Asymmetric synthesis of cyclic α-amino phosphonates using masked oxo sulfinimines (n-sulfinyl imines)

Article abstract of DOI:10.1021/jo040127x

Five-, six-, and seven-membered cyclic α-amino phosphonates, amino acid surrogates, are prepared in enantiomerically pure form via the highly diastereomeric addition of metal phosphonates to masked oxo sulfinimines. Hydrolysis of the resulting masked oxo

Full text of DOI:10.1021/jo040127x

Asym m etr ic Syn th esis of Cyclic r-Am in o P h osp h on a tes Usin g
Ma sk ed Oxo Su lfin im in es (N-Su lfin yl Im in es)
Franklin A. Davis,* Seung H. Lee, and He Xu
Department of Chemistry, Temple University, Philadelphia, Pennsylvania 19122
fdavis@temple.edu
Received February 5, 2004
Five-, six-, and seven-membered cyclic R-amino phosphonates, amino acid surrogates, are prepared
in enantiomerically pure form via the highly diastereomeric addition of metal phosphonates to
masked oxo sulfinimines. Hydrolysis of the resulting masked oxo R-amino phosphonates followed
by reduction of the intermediate cyclic imino phosphonates affords the title compounds in good
yield.
The importance of unnatural amino acids in the
modification of peptides to improve bioactivity and stabil-
ity and their utility in peptide therapeutics makes the
asymmetric synthesis of R- and â-amino phosphonic acids
a significant objective. R-Amino phosphonic acids are
considered to be surrogates for R-amino acids and as such
exhibit a broad range of biological activities.1 For ex-
ample, they have found utility as enzyme inhibitors,2-4
haptens for catalytic antibodies,5 antibacterial agents,6,7
anti-HIV agents,8 and biotrytcides.9 Proline and ho-
moproline analogues of R-amino phosphonates are inhibi-
tors of dipeptidyl peptidase4b and HIV.8
While a number of methods have been introduced for
the asymmetric synthesis of acyclic R-amino phos-
phonates,10 the diastereoselective addition of metal phos-
phites to aldehyde- and ketone-derived sulfinimines (N-
sulfinyl imines)11,12 and the regioselective ring-opening
of aziridine 2-phosphonates13 have proven to be particu-
larly useful. Not only are these methods general, provid-
ing access to diversely substituted examples, including
quaternary and â-hydroxy derivatives, they are also
highly efficient, highly diastereoselective, and afford the
amino phosphonate with predictable stereochemistry.
Fewer methods are available for the asymmetric
synthesis of cyclic R-amino phosphonates. For example,
Katritzky and co-workers employed the diastereoselective
addition of triethyl phosphite (Arbuzov reaction) to a
phenylglycinol-derived chiral oxazolopyrrolidine to pre-
pare 1, the phosphonate analogue of proline (Scheme 1).14
This cyclic amino phosphonate has also been prepared,
in a series of steps, by reducing one of the nitrogen atoms
in a chiral piperidazine 3-phosphonic acid.15 Several
asymmetric syntheses of piperidin-2-ylphosphonate 2
(homoproline analogue) have been reported. These in-
clude the cyclization of 5-iodo R-amino phosphonates16
(10) For reviews, see: (a) Dhawan B.; Redmore, D. Phosphorus,
Sulfur Silicon Relat. Elem. 1987, 32, 119. (b) Kukhar, V. P.; Solo-
shonok, V. A.; Solodenko, V. A. Phosphorus, Sulfur Silicon Relat. Elem.
1994, 92, 239. (c) Kolodiazhnyi, O. I. Tetrahedron: Asymmetry 1998,
9, 1279. (d) For leading references see Smith, A. B., III; Yager, K. M.;
Taylor, C. M. J . Am. Chem. Soc. 1995, 117, 10879.
(11) 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.
(12) R-Am in o P h osp h on a tes. (a) Lefebvre, I. M.; Evans, S. A., J r.
J . Org. Chem. 1997, 62, 7532. (b) Mikolajczyk, M.; Lyzwa, P.;
Drabowicz, J . Tetrahedron: Asymmetry 1997, 8, 3991. (c) Davis, F.
A.; Lee, S.; Yan, H.; Titus, D. D. Org. Lett. 2001, 3, 1757. (d)
Mikolajczyk, M.; Lyzwa, P.; Drabowicz, J . Tetrahedron: Asymmetry
2002, 13, 2571. (d) Davis, F. A.; Prasad, K. R. J . Org. Chem. 2003, 68,
7249.
(1) 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, U.K., 2000.
(2) Allen, M. C.; Fuhrer, W.; Tuck, B.; Wade, R.; Wood, J . M. J . Med.
Chem. 1989, 32, 1652.
(3) (a) Ding, J .; Fraser, M. E.; Meyer, J . H.; Bartlett, P. A.; J ames,
M. N. G. J . Am. Chem. Soc. 1998, 120, 4610. (b) Smith, W. W.; Bartlett,
P. A. J . Am. Chem. Soc. 1998, 120, 4622 and references therein.
(4) (a) Bird, J .; DeMello, R. C.; 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. (b) Boduszek, B.; Oleksyszyn, J .; Kam,
C.-M.; Selzler, J .; Smith, R. E.; Powers, J . C. J . Med. Chem. 1994, 37,
3969.
(5) 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.
(6) Allen, J . G.; Atherton, F. R.; Hall, M. J .; Hasssal, C. H.; Holmes,
S. W.; Lambert, R. W.; Nisbet, L. J .; Ringrose, P. S. Nature 1978, 272,
56.
(7) Atherton, F. R.; Hassall, C. H.; Lambert, R. W. J . Med. Chem.
1986, 29, 29.
(8) (a) Camp, N. P.; Hawkins, P. C. D.; Hitchcock, P. B.; Gani, D.
Bioorg. Med. Chem. Lett. 1992, 2, 1047. (b) Haebich, D.; Hansen, J .;
Paessens, A. Eur. Pat. Appl. EP 472077, 1992, Bayer AG; Chem. Abstr.
1992, 117, 27161z. (c) Powers, J . C.; Boduszek, B.; Oleksyszyn, J . PCT
Int. Appl. WO 95 29691, 1995, Georgia Technology Research Corp.;
Chem. Abstr. 1996, 124, 203102m.
(13) Azir id in e 2-P h osp h on a t es. (a) Davis, F. A.; McCoull, W.
Tetrahedron Lett. 1999, 40, 249. (b) Davis, F. A.; McCoull, W.; Titus,
D. D. Org. Lett. 1999, 1, 1053. (c) Davis, F. A.; Wu, Y.; Yan, H.; Prasad,
K. R.; McCoull, W. Org. Lett. 2002, 4, 655. (d) Davis, F. A.; Wu, Y.;
Yan, H.; McCoull, W.; Prasad, K. R. J . Org. Chem. 2003, 68, 2410. (c)
Davis, F. A.; Ramachandar, T.; Wu, Y. J . Org. Chem. 2003, 68, 6894.
(14) Katritzky, A. R.; Cui, X.; Yang, B.; Steel, P. J . J . Org. Chem.
1999, 64, 1979.
(15) Kaname, M.; Arakawa, Y.; Yoshifuji, S. Tetrahedron Lett. 2001,
42, 2713.
(16) J acquier, R.; Ouazzani, F.; Roumestant, M.-L.; Viallefont, P.
Phosphorus Sulfur 1988, 36, 73.
(9) Maier, L. Phosphorus, Sulfur Silicon 1990, 53, 43.
