Enzymatic synthesis of enantiopure precursors of chiral bidentate and tridentate phosphorus catalysts

Article abstract of DOI:10.1002/adsc.201100280

The Candida antarctica lipase (CAL-B)-catalyzed acetylation of racemic 2-hydroxymethylphenyl(methyl)phenylphosphine oxide, performed in diethyl ether, led to kinetic resolution with an unusually high enantioselectivity (E=3000). The CAL-B-mediated desymme

Full text of DOI:10.1002/adsc.201100280

FULL PAPERS
DOI: 10.1002/adsc.201100280
Enzymatic Synthesis of Enantiopure Precursors of Chiral
Bidentate and Tridentate Phosphorus Catalysts
a
a
a
´
Sylwia Kaczmarczyk, Małgorzata Kwiatkowska, Lidia Madalinska,
Agnieszka Barbachowska,a Michał Rachwalski,a,b Jarosław Błaszczyk,a
Lesław Sieron, and Piotr Kiełbasinski *
c
a,
´
´
a
Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Department of Heteroorganic Chemistry,
´
Sienkiewicza 112, 90-363 Łꢀdz, Poland
Fax : (+48)-42-680-3260; e-mail: piokiel@bilbo.cbmm.lodz.pl
Present address: Department of Organic and Applied Chemistry, University of Łꢀdz, Tamka 12, 91-403 Łꢀdz, Poland
Institute of General and Ecological Chemistry, Technical University of Łꢀdz, Zeromskiego 116, 90-924 Łꢀdz, Poland
b
c
´
´
˙
´
´
Received: April 13, 2011; Published online: August 25, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100280.
Abstract: The Candida antarctica lipase (CAL-B)- both cases the stereogenic or prostereogenic phos-
catalyzed acetylation of racemic 2-hydroxy- phorus atom and the reacting hydroxy oxygen are
ACHTUNGTRENNUNGmethylphenylACHTUNGTRENNUNG(methyl)phenylphosphine oxide, per- distant from each other by four bonds. The absolute
formed in diethyl ether, led to kinetic resolution with configurations of all the products were determined
an unusually high enantioselectivity (E=3000). The by a chemical correlation and X-ray analysis. The
CAL-B-mediated desymmetrization of prochiral products will be used as enantiopure substrates in
bis(2-hydroxymethylphenyl)methylphosphine oxide the preparation of a variety of chiral organophospho-
gave, via its enantioselective monoacetylation, the rus ligands/catalysts for asymmetric synthesis.
corresponding monoacetate in 80% yield and with
ee>98%. The latter transformation allowed us to ef- Keywords: biotransformations; configuration deter-
ficiently transform the prochiral substrate into the mination; desymmetrization; enzyme catalysis; kinet-
enantiomerically pure product in one single step. In ic resolution; phosphorus
Introduction
succeeded in the chemoenzymatic synthesis of a varie-
ty of tridentate ligands 3, containing a stereogenic sul-
Racemic and prochiral organosulfur and organophos- finyl moiety, an enantiomeric amine fragment and the
phorus compounds have proved to be good substrates hydroxy group (Scheme 1).[2] The crucial step was the
for various types of enzymes and many useful trans- enzyme-promoted desymmetrization of the prochiral
formations leading to non-racemic products have sulfoxide 1, which allowed us to obtain the desired
been described by us and others.[1a] In this way, enan- precursor 2 in one step in high yield and in an almost
tiomerically enriched products were obtained, having enantiomerically pure form. The ligands 3 proved to
a stereogenic centre located either on sulfur,[1b,c] phos- be excellent catalysts for the asymmetric organozinc
phorus[1d] or on a carbon atom of an organic substi- additions to aldehydes,[3,4] Michael additions to
tuent.[1e]
enones[5] and in the nitroaldol (Henry) reaction.[6] In
These positive results prompted us to continue in- all cases the products were obtained in the yields up
vestigations on the use of biocatalysis in heteroatom to 98% and with ees up to 98%.
chemistry. One of our long-term goals is to use enzy-
The results presented above encouraged us to con-
matic methodology in the synthesis of non-racemic sider a possibility of replacing the stereogenic sulfinyl
heteroorganic derivatives having a desired structure moiety in the catalysts with a stereogenic phosphorus-
and serving desired purposes. Our recent work has containing group in the hope of getting new classes of
been focused on the preparation of enantiopure heter- chiral catalysts. It should be stressed that the phos-
oatom compounds that could be used as chiral cata- phorus atom, in comparison with the sulfur atom, cre-
lysts in asymmetric synthesis. Thus, we have recently ates more possibilities of functionalization – from
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Adv. Synth. Catal. 2011, 353, 2446 – 2454

Enzymatic Synthesis of Enantiopure Precursors of Chiral Bidentate and Tridentate Phosphorus Catalysts
Scheme 1. Synthesis of chiral sulfinyl tridentate ligands.
