Asymmetric synthesis of aziridine 2-phosphonates from enantiopure sulfinimines (N-sulfinyl imines). Synthesis of α-amino phosphonates

Article abstract of DOI:10.1021/jo020707z

An aza-Darzens reaction, involving the addition of chloromethylphosphonate anions to enantiopure sulfinimines, has been developed for the asymmetric synthesis of aziridine 2-phosphonates. Best results involve cyclization of the syn and anti diastereomeric

Full text of DOI:10.1021/jo020707z

Asym m etr ic Syn th esis of Azir id in e 2-P h osp h on a tes fr om
En a n tiop u r e Su lfin im in es (N-Su lfin yl Im in es). Syn th esis of
r-Am in o P h osp h on a tes
Franklin A. Davis,* Yongzhong Wu, Hongxing Yan, William McCoull, and
Kavirayani R. Prasad
Department of Chemistry, Temple University, Philadelphia, Pennsylvania 19122
fdavis@temple.edu
Received November 21, 2002
An aza-Darzens reaction, involving the addition of chloromethylphosphonate anions to enantiopure
sulfinimines, has been developed for the asymmetric synthesis of aziridine 2-phosphonates. Best
results involve cyclization of the syn and anti diastereomerically pure R-chloro-â-amino phosphonates
to cis- and trans-N-sulfinyl aziridine 2-phosphonates, respectively, with n-BuLi. A transition-state
hypothesis is proposed wherein the chloromethylphosphonate anion adds to the C-N bond on the
side that is opposite the bulky p-tolyl sulfinyl group. The N-sulfinyl group is easily removed by
treatment with MeMgBr or TFA/MeOH, which affords the NH-aziridines in good yield. Using
transfer hydrogenation conditions, the NH-aziridines were regioselectively opened to the corre-
sponding enantiopure R-amino phosphonates without N-activation and in excellent yield.
Chiral aziridines have found widespread use in organic
synthesis.1 The highly strained three-membered ring
readily opens with excellent stereo- and regiocontrol to
afford a wide variety of more stable ring-opened or ring-
expanded chiral amines (Scheme 1). Consequently, aziri-
dine 2-phosphonates 1 are expected to be important
sources of diversely substituted amino phosphonates.
Amino phosphonates have found general use as sur-
rogates for amino acids and as such exhibit potent
biological activities.2 Activation of the aziridine nitrogen
by an electron-withdrawing group (acyl, sulfonyl), by
protonation, or by Lewis acids promotes either C-2 attack
to give â-amino phosphonates or C-3 attack to give
R-amino phosphonates (Scheme 1). The stereo- and
regioselectivity is determined by the ring substituents
and the reaction conditions, with the majority of nucleo-
philes expected to react at C-3.
Realizing the potential of aziridine 2-phosphonates 1
for the asymmetric synthesis of structurally diverse R-
and â-amino phosphonates requires practical and ef-
ficient methods for their preparation. Racemic aziridine
phosphonates have been synthesized by the reaction of
vinyl phosphonates with ethyl N-{[(4-nitrobenzene)-
sulfonyl]oxy}carbamate,3 copper-catalyzed aziridination
with [N-(p-toluenesulfonyl)imino]phenyliodonane,4 cy-
clization of 1-bromo-2-aminoethyl phosphonic acid,5 and
the Darzens-type addition of chloromethylphosphonate
anions to imines.6 The first asymmetric synthesis of
aziridine 2-phosphonates, a highly diastereoselective
addition of an enantiopure bicyclic chloromethylphos-
phonamide anion to imines, was described by Hanessian
and co-workers.7 More recently, enantiopure and optically
enriched 1 have been prepared by cyclization of R-hy-
droxy â-amino phosphonates8 and reduction of 2H-
azirine-2-phosphonates.9 However, with the exception of
the latter method, wherein the azirine was formed in less
than 24% ee, it was not possible to remove the N-
substituent to give the NH-aziridine without ring open-
ing.
In preliminary communications we reported the syn-
thesis of enantiopure N-sulfinylaziridine 2-phosphonates,
which were utilized as polyfunctionalized chiral building
blocks in highly stereoselective asymmetric syntheses of
R-amino phosphonates10 and R-methyl R-aminophospho-
nates.11 The derived NH-aziridine 2-phosphonates were
employed in the first asymmetric syntheses of the small-
est of the unsaturated nitrogen heterocycles 2H-azirine
2-phosphonaes, and 2H-aziridine 3-phosphonates.11 The
latter azirines represent a new class of chiral imino
(1) (a) For reviews on aziridines see: (a) McCoull, W.; Davis, F. A.
Synthesis 2000, 1347. (b) Tanner, D. Angew. Chem., Int. Ed. Engl.
1994, 33, 599. (c) Pearson, W. H.; Lian, B. W.; Bergmeier, S. C.
Aziridines and Azirines: Monocyclic. In Comprehensive Heterocyclic
Chemistry II; Padwa, A., Ed.; Pergamon Press: Oxford, UK, 1996; p
1. (d) Rai, K. M. L.; Hassner, A. Aziridines and Azirines: Fused-ring
Derivatives. In Comprehensive Heterocyclic Chemistry II; Padwa, A.,
Ed.; Pergamon Press: Oxford, UK, 1996; p 61.
(2) For reviews see: (a) Kafarski, P.; Lejczak, B. Phosphorus, Sulfur,
Silicon 1991, 63, 193. (b) Seto, H.; Kuzuyama, T. Nat. Prod. Rep. 1999,
16, 589. (c) Aminophosphonic and Aminophosphinic Acids. Chemistry
and Biological Activity; Kukhar, V. P., Hudson, H. R., Eds.; Wiley:
Chichester, UK, 2000.
(3) Fazio, A.; Loreto, M. A.; Tardella, P. A. Tetrahedron Lett. 2001,
42, 2185.
(4) Kim, D. Y.; Rhie, D. Y. Tetrahedron 1997, 53, 13603.
(5) Zygmunt, J . Tetrahedron 1985, 41, 4979.
(6) Coutrot, P.; Elgadi, A.; Grison, C. Heterocycles 1989, 28, 1179.
(7) Hanessian, S.; Bennani, Y. L.; Herve´, Y. Synlett 1993, 35.
(8) (a) Thomas, A. A.; Sharpless, K. B. J . Org. Chem. 1999, 64, 8379.
(b) Pousset, C.; Larcheveque, M. Tetrahedron Lett. 2002, 43, 5257.
(9) Palacios, F.; Ochoa de Retana, A. M.; Gil, J . I. Tetrahedron Lett.
2000, 41, 5363.
(10) Davis, F. A.; McCoull, W. Tetrahedron Lett. 1999, 40, 249.
(11) Davis, F. A.; McCoull, W.; Titus, D. D. Org. Lett. 2000, 1, 1053.
10.1021/jo020707z CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/22/2003
2410
J . Org. Chem. 2003, 68, 2410-2419

Synthesis of R-Amino Phosphonate
SCHEME 1
TABLE 1. Ad d ition of Lith iu m Dieth yl
SCHEME 2
r-Ha lom eth ylp h osp h on a tes to (S)-(+)-4b in THF a t -78
oC
2,
conditions
equiv 4b:2:base, temp (time)
entry X )
% yielda 5:6b
o
1
2
3
4
5
6
Cl 1:2:2, n-BuLi, -78 C to rt (2 h)c
<10
17
38
48
71
44:56
78:32
59:41
69:31
81:19
o
1:3:3, n-BuLi, -78 C to rt (8 h)
Br 1:3:3, n-BuLi, -78 to -20 °C (8 h)
I
1:3:3, n-BuLi, -78 to -45 °C (8 h)
1:2:2, LiHMDS, -78 to -40 °C (1 h)
1:1.1:1.1, NaHMDS,
(46)d 78:22
-78 to -40 °C (3 h)
a
b
Combined isolated yield of 5 and 6. Ratio of 5:6 determined
by proton NMR. c See ref 14. Isolated yield of 5 after repetitive
d
chromatography.
â-amino adducts, which can be more easily separated,
and then cyclize them to the corresponding aziridines.
Optimal reaction conditions involved treating 2 equiv of
the chloromethylphosphonate 2a or 7 and 1 equiv of the
sulfinimine 4 with the appropriate base at -78 °C
(Scheme 3). The reaction mixture was quenched at this
temperature with aqueous sat. NH4Cl and warmed to
room temperature. Under these conditions the aziridine
adducts were not detected, thus the difficulty in separat-
ing the aziridine isomers was avoided. The major â-amino
R-chlorophosphonates 8/9 and 10/11 were separated by
flash chromatography. Also detected in the crude reaction
mixture were products believed to be isomer adducts 12,
but these were difficult to isolate and appeared to be
unstable to chromatography. These results are sum-
marized in Table 2.
Complicating the separation of the â-amino-R-chloro-
phosphonates is the presence of excess chlorometh-
ylphosphonates 2a and 7. To avoid this problem the
following separation protocol was devised. First, a rough
flash chromatography separated the chloromethylphos-
phonate and minor isomers 12 from the major syn and
anti adducts 8/9 and 10/11. On concentration the major
syn adducts 8 and 10 solidified. The minor products, 9
and 11, were viscous oils and could be separated by
washing the mixture with a few milliliters of ether-
hexane. The n-BuLi base gave the best results with this
protocol. Interestingly, a variation in the rate of addition
of this base to dimethyl chloromethylphosphonate (7)
resulted in the formation of the â-amino-R-chloro phos-
phonate monoester 13. Dropwise addition of n-BuLi to
the reaction mixture over 15 min produced up to 30% of
13 (Table 2, entry 3). This side product was not detected
when all the base was added in one portion (see below).
dienophiles and were used in the first enantioselective
synthesis of quaternary piperidine phosphonates.12 In
this paper we give a full account of our asymmetric
synthesis of N-sulfinylaziridine 2-phosphonates from
sulfinimines (N-sulfinyl imines).