10.1021/jo040127x CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/04/2004
3774
J . Org. Chem. 2004, 69, 3774-3781

Asymmetric Synthesis of Cyclic R-Amino Phosphonates
SCHEME 1
SCHEME 3
SCHEME 2
Syn th esis of Su lfin im in es. Masked oxo sulfinimines
(S)-9, (S)-10, and (S)-11, new sulfinimine derived poly-
functionalized chiral building blocks,21 are prepared by
condensing commercially available (S)-(+)-p-toluenesulfin-
amide (5) with the corresponding masked oxo aldehydes
6 to 8 in the presence of 5 equiv of Ti(OEt)4 (Scheme 3).22
The masked oxo aldehydes were prepared by literature
methods that usually involved the careful, -78 °C,
DIBAL-H reduction of the corresponding esters.20
With the sulfinimines 9-11 in hand, treatment with
2 equiv of lithium diethyl phosphite, prepared in situ by
reaction of diethylphosphite with LiHMDS, afforded the
corresponding R-amino phosphonates 12-14 in good to
excellent yields (Scheme 4). As summarized in Table 1,
the de’s for the addition were excellent. The only excep-
tions were sulfinimines (S)-9c and (S)-10a where the
diastereoselectivities for 12c and 13a were 76 and 88%,
respectively (Table 1, entries 3 and 6), and unfortunately,
the diastereoisomers were inseparable. In an attempt to
improve the de’s, the effect of the counterion was evalu-
ated. The use of potassium diethyl phosphite with sulfin-
imine 10a afforded the amino phosphate (SS,R)-13a in
98% de and 91% isolated yield (Table 1, entry 8). No
improvement in the de was observed for similar additions
to 9c (Table 1, entry 4 and 5).
and the treatment of cyano17 and benzotriazole 6-oxazolo-
piperidines18 with phosphites. The enantioselective cata-
lytic hydrophosphonylation of imines to give cyclic amino
phosphonates such as 3 has also been reported.19 Ring-
opening of bicyclic aziridines, prepared in the Diels-
Alder reaction of dienes and enantiomerically pure 2H-
azirine 3-phosphonates, affords quaternary piperidine
phosphonates such as 4.13c However, many of these
procedures are limited by being target specific, lacking
in generality, and/or requiring the separation of diaster-
eomeric mixtures having poor de values. Here we report
that the highly diastereoselective addition of metal
phosphites to masked oxo sulfinimines represents a
simple route to stereodefined cyclic R-amino phospho-
nates derivatives.
The stereochemistry at the new stereogenic center is
predicted to have the (R)-configuration on the basis of
our earlier findings.12c These findings suggest that metal
phosphites add to the Si-face of the C-N double bond in
sulfinimines via a seven-membered twisted chairlike
transition state. This prediction was later confirmed by
conversion to a known compound (see below).
Syn th esis of Cyclic R-Am in o P h osp h on a tes. The
next step in the reaction sequence calls for treatment of
the masked oxo R-amino phosphonates 12-14 with acid
to remove the sulfinyl auxiliary and hydrolyze the acetal/
Resu lts a n d Discu ssion
The general features of our cyclic amino phosphonate
synthesis are outlined in Scheme 2. This strategy in-
volves the diastereoselective addition of a metal phos-
phite to a masked oxo sulfinimine to give the R-amino
phosphonate followed by hydrolysis and reduction of an
intermediate cyclic imino phosphonate. The sulfinimine-
mediated asymmetric Strecker synthesis and this pro-
tocol were recently employed in the asymmetric synthesis
of proline and pipecolic acid derivatives.20
(21) For a review on sulfinimine-derived polyfunctionalized chiral
building blocks, see: Davis, F. A.; Chao, B.; Andemichael, Y. W.;
Mohanty, P. K.; Fang, T.; Burns, D. M.; Rao, A.; Szewczyk J . M.
Heteroatom Chem. 2002, 13, 486.
(22) (a) Davis, F. A.; Zhang, Y.; Andemichael, Y.; Fang, T.; Fanelli,
D. L.; Zhang, H. J . Org. Chem. 1999, 64, 1403. (b) Fanelli, D. L.;
Szewczyk, J . M.; Zhang, Y.; Reddy, G. V.; Burns, D. M.; Davis, F. A.
Org. Synth. 2000, 77, 50.
(17) Maury, C.; Wang, Q.; Gharbaoui, T.; Chiadmi, M.; Tomas, A.;
Royer, J .; Husson, H.-P. Tetrahedron 1997, 53, 3627.
(18) Katritzky, A. R.; Qiu, G.; Yang, B.; Steel, P. J . J . Org. Chem.
1998, 63, 6699.
(19) Schlemminger, I.; Saida, Y.; Groeger, H.; Maison, W.; Durot,
N.; Sasai, H.; Shibasaki, M.; Martens, J . J . Org. Chem. 2000, 65, 4818.
(20) Davis, F. A.; Zhang, H.; Lee, S. H. Org. Lett. 2001, 3, 759.
J . Org. Chem, Vol. 69, No. 11, 2004 3775

Davis et al.
SCHEME 4
amino phosphonate (2R,7S)-(-)-21 in 49% yield (see
below). All attempts to obtain identifiable material from
the hydrolysis of (SS,R)-13d (n ) 4), under any of these
conditions, was unsuccessful. Thus, this methodology
reaches its limit with the production of seven-membered
cyclic R-amino phosphonates.
A variety of hydrogenation catalysts, Pd/C, Pd black,
and Raney Ni, were investigated for reduction of the
imines to the cyclic amino phosphonates, but these
catalysts systems resulted in decomposition and/or re-
covery of starting material. However, Adam’s catalyst
(PtO2) in ethanol for 12 h under atmospheric H2 afforded
the corresponding cyclic R-amino phosphonates 19 to 21
in 49-87% yields. It is interesting to note that reduction
of the related cyclic imino carboxylic acids was successful
using Pd/C/H2 within 5 h.20 In all cases, only a single
diastereoisomer was detected on the basis of the 31P NMR
spectra. The Mosher amide of (R)--(-)-O,O-diethyl (pyr-
rolidin-2-yl)phosphonate (19a ) indicated that it was
>95% enantiomerically pure. Comparison of the specific
rotation of (R)-(-)-19a with a literature value confirms
that the predicted absolute configuration (see above) was
indeed R.14,23 The cis geometry is expected in all cases
because H2 adds from the least hindered direction. This
stereochemical preference was also observed for the
hydrogenation of imino acids in the synthesis of cyclic
amino acid analogues.20 Furthermore, a NOESY study
of (2R,6R)-(-)-O,O-diethyl 6-phenylpiperidin-2-ylphos-
phonate (20b) confirmed the cis relationship of the 2,6-
substituents.
Cyclic Qu a ter n a r y R-Am in o P h osp h on a tes. To
prepare quaternary R-amino phosphonates using the
masked oxo sulfinimine protocol requires a sulfinimine
derived from a masked oxo ketone. 4,4-Dimethoxypen-
tanoic acid methyl ester (22) was treated with 1.25 equiv
of N,O-dimethylhydroxylamine hydrochloride followed by
8 equiv of methyl or phenylmagnesium bromide (Scheme
6). The corresponding ketones 23 (R ) Me, Ph) were
isolated in 75-80% yields by chromatography.24 Next, the
masked oxo ketones were treated with (S)-(+)-5 and Ti-
(OEt)4 in DCM, but the reaction proved to be very slow,
affording (S)-(+)-24 (R ) Me) in 68% yield after refluxing
for 30 h. No reaction between 23 (R ) Ph) and (S)-5 was
observed, and this may be due to a combination of
reduced reactivity of the phenyl ketone and steric hin-
drance. Because the barrier to planar inversion in ketone-
derived sulfinimines is low, (S)-(+)-24 was isolated as a
6:1 mixture of inseparable E/Z isomers.12c,25 The sulfin-
imine mixture was next treated with lithium diethyl
phosphite to give a 6:1 mixture of R-amino phosphonate
diastereoisomers (SS,R)-25 and (SS,S)-25, which were also
inseparable by chromatography. Amino phosphonate
(SS,R)-25 is predicted to be the major isomer based on
the stereoinduction model for phosphite addition to
sulfinimines (see above).12c
TABLE 1. Ad d ition of Meta l Dieth yl P h osp h ite to
(S)-Su lfin im in es a t -78 °C in THF
base (MHMDS)
R-amino
phosphonate (% de)b
% yielda
entry sulfinimines
M )
1
2
3
4
5
6
7
8
9
9a (n ) 1)
9b (n ) 2)
9c (n ) 3)
Li
Li
Li
Na
K
Li
Na
K
Li
Li
Li
Li
(SS,R)-12a
(SS,R)-12b
(SS,R)-12c
92 (93)
95 (94)
93c (76)
92c (72)
93c (74)
91c (88)
72c (82)
91 (98)
74 (98)
91 (94)
92 (97)
87 (94)
10a (n ) 1)
(SS,R)-13a
10b (n ) 2)
10c (n ) 3)
10d (n ) 4)
11
(SS,R)-13b
(SS,R)-13c
(SS,R)-13d
(SS,R)-14
10
11
12
a
Isolated yield of major diastereoisomer. b Determined from the
31P NMR spectra. c Mixture of diastereoisomers that were insepa-
rable.
ketal (Scheme 5). This produces the amino carbonyl 15,
which immediately cyclizes to give the imino phospho-
nates 16 and 17, and therefore was not detected. The
choice of hydrolysis and workup conditions is important.
