Asymmetric strecker-type reaction of α-aryl ketones. Synthesis of (S)- αM4CPG, (S)-MPPG, (S)-AIDA, and (S)-APICA, the antagonists of metabotropic glutamate receptors

Article abstract of DOI:10.1021/jo981297a

Heating a mixture of α-aryl ketone with (R)-phenylglycinol produces a mixture of imine and 1,3-dioxazolidine. Treatment of this mixture with trimethylsilyl cyanide followed by transformation of nitrile to ester gives Strecker-type reaction products. The diastereoselectivity of the generated α-amino esters is from 2/1 to 7/1, and the (R,S)isomer is found as the major product. The (R,S) and (R,R)isomers can be separated by conversion to their N-Cbz or cyclization derivatives. Using this methodology, four antagonists of metabotropic glutamate receptors, (S)-αM4CPG, (S)-MPPG, (S)AIDA, and (S)- APICA, are synthesized.

Full text of DOI:10.1021/jo981297a

120
J . Org. Chem. 1999, 64, 120-125
Asym m etr ic Str eck er -Typ e Rea ction of r-Ar yl Keton es. Syn th esis
of (S)-rM4CP G, (S)-MP P G, (S)-AIDA, a n d (S)-AP ICA, th e
An ta gon ists of Meta botr op ic Glu ta m a te Recep tor s
Dawei Ma,* Hongqi Tian, and Guixiang Zou
State Key Laboratory of Bioorganic and Natural Products Chemistry,
Shanghai Institute of Organic Chemistry, 354 Fenglin Lu, Shanghai 200032, China
Received J uly 6, 1998
Heating a mixture of R-aryl ketone with (R)-phenylglycinol produces a mixture of imine and 1,3-
dioxazolidine. Treatment of this mixture with trimethylsilyl cyanide followed by transformation of
nitrile to ester gives Strecker-type reaction products. The diastereoselectivity of the generated
R-amino esters is from 2/1 to 7/1, and the (R,S)isomer is found as the major product. The (R,S) and
(R,R)isomers can be separated by conversion to their N-Cbz or cyclization derivatives. Using this
methodology, four antagonists of metabotropic glutamate receptors, (S)-RM4CPG, (S)-MPPG, (S)-
AIDA, and (S)-APICA, are synthesized.
R,R-Disubstituted R-amino acids are now popular
replacements for proteinogenic amino acids in peptides.1
Because of the tetrasubstituted asymmetric carbon atom,
incorporation of these compounds into peptides results
in increased proteolytic stability and conformational
restrictions. They can therefore be used as enzyme inhib-
itors for the investigation of enzymatic mechanisms.1,2
In addition, many R,R-disubstituted R-amino acids also
possess important biological activity.3,4 For example,
some R-alkylated phenylglycine derivatives have recently
been found to be selective antagonists of metabotropic
glutamate receptor.4 Among these compounds, (S)-R-
methyl-4-carboxyphenylglycine ((S)-RM4CPG)4 and (S)-
R-methyl-4-phosphonophenylglycine ((S)-MPPG)5 showed
poor selectivity for different mGluR isoforms (Figure 1).
However, their racemic rigid analogues, 1-aminoindan-
1,5-dicarboxylic acid (AIDA)6 and 1-amino-5-phospho-
noindan-1-carboxylic acid (APICA),7 were found to have
improved selectivity for mGluR isoforms. Because it has
been found that (R)-RM4CPG had significant antagonist
F igu r e 1. Structures of (S)-RM4CPG, (S)-MPPG, AIDA, and
APICA.
activity at NMDA and AMPA receptors while (S)-
RM4CPG had only action at mGluRs,4a an efficient route
for synthesizing these compounds enantioselectively is
highly desirable to make them more useful as molecular
tools in seeking the roles of mGluRs in physiological
processes.8
In recent years, a number of methods for construction
of chiral R,R-disubstituted R-amino acids have been
reported.1,9-11 In most cases the stereogenic center is
established by alkylation of chiral, nonracemic enolates.
This method needs many steps for the preparation of the
target molecules. Moreover, synthesis of complex R,R-
disubstituted R-amino acids is restricted due to the
limited chiral pool.1,9,10 On the other hand, the Strecker
reaction is a well-known method for synthesizing R-amino
acids because of its convenient procedure.1b Asymmetric
Strecker reactions starting with chiral amines have been
successfully used in synthesizing chiral R-monosubsti-
tutedR-amino acids from aldehydes12 and some specific
chiral R,R-disubstituted R-amino acids such as phenyla-
lanine, serine, and threonine derivatives from ke-
(1) For reviews, see the following. (a) Williams, R. M.; Hendrix, J .
A. Chem. Rev. 1992, 92, 889. (b) Wirth, T. Angew. Chem., Int. Ed. Engl.
1997, 36, 225. (c) Seebach, D.; Sting, A. R.; Hoffmann, M. Angew.
Chem., Int. Ed. Engl. 1996, 35, 2708.
(2) (a) Baldwin, J . E.; Lee, V.; Schofield, C. J . Heterocycles 1992,
34, 903. (b) Shrader, W. D.; Marlowe, C. K. Bioorg. Med. Chem. Lett.