Scheme 2. Synthesis of 2-hydroxymethylphenylACHTNUGTRNEUNG(methyl)phenylphosphine oxide (6).
phosphines [PACHTUNGTRENNUNG(III)] through phosphine oxides to hydropyranyloxymethyl)phenylmagnesium bromide
phosphine sulfides and selenides [P(V)]. Although we with methylphenylphosphinyl chloride 4, followed by
were very lucky in the desymmetrization of the acidic removal of the tetrahydropyranyl protecting
hydoxy sulfoxide 1, in which the reacting site, the OH group from 5 (Scheme 2).
group, is in the g position with respect to the stereo-
To synthesize prochiral bis(2-hydroxymethylphe-
genic sulfur atom (thus the distance between the ste- nyl)phosphine oxides a similar approach was planned
reogenic sulfinyl centre and the hydroxy group is in which 2’-(2-tetrahydropyranyloxymethyl)phenyl-
equal to four bonds) (for other examples of similar magnesium bromide was subjected to a reaction with
transformations: kinetic resolutions of g, and e- dichlorophenylphosphine 7 (Scheme 3) or dichloro-
hydoxy sulfoxides with E=10 and 35, respectively, methylphosphine oxide 12 (Scheme 4). While the syn-
see refs.[7,8]), no such literature example can be found thesis of bis(2-hydroxymethylphenyl)phenylphosphine
in the case of P-chiral hydroxyphosphoryl analogues
(for an example of a kinetic resolution of b-hydroxy-
phosphines and phosphine oxides, thus with the hy-
droxy group located at a distance of three bonds from
the stereogenic phosphorus atom, with E up to 81, see
ref.[9]). To check whether the same procedure, as for
the transformation of the sulfoxide 1, will be effective
for the phosphoryl analogues, we decided to investi-
gate both the enzymatic kinetic resolution of racemic
and the desymmetrization of prochiral phosphine
oxides, bearing the reacting hydroxy group distant
from the stereogenic or prostereogenic phosphorus
atom by four bonds.
Results and Discussion
Synthesis of Substrates
The 2-2ydroxymethylphenyl
ACHTUNGERTN(NUNG methyl)phenylphosphine
Scheme 3. Synthesis of bis(2-hydroxymethylphenyl)phenyl-
oxide 6 was synthesized in the reaction of 2’-(2-tetra- phosphine oxide (10).
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6 (Scheme 5). All the reactions were carried out in or-
ganic solvents as reaction media. The acetate (+)-16
was separated from the unreacted alcohol (À)-6 using
column chromatography. The results are collected in
Table 1. Enantiomeric (+)-6 was obtained from
(+)-16 via its deacetylation using MeONa/MeOH. An
enantiomerically pure crystalline sample of (À)-6 was
subjected to X-ray analysis. On the basis of the mo-
lecular structure (Figure 1) its absolute configuration
was determined as (À)-(S).
Inspection of the data shown in Table 1 reveals that
the reaction time, yields and enantioselectivity strong-
ly depended on the lipase and the solvent used.
Except for the two experiments shown in entries 1
and 3, where no reaction was observed, in all other
cases the reaction proceeded quite smoothly. The best
results were obtained using lipase from Candida ant-
arctica CAL-B. From the point of view of stereoselec-
Scheme 4. Synthesis of bis(2-hydroxymethylphenyl)methyl-
phosphine oxide (14).
oxide 10 proceeded smoothly, with only slight forma- tivity, chloroform proved to be inferior to ethers. Al-
tion of the undesired spirophosphorane 11, which was though diisopropyl ether gave satisfactory results, a
produced during the removal of the THP protecting breakthrough was achieved when diethyl ether was
group using pyridinium p-toluenesulfonate, PPTS, applied as solvent. In this case, a certain trick was
(Scheme 3), the analogous deprotection of the methyl used which rests upon the fact that the starting alco-
analogue 13 led to the exclusive formation of spiro- hol 6 is almost insoluble in diethyl ether while the
phosphorane 15 (Scheme 4). After several unsuccess- acetate 16 dissolves in it reasonably well. Combina-
ful attempts, the desired bis(2-hydroxymethylphenyl)- tion of two effects – intrinsic stereoselectivity of the
methylphosphine oxide 14 was unexpectedly obtained enzyme and physical separation based on the differ-
when 13 was treated with a THF solution of the ence in solubility between the substrate and the prod-
borane/dimethyl sulfide complex, followed by a basic uct, resulted in the full enantioselectivity of the reac-
work-up. The latter was crucial, since the presence of tion (E=3000).
even traces of acids caused immediate formation of
15.
