Direct access to enantiomerically enriched α-amino phosphonic acid derivatives by organocatalytic asymmetric hydrophosphonylation of imines

Article abstract of DOI:10.1021/jo060708h

A simple and efficient organocatalytic enantioselective hydrophosphonylation of imines to enantiomerically enriched α-amino phosphonates is reported. By using 10 mol % of quinine as the catalyst in the enantioselective addition of diethyl phosphite to N-B

Full text of DOI:10.1021/jo060708h

Because the biological activity related to the R-amino
phosphonic acid units depends on their absolute configuration,
the access to optically active R-amino phosphonic acids by
stereoselective synthesis has been the object of great efforts in
organic chemistry.7 Most of the strategies are based on diaste-
reoselective hydrophosphonylation by addition of an appropriate
phosphorus nucleophile, in most cases a phosphite ester, to chiral
imines using stoichiometric amounts of a chiral auxiliary.8 In
contrast, only a few reports on the enantioselective catalytic
hydrophosphonylations of imines are available9 and especially
those based on organocatalytic protocols have been to date
scarcely investigated.10
Direct Access to Enantiomerically Enriched
r-Amino Phosphonic Acid Derivatives by
Organocatalytic Asymmetric
Hydrophosphonylation of Imines
Daniel Pettersen,* Mauro Marcolini, Luca Bernardi,
Francesco Fini,* Raquel P. Herrera, Valentina Sgarzani, and
Alfredo Ricci
Department of Organic Chemistry “A. Mangini”,
UniVersity of Bologna, V. Risorgimento 4, 40136 Bologna, Italy
dap@chem.gu.se; fini_f@libero.it
We have recently reported the successful use of cinchona
alkaloids as organocatalysts in the catalytic asymmetric aza-
Henry reaction of imines.11 Bearing this in mind, we were eager
to investigate their potential as catalysts in the preparation of
R-amino phosphonates by hydrophosphonylation of imines using
dialkyl phosphites as nucleophiles.12 At the outset of this study,
an initial screening of derivatives 1a-d in the addition of diethyl
phosphite to N-tosyl protected imine 2 in toluene revealed the
key role played by the free hydroxyl group in the cinchona
catalysts. Therefore, using ester 1a or carbamate 1b, lacking
the free hydroxyl group, as catalysts resulted (Table 1, entries
1 and 2) in significantly lower efficiency (conversion typically
<10%). In contrast, commercially available quinine 1c or its
“pseudoenantiomer”, quinidine 1d, afforded quantitative conver-
sion of the starting imine 2, but only moderate enantioselec-
tivities (entries 3 and 4, 48% and 46% ee, respectively) were
achieved.13 Further optimization revealed that the enantiose-
ReceiVed April 3, 2006
A simple and efficient organocatalytic enantioselective
hydrophosphonylation of imines to enantiomerically enriched
R-amino phosphonates is reported. By using 10 mol % of
quinine as the catalyst in the enantioselective addition of
diethyl phosphite to N-Boc protected imines, R-amino
phosphonates are obtained in moderate to good yields and
with up to 94% ee.
(5) (a) Allen, J. G.; Atherton, F. R.; Hall, M. J.; Hassal, C. H.; Holmes,
S. W.; Lambert, R. W.; Nisbet, L. J.; Ringrose, P. S. Nature 1978, 272,
56-58. (b) Atherton, F. R.; Hassall, C. H.; Lambert, R. W. J. Med. Chem.
1986, 29, 29-40.
(6) Alonso, E.; Solis, A.; del Pozo, C. Synlett 2000, 698-700.
(7) Gro¨ger, H.; Hammer, B. Chem.-Eur. J. 2000, 943-948.
(8) (a) Dhawan, B.; Redmore, D. Phosphorus Sulfur 1987, 32, 119-
144. (b) Kukhar, V. P.; Soloshonok, V. H.; Solodenko, V. A. Phosphorus,
Sulfur Silicon 1994, 92, 239-264. (c) Redmore, D. Top. Phosphorus Chem.
1976, 8, 515-585. (d) Weimer, D. F. Tetrahedron 1997, 53, 16609-16644.
