Enzymatic Approach to the Synthesis of Enantiomerically Pure Hydroxy Derivatives of 1,3,5-Triaza-7-phosphaadamantane

Article abstract of DOI:10.1021/acs.joc.0c02586

A series of enantiomerically pure derivatives of 6-(1-hydroxyalkyl)-1,3,5-triaza-7-phosphatricyclo[3.3.1.1]decane5were successfully synthesized for the first time. A series of hydrolytic enzymes was applied in a stereoselective acetylation performed under

Full text of DOI:10.1021/acs.joc.0c02586

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Enzymatic Approach to the Synthesis of Enantiomerically Pure
Hydroxy Derivatives of 1,3,5-Triaza-7-phosphaadamantane
́
́
Małgorzata Kwiatkowska,* Jarosław Błaszczyk, Lesław Sieron, and Piotr Kiełbasinski
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ABSTRACT: A series of enantiomerically pure derivatives of 6-(1-
hydroxyalkyl)-1,3,5-triaza-7-phosphatricyclo[3.3.1.1]decane 5 were
successfully synthesized for the first time. A series of hydrolytic
enzymes was applied in a stereoselective acetylation performed
under kinetic resolution conditions. Although the secondary
alcohols: α-aryl-hydroxymethyl-PTA (phosphines) 5b−d′, PTA-
oxides 8b−d′, and PTA-sulfides 9b−d′ were found to be totally
unreactive in the presence of all the enzymes and various
conditions applied, the primary alcohols, i.e., the hydroxymethyl derivatives PTA oxide 8a and PTA sulfide 9a, were successfully
resolved into enantiomers with moderate to good enantioselectivity (up to 95%). The absolute configurations of the products were
determined by an X-ray analysis and chemical correlation.
seems to be the introduction of a proper substituent at the
methylene group adjacent to the phosphorus atom of PTA
(“upper rim”). Moreover, this should result in the formation of
chiral PTA analogues with the stereogenic carbon atom located
close to the metal coordinating center on phosphorus.
Such a functionalization was presented in several papers, of
which the most important was the treatment of the reactive
synthon PTA-Li 2 with various electrophiles, e.g., with
dichlorophenylphosphine,2 carbon dioxide, aldehydes, ketones,
or imines (Scheme 1).3
INTRODUCTION
■
1,3,5-Triaza-7-phosphadamantane (PTA) 1, whose official
IUPAC name is 1,3,5-triaza-7-phosphatricyclo[3.3.1.1]decane,
is a water-soluble cage phosphine that has recently received
great interest from chemists and has been a subject of several
overviews.1
As mentioned above all the products bear a stereogenic
center at the carbon atom α to the phosphorus atom.
Additionally, the reaction of PTA-Li with prochiral electro-
philes, e.g., aldehydes or imines, leads to the diastereomeric
products, having two stereogenic centers, 5 and 7, respectively,
which could be separated by repeated crystallization. However,
in all cases only racemic products were described. Surprisingly,
no attempts to obtain enantiomerically pure (or at least
enriched) derivatives of PTA have been made thus far.
Therefore, we have decided to develop a methodology which
would enable one to produce chiral nonracemic derivatives of
PTA, which would then serve as chiral, water-soluble ligands or
catalysts.
Of particular importance are its variously substituted
derivatives, including a plethora of metal P-complexes
exhibiting different catalytic properties. First, PTA can be
functionalized either at the “upper rim”, on the phosphorus or
carbon atoms, or at the “lower rim”, essentially through
quaternization of the nitrogen atoms (Figure 1). The structural
modifications introduced in the “lower rim” lead to the
changes that are relatively far from the phosphorus atom, being
here an important metal coordinating center, and therefore
may have a limited influence on the catalytic properties of
these compounds. Therefore, a more interesting approach
In the frame of the research carried out in our laboratory,
enzymes were intensely used for the synthesis of optically
Received: October 30, 2020
Published: June 17, 2021
Figure 1. Functionalization of PTA.
