Asymmetric hydrophosphylation of chiral n-phosphonyl imines provides an efficient approach to chiral α-amino phosphonates

Article abstract of DOI:10.1111/j.1747-0285.2010.01013.x

Chiral N-phosphonylimines were found to react with lithium phosphites to provide various substituted chiral α-amino phosphonates in excellent yields (94-97%) and diastereoselectivities (93:7-99:1). The types of bases utilized for generating the nucleophil

Full text of DOI:10.1111/j.1747-0285.2010.01013.x

ª 2010 John Wiley & Sons A/S
doi: 10.1111/j.1747-0285.2010.01013.x
Chem Biol Drug Des 2010; 76: 314–319
Research Article
Asymmetric Hydrophosphylation of Chiral
N-Phosphonyl Imines Provides an Efficient
Approach to Chiral a-Amino Phosphonates
N-tert-butylsulfinyl-imines is a particularly useful approach to syn-
Parminder Kaur, Walter Wever, Trideep
Rajale and Guigen Li*
thesizing a-aminophosphonates (23,31). Although great progress has
been made on asymmetric catalysis, the development of chiral
imine-based methodologies is still highly demanded for practical
synthesis on larger scale.
Department of Chemistry and Biochemistry, Texas Tech University,
Lubbock, TX 79409-1061, USA
*Corresponding author: Guigen Li, guigen.li@ttu.edu
In the past several years, our group has been focusing on the
asymmetric addition of different nucleophiles to chiral N-phosphonyl
imines for synthesizing useful chiral amino products in good yields
and excellent diastereoselectivity (32–43). In continuation of our
work on chiral N-phosphonyl imine chemistry, we would like to
report herein a new asymmetric carbon–phosphorus bond formation
via the addition of diethyl phosphite onto chiral N-phosphonyl imines.
Chiral N-phosphonylimines were found to react
with lithium phosphites to provide various substi-
tuted chiral a-amino phosphonates in excellent
yields (94–97%) and diastereoselectivities (93:7–
99:1). The types of bases utilized for generating
the nucleophile are crucial for the effectiveness of
asymmetric induction. In addition, N,N-isopropyl
group on chiral N-phosphonylimine auxilliary was
proven to be superior to other protecting groups
in controlling diastereoselectivity. The absolute
configuration was unambiguously determined by
converting a chiral a-amino phosphonate into its
authentic N-Cbz derivative.
Experimental Section
General remarks: experimental section
General methods
All commercially available solvents, unless otherwise mentioned,
were used without purification. THF was distilled from sodium ⁄ ben-
zophenone ketyl. All the glasswares used were dried overnight at
100 ꢀC. All the melting points are uncorrected. The Nuclear mag-
netic resonance (NMR) spectra were recorded at 500, 125, 202 MHz
Key words: N-phosphonyl imine, chiral a-amino phosphonates
Received 7 May 2010, revised 8 June 2010 and accepted for publica-
tion 12 June 2010
1
for H, 13C, and 31P, respectively. Shifts are reported in ppm based
1
Organophosphorus compounds comprise an important family of ana-
logues, among which a-aminophosphonates are particularly useful
precursors of aminophosphonic acids and have been found to pos-
sess various important biological properties (1–11). These properties
can suppress bacterial and viral growth and enhance cellular mem-
brane transport, such as inactivating D-Ala ligase for peptidoglycan
synthesis (1–5). Aminophosphonic acids can act as HIV protease
inhibitors (1,6,7,12) and antiproliferative viral agents for tumor cells
(13,14). Also, the aminophosphonic acids can increase the perme-
ability of phospholipid bilayer membranes to alanine by serving as
carrier molecules (15). In addition, these compounds can also act as
chemical catalysts serving for asymmetric reactions for the synthe-
sis of chiral a-aminophosphonates, which has attracted considerable
attention recently (16–19). Various methods, such as diastereoselec-
tive addition of phosphite derivatives to chiral imines, (20–23) chi-
ral Lewis acid-catalyzed enantioselective addition of phosphites
to imines, (24–28) and several other methods for the synthesis
of a-aminophosphonates, have been reported (29–31). Among
the above methods, the use of chiral N-p-tolylsulfinylimines and
on an internal TMS standard (for H ⁄ CDCl3) or on residual solvent
peaks (for 13C ⁄ CDCl3). 31P NMR spectra were referenced to external
H3PO4 (0.00 ppm). Diethyl phosphite, 1.0 M solution of LiHMDS,
LDA, n-BuLi, t-BuLi were received from Aldrich and used as obtained
from commercial sources without any further purification.
