Highly diastereoselective addition of chiral H-phosphonate to tert-butylsulfinyl aldimines: a convenient approach to (R)-α-aminophosphonic acids

Article abstract of DOI:10.1016/j.tetasy.2015.06.008

Abstract A highly diastereoselective nucleophilic addition of chiral H-phosphonate, derived from a readily available TADDOL auxiliary, to (S)-N-tert-butylsulfinyl aldimines is reported. The reaction proceeds at room temperature in the presence of potassium carbonate and yields the corresponding aliphatic, aromatic and heteroaromatic α-aminophosphonates with dr >95:5. Subsequent simultaneous removal of both chiral auxiliaries leads to the desired α-aminophosphonic acids in very good yields with an (R)-configuration at the stereogenic α carbon.

Full text of DOI:10.1016/j.tetasy.2015.06.008

Tetrahedron: Asymmetry xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Highly diastereoselective addition of chiral H-phosphonate
to tert-butylsulfinyl aldimines: a convenient approach
to (R)-a-aminophosphonic acids
⇑
Tomasz K. Olszewski , Mateusz Majewski
_
Faculty of Chemistry, Wrocław University of Technology, ul. Wybrzeze Wyspian´skiego 27, 50-370 Wroclaw, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly diastereoselective nucleophilic addition of chiral H-phosphonate, derived from a readily avail-
able TADDOL auxiliary, to (S)-N-tert-butylsulfinyl aldimines is reported. The reaction proceeds at room
temperature in the presence of potassium carbonate and yields the corresponding aliphatic, aromatic
Received 16 May 2015
Accepted 4 June 2015
Available online xxxx
and heteroaromatic
ral auxiliaries leads to the desired
at the stereogenic carbon.
a-aminophosphonates with dr >95:5. Subsequent simultaneous removal of both chi-
a
-aminophosphonic acids in very good yields with an (R)-configuration
Ó 2015 Elsevier Ltd. All rights reserved.
a
1. Introduction
O
O
OH
OH
OH
OH
H
(R)
H2N
P
(R)
N
P
a-Aminophosphonates and
a-aminophosphonic acids as phos-
(S)
NH2
phorus analogues of natural
a
-amino acids have received consider-
O
able interest due to their interesting biological activities.1 The most
important examples include anticancer,2 antibacterial,3 antifungal4
and antiviral activities.5 Furthermore, as the consequence of the
(R)-phospholeucine
(S,R)-alafosfalin
(R)
OH
OH
H2N
replacement of the less bulky carboxylic group in the
acids by a tetrahedral phosphonic moiety in -aminophosphonic
a-amino
P
a
CO2H
O
acids, the latter compounds mimic the tetrahedral transition state
formed in enzyme mediated peptide bond cleavage and thus act as
excellent inhibitors of such important proteolytic enzymes as pro-
tein tyrosine phosphatases6 and HIV protease.7
(R)-amino-5-phosphonopentanoic acid
Figure 1. Most prominent examples of biologically active (R)-aminophosphonic
It is well established that the biological activity of
aminophosphonates and -aminophosphonic acids strongly
depends on the absolute configuration of the stereogenic -carbon
atom; derivatives with an (R)-configuration usually exhibit higher
activities than their (S)-enantiomers. The most prominent exam-
ples include: (R)-phospholeucine, which is more potent inhibitor
of leucine aminopeptidase than the opposite enantiomer;8 (S,R)-
alafosfalin, which exhibits the strongest antibacterial activity out
of four possible stereoisomers9 and (R)-amino-5-phosphonopen-
a-
acids.
a
a
methods for the preparation of a-aminophosphonic acids, the most
convenient approach appears to be the construction of the C–P
bond via nucleophilic addition of H-phosphonates to imines, that
is, the Pudovik reaction.12 One method used to perform this reac-
tion in an asymmetric fashion is the use of chiral directing groups
placed on the imine (originated either from chiral amine or chiral
carbonyl compound) and/or on the phosphorus (chiral H-phospho-
nates) in order to introduce the diastereoselectivity in the forma-
tion of the C–P bond.11a,d
tanoic acid, the N-methyl-D-aspartate (NMDA) antagonist, which
is again more active than the opposite enantiomer (Fig. 1).10
As a consequence, the development of asymmetric methods
In that respect, the N-tert-butylsulfinyl imines13 were recently
used in the asymmetric synthesis of
for the enantio- and diastereoselective preparation of
a-
aminophosphonic acids is of significant interest.11 From the known
a-aminophosphonates and
a-aminophosphonic acids. The N-tert-butylsulfinyl group serves
⇑
as a powerful chiral directing group that can be easily cleaved
under acidic conditions, and additionally activates the imine for
Corresponding author. Tel.: +48 71 320 32 10; fax: +48 71 320 24 27.
E-mail address: tomasz.olszewski@pwr.edu.pl (T.K. Olszewski).
http://dx.doi.org/10.1016/j.tetasy.2015.06.008
0957-4166/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Olszewski, T. K. ; Majewski, M. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/
j.tetasy.2015.06.008

2
T. K. Olszewski, M. Majewski / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
Table 1
Preliminary experiments of the hydrophosphonylation of sulfinamides 2e and 2ba
Ph
Ph
Ph
Ph
Ph
Ph
Ph
O
S
Ph
O
O
R
O
O
R
O
O
O
O
H
N
H
N
O
O
H
O
O
conditions
N
P
P
P
S
S
O
O
O
R
H
Ph
O
Ph
O
Ph
Ph
R = Ph 2e
2b
3
(R,R) - 1
= Et
Entry
R
Conditions
Conversionb (%)
drc
n.d.
n.d.
92:8
90:10
>95:5
89:11
82:18
89:11
>95:5
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Et
No base, CH2Cl2, rt, 24 h
Et3N, CH2Cl2, rt, 24 h
Cs2CO3, CH2Cl2, rt, 12 h
Na2CO3, CH2Cl2, rt, 12 h
K2CO3, CH2Cl2, rt, 12 h
RbCO2, CH2Cl2, rt, 12 h
K2CO3, Et2O, rt, 12 h
No reaction
<10
75
81
90
80
58
88
95
K2CO3, THF, rt, 12 h
K2CO3, CH2Cl2, rt, 12 h
n.d.—not determined.
a
Reactions were carried out using 1 mmol of 2, 1 mmol of (R,R)-1 and 1 mmol of base, in 10 mL of solvent. The progress of the reactions was monitored by 31P NMR.
Conversion based on 31P NMR spectra of the crude reaction mixture.
b
c
Ratio of diastereoisomers (dr) based on 31P NMR spectra of the crude reaction mixture.
nucleophilic additions. Yuan et al. reported the diastereoselective
synthesis of -(tert-butylsulfinylamino)phosphonates through the
be stored at room temperature on air. Importantly, the C2-symme-
try of the (R,R)-1 avoids the formation of a new stereogenic centre
at the phosphorus and thus facilitates the interpretation of the
results of the hydrophosphonylation reaction.
Initially, the hydrophosphonylation of the (S)-N-benzylidene-2-
methylpropane-2-sulfinamide 2e, as a model substrate, was inves-
tigated (Table 1).
We quickly realized that the base had a significant impact on
the outcome of the reaction. No reaction was observed in the
absence of a base (Table 1, entry 1). In the presence of Et3N vey
low conversion was observed (<10%, Table 1 entry 2). Much better
results were obtained with the use of Cs2CO3 (Table 1, entry 3,
conv. 75%, dr 92:8), Na2CO3 (Table 1, entry 4, conv. 81%, dr
90:10) and RbCO3 (Table 1, entry 6, conv. 80%, dr 89:11). The best
results however, were obtained when K2CO3 was used as the base
in CH2Cl2 as the solvent (Table 1, entry 5, conv. 90%, >dr 95:5). The
shift from CH2Cl2 to Et2O (Table 1, entry 7) or THF (Table 1, entry 8)
resulted in a lower conversion and diastereoselectivity of the
hydrophosphonylation.
a
addition of dialkyl H-phosphonates to (S)-N-tert-butylsulfinyl imi-
nes; however in addition to long reaction times (up to 30 h), the
obtained diastereoselectivity for aldehydes was moderate, for ali-
phatic aldehydes de 86.9% and de 81.8% for aromatic aldehydes.14
Recently, Ellman et al. reported that the diastereoselectivity of the
reaction could be enhanced, but low temperature was required
(À78 °C) along with the use of a strong base (KHMDS).15 In both
cases, the product of the hydrophosphonylation required chro-
matographic purification in order to obtain the major diastereoiso-
mer in pure form. To the best of our knowledge, the use of chiral
N-tert-butylsulfinyl imines in combination with chiral H-phospho-
nates has not been described in the literature thus far.
