution, the ratio of
According to the other approach, the selective
reduction of the α,β-double bond of a 3:1 mixture of
(−)-3-methyl and 5-methyl-4-chloro-1-phenyl-1,2-
dihydrophosphinine 1-oxides ((−)-3A and (−)-3B)
Heteroatom Chemistry DOI 10.1002/hc

Preparation of Optically Active Six-Membered P-Heterocycles 183
with an ee of 87% led to (−)-4-chloro-5-methyl-
1-phenyl-1,2,3,6-tetrahydrophosphinine 1-oxide
tensity of the signals belonging to the characteristic
groups of the resolving agent and the enantiomers.
The ee of 1–4 was determined by chiral HPLC.
[(−)-4] with an ee of 87% and in a yield of 20%
(Scheme 1/(4); Table 1, entry 10). In our previous
studies, it was established that only the 4-chloro-
3-methyl-1-phenyl-1,2-dihydrophosphinine 1-oxide
(3A) isomer reacts in this reaction due to steric
factors [15]. Hence, the other double bond isomer
played no role in the reduction and was removed
during the purification.
Both the resolution of racemic 1,2,3,6-
tetrahydrophosphinine oxide 4 and the reduction
of optically active 1,2-dihydrophosphinine oxide 3A
are suitable for the preparation of optically active
tetrahydrophosphinine oxide 4. It is favorable to
accomplish the resolution in the starting material
phase, as half of the borane reagent can be saved
during the reduction.
ꢀR
The ee of 1 and 4 was determined using Kromasil
5-Amycoat 250 × 4.6 mm ID, hexane/ethanol 85/15
as an eluent with a flow rate of 0.8 mL/min, T =
20◦C, a UV detector α = 254 nm. Retention time:
11.4 min for (R)-1 and 13.1 min for (S)-1; 15.8 min
for (+)-4 and 23.2 min for (−)-4. The ee of 2 was
ꢀR
determined using Kromasil 5-Amycoat 250 × 4.6
mm ID, hexane/ethanol 90/10 as an eluent with a
flow rate of 1.0 mL/min, T = 20◦C, the UV detector
α = 254 nm. Retention time: 13.4 min for (−)-2 and
15.6 min for (+)-2. The ee of 3 was determined using
Daicel Chem. Ind. Chiralpack AD-H column 250 ×
4.6 mm ID, using hexane/isopropanol 85/15 as the
eluent with a flow rate of 0.8 mL/min, T = 20◦C, the
UV detector α = 254 nm. Retention time: 13.6 and
15.9 min for 3A, 15.1 and 18.1 min for 3B. Optical
rotations were determined on a Perkin–Elmer 241
polarimeter.
CONCLUSIONS
Our methods for the resolution of optical iso-
mers seem to be reproducible, and the deviation
of the ee and yields are mostly within 2.5% after
repetitions.
In conclusion, first in the literature, the resolution of
6,6-dichloro-1-methyl-3-phenyl-3-phosphabicyclo-
[3.1.0]hexane 3-oxide (2) and 4-chloro-5-methyl-1-
phenyl-1,2,3,6-tetrahydrophosphinine 1-oxide (4)
was accomplished by coordination and molecu-
lar complex formation using the easily available
and relatively inexpensive calcium hydrogen (−)-
The
(4R,5R)-(−)-4,5-bis(diphenylhydroxy-
methyl)-2,2-dimethyldioxolane (7) [17], the (2R,
3R)-(−)-α,α,αꢁ,αꢁ-tetraphenyl-1,4-dioxaspiro
[4.5]
decan-2,3-dimethanol (8) [18], calcium hydro-
O,Oꢁ-dibezoyl-(2R,3R)-tartarate
[Ca(H-DBTA)2]
gen (−)-O,Oꢁ-dibezoyl-(2R,3R)-tartarate (5) [9],
(5) and calcium hydrogen (−)-O,Oꢁ-di-p-tolyl-
(2R,3R)-tartarate [Ca(H-DPTTA)2] (6), or TAD-
DOL derivatives (7 and 8), respectively. It was
also proved that during the dichlorocarbene
addition on the double bond of 3-methyl-1-
phenyl-3-phospholene 1-oxide (1), racemization
occurs, but the ring opening of 6,6-dichloro-1-
methyl-3-phenyl-3-phosphabicyclo[3.1.0]hexane
3-oxide (2) and the selective reduction of the
α,β-double bond of the 4-chloro-3-methyl-1-
phenyl-1,2-dihydrophosphinine 1-oxide (3A) can be
accomplished by preserving the configuration of the
chiral P-centers. Overall, considering the principles
of green chemistry, whenever it is possible, it is
better to start the synthesis from the optically active
starting materials.
the
racemic
3-methyl-1-phenyl-3-phospholene
1-oxide (1) [19], 6,6-dichloro-1-methyl-3-phenyl-
3-phosphabicyclo[3.1.0]hexane 3-oxide (2) [20],
3-methyl-
1,2-dihydrophosphinine 1-oxide (3A and 3B)
[21], and 4-chloro-5-methyl-1-phenyl-1,2,3,6-
and
5-methyl-1-phenyl-4-chloro-
tetrahydrophosphinine 1-oxide (4) [16] were
prepared as described earlier.