Desymmetrization of Bis(2-hydroxymethylphenyl)-
methylphosphine Oxide 14
Kinetic Resolution of 2-Hydroxymethylphenyl-
A
Prochiral phosphine oxides 10 and 14 were subjected
to acetylation with an excess of vinyl acetate in vari-
To achieve kinetic resolution of 6, several lipases ous solvents at 308C, using a number of lipases. Much
were screened for the enantioselective acetylation of to our surprise, the phosphine oxide 10 did not under-
Scheme 5. Kinetic resolution of 2-hydroxymethylphenylACTHNUTRGNEU(GN methyl)phenylphosphine oxide (6).
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Enzymatic Synthesis of Enantiopure Precursors of Chiral Bidentate and Tridentate Phosphorus Catalysts
Table 1. Kinetic resolution of 2-hydroxymethylphenylACHTUNGTRENNUNG
Entry
Enzyme
Time [days]
Solvent
Acetate 16
E
[a]
[a]
Yield [%]
[a]D
ee [%][b]
Yield [%]
[a]D
ee [%][b]
1
2
3
4
5
6
7
8
LPL
LPL
PS
AK
AK
CAL-B
CAL-B
CAL-B
58
28
56
32
18
100
6
CHCl3
–
44
–
43
43
65
47.5
48
–
–
83.6
–
2.6
72
8.4
93.4
99.9
–
41
–
39
40
28
47
46
–
+15
–
+10.4
+14.2
+15.8
+16.3
+20.3
–
81.7
–
56.5
78.2
77
88.5
99.5
–
26
–
4
17
9
G
E
À6.7
–
CHCl3
CHCl3
Et2O
À0.3
À6.9
À0.7
À7.5
À8.1
(i-Pr)2O
(i-Pr)2O
64
3000
2
[a]
In chloroform (c 1).
The ee values were determined by chiral HPLC
[b]
Scheme 6. Desymmetrization of bis(2-hydroxymethylphenyl)methylphosphine oxide (14).
go the desired reaction under any conditions applied. above). The reactions were monitored by 31P NMR.
This may be due the a large steric hindrance created After completion, the enzymes were filtered off, the
by three phenyl groups connected with phosphorus. solvents and excess of vinyl acetate were evaporated
On the contrary, acetylation of phosphine oxide 14 and the residue which, besides the desired monoace-
proceeded relatively smoothly (Scheme 6).
tate 17, contained also phosphorane 15, unreacted
However, the use of a basic additive, for example, substrate 14 and the corresponding diacetate, was sep-
pyridine, proved crucial, since in its absence spiro- arated via column chromatography. The results are
phosphorane 15 was the only product. This was due collected in Table 2. Inspection of Table 2 clearly
to the fact that vinyl acetate is partially hydrolyzed by shows that the best result was again obtained using
the water that is constitutionally bound in the enzyme CAL-B as the biocatalyst, but this time the solvent of
molecule, to form acetic acid. The latter, in turn, choice was dichloromethane. It is noteworthy that ap-
causes cyclization of the substrate (as discussed plication of the biocatalytic methodology made it pos-
sible to obtain the desired product in high yield and
with almost full stereoselectivity in one step. Such a
result could not be achieved using traditional chemi-
cal methods.
Since it turned out to be impossible to obtain the
product 17 in a crystalline form and to determine its
absolute configuration by an X-ray analysis, we had
to resort to a chemical correlation. To this end, the
enantiomerically enriched sample of (À)-17 was treat-
ed with methanesulfonic anhydride in the presence of
triethylamine to give the mesyl derivative 18. Its reac-
tion with sodium iodide in acetone led to the corre-
sponding iodo derivative 19, which was reduced under
radical conditions[10] to yield the acetate 20. This
product was purified by chiral HPLC using a recycling
chromatograph. Hence, the enantomeric excess of this
sample was increased to 100% at the expense of its
chemical yield. Finally, 20 was transformed into the
alcohol 21 (Scheme 7). Its absolute configuration was
determined in two ways. First, the CD spectrum of
(À)-21 was compared with the CD spectra of both
Figure 1. Molecular structure of the recovered alcohol (À)-
(S)-6.
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Table 2. Desymmetrization of bis(2-hydroxymethylphenyl)-
methylphosphine oxide (14).
The investigations of the transformation of the
enantiopure products, (À)-(S)-6, (+)-(R)-6 and (À)-
(R)-17 into of a variety of chiral organophosphorus li-
gands/catalysts and their use in asymmetric synthesis
are under way and the results will be published else-
where.