The optimum conditions were hydrolysis with 3 N HCl
in THF and neutralizing with solid NaHCO3 at 0 °C. For
example, these conditions produced (R)-16b (R ) Me) in
69% isolated yield, but if aqueous saturated NaHCO3
solution were employed to neutralize the reaction, the
yield was only 31%. It was also important to minimize
the contact times with silica gel to avoid decomposition.
Consequently, the imines were flushed through a short
pad of silica gel with DCM/MeOH (90:10) in less than 10
min for best results. All attempts to isolate 17a under
any of these conditions met with failure.
The NMR of the crude reaction mixture for the hy-
drolysis/cyclization of (SS,R)-(+)-13c (n ) 3) suggests that
it exists as an equilibrating mixture of the amino carbo-
nyl 15 (R ) Me, n ) 3) and the cyclic imine 18. This
conclusion was based on the appearance of two absorp-
tions in the 31P NMR, at δ 25.7 and 25.9, and the fact
that hydrogenation (see below) of the crude reaction
mixture gave the corresponding seven-membered cyclic
When the ketal amino phosphonates were hydrolyzed
with 6 N HCl, enantiomers (R)- and (S)-26 were obtained
in 75% yield. Hydrogenation, as before of (R)- and (S)-
26, can in principle give two diastereoisomers if H2 adds
from both faces of the C-N double bond. The fact that
(23) Groth, U.; Richter, L.; Schollkopf, U. Tetrahedron 1992, 48, 117.
(24) Williams, J . M.; J obson, R. B.; Yasuda, N.; Marchesini, G.;
Dolling, U.-H.; Grabowski, J . J . Tetrahedron Lett. 1995, 36, 5461.
(25) Davis, F. A.; Kluger, E. W. J . Am. Chem. Soc. 1976, 98, 302.
3776 J . Org. Chem., Vol. 69, No. 11, 2004

Asymmetric Synthesis of Cyclic R-Amino Phosphonates
SCHEME 5
SCHEME 6
27 gave a single absorption in the 31P NMR suggests H2
adds from the least hindered direction affording enanti-
omers (2R,5S)-27 and (2S,5R)-27. The Mosher amide
indicates that the enantiomeric purity is 50%, which
suggests that somewhere in the transformation of 25 to
27 the enantiomers failed to react at the same rate and/
or were lost. The major enantiomer is predicted to have
the (2R,5S) configuration based on the reasonable as-
sumption that amino phosphonate (SS,R)-25 is the major
diastereoisomer for phosphite addition (Scheme 6).
In summary, masked oxo sulfinimines are employed
in new methodology for the asymmetric synthesis of five-,
six-, and seven-membered cyclic R-amino phosphonates.
Modest ee values (50%) were observed in the preparation
of quaternary example 27 because the requisite ketone-
derived sulfinimines were formed as inseparable E,Z
mixtures.
Exp er im en ta l Section
4,4-Dimethoxybutanal (6a ),20 5,5-dimethoxypentanal (6b),26
6,6-dimethoxyhexanal (6c),26 4,4-(ethylenedioxy)pentanal (7a),20
J . Org. Chem, Vol. 69, No. 11, 2004 3777

Davis et al.
5,5-(ethylenedioxy)hexanal (7b),20 7,7-(ethylenedioxy)octanal
(7d ),27 methyl 6,6-(ethylenedioxy)heptanoate,28 5,5-(ethylene-
dioxy)-5-phenylpentanal (8),20 (S)-(+)-N-[5,5-(ethylenedioxy)-
5-phenyl-pentanylidene]-p-toluenesulfinamide (11),20 (S)-(+)-
N-(5,5-ethylenedipentanylidene)-p-toluenesulfinamide (10a ),
and (S)-(+)-N-[5,5-(ethylenedioxy)hexanylidene]-p-toluene-
sulfinamide (10b)20 were prepared according to literature
procedures.
6,6-(Eth ylen edioxy)h eptan al (7c). In an oven-dried, single-
necked, 100-mL, round-bottom flask equipped with a magnetic
stir bar and a rubber septum under an argon balloon was
placed methyl 6,6-(ethylenedioxy)heptanoate (0.50 g, 2.5 mmol)
in DCM (20 mL). The solution was cooled to -78 °C, DIBAL-H
(3.2 mL, 3.2 mmol, 1 M solution in CH2Cl2) was slowly added,
and the reaction mixture was stirred for 2 h. At this time, the
reaction was quenched at -78 °C by addition of MeOH (1.0
mL) and saturated Na2SO4 (3 mL). After the mixture was
stirred at rt for 18 h, anhydrous Na2SO4 (4 g) and MgSO4 (1
g) were added and the solution was stirred for 1 h. At this
time, the solution was filtered and concentrated. Chromatog-
raphy (EtOAc/hexane, 10:90) gave 0.31 g (72%) of an oil: 1H
NMR (CDCl3) δ 1.31 (s, 3 H), 1.47 (m, 2 H), 1.62 (m, 4 H), 2.48
(m, 2 H), 3.99 (m, 4 H), 9.76 (t, J ) 2.3 Hz, 1 H). Spectral
properties were consistent with literature values.29
85) gave an oil: yield 62%; [R]20D +262 (c 1.6 CHCl3); IR (neat)
1
2945, 1620, 1068 cm-1; H NMR (CDCl3) δ 1.25 (s, 3 H), 1.59
(m, 2 H), 1.63 (m, 4 H), 2.39 (s, 3 H), 2.48 (m, 2 H), 3.89 (m, 4
H), 7.28 (d, J ) 8.4 Hz, 2 H), 7.53 (d, J ) 8.2 Hz, 2 H), 8.20 (t,
J ) 4.8 Hz, 1 H); 13C NMR (CDCl3) δ 22.1, 24.3, 24.4, 26.2,
36.6, 39.5, 65.3, 110.6, 125.3, 130.5, 142.3, 142.6, 167.7; HRMS
calcd for C16H23NO3SNa (M + Na) 332.1296, found 322.1289.
(S)-(+)-N-[7,7-(E t h ylen ed ioxy)oct a n ylid en e]-p -t olu -
en esu lfin a m id e (10d ). Chromatography (EtOAc/hexane, 15:
85) gave an oil: yield 62%; [R]20D +228 (c 2.0 CHCl3); IR (neat)
1
2942, 1620, 1072 cm-1; H NMR (CDCl3) δ 1.30 (s, 3 H), 1.36
(m, 4 H), 1.60 (m, 4 H), 2.40 (s, 3 H), 2.48 (m, 2 H), 3.93 (m, 4
H), 7.30 (d, J ) 8.0 Hz, 2 H), 7.56 (d, J ) 8.1 Hz, 2 H), 8.22 (t,
J ) 4.8 Hz, 1 H); 13C NMR (CDCl3) δ 21.8, 24.1, 25.7, 29.6,
36.1, 39.4, 65.0, 110.3, 124.9, 130.2, 142.0, 142.3, 167.5. Anal.
Calcd for C17H25NO3S: C, 63.13; H, 7.79; N, 4.43. Found: C,
63.05; H, 8.12; N, 4.18.
