Asymmetric synthesis of stereogenic phosphorus P(V) centers using chiral nucleophilic catalysis

Article abstract of DOI:10.3390/molecules26123661

Organophosphates have been widely used in agrochemistry, as reagents for organic synthesis, and in biochemistry. Phosphate mimics possessing four unique substituents, and thereby a chirality center, are useful in transition metal catalysis and as nucleotide therapeutics. The catalytic, stereocontrolled synthesis of phosphorus‐stereogenic centers is challenging and traditionally depends on a resolution or use of stochiometric auxiliaries. Herein, enantioenriched phosphorus centers have been synthesized using chiral nucleophilic catalysis. Racemic H‐phosphinate species were coupled with nucleophilic alcohols under halogenating conditions. Chiral phosphonate products were synthesized in acceptable yields (33–95%) and modest enantioselectivity (up to 62% ee) was observed after identification of an appropriate chiral catalyst and optimization of the solvent, base, and temperature. Nucleophilic catalysis has a tremendous potential to produce enantioenriched phosphate mimics that could be used as prodrugs or chemical biology probes.

Full text of DOI:10.3390/molecules26123661

molecules
Article
Asymmetric Synthesis of Stereogenic Phosphorus P(V) Centers
Using Chiral Nucleophilic Catalysis
Ahmed Numan and Matthew Brichacek *
Department of Chemistry, University of Maine, Orono, ME 04469, USA; Ahmed.Numan@maine.edu
* Correspondence: mbrich@maine.edu; Tel.: +1-207-581-1243
Abstract: Organophosphates have been widely used in agrochemistry, as reagents for organic
synthesis, and in biochemistry. Phosphate mimics possessing four unique substituents, and thereby a
chirality center, are useful in transition metal catalysis and as nucleotide therapeutics. The catalytic,
stereocontrolled synthesis of phosphorus-stereogenic centers is challenging and traditionally depends
on a resolution or use of stochiometric auxiliaries. Herein, enantioenriched phosphorus centers
have been synthesized using chiral nucleophilic catalysis. Racemic H-phosphinate species were
coupled with nucleophilic alcohols under halogenating conditions. Chiral phosphonate products
were synthesized in acceptable yields (33–95%) and modest enantioselectivity (up to 62% ee) was
observed after identification of an appropriate chiral catalyst and optimization of the solvent, base,
and temperature. Nucleophilic catalysis has a tremendous potential to produce enantioenriched
phosphate mimics that could be used as prodrugs or chemical biology probes.
Keywords: asymmetric synthesis; nucleophilic catalyst; phosphorylation; stereogenic phosphorus;
dynamic kinetic resolution
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Citation: Numan, A.; Brichacek, M.
Asymmetric Synthesis of Stereogenic
1. Introduction
Phosphorus P(V) Centers Using
Organophosphorus compounds are common motifs in nucleotides, [1–3] pesticides, [4,5]
Chiral Nucleophilic Catalysis.
herbicides, [ ] and flame retardants [ ]. Commonly, phosphate mimics with tri, tertra,
or pentacoordinate geometries, with unique substitutions, create a chirality center on the
phosphorus atom as shown in Figure 1. These compounds normally have stable config-
6
,
7
8
Molecules 2021, 26, 3661. https://
doi.org/10.3390/molecules26123661
Academic Editor: Diego A. Alonso
urations depending on the nature of the substitution around the phosphorus center [
Chiral phosphate mimics have been extensively utilized in transition metal catalysts, [10
as chiral reagents, [11 13] and in coordination chemistry [14 15]. Furthermore, compounds
with stereogenic phosphonate centers are of great interest in biological applications [16].
For example, using phosphorus-stereogenic analogues in antisense therapy improves po-
tency, stability against enzymatic degradation, and bioavailability [17]. However, current
nucleotide therapeutics are stereoisomeric mixtures. Previous studies have shown that
nucleotide stereoisomers at phosphorus possess distinct therapeutic activities and physical
properties [18–21].
9].
]
Received: 25 May 2021
Accepted: 11 June 2021
Published: 15 June 2021
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4.0/).
Figure 1. Structure of asymmetric phosphate mimics.
Despite the importance of enantiopure P-stereogenic compounds, the chemical syn-
thesis remains unsolved. Various strategies have been pursued using P-O, P-N, or P-C
bond formations to create a stereogenic center [
9
]. Traditionally, P-stereogenic centers
Molecules 2021, 26, 3661. https://doi.org/10.3390/molecules26123661
https://www.mdpi.com/journal/molecules

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have been synthesized using multistep approaches involving the transfer of achiral phos-
phorus groups to chiral-pool amines and alcohol, as seen in Scheme 1a. However, the
desymmetrization of prochiral substrates is limited by substrate scope and modest stereos-
electivity [22].
Scheme 1. Synthetic approaches towards P-stereogenic organophosphorus compounds. (
a
) Desymmerization of prochiral
) using a chiral
) catalytic asymmetric synthesis, ( ) asymmetric
phosphorus substrate, ( ) P-stereogenic organophosphoryl compounds from enantiopure H-phosphinates, (
b
c
auxiliary or promotor for P-stereogenic organophosphorus synthesis, (
d
e
phosphorylation via chiral nucleophilic catalysis.
Another approach to chiral phosphorus centers involves the transformation of non-
racemic H-phosphinates ( ) to corresponding P-stereogenic compounds ( ) through a
8
9
dehydrogenative coupling known as the Atherton–Todd reaction (Scheme 1b). Although
H-phosphonates cleanly transfer the stereochemistry to the product, construction of the
enantiopure substrate often requires multiple synthetic steps [23]. Alternatively, a racemic
phosphorus center can be coupled with a chiral auxiliary or promotor, as shown Scheme 1c.

