The Synthesis of α-Aminophosphonates via Enantioselective Organocatalytic Reaction of 1-(N-Acylamino)alkylphosphonium Salts with Dimethyl Phosphite

Article abstract of DOI:10.3390/molecules25020405

α-Aminophosphonic acids are phosphorus analogues of α-amino acids. Compounds of this type find numerous applications in medicine and crop protection due to their unique biological activities. A crucial factor in these activities is the configuration of the stereoisomers. Only a few methods of stereoselective transformation of α-amino acids into their phosphorus analogues are known so far and all of them are based on asymmetric induction, thus involving the use of a chiral substrate. In contrast, we have focused our efforts on the development of an effective method for this type of transformation using a racemic mixture of starting N-protected α-amino acids and a chiral catalyst. Herein, a simple and efficient stereoselective organocatalytic α-amidoalkylation of dimethyl phosphite by 1-(N-acylamino)alkyltriphenylphosphonium salts to enantiomerically enriched α-aminophosphonates is reported. Using 5 mol% of chiral quinine- or hydroquinine-derived quaternary ammonium salts provides final products in very good yields up to 98% and with up to 92% ee. The starting phosphonium salts were easily obtained from α-amino acid derivatives by decarboxylative methoxylation and subsequent substitution with triphenylphosphonium tetrafluoroborate. The appropriate self-disproportionation of enantiomers (SDE) test for selected α-aminophosphonate derivatives via achiral flash chromatography was performed to confirm the reliability of the enantioselectivity results that were obtained.

Full text of DOI:10.3390/molecules25020405

molecules
Article
The Synthesis of α-Aminophosphonates via
Enantioselective Organocatalytic Reaction of
1-(N-Acylamino)alkylphosphonium Salts with
Dimethyl Phosphite
Alicja Wale˛cka-Kurczyk 1,2, Krzysztof Walczak 1 , Anna Kuz´nik 1,2, Sebastian Stecko 3 and
Agnieszka Paz´dzierniok-Holewa 1,2,
*
1
Department of Organic Chemistry, Bioorganic Chemistry and Biotechnology, Silesian University of
Technology, B. Krzywoustego 4, 44-100 Gliwice, Poland; alicja.walecka-kurczyk@polsl.pl (A.W.-K.);
krzysztof.walczak@polsl.pl (K.W.); anna.kuznik@polsl.pl (A.K.)
Biotechnology Center of Silesian University of Technology, B. Krzywoustego 8, 44-100 Gliwice, Poland
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland;
sebastian.stecko@icho.edu.pl
2
3
*
Correspondence: agnieszka.pazdzierniok-holewa@polsl.pl; Tel.: +48-032-237-2218; Fax: +48-032-237-2094
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
Academic Editor: Erika Bálint
Received: 2 December 2019; Accepted: 16 January 2020; Published: 18 January 2020
ꢀꢁꢂꢃꢄꢅꢆ
Abstract: α-Aminophosphonic acids are phosphorus analogues of α-amino acids. Compounds
of this type find numerous applications in medicine and crop protection due to their unique
biological activities. A crucial factor in these activities is the configuration of the stereoisomers.
Only a few methods of stereoselective transformation of
α-amino acids into their phosphorus
analogues are known so far and all of them are based on asymmetric induction, thus involving
the use of a chiral substrate. In contrast, we have focused our efforts on the development of an
effective method for this type of transformation using a racemic mixture of starting N-protected
α
-amino acids and a chiral catalyst. Herein, a simple and efficient stereoselective organocatalytic
-amidoalkylation of dimethyl phosphite by 1-(N-acylamino)alkyltriphenylphosphonium salts to
α
enantiomerically enriched α-aminophosphonates is reported. Using 5 mol% of chiral quinine- or
hydroquinine-derived quaternary ammonium salts provides final products in very good yields
up to 98% and with up to 92% ee. The starting phosphonium salts were easily obtained from
α
-amino acid derivatives by decarboxylative methoxylation and subsequent substitution with
triphenylphosphonium tetrafluoroborate. The appropriate self-disproportionation of enantiomers
(SDE) test for selected -aminophosphonate derivatives via achiral flash chromatography was
performed to confirm the reliability of the enantioselectivity results that were obtained.
α
Keywords: α-aminophosphonic acids;
α-amidoalkylation; Cinchona alkaloids
α-aminophosphonates; phosphonium salts; stereoselectivity;
1. Introduction
α
-Aminophosphonic acids are one of the most recognizable classes of organophosphorus
compounds. Structurally, they are analogues of -amino acids in which the planar carboxylic
group is replaced with a tetrahedral phosphonic acid group (Figure 1a). Almost 60 years of research
has shown that many naturally occurring and synthetic -aminophosphonic acids, as well as their
derivatives, exhibit multidirectional, significant biological activities [ ]. Compounds of this class
are increasingly used in the synthesis of various types of peptidomimetics, clearly showing greater
α
α
1,2
activity than the genuine peptides. Among the structurally diverse
α
-aminophosphonic acids and
Molecules 2020, 25, 405; doi:10.3390/molecules25020405
www.mdpi.com/journal/molecules

Molecules 2020, 25, 405
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their derivatives, enzyme inhibitors, antibacterial and antifungal agents, anticancer agents, as well as
herbicides and plant growth regulators can be found (Figure 1b) [1–7].
Figure 1.
(a) Structure of α-amino acid and α-aminophosphonic acid; (b) Selected examples of
biologically active phosphonic analogues of α-amino acids and their derivatives.
Due to the possibility of wide applications of
various methods for their synthesis have been developed over the past several decades [5,8–11].
It seems natural that -amino acids should be the most frequently used substrates for the synthesis
-aminophosphonic acids. However, to the best of our knowledge, only a few methods for the
transformation of -amino acids into their phosphonic analogues have been reported so far [12 24].
α-aminophosphonic acids and their derivatives,
α
of
α
α
–
Furthermore, only five of them can be classified as stereoselective processes. For example, Seebach
and Renaud [12] have described a diastereoselective transformation of a trans-4-hydroxy-L-proline
derivative into its phosphonic analogue (Scheme 1a). The proposed three-step path involved the
oxidative decarboxylation of a proline derivative leading to 2-methoxyproline, which by the Ti-catalyzed
addition of P(OMe)3 followed by acidic hydrolysis produced the generation of aminophosphonic
acids with high dr 96:4 via a carbenium ion (Scheme 1a). Seebach et al. [14] have also used the same
concept in a diastereoselective synthesis of acyclic N-protected phosphonodiesters, starting from
l-threonine (Scheme 1b). However, in this case, the Michaelis-Arbuzov-type reaction exhibited no
significant stereoselectivity, leading to an essentially equimolar mixture of products (Scheme 1b).
In 2002, Larchev
-aminophosphonic acid esters with high diastereoselectivity (Scheme 1c). The crucial step in this
strategy was the regioselective catalytic hydrogenation of N-Boc protected cis aziridines derived from
syn -hydroxy -aminophosphonates. In 2008, Kapoor et al. [19] described the reaction of ethyl esters
êque and Pousset [17] reported another method for the preparation of N-Boc-protected
α
α
β
of (S)-phenylglycine or (S)-phenylalanine with aryl aldehydes and dimethyl phosphite in the presence
of antimony trichloride adsorbed on alumina as a catalyst (Scheme 1d). The authors obtained the
expected mixtures of α-aminophosphonates in good yields and a diastereomeric ratio equal to 9:1
or 3:2. In 2013, Boto et al. [24] developed a sequential radical scission-oxidation/phosphorylation
protocol for the synthesis of 2-phosphonoproline derivatives (Scheme 1e). It was demonstrated that
the diastereoselectivity of this reaction was highly dependent on the nitrogen substituent type at the
C-4 position. For example, azanucleotide analogues were obtained with very good overall yields and
diastereomeric cis/trans ratios in the range from 98:2 to 15:85.