(SS,R)-(+)-O,O-Dieth yl N-(p-Tolu en esu lfin yl)-1-a m in o-
4,4-d im eth oxybu tylp h osp h on a te (12a ). Typ ica l P r oce-
d u r e. In an oven-dried, 100-mL, single-necked, round-bottom
flask fitted with a rubber septum and a magnetic stir bar
under an argon balloon was placed (S)-(+)-9a (0.27 g, 1.0
mmol) in THF (15 mL), which was then cooled to -78 °C. In
a separate 50-mL, single-necked, round-bottom flask fitted
with a rubber septum and a magnetic stir bar under an argon
balloon was placed diethyl phosphite (0.26 mL, 2.0 mmol) in
THF (15 mL). The solution was cooled -78 °C, and LiHMDS
(2.0 mL, 2.0 mmol) was slowly added. The reaction mixture
was stirred for 0.25 h, cannulated to the solution of (+)-9a ,
stirred for 1 h at -78 °C, and quenched by addition of
saturated NH4Cl (2 mL). The organic phase was extracted with
EtOAc (3 × 5 mL), washed with H2O (2 × 5 mL) and brine (5
mL), dried (MgSO4), and concentrated. Flash chromatography
(CH2Cl2/MeOH, 95:5) followed by recrystallization (EtOAc/
hexane, 1:10) afforded 0.37 g (92%) of a solid: mp 74-75 °C;
(S)-(+)-N-(4,4-Dim eth oxybu ta n ylid en e)-p-tolu en esu lf-
in a m id e (9a ). Typ ica l P r oced u r e. In an oven-dried, single-
necked, 25-mL, round-bottom flask equipped with a magnetic
stir bar and a rubber septum under an argon balloon were
placed (S)-(+)-5 (0.16 g, 1 mmol) and 6a (0.26 g, 2 mmol) in
DCM (10 mL). Titanium(IV) ethoxide (1.3 mL, 6 mmol) was
added, and the reaction mixture was stirred at rt for 2 h. At
this time, the reaction mixture was cooled to 0 °C, H2O (3 mL)
was added, and the reaction mixture was filtered through
Celite. The organic phase was washed with H2O (1 × 5 mL)
and brine (1 × 3 mL), dried (MgSO4), and concentrated.
Chromatography (EtOAc/hexane, 15:85) gave 0.18 g (67%) of
[R]20 +80.7 (c 1.0 CHCl3); IR (KBr) 3466, 3222, 2988, 1054
D
an oil: [R]20 +327 (c 1.0 CHCl3); IR (neat) 2945, 1601, 1442,
cm-1; 1H NMR (CDCl3) δ 1.33 (m, 6 H), 1.92 (m, 4 H), 2.41 (s,
3 H), 3.36 (s, 3 H), 3.38 (s, 3 H), 3.53 (m, 1 H), 4.12 (m, 4 H),
4.46 (t, J ) 5.1 Hz, 1 H), 4.58 (m, 1 H), 7.34 (d, J ) 8.1 Hz, 2
H), 7.56 (d, J ) 8.1 Hz, 2 H); 13C NMR (CDCl3) δ 16.7, 16.8,
21.7, 27.4, 29.1, 50.1 (d, J CP ) 154 Hz), 53.1, 53.3, 62.7 (d,
J COP ) 6.7 Hz), 63.1 (d, J COP ) 6.9 Hz), 104.5, 126.3, 129.9,
D
1087 cm-1
;
1H NMR (CDCl3) δ 1.99 (m, 2 H), 2.40 (s, 3 H),
2.56 (m, 2 H), 3.28 (s, 3 H), 3.29 (s, 3 H), 4.36 (t, J ) 5.9 Hz,
1 H), 7.30 (d, J ) 8.1 Hz, 2 H), 7.56 (d, J ) 8.1 Hz, 2 H), 8.24
(t, J ) 4.4 Hz, 1 H); 13C NMR (CDCl3) δ 22.0, 28.8, 31.7, 53.8,
53.9, 104.3, 125.2, 130.4, 142.3, 142.5, 167.0. Anal. Calcd for
141.5, 141.9; 31P NMR (CDCl3) δ 24.59. Anal. Calcd for C17H30
-
C
13H19NO3S: C, 57.97; H, 7.11; N, 5.20. Found: C, 57.84; H,
7.29; N, 5.46.
NO6PS: C, 50.11; H, 7.42; N, 3.44. Found: C, 49.99; H, 7.67;
N, 3.57.
(S)-(+)-N-(5,5-Dim eth oxypen tan yliden e)-p-tolu en esu lf-
in a m id e (9b). Chromatography (EtOAc/hexane, 15:85) gave
(SS,R)-(+)-O,O-Dieth yl N-(p-Tolu en esu lfin yl)-1-a m in o-
5,5-d im eth oxyp en tylp h osp h on a te (12b). Chromatography
an oil: yield 76%; [R]20 +232 (c 2.1 CHCl3); IR (neat) 2949,
D
1620, 1071 cm-1; H NMR (CDCl3) δ 1.64 (m, 4 H), 2.38 (s, 3
1
(CH2Cl2/MeOH, 95:5) gave an oil; yield 95%; [R]20 +63.2 (c
D
H), 2.49 (m, 2 H), 3.26 (s, 3 H), 3.27 (s, 3 H), 4.33 (t, J ) 5.5
Hz, 1 H), 7.28 (d, J ) 8.1 Hz, 2 H), 7.52 (d, J ) 8.1 Hz, 2 H),
8.21 (t, J ) 4.5 Hz, 1 H); 13C NMR (CDCl3) δ 20.8, 21.8, 32.2,
35.9, 53.2, 104.5, 124.9, 130.2, 142.1, 142.2, 167.1; HRMS calcd
for C14H21NO3SNa (M + Na) 306.1140, found 306.1140.
(S)-(+)-N-(6,6-Dim eth oxyh exa n ylid en e)-p-tolu en esu lf-
in a m id e (9c). Chromatography (EtOAc/hexane, 15:85) gave
0.7 CHCl3); IR (neat) 3452, 3099, 2977, 1577, 1092 cm-1; H
1
NMR (CDCl3) δ 1.23 (m, 6 H), 1.54 (m, 4 H), 1.81, (m, 1 H),
1.89 (m, 1 H), 2.34 (s, 3 H), 3.26 (s, 6 H), 3.41 (m, 1 H), 3.98
(m, 4 H), 4.32 (t, 1H, J ) 5.1 Hz), 4.47 (m, 1 H), 7.23 (d, J )
8.1 Hz, 2 H), 7.56 (d, J ) 8.1 Hz, 2 H); 13C NMR (CDCl3) δ
16.7, 16.8, 21.4, 21.8, 31.4, 32.3, 51.0 (d, J CP ) 154 Hz), 53.1,
53.2, 62.8 (d, J COP ) 6.7 Hz), 63.1 (d, J COP ) 6.8 Hz), 104.6,
126.2, 129.9, 141.7, 142.0; 31P NMR (CDCl3) δ 24.76. Anal.
Calcd for C18H32NO6PS: C, 51.29; H, 7.65; N, 3.32. Found: C,
51.41; H, 7.76; N, 3.47.
an oil: yield 52%; [R]20 +263 (c 0.9 CHCl3); IR (neat) 2945,
D
1620, 1492, 1096 cm-1; 1H NMR (CDCl3) δ 1.31 (m, 2 H), 1.51
(m, 4H), 2.31 (s, 3 H), 2.41 (m, 2 H), 3.20 (s, 3 H), 3.21 (s, 3
H), 4.23 (t, J ) 5.6 Hz), 7.21 (d, J ) 8.0 Hz, 2 H), 7.47 (d, J )
8.1 Hz, 2 H), 8.14 (t, J ) 4.7 Hz, 1 H); 13C NMR (CDCl3) δ
21.8, 24.5, 25.5, 32.6, 36.1, 53.1, 104.6, 124.9, 130.2, 142.0,
(SS,R)-(+)-O,O-Dieth yl N-(p-tolu en esu lfin yl)-1-a m in o-
6,6-d im eth oxyh exylp h osp h on a te (12c): inseparable mix-
ture (dr 88:12); yield 93% of an oil; [R]20 +40.9 (c 1.4 CHCl3);
D
142.3, 167.3; HRMS calcd for
320.1296, found 320.1288.