© 2021 The Authors. Published by
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https://doi.org/10.1021/acs.joc.0c02586
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Scheme 1. Reaction of PTA-Li 2 with Electrophiles
Scheme 3. Asymmetric Bioreduction of β-Activated
Vinylphosphonates
alcohols 5b−d′ were separated by a column chromatography
using dichloromethane/methanol or ethyl acetate/methanol as
solvents. The reaction of PTA-Li with paraformaldehyde was
performed for the first time in a similar way to give the hitherto
unknown racemic 1-hydroxymethyl derivative 5a (R = H). Due
to a susceptibility to oxidation of the phosphines obtained,
they were transformed into the corresponding phosphine
oxides 8 and phosphine sulfides 9 (Scheme 4), and the latter
were used in the ensuing transformations. The results are
collected in Table 1.
active heteroorganic compounds, particularly those containing
a stereogenic center located on a heteroatom−phosphorus4,5
or sulfur.6,7 Some time ago, we reported the synthesis of
phosphine oxide precursors of chiral bidentate and tridentate
phosphorus catalysts via hydrolytic enzyme-promoted kinetic
resolution of racemic P-chiral or desymmetrization of P-
prochiral phosphine oxides, which allowed us to obtain the
desired products in enantiopure forms (Scheme 2).8 For a
review see ref 9.
Scheme 4. Synthesis of Substrates for Enzymatic
Transformations
Scheme 2. Enzymatic Synthesis of Enantiomerically Pure
Phosphine Oxides
Attempts at the Enzymatic Kinetic Resolution of
Racemic Substrates. All of the substrates were subjected to
enzyme-catalyzed hydroxyl group acetylation under kinetic
resolution conditions (Scheme 5). The enzyme set consisted of
a variety of commonly accessible hydrolytic enzymes,
particularly lipases.
First, we started with the secondary alcohols 5b−d′, 8b−d′,
and 9b−d′ in the hope of getting more interesting
enantiomeric products due to the simultaneous presence of
two stereogenic centers in their easily separable racemic
diastereomers. However, the great disappointment for us was a
total lack of reactivity of these substrates, in spite of the use of
a broad variety of enzymes (for the list of enzymes see Table 2
and footnotes) and conditions. What was particularly
surprising was the fact that, according to the literature data,
the scope of secondary alcohols transformed by enzymes in
this way is practically unlimited!12
Another approach, this time concerning the synthesis of C-
chiral organophosphorus compounds, comprised asymmetric
bioreduction of β-activated vinylphosphonates using ene-
reductases, which resulted in the formation of almost
enantiomerically pure products (Scheme 3).10 Similar
satisfactory results were obtained using Mucor circinelloides
whole cells as a source of the desired enzymes.11
Taking advantage of these results, we decided to check
whether the enzymatic approach would be suitable for our
purposes.
RESULTS AND DISCUSSION
■
Synthesis of Substrates. We began our studies with the
synthesis of a number of racemic 1-hydroxyalkyl derivatives of
PTA using PTA-Li 2 as substrate. Its reactions with aryl
carbaldehydes were performed according to the literature
procedures,3a,c and the racemic diastereomers of secondary
As we assumed that in our case the lack of reactivity could
be due to the presence of two spatially demanding substituents
(PTA and an aryl group), we decided to resort to the use of
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a
Table 1. Racemic Substrates for Enzymatic Transformations
phosphine 5
phosphine oxide 8
yield (%)
31P NMR (δ)
phosphine sulfide 9
yield (%)
31P NMR (δ)
symbol
R
yield (%)
31P NMR (δ)
remarks
a
b
b′
c
c′
d
H
Ph
Ph
p-BrC6H4
p-BrC6H4
45
15
21
16
6
−102.2
−106.5
−103.0
−106.7
−102.4
−106.2
−102.7
24
40
41
31
13
30
10
−1.9
−5.1
−3.7
−5.0
−4.0
−5.0
−3.8
30
41
42
32
14
32
11
−15.5
−17.3
−13.5
−17.4
−13.3
−17.0
−13.0
diastereomers
diastereomers
diastereomers
p-Me2NC6H4
p-Me2NC6H4
17
7
d′
a
Conditions: 3.2 mmol of PTA, 3.3 mmol of n-BuLi, 3.5 mmol of aldehyde, THF (20 mL) under argon then an excess of 35% aqueous solution of
H2O2 or elemental sulfur (2 equiv)
Scheme 5. Enzymatic Kinetic Resolution of Racemic
Substrates 5−9
oxide 8a. Therefore, the ensuing experiments were performed
using PTA-oxide 8a and PTA-sulfide 9a as substrates for the
acetylation performed as shown in Scheme 5. The results are
collected in Table 2.