Herein we report on the first application of a double asymmet-
ric induction using (S)-N-tert-butylsulfinyl imines and chiral
TADDOL derived H-phosphonate (R,R)-1 for the highly diastereose-
lective synthesis of
nic acids. The reaction occurs at room temperature over 12 h to
give the desired -(tert-butylsulfinylamino)phosphonates with
a-aminophosphonates and a-aminophospho-
a
Finally, in order to verify the effect of the R group in the imine
on the outcome of the reaction under the optimized conditions, we
used (S)-2-methyl-N-propylidenepropane-2-sulfinamide 2b as the
high diastereoselectivity (dr >95:5). The major diastereoisomer
can be conveniently isolated by simple crystallization.
Subsequent, easy and simultaneous removal of both chiral direct-
ing groups under acidic conditions leads, in good yields, to the cor-
substrate, and the desired
a-aminophosphonate 3b was obtained
with 95% conversion and dr >95:5 (Table 1, entry 9). Importantly
the reaction under the optimized conditions using the (R)-enan-
tiomer of N-benzylidene-2-methylpropane-2-sulfinamide 2e gave
a mixture of diastereoisomers with dr 22:78. The 31P NMR of that
crude reaction mixture showed two signals, which corresponded to
the mixture of diastereoisomers with the major signal being
shifted upfield contrary to the 31P NMR of the reaction with the
use of the (S)-enantiomer of 2b, where the signal of the major
diastereoisomer was shifted downfield. This is in agreement with
the literature data since the stereochemistry present on the chiral
imine induces the opposite stereochemistry on the newly formed
responding
a-aminophosphonic acids in enantiomerically pure
form as (R)-enantiomers.
2. Results and discussion
Tetraaryl-1,3-dioxolane-4,5-dimethanols (TADDOL’s) are con-
sidered to be one of the most privileged scaffolds in asymmetric
synthesis and are readily obtained from inexpensive, naturally
occurring tartaric acid, which is commercially available in both
enantiomeric forms.16 We reasoned that the TADDOL scaffold
C-a
next to the phosphorus.11,14,15
With the optimized conditions in hand, a selected range of (S)-
could be used as the chiral auxiliary in the synthesis of
aminophosphonic acids.
a-
N-tert-butylsulfinyl imines 2 was examined in order to test the
scope of the presented protocol (Table 2).
A palette of aliphatic, aromatic and heteroaromatic (S)-N-tert-
butylsulfinyl imines 2a–n was subjected to the hydrophosphonyla-
tion with (R,R)-1. In each case, the ratio of diastereoisomers (dr)
The desired TADDOL derived H-phosphonate (R,R)-1 was easily
prepared by reacting (R,R)-TADDOL with PCl3 in the presence of
Et3N, followed by hydrolysis of the intermediate containing the
P–Cl bond with H2O.17 The (R,R)-1 was obtained in pure form after
simple recrystallization from methanol as a white solid and could
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T. K. Olszewski, M. Majewski / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
3
Table 2
Scope of the hydrophosphonylation of the (S)-N-tert-butylsulfinyl imines 2a–n with TADDOL derived H-phosphonate (R,R)-1a
Ph
Ph
Ph
O
S
Ph
O
O
R
O
O
H
N
K2CO3
O
O
H
O
O
N
P
P
S
CH2Cl2,
r.t., 12h
O
O
R
H
Ph
O
Ph
Ph
Ph
2a-n
(R,R) - 1
3a-n
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
O
O
H
O
O
O
O
O
O
O
O
O
H
N
O
O
O
O
H
N
H
N
P
P
P
P
N
S
O
O
S
O
S
S
O
O
O
Ph
Ph
O
Ph
O
Ph
O
Ph
3a, 87 %, dr 95:5
3b, 90 %, dr >95:5
3c, 83 %, dr >95:5
3d, 80 %, dr >95:5
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
O
O
O
O
O
O
O
O
H
H
N
O
P
P
O
O
O
H
N
O
O
H
N
O
O
S
S
O
O
P
P
N
S
O
Ph
Ph
S
O
Ph
O
Ph
O
Ph
Ph
Ph
O
Ph
O
3g, 80 %, dr >95:5
3f, 87 %, dr 95:5
F
O
3e
, 85 %, dr >95:5
3h
, 77 %, dr >95:5
Ph
Ph
Ph
Ph
Ph
O
Ph
Ph
O
O
H
O
O
H
O
O
P
N
Ph
P
Ph
O
O
O
O
N
N
H
S
O
S
O
O
P
O
P
O
H
N
Ph
O
S
O
Ph
O
Ph
O
N
O
S
O
Ph
O
Ph
3k, 89 %, dr >95:5
Ph
3j
O
, 80 %, dr >95:5
Ph
Ph
NO2
N
3i, 81 %, dr >95:5
Ph
Ph
3l, 75 %, dr >95:5
Ph
O
O
O
O
O
O
H
N
H
N
P
P
O
O
S
O
S
O
Ph
Ph
Ph
O
Ph
O
O
S
3n
3m
, 78 %, dr 95:5
, 80 %, dr 95:5
a
Reactions were carried out using 1.56 mmol of 2 (dissolved in 5 mL of CH2Cl2), 1.56 mmol of (R,R)-1 (dissolved in 15 mL of CH2Cl2) and
1.56 mmol of K2CO3. Ratio of diastereoisomers (dr) based on 31P NMR spectra of the crude reaction mixture. Yield is given for pure
isolated product.
was measured by 31P NMR of the crude reaction mixture. For ali-
phatic aldehydes, we observed that the diastereoselectivity of the
reaction was not influenced by the size of the aliphatic chain.
Yields however were slightly lower for branched (S)-N-tert-butyl-
sulfinyl imines 2c, 2d probably because of the steric hindrance
around the reaction centre and the difficulty of the (R,R)-1 to access
the C@N bond. Similar conclusions were drawn from the
hydrophosphonylation of aromatic (S)-N-tert-butylsulfinyl imines
2e–j, in which the diastereoselectivity of the process was only
slightly influenced by the substituents present in the aromatic ring.
The lowest yield (77%) was observed in the case of (S)-2-methyl-N-
(naphthalen-2-ylmethylene)propane-2-sulfinamide 2h, the most
sterically encumbered substrate. Finally, heteroaromatic (S)-N-
tert-butylsulfinyl imines 2k–n were reacted under optimized reac-
could be isolated by means of simple recrystallization, thus avoid-
ing the necessity of tedious chromatographic purification.
In order to complete the presented synthetic methodology, we
converted the synthesized
a-aminophosphonates into the desired
a-aminophosphonic acids. For this purpose, pure major diastereoiso-
mers of a-aminophosphonates 3c,e,f,m were selected as substrates
(Table 3). Both chiral auxiliaries were simultaneously removed in
one step by dissolving the a-aminophosphonates 3c,e,f,m in toluene,
treatment with aqueous 4 M HCl and heating at 100 °C for 6 h.18
After separation of the layers, the aqueous layer containing the
desired
the product was crystallized from absolute EtOH/propylene oxide
mixture. The specific rotation values obtained for the pure
a-aminophosphonic acids was evaporated to dryness and
a-
aminophosphonic acids 4a–d were in agreement with the values
reported in the literature and indicated in all four cases an (R)-con-
tion conditions with (R,R)-1 and the desired a-aminophosphonates
3k–n were obtained with very good diastereoselectivity and good
figuration at the stereogenic a-carbon attached to the phosphorus.
yields.