1995, 5, 2207. (c) Badorrey, R.; Cativiela, C.; Diaz-de-Villegas, M. D.;
Galvez, J . A. Tetrahedron: Asymmetry 1995, 6, 2787. (d) Boyce, R. J .;
Mulqueen, G. C.; Pattenden, G. Tetrahedron 1995, 51, 7321. (e)
Gershonov, E.; Granoth, R.; Tzehoval, E.; Gaoni, Y.; Fridkin, M. J .
Med. Chem. 1996, 39, 4833.
(3) (a) Knopfel, T.; Kuhn, R.; Allgeier, H. J . Med. Chem. 1995, 38,
1418. (b) Hatakeyama, S.; Yoshida, M.; Esumi, T.; Iwabuchi, Y.; Irie,
H.; Kawamoto, T.; Yamada, H.; Nishizawa, M. Tetrahedron Lett. 1997,
38, 7887.
(4) (a) Hayashi, Y.; Sekiyama, N.; Nakanishi, S.; J ane, D. E.; Sunter,
D. C.; Bire, E. F.; Udvarhelyi, P. M.; Watkins, J . C. J . Neurosci. 1994,
14, 3370. (b) Sekiyama, N.; Hayashi, Y. Nakanishi, S.; J ane, D. E.;
Tse, H.-W.; Birse, E. F.; Watkins, J . C. Br. J . Pharmacol. 1996, 117,
1493. (c) Ma, D.; Tian, H. Tetrahedron: Asymmetry 1996, 6, 1567.
(5) J ane, D. E.; Pittaway, K.; Sunter, D. C.; Thomas, N. K.; Watkins,
J . C. Neuropharmacology 1995, 34, 851.
(8) These compounds are now commercially available from the Tocris
Cookson Ltd., the Alexis Biochemicals Corporation, and the Research
Biochemicals International.
(9) (a) Schollkopf, U. Pure Appl. Chem. 1983, 55, 1799. (b) Hsiao,
Y.; Hegedus, L. S. J . Org. Chem. 1997, 62, 3586. (c) Zhang, L.; Finn,
J . M. J . Org. Chem. 1995, 60, 5719. (d) Smith, A. B.; Benowitz, A. B.;
Favor, D. A.; Sprengeler, P. A.; Hirschmann, R. Tetrahedron Lett. 1997,
38, 3809.
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(b) Ihara, M.; Takahashi, M.; Niitsuma, H.; Taniguchi, N.; Yasui, K.;
Fukumoto, K. J . Org. Chem. 1989, 54, 5413.
(11) Spero, D. M.; Kapadia, S. R. J . Org. Chem. 1996, 61, 7398.
(12) Chakraborty, T. K.; Hussain, K. A.; Reddy, G. V. Tetrahedron
1995, 51, 9179.
(6) Pellicciari, R.; Luneia, R.; Costantino, G.; Marinozzi, M.; Natalini,
B.; J akobsen, P.; Kanstrup, A.; Lombardi, G.; Moroni, F.; Thomsen,
C. J . Med. Chem. 1995, 38, 3717-3719.
(7) Ma, D.; Tian, H.; Sun, H.; Kozikowski, A. P.; Pshenichkin, S.;
Wroblewski, J . T. Bioorg. Med. Chem. Lett. 1997, 7, 1195-1198.
10.1021/jo981297a CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/11/1998

Asymmetric Strecker-Type Reaction of R-Aryl Ketones
J . Org. Chem., Vol. 64, No. 1, 1999 121
Sch em e 1
Sch em e 2
unstable aminonitrile was then transformed to ester 3a
by treatment with saturated methanolic HCl. The 1H
NMR spectrum of 3a indicated the formation of two
diastereoisomers in a ratio of about 2/1. These two
isomers could not be separated by column chromatogra-
phy. However, after protection with a Cbz group, we
found that the two isomers 4a and 5a were separable by
column chromatography. Thus, we could obtain pure
diastereomers 4a and 5a through asymmetric Strecker
reaction in 33.9% and 16.2% yields, respectively. Both
compounds could be transformed into the corresponding
(S)- or (R)-R-methylphenylglycine by carrying out a
simple operation.
tones.13,14 However, to the best of our knowledge, there
are no reports about asymmetric Strecker reaction of
R-aryl ketone for preparing R-alkylated phenylglycine
derivatives. In the course of studies of modulators for
metabotropic glutamate receptors,4c,7,15 we felt that it was
necessary to investigate the asymmetric Strecker reaction
of R-aryl ketone. The results of studies thus undertaken
are detailed herein.
