Enantioselective syntheses of homophenylalanine derivatives via nitrone 1,3-dipolar cycloaddition reactions with styrenes

Article abstract of DOI:10.1016/S0040-4039(01)00821-8

A new two-step route to derivatives of homophenylalanine is presented. Cycloaddition of a cyclic nitrone glycine template with various styrene derivatives affords good yields of 5-substituted cycloadducts. One-step hydrogenolysis (three bonds) then affords the optically pure α-amino acids related to homophenylalanine.

Full text of DOI:10.1016/S0040-4039(01)00821-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5343–5345
Enantioselective syntheses of homophenylalanine derivatives via
nitrone 1,3-dipolar cycloaddition reactions with styrenes
Alan Long and Steven W. Baldwin*
Paul M. Gross Chemical Laboratory, Department of Chemistry, Duke University, Durham, NC 27708-0346, USA
Received 28 March 2001; revised 7 May 2001; accepted 15 May 2001
Abstract—A new two-step route to derivatives of homophenylalanine is presented. Cycloaddition of a cyclic nitrone glycine
template with various styrene derivatives affords good yields of 5-substituted cycloadducts. One-step hydrogenolysis (three bonds)
then affords the optically pure a-amino acids related to homophenylalanine. © 2001 Published by Elsevier Science Ltd.
A recent report from this laboratory demonstrated that
nitrone 2 is a versatile partner in 1,3-dipolar cycloaddi-
tion reactions with a wide range of alkenes, a result that
establishes 2 as a useful chiral glycine template for the
synthesis of a-amino acids bearing unusual side-chains.1
We now wish to report that when styrene derivatives
are employed as dipolarophiles, the method also pro-
vides ready access to a wide range of derivatives of
homophenylalanine. Also reported is an improved
preparation of nitrone 2 based on an oxidation of the
parent secondary amine.
Anticipating some specific applications of this nitrone
cycloaddition methodology that would involve reaction
with styrene derivatives, the cycloaddition of 2 with
styrene itself was studied in some detail. Thus, reaction
of styrene with nitrone 2 in chloroform for 3 hours at
reflux led to a 73% yield of a 10/1 mixture of cycload-
ducts 3exo and 3endo. When conducted at room tem-
perature, the isomer ratio was essentially unchanged
although the reaction took several days to go to com-
pletion. The stereochemistry of the major cycloadduct
was anticipated based on the expectation of reaction
occurring at the less hindered a-face of nitrone 2. The
further expectation that the phenyl group would adopt
an exo orientation was based on our previous studies of
nitrone 2 with other monosubstituted alkenes as well as
results from the cycloaddition of other styrene deriva-
tives with cyclic nitrones.1,6 The structure of the minor
cycloadduct was assumed to be as indicated, with the
phenyl group in an endo orientation, an assumption
that was verified subsequently with other cycloadducts.
As originally reported, oxidation of amine 12 was
accomplished using in situ generated dimethyl dioxirane
(DMD).1 Although the yields by this process were often
excellent, they were not always reproducible and thus
another oxidation method was sought. Eventually it
was found that the methyltrioxorhenium/urea hydrogen
peroxide (MTO/UHP) system of Goti3 and Murray,4 a
catalytic oxidant with chemistry similar to DMD, gave
yields of 2 that are consistently in the 70–80% range on
a multi-gram scale (Scheme 1). The optical purity of 2
produced by this method was in excellent agreement
with that previously obtained.5
Cycloadducts 3exo and 3endo, each with three bonds
susceptible to hydrogenolysis conditions (NꢀO, benzylic
N
and O), are well suited for conversion to
O
O
O
O
H
N
H
N
O
O
O
O
H2NCONH2•H2O2
MeReO3 (cat)
PhCH=CH2
+
N+
Ph
Ph
NH
O
O-
O
(70-80%)
(73%)
(10/1)
Ph
Ph
Ph
Ph
1
2
3 exo
3 endo
Scheme 1.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0040-4039(01)00821-8

