Enantiomerically pure phosphonate analogues of cis- and trans-4-hydroxyprolines

Article abstract of DOI:10.1016/j.tetasy.2007.06.006

All the enantiomers of O,O-diethyl 4-hydroxypyrrolidinyl-2-phosphonates, phosphonate analogues of cis- and trans-4-hydroxyprolines, have been obtained for the first time. The synthetic strategy involved 1,3-dipolar cycloaddition of (R)- and (S)-N-(1-pheny

Full text of DOI:10.1016/j.tetasy.2007.06.006

Tetrahedron: Asymmetry 18 (2007) 1351–1363
Enantiomerically pure phosphonate analogues of cis- and trans-4-
hydroxyprolines
Dorota G. Piotrowska* and Iwona E. Głowacka
Bioorganic Chemistry Laboratory, Faculty of Pharmacy, Medical University of Ło´dz´, 90-151 Ło´dz´, Muszyn´skiego 1, Poland
Received 25 April 2007; accepted 5 June 2007
Abstract—All the enantiomers of O,O-diethyl 4-hydroxypyrrolidinyl-2-phosphonates, phosphonate analogues of cis- and trans-4-
hydroxyprolines, have been obtained for the first time. The synthetic strategy involved 1,3-dipolar cycloaddition of (R)- and (S)-N-(1-
phenylethyl)-C-(diethoxyphosphoryl)nitrones to allyl alcohol and separation of the corresponding O,O-diethyl 5-(hydroxymethyl)-2-(1-
phenylethyl)isoxazolidinyl-3-phosphonates, which were subsequently mesylated and hydrogenated to undergo intramolecular cyclisa-
tion. Absolute configurations of the enantiomeric proline phosphonates were established after N- and O-derivatization with (S)-O-meth-
ylmandelic acid employing the Trost model.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
Since the synthesis of racemic 2,30 several attempts have
been made to prepare various phosphoproline deriva-
tives,31 including 3-32 and 4-hydroxylated,33–35 as well as
3,4-dihydroxylated analogues,36 some of which have exhib-
ited promising biological activities.37–41
Proline 1 and its hydroxylated analogues are important
amino acids present in many natural and synthetic prod-
ucts.1–3 They received considerable attention due to their
biological activity, among others, as antibiotics4 and anti-
parasites5,6 or enzyme inhibitors.7,8 The structural frame-
work of proline has also been employed as an important
building block for organic synthesis.9 Moreover, proline
and its derivatives have been applied as extremely useful
enantioselective catalysts in asymmetric induction, for
example, aldol,10–16 Diels–Alder,16–18 Baylis–Hillman,19,20
Michael,21–25 Mannich reactions25–27 and Robinson annu-
lation.28 Among the various proline derivatives, phospho-
nate proline analogue 2, as well as its diethyl ester, were
also found to serve as an efficient chiral catalyst for the
aldol reaction.29
In 1986, Seebach and Renaud obtained the pure enantio-
mer of phosphonic acid 3 via the electrochemical oxidative
decarboxylation of 4-hydroxy-L-proline followed by TiCl4-
catalysed phosphonylation, but the absolute configuration
at C2 was not unambiguously assigned.33 Although the
synthesis of two isomers of racemic phosphonates 4 has
been reported, no attempts were made to establish their rel-
ative (cis or trans) configuration.34 Very recently, enantio-
merically pure N,O-diacetyl derivatives of O,O-dimethyl
(2S,4R)- and (2R,4R)-4-hydroxypyrrolidinyl-2-phospho-
nates have also been synthesised from N,O-diacetyl L-
hydroxyproline via a free radical decarboxylation–phos-
phorylation reaction.35
HO
Our recent achievements in application of the N-substi-
tuted C-phosphorylated nitrone42,43 prompted us to design
a new approach to enantiomerically pure phosphonate
analogues of 4-hydroxyproline 4, which, for the first
time, would have given all four enantiomerically pure
compounds (Scheme 1). Transformation of the hydroxy
function in 5 into a good leaving group led to an
intermediate, which was expected to cyclise to amino-
phosphonate 4, after hydrogenolytic cleavage of the N–O
bond and the removal of the chiral auxiliary.
COOH
P(O)(OH)2
P(O)(OR)2
N
H
N
H
N
H
1
2
3 R=H
4 R=Et
*
Corresponding author. Tel.: +48 42 677 92 35; fax: +48 42 678 83 98;
e-mail: dorota@ich.pharm.am.lodz.pl
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.06.006

1352
D. G. Piotrowska, I. E. Głowacka / Tetrahedron: Asymmetry 18 (2007) 1351–1363
OH
O
OH
O
HN
(EtO)2(O)P
Ph
N
Ph
N
(EtO)2(O)P
(EtO)2(O)P
4
5
(S)-6
Scheme 1. Retrosynthesis of 4-hydroxypyrrolidinyl-2-phosphonates 4.
2. Results and discussion
Since the pure isomer (3R,5S)-5b could not be separated
from the mixture of isoxazolidines obtained from nitrone
(S)-6, another approach was proposed. The application
of nitrone (R)-6 would have led to a mixture of isoxazoli-
dines (3S,5R)-8a, (3R,5S)-8b, (3S,5S)-8c and (3R,5R)-8d
from which (3R,5S)-8b should be easily separable, since it
is a mirror image of (3S,5R)-5a. Indeed, from (R)-6 and
allyl alcohol, a 13:30:21:36 mixture of the respective isoxaz-
olidines was formed and (3R,5S)-8b was separated
chromatographically in 22% yield (Scheme 5). In addition,
(3R,5R)-8d was isolated in 10% yield.
1,3-Dipolar cycloaddition of N-(1-phenylethyl)-C-phos-
phorylated nitrone (S)-6 and allyl alcohol led to a mixture
of isoxazolidines (3S,5R)-5a, (3R,5S)-5b, (3S,5S)-5c and
(3R,5R)-5d in a 25:16:36:23 ratio (Scheme 2). The reaction
appeared to be completely regioselective, but negligible ste-
reoselectivity was noticed. From this mixture two pure dia-
stereoisomers, (3S,5R)-5a (up to 25%) and (3S,5S)-5c (up
to 15%), could be isolated by column chromatography on
silica gel.
ZnCl2 or MgBr2-catalysed reaction of nitrone (S)-6 with
allyl alcohol gave an inseparable mixture of cis-isomers
(3S,5S)-5c and (3R,5R)-5d in a 1:1 ratio with no concomi-
tant trans-isomers (3S,5R)-5a and (3R,5S)-5b (Scheme 2).
However, a mixture of the corresponding acetates was
cleanly separated by column chromatography to give pure
(3S,5S)-7c and (3R,5R)-7d in 47% and 37% yield, respec-
tively (Scheme 3).
OAc
OH
O
O
a.
Ph
N
Ph
N
(EtO)2(O)P
(3S,5S)-7c
(EtO)2(O)P
(3S,5S)-5c
Scheme 4. Reagents and conditions: (a) NH4OH, EtOH, rt, 4 h, 87%.
After ammonolysis, isoxazolidine (3S,5S)-5c was recovered
from O-acetate (3S,5S)-7c in 87% yield (Scheme 4).44 In a
similar fashion, (3R,5R)-7d was transformed into
(3R,5R)-5d in 88% yield.
As expected, the reaction of (R)-6 with allyl alcohol in the
presence of MgBr2 gave a mixture of cis-isoxazolidines
(3S,5S)-8c and (3R,5R)-8d in a 1:1 ratio, which again was
OH
OH
O
O
Ph
N
Ph
N
+
(EtO)2(O)P
(EtO)2(O)P
OH
O
(3S,5R)-5a
(3R,5S)-5b
Ph
N
a. or b.
+
(EtO)2(O)P
OH
OH
O
N
O
N
(S)-6
Ph
Ph
+
(EtO)2(O)P
(3S,5S)-5c
Scheme 2. Reagents and conditions: (a) toluene, 60 ꢁC, 48 h; (b) CH2Cl2, ZnCl2, rt, 9 days or MgBr2-etherate, 24 h, rt.
(EtO)2(O)P
(3R,5R)-5d
OH
OH
OAc
+
OAc
O
O
O
O
a.
Ph
N
Ph
N
Ph
N
Ph
N
+
(EtO)2(O)P
(3S,5S)-5c
Scheme 3. Reagents and conditions: (a) Ac2O, NEt3, DMAP, rt, 24 h, 47% 7c and 37% 7d.
(EtO)2(O)P
(EtO)2(O)P
(EtO)2(O)P
(3R,5R)-7d
(3R,5R)-5d
(3S,5S)-7c

D. G. Piotrowska, I. E. Głowacka / Tetrahedron: Asymmetry 18 (2007) 1351–1363
1353
OH
OH
OH
O
O
Ph
N
Ph
N
+
(EtO)2(O)P
(EtO)2(O)P
OH
O
(3S,5R)-8a
(3R,5S)-8b
Ph
N
a. or b.
+
(EtO)2(O)P
OH
O
N
O
N
(R)-6
Ph
Ph
+
(EtO)2(O)P
(3S,5S)-8c
Scheme 5. Reagents and conditions: (a) toluene, 60 ꢁC, 48 h; (b) CH2Cl2, MgBr2-etherate, rt, 24 h.
(EtO)2(O)P
(3R,5R)-8d
separated as O-acetyl derivatives (3S,5S)-9c and (3R,5R)-
9d.
analogues (2S,4S)-4 and (2R,4R)-4 in 75% and 57% yield,
respectively, after column chromatography (Schemes 6
and 7).
In order to convert cis-isoxazolidines (3S,5S)-5c and
(3R,5R)-5d into trans-4-hydroxypyrrolidinyl-2-phospho-
nates (2S,4S)-4 and (2R,4R)-4, they were first mesylated
under standard reaction conditions to form (3S,5S)-10c
and (3R,5R)-10d in 96% and 88% yield, respectively.
O-Mesylates (3S,5S)-10c and (3R,5R)-10d were then sub-
jected to hydrogenolysis to execute the following transfor-
mations: cleavage of the N–O bond, removal of 1-
phenylethyl group and intramolecular SN2 substitution of
the mesyl group. The resulting ammonium mesylates
(3S,5S)-11c and (3R,5R)-11d were neutralised with potas-
sium carbonate in chloroform to provide 4-hydroxyproline
Similarly, trans-isoxazolidines (3S,5R)-5a and (3R,5S)-8b
were mesylated to give (3S,5R)-10a and (3R,5S)-12b in
91% and 81% yield, respectively, and the corresponding
O-mesylates were transformed into cis-proline phospho-
nates (2S,4R)-4 and (2R,4S)-4 in 72% and 69% yield
(Schemes 8 and 9).
Aminophosphonates 4 appeared to be stable enough to
survive purification on a silica gel column. However, they
underwent slow decomposition to N-alkylated products.
For example, when a sample of pure (2S,4S)-4 was left at
OH
a.
OMs
b.
MsO
O
O
OH
OH
c.
Ph
N
Ph
N
H2N
HN
(EtO)2(O)P
(3S,5S)-5c
Scheme 6. Reagents and conditions: (a) MsCl, NEt3, 0 ꢁC, 2 h, 96%; (b) H2/Pd(OH)2–C, EtOH, 7 days; (c) K2CO3, CHCl3, rt, 3 h, 75%.
(EtO)2(O)P
(EtO)2(O)P
(EtO)2(O)P
(2S,4S)-11c
(2S,4S)-4
(3S,5S)-10c
OH
a.
OMs
b.
MsO
H2N
O
O
OH
OH
c.
Ph
N
Ph
N
HN
(EtO)2(O)P
(3R,5R)-5d
Scheme 7. Reagents and conditions: (a) MsCl, NEt3, 0 ꢁC, 2 h, 88%; (b) H2/Pd(OH)2–C, EtOH, 7 days; (c) K2CO3, CHCl3, rt, 3 h, 57%.
(EtO)2(O)P
(EtO)2(O)P
(EtO)2(O)P
(2R,4R)-11d
(2R,4R)-4
(3R,5R)-10d
OH
a.
OMs
b.
MsO
H2N
O
O
OH
OH
c.
Ph
N
Ph
N
HN
(EtO)2(O)P
(3S,5R)-5a
Scheme 8. Reagents and conditions: (a) MsCl, NEt3, 0 ꢁC, 2 h, 91%; (b) H2/Pd(OH)2–C, EtOH, 7 days; (c) K2CO3, CHCl3, rt, 3 h, 72%.
(EtO)2(O)P
(EtO)2(O)P
(EtO)2(O)P
(2S,4R)-11a
(2S,4R)-4
(3S,5R)-10a