Preparation of the Optically Active
3-Methyl-1-phenyl-3-phospholene 1-Oxide
((S)-1, (R)-1)
The (R)- and (S)-enantiomers of 3-methyl-1-phenyl-
3-phospholene 1-oxide (1) were prepared as de-
scribed earlier by resolution with (−)-Ca(H-DBTA)2
(5) and (−)-Ca(DPTTA)2 (6), respectively [9]. Yield
of (R)-1: 42%, ee: 94%; yield of (S)-1: 49%, ee: 93%.
EXPERIMENTAL
The H and 31P NMR spectra were recorded on a
Bruker DRX-500 spectrometer operating at 500 and
202.4 MHz, respectively. Chemical shifts are down-
field relative to TMS and 85% H3PO4.
1
Preparation of 6,6-Dichloro-1-methyl-3-phenyl-
3-phosphabicyclo[3.1.0]hexane 3-oxide (2) from
3-methyl-1-phenyl-3-phospholene-1-oxide (1)
The composition of the diastereomeric com-
Method A. The solution of 3.9 g (96.4 mmol) of
sodium hydroxide and 3.8 mL of water was added
plexes was determined by 1H NMR comparing the in-
Heteroatom Chemistry DOI 10.1002/hc

184 Bagi, Laki, and Keglevich
dropwise to the solution of 0.65 g (3.4 mmol) of 3-
methyl-1-phenyl-3-phospholene 1-oxide (1) and 0.16
g (0.68 mmol) of TEBAC in 6 mL of chloroform.
The mixture was stirred for 3 h while the tempera-
ture rose to reflux. After filtration and separation of
the two phases, the organic phase was made up to
its original volume and 0.052 g (0.23 mmol) TEBAC
was added. The treatment with aqueous sodium hy-
droxide was repeated, all together, three times. Af-
ter separating the two phases, drying the organic
phase and evaporating the solvent, the crude prod-
uct was purified by column chromatography (silica
gel, 3% methanol in chloroform) to give 0.38 g (41%)
of product 2. 31P NMR (CDCl3) δ: 76.0, (δP[20] 75.6).
Starting from optically active (S)-3-methyl-
(33%) of complex Ca[(−)-2]2(H-DBTA)2 with a de
of 67%. The (−)-6,6-dichloro-1-methyl-3-phenyl-3-
phosphabicyclo[3.1.0]hexane 3-oxide [(−)-2] was re-
covered by treating the 2-mL chloroform solution of
the complex Ca[(−)-2]2(H-DBTA)2 with 2 mL of 10%
aqueous ammonia. The organic phase was washed
with 0.5 mL of water, dried (Na2SO4), and con-
centrated to give 0.025 g (30%) of (−)-2 with an
ee of 67%. 31P NMR (CDCl3) δ: 76.0, (δP[20] 75.6);
[α]25 = −9.7 (c 0.9; CHCl3).
D
Preparation of (−)-6,6-Dichloro-1-methyl-3-
phenyl-3-phosphabicyclo[3.1.0]hexane 3-oxide
[(−)-2] by Resolution with (−)-Ca(H-DPTTA)2
(6)
1-phenyl-3-phospholene
1-oxide
((S)-1)
(ee:
93%), racemic 6,6-dichloro-1-methyl-3-phenyl-
3-phosphabicyclo[3.1.0]hexane 3-oxide (2) was
obtained in a yield of 34%. 31P NMR (CDCl3) δ: 75.7,
(δP[20] 75.6).
To 0.034 g (0.09 mmol) of (−)-(R,R)-di-p-tolyl-
tartaric acid monohydrate and 0.0025 g (0.045
mmol) of CaO in 0.11 mL of
ture of ethanol–water, 0.049
of racemic 6,6-dichloro-1-methyl-3-phenyl-3-
a
10:1 mix-
g
(0.18 mmol)
Method B. The mixture of 0.20 g (1.0 mmol) of
3-methyl-1-phenyl-3-phospholene 1-oxide (1), 15.4 g
(83.0 mmol) of sodium trichloroacetate, and 0.10 g
(0.44 mmol) of TEBAC in 15 mL of chloroform was
stirred at reflux for 4 days. After filtration, the solvent
was evaporated and the crude product so obtained
was purified by column chromatography (silica gel,
3% methanol in chloroform) (97:3) to give 0.097 g
(yield: 34%) of 2. 31P NMR (CDCl3) δ: 74.8, (δP[20]
75.6).