C15H23NO3SNa (M + Na)
IR (neat) 3312, 3145, 2931, 1092 cm-1
;
1H NMR (CDCl3)
(major) δ 1.27 (m, 8 H), 1.57 (m, 4 H), 1.85, (m, 1 H), 1.92 (m,
1 H), 2.31 (s, 3 H), 3.27 (s, 6 H), 3.41 (m, 1 H), 4.01 (m, 4 H),
4.16 (t, J ) 5.0 Hz), 4.36 (m, 1 H), 7.19 (d, J ) 8.1 Hz, 2 H),
7.58 (d, J ) 8.1 Hz, 2 H); (minor) δ 1.27 (m, 8 H), 1.57 (m, 4
H), 1.85, (m, 1 H), 1.92 (m, 1 H), 2.31 (s, 3 H), 3.26 (s, 6 H),
3.41 (m, 1 H), 4.01 (m, 4 H), 4.16 (t, J ) 5.0 Hz), 4.36 (m, 1 H),
7.19 (d, J ) 8.1 Hz, 2 H), 7.58 (d, J ) 8.1 Hz, 2 H); 13C NMR
(S)-(+)-N-[6,6-(E t h ylen ed ioxy)h ep t a n ylid en e]-p -t olu -
en esu lfin a m id e (10c). Chromatography (EtOAc/hexane, 15:
(26) Schreiber, S. L.; Claus, R. E.; Reagan, J . Tetrahedron Lett. 1982,
23, 3867.
(27) Gu, J .-X.; Li, Z.-Y.; Lin, G.-Q. Tetrahedron: Asymmetry 1992,
3, 1523.
(28) Cavallaro, R. A.; Filocamo, L.; Caluppi, A.; Galione, A.; Brufani,
M.; Genazzani, A. A. J . Med. Chem. 1999, 42, 2527.
(29) Kim, S.; Kim, Y. G.; Kim, D.-I. Tetrahedron Lett. 1992, 33, 2565.
(CDCl3) δ 16.9, 17.0, 20.4, 25.1, 25.9, 29.8, 30.3, 51.6 (d, J CP
)
153 Hz), 54.0, 54.2, 63.9 (d, J COP ) 6.7 Hz), 64.2 (d, J COP ) 6.7
Hz), 104.6, 125.2, 129.1, 142.6, 143.9; 31P NMR (CDCl3) (major)
3778 J . Org. Chem., Vol. 69, No. 11, 2004

Asymmetric Synthesis of Cyclic R-Amino Phosphonates
δ 24.88, (minor) δ 25.16. Anal. Calcd for C19H34NO6PS: C,
mL) was slowly added, and the reaction mixture was stirred
for 2 h at this temperature, neutralized by addition of solid
NaHCO3 (0.5 g), dried (MgSO4), and concentrated. Chroma-
tography (CH2Cl2/MeOH, 95:5) gave 0.074 g (72%) of an oil:
52.40; H, 7.87; N, 3.22. Found: C, 52.11; H, 7.66; N, 3.38.
(SS,R)-(+)-O,O-Dieth yl N-(p-tolu en esu lfin yl)-1-a m in o-
4,4-(eth ylen ed ioxy)-p en tylp h osp h on a te (13a ): chroma-
[R]20 +86.5 (c 1.0 CHCl3); IR (neat) 2980, 1618, 1248, 1029
tography (CH2Cl2/MeOH, 95:5); yield 91%; mp 96-97 °C; [R]20
D
D
cm-1; 1H NMR (CDCl3) δ 1.34 (m, 6 H), 2.14 (m, 2 H), 2.68 (m,
2 H), 4.18 (m, 4 H), 4.40 (m, 1 H), 7.74 (m, 1 H); 13C NMR
(CDCl3) δ 16.8, 16.9, 22.5, 37.6, 62.6 (d, J COP ) 6.6 Hz), 63.0
+82.7 (c 0.6 CHCl3); IR (KBr) 3474, 3179, 2981, 1597, 1052
cm-1; 1H NMR (CDCl3) δ 1.30 (m, 6 H), 1.35 (s, 3 H), 1.84, (m,
1 H), 1.92 (m, 1 H), 2.01 (m, 2 H), 2.41 (s, 3 H), 3.56 (m, 1 H),
3.95 (s, 4 H), 4.02 (m, 4 H), 4.52 (m, 1 H), 7.29 (d, J ) 8.0 Hz,
2 H), 7.60 (d, J ) 8.1 Hz, 2 H); 13C NMR (CDCl3) δ 15.8, 15.9,
(d, J COP ) 6.7 Hz), 70.2 (d, J CP ) 159 Hz), 170.5 (d, J CNCP
)
-
15.4 Hz); 31P NMR (CDCl3) δ 25.45; HRMS calcd for C8H16
NO3PNa (M + Na) 228.0766, found 228.0773.
20.7, 23.3, 25.7, 34.2, 49.8 (d, J CP ) 154 Hz), 61.8 (d, J COP
6.5 Hz), 62.1 (d, J COP ) 6.8 Hz), 64.0, 64.1, 109.1, 125.2, 128.9,
140.8, 141.0; 31P NMR (CDCl3) δ 24.75. Anal. Calcd for C18H30
)
(R)-(+)-O,O-Dieth yl 5-Meth yl-3,4-d ih yd r o-2H-p yr r ole-
2-p h osp h on a te (16b). Chromatography (CH2Cl2/MeOH, 95:
-
5) gave an oil; yield 59%; [R]20 +98.3 (c 1.0 CHCl3); IR (neat)
NO6PS: C, 51.54; H, 7.21; N, 3.34. Found: C, 51.80; H, 7.47;
N, 3.39.
D
2982, 1643, 1246, 1055 cm-1
;
1H NMR (CDCl3) δ 1.32 (m, 6
H), 2.08 (m, 3 H), 2.19 (m, 2 H), 2.67 (m, 2 H), 4.15 (m, 4 H),
4.34 (m, 1 H); 13C NMR (CDCl3) δ 15.6, 18.8, 23.3, 38.3, 61.1
(d, J COP ) 6.7 Hz), 61,5 (d, J COP ) 6.7 Hz), 68.6 (d, J CP ) 157
Hz), 177.7 (d, J CNCP ) 14.8 Hz); 31P NMR (CDCl3) δ 26.21;
HRMS calcd for C9H19NO3P (M + H) 220.1103, found 220.1105.
(R)-(-)-O,O-Dieth yl 6-Meth yl-2,3,4,5-tetr a h yd r op yr i-
d in e-2-p h osp h on a te (17b). Chromatography (CH2Cl2/MeOH,
(SS,R)-(+)-O,O-Dieth yl N-(p-Tolu en esu lfin yl)-1-a m in o-
5,5-(eth ylen ed ioxy)h exylp h osp h on a te (13b). Chromatog-
raphy (CH2Cl2/MeOH, 95:5) gave an oil: yield 72%; [R]20
D
+60.5 (c 1.5 CHCl3); IR (neat) 3479, 3188, 2981, 1031 cm-1
;
1H NMR (CDCl3) δ 1.30 (m, 6 H), 1.32 (s, 3 H), 1.59 (m, 2 H),
1.61 (m, 2 H), 1.71 (m, 1 H), 1.93 (m, 1 H), 2.40 (s, 3 H), 3.51
(m, 1 H), 3.93 (m, 4 H), 4.05 (m, 4 H), 4.48 (m, 1 H), 7.29 (d,
J ) 8.0 Hz, 2 H), 7.62 (d, J ) 8.1 Hz, 2 H); 13C NMR (CDCl3)
δ 16.8, 16.9, 20.8, 21.8, 24.3, 32.3, 39.0, 51.0 (d, J CP ) 153 Hz),
62.8 (d, J COP ) 6.8 Hz), 63.2 (d, J COP ) 7.0 Hz), 65.1, 110.3,
126.1, 129.9, 142.0, 142.2; 31P NMR (CDCl3) δ 24.82. Anal.
Calcd for C19H32NO6PS: C, 52.64; H, 7.44; N, 3.23. Found: C,
52.38; H, 7.80; N, 2.83.
