Stereochemistry of the three-component reaction between the ley′s aldehyde, benzyl amines, and trialkyl phosphites. a new approach to the protected enantiomerically pure 1-amino-2,3-dihydroxypropylphosphonates

Article abstract of DOI:10.1080/10426507.2014.883624

Enantiomerically pure orthogonally protected dimethyl 1-aminophosphonates (2R,5R,6R,1′R)-and (2R,5R,6R,1′S)-10, phosphonate analogs of 4-hydroxythreonine, were prepared employing the three-component reaction between trimethyl phosphite, (2R,5R,6R)-5,6-dimethoxy-5,6-dimethyl-1,4-dioxane-2-carbaldehyde (Leys aldehyde), and benzhydrylamine. Since both aminophosphonates 10 exist in a chloroform solution as single rotamers, the absolute configurations at C1′ were unequivocally established based on ¹H and ¹³C NMR spectral data. Studies on stereochemistry of the addition of trialkyl phosphites showed that in chloroform in all cases the nucleophile preferentially attacks the si-face of the CN bond, while in alcohols the 1,2-stereoinduction is negligible, and sense of chirality of phenylethylamines is solely responsible for a π-facial discrimination in the 1,3-asymmetric inductions.

Full text of DOI:10.1080/10426507.2014.883624

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Stereochemistry of the Three-
Component Reaction Between
the Ley′S Aldehyde, Benzyl
Amines, and Trialkyl Phosphites.
A New Approach to the Protected
Enantiomerically Pure 1-Amino-2,3-
Dihydroxypropylphosphonates
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Dorota G. Piotrowskaa, Iwona E. Głowackaa & Andrzej E.
Wróblewskia
a Bioorganic Chemistry Laboratory, Faculty of Pharmacy, Medical
University of Łódź, Poland
Accepted author version posted online: 30 Apr 2014.Published
online: 04 Aug 2014.
To cite this article: Dorota G. Piotrowska, Iwona E. Głowacka & Andrzej E. Wróblewski (2014)
Stereochemistry of the Three-Component Reaction Between the Ley′S Aldehyde, Benzyl Amines,
and Trialkyl Phosphites. A New Approach to the Protected Enantiomerically Pure 1-Amino-2,3-
Dihydroxypropylphosphonates, Phosphorus, Sulfur, and Silicon and the Related Elements, 189:7-8,
1237-1253, DOI: 10.1080/10426507.2014.883624
To link to this article: http://dx.doi.org/10.1080/10426507.2014.883624
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Phosphorus, Sulfur, and Silicon, 189:1237–1253, 2014
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2014.883624
STEREOCHEMISTRY OF THE THREE-COMPONENT
REACTION BETWEEN THE LEYꢀS ALDEHYDE, BENZYL
AMINES, AND TRIALKYL PHOSPHITES. A NEW
APPROACH TO THE PROTECTED ENANTIOMERICALLY
PURE 1-AMINO-2,3-DIHYDROXYPROPYLPHOSPHONATES
Dorota G. Piotrowska, Iwona E. Głowacka,
and Andrzej E. Wro´blewski
Bioorganic Chemistry Laboratory, Faculty of Pharmacy, Medical University
of Ło´dz´, Poland
GRAPHICAL ABSTRACT
P(O)(OR')2
P(O)(OR')2
CHO
1' NHR
RHN
Me
OMe
Me
Me
6
+
2
O
O
O
O
OMe
OMe
3
O
O
OMe
Me
(2R,5R,6R)-6
OMe
Me
OMe
Me
5
(2R,5R,6R,1'S)-7
(2R,5R,6R,1'R)-7
Abstract Enantiomerically pure orthogonally protected dimethyl 1-aminophosphonates
(2R,5R,6R,1ꢁR)- and (2R,5R,6R,1ꢁS)-10, phosphonate analogs of 4-hydroxythreonine, were pre-
pared employing the three-component reaction between trimethyl phosphite, (2R,5R,6R)-5,6-
dimethoxy-5,6-dimethyl-1,4-dioxane-2-carbaldehyde (Ley’s aldehyde), and benzhydrylamine.
Since both aminophosphonates 10 exist in a chloroform solution as single rotamers, the abso-
lute configurations at C1ꢁ were unequivocally established based on 1H and 13C NMR spectral
data. Studies on stereochemistry of the addition of trialkyl phosphites showed that in chloro-
form in all cases the nucleophile preferentially attacks the si-face of the C N bond, while in
alcohols the 1,2-stereoinduction is negligible, and sense of chirality of phenylethylamines is
solely responsible for a π-facial discrimination in the 1,3-asymmetric inductions.
Keywords Chiral auxiliaries; conformation; configuration; reaction mechanism; Schiff bases
INTRODUCTION
Several polyhydroxy α-amino acids have been found as components of natural prod-
ucts. Polyoxamic acid [(2S,3S,4S)-2-amino-2,3,4-trihydroxypentanoic acid] (2S,3S,4S)-1
Received 5 November 2013; accepted 9 December 2013.
Dedicated to Professor Louis D. Quin on the occasion of his 85th birthday.
Address correspondence to Andrzej E. Wro´blewski, Bioorganic Chemistry Laboratory, Faculty of Pharmacy,
Medical University of Ło´dz´, 90-151 Ło´dz´, Muszyn´skiego 1, Poland. E-mail: andrzej.wroblewski@umed.lodz.pl
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/gpss.
1237