Resu lts a n d Discu ssion
Syn th esis of Azir id in es. Previously we described a
one-pot aza-Darzens synthesis of N-sulfinyl aziridine
2-carboxylates from sulfinimines and R-bromoenolates.13
This methodology appears to be particularly useful in
terms of its simplicity and ease of incorporating diverse
ring and nitrogen substituents. A similar protocol was
explored for the synthesis of N-sulfinyl aziridine 2-phos-
phonates 5 and 6 and involves the addition of (S)-(+)-N-
(benzylidene)-p-toluenesulfinamide (4b) to the anion of
diethyl R-halomethyl-phosphonates 2, at -78 °C and
warming to room temperature (Scheme 2). These condi-
tions afforded the cis and trans aziridines 5 and 6 in one
pot with isomer ratios varying from 44:56 to 81:19 (Table
1). Unfortunately, it proved to be exceedingly tedious to
separate the aziridine isomers and necessitated repetitive
chromatography, at least three times, which resulted in
poor product yields (Table 1, entry 6).
We found a more practical route to aziridine 2-phos-
phonates targets was to stop at the intermediate R-chloro-
(12) Davis, F. A.; Wu, Y.; Yan, H.; Prasad, K. R.; McCoull, W. Org.
Lett. 2002, 4, 655.
(13) Davis, F. A.; Liu, H.; Zhou, P.; Fang, T.; Reddy, G. V.; Zhang,
Y. J . Org. Chem. 1999, 64, 7559.
(14) Kim, D. Y.; Shu, K. H.; Choi, J . S.; Mang, J . Y.; Chang, S. K.
Synth. Commun. 2000, 30, 87. A 91% yield of 5 was reported by these
authors with these reaction conditions.
J . Org. Chem, Vol. 68, No. 6, 2003 2411

Davis et al.
SCHEME 3
TABLE 2. Rea ction of Ch lor om eth ylp h osp h on a tes w ith Su lfin im in es a t -78 °C for 0.5 h
8:9:12b (% yield)c
entry
sulfinimine 4 (R1 ))
4a (p-MeOPh)
phosphonate
basea
solvent
10:11:12
% majord
% minord
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
7 (Me)
LiHMDS
n-BuLi
THF
THF
THF
THF
THF
THF
Et2O
THF
THF
THF
THF
Et2O
THF
THF
DCM
THF
THF
54:46 (75)
66:34 (75)
66:34 (50)
55:30:15 (63)
77:8:15 (72)
64:22:14 (69)
65:4:31 (70)
41:53:6 (73)
38:54:8 (71)
76:8:16 (75)
42:50:8 (70)
59:5:36 (70)
59:41 (98)
1:1 (82)
(+)-8a , 32
(+)-8a , 51
(+)-8a , 24
(+)-10a , 25
(+)-10a , 48
(+)-8b, 58
n-BuLie
LiHMDS
n-BuLi
(+)-13, 30
2a (Et)
7 (Me)
4b (Ph)
LiHMDS
LiHMDS
NaHMDS
KHMDS
n-BuLi
n-BuLi/LiCl
n-BuLi
LiHMDS
n-BuLi
(+)-8b, 56
2a (Et)
(+)-10b, 58
(+)-11b, 40
(-)-9c, 24
4c (p-NO2Ph)
4d (p-CF3Ph)
7 (Me)
7 (Me)
LiHMDS
LiHMDS
n-BuLi
57:43 (56)
53:47 (64)
1:1 (60)
(-)-8c, 32
(+)-8d , 41
(+)-8d , 40
a
b
Base is added all at once to the reaction mixture. Ratio of R-chloro-â-amino isomers determined by 1H NMR on the crude reaction
mixture. Compound 12 is estimated to be the combined ratio of the other isomers, but was not isolated. c Combined yields of isomers.
Isolated yields e n-BuLi is added to the reaction mixture over 15 min.
d
The stereochemical assignment of the syn and anti
SCHEME 4
adducts ultimately rests on their conversion to the
corresponding aziridines, removal of the N-sulfinyl group,
and stereoselective ring opening to R-amino phosphonates
of known absolute configuration (see blow). The J 1,2
coupling constants for the C-1 and C-2 protons in the syn
adducts (SS,1S,2R)-8 and 10 appear at about 4 Hz while
the anti adducts (SS,1R,2R)-9 and 11 have a value of 5-6
Hz. Particularly diagnostic are the 31P and C-2 proton
coupling constants where the value for the syn adducts
is 18.5 Hz and that for the anti adducts is 12 Hz. The
structural assignment for monoester 13 is based on
HRMS and proton NMR, which confirms the loss of a
methyl group. The proton NMR of 13, taken in CD3OD
because it was insoluble in most organic solvents, reveals
that J 1,2 is observed at 6.4 Hz and J P,1 at 10.8 Hz. The
corresponding coupling constants in this solvent for 8 and
10 appear at 5.8-6.1 and 11.8-11.9 Hz, respectively,
indicating that 13 also has the syn (SS,1S,2R) structure.
In the minor anti isomer 9a (CD3OD), J 1,2 appears at 4.0
Hz. We speculate that the monoester 13 arises via attack
of n-BuLi on the methyl group of the major syn isomer
affording n-pentane (not detected). Demethylation of
dimethylanilinomethylphosphonate by NaOMe has been
reported.15 Additional support for this idea was found in
the formation of enamine (+)-16 in 51% and 79% yield
on treatment of aza enolate 15, derived from sulfinimine
(S)-(+)-14, with dimethyl chloromethylphosphonate (7)
or iodomethane, respectively (Scheme 4).
The results summarized in Table 2 reveal that in
all cases mixtures of the R-chloro-â-amino adducts
(15) Harger, M. J . P.; Williams, A. J . Chem. Soc. Perkin Trans. 1
1986, 1681.
2412 J . Org. Chem., Vol. 68, No. 6, 2003

Synthesis of R-Amino Phosphonate
SCHEME 5
SCHEME 7
SCHEME 6
(S)-(+)-N-tert-butanesulfinamide and benzaldehyde, were
treated with LiHMDS at -78 °C (Scheme 6). Importantly,
the aziridine (+)-21 formed directly, as a single isomer,
in 82 and 32% isolated yields, respectively. Unfortu-
nately, all attempts to remove the tert-butanesulfinyl
auxiliary without concomitant ring opening failed (see
below).
8:9/10:11 were obtained. Attempts to improve the isomer
ratio by altering the solvent, the base, or the chloro-
methylphosphonate ester group failed. The aryl substitu-
ent X in sulfinimines 4a -d also had little if any effect
on the adduct ratio. It has been suggested that aziridine
2-phosphonate formation can result from a reversible
equilibration of the R-chloro-â-amino adducts on warm-
ing.6 We found no evidence for this in our system. A
retained ratio of the aziridine (-)-5/(+)-6 was noted on
warming 10b and 11b over 3 h to - 5 °C. Our results
are consistent with the supposition that halomethylphos-
phonate anions 3, unlike enolate ions, have little if any
configurational stability and mixtures of products at the
R-position are to be expected.16
For this reason we next explored the addition of the
anion derived from diethylphosphonomethoxytosylate
(17)17 to (S)-(+)-4b. Here it was hoped that a bulkier
leaving group and/or intramolecular chelation within the
anion might restrict its conformational mobility, resulting
in improved adduct ratios. Unfortunately this was not
to be the case and mixtures of products 18:19, with ratios
similar to those found for the chloromethylphosphonate
anions, were observed, i.e., 69:31 (Scheme 5).
Str u ctu r e a n d F or m a tion of Azir id in es. With the
â-amino-R-chloro adducts in hand (Table 2), cyclization
to the corresponding aziridines was readily accomplished
by treatment with NaH at room temperature or n-BuLi
in THF at -78 °C (Table 3, Scheme 7). The stereochem-
ical assignments for the aziridines are based on the large
ring proton coupling constants observed for cis-(SS,2S,3R)
and trans-(SS,2R,3R) of 7.5-8.0 and 4.5-5.0 Hz, respec-
tively.19 Similar values for the coupling constants are
observed for the related N-sulfinyl aziridine 2-carboxy-
lates.13 The absolute stereochemistry of (-)-5 and (+)-6
was established by selective removal of the N-sulfinyl
group and ring opening to give the known (S)- and (R)-
diethyl-1-amino-2-phenylethyl phosphonates (+)-27 and
(-)-28, respectively (see below). By analogy, and on the
basis of similar coupling constants, the major aziridine
isomers 22 and 5 are assumed to have the cis geometry.
Rem ova l of th e N-Su lfin yl Gr ou p a n d Syn th eses
of R-Am in o P h osp h on a tes. An important advantage
of using the N-sulfinyl group in aziridine 2-carboxylate
syntheses is that it can be removed under such conditions
that ring opening does not occur.13 This affords enan-
tiopure 1H-aziridines that are valuable precursors of
N-substituted aziridines and can be elaborated to 2H-
azirines.20 Earlier syntheses of aziridine phosphonates
The influence of the sulfinyl auxiliary on the diaste-
reoselectivity of â-amino phosphonates was investigated
next (Scheme 6). Here the diethyl iodo- or tosylphospho-
nates 2c or 17 and sulfinimine (S)-(+)-20,18 derived from
(16) (a) Denmark, S. E.; Dorow, R. L. J . Am. Chem. Soc. 1990, 112,
864. (b) Denmark, S. E.; Dorow, R. L. J . Org. Chem. 1990, 55, 5926.
(c) Denmark, S. E.; Miller, P. C.; Wilson, S. R. J . Am. Chem. Soc. 1991,
113, 1468.
(17) Farrington G. K.; Kumar, A.; Wedler, F. C. J . Med. Chem. 1985,
28, 1668
(18) Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J . A.
J . Org. Chem. 1999, 64, 1278.
(19) Khusainova, N. G.; Bredikhina, Z. A.; Ishmaeva, E. A.; Musina,
A. A.; Pudovik, A. N. J . Gen. Chem., USSR 1981, 51, 409.
(20) Gentilucci, L.; Grijzen, Y.; Thija, L.; Zwanenburg, B. Tetra-
hedron Lett. 1995, 36, 4665.
J . Org. Chem, Vol. 68, No. 6, 2003 2413

Davis et al.
TABLE 3. F or m a tion of Azir id in es via Cycliza tion of r-Ch lor o â-Am in o Ad d u cts.
entry
chloro amino adduct
base/h/°C
aziridine (% isolated yield).
