Chiral base promoted enantioselective rearrangement of organophosphorus epoxides

Article abstract of DOI:10.1016/j.tet.2003.08.028

Cinchona alkaloids serve as effective chiral bases for enantioselective rearrangement of 3,4-epoxyphospholane oxides resulting in the formation of P,C-chirogenic 4-hydroxy-2-phospholene derivatives with up to 52% ee. A stereochemical course of the epoxide

Full text of DOI:10.1016/j.tet.2003.08.028

Tetrahedron 59 (2003) 8219–8226
Chiral base promoted enantioselective rearrangement of
organophosphorus epoxides
Zbigniew Pakulski,a Marek Koprowskib and K. Michał Pietrusiewicza,c
,
*
aInstitute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warszawa, Poland
b
´ ´
Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90-363 Łodz, Poland
cDepartment of Organic Chemistry, Maria Curie-Skl⁄odowska University, Gliniana 33, 20-614 Lublin, Poland
Received 25 March 2003; revised 24 July 2003; accepted 13 August 2003
Abstract—Cinchona alkaloids serve as effective chiral bases for enantioselective rearrangement of 3,4-epoxyphospholane oxides resulting
in the formation of P,C-chirogenic 4-hydroxy-2-phospholene derivatives with up to 52% ee. A stereochemical course of the epoxide
rearrangement involving anti b-proton abstraction is proposed. 3,4-Epoxy-1-phospholane-borane rearranges to 4-hydroxy-2-phospholene-
borane of 55% ee on treatment with sec-BuLi/sparteine base system.
q 2003 Elsevier Ltd. All rights reserved.
Asymmetric rearrangements of achiral epoxides to enantio-
merically enriched allylic alcohols by the action of chiral
lithium bases has emerged as one of the most useful
methodologies in the field of asymmetric synthesis.1 It is
widely accepted that these rearrangements proceed via
initial lithium coordination to the epoxy oxygen followed by
abstraction of a syn b-proton.2 In the last two decades, since
the pioneering work of Whitesell and Felman,3 a number of
successful strategies based on this transformation have been
developed for targeted synthesis of cyclic and acyclic
enantiopure compounds containing carbon stereogenic
centers.1,4,5
1. Synthesis of 3,4-epoxy-1-phenylphospholane 1-oxide
derivatives
1-Phenyl-3-phospholene 1-oxide (1), 3-methyl-1-phenyl-3-
phospholene 1-oxide (2) and 3,4-dimethyl-1-phenyl-3-
phospholene 1-oxide (3) were prepared by the McCormack
reaction according to the known procedure8,9 involving
addition of dibromophenylphosphine to 1,3-butadiene,
isoprene and 2,3-dimethyl-1,3-butadiene, respectively.
2-Methyl-1-phenyl-3-phospholene 1-oxide (4) and 2,5-di-
methyl-1-phenyl-3-phospholene 1-oxide (5) were prepared
by regioselective alkylation of 1.10
In the course of our research programme directed towards
the synthesis of P,C-stereogenic monophosphines6 we
wanted to utilize 3-phospholene epoxide derivatives easily
available on a large scale by oxidation of 1-phenyl-3-
phospholene 1-oxide derivatives. These epoxides open a
convenient way to the synthesis of phosphorus stereogenic
center embedded in the frame of a five-membered ring
containing endocyclic allylic functionality in its structure
(Scheme 1).7
Phospholenes 1–5 were converted into epoxides by
treatment with m-chloroperbenzoic acid in refluxing chloro-
form (Scheme 2) according to procedures described by
Arbuzov11a and by Quin11b who reported that the peracid
oxidation of 3-phospholene oxides occurred at only one face
of the ring and gave a single epoxide stereoisomer. This
methodology was utilized by Bodalski12 who described a
preparation of 3,4-epoxy-1-phenylphospholane 1-oxide (6).
As expected, epoxidations of 2–5, under the same
Scheme 1.
Keywords: phospholenes; epoxides; enantioselective rearrangement.
*
Corresponding author. Address: Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warszawa, Poland;
e-mail: kmp@icho.edu.pl
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.08.028

8220
Z. Pakulski et al. / Tetrahedron 59 (2003) 8219–8226
Scheme 2. Reagents and conditions: (i) (a) LDA, (b) MeI; (ii) m-CPBA; (iii) PhSiH3; (iv) S8; (v) BH3£THF.
conditions were completely stereoselective and led cleanly
to epoxides 7–10. 3,4-Epoxy-1-phenylphospholane 1-sul-
fide (11) and 3,4-epoxy-1-phenylphospholane 1-borane (12)
were prepared by reduction of 6 with phenylsilane13
followed by treatment with powdered sulfur or borane–
THF complex, respectively (Scheme 2). The expected
retention of configuration at phosphorus in the reduction
step was confirmed by X-ray analysis of 12 (Fig. 1).
alkylamines effectively decompose the phosphorus–boron
bond,14 to obtain alcohol 18 sec-BuLi/TMEDA in THF
solution was used to promote the desired rearrangement of
the epoxide 12.
We expected that the use of a chiral base in lieu of
triethylamine would render the studied rearrangement
asymmetric and would result in an efficient production of
13–18 in enantiomerically enriched forms. The asymmetric
version of this rearrangement was first studied with 6 as a
model phospholene epoxide (Scheme 3).
Figure 1. X-Ray diffraction structure (ORTEP) of compound 12.
2. Rearrangement of 3,4-epoxy-1-phenylphospholane
1-oxide derivatives
Scheme 3. Reagents and conditions: (i) chiral base, cf Table 1.
