Asymmetric synthesis of α-aminophosphonate esters by the addition of dialkyl phosphites to tert-butanesulfinyl imines

Article abstract of DOI:10.1055/s-0033-1339712

The KHMDS-mediated addition of dialkyl phosphites to N-tert-butanesulfinyl aldimines and ketimines proceeds in uniformly high yields and diastereoselectivities and thereby enables the rapid and general asymmetric synthesis of α-aminophosphonate esters. Ge

Full text of DOI:10.1055/s-0033-1339712

PAPER
▌3147
paper
Asymmetric Synthesis of α-Aminophosphonate Esters by the Addition of
Dialkyl Phosphites to tert-Butanesulfinyl Imines
Asymmetric Synthesis of α-Aminophosphonate Esters
Hasan A. Khan, Jonathan A. Ellman*
Department of Chemistry, Yale University, New Haven, CT 06520, USA
E-mail: jonathan.ellman@yale.edu
Received: 13.07.2013; Accepted after revision: 13.08.2013
phosphonate 2a was obtained in reasonable yield and with
good diastereoselectivity.
Abstract: The KHMDS-mediated addition of dialkyl phosphites to
N-tert-butanesulfinyl aldimines and ketimines proceeds in uniform-
ly high yields and diastereoselectivities and thereby enables the rap-
id and general asymmetric synthesis of α-aminophosphonate esters.
RS
O
S
RS RL
O
S
(RO)2POH
conditions
RO
RO
Key words: asymmetric synthesis, imines, amines, phosphorus, in-
hibitors
RL
N
P
N
H
O
Scheme 1 Asymmetric synthesis of N-tert-butanesulfinyl α-amino-
phosphonate esters
The serine protease GlpG is the archetypal member of the
physiologically important rhomboid family of proteases
that perform proteolysis within the hydrophobic environ-
ment of a membrane.1 For the purpose of better under-
standing the molecular basis of substrate binding and
proteolysis of the rhomboid membrane proteases, we have
embarked on the synthesis of peptidyl phosphonate inhib-
itors for X-ray structural analysis of GlpG inhibitor com-
plexes.2 To prepare these peptidyl phosphonate inhibitors
it is first necessary to synthesize the enantiomerically pure
α-aminophosphonate ester precursors, for which several
methods have been reported due to the importance of this
mechanism-based protease inhibitor motif.3
Table 1 Optimization of Reaction Conditions
O
O
(EtO)2POH
EtO
EtO
S
S
P
N
N
H
THF, –78 °C
O
1a
2a
Entry
Basea
Concentration (M) drb
Yield (%)c
1
2
3
4
5
KHMDS
KHMDS
KHMDS
BuLi
0.10
20:1
74
80
95
19
62
0.050
0.025
0.025
0.025
30:1
49:1
6:1
We elected to synthesize the α-aminophosphonate esters
by the diastereoselective addition of dialkyl phosphites to
N-tert-butanesulfinyl imines (Scheme 1).4,5 However, re-
peated attempts to use the previously reported conditions
of K2CO3 as base and CH2Cl2 as solvent for additions to
N-tert-butanesulfinyl aldimines resulted in variable, but
consistently poor reaction conversions,6a presumably due
to the very poor solubility of K2CO3 in CH2Cl2. In con-
trast, multiple publications,7 including the seminal work
by Mikolajczyk7a,e and Davis,7c,d have reported that the
addition of dialkyl phosphites to analogous N-toluenesul-
finyl imines proceeds in high yields through the use of sol-
uble amide bases in THF with the additions performed at
low temperature to achieve high diastereoselectivity.
Herein, we report our adaptation of these procedures for
the asymmetric synthesis of N-tert-butanesulfinyl α-ami-
nophosphonate esters by the addition of dialkyl phos-
phites to N-tert-butanesulfinyl imines using KHMDS as
base in THF at –78 °C.
LHMDS
9:1
a One equiv of base and 1.3 equiv of (EtO)2POH were used.
b Measured by 31P NMR analysis of unpurified material.
c Based upon mass balance after purification by chromatography.