1354
D. G. Piotrowska, I. E. Głowacka / Tetrahedron: Asymmetry 18 (2007) 1351–1363
OH
a.
OMs
b.
MsO
H2N
O
O
OH
OH
c.
Ph
N
Ph
N
HN
(EtO)2(O)P
(3R,5S)-8b
Scheme 9. Reagents and conditions: (a) MsCl, NEt3, 0 ꢁC, 2 h, 81%; (b) H2/Pd(OH)2–C, EtOH, 7 days; (c) K2CO3, CHCl3, rt, 3 h, 69%.
(EtO)2(O)P
(EtO)2(O)P
(EtO)2(O)P
(2R,4S)-11b
(2R,4S)-4
(3R,5S)-12b
+5 ꢁC for 7 days a less polar phosphonate was isolated and
identified as N-ethyl derivative (2S,4S)-13. Furthermore,
impure (2S,4S)-14 was eluted from the same column in
the most polar fractions.
6.6 Hz], a 1E-conformation of the isoxazolidine ring is pro-
posed for this isomer (Fig. 1). These findings prove the cis-
relative configurations between substituents at C3 and C5
in the diastereoisomeric pair (3S,5S)-5c and (3R,5R)-5d,
and as a consequence the trans-relationship in both isomers
(3S,5R)-5a and (3R,5S)-5b.
OH
OH
Et
H2N
N
Transformations of isoxazolidines 5 into the proline ana-
logues 4 proceed via an intramolecular SN2 reaction. Con-
sequently, from cis-isoxazolidines (3S,5S)-5c and (3R,5R)-
5d, trans-proline analogues (2S,4S)-4 and (2R,4R)-4 are
produced, whereas trans-isoxazolidines (3S,5R)-5a and
(3R,5S)-8b are transformed into the corresponding
cis-4-hydroxypyrrolidinyl-2-phosphonates (2S,4R)-4 and
(2R,4S)-4. Moreover, the cis-relative configuration of the
phosphonate (2R,4S)-4 or its enantiomer (2S,4R)-4 is addi-
tionally proven by the analysis of vicinal couplings [J(C5–
NC–P) = 8.9 Hz, J(C4–CC–P) = 3.7 Hz, J(H2–H3a) =
3.6 Hz, J(H2–H3b) = 10.5 Hz, J(H3a–P) = 15.0 Hz, J(H3b–
P) = 25.2 Hz, J(H3a–H4) = 0 Hz and J(H3b–H4) = 5.7 Hz]
O(EtO)(O)P
(EtO)2(O)P
(2S,4S)-13
(2S,4S)-14
As reported earlier, the thermal (60 ꢁC) cycloaddition of
the racemic C-phosphorylated nitrone to allyl alcohol pro-
ceeded with low diastereoselectivity and led to a 6:4 mix-
ture of the corresponding trans and cis-isoxazolidines,
whereas in the presence of ZnCl2 or MgBr2 the cis-isomer
was formed as a major product.42 Based on these observa-
tions, a similar reactivity was expected for the chiral nitro-
nes (R)- and (S)-6. Indeed, a negligible stereoselectivity was
observed when the cycloaddition was performed at 60 ꢁC.
On the other hand, the ZnCl2 or MgBr2-catalysed reactions
of (R)- and (S)-6 with allyl alcohol are diastereospecific
only providing the cis-isoxazolidines, while they again lack
enantioselectivity.
1
extracted from the H and 13C NMR spectra. In a pre-
ferred E-conformation, which is stabilised by an intramo-
5
lecular P(O)ꢀ ꢀ ꢀÆH–O hydrogen bond, the diethoxy-
phosphoryl and hydroxyl groups occupy pseudoaxial posi-
tions (Fig. 1).
To additionally prove the relative stereochemistry (at C3
and C5) of the cycloadducts 5a–5d, detailed conforma-
tional analyses of pure isoxazolidines were undertaken.
Fortunately, it was possible to unequivocally establish the
preferred conformations of both cis-isoxazolidines (3S,
5S)-5c and (3R,5R)-5d. Based on the vicinal couplings
In order to establish the absolute configurations, both
enantiomers of trans-phosphonates (2S,4S)-4 and
(2R,4R)-4 were transformed into the respective N,O-bis-
mandelic acid derivatives (2S,4S)-15c and (2R,4R)-15d
with (S)-O-methylmandelic acid in the presence of DCC
(Scheme 10).
[J(C–NC–P) = 18.3 Hz,
J(C5–CC–P) = 0 Hz,
J(H3–
H4a) = 3.3 Hz, J(H3–H4b) = 9.3 Hz, J(H4a–P) = 20.7 Hz,
J(H4b–P) = 27.0 Hz, J(H4a–H5) = 6.6 Hz and J(H4b–
Analyses of the 1H NMR spectra of (2S,4S)-15c and
(2R,4R)-15d show significant shielding effects on some pyr-
rolidine ring protons originating from the O-mandelate
fragment (Fig. 2). Thus, the phenyl ring of mandelic ester
in (2R,4R)-15d shifts the H–C(3) proton upfield to
1.85 ppm, when compared to the same proton in the iso-
meric (2S,4S)-15c (d = 2.19 ppm), as well as in the starting
trans-phosphonate (2S,4S)-4 (d = 2.10 ppm). On the other
hand, resonances of both H2C(5) in (2S,4S)-15c are only
1
H5) = 9.3 Hz] found in the H and 13C NMR spectra of
(3S,5S)-5c, it was concluded that the isoxazolidine ring ex-
ists in an 2E-conformation, in which 1-phenylethyl and
diethoxyphosphoryl groups occupy axial positions
(Fig. 1). From the couplings found for (3R,5R)-5d [J(C–
NC–P) = 13.2 Hz, J(C5–CC–P) = 4.0 Hz, J(H3–H4a) =
9.3 Hz, J(H3–H4b) = 5.4 Hz, J(H4a–P) = 19.5 Hz, J(H4b–
P) = 19.8 Hz, J(H4a–H5) = 8.1 Hz and J(H4b–H5) =
H
O
Ph
β
O4 Hβ
Hβ H
HOH2C
H
N
P(OEt)2
P(O)(OEt)2
5
O
H
H
2
3
N
H
N
3
4
H
CH2OH
O
H
H
αH
αH
(2R,4S)-4
Figure 1. Preferred conformations of isoxazolidines (3S,5S)-5c and (3R,5R)-5d and cis-proline (2S,4R)-4.
H
(EtO)2(O)P
Hα
Ph
Hα
(3S,5S)-5c
(3R,5R)-5d

D. G. Piotrowska, I. E. Głowacka / Tetrahedron: Asymmetry 18 (2007) 1351–1363
1355
OMe
Ph
O
O
H
HO
O
HO
O
a.
b.
c.
P(O)(OEt)2
P(O)(OEt)2
P(O)(OEt)2
P(O)(OEt)2
N
H
N
N
N
H
H
H
O
O
O
Ph
Ph
Ph
OMe
(2S,4S)-15c
Scheme 10. Reagents and conditions: (a) (S)-PhCH(OMe)COOH, DCC, DMAP, rt, 24 h; (b) NH4OH, EtOH, rt, 3 h; (c) Ac2O, NEt3, DMAP, rt, 24 h.
OMe
OMe
(2S,4S)-4
(2S,4S)-16c
(2S,4S)-17c
O
H
O
H
H
P
Ph
O
H
H
MeO
MeO
Me
O
3
O
O
5
P
3
5
N
H
H
N
O
H
H
H
H
H
OMe
= P(O)(OEt)2
(2S,4S)-15c
(2R,4R)-15d
P
Figure 2. Preferred conformations of N,O-bismandelates (2S,4S)-15c and (2R,4R)-15d.
1
slightly shifted upfield (to 3.80 and 3.41 ppm), as compared
to those in (2R,4R)-15d (d = 3.90 and 3.52 ppm). Although
N-mandelamide residues in (2S,4S)-15c and (2R,4R)-15d
cause a negligible influence on the pyrrolidine ring hydro-
gens, the shielding effects of the phenyl rings of this moiety
are observed. A signal of the methine proton of the
PhCH(OMe)–C(O)O grouping in (2R,4R)-15d is shifted
to 4.29 ppm from a normal region (ꢁ4.5–4.8 ppm), as a re-
sult of the shielding by the phenyl ring from the mandel-
amide function. Moreover, the CH3O protons of the
mandelamide residue in (2S,4S)-15c are shielded (d =
3.33 ppm), when compared to the same protons in
(2R,4R)-15d, which resonate at 3.50 ppm. Moreover, all
these observations comply very well with the Trost model,
which allows us to assign the absolute configurations in the
enantiomerically pure trans proline phosphonates (2S,4S)-
4 and (2R,4R)-4 (Fig. 2).
phonates (2S,4R)-4 and (2R,4S)-4. Comparison of the H
NMR spectra of the corresponding N,O-bismandelic acid
derivatives (2S,4R)-15a and (2R,4S)-15b shows two diag-
nostic shielding effects: one of the H–C(3) protons in
(2S,4R)-15a is shifted upfield to 2.15 ppm when compared
to the same proton in (2R,4S)-15b (d = 2.30 ppm), while
the signal of the H–C(5) proton in (2R,4S)-15b appeared
at 3.90 ppm, in contrast to H–C(5) in (2S,4R)-15a
(d = 4.21 ppm). These differences can be explained by
assuming that (2S,4R)-15a and (2R,4S)-15b exist in the
conformations shown in Figure 3.
To further prove these assignments and at the same time to
discriminate between the shielding effects of the phenyl
rings of the O- and N-mandelic acid residues, N-acetyl-O-
mandelate derivatives (2S,4R)-20a and (2R,4S)-20b were
synthesised from (2S,4R)-4 and (2R,4S)-4 (Scheme 11).
To ensure that the phenyl ring of N-mandelamide residue
does not shield the pyrrolidine ring protons, O-acetyl-N-
mandelates (2S,4S)-17c and (2R,4R)-17d were synthesised
O
H
O
H
Ph
OMe
H
H
MeO
H
MeO
O
3
O
5
1
5
H
O
(Scheme 10). Indeed, the H NMR spectra of (2S,4S)-17c
3
N
P
O
H
H
N
H
H
H
and (2R,4R)-17d were almost identical and no significant
differences in chemical shifts were noticed. This conclusion
proves that only the O-mandelate fragment is responsible
for diagnostic upfield shifts observed for the pyrrolidine
ring protons. Furthermore, based on these data, a pre-
ferred configuration around N–C(O) bond can be assigned,
in which a mandelic acid residue is trans-oriented to the
CHP(O)(OEt)2 moiety. This is in agreement with the gen-
eral tendency of amides derived from chiral acids and cyclic
secondary amines having stereogenic carbon atoms at the
a-position, to predominantly exist as an anti-rotamer
around the N–C(O) bond.45
P
H
OMe
(2S,4R)-15a
(2R,4S)-15b
O
H
O
H
H
H
H
MeO
MeO
O
3
O
5
5
H
O
3
N
O
H
H
N
H
H
P
P
(2S,4R)-20a
= P(O)(OEt)2
(2R,4S)-20b
P
The same methodology was attempted in assigning the
absolute configurations of both enantiomers of cis phos-
Figure 3. Preferred conformations of N,O-bismandelates (2S,4R)-15a and
(2R,4S)-15b and N-acetyl-O-mandelates (2S,4R)-20a and (2R,4S)-20b.