Typical procedure for the synthesis of
N-phosphonyl-substituted a-amino
phosphonates using chiral N-phosphonyl imines
and diethyl phosphite
In a dry vial, under inert gas protection, diethyl phosphite 7
(1.5 mmol) was dissolved in 3 mL of THF. The vial was cooled to
)78 ꢀC and into the resulting solution LiHMDS (1.5 M in THF,
1.5 mmol) was added dropwise. The reaction solution was stirred
at )78 ꢀC for 15 min and corresponding chiral N-phosphonyl imine
(1.00 mmol in 3 mL THF) was added to the reaction mixture at
)78 ꢀC. The reaction mixture was stirred for another 2 h before it
was quenched by adding saturated ammonium chloride solution
314

Asymmetric Hydrophosphylation of Chiral N-Phosphonyl Imines
followed by 6 mL of water. The reaction mixture was then extracted
(m, 1H), 3.44–3.38 (m, 1H), 3.27–3.19 (m, 1H), 2.91 (t, J = 7.0 Hz,
1H), 2.67 (t, J = 7.0 Hz, 1H), 2.05 (d, J = 6.5 Hz, 1H), 1.93 (d,
J = 7.5 Hz, 1H), 1.73–1.65 (m, 2H), 1.29 (t, J = 7.0 Hz, 7H), 1.19 (d,
J = 6.5 Hz, 6H), 1.00 (t, J = 7.0 Hz, 3H), 0.92 (d, J = 10.0 Hz, 3H),
0.64 (d, J = 6.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) d 161.2 (d,
J = 6.0 Hz), 159.2 (d, J = 5.8 Hz), 129.7, 129.4 (d, J = 7.8 Hz), 124.2
(d, J = 6.5 Hz), 115.4 (t, J = 22.3 Hz), 63.2 (d, J = 6.8 Hz), 62.5 (dd,
J = 6.8, 13.2 Hz), 60.1 (d, J = 10.8 Hz), 59.6 (d, J = 10.8 Hz), 58.9
(t, J = 4.8 Hz), 43.8 (dd, J = 12.3, 28.5 Hz), 31.3 (t, J = 10.7 Hz),
30.8 (t, J = 9.3 Hz), 24.3 (d, J = 11.3 Hz), 23.5 (d, J = 7.3 Hz), 23.2,
23.0 (dd, J = 3.5, 13.3 Hz), 19.8, 19.5 (d, J = 8.3 Hz), 19.2, 16.3 (d,
J = 6.0 Hz), 16.1 (d, J = 5.4 Hz). HRMS (ESI): m ⁄ z calcd for,
C23H41BrN3O4P2, 564.1751, found: 564.1760.
with 2 · 10 mL of ethyl acetate. Combined organic layers were
washed with water (1 · 20 mL), dried over anhydrous sodium sul-
fate. Sodium sulfate was filtered off, and the organic layer was
evaporated to obtain the desired product as pale yellow solid,
which on washing with hexanes gave pure product as white solid.