Inspection of Table 2 clearly shows that substrates 8a and 9a
were recognized and transformed by several enzymes, and the
corresponding 1-acetoxymethyl derivatives of PTA 11a and
12a, respectively, were formed and could be separated from the
unreacted substrates. The enantiomeric excess of the substrate
was determined using chiral HPLC. The same procedure was
used to determine the ee of the products 11a and 12a;
however, they had to be first hydrolyzed to the hydroxymethyl
derivatives 8a and 9a. Generally, better results were obtained
in the case of hydroxymethyl PTA-sulfide 9a than hydrox-
ymethyl PTA-oxide 8a, both in terms of yield and
less hindered molecules. The substrates of choice were the 1-
hydroxymethyl derivatives of PTA 5a, 8a, and 9a. Preliminary
experiments using phosphine 5a indicated that it was
impossible to avoid its substantial oxidation to the phosphine
Table 2. Enzymatic Kinetic Resolution of Racemic Substrates
recovered substrate
product, after hydrolysis
a
b
b
c
substrate
enzyme
solvent
time (day) yield (%) ee (%) abs conf yield (%) ee (%) abs conf
E
9a
9a
9a
9a
9a
9a
9a
9a
9a
9a
9a
9a
8a
8a
8a
8a
8a
8a
8a
8a
8a
8a
CAL-B
CRL
TL
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
C6H12
2
2
8
7
10
7
7
7
7
7
7
7
8
7
2
2
22
22
4
14
32
32
48
74
95
54
72
68
6
R
R
R
R
R
44
59
58
47
25
64
12
38
72
30
S
S
S
S
S
16
2
4.5
13
2
Mix: CAL-B, PFL, PS, CRL, CCL
Mix: PPL, MJ, AK, LPL, AH
PCP
WGL
PA
MJ
LPL
PFL
CCL
TL
34
41
59
53
70
46
38
49
47
45
44
33
23
24
7
12
10
10
10
18
R
R
R
R
R
R
R
R
R
R
36
54
32
27
20
19
13
1
32
30
27
32
14
19
7
9
11
20
S
S
S
S
S
S
S
S
S
S
3
2.5
2
2.5
1.5
2
Mix: PFL, CAL-B, PS, CRL, CCL
CAL-B
CRL
PFL
CCL
CRL
CRL
CRL
CRL
1
MeCN
Et2O
toluene
4
4
4
1.5
1.5
2
15
15
a
Enzymes: CAL-B, Candida antarctica lipase; PFL, Pseudomonas fluorescens lipase; PS, Pseudomonas species lipase; CRL, Candida rugose lipase; CCL,
Candida cylindracea lipase; TL, lipase from Pseudomonas stutzeri; PPL, Porcine pancreas lipase; MJ, Mucor javanicus lipase; AK, lipase AK
(AMANO); LPL, lipoprotein lipase; PCP, papain from Carica papaya; WGL, wheat germ lipase; AH, lipase AH (AMANO); PA, penicillin amidase.
b
The ee was determined using HPLC with chiral columns: AS-H, n-hexane (i-PrOH/EtOH 4:1) 75:25, Fl. 0.5 mL/min for PS derivatives 9a and
c
OD-H, n-hexane:(MeOH/EtOH 1:1) 75:25, Fl. 0.5 mL/min for PO derivatives 8a The enantiomer ratio E = ln[1 − c(1 + eep)]/ln[1 − c(1 −
eep)], c = ees/(ees + eep).13
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enantiomeric excess. The best result was achieved when the
racemic compound 9a was acetylated in the presence of CAL B
in dichloromethane.