1356
D. G. Piotrowska, I. E. Głowacka / Tetrahedron: Asymmetry 18 (2007) 1351–1363
OMe
Ph
O
O
H
HO
HO
O
O
a.
b.
c.
P(O)(OEt)2
P(O)(OEt)2
P(O)(OEt)2
P(O)(OEt)2
N
H
N
N
N
O
O
O
(2S,4R)-4
(2S,4R)-18
(2S,4R)-19
(2S,4R)-20a
Scheme 11. Reagents and conditions: (a) Ac2O, NEt3, DMAP, rt, 2 h; (b) NH4OH, EtOH, rt, 4 h; (c) (S)-PhCH(OMe)COOH, DCC, DMAP, rt, 24 h.
The H and 31P NMR spectra showed that the derivatives
(2S,4R)-20a and (2R,4S)-20b exist as mixtures of Z- and E-
rotamers in a 7:3 ratio, respectively. Taking into consider-
ation the spectra of both the major (Z) isomers of (2S,4R)-
20a and (2R,4S)-20b, again the upfield shift of one of the
H–C(3) protons in (2S,4R)-20a (d = 2.20 ppm) was ob-
served, as compared to the same proton in (2R,4S)-20b
(d = 2.50 ppm). Moreover, resonances of the H2C(5) pro-
tons in (2R,4S)-20b are shifted upfield to 3.90 and
3.33 ppm, when compared to the same protons in
(2S,4R)-20a (d = 4.10 and 3.53 ppm) (Fig. 3). These obser-
vations are in full agreement with the Trost model and fur-
ther support the absolute configurations of both cis-proline
phosphonates (2S,4R)-4 and (2R,4S)-4 established earlier
by employing the N,O-bismandelic acid derivatives.
and 121.5 MHz, respectively. IR spectra data were mea-
sured on an Infinity MI-60 FT-IR spectrometer. Melting
points were determined on a Boetius apparatus and are
uncorrected. Elemental analyses were performed by the
Microanalytical Laboratory of this Faculty on a Perkin
Elmer PE 2400 CHNS analyzer. Polarimetric measurements
were conducted on a Perkin–Elmer 241 MC apparatus. The
following absorbents were used: column chromatography,
Merck silica gel 60 (70–230 mesh); analytical TLC plastic
1
sheets silica gel 60 F254
.
4.1. Synthesis of nitrones (R)- and (S)-6
Nitrones (R)- and (S)-6 have been obtained from in situ
generated formylphosphonate (1.0 mmol)41 and the corre-
sponding (R)- or (S)-1-phenylethylhydroxylamine (1.0
mmol) and were purified by column chromatography fol-
lowed by crystallisation.
3. Conclusions
At 60 ꢁC, the 1,3-dipolar cycloaddition of nitrone (S)-6
with allyl alcohol led regiospecifically to a mixture of
four 3-diethoxyphosphoryl-5-(hydroxymethyl)isoxazolidines
5a–5d with low stereoselectivity, from which pure phospho-
nates (3S,5R)-5a and (3S,5S)-5c were isolated. In a ZnCl2-
catalysed cycloaddition, a 1:1 mixture of the cis-isoxazoli-
dines (3S,5S)-5c and (3R,5R)-5d was formed, which was effi-
ciently separated as O-acetyl derivatives. In order to obtain
the isomeric isoxazolidine with the (3R,5S) configuration,
the thermal cycloaddition of nitrone (R)-6 to allyl alcohol
was performed and isoxazolidine (3R,5S)-8b was isolated
efficiently.
4.1.1. N-[(R)-1-Phenylethyl]-C-(diethoxyphosphoryl)nitrone
(R)-6. Mp 59–61 ꢁC. IR (KBr): m = 3044, 2984, 1546,
20
1449, 1239, 1171, 1064, 1028, 962 cmꢂ1. ½aꢃD ¼ ꢂ6:6 (c
1
1.7, CHCl3). H NMR (CDCl3): d = 7.45–7.32 (m, 5H),
6.87 (d, J = 24.0 Hz, 0.07 · 1H, CH–P), 6.80 (d,
J = 26.1 Hz, 0.93 · 1H, CH–P), 5.12 (q, J = 6.9 Hz, 1H,
CH–CH3), 4.28–4.12 (m, 4H), 1.82 (d, J = 6.9 Hz,
0.93 · 3H, CH–CH3), 1.77 (d, J = 6.9 Hz, 0.07 · 3H,
CH–CH3), 1.30 (t, J = 7.2 Hz, 3H), 1.28 (t, J = 7.2 Hz,
3H). 13C NMR (CDCl3): d = 137.43, 129.22, 128.98,
127.27, 124.38 (J = 208.4 Hz, P–CH), 76.89 (d, J =
12.0 Hz, CH–Ph), 63.46 (d, J = 5.7 Hz), 63.34 (d,
J = 6.0 Hz), 19.43 (s, CH3CHN), 16.58 (d, J = 6.0 Hz),
15.54 (d, J = 6.0 Hz). 31P NMR (CDCl3): d = 6.66 (93%)
and 5.83 (7%). Anal. Calcd for C13H20NO4P: C, 54.73;
H, 7.07; N, 4.91. Found: C, 54.86; H, 7.18; N, 5.14.
The reaction sequence used in the transformation of each
of 3-diethoxyphosphoryl-5-(hydroxymethyl)isoxazolidines
(3S,5R)-5a, (3R,5S)-8b, (3S,5S)-5c and (3R,5R)-5d into 4-
hydroxyproline phosphonates (2S,4R)-4, (2R,4S)-4,
(2S,4S)-4 and (2R,4R)-4, respectively, consisted of a stan-
dard O-mesylation, a hydrogenolytic cleavage of the N–O
bond and the removal of the chiral auxiliary, which trig-
gered the formation of the pyrrolidine ring by an intramo-
lecular SN2 reaction.
4.1.2. N-[(S)-1-Phenylethyl]-C-(diethoxyphosphoryl)nitrone
20
(S)-6. Mp 59–60 ꢁC. ½aꢃD ¼ þ7:5 (c 1.9, CHCl3).
Anal. Calcd for C13H20NO4P: C, 54.73; H, 7.07; N, 4.91.
Found: C, 54.47; H, 7.34; N, 5.11.
4.2. Diethyl (3S,5R)-, (3R,5S)-, (3S,5S)- and (3R,5R)-5-
(hydroxymethyl)-2-[(S)-1-phenylethyl]isoxazolidinyl-3-phos-
phonates (3S,5R)-5a, (3R,5S)-5b, (3S,5S)-5c and (3R,5R)-
5d
4. Experimental
1H NMR spectra were recorded with a Varian Mercury-
300 spectrometer; chemical shifts d in ppm with respect
to TMS; coupling constants J in Hz. 13C and 31P NMR
spectra were recorded on a Mercury-300 machine at 75.5
4.2.1. Cycloaddition of the nitrone (S)-6 to allyl alcohol.
A
solution of nitrone (S)-6 (0.982 g, 3.44 mmol) and allyl
alcohol (0.60 mL, 6.88 mmol) in toluene (3 mL) was stirred

D. G. Piotrowska, I. E. Głowacka / Tetrahedron: Asymmetry 18 (2007) 1351–1363
1357
at 60 ꢁC for 48 h. All volatiles were removed in vacuo and
the crude product was purified by chromatography on sil-
ica gel with chloroform–methanol (100:1, v/v) to give pure
phosphonates (3S,5R)-5a (0.267 g, 23%) and (3S,5S)-5c
(0.177 g, 15%) both as colourless oils.
at room temperature for 9 days. After removal of the vol-
atiles, the crude product was purified by column chroma-
tography on silica gel to give an inseparable mixture of
(3S,5S)-5c and (3R,5R)-5d (0.153 g, 89%).
4.3. Diethyl (3S,5R)-, (3R,5S)-, (3S,5S)- and (3R,5R)-5-
(hydroxymethyl)-2-[(R)-1-phenylethyl]isoxazolidinyl-3-phos-
phonate (3S,5R)-8a, (3R,5S)-8b, (3S,5S)-8c and (3R,5R)-8d
4.2.1.1. Diethyl (3S,5R)-5-(hydroxymethyl)-2-[(S)-1-
phenylethyl]isoxazolidinyl-3-phosphonate (3S,5R)-5a. IR
(film): m = 3392, 2982, 2932, 1454, 1233, 1055, 1028,
20
970 cmꢂ1. ½aꢃD ¼ ꢂ3:8 (c 1.1, CHCl3). H NMR (CDCl3):
d = 7.40–7.20 (m, 5H), 4.38 (dddd, J = 9.3, 7.5, 5.1,
3.6 Hz, 1H, H–C5), 4.23–4.11 (m, 2H), 4.10–3.90 (m,
3H), 3.85 (br d, J = 12.5 Hz, 1H, H–C10), 3.65 (br d,
J = 12.5 Hz, 1H, H–C10), 3.54 (dt, J = 9.3, 2.4 Hz, 1H,
H–C3), 2.48 (dddd, J = 15.6, 12.9, 7.5, 2.4 Hz, 1H, H–
C4), 2.32 (ddt, J = 26.7, 12.9, 9.3 Hz, 1H, H–C4), 1.95
(br s, 1H, OH), 1.50 (d, J = 6.5 Hz, 3H, CH–CH3), 1.32
(t, J = 7.2 Hz, 3H), 1.25 (t, J = 7.2 Hz, 3H). 13C NMR
(CDCl3): d = 142.52, 128.56, 127.93, 127.76, 80.24 (d,
J = 2.0 Hz, C5), 66.33 (d, J = 14.3 Hz, CH–Ph), 64.08 (s,
C10), 63.02 (d, J = 7.2 Hz), 62.62 (d, J = 6.6 Hz), 59.55
(d, J = 174.3 Hz, C3), 31.21 (s, C4), 19.63 (s, CH–CH3),
16.80 (d, J = 5.7 Hz), 16.69 (d, J = 6.3 Hz). 31P NMR
(CDCl3): d = 24.14. Anal. Calcd for C16H26NO5P: C,
55.97; H, 7.63; N, 4.08. Found: C, 55.92; H, 7.72; N, 4.00.
4.3.1. Cycloaddition of the nitrone (R)-6 to allyl alcohol.
A
1
solution of nitrone (R)-6 (1.11 g, 3.89 mmol) and allyl alco-
hol (0.793 mL, 11.7 mmol) in toluene (3 mL) was stirred at
60 ꢁC for 48 h. All volatiles were removed in vacuo and the
crude product was purified by chromatography on silica gel
with chloroform–methanol (100:1, v/v) to give phospho-
nates (3R,5S)-8b (0.297 g, 22%) and (3R,5R)-8d (0.137 g,
10%).
4.3.1.1. Diethyl (3R,5S)-5-(hydroxymethyl)-2-[(R)-1-
phenylethyl]isoxazolidinyl-3-phosphonate (3R,5S)-8b (ent-
20
5a). ½aꢃD ¼ þ4:1 (c 1.0, CHCl3). Anal. Calcd for
C16H26NO5P: C, 55.97; H, 7.63; N, 4.08. Found: C,
55.95; H, 7.76; N, 4.07.
4.3.1.2. Diethyl (3R,5R)-5-(hydroxymethyl)-2-[(R)-1-
phenylethyl]isoxazolidinyl-3-phosphonate (3R,5R)-8d (ent-
20
4.2.1.2. Diethyl (3S,5S)-5-(hydroxymethyl)-2-[(S)-1-
phenylethyl]isoxazolidinyl-3-phosphonate (3S,5S)-5c. IR
(film): m = 3387, 2982, 2908, 1455, 1233, 1054, 1028,
5c). ½aꢃD ¼ þ1:6 (c 1.3, CHCl3). Anal. Calcd for
C16H26NO5P: C, 55.97; H, 7.63; N, 4.08. Found: C,
55.85; H, 7.87; N, 4.01.
20
1
971 cmꢂ1. ½aꢃD ¼ ꢂ2:6 (c 1.4, CHCl3). H NMR (CDCl3):
d = 7.40–7.25 (m, 5H), 4.48 (dddd, J = 9.3, 6.6, 3.0,
1.2 Hz, 1H, H–C5), 4.25–4.10 (m, 2H), 4.08–3.95 (m, 4H,
CH2OP, H–C10 and OH), 3.81 (dq, J = 6.3, 1.8 Hz, 1H,
HC–N), 3.67 (ddd, J = 13.2, 10.5, 3.0 Hz, 1H, H–C10),
3.41 (ddd, J = 13.5, 9.6, 3.3 Hz, 1H, H–C3), 2.62 (dddd,
J = 20.7, 13.2, 6.6, 3.3 Hz, 1H, H–C4), 2.54 (ddt,
J = 27.0, 13.2, 9.3 Hz, 1H, H–C4), 1.49 (d, J = 6.3 Hz,
3H, CH–CH3), 1.29 (t, J = 7.2 Hz, 3H), 1.23 (t, J =
7.2 Hz, 3H). 13C NMR (CDCl3): d = 141.75, 128.44,
127.83, 127.69, 77.63 (s, C5), 64.00 (d, J = 18.3 Hz, CH–
Ph), 63.51 (d, J = 7.2 Hz), 61.96 (d, J = 7.2 Hz), 61.30 (s,
C10), 59.70 (d, J = 178.1 Hz, C3), 28.17 (s, C4), 21.12 (s,
CH–CH3), 16.44 (d, J = 6.2 Hz), 16.33 (d, J = 6.0 Hz).
31P NMR (CDCl3): d = 25.27. Anal. Calcd for
C16H26NO5P: C, 55.97; H, 7.63; N, 4.08. Found: C,
55.73; H, 7.82; N, 4.08.
4.3.2. Cycloaddition of the nitrone (R)-6 to allyl alcohol in
the presence of MgBr2. To a freshly prepared solution of
MgBr2 (10 mmol) in Et2O, nitrone (R)-6 (0.725 g,
2.54 mmol) in methylene chloride (3 mL) was added fol-
lowed by allyl alcohol (0.864 mL, 12.7 mmol). The reaction
mixture was stirred at room temperature for 24 h. The
crude product was purified by column chromatography
on silica gel to give an inseparable mixture of (3S,5S)-8c
and (3R,5R)-8d (0.792 g, 90%).
4.4. Acetylation of isoxazolidines (3S,5S)-5c and (3R,5R)-5d
A mixture of isoxazolidines (3S,5S)-5c and (3R,5R)-5d
(0.958 g, 2.79 mmol), acetic anhydride (0.791 mL, 8.37
mmol) and triethylamine (1.28 mL, 9.21 mmol) containing
DMAP (0.034 g, 0.279 mmol) in methylene chloride
(10 mL) was stirred at room temperature for 24 h. The
reaction mixture was washed with water (3 · 5 mL), dried
over MgSO4, concentrated in vacuo and the residue chro-
matographed on silica gel with hexane–isopropanol (50:1,
v/v) to give phosphonates (3S,5S)-7c (0.507 g, 47%) and
(3R,5R)-7d (0.399 g, 37%).
4.2.2. Cycloaddition of the nitrone (S)-6 to allyl alcohol in
the presence of MgBr2. To a freshly prepared solution of
MgBr2 (10 mmol) in Et2O, nitrone (S)-6 (0.576 g,
2.02 mmol) in methylene chloride (3 mL) was added fol-
lowed by allyl alcohol (0.687 mL, 10.1 mmol). The reaction
mixture was stirred at room temperature for 24 h. After re-
moval of the volatiles, the crude product was purified by
column chromatography on silica gel to give an inseparable
mixture of (3S,5S)-5c and (3R,5R)-5d (0.587 g, 85%).
4.4.1. Diethyl (3S,5S)-5-(acetoxymethyl)-2-[(S)-1-phenyl-
ethyl]isoxazolidinyl-3-phosphonate (3S,5S)-7c. IR (film):
m = 3463, 2983, 2934, 1743, 1454, 1371, 1240, 1049,
20
968 cmꢂ1. ½aꢃD ¼ ꢂ12:2 (c 1.9, CHCl3). 1H NMR (CDCl3):
4.2.3. Cycloaddition of the nitrone (S)-6 to allyl alcohol in
the presence of ZnCl2. A solution of nitrone (S)-6
(0.143 g, 0.501 mmol) and allyl alcohol (0.034 mL, 0.502
mmol) in methylene chloride (2 mL) ZnCl2 (0.068 g,
0.501 mmol) was added. The reaction mixture was stirred
d = 7.40–7.20 (m, 5H), 4.47 (ddt, J = 8.4, 7.2, 4.2 Hz, 1H,
H–C5), 4.31 (dAB, JAB = 11.4 Hz, J = 4.2 Hz, 1H, H–
C10), 4.24 (dAB, JAB = 11.4 Hz, J = 7.2 Hz, 1H, H–C10),
4.16 (q, J = 7.2 Hz, 1H), 4.07–3.93 (m, 1H), 3.90–3.75
(m, 2H), 3.47 (ddd, J = 10.8, 10.0, 3.6 Hz, 1H, H–C3),