After we succeeded in the asymmetric Strecker reac-
tion of acetophenone and separation of two diastereo-
mers, the remaining problem was the assignment of the
absolute configuration of a new stereogenic center. We
planned to solve this problem by synthesizing (S)-
RM4CPG using the developed method. Accordingly,
starting with 4′-bromoacetophenone, we obtained two
isomers 4b and 5b following the same procedure men-
tioned above. The ratio of the two isomers was about 2.5/
1. When we submitted the major isomer to palladium-
catalyzed carbonylation under standard conditions,17 an
unexpected product, lactone 6, was isolated quantita-
tively. The formation of 6 implied that deprotection of
the Cbz group and lactonization occurred simultaneously
under these conditions. This cyclized product gave us a
chance to determine the stereochemistry of the new
stereogenic center by NMR techniques. In the NOESY
spectrum of 6, the marked NOE between 5-H and 3-Me
was observed and we could therefore assign the config-
uration to be the (R,S)form. With 6 in hand, we finished
the synthesis of (S)-RM4CPG by using the following steps
(Scheme 2): (i) opening of the lactone ring with NaOH/
MeOH; (ii) oxidation with Pb(OAc)2 to remove the chiral
auxiliary;12 (iii) acidic hydrolysis to remove all the
protecting groups; (iv) treatment of the generated amino
acid hydrochloride salt with propylene oxide to release
Initially, we used an asymmetric Strecker reaction of
acetophenone as our model reaction. We tried all the
reported procedures12,13 using (R)-R-methylbenzylamine
or (R)-phenylglycinol as the chiral source. It was found
that under the conditions reported no desired aminoni-
triles were prepared and the ketone was recovered. After
some experimentation, we realized that the problem
might come from the difficult formation of the Schiff base
in the first step. To promote the formation of the desired
Schiff base, we refluxed the mixture of acetophenone and
(R)-phenylglycinol in toluene with azeotropic removal of
water (Scheme 1). After both starting materials disap-
peared, the resultant solution was concentrated under
reduced pressure to give a mixture of the Schiff base 1a
1
and 1,3-oxazolidine 2a determined by H NMR. These
intermediates might exist as an equilibrium mixture of
the imine and 1,3-oxazolidine forms.16 After these un-
stable intermediates were treated with trimethylsilyl
cyanide in methylene chloride/methanol, we found that
the corresponding aminonitrile could be isolated. The
the free amino acid. This compound showed [R]25
)
D
+91.9 (c 0.47, 6 N HCl), which was identical with that
reported for (S)-RM4CPG.4 Thus, the stereochemistry of
the major Strecker reaction product of 4′-bromoacetophe-
(13) Cordi, A. A.; Lacoste, J .-M.; Borgne, F. L.; Herve, Y.; Vaysse-
Ludot, L.; Descombes, J .-J . Courchay, C.; Laubie, M.; Verbeuren, T.
J . J . Med. Chem. 1997, 40, 2931 and references therein.
(14) (a) Ohfune, Y.; Horikawa, M. J . Synth. Org. Chem. J pn. 1997,
55, 982. (b) Ohfune, Y.; Moon, S.-H.; Horikawa, M. Pure Appl. Chem.
1996, 68, 645.
(15) (a) Ma, D.; Tian, H. J . Chem. Soc., Perkin Trans. 1 1997, 3493.
(b) Ma, D.; Ma, Z.; J iang, J .; Yang, Z.; Zheng, C. Tetrahedron:
Asymmetry 1997, 8, 889. (c) Ma, D.; Ma, J .; Dai, L. Tetrahedron:
Asymmetry 1997, 8, 825. (d) Ma, D.; Ma, Z. Tetrahedron Lett. 1997,
38, 7599. (e) Ma, D.; Ma, Z.; Kozikowski, A. P.; Pshenichkin, S.;
Wroblewski, J . T. Bioorg. Med. Chem. Lett. 1998, 8, 2447.
(16) A similar equilibrium mixture of the imine and 1,3-oxazolidine
forms resulting from the reaction of phenylglycinol and aldehyde was
reported. See: (a) Yamauchi, T.; Takahashi, H.; Higashiyama, K.
Chem. Pharm. Bull. 1998, 46, 384. (b) Higashiyama, K.; Kyo, H.;
Takahashi, H. Synlett 1998, 489.
(17) (a) Schoenberg, A.; Bartolett, I.; Heck, R. F. J . Org. Chem. 1974,
39, 3318. (b) Huth, A.; Beetz, I.; Schumann, I.; Thielert, T. Tetrahedron
1987, 43, 1071.

122 J . Org. Chem., Vol. 64, No. 1, 1999
Ma et al.
Sch em e 3
Sch em e 4
none was further confirmed to be in the (R,S)form. By
1
comparing the H NMR spectra of 4a and 4b, we could
conclude that the stereochemistry of the major Strecker
reaction product of acetophenone was also in the (R,S)-
form.
The synthesis of (S)-MPPG was performed by employ-
ing the palladium-catalyzed phosphonation18 as a key
step (Scheme 3). Heating a mixture of 4b, diethyl
phosphite, and tetrakis(triphenylphosphine)palladium in
triethylamine at 100 °C afforded the diethyl arylphos-
phonate 7 in 86% yield. Next, the Cbz protecting group
of 7 was removed by hydrogenation under the Pd/C
catalysis to provide 8. The amino ester 8 was treated with
lead tetraacetate to afford the corresponding Schiff base.