(e) Mikołajczyk, M.; Drabowicz, J.; Kiełbasinski, P. In StereoselectiVe
Synthesis (Houben-Weyl); Helmchen, G., Hoffmann, R.-W., Mulzer, J.,
Schumann, E., Eds.; Thieme Verlag: Stuttgart, 1996; Vol. E 21e, pp 5701-
5712 and references therein.
(9) (a) Sasai, H.; Arai, S.; Tahara, Y.; Shibasaki, M. J. Org. Chem. 1995,
60, 6656-6657. (b) Gro¨ger, H.; Saida, Y.; Arai, S.; Martens, J.; Sasai, H.;
Shibasaki, M. Tetrahedron Lett. 1996, 37, 9291-9292. (c) Gro¨ger, H.; Saida,
Y.; Sasai, H.; Yamaguchi, K.; Martens, J.; Shibasaki, M. J. Am. Chem.
Soc. 1998, 120, 3089-3103. (d) Saida, Y.; Gro¨ger, H.; Maison, W.; Durot,
N.; Sasai, H.; Shibasaki, M.; Martens, J. J. Org. Chem. 2000, 65, 4818-
4825.
(10) (a) Joly, G. D.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 4102-
4103. (b) Akiyama, T.; Morita, H.; Itoh, J.; Fuchibe, K. Org. Lett. 2005, 7,
2583-2585.
(11) (a) Fini, F.; Sgarzani, V.; Pettersen, D.; Herrera, R. P.; Bernardi,
L.; Ricci, A. Angew. Chem., Int. Ed. 2005, 44, 7975-7978. (b) Bernardi,
L.; Fini, F.; Herrera, R. P.; Ricci, A.; Sgarzani, V. Tetrahedron 2006, 62,
375-380. For reviews on the use of cinchona alkaloids as chiral bases for
catalytic enantioselective transformations, see: (c) Wynberg, H. Top.
Stereochem. 1986, 16, 87-129. (d) Kacprzak, K.; Gawronski, J. Synthesis
2001, 961-998. (e) Tian, S.-K.; Chen, Y.; Hang, J.; Tang, L.; McDaid, P.;
Deng, L. Acc. Chem. Res. 2004, 37, 621-631.
(12) For quinine-catalyzed addition of phosphites to aldehydes, see: (a)
Wynberg, H.; Smaardijk, A. A. Tetrahedron Lett. 1983, 24, 5899-5900.
(b) Smaardijk, A. A.; Noorda, S.; van Bolhuis, F.; Wynberg, H. Tetrahedron
Lett. 1985, 26, 493-496.
(13) Several cinchona-derived catalysts with an acidic proton moiety were
tested and found to be inferior to quinine and quinidine.
The addition of compounds containing phosphorus-hydrogen
bonds to C-C or C-X double bonds provides an atom-
economic method for the synthesis of organophosphorus deriva-
tives. Among phosphorus compounds, R-amino phosphonic
acids and their derivatives have received considerable attention
in the recent years because they exhibit intriguing biological
activities.1
Being considered as R-amino acid analogues,2 they have
found widespread use as biologically attractive peptide mimics
which have been employed, for example, as inhibitors of
protease3 and as catalytic antibodies.4 In addition, they have
been used as antibacterial5 and anti-HIV agents.6
(1) For reviews of the biological activity of R-amino phosphonic acids,
see: (a) Hiratake, J.; Oda, J. Biosci. Biotechnol. Biochem. 1997, 61, 211-
218. (b) Kafarski, P.; Lejczak, B. Phosphorus, Sulfur Silicon 1991, 63, 193-
215. (c) Kaplan, A. P.; Bartlett, P. A. Biochemistry 1991, 30, 8165-8170.
(d) Aminophosphonic and Aminophosphinic Acids; Kukhar, V. P., Hudson,
H. R., Eds.; John Wiley & Sons: New York, 2000.
(2) Smith, A. B., III; Yager, K. M.; Taylor, C. M. J. Am. Chem. Soc.
1995, 117, 10879-10888.