Molecules 2020, 25, 405
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Scheme 1. The stereoselective transformation of N-protected
their phosphorus analogues—known synthetic routes (a–e).
α-amino acids and their derivatives into
In 2012, we described an efficient protocol for the synthesis of 1-(N-acylamino)alkylphosphonium
from N-acyl- -amino acids (Scheme 2b) [25], which may serve as attractive precursors
of 1-(N-acylamino)alkylphosphonic and phosphinic acid esters via the Michaelis-Arbuzov-type
reaction [26 27]. In an extension of these studies, in 2016, Mazurkiewicz et al. [28] targeted pure
enantiomers of -aminoalkylphosphonic acids and -aminophosphonates by the enzymatic kinetic
salts
2
α
1
,
α
α
resolution of their racemic mixtures (Scheme 2a) in the presence of Penicillin G acylase to provide
the corresponding enantiomers with high ee (enantiomeric excess) values. Of course, the maximum
50% yield of such an approach was its main limitation. So far, there are no reports on purely
enantioselective methods for the preparation of enantiomerically enriched phosphonic acid esters
directly from phosphonium salts in a carbon–phosphorus bond-forming reaction in the presence of an
enantiodifferentiating agent.

Molecules 2020, 25, 405
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Scheme 2. The transformation of N-protected
via 1-(N-acylamino)alkylphosphonium salts: (
racemic mixtures of -aminoalkylphosphonic acids and
based on enantioselective catalytic -amidoalkylation of dimethyl phosphite with phosphonium salts.
α
-amino acids into
) The method based on enzymatic kinetic resolution of
-aminophosphonates; ( ) A new approach
α-aminophosphonate derivatives
a
α
α
b
α
Here, we present our recent results on the enantioselective catalytic
phosphite with 1-(N-acylamino)alkylphosphonium salts in the presence of a chiral catalyst. Taking
into account that the starting 1-(N-acylamino)alkylphosphonium tetrafluoroborates are readily
, the presented approach can be considered a new strategy for
α-amidoalkylation of dimethyl
2
2
available from N-acyl-
α
-amino acids
1
the transformation of N-acyl-
α
-amino acids 1 into non-racemic 1-(N-acylamino)alkylphosphonic acid
esters 3 (Scheme 2b).
2. Result s and Discussion
At the outset of our studies, systematic exploration of different reaction conditions was
conducted in order to optimize the yield and enantioselectivity. This initial screening was
performed using two phosphonium salts, 2a and 2b, obtained from N-benzyloxycarbonyl alanine
(Cbz-Ala-OH) and N-benzyloxycarbonyl phenylalanine (Cbz-Phe-OH), respectively (Scheme 3, Table 1).
Four chiral quaternary ammonium salts 4–7, derived from hydroquinine or quinine, were selected as
stereo-differentiating agents. We decided to use this type of chiral catalysts in our reaction for several
reasons. First, these Cinchona alkaloid derivatives can be obtained by simple and low-cost methods
from commercially available substrates [29
as a useful chiral base, as well as chiral phase transfer (PT) catalysts for the reaction of stable or in
situ generated N-acylimines with various nucleophiles, for example carbon nucleophiles [30 34] and
phosphorus nucleophiles, such as dialkyl phosphites [30 34 39]. Therefore, we expected the use of
chiral catalysts for the stereoselective -amidoalkylation of dimethyl phosphite with phosphonium
,30]. Moreover, this class of organocatalysts has emerged
–
,
–
4–
7
α
salts 2 to provide satisfactory results (Scheme 3).
Initially, salt 2a was reacted with dimethyl phosphite in toluene, using 2-fluoro substituted
N-benzylhydroquininium bromide
1). After three days, the expected dimethyl N-protected
4
as the catalyst (5 mol%) and excess K2CO3 at
−
70◦C (Table 1, entry
α
-aminoethylphosphonate 3a was obtained
with a moderate yield and enantioselectivity. The same reaction carried out in the presence of 3 equiv.
of KOH as a base allowed us to increase the yield of 3a to 84% and enhanced the enantiomeric excess to
84% (Table 1, entry 2). In order to improve the solubility of phosphonium salt 2a in the reaction mixture,
a further experiment with the addition of a small amount of CH2Cl2 was performed. Unfortunately, we
obtained the expected product 3a in a lower yield and enantioselectivity (cf. Table 1, entries 2 and 3).
Next, screening of catalysts for the reaction of phosphonium salt 2a with dimethyl phosphite
was performed (Scheme 3, Table 1, entry 5 to 7). The reactions were carried out under standard
conditions using 3 equiv. of KOH, 5 mol% of catalysts
5 to 7 (all bearing an ortho substituent at the
benzylic quinuclidinic moiety) in toluene at
−
70◦C (Table 1, entries 5 to 7). Among the examined

