Use of optically active cyclic diethyl sulfamidate 2-phosphonates as chiral synthons for the synthesis of β-substituted α-amino phosphonates

Article abstract of DOI:10.1016/j.tetasy.2005.02.014

Optically active protected sulfamidate 2-phosphonates have been synthesized from either (R)- or (S)-N-benzyl-2-phosphonoserine for use as chiral synthons. These sulfamidates have been shown to undergo nucleophilic substitution with select nucleophiles, to

Full text of DOI:10.1016/j.tetasy.2005.02.014

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 1583–1594
Use of optically active cyclic diethyl sulfamidate 2-phosphonates
as chiral synthons for the synthesis of b-substituted a-amino
phosphonates
E. Kurt Dolence,* Gabriele Mayer and Brenda D. Kelly
1000 E. University Avenue Department 3375, School of Pharmacy, University of Wyoming, Laramie, WY 82071-3375, USA
Received 13 October 2004; revised 31 January 2005; accepted 1 February 2005
Abstract—Optically active protected sulfamidate 2-phosphonates have been synthesized from either (R)- or (S)-N-benzyl-2-phos-
phonoserine for use as chiral synthons. These sulfamidates have been shown to undergo nucleophilic substitution with select nucleo-
philes, to afford following N-sulfate removal, the b-substituted a-amino-2-phosphonates. N-Sulfate removal wasaccomplihsed
using boron trifluoride etherate in the presence of either n-propylthiol or N-hydroxysuccinimide allowing retention of the diet-
hylphosphonate ester groups. Replacement of the unpleasant smelling n-propylthiol with N-hydroxysuccinimide provides higher
yields of the desired products. Synthesis of b-S-substituted analogues required the use of cesium carbonate as a base. The sulfam-
idates described have excellent stability and have been demonstrated, using chiral HPLC, to be greater than 97% enantiomerically
pure.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
sis of both racemic and enantioenriched compounds,
there istsill room for improvement in methodology
that can rapidly produce a variety of side chain ana-
logues from a common chiral precursor molecule such
as a chiral synthon. This is especially important if a
combinatorial approach isneeded to generate a large
number of compoundsrapidly. Thislaboratory has
investigated16 the nucleophilic substitution of enantio-
merically enriched N-tosyl aziridine 2-phosphonates as
a chiral synthon for this approach and found it to be
useful but with a significant limitation. This limitation
involvesthe often difficult to remove N-tosyl group, in
which only a dissolving sodium metal reduction in liquid
ammonia proved successful in removing this protecting
group with the amino phosphonates we have studied.
Herein we report the use of chiral sulfamidates as a chi-
ral synthon with the easily removable N-benzyl protect-
ing group and determine what advantagesthey may
possess with respect to nucleophilic attack by common
nucleophiles. Melendez and Lubell have recently
reviewed30 both sulfamidite and sulfamidate chemistry.
Proteases play critical roles physiologically in a number
of disease states including arthritis, AlzheimerÕsdisease,
osteoporosis, cancer cell invasion, viral infections, the
apoptosis process, while their rich chemistry has been re-
cently reviewed.18,19,33,44 Medicinally, a-amino-a-alkyl-
phosphonic acids and their analogues including
phosphinic acids show promise as potential protease
inhibition agentsin addition to pesticidal and herbicidal
activity.23,29,39 Substitution of the amino acid carboxyl
group with a phosphonate group has produced organ-
ophosphonate analogues of nearly all the natural amino
acids.8 The synthesis of phosphonopeptides from the
a-amino-a-alkylphosphonic acids has resulted in the
production of tetrahedral transition state analogue
4,5
inhibitorsof a variety of natural proteaes enzyme.s
However, with the increasing focus on the enantiomeric
purity of drugsin the pharmaceutical indutsry, there
isa need for methodology to ysntheisze enantiopure
a-amino-a-alkylphosphonic acids with various unnatu-
ral
sidechains.
Although
numerous
methods
exist1–3,6,9–15,17,21,22,25–27,31,32,34–37,42,43,45 for the synthe-
2. Results and discussion
*
The key starting materials, the highly enantioenriched
(R)- and (S)-phosphonoserines, were independently
Corresponding author. Tel.: +1 307 766 2954; fax: +1 307 766
2953; e-mail: kdolence@uwyo.edu
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.02.014

1584
E. K. Dolence et al. / Tetrahedron: Asymmetry 16 (2005) 1583–1594
produced using the method reported by Smith et al.40,41
A large scale synthesis of these two enantiopodes has
been described in detail in our previous report.16 Each
phosphonoserine enantiomer was independently carried
forward to the sulfamidates 1 and 2 asdecsribed in
Scheme 1. Treatment of the amino alcohols 3 and 4 with
benzaldehyde followed by reduction with sodium cyano-
borohydride in ethanol and acetic acid afforded the N-
benzyl amines 5 and 6 in 70% and 64% yield, respec-
tively. Conversion of 5 and 6 to the sulfamidates was
accomplished by the method of Wei and Lubell46 involv-
ing dropwise treatment with a solution of thionyl chlo-
ride in chloroform in the presence of triethylamine and
imidazole. Thisproduced 7 and 8 asequal mixturesof
diastereomers at the sulfamidite stereocenter as ob-
served by NMR spectroscopy. These crude reaction
mixtureswere directly us bjected to ruthenium chloride
catalyzed periodate oxidation converting the sulfami-
ditesto sulfamidates 1 and 2 in 70% and 63% yields, fol-
lowing flash silica chromatography. This conversion
required monitoring by 31P NMR since the sulfamidites
and sulfamidates did not separate on silica thin-layer
chromatography. Additionally to ensure successful con-
version, the ruthenium chloride was ground to a fine
powder prior to use.
The enantiomeric purity of the sulfamidates 1 and 2 was
established using Whelk O-2 chiral HPLC as depicted in
Scheme 2. The specific rotations of the sulfamidates 1
and 2 were determined to be ꢀ25.1 and +24.9, respec-
tively, and in each case chiral HPLC confirmed an enan-
tiomeric excess of at least 97%. These two sulfamidate
oils proved to be very stable when stored for up to a year
at ꢀ20 ꢁC.
O
O
OH
P(OEt)2
OH
P(OEt)2
O2S
OS
a, b
c
d
N
N
BzNH
P(OEt)2
NH2
P(OEt)2
Bz
Bz
O
O
O
O
3
5
(1R)-(-)-1
7
O
O
OH
P(OEt)2
OH
P(OEt)2
OS
O2S
a, b
c
d
N
N
BzNH
P(OEt)2
P(OEt)2
NH2
Bz
Bz
O
O
O
O
8
(1S)-(+)-2
4
6
Scheme 1. Synthesis of the (1R)-(ꢀ)- and (1S)-(+)-sulfamidates 1 and 2. Reagents: (a) PhCHO, EtOH, HOAc; (b) NaCNBH3; (c) SOCl2, imidazole,
Et3N, CH2Cl2; (d) RuCl3, NaIO4, aqueousCH 3CN.
Scheme 2. Whelk O-2 chiral HPLC of the sulfamidates 1 and 2 (retention times: (1R)-(ꢀ)-1: tR = 22.73 min, (1S)-(+)-2: tR = 25.02 min).

E. K. Dolence et al. / Tetrahedron: Asymmetry 16 (2005) 1583–1594
1585
Table 1. Reaction of (1R)-(ꢀ)- and (1S)-(+)-sulfamidates 1 and 2 with nucleophiles
Nuc
O
O2S
Nuc
O
O2S
Nucleophile
Nucleophile
N
P(OEt)2
N
Bz
BzN
R
P(OEt)2
BzN
R
P(OEt)2
P(OEt)2
Bz
O
O
O
O
(1S)-(+)-2
R = H (1R)-9a, 9c-h
R = H (1S)-10a, 10c-h
(1R)-(-)-1
-
-
R = SO3 (1R)-9b
R = SO3 (1S)-10b
20
D
Nucleophile
Product
Isolated yield (%)
½aŠ
NaCN, DMF
9a
10a
30 (51a)
42 (77a)
ꢀ11.2 (c 0.760)
+10.2 (c 0.760)
Phenethylamine, THF
9b
64
50
79
79
ꢀ46.3 (c 0.640)
+46.4 (c 0.724)
ꢀ17.7 (c 0.608)
+18.5 (c 0.840)
10b
9c
10c
Imidazole, THF
9d
10d
23 (38a)
25
ꢀ26.0 (c 0.238)
+26.0 (c 0.266)
N-Hydroxysuccinimide, Et3N, CH3CN
NaBH4, THF
9e
10e
72
76
ꢀ6.6 (c 0.802)
+6.5 (c 0.840)
9f
10f
35 (84a)
64
ꢀ6.0 (c 0.212)
+6.2 (c 0.422)
n-PrSH, Cs2CO3, DMF
9g
10g
57
71
ꢀ90.3 (c 0.568)
+84.9 (c 0.708)
2-Naphthalenethiol, Cs2CO3, DMF
9h
10h
79
70
ꢀ81.2 (c 0.894)
+83.6 (c 0.860)
a Product yield afforded using N-hydroxysuccinimide/boron trifluoride etherate to remove the N-sulfate.
Reaction of the sulfamidates with a variety of nucleo-
philesisshown in Table 1. A number of methods30 for
the removal of the N-sulfate group that results following
nucleophilic attack at the b-position are available, how-
ever most are highly acidic involving protic acids or the
Lewisacid boron trifluoride etherate. In order to pre-
serve the phosphonate ethyl groups we have utilized
the boron trifluoride etherate and n-propylthiol method
of Kim and So.24
peated by substituting N-hydroxysuccinimide for the
foul smelling n-propylthiol. In each case, as reported
in Table 1, N-sulfate removal occurred increasing yields
from 15% to 30% for the reactionsinvestigated.
