A facile synthesis of chiral 4-(tert-butylsulfinylamino)-2-oxophosphonates and their conversion into 5,5-disubstituted 2-benzylidene-3-oxopyrrolidines

Article abstract of DOI:10.1055/s-2008-1032127

The addition of the dianion derived from 2-oxophosphonates to chiral N-(tert-butylsulfinyl)ketimines or -aldimine under mild reaction conditions afforded 4-(tert-butylsulfinylamino)-2-oxoalkylphosphonates with good to excellent diastereoselectivity. The l

Full text of DOI:10.1055/s-2008-1032127

PAPER
1085
A Facile Synthesis of Chiral 4-(tert-Butylsulfinylamino)-2-oxophosphonates
and Their Conversion into 5,5-Disubstituted 2-Benzylidene-3-oxopyrrolidines
S
ynthesis and Con
i
version
a
of
C
hiral
4
n
-
(
tert-Butyls
y
ulfinylamino
i
)
-2-oxophos
C
State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 354 Fenglin Lu, Shanghai 200032, P. R. of China
Fax +86(21)54925379; E-mail: yuancy@mail.sioc.ac.cn
Received 26 September 2007; revised 20 December 2007
O
S
O
S
Abstract: The addition of the dianion derived from 2-oxophospho-
nates to chiral N-(tert-butylsulfinyl)ketimines or -aldimine under
mild reaction conditions afforded 4-(tert-butylsulfinylamino)-2-
oxoalkylphosphonates with good to excellent diastereoselectivity.
The latter was then converted into an enantiopure 5,5-disubstituted
2-(dimethoxyphosphoryl)pyrrolidin-3-one via an intramolecular
N–H insertion. Subsequent Horner–Wadsworth–Emmons reaction
gave the corresponding 2-benzylidene derivatives.
O
O
P
O
O
P
NH
R2
N
OR3
OR3
OR3
OR3
(a)
+
R1
R1
R2
1
2
R1 = Ph, 4-MeC6H4, 4-FC6H4, 4-ClC6H4, 1-naphthyl, biphenyl-4-yl, Et,
n-Bu, t-Bu, n-Hex
R2 = H, Me; R3 = Et, Me
Key words: chiral N-substituted 4-amino-2-oxophosphonates, N-
sulfinylimines, asymmetric-induced addition, pyrrolidinone, in-
tramolecular N–H insertion, Horner–Wadsworth–Emmons reaction
Scheme 1 Reaction conditions: LiHMDS, THF, –78 °C.
with dialkyl phosphites at room temperature in the pres-
ence of potassium carbonate. Herein, we wish to report
our synthetic approach to chiral 4-amino-2-oxophospho-
nates from enantiopure Ellman’s N-(sulfinyl)imines via
the nucleophilic addition of a dianion derived from oxo-
phosphonate to the sp2 carbon atom of the C=N linkage.
The chemical transformations of these molecules are also
examined. This study will provide information concern-
ing the difference in chemical reactivity and diastereo-
selectivity between these two N-sulfinylimines. Very
recently, as reported by Davis,4d the steric effects of sub-
stituents on the chiral center have been shown to have a
significant effect on the stereochemical-directing behav-
ior of such molecules. In addition, the use of functional-
ized nucleophiles with Ellman’s reagent will broaden the
scope of Ellman’s N-(tert-butylsulfinyl)imine methodolo-
gy.
The synthesis of oxophosphonates bearing a chiral moiety
has aroused significant interest in organic chemistry be-
cause of their wide use as building blocks for the construc-
tion of compounds with potential biological activity. One
of their most important synthetic uses is their conversion
to chiral enones via the Horner–Wadsworth–Emmons re-
action. These optically active 2-oxophosphonates can also
be transformed into enantiopure polyfunctionalized pyr-
rolidinones that are useful as chiral auxiliaries or ligands
in asymmetric synthesis.1 The classic synthetic routes
leading to racemic 2-oxophosphonates are mainly based
on the Michaelis–Arbuzov reaction and the acylation of
alkylphosphonates.2 A more convenient chemoenzymatic
synthesis of chiral 4-hydroxy-2-oxoalkanephosphonates
was reported by our group.3 To the best of our knowledge,
synthetic methods for chiral 4-amino-2-oxoalkanephos-
phonates are limited. Recently, Davis’ group reported a
highly stereoselective synthetic protocol based on in-
tramolecular metal carbenoid N–H insertion from an N-
(4-tolylsulfinyl)aldimine-derived 4-amino-1-diazo-2-oxo-
alkylphosphonate and subsequent conversion into ring-
functionalized cis-2,5-disubstituted 3-oxopyrrolidines.4
Davis’ N-(4-tolylsulfinyl)imine (sulfinimine) has been
shown to be an effective chiral auxiliary. However, the
behavior of N-(tert-butylsulfinyl)aldimine or -ketimine
(known as Ellman’s sulfinimines) show more specific ste-
reochemical reactivities due to the presence of a bulky
tert-butyl group on the chiral center of the reagent. As we
have previously shown,5 Ellman’s N-(sulfinyl)aldimines
and/or -ketimines undergo smoothly nucleophilic addition
As a new family of ligands for the asymmetric synthesis
of amino compounds by nucleophilic 1,2-addition,
Ellman’s N-(sulfinyl)imines6 are specific due to steric ef-
fects. By reacting commercially available (–)-(S)-tert-
butanesulfinamide with various aldehyde and ketone,
(–)-(S)-N-(tert-butylsulfinyl)aldimine 1a and the corre-
sponding ketimines 1b–k were prepared in the presence of
two equivalents of titanium(IV) ethoxide in good yield.
Enantiopure 4-(tert-butylsulfinylamino)-2-oxophospho-
nates 2 resulted from treatment of the N-(tert-butylsulfi-
nyl)aldimine or -ketimines with dimethyl 2-oxopro-
pylphosphonates as the lithium salt, prepared by treatment
with lithium hexamethyldisilazanide, in tetrahydrofuran
at –78 °C (Scheme 1); the results are summarized in
Table 1.
As shown in Table 1, both N-(tert-butylsulfinyl)aldimine
1a and -ketimines 1b–k gave fair chemical yields in their
nucleophilic addition with lithium 2-oxoalkylphospho-
nates; however, ketimines provided excellent diastereo-
SYNTHESIS 2008, No. 7, pp 1085–1093
Advanced online publication: 06.03.2008
DOI: 10.1055/s-2008-1032127; Art ID: F17307SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
0
8

1086
Q. Chen, C. Yuan
PAPER
O
S
Table 1 Synthesis of 4-(tert-Butylsulfinylamino)-2-oxoalkylphos-
phonates
O
O
P
N
O
O
+
Entry Substrate 1
Product 2
R1
R2
R1
R2
H
R3
Yielda deb (%)
(%)
1
1
1a
1b
1c
1d
1e
1f
Ph
2a Me 85
52.7 (95c)
>95
2
Ph
Me 2b Me 82
Me 2c Me 81
Me 2d Me 80
Me 2e Me 84
Me 2f Me 81
Me 2g Me 79
Me 2h Me 80
Me 2i Me 83
Me 2j Me 82
Me 2k Me 84
S
N
O
M
3
4-MeC6H4
4-FC6H4
4-ClC6H4
1-naphthyl
biphenyl-4-yl
Et
>95
O
R1
P(O)(OMe)2
4
>95
R2
5
>95
A
6
>95
7
1g
1h
1i
>95
2 (major)
8
69.8d
83.5d
>95
Scheme 2
9
Bu
O
S
10
11
1j
t-Bu
3 O
O
O
P
NHR
O
O
NH
R2
a
1k
(CH2)5Me
>95
O
O
P
R1
O
R1
b or c
R2
a Isolated yield of the diastereomeric mixture.
b Determined by 31P NMR of the crude reaction mixture.
c The value after column chromatography.
3
2
O
3 O
O
P
R2
R1
NHR
e
O
O
d Two diasteromers were inseparable by column chromatography.