(3) Hirschmann, R.; Smith, A. B., III; Taylor, C. M.; Benkovic, P. A.;
Taylor, S. D.; Yager, K. M.; Sprengler, P. A.; Benkovic, S. J. Science 1994,
265, 234-237.
(4) (a) Allen, M. C.; Fuhrer, W.; Tuck, B.; Wade, R.; Wood, J. M. J.
Med. Chem. 1989, 32, 1652-1661. (b) Ding, J.; Fraser, M. E.; Meyer, J.
H.; Bartlett, P. A.; James, M. N. G. J. Am. Chem. Soc. 1998, 120, 4610-
4621. (c) Smith, W. W.; Bartlett, P. A. J. Am. Chem. Soc. 1998, 120, 4622-
4628 and references therein. (d) Bird, J.; Mello, R. C. D.; Harper, G. P.;
Hunter, D. J.; Karran, E. H.; Markwell, R. E.; Miles-Williams, A. J.;
Rahman, S. S.; Ward, R. W. J. Med. Chem. 1994, 37, 158-169.
10.1021/jo060708h CCC: $33.50 © 2006 American Chemical Society
Published on Web 07/08/2006
J. Org. Chem. 2006, 71, 6269-6272
6269

TABLE 1. Initial Screening of Catalysts, Solvents, and Protecting
Groupsa
TABLE 2. Enantioselective Hydrophosphonylation of Iminesa
time
temp
entry product
Ar
(days) (°C) yield (%)b ee (%)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
5a
5b
5c
5d
5e
5f
5g
5h
5i
5a
5c
5d
5e
5g
5i
C6H5
3
2
2
3
3
3
2
3
2
3
4
6
6
7
4
20
20
20
20
20
20
20
20
20
-20
-20
-20
-20
-20
-20
83
76
80
72
85
78
86
86
88
48
77
88
92
94
93
94
89
1-naphthyl
2-naphthyl
m-MeC6H4
p-MeC6H4
2,5-diMeC6H3
p-MeOC6H4
3-pyridyl
82
71d
65d
50
entry
R1
Ts
Ts
Ts
catalyst solvent time (h) conversion (%)b ee (%)c
50d
72
1
2
3
4
5
6
7
1a
1b
1c
1d
1c
1d
1c
toluene
toluene
toluene
toluene
toluene
toluene
xylene
42
77
24
24
48
48
72
<10
0
-
-
p-ClC6H4
C6H5
57
52
69
>95
>95
>95
>95
>95
48
46d
68
48d
80
2-naphthyl
m-MeC6H4
p-MeC6H4
p-MeOC6H4
p-ClC6H4
Ts
61d
62d
57d
62
Boc
Boc
Boc
a The reactions were carried out at 20 °C using 0.1 mmol of imine, 0.2
mmol of phosphite, and 0.01 mmol of catalyst in 1 mL of solvent.
b Conversions were determined by 1H NMR. c The enantiomeric excess was
determined by chiral HPLC. d The reactions performed by quinidine 1d gave
the opposite enantiomers (R)-4 and (R)-5a.
a The reactions were carried out using 0.1 mmol of imine, 0.2 mmol of
phosphite, and 0.01 mmol of catalyst in 1 mL of solvent. b Yields are given
for isolated products. c The enantiomeric excess was determined by chiral
HPLC. d Reactions carried out on a 0.3 mmol scale.
lectivity could be raised to a more satisfactory level by changing
the imine 2 into N-Boc protected imine 3a (entry 5, 68% ee).14
Finally, a screening of solvents15 suggested a significant solvent
dependence with xylene affording products (S)-5a16 with
improved enantioselectivity (80% ee) and good conversion,
when using quinine 1c as the organocatalyst (entry 7).17
With this information in hand, we proceeded to evaluate the
quinine (1c)-catalyzed addition of diethyl phosphite to a
representative selection of substituted N-Boc aromatic imines.