95:5) gave an oil; yield 82%; [δ]20 -15.4 (c 0.4 CHCl3); IR
D
1
(neat) 2941, 1659, 1248, 1055 cm-1; H NMR (CDCl3) δ 1.26
(m, 6 H), 1.52 (m, 1 H), 1.64 (m, 1 H), 1.87 (m, 2 H), 1.95 (m,
3 H), 2.06 (m, 2 H), 3.81 (m, 1 H), 4.15 (m, 4 H); 13C NMR
(CDCl3) δ 16.8, 18.5, 18.6, 21.8, 28.2, 30.4, 57.6 (d, J CP ) 166
Hz), 62.4 (d, J COP ) 6.8 Hz), 63.1 (d, J COP ) 6.9 Hz), 171.7 (d,
J CNCP ) 15.8 Hz); 31P NMR (CDCl3) δ 25.58; HRMS calcd for
(SS,R)-(+)-O,O-Dieth yl N-(p-Tolu en esu lfin yl)-1-a m in o-
6,6-(eth ylen ed ioxy)h ep tylp h osp h on a te (13c). Chromatog-
C
10H21NO3P (M + H) 234.1259, found 234.1254.
raphy (CH2Cl2/MeOH, 95:5) gave an oil: yield 91%; [R]20
(R)-(-)-O,O-Dieth yl 6-P h en yl-2,3,4,5-tetr a h yd r op yr i-
D
+80.2 (c 0.5 CHCl3); IR (neat) 3501, 3112, 2941, 1075 cm-1
;
d in e-2-p h osp h on a te (17c). Chromatography (CH2Cl2/MeOH,
95:5) gave an oil: yield 80%; [R]20 -89.8 (c 0.8 CHCl3); IR
1H NMR (CDCl3) δ 1.28 (m, 6 H), 1.31 (s, 3 H), 1.62 (m, 6 H),
1.82 (m, 1 H), 1.94 (m, 1 H), 2.41 (s, 3 H), 3.52 (m, 1 H), 4.01
(m, 4 H), 4.12 (m, 4 H), 4.38 (m, 1 H), 7.30 (d, J ) 8.1 Hz, 2
H), 7.62 (d, J ) 8.1 Hz, 2 H); 13C NMR (CDCl3) δ 16.8, 21.8,
24.2, 26.4, 26.5, 32.2, 39.3, 51.6 (d, J CP ) 154 Hz), 62.9 (d,
J COP ) 6.9 Hz), 63.1 (d, J COP ) 6.9 Hz), 65.0, 110.4, 126.2,
130.0, 141.8, 142.0; 31P NMR (CDCl3) δ 24.90. Anal. Calcd for
D
1
(neat) 2980, 1660, 1248, 1026 cm-1; H NMR (CDCl3) δ 1.35
(m, 6 H), 1.70 (m, 1 H), 1.73 (m, 1 H), 2.01 (m, 1 H), 2.13 (m,
1 H), 2.62 (m, 1 H), 2.74 (m, 1 H), 4.22 (m, 5 H), 7.38 (m, 3 H),
7.83 (d, J ) 7.0 Hz, 2 H); 13C NMR (CDCl3) δ 16.8, 17.1, 21.5,
28.1, 54.8 (d, J CP ) 159 Hz), 63.8 (d, J COP ) 6.7 Hz), 64.0 (d,
J COP ) 6.9 Hz), 127.7, 129.3, 133.1, 135.8, 176.5; 31P NMR
(CDCl3) δ 24.85; HRMS calcd for C15H23NO3P (M + H)
296.0.1416, found 296.1420.
C
20H34NO6PS: C, 53.68; H, 7.66; N, 3.13. Found: C, 53.92; H,
7.89; N, 2.98.
(R)-(-)-O,O-Dieth yl P yr r olid in e-2-p h osp h on a te (19a ).
Typ ica l P r oced u r e. In a 25-mL, single-necked, round-bottom
flask fitted with a magnetic stir bar under a hydrogen balloon
was placed PtO2 (ca. 4 mg) and (R)-(+)-16a (0.050 g, 0.24
mmol) in EtOH (5 mL). The reaction mixture was stirred at
rt for 16 h, filtered through Celite, and concentrated. Chro-
matography (CH2Cl2/MeOH, 95:5) gave 0.031 g (62%) of an
oil: [R]20D -16.7 (c 0.5 CHCl3) [lit.23 [R]20D +16.4 (c 1.0, CHCl3)
for the (S) isomer]. Spectral properties were consistent with
literature values.14,23
(SS,R)-(+)-O,O-Dieth yl N-(p-Tolu en esu lfin yl)-1-a m in o-
7,7-(eth ylen ed ioxy)octylp h osp h on a te (13d ). Chromatog-
raphy (CH2Cl2/MeOH, 95:5) gave an oil: yield 92%; [R]20
D
+66.1 (c 0.8 CHCl3); IR (neat) 3524, 3178, 2940, 1092 cm-1
;
1H NMR (CDCl3) δ 1.23 (m, 6 H), 1.26 (s, 3 H), 1.54 (m, 8 H),
1.78 (m, 1 H), 1.84 (m, 1 H), 2.34 (s, 3 H), 3.49 (m, 1 H), 3.89
(m, 4 H), 4.11 (m, 4 H), 4.38 (m, 1 H), 7.24 (d, J ) 8.0 Hz, 2
H), 7.54 (d, J ) 8.1 Hz, 2 H); 13C NMR (CDCl3) δ 16.7, 16.8,
21.7, 24.3, 26.2, 30.0, 31.7, 32.2, 39.5, 50.8 (d, J CP ) 154 Hz),
62.7 (d, J COP ) 6.9 Hz), 62.8 (d, J COP ) 7.0 Hz), 65.0, 110.5,
126.1, 129.9, 141.9, 142.0; 31P NMR (CDCl3) δ 24.95. Anal.
Calcd for C21H36NO6PS: C, 54.65; H, 7.86; N, 3.03. Found: C,
54.52; H, 7.99; N, 2.92.
(2R,5S)-(-)-O,O-Dieth yl 5-Meth ylp yr r olid in e-2-p h os-
p h on a te (19b). Chromatography (CH2Cl2/MeOH, 95:5) gave
an oil: yield 85%; [R]20 -6.8 (c 0.5 CHCl3); IR (neat) 3584,
D
2955, 1236, 1028 cm-1
;
1H NMR (CDCl3) δ 1.12 (d, J ) 6.2
(SS,R)-(+)-O,O-Dieth yl N-(p-Tolu en esu lfin yl)-1-a m in o-
5,5-(et h ylen ed ioxy)-5-p h en ylp en t ylp h osp h on a t e (14).
Chromatography (CH2Cl2/MeOH, 97:3) gave an oil: yield 87%;
Hz, 3 H), 1.26 (m, 6 H), 1.92 (m, 4 H), 2.14 (m, 1 H), 3.10 (m,
1 H), 3.29 (m, 1 H), 4.11 (m, 4 H); 13C NMR (CDCl3) δ 6.9,
[R]20 +42.0 (c 2.5 CHCl3); IR (neat) 3184, 2926, 1093 cm-1
;
21.1, 27.3, 33.9, 34.0, 54.8 (d, J CP ) 163 Hz), 62.5 (d, J COP
)
D
6.8 Hz), 62.8 (d, J COP ) 6.5 Hz); 31P NMR (CDCl3) δ 28.26;
HRMS calcd for C9H21NO3P (M + H) 222.1259, found 222.1250.
