Optically active diethyl N-(p-toluenesulfonyl)-aziridine 2-phosphonates as chiral synthons for the synthesis of β-substituted α-amino phosphonates

Article abstract of DOI:10.1016/j.tetasy.2004.08.034

A versatile approach for the synthesis of both protected enantiomers of aziridine 2-phosphonates for use as chiral synthons has been developed. The aziridines arise from either (R)- or (S)-phosphonoserine diethyl esters followed by N-tosylation, O-mesylat

Full text of DOI:10.1016/j.tetasy.2004.08.034

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 3307–3322
Optically active diethyl N-(p-toluenesulfonyl)-aziridine
2-phosphonates as chiral synthons for the synthesis of b-substituted
a-amino phosphonates
E. Kurt Dolence* and Jason B. Roylance
1000 E. University Ave. Department 3375, School of Pharmacy, University of Wyoming, Laramie, WY 82071-3375, USA
Received 12 August 2004; accepted 20 August 2004
Available online 2 October 2004
Abstract—A versatile approach for the synthesis of both protected enantiomers of aziridine 2-phosphonates for use as chiral syn-
thons has been developed. The aziridines arise from either (R)- or (S)-phosphonoserine diethyl esters followed by N-tosylation, O-
mesylation and cyclization with sodium hydride. These highly enantio-enriched aziridine 2-phosphonates have been shown to react
with carbon, nitrogen, sulfur, hydride, fluoride, and phosphorus nucleophiles allowing for the rapid production of a variety of b-
substituted a-amino phosphonates in either the (R)- or (S)-configurations. In the case of thiol nucleophiles, use of a stoichiometric
amount of tri-n-butylphosphine was necessary to cleanly produce the corresponding sulfide products. Chiral HPLC methods were
utilized to monitor the synthetic processes to evaluate the enantiomeric excess of the products obtained when possible.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
ral aziridines with the highly strained three-member ring
have been shown to open with both stereo- and regio-
control to produce chiral amines as recently re-
viewed.29–31 Aziridine 2-phosphonates23,32–38 have been
produced by a variety of methods and have shown
promise as a flexible electrophile. Due to the activating
effect of the N-tosyl group of the nitrogen of aziridines
such as 1 and 2 (Scheme 1), the potential for nucleophi-
lic attack at the C-3 methylene carbon should provide a
smooth route to a structurally diverse class of b-substi-
tuted a-amino phosphonates under mild conditions with
minimum potential for loss of stereochemical integrity.
Herein, we report on our investigations in the use of
aziridine-2-phosphonates 1 and 2, derived from either
(R)- or (S)-phosphonoserine, and their reactions with
commercially available heteroatoms and other select
nucleophiles.
The diverse biological activities of a-aminoalkylphos-
phonic acids and their analogues have stimulated
increasing attention among scientists in a wide number
of disciplines. The antibacterial, antiviral, anticancer,
pesticide, and herbicidal activity of these amino acid
structural analogues have been well documented1–3
and will only continue to expand in the future. Numer-
ous methods4–25 for the racemic and enantioselective
synthesis of this important group of compounds have
been undertaken over the last two decades. Recent
reports on catalytic asymmetric synthesis26,27 and the
asymmetric synthesis of a-amino thiophosphonates28
demonstrate the continuing interest in methods that
produce a defined configuration a to the phosphorus
atom. Despite the many elegant methods for enantiose-
lective synthesis, a need exists for an available chiral
synthon to rapidly produce diverse side chain analogues
from commercially available nucleophiles especially for
combinatorial chemistry libraries. This would avoid
the dependence on Ôchelation controlÕ for asymmetric
induction and for the independent synthesis of each side
chain precursor for each unique compound desired. Chi-
2. Results and discussion
2.1. Synthesis of aziridine 2-phosphonates 1 and 2
Success and further application of this approach for
combinatorial approaches relies on the production of
large amounts of both (R)- and (S)-phosphonoserine
in high enantiomeric excess. To achieve this goal, we
have chosen the elegant method of Smith39,40 involving
*
Corresponding author. Tel.: +1 307 766 2954; fax: +1 307 766
2953; e-mail: kdolence@uwyo.edu
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.08.034

3308
E. K. Dolence, J. B. Roylance / Tetrahedron: Asymmetry 15 (2004) 3307–3322
OH
H
O
OEt
OH
H
HN
P
OMe
OEt
OEt
OEt
b
H
O
a
N
H
P
OEt
OEt
O
O
H2N
P
O2N
O
(1R)-7
NO2
(1R)-(-)-5
(1R,1R)-(-)-3
c
O
S
O
H
OH
O
OEt
H
H
N
O
S
O
S
P
O
OEt
OEt
OEt
OEt
OEt
e
d
S
N
H
P
N
P
O
O
H
O
O
O
O
(1R)-(-)-9
(1R)-(-)-11
(1R)-(-)-1
b
a
(1S,1S)-(+)-4
(1S)-(+)-6
(1S)-8
H
c
OEt
N
P
O
OEt
S
d
e
(1S)-(+)-12
O
(1S)-(+)-10
O
(1S)-(+)-2
Scheme 1. Syntheses of (1R)-(À)-1 and (1S)-(+)-2 aziridine phosphonates. Reagents and conditions: (a) 20% Pd(OH)2/C, 50psi H2, EtOH; (b) 3,5-
dinitrobenzoyl chloride, Et3N, CH2Cl2; (c) TsCl, Et3N, CH2Cl2; (d) MsCl, Et3N, CH2Cl2; (e) NaH, THF.
the addition of lithium diethylphosphite to the imine de-
rived from (O-benzyl)acetaldehyde41 and the appropri-
ate chiral auxiliary (O-methyl)-phenylglycinol.42,43 This
method proved to be very amenable to reaction scale-
up (0.250–0.317mol) producing both 3 and 4 in 72%
and 67% yields (Scheme 1), respectively, following flash
silica chromatography and providing enantiomeric ex-
cesses of >98% as determined by chiral phase HPLC
on a Whelk O-2 column. Both enantiomers were carried
forward in parallel in order to monitor stereochemical
integrity in all further manipulations when feasible using
chiral phase HPLC. The N- and O-benzyl protecting
groups were removed from 3 and 4 by hydrogenation
in ethanol to afford the phosphonoserine amino alcohols
5 and 6 in 83% and 86% yield, respectively. Each amino
alcohol was converted to the 3,5-dinitrobenzoyl amide
derivatives 7 and 8 and examined using a (S)-Leu and
(R)-NEA chiral HPLC column44,45 affording ee values
ranging from 97% to 98%. Both of the amino alcohols
5 and 6 were determined to be stable for a minimum
of three months without loss of optically integrity when
stored at 0ꢁC as the free amines.
addition of a solution of tosylchloride at 0ꢁC. Although
both aziridines 1 and 2 could be produced from an N-,
O-ditosylate cyclization, we chose the O-mesylate due
to ease of purification prior to base induced cyclization
when compared to the ditosylate. Conversion to the O-
mesylates 11 and 12 was accomplished smoothly in 75%
and 71% yield, respectively, following silica gel chroma-
tography. Purification and characterization of 11 and 12
were complicated by the fact that the mesylates are
prone to some degree to spontaneous cyclization. Cycli-
zation of 11 and 12 was accomplished using either NaH
in THF or Et3N in CH2Cl2. The Et3N reaction rate was
sluggish when compared to the rapid NaH reaction and
produced lower yields of 50–60% when compared to 88–
90% for NaH. The aziridine 2-phosphonates 1 and 2
were easily purified by flash silica chromatography and
were isolated as oils that can be stored at ambient room
temperature for up to one year without any sign of deg-
radation as monitored by TLC and NMR analysis. Spe-
cific rotations for each enantiomer are practically
20
D
identical except for the sign {½aŠ ¼ À29:8 for 1 and
+29.6 for 2}, however, analysis by chiral HPLC using
a Whelk O-2 chiral column proved difficult with incom-
plete baseline separation despite extensive work on sol-
vent optimization. Chiral HPLC analysis of the
Conversion of each phosphonoserine enantiomer to the
N-tosylates 9 (74%) and 10 (54%) was achieved by slow

E. K. Dolence, J. B. Roylance / Tetrahedron: Asymmetry 15 (2004) 3307–3322
3309
various nucleophile derived products derived from these
aziridines 1 and 2 demonstrate (vida infra) that signifi-
cant racemization did not occur during the three syn-
thetic steps from the phosphonoserines 5 and 6.
determined % ee values. Scheme 2 describes reactions
with the select carbon nucleophiles cyanide and malo-
nate anions. Reaction of aziridines 1 and 2, with NaCN
in DMF afforded cyano adducts 13 and 14 in 87% and
90% yields, respectively. Incomplete separation of the
two enantiomers was observed by chiral HPLC making
ee determination difficult. Reaction with the anion of
diethylmalonate in THF produced 15 and 16 in good
yield (81% and 52%, respectively). Analysis of 15 and
16 by Whelk O-2 HPLC revealed no significant loss of
enantiomeric excess (98% ee) during the reaction with
malonate anion despite specific rotation values differing
by 1.1ꢁ (+20.8 vs À21.9). These two malonates will
prove useful since future elaboration into glutamate,
norvaline, pyroglutamate, and proline derivatives are
straightforward and will be reported in due course.
2.2. Reaction of aziridine 2-phosphonates 1 and 2 with
nucleophiles
Table 1 summarizes the results of the reactions of enan-
tiomeric aziridine 2-phosphonates with various nucleo-
philes and includes the specific rotation and HPLC
Table 1. Addition of select nucleophiles to aziridine 2-phosphonates 1
and 2
20
D
f
a
Nucleophile
Entry and
configuration
% Yield ½aŠ
% Ee
Scheme 3 describes the reactions of the nitrogen nucleo-
philes sodium azide, phenethylamine, and imidazole
with the aziridines 1 and 2. Reactions with sodium azide
in DMF followed by hydrogenation of the intermediate
alkylazide with 20% Pd(OH)2 on carbon in ethanol
afforded primary amines 17 and 18 in 70–80% yields.
Phenethylamine in CH3CN produced secondary amines
21 and 22 in 61–70% yields. The reaction with imidazole
was sluggish at room temperature and proved concen-
tration dependent but after extended reaction times,
analogues 25 and 26 were isolated in 42–72% yields.
Attempts to analyze these b-substituted amines by
Whelk O-2 HPLC using a variety of solvents systems
failed to produce any sign of enantiomer separation.
Derivatization of 17, 18, 21, and 22 as 3,5-dinitro-
benzoyl amides 19, 23, 20, and 24 was undertaken, yet
examination using an (S)-Leu and (R)-NEA chiral
HPLC column failed to produce any sign of enantiomer
resolution. Surprisingly, use of the Whelk O-2 column,
which contained a 3,5-dinitrobenzoyl modified solid
phase, produced excellent separation. Despite this
apparent mismatch of analyte and chiral stationary
phase, in which both contained the 3,5-dinitrobenzoyl
group, retention time differences on the order of 8–
10min were observed for the enantiomers. In both cases,
the enantiomeric excesses observed were 97–98% ee
demonstrating again that the starting aziridines 1 and
2 had not been configurationally compromised during
the synthetic manipulations from the phosphonoserines
5 and 6 (vida ante).
—
—
5R
6S
—
—
—
—
87
90
81
52
70
80
60
71
78
68
36
43
46
78
80
92
53
57
64
33
À9.1 98b,d
+11.7 98b,d
—
—
1R
2S
À29.8 Incomplete
+29.6 Resolutionc
+13.5 Incomplete
À14.1 Resolutionc
+20.8 98c
NaCN
13R
14S
Sodium malonate 15R
16S
À21.9 98c
NaN3
17R
18S
21R
22S
25R
26S
27R
28S
29R
30S
32R
33S
34R
35S
36R
37S
À18.5 98c,e
+17.0 98c,e
Phenethylamine
Imidazole
+6.8 98c d
,
À6.9 98c,d
+18.5 Inseparablec
À13.3
n-Propylthiol
À19.3 Inseparablec
+18.0
Triphenylmethyl
Mercaptan
NaBH4
+1.4 Inseparablec
À1.4
À17.4 98c
+15.0 98c
(n-Bu)4NF
À11.2 Inseparablec
+10.2
Lithium diethyl
Phosphite
À3.7 Inseparablec
+4.1
a As determined by chiral phase HPLC.
b Using a Pirkle (S)-Leu and (R)-NEA chiral phase column.
c Using an (S,S)-Whelk O-2 chiral phase column.
d Following conversion to the 3,5-dinitrobenzoyl derivative.
e Following reduction and conversion to the 3,5-dinitrobenzoyl
derivative.
f Concentration and solvent are listed in Section 4.
O
O
H
OEt
CN
H
N
EtO
OEt
P
O
OEt
S
O
H
O
O
S
OEt
OEt
O
a
b
OEt
OEt
S
N
P
N
H
P
H
O
O
O
O
(1R)-(-)-1
(1R)-(+)-13
(1R)-(+)-15
a
b
(1S)-(-)-16
(1S)-(+)-2
(1S)-(-)-14
Scheme 2. Select carbon nucleophile reactions with 1 and 2. Reagents and conditions: (a) NaH, diethylmalonate, THF; (b) NaCN, DMF.

3310
E. K. Dolence, J. B. Roylance / Tetrahedron: Asymmetry 15 (2004) 3307–3322
NO2
NH2
H
O
O
OEt
a, b
c
O2N
(1R)-(-)-1
S
N
P
H
OEt
NH
O
O
H
O
S
OEt
OEt
(1R)-(-)-17
N
P
H
O
O
d
e
(1R)-19
O2N
NO2
N
N
NH
N
O
H
O
H
H
O
S
OEt
O
OEt
c
OEt
OEt
S
N
P
N
P
S
N
P
H
OEt
H
OEt
H
O
O
O
O
O
O
(1R)-(+)-25
(1R)-(-)-21
(1R)- 23
c
a, b
(1S)-(+)-18
(1S)-20
(1S)-24
(1S)-(+)-2
e
d
c
(1S)-(+)-22
(1S)-(-)-26
Scheme 3. Select nitrogen nucleophile reactions with 1 and 2. Reagents and conditions: (a) NaN3, DMF; (b) 20% Pd(OH)2/C, H2, EtOH; (c) 3,5-
dinitrobenzoyl chloride, Et3N, CH2Cl2; (d) imidazole, CH3CN; (e) phenethylamine, CH3CN.
Initially, reaction with simple thiols proved problematic.
Scheme 4 shows the reactions of 1 and 2 with the
selected thiols n-propylthiol and triphenylmethylmer-
captan. Treatment of 1 with n-propylthiol in the pres-
ence of triethylamine produced no trace of desired
product 27 and only decomposition of the starting azir-
idine. Reaction of aziridine 1 with the sodium anion of
triphenylmethylmercaptan in THF afforded the desired
SCPh3
H
O
OEt
S
N
P
H
OEt
O
O
H
OEt
N
S
P
O
OEt
(1R)-(+)-29
S
H
O
S
O
O
a
b or c
OEt
OEt
+
N
P
H
O
O
SSCPh3
H
O
OEt
S
N
P
(1R)-(-)-1
(1R)-(-)-27
H
OEt
O
O
(1R)-(-)-31
c
a
(1S)-(+)-2
(1S)-(+)-28
(1S)-(-)-30
Scheme 4. Select thiol nucleophile reactions with 1 and 2. Reagents and conditions: (a) n-Bu3P, CH3CN, n-PrSH; (b) NaH, THF, HSCPh3;
(c) nBu3P, CH3CN, HSCPh3.