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However, a stoichiometric amount of chiral auxiliary is always required to achieve high
stereoselectivity in the products. Moreover, a chiral auxiliary is covalently bonded to the
product, necessitating subsequent chemical reactions and purifications to remove it from
the desired product [24].
In 2010, Jordan et al. synthesized a phosphate moiety through a highly selective
kinetic resolution using a chiral, peptide-based phosphorylation catalyst [25]. The chiral
peptide was able to efficiently mimic enzyme catalysts that phosphorylate nucleotides
using nucleophilic activation, leaving group activation, and oxyanion-hole transition state
stabilization [26,27]. However, this approach is limited in scope because each peptide is
optimized for a single substrate. Based on this work, DiRoco et al. designed a general
chiral nucleophilic catalyst for the synthesis of enantiopure prodrugs via a dynamic kinetic
asymmetric transformation (DKAT), as seen in in Scheme 1d [28]. The prodrug moiety
contains an amino acid that makes hydrogen bonds to the nucleophilic catalyst to stabilize
the transition state. Therefore, DiRoco’s catalyst is limited to phosphates with amino
acid substituents [28]. Other approaches to produce P-stereogenic compounds, which are
not shown in Scheme 1, include chiral-stationary phase separation and resolution using
physical properties [9,29–32].
To overcome the synthetic limitations found in the synthesis of P-stereogenic phos-
phate mimics, a DKAT utilizing a chiral nucleophilic catalyst was pursued (Scheme 1e).
A racemic H-phosphinate moiety (16) can be coupled to nucleophilic alcohols under halo-
genation conditions to produce chiral phosphonate products, as shown in Scheme 1e. This
general approach would utilize a catalytic amount of a chiral substance, and a wide range of
racemic phosphorus substrates could be used, including nucleotides or prodrug structures.
2. Results and Discussion
H-phosphinates and H-phosphonates are useful precursors to a wide range of
P-stereogenic compounds [33–35]. Therefore, the racemic H-phosphinate moiety (18)
was an ideal substrate to investigate the proposed DKAT using chiral nucleophilic catal-
ysis. To obtain substrate 18, esterification of phenyl phosphinic acid in neat isopropanol
◦
at an elevated temperature (138 C) was performed and provided the product in 70%
yield. Coupling of H-phosphinate 18 with phenol (19) under halogenation conditions
(CCl4, 4 equiv.) provides the phosphonate product (20) in 76% yield. Stoichiometric
amounts of N,N-diisopropylethylamine are included to consume the HCl byproduct of the
halogenation process.
Using optimized conditions for the racemic formation of 20, a wide a variety of
chiral nucleophilic catalysts were screened to quantify the enantiomeric enrichment of
the phosphorus center (Scheme 2). Using the catalyst developed by DiRoco et al. (23
and 24), minimal stereoselectivity ( 9% ee and 8% ee, respectively) was observed [28].
−
The suboptimal enantioselectivities are likely due to the remote chiral site being unable
to effectively induce asymmetry in substrates that do not possess a rigid H-bonding
functionality. Planar-chiral catalyst 25, known as Fu’s catalyst, is a ferrocene analogue of
4-Diethylaminopyridine (DMAP) with high nucleophilicity and low steric hindrance at the
nucleophilic nitrogen atom [36]. The product 20 was obtained with an improved selectivity
of 34% ee and a moderate yield of 45%. Alternative heterocyclic nucleophilic catalysts 26
and 27 provide inferior enantioselectivities (-24% and 11% ee) and chemical yields (38% and
42%). Chiral thiourea 28, which does not operate as a nucleophilic catalyst, does not induce
significant levels of stereoselectivity (10% ee) while resulting in a dramatically diminished
yield of 14%. Despite limited success with common chiral catalysts, the results demonstrate
the enantiomeric enrichment was significantly impacted by catalyst structure.

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Scheme 2. Nucleophilic catalysts investigated. Yield and enantiomeric excess of isolated products are given. Conditions: 21
(1 equiv.), CCl4 (4 equiv.), PhOH (0.5 equiv.) i-Pr2NEt (2 equiv.), Cat. 20 mol%, CH2Cl2 (0.1 M solution), 7 h; enantiomeric
b
excess (ee) was determined by HPLC analysis; a catalyst 10 mol%. catalyst 50 mol%.
Benzotetramisole (BTM, 21) was originally developed by Briman et al. for the kinetic
resolution of alcohols and is now commercially available [37–39]. BTM was tested in
the standard H-phosphinate coupling of 18 and 19 under halogenation conditions and
was found to produce the highest levels of enantioselectivity. Specifically, 20 mol% of
(S)-BTM produced phosphonate 20 in 58% yield and 49% ee (Scheme 2). Increasing the
catalyst loading from 10 mol% to 20 mol% and to 50 mol% resulted in small increases in
enantioselectivity of 46%, 49%, and 54% ee, respectively. Structurally similar Tetramisole (22)
is a capable catalyst providing 20 in 45% yield and 44% ee. Mechanistically, we envisioned
the nucleophilic BTM catalyst becoming covalently bonded to the phosphoryl center
while facilitating racemization to produce the observed enantioenrichment. Consequently,
BTM was identified as the optimal catalyst for the DKAT of racemic H-phosphinates into
chiral phosphonates.
In order to optimize the yield and enantioselectivity of 20, the effect of the base
was investigated, and results are shown in Table 1. As established in the catalyst screen,
N,N-diisopropylethylamine (DIPEA) has the highest enantioselectivity (49% ee) and a
respectable yield of 58% (Table 1, Entry 7). Among the investigated bases, potassium
tert-butoxide (KOtBu) provided the highest chemical yield of 63%, but with near-complete
loss of enantioselectivity (7% ee). Non-nucleophilic amine bases, including DBU, ABCO,
and DABCO, provided 20 with diminished enantioselectivities of 20%, 30%, and 33% ee,
respectively. The starting material was recovered, and no product was observed when
using hindered bases such as proton sponge (1,8-bis(dimethylamino)naphthalene) or di-tert-
butyl pyridine (Table 1, Entries 5 and 6). All other reactions showed complete consumption
of the H-phosphinate starting material and no ongoing product formation as judged by
31P NMR.

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Table 1. Base effects on the reaction conditions.
Entry a
Base
*pKa in DMSO
ee (%) c
Yield (%) b
1
2
3
4
5
6
7
KOtBu
DBU
ABCO
19.2 [40]
12 [40]
9.8 [41]
63
60
50
15
0
0
58
7
20
32
33
—
—
49
DABCO
Proton Sponge
DTBP
2.97, 8.9 [41,42]
7.50 [41]
0.81 [43]
9 [40]
DIPEA
a
Conditions: 18 (1 equiv.), CCl4 (4 equiv.), PhOH (1 equiv.), Base (2 equiv.), 21 (20 mol%), CH2Cl2 (0.1 M
solution), 7 h; yields were determined by HPLC analysis.
b
c
ee value was determined by HPLC analy-
sis. KOtBu = Potassium tert-butoxide; DBU = 1,8-diazabicyclo [5.4.0] undec-7-ene; ABCO = Quinuclidine;
DABCO = 1,4-diazabicyclo[2.2.2]octane; Proton Sponge = 1,8-Bis(dimethylamino)naphthalene; DTBP = Di-tert-
butyl pyridine; DIPEA = N,N-diisopropylethyl amine. *pKa for conjugate acid.
After identifying N,N-diisopropylethylamine as the optimal base, the effect of solvent
and temperature were evaluated, and results are shown in Table 2. The nonpolar solvent
toluene results in nearly identical enantioselectivity when compared to the standard solvent
methylene chloride, except with a dramatic decrease in yield to 17%. In contrast, acetonitrile
reduced the enantioselectivity to 26% ee but formed the product in similar efficiency (47%)
to methylene chloride. Interestingly, the production of 20 is nearly eliminated when using
tetrahydrofuran (THF) with respectable recovery of the starting material.
Table 2. The effects of solvent and temperature on the phosphorylation reaction.
Entry a
Solvent
T (◦C)
ee (%) c
Yield (%) b
1
2
3
4
5
6
THF
0
0
0
0
25
−40
4
17
47
55
51
26
49
45
44
Toluene
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
58
53 d
7 e
a
Conditions: 18 (1 equiv.), CCl4 (4 equiv.), PhOH (1 equiv.), i-Pr2NEt (2 equiv.), 21. (20%), solvent (0.1 M solution),
7 h; b yields were determined by HPLC analysis; cee value was determined by HPLC analysis; d 2hours; e 16 h.
After confirming dichloromethane as a suitable solvent for the DKAT, temperature
effects on enantioselectivity were explored. Phosphorylation of 19 at
−
40 ◦C, 0 ◦C, and
25 ◦C resulted in enantioselectivities of 44%, 49%, and 45% ee, respectively. Therefore, the
optimal temperature was determined to be 0 ◦C, but a smaller than expected influence
on enantioselectivity was observed. In addition, the product was obtained in the highest
yield at 0 ◦C (58%), while increasing or decreasing the temperature resulted in a reduction
in yield.