1
2
3
4
5
6
7
8
8a (X ) p-MeO, R ) Me)
8b (X ) H, R ) Me)
n-BuLi/1/-78 to rt
NaH/0.5/rt
n-BuLi/1/-78 to rt
NaH/1/-78 to rt
NaH/1/-78 to rt
NaH/1/rt
(SS,2S,3R)-(-)-22a (82)
(SS,2S,3R)-(-)-22b (73)
(SS,2S,3R)-(-)-22b (85)
(SS,2S,3R)-(-)-5 (76)
(SS,2R,3R)-(+)-6 (75)
(SS,2S,3R)-(-)-22c (80)
(SS,2R,3R)-(+)-23c (64)
(SS,2S,3R)-(-)-22d (78)
8b (X ) H, R ) Me)
10b (X ) H, R ) Et)
11b (X ) H, R ) Et)
8c (X ) p-NO2, R ) Me)
9c (X ) p-NO2, R ) Me)
8d (X ) p-CF3, R ) Me)
NaH/1/rt
n-BuLi/1/-78 to rt
SCHEME 8
SCHEME 9
that transfer hydrogenation of unactivated N-H-aziri-
dines 24, 25, and 26 proceeds at the benzylic position
with conservation of the stereochemistry R to the phos-
phorus to give 1-amino-2-arylethyl phosphonates 27-29
(Scheme 9). The lowest yield was for (-)-26c (X ) p-CF3)
furnishing the amino phosphonate (S)-(+)-29 in 67%
yield. The other amino acids were isolated in 80-98%.
The fact that ring opening occurs without activation at
nitrogen means that a deprotection step is not required
to give the amino phosphonates. Because amino phos-
phonates (S)-(+)-2722 and (R)-(-)-2823 have been de-
scribed earlier, we can establish the absolute configura-
tion of the corresponding aziridines and the â-amino
chlorophosphonates (see above).
The structures resulting from the addition of organo-
metallic reagents to the C-N bond of sulfinimines can
generally be predicted by assuming chelated, chairlike
transition states resulting from the coordination of the
metal and the sulfinyl oxygen.24 By contrast the exclusive
(R)-absolute configuration at C-2 in 8/9 and 10/11 is
opposite to that found in the analogous aza-Darzens
reactions of the bromo enolates that furnish aziridine
carboxylates.13 Thus the addition of halomethylphospho-
nate anions to sulfinimines is under steric control and
the anion adds to the C-N bond on the side that is
opposite to the bulky p-tolylsulfinyl group, i.e., TS-1. We
had N-substituents that could not be removed without
aziridine ring opening.
Treatment of N-sulfinyl aziridine cis-(-)-5 with 50
equiv of trifluoroacetic acid (TFA) at room temperature
afforded aziridine (2S,3R)-(-)-24 in 84% isolated yield
(Scheme 8). However, these conditions with trans-(+)-6
furnished (+)-25 in less than 22% yield with extensive
ring opening and decomposition. The higher reactivity
of the trans aziridine probably reflects unfavorable steric
interactions between the N-sulfinyl group and aziridine
ring substituents that are absent in the cis analogues.
By performing the desulfinylation process reaction at 0
°C for 15 min with only 5 equiv of TFA the trans-(2R,3R)-
(+)-25 could be isolated in 91% yield. However, even with
these milder conditions aziridine (-)-22a , which contains
the ring-activating 3-(p-methoxyphenyl) group, afforded
only ring-opening and decomposition products. We found
that the best method for removing the N-sulfinyl group
is treatment of the aziridine phosphonate 22 with 2 equiv
of MeMgBr at -78 °C. The corresponding N-H aziridines
26 were obtained in 70-82% yield (Scheme 8). Unfortu-
nately all attempts to remove the tert-butanesulfinyl
group in (+)-21 with use of acid or MeMgBr resulted in
complex mixtures of decomposition products.
(21) Lim, Y.; Lee, W. K. Tetrahedron Lett. 1995, 36, 8431.
(22) Cabella, G.; J ommi, G.; Pagliarin, R.; Sello, G.; Sisti, M.
Tetrahedron 1995, 51, 1817.
(23) J acquier, R.; Ouazzani, F.; Roumestant, M.-L.; Viallefont, P.
Phosphorus, Sulfur, Silicon Relat. Elem. 1988, 36, 73.
(24) For reviews on the chemistry of sulfinimines see: (a) Zhou, P.;
Chen, B.-C.; Davis, F. A. In Advances in Sulfur Chemistry; Rayner, C.
M., Ed.; J AI Press: Stamford, CT, 2000; Vol. 2, pp 249-282. (b) Davis,
F. A.; Zhou, P.; Chen. B.-C. Chem. Soc. Rev. 1998, 27, 13. (c) Ellman,
J . A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984.
It is generally thought that N-activation is necessary
for aziridine ring opening.1,21 Importantly, we have found
2414 J . Org. Chem., Vol. 68, No. 6, 2003

Synthesis of R-Amino Phosphonate
n-BuLi (1.5 mL, 2.0 M in cyclohexane, 3.0 mmol) was added
dropwise via syringe. The reaction mixture was slowly warmed
to -45 °C and kept at that temperature for 8 h. At this time
the reaction mixture was quenched by addition of saturated
aqueous NH4Cl (2 mL) and warmed to room temperature. After
dilution with H2O (5 mL) the solution was extracted with Et2O
(2 × 20 mL) and EtOAc (3 × 20 mL). The combined organic
phases were dried (MgSO4), filtered, and concentrated to give
a yellow oil. Flash chromatography (CH2Cl2-EtOAc, 5:1) gave
a mixture of (-)-5 and (+)-6 (69:31, 0.189 g, 48%) as a colorless
oil. An additional two flash chromatography separations afford
pure (-)-5 as a yellow oil; [R]20D -33.7 (c 1.1, CHCl3); IR (neat)
1250, 1026 cm-1; 1H NMR (CDCl3) δ 1.14 (t, 3J ) 7.0 Hz, 3 H),
speculate that this difference reflects the much larger size
of the halomethylphosphonate anion compared to an
enolate as well as the anion’s tetrahedral structure. It is
worth mentioning that addition of methyl phosphonate
anions to sulfinimines to give â-amino phosphonates
exhibits a similar reversal in stereochemisty.25
3
2
1.15 (t, J ) 7.0 Hz, 3 H), 2.38 (s, 3 H), 2.86 (dd, J HP ) 16.0
Hz, 3J ) 8.0 Hz, 1 H), 3.67-3.73 (m, 1 H), 3.83-3.97 (m, 4 H),
7.04-7.08 (m, 2 H), 7.15-7.17 (m, 3 H), 7.29-7.31 (m, 2 H),
7.67-7.69 (m, 2 H); 13C NMR (CDCl3) δ 16.1, 21.4, 34.1 (d,
In summary, practical methodology involving an aza-
Darzens-type addition of chloromethylphosphonate an-
ions to sulfinimines has been developed for the asym-
metric synthesis of cis-N-sulfinyl aziridine 2-phosphonates.
Removal of the N-sulfinyl group to give the corresponding
N-H-aziridines was readily accomplished, without ring
opening, by treatment with excess methylmagnesium
bromide.
1
2
2J CP ) 4.0 Hz), 34.8 (d, J CP ) 207.0 Hz), 62.1 (d, J CP ) 6.0
2
Hz), 63.1 (d, J CP ) 6.0 Hz), 124.5, 127.5, 127.6, 127.8, 129.7,
132.9, 140.7, 142.4; 31P NMR (CDCl3) δ 17.76; HRMS calcd
for C19H25NO4PS (M + H) 394.1242, found 394.1234. Anal.
Calcd for C19H24NO4PS: C, 58.00; H, 6.15; N, 3.56. Found: C,
57.74; H, 6.27; N, 3.53.
Gen er a l P r oced u r e for th e Syn th esis of R-Ch lor o-â-
a m in op h osp h on a tes. Dim eth yl (SS,1S,2R)-(+)-1-Ch lor o-
2-(4-m eth oxyph en yl)-2-(p-tolu en esu lfin a m id e)eth ylp h os-
p h on a te (8a ). In a 500-mL, round-bottom flask equipped with
a magnetic stirring bar, rubber septum, and argon balloon was
placed (S)-(+)-N-(4-methoxybenzylidene)-p-toluenesulfinamide
(4a ) (2.07 g, 7.7 mmol) and dimethyl chloromethylphosphonate
(7) (2.50 g, 15.8 mmol) in THF (300 mL). The solution was
stirred and cooled to -78 °C, and after 10 min n-BuLi (8.0
mL, 2.0 M in cyclohexane, 16.0 mmol) was quickly added (<10
s) via syringe. After being stirred at -78 °C for 30 min, the
reaction mixture was quenched by addition of saturated
aqueous NH4Cl (5 mL), warmed to room temperature, and
diluted with H2O (50 mL). The solution was extracted with
Et2O (2 × 100 mL) and EtOAc (3 × 50 mL), and the combined
organic phases were dried (MgSO4), filtered, and concentrated
to give a yellow oil. Purification by flash chromatography (CH2-
Cl2-EtOAc, 5:1) gave the isomeric amino chlorophosphonates
that on washing with hexane (10 mL) and diethyl ether (5 mL)
Exp er im en ta l Section
Gen er a l P r oced u r es. Column chromatography was per-
formed on silica gel, Merck grade 60 (230-400 mesh). TLC
plates were visualized with UV, in an iodine chamber, or with
1
phosphomolybdic acid, unless otherwise noted. H NMR and
13C NMR spectra were recorded at 500 and 125 MHz, respec-
tively.
THF and Et2O were freshly distilled under argon from a
purple solution of sodium and benzophenone. Unless stated
otherwise, all the reagents were purchased from commercial
sources and used without additional purification.