Based on the aforementioned results, it can be concluded that
3. Conclusion
the presented methodology affords the desired
a-aminophospho-
nates with very good diastereoselectivity and yields and thus can
be considered as general. Additionally, it should be mentioned that
In conclusion, we have described the first highly diastereoselec-
tive synthesis of -aminophosphonates and -aminophosphonic
acids via hydrophosphonylation of (S)-N-tert-butylsulfinyl imines
with chiral TADDOL derived H-phosphonate (R,R)-1 using double
asymmetric induction phenomenon. The use of (R,R)-1 as a readily
a
a
due to the presence of the TADDOL moiety in the final
a-
aminophosphonates 3a–n, in each case the major diastereoisomer
Please cite this article in press as: Olszewski, T. K. ; Majewski, M. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/
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T. K. Olszewski, M. Majewski / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
Table 3
4.2. Diastereoselective hydrophosphonylation of (S)-N-tert-
butylsulfinyl aldimines 2a–n with TADDOL H-phosphonate 1:
general procedure
Removal of chiral auxiliaries: the synthesis of (R)-
a
-aminophosphonic acids 4a–da
Ph
Ph
O
O
O
R
O
O
H
N
O
HO
HO
aq. 4M HCl
P
P
TADDOL H-phosphonate 1 (1 equiv) was dissolved in dry CH2Cl2
and to the resulting solution anhydrous K2CO3 (1 equiv) was
added. Next, a solution of the appropriate (S)-N-tert-butylsulfi-
namides 2a–n in CH2Cl2 was injected. The resulting reaction was
vigorously stirred at room temperature for 12 h before quenching
with H2O. The layers were separated and the aqueous layer was
extracted with CH2Cl2. The combined organic extracts were dried
over anhydrous Na2SO4 and concentrated under reduced pressure
to afford crude products 3a–n, which were further purified by crys-
tallization from diethyl ether.
NH2
S
toluene,
100 oC, 6h
Ph
R
Ph
O
4a-d
3c,e,f,m
HO
HO
O
O
HO
P
P
NH2
NH2
HO
(R)-4b, 78 %
(R)-4a, 92 %
HO
P
O
HO
HO
O
4.2.1. (S)-N-((R)-1-((3aR,8aR)-2,2-Dimethyl-6-oxido-4,4,8,8-tetra-
phenyl-tetrahydro-[1,3]dioxolo[4,5-e][1,3,2]dioxaphosphepin-6-yl)
ethyl)-2-methyl-propane-2-sulfinamide 3a
Prepared following the general procedure from TADDOL H-phos-
phonate (0.80 g, 1.56 mmol) in CH2Cl2 (15 mL), (S)-N-ethylidene-2-
methylpropane-2-sulfinamide 2a (0.23 g, 1.56 mmol) in CH2Cl2
(5 mL) and anhydrous K2CO3 (0.21 g, 1.56 mmol). White solid,
0.89 g (87% yield, dr 95:5). Recrystallization from diethyl ether fur-
nished pure major diastereoisomer as white solid, mp 90–92 °C,
NH2
P
HO
NH2
(R)-4d, 85 %
S
F
4c
(R)- , 91 %
a
Reaction was carried out at 100 °C for 6 h. The free (R)-
acids 4a–d were isolated after crystallization from EtOH.
a
-aminophosphonic
[
a D
]
20 = À170.0 (c 1.0, CHCl3). 1H NMR (600 MHz, CDCl3): 7.55–7.25
available and affordable chiral auxiliary enables the reaction to
proceed with high diastereoselectivity (dr >95:5) and permits the
isolation of major diastereoisomer by simple crystallization. The
described protocol was efficiently applied to various aliphatic, aro-
matic and heteroaromatic (S)-N-tert-butylsulfinyl imines, thus
showing its broad applicability. Finally, a simple, one-step depro-
3
3
(m, 20H), 5.55 (d, JHH = 7.8 Hz, 1H), 5.22 (d, JHH = 7.8 Hz, 1H),
3
3
3.87–3.86 (m, 1H), 1.52 (dd, JHH = 7.2 Hz, JHP = 18.5 Hz, 3H), 1.38
(s, 9H), 0.78 (s, 3H), 0.55 (s, 3H). 13C NMR (150 MHz, CDCl3):
144.6, 143.6, 139.5, 139.3, 129.7, 128.7, 128.4, 128.3, 128.2, 128.1,
2
127.8, 127.4, 127.3, 127.1, 126.7, 114.0, 91.0 (d, JCP = 13.2 Hz), 86.7
2
(d, JCP = 8.25 Hz), 79.8, 78.9, 55.9, 47.8 (d, JCP = 166.3 Hz), 26.9,
tection of the synthesized
ditions leads to optically active
yields with an (R)-configuration at the
importance of optically active -aminophosphonates and
a
-aminophosphonates under acidic con-
-aminophosphonic acids in good
-carbon. Considering the
26.4, 22.4, 15.5 (d, JCP = 3.15 Hz). 31P NMR (243 MHz, CDCl3):
2
a
19.52 (s). IR, mmax (KBr): 3430, 3060, 2932, 2984, 1450, 1450, 1380,
1375, 1250, 1220, 1170, 1090, 1051, 988, 919, 940, 860, 790, 745,
a
a
a-
730, 700, 650. HRMS (ESI): calcd for
C37H43NO6PS 660.2549
aminophosphonic acids as biologically relevant compounds, the
presented methodology represents an interesting improvement
to the already described methods and could be used to further
investigate the role of optically active (R)-
and (R)- -aminophosphonic acids in biological processes.
(M+H)+. Found 660.2556.
4.2.2. (S)-N-((R)-1-((3aR,8aR)-2,2-Dimethyl-6-oxido-4,4,8,8-tetra-
phenyltetrahydro-[1,3]dioxolo[4,5-e][1,3,2]dioxaphos- phepin-6-
yl)propyl)-2-methylpropane-2-sulfinamide 3b
a-aminophosphonates
a
Prepared following the general procedure from TADDOL H-phos-
phonate (0.80 g, 1.56 mmol) in CH2Cl2 (15 mL), (S)-2-methyl-N-
propylidenepropane-2-sulfinamide 2b (0.25 g, 1.56 mmol) in
CH2Cl2 (5 mL) and anhydrous K2CO3 (0.21 g, 1.56 mmol). White
solid, 0.93 g (90% yield, dr >95:5). Recrystallization from diethyl
ether furnished pure major diastereoisomer as white solid, mp 89–
4. Experimental
4.1. General
1H (600 MHz), 13C (150 MHz) and 31P (243 MHz) NMR spectra
were recorded on a Bruker Avance II (600 MHz) spectrometer.
Chemical shifts (d) are reported in parts per million relative to inter-
nal tetramethylsilane (Me4Si, d 0.0) for 1H NMR, and CDCl3 (d 77.0)
for 13C NMR. Coupling constants (J) are reported in Hertz. HRMS
analyses were performed on LCT Premier XE Waters apparatus, on
91 °C, [a D
]
20 = À159.0 (c 1.0, CHCl3). 1H NMR (600 MHz, CDCl3):
3
7.60–7.22 (m, 20H), 5.57 (d, JHH = 7.8 Hz, 1H), 5.29 (d,
3JHH = 7.8 Hz, 1H), 3.74–3.70 (m, 1H), 1.96–1.86 (m, 2H), 1.34–1.30
(m, 3H), 1.02 (s, 9H), 0.76 (s, 3H), 0.56 (s, 3H). 13C NMR (150 MHz,
CDCl3): 144.7, 143.9, 139.5, 129.9, 129.0, 128.4, 128.3, 128.2, 128.1,
127.7, 127.6, 127.4, 127.3, 127.2, 126.8, 126.4, 114.0, 91.7 (d,
mode ESI+ (TOF MS ES+). IR spectra were recorded on
a
2
2JCP = 14.1 Hz), 87.1 (d, JCP = 8.25 Hz), 79.5, 78.8, 56.3, 54.5 (d,
PerkinElmer 1600 FTIR spectrometer. Reported melting points are
uncorrected. Optical rotations were measured on Shanghai YiCe
Apparatus & Equipment co., LTD, WZZ-2B Automatic Polarimeter
in 1 dm cell at 20 °C. All reagents were used as received from the
commercial supplier. Unless otherwise stated, all reactions were car-
ried out under an inert atmosphere of argon. All solvents for extrac-
tions and reactions were technical grade and were dried before use
using standard techniques. The (S)-N-tert-butylsulfinyl aldimines
2a–n were obtained using an original procedure described by
Ellman and involving condensation of the appropriate aldehyde with
(S)-N-tert-butanesulfinamide in the presence of Ti(OEt)4 at room
temperature,19 and their spectroscopic characterization was consis-
tent with the data reported previously in the literature; 2a-c,20
JCP = 156.4 Hz), 27.0, 24.8, 24.2, 10.5. 31P NMR (243 MHz, CDCl3):
18.92 (s). IR, mmax (KBr): 3428, 3062, 2984, 2932, 2984, 1600, 1496,
1448, 1383, 1372, 1249, 1216, 1166, 1054, 1088, 987, 938, 919,
858, 744, 726, 698. HRMS (ESI): calcd for C38H45NO6PS 674.2705
(M+H)+. Found 674.2708.