O
d
R1
P
N
R2
R3
O
O
N2
4
5
R2 = Boc or Cbz
selectivity as represented by higher de values (Table 1,
entries 2–7, 10, 11). Only one isomer could be detected in
the 31P NMR spectra of the crude reaction mixtures. Low
de values for entries 8 and 9 in Table 1 might be associat-
ed with the presence of both Z- and E-isomers of 1h and
1i.4d It is also necessary to point out that during the course
of our reaction, the sulfinylimine attacked at position 4 of
the 2-oxoalkylphosphonate rather than position 2, which
would be expected due to steric effects. The reaction prob-
ably underwent a suggested Zimmerman–Traxler-type
six-membered transition state A (Scheme 2), the metal
cation chelated to three heteroatoms at the same time,
making the approach of the 2-oxophosphonate from the
re-face of 1.
f
O
R2
R1
Ph
N
R3
6
Scheme 3 Reaction conditions: (a) 4 M HCl in MeOH; (b) (Boc)2O,
Et3N, DMAP, 0 °C, 5 h; (c) CbzCl, 5% aq NaHCO3, 0 °C, 3 h; (d)
K2CO3, TsN3, Et2O, r.t.; (e) 5 mol% Rh2(OAc)4, CH2Cl2, r.t.; (f)
PhCHO, K2CO3, THF, H2O, r.t.
Compounds 4c–g were treated with dirhodium tetraace-
tate as catalyst in dichloromethane for 24 hours at room
temperature to afford the corresponding 5-substituted 2-
(dimethoxyphosphoryl)pyrrolidin-3-ones 5c–g. However,
4h gave 5h in only very low yields under similar condi-
tions; this might be associated with the steric hindrance of
the bulky tert-butyl group. Enhancement of the reaction
conditions including raising the reaction temperature and
extending the reaction time only led to decomposition of
the reaction mixture.
Our unsuccessful attempts to convert N-(tert-butylsulfi-
nylamino)-1-diazo-2-oxophosphonates into pyrrolidine
derivatives could be rationalized by the presence of a
strong electron-withdrawing oxygen atom on the sulfox-
ide and the bulky tert-butylsulfinyl group on the amino ni-
trogen. Based on this postulation, it is not surprised that
upon reaction of 4-(benzyloxycarbonylamino- or 4-(tert-
butoxycarbonylamino)-1-diazo-2-oxophosphonates 4 un-
derwent intramolecular cyclization based on an N–H in-
sertion reaction affording the corresponding 5-substituted
2-(dimethoxyphosphoryl)pyrrolidin-3-ones 5 in fair yield
(Scheme 3). Subsequent Horner–Wadsworth–Emmons
reaction of 5 with benzaldehyde gave the (E)-benzylidene
derivatives 6 in the usual manner (Table 2).
Compounds 5c–g reacted smoothly with benzaldehyde in
tetrahydrofuran–water solution in the presence of excess
potassium carbonate at room temperature for about five
hours to afford 2-benzylidenepyrrolidin-3-ones 6c–g as
expected in over 90% yield.
In summary, we have developed a new method for the
asymmetric synthesis of chiral 4-amino-2-oxophospho-
nates by a highly diastereoselective addition of 2-oxo-
Synthesis 2008, No. 7, 1085–1093 © Thieme Stuttgart · New York

PAPER
Synthesis and Conversion of Chiral 4-(tert-Butylsulfinylamino)-2-oxophosphonates
1087
(S)-2-Methyl-N-[1-(4-methylphenyl)ethylidene]propane-2-sul-
finamide (1c)
Yellow solid; yield: 87%; mp 51–54 °C.
Table 2 Preparation of Substituted 2-Benzylidenepyrrolidinones 6
Entry R1
R2 R3 3–6a
Yieldb (%)
[a]D20 –11.1 (c 1.0, CHCl3).
IR (KBr): 2962, 1596, 1567, 1277, 1186, 1068, 823 cm–1.
1H NMR (CDCl3): d = 1.30 (s, 9 H), 2.38 (s, 3 H), 2.73 (s, 3 H), 7.20
(d, J = 8.4 Hz, 2 H), 7.78 (d, J = 8.1 Hz, 2 H).
3
4
5
6
–
–
1
2
3
4
5
6
7
8
Ph
H
Boc
a
b
c
d
e
f
87
–
–
4-MeC6H4
4-MeC6H4
Ph
Me Cbz
Me Boc
Me Boc
Me Boc
Me Boc
Me Boc
Me Boc
83 86 64
MS (ESI): m/z = 238.1 [M + H]+.
81 85 61 91
80 87 65 93
78 84 74 89
75 84 71 91
Anal. Calcd for C13H19NOS: C, 65.78; H, 8.07; N, 5.90. Found: C,
65.40; H, 8.24; N, 5.70.
1-naphthyl
biphenyl-4-yl
(CH2)5Me
t-Bu
(S)-N-[1-(4-Fluorophenyl)ethylidene]-2-methylpropane-2-sul-
finamide (1d)
Colorless oil; yield: 83%.
[a]D20 +4.5 (c 3.0, CHCl3).
IR (KBr): 2963, 1687, 1581, 1267, 1068, 840 cm–1.
g
85 86 77 92
c
h
73 83
–
–
1H NMR (CDCl3): d = 1.29 (s, 9 H), 2.73 (s, 3 H), 7.08 (t, J = 9.0
Hz, 2 H), 7.87 (t, J = 6.0 Hz, 2 H).
MS (ESI): m/z = 242.2 [M + H]+.
a The absolute configuration of 3 was based on the comparison of the
sign of its optical rotation with that reported in the literature.4a
b Isolated yield.
c Most of compound decomposed during the reaction.
Anal. Calcd for C12H16FNOS: C, 59.72; H, 6.68; N, 5.80. Found: C,
59.37; H, 6.72; N, 5.49.
phosphonate to enantiopure N-(tert-butylsulfinyl)ket-
imines. The products thus obtained serve as building
blocks for the construction of 5-substituted 2-(dimethoxy-
phosphoryl)pyrrolidin-3-one by intramolecular cycliza-
tion based on an N–H insertion reaction. The resulting
phosphorylpyrrolidinone was then transformed to the cor-
responding 2-benzylidenepyrrolidinones using Horner–
Wadsworth–Emmons chemistry.
(S)-N-[1-(4-Chlorophenyl)ethylidene]-2-methylpropane-2-sul-
finamide (1e)
Yellow solid; yield: 86%; mp 84–86 °C.
[a]D20 –67.5 (c 0.5, CHCl3).
IR (KBr): 2964, 1687, 1589, 1262, 1095, 1013, 832 cm–1.
1H NMR (CDCl3): d = 1.26 (s, 9 H), 2.75 (s, 3 H), 7.96 (d, J = 8.4
Hz, 2 H), 8.19 (d, J = 8.7 Hz, 2 H).
MS (ESI): m/z = 258.2 [M + H]+.
Anal. Calcd for C12H16ClNOS: C, 55.91; H, 6.26; N, 5.43. Found:
C, 55.92; H, 6.22; N, 5.23,
All solvents used were dried by standard procedures. IR spectra
were taken on an Shimadzu IR 440 spectrophotometer, H NMR
1
spectra were recorded at 300 MHz in CDCl3 (unless otherwise indi-
cated), on an Avance 300 or a Mercury 300 spectrometer and 31P
NMR spectra were recorded at 120 MHz in CDCl3 on a Varian EM
390 or a Bruker AM 300 spectrometer (external 85% H3PO4). EI-
MS measurements were performed on a HP 5989A apparatus.
HRMS data were recorded on a Finnigan MAT 8430 spectrometer.
Elemental analyses were conducted on a Heraeus Rapid – CHNO
apparatus. The optical rotatory value was taken on a Perkin Elmer
241MC polarimeter.
(S)-2-Methyl-N-[1-(1-naphthyl)ethylidene]propane-2-sulfin-
amide (1f)
Yellow solid; yield: 88%; mp 120–122 °C.
[a]D20 –16.7 (c 1.0, CHCl3).
IR (KBr): 2956, 1689, 1592, 1258, 1091,1019, 827 cm–1.
1H NMR (CDCl3): d = 1.36 (s, 9 H), 2.89 (s, 3 H), 7.56 (m, 2 H),
7.84–8.06 (m, 5 H).
MS (ESI): m/z = 274.2 [M + H]+.
N-(tert-Butylsulfinyl)ketimines 1b–k; General Procedure
In a 20-mL, single-necked, round-bottom flask equipped with a
magnetic stirring bar, was placed (–)-(S)-tert-butanesulfinamide
(1.212 g, 10.0 mmol) in THF (5 mL), then the corresponding ketone
(12 mmol) and Ti(OEt)4 (4.565 g, 20 mmol) were added to the soln.
