Improved asymmetric synthesis of aziridine 2-phosphonates using (S)-(+)-2,4,6-trimethylphenylsulfinamide

Article abstract of DOI:10.1021/jo030142m

The aza-Darzens reaction of lithium diethyl iodomethylphosphonate with enantiopure N-(2,4,6-trimethylphenylsulfinyl)imines affords a single diastereomeric N-sulfinylaziridine 2-phosphonate which, on treatment with MeMgBr, gives the corresponding NH-azirid

Full text of DOI:10.1021/jo030142m

Im p r oved Asym m etr ic Syn th esis of Azir id in e 2-P h osp h on a tes
Usin g (S)-(+)-2,4,6-Tr im eth ylp h en ylsu lfin a m id e
Franklin A. Davis,* Tokala Ramachandar, and Yongzhong Wu
Department of Chemistry, Temple University, Philadelphia, Pennsylvania 19122
fdavis@temple.edu
Received April 24, 2003
The aza-Darzens reaction of lithium diethyl iodomethylphosphonate with enantiopure N-(2,4,6-
trimethylphenylsulfinyl)imines affords a single diastereomeric N-sulfinylaziridine 2-phosphonate
which, on treatment with MeMgBr, gives the corresponding NH-aziridine 2-phosphonate chiral
building blocks. An improved asymmetric synthesis of (S)-(+)-2,4,6-trimethylphenylsulfinamide is
also given.
Aziridine 2-phosphonates are valuable polyfunction-
alized chiral building blocks for the asymmetric synthesis
of amino phosphonates because of their ability to undergo
highly regio- and stereospecific ring-opening reactions.1-6
Oxidation of NH-aziridine 2-phosphonates provides 2H-
azirine 2-phosphonates and 2H-azirine 3-phosphonates.4,7
The latter azirines are a new class of chiral imino
dienophiles that undergo Diels-Alder reactions to pro-
duce bicyclic aziridines that can be transformed into the
first examples of quaternary piperidine phosphonates.7
Chiral nonracemic amino phosphonic acids are important
amino acid analogues because many exhibit antibacterial,
anticancer, and antiviral activity as well as pesticidal,
insecticidal, and herbicidal properties.8
Recently, we described a new methodology for the
asymmetric synthesis of aziridine 2-phosphonates that
involves the addition of the anion of halomethylphospho-
nates 1 to enantiopure N-p-toluenesulfinylimines (S)-(+)-
2.2 In this aza-Darzens reaction, the aziridines were
formed as cis and trans mixtures of 3/4 that were difficult
to separate (Scheme 1). To circumvent this problem, the
intermediate R-chloro â-amino phosphonates 5 and 6
were isolated and cyclized with n-butyllithium to give the
enantiopure aziridines (SS,2S,3R)-3 and (SS,2R,3R)-4.
However, it was noted in one case that if the bulky N-tert-
butanesulfinylimine (S)-(+)-7 was used, the aziridine
(+)-8 was formed in good yield as a single diastereoiso-
mer. Unfortunately, all attempts, under acid or base
conditions, to remove the N-tert-butanesulfinyl auxiliary
without aziridine ring opening failed.
The advantage of the N-tert-butanesulfinyl versus the
N-p-toluenesulfinyl group is that Grignard reagents add
to the C-N bond to give amines in the former, while with
the latter auxiliary, attack at the sulfinyl sulfur produces
sulfoxides.9 This difference in reactivity was employed
in a highly selective method to deprotect N-p-toluene-
sulfinylaziridines by treating them with methylmagne-
sium bromide.2,10 This protocol affords the valuable NH-
aziridines, in excellent yield, without ring-opening, even
with highly activated examples. What we required was
an N-sulfinyl auxiliary that is large enough to produce
high diastereoselectivities in the aza-Darzens reaction
while permitting selective deprotection using our Grig-
nard protocol. The N-(2,4,6-trimethylphenylsulfinyl) aux-
iliary meets these requirements, as described herein.