1358
D. G. Piotrowska, I. E. Głowacka / Tetrahedron: Asymmetry 18 (2007) 1351–1363
2.67 (dddd, J = 21.0, 12.9, 10.0, 8.4 Hz, 1H, H–C4), 2.22
(dddd, J = 20.7, 12.9, 7.2, 3.6 Hz, 1H, H–C4), 2.10 (s,
3H, CH3C(O)), 1.47 (d, J = 6.6 Hz, 3H, CH–CH3), 1.31
(t, J = 7.2 Hz, 3H), 1.21 (t, J = 7.2 Hz, 3H). 13C NMR
(CDCl3): d = 170.88, 142.08, 128.67, 128.09, 127.98, 74.71
(d, J = 1.7 Hz, C5), 65.04 (d, J = 16.6 Hz, CH–Ph),
65.06, 63.11 (d, J = 7.5 Hz), 62.56 (d, J = 6.6 Hz), 59.35
(d, J = 176.6 Hz, C3), 32.43 (s, C4), 21.16, 20.89, 16.79
(d, J = 6.0 Hz), 16.67 (d, J = 6.0 Hz). 31P NMR (CDCl3):
d = 24.38. Anal. Calcd for C18H28NO6P: C, 56.10; H,
7.32; N, 3.64. Found: C, 56.01; H, 7.59; N, 3.68.
4.6.1. Ammonolysis of (3S,5S)-7c. From acetate (3S,5S)-
7c (0.507 g, 1.32 mmol), phosphonate (3S,5S)-5c (0.397 g,
87%) was obtained as a colourless oil identical in all
respects with the material described in Section 4.2.1.2.
4.6.2. Ammonolysis of (3R,5R)-7d. From acetate (3R,5R)-
7d (0.399 g, 1.04 mmol), phosphonate (3R,5R)-5d (0.314 g,
88%) was obtained as a colourless oil.
4.6.2.1. Diethyl (3R,5R)-5-(hydroxymethyl)-2-((S)-1-
phenylethyl)isoxazolidinyl-3-phosphonate (3R,5R)-5d. IR
(film): m = 3399, 2981, 1454, 1230, 1053, 1029, 969 cmꢂ1
.
20
½aꢃD ¼ ꢂ63:6 (c 1.5, CHCl3). 1H NMR (CDCl3):
d = 7.40–7.20 (m, 5H), 4.36–4.15 (m, 4H, 2 · CH2OP),
4.09 (dddd, J = 8.1, 6.6, 3.6, 2.1 Hz, 1H, H–C5), 4.02
(dq, J = 6.3, 1.5 Hz, 1H, HC–N), 3.71 (dd, J = 12.3,
2.1 Hz, 1H, H–C10), 3.56 (dt, J = 9.3, 5.4 Hz, 1H, H–C3),
3.53 (dd, J = 12.3, 3.6 Hz, 1H, H–C10), 3.20 (br s, 1H,
OH), 2.62 (dddd, J = 19.8, 12.9, 6.6, 5.4 Hz, 1H, H–C4),
2.43 (dddd, J = 19.5, 12.9, 9.3, 8.1 Hz, 1H, H–C4), 1.47
(d, J = 6.3 Hz, 3H, CH–CH3), 1.38 (t, J = 6.9 Hz, 3H),
1.36 (t, J = 6.9 Hz, 3H). 13C NMR (CDCl3): d = 141.13,
128.31, 128.25, 127.53, 77.35 (d, J = 4.0 Hz, C5), 64.10
(d, J = 13.2 Hz, CH–Ph), 63.73 (d, J = 6.9 Hz), 62.77 (d,
J = 6.9 Hz), 62.23 (s, C10), 59.20 (d, J = 176.1 Hz, C3),
30.91 (s, C4), 21.74 (s, CH–CH3), 16.87 (d, J = 5.7 Hz),
16.75 (d, J = 5.7 Hz). 31P NMR (CDCl3): d = 24.36. Anal.
Calcd for C16H26NO5P: C, 55.97; H, 7.63; N, 4.08. Found:
C, 55.70; H, 7.86; N, 3.89.
4.4.2. Diethyl (3R,5R)-5-(acetoxymethyl)-2-[(S)-1-phenyl-
ethyl]isoxazolidinyl-3-phosphonate (3R,5R)-7d. IR (film):
m = 3464, 2982, 2936, 1743, 1236, 1048, 1027, 968 cmꢂ1
.
20
½aꢃD ¼ ꢂ74:4 (c 1.2, CHCl3). 1H NMR (CDCl3):
d = 7.42–7.22 (m, 5H), 4.31–4.13 (m, 5H), 4.11 (dAB,
JAB = 11.4 Hz, J = 5.4 Hz, 1H, H–C10), 4.08 (dAB,
JAB = 11.4 Hz, J = 4.5 Hz, 1H, H–C10), 3.92 (dddd,
J = 8.1, 6.9, 5.4, 4.5 Hz, 1H, H–C5), 3.35 (ddd, J = 8.4,
8.1, 4.2 Hz, 1H, H–C3), 2.37 (dddd, J = 12.6, 9.0, 8.4,
6.9, 1H, H–C4), 2.17 (ddt, J = 18.9, 12.6, 8.1 Hz, 1H, H–
C4), 2.04 (s, 3H, CH3C(O)), 1.56 (d, J = 6.9 Hz, 3H,
CH–CH3), 1.37 (t, J = 7.2 Hz, 3H), 1.34 (t, J = 7.2 Hz,
3H). 13C NMR (CDCl3): d = 170.79, 139.79, 129.26,
128.20, 127.66, 73.98 (d, J = 6.9 Hz, C5), 64.72, 64.66 (d,
J = 8.6 Hz, CH–Ph), 63.59 (d, J = 6.6 Hz), 62.67 (d,
J = 7.2 Hz), 58.34 (d, J = 173.5 Hz, C3), 34.62 (d,
J = 1.7 Hz, C4), 21.20, 21.10, 16.87 (d, J = 5.4 Hz), 16.79
(d, J = 5.7 Hz). 31P NMR (CDCl3): d = 23.71. Anal. Calcd
for C18H28NO6P: C, 56.10; H, 7.32; N, 3.64. Found: C,
55.89; H, 7.33; N, 3.59.
4.7. Mesylation of (3S,5R)-5a, (3S,5S)-5c, (3R,5R)-5d and
(3R,5S)-8b (general procedure)
To a solution of phosphonate (3S,5R)-5a, (3S,5S)-5c,
(3R,5R)-5d or (3R,5S)-8d (0.343 g, 1.00 mmol) in methyl-
ene chloride (10 mL), triethylamine (0.418 mL, 3.00 mmol)
was added at 0 ꢁC followed by mesyl chloride (0.116 mL,
1.50 mmol). The reaction mixture was stirred at this tem-
perature for 2 h, washed with water (3 · 5 mL), dried over
MgSO4, concentrated in vacuo and the residue was chro-
matographed on silica gel with chloroform–methanol
(100:1, v/v).
4.5. Acetylation of isoxazolidines (3S,5S)-8c and (3R,5R)-8d
A mixture of isoxazolidines (3S,5S)-8c and (3R,5R)-8d
(0.692 g, 2.02 mmol) was acetylated as described in Section
4.4 to give phosphonates (3S,5S)-9c (0.272 g, 35%) and
(3R,5R)-9d (0.163 g, 21%).
4.5.1. Diethyl (3S,5S)-5-(acetoxymethyl)-2-[(R)-1-phenyl-
ethyl]isoxazolidinyl-3-phosphonate (3S,5S)-9c (ent-7d).
20
½aꢃD ¼ þ76:3 (c 1.8, CHCl3). Anal. Calcd for C18H28NO6P:
4.7.1. Diethyl (3S,5R)-5-(mesyloxymethyl)-2-[(S)-1-phenyl-
(3S,5R)-10a. From
C, 56.10; H, 7.32; N, 3.64. Found: C, 55.95; H, 7.56; N,
3.55.
ethyl]isoxazolidinyl-3-phosphonate
phosphonate (3S,5R)-5a (0.267 g, 0.776 mmol), mesylate
(3S,5R)-10a (0.30 g, 91%) was obtained as a colourless
4.5.2. Diethyl (3R,5R)-5-(acetoxymethyl)-2-[(R)-1-phenyl-
ethyl]isoxazolidinyl-3-phosphonate (3R,5R)-9d (ent-7c).
Anal. Calcd for C18H28NO6P: C, 56.10; H, 7.32; N, 3.64.
Found: C, 55.85; H, 7.13; N, 3.67.
oil. IR (film): m = 2984, 2935, 1454, 1355, 1241, 1175,
20
1053, 1027, 965 cmꢂ1. ½aꢃD ¼ ꢂ19:0 (c 3.0, CHCl3). 1H
NMR (CDCl3): d = 7.40–7.20 (m, 5H), 4.54 (ddt, J = 9.0,
6.9, 5.1, 1H, H–C5), 4.34 (d, J = 5.1 Hz, 2H, H2C-10),
4.23–4.12 (m, 2H), 4.10–3.92 (m, 3H), 3.55 (ddd, J = 9.6,
9.3, 1.8 Hz, 1H, H–C3), 3.05 (s, 3H), 2.58 (dddd,
J = 14.7, 13.2, 6.9, 1.8 Hz, 1H, H–C4), 2.32 (dddd, J =
29.4, 13.2, 9.3, 9.0 Hz, 1H, H–C4), 1.50 (d, J = 6.5 Hz,
3H, CH–CH3), 1.32 (t, J = 7.2 Hz, 3H), 1.26 (t,
J = 7.2 Hz, 3H). 13C NMR (CDCl3): d = 142.29, 128.62,
127.90, 127.87, 77.10 (d, J = 2.0 Hz, C5), 69.82, 66.42 (d,
J = 14.0 Hz, CH–Ph), 63.15 (d, J = 7.2 Hz), 62.71 (d,
J = 6.9 Hz), 59.37 (d, J = 174.3 Hz, C3), 37.99, 31.82,
19.54, 16.77 (d, J = 6.6 Hz), 16.68 (d, J = 6.3 Hz). 31P
NMR (CDCl3): d = 22.74. Anal. Calcd for C17H28NO7SP:
4.6. Ammonolysis of (3S,5S)-7c and (3R,5R)-7d (general
procedure)
A solution of phosphonate (3S,5S)-7c or (3R,5R)-7d
(0.385 g, 1.00 mmol) in ethanol (10 mL) containing aque-
ous NH3 (25%, 15 mL) was left at room temperature for
4 h. The volatiles were removed and the residue was evap-
orated with anhydrous ethanol (3 · 10 mL), chloroform
(3 · 10 mL) and finally chromatographed on silica gel with
chloroform–methanol (50:1, v/v).