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To assess the H-phosphinate substrate scope, the alcohol and the aryl group were
varied and coupled with phenol under the optimized reaction conditions (Table 3). Of note,
the experiments in Table 3 were performed with an altered stoichiometry (0.5 equiv. of
alcohol) to improve the enantioselectivity of the transformation at the expense of chemical
yield. The products (30–33) of ethyl-substituted H-phosphinates are obtained in comparable
enantioselectivities but with typically higher yield than 20 due to the decreased steric
environment around the phosphorus center (Table 3, Entries 3–6). As an aside, the HPLC
elution order of methyl-substituted phosphonate (29) was reversed compared to other
synthetic phosphonate analogues due to indeterminate interactions with the stationary
phase (Figure S58 in Supplementary Materials). Modulation of the aromatic group on the
H-phosphinate was also investigated. When dramatically altering the steric environment
around the phosphorus by replacing the phenyl group with an o-tolyl (Entries 3 and 4), the
yield is unsurprisingly decreased from 95% to 67%. However, the increased steric hindrance
did not improve the enantioselectivity. Additionally, electronic effects were studied by
substituting the phenyl group with a 4-methoxy- and a 4-fluoro-phenyl group, respectively.
A decline in enantioselectivity to 22% ee was obtained with both the electron-withdrawing
and -donating substituents as shown in Table 3, Entries 5 and 6. The substrate scope for
the H-phosphinate coupling was found to be very sensitive to the steric and electronic
environment around the phosphorus center with improved yields and enantioselectivities
observed when compared to the model substrate (18), but with varied results even under
the optimized conditions.
Table 3. Base effects of electrophilic on phosphorylation reaction.
Entry a
R
R’
Product
ee (%) c
Yield (%) b
47
40
55
1
i-Pr
Ph
−54 d
2
3
4
Me
Et
Ph
Ph
33
95
67
61
62
48
Et
2-MePh

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Table 3. Cont.
Product
Entry a
R
R’
ee (%) c
Yield (%) b
5
Et
4-OMePh
88
22
22
6
Et
4-F-Ph
93
a
Conditions: 18 (1 equiv.), CCl4 (4 equiv.), PhOH (0.5 equiv.), i-Pr2NEt (2 equiv.), 21. 20 mol%, CH2Cl2 (0.1 M
solution), 7 h; b Isolated yield; c ee value was determined by HPLC analysis; d (R)-(21) was used.
In the process of exploring the substrate scope in Table 3, known compounds 29 and
30 were prepared to correlate the observed enantioselectivity to an absolute configuration.
High performance liquid chromatography (HPLC) on a chiral stationary phase was used to
measure all enantioselectivities reported. As seen in Figure 2, using a normal phase eluent
of hexane and ethanol with 0.1% trifluoroacetic acid (TFA) baseline resolves a racemic
sample of 30 (red trace) formed when no chiral catalyst is used. The enantioenriched
product from Table 3, Entry 3, shows the correlating imbalance in peak areas (62% ee)
when using (
−
)- or (S)-◦benzotetramisole (Figure 2, black trace). Correspondingly, 30 has a
measured [α]2D0 of +21.7 (c 0.43, CHCl3). Using the published data and sign for (R)-30
(
[α]2D0
+ 34.4◦ (c 2.16, CHCl3), we observe that (S)-BTM produces the (R) enantiomer of 30 as the
major product [44]. In addition, (R)-29 was produced using (S)-BTM because the specific
rotation agrees with reported values [44]. Finally, when the enantiomer of the catalyst
((R)-21) was used to synthesize 20, a near-equal yield, but with opposite enantioselectivity
(−54% ee), was observed, as expected.
Figure 2. HPLC chromatograms of racemic (red) and chiral phosphonate analogues (black) of 30 using (S)-21. Conditions.
Phenomenex Lux amylose-2 chiral column (250
detection = 254 nm, flow rate = 0.5 mL/min, temperature = 25 C.
×
4.6 mm), ◦eluent = hexane: ethanol (15:95 to 20:80) with 0.1% TFA,
Using catalyst (S)-21, a number of alcohols were tested as nucleophiles in the phos-
phorylation reaction to produce the corresponding phosphonates in Table 4. Our standard
phosphorylation reaction utilized an aromatic alcohol (19) as a nucleophile, so it was
encouraging that BTM was an effective catalyst for alcohols such as allyl, benzyl, methyl,
or phenethyl alcohol. Under the optimized conditions, allyl alcohol, which differs greatly
in structure from phenol, reacted with isopropyl-H-phosphinate in similar efficiency (49%
yield and 43% ee). Small decreases in enantioselectivity (28% and 35% ee) were observed
when using phenethyl alcohol or benzyl alcohol as nucleophiles, but comparable yields

