A Catalytic Asymmetric Synthesis of N-Boc-β-Methylphenylalanines

Article abstract of DOI:10.1021/jo971178f

An efficient, stereodivergent, and enantioselective synthesis of the syn and anti diastereomers of N-Boc-β-methylphenylalanine has been developed. Starting from enantiomerically pure (2S,3S)-2,3-epoxy-3-phenyl-1-propanol, a three-step sequence, consisting of the oxidation of the primary alcohol up to the carboxyl stage, ring opening of the epoxy acid with Me₂CuCNLi₂, and esterification of the resulting hydroxy acid with methyl iodide, leads to the hydroxy ester anti-W, which has been converted in a stereodivergent manner into both the (2S,3R) and the (2R,3R) diastereomers of N-Boc-β-methylphenylalanine, syn-1 and anti-1, respectively. Activation of the secondary hydroxy group in anti-10 as a mesylate, followed by nucleophilic displacement with sodium azide, hydrogenolysis with simultaneous protection of the amino group, and saponification with LiOH, affords syn-1. The same reaction sequence applied to syn-10, obtained in turn by Mitsunobu reaction of anti-10 with p-nitrobenzoic acid followed by the hydrolysis of the resulting p-nitrobenzoate, leads to anti-1. Both products have been obtained with ≥99% enantiomeric excess.

Full text of DOI:10.1021/jo971178f

J . Org. Chem. 1997, 62, 8425-8431
8425
A Ca ta lytic Asym m etr ic Syn th esis of
N-Boc-â-Meth ylp h en yla la n in es
Mireia Pasto´, Albert Moyano, Miquel A. Perica`s,* and Antoni Riera*
Unitat de Recerca en Sı´ntesi Asime`trica (URSA), Departament de Quı´mica Orga`nica, Universitat de
Barcelona, c/ Martı´ i Franque`s, 1-11, 08028-Barcelona, Spain
Received J une 27, 1997X
An efficient, stereodivergent, and enantioselective synthesis of the syn and anti diastereomers of
N-Boc-â-methylphenylalanine has been developed. Starting from enantiomerically pure (2S,3S)-
2,3-epoxy-3-phenyl-1-propanol, a three-step sequence, consisting of the oxidation of the primary
alcohol up to the carboxyl stage, ring opening of the epoxy acid with Me2CuCNLi2, and esterification
of the resulting hydroxy acid with methyl iodide, leads to the hydroxy ester anti-10, which has
been converted in a stereodivergent manner into both the (2S,3R) and the (2R,3R) diastereomers
of N-Boc-â-methylphenylalanine, syn-1 and anti-1, respectively. Activation of the secondary hydroxy
group in anti-10 as a mesylate, followed by nucleophilic displacement with sodium azide,
hydrogenolysis with simultaneous protection of the amino group, and saponification with LiOH,
affords syn-1. The same reaction sequence applied to syn-10, obtained in turn by Mitsunobu reaction
of anti-10 with p-nitrobenzoic acid followed by the hydrolysis of the resulting p-nitrobenzoate, leads
to anti-1. Both products have been obtained with G99% enantiomeric excess.
In tr od u ction
The preparation of these amino acids in homochiral
form has been performed by classical resolution,8b by
using threonine as starting material,9 by the chiral
auxiliary approach3,4,5,10 or by enantioselective hydroge-
nation.11 Due to its importance, a practical and efficient
asymmetric synthesis of these compounds is a subject of
current interest.
Unnatural, enantiomerically pure amino acids are
gaining an increasing interest as components of biologi-
cally active peptides.1 Hruby and co-workers have shown
that the incorporation of conformationally constrained
amino acids into peptides results in an increased rigidity,
leading to enhanced resistance toward protease enzymes
and to different biological activity and selectivity.2 â-Meth-
yl-R-amino acids such as â-methylphenylalanine (I),3
â-methyltyrosine II),4 and 2′,6′-dimethyl-â-methylty-
rosine (III)5 have been incorporated into peptides confer-
ring them a conformational side-chain rigidity that has
allowed the study of both the bioactive peptide conforma-
tion6,7 and the synthesis of new receptor-selective peptide
ligands.7 On the other hand, â-methylphenylalanine {I)
has been found to be a component of the peptidic
antibiotic Bottromycin.8
In a project devoted to the enantioselective synthesis
of modified amino acids from chiral epoxy alcohols12 we
envisaged the preparation of the N-Boc derivatives of syn-
and anti-â-methylphenylalanine I (syn-1 and anti-1),
through a regio and stereoselective ring-opening of cin-
namyl epoxides 2 and 3 by a methyl nucleophilic equiva-
lent to give, after the necessary functional group ma-
nipulation, mesylates syn-4 and anti-4 which, in turn,
would afford the target â-methylphenylalanines via a SN2
substitution with an amino synthetic equivalent (Scheme
1).
X Abstract published in Advance ACS Abstracts, November 1, 1997.
(1) (a) Williams, R. M.; Baldwin, J . E.; Magnus, P. D. Synthesis of
Optically Active R-Amino Acids, Organic Chemistry Series, Vol. 7;
Pergamon Press: Oxford, 1989. (b) Synthetic Peptides: A users guide;
Grant, G. A., Ed., U.W.B.C. Biotechnical Resource Series, W. H.
Freeman & Co.: New York, 1992.
(2) Hruby, V. J .; Al-Obeidi, F.; Kazmierski, W. Biochem. J . 1990,
268, 249-262, and references therein.
(3) (a) Dharanipragada, R.; Nicola´s, E.; Toth, G.; Hruby, V. J .
Tetrahedron Lett. 1989, 30, 6841-6844. (b) Dharanipragada, R.;
VanHulle, K.; Bannister, A.; Bear, S.; Kennedy, L.; Hruby, V. J .
Tetrahedron 1992, 48, 4733-4748.
(4) (a) Nicola`s, E.; Dharanipragada, R.; Toth, G.; Hruby, V. J .
Tetrahedron Lett. 1989, 30, 6845-6848. (b) Nicola´s, E.; Russell, K. C.;
Knollenberg, J .; Hruby, V. J . J . Org. Chem. 1993, 58, 7565-7571.
(5) Qian X.; Russell, K. C.; Boteju, L. W.; Hruby, V. J . Tetrahedron
1995, 51, 1033-1054.
(6) (a) Qian, X.; Shenderovich, M. D.; Ko¨ve´r, K. E.; Davis, P.;
Horva´th, R.; Zalewska, T.; Yamamura, H. I; Porreca, F.; Hruby, V. J .
J . Am. Chem. Soc. 1996, 118, 7280-7290. (b); Yamamura, H. I.; Hruby,
V. J . J . Med. Chem. 1994, 37, 1746-1757. (c) Huang, Z.; He, Y.-B.;
Raynor, K.; Tallent, M.; Reisine, T.; Goodman, M. J . Am. Chem. Soc.
1992, 114, 9390-9401.
(7) Hruby, V. J .; Toth, G.; Gherig, C. A.; Kao, L.-F.; Knapp, R.; Lui,
G. K.; Yamamura, H. I.; Kramer, T. H.; Davis, P.; Burks, T. F. J . Med.
Chem. 1991, 34, 1823-1830.
We report in the present paper a new approach to the
asymmetric synthesis of both the 2S,3R and the 2R,3R
diastereomers of N-Boc-â-methylphenylalanine syn-1 and
(9) Effenberger, F.; Weber, T. Angew. Chem., Int. Ed. Engl. 1987,
26, 142-143.
(10) (a) Tsuchihashi, G.; Mitamura, S.; Ogura, K. Bull. Chem. Soc.
J pn. 1979, 52, 2167-2168. (b) Shapiro, G.; Buechler, D.; Marzi, M.;
Schmidt, K.; Gomez-Lor, B. J . Org. Chem. 1995, 60, 4978-4979.
(11) Burk, M. J .; Gross, M. F.; Mart´ınez, J . P. J . Am. Chem. Soc.