It was already known that epoxide 6 rearranges efficiently
to racemic 4-hydroxy-1-phenyl-2-phospholene 1-oxide (13)
in the presence of triethylamine in refluxing ethanol.11a,12
We used the same procedure for the synthesis of racemic
4-hydroxy-5-methyl-1-phenyl-2-phospholene 1-oxide (14)
and 3,4-dimethyl-4-hydroxy-1-phenyl-2-phospholene
1-oxide (15) starting from epoxides 7 and 10, respectively.
The rearrangement of epoxide 9 led to the formation of
4-hydroxy-4-methyl-1-phenyl-2-phospholene 1-oxide (16)
as the main product but a minor amount of regioisomer 17
(6%) was also detected in this reaction. Epoxide 8 was
completely unaffected by triethylamine, whereas sulfide 11
was decomposed under the reaction conditions. Because
Treatment of the model epoxide 6 with chiral lithium base
systems such as LDA/S-(þ)-1-(2-pyrrolidinylmethyl)pyrro-
lidine (79, 0% op),15 sec-BuLi/sparteine (71, 0% op),
n-BuLi/sparteine (53, 0% op), LDA/sparteine (68, 0% op) or
n-BuLi/bis(S-1-phenylethyl)amine (61, 8% op), known as
very effective catalysts for enantioselective epoxide
rearrangement reactions,16,17 afforded the desired hydroxy-
phospholene 13 in good chemical yields but with only very
little or even no induction. Similar results were obtained
when quinine/LDA and quinidine/n-BuLi were used as
bases (chemical yields: 29 and 54%; ees: 0 and 8%,
respectively). All reactions were performed in THF solution

Z. Pakulski et al. / Tetrahedron 59 (2003) 8219–8226
Table 1. Rearrangement of 6 in the presence of chiral bases
8221
Entry
Base (equiv.)/solvent
Temperature (8C) Time Isolated yield (%) Dominating enantiomer [a]2D0 (CHCl3) Optical purity (%)a
1
2
3
4
5
6
7
8
19 (3.0)/EtOH
20 (3.0)/EtOH
21 (0.5)/EtOH
22 (0.5)/CH2Cl2
23 (0.5)/EtOH
24 (0.5)/EtOH
Quinine (0.5)/CH2Cl2
Quinine (1.0)/CH2Cl2
Cinchonidine (0.5)/CH2Cl2
Cinchonidine (1.0)/CH2Cl2
Cinchonine (0.5)/CH2Cl2
Cinchonine (1.0)/CH2Cl2
Quinidine (0.5)/CH2Cl2
Quinidine (0.5)/CH2Cl2
Quinidine (1.0)/CH2Cl2
Sparteine (1.0)/CH2Cl2
Brucine (1.0)/CH2Cl2
O-acetyl quinidine (1.0)/CH2Cl2
20
20
20
80
80
80
55
20
60
20
60
20
60
20
20
20
20
20
60 d
3 d
27 d
5 d
70 h
70 h
5 d
90 d
2 d
90 d
2 d
90 d
2 d
90 d
90 d
90 d
90 d
90 d
54
57
64
38
55
55
25
60
19
62
13
77
22
41
72
78
40
0
13b
–
–
13a
–
13b
13a
13a
13a
13a
13b
13b
13b
13b
13b
–
212, c 1.0
–
–
7
0
0
6
0
7
19
18
6
21
21
47
27
52
39
0
þ10, c 1.0
–
212, c 1.0
þ36, c 1.0
þ34, c 1.1
þ11, c 1.0
þ39, c 0.8
239, c 1.0
287, c 0.9
250, c 1.0
296, c 0.3
272, c 1.5
–
9
10
11
12
13
14
15
16
17
18
–
–
–
–
0
–
Ops were determined by comparison of optical rotation values with the known value for pure SP,RC-(þ)-13a ([a]2D0¼þ184.8, c 1.98 in chloroform)12 and for
a
1
products of entries 10 and 14 were additionally confirmed by H NMR measurements in the presence of the Kagan’s shift reagent.19
at 2788C. Due to extremely low solubility of epoxide 6 in
diethyl ether no reactions were observed in this solvent.
Attempted rearrangement of epoxide 6 in the presence of
n-BuLi/bis(S-1-phenylethyl)amine and equimolar amount
of LiCl in THF solution at 21008C18 caused decomposition
of the starting material.
rearrangement of 6. The test reactions with these bases were
carried out at 20 or 608C using 0.5 or 1.0 equiv. of base in
ethanol or in methylene chloride (which proved to be a
better solvent) and were typically kept for prolonged times
in order to achieve higher conversions.
As shown in Table 1, the highest optical purities of alcohol
13 were obtained for the reactions performed in the presence
of quinidine (52% op, entry 14) and cinchonine (47% op,
entry 12) which both favored the formation of (2)-13b. The
two quasi-enantiomeric bases, quinine and cinchonidine,
afforded predominantly (þ)-13a (entries 7–10). O-Acetyl-
ated quinidine was completely ineffective (entry 18).
Next, a series of chiral free amines 19–24, brucine,
sparteine and a set of four Cinchona alkaloids were used
as bases to promote the rearrangement of 6. The results of
this screening are presented in Table 1. Bases 19–24
(entries 1–6), as well as sparteine (entry 16) and brucine
(entry 17), gave unexpectedly poor results in terms of
asymmetric induction.