Moreover, the sense of induction was rigorously con-
firmed by cleavage of the sulfinyl group with HCl fol-
lowed by comparison of the optical rotation of the
resulting HCl salt of the α-aminophosphonate with the lit-
erature value.8 Further optimization was then accom-
plished by varying the reaction concentration, with
dilution of the reaction solution significantly improving
both the yield and diastereoselectivity (entries 2 and 3).
The more coordinating lithium counterion was next ex-
plored, but butyllithium (entry 4) or LHMDS (entry 5) as
base resulted in lower yields and selectivities.
The scope and generality for the additions of dialkyl phos-
phites to tert-butanesulfinyl imines were next explored
(Table 2). For each α-aminophosphonate addition product
2, authentic diastereomer mixtures were prepared accord-
ing to previously reported HCl-mediated sulfinyl group
cleavage and subsequent base-mediated resulfinylation
procedures for rigorous assignment of reaction diastereo-
selectivity.9
The addition of diethyl phosphite to sulfinyl imine 1a was
first explored at 0.1 M concentration using KHMDS in
THF at –78 °C (Table 1, entry 1). The diethyl α-amino-
SYNTHESIS 2013, 45, 3147–3150
Advanced online publication: 06.09.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1339712; Art ID: SS-2013-M0483-OP
© Georg Thieme Verlag Stuttgart · New York

3148
H. A. Khan, J. A. Ellman
PAPER
Table 2 Imine and Dialkylphosphite Substrate Scopea
demonstrating that dibenzyl phosphite additions are
equally effective to the more extensively studied dimethyl
phosphite additions.
RS
O
S
(RO)2POH
KHMDS
RS RL
O
S
RO
RO
RL
N
P
N
In summary, the addition of dialkyl phosphites to diverse
N-tert-butanesulfinyl imines 1 with KHMDS as base in
THF at –78 °C provides the desired α-aminophosphonate
esters 2 in uniformly high yields and diastereoselectivi-
ties. This procedure should prove generally useful for the
synthesis of α-aminophosphonates and related peptide de-
rivatives. We are currently applying this procedure to the
synthesis of mechanism-based peptidyl phosphonate in-
hibitors of the rhomboid membrane protease GlpG.
H
THF, –78 °C
O
Product
RL
RS
R
drb
Yield (%)c
2b
2c
2d
2e
2f
Me
i-Pr
i-Bu
Bn
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
Bn
Bn
Bn
Bn
49:1
24:1
49:1
20:1
49:1
12:1
99:1
99:1
20:1
30:1
99:1
95
91
95
92
96
86
94
90
88
96
91
2-MeOC6H4
4-MeC6H4
t-Bu
H
The N-tert-butanesulfinyl imines were all prepared according to
previously reported conditions.12 Commercial reagents were pur-
chased from Sigma-Aldrich or Alfa Aesar and were used as re-
ceived. All reactions were carried out under N2 atmosphere, unless
otherwise indicated. Reactions were monitored by TLC on EMD
Silica Gel 60 F254 plates or using an Agilent 6120 Quadrupole
LCMS. Visualization of the developed chromatogram was per-
formed by fluorescence quenching or staining with KMnO4 stain.
Organic solutions were concentrated under reduced pressure on a
Büchi rotary evaporator. 1H, 19F, 31P, and 13C NMR spectra were re-
corded on an Agilent Oxford AS400 NMR spectrometer. NMR
spectra were internally referenced to residual protio solvent signals.
2g
2h
2i
H
Me
H
Me
2j
i-Pr
H
2k
2l
Bn
H
t-Bu
Me
a One equiv of base and 1.3 equiv of (EtO)2POH were used.
b Measured by 31P NMR analysis of unpurified material.
c Based upon isolated yield of the major diastereomer after purifica-
tion by chromatography.
1
Data for H NMR spectra are reported as follows: chemical shift,
multiplicity (standard abbreviations), coupling constant (Hz), and
integration. Data for 13C NMR are reported in terms of chemical
shift (δ ppm). High-resolution mass spectra were recorded on an
Agilent 6550 iFunnel QTOF LCMS. IR spectra were collected on
an Agilent Cary 630 FTIR Spectrometer using diamond ATR. Col-
umn chromatography was performed using Silicycle Silica-P Flash
Silica Gel, using either glass columns or a Teledyne Isco Combi-
Flash Rf. All salts were purchased from Aldrich and used without
purification. Solvents were purchased from Brand-Nu Laboratories,
Inc. and were used as received.
