Stereoselective synthesis of β-benzyl-α-alkyl-β-amino acids from l-aspartic acid

Article abstract of DOI:10.1021/jo991241w

A stereoselective synthesis of β-benzyl-α-alkyl-β-amino acids 1 and 2 from L-aspartic acid 3 has been developed. Methyl 5-phenyloxazolidin-2-one-4-acetate 4 was prepared from L-aspartic acid 3 through the acylation of benzene or phenyllithium with a-amino carboxyl group of L-aspartic acid skeleton. Alkylation of a dianion of 4 with alkyl halides and subsequent hydrogenation afforded cmfi-disubstituted /J-amino acids Ib and le in high stereoselectivities. Complete reversal of the stereoselection was realized by the alkylation of 4-phenyl-3-feri-butoxycarbonylamino-4-butanolide 6 which was obtained in a single step from 4. The 2,3,4-trisubstituted amino lactone 7 thus obtained was hydrogenated to give a syra-disubstituted β-amino acid 2a. The syn-products 2b, 2c, and 2d were alternatively prepared via aldol condensation of 6 with aromatic or aliphatic aldehydes followed by stereoselective reduction of the double bond with nickel chloride-sodium borohydride.

Full text of DOI:10.1021/jo991241w

1298
J . Org. Chem. 2000, 65, 1298-1304
Ster eoselective Syn th esis of â-Ben zyl-r-a lk yl-â-a m in o Acid s fr om
L-Asp a r tic Acid 1
Masahiko Seki,* Toshiaki Shimizu, and Kazuo Matsumoto2
Product & Technology Development Laboratory, Tanabe Seiyaku Co., Ltd., 3-16-89, Kashima,
Yodogawa-ku, Osaka 532-8505, J apan
Received August 5, 1999
A stereoselective synthesis of â-benzyl-R-alkyl-â-amino acids 1 and 2 from L-aspartic acid 3 has
been developed. Methyl 5-phenyloxazolidin-2-one-4-acetate 4 was prepared from L-aspartic acid 3
through the acylation of benzene or phenyllithium with R-amino carboxyl group of L-aspartic acid
skeleton. Alkylation of a dianion of 4 with alkyl halides and subsequent hydrogenation afforded
anti-disubstituted â-amino acids 1b and 1c in high stereoselectivities. Complete reversal of the
stereoselection was realized by the alkylation of 4-phenyl-3-tert-butoxycarbonylamino-4-butanolide
6 which was obtained in a single step from 4. The 2,3,4-trisubstituted amino lactone 7 thus obtained
was hydrogenated to give a syn-disubstituted â-amino acid 2a . The syn-products 2b, 2c, and 2d
were alternatively prepared via aldol condensation of 6 with aromatic or aliphatic aldehydes followed
by stereoselective reduction of the double bond with nickel chloride-sodium borohydride.
In tr od u ction
butyl dicarbonate and cesium carbonate.8 Pioneering
works accomplished by McGarvey and co-workers showed
that oxazolin-4-acetic acid derivatives and 3-benzoyl-
amino-4-butanolides derived from L-aspartic acid gave
complementary alkylation products with excellent stereo-
selectivities.9,10
â-Amino acids have aroused considerable attention due
to their having important biological properties in drugs
and natural products.3 Although many approaches have
been devised for their efficient syntheses,4 versatile and
stereoselective accesses to R,â-disubstituted â-amino
acids such as 1 and 2 are rare and await further
investigation. A recently developed approach involved the
use of stereoselective hydroxylation of a 3-tosylamino-4-
butanolide derivative and substitution with organocu-
prates.5 The method, however, needs excess amount of
organocuprates to obtain good yields of products. Another
approach employed R-amino acids as the starting mate-
rial and constructed the second stereogenic center by
hydroboration.6 However, the stereoselectivities of the
hydroboration are extremely sensitive to the structure
of the substrates and are not always high.
Combining these observations suggests that an oxazo-
lidin-2-one-4-acetic acid derivative 4 can serve as an
intermediate to either syn- or anti-â-benzyl-R-alkyl-â-
amino acids 1 and 2 (Scheme 1). We report herein a facile
and stereoselective synthesis of syn- and anti-â-benzyl-
R-alkyl-â-amino acids 1 and 2 from readily accessible
(3) For example, see: (a) Suda, H.; Takita, T.; Aoyagi, T.; Umezawa,
H. J . Antibiot. 1976, 29, 100. (b) Chaturved, N. C.; Park, W. K.; Smeby,
R. P.; Bumpus, K. M. J . Med. Chem. 1970, 13, 177. (c) Iizuka, K.;
Kamijo, T.; Harada, H.; Akahane, K.; Kubota, T.; Umeyama, H.; Kiso,
Y. J . Chem. Soc. Chem. Commun. 1989, 1678. (d) Okino, T.; Matsuda,
H.; Murakami, M.; Yamaguchi, K. Tetrahedron Lett. 1993, 34, 501.(e)
Bovy, P. R.; Tjoeng, F. S.; Rico, J . G.; Rogers, T. E.; Lindmark, R. J .;
Zablocki, J . A.; Garland, R. B.; McMackins, D. E.; Dayringer, H.; Toth,
M. V.; Zupec, M. E.; Rao, S.; Panzer-Knodle, S. G.; Nicholson, N. S.;
Salyers, A.; Taite, B. B.; Herin, M.; Miyano, M.; Feigen, L. P.; Adams,
S. P. Bioorg. Med. Chem. 1994, 2, 881. (f) Denis, J . N.; Correa, A.;
Greene, A. E. J . Org. Chem. 1990, 55, 1957.
(4) For a review, see Cole, D. C. Tetrahedron 1994, 50, 9517.
(5) J efford, C. W.; McNulty, J .; Lu, Z.-H.; Wang, J . B. Hel. Chim.
Acta 1996, 79, 1203.
(6) Burgess, K.; Liu, T. L.; Pal. B. J . Org. Chem. 1993, 58, 4758.
(7) (a) Seki, M.; Matsumoto, K. Tetrahedron Lett. 1996, 37, 3165.
(b) Seki, M.; Matsumoto, K. Biosci. Biotech. Biochem. 1996, 60, 916.
(8) Kouyama, T.; Matsunaga, H.; Ishizuka, T.; Kunieda, T. Hetero-
cycles 1987, 28, 4185.
(9) (a) McGarvey, G. J .; Hiner, R. N.; Matsubara, Y.; Oh, T.
Tetrahedron Lett. 1983, 24, 2733. (b) McGarvey, G. J .; Williams, J .
M.; Hiner, R. N.; Matsubara, Y.; Oh, T. J . Am. Chem. Soc. 1986, 108,
4943. (c) McGarvey, G. J .; Hiner, R. N.; Williams, J . M.; Matsubara,
Y.; Poarch, J . W. J . Org. Chem. 1986, 51, 3744. (d) Overly, K. R.;
Williams, J . M.; McGarvey, G. J . Tetrahedron Lett. 1990, 31, 4573. (e)
McGarvey, G. J .; Wilson, K. J .; Shanholtz, C. E. Tetrahedron Lett. 1992,
33, 2641.
(10) Other examples on the stereoselective alkylation of oxazolidin-
2-one-4-aceate or 3-amino-4-butanolide derivatives, see (a) Ha, D.-C.;
Kil, K.-E.; Choi, K.-S.; Park, H.-S. Tetrahedron Lett. 1996, 37, 5723.
(b) Takahashi, Y.; Hasegawa, S.; Izawa, T.; Kobayashi, S.; Ohno, M.
Chem. Pharm. Bull. 1986, 34, 3020. (c) Rinehart, K. L.; Harada, K.;
Namikoshi, M.; Chen, C.; Harvis, C. A. J . Am. Chem. Soc. 1988, 110,
0, 8557. (d) Namikoshi, M.; Rinehart, K. L.; Dahlem, A. M.; Beasley,
V. R. Tetrahedron Lett. 1989, 30, 4349. (e) Yoda, H.; Nakagami, Y.;
Takabe, K.Tetrahedron: Asymmetry 1994, 2, 169.