4.2.3. (S)-N-((R)-1-((3aR,8aR)-2,2-Dimethyl-6-oxido-4,4,8,8-tetra-
phenyltetrahydro-[1,3]dioxolo[4,5-e][1,3,2]dioxaphosphepin-6-
yl)-2-methylpropyl)-2-methylpropane-2-sulfinamide 3c
Prepared following the general procedure from TADDOL H-
phosphonate (0.80 g, 1.56 mmol) in CH2Cl2 (15 mL), (S)-2-
methyl-N-(2-methylpropylidene)propane-2-sulfinamid 2c (0.27 g,
1.56 mmol) in CH2Cl2 (5 mL) and anhydrous K2CO3 (0.21 g,
2d,21 2e,g,h,j,22 2f,k,23 2i,n,24 2l and 2m.26
25
Please cite this article in press as: Olszewski, T. K. ; Majewski, M. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/
j.tetasy.2015.06.008

T. K. Olszewski, M. Majewski / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
5
1.56 mmol). White solid, 0.87 g (83% yield, dr >95:5).
Recrystallization from diethyl ether furnished pure major
[
a D
]
20 = À91.0 (c 1.0, CHCl3). 1H NMR (600 MHz, CDCl3): 7.60–7.20
(m, 20H), 6.95–6.90 (m, 2H), 6.75–6.70 (m, 2H), 5.41 (d,
3JHH = 7.8 Hz, 1H), 4.93–4.89 (m, 2H), 1.45 (s, 9H), 0.82 (s, 3H), 0.43
(s, 3H). 13C NMR (150 MHz, CDCl3): 163.4 (d, JCF = 245.1 Hz), 143.9
(d, JCP = 7.5 Hz), 143.5, 139.1 (d, JCP = 9.7 Hz), 130.7, 129.8, 128.5,
128.4, 128.2, 128.2, 128.1, 127.9, 127.8, 127.5, 127.3, 127.2, 126.4,
diastereoisomer as white solid, mp 86–88 °C, [a D
]
20 = À163.0 (c 1.0,
CHCl3). 1H NMR (600 MHz, CDCl3): 7.70–7.25 (m, 20H), 5.75 (d,
3
2
3
3JHH = 7.8 Hz, 1H), 5.50 (d, JHH = 8.0 Hz, 1H), 3.75–3.70 (m, 1H),
3
2.50–2.47 (m, 1H), 1.15 (s, 9H), 1.14 (d, JHH = 6.2 Hz, 3H), 1.12 (d,
3JHH = 6.7 Hz, 3H), 0.90 (s, 3H), 0.75 (s, 3H). 13C NMR (150 MHz,
115.2, 113.9, 91.7 (d, JCP = 13.05 Hz), 86.9 (d, JCP = 7.95 Hz), 79.1,
2
2
CDCl3): 135.5, 128.9, 128.7, 128.6, 128.1, 128.0, 127.9, 127.7, 127.4,
79.1, 56.1, 55.2 (d, JCP = 162.3 Hz), 27.0, 26.2, 24.2. 31P NMR
2
127.3, 127.2, 126.5, 113.8, 91.5 (d, JCP = 12.8 Hz), 86.8 (d,
(243 MHz, CDCl3): 15.91 (s). IR, mmax (KBr): 3338, 3067, 1951, 1610,
2JCP = 8.2 Hz), 79.4, 79.2, 56.1, 56.2 (d, JCP = 159.0 Hz), 31.0 (d,
2JCP = 7.0 Hz), 22.2, 19.7, 19.5, 18.8. 31P NMR (243 MHz, CDCl3):
20.66 (s). IR, mmax (KBr): 3428, 3062, 2932, 1958, 1601, 1496, 1448,
1383, 1249, 1166, 1087, 1038, 938, 917, 743, 699, 641. HRMS
(ESI): calcd for C39H47NO6PS 688.2862 (M+H)+. Found 688.2867.
1491, 1377, 1260, 1224, 1090, 1053, 989, 921, 747, 697. HRMS (ESI):
calcd for C42H44FNO6PS 740.2611 (M+H)+. Found 740.2615.
4.2.7. (S)-N-((R)-((3aR,8aR)-2,2-Dimethyl-6-oxido-4,4,8,8-tetra-
phenyltetrahydro-[1,3]dioxolo[4,5-e][1,3,2]dioxaphosphepin-6-
yl)(4-methoxyphenyl)methyl)-2-methylpropane-2-sulfinamide
3g
Prepared following the general procedure from TADDOL H-phos-
phonate (0.80 g, 1.56 mmol) in CH2Cl2 (15 mL), (S)-N-(4-methoxy-
benzylidene)-2-methylpropane-2-sulfinamide 2g (0.37 g, 1.56 mmol)
in CH2Cl2 (5 mL) and anhydrous K2CO3 (0.21 g, 1.56 mmol). White
solid, 0.92 g (80% yield, dr >95:5). Recrystallization from diethyl ether
furnished pure major diastereoisomer as white solid, mp 101–103 °C,
4.2.4. (S)-N-((R)-1-((3aR,8aR)-2,2-Dimethyl-6-oxido-4,4,8,8-tetra-
phenyltetrahydro-[1,3]dioxolo[4,5-e][1,3,2]dioxaphosphepin-6-
yl)-3-methylbutyl)-2-methylpropane-2-sulfinamide 3d
Prepared following the general procedure from TADDOL H-
phosphonate (0.80 g, 1.56 mmol) in CH2Cl2 (15 mL), (S)-2-
methyl-N-(3-methylbutylidene)propane-2-sulfinamide 2d (0.29 g,
1.56 mmol) in CH2Cl2 (5 mL) and anhydrous K2CO3 (0.21 g,
1.56 mmol). White solid, 0.85 g (80% yield, dr >95:5).
Recrystallization from diethyl ether furnished pure major
[a D
]
20 = À109.0 (c 1.0, CHCl3). 1H NMR (600 MHz, CDCl3): 7.62–7.26
3
(m, 22H), 7.02–6.97 (m, 2H), 5.67 (d, JHH = 8.0 Hz, 1H), 5.07 (d,
3JHH = 7.8 Hz, 1H), 4.47 (d, JHP = 19.8 Hz, 1H), 3.80 (s, 3H), 1.50 (s, 9H),
0.87 (s, 3H), 0.45 (s, 3H). 13C NMR (150 MHz, CDCl3): 160.1, 144.3,
143.8, 138.9, 131.6, 130.2, 129.7, 129.0, 128.9, 128.5, 128.2, 128.0,
diastereoisomer as white solid, mp 120–123 °C, [
a
]
20 = À133.0 (c
D
1.0, CHCl3). 1H NMR (600 MHz, CDCl3): 7.67–7.29 (m, 20H), 5.60
3
3
(d, JHH = 7.8 Hz, 1H), 5.35 (d, JHH = 8.0 Hz, 1H), 3.71–3.67 (m,
3
2
1H), 1.90–1.75 (m, 3H), 1.14 (s, 9H), 0.88 (d, JHH = 6.6 Hz, 6H),
127.9, 127.6, 127.4, 127.0, 126.3, 121.0, 113.9, 89.9 (d, JCP = 12.1 Hz),
0.81 (s, 3H), 0.78 (s, 3H). 13C NMR (150 MHz, CDCl3): 144.6,
143.8, 139.7, 129.9, 128.9, 128.4, 128.3, 128.1, 127.7, 127.5,
83.4 (d, JCP = 7.9 Hz), 79.5, 78.0, 57.0, 55.2, 54.3 (d, JCP = 160.1 Hz),
2
27.4, 26.0, 25.3. 31P NMR (243 MHz, CDCl3): 16.10 (s). HRMS (ESI): calcd
for C43H47NO7PS 752.2811 (M+H)+. Found 752.2819.