Addition of dimethyl phosphite to N-sulfinyl aldimine 1a
provided α-aminophosphonate 2b in the same yield and
selectivity as observed for the addition of diethyl phos-
phite (see Table 1, entry 3). Moreover, dimethyl phosphite
additions to branched alkyl imines were also effective,
with α-branched product 2c and β-branched products 2d
and 2e each obtained in high yield and with high diaste-
reoselectivity. Even additions to electron-rich aromatic al-
dimines proceeded in high yields (2f and 2g). Notably, the
ortho-substituted N-sulfinyl benzaldimine gave product
2f with higher selectivity than that observed for the para-
substituted N-sulfinyl benzaldimine derivative 2g.
Addition of Dialkyl Phosphites to tert-Butanesulfinyl Imines;
General Procedure
To a flame-dried round-bottomed flask purged with N2 and
equipped with a magnetic stir bar was added THF (10 mL) and re-
spective tert-butanesulfinyl imine (0.5 mmol). This solution was
stirred and cooled to –78 °C in an acetone/dry ice bath. In another
flame-dried round-bottomed flask equipped with a magnetic stir
bar, was added the required phosphite (0.65 mmol, 1.3 equiv) and
THF (10 mL). This solution was cooled to –78 °C, and then a solu-
tion of KHMDS (0.91M in THF, 550 μL, 0.5 mmol, 1.0 equiv) was
added under N2 pressure. The KHMDS-phosphite solution was then
cannulated under N2 pressure into the imine solution and the result-
ing reaction mixture was stirred for 20 min at –78 °C. The reaction
was then quenched by the addition of sat. NH4Cl (1 mL), and the re-
action mixture was allowed to warm to r.t. The THF was removed
under reduced pressure. Crude diastereomeric ratios were ascer-
tained by 31P NMR with comparison to authentic diastereomer
mixture prepared according to previously reported desulfinyl-
ation/resulfinylation procedures.9 The crude material was purified
by silica gel chromatography to afford the desired N-sulfinyl α-ami-
nophosphonate esters as single diastereomers.
To evaluate the applicability of the method to sterically
encumbered substrates, dimethyl phosphite addition to the
ketimine derived from pinacolone was also explored.
Product 2h was obtained in very high yield and selectivi-
ty, and is consistent with the high selectivity previously
reported for dialkyl phosphite additions to N-toluenesulfi-
nyl ketimines.7c
Cleavage of both of the methyl groups from dimethyl α-
aminophosphonates requires strongly acidic reaction con-
ditions.10 Therefore, the preparation of dibenzyl α-amino-
phosphonates was also investigated because the benzyl
groups can be removed by hydrogenolysis under mild
conditions.11 The synthesis of dibenzyl α-aminophospho-
nates 2i to 2l proceeded in comparable yields and diaste-
reoselectivities to that previously observed for the
synthesis of the dimethyl α-aminophosphonates, thereby
Diethyl ((R)-1-{[(S)-tert-Butanesulfinyl]amino}ethyl)phospho-
nate (2a)
From (S,E)-N-ethylidene-2-methylpropane-2-sulfinamide (14 mg)
and diethyl phosphite (15 μL). Crude dr was determined to be 49:1.
The product was isolated as a colorless oil (27 mg, 95%) using a
Teledyne Isco RediSep Rf 4 g column. Solvent gradient: 20% to
100% acetone in hexanes, 18 mL/min, for 25 min.
Synthesis 2013, 45, 3147–3150
© Georg Thieme Verlag Stuttgart · New York

PAPER
Asymmetric Synthesis of α-Aminophosphonate Esters
3149
IR (ATR): 2961, 1452, 1232, 1028, 830 cm–1.