Molecules 2021, 26, 3661
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were obtained. Under the optimized reaction conditions, (S)-BTM (21) provided the same
stereochemical outcome as the (R)-phosphonate analogues in Table 4. However, due to
Cahn–Ingold–Prelog rules, the priority of the substituents on phosphorus changed and
resulted in the formation of (S)-34 through (S)-37. Finally, even when using sterically
unencumbered methanol, the product (37) yield and enantioselectivity were not decreased
(56% yield and 51% ee). Similar to compound 29, the HPLC elution order of the methyl
phosphonate analogue (37) was reversed from the normal pattern (Supplementary Materi-
als, Figure S70). Moreover, (S)-37 had a positive specific optical rotation which is consistent
with analogous phosphonates [45].
Table 4. Effects of the nucleophile on the phosphorylation reaction.
Entry a
ROH
Product
ee (%) c
Yield (%) b
1
Phenol
47
55
2
allyl alcohol
49
43
2-phenethyl
alcohol
3
4
5
68
51
56
28
35
51
Benzyl alcohol
Methanol
a
Conditions: 18 (1 equiv.), CCl4 (4 equiv.), alcohols (0.5 equiv.), i-Pr2NEt (2 equiv.), 21 (20 mol%), CH2Cl2 (0.1 M
solution), 7h; b Isolated yield; c ee was determined by HPLC analysis.
Based on the Atherton–Todd reaction, a mechanism is proposed that explains the
formation of enantioenriched phosphonates (30) using the chiral nucleophilic catalyst
21 [46]. First, the chlorination of the H-phosphinate moiety (40) using tetrachloromethane
as the stoichiometric oxidant results in the formation of racemic phosphonochloridate 41
(Scheme 3). While monitoring the reaction using 31P NMR, a species (29.3 ppm) consistent
with a phosphonochloridate (41) was observed with concomitant consumption of the

Molecules 2021, 26, 3661
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H-phosphinate [47]. Next, catalyst (S)-(21) attacks the phosphonochloridate and results
in diastereomers 42 and 43 after substitution of the chlorine. Unfortunately, 31P NMR
did not allow unambiguous identification of an intermediate where the BTM catalyst was
bonded to the phosphoryl center. Substitution reactions at phosphorus centers typically
involve either 1) a dissociative SN1-type mechanism through the formation of stable
metaphosphate (PO3−) or 2) an associative, two-step addition-elimination mechanism
through the formation of a phosphorane intermediate [48]. In this case, the elementary
steps of the substitution process are inconsequential to the product outcome.
Scheme 3. Proposed asymmetric phosphorylation mechanism based on the dynamic kinetic asymmetric transformation of
H-phosphinate 40 to phosphonate (R)-30 and (S)-30 using chiral nucleophilic catalyst 21.
Nucleophilic addition by phenol forms pentavalent intermediates 44 and 45. Addi-
tional pentavalent intermediate isomers are likely formed in the reaction but not shown
in Scheme 3. Elimination of the BTM catalyst from the apical position of intermediate 44
provides the observed product 30 in the observed (R) configuration [48]. Elimination from
pentavalent 44 is preferable to elimination from 45 because steric interactions between the
phenyl groups on the phosphonate and the catalyst (S)-(21) are avoided. Alternatively, the
stereoselectivity could be a result of
π-
π
or
π-cation interactions between the catalyst and
phosphorus substrate, analogous to previously published acylation studies with 21
[
37].
It is known from the literature that trigonal bipyramidal phosphorus centers, such as 44 and
45, readily undergo pseudorotation and provide an equilibration mechanism consistent
with the dynamic kinetic transformation observed [48]. Alternatively, diastereomers 42
and 43 are potentially equilibrating during the reaction process, but as mentioned above,
this could not be spectroscopically observed. Thus, enantiomeric enrichment is a result of
the faster elimination (k1 > k2) of 44 and constitutes the stereodetermining step.
Collectively, the reaction stereoselectivity was dependent on the solvent, catalyst
structure and loading, and the nature of the base. The proposed mechanism explains the
enantioselectivity dependence on the reaction conditions perturbing the relative rates of
elimination (k1, k2). The similarity of these rates of elimination results in the modest stere-
oselectivity observed in this study. In contrast, the enantioselectivity was largely unaffected
by the reaction temperature, indicating that kinetic control was observed as opposed to
thermodynamic control. Finally, the proposed reaction mechanism in Scheme 3 shows the
selective formation of the (R)-phosphonate using (S)-( )-benzotetramisole catalyst (21)
−
consistent with optical rotations and absolute configurations [44]. Modifying the BTM
catalyst by increasing the steric hindrance of the phenyl group or electronically perturbing
the fused benzo system may provide an opportunity to improve the stereoinduction.

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3. Materials and Methods
3.1. General Information
All reactions were carried out under a nitrogen atmosphere in oven-dried glass-
ware. The products were purified by flash column chromatography using silica gel 60
(230–400 mesh Silicycle, Quebec City, Quebec, Canada). Solvent, reagents, and chemicals
were received from a commercial vendor and further dried under activated 4 Å molecular
sieves. Methylene chloride and THF were dried using the PURE SOLV MICRO purification
system. Thin-layer chromatography (TLC) analysis was performed on Merck 0.25 mm silica
1
gel 60 F254 plates. H NMR was recorded using an Oxford Varian Unity Instrument (Palo
Alto, Santa Clara, CA, USA) at 400 MHz and referenced using the residual solvent peak of
CDCl3 at 7.26 ppm. 13P NMR spectra were acquired at 162 MHz and externally referenced
to 85% H3PO4 at (0 ppm). The 13C NMR were acquired at 101 MHz and referenced to
77.1 ppm for the CDCl3 solvent. The NMR data was processed with MestReNova11 NMR
software. HPLC was performed using a Gilson GX-271 instrument (Middleton, Wisconsin,
United States of America) at 254 nm with Trilution LC V3 software. Analytical HPLC
was carried out using a 5
µ
m 250
×
4.6 mm Phenomenex Lux chiral column (Amylose-
2 or Cellulose-2). In analytical HPLC, the normal phase separation method used was:
eluent = hexane: ethanol (15:9◦5 to 20:80) with 0.1% TFA, detection (254 nm), flow rate
(0.5 mL/min), temperature (25 C), and run time (20 min). Mass spectra were measured by
the University of Illinois Mass Spectrometry Laboratory using the electrospray ionization
technique (ESI). The optical rotations were measured for purified samples using the digital
polarimeter JASCO (model DIP-370). Specific rotation ([α]2D0) was reported for samples
◦
in solution at 20 C in which the symbol D represents the sodium D line (589 nm) and
concentration in units of g/100 mL.
Isopropyl (phenyl)-H-phosphinate (18)
A mixture of phosphinic acid (1.00 g, 7.04 mmol, 1.0 equiv.) and isopropanol (10 mL,
0.131 mol, 18.6 equiv.) was stirred in a well-sealed, 20 mL vial for 15 h at 138 ◦C. Then, the
solvent was evaporated under vacuum. The crude product was purified using silica gel
column chromatography with 5% MeOH: 95% CH2Cl2 as an eluent to provide a colorless
1
oil in 70% yield (0.90 g). The NMR data matched previously published results [49]. H
NMR (400 MHz, CDCl3)
(m, 1H), 7.52–7.44 (m, 2H), 4.73–4.67 (m, 1H, OCH), 1.41 (d, J = 6.1 Hz, 3H, CH3), 1.33
(d, J = 6.1 Hz, 3H, CH3). 13C NMR (101 MHz, CDCl3)
133.1 (d, J = 2.9 Hz), 131.0 (d,
δ 7.81–7.70 (m, 2H), 7.59 (d, J = 558.7 Hz, 1H, PH), 7.60–7.52
δ
J = 11.9 Hz), 130.6 (d, J = 133.0 Hz), 128.8 (d, J = 13.9 Hz), 71.5 (d, J = 5.5 Hz), 24.4 (d,
J = 4.5 Hz), 24.0 (d, J = 4.2 Hz). 31P NMR (162 MHz, CDCl3) δ 22.5 (d, J = 21.5 Hz).
Ethyl (phenyl)-H-phosphinate (40)
A mixture of phosphinic acid (1.00 g, 7.04 mmol, 1.0 equiv.) in eth◦anol (10 mL,
0.171 mol, 24.4 equiv.) was stirred in a well-sealed, 20 mL vial for 15 h at 133 C. Then, the
solvent was evaporated under vacuum. The product was purified by flash chromatography
on silica gel using 5% MeOH: 95% CH2Cl2 as an eluent to produce a colorless oil in
1
55% yield (0.65 g). The NMR data matched previously published results [33]. H NMR
(400 MHz, CDCl3)
δ
7.74 (m, 2H), 7.59–7.51 (m, 1H), 7.54 (d, J = 562.5 Hz, 1H, PH), 7.50–7.42
133.2
(m, 2H), 4.17–4.05 (m, 2H), 1.33 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3)
δ
(d, J = 2.8 Hz), 131.0 (d, J = 11.9 Hz), 129.9 (d, J = 132.3 Hz), 128.9 (d, J = 13.9 Hz), 62.3 (d,
J = 6.5 Hz), 16.5 (d, J = 6.5 Hz). 31P NMR (162 MHz, CDCl3) δ 24.96 (d, J = 19.3 Hz).
Methyl (phenyl)-H-phosphinate (46)
A mixture of phosphinic acid (1.00 g, 7.04 mmol, 1.0 equiv.) in methanol (15 mL,
0.370 mol, 52.9 equiv.) was stirred in a well-sealed, 20 mL vial for 15 h at 125 ◦C. Then,
the solvent was evaporated under vacuum. The crude product was purified by flash
chromatography on silica gel using 5% MeOH: 95% CH2Cl2 as an eluent to produce a
colorless oil in 62% yield (0.68 g). The NMR data matched previously published results [50].