Diethyl 2-chloro- and 2-iodomethylphosphonates 2a and 2c
were purchased from commercial sources. Diethyl 2-bromo-
methylphosphonate (2b )26 and diethylphosphonomethoxy-
tosylate (17)17 were prepared by literature procedures. Sulfin-
imines (S)-4 and (S)-14 were prepared by condensation of
commercially available (S)-(+)-p-toluenesulfinamide with the
appropriate aldehyde or ketone as previously described.27
Sulfinimine (S)-(+)-20 was prepared by a literature proce-
dure.18
afforded 1.63 g (51%) of a white solid, mp 131-133 °C; [R]20
D
+8.5 (c 1.6, CHCl3); IR (KBr) 3207, 3005, 2952, 1252, 1049
3
cm-1;1H NMR (CDCl3) δ 2.34 (s, 3 H), 3.62 (d, J HP ) 10.5 Hz,
3 H), 3.82 (d, 3J HP ) 10.5 Hz, 3 H), 3.84 (s, 3 H), 4.43 (dd, 2J HP
3
3
3
) 11.5 Hz, J ) 4.0 Hz, 1 H), 4.84 (ddd, J HP ) 19.0 Hz, J )
Dim eth yl Ch lor om eth ylp h osp h on a te (7). In a 500-mL,
single-necked, round-bottom flask equipped with a magnetic
stirring bar, rubber septum, and argon balloon was placed
chloromethylphosphoric dichloride (20.0 g, 120 mmol) and
anhydrous methanol (23.1 g, 29.2 mL, 720 mmol) in Et2O (150
mL). The stirred solution was cooled to 0 °C and triethylamine
(33 mL, 240 mmol) was slowly added. The reaction mixture
was stirred for 18 h at room temperature, filtered, and
concentrated. Kugelrohr vaccum distillation (80 °C at 1 mmHg)
afforded 16.4 g (88%) of a colorless oil; 1H NMR (CDCl3) δ 3.56
3
3
8.5 Hz, J ) 4.0 Hz, 1 H), 5.80 (d, J ) 8.0 Hz, 1 H), 6.76 (d,
J ) 8.0 Hz, 2 H), 7.15 (d, J ) 8.0 Hz, 2 H), 7.20 (d, J ) 9.0 Hz,
2 H), 7.51 (d, J ) 8.5 Hz, 2 H); 13C NMR (CDCl3) δ 21.7, 54.3
(d, 2J CP ) 6.8 Hz), 54.6 (d, 2J CP ) 6.8 Hz), 55.7, 55.6 (d, 1J CP
)
122.0 Hz), 57.2, 113.7, 126.4, 129.4, 129.7, 130.2 (d, J ) 6.0
Hz), 141.1, 141.6, 159.6; 31P NMR (CDCl3) δ 19.77; HRMS calcd
for C18H23O5NPSClNa (M + Na) 454.0621, found 454.0628.
Anal. Calcd for C18H23O5NPSCl: C, 50.06; H, 5.37; N, 3.24.
Found: C, 49.97; H, 5.47; N, 2.63.
2
3
(d, J PH ) 10.0 Hz, 2 H), 3.84 (d, J PH ) 11.0 Hz, 6 H); 31P
Dim eth yl (SS,1S,2R)-(+)-1-Ch lor o-2-p h en yl-2-(p-tolu -
en esu fin a m id e)eth ylp h osp h on a te (8b). Yield 58%; mp
NMR (CDCl3) δ 21.24.
124.5-125.5 °C; [R]20 +27.2 (c 1.0, CHCl3); IR (KBr) 3295,
On e-P ot Syn th esis of Azir id in es 2-P h osp h on a tes. Di-
eth yl (SS,2S,3R)-(-)-N-(p-Tolu en esu lfin yl)-3-p h en yla zir i-
d in e-2-p h osp h on a te (5). In a 100-mL, round-bottom flask
equipped with a magnetic stirring bar, rubber septum, and
argon balloon was placed (S)-(+)-4b (0.243 g, 1.0 mmol) and
diethyl iodomethylphosphonate (2c) (0.834 g, 3.0 mmol) in
THF (40 mL). The stirred solution was cooled to -78 °C and
D
1
2938, 1250, 1050 cm-1; H NMR (CDCl3) δ 2.38 (s, 3 H), 3.61
(d, J ) 10.7 Hz, 3 H), 3.84 (d, J ) 11.0 Hz, 3 H), 4.46 (dd, 2J HP
3
3
3
) 11.7 Hz, J ) 4.0 Hz, 1 H), 4.93 (ddd, J HP ) 18.7 Hz, J )
3
4.0 Hz, J ) 8.4 Hz, 1 H), 5.85 (d, J ) 8.4 Hz, 1 H), 7.17 (d, J
) 8.1 Hz, 2 H), 7.26 (m, 5 H), 7.53 (d, J ) 8.1 Hz, 2 H); 13C
NMR (CDCl3) δ 21.2, 53.8, 54.2, 54.8, 56.7, 56.8, 126.0, 127.1,
127.7, 129.2, 137.6, 140.5, 141.2; 31P NMR (CDCl3) δ 19.66;
HRMS calcd for C17H22NO4PS35Cl (M + H) 402.0695, found
402.0697. Anal. Calcd for C17H21NO4PSCl: C, 50.81; H, 5.27;
N, 3.49. Found: C, 51.16; H, 4.85; N, 3.26.
(25) Mikolajczyk, M.; Lyzwa, P.; Drabowicz, J .; Wieczorek, M. W.;
Blaszczyk, J . Chem. Commun. 1996, 1503.
(26) Gajda, T. Phosphorus, Sulfur Silicon Relat. Elem. 1990, 53, 327.
(27) (a) Davis, F. A.; Zhang, Y.; Andemichael, Y.; Fang, T.; Fanelli,
D. L.; Zhang, H. J . Org. Chem. 1999, 64, 1043. (b) Fanelli, D. L.;
Szewczyk, J . M.; Zhang, Y.; Reddy, G. V.; Burns, D. M.; Davis, F. A.
Org. Synth. 1999, 77, 50.
Dim eth yl (SS,1S,2R)-(-)-1-Ch lor o-2-(4-n itr op h en yl)-2-
(p-tolu en esu lfin a m id e)eth ylp h osp h on a te (8c). Yield 32%;
mp 171-172 °C; [R]20D-45.4 (c 1.1, CHCl3); IR (KBr) 3264,
J . Org. Chem, Vol. 68, No. 6, 2003 2415

Davis et al.
3047, 2854, 1514, 1350, 1243, 1051 cm-1;1H NMR (CDCl3) δ
2.27 (s, 3 H), 3.67 (d, 3J HP ) 11.0 Hz, 3 H), 3.89 (d, 3J HP )11.0
4.08 (m, 4 H), 4.56 (dd, 2J HP ) 12.5 Hz, 3J ) 5.0 Hz, 1 H), 4.98
3
3
3
(ddd, J HP ) 12.0 Hz, J ) 7.5 Hz, J ) 5.0 Hz, 1 H), 5.59 (d,
3J ) 7.5 Hz, 1 H), 7.17-7.19 (m, 2 H), 7.22-7.28 (m, 5 H),
2
Hz, 3 H), 4.35 (dd, J HP ) 12.3 Hz, 3J ) 4.0 Hz, 1 H), 4.99
3
3
3
3
(ddd, J HP ) 18.9 Hz, J ) 7.0 Hz, J ) 4.0 Hz, 1 H), 6.18 (d,
J ) 7.0 Hz, 1 H), 7.06 (d, J ) 7.5 Hz, 2 H), 7.37 (d, J ) 8.0 Hz,
2 H), 7.39 (d, J ) 8.0 Hz, 2 H), 8.01 (d, J ) 9.0 Hz, 2 H); 13C
7.52-7.55 (m, 2 H); 13C NMR (CDCl3) δ 16.1 (d, J CP ) 6.0
3
1
Hz), 16.3 (d, J CP ) 6.0 Hz), 21.4, 56.6 (d, J CP ) 153.0 Hz),
2
2
57.6, 63.8 (d, J CP ) 6.0 Hz), 64.1(d, J CP ) 6.0 Hz), 126.0,
128.1, 128.3, 129.4, 137.8, 140.8, 141.4; 31P NMR (CDCl3) δ
17.51.
2
NMR (CDCl3) δ 21.6, 54.7 (2 × d, J CP ) 6.5 Hz), 54.5, 56.0,
123.2, 126.3, 129.5, 129.7, 140.2, 142.2, 145.3, 147.7; 31P NMR
(CDCl3) δ 18.92. Anal. Cacld for C17H20O6N2PSCl: C, 45.69;
H, 4.51; N, 6.27. Found: C, 45.91; H, 4.12; N, 6.32%.
(SS,1S,2R)-(+)-[1-Ch lor o-2-(4-m eth oxyp h en yl)-2-(p-tol-
u en esu lfin a m id e)eth yl]p h osp h on ic Acid Mon om eth yl
Ester (13). In a 500-mL, round-bottom flask equipped with a
magnetic stirring bar, rubber septum, and argon balloon was
placed (S)-(+)-4a (2.50 g, 9.6 mmol) and dimethyl chloro-
methylphosphonate (7) (2.93 g, 18.52 mmol) in THF (300 mL).
The solution was cooled to -78 °C and after stirring for 10
min, n-BuLi (9.3 mL, 2.0 M in cyclohexane, 18.60 mmol) was
added dropwise over 15 min via syringe. Stirring was contin-
ued for an additional 30 min, at which time the reaction
mixture was quenched by addition of saturated aqueous NH4-
Cl (5 mL) at -78 °C. On warming to room temperature a white
cotton-like precipitate formed and was collected by filtration.
The white precipitate was washed with EtOAc (2 × 100 mL)
and dried under high vacuum to 1.2 g (30%) of (+)-13 as a
white solid. The solution was concentrated and the reaction
mixture was worked-up as described earlier to give 0.99 g
(24%) of (+)-8a .
Dim eth yl (SS,1S,2R)-(+)-1-Ch lor o-2-(4-tr iflu or om eth -
ylph en yl)-2-(p-tolu en esu lfin am ide)eth ylph osph on ate (8d).
Yield 40%; white solid, mp 158-159 °C; [R]20 15.8 (c 0.5,
D
CHCl3); IR (KBr) 3262, 2953, 2854, 1240, 1047 cm-1; 1H NMR
3
(CDCl3) δ 2.44 (s, 3 H), 3.82 (d, J HP ) 10.8 Hz, 3 H), 4.04 (d,
3J HP ) 10.8 Hz, 3 H), 4.49 (dd, 3J ) 12.0 Hz, 3J ) 3.6 Hz, 1 H),
5.14 (ddd, J ) 6.7 Hz, J ) 3.5 Hz, J ) 17.4 Hz, 1 H), 6.19 (d,
J ) 6.9 Hz, 1 H), 7.20 (d, J ) 8.0 Hz, 2 H), 7.56-7.59 (m, 4
H), 7.47 (d, J ) 8.1 Hz, 2 H); 13C NMR (CDCl3) δ 21.5, 54.7 (d,
2
2
1J CP ) 34.6 Hz), 55.0 (d, J CP ) 6.0 Hz), 55.4 (d, J CP ) 6.0
Hz), 56.6, 125.0 (d, J ) 3.5 Hz), 126.2, 128.8, 129.1, 129.6,
140.2, 141.9, 142.1, 142.2; 31P NMR (CDCl3) δ 19.25; 19F NMR
(CDCl3) δ -63.073; HRMS calcd for C18H20ClF3NO4PSNa (M
+ Na) 492.0389, found 492.0375.