1H NMR (400 MHz, CDCl3): δ = 4.12–4.22 (m, 4 H), 3.64–3.73 (m,
2 H), 1.44 (dd, J = 20, 8 Hz, 3 H), 1.34 (t, J = 8 Hz, 6 H), 1.22 (s, 9
H).
31P NMR (162 MHz, CDCl3): δ = 25.6.
HRMS: m/z [M + H]+ calcd for C8H25NO4PS: 286.3502; found:
Dimethyl ((R)-1-{[(S)-tert-Butanesulfinyl]amino}-2-phenyl-
ethyl)phosphonate (2e)
From
(S,E)-2-methyl-N-(2-phenylethylidene)propane-2-sulfin-
amide (110 mg) and dimethyl phosphite (60 μL). Crude dr was de-
termined to be 20:1. The product was isolated as a white solid (153
mg, 92%) using a Teledyne Isco RediSep Rf 40 g column. Solvent
gradient: 20% to 100% acetone in hexanes, 40 mL/min, for 25 min;
mp 52–55 °C; [α]D20 +58.8 (c 1.7, CHCl3).
286.3522.
IR (ATR): 3181, 2949, 2846, 1456, 1363, 1247, 1233, 1072, 1033
cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.26–7.30 (m, 2 H), 7.19–7.22 (m,
3 H), 3.83 (d, J = 12 Hz, 3 H), 3.79 (d, J = 12 Hz, 3 H), 3.60 (t, J =
8 Hz, 1 H), 3.24 (ddd, J = 16, 8, 6 Hz, 1 H), 2.83–2.92 (m, 1 H), 0.95
(s, 9 H).
Diethyl (R)-(1-Aminoethyl)phosphonate8
To a round-bottomed flask containing 2a (54 mg) was added 4 M
HCl in 1,4-dioxane (250 μL, 1 mmol, 5 equiv), and the reaction
mixture was stirred at r.t. for 1 h. Volatiles were then removed under
reduced pressure, affording the deprotected aminophosphonate
quantitatively. Full characterization data are given in reference 8;
[α]D25 –5.3 (c 3.0, CHCl3) {Lit.8 [α]D –5.4 (c 1.8, CHCl3)}.
31P NMR (162 MHz, CDCl3): δ = 28.35.
HRMS: m/z [M + H]+ calcd for C12H25NOPS: 334.1241; found:
334.1236.
Dimethyl ((R)-1-{[(S)-tert-Butanesulfinyl]amino}ethyl)phos-
phonate (2b)
From (S,E)-N-ethylidene-2-methylpropane-2-sulfinamide (70 mg)
and dimethyl phosphite (60 μL). Crude dr was determined to be
49:1. The product was isolated as a colorless oil (124 mg, 95%) us-
ing a Teledyne Isco RediSep Rf 40 g column. Solvent gradient: 20%
to 100% acetone in hexanes, 40 mL/min, for 25 min; [α]D20 +69.8 (c
1.6, CHCl3).
IR (ATR): 2959, 1457, 1231, 1021, 826, 784 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.83 (d, J = 8 Hz, 3 H), 3.80 (d,
J = 8 Hz, 3 H) 3.71 (m, 2 H), 1.44 (dd, J = 16, 8 Hz, 3 H), 1.22 (s, 9
H).
31P NMR (162 MHz, CDCl3): δ = 28.1.
HRMS: m/z [M + H]+ calcd for C8H21NO4PS: 258.0929; found:
Dimethyl ((R)-{[(S)-tert-Butanesulfinyl]amino}(2-methoxyphe-
nyl)methyl)phosphonate (2f)
From (S,E)-2-methyl-N-(4-methoxybenzylidene)propane-2-sulfin-
amide (120 mg) and dimethyl phosphite (60 μL). Crude dr was de-
termined to be 49:1. The product was isolated as a white solid (167
mg, 96%) using a Teledyne Isco RediSep Rf 40 g column. Solvent
gradient: 20% to 100% acetone in hexanes, 40 mL/min, for 25 min;
mp 57–60 °C; [α]D20 +109.8 (c 0.8, CHCl3).