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1H NMR (400 MHz, CDCl3)
δ
7.85–7.73 (m, 2H), 7.65–7.56 (m, 1H), 7.56 (d, J = 565.8 Hz,
1H, PH), 7.55–7.47 (m, 2H), 3.79 (d, J = 12.0 Hz, 3H). 13C NMR (101 MHz, CDCl3)
δ 133.4
(d, J = 2.8 Hz), 131.2 (d, J = 11.9 Hz), 130.3 (d, J = 47.2 Hz), 129.0 (d, J = 13.8 Hz), 52.3 (d,
J = 6.6 Hz). 31P NMR (162 MHz, CDCl3) δ 27.46 (d, J = 21.6 Hz).
Ethyl (2-methylphenyl)-H-phosphinate (47)
A solution of P(OEt)3 (0.970 g, 5.84 mmol, 1.0 equiv.) in diethylether (0.71 mL) was
added dropwise under N2 to a solution of o-tolyl magnesium bromide (5◦.14 mL, 2 M,
10.28 mmol, 1.76 equiv.) in diethyl ether. After stirring the mixture at 34 C for 5 h, a
solution of 1 M HCl was added at room temperature until the pH of the solution was 2.
After stirring the mixture for another hour, the mixture was extracted with ethyl acetate
(
2 mL × 4). The combined organic layers were dried over MgSO4. The solvent was
removed under reduced pressure and purified by flash chromatography on silica gel using
5% MeOH: 95% CH2Cl2 to give an oily product in 63% yield (0.675 g). H NMR (400 MHz,
1
CDCl3)
7.26–7.19 (m, 1H), 4.13 (m, J = 8.8, 7.1 Hz, 2H), 2.53 (s, 3H), 1.34 (t, J = 7.1 Hz, 6H). 13C NMR
(101 MHz, CDCl3) 141.2 (d, J = 10.8 Hz), 133.1 (d, J = 3.2 Hz), 132.1 (d, J = 7.2 Hz), 131.3
δ 7.77 (m, 1H), 7.60 (d, J = 555.1 Hz, 1H, PH), 7.48–7.40 (m, 1H), 7.29 (m, 1H),
δ
(d, J = 5.0 Hz), 128.2 (d, J = 131.1 Hz), 126.0 (d, J = 14.1 Hz), 62.2 (d, J = 6.0 Hz), 20.1 (d,
J = 6.9 Hz), 16.5 (d, J = 3.1 Hz). 31P NMR (162 MHz, CDCl3) δ 25.93 (d, J = 14.8 Hz).
Ethyl (4-methoxyphenyl)-H-phosphinate (48)
A solution of P(OEt)3 (0.100 g, 0.602 mmol, 1.0 equiv.) in THF (1.2 mL) was added
dropwise under N2 to a solution of 4-methoxyphenylmegnesium-bromide (1.8 mL, 0.5 M,
0.900 mmol, 1.5 equiv.) in THF. After stirring the mixture at 66 ◦C for 5 h, a solution of
1 M HCl was added at room temperature until the pH of the solution was 2. After stirring
the mixture for another hour, the mixture was extracted with ethyl acetate (2 mL
The combined organic layers were dried over MgSO4. The solvent was removed under
reduced pressure and purified by flash chromatography on silica gel using 5% MeOH: 95%
×
4).
CH2Cl2 to give an oily product in 87% yield (105 mg). The NMR data matched previously
1
published results [33]. H NMR (400 MHz, CDCl3)
δ
7.76–7.64 (m, 2H), 7.54 (d, J = 561.7 Hz
,
1H, HP), 7.00 (m, 2H), 4.16–4.08 (m, 2H), 3.85 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H). 13C NMR
(
101 MHz, CDCl3) δ 163.5 (d, J = 3.2 Hz), 133.2 (d, J = 13.2 Hz), 121.3 (d, J = 138.8 Hz), 114.5
(d, J = 14.9 Hz), 61.9 (d, J = 6.4 Hz), 55.6 – 55.5 (m), 16.6 (d, J = 6.6 Hz). 31P NMR (162 MHz,
CDCl3) δ 23.68 (d, J = 17.1 Hz).
Ethyl (4-fluorophenyl)-H-phosphinate (49)
A solution of P(OEt)3 (0.500 g, 3.01 mmol, 1.0 equiv.) in THF (3.76 mL) was added
dropwise under N2 to solution of 4-fluoro magnesium bromide (4.5 mL, 0.8 M, 3.60 mmol,
1.2 equiv.) in THF. After stirring the mixture at 66 ◦C for 12 h, a solution of 1 M HCl was
added at room temperature until the pH of the solution was 2. After stirring the mixture
for another hour, the mixture was extracted with ethyl acetate (2 mL
organic layers were dried over MgSO4. The solvent was removed under reduced pressure
and purified by flash chromatography on silica gel using 5% MeOH: 95% CH2Cl2 to give
×
4). The combined
an oily product in 27% yield (153 mg). The NMR data matched previously published
1
results [33]. H NMR (400 MHz, CDCl3)
δ 7.81–7.73 (m, 2H,), 7.55 (d, J = 567.1 Hz, 1H,
PH) 7.18 (m, 2H), 4.27–4.06 (m, 2H, OCH2), 1.36 (t, J = 7.1 Hz, 3H, CH3). 13C NMR
101 MHz, CDCl3) 167.2 (d, JCP = 3.2 Hz), 164.7 (d, JCF = 3.4 Hz), 133.8 (dd, JCP = 22.2 Hz
(
δ
JCF = 4.1 Hz), 127.6 (dd, JCP = 7.3 Hz, JCF = 7.9 Hz), 116.4 (dd, JCP = 36.7 Hz, JCF = 6.5 Hz),
62.4 (d, JCP = 6.2 Hz), 16.5 (d, JCP = 6.6 Hz). 31P NMR (162 MHz, CDCl3)
δ 23.48 (d,
J = 18.0 Hz).
General procedure for isopropyl (alkyl)-phenyl-phosphonate
Isopropyl phenyl-H-phosphinate (18) (0.100 g, 0.543 mmol, 1.0 equiv.) and carbon
tetrachloride (0.21 mL, 2.170 mmol, 4.0 equiv.) were added to a 7-mL reaction vial under an
atmosphere of N2. Next, anhydrous CH2Cl2 (0.3 M solution) was added, and the solution