D. G. Piotrowska, I. E. Głowacka / Tetrahedron: Asymmetry 18 (2007) 1351–1363
1359
C, 48.45; H, 6.70; N, 3.32. Found: C, 48.19; H, 6.67; N,
3.36.
for 7 days. The suspension was filtered through a layer of
Celite and the solution was concentrated to give pure
ammonium mesylate [(3S,5R)-10a, (3S,5S)-10c, (3R,5R)-
10d or (3R,5S)-12b], which was dissolved in chloroform
(5 mL) and stirred with potassium carbonate (0.276 g,
2.00 mmol) at room temperature for 3 h. Then anhydrous
MgSO4 was added and the suspension was filtered through
a pad of Celite. The solution was concentrated and the res-
idue chromatographed on a silica gel column with chloro-
form–methanol (first 50:1 and later 10:1, v/v).
4.7.2. Diethyl (3S,5S)-5-(mesyloxymethyl)-2-[(S)-1-phenyl-
ethyl]isoxazolidinyl-3-phosphonate
(3S,5S)-10c. From
phosphonate (3S,5S)-5c (0.095 g, 0.277 mmol), mesylate
(3S,5S)-10c (0.112 g, 96%) was obtained as a colourless
oil. IR (film): m = 3463, 2984, 2935, 1455, 1356, 1243,
20
1175, 1052, 1028, 965 cmꢂ1. ½aꢃD ¼ þ2:8 (c 1.2, CHCl3).
1H NMR (CDCl3): d = 7.40–7.20 (m, 5H), 4.55 (dddd,
J = 8.4, 7.2, 6.0, 3.6 Hz, 1H, H–C5), 4.46 (dAB, JAB
=
=
10.8 Hz, J = 7.2 Hz, 1H, H–C10), 4.35 (dAB, JAB
10.8 Hz, J = 3.6 Hz, 1H, H–C10), 4.23–4.08 (m, 2H),
4.07–3.84 (m, 3H), 3.48 (ddd, J = 10.8, 9.6, 3.6 Hz, 1H,
H–C3), 3.01 (s, 3H), 2.69 (dddd, J = 21.9, 13.2, 9.6,
8.4 Hz, 1H, H–C4), 2.22 (dddd, J = 19.5, 13.2, 6.0,
3.6 Hz, 1H, H–C4), 1.48 (d, J = 6.3 Hz, 3H, CH–CH3),
1.32 (t, J = 7.2 Hz, 3H), 1.24 (t, J = 7.2 Hz, 3H).
13C NMR (CDCl3): d = 141.88, 128.70, 128.03, 127.99,
74.72 (d, J = 2.3 Hz, C5), 70.09, 64.74 (d, J = 15.5 Hz,
CH–Ph), 63.22 (d, J = 7.2 Hz), 62.54 (d, J = 6.6 Hz),
58.96 (d, J = 176.6 Hz, C3), 37.63, 31.95, 19.88, 16.76 (d,
J = 6.3 Hz), 16.67 (d, J = 6.3 Hz). 31P NMR (CDCl3):
d = 23.57. Anal. Calcd for C17H28NO7SP: C, 48.45; H,
6.70; N, 3.32. Found: C, 48.20; H, 6.77; N, 3.30.
4.8.1. Diethyl (2S,4R)-4-hydroxypyrrolidinyl-2-phosphonate
(0.222 g,
0.527 mmol), phosphonate (2S,4R)-4 (0.084 g, 72%) was
(2S,4R)-4. From
mesylate
(3S,5R)-10a
obtained as a colourless oil. IR (film): m = 3400, 2983,
20
1657, 1444, 1393, 1217, 1026, 969 cmꢂ1. ½aꢃ ¼ þ10:7 (c
D
1
1.1, MeOH). H NMR (CDCl3): d = 4.36 (br m, 1H, H–
C4), 4.30–4.10 (m, 4H, 2 · CH2OP), 3.47 (ddd, J(2–3b)
=
10.5 Hz, J(2–P) = 5.1 Hz, J(2–3a) = 3.6 Hz, 1H, H–C2), 3.12
(br tAB, JAB = 10.5 Hz, J(5-4) = J(5-NH) = 1.2 Hz, 1H,
H–C5), 4.35 (dAB, JAB = 10.8 Hz, J(5-4) = 4.2 Hz, 1H,
H–C5), 3.28 (dddd, J(3b–P) = 25.2 Hz, J(3a–3b) = 14.7 Hz,
J(3b–2) = 10.5 Hz, J(3b–4) = 5.7 Hz, 1H, Hb–C3), 3.11
(ddd, J(3a–P) = 15.0 Hz, J(3a–3b) = 14.7 Hz, J(3a–2)
=
3.6 Hz, 1H, Ha–C3), 1.80 (br s, 2H, OH and NH), 1.36
(t, J = 7.2 Hz, 3H), 1.35 (t, J = 7.2 Hz, 3H). 13C NMR
(CDCl3): d = 72.32 (d, J = 3.7 Hz, C4), 63.40 (d,
J = 7.2 Hz), 62.64 (d, J = 7.2 Hz), 56.64 (d, J = 8.9 Hz,
C5), 52.84 (d, J = 162.3 Hz, C2), 36.51 (s, C3), 16.84 (d,
J = 5.7 Hz), 16.81 (d, J = 5.7 Hz). 31P NMR (CDCl3):
d = 29.96. Anal. Calcd for C8H18NO4P: C, 43.05; H,
8.13; N, 6.28. Found: C, 43.06; H, 8.27; N, 6.01.
4.7.3. Diethyl (3R,5R)-5-(mesyloxymethyl)-2-[(S)-1-phenyl-
(3R,5R)-10d. From
ethyl]isoxazolidinyl-3-phosphonate
phosphonate (3R,5R)-5d (0.266 g, 0.775 mmol), mesylate
(3R,5R)-10d (0.286 g, 88%) was obtained as a colourless
oil. IR (film): m = 3460, 2982, 1454, 1355, 1246, 1175,
20
1051, 1025, 963 cmꢂ1. ½aꢃD ¼ ꢂ54:3 (c 2.1, CHCl3). 1H
NMR (CDCl3): d = 7.41–7.25 (m, 5H), 4.38–4.08 (m, 8H,
2 · CH2OP, CH2–OMs, H–C5 and CH–CH3), 3.34 (ddd,
J = 9.0, 7.5, 5.1, 1H, H–C3), 2.91 (s, 3H), 2.43 (dddd,
J = 12.9, 12.0, 9.0, 7.5 Hz, 1H, H–C4), 2.19 (dddd, J =
18.9, 12.0, 7.5, 7.2 Hz, 1H, H–C4), 1.54 (d, J = 6.9 Hz,
3H, CH–CH3), 1.38 (t, J = 7.2 Hz, 3H), 1.35 (t,
J = 7.2 Hz, 3H). 13C NMR (CDCl3): d = 139.75, 129.05,
128.26, 127.73, 73.91 (d, J = 6.0 Hz, C5), 70.09, 64.62 (d,
J = 8.3 Hz, CH–Ph), 63.40 (d, J = 6.9 Hz), 62.86 (d,
J = 6.9 Hz), 58.09 (d, J = 174.1 Hz, C3), 37.75, 33.80,
21.27, 16.84 (d, J = 4.6 Hz), 16.77 (d, J = 5.4 Hz). 31P
NMR (CDCl3): d = 22.93. Anal. Calcd for C17H28NO7SP:
C, 48.45; H, 6.70; N, 3.32. Found: C, 48.44; H, 6.66; N,
3.41.
4.8.2. Diethyl (2R,4S)-4-hydroxypyrrolidinyl-2-phosphonate
(2R,4S)-4. From
mesylate
(3R,5S)-12b
(0.160 g,
0.378 mmol), phosphonate (2R,4S)-4 (0.059 g, 69%) was
20
obtained as a colourless oil. ½aꢃD ¼ ꢂ9:8 (c 1.6, MeOH).
Anal. Calcd for C8H18NO4P: C, 43.05; H, 8.13; N, 6.28.
Found: C, 43.26; H, 8.26; N, 6.01.
4.8.3. Diethyl (2S,4S)-4-hydroxypyrrolidinyl-2-phosphonate
(0.285 g,
(2S,4S)-4. From
mesylate
(3S,5S)-10c
0.676 mmol), phosphonate (2S,4S)-4 (0.112 g, 75%) was
obtained as a colourless oil. IR (film): m = 3349, 2982,
2936, 2910, 1442, 1392, 1224, 1052, 1029, 965 cmꢂ1
.
20
1
4.7.4. Diethyl (3R,5S)-5-(mesyloxymethyl)-2-[(R)-1-phenyl-
ethyl]isoxazolidinyl-3-phosphonate (3R,5S)-12b (ent-10a).
From phosphonate (3R,5S)-8b (0.210 g, 0.611 mmol), mes-
½aꢃD ¼ ꢂ4:6 (c 1.0, MeOH). H NMR (CDCl3): d = 4.52–
4.47 (br m, 1H, H–C4), 4.24–4.10 (m, 4H, 2 · CH2OP),
3.64 (ddd, J = 8.7, 8.4, 5.7 Hz, 1H, H–C2), 3.07 (dAB,
JAB = 12.0 Hz, J(5-4) = 3.9 Hz, 1H, H–C5), 4.35 (tAB,
JAB = 10.8 Hz, J = 1.5 Hz, 1H, H–C5), 2.20–2.00 (m, 2H,
H2C-3), 1.73 (br s, 2H, NH and OH), 1.34 (t, J = 7.2 Hz,
ylate (3R,5S)-12b (0.208 g, 81%) was obtained as a colour-
20
less oil. ½aꢃD ¼ þ19:6 (c 1.4, CHCl3). Anal. Calcd for
C17H28NO7SP: C, 48.45; H, 6.70; N, 3.32. Found: C,
48.47; H, 6.62; N, 3.09.
1
3H), 1.33 (t, J = 7.2 Hz, 3H). H NMR (C6D6): d = 4.20–
3.95 (m, 5H, 2 · CH2OP and H–C4), 3.61 (ddd, J = 9.0,
8.1, 5.4 Hz, 1H, H–C2), 2.88 (dAB, JAB = 11.7 Hz,
J = 3.9 Hz, 1H, H–C5), 2.72 (tAB, JAB = 11.7 Hz,
J = 1.5 Hz, 1H, H–C5), 2.08 (dddd, J = 19.2, 13.2, 9.0,
4.8 Hz, 1H, H–C3), 2.00–1.90 (m, 1H, H–C3), 1.30 (br s,
2H, NH and OH), 1.08 (t, J = 7.2 Hz, 3H), 1.06 (t,
J = 7.2 Hz, 3H). 13C NMR (CDCl3): d = 72.10 (d, J =
7.4 Hz, C4), 62.56 (d, J = 6.9 Hz), 55.84 (d, J = 7.7 Hz,
4.8. Synthesis of the proline phosphonates 4 from the
mesylates (3S,5R)-10a, (3S,5S)-10c, (3R,5R)-10d and
(3R,5S)-12b (general procedure)
A solution of O-mesylate (0.422 g, 1.00 mmol) in ethanol
(5 mL) was kept under an atmospheric pressure of hydro-
gen over 20% Pd(OH)2–C (10 mg) at room temperature