Analogous asymmetric rearrangements of chiral non-
symmetrically substituted phospholene epoxides 7 and 9
could potentially serve for kinetic resolutions of the racemic
substrates. Table 2 shows results obtained for the rearrange-
ment of epoxides 7 and 9 in the presence of Cinchona
alkaloids. Even though very long reaction times (90–120
days) were applied for these substrates, their conversions
were usually low or moderate at most. In addition, the
desired kinetic resolution process was also found poorly
efficient. Treatment of 7 with cinchonine gave allylic
Much more promising results were obtained when Cinchona
alkaloids were used as free amine catalysts for the studied
Table 2. Rearrangement of the epoxides 7 and 9 in the presence of alkaloid bases in dichloromethane solution at 208C
Entry
Base (equiv.)
Epoxide Recovered epoxide (%) (% ee) Isolated yield (%) [a]2D0 (CHCl3) % eea of the product Configurationb
1
2
3
4
5
6
7
8
9
Cinchonine (1.0)
Quinidine (1.0)
Quinidine (0.5)
Quinine (1.0)
Cinchonidine (1.0)
Cinchonidine (1.0)
Quinine (1.0)
7
7
7
7
7
9
9
9
9
33 (9)c
55
55
19
23
Traces
12d
13d
13d
35d
27.3, c 1.0
27.6, c 1.1
219.5, c 0.6
N.d.
–
–
–
–
–
3
8
12
2
–
25
36
35
36
RPSC
RPSC
RPSC
RPSC
–
SPRC
SPRC
RPSC
RPSC
40 (12)c
77 (4)c
76 (n.d.)
96 (n.d.)
79d (n.d.)
78d (n.d.)
79d (7)e
59d (14)e
Cinchonine (1.0)
quinidine (1.0)
a
1
Ees were determined by H NMR in the presence of the Kagan’s shift reagent.19
Postulated configuration of alcohols 14 (from epoxide 7) or 16 (from epoxide 9).
b
c
d
1
Ees were determined by H NMR in the presence of (2)-O,O0-dibenzoyl-L-tartaric acid as chiral shift reagent.20
Inseparable mixture of recovered epoxide 9 and allylic alcohol 16. Composition of the mixtures were determined by HPLC (LiChrospher 100 RP-18,
methanol–water, 40:60 as eluent). In all cases proportion of 16/17 was about 94:6.
e
31
Ees were determined by P NMR in the presence of (2)-O,O0-dibenzoyl-L-tartaric acid as chiral shift reagent.20

8222
Z. Pakulski et al. / Tetrahedron 59 (2003) 8219–8226
alcohol 14 with 3% ee only (9% ee of the recovered 7).
Similar reaction with quinidine (0.5 equiv.) afforded 14 with
12% ee (4% ee of the recovered 7) but the chemical yield
was low. Equimolar amount of quinidine increased the
chemical yield to 55%, however, the enantiomeric purity of
the product was lowered to 8% (12% ee of the recovered 7).
Rearrangement of epoxide 9 in the presence of Cinchona
alkaloids yielded allylic alcohol 16 with much better
enantioselectivity (25–36% ee), but the chemical yields
were again low (12–13%) and reached 35% only in the
presence of quinidine.
Scheme 4. Preferred quinidine approach to epoxide 6.
metal cations.27 It is thus reasonable to assume that in the
studied case the rearrangement process is initiated by
coordination of the alkaloid molecule to epoxide 6 through
hydrogen bonding between alkaloid hydroxyl and phos-
phoryl functionalities as shown in Scheme 4.
Treatment of epoxides 8, 10 and 11 with quinidine at room
temperature as described above, gave only recovered
starting material and no epoxide ring opening was observed.
In the next step, the anchored base abstracts the more easily
accessible one of the two enantiotopic b-protons anti to
epoxide oxygen depending on the stereochemistry of the
alkaloid molecule. The absolute configurations of 13b,
prevailing in the reactions catalyzed by quinidine and
cinchonine, and of 13a, formed predominantly in the
reactions with quinine and cinchonidine, are in accord
with the proposed picture.
Based on literature precedents on the enantioselective
deprotonation of phosphine–boranes by sec-BuLi/sparteine
at low temperature21 we treated epoxy phosphine–borane
12 with this base system in THF at 2788C. The formation of
the expected alcohol 18 with 83% yield was observed but
the product was found to be racemic. By comparison, the
same reaction carried out in diethyl ether at 2788C22
afforded allylic alcohol 18 with [a]2D0¼272.1 (c 0.32,
chloroform). For determination of its enantiomeric purity
(2)-18 obtained above was treated with DABCO followed
by hydrogen peroxide oxidation23 and gave oxide 13b with
55% ee (determined by 31P NMR in the presence of the
Kagan’s shift reagent).19
In line with the above proposal is also an additional
observation that the corresponding epoxy phospholene
sulfide 11 unable to participate in similar hydrogen bonding,
failed to undergo the rearrangement under the same
conditions.
In summary, we have demonstrated that the asymmetric
rearrangement of phospholene epoxides can be used to
generate a phosphorus stereogenic center in the cyclic five-
membered ring system. Cinchona alkaloids are the most
effective catalysts for the rearrangements of epoxy phos-
pholene oxides and, unlike the lithium amide bases, are
most likely to operate in the studied system via the
mechanism involving anti b-proton abstraction. For the
rearrangement of epoxy phospholene–borane the highest
enantioselectivity (55% ee) has been achieved with sec-
BuLi/sparteine base system as a promoter.