The mixture was stirred at 60 °C for 6 h and then quenched with
H2O (5 mL). EtOAc (10 mL) was added to the mixture and the aque-
ous phase was extracted with EtOAc (2 × 5 mL). The combined or-
ganic phases were washed with brine (20 mL) and dried (Na2SO4).
Removal of the solvent and the residue was subjected to flash col-
umn chromatography (silica gel, petroleum ether–CH2Cl2, 2:1).
Anal. Calcd for C16H19NOS: C, 70.29; H, 7.00; N, 5.12. Found: C,
70.18; H, 6.99; N, 4.79.
(S)-N-[1-(Biphenyl-4-yl)ethylidene]-2-methylpropane-2-sul-
finamide (1g)
Yellow solid; yield: 83%; mp 138–140 °C.
[a]D20 –89.01 (c 1.0, CHCl3).
IR (KBr): 2978, 1591, 1364, 1087, 767 cm–1.
1H NMR (CDCl3): d = 1.34 (s, 9 H), 2.80 (s, 3 H), 7.26 (m, 3 H),
7.61 (m, 4 H), 7.96 (m, 2 H).
MS (ESI): m/z = 300.2 [M + H]+.
(S)-2-Methyl-N-(1-phenylethylidene)propane-2-sulfinamide
(1b)6
Anal. Calcd for C18H21NOS: C, 72.20; H, 4.68; N, 7.07. Found: C,
72.21; H, 4.42; N, 6.99.
Colorless oil; yield: 85%.
1H NMR (CDCl3): d = 1.32 (s, 9 H), 2.77 (s, 3 H), 7.45 (m, 3 H),
7.89 (d, J = 7.5 Hz, 2 H).
(S)-2-Methyl-N-(1-methylpropylidene)propane-2-sulfinamide
(1h)4e
Colorless oil; yield: 74%.
Synthesis 2008, No. 7, 1085–1093 © Thieme Stuttgart · New York

1088
Q. Chen, C. Yuan
PAPER
IR (KBr): 3473, 2960, 1710, 1255, 1036, 813, 702, 539 cm–1.
1H NMR (CDCl3): d = 1.20 (s, 9 H), 1.57 (s, 3 H), 2.82–3.48 (m, 4
H), 3.60 (d, JHP = 11.1 Hz, 3 H), 3.65 (d, JHP = 11.1 Hz, 3 H), 5.15
(s, 1 H), 7.10–7.39 (m, 5 H).
1H NMR (CDCl3): d = 0.63 (t, J = 7.8 Hz, 3 H), 0.76 (s, 9 H), 1.84
(s, 3 H), 1.96 (m, 2 H).
(S)-2-Methyl-N-(1-methylpentylidene)propane-2-sulfinamide
(1i)6
31P NMR (CDCl3): d = 22.04.
MS (ESI): m/z = 412.0 [M + Na]+.
Colorless oil, yield: 75%.
1H NMR (CDCl3): d = 0.47 (m, 3 H), 0.78 (s, 9 H), 0.90 (m, 2 H),
1.13 (m, 2 H), 1.86 (s, 3 H), 1.95 (m, 2 H).
Anal. Calcd for C17H28NO5PS: C, 52.43; H, 7.25; N, 3.60. Found:
C, 52.19; H, 7.06; N, 3.30.
(S)-2-Methyl-N-(1,2,2-trimethylpropylidene)propane-2-sul-
finamide (1j)6
Colorless oil, yield: 71%.
1H NMR (CDCl3): d = 1.32 (s, 9 H), 2.77 (s, 9 H), 2.81 (m, 3 H).
Dimethyl (S)-4-[(S)-tert-Butylsulfinylamino]-4-(4-methylphe-
nyl)-2-oxopentylphosphonate (2c)
Colorless oil; yield: 81%; >95% de.
[a]D20 –48.7 (c 1.0, CHCl3).
IR (KBr): 3473, 2960, 1710, 1255, 1036, 813, 702, 539 cm–1.
1H NMR (CDCl3): d = 1.27 (s, 9 H), 1.62 (s, 3 H), 2.31 (s, 3 H),
2.90–3.41 (m, 4 H), 3.70 (d, JHP = 11.4 Hz, 3 H), 3.76 (d, JHP = 12.3
Hz, 3 H), 5.15 (s, 1 H), 7.13 (d, J = 8.4 Hz, 2 H), 7.30 (d, J = 7.8 Hz,
2 H).
(S)-2-Methyl-N-(1-methylheptylidene)propane-2-sulfinamide
(1k)
Colorless oil, yield: 71%.
[a]D20 +138.7.
IR (KBr): 3240, 2930, 1713, 1592, 1365, 1035, 884, 586 cm–1.
1H NMR (CDCl3): d = 0.21 (t, J = 6.9 Hz, 3 H), 0.56 (s, 9 H), 0.62
31P NMR (CDCl3): d = 22.71.
MS (ESI): m/z = 426.2 [M + Na]+.
(m, 6 H), 0.90 (m, 2 H), 1.64 (s, 3 H), 1.72 (m, 2 H).
MS (ESI): m/z = 232.2 [M + H]+.
Anal. Calcd for C18H30NO5PS: C, 53.58; H, 7.49; N, 3.47. Found:
C, 53.11; H, 7.73; N, 3.22.
Anal. Calcd for C12H25NOS: C, 62.29; H, 10.89; N, 6.05. Found: C,
62.01; H, 10.90; N, 5.71.
Dimethyl (S)-4-[(S)-tert-Butylsulfinylamino]-4-(4-fluorophe-
nyl)-2-oxopentylphosphonate (2d)
Colorless oil; yield: 80%; >95% de.
4-(tert-Butylsulfinylamino)-2-oxoalkylphosphonates 2; General
Procedure
In a 100-mL, 2-necked, round-bottom flask equipped with a mag-
netic stirring bar, rubber septum, and argon balloon were placed
dimethyl 2-oxopropylphosphonate (10.0 mmol) in THF (20 mL).
The mixture was then cooled to –40 to –20 °C, and followed by ad-
dition of 1 M LiHMDS in hexane (22 mL, 22 mmol) with a syringe.
After 1 h, the mixture was cooled to –78 °C and the sulfinylamine 1
(3.0 mmol) in THF (2 mL) was added carefully over 10 min. The
soln was stirred at –78 °C for an additional 2–5 h, the reaction was
quenched by the addition of sat. aq NH4Cl (10 mL) and warmed to
r.t. The soln was diluted with H2O (10 mL) and extracted with Et2O
(10 mL) and EtOAc (2 × 10 mL). The combined organic layers
were washed with brine (2 × 10 mL), dried (Na2SO4), and concen-
trated. For removal of unreacted dimethyl 2-oxopropylphospho-
nate, the residue was vacuum distilled (80 °C/2.7 mbar) and then
subject to column chromatography (silica gel, acetone–EtOAc,
1:1).
[a]D20 –26.7 (c 1.5, CHCl3).
IR (KBr): 3473, 2960, 1710, 1255, 1036, 813, 702, 539 cm–1.
1H NMR (CDCl3): d = 1.27 (s, 9 H), 1.62 (s, 3 H), 2.90–3.45 (m, 4
H), 3.69 (d, JHP = 11.4 Hz, 3 H), 3.75 (d, JHP = 11.1 Hz, 3 H), 5.17
(s, 1 H), 7.02 (m, 2 H), 7.41 (m, 2 H).
31P NMR (CDCl3): d = 22.01.
MS (ESI): m/z = 430.2 [M + Na]+.
Anal. Calcd for C17H27FNO5PS: C, 50.11; H, 6.68; N, 3.44. Found:
C, 49.95; H, 6.79; N, 3.30.
Dimethyl (S)-4-[(S)-tert-Butylsulfinylamino]-4-(4-chlorophe-
nyl)-2-oxopentylphosphonate (2e)
Colorless oil; yield: 84%; >95% de.
[a]D20 –41.1 (c 1.2, CHCl3).
IR (KBr): 3466, 2960, 1710, 1255, 1031, 813, 539 cm–1.
Dimethyl (S)-4-[(S)-tert-Butylsulfinylamino]-4-phenyl-2-oxobu-
tylphosphonate (2a)
Colorless oil; yield: 85%; 52.7% de.
[a]D20 –58.9 (c 1.2, CHCl3).
IR (KBr): 3450, 2979, 1720, 1504, 1254, 1057, 733 cm–1.
