New Chiral Didehydroamino Acid Derivatives from a Cyclic Glycine Template with 3,6-Dihydro-2H-1,4-oxazin-2-one Structure: Applications to the Asymmetric Synthesis of Nonproteinogenic α-Amino Acids

Article abstract of DOI:10.1021/jo991736l

New chiral (Z)-α,β-didehydroamino acid (DDAA) derivatives with 3,5-dihydro-2H-1,4-oxazin-2-one structure 11a-f have been stereoselectively prepared after condensation of chiral glycine equivalent 7 with aldehydes in the presence of K₂CO₃ under mild solid-liquid phase-transfer catalysis reaction conditions. These new systems have been used in diastereoselective cyclopropanation reactions using Corey's ylide for the asymmetric synthesis of 1-aminocyclopropane-1-carboxylic acids (ACCs) such as allo-corononamic and allo-norcoronamic acids. The hydrogenation reaction of these systems at ambient pressure in the presence of formaldehyde affords saturated oxazinones and N-methylated oxazinones which have been transformed into the N-methyl-α-amino acids (N-MAAs) (S)-2-(methylamino)butanoic acid and (S)-N-methylleucine. In addition, the parent α,β-didehydroalanine derivative 11g has been prepared by a direct aminomethylation-elimination sequence from 7 and Eschenmoser's salt and has been used in Diels-Alder cycloaddition with endo selectivity for the synthesis of the enantiomerically pure bicyclic α-amino acids (-)-2-aminobicyclo[2.2.1]heptane-2-carboxylic and (-)-2-aminobicyclo[2.2.2]octane-2-carboxylic acids.

Full text of DOI:10.1021/jo991736l

3034
J . Org. Chem. 2000, 65, 3034-3041
New Ch ir a l Did eh yd r oa m in o Acid Der iva tives fr om a Cyclic
Glycin e Tem p la te w ith 3,6-Dih yd r o-2H-1,4-oxa zin -2-on e Str u ctu r e:
Ap p lica tion s to th e Asym m etr ic Syn th esis of Non p r otein ogen ic
r-Am in o Acid s
Rafael Chinchilla,† Larry R. Falvello,‡,§ Nuria Galindo,† and Carmen Na´jera*,†
Departamento de Quı´mica Orga´nica, Universidad de Alicante, Apartado 99, 03080 Alicante, Spain, and
Departamento de Quı´mica Inorga´nica, Instituto de Ciencias de los Materiales de Arago´n, Facultad de
Ciencias, Universidad de Zaragoza-CSIC, 50009 Zaragoza, Spain
Received November 5, 1999
New chiral (Z)-R,â-didehydroamino acid (DDAA) derivatives with 3,5-dihydro-2H-1,4-oxazin-2-one
structure 11a -f have been stereoselectively prepared after condensation of chiral glycine equivalent
7 with aldehydes in the presence of K2CO3 under mild solid-liquid phase-transfer catalysis reaction
conditions. These new systems have been used in diastereoselective cyclopropanation reactions
using Corey’s ylide for the asymmetric synthesis of 1-aminocyclopropane-1-carboxylic acids (ACCs)
such as allo-corononamic and allo-norcoronamic acids. The hydrogenation reaction of these systems
at ambient pressure in the presence of formaldehyde affords saturated oxazinones and N-methylated
oxazinones which have been transformed into the N-methyl-R-amino acids (N-MAAs) (S)-2-
(methylamino)butanoic acid and (S)-N-methylleucine. In addition, the parent R,â-didehydroalanine
derivative 11g has been prepared by a direct aminomethylation-elimination sequence from 7 and
Eschenmoser’s salt and has been used in Diels-Alder cycloaddition with endo selectivity for the
synthesis of the enantiomerically pure bicyclic R-amino acids (-)-2-aminobicyclo[2.2.1]heptane-2-
carboxylic and (-)-2-aminobicyclo[2.2.2]octane-2-carboxylic acids.
In tr od u ction
sulfoxonium ylides4a,6 leads to important 1-aminocyclo-
propane-1-carboxylic acids (ACCs).7 The carbon-carbon
double bond is active in ene reactions, hydrogenation,
nucleophilic or radical additions,3 Heck coupling with aryl
halides,8 and as a dienophile in asymmetric Diels-Alder
cycloaddition reactions for the preparation of bicyclic
R-amino acids with interesting biological activities.9
Several chiral DDAA derivatives have been previously
R,â-Didehydro-R-amino acids (DDAAs) constitute a
family of conformationally constrained amino acids found
in many biologically active natural peptides.1 Their
presence in peptide chains enhances resistance to enzy-
matic and chemical degradation.2 Chiral DDAA deriva-
tives are versatile intermediates in the synthesis of a
variety of R-amino acids. For example, the asymmetric
hydrogenation of chiral DDAA derivatives has been used
for the synthesis of enantiomerically enriched monoalkyl-
ated R-amino acids,3 and the diastereoselective cyclo-
propanation with diazoalkanes4 and phosphonium5 or
described showing E (1,10 24a) and Z (3,11 4,4f 5,4b,c,6
)
configuration. Their preparation has been achieved (a)
by direct condensation with aldehydes under strong basic
conditions (t-BuOK) and very low reaction temperature
for the pinanone derivative 54b,c,6 and diketopiperazine
311 giving Z-derivatives, respectively, with low diastereo-
selectivity, (b) by Horner-Wadsworth-Emmons olefina-
tion of phosphonate derivatives for imidazolidinones 110b
and oxazinones 2,4a and (c) by transformation of (Z)-
alkylidenoxazolones into diketopiperazines 4.4f
* To whom the correspondence should be addressed. E-mail:
cnajera@ua.es. URL: www.ua.es/dept.quimorg.
† Universidad de Alicante.
‡ To whom the correspondence on X-ray structures should be
addressed. E-mail: falvello@lrf1.unizar.es.
§ Universidad de Zaragoza-CSIC.
The cyclopropanation of some of these chiral DDAA
derivatives has been carried out by (a) 1,3-dipolar cyclo-
addition of diazomethane with rather low diastereo-
(1) (a) Alvarez-Ibarra, C.; Csa´ky¨, A. G.; Murcia, M. C. J . Org. Chem.
1998, 63, 8736-8734, and references therein.
(2) Some examples: (a) Sano, T.; Kaya, K. Tetrahedron 1998, 54,
463-470. (b) Umemura, K.; Noda, H.; Yoshimura, J .; Konn, A.;
Yonezawa, Y.; Shin, C. Tetrahedron Lett. 1997, 38, 3539-3542. (c)
Ward, D. E.; Va´zquez, A.; Pedras, M. S. C. J . Org. Chem. 1999, 64,
1657-1666. (d) Bryant, H. J .; Dardonville, C. Y.; Hodgkinson, T. J .;
Hursthouse, M. B.; Malik, K. M. A.; Shipman, M. J . Chem. Soc., Perkin
Trans. 1 1998, 1249-1255.
(5) Chinchilla, R.; Na´jera, C.; Garc´ıa-Granda, S.; Mene´ndez-Vela´z-
quez, A. Tetrahedron Lett. 1993, 34, 5799-5802.
(6) Calmes, M.; Daunis, J .; Escale, F. Tetrahedron: Asymmetry 1996,
7, 395-396.
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172. (b) Williams, R. M. Synthesis of Optically Active Amino Acids;
Pergamon Press: Oxford, 1989; Chapter 6. (c) Duthaler, R. O.
Tetrahedron 1994, 50, 1539-1650.
(4) (a) Williams, R. M.; Fegrey, G. J . J . Am. Chem. Soc. 1991, 113,
8796-8806. (b) Alami, A.; Calmes, M.; Daunis, J .; Escale, F.; J acquier,
R.; Roumestant, M.-L.; Viallefont, P. Tetrahedron: Asymmetry 1991,
2, 175-178. (c) Cativiela, C.; Diaz-de-Villegas, M. D.; Ga´lvez, J . A.
Tetrahedron: Asymmetry 1992, 3, 567-572. (d) J ime´nez, J . M.; Casas,
R.; Ortun˜o, R. M. Tetrahedron Lett. 1994, 35, 5945-5948. (e) Cativiela,
C.; Diaz-de Villegas, M. D.; J ime´nez, A. I. Tetrahedron: Asymmetry
1995, 6, 177-182. (f) Alcaraz, C.; Ferna´ndez, M. D.; de Frutos, M. P.;
Marco, J . L.; Bernabe´, M.; Foces-Foces, C.; Cano, F. H. Tetrahedron
1994, 50, 12433-12456.
(7) For reviews, see: (a) Stammer, C. H. Tetrahedron 1990, 46,
2231-2254. (b) Burgess, K.; Ho, K.-K.; Mye-Sherman, D. Synlett 1994,
575-583.
(8) (a) Cutolo, M.; Fiandese, V.; Maso, F.; Sciacovelli, O. Tetrahedron
Lett. 1983, 24, 4603-4606. (b) Carlstro¨m, A. S.; Frejd, T. Synthesis
1989, 414-418.