Resu lts a n d Discu ssion
Senanayake and co-workers recently introduced meth-
odology for the asymmetric synthesis of diversely sub-
stituted sulfinamides (RS(O)NH2), which are the precur-
sors of sulfinimines (N-sulfinyl imines).11 This procedure
involves reacting Grignard reagents, such as 2,4,6-
trimethylphenylmagnesium bromide, with endo-(-)-1,2,3-
oxathiazolidine-2-oxide 9 to give the corresponding sul-
finate ester (-)-10 (Scheme 2). It was reported that on
treatment of 10 with sodium bis(trimethylsilyl)amide
(NaHMDS), (S)-(+)-2,4,6-trimethylphenylsulfinamide (11)
(1) (a) For a 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, 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, 1996; p 61.
(2) Davis, F. A.; Wu, Y.; Yan, H.; McCoull, W.; Prasad, K. R. J . Org.
Chem. 2003, 68, 2410.
(3) Pouset, C.; Larcheveque, M. Tetrahedron Lett. 2002, 34, 5257.
(4) Davis, F. A.; McCoull, W. Tetrahedron Lett. 1999, 40, 249.
(5) Davis, F. A.; McCoull, W.; Titus, D. D. Org. Lett. 2000, 1, 1053.
(6) Hanessian, S.; Bennani, Y. L.; Herve, Y. Synlett 1993, 35.
(7) Davis, F. A.; Wu, Y.; Yan, H.; Prasad, K. R.; McCoull, W. Org.
Lett. 2002, 4, 655.
(8) 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.
(9) 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.
(10) Davis, F. A.; Liu, H.; Zhou, P.; Fang, T.; Reddy, G. V.; Zhang,
Y. J . Org. Chem. 1999, 64, 7559.
(11) Han, Z.; Krishnamurthy, D.; Grover, P.; Fang, Q. K.; Senan-
ayake, C. H. J . Am. Chem. Soc. 2002, 124, 7880.
10.1021/jo030142m CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/15/2003
6894
J . Org. Chem. 2003, 68, 6894-6898

Asymmetric Synthesis of Aziridine 2-Phosphonates
SCHEME 1
SCHEME 2
(-)-menthyl-(S)-p-toluenesulfinate, LiHMDS, and alde-
hydes it was noted that if NaHMDS were used the ee’s
dropped form >98% to 66% ee.13 We attributed this result
to racemization of the sulfinimine by the more reactive
nucleophile. With this in mind, we treated (-)-10 with
2.2 equiv of LiHMDS at -78 °C to room temperature and
obtained a 70% isolated yield of (S)-(+)-11, following
chromatography and crystallization. Importantly the
specific rotation of the product had increased to +177.8°
and chiral HPLC indicated that the enantiomeric purity
was >98%.
With enantiopure (S)-(+)-2,4,6-trimethylphenylsul-
finamide (11) in hand, we proceeded to condense it in
the usual manner with 4-methoxybenzaldehyde, benzal-
dehyde, 4-trifluoromethylbenzaldehyde, and 4-nitroben-
zaldehyde in the presence of excess Ti(OEt)4.14 The
corresponding sulfinimines (S)-(+)-12a -d were isolated
in 78-82% yield (Scheme 2). Next, a solution of (S)-(+)-
12 and 2 equiv of diethyl iodomethylphosphonate were
treated at -78 °C with 2 equiv of LiHMDS (Scheme 3).