1238
D. G. PIOTROWSKA ET AL.
Figure 1 Polyoxamic acid and related polyhydroxy amino acids.
(Figure 1)1–6 seems to be the best recognized among them since this molecule is incorpo-
rated into peptidyl nucleoside antibiotics, called polyoxins.7 Less known antifungal sph-
ingofungins A–D contain 3,4-diepipolyoxamic acid (2S,3R,4R)-1.1,2,6 On the other hand,
in sphingofungins E and F,8–10 potent immunosuppressants mycestericins A–G11–15 and
myriocin16–18 various α-branched polyhydroxy α-amino acid moieties 2 serve as a polar
end of long chain molecules.
Also 4-hydroxy-L-threonine [(2S,3S)-2-amino-3,4-dihydroxybutyric acid] (2S,3S)-3
and its stereoisomers (Figure 1) were found as constituents of natural products (e.g., Lobo-
cyclamide B, Actinomycin Z1)19,20 or were produced by several species.19–24 It is firmly
established that 4-hydroxy-L-threonine is a precursor of vitamin B625 in Rhizobium26 and in
Escherichia coli.27 The interest in syntheses of 4-hydroxy-L-threonine19,28–33 is stimulated
not only by its occurrence in nature but also by its intermediacy in biosynthesis of vitamin
B6 and chemical synthesis of the monobactam antibiotic carumonam.34 Stereochemistry of
2-amino-3,4-dihydroxybutyric acids, including 4-hydroxy-L-threonine, was established by
the correlation with D-glyceraldehyde.35
Studies on biological activity of aminophosphonates as bioisosters of amino
acids are still an active field of research.36 For this reason, the demand for new
enantiomerically pure aminoalkylphosphonates continues.37,38 The first synthesis of
phosphonate analogs of 4-hydroxythreonines took advantage of the HO–C1 for H2N–C1
replacement in diastereoisomeric adducts of dimethyl hydrogen phosphonate to 2,3-O-
isopropylidene-D-glyceraldehyde via triflation, nucleophilic substitution with azide, and
reduction and made both phosphonates (1R,2R)- and (1S,2R)-4 synthetically available
(Scheme 1).39 In a recent approach, addition of diethyl hydrogen phosphonate to
N-benzyl nitrone derived from 2,3-O-isopropylidene-D-glyceraldehyde in the presence of
tert-butyldimethylsilyl triflate (TBDMSOTf) followed by the reduction of the respective
hydroxylamine led to the formation of phosphonate (1S,2R)-5 as a single diastereoisomer
(Scheme 1).40
Scheme 1 The existing methods for the synthesis of the phosphonate analogs of 4-hydroxytheonines.

STEREOCHEMISTRY OF THE THREE-COMPONENT
1239
Table 1 Stereochemistry of the formation of 1-aminophosphonates 8
1-aminophosphonates, 8
31P NMR shifts
Stereochemistry
Entry
Amine R
Major
Minor
Ratio of diastereoisomers
Major
Minor
9,%
a
b
c
d
e
PhCH2
Ph2CH
(S)-1-phenylethyl
(R)-1-phenylethyl
(R)-1-(1-naphthyl)ethyl
26.03
27.03
27.43
27.05
26.70
25.62
25.80
25.33
25.74
26.10
55:45
52:48
81:19
60:40
60:40
(1ꢁR)
(1ꢁR)
(1ꢁR)
(1ꢁS)
(1ꢁS)
(1ꢁS)
(1ꢁS)
(1ꢁS)
(1ꢁR)
(1ꢁR)
7
25
6
6
9
Our successful preparation of enantiomerically pure protected 1,2,3-
trihydroxypropylphosphonates41 employing (2R,5R,6R)-5,6-dimethoxy-5,6-dimethyl-1,4
-dioxane-2-carbaldehyde 6 (the Ley’s aldehyde) easily prepared from D-mannitol in two
steps42–44 has prompted us to apply this aldehyde in the synthesis of the phosphonate
analogs of 4-hydroxytheonines. Herein, we wish to describe our studies on the syn-
thesis and separation of diastereoisomeric 1-aminophosphonates (2R,5R,6R,1ꢁS)-7 and
(2R,5R,6R,1ꢁR)-7 prepared from the aldehyde 6, selected primary amines and trialkyl
phosphites (Scheme 2).
Scheme 2 Addition of trialkyl phosphites to a mixture of the aldehyde (2R,5R,6R)-6 and amines RNH2 in
2,2,2-trifluoroethanol.
RESULTS AND DISCUSSION
Synthesis
In search for the conditions to successfully accomplish the three-component reac-
tion between aldehydes, primary amines, and trialkyl phosphites, the methodology elabo-
rated by Heydari45 was selected since by application of 2,2,2-trifluoroethanol the synthesis
is carried out at room temperature, which we consider as a prerequisite for the future
studies on protected sugar aldehydes. The preliminary studies on the three-component
reaction between the aldehyde 6, triethyl phosphite, and selected primary amines in
2,2,2-trifluoroethanol showed the formation of the expected diethyl 1-aminophosphonates
(2R,5R,6R,1ꢁR)-8 and (2R,5R,6R,1ꢁS)-8 (Scheme 3), which were contaminated with the re-
spective 1-hydroxyphosphonates (2R,5R,6R,1ꢁR/S)-941 (Table 1) and, in consequence, with
the unreacted amines.

1240

STEREOCHEMISTRY OF THE THREE-COMPONENT
1241
The addition of triethyl phosphite to the aldehyde 6 in the presence of the selected
substituted benzyl amines (Table 1) was accompanied by the formation of up to 25% of
diastereoisomeric 1-hydroxyphosphonates 9 when benzhydrylamine was used. The signif-
icant increase in the amount of 1-hydroxyphosphonates in the latter reaction results from
the bulkiness of the diphenylmethylamino group making the competing Abramov reaction
more feasible. Moreover, when tritylamine was applied only 1-hydroxyphosphonates 9
were produced.
Diastereoselectivity of the additions performed in the presence of benzylamine
or benzhydrylamine appeared to be very low, and the respective 1-aminophosphonates
(2R,5R,6R,1ꢁR)-8a and (2R,5R,6R,1ꢁR)-8b were formed as major products. To improve
diastereoselectivity double asymmetric induction was tried with (S)- and (R)-1-
phenylethylamine and (R)-1-(1-naphthyl)ethylamine. Good diastereoisomeric excess
(62%) was noticed when (S)-1-phenylethylamine was applied, and 1-aminophosphonate
(2R,5R,6R,1ꢁR)-8c was obtained as a major product. On the other hand, reactions
carried out with (R)-1-phenyl- and (R)-1-(1-naphthyl)ethylamines again showed poor
diastereoselectivities (20%) but in these cases the 1-aminophosphonates (2R,5R,6R,1ꢁS)-8d
and (2R,5R,6R,1ꢁS)-8e were formed preferentially. All attempts to purify the crude
reaction mixtures failed to give pure compounds as well as to separate diastereoisomeric
1-aminophosphonates 8.
Application of trimethyl phosphite in the reaction with the aldehyde 6 and ben-
zhydrylamine led to the formation of a 56:44 mixture of dimethyl 1-aminophosphonates
(2R,5R,6R,1ꢁR)- and (2R,5R,6R,1ꢁS)-10 (Scheme 4). After careful optimization of the re-
action condition it was established that application of 0.9 equivalent of trialkyl phos-
phite and 0.85 equivalent of benzyl amines minimized the formation of unwanted 1-
hydroxyphosphonates and facilitated the purification of the reaction mixtures especially the
separation of the aminophosphonates and unreacted benzyl amines. The crude product con-
tained up to 25% of the respective dimethyl 1-hydroxyphosphonates (2R,5R,6R,1ꢁR/S)-11.
Diastereoisomeric 1-aminophosphonates (2R,5R,6R,1ꢁR)-10 and (2R,5R,6R,1ꢁS)-10 were
successfully separated on silica gel columns to give both pure compounds as colorless oils
in 20% yields.
Scheme 4 Synthesis of dimethyl 1-aminophosphonates (2R,5R,6R,1ꢁS)- and (2R,5R,6R,1ꢁR)-10. Reaction con-
ditions: (a) 6 (1.0 equiv.), (MeO)3P (0.9 equiv.), Ph2CHNH2 (0.85 equiv.), 2,2,2-trifluoroethanol, r.t., 24 h.