3. Determination of configuration and proposed
mechanism for phospholene epoxide ring
rearrangement in the presence of Cinchona alkaloids
Absolute configuration of allylic alcohol 13 was determined
by comparison of optical rotation value with the available
enantiomer of 13a of known configuration (SPRC).12
1
Additionally we have found that H NMR spectroscopy of
13b in the presence of (S)-(þ)-N-(3,5-dinitrobenzoyl)-1-
phenylethylamine (Kagan’s shift reagent)24 shows strong
H-2 proton deshielding (Dd 221.9 Hz)25 by comparison
with the appropriate signal for 13a. According to the above
H-2 proton shift and the unidirectional shift observed for the
series of 2-phospholene 1-oxide derivatives of known
configuration,19 we could tentatively assign the RPSC
configuration to the dominating stereoisomer of 14 (Dd
211.8 Hz for H-2 proton). Similarly, for rearrangement of
epoxide 9 in the presence of cinchonine and quinidine the
formation of (RPSC)-16 (Dd 213.1 Hz for H-2 proton) was
preferred whereas in the presence of cinchonidine and
quinine (SPRC)-16 prevailed.
4. Experimental
Tetrahydrofuran (THF) was distilled from LiAlH4 under a
stream of argon prior to use. Other solvents were purified
and dried according to literature methods. TLC was
performed on Silica Gel HF-254 and column chromatog-
raphy on Silica Gel 230–400 mesh (Merck). NMR spectra
were recorded with a Bruker AM-500 (500 MHz) spectro-
meter in deuterochloroform (CDCl3) with Me4Si as internal
standard. High resolution mass spectra (HR-MS) were
measured with AMD-604 mass spectrometer. Optical
rotations were measured with a JASCO DIP-360 automatic
polarimeter. IR spectra were recorded on Perkin–Elmer
1640 FT-IR spectrophotometer.
The above stereochemical results and the failure of chiral
lithium amide bases to induce asymmetry in the studied
rearrangement of epoxyphospholene oxides are most likely
to result from the effects of the Ph–PvO functionality
present in the substrate structure. It has been already
demonstrated that Ph–PvO group in five-membered rings
facilitates abstraction of adjacent protons which are syn to
phosphoryl oxygen.26 It is also well known that basic
phosphoryl oxygen is an efficient donor site for protons and
4.1. X-Ray structure determination of 12
Suitable crystals were grown from an ethyl ether solution.

Z. Pakulski et al. / Tetrahedron 59 (2003) 8219–8226
Table 3. Crystal data and structure refinement for 12
8223
2.0 mM) was added and stirred for 10 min. Methyl iodide
(284 mg, 2.0 mM) was added and stirring was continued for
1 h at 2788C. Water (five drops) was added and solvents
were evaporated to dryness. Column chromatography
(hexane–ethyl acetate–methanol, 5:3:1 as eluent) of the
residue gave 227 mg (59%) of the title compound as thick
colourless syrup. nmax (film): 1437, 1186, 1113, 721, 697,
Empirical formula
Formula weight
Temperature (K)
C40H56B4O4P4
767.97
293(2)
1.54184
Monoclinic, P21/a
˚
Wavelength (A)
Crystal system, space group
Unit cell dimensions
˚
a (A)
10.414
8.497
558 cm21
.
192.0704. Found: 192.0700.
HR-MS(EI) calcd for C11H13OP (M)þ:
˚
b (A)
˚
c (A)
11.889
90
99.50
90
1037.5
1, 1.229
1.979
408
a (8)
b (8)
g (8)
4.1.2. 2,5-Dimethyl-1-phenyl-3-phospholene 1-oxide (5).
To a solution of a freshly prepared LDA (5.0 mM) cooled to
2788C 1-phenyl-3-phospholene 1-oxide (1, 356 mg,
2.0 mM) was added and stirred for 10 min. Methyl iodide
(4.26 g, 30 mM) was added and stirring was continued for
1 h at 2788C. Water (five drops) was added and solvents
were evaporated to dryness. Column chromatography
(hexane–ethyl acetate–methanol, 5:3:1 as eluent) of the
3
˚
Volume (A )
Z, calculated density (mg/m3)
Absorption coefficient (mm21
F(000)
)
Crystal size (mm)
u-range for data collection (8)
Limiting indices
0.49£0.28£0.245
3.77–73.98
0#h#12
0#k#10
214#l#14
1633/1633 [Rint¼0.0000]
Full-matrix least-squares on F2
1633/0/139
residue gave 341 mg (83%) of the title compound as
1
Reflections collected/unique
Refinement method
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I.2s(I)]
R indices (all data)
colourless syrup. H NMR (CDCl3), d 5.96 (dd, 2H, JH,P
27.7 Hz, J¼0.7 Hz, H-3,4), 2.76 (m, 2H, H-2,5), 1.36 (dd,
6H, JH,P¼14.8 Hz, JMe,2(5)¼7.5 Hz, CH3). 13C NMR
¼
1.054
R1¼0.0430, wR2¼0.1153
R1¼0.0430, wR2¼0.1153
0.0148(16)
(CDCl3), d 134.40 (d, JC,P¼100.0 Hz), 133.38 (d, JC,P
13.8 Hz, C-3,4), 131.68 (d, JC,P¼2.6 Hz), 129.81 (d, JC,P
¼
¼
Extinction coefficient
Largest diff. peak and hole (e A
9.0 Hz), 128.56 (d, JC,P¼11.1 Hz), 37.83 (d, JC,P¼66.9 Hz,
C-2,5), 14.14 (d, JC,P¼4.2 Hz, CH3). 31P NMR (CDCl3), d
55.15. nmax (film): 1437, 1185, 1113, 744, 718, 697,
23
)
˚
0.432 and 20.365
562 cm21
.