Molecules 2020, 25, 405
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catalysts, 4-F-substituted catalyst
4
, derived from hydroquinine, and 2-methoxy substituted catalyst
5
, derived from quinine, gave the best results (see Table 1, entries 2 and 5). Taking into account the
strong amidoalkylating properties of phosphonium salts 2 [40,41], we decided to perform the next
experiment with the amount of KOH decreased by half. However, this decrease in the base loading
caused a drop in yield and enantioselectivity (Table 1, entry 4).
Scheme 3. Reaction of phosphonium salts 2a-b with dimethyl phosphite in the presence of chiral
catalysts 4-7.
Table 1. Screening of the reaction conditions for PT-catalyzed stereoselective
reaction 1.
α-amidoalkylation
Catalyst
(5 mol%)
Base
(equiv.)
Time
[days]
Entry
Salt
R
Yield 2 [%]
ee 3 [%]
1
2
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
2b
2b
2b
Me
Me
Me
Me
Me
4
4
4
4
5
6
7
4
4
4
4
4
5
5
5
K2CO3 (3)
KOH (3)
KOH (3)
KOH (1.5)
KOH (3)
KOH (3)
KOH (3)
KOH (3)
KOH (3)
KOH (1.5)
KOH (2)
KOH (1.5)
KOH (3)
KOH (3)
KOH (3)
3
3
3
3
3
3
3
3
1
3
1
1
3
2
1
62
84
71
64
84
75
82
87
78
47 5
70
63
84
79
71
49
84
59
78
83
81
72
65
68
78
73
70
73
70
74
3 4
4
5
6
7
8
Me
Me
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
9
10
11
12
13
14
15
1
Reaction conditions: Phosphonium salt
(0.01 mmol, 5 mol%), toluene (2 mL),
2 (0.2 mmol), dimethyl phosphite (0.6 mmol, 3 equiv.), catalyst 4–7
3
−
70 ◦C. 2 Isolated yield. The enantiomeric excess (ee) was determined by
4
HPLC using a column with a chiral stationary phase. The reaction was carried out in a mixture of toluene/CH2Cl2
9:1 (2 mL) 5 The reaction mixture additionally contained benzyl N-(1-hydroxy-2-phenylethyl)carbamate.
Next, phosphonium salt 2b with a larger substituent at the α-position was subjected to the model
reaction as a starting material (Scheme 3, Table 1, entries 8–15). The influence of the catalyst type and
the amount of KOH on the reaction efficiency was investigated. As highlighted in Table 1, the reaction
of phosphonium salt 2b with dimethyl phosphite in toluene conducted for 3 days at
presence of chiral catalyst and KOH (3 equiv.) gave the most satisfactory results. The expected
-aminophosphonate 3b was obtained with a high yield and good enantioselectivity (Table 1, entry 13,
−
70◦C in the
5
α
84% yield, 73% ee). Additionally, in order to examine the possibility of racemization of the product
under these reaction conditions, subsequent experiments were performed during a shorter time of 1 or
2 days. Based on the results obtained, we excluded the probability of such side processes (Table 1,
entries 14 to 15).

Molecules 2020, 25, 405
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Thus, we decided that the best reaction conditions for the stereoselective
α
-amidoalkylation of
dimethyl phosphite by phosphonium salts were three equivalents of KOH and three days in toluene at
the temperature of −70◦C, in the presence of chiral PT catalyst 4 or 5.
With the optimized conditions in hand, the scope of the stereoselective
α
-amidoalkylation of
dimethyl phosphite with various phosphonium salts 2a
–
k
, catalyzed by chiral ammonium salts or 5
4
was investigated (Scheme 4, Table 2).
Scheme 4.
Enantioselective organocatalytic α-amidoalkylation of dimethyl phosphite with
phosphonium salts 2.
Table 2. Substrate scope of the stereoselective reaction of phosphonium salts
2
with dimethyl phosphite 1.
Entry
Product 3
Catalyst
Yield 2 [%]
ee 3 [%]
4
5
84
84
84
83
3a
1
2
3b
4
84
73
4
5
93
73
72
61
3
4
3c
3d
4
4
82
88
56
23 4
5
6
3e
3f
4
5
82
60
80
79
7
3g
4
4
85
80
80
92
8
9
3h
3i
4
5
79
69
65
55
4
5
98
88
53
54
3j
10
11
4
5
69
84
42
53
3k
1
The reaction was carried out with phosphonium salt
in the presence of catalyst or (0.01 mmol, 5 mol%) and KOH (0.6 mmol, 3 equiv.) in toluene (2 mL), at
Isolated yield. The enantiomeric excess (ee) was determined by HPLC using a column with a chiral stationary
2
(0.2 mmol) and dimethyl phosphite (0.6 mmol, 3 equiv.)
4
5
−
70 ◦C.
2
3
4
phase. Determined after Boc deprotection and Cbz derivatisation.