Chiral HPLC, to confirm enantiopurity directly on the
N-benzylamine isolated products using a Whelk O-2 chi-
ral column, wasplagued by long retention timesand
severe broadening, despite the addition of additives to
the mobile phase. Derivatization as the N-benzyl-N-
3,5-dinitrobenzoyl analogue and analysis conducted
using a Pirkle (S)-Leu and (R)-NEA chiral phase proved
useful as depicted for 9a and 10a in Scheme 3. Although
conversion to 11 and 12 afforded incomplete baseline
separation and long retention times, it established that
extensive racemization had not occurred during the
nucleophilic ring opening or the subsequent N-sulfate
removal process.
Carbon nucleophiles such as cyanide, react with the sulf-
amidatesto provide the nitrile products 9a and 10a in
modest yield ranging from 30% to 42%, respectively, uti-
lizing the boron trifluoride etherate and thiol method for
N-sulfate removal. Malonate anion produced modest
amounts of product but rapidly decomposed. Use of
N-hydroxysuccinimide as the nucleophile and triethyl-
amine asa baes afforded good yieldsof products
9e
(76%) and 10e (72%). Reduction of the sulfamidates
with NaBH4 provided the methyl analogues 9f and 10f
in 35% and 64% yields, respectively. The amino nucleo-
philesphenethylamine ( Scheme 4) and imidazole pro-
vided lower yieldsthan expected, asreported in Table
1. The results from the N-hydroxysuccinimide reaction
suggest that the lower product yields were not caused
by removal28,38 of an alkyl group from the phosphonate
moiety by the boron trifluoride etherate and thiol meth-
od. Thisled usto speculate that N-hydroxysuccinimide
may serve as an effective nucleophile in the removal of
the N-sulfate group. A number of the reactions were re-
It wasobserved that the boron trifluoride etherate med-
iated thiol method fails to successfully remove the N-sul-
fate group in the case of the phenethylamine adducts
(Scheme 4). Using n-propylthiol, the N-sulfate products
9b and 10b (zwitterionic) were isolated by silica gel chro-
matography. Electrospray ionization mass spectroscopy
produced identical spectra for 9b, 10b, 9c, and 10c in the
1
mass range of 0–750 mass units although the H NMR
spectra for 9b and 10b were different from the reaction
products 9c and 10c using N-hydroxysuccinimide. Dur-
ing ESI-MS analysis, 9b and 10b easily lose SO3 and

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E. K. Dolence et al. / Tetrahedron: Asymmetry 16 (2005) 1583–1594
Scheme 3. Derivatization of 9a and 10a and Pirkle phase chiral HPLC of 11 and 12 (retention times: (1R)-(ꢀ)-11: tR = 44.98 min, (1S)-(+)-22:
tR = 47.98 min).
afforded m/z peaksof 391.1 (M ꢀSO3+H) and 413.1
(MꢀSO3+Na). Reacquisition of the ESI-MS for 9b in
the mass range of m/z 0–2000 revealed the additional
ion clusters: 2M + Na (m/z 963.0), 3M + Na (m/z
1432.9), and 4M + Na (1902.7). The 13C NMR revealed
only slight differences in the benzylic methylene carbon
chemical shift values at 50.6 ppm (amine) versus
49.2 ppm (N-sulfate). The 31P NMR chemical shifts
were significantly different (27.4 ppm for 9c and 10c
and 19.7 ppm for 9b and 10b). Further evidence sup-
porting the N-sulfate adduct for 9b and 10b wasob-
served in the IR spectra with a broad signal ranging
from 3300 to 2500 cmꢀ1 (zwitterionic) and a strong
1175 cmꢀ1 band for the organic N-SOꢀ3 functional
group, which wasabsent in the IR for 9c and 10c.
Scheme 4. Treatment of the sulfamidate 1 with pheneth-
ylamine followed by acetic anhydride and N-sulfate
removal using boron trifluoride etherate and
N-hydroxysuccinimide produced a 69% yield of the
N-acetyl derivative 13 (31P NMR 26.06 ppm). This
should provide a useful method to expand upon the
diversity of side chains in the b-amino substituted a-
aminophosphonates.
Cesium carbonate proved to be a superior base for the
reaction of thiolswith the sulfamidates 1 and 2. Follow-
ing the method reported by Boulton et al.7 exposure of
the sulfamidates to 2 equiv of n-propylthiol or 2-napht-
halenethiol and Cs2CO3 in DMF for 2 h followed by N-
sulfate removal afforded the thiol adducts 9g, 10g, 9h,
and 10h cleanly in 57–79% isolated yield. Use of tri-n-
butylphosphine20 in the presence of 2-naphthalenethiol
in refluxing acetonitrile afforded only 36% yield of 9h.
Boron trifluoride etherate in the presence of thiol at re-
flux in acetonitrile failed to produce any trace of desired
The stability of a N-sulfate group following reaction
with a primary amine offersan opportunity to use it as
a temporary blocking group to allow further differentia-
tion of the amino nucleophile nitrogen asdepicted in

E. K. Dolence et al. / Tetrahedron: Asymmetry 16 (2005) 1583–1594
1587
4. Experimental
O
O2S
4.1. General
a, b
N
P(OEt)2
Bz
The solvent 1,2-dichloroethane, NaBH4, and other
chemicals were purchased from Acros/Fisher or Aldrich
Chemical Company. THF was distilled from sodium
benzophenone, Et3N, CH3CN, and CH2Cl2 were dis-
tilled from CaH2. DMF wasvacuum ditsilled from
CaH2. CHCl3 for the reactionswasdtisilled from
P2O5. EtOAc and hexanes were distilled prior to use.
All reactionsand ditsillationswere conducted under
an inert nitrogen atmosphere. Analytical thin-layer
chromatography wascarried out on E. Merck precoated
silica gel 60 (0.2 mm, aluminum or glass support) TLC
plates. Preparative TLC including radial chromatogra-
phy was carried out using E. Merck silica gel 60. Flash
silica gel column chromatography was carried out using
Mallinckrodt silica gel 60, 230–400 mesh. Chiral HPLC
NH
P(OEt)2
O
(1R)-(-)-1
BzNH
O
(1R)-9c
a, c
a, d, b
b
CH3
+
wascarried out uinsg a Regis(
S,S) Whelk O-2
NH2
N
250 · 4.60 mm column or a Phenomenexꢂ Chirex (S)-
Leu and (R)-NEA 250 · 4.60 mm column with monitor-
ing at 254 nm. All HPLC solvents were filtered through
a 0.45 lm filter prior to use. The term ÔdriedÕ refersto
drying of a solution over anhydrous magnesium sulfate.
Distilled deionized water was obtained from a Millipore
O
BzN
SO3
(1R)-9b
P(OEt)2
BzNH
P(OEt)2
-
O
O
(1R)-13
Scheme 4. Reaction of 1 with phenethylamine and the boron triflu-
oride etherate mediated N-sulfate removal to afford 9b and 9c and
selective N-modification to afford 13. Reagents: (a) phenethylamine,
THF; (b) boron trifluoride etherate, N-hydroxysuccinimide, CH2Cl2;
(c) boron trifluoride etherate, n-propylthiol, CH2Cl2; (d) CH2Cl2,
Et3N, Ac2O.
1
NanoPure system. H, 13C, and 31P NMR spectra were
obtained using a Bruker Avance 400 MHz NMR and
were referenced to either TMS or the residual NMR
solvent signal for d6-DMSO at 2.50 ppm for 1H or
39.5 ppm for 13C. 31P NMR wassubject to external refe-
rence using H3PO4 at 0.00 ppm. Optical rotationswere
obtained in spectral grade solvents using a Perkin–Elmer
341 polarimeter. Infrared spectra were obtained as thin
films on NaCl plates using a Perkin–Elmer 457 spectro-
photometer. Electrospray mass spectra were obtained
on a Finnigan electrospray mass spectrometer located
in the University of Wyoming Department of Chemistry
using a solution of 1:1 acetonitrile–water containing
0.1% trifluoroacetic acid or in methanol and water.
product. Additionally, the sulfamidates failed to pro-
duce useful adducts by reaction with sodium iodide in
acetone, tetrabutylammonium fluoride in THF, or tri-
methylphosphite in THF. The sulfamidate 1 would react
with methanol at reflux in the presence of excess boron
trifluoride etherate to produce the b-O-methyl analogue
(31% yield) but only after very long reaction times.
Refluxing methanol in the presence of triethylamine,
tri-n-butylphosphine or Cs2CO3 failed to produce any
b-O-methyl products.
4.2. General procedure for N-benzylation of amino
alcohols 3 and 4
4.2.1. Diethyl (1R)-(1-(N-benzylamino))-2-hydroxyethyl
phosphonate 5. To a solution of amino alcohol 3
(1.11 g, 5.605 mmol) in 22 mL of absolute EtOH was
added glacial acetic acid (0.60 mL, 11.210 mmol) fol-
lowed by benzaldehyde (0.654 g, 6.165 mmol) and so-
dium cyanoborohydride (0.528 g, 8.400 mmol). This
solution was stirred under N2 for 18 h. Solid NaHCO3
(1.41 g, 16.80 mmol) wasadded and the EtOH wasre-
moved in vacuo. To the residue was added 50 mL of
water followed by extraction with two 50 mL portions
of CH2Cl2. The pooled organic phases were dried over
Na2SO4, filtered, and evaporated in vacuo to afford
1.41 g of a clear oil. Thisoil waspurified by column
chromatography using 120 mL volume of silica eluting
3. Conclusion
In summary, we have demonstrated that N-benzyl sulf-
amidate 2-phosphonates 1 and 2 are stable, useful
and highly enantioenriched chiral synthons. The rapid
synthesis of b-substituted a-aminophosphonates was
accomplished by facile reaction of 1 and 2 with carbon,
amino, hydride, oxygen, and sulfur nucleophiles. Suc-
cessful removal of the N-sulfate group was achieved in
difficult cases, such as the phenethylamine adduct by
using boron trifluoride etherate and N-hydroxy-
succinimide, while preserving the O-ethyl groupsof the
phosphonate. In the case of a primary amino nucleo-
phile, the N-sulfate group can act further as a temporary
blocking group to allow acylation at the b-amino group.