Importantly, sulfinimines 12a and 12b, having the
4-methoxyphenyl and phenyl groups, afford aziridines
(SS,2S,3R)-(-)-13a and (SS,2S,3R)-(-)-13b as single di-
astereoisomers in one pot and in 75-78% isolated yield
(Table 1, entries 1 and 3). The cis stereochemistry is
supported by the H2,3 proton coupling constants of J )
was obtained in 80% yield. The enantiomerically purity
was judged to be 99% by chiral HPLC analysis.11
However, in our hands, treatment of (-)-10 with
NaHMDS at -78 °C to room temperature gave a 55%
yield of sulfinamide 11 with a specific rotation of +98.0°.12
Chiral HPLC analysis indicated that sulfinamide (S)-(+)-
11 was only 55% enantiomerically pure. Attempts to
improve the purity by varying the equivalents of base,
temperature, and time were without success. In our
earlier studies on the one-pot synthesis of enantiopure
sulfinimines from the Andersen reagent, (1R,2S,5R)-
(13) Davis, F. A.; Reddy, R. E.; Szewczyk J . M.; Reddy, G. W.;
Portonovo, P. S.; Zhang, H.; Fanelli, D.; Thimma-Reddy, R.; Zhou, P.;
Carroll, P. J . J . Org. Chem. 1997, 62, 2555.
(14) (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.
Organic Syntheses 1999, 77, 50.
(12) In our work, we prepared and used the enantiomers of the
compounds described in ref 11. Specific rotations and melting points
were not provided.
J . Org. Chem, Vol. 68, No. 18, 2003 6895

Davis et al.
SCHEME 3
TABLE 1. Ad d ition of Lith iu m Ha lom eth ylp h osp h on a te
An ion s to Su lfin im in es (S)-(+)-12
SCHEME 4
â-amino
sulfinimine
aziridine 13a R-chlorophosphonate
entry
(X ))
1 (Z ))
(% yield)b
15/16 (% yield)b
1
2
3
4
5
6
7
12a (4-MeO)
I
Cl
I
I
Cl
I
(+)-13a (75%)
77:23 (70%) [77:23]d
12b (H)
12c (4-CF3)
(+)-13b (78%)
(+)-8b (72%)
43:57c (82%)
23:77 (70%) [1:1]d
53:47c (78%)
to the bulky N-sulfinyl group R. However, this alone
would not predispose the transition state toward a single
diastereomeric aziridine. The transformation also re-
quires that the iodo group occupy the axial position in
the transition state. Because halomethylphosphonate
anions, unlike enolates, lack configuration stability, we
suggest that the reason this position is preferred is that
there are fewer gauche interactions between the iodo and
ethoxy phosphonate groups when the former is in axial
position.
The explanation for the much lower selectivity on
addition of the lithium anion of 1 to sulfinimines 12c and
12d , which have electron-attracting groups, is less ap-
parent. One possibility is that π-acid π-base interactions
(π-stacking) between the 2,4,6-trimethylphenyl group and
the imino aryl group as in TS-2 may sterically alter the
equatorial-axial ratio of the iodo group which would
result in poorer selectivity. In support of this hypothesis
is the fact that sulfinimine 7b (X ) 4-CF3), having the
N-tert-butanesulfinyl auxiliary where π-stacking is un-
likely, affords a single diastereomeric aziridine (SS,2S,3R)-
(+)-8b in 72% yield (Scheme 1).
12d (4-NO2)
7b (4-CF3)
I
a
b
Aziridines were >98:2. Isolated yield. c Ratio of aziridine
d
diastereoisomers to â-amino R-iodophosphonate mixtures. Ratio
of 15/16 using the p-toluenesulfinyl auxiliary. See ref 2.
7.6 Hz2 and their conversion into known compounds (see
below). By contrast, sulfinimines 12c and 12d , having
the electron-attracting 4-trifluoromethylphenyl and 4-ni-
trophenyl groups, gave complex mixtures of products
consisting of the aziridines diastereomers 13c,d and
isomeric mixtures of the â-amino R-iodophosphonates 14.
All attempts to separate these mixtures proved unsuc-
cessful.
In an attempt to fix this problem, as we had done
previously, the â-amino R-chlorophosphonates 15c/16c
were prepared from (S)-(+)-12c and the lithium anion
of dimethyl chloromethylphosphonate (Scheme 3). For
comparison, a similar study was carried out with (+)-
12a , and these results are summarized in Table 1.