(9) (a) Tager, H. S.; Christensen, H. N. J . Am. Chem. Soc. 1972, 94,
968-972. (b) Zand, R.; Sellinger, O. Z.; Water, R.; Harris, R. J .
Neurochem. 1974, 23, 1201-1206.
(10) (a) Zimmermann, J .; Seebach, D. Helv. Chim. Acta 1987, 70,
1104-1114. (b) Schickli, C. P.; Seebach, D. Liebigs Ann. Chem. 1991,
655-668.
(11) Oba, M.; Nakajima, S.; Nishiyama, K. Chem. Commun. 1996,
1875-1876.
10.1021/jo991736l CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/19/2000

New Chiral Didehydroamino Acid Derivatives
J . Org. Chem., Vol. 65, No. 10, 2000 3035
selectivity in the case of compounds 2,4a 4,4f and 5,4b,c and
(b) Michael addition of sulfoxonium4a,6 or phosphonium5
ylides in the case of compounds 1 (X ) O) and 26 or 5,4a
Sch em e 1
Sch em e 2
respectively. In addition, the diastereoselective hydro-
genation of chiral DDAA derivatives has been studied on
diketopiperazine derivatives 311 and 43a and also on cyclic
imino esters 5.4c Diastereoselective Diels-Alder reactions
have been carried out using oxazolidinones 1 (X ) O, R2 )
H) or related,12 chiral acyclic didehydroalanine deriva-
tives13 or even nonchiral systems employing chiral cata-
lysts.13
Resu lts a n d Discu ssion
All these antecedents suggest that the development of
synthetically useful chiral DDAA derivatives by means
of a simple and stereoselective direct condensation reac-
tion between a chiral glycine equivalent and carbonyl
compounds under mild reaction conditions should be
desirable.
Starting chiral (S)-oxazinone 7 was prepared by reac-
tion between (S)-2-hydroxyisovalerophenone 9 and N-
Boc-glycine in the presence of 1,3-dicyclohexylcarbodi-
imide (DCC) to give the chiral ester 10. Further de-
protection of the Boc group and subsequent treatment
with a CH2Cl2 solution of Me3N afforded oxazine 7 in
56% overall yield. The synthesis of the chiral auxiliary
9 was carried out from (S)-2-hydroxyisovaleric acid17
by amidation with dimethylamine hydrochloride under
DCC-1-hydroxy-1H-benzotriazole (HOBt) conditions,18
followed by addition of 3 equiv of phenylmagnesium
bromide (Scheme 1) (53% overall yield).
We have recently reported the synthesis of a new
iminic alanine chiral template with the 3,6-dihydro-2H-
1,4-oxazin-2-one structure 6 prepared from R-bromoiso-
valerophenone and (S)-alanine.14 This heterocycle can be
alkylated with high diastereoselectivity at room temper-
ature under a variety of mild reaction conditions, such
as phase-transfer or palladium(0) catalysis or using
organic bases giving rise to an asymmetric synthesis of
R-methyl-R-amino acids. In the present paper we describe
the stereoselective synthesis of new chiral (Z)-DDAA
derivatives from an enantiomerically pure glycine equiva-
lent 7 with an analogous 1,4-oxazin-2-one structure.15
The synthetic applications of these new chiral DDAA de-
rivatives in diastereoselective cyclopropanation,15 hydro-
genation, and Diels-Alder16 reactions are also studied.
The reaction of (S)-oxazinone 719 with aldehydes was
carried out under solid-liquid-phase transfer catalysis
(PTC) conditions using K2CO3 (3 equiv) as base and
tetrabutylammonium bromide (TBAB, 0.1 equiv) as
phase transfer reagent in CH3CN as solvent at room
temperature, yielding stereoselectively the (Z)-DDAA
derivatives 11 in 96% diastereomeric excess indepen-
dently of the substitution on the aldehyde, the pure
Z-isomers being isolated after flash chromatography
(see Scheme 2 and Table 1). In the case of the condensa-
tion of 7 with benzaldehyde (see Table 1, entry 5), the
reaction was carried out at 0 °C for ca. 8 h in order to
avoid partial isomerization of the double bonds to an all-
endo conjugated position. When the condensation reac-
tion was carried out using ketones such as acetone or
benzophenone, the reaction failed and only partial de-
composition of the starting oxazinone was observed.
(12) (a) Pyne, S. G.; Dikic, B.; Gordon, P. A.; Skelton, B. W.; White,
A. H. J . Chem. Soc., Chem. Commun. 1991, 1505-1506. (b) Pyne, S.
G.; Dikic, B.; Gordon, P. A.; Skelton, B. W.; White, A. H. Aust. J . Chem.
1993, 46, 73-93. (c) Pyne, S. G.; Safaei-G, J . J . Chem. Res. (S) 1996,
160-161.
(13) (a) Cativiela, C.; Lo´pez, P.; Mayoral, J . A. Tetrahedron: Asym-
metry 1991, 2, 1295-1304. (b) Cativiela, C.; Lo´pez, P.; Mayoral, J . A.
Tetrahedron: Asymmetry 1990, 1, 379-388.
(14) (a) Chinchilla, R.; Falvello, L. R.; Galindo, N.; Na´jera, C. Angew
Chem. Int. Ed. Engl. 1997, 36, 995-997. (b) Chinchilla, R.; Galindo,
N.; Na´jera, C. Tetrahedron: Asymmetry 1998, 9, 2769-2772. (c)
Chinchilla, R.; Galindo, N.; Na´jera, C. Synthesis 1999, 704-717.
(15) Preliminary communication: Chinchilla, R.; Falvello, L. R.;
Galindo, N. Na´jera, C. Tetrahedron: Asymmetry 1998, 9, 2223-2227.
1
Configurational assignments were made from H NMR
spectra (300 MHz, CDCl3) of crude Z/E diastereomeric
(16) Preliminary communication: Chinchilla, R.; Falvello, L. R.;
Galindo, N.; Na´jera, C. Tetrahedron: Asymmetry 1999, 10, 821-825.
(17) This acid is commercially available (Aldrich) or can be prepared
by diazotization of L-valine: Li, W.-R.; Ewing, W. R.; Harris, B. D.;
J ouille´, M. M. J . Am. Chem. Soc. 1990, 112, 7659-7672.
(18) Ward, D. E.; Va´zquez, A.; Pedras, M. S. C. J . Org. Chem. 1996,
61, 8008-8009.
(19) The S-configuration of compound 7 is the appropriate for the
preparation of S-amino acids.

3036 J . Org. Chem., Vol. 65, No. 10, 2000
Chinchilla et al.
Ta ble 1. Syn th esis of Ch ir a l r,â-Did eh yd r oa m in o Acid
Der iva tives 11
entry
R
no.
reaction time (h) yielda (%)
1
2
3
4
5
6
Me
Et
i-Pr
t-Bub
Ph
11a
11b
11c
11d
11e
12
12
12
40
50
55
63
62
64
60
8c
N-Boc-2-indolyl 11f
24
a
Isolated yield after flash chromatography (silica gel) based on
b
7; partial decomposition was observed. 2 equiv of pivalaldehyde
were used. c The reaction was carried out at 0 °C.
F igu r e 1. X-ray structure of compound 12b.
Sch em e 3
Sch em e 4
mixtures, with chemical shifts for the olefinic protons
ranging between 6.74 and 7.00 ppm for Z-isomers and
lower values of 6.48-6.73 ppm for E-isomers, and also
from the vicinal CH coupling constants close to 5 Hz in
proton-coupled 13C NMR which is typical of a Z-config-
uration.4c The assignment of the Z stereochemistry was
unequivocally stablished for 11a by X-ray crystallo-
graphic analysis.15
facial diastereoselectivity of this reaction is in agreement
with expectations that attack of the cyclopropanating
reagent should occur anti to the isopropyl group from the
less-hindered face of the oxazinone. The minor diastereo-
isomers result presumably from attack to the opposite
side, instead from a â,γ-rotation of the enolate adduct
prior to the intramolecular displacement of DMSO.23
This methodology was applied to the synthesis of (-)-
allo-norcoronamic (13a ) and (-)-allo-coronamic (13b)
acids, which play an important role in the control of
enzymatic processes for plant growth and fruit ripening.
For example, allo-norcoronamic acid is the strongest
known competitive inhibitor of the ethylene-forming en-
zyme (EFE) in mung bean hypocotyls.24 Thus, spirocyclic
compounds 12a and 12b were hydrolyzed with 6 N HCl
at 150 °C (pressure tube) for 1 d and, after treatment of
the corresponding hydrochlorides with propylene oxide,
the free amino acids 13a and 13b were obtained in 60
and 67% yield, respectively (Scheme 4).