1H NMR (CDCl3): d = 1.18 (s, 9 H), 2.85–3.25 (m, 4 H), 3.73 (m, 6
H), 4.45 (m, 1 H), 4.85 (s, 1 H), 7.35 (m, 5 H).
13C NMR (CDCl3): d = 200.8, 155.8, 143.0, 132.8, 128.0, 127.5,
126.3, 123.7, 59.2, 53.3, 52.8, 41.4, 29.1 23.0.
1H NMR (CDCl3): d = 1.27 (s, 9 H), 1.61 (s, 3 H), 2.92–3.43 (m, 4
H), 3.67 (d, JHP = 11.1 Hz, 3 H), 3.74 (d, JHP = 11.1 Hz, 3 H), 5.16
(s, 1 H), 7.01 (m, 2 H), 7.40 (m, 2 H).
31P NMR (CDCl3): d = 21.98.
MS (ESI): m/z = 446.2 [M + Na]+.
Anal. Calcd for C17H27ClNO5PS: C, 48.17; H, 6.42; N, 3.30. Found:
C, 48.39; H, 6.37; N, 3.07
31P NMR (CDCl3): d = 22.44.
MS (ESI): m/z = 398.2 [M + Na]+.
HRMS: m/z [M + H]+ calcd for C16H27NO5PS: 376.1352; found:
376.1342.
Dimethyl (S)-4-[(S)-tert-Butylsulfinylamino]-4-(1-naphthyl)-2-
oxopentylphosphonate (2f)
Colorless oil; yield: 81%; >95% de.
[a]D20 –57.2 (c 0.4, CHCl3).
IR (KBr): 3461, 2960, 1710, 1458, 1382, 1252, 1031, 821, 568
cm–1.
1H NMR (CDCl3): d = 1.31 (s, 9 H), 1.79 (d, J = 28.8 Hz, 3 H),
2.93–3.50 (m, 4 H), 3.66 (d, JHP = 11.1 Hz, 3 H), 3.74 (d, JHP = 11.7
Hz, 3 H), 5.32 (s, 1 H), 7.46 (m, 2 H), 7.58 (m, 1 H), 7.83 (m, 4 H).
Dimethyl (S)-4-[(S)-tert-Butylsulfinylamino]-4-phenyl-2-oxo-
pentylphosphonate (2b)
Colorless oil; yield: 82%; >95% de.
[a]D20 –29.7 (c 0.7, CHCl3).
Synthesis 2008, No. 7, 1085–1093 © Thieme Stuttgart · New York

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Synthesis and Conversion of Chiral 4-(tert-Butylsulfinylamino)-2-oxophosphonates
1089
13C NMR (CDCl3): d = 201.2, 143.2, 133.2, 132.4, 128.3 (d,
J = 38.4 Hz), 127.4, 126.1 (d, J = 44.1 Hz), 123.9 (d, J = 43.4 Hz),
59.3, 56.1, 53.2, 52.9, 43.2, 41.5, 29.1 22.9.
31P NMR (CDCl3): d = 22.05.
31P NMR (CDCl3): d = 24.09.
MS (ESI): m/z = 392.2 [M + Na]+.
Anal. Calcd for C15H32NO5PS: C, 48.76; H, 8.74; N, 3.79. Found:
C, 48.80; H, 8.79; N, 3.69.
MS (ESI): m/z = 462.3 [M + Na]+.
Dimethyl (R)-4-[(S)-tert-Butylsulfinylamino]-4-methyl-2-oxo-
decylphosphonate (2k)
Colorless oil; yield: 84%; >95% de.
HRMS: m/z [M]+ calcd for C21H30NO5PS: 462.1492; found:
462.1475.
Dimethyl (S)-4-(Biphenyl-4-yl)-4-[(S)-tert-butylsulfinylamino]-
2-oxopentylphosphonate (2g)
Colorless oil; yield: 79%; >95% de.
[a]D20 –61.4 (c 0.25, CHCl3).
[a]D20 +19.2 (c 1.1, CHCl3).
IR (KBr): 3443, 2958, 1713, 1459, 1366, 1250, 1033, 819, 732
cm–1.
1H NMR (CDCl3): d = 0.80 (m, 3 H), 1.12 (s, 9 H), 1.18–1.24 (m,
11 H), 1.55 (m, 2 H), 2.75–3.10 (m, 4 H), 3.69 (s, 3 H), 3.72 (s, 3
H), 4.58 (s, 1 H).
IR (KBr): 3442, 2961, 1710, 1488, 1348, 1250, 1039, 841, 768
cm–1.
1H NMR (CDCl3): d = 1.29 (s, 9 H), 1.72 (d, J = 25.8 Hz, 3 H),
2.92–3.47 (m, 4 H), 3.69 (d, JHP = 11.4 Hz, 3 H), 3.75 (d, JHP = 11.4
Hz, 3 H), 5.23 (s, 1 H), 7.35 (m, 2 H), 7.42 (m, 2 H), 7.56 (m, 5 H).
31P NMR (CDCl3): d = 22.08.
31P NMR (CDCl3): d = 23.20.
MS (ESI): m/z = 420.3 [M + Na]+.
Anal. Calcd for C17H36NO5PS: C, 51.37; H, 9.13; N, 3.52. Found:
C, 51.37; H, 9.30; N, 3.40.
MS (ESI): m/z = 488.3 [M + Na]+.
Synthesis of Boc- or Cbz-Protected 4-Amino-2-oxoalkylphos-
phonates 3; General Procedure
Anal. Calcd for C23H32NO5PS: C, 59.34; H, 6.93; N, 3.01. Found:
C, 59.63; H, 6.88; N, 2.58.
In a 20-mL, single-necked, round-bottom flask equipped with a
magnetic stirrer bar was placed 2 (1.0 mmol) in MeOH (5 mL), then
4 M HCl (5 mL) was added to the soln. The mixture was stirred at
r.t. and after 6 h concentrated under vacuum for an additional 0.5 h.
CH2Cl2 (10 mL) was added to the flask, the soln was cooled to 0 °C
in an ice bath, and Et3N was added until the soln was pH 7. Then
Et3N (0.4 mL, 3 mmol), DMAP (0.0030 g), and (Boc)2O (0.3 g, 1.5
mmol) were added in sequence. The mixture was stirred at 0 °C for
3–6 h, and quenched by the addition of H2O (5 mL). The aqueous
layer was extracted with CH2Cl2 (2 × 5 mL). The combined organic
phases were washed with brine (10 mL) and dried (Na2SO4). The
solvent was removed and the residue was subjected to column chro-
matography (silica gel; petroleum ether–EtOAc, 1:1) For the syn-
thesis of Cbz-protected 4-amino--2-oxoalkylphosphonates, Cbz-Cl
(0.26 g, 1.5 mmol) was used and reaction was performed in aqueous
soln using NaHCO3 as a base.
Dimethyl (R)-4-[(S)-tert-Butylsulfinylamino]-4-methyl-2-oxo-
hexylphosphonate (2h)
Colorless oil; yield: 80%; 69.8% de.
[a]D20 +25.9 (c 3.8, CHCl3).
IR (KBr): 3436, 2966, 1710, 1459, 1248, 1036, 817 cm–1.
1H NMR (CDCl3): d = 0.71 (t, 3 H), 1.04 (s, 9 H), 1.14 (s, 3 H), 1.52
(m, 2 H), 2.68–3.05 (m, 4 H), 3.60 (s, 3 H), 3.64 (s, 3 H), 4.52 (s, 1
H).
31P NMR (CDCl3): d = 23.09.
MS (ESI): m/z = 364.2 [M + Na]+.
Anal. Calcd for C13H28NO5PS: C, 45.74; H, 8.27; N, 4.10. Found:
C, 45.38; H, 8.29; N, 3.79.
Dimethyl (R)-4-[(S)-tert-Butylsulfinylamino]-4-methyl-2-oxo-
octylphosphonate (2i)
Colorless oil; yield: 83%; 83.5% de.
[a]D20 +19.30 (c 1.5, CHCl3).
IR (KBr): 3436, 2962, 1706, 1364, 1255, 1037 cm–1.
1H NMR (CDCl3): d = 0.40 (m, 3 H), 0.70 (s, 9 H), 0.80 (s, 7 H),
1.25 (m, 2 H), 2.35–2.71 (m, 4 H), 3.62 (d, JHP = 11.4 Hz, 6 H), 4.52
(s, 1 H).