As shown in Table 2, both electron-donating (-Me, -OMe)
and electron-withdrawing (-Cl) substituents on the aromatic
ring were applicable and gave the corresponding products with
acceptable yields within 2 or 3 reaction days at 20 °C. Some
effect of the substitution pattern in the aromatic substituent of
the imines could be observed in the case of imines 3b (1-napht)
and 3c (2-napht), wherein the former afforded the corresponding
R-amino phosphonate 5b with a considerably poorer asymmetric
induction (72% ee), with respect to the adduct 5c obtained from
3c in 85% ee (compare entries 2 and 3). Using methyl- and
methoxy-substituted imines 3d-g resulted in an enantiomeric
excess in the range of 78-88% (entries 4-7), whereas the
3-pyridinyl- and p-Cl-substituted imines 3h,i gave the product
FIGURE 1. Proposed mechanism for the hydrophosphonylation of
N-Boc imines catalyzed by quinine.
with 48% and 77% ee, respectively (entries 8 and 9), indicating
that an electronic effect is also involved in the enantiodiscrimi-
nation process (compare entries 4-7 and 8-9).
Finally, an enantioselectivity/temperature profile documented
that in all cases enhanced enantioselectivities were available
after a prolonged reaction time (entries 10-15), by running the
reactions at -20 °C. Under these conditions, R-amino phos-
phonates 5d and 5g were obtained with enantiomeric excesses
up to 94% (entries 12 and 14).
A mechanistic proposal for the role of quinine 1c as the
catalyst in the hydrophosphonylation is shown in Figure 1. As
the initial screening of catalysts showed the importance of the
acidic hydroxyl group, we believe that the imines are activated
by a hydrogen bonding from the catalyst.11c,12 Regarding the
phosphorus nucleophile, it is known that it is the phosphite and
not the phosphonate form that is the actual nucleophilic
species.8d This equilibrium, which under neutral conditions is
completely shifted toward the unreactive phosphonate, can be
influenced by the presence of a base.18 Therefore, it cannot be
(14) Using a Cbz-protected imine gave a product with lower enantiose-
lectivity compared to the analogous Boc-protected imine. This observation
in combination with the more tedious preparation of Cbz imines resulted
in no further consideration of Cbz imines as substrates.
(15) A screening of solvents showed that xylene gave better results than,
e.g., toluene and polar protic and aprotic solvents. Use of fluorobenzene or
mesitylene lowered the selectivity with respect to xylene. No difference
could be observed between using a mixture of xylenes or p-xylene as solvent.
(16) Deprotection of the N-Boc moiety by treatment with TFA gave the
free amine having an (S)-configuration with [R]25 ) -15.8° (c ) 1.0,
D
CHCl3) by comparison of the literature data [amine having an (R)-
configuration; [R]25 ) 17.2° (c ) 1.0, CHCl3): Davis, F. A.; Lee, S.;
D
Yan, H.; Titus, D. D. Org. Lett. 2001, 3, 1757-1760].
(17) Changing the nucleophile to diisopropyl phosphite lowered the
reactivity and selectivity of the reaction, whereas dimethyl phosphite was
unreactive.
(18) Springs, B.; Haake, P. J. Org. Chem. 1977, 42, 472-474.
6270 J. Org. Chem., Vol. 71, No. 16, 2006

126.5, 127.07, 127.12, 127.9, 128.3, 128.5, 133.0, 133.3 (d, J )
20.6 Hz). 31P NMR (161 MHz, CDCl3): δ 22.4. Chiral HPLC
analysis (Chiralpak AD-H, 90:10 n-hexane/i-PrOH, 0.75 mL/min,
λ ) 254 nm) indicated 92% ee. tR(minor) ) 31.0 min, tR(major) )
22.1 min. [R]20D) -27.1 (c ) 0.89, CHCl3). HRMS calcd for
C20H28NO5P, m/z 393.1705; found, 393.1702.
ruled out that the basic quinuclidinic nitrogen in the catalyst
might shift the phosphite-phosphonate equilibrium toward the
phosphite form and that its attack to the electrophilic azomethine
carbon could be affected by the chiral environment generated
by the catalyst.
In conclusion, we have provided a new straightforward
organocatalytic approach for hydrophosphonylations of imines
using commercially available and nonexpensive quinine as the
catalyst and diethyl phosphite as the nucleophile. This simple
protocol which leads to R-amino phosphonates in satisfactory
yields and with up to 94% ee makes this asymmetric transfor-
mation practically important and extends the generality of
catalytic enantioselective hydrophosphonylations.