Further work in the area of b-O-alkyl adductsby reac-
tion with alcoholsand other nucleophilesisin progres
and will be reported in due course.
with 1:10 MeOH–CHCl3 to afford 1.118 g (70% yield)
20
D
(TF) 3350, 3040, 2995, 2960, 1610, 1502, 1460, 1400,
of 5 asa clear oil: ½aŠ ¼ ꢀ23:8 (c 0.800, CHCl3); IR
1
1375, 1230, 1045, 975, 795, 750, 710 cmꢀ1; H NMR
(CDCl3): d 1.32–1.37 (m, 6H, CH3), 2.98–3.07 (m, 1H,

1588
E. K. Dolence et al. / Tetrahedron: Asymmetry 16 (2005) 1583–1594
CHP), 3.68–3.83 (m, 2H, PCHCH2OH), 3.84–4.02 (m,
2H, benzylic CH2), 4.10–4.23 (m, 4H, POCH2),
7.22–7.37 (m, 5H, aromatic H); 13C NMR (CDCl3): d
16.44 (t, JCCOP = 5.7 Hz, CH3CH2OP), 52.02 (d,
JCCP = 6.8 Hz, HOCH2CHP), 55.70 (d, JCP = 146.9 Hz,
CHP), 60.09 (d, JCNCP = 4.4 Hz, benzylic CH2),
62.09 (d, JCOP = 6.9 Hz, CH3CH2OP), 62.42 (d,
JCOP = 6.8 Hz, CH3CH2OP), 127.20, 128.23, 128.38,
139.40; 31P NMR (CDCl3): d 26.77. Positive ion ESMS:
calculated: C13H23O4N1P1 m/z (M+H) 288.1. Found:
C13H23O4N1P1 m/z (M+H) 288.1 (100%).
4.43 (d, 1H, J = 14.6 Hz, diastereotopic benzylic CH2),
4.54–4.60 (m, 2H, PCHCH2OS), 4.66 (d, 1H,
J = 14.6 Hz, diastereotopic benzylic CH2), 7.30–7.40
(m, 3H, aromatic H), 7.47–7.51 (m, 2H, aromatic H);
13C NMR (CDCl3):
d 16.28 (d, JCCOP = 5.7 Hz,
CH3CH2OP), 16.41 (d, JCCOP = 5.4 Hz, CH3CH2OP),
51.61, 54.16 (d, JCP = 172.3 Hz, CHP), 62.97 (d,
JCOP = 6.9 Hz, CH3CH2OP), 64.47 (d, JCOP = 6.7 Hz,
CH3CH2OP), 65.28, 128.48, 128.60, 129.59, 133.58; 31P
NMR (CDCl3): d 16.99. Positive ion ESMS: calculated:
C13H20N1P1S1O6Na1 m/z (M+Na) 372.1. Found:
C13H20N1P1S1O6Na1 m/z (M+Na) 372.1 (100%); Chiral
HPLC using a WHELK O-2 column eluting with
10:120:40 2-propanol–hexanes–1,2-dichloroethane at
1 mL/min afforded 97.4% (R)-enantiomer (tR =
22.73 min) and 2.6% of the contaminating (S)-enantio-
mer (tR = 25.02 min).
4.2.2. Characterization data for diethyl (1S)-(1-(N-benz-
ylamino))-2-hydroxyethyl phosphonate 6. Yield 64%;
20
D
2995, 2960, 1610, 1502, 1460, 1400, 1375, 1230, 1045,
½aŠ ¼ þ20:0 (c 0.226, CHCl3); IR (TF) 3350, 3040,
975, 795, 750, 710 cmꢀ1
;
1H NMR (CDCl3):
d 1.32–1.37 (m, 6H, CH3), 2.98–3.07 (m, 1H, CHP),
3.68–3.83 (m, 2H, PCHCH2OH), 3.84–4.02 (m, 2H,
benzylic CH2), 4.10–4.23 (m, 4H, POCH2), 7.22–7.37
(m, 5H, aromatic H); 13C NMR (CDCl3): d 16.44 (t,
JCCOP = 5.7 Hz, CH3CH2OP), 52.02 (d, JCCP = 6.8 Hz,
HOCH2CHP), 55.70 (d, JCP = 146.9 Hz, CHP),
60.09 (d, JCNCP = 4.4 Hz, benzylic CH2), 62.09 (d,
JCOP = 6.9 Hz, CH3CH2OP), 62.42 (d, JCOP = 6.8 Hz,
CH3CH2OP), 127.20, 128.22, 128.38, 139.36; 31P NMR
(CDCl3): d 26.54. Positive ion ESMS: calculated:
4.3.2. Characterization data for diethyl ((4S)-3-benzyl-
1,2,3-oxathiazolidine 2,2-dioxide)-4-phosphonate 2. Yield
63%; ½aŠ ¼ þ24:9 (c 1.06, CHCl3); IR (TF) 3040, 2995,
20
D
2960, 1602, 1460, 1450, 1355, 1245, 1195, 1020 (br),
740 cmꢀ1 1H NMR (CDCl3): d 1.32–1.38 (m, 6H,
;
CH3), 3.80 (t, J = 7.2 and 7.4 Hz, 1H, CHP), 4.14–4.31
(m, 4H, POCH2), 4.43 (d, 1H, J = 14.6 Hz, diastereo-
topic benzylic CH2), 4.54–4.60 (m, 2H, PCHCH2OS),
4.67 (d, 1H, J = 14.6 Hz, diastereotopic benzylic CH2),
7.30–7.40 (m, 3H, aromatic H), 7.47–7.51 (m, 2H,
C13H23O4N1P1
m/z
(M+H)
288.1.
Found:
C13H23O4N1P1 m/z (M+H) 288.1 (100%).
aromatic H); 13C NMR (CDCl3):
d 16.29 (d,
JCCOP = 5.5 Hz, CH3CH2OP), 16.42 (d, JCCOP = 5.4 Hz,
CH3CH2OP), 51.61, 54.13 (d, JCP = 172.7 Hz, CHP),
62.97 (d, JCOP = 7.1 Hz, CH3CH2OP), 64.50 (d,
JCOP = 6.9 Hz, CH3CH2OP), 65.27, 128.49, 128.61,
129.55, 133.55; 31P NMR (CDCl3): d 17.00. Positive
ion ESMS: calculated: C13H20N1P1S1O6Na1 m/z
(M+Na) 372.1. Found: C13H20N1P1S1O6Na1 m/z
(M+Na) 372.1 (100%); Chiral HPLC using a WHELK
O-2 column eluting with 10:120:40 2-propanol–hex-
anes–1,2-dichloroethane at 1 mL/min afforded the con-
taminating (R)-enantiomer (tR = 22.7 min) asa very
small unresolved shoulder superimposed on the (S)-
enantiomer (tR = 25.02 min).
4.3. General procedure for the synthesis of sulfamidates
1 and 2
4.3.1. Diethyl ((4R)-3-benzyl-1,2,3-oxathiazolidine 2,2-
dioxide)-4-phosphonate 1. To a solution of amino alco-
hol
5
(0.897 g, 3.114 mmol), imidazole (0.849 g,
12.450 mmol), Et3N (0.630 g, 6.227 mmol) in 10 mL of
CH2Cl2 at 0 ꢁC wasadded dropwise 2 M thionyl chlo-
ride in CHCl3 (1.71 mL, 3.425 mmol). Thismixture
was stirred for 30 min followed by transfer to a separa-
tory funnel with the aid of 50 mL of CH2Cl2 and 20 mL
of water. The aqueousphaes wasextracted with two
20 mL portionsof CH Cl2. The pooled organic layers
2
were washed with three 25 mL portions of water, brine,
dried, filtered, and evaporated in vacuo to afford 1.108 g
of crude 7 asa clear oil. To thisoil wasadded 90 mL of
CH3CN and cooled to 0 ꢁC. Powdered RuCl3 (0.010 g,
0.048 mmol) and NaIO4 (1.33 g, 6.227 mmol) were
added followed by the dropwise addition of 90 mL of
water over 30 min. The mixture wastsirred overnight
while warming to room temperature. The CH3CN was
evaporated in vacuo and the solution transferred to a
separatory funnel and extracted with three 50 mL portions
of Et2O. The pooled organic phases were washed with
50 mL of saturated aqueous NaHCO3, brine, dried, fil-
tered, and evaporated in vacuo. The residue was purified
by column chromatography using a 70 mL volume of
4.4. General procedure for reaction of sulfamidates
1 and 2 with sodium cyanide
4.4.1. Diethyl (2R)-cyano-{N-benzylamino}methylphos-
phonate 9a. To a solution of the (R)-sulfamidate 1
(0.050 g, 0.1428 mmol) in 0.5 mL of dry DMF under
N2 wasadded solid NaCN (0.008 g, 0.1570 mmol) ( Cau-
tion: conduct reaction in a fume hood). The mixture was
stirred overnight followed by removal of the DMF in
vacuo.