Attempted preparation of the methylenic DDAA de-
rivative 11g (11, R ) H) by condensation of oxazinone 7
with aqueous or organic solutions of formaldehyde under
different basic reaction conditions proved sluggish, and
very low yields of 11g were detected. However, an in situ
procedure was developed consisting of treatment of the
hydrochoride obtained from deprotection of 10 with diiso-
propylethylamine, followed by addition of N,N-dimethyl-
methyleneammonium iodide (Eschenmoser’s salt) (Scheme
3). Thus, the chiral R,â-didehydroalanine derivative 11g
was obtained in 50% isolated yield after this one-pot
cyclization-aminomethylation-elimination process, crude
purity being high enough for synthetic purposes (>90%
1
by GLC and 300 MHz H NMR).16
Corey’s dimethylsulfoxonium methylide,20 prepared
with NaH in DMF, was the less toxic and safest reagent
to carry out the stereoselective cyclopropanation21 of
DDAA derivatives 11. Upon treatment of 11a and 11b
with this ylide during 1 h at room temperature, a ca. 9:1
mixture of diastereomers (determined by GC and 1H
NMR) was obtained, the major diastereomers 12a and
12b being isolated after flash chromatography in 52 and
63% yield, respectively (Scheme 4). When the cyclopro-
panation reaction was carried out at -55 °C in DMF,
similar diastereoselectivities were observed. The config-
uration of compounds 12 was unequivocally stablished
by X-ray diffraction analysis of 12b 22 (Figure 1). The
The diastereoselective hydrogenation of derivatives 11
25
took place under heterogeneous catalysis with PtO2 in
MeOH at room temperature and normal pressure in 30
min to give the all-cis saturated oxazinones 14 (see Table
2). When the same reaction was carried out in the
presence of aqueous formaldehyde, the corresponding all-
cis saturated N-methyloxazinones 15 were stereoselec-
tively obtained (see Scheme 5 and Table 2).
The hydrogenation of the carbon-nitrogen double bond
of 11 showed highly stereoselective, and only on the
(23) It has been proposed that the formation of the spirocyclic adduct
occurs prior to bond rotation: (a) Landor, S. R.; Punja, N. J . Chem.
Soc (C) 1967, 2495-2500. (b) Shiraishi, K.; Ichihara, A.; Sakamura,
S. Agric. Biol. Chem. 1977, 41, 2497-2498.
(24) Pirrung, H. C.; McGeehan, G. H. J . Org. Chem. 1986, 51, 2103-
2106.
(20) Corey, E. J .; Chaykovsky, M. J . Am. Chem. Soc. 1965, 87, 1353-
1364.
(21) For a recent review on asymmetric ylide reactions see: Li,
A.-H.; Dai, L.-X.; Aggarzwal, V. K. Chem. Rev. 1997, 97, 2341-2372.
(22) For the structural details, see the Supporting Information.
(25) The hydrogenation reaction using Pd/C as catalyst gave lower
ds (ca. 75% de).

New Chiral Didehydroamino Acid Derivatives
J . Org. Chem., Vol. 65, No. 10, 2000 3037
Sch em e 5
Sch em e 6
result particularly attractive, as they are potential
precursors of enantiomerically enriched N-methyl-R-
amino acids (N-MAAs). This family of R-amino acids are
constituents of various peptides and depsipeptides iso-
lated from plant strains, microorganisms, and marine
species. They can also be incorporated into strategic
positions of peptides, leading to enhanced proteolytic
stability, to an increase in lipophilicity, and to profound
conformational changes, their synthesis being therefore
of high interest.29
The liberation of the free amino acids from heterocycles
14 proved troublesome. All attempted hydrogenolytic
procedures using ambient or high hydrogen pressure, or
transfer hydrogenation or other conditions used with
similar oxazinones,30 failed or afforded the final amino
acids contaminated with mixtures of peptides of different
length. However, it was possible to obtain the corre-
sponding enantiomerically enriched N-MAAs from the
N-methylated oxazinones 15. Thus, hydrogenolysis of
oxazinones 15a and 15c at 3.5 bar with Pearlman’s
catalyst28b in the presence of trifluoroacetic acid (TFA),
followed by hydrolysis with 6 N HCl and final treatment
with propylene oxide, afforded (S)-2-(methylamino)-
butanoic acid (16a ) and (S)-N-methylleucine (16c) in 66
and 83% overall yields, respectively (Scheme 6).
Ta ble 2. Hyd r ogen a tion of Ch ir a l DDAA Der iva tives 11
entry
R
no.
dra
yieldb (%)
1
2
3
4
5
6
7
i-Pr
t-Bu
Ph
14c
14d
14e
15a
15c
15d
15e
97:3
97:3
96:4
98:2
97:3
95:5
91:9
95
62c
83
72
70
63c
75
Me
i-Pr
t-Bu
Ph
a
Determined by GC for (3S,5R,6S) and (3R,5R,6S) diastereo-
b
mers. Isolated yield of the major isomer after flash chromatog-
raphy based on compound 11. c After crystallization.
When use of DDAA derivatives 11a and 11b as
dienophiles was attempted for Diels-Alder cycloaddition
reactions with cyclopentadiene under thermal conditions,
only recovery of the starting material was observed.
However, the methylenic DDAA derivative 11g reacted
readily with cyclopentadiene, and total consumption of
the starting material was observed in 3 h at room tem-
perature (Scheme 7). Analysis of the reaction crude
(1H NMR, 300 MHz) showed the presence of a major
diastereomer 17a (85% 17a + 15% other diastereomers)
which was isolated in 55% yield after flash chromatog-
raphy (Scheme 7), its endo stereochemistry being un-
equivocally determined by X-ray diffraction analysis.16,22
The high reactivity of 11g toward cyclopentadiene com-
pared with other DDAA derivatives12a,b could be justified
by its rather low energy of its LUMO.31
Similarly, this cycloaddition reaction was carried out
using 1-methoxy-1,3-cyclohexadiene as diene at room
tempererature, affording again a major diastereomer 17b
(94% 17b + 6% other diastereomers, 1H NMR, 300 MHz)
(Scheme 7). This isomer was isolated in 66% after flash
chromatography, and its absolute stereochemistry was
assigned by X-ray diffraction analysis22 (Figure 3) show-
F igu r e 2. X-ray structure of compound 15d .
olefinic system was detected the formation of diastereo-
mers. The phenyl group seems to be the cause of the easy
hydrogenation of the imine group,26 because oxazinones
5 do not react under similar reaction conditions.4c The
all-cis configuration for compounds 14 and 15 were
stablished on the basis of the coupling constant values
between H5 and H6 (ca. 4 Hz) which are consistent with
a cis configuration, as shown by the most stable confor-
mation of 14c determined using molecular mechanics
calculations.27 This assignation was also supported by
NOESY experiments which showed correlations between
H6, H5, and H3. The configuration was fully confirmed
by X-ray diffraction analysis in the case of oxazinone 15d
(Figure 2).22
Saturated oxazinones with similar structural features
than 14 have been used as a source of chiral azomethine
ylids in asymmetric 1,3-dipolar cycloaddition reactions
for the synthesis of different enantiomerically enriched
amino acids.28 In addition, N-methylated oxazinones 15
(26) It has been shown that substituted 3,6-dihydro-2H-1,4-oxazin-
2-ones suffer hydrogenation at atmospheric pressure: (a) Caplar, V.;
Kajfez, F.; Kolbah, D.; Sunjic, V. J . Org. Chem. 1978, 43, 1355-1360.
(b) Lingibe´, O.; Graffe, B.; Sacquet, M.-C.; Lhommet, G. Heterocycles
1994, 37, 1469-1472.
(29) Spengler, J .; Burger, K. Synthesis 1998, 67, and references cited
therein.
(30) (a) Dellaria, J . F., J r.; Santarsiero, B. D. Tetrahedron Lett. 1988,
29, 6079-6082. (b) Dellaria, J . F., J r.; Santarsiero, B. D. J . Org. Chem.
1989, 54, 3916-3926. (c) Williams, R. M.; Im, M. N. J . Am. Chem.
Soc. 1991, 113, 9276-9286.
(27) Hyperchem 5.0 from Hypercube Inc.
(28) (a) Williams, R. M.; Zhai, W.; Aldous, D. J .; Aldous, S. C.
J . Org. Chem. 1992, 57, 6527-6532. (b) Alker, D.; Hamblett, G.;
Harwood: L. M.; Robertson, S. M.; Watkin, D. J .; Williams, C. E.
Tetrahedron 1998, 54, 6089-6098, and references therein.
(31) AM1 calculated frontier orbital energies of compound 7: EHOMO
) -9.46 eV, ELUMO ) -0.94 eV. For example, for compound 1 (X ) O,
R1 ) Ph, R2 ) H): EHOMO ) -9.60 eV, ELUMO ) -0.33 eV (Hyperchem
5.0 from Hypercube, Inc.).

3038 J . Org. Chem., Vol. 65, No. 10, 2000
Chinchilla et al.