In our previous paper was described a facile synthesis
of a â-benzyl-â-amino acid 1 (R ) H) from L-aspartic acid
by the use of a methodology for converting the R-car-
boxylate group of L-aspartic acid to benzyl moiety via an
oxazolidin-2-one-4-acetic acid derivative 4.7 Kunieda and
co-workers demonstrated that oxazolidin-2-one-4-acetic
acid derivatives could be converted into 3-tert-butoxy-
carbonylamino-4-butanolides by treatment with di-tert-
(1) Synthesis of Amino Acids and Related Compounds. 49. Part 48:
Seki, M.; Nakao, K. Biosci. Biotech. Biochem., in press.
(2) Present: Healthcare Information Division, Tanabe Seiyaku Co.,
Ltd., 26, 3-Banchou, Chiyoda-ku, Tokyo 102-0075, J apan.
10.1021/jo991241w CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/15/2000

Synthesis of â-Benzyl-R-alkyl-â-amino Acids
J . Org. Chem., Vol. 65, No. 5, 2000 1299
Sch em e 1
Sch em e 3
L-aspartic acid11 through stereoselective alkylation of an
oxazolidin-2-one-4-acetic acid 4 or a 3-tert-butoxycarbo-
nylamino-4-butanolide 6 and subsequent ring-cleavage
by hydrogenation.
a
Key: (a) (i) Ca(BH4)2, (ii) HCl; (b) (i) pyrrolidine, AlMe3, (ii)
TBS-Cl, imidazole; (c) PhLi; (d) (i) H2/Pd-C, (ii) ClCO2CCl3, Et3N,
(iii) HCl; (e) (i) RuCl2‚xH2O, NaIO4, (ii) SOCl2, MeOH.
L-methionine.12 Amidation of 12 with pyrrolidine was
cleanly conducted by the reaction with trimethyl-
aluminum.7a After protection of the hydroxyl group with
the tert-butyldimethylsilyl group, the pyrrolidinamide 13
was allowed to react with phenyllithium to give an
R-amino phenyl ketone 14 in high yield.7a The 4,5-cis
configuration of 4 was planned to be set by hydrogena-
tion. The compound 14 was thus allowed to hydrogenate
over palladium on charcoal, and upon cyclization with
trichloromethyl chloroformate expectedly provided the
desired cis-oxazolidin-2-one derivative 16 in good yield.
Oxidation of the primary hydroxyl group of 16 followed
by esterification gave 4 in high yield. The optical rotation
Resu lts a n d Discu ssion
P r ep a r a tion of th e Asp a r tic Acid Der iva tives 4
a n d 6. 5-Substituted oxazolidin-2-one-4-acetate 4 was
prepared in two ways. One approach is based on our
previously documented procedure outlined in Scheme 2.7b
Friedel-Crafts acylation of aspartic acid derivative 8
with benzene, subsequent reduction of the carbonyl group
of the R-amino ketone 9, and final treatment of the
resultant amino lactone 10 with sodium methoxide
provided 4 in good yield. This method is not completely
satisfactory, because poor regioselectivity is often ob-
served in the Friedel-Crafts acylation when other aro-
matic compounds other than benzene were employed as
the nucleophile.
1
and H NMR spectrum of the product 4 obtained by this
method was in complete accordance with those of the
authentic sample prepared by the method described in
Scheme 2, indicating no racemization and/or epimeriza-
tion occurred during the reaction sequence.
Sch em e 2
Of the two methods described above which led to the
compound 4, the latter approach described in Scheme 3
is more versatile than the former one based on the
Friedel-Crafts acylation, because various aryl groups can
be introduced at the C-5 position of the compound 4
through the condensation with readily accessible aryl-
lithium reagents.
The ring-transformation of oxazolidin-2-one-4-acetate
4 to 4-butanolide derivative 6 was carried out according
to the Kunieda’s procedure8 to give the desired Boc-
protected 3-amino-4-butanolide derivative 6 in good yield.
Syn th esis of â-Ben zyl-R-alkyl-â-am in o Acids. Alkyl-
ation of â-heteroatom enolates has been a subject of keen
interest. Of these, diastereoselective alkylation of the
â-ester enolate of aspartic acid derivative has well been
studied.9,10,13 Most of the undesirable side reactions are
initiated by â-elimination of the R-amino group of the
aspartic acid skeleton. The â-elimination has been sup-
pressed by formation of an enolate dianion. The oxazo-
a
Key: (a) (i) PCl5, (ii) PhH, AlCl3; (b) PhSiHMe2, TFA; (c)
NaOMe.
Use of organolithium reagents should provide a more
attractive access to the compound 4 (Scheme 3). Selective
reduction of the â-ester group of aspartic acid derivative
11 with calcium borohydride followed by treatment with
hydrochloric acid gave an amino lactone 12 in good yield.
The amino lactone 12 obtained by this method showed
the same spectroscopic properties as the one derived from
(12) Sugano, H.; Miyoshi, M. Bull. Chem. Soc. J pn. 1973, 46, 669.
(13) (a) Sardina, F. J .; Paz, M. M.; Fernadez-Megia, E.; de Boer, R.
F.; Pilar Alvarez, M. Tetrahedron Lett. 1992, 33, 4637. (b) Dener, J .
M.; Zhang, L.-H.; Rapoport, H. J . Org. Chem. 1993, 58, 1159. (c) Cotton,
R,; J ohnstone, A. N. C.; North, M. Tetrahedron Lett. 1994, 35, 8859.
(d) Hanessian, S.; Margarita, R.; Hall, A.; Luo, X. Tetrahedron Lett.
1998, 39, 5883.
(11) For reviews on the utilization of aspartic acid to drug synthesis,
see (a) Matsumoto, K.; Seki, M. J . Synth. Org. Chem. J pn. 1991, 49,
26. (b) Seki, M.; Matsumoto, K. Bioindustry 1995, 12(6), 5.

1300 J . Org. Chem., Vol. 65, No. 5, 2000
Seki et al.
Sch em e 4
Sch em e 5
a
Key: (a) RX, LDA -78 °C f -40 °C; (b) H2/Pd-C.
Sch em e 6
a
Key: (a) RX, LDA or NaHMDS, -78 °C f -40 °C; (b) H2/
Pd-C, HCl.
lidin-2-one-4-acetate 4 was thus allowed to react with 2
equiv of lithium diisopropylamide (LDA) at -78 °C to
ensure the formation of the enolate dianion. The result-
ant enolate solution was treated with various alkyl
halides as shown in Scheme 4. Although use of methyl
iodide as an electrophile gave an anti-alkylated product
5a in a poor selectivity (dr ) 2:1), more sterically
demanding propargyl bromide and benzyl bromide pro-
vided 5b and 5c with good to high selectivities (dr ) 7.6:1
and 12:1, respectively) (Scheme 4). An improved stereo-
selectivity was described by Ha et al.10a when the sodium
enolate of a close analogue of oxazolidin-2-one 4 was used
in an alkylation with methyl iodide. The conditions using
sodium bis(trimethylsilylamide) (NaHMDS) as a base
was applied to the methylation of 4 to provide 5a with
excellent selectivity (dr ) 23:1). The stereoselection in
favor of the anti-isomer 5 is most reasonably explained
by the chelation control model. The alkylation from the
less hindered face, i.e., the re face of the chelated enolate
17 should result in the formation of the anti-products 5.
a
Key: (a) (i) R′CHO, LDA, -78 °C, (ii) MsCl, Et3N iii), DBU
(b) NiCl2‚6H2O, NaBH4, 5 °C; (c) H2/Pd-C.