(S)-Diethyl (t-Butoxycarbonylamino-3-methylphenyl-methyl)
Phosphonate (5d). Following the general procedure and performing
the reaction on a 0.3 mmol scale, compound 5d was obtained after
1
6 days at -20 °C as a white solid in 61% yield (57.2 mg). H
NMR (300 MHz, CDCl3): δ (ppm) 1.12 (t, J ) 7.0 Hz, 3H), 1.31
(t, J ) 7.0 Hz, 3H), 1.42 (s, 9H), 2.35 (s, 3H), 3.74 (m, 1H), 3.95
(m, 1H), 4.12 (m, 2H), 5.07 (dd, J ) 9.9, 21.4 Hz, 1H), 5.45 (br
s, 1H), 7.24-7.47 (m, 4H). 13C NMR (100 MHz, CDCl3): δ (ppm)
16.1 (d, J ) 5.8 Hz), 16.4 (d, J ) 6.0 Hz), 21.4, 28.2, 51.7 (d, J
) 152.8 Hz), 63.0 (d, J ) 7.3 Hz), 63.2 (d, J ) 7.2 Hz), 80.2,
124.8 (d, J ) 6.0 Hz), 128.4, 128.5 (d, J ) 5.5 Hz), 128.8 (d, J )
2.3 Hz), 135.3, 138.2, 154.8 (d, J ) 11.2 Hz). 31P NMR (161 MHz,
CDCl3): δ 22.6. Chiral HPLC analysis (Chiralpak AD-H, 95:5
n-hexane/i-PrOH, 0.75 mL/min, λ ) 254 nm) indicated 94% ee.
tR(minor) ) 20.9 min, tR(major) ) 16.7 min. [R]20D ) -30.1 (c )
0.12, CHCl3). HRMS calcd for C17H28NO5P, m/z 357.1705; found,
357.1703.
Experimental Section
General Procedure for the Enantioselective Hydrophospho-
nylation. To a solution of imine 5a-i (0.1 mmol) in xylene (900
µL) was added quinine 1c (0.01 mmol, 100 µL, 0.1 M stock solution
in xylene) followed by diethyl phosphite (0.2 mmol, 26 µL). The
reaction was stirred at 20 °C or -20 °C for the time stated, after
which the R-amino phosphonate (5a-i) was obtained through direct
purification of the reaction mixture by column chromatography on
silica gel (ethyl acetate/n-hexane 2:3).
(S)-Diethyl (tert-Butoxycarbonylamino-4-methylphenyl-meth-
yl) Phosphonate (5e). Following the general procedure and
performing the reaction on a 0.3 mmol scale, compound 5e was
obtained after 5 days at -20 °C as a white solid in 62% yield (58.4
(S)-Diethyl (t-Butoxycarbonylamino-phenyl-methyl) Phos-
phonate (5a). Following the general procedure, compound 5a was
obtained after 3 days at 20 °C as a white solid in 83% yield (28.3
1
mg). H NMR (300 MHz, CDCl3): δ (ppm) 1.12 (t, J ) 7.2 Hz,
1
3H), 1.29 (t, J ) 7.2 Hz, 3H), 1.41 (s, 9H), 2.32 (s, 3H), 3.69-
3.80 (m, 1H), 3.88-3.99 (m, 1H), 4.04-4.16 (m, 2H), 5.06 (dd, J
) 9.7, 21.9 Hz, 1H), 5.48 (br s, 1H), 7.14 (d, J ) 8.2 Hz, 2H),
7.28 (d, J ) 8.2 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ (ppm)
16.1 (d, J ) 5.8 Hz), 16.4 (d, J ) 5.8 Hz), 21.1, 28.2, 51.5 (d, J
) 154.9 Hz), 62.9 (d, J ) 6.7 Hz), 63.1 (d, J ) 6.7 Hz), 80.2,
127.6 (d, J ) 6.0 Hz), 129.2 (d, J ) 2.3 Hz), 132.4, 137.7 (d, J )
2.7 Hz), 154.8 (d, J ) 9.7 Hz). 31P NMR (161 MHz, CDCl3): δ
23.2. Chiral HPLC analysis (Chiralpak AD-H, 80:20 n-hexane/i-
PrOH, 0.75 mL/min, λ ) 254 nm) indicated 93% ee. tR(minor) )
18.8 min, tR(major) ) 10.5 min. [R]20D ) -1.9 (c ) 1.1, CHCl3).