Finally, (S)-MPPG was obtained in 84% overall yield by
refluxing this Schiff base in 6 N HCl and subsequent
reaction of the generated hydrochloride salt with propy-
lene oxide. Thus, we have developed a new route for
synthesis of (S)-RM4CPG and (S)-MPPG. The overall
yields from 4′-bromoacetophenone were 20% and 27% for
(S)-RM4CPG and (S)-MPPG, respectively. This new
protocol is obviously more efficient than the old one.15a
To demonstrate the further applications of the present
methodology, we undertook the synthesis of (S)-AIDA and
(S)-APICA using the reaction sequence reported in
Schemes 4 and 5. The starting material, 5-bromo-1-
indanone,19 was prepared from 3-bromobenzylaldehyde
in 71% yield through Perkin reaction, hydrogenation of
the olefin, and intramolecular acylation. Refluxing of this
indanone with (R)-phenylglycinol in toluene with azeo-
tropic removal of water afforded the corresponding
mixture of the imine and 1,3-dioxazolidine forms, which
was reacted with trimethylsilyl cyanide followed by
treatment with saturated methanolic HCl to produce
amino ester 9. The overall yield of 9 (61% based on 30%
ketone recovery) was lower due to the recovery of
5-bromo-1-indanone. However, the diastereoselectivity in
this case was excellent and the ratio of the two diaster-
eomers was about 7/1 as determined by 1H NMR. At-
tempts to separate the two isomers by converting them
to N-Cbz derivatives failed because the generated two
isomers were found to be inseparable by column chro-
matography. Fortunately, refluxing 9 in toluene provided
cyclized products 10 and 11 in 59% total yield, together
with some decomposed products. The diastereomers 10
and 11 could easily be separated by column chromatog-
raphy. The lactone 10 was a fine crystalline solid, which
allowed us to determine its structure by X-ray crystal-
lography. As shown in Figure 2, X-ray analysis of 10
clearly indicated the configuration of the new stereogenic
center to be in the (S)form.
Starting from 10, we could finish the synthesis of (S)-
AIDA and (S)-APICA through two palladium-catalyzed
reactions. Thus, palladium-catalyzed carbonylation and
phosphonation of 10 were carried out to afford 12 and
14, respectively. Both intermediates could be transformed
into (S)-AIDA and (S)-APICA by following the procedure
of preparing (S)-RM4CPG from 6. To our best knowledge,
this is the first asymmetric synthesis of these two
biologically important compounds.
In conclusion, we have developed a successful proce-
dure for the asymmetric Strecker reaction of an R-aryl
ketone. The configuration of the new stereogenic center
was always the (S)form when (R)-phenylglycinol was
used as the chiral source in our tested cases. Although
the diastereoselectivity and yield of the asymmetric
Strecker reaction is not satisfactory, this synthetic
(18) Hirao, T. Masunaga, T.; Yamada, N.; Ohshiro, Y.; Agawa, T.
Bull. Chem. Soc. J pn. 1982, 55, 909.
(19) Quere, J . P.; Marechal, E. Bull. Soc. Chim. Fr. 1971, 2983.

Asymmetric Strecker-Type Reaction of R-Aryl Ketones
J . Org. Chem., Vol. 64, No. 1, 1999 123
and the reaction mixture was stirred at room temperature for
24 h. The solution was concentrated at reduced pressure, and
the residue was dissolved in 10 mL of saturated methanolic
HCl. After stirring for 12 h, the methanol was evaporated and
the residue was diluted was 100 mL of ethyl acetate. The
organic layer was washed with 10% aqueous NaHCO3, water,
and brine, respectively, and dried over Na2SO4. After removal
of the solvent, the amino esters were obtained by column
chromatography (silica gel, 1/3 ethyl acetate/petroleum ether
as eluent) as a mixture of diastereomers.
N-[(R)-(2-H yd r oxy-1-p h en ylet h yl)]-(S)-2-a m in o-2-m e-
th ylp h en yla cetic a cid , m eth yl ester a n d N-[(R)-(2-h y-
d r oxy-1-p h en ylet h yl)]-(R)-2-a m in o-2-m et h ylp h en yla ce-
tic a cid , m eth yl ester (3a ): 1H NMR (300 MHz, CDCl3) δ
7.44-7.18 (m, 10H), 3.80-3.72 (m, 1H), 3.69 (s, 3H, major
isomer), 3.63-3.41 (m, 2H), 3.28 (s, 3H, minor isomer), 2.86
(br s, 2H), 1.55 (s, 3H, minor isomer), 1.42 (s, 3H, major
isomer); MS m/z 300 (M+ + H+).
N-[(R)-(2-Hyd r oxy-1-p h en yleth yl)]-(S)-2-a m in o-2-m eth -
yl-(4′-br om op h en yl)a cetic a cid , m eth yl ester a n d N-[(2-
h yd r oxy-1-p h en ylet h yl)]-(R)-2-a m in o-2-m et h yl-(4′-b r o-
m op h en yl)a cetic a cid , m eth yl ester (3b): 1H NMR (300
MHz, CDCl3) δ 7.49-7.17 (m, 9H), 3.77-3.73 (m, 1H), 3.70 (s,
3H, major isomer), 3.65-3.42 (m, 2H), 3.32 (s, 3H, minor
isomer), 2.63 (br s, 2H), 1.52 (s, 3H, minor isomer), 1.41 (s,
F igu r e 2. X-ray crystal structure of 10.
Sch em e 5
3H, major isomer); MS m/z 380 (M+ + H+, 81Br), 378 (M+
+
H+, 79Br).