206.0860. Found: 206.0863.
HR-MS(EI) calcd for C12H15OP (M)þ:
The measurement was run on a Nonius BV MACH3
diffractometer. The structure was solved by the SHELXS-
8628 and refined with the SHELXS-9729 programs. Crystal-
lographic data reported in this paper have been deposited at
the Cambridge Crystallographic Data Centre as a supple-
mentary material number CCDC 212774 (Tables 3 and 4).
4.2. General procedure for the synthesis of 3,4-epoxy-1-
phenylphospholane 1-oxide derivatives
To a solution of 1-phenyl-3-phospholene 1-oxide derivative
(2.0 mM) in chloroform (10 mL) m-chloroperbenzoic acid
(3.0 mM) was added. The reaction mixture was refluxed for
12 h, washed with sat. NaHCO3, 10% aq. Na2S2O3, dried
(Na2SO4) and evaporated to dryness. Column chroma-
tography (hexane–ethyl acetate–methanol, 5:3:1 as eluent)
of the residue yielded pure epoxide.
4.1.1. 2-Methyl-1-phenyl-3-phospholene 1-oxide (4).10a
To a solution of a freshly prepared LDA (2.1 mM) cooled
to 2788C 1-phenyl-3-phospholene 1-oxide (1, 356 mg,
˚
Table 4. Selected bond lengths (A) and angles (8) for 12
P(1)–B(13)
P(1)–C(4)
P(1)–C(5)
P(1)–C(6)
O(2)–C(9)
O(2)–C(10)
C(4)–C(9)
C(9)–C(10)
C(5)–C(10)
C(6)–P(1)–B(13)
C(4)–P(1)–B(13)
C(5)–P(1)–B(13)
C(4)–P(1)–C(5)
C(9)–O(2)–C(10)
O(2)–C(9)–C(10)
O(2)–C(10)–C(9)
B(13)–P(1)–C(4)–C(9)
B(13)–P(1)–C(5)–C(10)
B(13)–P(1)–C(6)–C(3)
P(1)–C(4)–C(9)–C(10)
P(1)–C(5)–C(10)–C(9)
C(4)–C(9)–C(10)–C(5)
C(4)–P(1)–C(5)–C(10)
C(5)–P(1)–C(4)–C(9)
C(6)–P(1)–C(4)–C(9)
C(6)–P(1)–C(5)–C(10)
P(1)–C(4)–C(9)–O(2)
C(4)–P(1)–C(6)–C(3)
1.917(3)
1.833(2)
1.833(2)
1.807(2)
1.440(3)
1.443(4)
1.495(3)
1.460(4)
1.498(3)
114.12(11)
113.44(13)
113.79(13)
95.89(11)
60.86(17)
59.67(17)
59.47(18)
2127.0(2)
126.48(19)
8.4(2)
5.9(3)
25.5(3)
20.3(4)
7.6(2)
27.8(2)
103.74(19)
2105.76(19)
260.4(3)
137.36(18)
4.2.1. 3,4-Epoxy-2-methyl-1-phenylphospholane 1-oxide
(7). Yield 73%. Mp: 93–958C. 1H NMR (CDCl3), d 3.73 (m,
1H, JH,P¼27.4 Hz, J3,4¼3.0 Hz, H-4), 3.53 (dd, 1H, JH,P
¼
0
24.5 Hz, H-3), 2.57 (d, 1H, J5,5 ¼16.5 Hz, H-5), 2.49 (q, 1H,
JMe,2¼7.9 Hz, H-2), 2.38 (ddd, 1H, J¼18.1, 2.6 Hz, H-50),
1.40 (dd, 3H, JH,P¼14.6 Hz, CH3). 13C NMR (CDCl3), d
133.14 (d, JC,P¼93.2 Hz), 131.71 (d, JC,P¼2.9 Hz), 131.03
(d, JC,P¼10.3 Hz), 128.43 (d, JC,P¼12.2 Hz), 59.60
(d, JC,P¼8.0 Hz, C-3 or C-4), 53.51 (d, JC,P¼5.1 Hz, C-4
or C-3), 34.50 (d, JC,P¼66.0 Hz, C-2), 31.56 (d, JC,P
¼
63.6 Hz, C-5), 9.96 (d, JC,P¼5.0 Hz, CH3). 31P NMR
(CDCl3), d 61.13. nmax (film): 1438, 1235, 1175, 1110,
816, 739, 564 cm21. HR-MS(EI) calcd for C11H13O2P
(M)þ: 208.0653. Found: 208.0646.
4.2.2. 3,4-Epoxy-2,5-dimethyl-1-phenylphospholane
1
1-oxide (8). Yield 71%. Mp: 83–868C. H NMR (CDCl3),
d 3.50 (d, 2H, JH,P¼25.4 Hz, H-3,4), 2.54 (q, 2H, JMe,2
¼
JMe,5¼7.9 Hz, H-2,5), 1.38 (dd, 6H, JH,P¼14.2 Hz, 2£CH3).
13C NMR (CDCl3), d 132.14 (d, JC,P¼2.7 Hz), 131.65 (d,
JC,P¼9.7 Hz), 128.91 (d, JC,P¼11.7 Hz), 59.77 (d, JC,P
¼
8.8 Hz, C-3,4), 34.90 (d, JC,P¼64.0 Hz, C-2,5), 11.15 (d,

8224
Z. Pakulski et al. / Tetrahedron 59 (2003) 8219–8226
JC,P¼5.2 Hz, CH3). 31P NMR (CDCl3), d 62.58. nmax (film):
1453, 1438, 1182, 1108, 814, 718, 563 cm21. HR-MS(EI)
calcd for C12H15O2P (M)þ: 222.0810. Found: 222.0803.