(2R,6S)-(-)-O,O-Diet h yl 6-Met h ylp ip er id in e-2-p h os-
p h on a te (20a ). Chromatography (CH2Cl2/MeOH, 95:5) gave
1H NMR (CDCl3) δ 1.23 (m, 6 H), 1.58 (m, 4 H), 1.83 (m, 2 H),
2.36 (s, 3 H), 3.46 (m, 1 H), 3.74 (m, 2 H), 4.01 (m, 6 H), 4.43
(m, 1 H), 7.23 (m, 5 H), 7.29 (d, J ) 8.0 Hz, 2 H), 7.45 (d, J )
8.1 Hz, 2 H); 13C NMR (CDCl3) δ 16.8, 16.9, 20.8, 21.8, 24.3,
32.3, 39.0, 51.0 (d, J CP ) 153 Hz), 62.8 (d, J COP ) 6.8 Hz), 63.2
(d, J COP ) 7.0 Hz), 65.1, 110.3, 126.2, 126.8, 129.2, 129.9, 130.5,
139.6, 141.8, 142.0; 31P NMR (CDCl3) δ 24.82. Anal. Calcd for
an oil: yield 87%; [δ]20 -8.4 (c 0.5 CHCl3); IR (neat) 3505,
D
2931, 1234, 1028 cm-1
;
1H NMR (CDCl3) δ 1.06 (d, J ) 6.2
Hz, 3 H), 1.33 (m, 7 H), 1.39 (m, 1 H), 1.58 (m, 1 H), 1.71 (m,
2 H), 1.85 (m, 2 H), 2.57 (m, 1 H), 2.98 (m, 1 H), 4.15 (m, 4 H);
13C NMR (CDCl3) δ 16.9, 23.3, 25.1, 25.2, 26.1, 34.2, 55.0 (d,
J CP ) 162 Hz), 62.5 (d, J COP ) 6.7 Hz), 62.7 (d, J COP ) 6.8 Hz);
31P NMR (CDCl3) δ 27.04; HRMS calcd for C10H23NO3P (M +
H) 236.1416, found 236.1414.
C
24H34NO6PS: C, 58.17; H, 6.92; N, 2.83. Found: C, 58.19; H,
7.06; N, 2.70
(R)-(+)-O,O-Diet h yl 3,4-Dih yd r o-2H -p yr r ole-2-p h os-
p h on a te (16a ). Typ ica l P r oced u r e. In a 25-mL, single-
necked, round-bottom flask equipped with a magnetic stir bar
was placed (S,R)-(+)-12a (0.20 g, 0.5 mmol) in THF (15 mL),
and the solution was cooled to 0 °C. At this time, 3 N HCl (2
(2R,6R)-(-)-O,O-Dieth yl 6-P h en yl-p ip er id in e-2-p h os-
p h on a te (20b). Chromatography (CH2Cl2/MeOH, 95:5) gave
J . Org. Chem, Vol. 69, No. 11, 2004 3779

Davis et al.
an oil: yield 87%; [R]20 +22.6 (c 1.5 CHCl3); IR (neat) 3466,
round-bottom flask equipped with a stirring bar and a rubber
septum under argon was placed (S)-(+)-5 (0.088 g, 0.57 mmol)
and 23 (0.4550 g, 2.84 mmol) in DCM (20 mL). To the solution
was added Ti(OEt)4 (1.8 mL, 8.52 mmol) and the solution was
refluxed for 30 h. At this time, the reaction mixture was cooled
to 0 °C, H2O (10 mL) was added, and the solution was filtered
through Celite. The organic phase was washed with H2O (2 ×
10 mL) and brine (5 mL), dried (Na2SO4), and concentrated.
Chromatography (EtOAc/hexane 35:65) gave 0.11 g (67%) of
a viscous oil as a 6:1 mixture of inseparable diastereoisomers;
D
2933, 1230, 1028 cm-1; 1H NMR (CDCl3) δ 1.24 (m, 6 H), 1.42
(m, 2 H), 1.61 (m, 1 H), 1.78 (m, 1 H), 1.94 (m, 3 H), 3.16 (m,
1 H), 3.60 (m, 1 H), 4.18 (m, 4 H), 7.27 (m, 5 H); 13C NMR
(CDCl3) δ 16.9, 25.3, 25.4, 25.7, 30.1, 34.4, 55.1 (d, J CP ) 162
Hz), 62.8 (d, J COP ) 6.5 Hz), 63.2 (d, J COP ) 6.7 Hz), 127.3,
127.8, 128.8; 31P NMR (CDCl3) δ 26.61; HRMS calcd for C15H24
NO3PNa (M + Na) 320.1392, found 320.1402.
-
(2R,7S)-(-)-O,O-Dieth yl 7-Meth yla zep a n e-2-p h osp h o-
n a te (21). In a 25-mL, single-necked, round-bottom flask fitted
with a magnetic stir bar was placed (S,R)-(+)-13c (0.12 g, 0.25
mmol) in THF (10 mL). The solution was cooled to 0 °C, 3 N
HCl (1 mL) was slowly added, and the reaction mixture was
stirred for 2 h at 0 °C. At this time, the reaction mixture was
neutralized with solid NaHCO3 (0.5 g), dried (MaSO4), and
concentrated. The crude mixture was loaded onto a short pad
of silica gel, washed (EtOAc/hexane, 60:40) to remove the
sulfinyl byproducts, and eluted (CH2Cl2/MeOH, 95:5). The
solution was concentrated, and the residue was dissolved in
EtOH (5 mL) and hydrogenated over PtO2 (2 mg) at balloon
pressure for 16 h. At this time, the reaction mixture was
filtered through Celite and concentrated. Chromatography
(CH2Cl2/MeOH, 95:5) gave 0.031 g (49%) of an oil: [R]20D -5.8
(c 0.7 CHCl3); IR (neat) 3516, 2963, 1212, 1025 cm-1; 1H NMR
(CDCl3) δ 1.02 (d, J ) 6.1 Hz, 3 H), 1.26 (m, 6 H), 1.68 (m, 8
H), 1.97 (m, 1 H), 2.76 (m, 1 H), 2.98 (m, 1 H), 4.12 (m, 4 H);
13C NMR (CDCl3) δ 16.5, 16.6, 21.3, 22,6, 24.1, 25.2, 26.1, 34.2,
[R]20 +30.3 (c 0.4, CHCl3); IR (neat) 1618, 1130, 1053 cm-1
;
D
1H NMR (CDCl3) δ 1.15 (s, 3 H), 1.83 (t, J ) 7.8 Hz, 2 H), 2.32
(s, 3 H), 2.34 (s, 3 H), 2.36 (m, 2 H), 3.06 (d, J ) 7 Hz, 6 H),
7.22 (d, J ) 7.8 Hz, 2 H), 7.57 (d, J ) 8.1 Hz, 2 H); 13C NMR
(CDCl3) δ 21.3, 21.9, 23.6, 32.3, 38.5, 48.6, 101.5, 125.5, 130.2,
142.2, 143.6, 182.3; HRMS calcd for C15H23NO3S (M + Na)
320.1296, found 320.1304.
(SS,R)-(+)-O,O-Dieth yl N-(p-Tolu en esu lfin yl)-1-a m in o-
4,4-d im eth oxy-1-m eth ylp en tylp h osp h on a te (25). In an
oven-dried, 100-mL, single-neck, round-bottom flask fitted with
a rubber septum and a magnetic stir bar under argon was
placed (S)-24 (0.23 g, 0.77 mmol) in THF (15 mL) and the
solution was cooled to -78 °C. In a second 50-mL, single-neck,
round-bottom flask fitted with a rubber septum and a magnetic
stirring bar under argon was placed diethyl phosphite (0.20
mL, 1.55 mmol) in THF (15 mL), the solution was cooled to
-78 °C, and LiHMDS (1.55 mL, 1.55 mmol) was slowly added.
The reaction mixture was stirred for 0.5 h and cannulated to
the solution of (S)-24, and the reaction mixture stirred for 1
h. At this time, the reaction was quenched by addition of
saturated NH4Cl (10 mL). The organic phase was separated,
washed with H2O (2 × 5 mL) and brine (5 mL), dried (MgSO4),
and concentrated. Chromatography (EtOAc) gave 0.33 g (94%)
of a viscous oil of a 6:1 inseparable mixture of diastereoiso-
56.7 (d, J CP ) 157 Hz), 61.2 (d, J COP ) 6.9 Hz), 61.7 (d, J COP
)
-
6.8 Hz); 31P NMR (CDCl3) δ 28.45; HRMS calcd for C11H24
NO3PNa (M + Na) 272.1392, found 272.1382.
Gen er al P r ocedu r e for P r epar ation of Mosh er Am ides.
