Functionalization of α-hydroxyphosphonates as a convenient route to: N -tosyl-α-aminophosphonates

Article abstract of DOI:10.1039/c8ra01656a

Direct conversion of the α-hydroxyl group by para-toluenesulfonamide to yield α-(N-tosyl)aminophosphonates is reported. α-Aminophosphonates 23a,b-37a,b were obtained from the corresponding α-hydroxyphosphonates 6a,b-21a,b in the presence of K₂CO₃, via the retro-Abramov reaction of the appropriate aldehydes, 1-5. The subsequent formation of imines with simultaneous addition of diethyl phosphite provided access to the α-sulfonamide phosphonates 23a,b-37a,b with better diastereoselectivity than in the case of the Pudovik reaction. The mechanism for this transformation is proposed herein. When Cbz N-protected aziridine 9a,b and phenylalanine analogue 12a,b were exploited, intramolecular substitution was observed, leading to the corresponding epoxide 38 as the sole product, or oxazolidin-2-one 39 as a minor product. Analogous substitution was not observed in the case of proline 18a,b and serine 21a,b derivatives.

Full text of DOI:10.1039/c8ra01656a

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Functionalization of a-hydroxyphosphonates as
a convenient route to N-tosyl-a-
aminophosphonates†
Cite this: RSC Adv., 2018, 8, 11957
ab
a
Patrycja Kaczmarek,a
*
Tomasz Cytlak,
Marcin Kazmierczak,
Monika Skibinska,
´
Magdalena Rapp,a Maciej Kubickia and Henryk Koroniaka
ab
´
Direct conversion of the a-hydroxyl group by para-toluenesulfonamide to yield a-(N-tosyl)
aminophosphonates is reported. a-Aminophosphonates 23a,b–37a,b were obtained from the
corresponding a-hydroxyphosphonates 6a,b–21a,b in the presence of K2CO3, via the retro-Abramov
reaction of the appropriate aldehydes, 1–5. The subsequent formation of imines with simultaneous
addition of diethyl phosphite provided access to the a-sulfonamide phosphonates 23a,b–37a,b with
better diastereoselectivity than in the case of the Pudovik reaction. The mechanism for this
transformation is proposed herein. When Cbz N-protected aziridine 9a,b and phenylalanine analogue
12a,b were exploited, intramolecular substitution was observed, leading to the corresponding epoxide 38
as the sole product, or oxazolidin-2-one 39 as a minor product. Analogous substitution was not
observed in the case of proline 18a,b and serine 21a,b derivatives.
Received 24th February 2018
Accepted 14th March 2018
DOI: 10.1039/c8ra01656a
rsc.li/rsc-advances
phosphite nucleophiles to imines or enamines.6 The major
disadvantage of this approach is the stability of the imine/
Introduction
enamine prepared from the aliphatic amine. Transformation
of the a-hydroxyphosphonates seems to provide an encouraging
a-Sulfonamide phosphonates constitute a very interesting class
of compounds. They can be potential candidates for uores-
cent-b-lactamase1 and matrix metalloproteinase (MMPs) inhib-
itors2 such as compounds containing carboxylate and
hydroxamate moieties, which are well known MMP inhibitors.
Moreover, these compounds are promising substrates for the
synthesis of N-deprotected a-aminophosphonates, which are
important isosteres of a-amino acids, possessing a wide range
of biological activities. They act as antibiotics, herbicides,
antifungal agents, enzyme inhibitors, and pharmacological
agents.3
There are several routes for the synthesis of a-amino-
phosphonates. One of the most important protocols is the
Kabachnik–Fields (or phospha-Mannich) reaction involving the
condensation of dialkyl phosphite, carbonyl compounds and
primary or secondary amines;4 however, the reaction mecha-
nism is still under investigation.5 There are several other
possibilities for the preparation of a-aminophosphonates,
among which a very convenient route is the addition of
method
for
achieving
a-aminophosphonates.
These
compounds are easily obtained using the Abramov reaction7
and its modications,8 giving access to the synthesis of different
types of a-functionalized phosphonates.9
a-Hydroxyphosphonates exhibit interesting medicinal prop-
erties as potential antibacterial, antiviral and anticancer
agents,10 as well as enzyme inhibitors such as protease, EPSP
synthase, human rennin, human calpain I and tyrosine-specic
protein kinase.11 Among the methods of synthesis of a-amino-
phosphonates utilizing a-hydroxyphosphonates, Mitsunobu
azidation followed by the Staudinger reduction is commonly
applied with good yields and is well-known in the literature.12
Unfortunately, using the volatile and highly toxic hydrazoic acid
is the main disadvantage of this method. Another type of
conversion of a-hydroxyphosphonates into a-amino-
phosphonates is nucleophilic substitution at C1, but this
method is rather difficult due to the hindered hydroxy func-
tion,13 although substitution of the hydroxyl group in primary a-
hydroxyphosphonates by a good leaving group, e.g. triate,14
mesylate,15 tosylates,16 or via acid-mediated displacement,17 has
been described in the literature. To our knowledge, only one
paper reported the substitution of the hydroxyl group by an
amine at the secondary centre, under microwave-assisted and
solvent-free conditions.18
a
´
Faculty of Chemistry, Adam Mickiewicz University in Poznan, Umultowska 89b,
´
61-614 Poznan, Poland
bCentre for Advanced Technologies, Adam Mickiewicz University in Poznan,
´
´
Umultowska 89c, 61-614 Poznan, Poland. E-mail: cytlak@amu.edu.pl
† Electronic supplementary information (ESI) available: Experimental details,
compounds characterization, 1H, 13C, 31P and 2D NMR spectra of compounds
and crystallographic data. CCDC 1568454–1568458 and 1569663. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c8ra01656a
In the literature there exist methods of conversion of primary
a-hydroxyphosphonates to a-amino analogues, such as
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intramolecular cyclodehydration via the alkoxyphosphonium originating from amino acids, possessing various amino pro-
salt19 or phosphonation via the retro-Abramov reaction,13d tecting groups, e.g. benzyl (Bn) 1a–5a, tert-butoxycarbonyl (Boc)
which is an effort to explain the Kabachnik–Fields reaction 2b–5b, carboxybenzyl (Cbz) 2c–5c were chosen. All aldehydes
mechanism (Scheme 1).
were prepared from the corresponding alcohols according to
In this mechanism, one possibility is that an imine is formed the literature data (see Experimental section). The introduction
from the carbonyl compound and primary amine (or iminium of a new C–P bond, yielding a-hydroxyphosphonates, was con-
salt when a secondary amine is applied). Then, the addition ducted by the three main methodologies. First, aldehydes 1a, 2,
reaction of dialkyl phosphite to the imine leads to a-amino- 3 were used in the reactions with lithium diethyl phosphite in
phosphonate.4b The second possibility is based on the amine dry THF at ꢀ30 C. This strategy afforded phosphonates 6a,b,
ꢁ
promoted (especially by the highly basic amines) addition of 10a,b–12a,b and 13a,b–15a,b. The yields varied from moderate
dialkyl phosphite to the carbonyl group, leading to a-hydrox- in the case of (S)-phenylalanine 10a,b–12a,b and (S)-valine
yphosphonate, in a reversible step, and then nucleophilic analogues 13a,b–15a,b, to very good for aziridines 6a,b, while
substitution of the hydroxyl group by an amine moiety.20 The the diastereoselectivity of this reaction varied from poor in the
rst approach is based on the reversibility of the addition of case of 6a,b, to very good for 10a,b. Moreover, phosphonates
dialkyl phosphite to the carbonyl group (retro-Abramov reac- 6a,b were transformed to N-unprotected a-hydrox-
tion) with subsequent irreversible imine formation followed by yphosphonates 7a,b with the subsequent introduction of the
immediate dialkyl phosphite addition.21 The second approach protecting groups, Boc 8a,b and Cbz 9a,b. In the case of trans-
argues that a-aminophosphonates are obtained at high formations of 7a,b yielding 9a,b, due to steric hindrance
temperatures. During heating, the disappearance of the a- between the Cbz group and the phosphonate moiety in 9a, we
hydroxyphosphonate in favour of the a-aminophosphonate observed a small predominance of diastereoisomer 9b (1 : 1.2,
formation is postulated.22 On the basis of kinetic studies, it is d.r. 19F, 31P NMR). Thus, the stereochemistry of aziridine 9a was
suggested that the mechanism depends on the nature of the analogous to the major diastereoisomer of 6a and parallel to
reacting substrates.5a The reaction of benzaldehyde, aniline and a study reported previously (for comparison see Fig. 1 and N-
dialkyl phosphite supports the imine pathway. The formation of benzyl protected aziridines 6a,b).26 In the case of Boc protected
the hydrogen bond between the phosphoryl group of the dialkyl aziridine, the reaction gave only one diastereoisomer 8b as the
phosphite and amine promotes the formation of imine without sole product, where 7a was le unreacted in the reaction
additional catalyst.23 On the other hand, aniline is too weak mixture. Moreover, 8b existed as a mixture of two rotamers
a base to promote the addition of dialkyl phosphite to the (1.9 : 1 NMR ratio) that could be separated by chromatography
carbonyl group. Cherkasov et al. performed the reaction of the techniques. In the second route, the TEA-catalyzed addition of
more nucleophilic cyclohexylamine with benzaldehyde and HP(O)(OEt)2 to appropriate aldehydes at room temperature with
ꢁ
dialkyl phosphite and they suggested the hydroxyphosphonate 0.1 eq. TEA or 0.2 eq. TEA at r.t. or 50 C led to products 6a,b,
path where the amine was basic enough to interact with the 17a,b–21a,b, in yields ranging from moderate for 19a,b to
hydrogen of the phosphite to promote the attack of phosphite excellent in the case of 20a,b; there was also good diaster-
on the carbonyl carbon.5a,24 Subsequent papers provided more eoselectivity for 18a,b and excellent diastereoselectivity in the
evidence supporting the imine pathway, even when hard case of aziridines 6a,b and serine analogues 20a,b. Only in case
nucleophilic amines were applied to the reaction.24,25
of the synthesis of 16a,b was the application of i-Pr2EtN needed
(Table 1).
The stereochemistry of the addition of dialkyl phosphite to
N-protected (S)-amino aldehydes [or (R)- in the case of 4c] was
a consequence of the steric hindrance on the adjacent stereo-
genic centre. Moreover, the Pudovik reaction conducted on N-
protected aldehydes 2, 3 derived from phenylalanine and valine
led to anti addition, giving rise to major diastereoisomers
(1R,2S) according to the data reported for nucleophilic addi-
tions to (N,N-dibenzylamino)aldehydes.27 These assumptions
Results and discussion
In the course of our studies, we were able to synthesize a wide
range of a-hydroxyphosphonates that were subsequently used
in reactions with para-toluenesulfonamide towards obtaining a-
aminophosphonate derivatives.
As the convenient starting materials, the N-protected amino
aldehydes such as aziridine 1, as well as aldehydes 2–5
Scheme 1 Kabachnik–Fields reaction.
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Table 1 Preparation of a-hydroxyphosphonatesa
Aldehyde Product
PG Cond. Yieldb [%] d.r.c
1a
1a
1a
1a
1a
2a
2b
2c
3a
3b
3c
6a,b
6a,b
7a,b
8a,b
9a,b
10a,b Bn2
11a,b Boc
12a,b Cbz
13a,b Bn2
14a,b Boc
15a,b Cbz
Bn
Bn ii
H
Boc iv
Cbz
i
84
77
97
43
74
52
61
52
44
55
41
1 : 1
20 : 1
1 : 1
iii
1 : 99
1 : 1.2
11 : 1
2.1 : 1
2.3 : 1
1.9 : 1
3.4 : 1
2.3 : 1
v
i
i
i
i
i
i
Fig. 1 A perspective view of 9a, showing the numbering scheme.
Ellipsoids were drawn at the 30% probability level, hydrogen atoms are
represented by spheres of arbitrary radii.
4ad
4bd
4ce
16a,bd Bn vi
17a,bd Boc ii
18a,be Cbz ii
61
77
76
1.3 : 1
3.7 : 1
2.9 : 1
were conrmed by the absolute stereochemistry of compound
10a determined by X-ray diffraction analysis (Fig. 2).
At the same time, the addition performed on (2S)-prolinal
and (4S)-serial derivatives yielded (1R,2S)16a–17a, and (R,4S)
19a–21a as major diastereoisomers, conrmed by NOESY
experiments or X-ray diffraction analysis. The diaster-
5a
5b
5c
19a,b Bn ii
20a,b Boc ii
21a,b Cbz ii
40
94
67
3.1 : 1
95 : 5
13 : 1
a
(i) LiP(O)(OEt)2, ꢀ30 ꢁC / rt, 16–18 h; (ii) HP(O)(OEt)2, 0.1 or 0.2 eq.
TEA, neat, r.t. or 50 ꢁC, 1 d or 7 d; (iii) 6a,b, H2/Pd/C, EtOH; 0 ꢁC / rt;
(iv) 7a,b, Boc2O, DMAP, MeCN, r.t., 1 d; (v) 7a,b, CbzCl, NaHCO3,
CH2Cl2, 0 ꢁC / rt, 1 d; (vi) HP(O)(OEt)2, 1 eq. i-Pr2EtN, CH2Cl2.
eoselectivity of the Pudovik reaction in the case of 20a,b–21a,b
28
´
was analogous to that obtained by Wroblewski et al.
b
d
c
Isolated yield. Crude reaction mixture (19F NMR and/or 31P NMR).
Conguration (2S). e Conguration (2R).
Considering only a few examples of ring opening reactions of
triuoromethylated N-unactivated aziridines with nitrogen
nucleophiles in the literature,29 we tried to open the ring of
aziridin-2-ylphosphonates 6a,b with BnNH2 under acidic
conditions, in the presence of Sc(OTf)3, Yb(OTf)3, Bi(OTf)3,
PBu3, B(C6F5)3, BiCl3, TiCl4 in different solvents, but all
attempts failed. Only unreacted 6a,b were observed in the
reaction mixtures. Then, we decided to carry out the reaction
under basic conditions in the presence of K2CO3 and acetoni-
case of the uorene molecule when stronger amines were used
by Gancarz et al.30
Moreover, the application of MeNH2 or BzNH2 (instead of
BnNH2), under the same conditions, as well as using K2CO3
trile as a solvent. As a result, the phosphate 22 (d ¼ ꢀ5.01 in 31
P
NMR) was formed (Scheme 2).
During the experiment, we observed the formation of diethyl
phosphite (d ¼ 7.32 in 31P NMR) and an aldehyde 1a (d ¼ 9.30 in
1H NMR), which vanished at the end of the reaction. Apparently,
besides the rearrangement of the a-hydroxyphosphonate, due to
proton extraction from the hydroxyl group by base the aldehyde
was formed with concomitant phosphonate elimination, sup-
porting the retro-Abramov reaction mechanism proposed by
Gancarz.13d Furthermore, the presence of the electron-
withdrawing CF3 moiety in the aziridine ring allowed the a-
hydroxyphosphonate intramolecular rearrangement with
subsequent aziridine ring opening to phosphate 22. The
phosphonate/phosphate conversion was already studied in the
Fig. 2 A perspective view of 10a, showing the numbering scheme.
Ellipsoids were drawn at the 30% probability level; hydrogen atoms are
represented by spheres of arbitrary radii.
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without nitrogen nucleophiles, gave phosphate 22 (Scheme 2).
Surprisingly, when para-toluenesulfonamide (TsNH2) was used
along with K2CO3, aminophosphonates 23a,b were obtained as
the sole products. The structure and stereochemistry of
compound 23a was determined by X-ray diffraction analysis and
indicated the rac(1S,2R,3S)-23a conguration, analogous to
6a,26 obtained by Pudovik addition (Fig. 3).
The obtained results were contrary to known methods
leading to N-tosylamide derivatives. Usually, the hydroxyl group
reacts with sulfonamides under acidic conditions,17 or under
basic conditions the substitution of leaving groups such as O-
mesyl is applied.15a On the other hand, a similar transformation
of hydroxyphosphonates to aminophosphonates with amines in
a basic environment was reported by Gancarz.20 Likewise, the
application of Lewis bases such as CaCl2 with aniline was
announced by Kaboudin et al.31 The results concerning the
applied reaction conditions in the case of compounds 6a,b with
TsNH2 are presented below (Table 2).
Scheme 2 Reactions of 6a,b with different nitrogen nucleophiles
under K2CO3 conditions.
The presented experiments indicate that the best conditions
leading to 23a,b involved 1.2 eq. (5 eq.) of K2CO3 and MeCN as
a solvent, while the reaction mixture was reuxed for 8 h. When
ꢁ
we monitored this reaction at lower temperatures (40 C / 60
ꢁC), only signals of substrates were detected (19F, 31P NMR).
Besides, increasing the amount of K2CO3 from 1.2 eq. to 12 eq.
led to slightly better yields and higher diastereoselectivity (Table
2, entry 2, 5). The application of THF as a solvent gave no
reaction, while reaction in DMF led to the decomposition of the
starting material to a number of undened products. Moreover,
reaction in EtOH, contrary to results reported by Gancarz,13d
decreased the reaction yield (60% 19F, 31P NMR). On the other
hand, the reaction without base failed. Surprisingly, the
Fig. 3 A perspective view of 23a, showing the numbering scheme.