1995, 117, 9375-9376.
(12) (a) Poch, M.; Alco´n, M.; Moyano, A.; Perica`s, M. A.; Riera, A.
Tetrahedron Lett. 1993, 34, 7781-7784. (b) Alco´n, M.; Canas, M., Poch,
M.; Moyano, A.; Perica`s, M. A.; Riera, A. Tetrahedron Lett. 1994, 35,
1589-1592. (c) Pasto´, M.; Moyano, A.; Perica`s, M. A.; Riera, A.
Tetrahedron: Asymmetry 1995, 6, 2329-2342. (d) Castejo´n, P.; Moy-
ano, A.; Perica`s, M. A.; Riera, A. Tetrahedron 1996, 52, 7063-7086
(e) Castejon, P.; Moyano, A.; Perica`s, M. A.; Riera, A. Chem. Eur. J .
1996, 2, 1001-1006. (f) Pasto´, M.; Moyano, A.; Perica`s, M. A.; Riera,
A. Tetrahedron: Asymmetry 1996, 7, 243-262. (g) Pasto´, M.; Castejo´n,
P.; Moyano, A.; Perica`s, M. A.; Riera, A. J . Org. Chem. 1996, 61, 6033-
6037. (h) Medina, E.; Vidal-Ferran, A.; Moyano, A.; Perica`s, M. A.;
Riera, A. Tetrahedron: Asymmetry 1997, 8, 1581-1586.
(8) (a) Waisvisz, J . M.; van der Hoeven, M. G.; Peppen, van J .;
Zwennis, W. C. M. J . Am. Chem. Soc. 1957, 79, 4520-4521. (b)
Kataoka, Y.; Seto, Y.; Yamamoto, M.; Yamamoto, M.; Yamada, T.;
Kuwata, S.; Watanabe, H. Bull. Chem. Soc. J pn. 1976, 49, 1081-1084.
S0022-3263(97)01178-X CCC: $14.00 © 1997 American Chemical Society

8426 J . Org. Chem., Vol. 62, No. 24, 1997
Pasto´ et al.
Sch em e 1
Sch em e 3
Sch em e 2
ity. Chemoselective protection of the primary hydroxy
group was easily achieved (78% yield) by treatment of
anti-5 with tert-butyldimethylsilyl chloride/imidazole in
DMF. Subsequent treatment with methanesulfonyl chlo-
ride in the presence of triethylamine and 4-(N,N-di-
methylamino)pyridine provided access to anti-7 in 90%
yield. To allow oxidation at the primary hydroxyl site,
the silyl ether was selectively cleaved by treatment with
tetrabutylammonium fluoride in THF. The resulting
alcohol anti-8, obtained in 82% yield, was then oxidized
with J ones reagent15 in acetone, and the free acid was
finally converted into its methyl ester by using methyl
iodide in the presence of potassium hydrogen carbonate
in dimethylformamide at room temperature16 (Scheme
2).
Although the preparation of mesylate anti-4 through
this route is practical and convenient, taking place in 31%
overall yield, we decided to explore shorter synthetic
routes to this important intermediate. We reasoned that
by simply inverting the sequence of the ring opening and
oxidation operations, protecting group manipulation
could be avoided. Obviously, if the epoxide ring-opening
could be conveniently performed on the corresponding
epoxy acid,17 the protection of the primary alcohol would
be no longer necessary. To test this possibility, epoxy
alcohol 2 was first oxidized using ruthenium trichloride-
sodium periodate,18 and, because of its unstability, the
resulting free acid 9 was directly submitted to ring-
opening by Me2CuCNLi2 without purification (Scheme 3).
Quite interestingly, the reaction took place with complete
regioselectivity and with excellent diastereoselectivity,
and the single hydroxy acid isomer formed was converted
into its methyl ester anti-10 by treatment with methyl
iodide in the presence of potassium hydrogen carbonate.
The overall yield for the preparation of anti-10 from 2 is
39%, and the final mesylation of the secondary hydroxy
group took place in 82% yield leading to anti-4. In
summary, the mesylate anti-4 has been prepared by two
alternative routes. Although both took place with similar
overall yield, the sequence involving the epoxy acid is
substantially shorter both in number of steps and in
execution time, involving a single intermediate purifica-
tion.
anti-1, respectively, based on the retrosynthetic analysis
shown in Scheme 1, by using the Sharpless catalytic
epoxidation13 as the sole source of chirality. Obviously,
by simply changing the enantiomeric series of the tar-
trate ester employed in the epoxidation, the 2R,3S and
the 2S,3S diastereomers, which are enantiomers of syn-1
and anti-1, respectively, would be equally available.
Resu lts a n d Discu ssion
(A) P r ep a r a tion of Meth yl (2R,3R)-2-(Meth a n e-
su lfon yloxy)-3-p h en ylbu ta n oa te, a n ti-4. According
to our retrosynthetic scheme, mesylate anti-4 is the key
intermediate in the synthesis of syn (threo) N-Boc-â-
methyl-L-phenylalanine (syn-1). For the preparation of
this intermediate, (2S,3S)-2,3-epoxy-3-phenyl-1-propanol
(2), readily accessible in multigram scale and in high
enantiomeric purity by the Sharpless asymmetric
epoxidation,13d,g seemed to be an excellent starting mate-
rial (Scheme 2).
In our initial approach the planned regioselective ring-
opening at the benzylic center was performed using Me2-
CuCNLi2 as described by Takano,14 yielding diol anti-5
in good yield (77%) and with excellent diastereoselectiv-
(13) (a) Katsuki, T.; Sharpless, K. B. J . Am. Chem. Soc. 1980, 102,
5974-5976. (b) Rossiter, B. E. In Asymmetric Synthesis; Morrison, J .
D., Ed.; Academic Press: New York, 1985; Vol. 5, pp 193-246. (c) Finn,
M. G.; Sharpless, K. B. In Asymmetric Synthesis; Morrison, J . D., Ed.;
Academic Press: New York, 1985; Vol. 5, pp 247-308. (d) Gao, Y.;
Hanson, R. M.; Klunder, J . M.; Ko, S. Y.; Masamune, H.; Sharpless,
K. B. J . Am. Chem. Soc. 1987, 109, 5765-5780. (e) Sharpless, K. B.;
Wooddard, S. S.; Finn, M. G. Pure Appl. Chem. 1983, 55, 1823-1836.
(f) Sharpless, K. B.; Behrens, C. H.; Katsuki, T.; Lee, A. W. M.; Mart´ın,
V. S.; Takatani, M.; Viti, S. M.; Walker, F. J .; Woodard, S. S. Pure
Appl. Chem. 1983, 55, 589-604. (g) Katsuki, T.; Martin, V. S. In
Organic Reactions; Paquette, L. A., Ed.; J ohn Wiley & Sons, Inc.: New
York, 1996; Vol. 48, pp 1-299.
(B) P r ep a r a tion of Meth yl (2S,3R)-2-(Meth a n e-
su lfon yloxy)-3-p h en ylbu ta n oa te, syn -4. The applica-
tion of the same methodologies to cis-2,3-epoxy-3-phenyl-
1-propanol (3) should similarly allow the preparation of
(15) Bealieu, P. L.; Duceppe, J . S.; J ohnson, C. J . Org. Chem. 1991,
56, 4196-4204.
(16) Hamada, Y.; Shibata, M.; Sugiura, T.; Kato, S.; Shiori, T. J .
Org. Chem. 1987, 52, 1252-1255.
(17) Chong, J . M.; Sharpless, K. B. Tetrahedron Lett. 1985, 26,
4683-4686.
(14) Takano, S.; Yanase, M.; Ogasawara, K. Heterocycles 1989, 29,
249-252.
(18) Carlsen, P. H. J .; Katsuki, T.; Mart´ın, V. S.; Sharpless, K. B.
J . Org. Chem. 1981, 46, 3936-3938.