Compound 13a. White solid; yield (0.211 g, 97%); mp 184–186 ꢀC;
25
½aꢀD = )9.5ꢀ (c 1.00, CHCl3); 1H NMR (500 MHz, CDCl3) d 7.43–
7.41(m, 2H), 7.31 (t, J = 8.0 Hz, 2H), 7.25 (t, J = 7.5 Hz, 1H), 4.18–
4.67 (m, 1H), 4.17–4.01 (m, 2H), 3.84–3.77 (m, 1H), 3.56–3.43 (m,
2H), 3.18–2.99 (m, 2H), 2.93–2.87 (m, 1H), 2.73–2.71 (m, 1H), 2.01–
1.93 (m, 3H), 1.72 (d, J = 6.5 Hz, 2H), 1.31 (t, J = 7.5 Hz, 8H), 1.13
(dd, J = 6.5, 20.0 Hz, 3H), 1.03–0.886 (m, 10H); 13C NMR (125 MHz,
CDCl3) d 138.2, 137.9, 128.4–128.3 (m, 2C), 128.1 (d, J = 5.8 Hz),
127.7, 63.1 (d, J = 6.8 Hz), 62.1 (dd, J = 7.3, 18.2 Hz), 59.9 (d,
J = 10.8 Hz), 58.9 (t, J = 10.3 Hz), 54.1, 52.9, 43.8 (dd, J = 12.3,
28.5 Hz), 31.4 (t, J = 11.8 Hz), 30.8 (t, J = 9.3 Hz), 24.3 (d,
J = 6.3 Hz), 23.5 (d, J = 7.8 Hz), 23.0 (dd, J = 4.0 Hz), 22.8 (d,
J = 3.5 Hz), 19.8, 19.4, 16.3 (d, J = 6.5 Hz), 16.1 (t, J = 4.0 Hz).
Compound 13e. White semi-solid; yield (0.334 g, 96%);
25
1
½aꢀD = )4.10ꢀ (c 1.00, CHCl3); H NMR (500 MHz, CDCl3) d 7.46 (t,
J = 9.0 Hz, 1H), 7.18 (t, J = 6.5 Hz, 1H), 7.11 (t, J = 8.0 Hz, 2H),
5.09–4.98 (m, 1H), 4.14–4.02 (m, 2H), 3.79–3.71 (m, 1H), 3.46–3.35
(m, 2H), 3.31–3.25 (m, 1H), 3.11–3.02 (m, 1H), 2.90–2.85 (m, 1H),
2.70–2.66 (m, 1H), 2.45 (s, 3H), 2.00 (t, J = 13.5 Hz, 2H), 1.72 (d,
J = 7.5 Hz, 2H), 1.33–1.19 (m, 8H), 1.10 (d, J = 7.0 Hz, 2H), 1.02–
0.95 (m, 12H); 13C NMR (125 MHz, CDCl3) d 156.3, 136.7, 136.1,
130.1, 127.5, 126.0, 63.2 (d, J = 7.0 Hz), 62.1 (d, J = 7.3 Hz), 59.7
(d, J = 11.3 Hz), 58.8 (t, J = 9.8 Hz), 43.8 (d, J = 5.3 Hz), 43.7 (d,
J = 3.8 Hz), 31.6, 31.5, 30.9, 30.8 (t, J = 9.3 Hz), 24.3 (d,
J = 8.3 Hz), 23.7 (d, J = 7.8 Hz), 23.0 (d, J = 3.3 Hz), 19.7, 19.4,
19.1, 16.3 (d, J = 6.0 Hz), 16.0 (d, J = 5.3 Hz).
Compound 13b. White solid; yield (0.382 g, 96%); mp 186–188 ꢀC;
25
½aꢀD = )5.80ꢀ (c 1.00, CHCl3); 1H NMR (500 MHz, CDCl3) d 7.58
(d, J = 7.5 Hz, 1H), 7.34–7.31 (m, 1H), 7.27 (t, J = 10.0 Hz, 1H),
7.19 (t, J = 10.5 Hz, 1H), 5.39–5.05 (m, 1H), 4.19–4.07 (m, 2H),
3.84–3.76 (m, 1H), 3.58–3.46 (m, 2H), 3.32–3.17 (m, 1H), 2.96–2.85
(m, 1H), 2.07–1.89 (m, 3H), 1.72 (bs, 2H), 1.33–1.21 (m, 8H), 1.16–
1.12 (m, 7H), 1.05–1.01 (m, 4H), 0.98 (d, J = 9.5 Hz, 2H), 0.74 (d,
J = 6.5 Hz, 1H), 0.36 (d, J = 7 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d 136.3, 133.5, 129.5 (d, J = 3.5 Hz), 129.0 (d, J = 1.5 Hz), 128.9 (t,
J = 3.0 Hz), 127.0, 63.1 (d, J = 6.8 Hz), 62.8 (d, J = 6.8 Hz), 60.2
(d, J = 10.8 Hz), 59.5 (d, J = 11.8 Hz), 44.1 (d, J = 17.2 Hz), 43.6 (d,
J = 3.5 Hz), 31.4 (d, J = 11.8 Hz), 31.1 (d, J = 8.3 Hz), 24.3
(d, J = 14.7 Hz), 23.7 (t, J = 14.7 Hz), 22.7 (d, J = 9.3 Hz), 20.1 (d,
J = 2.5 Hz), 19.5, 19.3, 18.8, 16.3 (d, J = 6.0 Hz), 16.0
(d, J = 5.5 Hz).