Ellipsoids were drawn at the 50% probability level and hydrogen atoms
are represented by spheres of arbitrary radii.
Table 2 Optimization of the reaction of compounds 6a,b with para-toluenesulfonamide
Entry
d.r.
Base (eq.)
Solvent
Temp. [ꢁC]
Product
Yielda [%]
d.r.b
1
2
3
4
5
6
7
8
20 : 1
1 : 1
1 : 1
20 : 1
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
K2CO3 (1.2 eq.)
K2CO3 (1.2 eq.)
K2CO3 (5 eq.)
K2CO3 (12 eq.)
K2CO3 (12 eq.)
K2CO3 (1.2 eq.)
K2CO3 (1.2 eq.)
K2CO3 (1.2 eq.)
None
TEA (1.2 eq.)
TEA (1.2 eq.)
NaHCO3 (1.2 eq.)
NaHCO3 (12 eq.)
NaH (1.2 eq.)
MeCN
MeCN
MeCN
MeCN
MeCN
DMF
Reux
Reux
Reux
Reux
Reux
100
Reux
Reux
Reux
Reux
Reux
Reux
Reux
Reux
23a,b
23a,b
23a,b
23a,b
23a,b
Decomp.
n.r.
23a,b
n.r.
n.r.
74
87
73
80
96
—
—
60
—
—
—
20
20
18
6 : 1
6 : 1
9 : 1
9 : 1
9 : 1
—
—
7 : 1
—
—
—
—
—
THF
EtOH
MeCN
MeCN
EtOH
MeCN
MeCN
THF
9
10
11
12
13
14
n.r.
1a
1a
23a,b
8 : 1
a 19F NMR and/or 31P NMR yield. b Crude reaction mixture (19F NMR and/or 31P NMR).
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employment of other bases led to distinct results. In the pres- decreasing yields in some cases led us to choose 1.2 eq. as
ence of TEA, there were no reactions in MeCN, neither in EtOH. a standard base concentration (Table 3).
When NaHCO3 was used, mainly unreacted substrates were
It is noteworthy that the stereoselectivity as well as the
observed, together with diethyl phosphite and aldehyde 1a stereochemistry of the major diastereoisomers of 23a,b–37a,b
(NMR) but with lower yield, likewise in the case of reactions were always analogous to the ratio and congurations of those
with BnNH2, MeNH2 and BzNH2. The last examined base, NaH obtained in the Pudovik reaction, the major isomers of 6a,b–
(in anhydrous THF), allowed a-aminophosphonates 23a,b, but 21a,b; slightly different results were reported by Dimukhame-
with very poor yields (Table 2, entry 14). Additionally, we tov.33 Thus, higher stereoselectivity was obtained in the case of
decided to examine the reaction of 1a with TsNH2 in detail the application of chiral imines in the Pudovik reaction,
using 19F NMR monitoring. Similar to studies reported by compared to the use of chiral amines in the three-component
Keglevich et al.,5b the appropriate N-tosylaldimine 1a0 as a tran- Kabachnik–Fields reaction. The employment of two diastereo-
sient species was detected during the reaction in a crude isomers of 6a,b (1 : 1, NMR ratio) under standard conditions led
mixture but in very low concentration (d ¼ ꢀ78.16 ppm in 19F to the corresponding 23a,b with very good yield. On the
NMR, which corresponded to the chemical shis of b-CF3– contrary, in the case of 12a,b and 15a,b, the reactions proceeded
imines in the literature ref. 32). Subsequent addition of diethyl with moderate yields. The stereochemistry of 24a,b, 26a,b–
phosphite and K2CO3 (1.2 eq.) to the reaction led to 23a,b but in
poor yields (30% in 31P NMR, with accompanying dominance of
the diethyl phosphite signal). Finally, we decided to monitor the
reactions of 6a,b with TsNH2 and K2CO3 (1.2 eq.). In the
Table 3 Preparation of a-(N-tosyl)aminophosphonates
employed basic conditions, the elimination of the hydroxyl
group gave rise to aldimine 1a0, which most probably occurred
by the E1cB mechanism involving the participation of the sul-
fonimidate anion; we observed the same signal of imine 1a0 in
the 19F NMR during the reaction. This signal was completely
suppressed at the end of the reaction. Subsequent nucleophilic
addition of dialkyl phosphite to the C]N bond of imine 1a0
(Pudovik reaction) gave 23a,b (Scheme 3). These observations
support the imine path of the Kabachnik–Fields reaction (KFR),
proving that the imine is the most rational intermediate in the
Substrate d.r.
Product
PG Yielda [%] d.r.b
synthesis of a-aminophosphonates.
The optimized results prompted us to examine the scope of
this particular transformation in the reactions of aziridines
6a,b–9a,b as well as the amino acid origin of a-hydrox-
yphosphonates 10a,b–12a,b to N-tosylamide phosphonates
23a,b–37a,b. Initially, we used 12 eq. of K2CO3 as a base, but
6a,b
7a,b
8a,b
1 : 1
1 : 1
1 : 99
23a,b Bn 87
6 : 1
6 : 1
—
24a,b
H
80
25a,b Boc
—
9a,b
3 : 1
38
Cbz 41(74)c
—
10a,b
11a,b
19 : 1
1.9 : 1
26a,b Bn2 81
27a,b Boc 78
99 : 1
2.5 : 1
28a,b
40
2.4 : 1
99 : 1
12a,b
2.7 : 1
Cbz
39
11
13a,b
14a,b
15a,b
9 : 1
5.4 : 1
1.7 : 1
29a,b Bn2
30a,b Boc 51
31a,b Cbz 42
—
—
3.6 : 1
5.2 : 1
16a,bd
17a,bd
18a,be
19a,b
20a,b
21a,b
1.3 : 1
4 : 1
3.3 : 1
2.6 : 1
99 : 1
13 : 1
32a,b Bn
—
—
33a,bd Boc 59
4.4 : 1
3.7 : 1
—
12 : 1
12 : 1
34a,be Cbz 75
35a,b Bn
36a,b Boc 72
37a,b Cbz 75
—
a
b
Isolated yield. Crude reaction mixture (19F NMR and/or 31P NMR).
c
e
d
Scheme 3 Proposed reaction mechanism of 6a,b with TsNH2 under
K2CO3 conditions.
Aer additional 10 hours of heating.
Conguration (2R).
Conguration (2S).
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Scheme 4 The Felkin–Ahn model of the addition of diethyl phosphite to a-hydroxyphosphonate 20a.
31a,b/33a,b, 37a,b was conrmed by NMR as well as NOESY took place. Thus, in the reaction mixture only diethyl phosphite
experimental analysis. Moreover, the steric hindrance in 8b, and the appropriate aldehydes 3a–5a were detected (monitored
between the N-Boc substituent and the phosphonate moiety by NMR). Additionally, in the case of reactions of 10a,b and
(conrmed by interactions between protons on 1D ROESY 20a,b [(R,S)/(S,S) 19 : 1 and 99 : 1 ratios, respectively] with
experiments) caused no access to the hydroxyl group by the base K2CO3 (1.2 eq.) as well as with K2CO3 and amines (MeNH2,
(K2CO3) and subsequently, only the substrate 8b was observed BnNH2) or benzamide (BzNH2), partial racemization at carbon
in the reaction mixture. On the other hand, the very good dia- a regarding phosphonate moieties occurred, leading to 10a,b
stereoselectivity of the addition, yielding 36a,b and 37a,b, can and 20a,b [(R,S)/(S,S) in 1.5 : 1 ratio and 3.6 : 1 ratio, respec-
be explained by the Felkin–Ahn model as well as additional tively]. These results conrmed the formation of aldehydes due
interactions substantiated the addition of the dialkyl phosphite to base treatment (K2CO3) during the analyzed reactions.
on the C]N unit of N-tosylimine 5a0 derived from the appro- Similar observations were reported by Wroblewski et al.36 Thus,
´
priate aldehyde 5a. According to this, a H-bond was formed treatment of the single diastereomeric 1,2-oxaphospholane
between the P(O)H moiety of the phosphite and the nitrogen derivative with sodium methoxide led to the retro-Abramov
atom of the pyrrolidine, arranging the ve-membered transition reaction followed by phosphite addition and cyclization,
state (Scheme 4). It seems probable that the actual mechanism yielding the corresponding mixture of diastereoisomers. On the
is dependent on the components of the reaction since the other hand, these observations were in contradiction to the
reaction of carbohydrate derived a-hydroxyphosphonates (e.g. results of the analogous reactions of 6a,b, which led almost
two epimeric carbohydrates, 5C-phosphonate with L-ido- or D- exclusively to phosphate 22. Gancarz et al. explained the
gluco-congurations)34 with TsNH2 failed, presumably due to distinction between the retro-Abramov reaction yielding alde-
a lack of nitrogen heteroatoms in the analogous neighborhood hyde and the intramolecular rearrangement towards phos-
of the reaction center.
phate, based on kinetic and NMR studies.30 Their observations
Additionally, the X-ray crystal structure determinations in were based on the reactions between various a-hydrox-
the case of 34a and 36a (Fig. 4) were performed. Interestingly, yphosphonates and amines, assuming that the differentiation
both compounds existed as a racemic mixture rac(1S,2R)-34a of these two routes was dependent on the electronic effect of the
and rac(R,4S)-36a in the studied crystals. Apparently, during the substituents. They concluded that the retro-Abramov reaction is
reaction of 20a,b (K2CO3, TsNH2) yielding 36a,b, besides the N- preferred when the electron-donating substituents appear in
tosylimine formation via aldehyde 5b, the competitive enoliza- the a-hydroxyphosphonates. In our case, the presence of the
tion took place, followed by proton addition from both sides of strongly electron-withdrawing CF3 group in 6a,b facilitated the
the enol double bond leading to racemization at C4. The intramolecular rearrangement over the retro-Abramov reaction.
phenomenon of partial racemization during aldehyde forma- In this particular reaction, the in situ formed alkoxide ion
tion was already reported in the case of serine derivatives.35
substituted the phosphorus atom, leading to the formation of
In the case of the reactions of 13a,b, 16a,b and 19a,b with the three-membered cyclic intermediate. Subsequent electron
TsNH2 in the presence of K2CO3, the retro-Abramov reactions pair transfer led to phosphate while stabilization of the partial
negative charge on the a-carbon atom followed by aziridine ring
opening nally gave the vinyl phosphate 22.37
On the other hand, the reactions of 9a,b (1 : 1.2, d.r.) with
TsNH2 (1.2 eq. K2CO3, MeCN, reux) aer 8 h of heating, gave
only one diastereoisomer of epoxide 38 (41%), while the
remaining diastereoisomer 9b was present in the reaction
mixture. In the 31P NMR spectrum, the signal of epoxide 38 was
shied distinctly upeld compared to the aziridinyl substrates
9a,b and a-sulfonamide derivatives 23a,b–24a,b (dP ¼ 15.89 vs.
approx. 20 ppm). Furthermore, additional heating of the
remaining reaction mixture for 10 h under the same reaction
conditions led to 38 (74% aer isolation), due to the total
Fig. 4 A perspective view of 34a and 36a showing the numbering
consumption of starting materials 9a,b. The reaction was
scheme. Ellipsoids were drawn at the 50% probability level and
monitored by 19F and 31P NMR. Apparently, treatment of a-
hydrogen atoms are represented by spheres of arbitrary radii. Only one
hydroxyphosphonate 9a with base led to aziridine ring opening
of the alternative conformations of the C4–C5 ethyl group is shown.
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Scheme 5 Reaction of N-Cbz protected aziridines 9a,b under K2CO3
conditions.
Scheme 6 Reaction of N-Cbz protected phenylalanine derivatives
12a,b under K2CO3 conditions.
by the attack of a previously formed alkoxide anion on an
adjacent nitrogen atom (anti to alkoxide ion) of the Cbz moiety.
Furthermore, due to proton abstraction followed by aldehyde 1c
(PG ¼ Cbz) formation, the racemization, such as in case of 5b,
via enol took place. Subsequent phosphite addition to the C]O
bond of aldehyde 1c led to 9a,b as an equilibrating mixture of
diastereoisomers, where only one diastereoisomer 9a reacted
with base to give 38 (Scheme 5). The structure and stereo-
chemistry of 38 as rac(1S,2S,3S) were conrmed by NMR anal-
ysis and X-ray crystal structure determination (Fig. 5).
This aza-Payne rearrangement of non-uorinated N-Boc38
protected aziridinemethanols, as well as Ts,38,39 Mts40 and Ms38
protected aziridinemethanols, was previously reported. To the
best of our knowledge, there are limited numbers of publica-
tions reporting the synthesis of triuoromethylated epoxide
phosphonates41 that could be biologically promising derivatives
of non-uorinated epoxide phosphonates possessing antibiotic
activity.42 On the other hand, epoxide 38 can easily provide tri-
uoromethylated hydroxyphosphonates, whose biological
activities were already evaluated.43
When phenylalanine N-Cbz protected derivatives 12a,b
(2.7 : 1, d.r.) were subjected to the reaction with TsNH2 under
the same conditions, the a-(N-tosyl)aminophosphonates
28a,b were obtained as major products, together with
compound 39 (Scheme 6). Apparently, the alkoxide ion
formed from a-hydroxyphosphonate attacked the carbonyl
carbon atom of the Cbz moiety, instead of the adjacent
carbon, as was in the case of 9b where the formation of fused
three and ve membered rings was excluded. Subsequent
leaving of the benzyloxide ion led to the formation of the
oxazolidin-2-one function in 39. A similar displacement of
the N-amide group leading to the corresponding oxazolidin-
2-one was reported by Patel et al.11f Based on the detailed
analysis of 1H NMR data we were able to assign the stereo-
chemistry of compound 39. Thus, diagnostic signals
appeared at 4.45 (dd, J ¼ 6.1, 0.7 Hz, CHP) and 4.33–4.25 ppm
(m, CHN) in 1H NMR, which corresponded to the (1S,2S)
diastereoisomer of 39.44 These data indicated that during the
reaction of Cbz protected phenylalanine derivatives 12a,b
under basic conditions with TsNH2, only the (1S,2S)-12b
diastereoisomer reacted towards (1S,2S)-39.
Fig. 1–5 show the perspective views of the molecules. Of all
six compounds, only 10a crystallized in the chiral P41212
space group as a single enantiomer (1R,2S). All other
compounds crystallized in the centrosymmetric space group,
which means that both enantiomers were present in the
crystals. This difference was also visible in the supramolec-
ular motifs created by hydrogen bonds in the crystal struc-
tures. In 10a the O–H/O hydrogen bonds connect molecules
into innite chains (Fig. 1 and Table 2 in ESI†), expanding
along the z-direction (molecules related by fourfold, right-
hand screw axis). In all other crystal structures, the well-
dened, directional O–H/O or N–H/O (Fig. 2 and Table 2
in ESI†) hydrogen bonds made centrosymmetric dimers,
arranged by two different enantiomers. In compound 23a,
each of the symmetry-independent molecules made the
dimer with its own symmetry-related mate (i.e. A–A and B–B).
It is possible that the relative ease of making centrosym-
metric dimers is one of the reasons that all these compounds
crystallized as racemates.
Conclusions
In summary, our results demonstrate the synthesis of a wide
range of a-hydroxyphosphonates that subsequently underwent
reactions with nitrogen nucleophiles. Only para-toluenesulfo-
namide provided access to uorinated3k,45 and non-uorinated
a-aminophosphonates,46 an important group of compounds
that are mimics of the naturally occurring a-amino acids,47 and
could be explored as versatile substrates in the synthesis of
biologically active species. Further deprotection of the a-amino
group could be considered in the design of important phos-
phonated building blocks employed in the synthesis of useful
compounds such as peptide analogues. According to the
establishments concerning the reaction mechanism, this study
gives further proof that the Kabachnik–Fields reaction occurs
via the imine intermediate, which immediately undergoes the
Fig. 5 A perspective view of 38 showing the numbering scheme.
Ellipsoids were drawn at the 50% probability level, hydrogen atoms are
represented by spheres of arbitrary radii.
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addition
aminophosphonates.
of
dialkyl
phosphite
towards
N-tosyl-a- from large thermal motion; additionally, in 9a, 34a and 38 weak
constraints were applied to the selected anisotropic displace-
ment parameters. Relevant crystal data are listed in Table 1 (see
ESI†), together with renement details. In structure 34a one of
the ethyl groups was disordered over two alternative confor-
mations; an s.o.f. of 0.5 was assigned to both positions.
Experimental section
General methods
1H NMR, 13C NMR, 19F NMR and 31P NMR spectral measure-
Crystallographic data for the structural analysis was depos-
ments were performed on Bruker ASCEND 400 (400 MHz), ited with the Cambridge Crystallographic Data Centre, no.