2
127.4, 127.3, 127.2, 126.9, 114.0, 91.5 (d, JCP = 9.0 Hz), 87.1 (d,
2JCP = 8.7 Hz), 79.4, 78.9, 56.4, 51.3 (d, JCP = 158.8 Hz), 40.25, 26.6,
24.4, 23.0, 22.5, 21.50. 31P NMR (243 MHz, CDCl3): 17.35 (s). IR,
mmax (KBr): 3419, 3075, 2965, 1942, 1490, 1450, 1376, 1237,
1165, 1058, 940, 745, 720, 640. HRMS (ESI): calcd for
4.2.8. (S)-N-((R)-((3aR,8aR)-2,2-Dimethyl-6-oxido-4,4,8,8-tetra-
phenyltetrahydro-[1,3]dioxolo[4,5-e][1,3,2]dioxaphosphepin-
6-yl)(naphthalen-2-yl)methyl)-2-methylpropane-2-sulfinamide
3h
C
40H49NO6PS 702.3018 (M+H)+. Found 702.3023.
Prepared following the general procedure from TADDOL H-phos-
phonate (0.80 g, 1.56 mmol) in CH2Cl2 (15 mL), (S)-2-methyl-N-(naph-
thalen-2-ylmethylene)propane-2-sulfinamide 2h (0.40 g, 1.56 mmol)
in CH2Cl2 (5 mL) and anhydrous K2CO3 (0.21 g, 1.56 mmol). White solid,
0.91 g (77% yield, dr >95:5). Recrystallization from diethyl ether fur-
nished pure major diastereoisomer as white solid, mp 129–132 °C,
4.2.5. (S)-N-((R)-((3aR,8aR)-2,2-Dimethyl-6-oxido-4,4,8,8-tetra-
phenyltetrahydro-[1,3]dioxolo[4,5-e][1,3,2]dioxaphosphepin-6-
yl)(phenyl)methyl)-2-methylpropane-2-sulfinamide 3e
Prepared following the general procedure from TADDOL H-phospho-
nate (0.80 g, 1.56 mmol) in CH2Cl2 (15 mL), (S)-N-benzylidene-2-methyl-
propane-2-sulfinamide 2e (0.33 g, 1.56 mmol) in CH2Cl2 (5 mL) and
anhydrous K2CO3 (0.21 g, 1.56 mmol). White solid, 0.97 g (85% yield,
dr >95:5). Recrystallization from diethyl ether furnished pure major
[
a D
]
20 = À103.0 (c 1.0, CHCl3). 1H NMR (600 MHz, CDCl3): 7.71–6.90
3
(m, 27H), 5.49 (d, JHH = 7.8 Hz, 1H), 5.24 (d, JHP = 19.2 Hz, 1H), 4.83
(d, JHH = 7.8 Hz, 1H), 1.36 (s, 9H), 0.89 (s, 3H), 0.40 (s, 3H). 13C NMR
3
diastereoisomer as white solid, mp 88–90 °C, [a D
]
20 = À122.0 (c 1.0,
(150 MHz, CDCl3): 144.0, 143.6, 139.0, 133.2, 133.0, 130.9, 129.7,
128.5, 128.3, 128.1, 127.9, 127.6, 127.5, 127.3, 127.0, 126.4, 126.2,
CHCl3). 1H NMR (600 MHz, CDCl3): 7.51–7.19 (m, 23H), 6.63–6.60 (m,
3
2
2
2H), 5.31 (d, JHH = 7.8 Hz, 1H), 4.87 (d, JHP = 19.2 Hz, 1H), 4.76 (d,
113.8, 91.4 (d, JCP = 13.2 Hz), 86.8 (d, JCP = 8.25 Hz), 79.4, 79.2, 56.3,
56.1 (d, JCP = 153.9 Hz), 27.0, 26.1, 22.6. 31P NMR (243 MHz, CDCl3):
16.21 (s). IR, mmax (KBr): 3425, 3075, 2937, 1963, 1630, 1600, 1495,
1439, 1392, 1325, 1263, 1221, 1176, 1152, 1090, 1061, 997, 945, 740,
703, 665, 587. HRMS (ESI): calcd for C46H47NO6PS 772.2862 (M+H)+.
Found 772.2868.
3JHH = 7.8 Hz, 1H), 1.16 (s, 9H), 0.74 (s, 3H), 0.29 (s, 3H). 13C NMR
(150 MHz, CDCl3): 139.0, 133.2, 133.1, 129.7, 128.2, 128.1, 127.6,
2
127.2, 127.4, 127.1, 126.4, 113.8, 90.2 (d, JCP = 13.05 Hz), 86.8 (d,
2JCP = 7.95 Hz), 79.4, 79.2, 56.1, 56.0 (d, JCP = 160.95 Hz), 27.0, 26.1,
24.2. 31P NMR (243 MHz, CDCl3): 16.22 (s). IR, mmax (KBr): 3429, 3063,
2930, 1959, 1628, 1604, 1495, 1449, 1382, 1317, 1251, 1216, 1166,
1132, 1087, 1054, 991, 939, 745, 699, 657, 576. HRMS (ESI): calcd for
4.2.9. (S)-N-((R)-((3aR,8aR)-2,2-Dimethyl-6-oxido-4,4,8,8-tetra-
phenyltetrahydro-[1,3]dioxolo[4,5-e][1,3,2]dioxaphosphepin-6-
yl)(p-tolyl)methyl)-2-methylpropane-2-sulfinamide 3i
C
42H44NO6PSNa 744.2524 (M+Na)+. Found 744.2520.
4.2.6. (S)-N-((R)-((3aR,8aR)-2,2-Dimethyl-6-oxido-4,4,8,8-tetra-
phenyltetrahydro-[1,3]dioxolo[4,5-e][1,3,2]dioxaphosphepin-6-
yl)(4-fluorophenyl)methyl)-2-methylpropane-2-sulfinamide 3f
Prepared following the general procedure from TADDOL H-phospho-
nate (0.80 g, 1.56 mmol) in CH2Cl2 (15 mL), (S)-N-(4-fluorobenzyli-
dene)-2-methylpropane-2-sulfinamide 2f (0.35 g, 1.56 mmol) in
CH2Cl2 (5 mL) and anhydrous K2CO3 (0.21 g, 1.56 mmol). White
solid, 1.0 g (87% yield, dr 95:5). Recrystallization from diethyl ether
furnished pure major diastereoisomer as white solid, mp 96–97 °C,
Prepared following the general procedure from TADDOL H-
phosphonate (0.80 g, 1.56 mmol) in CH2Cl2 (15 mL), (S)-2-
methyl-N-(4-methylbenzylidene)propane-2-sulfinamide
2i
(0.35 g, 1.56 mmol) in CH2Cl2 (5 mL) and anhydrous K2CO3
(0.21 g, 1.56 mmol). White solid, 0.93 g (81% yield, dr >95:5).
Recrystallization from diethyl ether furnished pure major
diastereoisomer as white solid, mp 112–114 °C, [
a
]
20 = À117.0 (c
D
1.0, CHCl3). 1H NMR (600 MHz, CDCl3): 7.66–7.31 (m, 22H), 7.0–
3
6.95 (m, 2H), 5.71 (d, JHH = 7.8 Hz, 1H), 5.17 (m, 1H), 4.97 (d,
Please cite this article in press as: Olszewski, T. K. ; Majewski, M. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/
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6
T. K. Olszewski, M. Majewski / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
3JHH = 7.8 Hz, 1H), 2.20 (s, 3H), 1.46 (s, 9H), 0.85 (s, 3H), 0.51 (s, 3H).