HRMS calcd for C17H28NO5P, m/z 357.1705; found, 357.1704.
mg). H NMR (300 MHz, CDCl3): δ (ppm) 1.12 (t, J ) 7.2 Hz,
3H), 1.31 (t, J ) 7.1 Hz, 3H), 1.43 (s, 9H), 3.74 (m, 1H), 3.95 (m,
1H), 4.12 (m, 2H), 5.11 (dd, J ) 9.7, 21.8 Hz, 1H), 5.51 (br s,
1H), 7.24-7.47 (m, 5H). 13C NMR (100 MHz, CDCl3): δ (ppm)
16.4 (d, J ) 5.7 Hz), 16.6 (d, J ) 5.7 Hz), 28.5, 52.1 (d, J ) 154.4
Hz), 63.3 (d, J ) 7.3 Hz), 63.4 (d, J ) 6.9 Hz), 80.6, 128.0 (d, J
) 5.8 Hz), 128.2 (d, J ) 2.9 Hz), 128.8 (d, J ) 2.0 Hz), 135.7,
155.1. 31P NMR (161 MHz, CDCl3): δ 23.0. Chiral HPLC analysis
(Chiralpak AD-H, 95:5 n-hexane/i-PrOH, 0.75 mL/min, λ ) 254
nm) indicated 80% ee. tR(minor) ) 31.1 min, tR(major) ) 22.4
min. [R]20D ) -11.8 (c ) 0.97, CHCl3). HRMS calcd for C16H26-
NO5P, m/z 343.1549; found, 343.1547.
(S)-Diethyl (t-Butoxycarbonylamino-2,5-dimethylphenyl-meth-
yl) Phosphonate (5f). Following the general procedure, compound
5f was obtained after 3 days at 20 °C as a pale yellow solid in
50% yield (18.6 mg). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.06
(t, J ) 7.3 Hz, 3H), 1.33 (t, J ) 7.3 Hz, 3H), 1.42 (s, 9H), 2.31 (s,
3H), 2.41 (s, 3H), 3.56-3.67 (m, 1H), 3.83-3.94 (m, 1H), 4.09-
4.20 (m, 2H), 5.36 (dd, J ) 9.9, 21.8 Hz, 1H), 5.52 (br s, 1H),
6.99 (d, J ) 8.0 Hz, 1H) 7.05 (d, J ) 8.0 Hz, 1H), 7.20 (br s, 1H).
13C NMR (100 MHz, CDCl3): δ (ppm) 16.1 (d, J ) 5.2 Hz), 16.4
(d, J ) 5.2 Hz), 19.2, 21.1, 28.3, 47.8 (d, J ) 154.7 Hz), 62.9 (d,
J ) 7.0 Hz), 63.2 (d, J ) 7.0 Hz), 80.2, 127.9, 128.7, 130.4, 133.4,
133.9, 135.7, 154.8 (d, J ) 8.1 Hz). 31P NMR (161 MHz, CDCl3):
δ 23.4. Chiral HPLC analysis (Chiralpak AD-H, 95:5 n-hexane/i-
PrOH, 0.75 mL/min, λ ) 254 nm) indicated 86% ee. tR(minor) )
11.6 min, tR(major) ) 9.2 min. [R]20D ) -18.6 (c ) 1.0, CHCl3).
HRMS calcd for C18H30NO5P, m/z 371.1862; found, 371.1860.