5344
A. Long, S. W. Baldwin / Tetrahedron Letters 42 (2001) 5343–5345
homophenylalanine (4). Thus, hydrogenolysis (60 psi)
of 3 in the presence of Pearlman’s catalyst in a diox-
ane–trifluoroacetic acid (10/1) solvent system afforded
pure homophenylalanine in 50% yield after trituration
with ether (Scheme 2). Alternatively, pure homophenyl-
alanine could be obtained by ion-exchange chromato-
graphy of the crude product. The specific rotation of
the crude product ([h]D=+41°) was in good agreement
with the literature value for the (S) enantiomer ([h]D=
+45°),7 confirming that the cycloaddition reaction had
indeed occurred from the less hindered a face of nitrone
2. Based on our earlier work, including the isolation of
intermediates along the reaction pathway, the one-pot
conversion of cycloadducts 3 to homophenylalanine (4)
under the indicated hydrogenolysis conditions is
thought to proceed as indicated, with initial NꢀO cleav-
O
O
OH
H
N
H
Ph
H
O
HO2C
Ph
H2 , Pd(OH)2/C
dioxane/TFA
O
3
NH OH
(50%)
NH2
Ph
Ph
Ph
6
5
4
Scheme 2.
Table 1. Isoxazolidine 8a–f and homophenylalanine derivatives 9a–f produced from substituted styrenes and 2
yieldb;
exo/endoc
yield; [α]D;
mp (oC)
substituted
homophenylalanine
styrene
cycloadducta
O
H
Me
71%; 10/1
Me
t-Bu
Me
50%;
O
+51o (c=0.17, 1N HCl);
285-95o (HCl salt)
H
-
CO2
N
O
O
O
O
O
O
Me
+
NH3
Ph
9a
7a
8a
O
t-Bu
85%; 7/1
H
74%;
O
O
O
O
O
H
-
+31o (c=0.20, MeOH);
232-34o
CO2
N
t-Bu
+
NH3
Ph
O
9b
9c
9d
9e
9f
7b
8b
Me
Me
H
49%;
H
-
49%; >20/1
+37o (c=0.19, MeOH);
220-226o (HCl salt)
CO2
N
Me
Me
Me
Me
+
Me
Me
NH3
Ph
7c
8c
O
H
27%;
H
-
+33o (c=0.18, MeOH);
227-232o (HCl salt)
55%; 5/1
CO2
N
Me
Me
+
NH3
Me
Ph
O
7d
7e
7f
8d
OAc
H
HO
45%;
H
-
84%; 5/1
CO2
+34o (c=0.11, 1N HCl);
215-220o (dec)
N
OAc
+
NH3
Ph
8e
O
H
54%;
H
-
70%; 10/1
+28o (c=0.20, 1N HCl);
225o (dec)
CO2
N
+
NH3
Ph
8f
aReactions were performed with 1.5 - 5 eq. styrene in CHCl3 at reflux for 3 - 5 hours.
bCombined yields (unoptimized) of exo and endo isomers isolated chromatographically.
cDetermined by integration of 1H NMR spectra of unpurified reaction mixture.