4.4.1.1. N-Sulfate removal using the boron trifluoride
etherate and n-propylthiol procedure. To the residue
under N2 wasadded 1 mL of dry CH Cl2 and the mix-
2
silica eluting with 1:20 MeOH–CHCl3 to afford 0.766 g
of 1 (70% yield) asa clear oil. ½aŠ ¼ ꢀ25:1 (c 1.06,
ture cooled to 0 ꢁC. To this suspension was added by
a microliter syringe boron trifluoride etherate (73 lL,
0.5712 mmol) followed by 30 min of stirring. n-Propyl-
thiol (52 lL, 0.5712 mmol) wasthen added, the cooling
bath removed and the mixture stirred for 2 h. At this
time concd NH4OH (2 mL) wasadded and the mixture
20
D
CHCl3); IR (TF) 3040, 2995, 2960, 1602, 1460, 1450,
1355, 1245, 1195, 1020 (br), 740 cmꢀ1
;
1H NMR
(CDCl3): d 1.32–1.38 (m, 6H, CH3), 3.79 (t, J = 7.2
and 7.5 Hz, 1H, CHP), 4.14–4.31 (m, 4H, POCH2),

E. K. Dolence et al. / Tetrahedron: Asymmetry 16 (2005) 1583–1594
1589
transferred to a separatory funnel with the aid of 5 mL
water and 15 mL of CH2Cl2. The aqueousphase wasex-
tracted with 15 mL of CH2Cl2 followed by drying of the
pooled organic phases, filtering, and evaporation in
vacuo to afford 21.2 mg of an oil. Thisoil waspurified
by silica TLC eluting with 1:20 MeOH–CHCl3 to afford
12.6 mg (30% yield) of 9a asan oil.
(EtOAc) showed remaining 9a so another portion of
the acid chloride and Et3N were added. After 30 min,
the mixture wasdiluted with 10 mL of CH Cl2, trans-
2
ferred to a separatory funnel and washed with 5 mL
each of 1 M AcOH, water, saturated aq NaHCO3, and
brine. The organic phase was dried, filtered, and evapo-
rated in vacuo to afford 23 mg of residue. This was puri-
fied by silica TLC eluting with EtOAc to afford 13.9 mg
20
D
4.4.1.2. N-Sulfate removal using the boron trifluoride
etherate and N-hydroxysuccinimide procedure. This
(61% yield) 11 of an oil. ½aŠ ¼ ꢀ23:0 (c 0.248, CHCl3);
1H NMR (CDCl3): d 1.30–1.45 (m, 6H, CH3), 2.90–3.04
(m, 1H, diastereotopic CH2CN), 3.30–3.40 (m, 1H, dia-
stereotopic CH2CN), 4.00–4.52 (m, 5H, POCH2 and
CHP), 4.70 (s, 2H, benzylic CH2), 7.26–7.45 (m, 5H,
aromatic H), 8.60 (br s, 2H, aromatic H), 9.05 (br s,
1H, aromatic H); 31P NMR (CDCl3): d 19.51. Positive
ion ESMS: calculated: C21H24N4P1O8 m/z (M+H)
491.1 and C21H23N4P1O8Na1 m/z (M+Na) 513.1.
Found: C21H24N4P1O8 m/z (M+H) 491.0 (30%) and
C21H23N4P1O8Na1 m/z (M+Na) 513.1 (100%); Chiral
procedure isexactly asdescribed previously for
ylthiol except N-hydroxysuccinimide
n-prop-
(0.066 g,
0.5712 mmol) is substituted for n-propylthiol. Thisafford-
ed 29.5 mg of crude product and following silica TLC
21.6 mg (51% yield) of 9a wasobtained.
20
4.4.1.3. Characterization data for 9a. ½aŠ ¼ ꢀ11:2
D
(c 0.760, CHCl3); IR (TF) 3320, 3040, 2995, 2960,
1
2260, 1470, 1260, 1050, 980, 760, 720 cmꢀ1; H NMR
(CDCl3): d 1.36 (t, J = 7.1 Hz, 6H, CH3), 2.01 (br s,
1H, NH), 2.64–2.74 (m, 1H, diastereotopic CH2CN),
2.76–2.86 (m, 1H, diastereotopic CH2CN), 3.15–3.23
(m, 1H, CHP), 4.01 (q, 2H, J = 15.2 and 15.9 Hz, benz-
ylic CH2), 4.13–4.27 (m, 4H, POCH2), 7.26–7.40 (m,
5H, aromatic H); 13C NMR (CDCl3): d 16.46 (d,
HPLC using a
Phenomenexꢂ Chirex S-Leu and
R-NEA 250 · 4.60 mm column eluting with 5% 2-propa-
nol in hexanesat 2 mL/min and monitoring at 254 nm to
afford the (R)-enantiomer (tR = 37.90 min) and no sign
of the (S)-enantiomer due to tailing of the other
enantiopode.
JCCOP = 5.6 Hz, CH3CH2OP), 19.75 (d, JNCCCP
4.3 Hz, CH2CN), 50.19 (d, JCP = 155.2 Hz, CHP),
51.76 (d, JCNCP = 7.3 Hz, benzylic), 63.02 (d, JCOP
7.0 Hz, CH3CH2OP), 117.06 (d, JNCCCP = 12.4 Hz,
CN), 127.65, 128.50, 128.57, 138.06; 31P NMR (CDCl3):
d 23.72. Positive ion ESMS: calculated: C14H21N2P1O3-
Na1 m/z (M+Na) 319.1. Found: C14H21N2P1O3Na1 m/z
(M+Na) 319.1 (100%).
=
4.5.2. Characterization data for diethyl (2S)-cyano-{N,N-
benzyl-3,5-dinitrobenzoyl}methylphosphonate 12. Yield
=
20
D
51%; ½aŠ ¼ þ21:0 (c 0.280, CHCl3); 1H NMR
(CDCl3): d 1.30–1.45 (m, 6H, CH3), 2.90–3.04 (m, 1H,
diastereotopic CH2CN), 3.30–3.40 (m, 1H, diastereo-
topic CH2CN), 4.00–4.52 (m, 5H, POCH2 and CHP),
4.70 (s, 2H, benzylic CH2), 7.26–7.45 (m, 5H, aromatic
H), 8.60 (br s, 2H, aromatic H), 9.05 (br s, 1H, aromatic
H); 31P NMR (CDCl3): d 19.51. Positive ion ESMS: cal-
culated: C21H24N4P1O8 m/z (M+H) 491.1 and
C21H23N4P1O8Na1 m/z (M+Na) 513.1. Found:
C21H24N4P1O8 m/z (M+H) 491.0 (50%) and
C21H23N4P1O8Na1 m/z (M+Na) 513.1 (100%); Chiral
4.4.1.4. Characterization data for diethyl (2S)-cyano-
{N-benzylamino}methylphosphonate 10a. Yield 77%;
20
D
2995, 2960, 2275, 1465, 1255, 1050, 980, 750,
½aŠ ¼ þ10:2 (c 0.760, CHCl3); IR (TF) 3320, 3040,
720 cmꢀ1 1H NMR (CDCl3): d 1.36 (t, J = 7.1 Hz,
;
6H, CH3), 2.02 (br s, 1H, NH), 2.64–2.72 (m, 1H, diaste-
reotopic CH2CN), 2.76–2.85 (m, 1H, diastereo-
topic CH2CN), 3.14–3.23 (m, 1H, CHP), 4.00 (q,
2H, J = 13.2 and 13.6 Hz, benzylic CH2), 4.13–4.25
(m, 4H, POCH2), 7.24–7.41 (m, 5H, aromatic H);
HPLC using a
Phenomenexꢂ Chirex S-Leu and
R-NEA 250 · 4.60 mm column eluting with 5% 2-propa-
nol in hexanesat 2 mL/min and monitoring at 254 nm to
afford the contaminating (R)-enantiomer (1.6%, tR =
39.02 min) and the (S)-enantiomer (98.4%, tR =
41.20 min) with incomplete baseline separation.
13C NMR (CDCl3):
d
16.35 (d, JCCOP = 5.3 Hz,
CH3CH2OP), 19.76 (d, JNCCCP = 5.1 Hz, CH2CN),
50.11 (d, JCP = 154.9 Hz, CHP), 51.66 (d, JCNCP
=
4.6. General procedure for the reaction of 1 and 2 with
phenethylamine: use of boron trifluoride etherate and
n-propylthiol to afford the N-sulfates of 9b and 10b
7.6 Hz, benzylic), 62.76 (d, JCOP = 7.0 Hz, CH3CH2OP),
117.10 (d, JNCCCP = 13.0 Hz, CN), 127.35, 128.50,
128.21, 138.50; 31P NMR (CDCl3): d 23.61. Positive
ion ESMS: calculated: C14H21N2P1O3Na1 m/z (M+Na)
319.1. Found: C14H21N2P1O3Na1 m/z (M+Na) 319.0
(100%).