To develop a more versatile method to introduce a
substituent on compound 6, the aldol reaction of 6 with
aldehydes and subsequent reduction of the olefinic
intermediates 18 were investigated as shown in Scheme
6. The aldol reaction of 6 was cleanly performed by
generation of a dianion with 2 equiv of LDA followed by
the reaction with aromatic and aliphatic aldehydes. The
resultant aldol was mesylated and upon treatment with
diazabicyclo[5.4.0]undec-7-ene (DBU) provided the ole-
finic intermediates 18b, 18c, and 18d in good yields.
Reduction of the compounds 18b, 18c, and 18d with
nickel chloride-sodium borohydride14 was next examined
and was found to be highly stereoselective to predomi-
nantly afford trans products 7b, 7c, and 7d in high
selectivities (dr > 95:5). The excellent stereochemical
outcome should be attributed to the 1,3-allylic strain
around the double bond of the enolate anion 19 generated
in situ by the reduction of 18. The bulky R group of 19
should be placed on the opposite face of the bulky tert-
butoxycarbonylamino group, thus shielding the si face
of the enolate double bond. This ensures the protonation
of 19 from the re face of the enolate to provide 7 with
high stereoselectivities. Hydrogenation of the compounds
The alkylated compounds 5b and 5c were readily
purified either by silica gel column chromatography or
recrystallization and upon hydrogenation provided the
desired anti-â-amino acids 1b and 1c in good yields.
Alkylation of the 4-butanolide 6 is the next subject for
our investigation to obtain syn-â-amino acids. Methyla-
tion of 6 was undertaken as shown in a typical example
(Scheme 5). Use of the same reaction conditions as for
the alkylation of 4 provided trans methylated product 7a
in a good selectivity (dr ) 9:1). However, when a more
sterically demanding benzyl bromide was employed as
the electrophile, the alkylation did not take place at all.
The stereoselection in favor of the trans-isomer 7a is
consistent with the alkylation from the more accessible
face, i.e., the si face of the enolate dianion of 6. Following
purification of the crude product 7a by crystallization,
hydrogenation produced 84% yield of the desired syn-â-
amino acid 2a .
(14) The stereoselective synthesis of R-benzylidene-γ-butyrolactone
by the use of nickel(II) chloride-sodium borohydride was reported in
a more simple case employing R-benzylidene-â-benzyl-γ-butyrolactone.
The reaction mechanism was discussed based on the MO caluculations
using MNDO Hamiltonian implemented in MOPAC 5.0 and the
deuteriation experiments using deuterated reductant (NaBD4) and
solvent (MeOD): Moritani, Y.; Fukushima, C.; Miyagishima, T.;
Ohmizu, H.; Iwasaki, T. Bull. Chem. Soc. J pn. 1996, 69, 2281.

Synthesis of â-Benzyl-R-alkyl-â-amino Acids
J . Org. Chem., Vol. 65, No. 5, 2000 1301
Sch em e 7
Sch em e 9. 1H-NMR Sp ectr a of th e Dia ster eom er ic
Ur ea s 24 a n d 25
a
Key: (a) (i) HCl-MeOH, (ii) TsCl, K2CO3.
Sch em e 8. NOE in th e 1H-NMR Sp ectr oscop y of
th e Com p ou n d s 22 a n d 23
a
Key: (a) 6 N HCl; (b) (Boc)2O, NaOH; (c) DPPA, Et3N.
7b, 7c, and 7d afforded the syn-â-amino acids 2b, 2c,
and 2d in good yields.
a
Key: (a) (R)-1-methylbenzyl isocyanate, Et3N; (b) (S)-1-me-
thylbenzyl isocyanate, Et3N; (c) HCl.
meric R-methylbenzylureas 24a ,b and 25a ,b (Scheme 9).
In their 1H NMR spectra, any signals assigned to the
corresponding stereoisomer were not observed. This
shows that the compounds 1c and 7b are >95% enan-
tiomerically pure.
Con clu sion
Deter m in a tion of th e Rela tive Con figu r a tion a n d
Op tica l P u r ity of th e P r od u cts. The structure of the
trisubstituted 4-butanolides 7a and 7c, direct precursors
of the syn-â-amino acids 2a and 2c, was substantiated
by X-ray analyses15 of the corresponding tosylamides 20
and 21 which were prepared through cleavage of the Boc
group followed by tosylation (Scheme 7). The anti ster-
eochemistry of 1c was determined by conversion to the
trans-imidazolidin-2-one derivative 22 which was com-
pared with the cis-compound 23 derived from the syn-â-
amino acid 2b (Scheme 8). The relative configuration (4,5-
cis) of the compound 23 was established by NOE
Homochiral â-benzyl-R-alkyl-â-amino acids were ef-
ficiently synthesized by stereoselective alkylation of the
aspartic acid derivatives 4 and 6 which were readily
prepared from inexpensive L-aspartic acid. Although the
C-4 substituent of the â-amino acid should be a phenyl
group to ensure the reductive cleavage of the alkylated
products 5 and 7, the present method would permit easy
access to either diastereomeric form of various disubsti-
tuted â-amino acids.
1
Exp er im en ta l Section
experiments with H NMR spectroscopy: enhancement
(20%) of the C-4 hydrogen atom was observed in the
compound 23 when the C-5 hydrogen signal was irradi-
ated.
Optical integrity of the products was checked for the
anti-â-amino acid 1c and 7b, the direct precursor of the
syn-â-amino acid 2b. They were converted to diastereo-
Gen er a l. Melting points are uncorrected. Infrared spectra
1
are reported as λmax (cm-1). H NMR are reported in δ values.
Mass spectra were taken at an ionizing potential of 70 eV.
Thin-layer chromatography was performed on E. Merck 0.25
mm precoated glass backed plates (60 F254). Development was
accomplished using either 20% phosphomolybdic acid in etha-
nol-heat or visualized by UV-light where feasible. Flash
chromatography was accomplished using Kieselgel 60 (230-
400 mesh, E. Merck).
(15) The X-ray data of the compounds 20 and 21 have been deposited
to Cambridge Crystallographic Data Centre.

1302 J . Org. Chem., Vol. 65, No. 5, 2000
Seki et al.
Tetrahydrofuran was distilled from calcium hydride and
stored over molecular sieves 4 Å. Other solvents and reagents
were used as received.
residue was purified by silica gel column chromatography (n-
hexane:AcOEt ) 2:1 to CHCl3:MeOH ) 9:1) to afford the amino
alcohol. Into a solution of the amino alcohol 15 and triethyl-
amine (0.306 mL, 2 mmol) in dichloromethane (2 mL) was
added trichloromethyl chloroformate (198 mg, 1 mmol) at 0
°C, and the mixture was stirred at 0 °C for 1 h. The mixture
was washed with water, dried over anhydrous magnesium
sulfate, and evaporated. The residue was dissolved in methanol
(2 mL) and treated with 6 N hydrogen chloride in 1,4-dioxane
(0.1 mL) at 25 °C, The mixture was evaporated, and the
residue was crystallized by adding n-hexane to afford 16 (157
mg, 76%) in colorless crystals: mp 100-102 °C; IR (KBr) 3420,
(S)-2-Ben zyloxyca r bon yla m in o-4-bu ta n olid e (12). Into
a solution of anhydrous calcium chloride (81.9 g, 0.738 mol)
in ethanol (730 mL) was added a solution of sodium borohy-
dride (77.7 g, 2.04 mol) in ethanol (1.94 L) at -10 °C, and the
mixture was stirred at -10 °C for 30 min. The compound 11
(71.8 g, 0.243 mol) was dissolved in ethanol (710 mL), and
potassium tert-butoxide (27.3 g, 0.243 mol) was portionwise
added at 10 °C. The potassium salt formed was added to the
calcium borohydride solution at -10 °C for 10 min. The
mixture was gradually warmed to 25 °C and stirred for 17 h.