13C NMR (CDCl3): d = 201.9, 132.5, 56.5, 55.6, 54.1, 53.0, 43.3,
41.6, 29.3, 25.7, 25.3, 22.7.
31P NMR (CDCl3): d = 22.46.
MS (ESI): m/z = 392.2 [M + Na]+.
HRMS: m/z [M + Na]+ calcd for C15H32NNaO5PS: 392.1650; found:
392.1631.
Dimethyl (S)-4-(tert-Butoxycarbonylamino)-4-phenyl-2-oxo-
butylphosphonate (3a)
Colorless oil; yield: 87%.
[a]D20 +11.4 (c 1.5, CHCl3).
1H NMR (CDCl3): d = 1.40 (s, 9 H), 2.95–3.30 (m, 4 H), 3.69 (d,
JHP = 2.4 Hz, 3 H), 3.73 (d, JHP = 3.0 Hz, 3 H), 5.10 (m, 1 H), 5.50
(m, 1 H), 7.31 (m, 5 H).
Dimethyl (S)-4-(Benzyloxycarbonylamino)-4-(4-methylphe-
nyl)-2-oxopentylphosphonate (3b)
Colorless oil; yield: 83%.
[a]D20 +17.2 (c 0.25, CHCl3).
IR (KBr): 3286, 2956, 1721, 1255, 1031, 817, 733 cm–1.
1H NMR (CDCl3): d = 1.75 (s, 3 H), 2.29 (s, 3 H), 2.82–3.19 (m, 4
H), 3.67 (d, JHP = 4.2 Hz, 3 H), 3.71 (d, JHP = 4.5 Hz, 3 H), 5.01 (s,
2 H), 6.00 (s, 1 H), 7.11 (d, J = 8.1 Hz, 2 H), 7.23 (d, J = 8.4 Hz, 2
H), 7.30 (s, 5 H).
Dimethyl (S)-4-[(S)-tert-Butylsulfinylamino]-4,5,5-trimethyl-2-
oxohexylphosphonate (2j)
Colorless oil; yield: 82%; >95% de.
31P NMR (CDCl3): d = 22.83.
MS (ESI): m/z = 456.2 [M + Na]+.
[a]D20 +25.9 (c 3.8, CHCl3).
IR (KBr): 3432, 2958, 1704, 1362, 1252, 1034, 815 cm–1.
Anal. Calcd for C22H28NO6P: C, 60.96; H, 6.51; N, 3.23. Found: C,
60.70; H, 6.45; N, 3.01.
1H NMR (CDCl3): d = 0.94 (t, 9 H), 1.28 (s, 9 H), 1.43 (s, 3 H),
3.04–3.60 (m, 4 H), 3.76 (d, JHP = 6.3 Hz, 3 H), 3.81 (d, JHP = 6.3
Hz, 3 H), 5.36 (s, 1 H).
Synthesis 2008, No. 7, 1085–1093 © Thieme Stuttgart · New York

1090
Q. Chen, C. Yuan
PAPER
Dimethyl (S)-4-(tert-Butoxycarbonylamino)-4-(4-methylphe-
nyl)-2-oxopentylphosphonate (3c)
Colorless oil; yield: 81%.
[a]D20 +28.7 (c 1.1, CHCl3).
IR (KBr): 2982, 1717, 1255, 1170, 1033, 817 cm–1.
[a]D20 +7.6 (c 1.5, CHCl3).
IR (KBr): 3318, 2931, 1716, 1253, 1172, 1034, 755 cm–1.
1H NMR (CDCl3): d = 0.88 (t, J = 6.6 Hz, 3 H), 1.28 (m, 11 H), 1.42
(s, 9 H), 1.57 (m, 2 H), 2.89–3.16 (m, 4 H), 3.78 (s, 3 H), 3.81 (s, 3
H), 4.75 (s, 1 H).
1H NMR (CDCl3): d = 1.30 (s, 9 H), 1.65 (s, 3 H), 2.24 (s, 3 H),
2.78–3.06 (m, 4 H), 3.64 (d, JHP = 3.9 Hz, 3 H), 3.68 (d, JHP = 3.9
Hz, 3 H), 5.48 (s, 1 H), 7.05 (d, J = 8.1 Hz, 2 H), 7.19 (d, J = 7.5 Hz,
2 H).
13C NMR (CDCl3): d = 200.8, 154.6, 136.5, 129.2, 124.6, 56.5, 53.0
(dd, J = 10.2 Hz), 52.9, 43.6, 41.9, 29.3, 27.8, 20.9.
13C NMR (CDCl3): d = 200.9, 154.8, 53.9, 52.9 (d, J = 19.8 Hz),
50.9, 43.4, 41.6, 39.3, 29.4, 28.4, 24.7, 23.3, 22.5, 14.0.
31P NMR (CDCl3): d = 22.88.
MS (ESI): m/z = 416.3 [M + Na]+.
Anal. Calcd for C18H36NO6P: C, 54.95; H, 9.22; N, 3.56. Found: C,
54.38; H, 8.86; N, 3.40.
31P NMR (CDCl3): d = 22.41.
MS (ESI): m/z = 422.3 [M + Na]+.
Dimethyl (S)-4-(tert-Butoxycarbonylamino)-4,5,5-trimethyl-2-
oxohexylphosphonate (3h)
Colorless oil; yield: 73%.
[a]D20 +34.4 (c 0.65, CHCl3).
Anal. Calcd for C19H30NO6P: C, 57.13; H, 7.57; N, 3.51. Found: C,
56.67; H, 7.33; N, 3.04.
Dimethyl (S)-4-(tert-Butoxycarbonylamino)-4-phenyl-2-oxo-
pentylphosphonate (3d)
Colorless oil; yield: 80%.
[a]D20 +21.4 (c 1.0, CHCl3).
IR (KBr): 2979, 1716, 1253, 1170, 1031, 759 cm–1.
IR (KBr): 3419, 2978, 1716, 1252, 1171, 1031, 701 cm–1.
1H NMR (CDCl3): d = 0.87 (s, 9 H), 1.21 (s, 9 H), 1.36 (s, 3 H), 2.66
(d, J = 16.2 Hz, 1 H), 3.05 (m, 1 H), 3.17 (d, J = 16.5 Hz, 1 H), 3.47
(m, 1 H), 3.69 (d, JHP = 6.0 Hz, 3 H), 3.73 (d, JHP = 6.6 Hz, 3 H),
5.29 (s, 1 H).
1H NMR (CDCl3): d = 1.30 (s, 9 H), 1.68 (s, 3 H), 2.78–3.08 (m, 4
H), 3.64 (d, JHP = 5.7 Hz, 3 H), 3.68 (d, JHP = 5.4 Hz, 3 H), 5.51 (s,
1 H), 7.28 (m, 5 H).
31P NMR (CDCl3): d = 23.74.
31P NMR (CDCl3): d = 22.78.
MS (ESI): m/z = 388.2 [M + Na]+.
HRMS: m/z [M + Na]+ calcd for C16H32NNaO6P: 388.1578; found:
388.1577.
MS (ESI): m/z = 408.1 [M + Na]+.
Boc-Protected 4-Amino-1-diazo-2-oxoalkylphosphonates 4;
General Procedure
Anal. Calcd for C18H28NO6P: C, 56.10; H, 7.32; N, 3.63. Found: C,
55.94; H, 7.69; N, 3.31.
In a 20-mL, single-necked, round-bottom flask equipped with a
magnetic stirring bar was placed 3 (1 mmol) and TsN3 (0.23 g, 1.2
mmol) in Et2O (10 mL), K2CO3 (0.63 g, 4 mmol) was added. After
stirring at r.t. for 3 h, the mixture was quenched by addition of sat.
aq NH4Cl (5 mL) and extracted with EtOAc (2 × 5 mL). The com-
bined organic phases were washed with brine (5 mL) and dried
(Na2SO4). The solvent was then remove under diminished pressure,
the residue thus obtained was subject to column chromatography
(silica gel, petroleum ether–EtOAc, 3:1).
Dimethyl (S)-4-(tert-Butoxycarbonylamino)-4-(1-naphthyl)-2-
oxopentylphosphonate (3e)
Colorless oil; yield: 78%.
[a]D20 +22.5 (c 2.8, CHCl3).
IR (KBr): 3293, 2978, 1716, 1253, 1171, 1033, 818 cm–1.