Unfortunately, chromatographically inseparable mix-
tures of the corresponding â-amino R-chlorophosphonates
15/16 were produced in both cases (Table 1, entries 2 and
5). This contrasts sharply with the results obtained when
the N-p-toluenesulfinyl auxiliary was employed and
separable mixtures of 15/16 (p-tolyl instead of mes) were
produced.2 This result may reflect the greater lipophilicity
of the mes group versus the p-tolyl group. It is interesting
to note that for 12a (X ) 4-MeO) similar ratios of 15/16
were observed for the N-2,4,6-trimethylphenylsulfinyl
and N-p-tolylsulfinyl auxiliaries (Table 1, entry 2),
whereas the ratios for 12c (X ) 4-CF3) were 23:77 and
1:1, respectively (Table 1, entry 5).
Rem ova l of th e N-Su lfin yl Au xilia r y. Reaction of
aziridines (S)-(+)-13a and (S)-(+)-13b with 2 equiv of
MeMgBr at -78 °C readily removed the 2,4,6-trimeth-
ylphenyl-sulfinyl group affording the corresponding NH-
aziridines (2S,3R)-(-)-17a and (2S,3R)-(-)-17b in 72 and
77% isolated yield (Scheme 4). Their physical properties
were in agreement with literature values,2 which further
serves to confirm the cis geometry of these aziridines.
We propose that the greater selectivity observed in the
aza-Darzens reaction of lithium iodomethylphosphonate
with sulfinimines having bulky N-sulfinyl auxiliaries is
primarily due to two types of steric interactions in
transition state TS-1. First, the iodomethylphosphonate
anion is highly favored to attack the C-N double opposite
6896 J . Org. Chem., Vol. 68, No. 18, 2003

Asymmetric Synthesis of Aziridine 2-Phosphonates
1
0.5, CHCl3); IR (neat) 3050, 1607, 1576, 1461 cm-1; H NMR
In summary, improved methodology has been intro-
duced for the asymmetric synthesis of NH-aziridine
2-phosphonates, which are valuable polyfunctionalized
chiral building blocks for R-amino phosphonates and 2H-
azirine 3-phosphonate synthesis. This new procedure
employs the N-(2,4,6-trimethylphenylsulfinyl)imines (S)-
(+)-12 and lithium diethyl iodomethylphosphonate. How-
ever, aryl sulfinimines containing electron-attracting
groups give complex mixtures with this protocol. Al-
though â-amino R-chloro phosphonates were produced
with improved diastereomeric ratios compared to the
N-(p-tolylsulfinyl) auxiliary, they were chromatographi-
cally inseparable, which may reflect the greater lipophi-
licity of the former auxiliary. In addition it was found
that the use of LiHMDS in place of NaHMDS in the
synthesis of (S)-(+)-2,4,6-trimethyl-phenylsulfinamide
(11) results in an enantiomerically pure product.
(CDCl3) δ 2.28 (s, 3 H), 2.50 (s, 6 H), 6.88 (s, 2 H), 7.46-7.47
(m, 3 H), 7.84-7.86 (m, 2 H), 8.83 (s, 1H); 13C NMR (CDCl3) δ
19.3, 21.5, 129.3, 129.9, 131.2, 132.9, 134.2, 135.7, 138.8, 142.1,
162.0. Anal. Calcd for C16H17NOS: C, 70.81; H, 6.31; N, 5.16.
Found: C, 71.13, H, 6.23, N, 4.97.
(S)-(+)-N-(p-Meth oxyben zylid en e)-2,4,6-tr im eth ylp h e-
n ylsu lfin a m id e (12a ): yield 78%; mp 67-68 °C; [R]20 98.8
D
(c 0.5, CHCl3); IR (neat) 1594, 1072 cm-1; H NMR (CDCl3) δ
1
2.28 (s, 3 H), 2.50 (s, 6 H), 3.86 (s, 3 H), 6.85 (s, 2 H), 6.94 (d,
J ) 9 Hz, 2 H), 7.79 (d, J ) 9 Hz, 2 H), 8.75 (s, 1 H); 13C NMR
(CDCl3) δ 17.6, 19.8, 54.2, 113.0, 125.7, 129.5, 130.2, 134.4,
137.1, 140.3, 159.5, 161.8. Anal. Calcd for C17H19NO2S: C,
67.74; H, 6.35; N, 4.65. Found: C, 67.52, H, 6.44, N, 4.06.