phosphabicyclo[3.1.0]hexane 3-oxide (2) in 0.1 mL
of ethanol was added. After standing at 26◦C for
72 h, the crystals were filtered off to give 0.020 g
(32%) of complex Ca[(+)-2]2(H-DPTTA)2 with a de
of 22%. The (+)-6,6-dichloro-1-methyl-3-phenyl-3-
phosphabicyclo[3.1.0]hexane 3-oxide [(+)-2] was
recovered by treating the 2-mL chloroform solution
of the complex with 1 mL of a 10% aqueous am-
monia. The organic phase was washed with 0.5 mL
of water, dried (Na2SO4), and concentrated to give
0.0073 g (30%) of (+)-2 with an ee of 22%. 31P NMR
(CDCl3) δ: 76.1, (δP[20] 75.6).
The reaction using (S)-3-methyl-1-phenyl-
3-phospholene 1-oxide ((S)-1) (ee: 93%) led
to
racemic
6,6-dichloro-1-methyl-3-phenyl-3-
phosphabicyclo[3.1.0]hexane 3-oxide (2) in a yield
of 34%. 31P NMR (CDCl3) δ: 74.8, (δP[20] 75.6).
Preparation of (+)-6,6-Dichloro-1-methyl-3-
phenyl-3-phosphabicyclo[3.1.0]hexane 3-oxide
[(+)-2] by Resolution with (−)-Ca(H-DBTA)2
(5)
Preparation of (+)-6,6-Dichloro-1-methyl-3-
phenyl-3-phosphabicyclo[3.1.0]hexane 3-oxide
[(+)-2] by Resolution with (−)-spiro-TADDOL
(8)
To 0.12 g (0.15 mmol) of (−)-Ca(H-DBTA)2 (5) in
0.35 mL of ethanol and 0.07 mL of water, 0.16
g (0.60 mmol) of racemic 6,6-dichloro-1-methyl-
3-phenyl-3-phosphabicyclo[3.1.0]hexane 3-oxide (2)
in 0.35 mL of ethanol was added. Immediately af-
ter the addition, colorless crystals appeared. After
standing at room temperature for 24 h, the precip-
itate was filtered off to give 0.086 g (44%) of com-
plex Ca[(−)-2]2(H-DBTA)2, de 63% (determined by
HPLC). The complex was taken up in the mixture
of 0.7 mL of ethanol and 0.07 mL of water, and
the suspension was stirred for 8 h to give 0.065 g
To 0.047 g (0.17 mmol) of racemic 6,6-dichloro-1-
methyl-3-phenyl-3-phosphabicyclo[3.1.0]hexane 3-
oxide (2) and 0.043 g (0.085 mmol) of (−)-spiro-
TADDOL (8) in 0.1 mL of hot ethyl acetate, 0.90
mL of hexane was added. Immediately after the ad-
dition, colorless crystalline complex appeared. After
3 h, the crystals were separated by filtration to give
0.042 g (63%) of complex [(+)-2](spiro-TADDOL)]
with a de of 55%. Column chromatography (silica
gel, chloroform) of the complex regenerated 0.013 g
(58%) of (+)-2 with an ee of 55%. 31P NMR (CDCl3)
δ: 75.8, (δP[20] 75.6).
Heteroatom Chemistry DOI 10.1002/hc

Preparation of Optically Active Six-Membered P-Heterocycles 185
(28%) of (+)-4 with an ee of 99%. 31P NMR (CDCl3)
Preparation of (+)-3-Methyl- and 5-Methyl-4-
chloro-1-phenyl-1,2-dihydrophosphinine
1-oxides [(+)-3A and (+)-3B] from
(−)-6,6-Dichloro-1-methyl-3-phenyl-3-
phosphabicyclo[3.1.0]hexane 3-oxide [(−)-2] by
Thermolysis
δ: 27.9, (δP[16] 28.3); [α]25 = +19.7 (c 0.7; CHCl3).