E. K. Dolence, J. B. Roylance / Tetrahedron: Asymmetry 15 (2004) 3307–3322
3311
H
OEt
F
N
P
O
OEt
H
H
O
S
O
S
S
OEt
OEt
OEt
OEt
O
a
O
b
N
P
N
P
H
H
O
O
O
O
(1R)-(-)-32
(1R)-(-)-1
(1R)-(-)-34
e
c, d
OEt
OEt
O
P
O
H
H
OEt
OEt
O
OEt
O
N
P
S
N
P
H
H
OEt
O
O
O
(1R)-(-)-38
(1R)-(-)-36
a
b
(1S)-(+)-2
(1S)-(+)-33
(1S)-(+)-35
e
(1S)-(+)-37
Scheme 5. Other nucleophile reactions with 1 and 2. Reagents and conditions: (a) NaBH4, THF; (b) TBAF, THF; (c) Na/NH3, EtOH, THF, À78ꢁC;
(d) Cbz-Cl, NaHCO3, THF, H2O; (e) n-BuLi, HPO(OEt)2, THF.
sulfide product 29 (36%), recovered aziridine 1 (26%)
and the interesting disulfide 31 (5%). This unusual disul-
fide product was very difficult to remove by silica
chromatography and its identity was confirmed spec-
troscopically and by ESI-MS. Inclusion of 1.0 equiv of
tri-n-butylphosphine46 in the reaction and a slight excess
of thiol in the complete absence of any additional base
suppressed the formation of the disulfide and afforded
the analogues 29 and 30 in the 60–80% yield range on
a 0.1426mmol scale. Scale-up production of 29 to a
8.102mmol scale afforded a 46% yield following flash
silica gel chromatography with complete absence of
disulfide 31. Reaction of 1 and 2 with n-propylthiol
and tri-n-butylphosphine afforded sulfides 27 and 28 in
36% and 43% yields, respectively. Boron trifluoride
etherate in an equimolar amount and in the presence
of excess n-propylthiol (as the solvent) at reflux did
afford 27 and 28 but was an undesirable approach since
not all thiols can be used as a reflux solvent. Use of a
catalytic amount of tri-n-butylphosphine as reported
by Hou et al.46 in the reaction with aziridines 1 and 2
produced only trace amounts of products as monitored
by silica TLC.
32 and 33 with no evidence of racemization. Removal
of the N-tosyl group was accomplished using dissolving
metal (Na in NH3) reduction followed by N-protection
with Cbz-Cl to afford 38 in 68% yield. Attempts at re-
moval47 of the N-tosylate group using Mg metal in
methanol/ultrasound or with sodium naphthalide were
unsuccessful. Despite these difficulties, this established
that dissolving metal (Na) mediated deprotection could
be utilized for N-tosyl group removal without extensive
loss of enantiomeric excess. Attempts at chiral HPLC of
N-tosylate 32 failed, however once replaced with the N-
Cbz group successful separation occurred (90% ee).
Reaction of the enantiomeric aziridines with tetrabutyl-
ammonium fluoride in THF48 smoothly produced the b-
substituted monofluoro analogues 34 and 35 in 53% and
57% yields, respectively, at ambient room temperature.
Treatment of 1 and 2 with lithium diethylphosphite in
THF afforded the optically active diphosphonates 36
(64%) and 37 (33%). Analysis of the enantiomeric pairs
of 34 and 35, and 36 and 37, using a Whelk O-2 chiral
column failed to produce any sign of enantiomeric reso-
lution under a variety of solvent conditions.
Reactions of 1 and 2 with several other commercial
nucleophiles of interest are shown in Scheme 5. Reduc-
tion by NaBH4 in THF conveniently afforded near
quantitative yields of the protected phosphonoalanines
3. Conclusion
In summary, we have demonstrated that aziridine
2-phosphonates 1 and 2 are valuable, stable chiral

3312
E. K. Dolence, J. B. Roylance / Tetrahedron: Asymmetry 15 (2004) 3307–3322
synthons for the rapid synthesis of b-substituted a-ami-
nophosphonates. A variety of nucleophiles are capable
of reaction and we have observed that the inclusion of
tri-n-butylphosphine in a stoichiometric amount is nec-
essary for a slight excess of thiol nucleophiles to react
successfully. Parallel synthesis and the use of both
enantiomers demonstrate that separation of nucleophile
derived products by chiral HPLC is not always success-
ful nor predictable. Successful resolution by chiral
HPLC further reinforces the notion that the specific
rotation can often afford misleading conclusions with
respect to absolute enantiopurity. We have observed
an apparent mismatch of 3,5-dinitrobenzoyl derivatized
analyte and chiral Whelk O-2 column that successfully
produced excellent resolution of optical isomers when
a matched (S)-Leu and (R)-NEA chiral HPLC column
failed to resolve the enantiomers. Evaluation of these
important synthons is currently underway to investigate
their reactions with nucleophiles such as cuprates and
their potential use in the rapid production of libraries
of S- and N-b-substituted a-amino phosphonates.
obtained using a mixture of 1:1 acetonitrile/water con-
taining 0.1% trifluoroacetic acid.
4.1.1. Diethyl (2R)-1-[(4-methylphenyl)sulfonyl]aziridin-
2-ylphosphonate 1. To a solution of (2R)-2-(diethoxy-
phosphoryl)-2-{[(4-methylphenyl)sulfonyl]amino}ethyl-
methanesulfonate 11 (4.17g, 9.70mmol) in 100mL of
THF at 0ꢁC was added 60% NaH (0.39g, 9.70mmol).
The ice bath was removed and the reaction stirred for
3h at which time TLC (2:1 EtOAc/hexanes) revealed
an absence of any starting material. The THF was re-
moved in vacuo and the residue transferred to a separa-
tory funnel using 100mL of EtOAc. This was washed
with 50mL of saturated aqueous NaHCO3 and 50mL
of brine. Both aqueous layers were back extracted with
two 50mL portions of EtOAc. The pooled organic
phases were dried, filtered, and evaporated in vacuo to
afford 3.51g of a crude oil. The oil was purified by grav-
ity silica gel chromatography (300mL silica gel) eluting
with 2:1 EtOAc/hexanes collecting 20mL fractions.
Homogenous fractions were pooled and evaporated in
vacuo to afford 2.86g (88% yield) of 1 as an oil.
20
D
1604, 1460, 1405, 1340, 1270, 1175, 1035, 920, 830,
½aŠ ¼ À29:8 (c 1.00, CHCl3); IR (TF) 3040, 2965,
4. Experimental
4.1. General
1
725cmÀ1; H NMR (CDCl3) d 1.23 (t, 3H, J = 7.0Hz,
CH3), 1.29 (t, 3H, J = 7.0Hz, CH3), 2.46 (s, 3H, CH3),
2.51(dd, 1H, J = 4.6 and 9.1Hz, diastereotopic CH2),
2.74 (dd, 1H, J = 7.7 and 9.1Hz, diastereotopic CH2),
2.81–2.89 (m, 1H, CHP), 3.94–4.14 (m, 4H, POCH2),
7.36 (d, 2H, J = 8.3Hz, aromatic H), 7.84 (d, 2H,
J = 8.3Hz, aromatic H); 13C NMR (CDCl3) d 16.19 (t,
JCCOP = 5.6Hz, CH3CH2OP), 21.58, 30.20, 31.25 (d,
JCP = 202Hz,), 62.81 (d, JCOP = 6.3Hz, CH3CH2OP),
63.46 (d, JCOP = 6.3Hz, CH3CH2OP), 128.26, 129.71,
133.83, 145.16; 31P NMR (CDCl3) d 16.98; positive
ion ESMS: calculated: C13H20O5N1P1S1Na1 m/z
(M + Na) 356.1. Found: C13H20O5N1P1S1Na1 m/z
(M + Na) 356.1.
The solvent THF was distilled from sodium benzophe-
none. Toluene, Et3N, and CH2Cl2 were distilled from
CaH2. DMF was vacuum distilled from CaH2. Absolute
ethanol and CHCl3 were commercial grade and used as
purchased. EtOAc and hexanes were distilled prior to
use. n-Butyllithium was titrated prior to use using 2,3-
dimethoxybenzyl alcohol in THF. All reactions and
distillations were conducted under an inert nitrogen
atmosphere. Analytical thin-layer chromatography was
carried out on E. Merck precoated silica gel 60
(0.2mm, aluminum or glass support) TLC plates.
Preparative TLC including radial chromatography was
carried out using E. Merck silica gel 60. Flash silica
gel column chromatography was carried out using
Mallinckrodt silica gel 60, 230–400mesh. Chiral HPLC
was carried out using either a Phenomenexꢂ Chirex
(S)-Leu and (R)-NEA 250 · 4.60mm column or a Regis
(S,S) Whelk O-2 250 · 4.60mm column with monitor-
ing at 254nm. Normal silica phase HPLC was carried
out using an Alltech Adsorbosphere SI 5lm-
250 · 4.6mm column with monitoring at 254nm. All
HPLC solvents were filtered through a 0.45lm filter
prior to use. The term ÔdriedÕ refers to drying of a solu-
tion over anhydrous magnesium sulfate. Distilled deion-
ized water was obtained from a Millipore NanoPure
system.
4.1.2. Diethyl (2S)-1-[(4-methylphenyl)sulfonyl]aziridin-2-
ylphosphonate 2. To a solution of (2S)-2-(diethoxy-
phosphoryl)-2-{[(4-methylphenyl)sulfonyl]amino}ethyl-
methanesulfonate 12 (0.576g, 1.339mmol) in 114mL of
THF at 0ꢁC was added 60% NaH (0.054g, 1.339mmol).
The ice bath was removed and the reaction stirred for 3h
at which time TLC (2:1 EtOAc/hexanes) revealed an ab-
sence of starting material. The THF was removed in
vacuo and the residue transferred to a separatory funnel
using 50mL of EtOAc. This was washed with 50mL of
saturated aqueous NaHCO3 and 50mL of brine. Both
aqueous layers were back extracted with two 50mL por-
tions of EtOAc. The pooled organic phases were dried,
filtered, and evaporated in vacuo to afford 0.500g of a
crude oil. This was purified by gravity silica gel chroma-
tography (50mL silica gel) eluting with 2:1 EtOAc/hex-
anes collecting 5mL fractions. Homogenous fractions
1H, 13C, 31P, and 19F NMR spectra were obtained using
a Bruker Avance 400MHz NMR and referenced to
either TMS or the residual NMR solvent signal for d6-
DMSOat 2.50ppm for 1H or 39.5ppm for 13C. 19F
NMR was subject to external reference using hexafluoro-
benzene at 164.9ppm and 31P NMR using H3PO4 at
0.00ppm. Specific rotations were obtained in spectral
grade solvents. Infrared spectra were obtained as thin
films on NaCl plates. Electrospray mass spectra were
were pooled and evaporated in vacuo to afford 0.404g
20
D
IR (TF) 3040, 2965, 1602, 1450, 1400, 1335, 1260, 1170,
(90% yield) of 2 as an oil. ½aŠ ¼ þ29:6 (c 0.80, CHCl3);
1
1025, 915, 820, 720cmÀ1; H NMR (CDCl3) d 1.23 (t,
3H, J = 7.1Hz, CH3), 1.29 (t, 3H, J = 7.1Hz, CH3),
2.46 (s, 3H, CH3), 2.51 (dd, 1H, J = 4.6 and 9.2Hz, dia-
stereotopic CH2), 2.74 (dd, 1H, J = 7.6 and 9.1Hz, dia-