(S)-(+)-N-(4-Tr iflu or om eth ylben zylid en e)-2,4,6-tr im e-
th ylp h en ylsu lfin a m id e (12c): yield 78%; mp 92-93 °C;
[R]20D 104.4 (c 0.5, CHCl3); IR (neat) 1571, 1449 cm-1; 1H NMR
(CDCl3) δ 2.29 (s, 3 H), 2.49 (s, 6 H), 6.88 (s, 2 H), 7.71 (d, J
) 8 Hz, 2 H), 7.96 (d, J ) 8 Hz, 2 H), 8.87 (s, 1 H); 13C NMR
(CDCl3) δ 19.3, 21.5, 125.3, 126.3, 130.1, 131.3, 134.3, 135.1,
137.1, 138.9, 142.4, 160.2. Anal. Calcd for C17H16F3NOS: C,
60.16; H, 4.75; N, 4.13. Found: C, 60.21 H, 4.79; N, 4.02.
Exp er im en ta l Section
(S)-(+)-N-(4-Nitr oben zylid en e)-2,4,6-tr im eth ylp h en yl-
Diethyl 2-chloro- and 2-iodomethylphosphonates were pur-
chased from commercial sources. (S)-(+)-2-Methyl-N-[(1E)-[4-
(trifluoromethyl)phenyl]methylene]-2-propanesulfinamide (7b)
su lfin a m id e (12d ): yield 79%; mp 141-142 °C; [R]20 40.2
D
(c 0.5, CHCl3); IR (neat) 1583, 1534, 1344, 1105 cm-1; 1H NMR
(CDCl3) δ 2.28 (s, 3 H), 2.48 (s, 6 H), 6.87 (s, 2 H), 8.0 (d, J )
11 Hz, 2 H), 8.29 (d, J ) 11 Hz, 2 H), 8.89 (s, 1 H); 13C NMR
(CDCl3) δ 19.2, 21.5, 124.5, 130.5, 131.4, 134.8, 138.9, 139.2,
142.5, 150.2, 159.6. Anal. Calcd for C16H16N2O3S: C, 60.74;
H, 5.10; N, 8.85. Found: C, 61.16, H, 5.02, N, 8.37.
[[R]20 81 (c 0.68, CHCl3)] was prepared in 78% yield as
D
described earlier.15,16
(1S,2R)-(-)-N-2-Mesityla m in od ia n ol (9) [mp 160-161
°C; [R]20 -37.4 (c 1.0 CHCl3), IR (neat) 3101, 1574 cm-1] and
D
(RS,1S,2R)-(-)-2,4,6-tr im eth ylben zen esu lfin ic acid 1-(2,4,6-
tr im eth ylben zen esu lfon ylam in o)in dan -2-yl ester (10) [mp
Typ ica l On e-P ot Syn th esis of Azir id in e 2-P h osp h o-
n a tes. (SS,2S,3R)-(+)-N-(2,4,6-Mesitylsu lfin yl)-3-p h en y-
la zir id in e-2-p h osp h on a te (13b). In a 25-mL, two-neck,
round-bottom flask equipped with a magnetic stirring bar,
rubber septum, and argon balloon were placed 0.10 g (0.368
mmol) of (+)-12b and 0.21 g (0.737 mmol) of diethyl 2-iodom-
ethylphosphonate in THF (10 mL). The solution was cooled to
-78 °C, and after 10 min, 0.737 mL (0.737 mmol, 1 M in THF)
of LiHMDS was added via syringe. After being stirred at this
temperature for 30 min, the solution was quenched by addition
of saturated aqueous NH4Cl (5 mL) and the solution was
warmed to room temperature. At this time, the reaction
mixture was diluted with water (10 mL) and the solution was
extracted with EtOAc (2 × 25 mL). The combined organic