Compound 13f. White solid; yield (0.198 g, 91%); mp 196 ꢀC;
25
1
½aꢀD = )3.7ꢀ (c 1.70, CHCl3); H NMR (500 MHz, CDCl3) d 7.39–
7.36 (m, 2H), 6.98 (t, J = 8.5 Hz, 2H), 4.78–4.66 (m, 1H), 4.14–3.99
(m, 2H), 3.84–3.76 (m, 1H), 3.58–3.40 (m, 2H), 3.11–3.05 (m, 1H),
3.01–2.91 (m, 1H), 2.90–2.82 (m, 1H), 2.68 (t, J = 9.0 Hz, 1H), 1.97
(d, J = 10.0, 2H), 1.69 (d, J = 7.5 Hz, 2H), 1.28 (t, J = 7.0 Hz, 8H),
1.11 (d, J = 6.5 Hz, 4H), 1.02–0.97 (m, 5H), 0.94–0.87 (m, 5H); 13C
NMR (125 MHz, CDCl3) d 163.7, 161.3, 134.2 (t, J = 1.8 Hz), 130.0
(d, J = 6.3 Hz), 115.2 (d, J = 4.0 Hz), 115.0 (d, J = 4.0 Hz), 63.2 (dd,
J = 2.3, 6.8 Hz), 62.4 (d, J = 7.3Hz), 59.7 (d, J = 11.3 Hz), 58.7 (d,
J = 9.8 Hz), 53.4 (d, J = 36.0 Hz), 52.2 (d, J = 37.5 Hz), 43.7 (dd,
J = 8.8, 30.6 Hz), 31.3 (t, J = 12.8 Hz), 30.7 (dd, J = 9.8, 25.6 Hz),
24.1 (d, J = 6.0 Hz), 23.4 (dd, J = 7.8, 31.8 Hz), 23.3 (dd, J = 4.3,
33.7 Hz), 19.7, 19.4 (d, J = 1.5 Hz), 19.3, 16.2 (d, J = 6.5 Hz), 16.0
(t, J = 5.8 Hz). HRMS (ESI): m ⁄ z calcd for, C23H41FN3O4P2, 504.2551,
found: 504.2569.
Compound 13c. White solid; yield (0.220 g, 98%); mp 188 ꢀC;
25
½aꢀD = )5.1ꢀ (c 1.30, CHCl3); 1H NMR (500 MHz, CDCl3) d 7.48
(t, J = 6.5 Hz, 1H), 7.24 (t, J = 6.5 Hz, 1H), 7.13 (t, J = 7.5 Hz, 1H),
7.02 (t, J = 9.0 Hz, 1H), 5.18–4.95 (m, 1H), 4.19–4.06 (m, 2H), 3.92–
3.84 (m, 1H), 3.69–3.66 (m, 1H), 3.46–3.28 (m, 2H), 3.20–3.15 (m,
1H), 2.92–2.88 (m, 1H), 2.03–1.95 (m, 4H), 1.73 (bs, 2H), 1.30 (t,
J = 7.0 Hz, 7H), 1.19 (d, J = 6.5 Hz, 2H), 1.12–1.01 (m, 12H); 13C
NMR (125 MHz, CDCl3)
d 161.2 (d, J = 6.0 Hz), 159.2 (d,
J = 5.8 Hz), 129.7, 129.4 (d, J = 7.8 Hz), 124.2 (d, J = 6.5 Hz), 115.4
(t, J = 22.3 Hz), 63.2 (d, J = 6.8 Hz), 62.5 (dd, J = 6.8, 13.2 Hz),
60.1 (d, J = 10.8 Hz), 59.6 (d, J = 10.8 Hz), 58.9 (t, J = 4.8 Hz), 43.8
(dd, J = 12.3, 28.5 Hz), 31.3 (t, J = 10.7 Hz), 30.8 (t, J = 9.3 Hz),
24.3 (d, J = 11.3 Hz), 23.5 (d, J = 7.3 Hz), 23.2, 23.0 (dd, J = 3.5,
13.3 Hz), 19.8, 19.5 (d, J = 8.3 Hz), 19.2, 16.3 (d, J = 6.0 Hz), 16.1
(d, J = 5.4 Hz). HRMS (ESI): m ⁄ z calcd for, C23H41FN3O4P2,
504.2551, found: 504.2569.