Dim eth yl (SS,1R,2R)-(-)-1-Ch lor o-2-(4-n itr op h en yl)-2-
(p-tolu en esu lfin a m id e)eth ylp h osp h on a te (9c). Yield 24%;
20
(+)-13: mp 180-182 °C dec; [R]20 +8.1 (c 0.2, CH3OH); IR
mp 120-122°C; [R]D -43.1 (c 0.61, CHCl3); IR (KBr) 3199,
D
3004, 2958, 2856, 1606, 1521, 1348, 1257, 1048 cm-1;1 H NMR-
(KBr) 3401, 3192, 3003, 2952, 1244, 1053 cm-1; 1H NMR (CD3-
3
OD) δ 2.37 (s, 3 H), 3.45 (d, 3J HP ) 10.4 Hz, 3 H), 3.79 (s, 3 H),
(CDCl3) δ 2.31 (s, 3 H), 3.64 (d, J HP ) 11.0 Hz, 3 H), 3.72 (d,
2
3
3J HP ) 10.5 Hz, 3 H), 4.43 (dd, J HP ) 12.5 Hz, J ) 5.5 Hz, 1
H), 5.02 (m, 1 H), 5.86 (d, J ) 8.5 Hz, 1 H), 7.09 (d, J ) 8.0
Hz, 2 H), 7.33 (d, J ) 8.5 Hz, 2 H), 7.39 (d, J ) 8.0 Hz, 2 H),
8.03 (d, J ) 9.0 Hz, 2 H); 13C NMR (CDCl3) δ 21.6, 54.1 (2 ×
2
3
3
4.26 (dd, J HP ) 10.8 Hz, J ) 6.4 Hz, 1 H), 4.88 (dd, J HP
)
9.6 Hz, 3J ) 6.4 Hz, 1 H), 6.74 (d, J ) 8.2 Hz, 2 H), 7.21-7.25
(m, 4 H), 7.49 (d, J ) 8.2 Hz, 2 H); 1H NMR (d6-DMSO) δ 2.19
(s, 3 H), 3.24 (d, J ) 3.9 Hz, 3 H), 3.61 (s, 3 H), 3.82 (t, J ) 8.7
Hz, 1 H), 4.46 (d × t, J ) 3.3 Hz, J ) 8.6 Hz, 1 H), 6.56 (d, J
) 8.6 Hz, 2 H), 7.00 (d, J ) 8.7 Hz, 2 H), 7.03 (d, J ) 8.2 Hz,
2 H), 7.17 (br s, 1 H, -OH), 7.22 (d, J ) 8.0 Hz, 2 H), 8.07 (d,
J ) 2.8 Hz, 1 H, -NH); 13C NMR (CD3OD) δ 21.6, 53.6, 56.0,
59.0 (d, 1J CP ) 140.2 Hz), 60.0, 114.3, 127.4, 130.7, 131.5, 132.9,
142.3, 142.8, 160.8; 31P NMR (CDCl3) δ 12.85; HRMS calcd
for C17H21ClNO5PS (M) 417.0567, found 417.0571.
2
1
d, J CP ) 6.7 Hz), 55.3 (d, J CP ) 24.8 Hz), 56.5, 123.3, 126.2,
129.70, 129.75, 140.3, 142.2, 145.4, 147.7; 31P NMR (CDCl3) δ
18.07. Anal. Calcd for C17H20O6N2PSCl: C, 45.69; H, 4.51; N,
6.27. Found: C, 45.97; H, 4.28; N, 6.31.
Dieth yl (SS,1S,2R)-(+)-1-Ch lor o-2-p h en yl-2-(p-tolu en e-
su lfin a m id e)eth ylp h osp h on a te (10b), Dieth yl (SS,1R,2R)-
(+)-1-Ch lor o-2-ph en yl-2-(p-tolu en esu lfin am ide)eth ylph os-
p h on a te (11b). In a 500-mL, round-bottom flask equipped
with a magnetic stirring bar, rubber septum, and argon balloon
was placed (S)-(+)-N-(benzylidene)-p-toluenesulfinamide (4b)
(1.83 g, 7.52 mmol) and diethyl chloromethylphosphonate (3.18
g, 17.0 mmol) in THF (200 mL). The solution was cooled to
-78 °C and LiHMDS (17.0 mL, 1 M in THF, 17.0 mmol) was
added dropwise via syringe. After being stirred at -78 °C for
30 min, the reaction mixture was quenched by addition of
saturated aqueous NH4Cl (3 mL) and warmed to room tem-
perature. The reaction mixture was diluted with H2O (50 mL)
and the solution was extracted with Et2O (250 mL) and CH2-
Cl2 (3 × 100 mL). The combined organic phases were dried
(MgSO4), filtered, and concentrated to give an orange oil. Flash
chromatography (CH2Cl2-EtOAc, 5:1) afforded 1.86 g (58%)
of (+)-10b and 1.29 g (40%) of (+)-11b as colorless oils that
solidified on storage at 5 °C.
(SS)-(+)-N-(p-Tolu en esu lfin yl)-N-m eth yl-1-ph en ylvin yl-
a m in e (16) P r ep a r ed fr om Dim eth yl Ch lor om eth ylp h os-
p h on a t e. In a 50-mL, round-bottom flask equipped with a
magnetic stirring bar, rubber septum, and argon balloon was
placed sulfinimine (S)-(+)-14 (0.14 g, 0.545 mmol) in THF (15
mL). The solution was cooled to 0 °C, LiHMDS (1 M in THF,
0.60 mL, 0.6 mmol, 1.1 equiv) was added via syringe, and after
10 min, 7 (0.086 g, 0.545 mmol) was added dropwise via
syringe. The reaction mixture was stirred for 16 h at which
time saturated aqueous NH4Cl (1 mL) and H2O (3 mL) were
added. The reaction mixture was extracted with Et2O (10 mL),
and EtOAc (3 × 10 mL) and the combined organic phases were
dried (MgSO4), filtered, and concentrated to give a brown oil.
Flash chromatography (CH2Cl2-EtOAc, 4:1) afforded 0.075 g
(51%) of a slightly yellow oil; [R]20 +53.6 (c 0.3, CHCl3); IR
D
(neat) 2955, 1253, 1031 cm-1; 1H NMR (CDCl3) δ 2.35 (s, 3 H),
2
2
(+)-10b: mp 96-97 °C; [R]20D +30.8 (c 3.2, CHCl3); IR (KBr)
2.51 (s, 3 H), 4.67 (d, J HH ) 0.8 Hz, 1 H), 4.72 (d, J HH ) 0.96
Hz, 1 H), 7.18-7.52 (m, 11 H); 13C NMR (CDCl3) δ 21.8, 29.9,
99.8, 125.9, 128.3, 128.9, 129.3, 130.1, 138.1, 140.2, 141.9,
3226, 1254, 1026 cm-1
;
1H NMR (CDCl3) δ 1.12 (t, 3J ) 7.0
3
Hz, 3 H), 1.37 (t, J ) 7.0 Hz, 3 H), 2.34 (s, 3 H), 3.92-3.97
151.6; HRMS calcd for
271.1037.
C16H17NOS (M) 271.1031, found
(m, 1 H), 4.02-4.97 (m, 1 H), 4.18-4.27 (m, 2 H), 4.42 (dd,
3
3
2J HP ) 11.5 Hz, J ) 4.0 Hz, 1 H), 4.94 (ddd, J HP ) 18.5 Hz,
3J ) 8.5 Hz, 3J ) 4.0 Hz, 1 H), 5.90 (d, 3J ) 8.5 Hz, 1 H),
7.14-7.16 (m, 2 H), 7.22-7.31 (m, 5 H), 7.53-7.55 (m, 2 H);
F r om Iod om eth a n e. In a 25-mL, oven-dried, two necked,
round-bottom flask fitted with a magnetic stirring bar, a
rubber septum, and an argon balloon was placed (S)-(+)-14
(0.11 g, 0.43 mmol) in THF (5 mL). The solution was cooled to
0 °C, and LiHMDS (1 M in THF, 0.5 mL, 0.5 mmol) was added
via syringe. After the reaction mixture was stirred for 15 min,
iodomethane (0.072 mL, 0.50 mmol) was added, and the
solution was stirred for 30 min at 0 °C, warmed to room
temperature for 20 min, and cooled to °C. To the reaction
mixture was added H2O (1 mL) and ethyl acetate (5 mL), the
organic phase was separated, and the aqueous phase was
13C NMR (CDCl3) δ 16.2 (d, J CP ) 6.0 Hz), 16.4 (d, J CP ) 6.0
3
3
1
2
Hz), 21.3, 56.4 (d, J CP ) 153.0 Hz), 56.9, 63.7 (d, J CP ) 6.0
2
3
Hz), 64.7 (d, J CP ) 6.0 Hz), 126.2, 127.9, 129.4, 137.9 (d, J CP
) 8.0 Hz), 140.8, 141.3; 31P NMR (CDCl3) δ 18.28. Anal. Calcd
for C19H25NO4PSCl: C, 53.08; H, 5.86; N, 3.26. Found: C,
53.40; H, 5.94; N, 3.18.
(+)-11b: mp 71-71.5 °C; [R]20 +28.1 (c 2.1, CHCl3); IR
D
(KBr) 3207, 1254, 1030 cm-1; 1H NMR (CDCl3) δ 1.12 (t, J )
3
7.0 Hz, 3 H), 1.18 (t, 3J ) 7.0 Hz, 3 H), 2.36 (s, 3 H), 3.89-
2416 J . Org. Chem., Vol. 68, No. 6, 2003

Synthesis of R-Amino Phosphonate
extracted with EtOAc (2 × 5 mL). The combined organic
phases were washed with brine (5 mL), dried (MgSO4), and
concentrated to give a brown oil. Flash chromatography
(hexanes-EtOAc, 9:1) afforded 0.094 g (79%) of (+)-16 as a
slightly yellow oil.