Determination of the Absolute Configuration of 9a:
X-ray Analysis. To perform an X-ray analysis, the
enantiomerically enriched hydroxymethyl PTA-sulfide deriva-
tives obtained were crystallized from methanol to give crystals
of pure enantiomers of 9a. Both (R) and (S) enantiomers
crystallize in the noncentrosymmetric space group P2(1)2(1)-
2(1) of the orthorhombic system. Asymmetric parts of the unit
cells of both compounds are composed of individual molecules
(Figure 2). Both enantiomers are isostructural: enantiomer
Figure 3. Fragment of the packing of molecules in the crystal of
compound 9a with a marked chain of intermolecular hydrogen bonds
extending along the axis b of the unit cell.
Table 3. Hydrogen-Bonding Geometry for 9a (Å/deg)
H···A
D···A
D−H···A
symmetry
O1−
H1···N1
O1−
H1···N2
C1−
H2···N3
C1−
H11···O1
2.41/2.41
2.867(4)/2.872(3)
115/115
Figure 2. Ellipsoidal view (ORTEP) of the enantiomeric molecule
(R)-9a (left) and (S)-9a (right), showing the single molecules present
in the asymmetric units, the atom numbering scheme, and the
absolute configuration of the substituents at the carbon atom C2.
Ellipsoids are drawn with 50% probability level.
2.09/2.08
2.56/2.55
2.20/2.23
2.800(4)/2.798(3)
3.534(5)/3.531(4)
3.151(7)/3.153(5)
143/143 1 − x, 1/2 +
y, 3/2 − z
166/167 1 + x, y, z
162/162 −1/2 + x, 3/
2 − y,
1 − z
(+)-(R)-9a ([α]389 +3.25, c = 1.3, MeOH) and the opposite
enantiomer (−)-(S)-9a ([α]389 −3.24, c = 0.9, MeOH) have
nearly identical geometry and conformation. The enantiomer
(R) and the mirror image of the enantiomer (S) superimpose
very well, and the rmsd value is less than 0.001 Å. Of particular
interest, the rotation of the O1−C1 bond around the C1−C2
bond in both structures is nearly identical, as shown by the
values of the torsion angle P1−C2−C1−O1, equal to 175.2° in
(R)-9a and 174.6° in (S)-9a. The molecule 9a has an
urotropine-type structure in which one nitrogen atom has been
replaced by a phosphorus atom and is bonded to a sulfur atom.
All P−C bond lengths in both structures are equal within
experimental error with an average distance of 1.831 Å. The
location of the hydroxyl group appears to be determined and
supported by the weak intramolecular hydrogen bond O1−
H(O1)···N1 with an O···N distance of 2.870 Å and O−H···N
angle of 115° (calculated as the average of both enantiomers).
The crystal packing system is built of molecules connected by
intermolecular hydrogen bonds O1−H(O1)···N2 (1 − x, y −
1/2, 1/2 − z), with the distances H(O1)···N2 equal to 2.085 Å
(calculated as the average of both enantiomers), forming one-
dimensional chains running along b axis of the unit cell (Figure
3). The N3 and O1 atoms are donors of weak C−H···N and
C−H···O intermolecular contacts assembling a 3D supra-
molecular network (Table 3).
damantane) P-sulfide 9a have been deposited with the
Cambridge Crystallographic Data Centre, and the reference
codes are CCDC 1842806 for enantiomer (R)-9a and CCDC
1842807 for enantiomer (S)-9a.