Asymmetric Synthesis of N-Boc-â-Methylphenylalanines
J . Org. Chem., Vol. 62, No. 24, 1997 8427
Sch em e 4
Sch em e 5
the stereoisomeric mesylate syn-4, the key intermediate
for the preparation of anti (erythro) N-Boc-â-methyl-D-
phenylalanine (anti-1) (Scheme 1). Consequently, the
synthesis should involve an asymmetric epoxidation of
(Z)-3-phenyl-2-propen-1-ol followed by a regioselective
ring-opening of the epoxide by a methyl nucleophile and
a selective oxidation of the primary hydroxyl, or the
reversal in the order of these operations. This approach,
however, encountered unavoidable difficulties. In first
place, the Sharpless epoxidation of (Z)-3-phenyl-2-propen-
1-ol proceeds slowly and with low enantioselectivity even
in the presence of stoichiometric amounts of catalyst.19
Moreover, when the nucleophilic ring opening of the cis-
epoxy alcohol 3 was attempted by using Me2CuCNLi2,
the reaction showed to be not regioselective, affording a
1:1 mixture of the 1,2- and 1,3-diols syn-5 and syn-11,
respectively. In an attempt to circumvent this difficulty,
the use of trimethylaluminum as nucleophilic reagent
was also tested. However, the reaction was not stereo-
selective, yielding a 2:1 mixture of the diastereomeric 1,2-
diols syn-5 and anti-5 (Scheme 4).
The alternative procedure, involving oxidation of the
primary hydroxy group in 3 and subsequent ring opening,
would be hampered by the low enantiomeric purity in
which 3 is available through Sharpless epoxidation.19
This fact prompted us to consider a change in the source
of chirality employed in our synthesis. Thus, besides the
epoxidation/oxidation route, the cis-epoxy acid 12 is
directly available in high enantiomeric purity through
J acobsen’s catalytic epoxidation of cis-ethyl cinnamate
(13).20 However, when we performed the oxidation, we
could observe that the corresponding trans-epoxide, co-
generated with low enantiomeric purity, is a significant
byproduct of the epoxidation reaction, and that the
complete separation of the diastereomeric epoxides by
flash chromatography is extremely difficult. When cis-
2,3-epoxy-3-phenyl-1-propanoic acid (12) (contaminated
with 15% of its trans isomer), generated by saponification
of 13, was allowed to react with Me2CuLi, the nucleophilic
ring opening of both epoxy acid diastereomers took place
in low yield (Scheme 5). Disappointingly, the syn/ anti
ratio in the derived diastereomeric methyl esters 10 was
much lower than the cis/ trans ratio in the starting
material (1.8:1 vs 5.4:1), thus indicating that either the
ring-opening of the trans-epoxy acid 9 takes place more
efficiently than that of cis-12 or the ring opening of 9 was
Sch em e 6
not stereoselective. Moreover, the enantiomeric excess
of the final hydroxy ester syn-10 (87% ee) was lower than
that of the starting epoxy ester 13, probably as a
combination of two factors: low enantiomeric purity of
9 and low stereoselectivity in the ring-opening of this
byproduct.
In view of these results, we turned our attention to the
possibility of performing an inversion of configuration at
C-2 on some intermediate in the routes to anti-4. The
derived synthetic routes to mesylate syn-4, albeit less
straightforward, could benefit in this way from an
optimal stereocontrol, as already discussed for the prepa-
ration of anti-4.
Alcohol anti-6 was first chosen as the substrate for the
inversion through the use of Mitsunobu methodology.21
Accordingly, anti-6 was treated with p-nitrobenzoic acid
in benzene in the presence of triphenylphosphine and
diethyl azodicarboxylate, yielding (51%) the inverted
p-nitrobenzoate syn-14, which was reduced with DIBALH
in CH2Cl2 to afford (79% yield) the secondary alcohol
syn-6 without any loss of stereochemical purity (Scheme
6).12f With the inverted alcohol in hand, the preparation
of syn-4 only required the application of the methodology
that we had already applied with success to the prepara-
tion of anti-4. The required conversion into mesylate
syn-7 took place with excellent yield (89%) by treatment
with methanesulfonyl chloride in the presence of triethyl-
amine and 4-(N,N-dimethylamino)pyridine, the primary
(19) Denis, J . N.; Greene, A. E.; Serra, A. A.; Luche, M. J . J . Org.
Chem. 1986, 51, 46-50.
(20) (a) Deng, L.; J acobsen, E. N. J . Org. Chem. 1992, 57, 4320-
4323. (b) J acobsen, E. N.; Deng, L.; Furukawa, Y.; Mart´ınez, L. E.
Tetrahedron 1994, 50, 4323-4334.
(21) Martin, S. F.; Dodge, J . A. Tetrahedron Lett. 1991, 32, 3017-
3020.

8428 J . Org. Chem., Vol. 62, No. 24, 1997
Pasto´ et al.
Sch em e 7
different relative stereochemistry of the two adjacent
chiral centers, the introduction of the amino group took
place as expected to afford (2R,3R)-N-Boc-â-methylphen-
ylalanine methyl ester anti-16 in good yield. To check
its enantiomeric purity, this ester was reduced to alcohol
by treatment with DIBALH, and the corresponding
Mosher ester was analyzed by 19F NMR. In full agree-
ment with the enantiomeric purity of the starting mate-
rial, a single peak was observed. Finally, basic hydrolysis
of anti-16 with lithium hydroxide in THF afforded the
target anti N-Boc-â-methyl-D-phenylalanine anti-1 in
excellent yield (Scheme 8).
Con clu sion s
hydroxy group was then selectively deprotected by treat-
ment with tetrabutylammonium fluoride in THF, and the
resulting alcohol syn-8 was oxidized and finally converted
to the target mesylate syn-4 by nucleophilic esterification.
Whereas the present sequence takes place with full
stereochemical control, it suffers from nonoptimal yields
in its final steps. The main chemoselectivity problem in
these steps resides in the conversion of syn-7 to syn-8,
which is accompanied by a competing intramolecular
cyclization reaction leading to the corresponding terminal
epoxide.
Once again, the sequence could be shortened in its
number of steps and significantly improved in terms of
yield by simply performing the inversion of configuration
at C-2 on anti-10, where the oxidation of C-1 has already
been performed, instead of performing it on anti-6. Using
p-nitrobenzoic acid as the nucleophile, the inverted
p-nitrobenzoate syn-15 was obtained in an excellent
(93%) yield. In comparing with the parallel reaction
performed on anti-6 (see above), it is clear that the
presence of the adjacent alkoxycarbonyl group greatly
facilitates the Mitsunobu inversion. To avoid ester
reduction, the elaboration of syn-15 was performed by
saponification with LiOH. Although the methyl ester
was also affected, the resulting hydroxy acid was con-
verted back to this ester by treatment with methyl iodide
in the presence of KHCO3. Hydroxy ester syn-10, which
was obtained in this way in 80% yield from syn-15, was
finally converted to the target mesylate syn-4 in 91%
yield (Scheme 7).
(C) Syn th esis of (2S,3R)-N-Boc-â-Meth ylp h en yl-
a la n in e, syn -1. With mesylate anti-4 in hands, the
preparation of syn-1 only required the introduction of the
amino functionality and hydrolysis of the methyl ester.
The amino group was incorporated by SN2 substitution
with sodium azide in DMF followed by reduction and in
situ protection by treatment with H2/Pd-C in the pres-
ence of Boc2O. In this way, the N-Boc-amino ester syn-
16 was obtained in 83% yield from anti-4. The enanti-
omeric excess was determined at this point by chiral
HPLC (Chiralcel OD and OD-R) against the racemic
compound (prepared from racemic 2). According to our
expectations, only one enantiomer was detected (>99%
ee), in good agreement with the optical purity of the
starting material. The methyl ester syn-16 could be
easily hydrolyzed in quantitative yield to the target
(2S,3R)-N-Boc-â-methylphenylalanine syn-1, which is
ready for use in peptide synthesis (Scheme 8).