Molecules 2020, 25, 405
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Similarly as for the above mentioned reaction of N-Cbz-protected salt 2b with dimethyl phosphite,
the same reaction of N-Boc-protected phosphonium salt 2c resulted in a very good yield of 93% and
72% ee (compare Table 2, entries 2 to 3). In the case of more sterically hindered salts, such as 2d and
2i–k, the reaction with dimethyl phosphite furnished generally good yields in the range of 69%–98%
and moderate 42%–65% ee (see Table 2, entries 4, 9 to 11). Interestingly, in the case of N-Boc-protected
valine-derivative 2e, a significant decrease in enantioselectivity (to 23% ee) was observed (Table 2,
entry 5), indicating that the steric hindrance at the β-position of the amino acid moiety could affect the
transition state responsible for enantiodifferentiation. In comparison, the removal of the unfavorable
steric interaction, as in the case of leucine-derived salt 2f, led to a respectable stereoselectivity level
to provide product 3f in good yields and with ee values of 80% (with cat.
respectively (see Table 2, entry 6). To our delight, under these conditions, phosphonium salts derived
from unnatural amino acids, such as norvaline 2g and norleucine 2h, gave the expected products 3g
4) and 79% (with cat. 5),
,h
with very good yields and useful enantioselectivities (see Table 2, entry 7, 85% yield, 80% ee and entry
8, 80% yield, 92% ee).
It is well known that ee values can be improved via recrystallization, which leads to the
self-disproportionation of enantiomers (SDE) phenomenon [42]. Additionally, it has been demonstrated
that some compounds, e.g., enantiomerically enriched
α and β-amino acid derivatives [43,44] and
especially -amino- -difluorophosphonic acid derivatives [45] exhibit pronounced SDE during
β
α,α
achiral column chromatography. The occurrence of the SDE phenomenon may cause mistakes in the
reporting of the ee value of catalytic asymmetric reactions. Thus, we conducted the SDE test via achiral
flash chromatography in order to confirm that the values of enantiomeric excess that were obtained
were reliable. After performing the appropriate test, we found that no SDE phenomenon was present
in our case (for details, see Supplementary Materials).
The comparison of the optical rotation of two selected dimethyl aminophosphonate derivatives
3a and 3f with literature values allowed us to determine the absolute configuration of the products to
be R (see paragraph in Materials and Methods). It has been found that phosphonic acid derivatives
possessing the (R)-configuration, corresponding to the stereochemistry of proteinogenic L-
α-amino
acids, exhibit higher biological activities than their S analogues [ ]. For example, the R enantiomer of the
2
phosphonic acid analogue of leucine is a significantly more potent inhibitor of leucine aminopeptidase
than its S enantiomer [46].
In conclusion, we developed a simple and effective enantioselective route for the α-amidoalkylation
of dimethyl phosphite with 1-(N-acylamino)alkyltriphenylphosphonium tetrafluoroborates in the
presence of inexpensive and easily available chiral Cinchona alkaloid derivatives under PTC conditions.
The methodology provided constitutes a convenient approach for the synthesis of enantiomerically
enriched, especially sterically unhindered dimethyl N-protected
values above 80%. Taking into account that the starting phosphonium salts are readily available from
the corresponding -amino acids, the presented procedure can be considered a new strategy for the
α-aminophosphonates, with useful ee
α
enantioselective construction of non-racemic
sets the basis for further developments.
α-aminophosphonates from N-acyl-α-amino acids and
3. Materials and Methods
3.1. General Information
Infrared spectra (IR) were recorded on a Nicolet 6700 FT-IR spectrophotometer, Thermo Scientific,
1
USA (ATR method). H-NMR spectra were acquired on Varian 400 at 400 MHz. Data were given as
follows: chemical shift in ppm with tetramethylsilane (TMS) as the internal standard, multiplicity
(
s = singlet; d = doublet; t = triplet; q = quartet; br = broad; m = multiplet), coupling constant (Hz),
and integration. 13C-NMR spectra were measured on Varian 400 at 100 MHz. Chemical shifts were
reported in ppm from the solvent resonance employed as the internal standard (CDCl3 at 77.0 ppm).