Determination of the Absolute Configuration of 8a:
Chemical Correlation. To determine the absolute config-
uration of hydroxy derivative of PTA(O) 8a, whose pure
enantiomer could not be obtained by crystallization, a chemical
correlation was performed. To this end, the enantiomerically
enriched acetyl derivative 11a, i.e., the product of the
enzymatic acetylation of 8a under the kinetic resolution, was
chosen and transformed into 9a (Scheme 6). First, compound
11a was hydrolyzed to the corresponding nonracemic
derivative 8a whose ee was determined using chiral HPLC to
be 16% ([α]389 −5.72, c = 0.7, MeOH). In the next step, the
PO moiety was reduced using phenylsilane to form
phosphine derivative 5a (based on the 31P NMR analysis of
the crude reaction mixture). Then elemental sulfur was added
to produce the sulfur analogue (S)-9a ([α]389 −0.52, c = 0.4,
MeOH). The latter exhibited the same enantiomeric excess as
the starting 8a, and its prevailing enantiomer corresponded
directly to the prevailing enantiomer of 8a. Since in all the
transformations the stereogenic center on the α-carbon atom
remained untouched, it may be concluded that in both cases
the same enantiomer (S)-8a of the substrate was recognized by
the active center of the enzyme and converted into the
corresponding acetyl derivative (Scheme 6).
The absolute configuration of each enantiomer was
determined as a result of the analysis of anomalous X-ray
scattering. The Flack x parameters determined for the (R)-9a
and (S)-9a enantiomers have values of 0.005(10) and
−0.012(8), respectively.
CIF files containing complete information on both studied
enantiomers of 6-(1-hydroxymethyl)(1,3,5-triaza-7-phosphoa-
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Scheme 6. Determination of the Absolute Configuration of 8a by a Chemical Correlation
(CD3COCD3, 200 MHz): δ 4.81−4.65 (m, 1H, CH), 4.58−3.48 (m,
12H, CH2).
CONCLUSIONS
■
We have applied a series of hydrolytic enzymes in a
stereoselective acetylation of 1-hydroxyalkyl derivatives of
PTA under the kinetic resolution conditions. Although the
secondary alcohols 5b−d′, 8b−d′, and 9b−d′ turned out to be
totally unreactive in the presence of all the enzymes and under
various conditions applied, the hydroxymethyl derivatives 8a
and 9a were successfully resolved into enantiomers with
moderate to good enantioselectivity. The absolute config-
uration of pure enantiomers of 9a was determined by an X-ray
analysis, while that of 8a was determined by a chemical
correlation. This is the first successful synthesis of enantiomeri-
cally pure derivatives of PTA, and it paves the way for the
synthesis of enantiomeric organocatalysts and ligands for metal
complexes which can be used as chiral catalysts in asymmetric
synthesis, e.g., the reactions which have so far been performed
only in an achiral manner. The results of the transformations
and functionalization of the compounds obtained, including
formation of metal complexes, as well as their application in
asymmetric synthesis will be published elsewhere.
Synthesis of the Racemic Substrate 6-(1-Hydroxymethyl)-
(1,3,5-triaza-7-phosphaadamantane) P-Oxide (8a). To obtain
the oxide derivatives of PTA, 8a, to the suspension of crude 5a (0.275
g, 1.471 mmol) in distilled water (20 mL) was added an excess of 35%
aqueous solution of H2O2 (3 mmol). After 30 min, 31P NMR analysis
of the crude reaction mixture showed the formation of corresponding
oxide compounds. Crude reaction product was purified by column
chromatography using ethyl acetate−methanol in gradient with the
addition of triethylamine (0.03% vol) to give pure 8a as a white solid
(isolated yield: 0.072 g, 24%). 31P{1H} NMR (CD3OD, 202 MHz): δ
1
−1.9. H NMR (CD3OD, 500 MHz): δ 4.77−4.64 (m, 1H, CH),
4.52−3.81 (m, 12H, CH2). 13C{1H} NMR (CD3OD, 126 MHz): δ
3
3
73.6 (d, JCP = 6 Hz, CH2N), 71.5 (d, JCP = 9 Hz, CH2N), 65.9 (d,
3JCP = 12 Hz, CH2N), 65.2 (d, 1JCP = 2 Hz, CHP), 59.5 (s, CH2OH),
54.6 (d, 1JCP = 51 Hz, CH2P), 52.6 (d, 1JCP = 50 Hz, CH2P). MS (CI)
m/z: [M + H]+ 204; HRMS (TOF MS ES+) m/z: [M + H]+ Calcd
for C7H15N3O2P 204.0902; Found 204.0900.