J¼45.5, 103.7 Hz). nmax (film): 2374, 1400, 1066 cm21
.
HR-MS(EI) calcd for C10H11OP (M2BH3)þ: 178.0547.
Found: 178.0545.
4.2.3. 3,4-Epoxy-3-methyl-1-phenylphospholane 1-oxide
1
4.3. General procedure for the rearrangement of the
phospholene epoxides in the presence of triethylamine
(9). Yield 83%. Mp: 69–718C (lit.30 Mp: 898C). H NMR
(CDCl3), d 3.57 (dd, 1H, J¼2.3, 27.6 Hz, H-4), 2.54 (m,
3H, H-2,5,50), 2.37 (dd, 1H, J¼16.5, 18.1 Hz, H-20), 1.59
(d, 3H, J¼0.5 Hz, CH3). 13C NMR (CDCl3), d 132.97
(d, JC,P¼95.6 Hz), 131.79 (d, JC,P¼3.0 Hz), 130.97 (d,
A mixture of phospholene epoxide (0.5 mM), ethanol (96%,
5 mL) and triethylamine (0.4 mL) was heated at 1008C in a
tube with screw cap for 24–70 h. Solvents were evaporated.
Column chromatography (hexane–ethyl acetate–methanol,
5:3:1) of the residue yielded 4-hydroxy-1-phenyl-2-phos-
pholene 1-oxide derivative.
JC,P¼10.4 Hz), 128.43 (d, JC,P¼12.4 Hz), 61.96 (d, JC,P
¼
¼
6.2 Hz, C-3), 60.49 (d, JC,P¼2.9 Hz, C-4), 36.51 (d, JC,P
67.0 Hz, C-2 or C-5), 33.50 (d, JC,P¼65.8 Hz, C-5 or C-2),
20.39 (d, JC,P¼10.2 Hz, CH3). 31P NMR (CDCl3), d 59.34.
n
max (film): 1438, 1393, 1227, 1190, 1154, 913, 748 cm21
.
4.3.1. 4-Hydroxy-5-methyl-1-phenyl-2-phospholene
1-oxide (14). Yield 85%. Mp: 118–1208C. 1H NMR
HR-MS(EI) calcd for C11H13O2P (M)þ: 208.0653. Found:
208.0645.
(CDCl3), d 7.09 (ddd, 1H, JH,P¼44.3, J3,2¼8.5, J3,4
¼
1.6 Hz, H-3), 6.25 (ddd, 1H, JH,P¼21.3, J2,4¼0.9 Hz, H-2),
4.78 (m, 2H, H-4, OH), 2.06 (m, 1H, H-5), 1.37 (dd, 3H,
JH,P¼15.3 Hz, JMe,5¼7.4 Hz, CH3). 13C NMR (CDCl3), d
156.14 (d, JC,P¼14.5 Hz, C-2), 132.24 (d, JC,P¼98.5 Hz),
132.13 (d, JC,P¼2.8 Hz), 131.00 (d, JC,P¼10.7 Hz), 128.65
(d, JC,P¼12.2 Hz), 125.87 (d, JC,P¼85.0 Hz, C-3), 80.04 (d,
JC,P¼21.5 Hz, C-4), 41.44 (d, JC,P¼71.9 Hz, C-5), 9.97 (d,
JC,P¼1.9 Hz, CH3). 31P NMR (CDCl3), d 55.67. nmax (film):
1438, 1163, 1081, 749, 728 cm21. HR-MS(EI) calcd for
C11H13O2P (M)þ: 208.0653. Found: 208.0650.
4.2.4. 3,4-Epoxy-3,4-dimethyl-1-phenylphospholane
1-oxide (10). Yield 79%. Mp: 148–1508C. 1H NMR
(CDCl3), d 2.63 (dd, 2H, JH,P¼3.5 Hz, JHCH¼16.5 Hz,
H-2,5), 2.41 (dd, 2H, JH,P¼18.6 Hz, H-20,50), 1.53 (d, 6H,
JH,P¼1.2 Hz, CH3). 13C NMR (CDCl3), d 132.97 (d, JC,P
95.8 Hz), 131.72 (d, JC,P¼2.8 Hz), 131.011 (d, JC,P
10.2 Hz), 128.38 (d, JC,P¼12.1 Hz), 65.75 (d, JC,P
¼
¼
¼
4.6 Hz, C-3,4), 38.29 (d, JC,P¼67.6 Hz, C-2,5), 17.61
(d, JC,P¼11.4 Hz, CH3). 31P NMR (CDCl3), d 50.96. nmax
(film): 1438, 1251, 1207, 1179, 1144, 1108, 1028, 879,
756 cm21
.
222.0810. Found: 222.0804.
HR-MS(EI) calcd for C12H15O2P (M)þ:
4.3.2. 4-Hydroxy-3,4-dimethyl-1-phenyl-2-phospholene
1-oxide (15). Yield 86%. Mp: 197–1988C. 1H NMR
(CDCl3), d 5.81 (m, 1H, JH,P¼21.7 Hz, H-2), 2.39 (m, 2H,
H-5,50), 2.08 (m, 3H, CH3), 1.63 (s, 3H, CH3). 13C NMR
4.2.5. 3,4-Epoxy-1-phenylphospholane 1-sulfide (11). A
mixture of 3,4-epoxy-1-phenylphospholane 1-oxide (6,
400 mg, 2.06 mM) toluene (2 mL) and phenylsilane
(1.7 mM) was heated at 1108C (oil bath temperature) for
3 h under an argon atmosphere. Solvents were evaporated.