In summary, we have developed a general and efficient
method for the stereodivergent preparation of the (2S,3R)
(syn) and the (2R,3R) (anti) diastereomers of N-Boc-â-
methylphenylalanine from readily available (2S,3S)-2,3-
epoxy-3-phenyl-1-propanol. The synthesis of the syn
diastereomer involves only four synthetic operations,
taking place in 26,5% overall yield, whereas the synthesis
of the anti diastereomer involves six synthetic operations
and takes place in 16% overall yield. Both routes are
characterized by an excellent stereocontrol, the final
products being obtained with G99% enantiomeric excess
starting from an epoxy alcohol of the same enantiomeric
purity. It is worth noting that, since the sole source of
chirality in these synthetic sequences is a catalytic
Sharpless epoxidation, a simple reversal in the enantio-
meric series of the tartrate ester employed at that stage
would provide access to the (2R,3S) and the (2S,3S)
diastereomers of N-Boc-â-methylphenylalanine. More-
over, when the regio- and stereoselective introduction of
the â-methyl substituent is considered, the present
procedure appears as a very promising alternative for the
general synthesis of â-alkyl-â-aryl-R-amino acids in di-
astereomerically and enantiomerically pure form. Work
along these lines is in progress in our laboratories and
will be published in due course.
Exp er im en ta l Section
Gen er a l. Melting points were determined in an open
capillary tube and are uncorrected. Optical rotations were
measured at room temperature (23 °C) on a Perkin-Elmer 241
MC polarimeter. Infrared spectra were recorded on a Perkin-
Elmer 681 or on a Nicolet 510 FT-IR instrument using NaCl
film or KBr pellet techniques. 1H NMR spectra were recorded
at 200 or 300 MHz in CDCl3 unless specified otherwise (s )
singlet, d ) doublet, t ) triplet, q ) quartet, quint
)
quintuplet). J values are given in hertz. 13C NMR spectra
were recorded at 50.3 or 75.4 MHz in CDCl3 unless specified
otherwise. Signal multiplicities have been assigned by DEPT
experiments. In all cases, chemical shifts are in ppm downfield
of TMS. Mass spectra were recorded at 70 eV ionizing voltage;
ammonia was used for chemical ionization (CI). Elemental
analyses were performed by the “Servei d’Ana`lisis Elementals
del CSIC de Barcelona”. THF and diethyl ether were distilled
from sodium benzophenone ketyl; CH2Cl2 was distilled from
CaH2 and triethylamine from KOH. All reactions were
performed in oven-dried glassware under a N2 atmosphere.
Reaction progress was followed by TLC (Merck DC-Alufolien
KIESELGEL 60 F254). Chromatographic separations were
carried out using Et3N pretreated (2.5% v/v) silica gel 60
(particle size: 60-200 µm for column chromatography and 35-
70 µm for flash chromatography), eluting with hexane/ethyl
acetate mixtures of increasing polarity. HPLC analyses were
performed with Chiralcel OD and OD-R (25 cm) columns.
(2R,3R)-3-P h en yl-1,2-bu ta n ed iol, a n ti-5. To a stirred
slurry of CuCN (2.69 g, 0.03 mol) in anhydrous diethyl ether
(D) Syn th esis of (2R,3R)-N-Boc-â-Meth ylp h en yl-
a la n in e, a n ti-1. The preparation of the (2R,3R) diaste-
reomer of the target N-Boc-â-methylphenylalanine, anti-
1, could be performed in the same way described above
for syn-1, but starting from mesylate syn-4. Despite the

Asymmetric Synthesis of N-Boc-â-Methylphenylalanines
Sch em e 8
J . Org. Chem., Vol. 62, No. 24, 1997 8429
at -68 °C was added MeLi (37.5 mL, 1.6 M in diethyl ether),
and the mixture was stirred at this temperature for 1 h. A
solution of (2S,3S)-2,3-epoxy-3-phenyl-1-propanol (2) (1.5 g,
0.01 mol, G99% ee) in diethyl ether (36 mL) was added via
cannula to the cyanocuprate solution at -68 °C, and the
mixture was allowed to warm to 0 °C over 3 h under N2. When
no starting material could be detected by TLC, saturated
aqueous NH4Cl (80 mL) and NH4OH (10 mL) were added to
the reaction mixture, and the organic layer was extracted with
diethyl ether. The combined organic phases were dried over
MgSO4 and concentrated in vacuo. The residue was purified
by flash chromatography, yielding 1.28 g of anti-5 (77% yield)
as an oil: [R]D ) 16.3 (c ) 0.82, CHCl3). IR (film) νmax 3400,
3100, 3070, 3040, 2980, 2940, 2890, 1500, 1460, 1105, 1460,
(d, J ) 4.4 Hz, 2H), 4.6-4.8 (m, 1H), 7.2-7.4 (m, 5H) ppm.
13C NMR (50 MHz, CDCl3) δ -5.6 (CH3), -5.5 (CH3), 16.7
(CH3), 19 (C), 25.8 (CH3), 37.8 (CH3), 40.7 (CH), 63.3 (CH2),
88.3 (CH), 127.0 (CH), 128.2 (CH), 128.4 (CH), 141.9 (C) ppm.
MS (EI) m/e ) 153 (97%), 131 (100%), 105 (77%).
(2R,3R)-2-(Met h a n esu lfon yloxy)-3-p h en yl-1-b u t a n ol,
a n ti-8. To a solution of anti-7 (1.67 g, 4.66 mmol) in THF (47
mL) at 0 °C was added tetrabutylammonium fluoride (8.5 mL,
1.1 M in THF), and the reaction progress was monitored by
TLC. After stirring for 20 min, the starting material could be
no longer detected; the mixture was then concentrated in
vacuo, the residue diluted with CH2Cl2, and the resulting
solution washed with saturated aqueous NH4Cl. The organic
phase was dried over MgSO4 and concentrated in vacuo, and
the residue was purified by flash chromatography to yield 0.93
g (82% yield) of anti-8 as a white solid: [R]D ) 21.9 (c ) 1.43,
CHCl3). Mp: 74-75 °C. IR (KBr) νmax 3550, 3030, 2980, 2950,
1490, 1450, 1410, 1380, 1330, 1170, 1135, 1075, 1060, 1020,
1105, 1090, 1060, 1020, 1010, 765 cm-1 1H NMR (200 MHz,
.
CDCl3) δ 1.28 (d, 3H, J ) 7.1 Hz), 1.85 (m, 1H, OH), 2 (m, 1H,
OH), 2.88 (pseudo quint, J ) 7 Hz), 3.4-3.6 (m, 1H), 3.7-3.9
(m, 2H), 7.2-7.5 (m, 5H) ppm. 13C NMR (50 MHz, CDCl3) δ
17.7 (CH3), 42.6 (CH), 64.4 (CH2), 76.2 (CH), 126.6 (CH), 127.9
(CH), 128.5 (CH), 148.2 (C) ppm. MS (EI) m/e ) 166 (M+, 1%),
106 (100%), 105 (70%), 91 (77%), 77 (32%).
970, 945, 920, 830, 760 cm-1
.
1H NMR (200 MHz, CDCl3) δ
1.37 (d, J ) 7.2 Hz, 3H), 2.1-2.3 (m, 1H, OH), 2.47 (s, 3H),
3.20 (pseudo quint, J ) 7.4 Hz, 1H), 3.75-3.92 (dd ABX, J AB
) 12.8 Hz, J AX ) 5.9 Hz, J BX ) 2.6 Hz, 2H), 4.8 (m, 1H), 7.1-
7.5 (m, 5H) ppm. 13C NMR (50 MHz, CDCl3) δ 17.2 (CH3),
37.7 (CH3), 40.7 (CH), 63.0 (CH2), 88.7 (CH), 127.2 (CH), 128.1
(CH), 128.6 (CH), 142.1 (C) ppm. MS (CI) m/e ) 148 (18%),
105 (100%). Anal. Calcd for C11H16O4S: C, 54.08%; H, 6.60%;
S, 13.13%. Found: C, 54.16%; H, 6.65%; S, 13.03%.