The mixture was acidified by adding concentrated hydrochloric
acid under cooling with ice. The mixture was extracted with
dichloromethane, dried over anhydrous magnesium sulfate and
evaporated. The crystals formed were recrystallized from ethyl
acetate-n-hexane to afford 12 (38.3 g, 67%) in colorless
crystals: mp 126-127 °C (lit.12 mp 126-127 °C); IR (KBr)
1780, 1698 cm-1; 1H NMR (CDCl3) δ 2.10-2.32 (m, 1H), 2.68-
2.81 (m, 1H), 4.16-4.29 (m, 1H), 4.35-4.48 (m, 2H), 5.12 (s,
1
1728 cm-1; H NMR (CDCl3) δ 1.01-1.35 (m, 2H), 3.01 (brs,
1H), 3.57-3.79 (m, 2H), 4.27-4.31 (m, 1H), 5.70 (d, 1H, J )
8.3 Hz), 6.79 (brs, 1H), 7.07-7.42 (m, 5H). SIMS m/z 208 (M+
+ 1); [R]25 +98.8° (c, 0.34, MeOH). Anal. Calcd for C11H13
-
D
NO3: C, 63.75; H, 6.32; N, 6.76. Found: C, 63.56; H, 6.44; N,
6.56.
(4S,5R)-4-Meth oxycar bon ylm eth yl-5-ph en yloxazolidin -
2-on e (4). Into a mixture of 16 (200 mg, 0.97 mmol), sodium
periodate (836 mg, mmol) in acetonitrile (1.9 mL), carbon
tetrachloride (1.9 mL), and water (2.9 mL) was added ruthe-
nium chloride hydrate (16 mg) at 25 °C. The mixture was
stirred at 25 °C for 1.5 h and extracted with AcOEt (2 × 5
mL). The combined extracts were washed with water, dried
over anhydrous MgSO4, and evaporated. The residue was
dissolved in methanol and treated with thionyl chloride (0.22
mL) at 0 °C, and the mixture was stirred at 25 °C for 17 h.
The mixture was evaporated, and the residue was crystallized
by adding n-hexane to afford 4 (194 mg, 85%) in colorless
2H), 5.45 (brs, 1H), 7.26-7.41 (m, 5H); SIMS m/z 236 (M+
+
1); [R]25 -30.7° (c, 1.2, MeOH) (lit.12 [R]25 -30.5° (c, 1.0,
D
D
MeOH)). Anal. Calcd for C12H13NO4: C, 61.27; H, 5.57; N, 5.95.
Found: C, 61.52; H, 6.00; N, 5.96.
(S)-2-Ben zyloxyca r b on yla m in o-4-ter t-b u t yld im et h yl-
silyloxybu ta n p yr r olid in a m id e (13). Into a solution of pyr-
rolidine (2.13 g, 12.5 mmol) in dichloromethane (20 mL) was
carefully added trimethylaluminum (2 mol in hexane, 15 mL,
30 mmol) at 25 °C. The compound 12 (2.35 g, 10 mmol) in
dichloromethane (20 mL) was added to the aluminumamide
solution at 25 °C, and the mixture was stirred at 25 °C for 17
h. Into the mixture was added 2 N hydrochloric acid (15 mL)
at 10 °C, and the organic layer was washed with water, dried
over anhydrous magnesium sulfate, and evaporated. The
residue was dissolved in N,N-dimethylformamide, and tert-
butyldimethylsilyl chloride (1.51 g, 10 mmol) and imidazole
(1.15 g, 16.9 mmol) were added. The mixture was stirred at
25 °C for 17 h. Water was added to the mixture, and the
product was extracted with ethyl acetate, washed with water,
dried over anhydrous magnesium sulfate, and evaporated. The
residue was purified by silica gel column chromatography (n-
hexane:AcOEt ) 4:1 to 2:1) to afford 13 (3.24 g, 77%) in
crystals: mp 115-117 °C; IR (KBr) 1745, 1726, 1700 cm-1
;
1H NMR (CDCl3) δ 1.96-2.28 (m, 2H), 3.58 (s, 3H), 4.43-4.55
(m, 1H), 5.77 (d, 1H, J ) 8.1 Hz), 6.54 (s, 1H), 7.26-7.45 (m,
5H); SIMS m/z 236 (M+ + 1); [R]25D -72.0° (c, 1.0, MeOH) (lit.7b
[R]25 -71.7° (c, 0.95, MeOH)). Anal. Calcd for C12H13NO4: C,
D
61.27; H, 5.57; N, 5.95. Found: C, 61.33; H, 5.62; N, 6.01.
(3S,4R)-3-ter t-Bu t oxyca r b on yla m in o-4-p h en yl-4-b u -
ta n olid e (6). A mixture of 4 (10 g, 42.5 mmol), di-tert-butyl
dicarbonate (12.1 g, mmol), triethylamine (7.23 mL, 51.9
mmol), and 4-(N,N-dimethylamino)pyridine (1.04 g, 8.5 mmol)
in tetrahydrofuran was stirred at 25 °C for 17 h. The mixture
was diluted with ethyl acetate and washed with water, dried
over anhydrous magnesium sulfate, and evaporated. The
residue was crystallized by adding n-hexane. The crystals
obtained were dissolved in methanol. Cesium carbonate (2.63
g, 8.06 mmol) was added to the mixture, stirred at 25 °C for
17 h, and evaporated. The residue was purified by silica gel
column chromatography (n-hexane:AcOEt ) 2:1 to 1:2) to
afford 6 (7.51 g, 67%) in colorless crystals: mp 143-145 °C;
1
colorless oil: IR (Nujol) 1718, 1636 cm-1; H NMR (CDCl3) δ
-0.038 (s, 3H), 0.016 (s, 3H), 0.85 (s, 9H), 1.64-1.95 (m, 6H),
3.30-3.75 (m, 6H), 4.56-4.67 (m, 1H), 5.00 (d, 1H, J ) 12 Hz),
5.10 (d, 1H, J ) 12 Hz), 5.61 (d, 1H, J ) 8 Hz), 7.23-7.31 (m,
5H). SIMS m/z 421 (M+ + 1); [R]25 +3.3° (c, 0.86, MeOH).
D
Anal. Calcd for C22H36N2O4Si: C, 62.82; H, 8.63; N, 6.66.
Found: C, 62.88; H, 8.57; N, 6.45.
1
IR (KBr) 3358, 1796, 1682 cm-1; H NMR (CDCl3) δ 1.46 (s,
(S)-2-Ben zyloxyca r b on yla m in o-4-ter t-b u t yld im et h yl-
silyloxy-1-p h en ylbu ta n -1-on e (14). n-Butyllithium (5.7 mL,
9.1 mmol) was added to a solution of bromobenzene (1.4 g, 8.9
mmol) in tetrahydrofuran (14 mL) at -78 °C, and the mixture
was stirred at -78 °C for 1 h. To this solution was added 13
(1.5 g, 3.6 mmol) in tetrahydrofuran (21 mL) at -78 °C. The
mixture was gradually warmed to -40 °C for 1 h and treated
with saturated aqueous ammonium chloride (30 mL). The
mixture was extracted with ethyl acetate, dried over anhy-
drous magnesium sulfate, and evaporated. The residue was
purified by silica gel column chromatography (n-hexane:AcOEt
) 30:1 to 4:1) to afford 14 (1,16 g, 76%) in colorless oil: IR
9H), 2.45-2.58 (m, 1H), 2.83-2.96 (m, 1H), 4.20-4.35 (m, 1H),
5.18 (brs, 1H), 5.48 (brs, 1H), 7.27-7.50 (m, 5H); SIMS m/z
278 (M+ + 1); [R]25 +45.7° (c, 0.50, MeOH). Anal. Calcd for
D
C
15H19NO4: C, 64.97; H, 6.91; N, 5.05. Found: C, 64.87; H,
6.94; N, 5.12.