Sch em e 8
F igu r e 3. X-ray structure of compound 17b.
releasing factor, and also inhibits the flavoprotein amino
acid oxidases,9a whereas 18c and its homologues 2-amino-
bicyclo[2.2.2]octane-2-carboxylic acids perturb selectively
the levels of neutral amino acids in the cerebral cortex.9b
Sch em e 7
Con clu sion s
We conclude that oxazinone 7 is an appropriate glycine
template for the stereoselective synthesis of new enan-
tiomerically pure (Z)-R,â-didehydroamino acid (DDAA)
derivatives. The preparation of these derivatives takes
place in an easier and milder way than when using other
previously described systems, just by simple condensation
with aldehydes under easily scalable PTC conditions at
room temperature and, in the case of the methylenic
derivative, by a direct aminomethylation-elimination
sequence. These new chiral DDAA derivatives can be
easily and diastereoselectively cyclopropanated or hy-
drogenated to the immediate precursors of interesting
enantiomerically pure 1-aminocyclopropane carboxylic
acids (ACCs) or N-methyl-R-amino acids (N-MAAs). The
corresponding R,â-didehydroalanine derivative can be
employed as a very reactive dienophile for the asym-
metric synthesis of bicyclic R-amino acids.
ing the expected regiochemistry in the Diels-Alder
reaction between an electron-deficient dienophile and an
electron-rich diene. As previously, an endo-carbonyl selec-
tivity with approximation of the diene by the less-
hindered face of the dienophile was observed.
The cycloaddition reaction was also performed using
cyclohexa-1,3-diene, but now heating at 90 °C during 6
h was necessary to get full completion. Analysis of the
crude (1H NMR, 300 MHz) showed a major diastereomer
17c (88% 17c + 12% other diastereomers) which was
isolated by flash chromatography as an oil in 49% yield
(Scheme 2). The absolute stereochemistry of this major
compound 17c could not be determined, although it can
be tentatively assigned as an endo-adduct.
Acid hydrolysis of the imine moiety of cycloadduct 17a
with 2 N HCl in THF, followed by catalytic hydrogenation
at normal pressure of the double bond and subsequent
hydrolysis of the ester function with 6 N HCl at 150 °C
(pressure tube), yielded the corresponding amino acid
hydrochloride (Scheme 8). Final treatment with propyl-
ene oxide in refluxing ethanol allowed the isolation of
the free enantiomerically pure (-)-(1R,2R,4S)-2-amino-
bicyclo[2.2.1]heptane-2-carboxylic acid (18a ) in 85% over-
all yield. An identical hydrolytic procedure from cyclo-
adduct 17c afforded (-)-(1R,2R,4S)-2-aminobicyclo[2.2.2]-
octane-2-carboxylic acid (18c) in 75% overall yield, its
absolute stereochemistry confirmed by 1H NMR data and
optical rotation values (see Experimental Section). These
bicyclic amino acids have shown interesting biological
properties; thus, 18a inhibits the transport of nonpolar
amino acids across cell membranes, acts as an insulin-
Exp er im en ta l Section
Gen er a l. Melting points are uncorrected. NMR spectra
1
were determined at 300 MHz for H and 75 MHz for 13C using
CDCl3 as solvent and TMS as internal standard unless
otherwise stated. Mass spectra (EI) were obtained at 70 eV.
Elemental analyses were performed by the Microanalyses
Service of the University of Alicante. High-resolution mass
spectra (EI) were determined by the corresponding services
at the University of Zaragoza or Alicante. X-ray data were
collected using Mo KR radiation (graphite crystal monochro-
mator, λ ) 0.71073 Å).
(S)-2-Hyd r oxy-3,N,N-tr im eth ylbu ta n a m id e (8).32 To a
magnetically stirred mixture of (S)-hydroxyisovaleric acid (2.36
g, 20 mmol), dimethylamine hydrochloride (1.63 g, 20 mmol),
and 1-hydroxy-1H-benzotriazole (2.70 g, 20 mmol) in THF (10
mL) was added diisopropylethylamine (3.49 mL, 20 mmol)
dropwise at -20 °C under argon. After 2 min, dicyclohexyl-
carbodiimide (DCC, 4.34 g, 21 mmol) was added at once, and
the mixture was stirred overnight, allowing the temperature
to rise to room temperature. The formed precipitate was
filtered off and washed with EtOAc. The combined filtrates
were concentrated in vacuo and filtered through a plug of silica
gel (hexane/EtOAc ) 7/3). The solvent was evaporated in vacuo
and the residue distilled (ku¨gelrohr, 150 °C, 0.01 Torr) to afford
8 (2.18 g, 75%): [R]25 +54.0 (c ) 1; CHCl3); IR (thin film) ν
D
3423, 1640 cm-1; 1H NMR δ 4.26 (d, 1 H, J ) 3.0 Hz), 3.66 (br
(32) Ohta, H.; Ikemoto, M.; Ti, H.; Okamoto, Y.; Tsuchihashi, G.
Chem. Lett. 1986, 1169-1172.

New Chiral Didehydroamino Acid Derivatives
J . Org. Chem., Vol. 65, No. 10, 2000 3039
s, 1 H), 3.01 (s, 3 H), 3.00 (s, 3 H), 1.90 (dsept, 1 H, J ) 6.9,
3.0 Hz), 1.07 (d, 3 H, J ) 6.9 Hz), 0.80 (d, 3 H, J ) 6.9 Hz);
13C NMR δ 173.9, 72.1, 36.5, 35.8, 31.1, 19.7, 15.0; MS m/e
(relative intensity) 145 (M+, 1), 73 (100).
7/3); mp 111-112 °C (hexane/EtOAc); [R]25 -477.2 (c ) 1;
D
CH2Cl2); IR (KBr) ν 1715, 1632 cm-1
;
1H NMR δ 7.87 (m, 2
H), 7.47 (m, 3 H), 7.00 (q, 1 H, J ) 7.2 Hz), 5.56 (d, 1 H, J )
3.4 Hz), 2.18 (d, 3 H, J ) 7.2 Hz), 2.18 (m, 1 H), 1.12 (d, 3 H,
J ) 6.7 Hz), 0.80 (d, 3 H, J ) 6.7 Hz); 13C NMR δ 161.3, 160.4,
137.2, 135.1, 131.5, 131.2, 128.7, 126.9, 84.6, 33.7, 19.1, 15.6,
12.9; MS m/e (relative intensity) 243 (M+, 29), 143 (100). Anal.
Calcd for C15H17NO2: C, 74.04; H, 7.05; N, 5.76. Found: C,
74.32; H, 7.09; N, 5.42.
(S)-R-Hyd r oxyisova ler op h en on e (9). To a solution of 8
(2.18 g, 15 mmol) in THF (60 mL) was added dropwise
phenylmagnesium bromide (3 M solution in ether, 15 mL, 45
mmol) at 0 °C under argon, and the mixture was stirred
overnight, allowing the temperature to rise to room temper-
ature. The reaction was quenched at 0 °C with saturated NH4-
Cl and water and extracted with EtOAc. The organics were
dried (Na2SO4), filtered, and evaporated in vacuo, and the
residue was purified by column chromatography (silica gel) to
afford 9 (1.87 g, 70%): Rf 0.59 (hexane/EtOAc ) 7/3); [R]546
+25.4 (c ) 2.2; EtOH) (lit.33 [R]546 +20 (c ) 2.2; EtOH)); IR
(6S)-6-Isop r op yl-5-p h en yl-3-[(Z)-p r op ylid en e]-3,6-d ih y-
d r o-2H-1,4-oxa zin -2-on e (11b). Rf 0.55 (hexane/EtOAc )
7/3); [R]25 -417.4 (c ) 2; CH2Cl2); IR (thin film) ν 1727, 1631
D
cm-1; 1H NMR δ 7.86 (m, 2 H), 7.48 (m, 3 H), 6.92 (t, 1 H, J )
7.8 Hz), 5.56 (d, 1 H, J ) 3.3 Hz), 2.82-2.57 (m, 2 H), 2.19
(dsept, 1 H, J ) 6.9, 3.3 Hz), 1.14 (t, 3 H, J ) 7.6 Hz), 1.13 (d,
3 H, J ) 6.9 Hz), 0.80 (d, 3 H, J ) 6.9 Hz); 13C NMR δ 161.6,
160.5, 143.4, 135.2, 131.2, 130.3, 128.8, 126.9, 82.7, 33.8, 20.3,
19.1, 15.7, 13.0; MS m/e (relative intensity) 257 (M+, 25), 54
(100); HRMS m/e Calcd for C16H19NO2: 257.1416. Found:
257.1416.
1
(thin film) ν 3474, 1678 cm-1; H NMR δ 7.90 (m, 2 H), 7.62
(m, 1 H), 7.50 (m, 2 H), 4.98 (dd, 1 H, J ) 6.4, 2.4 Hz), 3.61 (d,
1 H, J ) 6.4 Hz), 2.14 (dsept, 1 H, J ) 6.7, 2.4 Hz), 1.17 (d, 3
H, J ) 6.7 Hz), 0.66 (d, 3 H, J ) 6.7 Hz); 13C NMR δ 202.2,
134.1, 133.8, 128.8, 128.4, 77.3, 32.6, 20.1, 14.3; MS m/e
(relative intensity) 178 (M+, 1), 105 (100).