Synthesis of the Racemic Substrate 6-(1-Hydroxymethyl)-
(1,3,5-triaza-7-phosphaadamantane) P-Sulfide (9a). To obtain
the sulfur derivative of PTA 9a, to the suspension of crude 5a (0.275
g, 1.471 mmol) in dichloromethane (20 mL) under nitrogen
elemental sulfur (0.094 g, 2.947 mmol) was added. The mixture
was stirred at room temperature until the substrate disappeared,
which was found by 31P NMR. Then the reaction mixture was filtered
through Celite and the solvent was evaporated. The crude reaction
mixture was purified by column chromatography using ethyl acetate−
methanol in gradient with the addition of triethylamine (0.03% vol)
to give pure 9a as a white solid (isolated yield: 0.097 g, 30%). 31P{1H}
NMR (CD3OD, 81 MHz): δ −15.5. 1H NMR (CD3OD, 500 MHz):
δ 4.75−4.69 (m, 1H, CH), 4.59−3.83 (m, 12H, CH2). 13C{1H} NMR
EXPERIMENTAL SECTION
■
General Methods. The synthesized products were purified by
column chromatography on Merck 60 silica gel (0.063−0.200 mm) or
preparative plate chromatography using Merck 60 F254 silica gel plate
(2.5 mm). TLC was performed on a Merck 60 F254 silica gel plate
(0.25 mm). Solvents were dried using general procedures and distilled
prior to use. The NMR spectra were recorded in CDCl3, D2O, or
MeOD with a Bruker AV 200 spectrometer. The chemical shifts (δ)
are expressed in ppm, and the coupling constants (J) are given in
hertz. Mass spectra were recorded with a Finnigan MAT95 Voyager
Elite spectrometer. Optical rotations were measured on a Perkin−
Elmer 241 MC polarimeter. HPLC analysis were made using Varian
Pro Star 210 instrument using column with chiral filling Chiralcel
OD-H or Chiralpak AS-H. The enzymes are defined in Table 2.
The X-ray data for compounds (S)-9a and (R)-9a were collected
with a Bruker APEX-II CCD diffractometer at room temperature
using CuKα radiation, and the crystal structures and absolute
configurations were determined with SHELXL-97.14
(CD3OD, 126 MHz): δ 74.1 (d, 3JCP = 6 Hz, CH2N), 71.6 (d, 3JCP
=
1
3
9 Hz, CH2N), 66.5 (d, JCP = 37 Hz, CHP), 65.4 (d, JCP = 12 Hz,
2
1
CH2N), 58.8 (d, JCP = 4 Hz, CH2OH), 58.2 (d, JCP = 37 Hz,
CH2P), 55.5 (d, 1JCP = 35 Hz, CH2P). MS (CI) m/z: [M + H]+ 220.
HRMS (TOF MS ES+) m/z: [M + H]+ Calcd for C7H15N3OPS
220.0673; Found 220.0674.
General Procedure for the Enzymatic Acetylation of the
Racemic Substrates 8a and 9a. To a solution of the racemic
substrate 8a or 9a (20.3 mg for 8a or 21.9 mg for 9a, 0.1 mmol) in a
solvent (5 mL) were added vinyl acetate (0.5 mL) and an enzyme (5
mg). The whole mixture was stirred at room temperature. The
conversion degree was determined by 31P NMR. Then the enzyme
was filtered off and the solvent evaporated. The crude reaction
mixture was separated by column chromatography using ethyl
acetate−methanol in gradient from 20:1 to 1:1 with the addition of
triethylamine (0.03% vol) as eluent to give the pure enantiomerically
enriched substrates 8a (yield: 6.9−14.2 mg; 34−70%) or 9a (yield:
3.1−16.2 mg; 14−74%) and O-acetyl products 11a (yield: 0.2−7.8
mg; 1−32%), or 12a (yield: 6.5−15.4 mg; 25− 59%) as a white solids.