A Typ ica l P r oced u r e for th e Alk yla tion of 4: (1′S,4S,5R)-
4-[(1′-Met h oxyca r b on yl-1′-b en zyl)m et h yl]-5-p h en ylox-
a zolid in -2-on e (5c). n-Butyllithium (1.6 M in hexane, 0.7 mL,
1.12 mmol) was added to a solution of N,N-diisopropylamine
(0.15 mL, 1.14 mmol) in tetrahydrofuran (1 mL) at -60 °C,
and the solution was stirred at 0 °C for 15 min. Into the lithium
diisopropylamide solution was added 4 (100 mg, 0.43 mmol)
at -78 °C, and the mixture was gradually warmed to -50 °C
over 1.5 h. Benzyl bromide (221 mg, 1.29 mmol) was added at
-78 °C, and the mixture was gradually warmed to -10 °C
over 2 h. Saturated aq ammonium chloride (10 mL) was added
to the mixture, and it was extracted with ethyl acetate, washed
with water, dried over anhydrous magnesium sulfate, and
evaporated. The residue was purified by silica gel column
chromatography (n-hexane:CHCl3:AcOEt ) 10:10:1) to afford
5c (78 mg, 56%) in colorless crystals 1′S:1′R ) 12:1; 1′S
isomer: mp 115-117 °C; IR (KBr) 3269, 1764 cm-1; 1H NMR
(CDCl3) δ 2.44-2.47 (m, 1H), 2.61-2.73 (m, 2H), 3.50 (s, 3H),
4.24-4.33 (m, 1H), 5.49 (brs, 1H), 5.75 (d, 1H, J ) 8 Hz), 6.58-
6.63 (m, 2H), 7.14-7.17 (m, 3H), 7.39-7.47 (m, 5H); SIMS m/z
(Nujol) 1725, 1692 cm-1 1H NMR (CDCl3) δ 0.0085 (s, 3H),
;
0.025 (s, 3H), 0.879 (s, 9H), 1.70-1.90 (m, 1H), 2.05-2.30 (m,
1H), 3.64-3.78 (m, 2H), 5.07 (d, 1H, J ) 12 Hz), 5.15 (d, 1H,
J ) 12 Hz), 5.43-5.53 (m, 1H), 5.88 (d, 1H, J ) 7.4 Hz), 7.25-
7.43 (m, 5H), 7.43-7.62 (m, 3H), 8.01-8.04 (m, 2H). SIMS m/z
428 (M+ + 1); [R]25 +2.5° (c, 0.36, MeOH). Anal. Calcd for
D
C
24H33NO4Si: C, 67.41; H, 7.78; N, 3.28. Found: C, 67.12; H,
8.01; N, 3.22.
(4S,5R)-4-Hyd r oxyeth yl-5-p h en yloxa zolid in -2-on e (16).
A mixture of 14 (428 mg, 1 mmol) and 10% palladium on
charcoal (150 mg) in ethanol (20 mL) was hydrogenated at 25
°C for 10 h in Parr apparatus (H2: 3.5 kg/cm2). The mixture
was filtered, the filtrate was evaporated in vacuo, and the

Synthesis of â-Benzyl-R-alkyl-â-amino Acids
J . Org. Chem., Vol. 65, No. 5, 2000 1303
326 (M+ + 1); [R]25 -77.8° (c, 0.64, MeOH); 1′R isomer: 1H
(M+ + 1); [R]25D +43.9° (c, 0.30, MeOH). Anal. Calcd for C16H21
NO4: C, 65.96; H, 7.27; N, 4.81. Found: C, 66.02; H, 7.52; N,
4.26.
-
D
NMR (CDCl3) δ 2.48-2.59 (m, 1H), 2.71-2.89 (m, 2H), 3.26
(s, 3H), 4.41-4.49 (m, 1H), 5.82 (d, 1H, J ) 8 Hz), 5.92 (brs,
1H), 6.77-6.82 (m, 2H), 7.17-7.20 (m, 3H), 7.20-7.47 (m, 5H);
Anal. Calcd for C19H19NO4: C, 70.14; H, 5.89; N, 4.31. Found:
C, 70.08; H, 6.03; N, 4.21.
A Typ ica l P r oced u r e for th e Syn th esis of th e Olefin ic
Com p ou n d s fr om 6. (3S,4R)-2-Ben zylid en e-3-ter t-bu toxy-
ca r bon yla m in o-4-p h en yl-4-bu ta n olid e (18b). Into a solu-
tion of N,N-diisopropylamine (2.52 mL, 19.2 mmol) in tetrahy-
drofuran (16 mL) was added n-butyllithium (1.6 M in hexane,
12 mL, 19.2 mmol) at -78 °C, and the mixture was stirred at
0 °C for 15 min. The compound 6 (2 g, 7.1 mmol) in tetrahy-
drofuran (24 mL) was added at -78 °C, and the mixture was
stirred at -78 °C for 1 h. Into the mixture was added
benzaldehyde (1.68 g, 16 mmol) at -78 °C, and the mixture
was stirred at -78 °C for 2 h. The mixture was treated with
2 N hydrochloric acid (6 mL), and it was extracted with ethyl
acetate. The combined extracts were washed with water, dried
over anhydrous magnesium sulfate, and evaporated. The
residue was purified by silica gel column chromatography (n-
hexane:AcOEt ) 4:1) to give the alcohol. Into the alcohol in
dichloromethane (10 mL) were added triethylamine (795 mg,
7.87 mmol) and methanesulfonyl chloride (601 mg, 5.25 mmol)
at 0 °C, and the mixture was stirred at 0 °C for 1 h. The
mixture was washed with water, dried over anhydrous mag-
nesium sulfate, and evaporated. The residue was dissolved in
tetrahydrofuran (15 mL) and treated with DBU (1.34 g, 8.8
mmol) at 10 °C. The mixture was diluted with ethyl acetate
and washed with water, dried over anhydrous magnesium
sulfate, and evaporated. The residue was purified by silica gel
column chromatography (n-hexane:AcOEt ) 4:1) to afford 18b
(1′S,4S,5R)-4-[(1′-Meth oxyca r bon yl-1′-m eth yl)m eth yl]-
5-p h en yloxa -zolid in -2-on e (5a ). 1′S:1′R ) 2:1; characteriza-
tion data of the mixture of 1′S and 1′R isomers: IR (Nujol)
1
3292, 1784 cm-1; H NMR (CDCl3) δ 0.82 (d, J ) 7.1 Hz, 1′S)
and 1.14 (d, J ) 7.1 Hz, 1′R) (3H), 2.13-2.48 (m, 1H), 3.41 (s,
1′R) and 3.67 (s, 1′S) (3H), 4.20-4.29 (m, 1′S) and 4.41-4.54
(m, 1′R) (1H), 5.65 (d, J ) 8.1 Hz, 1′S) and 5.80 (d, J ) 8.3
Hz, 1′R) (1H), 6.28 (s, 1′S) and 6.86 (s, 1′R) (1H), 7.17-7.43
(m, 5H); SIMS m/z 250 (M+ + 1).
(1′S ,4S ,5R )-4-[(1′-Me t h o x y c a r b o n y l-1′-p r o p a r g y l)-
m eth yl]-5-p h en yloxa zolid in -2-on e (5b). 1′S:1′R ) 7.6:1; 1′S
isomer (obtained by recrystallization from ethyl acetate-n-
hexane): mp 119-120 °C; IR (Nujol) 3289, 1764 cm-1;1H NMR
(CDCl3) δ 1.78-1.91 (m, 1H), 2.04-2.07 (m, 1H), 2.22-2.34
(m, 1H), 2.46-2.56 (m, 1H), 3.71 (s, 3H), 4.54-4.63 (m, 1H),
5.70 (d, 1H, J ) 8 Hz), 5.96 (brs, 1H), 7.30-7.50 (m, 5H); SIMS
m/z 274 (M+ + 1); [R]25 -82.9° (c, 1.03, MeOH). Anal. Calcd
D
for C15H15NO4: C, 65.92; H, 5.53; N, 5.13. Found: C, 65.96;
H, 5.81; N, 5.22. 1′R isomer (obtained from the mother liquor
as a mixture of 1′S and 1′R isomers): 1H NMR (CDCl3) δ 3.44
(s, 3H), 4.63-4.73 (m, 1H), 5.82 (d, 1H, J ) 8.4 Hz). Other
signals were not identified.