phases were washed with saturated sodium thiosulfate (10
mL) and brine (15 mL), dried (Na2SO4), and concentrated to
give a yellow oil. Flash chromatography (EtOAc-hexane, 6:4)
145-146 °C; [R]20 -55.4 (c 1.0 CHCl3); IR (neat) 3210, 3092
D
cm-1] were prepared as previously described11 from com-
mercially available (1S,2R)-(-)-cis-1-amino-2-indanol and had
spectral properties consistent with literature values.11
(S)-(+)-2,4,6-Tr im et h ylp h en ylsu lfin a m id e (11). In
a
100-mL, one-necked, round-bottom flask equipped with a
magnetic stirring bar, rubber septum, and argon balloon was
placed 1.0 g (0.0021 mol) of (-)-10 in THF (15 mL). The
solution was cooled to -78 °C, and 4.2 mL (0.0042 mol, 1 M
solution) of lithium bis(trimethylsilyl)amide (LiHMDS) was
added via syringe. The reaction mixture was slowly warmed
to room temperature, stirred for 4 h, and quenched at -78 °C
by addition of 30% NH4Cl (10 mL). The reaction mixture was
diluted with water (20 mL) and extracted with EtOAc (2 × 25
mL), and the combined organic phases were dried (Na2SO4)
and concentrated. Purification by chromatography (EtOAc) and
crystallization from EtOAc at -20 °C afforded 0.26 g (70%) of
afforded 0.121 g (78%) as a colorless oil: [R]20 56.4 (c 0.5,
D
CHCl3); IR (neat) 2976, 2927, 1244, 1103 cm-1
;
1H NMR
a white solid: mp 125-126 °C; [R]20 +177.8 (c 0.5, CHCl3);
D
IR (neat) 3205, 3092 cm-1. The H NMR and 13C NMR spectra
1
(CDCl3) δ 0.97 (t, J ) 8 Hz, 3 H), 1.06 (t, J ) 8 Hz, 3 H), 2.22
2
(s, 3 H), 2.50 (s, 6 H), 2.68 (dd, J HP ) 16.4 Hz, J ) 7.6 Hz, 1
were identical with the enantiomer (+)-11 previously re-
ported.11 The enantiomeric purity was determined using a
Chiralcel OD, 4-6 × 250 mm, 10 µm; 9:1 (hexane/i-PrOH),
1.0 mL/min, 250 nm; (S)-10, retention 17.5 min.
3
H), 3.50-3.53 (m, 1 H), 3.71-3.86 (m, 3 H), 4.10 (dd, J CP
)
C
7.8 Hz, J ) 7.6 Hz, 1 H), 6.70 (s, 2 H), 7.08-7.15 (m, 5 H); 13
3
NMR (CDCl3) δ 16.6 (d, J CP ) 5.7 Hz), 19.6, 21.5, 34.1 (d,
1J CP ) 229.4 Hz), 38.5, 62.5 (2 x d, 2J CP ) 6.1 Hz), 128.2, 128.3,
128.4, 131.5, 133.4, 136.1, 138.5, 142.1; 31P NMR (CDCl3) δ
19.0; HRMS calcd for C21H28NO4PS (M + Na) 444.1374, found
444.1364.
Typ ica l P r oced u r e for th e Syn th esis of Su lfin im in es
fr om Ald eh yd es Usin g Tita n iu m (IV) Eth oxid e. (S)-(+)-
N-(Ben zylid en e)-2,4,6-tr im eth ylp h en ylsu lfin a m id e (12b).