E. K. Dolence, J. B. Roylance / Tetrahedron: Asymmetry 15 (2004) 3307–3322
3313
stereotopic CH2), 2.81–2.89 (m, 1H, CHP), 3.94–4.14
(m, 4H, POCH2), 7.36 (d, 2H, J = 8.3Hz, aromatic H),
7.84 (d, 2H, J = 8.3Hz, aromatic H); 13C NMR (CDCl3)
d 16.21 (t, JCCOP = 5.4Hz, CH3CH2OP), 21.59, 30.22,
31.27 (d, JCP = 202Hz,), 62.83 (d, JCOP = 6.3Hz,
CH3CH2OP), 63.47 (d, JCOP = 6.3Hz, CH3CH2OP),
128.27, 129.72, 133.84, 145.17; 31P NMR (CDCl3) d
16.96; positive ion ESMS: calculated: C13H20O5-
N1P1S1Na1 m/z (M + Na) 356.1. Found: C13H20O5-
N1P1S1Na1 m/z (M + Na) 356.1.
JCCOP = 5.7Hz, CH3), 52.67 (d, JCP = 141.7Hz,),
58.47, 59.98, 61.80 (t, JCOP = 6.5 and 6.9Hz, CH2OP),
70.47 (d, JCCP = 3.1Hz, CH2), 73.04, 77.77, 127.38,
127.48, 127.53, 127.90, 128.13, 128.27, 138.03, 140.19;
31P NMR (CDCl3) d 27.67; positive ion ESMS: calcu-
lated: C22H32O5N1P1 m/z (M + Na) 444.2. Found:
C22H32O5N1P1 m/z (M + Na) 444.2; Silica HPLC 97%
pure (tR = 14.85min) eluting at 1.0mL/min with 2:1 eth-
ylacetate/hexanes. Chiral HPLC with detection at
254nm using a Whelk O-2 column eluting at 1.0mL/
min with 80:20:5 hexanes/2-propanol/1,2-dichloroethane
to afford a 99:1 ratio of R:S-enantiomers (R-tR =
10.5min and S-tR = 8.8min) or 98% ee.
4.1.3. Diethyl (1R)-(2-O-benzyl)-1-{[(1R)-2-methoxy-1-
phenylethyl]amino}ethyl phosphonate 3.39,40 To an
oven dried, 5L round bottom flask equipped with
mechanical stirrer and 60mL addition funnel were added
500g of anhydrous Na2SO4, (R)-(À)-1-amino-1-phenyl-2-
methoxyethane (48.0g, 0.317mol) and 950mL of dry tol-
uene. This mixture was stirred vigorously and cooled to
0ꢁC using an ice bath. To this cooled suspension was
added dropwise over 30min neat O-benzyl-a-hydroxy-
acetaldehyde (47.5g, 0.317mol) followed by removal of
the ice bath with stirring continued for 1.5h. The solid
was removed by suction filtration directly into a 3L round
bottom flask using 500mL of toluene to aid in the proc-
ess. The toluene was removed in vacuo to afford the crude
imine as a pale yellow oil. THF (500mL) was added and
the flask stored under a nitrogen environment.
4.1.4. Diethyl (1S)-(2-O-benzyl)-1-{[(1S)-2-methoxy-1-
phenylethyl]amino}ethylphosphonate 4. Diastereomer 4
was synthesized as described above for 3. The imine
was produced from (S)-(+)-1-amino-1 phenyl-2-meth-
oxyethane (38.36g, 0.253mol) and O-benzyl-a-hydroxy-
acetaldehyde (37.95g, 0.253mol). This imine was
reacted with the phosphite anion generated from dieth-
ylphosphite (69.88g, 0.506mol) and 2.53M n-butyllith-
ium (100mL, 0.253mol). Work-up was done as
described previously with silica gel chromatography
20
D
(c 0.60, CHCl3); IR (TF) 3360, 3010, 1610, 1465, 1400,
affording 71.4g (67%) of 4 as a clear oil. ½aŠ ¼ þ48:2
1
1370, 1255, 1040, 970, 715cmÀ1; H NMR (CDCl3) d
1.27 (t, 3H, CH3, J = 7.1Hz), 1.31 (t, 3H, CH3,
J = 7.1Hz), 2.60 (br s, 1H, NH), 2.96–3.05 (m, 1H,
CHP), 3.36 (s, 3H, OCH3), 3.39–3.50 (m, 2H, OCH2),
3.61–3.75 (m, 2H, OCH2), 4.00–4.20 (m, 4H, POCH2);
4.38–4.43 (m, 1H, benzylic CH), 4.47 (t, 2H, benzylic
CH2, J = 12.0 and 13.3Hz), 7.22–7.40 (m, 10 H, aro-
matic H); 13C NMR (CDCl3) 16.33 (d, JCCOP = 5.9Hz,
CH3), 16.44 (d, JCCOP = 6.0Hz, CH3), 52.61 (d,
JCP = 141.5Hz,), 58.46, 59.93, 61.79 (t, JCOP = 7.2 and
7.6Hz, CH2OP), 70.43 (d, JCCP = 3.1Hz, CH2), 73.02,
77.74, 127.38, 127.37, 127.48, 127.52, 127.88, 128.15,
128.26, 137.99, 140.14; 31P NMR (CDCl3) d 27.68; pos-
itive ion ESMS: calculated: C22H32O5N1P1 m/z
(M + Na) 444.2. Found: C22H32O5N1P1 m/z (M + Na)
444.2; Silica HPLC 97% pure (tR = 14.85 min) eluting
at 1.0mL/min with 2:1 ethylacetate/hexanes. Chiral
HPLC with detection at 254nm using a Whelk O-2 col-
umn eluting at 1.0mL/min with 80:20:5 hexanes/2-pro-
panol/1,2-dichloroethane to afford a 0:100 ratio of
R:S-enantiomers (R-tR = undetectable and S-tR =
8.3min) or >99% ee.
To an oven dried, 5L round bottom flask equipped with
mechanical stirrer and septa were added diethylphos-
phite (86.46g, 0.486mol) and 1.0L of THF. This mix-
ture was cooled to 0ꢁC using an ice bath. A 2.5M
solution of n-butyllithium (100mL, 0.250mol) was
added over 15min using a stainless steel canula. Stirring
was continued for 30min at 0ꢁC followed by removal of
the ice bath and another 1h of stirring to ensure com-
plete phosphite anion formation.
The phosphite anion solution was added as fast as pos-
sible using a canula to the imine solution at ambient
room temperature. THF (50mL) was used to aid in
completing transfer. The reaction mixture was stirred
for 12h followed by the addition of 500mL of water
after which the THF was removed in vacuo. The oil
was transferred to a 2L separatory funnel, 500mL of
water was added, and the mixture extracted with five
500mL portions of EtOAc. The organic phases were
each washed with 250mL of brine, dried, filtered, and
the solvent removed in vacuo to afford 140.4g of a yel-
low oil. This oil was purified by flash silica gel chroma-
tography (4L volume of silica gel) eluting first with 2:1
4.2. General method for the hydrogenation of 3 and 4 to
afford amino alcohols 5 and 6
EtOAc/hexanes and finally with EtOAc to afford 96.0g
20
D
(72% yield) of 3 as a clear oil. ½aŠ ¼ À47:3 (c 0.60,
4.2.1. Diethyl (1R)-1-amino-2-hydroxyethylphosphonate
5.39,40 A mixture of 3 (10.75g, 0.025mol) and 20%
Pd(OH)2/C (10.7g, 60% water by weight) in 100mL of
absolute EtOH was exposed to 50psi H2 with shaking
for 48h. The mixture was filtered through a bed of Celite
filter aid and the filter pad washed with 100mL EtOH.
The solvents were removed in vacuo to afford 6.47g of
a yellow oil. This was purified by flash silica gel chroma-
tography (250mL silica gel) eluting with 1:5 EtOH/
CHCl3 (containing 0.1% NH4OH) collecting 50mL frac-
tions. TLC analysis of the fractions and pooling
25
CHCl3); lit.39,40 ½aŠ ¼ À49 (c 0.65, CHCl3); IR (TF)
D
3360, 3010, 1610, 1465, 1400, 1370, 1255, 1040, 970,
715cmÀ1 1H NMR (CDCl3) d 1.27 (t, 3H, CH3,
;
J = 7.1Hz), 1.31 (t, 3H, CH3, J = 7.1Hz), 2.57 (br s,
1H, NH), 2.99–3.05 (m, 1H, CHP), 3.36 (s, 3H,
OCH3), 3.39–3.50 (m, 2H, OCH2), 3.62–3.73 (m, 2H,
OCH2), 4.05–4.20 (m, 4H, POCH2); 4.38–4.42 (m, 1H,
benzylic CH), 4.46 (t, 2H, benzylic CH2, J = 12.1 and
12.9Hz), 7.22–7.41 (m, 10H, aromatic H); 13C NMR
(CDCl3) d 16.34 (d, JCCOP = 6.0Hz, CH3), 16.45 (d,

3314
E. K. Dolence, J. B. Roylance / Tetrahedron: Asymmetry 15 (2004) 3307–3322
produced 4.19g (83% yield) of 5 as a clear oil.
(m, 2H, HOCH2), 4.52–4.65 (m, 1H, CHP), 5.08 (t,
1H, J = 6.5Hz, HOCH2), 8.95 (t, 1H, J = 2.5 and
2.9Hz, aromatic H), 9.12 (d, 2H, J = 2.1Hz, aromatic
H), 9.47 (d, 1H, J = 9Hz, NH); 31P NMR (CDCl3) d
22.09; positive ion ESMS: calculated: C26H36O18-
N6P2Na1 m/z (2M + Na) 805.1. Found: C26H36O18-
N6P2Na1 m/z (2M + Na) 804.7; chiral HPLC with
detection at 254nm using a Chirexꢂ column eluting at
1.0mL/min with 100:100:50:0.25 hexanes/1,2-dichloro-
ethane/2-propanol/trifluoroacetic acid to afford a 7:93
ratio of R:S-enantiomers (R-tR = 25.88min and S-
tR = 22.17min). Accuracy of this determination reflects
more (S)-enantiomer than actually present due to tailing
of the (R)-enantiomer making integration of the peak
area more difficult.
20
25
½aŠ ¼ À9:1 (c 1.0, CHCl3), lit.39,40 ½aŠ ¼ À10:6 (c
D
D
1.5, CHCl3); 1H NMR (CDCl3) d 1.32–1.39 (m, 6H,
CH3), 2.38 (br s, 3H, OH and NH2), 3.13–3.20 (m,
1H, CHP), 3.70–3.90 (m, 2H, HOCH2), 4.10–4.24 (m,
4H, POCH2); 13C NMR (CDCl3) d 16.30–16.40 (m,
CH3), 50.58 (d, JCP = 146.8Hz), 61.88 (d, JCP = 3.8Hz,),
62.16 (d, JCOP = 6.9Hz, CH2OP), 62.31 (d,
JCOP = 7.1Hz, CH2OP), 31P NMR (CDCl3) d 26.94.
4.2.2. Characterization data for diethyl (1S)-1-amino-2-
20
D
hydroxyethylphosphonate 6.49 86% yield; ½aŠ ¼ þ11:7
25
(c 1.0, CHCl3), lit.49 ½aŠ ¼ þ9:0 (c 1.0, CHCl3); IR
D
(TF) 3320 (br), 2965, 1600, 1450, 1400, 1225, 1050,
1
975, 800, 740cmÀ1; H NMR (CDCl3) d 1.35 (t, 6H,
J = 7.1Hz, CH3), 2.63 (br s, 3H, OH and NH2), 3.14–
3.21 (m, 1H, CHP), 3.69–3.77 (m, 1H, HOCH2), 3.82–
3.90 (m, 1H, HOCH2), 4.09–4.24 (m, 4H, POCH2);
13C NMR (CDCl3) d 16.30–16.40 (m, CH3), 50.57 (d,
JCP = 146.6Hz), 61.97 (d, JCP = 3.8Hz,), 62.17 (d,
JCOP = 7.0Hz, CH2OP), 62.33 (d, JCOP = 7.0Hz,
CH2OP), 31P NMR (CDCl3) d 26.95.
4.4. General method for N-tosylation of amino alcohols 5
and 6
4.4.1. Diethyl (1R)-2-hydroxy-1-{[(4-methylphenyl)sulfon-
yl]amino}ethylphosphonate 9. Diethyl (1R)-1-amino-
2-hydroxyethylphosphonate 5 (8.89g, 0.0449mol) in
250mL of anhydrous CH2Cl2 was treated simultane-
ously by dropwise addition of p-toluenesulfonyl chloride
(8.56g, 0.0449mol) in 100mL anhydrous CH2Cl2 and
Et3N (6.26mL, 0.0449mol). The reaction was stirred
for 18h. The mixture was diluted with 250mL of
CH2Cl2 and washed with 250mL portions of 1M aque-
ous AcOH, water, saturated aqueous NaHCO3, and
brine. The organic phase was dried, filtered and evapo-
rated to afford 15.95g of a pale yellow solid. The solid
was purified by flash silica gel chromatography (1L vol-
ume of silica gel) eluting first with EtOAc followed by
1:10 EtOH/EtOAc collecting 100mL fractions. Pure
fractions were pooled and evaporated to afford 11.70g
4.3. General method for 3,5-dinitrobenzoylation of amino
alcohols 5 and 6 for chiral HPLC analysis
4.3.1.
hydroxyethylphosphonate 7.
Diethyl
(1R)-1-[(3,5-dinitrobenzoyl)amino]-2-
mixture of diethyl
A
(1R)-1-amino-2-hydroxyethylphosphonate 5 (20.0mg,
0.101mmol) and 3,5-dinitrobenzoyl chloride (29.1mg,
0.126mmol) and triethylamine (18lL, 0.126mmol) in
1.0mL of anhydrous CH2Cl2 were stirred with TLC
monitoring using 1:5 EtOH/CHCl3. After 1h, no start-
ing amine remained. The reaction mixture was diluted
with 10mL CH2Cl2 and washed with 10mL each of
1M aqueous AcOH, saturated NaHCO3, and brine.
The organic phase was dried, filtered, and evaporated
in vacuo to afford 29.3mg of a white solid. This was ap-
plied using CH2Cl2 to one glass backed Merck silica gel
TLC plate and eluted with 1:20 EtOH/EtOAc. The ma-
jor UV active band of Rf 0.28 was scraped off and the
silica eluted with 1:5 EtOH/CHCl3 to afford the follow-
ing evaporation in vacuo 18.5mg (47% yield) of 7 as a
(74% yield) of 9 as a white solid. This solid resisted all
attempts at recrystallization. Mp 97–99ꢁC; ½aŠ
20
D
¼
À11:7 (c 1.00, CHCl3); IR (TF) 3220 (br), 2965, 1602,
1
1450, 1335, 1230, 1165, 1055, 970, 825, 740cmÀ1; H
NMR (CDCl3) d 1.25–1.32 (m, 6H, CH3), 2.42 (s, 3H,
CH3), 3.43–3.54 (m, 1H), 3.69–3.85 (m superimposed
with br s, 3 H), 4.07–4.27 (m, 4H, POCH2); 6.86 (d,
1H, J = 9.6Hz, NH), 7.29 (d, 2H, J = 8.2Hz, aromatic
H), 7.80 (d, 2H, J = 8.3Hz, aromatic H); 13C NMR
(CDCl3) d 16.19–16.35 (m, CH3CH2OP), 21.45, 52.74
(d, JCP = 160.0Hz,), 61.43, 63.04 (d, JCOP = 7.0Hz,
CH3CH2OP), 64.06 (d, JCOP = 7.1Hz, CH3CH2OP),
127.07, 129.63, 138.08, 143.46; 31P NMR (CDCl3) d
22.53; positive ion ESMS: calculated: C13H22O6N1-
P1S1Na1 m/z (M + Na) 374.1. Found: C13H22O6N1-
P1S1Na1 m/z (M + Na) 374.1; Anal Calcd for
C13H22N1O6P1S1: C, 44.43; H, 6.32; N, 3.99%. Found:
C, 44.68; H, 6.67; N, 3.95%. Silica HPLC 100% pure
(tR = 6.82min) eluting at 1.0mL/min with 1:10 EtOH/
EtOAc. Attempts at chiral HPLC using a Whelk O-2
column were unsuccessful under a variety of conditions.
white solid. 1H NMR (CDCl3)
d 1.21 (t, 3H,
J = 7.0Hz, CH3), 1.41 (t, 3H, J = 7.0Hz, CH3), 3.00–
3.80 (br s, 1H, OH), 3.94–4.35 (m, 6H, OCH2), 4.84–
4.92 (m, 1H, CHP), 8.83 (d, 1H, J = 9.5Hz, NH),
9.19–9.44 (m, 3H, aromatic H); 31P NMR (CDCl3) d
22.17; positive ion ESMS: calculated: C13H18O9-
N3P1Na1 m/z (M + Na) 414.1 and C26H36O18N6P2Na1
m/z (2M + Na) 805.1. Found: C13H18O9N3P1Na1
m/z (M + Na) 414.0 and C26H36O18N6P2Na1 m/z
(2M + Na) 804.7; chiral HPLC with detection at
254nm using a Chirexꢂ column eluting at 1.0mL/min
with 100:100:50:0.25 hexanes/1,2-dichloroethane/2-pro-
panol/trifluoroacetic acid to afford a 98.5:1.5 ratio of
R:S-enantiomers
22.72min) or 97% ee.
(R-tR = 25.18min
and
S-tR =
4.4.2. Characterization data for diethyl (1S)-2-hydroxy-1-
{[(4-methylphenyl)sulfonyl]amino}ethylphosphonate 10.
54% yield; This solid resisted all attempts at recrystalli-
4.3.2. Characterization data for diethyl (1S)-1-[(3,5-
dinitrobenzoyl)amino]-2-hydroxyethylphosphonate
20
8.
zation. Mp 97–99ꢁC; ½aŠ ¼ þ11:7 (c 1.00, CHCl3); IR
D
(TF) 3200 (br), 2965, 1602, 1450, 1340, 1230, 1165,
52% yield; 1H NMR (DMSO-d6) d 1.18 (t, 3H, J =
7.0Hz, CH3), 1.24 (t, 3H, J = 7.0Hz, CH3), 3.95–4.12
1050 (br), 970, 820, 780cmÀ1 1H NMR (CDCl3) d
;