31P NMR spectra were measured on a Varian 400 spectrometer at 162 MHz without the resonance shift

Molecules 2020, 25, 405
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standard, with respect to H3PO4 as zero ppm. Melting points were determined in capillaries in a Stuart
Scientific SMP3 melting point apparatus and were uncorrected. The high-resolution mass spectra
(HRMS) were obtained by electrospray ionization (ESI) using a Waters Corporation Xevo G2 QTOF
instrument. Sonication was carried out using Elmasonic 10H laboratory ultrasonic bath (37 kHz, 30 W).
α
-Amidoalkylation reactions of dimethyl phospite were performed at
−
70◦C using Julabo
ultra-low refrigerated-circulator F81-ME. For TLC analysis, Merck TLC silica gel 60 F254 plates
were used. The plates were visualized by UV light (254 nm) and/or dipped in a solution of cerium
sulfate and tetrahydrate of ammonium heptamolybdate in H2SO4aq and heated. Kieselgel 60 (Merck,
0.040–0.063 mm) was used for column chromatography. The enantiomeric excess (ee) of the products
was determinated by HPLC using Hitachi, LaChrom Elite, HPLC Chromatograph, Tokyo, Japan
(Diode Array L-2450 detector) or Knauer HPLC Chromatograph, Berlin, Germany (UV WellChrom
K-2501 detector, RI WellChrom K-2301 detector) using Daicel Chiralpak IA, AD-H, OD-H column.
Optical rotations were measured on a JASCO V-650 polarimeter and reported as follows: [α]TD (c in
g/100 mL solvent).
Materials. All solvents and common reagents were obtained from commercial suppliers. Dimethyl
phosphite was purchased from Alfa Aesar. 3-(1-Piperidino)propyl-functionalized silica gel (SiO2-Pip)
was purchased from Sigma-Aldrich.
Racemic samples rac 3a–k were obtained using tetrabutylammonium bromide as the catalyst.
The chiral catalysts 4 [36], 5 [32], 6 [31], and 7 [33] were obtained following literature procedures.
3.2. Substrate Synthesis
The starting phosphonium salts 2a
two-step protocol [25], which consists of electrochemical decarboxylative
N-acyl- -amino acids (Step 1) and transformation of the resulting N-(1-methoxyalkyl)carbamates to
1-(N-acylamino)alkyltriphenylphosphonium tetrafluoroborates (Step 2). The analytical data and
spectra of compounds 2a f,j,k were identical to those previously described [25 41]. For previously
–
k
were synthesized by a previously described
α
-methoxylation of
α
2
–
,
unknown phosphonium salts 2g–i, analytical and spectroscopic data are reported below.
General Procedure for the Synthesis of 1-(N-acylamino)alkyltriphenylphosphonium
Tetrafluoroborates 2
Step 1: Methanol (30 cm3), N-acyl-
α-amino acid (3.0 mmol), and SiO2-Pip (200 mg, 0.22 mmol)
were added to an undivided cylindrical glass electrolyzer (85 cm3) with a thermostatic jacket, equipped
with a magnetic stirrer, a cylindrical Pt mesh anode (47 cm2), and a similar cathode (44 cm2), all arranged
concentrically to one another at a distance of 2.5
stirring at a current density of 0.3 A/dm2 at 10◦C until 3.5–3.75 F/mol charge had passed [3.5 F/mol for
N-Cbz-valine and 3.75 F/mol for other N-protected -amino acids]. When the process of electrolysis
±
0.5 mm. The electrolysis was conducted while
α
was finished, SiO2-Pip was filtered out and methanol was evaporated under reduced pressure to afford
the corresponding N-(1-methoxyalkyl)carbamates. Crude N-(1-methoxyalkyl)carbamates were used in
the next step without purification.
Step 2: A mixture of the corresponding N-(1-methoxyalkyl)carbamates and Ph3P
in CH2Cl2 (2 cm3) was stirred at 25◦C for 30 min and then the solvent was removed under
reduced pressure. The crude 1-(N-acylamino)alkyltriphenylphosphonium salts 2g were used
·
HBF4 (0.98 equiv.)
–
i
in the reaction with dimethyl phosphite without further purification. Recrystallization from the
mixture of CH2Cl2/Et2O failed.
1-(N-Benzyloxycarbonylamino)butyltriphenylphosphonium tetrafluoroborate (2g). White solid; 96% yield
(1.60 g); mp 110◦C to 111◦C. 1H-NMR (400 MHz, CDCl3):
δ 7.88–7.60 (m, 15H), 7.35–7.20 (m, 5H), 6.97
(br d, J = 9.2 Hz, 1H), 5.54–5.46 (m, 1H), 4.99 (d, J = 12.4 Hz, 1H), 4.89 (d, J = 12.4 Hz, 1H), 2.33–2.21
(m, 1H), 1.75–1.56 (m, 2H), 1.56–1.43 (m, 1H), 0.92 (t, J = 7.2 Hz, 3H). 13C-NMR (100 MHz, CDCl3):
δ
156.6 (d, J = 3.0 Hz), 135.9, 135.1 (d, J = 2.9 Hz), 134.1 (d, J = 9.3 Hz), 130.3 (d, J = 12.1 Hz), 128.4,
127.9, 127.8, 116.9 (d, J = 80.7 Hz), 67.3, 50.6 (d, J = 53.1 Hz), 32.9 (d, J = 5.4 Hz), 19.7 (d, J = 13.0 Hz),