1242
D. G. PIOTROWSKA ET AL.
Figure 2 The preferred conformation 12 of the major phosphonate (2R,5R,6R,1ꢁR)-10.
Configurational Studies
The absolute configurations at C1ꢁ in dimethyl 1-aminophosphonates (1ꢁS)-10 and
(1ꢁR)-10 were established based on detailed analysis of 1H and 13C NMR spectral data. In
a chloroform solution, the major 1-aminophosphonate (1ꢁR)-10 exits as a single rotamer
in a conformation 12 (Figure 2). The antiperiplanar orientation of the phosphorus atom
and C3 (projection 13) is proved by the value of 3J(PC1ꢁC2C3) = 14.0 Hz,46,47 while the
gauche arrangements of the hydrogen atoms HC1ꢁ–C2H and the phosphorus atom and
3
HC2 (PC1ꢁ–C2H) can be concluded from the values of J(HC1ꢁC2H) = 3.2 Hz48 and
3J(PC1ꢁC2H) = 10.6 Hz,49,50 respectively. Undoubtedly, this conformation is stabilized by
a strong intramolecular hydrogen bond.41 These conclusions received additional support
by the observation of NOESY correlation signals between hydrogen atoms HC1ꢁ and
HC3eq, HC1ꢁ and HC2, HC1ꢁ and HCPh2, but not between HC1ꢁ and HC3ax (Figure 2,
3
blue arrows). Furthermore, from the value of J(PC1ꢁNC) = 3.1 Hz one may suggest the
gauche orientation 14 of the diphenylmethyl and the dimethoxyphosphoryl groups and, in
consequence, the restricted rotation along the C1ꢁ–N bond. This conclusion receives further
support by lack of shielding effects by the aromatic rings on the hydrogen atoms attached
to the 1,3-dioxane ring.
The same approach was applied in configurational studies of diastereoisomeric diethyl
1-aminophosphonates 8a–f. The absolute stereochemistry (2R,5R,6R,1ꢁR) was assigned
3
to the diastereoisomers (Table 1) displaying the following values of J(PC1ꢁC2C3) =
12.8–14.6 Hz and 3J(HC1ꢁC2H) = 2.4–4.0 Hz in their 1H and 13C NMR spectra.
On the other hand, in a chloroform solution the minor 1-aminophosphonate (1ꢁS)-10
exists almost exclusively in a conformation 15 (Figure 3) in which the phosphorus atom
3
and C3 adopt the gauche-orientation 16, since the following values of J(PC1ꢁC2C3) =
4.3 Hz,46,47 3J(HC1ꢁC2H) = 4.4 Hz,48 and 3J(PC1ꢁC2H) = 14.2 Hz49,50 were observed in
Figure 3 The preferred conformation 15 of the minor phosphonate (2R,5R,6R,1ꢁS)-10.

STEREOCHEMISTRY OF THE THREE-COMPONENT
1243
the respective 1H and 13C NMR spectra. Opposite to the restricted rotation of the diphenyl-
methylamino group along the C1ꢁ–N bond observed in the major 1-aminophosphonate
(1ꢁR)-10, in the minor diastereoisomer (1ꢁS)-10 this group freely rotates, since the value of
3J(PC1ꢁNC) = 7.7 Hz was observed.
Mechanistic Considerations
The accepted mechanism of the three-component reaction between trialkyl phos-
phites, aldehydes, and amines relies on the nucleophilic addition of the phosphorus
nucleophiles to the preformed imines 17 or the respected iminium ions to produce 1-
aminoalkylphosphonates 18 (Scheme 5).51–57 The alternative mechanistic pathway to phos-
phonates 18 involves formation of 1-hydroxyalkylphosphonates 19, which in the presence of
amines are supposed to undergo a retro-Abramov reaction affording 1-aminophosphonates
18 through imines 17.52,55,57
Scheme 5 Mechanisms of the three-component reaction between trialkyl phosphites, aldehydes, and amines.
To verify the latter pathway diethyl (R)-hydroxy-[(2R,5R,6R)-5,6-dimethoxy-5,6-
dimethyl-1,4-dioxan-2-yl]methylphosphonate (2R,5R,6R,1ꢁR)-9c41 was treated with (S)-1-
phenylethylamine in 2,2,2-trifluoroethanol at room temperature. After 48 h the 1H and 31
P
NMR spectra showed the presence of a 1:1 mixture of the starting materials and no traces of
diastereoisomeric diethyl 1-aminophosphonates (2R,5R,6R,1ꢁR)-8c and (2R,5R,6R,1ꢁS)-8c
were detected. Since 1-hydroxyphosphonate (1ꢁR)-9c remained unchanged, these observa-
tions exclude the reversibility of the Abramov reaction (Scheme 5), which would provide
an equilibrium mixture of (1ꢁR)-9c and (1ꢁS)-9c.
To get further insight into the mechanism of the investigated reaction, imine 2058
was synthesized from the aldehyde (2R,5R,6R)-6 and (S)-1-phenylethylamine and fur-
ther subjected to the reaction with triethyl phosphite in 2,2,2-trifluoroethanol (Scheme 6).
After 48 h the formation of a 77:23 mixture of diethyl 1-aminophosphonates (1ꢁR)-8c
and (1ꢁS)-8c was observed by the 31P NMR spectroscopy, while the respective diethyl 1-
hydroxyphosphonates (1ꢁR)-9c and (1ꢁS)-9c were not detected in the crude reaction mixture.
The similar reactivity pattern was found for trimethyl phosphite. These observations clearly
showed that application of pre-formed imines 17 (Scheme 5) is a better approach in the
synthesis of 1-aminoalkylphosphonates 18 than conducting a three-component reaction.