N-[(R)-(2-Hyd r oxy-1-p h en yleth yl)]-(S)-1-a m in o-1-ca r b-
m eth oxy-5-br om oin d a n a n d N-[(R)-(2-h yd r oxy-1-p h en yl-
eth yl)]-(R)-1-a m in o-1-ca r bm eth oxy-5-br om oin d a n (9): 1H
NMR (300 MHz, CDCl3) δ 7.31 (s, 1H), 7.26-7.10 (m, 6H), 7.00
(d, J ) 7.9 Hz, 1H), 3.70-3.64 (m, 1H), 3.62 (s, 3H, major
isomer), 3.53 (dd, J ) 10.8, 4.7 Hz, 1H, major isomer), 3.38 (t,
J ) 10.8 Hz, 1H, major isomer), 3.29 (s, 3H, minor isomer),
2.82 (m, 3H), 2.49 (m, 2H), 1.86 (m, 1H); MS m/z 358 (M+
CH2OH, 81Br), 356 (M+ - CH2OH, 79Br).
-
N-Ca r boben zyloxy-N-[(R)-(2-h yd r oxy-1-p h en yleth yl)]-
(S)-2-a m in o-2-m eth ylp h en yla cetic Acid , Meth yl Ester
(4a ) a n d N-Ca r boben zyloxy-N-[(R)-(2-h yd r oxy-1-p h en yl-
eth yl)]-(R)-2-a m in o-2-m eth ylp h en yla cetic Acid , Meth yl
Ester (5a ). To a solution of 3a (1.76 g, 5.8 mmol) in 50 mL of
THF were added DMAP (0.86 g, 7.0 mmol), triethylamine (2
mL, 14.3 mmol), and benzyl chloroformate (1.20 g, 7.0 mmol),
respectively. The resulting solution was stirred at room
temperature for 12 h before it was partitioned between 100
mL of ethyl acetate and 50 mL of water. The organic layer
was separated, and the aqueous layer was extracted with ethyl
acetate (2 × 50 mL). The combined organic layers were washed
with brine, dried over Na2SO4, and concentrated. The residual
oil was chromatographed, eluting with 1/3 ethyl acetate/
petroleum ether to afford 1.1 g (44% yield) of 4a and 0.42 g
(17% yield) of 5a . 4a : yellow oil, [R]25D ) +6.3 (c 0.17, CHCl3);
IR (KBr) 3400, 3064, 1735 cm-1; 1H NMR (300 MHz, CDCl3) δ
7.54-7.23 (m, 15H), 5.16 (s, 2H), 4.24 (dd, J ) 10.8, 4.0 Hz,
1H), 4.08 (t, J ) 8.9 Hz,1H), 4.03 (dd, J ) 8.8, 5.8 Hz, 1H),
3.63 (s, 3H), 1.29 (s, 3H); MS m/z 434 (M+ + H+); HRMS found
m/z 374.1749 (M+ - CO2Me), C24H24NO3 requires 374.1756.
method is still useful due to its easy manipulation. The
power of this new methodology has been demonstrated
by the facile synthesis of (S)-RM4CPG, (S)-MPPG, (S)-
AIDA, and (S)-APICA. Further optimization of the reac-
tion conditions as well as application of this methodology
to the synthesis of other biologically important R,R-
disubstituted R-amino acids is being pursued in our
laboratory and will be reported in due course.
Exp er im en ta l Section
5a : yellow oil, [R]25 ) -46 (c 0.75, CHCl3); IR (KBr) 3400,
D
Gen er al P r ocedu r es. Analytically pure toluene and DMSO
were used directly without further purification. CH2Cl2 was
distilled from CaH2, and THF was distilled from a deep blue
ketyl prior to use. All other solvents were reagent grade quality
and used as received. Na2SO4 was used as the drying agent
in all workup procedures. All reactions were run in flame-dried
glassware under a nitrogen atmosphere unless stated other-
wise.
Gen er a l P r oced u r e for Asym m etr ic Str eck er Rea ction
of r-Ar yl Keton e. A mixture of R-aryl ketone (5 mmol) and
(R)-phenylglycinol (5 mmol) in toluene (5 mL) was refluxed
with azeotropic removal of water until the starting material
disappeared (monitored by TLC). After removal of the solvent
at reduced pressure, the residual oil was dissolved in 5 mL of
dry methylene chloride. The resulting solution was cooled with
ice-water, and then trimethylsilyl cyanide (7.5 mmol) and dry
methanol (2 mL) were added. The cooling bath was removed,
3064, 1741 cm-1
;
1H NMR (300 MHz, CDCl3) δ 7.46-7.23
(m, 15H), 5.13 (s, 2H), 4.16 (m, 2H), 3.83 (dd, J ) 7.7, 5.8 Hz,
1H), 3.45 (s, 3H), 1.49 (s, 3H); MS m/z 342 (M+ -91); HRMS
found m/z 374.1766 (M+ - CO2Me), C24H24NO3 requires
374.1756.