1H NMR (CDCl3): d = 1.38 (s, 9 H), 1.83 (s, 3 H), 2.88–3.29 (m, 4
H), 3.68 (d, JHP = 7.5 Hz, 3 H), 3.72 (d, JHP = 7.8 Hz, 3 H), 5.73 (s,
1 H), 7.50 (m, 3 H), 7.79 (m, 4 H).
31P NMR (CDCl3): d = 22.26.
MS (ESI): m/z = 458.2 [M + Na]+.
HRMS: m/z [M + Na]+ calcd for C22H30NNaO6P: 458.1717; found:
Dimethyl (S)-4-(tert-Butoxycarbonylamino)-1-diazo-4-(4-meth-
ylphenyl)-2-oxopentylphosphonate (4c)
Colorless oil; yield: 85%.
[a]D20 +40.0 (c 0.5, CHCl3).
IR (KBr): 3379, 2979, 2123, 1716, 1272, 1165, 1025, 837 cm–1.
458.1703.
1H NMR (CDCl3): d = 1.28 (s, 9 H), 1.79 (s, 3 H), 2.30 (s, 3 H), 2.96
(d, J = 15.6 Hz, 1 H), 3.25 (d, J = 15.3 Hz, 1 H), 3.73 (d, JHP = 4.8
Hz, 3 H), 3.77 (d, JHP = 4.8 Hz, 3 H), 6.13 (s, 1 H), 7.12 (d, J = 8.7
Hz, 2 H), 7.23 (d, J = 8.7 Hz, 2 H).
31P NMR (CDCl3): d = 13.77.
MS (ESI): m/z = 448.3 [M + Na]+.
Dimethyl (S)-4-(Biphenyl-4-yl)-4-(tert-butoxycarbonylamino)-
2-oxopentylphosphonate (3f)
Colorless oil; yield: 75%.
[a]D20 +18.5 (c 0.2, CHCl3).
IR (KBr): 3416, 2979, 1718, 1254, 1170, 1033, 766 cm–1.
1H NMR (CDCl3): d = 1.39 (s, 9 H), 1.78 (s, 3 H), 2.91–3.20 (m, 4
H), 3.72 (d, JHP = 5.4 Hz, 3 H), 3.76 (d, JHP = 5.7 Hz, 3 H), 5.63 (s,
1 H), 7.43 (m, 5 H), 7.58 (m, 4 H).
Anal. Calcd for C19H28N3O6P: C, 53.64; H, 6.63; N, 9.88. Found: C,
53.33; H, 6.60; N, 9.52.
31P NMR (CDCl3): d = 22.28.
MS (ESI): m/z = 484.3 [M + Na]+.
Dimethyl (S)-4-(tert-Butoxycarbonylamino)-1-diazo-4-phenyl-
2-oxopentylphosphonate (4d)
Colorless oil; yield: 87%.
[a]D20 +15.1 (c 0.75, CHCl3).
IR (KBr): 3381, 2979, 2123, 1717, 1270, 1167, 1029, 733 cm–1.
Anal. Calcd for C24H32NO6P: C, 62.46; H, 6.99; N, 3.04. Found: C,
62.14; H, 7.31; N, 3.27.
Dimethyl (R)-4-(tert-Butoxycarbonylamino)-4-methyl-2-oxo-
decylphosphonate (3g)
Colorless oil; yield: 85%.
Synthesis 2008, No. 7, 1085–1093 © Thieme Stuttgart · New York

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Synthesis and Conversion of Chiral 4-(tert-Butylsulfinylamino)-2-oxophosphonates
1091
1H NMR (CDCl3): d = 1.30 (s, 9 H), 1.74 (s, 3 H), 2.90 (d, J = 15.3
Hz, 1 H), 3.18 (d, J = 15.3 Hz, 1 H), 3.63 (d, JHP = 4.5 Hz, 3 H), 3.67
(d, JHP = 5.1 Hz, 3 H), 6.18 (s, 1 H), 7.25 (m, 5 H).
31P NMR (CDCl3): d = 15.10.
MS (ESI): m/z = 434.3 [M + Na]+.
HRMS: m/z [M + K]+ calcd for C18H26KN3O6P: 450.1200; found:
13C NMR (CDCl3): d = 189.0, 167.6, 129.8, 126.5, 116.6 (d,
J = 40.2 Hz), 53.5, 40.1, 28.8 (d, J = 42.0 Hz), 25.7, 21.5, 16.1.
31P NMR (CDCl3): d = 15.41.
MS (ESI): m/z = 414.2 [M + Na]+.
HRMS: m/z [M + Na]+ calcd for C16H30N3NaO6PS: 414.1779;
found: 414.1765.
450.1191.
5-Substituted 2-(Dimethoxyphosphoryl)pyrrolidin-3-ones 5;
General Procedure
Dimethyl (S)-4-(tert-Butoxycarbonylamino)-1-diazo-4-(1-naph-
thyl)-2-oxopentylphosphonate (4e)
Colorless oil; yield: 84%.
[a]D20 +39.1 (c 2.8, CHCl3).
IR (KBr): 3389, 2872, 2123, 1716, 1272, 1171, 1030, 839 cm–1.
1H NMR (CDCl3): d = 1.28 (s, 9 H), 1.93 (s, 3 H), 3.02 (d, J = 15.3
Hz, 1 H), 3.40 (d, J = 13.8 Hz, 1 H), 3.64 (d, JHP = 5.4 Hz, 3 H), 3.68
(d, JHP = 5.1 Hz, 3 H), 6.35 (s, 1 H), 7.48 (m, 3 H), 7.79 (m, 4 H).
31P NMR (CDCl3): d = 13.57.
In a 50-mL round-bottom flask equipped with a magnetic stirring
bar and an argon balloon was placed diazophosphonate 4 (1.0
mmol) and Rh2(OAc)4 (0.020 g, 5 mol%) in CH2Cl2 (40 mL). The
mixture was stirred at r.t. for 24 h. Then the soln mixture was
washed with H2O (2 × 10 mL) and extracted with CH2Cl2 (2 × 10
mL). The combined organic layers were washed with brine (10 mL)
and dried (Na2SO4). The solvent was removed and residue was sub-
jected to column chromatography (silica gel, petroleum ether–
EtOAc, 3:1).
MS (ESI): m/z = 484.3 [M + Na]+.
HRMS: m/z [M + Na]+ calcd for C22H28N3NaO6P: 484.1619; found:
(5S)-1-(Benzyloxycarbonyl)-2-(dimethoxyphosphoryl)-5-meth-
yl-5-(4-tolyl)pyrrolidin-3-one (5b)
Colorless oil; yield: 64%.
IR (KBr): 2959, 1702, 1345, 1255, 1048, 820, 699 cm–1.
484.1608.
Dimethyl (S)-(4-Biphenyl-4-yl)-4-(tert-butoxycarbonylamino)-
1-diazo-2-oxopentylphosphonate (4f)
Colorless oil; yield: 84%.
[a]D20 +15.3 (c 0.2, CHCl3).
IR (KBr): 3384, 2978, 2123, 1716, 1271, 1170, 1029, 769 cm–1.
1H NMR (CDCl3): d = 1.39 (s, 9 H), 1.85 (s, 3 H), 3.00 (d, J = 15.3
Hz, 1 H), 3.31 (d, J = 15.6 Hz, 1 H), 3.73 (d, JHP = 1.2 Hz, 3 H), 3.77
(d, JHP = 1.8 Hz, 3 H), 6.24 (s, 1 H), 7.42 (m, 5 H), 7.56 (m, 4 H).
1H NMR (CDCl3): d = 1.74 (s, 1.5 H), 2.08 (s, 1.5 H), 2.30 (d,
J = 9.0 Hz, 3 H), 2.70–3.20 (m, 2 H), 3.78 (m, 6 H), 4.66 (d, J = 16.5
Hz, 1 H), 4.87 (s, 2 H), 6.81–7.52 (m, 9 H).
31P NMR (CDCl3): d = 17.59.
MS (ESI): m/z = 454.2 [M + Na]+.
Anal. Calcd for C22H26NO6P: C, 61.25; H, 6.07; N, 3.25. Found: C,
61.46; H, 6.44; N 2.92.
31P NMR (CDCl3): d = 13.65.
MS (ESI): m/z = 510.3 [M + Na]+.
(5S)-1-(tert-Butoxycarbonyl)-2-(dimethoxyphosphoryl)-5-
methyl-5-(4-tolyl)pyrrolidin-3-one (5c)
Colorless oil; yield: 61%.