IR (ATR): 3168, 2953, 1493, 1462, 1235, 1062, 1022, 760 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.45 (dt, J = 6, 2 Hz, 1 H), 7.26–
7.30 (m, 1 H), 6.97 (t, J = 6 Hz, 1 H), 6.89 (d, J = 8 Hz, 1 H), 5.38
(dd, J = 16, 4 Hz, 1 H), 4.19 (dd, J = 6, 2 Hz, 1 H), 3.86 (s, 3 H),
3.81 (d, J = 8 Hz, 3 H), 3.52 (d, J = 8 Hz, 3 H), 1.19 (s, 9 H).
31P NMR (162 MHz, CDCl3): δ = 24.4.
HRMS: m/z [M + H]+ calcd for C14H25O5PS: 350.1191; found:
258.0974.
Dimethyl ((R)-1-{[(S)-tert-Butanesulfinyl]amino}-2-methylpro-
pyl)phosphonate (2c)6a
350.1190.
From (S,E)-2-methyl-N-(2-methylpropylidene)propane-2-sulfin-
amide (88 mg) and dimethyl phosphite (60 μL). Crude dr was deter-
mined to be 24:1. The product was isolated as an amorphous solid
(129 mg, 91%) using a Teledyne Isco RediSep Rf 40 g column. Sol-
vent gradient: 20% to 100% acetone in hexanes, 40 mL/min, for 25
min.
Dimethyl ((R)-{[(S)-tert-Butanesulfinyl]amino}(p-tolyl)meth-
yl)phosphonate (2g)6a
From (S,E)-2-methyl-N-(4-methylbenzylidene)propane-2-sulfin-
amide (110 mg) and dimethyl phosphite (60 μL). Crude dr was de-
termined to be 12:1. The product was isolated as a white solid (143
mg, 86%) using a Teledyne Isco RediSep Rf 40 g column. Solvent
gradient: 20% to 100% acetone in hexanes, 40 mL/min, for 25 min;
mp 28–30 °C; [α]D20 +112.1 (c 1.2, CHCl3).
IR (ATR): 2958, 1466, 1234, 1024, 827, 786 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.83 (d, J = 12 Hz, 3 H), 3.77 (d,
J = 12 Hz, 3 H) 3.70 (dd, J = 12 Hz, 8 Hz, 1 H), 3.44 (ddd, J = 20,
12, 4 Hz, 1 H), 2.17–2.24 (m, 1 H), 1.25 (s, 9 H), 0.99 (dd, J = 8, 4
Hz, 3 H), 0.97 (d, J = 8 Hz, 3 H).
31P NMR (162 MHz, CDCl3): δ = 27.44.
HRMS: m/z [M + H]+ calcd for C10H25NO4PS: 286.1242; found:
IR (ATR): 3220, 2957, 1579, 1457, 1362, 1021 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.37 (dd, J = 8, 2 Hz, 2 H), 7.19
(d, J = 8 Hz, 2 H), 5.01 (d, J = 8 Hz, 1 H), 3.72 (d, J = 12 Hz, 3 H),
3.67 (d, J = 12 Hz, 3 H), 2.35 (d, J = 2 Hz, 3 H), 1.23 (s, 9 H).
31P NMR (162 MHz, CDCl3): δ = 23.58.
286.1225.
HRMS: m/z [M + Na]+ calcd for C10H24NO4PS + Na: 356.1061;
found: 356.1044.
Dimethyl ((R)-1-{[(S)-tert-Butanesulfinyl]amino}-3-methylbu-
tyl)phosphonate (2d)
From
(S,E)-2-methyl-N-(3-methylbutylidene)propane-2-sulfin-
Dimethyl ((R)-2-{[(S)-tert-Butanesulfinyl]amino}-3,3-dimethyl-
butan-2-yl)phosphonate (2h)6a
amide (100 mg) and dimethyl phosphite (60 μL). Crude dr was de-
termined to be 49:1. The product was isolated as an amorphous
solid (142 mg, 95%) using a Teledyne Isco RediSep Rf 40 g col-
umn. Solvent gradient: 20% to 100% acetone in hexanes, 40
mL/min, for 25 min; [α]D20 +66.5 (c 1.8, CHCl3).