(2R,3R)-1-[(ter t-Bu t yld im et h ylsilyl)oxy]-3-p h en yl-2-
bu ta n ol, a n ti-6. To a solution of anti-5 (1.26 g, 7.6 mmol) in
N,N-dimethylformamide (37 mL) were added tert-butyldi-
methylsilyl chloride (1.72 g, 11.4 mmol) and imidazole (1.14
g, 16.7 mmol), and the reaction progress was monitored by
TLC. After 24 h, the mixture was diluted with diethyl ether
(40 mL) and washed with saturated aqueous NH4Cl. The
organic layer was separated, dried over MgSO4, and evapo-
rated in vacuo. The residue (2.5 g) was purified by column
chromatography to afford 1.45 g of anti-6 (78% yield) as an
oil, along with 0.04 g (2% yield) of (2R,3R)-2-[(tert-butyldi-
methylsilyl)oxy]-3-phenyl-1-butanol and 0.17 g of starting
material (87% conversion). [R]D ) 7.25 (c ) 1.05, CHCl3). IR
(film) νmax 3500, 3030, 2960, 2930, 2860, 1470, 1260, 1120,
Meth yl (2R,3R)-2-(Meth a n esu lfon yloxy)-3-p h en ylbu -
ta n oa te, a n ti-4. (a ) F r om a n ti-8: To a solution of anti-8
(0.87 g, 3.56 mmol) in acetone (75 mL) freshly prepared J ones
reagent (7.35 mL, 14 mmol) was added dropwise. The reaction
mixture was stirred at room temperature until no starting
material could be detected by TLC (ca. 4 h), 2-propanol (5 mL)
was added, and acetone was removed under reduced pressure.
The residue was partitioned between water and CH2Cl2; the
aqueous phase was extracted with CH2Cl2, and the combined
organic phases were washed with brine, dried over MgSO4,
and concentrated in vacuo to afford 1.0 g of (2R,3R)-2-
(methanesulfonyloxy)-3-phenylbutanoic acid as an oil. To a
solution of the crude acid in N,N-dimethylformamide (6.2 mL)
were added KHCO3 (0.77 g, 7.7 mmol) and methyl iodide (0.4
mL, 6.42 mmol), and the reaction mixture was stirred at room
temperature for 5 h. Water was then added, and the organic
layer was extracted with ethyl acetate. The combined organic
phases were successively washed with saturated aqueous Na2-
SO3 and brine and dried over MgSO4. Removal of the solvent
gave an oil that was purified by column chromatography to
yield 0.68 g (70% yield) of anti-4 as a colorless oil.
1100, 840, 780 cm-1
.
1H NMR (200 MHz, CDCl3) δ 0.07 (s,
6H), 0.90 (s, 9H), 1.29 (d, J ) 7.3 Hz, 3H), 2.2-2.4 (m, 1H,
OH), 2.89 (pseudo quint, J ) 7.1 Hz, 1H), 3.49 (dd, J ) 9.8
Hz, J ) 7.2 Hz, 1H), 3.62-3.84 (m, 2H), 7.1-7.5 (m, 5H) ppm.
13C NMR (50 MHz, CDCl3) δ -5.4 (CH3), -5.3 (CH3), 17.7
(CH3), 19.0 (C), 25.8 (CH3), 42.3 (CH), 65.1 (CH2), 75.7 (CH),
126.4 (CH), 128.0 (CH), 128.3 (CH), 143 (C) ppm. MS (EI) m/e
) 280 (M+, 0.01%), 131 (20%), 105 (100%).
(2R,3R)-1-[(ter t-Bu t yld im et h ylsilyl)oxy]-2-(m et h a n e-
su lfon yloxy)-3-p h en ylbu ta n e, a n ti-7. To a solution of
anti-6 (1.45 g, 5.2 mmol) in CH2Cl2 (8 mL) at 0 °C were added
triethylamine (1.8 mL, 12.8 mmol), 4-(N,N-dimethylamino)-
pyridine (30 mg), and methanesulfonyl chloride (0.9 mL, 11.4
mmol). The mixture was stirred for 5 h at room temperature,
the reaction progress being monitored by TLC. When no
starting material could be detected, water (10 mL) was added,
the aqueous phase was extracted with CH2Cl2 (3 × 15 mL),
and the combined organic phases were dried over MgSO4,
concentrated in vacuo, and purified by column chromatography
to afford 1.7 g (90% yield) of anti-7 as an oil: [R]D ) 19.3 (c )
0.83, CHCl3). IR (film) νmax 3050, 3020, 2920, 2880, 2840, 1490,
(b) F r om a n ti-10: The same procedure described above
for the preparation of anti-7 was followed starting from anti-
10 (8.0 mg, 0.04 mmol). After purification by column chro-
matography, anti-4 (9.0 mg, 82% yield) was obtained as a
colorless oil, identical in all respects to the product obtained
from anti-8: [R]D ) 23.5 (c ) 1.24, CHCl3). IR (film) νmax 3020,
2980, 2940, 1750, 1490, 1450, 1435, 1360, 1210, 1175, 1095,
1020, 960, 840, 790 cm-1 1H NMR (200 MHz, CDCl3) δ 1.44
.
(d, J ) 7.2 Hz, 3H), 2.88 (s, 3H), 3.3-3.5 (m 1H), 3.72 (s, 3H),
5.11 (d, J ) 5.9 Hz, 1H), 7.2-7.4 (m, 5H) ppm. 13C NMR (50
MHz, CDCl3) δ 17.4 (CH3), 38.6 (CH3), 41.7 (CH), 52.5 (CH3),
1460, 1350, 1250, 1170, 1115, 960, 910, 830, 770, cm-1
.
1H
NMR (200 MHz, CDCl3) δ 0.05 (s, 3H), 0.06 (s, 3H), 0.9 (s,
9H), 1.38 (d, J ) 7 Hz, 3H), 2.54 (s, 3H), 3.1-3.4 (m, 1H), 3.77

8430 J . Org. Chem., Vol. 62, No. 24, 1997
Pasto´ et al.
81.9 (CH), 127.5 (CH), 128.0 (CH), 128.5 (CH), 139.9 (C), 168.5
(C) ppm. MS (EI) m/e ) 213 (2%), 176 (17%), 105 (100%).
Meth yl (2R,3R)-2-Hyd r oxy-3-p h en ylbu ta n oa te, a n ti-10.
To a vigorously stirred mixture of the epoxy alcohol 2 (0.41 g,
2.73 mmol) and 20 mL of a 1/1/1.5 CCl4/CH3CN/H2O mixture
were added sodium bicarbonate (1.16 g, 13.8 mmol), sodium
periodate (1.77 g, 8.27 mmol), and ruthenium trichloride
trihydrate (21 mg, 0.08 mmol). The reaction mixture was
stirred for 48 h, the acidic material was carefully extracted
into diethyl ether at 0 °C, and the ethereal solution was briefly
dried over sodium sulfate. Evaporation to dryness gave a
residue (epoxy acid 9) that was dissolved again in ether (10
mL) and added via cannula to a stirred suspension of Me2-
CuCNLi2 prepared in situ from CuCN (0.74 g, 8.26 mmol) in
ether (80 mL) and MeLi (10 mL, 16 mmol, 1.6 M in hexanes)
at 0 °C. After 4 h at 0 °C, the reaction mixture was acidified
with 5% aqueous HCl. The resulting mixture was filtered
through a pad of Celite, and the filtrate was extracted with
diethyl ether. The organic layer was dried over sodium sulfate,
and the solvent was evaporated. The oily residue was dis-
solved in N,N-dimethylformamide (4.5 mL), and KHCO3 (0.55
g, 5.54 mmol) and methyl iodide (0.27 mL, 4.33 mmol) were
added. This reaction mixture was stirred at room temperature
for 12 h, water was added, and the organic layer was extracted
with ethyl acetate (3 × 10 mL). The combined organic phases
were successively washed with a saturated aqueous Na2SO3
solution and with brine and dried over MgSO4. Removal of
the solvents gave an oil that was purified by column chroma-
dure described for the preparation of anti-7, syn-6 (0.05 g, 0.18
mmol) was converted into syn-7 (0.06 g, 89% yield). Colorless
oil: [R]D ) -5.9 (c ) 2.2, CHCl3). IR (film) νmax 3060, 2980,
2960, 2920, 2890, 1475, 1370, 1270, 1190, 1130, 980, 920, 845,
790 cm-1 1H NMR (200 MHz, CDCl3) δ-0.02 (s, 3H), 0.00 (s,
.