Molecules 2021, 26, 3661
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◦
was cooled to 0 C. A solution of N,N-diisopropylethylamine (0.14 g, 1.080 mmol, 2 equiv.),
benzotetramisole (21) (0.03 g 0.110 mmol, 0.2 equiv.), and an alcohol (0.270 mmol, 0.5 equiv.)
that was previously dried over 4 Å molecular sieves, in anhydrous CH2Cl2 (0.3 mL), was
prepared. The alcohol ◦solution was added dropwise to the original phosphinate solution
and stirred for 9 h at 0 C. The mixture was quenched with 1M HCl (1.0 mL) and extracted
three times with ethyl acetate and then dried using NaSO4. The product was purified by
silica gel chromatography with ethyl acetate: hexane (30:70) as an eluent. The following
products were synthesized.
(R)-Isopropyl (phenyl)-phenyl-phosphonate (20)
1
Yield 35 mg (47%). The NMR data matched for previously published results [16]. H
NMR (400 MHz, CDCl3)
J = 7.9 Hz, 1H), 7.16–7.12 (m, 2H), 7.12 – 7.06 (m, 3H), 4.91–4.81 (m, 1H), 1.35 (d, J = 6.2 Hz
3H), 1.30 (d, J = 6.2 Hz, 3H). 13C NMR (101 MHz, CDCl3)
150.8 (d, J = 7.3 Hz), 132.7 (d,
δ 7.89–7.82 (m, 2H), 7.56–7.50 (m, 1H), 7.47–7.41 (m, 2H), 7.25 (t,
,
δ
J = 7.9 Hz), 132.1 (d, J = 16.1 Hz), 129.7 (d, J = 7.7 Hz), 128.6 (d, J = 25.9 Hz), 128.6 (dd,
J = 108.8, 82.8 Hz), 120.8 (d, J = 2.6 Hz), 72.3 (d, J = 5.9 Hz), 24.1 (d, J = 2.3 Hz), 24.0 (d,
J = 5.6 Hz). 31P NMR (162 MHz, CDCl3) 14.92. [α]D20 + 15.1◦ (c 0.26, CHCl3, 55% ee). The
δ
absolute configuration of compound 20 is designated the (R)-configuration based on the
optical rotation of the previously published analogue 30.
(S)-Isopropyl (allyl)-phenyl-phosphonate (34)
1
Yield 31.8 mg (49%). H NMR (400 MHz, CDCl3)
δ 7.85–7.74 (m, 2H), 7.56–7.49 (m,
1H), 7.47–7.39 (m, 2H), 5.90 (m 2H), 5.30 (dq, J = 17.1, 1.6 Hz, 2H), 5.18 (dq, J = 10.4, 1.4 Hz,
1H), 4.73 (m, 1H), 4.58–4.41 (m, 1H), 1.30 (dd, J = 48.2, 6.2 Hz, 6H). 13C NMR (101 MHz,
CDCl3)
J = 15.2 Hz), 71.3 (d, J = 6.6 Hz), 66.4 (d, J = 4.7 Hz), 24.2 (d, J = 3.6 Hz), 24.0 (d, J = 4.9 Hz).
31P NMR (162 MHz, CDCl3) 18.53. HRMS (ES): m/z [M + H]+: calcd for C12H18O3P
241.0994; found: 241.0983. [α]2D0 1.3◦ (c 0.23, CHCl3). The absolute configuration of
δ 133.1 (d, J = 6.5 Hz), 132.5 (d, J = 2.2 Hz), 131.9 (d, J = 10.0 Hz), 130.0 (s), 128.6 (d,
δ
−
compound 34 is designated to be the (S)-configuration based on the analogous reactivity
of 30.
(S)-Phenethyl (isopropyl)-phenyl-phosphonate (35)
1
Yield 55.9 mg (68%). H NMR (400 MHz, CDCl3)
δ 7.76–7.68 (m, 2H), 7.54–7.48 (m,
1H), 7.44–7.36 (m, 2H), 7.30–7.14 (m, 5H), 4.73–4.60 (m, 1H), 4.30–4.08 (m, 2H), 2.97 (t,
J = 7.1 Hz, 2H), 1.27 (dd, J = 41.1, 6.2 Hz, 6H). 13C NMR (101 MHz, CDCl3)
δ
137.5 (s),
132.4 (d, J = 6.9 Hz), 131.9 (d, J = 8.0 Hz), 129.2 (d, J = 2.8 Hz), 129.0 (d, J = 188.6 Hz),
128.6 (d, J = 2.2 Hz), 128.5 (d, J = 9.6 Hz), 126.8 (d, J = 2.8 Hz), 71.2 (d, J = 14.7 Hz), 66.4 (d,
J = 5.6 Hz), 37.1 (d, J = 6.7 Hz), 24.2 (d, J = 9.0 Hz), 24.0 (d, J = 9.9 Hz). 31P NMR (162 MHz,
CDCl3) δ
18.15. HRMS (ES)+: m/z [M + H]+ calcd for C17H22O3P: 305.1307; found: 305.1302.
[α]2D0 − 2.9◦ (c 0.68, CHCl3). The absolute configuration of compound 35 is designated to
be the (S)-configuration based on the analogous reactivity of 30.
(S)-Benzyl (isopropyl)- phenyl-phosphonate (36)
1
Yield 40.0 mg (51%). H NMR (400 MHz, CDCl3)
δ 7.84–7.77 (m, 2H), 7.55–7.50 (m,
1H), 7.43 (m, 2H), 7.35–7.26 (m, 5H), 5.04 (m 2H), 4.73 (m, 1H), 1.29 (dd, J = 37.2, 6.2 Hz,
6H). 13C NMR (101 MHz, CDCl3)
δ
136.5 (d, J = 7.2 Hz), 132.5 (d, J = 3.0 Hz), 131.9 (d,
J = 9.9 Hz), 129.0 (d, J = 189.1 Hz), 128.6 (s), 128.5 (s), 128.4 (s), 127.9 (s), 71.4 (d, J = 4.0 Hz),
67.4 (d, J = 5.1 Hz), 24.2 (d, J = 4.1 Hz), 24.0 (d, J = 4.9 Hz). 31P NMR (162 MHz, CDCl3)
δ
19.25. HRMS (EI) m/z [M + H]+ calcd for C16H19O3P: 290.10719; found: 290.10667.
[α]2D0 − 6.3 (c 0.44, CHCl3). The absolute configuration of compound 36 is designated to be
the (S)-configuration based on the analogous reactivity of 30.
(S)-Isopropyl (methyl)-phenyl-phosphonate (37)
1
Yield 32.4 mg (56%). The NMR data matched previously published results [16]. H
NMR (400 MHz, CDCl3)
δ 7.80–7.73 (m, 2H), 7.54–7.48 (m, 1H), 7.45–7.38 (m, 2H), 4.70