1244
D. G. PIOTROWSKA ET AL.
Scheme 6 Addition of triethyl phosphite to the imine 20. Reaction conditions: (a) 20 (1.0 equiv.), (EtO)3P (1.0
equiv.), 2,2,2-trifluoroethanol, r.t., 48 h.
Replacement of 2,2,2-trifluoroethanol with anhydrous ethanol significantly slowed
the three-component reaction down, which was complete in about 2 weeks. Under the same
conditions, addition of triethyl phosphite to the imine 20 was even slower. In both cases, a
7:3 diastereoselectivity was observed, and 1-aminophosphonate (1ꢁR)-8c was formed as a
major product.
When the reaction between the aldehyde (2R,5R,6R)-6, benzylamine, and triethyl
phosphite was performed in chloroform at room temperature, a 20:80 mixture of the ex-
pected diethyl 1-aminophosphonates (1ꢁR)-8a and (1ꢁS)-8a was obtained in less than 4 days.
Similar diastereoselectivity (25:75) was noticed in the three-component reaction when
benzylamine was replaced with benzhydrylamine. Application of (R)-1-phenylethylamine
instead of benzylamine led to the formation of a 13:87 mixture of phosphonates (1ꢁR)-8d
and (1ꢁS)-8d while with (S)-1-phenylethylamine the 1-aminophosphonates (1ꢁR)-8c and
(1ꢁS)-8c were produced in a 31:69 ratio.
Transition State Models for the Addition of Trialkyl Phosphites
to C N Bonds
It is firmly established that imines exist in a preferred conformation in which hy-
drogen atoms within a H–C N–C–H fragment are eclipsed to minimize the 1,3-allylic
strain.59 For this reason, aldimines formed from the aldehyde (2R,5R,6R)-6 and benzy-
lamines (Table 1) would adopt a conformation 21 (Figure 4) in which rotation around the
N–CHRꢁꢁRꢁꢁꢁ is restricted. Thus, any π-facial discrimination resulted from the additions
of trialkyl phosphites to the C N bond would incorporate the 1,2-asymmetric induction
generated by the chirality at C2 and the 1,3-asymmetric induction if chiral amines are
employed.
In attempts at rationalizing the stereochemical outcome of the three-component reac-
tions performed in chloroform transition states without chelation can be only considered.
However, the nonchelation transition state models for nucleophilic additions to imines
are rarely discussed in the literature31,60 although sound evidence was gathered in favor
Figure 4 The preferred conformation 21 of imines formed from the aldehyde (2R,5R,6R)-6 and benzylamines.

STEREOCHEMISTRY OF THE THREE-COMPONENT
1245
Figure 5 Transition state models of additions to the C N bond in the three-component reactions without chelation
(22–24) and to the C O bond in the Abramov reaction (25).
of the “Felkin-Ahn polar model” in which the incoming nucleophile enters from the op-
posite side of the electronegative substituent at the stereogenic center.61 We suggest that
triethyl phosphite preferentially approaches the si face of the C N bond in the imine
21 (Rꢁꢁ = H, Rꢁꢁꢁ = Ph) on a Bu¨rgi–Dunitz trajectory62,63 in a transition state 22 resem-
bling the Felkin-Ahn polar model in which the oxygen atom (O1) serves as the largest
substituent to give (1ꢁS)-aminophosphonates 8 as major diastereoisomers (Figure 5). The
stereogenic centers present in the imine obtained from the aldehyde (2R,5R,6R)-6 and
(R)-1-phenylethylamine form a “matched-pair” (TS 23) since better diastereoselectivity
(13:87) is observed in comparison to the 1,2-asymmetric induction (20:80) found in the
former case. Because the diastereoselectivity of the addition to the imine produced from
the aldehyde (2R,5R,6R)-6 and (S)-1-phenylethylamine drops down significantly (31:69), a
“mismatched-pair” of stereogenic centers (TS 24) is characteristic of this diastereoisomer.
In support to these conclusions, it was noticed that a similar Felkin-Ahn model 25 acknowl-
edges the sense of 1,2-stereoinduction of dialkyl hydrogen phosphonates to the aldehyde
(2R,5R,6R)-6.41
Opposite to the preferential formation of (1ꢁS)-aminophosphonates 8 in reactions
conducted in chloroform regardless of the structural features of amines used, the absolute
configuration of major 1-aminophosphonates 8 obtained in additions carried out in 2,2,2-
trifluoroethanol (Table 1) or in ethanol strongly depends on the structure of amines used. To
accommodate the observed results, we suggest that in alcohols (e.g., 2,2,2-trifluoroethanol;
pKa = 12.4) the respective iminium ions are subjected to the nucleophilic attack by triethyl
phosphite. However, in order to avoid the 1,3-allylic strain, protonated imines are expected
to adopt a conformation 26 (Figure 6) in which hydrogen atoms in the H–C2–C N+–H
moiety are eclipsed.
Figure 6 The preferred conformation 26 of protonated imines formed from the aldehyde (2R,5R,6R)-6 and
benzylamines.