4.6.1. Diethyl (1R)-1-{N-benzylaminosulfate}-2-[(2-phen-
ylethyl)amino]ethylphosphonate 9b. To a solution of
the (R)-sulfamidate 1 (0.050 g, 0.1428 mmol) in 0.5 mL
of THF under N2 wasadded phenethylamine (0.035 g,
0.2856 mmol). The mixture wastsirred overnight fol-
lowed by removal of the THF in vacuo. To the residue
4.5. General method for the 3,5-dinitrobenzoylation of
amines for chiral HPLC analysis
under N2 wasadded 1.0 mL of CH Cl2, cooled to 0 ꢁC
2
4.5.1. Diethyl (2R)-cyano-{N,N-benzyl-3,5-dinitrobenzo-
yl}methylphosphonate 11. To a solution of the amine
9a (0.014 g, 0.0466 mmol) in 1.0 mL of CH2Cl2 under
N2 wasadded 3,5-dinitrobenzoyl chloride olsid
(0.014 g, 0.0583 mmol) followed by Et3N (8.1 lL,
0.0583 mmol). Silica TLC monitoring after 10 min
and boron trifluoride etherate (73 lL, 0.5712 mmol)
added via microliter syringe. This solution was stirred
for 30 min and then n-propylthiol (52 lL, 0.5712 mmol)
added followed by stirring for 1 h. At this time 1 mL of
concd NH4OH wasadded, the mixture transferred to a
separatory funnel and the aqueous phase extracted with

1590
E. K. Dolence et al. / Tetrahedron: Asymmetry 16 (2005) 1583–1594
three 5 mL portionsof CH 2Cl2. The pooled organic
phases were washed with brine, dried, filtered, and evap-
orated in vacuo to afford 97 mg of residue. This resi-
due waspurified by preparative islica TLC eluting
twice with 1:20 MeOH–CHCl3 containing 0.1% concd
NH4OH. The highest Rf major UV active band wasiso-
4.6.3. Synthetic procedure for the synthesis and isolation
of the diamines 9c and 10c. The procedure isasde-
scribed above for 9b except N-hydroxysuccinimide
(0.066 g, 0.5712 mmol) was substituted for n-
propylthiol.
lated to afford 0.048 g (64% yield) of the N-sulfate 9b as
an oil. ½aŠ ¼ ꢀ46:3 (c 0.640, CHCl3); IR (TF) 3460,
4.6.3.1. Diethyl (1R)-1-{N-benzylamino}-2-[(2-phenyl-
20
D
3040, 2995, 2965, 1610, 1505, 1460, 1270, 1175, 1035,
20
D
ethyl)amino]ethylphosphonate 9c. Yield 79%; ½aŠ ¼
ꢀ17:7 (c 0.608, CHCl3); IR (TF) 3310, 3045, 2995,
975, 760, 710 cmꢀ1
;
1H NMR (CDCl3): d 1.24–1.36
2910, 1601, 1500, 1455, 1400, 1210 (br), 1060, 1035,
(m, 6H, CH3), 2.04–2.20 (m, 1H), 2.69–2.75 (m, 2H),
2.82–2.90 (m, 1H), 2.99–3.05 (m, 1H), 3.32–3.37 (m,
1H), 4.10–4.32 (m, 4H, POCH2), 4.62 (d, 1H,
J = 16.1 Hz, diastereotopic benzylic CH2), 4.76 (dd,
1H, J = 11.3 Hz, CHP), 5.04 (d, 1H, J = 16.0 Hz, diaste-
reotopic benzylic CH2), 7.08–7.20 (m, 2H, aromatic
H), 7.21–7.32 (m, 6H, aromatic H), 7.65–7.70 (m,
970, 790, 750, 710 cmꢀ1 1H NMR (CDCl3): d 1.27–
;
1.35 (m, 6H, CH3), 1.93 (br s, 2H, NH), 2.74–2.82 (m,
5H), 2.90–3.07 (m, 2H), 3.84 (d, J = 13.1 Hz, 1H, diaste-
reotopic benzylic CH2), 4.01 (d, J = 13.1 Hz, 1H, diaste-
reotopic benzylic CH2), 4.07–4.20 (m, 4H, CH3CH2OP),
7.17–7.33 (m, 10H, aromatic H); 13C NMR (CDCl3): d
16.45–16.54 (m, CH3CH2OP), 36.26, 48.64 (d,
JNCCP = 5.3 Hz, NCH2CHP), 50.60, 52.31 (d,
2H, aromatic H); 13C NMR (CDCl3):
d 16.33
(d, JCCOP = 5.1 Hz, CH3CH2OP), 32.13, 46.66 (d,
JCCP = 16.2 Hz, PCHCH2N), 49.28, 49.92, 52.05
(d, JCP = 157.0 Hz, CHP), 62.78 (d, J = 7.1 Hz,
CH3CH2OP), 62.93 (d, J = 7.0 Hz, CH3CH2OP),
127.14, 127.62, 128.65, 128.75, 129.37, 135.75, 140.04;
31P NMR (CDCl3): d 19.64. Positive ion ESMS m/z
range 0–750: calculated: C21H32N2P1O3 m/z (MꢀSO3+
H) 391.1 and C21H31N2P1O3Na1 m/z (MꢀSO3+Na)
413.1. Found: C21H32N2P1O3 m/z (MꢀSO3+H) 391.1
(40%) and C21H31N2P1O3Na1 m/z (MꢀSO3+Na) 413.1
(100%). Positive ion ESMS m/z range 0–2000: calcu-
lated: C21H32N2P1O3 m/z (MꢀSO3+H) 391.1, C21H31-
N2P1O3Na1 m/z (MꢀSO3+Na) 413.1, C42H62N4-
P2O12S2Na1 m/z (2M+Na) 963.3, C63H93N6P3O18S3Na1
m/z (3M+Na) 1433.4, C84H124N8P4O24S4Na1 m/z
(4M+Na) 1903.6. Found: C21H32N2P1O3 m/z (MꢀSO3+H)
391.1 (8%), C21H31N2P1O3Na1 m/z (MꢀSO3+Na) 413.1
(20%), C42H62N4P2O12S2Na1 m/z (2M+Na) 963.0 (70%),
C63H93N6P3O18S3Na1 m/z (3M+Na) 1432.9 (100%),
C84H124N8P4O24S4Na1 m/z (4M+ Na) 1902.7 (60%).
JCNCHP = 4.2 Hz, benzylic CH2), 53.61 (d, JCP =
148.9 Hz, CHP), 61.92–62.04 (m, CH3CH2OP), 126.08,
127.01, 128.28, 128.36, 128.64, 139.80, 139.89; 31P
NMR (CDCl3): d 27.37. Positive ion ESMS: calculated:
C17H22N2 m/z (MꢀPO(OEt)2+H) 253.1, C21H32N2P1O3
m/z (M+H) 391.1, and C21H31N2P1O3Na1 m/z (M+Na)
413.1. Found: C17H22N2 m/z (MꢀPO(OEt)2+H) 253.1
(100%), C21H32N2P1O3 m/z (M+H) 391.1 (10%), and
C21H31N2P1O3Na1 m/z (M+Na) 413.1 (10%).
4.6.3.2. Diethyl (1S)-1-{N-benzylamino}-2-[(2-phenyl-
¼
20
D
ethyl)amino]ethylphosphonate 10c. Yield 79%; ½aŠ
þ18:5 (c = 0.840, CHCl3); IR (TF) 3310, 3035, 2990,
2910, 1601, 1495, 1455, 1400, 1245, 1060, 1035, 970,
790, 755, 710 cmꢀ1 1H NMR (CDCl3): d 1.28–1.34
;
(m, 6H, CH3), 2.02 (br s, 2H, NH), 2.74–2.82 (m, 5H),
2.90–3.07 (m, 2H), 3.84 (d, J = 13.1 Hz, 1H, diastereo-
topic benzylic CH2), 4.01 (d, J = 13.1 Hz, 1H, diastereo-
topic benzylic CH2), 4.07–4.20 (m, 4H, CH3CH2OP),
7.17–7.33 (m, 10H, aromatic H); 13C NMR (CDCl3): d
16.44–16.53 (m, CH3CH2OP), 36.26, 48.65 (d, JNCCP
=
4.6.2. Characterization data for diethyl (1S)-1-{N-benz-
ylaminosulfate}-2-[(2-phenylethyl)amino]ethylphosphonate
10b. Yield 50%, ½aŠ ¼ þ46:4 (c 0.724, CHCl3); IR
5.3 Hz, NCH2CHP), 50.62, 52.31 (d, JCNCHP = 4.3 Hz,
benzylic CH2), 53.65 (d, JCP = 148.9 Hz, CHP), 61.92–
62.03 (m, CH3CH2OP), 126.06, 127.00, 128.27, 128.40,
128.64, 139.85, 139.91; 31P NMR (CDCl3): d 27.45. Po-
sitive ion ESMS: calculated: C17H22N2 m/z (Mꢀ
PO(OEt)2+H) 253.1, C21H32N2P1O3 m/z (M+H) 391.1,
and C21H31N2P1O3Na1 m/z (M+Na) 413.1. Found:
C17H22N2 m/z (MꢀPO(OEt)2+H) 253.1 (100%),
C21H32N2P1O3 m/z (M+H) 391.1 (10%), and C21H31-
N2P1O3Na1 m/z (M+Na) 413.1 (10%).
20
D
(TF) 3460, 3040, 2995, 2965, 1610, 1505, 1460, 1270,
1
1175, 1035, 975, 760, 710 cmꢀ1; H NMR (CDCl3): d
1.30–1.35 (m, 6H, CH3), 2.15–2.30 (m, 1H), 2.63–2.76
(m, 2H), 2.81–2.90 (m, 1H), 3.00–3.06 (m, 1H), 3.32–
3.38 (m, 1H), 4.12–4.31 (m, 4H, POCH2), 4.62 (d, 1H,
J = 16.1 Hz, diastereotopic benzylic CH2), 4.77 (dd,
1H, J = 10.9 and 11.1 Hz, CHP), 5.04 (d, 1H,
J = 16.1 Hz, diastereotopic benzylic CH2), 7.08–7.19
(m, 2H, aromatic H), 7.21–7.31 (m, 6H, aromatic H),
7.67–7.70 (m, 2H, aromatic H); 13C NMR (CDCl3): d
16.00–16.36 (m, CH3CH2OP), 32.08, 46.61 (d,
JCCP = 17.0 Hz, PCHCH2N), 49.24, 49.90, 52.00 (d,
4.7. General procedure for the reaction of 1 and 2 with
imidazole
4.7.1. Diethyl (1R)-2-(1H-imidazol-1-yl)-1-{N-benzyl-
amino}ethylphosphonate 9d. To a solution of (R)-sulf-
amidate 1 (0.050 g, 0.1428 mmol) in 2.0 mL of THF
under N2 wasadded imidazole (0.029 g, 0.4284 mmol).