(6S)-6-Isop r op yl-3-[(Z)-2-m eth ylp r op ylid en e]-5-p h en -
yl-3,6-d ih yd r o-2H-1,4-oxa zin -2-on e (11c). Rf 0.65 (hexane/
(1S)-1-Ben zoyl-2-(ter t-bu toxyca r bon yla m in o)-2-m eth -
ylp r op yl Eth a n oa te (10). To a solution of DCC (2.27 g, 11
mmol), N-Boc-glycine (1.89 g, 10 mmol), and a catalytic amount
of N,N-(dimethylamino)pyridine (DMAP) in CH2Cl2 (25 mL)
was added a solution of hydroxy ketone 9 (1.78 g, 10 mmol) in
CH2Cl2 (25 mL), and the mixture was stirred overnight at room
temperature. The formed precipitate was filtered off, the
filtrate concentrated in vacuo, and the residue purified by
column chromatography to afford compound 10 (2.68 g, 80%):
EtOAc ) 7/3); [R]25 -381.8 (c ) 1; CH2Cl2); IR (thin film) ν
D
1727, 1631 cm-1; 1H NMR δ 7.86 (m, 2 H), 7.48 (m, 3 H), 6.74
(d, 1 H, J ) 9.8 Hz), 5.56 (d, 1 H, J ) 3.4 Hz), 3.51 (m, 1 H),
2.20 (dsept, 1 H, J ) 6.9, 3.4 Hz), 1.15 (d, 6 H, J ) 7.0 Hz),
1.11 (d, 3 H, J ) 6.9 Hz), 0.80 (d, 3 H, J ) 6.9 Hz); 13C NMR
δ 161.9, 160.5, 148.0, 135.1, 131.2, 129.1, 128.8, 126.9, 82.7,
33.8, 26.2, 22.1, 21.7, 19.1, 15.6; MS m/e (relative intensity)
271 (M+, 17), 228 (100); HRMS m/e Calcd for C17H21NO2:
271.1572. Found: 271.1577.
Rf 0.43 (hexane/EtOAc ) 7/3); [R]25 +17.5 (c ) 1.5; CHCl3);
D
1
IR (thin film) ν 3390, 1754, 1698 cm-1; H NMR δ 7.93 (m, 2
(6S)-3-[(Z)-2,2-Dim e t h ylp r op ylid e n e ]-6-isop r op yl-5-
ph en yl-3,6-dih ydr o-2H-1,4-oxazin -2-on e (11d). Rf 0.66 (hex-
H), 7.59 (m, 1 H), 7.48 (m, 2 H), 5.80 (d, 1 H, J ) 4.6 Hz), 5.1
(br s, 1 H), 4.13 (dd, 1 H, J ) 18.3, 6.4 Hz), 4.00 (dd, 1 H, J )
18.3, 5.2 Hz), 2.31 (dsept, 1 H, J ) 6.7, 4.6 Hz), 1.44 (s, 9 H)
1.05 (d, 3 H, J ) 6.7 Hz), 0.92 (d, 3 H, J ) 6.7 Hz); 13C NMR
δ 196.1, 170.2, 155.6, 135.2, 133.5, 128.7, 128.3, 80.0, 79.8, 42.2,
30.1, 28.2, 19.4, 16.7.
ane/EtOAc ) 7/3); [R]25 -277.6 (c ) 0.7; CH2Cl2); IR (thin
D
film) ν 1728, 1622 cm-1
;
1H NMR δ 7.85 (m, 2 H), 7.50 (m,
3 H), 6.90 (s, 1 H), 5.54 (d, 1 H, J ) 3.2 Hz), 2.23 (dsept, 1 H,
J ) 6.9, 3.2 Hz), 1.37 (s, 9 H), 1.12 (d, 3 H, J ) 6.9 Hz), 0.83
(d, 3 H, J ) 6.9 Hz); 13C NMR δ 162.4, 159.7, 149.1, 135.2,
131.3, 130.0, 128.9, 126.9, 82.4, 34.0, 33.9, 30.3, 19.1, 15.9; MS
m/e (relative intensity) 285 (M+, 28); HRMS m/e Calcd for
(6S)-6-Isop r op yl-5-p h en yl-3,6-d ih yd r o-2H-1,4-oxa zin -2-
on e (7). A saturated solution of HCl in EtOAc (25 mL) was
added to compound 10 (2.68 g, 8 mmol), and the mixture was
stirred 1 h. The solvent was evaporated in vacuo, and the solid
was washed with ether and filtered. The solid was dissolved
in CH2Cl2 (3 mL) and a solution of Me3N in CH2Cl2 (5 mL),
obtained by extracting a NaCl saturated 45% solution of Me3N
in water (3 mL) with CH2Cl2 (6 mL), was added. The resulting
mixture was stirred 1 h and cooled to 0 °C, hexane (8 mL)
was added, and the formed precipitate was filtered off and
washed with a 1/1 hexane/CH2Cl2 mixture (2 × 5 mL). The
combined filtrates were evaporated in vacuo, affording crude
oxazinone 7 (1.73 g, 85% pure by GC). A sample was purified
by flash chromatography (neutral silica gel) for analytical
C
18H23NO2: 285.1729. Found: 285.1732.
(6S)-6-Isopr opyl-5-ph en yl-3-[(Z)-1-ph en ylm eth yliden e]-
3,6-d ih yd r o-2H-1,4-oxa zin -2-on e (11e). Rf 0.54 (hexane/
EtOAc ) 7/3); [R]25 -800.0 (c ) 0.94; CH2Cl2); IR (thin film)
D
ν 1726, 1614 cm-1
;
1H NMR δ 8.09 (m, 2 H), 7.92 (m, 2 H),
7.55-7.36 (m, 7 H), 5.61 (d, 1 H, J ) 3.5 Hz), 2.25 (dsept, 1 H,
J ) 6.6, 3.5 Hz), 1.14 (d, 3 H, J ) 6.6 Hz), 0.88 (d, 3 H, J ) 6.6
Hz); 13C NMR δ 162.3, 162.1, 135.0, 134.3, 133.3, 132.5, 131.5,
129.8, 129.1, 128.9, 128.4, 127.1, 82.5, 34.0, 19.1, 15.9; MS m/e
(relative intesity) 305 (M+, 40), 262 (100); HRMS m/e Calcd
for C20H19NO2: 305.1416. Found: 305.1427.
(S)-ter t-Bu t yl 3-[(6S)-6-Isop r op yl-2-oxo-5-p h en yl-3,6-
d ih yd r o-2H-1,4-oxa zin -3-ylid en m eth yl]-1H-1-in d oleca r -
boxyla te (11f). Rf 0.47 (hexane/EtOAc ) 7/3); mp 145-146
°C (EtOAc); [R]25D -17.2 (c ) 1; CH2Cl2); IR (KBr) ν 1731, 1615
purposes: Rf 0.34 (hexane/EtOAc ) 7/3); [R]25 +102.6 (c )
D
1.13; CH2Cl2), IR (thin film) ν 1746, 1693 cm-1; 1H NMR δ 7.70
(m, 2 H), 7.48 (m, 3 H), 5.52 (m, 1 H), 4.75 (dd, 1 H, J ) 22.3,
2.1 Hz), 4.36 (dd, 1 H, J ) 22.3, 2.1 Hz), 2.20 (d sept, 1 H, J
) 6.9, 2.9 Hz), 1.09 (d, 3 H, J ) 6.9 Hz), 0.90 (d, 3 H, J ) 6.9
Hz); 13C NMR δ 167.0, 165.3, 135.5, 131.1, 128.9, 126.6, 83.9,
50.3, 32.9, 19.1, 16.1; MS m/e (relative intensity) 217 (M+, 11),
117 (100).
1
cm-1; H NMR δ 8.76 (s, 1 H), 8.25 (m, 1 H), 7.95 (m, 2 H),
7.84 (m, 2 H), 7.50 (m, 3 H), 7.37 (m, 2 H), 5.65 (d, 1 H, J )
3.4 Hz), 2.26 (dsept, 1 H, J ) 6.9, 3.4 Hz), 1.73 (s, 9 H), 1.16
(d, 3 H, J ) 6.9 Hz), 0.89 (d, 3 H, J ) 6.9 Hz); 13C NMR δ
161.7, 161.5, 149.2, 135.4, 135.1, 131.4, 130.9, 129.8, 130.0,
128.2, 127.2, 125.1, 124.6, 123.5, 118.7, 115.3, 114.9, 84.3, 82.8,
34.1, 28.2, 15.9, 14.1; MS m/e (relative intensity) 444 (M+, 8),
273 (100). Anal. Calcd for C27H28N2O4: C, 72.95; H, 6.35; N,
6.30. Found: C, 71.17; H, 6.65; N, 5.66.
Syn th esis of Did eh yd r oa m in o Acid Der iva tives 11a -
f. Gen er a l P r oced u r e. A heterogeneous mixture of crude 7
(255 mg, equiv to 1 mmol), tetrabutylammonium bromide (33
mg, 0.1 mmol), finely ground, technical-grade K2CO3 (414 mg,
3 mmol), and the corresponding aldehyde (1.2 mmol) in CH3-
CN (3 mL) was stirred at room temperature until total
consumption of the starting material (GC, see Table 1). The
mixture was filtered through a pad of silica gel, the solvent
removed in vacuo, and the residue purified by flash chroma-
tography on silica gel to afford derivatives 11a -f.