Entry Enzyme
Solvent
Monoacetate 17
[a]
Yield [a]D
[%]
ee
Abs.
[%][b] conf.
1
2
3
4
5
AK
PS
CAL-B
CAL-B
CAL-B
N
30
15
42
60
80
À2.1
À2.6
À4.3
À5.6
35
42
66
85
(R)
(R)
(R)
(R)
(R)
Conclusions
CHCl3
CH2Cl2
À6.6 >98
Biocatalytic transformations proved again to be a val-
uable synthetic methodology in the synthesis of enan-
tiomerically pure P-chiral organophosphorus deriva-
[a]
[b]
In acetone (c 1).
Determined by chiral HPLC.
tives.
hydroxymethylphenyl
via its CAL-B-catalyzed acetylation, performed in the
Kinetic
resolution
of
racemic
2-
AHCTUNGTRENNUNG
enantiomers of the alcohol 6. It turned out that the properly selected solvent – diethyl ether in which the
CD curves of (+)-(R)-6 and the levorotatory 21 were substrate was insoluble and the product dissolved
of the same shape and exhibited the same sign of the quite well – resulted in an unusually high enantiose-
Cotton effect (Figure 2). Since both compounds are lectivity (E=3000). In turn, CAL-B-mediated desym-
closely related (the phosphorus atom is in each case metrization of prochiral bis(2-hydroxymethylphenyl)-
linked to three identical substitutents, and the fourth methylphosphine oxide gave, via its enantioselective
one, that is, the aryl group, differs only by the pres- monoacetylation, the corresponding monoacetate in
ence of the ortho-methyl group), it seems very reason- high yield and with ee>98%. It is noteworthy that in
able to assume that the absolute configuration of (À)- both cases the distance between the stereogenic or
21 is also (R).
prostereogenic phosphorus atom and the reacting hy-
The ultimate proof was provided by the X-ray anal- droxy oxygen was equal to four bonds, which proves
ysis of the enantiopure sample of (À)-21, which un- that the enzymes are capable of recognizing remote
doubtedly confirmed the above considerations heteroatom centres of chirality. Moreover, in the case
(Figure 3). Since all the transformations presented in of the desymmetrization the biocatalytic procedure
Scheme 7 proceeded outside of the stereogenic phos- made it possible to efficiently transform a prochiral
phorus atom, its absolute configuration must have re- substrate into an enatiomerically pure product in one
mained unchanged. Hence, the absolute configuration single step – a transformation which would be very
of the enzymatic desymmetrization product (À)-17 difficult to achieve by traditional chemical methods.
must be (R).
The products obtained, whose absolute configurations
Scheme 7. Determination of the absolute configuration of 17 by chemical correlation.
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Enzymatic Synthesis of Enantiopure Precursors of Chiral Bidentate and Tridentate Phosphorus Catalysts
Figure 2. Comparison of CD curves of 6 and 21.
Lipases: CAL-B Candida antarctica lipase B (Novozym
435), AK Lipase AK (AMANO), PS Lipase PS (AMANO),
LPL Lipoprotein lipase were used.
The X-ray data for compounds (À)-(S)-6 and (À)-(R)-21
were collected with a Bruker APEX-II CCD diffractometer
at room temperature using CuKa radiation, and the crystal
structures and absolute configurations were determined with
SHELXL-97.[11]
Synthesis of Methylphenylphosphinyl Chloride (4)
To methyl methylphenylphosphinate[12] (16.5 g, 0.097 mol),
placed in a two-neck round-bottom flask equipped with a
mechanical stirrer, dropping funnel and reflux condenser
with a CaCl2 tube, SOCl2 (11.54 g, 0.097 mol) was slowly
added. After the addition, the mixture was stirred and
heated (oil bath temperature 608C) for 2 h. The reaction
was monitored by 31P NMR. After cooling to room tempera-
ture, the excess of SOCl2 was evaporated under vacuum and
the residue was distilled at 103–1048 (0.1 mmHg). The prod-
uct 4 was obtained as a colourless liquid; yield: 13.2 g
(78%). 1H NMR (CDCl3): d=2.16 (d, J=14.01 Hz, 3H),
7.41–7.89 (m, 5H, Ar-H); 31P NMR (CDCl3): d=51.72.
Figure 3. Molecular structure of (À)-(R)-21.
were determined by a chemical correlation and X-ray
analysis, will be used as enantiopure substrates in the
preparation of a variety of chiral organophosphorus
ligands/catalysts for asymmetric synthesis.