From (S,E)-N-(3,3-dimethylbutan-2-ylidene)-2-methylpropane-2-
sulfinamide (100 mg) and dimethyl phosphite (60 μL). Crude dr
was determined to be 99:1. The product was isolated as an amor-
phous solid (147 mg, 94%) using a Teledyne Isco RediSep Rf 40 g
column. Solvent gradient: 20% to 100% acetone in hexanes, 40
mL/min, for 25 min; [α]D20 +38.9 (c 0.9, CHCl3).
IR (ATR): 2954, 2869, 1469, 1258, 1231, 1023, 829, 807 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.85 (d, J = 8 Hz, 3 H), 3.79 (d,
J = 8 Hz, 3 H), 3.53–3.65 (m, 2 H), 1.77–1.83 (m, 1 H), 1.66 (m, 1
H), 1.56 (m, 1 H), 1.23 (s, 9 H), 0.94 (d, J = 8 Hz, 3 H), 0.89 (d, J =
8 Hz, 3 H).
IR (ATR): 2954, 1472, 1379, 1242, 1073, 1018, 827, 801 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.89 (d, J = 8 Hz, 1 H), 3.83 (d,
J = 8 Hz, 3 H), 3.77 (d, J = 8 Hz, 3 H), 1.54 (d, J = 16 Hz, 3 H), 1.22
(s, 9 H), 1.05 (s, 9 H).
31P NMR (162 MHz, CDCl3): δ = 28.5.
HRMS: m/z [M + H]+ calcd for C11H27NO4PS: 300.1400; found:
300.1381.
31P NMR (162 MHz, CDCl3): δ = 29.71.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3147–3150

3150
H. A. Khan, J. A. Ellman
PAPER
HRMS: m/z [M + H]+ calcd for C12H29NOPS: 314.1555; found:
314.1547.
1H NMR (400 MHz, CDCl3): δ = 7.25–7.42 (m, 10 H), 5.09–5.20
(m, 2 H), 4.90 (dd, J = 12, 8 Hz, 1 H), 4.77 (dd, J = 12, 8 Hz, 1 H),
4.12 (d, J = 8 Hz, 1 H), 1.61 (d, J = 16 Hz, 3 H), 1.26 (s, 9 H), 1.08
(s, 9 H).
31P NMR (162 MHz, CDCl3): δ = 28.35.
HRMS: m/z [M + Na]+calcd for C24H36NOPS + Na: 488.2000;
Dibenzyl ((R)-1-{[(S)-tert-Butanesulfinyl]amino}ethyl)phos-
phonate (2i)
From (S,E)-N-ethylidene-2-methylpropane-2-sulfinamide (70 mg)
and dibenzyl phosphite (140 μL). Crude dr was determined to be
99:1. The product was isolated as a colorless oil (184 mg, 90%) us-
ing a Teledyne Isco RediSep Rf 40 g column. Solvent gradient: 20%
to 100% EtOAc in hexanes, 40 mL/min, for 25 min; [α]D20 +35.8 (c
1.1, CHCl3).
found: 488.1999.
Acknowledgment
IR (ATR): 3449, 2955, 1455, 1228, 989, 733, 695 cm–1.
This work was supported by the NSF (CHE-1049571). We also
thank Dr. Hai-chao Xu for helpful suggestions and initial experi-
ments.
1H NMR (400 MHz, CDCl3): δ = 7.31–7.37 (m, 10 H), 4.95–5.14
(m, 4 H), 3.69–3.73 (m, 2 H), 1.42 (dd, J = 20, 8 Hz, 3 H), 1.17 (s,
9 H).
31P NMR (162 MHz, CDCl3): δ = 26.60.
HRMS: m/z [M + H]+ calcd for C20H29NO4PS: 410.1555; found:
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
410.1553.
Dibenzyl ((R)-1-{[(S)-tert-Butanesulfinyl]amino}-2-methylpro-
pyl)phosphonate (2j)
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gradient: 20% to 100% EtOAc in hexanes, 40 mL/min, for 25 min;
[α]D20 +30.4 (c 0.4, CHCl3).