D
Preparation of (–)-4-Chloro-5-methyl-1-phenyl-
1,2,3,6-tetrahydrophosphinine 1-oxide [(–)-4] by
resolution with (–)-TADDOL (7)
0.018 g (0.64 mmol) of (–)-6,6-dichloro-1-methyl-3-
phenyl-3-phosphabicyclo[3.1.0]hexane 3-oxide [(−)-
2] (ee 67%) was heated at 135◦C until the evolu-
tion of hydrochloric acid ceased (ca. 2 min). The
crude product was purified by column chromatogra-
phy (silica gel, 3% methanol in chloroform) to give
0.0030 g (20%) of (+)-3 as a 3:1 mixture of 3A and
3B; ee: 67% for both isomers. 31P NMR (CDCl3) δ:
To 0.054 g (0.22 mmol) of racemic 4-chloro-
5-methyl-1-phenyl-1,2,3,6-tetrahydrophosphinine 1-
oxide (4) and 0.052 g (0.11 mmol) of (–)-TADDOL
(7) in 0.3 mL of hot ethyl acetate, 0.5 mL of hexane
was added. Immediately after the addition, colorless
crystalline complex appeared. After 4 h, the crystals
were separated by filtration to give 0.042 g (67%) of
complex [(–)-4]4(TADDOL)3] with a de of 38%. The
complex was purified by recrystallization in 0.3 mL
of ethyl acetate and 0.5 mL of hexane to afford 0.013
g (21%) of complex [(–)-4]4(TADDOL)3] with a de of
65%. 31P NMR (CDCl3) δ: 28.0, (δP[16] 28.3).
16.1 (75%), 15.0 (25%), (δP[21] 16.1, 15.0). [α]25
+5.5 [c 0.2; CHCl3].
=
D
Preparation of (−)-3-Methyl- and 5-Methyl-4-
chloro-1-phenyl-1,2-dihydrophosphinine
1-oxides [(−)-3A, (−)-3B] by resolution with
(−)-spiro-TADDOL (8)
The enantiomers of (−)-3-methyl- and 5-methyl-
4-chloro-1-phenyl-1,2-dihydrophosphinine 1-oxides
[(−)-3A and (−)-3B] were prepared as described ear-
lier, by resolution with (−)-spiro-TADDOL (8) [13].
The yield of (−)-3: 39% as a 3:1 mixture of 3A and
3B. The ee for 3A and 3B is 87%. 31P NMR (CDCl3)
δ: 15.7 (75%), 14.6 (25%), (δP[21] 16.1, 15.0).
Preparation of (–)-4-Chloro-5-methyl-1-phenyl-
1,2,3,6-tetrahydrophosphinine 1-oxide [(–)-4]
from (−)-4-Chloro-3-methyl-1-phenyl-1,2-
dihydrophosphinine 1-oxide
[(−)-3A]
To the solution of 0.090 g (0.38 mmol) of 3:1 mixture
of optically active (–)-3-methyl- and (–)-5-methyl-
4-chloro-1-phenyl-1,2-dihydrophosphinine 1-oxide
[(−)-3A, (−)-3B]* (ee 87% for both isomers) in 2 mL
of dichloromethane, 0.28 mL (0.56 mmol) of 2 M
borane-dimethyl sulfide in THF was added and the
mixture was stirred at room temperature for 24 h.
After the completion of the reaction, 1 mL of water
was added and the mixture was stirred for 15 min.
The white precipitate was filtered, the two phases
were separated, and the organic phase was dried
(Na2SO4). The crude product was purified by column
chromatography (silica gel, 3% methanol in chloro-
form) to give 0.018 g (yield: 20%) of (–)-4 with ee of
Preparation of (+)-4-Chloro-5-methyl-1-phenyl-
1,2,3,6-tetrahydrophosphinine 1-oxide [(+)-4]
by Resolution with (−)-Ca(H-DPTTA)2 (6)
To 0.12 g (0.32 mmol) of (−)-(R,R)-di-p-tolyl-tartaric
acid monohydrate and 0.0090 g (0.16 mmol) of CaO
in 0.48 mL of 5:1 mixture of ethanol–water, 0.16 g
(0.64 mmol) of racemic 4-chloro-5-methyl-1-phenyl-
1,2,3,6-tetrahydrophosphinine 1-oxide (4) in 0.4 mL
of ethanol was added. After standing at 26◦C for
24 h, the crystals were filtered off to give 0.14 g
(66%) of complex Ca[(+)-4]2(H-DPTTA)2 with a de
of 86%. The complex was purified by two diges-
tions, the crystals were taken up in 0.88 mL of a
10:1 mixture of ethanol and water, and the suspen-
sion was stirred for 24 h at 26◦C to give 0.068 g
(32%) of complex Ca[(+)-4]2(H-DPTTA)2 with a de
of 99%. The (+)-4-chloro-5-methyl-1-phenyl-1,2,3,6-
tetrahydrophosphinine-1-oxide [(+)-4] was recov-
ered by treating the chloroform solution (2 mL) of
the complex with 1 mL of 10% aqueous ammonia.
The organic phase was washed with 0.5 mL of wa-
ter, dried (Na2SO4), and concentrated to give 0.022 g
87%. 31P NMR (CDCl3) δ: 28.6, (δP[16] 28.3); [α]25
D
= –8.5 [c 0.6; CHCl3]. *isomer 3B did not take place
in the reaction.
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