3H), 0.86 (s, 9H), 1.39 (d, 3H, J ) 7.2 Hz), 2.81 (s, 3H), 3.17
(pseudo quint, J ) 7 Hz, 1H), 3.5-3.8 (m, 2H), 4.6-4.8 (m,
1H), 7.2-7.4 (m, 5H) ppm. 13C NMR (50 MHz, CDCl3) δ -5.6
(CH3), 16.3 (CH3), 19 (C), 25.8 (CH3), 38.2 (CH3), 40.1 (CH),
63.1 (CH2), 88.2 (CH), 127.1 (CH), 127.8 (CH), 128.7 (CH),
142.2 (C) ppm.
(2S,3R)-3-P h en yl-2-(m et h a n esu lfon yloxy)-1-b u t a n ol,
syn -8. Following the procedure described for the preparation
of anti-8, syn-7 (0.05 g, 0.14 mmol) was converted into syn-8
(18 mg, 50% yield). Colorless oil: [R]D ) -30.4 (c ) 0.89,
CHCl3). IR (film) νmax 3536, 2938, 1495, 1454, 1335, 1173,
1068, 1014, 970, 906, 766 cm-1 1H NMR (200 MHz, CDCl3) δ
.
1.41 (d, 3H, J ) 7 Hz), 2-2.2 (m, 1H, OH), 2.93 (s, 3H), 3-3.2
(m, 1H), 3.5-3.8 (m, 2H), 4.7-4.9 (m, 1H), 7.1-7.5 (m, 5H)
ppm. 13C NMR (50 MHz, CDCl3) δ 17.0 (CH3), 38.2 (CH3), 40.9
(CH), 63.2 (CH2), 88.3 (CH), 127.3 (CH), 127.7 (CH), 128.9
(CH), 141.7 (C) ppm.
Met h yl (2S,3R)-2-(Met h a n esu lfon yloxy)-3-p h en ylb u -
ta n oa te, syn -4. (a ) F r om syn -8: The same procedure
described above for the preparation of anti-4, was followed
starting from syn-8 (18 mg, 0.07 mmol). After purification by
chromatography syn-4 (11 mg, 54% yield) was obtained as a
colorless oil.
tography to yield 0.18 g (39% yield) of anti-10 as an oil: [R]D
8.4 (c ) 2.21, CHCl3). IR (film) νmax 3500, 3040, 2980, 2940,
1745, 1500, 1460, 1440, 1275, 1220, 1130 cm-1 1H NMR (200
)
(b) F r om syn -10: The same procedure described above for
the preparation of anti-7 was followed starting from syn-10
(0.12 g, 0.61 mmol). After purification by chromatography,
syn-4 (0.15 g, 91% yield) was obtained as a colorless oil. The
product was spectroscopically identical with the one obtained
from syn-8. Colorless oil. [R]D ) -11.5 (c ) 1.93, CHCl3). IR
.
MHz, CDCl3) δ 1.45 (d, J ) 7.2 Hz, 3H), 2.4-2.7 (m, 1H, OH),
3.2-3.4 (m, 1H), 3.70 (s, 3H), 4.3-4.4 (m, 1H), 7.1-7.5 (m,
5H) ppm. 13C NMR (50 MHz, CDCl3) δ 17.5 (CH3), 43.4 (CH),
52.2 (CH3), 75.0 (CH), 127.0 (CH), 128.0 (CH), 128.2 (CH), 140
(C), 174 (C) ppm. MS (CI-NH3) m/e ) 212 (M+ + 18, 100%).
(2S,3R)-1-[(ter t-Bu tyld im eth ylsilyl)oxy]-3-p h en yl-2-[(p-
n itr oben zoyl)oxy]bu ta n e, syn -14. To a solution of anti-6
(0.17 g, 0.61 mmol) in benzene (12 mL) were added PPh3 (0.77
g, 2.93 mmol), p-nitrobenzoic acid (0.44 g, 2.63 mmol), and
diethyl azodicarboxylate (0.46 mL, 2.92 mmol). The reaction
mixture was stirred at room temperature for 12 h and was
subsequently concentrated in vacuo and the residue submitted
to column chromatography to yield 0.135 g of syn-14 (51%
yield) as an oil: [R]D ) -27.5 (c ) 1.25, CHCl3). IR (film) νmax
2980, 2950, 2910, 2880, 1740, 1620, 1540, 1470, 1360, 1280,
(film) νmax 1761, 1454, 1369, 1177, 1086, 957, 848, 773 cm-1
.
1H NMR (200 MHz, CDCl3) δ 1.39 (d, 3H, J ) 7.2 Hz), 2.73 (s,
3H), 3.4-3.6 (m, 1H), 3.73 (s, 3H), 5.02 (d, 1H, J ) 4.2 Hz),
7.2-7.4 (m, 5H) ppm. 13C NMR (50 MHz, CDCl3) δ 14.4 (CH3),
38.2 (CH3), 41.5 (CH), 52.6 (CH3), 82.3 (CH), 127.6 (CH), 127.8
(CH), 128.6 (CH), 140.1 (C), 168.6 (C) ppm. MS (EI) m/e )
290 (M+ + 18, 100%).
Met h yl (2S,3R)-3-P h en yl-2-[(p -n it r ob en zoyl)oxy]b u -
ta n oa te, syn -15. To a solution of anti-10 (0.2 g, 1.03 mmol)
in benzene (20 mL) were added 1.29 g of PPh3 (4.9 mmol),
p-nitrobenzoic acid (0.73 g, 4.37 mmol), and diethyl azodicar-
boxylate (0.8 mL, 5 mmol). The reaction mixture was stirred
at room temperature for 12 h and then concentrated in vacuo,
and the residue purified by column chromatography to yield
0.33 g of syn-15 (93% yield) as an oil: [R]D ) -72.9 (c ) 1.46,
CHCl3). IR (film) νmax 2960, 1760, 1735, 1615, 1535, 1510,
1130, 1110, 845, 790, 730 cm-1 1H NMR (200 MHz, CDCl3) δ
.
-0.01 (s, 3H), 0.00 (s, 3H), 0.89 (s, 9H), 1.42 (d, 3H, J ) 7
Hz), 3.38 (m, 1H), 3.60-3.75 (dd ABX, J AB ) 11.2 Hz, J AX ) 5
Hz, J BX ) 3.4 Hz, 2H), 5.3-5.5 (m, 1H), 7.4 (s, 5H), 8.35 (m,
4H) ppm. 13C NMR (50 MHz, CDCl3) δ -5.6 (CH3), 17.6 (CH3),
25.7 (CH3), 40.0 (CH), 62.4 (CH2), 80.2 (CH), 123.5 (CH), 126.9
(CH), 127.7 (CH), 128.2 (CH), 128.6 (CH), 130.7 (CH), 135.9
(C), 142.6 (C), 150.5 (C), 164.3 (C) ppm. MS (EI) m/e ) 447
(M+ + 18, 100%), 430 (M+ + 1, 60%).