IR (neat) 3124, 2956, 1250, 1032 cm-1; 1H NMR (CDCl3) δ 2.38
3 2
(s, 3 H), 2.80 (dd, J ) 7.5 Hz, J HP ) 16.5 Hz, 1 H), 3.41 (d,
3
3J HP ) 11.0 Hz, 3 H), 3.53 (d, J HP ) 11.0 Hz, 3 H), 3.71 (s, 3
H), 3.90-3.91 (m, 1 H), 6.68 (d, J ) 8.5 Hz, 2 H), 6.98 (d, J )
9.0 Hz, 2 H), 7.28 (d, J ) 8.5 Hz, 2 H), 7.65 (d, J ) 8.0 Hz, 2
2
H); 13C NMR (CDCl3) δ 22.2, 34.4, 36.1, 53.4 (d, J CP
)
Dieth yl (SS,1S,2R)-(+)-1-(p-Tolu en esu lfon yloxy)-2-ph en -
yl-2-(p-tolu en esu lfin a m id e)eth ylp h osp h on a te (18). In a
100-mL, two-necked, round-bottom flask equipped with a
magnetic stirring bar, rubber septum, and argon balloon was
placed (S)-(+)-4b (0.24 g, 1.0 mmol) and diethyl-p-toluene-
sulfonyloxymethyl phosphonate (17) (0.62 g, 2.0 mmol) in THF
(20 mL). The solution was cooled to -78 °C, and after 10 min,
LiHMDS (1 M solution in THF, 2.0 mL, 2.0 mmol) was added
via syringe. After stirring at -78 °C for 30 min, the reaction
mixture was quenched by addition of saturated aqueous NH4-
Cl (5 mL) and warmed to room temperature. After dilution
with water (20 mL), the reaction mixture was extracted with
EtOAc (3 × 25 mL) and the combined organic phases were
dried (MgSO4) and concentrated to give a viscous mass. Flash
chromatography (hexanes-EtOAc, 50:50) afforded 0.29 g (52%)
of a viscous mass; [R]D +53.2 (c 0.5, CHCl3); IR (neat) 3286,
3059, 1373, 1249 cm-1; 1H NMR (CDCl3) δ 0.71 (t, J ) 7.1 Hz,
3 H), 0.97 (t, J ) 7.1 Hz, 3 H), 2.18 (s, 3 H), 2.31 (s, 3 H),
3.49-3.33 (m, 1 H), 3.56-3.51 (m, 2 H), 3.85-3.79 (m, 1 H),
4.66 (ddd, J ) 5.2 Hz, J ) 10.2 Hz, J ) 30.0 Hz, 1 H), 5.19
(dd, J ) 5.2 Hz, J ) 10.2 Hz, 1 H), 6.31 (d, J ) 10.2 Hz, 1 H),
7.04-6.98 (m, 7 H), 7.21(d, J ) 8.2 Hz, 2 H), 7.32 (d, J ) 8.2
Hz, 2 H), 7.77 (d, J ) 8.4 Hz, 2 H); 13C NMR (CDCl3) δ 16.22
6.0 Hz), 53.6 (d, 2J CP ) 6.0 Hz), 55.8, 113.9, 125.3, 125.6, 129.7,
130.4, 141.5, 143.2, 159.8; 31P NMR (CDCl3)
δ
20.37;
HRMS calcd for C18H22O5NPSClNa (M + Na) 418.0854, found
418.0840.
Dim et h yl
(SS,2S,3R)-(-)-N-(p -Tolu en esu lfin yl)-3-
p h en yla zir id in e-2-p h osp h on a te (22b). Yield 85%; [R]20
D
-46.1 (c 0.9, CHCl3); IR (neat) 2956, 1249, 1030 cm-1; 1H NMR
2
3
(CDCl3) δ 2.39 (s, 3 H), 2.88 (dd, J HP ) 16.5 Hz, J ) 7.3 Hz,
1 H), 3.37 (d, J ) 10.7 Hz, 3 H), 3.54 (d, J ) 11.0 Hz, 3 H),
3.97 (m, 1 H), 7.06 (m, 2 H), 7.17 (m, 3 H), 7.30 (d, J ) 8.0 Hz,
2 H), 7.68 (d, J ) 8.4 Hz, 2 H); 13C NMR (CDCl3) δ 21.4, 33.1,
33.9, 35.9, 52.5, 52.8, 124.5, 127.7, 129.7, 132.9, 140.6, 142.4;
31P NMR (CDCl3) δ 20.14; HRMS calcd for C17H21NO4PS (M
+ H) 366.0928, found 366.0930. Anal. Calcd for C17H20NO4-
PS: C, 55.88; H, 5.52; N, 3.83. Found: C, 55.51; H, 5.23; N,
3.59.
Diet h yl (SS,2R,3R)-(+)-N-(p -Tolu en esu lfin yl)-3-p h en -
yla zir id in e-2-p h osp h on a te (6). Yield 73%; [R]20 +147.0 (c
D
0.46, CHCl3); IR (neat) 1254, 1023 cm-1; H NMR (CDCl3) δ
1
3
3
1.11 (t, J ) 7.0 Hz, 3 H), 1.30 (t, J ) 7.0 Hz, 3 H), 2.42 (s, 3
2
3
H), 3.45 (dd, J HP ) 15.5 Hz, J ) 4.5 Hz, 1 H), 3.58-3.63 (m,
1 H), 3.89-3.94 (m, 1 H), 4.07-4.14 (m, 3 H), 7.20-7.32 (m, 2
H), 7.36-7.44 (m, 5 H), 7.64-7.66 (m, 2 H); 13C NMR (CDCl3)
3
3
(d, J CP ) 6.1 Hz), 16.44 (d, J CP ) 6.1 Hz), 21.7, 22.1, 54.9,
2
2
1
3
3
63.37 (d, J CP ) 6.2 Hz), 64.35 (d, J CP ) 7.6 Hz), 76.7 (d, J CP
) 159.0 Hz), 126.8, 128.0, 128.24, 128.29, 129.1, 130.3, 132.9,
137.15, 137.19, 140.0, 141.5, 145.6; 31PNMR (CDCl3) δ 15.88;
HRMS calcd for C26H32NO7PS2Na (M + Na) 588.1256, found
588.1276.
δ 16.8 (d, J CP ) 6.0 Hz), 17.0 (d, J CP ) 4.0 Hz), 21.4, 29.7,
44.4 (d, J CP ) 8.0 Hz), 62.7 (d, J CP ) 6.0 Hz), 62.9 (d, J CP
2
2
2
)
6.0 Hz), 125.2, 128.6, 128.9, 129.1, 129.4, 131.8, 141.8, 142.2;
31P NMR (CDCl3) δ 24.03. Anal. Calcd for C19H24NO4PS: C,
58.00; H, 6.15; N, 3.56. Found: C, 58.23; H, 6.15; N, 3.46.
Dim eth yl (SS,2S,3R)-(-)-N-(p-Tolu en esu lfin yl)-3-(p-n i-
tr op h en yl)a zir id in e-2-p h osp h on a te (22c). Yield 82%; mp
123-124°C; [R]20D -126.2 (c 0.48, CHCl3); IR (KBr) 3031, 2955,
Dieth yl (SS,2S,3R)-(+)-N-(ter t-Bu ta n esu lfin yl)-3-p h en -
yla zir id in e-2-p h osp h on a te (21). In a 25-mL, two-neck,
round-bottom flask equipped with a magnetic stirring bar,
rubber septum, and argon balloon were placed sulfinimine (+)-
20 (0.13 g, 0.61 mmol) and diethyl iodomethylphosphonate (2c)
(0.28 g, 1.0 mmol) in THF (10 mL). The solution was cooled to
-78 °C, and after 10 min LiHMDS (1 M in THF, 1.0 mL, 1.0
mmol) was added via syringe. After being stirred at -78 °C
for 30 min, the solution was quenched by addition of saturated
aqueous NH4Cl (5 mL) and warmed to room temperature. The
solution was diluted with water (25 mL) and the reaction
mixture was extracted with EtOAc (2 × 25 mL). The combined
organic phases were washed with sat. sodium thiosulfate and
brine, dried (MgSO4), and concentrated to give a yellow oil.
Flash chromatography (EtOAc-hexane, 1:1) afforded 0.17 g
1
2852, 1520, 1348, 1263, 1028 cm-1; H NMR (CDCl3) δ 2.33
2
(s, 3 H), 2.84 (dd, J HP ) 4.0 Hz, 3J ) 7.6 Hz, 1 H), 3.49 (d,
3
3J HP ) 10.96 Hz, 3 H), 3.52 (d, J HP ) 10.96 Hz, 3 H), 3.87 (t,
3J ) 7.6 Hz, 1 H), 7.13 (d, J ) 8.8 Hz, 2 H), 7.26 (d, J ) 8.0
Hz, 2 H), 7.58 (d, J ) 8.0 Hz, 2 H), 7.95 (d, J ) 6.8 Hz, 2 H);
2
1
13C NMR (CDCl3) δ 21.9, 33.4 (d, J CP ) 5.0 Hz), 34.3 (d, J CP
2
) 204.8 Hz), 53.3 (2 × d, J CP ) 6.3 Hz), 123.4, 124.8, 129.2,
130.3, 140.8, 143.4, 147.9; 31P NMR (CDCl3) δ 19.22; MS m/z
433.1 (100%, M + Na); HRMS calcd for C17H19N2O6PSNa (M
+ Na) 433.0599, found 433.0610.