Bruker ASCEND 600 (600 MHz) spectrometers. All 2D and 1D CCDC – 1568454 (9a), CCDC – 1569663 (10a), CCDC – 1568455
selective NMR spectra were recorded on the Bruker ASCEND 600 (23a), CCDC – 1568456 (34a), CCDC – 1568457 (36a) and CCDC –
(600 MHz) spectrometer. Chemical shis of 1H NMR were 1568458 (38).
expressed in parts per million downeld from tetramethylsilane
(TMS) as an internal standard (d ¼ 0) in CDCl3 or using the Procedure for the synthesis of aldehydes 1–5
residual solvent peak in the case of CD3CN (d ¼ 1.96). Chemical
All aldehydes were prepared from the corresponding alcohols.
shis of 13C NMR were expressed in parts per million downeld
Compounds 1a,26 2–3,27b 4a,50 4c,51 5a,52 5b53 were prepared as
and upeld from CDCl3 as an internal standard (d ¼ 77.0).
Chemical shis of 19F NMR were expressed in parts per million
upeld from CFCl3 as an internal standard (d ¼ 0) in CDCl3.
Chemical shis of 31P NMR were expressed in parts per million
in CDCl3 and CD3CN. All d.r. ratios were evaluated on the basis
of 19F NMR or/and 31P NMR in the crude reaction mixture. High-
resolution mass spectra were recorded by electron spray (MS-
ESI) techniques using a QToF Impact HD Bruker spectrom-
eter. The melting points were measured on a Boetius apparatus
and were uncorrected. Reagent grade chemicals were used.
Solvents were dried by reuxing with sodium metal-benzophe-
none$(THF), CaH2$(CH2Cl2, CH3CN) and NaH$(Et2O), then
distilled under an argon atmosphere. Absolute ethanol was
described. The NMR data for 2–3,54 4b,27b 5c55 were in good
agreement.
Racemic mixture of (2R,3S)-1-benzyl-3-(triuoromethyl)
aziridine-2-carbaldehyde (rac 1a). Pale yellow oil (1 g, >99%
1H, 19F NMR): 1H NMR (400 MHz, CDCl3) d ¼ 9.30 (dq, J ¼ 5.3,
2.6 Hz, 1H, CHO), 7.45–7.31 (m, 5H, Ph), 3.80 (d, J ¼ 13.3 Hz,
1H, CHHPh), 3.75 (d, J ¼ 13.4 Hz, 1H, CHHPh), 2.65 (“quintet”, J
1
¼ 6.3 Hz, 1H, CHCF3), 2.50 (t, J ¼ 6.1 Hz, 1H, CHCHCF3). H
{/19F} NMR (376 MHz, CDCl3) d ¼ 9.30 (d, J ¼ 5.7 Hz, 1H, CHO),
7.44–7.24 (m, 5H, Ph), 3.79 (d, J ¼ 13.4 Hz, 1H, CHHPh), 3.75 (d,
J ¼ 13.4 Hz, 1H, CHHPh), 2.68–2.61 (m, 1H, CHCF3), 2.50 (t, J ¼
6.1 Hz, 1H, CHCHCF3). 13C NMR (101 MHz, CDCl3) d ¼ 196.74
(q, J ¼ 1.9 Hz, C]O), 135.66, 128.77, 128.23, 128.14 (4 ꢂ s, Ph),
123.46 (q, J ¼ 274.7 Hz, CF3), 62.37 (s, CH2Ph), 47.39 (s,
CHCHCF3), 44.47 (q, J ¼ 40.8 Hz, CHCF3). 19F NMR (376 MHz,
CDCl3) d ¼ ꢀ66.26 (dd, J ¼ 6.2, 2.7 Hz).
˚
stored under argon and over molecular sieves (3 A). All moisture
sensitive reactions were carried out under an argon atmosphere
using oven-dried glassware. Reactions at temperatures below
0 ꢁC were performed using a cooling bath (liquid N2/n-hexane or
liquid N2/i-PrOH). TLC was performed on Merck Kieselgel 60-
F254 with EtOAc/n-hexane and MeOH/CHCl3 as developing
systems, and products were detected by inspection under UV
light (254 nm) and with a solution of potassium permanganate.
Merck Kieselgel 60 (0.063–0.200 mm), Merck Kieselgel 60 (0.040–
0.063 mm), Merck Kieselgel 60 (0.015–0.004 mm), were used for
Procedure for the addition of diethyl phosphite to aldehyde 1a
Compounds 6a,b26 were prepared as described. The NMR data
for 6a were in good agreement.
Procedure for N-deprotection of 6a,b
column chromatography. X-ray diffraction data were collected To a round-bottom ask with aziridinyl phosphonates 6a,b
by the u-scan technique on a Rigaku four-circle Xcalibur (Eos (1 : 1, d.r.) (1.68 mmol, 616 mg) dissolved in ethanol (10 mL),
detector) diffractometer with graphite-monochromatized MoKa a catalytic amount of palladium hydroxide was added. The ask
˚
radiation (l ¼ 0.71073 A): for 9a, 10a and 36a at room temper- was then connected by three-way valve to a vacuum pump and
ature, for 23a and 38 at 130(1) K, and for 34a at 100(1) K. The a gasbag lled with gaseous hydrogen. Hydrogen was then
ꢁ
data were corrected for Lorentz-polarization and absorption introduced inside the ask at 0 C and vigorously stirred. This
effects.48 Accurate unit-cell parameters were determined by cycle was repeated 10 times and the reaction mixture was stirred
a least-squares t of 7906 (9a), 4321 (10a), 6595 (23a), 3219 (34a), overnight at room temperature. The catalyst was then ltered
7252 (36a) and 1078 (38) reections of highest intensity, chosen out and crude products 7a,b were isolated using column chro-
from the whole experiment. The structures were solved with matography (chloroform/methanol 99 : 1, v/v).
SHELXT49 and rened with the full-matrix least-squares proce-
Racemic
mixture
of
diethyl((S)-hydroxy((2R,3S)-3-
dure on F2 by SHELXL-2014/7.49 All non-hydrogen atoms were (triuoromethyl)aziridin-2-yl)methyl)phosphonate (rac 7a).
1
rened anisotropically, hydrogen atoms were placed in the Pale yellow oil (228 mg, 49%): H NMR (400 MHz, CDCl3) d ¼
calculated positions and rened as the ‘riding model’ with the 4.24 (q, J ¼ 7.2 Hz, 2H, OCH2CH3), 4.19 (q, J ¼ 7.2 Hz, 2H,
isotropic displacement parameters set at 1.2 (1.5 for methyl OCH2CH3), 3.76 (br t, J ¼ 7.8 Hz, 1H, CHP), 2.84–2.70 (m, 2H,
groups) times the Ueq. value for the appropriate non-hydrogen CHCF3, CHCHCF3), 2.05 (br s, 1H, OH), 1.63 (br t, J ¼ 8.8 Hz, 1H,
atoms. In 9a, 34a, 36a and 38, the lengths of terminal C–C NH), 1.38 (t, J ¼ 7.1 Hz, 3H, OCH2CH3), 1.37 (t, J ¼ 7.1 Hz, 3H,
bonds in the ethyl groups C4–C5 and C7–C8 were constrained to OCH2CH3). 13C NMR (101 MHz, CDCl3) d ¼ 124.58 (q, J ¼
the typical values, due to the signicant shortening resulting 274.0 Hz, CF3), 66.79 (d, J ¼ 158.9 Hz, CHP), 63.26 (d, J ¼ 7.0 Hz,
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OCH2CH3), 63.18 (d, J ¼ 6.9 Hz, OCH2CH3), 34.51 (d, J ¼ 3.7 Hz, 2 ꢂ OCH2CH3). 13C NMR (151 MHz, CDCl3) d ¼ 151.60 (s, C]O),
CHCHCF3), 33.28 (dq, J ¼ 39.7, 12.8 Hz, CHCF3), 16.47 (d, J ¼ 124.13 (q, J ¼ 275.5 Hz, CF3), 83.43 (s, C(CH3)3), 69.42 (d, J ¼
5.1 Hz, OCH2CH3), 16.43 (d, J ¼ 5.3 Hz, OCH2CH3). 19F NMR 164.1 Hz, CHP), 63.32 (d, J ¼ 7.1 Hz, OCH2CH3), 63.26 (d, J ¼
(376 MHz, CDCl3) d ¼ ꢀ66.75 (br s). 19F{/1H} NMR (376 MHz, 6.8 Hz, OCH2CH3), 33.58 (dq, J ¼ 39.7, 11.2 Hz, CHCF3), 32.66
CDCl3) d ¼ ꢀ66.76 (d, J ¼ 3.0 Hz). 31P{/1H} NMR (162 MHz, (d, J ¼ 2.6 Hz, CHCHCF3), 27.54 (s, C(CH3)3), 16.43 (d, J ¼ 5.8 Hz,
CDCl3) d ¼ 22.53 (d, J ¼ 2.9 Hz). HRMS (ESI) calcd for C8H15
-
OCH2CH3), 16.35 (d, J ¼ 6.0 Hz, OCH2CH3). 19F NMR (376 MHz,
CDCl3) d ¼ ꢀ66.95 (br s). 19F{/1H} NMR (376 MHz, CDCl3) d ¼
F3NO4PNa ([M + Na]+): 300.0589, found: 300.0589.
Racemic
mixture
of
diethyl((R)-hydroxy((2R,3S)-3- ꢀ66.96 (s). 31P{/1H} NMR (162 MHz, CDCl3) d ¼ 17.64 (s). HRMS
(triuoromethyl)aziridin-2-yl)methyl)phosphonate (rac 7b). (ESI) calcd for C13H23F3NO6PK ([M + K]+): 416.0852, found:
1
Pale yellow oil (227 mg, 49%): H NMR (400 MHz, CDCl3) d ¼ 416.0846.
4.28–4.17 (m, 4H, 2 ꢂ OCH2CH3), 3.90 (t, J ¼ 8.1 Hz, 1H, CHP),
2.94–2.75 (m, 2H, CHCF3, CHCHCF3), 1.86 (br s, 1H, OH), 1.81
Procedure for the introduction of the Cbz protecting group
into 7a,b
(br t, J ¼ 8.8 Hz, 1H, NH), 1.37 (t, J ¼ 7.1 Hz, 3H, OCH2CH3), 1.36
(t, J ¼ 7.1 Hz, 3H, OCH2CH3). 13C NMR (101 MHz, CDCl3) d ¼
124.29 (q, J ¼ 273.6 Hz, CF3), 65.72 (dd, J ¼ 167.1, 1.5 Hz, CHP), Aziridinyl phosphonates 7a,b (1 : 1, d.r.) (0.72 mmol, 200 mg, 1
63.25 (d, J ¼ 7.1 Hz, OCH2CH3), 62.98 (d, J ¼ 7.3 Hz, OCH2CH3), eq.) were dissolved in CH2Cl2 (5 mL) under argon at 0 ꢁC.
36.06 (d, J ¼ 8.8 Hz, CHCHCF3), 35.27 (q, J ¼ 39.8 Hz, CHCF3), NaHCO3 (0.87 mmol, 67 mg, 1.2 eq.) was added and the reaction
16.38 (d, J ¼ 5.4 Hz, OCH2CH3), 16.34 (d, J ¼ 5.4 Hz, OCH2CH3). mixture was stirred for 15 min. Benzyl chloroformate (95%,
19F NMR (376 MHz, CDCl3) d ¼ ꢀ66.65 (d, J ¼ 6.4 Hz). 19F{/1H} 1.08 mmol, 194 mg, 162 mL, 1.5 eq.) was introduced and the
NMR (376 MHz, CDCl3) d ¼ ꢀ66,65 (s). 31P{/1H} NMR (162 MHz, reaction mixture was stirred overnight at room temperature.
CDCl3) d ¼ 20.87 (s). HRMS (ESI) calcd for C8H15F3NO4PNa ([M + Next, the reaction mixture was diluted with water (10 mL) then
Na]+): 300.0589, found: 300.0585.
extracted with CH2Cl2 (3 ꢂ 10 mL). The organic layers were
dried over MgSO4, ltered and concentrated under reduced
pressure. The crude products 9a,b were isolated using column
chromatography (n-hexane/ethyl acetate 10 : 90, v/v / ethyl
acetate/methanol 99 : 1, v/v).
Procedure for the introduction of the Boc protecting group
into 7a,b
Aziridinyl phosphonates 7a,b (1 : 1, d.r.) (0.72 mmol, 200 mg, 1
Racemic mixture of benzyl(2R,3S)-2-((S)-(diethox-
ꢁ
eq.) were dissolved in acetonitrile (5 mL) under argon at 0 C. yphosphoryl)(hydroxy)methyl)-3-(triuoromethyl)aziridine-
DMAP (0.87 mmol, 106 mg, 1.2 eq.) was added and the reaction 1-carboxylate (rac 9a). Pale yellow oil, slowly crystallizing
mixture was stirred for 15 min. Next, di-tert-butyl dicarbonate (118 mg, 34%): 1H NMR (600 MHz, CDCl3) d ¼ 7.42–7.33 (m, 5H,
(99%, 1.08 mmol, 238 mg, 1.5 eq.) was introduced and the Ph), 5.19 (d, J ¼ 12.3 Hz, 1H, CHHPh), 5.16 (d, J ¼ 12.3 Hz, 1H,
reaction mixture was stirred overnight at room temperature. CHHPh), 4.25–4.10 (m, 4H, 2 ꢂ OCH2CH3), 3.80 (br t, J ¼ 8.3 Hz,
The reaction mixture was then diluted with water (10 mL), 1H, CHP), 3.17 (br q, J ¼ 6.4 Hz, 1H, CHCHCF3), 3.11 (“quintet”,
extracted with CH2Cl2 (3 ꢂ 10 mL) and the layers were sepa- J ¼ 5.7 Hz, 1H, CHCF3), 1.28 (t, J ¼ 7.0 Hz, 3H, OCH2CH3), 1.27
rated. The organic layers were dried over MgSO4, ltered and (t, J ¼ 6.9 Hz, 3H, OCH2CH3). 13C NMR (151 MHz, CDCl3) d ¼
concentrated under reduced pressure. The crude product 8b 160.52 (s, C]O), 134.92, 128.61, 128.44, 128.16 (4 ꢂ s, Ph),
was isolated using column chromatography (n-hexane/ethyl 122.98 (q, J ¼ 275.0 Hz, CF3), 69.06 (s, CH2Ph), 65.22 (d, J ¼
acetate 10 : 90, v/v / ethyl acetate/methanol 99 : 1, v/v).
161.6 Hz, CHP), 63.42 (d, J ¼ 7.3 Hz, OCH2CH3), 63.26 (d, J ¼
Racemic mixture of
tert-butyl(2R,3S)-2-((R)-(diethox- 7.0 Hz, OCH2CH3), 40.88 (d, J ¼ 4.8 Hz, CHCHCF3), 38.71 (dq, J
yphosphoryl)(hydroxy)methyl)-3-(triuoromethyl)aziridine-1-
¼ 40.6, 12.4 Hz, CHCF3), 16.34 (d, J ¼ 5.5 Hz, OCH2CH3), 16.28
carboxylate (rac 8b). Pale yellow oil (117 mg, 43%, 1.9 : 1 r.r. that (d, J ¼ 5.6 Hz, OCH2CH3). 19F NMR (565 MHz, CDCl3) d ¼
could be isolated). Major rotamer: H NMR (600 MHz, CDCl3) ꢀ67.26 (br s). 19F{/1H} NMR (565 MHz, CDCl3) d ¼ ꢀ67.27 (d, J ¼
1
d ¼ 5.03 (t, J ¼ 9.6 Hz, 1H, CHP), 4.30–4.15 (m, 4H, 2 ꢂ 2.2 Hz). 31P{/1H} NMR (243 MHz, CDCl3) d ¼ 20.68 (s). HRMS
OCH2CH3), 2.97–2.84 (m, 2H, CHCF3, CHCHCF3), 1.53 (s, 9H, (ESI) calcd for C16H21F3NO6PNa ([M + Na]+): 434.0956, found:
C(CH3)3), 1.36 (t, J ¼ 7.1 Hz, 6H, 2 ꢂ OCH2CH3). 13C NMR (151 434.0952.