Molecules 2020, 25, 405
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13.1 (d, J = 0.7 Hz). 31P NMR (162 MHz, CDCl3):
δ
25.5. IR (ATR): 3321, 2964, 1716, 1521, 1438, 1234,
1051 cm−1. HMRS (ESI) m/z: calcd for C30H31NO2P [M+] 468.2092, found 468.2092.
1-(N-Benzyloxycarbonylamino)pentyltriphenylphosphonium tetrafluoroborate (2h). White solid; 92% yield
(1.57 g); mp 114◦C. 1H-NMR (400 MHz, CDCl3):
δ 7.78–7.59 (m, 15H), 7.32–7.27 (m, 3H), 7.24–7.20 (m,
2H), 6.95 (br d, J = 9.2 Hz, 1H), 5.51–5.43 (m, 1H), 4.99 (d, J = 12.4 Hz, 1H), 4.89 (d, J = 12.4 Hz, 1H),
2.29–2.17 (m, 1H), 1.72–1.58 (m, 2H), 1.49–1.23 (m, 3H), 0.82 (t, J = 7.2 Hz, 3H). 13C-NMR (100 MHz,
CDCl3):
δ 156.6 (d, J = 3.0 Hz), 136.0, 135.1 (d, J = 3.0 Hz), 134.1 (d, J = 9.2 Hz), 130.4 (d, J = 12.3 Hz),
128.4, 127.9, 127.8, 116.9 (d, J = 80.7 Hz), 67.3, 50.9 (d, J = 52.6 Hz), 30.8 (d, J = 5.5 Hz), 28.5 (d,
J = 12.5 Hz), 21.7 (d, J = 1.0 Hz), 13.7. 31P NMR (162 MHz, CDCl3): δ 25.5. IR (ATR): 3320, 2960, 1716,
1519, 1438, 1236, 1051. HMRS (ESI) m/z: calcd for C31H33NO2P [M+] 482.2249, found 482.2254.
1-(N-Benzyloxycarbonylamino)cyclohexylmethyltriphenylphosphonium tetrafluoroborate (2i). White solid;
90% yield (1.61 g); mp 119 ◦C to 120 ◦C. 1H-NMR (400 MHz, CDCl3):
δ 7.80–7.67 (m, 9H), 7.65–7.56
(m, 6H), 7.31–7.25 (m, 3H), 7.17–7.12 (m, 2H), 7.00 (br d, J = 8.8 Hz, 1H), 5.34 (q, J = 8.9 Hz, 1H), 4.84
(d, J = 12.4 Hz, 1H), 4.75 (d, J = 12.4 Hz, 1H), 2.39–2.26 (m, 1H), 1.80–1.30 (m, 6H), 1.22–1.06 (m, 3H),
0.89–0.75 (m, 1H). 13C-NMR (100 MHz, CDCl3):
δ 156.3 (d, J = 1.8 Hz), 135.7, 134.6 (d, J = 3.0 Hz),
134.5 (d, J = 9.2 Hz), 130.0 (d, J = 12.2 Hz), 128.4, 127.9, 127.8, 118.4 (d, J = 79.5 Hz), 67.1, 55.4 (d,
J = 45.9 Hz) 38.8 (d, J = 5.8 Hz), 32.3 (d, J = 2.9 Hz), 29.6 (d, J = 7.9 Hz), 25.6 (d, J = 11.2 Hz), 25.6. 31P
NMR (162 MHz, CDCl3):
δ
27.4. IR (ATR): 3339, 2932, 1713, 1519, 1438, 1233, 1051 cm−1. HMRS (ESI)
m/z: calcd for C33H35NO2P [M+] 508.2400, found 508.2410.
3.3. General Procedure for the PT-Catalyzed Reaction of 1-(N-acylamino)alkyltriphenylphosphonium Salts 2
with Dimethyl Phosphite
1-(N-Acylamino)alkyltriphenylphosphonium salt
and toluene (2 mL) were placed in a test tube. The mixture was sonicated in an ultrasonic bath for
10 min and dimethyl phosphite (55 L, 66 mg, 0.6 mmol) was added. After cooling the resulting
mixture to
70 ◦C, solid KOH (34 mg, 0.6 mmol) was added. After vigorously stirring at the same
temperature (
70 ◦C) for 3 days, the reaction mixture was treated with saturated NH4Cl (4 to 5 mL).
2 (0.2 mmol), catalyst 4 or 5 (0.01 mmol),
µ
−
−
The mixture was allowed to warm to room temperature and then extracted three times with CH2Cl2.
The organic layers were combined, dried over anhydrous Na2SO4, and concentrated under reduced
pressure. The residue was purified by flash column chromatography on silica gel using mixtures of
hexane/EtOAc/acetone (5:3:2) as the eluent.
(R)-Benzyl N-[1-(dimethoxyphosphoryl)ethyl]carbamate (3a) [36]. Colorless oil; 84% yield (48.4 mg).
The enantiomeric excess (84% ee for catalyst 4) was determined by HPLC using Chiralpak AD-H
column (n-hexane/isopropanol = 90/10, flow rate 0.75 mL/min,
λ
= 210 nm) t (major) = 17.0 min, t
7.38–7.31 (m, 5H),
(minor) = 20.8 min. [α]D24
=
−
15 (CHCl3, c = 0.5). H-NMR (400 MHz, CDCl3):
δ
1
5.23 (br d, J = 9.6 Hz, 1H), 5.12 (s, 2H), 4.25–4.14 (m, 1H), 3.76 (d, J = 10.8 Hz, 3H), 3.73 (d, J = 10.8 Hz,
3H), 1.39 (dd, J1 = 16.6 Hz, J2 = 7.4 Hz, 3H). 13C-NMR (100 MHz, CDCl3):
155.6 (d, J = 6.0 Hz), 136.2,
128.4, 128.1, 128.0, 67.1, 53.2 (d, J = 7.0 Hz) 53.0 (d, J = 6.0 Hz), 42.8 (d, J = 158.0 Hz), 15.8. 31P NMR
(162 MHz, CDCl3): δ 27.9. IR (ATR): 3239, 2955, 1714. 1537, 1225, 1022 cm−1
δ
.
The absolute configuration of compound 3a was determined to be R by comparison of its optical
rotation with a literature value:
Measured optical rotation (84% ee): [α]2D4 = −15 (CHCl3, c = 0.5)
Literature data: [α]2D0 = -17.5 (CHCl3, c = 1.0) for the (R)-isomer [47].
(R)-Benzyl N-[1-(dimethoxyphosphoryl)-2-phenylethyl]carbamate (3b) [48] Colorless oil; 84% yield (60.9 mg).
The enantiomeric excess (73% ee for the catalyst 4) was determined by HPLC using Chiralpak AD-H
column (n-hexane/isopropanol = 85:15, flow rate 0.8 mL/min,
λ
= 210 nm) t (major) = 20.6 min, t (minor)
7.34–7.20 (m, 10H), 5.05 (br d,
= 28.7 min. [α]2D4
=
−
28 (CHCl3, c = 0.5). H-NMR (400 MHz, CDCl3):
δ
1
J = 10.0 Hz, 1H), 5.00 (s, 2H), 4.48–4.37 (m, 1H), 3.74 (d, J = 10.4 Hz, 3H), 3.70 (d, J = 10.8 Hz, 3H), 3.22