The mixture wastsirred for 52 h followed by removal
of the THF in vacuo. To the residue under N2 was
added 1.0 mL of CH2Cl2, it wascooled to 0 ꢁC and bor-
on trifluoride etherate (73 lL, 0.5712 mmol) added via
microliter syringe. n-Propylthiol (52 lL, 0.5712 mmol)
wasthen added, the cooling bath wasremoved and the
JCP = 156.6 Hz,
CHP),
62.76
(d,
J = 7.1 Hz,
CH3CH2OP), 63.88 (d, J = 6.9 Hz, CH3CH2OP),
127.10, 127.57, 128.63, 128.72, 128.96, 135.76, 140.03;
31P NMR (CDCl3): d 19.70. Positive ion ESMS m/z
range 0–750: calculated: C21H32N2P1O3 m/z (MꢀSO3+
H) 391.1 and C21H31N2P1O3Na1 m/z (MꢀSO3+Na)
413.1. Found: C21H32N2P1O3 m/z (MꢀSO3+H) 391.0
(100%) and C21H31N2P1O3Na1 m/z (MꢀSO3+Na)
413.1 (70%).

E. K. Dolence et al. / Tetrahedron: Asymmetry 16 (2005) 1583–1594
1591
mixture stirred for 2 h. At this time 1 mL of concd
NH4OH wasadded, the mixture transferred to a separa-
tory funnel, and the aqueousphase extracted with three
(0.049 g, 0.4284 mmol) and Et3N (60 ll, 0.4284 mmol).
The mixture wastsirred for 22 h followed by removal
of the THF in vacuo. To the residue under N2 wasadded
1.0 mL of CH2Cl2. It wasthen cooled to 0 ꢁC and boron
trifluoride etherate (73 lL, 0.5712 mmol) added via
microliter syringe. n-Propylthiol (52 lL, 0.5712 mmol)
wasthen added, the cooling bath removed, and the mix-
ture stirred for 1 h. At this time 1 mL of concd NH4OH
was added, the mixture transferred to a separatory fun-
nel and the aqueousphaes extracted with three 5 mL
portionsof CH 2Cl2. The pooled organic phases were
washed with brine, dried, filtered, and evaporated in va-
cuo to afford 57.2 mg. Thisresidue waspurified by pre-
parative silica TLC eluting with 1:10 MeOH–CHCl3.
5 mL portionsof CH Cl2. The pooled organic phases
2
were washed with brine, dried, filtered, and evaporated
in vacuo to afford 24.1 mg of the residue. This residue
waspurified by islica TLC eluting with 1:10 MeOH–
CHCl3 containing 0.1% concd NH4OH. The Rf 0.53
UV active band wasioslated to afford 0.012 g (23%
20
D
IR (TF) 3160, 3040, 2995, 2965, 1570, 1470, 1410,
yield) of 9d asan oil. ½aŠ ¼ ꢀ26:0 (c 0.238, CHCl3);
1390, 1250, 1140, 1040, 990, 915, 820, 770, 720 cmꢀ1
;
1H NMR (d6-DMSO): d 1.26 (t, J = 7.0 Hz, 6H, CH3),
2.03–2.08 (m, 1H, NH), 3.28–3.39 (m, 1H, CHP),
3.62–3.68 (m, 1H, diastereotopic benzylic CH2), 3.77–
3.85 (m, 1H, diastereotopic benzylic CH2), 4.00–4.13
(m, 4H, CH3CH2OP), 4.17–4.24 (m, 1H), 4.37–4.45
(m, 1H), 6.94–7.16 (m, 5H, aromatic H), 7.48 (s, 1H,
imidazoyl), 7.61 (d, J = 19.8 Hz, 1H, imidazoyl), 8.73
(d, J = 18.2 Hz, 1H, imidazoyl); 13C NMR (d6-DMSO):
d 16.34–16.38 (m, CH3CH2OP), 47.80–48.04 (m), 50.70–
50.80 (m), 53.69 (dd, JCP = 145.6 and 158.3 Hz, CHP),
61.80–62.10 (m, CH3CH2OP), 121.27, 122.21, 122.54,
126.80, 126.83, 127.48, 127.77, 128.16, 136.70, 137.06,
139.90, 139.92; 31P NMR (d6-DMSO): d 24.01, 24.08.
Positive ion ESMS: calculated: C16H24N3P1O3 m/z
(M+H) 338.1. Found: C16H24N3P1O3 m/z (M+H)
338.0 (100%). NMR spectra in CDCl3 were broad and
complex. Using the N-hydroxysuccinimide and boron
trifluoride etherate method of N-sulfate removal afford-
ed 38% yield of 9d.
The UV active band wasioslated to afford 0.040 g
20
D
(72% yield) of 9e asan oil. ½aŠ ¼ ꢀ6:6 (c 0.802, CHCl3);
IR (TF) 3320, 3040, 2995, 2960, 1790, 1730, 1501, 1459,
1395, 1375, 1250, 1210, 1170, 1050, 970, 840, 795, 750,
705, 655 cmꢀ1
;
1H NMR (CDCl3):
d
1.33 (t,
J = 7.1 Hz, 6H, CH3), 2.68 (s, 4H, OCCH2CH2CO),
3.29–3.37 (m, 1H, CHP), 3.99–4.08 (m, 2H, benzylic
CH2), 4.12–4.22 (m, 4H, CH3CH2OP), 4.25–4.32 (m,
1H, diastereotopic PCHCH2ON), 4.44–4.51 (m, 1H, dia-
stereotopic PCHCH2ON), 7.22–7.41 (m, 5H, aromatic
H); 13C NMR (CDCl3): d 16.35–16.43 (m, CH3CH2OP),
25.34, 53.12 (d, JCNCHP = 7.5 Hz, benzylic CH2), 54.17
(d, JCP = 157.5 Hz, CHP), 62.15–62.75 (m, CH3CH2OP),
75.84 (d, JCNCHP = 11.3 Hz, CH2CHP), 127.01, 128.02,
128.50, 139.56, 171.03; 31P NMR (CDCl3): d 22.73. Posi-
tive ion ESMS: calculated: C17H26N2P1O6 m/z (M+H)
385.1 and C17H25N2P1O6 Na1 m/z (M+Na) 407.1.
Found: C17H26N2P1O6 m/z (M+H) 385.0 (25%) and
C17H25N2P1O6 Na1 m/z (M+Na) 407.0 (100%).
4.7.2. Characterization data for diethyl (1S)-2-(1H-imi-
dazol-1-yl)-1-{N-benzylamino}ethylphosphonate
10d.
20
D
3160, 3040, 2990, 2960, 1570, 1470, 1410, 1390, 1250,
Yield 25%; ½aŠ ¼ þ26:0 (c 0.266, CHCl3); IR (TF)
4.8.2. Characterization data for diethyl 1-[(2S)-(2-N-
benzylamino)-2-(oxophosphino)ethoxy]pyrrolidine-2,5-di-
1150, 1040, 980, 910, 810, 770, 725 cmꢀ1 1H NMR
;
20
D
one 10e. Yield 76%; ½aŠ ¼ þ6:5 (c 0.840, CHCl3);
(d6-DMSO): d 1.26 (t, J = 7.0 Hz, 6H, CH3), 2.03–2.08
(m, 1H, NH), 3.28–3.39 (m obscured by water, 1H,
CHP), 3.62–3.68 (m, 1H, diastereotopic benzylic CH2),
3.77–3.85 (m, 1H, diastereotopic benzylic CH2), 4.00–
4.13 (m, 4H, CH3CH2OP), 4.17–4.24 (m, 1H), 4.37–
4.45 (m, 1H), 6.94–7.16 (m, 5H, aromatic H), 7.48 (s,
1H, imidazoyl), 7.61 (d, J = 19.8 Hz, 1H, imidazoyl),
8.73 (d, J = 18.2 Hz, 1H, imidazoyl); 13C NMR (d6-
DMSO): d 16.34–16.38 (m, CH3CH2OP), 47.80–48.04
(m), 50.70–50.80 (m), 53.69 (dd, JCP = 145.6 and
158.3 Hz, CHP), 61.80–62.10 (m, CH3CH2OP), 121.28,
122.08, 122.54, 126.80, 126.82, 127.70, 127.78, 128.15,
136.80, 137.06, 139.89, 139.93; 31P NMR (d6-DMSO):
IR (TF) 3320, 3040, 2995, 2960, 1790, 1730, 1501,
1459, 1395, 1375, 1250, 1210, 1170, 1050, 970, 820,
1
795, 750, 705, 655 cmꢀ1; H NMR (CDCl3): d 1.33 (t,
J = 7.1 Hz, 6H, CH3), 2.68 (s, 4H, OCCH2CH2CO),
3.28–3.37 (m, 1H, CHP), 3.99–4.10 (m, 2H, benzylic
CH2), 4.13–4.22 (m, 4H, CH3CH2OP), 4.25–4.31 (m,
1H, diastereotopic PCHCH2ON), 4.45–4.52 (m, 1H,
diastereotopic PCHCH2ON), 7.22–7.45 (m, 5H, aro-
matic H); 13C NMR (CDCl3): d 16.39 (d, J = 5.6 Hz,
CH3CH2OP), 25.35, 52.15 (d, JCNCHP = 7.4 Hz, benzylic
CH2), 54.19 (d, JCP = 157.7 Hz, CHP), 62.59–62.76 (m,
CH3CH2OP), 75.85 (d, JCNCHP = 7.0 Hz, CH2CHP),
126.97, 128.26, 128.51, 139.58, 171.03; 31P NMR
(CDCl3): d 22.73. Positive ion ESMS: calculated:
C17H26N2P1O6 m/z (M+H) 385.1 and C17H25N2P1O6
Na1 m/z (M+Na) 407.1. Found: C17H26N2P1O6 m/z
(M+H) 385.0 (25%) and C17H25N2P1O6 Na1 m/z
(M+Na) 407.0 (100%).
d
24.11, 24.15. Positive ion ESMS: calculated:
C16H25N3P1O3 m/z (M+H) 338.1 and C16H24N3P1O3-
Na1 m/z (M+Na) 360.1. Found: C16H25N3P1O3 m/z
(M+H) 338.0 (100%) and C16H24N3P1O3Na1 m/z
(M+Na) 360.1 (10%).