1360
D. G. Piotrowska, I. E. Głowacka / Tetrahedron: Asymmetry 18 (2007) 1351–1363
C5), 52.47 (d, J = 170.6 Hz, C2), 36.63 (s, C3), 16.73 (d,
J = 5.4 Hz). 31P NMR (CDCl3): d = 28.92. Anal. Calcd
for C8H18NO4P: C, 43.05; H, 8.13; N, 6.28. Found: C,
42.91; H, 8.37; N, 6.12.
1H NMR (CDCl3): d = 7.43–7.26 (m, 10H), 5.00–4.89 (br
m, 1H, H–C4), 4.87 (s, 1H, CHC(O)N), 4.74 (s, 1H,
CHC(O)O), 4.65–4.53 (br m, 1H, H–C2), 4.21 (dd,
J = 11.4, 7.2 Hz, 1H, H–C5), 4.20–4.03 (m, 4H), 3.43 (s,
3H, H3CO–CH–C(O)N), 3.36 (s, 3H, H3CO–CH–
C(O)O), 3.28 (dd, J = 11.7, 6.3 Hz, 1H, H–C5), 2.58–2.30
(m, 1H, H–C3), 2.15 (ddt, J = 17.7, 14.4, 4.8 Hz, 1H, H–
C3), 1.29 (t, J = 7.2 Hz, 3H), 1.27 (t, J = 7.2 Hz, 3H).
13C NMR (CDCl3): d = 170.37, 168.59 (d, J = 1.6 Hz),
135.72, 135.60, 128.99, 128.85, 128.80, 128.75, 127.38,
127.36, 84.05, 82.29, 72.53, 63.01 (d, J = 6.8 Hz), 62.61
(d, J = 5.3 Hz), 57.85, 57.47, 51.71 (d, J = 156.0 Hz, C2),
50.68, 31.17, 16.78 (d, J = 6.0 Hz), 16.65 (d, J = 6.9 Hz).
31P NMR (CDCl3): d = 23.83.
4.8.4. Diethyl (2R,4R)-4-hydroxypyrrolidinyl-2-phosphonate
(2R,4R)-4. From
mesylate
(3R,5R)-10d
(0.264 g,
0.626 mmol), phosphonate (2R,4R)-4 (0.192 g, 57%) was
20
obtained as a colourless oil. ½aꢃD ¼ þ3:8 (c 7.0, MeOH).
Anal. Calcd for C8H18NO4P: C, 43.05; H, 8.13; N, 6.28.
Found: C, 43.39; H, 8.36; N, 5.96.
4.8.5. Decomposition products of (2S,4S)-4. A sample
(0.159 g) of phosphonate (2S,4S)-4, which was left at
+5 ꢁC for 7 days, was chromatographed on silica gel with
chloroform–methanol (50:1, v/v) to give phosphonate
(2S,4S)-13 (0.028 g, 18%) and (2S,4S)-4 (0.139 g, 87%).
Further elution with methanol gave impure (2S,4S)-14
(0.013 g, 8%).
4.9.2. Diethyl (2R,4S)-4-[(S)-2-methoxy-2-phenylacetoyl-
oxy]-1-[(S)-2-methoxy-2-phenylacetyl]pyrrolidinyl-2-phos-
phonate (2R,4S)-15b. From (2R,4S)-4 (0.045 g, 0.202
mmol), phosphonate (2R,4S)-15b (0.086 g, 82%) was ob-
1
tained as a colourless oil. H NMR (CDCl3): d = 7.41–
7.26 (m, 10H), 5.38 (s, 0.13 · 1H), 5.00 (dddd, J = 9.9,
6.6, 5.7, 4.8 Hz, 1H, H–C4), 4.94 (s, 0.87 · 1H, CHC(O)N),
4.76 (s, 0.13 · 1H), 4.74 (s, 0.87 · 1H, CHC(O)O), 4.65
(ddd, J = 10.5, 7.5, 4.8 Hz, 1H, H–C2), 4.25–3.98 (m,
4H), 3.90 (dd, J = 12.0, 6.6 Hz, 1H, H–C5), 3.47 (s,
0.87 · 3H, H3CO–CH–C(O)N), 3.42 (s, 0.13 · 3H), 3.39
(s, 0.13 · 3H), 3.37 (s, 0.87 · 3H, H3CO–CH–C(O)O),
3.20 (dd, J = 12.0, 5.7 Hz, 1H, H–C5), 2.50 (dddd,
J = 20.4, 14.4, 9.9, 7.5 Hz, 1H, H–C3), 2.30 (ddt, J =
19.8, 14.4, 4.8 Hz, 1H, H–C3), 1.33 (t, J = 7.2 Hz, 3H),
1.18 (t, J = 7.2 Hz, 3H). 13C NMR (CDCl3): d = 170.14
(major), 169.56 (minor), 169.12 (d, J = 1.4 Hz), 135.77,
135.45, 129.35 (minor), 129.20, 129.00, 128.86 (minor),
128.78 (minor), 128.70, 128.66, 128.41, 128.37 (minor),
127.28, 126.53, 83.78 (major), 82.33 (minor), 82.24 (major),
81.10 (minor), 72.67 (major), 70.89 (minor), 63.15 (d,
J = 6.6 Hz, minor), 62.63 (d, J = 6.8 Hz, major), 62.57 (d,
J = 6.0 Hz, major), 57.53, 57.45, 51.59 (d, J = 159.2 Hz,
C2), 50.63, 33.82 (minor), 31.20 (major), 16.65 (d,
J = 6.4 Hz), 16.58 (d, J = 6.0 Hz). 31P NMR (CDCl3):
d = 24.09 (87%) and 23.25 (13%).
4.8.5.1. O,O-Diethyl (2S,4S)-1-ethyl-4-hydroxypyrrolidin-
yl-2-phosphonate (2S,4S)-13. IR (film): m = 3389, 2978,
20
2934, 1445, 1222, 1026, 964 cmꢂ1. ½aꢃD ¼ þ37:4 (c 1.65,
CHCl3). 1H NMR (CDCl3): d = 4.50–4.22 (m, 1H, H–
C4), 4.21–4.10 (m, 4H), 3.36 (dd, J = 9.9, 5.1 Hz, 1H, H–
C5), 3.19–3.07 (m, 2H), 2.62–2.51 (m, 2H), 2.42 (ddd,
J = 9.9, 4.8, 0.9 Hz, 1H, H–C5), 2.26 (dddd, J = 17.1,
13.8, 8.1, 6.0 Hz, 1H, H–C3), 2.01 (ddddd, J = 13.8, 12.3,
8.7, 4.2, 0.9 Hz, 1H, H–C3), 1.32 (t, J = 7.2 Hz, 6H), 1.08
(t, J = 7.2 Hz, 3H). 13C NMR (CDCl3): d = 70.68 (d,
J = 7.5 Hz, C4), 62.70 (d, J = 6.8 Hz), 62.32 (d, J =
7.5 Hz), 61.16 (d, J = 13.6 Hz), 58.96 (d, J = 175.1 Hz,
C2), 50.77 (d, J = 2.3 Hz), 36.83 (d, J = 1.5 Hz, C3),
16.85 (d, J = 5.3 Hz), 13.86. 31P NMR (CDCl3): d =
27.44. Anal. Calcd for C10H22NO4P: C, 47.80; H, 8.82;
N, 5.58. Found: C, 47.63; H, 8.89; N, 5.37.
4.8.5.2. O-Ethyl (2S,4S)-4-hydroxypyrrolidinyl-2-phos-
phonate (2S,4S)-14. 1H NMR (CD3OD): d = 4.58–4.55
(br m, 1H), 3.98 (qu, J = 7.1 Hz, 2H), 3.78–3.60 (m, 1H),
3.34 (dd, J = 12.0, J = 4.0 Hz, 1H), 3.15 (d, J = 12.0 Hz,
1H), 2.21–2.05 (m, 2H), 1.29 (t, J = 7.1 Hz, 3H). 31P
NMR (CD3OD): d = 15.13.
4.9.3. Diethyl (2S,4S)-4-[(S)-2-methoxy-2-phenylacetoyl-
oxy]-1-[(S)-2-methoxy-2-phenylacetyl]pyrrolidinyl-2-phos-
phonate
(2S,4S)-15c. From
(2S,4S)-4
(0.020 g,
4.9. Synthesis of N,O-bismandelic acid derivatives 15
(general procedure)
0.090 mmol), phosphonate (2S,4S)-15c (0.33 g, 72%) was
obtained as a colourless oil. H NMR (CDCl3): d = 7.40–
1
7.25 (m, 10H), 5.30 (br m, 1H, H–C4), 4.75 (s, 1H,
CHC(O)N), 4.67 (dt, J = 9.3, 5.4 Hz, 1H, H–C2), 4.62 (s,
1H, CHC(O)O), 4.22–3.96 (m, 4H), 3.80 (br dt, J = 12.3,
1.2 Hz, 1H, H–C5), 3.41 (dd, J = 12.3, 5.1 Hz, 1H, H–
C5), 3.33 (s, 3H, H3CO–CH–C(O)N), 3.29 (s, 3H,
H3CO–CH–C(O)O), 2.57 (dddd, J = 18.3, 15.0, 5.7,
5.4 Hz, 1H, H–C3), 2.19 (dddd, J = 19.5, 15.0, 9.3,
3.9 Hz, 1H, H–C3), 1.30 (t, J = 7.2 Hz, 3H), 1.23 (t,
J = 7.2 Hz, 3H). 13C NMR (CDCl3): d = 170.15, 168.76
(d, J = 1.6 Hz), 135.85, 135.76, 129.05, 128.85, 128.62,
128.48, 127.34, 127.25, 127.00, 84.60, 82.54, 74.31 (d,
J = 2.3 Hz, C4), 62.97 (d, J = 7.2 Hz), 62.87 (d,
J = 6.9 Hz), 57.55, 57.50, 51.56 (d, J = 160.6 Hz, C2),
51.41, 32.24, 16.68 (d, J = 5.3 Hz), 16.57 (d, J = 5.3 Hz).
31P NMR (CDCl3): d = 24.27.
To a solution of the phosphonate 4 (0.018 g, 0.080 mmol)
and (S)-O-methylmandelic acid (0.033 g, 0.202 mmol) in
methylene chloride (2 mL) containing DMAP (two crys-
tals) DCC (0.045 g, 0.218 mmol) was added. After stirring
for 24 h at room temperature DCU was filtered off, the
residue was concentrated and filtered though a pad of
silica gel. A crude product was dissolved in chloroform-D
1
and H, 13C and 31P NMR spectra were taken.
4.9.1. Diethyl (2S,4R)-4-[(S)-2-methoxy-2-phenylacetoyl-
oxy]-1-[(S)-2-methoxy-2-phenylacetyl]pyrrolidinyl-2-phosph-
onate (2S,4R)-15a. From (2S,4R)-4 (0.018 g, 0.080 mmol)
the phosphonate (2S,4R)-15a (0.02 g, 50%) was obtained as
a colourless oil.