Syn th esis of Did eh yd r oa m in o Acid Der iva tive 11g. A
saturated solution of HCl in EtOAc (5 mL) was added to
compound 10 (335 mg, 1 mmol), and the mixture was stirred
1 h. The solvent was evaporated in vacuo, and the solid was
washed with ether and filtered. The solid was dissolved in dry
CH2Cl2 (1 mL), N,N-diisopropylethylamine (174 µL, 1 mmol)
was added, and the mixture was stirred for 1 h at room
temperature. The mixture was diluted with dry CH2Cl2 (7 mL),
N,N-dimethylmethyleneammonium iodide was added (371
mg, 2 mmol), and the suspension was stirred overnight at room
temperature. The slurry was filtered through a plug of silica
(6S)-3-[(Z)-Eth ylid en e]-6-isop r op yl-5-p h en yl-3,6-d ih y-
d r o-2H-1,4-oxa zin -2-on e (11a ). Rf 0.60 (hexane /EtOAc )
(33) Maigrot, N.; Mazaleyrat, J .-P.; Welvart, Z. J . Org. Chem. 1985,
50, 3916-3918.

3040 J . Org. Chem., Vol. 65, No. 10, 2000
Chinchilla et al.
gel (hexane/EtOAc ) 8/2), and the solvent was evaporated
in vacuo yielding 128 mg of crude 11g (90% pure, GLC). An
analytical sample was obtained after flash chromatography
(3S,5R,6S)-3-Isobu tyl-6-isop r op yl-5-p h en yltetr a h yd r o-
2H-1,4-oxa zin -2-on e (14c). Rf 0.57 (hexane/EtOAc ) 7/3);
[R]25 -120.5 (c ) 1.8; CH2Cl2); IR (thin film) ν 3359, 3321,
D
using neutral silica gel: Rf 0.63 (hexane/EtOAc) ) 7/3); [R]25
1741 cm-1; 1H NMR δ 7.33 (m, 5 H), 4.43 (d, 1 H, J ) 4.3 Hz),
4.24 (dd, 1 H, J ) 8.2, 4.3 Hz), 3.73 (m, 1 H), 1.89 (m, 2 H),
1.65-1.42 (m, 3 H), 1.03 (d, 3 H, J ) 6.7 Hz), 0.96 (m, 6 H),
0.83 (d, 3 H, J ) 6.7 Hz); 13C NMR δ 173.6, 139.8, 128.8, 127.9,
84.2, 59.0, 53.0, 40.1, 28.9, 24.4, 23.3, 21.5, 19.1, 19.1; MS m/e
(relative intensity) 275 (M+, 2), 132 (100).
D
-360 (c ) 2.0; CH2Cl2); IR (thin film) ν 1739, 1615 cm-1
;
1H NMR δ 7.84 (m, 2H), 7.49 (m, 3H), 6.38 (s, 1H), 5.94 (s,
1H), 5.60 (d, 1H, J ) 3.4 Hz), 2.20 (dsept, 1H, J ) 6.9, 3.4
Hz), 1.14 (d, 3H, J ) 6.9 Hz), 0.81 (d, 3H, J ) 6.9 Hz); 13C
NMR δ 163.6, 160.8, 137.4, 134.7, 131.6, 128.9, 127.0, 124.0,
83.7, 33.9, 19.1, 15.6; MS m/e (relative intensity) 229 (M+, 39),
129 (100); HRMS m/e Calcd for C14H15NO2: 229.1103. Found:
229.1098.
(3S,5R,6S)-6-Isopr opyl-3-n eopen tyl-5-ph en yltetr ah ydr o-
2H-1,4-oxa zin -2-on e (14d ). Rf 0.67 (hexane/EtOAc ) 7/3); mp
132-134 °C (hexane/EtOAc); [R]25 -150.8 (c ) 1; CH2Cl2);
D
Cyclopr opan ation of 11. Gen er al P r ocedu r e. Trimethyl-
sulfoxonium iodide (440 mg, 2 mmol) was added to a suspen-
sion of NaH (60% in mineral oil, 80 mg, 2 mmol) in dry DMF
(1.5 mL), and the mixture was stirred under argon at room
temperature for 30 min. A solution of 11 (1 mmol) in DMF
(1.5 mL) was then added, and the resulting mixture was
stirred under argon at room temperature for 1 h. The suspen-
sion was diluted with EtOAc (15 mL) and filtered through a
pad of silica gel, the eluted solution washed with water, the
solvent dried (Na2SO4), removed in vacuo, and the residue
purified by flash chromatography on silica gel to afford
compounds 12.
IR (KBr) ν 3357, 1751 cm-1; 1H NMR δ 7.32 (m, 5 H), 4.44 (d,
1 H, J ) 4.3 Hz), 4.25 (dd, 1 H, J ) 8.2, 4.3 Hz), 3.72 (dd, 1 H,
J ) 7.3, 3.1 Hz), 2.31 (dd, 1 H, J ) 14.7, 3.1 Hz), 1.58 (m, 1
H), 1.30 (dd, 1 H, J ) 14.7, 7.3 Hz), 1.03 (d, 3 H, J ) 6.7 Hz),
1.00 (s, 9 H), 0.83 (d, 3 H, J ) 6.7); 13C NMR δ 173.9, 140.0,
128.7, 128.0, 128.0, 84.0, 59.1, 52.5, 44.3, 30.1, 29.8, 28.9, 19.1,
19.0; MS m/e (relative intensity) 289 (M+, 1), 132 (100). Anal.
Calcd for C18H27NO2: C, 74.70; H, 9.40; N, 4.84. Found: C,
74.30; H, 9.47; N, 4.73.
(3S,5R,6S)-3-Ben zyl-6-isop r op yl-5-p h en ylt et r a h yd r o-
2H-1,4-oxa zin -2-on e (14e). Rf 0.55 (hexane/EtOAc ) 7/3); mp
111-112 °C (hexane/EtOAc); [R]25 -178.2 (c ) 1; CH2Cl2);
D
1
(1R,3S,6S)-6-Isop r op yl-1-m eth yl-7-p h en yl-5-oxa -8-a za -
sp ir o[2.5]oct-7-en -4-on e (12a ). Rf 0.64 (hexane/EtOAc ) 7/3);
IR (thin film) ν 3345, 3315, 1740 cm-1; H NMR δ 7.33-7.25
(m, 10 H), 4.39 (d, 1 H, J ) 4.3 Hz), 4.24 (dd, 1 H, J ) 6.7, 4.3
Hz), 3.97 (dd, 1 H, J ) 9.2, 3.7 Hz), 3.49 (dd, 1 H, J ) 14.0,
3.7 Hz), 2.89 (dd, 1 H, J ) 14.0, 9.2 Hz), 1.63 (br s, 1 H), 1.56
(m, 1 H), 0.98 (d, 3 H, J ) 6.7 Hz), 0.77 (d, 3 H, J ) 6.7 Hz);
13C NMR δ 172.0, 139.4, 137.5, 129.4, 128.7, 128.0, 127.6,
126.9, 85.3, 59.0, 57.5, 37.7, 28.7, 20.0, 18.6; MS m/e (relative
intensity) 309 (M+, 5), 91 (100). Anal. Calcd for C20H23NO2:
C, 77.64; H, 7.49; N, 4.53. Found: C, 78.06; H, 7.61; N, 4.43.
(3S,5R,6S)-3-E t h yl-6-isop r op yl-4-m et h yl-5-p h en ylt et -
r a h yd r o-2H-1,4-oxa zin -2-on e (15a ). Rf 0.65 (hexane/EtOAc
) 7/3); mp 76-77 °C (hexane/Et2O); [R]25D -62.5 (c ) 1.0; CH2-
Cl2); IR (thin film) ν 1754 cm-1; 1H NMR δ 7.30 (m, 5 H), 4.13
(dd, 1 H, J ) 8.6, 4.0), 3.69 (d, 1 H, J ) 4.0), 3.40 (dd, 1 H,
J ) 6.1, 2.4), 2.37 (s, 3 H), 2.02 (dsept, 1 H, J ) 7.3, 2.4), 1.88,
1.53 (2 m, 2 H), 1.02 (t, 3 H, J ) 7.3), 0.97, 0.85 (2 d, 6 H, J )
6.4); 13C NMR δ 172.0, 139.1, 129.0, 128.1, 127.6, 82.4, 70.0,
61.7, 41.1, 28.6, 22.0, 19.1, 18.9, 9.0; MS m/e (relative intensity)
261 (M+, 3), 42 (100).
[R]25 -131.4 (c )1.63; CH2Cl2); IR (thin film) ν 1735, 1644;
D
1H NMR δ 7.68 (m, 2 H), 7.44 (m, 3 H), 5.62 (d, 1 H, J ) 2.8
Hz), 2.22-2.04 (m, 3 H), 1.45 (dd, 1 H, J ) 7.6, 3.7 Hz), 1.37
(d, 3 H, J ) 6.1 Hz), 1.13 (d, 3 H, J ) 7.0 Hz), 0.86 (d, 3 H,
J ) 7.0 Hz); 13C NMR δ 170.5, 163.0, 135.6, 130.5, 128.7, 126.2,
83.3, 44.6, 32.5, 30.4, 30.1, 19.0, 15.6, 13.0; MS m/e (relative
intensity) 257 (M+, 20), 54 (100); HRMS m/e Calcd for C16H19
-
NO2: 257.1416. Found: 257.1427.