E. K. Dolence, J. B. Roylance / Tetrahedron: Asymmetry 15 (2004) 3307–3322
3315
1.25–1.31 (m, 6H, CH3), 2.41 (s, 3H, CH3), 3.44–3.55
(m, 1H), 3.70–3.79 (m, 2H), 3.92–4.02 (m, 1H), 4.09–
4.28 (m, 4H, POCH2); 7.10 (d, 1H, J = 9.8Hz, NH),
7.30 (d, 2H, J = 8.0Hz, aromatic H), 7.81 (d, 2H,
CH2CHP), 127.03, 129.63, 137.80, 143.70; 31P NMR
(CDCl3) d 18.36; positive ion ESMS: calculated:
C14H24O8N1P1S2Na1 m/z (M + Na) 452.1. Found:
C13H22O6N1P1S1Na1 m/z (M + Na) 452.0.
J = 8.2Hz, aromatic H); 13C NMR (CDCl3)
d
16.15–16.31 (m, CH3CH2OP), 21.41, 52.84 (d,
JCP = 160.3Hz,), 61.38, 63.03 (d, JCOP = 6.9Hz,
CH3CH2OP), 64.03 (d, JCOP = 7.0Hz, CH3CH2OP),
127.00, 129.57, 138.07, 143.36; 31P NMR (CDCl3) d
22.61; positive ion ESMS: calculated: C13H22O6-
N1P1S1Na1 m/z (M + Na) 374.1. Found: C13H22O6-
N1P1S1Na1 m/z (M + Na) 374.1. Attempts at chiral
HPLC using a Whelk O-2 column were unsuccessful
under a variety of conditions.
4.6. General procedure for cyanide addition to aziridines
4.6.1. Diethyl (2R)-cyano{[(4-methylphenyl)sulfonyl]-
amino}methylphosphonate 13. To L-aziridine 1 (3.48g,
10.43mmol) in 70mL DMF was added solid NaCN
(0.64g, 13.038mmol). The reaction was stirred for 21h
followed by removal of the DMF in vacuo. The residue
was diluted with 100mL of EtOAc and 50mL of 10%
aqueous citric acid (caution: work-up must be conducted
in a fume hood) and the mixture stirred until all solid
material had dissolved. The aqueous phase was
extracted with three 100mL portions of EtOAc and
the pooled organic phases washed with brine, dried,
filtered, and evaporated in vacuo to afford 3.86g of an
oil. This oil was purified by flash silica gel chromatogra-
phy (300mL silica gel) eluting with EtOAc and collect-
ing 20mL fractions. Pooled homogenous fractions
4.5. General method for the O-mesylation of alcohols 9
and 10
4.5.1. (2R)-2-(Diethoxyphosphoryl)-2-{[(4-methylphen-
yl)sulfonyl]amino}ethylmethanesulfonate
cooled solution at 0ꢁC of diethyl (1R)-2-hydroxy-1-
[(4-methylphenyl)sulfonyl]aminoethylphosphonate
11. To
a
9
(4.70g, 0.013mol) in 67mL of anhydrous CH2Cl2 and
Et3N (2.33mL, 0.017mol) was added dropwise via syr-
inge methanesulfonyl chloride (1.30mL, 0.017mol).
The solution was stirred for 15min followed by removal
of the ice bath and stirring for 2h. The mixture was
transferred to a separatory funnel and washed with
100mL of saturated aqueous NaHCO3 and brine. The
organic phase was dried, filtered, and evaporated to
afford 6.24g of an oily semi-solid. This was purified by
flash chromatography (600mL volume silica gel) eluting
with EtOAc and collecting 75mL fractions. Pooled frac-
tions were evaporated in vacuo to afford 4.40g (77%
were evaporated in vacuo to afford 3.26g (87% yield)
of 13 as an oil. ½aŠ ¼ þ13:5 (c 2.108, CHCl3); IR
;
1165, 1035, 980, 840, 670cmÀ1 1H NMR (CDCl3)
20
D
(TF) 3100 (br), 2995, 2260, 1601, 1450, 1340, 1240,
d 1.29–1.34 (m, 6H, CH3CH2OP), 2.43 (s, 3H, CH3),
2.64–2.80 (m, 2H, CH2CN), 3.84–3.95 (m, 1H, CHP),
4.07–4.29 (m, 4H, POCH2), 6.86 (dd, 1H, J = 4.5 and
9.4Hz, NH), 7.32 (d, 2H, J = 7.7Hz, aromatic H), 7.81
(d, 2H, J = 8.3Hz, aromatic H); 13C NMR (CDCl3)
d 16.14–16.22 (m, CH3CH2OP), 19.98 (d, JCCP = 3.3Hz,
CH2CHP), 21.47, 46.33 (d, JCP = 164Hz, CHP), 63.45
(d, JCOP = 7.3Hz, CH3CH2OP), 64.58 (d, JCOP = 7.1Hz,
CH3CH2OP), 115.83 (d, J = 6.8Hz, CN), 126.98, 129.77,
137.62, 143.91; 31P NMR (CDCl3) d 19.11; positive
ion ESMS: calculated: C14H21O5N2P1S1Na1 m/z
(M + Na) 383.1. Found: C14H21O5N2P1S1Na1 m/z
(M + Na) 383.1. Chiral HPLC using a Whelk O-2
column eluting with 10:120:40 2-propanol/hexanes/
yield) of 11 as an oil that slowly crystallized.
20
D
2965, 2880, 1602, 1450, 1340, 1240, 1170, 1030, 970,
½aŠ ¼ À7:1 (c 1.00, benzene); IR (TF) 3200, 3050,
1
820, 720, 670cmÀ1; H NMR (CDCl3) d 1.30 (t, 6H,
J = 7.1Hz, CH3), 2.42 (s, 3H, CH3), 2.89 (s, 3H, CH3),
3.95–4.32 (m, 7H), 6.59 (dd, 1H, J = 9.4 and 3.2Hz,
NH), 7.31 (d, 2H, J = 8.2Hz, aromatic H), 7.79 (d,
2H, J = 8.3Hz, aromatic H); 13C NMR (CDCl3) d
16.18–16.33 (m, CH3CH2OP), 21.47, 36.93, 49.81 (d,
JCP = 159.7Hz,), 63.24 (d, JCOP = 6.9Hz, CH3CH2OP),
64.30 (d, JCOP = 6.9Hz, CH3CH2OP), 67.58 (d,
JCCP = 6.5Hz, CH2CHP), 127.04, 129.65, 137.79,
143.73; 31P NMR (CDCl3) d 18.37; positive ion ESMS:
calculated: C14H24O8N1P1S2Na1 m/z (M + Na) 352.1.
Found: C13H22O6N1P1S1Na1 m/z (M + Na) 352.0.
1,2-dichloroethane at 1.0mL/min affords
19.47min. Incomplete baseline separation of a 1:1 mix-
a
tR =
ture of enantiomers (L-tR = 20.12 min and D-tR =
when
19.47min) occurs
simultaneously.
both
are
injected
4.6.2. Characterization data for diethyl (2S)-cyano{[(4-
methylphenyl)sulfonyl]amino}methylphosphonate
14.
20
D
90% yield; ½aŠ ¼ À14:1 (c 1.932, CHCl3); 1H NMR
(CDCl3) d 1.29–1.34 (m, 6H, CH3CH2OP), 2.44 (s,
3H, CH3), 2.63–2.82 (m, 2H, CH2CN), 3.80–3.93 (m,
1H, CHP), 4.05–4.27 (m, 4H, POCH2), 6.32 (dd, 1H,
J = 5.1 and 9.1Hz, NH), 7.33 (d, 2H, J = 8.2Hz, aro-
matic H), 7.81 (d, 2H, J = 8.3Hz, aromatic H); 31P
NMR (CDCl3) d 19.13; positive ion ESMS: calculated:
C14H21O5N2P1S1Na1 m/z (M + Na) 383.1. Found:
C14H21O5N2P1S1Na1 m/z (M + Na) 383.1. Chiral HPLC
using a Whelk O-2 column eluting with 10:120:40 2-pro-
panol/hexanes/1,2-dichloroethane at 1.0mL/min affords
a tR = 20.12. Incomplete baseline separation of a 1:1
mixture of enantiomers (L-tR = 20.12min and D-
tR = 19.47min) occurs when both are injected
simultaneously.
4.5.2. Characterization data for (2S)-2-(diethoxyphos-
phoryl)-2-{[(4-methylphenyl)sulfonyl]amino}ethylmethane-
sulfonate 12. 71% yield; ½aŠ ¼ þ9:2 (c 0.972,
20
D
benzene); IR (TF) 3260, 3120, 2995, 2940, 1602, 1450,
1340, 1245, 1170, 1040, 970, 840, 720, 670cmÀ1 1H
;
NMR (CDCl3) d 1.30 (t, 6H, J = 7.1Hz, CH3), 2.42 (s,
3H, CH3), 2.89 (s, 3H, CH3), 3.94–4.33 (m, 7H), 6.63
(dd, 1H, J = 9.4 and 3.2Hz, NH), 7.31 (d, 2H,
J = 8.1Hz, aromatic H), 7.79 (d, 2H, J = 8.3Hz, aro-
matic H); 13C NMR (CDCl3) d 16.17–16.38 (m,
CH3CH2OP), 21.46, 36.89, 49.81 (d, JCP = 159.8Hz,),
63.21 (d, JCOP = 7.2Hz, CH3CH2OP), 64.30 (d,
JCOP = 7.1Hz, CH3CH2OP), 67.57 (d, JCCP = 6.5Hz,