A. Long, S. W. Baldwin / Tetrahedron Letters 42 (2001) 5343–5345
5345
age followed by rapid translactonization to give g-lac-
tone 6. This lactone can be isolated under different
financial assistance in the purchase of the 400 MHz
NMR instrument used in support of this work. A.L.
acknowledges with appreciation support from the Bur-
roughs Wellcome Foundation in the form of a graduate
fellowship.
hydrogenolysis conditions.8 Conversion of
6
to
homophenylalanine (4) then involves cleavage of the
remaining benzylic oxygen and nitrogen bonds.
The cycloaddition/hydrogenolysis protocols also work
well for other styrene derivatives. Table 1 summarizes
the results of cycloadditions of nitrone 2 with a total of
six additional styrene compounds 7a–f. The unop-
timized yields of purified products for these reactions
ranged from 49 to 85% with exo/endo isomer ratios
ranging from a low of 5/1 (8d and 8e) to essentially all
exo (8c). The exo/endo stereochemical assignments of
References
1. Baldwin, S. W.; Young, B. G.; McPhail, A. T. Tetra-
hedron Lett. 1998, 39, 6819.
2. Dellaria, J.; Santasiero, B. J. Org. Chem. 1989, 54,
3916.
3. Goti, A.; Nanelli, L. Tetrahedron Lett. 1996, 37, 6025.
4. Murray, R.; Iyanar, K. J. Org. Chem. 1996, 61, 8099.
5. After our initial development work was completed,
nitrone 2 was prepared by an alternative synthesis and
several cycloaddition reactions were reported. (a)
Tamura, O.; Gotanda, K.; Terashima, R.; Kikuchi, M.;
Miyawaki, T.; Sakamoto, M. Chem. Commun. 1996,
1861; (b) Tamura, O.; Kuroki, T.; Sakai, Y.; Takizawa,
J.; Yoshino, J.; Morita, Y.; Mita, N.; Gotanda, K.;
Sakamoto, M. Tetrahedron Lett. 1999, 40, 895; (c)
Tamura, O.; Gotanda, K.; Yoshino, J.; Mirita, Y.;
Terashima, R.; Mayumi, K.; Miyaweaki, T.; Mita, N.;
Yamashita, M.; Ishibashi, H.; Sakamoto, M. J. Org.
Chem. 2000, 65, 8544–8551.
6. Tufariello, J.; Ali, A. Tetrahedron Lett. 1978, 4647.
7. Weller, H. N.; Gordon, E. M. J. Org. Chem. 1982, 47,
4160.
8. Treatment of styrene adduct 3exo with Zn/HOAc
afforded lactone 6 as the acetate, hydrolysis of which
(K2CO3/MeOH) afforded pure 6 (cis). Exposure of 6 to
hydrogen (60 psi; Pearlman’s catalyst) in dioxane–TFA
(10/1) and isolation as before then afforded homophenyl-
alanine (4).
9. (a) Zambias, R. A.; Hammond, M. L.; Heck, J. V.;
Bartizal, K.; Trainor, C.; Abruzzo, G.; Schmatz, D.
M.; Nolstadt, K. M. J. Med. Chem. 1992, 35, 2843; (b)
Melillo, D. G.; Lawsen, R. D.; Mathre, D. J.; Shukis,
W. F.; Wood, A. W.; Collelvori, J. R. J. Org. Chem.
1987, 52, 5143.
10. The structures of all compounds reported in this work
were confirmed by 1H and 13C NMR, mass spectrome-
try and IR where appropriate. Suitably purified samples
of nitrone 2, all new homoaromatic a-amino acids, and
selected cycloadducts also exhibited consistent high reso-
lution mass spectral data for their molecular ions.
11. Racemic 9a has been previously described and racemic
9c mentioned in the following reference: Oldfield, M.
F.; Bennett, R. N.; Kiddle, G.; Wallsgrove, R. M.;
Botting, N. P. Plant Physiol. Biochem. 1999, 37, 99.
1
cycloadducts 8 were verified by their H and 13C NMR
spectra, including NOE experiments.
As summarized in Table 1, exposure of the cycload-
ducts 8 to the hydrogenolysis protocol described pre-
viously afforded the corresponding a-amino acids in a
single operation. This represents a particularly facile
preparation of these novel materials. All optically active
homophenylalanine derivatives except homotyrosine
(9e)9 are new compounds.10,11
A further demonstration that the two cycloadduct iso-
mers 8 are endo/exo isomers rather than the result of
poor nitrone facial selectivity was seen in the
hydrogenolysis of cycloadduct 8b, derived from 4-tert-
butylstyrene. Hydrogenolysis of the pure major
stereoisomer of 8b (exo) afforded crude a-amino acid
9b that exhibited a specific rotation of +25°. The spe-
cific rotation of the crude a-amino acid derived from
hydrogenolysis of a 1/1 mixture of the isomeric 8b
cycloadducts (exo and endo) was +29°. Had the two
stereoisomers been the result of different nitrone facial
selectivity in the cycloaddition reaction the specific
rotation of this product would have approached zero.
The specific rotation of purified 9b is +31°.
These results demonstrate the value of nitrone 2 for the
formation of uncommon derivatives of homophenylala-
nine. Cycloaddition with various styrene derivatives
followed by one-step hydrogenolysis affords novel opti-
cally pure a-amino acids in a total of two synthetic
operations. Further application of the method to other
types of targets will be reported subsequently.
Acknowledgements
We gratefully acknowledge NSF (CHE 95 22580) for
.