In a 50-mL, round-bottom flask equipped with a stirring bar
and argon balloon was placed 0.10 g (0.546 mmol) of (+)-11,
0.055 mL (0.546 mmol) of benzaldehyde, and 0.572 mL (2.73
mmol) of titanium(IV) ethoxide in CH2Cl2 (15 mL). After being
stirred at room temperature for 4 h (monitoring for completion
by TLC), the reaction mixture was quenched by addition of
H2O (10 mL). The turbid solution was filtered through Celite,
and the filter cake was washed with CH2Cl2 (2 × 10 mL). The
mixture was extracted with CH2Cl2 (10 mL), and the combined
organic phases were dried (Na2SO4) and concentrated to give
(SS,2S,3R)-(+)-N-(2,4,6-Mesit ylsu lfin yl)-3-(p -m et h ox-
yp h en yl)a zir id in e-2-p h osp h on a te (13a ): yield 75%; [R]20
D
37.7 (c 1.0, CHCl3); IR (neat) 2979, 2931, 1612, 1026 cm-1; 1H
NMR (CDCl3) δ 1.15 (2 x t, J ) 6.4 Hz, 6 H), 2.32 (s, 3 H), 2.60
(s, 6 H), 2.71 (dd, 2J HP ) 16.8, J ) 6.8 Hz, 1 H), 3.69-3.70 (m,
1 H), 3.71 (s, 3 H), 3.88-3.96 (m, 3 H). 4.10-4.15 (m, 1 H),
6.77 (d, J ) 7.6 Hz, 2 H), 6.87 (s, 2 H), 7.14 (d, J ) 7.6 Hz, 2
1
H); 13C NMR (CDCl3) δ 16.7, 19.6, 21.5, 34.2 (d, J CP ) 208.6
Hz), 38.1, 55.6 (2 x d, 2J CP ) 6.0 Hz), 113.7, 125.3, 129.6, 131.5,
136.2, 138.5, 142.0, 159.6; 31P NMR (CDCl3) δ 19.2; HRMS
calcd for C22H30NO5PS (M + Na) 474.1480, found 444.1474.
0.121 g (82%) of a white solid: mp 100-101 °C; [R]20 127 (c
D
Typ ica 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 15 a n d 16. In a 50-mL, round-bottom
flask equipped with a magnetic stirring bar, rubber septum,
(15) Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J . A.
J . Org. Chem. 1999, 64, 1278.
(16) Plobeck, N.; Powell, D. Tetrahedron: Asymmetry 2002, 13, 303.
J . Org. Chem, Vol. 68, No. 18, 2003 6897

Davis et al.
and argon balloon were placed 0.05 g (0.166 mmol) of (S)-(+)-
12a and 0.052 g (0.322 mmol) of dimethyl chloromethylphos-
phonate in THF (20 mL). The mixture was cooled to -78 °C,
and after 10 min, 0.166 mL (0.322 mmol, 2.0 M in cyclohexane)
of n-BuLi was added quickly via syringe. After being stirred
at this temperature for 30 min, the reaction mixture was
quenched by addition of saturated aqueous NH4Cl (5 mL),
warmed to room temperature, and diluted with H2O (10 mL).
The solution was extracted with Et2O (2 × 10 mL), and the
combined organic phases were dried (Na2SO4) and concen-
trated to give a yellow oil. Purification by flash chromatogra-
phy (EtOAC-hexane, 6:1) gave 0.053 g (70%) of an inseparable
mixture of 15a /16a as an oil in a ratio of 77:23.
C13H20NO4P: C, 54.73; H, 7.07; N, 4.91. Found: C, 54.86; H,
7.37; N, 4.83.
(SS,2S,3R)-(+)-N-[1-(2-Meth ylp r op a n e-2-su lfin yl)-3-(4-
tr iflu or om eth ylph en yl)azir idin -2-yl]ph osph on ic Acid Di-
eth yl Ester (8b). In a 25-mL, two-neck, round-bottom flask
equipped with a magnetic stirring bar, rubber septum, and
argon balloon were placed 0.1 g (0.365 mmol) of (+)-7b and
0.203 g (0.731 mmol) of diethyl 2-iodomethylphosphonate in
THF (10 mL). The solution was cooled to -78 °C, and after 10
min, 0.731 mL (1 M in THF, 0.731 mmol) of LiHMDS was
added via syringe. After being stirred at this temperature 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 (10 mL), and the reaction
mixture was extracted with EtOAc (2 × 25 mL). The combined
organic phases were washed with saturated sodium thiosulfate
(10 mL) and brine (15 mL), dried (Na2SO4), and concentrated.