MHz, CDCl3) d ¼ 152.13 (s, C]O), 124.08 (q, J ¼ 274.5 Hz, CF3),
Racemic
mixture
of
benzyl(2R,3S)-2-((R)-(diethox-
83.54 (s, C(CH3)3), 69.87 (d, J ¼ 169.3 Hz, CHP), 63.43 (d, J ¼ yphosphoryl)(hydroxy)methyl)-3-(triuoromethyl)aziridine-1-
6.8 Hz, OCH2CH3), 62.95 (d, J ¼ 6.7 Hz, OCH2CH3), 35.02 (q, J ¼ carboxylate (rac 9b). Pale yellow oil, slowly crystallizing (101 mg,
41.4 Hz, CHCF3), 34.27 (d, J ¼ 8.9 Hz, CHCHCF3), 27.68 (s, 40%) 1H NMR (600 MHz, CDCl3) d ¼ 7.41–7.36 (m, 5H, Ph), 5.23
C(CH3)3), 16.36 (d, J ¼ 5.9 Hz, OCH2CH3), 16.23 (d, J ¼ 5.8 Hz, (d, J ¼ 12.2 Hz, 1H, CHHPh), 5.20 (d, J ¼ 12.3 Hz, 1H, CHHPh),
OCH2CH3). 19F NMR (565 MHz, CDCl3) d ¼ ꢀ66.94 (d, J ¼ 6.6 4.28–4.18 (m, 4H, 2 ꢂ OCH2CH3), 3.98 (br t, J ¼ 8.4 Hz, 1H,
Hz). 19F{/1H} NMR (565 MHz, CDCl3) d ¼ ꢀ66.94 (s). 31P{/1H} CHP), 3.24 (“quintet”, J ¼ 6.2 Hz, 1H, CHCF3), 3.21–3.15 (m, 1H,
NMR (243 MHz, CDCl3) d ¼ 16.47 (s). HRMS (ESI) calcd for OH), 3.09 (dt, J ¼ 9.3, 4.9 Hz, 1H, CHCHCF3), 1.36 (t, J ¼ 7.0 Hz,
C
13H23F3NO6PNa ([M + Na]+): 400.1112, found: 400.1119. Minor 3H, OCH2CH3), 1.35 (t, J ¼ 7.0 Hz, 3H, OCH2CH3). 13C NMR (151
rotamer: 1H NMR (400 MHz, CDCl3) d ¼ 4.88 (t, J ¼ 9.5 Hz, 1H, MHz, CDCl3) d ¼ 160.62 (s, C]O), 134.84, 128.52, 128.35, 128.06
CHP), 4.32–4.18 (m, 4H, 2 ꢂ OCH2CH3), 3.00–2.70 (m, 2H, (4 ꢂ s, Ph), 122.91 (q, J ¼ 275.1 Hz, CF3), 68.95 (s, CH2Ph), 65.09
CHCF3, CHCHCF3), 1.51 (s, 9H, C(CH3)3), 1.38 (t, J ¼ 7.1 Hz, 6H, (dd, J ¼ 161.7, 1.2 Hz, CHP), 63.32 (d, J ¼ 7.3 Hz, OCH2CH3),
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Paper
63.15 (d, J ¼ 7.0 Hz, OCH2CH3), 40.82 (d, J ¼ 5.2 Hz, CHCHCF3), OCH2CH3). 13C NMR (151 MHz, CDCl3) d ¼ 156.09 (s, C]O),
38.61 (dq, J ¼ 40.5, 12.6 Hz, CHCF3), 16.25 (d, J ¼ 5.7 Hz, 137.84, 136.66, 129.43, 128.43, 128.39, 128.34, 127.88, 126.44 (8
OCH2CH3), 16.19 (d, J ¼ 5.9 Hz, OCH2CH3). 19F NMR (565 MHz, ꢂ s, Ph), 67.52 (d, J ¼ 162.7 Hz, CHP), 66.43 (s, OCH2Ph), 63.15
CDCl3) d ¼ ꢀ67.18 (d, J ¼ 6.0 Hz). 19F{/1H} NMR (565 MHz, (d, J ¼ 7.0 Hz, OCH2CH3), 62.64 (d, J ¼ 7.2 Hz, OCH2CH3), 53.51
CDCl3) d ¼ ꢀ67.18 (s). 31P{/1H} NMR (243 MHz, CDCl3) d ¼ 19.15 (s, CHCH2Ph), 38.03 (s, CH2Ph), 16.28 (d, J ¼ 4.5 Hz, OCH2CH3),
(s). HRMS (ESI) calcd for C16H21F3NO6PNa ([M + Na]+): 16.24 (d, J ¼ 5.7 Hz, OCH2CH3). 31P{/1H} NMR (243 MHz, CDCl3)
434.0956, found: 434.0935.
d ¼ 23.06 (s). HRMS (ESI) calcd for C21H28NO6PNa ([M + Na]+):
444.1552, found: 444.1543.
Benzyl((1S,2S)-1-(diethoxyphosphoryl)-1-hydroxy-3-phenylpropan-
2-yl)carbamate (12b). 31P{/1H} NMR (243 MHz, CDCl3) d ¼
22.63 (s).
Procedure for the addition of diethyl phosphite to aldehydes
2–5
Compounds 10–15 were prepared according to the previously
tert-Butyl((1R,2S)-1-(diethoxyphosphoryl)-1-hydroxy-3-
reported procedure.27b The NMR data for 10,27b 13,27b 17,56 2028 methylbutan-2-yl)carbamate (14a). The white solid was iso-
were in good agreement.
lated as a mixture with 14b that could not be separated by the
Procedure A. To the respective aldehydes, diethyl phosphite chromatography techniques employed in this study (351 mg,
1
(1 eq.) and TEA (0.2 eq.) were added and the reaction mixture 55%): H NMR (600 MHz, CDCl3) d ¼ 5.47 (d, J ¼ 9.3 Hz, 1H,
ꢁ
was kept at 50 C for 1 day (monitored by TLC or NMR). The NH), 5.06 (d, J ¼ 5.5 Hz, 1H, OH), 4.26–4.08 (m, 5H, 2 ꢂ
reaction mixture was then diluted with water (20 mL) and OCH2CH3, CHP), 3.52 (tdd,
J
¼
8.5, 4.5, 2.6 Hz, 1H,
extracted with CH2Cl2 (3 ꢂ 20 mL). The combined extracts were CHCH(CH3)2), 2.11 (dq, J ¼ 13.4, 7.0 Hz, 1H, CH(CH3)2), 1.44 (s,
washed with aqueous sodium bicarbonate then brine, dried 9H, C(CH3)3), 1.38–1.30 (m, 6H, 2 ꢂ OCH2CH3), 0.97 (“t”, J ¼
over Na2SO4, ltered and concentrated under reduced pressure. 6.3 Hz, 6H, 2 ꢂ CH3). 13C NMR (151 MHz, CDCl3) d ¼ 156.38 (s,
The crude products were isolated using column chromatog- C]O), 79.14 (s, C(CH3)3), 68.32 (d, J ¼ 162.7 Hz, CHP), 63.02 (d,
raphy (chloroform/methanol 99 : 1, v/v
methanol 95 : 5).
/
chloroform/ J ¼ 7.0 Hz, OCH2CH3), 62.55 (d, J ¼ 7.6 Hz, OCH2CH3), 56.76 (s,
CHCH(CH3)2), 29.89 (d, J ¼ 11.9 Hz, CH(CH3)2), 28.38 (s,
Procedure B. Analogous treatment of aldehyde 4a and diethyl C(CH3)3), 19.67 (s, CH3), 19.19 (s, CH3), 16.48 (d, J ¼ 4.6 Hz,
phosphite (1 eq.) and i-Pr2EtN (1.1 eq.) in CH2Cl2, (reux) for 1 OCH2CH3), 16.45 (d, J ¼ 4.2 Hz, OCH2CH3). 31P{/1H} NMR (162
day gave crude products 16a,b, which were isolated using MHz, CDCl3) d ¼ 23.47 (s). HRMS (ESI) calcd for C14H31NO6P
column chromatography (chloroform/methanol 99 : 1, v/v / ([M + H]+): 340.1889, found: 340.1882.
chloroform/methanol 95 : 5).
tert-Butyl((1S,2S)-1-(diethoxyphosphoryl)-1-hydroxy-3-
methylbutan-2-yl)carbamate (14b). 31P{/1H} NMR (162 MHz,
tert-Butyl((1R,2S)-1-(diethoxyphosphoryl)-1-hydroxy-3-
phenylpropan-2-yl)carbamate (11a). A white solid was iso- CDCl3) d ¼ 23.04 (s).
lated as a mixture with 11b, which could not be separated by the
Benzyl((1R,2S)-1-(diethoxyphosphoryl)-1-hydroxy-3-
chromatography techniques employed in this study (396 mg, methylbutan-2-yl)carbamate (15a). A white oil, slowly
61%): 1H NMR (600 MHz, CDCl3) d ¼ 7.31–7.16 (m, 5H, Ph), 5.84 crystallizing, was isolated as a mixture with 15b that could not
(d, J ¼ 9.2 Hz, 1H, NH), 5.73–5.65 (m, 1H, OH), 4.32–4.00 (m, 5H, be separated by the chromatography techniques employed in
2 ꢂ OCH2CH3, CHCH2Ph), 3.92–3.82 (m, 1H, CHP), 2.97 (d, J ¼ this study (298 mg, 41%): 1H NMR (600 MHz, CDCl3) d ¼ 7.40–
7.9 Hz, 2H, CH2Ph), 1.40 (s, 9H, C(CH3)3), 1.32 (t, J ¼ 6.6 Hz, 3H, 7.27 (m, 5H, Ph), 5.99 (d, J ¼ 9.6 Hz, 1H, NH), 5.30 (dd, J ¼ 8.1,
OCH2CH3), 1.25 (t, J ¼ 7.1 Hz, 3H, OCH2CH3). 13C NMR (151 2.0 Hz, 1H, OH), 5.08 (s, 2H, CH2Ph), 4.15–4.01 (m, 5H, 2ꢂ
MHz, CDCl3) d ¼ 155.50 (s, C]O), 138.07, 129.37, 128.25, 126.22 OCH2CH3, CHP), 3.64 (tdd,
J
¼
9.1, 4.6, 2.3 Hz, 1H,
(4 ꢂ s, Ph), 78.95 (s, C(CH3)3), 67.63 (d, J ¼ 163.0 Hz, CHP), CHCH(CH3)2), 2.07–2.01 (m, 1H, CH(CH3)2), 1.29 (t, J ¼ 7.1 Hz,
62.96 (d, J ¼ 7.1 Hz, OCH2CH3), 62.43 (d, J ¼ 7.3 Hz, OCH2CH3), 3H, OCH2CH3), 1.20 (t, J ¼ 7.1 Hz, 3H, OCH2CH3), 1.00–0.95 (m,
52.89 (s, CHCH2Ph), 38.12 (s, CH2Ph), 28.26 (s, C(CH3)3), 16.42– 6H, 2 ꢂ CH3). 13C NMR (151 MHz, CDCl3) d ¼ 156.57 (s, C]O),
16.27 (m, 2 ꢂ OCH2CH3). 31P{/1H} NMR (162 MHz, CDCl3) d ¼ 136.79, 128.35, 127.99, 127.96 (4 ꢂ s, Ph), 67.84 (d, J ¼ 163.3 Hz,
23.25 (s). HRMS (ESI) calcd for C18H30NO6PNa ([M + Na]+): CHP), 66.51 (s, CH2Ph), 63.19 (d, J ¼ 7.3 Hz, OCH2CH3), 62.57
410.1708, found: 410.1701.
(d, J ¼ 7.4 Hz, OCH2CH3), 56.90 (s, CHCH(CH3)2), 30.39 (d, J ¼
12.3 Hz, CH(CH3)2), 19.54 (s, CH3), 19.21 (s, CH3), 16.40 (d, J ¼
tert-Butyl((1S,2S)-1-(diethoxyphosphoryl)-1-hydroxy-3-
phenylpropan-2-yl)carbamate (11b). 31P{/1H} NMR (162 5.4 Hz, OCH2CH3), 16.30 (d, J ¼ 6.1 Hz, OCH2CH3). 31P{/1H}
MHz, CDCl3) d ¼ 22.89 (s).
NMR (243 MHz, CDCl3) d ¼ 23.23 (s). HRMS (ESI) calcd for
Benzyl((1R,2S)-1-(diethoxyphosphoryl)-1-hydroxy-3-
phenylpropan-2-yl)carbamate (12a). Pale yellow oil, isolated
C
17H29NO6P ([M + H]+): 374.1732, found: 374.1736.
Benzyl((1S,2S)-1-(diethoxyphosphoryl)-1-hydroxy-3-methylbutan-
as a mixture with 12b, which could not be separated by the 2-yl)carbamate (15b). 31P{/1H} NMR (243 MHz, CDCl3) d ¼
chromatography techniques employed in this study (412 mg, 23.17 (s).
1
52%): H NMR (600 MHz, CDCl3) d ¼ 7.33–7.17 (m, 10H, Ph),
Diethyl((R)-((S)-1-benzylpyrrolidin-2-yl)(hydroxy)methyl)
6.19 (d, J ¼ 9.1 Hz, 1H, NH), 5.41 (d, J ¼ 8.4 Hz, 1H, OH), 5.07– phosphonate (16a). A white solid was isolated as a mixture with
4.99 (m, 2H, OCH2Ph), 4.22–3.96 (m, 5H, 2 ꢂ OCH2CH3, 16b, which could not be separated by the chromatography
CHCH2Ph), 3.89–3.82 (m, 1H, CHP), 2.98 (d, J ¼ 7.9 Hz, 2H, techniques employed in this study (1062 mg, 61%): 1H NMR
CH2Ph), 1.38–1.24 (m, 3H, OCH2CH3), 1.23–1.17 (m, 3H, (600 MHz, CDCl3) d ¼ 7.50–7.42 (m, 2H, Ph), 7.34–7.31 (m, 2H,
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Ph), 7.24–7.26 (m, 1H, Ph), 4.73 (d, J ¼ 13.3 Hz, 1H, CHHPh), MHz, CDCl3) d ¼ 154.70 (s, C]O), 136.46, 128.49, 128.06, 127.88
4.35–4.20 (m, 4H, 2 ꢂ OCH2CH3), 4.12 (ddd, J ¼ 10.3, 8.3, (4 ꢂ s, Ph), 70.08 (d, J ¼ 156.4 Hz, CHP), 67.19 (br s, CH2Ph),
7.1 Hz, 1H, CHP), 3.91 (d, J ¼ 7.2 Hz, 1H, CHCHP), 3.67 (d, J ¼ 62.68 (d, J ¼ 7.2 Hz, OCH2CH3), 62.53 (d, J ¼ 6.8 Hz, OCH2CH3),
13.3 Hz, 1H, CHHPh), 3.41 (m, 1H, NCHH), 3.00 (d, J ¼ 13.6 Hz, 58.16 (d, J ¼ 10.0 Hz, CHCHP), 47.58 (s, NCH2), 26.53 (s,
1H, NCHH), 2.96 (ddd, J ¼ 10.0, 7.5, 2.9 Hz, 1H, CHHCH), 2.49 CH2CH), 24.34 (s, NCH2CH2), 16.51–16.44 (m, 2 ꢂ OCH2CH3).
(td, J ¼ 9.3, 7.2 Hz, 1H, CHHCH), 2.24 (dt, J ¼ 13.5, 10.0 Hz, 1H, 31P{/1H} NMR (162 MHz, CDCl3) d ¼ 22.47 (s). HRMS (ESI) calcd
NCH2CHH), 2.09 (ddd, J ¼ 13.6, 8.7, 1.5 Hz, 1H, NCH2CHH), for C17H27NO6P ([M + H]+): 372.1571, found: 372.1579.
1.37 (t, J ¼ 7.1 Hz, 3H, OCH2CH3), 1.26 (t, J ¼ 7.1 Hz, 3H,
Benzyl(R)-2-((R)-(diethoxyphosphoryl)(hydroxy)methyl)
OCH2CH3). 13C NMR (151 MHz, CDCl3) d ¼ 138.26, 128.41, pyrrolidine-1-carboxylate (18b). Mixture of two rotamers
128.21, 126.71 (4 ꢂ s, Ph), 71.76 (d, J ¼ 154.6 Hz, CHP), 69.42 (d, (8.3 : 1, r.r.). Major rotamer: 1H NMR (400 MHz, CDCl3) d ¼
J ¼ 2.9 Hz, CHCHP), 62.75 (d, J ¼ 7.4 Hz, OCH2CH3), 62.22 (d, J 7.39–7.32 (m, 5H, Ph), 5.21 (br s, 1H, OH), 5.17 (d, J ¼ 12.0 Hz,
¼ 7.5 Hz, OCH2CH3), 53.56 (s, CH2Ph), 53.12 (s, NCH2), 36.25 (d, 1H, CHHPh), 5.15 (d, J ¼ 12.0 Hz, 1H, CHHPh), 4.32 (ddd, J ¼
J ¼ 12.6 Hz, CH2CH), 23.17 (d, J ¼ 2.0 Hz, NCH2CH2), 16.50 (d, J 10.1, 6.9, 3.7 Hz, 1H, CHCHP), 4.28–4.14 (m, 4H, 2 ꢂ OCH2CH3),
¼ 5.6 Hz, OCH2CH3), 16.36 (d, J ¼ 5.2 Hz, OCH2CH3). 31P{/1H} 3.83 (dd, J ¼ 9.4, 4.6 Hz, 1H, CHP), 3.53 (br q, J ¼ 7.9 Hz, 1H,
NMR (243 MHz, CDCl3) d ¼ 23.21 (s). HRMS (ESI) calcd for NCHH), 3.43 (ddd, J ¼ 11.0, 7.5, 4.7 Hz, 1H, NCHH), 2.26–2.21
C
16H27NO4P ([M + H]+): 328.1672, found: 328.1667.