A Typ ica l P r oced u r e for th e Hyd r ogen a tion of Ox-
a zolid in -2-on es 5. (2R,3R)-Meth yl 3-Am in o-2-ben zyl-4-
p h en ylbu ta n oa te Hyd r och lor id e 1c. A mixture of 5c (379
mg, 1.16 mmol), concentrated hydrochloric acid (0.15 mL), and
10% palladium on charcoal (60 mg) in methanol (5 mL) was
hydrogenated at 25 °C in Parr apparatus (H2: 3.5 kg/cm2) for
2 h. The mixture was filtered, and the filtrate was evaporated.
The residue was crystallized by adding ether to afford 1c (245
mg, 66%) in colorless crystals: mp 208-210 °C; IR (KBr) 2926,
(1 g, 78%) in colorless oil: IR (Nujol) 3306, 1768, 1673 cm-1
;
1H NMR (CDCl3) δ 1.50 (s, 9H), 5.00-5.20 (m, 2H), 5.61 (s,
1H), 7.26-7.55 (m,10H), 7.12 and 7.78 (s, 1H); SIMS m/z 366
(M+ + 1).
(4R,3S)-3-ter t-Bu toxyca r bon yla m in o-4-p h en yl-2-(3,4,5-
tr im eth oxyben zylid en e)-4-bu ta n olid e (18c). Colorless oil.
1
IR (Nujol) 3341, 1755, 1703 cm-1; H NMR (CDCl3) δ 1.49 (s,
9H), 3.83-3.90 (m, 9H), 4.84-4.87 and 5.02-5.06 (m, 1H),
5.25-5.50 (m, 1H), 5.58 (s, 1H), 6.80 (s, 2H), 6.99-7.00 (m)
and 7.65 (s) (1H), 7.27-7.45 (m, 5H); SIMS m/z 455 (M+).
(4R ,3S )-3-t er t -B u t o x y c a r b o n y la m in o -4-p h e n y l-2-
(p h en ylp r op ylid en e)-4-bu ta n olid e (18d ). Colorless crys-
tals. mp 84-85 °C; IR (KBr) 3471, 1760, 1700, 1670 cm-1;1H
NMR (CDCl3) δ 1.47 (s, 9H), 2.50-2.65, 2.72-2.85, 3.05-3.20
and 3.40-3.43 (m, 4H), 4.44-4.75 (m, 2H), 5.26 and 5.39 (s,
1H), 6.99-7.47 (m, 10H); SIMS m/z 394 (M+ + 1).
1
1735 cm-1; H NMR (DMSO-d6) δ 2.81-3.10 (m, 5H), 3.49 (s,
3H), 3.54-3.70 (m, 1H), 7.12-7.36 (m, 10H), 8.53 (brs, 3H);
13C NMR (DMSO-d6) δ 32.3, 35.9 (2t), 47.4 (d), 51.8 (q), 52.8
(d), 126.31, 126.9, 128.2, 128.4, 128.6, 129.2 (6d), 135.9, 138.3,
171.3 (3s); SIMS m/z 284 (M+ - HCl + 1); [R]25 -22.5° (c,
D
0.17, MeOH). Anal. Calcd for C18H22NO2Cl: C, 67.60; H, 6.93;
N, 4.38. Found: C, 67.87; H, 6.73; N, 4.24.
(2R,3R)-Meth yl 3-a m in o-2-p r op yl-4-p h en ylbu ta n oa te
Hyd r och lor id e 1b : mp 135-137 °C; IR (KBr) 2942, 1740
A Typ ica l P r oced u r e for th e Red u ction of th e Olefin ic
Com p ou n d s 18. (2S,3S,4R)-2-Ben zyl-3-ter t-bu toxyca r bo-
n yla m in o-4-p h en yl-4-b u t a n olid e (7b ). Into a solution of
18b (768 mg, 2.1 mmol) and nickel chloride hexahydrate (498
mg, 4.2 mmol) in a mixed solvent of tetrahydrofuran (4 mL)
and methanol (6 mL) was portionwise added sodium borohy-
dride (318 mg, 8.4 mmol) at 0 °C for 30 min. After the mixture
was stirred at 0 °C for 10 min, the mixture was evaporated.
The residue was partitioned by ethyl acetate and water. The
organic phase was washed with water, dried over anhydrous
magnesium sulfate, and evaporated. The residue was purified
by silica gel column chromatography (n-hexane:AcOEt ) 4:1)
to afford 7b (510 mg, 66%) in colorless crystals: mp 166-168
°C; IR (Nujol) 3349, 1795, 1683 cm-1; 1H NMR (CDCl3) δ 1.35
(s, 9H), 2.85-3.45 (m, 3H), 3.80-4.00 (m, 1H), 4.40-4.70 (m,
1H), 5.10-5.35 (m, 1H), 7.20-7.35 (m,10H); SIMS m/z 367
1
cm-1; H NMR (DMSO-d6) δ 0.81 (tri, 3H, J ) 10 Hz), 1.14-
1.25 (m, 2H), 1.58-1.70 (m, 2H), 3.00-3.16 (m, 1H), 3.37 (s,
3H), 3.50-3.70 (m, 3H), 7.27-7.38 (m, 5H), 8.41 (brs, 3H); 13
C
NMR (DMSO-d6) δ 13.4 (q), 20.1, 28.7, 35.9 (3t), 45.2 (d), 51.8
(q), 53.0, 126.8, 128.4, 129.2 (3d), 136.1, 172.2 (2s); SIMS m/z
236 (M+ - HCl + 1); [R]25D -17.3° (c, 0.28, MeOH). Anal. Calcd
for C14H22NO2Cl: C, 61.87; H, 8.16; N, 5.15. Found: C, 61.87;
H, 8.18; N, 5.01.
(2S,3S,4R)-3-ter t-Bu t oxyca r b on yla m in o-2-m et h yl-4-
p h en yl-4-bu ta n olid e (7a ). Into a solution of N,N-diisopro-
pylamine (0.62 mL, 4.73 mmol) in tetrahydrofuran (6 mL) was
added n-butyllithium (1.6 M in hexane, 2.8 mL, 4.5 mmol) at
-78 °C, and the mixture was stirred at 0 °C for 15 min. The
compound 6 (555 mg, 2 mmol) in tetrahydrofuran (10 mL) was
added at -78 °C, and the mixture was warmed to -40 °C for
4 h. Into the mixture was added methyl iodide (0.5 mL, 8
mmol) at -78 °C and warmed to -40 °C over 3 h. Into the
mixture was added saturated aqueous ammonium chloride,
and it was extracted with ethyl acetate. The combined extracts
were washed with water, dried over anhydrous magnesium
sulfate, and evaporated. The residue (2S:2R ) 9:1) was purified
by silica gel column chromatography (n-hexane:AcOEt ) 3:1)
to afford 7a (351 mg, 60%) in colorless crystals: mp 160-162
°C; IR (Nujol) 3356, 1784, 1683 cm-1; 1H NMR (CDCl3) δ 1.33
(d, 3H, J ) 7 Hz), 1.40 (s, 9H), 2.65-3.00 (m, 1H), 3.81-3.95
(M+); [R]25 +79.3° (c, 0.90, MeOH). Anal. Calcd for C22H25
-
D
NO4: C, 71.91; H, 6.86; N, 3.81. Found: C, 72.11; H, 7.03; N,
3.70.