Dim eth yl (SS,2R,3R)-(+)-N-(p-Tolu en esu lfin yl)-3-(p-n i-
tr op h en yl)a zir id in e-2-p h osp h on a te (23c). Yield 64%; col-
20
orless oil; [R]20 +147.1 (c 0.35, CHCl3); IR (neat) 3049, 2955,
(82%) as a colorless oil; [R]D +46.8 (c 0.6, CHCl3); IR (neat)
D
1250, 1027 cm-1; 1H NMR (CD3Cl) δ 1.05 (t, J ) 7.1 Hz, 3 H),
1.14 (t, J ) 7.1 Hz, 3 H), 1.19 (s, 9 H), 2.51 (dd, J ) 7.4 Hz,
15.9 Hz, 1 H), 3.88-3.76 (m, 5 H), 7.28-7.22 (m, 3 H), 7.44-
2853, 1521, 1347, 1257, 1030 cm-1; 1H NMR (CDCl3) δ 2.40 (s,
3
3 H), 3.32-3.35 (br s, 1 H), 3.43 (d, J HP ) 11.0 Hz, 3 H), 3.73
3
3
3
(d, J HP ) 11.0 Hz, 3 H), 4.13 (dd, J HP ) 9.0 Hz, J ) 5.0 Hz,
1 H), 7.29 (d, J ) 8.0 Hz, 2 H), 7.51 (d, J ) 8.0 Hz, 2 H), 7.60
(d, J ) 8.0 Hz, 2 H), 8.19 (d, J ) 8.5 Hz, 2 H); 13C NMR (CDCl3)
3
7.41 (m, 2 H); 13C NMR (CD3Cl) δ 16.61 (d, J CP ) 5.8 Hz),
3
1
16.69 (d, J CP ) 6.0 Hz), 23.0, 33.6 (d, J CP ) 209.1 Hz), 36.2,
57.7, 62.50 (d, 2J CP ) 6.0 Hz), 62.70 (d, 2J CP ) 5.8 Hz), 128.43,
128.54, 128.9, 133.1; 31P NMR (CD3Cl) δ 18.40; HRMS calcd
for C17H27NO4PS (M + H) 360.1398, found 360.1392.
2
δ 21.8, 33.5, 42.6, 53.7 (2 × d, J CP ) 6.3 Hz), 124.1, 125.3,
130.1, 130.3, 140.2, 141.9, 142.8, 148.4; 31P NMR (CDCl3) δ
20.81. All attempts to obtain an HRMS of this material were
unsuccessful because of its instability.
Dim et h yl (SS,2S,3R)-(-)-N-(p -Tolu en esu lfin yl)-3-(p -
m eth oxyp h en yl)a zir id in e-2-p h osp h on a te (22a ): Typ ica l
P r oced u r e. In a 500-mL, round-bottom flask equipped with
a magnetic stirring bar, rubber septum, and argon balloon was
placed (+)-8a (1.27 g, 2.96 mmol) in THF (150 mL). The stirred
solution was cooled to -78 °C and after 10 min n-BuLi (1.78
mL, 2.0 M in cyclohexane, 3.56 mmol) was added dropwise
via syringe. The solution was slowly warmed to room temper-
ature, stirred for 1 h, and quenched with saturated aqueous
NH4Cl (10 mL). The mixture was extracted with Et2O (100
mL) and EtOAc (3 × 50 mL) and the combined organic phases
were dried (MgSO4), filtered, and concentrated to give a
colorless oil. Flash chromatography (CH2Cl2-EtOAc, 3:1) af-
forded 0.97 g (82%) of a colorless oil; [R]20D -66.0 (c 1.9, CHCl3);
Dim eth yl (SS,2S,3R)-(-)-N-(p-Tolu en esu lfin yl)-3-(p-tr i-
flu or om eth ylph en yl)azir idin e-2-ph osph on ate (22d). Yield
78%; colorless oil; [R]20D -28.4 (c 0.28, CHCl3); IR (NaCl) 3070,
1
2958, 2875, 1326, 1253, 1066 cm-1; H NMR (CDCl3) δ 2.33
3
2
(s, 3 H), 2.81 (dd, J ) 7.44 Hz, J HP ) 16.1 Hz, 1 H), 3.41 (d,
3J HP ) 10.9 Hz, 3 H), 3.47 (d, J HP ) 10.9 Hz, 3 H), 3.89 (m, 1
3
H), 7.08 (d, J ) 8.3 Hz, 2 H), 7.24 (d, J ) 8.0 Hz, 2 H), 7.35 (d,
J ) 8.2 Hz, 2 H), 7.59 (d, J ) 8.2 Hz, 2 H); 13C NMR (CDCl3)
2
1
δ 21.9, 33.8 (d, J CP ) 5.0 Hz), 34.0 (d, J CP ) 208.3 Hz), 53.1
2
2
(d, J CP ) 6.3 Hz), 53.4 (d, J CP ) 6.0 Hz), 124.9, 125.2 (d, J )
3.1 Hz), 128.7, 129.6, 130.3, 137.5, 140.9, 143.2, 145.0; 31P NMR
(CDCl3) δ 19.64; 19F NMR (CDCl3) δ -63.05; HRMS calcd for
C
18H19F3NO4PSNa (M + Na) 456.0622, found 456.0614.
J . Org. Chem, Vol. 68, No. 6, 2003 2417

Davis et al.
Dim et h yl (2S,3R)-(-)-3-P h en yla zir id in e-2-p h osp h o-
n a te (24). In a 25-mL, round-bottom flask equipped with a
magnetic stirring bar, rubber septum, and argon balloon was
placed N-sulfinyl aziridine (-)-5 (0.121 g, 0.308 mmol) dis-
solved in acetone-H2O (1:1, 3 mL). To the vigorously stirred
solution was added TFA (1.2 mL, 15.6 mmol) via syringe. After
being stirred for 1 h, the reaction mixture was diluted with
H2O (10 mL) and aq NH4OH added until pH 9 was attained.
The reaction mixture was extracted with Et2O (2 × 20 mL)
and CH2Cl2 (2 × 20 mL), the combined organic phases were
dried (MgSO4), filtered, and concentrated to give a green oil.
Flash chromatography (EtOAc) afforded 0. 066 g (84%) of a
colorless oil; [R]20D -36.5 (c 0.85, CHCl3); IR (KBr) 3252, 1239,
(M + H) 228.0789, found 228.0792. Anal. Calcd for C10H15-
NO3P: C, 52.86; H, 6.21; N, 6.17. Found: C, 52.88; H, 6.09;
N, 5.84.
Dim et h yl (2S,3R)-(-)-3-(p -Nit r op h en yl)a zir id in e-2-
p h osp h on a te (26c). Yield 82%; mp 145-147 °C; [R]20D -50.0
(c 0.25, CHCl3); IR (KBr) 3281, 3241, 3001, 2956, 2863, 1508,
1344, 1027 cm-1; 1H NMR (CDCl3) δ 1.70 (br s, 1 H, NH), 2.58-
3
3
2.61 (br s, 1 H), 3.49 (d, J HP ) 11.0 Hz, 3 H), 3.56 (d, J HP
)
10.5 Hz, 3 H), 3.64 (m, 1 H), 7.64 (d, J ) 9.0 Hz, 2 H), 8.20 (d,
J ) 10.5 Hz, 2 H); 13C NMR (CDCl3) δ 30.9 (d, J CP ) 213.9
1
2
Hz), 37.1, 52.9 (d, J CP ) 38.5 Hz), 123.5, 129.3, 143.5, 147.8;
31P NMR (CDCl3) δ 23.6059; HRMS calcd for C10H14N2O5P
(M + H) 273.0640, found 273.0637.
1
3
1030 cm-1; H NMR (CDCl3) δ 1.11(t, J ) 7.0 Hz, 3 H), 1.15
Dim et h yl (2S,3R)-(-)-3-(p -Tr iflu or om et h ylp h en yl)-
3
(t, J ) 7.0 Hz, 3 H), 1.26 (s, 1 H), 2.39-2.45 (m, 1 H), 3.52-
a zir id in e-2-p h osp h on a te (26d ). Yield 72%; white solid, mp
3.63 (m, 2 H), 3.78-3.91 (m, 3 H), 7.25-7.28 (m, 1 H), 7.32-
90-92 °C; [R]20 -44.8 (c 0.65, CHCl3); IR (KBr) 3226, 2995,
D
7.35 (m, 2 H), 7.46-7.48 (m, 2 H); 13C NMR (CDCl3) δ 16.0,
2851, 1264, 1050 cm-1
;
1H NMR (CDCl3) δ 1.57 (br s, 1 H),
2.48-2.57 (m, 1 H), 3.29 (d, 3J HP ) 10.8 Hz, 3 H), 3.48 (d, 3J HP
1
2
16.1, 31.4 (d, J CP ) 208.0 Hz), 37.5, 61.5 (d, J CP ) 6.0 Hz),
) 10.8 Hz, 3 H), 3.53-3.59 (m, 1 H), 7.51-7.56 (m, 4 H); 13C
62.6 (d, J CP ) 4.0 Hz), 127.3, 127.7, 127.8, 135.5; 31P NMR
2
1
2
NMR (CDCl3) δ 30.7 (d, J CP ) 216.5 Hz), 36.9 (d, J CP )3.1
(CDCl3) δ 22.46; HRMS calcd for C12H19NO3P (M + H)
2
2
Hz), 52.7 (d, J CP ) 5.8 Hz), 53.2 (d, J CP ) 5.6 Hz), 125.2,
128.8, 129.6, 130.5, 140.3; 31P NMR (CDCl3) δ 23.9; 19F NMR
(CDCl3) δ -62.89. Anal. Calcd for C11H13F3NO3P: C, 44.76;
H, 4.44; N, 4.74. Found: C, 44.44; H, 4.54; N, 4.33.
256.1103, found 256.1090.
Dim et h yl (2R,3R)-(+)-3-P h en yla zir id in e-2-p h osp h o-
n a te (25). In a 100-mL, round-bottom flask equipped with a
magnetic stirring bar, rubber septum, and argon balloon was
placed sulfinyl aziridine (+)-6 (0.366 g, 0.93 mmol) dissolved
in acetone-H2O (1:1, 12 mL). To the vigorously stirred solution
at 0 °C was added TFA (358 µL, 4.65 mmol) via syringe. After
being stirred for 15 min at 0 °C, the reaction mixture was
diluted with H2O (50 mL), aqueous NH4OH was added until
pH 9 was attained, and the solution was extracted with Et2O
(2 × 75 mL). The combined organic phases were dried (MgSO4),
filtered, and concentrated to give a colorless oil. Flash chro-
matography (CH2Cl2-EtOAc, 5:1) afforded 0.215 g (91%) of a
colorless oil; [R]20D +38.5 (c 0.89, CHCl3); IR (KBr) 3238, 1239,
Gen er a l P r oced u r e for Hyd r ogen a tion of Azir id in es:
Dieth yl (S)-(+)-1-Am in o-2-p h en yleth ylp h osp h on a te (27).