[a]D20 +28.1 (c 0.5, CHCl3).
Anal. Calcd for C24H30N3O6P: C, 59.13; H, 6.20; N, 8.62. Found: C,
59.28; H, 6.48; N, 8.26.
IR (KBr): 2977, 1763, 1694, 1367, 1255, 1162, 1037, 819 cm–1.
Dimethyl (R)-4-(tert-Butoxycarbonylamino)-1-diazo-4-methyl-
2-oxodecylphosphonate (4g)
Colorless oil; yield: 86%.
[a]D20 +1.42 (c 1.0, CHCl3).
1H NMR (CDCl3): d = 1.01 (s, 9 H), 1.67 (s, 1.5 H), 2.01 (s, 1.5 H),
2.25 (d, J = 7.8 Hz, 3 H), 3.05–3.40 (m, 2 H), 3.76 (d, JHP = 3.0 Hz,
3 H), 3.79 (d, JHP = 3.3 Hz, 3 H), 4.55 (d, J = 16.5 Hz, 1 H), 6.92 (d,
J = 8.4 Hz, 2 H), 7.02 (d, J = 7.2 Hz, 2 H).
IR (KBr): 3322, 2932, 2123, 1713, 1270, 1171, 1029, 838 cm–1.
31P NMR (CDCl3): d = 17.50.
1H NMR (CDCl3): d = 0.80 (t, J = 6.6 Hz, 3 H), 1.20 (s, 8 H), 1.27
(s, 3 H), 1.35 (s, 9 H), 1.73 (m, 2 H), 2.75 (d, J = 15.3 Hz, 1 H), 2.96
(d, J = 15.3 Hz, 1 H), 3.75 (s, 3 H), 3.79 (s, 3 H), 4.87 (s, 1 H).
31P NMR (CDCl3): d = 14.34.
MS (ESI): m/z = 420.2 [M + Na]+.
HRMS: m/z [M + Na]+ calcd for C19H28NNaO6P: 420.1560; found:
420.1546.
(5S)-1-(tert-Butoxycarbonyl)-2-(dimethoxyphosphoryl)-5-
methyl-5-phenylpyrrolidin-3-one (5d)
Colorless oil; yield: 65%.
[a]D20 +14.1 (c 0.75 CHCl3).
MS (ESI): m/z = 442.3 [M + Na]+.
Anal. Calcd for C18H34N3O6P: C, 51.54; H, 8.17; N, 10.02. Found:
C, 51.66; H, 8.38; N, 9.82.
IR (KBr): 2977, 1697, 1367, 1254, 1162, 1037, 820 cm–1.
Dimethyl (S)-4-(tert-Butoxycarbonylamino)-1-diazo-4,5,5-tri-
methyl-2-oxohexylphosphonate (4h)
Colorless oil; yield: 83%.
[a]D20 +0.08 (c 0.5, CHCl3).
1H NMR (CDCl3): d = 1.25 (s, 9 H), 1.75 (s, 3 H), 2.86–3.18 (m, 2
H), 3.64 (d, JHP = 4.5 Hz, 3 H), 3.69 (d, JHP = 4.8 Hz, 3 H), 4.05 (m,
1 H), 7.28 (m, 5 H).
13C NMR (CDCl3): d = 200.7, 154.9, 128.5, 126.9, 124.8, 57.4,
56.7, 53.0 (d, J = 26.1 Hz), 43.6, 42.0, 28.3, 27.8.
IR (KBr): 3326, 2966, 2123, 1715, 1267, 1165, 1027, 840, 587
cm–1.
1H NMR (CDCl3): d = 0.95 (s, 9 H), 1.39 (s, 9 H), 1.43 (s, 3 H), 2.41
(d, J = 16.2 Hz, 1 H), 3.55 (d, J = 16.5 Hz, 1 H), 3.81 (d, JHP = 3.9
Hz, 3 H), 3.85 (d, JHP = 4.5 Hz, 3 H), 6.28 (s, 1 H).
31P NMR (CDCl3): d = 18.09.
MS (ESI): m/z = 406.1 [M + Na]+.
HRMS: m/z [M + Na]+ calcd for C18H26NNaO6P: 406.1406; found:
406.1390.
Synthesis 2008, No. 7, 1085–1093 © Thieme Stuttgart · New York

1092
Q. Chen, C. Yuan
PAPER
(5S)-1-(tert-Butoxycarbonyl)-2-(dimethoxyphosphoryl)-5-
methyl-5-(1-naphthyl)pyrrolidin-3-one (5e)
Colorless oil; yield: 74%.
1H NMR (CDCl3): d = 1.17 (s, 9 H), 1.93 (s, 3 H), 2.34 (s, 3 H), 2.76
(m, 2 H), 7.16 (d, J = 6.9 Hz, 2 H), 7.24 (m, 5 H), 7.54 (d, J = 6.9
Hz, 2 H), 7.80 (s, 1 H).
[a]D20 +20.4 (c 0.5, CHCl3).
IR (KBr): 2977, 1763, 1697, 1367, 1161, 1040, 826 cm–1.
1H NMR (CDCl3): d = 0.82 (s, 9 H), 2.15 (s, 3 H), 2.65 (m, 2 H),
3.79 (d, JHP = 2.4 Hz, 3 H), 3.82 (d, JHP = 2.1 Hz, 3 H), 5.21 (s, 1 H),
7.40 (m, 3 H), 7.73 (m, 4 H).
13C NMR (CDCl3): d = 196.8, 152.6, 144.2, 136.5, 134.7, 130.0,
129.2, 127.7, 127.6, 124.4, 121.3, 81.7, 62.9, 54.9, 27.9, 25.9, 21.0.
MS (ESI): m/z = 400.3 [M + Na]+.
HRMS: m/z [M + Na]+ calcd for C24H27NNaO3: 400.1893; found:
400.1883.
31P NMR (CDCl3): d = 17.35.
MS (ESI): m/z = 456.2 [M + Na]+.
HRMS: m/z [M + Na]+ calcd for C22H28NNaO6P: 456.1562; found:
(5S)-2-Benzylidene-1-(tert-butoxycarbonyl)-5-methyl-5-phe-
nylpyrrolidin-3-one (6d)
Yellow solid; yield: 93%; mp 103–105 °C.
[a]D20 –1.5 (c 0.7, CHCl3).
456.1546.
IR (KBr): 2982, 1738, 1697, 1333, 1155, 816, 692 cm–1.
1H NMR (CDCl3): d = 1.15 (s, 9 H), 1.96 (s, 3 H), 2.78 (m, 2 H),
7.36 (m, 10 H), 7.82 (s, 1 H).
13C NMR (CDCl3): d = 196.8, 152.4, 144.0, 136.3, 134.5, 130.0,
129.1, 127.2, 127.3, 124.2, 121.1, 81.5, 62.9, 54.7, 27.9, 21.1.
Anal. Calcd for C22H28NO6P: C, 60.96; H, 6.51; N, 3.23. Found: C,
60.65; H, 6.77; N, 2.88.
(5S)-5-(Biphenyl-4-yl)-1-(tert-butoxycarbonyl)-2-(dimethoxy-
phosphoryl)-5-methylpyrrolidin-3-one (5f)
Colorless oil; yield: 71%.
[a]D20 +42.5 (c 0.5, CHCl3).
IR (KBr): 2977, 1764, 1699, 1367, 1160, 1033, 769 cm–1.
MS (ESI): m/z = 386.3 [M + Na]+.
HRMS: m/z [M + Na]+ calcd for C23H25NNaO3: 386.1739; found:
386.1727.
1H NMR (CDCl3): d = 1.10 (s, 9 H), 1.80 (s, 3 H), 2.65 (m, 1 H),
3.25 (m, 1 H), 3.85 (d, JHP = 3.3 Hz, 3 H), 3.89 (d, JHP = 3.3 Hz, 3
H), 4.63 (s, 1 H), 7.43 (m, 4 H), 7.59 (m, 5 H).
31P NMR (CDCl3): d = 17.49.
MS (ESI): m/z = 482.3 [M + Na]+.
HRMS: m/z [M + Na]+ calcd for C24H30NNaO6P: 482.1716; found:
(5S)-2-Benzylidene-1-(tert-butoxycarbonyl)-5-methyl-5-
(1-naphthyl)pyrrolidin-3-one (6e)
Yellow solid; yield: 89%; mp 136–139 °C.