(4R,3S,2S)-3-ter t -Bu t oxyca r b on yla m in o-4-(3,4,5-t r i-
m eth oxyben zyl)-4-p h en yl-4-bu ta n olid e (7c): mp 125-127
°C; IR (Nujol) 3356, 1780, 1716 cm-1; 1H NMR (CDCl3) δ 1.35
(s, 9H), 2.80-3.25 (m, 3H), 3.81 (s, 9H), 3.95-4.17 (m, 1H),
4.70-4.85 (m, 1H), 5.10-5.25 (m, 1H), 6.45 (s, 2H), 7.21-7.35
(m, 5H); SIMS m/z 457 (M+ + 1); [R]25D +55.8° (c, 0.32, MeOH).
Anal. Calcd for C25H31NO7: C, 65.63; H, 6.83; N, 3.06. Found;
C, 65.82; H, 7.04; N, 3.36.
(m, 1H), 4.95 (brs, 1H), 5.19 (brs, 1H), 7.26-7.40 (m, 5H); 13
C
(4R,3S,2S)-3-ter t-Bu toxyca r bon yla m in o-4-p h en ylp r o-
p yl-4-p h en yl-4-bu ta n olid e (7d ): mp 145-147 °C; IR (KBr)
3357, 1780, 1684 cm-1; 1H NMR (CDCl3) δ 1.00-2.00 (m, 13H),
NMR (DMSO-d6) δ 8.8, 28.3 (2q), 35.5, 58.2 (2d), 80.6 (s), 84.7,
124.9, 128.5, 128.8 (4d), 136.9, 155.3, 177.8 (3s); SIMS m/z 292

1304 J . Org. Chem., Vol. 65, No. 5, 2000
Seki et al.
2.50-3.00 (m, 3H), 3.92-4.05 (m, 1H), 4.70-4.74 (m, 1H),
Hz, 2H), 6.95-7.33 (m, 7H); SIMS m/z 511 (M+); [R]25D +32.5°
(c, 0.34, MeOH). Anal. Calcd for C27H29NO7S: C, 63.37; H, 5.71;
N, 2.74. Found: C, 63.58; H, 5.46; N, 3.01.
5.10-5.30 (m, 1H), 7.14-7.36 (m, 10H); SIMS m/z 396 (M+
+
1); [R]25 +55.7° (c, 0.68, MeOH). Anal. Calcd for C24H29NO4:
D
C, 72.89; H, 7.39; N, 3.54. Found; C, 72.76; H, 7.52; N, 3.77.
A Typ ica l P r oced u r e for th e Hyd r ogen a tion of th e
Alk yla ted 4-Bu ta n olid es 7. (2S,3R)-3-ter t-Bu toxyca r bo-
n yla m in o-2-m eth yl-4-p h en ylbu ta n oic Acid 2a . A mixture
of 7a (200 mg, 0.686 mmol) and 10% palladium on charcoal
(20 mg) in methanol (5 mL) was hydrogenated at 25 °C in Parr
apparatus (H2: 3.5 kg/cm2) for 2 h. The mixture was filtered,
and the filtrate was evaporated. The residue was crystallized
by adding ether to afford 2a (170 mg, 84%) in colorless
crystals: mp 156-157 °C; IR (KBr) 3360, 1690 cm-1; 1H NMR
(CDCl3) δ 1.25 (d, 3H, J ) 6.8 Hz), 1.32 (s, 9H), 2.68-2.90 (m,
2H), 3.95-4.30 (m, 1H), 4.65-4.90 (m, 1H), 7.18-7.35 (m, 5H),
8.50-9.50 (br, 1H); 13C NMR (CDCl3) δ 13.1, 28.2 (2q), 38.2
(t), 43.5, 53.5, 126.5, 128.4, 129.3 (5d), 138.0, 150.0, 155.7 (3s);
(4S,5R)-4,5-Diben zyl-1-ter t-bu toxyca r bon ylim id a zoli-
d in -2-on e (22). After a mixture of 1c (112 mg, 0.35 mmol),
concentrated hydrochloric acid (1.5 mL), and water (1.5 mL)
was refluxed for 4 h, the mixture was evaporated. The
crystalline residue was dissolved in a mixed solvent of tet-
rahydrofuran and water (2:1, 3 mL). Into the mixture were
added di-tert-butyl dicarbonate (143 mg, 0.654 mmol) and 2
N aq NaOH (0.49 mL, 0.98 mmol) at 10 °C, and the mixture
was stirred for 2 h. Tetrahydrofuran was evaporated, and the
aqueous residue was washed with ether and acidified to pH 2
with aq citric acid. The mixture was extracted with ethyl
acetate, washed with water, dried over anhydrous magnesium
sulfate, and evaporated. The residue was purified by silica gel
column chromatography (CHCl3 to CHCl3:MeOH ) 10:1), and
the carboxylic acid obtained was dissolved in acetonitrile. To
the solution were added diphenylphosphoryl azide (96.3 mg,
0.35 mmol) and triethylamine (35.4 mg, 0.35 mmol). The
mixture was stirred at 70 °C for 5 h and evaporated. The
residue was purified by silica gel column chromatography (n-
hexane:AcOEt ) 2:1) to afford 22 (78.2 mg, 61%) in colorless
SIMS m/z 294 (M+ + 1); [R]25 +4.9° (c, 0.20, MeOH). Anal.
D
Calcd for C16H23NO4: C, 65.50; H, 7.90; N, 4.77. Found: C,
65.73; H, 7.74; N, 4.59.
(2S ,3R )-3-t er t -B u t o x y c a r b o n y la m in o -2-b e n z y l-4-
p h en ylbu ta n oic Acid 2b: mp 175-176 °C; IR (KBr) 2978,
1
1703, 1654 cm-1; H NMR (CDCl3) δ 1.31 (s, 9H), 2.67-3.00
(m, 4H), 4.00-4.27 (m, 1H), 4.60-4.82 (m, 1H), 6.00-6.20 (m,
1H), 6.90-7.40 (m, 10H), 7.90-8.80 (br, 1H); 13C NMR (CDCl3)
δ 28.2 (q), 34.6, 38.3 (2t), 51.6, 53.3 (2d), 79.9 (s), 126.5, 128.4,
128.6, 128.9, 129.4 (6d), 137.9, 138.9, 156.0, 178.3 (4s); SIMS
oil: IR (Nujol) 3240, 1764 cm-1 1H NMR (CDCl3) δ 1.57 (s,
;
9H), 2.41-2.75 (m, 3H), 3.20-3.28 (m, 1H), 3.44-3.50 (m, 1H),
4.09-4.14 (m, 1H), 5.30 (s, 1H), 6.89-6.94 (m, 2H), 7.09-7.31
(m, 8H); SIMS m/z 367 (M+ + 1).
m/z 370 (M+ + 1); [R]25 -11.4° (c, 0.21, MeOH). Anal. Calcd
(4S,5R)-4, 5-Diben zyl-1-ter t-bu toxyca r bon ylim id a zo-
lid in -2-on e (23). A mixture of 2b (50 mg, 0.135 mmol),
diphenylphosphoryl azide (44.7 mg, 0.162 mmol), and triethy-
lamine (16.4 mg, 0.162 mmol) in acetonitrile (1 mL) was stirred
at 70 °C for 5 h and evaporated. The residue was purified by
silica gel column chromatography (n-hexane:AcOEt ) 2:1) to
afford 23 (50 mg, quant) in colorless oil: IR (Nujol) 3297, 1782
cm-1; 1H NMR (CDCl3) δ 1.42 (s, 9H), 2.69-2.81 (m, 2H), 3.01-
3.22 (m, 2H), 3.97-43.08 (m, 1H), 4.59-4.70 (m, 2H), 7.09-
7.13 (m, 2H), 7.13-7.33 (m, 8H); SIMS m/z 367 (M+ + 1).