Compound 13g. White solid; yield (0.209 g, 95%); mp 198 ꢀC;
25
1
½aꢀD = )5.9ꢀ (c 1.10, CHCl3); H NMR (500 MHz, CDCl3) d 7.45 (d,
J = 8.0 Hz, 2H), 7.32–7.29 (m, 2H), 4.80–4.66 (m, 1H), 4.20–4.01 (m,
2H), 3.89–3.81(m, 1H), 3.65–3.55 (m, 1H), 3.53–3.44 (m, 2H), 3.11–
2.95 (m, 1H), 2.93–2.86 (m, 1H), 2.71 (t, J = 8.5 Hz, 1H), 2.00 (d,
J = 9.5, 2H), 1.72 (d, J = 7.5 Hz, 2H), 1.30 (t, J = 7.0 Hz, 6H), 1.24
(d, J = 6.5 Hz, 2H), 1.13 (t, J = 6.5 Hz, 3H), 1.06 (q, J = 7.0 Hz, 3H),
1.02 (d, J = 6.5 Hz, 2H), 0.98 (d, J = 7.0 Hz, 2H), 0.948–0.928 (m,
4H); 13C NMR (125 MHz, CDCl3) d 137.4 (d, J = 5.3 Hz), 131.4(2C),
130.1 (d, J = 6.0 Hz), 129.8 (d, J = 6.0 Hz), 121.7 (t, J = 3.0 Hz),
63.2 (dd, J = 3.0, 6.8 Hz), 62.4 (dd, J = 7.3, 21.0 Hz), 59.7 (dd,
J = 10.8, 29.0 Hz), 58.8 (d, J = 10.3, 20.0 Hz), 53.7 (d, J = 36.0 Hz),
52.5 (d, J = 37.5 Hz), 43.7 (dd, J = 8.8, 38.0 Hz), 31.4 (t,
Compound 13d. Thick yellow oil; yield (0.217 g, 96%); 1H NMR
(500 MHz, CDCl3) d 7.48 (t, J = 6.5 Hz, 1H), 7.24 (t, J = 6.5 Hz, 1H),
7.13 (t, J = 7.5 Hz, 1H), 7.02 (t, J = 9.0 Hz, 1H), 5.18–4.95 (m, 1H),
4.19–4.06 (m, 2H), 3.78–3.72 (m, 1H), 3.67–3.59 (m, 1H), 3.54–3.47
Chem Biol Drug Des 2010; 76: 314–319
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Kaur et al.
J = 10.8 Hz), 30.7 (dd, J = 9.8, 25.6 Hz), 24.2 (d, J = 5.5 Hz), 23.4
(dd, J = 7.3, 31.8 Hz), 23.3 (dd, J = 7.8, 36.7 Hz), 19.7, 19.5 (d,
J = 1.5 Hz), 19.4, 16.3 (d, J = 6.0 Hz), 16.1 (t, J = 5.5 Hz). HRMS
(ESI): m ⁄ z calcd for, C23H41BrN3O4P2, 564.1751, found: 564.1760.