N-Ca r boben zyloxy-N-[(R)-(2-h yd r oxy-1-p h en yleth yl)]-
(S)-2-am in o-2-m eth yl-(4′-br om oph en yl)acetic Acid, Meth -
yl Ester (4b) a n d N-Ca r boben zyloxy-N-[(R)-(2-h yd r oxy-
1 -p h e n y l e t h y l )]-(R )-2 -a m i n o -2 -m e t h y l -(4′-b r o m o -
p h en yl)a cetic Acid , Meth yl Ester (5b). Following the
procedure for preparing 4a and 5a from 3a , 4b and 5b were
obtained from 3b in 58% and 23% yields, respectively. 4b:
yellow oil, [R]25D ) +73.4 (c 0.25, CHCl3); IR (KBr) 3348, 1743
1
cm-1; H NMR (300 MHz, CDCl3) δ 7.44-7.22 (m, 14H), 5.14
(s, 2H), 4.22 (dd, J ) 11.0, 4.1 Hz, 1H), 4.05 (t, J ) 11.0 Hz,
1H), 3.98 (dd, J ) 9.0, 4.1 Hz, 1H), 3.60 (s, 3H), 1.26 (s, 3H);
MS m/z 514 (M+ + H+, 81Br), 512 (M+ + H+, 79Br); HRMS found

124 J . Org. Chem., Vol. 64, No. 1, 1999
Ma et al.
1
m/z 452.0848 (M+ - CO2Me), C24H23BrNO3 requires 452.0861.
yield) of 8 as a colorless oil: [R]25 ) +5.8 (c 0.7, CHCl3); H
D
5b: yellow oil, [R]25 ) -37.7 (c 1.0, CHCl3); 1H NMR (300
NMR (300 MHz, CDCl3) δ 7.70 (dd, J ) 12.8, 8.4 Hz, 2H), 7.50
(dd, J ) 6.0, 3.6 Hz, 2H), 7.31-7.17 (m, 5H), 4.06 (m, 4H),
3.77 (dd, J ) 8.9, 4.2 Hz, 1H), 3.68 (s, 3H), 3.63 (dd, J ) 11.0,
4.5 Hz, 1H), 3.46 (dd, J ) 10.8, 9.2 Hz, 1H), 3.01 (br s, 2H),
1.41 (s, 3H), 1.27 (t, J ) 6.7 Hz, 6H); MS m/z 436 (M+ + H+);
HRMS found m/z 404.1627 (M+ - OMe), C22H30NO6P requires
404.1629.
D
MHz, CDCl3) δ 7.46-7.19 (m, 14H), 5.13 (s, 2H), 4.18 (m, 2H),
3.85 (dd, J ) 7.7, 5.8 Hz, 1H), 3.46 (s, 3H), 1.50 (s, 3H); MS
m/z 514 (M+ + H+, 81Br), 512 (M+ + H+, 79Br); HRMS found
m/z 452.0871 (M+ - CO2Me), C24H23BrNO3 requires 452.0861.
(3S,5R)-3-Met h yl-3-(4′-ca r b et h oxyp h en yl)-5-p h en yl-
2,3,5,6-tetr a h yd r o-1,4-oxa zin -2-on e (6). To a solution of 4b
(263 mg, 0.51 mmol), 1,3-bis(diphenylphosphino)propane (dppp,
43 mg, 0.13 mmol), anhydrous ethanol (5 mL), and triethy-
lamine (0.72 mL, 5.1 mmol) in DMSO (5 mL) was added
palladium acetate (24 mg, 0.10 mmol). The resultant solution
was stirred under carbon monoxide (1 atm) at 70 °C for 3 h.
After being cooled to room temperature, the reaction mixture
was partitioned between 50 mL of ethyl acetate and 10 mL of
water. The organic layer was separated, washed with water
and brine, and dried over Na2SO4. After removal of the solvent,
the residual oil was chromatographed to give 183 mg (100%)
(S)-r-Meth yl-4-p h osp h on op h en ylglycin e ((S)-MP P G).
To a solution of 8 (672 mg, 1.54 mmol) in methylene chloride
(7.4 mL) and methanol (3.7 mL) was added lead tetraacetate
(687 mg, 1.54 mmol) at 0 °C. After the resultant mixture was
stirred for 30 min, 20 mL of phosphate buffer (0.2 M, pH 7)
was added to quench the reaction. The mixture was filtered
through Celite, and the organic layer was separated, washed
with water, and concentrated to dryness. The residual oil
was mixed with 15 mL of 6 N HCl, and the resultant mixture
was heated at reflux for 24 h. After being cooled to room
temperature, the solution was extracted with methylene
chloride and the aqueous layer was concentrated to dryness
under reduced pressure. The residual solid was dissolved in 5
mL of anhydrous ethanol, and 0.2 mL of propylene oxide was
added. After the mixture was heated at reflux for 15 min, the
solvents were evaporated and the residue was chromato-
graphed (C18 reverse-phase column, H2O as eluent) to afford
of 6 as a pale yellow oil: [R]25 ) +130.6 (c 0.36, CHCl3); IR
D
(KBr) 3355, 1749, 1717 cm-1
;
1H NMR (300 MHz, CDCl3) δ
8.08 (d, J ) 7.8 Hz, 2H), 7.85 (d, J ) 7.8 Hz, 2H), 7.45 (d, J )
7.7 Hz, 2H), 7.40-7.30 (m, 3H), 4.60 (dd, J ) 11.3, 3.7 Hz,
1H), 4.38 (q, J ) 7.1 Hz, 2H), 4.19 (dd, J ) 11.3, 3.8 Hz, 1H),
4.00 (t, J ) 11.3 Hz, 1H), 1.73 (s, 3H), 1.40 (t, J ) 7.2 Hz, 3H);
MS m/z 294 (M+ - 45); HRMS found m/z 339.1449 (M+),
C
20H21NO4 requires 339.1471.