Then the acetyl products were hydrolyzed using catalytic amount of
MeONa in MeOH (3 mL) to give pure enantiomerically enriched
opposite enantiomers of the substrates 8a or 9a, respectively. The
enantiomeric excesses of the alcohols obtained were determined by
HPLC using column with chiral filling: OD-H for PO derivatives
8a (n-hexane/(MeOH/EtOH 1:1) 75:25%; Fl. 0.5 mL/min;
wavelength 224 nm; 18.9 min for (R) enantiomer and 20.1 min for
(S) enantiomer) and AS-H for P = S derivatives 9a (n-hexane/(i-
Synthesis of the Racemic Substrate 6-(1-Hydroxy(1-aryl)-
alkyl)(1,3,5-triaza-7-phosphaadamantane) 5b−d. These com-
pounds were synthesized according to the literature procedures
described in ref 3a,c.
Synthesis of the Racemic Substrate 6-(1-Hydroxymethyl)-
(1,3,5-triaza-7-phosphaadamantane) (5a). To a suspension of
PTA (0.5 g, 3.185 mmol) in THF (15 mL) under nitrogen was added
n-BuLi (1.1 eq, 1.25 mL 3.503 mmol; 2.7 M solution in n-heptane)
dropwise at room temperature. The mixture was stirred for 3 h at
room temperature, and then paraformaldehyde (1.0 g, 35 mmol) was
added in portions. The stirring was continued at room temperature,
and the progress of the reaction was monitored by 31P NMR of the
crude reaction mixture. Then methanol (10 mL) was added, and
solvents were evaporated. The crude product was used for further
transformations (yield of crude product as a white solid: 0.268 g,
45%). 31P{1H} NMR (CD3COCD3, 81 MHz): δ −102.2. H NMR
1
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Article
PrOH/EtOH 4:1) 75%: 25%; Fl. 0.5 mL/min; wavelength 224 nm;
36.4 min for (S) enantiomer and 40.8 min for (R) enantiomer). The
results are collected in Table 2.
́
Academy of Sciences, 90-363 Łódz, Poland; orcid.org/
0000-0001-6243-6561; Email: gosia@cbmm.lodz.pl
Acetoxymethyl Oxide 11a. 31P{1H} NMR (CDCl3, 202 MHz): δ
Authors
1
−3.3. H NMR (CD3OD, 500 MHz): δ 4.92−4.86 (m, 1H, CH),
Jarosław Błaszczyk − Division of Organic Chemistry, Centre of
Molecular and Macromolecular Studies, Polish Academy of
4.58−3.85 (m, 12H, CH2), 2.09 (s, 3H, Me). 13C{1H} NMR
3
(CD3OD, 126 MHz): δ 179.0 (s, C = O), 73.6 (d, JCP = 6 Hz,
́
Sciences, 90-363 Łódz, Poland
CH2N), 71.5 (d, 3JCP = 9 Hz, CH2N), 65.9 (d, 3JCP = 12 Hz, CH2N),
65.2 (d, 1JCP = 52 Hz, CHP), 59.5 (s, CH2O), 54.6 (d, 1JCP = 51 Hz,
́
Lesław Sieron − Institute of General and Ecological Chemistry,
Faculty of Chemistry, Lodz University of Technology, 90-924
1
CH2P), 52.6 (d, JCP = 50 Hz, CH2P), 22.7 (s, CH3). MS (CI) m/z:
́
[M + H]+ 246; HRMS (TOF MS ES+) m/z: [M + H]+ Calcd for
C9H17N3O3P 246.1008; Found 246.1007.