13C NMR (150 MHz, CDCl3): 144.5, 140.0, 139.3, 130.9, 130.7, 129.8,
129.4, 128.9, 128.7, 128.3, 128.1, 127.8, 127.5, 127.2, 126.9, 126.5,
114.0, 88.2 (d, 2JCP = 11.9 Hz), 81.9 (d, 2JCP = 8.0 Hz), 79.3, 77.9, 56.9,
53.1 (d, JCP = 158.9 Hz), 31.0, 28.1, 24.0, 19.3. 31P NMR (243 MHz,
CDCl3): 16.93 (s). IR, mmax (KBr): 3348, 3134, 1947, 1625, 1501,
1400, 1299, 1234, 1110, 956, 767, 707. HRMS (ESI): calcd for
26.9, 26.0, 23.4. 31P NMR (243 MHz, CDCl3): 15.37 (s). IR, mmax
(KBr): 3435, 2942, 2897, 1960, 1619, 1514, 1445, 1370, 1250,
1151, 1080, 1045, 1024, 919, 745, 702, 675. HRMS (ESI): calcd for
C
45H46N2O6PS 773.2814 (M+H)+. Found 773.2817.
4.2.13. (S)-N-((R)-((3aR,8aR)-2,2-Dimethyl-6-oxido-4,4,8,8-tetra-
phenyltetrahydro-[1,3]dioxolo[4,5-e][1,3,2]dioxaphosphepin-6-
yl)(thiophen-2-yl)methyl)-2-methylpropane-2-sulfinamide 3m
Prepared following the general procedure from TADDOL H-phos-
phonate (0.80 g, 1.56 mmol) in CH2Cl2 (15 mL), (S)-2-methyl-N-
C
43H47NO6PS 736.2862 (M+H)+. Found 736.2870.
4.2.10. (S)-N-((R)-((3aR,8aR)-2,2-Dimethyl-6-oxido-4,4,8,8-tetra-
phenyltetrahydro-[1,3]dioxolo[4,5-e][1,3,2]dioxaphosphepin-6-
yl)(4-nitrophenyl)methyl)-2-methylpropane-2-sulfinamide 3j
Prepared following the general procedure from TADDOL H-phos-
phonate (0.80 g, 1.56 mmol) in CH2Cl2 (15 mL), (S)-2-methyl-N-(4-
nitrobenzylidene)propane-2-sulfinamide 2j (0.39 g, 1.56 mmol) in
CH2Cl2 (5 mL) and anhydrous K2CO3 (0.21 g, 1.56 mmol). White
solid, 0.94 g (80% yield, dr >95:5). Recrystallization from diethyl
ether furnished pure major diastereoisomer as white solid, mp
(thiophen-2-ylmethylene)propane-2-sulfinamide
2m
(0.33 g,
1.56 mmol) in CH2Cl2 (5 mL) and anhydrous K2CO3 (0.21 g,
1.56 mmol). White solid, 0.88 g (80% yield, dr 95:5).
Recrystallization from diethyl ether furnished pure major
diastereoisomer as white solid, mp 97–99 °C, [a D
]
20 = À157.0 (c 1.0,
CHCl3). 1H NMR (600 MHz, CDCl3): 7.58–7.15 (m, 20H), 6.90–6.86
3
(m, 1H), 6.82 (d, JHH = 7.2 Hz, 1H), 6.60–6.57 (m, 1H), 5.42 (d,
3JHH = 7.8 Hz, 1H), 5.24 (d, JHP = 19.5 Hz, 1H) 4.98 (d, JHH = 7.9 Hz,
3
123–125 °C,
[
a D
]
20 = À124.0 (c 1.0, CHCl3). 1H NMR (600 MHz,
1H), 1.23 (s, 9H), 0.81 (s, 3H), 0.44 (s, 3H). 13C NMR (150 MHz,
CDCl3): 144.1 (d, 2JCP = 7.2 Hz), 143.5, 139.0, 137.1 (d,
3JCP = 11.25 Hz), 129.7, 128.6, 128.4, 128.2, 128.1, 127.9, 127.6,
127.5, 127.3, 127.1, 126.8, 126.4, 125.8, 114.0, 91.6 (d,
3
CDCl3): 7.58–7.09 (m, 24H), 5.67 (d, JHH = 7.8 Hz, 1H), 5.23 (m,
3
1H), 4.96 (d, JHH = 7.8 Hz, 1H), 1.46 (s, 9H), 0.81 (s, 3H), 0.53 (s,
3H). 13C NMR (150 MHz, CDCl3): 143.9, 141.0, 139.2, 131.7, 130.9,
129.9, 129.1, 128.9, 128.1, 128.0, 127.9, 127.6, 127.3, 127.1, 126.9,
2JCP = 12.30 Hz), 87.0 (d, JCP = 8.25 Hz), 79.4, 79.1, 56.4, 52.6 (d,
2
2
2
126.3, 113.9, 89.7 (d, JCP = 11.9 Hz), 82.1 (d, JCP = 8.0 Hz), 79.1,
77.9, 57.2, 54.0 (d, JCP = 160.3 Hz), 28.0, 23.7, 18.9. 31P NMR
(243 MHz, CDCl3): 17.23 (s). HRMS (ESI): calcd for C42H44N2O8PS
767.2556 (M+H)+. Found 767.2561.
JCP = 166.5 Hz), 27.0, 26.2, 24.2. 31P NMR (243 MHz, CDCl3): 14.68
(s). IR, mmax (KBr): 3427, 2932, 2873, 1957, 1601, 1496, 1447, 1372,
1249, 1166, 1086, 1038, 1019, 919, 901, 744, 698, 640.
HRMS (ESI): calcd for C40H43NO6PS2 728.2269 (M+H)+. Found
728.2271.
4.2.11. (S)-N-((R)-((3aR,8aR)-2,2-Dimethyl-6-oxido-4,4,8,8-tetra-
phenyltetrahydro-[1,3]dioxolo[4,5-e][1,3,2]dioxaphosphepin-6-
yl)(pyridin-3-yl)methyl)-2-methylpropane-2-sulfinamide 3k
Prepared following the general procedure from TADDOL H-phos-
phonate (0.80 g, 1.56 mmol) in CH2Cl2 (15 mL), (S)-2-methyl-N-(pyr-
idin-3-ylmethylene)propane-2-sulfinamide 2k (0.32 g, 1.56 mmol)
in CH2Cl2 (5 mL) and anhydrous K2CO3 (0.21 g, 1.56 mmol). White
solid, 0.98 g (89% yield, dr >95:5). Recrystallization from diethyl
ether furnished pure major diastereoisomer as white solid, mp 90–
4.2.14. (S)-N-((R)-((3aR,8aR)-2,2-Dimethyl-6-oxido-4,4,8,8-tetra-
phenyltetrahydro-[1,3]dioxolo[4,5-e][1,3,2]dioxaphosphepin-6-
yl)(furan-2-yl)methyl)propane-2-sulfinamide 3n
Prepared following the general procedure from TADDOL H-
phosphonate (0.80 g, 1.56 mmol) in CH2Cl2 (15 mL), (S)-N-(furan-
2-ylmethylene)-2-methylpropane-2-sulfinamide
2n
(0.31 g,
1.56 mmol) in CH2Cl2 (5 mL) and anhydrous K2CO3 (0.21 g,
1.56 mmol). White solid, 0.86 g (78% yield, dr 95:5).