1246
D. G. PIOTROWSKA ET AL.
Figure 7 Transition state models of additions to the C = N bond in the three-component reactions performed in
alcohols (27–29).
Thus, a negligible diastereoselectivity observed in addition of trialkyl phosphites to
imines formed from the aldehyde (2R,5R,6R)-6 and benzylamine as well as benzhydry-
lamine reflects lack of facial discrimination as depicted in a TS model 27 (HaxC3Heq vs.
lone pairs at O1) (Figure 7).
A significant diastereoselectivity observed in the reaction of triethyl phosphite with
the imine prepared from the aldehyde (2R,5R,6R)-6 and (S)-1-phenylethylamine providing
(2R,5R,6R,1ꢁR)-8c as a major diastereoisomer can be explained by the preferential attack
of the nucleophile at the less hindered re face (TS 28) as a result of the 1,3-asymmetric
induction only. For the same reason, the approaching nucleophile favors the si face (TS 29)
of the imine prepared from the aldehyde (2R,5R,6R)-6 and (R)-1-phenylethylamine as well
as from (R)-1-(1-naphthyl)ethylamine thus leading to the formation of (1ꢁS)-8e and (1ꢁS)-8f
as major products.
CONCLUSIONS
(2R,5R,6R)-5,6-Dimethoxy-5,6-dimethyl-1,4-dioxane-2-carbaldehyde (Ley’s alde-
hyde) was efficiently employed in the three-component reaction with trimethyl phos-
phite and benzhydrylamine to give enantiomerically pure dimethyl 1-aminophosphonates
(2R,5R,6R,1ꢁR)-10 (20%) and (2R,5R,6R,1ꢁS)-10 (20%) after chromatographic separation
on silica gel columns.
The absolute configurations at C1ꢁ in 1-aminophosphonates (2R,5R,6R,1ꢁR)-10 (ma-
1
jor) and (2R,5R,6R,1ꢁS)-10 (minor) were unequivocally established based on H and 13C
NMR spectral data since in chloroform they exist as single rotamers, and the major di-
astereoisomer is additionally stabilized by a strong intramolecular hydrogen bond. Gen-
erally, for other 1-aminophosphonates, the (2R,5R,6R,1ꢁR) absolute stereochemistry is as-
3
3
signed to the diastereoisomer having J(HC1ꢁC2H) = 2.4–4.0 Hz and J(PC1ꢁC2C3) =
12.8–14.6 Hz.
Diastereoselectivity of the additions of trialkyl phosphites to the C = N bond of
intermediate imines (iminium ions) formed in the three-component reactions strongly de-
pends on the solvent. Regardless the amine used in reactions carried out in chloroform,
diethyl (2R,5R,6R,1ꢁS)-1-aminophosphonates are formed as major products with d.e. up to
74%. The sense of chirality of major 1-aminophosphonates produced in alcohols solely
depends on the configuration of the amines. When (S)-1-phenylethylamine was applied,
(2R,5R,6R,1ꢁR)-1-aminophosphonate was obtained as a major diastereoisomer (d.e. 62%),

STEREOCHEMISTRY OF THE THREE-COMPONENT
1247
while from (R)-1-phenylethylamine (2R,5R,6R,1ꢁS)-1-aminophosphonate (d.e. 20%) was
formed.
The Felkin-Ahn polar models of transition states proposed for the addition of trialkyl
phosphites in chloroform account for preferential attack on the si face of the C N bond and
the 1,2-asymmetric induction is found more influential than the 1,3-asymmetric induction.
The transition state models suggested for the reactions performed in alcohols well corre-
late with the negligible 1,2-diastereoselection and invoke the 1,3-asymmetric induction to
rationalize the observed π-facial discrimination.
EXPERIMENTAL
General
1H NMR spectra were recorded with a Varian Mercury-300 spectrometer; chemi-
cal shifts δ in ppm with respect to tetramethylsilane (TMS); coupling constants J in Hz.
13C and 31P NMR spectra were recorded on a Varian Mercury-300 machine at 75.5 and
121.5 MHz, respectively. Two-dimensional NMR (COSY and NOE) measurements were
performed on a Bruker Avance III (600 MHz) spectrometer. IR spectral data were measured
on an Infinity MI-60 FT-IR spectrometer. Melting points were determined on a Boetius ap-
paratus and are uncorrected. Elemental analyses were performed by the Microanalytical
Laboratory of this Faculty on a Perkin Elmer PE 2400 CHNS analyzer and their results
were found to be in good agreement ( 0.3%) with the calculated values. Polarimetric
measurements were conducted on an Optical Activity PolAAr 3001 apparatus. The follow-
ing absorbents were used: column chromatography, Merck silica gel 60 (70−230 mesh),
cat.#1.07734.9025 (Darmstadt, Germany); analytical TLC, Merck TLC plastic sheets silica
gel 60 F254, cat.#1.05735.0001 (Darmstadt, Germany).
The Three-component Reaction of (2R,5R,6R)-5,6-dimethoxy-5,6-dime-
thyl-1,4-dioxane-2-carboxaldehyde (2R,5R,6R)-6 with Benzhydrylamine and
Trimethyl Phosphite
To a solution of the aldehyde (2R,5R,6R)-6 (3.30 g, 16.6 mmol) in 2,2,2-
trifluoroethanol (3 mL), benzhydrylamine (2.52 g, 13.7 mmol) was added followed by
trimethyl phosphite (1.85 g, 14.9 mmol) and the reaction mixture was stirred at room
temperature for 24 h. After removal of all volatiles in vacuum (0.1 mm Hg), the oily
residue was analyzed by 1H and 31P NMR spectroscopy and subjected to chromatographic
purification to give of dimethyl 1-aminophosphonates (2R,5R,6R,1ꢁS)-10 (1.26 g, 20%)
and (2R,5R,6R,1ꢁR)-10 (1.22 g, 20%) as colorless oils.
Dimethyl (S)-[(2R,5R,6R)-5,6-dimethoxy-5,6-dimethyl-1,4-dioxan-2-yl]
(diphenylmethylamino)methylphosphonate (2R,5R,6R,1ꢀS)-10
[α]2D0 = −72.7 (c 0.9, CHCl3). IR (film): ν [cm−1] 3480, 3335, 2992, 2952, 1599,
1
1493, 1453, 1374, 1245, 1142, 1037, 879, 827, 749, 705. H NMR (300 MHz, CDCl3) δ
[ppm]: 7.45–7.40 (m, 4H), 7.40–7.19 (m, 6H), 5.41 (s, 1H, HCPh2), 4.29 (dddd, J2–P
14.2, J2–3ax = 11.3, J2–1 = 4.4, J2–3eq = 3.3 Hz, 1H, HCCP), 3.93 (t, J3ax–3eq = J3ax–2
=
=
11.3 Hz, 1H, HaxCCCP), 3.83 (d, J = 10.7 Hz, 3H, POCH3), 3.79 (d, J = 10.7 Hz, 3H,
POCH3), 3.62 (dd, J3eq–3ax = 11.3, J3eq–2 = 3.3 Hz, 1H, HeqCCCP), 3.30 (s, 3H, OCH3),
3.25 (s, 3H, OCH3), 3.04 (dd, J1–P = 17.7, J1–2 = 4.4 Hz, 1H, HCP), 2.09 (very br s,