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(m J = 2H), 3.68 (d, J = 11.2 Hz, 3H), 1.35 (d, J = 6.2 Hz, 3H), 1.22 (d, J = 6.2 Hz, 3H). 13
C
NMR (101 MHz, CDCl3)
δ
132.5 (d, J = 2.9 Hz), 131.9 (d, J = 9.8 Hz), 128.6 (d, J = 15.0 Hz),
128.6 (d, J = 188.7 Hz), 71.3 (d, J = 5.4 Hz), 52.5 (d, J = 2.8 Hz), 24.2 (d, J = 3.9 Hz), 24.0
(d, J = 4.9 Hz). 31P NMR (162 MHz, CDCl3) 19.12. [α]2D0 + 0.19◦ (c 0.54, CHCl3). The
δ
absolute configuration of compound 37 is designated to be the (S)-configuration based on
the analogous structure (S)-Ethyl (Methyl)-phenyl-phosphonate [45].
(R)-Methyl (phenyl)-phenyl-phosphonate (29)
Methyl phenyl-H-phosphinate (46) (0.100 g, 0.641 mmol, 1.0 equiv.) and carbon
tetrachloride (0.23 mL, 2.422 mmol, 3.8 equiv.) were added to a 7-mL reaction vial under an
atmosphere of N2. Next, anhydrous CH2Cl2 (0.3 M solution) was added, and the solution
◦
was cooled to 0 C. A solution of N,N-diisopropylethylamine (0.16 g, 1.211 mmol, 2.0 equiv.),
benzotetramisole (S)-21 (0.031 g, 0.121 mmol, 0.19 equiv.), and phenol (28.2 mg, 0.300 mmol,
0.47 equiv.) that was previously dried over 4 Å molecular sieves was prepared in anhydrous
CH2Cl2 (0.3 mL). The alcohol solution was added dropwise to the phosphinate solution
and stirred for 9 h at 0 ◦C. The mixture was quenched with 1 M HCl (1 mL) and extracted
three times with ethyl acetate then dried with Na2SO4. The product was purified by silica
gel chromatography with ethyl acetate: hexane (50:50) as eluent. The NMR data matched
1
previously published results [16]. Yield 24.6 mg, (33%). H NMR (400 MHz, CDCl3)
δ 7.86
(m, 1H), 7.59–7.52 (m, 2H), 7.50–7.42 (m, 1H), 7.29–7.23 (m, 2H), 7.17–7.07 (m, 5H), 3.84 (d,
J = 11.3 Hz, 1H). 13C NMR (101 MHz, CDCl3)
150.7 (d, J = 7.2 Hz), 133.1 (d, J = 3.0 Hz),
132.2 (d, J = 10.1 Hz), 129.8 (s), 128.8 (d, J = 15.5 Hz), 127.1 (d, J = 191.0 Hz), 125.1 (s), 120.7
(d, J = 4.5 Hz), 53.31 (d, J = 3.5 Hz). 31P NMR (162 MHz, CDCl3) 17.39 (s). [α]2D0 + 19.7◦
(c 0.14, CHCl3). The absolute configuration of compound 29 was determined to be (R)-
δ
δ
configuration based on the previously published optical rotation of the 29 (
[α]2D0 + 38.1◦
(c 1.45, CHCl3)), which was defined using chiral shift reagents [44].
General procedure for synthesis Ethyl (Aryl)-phenyl-phosphonate
Ethyl aryl-H-phosphinate (11) (0.100 g, 0.588 mmol, 1.0 equiv.) and carbon tetra-
chloride (0.21 mL, 2.170 mmol, 3.7 equiv.) were added to a 7-mL reaction vial under an
atmosphere of N2. Next, anhydrous CH2Cl2 (0.3 mL solution) was added, and the solu-
tion was cooled to 0 ◦C. A solution of N,N-diisopropylethylamine (0.140 g, 1.100 mmol,
1.9 equiv.), benzotetramisole (S)-21 (0.027 g 0.110 mmol, 0.19 equiv.), and phenol (0.024 g,
0.25 mmol, 0.43 equiv.) that was previously dried over 4 Å molecular sieves was prepared
in anhydrous CH2Cl2 (0.3 mL). The alcohol solution was added dropwise to the phosphi-
nate solution and stirred for 9 h at 0 ◦C. The mixture was quenched with 1 M HCl (1 mL),
extracted three times with ethyl acetate, and then dried with Na2SO4. The product was
purified by silica gel chromatography with ethyl acetate: hexane (30:70) as the eluent. The
following products were synthesized.
(R)-Ethyl (phenyl)-phenyl-phosphonate (30)
Yield 62.3 mg (95%). The NMR data matched with previously published results [16].
1H NMR (400 MHz, CDCl3)
δ
7.91–7.81 (m, 2H), 7.59–7.51 (m, 1H), 7.50–7.40 (m, 2H),
7.28–7.23 (m, 2H), 7.16–7.07 (m, 3H), 4.29–4.18 (m, 2H), 1.34 (t, J = 7.1 Hz, 3H). 13C
NMR (101 MHz, CDCl3) 150.7 (d, J = 7.0 Hz), 132.9 (s), 132.19 (d, J = 10.1 Hz), 128.7
(d, J = 15.5 Hz), 127.4 (d, J = 485.6 Hz), 126.9 (s), 124.1 (s), 120.7 (d, J = 4.5 Hz), 63.0
δ
(d, J = 5.6 Hz), 16.5 (d, J = 7.3 Hz). 31P NMR (162 MHz, CDCl3)
δ 14.43 (d, J = 12.7 Hz).
[α]2D0 + 21.7◦ (c 0.43, CHCl3). The absolute configuration of compound 30 was deter-
mined to be the (R)-configuration based on the previously published optical rotation of 30
([α]2D0 + 34.4◦ (c 2.16, CHCl3)), which was defined using chiral shift reagents [44].
(R)-Ethyl (2-methylphenyl)-phenyl-phosphonate (31)
1
Yield 46.3 mg (67%). H NMR (400 MHz, CDCl3)
δ 7.91–7.82 (m, 2H), 7.29–7.23 (m,
2H), 7.17–7.07 (m, 5H), 4.29–4.18 (m, 2H), 1.33 (td, J = 7.1, 0.6 Hz, 3H). 13C NMR (101 MHz,