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(7) (a) Mikołajczyk, M.; Łyżwa, P.; Drabowicz, J. Tetrahedron:
Asymmetry 1997, 8, 3991. (b) Lefebvre, I. M.; Evans, S. A.
J. Org. Chem. 1997, 62, 7532. (c) Davis, F. A.; Lee, S.; Yan,
H.; Titus, D. D. Org. Lett. 2001, 3, 1757. (d) Davis, F. A.;
Prasad, K. R. J. Org. Chem. 2003, 68, 7249. (e) Łyżwa, P.;
Błaszczyk, J.; Sieroń, L.; Mikołajczyk, M. Eur. J. Org.
Chem. 2013, 2106.
IR (ATR): 2961, 1456, 1232, 1010, 990, 727, 695 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.28–7.40 (m, 10 H), 5.13–5.15
(m, 2 H), 4.97 (dd, J = 12, 8 Hz, 1 H), 4.85 (dd, J = 12, 8 Hz, 1 H),
3.90 (dd, J = 10, 8 Hz, 1 H), 3.48 (ddd, J = 16, 8, 2 Hz, 1 H), 2.22
(m, 1 H), 1.26 (s, 9 H), 0.97 (d, J = 4 Hz, 3 H), 0.96 (dd, J = 8, 2 Hz,
3 H).
31P NMR (162 MHz, CDCl3): δ = 26.00.
HRMS: m/z [M + H]+ calcd for C22H33NO4PS: 438.1868; found:
438.1835.
Dibenzyl ((R)-1-{[(S)-tert-Butanesulfinyl]amino}-2-phenyl-
ethyl)phosphonate (2k)
From
(S,E)-2-methyl-N-(2-phenylethylidene)propane-2-sulfin-
amide (110 mg) and dibenzyl phosphite (140 μL). Crude dr was de-
termined to be 30:1. The product was isolated as a light yellow oil
(232 mg, 96%) using a Teledyne Isco RediSep Rf 40 g column. Sol-
vent gradient: 20% to 100% acetone in hexanes, 40 mL/min, for 25
min; [α]D20 +38.6 (c 0.7, CHCl3).
IR (ATR): 3175, 2920, 1455, 1239, 988, 736, 696 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.13–7.37 (m, 15 H), 5.13–5.10
(m, 2 H), 4.92 (ddd, J = 36, 12, 8 Hz, 2 H), 3.79–3.88 (m, 1 H), 3.65
(t, J = 8 Hz, 1 H), 3.21 (ddd, J = 12, 8, 4 Hz, 1 H), 2.82–2.91 (m, 1
H), 0.95 (s, 9 H).
31P NMR (162 MHz, CDCl3): δ = 25.62.
HRMS: m/z [M + H]+ calcd for C26H33NOPS: 486.1868; found:
486.1843.
Dibenzyl ((R)-2-{[(S)-tert-Butanesulfinyl]amino}-3,3-dimethyl-
butan-2-yl)phosphonate (2l)6a
(8) Smith, A. B.; Yager, K. M.; Taylor, C. M. J. Am. Chem. Soc.
1995, 117, 10879.
(9) Brak, K.; Barrett, K. T.; Ellman, J. A. J. Org. Chem. 2009,
74, 3606.
(10) Soroka, M.; Zygmunt, J. Synthesis 1988, 301.
(11) Verbrugghen, T.; Vandurm, P.; Pouyez, J.; Maes, L.;
Wouters, J.; Van Calenbergh, S. J. Med. Chem. 2013, 56,
376.
(12) Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J.
A. J. Org. Chem. 1999, 64, 1278.
From (S,E)-N-(3,3-dimethylbutan-2-ylidene)-2-methylpropane-2-
sulfinamide (100 mg) and dibenzyl phosphite (140 μL). Crude dr
was determined to be 99:1. The product was isolated as a light yel-
low oil (205 mg, 91%) using a Teledyne Isco RediSep Rf 40 g col-
umn. Solvent gradient: 20% to 100% EtOAc in hexanes, 40
mL/min, for 25 min.
IR (ATR): 2957, 1455, 1379, 1240, 1213, 1072, 986, 732, 695 cm–1.
Synthesis 2013, 45, 3147–3150
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