In a 10-mL, round-bottom flask equipped with a magnetic
stirring bar, rubber septum, and argon balloon was placed
aziridine (-)-24 (0.033 g, 0.129 mmol) and Pd/C (0.035 g, 10%
Pd) in MeOH (1 mL). To the stirred solution was added HCO2-
NH4 (0.070 g, 1.11 mmol) in one portion, and after being stirred
for 16 h, the reaction mixture was filtered through Celite and
the residue was washed with MeOH (2 × 5 mL) and Et2O (2
× 5 mL). The combined organic phases were dried (MgSO4),
filtered, and concentrated to give a pale yellow oil. Flash
chromatography (EtOAc-MeOH, 19:1) afforded 0.033 g (99%)
of a yellow oil; [R]20 +16.9 (c 0.9, CHCl3) [lit.19 [R]25 +17.9];
3
1023 cm-1; 1H NMR (CDCl3) δ 1.36 (t, J ) 7.0 Hz, 3 H), 1.40
3
(t, J ) 7.0 Hz, 3 H), 1.61 (s, 1 H), 1.92-1.97 (m, 1 H), 3.40-
D
D
3.44 (m, 1 H), 4.14-4.24 (m, 4 H), 7.24-7.35 (m, 5 H); 13C NMR
IR (neat) 3376, 3299, 1242, 1026 cm-1; 1H NMR (CDCl3) δ 1.28
(br s, 2 H), 1.37 (t, 3J ) 7.0 Hz, 3 H), 1.38 (t, 3J ) 7.0 Hz, 3 H),
2.65-2.72 (m, 1 H), 3.22-3.32 (m, 2 H), 4.17-4.24 (m, 4 H),
7.25-7.28 (m, 3 H), 7.33-7.36 (m, 2 H); 13C NMR (CDCl3) δ
1
(CDCl3) δ 16.4, 16.5, 33.2 (d, J CP ) 187.0 Hz), 36.1, 62.6 (d,
2
2J CP ) 6.0 Hz), 62.7 (d, J CP ) 6.0 Hz), 125.9, 127.7, 128.6,
137.8; 31P NMR (CDCl3) δ 24.59. Anal. Calcd for C12H18O3NP:
C, 56.47; H, 7.11; N, 5.49. Found: C, 56.28; H, 7.29; N, 5.35.
1
2
16.4, 16.5, 37.8, 50.2 (d, J cp ) 155.0 Hz), 61.2 (d, J cp ) 6.0
Dim eth yl (2S,3R)-(-)-3-(p-Meth oxyp h en yl)a zir id in e-2-
p h osp h on a te (26a ): Typ ica l P r oced u r e. In a 250-mL,
round-bottom flask equipped with a magnetic stirring bar,
rubber septum, and argon balloon was placed (-)-22a (0.954
g, 2.42 mmol) in THF (100 mL). The solution was cooled to
-78 °C and after 10 min, MeMgBr (1.61 mL, 3.0 M in Et2O)
was added dropwise via syringe. After being stirred at -78
°C for 2 h, the reaction mixture was quenched by addition of
H2O (5 mL) and warmed to room temperature. Aqueous NH4-
OH was added until pH 10 was attained and the reaction
mixture was extracted with EtOAc (3 × 50 mL). The combined
organic phases were dried (MgSO4), filtered, and concentrated
to give a colorless oil. Flash chromatography (CH2Cl2-EtOAc,
2
3
Hz), 62.3 (d, J cp ) 6.0 Hz), 126.6, 128.5, 129.1, 137.8 (d, J cp
) 16.0 Hz); 31P NMR (CDCl3) δ 28.07; HRMS calcd for C12H21
NO3P (M + H) 258.1249, found 258.1259. Anal. Calcd for
12H20NO3P: C, 56.02; H, 7.84. Found C, 56.21; H, 7.84.
-
C
Mosher amide from (+)-Mosher’s acid chloride δF -69.44
(internal reference CFCl3) indicated that (S)-(+)-27 was >96%
ee.
Diet h yl (R)-(-)-1-Am in o-2-p h en ylet h ylp h osp h on a t e
(28). The same procedure as for the preparation of (+)-27 was
applied. Flash chromatography (EtOAc-MeOH, 19:1) afforded
(-)-28 as a colorless oil (83%, 0.108 mmol scale), which
exhibited spectroscopic data as for (+)-27. [R]20 -16.5 (c 0.9,
D
CHCl3) [lit.20 [R] -18.1 (c 1.66, CHCl3)]. Mosher amide from
(+)-Mosher’s acid chloride δF -69.55 (internal reference
CFCl3).
4:1) afforded 0.49 g (79%) of a white solid; mp 50-51 °C; [R]20
D
-28.0 (c 0.5, CHCl3); IR (KBr) 3433, 3279, 3011, 2980, 1249,
1
1033 cm-1; H NMR (CDCl3) δ 1.52 (br s, 1 H), 2.50 (br s, 1
Dim et h yl (S)-(+)-1-Am in o-2-(p -m et h oxyp h en yl)et h -
H), 3.30∼3.56 (m, 7 H), 3.79 (s, 3 H), 6.87 (d, J ) 8.5 Hz, 2 H),
ylp h osp h on a te (29a ). Yield 81%; [R]20D +19.2 (c 1.2, CHCl3);
1
7.41 (br s, 2 H); 13C NMR (CDCl3) δ 31.0 (d, J CP ) 216.0 Hz),
1
IR (neat) 3374, 3301, 3055, 2952, 1246, 1032 cm-1; H NMR
37.1, 52.9, 53.4, 55.9, 114.0, 129.3, 129.7, 159.7; 31P NMR
(CDCl3) δ 24.72; HRMS calcd for C11H16O4NPNa (M + Na)
280.0715, found 280.0719. Anal. Calcd for C11H16O4NP: C,
51.36; H, 6.27; N, 5.45. Found: C, 51.50; H, 6.37; N, 5.42.
(CDCl3) δ 1.45 (br s, 2 H), 2.57-2.64 (m, 1 H), 3.12-3.17 (m,
3
1 H), 3.22-3.28 (m, 1 H), 3.78 (s, 3 H), 3.79 (d, J HP ) 6.0 Hz,
3
3 H), 3.81 (d, J HP ) 5.5 Hz, 3 H), 6.84 (d, J ) 8.5 Hz, 2 H),
7.13 (d, J ) 8.5 Hz, 2 H); 13C NMR(CDCl3) δ 37.3, 49.8 (d,
1J CP ) 153.3 Hz), 53.4 (2 × d, 2J CP ) 9.8 Hz), 55.7, 114.4, 129.8
Dim et h yl (2S,3R)-(-)-3-P h en yla zir id in e-2-p h osp h o-
3
(d, J CP ) 16.1 Hz), 130.6, 158.9; 31P NMR (CDCl3) δ 30.47;
n a te (26b). Yield 70%; mp 55-56 °C; [R]20 -49.0 (c 1.0,
D
1
CHCl3); IR (KBr) 3235, 1266, 1042 cm-1; H NMR (CDCl3) δ
HRMS calcd for C11H18NO4PNa (M + Na) 282.0871, found
282.0878.
1.71 (br, 1 H), 2.45 (m, 1 H), 3.31 (d, J ) 9.0 Hz, 3 H), 3.50 (d,
J ) 10.6 Hz, 3 H), 3.58 (m, 1 H), 7.27 (m, 1 H), 7.34 (m, 2 H),
7.47 (d, J ) 7.3 Hz, 2 H); 13C NMR (CDCl3) δ 30.9, 32.5, 37.7,
52.8 (d, J ) 6.1 Hz), 53.2 (d, J ) 6.1 Hz), 128.0, 128.4, 128.5,
136.4; 31P NMR (CDCl3) δ 24.84; HRMS calcd for C10H15NO3P
Dim eth yl (S)-(+)-1-Am in o-2-p h en yleth ylp h osp h on a te
(29b). Yield 98%; [R]20 +25.9 (c 0.9, CHCl3); IR (neat) 3377,
D
3308, 2952, 1244, 1031 cm-1; H NMR (CDCl3) δ 1.41 (br s, 2
1
H), 2.68 (m, 1 H), 3.22 (m, 1 H), 3.32 (m, 1 H), 3.81 (d, J ) 5.9
2418 J . Org. Chem., Vol. 68, No. 6, 2003

Synthesis of R-Amino Phosphonate
Hz, 3 H), 3.83 (d, J ) 5.8 Hz, 3 H), 7.25 (m, 3 H), 7.33 (m, 2
H); 13C NMR (CDCl3) δ 38.2, 50.4 (d, 1J CP ) 155.1 Hz), 53.5 (2
× d, J ) 11.1 Hz), 127.2, 129.0, 129.6, 138.1; 31P NMR (CDCl3)
δ 30.35; HRMS calcd for C10H16NO3PNa (M + Na) 252.0762,
found 252.0774.
NMR (CDCl3) δ -62.912; HRMS calcd for C11H15NO3F3PNa
(M + Na) 320.0639, found 320.0649.
Ack n ow led gm en t. We thank Professor Louis D.
Quin for stimulating discussions. This work was sup-
ported by a grant from the National Institute of General
Medical Sciences (NIGMS 57870).
Dim et h yl (S)-(+)-1-Am in o-2-(p -t r iflu or om et h ylp h en -
yl)eth ylp h osp h on a te (29c). Colorless oil; yield 67%; [R]20
D
+16.5 (c 1.0, CHCl3); IR (neat) 3370, 3305, 1245, 1030 cm-1
;
1H NMR (CDCl3) δ 1.19 (br s, 2 H), 2.64-2.74 (m, 1 H), 3.15-
3.19 (m, 1 H), 3.21-3.27 (m, 1 H), 3.73 (d, 3J HP ) 4.3 Hz, 3 H),
Su p p or tin g In for m a tion Ava ila ble: Spectral data for
compounds where only HRMS is available. This material is
available free of charge via the Internet at http://pubs.acs.org.
3
3.76 (d, J HP ) 4.3 Hz, 3 H), 7.28 (d, J ) 8.0 Hz, 2 H), 7.52 (d,
1
J ) 8.0 Hz, 2 H); 13C NMR (CDCl3) δ 38.5, 49.9 (d, J CP
)
2
152.7 Hz), 53.9 (2 × d, J CP ) 6.8 Hz), 126.3, 129.8, 130.4,
130.6, 142.7 (d, 3J CP ) 16.7 Hz); 31P NMR (CDCl3) δ 29.72; 19
F
J O020707Z
J . Org. Chem, Vol. 68, No. 6, 2003 2419