4.8. General procedure for the reaction of 1 and 2 with N-
hydroxysuccinimide
4.9. General procedure for the reaction of 1 and 2 with
sodium borohydride
4.8.1. Diethyl 1-[(2R)-(2-N-benzylamino)-2-(oxophos-
phino)ethoxy]pyrrolidine-2,5-dione 9e. To a solution of
the (R)-sulfamidate 1 (0.050 g, 0.1428 mmol) in 0.5 mL
of CH3CN under N2 wasadded N-hydroxysuccinimide
4.9.1. Diethyl (1R)-1-{N-benzylamino}ethylphosphonate
9f. To a solution of (R)-sulfamidate 1 (0.050 g,
0.1428 mmol) in 0.5 mL of THF under N2 wasadded

1592
E. K. Dolence et al. / Tetrahedron: Asymmetry 16 (2005) 1583–1594
NaBH4 (0.006 g, 0.1570 mmol). The mixture wasstirred
for 18 h followed by removal of the THF in vacuo. To
the residue under N2 wasadded 1.0 mL of CH Cl2. It
and cesium carbonate (0.094 g, 0.2856 mmol). The mix-
ture wasstirred for 2 h followed by removal of the DMF
in vacuo. To the residue under N2 wasadded 1.0 mL of
CH2Cl2. It wasthen cooled to 0 ꢁC and boron trifluoride
etherate (73 lL, 0.5712 mmol) added via microliter syr-
inge. n-Propylthiol (52 lL, 0.5712 mmol) wasthen
added, the cooling bath removed and the mixture stirred
for 1 h. At thistime the mixture wastranfserred to a
separatory funnel with the aid of 15 mL of CH2Cl2
and 5 mL of water. The aqueousphaes wasextracted
with three 5 mL portionsof CH 2Cl2. The pooled organic
phases were washed with brine, dried, filtered, and evap-
orated in vacuo to afford 36.0 mg of the residue. The res-
idue waspurified by silica TLC eluting with EtOAc. The
2
wasthen cooled to 0 ꢁC and boron trifluoride etherate
(73 lL, 0.5712 mmol) added via microliter syringe. n-
Propylthiol (52 lL, 0.5712 mmol) wasthen added, the
cooling bath removed and the mixture stirred for 1 h.
At thistime 1 mL of concd NH 4OH wasadded, the mix-
ture transferred to a separatory funnel and the aqueous
phase extracted with three 5 mL portions of CH2Cl2.
The pooled organic phases were washed with brine,
dried, filtered, and evaporated in vacuo to afford
22.1 mg of a residue that appeared pure by NMR. This
residue was purified by silica TLC eluting with 1:10
MeOH–CHCl3 containing 0.1% concd NH4OH. The
UV active band (Rf 0.57) wasisolated to afford 0.028 g
20
D
CHCl3); IR (TF) 3330, 3040, 2990, 2970, 1501, 1460,
UV active band wasioslated to afford 0.014 g (35%
(57% yield) of 9g asan oil. ½aŠ ¼ ꢀ90:3 (c 0.568,
20
D
(TF) 3320, 3040, 2995, 2965, 1510, 1460, 1410, 1380,
yield) of 9f asan oil. ½aŠ ¼ ꢀ6:0 (c 0.212, MeOH); IR
1400, 1250, 1060, 1030, 965, 800, 745, 710 cmꢀ1 1H
;
1
1250, 1050, 1040, 970, 810, 750, 710 cmꢀ1; H NMR
NMR (CDCl3): d 0.94 (t, 3H, J = 7.2 and 7.5 Hz,
SCH2CH2CH3), 1.32–1.37 (m, 6H, CH3CH2OP), 1.47–
1.58 (m, 2H, SCH2CH2CH3), 2.23–2.36 (m, 2H,
SCH2CH2CH3), 2.50 (br s, 1H, NH), 2.66–2.75 (m,
1H, CHP), 2.99–3.07 (m, 2H, SCH2CHP), 3.98 (d,
J = 13.2 Hz, 1H, diastereotopic benzylic CH2), 4.10 (d,
J = 13.2 Hz, 1H, diastereotopic benzylic CH2), 4.15–
4.25 (m, 4H, CH3CH2OP), 7.24–7.43 (m, 5H, aromatic
H); 13C NMR (CDCl3): d 13.36 (CH3), 16.53 (d,
JCCOP = 5.3 Hz, CH3CH2OP), 22.56 (SCH2CH2CH3),
32.59 (d, JSCCP = 2.4 Hz, SCH2CHP), 33.84 (SCH2CH2-
CH3), 52.38 (d, JCNCHP = 3.3 Hz, benzylic CH2), 52.72
(d, JCP = 156.8 Hz, CHP), 62.30 (d, JCOP = 7.1 Hz,
CH3CH2OP), 62.57 (d, JCOP = 7.2 Hz, CH3CH2OP),
127.17, 128.34, 128.59, 139.20; 31P NMR (CDCl3):
d 25.55. Positive ion ESMS: calculated: C12H19N1S1
m/z (MꢀPO(OEt)2+H) 208.2, C16H29N1P1O3S1 m/z
(M+H) 346.1, C16H28N1P1O3S1Na1 m/z (M+Na)
368.1, and C16H28N1P1O3S1K1 m/z (M+K) 384.2.
Found: C12H19N1S1 m/z (Mꢀ PO(OEt)2+H) 208.2
(100%), C16H29N1P1O3S1 m/z (M+H) 346.1 (40%),
C16H28N1P1O3S1Na1 m/z (M+ Na) 368.2 (23%), and
C16H28N1P1O3S1K1 m/z (M+K) 384.2 (20%).
(CDCl3): d 1.30–1.38 (m, 9H, CH3), 1.95 (br s, 1H,
NH), 2.96–3.06 (m, 1H, CHP), 3.90 (d, J = 13.3 Hz,
1H, diastereotopic benzylic CH2), 3.97 (d, J = 13.5 Hz,
1H, diastereotopic benzylic CH2), 4.09–4.21 (m, 4H,
CH3CH2OP), 7.22–7.37 (m, 5H, aromatic H); 13C
NMR (CDCl3):
d 15.06 (CH3), 16.48–16.58 (m,
CH3CH2OP), 49.14 (d, JCP = 154.7 Hz, CHP), 51.41
(d, JCNCHP = 10.9 Hz, benzylic CH2), 62.00–62.12 (m,
CH3CH2OP), 127.10, 128.16, 128.49, 139.57; 31P NMR
(CDCl3): d 28.70. Positive ion ESMS: calculated:
C13H23N1P1O3 m/z (M+H) 272.1 and C13H22N1P1O3-
Na1 m/z (M+Na) 294.1. Found: C13H23N1P1O3 m/z
(M+H) 272.0 (40%) and C13H22N1P1O3Na1 m/z (M+
Na) 294.0 (100%). Using the N-hydroxysuccinimide
and boron trifluoride etherate method of N-sulfate
removal afforded 84% yield of 9f.
4.9.2. Characterization data for diethyl (1S)-1-{N-ben-
zylamino}ethylphosphonate 10f. Yield 64%; ½aŠ
20
D
¼
þ6:2 (c 0.422, MeOH); IR (TF) 3310, 3040,
2995, 2960, 1501, 1465, 1400, 1380, 1245, 1065, 1035,
970, 805, 750, 710 cmꢀ1 1H NMR (CDCl3): d 1.30–
;
1.37 (m, 9H, CH3), 1.74 (br s, 1H, NH), 2.96–3.05 (m,
1H, CHP), 3.88 (d, J = 13.3 Hz, 1H, diastereotopic benz-
ylic CH2), 3.96 (d, J = 13.2 Hz, 1H, diastereotopic benz-
ylic CH2), 4.10–4.21 (m, 4H, CH3CH2OP), 7.22–7.36
(m, 5H, aromatic H); 13C NMR (CDCl3): d 15.05
4.10.2. Diethyl (1S)-2-(propylsulfanyl)-1-{N-benzyl-
amino}ethylphosphonate 10g. Yield 71%; ½aŠ ¼ þ84:9
20
D
(c 0.708, CHCl3); IR (TF) 3310, 3040, 2985, 2970,
1501, 1460, 1400, 1250, 1055, 1030, 965, 800, 750,
0.94 (t, 3H,
705 cmꢀ1
;
1H NMR (CDCl3):
d
(CH3), 16.44–16.53 (m, CH3CH2OP), 49.06 (d, JCP
=
J = 7.3 Hz, SCH2CH2CH3), 1.32–1.38 (m, 6H,
CH3CH2OP), 1.47–1.58 (m, 2H, SCH2CH2CH3), 2.23–
2.36 (m, 2H, SCH2CH2CH3), 2.55 (br s, 1H, NH),
2.67–2.76 (m, 1H, CHP), 2.99–3.07 (m, 2H, SCH2CHP),
3.99 (d, J = 13.2 Hz, 1H, diastereotopic benzylic CH2),
4.10 (d, J = 13.2 Hz, 1H, diastereotopic benzylic CH2),
4.12–4.25 (m, 4H, CH3CH2OP), 7.24–7.42 (m, 5H, aro-
matic H); 13C NMR (CDCl3): d 13.36 (CH3), 16.53 (d,
JCCOP = 5.6 Hz, CH3CH2OP), 22.56 (SCH2CH2CH3),
32.58 (SCH2CHP), 33.86 (SCH2CH2CH3), 52.35 (d,
154.8 Hz, CHP), 51.38 (d, JCNCHP = 11.3 Hz, benzylic
CH2), 61.98–62.13 (m, CH3CH2OP), 127.01, 128.11,
128.40, 139.67; 31P NMR (CDCl3): d 28.50. Positive
ion ESMS: calculated: C13H23N1P1O3 m/z (M+H)
272.1 and C13H22N1P1O3Na1 m/z (M+Na) 294.1.