the reaction was indicated by the disappearance of the starting
material on TLC. Volatiles were evaporated under vacuum and then
dichloromethane was added to the solid residue followed by the
addition of 5% NaHCO3. The reaction was brought to 0 ꢀC and
CbzCl was added. The reaction was allowed to stir at room temper-
ature for 5 h. After the completion, the resulting reaction mixture
was extracted with water and dichloromethane. The organic layer
was dried over sodium sulfate. Sodium sulfate was filtered off, and
the organic layer was dried under vacuum to get the product, which
was then washed with hexanes to obtain the pure product 14 as a
Compound 13h. White solid; yield (0.217 g, 96%); mp 164 ꢀC;
25
1
½aꢀD = )8.9ꢀ (c 1.00, CHCl3); H NMR (500 MHz, CDCl3) d 7.31–
7.28 (m, 2H), 7.13–7.10 (m, 2H), 4.78–4.64 (m, 1H), 4.16–4.01 (m,
2H), 3.85–3.80 (m, 1H), 3.58–3.44 (m, 2H), 3.14–3.03 (m, 2H), 2.94–
2.87 (m, 1H), 2.73–2.71 (m, 1H), 2.31 (s, 3H), 2.01 (d, J = 10.5, 2H),
1.73 (bs, 2H), 1.31 (t, J = 7.0 Hz, 6H), 1.12 (d, J = 7.0 Hz, 2H), 1.13
(d, J = 6.5 Hz, 2H), 1.09 (d, J = 6.5 Hz, 2H), 1.04 (q, J = 7.0 Hz,
5H), 0.98 (d, J = 6.5 Hz, 1H), 0.95–0.89 (m, 4H); 13C NMR
(125 MHz, CDCl3) d 137.43 (d, J = 13.5 Hz), 135.1, 129.0 (d,
J = 7.5 Hz), 128.9 (d, J = 7.5 Hz), 128.2, 128.0, 63.2 (d, J = 6.3 Hz),
62.1 (d, J = 7.3 Hz), 59.6 (d, J = 11.3 Hz), 58.8 (d, J = 10.3 Hz),
53.8, 52.6, 43.7 (dd, J = 3.5, 28.6 Hz), 31.4 (t, J = 11.8 Hz), 30.8 (t,
J = 8.8 Hz), 24.3 (d, J = 7.3 Hz), 23.6 (d, J = 7.8 Hz), 23.3
(d, J = 7.8 Hz), 22.9 (d, J = 3.5 Hz), 21.1, 19.8, 19.5, 16.3 (d,
J = 6.3 Hz), 16.1 (d, J = 3.8 Hz).
25
thick colorless oil, (0.234 g, 92%); ½aꢀD = 8.9ꢀ (c 1.30, CHCl3),
25
reported ½aꢀD = 10.6ꢀ (in CHCl3).20a10.0 (c 0.74, CHCl3)
Results and Discussion
The chiral N-phosphonyl imine 1 attached to N-benzyl group was
initially employed as the electrophile (Scheme 1). The lithium phos-
phite was generated in situ by treating diethyl phosphite 7 with
LiHMDS in THF at )78 ꢀC for <15 min. Into the resulting mixture,
chiral N-phosphonyl imine 1, dissolved in THF, was slowly added.
The reaction was stirred at )78 ꢀC for 2 h and constantly moni-
tored by TLC (hexane:EtOAc, 2:8, v ⁄ v) before it was quenched with
saturated ammonium chloride solution. The product 8 was isolated
in good yield (85%) although modest diastereoselectivity (dr =
73:27) was observed.