1248
D. G. PIOTROWSKA ET AL.
1H, NH), 1.29 (s, 3H, CH3), 1.28 (s, 3H, CH3). 13C NMR (75.5 MHz, CDCl3) δ [ppm]:
143.1, 143.1, 128.4, 128.4, 127.8, 127.4, 127.3, 127.1, 99.4, 97.3, 67.7 (d, J = 6.6 Hz),
65.0 (d, J = 7.7 Hz), 60.6 (d, J = 4.3 Hz, CCCP), 53.5 (d, J = 148.3 Hz, CP), 53.1 (d,
J = 6.6 Hz), 52.7 (d, J = 6.9 Hz), 48.3, 48.0, 17.9, 17.7. 31P NMR (121.5 MHz, CDCl3)
δ [ppm]: 28.58 ppm. Anal. Calcd. for C24H34NO7P: C, 60.12; H, 7.15; N, 2.92. Found: C,
59.90; H, 7.19; N, 2.86.
Dimethyl (R)-[(2R,5R,6R)-5,6-dimethoxy-5,6-dimethyl-1,4-dioxan-2-yl]
(diphenylmethylamino)methylphosphonate (2R,5R,6R,1ꢀR)-10
[α]2D0 = −110.5 (c 1.0, CHCl3). IR (film): ν [cm−1] 3480, 3355, 2990, 2951, 1599,
1
1493, 1454, 1374, 1248, 1142, 1033, 878, 813, 747, 700. H NMR (300 MHz, CDCl3) δ
[ppm]: 7.48–7.44 (m, 2H), 7.42–7.38 (m, 2H), 7.34–7.21 (m, 6H), 5.25 (d, J = 3.2 Hz,
1H, HCPh2), 4.32 (dddd, J2–3ax = 11.3, J2–P = 10.6, J2–1 = 3.2, J2–3eq = 3.2 Hz, 1H,
HCCP), 4.20 (t, J3ax–3eq = J3ax–2 = 11.3 Hz, 1H, HaxCCCP), 3.82 (d, J = 10.6 Hz, 3H,
CH3OP), 3.73 (d, J = 10.7 Hz, 3H, CH3OP), 3.36 (s, 3H, OCH3), 3.33 (s, 3H, OCH3),
3.30 (dd, J3eq–3ax = 11.1, J3eq–2 = 3.2 Hz, 1H, HeqCCCP), 2.85 (dd, J1–P = 15.0, J1–2
=
3.2 Hz, 1H, HCP), 1.90–1.30 (br s, 1H, NH), 1.29 (s, 3H, CH3), 1.28 (s, 3H, CH3). 13C
NMR (75.5 MHz, CDCl3) δ [ppm]: 143.7, 142.5, 128.4, 127.7, 127.2, 127.2, 127.1, 99.4,
97.7, 68.9 (d, J = 1.7 Hz), 65.2 (d, J = 3.1 Hz), 60.8 (d, J = 14.0 Hz, CCCP), 53.0 (d,
J = 6.3 Hz), 52.9 (d, J = 142.8 Hz, CP), 51.9 (d, J = 6.6 Hz), 48.38, 48.0, 17.8, 17.7. 31P
NMR (121.5 MHz, CDCl3): δ [ppm]: 30.24 ppm. Anal. Calcd. for C24H34NO7P: C, 60.12;
H, 7.15; N, 2.92. Found: C, 60.01; H, 6.99; N, 2.72.
The Three-component Reaction (General Procedure)
To a solution of the aldehyde (2R,5R,6R)-6 (1.00 mmol) in appropriate solvent: 2,2,2-
trifluoroethanol, ethanol, or chloroform-d (0.5 mL), substituted benzylamine (1.00 mmol)
was added followed by trialkyl phosphite (1.00 mmol) and the progress of the reaction
1
was monitored by H and 31P NMR spectra until signals of the starting aldehyde or the
respective imines disappeared. For the reactions performed in 2,2,2-trifluoroethanol, the
crude products were subjected to chromatography on silica gel columns to give mixtures
of the respective diastereoisomers usually contaminated with traces of unreacted amines.
The spectral data (vide infra) were calculated from mixtures of diastereoisomers.
Diethyl (R)-[(2R,5R,6R)-5,6-dimethoxy-5,6-dimethyl-1,4-dioxan-2-yl]
(phenylmethylamino)methylphosphonate (2R,5R,6R,1ꢀR)-8a
1H NMR (300 MHz, CDCl3) δ [ppm]: 7.40–7.21 (m, 5H), 4.35–3.65 (m, 9H), 3.35 (s,
3H, OCH3), 3.28 (s, 3H, OCH3), 2.83 (dd, J1–P = 14.3, J1–2 = 4.0 Hz, 1H, HCP), 2.20–1.90
(br s, 1H, NH), 1.40–1.20 (m, 12H). 13C NMR (75.5 MHz, CDCl3) δ [ppm]: 140.0, 128.5,
128.3, 127.1, 99.5, 97.9, 67.1 (d, J = 3.6 Hz, CCP), 62.5 (d, J = 6.9 Hz), 61.8 (d, J =
7.5 Hz), 61.1 (d, J = 12.8 Hz, CCCP), 55.2 (d, J = 148.4 Hz, CP), 52.9 (d, J = 3.2 Hz,
NCH2Ph), 48.6, 48.2, 18.0, 17.9, 16.9, and 16.8 (2 × d, J = 6.3 Hz). 31P NMR (121.5 MHz,
CDCl3) δ [ppm]: 26.03 ppm.