(m, 1H, CHHCH), 2.08–2.03 (m, 1H, CHHCH), 1.96–1.90 (m, 1H,
NCH2CHH), 1.90–1.85 (m, 1H, NCH2CHH), 1.37 (br t, J ¼ 6.6 Hz,
Diethyl((S)-((S)-1-benzylpyrrolidin-2-yl)(hydroxy)methyl)
phosphonate (16b). d 1H NMR (400 MHz, CDCl3) d ¼ 7.48–7.43 6H, 2 ꢂ OCH2CH3). 13C NMR (101 MHz, CDCl3) d ¼ 158.65 (s,
(m, 1H, Ph), 7.38–7.29 (m, 2H, Ph), 7.30–7.25 (m, 2H, Ph), 4.59 C]O), 136.14, 128.54, 128.20, 127.96 (4 ꢂ s, Ph), 72.68 (d, J ¼
(s, 1H, OH), 4.36–4.25 (m, 4H, 2 ꢂ OCH2CH3), 4.26–4.16 (m, 1H, 159.4 Hz, CHP), 67.77 (s, CH2Ph), 63.14 (d, J ¼ 7.3 Hz,
CHP), 3.99 (d, J ¼ 13.5 Hz, 1H, CHHPh), 3.97 (d, J ¼ 6.2 Hz, 1H, OCH2CH3), 62.55 (d, J ¼ 7.0 Hz, OCH2CH3), 59.88 (d, J ¼ 8.9 Hz,
CHCHP), 3.82 (d, J ¼ 12.8 Hz, 1H, CHHPh), 3.38 (d, J ¼ 14.2 Hz, CHCHP), 46.96 (s, NCH2), 28.27 (s, CH2CH), 24.10 (s,
1H, NCHH), 3.05 (d, J ¼ 14.3 Hz, 1H, NCHH), 2.82 (td, J ¼ 9.0, NCH2CH2), 16.51 (d, J ¼ 6.1 Hz, OCH2CH3), 16.45 (d, J ¼ 5.7 Hz,
4.8 Hz, 1H, CHHCH), 2.35 (td, J ¼ 9.6, 6.0 Hz, 1H, CHHCH), OCH2CH3). 31P{/1H} NMR (162 MHz, CDCl3) d ¼ 21.22 (s). Minor
2.26–2.19 (m, 1H, NCH2CHH), 2.14 (ddd, J ¼ 13.2, 9.3, 3.2 Hz, rotamer: 31P{/1H} NMR (162 MHz, CDCl3) d ¼ 22.08 (s).
1H, NCH2CHH), 1.43 (s, 3H, OCH2CH3), 1.42 (s, 3H, OCH2CH3).
Diethyl((R)-((S)-3-benzyl-2,2-dimethyloxazolidin-4-yl)(hydroxy)
13C NMR (101 MHz, CDCl3) d ¼ 139.02, 128.69, 128.13, 127.17 (4 methyl)phosphonate (19a). Slightly yellow oil (269 mg, 40%): 1H
ꢂ s, Ph), 69.55 (d, J ¼ 166.8 Hz, CHP), 69.51 (d, J ¼ 5.0 Hz, NMR (600 MHz, CDCl3) d ¼ 7.35–7.31 (m, 4H, Ph), 7.30–7.26 (m,
CHCHP), 63.17 (d, J ¼ 7.2 Hz, OCH2CH3), 62.15 (d, J ¼ 6.8 Hz, 1H, Ph), 4.23–4.18 (m, 2H, OCH2CH3), 4.20 (dd, J ¼ 8.2, 3.8 Hz,
OCH2CH3), 52.22 (s, CH2Ph), 51.13 (s, NCH2), 30.18 (d, J ¼ 1H, CHP), 4.16 (“quintet”, J ¼ 7.0 Hz, 2H, OCH2CH3), 3.86 (d, J ¼
2.2 Hz, CH2CH), 20.93 (s, NCH2CH2), 16.61 (d, J ¼ 5.6 Hz, 14.3 Hz, 1H, CHHPh), 3.57 (d, J ¼ 14.3 Hz, 1H, CHHPh), 3.42–
OCH2CH3), 16.57 (d, J ¼ 5.7 Hz, OCH2CH3). 31P{/1H} NMR (243 3.40 (m, 1H, OCHH), 3.40–3.39 (m, 1H, CHCHP), 3.28 (dd, J ¼
MHz, CDCl3) d ¼ 24.22 (s).
11.9, 3.8 Hz, 1H, OCHH), 1.38 (s, 3H, C(CH3)2), 1.36 (t, J ¼
7.1 Hz, 3H, OCH2CH3), 1.33 (t, J ¼ 7.1 Hz, 3H, OCH2CH3), 1.32
Benzyl(R)-2-((S)-(diethoxyphosphoryl)(hydroxy)methyl)
pyrrolidine-1-carboxylate (18a). White solid (860 mg, 76%). (s, 3H, C(CH3)2). 13C NMR (151 MHz, CDCl3) d ¼ 139.38, 128.59,
Compound 18a is a mixture of two rotamers (3 : 1, r.r.). Major 127.84, 127.43 (4 ꢂ s, Ph), 98.14 (d, J ¼ 6.0 Hz, C(CH3)2), 72.09
rotamer: 1H NMR (400 MHz, CDCl3) d ¼ 7.39–7.29 (m, 5H, Ph), (d, J ¼ 170.1 Hz, CHP), 65.43 (d, J ¼ 4.4 Hz, CHCHP), 62.97 (d, J
5.18 (d, J ¼ 12.7 Hz, 1H, CHHPh), 5.12 (d, J ¼ 12.6 Hz, 1H, ¼ 7.0 Hz, OCH2CH3), 62.37 (d, J ¼ 6.8 Hz, OCH2CH3), 59.47 (d, J
CHHPh), 4.35 (br d, J ¼ 5.6 Hz, 1H, CHP), 4.26–4.14 (m, 5H, 2 ꢂ ¼ 2.9 Hz, OCH2), 52.63 (s, CH2Ph), 28.13 (s, C(CH3)2), 22.16 (s,
OCH2CH3, CHCHP), 3.64 (ddd, J ¼ 11.3, 7.9, 4.0 Hz, 1H, NCHH), C(CH3)2), 16.36 (d, J ¼ 5.7 Hz, OCH2CH3), 16.34 (d, J ¼ 5.5 Hz,
3.46–3.41 (m, 1H, NCHH), 2.35–2.25 (m, 1H, CHHCH), 2.13–2.04 OCH2CH3). 31P{/1H} NMR (243 MHz, CDCl3) d ¼ 22.36 (s). HRMS
(m, 1H, CHHCH), 2.04–1.96 (m, 1H, NCH2CHH), 1.77–1.70 (m, (ESI) calcd for C17H29NO5P ([M + H]+): 358.1778, found:
1H, NCH2CHH), 1.35 (t, J ¼ 7.1 Hz, 3H, OCH2CH3), 1.29 (t, J ¼ 358.1775.
7.1 Hz, 3H, OCH2CH3). 13C NMR (101 MHz, CDCl3) d ¼ 156.60
Diethyl((S)-((S)-3-benzyl-2,2-dimethyloxazolidin-4-yl)(hydroxy)
(s, C]O), 136.46, 128.49, 128.06, 127.88 (4 ꢂ s, Ph), 70.16 (d, J ¼ methyl)phosphonate (19b). Isolated as a mixture with 19a,
156.0 Hz, CHP), 67.19 (s, CH2Ph), 62.68 (d, J ¼ 7.2 Hz, which could not be separated by the chromatography tech-
1
OCH2CH3), 62.53 (d, J ¼ 6.8 Hz, OCH2CH3), 60.74 (d, J ¼ 5.4 Hz, niques employed in this study: H NMR (400 MHz, CDCl3) d ¼
CHCHP), 47.58 (s, NCH2), 27.51 (s, CH2CH), 24.54 (s, 7.34–7.25 (m, 4H, Ph), 7.27–7.18 (m, 1H, Ph), 4.16 (“quintet”, J ¼
NCH2CH2), 16.51–16.44 (m, 2 ꢂ OCH2CH3). 31P{/1H} NMR (162 7.0 Hz, 2H, OCH2CH3), 4.10 (“quintet”, J ¼ 7.0 Hz, 2H,
1
MHz, CDCl3) d ¼ 21.90 (s). Minor rotamer: H NMR (400 MHz, OCH2CH3), 4.02–3.96 (m, 2H, OCH2), 3.87 (d, J ¼ 13.9 Hz, 1H,
CDCl3) d ¼ 7.39–7.29 (m, 5H, Ph), 5.16 (d, J ¼ 12.7 Hz, 1H, CHHPh), 3.57 (d, J ¼ 13.8 Hz, 1H, CHHPh), 3.40–3.39 (m, 1H,
CHHPh), 5.11 (d, J ¼ 12.6 Hz, 1H, CHHPh), 4.45 (d, J ¼ 11.1 Hz, CHP), 3.39–3.37 (m, 1H, CHCHP), 1.31 (s, 3H, C(CH3)2), 1.28 (t, J
1H, CHP), 4.15–4.05 (m, 5H, 2 ꢂ OCH2CH3, CHCHP), 3.61–3.57 ¼ 7.1 Hz, 3H, OCH2CH3), 1.27 (s, 3H, C(CH3)2), 1.23 (t, J ¼
(m, 1H, NCHH), 3.46–3.41 (m, 1H, NCHH), 2.35–2.25 (m, 1H, 7.1 Hz, 3H, OCH2CH3). 13C NMR (151 MHz, CDCl3) d ¼ 139.13,
CHHCH), 2.13–2.04 (m, 1H, CHHCH), 2.04–1.96 (m, 1H, 128.56, 128.03, 127.44 (4 ꢂ s, Ph), 95.14 (s, C(CH3)2), 65.41 (d, J
NCH2CHH), 1.77–1.70 (m, 1H, NCH2CHH), 1.29 (t, J ¼ 7.1 Hz, ¼ 166.2 Hz, CHP), 63.68 (d, J ¼ 5.2 Hz, CHCHP), 63.37 (d, J ¼
3H, OCH2CH3), 1.24 (t, J ¼ 7.1 Hz, 3H, OCH2CH3). 13C NMR (101 1.3 Hz, OCH2), 62.66 (d, J ¼ 7.1 Hz, OCH2CH3), 62.27 (d, J ¼
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6.7 Hz, OCH2CH3), 53.12 (s, CH2Ph), 27.33 (s, C(CH3)2), 19.73 (s,
C(CH3)2), 16.26 (d, J ¼ 5.6 Hz, OCH2CH3), 16.20 (d, J ¼ 5.9 Hz,
OCH2CH3). 31P{/1H} NMR (243 MHz, CDCl3) d ¼ 21.86 (s).
Benzyl(S)-4-((R)-(diethoxyphosphoryl)(hydroxy)methyl)-
2,2-dimethyloxazolidine-3-carboxylate (21a). Pale yellow oil
(477 mg, 67%). Compound 21a is a mixture of two rotamers
(1.8 : 1, r.r.). Major rotamer: 1H NMR (600 MHz, CD3CN) d ¼
7.45–7.36 (m, 5H, Ph), 5.17–5.11 (m, 2H, CH2Ph), 4.36 (dd, J ¼
12.4, 7.2 Hz, 1H, CHP), 4.32 (br dd, J ¼ 9.2, 2.6 Hz, 1H, OCHH),
4.26–4.21 (m, 1H, CHCHP), 4.15–4.10 (m, 2H, OCH2CH3), 4.08–
3.96 (m, 3H, OCHH, OCH2CH3), 1.59 (s, 3H, C(CH3)2), 1.50 (s,
3H, C(CH3)2), 1.25 (t, J ¼ 7.1 Hz, 3H, OCH2CH3), 1.22 (t, J ¼
7.1 Hz, 3H, OCH2CH3). 13C NMR (151 MHz, CD3CN) d ¼ 153.54
(s, C]O), 138.28, 129.96, 129.45, 129.30 (4 ꢂ s, Ph), 95.44 (s,
C(CH3)2), 68.03 (d, J ¼ 159.9 Hz, CHP), 67.78 (s, CH2Ph), 64.80
(s, OCH2), 64.02 (d, J ¼ 7.0 Hz, OCH2CH3), 63.56 (d, J ¼ 6.9 Hz,
OCH2CH3), 59.04 (d, J ¼ 13.6 Hz, CHCHP), 26.33 (s, C(CH3)2),
24.16 (s, C(CH3)2), 17.27 (d, J ¼ 5.4 Hz, OCH2CH3), 17.25 (d, J ¼
Racemic mixture of (E)-3-(benzylamino)-4,4,4-triuorobut-1-
en-1-yl-diethyl phosphate (rac 22). Pale yellow oil (33 mg, 65%):
1H NMR (600 MHz, CDCl3) d ¼ 7.40–7.27 (m, 5H, Ph), 6.68 (dd, J
¼ 12.1, 6.7 Hz, 1H, OCH]CH), 5.33 (ddd, J ¼ 12.1, 9.0, 0.8 Hz,
1H, OCH]CH), 4.23–4.15 (m, 4H, 2 ꢂ OCH2CH3), 3.93 (d, J ¼
13.4 Hz, 1H, CHHPh), 3.79 (d, J ¼ 13.4 Hz, 1H, CHHPh), 3.53 (m,
1H, CHCF3), 1.38 (t, J ¼ 6.8 Hz, 3H, OCH2CH3), 1.37 (t, J ¼
6.7 Hz, 3H, OCH2CH3). 13C NMR (151 MHz, CDCl3) d ¼ 141.86
(d, J ¼ 5.2 Hz, OCH]CH), 138.71, 128.62, 128.13, 127.45 (4 ꢂ s,
Ph), 125.25 (q, J ¼ 281.7 Hz, CF3), 109.3 (d, J ¼ 10.5, 1.8 Hz,
OCH]CH), 64.74 (d, J ¼ 6.0 Hz, 2 ꢂ OCH2CH3), 50.56 (s,
CH2Ph), 16.07 (d, J ¼ 6.8 Hz, OCH2CH3), 16.06 (d, J ¼ 6.5 Hz,
OCH2CH3). 19F NMR (565 MHz, CDCl3) d ¼ ꢀ75.84 (d, J ¼ 6.9
Hz). 19F{/1H} NMR (565 MHz, CDCl3) d ¼ ꢀ75.84 (s). 31P{/1H}
NMR (243 MHz, CDCl3) d ¼ ꢀ5.02 (s). HRMS (ESI) calcd for
C
15H22F3NO4P ([M + H]+): 368.1239, found: 368.1236.
Note 1: An analogous reaction of 6a,b with K2CO3 (1.2 eq.) in
acetonitrile (reux, 8 h) according to the above procedure gave
22.
5.8 Hz, OCH2CH3). 31P{/1H} (243 MHz, CD3CN) d ¼ 21.72 (s). 31
P
1
{/1H} NMR (243 MHz, CDCl3) d ¼ 21.84 (s). Minor rotamer: H
NMR (600 MHz, CD3CN) d ¼ 7.45–7.36 (m, 5H, Ph), 5.20 (d, J ¼
12.5 Hz, 1H, CHHPh), 5.17–5.11 (m, 1H, CHHPh), 4.52 (dd, J ¼
11.4, 7.1 Hz, 1H, CHP), 4.28 (br dd, J ¼ 8.3, 3.3 Hz, 1H, OCHH),
4.26–4.21 (m, 1H, CHCHP), 4.15–4.10 (m, 1H, OCHH), 4.08–3.96
(m, 4H, 2 ꢂ OCH2CH3), 1.54 (s, 3H, C(CH3)2), 1.47 (s, 3H,
C(CH3)2), 1.25 (t, J ¼ 7.1 Hz, 3H, OCH2CH3), 1.22 (t, J ¼ 7.1 Hz,
3H, OCH2CH3). 13C NMR (151 MHz, CD3CN) d ¼ 154.32 (s, C]
O), 138.28, 129.96, 129.45, 129.30 (4 ꢂ s, Ph), 95.12 (s, C(CH3)2),
68.12 (s, CH2Ph), 66.70 (d, J ¼ 159.9 Hz, CHP), 64.33 (s, OCH2),
64.16 (d, J ¼ 7.1 Hz, OCH2CH3), 63.56 (d, J ¼ 6.9 Hz, OCH2CH3),
60.17 (d, J ¼ 12.7 Hz, CHCHP), 26.99 (s, C(CH3)2), 25.94 (s,
C(CH3)2), 17.27 (d, J ¼ 5.4 Hz, OCH2CH3), 17.20 (d, J ¼ 5.8 Hz,
Note 2: Reaction of 10a,b (19 : 1, d.r.) with K2CO3 (1.2 eq.) or
K2CO3 (1.2 eq.) and BzNH2 (1.2 eq.) or with K2CO3 (1.2 eq.) and
BnNH2 (1.2 eq.) in acetonitrile (reux, 8 h) according to the
above procedure gave a partially racemized mixture of 10a,b
(1.5 : 1, d.r.).