Molecules 2020, 25, 405
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(ddd, J1 = 14.0 Hz, J2 = 8.8 Hz, J3 = 4.7 Hz, 1H), 2.87 (dt, J1 = 20.2 Hz, J2 = 10.0 Hz, 1H). 13C-NMR
(100 MHz, CDCl3): 155.7 (d, J = 5.4 Hz), 136.4, 136.2, 129.2, 128.4, 128.4, 128.0, 127.8, 126.8, 67.0, 53.2
(d, J = 7.1 Hz), 53.0 (d, J = 6.6 Hz), 48.2 (d, J = 155.9 Hz) 35.8 (d, J = 3.6 Hz).31P NMR (162 MHz, CDCl3):
δ 26.4. IR (ATR): 3223, 2954, 1708, 1542, 1255, 1222, 1028 cm−1
δ
.
(R)-tert-Butyl N-[1-(dimethoxyphosphoryl)-2-phenylethyl]carbamate (3c) [36]. White solid; 93% yield
(61.1 mg); mp 77 ◦C to 79 ◦C. The enantiomeric excess (72% ee for the catalyst
) was determined by
4
HPLC using Chiralpak AD-H column (n-hexane/isopropanol = 85:15, flow rate 0.5 mL/min, λ = 210 nm
)
t (major) = 26.4 min, t (minor) = 19.1 min. [α]D25
= 21 (CHCl3, c = 0.5). Compound 3c exists as
a 85:15 mixture of rotamers at 25 C in CDCl3. The spectra for the major rotamer are as follows:
−
◦
1H-NMR (400 MHz, CDCl3):
δ
7.31–7.20 (m, 5H), 4.70 (br d, J = 10.0 Hz, 1H), 4.44–4.33 (m, 1H), 3.75 (d,
J = 10.4 Hz, 6H), 3.21 (ddd, J1 = 13.6 Hz, J2 = 8.8 Hz, J3 = 4.8 Hz, 1H), 2.84 (dd, J1 = 14.4 Hz, J2 = 10.2 Hz,
1H), 1.32 (s, 9H). 13C-NMR (100 MHz, CDCl3):
154.9 (d, J = 7.0 Hz), 136.5 (d, J = 13.1 Hz), 129.2, 128.3,
126.7, 80.0, 53.2 (d, J = 7.1 Hz), 52.9 (d, J = 6.7 Hz), 47.5 (d, J = 155.6 Hz) 36.0 (d, J = 3.8 Hz), 28.1.31P
NMR (162 MHz, CDCl3): δ 32.1. IR (ATR): 3255, 2981, 1706, 1525, 1237, 1155, 1043 cm−1
δ
.
(R)-Benzyl N-[1-(dimethoxyphosphoryl)-2-methylpropyl]carbamate (3d) [49]. Colorless oil; 85% yield
(53.7 mg). The enantiomeric excess (56% ee for the catalyst ) was determined by HPLC using
4
Chiralpak AD-H column (n-hexane/isopropanol = 90:10, flow rate 0.75 mL/min,
λ
= 210 nm) t (major) =
7.37–7.31 (m,
14.5 min, t (minor) = 23.0 min. [α]D24
=
−
5 (CHCl3, c = 0.5). H-NMR (400 MHz, CDCl3):
δ
1
5H), 5.16 (d, J = 12.0 Hz, 1H), 5.11 (d, J = 12.4 Hz, 1H), 5.08 (br d, J = 9.6 Hz, 1H), 4.05 (ddd, J1 = 18.6 Hz,
J2 = 10.4 Hz, J3 = 4.2 Hz, 1H), 3.75 (d, J = 10.8 Hz, 3H), 3.71 (d, J = 10.8 Hz, 3H), 2.25–2.15 (m, 1H),
1.03 (d, J = 6.8 Hz, 3H), 1.00 (d, J = 6.8 Hz, 3H). 13C-NMR (100 MHz, CDCl3):
δ
156.3 (d, J = 6.4 Hz),
136.2, 128.5, 128.2, 128.0, 67.2, 52.9 (d, J = 6.3 Hz), 52.8 (d, J = 7.2 Hz), 52.2 (d, J = 151.8 Hz), 28.9 (d,
J = 4.4 Hz), 20.3 (d, J = 12.6 Hz), 17.7 (d, J = 4.1 Hz).31P NMR (162 MHz, CDCl3):
26.7. IR (ATR) 3239,
2958, 1710, 1533, 1289, 1228, 1024 cm−1
δ
.
(R)-tert-Butyl N-[1-(dimethoxyphosphoryl)-2-methylpropyl]carbamate (3e) [50]. White solid; 88% yield
(49.4 mg); mp 83◦C to 84◦C. The enantiomeric excess (23% ee for the catalyst
) of the product
4
3e was determined by HPLC, after transformation into its Cbz derivative 3e’ through Boc
deprotection followed by CbzCl derivatization as described by Ricci et al. [36], using Chiralpak
IA column (n-hexane/isopropanol = 90:10, flow rate 0.75 mL/min,
t (minor) = 19.8 min. 1H-NMR (400 MHz, CDCl3):
4.76 (br d, J = 9.6 Hz, 1H), 3.99 (ddd, J1 = 18.4 Hz,
J2 = 10.8 Hz, J3 = 4.4 Hz, 1H), 3.76 (d, J = 10.8 Hz, 6H), 2.22–2.10 (m, 1H), 1.45 (s, 9H), 1.01 (dd,
J1 = 6.8 Hz, J2 = 1.2 Hz, 3H), 0.99 (d, J = 7.2 Hz, 3H). 13C-NMR (100 MHz, CDCl3):
155.6 (d,
J = 6.3 Hz), 80.0, 52.9 (d, J =7.2 Hz), 52.7 (d, J = 6.7 Hz), 51.5 (d, J = 151.4 Hz), 28.9 (d, J = 4.8 Hz), 28.2,
20.3 (d, J = 12.6 Hz), 17.8 (d, J = 4.2 Hz). 31P NMR (162 MHz, CDCl3):
27.2. IR (ATR): 3267, 2972,
1701, 1530, 1293, 1233, 1163, 1035 cm−1
λ = 210 nm) t (major) = 13.3 min,
δ
δ
δ
.
(R)-Benzyl N-[1-(dimethoxyphosphoryl)-3-methylbutyl]carbamate (3f) [36]. Colorless oil; 82% yield (54.1 mg).
The enantiomeric excess (80% ee for the catalyst ) was determined by HPLC using Chiralpak IA
4
column (n-hexane/isopropanol = 85/15, flow rate 0.75 mL/min,
λ
= 254 nm) t (major) = 10.1 min, t
7.37–7.28 (m, 5H),
(minor) = 13.4 min. [α]D25
=
−
32 (CHCl3, c = 1.0). H-NMR (400 MHz, CDCl3):
δ
1
5.16 (d, J = 12.4 Hz, 1H), 5.08 (d, J = 12.4 Hz, 2H), 4.25–4.14 (m, 1H), 3.75 (d, J = 10.4 Hz, 3H), 3.70 (d,
J = 10.4 Hz, 3H), 1.79–1.68 (m, 1H), 1.58 (q, J = 7.2 Hz, 2H), 0.94 (d, J = 2.4 Hz, 3H), 0.92 (d, J = 2.0 Hz,
3H). 13C-NMR (100 MHz, CDCl3):
δ
155.9 (d, J = 4.6 Hz), 136.3, 128.4, 128.1, 127.9, 67.0, 53.1 (d,
J = 7.1 Hz), 52.9 (d, J = 6.5 Hz), 45.5 (d, J = 155.6 Hz), 38.3 (d, J = 2.4 Hz), 24.3 (d, J = 13.2 Hz), 23.2, 21.0.
31P NMR (162 MHz, CDCl3): δ 29.0. IR (ATR): 3274, 2955, 1686, 1541, 1267, 1233, 1027 cm−1
.
The absolute configuration of compound 3f was determined to be R by comparison of its optical
rotation with a literature value:
Measured optical rotation (80% ee): [α]2D5 = −32 (CHCl3, c = 1.0)
Literature data: [α]2D0 = −36.4 (CHCl3, c = 1.0) for the (R)-isomer [51].