STEREOCHEMISTRY OF THE THREE-COMPONENT
1249
Diethyl (S)-[(2R,5R,6R)-5,6-dimethoxy-5,6-dimethyl-1,4-dioxan-2-yl]
(phenylmethylamino)methylphosphonate (2R,5R,6R,1ꢀS)-8a
1H NMR (300 MHz, CDCl3) δ [ppm]: 7.40–7.20 (m, 5H), 4.35–3.65 (m, 9H), 3.32
(s, 3H, OCH3), 3.25 (s, 3H, OCH3), 3.04 (dd, J1–P = 15.5, J1–2 = 5.7 Hz, 1H, HCP),
2.20–1.90 (br s, 1H, NH), 1.40–1.20 (m, 12H). 13C NMR (75.5 MHz, CDCl3) δ [ppm]:
139.9, 128.5, 128.3, 127.1, 99.5, 98.0, 67.0 (d, J = 7.3 Hz, CCP), 62.2 (d, J = 7.0 Hz),
62.2 (d, J = 7.0 Hz), 61.0 (d, J = 4.5 Hz, CCCP), 56.2 (d, J = 149.1 Hz, CP), 52.9 (d,
J = 6.7 Hz, NCH2Ph), 48.4, 48.2, 18.0, 17.8, 16.8, and 16.8 (2 × d, J = 6.3 Hz). 31P NMR
(121.5 MHz, CDCl3) δ [ppm]: 25.62 ppm.
Diethyl (R)-[(2R,5R,6R)-5,6-dimethoxy-5,6-dimethyl-1,4-dioxan-2-yl]
(diphenylmethylamino)methylphosphonate (2R,5R,6R,1ꢀR)-8b
1H NMR (300 MHz, CDCl3) δ [ppm]: 7.50–7.15 (m, 10H), 5.30 (d, J = 3.2 Hz, 1H,
HCPh2), 4.35–3.60 (m, 6H), 3.34 (s, 3H, OCH3), 3.32 (s, 3H, OCH3), 3.31 (dd, J3eq–3ax
=
10.9, J3eq–2 = 3.0 Hz, 1H, HeqCCCP), 2.83 (dd, J1–P = 16.9, J1–2 = 2.4 Hz, 1H, HCP),
2.20–1.90 (br s, 1H, NH), 1.40–1.20 (m, 12H). 13C NMR (75.5 MHz, CDCl3) δ [ppm]:
143.9, 142.6, 128.4, 127.8, 127.3, 127.3, 127.2, 127.0, 99.4, 97.8, 67.0 (d, J = 2.3 Hz,
CCP), 65.0 (d, J = 3.4 Hz, CPh2), 62.2 (d, J = 6.5 Hz), 61.5 (d, J = 6.4 Hz), 61.0 (d, J =
14.0 Hz, CCCP), 53.2 (d, J = 143.6 Hz, CP), 48.5, 48.1, 17.8, 17.8, 16.8 (d, J = 6.7 Hz),
16.7 (d, J = 6.5 Hz). 31P NMR (121.5 MHz, CDCl3) δ [ppm]: 27.03 ppm.
Diethyl (S)-[(2R,5R,6R)-5,6-dimethoxy-5,6-dimethyl-1,4-dioxan-2-yl]
(diphenylmethylamino)methylphosphonate [(2R,5R,6R,1ꢀS)-8b
1H NMR (300 MHz, CDCl3) δ [ppm]: 7.50–7.15 (m, 10H), 5.47 (s, 1H, HCPh2),
4.35–3.60 (m, 5H), 3.92 (t, J3ax–3eq = J3ax–2 = 11.3 Hz, 1H, HaxCCCP), 3.67 (dd, J3eq–3ax
= 11.3, J3eq–2 = 3.3 Hz, 1H, HeqCCCP), 3.27 (s, 3H, OCH3), 3.24 (s, 3H, OCH3), 3.01 (dd,
J1–P = 18.0, J1–2 = 4.2 Hz, 1H, HCP), 2.20–1.90 (br s, 1H, NH), 1.40–1.20 (m, 12H). 13
C
NMR (75.5 MHz, CDCl3) δ [ppm]: 143.3, 143.2, 128.4, 127.8, 127.4, 127.3, 127.2, 127.1,
99.4, 97.9, 67.7 (d, J = 7.5 Hz, CCP), 64.9 (d, J = 8.1 Hz, CPh2), 62.4 (d, J = 6.5 Hz),
62.0 (d, J = 7.2 Hz), 60.6 (d, J = 4.0 Hz, CCCP), 53.7 (d, J = 149.3 Hz, CP), 48.3, 48.1,
17.9, 17.7, 16.8 (d, J = 6.0 Hz), 16.7 (d, J = 6.0 Hz). 31P NMR (121.5 MHz, CDCl3)
δ [ppm]: 25.80 ppm.
Diethyl (R)-[(2R,5R,6R)-5,6-dimethoxy-5,6-dimethyl-1,4-dioxan-2-yl]
[(S)-1-phenylethylamino]methylphosphonate (2R,5R,6R,1ꢀR)-8c
1H NMR (300 MHz, CDCl3) δ [ppm]: 7.30–7.20 (m, 5H), 4.35–4.00 (m, 7H), 3.34 (s,
3H, OCH3), 3.30 (s, 3H, OCH3), 3.06 (dd, J3eq–3ax = 11.3, J3eq–2 = 3.5 Hz, 1H, HeqCCCP),
2.63 (dd, J1–P = 14.6, J1–2 = 2.8 Hz, 1H, HCP), 2.05–1.85 (br s, 1H, NH), 1.40–1.20 (m,
15H). 13C NMR (75.5 MHz, CDCl3) δ [ppm]: 144.8, 128.3, 127.3, 127.2, 99.48, 97.9, 67.1
(d, J = 1.5 Hz, CCP), 62.1 (d, J = 6.3 Hz), 61.4 (d, J = 7.1 Hz), 60.8 (d, J = 14.6 Hz,
CCCP), 56.5 (CPh), 53.7 (d, J = 152.6 Hz, CP), 48.6, 48.1, 25.2, 17.9, 16.9 (d, J = 5.7 Hz),
16.8 (d, J = 5.7 Hz). 31P NMR (121.5 MHz, CDCl3) δ [ppm]: 27.43 ppm.