375 mg (84%) of (S)-MPPG: mp 243 °C; [R]25 ) +60.1 (c 0.1,
D
1
(S)-r-Meth yl-4-ca r boxyp h en ylglycin e ((S)-rM4CP G). A
6 N HCl); H NMR (300 MHz, D2O) δ 7.73 (dd, J ) 12.4, 8.3
mixture of 6 (152 mg, 0.45 mmol) and 1 N NaOH (1 mL) in 3
mL of methanol was stirred at room temperature for 2 h. After
the pH was adjusted to 4 by addition of 1 N HCl, the solution
was concentrated at reduced pressure and the residue was
dissolved in 2 mL of MeOH and 4 mL of methylene chloride.
To the resulting solution was added lead tetraacetate (220 mg,
0.50 mmol) at 0 °C. After the suspension solution was stirred
for 30 min, 10 mL of phosphate buffer (0.2 M, pH 7) was added
to quench the reaction. The mixture was filtered through
Celite, and the organic layer was separated, washed with
water, and concentrated to dryness. The residual oil was mixed
with 5 mL of 3 N HCl, and the resultant mixture was heated
at reflux for 12 h. After being cooled to room temperature, the
solution was extracted with methylene chloride and the
aqueous layer was concentrated to dryness under reduced
pressure. The residual solid was dissolved in 2 mL of anhy-
drous ethanol, and 0.2 mL of propylene oxide was added. After
the mixture was heated at reflux for 15 min, the solvents were
evaporated and the residue was chromatographed (C18 reverse-
phase column, H2O as eluent) to afford 28 mg (47%) of (S)-
Hz, 2H), 7.55 (dd, J ) 8.3, 2.8 Hz, 2H), 1.75 (s, 3H); MS m/z
(FAB) 246 (M+).
Cycliza tion of 9. A solution of 9 (378 mg, 1.0 mmol) in 50
mL of toluene was stirred at reflux for 24 h. After removal of
the solvent, the residual oil was chromatographed (silica gel,
1/5 ethyl acetate/petroleum ether as eluent) to afford 185 mg
(52% yield) of 10: mp 197 °C; [R]25 ) -42.7 (c 0.66, CHCl3);
D
IR (KBr) 3400, 1723 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.47-
7.32 (m, 9H), 4.52 (dd, J ) 9.1, 4.8 Hz, 1H), 4.44 (m, 2H),
3.20 (m,1H), 3.05 (m, 2H), 2.17 (m, 1H), 1.97 (br s, 1H);
MS m/z 360 (M+ + H+, 81Br), 358 (M+ + H+, 79Br). Anal.
Calcd for C18H16BrNO2: C, 60.34; H, 4.47. Found: C, 60.43;
H, 4.61.
N-[(R)-(2-Hyd r oxy-1-p h en yleth yl)]-(S)-1-a m in o-1,5-d i-
ca r bm eth oxyin d a n (13). Following the similar procedure for
preparing 6 from 4b, ester 12 was obtained in 67% yield from
10. To a solution of 12 (135 mg, 0.38 mmol) in 2 mL of absolute
methanol was added anhydrous potassium carbonate (106 mg,
0.78 mmol). The resultant suspension solution was stirred at
room temperature for 12 h before the solvent was evaporated
via a rotoevaporator. Chromatography of the residue, eluting
with 1/3 ethyl acetate/petroleum ether, afforded 122 mg (87%)
RM4CPG as a white solid: mp 340 °C (dec); [R]25 ) +91.9 (c
D
1
0.47, 6 N HCl); H NMR (300 MHz, D2O) δ 8.02 (d, J ) 8.1
Hz, 2H), 7.58 (d, J ) 8.1 Hz, 2H), 1.93 (s, 3H); MS m/z (FAB)
of 13 as a yellow oil: [R]25 ) +88.1 (c 0.09, CHCl3); IR (KBr)
D
209 (M+).
3449, 3326, 1723 cm-1; H NMR (300 MHz, CDCl3) δ 7.89 (s,
1
N-Ca r boben zyloxy-N-[(R)-(2-h yd r oxy-1-p h en yleth yl)]-
(S)-2-a m in o-2-m et h yl-(4′-d iet h ylp h osp h on op h en yl)a ce-
tic Acid , Meth yl Ester (7). Into a sealed tube were placed
4b (1.51 g, 2.93 mmol), diethyl phosphite (0.61 g, 4.39 mmol),
20 mL of triethylamine, and Pd(PPh3)4 (678 mg, 0.58 mmol).
The resulting suspension solution was heated at 100 °C for 4
h. After being cooled to room temperature, the solution was
poured into 20 mL of water and then extracted with ethyl
acetate (3 × 50 mL). The combined organic layer was washed
with water and brine, dried over Na2SO4, and concentrated.