(1R,3S,6S)-1-E t h yl-6-isop r op yl-7-p h en yl-5-oxa -8-a za -
sp ir o[2.5]oct-7-en -4-on e (12b). Rf 0.57 (hexane/EtOAc ) 7/3);
mp 94-95 °C (hexane/EtOAc); [R]25 -91.4 (c ) 2.1; CH2Cl2);
D
IR (thin film) ν 1735, 1646 cm-1
;
1H NMR δ 7.65 (m, 2 H),
7.43 (m, 3 H), 5.61 (d, 1 H, J ) 3.1 Hz), 2.21-2.02 (m, 3 H),
1.75 (m, 2 H), 1.45 (dd, 1H, J ) 6.9, 2.9 Hz), 1.11 (d, 3 H, J )
7.3 Hz), 1.07 (t, 3 H, J ) 7.3 Hz), 0.87 (d, 3 H, J ) 6.7 Hz); 13
C
NMR δ 170.4, 162.7, 135.9, 130.5, 128.7, 126.2, 83.4, 44.8, 37.1,
32.7, 29.5, 21.5, 19.0, 15.4, 13.3; MS m/e (relative intensity)
271 (M+, 16), 228 (100). Anal. Calcd for C17H21NO2: C, 75.23;
H, 7.81; N, 5.16. Found: C, 75.59; H, 7.86; N, 4.99.
(3S,5R,6S)-3-Isobu tyl-6-isopr opyl-4-m eth yl-5-ph en yltet-
r a h yd r o-2H-1,4-oxa zin -2-on e (15c). Rf 0.69 (hexane/EtOAc
) 7/3); mp 75-76 °C (hexane/Et2O); [R]25 -54.1 (c ) 1; CH2-
Hyd r olysis of 12. Gen er a l P r oced u r e. Compounds 12
(110 mg, 0.4 mmol) were dissolved in 6 N HCl (1.5 mL) and
heated at 150 °C in a pressure tube for 1 d. Water (5 mL) was
added, and the mixture was extracted with EtOAc (2 × 5 mL).
The aqueous layer was evaporated in vacuo and the solid
residue dissolved in ethanol (2 mL). Propylene oxide was added
(1 mL) and the mixture refluxed for 30 min. The solid was
filtered, washed with ethanol, and dried, affording amino acids
13a (28 mg, 60%) and 13b (35 mg, 67%).
D
Cl2); IR (thin film) ν 1749 cm-1; 1H NMR δ 7.29 (m, 5 H), 4.16
(dd, 1 H, J ) 8.7, 4.1 Hz), 3.73 (d, 1 H, J ) 3.7 Hz), 3.29 (dd,
1 H, J ) 7.6, 3.1 Hz), 1.98 (m, 2 H), 1.62 (m, 1 H), 1.45 (m, 1
H), 1.01 (d, 3 H, J ) 6.7 Hz), 0.99 (d, 3 H, J ) 6.4 Hz), 0.94 (d,
3 H, J ) 6.1 Hz), 0.86 (d, 3 H, J ) 6.4 Hz); 13C NMR δ 172.8,
138.6, 128.8, 128.3, 127.7, 82.6, 67.0, 60.3, 42.0, 39.7, 28.5, 26.0,
23.5, 22.2, 19.3, 18.9; MS m/e (relative intensity) 289 (M+, 2),
100 (39). Anal. Calcd for C18H27NO2: C, 74.7; H, 9.40; N, 4.84.
Found: C, 73.27; H, 9.22; N, 4.70.
(-)-a llo-Nor cor on a m ic a cid (13a ). [R]25 -72 (c ) 0.3;
D
H2O) (lit.34 [R]D -69 (c ) 0.3; H2O)); 1H NMR (D2O) δ 1.45 (m,
1 H), 1.24 (dd, 1 H, J ) 9.8, 6.1 Hz), 0.99 (d, 3 H, J ) 6.7 Hz),
0.68 (t, 1 H, J ) 6.7 Hz); 13C NMR (D2O, acetone) δ 176.2,
40.0, 19.2, 18.5, 11.8.
(3S,5R,6S)-6-Isop r op yl-4-m et h yl-3-n eop en t yl-5-p h en -
yltetr a h yd r o-2H-1,4-oxa zin -2-on e (15d ). Rf 0.71 (hexane/
EtOAc ) 7/3); mp 100-101 °C (hexane/EtOAc); [R]25 -39.0
D
(c ) 1; CH2Cl2); IR (KBr) ν 1749 cm-1; H NMR δ 7.33-7.20
1
(-)-a llo-Cor on a m ic a cid (13b). [R]25D -51 (c )1.83; H2O)
(m, 5 H), 4.18 (dd, 1 H, J ) 9.3, 3.5 Hz), 3.80 (d, 1 H, J ) 3.4
Hz), 3.24 (d, 1 H, J ) 6.9 Hz), 2.51 (s, 1 H), 2.42 (dd, 1 H, J )
15.0, 6.9 Hz), 1.63 (m, 1 H), 1.42 (d, 1 H, J ) 15.0 Hz), 1.02 (d,
3 H, J ) 6.7 Hz), 0.98 (s, 9 H), 0.94 (d, 3 H, J ) 6.7 Hz); 13C
NMR δ 173.5, 138.8, 128.7, 128.2, 127.6, 81.7, 66.6, 58.6, 42.9,
42.7, 30.3, 29.7, 28.6, 19.1, 19.0; MS m/e (relative intensity)
303 (M+, 0.3), 42 (100). Anal. Calcd for C19H29NO2: C, 75.21;
H, 9.63; N, 4.59. Found: C, 74.69; H, 9.59; N, 4.59.
1
(lit.4b [R]D -52 (c ) 1.83; H2O)); H NMR (D2O) δ 1.38-1.11
(m, 4 H), 0.85 (t, 3 H, J ) 7.0 Hz), 0.70 (m, 1 H); 13C NMR
(D2O, acetone) δ 176.3, 40.1, 26.0, 20.9, 18.1, 13.1.
Hyd r ogen a tion of 11. Gen er a l P r oced u r e. A mixture of
11 (1 mmol) and PtO2 (40 mg) in MeOH (3 mL) was stirred
under
a hydrogen atmosphere (1 atm) for 30 min. The
suspension was filtered through Celite, the solvent removed
in vacuo, and the residue purified by flash chromatography
or crystallization to afford 14. The preparation and isolation
of 15 was similar: a solution of CH2O (33% in water, 0.9 mL)
was added to a mixture of 11 and PtO2 in MeOH (12 mL) and
stirred under hydrogen (1 atm) for 2 h.
(3S,5R,6S)-3-Ben zyl-6-isop r op yl-4-m eth yl-5-p h en yltet-
r a h yd r o-2H-1,4-oxa zin -2-on e (15e). Rf 0.60 (hexane/EtOAc
) 7/3); mp 73-74 °C (hexane/EtOAc); [R]25D -88.1 (c ) 1; CH2-
1
Cl2); IR (thin film) ν 1749 cm-1; H NMR δ 7.36-7.17 (m, 10
H), 4.13 (dd, 1H, J ) 8.2, 3.7 Hz), 3.61 (m, 1 H), 3.41 (dd, 1 H,
J ) 14.3, 5.8 Hz), 3.06 (dd, 1 H, J ) 14.3, 4.6 Hz), 2.40 (s,
3H), 1.60 (m, 1 H), 0.86 (d, 3 H, J ) 6.7 Hz), 0.77 (d, 3 H, J )
6.7 Hz); 13C NMR δ 171.6, 138.7, 138.2, 129.8, 128.7, 128.2,
(34) Baldwin, J . E.; Adlington, R. M.; Rawlings, B. J .; J ones, R. H.
Tetrahedron Lett. 1985, 26, 485-488.

New Chiral Didehydroamino Acid Derivatives
J . Org. Chem., Vol. 65, No. 10, 2000 3041
128.1, 127.6, 126.2, 82.9, 66.7, 64.3, 42.6, 36.4, 28.4, 19.4, 18.6;
MS m/e (relative intensity) 321 (M+ - H2, 2), 232 (100). Anal.
Calcd for C21H25NO2: C, 77.99; H, 7.79; N, 4.33. Found: C,
77.30; H, 7.74; N, 4.33.
0.67 (d, 3 H, J ) 6.7 Hz); 13C NMR δ 170.9, 162.0, 136.8, 133.8,
132.2, 130.1, 128.4, 126.7, 84.9, 83.6, 65.4, 51.7, 45.6, 31.9, 30.3,
24.0, 23.4, 19.1, 15.0. Anal. Calcd for C21H25NO3: C, 74.31; H,
7.42; N, 4.13. Found: C, 73.94; H, 7.32; N, 4.20.