́
Łódz, Poland
́
Piotr Kiełbasinski − Division of Organic Chemistry, Centre of
Molecular and Macromolecular Studies, Polish Academy of
Sciences, 90-363 Łódz, Poland; orcid.org/0000-0002-
Acetoxymethyl Sulfide 12a. 31P{1H} NMR (CDCl3, 81 MHz): δ
1
−18.3. H NMR (CD3OD, 500 MHz): δ 5.09−4.91 (m, 1H, CH),
́
4.60−3.85 (m, 12H, CH2), 2.07 (s, 3H, Me). 13C{1H} NMR
0020-2492
3
(CD3OD, 126 MHz): δ 170.9 (s, C = O), 73.8 (d, JCP = 6 Hz,
CH2N), 71.5 (d, 3JCP = 9 Hz, CH2N), 65.2 (d, 3JCP = 11 Hz, CH2N),
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02586
1
2
63.8 (d, JCP = 36 Hz, CHP), 60.5 (d, JCP = 7 Hz, CH2O), 58.1 (d,
1JCP = 37 Hz, CH2P), 55.3 (d, JCP = 35 Hz, CH2P), 19.4 (s, CH3).
1
MS (CI) m/z: [M + H]+ 262; HRMS (TOF MS ES+) m/z: [M +
Notes
H]+ Calcd for C9H17N3O2PS 262.0779; Found 262.0780.
The authors declare no competing financial interest.
Chemical Correlation. To the enantiomerically enriched acetyl
derivative of PTA(O) 11a (7.3 mg, 0.029 mmol) in methanol (2 mL)
was added a catalytic amount of MeONa (2 M in methanol). The
reaction mixture was stirred at room temperature until the substrate
disappeared (TLC ethyl acetate/methanol 5:1 or 31P NMR). Then
the solvent was evaporated, and the product was purified by column
chromatography using ethyl acetate: methanol in gradient (from 20:1
to 1:5) to give with quantitative yield hydroxyl derivative 8a (whose
ee was determined using chiral HPLC column with chiral filling: OD-
H (n-hexane/(MeOH: /EtOH 1:1) 75:25; Fl. 0.5 mL/min;
wavelength 224 nm; 18.9 min for (R) enantiomer and 20.1 min for
(S) enantiomer). In the next step, to the solution of substrate 8a (6.1
mg, 0.029 mmol) in toluene (2 mL) under nitrogen atmosphere was
added phenylsilane (0.097 g, 30 equiv, 0.09 mmol). The reaction
mixture was refluxed using an oil bath until the substrate disappeared
(based on 31P NMR of the crude reaction mixture). After cooling to
room temperature, elemental sulfur (1.9 mg, 2 equiv, 0.060 mmol)
was added. The reaction mixture was stirred overnight, and then the
precipitate was filtered off through Celite and washed with methanol.
The solvents were evaporated, and the crude product was purified by
column chromatography using ethyl acetate/methanol in a gradient
with the addition of triethylamine (0.03% vol) as eluent to afford
sulfur derivative 9a (isolated yield after two steps: 5 mg, 76%). The
enantiomeric excess was determined using chiral HPLC (AS-H (n-
hexane/(i-PrOH/EtOH 4:1) 75:25%; Fl. 0.5 mL/min; wavelength
224 nm; 36.4 min for (S) enantiomer and 40.8 min for (R)
enantiomer).
ACKNOWLEDGMENTS
■
The project is financed by the European Union with European
Regional Development Fund, Foundation for Polish Science,
Grant for Innovation upon Operational Programme −
Innovative Economy, Priority 1: Research and development
for new technologies, Measure 1.2: Improvement of the human
potential of science; Parent Bridge Programme POMOST/
2013-8/9 (to M.K.).
DEDICATION
■
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́
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Dedicated to Professor Grzegorz Mloston, University of Łodz,
on the occasion of his 70th birthday.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02586.
■
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AUTHOR INFORMATION
Corresponding Author
Małgorzata Kwiatkowska − Division of Organic Chemistry,
Centre of Molecular and Macromolecular Studies, Polish
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