[a]D20 –32.2 (c 0.2, CHCl3).
IR (KBr): 3058, 1734, 1689, 1338, 1153, 821, 757 cm–1.
1H NMR (CDCl3): d = 1.05 (s, 9 H), 2.07 (s, 3 H), 2.85 (m, 2 H),
7.30 (m, 3 H), 7.51 (m, 5 H), 7.84 (m, 4 H), 7.88 (s, 1 H).
13C NMR (CDCl3): d = 196.5, 144.2, 134.6, 133.4, 133.1, 132.2,
130.0, 128.8, 127.9, 127.8, 127.7, 127.6, 126.5, 126.0, 123.0, 122.8,
121.8, 81.8, 63.2, 54.6, 27.8, 25.7.
482.1703
(5R)-1-(tert-Butoxycarbonyl)-2-(dimethoxyphosphoryl)-5-hex-
yl-5-methylpyrrolidin-3-one (5g)
Colorless oil; yield: 77%.
[a]D20 +3.7 (c 0.5, CHCl3).
IR (KBr): 2931, 1764, 1705, 1252, 1165, 1034, 817 cm–1.
1H NMR (CDCl3): d = 0.80 (m, 3 H), 1.23 (m, 9 H), 1.42 (s, 9 H),
1.57 (m, 2 H), 2.30 (m, 2 H), 2.89 (m, 2 H), 3.72 (m, 6 H), 4.45 (m,
1 H).
13C NMR (CDCl3): d = 200.5, 154.3, 128.8, 127.0, 125.0, 53.7,
31.4, 27.9, 23.1.
31P NMR (CDCl3): d = 17.66.
MS (ESI): m/z = 414.3 [M + Na]+.
HRMS: m/z [M + Na]+ calcd for C18H34NNaO6P: 414.2034; found:
414.2016.
MS (ESI): m/z = 436.3 [M + Na]+.
HRMS: m/z [M + Na]+ calcd for C27H27NNaO3: 436.1886; found:
436.1883.
(5S)-2-Benzylidene-5-(biphenyl-4-yl)-1-(tert-butoxycarbonyl)-
5-methylpyrrolidin-3-one (6f)
Yellow solid; yield: 91%; mp 164–166 °C.
[a]D20 –17.7 (c 0.2, CHCl3).
IR (KBr): 2976, 1733, 1691, 1375, 1173, 773, 690 cm–1.
1H NMR (CDCl3): d = 1.11 (s, 9 H), 1.92 (s, 3 H), 2.74 (m, 2 H),
7.19–7.54 (m, 14 H), 7.76 (s, 1 H).
13C NMR (CDCl3): d = 196.5, 146.2, 140.5, 139.8, 134.6, 130.0,
128.9, 127.8, 127.6, 127.4, 127.2, 127.0, 124.9, 121.6, 81.9, 63.0,
54.8, 28.0, 25.8 .
MS (ESI): m/z = 462.3 [M + Na]+.
HRMS: m/z [M + Na]+ calcd for C29H29NNaO3: 462.2037; found:
5-Substituted 2-Benzylidenepyrrolidin-3-ones 6; General Pro-
cedure
A soln of 5 (0.5 mmol), K2CO3 (0.2 g, 1.5 mmol), THF (2 mL), H2O
(2 mL), and benzaldehyde (1 mmol) was stirred for 2.5 h. Then
brine (5 mL) was added to the mixture followed by extraction with
EtOAc (2 × 5 mL). The combined organic extracts were dried
(Na2SO4). After removal of the solvent, the residue was subjected to
column chromatography (silica gel, petroleum ether–CH2Cl2, 3:2).
462.2039.
(5R)-2-Benzylidene-1-(tert-butoxycarbonyl)-5-hexyl-5-meth-
ylpyrrolidin-3-one (6g)
Colorless oil: yield: 92%.
[a]D20 –11.4 (c 1.5, CHCl3).
IR (KBr): 2931, 1738, 1699, 1379, 1159, 857, 765, 693 cm–1.
1H NMR (CDCl3): d = 0.88 (m, 3 H), 1.28 (m, 8 H), 1.56 (s, 3 H),
1.58 (s, 9 H), 1.61 (m, 1 H), 2.15 (m, 1 H), 2.51 (m, 2 H), 7.29–7.44
(m, 5 H), 7.59 (s, 1 H).
(5S)-2-Benzylidene-1-(tert-butoxycarbonyl)-5-methyl-5-
(4-tolyl)pyrrolidin-3-one (6c)
Colorless oil; yield: 91%.
[a]D20 –2.1 (c 0.7, CHCl3).
IR (KBr): 2933, 1762, 1702, 1251, 1170, 1029, 815 cm–1.
Synthesis 2008, No. 7, 1085–1093 © Thieme Stuttgart · New York

PAPER
Synthesis and Conversion of Chiral 4-(tert-Butylsulfinylamino)-2-oxophosphonates
1093
13C NMR (CDCl3): d = 197.3, 129.8, 127.6, 127.5, 121.2, 81.8,
(2) (a) Rosen, T.; Heathcock, C. H. J. Am. Chem. Soc. 1985,
61.7, 49.5, 39.9, 31.7, 29.5, 28.5, 27.8, 23.9, 22.6, 14.1.
107, 3731. (b) Karanewsky, D. S.; Malley, M. F.;
Gougoutas, J. Z. J. Org. Chem. 1991, 56, 3744.
MS (ESI): m/z = 394.3 [M + Na]+.
HRMS: m/z [M + Na]+ calcd for C23H33NNaO3: 394.2362; found:
(c) Altenbach, H. J.; Holzapfel, W. Angew. Chem., Int. Ed.
Engl. 1990, 29, 67. (d) Narkunan, K.; Nagarajan, M. J. Org.
Chem. 1994, 59, 6386. (e) Kojina, K.; Saito, S. Synthesis
1992, 949. (f) Koskinen, A. M. P.; Krische, M. J. Synlett
1990, 665. (g) Berkowitz, D. B.; Eggen, M.; Shen, Q.;
Shoemaker, R. K. J. Org. Chem. 1996, 61, 4666.
394.2352.
Acknowledgment
(3) (a) Yuan, C. Y.; Zhang, Y. H.; Xu, C. F.; Li, J. F.
Tetrahedron: Asymmetry 2003, 14, 63. (b) Yuan, C. Y.; Xu,
C. F.; Zhang, Y. H. Eur. J. Org. Chem. 2004, 2253.
(4) (a) Davis, F. A.; Wu, Y.; Xu, H.; Zhang, J. Org. Lett. 2004,
6, 4523. (b) Davis, F. A.; Wu, Y. Org. Lett. 2004, 6, 1269.
(c) Davis, F. A.; Xu, H.; Wu, Y. Z.; Zhang, J. Org. Lett.
2006, 8, 2273. (d) Davis, F. A.; Song, M. Org. Lett. 2007, 9,
2413. (e) Davis, F. A.; Lee, S.; Zhang, H.; Fanelli, D. L.
J. Org. Chem. 2000, 65, 8704.
(5) Chen, Q. Y.; Yuan, C. Y. Synthesis 2007, 3779.
(6) (a) Tony, P. T.; Ellman, J. A. J. Org. Chem. 1999, 64, 12.
(b) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res.
2002, 35, 984. (c) Tanuwidjaja, J.; Peltier, H. M.; Ellman, J.
A. J. Org. Chem. 2007, 72, 626. (d) Patterson, A. W.;
Ellman, J. A. J. Org. Chem. 2006, 71, 7110.
Project supported by the National Natural Science Foundation of
China (No 20372076 and 20672132)
References
(1) (a) Kim, B. H.; Lee, H. B.; Hwang, J. K.; Kim, Y. G.
Tetrahedron: Asymmetry 2005, 16, 1215. (b) Nyerges, M.;
Bendell, D.; Arany, A.; Hibbs, D. E.; Coles, S. J.;
Hursthouse, M. D.; Groundwater, P. W.; Meth-Cohn, O.
Synlett 2003, 947. (c) Fache, F.; Schultz, E.; Tomasino, M.
L.; Lemaire, M. Chem. Rev. 2000, 100, 2159. (d)Whitesell,
J. K. Chem. Rev. 1989, 89, 1581.
Synthesis 2008, No. 7, 1085–1093 © Thieme Stuttgart · New York