1250
D. G. PIOTROWSKA ET AL.
Diethyl (S)-[(2R,5R,6R)-5,6-dimethoxy-5,6-dimethyl-1,4-dioxan-2-yl]
[(S)-1-phenylethylamino]methylphosphonate (2R,5R,6R,1ꢀS)-8c
1H NMR (300 MHz, CDCl3) δ [ppm]: 7.30–7.20 (m, 5H), 4.35–4.0 (m, 7H), 3.60 (dd,
J3eq–3ax = 11.3, J3eq–2 = 3.1 Hz, 1H, HeqCCCP), 3.30 (s, 3H, OCH3), 3.29 (s, 3H, OCH3),
2.91 (dd, J1–P = 20.8, J1–2 = 3.6 Hz, 1H, HCP), 2.05–1.85 (br s, 1H, NH), 1.40–1.20 (m,
15H). 13C NMR (75.5 MHz, CDCl3) δ [ppm]: 144.7, 128.3, 127.2, 127.1, 99.5, 97.9, 66.7
(d, J = 6.3 Hz, CCP), 62.6 (d, J = 6.3 Hz), 61.9 (d, J = 6.9 Hz), 60.6 (d, J = 2.9 Hz,
CCCP), 56.0 (d, J = 12.0 Hz, CPh), 53.5 (d, J = 141.4 Hz, CP), 48.2, 48.1, 24.6, 17.9, 16.8
(d, J = 6.3 Hz), 16.6 (d, J = 6.3 Hz). 31P NMR (121.5 MHz, CDCl3) δ [ppm]: 25.33 ppm.
Diethyl (R)-[(2R,5R,6R)-5,6-dimethoxy-5,6-dimethyl-1,4-dioxan-2-yl]
[(R)-1-phenylethylamino]methylphosphonate (2R,5R,6R,1ꢀR)-8d
1H NMR (300 MHz, CDCl3) δ [ppm]: 7.40–7.15 (m, 5H), 4.30–3.60 (m, 7H), 3.46
(dd, J3eq–3ax = 11.1, J3eq–2 = 3.2 Hz, 1H, HeqCCCP), 3.35 (s, 3H, OCH3), 3.27 (s, 3H,
OCH3), 2.85 (dd, J1–P = 18.6, J1–2 = 3.6 Hz, 1H, HCP), 2.50–1.90 (br s, 1H, NH), 1.40–1.20
(m, 15H). 13C NMR (75.5 MHz, CDCl3) δ [ppm]: 145.1, 128.3, 127.1, 127.0, 99.4, 97.9,
67.2 (d, J = 4.7 Hz, CCP), 62.5 (d, J = 6.9 Hz), 61.5 (d, J = 7.3 Hz), 61.2 (d, J = 13.8 Hz,
CCCP), 57.1 (d, J = 10.3 Hz, CPh), 53.3 (d, J = 152.9 Hz, CP), 48.4, 48.0, 23.9, 17.9,
17.7, 16.7 (d, J = 6.3 Hz), 16.6 (d, J = 6.3 Hz). 31P NMR (121.5 MHz, CDCl3) δ [ppm]:
25.74 ppm.
Diethyl (S)-[(2R,5R,6R)-5,6-dimethoxy-5,6-dimethyl-1,4-dioxan-2-yl]
[(R)-1-phenylethylamino]methylphosphonate (2R,5R,6R,1ꢀS)-8d
1H NMR (300 MHz, CDCl3) δ [ppm]: 7.40–7.15 (m, 5H), 4.35–4.0 (m, 6H), 3.29 (s,
3H, OCH3), 3.16 (s, 3H, OCH3), 3.64 (dd, J3eq–3ax = 11.3, J3eq–2 = 3.3 Hz, 1H, HeqCCCP),
3.51 (t, J3ax–3eq = J3ax–2 = 11.3 Hz, 1H, HaxCCCP), 2.80 (dd, J1–P = 13.4, J1–2 = 6.6 Hz,
1H, HCP), 2.50–1.90 (br s, 1H, NH), 1.43–1.21 (m, 15H). 13C NMR (75.5 MHz, CDCl3)
δ [ppm]: 144.6, 128.2, 127.4, 127.1, 99.3, 97.8, 67.8 (d, J = 5.7 Hz, CCP), 62.1 (d, J =
7.5 Hz), 61.8 (d, J = 7.9 Hz), 61.3 (d, J = 8.2 Hz, CCCP), 56.9 (d, J = 1.7 Hz, CPh),
54.1 (d, J = 145.5 Hz, CP), 48.3, 48.0, 24.4, 17.8, 17.7, 16.8 (d, J = 6.3 Hz), 16.7 (d, J =
6.3 Hz). 31P NMR (121.5 MHz, CDCl3) δ [ppm]: 27.05 ppm.
Diethyl (R)-[(2R,5R,6R)-5,6-dimethoxy-5,6-dimethyl-1,4-dioxan-2-yl]
[(R)-1-(1-naphthyl)ethylamino]methylphosphonate [(2R,5R,6R,1ꢀR)-8e
1H NMR (300 MHz, CDCl3) δ [ppm]: 8.30–7.40 (m, 7H), 5.07 (q, J = 7.1 Hz, 1H,
HCNh), 4.40–3.30 (m, 7H), 3.37 (s, 3H, OCH3), 3.29 (s, 3H, OCH3), 2.94 (dd, J1–P
=
18.3, J1–2 = 3.7 Hz, 1H, HCP), 2.50–1.90 (br s, 1H, NH), 1.40–1.20 (m, 15H). 13C NMR
(75.5 MHz, CDCl3) δ [ppm]: 140.8, 133.9, 131.3, 128.9, 127.3, 125.7, 124.1, 123.8, 123.3,
123.3, 99.5, 97.9, 66.9 (d, J = 4.7 Hz, CCP), 62.6 (d, J = 6.8 Hz), 61.7 (d, J = 7.0 Hz),
61.6 (d, J = 12.8 Hz, CCCP), 53.2 (d, J = 153.1 Hz, CP), 52.2 (d, J = 10.0 Hz, CNh), 48.4,
48.2, 23.2, 17.9, 17.8, 16.7 (d, J = 6.0 Hz), 16.7 (d, J = 6.0 Hz). 31P NMR (121.5 MHz,
CDCl3) δ [ppm]: 26.10 ppm.

STEREOCHEMISTRY OF THE THREE-COMPONENT
1251
Diethyl (S)-[(2R,5R,6R)-5,6-dimethoxy-5,6-dimethyl-1,4-dioxan-2-yl]
[(R)-1-(1-naphthyl)ethylamino]methylphosphonate (2R,5R,6R,1ꢀS)-8e
1H NMR (300 MHz, CDCl3) δ [ppm]: 8.30–7.40 (m, 7H), 5.20 (q, J = 6.1 Hz, 1H,
HCNh), 4.40–3.30 (m, 7H), 3.30 (s, 3H, OCH3), 3.14 (s, 3H, OCH3), 2.93 (dd, J1–P
=
14.3, J1–2 = 5.5 Hz, 1H, HCP), 2.50–1.90 (br s, 1H, NH), 1.40–1.20 (m, 15H). 13C NMR
(75.5 MHz, CDCl3) δ [ppm]: 144.7, 133.9, 131.8, 128.8, 127.3, 125.7, 125.7, 125.5, 125.3,
125.3, 99.4, 97.9, 68.1 (d, J = 7.0 Hz, CCP), 62.2 (d, J = 7.0 Hz), 62.0 (d, J = 7.0 Hz),
61.0 (d, J = 6.3 Hz, CCCP), 54.5 (d, J = 145.0 Hz, CP), 51.9 (d, J = 1.5 Hz, CPh), 48.3,
48.0, 24.1, 17.9, 17.8, 16.8 (d, J = 6.0 Hz), 16.7 (d, J = 6.0 Hz). 31P NMR (121.5 MHz,
CDCl3) δ [ppm]: 26.70 ppm.
ACKNOWLEDGMENTS
The authors wish to express their gratitude to Mrs. Jolanta Płocka and Mrs. Edyta
Grzelewska for excellent technical assistance.
FUNDING
Financial support from the Medical University of Ło´dz´ (503-3014-01) is gratefully
acknowledged.
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