Synthesis of 2-Hydroxymethylphenyl
phenylphosphine Oxide (6)
ACHTUNGTRENN(UNG methyl)-
To a stirred solution of 2-bromobenzyl alcohol (11.6 g, 0.062
mol) in dichloromethane (200 mL) was added dihydropyran
(7.81 g, 0.093 mol) and PPTS (1.55 g, 0.0062 mol). The solu-
tion was stirred for 4 h. After this time the solvent was re-
moved under vacuum and brine was added. The aqueous
layer was extracted with diethyl ether (3ꢂ50 mL). The
phases were separated and the organic layer was dried over
anhydrous MgSO4. The solvent was evaporated and the resi-
due was distilled (96–1008; 0.2 mmHg) to give 2’-(2-tetrahy-
dropyranyloxymethyl)bromobenzene; yield: 5.15 g (90%).
1H NMR (CDCl3): d=1.51–1.93 (m, 6H), 3.50–3.97 (m,
2H), 4.53–4.86 (m, 3H), 7.05–7.59 (m, 4H, Ar-H).
Experimental Section
General Remarks
The enzymes were purchased from AMANO or SIGMA.
NMR spectra were recorded on a Bruker instrument at
200 MHz with CDCl3 and CD3OD as solvents. Mass spectra
including HR-MS were measured on a Finnigan MAT in-
strument Optical rotations were measured on a Perkin–
Elmer 241 MC polarimeter (c=1). Column chromatography
was carried out using Merck 60 silica gel. TLC was per-
formed on Merck 60 F254 silica gel plates. The enantiomeric
excess (ee) values were determined by chiral HPLC (Varian
Pro Star 210, Chiralpak AS, Chiralcel OD).
Magnesium (1.4 g, 0.055 mol) and THF (10 mL) were
placed in a three-neck round-bottom flask equipped with a
mechanical stirrer, reflux condenser, and argon inlet. 10 mL
of a solution of the total amount of 2’-(2-tetrahydropyranyl-
AHCTUNGTRENNUNG
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The mixture was heated until the formation of the Grignard
reagent began. Then, the next portions of the solution of 2’-
(2-tetrahydropyranyloxymethyl)bromobenzene in THF were
added and the reaction mixture was refluxed until magnesi-
um disappeared. The solution was cooled to room tempera-
ture and methylphenylphosphinyl chloride 4 (8.02 g, 0.046
mol) was added in small portions. The reaction was moni-
tored by 31P NMR. After the reaction was completed THF
was evaporated, the residue was dissolved in dichlorome-
thane (60 mL) and washed with a solution of NH4Cl (3ꢂ
30 mL). After drying over anhydrous MgSO4 and evapora-
tion of the solvent, the residue was purified by column chro-
matography (dichloromethane/methanol in gradient from
100:1 to 1:1) to give pure 2’-(2-tetrahydropyranyloxymethyl-
form/methanol in gradient from 70:1 to 1:1) to give (+)-(R)-
6; yield: 0.494 g (88%).
Synthesis of Bis[2-(2’-tetrahydropyranyloxy)methyl-
phenyl]phenylphosphine Oxide (9)
To magnesium (0.264 g, 0.01 mol) under argon was added a
solution of 2’-(2-tetrahydropyranyloxymethyl)bromobenzene
(3 g, 0.01 mol) in THF (8 mL) followed by a small crystal of
iodine. The mixture was gently heated to initiate the
Grignard reagent formation. After magnesium had com-
pletely dissolved, dichlorophenylphosphine
7
(0.985 g,
0.0055 mol) was added and the solution was stirred for 3 h.
THF was evaporated, water was added to the residue and
the mixture was extracted with Et2O (3ꢂ10 mL). The organ-
ic solution was dried over MgSO4 and the solvent was re-
moved to give crude phosphine 8; yield: 2.42 g (90%).
phenyl)ACHTUNGTRENNUNG(methyl)phenylphosphine oxide (5); yield: 12.72 g
1
(70%); white powder; m.p. 87–908C. H NMR (CDCl3): d=
1.27–1.69 (m, 6H), 2.02 (d, J=13.27 Hz, 3H), 3.31–3.79 (m,
2H), 4.37–4.95 (m, 3H), 7.22–7.68 (m, 9H, Ar-H); 31P NMR
(CDCl3): d=31.92.