(S)-Diethyl (t-Butoxycarbonylamino-1-naphthyl-methyl) Phos-
phonate (5b). Following the general procedure, compound 5b was
obtained after 2 days at 20 °C as a white solid in 76% yield (29.9
1
mg). H NMR (300 MHz, CDCl3): δ (ppm) 0.83 (t, J ) 7.4 Hz,
3H), 1.37 (t, J ) 8.0 Hz, 3H), 1.42 (s, 9H), 3.45 (m, 1H), 3.80 (m,
1H), 4.21 (m, 2H), 5.64 (br s, 1H), 6.01 (dd, J ) 9.3, 22.2 Hz,
1H), 7.45-7.60 (m, 3H), 7.70-7.76 (m, 1H), 7.79-7.89 (m, 2H),
8.19-8.25 (m, 1H). 13C NMR (100 MHz, CDCl3): δ (ppm) 16.1
(d, J ) 5.6 Hz), 16.7 (d, J ) 5.6 Hz), 28.5, 47.6 (d, J ) 155.2 Hz),
63.3 (d, J ) 7.8 Hz), 63.4 (d, J ) 7.5 Hz), 80.6, 155.1. The aromatic
carbons showed the following signals and are given without
consideration of splitting: 123.7, 125.5, 126.0, 126.1, 126.8, 129.0,
131.47, 131.54, 132.3, 134.0. 31P NMR (161 MHz, CDCl3): δ 22.9.
Chiral HPLC analysis (Chiralpak AD-H, 90:10 n-hexane/i-PrOH,
0.75 mL/min, λ ) 254 nm) indicated 72% ee. tR(minor) ) 22.6
min, tR(major) ) 15.4 min. [R]20 ) +11.5 (c ) 0.87, CHCl3).
D
HRMS calcd for C20H28NO5P, m/z 393.1705; found, 393.1702.
(S)-Diethyl (t-Butoxycarbonylamino-2-naphthyl-methyl) Phos-
phonate (5c). Following the general procedure, compound 5c was
obtained after 4 days at -20 °C as a white solid in 69% yield (27.1
(S)-Diethyl (t-Butoxycarbonylamino-4-methoxyphenyl-meth-
yl) Phosphonate (5g). Following the general procedure and
performing the reaction on a 0.3 mmol scale, compound 5g was
obtained after 7 days at -20 °C as a pale yellow solid in 57%
1
1
mg). H NMR (300 MHz, CDCl3): δ (ppm) 1.10 (t, J ) 6.8 Hz,
yield (63.7 mg). H NMR (300 MHz, CDCl3): δ (ppm) 1.13 (t, J
3H), 1.32 (t, J ) 6.9 Hz, 3H), 1.44 (s, 9H), 3.75 (m, 1H), 3.95 (m,
1H), 4.15 (m, 2H), 5.29 (dd, J ) 9.3, 22.0 Hz, 1H), 5.65 (br s,
1H), 7.43-7.60 (m, 3H), 7.78-7.93 (m, 4H). 13C NMR (100 MHz,
CDCl3): δ (ppm) 16.4 (d, J ) 5.7 Hz), 16.6 (d, J ) 5.6 Hz), 28.5,
52.3 (d, J ) 156.1 Hz), 63.3 (d, J ) 7.3 Hz), 63.5 (d, J ) 6.8 Hz),
80.7, 155.2. The aromatic carbons showed the following signals
and are given without consideration of splitting: 125.8, 126.3,
) 6.9 Hz, 3H), 1.31 (t, J ) 7.0 Hz, 3H), 1.42 (s, 9H), 3.77 (m +
s, 1H + 3H), 3.94 (m, 1H), 4.12 (m, 2H), 5.05 (dd, J ) 9.4, 21.0
Hz, 1H), 5.44 (br s, 1H), 6.83-6.91 (m, 2H), 7.29-7.39 (m, 2H).