1
1355, 1300, 1280, 1260, 1220, 1120, 1110, 1020, 720 cm-1. H
NMR (200 MHz, CDCl3) δ 1.51 (d, 3H, J ) 6.8 Hz), 3.5-3.7
(m, 1H), 3.70 (s, 3H), 5.37 (d, 1H, J ) 4.8 Hz), 7.2-7.4 (m,
5H) 8.21 (d, 2H, J ) 9.2 Hz), 8.31 (d, 2H, J ) 9.2 Hz) ppm. 13
C
NMR (50 MHz, CDCl3) δ 15.3 (CH3), 41.1 (CH), 52.4 (CH3),
77.7 (CH), 123.6 (CH), 127.3 (CH), 127.6 (CH), 128.6 (CH),
130.9 (CH), 134.8 (C), 140.9 (C), 169.2 (C) ppm. MS (EI) m/e
) 361 (M+ + 18, 100%).
(2S,3R)-1-[(ter t-Bu tyld im eth ylsilyl)oxy]-3-p h en yl-2-bu -
ta n ol, syn -6. To a solution of syn-14 (0.06 g, 0.14 mmol) in
CH2Cl2 (1 mL) at - 20 °C was added DIBALH (0.4 mL, 0.4
mmol, 20% in hexanes). The mixture was stirred at -20 °C
until no starting material was observed by TLC (approximately
1 h), CH2Cl2 (0.5 mL) was then added, and the resulting
solution was treated with 10% hydrochloric acid (0.8 mL). The
aqueous phase was extracted with CH2Cl2, and the combined
organic extracts were dried over MgSO4 and concentrated in
vacuo. The residue was purified by flash cromatography to
afford 0.03 g (79% yield) of syn-6: [R]D ) 11.8 (c ) 1.25, CHCl3).
IR (film) νmax 3500, 3060, 2980, 2960, 2910, 2890, 1475, 1260,
Meth yl (2S,3R)-2-Hyd r oxy-3-p h en ylbu ta n oa te, syn -10.
To a solution of syn-15 (0.33 g, 0.96 mmol) in THF (10 mL)
was added 2 mL of a 2 M LiOH aqueous solution. The mixture
was warmed to 70 °C and stirred at that temperature for 35
min and then cooled to room temperature and acidified with
10% aqueous HCl. Phases were separated, the aqueous one
was extracted with CH2Cl2, and the combined organic phases
were dried over anhydrous Na2SO4 and concentrated in vacuo.
The crude hydroxy acid (0.29 g) was dissolved in dimethylform-
amide (3 mL) and treated with KHCO3 (0.39 g, 3.9 mmol) and
methyl iodide (0.19 mL, 3.05 mmol) at room temperature for
5 h. Water (5 mL) was then added, and the aqueous layer
was extracted with ethyl acetate. The combined organic
phases were successively washed with saturated aqueous Na2-
SO3 and brine and dried over MgSO4. Solvent removal and
purification by column chromatography yielded 0.15 g of syn-
10 (80% yield) as white solid: [R]D ) 34.7 (c ) 1.09, CHCl3).
IR (film) νmax 3498, 2956, 1744, 1495, 1452, 1261, 1126, 1049,
1130, 1110, 1090, 1030, 840, 785 cm-1
.
1H NMR (200 MHz,
CDCl3) δ 0.08 (s, 6H), 0.80 (s, 9H), 1.30 (d, J ) 6.8 Hz, 3H),
2.48 (m, 1H, OH), 2.71 (pseudo quint, J ) 7.5 Hz, 1H), 3.21-
3.34 (dd ABX, J AB ) 10 Hz, J AX ) 6.6 Hz, J BX ) 3.4 Hz, 2H),
3.6 (m, 1H), 7-7.3 (m, 5H) ppm. 13C NMR (50 MHz, CDCl3)
δ -5.5 (CH3), 18.0 (CH3), 25.8 (CH3), 42.8 (CH), 65.2 (CH2),
76.1 (CH), 126.4 (CH), 127.6 (CH), 128.5 (CH), 144(C) ppm.
(2S,3R)-1-[(ter t-Bu t yld im et h ylsilyl)oxy]-3-p h en yl-2-
(m eth a n esu lfon yloxy)bu ta n e, syn -7. Following the proce-

Asymmetric Synthesis of N-Boc-â-Methylphenylalanines
1014, 769 cm-1 1H NMR (200 MHz, CDCl3) δ 1.29 (d, 3H, J
) 6.8 Hz), 3.23 (dq, 1H, J ) 7.3 Hz, J ) 3.8 Hz), 3.76 (s, 3H),
4.33 (d, 1H, J ) 3.6 Hz), 7.2-7.4 (m, 5H) ppm. 13C NMR (50
MHz, CDCl3) δ 14.4 (CH3), 43.2 (CH3), 52.5 (CH), 75.0 (CH),
126.8 (CH), 127.7 (CH), 128.3 (CH), 142.4 (C), 174.6 (C) ppm.
MS (CI-NH3) m/e ) 212 (M+ + 18, 100%). Anal. Calcd for
C11H14O3: C, 68.02%; H, 7.26%. Found: C, 68.12%; H, 7.44%.
J . Org. Chem., Vol. 62, No. 24, 1997 8431
.
resulting mixture was hydrogenated at atmospheric pressure.
When no starting material could be detected by TLC, the
mixture was filtered through
evaporated. The residue was purified by column chromatog-
raphy to yield 0.07 g (65%yield) of anti-16 as an oil: [R]D
-32 (c ) 1.72, CHCl3). IR (film) νmax 3372, 2979, 1752, 1713,
1495, 1454, 1368, 1157, 1074, 764 cm-1 1H NMR (200 MHz,
a short pad of Celite and
)
.
Met h yl
(2S,3R)-2-[(ter t-Bu t oxyca r b on yl)a m in o]-3-
CDCl3) δ 1.36 (d, J ) 7 Hz, 3H), 1.40 (s, 9H), 3.2-3.4 (m, 1H),
3.69 (s, 3H), 4.6-4.8 (m, 1H), 4.7-4.9 (m, 1H, NH), 7.1-7.5
(m, 5H) ppm. 13C NMR (50 MHz, CDCl3) δ 17.6 (CH3), 28.2
(CH3), 42.1 (CH), 52.0 (CH3), 58.7 (CH), 79.8 (C), 127.2 (CH),
127.6 (CH), 128.5 (CH), 140.8 (C) ppm. MS (CI-NH3) m/e )
311 (M+ + 18, 100%), 294 (M+ + 1, 16%).
Deter m in a tion of th e Op tica l P u r ity of a n ti-16. To a
solution of anti-16 (0.027 g, 0.092 mmol) in CH2Cl2 (0.8 mL)
at -20 °C was added DIBALH (0.4 mL, 0.4 mmol, 20% in
hexanes). After 5 h at -20 °C, the solution was treated with
5% aqueous HCl, phases were separated, and the organic one
was extracted with CH2Cl2 (3 × 5 mL). The combined organic
phases were dried over MgSO4 and concentrated in vacuo, and
the residue was purified by flash chromatography to yield 0.02
g (81% yield) of (2R,3R)-2-[(tert-butoxycarbonyl)amino]-3-
phenylbutanol: 1H NMR (200 MHz, CDCl3) δ 1.34 (d, 3H, J )
7.2 Hz), 1.37 (s, 9H), 2-2.2 (m, 1H, OH), 3.1 (m, 1H), 3.5-3.9
(m, 3H), 4.4-4.5 (m, 1H, NH), 7.1-7.4 (m, 5H) ppm.
To a solution of this alcohol (0.03 g, 0.11 mmol) in dry CH2-
Cl2 (0.35 mL) at room temperature were sequentially added
4-(N,N-dimethylamino)pyridine (0.014 g), triethylamine (0.073
mL), and (+)-R-methoxy-R-(trifluoromethyl)phenylacetyl chlo-
ride (0.022 mL), and the resulting orange solution was stirred
for 60 min, until no starting material could be detected by TLC.