3316
E. K. Dolence, J. B. Roylance / Tetrahedron: Asymmetry 15 (2004) 3307–3322
4.7. General procedure for malonate anion addition to
aziridines
C20H32O9N1P1S1Na1 m/z (M + Na) 516.1. Chiral HPLC
using a Whelk O-2 column eluting with 10:120:40 2-pro-
panol/hexanes/1,2-dichloroethane at 1.0mL/min affords
a tR = 11.37min. Incomplete baseline separation of a
1:1 mixture of enantiomers (L-tR = 11.37min and D-
tR = 12.12min) occurs when both are injected
simultaneously.
4.7.1. Diethyl [(2R)-1-{[(4-methylphenyl)sulfonyl]amino}-
2-amino-2-(diethoxyphosphoryl)ethyl]malonate 15.
A
solution of diethylmalonate (1.33g, 8.297mmol) in
40mL of THF at 0ꢁC was treated with 60% NaH
(0.33g, 8.297mmol). The mixture was stirred briskly
for 30min then transferred via canula to a flask contain-
ing L-aziridine 1 (2.22g, 6.637mmol) in 10mL of
THF followed by a 6mL THF wash. The reaction
was stirred for 60h at ambient room temperature at
which time TLC monitoring (EtOAc) indicated an
absence of starting 1. The THF was evaporated in
vacuo, the residue dissolved in 100mL of EtOAc and
washed with 50mL of brine containing 5mL of 1M
AcOH. The aqueous phase was extracted with two
50mL portions of EtOAc, washed with brine, dried,
filtered, and evaporated in vacuo to afforded 4.15g of
a crude oil. This was purified by gravity silica column
chromatography (400mL volume silica) eluting with
EtOAc and collecting 10mL fractions. Homogenous
4.8. General method for azide anion addition to aziridines
and hydrogenation
4.8.1. Diethyl (1R)-2-amino-1-{[(4-methylphenyl)sulfon-
yl]amino}ethylphosphonate 17. To the L-aziridine 1
(50.0mg, 0.1496mmol) in 1mL of DMF was added
solid NaN3 (12.2mg, 0.1870mmol). The reaction was
stirred for 14h followed by removal of the DMF in
vacuo. The residue was diluted with 2mL of EtOH,
20% Pd(OH)2/C (25mg) then added and the mixture
exposed to a balloon of H2 for 3h. The catalyst was
removed by filtration through a bed of Celite that was
washed with 10mL of EtOH. The solvent was removed
in vacuo and the residue purified by thin-layer chroma-
tography eluting with 1:5 MeOH/CHCl3 containing
0.1% NH4OH. The major UV positive band was re-
fractions were pooled and evaporated in vacuo to afford
20
D
(c 0.838, CHCl3); IR (TF) 3120 (br), 2995, 2920, 1740,
2.50g (76% yield) of malonate 15 as an oil. ½aŠ ¼ þ20:8
moved and eluted with the same solvent to afford
1602, 1450, 1345, 1240, 1170, 1030, 980, 825, 675cmÀ1
;
20
D
0.460, CHCl3); IR (TF) 3120 (br), 2995, 1602, 1450,
37mg (70% yield) of 17 as an oil. ½aŠ ¼ À18:5 (c
1H NMR (CDCl3)
CH3CH2OP), 1.22–1.32 (5, 9H, CH3CH2O
d
1.16 (t, 3H, J = 7.0Hz,
and
P
1
1340, 1240, 1170, 1030, 970, 825, 675cmÀ1; H NMR
CH3CH2OCO), 1.98–2.10 (m, 1H, diastereotopic CH2),
2.32–2.46 (m, 1H, diastereotopic CH2), 2.41 (s, 3H,
CH3), 3.77 (dd, 1H, J = 9.6Hz, O2CCHCO2), 3.81–
4.27 (m, 9H, CHP and CH3CH2OP), 5.75 (dd, 1H,
J = 4.7 and 9.5Hz, NH), 7.28 (d, 2H, J = 8.0Hz, aro-
matic H), 7.75 (d, 2H, J = 8.1Hz, aromatic H); 13C
(CDCl3) d 1.25–1.30 (m, 6H, CH3CH2OP), 2.42 (s,
3H, CH3), 2.60–2.72 (m, 1H, diastereotopic CH2N),
2.91–2.98 (m, 1H, diastereotopic CH2N), 3.10 (br s,
2H, NH2) 3.59–3.67 (m, 1H, CHP), 4.02–4.20 (m, 4H,
POCH2), 7.29 (d, 2H, J = 8.2Hz, aromatic H), 7.79 (d,
2H, J = 8.3Hz, aromatic H); 13C NMR (CDCl3) d
16.19–16.35 (m, CH3CH2OP), 21.43, 41.32 (d,
JCCP = 3.3Hz, CH2CHP), 51.89 (d, JCP = 157.8Hz,
CHP), 62.41 (d, JCOP = 6.9Hz, CH3CH2OP), 63.54 (d,
JCOP = 7.1Hz, CH3CH2OP), 126.96, 129.58, 138.09,
143.41; 31P NMR (CDCl3) d 22.45; positive ion ESMS:
calculated: C13H24O5N2P1S1 m/z (M + H) 351.1 and
C13H23O5N2P1S1Na1 m/z (M + Na) 373.1. Found:
C13H24O5N2P1S1Na1 m/z (M + H) 351.1 and C13H23-
O5N2P1S1Na1 m/z (M + Na) 373.1. Chiral HPLC was
conducted after derivatization with 3,5-dinitrobenzoyl-
chloride to afford 19.
NMR (CDCl3)
d
13.94 (d, JCCOP = 5.7Hz,
CH3CH2OP), 16.20, 21.44, 29.75 (d, J = 6.1Hz), 47.84
(d, JCCP = 12.2Hz, CH2CHP), 48.18 (d, JCP = 157.7Hz,
CHP), 61.55, 61.59, 62.78 (d, JCOP = 7.1Hz,
CH3CH2OP), 63.03 (d, JCOP = 7.0Hz, CH3CH2OP),
127.11, 129.41, 137.92, 143.28, 168.7, 169.2; 31P
NMR (CDCl3) d 22.82; positive ion ESMS: calculated:
C20H32O9N1P1S1Na1 m/z (M + Na) 516.1. Found:
C20H32O9N1P1S1Na1 m/z (M + Na) 516.1. Chiral HPLC
using a Whelk O-2 column eluting with 10:120:40 2-pro-
panol/hexanes/1,2-dichloroethane at 1.0mL/min affords
a tR = 12.10min. Incomplete baseline separation of a
1:1 mixture of enantiomers (L-tR = 11.37min and D-
tR = 12.12min) occurs when both are injected
simultaneously.
4.8.2. Characterization data for diethyl (1S)-2-amino-1-
{[(4-methylphenyl)sulfonyl]amino}ethylphosphonate 18.
20
80% yield; ½aŠ ¼ þ17:0 (c 0.154, CHCl3); 1H
4.7.2. Characterization data for diethyl [(2S)-1-{[(4-
methylphenyl)sulfonyl]amino}-2-amino-2-(diethoxyphos-
NMR (CDCl3) dD1.26–1.30 (m, 6H, CH3CH2OP), 2.42
(s, 3H, CH3), 2.59–2.72 (m, 1H, diastereotopic CH2N),
2.94–3.02 (m, 1H, diastereotopic CH2N), 3.10 (br s,
2H, NH2), 3.58–3.66 (m, 1H, CHP), 4.01–4.19 (m, 4H,
POCH2), 7.30 (d, 2H, J = 8.3Hz, aromatic H),
7.79 (d, 2H, J = 8.4Hz, aromatic H); 31P NMR
(CDCl3) d 22.45; positive ion ESMS: calculated:
C13H24O5N2P1S1Na1 m/z (M + H) 351.1 and C13H23O5-
N2P1S1Na1 m/z (M + Na) 373.1. Found: C13H24O5N2-
P1S1 m/z (M + H) 351.0 and C13H23O5N2P1S1Na1
m/z (M + Na) 373.1. Chiral HPLC was conducted after
derivatization with 3,5-dinitrobenzoylchloride to afford
20.
20
phoryl)ethyl]malonate (16). 52% yield; ½aŠ ¼ À21:9 (c
D
1.540, CHCl3); 1H NMR (CDCl3) d 1.17 (t, 3H,
J = 7.1Hz, CH3CH2OP), 1.22–1.31 (5, 9H, CH3CH2OP
and CH3CH2OCO), 1.98–2.10 (m, 1H, diastereotopic
CH2), 2.33–2.46 (m, 1H, diastereotopic CH2), 2.42 (s,
3H, CH3), 3.74 (dd, 1H, J = 9.6Hz, O2CCHCO2),
3.79–4.27 (m, 9H, CHP and CH3CH2OP), 5.20 (dd,
1H, J = 5.5 and 9.6Hz, NH), 7.29 (d, 2H, J = 8.1Hz,
aromatic H), 7.75 (d, 2H, J = 8.2Hz, aromatic H); 31P
NMR (CDCl3) d 22.86; positive ion ESMS: calculated:
C20H32O9N1P1S1Na1 m/z (M + Na) 516.1. Found:

E. K. Dolence, J. B. Roylance / Tetrahedron: Asymmetry 15 (2004) 3307–3322
3317
4.9. General method for addition of phenethylamine to
aziridines
0.0290mmol) and 3,5-dinitrobenzoyl chloride (8.4mg,
0.0363mmol) and Et3N (5.1lL, 0.0363mmol) in
0.25mL of CH2Cl2 were stirred overnight. TLC moni-
toring using 1:5 MeOH/CHCl3 revealed the absence of
starting amine. The reaction mixture was applied di-
rectly to one glass backed silica gel TLC plate and eluted
with EtOAc. The major UV active band (Rf 0.39) was
removed and the silica eluted with 1:5 MeOH/CHCl3
to afford, following evaporation in vacuo, 9.8mg
4.9.1. Diethyl (1R)-1-{[(4-methylphenyl)sulfonyl]amino}-
2-[(2-phenylethyl)amino]ethylphosphonate 21. To L-
aziridine 1 (50.0mg, 0.1496mmol) was added phenethyl-
amine (47mg, 0.1870mmol) in 1mL of CH3CN. The
reaction was stirred for 14h followed by dilution with
20mL of n-BuOH and 10mL of water. The aqueous
phase was extracted with two 10mL portions of n-
BuOH. The solvent was removed in vacuo with the aid
of a vacuum pump to afford 90mg of an oil. The residue
was purified by preparative thin-layer chromatography
eluting with 1:10 MeOH/CHCl3. The major UV positive
band (Rf 0.40) was removed and eluted with the same
1
(88% yield) of 19 as an oil. H NMR (CDCl3) d 1.21–
1.28 (m, 6H, CH3), 2.35 (s, 3H, CH3), 3.58–3.67 (m,
1H, diastereotopic CH2N), 3.72–3.81 (m, 1H, diastereo-
topic CH2N), 3.98–4.18 (m, 5H, OCH2 and CHP), 6.47
(br s, 1H, NH), 7.24 (d, 2H, J = 8.2Hz, aromatic H),
7.76 (d, 2H, J = 8.2Hz, aromatic H), 8.14 (br s, 1H,
NH), 9.03 (d, 2H, J = 2.0Hz, aromatic H), 9.11 (t, 1H,
J = 2.0Hz, aromatic H); 31P NMR (CDCl3) d 20.71;
positive ion ESMS: calculated: C20H25O10N4P1S1Na1
m/z (M + Na) 567.1, C40H50O20N8P2S2Na1 m/z
(2M + Na) 1111.2 and C60H75O30N12P3S3Na1 m/z
(3M + Na) 1655.3. Found: C20H25O10N4P1S1Na1
m/z (M + Na) 567.1 (82%), C40H50O20N8P2S2Na1 m/z
(2M + Na) 1110.7 (100%) and C60H75O30N12P3S3Na1
m/z (3M + Na) 1654.2 (10%); chiral HPLC with detec-
tion at 254nm using a Chirexꢂ column eluting at
1.0mL/min with 20% 2-propanol in hexanes produced
no separation. However, excellent separation occurred
using a Whelk O-2 column 10:120:40: 2-propanol/hexa-
nes/1,2-dichloroethane to afford a 99:1 ratio of L:D-
enantiomers (L-tR = 24.65min and D-tR = 35.77min) or
98% ee.
solvent to afford 63mg (71% yield) of 21 as an oil.
20
D
2995, 2965, 1602, 1500, 1460, 1340, 1240, 1165, 1025,
½aŠ ¼ À6:9 (c 1.134, CHCl3); IR (TF) 3220 (br), 3035,
975, 820, 705, 670cmÀ1 1H NMR (CDCl3) d 1.23–
;
1.28 (m, 6H, CH3CH2OP), 2.26–2.38 (m, 1H, diastereo-
topic CH2N), 2.40 (s, 3H, CH3), 2.48–2.56 (m, 1H, dia-
stereotopic CH2N), 2.63 (t, 2H, J = 6.7 and 7.2Hz,
ArCH2), 2.70–2.77 (m, 1H, diastereotopic CH2N),
2.89–2.95 (m, 1H, diastereotopic CH2N), 3.63–3.71
(dq, 1H, CHP), 3.97–4.20 (m, 4H, POCH2), 7.13–7.32
(m, 7H, aromatic H), 7.69 (d, 2H, J = 8.3Hz, aromatic
H); 13C NMR (CDCl3) d 16.16–16.34 (m, CH3CH2OP),
21.42, 36.30, 47.67, 49.55 (d, JCP = 157.8Hz, CHP),
50.93, 62.40 (d, JCOP = 7.0Hz, CH3CH2OP), 63.59 (d,
JCOP = 7.2Hz, CH3CH2OP), 126.09, 126.99, 128.33,
128.57, 129.55, 137.79, 139.82, 143.46; 31P NMR
(CDCl3) d 22.54; positive ion ESMS: calculated:
C21H32O5N2P1S1 m/z (M + H) 455.2 and C21H31O5N2-
P1S1Na1 m/z (M + Na) 477.2. Found: C21H32O5N2P1S1
m/z (M + H) 455.2 and C21H31O5N2P1S1Na1 m/z
(M + Na) 477.1. Chiral HPLC was conducted after der-
ivatization with 3,5-dinitrobenzoylchloride to afford 23.
4.10.2. Characterization data for diethyl (1S)-2-amino-1-
{[(4-methylphenyl)sulfonyl]-[3,5-dinitrobenzoyl-amino]}-
1
ethylphosphonate 20. 86% yield; H NMR (CDCl3) d
1.21–1.28 (m, 6H, CH3), 2.35 (s, 3H, CH3), 3.58–3.67
(m, 1H, diastereotopic CH2N), 3.71–3.81 (m, 1H, dia-
stereotopic CH2N), 3.98–4.18 (m, 5H, OCH2 and
CHP), 6.45 (dd, 1H, J = 3.3 and 9.1Hz, NH), 7.24 (d,
2H, J = 8.2Hz, aromatic H), 7.76 (d, 2H, J = 8.2Hz,
4.9.2. Characterization data for diethyl (1S)-1-{[(4-meth-
ylphenyl)sulfonyl]amino}-2-[(2-phenylethyl)amino]ethyl-
20
phosphonate 22. 60% yield; ½aŠ ¼ þ6:8 (c 0.306,
CHCl3); 1H NMR (CDCl3) d D1.24–1.28 (m, 6H,
CH3CH2OP), 2.21–2.37 (m, 1H, diastereotopic CH2N),
2.41 (s, 3H, CH3), 2.45–2.59 (m, 1H, diastereotopic
CH2N), 2.64 (t, 2H, J = 6.8 and 7.1Hz, ArCH2), 2.72–
2.80 (m, 1H, diastereotopic CH2N), 2.90–2.96 (m, 1H,
diastereotopic CH2N), 3.62–3.69 (dq, 1H, CHP), 3.99–
4.18 (m, 4H, POCH2), 7.14–7.32 (m, 7H, aromatic H),
7.69 (d, 2H, J = 8.3Hz, aromatic H); 31P NMR (CDCl3)
aromatic H), 8.14 (t, 1H, J = 5.4Hz, NH), 9.03 (d, 2H,
J = 2.0Hz, aromatic H), 9.12 (t, 1H, J = 2.0Hz, aro-
matic H); 31P NMR (CDCl3) d 20.71; positive ion
ESMS:
Calculated:
C20H25O10N4P1S1Na1
m/z
(M + Na) 567.1, C40H50O20N8P2S2Na1 m/z (2M + Na)
1111.2 and C60H75O30N12P3S3Na1 m/z (3M + Na)
1655.3. Found: C20H25O10N4P1S1Na1 m/z (M +
Na) 567.1 (55%), C40H50O20N8P2S2Na1 m/z (2M + Na)
1110.8 (100%) and C60H75O30N12P3S3Na1 m/z
(3M + Na) 1654.1 (15%); Chiral HPLC with detection
at 254nm using a Chirexꢂ column eluting at 1.0mL/
min with 20% 2-propanol in hexanes produced no sepa-
ration. However, excellent separation occurred using a
Whelk O-2 column 10:120:40: 2-propanol/hexanes/1,2-
dichloroethane to afford a 98:2 ratio of L:D-enantiomers
(L-tR = 26.42min and D-tR = 30.82min) or 96% ee.
d
22.52;
positive
ion
ESMS:
calculated:
C21H32O5N2P1S1 m/z (M + H) 455.2 and C21H31O5N2-
P1S1Na1 m/z (M + Na) 477.2. Found: C21H32O5N2P1S1
m/z (M + H) 455.1 and C21H31O5N2P1S1Na1 m/z
(M + Na) 477.1. Chiral HPLC was conducted after der-
ivatization with 3,5-dinitrobenzoylchloride to afford 24.
4.10. General method for 3,5-dinitrobenzoylation of
amines 17, 18, 21, and 22 for chiral HPLC analysis
4.10.3. Characterization data for diethyl (1R)-1-{[(4-
methylphenyl)sulfonyl]amino}-2-[(2-phenylethyl)-(3,5-di-
1
nitrobenzoyl)amino]ethylphosphonate 23. 89% yield; H
4.10.1. Diethyl (1R)-2-amino-1-{[(4-methylphenyl)sulfon-
yl]-[3,5-dinitrobenzoyl-amino]}ethylphosphonate 19.
mixture of diethyl (1R)-2-amino-1-{[(4-methylphen-
yl)sulfonyl]amino}ethylphosphonate 17 (10.2mg,
A
NMR (CDCl3) d 1.18 (t, 3H, J = 7.1Hz, CH3), 1.88 (t,
3H, J = 7.1Hz, CH3), 2.43 (s, 3H, CH3), 2.76 (t, 3H,
J = 6.0 and 6.2Hz, ArCH2), 3.67–4.15 (m, 8H, CH2N