This was dissolved in methanol (20 mL) and a 30% solu-
tion of H2O2 was slowly added with external cooling. After
30 min MeOH was evaporated, water was added and the
mixture was extracted with CHCl3 . The organic solution
was dried over MgSO4, and the solvent evaporated to give
Product 5 (12.72 g, 0.0385 mol) was dissolved in ethanol
(110 mL), PPTS (0.97 g, 0.00385 mol) was added and the re-
action mixture was stirred at 558C for 4 h and monitored by
TLC. After this time, ethanol was evaporated, the residue
was dissolved in dichloromethane and washed with a solu-
tion of Na2CO3 (2ꢂ20 mL). After drying over anhydrous
MgSO4 and evaporation of CH2Cl2, the residue was purified
by column chromatography (dichloromethane/methanol in
gradient from 200:1 to 1:1) to afford 6; yield: 8.24 g (87%);
1
9; yield: 2.43 g (85%). 31P NMR (CDCl3): d=34.8; H NMR
(CDCl3): d=1.7–2.1 (m, 12H), 3.57 (m, 2H), 3.89 (m, 2H),
4.72 (AB, 2H), 5.1 (m, 2H), 7.48–7.56 (m, 13H). The crude
product was used in the ensuing reaction.
Synthesis of Bis-(2-hydroxymethylphenyl)phenyl-
phosphine Oxide (10)
1
white powder; m.p. 168–1718C. H NMR (CDCl3): d=2.04
(d, J=13.23 Hz, 3H), 4.57 (AB, 2H), 7.39–7.68 (m, 9H, Ar-
H); 31P NMR (CDCl3): d=36.52; MS (CI): m/z=247 (M+
H); HRMS (CI): m/z=247.0885, calcd for C14H16PO2 (M+
H), 247.0887.
To a solution of crude phosphine oxide 9 (2.74 g, 0.0054
mol) in EtOH (40 mL) PPTS (2.7 g, 0.0108 mol) was added
and the mixture was stirred at 558C for 7 h. EtOH was
evaporated and the residue was separated and purified by
column chromatography using CHCl3 as eluent to give the
product 10; yield: 1.56 g (85%). 31P NMR (CDCl3): d=40.7;
1H NMR (CDCl3): d=4.49–4.68 (m, 4H), 5.25 (t,J=6.98 Hz,
2H; OH), 6.83–7.78 (m, 13H); MS (CI): m/z=339 (M+H);
HR-MS (CI): m/z=339.3378, calcd for C20H20PO3 (M+H),
339.3369.
Kinetic Resolution of Racemic 2-Hydroxymethyl-
phenylACHTUNGTRENNUNG(methyl)phenylphosphine Oxide (6); General
Procedure
Racemic substrate 6 (0.20 g, 0.00081 mol) was dissolved in a
solvent (5 mL) and an enzyme (50 mg) and vinyl acetate
(1.5 mL) were added. The mixture was stirred at room tem-
perature and the reaction was monitored by 31P NMR and
stopped at the 50% conversion. The enzyme was filtered off
and the solvent was removed under vacuum. The residue
was purified by column chromatography (dichloromethane/
isopropanol in gradient from 80:1 to 1:1) to give unreacted
alcohol (À)-(S)-6 and (+)-(R)-2-acetoxymethylphenyl-
Spirophosphorane 11[13] 1H NMR (CDCl3): d=4.92–5.13
:
(2ꢂAB, 4H), 7.26–7.65 (m, 11H), 8.31–8.40 (m, 2H);
31P NMR (CDCl3): d=À38.1; MS (CI): m/z=321 (M+H).
Synthesis of Bis[2-(2’-tetrahydropyranyloxy)methyl-
phenyl]methylphosphine Oxide (13)
Magnesium (0.73 g, 0.03 mol) and THF (5 mL) were placed
under argon and 5 mL of a solution of the total amount of
ACHTUNGTRENNUNG(methyl)phenylphosphine oxide [(+)-(R)-16]. The results
are shown in Table 1.
2’-(2-tetrahydropyranyloxymethyl)bromobenzene
(8.27 g,
(+)-(R)-2-Acetoxymethylphenyl
(methyl)phenylphosphine
0.03 mol) in THF (60 mL) were added, followed by a few
drops of 1,2-dibromoethane. The mixture was heated until
the formation of the Grignard reagent began. Then, the next
portions of the solution of 2’-(2-tetrahydropyranyloxyme-
thyl)bromobenzene in THF were added and the reaction
mixture was refluxed for 2 h. After cooling the solution to
room temperature, dichloromethylphosphine oxide 12 (1.9 g,
0.015 mol) in THF (10 mL) was added dropwise and the re-
sulting mixture was stirred for 24 h. THF was removed
under vacuum. To the residue aqueous NH4Cl solution was
added and the mixture was extracted with dichloromethane
(3ꢂ25 mL). The combined organic layers were dried over
MgSO4. The solvent was evaporated to give the crude prod-
1
oxide [(+)-(R)-16]: H NMR (CDCl3): d=1.84 (s, 3H), 2.05
(d, J=13.2 Hz, 3H), 5.35 (s, 2H), 7.34–7.7 (m, 9H, Ar-H);
31P NMR (CDCl3): d=32.08; MS (CI): m/z=289 (M+H).