Note 3: Reaction of 20a,b (99 : 1, d.r.) with K2CO3 (1.2 eq.) or
K2CO3 (1.2 eq.) and BzNH2 (1.2 eq.) or with K2CO3 (1.2 eq.) and
BnNH2 (1.2 eq.) in acetonitrile (reux, 8 h) according to the
above procedure gave a partially racemized mixture of 20a,b
(3.6 : 1, d.r.).12
Procedure for the reactions of 6a,b–21a,b with TsNH2
OCH2CH3). 31P{/1H} NMR (243 MHz, CD3CN) d ¼ 22.04 (s). 31P To a solution of para-toluenesulfonamide (1.2 eq.) in acetoni-
{/1H} NMR (243 MHz, CDCl3) d ¼ 22.13 (s). HRMS (ESI) calcd for trile (5 mL), potassium carbonate (1.2 eq.) was added. Aer
C
18H28NO7PNa ([M + Na]+): 424.1496, found: 424.1495.
30 min, the a-hydroxyphosphonates 6a,b–21a,b (1 eq.) were
Benzyl(S)-4-((S)-(diethoxyphosphoryl)(hydroxy)methyl)-2,2- added to the stirred reaction mixture. The solution was reuxed
dimethyloxazolidine-3-carboxylate (21b). Detected in the crude for 8 hours. When the reaction was completed, the reaction
reaction mixture as one rotamer (not isolated, signals in NMR mixture was diluted with H2O (10 mL) and extracted with a few
overlapped by major diastereoisomer): 31P{/1H} NMR (243 MHz, portions of CH2Cl2. The organic layers were dried over MgSO4,
CD3CN) d ¼ 21.72 (s). 31P{/1H} NMR (243 MHz, CDCl3) d ¼ ltered and concentrated under reduced pressure. The crude
22.13 (s).
products 23a,b–39 were isolated using column chromatography
(chloroform/methanol or n-hexane/ethyl acetate
/ ethyl
acetate/methanol).
Racemic
mixture
of
diethyl((S)-((2R,3S)-1-benzyl-
Procedure for reactions of 6a,b, 10a,b and 20a,b with nitrogen
nucleophiles (BnNH2, MeNH2, BzNH2) and/or with K2CO3
3-(triuoromethyl)aziridin-2-yl)((4-methylphenyl)sulfonamido)
methyl)phosphonate (rac 23a). Pale yellow oil, slowly crystal-
To a solution of benzylamine or methylamine (HCl salt) or lising (44 mg, 75%): 1H NMR (400 MHz, CDCl3) d ¼ 7.69 (d, J ¼
benzamide (1.2 eq.) in acetonitrile (5 mL), potassium carbonate 8.3 Hz, 2H, Ar), 7.30–7.10 (m, 7H, Ph, Ar), 6.30 (br s, 1H, NHSO2),
(1.2 eq. or 2.2 eq. in the case of methylamine HCl) was added. 4.30 (d, J ¼ 13.6 Hz, 1H, CHHPh), 4.18–3.95 (m, 4H, 2 ꢂ
Aer 30 min, the a-hydroxyphosphonates (1 eq.) were added to OCH2CH3), 3.76 (dt, J ¼ 17.8, 8.7 Hz, 1H, CHP), 2.94 (d, J ¼
the stirred solution. The reaction mixture was reuxed for 8 h. 13.6 Hz, 1H, CHHPh), 2.31 (s, 3H, ArCH3), 2.12 (br t, J ¼ 6.5 Hz,
When the reaction was completed, water was added (10 mL) 1H, CHCHCF3), 1.91 (“quintet”, J ¼ 5.8 Hz, 1H, CHCF3), 1.25 (t, J
followed by extraction with a few portions of CH2Cl2. The ¼ 7.0 Hz, 3H, OCH2CH3), 1.22 (t, J ¼ 7.0 Hz, 3H, OCH2CH3). 13
C
organic layers were dried over MgSO4, ltered and concentrated NMR (101 MHz, CDCl3) d ¼ 143.31, 138.08, 135.94, 129.39,
under reduced pressure. The crude products were isolated 128.58, 128.46, 127.69, 127.08 (8 ꢂ s, Ar, Ph), 124.12 (q, J ¼
using column chromatography (chloroform/methanol or n- 274.5 Hz, CF3), 63.66 (d, J ¼ 7.2 Hz, OCH2CH3), 63.31 (d, J ¼
hexane/ethyl acetate / ethyl acetate/methanol).
6.9 Hz, OCH2CH3), 61.98 (s, CH2Ph), 47.95 (d, J ¼ 153.7 Hz,
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CHP), 42.74 (d, J ¼ 3.9 Hz, CHCHCF3), 40.93 (dq, J ¼ 38.6, 2.39 (s, 3H, ArCH3), 1.17 (t, J ¼ 7.2 Hz, 3H, OCH2CH3), 1.14 (t, J ¼
12.0 Hz, CHCF3), 21.50 (s, ArCH3), 16.33 (d, J ¼ 6.0 Hz, 2 ꢂ 7.1 Hz, 3H, OCH2CH3). 13C NMR (101 MHz, CDCl3) d ¼ 142.89,
OCH2CH3). 19F NMR (565 MHz, CDCl3) d ¼ ꢀ65.85 (d, J ¼ 5.8 139.09, 138.97, 136.84, 129.51, 129.38, 128.87, 128.40, 128.31,
Hz). 19F{/1H} NMR (565 MHz, CDCl3) d ¼ ꢀ65.85 (s). 31P{/1H} 127.18, 127.11, 126.17 (12 ꢂ s, Ar, Ph), 63.44 (d, J ¼ 2.9 Hz,
NMR (243 MHz, CDCl3) d ¼ 20.79 (s). HRMS (ESI) calcd for CHCH2Ph), 63.08 (d, J ¼ 7.7 Hz, OCH2CH3), 62.38 (d, J ¼ 6.7 Hz,
C
22H28F3N2O5PS ([M + H]+): 521.1487, found: 521.1500.
Racemic mixture of
(triuoromethyl)aziridin-2-yl)((4-methylphenyl)sulfonamido)
OCH2CH3), 54.50 (s, NHCH2Ph), 48.66 (d, J ¼ 154.1 Hz, CHP),
diethyl((R)-((2R,3S)-1-benzyl-3- 31.46 (s, CHHPh), 21.50 (s, ArCH3), 16.20 (d, J ¼ 5.2 Hz,
OCH2CH3), 16.18 (d, J ¼ 6.0 Hz, OCH2CH3). 31P{/1H} NMR (162
methyl)phosphonate (rac 23b). Pale yellow oil slowly crystallis- MHz, CDCl3) d ¼ 22.27 (s). HRMS (ESI) calcd for C34H42N2O5PS
ing (7 mg, 12%): H NMR (400 MHz, CDCl3) d ¼ 7.74 (d, J ¼ ([M + H]+): 621.2552, found: 621.2560.
1
8.1 Hz, 2H, Ar), 7.30–6.90 (m, 7H, Ph, Ar), 5.52 (br s, 1H, NHSO2),
tert-Butyl((1R,2S)-1-(diethoxyphosphoryl)-1-((4-methylphenyl)
4.25–4.00 (m, 4H, 2 ꢂ OCH2CH3), 3.83 (“quintet”, J ¼ 9.5 Hz, sulfonamido)-3-phenylpropan-2-yl)carbamate (27a). White solid
1H, CHP), 3.44 (d, J ¼ 13.4 Hz, 1H, CHHPh), 2.63 (d, J ¼ 13.5 Hz, (37 mg, 72%): 1H NMR (600 MHz, CD3CN) d ¼ 7.89–7.78 (d, J ¼
1H, CHHPh), 2.18 (s, 3H, ArCH3), 2.10–2.02 (m, 1H, CHCHCF3), 8.0 Hz, 2H, Ar), 7.40 (d, J ¼ 8.0 Hz, 2H, Ar), 7.26–7.15 (m, 3H, Ar),
1.98 (“quintet”, J ¼ 6.1 Hz, 1H, CHCF3), 1.29 (t, J ¼ 7.1 Hz, 3H, 7.03–6.93 (d, J ¼ 6.8 Hz, 2H, Ar), 6.41 (br s, 1H, NHSO2), 5.41 (d, J
OCH2CH3), 1.25 (t, J ¼ 7.1 Hz, 3H, OCH2CH3). 13C NMR (151 ¼ 9.4 Hz, 1H, NHBoc), 4.27–3.87 (m, 6H, 2 ꢂ OCH2CH3, CHP,
MHz, CDCl3) d ¼ 143.43, 138.30, 136.11, 129.45, 128.28, 128.10, CHCH2Ph), 2.88 (dd, J ¼ 13.9, 3.4 Hz, 1H, CHHPh), 2.60 (dd, J ¼
127.49, 127.41 (8 ꢂ s, Ar, Ph), 124.05 (q, J ¼ 274.2 Hz, CF3), 64.59 13.9, 10.6 Hz, 1H, CHHPh), 2.44 (s, 3H, ArCH3), 1.31 (s, 9H,
(d, J ¼ 7.0 Hz, OCH2CH3), 62.90 (d, J ¼ 6.6 Hz, OCH2CH3), 62.61 C(CH3)3), 1.27 (t, J ¼ 7.1 Hz, 3H, OCH2CH3), 1.22 (t, J ¼ 7.1 Hz,
(s, CH2Ph), 49.98 (dd, J ¼ 157.8, 1.6 Hz, CHP), 43.29 (d, J ¼ 3H, OCH2CH3). 13C NMR (101 MHz, CDCl3) d ¼ 155.56 (s, C]O),
11.4 Hz, CHCHCF3), 42.58 (q, J ¼ 39.1 Hz, CHCF3), 21.38 (s, 143.40, 138.02, 137.54, 129.53, 129.36, 128.35, 127.17, 126.46 (8
ArCH3), 16.43 (d, J ¼ 5.8 Hz, OCH2CH3), 16.15 (d, J ¼ 5.7 Hz, ꢂ s, Ar, Ph), 79.58 (s, C(CH3)3), 63.15–62.87 (m, 2ꢂ OCH2CH3),
OCH2CH3). 19F NMR (376 MHz, CDCl3) d ¼ ꢀ65.68 (d, J ¼ 6.1 53.37 (d, J ¼ 153.7 Hz, CHP), 52.25 (s, CHCH2Ph), 37.94 (s,
Hz). 19F{/1H} NMR (565 MHz, CDCl3) d ¼ ꢀ65.69 (s). 31P{/1H} CH2Ph), 28.20 (s, C(CH3)3), 21.49 (s, ArCH3), 16.35 (d, J ¼ 5.7 Hz,
NMR (162 MHz, CDCl3) d ¼ 19.55 (s). HRMS (ESI) calcd for OCH2CH3), 16.24 (d, J ¼ 5.8 Hz, OCH2CH3). 31P{/1H} NMR (162
C
22H28F3N2O5PSNa ([M + Na]+): 543.1306, found: 543.1290.
Racemic mixture of diethyl((S)-((4-methylphenyl)sulfonami- PSNa ([M + Na]+): 563.1957, found: 563.1954.
do)((2R,3S)-3-(triuoromethyl)aziridin-2-yl)methyl) tert-Butyl((1S,2S)-1-(diethoxyphosphoryl)-1-((4-methylphenyl)
MHz, CDCl3) d ¼ 21.41 (s). HRMS (ESI) calcd for C25H37N2O7-
phosphonate (rac 24a). Pale yellow oil, isolated as a mixture sulfonamido)-3-phenylpropan-2-yl)carbamate (27b). White solid,
with rac 24b, which could not be separated by the chromatog- isolated as a mixture with 27a, which could not be separated by
raphy techniques employed in this study (35 mg, 80%): 1H NMR the chromatography techniques employed in this study (3 mg,
(600 MHz, CDCl3) d ¼ 7.77 (d, J ¼ 8.3 Hz, 2H, Ar), 7.27 (d, J ¼ 6%): 1H NMR (400 MHz, CDCl3) d ¼ 7.59 (d, J ¼ 8.0 Hz, 2H, Ar),
8.3 Hz, 2H, Ar), 6.30 (br s, 1H, NHSO2), 4.22–4.02 (m, 4H, 2 ꢂ 7.26–7.19 (m, 5H, Ar), 6.96 (dd, J ¼ 6.7, 2.8 Hz, 2H, Ar), 6.02–5.93
OCH2CH3), 3.76 (dt, J ¼ 18.2, 8.6 Hz, 1H, CHP), 2.67–2.55 (m, (br d, 1H, NHSO2), 5.18 (d, J ¼ 8.6 Hz, 1H, NHBoc), 4.25–4.06 (m,
2H, CHCHCF3, CHCF3), 2.42 (s, 3H, ArCH3), 1.32 (t, J ¼ 7.1 Hz, 4H, 2 ꢂ OCH2CH3), 3.83–3.62 (m, 2H, CHP, CHCH2Ph), 2.96
3H, OCH2CH3), 1.27 (t, J ¼ 7.1 Hz, 3H, OCH2CH3). 13C NMR (151 (dd, J ¼ 13.9, 7.6 Hz, 1H, CHHPh), 2.73 (dd, J ¼ 14.0, 8.0 Hz, 1H,
MHz, CDCl3) d ¼ 143.25, 138.28, 129.36, 126.98 (4 ꢂ s, Ar), CHHPh), 2.42 (s, 3H, ArCH3), 1.39 (s, 9H, C(CH3)3), 1.36–1.27 (m,
124.29 (q, J ¼ 274.8 Hz, CF3), 63.65 (d, J ¼ 7.3 Hz, OCH2CH3), 6H, 2 ꢂ OCH2CH3). 13C NMR (101 MHz, CDCl3) d ¼ 156.10 (s,
63.50 (d, J ¼ 6.8 Hz, OCH2CH3), 48.28 (d, J ¼ 154.9 Hz, CHP), C]O), 143.44, 137.17, 137.04, 129.76, 129.08, 128.50, 127.25,
35.15 (br s, CHCHCF3), 34.16 (dq, J ¼ 39.6, 13.2 Hz, CHCF3), 126.63 (8 ꢂ s, Ar, Ph), 79.95 (s, C(CH3)3), 64.08 (d, J ¼ 7.4 Hz,
21.51 (s, ArCH3), 16.30 (d, J ¼ 7.3 Hz, OCH2CH3), 16.26 (d, J ¼ OCH2CH3), 62.82 (d, J ¼ 6.7 Hz, OCH2CH3), 53.39 (d, J ¼
6.8 Hz, OCH2CH3). 19F NMR (376 MHz, CDCl3) d ¼ ꢀ67.10 (d, J 159.1 Hz, CHP), 51.92 (s, CHCH2Ph), 38.07 (s, CH2Ph), 28.27 (s,
¼ 5.9 Hz). 19F{/1H} NMR (376 MHz, CDCl3) d ¼ ꢀ67.10 (s). 31P C(CH3)3), 21.55 (s, ArCH3), 16.43 (d, J ¼ 5.6 Hz, OCH2CH3), 16.30
{/1H} NMR (162 MHz, CDCl3) d ¼ 21.08 (s). HRMS (ESI) calcd for (d, J ¼ 6.1 Hz, OCH2CH3). 31P{/1H} NMR (162 MHz, CDCl3) d ¼
C
15H22F3N2O5PSNa ([M + Na]+): 453.0837, found: 453.0839.
20.34 (s). HRMS (ESI) calcd for C25H37N2O7PSNa ([M + Na]+):
Racemic mixture of diethyl((R)-((4-methylphenyl)sulfona- 563.1957, found: 563.1964.
mido)((2R,3S)-3-(triuoromethyl)aziridin-2-yl)methyl)
Benzyl((1R,2S)-1-(diethoxyphosphoryl)-1-((4-methylphenyl)
phosphonate (rac 24b). 19F NMR (376 MHz, CDCl3) d ¼ ꢀ66.98 sulfonamido)-3-phenylpropan-2-yl)carbamate (28a). White
(d, J ¼ 6.2 Hz). 19F{/1H} NMR (376 MHz, CDCl3) d ¼ ꢀ66.98 (s). solid, isolated as a mixture with 28b, which could not be sepa-
31P{/1H} NMR (162 MHz, CDCl3) d ¼ 19.60 (s).
rated by the chromatography techniques employed in this study
(26 mg, 40%): 1H NMR (600 MHz, CDCl3) d ¼ 7.75 (d, J ¼ 7.9 Hz,
Pale 2H, Ar), 7.38–7.01 (m, 12H, Ar, Ph), 5.76 (s, 1H, NHSO2), 5.31 (d,
Diethyl((1R,2S)-2-(dibenzylamino)-1-((4-methylphenyl)
sulfonamido)-3-phenylpropyl)phosphonate
(26a).
yellow solid (42 mg, 81%): 1H NMR (400 MHz, CDCl3) d ¼ 7.32– J ¼ 9.6 Hz, 1H, NHCbz), 5.00 (d, J ¼ 12.4 Hz, 1H, OCHHPh), 4.97
7.03 (m, 19H, Ar, Ph), 5.28 (dd, J ¼ 9.2, 1.9 Hz, 1H, NHSO2), (d, J ¼ 12.4 Hz, 1H, OCHHPh), 4.22–4.11 (m, 1H, CHCH2Ph),
4.13–3.74 (m, 6H, 2 ꢂ OCH2CH3, NHCH2Ph), 3.61–3.45 (m, 3H, 4.12–3.92 (m, 5H, 2 ꢂ OCH2CH3, CHP), 2.96 (dd, J ¼ 14.0,
CHP, NHCH2Ph), 3.24 (dd, J ¼ 13.3, 9.7 Hz, 1H, CHHPh), 3.14– 5.1 Hz, 1H, CHHPh), 2.81 (dd, J ¼ 14.1, 9.3 Hz, 1H, CHHPh),
2.94 (m, 1H, CHCH2Ph), 2.80 (dd, J ¼ 13.3, 5.6 Hz, 1H, CHHPh), 2.40 (s, 3H, ArCH3), 1.26–1.18 (m, 6H, 2 ꢂ OCH2CH3). 13C NMR
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(151 MHz, CDCl3) d ¼ 156.11 (s, C]O), 143.56, 139.10, 137.99, Could not be separated by the chromatography techniques
137.23, 136.36, 129.69, 129.63, 129.23, 128.41, 127.88, 127.14, employed in this study, detected in the crude reaction mixture:
126.46 (12 ꢂ s, Ar, Ph), 66.67 (s, OCH2Ph), 63.16 (d, J ¼ 6.7 Hz, 31P{/1H} NMR (162 MHz, CDCl3) d ¼ 20.24 (s).