3318
E. K. Dolence, J. B. Roylance / Tetrahedron: Asymmetry 15 (2004) 3307–3322
1
and OCH2), 4.25–4.37 (m, 1H, CHP), 5.70 (dd, 1H,
J = 4.5 and 9.3Hz, NH), 6.83 (d, 2H, J = 8.0Hz, aro-
matic H), 7.15–7.36 (m, 5H, aromatic H), 7.78 (d, 2H,
J = 8.3Hz, aromatic H), 8.21 (d, 2H, J = 2.0Hz, aro-
matic H), 8.93 (t, 1H, J = 2.1Hz, aromatic H); 31P
NMR (CDCl3) d 20.81; positive ion ESMS: calculated:
C28H33O10N4P1S1Na1 m/z (M + Na) 671.2 and
C56H66O20N8P2S2Na1 m/z (2M + Na) 1319.3. Found:
C28H33O10N4P1S1Na1 m/z (M + Na) 671.1 (100%) and
C56H66O20N8P2S2Na1 m/z (2M + Na) 1318.8 (20%).
Chiral HPLC with detection at 254nm using a Chirexꢂ
column eluting at 1.0mL/min with 20% 2-propanol in
hexanes produced very poor separation. However, sur-
prisingly, excellent separation occurred using a Whelk
O-2 column 10:120:40: 2-propanol/hexanes/1,2-dichlo-
roethane at 2mL/min to afford a 98:2 ratio of (R):(S)-
enantiomers (R)-tR = 21.82min and (S)-tR = 13.32min)
or 96% ee.
1340, 1240, 1170, 1030, 960, 835, 675cmÀ1; H NMR
(CDCl3) d 1.19–1.27 (m, 6H, CH3CH2OP), 2.41 (s,
3H, CH3), 3.93–4.30 (m, 7H, CH2ON, CHP, POCH2),
6.88 (d, 2H, J = 5.8Hz, NCHCHN imidazoyl), 7.26 (d,
2H, J = 8.2Hz, aromatic H), 7.44 (s, 1H, NCHN imid-
azoyl), 7.67 (d, 2H, J = 8.3Hz, aromatic H); 13C
NMR (CDCl3) d 16.09–16.24 (m, CH3CH2OP), 21.40,
46.76 (d, JCCP = 5.4Hz, CH2CHP), 51.03 (d,
JCP = 157.6Hz, CHP), 62.85 (d, JCOP = 7.1Hz,
CH3CH2OP), 63.93 (d, JCOP = 7.0Hz, CH3CH2OP),
119.54, 126.68, 128.78, 129.63, 137.98, 138.08, 143.46;
31P NMR (CDCl3) d 19.83; positive ion ESMS: calcu-
lated: C16H25O5N3P1S1 m/z (M + H) 402.1. Found:
C16H25O5N3P1S1 m/z (M + H) 402.1. Chiral HPLC
failed due to severe broadening under conditions and
columns attempted.
4.11.2. Characterization data for diethyl (1S)-2-(1H-
imidazol-1-yl)-1-{[(4-methylphenyl)sulfonyl]amino}ethyl-
20
4.10.4. Characterization data for diethyl (1S)-1-{[(4-
methylphenyl)sulfonyl]amino}-2-[(2-phenylethyl)-(3,5-di-
nitrobenzoyl)amino] ethylphosphonate 24. 80% yield;
1H NMR (CDCl3) d 1.19 (t, 3H, J = 7.1Hz, CH3),
1.27 (t, 3H, J = 7.1Hz, CH3), 2.43 (s, 3H, CH3), 2.76
(t, 3H, J = 6.0Hz, ArCH2), 3.68–4.15 (m, 8H, CH2N
and OCH2), 4.25–4.37 (m, 1H, CHP), 5.55–5.58 (br m,
1H, NH), 6.84 (d, 2H, J = 6.8Hz, aromatic H), 7.16–
7.37 (m, 5H, aromatic H), 7.78 (d, 2H, J = 8.2Hz, aro-
matic H), 8.21 (d, 2H, J = 2.0Hz, aromatic H), 8.93 (t,
1H, J = 2.0Hz, aromatic H); 31P NMR (CDCl3) d
20.79; positive ion ESMS: calculated: C28H33O10N4-
P1S1Na1 m/z (M + Na) 671.2 and C56H66O20N8P2S2Na1
m/z (2M + Na) 1319.3. Found: C28H33O10N4P1S1Na1 m/
z (M + Na) 671.2 (100%) and C56H66O20N8P2S2Na1 m/z
(2M + Na) 1318.9 (34%). Chiral HPLC with detection at
254nm using a Chirexꢂ column eluting at 1.0mL/min
with 20% 2-propanol in hexanes produced very poor
separation. However, excellent separation occurred
using a Whelk O-2 column 10:120:40: 2-propanol/hexa-
nes/1,2-dichloroethane at 2mL/min to afford a 1:99 ratio
of L:D-enantiomers L-tR = 22.45min and D-tR =
12.32min) or 98% ee.
phosphonate 26. 68% yield; ½aŠ ¼ À13:3 (c 0.744,
CHCl3); 1H NMR (CDCl3) d D1.19–1.25 (m, 6H,
CH3CH2OP), 2.42 (s, 3H, CH3), 3.92–4.12 (m, 5H,
CHP and POCH2), 4.25–4.30 (m, 2H, CH2N), 6.94 (d,
2H, J = 6.9Hz, NCHCHN imidazoyl), 7.29 (d, 2H,
J = 8.1Hz, aromatic H), 7.56 (s, 1H, NCHN imidazoyl),
7.69 (d, 2H, J = 8.3Hz, aromatic H); 31P NMR (CDCl3)
d 19.55; positive ion ESMS: calculated: C16H25O5N3P1S1
m/z (M + H) 402.1. Found: C16H25O5N3P1S1 m/z
(M + H) 402.1. Chiral HPLC failed due to severe broad-
ening under conditions and columns attempted.
4.12. General procedures for the addition of thiols to
aziridines
4.12.1. Diethyl (1R)-1-{[(4-methylphenyl)sulfonyl]amino}-
2-(propylsulfanyl)ethylphosphonate 27. To an ambient
room temperature solution of n-propylthiol (17lL,
0.1795mmol) and L-aziridine 1 (50.0mg, 0.1496mmol)
in 1.0mL of CH3CN was added by syringe tri-n-butyl-
phosphine (36lL, 0.1496mmol). The reaction was stir-
red overnight. CH3CN was evaporated in vacuo and
the residue purified by silica TLC eluting with 2:1 ethyl-
acetate/hexanes to afford 22.2mg (36% yield) of 27 as an
20
D
2995, 2920, 1602, 1460, 1345, 1245, 1170, 1100, 1050,
4.11. General method for the addition of imidazole to
aziridines
oil. ½aŠ ¼ À19:3 (c 0.344, CHCl3); IR (TF) 3140 (br),
1
1030, 980, 825, 675cmÀ1; H NMR (CDCl3) d 0.91 (t,
4.11.1. Diethyl (1R)-2-(1H-imidazol-1-yl)-1-{[(4-methyl-
phenyl)sulfonyl]amino}ethylphosphonate 25. To L-azir-
idine 1 (50.0mg, 0.1496mmol) was added imidazole
(39.0mg, 0.5611mmol) in 1mL of CH3CN. TLC moni-
toring indicated after 72h that all starting 1 had been
consumed. The reaction was diluted with 20mL of
EtOAc and 10mL of water. The aqueous phase was ex-
tracted with two 10mL portions of 2:5 n-BuOH/EtOAc.
The solvent was removed in vacuo with the aid of a vac-
uum pump to afford 77mg of an oil. The residue was
purified by preparative thin-layer chromatography elut-
ing with 1:10 MeOH/CHCl3 containing 0.1% NH4OH.
The major UV positive band (Rf 0.38) was removed
and eluted with 1:5 MeOH/CHCl3 containing 0.1%
3H, J = 7.3Hz, CH3), 1.29 (t, 6H, J = 7.0Hz,
CH3CH2OP), 1.42–1.52 (m, 2H, CH2), 2.34 (t, 3H,
J = 7.3Hz, SCH2), 2.42 (s, 3H, CH3), 2.70–2.84 (m,
2H, CH2S), 3.81–3.92 (m, 1H, CHP), 4.03–4.21 (m,
4H, POCH2CH3), 5.62 (dd, 1H, J = 3.1 and 9.3Hz,
NH), 7.29 (d, 2H, J = 8.1Hz, aromatic H), 7.80 (d,
2H, J = 8.2Hz, aromatic H); 13C NMR (CDCl3) d
13.30, 16.23–16.40 (m, CH3CH2OP), 21.48, 22.62,
32.99 (d, JCCP = 4.3Hz, CH2CHP), 34.99, 49.93 (d,
JCP = 159.0Hz, CHP), 62.80 (d, JCOP = 7.0Hz,
CH3CH2OP), 63.53 (d, JCOP = 6.6Hz, CH3CH2OP),
127.19, 129.47, 138.06, 143.47; 31P NMR (CDCl3) d
21.69 ppm; positive ion ESMS: calculated: C16H28O5-
N1P1S2Na1 m/z (M + Na) 432.1. Found: C16H28O5-
N1P1S2Na1 m/z (M + Na) 432.1 (100%). Chiral HPLC
using a Whelk O-2 column was unsuccessful under a
variety of conditions.
NH4OH to afford 47mg (78% yield) of 25 as an oil.
20
D
(br), 3140, 3035, 2995, 2965, 1608, 1535, 1450, 1400,
½aŠ ¼ þ18:5 (c 0.740, CHCl3); IR (TF) 3400–2200