Synthesis of (+)-(R)-2-Hydroxymethylphenyl-
ACHTUNGTRENNUNG(methyl)phenylphosphine Oxide [(+)-(R)-6]
To the acetyl derivative (+)-(R)-16 (0.656 g, 0.00228 mol)
MeONa/MeOH (2 mL) was added. After the addition, the
mixture was stirred for 2 h. After this time TLC indicated
completion of the reaction. Methanol was evaporated and
the residue was purified by column chromatography (chloro-
2452
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ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 2446 – 2454

Enzymatic Synthesis of Enantiopure Precursors of Chiral Bidentate and Tridentate Phosphorus Catalysts
uct 13 as a diastereomer mixture; yield: 6.189 g (98%).
31P NMR (CDCl3): d=32.50, 32.89, 33.08. The crude product
was used in the ensuing reaction.
Synthesis of (+)-(S)-19: A mixture of (+)-(S)-18 (291 mg,
0.735 mmol) and sodium iodide (441 mg, 2.939 mmol) in
acetone (10 mL) was stirred overnight at room temperature
(TLC control: CH2Cl2:acetone 3:2). Acetone was removed
under vacuum, the residue was dissolved in dichloromethane
and washed with H2O and an aqueous solution of Na2S2O3.
The organic layer was dried with MgSO4 and evaporated.
The crude product was purified by preparative TLC
(CH2Cl2:acetone 3:2) to give pure 19; yield: 179 mg (57%);
[a]D: +24.51 (c 1.22, CHCl3); ee=86%. 31P NMR (CDCl3):
Synthesis of Bis-(2-hydroxymethylphenyl)methyl-
phosphine Oxide (14)
To 13 (6.397 g, 0.0144 mol) was added BH3/Me2S (2M in
THF, 29.4 mL, 0.3312 mol; 23 equiv.) and the solution was
stirred at room temperature for 50 h. The reaction was
quenched by a slow addition of 5% K2CO3 (12 mL). The or-
ganic solvents were evaporated, water was added and the
mixture was extracted with chloroform (3ꢂ50 mL). The
combined organic layers were dried over MgSO4, the sol-
vent was evaporated and the residue was purified by column
chromatography using dichloromethane/acetone in gradient
from 10:1 to 1:1 to afford 14; yield: 2.39 g (60%); white
powder; m.p. 153–1558C. 1H NMR (CDCl3): d=1.2 (br. s,
2H), 2.16 (d, J=13.22 Hz, 3H), 4.60–4.80 (AB, 4H), 7.23–
7.69 (m, 8H, Ar-H); 31P NMR (CDCl3): d=42.49; MS (CI):
m/z=277 (M+H); HR-MS (FAB): m/z=277.09893, calcd.
for C15H18PO3 (M+H), 277.099358; anal. calcd. for
C15H17O3P: C 65.22, H 6.16, P 11.23, O 17.39; found: C
65.03, H 6.11, P 10.97, O 17.51.
1
d=34.17; H NMR (CDCl3): d=1.88 (s, 3H, Ac), 2.18 (d,
J=13.24 Hz, 3H, P-Me), 4.97 (AB, 2H, CH2I), 5.34 (d, J=
2.52 Hz, 2H, CH2OAc), 7.30–7.68 (m, 8H, aromat.); MS
(CI): m/z=429 (M+H); HR-MS: m/z=429.011653, calcd.
for C17H19IPO3: 429.01055.
Synthesis of (À)-(R)-20: A mixture of (+)-(S)-19 (164 mg,
0.735 mmol), AIBN (a few milligrams) and Bu3SnH
(133 mg, 0.460 mmol) in dry benzene (20 mL) was refluxed
for 6 days [TLC (CH2Cl2:acetone 3:2) and 31P NMR con-
trol]. After evaporation of the solvent the residue was puri-
fied by preparative chiral HPLC [CYCLOBOND DMT
hexane (i-PrOH-EtOH 4:1) 15%; flow 3.6 mLminÀ1] to give
pure 20; yield: 46 mg (40%); [a]D: À7.31 (c 1.34, CHCl3);
1
ee=100%. 31P NMR (CDCl3): d=32.76; H NMR (CDCl3):
1
Spirophosphorane 15: H NMR (CDCl3): d=1.96 (d, J=
d=1.93 (s, 3H, Ac), 2.11 (d, J=13.12 Hz, 3H, P-Me), 2.34
(s, 3H, CH3), 5.29 (AB, 2H, CH2OAc), 7.30–7.68 (m, 8H,
aromat.); MS (CI): m/z=303 (M+H); HR-MS: m/z=
303.115008, calcd. for C17H20PO3 303.11598.