13C NMR (100 MHz, CDCl3): δ (ppm) 16.4 (d, J ) 5.8 Hz), 16.6
(d, J ) 5.8 Hz), 28.5, 51.4 (d, J ) 153.4 Hz), 63.2 (d, J ) 67.1
Hz), 63.4 (d, J ) 6.5 Hz), 80. 4, 114.2, 127.8, 129.2, 129.3, 155.1
(d, J ) 9.7 Hz), 159.6. 31P NMR (161 MHz, CDCl3): δ 22.8. Chiral
J. Org. Chem, Vol. 71, No. 16, 2006 6271

HPLC analysis (Chiralpak AD-H, 80:20 n-hexane/i-PrOH, 0.75 mL/
min, λ ) 254 nm) indicated 94% ee. tR(minor) ) 21.0 min, tR-
Hz, 3H), 1.30 (t, J ) 6.9 Hz, 3H), 1.41 (s, 9H), 3.81 (m, 1H), 3.97
(m, 1H), 4.11 (m, 2H), 5.06 (dd, J ) 9.2, 21.6 Hz, 1H), 5.47 (br
s, 1H), 7.29-7.47 (m, 4H). 13C NMR (100 MHz, CDCl3): δ (ppm)
16.4 (d, J ) 6.0 Hz), 16.6 (d, J ) 6.0 Hz), 28.5, 51.5 (d, J ) 155.1
Hz), 63.4 (d, J ) 7.6 Hz), 63.5 (d, J ) 7.3 Hz), 80.8, 128.9, 129.3,
134.3 (d, J ) 33.0 Hz), 155.0. 31P NMR (161 MHz, CDCl3): δ
22.4. Chiral HPLC analysis (Chiralpak AD-H, 90:10 n-hexane/i-
PrOH, 0.75 mL/min, λ ) 254 nm) indicated 89% ee. tR(minor) )
17.1 min, tR(major) ) 13.0 min. [R]20D ) -13.9 (c ) 1.28, CHCl3).
HRMS calcd for C16H25NO5PCl, m/z 377.1159; found, 377.1156.
(major) ) 12.0 min. [R]20 ) -24.6 (c ) 1.25, CHCl3). HRMS
D
calcd for C17H28NO6P, m/z 373.1654; found, 373.1652.
(S)-Diethyl (t-Butoxycarbonylamino-pyridin-3-yl-methyl) Phos-
phonate (5h). Following the general procedure, compound 5h was
obtained after 3 days at 20 °C as a colorless oil in 72% yield (24.8
1
mg). H NMR (300 MHz, CDCl3): δ (ppm) 1.19 (t, J ) 7.0 Hz,
3H), 1.34 (t, J ) 7.0 Hz, 3H), 1.45 (s, 9H), 3.90 (m, 1H), 4.03 (m,
1H), 4.16 (m, 2H), 5.14 (dd, J ) 8.7, 23.2 Hz, 1H), 5.52 (br s,
1H), 7.33 (m, 1H), 7.80 (m, 1H), 8.43 (m, 2H). 13C NMR (100
MHz, CDCl3): δ (ppm) 16.4 (d, J ) 5.6 Hz), 16.6 (d, J ) 5.5
Hz), 28.5, 50.1 (d, J ) 155.9 Hz), 63.57 (d, J ) 5.0 Hz), 63.64 (d,
J ) 5.0 Hz), 80.9, 132.5, 135.6, 149.4, 155.0. 31P NMR (161 MHz,
CDCl3): δ 21.8. Chiral HPLC analysis (Chiralpak AD-H, 55:45
n-hexane/i-PrOH, 0.5 mL/min, λ ) 254 nm) indicated 48% ee. tR-
Acknowledgment. We acknowledge financial support by
the “Consorzio CINMPIS”, by the National Project “Stereo-
selezione in Sintesi Organica Metodologie ed Applicazioni
2005”, and by the EC-RTN project, contract HPRN-CT-2001-
00172.
(minor) ) 9.4 min, tR(major) ) 10.8 min. [R]20 ) -14.2 (c )
D
0.80, CHCl3). HRMS calcd for C15H25N2O5P, m/z 344.1501; found,
344.1503.
Supporting Information Available: General experimental
information and 1H and 13C NMR spectra of products 5a-i.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(S)-Diethyl (t-Butoxycarbonylamino-4-chlorophenyl-methyl)
Phosphonate (5i). Following the general procedure, compound 5i
was obtained after 4 days at -20 °C as a white solid in 62% yield
(26.0 mg). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.15 (t, J ) 6.9
JO060708H
6272 J. Org. Chem., Vol. 71, No. 16, 2006