In an oven-dried, 10-mL, single-necked, round-bottom flask
equipped with a magnetic stir bar and a rubber septum under
an argon balloon was placed approximately 0.015 g of (-)-19a
in dry THF (2 mL). To the solution was added 0.017 g of
Mosher’s chloride and of Et3N (0.085 mL). The reaction
mixture was stirred for 1 h at rt and quenched by addition of
saturated NH4Cl (1 mL). The solution was extracted with
EtOAc (2 × 2 mL), washed with H2O (1 mL) and brine (1 mL),
dried (MgSO4), and concentrated. The racemic Mosher amides
were prepared in a similar manner. Evaluation of the 19F, 1H,
and 31P NMR spectra of crude mixtures was used to determine
the enantiomeric purity of the ester.
mers: [R]20 56.0 (c 0.4, CHCl3); IR (neat) 1390, 1236, 1051,
D
963 cm-1; 1H NMR (CDCl3) δ 1.18 (t, J ) 7.2 Hz, 2 H), 1.22 (s,
3 H), 1.27 (m, 6 H), 1.56, 1.87 (m, 2 H), 1.98 (s, 3 H), 2.33 (s,
3 H), 3.10 (d, J ) 8.8 Hz, 6 H), 4.07 (m, 4 H), 4.28 (d, J ) 4.8
Hz, 1 H), 7.21 (d, J ) 7.9 Hz, 2 H), 7.54 (d, J ) 8.0 Hz, 2 H);
13C NMR (CDCl3) δ 16.9, 21.3, 21.8 (d, J CCP ) 11 Hz), 30.4,
31.8, 48.5, 58.7 (d, J CP ) 156.2 Hz), 60.8, 63.2 (d, J COP ) 7.4
Hz), 63.8 (d, J COP ) 7.0 Hz), 101.8, 125.8, 130.0, 141.7, 143.6;
31P NMR δ 26.32 (major), 26.62 (minor); HRMS calcd for
C19H34NO6PS (M + Na) 458.1742, found 458.1743.
5,5-Dim eth oxyh exa n -2-on e (23). In an oven-dried, single-
neck, 250-mL, round-bottom flask equipped with a stirring bar
and a rubber septum under argon was placed 2230 (2.00 g,
11.35 mmol) and dimethylhydroxylamine hydrochloride (1.38
g, 14.19 mmol) in THF (75 mL). The mixture was cooled to
-5 °C, and MeMgCl (38 mL, 114 mmol, 3 M solution in THF)
was added in over 2 h while the temperature was maintained
at -5 to -2 °C. At this time the reaction mixture was slowly
warm to room temperature, stirred for 8 h, and quench with
saturated NH4Cl solution (50 mL). The organic phase was
washed with H2O (2 × 15 mL) and brine (10 mL), dried (Na2-
SO4), and concentrated. Chromatography (EtOAc/hexane 20:
80) gave 1.45 g (80%) of a viscous oil: IR (neat) 1720, 1379,
(R)-(+)-O,O-Dieth yl 5-Meth yl-3,4-d ih yd r o-2-m eth ylp yr -
r ole-2-p h osp h on a t e (26). In a 25-mL, single-neck, round-
bottom flask fitted with a magnetic stirring bar was placed
25 (0.22 g, 0.5 mmol) in THF (15 mL). The solution was cooled
to 0 °C, 6 N HCl (1 mL) was slowly added, and the reaction
mixture was stirred for 2 h. At this time, the reaction was
neutralized with solid NaHCO3 (0.5 g), dried (MgSO4), and
concentrated. Chromatography (EtOAc/MeOH 90:10) gave
0.087 g (75%) of a viscous oil: [R]20 +20.2 (c 0.7, CHCl3); IR
D
(neat) 1643, 1251,1054, 960 cm-1; 1H NMR (CDCl3) δ 1.25 (m,
6 H), 1.42 (d, J ) 16 Hz, 3 H), 1.60 (m, 1 H), 2.00 (d, J ) 4.0
Hz, 3 H), 2.40 (m, 1 H), 2.58 (m, 2 H), 4.08 (m, 4 H); 13C NMR
(CDCl3) δ 16.9 (d, J CCP ) 4.0 Hz), 20.2, 24.1, 32.8, 40.1, 62.7
(d, J COP ) 7.0 Hz), 62.9 (d, J COP ) 7.0 Hz), 75.8 (d, J CP ) 158.1
Hz), 177.7 (d, J CNCP ) 13.4 Hz); 31P NMR δ 28.53; HRMS calcd
for C10H20NO3P (M + Na) 256.1078, found 256.1078.
1
1053 cm-1; H NMR (CDCl3) δ 1.06 (s, 3 H), 1.73 (t, J ) 7.9
Hz, 2 H), 1.98 (s, 3 H), 2.30 (t, J ) 7.9 Hz, 2 H), 3.00 (s, 6 H);
13C NMR (CDCl3) δ 208.4, 101.5, 48.6, 39.2, 30.5, 30.4, 21.4.
An HMRS could not be obtained due to compound instability.
4,4-Dim eth oxy-1-p h en ylp en ta n -1-on e. Chromatography
(EtOAc/hexane 5:95) gave 1.89 g (75%) of a viscous oil: IR
(2R,5S):(2S,5R)-(-)-O,O-Dieth yl 5-Meth yl-2-m eth ylp yr -
r olidin e-2-ph osph on ate (27). In an oven-dried, 25-mL single-
neck, round-bottom flask fitted with a magnetic stirring bar
was placed PtO2 (10 mg) (+)-26 (0.047 g, 0.20 mmol) in EtOH
(5 mL). The reaction mixture was stirred under a balloon
hydrogen atmosphere for 16 h and filtered through Celite.
Chromatography (EtOAc/MeOH 90:10) gave 0.039 g (82%) of
a white solid: mp 61-64; [R]20D -3.7 (c 0.32, CHCl3); IR (neat)
(neat) 1687, 1448-1053 cm-1 1H NMR (CDCl3) δ 2.19 (s, 3
;
H), 2.82 (t, J ) 6.3 Hz, 2 H), 3.21 (t, J ) 6.3 Hz, 2 H), 7.39 (m,
2 H), 7.49 (m, 1 H), 7.90 (m, 2 H); 13C NMR (CDCl3) δ 21.5,
30.9, 34.2, 48.7, 101.7, 128.4, 129.0, 130.0, 133.4, 137.3, 200.0;
HRMS calcd for C13H18O3 (M + Na), found 245.1145.
(S)-(+)-N-(4,4-Dim eth oxy-1-m eth ylp en tylid en e)-p-tolu -
en esu lfin a m id e (24). In an oven-dried, single-neck, 50-mL,
(30) Hodgson, D. M.; Glen, R.; Grant, G. H.; Redgrave, A. J . J . Org.
Chem. 2003, 68, 581.
(31) Roubaud, V.; Bliek, C.; Lauricella, R. Vila, F.; Siri, D.; Tordo,
P. Phosphorus, Sulfur, Silicon 1996, 112, 143.
3780 J . Org. Chem., Vol. 69, No. 11, 2004

Asymmetric Synthesis of Cyclic R-Amino Phosphonates
1225, 1031, 958 cm-1; 1H NMR (CDCl3) δ 1.25 (d, J ) 2.4 Hz,
3 H), 1.26 (m, 6 H), 1.30 (d, J ) 16 Hz, 3 H), 1.36 (m, 1 H),
1.53 (m, 2 H), 1.85 (m, 1 H), 2.24 (m, 1 H), 3.30 (m, 1 H), 4.10
(m, 4 H); 13C NMR (CDCl3) δ 16.9, 21.5 (d, J CCP ) 7 Hz), 24.8,
34.4, 35.6, 53.8 (d, J CCP ) 11.2 Hz), 60.5 (d, J CP ) 165.1 Hz),
62.3 (d, J COP ) 7.1 Hz), 63.6 (d, J COP ) 7 Hz); 31P NMR δ 30.22;
HRMS calcd for C10H22NO3P (M + Na) 236.1415, found
236.1415. The Mosher amide indicated that the compound was
50% enantiomeric pure. Compound 27 has been prepared in
racemic form.31
Ack n ow led gm en t. This work was supported by a
grant from the National Institutes of General Medical
Sciences (NIGMS 57870).
Su p p or tin g In for m a tion Ava ila ble: General experimen-
1
tal procedures and copies of H and 13C NMR spectra for all
new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
J O040127X
J . Org. Chem, Vol. 69, No. 11, 2004 3781