16.33 Hz, 3H), 4.88–5.22 (m, 4H), 7.25–7.56 (m, 6H, Ar-H),
8.08 (m, 2H); 31P NMR (CDCl3): d=À30.19; MS (CI): m/
z=259 (M+H).
Synthesis of (À)-(R)-21: To a solution of (À)-(R)-20
(22 mg, 0.073 mmol) in MeOH (2 mL) was added NaOMe
(a few milligrams in methanol) and the mixture was stirred
at room temperature for several minutes until the substrate
disappeared (TLC control: CH2Cl2:acetone 3:2). After evap-
oration of the solvent the residue was purified by prepara-
tive TLC (CH2Cl2:acetone 3:2) to give pure 21; yield:12 mg
(60%); [a]D: À9.56 (c 1.13, CHCl3); ee=100%. 31P NMR
(CDCl3): d=38.54; 1H NMR (CDCl3): d=2.10 (d, J=
13.10 Hz, 3H, P-Me), 2.43 (s, 3H, CH3), 4.71(d, J=7.5 Hz,
2H, CH2OH), 5.82 (t, J=7.52 Hz, 1H, OH), 7.18–7.75 (m,
8H, aromat.); MS (CI): m/z=261 (M+H); HR-MS: m/z=
261.104444, calcd. for C15H18PO2: 261.10391.
Enzymatic Desymmetrization of Bis-(2-hydroxy-
methylphenyl)methylphosphine Oxide (14)
To the diol 14 (2.12 g, 7.69 mmol), dissolved in CH2Cl2
(50 mL), were added pyridine (1.86 mL, 23.07 mmol,
3 equiv), CAL-B (immobilized, Novozym 435; 500 mg) and
vinyl acetate (5 mL). The mixture was stirred at room tem-
perature and the reaction was monitored by 31P NMR. After
5 days the enzyme was filtered off, the solvents were evapo-
rated and the crude reaction mixture was purified by
column chromatography using CH2Cl2/acetone in gradient
from 10:1 to 1:1 to give pure (À)-(R)-17 as an oil; yield:
1.96 g (80%); [a]D: À6.6; ee> 98% (for other examples see
Table 2). 1H NMR (CDCl3): d=1.88 (s, 3H), 2.13 (d, J=
13.24 Hz, 3H), 4.55–4.73 (m, 2H), 5.39–5.51 (m, 2H), 7.26–
7.55 (m, 8H, Ar-H); 31P NMR (CDCl3): d=38.62; MS (CI):
m/z=319 (M+H); HR-MS (CI): m/z=319.109170, calcd.
for C17H20PO4 (M+H): 319.109923.
Crystallographic Data
See Supporting Information. Crystallographic data for (À)-
(S)-6 and (À)-(R)-21 have been deposited with the Cam-
bridge Crystallographic Data Centre as entries CCDC
785937 and CCDC 810782, respectively. These data can be
obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/
cif.
Chemical Correlations
Synthesis of (+)-(S)-18: To
a
solution of (À)-(R)-17
(263 mg,0.826 mmol, [a]D: À5.88 (c 1.7, acetone; ee=86%)
in dichlorometane (10 mL) were added methanesulfonic an-
hydride (288 mg, 1.653 mmol) and triethylamine (167 mg,
1.653 mmol) and the mixture was stirred at room tempera-
ture for 3 h [TLC (CH2Cl2:acetone 3:2) and 31P NMR con-
trol]. Then the solution was washed with water and dried
with MgSO4. The solvent was evaporated to give pure 18;
yield: 311 mg (95%); [a]D: +24.75 (c 1.6, CHCl3); ee=86%.
Acknowledgements
1
31P NMR (CDCl3): d=35.44; H NMR (CDCl3): d=1.85 (s,
Financial support by the Polish Ministry of Science and
Higher Education, grant No N204 131 140 (for P. K.), is
gratefully acknowledged. J.B. would like to thank Dr. Grze-
3H, Ac), 2.14 (d, J=13.23 Hz, 3H, P-Me), 2.99 (s, 3H,
CH3SO2), 5.37 (s, 2H, CH2OAc), 5.68 (AB, 2H, CH2OMs),
7.31–7.62 (m, 8H, aromat.).
´
gorz M. Salamonczyk (CMMS PAS) for helpful discussions.
Adv. Synth. Catal. 2011, 353, 2446 – 2454
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2453

Sylwia Kaczmarczyk et al.
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Adv. Synth. Catal. 2011, 353, 2446 – 2454