D. G. Piotrowska, I. E. Głowacka / Tetrahedron: Asymmetry 18 (2007) 1351–1363
1361
4.9.4. Diethyl (2R,4R)-4-[(S)-2-methoxy-2-phenylacetoyl-
oxy]-1-[(S)-2-methoxy-2-phenylacetyl]pyrrolidinyl-2-phospho-
nate (2R,4R)-15d. From (2R,4R)-4 (0.030 g, 0.130 mmol)
phosphonate (2R,4R)-15d (0.052 g, 74%) was obtained as a
4.10.3. Diethyl (2S,4S)-4-hydroxy-1-[(S)-2-methoxy-2-phen-
ylacetyl]pyrrolidinyl-2-phosphonate (2S,4S)-16c. From
(2S,4S)-15c (0.028 g, 0.054 mmol) phosphonate (2S,4S)-
16c (0.016 g, 80%) was obtained as a colourless oil. 1H
NMR (CDCl3): d = 7.50–7.40 (m, 2H), 7.40–7.30 (m,
3H), 4.92 (s, 1H, CHC(O)N), 4.77–4.68 (m, 1H, H–C2),
4.55–4.47 (br m, 1H, H–C4), 4.25–4.00 (m, 4H), 3.70 (br
d, J = 11.7 Hz, 1H, H–C5), 3.46 (s, 3H, H3CO–CH–
C(O)N), 3.40 (dd, J = 11.7, 4.8 Hz, 1H, H–C5), 2.50–2.30
(m, 1H, H–C3), 2.15–1.95 (m, 1H, H–C3), 1.70 (br s, 1H,
OH), 1.33 (t, J = 7.2 Hz, 3H), 1.26 (t, J = 7.2 Hz, 3H).
31P NMR (CDCl3): d = 24.81.
1
colourless oil. H NMR (CDCl3): d = 7.55–7.20 (m, 10H),
5.51 (s, 0.12 · 1H), 5.35–5.26 (br m, 0.12 · 1H), 5.25–5.17
(br m, 0.88 · 1H, H–C4), 4.98 (s, 0.88 · 1H, CHC(O)N),
4.56 (dt, J = 9.6, 6.6 Hz, 1H, H–C2), 4.44 (s, 0.12 · 1H),
4.29 (s, 0.88 · 1H, CHC(O)O), 4.25–3.98 (m, 4H), 3.90
(br d, J = 12.9 Hz, 1H, H–C5), 3.52 (dd, J = 12.9,
4.5 Hz, 1H, H–C5), 3.50 (s, 0.88 · 3H, H3CO–CH–
C(O)N), 3.45 (s, 0.12 · 3H), 3.35 (s, 0.12 · 3H), 3.28 (s,
0.88 · 3H, H3CO–CH–C(O)O), 2.36 (ddt, J = 19.5, 14.7,
6.6 Hz, 1H, H–C3), 1.85 (dddt, J = 18.6, 14.7, 9.6,
1.8 Hz, 1H, H–C3), 1.30 (t, J = 7.2 Hz, 3H), 1.23 (t, J =
7.2 Hz, 3H). 13C NMR (CDCl3): d = 169.76, 169.64 (d,
J = 1.6 Hz), 136.02, 135.60, 129.17, 128.96, 128.81,
128.65, 128.32, 127.01, 126.39, 84.03, 81.89, 73.91 (d,
J = 3.4 Hz, C4), 62.78 (d, J = 6.0 Hz), 62.66 (d, J =
7.2 Hz), 57.61, 57.31, 52.23, 50.74 (d, J = 161.8 Hz, C2),
31.70, 16.67 (d, J = 6.0 Hz), 16.64 (d, J = 6.0 Hz). 31P
NMR (CDCl3): d = 24.58 (88%) and 23.08 (12%).
4.10.4. Diethyl (2R,4R)-4-hydroxy-1-[(S)-2-methoxy-2-phen-
(2R,4R)-16d. From
ylacetyl]pyrrolidinyl-2-phosphonate
(2R,4R)-15d (0.033 g, 0.064 mmol), phosphonate (2R,4R)-
1
16d (0.024 g, 99%) was obtained as a colourless oil. H
NMR (CDCl3): d = 7.50–7.40 (m, 2H), 7.40–7.30 (m,
3H), 5.51 (s, 0.17 · 1H), 5.00 (s, 0.83 · 1H, CHC(O)N),
4.80 (dt, J = 9.6, 6.0 Hz, 1H, H–C2), 4.50–4.40 (br m,
1H, H–C4), 4.30–3.90 (m, 4H), 3.61 (dt, J = 12.0, 1.5 Hz,
1H, H–C5), 3.50 (s, 0.83 · 3H, H3CO–CH–C(O)N), 3.46
(s, 0.17 · 3H), 3.44 (dd, J = 12.0, 4.5 Hz, 1H, H–C5),
2.39 (ddt, J = 19.5, 13.8, 5.7 Hz, 1H, H–C3), 2.08 (ddddd,
J = 17.4, 13.8, 9.6, 3.6, 1.5 Hz, 1H, H–C3), 1.60 (br s, 1H,
OH), 1.33 (t, J = 7.2 Hz, 3H), 1.21 (t, J = 7.2 Hz, 3H). 31P
NMR (CDCl3): d = 25.06 (83%) and 23.92 (17%).
4.10. Ammonolysis of N,O-bismandelic acid derivatives 15
(general procedure)
A solution of phosphonate 15 (0.028 g, 0.054 mmol) in eth-
anol (1.5 mL), containing aqueous NH3 (25%, 2 mL) was
left for 3 h. Volatiles were removed and the residue was
evaporated with anhydrous ethanol (3 · 5 mL), chloroform
(3 · 5 mL) and filtered though a pad of silica gel. Crude
4.11. Acetylation of 16
Phosphonates 16 were acetylated as described in Section
4.4 to give crude products 17, which were dissolved in chlo-
1
products 16 were dissolved in chloroform-D and H and
1
roform-D and H and 31P NMR spectra were taken.
31P NMR spectra were taken.
4.11.1. Diethyl (2S,4R)-4-acetoxy-1-[(S)-2-methoxy-2-phen-
ylacetyl]pyrrolidinyl-2-phosphonate
4.10.1. Diethyl (2S,4R)-4-hydroxy-1-[(S)-2-methoxy-2-phen-
ylacetyl]pyrrolidinyl-2-phosphonate
(2S,4R)-17a. From
(2S,4R)-16a. From
(2S,4R)-16a (0.010 g, 0.027 mmol) phosphonate (2S,4R)-
1
(2S,4R)-15a (0.031 g, 0.060 mmol) phosphonate (2S,4R)-
16a (0.01 g, 50%) was obtained as a colourless oil. 1H
NMR (CDCl3): d = 7.42–7.25 (m, 5H), 5.69 (br d,
J = 10.8 Hz, 1H, OH), 4.82 (s, 1H, CHC(O)N), 4.71 (t,
J = 9.6 Hz, 1H, H–C2), 4.42–4.32 (br m, 1H, H–C4),
4.32–4.00 (m, 4H), 3.73 (dd, J = 11.7, 5.7 Hz, 1H, H–C5),
3.61 (d, J = 11.7 Hz, 1H, H–C5), 3.39 (s, 3H, H3CO–
CH–C(O)N), 2.34–2.22 (m, 1H, H–C3), 2.22–2.05 (m,
1H, H–C3), 1.36 (t, J = 7.2 Hz, 3H), 1.33 (t, J = 7.2 Hz,
3H). 31P NMR (CDCl3): d = 26.34.
17a (0.011 g, 100%) was obtained as a colourless oil. H
NMR (CDCl3): d = 7.42–7.25 (m, 5H), 5.04–4.90 (br m,
1H, H–C4), 4.88 (s, 1H, CHC(O)N), 4.66–4.55 (m, 1H,
H–C2), 4.25–4.10 (m, 4H), 4.07 (dd, J = 11.7, 6.6 Hz, 1H,
H–C5), 3.45 (s, 3H, H3CO–CH–C(O)N), 3.33 (dd,
J = 11.7, 5.4 Hz, 1H, H–C5), 2.52–2.30 (m, 2H, H2C-3),
2.04 (s, 3H, H3CC(O)), 1.34 (t, J = 6.9 Hz, 3H), 1.29 (t,
J = 6.9 Hz, 3H). 31P NMR (CDCl3): d = 24.07.
4.11.2. Diethyl (2R,4S)-4-acetoxy-1-[(S)-2-methoxy-2-phen-
ylacetyl]pyrrolidinyl-2-phosphonate
(2R,4S)-17b. From
4.10.2. Diethyl (2R,4S)-4-hydroxy-1-[(S)-2-methoxy-2-
phenylacetyl]pyrrolidinyl-2-phosphonate (2R,4S)-16b. From
(2R,4S)-15b (0.067 g, 0.129 mmol) phosphonate (2R,4S)-16b
(2R,4S)-16b (0.037 g, 0.100 mmol), phosphonate (2R,4S)-
17b (0.040 g, 99%) was obtained as a colourless oil. H
1
NMR (CDCl3): d = 7.41–7.26 (m, 5H), 5.38 (s,
0.15 · 1H), 4.97 (s, 0.85 · 1H, CHC(O)N), 4.95 (dddd,
J = 10.2, 6.9, 6.0, 4.8 Hz, 1H, H–C4), 4.68 (ddd, J =
10.5, 7.5, 4.8 Hz, 1H, H–C2), 4.26–4.12 (m, 2H), 4.12–
4.00 (m, 2H), 4.02 (dd, J = 12.0, 6.9 Hz, 1H, H–C5), 3.50
(s, 0.85 · 3H, H3CO–CH–C(O)N), 3.44 (s, 0.15 · 3H),
3.32 (dd, J = 12.0, 6.0 Hz, 1H, H–C5), 2.48 (dddd,
J = 21.0, 14.4, 10.2, 7.5 Hz, 1H, H–C3), 2.30 (ddt,
J = 18.0, 14.4, 4.8 Hz, 1H, H–C3), 2.06 (s, 0.15 · 3H,
H3CC(O)), 2.03 (s, 0.85 · 3H, H3CC(O)), 1.42 (t,
J = 7.2 Hz, 0.15 · 3H), 1.38 (t, J = 7.2 Hz, 0.15 · 3H),
1.33 (t, J = 7.2 Hz, 0.85 · 3H), 1.23 (t, J = 7.2 Hz,
1
(0.037 g, 48%) was obtained as a colourless oil. H NMR
(CDCl3): d = 7.41–7.26 (m, 5H), 5.56 (br d, J = 11.1 Hz,
1H, OH), 5.10 (s, 0.1 · 1H), 4.93 (s, 0.9 · 1H, CHC(O)N),
4.85–4.77 (m, 1H, H–C2), 4.47–4.36 (br m, 1H, H–C4),
4.30–4.00 (m, 3H), 3.90–3.75 (m, 2H), 3.59 (d,
J = 12.0 Hz, 1H, H–C5), 3.44 (s, 0.9 · 3H, H3CO–CH–
C(O)N), 3.40 (s, 0.1 · 3H), 2.30–2.05 (m, 2H, H2C-3), 1.43
(t, J = 7.2 Hz, 0.1 · 3H), 1.40 (t, J = 7.2 Hz, 0.1 · 3H),
1.35 (t, J = 7.2 Hz, 0.9 · 3H), 1.22 (t, J = 7.2 Hz,
0.9 · 3H). 31P NMR (CDCl3): d = 26.83 (10%) and 26.24
(90%).