The residual oil was chromatographed to afford 1.43 g (86%)
of 7: [R]25D ) -10.3 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3)
δ 7.67 (dd, J ) 11.8, 8.4 Hz, 2H), 7.50 (dd, J ) 6.4, 2.2 Hz,
2H), 7.35-7.15 (m, 10H), 5.06 (s, 2H), 4.18-3.92 (m, 6H), 3.51
(s, 3H), 1.22 (t, J ) 6.5 Hz, 6H), 1.19 (s, 3H); MS m/z 570 (M+
+ H+); HRMS found m/z 510.2061 (M+), C28H33NO6P requires
510.2047.
N-[(R)-(2-Hydr oxy-1-p h en yleth yl)]-(S)-2-a m in o-2-m eth -
yl-(4′-d ieth ylp h osp p h on op h en yl)a cetic Acid , Meth yl Es-
ter (8). A suspension of 7 (1.20 g, 2.1 mmol) and Pd/C (10%,
150 mg) in 15 mL of methanol was stirred under hydrogen (1
atm) until the starting material disappeared (monitored by
TLC). After the catalyst was filtered out, the filtrate was
concentrated and then chromatographed to afford 918 mg (88%
1H), 7.80 (d, J ) 7.8 Hz, 1H), 7.32-7.19 (m, 6H), 3.93 (s, 3H),
3.77 (dd, J ) 8.4, 5.0 Hz, 1H), 3.70 (s, 3H), 3.60 (dd, J ) 10.9,
4.5 Hz, 1H), 3.47 (t, J ) 10.6 Hz, 1H), 2.95 (m, 2H), 2.82 (br,
s, 2H), 2.52 (m, 1H), 2.01 (m, 1H); MS m/z 370 (M+ + H+);
HRMS found m/z 338.1392 (M+ - OMe), C20H20NO4 requires
338.1380.
(S)-1-Am in oin d a n -1,5-d ica r b oxylic Acid ((S)-AIDA).
Following the procedure for preparing (S)-MPPG from 8, (S)-
AIDA was obtained from 13 in 65% yield: mp 287 °C; [R]25
)
D
+86.3 (c 0.8, 6 N HCl); 1H NMR (300 MHz, D2O) δ 8.01 (s,
1H), 7.95 (d, J ) 8.2 Hz, 1H), 7.52 (d, J ) 8.2 Hz, 1H), 3.26 (t,
J ) 7.3 Hz, 2H), 2.93 (dt, J ) 14.3, 7.3 Hz, 1H), 2.47 (dt, J )
14.3, 7.3 Hz, 1H); MS m/z (FAB) 221 (M+).
N-[(R)-(2-Hyd r oxy-1-p h en yleth yl)]-(S)-1-a m in o-1-ca r b-
m eth oxy-5-d ieth ylp h osp h on oin d a n (15). Following the
similar procedure for preparing 7 from 4b, aryl phosphonate
14 was obtained in 83% yield from 10. To a solution of 12 (47
mg, 0.11 mmol) in 2 mL of absolute methanol was added
anhydrous potassium carbonate (32 mg, 0.22 mmol). The
resultant suspension solution was stirred at room temperature
for 12 h before the solvent was evaporated via rotevaporator.
Chromatography of the residue, eluting with 1/3 ethyl acetate/
petroleum ether, afforded 43 mg (85% yield) of 15 as a yellow
1
oil: [R]25 ) +5.6 (c 0.2, CHCl3); H NMR (300 MHz, CDCl3)
D

Asymmetric Strecker-Type Reaction of R-Aryl Ketones
J . Org. Chem., Vol. 64, No. 1, 1999 125
δ 7.65 (d, J ) 13.4 Hz, 1H), 7.54 (dd, J ) 12.9, 7.7 Hz, 1H),
7.31-7.18 (m, 6H), 4.10 (m, 4H), 3.73 (dd, J ) 9.4, 4.4 Hz,
1H), 3.67 (s, 3H), 3.60 (dd, J ) 10.9, 4.4 Hz, 1H), 3.44 (t, J )
10.2 Hz, 1H), 2.92 (m, 2H), 2.53 (m, 1H), 1.94 (m, 1H), 1.30 (t,
J ) 7.1 Hz, 6H); MS m/z 447 (M+); HRMS found m/z 447.1806,
Ack n ow led gm en t. The authors are grateful to the
Chinese Academy of Sciences and National Natural
Science Foundation of China (Grant 29725205) for their
financial support.
C
23H30NO6P requires 447.1810.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
compounds 4a , 4b, 5a , (S)-RM4CPG, 7, 8, (S)-MMPG, 10, 13,
(S)-AIDA, 15, and (S)-APICA (13 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
(S)-1-Am in o-5-p h osp h on oin d a n -1-ca r boxylic Acid ((S)-
AP ICA). Following the procedure for preparing (S)-MPPG
from 8, (S)-APICA was obtained from 15 in 65% yield: mp
1
198 °C; [R]25 ) +66.8 (c 1.7, 6 N HCl); H NMR (300 MHz,
D
D2O) δ 7.69 (d, J ) 12.9 Hz, 1H), 7.61 (dd, J ) 12.3, 7.8 Hz,
1H), 7.39 (dd, J ) 7.9, 2.7 Hz, 1H), 3.20 (t, J ) 7.5 Hz, 2H),
2.78 (dt, J ) 14.4, 7.7 Hz, 1H), 2.35 (dt, J ) 14.4, 7.6 Hz, 1H);
MS m/z (FAB) 258 (M+).
J O981297A