E. K. Dolence, J. B. Roylance / Tetrahedron: Asymmetry 15 (2004) 3307–3322
3319
4.12.2. Characterization data for diethyl (1S)-1-{[(4-
methylphenyl)sulfonyl]amino}-2-(propylsulfanyl)ethylphos-
(2M + Na) 1240.9 (25%). Chiral HPLC using a Whelk
O-2 column was unsuccessful under a variety of
conditions.
20
D
phonate 28. 43% yield;
CHCl3); IR (TF) 3140 (br), 2995, 2940, 1610, 1470,
½aŠ ¼ þ18:0 (c 0.128,
1
1330, 1250, 1175, 1105, 1040, 985, 830, 680cmÀ1; H
4.12.4. Characterization data for diethyl (1R)-1-{[(4-
methylphenyl)sulfonyl]amino}-2-(triphenylmethyl-disulfan-
NMR (CDCl3) d 0.91 (t, 3H, J = 7.3Hz, CH3), 1.25–
1.31 (m, 6H, CH3CH2OP), 1.43–1.52 (m, 2H, CH2),
2.35 (t, 3H, J = 7.3Hz, SCH2), 2.42 (s, 3H, CH3),
2.70–2.84 (m, 2H, CH2S), 3.81–3.92 (m, 1H, CHP),
4.03–4.22 (m, 4H, POCH2CH3), 5.44–5.47 (m, 1H,
NH), 7.29 (d, 2H, J = 8.1Hz, aromatic H), 7.79 (d,
2H, J = 8.2Hz, aromatic H); 31P NMR (CDCl3) d
21.66ppm; positive ion ESMS: calculated: C16H28O5-
N1P1S2Na1 m/z (M + Na) 432.1. Found: C16H28O5-
N1P1S2Na1 m/z (M + Na) 432.1 (100%). Chiral HPLC
using a Whelk O-2 column was unsuccessful under a
variety of conditions.
20
D
yl)ethylphosphonate 31. ½aŠ ¼ À59:1 (c 0.310, CHCl3);
IR (TF) 3110 (br), 3045, 2995, 2910, 1602, 1500, 1450,
1345, 1245, 1170, 1100, 1060, 1035, 970, 825, 745, 710,
675cmÀ1 1H NMR (CDCl3) d 1.23–1.28 (m, 6H,
;
CH3CH2OP), 1.92–2.09 (m, 2H, CH2SS), 2.36 (s, 3H,
CH3), 3.58–3.70 (m, 1H, CHP), 3.93–4.15 (m, 4H,
POCH2CH3), 4.82 (dd, 1H, J = 3.3 and 9.6Hz, NH),
7.13–7.31 (m, 17H, aromatic H), 7.72 (d, 2H,
J = 8.4Hz, aromatic H); 13C NMR (CDCl3) d 16.27–
16.43 (m, CH3CH2OP), 21.49, 38.84 (d, JCCP = 5.6Hz,
CH2CHP), 49.72 (d, JCP = 157.9Hz, CHP), 62.65
(d, JCOP = 6.9Hz, CH3CH2OP), 63.61 (d, JCOP
=
7.2Hz, CH3CH2OP), 71.22, 126.97, 127.05, 127.21,
127.31, 127.84, 129.22, 129.25, 129.95, 130.27, 137.92,
143.47, 143.50; 31P NMR (CDCl3) 20.97; positive ion
ESMS: calculated: C13H21O5N1P1S3Na1 m/z (M À
C(C6H5)3 + Na) 421.0, C32H36O5N1P1S3Na1 m/z (M +
Na) 664.1 and C64H72O10N2P2S6Na1 m/z (2M + Na)
1305.3. Found: C13H21O5N1P1S3Na1 m/z (M À
C(C6H5)3 + Na) 420.9, C32H36O5N1P1S3Na1 m/z (M +
Na) 663.9 and C64H72O10N2P2S6Na1 m/z (2M + Na)
1304.8.
4.12.3. Diethyl (1R)-1-{[(4-methylphenyl)sulfonyl]amino}-
2-(triphenylmethylsulfanyl)ethylphosphonate 29
4.12.3.1. Sodium hydride derived thiolate reac-
tion. To an ambient room temperature solution of
triphenylmethylmercaptan (42mg, 0.1496mmol) in
2mL of THF was added 60% NaH (6.0mg,
0.1496mmol). This was stirred for 5min at which time
H2 evolution had ceased. L-Aziridine
1 (50mg,
0.1496mmol) in 1.0mL of THF was added via syringe
followed by stirring overnight. The THF was evapo-
rated in vacuo and the residue dissolved in 20mL of
EtOAc and washed with brine, dried, filtered, and evap-
orated in vacuo to afford 96mg of an oil. This oil was
purified by silica gel column chromatography (20mL sil-
ica gel) eluting with 2:1 EtOAc/hexanes to afford
27.3mg. Impure fractions were further purified by ana-
lytical silica TLC using the same solvent. Three purified
fractions were obtained: 1. Rf = 0.63, 32mg (36% yield)
of desired sulfide 29; 2. Rf = 0.54, 5mg (5% yield) of
the disulfide 31 and 13mg (26% recovery) of unreacted
L-aziridine 1: The desired sulfide product 29 was a
4.12.4.1. Tri-n-butylphosphine reaction. To an ambi-
ent room temperature solution of triphenylmethylmer-
captan (2.69g, 9.722mmol) and L-aziridine 1 (2.71g,
8.102mmol) in 30mL of CH3CN was added by syringe
tri-n-butylphosphine (2.0mL, 8.102mmol). The suspen-
sion was stirred overnight. CH3CN was evaporated in
vacuo and the residue purified by silica gel column chro-
matography (500mL silica gel) eluting with 2:1 EtOAc/
hexanes to afford 2.26g (46% yield) of 29 as a white
foam. This material was spectroscopically identical to
the material described above. There was no sign of the
presence of the undesired disulfide product 31 or recov-
ered aziridine 1.
foam that resisted all attempts at recrystallization:
20
D
mp 61–63ꢁC; ½aŠ ¼ þ1:4 (c 1.00, CHCl3); IR
(TF) 3110 (br), 3040, 2995, 2920, 1602, 1500, 1455,
1345, 1245, 1170, 1100, 1060, 1035, 985, 840, 735,
1
710, 675cmÀ1; H NMR (CDCl3) d 1.16–1.29 (m, 6H,
CH3CH2OP), 2.32–2.41 (m, 1H, diastereotopic
CH2S), 2.34 (s, 3H, CH3), 2.46–2.54 (m, 1H, diastereo-
topic CH2S), 3.56–3.67 (m, 1H, CHP), 3.90–4.14
(m, 4H, POCH2CH3), 4.92 (dd, 1H, J = 3.8 and
9.4Hz, NH), 7.13–7.30 (m, 17H, aromatic H), 7.72 (d,
2H, J = 8.3Hz, aromatic H); 13C NMR (CDCl3) d
16.18–16.37 (m, CH3CH2OP), 21.52, 32.85 (d,
JCCP = 7.0Hz, CH2CHP), 49.86 (d, JCP = 156.5Hz,
CHP), 62.76 (d, JCOP = 6.9Hz, CH3CH2OP), 63.52
(d, JCOP = 6.9Hz, CH3CH2OP), 67.00, 126.71, 126.97,
127.05, 127.29, 127.39, 127.87, 129.21, 129.27,
129.46, 130.02, 137.96, 143.24, 144.23; 31P NMR
(CDCl3) d 21.06; positive ion ESMS: calculated:
C32H36O5N1P1S2Na1 m/z (M + Na) 632.2, C32H36O5-
N1P1S2K1 m/z (M + K) 648.1 and C64H72O10N2P2S4Na1
m/z (2M + Na) 1241.3. Found: C32H36O5N1P1S2Na1
m/z (M + Na) 632.1 (100%), C32H36O5N1P1S2K1 m/z
(M + K) 648.1 (50%) and C64H72O10N2P2S4Na1 m/z
4.12.5. Diethyl (1S)-1-{[(4-methylphenyl)sulfonyl]amino}-
2-(triphenylmethylsulfanyl)ethylphosphonate 30. 78%
yield. This foam resisted all attempts at recrystallization.
20
Mp 61–63ꢁC; ½aŠ ¼ À1:4 (c 0.580, CHCl3); IR (TF)
D
3110 (br), 3040, 2995, 2920, 1602, 1495, 1450, 1340,
1240, 1165, 1095, 1030, 980, 820, 750, 705, 670cmÀ1
;
1H NMR (CDCl3) d 1.16–1.25 (m, 6H, CH3CH2OP),
2.30–2.51 (m, 2H, CH2S), 2.33 (s, 3H, CH3), 3.54–3.66
(m, 1H, CHP), 3.90–4.14 (m, 4H, POCH2CH3), 5.18
(dd, 1H, J = 3.3 and 9.4Hz, NH), 7.14–7.29 (m, 17H,
aromatic H), 7.72 (d, 2H, J = 8.1Hz, aromatic H); 31P
NMR (CDCl3) d 21.11; positive ion ESMS: calculated:
C32H36O5N1P1S2Na1 m/z (M + Na) 632.2 and C64H72-
O10N2P2S4Na1 m/z (2M + Na) 1241.3. Found: C32H36-
O5N1P1S2Na1 m/z (M + Na) 632.1 (55%) and
C64H72O10N2P2S4Na1 m/z (2M + Na) 1241.0 (100%).
Chiral HPLC using a Whelk O-2 column was unsuccess-
ful under a variety of conditions.

3320
E. K. Dolence, J. B. Roylance / Tetrahedron: Asymmetry 15 (2004) 3307–3322
4.13. General procedure for the reaction of NaBH4 with
aziridines
red overnight and then diluted with 20mL of EtOAc
and 10mL of water. The aqueous phase was extracted
with two 5mL of EtOAc. The pooled organic layer
was washed with brine, dried, filtered, and evaporated
in vacuo to afford 50.8mg of residue that was purified
by silica TLC. Two elutions with 2:1 ethylacetate/hexa-
4.13.1. Diethyl (1R)-1-{[(4-methylphenyl)sulfonyl]amino}-
ethylphosphonate 32. To L-aziridine
1
(2.40g,
7.19mmol) in 25mL of THF was added in one portion
NaBH4 (0.29g, 7.545mmol). The reaction was stirred
for 18h and THF evaporated in vacuo. The residue
was diluted with 100mL of EtOAc and 50mL of water
containing 3mL of glacial AcOH. The aqueous phase
was extracted with two 50mL portions of EtOAc. The
pooled organic phases were washed with brine, dried, fil-
tered, and evaporated in vacuo to afford 2.54g of a semi-
solid. This was purified by radial silica gel chromatogra-
phy using a 4mm plate eluting with EtOAc to afford
2.33g (96%) of 32 as an oil. The same product could
nes afforded 28.0mg (53% yield) of 34 as an oil.
20
D
2995, 2920, 1602, 1465, 1350, 1250, 1180, 1040, 830,
½aŠ ¼ À11:2 (c 0.366, CHCl3); IR (TF) 3140 (br),
680cmÀ1 1H NMR (CDCl3) d 1.25–1.31 (m, 6H,
;
CH3CH2OP), 2.42 (s, 3H, CH3), 3.80–3.97 (m, 1H,
CHP), 4.03–4.23 (m, 4H, POCH2CH3), 4.35–4.68 (m,
2H, CH2F), 5.93 (dd, 1H, J = 3.8 and 9.5Hz, NH),
7.29 (d, 2H, J = 8.4Hz, aromatic H), 7.78 (d, 2H,
J = 8.3Hz, aromatic H); 13C NMR (CDCl3) 16.15–
16.35 (m, CH3CH2OP), 21.47, 50.94 (dd, JCP = 156.7Hz
and JFCCP = 20.9Hz, CHP), 62.98 (d, JCOP = 7.1Hz,
CH3CH2OP), 63.79 (d, JCOP = 6.9Hz, CH3CH2OP),
81.81 (dd, JCF = 175.3Hz and JFCCP = 2.4 and 2.9Hz,
CH2F), 127.05, 129.57, 137.85, 143.60; 31P NMR
(CDCl3) d 19.10 (d, JFCCP = 20.0Hz); 19F NMR
(CDCl3) 100.03–100.41 (m); positive ion ESMS: calcu-
lated: C13H22F1O5N1P1S1 m/z (M + H) 354.1 and
C13H21F1O5N1P1S1Na1 m/z (M + Na) 376.1. Found:
be obtained by catalytic transfer hydrogenation in 50%
20
D
3010, 2965, 1610, 1460, 1405, 1350, 1245, 1175, 1035,
yield. ½aŠ ¼ À17:0 (c 1.00, CHCl3); IR (TF) 3115 (br),
1
970, 830, 790, 720cmÀ1; H NMR (CDCl3) d 1.17 (dd,
3H, J = 7.2 and 16.9Hz, CH3), 1.25–1.33 (m, 6H,
CH3CH2OP), 2.42 (s, 3H, CH3), 3.60–3.74 (m, 1H,
CHP), 4.01–4.26 (m, 4H, POCH2), 6.14 (dd, 1H,
J = 2.4 and 9.4Hz, NH), 7.28 (d, 2H, J = 8.2Hz, aro-
matic H), 7.80 (d, 2H, J = 8.4Hz, aromatic H); 13C
NMR (CDCl3) d 15.79, 16.23–16.42 (m, CH3CH2OP),
21.44, 45.91 (d, JCP = 162Hz, CHP), 62.39 (d,
JCOP = 7.2Hz, CH3CH2OP), 63.74 (d, JCOP = 7.1Hz,
CH3CH2OP), 128.01, 129.55, 133.36, 143.26; 31P NMR
(CDCl3) d 24.06; positive ion ESMS: calculated:
C13H23O5N1P1S1 m/z (M + H) 336.1, C13H22O5N1-
P1S1Na1 m/z (M + Na) 358.1, C13H22O5N1P1S1K1 m/z
(M + K) 374.1. Found: C13H23O5N1P1S1 m/z (M + H)
336.0 (64%), C13H22O5N1P1S1Na1 m/z (M + Na) 358.1
(100%), C13H22O5N1P1S1K1 m/z (M + K) 374.0 (24%).
Chiral HPLC using a Whelk O-2 column eluting with
20% 2-propanol in hexanes at 1.0mL/min to afforded
a 99:1 ratio of L:D-enantiomers (L-tR = 18.22 min and
D-tR = 21.55min).
C13H22F1O5N1P1S1
m/z
(M + H)
354.0
and
C13H21F1O5N1P1S1Na1 m/z (M + Na) 376.1. Chiral
HPLC using a Whelk O-2 column was unsuccessful un-
der a variety of conditions.
4.14.2. Characterization data for diethyl (1S)-2-fluoro-1-
{[(4-methylphenyl)sulfonyl]amino}ethylphosphonate 35.
20
57% yield; ½aŠ ¼ þ10:2 (c 1.200, CHCl3); 1H
NMR (CDCl3) dD1.23–1.33 (m, 6H, CH3CH2OP), 2.43
(s, 3H, CH3), 3.78–3.95 (m, 1H, CHP), 4.01–4.22 (m,
4H, POCH2CH3), 4.35–4.70 (m, 2H, CH2F), 5.51 (dd,
1H, J = 4.0 and 9.4Hz, NH), 7.30 (d, 2H, J = 8.1Hz,
aromatic H), 7.77 (d, 2H, J = 8.2Hz, aromatic H); 31P
NMR (CDCl3) d 19.09 (d, JFCCP = 18.4Hz); 19F NMR
(CDCl3) d 100.14–100.51 (m); positive ion ESMS: calcu-
lated: C13H21F1O5N1P1S1Na1 m/z (M + Na) 376.1.
Found: C13H21F1O5N1P1S1Na1 m/z (M + Na) 376.1.
Chiral HPLC using a Whelk O-2 column was unsuccess-
ful under a variety of conditions.
4.13.2. Characterization data for diethyl (1S)-1-{[(4-
methylphenyl)sulfonyl]amino}ethylphosphonate 33. 54%
20
D
yield; ½aŠ ¼ þ15:0 (c 0.276, CHCl3); 1H NMR (CDCl3)
d 1.19 (dd, 3H, J = 7.2 and 16.8Hz, CH3), 1.25–1.33 (m,
6H, CH3CH2OP), 2.42 (s, 3H, CH3), 3.60–3.74 (m, 1H,
CHP), 4.01–4.24 (m, 4H, POCH2), 5.61 (dd, 1H, J = 3.0
and 9.4Hz, NH), 7.30 (d, 2H, J = 8.2Hz, aromatic H),
7.78 (d, 2H, J = 8.3Hz, aromatic H); 31P NMR (CDCl3)
d 24.11; positive ion ESMS: calculated: C13H22O5N1-
P1S1Na1 m/z (M + Na) 358.1. Found: C13H22O5N1-
P1S1Na1 m/z (M + Na) 358.1. Chiral HPLC using a
Whelk O-2 column eluting with 20% 2-propanol in hex-
anes at 1.0mL/min to afford an undetectable amount of
the L-enantiomer (D-tR = 20.07min).
4.15. General procedure for the reaction of lithium
diethylphosphite with aziridines
4.15.1. Diethyl (1R)-(2-diethylphosphoryl)-1-{[(4-methyl-
phenyl)sulfonyl]amino} ethylphosphonate 36. To a solu-
tion of freshly distilled diethylphosphite (52mg,
0.3740mmol) in 1mL of THF at 0ꢁC was added via syr-
inge 2.29M n-butyllithium (82lL, 0.1870mmol). The
cooling bath was removed and the mixture stirred for
1.25h. This anion solution was transferred via canula
to L-aziridine 1 (50mg, 0.1496mmol) with the aid of
1mL of THF. The solution was stirred overnight. The
reaction was diluted with 20mL of EtOAc and washed
with a mixture of 10mL of brine and 0.5mL of 1M
AcOH. The aqueous phase was extracted with two
15mL portions of EtOAc and the pooled organic phases
dried, filtered, and evaporated in vacuo to afford
84.8mg of residue. This was purified by preparative
TLC eluting twice with 1:20 MeOH/CHCl3. The
4.14. General procedure for the reaction of (n-Bu)4NF
with aziridines
4.14.1. Diethyl (1R)-2-fluoro-1-[(4-methylphenyl)sulfon-
yl]aminoethylphosphonate 34. To a solution of L-aziri-
dine 1 (50.0mg, 0.1496mmol) in 1.0mL of THF was
added by syringe 1.0M tetrabutylammonium fluoride
in THF (0.16mL, 0.1571mmol). The reaction was stir-