Syn t h esis of N-Met h yl-R-a m in o Acid s 16. Gen er a l
P r oced u r e. To a solution of 15a or 15c (1 mmol) in MeOH
(13 mL), H2O (1.5 mL), and TFA (270 µL) was added Pd(OH)2
on carbon (270 mg). The reaction vessel was charged with H2,
and the mixture was hydrogenated at 3.5 bar for 36 h. The
mixture was then purged with nitrogen and filtered (Celite)
to remove the catalyst. The filtrate was evaporated (15 Torr),
and the resulting residue was dissolved in 6 N HCl (3 mL)
and heated at 150 °C (pressure tube) for 24 h. Water was
added, and the mixture was extracted with AcOEt. The
aqueous layer was evaporated (15 Torr), and the solid residue
was dissolved in EtOH (3 mL). Propylene oxide (2 mL) was
added, and the mixture was refluxed for 30 min. The formed
precipitate was filtered and washed with EtOH affording
N-MAAs 16a (77 mg, 66%) or 16c (120 mg, 83%).
(6′S)-Bicyclo[2.2.2]oct -5-en -2-sp ir o{3′[6′-isop r op yl-5′-
p h en yl-3′,6′-d ih yd r o-2′H-1′,4′-oxa zin -2′-on e]} (17c): 49%.
Rf 0.61 (hexane/EtOAc ) 7/3); [R]25 -45.1 (c ) 1.3; CH2Cl2);
D
IR (thin film) ν 1742, 1657 cm-1
;
1H NMR δ 7.69 (m, 2 H),
7.43 (m, 3 H), 6.45 (t, 1 H, J ) 7.3 Hz), 6.37 (t, 1 H, J ) 7.3
Hz), 5.47 (d, 1 H, J ) 4.3 Hz), 2.74 (s, 1 H), 2.66 (m, 1 H), 2.42
(m, 1 H,), 2.10 (m, 2 H), 1.77 (m, 1 H), 1.64 (dd, 1 H, J ) 12.2,
2.4 Hz), 1.35 (dt, 1 H, J ) 6.7, 3.7 Hz), 1.04 (d, 3 H, J )
6.7 Hz), 0.86 (m, 1 H), 0.78 (d, 3 H, J ) 6.7 Hz); 13C NMR
δ 172.1, 161.4, 136.5, 134.0, 132.4, 130.3, 128.5, 126.7, 84.0,
61.7, 44.2, 40.7, 32.5, 30.2, 22.8, 21.1, 19.3, 16.1; MS m/e
(relative intensity) 309 (M+, 13), 229 (100); HRMS m/e Calcd
for C20H23NO2: M+ 309.1729. Found: M+ 309.1721.
Syn th esis of th e Bicyclic R-Am in o Acid s 18a a n d 18c.
Gen er a l P r oced u r e. A mixture of the corresponding bicyclic
oxazinone 17a or 17c (0.5 mmol) in 2 N HCl (2 mL) and THF
(1.5 mL) was stirred at room temperature for 3 h. The solvent
was evaporated (15 Torr) and the residue disolved in MeOH
(3 mL). To this solution was added Pd/C 10% (40 mg), and the
mixture was stirred under an hydrogen atmosphere (1 atm)
for 3 h. The resulting suspension was filtered through Celite
and the solvent evaporated (15 Torr). The residue was heated
in 6 N HCl at 150 °C (bath temperature) in a pressure tube
for 24 h. The mixture was diluted with water (15 mL) and
washed with EtOAc (10 mL) and the aqueous layer evaporated
(15 Torr). The resulting solid hydrochloride was disolved in
ethanol (3 mL) and refluxed with propylene oxide (2 mL) for
30 min. The formed precipitate was filtered off, yielding the
corresponding free amino acids 18a or 18c in 85 and 75%
yields, respectively.
(S)-2-Meth yla m in obu ta n oic a cid (16a ). [R]25 +23.1 (c
D
) 0.85; 6 N HCl) (lit.35 [R]25 +24.8 (c ) 0.85; 6 N HCl)); H
1
D
NMR δ 3.53 (t, 1 H, J ) 5.5), 2.68 (s, 3H), 1.88 (m, 2 H), 0.92
(t, 3 H, J ) 7.6).
(S)-N-Meth ylleu cin e (16c). [R]25 +22.7 (c ) 1.0; H2O)
D
(lit.36 [R]D +21.4); 1H NMR δ 3.55 (m, 1 H), 2.68 (s, 3 H), 1.69
(m, 3 H), 0.93 (m, 6 H).
Diels-Ald er r ea ction of 11g. Gen er a l P r oced u r e. To a
solution of the oxazinone 11g (254 mg of crude of 90% purity,
equivalent to 229 mg of pure compound, 1 mmol) in toluene
(2 mL) was added the corresponding diene (20 mmol for
cyclopentadiene or 1,3-cyclohexadiene, 10 mmol for 1-methoxy-
1,3-cyclohexadiene), and the mixture was stirred at room
temperature (3 h for cyclopentadiene, 4 h for 1-methoxy-1,3-
cyclohexadiene) or 90 °C (6 h for 1,3-cyclohexadiene). The
solvent was evaporated (15 Torr), and the residue was purified
by flash chromatography (silica gel, hexane/EtOAc gradients),
affording pure major diastereomers.
(-)-(1R,2R,4S)-2-Am in obicyclo[2.2.1]h ep ta n e-2-ca r box-
ylic Acid (18a ). [R]25D -61.0 (c ) 1.0; H2O) (lit.9a [R]D25 -61.4
1
(c, 1; H2O)); H NMR δ (D2O) 2.33 (s, 2 H), 2.06 (dd, 1 H, J )
(1S,2R,4S,6′S)-Bicyclo[2.2.1]h ep t-5-en -2-sp ir o{3′[6′-iso-
pr opyl-5′ph en yl-3′,6′-dih ydr o-2′H-1′,4′-oxazin -2′-on e]} (17a).
55%. Rf 0.63 (hexane/EtOAc ) 7/3); mp 86-87 °C (hexane/
13.5, 2.5 Hz), 1.59 (d, 1 H, J ) 10.8 Hz), 1.49-1.36 (m, 4 H),
1.28 (m, 1 H), 1.19 (m, 1 H).
(-)-(1R,2R,4S)-2-a m in obicyclo[2.2.2]octa n e-2-ca r box-
Et2O); [R]25 -60.0 (c ) 1.4; CH2Cl2); IR (KBr) ν 1738, 1657
ylic Acid (18c). 18c‚HCl [R]25 -12.8 (c ) 0.5; H2O) (lit.12c
D
D
1
cm-1; H NMR δ 7.66 (m, 2 H), 7.42 (m, 3 H), 6.38 (m, 1 H),
25
1
(2S-enantiomer) [R]D +12.4 (c, 0.5; H2O)); H NMR δ (D2O)
2.49 (dt, 1 H, J ) 14.6, 2.7 Hz), 1.81 (m, 1 H), 1.75 (m, 1 H),
1.73-1.42 (m, 9 H).
6.25 (m, 1 H), 5.48 (d, 1 H, J ) 4.3 Hz), 3.08 (s, 1 H), 2.97 (s,
1 H), 2.41 (d, 1 H, J ) 8.2 Hz), 2.13 (m, 1 H), 1.95 (br s, 2 H),
1.55 (d, 1 H, J ) 8.2 Hz), 1.02 (d, 3 H, J ) 6.7 Hz), 0.83 (d, 3
H, J ) 6.7 Hz); 13C NMR δ 171.6, 162.6, 138.5, 136.7, 134.6,
130.4, 128.6, 126.7, 83.9, 66.1, 56.3, 48.5, 45.7, 43.5, 32.5, 19.4,
16.4.
Ack n ow led gm en t. We thank the Direccio´n General
de Investigacio´n Cient´ıfica y Te´cnica (DGICYT) of the
Spanish Ministerio de Educacio´n y Cultura (MEC)
(PB97-0123 and PB95-0792) for financial support. N.G.
thanks MEC for a grant.
(1R,2R,4R,6′S)-1-Meth oxybicyclo[2.2.2]oct-5-en -2-sp ir o-
{3′[6′-isop r op yl-5′p h en yl-3′,6′-d ih yd r o-2′H-1′,4′-oxa zin -2′-
on e]} (17b). 66% Rf 0.54 (hexane/EtOAc ) 7/3), mp 138-139
°C (hexane/EtOAc); IR (KBr) ν 1737, 1664 cm-1 1H NMR δ
;
7.67 (m, 2 H), 7.43 (m, 3 H), 6.51 (d, 1 H, J ) 8.6 Hz), 6.37 (m,
1 H), 5.52 (d, 1 H, J ) 2.4 Hz), 3.27 (s, 3 H), 2.71 (bs, 1 H),
2.22-2.07 (m, 3 H), 1.95 (m, 1 H), 1.79 (dd, 1 H, J ) 12.2, 3.1
Hz), 1.48 (m, 1 H), 1.36 (m, 1 H), 1.11 (d, 3 H, J ) 6.7 Hz),
Su p p or tin g In for m a tion Ava ila ble: X-ray crystallo-
graphic data for compounds 12b, 15d , and 17b including
atomic position and atomic displacement parameters as well
as a complete list of bond lengths and bond angles. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(35) Agami, C.; Couty, B.; Prince, B.; Puchou, C. Tetrahedron 1991,
47, 4343-4354.
(36) Dictionary of Organic Compounds; Chapman & Hall. New York,
1982.
J O991736L