A Typ ica l P r oced u r e for th e Syn th esis of Dia ster eo-
m er ic Ur ea s. (2S,3S,4R,1′R)-2-Ben zyl-3-(1′-m eth ylben zyl-
a m in o)-4-p h en yl-4-bu ta n olid e (25a ). A mixture of 7b (100
mg, 0.272 mmol) and 4 N hydrogen chloride in 1,4-dioxane (1
mL) was stirred at 25 °C for 17 h, and the mixture was
evaporated. Into the residue were added dichloromethane (1
mL), triethylamine (0.11 mL, 0.82 mmol), and (R)-1-methyl-
benzyl isocyanate (60 mg, 0.41 mmol) at 10 °C, and the mixture
was stirred at 25 °C for 17 h. The mixture was evaporated,
and the residue was purified by silica gel plate (n-hexane:
AcOEt ) 2:1) to afford 25a (82.6 mg, 73%) in colorless oil: IR
D
for C22H27NO4: C, 71.52; H, 7.37; N, 3.79. Found: C, 71.36;
H, 7.57; N, 4.02.
(2S,3R)-3-ter t-Bu toxyca r bon yla m in o-2-(3,4,5-tr im eth -
oxyben zyl)-4-p h en ylbu ta n oic Acid 2c: mp 182-185 °C; IR
(KBr) 3360, 1688 cm-1 1H NMR (DMSO-d6) δ 1.27 (s, 9H),
;
2.50-2.86 (m, 4H), 3.61 (s, 3H), 3.73 (s, 6H), 3.67-3.90 (m,
2H), 6.46 (s, 2H), 6.83 (d, 1H, J ) 9.4 Hz), 7.15-7.29 (m, 5H);
13C NMR (DMSO-d6) δ 41.6 (q), 48.3, 52.6 (2t), 65.7, 66.6 (2d),
69.2, 73.4 (2q), 90.9 (s), 119.6, 139.3, 141.4, 142.6 (3d), 149.0,
152.4, 166.0, 168.6, 188.6 (5s); SIMS m/z 460 (M+ + 1); [R]25
D
-0.22° (c, 0.45, MeOH). Anal. Calcd for C25H33NO7: C, 65.34;
H, 7.24; N, 3.05. Found: C, 65.56; H, 7.51; N, 3.11.
(2S,3R)-3-ter t-Bu toxyca r bon yla m in o-2-p h en ylp r op yl-
4-p h en ylbu ta n oic Acid 2d: mp 138-140 °C; IR (KBr) 2932,
1695 cm-1; 1H NMR (CDCl3) δ 1.31 (s, 9H), 1.50-1.90 (m, 4H),
2.59-2.91 (m, 5H), 3.80-4.20 (m, 1H), 4.50-4.70 (m, 1H),
7.14-7.30 (m, 10H); 13C NMR (CDCl3) δ 28.1, 29.2, 35.7 (4t),
28.2 (q), 38.4, 49.4 (2d), 125.9, 126.5, 128.3, 128.4, 129.4 (6d),
137.8, 141.9, 155.7, 178.8 (4s); SIMS m/z 398 (M+ + 1); [R]25
D
-8.6° (c, 0.57, MeOH). Anal. Calcd for C24H31NO4: C, 72.52;
1
H, 7.86; N, 3.52. Found: C, 72.78; H, 7.57; N, 3.44.
(Nujol) 1795, 1652 cm-1; H NMR (CDCl3) δ 1.29 (d, 3H, J )
(2S,3S,4R,)-2-Meth yl-4-ph en yl-3-(p-tolu en esu lfon ylam i-
n o)-4-bu ta n olid e (20). A mixture of 7a (300 mg, 1.03 mmol)
and 4 N hydrogen chloride in 1,4-dioxane (5 mL) was stirred
at 25 °C for 1 h. The mixture was evaporated, and the residue
was crystallized by adding ether to afford an amine hydro-
chloride. It was dissolved in a mixture of water and ethyl
acetate (1:1, 10 mL), and p-toluenesulfonyl chloride (296 mg,
1.55 mmol) and potassium carbonate (847 mg, 6.13 mmol) were
added. The mixture was stirred at 25 °C for 17 h. The organic
layer was separated and washed with water, dried over
anhydrous magnesium sulfate, and evaporated. The residue
was purified by silica gel column chromatography (n-hexane:
AcOEt ) 4:1) to afford 20 (292 mg, 82%) in colorless crystals:
6.4 Hz), 2.78-2.89 (m, 1H), 3.09-3.30 (m, 2H), 3.80 (q, 1H, J
) 7.8 Hz), 4.46-4.75 (m, 3H), 5.29 (d, 1H, J ) 7.8 Hz), 7.08-
7.37 (m, 15H); SIMS m/z 415 (M+ + 1).
(2R,3R,1′R)-Meth yl 3-(1′-Meth ylben zyla m in oca r bon yl-
a m in o)-2-ben zyl-4-p h en ylbu ta n oa te (24a ). IR (Nujol) 1728,
1627 cm-1; 1H NMR (CDCl3) δ 1.39 (d, 3H, J ) 6.6 Hz), 2.51-
2.76 (m, 3H), 2.85-2.95 (m, 1H), 3.52 (s, 3H), 4.02-4.19 (m,
1H), 4.68-4.84 (m, 3H), 5.58 (d, 1H, J ) 9 Hz), 6.89-7.36 (m,
15H); SIMS m/z 431 (M+ + 1).
(2R, 3R, 1′S)-Meth yl 3-(1′-Meth ylben zyla m in oca r bo-
n yla m in o)-2-ben zyl-4-p h en ylbu ta n oa te (24b). IR (Nujol)
1722, 1632 cm-1; 1H NMR (CDCl3) δ 1.45 (d, 3H, J ) 6.6 Hz),
2.45-2.55 (m, 1H), 2.70-2.94 (m,4H), 3.54 (s, 3H), 4.13-4.26
(m, 1H), 4.62-4.79 (m, 2H), 5.37 (d, 1H, J ) 9.4 Hz), 6.98-
7.41 (m, 15H); SIMS m/z 431 (M+ + 1).
1
mp 129-132 °C; IR (KBr) 3170, 1768 cm-1; H NMR (CDCl3)
δ 1.26 (d, 3H, J ) 7.2 Hz), 2.36 (s, 3H), 2.59-2.90 (m, 1H),
3.61-3.75 (m, 1H), 4.94 (d, 1H, J ) 8.6 Hz), 5.67 (d, 1H, J )
(2S,3S,4R,1′S)-2-Ben zyl-3-(1′-m et h ylb en zyla m in o)-4-
1
8.8 Hz), 7.02-7.45 (m, 9H); SIMS m/z 346 (M+ + 1); [R]25
p h en yl-4-bu ta n olid e (25b). IR (Nujol) 1780, 1632 cm-1; H
D
+31.3° (c, 0.43, MeOH). Anal. Calcd for C18H19NO4S: C, 62.59;
NMR (CDCl3) δ 1.34 (d, 3H, J ) 6.7 Hz), 2.97-3.28 (m, 3H),
3.86 (q, 1H, J ) 8 Hz), 4.50-4.76 (m, 3H), 5.13 (d, 1H, J ) 7.9
Hz), 7.06-7.39 (m, 10H); SIMS m/z 415 (M+ + 1).
H, 5.54; N, 4.06. Found: C, 62.44; H, 5.81; N, 4.22.
(2S,3S,4R)-4-P h en yl-3-(p-tolu en esu lfon ylam in o)-2-(3,4,5-
tr im eth oxyben zyl)-4-bu ta n olid e (21). According to the
procedure for the synthesis of 20, the compound 21 was
obtained in 91% yield from 7c: mp 149-151 °C; IR (KBr) 3250,
1794 cm-1; 1H NMR (CDCl3) δ 2.33 (s, 3H), 2.95-3.16 (m, 3H),
3.81 (s, 6H), 3.87 (s, 3H), 3.97-4.22 (m, 1H), 4.93 (d, 1H, J )
7.2 Hz), 5.68 (d, 1H, J ) 8 Hz), 6.51 (s, 2H), 6.68 (d, J ) 7.2
Ack n ow led gm en t. The authors are indebted to Mr.
Hajime Hiramatsu in this company for the X-ray
analyses.
J O991241W