E. K. Dolence, J. B. Roylance / Tetrahedron: Asymmetry 15 (2004) 3307–3322
3321
20
oil. ½aŠ ¼ À12:5 (c 1.18, CHCl3); IR (TF) 3215 (br),
Rf = 0.37 band was removed and eluted with 1:5 MeOH/
CHCl3 followed by evaporation to afford 45mg (64%
yield) of 36 as an oil. ½aŠ ¼ À3:7 (c 0.810, CHCl3);
D
3005, 2990, 2915, 1715, 1530, 1450, 1390, 1300, 1250,
20
D
IR (TF) 3120 (br), 2995, 2920, 1602, 1450, 1400, 1340,
1
1170, 1040 (br), 965, 800, 740, 700cmÀ1; H NMR (d6-
DMSO) d 1.15–1.28 (m, 9H, CH3CH2OP and CH3),
3.87–4.10 (m, 5H, CHP and POCH2CH3), 5.04 (q, 2H,
J = 23.7Hz, benzylic CH2), 7.30–7.39 (m, 5, aromatic
H), 7.65 (d, 1H, J = 9.3Hz, NH); 13C NMR (d6-DMSO)
d 15.15, 16.24 (t, JCCOP = 4.3 and 4.6Hz, CH3CH2OP),
42.85 (d, JCP = 158Hz, CHP), 61.59 (d, JCOP = 6.6Hz,
CH3CH2OP), 61.90 (d, JCOP = 6.8Hz, CH3CH2OP),
65.53, 127.72, 127.79, 128.30, 137.00, 155.56 (d,
JCONHCHP = 5.0Hz, carbonyl); 31P NMR (d6-DMSO)
d 25.89; positive ion ESMS: calculated: C14H22O5N1-
P1Na1 m/z 338.1 (M + Na). Found: C14H22O5N1P1Na1
m/z 338.1 (M + Na). Chiral HPLC using a Whelk O-2
column eluting with 10:120:40: 2-propanol/hexanes/1,2-
dichloromethane at 1mL/min to afford a 95:5 ratio
of (R):(S)-enantiomers (R)-tR = 12.78min and (S)-
tR = 10.42min).
1
1250, 1170, 1040 (br), 975, 820, 670 cmÀ1; H NMR
(CDCl3) d 1.12–1.33 (m, 12H, CH3CH2OP), 1.93–2.18
(m, 2H, CH2P), 2.41 (s, 3H, CH3), 3.86–4.22 (m, 9H,
CHP and POCH2CH3), 6.32 (dd, 1H, J = 1.7 and
9.4Hz, NH), 7.29 (d, 2H, J = 7.8Hz, aromatic H), 7.82
(d, 2H, J = 8.3Hz, aromatic H); 13C NMR (CDCl3) d
16.00–16.35 (m, CH3CH2OP), 21.40, 25.72 (dd,
JCP = 142.0Hz and JPCCP = 3.7Hz, CH2P), 45.90 (dd,
JCP = 165.4Hz and JPCCP = 5.4Hz, CHP), 61.82 (d,
JCOP = 6.3Hz, CH3CH2OP), 62.26 (d, JCOP = 6.6Hz,
CH3CH2OP), 62.85 (d, JCOP = 6.8Hz, CH3CH2OP),
63.69 (d, JCOP = 7.3Hz, CH3CH2OP), 127.19, 129.37,
138.28, 143.26; 31P NMR (CDCl3)
d 20.87 (d,
JPCCP = 31.0Hz), 26.21 (d, JPCCP = 31.0Hz); posi-
tive ion ESMS: calculated: C17H31O8N1P2S1Na1
m/z (M + Na) 494.1 and C34H62O8N1P2S1Na1 m/z
(2M + Na)
965.2.
Found:
C17H31O8N1P2S1Na1
m/z (M + Na) 494.0 (100%) and C34H62O8N1P2S1Na1
m/z (2M + Na) 965.2 (10%). Chiral HPLC using a
Whelk O-2 column was unsuccessful under a variety of
conditions.
Acknowledgements
We gratefully acknowledge financial support by the
NIH (GM062139–01). We also appreciate the use of
the NMR and ESI-MS facilities at the Department of
Chemistry University of Wyoming and the purchase of
the polarimeter by the University of Wyoming College
of Health Sciences NIH BRIN (RR16474).
4.15.2. Characterization data for diethyl (1S)-(2-diethyl-
phosphoryl)-1-{[(4-methylphenyl)sulfonyl]amino}ethyl-
20
phosphonate 37. 33% yield; ½aŠ ¼ þ4:1 (c 0.924,
D
CHCl3); 1H NMR (CDCl3) d 1.20–1.32 (m, 12H,
CH3CH2OP), 1.90–2.16 (m, 2H, CH2P), 2.42 (s, 3H,
CH3), 3.85–4.22 (m, 9H, CHP and POCH2CH3), 6.08
(dd, 1H, J = 1.9 and 9.4Hz, NH), 7.30 (d, 2H,
J = 7.8Hz, aromatic H), 7.82 (d, 2H, J = 8.3Hz,
References
1. Kafarski, P.; Lejczak, B. Phosphorus Sulfur and Silicon
1991, 63, 193–215.
aromatic H); 31P NMR (CDCl3)
d
20.74 (d,
2. Kukhar, V. P.; Hudson, H. R. Aminophosphonic and
Aminophosphinic Acids—Chemistry and Biological Activ-
ity; John Wiley and Sons: Chichester, 2000.
3. Seto, H.; Kuzuyama, T. Nat. Prod. Rep. 1999, 16, 589–
596.
4. Agami, C.; Couty, F.; Rabasso, N. Tetrahedron Lett.
2002, 43, 4633–4636.
5. Amedjkouh, M.; Westerlund, K. Tetrahedron Lett. 2004,
45, 5175–5177.
JPCCP = 28.7Hz), 26.28 (d, JPCCP = 28.7Hz); positive
ion ESMS: calculated: C17H31O8N1P2S1Na1 m/z
(M + Na) 494.1 and C34H62O8N1P2S1Na1 m/z (2M +
Na) 965.2. Found: C17H31O8N1P2S1Na1 m/z (M + Na)
494.1 (100%) and C34H62O8N1P2S1Na1 m/z (2M + Na)
964.9 (30%). Chiral HPLC using a Whelk O-2 column
was unsuccessful under a variety of conditions.
6. Azizi, N.; Saidi, M. R. Tetrahedron 2003, 59, 5329–
5632.
7. Blazewska, K.; Sikora, D.; Gajda, T. Tetrahedron Lett.
2003, 44, 4747–4750.
8. Davis, F. A.; McCoull, W.; Titus, D. D. Org. Lett. 1999, 1,
1053–1055.
9. Davis, F. A.; Lee, S.; Yan, H.; Titus, D. D. Org. Lett.
2001, 3, 1757–1760.
10. Davis, F. A.; McCoull, W. Tetrahedron Lett. 1999, 40,
249–252.
11. Davis, F. A.; Wu, Y.; Yan, H.; Prasad, K. R.; McCoull,
W. Org. Lett. 2002, 4, 655–658.
12. Davis, F. A.; Wu, Y.; Yan, H.; McCoull, W.; Prasad,
K. R. J. Org. Chem. 2003, 68, 2410–2419.
13. Davis, F. A.; Prasad, K. R. J. Org. Chem. 2003, 68, 7249–
7253.
14. Davis, F. A.; Lee, S. H.; Xu, H. J. Org. Chem. 2004, 69,
3774–3781.
4.15.3. Diethyl (1R)-1-{[(carbobenzyloxy]amino}ethyl-
phosphonate 38. To 10mL of double distilled (from so-
dium metal) liquid NH3 at À78ꢁC were added sodium
slivers (34mg, 1.4782mmol) and stirred for 5min. To
this blue solution was added dropwise via syringe tosyl-
ate 32 (100mg, 0.2985mmol) in a total of 1.5mL of
anhydrous THF. This mixture was stirred for 10min fol-
lowed by quenching by addition of 1mL of absolute
EtOH. The NH3 was evaporated under a stream of
nitrogen and the ethanol evaporated in vacuo. To this
residue was added 2mL of water and solid NaHCO3
(125mg, 1.4925mmol) followed by Cbz-Cl (62mg,
0.3582mmol) in 2mL of THF. This mixture was stirred
for 2h followed by evaporation of THF. The residue
was transferred to a separatory funnel with 15mL of
EtOAc and 5mL of brine. The aqueous phase was
extracted with 2 · 15mL of EtOAc. The pooled organic
phases were dried, filtered, and evaporated. The crude
product was purified by preparative silica TLC eluting
with EtOAc to afford 65mg (68% yield) of 38 as an
15. Drag, M.; Latajka, R.; Gumienna-Kontecka, E.; Kozlow-
ski, H.; Kafarski, P. Tetrahedron: Asymmetry 2003, 14,
1837–1845.
16. Kaboudin, B. Tetrahedron Lett. 2003, 44, 1051–1053.

3322
E. K. Dolence, J. B. Roylance / Tetrahedron: Asymmetry 15 (2004) 3307–3322
17. Klepacz, A.; Zwierzak, A. Tetrahedron Lett. 2002, 43,
1079–1080.
34. Kowalik, J.; Zygmundt, J.; Mastalerz, P. Pol. J. Chem.
1981, 55, 713–715.
18. Kolodiazhnyi, O. I. Tetrahedron: Asymmetry 1998, 9,
1279–1332.
35. Vanderhoydonck, B.; Stevens, C. V. Synthesis 2004, 722–
734.
19. Mikolajczyk, M.; Byzwa, P.; Drabowicz, J. Tetrahedron:
Asymmetry 2002, 13, 2571–2576.
20. Palacios, F.; Aparicio, D.; Ochoa de Retana, A. M.; de los
Santos, J. M.; Gil, J. I.; Lopez de Munain, R. Tetrahedron:
Asymmetry 2004, 14, 689–700.
36. Zygmundt, J. Tetrahedron 1985, 41, 4979–4982.
37. Zygmundt, J.; Mastalerz, P. Pol. J. Chem. 1978, 52, 2271–
2273.
38. Zygmundt, J.; Mastalerz, P. Pol. J. Chem. 1981, 55, 411–
414.
21. Palacios, F.; Aparicio, D.; Lopez, Y.; de los Santos, J. M.
Tetrahedron Lett. 2004, 45, 4345–4348.
39. Smith, A. B., III. Yager, K. M.; Taylor, C. M. J. Am.
Chem. Soc. 1995, 117, 10879–10888.
22. Piotrowska, D. G.; Wroblewski, A. E. Tetrahedron 2003,
59, 8405–8410.
40. Smith, A. B., III. Yager, K. M.; Phillips, B. W.; Taylor,
C. M. Org. Synth. 1997, 19–29.
23. Pousset, C.; Larcheveque, M. Tetrahedron Lett. 2002, 43,
5257–5260.
41. Shiao, M.; Yang, C.; Lee, S.; Wu, T. Synth. Commun.
1988, 18, 359–366.
24. Soroka, M.; Kolodziejczyk, K. Tetrahedron Lett. 2003, 44,
1863–1865.
42. McKennon, M. J.; Meyers, A. I.; Drauz, K.; Schwarm, M.
J. Org. Chem. 1993, 58, 3568–3571.
25. Tesson, N.; Dorigneux, B.; Fadel, A. Tetrahedron: Asym-
metry 2002, 13, 2267–2276.
43. Meyers, A. I.; Poindexter, G. S.; Brich, Z. J. Org. Chem.
1978, 43, 892–898.
26. Joly, G. D.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126,
4102–4103.
44. Pirkle, W. H.; Pochapsky, T. C.; Mahler, G. S.; Corey, D.
E.; Reno, D. S.; Alessi, D. M. J. Org. Chem. 1986, 51,
4991–5000.
45. Pirkle, W. H.; Brice, L. J.; Caccamese, S.; Principato, G.;
Failla, S. J. Chromatogr. A 1996, 721, 241–246.
46. Hou, X.; Fan, R.; Dai, L. J. Org. Chem. 2002, 67, 5295–
5300.
47. Alonso, D. A.; Andersson, P. G. J. Org. Chem. 1998, 63,
9455–9461.
48. Fan, R.; Zhou, Y.; Zhang, W.; Hou, X.; Dai, L. J. Org.
Chem. 2004, 69, 335–338.
27. Kobayashi, S.; Kiyohara, H.; Nakamura, Y.; Matsubara,
R. J. Am. Chem. Soc. 2004, 126, 6558–6559.
28. Tongcharoensirikul, P.; Suarez, A. I.; Voelker, T.;
Thompson, C. M. J. Org. Chem. 2004, 69, 2322–2326.
29. Hu, X. E. Tetrahedron 2004, 60, 2701–2743.
30. McCoull, W.; Davis, F. A. Synthesis 2002, 1347–1365.
31. Sweeney, J. B. Chem. Soc. Rev. 2002, 31, 247–258.
32. Davis, F. A.; Ramachandar, T.; Wu, Y. J. Org. Chem.
2003, 68, 6894–6898.
33. Kim, D. Y.; Rhie, D. Y. Tetrahedron 1997, 53, 13603–
13608.
49. Huber, R.; Knierzinger, A.; Obrecht, J. P.; Vasella, A.
Helv. Chim. Acta 1985, 68, 1730–1747.