Recrystallization from diethyl ether furnished pure major
93 °C, [a D
]
20 = À119.0 (c 1.0, CHCl3). 1H NMR (600 MHz, CDCl3): 8.65
3
3
(s, 1H), 8.30 (d, JHH = 5.0 Hz, 1H), 7.70 (d, JHH = 7.9 Hz, 1H), 7.50–
diastereoisomer as white solid, mp 105–107 °C, [
a
]
20 = À167.0 (c
D
3
7.31 (m, 21H), 5.50 (d, JHH = 7.8 Hz, 1H), 5.03–4.96 (m, 1.30 (s,
1.0, CHCl3). 1H NMR (600 MHz, CDCl3): 7.60–7.10 (m, 22H), 6.90–
9H), 0.81 (s, 3H), 0.47 (s, 3H). 13C NMR (150 MHz, CDCl3): 149.1,
143.2, 138.7, 135.9, 134.7, 130.2, 130.0, 128.7, 128.8, 128.5, 128.4,
128.1, 127.9, 127.5, 127.3, 127.0, 126.9, 126.5, 125.9, 115.1, 91.9
6.86 (m, 1H), 5.45 (d, JHH = 7.8 Hz, 1H), 5.07 (d, JHH = 7.8 Hz,
1H), 4.67 (d, JHP = 16.5 Hz, 1H), 1.25 (s, 9H), 0.83 (s, 3H), 0.45 (s,
3H). 13C NMR (150 MHz, CDCl3): 149.7, 143.3, 139.5, 138.2,
130.1, 129.5, 129.3, 128.1, 128.0, 127.7, 127.5, 127.4, 127.2,
127.1, 127.0, 126.8, 125.9, 114.0, 110.0, 108.7, 90.1 (d,
3
3
2
2
(d, JCP = 10.0 Hz), 88.2 (d, JCP = 9.0 Hz), 78.7, 77.9, 57.1, 53.2 (d,
JCP = 160.8 Hz), 27.1, 26.1, 24.2. 31P NMR (243 MHz, CDCl3): 15.33
(s). HRMS (ESI): calcd for C41H44N2O6PS 723.2658 (M+H)+. Found
723.2661.
2
2JCP = 10.2 Hz), 86.3 (d, JCP = 8.2 Hz), 79.7, 80.1, 57.2, 52.9
(d, JCP = 167.2 Hz), 27.3, 26.0, 25.1. 31P NMR (243 MHz, CDCl3):
15.82 (s). IR, mmax (KBr): 3349, 2930, 2879, 1965, 1587,
1494, 1452, 1370, 1259, 1172, 1097, 1040, 1021, 917, 740, 701.
HRMS (ESI): calcd for C40H43NO7PS 712.2498 (M+H)+. Found
712.2503.
4.2.12. (S)-N-((R)-((3aR,8aR)-2,2-Dimethyl-6-oxido-4,4,8,8-tetra-
phenyltetrahydro-[1,3]dioxolo[4,5-e][1,3,2]dioxaphosphepin-6-
yl)(quinolin-3-yl)methyl)-2-methylpropane-2-sulfinamide 3l
Prepared following the general procedure from TADDOL H-
phosphonate (0.80 g, 1.56 mmol) in CH2Cl2 (15 mL), (S)-2-
4.3. Cleavage of the chiral auxiliary and the synthesis of (R)-a-
methyl-N-(quinolin-3-ylmethylene)propane-2-sulfinamide
2l
aminophosphonic acids: general procedure
(0.40 g, 1.56 mmol) in CH2Cl2 (5 mL) and anhydrous K2CO3
(0.21 g, 1.56 mmol). White solid, 0.88 g (75% yield, dr >95:5).
Recrystallization from diethyl ether furnished pure major
The appropriate
a-aminophosphonate, major diastereoisomer,
was dissolved in toluene and aq 4 M HCl was added. The result-
ing reaction mixture was stirred at 100 °C for 6 h, after which the
mixture was cooled down to room temperature and the layers
were separated. The organic layer was discarded and the aqueous
layer was evaporated to dryness. The resulting crude product was
dissolved in EtOH (5 mL), propylene oxide was added and the
resulting solution was placed in the refrigerator for crystalliza-
tion. The precipitate formed was filtered off and washed with
diastereoisomer as white solid, mp 67–69 °C, [
a
]
20 = À142.0 (c
D
1.0, CHCl3). 1H NMR (600 MHz, CDCl3): 7.81–7.11 (m, 24H), 6.80
3
3
(t, JHH = 8.1 Hz 1H), 6.55 (d, JHH = 7.8 Hz, 1H), 5.43 (d,
3JHH = 8.4 Hz, 1H), 5.17 (d, JHP =19.8 Hz, 1H), 4.80 (d, JHH = 7.8 Hz,
3
1H), 1.29 (s, 9H), 0.79 (s, 3H), 0.37 (s, 3H). 13C NMR (150 MHz,
CDCl3): 144.7, 143.5, 139.5, 134.1, 133.7, 130.4, 130.0, 129.7,
129.0, 128.8, 128.6, 128.4, 128.0, 127.9, 127.6, 127.4, 127.2,
2
127.0, 126.7, 126.4, 125.9, 125.3, 114.0, 92.0 (d, JCP = 11.0 Hz),
diethyl ether affording the corresponding a-aminophosphonic
acids 4a–d.
2
87.3 (d, JCP = 9.2 Hz), 79.2, 78.9, 56.4, 54.5 (d, JCP = 161.2 Hz),
Please cite this article in press as: Olszewski, T. K. ; Majewski, M. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/
j.tetasy.2015.06.008

T. K. Olszewski, M. Majewski / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
7
Yao, G.-Y.; Pan, Y.-M.; Liao, Z.-X.; Zhang, Y.; Wang, H.-S. Eur. J. Med. Chem.
2014, 83, 116; (d) Kraicheva, I.; Vodenicharova, E.; Shenkov, S.; Tashev, E.;
Tosheva, T.; Tsacheva, I.; Kril, A.; Topashka-Ancheva, M.; Georgieva, A.; Iliev, I.;
Vladov, I.; Gerasimova, Ts.; Troev, K. Bioorg. Med. Chem. 2014, 22, 874.
3. For recent examples see: (a) Ali, N.; Ali, S.; Zakir, S.; Patel, M.; Farooqui, M. Eur.
J. Med. Chem. 2012, 50, 39; (b) Juribasic, M.; Molcanov, K.; Kojic-Prodic, B.;
Bellotto, L.; Kralj, M.; Zani, F.; Tusek-Bozic, L. J. Inorg. Biochem. 2011, 105, 867;
(c) Dake, S. A.; Raut, D. S.; Kharat, K. R.; Mhaske, R. S.; Deshmukh, S. U.; Pawar,
R. P. Bioorg. Med. Chem. Lett. 2011, 21, 2527.
4.3.1. (R)-(
a
-1-Amino-2-methylpropyl)phosphonic acid 4a
Prepared following the general procedure from
phonate 3c (0.6 g, 0.87 mmol) in toluene (20 mL), and aq 4 M HCl
a
-aminophos-
(20 mL). White solid, 0.12 g (92% yield), mp 260–263 °C,
[a] [a]
20 = +1.0 (c 1.0, 2 M NaOH), {lit.27 20 = +1.0 (c 1.0 2 M
D D
NaOH)}.1H NMR (600 MHz, D2O): 3.46 (dd, JHP = 13.7 Hz,
JHH = 6.0 Hz, 1H), 2.17–2.14 (m, 1H), 0.9 (d, JHH = 6.0 Hz, 6H), 31P
3
4. (a) Qin, Y.; Xing, R.; Liu, S.; Yu, H.; Li, K.; Hu, Li; Li, P. Int. J. Biol. Macromol. 2014,
63, 83; (b) Maier, L.; Diel, P. J. Phosphorus, Sulfur Silicon Relat. Elem. 1991, 57, 57;
(c) Maier, L.; Diel, P. J. Phosphorus, Sulfur Silicon Relat. Elem. 1994, 90, 259.
5. (a) Wu, L.; Song, B.; Bhadury, P. S.; Yang, S.; Hu, D.; Jin, L. J. Heterocycl. Chem.
2011, 48, 389; (b) Chen, M.-H.; Chen, Z.; Song, B.-A.; Bhadury, P. S.; Yang, S.;
Cai, X.-J.; Hu, D.-Y.; Xue, W.; Zeng, S. J. Agric. Food Chem. 2009, 57, 1383; (c) Hu,
D.-Y.; Wan, Q.-Q.; Yang, S.; Song, B.-A.; Bhadury, P. S.; Jin, L.-H.; Yan, K.; Liu, F.;
Chen, Z.; Xue, W. J. Agric. Food Chem. 2008, 56, 998.