Found: C13H23N1P1O3 m/z (M+H) 272.0 (40%) and
C13H22N1P1O3Na1 m/z (M+Na) 294.0 (100%).
4.10. General procedure for the reaction of 1 and 2 with
thiols using cesium carbonate
JCNCHP = 3.3 Hz, benzylic CH2), 52.72 (d, JCP
=
156.4 Hz, CHP), 62.33 (d, JCOP = 7.1 Hz, CH3CH2OP),
62.59 (d, JCOP = 6.9 Hz, CH3CH2OP), 127.19, 128.35,
128.61, 139.20; 31P NMR (CDCl3): d 25.47. Positive
ion ESMS: calculated: C12H19N1S1 m/z (MꢀPO-
(OEt)2+H) 208.2, C16H29N1P1O3S1 m/z (M+H) 346.1,
4.10.1. Diethyl (1R)-2-(propylsulfanyl)-1-{N-benzyl-
amino}ethylphosphonate 9g. To a solution of (R)-sulf-
amidate 1 (0.050 g, 0.1428 mmol) in 0.25 mL of DMF
under N2 wasadded n-propylthiol (26 lL, 0.2856 mmol)

E. K. Dolence et al. / Tetrahedron: Asymmetry 16 (2005) 1583–1594
1593
C16H28N1P1O3S1Na1 m/z (M+Na) 368.1, and C16H28-
N1P1O3S1K1 m/z (M+K) 384.2. Found: C12H19N1S1
m/z (MꢀPO(OEt)2+H) 208.2 (100%), C16H29N1P1O3S1
m/z (M+H) 346.1 (50%), C16H28N1P1O3S1Na1 m/z
(M+Na) 368.2 (33%), and C16H28N1P1O3S1K1 m/z
(M+K) 384.2 (50%).
under N2 wasadded 0.5 mL of CH Cl2, Et3N (20 lL,
2
0.1428 mmol) followed by acetic anhydride (41 lL,
0.4284 mmol), and then another portion of Et3N
(40 lL, 0.2856 mmol). The reaction mixture wasstirred
for 1 h, then cooled to 0 ꢁC and boron trifluoride ether-
ate (146 lL, 1.1424 mmol) added via microliter syringe.
This solution was stirred for 30 min and then solid N-
hydroxysuccinimide (0.132 g, 1.1424 mmol) was added
followed by stirring for 1 h. At this time 1 mL of concd
NH4OH was added, the mixture transferred to a separ-
atory funnel and the aqueousphase extracted with three
4.10.3. Diethyl (1R)-2-(2-naphthalenesulfanyl)-1-{N-ben-
zylamino}ethylphosphonate 9h. Yield 79%; ½aŠ
20
D
¼
ꢀ81:2 (c 0.894, CHCl3); IR (TF) 3310, 3030,
2995, 2970, 1740, 1601, 1500, 1460, 1400, 1250, 1050,
;
1030, 970, 820, 750, 710 cmꢀ1
1H NMR (CDCl3): d
5 mL portionsof CH Cl2. The pooled organic phases
2
1.31 (t, J = 7.1 Hz, 3H, CH3CH2OP), 1.35 (t, J =
7.1 Hz, 3H, CH3CH2OP), 3.10–3.27 (m, 2H,
SCH2CHP), 3.56–3.63 (m, 1H, CHP), 3.95 (d,
J = 13.0 Hz, 1H, diastereotopic benzylic CH2), 4.08 (d,
J = 13.0 Hz, 1H, diastereotopic benzylic CH2), 4.10–
4.25 (m, 4H, CH3CH2OP), 7.17–7.50 (m, 8H, aromatic
H), 7.70–7.80 (m, 4H, aromatic H); 13C NMR (CDCl3):
d 16.45–16.54 (m, CH3CH2OP), 34.80 (SCH2CHP),
52.28 (d, JCNCHP = 3.7 Hz, benzylic CH2), 52.97 (d,
JCP = 153.8 Hz, CHP), 62.51 (d, JCOP = 7.2 Hz,
CH3CH2OP), 62.69 (d, JCOP = 7.2 Hz, CH3CH2OP),
125.93, 126.56, 127.13, 127.28, 127.63, 127.68, 128.21,
128.60, 128.61, 131.94, 132.33, 133.62; 31P NMR
(CDCl3): d 24.58. Positive ion ESMS: calculated:
C19H19N1S1 m/z (MꢀPO(OEt)2+H) 292.2, C23H29-
N1P1O3S1 m/z (M+H) 430.1, C23H28N1P1O3S1Na1 m/z
(M+Na) 452.1, and C23H28N1P1O3S1K1 m/z (M+K)
468.2. Found: C19H19N1S1 m/z (MꢀPO(OEt)2+H)
292.2 (100%), C23H29N1P1O3S1 m/z (M+H) 430.1
(40%), C23H28N1P1O3S1Na1 m/z (M+Na) 452.1 (20%),
and C23H28N1P1O3S1K1 m/z (M+K) 468.2 (25%).
were washed with brine, dried, filtered, and evaporated
in vacuo to afford 84 mg of the residue. This residue
waspurified by preparative islica TLC eluting with
EtOAc to afford (Rf 0.28) 0.043 g (69% yield) of the
20
D
N-acetyl 13 asan oil; ½aŠ ¼ ꢀ33:5 (c 0.860, CHCl3);
IR (TF) 3300, 3030, 3015, 2990, 2970, 1650, 1601,
1505, 1465, 1380, 1255, 1175, 1050 (br), 975, 801, 760,
715 cmꢀ1 1H NMR (CDCl3): d 1.31–1.42 (m, 6H,
;
CH3), 1.79 and 2.11 (s, 3H, acetyl CH3 rotomers),
2.69–2.81 (m, 2H), 2.95–3.48 (m, 4H), 3.56–3.71 (m,
1H), 3.79–3.86 (m, 1H, diastereotopic benzylic CH2),
4.00 (d, 1H, J = 13.5 Hz, diastereotopic benzylic CH2),
4.08–4.26 (m, 4H, POCH2), 7.08–7.36 (m, 10H, aromatic
H); 13C NMR (CDCl3): d 16.44–16.54 (m, CH3CH2OP),
21.16 and 21.91 (acetyl CH3), 33.52, 34.74, 45.82, 45.91,
47.64, 49.51, 49.61, 51.17, 51.83, 51.99, 52.50, 52.54,
52.75, 53.32, 53.41, 62.22–62.34 (m, CH3CH2OP),
126.19, 126.66, 126.99, 127.35, 128.24, 128.31, 128.38,
128.45, 128.51, 128.64. 128.68, 128.73, 137.95, 139.02,
139.21, 139.87, 170.91, and 171.47 (acetyl carbonyl);
31P NMR (CDCl3): d 26.06. Positive ion ESMS: calcu-
lated: C23H33N2P1O4 m/z (M+Na) 455.2; Found:
C23H33N2P1O4 m/z (M+Na) 455.2 (100%).
4.10.4. Diethyl (1S)-2-(2-naphthalenesulfanyl)-1-{N-ben-
zylamino}ethylphosphonate 10h. Yield 70%; ½aŠ
20
D
¼
þ83:6 (c 0.860, CHCl3); IR (TF) 3305, 3030,
2995, 2960, 1740, 1630, 1601, 1510, 1470, 1400, 1255,
Acknowledgements
1
1050 (br), 975, 830, 760, 720 cmꢀ1; H NMR (CDCl3):
d 1.33 (m, 3H, CH3CH2OP), 2.42 (br s, 1H, NH),
3.08–3.21 (m, 2H, SCH2CHP), 3.54–3.62 (m, 1H,
CHP), 3.91 (d, J = 13.0 Hz, 1H, diastereotopic benzylic
CH2), 4.04 (d, J = 13.0 Hz, 1H, diastereotopic benzylic
CH2), 4.12–4.24 (m, 4H, CH3CH2OP), 7.18–7.50 (m,
8H, aromatic H), 7.68–7.80 (m, 4H, aromatic H); 13C
NMR (CDCl3): d 16.46–16.52 (m, CH3CH2OP), 35.04
We gratefully acknowledge financial support by the
NIH (GM062139-01) and the American Association of
Collegesof Pharmacy Merck Research Scholar program
award to Brenda Kelly. We also appreciate the use of
the NMR and ESI-MS facilitiesat the Department of
Chemistry University of Wyoming and the purchase of
the polarimeter by the University of Wyoming College
of Health SciencesNIH BRIN (RR16474).
(d, J = 4.5 Hz, 2H, SCH2CHP), 52.44 (d, JCNCHP
=
4.5 Hz, benzylic CH2), 53.18 (d, JCP = 153.0 Hz,
CHP), 62.43 (d, JCOP = 7.2 Hz, CH3CH2OP), 62.58 (d,
JCOP = 7.3 Hz, CH3CH2OP), 125.90, 126.56, 127.11,
127.14, 127.63, 127.68, 128.16, 128.29, 128.44, 128.60,
131.92, 132.46, 133.62; 31P NMR (CDCl3): d 25.10.
Positive ion ESMS: calculated: C19H19N1S1 m/z
(MꢀPO(OEt)2+H) 292.2, C23H29N1P1O3S1 m/z (M+H)
430.1. Found: C19H19N1S1 m/z (MꢀPO(OEt)2+H)
292.2 (85%), C23H29N1P1O3S1 m/z (M+H) 430.1 (100%).
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