The residue was dissolved in benzene (2 mL) and powdered
sulfur (120 mg) was added. Suspension was stirred over-
night at room temperature. Column chromatography
(hexane–ethyl acetate, 7:3) afforded 412 mg (95%) of the
(CDCl3), d 169.13 (d,JC,P¼17.8 Hz, C-3), 132.95 (d, JC,P
100.5 Hz), 131.73 (d, JC,P¼2.8 Hz), 131.09 (d, JC,P
10.7 Hz), 128.44 (d, JC,P¼12.2 Hz), 120.70 (d, JC,P
¼
¼
¼
94.1 Hz, C-2), 79.70 (d, JC,P¼13.9 Hz, C-4), 43.74 (d,
JC,P¼69.2 Hz, C-5), 29.31 (d, JC,P¼4.0 Hz, CH3), 15.51 (d,
JC,P¼19.1 Hz, CH3). 31P NMR (CDCl3), d 48.78. nmax
(film): 1438, 1168, 1137, 1103, 745 cm21. HR-MS(EI)
calcd for C12H15O2P (M)þ: 222.0810. Found: 222.0801.
1
title compound. Mp: 65–668C. H NMR (CDCl3), d 3.85
(dm, 2H, J¼0.6, 1.8, 26.6 Hz, H-3,4),2.93 (dd, 2H, J¼2.1,
16.6 Hz, H-2,5),2.63 (m, 2H, H-20,50). 13C NMR (CDCl3),
d 131.98 (d, JC,P¼74.6 Hz), 131.72 (d, JC,P¼11.5 Hz),
131.57 (d, JC,P¼3.1 Hz), 128.38 (d, JC,P¼12.6 Hz), 56.33 (s,
C-3,4), 39.44 (d, JC,P¼52.2 Hz, C-2,5). 31P NMR (CDCl3),
4.3.3. 4-Hydroxy-4-methyl-1-phenyl-2-phospholene
1-oxide (16). Quantitative yield (contains approximately
6% of 4-hydroxy-3-methyl-1-phenyl-2-phospholene 1-oxide,
17). 1H NMR (CDCl3), d 6.90 (dd, 1H, JH,P¼45.8 Hz,
J3,2¼8.1 Hz, H-3), 6.15 (dd, 1H, JH,P¼22.4 Hz, H-2), 2.34
(m, 2H, H-5,50), 1.67 (s, 3H, CH3). 13C NMR (CDCl3), d
157.65 (d, JC,P¼17.2 Hz, H-2), 132.44 (d, JC,P¼99.2 Hz),
131.97 (d, JC,P¼2.8 Hz), 131.02 (d, JC,P¼11.2 Hz), 128.57
(d, JC,P¼12.3 Hz), 125.44 (d, JC,P¼87.7 Hz, H-3), 78.76
(d, JC,P¼15.2 Hz, H-4), 42.02 (d, JC,P¼70.3 Hz, H-5), 30.74
(d, JC,P¼4.1 Hz, CH3). 31P NMR (CDCl3), d 58.93. nmax
(film): 1438, 1157, 1104, 746 cm21. HR-MS(EI) calcd for
C11H13O2P (M)þ: 208.0653. Found: 208.0658.
d 61.66. nmax (film): 1434, 1396, 1105, 955, 841, 740 cm21
.
HR-MS(EI) calcd for C10H11OPS (M)þ: 210.0268. Found:
210.0261.
4.2.6. 3,4-Epoxy-1-phenylphospholane 1-borane (12).
3,4-Epoxy-1-phenylphospholane 1-oxide (6, 970 mg,
5.0 mM) was reduced as described for 11 and to the
solution of free phosphine in toluene (3 mL) borane–THF
complex (5.0 mM) was added. Column chromatography
(hexane–ethyl acetate, 9:1) gave 835 mg (87%) of the title
compound. Mp: 94–958C. 1H NMR (CDCl3), d 3.78 (d, 2H,
J¼17.9 Hz, H-3,4), 2.55 (dd, 2H, J¼5.8, 16.2 Hz, H-2,5),
2.45 (dd, 2H, J¼5.1, 16.2 Hz, H-20,50), 0.0–1.4 (m, 3H,
BH3). 13C NMR (CDCl3), d 133.11 (d, JC,P¼10.3 Hz),
131.44 (d, JC,P¼2.5 Hz), 129.14 (d, JC,P¼49.9 Hz), 128.65
(d, JC,P¼10.2 Hz), 58.07 (d, JC,P¼4.4 Hz, C-3,4) 29.43
(d, JC,P¼34.9 Hz, C-2,5). 31P NMR (CDCl3), d 34.05 (dd,
4.3.4. 4-Hydroxy-1-phenyl-2-phospholene 1-borane (18).
To a solution of sparteine (47 mg, 0.2 mM) in THF (8 mL)
cooled to 2788C sec-butyllithium (1.2 mM) was added
and stirred for 30 min. 3,4-Epoxy-1-phenylphospholane
1-borane (12, 192 mg, 1.0 mM) in THF (2 mL) was added
and stirred at 2788C for 2 h. Few drops of water were
added, solvents were evaporated to dryness and product
was separated by column chromatography (hexane–ethyl

Z. Pakulski et al. / Tetrahedron 59 (2003) 8219–8226
8225
acetate, 7:3 as eluent) to afford 160 mg (83%) of the title
1
compound as colourless wax. H NMR (CDCl3), d 6.81
References
(ddd, 1H, JH,P¼33.3 Hz, J2,3¼7.7 Hz, J2,4(3,4)¼2.3 Hz, H-2
or H-3), 6.23 (ddd, 1H, JH,P¼29.0 Hz, J2,4(3,4)¼1.3 Hz, H-2
or H-3), 5.23 (m, 1H, H-4), 2.77 (ddd, 1H, JH,P¼7.7 Hz,
0
1. Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz,
A., Yamamoto, H., Eds.; Springer: Berlin, 2000. Eames, J.