The reaction was then quenched by addition of 3-(dimethyl-
amino)propylamine, and the solvent was removed under
vacuum. Filtration of the residue through a short pad of silica
gel afforded 0.031 g (58% yield) of the corresponding Mosher
ester. According to 19F NMR (282.2 MHz, CDCl3) only one
signal (-72.3 ppm) was obseved. The 19F NMR spectra (282.2
MHz, CDCl3) of a racemic mixture consists of two well resolved
signals: δ -72.3(2R,3R), -72.4(2S,3S) ppm.
p h en ylbu ta n oa te, syn -16. To a solution of anti-4 (0.36 g,
1.3 mmol) in dimethylformamide (2 mL) was added sodium
azide (0.17 g, 2.6 mmol), and the mixture was heated to 80 °C
under stirring. After 12 h the reaction mixture was cooled to
room temperature, water (5 mL) was added, and the mixture
was extracted with ethyl acetate (3 × 10 mL). The combined
organic phases were dried over MgSO4 and concentrated in
vacuo to yield an oil that was dissolved in ethyl acetate (4.4
mL). To this solution were added Boc2O (0.38 g, 1.74 mmol)
and 10% Pd/C (35 mg), and the mixture was hydrogenated at
atmospheric pressure. After 12 h, the reaction mixture was
filtered through a pad of Celite, evaporated, and submitted to
column chromatography to afford 0.32 g (83%yield) of syn-16
as a white solid: [R]D ) 33 (c ) 1.03, CHCl3). Mp: 58-60 °C.
IR (KBr) νmax 3360, 2980, 1745, 1680, 1510, 1365, 1295, 1240,
1170, 1155 cm-1 1H NMR (200 MHz, CDCl3) δ 1.35 (d, 3H, J
.
) 7.4 Hz), 1.40 (s, 9H), 3.18 (pseudo quint, J ) 6.9 Hz, 1H),
3.56 (s, 3H), 4.49 (m, 1H), 5-5.2 (m, 1H, NH), 7.1-7.4 (m,
5H) ppm. 13C NMR (50 MHz, CDCl3) δ 16.5 (CH3), 28.2 (CH3),
42.8 (CH), 51.9 (CH3), 59.0 (CH), 80 (C), 127.0 (CH), 127.6
(CH), 128.3 (CH), 142 (C), 156 (C), 172 (C) ppm. MS (EI) m/e
) 293 (M+, 2%), 176 (26%), 105 (71%). Anal. Calcd for C16H23
-
NO4: C, 65.51%; H, 7.90%; N, 4.77%. Found: C, 65.54%; H,
7.84%; N, 4.76%. Conditions for Chiral HPLC analysis:
CHIRALCEL OD (25 cm) column, hexane/2-propanol 98/2, 0.5
mL/min λ ) 220 nm. tR(2R,3S): 17.5 min, tR(2S,3R): 16.3 min.
CHIRALCEL® OD-R (25 cm) column, 35% MeOH/0.5 M
NaClO4, 0.5 mL/min, λ ) 220 nm. tR(2R,3S): 31.1 min, tR-
(2S,3R): 33.0 min.
(2S,3R)-2-[(ter t-Bu t oxyca r b on yl)a m in o]-3-p h en ylb u -
ta n oic a cid , syn -1. To a solution of syn-16 (0.04 g, 0.14 mmol)
in THF (1.5 mL) were added 0.3 mL of a 3.5 M LiOH aqueous
solution. The mixture was heated to 70 °C and stirred for 60
min at that temperature. The reaction mixture was then
cooled to room temperature and acidified by addition of a
aqueous 5% HCl solution. Phases were separated, the aqueous
one was extracted with CH2Cl2 (3 × 10 mL), and the combined
organic phases were dried over Na2SO4 and concentrated to
yield 0.04 g (100% yield) of syn-1 as a white solid: [R]D ) 17
(c ) 1.7, CHCl3). Mp: 117 °C. IR (KBr) νmax 3300, 3200-
2600 (b), 2969, 1728, 1659, 1410, 1371, 1269, 1167, 1068, 771
(2R,3R)-2-[(ter t-Bu t oxyca r b on yl)a m in o]-3-p h en ylb u -
ta n oic a cid , a n ti-1. Following the procedure described for
the preparation of syn-1, anti-16 (36 mg, 0.12 mmol) was
converted into anti-1 (32 mg, 94% yield). Colorless oil. [R]D
) -9.5 (c ) 1.58, CHCl3). IR (film) νmax 3400-2600 (b), 2979,
1719, 1497, 1454, 1396, 1369, 1163, 1074, 1024, 854, 762 cm-1
.
1H NMR (200 MHz, CDCl3) δ 1.2 (b s, 3H), 1.40 (s, 9H), 3.3-
3.5 (m, 1H), 4.4-4.6 (m, 1H), 4.8 (m, 1H), 7.2-7.4 (m., 5H),
9-9.4 (m, broad, 1H) ppm. 13C NMR (50 MHz, CDCl3) δ 17.8
(CH3), 28.2 (CH3), 41.6 (CH), 58.8 (CH), 80 (C), 127.3 (CH),
127.7 (CH), 128.6 (CH), 141 (C), 156 (C), 176.6 (C) ppm. MS
(EI) m/e ) 178 (10%), 119 (18%), 105 (100%), 91 (43%).
cm-1 1H NMR (200 MHz, CDCl3) δ 1.2 (b s, 3H), 1.4 (s, 9H),
.
3.3 (m, 1H), 4.4 (m, 1H), 4.6 (m, 1H, rotamer), 5.1 (m, 1H, NH),
6.5 (m, 1H, NH, rotamer), 7.1-7.3 (m, 5H), 9.2-9.4 (m, broad,
1H) ppm. 13C NMR (50 MHz, CDCl3) Rotamer 1: δ 16.1 (CH3),
28.2 (CH3), 42.1 (CH), 58.6 (CH), 80.1 (C), 127.0 (CH), 127.7
(CH), 128.4 (CH), 141.3 (C), 155 (C), 176.2 (C) ppm. Rotamer
2: δ 14.5 (CH3), 27.8 (CH3), 41.8 (CH), 60.1 (CH), 81 (C), 142
(C), 156 (C), 176 (C) ppm. MS (EI) m/e ) 178 (13%), 119 (26%),
105 (100%), 91 (21%). Anal. Calcd for C15H21NO4: C, 64.50%;
H, 7.58%; N, 5.01%. Found: C, 63.97%; H, 7.60%; N, 4.95%.
Ack n ow led gm en t. Financial support from CIRIT-
CICYT through grant QFN93-4407 is gratefully ac-
knowledged. M. Pasto´ thanks CIRIT (Generalitat de
Catalunya) for a predoctoral fellowship.
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR of syn and/or anti stereoisomers of compounds 1, 4-8,
10, and 14-16, experimental procedures for the preparation
of syn-5 and syn-10 according to Schemes 4 and 5, 19F NMR
spectrum used for enantiomeric purity determination of anti-
16, and HPLC chromatogram of syn-16 on a Chiralcel-ODR
column (39 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.
Met h yl
(2R,3R)-2-[(ter t-Bu t oxyca r b on yl)a m in o]-3-
p h en ylbu ta n oa te, a n ti-16. To a solution of syn-4 (0.1 g, 0.37
mmol) in N,N-dimethylformamide (0.6 mL) was added sodium
azide (0.05 g, 0.77 mmol), and the mixture was heated to 80
°C under stirring. After 12 h, the reaction mixture was
allowed to cool to room temperature and quenched with water
(0.5 mL). The mixture was then extracted with ethyl acetate
(3 × 5 mL), and the combined organic phases were dried over
MgSO4 and concentrated in vacuo to yield an oil that was
dissolved in ethyl acetate (1.6 mL). To this solution, Boc2O
(0.1 g, 0.46 mmol) and 10% Pd/C (10 mg) were added, and the
J O971178F