Compound 13i. White solid; yield (0.217 g, 96%); mp 186 ꢀC;
25
1
½aꢀD = )15.6ꢀ (c 0.50, CHCl3); H NMR (500 MHz, CDCl3) d 7.35–
7.33 (m, 2H), 6.86–6.84 (m, 2H), 4.76–4.66 (m, 1H), 4.16–4.02 (m,
2H), 3.86–3.81 (m, 1H), 3.79 (s, 3H), 3.57–3.44 (m, 2H), 3.11–3.01
(m, 1H), 2.93–2.87 (m, 1H), 2.71 (t, J = 7.0 Hz, 1H), 2.01–1.99 (m,
2H), 1.76–1.74 (m, 3H), 1.31 (t, J = 7.0 Hz, 8H), 1.12 (dd, J = 7.0,
11.5 Hz, 5H), 1.06–1.02 (m, 5H), 0.94 (m, 4H); 13C NMR (125 MHz,
CDCl3) d 159.2 (d, J = 3.0 Hz), 130.3, 129.5 (d, J = 6.3 Hz), 129.3
(d, J = 6.3 Hz), 113.7 (d, J = 2.0 Hz), 113.6 (d, J = 2.0 Hz), 63.1 (d,
J = 7.0 Hz), 62.1 (d, J = 7.5 Hz), 59.6 (d, J = 10.8 Hz), 58.8 (d,
J = 9.8 Hz), 55.2, 53.4, 52.2, 43.8 (d, J = 4.3Hz), 43.7 (d, J = 4.5Hz),
31.5 (t, J = 11.8 Hz), 30.6 (t, J = 9.3 Hz), 24.3 (d, J = 6.8 Hz), 23.7
(d, J = 7.8 Hz), 22.8 (d, J = 3.3 Hz), 19.5, 19.4 (d, J = 1.5 Hz), 16.3
(d, J = 6.3 Hz), 16.2 (d, J = 5.8 Hz).
Next, we explored different bases and their effects on both the
yield and diastereoselectivity. It was found that NaHMDS and
KHMDS resulted in poor diastereoselectivity of dr = 60:40 (for Na)
and dr = 55:45 (for K), respectively. The use of Lithium diisopropyla-
mide (LDA) did not improve diastereoselectivity (dr = 55:45) either.
In addition, the use of n-BuLi and t-BuLi did not bring any improve-
ments. Based on these observations, LiHMDS was thus chosen as
the best base.
The effects of different N, N'-R groups on chiral N-phosphonyl aux-
iliary (Scheme 2) were then studied. These protecting groups
include benzyl, iso-butyl, neo-pentyl, CH2-1-naphthyl, cyclopentyl,
and iso-propyl groups. As shown in Table 1, iso-propyl group-pro-
tected chiral N-phosphonyl imines showed high chemical yields of
97% and excellent diastereoselectivities (dr 99:1) (Table 1, entry 6)
Procedure for the removal of auxiliary and
synthesis of N-Cbz derivative
Into a 50-mL round bottom flask, 0.438 g of product 13a was dis-
solved in 6.0 mL of methanol. To this solution, 3 N HCl (8.0 equiva-
lent) was added at 0 ꢀC and the reaction was stirred at 0 ꢀC for
30 min and then at room temperature for 2 h. The reaction was
monitored by thin-layer chromatography (TLC), and completion of
1
as determined by H-NMR analysis of crude products. CH2-1-naph-
thyl group showed the best results for the synthesis of chiral
H
H
H
H
O
Metal ion
Bn
N
N
O
Bn
OEt
OEt
Bn
N
N
O
Bn
P
P
H
+
P
THF, –78 oC, 2 h
N
HN
O
OEt
OEt
P
1
7
8
Scheme 1: Asymmetric hydrophosphylation of chiral N-phosphonyl imine 1.
316
Chem Biol Drug Des 2010; 76: 314–319

Asymmetric Hydrophosphylation of Chiral N-Phosphonyl Imines
H
H
H
H
O
P
R
N
N
O
R
LiHMDS (1.5 equiv.)
THF, –78 oC, 2 h
OEt
OEt
R
N
N
O
R
P
+
H
P
N
HN
O
OEt
OEt
P
1-5,6a
7
8-12, 13a
Scheme 2: Effect of different R groups on hydrophosphylation of chiral N-phosphonyl imines.