Eur. J. Org. Chem. 2002, 393–401, and references cited
therein.
J5,5 ¼15.0 Hz, J5,4¼1.1 Hz, H-5), 2.05 (ddd, 1H, JH,P
¼
0
12.0 Hz, J5 ,4¼3.8 Hz, H-5 ), 0.00–1.80 (m, 3H, BH3). 13C
0
2. Hodgson, D. M.; Gibbs, A. R.; Lee, G. P. Tetrahedron 1996,
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48.6 Hz, C-2), 75.47 (d, JC,P¼4.6 Hz, C-4), 34.07 (d,
JC,P¼35.6 Hz, C-5). 31P NMR (CDCl3), d 38.56 (m). nmax
(KBr): 2377, 1438, 1313, 1113, 745 cm21. HR-MS(EI)
calcd for C10H11OP (M-BH3)þ: 178.0547. Found:
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Reactions; Hamer, J., Ed.; Academic Press: New York,
1967, pp. 47–96.
The same reaction carried out in Et2O solution and in
the presence of sec-BuLi/sparteine complex (1.05 equiv.)
gave (2)-18 with 73% yield and [a]2D0¼272.1 (c 0.32,
chloroform).
4.4. Transformation of (2)-18 into 13b
9. Quin, L. D. The Heterocyclic Chemistry Of Phosphorus;
Wiley: New York, 1981. Quin, L. D. A Guide to Organo-
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10. Magiera, D.; Moeller, S.; Drzazga, Z.; Pakulski, Z.;
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(2)-18 obtained above (70 mg, 0.36 mM) and DABCO
(125 mg, 1.1 mM) in benzene (2 mL) was heated at 40–
458C for 24 h. Then the whole mixture was evaporated to
dryness at 408C under reduced pressure (1 mmHg),
dissolved in benzene (1 mL) and stirred overnight with
15% H2O2, evaporated and purified by column chroma-
tography (hexane–iso-propyl alcohol, 1:1 as eluent) to yield
63 mg (89%) of the title compound.
4.5. General procedure for the rearrangement of the
phospholene epoxide 6 in the presence of chiral lithium
amides
´
12. Bodalski, R.; Janecki, T.; Gałdecki, Z.; Gl⁄owka, M.
Phosphorus Sulfur 1982, 14, 15–21.
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15. Attempted rearrangement of epoxide 6 under original Asami’s
conditions (LDA/S-(þ)-1-(2-pyrrolidinylmethyl)pyrrolidine/
DBU, 0–208C, THF) led to decomposition of the starting
epoxide.16a
To a solution of chiral amine (see text, 0.55 mM) in THF
(4 mL) cooled to 2788C alkyllithium (see text, 0.5 mM)
was added and stirred for 15 min. A solution of 6 (97 mg,
0.5 mM) in THF (1 mL) was added and stirred for additional
2 h at 2788C, quenched by addition of water (0.5 mL) and
purified by column chromatography (hexane–iso-propyl
alcohol, 1:1 as eluent).
16. Asami, M.; Ishizaki, T.; Inoue, S. Tetrahedron: Asymmetry
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Tetrahedron 2002, 58, 4589–4602.
4.6. General procedure for the rearrangement of the
phospholene epoxides in the presence of Cinchona
alkaloids
To a solution of phospholene epoxide (0.5 mM) in
dichloromethane (1 mL) quinidine (0.25 mM) was added
and kept at room temperature for 90–120 days. Solvents
were evaporated. Column chromatography (hexane–iso-
propyl alcohol, 1:1 or hexane–ethyl acetate–methanol,
5:3:1 as eluent) of the residue yielded 4-hydroxy-1-phenyl-
2-phospholene 1-oxide derivatives (Tables 1 and 2).
´
19. Pakulski, Z.; Demchuk, O. M.; Kwiatosz, R.; Osinski, P. W.;
´
Swierczynska, W.; Pietrusiewicz, K. M. Tetrahedron:
´
Asymmetry 2003, 14, 1459–1462.
20. Demchuk, O. M.; Frelek, J.; Stankevic, M.; Swierczynska, W.;
´
ˇ
´
Pietrusiewicz, K. M. To be published.
21. For previous enantioselective deprotonations of phosphine–
boranes see: (a) Muci, A. R.; Campos, K. R.; Evans, D. A.
J. Am. Chem. Soc. 1995, 117, 9075–9076. Imamoto, T.;
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Matsukawa, S.; Yamaguchi, K. J. Am. Chem. Soc. 1998, 120,
1635–1636. Kobayashi, S.; Shiraishi, N.; Lam, W. W. L.;
Manabe, K. Tetrahedron Lett. 2001, 42, 7303–7306.
Acknowledgements
We are grateful to Ms Beata Szcze˛sna for X-ray analysis.
This work was supported by the State Committee for
Scientific Research, Poland, grant no. 7 T09A 068 20.

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Z. Pakulski et al. / Tetrahedron 59 (2003) 8219–8226
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¨
Crystal Structures; University of Gottingen: Germany, 1985.
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¨
Crystal Structures; University of Gottingen: Germany, 1996.
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