Molecules 2020, 25, 405
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(R)-Benzyl N-[1-(dimethoxyphosphoryl)butyl]carbamate (3g). Colorless oil; 85% yield (53.4 mg).
The enantiomeric excess (80% ee for the catalyst ) was determined by HPLC using Chiralpak
4
AD-H column (n-hexane/isopropanol = 90/10, flow rate 0.75 mL/min,
λ
= 210 nm) t (major) = 18.1 min,
7.38–7.30 (m, 5H),
t (minor) = 24.9 min. [α]D25
=
−
25 (CHCl3, c = 0.5). H-NMR (400 MHz, CDCl3):
δ
1
5.15 (d, J = 12.4 Hz, 1H), 5.10 (d, J = 12.4 Hz, 1H), 4.93 (br d, J = 10.4 Hz, 1H), 4.17–4.07 (m, 1H), 3.76 (d,
J = 10.8 Hz, 3H), 3.72 (d, J = 10.4 Hz, 3H), 1.87–1.80 (m, 1H), 1.63–1.33 (m, 3H), 0.93 (t, J = 7.2 Hz, 3H).
13C-NMR (100 MHz, CDCl3):
δ
156.0 (d, J = 5.5 Hz), 136.2, 128.5, 128.2, 128.0, 67.2, 53.1 (d, J = 7.2 Hz),
53.0 (d, J = 6.5 Hz), 46.9 (d, J = 155.0 Hz), 31.8 (d, J = 2.4 Hz), 19.0 (d, J = 12.7 Hz), 13.5. 31P NMR
(162 MHz, CDCl3):
δ
27.5. IR (ATR): 3239, 2957, 1714, 1537, 1226, 1025cm−1. HMRS (ESI) m/z: calcd for
C14H22NO5NaP [M+Na]+ 338.1133, found 338.1135.
(R)-Benzyl N-[1-(dimethoxyphosphoryl)pentyl]carbamate (3h) [52]. Colorless oil; 80% yield (53.0 mg).
The enantiomeric excess (92% ee for the catalyst
column (n-hexane/isopropanol = 90/10, flow rate 0.75 mL/min,
(minor) = 23.2 min. [α]2D4 23 (CHCl3, c = 0.5).1H-NMR (400 MHz, CDCl3):
δ
4
) was determined by HPLC using Chiralpak AD-H
= 210 nm) t (major) = 15.7 min, t
7.36–7.29 (m, 5H), 5.15
λ
=
−
(d, J = 12.0 Hz, 1H), 5.11 (d, J = 12.4 Hz, 1H), 5.02 (br d, J = 10.4 Hz, 1H), 4.15–4.05 (m, 1H), 3.75 (d,
J = 10.8 Hz, 3H), 3.72 (d, J = 10.4 Hz, 3H), 1.87–1.80 (m, 1H), 1.62–1.26 (m, 5H), 0.89 (t, J = 7.0 Hz, 3H).
13C-NMR (100 MHz, CDCl3):
δ
156.0 (d, J = 5.7 Hz), 136.2, 128.5, 128.1, 128.0, 67.1, 53.1 (d, J = 7.2 Hz),
52.9 (d, J = 6.5 Hz), 47.2 (d, J = 155.0 Hz), 29.5 (d, J = 2.7 Hz), 27.8 (d, J = 12.4 Hz), 22.1, 13.8. 31P NMR
(162 MHz, CDCl3): δ 27.4. IR (ATR): 3242, 2955, 1715, 1537, 1223, 1026 cm−1
.
(R)-Benzyl N-[cyclohexyl(dimethoxyphosphoryl)methyl]carbamate (3i) [36]. White solid; 71% yield (50.6 mg);
mp 61.5◦C to 62.5◦C. The enantiomeric excess (65% ee for the catalyst
) was determined by HPLC
4
using Chiralpak IA column (n-hexane/isopropanol = 85:15, flow rate 0.75 mL/min,
λ
= 205 nm) t (major)
7.37–7.30
= 15.6 min, t (minor) = 20.9 min. [α]D24
=
−
3 (CHCl3, c = 0.5). H-NMR (400 MHz, CDCl3):
δ
1
(m, 5H), 5.16 (d, J = 12.4 Hz, 1H), 5.10 (d, J = 12.0 Hz, 1H), 5.02 (br d, J = 10.4 Hz, 1H), 4.04 (ddd,
J1 = 18.7 Hz, J2 = 10.8 Hz, J3 = 4.3 Hz, 1H), 3.75 (d, J = 10.4 Hz, 3H), 3.70 (d, J = 10.8 Hz, 3H), 1.89–1.63
(m, 6H), 1.33–1.00 (m, 5H). 13C-NMR (100 MHz, CDCl3):
δ 156.2 (d, J = 6.4 Hz), 136.2, 128.5, 128.2,
128.0, 67.2, 52.9 (d, J = 6.5 Hz), 52.8 (d, J = 7.2 Hz), 52.0 (d, J = 151.3 Hz), 38.6 (d, J = 4.2 Hz), 30.5 (d,
J = 11.4 Hz), 28.0 (d, J = 4.3 Hz), 26.1 (d, J = 1.7 Hz), 25.9 (d, J = 10.9 Hz). 31P NMR (162 MHz, CDCl3):
δ 26.7. IR (ATR): 3243, 2927, 1715, 1545, 1219, 1030 cm−1
.
(R)-Benzyl N-[2-(tert-butoxy)-1-(dimethoxyphosphoryl)ethyl]carbamate (3j). White solid; 98% yield (70.6 mg);
mp 67◦C to 69◦C. The enantiomeric excess (53% ee for the catalyst
) was determined by HPLC using
4
Chiralpak AD-H column (n-hexane/isopropanol = 90:10 flow rate 0.75 mL/min,
λ
= 210 nm) t (major) =
7.37–7.30 (m,
18.8 min, t (minor) = 22.3 min. [α]D25 = 3 (CHCl3, c = 0.5). H-NMR (400 MHz, CDCl3):
δ
1
5H), 5.30 (br d, J = 9.6 Hz, 1H), 5.13 (s, 2H), 4.33–4.21 (m, 1H), 3.79–3.74 (m, 1H), 3.76 (d, J = 10.8 Hz,
6H), 3.58 (ddd, J1 = 28.0 Hz, J2 = 9.4 Hz, J3 = 3.8 Hz, 1H), 1.18 (s, 9H). 13C-NMR (100 MHz, CDCl3):
155.8 (d, J = 6.4 Hz), 136.2, 128.5, 128.2, 128.1, 73.7, 67.2, 60.6, 53.3 (d, J = 5.9 Hz), 52.7 (d, J = 6.4 Hz),
48.3 (d, J = 155.5 Hz), 27.3. 31P NMR (162 MHz, CDCl3):
δ 26.1. IR (ATR): 3229, 2971, 1706, 1551, 1277,
1223, 1183, 1033 cm−1. HMRS (ESI) m/z: calcd for C16H26NO6NaP [M+Na]+ 382.1395, found 382.1398.
(R)-tert-Butyl N-[2-(benzyloxy)-1-(dimethoxyphosphoryl)ethyl]carbamate (3k). Colorless oil; 84% yield
(60.2 mg). The enantiomeric excess (53% ee for the catalyst 5) was determined by HPLC using Chiralpak
OD-H column (n-hexane/isopropanol = 97:3, flow rate 0.5 mL/min,
λ
= 212 nm) t (major) = 54.1 min, t
7.35–7.27 (m, 5H), 5.06
(minor) = 62.0 min. [α]2D5 = 2 (CHCl3, c = 1.0). H-NMR (400 MHz, CDCl3):
δ
1
(br d, J = 9.2 Hz, 1H), 4.56 (s, 2H), 4.36–4.24 (m, 1H), 3.85–3.79 (m, 1H), 3.75 (d, J = 10.4 Hz, 3H), 3.75 (d,
J = 10.4 Hz, 3H), 3.70 (ddd, J1 = 24.0 Hz, J2 = 9.8 Hz, J3 = 3.8 Hz 1H), 1.45 (s, 9H). 13C-NMR (100 MHz,
CDCl3): 155.1 (d, J = 7.4 Hz), 137.6, 128.4, 127.8, 127.7, 80.2, 73.3, 68.8 (d, J = 2.3 Hz), 53.3 (d, J = 6.3 Hz),
52.8 (d, J = 6.3 Hz), 47.4 (d, J = 155.0 Hz), 28.3. 31P NMR (162 MHz, CDCl3):
δ 25.7. IR (ATR): 3263,
2956, 1708, 1497, 1365, 1242, 1165, 1026 cm−1. HMRS (ESI) m/z: calcd for C16H26NO6NaP [M+Na]+
382.1395, found 382.1390.

Molecules 2020, 25, 405
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Supplementary Materials: The following are available online. Supporting information includes 1H-, 13C-,
31P-NMR, HRMS spectra of all new compounds
, and HPLC data for compounds and results of the SDE test.
2,
3
3
Author Contributions: Conceptualization, A.P.-H.; Methodology, A.P.-H. and A.W.-K.; Formal analysis,
A.P.-H., A.W.-K., A.K., and S.S.; Investigation, A.P.-H., A.W.-K., A.K., and S.S.; Supervision, A.P.-H. and
K.W. Writing—original draft preparation, A.P.-H.; Writing—review and editing, A.P.-H., A.W.-K., and A.K.
All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Conflicts of Interest: The authors declare no conflict of interest.
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