1362
D. G. Piotrowska, I. E. Głowacka / Tetrahedron: Asymmetry 18 (2007) 1351–1363
0.85 · 3H). 31P NMR (CDCl3): d = 24.23 (85%) and 23.47
4.44 (m, 1H), 4.30–4.3 (m, 4H), 3.83 (ddd, J = 11.4, 6.0,
1.2 Hz, 1H, H–C5), 3.64 (br d, J = 11.4 Hz, 0.7 · 1H, H–
C5), 3.43 (br d, J = 11.4 Hz, 0.3 · 1H, H–C5), 2.40–2.22
(m, 2H, H2C-3), 2.17 (s, 0.3 · 3H, H3CC(O)), 2.09 (s,
0.7 · 3H, H3CC(O)), 1.38 (t, J = 7.2 Hz, 0.3 · 3H), 1.37
(t, J = 7.2 Hz, 0.7 · 3H), 1.36 (t, J = 7.2 Hz, 0.3 · 3H),
1.33 (t, J = 7.2 Hz, 0.7 · 3H). 31P NMR (CDCl3)
d = 26.85 (30%) and 26.79 (70%).
(15%).
4.11.3. Diethyl (2S,4S)-4-acetoxy-1-[(S)-2-methoxy-2-phen-
ylacetyl]pyrrolidinyl-2-phosphonate
(2S,4S)-17c. From
(2S,4S)-16c (0.016 g, 0.043 mmol) phosphonate (2S,4S)-
17c (0.017 g, 99%) was obtained as a colourless oil. 1H
NMR (CDCl3): d = 7.50–7.30 (m, 5H), 5.20–5.12 (br m,
1H, H–C4), 4.86 (s, 1H, CHC(O)N), 4.75 (dt, J = 9.6,
6.3 Hz, 1H, H–C2), 4.30–4.05 (br m, 4H), 3.94 (br d,
J = 12.3 Hz, 1H, H–C5), 3.44 (s, 3H, H3CO–CH–
C(O)N), 3.43 (dd, J = 12.3, 4.5 Hz, 1H, H–C5), 2.51 (ddt,
J = 18.9, 14.7, 6.3 Hz, 1H, H–C3), 2.27–2.12 (m, 1H, H–
C3), 1.76 (s, 3H, H3CC(O)), 1.34 (t, J = 7.2 Hz, 3H), 1.28
(t, J = 7.2 Hz, 3H). 31P NMR (CDCl3): d = 24.63.
To a solution of phosphonate (2S,4R)-19 or (2R,4S)-19
(0.021 g, 0.080 mmol) and (S)-O-methylmandelic acid
(0.022 g, 0.130 mmol) in methylene chloride (2 mL) con-
taining DMAP (two crystals) DCC (0.031 g, 0.150 mmol)
was added. After stirring for 24 h at room temperature,
the DCU was filtered off, and the residue was concentrated
and filtered though a pad of silica gel. Crude products
(2S,4R)-20a or (2R,4S)-20b were dissolved in chloroform-
4.11.4. Diethyl (2R,4R)-4-acetoxy-1-[(S)-2-methoxy-2-phen-
ylacetyl]pyrrolidinyl-2-phosphonate
1
(2R,4R)-17d. From
D and H and 31P NMR spectra were taken.
(2R,4R)-16d (0.024 g, 0.070 mmol) phosphonate (2R,4R)-
1
17d (0.023 g, 79%) was obtained as a colourless oil. H
4.12.1. Diethyl (2S,4R)-4-[(S)-2-methoxy-2-phenylacetoyl-
oxy]-1-acetylpyrrolidinyl-2-phosphonate
NMR (CDCl3): d = 7.50–7.40 (m, 2H), 7.40–7.30 (m,
3H), 5.52 (s, 0.1 · 1H), 5.25–5.16 (br m, 0.1 · 1H), 5.16–
5.10 (br m, 0.9 · 1H, H–C4), 5.01 (s, 0.9 · 1H, CHC(O)N),
4.79 (dt, J = 9.6, 6.3 Hz, 1H, H–C2), 4.30–4.00 (m, 4H),
3.86 (dt, J = 12.9, 1.5 Hz, 1H, H–C5), 3.51 (s, 0.9 · 3H,
H3CO–CH–C(O)N), 3.49 (dd, J = 12.9, 4.5 Hz, 1H, H–
C5), 3.47 (s, 0.1 · 3H), 2.48 (ddt, J = 19.5, 12.3, 6.3 Hz,
1H, H–C3), 2.19 (dddt, J = 17.5, 12.3, 9.6, 1.5 Hz, 1H,
H–C3), 1.84 (s, 0.1 · 3H), 1.69 (s, 0.9 · 3H, H3CC(O)),
1.34 (t, J = 6.9 Hz, 3H), 1.27 (t, J = 6.9 Hz, 3H). 31P
NMR (CDCl3): d = 24.91 (90%) and 23.37 (10%).
(2S,4R)-20a.
From (2S,4R)-4 (0.029 g, 0.130 mmol) phosphonate
1
(2S,4R)-20a (0.036 g) was obtained as a colourless oil. H
NMR (CDCl3): d = 7.50–7.30 (m, 5H), 5.24–5.15 (m, 1H,
H–C4), 4.81 (s, 0.71 · 1H, CHC(O)N), 4.78 (s,
0.29 · 1H), 4.61–4.48 (m, 1H, H–C2), 4.20–4.00 (m, 5H,
2 · CH2OP and H–C5), 3.53 (dd, J = 11.4, 6.3 Hz,
0.71 · 1H, H–C5), 3.40 (s, 3H, H3CO–CH–C(O)N), 3.22
(dd, J = 12.9, 5.7 Hz, 0.29 · 1H, H–C5), 2.60–2.40 (m,
1H, H–C3), 2.38–2.10 (m, 1H, H–C3), 2.19 (s, 0.29 · 3H),
2.09 (s, 0.71 · 3H, H3CC(O)), 1.33 (t, J = 7.2 Hz, 3H),
1.30 (t, J = 7.2 Hz, 3H). 31P NMR (CDCl3): d = 24.22
(71%) and 23.09 (29%).
4.12. Synthesis of N-acetyl-O-mandelates (2S,4R)-20a and
(2R,4S)-20b (general procedure)
A solution of phosphonate (2S,4R)-4 or (2R,4S)-4 (0.029 g,
0.130 mmol), acetic anhydride (0.037 mL, 0.390 mmol) and
triethylamine (0.060 mL, 0.430 mmol) containing DMAP
(two crystals) in methylene chloride (2 mL) was stirred at
room temperature for 2 h. The reaction mixture was fil-
tered though a pad of silica gel to give crude products
4.12.2. Diethyl (2R,4S)-4-[(S)-2-methoxy-2-phenylacetoylox-
y]-1-acetylpyrrolidinyl-2-phosphonate (2R,4S)-20b. From
(2R,4S)-4 (0.023 g, 0.100 mmol) phosphonate (2R,4S)-20b
(0.043 g) was obtained as a colourless oil.
1H NMR (CDCl3): d = 7.50–7.30 (m, 5H), 5.24–5.15 (m,
1H, H–C4), 4.81 (s, 0.69 · 1H, CHC(O)N), 4.79 (s,
0.31 · 1H), 4.57 (ddd, J = 10.2, 7.5, 4.8 Hz, 1H, H–C2),
4.29 (dd, J = 12.9, 6.9 Hz, 0.31 · 1H, H–C5), 4.20–4.06
(m, 4H), 3.90 (dd, J = 12.0, 6.9 Hz, 0.69 · 1H, H–C5),
3.43 (s, 0.31 · 3H), 3.41 (s, 0.69 · 3H, H3CO–CH–
C(O)N), 3.33 (dd, J = 12.0, 5.7 Hz, 0.69 · 1H, H–C5),
3.14 (dd, J = 12.9, 4.2 Hz, 0.31 · 1H), 2.80–2.40 (m, 2H,
H2C-3), 2.19 (s, 0.31 · 3H), 2.05 (s, 0.69 · 3H, H3CC(O)),
1.33 (t, J = 7.2 Hz, 3H), 1.30 (t, J = 7.2 Hz, 3H). 31P
NMR (CDCl3): d = 24.29 (69%) and 23.32 (31%).
1
(2S,4R)-18 or (2R,4S)-18 (0.027 g) as colourless oils. H
NMR (CDCl3) d = 5.21–5.13 (m, 1H, H–C4), 4.59 (ddd,
J = 9.0, 7.2, 5.1 Hz, 1H, H–C2), 4.33 (dd, J = 12.9,
7.2 Hz, 0.31 · 1H, H–C5), 4.23–4.01 (m, 4H), 4.00 (dd,
J = 11.4, 6.6 Hz, 0.69 · 1H, H–C5), 3.54 (dd, J = 11.4,
5.1 Hz, 0.69 · 1H, H–C5), 3.32 (dd, J = 12.9, 5.1 Hz,
0.31 · 1H, H–C5), 2.75–2.39 (m, 2H, H2C-3), 2.21 (s,
0.31 · 6H, 2 · H3CC(O)), 2.09 (s, 0.69 · 6H, 2 ·
H3CC(O)), 1.35 (t, J = 7.2 Hz, 0.31 · 6H), 1.33 (t, J =
7.2 Hz, 0.69 · 6H). 31P NMR (CDCl3) d = 24.42 (69%)
and 23.51 (31%).
A solution of phosphonate (2S,4R)-18 or (2R,4S)-18
(0.027 g, 0.080 mmol) in ethanol (0.7 mL) containing aque-
ous NH3 (25%, 4 mL) was left at room temperature for 4 h.
Volatiles were removed and the residues evaporated with
anhydrous ethanol (3 · 5 mL), chloroform (3 · 5 mL) and
filtered though a pad of silica gel to give crude products
Acknowledgements
´
The authors are grateful to Professor Andrzej E. Wroblew-
ski for support and stimulating discussions. Mrs. Małgorz-
ata Pluskota is acknowledged for her technical assistance.
This work was supported by the Medical University of
1
(2S,4R)-19 or (2R,4S)-19 (0.021 g) as colourless oils. H
´ ´
3014-1).
NMR (CDCl3) d = 5.82 (d, J = 11.7 Hz, 0.7 · 1H, OH),
5.29 (d, J = 12.0 Hz, 0.3 · 1H), 4.72–4.65 (m, 1H), 4.56–
Łodz internal funds (502-13-332, 502-13-487 and 503-

D. G. Piotrowska, I. E. Głowacka / Tetrahedron: Asymmetry 18 (2007) 1351–1363
1363
23. List, B.; Pojarliev, P.; Martin, H. J. Org. Lett. 2001, 3, 2423–
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