Table 1: Effect of different R groups on asymmetric additions of
chiral N-phosphonyl imine with lithium diethyl phosphitea
Table 2: Results of the synthesis of N-phosphonyl-substituted
a-amino phosphonates 13a–i (7)a
Entry
Substrate
R
Product
Yield (%)b
drc
Entry
Substrate
R1
Product
Yield (%)b
drc
1
2
3
4
5
6
1
benzyl
iso-butyl
neo-pentyl
CH2-1-naphthyl
cyclopentyl
isopropyl
8
9
85
70
60
90
92
97
73:27
50:50
50:50
82:18
88:12
99:1
1
2
3
4
5
6
7
8
9
6a
6b
6c
6d
6e
6f
H
13a
13b
13c
13d
13e
13f
97
95
96
95
96
97
96
95
94
99:1
93:7
93:7
96:4
95:5
99:1
99:1
99:1
99:1
2
o-chloro
o-fluoro
o-bromo
o-methyl
p-fluoro
p-bromo
p-methyl
p-methoxy
3
10
11
12
13a
4
5
6a
6g
6h
6i
13g
13h
13i
aAll reactions were carried out at )78 ꢀC in 0.05 M solution of imine in
THF.
bCombined yields of both isomers.
cDiastereomeric ratio has been determined by using 1H-NMR of crude
products.
aAll reactions were carried out at )78 ꢀC in 0.06 M solution of imine in
THF.
bCombined yields of both isomers.
cDiastereomeric ratio was determined by crude H-NMR analysis.
1
b-amino phosphonates (39). However, this group resulted in modest
diastereoselectivity (dr = 82:18) in the present system, albeit the
yield is still good (90%, Table 1, entry 4). Surprisingly, iso-butyl and
neo-pentyl group did not exhibit any diastereoselectivity (Table 1,
entries 2 & 3). However, cyclopentyl gives good yield (92%) and
better selectivity (dr = 88:12). Obviously, iso-propyl group was pro-
ven to be the most efficient one for the present asymmetric synthe-
sis, which is in accordance with most of our previous results of
asymmetric reactions using chiral N-phosphonyl imines (40–43,
manuscript submission).
different aldehydes were synthesized and subjected to the addition
reaction with lithium diethyl phosphite, which was generated by
treating diethyl phosphite with 1.0 M of LiHMDS in THF (Scheme 3).
As indicated in Table 2, substituents on the phenyl rings of chiral
N-phosphonyl imines have no significant effect on both yield and
diastereoselectivity. Single isomeric products were obtained in the
case of p-fluoro and p-methyl chiral N-phosphonyl imines (Table 2,
entry 6 & 8).
With the optimal condition in our hands, the substrate scope was
carefully examined. Several chiral N-phosphonyl imines derived from
As shown in Scheme 4, the resulting configuration of the asymmetric
products of this reaction was determined by deprotecting the
H
H
H
H
O
P
N
N
O
LiHMDS (1.5 equiv.)
THF, –78 oC, 2 h
OEt
OEt
N
N
O
P
+
H
P
N
HN
O
OEt
OEt
P
R1
R1
6a-i
7
13a-i
Scheme 3: Asymmetric hydrophosphylation of chiral N-phosphonyl imine 6a-6i.
Chem Biol Drug Des 2010; 76: 314–319
317

Kaur et al.
O
H
H
O
NH
O
P
N
N
O
(1) 4 M HCl, MeOH, rt, 5 h
(2) 5% NaHCO3, CH2Cl2, CbzCl, 0 oC, 5 h
P
O
P
OEt
OEt
HN
OEt
OEt
13a
14
Scheme 4: Removal of chiral auxiliary and in situ protection using CbzCl.
N-phosphonyl group of 13a with aqueous HCl in methanol (3 N) at
room temperature, which was followed by protection with a CBZ
group to afford a known a-amino phosphonate. The optical rotation
of the product 14 was confirmed to be consistent with that of the
known sample (31). Hence, the present reaction provides the R-con-
figuration, i.e., the nucleophile, lithium phosphate, attacks chiral
N-phosphonylimines from their re face.
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We thank Robert A. Welch Foundation (D-1361) and NIH
(R03DA026960) for their generous support. The content is solely the
responsibility of the authors and does not necessarily represent
the official views of the National Institute on Drug Abuse or
the National Institutes of Health. We also thank our co-workers
Dr Zhiqian Wang, Ai Teng, Suresh Pindi, Venkatesh Kattamuri, and
Hao Sun for their assistance and discussions. The authors thank
David W. Purkiss for his assistance on NMR determination.
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