NMR (243 MHz, D2O): 9.96 (s). HRMS (ESI): calcd for C4H13NO3P
154.0633 (M+H)+. Found 154.0637.
4.3.2. (R)-(a-Amino(phenyl)methyl)phosphonic acid 4b
Prepared following the general procedure from
a
-aminophos-
phonate 3e (1.0 g, 1.38 mmol) in toluene (20 mL), and aq 4 M HCl
6. For recent articles see: (a) Wang, Q.; Zhu, M.; Zhu, R.; Lu, Liping; Yuan, C.; Xing,
S.; Fu, X.; Mei, Y.; Hang, Q. Eur. J. Med. Chem. 2012, 49, 354; (b) Wang, Q. M.; Lu,
L. P.; Zhu, M. L.; Yuan, C. X.; Shu, X.; Fu, X. Q. Dalton Trans. 2011, 40, 12926; (c)
Wang, Q. M.; Lu, L. P.; Yuan, C. X.; Pei, K.; Liu, Z. W.; Guo, M. L.; Zhu, M. L. Chem.
Commun. 2010, 3547.
7. (a) Bhattacharya, A. K.; Rana, K. C.; Pannecouque, C.; De Clercq, E.
ChemMedChem 2012, 7, 1601; (b) Senten, K.; Daniels, L.; Var der Veken, P.;
De Meester, I.; Lambeir, A.-M.; Scharpe, S.; Haemers, A.; Augustyns, K. J. Comb.
Chem. 2003, 5, 336.
8. Stamper, C.; Bennet, B.; Edwards, T.; Holz, R. C.; Ringe, D.; Petsko, G.
Biochemistry 2001, 40, 7035.
9. Solodenko, V. A.; Kukhar, V. P. Tetrahedron Lett. 1989, 32, 66.
10. Evans, R. H.; Francis, A. A.; Jones, A. W.; Smith, D. A. S.; Wathius, J. W. Br. J.
Pharmacol. 1982, 75, 65.
(20 mL). White solid, 0.23 g (78% yield), mp 285–287 °C,
[a] [a]
20 = +19.0 (c 1.0, 1 M NaOH), {lit.28 20 = +19.9 (c 1.16 1 M
D D
NaOH)}. 1H NMR (600 MHz, D2O): 7.36–7.29 (m, 5H), 4.20 (d,
JHP = 17.0 Hz, 1H). 31P NMR (243 MHz, D2O): 10.87 (s). HRMS
(ESI): calcd for C7H11NO3P 188.0477 (M+H)+. Found 188.0489.
4.3.3. (R)-(a-Amino(4-fluorophenyl)methyl)phosphonic acid 4c
Prepared following the general procedure from
a
-aminophos-
phonate 3f (0.7 g, 0.95 mmol) in toluene (20 mL), and aq 4 M HCl
(20 mL). White solid, 0.17 g (91% yield), mp 283–285 °C,
[
a
]
20 = +19.0 (c 1.0, 1 M NaOH), {lit.28
[
a
]
20 = À19.3 (c 0.54 1 M
D
D
11. For recent review article on asymmetric synthesis of a-aminophosphonic acids
NaOH for the (S)-enantiomer)}. 1H NMR (600 MHz, D2O): 7.57–
7.50 (m, 1H), 7.30–7.24 (m, 3H), 4.80 (d, JHP = 17.1 Hz, 1H). 31P
NMR (243 MHz, D2O): 11.72 (s). HRMS (ESI): calcd for
C7H10FNO3P 206.0382 (M+H)+. Found 206.0387.
see: (a) Ordoñez, M.; Viveros-Ceballos, J. L.; Cativiela, C.; Sayago, F. J.
Tetrahedron 2015, 71, 1745; (b) Rulev, A. Yu. RSC Adv. 2014, 4, 26002; (c)
Kolodiazhnyi, O. I.; Kukhar, V. P.; Kolodiazhna, A. O. Tetrahedron: Asymmetry
2014, 25, 865; (d) Ordoñez, M.; Sayago, F. J.; Cativiela, C. Tetrahedron 2012, 68,
6369; (e) Odinets, I. L.; Matveeva, E. V. Curr. Org. Chem. 2010, 14, 1171.
12. (a) Pudovik, A. N. Dokl. Akad. Nauk SSSR 1952, 83, 865; (b) Romanenko, V. D.;
Kukhar, V. P. Chem. Rev. 2006, 106, 3868.
13. For recent articles on the synthesis and applications of tert-butanesulfinamide
see: (a) Collados, J. F.; Toledano, E.; Guijarro, D.; Yus, M. J. Org. Chem. 2012, 77,
5744; (b) Robak, M. T.; Herbage, M. A.; Ellman, J. A. Chem. Rev. 2010, 110, 3600;
(b) Ferreira, F.; Botuha, C.; Chemla, F.; Perez-Luna, A. Chem. Soc. Rev. 2009, 38,
1162.
14. (a) Chen, Q.; Yuan, C. Synthesis 2007, 24, 3779; (b) Chen, Q.; Li, J.; Yuan, C.
Synthesis 2008, 18, 2986.
15. Khan, H.; Ellman, J. A. Synthesis 2013, 45, 3147.
16. For general recent reviews on TADDOL’s and their use in asymmetric synthesis,
see: (a) Gratzer, K.; Gururaja, G. N.; Waser, M. Eur. J. Org. Chem. 2013, 4471; (b)
Pellissier, H. Tetrahedron 2008, 64, 10279.
4.3.4. (R)-(
Prepared following the general procedure from
phonate 3m (0.85 g, 1.17 mmol) in toluene (20 mL), and aq 4 M
a
-Amino(thiophen-2-yl)methyl)phosphonic acid 4d
a
-aminophos-
20
HCl (20 mL). White solid, 0.18 g (85% yield), mp 255–258 °C, [a]
D
+5.0 (c 1.0, 1 M NaOH), [lit.28
[
a]
+4.8 (c 0.35 1 M NaOH]. 1H
20
D
NMR (600 MHz, D2O): 7.25–7.19 (m, 2H), 7.05 (m, 1H), 4.47 (d,
JHP = 17.8 Hz, 1H). 31P NMR (243 MHz, D2O): 10.20 (s). HRMS
(ESI): calcd for C5H9NO3PS 194.0041 (M+H)+. Found 194.0046.
17. (a) Beck, A. K.; Bastani, B.; Plattner, D. A.; Petter, W.; Seebach, D.;
Braunschweig, H.; Gysi, P.; La Vacchia, L. Chimia 1991, 45, 238; For selected
other applications of TADDOL H-phosphonate as chiral auxiliary see: (b)
Enders, D.; Tedeschi, L.; Bats, J. W. Angew. Chem., Int. Ed. 2000, 39, 4605; (c)
Enders, D.; Tedeschi, L.; Foerster, D. Synthesis 2006, 9, 1447; (d) Tedeschi, L.;
Enders, D. Org. Lett. 2001, 3, 3515; For recent applications of TADDOL H-
Acknowledgements
T.K.O. acknowledges the Ministry of Science and Higher
Education of Republic of Poland for financial support of this inves-
tigation within the ‘Iuventus Plus’ programme Grant. No. IP2012
036372. Funding from a statutory activity subsidy from the
Polish Ministry of Science and Higher Education for the Faculty
of Chemistry, Wrocław University of Technology, is also
acknowledged.
phosphonate in the diastereoselective synthesis of
a-hydroxyphosphonates
and phosphonic acids see: (e) Olszewski, T. K. Tetrahedron: Asymmetry 2015, 26,
393. Due to the differences in reactivity and the structure of the applied N-tert-
butylsulfinyl imines applied here compared the achiral aldehydes used in our
previous work, the latter required the hydrophosphonylation to be carried out
using different conditions (À78 °C, presence of LDA or Et2Zn) to achieve good
diastereoselectivity.
18. The TADDOL derived chiral auxiliary is destroyed during the deprotection step
and thus it was not possible to recover it.
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Please cite this article in press as: Olszewski, T. K. ; Majewski, M. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/
j.tetasy.2015.06.008