Molecules 2021, 26, 3661
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CDCl3) δ 167.0 (d, J = 3.9 Hz), 164.4 (d, J = 3.8 Hz), 150.6 (d, J = 7.4 Hz), 134.8 (dd, J = 11.6,
9.0 Hz), 129.8 (s), 125.1 (s), 120.7 (d, J = 4.6 Hz), 116.1 (dd, J = 21.5, 16.8 Hz), 63.2 (d,
J = 6.1 Hz), 16.5 (d, J = 6.5 Hz). 31P NMR (162 MHz, CDCl3)
[
δ
14.78. HRMS (EI) m/z
M + H]+ calcd for C15H17O3P: 276.09154; found: 276.09189; [α]D20 + 17.4 (c 0.55, CHCl3).
The absolute configuration of compound 31 is designated to be the (R)-configuration based
on the analogous reactivity of 30.
(R)-Ethyl (4-methoxyphenyl)- phenyl- phosphonate (32)
1
Yield 64.3 mg (88%). H NMR (400 MHz, CDCl3)
δ 8.01–7.92 (m, 1H), 7.43 (m, 1H),
7.29–7.22 (m, 5H), 7.15 (m, 1H), 7.13–7.07 (m, 1H), 4.24 (m, 2H), 2.65 (d, J = 1.7 Hz, 3H), 1.33
(t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3)
δ
155.1 (d, J = 6.9 Hz), 146.4 (d, J = 10.4 Hz),
138.6 (d, J = 10.6 Hz), 137.3 (s), 135.8 (d, J = 15.3 Hz), 134.1 (s), 130.0 (d, J = 15.4 Hz), 129.2 (s),
124.8 (d, J = 4.4 Hz), 67.7 (d, J = 6.0 Hz), 25.8 (d, J = 3.4 Hz), 20.7 (d, J = 6.4 Hz). 31P NMR
(162 MHz, CDCl3)
δ
16.84. HRMS (EI) m/z [M + H]+ calcd for C15H17O4P: 292.08645; found:
292.08532. [α]2D0 + 9.7 (c 0.6713, CHCl3). The absolute configuration of compound 32 is
designated to be the (R)-configuration based on the analogous reactivity of 30.
(R)-Ethyl (4-fluorophenyl)-phenyl-phosphonate (33)
1
Yield 65.3 mg (93%). H NMR (400 MHz, CDCl3)
δ 7.78 (m, 2H), 7.27–7.21 (m, 2H),
7.15–7.04 (m, 3H), 6.97–6.91 (m, 2H), 4.26–4.15 (m, 2H), 3.81 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H).
13C NMR (101 MHz, CDCl3)
δ
163.3 (d, J = 3.4 Hz), 150.9 (d, J = 7.0 Hz), 134.2 (d, J = 11.6 Hz),
129.8 (s), 124.9 (s), 120.8 (d, J = 4.4 Hz), 119.0 (d, J = 198.1 Hz), 114.3 (d, J = 16.6 Hz), 62.8
(d, J = 5.5 Hz), 55.5 (d, J = 2.3 Hz), 16.5 (d, J = 6.6 Hz). 31P NMR (162 MHz, CDCl3)
δ
16.88. HRMS (EI)+ m/z [M + H]+: calcd for C14H14O3PF: 280.06646; found: 280.06528.
[α]2D0 + 3.8 (c 0.55, CHCl3). The absolute configuration of compound 33 is designated to be
the (R)-configuration based on the analogous reactivity of 30.
4. Conclusions
A dynamic kinetic transformation that produces stereogenic-phosphorus centers
using an asymmetric nucleophilic catalyst was developed. Alcohols, both aliphatic and
aromatic, were coupled to racemic H-phosphinates under halogenation conditions. After
the optimization of the solvent, base, temperature, and catalyst loading, benzotetramisole
was observed to provide asymmetric phosphonates in acceptable yield (33%–95%) with
moderate enantioselectivity (up to 62% ee). The reaction conditions were tolerant to a
variety of alcohol and H-phosphinate substrates. Furthermore, a mechanism of selective
phosphorylation was proposed that accounts for the stereoselectivity. Future development
of the benzotetramisole catalyst could improve enantioselectivity and enable the synthesis
of prodrugs for pharmaceutical or biological application.
Supplementary Materials: The following are available online. Copies of the 1H, 13C, and 31P NMR
spectra for all compounds are available online. HPLC of racemic, chiral products and HRMS of novel
compounds (31–36) are also available online.
Author Contributions: M.B. conceptualized the idea, supervised the research, outlined the research
strategy and idea, and edited the manuscript. A.N. designed and preformed all the experimental
procedures. A.N. also wrote the manuscript. Both authors have read and agreed to the published
version of the manuscript.
Funding: Higher Committee of Education Development in Iraq (HCED Iraq) for funding the au-
thor’s scholarship.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: The following are available on at the Supplementary Materials. (1) 1H,
13C, and 31P NMR spectra; (2) HPLC chromatograms; and mass spectra of the obtained compounds.

Molecules 2021, 26, 3661
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Acknowledgments: The authors would like to thank the Higher Committee of Education Develop-
ment in Iraq (HCED Iraq) for the fellowship for A.N.
Conflicts of Interest: The authors declare no conflict of interest.
Sample Availability: Samples of the compounds (20, 29–37) are available from the authors.
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