Flash chromatography (EtOAc-hexane, 6:4) afforded 0.112 g
Typ ica l Dep r ot ect ion P r oced u r e. Diet h yl (2S,3R)--
(-)-3-P h en yla zir id in e-2-p h osp h on a te (17b). In a 25-mL,
round-bottom flask equipped with a magnetic stirring bar,
rubber septum, and argon balloon was placed 0.10 g (0.237
mmol) of (+)-13b in THF (10 mL). The solution was cooled to
-78 °C, and after 10 min, 0.156 mL (0.468 mmol, 3.0 M in
Et2O) of MeMgBr was added dropwise via syringe. After being
stirred at this temperature for 2 h, the reaction mixture was
quenched by addition of saturated aqueous NH4Cl (5 mL) and
the solution was warmed to room temperature. At this time,
the solution was extracted with EtOAc (2 × 25 mL), and the
combined organic phases were dried (Na2SO4) and concen-
trated to give a green oil. Flash chromatography (CH2Cl2-
EtOAc, 4:1) afforded 0.466 g (77%) of colorless oil: [R]20D -36.1
(72%) as a colorless oil: [R]20 42.4 (c 1.25, CHCl3); IR (neat)
D
1
2989, 1314, 1267, 2273 cm-1; H NMR (CDCl3) δ 1.05 (t, J )
6.8 Hz, 3 H), 1.15 (t, J ) 6.8 Hz, 3 H), 1.18 (s, 9 H), 2.55 (dd,
2J HP ) 15.2 Hz, J ) 7.2 Hz, 1 H), 3.72-3.81 (m, 2 H), 3.85-
3.95 (m, 3 H), 7.52-7.57 (m, 4 H); 13C NMR (CDCl3) δ 16.6 (2
3
1
x d, J CP ) 5.5 Hz), 23.0, 33.8 (d, J CP ) 209.7 Hz), 35.7, 57.9,
62.8 (d, J ) 5.5 Hz), 125.4, 128.8, 129.4, 130.7, 137.4; 31P NMR
(CDCl3) δ 17.70; HRMS calcd for C17H25F3NO4PS (M + Na)
450.1094, found 450.1092
(c 0.80, CHCl3) [lit.2 [R]20 -36.5 (c 0.85, CHCl3)]. Spectral
D
properties were consistent with literature values.2
Ack n ow led gm en t. This work was supported by the
National Institutes of General Medical Sciences (NIGMS
57870).
Dieth yl (2S,3R)-(-)-3-(p-m eth oxyp h en yl)a zir id in e-2-
p h osp h on a te (17a ): yield 72%; mp 33-34 °C; [R]20D -25.0 (c
0.65, CHCl3); IR (KBr) 3237, 1250, 1031 cm-1; 1H NMR(CDCl3)
δ 1.07-1.19 (m, 6 H), 1.50 (brs, 1 H), 2.46 (m, 1 H), 3.30-3.55
(m, 2 H), 3.70-3.95 (m, 6 H), 6.83 (d, J ) 8 Hz, 2 H), 7.29-
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.
1
7.41 (brs, 2 H); 13C NMR(CDCl3) δ 16.9, 31.4(d, J CP ) 218
2
Hz), 37.2, 55.9, 62.3 (t, J CP ) 16.2 Hz), 113.9, 129.4, 129.9,
159.7; 31P NMR (CDCl3)
δ
22.26. Anal. Calcd. for
J O030142M
6898 J . Org. Chem., Vol. 68, No. 18, 2003