OCH2CH3), 63.12 (d, J ¼ 7.0 Hz, OCH2CH3), 53.20 (d, J ¼
tert-Butyl (S)-2-((R)-(diethoxyphosphoryl)(4-methylphenyl-
152.8 Hz, CHP), 52.73 (s, CHCH2Ph), 37.66 (s, CH2Ph), 21.51 (s, sulfonamido)methyl)pyrrolidine-1-carboxylate (33a). Trans-
ArCH3), 16.32 (d, J ¼ 5.6 Hz, OCH2CH3), 16.20 (d, J ¼ 5.9 Hz, parent oil, slowly crystallising, isolated as a mixture with 33b,
OCH2CH3). 31P{/1H} NMR (243 MHz, CDCl3) d ¼ 20.97 (s). HRMS which could not be separated by the chromatography tech-
(ESI) calcd for C28H36N2O7PS ([M + H]+): 575.1981, found: niques employed in this study (68 mg, 59%). Compound 33a is
575.1980.
ꢁ
a mixture of two rotamers (1.5 : 1, r.r.), mp. 119–121 C. Major
rotamer: 1H NMR (400 MHz, CDCl3) d ¼ 7.76 (d, J ¼ 8.1 Hz, 2H,
Benzyl((1S,2S)-1-(diethoxyphosphoryl)-1-((4-methylphenyl)
sulfonamido)-3-phenylpropan-2-yl)carbamate (28b). 31P{/1H} Ar), 7.27 (d, J ¼ 8.1 Hz, 2H, Ar), 4.30 (dd, J ¼ 21.4, 0.9 Hz, 1H,
NMR (243 MHz, CDCl3) d ¼ 19.66 (s).
CHP), 4.18–4.05 (m, 4H, 2 ꢂ OCH2CH3), 4.04–3.91 (m, 1H,
tert-Butyl
((1R,2S)-1-(diethoxyphosphoryl)-3-methyl-1-((4- CHCHP), 3.13–2.96 (m, 2H, NCH2), 2.41 (s, 3H, ArCH3), 2.10–
methylphenyl)sulfonamido)butan-2-yl)carbamate (30a). Pale 1.98 (m, 1H, CHHCH), 1.98–1.81 (m, 2H, NCH2CHH, CHHCH),
yellow oil, slowly crystallising (37 mg, 51%): 1H NMR (600 MHz, 1.64–1.58 (m, 1H, NCH2CHH), 1.48 (s, 9H, C(CH3)3), 1.33 (t, J ¼
CDCl3) d ¼ 7.77 (d, J ¼ 8.1 Hz, 2H, Ar), 7.29 (d, J ¼ 8.2 Hz, 2H, 7.2 Hz, 3H, OCH2CH3), 1.31 (t, J ¼ 7.2 Hz, 3H, OCH2CH3). 13C
Ar), 5.83 (dd, J ¼ 9.4, 4.6 Hz, 1H, NHSO2), 4.85 (d, J ¼ 10.1 Hz, NMR (101 MHz, CDCl3) d ¼ 155.34 (s, C]O), 142.95, 138.36,
1H, NHBoc), 4.07–3.86 (m, 4H, 2 ꢂ OCH2CH3), 3.84 (ddd, J ¼ 129.44, 127.18 (4 ꢂ s, Ar), 79.66 (s, C(CH3)3), 62.74 (d, J ¼ 6.8 Hz,
18.9, 9.1, 5.4 Hz, 1H, CHP), 3.67 (ddd, J ¼ 13.2, 10.6, 6.8 Hz, 1H, 2 ꢂ OCH2CH3), 58.26 (d, J ¼ 8.1 Hz, CHCHP), 52.25 (d, J ¼
CHCH(CH3)2), 2.42 (s, 3H, ArCH3), 2.04 (sep, J ¼ 6.8 Hz, 1H, 150.5 Hz, CHP), 47.10 (s, NCH2), 28.47 (s, C(CH3)3), 27.99 (s,
CH(CH3)2), 1.43 (s, 9H, C(CH3)3), 1.21 (t, J ¼ 7.1 Hz, 6H, 2 ꢂ CH2CH), 24.38 (s, NCH2CH2), 21.47 (s, ArCH3), 16.52–16.22 (m,
OCH2CH3), 0.95 (d, J ¼ 6.6 Hz, 3H, CH3), 0.88 (d, J ¼ 6.8 Hz, 3H, 2 ꢂ OCH2CH3). 31P{/1H} NMR (162 MHz, CDCl3) d ¼ 21.03 (s).
CH3). 13C NMR (151 MHz, CDCl3) d ¼ 156.43 (s, C]O), 143.23, Minor rotamer: 1H NMR (400 MHz, CDCl3): d ¼ 7.68 (d, J ¼
138.29, 129.38, 127.09 (4 ꢂ s, Ar), 79.58 (s, C(CH3)3), 62.87 (d, J ¼ 8.1 Hz, 2H, Ar), 7.27 (d, J ¼ 8.1 Hz, 2H, Ar), 4.60 (dd, J ¼ 22.9,
7.1 Hz, 2 ꢂ OCH2CH3), 56.03 (d, J ¼ 5.9 Hz, CHCH(CH3)2), 52.09 1.4 Hz, 1H, CHP), 4.04–3.91 (m, 4H, 2 ꢂ OCH2CH3), 3.93–3.86
(d, J ¼ 155.7 Hz, CHP), 29.21 (d, J ¼ 7.4 Hz, CH(CH3)2), 28.30 (s, (m, 1H, CHCHP), 3.86–3.79 (m, 1H, NCHH), 3.36–3.25 (m, 1H,
C(CH3)3), 21.48 (s, ArCH3), 20.38 (s, CH3), 17.45 (s, CH3), 16.32 NCHH), 2.41 (br s, 3H, ArCH3), 2.23–2.10 (m, 1H, CHHCH),
(d, J ¼ 5.7 Hz, OCH2CH3), 16.23 (d, J ¼ 5.7 Hz, OCH2CH3). 31P 1.98–1.81 (m, 2H, NCH2CHH, CHHCH), 1.64–1.58 (m, 1H,
{/1H} NMR (243 MHz, CDCl3) d ¼ 22.29 (s). HRMS (ESI) calcd for NCH2CHH), 1.55 (s, 9H, C(CH3)3), 1.26 (t, J ¼ 7.2 Hz, 3H,
C
21H37N2O7PSNa ([M + Na]+): 515.1957, found: 515.1952.
OCH2CH3), 1.19 (t, J ¼ 7.1 Hz, 3H, OCH2CH3). 13C NMR (101
tert-Butyl((1S,2S)-1-(diethoxyphosphoryl)-3-methyl-1-((4- MHz, CDCl3) d ¼ 153.67 (s, C]O), 142.86, 138.91, 129.53, 126.58
methylphenyl)sulfonamido)butan-2-yl)carbamate
(30b). (4 ꢂ s, Ar), 80.48 (s, C(CH3)3), 63.02 (d, J ¼ 7.4 Hz, 2 ꢂ
Could not be separated by the chromatography techniques OCH2CH3), 57.03 (d, J ¼ 14.0 Hz, CHCHP), 52.17 (d, J ¼
employed in this study, detected in the crude reaction mixture. 147.0 Hz, CHP), 46.01 (s, NCH2), 28.45 (s, C(CH3)3), 27.31 (s,
31P{/1H} NMR (162 MHz, CDCl3) d ¼ 20.58 (s).
CH2CH), 23.92 (s, NCH2CH2), 21.47 (s, ArCH3), 16.52–16.22 (m,
2 ꢂ OCH2CH3). 31P{/1H} NMR (162 MHz, CDCl3) d ¼ 21.54 (s).
Benzyl((1R,2S)-1-(diethoxyphosphoryl)-3-methyl-1-((4-
methylphenyl)sulfonamido)butan-2-yl)carbamate
Pale yellow oil, slowly crystallising (26 mg, 42%): H NMR (400 491.1986.
(31a). HRMS (ESI) calcd for C21H36N2O7PS ([M + H]+): 491.1975, found:
1
MHz, CDCl3) d ¼ 7.75 (d, J ¼ 8.3 Hz, 2H, Ar), 7.35 (m, 4H, Ph),
tert-Butyl(S)-2-((S)-(diethoxyphosphoryl)(4-methylphenyl-
7.28–7.22 (m, 3H, Ph, Ar), 5.83 (dd, J ¼ 9.3, 4.6 Hz, 1H, NHSO2), sulfonamido)methyl)pyrrolidine-1-carboxylate (33b). Mixture
5.22 (d, J ¼ 9.9 Hz, 1H, NHCbz), 5.13 (d, J ¼ 12.3 Hz, 1H, of two rotamers (2.2 : 1, r.r.). Major rotamer: 1H NMR (400 MHz,
OCHHPh), 5.02 (d, J ¼ 12.3 Hz, 1H, OCHHPh), 4.07–3.80 (m, 5H, CDCl3) d ¼ 7.73 (d, J ¼ 8.1 Hz, 2H, Ar), 7.27 (d, J ¼ 8.1 Hz, 2H,
2 ꢂ OCH2CH3, CHP), 3.82–3.68 (m, 1H, CHCH(CH3)2), 2.39 (s, Ar), 4.18–4.05 (m, 5H, 2 ꢂ OCH2CH3, CHP), 3.55 (dd, J ¼ 14.6,
3H, ArCH3), 2.06 (sep, J ¼ 6.8 Hz, 1H, CH(CH3)2), 1.19 (t, J ¼ 10.4 Hz, 1H, CHCHP), 3.36–3.25 (m, 1H, NCHH), 2.79–2.71 (m,
6.0 Hz, 3H, OCH2CH3), 1.18 (t, J ¼ 8.0 Hz, 3H, OCH2CH3), 0.95 1H, NCHH), 2.41 (s, 3H, ArCH3), 2.23–2.10 (m, 1H, CHHCH),
(d, J ¼ 6.6 Hz, 3H, CH3), 0.86 (d, J ¼ 6.8 Hz, 3H, CH3). 13C NMR 1.81–1.74 (m, 1H, NCH2CHH), 1.64–1.58 (m, 2H, CHHCH,
(101 MHz, CDCl3) d ¼ 156.98 (s, C]O), 143.29, 138.26, 136.43, NCH2CHH), 1.46 (s, 9H, C(CH3)3), 1.26 (t, J ¼ 7.2 Hz, 3H,
129.41, 128.45, 128.03, 127.98, 127.02 (8 ꢂ s, Ar, Ph), 66.89 (s, OCH2CH3), 1.19 (t, J ¼ 7.1 Hz, 3H, OCH2CH3). 13C NMR (101
OCH2Ph), 62.95 (d, J ¼ 7.5 Hz, OCH2CH3), 62.93 (d, J ¼ 6.9 Hz, MHz, CDCl3) d ¼ 157.30 (s, C]O), 142.90, 138.45, 129.37, 127.07
OCH2CH3), 56.62 (d, J ¼ 5.9 Hz, CHCH(CH3)2), 52.06 (d, J ¼ (4 ꢂ s, Ar), 80.05 (s, C(CH3)3), 62.50 (d, J ¼ 6.8 Hz, 2 ꢂ
155.4 Hz, CHP), 29.12 (d, J ¼ 6.9 Hz, CH(CH3)2), 21.47 (s, OCH2CH3), 56.62 (d, J ¼ 11.1 Hz, CHCHP), 55.13 (d, J ¼
ArCH3), 20.39 (s, CCH3), 17.45 (s, CCH3), 16.28 (d, J ¼ 6.0 Hz, 156.8 Hz, CHP), 46.55 (s, NCH2), 29.47 (s, CH2CH), 28.41 (s,
OCH2CH3), 16.21 (d, J ¼ 6.1 Hz, OCH2CH3). 31P{/1H} NMR (162 C(CH3)3), 23.38 (s, NCH2CH2), 21.47 (s, ArCH3), 16.52–16.22 (m,
MHz, CDCl3) d ¼ 21.79 (s). HRMS (ESI) calcd for C24H36N2O7PS 2 ꢂ OCH2CH3). 31P{/1H} NMR (162 MHz, CDCl3) d ¼ 21.27 (s).
([M + H]+): 527.1981, found: 527.1978.
Minor rotamer: 31P{/1H} NMR (162 MHz, CDCl3) d ¼ 21.40 (s).
Racemic mixture of benzyl (R)-2-((S)-(diethoxyphosphoryl)(4-
Benzyl((1S,2S)-1-(diethoxyphosphoryl)-3-methyl-1-((4-
methylphenyl)sulfonamido)butan-2-yl)carbamate (31b). methylphenylsulfonamido)methyl)pyrrolidine-1-carboxylate
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126.69 (8 ꢂ s, Ar, Ph), 67.38 (s, CH2Ph), 63.48 (d, J ¼ 7.5 Hz,
OCH2CH3), 62.63 (d, J ¼ 6.9 Hz, OCH2CH3), 57.26 (d, J ¼
11.1 Hz, CHCHP), 55.15 (d, J ¼ 156.3 Hz, CHP), 46.40 (s, NCH2),
29.20 (s, CH2CH), 23.37 (s, NCH2CH2), 21.38 (s, ArCH3), 16.21 (d,
J ¼ 6.1 Hz, 2 ꢂ OCH2CH3). 31P{/1H} NMR (162 MHz, CDCl3) d ¼
20.49 (s). Minor rotamer: 31P{/1H} NMR (162 MHz, CDCl3) d ¼
20.88 (s).
(rac 34a). Transparent oil, slowly crystallising (60 mg, 75%).
Isolated as a mixture with rac 34b, which could not be separated
by the chromatography techniques employed in this study.
