subsequently crystallized 15% of pure (S
1
P
R
C
)/(R
05-107 °C) that exhibited a P NMR resonance at δ 75.26
CDCl ).
The preparation of 9 from 8 was then repeated using (S)-
P
S
C
)-9 (mp
phonothioic acid (6).1b,12,14 The hydroxide cleavage of Me-
31
4a,24,25
EPN occurs with inversion,
so we illustrate the forma-
2
6
(
3
tion of (S
The enantiomeric purity of (S
NMR in the presence of 3 equiv of (S)-R-methylbenzylamine
P
)-(-)-6 as shown in the second step of eq 2.
P
)-6 was determined by proton
20
(
-)-1-(1-naphthyl)ethylamine, now affording only (S
P C
S )-9
1
2,14,27
1
P C
and (R S )-9. These diastereomers were separated by exten-
in pyridine-d
O-Me resonance of the (R
doublet (JP-H ) 12.9 Hz) at δ 3.783 and 3.740, whereas the
O-Me doublet of the (S )-6/(S )-amine salt appears at δ 3.804
5
.
Under these conditions, the H NMR
sive repetitive spinning TLC on a Harrison Research chro-
matotron, fitted with a 4 mm preparative silica plate and
P
)-6/(S )-amine salt appears as a
C
using 30:70 ether/hexanes as eluent. The S
eluted first (R ) 0.38, vs R ) 0.32 for the R
stereomer). Diastereomer compositions were monitored via
P
S
C
diastereomer
P
C
f
f
P
S
C
dia-
and 3.761; see Figure 2A. From NMR integration, product
31
31
TLC, HPLC, and P NMR; the retention times and P NMR
21
22
chemical shifts of the isolated S
of 9 were identical to those of the previously examined
)/(R ) and (S )/(R ) racemic diastereomers.
Acid-catalyzed methanolysis of 150 mg of (R )-9 (92%
, 8% S ; 0.5 M H SO in MeOH, 45 °C, 4 d), followed
by chomatotron purification, gave 74 mg (72%) of (-)-Me-
S
P C
and R
P
S
C
stereoisomers
(S
P
S
C
P
R
C
P
R
C
P C
S
P C
S
R S
P C
S
P C
2
4
2
3
EPN (5). Acidic methanolysis of 9 should proceed with
inversion at P,15 so we represent this transformation by the
P
first step of eq 2. The levorotatory sense of (S )-5 corresponds
to that of related O-aryl O-alkyl phenylphosphonothioates.24
Hydrolysis of (S )-5 with 0.5 M KOH in 1:1 aqueous
MeCN (25 °C, 1 h) gave (S )-(-)-O-methyl phenylphos-
P
P
(
10) The rate acceleration in the cleavage of, e.g., Me-EPN by micellar
is largely due to concentration of the substrate and the metal complex
into the condensed aggregate pseudophase, as well as the enhanced acidity
4
9
a
of the Cu-bound water molecules in the cationic micelles.
(
11) We chose Me-EPN (5) rather than EPN (2)4a because of the simpler
1
proton NMR spectrum of the former; the OMe resonance is ideal for tracking
the stereochemistry (see below).
Figure 2. (A) “Raw” H NMR O-Me signals of 86% (S
P
)-6 from
P
the KOH cleavage of (S )-5; signals due to ∼14% of (R )-6 are
P
(12) DeBruin, K. E.; Tang, C.-I. W.; Johnson, D. M.; Wilde, R. L. J.
also visible. The spectrum was determined in the presence of 3
Am. Chem. Soc. 1989, 111, 5871. Specific rotations and configurational
correlations for 6 and 7 appear in this article.
1
equiv of (S)-R-methylbenzylamine in pyridine-d
NMR O-Me signals of (S )-6 from the cleavage of (S
metallomicellar 4 (under the same NMR conditions). The decon-
voluted S /R distribution (87/13) is identical to the deconvoluted
distribution from the KOH cleavage in (A).
5
. (B) “Raw” H
P
P
)-5 by
(
13) Corriu, R. J. P.; Lanneau, G. F.; Leclerq, D. Tetrahedron 1980, 36,
617.
14) Details appear in Morales-Rojas, H. Ph.D. Dissertation, Rutgers
University, New Brunswick, NJ, 2001; pp 44-52, 65-68.
15) Hall, C. R.; Inch, T. D. Tetrahedron Lett. 1977, 18, 3761, 3765.
Hall, C. R.; Inch, T. D. J. Chem. Soc., Perkin Trans. 1 1979, 1646
1
(
P
P
(
(
(
(
(
16) Koizumi, T.; Takagi, H.; Yoshii, E. Chem. Lett. 1980, 1403.
17) Purnanand; Batra, B. S.; Lal, G. Tetrahedron Lett. 1994, 35, 4641.
18) Purnanand; Danikel, R. K. Synthesis 1983, 731.
(
S
P
)-6 was 86% enantiomerically pure, i.e., 14% of (R
was also present. Thus, starting from 92% diastereomerically
pure (R )-9, the reactions of eq 2 afforded 86% enantio-
merically pure (S
)-6; ∼6% of racemization occurred,
presumably during methanolysis.
In parallel experiments, (S
converted with acidic methanol to (R
P
)-6
19) Cf., Tawfik, D. S.; Eshar, Z.; Bentolila, A.; Green, B. S. Synthesis
1
993, 968.
20) For related usage of this chiral auxiliary, see: Uznanski, B.;
P
(
Grajkowski, A.; Krzyzanowska, B.; Kazmierkowska, A.; Stec, W. J.;
Wieczorek, M. W.; Blaszczyk, J. J. Am. Chem. Soc. 1992, 114, 10197.
P
1
5
2
0
31
(
21) [R] D +65.2° (c ) 4.0, CHCl3, 95% SPSC, 5% RPSC by P NMR).
1
P
S
C
)-9 (86-90% S
P
) was
)-5 in 70% yield.
An appropriate H NMR and satisfactory C, H, N microanalysis were
obtained.
2
8
P
22) [R] D +55.2° (c ) 4.0, CHCl3, 92% RPSC, 8% SPSC by 31P NMR).
20
(
1
An appropriate H NMR and satisfactory C, H, N microanalysis were
obtained.
(23) [R]20D -30.8° (c ) 4.0, CHCl3); 31P NMR δ ) 87.8 (CDCl3).
1837
Org. Lett., Vol. 4, No. 11, 2002