Compound rac 34a is a mixture of two rotamers (2.5 : 1, r.r.),
mp. 136–138 ꢁC. Major rotamer: 1H NMR (600 MHz, CDCl3) d ¼
7.74 (d, J ¼ 8.3 Hz, 2H, Ar), 7.42–7.35 (m, 5H, Ph), 7.22 (d, J ¼
8.3 Hz, 2H, Ar), 6.35 (br s, 1H, NH), 5.16 (d, J ¼ 12.4 Hz, 1H,
CHHPh), 5.12 (d, J ¼ 12.5 Hz, 1H, CHHPh), 4.36 (dd, J ¼ 22.1,
9.8 Hz, 1H, CHP), 4.17–4.09 (m, 2H, OCH2CH3), 4.07–4.00 (m,
2H, OCH2CH3), 3.97–3.91 (m, 1H, CHCHP), 3.43 (ddd, J ¼ 12.0,
7.8, 4.7 Hz, 1H, NCHH), 3.15–3.11 (m, 1H, NCHH), 2.36 (br s,
3H, ArCH3), 2.13–2.07 (m, 1H, CHHCH), 2.01–1.94 (m, 1H,
CHHCH), 1.92–1.88 (m, 1H, NCH2CHH), 1.66–1.59 (m, 1H,
NCH2CHH), 1.30 (t, J ¼ 7.2 Hz, 3H, OCH2CH3), 1.21 (t, J ¼
7.1 Hz, 3H, OCH2CH3). 13C NMR (101 MHz, CDCl3) d ¼ 155.61
(s, C]O), 143.05, 138.3, 136.63, 129.48, 128.45, 127.96, 127.83,
127.04 (8 ꢂ s, Ar, Ph), 66.93 (s, CH2Ph), 63.17 (d, J ¼ 7.3 Hz,
OCH2CH3), 62.89 (d, J ¼ 7.0 Hz, OCH2CH3), 58.73 (d, J ¼ 8.8 Hz,
CHCHP), 51.94 (d, J ¼ 150.4 Hz, CHP), 46.89 (s, NCH2), 27.87 (s,
CH2CH), 24.45 (s, NCH2CH2), 21.44 (s, ArCH3), 16.30 (d, J ¼
5.9 Hz, 2 ꢂ OCH2CH3). 31P{/1H} NMR (162 MHz, CDCl3) d ¼
20.49 (s). Minor rotamer: 1H NMR (600 MHz, CDCl3) d ¼ 7.57 (d,
J ¼ 8.0 Hz, 2H, Ar), 7.42–7.35 (m, 5H, Ph), 7.22 (d, J ¼ 8.0 Hz, 2H,
Ar), 5.55 (dd, J ¼ 9.7, 6.9 Hz, 1H, NH), 5.23 (d, J ¼ 12.0 Hz, 1H,
CHHPh), 5.12 (d, J ¼ 12.0 Hz, 1H, CHHPh), 4.49 (ddd, J ¼ 22.5,
9.7, 2.0 Hz, 1H, CHP), 4.24–4.20 (m, 2H, OCH2CH3), 4.00–3.91
(m, 2H, OCH2CH3), 3.92–3.87 (m, 1H, CHCHP), 3.27 (dt, J ¼ 9.8,
6.6 Hz, 1H, NCHH), 2.61 (dt, J ¼ 10.7, 6.8 Hz, 1H, NCHH), 2.41
(s, 3H, ArCH3), 2.28–2.20 (m, 1H, CHHCH), 2.00–1.94 (m, 1H,
CHHCH), 1.92–1.88 (m, 1H, NCH2CHH), 1.66–1.59 (m, 1H,
NCH2CHH), 1.25 (t, J ¼ 7.1 Hz, 3H, OCH2CH3), 1.19 (t, J ¼
7.0 Hz, 3H, OCH2CH3). 13C NMR (101 MHz, CDCl3) d ¼ 154.15
(s, C]O), 143.00, 138.56, 136.16, 129.48, 128.53, 127.96, 127.83,
126.65 (8 ꢂ s, Ar, Ph), 67.43 (s, CH2Ph), 63.17 (d, J ¼ 7.3 Hz,
OCH2CH3), 62.89 (d, J ¼ 7.0 Hz, OCH2CH3), 57.13 (d, J ¼
13.7 Hz, CHCHP), 51.71 (d, J ¼ 146.6 Hz, CHP), 46.40 (s, NCH2),
27.60 (s, CH2CH), 23.94 (s, NCH2CH2), 21.50 (s, ArCH3), 16.48 (d,
J ¼ 5.6 Hz, 2 ꢂ OCH2CH3). 31P{/1H} NMR (162 MHz, CDCl3) d ¼
20.71 (s). HRMS (ESI) calcd for C24H34N2O7PS ([M + H]+):
525.1819, found: 525.1834.
Racemic
mixture
of
tert-butyl(S)-4-((R)-(diethox-
yphosphoryl)(4-methylphenylsulfonamido)methyl)-2,2-
dimethyloxazolidine-3-carboxylate (rac 36a). White solid
(54 mg, 72%). Compound rac 36a is a mixture of two rotamers
(1.4 : 1, r.r.), mp. 152–153 ꢁC. Major rotamer: 1H NMR (400
MHz, CDCl3) d ¼ 7.78 (d, J ¼ 8.1 Hz, 2H, Ar), 7.29 (d, J ¼ 8.6 Hz,
2H, Ar), 5.39 (dd, J ¼ 10.0, 4.2 Hz, 1H, NH), 4.53–4.45 (m, 1H,
CHP), 4.28–4.22 (m, 2H, CHCHP, OCHH), 4.07–4.00 (m, 2H,
OCHH, OCHHCH3), 3.96–3.90 (m, 1H, OCHHCH3), 3.90–3.86
(m, 1H, OCHHCH3), 3.62–3.56 (m, 1H, OCHHCH3), 2.42 (s, 3H,
ArCH3), 1.67 (s, 3H, C(CH3)2), 1.56 (s, 9H, C(CH3)3), 1.47 (s, 3H,
C(CH3)2), 1.25–1.21 (m, 3H, OCH2CH3), 1.10 (t, J ¼ 7.1 Hz, 3H,
OCH2CH3). 13C NMR (101 MHz, CDCl3) d ¼ 152.57 (s, C]O),
143.06, 138.47, 129.33, 127.35 (4 ꢂ s, Ar), 94.30 (s, C(CH3)2),
80.80 (s, C(CH3)3), 63.83 (s, OCH2), 62.66 (d, J ¼ 7.1 Hz,
OCH2CH3), 62.56 (d, J ¼ 7.3 Hz, OCH2CH3), 57.28 (d, J ¼
13.0 Hz, CHCHP), 49.80 (d, J ¼ 151.6 Hz, CHP), 28.45 (s,
C(CH3)3), 26.10 (s, C(CH3)2), 24.48 (s, C(CH3)2), 21.46 (s, ArCH3),
16.29 (d, J ¼ 5.6 Hz, OCH2CH3), 16.18 (d, J ¼ 5.5 Hz, OCH2CH3).
31P{/1H} NMR (162 MHz, CDCl3) d ¼ 21.34 (s). Minor rotamer:
1H NMR (400 MHz, CDCl3) d ¼ 7.76 (d, J ¼ 8.4 Hz, 2H, Ar), 7.29
(d, J ¼ 8.6 Hz, 2H, Ar), 5.08 (dd, J ¼ 9.2, 3.4 Hz, 1H, NH), 4.53–
4.45 (m, 1H, CHP), 4.28–4.22 (m, 2H, CHCHP, OCHH), 4.07–4.00
(m, 4H, OCHH, OCHHCH3, OCH2CH3), 3.90–3.86 (m, 1H,
OCHHCH3), 2.42 (s, 3H, ArCH3), 1.58 (s, 9H, C(CH3)3), 1.44 (s,
3H, C(CH3)2), 1.39 (s, 3H, C(CH3)2), 1.28 (t, J ¼ 7.1 Hz, 3H,
OCH2CH3), 1.25–1.21 (m, 3H, OCH2CH3). 13C NMR (101 MHz,
CDCl3) d ¼ 151.43 (s, C]O), 143.27, 138.84, 129.44, 126.98 (4
ꢂ s, Ar), 94.61 (s, C(CH3)2), 80.66 (s, C(CH3)3), 64.06 (s, OCH2),
62.97 (d, J ¼ 7.3 Hz, OCH2CH3), 62.45 (d, J ¼ 7.0 Hz, OCH2CH3),
56.36 (d, J ¼ 14.3 Hz, CHCHP), 51.59 (d, J ¼ 152.1 Hz, CHP),
28.45 (s, C(CH3)3), 24.99 (s, C(CH3)2), 22.51 (s, C(CH3)2), 21.46 (s,
ArCH3), 16.35 (d, J ¼ 5.6 Hz, OCH2CH3), 16.31 (d, J ¼ 6.0 Hz,
OCH2CH3). 31P{/1H} NMR (162 MHz, CDCl3) d ¼ 21.19 (s). HRMS
(ESI) calcd for C22H38N2O8PS ([M + H]+): 521.2081, found:
521.2090.
tert-Butyl(S)-4-((S)-(diethoxyphosphoryl)(4-methylphenyl-
sulfonamido)methyl)-2,2-dimethyloxazolidine-3-carboxylate
(36b). Detected in the crude reaction mixture as one rotamer
(not isolated): 31P{/1H} NMR (162 MHz, CDCl3) d ¼ 21.03 (s).
Benzyl(S)-4-((R)-(diethoxyphosphoryl)(4-
methylphenylsulfonamido)methyl)-2,2-dimethyloxazolidine-3-
carboxylate (37a). White solid (47 mg, 75%). Compound 37a is
a mixture of two rotamers (1.2 : 1, r.r.). Major rotamer: 1H NMR
(600 MHz, CDCl3) d ¼ 7.60 (d, J ¼ 8.3 Hz, 2H, Ar), 7.50–7.47 (m,
2H, Ph), 7.41–7.36 (m, 3H, Ph), 7.22 (d, J ¼ 8.0 Hz, 2H, Ar), 5.47
(dd, J ¼ 9.6, 4.1 Hz, 1H, NH), 5.26 (d, J ¼ 12.0 Hz, 1H, CHHPh),
5.12 (d, J ¼ 12.0 Hz, 1H, CHHPh), 4.36 (ddd, J ¼ 19.2, 9.5, 2.6 Hz,
1H, CHP), 4.28–4.22 (m, 2H, OCHH, CHCHP), 4.07–4.02 (m, 2H,
OCHH, OCHHCH3), 3.98–3.95 (m, 1H, OCHHCH3), 3.90–3.85
Racemic mixture of benzyl(R)-2-((R)-(diethoxyphosphoryl)(4-
methylphenylsulfonamido)methyl)pyrrolidine-1-carboxylate
(rac 34b). Isolated as a mixture with rac 34a, which could not be
separated by the chromatography techniques employed in this
1
study. Mixture of two rotamers (4.5 : 1, r.r.). Major rotamer: H
NMR (400 MHz, CDCl3) d ¼ 7.67 (d, J ¼ 8.2 Hz, 2H, Ar), 7.42–7.35
(m, 5H, Ph), 7.16 (d, J ¼ 8.0 Hz, 2H, Ar), 6.22 (d, J ¼ 8.3 Hz, 1H,
NH), 5.09 (d, J ¼ 12.4 Hz, 1H, CHHPh), 5.02 (d, J ¼ 12.4 Hz, 1H,
CHHPh), 4.29–4.25 (m, 3H, CHCHP, OCH2CH3), 4.07–4.00 (m,
2H, OCH2CH3), 3.66–3.60 (m, 1H, CHP), 3.15–3.11 (m, 1H,
NCHH), 2.72 (ddd, J ¼ 10.3, 7.1, 3.1 Hz, 1H, NCHH), 2.31 (s, 3H,
ArCH3), 2.13–2.07 (m, 1H, CHHCH), 2.01–1.94 (m, 1H, CHHCH),
1.84–1.81 (m, 1H, NCH2CHH), 1.74–1.70 (m, 1H, NCH2CHH),
1.30 (t, J ¼ 7.1 Hz, 3H, OCH2CH3), 1.19 (t, J ¼ 7.0 Hz, 3H,
OCH2CH3). 13C NMR (101 MHz, CDCl3) d ¼ 157.43 (s, C]O),
143.05 (br s), 138.36, 136.40, 129.52, 128.57, 127.83, 126.14,
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(m, 1H, OCHHCH3), 3.80–3.75 (m, 1H, OCHHCH3), 2.40 (s, 3H, CHP), 64.03 (d, J ¼ 6.7 Hz, OCH2CH3), 63.54 (d, J ¼ 6.8 Hz,
ArCH3), 1.56 (s, 3H, C(CH3)2), 1.49 (s, 3H, C(CH3)2), 1.09 (t, J ¼ OCH2CH3), 54.90 (s, CHCH2Ph), 42.22 (d, J ¼ 8.9 Hz, CH2Ph),
7.1 Hz, 3H, OCH2CH3), 1.10 (t, J ¼ 7.1 Hz, 3H, OCH2CH3). 13C 16.49 (d, J ¼ 4.4 Hz, OCH2CH3), 16.46 (d, J ¼ 4.4 Hz, OCH2CH3).
NMR (151 MHz, CDCl3) d ¼ 152.03 (s, C]O), 143.33, 138.51, 31P{/1H} NMR (243 MHz, CDCl3) d ¼ 15.91 (s). HRMS (ESI) calcd
136.29, 128.67, 128.31, 128.08, 127.41, 127.14 (8 ꢂ s, Ar, Ph), for C14H21NO5P ([M + H]+): 314.1157, found: 314.1155.
95.19 (s, C(CH3)2), 67.39 (s, CH2Ph), 64.37 (s, OCH2), 63.02 (d, J
¼ 7.7 Hz, OCH2CH3), 62.70 (d, J ¼ 6.9 Hz, OCH2CH3), 56.41 (d, J
Conflicts of interest
¼ 14.6 Hz, CHCHP), 50.77 (d, J ¼ 150.2 Hz, CHP), 25.06 (s,
C(CH3)2), 23.03 (s, C(CH3)2), 21.57 (s, ArCH3), 16.32 (d, J ¼ There are no conicts to declare.
5.9 Hz, OCH2CH3), 16.31 (d, J ¼ 5.9 Hz, OCH2CH3). 31P{/1H}
NMR (243 MHz, CDCl3) d ¼ 20.56. Minor rotamer: 1H NMR (600
References
MHz, CDCl3) d ¼ 7.77 (d, J ¼ 8.3 Hz, 2H, Ar), 7.41–7.34 (m, 5H,
Ph), 7.24 (d, J ¼ 8.1 Hz, 2H, Ph), 5.65 (dd, J ¼ 9.7, 4.6 Hz, 1H,
NH), 5.23 (d, J ¼ 12.3 Hz, 1H, CHHPh), 5.17 (d, J ¼ 12.3 Hz, 1H,
CHHPh), 4.58 (ddd, J ¼ 19.7, 9.6, 2.5 Hz, 1H, CHP), 4.28–4.22
(m, 2H, OCHH, CHCHP), 4.07–4.02 (m, 1H, OCHH), 3.98–3.95
(m, 1H, OCHHCH3), 3.75–3.62 (m, 3H, OCH2CH3, OCHHCH3),
2.38 (s, 3H, ArCH3), 1.54 (s, 3H, C(CH3)2), 1.42 (s, 3H, C(CH3)2),
1.24 (t, J ¼ 7.1 Hz, 3H, OCH2CH3), 1.14 (t, J ¼ 7.1 Hz, 3H,
OCH2CH3). 13C NMR (151 MHz, CDCl3) d ¼ 153.42 (s, C]O),
143.29, 138.42, 136.14, 128.67, 128.23, 128.08, 127.41, 127.14 (8
ꢂ s, Ar, Ph), 94.71 (s, C(CH3)2), 67.61 (s, CH2Ph), 64.03 (s, OCH2),
63.10 (d, J ¼ 7.3 Hz, OCH2CH3), 62.94 (d, J ¼ 6.9 Hz, OCH2CH3),
57.79 (d, J ¼ 13.5 Hz, CHCHP), 49.63 (d, J ¼ 151.2 Hz, CHP),
25.97 (s, C(CH3)2), 24.81 (s, C(CH3)2), 21.55 (s, ArCH3), 16.36 (d, J
¼ 5.8 Hz, OCH2CH3), 16.23 (d, J ¼ 5.8 Hz, OCH2CH3). 31P{/1H}
NMR (243 MHz, CDCl3) d ¼ 20.89 (s). HRMS (ESI) calcd for
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C
25H36N2O8PS ([M + H]+): 555.1924, found: 555.1919.
Benzyl(S)-4-((S)-(diethoxyphosphoryl)(4-methylphenyl-
sulfonamido)methyl)-2,2-dimethyloxazolidine-3-carboxylate
(37b). Detected in the crude reaction mixture as one rotamer
(not isolated): 31P{/1H} NMR (243 MHz, CDCl3) d ¼ 20.50 (s).
Racemic mixture of benzyl((S)-1-((2S,3S)-3-(diethoxyphosphoryl)-
oxiran-2-yl)-2,2,2-triuoroethyl)carbamate (rac 38). Pale yellow oil
1
slowly crystallising (44 mg, 74%): H NMR (400 MHz, CDCl3) d ¼
¨
7.44–7.32 (m, 5H, Ph), 5.16 (s, 2H, CH2Ph), 4.81–4.70 (m, 1H, CHP),
4.28–4.11 (m, 4H, 2 ꢂ OCH2CH3), 3.69–3.64 (m, 1H, CHCHCF3),
2.93 (dd, J ¼ 27.6, 2.4 Hz, 1H, CHCF3), 1.68 (s, 1H, OH), 1.38 (t, J ¼
7.1 Hz, 6H, 2 ꢂ OCH2CH3). 13C NMR (151 MHz, CDCl3) d ¼ 155.58
(s, C]O), 135.34, 128.68, 128.59, 128.25 (4 ꢂ s, Ph), 124.04 (q, J ¼
282.4 Hz, CF3), 68.04 (s, CH2Ph), 63.59 (d, J ¼ 6.2 Hz, OCH2CH3),
63.29 (d, J ¼ 6.3 Hz, OCH2CH3), 51.72 (d, J ¼ 1.6 Hz, CHCHCF3),
51.24 (q, J ¼ 31.5 Hz, CHCF3), 45.81 (d, J ¼ 204.2 Hz, CHP), 16.45 (d,
J ¼ 5.4 Hz, OCH2CH3), 16.43 (d, J ¼ 5.6 Hz, OCH2CH3). 19F NMR
(376 MHz, CDCl3) d ¼ ꢀ75.49 (d, J ¼ 7.8 Hz). 19F{/1H} NMR (565
MHz, CDCl3) d ¼ ꢀ75.49 (s). 31P{/1H} NMR (243 MHz, CDCl3) d ¼
15.89 (s). HRMS (ESI) calcd for C16H21F3NO6P ([M + Na]+): 434.0956,
found: 434.0955.
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(600 MHz, CDCl3) d ¼ 7.35 (t, J ¼ 7.4 Hz, 2H, Ph), 7.29 (t, J ¼
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